PMID- 24141788 TI - YB-1 disrupts mismatch repair complex formation, interferes with MutSalpha recruitment on mismatch and inhibits mismatch repair through interacting with PCNA. AB - Y-box binding protein-1 (YB-1) is highly expressed in tumors and it participates in various cellular processes. Previous studies indicated that YB-1 binds to mispaired DNA and interacts with several mismatch repair (MMR)-related factors. However, its role in the MMR system remains undefined. Here, we found that YB-1 represses mutS homolog 6 (MSH6)-containing MMR complex formation and reduces MutSalpha mismatch binding activity by disrupting interactions among MMR-related factors. In an effort to elucidate how YB-1 exerts this inhibitory effect, we have identified two functional proliferating cell nuclear antigen (PCNA) interacting protein (PIP)-boxes that mediate YB-1/PCNA interaction and locate within the C-terminal region of YB-1. This interaction is critical for the regulatory role of YB-1 in repressing MutSalpha mismatch binding activity, disrupting MutSalpha/PCNA/G/T heteroduplex ternary complex formation and inhibiting in vitro MMR activity. The differential regulation of 3' and 5' nick directed MMR activity by YB-1 was also observed. Moreover, YB-1 overexpression is associated with the alteration of microsatellite pattern and the enhancement of N methyl-N'-nitro-N-nitrosoguanidine (MNNG)-induced and spontaneous mutations. Furthermore, upregulation of other PIP-box-containing proteins, such as myeloid cell leukemia-1 (Mcl-1) and inhibitor of growth protein 1b (ING1b), has no impact on MMR complex formation and mutation accumulation, thus revealing the significant effect of YB-1 on regulating the MMR system. In conclusion, our study suggests that YB-1 functions as a PCNA-interacting factor to exert its regulatory role on the MMR process and involves in the induction of genome instability, which may partially account for the oncogenic potential of YB-1. PMID- 24141789 TI - FOXM1 targets NBS1 to regulate DNA damage-induced senescence and epirubicin resistance. AB - FOXM1 is implicated in genotoxic drug resistance but its mechanism of action remains elusive. We show here that FOXM1-depletion can sensitize breast cancer cells and mouse embryonic fibroblasts (MEFs) into entering epirubicin-induced senescence, with the loss of long-term cell proliferation ability, the accumulation of gammaH2AX foci, and the induction of senescence-associated beta galactosidase activity and cell morphology. Conversely, reconstitution of FOXM1 in FOXM1-deficient MEFs alleviates the accumulation of senescence-associated gammaH2AX foci. We also demonstrate that FOXM1 regulates NBS1 at the transcriptional level through an forkhead response element on its promoter. Like FOXM1, NBS1 is overexpressed in the epirubicin-resistant MCF-7Epi(R) cells and its expression level is low but inducible by epirubicin in MCF-7 cells. Consistently, overexpression of FOXM1 augmented and FOXM1 depletion reduced NBS1 expression and epirubicin-induced ataxia-telangiectasia mutated (ATM)phosphorylation in breast cancer cells. Together these findings suggest that FOXM1 increases NBS1 expression and ATM phosphorylation, possibly through increasing the levels of the MRN(MRE11/RAD50/NBS1) complex. Consistent with this idea, the loss of P-ATM induction by epirubicin in the NBS1-deficient NBS1-LBI fibroblasts can be rescued by NBS1 reconstitution. Resembling FOXM1, NBS1 depletion also rendered MCF-7 and MCF-7Epi(R) cells more sensitive to epirubicin induced cellular senescence. In agreement, the DNA repair-defective and senescence phenotypes in FOXM1-deficent cells can be effectively rescued by overexpression of NBS1. Moreover, overexpression of NBS1 and FOXM1 similarly enhanced and their depletion downregulated homologous recombination (HR) DNA repair activity. Crucially, overexpression of FOXM1 failed to augment HR activity in the background of NBS1 depletion, demonstrating that NBS1 is indispensable for the HR function of FOXM1. The physiological relevance of the regulation of NBS1 expression by FOXM1 is further underscored by the strong and significant correlation between nuclear FOXM1 and total NBS1 expression in breast cancer patient samples, further suggesting that NBS1 as a key FOXM1 target gene involved in DNA damage response, genotoxic drug resistance and DNA damage-induced senescence. PMID- 24141790 TI - Potential role of vitamin D deficiency on Fabry cardiomyopathy. AB - Patients with Fabry disease frequently develop left ventricular (LV) hypertrophy and renal fibrosis. Due to heat intolerance and an inability to sweat, patients tend to avoid exposure to sunlight. We hypothesized that subsequent vitamin D deficiency may contribute to Fabry cardiomyopathy. This study investigated the vitamin D status and its association with LV mass and adverse clinical symptoms in patients with Fabry disease. 25-hydroxyvitamin D (25[OH]D) was measured in 111 patients who were genetically proven to have Fabry disease. LV mass and cardiomyopathy were assessed by magnetic resonance imaging and echocardiography. In cross-sectional analyses, associations with adverse clinical outcomes were determined by linear and binary logistic regression analyses, respectively, and were adjusted for age, sex, BMI and season. Patients had a mean age of 40 +/- 13 years (42% males), and a mean 25(OH)D of 23.5 +/- 11.4 ng/ml. Those with overt vitamin D deficiency (25[OH]D <= 15 ng/ml) had an adjusted six fold higher risk of cardiomyopathy, compared to those with sufficient 25(OH)D levels >30 ng/ml (p = 0.04). The mean LV mass was distinctively different with 170 +/- 75 g in deficient, 154 +/- 60 g in moderately deficient and 128 +/- 58 g in vitamin D sufficient patients (p = 0.01). With increasing severity of vitamin D deficiency, the median levels of proteinuria increased, as well as the prevalences of depression, edema, cornea verticillata and the need for medical pain therapy. In conclusion, vitamin D deficiency was strongly associated with cardiomyopathy and adverse clinical symptoms in patients with Fabry disease. Whether vitamin D supplementation improves complications of Fabry disease, requires a randomized controlled trial. PMID- 24141791 TI - Novel quercetin derivatives in treatment of peroxynitrite-oxidized SERCA1. AB - Sarco/endoplasmic reticulum calcium ATP-ase (SERCA) is regulated by low concentrations of peroxynitrite and inhibited by high levels, as indicated in human diseases. We studied quercetin (Q) and its novel derivatives monochloropivaloylquercetin (MPQ) and chloronaphthoquinonequercetin (CHQ) as agents with expected preventive properties against peroxynitrite-induced SERCA impairment. Q and MPQ protected the SERCA1 against peroxynitrite induced activity decrease, while CHQ potentiated the inhibitory effect of peroxynitrite. Quercetin derivatives were found to be weaker antioxidants compared with Q, as indicated by their ability to scavenge peroxynitrite and prevent of SERCA1 carbonylation, both decreasing in the order (Q > MPQ > CHQ). Quantum-chemical values of theoretical parameter E HOMO also indicated lower antioxidant capacities for MPQ and CHQ. Prooxidant properties estimated by calculations of frontier molecular orbitals (E LUMO) correlated with experimentally determined SH-group decrease induced by the compounds studied. Both methods showed a decrease of prooxidant properties as follows: CHQ > MPQ > Q. In addition, experimentally measured half-wave potentials indicated stronger prooxidant properties of quercetin derivatives as compared to Q. More expressive alterations of conformation in the transmembrane region of SERCA1 induced by quercetin derivatives, as compared with Q, may at least partially correlate with their higher lipophilicities. The protective effects of Q and MPQ on different isoforms of SERCA activity may be useful in prevention and treatment of inflammation or muscle diseases. The inhibitory effect of CHQ on SERCA isoforms may be beneficial in therapeutic approaches aimed at anti-tumor treatment. PMID- 24141792 TI - Neuroprotective effects of vitexin by inhibition of NMDA receptors in primary cultures of mouse cerebral cortical neurons. AB - The accumulation of glutamate can excessively activate the N-methyl-D-aspartate (NMDA) receptors and cause excitotoxicity. Vitexin (5, 7, 4-trihydroxyflavone-8 glucoside, Vit) is a c-glycosylated flavone which was found in the several herbs, exhibiting potent hypotensive, anti-inflammatory, and neuroprotective properties. However, little is known about the neuroprotective effects of Vit on glutamate induced excitotoxicity. In present study, primary cultured cortical neurons were treated with NMDA to induce the excitotoxicity. Pretreatment with Vit significantly prevented NMDA-induced neuronal cell loss and reduced the number of apoptotic neurons. Vit significantly inhibited the neuronal apoptosis induced by NMDA exposure by regulating balance of Bcl-2 and Bax expression and the cleavages of poly (ADP-ribose) polymerase and pro-caspase 3. Furthermore, pretreatment of Vit reversed the up-regulation of NR2B-containing NMDA receptors and the intracellular Ca(2+) overload induced by NMDA exposure. The neuroprotective effects of Vit are related to inhibiting the activities of NR2B-containing NMDA receptors and reducing the calcium influx in cultured cortical neurons. PMID- 24141793 TI - A repertoire of biomarkers helps in detection and assessment of therapeutic response in epithelial ovarian cancer. AB - In epithelial ovarian cancer (EOC), the cancer antigen 125 (CA-125) has been conventionally used to help in diagnosis and assessment of response to treatment. Currently, YKL-40 (Tyrosine-Lysine-Leucine-40) and circulating cell-free DNA are being evaluated for possession of similar ability. In this study, we aimed to assess the ability of a repertoire of potential biomarkers in detecting and assessing therapeutic response, in advanced EOC. Blood levels of CA-125, YKL-40, total cell-free DNA (CFDNA), cell-free nuclear DNA (CFnDNA), and cell-free mitochondrial DNA (CFmDNA) levels were measured in 100 untreated patients of advanced EOC from November 2009 to June 2011, and again on treatment completion from the 20 patients who appeared for follow-up analysis. Significantly, higher proportion of untreated patients had serum CA-125 >3 times upper limit of normal (ULN) (90.0%; P < 0.0001) and plasma YKL-40 >ULN (77.0%; P < 0.0001), both of which significantly decreased, Posttherapy. posttherapy, CFDNA (P < 0.0001), and CFnDNA (P < 0.0001) levels significantly decreased as compared to pretreatment levels. Positive and significant correlations existed between pretherapy CFDNA and CFnDNA [Spearman rho (rho) = 1.000; P < 0.0001], and also with CFmDNA (rho = 0.301; P = 0.002), separately between CFnDNA and CFmDNA (rho = 0.303; P = 0.002), as well as between plasma YKL-40 and patient age (rho = 0.353; (P < 0.0001). On treatment completion, CFDNA and CFnDNA levels showed positive and significant correlation (rho = 1.000; P < 0.0001). Therefore serum CA-125 and plasma YKL-40 aid detection and assessment of therapeutic response, in advanced EOC. CFDNA and CFnDNA help in estimating extent of therapeutic response in advanced EOC. PMID- 24141794 TI - The Declaration of Helsinki, 50 years later. PMID- 24141795 TI - Human opinion dynamics: an inspiration to solve complex optimization problems. AB - Human interactions give rise to the formation of different kinds of opinions in a society. The study of formations and dynamics of opinions has been one of the most important areas in social physics. The opinion dynamics and associated social structure leads to decision making or so called opinion consensus. Opinion formation is a process of collective intelligence evolving from the integrative tendencies of social influence with the disintegrative effects of individualisation, and therefore could be exploited for developing search strategies. Here, we demonstrate that human opinion dynamics can be utilised to solve complex mathematical optimization problems. The results have been compared with a standard algorithm inspired from bird flocking behaviour and the comparison proves the efficacy of the proposed approach in general. Our investigation may open new avenues towards understanding the collective decision making. PMID- 24141796 TI - Nonprotective responses to pediatric vaccines occur in children who are otitis prone. AB - OBJECTIVE: We recently found that children who experience recurrent otitis media despite individualized care (stringently-defined otitis prone [sOP]) do not develop an antibody response to several vaccine candidate protein antigens expressed by Streptococcus pneumonia (Spn) and Haemophilus influenzae. Here we sought to determine if these same children also failed to develop antibody to routine pediatric vaccinations. STUDY DESIGN: One hundred forty sera collected from children age 6-24 months were analyzed. sOP (n=34) and age-matched non-sOP (n=34) children were assessed for IgG concentrations to diphtheria toxoid, tetanus toxoid, pertussis toxoid, filamentous hemagglutinin, pertactin (DTaP), polio, hepatitis B, H. influenzae type b capsule polyribosyl-ribitol-phosphate (PRP) and Spn capsular polysaccharide conjugate vaccine. RESULTS: IgG protective titers to diphtheria toxoid (P=0.006), tetanus toxoid (P<0.0001), pertussis toxoid (P<0.0001), filamentous hemagglutinin (P=0.001), pertactin (P=0.005), hepatitis B (P<0.0001), polio 3 (P=0.03) and Spn 23F (P=0.01) but not polio 1,2, PRP or Spn 6B, and 14 were decreased in sOP versus non-sOP children using generalized estimating equations. A high percentage of sOP children had nonprotective antibody values that persisted until 24 months of age despite routine boosters. CONCLUSION: sOP children may fail to achieve protective antibody concentrations after several routine vaccinations. PMID- 24141797 TI - Risk of repeated Moraxella catarrhalis colonization is increased in children with Toll-like receptor 4 Asp299Gly polymorphism. AB - BACKGROUND: Moraxella catarrhalis is a common causative agent of acute otitis media and other respiratory infections in children. Toll-like receptor (TLR) 4 is an important protein of human innate immunity. One polymorphic site Asp299Gly of TLR4 is proven to result in an impaired response to lipopolysaccharide from Gram negative bacteria. We investigated whether Finnish children who carry Asp299Gly had increased risk of M. catarrhalis colonization during their first 2 years of life. METHODS: This was a prospective cohort study carried out in Turku, Finland. We studied M. catarrhalis colonization in 161 Finnish children, whose nasopharyngeal specimens were taken at 2, 12 and 24 months of age. The semiquantitative culture method was used for identification of different bacterial species and the pyrosequencing-based method for detection of TLR4 Asp299Gly. RESULTS: Of 161 subjects, 126 (78%) were TLR4 A/A wild type and 35 (22%) were A/G heterozygote variants. The prevalence of M. catarrhalis increased from 24% at 2 months to 48% at 12 months and to 58% at 24 months of age. Of the 35 subjects with TLR4 variant, 15 (43%) were M. catarrhalis positive at all 3 time points, whereas only 11 (9%) subjects with TLR4 wild type were positive at these time points (relative risk 4.91, 95% confidence interval: 2.482-9.711, P=0.0001). Moreover, subjects with TLR4 variant had significantly higher bacterial load of M. catarrhalis in their nasopharynx than those with TLR4 wild type (P=0.0032). CONCLUSIONS: Our results indicate that children with TLR4 Asp299Gly polymorphism have an increased risk of repeated M. catarrhalis colonization. PMID- 24141798 TI - Neonatal herpes simplex virus infections: past progress and future challenges. PMID- 24141800 TI - Review of guidelines for evidence-based management for childhood community acquired pneumonia in under-5 years from developed and developing countries. PMID- 24141801 TI - Varicella zoster virus central nervous system immune reconstitution inflammatory syndrome presenting in a child. AB - A HIV-positive child presented with acute onset of right hemiplegia, facial palsy and dysphasia 4 weeks after commencing highly active antiretroviral therapy. Magnetic resonance imaging confirmed a left-sided cerebral infarct. Cerebrospinal fluid polymerase chain reaction was positive for varicella zoster virus. This is the first reported pediatric case of varicella zoster virus-related immune reconstitution inflammatory syndrome involving the central nervous system. PMID- 24141802 TI - Increasing incidence of tuberculosis in Tuscan youth, 1997 to 2011. AB - Data from 484 children (median age: 6 years; 46.5% immigrants) hospitalized for tuberculosis in 31 Tuscan hospitals in 1997-2011 were analyzed. Incidence increased from 7.3 (95% confidence interval: 4.9-9.4) to 12.5 (95% confidence interval: 9.6-15.4) per 100,000 (P=0.009). Increases were particularly profound in children<5 years of age, reaching 13.3 (95% confidence interval: 7.8-18.9; P<0.0001 for 2011 vs.1997) per 100,000. Pediatric tuberculosis is a major issue in Tuscany. PMID- 24141803 TI - Kawasaki disease: relationship between acute surgical abdomen and cytokine profiles. PMID- 24141804 TI - Early-onset Streptococcus pneumoniae neonatal sepsis and meningitis in the 13 valent vaccine era. PMID- 24141805 TI - A second case of foul smelling urine in a boy caused by Aerococcus urinae. PMID- 24141806 TI - Spontaneous regression of multiple Rasmussen aneurysms in a child with Lemierre syndrome and pulmonary abscesses. PMID- 24141807 TI - Long-term follow-up of International Prostate Symptom Score (IPSS) in men following prostate brachytherapy. AB - OBJECTIVE: To investigate variation in the International Prostate Symptom Score (IPSS) in men following prostate brachytherapy. METHODS: From January 2004 to November 2009, 524 consecutive patients underwent prostate brachytherapy either alone or in combination with external beam radiation therapy for T1c-T3b prostate cancer. The IPSS was assessed preimplant and at 1, 6, 12, 24, 36, and 48 months after treatment. Clinical and treatment-related factors were assessed for correlations with the IPSS increase. RESULTS: The mean preimplant IPSS was 7.4, with the greatest mean score of 16.0 at 1 month. At 6 months, the mean total IPSS had decreased to 11.5, but it was still statistically significantly greater than that at baseline (<0.001). At 12 months, the IPSS was decreased to 8.6, slightly greater than baseline (p = 0.001). The IPSS of 45.4 % (69/152) patients gradually returned to preimplant levels and that of 71.1 % (108/152) patients returned to within 3 points of the baseline at 24 months. At 24, 36, and 48 months after seed implantation, the IPSS was 8.6, 7.7, and 8.2, respectively, and none of these values differed statistically significantly from baseline (p > 0.05). Sixteen patients (3.1 %) showed AUR, and 11 patients required catheterization. On univariate and multivariate analyses, the IPSS increase was best predicted by lower preimplant IPSS. CONCLUSION: In our series, IPSS after prostate brachytherapy peaked at 1 month and gradually returned to approximately baseline at 24 months. The IPSS increase was best predicted by lower preimplant IPSS. PMID- 24141808 TI - Stress ulcer prophylaxis versus placebo or no prophylaxis in critically ill patients. A systematic review of randomised clinical trials with meta-analysis and trial sequential analysis. AB - PURPOSE: To assess the effects of stress ulcer prophylaxis (SUP) versus placebo or no prophylaxis on all-cause mortality, gastrointestinal (GI) bleeding and hospital-acquired pneumonia in adult critically ill patients in the intensive care unit (ICU). METHODS: We performed a systematic review using meta-analysis and trial sequential analysis (TSA). Eligible trials were randomised clinical trials comparing proton pump inhibitors or histamine 2 receptor antagonists with either placebo or no prophylaxis. Two reviewers independently assessed studies for inclusion and extracted data. The Cochrane Collaboration methodology was used. Risk ratios/relative risks (RR) with 95% confidence intervals (CI) were estimated. The predefined outcome measures were all-cause mortality, GI bleeding, and hospital-acquired pneumonia. RESULTS: Twenty trials (n = 1,971) were included; all were judged as having a high risk of bias. There was no statistically significant difference in mortality (fixed effect: RR 1.00, 95% CI 0.84-1.20; P = 0.87; I(2) = 0%) or hospital-acquired pneumonia (random effects: RR 1.23, 95% CI 0.86-1.78; P = 0.28; I(2) = 19%) between SUP patients and the no prophylaxis/placebo patients. These findings were confirmed in the TSA. With respect to GI bleeding, a statistically significant difference was found in the conventional meta-analysis (random effects: RR 0.44, 95% CI 0.28-0.68; P = 0.01; I(2) = 48%); however, TSA (TSA adjusted 95% CI 0.18-1.11) and subgroup analyses could not confirm this finding. CONCLUSIONS: This systematic review using meta analysis and TSA demonstrated that both the quality and the quantity of evidence supporting the use of SUP in adult ICU patients is low. Consequently, large randomised clinical trials are warranted. PMID- 24141809 TI - gamma-Amino acid mutated alpha-coiled coils as mild thermal triggers for liposome delivery. AB - The stability and compatibility of designed coiled coil peptides towards the selective incorporation of gamma(4)-amino acids at the hydrophobic positions of the heptad repeat are studied. Investigations reveal that the low thermal denaturation temperature of gamma(4)-residue mutated coiled coils can be utilized as a mild hyperthermia trigger in liposomes. PMID- 24141810 TI - Suspected migration of cervical epidural catheter into the brainstem after a difficult catheter insertion. AB - We report a case of diplopia during continuous epidural injection presumably caused by catheter migration. A 61-year-old woman underwent shoulder surgery under general anesthesia with cervical epidural anesthesia. The epidural catheter was placed in the C6-C7 epidural space with some difficulty before general anesthesia. The depth of the catheter placed under the skin was 10 cm. On POD 2, the patient noticed diplopia and developed dysarthria despite of good pain control so far. She complained of sudden headache after the rate of continuous epidural infusion was increased to relieve postoperative pain. Computed tomography and T2-weighted cerebral magnetic resonance imaging revealed an air image and surrounding edema in the pons. Diplopia and dysarthria disappeared after ceasing continuous epidural injection. A 15-cm-long mark under the skin and leak of colorless clear fluid from the puncture site were noted at removal of the catheter. On POD 13, diplopia recurred, which improved gradually. On the 9-month radiologic follow-up, we considered that the symptoms on POD 2 were caused by migration of the epidural catheter into the pons and that her later diplopia was induced by intracranial hypotension syndrome. One should be aware that such an unexpected migration of the catheter can occur following a difficult insertion. PMID- 24141811 TI - ANGPTL4 is produced by entero-endocrine cells in the human intestinal tract. AB - Gut hormones produced by entero-endocrine cells (EEC) located throughout the gastrointestinal tract play a major role in the regulation of glucose and energy homeostasis. Angiopoietin-like 4 (ANGPTL4, also referred to as fasting induced adipose factor) is a secreted factor involved in regulation of lipid homeostasis and has been proposed as circulating mediator between the gut microbiota and fat storage in adipose tissue, although discordant data exist. Currently, little is known about the site and regulation of ANGPTL4 production in the intestine. Here, we show using immunohistochemistry and immunofluorescence that cells positive for ANGPTL4 are scattered along the epithelial layer in the human small and large intestine. ANGPTL4-positive cells exhibit typical features of EEC characterized by large ANGPTL4-positive secretory granules directed towards the basolateral side. In support, extensive overlap was observed between ANGPTL4-positive cells and cells positive for the entero-endocrine marker chromogranin A. Higher resolution images revealed that ANGPTL4 and chromogranin A are partially present in distinct intracellular vesicles. Using entero-endocrine HuTu-80 cells, ANGPTL4 secretion was shown to be induced by short chain fatty acids and reduced by bile acids. Finally, levels of ANGPTL4 in human plasma were significantly decreased following meal consumption. In conclusion, ANGPTL4 is produced by EEC in human intestine and expression may be regulated by short chain fatty acids and bile acids. PMID- 24141812 TI - A century of progress: the Journal of the American Dental Association celebrates its centennial. PMID- 24141813 TI - The X-ray in dentistry, and the legacy of C. Edmund Kells: a commentary on Kells CE. The X-ray in dental practice. J Natl Dent Assoc 1920;7(3):241-272. PMID- 24141814 TI - The contributions of Dr. Gies: Promoting standards of dental education, research. 1924. PMID- 24141815 TI - A landmark report on understanding the human dentition. 1941. PMID- 24141816 TI - How the development of the high-speed turbine handpiece changed the practice of dentistry. 1953. PMID- 24141817 TI - Drs. Tiecke and Bernier: pioneers in oral pathology. 1954. PMID- 24141818 TI - Pointing the way to better oral health. 1956. PMID- 24141819 TI - Beginnings of the dental composite revolution. 1963. PMID- 24141820 TI - How the introduction of the acid-etch technique revolutionized dental practice. 1971. PMID- 24141821 TI - The role of the dental profession in addressing the human immunodeficiency virus epidemic. 1986. PMID- 24141822 TI - Evidence-based outcomes of periodontal therapy: a legacy of Sigurd P. Ramfjord. 1987. PMID- 24141823 TI - The need for better studies to assess the safety of providing dental care for medically complex patients. PMID- 24141824 TI - Others in dentistry join JADA in marking their own milestones. PMID- 24141825 TI - A century of success, a promising future. Introduction. PMID- 24141826 TI - JADA celebrates its first 100 years: landmark articles, commentaries highlight centennial. PMID- 24141827 TI - Long-lived photoinduced charge separation for solar cell applications in supramolecular complexes of multi-metalloporphyrins and fullerenes. AB - Monomers, dimers, trimers, dendrimers and oligomers of metalloporphyrins form supramolecular complexes with fullerene derivatives via electrostatic interactions, pi-pi interactions and coordination bonds. Photoexcitation of the supramolecular complexes resulted in photoinduced electron transfer from the porphyrin moiety to the fullerene moiety to produce the charge-separated states as revealed by laser flash photolysis measurements. The rate constants of photoinduced charge separation and charge recombination in supramolecular complexes of multi-metalloporphyrins and fullerenes were also determined by laser flash photolysis measurements and the results depending on the number of porphyrins in the supramolecular complexes are discussed in terms of efficiency of photoinduced energy transfer and charge separation as well as the lifetimes of charge-separated states. The photoelectrochemical performances of solar cells composed of supramolecular complexes of monomers, dimers, dendrimers and oligomers of metalloporphyrins with fullerenes are compared in relation to the rate constants of photoinduced charge separation and charge recombination. PMID- 24141828 TI - Optimization of preoperative status in hypoplastic left heart syndrome with intact atrial septum by left atrial decompression and bilateral pulmonary artery bands. AB - Hypoplastic left heart syndrome (HLHS) with intact (IAS) or highly restrictive atrial septum (RAS) has extremely poor outcomes largely related to pulmonary pathology. At birth, immediate left atrial (LA) decompression is required to remain viable, but there is a tradeoff between residual increase in LA pressure and pulmonary overcirculation, either of which exacerbates the pulmonary status. From August 2010 to April 2013, a retrospective chart review was performed on consecutive patients with a prenatal diagnosis of HLHS with IAS/RAS presenting to a single center. The management strategy was immediate LA decompression followed by placement of bilateral pulmonary artery bands (bPAB) and subsequent conventional Norwood procedure. Six patients were born with HLHS with IAS/RAS during this time period with this planned management strategy. Four patients underwent LA decompression and subsequently developed low cardiac output with pulmonary overcirculation. bPAB were used with improvement in cardiac output and pronounced diuresis. These patients all survived the Norwood and subsequent Glenn procedures and remain alive [median follow-up 2.2 years (range 11 months-2.7 years)]. Two patients did not survive with therapy being withdrawn before the Norwood procedure. It is hypothesized that a strategy of total LA decompression followed by bPAB maximizes preoperative systemic perfusion and minimizes ongoing injury to the pulmonary system. This may enhance patient candidacy for the Norwood procedure and long-term survival. PMID- 24141829 TI - Attention deficit hyperactivity disorder screening electrocardiograms: a community-based perspective. AB - Screening electrocardiograms (EKGs) for attention deficit hyperactivity disorder (ADHD) medication administration is controversial. We reviewed our experience as a community-based cardiology group. We reviewed all ADHD screening EKGs during a 2-year period. We evaluated whether screening EKGs resulted in further consultation and if management was altered. We also evaluated differences between patients on ADHD medications and those starting ADHD medications and further stratified the patients into stimulant versus nonstimulant groups. A total of 691 screening EKGs met our criteria. Forty-two patients (6.1%) were recommended for further consultation. EKG findings requiring consultation included the following: left-ventricular hypertrophy, right atrial enlargement, arrhythmia, prolonged QT, and axis deviation. Studies performed during consultation included 39 echocardiograms, 2 stress tests, 2 Holter monitors, and 1 heart card. Five patients (0.72%) were identified to have cardiac disease, one of whom decided against starting ADHD medications due to an arrhythmia, resulting in a change in management (0.14%). Results comparing mean age, heart rate, and corrected QT interval between patients on medication and patients starting medications were as follows: 10.06 years, 82.87, bpm and 405.24 ms compared with 9.99 years, 80.05 bpm, and 405.82 ms, respectively (p = not significant [NS], p = 0.013 [NS], respectively). Results comparing mean age, heart rate, and corrected QT interval between patients on stimulant versus nonstimulant medications were as follows: 9.68 years, 83.10 bpm, and 403.04 ms compared with 9.81 years, 80.10 bpm, and 407.08 ms, respectively (p = NS for all). In our population, screening EKGs rarely resulted in management changes for patients taking or starting ADHD medications. PMID- 24141830 TI - Nuclear DNA fragmentation negatively affects zona binding competence of Y bearing mouse spermatozoa. AB - PURPOSE: To investigate the influence of sperm DNA integrity on the zona binding ability of mouse spermatozoa in relation to their sex chromosomal constitution. METHOD(S): In this prospective experimental study, the sperm DNA fragmentation was induced by exposing testicular area of Swiss Albino mice (Mus musculus) to different doses of gamma-radiation (0, 2.5, 5.0 and 10.0 Gy). Sperm DNA fragmentation was quantified by single cell gel electrophoresis (comet assay). In vitro sperm zona binding assay was performed and the numbers of zona bound X and Y bearing spermatozoa were determined using fluorescence in situ hybridization (FISH). RESULT(S): The assessment of zona pellucida bound X and Y-bearing spermatozoa using fluorescence in situ hybridization has revealed a unique binding pattern. The number of zona bound Y-spermatozoa declined significantly (P < 0.01 to 0.0001) with increase in the DNA damage. The skewed binding pattern of X and Y-bearing sperm was strongly correlated with the extent of sperm DNA damage. CONCLUSION(S): The zona pellucida may have a role in preventing DNA damaged mouse sperm binding especially towards Y-bearing sperm. However, the exact mechanism behind this observation needs to be elucidated further. PMID- 24141831 TI - The risks of information in health care: do we need a new decision aid? PMID- 24141832 TI - Preliminary analysis of knee stress in full extension landing. AB - OBJECTIVE: This study provides an experimental and finite element analysis of knee-joint structure during extended-knee landing based on the extracted impact force, and it numerically identifies the contact pressure, stress distribution and possibility of bone-to-bone contact when a subject lands from a safe height. METHODS: The impact time and loads were measured via inverse dynamic analysis of free landing without knee flexion from three different heights (25, 50 and 75 cm), using five subjects with an average body mass index of 18.8. Three dimensional data were developed from computed tomography scans and were reprocessed with modeling software before being imported and analyzed by finite element analysis software. The whole leg was considered to be a fixed middle hinged structure, while impact loads were applied to the femur in an upward direction. RESULTS: Straight landing exerted an enormous amount of pressure on the knee joint as a result of the body's inability to utilize the lower extremity muscles, thereby maximizing the threat of injury when the load exceeds the height safety threshold. CONCLUSIONS: The researchers conclude that extended-knee landing results in serious deformation of the meniscus and cartilage and increases the risk of bone-to-bone contact and serious knee injury when the load exceeds the threshold safety height. This risk is considerably greater than the risk of injury associated with walking downhill or flexion landing activities. PMID- 24141833 TI - The skin tissue is adversely affected by TNF-alpha blockers in patients with chronic inflammatory arthritis: a 5-year prospective analysis. AB - OBJECTIVE: We evaluated the incidence of and the main risk factors associated with cutaneous adverse events in patients with chronic inflammatory arthritis following anti-TNF-alpha therapy. METHODS: A total of 257 patients with active arthritis who were taking TNF-alpha blockers, including 158 patients with rheumatoid arthritis, 87 with ankylosing spondylitis and 12 with psoriatic arthritis, were enrolled in a 5-year prospective analysis. Patients with overlapping or other rheumatic diseases were excluded. Anthropometric, socioeconomic, demographic and clinical data were evaluated, including the Disease Activity Score-28, Bath Ankylosing Spondylitis Disease Activity Index and Psoriasis Area Severity Index. Skin conditions were evaluated by two dermatology experts, and in doubtful cases, skin lesion biopsies were performed. Associations between adverse cutaneous events and clinical, demographic and epidemiological variables were determined using the chi-square test, and logistic regression analyses were performed to identify risk factors. The significance level was set at p<0.05. RESULTS: After 60 months of follow-up, 71 adverse events (73.85/1000 patient-years) were observed, of which allergic and immune-mediated phenomena were the most frequent events, followed by infectious conditions involving bacterial (47.1%), parasitic (23.5%), fungal (20.6%) and viral (8.8%) agents. CONCLUSION: The skin is significantly affected by adverse reactions resulting from the use of TNF-alpha blockers, and the main risk factors for cutaneous events were advanced age, female sex, a diagnosis of rheumatoid arthritis, disease activity and the use of infliximab. PMID- 24141834 TI - Magnetic resonance imaging and neuropsychological testing in the spectrum of normal aging. AB - OBJECTIVE: To understand the relationships between brain structures and function (behavior and cognition) in healthy aging. METHOD: The study group was composed of 56 healthy elderly subjects who underwent neuropsychological assessment and quantitative magnetic resonance imaging. Cluster analysis classified the cohort into two groups, one (cluster 1) in which the magnetic resonance imaging metrics were more preserved (mean age: 66.4 years) and another (cluster 2) with less preserved markers of healthy brain tissue (mean age: 75.4 years). RESULTS: The subjects in cluster 2 (older group) had worse indices of interference in the Stroop test compared with the subjects in cluster 1 (younger group). Therefore, a simple test such as the Stroop test could differentiate groups of younger and older subjects based on magnetic resonance imaging metrics. CONCLUSION: These results are in agreement with the inhibitory control hypotheses regarding cognitive aging and may also be important in the interpretation of studies with other clinical groups, such as patients with dementia and mild cognitive impairment. PMID- 24141835 TI - Comparison of the direct fluorescence assay and real-time polymerase chain reaction for the detection of influenza virus A and B in immunocompromised patients. AB - OBJECTIVE: This study evaluated the diagnostic performance of two methods for the detection of influenza virus in immunocompromised transplant patients. METHODS: A total of 475 respiratory samples, 236 from patients in a hematopoietic stem cell transplantation program and 239 from kidney transplant patients, were analyzed by a direct fluorescence assay and the Centers for Disease Control real-time polymerase chain reaction protocol for influenza A and B detection. RESULTS: Influenza detection using either method was 7.6% in the hematopoietic stem cell transplant group and 30.5% in the kidney transplant patient group. Influenza detection by real-time polymerase chain reaction yielded a higher positive rate compared with fluorescence than that reported by other studies, and this difference was more pronounced for influenza A. The fluorescence assay sensitivity, specificity, positive and negative predictive values, and kappa coefficient were 17.6%, 100%, 1, 0.83, and 0.256, respectively, and lower detection rates occurred in the kidney transplant patients. CONCLUSIONS: The real time polymerase chain reaction performance and the associated turnaround time for a large number of samples support the choice of this method for use in different routine diagnostic settings and influenza surveillance in high-risk patients. PMID- 24141836 TI - Acute effects of physiotherapeutic respiratory maneuvers in critically ill patients with craniocerebral trauma. AB - OBJECTIVE: To evaluate the effects of physiotherapeutic respiratory maneuvers on cerebral and cardiovascular hemodynamics and blood gas variables. METHOD: A descriptive, longitudinal, prospective, nonrandomized clinical trial that included 20 critical patients with severe craniocerebral trauma who were receiving mechanical ventilation and who were admitted to the intensive care unit. Each patient was subjected to the physiotherapeutic maneuvers of vibrocompression and increased manual expiratory flow (5 minutes on each hemithorax), along with subsequent airway suctioning with prior instillation of saline solution, hyperinflation and hyperoxygenation. Variables related to cardiovascular and cerebral hemodynamics and blood gas variables were recorded after each vibrocompression, increased manual expiratory flow and airway suctioning maneuver and 10 minutes after the end of airway suctioning. RESULTS: The hemodynamic and blood gas variables were maintained during vibrocompression and increased manual expiratory flow maneuvers; however, there were increases in mean arterial pressure, intracranial pressure, heart rate, pulmonary arterial pressure and pulmonary capillary pressure during airway suctioning. All of the values returned to baseline 10 minutes after the end of airway suctioning. CONCLUSION: Respiratory physiotherapy can be safely performed on patients with severe craniocerebral trauma. Additional caution must be taken when performing airway suctioning because this technique alters cerebral and cardiovascular hemodynamics, even in sedated and paralyzed patients. PMID- 24141837 TI - Variation of the Anthropometric Index for pectus excavatum relative to age, race, and sex. AB - OBJECTIVES: To determine possible variations in the Anthropometric Index for pectus excavatum relative to age, race, and sex in individuals free of thoracic wall deformities. METHODS: Between 2002 and 2012, 166 individuals with morphologically normal thoracic walls consented to have their chests and the perimeter of the lower third of the thorax measured according to the Anthropometric Index for pectus excavatum. The participant characteristics are presented (114 men and 52 women; 118 Caucasians and 48 people of African descent). RESULTS: Measurements of the Anthropometric Index for pectus excavatum were statistically significantly different between men and women (11-40 years old); however, no significant difference was found between Caucasians and people of African descent. For men, the index measurements were not significantly different across all of the age groups. For women, the index measurements were significantly lower for individuals aged 3 to 10 years old than for individuals aged 11 to 20 years old and 21 to 40 years old; however, no such difference was observed between women aged 11 to 20 years old and those aged 21 to 40 years old. CONCLUSION: In the sample, significant differences were observed between women aged 11 to 40 years old and the other age groups; however, there was no difference between Caucasian and people of African descent. PMID- 24141838 TI - Thymosin beta4 expression in colorectal polyps and adenomas. AB - OBJECTIVE: Thymosin beta 4 (Tbeta4) is a ubiquitous peptide that plays pivotal roles in the cytoskeletal system and in cell differentiation. Recently, a role for Tbeta4 has been proposed in experimental and human carcinogenesis, including gastrointestinal cancer. This study was aimed at evaluating the relationship between Tbeta4 immunoreactivity and the initial steps of carcinogenesis. METHODS: In total, 60 intestinal biopsies, including 10 hyperplastic polyps, 10 sessile serrated adenomas/polyps, 15 colorectal adenomas with low-grade dysplasia, 15 adenomas with high-grade dysplasia, 15 adenocarcinomas and 10 samples of normal colon mucosa, were analyzed for Tbeta4 expression by immunohistochemistry. RESULTS: Weak cytoplasmic reactivity for Tbeta4 was detected in the normal colon mucosa. No reactivity for Tbeta4 was found in hyperplastic and sessile serrated polyps/adenomas. Tbeta4 expression was observed in 10/15 colorectal adenocarcinomas. In adenomas with low-grade dysplasia, Tbeta4 immunoreactivity was mainly detected in dysplastic glands but was absent in hyperplastic glands. Tbeta4 immunoreactivity was characterized by spot-like perinuclear staining. In high-grade dysplastic polyps, immunostaining for Tbeta4 appeared diffuse throughout the entire cytoplasm of dysplastic cells. Spot-like perinuclear reactivity was detected in adenocarcinoma tumor cells. CONCLUSIONS: Our study shows for the first time that Tbeta4 is expressed during different steps of colon carcinogenesis. The shift of Tbeta4 immunolocalization from low-grade to high grade dysplastic glands suggests a role for Tbeta4 in colorectal carcinogenesis. However, the real meaning of Tbeta4 reactivity in dysplastic intestinal epithelium remains unknown. PMID- 24141839 TI - Right ventricular involvement in anterior myocardial infarction: a tissue Doppler derived strain and strain rate study. AB - OBJECTIVE: Strain and strain rate imaging is currently the most popular echocardiographic technique that reveals subclinical myocardial damage. There are currently no available data on this imaging method with regard to assessing right ventricular involvement in anterior myocardial infarction. Therefore, we aimed to evaluate right ventricular regional functions using a derived strain and strain rate imaging tissue Doppler method in patients who were successfully treated for their first anterior myocardial infarction. METHODS: The patient group was composed of 44 patients who had experienced their first anterior myocardial infarction and had undergone successful percutaneous coronary intervention. Twenty patients were selected for the control group. The right ventricular myocardial samplings were performed in three regions: the basal, mid, and apical segments of the lateral wall. The individual myocardial velocity, strain, and strain rate values of each basal, mid, and apical segment were obtained. RESULTS: The right ventricular myocardial velocities of the patient group were significantly decreased with respect to all three velocities in the control group. The strain and strain rate values of the right mid and apical ventricular segments in the patient group were significantly lower than those of the control group (excluding the right ventricular basal strain and strain rate). In addition, changes in the right ventricular mean strain and strain rate values were significant. CONCLUSION: Right ventricular involvement following anterior myocardial infarction can be assessed using tissue Doppler based strain and strain rate. PMID- 24141840 TI - Ulinastatin attenuates oxidation, inflammation and neural apoptosis in the cerebral cortex of adult rats with ventricular fibrillation after cardiopulmonary resuscitation. AB - OBJECTIVE: The role of Ulinastatin in neuronal injury after cardiopulmonary resuscitation has not been elucidated. We aim to evaluate the effects of Ulinastatin on inflammation, oxidation, and neuronal injury in the cerebral cortex after cardiopulmonary resuscitation. METHODS: Ventricular fibrillation was induced in 76 adult male Wistar rats for 6 min, after which cardiopulmonary resuscitation was initiated. After spontaneous circulation returned, the rats were split into two groups: the Ulinastatin 100,000 unit/kg group or the PBS treated control group. Blood and cerebral cortex samples were obtained and compared at 2, 4, and 8 h after return of spontaneous circulation. The protein levels of tumor necrosis factor alpha (TNF-alpha) and interleukin 6 (IL-6) were assayed using an enzyme-linked immunosorbent assay, and mRNA levels were quantified via real-time polymerase chain reaction. Myeloperoxidase and Malondialdehyde were measured by spectrophotometry. The translocation of nuclear factor-kappaB p65 was assayed by Western blot. The viable and apoptotic neurons were detected by Nissl and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL). RESULTS: Ulinastatin treatment decreased plasma levels of TNF alpha and IL-6, expression of mRNA, and Myeloperoxidase and Malondialdehyde in the cerebral cortex. In addition, Ulinastatin attenuated the translocation of nuclear factor-kappaB p65 at 2, 4, and 8 hours after the return of spontaneous circulation. Ulinastatin increased the number of living neurons and decreased TUNEL-positive neuron numbers in the cortex at 72 h after the return of spontaneous circulation. CONCLUSIONS: Ulinastatin preserved neuronal survival and inhibited neuron apoptosis after the return of spontaneous circulation in Wistar rats via attenuation of the oxidative stress response and translocation of nuclear factor-kappaB p65 in the cortex. In addition, Ulinastatin decreased the production of TNF-alpha, IL-6, Myeloperoxidase, and Malondialdehyde. PMID- 24141841 TI - Effect of hyperbaric oxygen therapy combined with autologous platelet concentrate applied in rabbit fibula fraction healing. AB - OBJECTIVES: The purpose is to study the effects of hyperbaric oxygen therapy and autologous platelet concentrates in healing the fibula bone of rabbits after induced fractures. METHODS: A total of 128 male New Zealand albino rabbits, between 6-8 months old, were subjected to a total osteotomy of the proximal portion of the right fibula. After surgery, the animals were divided into four groups (n = 32 each): control group, in which animals were subjected to osteotomy; autologous platelet concentrate group, in which animals were subjected to osteotomy and autologous platelet concentrate applied at the fracture site; hyperbaric oxygen group, in which animals were subjected to osteotomy and 9 consecutive daily hyperbaric oxygen therapy sessions; and autologous platelet concentrate and hyperbaric oxygen group, in which animals were subjected to osteotomy, autologous platelet concentrate applied at the fracture site, and 9 consecutive daily hyperbaric oxygen therapy sessions. Each group was divided into 4 subgroups according to a pre-determined euthanasia time points: 2, 4, 6, and 8 weeks postoperative. After euthanasia at a specific time point, the fibula containing the osseous callus was prepared histologically and stained with hematoxylin and eosin or picrosirius red. RESULTS: Autologous platelet concentrates and hyperbaric oxygen therapy, applied together or separately, increased the rate of bone healing compared with the control group. CONCLUSION: Hyperbaric oxygen therapy and autologous platelet concentrate combined increased the rate of bone healing in this experimental model. PMID- 24141842 TI - Effects of ovariectomy and resistance training on oxidative stress markers in the rat liver. AB - OBJECTIVE: The objective of this study was to assess the effects of resistance training on oxidative stress markers in the livers of ovariectomized rats. METHOD: Adult Sprague-Dawley rats were divided into the following four groups (n = 8 per group): sham-operated sedentary, ovariectomized sedentary, sham-operated resistance training, and ovariectomized resistance training. During the resistance training period, the animals climbed a 1.1-m vertical ladder with weights attached to their tails; the sessions were conducted 3 times per week, with 4-9 climbs and 8-12 dynamic movements per climb. The oxidative stress was assessed by measuring the levels of reduced glutathione and oxidized glutathione, the enzymatic activity of catalase and superoxide dismutase, lipid peroxidation, vitamin E concentrations, and the gene expression of glutathione peroxidase. RESULTS: The results showed significant reductions in the reduced glutathione/oxidized glutathione ratio (4.11+/-0.65 nmol/g tec), vitamin E concentration (55.36+/-11.11 nmol/g), and gene expression of glutathione peroxidase (0.49+/-0.16 arbitrary units) in the livers of ovariectomized rats compared with the livers of unovariectomized animals (5.71+/-0.71 nmol/g tec, 100.14+/-10.99 nmol/g, and 1.09+/-0.54 arbitrary units, respectively). Moreover, resistance training for 10 weeks was not able to reduce the oxidative stress in the livers of ovariectomized rats and induced negative changes in the hepatic anti-oxidative/oxidative balance. CONCLUSION: Our findings indicate that the resistance training program used in this study was not able to attenuate the hepatic oxidative damage caused by ovariectomy and increased the hepatic oxidative stress. PMID- 24141843 TI - Phytoestrogen alpha-zearalanol ameliorates memory impairment and neuronal DNA oxidation in ovariectomized mice. AB - OBJECTIVE: The aim of this study was to evaluate the effect of a novel phytoestrogen, alpha-Zearalanol, on Alzheimer's disease-related memory impairment and neuronal oxidation in ovariectomized mice. METHODS: Female C57/BL6 mice were ovariectomized or received sham operations and treatment with equivalent doses of 17beta-estradiol or alpha-Zearalanol for 8 weeks. Their spatial learning and memory were analyzed using the Morris water maze test. The antioxidant enzyme activities and reactive oxygen species generation, neuronal DNA oxidation, and MutT homolog 1 expression in the hippocampus were measured. RESULTS: Treatment with 17beta-estradiol or alpha-Zearalanol significantly improved spatial learning and memory performance in ovariectomized mice. In addition, 17beta-estradiol and alpha-Zearalanol attenuated the decrease in antioxidant enzyme activities and increased reactive oxygen species production in ovariectomized mice. The findings indicated a significant elevation in hippocampi neuronal DNA oxidation and reduction in MutT homolog 1 expression in estrogen-deficient mice, but supplementation with 17beta-estradiol or alpha-Zearalanol efficaciously ameliorated this situation. CONCLUSION: These results demonstrate that alpha Zearalanol is potentially beneficial for improving memory impairments and neuronal oxidation damage in a manner similar to that of 17beta-estradiol. Therefore, the compound may be a potential therapeutic agent that can ameliorate neurodegenerative disorders related to estrogen deficiency. PMID- 24141844 TI - The effect of school-based physical activity interventions on body mass index: a meta-analysis of randomized trials. AB - This study reviewed the effectiveness of school-based physical activity interventions aimed at reducing overweight, obesity and hypertension in children. We searched 14 databases and analyzed studies published between April 2009 and September 2012. Only randomized controlled trials performed at the school level that included elements of physical activity but did not include nutritional co interventions were analyzed. Studies were assessed by two recommended tools (EPHPP and GRADE), and the standardized mean differences with 95% confidence intervals were collected for a random-effect meta-analysis. A total of 12 papers were included in the meta-analysis, and these were divided according to three outcomes: body mass index (11 trials, n = 4,273, -0.02, 95% CI: -0.13 to 0.17, p = 0.8); body weight (5 trials, n = 1,330, -0.07, 95% CI: -0.18 to 0.04, p = 0.2); and blood pressure (6 trials, n = 1,549), including systolic (0.11, 95% CI: -0.10 to 0.31, p = 0.3) and diastolic pressure (-0.00, 95% CI: -0.10 to 0.10, p = 0.9). This meta-analysis of data from 11 randomized, school-based physical activity interventions suggests that, regardless of the potential benefits of physical activity in the school environment, the interventions did not have a statistically significant effect. However, it is difficult to generalize from these results because the duration, intensity and type of physical activity used in the interventions varied greatly. PMID- 24141846 TI - Increased red cell distribution width in patients with slow coronary flow. PMID- 24141845 TI - Assessment of depression in medical patients: a systematic review of the utility of the Beck Depression Inventory-II. AB - To perform a systematic review of the utility of the Beck Depression Inventory for detecting depression in medical settings, this article focuses on the revised version of the scale (Beck Depression Inventory-II), which was reformulated according to the DSM-IV criteria for major depression. We examined relevant investigations with the Beck Depression Inventory-II for measuring depression in medical settings to provide guidelines for practicing clinicians. Considering the inclusion and exclusion criteria seventy articles were retained. Validation studies of the Beck Depression Inventory-II, in both primary care and hospital settings, were found for clinics of cardiology, neurology, obstetrics, brain injury, nephrology, chronic pain, chronic fatigue, oncology, and infectious disease. The Beck Depression Inventory-II showed high reliability and good correlation with measures of depression and anxiety. Its threshold for detecting depression varied according to the type of patients, suggesting the need for adjusted cut-off points. The somatic and cognitive-affective dimension described the latent structure of the instrument. The Beck Depression Inventory-II can be easily adapted in most clinical conditions for detecting major depression and recommending an appropriate intervention. Although this scale represents a sound path for detecting depression in patients with medical conditions, the clinician should seek evidence for how to interpret the score before using the Beck Depression Inventory-II to make clinical decisions. PMID- 24141847 TI - Authors' comments on: Higher red cell distribution width in patients with slow coronary flow. PMID- 24141848 TI - The Yin and Yang of dyspnea in the emergency department: heart failure or COPD? PMID- 24141849 TI - Is there a relationship between left atrium size and p-wave dispersion in patients with lichen planus? PMID- 24141851 TI - Comment on "multiplex B cell characterization in blood, lymph nodes, and tumors from patients with malignancies". PMID- 24141852 TI - Response to comment on "multiplex B cell characterization in blood, lymph nodes, and tumors from patients with malignancies". PMID- 24141853 TI - Pattern recognition theory and the launch of modern innate immunity. PMID- 24141854 TI - Pillars article: approaching the asymptote? Evolution and revolution in immunology. Cold spring harb symp quant biol. 1989. 54: 1-13. PMID- 24141855 TI - Taming the beast within: regulation of innate lymphoid cell homeostasis and function. AB - Although substantial parallels have been made between transcription factor regulation of cytokine production by innate lymphoid cell (ILC) and Th cell subsets, we are still learning how ILC subsets are regulated during immune responses. Critical factors that promote ILC development and stimulate their effector functions have been identified, but mechanisms that control their homeostasis and downregulate their cytokine secretion remain poorly understood. In this review, we consider some of the potential positive and negative regulators of ILC homeostasis and function in physiological and pathological conditions. PMID- 24141856 TI - In vitro drug metabolism by human carboxylesterase 1: focus on angiotensin converting enzyme inhibitors. AB - Carboxylesterase 1 (CES1) is the major hydrolase in human liver. The enzyme is involved in the metabolism of several important therapeutic agents, drugs of abuse, and endogenous compounds. However, no studies have described the role of human CES1 in the activation of two commonly prescribed angiotensin-converting enzyme inhibitors: enalapril and ramipril. Here, we studied recombinant human CES1- and CES2-mediated hydrolytic activation of the prodrug esters enalapril and ramipril, compared with the activation of the known substrate trandolapril. Enalapril, ramipril, and trandolapril were readily hydrolyzed by CES1, but not by CES2. Ramipril and trandolapril exhibited Michaelis-Menten kinetics, while enalapril demonstrated substrate inhibition kinetics. Intrinsic clearances were 1.061, 0.360, and 0.02 ml/min/mg protein for ramipril, trandolapril, and enalapril, respectively. Additionally, we screened a panel of therapeutic drugs and drugs of abuse to assess their inhibition of the hydrolysis of p-nitrophenyl acetate by recombinant CES1 and human liver microsomes. The screening assay confirmed several known inhibitors of CES1 and identified two previously unreported inhibitors: the dihydropyridine calcium antagonist, isradipine, and the immunosuppressive agent, tacrolimus. CES1 plays a role in the metabolism of several drugs used in the treatment of common conditions, including hypertension, congestive heart failure, and diabetes mellitus; thus, there is a potential for clinically relevant drug-drug interactions. The findings in the present study may contribute to the prediction of such interactions in humans, thus opening up possibilities for safer drug treatments. PMID- 24141857 TI - Nonlinear pharmacokinetics of (+/-)3,4-methylenedioxymethamphetamine (MDMA) and its pharmacodynamic consequences in the rat. AB - 3,4-Methylenedioxymethamphetamine (MDMA) is a widely abused illicit drug that can cause severe and even fatal adverse effects. However, interest remains for its possible clinical applications in posttraumatic stress disorder and anxiety treatment. Preclinical studies to determine MDMA's safety are needed. We evaluated MDMA's pharmacokinetics and metabolism in male rats receiving 2.5, 5, and 10 mg/kg s.c. MDMA, and the associated pharmacodynamic consequences. Blood was collected via jugular catheter at 0, 0.5, 1, 2, 4, 6, 8, 16, and 24 hours, with simultaneous serotonin (5-HT) behavioral syndrome and core temperature monitoring. Plasma specimens were analyzed for MDMA and the metabolites (+/-)-3,4 dihydroxymethamphetamine (HHMA), (+/-)-4-hydroxy-3-methoxymethamphetamine (HMMA), and (+/-)-3,4-methylenedioxyamphetamine (MDA) by liquid chromatography-tandem mass spectrometry. After 2.5 mg/kg MDMA, mean MDMA Cmax was 164 +/- 47.1 ng/ml, HHMA and HMMA were major metabolites, and <20% of MDMA was metabolized to MDA. After 5- and 10-mg/kg doses, MDMA areas under the curve (AUCs) were 3- and 10 fold greater than those after 2.5 mg/kg; HHMA and HMMA AUC values were relatively constant across doses; and MDA AUC values were greater than dose-proportional. Our data provide decisive in vivo evidence that MDMA and MDA display nonlinear accumulation via metabolic autoinhibition in the rat. Importantly, 5-HT syndrome severity correlated with MDMA concentrations (r = 0.8083; P < 0.0001) and core temperature correlated with MDA concentrations (r = 0.7595; P < 0.0001), suggesting that MDMA's behavioral and hyperthermic effects may involve distinct mechanisms. Given key similarities between MDMA pharmacokinetics in rats and humans, data from rats can be useful when provided at clinically relevant doses. PMID- 24141858 TI - Uterine compression sutures for management of severe postpartum haemorrhage: five year audit. AB - OBJECTIVES: To audit the use of compression sutures for the management of massive postpartum haemorrhage and compare outcomes to those documented in the literature. DESIGN: Retrospective study. SETTING: A regional obstetric unit in Hong Kong. PATIENTS: Patients with severe postpartum haemorrhage encountered over a 5-year period from January 2008 to December 2012, in which compression sutures were used for management. MAIN OUTCOME MEASURES: Successful management with prevention of hysterectomy. RESULTS: In all, 35 patients with massive postpartum haemorrhage with failed medical treatment, for whom compression sutures were used in the management, were identified. The overall success rate for the use of B Lynch compression sutures alone to prevent hysterectomy was 23/35 (66%), and the success rate of compression sutures in conjunction with other surgical procedures was 26/35 (74%). This reported success rate appeared lower than that reported in the literature. CONCLUSION: Uterine compression was an effective method for the management of massive postpartum haemorrhage in approximately 70% of cases, and could be used in conjunction with other interventions to increase its success rate in terms of avoiding hysterectomy. PMID- 24141859 TI - Sperm cryopreservation for Chinese male cancer patients: a 17-year retrospective analysis in an assisted reproductive unit in Hong Kong. AB - OBJECTIVE: To review sperm cryopreservation usage rates, corresponding reproductive outcomes, and the current situation in our locality. DESIGN: Retrospective case series. SETTING: Assisted Reproductive Technology Unit of the Department of Obstetrics and Gynaecology, Prince of Wales Hospital and the Chinese University of Hong Kong. PARTICIPANTS: There were 130 Chinese male patients who underwent sperm cryopreservation before proceeding to gonadotoxic treatment from January 1995 to January 2012. MAIN OUTCOME MEASURES: Demographic data, type of cancers and treatments, semen analysis, and reproductive outcomes. RESULTS: The median patient age was 27 (range, 15-43) years. Most (85%) were single at the time of referral. Over half of the patients (51%) had testicular cancer. Five patients declined sperm cryopreservation after counselling. Among the remaining 125 men, 122 men were able to produce sperm by masturbation but 12 were found to have azoospermia, leaving a total of 110 who proceeded to semen cryopreservation. There were no significant differences in semen parameters between different cancer types. After gonadotoxic treatment, in up to 32% (n=11/34) of the patients, semen analysis yielded deterioration; four patients had azoospermia. Four patients (4%, n=4/110) came back to use their thawed semen for in-vitro fertilisation (intracytoplasmic sperm injection), which resulted in three successful singleton pregnancies. CONCLUSION: Sperm cryopreservation is a simple and effective way of preserving the fertility potential of male patients undergoing gonadotoxic treatment. This procedure is underutilised and deserves increased awareness by all possible means. PMID- 24141860 TI - Perioperative antithrombotic management in joint replacement surgeries. AB - OBJECTIVES: To determine optimal perioperative antithrombotic management for patients with cardiac diseases undergoing joint replacement surgeries. DATA SOURCES: MEDLINE and PubMed database search up to January 2013. STUDY SELECTION: Those dealing with perioperative antithrombotic management of patients undergoing orthopaedic operations, especially joint replacement, and also those undergoing general surgery. Various combinations of the following key words were used in our search: "antiplatelet", "antithrombotic", "anticoagulant", "coronary stent", "perioperative", "venous thromboembolism", "cardiovascular", "surgery", "orthopaedic", "knee replacement", "hip replacement", "joint replacement", and "arthroplasty". DATA EXTRACTION: Literature review, original articles, and best practice guidelines. DATA SYNTHESIS: Patients should be stratified according to their risk of developing arterial thromboembolism in order to decide the most appropriate perioperative antiplatelet or anticoagulant regimen for them. After recent coronary stenting, including bare-metal stents implanted within 6 weeks and drug-eluting stents implanted within 6 months, surgery should be deferred. For venous thromboembolism prophylaxis in patients already on aspirin, the dosage should be adjusted as necessary or additional low-molecular-weight heparin administered. CONCLUSION: The perioperative management of patients with cardiac diseases in receipt of antithrombotic agents is based upon a delicate balance between the perceived risk of arterial thromboembolism and the perceived risk of perioperative bleeding. One must exercise good judgement in deciding the most appropriate perioperative antithrombotic regimen. Venous thromboembolism is also a common problem after joint replacement surgeries. For patients already on aspirin, optimal venous thromboembolism prophylaxis is still being debated. PMID- 24141861 TI - ADAM33 polymorphisms are associated with asthma and a distinctive palm dermatoglyphic pattern. AB - A close correlation between asthma and palm dermatoglyphic patterns has been observed in previous studies, but the underlying genetic mechanisms have not been investigated. A disintegrin and metalloprotein-33 (ADAM33) polymorphisms are important in the development of asthma and other atopic diseases. To investigate the underlying mechanisms of the association between asthma and distinctive palm dermatoglyphic patterns, thirteen ADAM33 single-nucleotide polymorphisms (SNPs) were analyzed for the association between asthma and palm dermatoglyphic patterns in a population of 400 asthmatic patients and 200 healthy controls. Based on the results, five SNPs, rs44707 (codominant model, P=0.031; log-additive model, P=0.0084), rs2787094 (overdominant model, P=0.049), rs678881 (codominant model, P=0.028; overdominant model, P=0.0083), rs677044 (codominant model, P=0.013; log additive model, P=0.0033) and rs512625 (dominant model, P=0.033), were associated with asthma in this population. Two SNPs, rs44707 (dominant model, P=0.042) and rs2787094 (codominant model, P=0.014; recessive model, P=0.0038), were observed in the asthma patients with the distinctive palm pattern. As rs44707 and rs2787094 are associated with asthma and a distinctive palm pattern, the data suggest that ADAM33 polymorphisms are correlated with asthma and may be the underlying genetic basis of the association between asthma and palm dermatoglyphic patterns. PMID- 24141862 TI - Falling monsoon depression frequency: a Gray-Sikka conditions perspective. AB - In this study, we show that the annual monsoon depression (MD) frequency making landfall on the east coast of India shows a statistically significant decreasing trend for the period 1979-2010. Importantly, about 80% of this fall is confined to the south of 20 degrees N. To understand the plausible reason(s) for the weakening frequency of MDs in the southern Bay of Bengal in recent decades, we examine some of the seasonal average in-situ atmospheric parameters important for tropical cyclogenesis; we use various observational data from the IMD, and three atmospheric climate reanalysis datasets to account for possible quality constraints in them. Our findings suggest that the observed weakening of MD frequency south of 20 degrees N in the Bay of Bengal since 1950s is likely due to a declining trend in the mid-tropospheric relative humidity over the Indian region. Our numerical sensitivity experiments support this finding. PMID- 24141863 TI - Prokaryotic expression and functional analysis of the Mb1514 gene in Mycobacterium bovis. AB - The ability of mycobacteria to grow and invade target tissues is the key component in the process of Mycobacterium bovis infection. Therefore, analysis of the proteins responsible for cell invasion will assist clinicians in combating bovine tuberculosis. The Mb1514 gene of M. bovis encodes a hypothetical invasion protein (designated here as MbINV protein), whose function has not yet been directly identified. In this study, the Mb1514 gene from M. bovis was cloned, and expressed in E. coli. The recombinant MbINV protein (a single band of approximately 28 kDa) was purified for biological analysis. Our data demonstrated that recombinant MbINV protein significantly inhibited the viability of RAW264.7 macrophages in a dose-dependent manner (P < 0.05), and induced cell necrosis, indicating that the protein is toxic. MbINV protein infection significantly enhanced the mRNA expression levels of TNF-alpha, IL-1beta, and NOS2 (P < 0.01), suggesting that MbINV protein may be one of the virulence factors which directly interact with macrophages and modulate the host immune response to M. bovis. An invasion inhibition assay showed that MbINV-inhibited M. bovis invasion of RAW264.7 cells in a concentration-dependant manner, demonstrating it is an invasion protein. PMID- 24141864 TI - Middle East respiratory syndrome coronavirus and the upcoming Hajj. PMID- 24141865 TI - Awareness of occupational injuries and utilization of safety measures among welders in coastal South India. AB - BACKGROUND: Awareness of occupational hazards and its safety precautions among welders is an important health issue, especially in developing countries. OBJECTIVE: To assess the awareness of occupational hazards and utilization of safety measures among welders in coastal South India. METHODS: A cross-sectional study was conducted among 209 welders in Puducherry, South India. Baseline characteristics, awareness of health hazards, safety measures and their availability to and utilization by the participants were assessed using a pre tested structured questionnaire. RESULTS: The majority of studied welders aged between 20 and 40 years (n=160, 76.6%) and had 1-10 years of education (n=181, 86.6%). They were more aware of hazards (n=174, 83.3%) than safety measures (n=134, 64.1%). The majority of studied welders utilized at least one protective measure in the preceding week (n=200, 95.7%). Many of them had more than 5 years of experience (n=175, 83.7%), however, only 20% of them had institutional training (n=40, 19.1%). Age group, education level, and utilization of safety measures were significantly associated with awareness of hazards in univariate analysis (p<0.05). CONCLUSION: Awareness of occupational hazards and utilization of safety measures is low among welders in coastal South India, which highlights the importance of strengthening safety regulatory services towards this group of workers. PMID- 24141866 TI - Assessment of fluoride level in groundwater and prevalence of dental fluorosis in Didwana block of Nagaur district, Central Rajasthan, India. AB - BACKGROUND: In India, for the high concentration of fluoride in groundwater, people are at risk of dental fluorosis. The problem is common in various states of India. The condition in Rajasthan is worse where all districts have such a problem. OBJECTIVE: To study the fluoride concentration in groundwater and prevalence of dental fluorosis in Didwana block of Nagaur district, Central Rajasthan, India. METHODS: The fluoride concentration in water of 54 villages was measured electrochemically, using fluoride ion selective electrode. Dental fluorosis was assessed in 1136 people residing in study area by Dean's classification for dental fluorosis. RESULTS: The fluoride concentration in groundwater in studied sites ranged from 0.5 to 8.5 mg/L. The concentration of fluoride was more than the maximum permissible limit set by WHO and Bureau of Indian Standards (1 mg/L) in 48 groundwater sources. Of 1136 people studied, 788 (69.4%; 95% CI: 66.7%-72.1%) had dental fluoros---252 had mild and 74 had severe dental fluorosis. CONCLUSION: High level of fluoride in drinking water of Didwana block of Nagaur district, Central Rajasthan, India, causes dental fluorosis in most people in the region and is an important health problem that needs prompt attention. PMID- 24141867 TI - Post-traumatic stress disorder: a neglected health concern among commercial motor vehicle drivers. AB - BACKGROUND: Post-traumatic stress disorder (PTSD) is an anxiety disorder that may develop following a trauma. Iranian commercial motor vehicle drivers experience many road traffic accidents during their working life; this may increase the probability for developing PTSD, which in turn may lead to increased human errors as well as decreased work efficiency. OBJECTIVE: To examine the prevalence of PTSD and its associated factors among a group of Iranian commercial motor vehicle drivers. METHODS: In a cross-sectional study, 424 drivers who referred to participate in an annually training program were selected using a simple random sampling technique. They were requested to complete the Persian version of PCL-C and a data collection sheet about their occupational and demographic features. RESULTS: 385 (90.8%) of 424 studied drivers completed the study. 265 (68.8%) of the drivers had first-grade driving license. The mean+/-SD on-the-job daily driving was 10.2+/-2.8 h. 74 of 385 (19.2%; 95% CI: 15.3%-23.2%) met the PTSD criteria. Higher age and job experience as a professional driver, and having past history or past familial history of psychiatric disorders, were independent predictors of developing PTSD. The disease was more prevalent among drivers with first-grade driving license. CONCLUSION: The prevalence of PTSD among Iranian commercial motor vehicle drivers is higher than the figures reported elsewhere. Measures to diagnose of such drivers and to ensure optimum follow-up of victims before return to professional driving should be considered. PMID- 24141868 TI - Prevalence of musculoskeletal symptoms among employees of Iranian petrochemical industries: October 2009 to December 2012. AB - BACKGROUND: Work-related musculoskeletal disorders (WMSDs) are a common health problem throughout the world and a major cause of disability in the workplace. OBJECTIVE: To determine the prevalence rate of MSDs, assessment of ergonomics working conditions and identification of major risk factors associated with MSDs symptoms among employees of Iranian petrochemical industries between October 2009 and December 2012. METHODS: In this study, we studied 1184 randomly selected employees of 4 Iranian petrochemical companies with at least one year of work experience in office or operational units. For those with office jobs, data were collected using Nordic Musculoskeletal disorders Questionnaire (NMQ) and ergonomics checklist for the assessment of working conditions. For those with operational jobs, NMQ and Quick Exposure Check (QEC) method were used for data collection. RESULTS: The most prevalent MSD symptoms were reported in lower back (41.5%) and neck (36.5%). The prevalence of MSDs in all body regions but elbows and thighs of the office staff was significantly higher than that of operational workers. Assessment of working conditions in office staff revealed that the lowest index was attributed to workstation. QEC technique among operational workers showed that in 73.8% of the workers studied, the level of exposure to musculoskeletal risks was "high" or "very high." MSDs were associated with type of job, age, body mass index, work experience, gender, marital status, educational level and type of employment. CONCLUSION: The prevalence of MSDs in the office staff was higher than that of operational workers. Level of exposure to MSDs risk was high in operational workers. Corrective measures are thus necessary for improving working conditions for both office and operational units. PMID- 24141869 TI - Analysis of accidents in nine Iranian gas refineries: 2007-2011. AB - BACKGROUND: Occupational accidents are one of the major health hazards in industries and associated with high mortality, morbidity, spiritual damage and economic losses in the world. OBJECTIVE: To determine the incidence of occupational accidents in 9 Iranian gas refineries between March 2007 and February 2011. METHODS: Data on all occupational accidents occurred between March 2007 and February 2011, as well as other possible associated variables including time of accident, whether the accident was due to a personal or systemic fault, type of accident and its outcomes, age and gender of the victim, the injured parts of the body, job experience, and type of employment, were extracted from HSE reports and notes of health care services. Based on these data, we calculated the incidence rate of accidents and assessed the associated factors. RESULTS: During the 5 studied years, 1129 accidents have been recorded. The incidence of fatal accidents was 1.64 per 100 000 and of nonfatal accidents was 1857 per 100 000 workers per year. 99.4% of injured workers were male. The mean+/-SD age of injured people was 29.6+/-7.3 years. Almost 70% of injured workers aged under 30 years. The mean+/-SD job experience was 5.3+/-5.3 years. Accidents occurred more commonly around 10:00. More than 60% of accidents happened between 8:00 and 15:00. July had the highest incidence rate. The most common type of accident was being struck by an object (48%). More than 94% of accidents are caused by personal rather than systemic faults. Hands and wrists were the most common injured parts and involved in more than one-third of accidents. 70% of injured workers needed medical treatment and returned to work after primary treatment. CONCLUSION: The pattern of occupational accidents in Iranian gas refineries is similar to other previous reports in many ways. The incidence did not change significantly over the study period. Establishment of an online network for precise registration, notification and meticulous data collection seems necessary. PMID- 24141870 TI - Persistent respiratory symptoms following prolonged capsaicin exposure. AB - Capsaicin causes direct irritation of the eyes, mucous membranes, and respiratory tract. It is used in self-defense, in crowd control, and as a less lethal weapon in police work. Controlled trials suggest that capsaicin has minimal serious acute effects. Herein, we report a woman who had a 20-minute exposure to capsaicin during a jail riot. She subsequently developed episodic dyspnea and cough, and increased sensitivity to scents, perfumes, and cigarette smoke. She has not had wheezes on physical examination or abnormal pulmonary function tests. Her response to inhaled steroids and long-acting beta-agonists has been incomplete. She appears to have developed airway sensory hyperreactivity syndrome after the inhalation of capsaicin, which likely injured sensory nerves and/or caused persistent neurogenic inflammation. PMID- 24141871 TI - Correlation between fluoride level in drinking water and the prevalence of hypertension: an ecological correlation study. PMID- 24141872 TI - Toluene 2,4-diisocyanate and bowel obstruction: occupational medicine aspect of a case report. PMID- 24141873 TI - Validation of the English language pain sensitivity questionnaire. AB - BACKGROUND AND OBJECTIVES: The Pain Sensitivity Questionnaire (PSQ) is predictive of pain-related responses to experimental stimuli in German-speaking individuals. Here, we explored the validation of the English translation of the PSQ (PSQ-E). METHODS: One hundred thirty-six patients scheduled to undergo a low back interventional procedure completed the PSQ-E and other questionnaires including the Brief Pain Inventory. Pain ratings on a visual analog scale (VAS) were obtained following 2 standardized injections of subcutaneous lidocaine (VAS 1, infiltration in hand; VAS 2, infiltration of procedural site). The VAS measures were compared with the PSQ-E data and other inventories using linear regression analysis with stepwise selection of variables. RESULTS: The PSQ-E properties were in all respects similar to those of the original German PSQ. VAS 1 magnitude was predicted by PSQ-E-minor (r = 0.26, P < 0.01). VAS 2 magnitude was predicted by PSQ-E-minor (r = 0.34, P < 0.001), and the prediction was significantly enhanced by further inclusion of the Brief Pain Inventory interference score (total r = 0.40, P < 0.001). CONCLUSIONS: The study demonstrated that a significant correlation exists between the PSQ-E and clinically relevant pain ratings. This study validates the PSQ-E both in terms of measuring pain sensitivity and as possible means of recognizing patients with high pain sensitivity. Defining this subset of patients may have clinical utility in the future. PMID- 24141874 TI - Musculoskeletal pain, fear avoidance behaviors, and functional decline in obesity: potential interventions to manage pain and maintain function. AB - Individuals with musculoskeletal pain exhibit abnormal movement patterns, including antalgic gait, postural dysfunction, increased thoracolumbar stiffness, decreased proprioception, and altered activation of abdominal and extensor muscles. Additionally, aberrant or increased biomechanical forces over time produce joint or structural damage that results in pain. A large body habitus resulting from excessive weight can accelerate these musculoskeletal complaints. Irrespective of age, obesity contributes to chronic musculoskeletal pain, impairment of mobility, and eventual physical disability. Potential mechanisms that may mediate the relationships between obesity-related pain and functional decline include skeletal muscle strength deterioration, systemic inflammation, and psychosocial characteristics (eg, pain catastrophizing, kinesiophobia, and depression). Treatment considerations for obese patients with musculoskeletal pain include assessment of kinesiophobia levels, biomechanical analysis, and pain medication use. Ideally, a multidisciplinary team of physicians, psychologists, and physical therapists should optimize the design of interventions specific to the patient. In some cases, the use of appropriate pain medications or intra articular injectable agents may help control pain, fostering sustained activity, caloric expenditure, and weight loss. Morbid obesity is a medical condition that alters biomechanical forces on the tissues of the body. This condition provides the opportunity to examine accelerated development of musculoskeletal pain syndromes and etiology. The proposed therapeutic interventions can have multiple benefits in the obese population including weight loss, improved psychological outlook and self-efficacy, reduced kinesiophobia levels, reduced risk of functional dependence, and improved quality of life. PMID- 24141875 TI - Analysis of inadvertent intradiscal and intravascular injection during lumbar transforaminal epidural steroid injections: a prospective study. AB - BACKGROUND AND OBJECTIVES: Inadvertent intradiscal injection during a lumbar transforaminal epidural steroid injection (TFESI) can be critical given the possibility of discitis and disc degeneration. Intravascular steroid injection can result in devastating neurologic complications. We sought to identify the incidence of intradiscal and intravascular injection during lumbar TFESI and determine whether an aspiration test and static fluoroscopic image can be used to predict intravascular needle placement. METHODS: We evaluated 251 TFESIs in 219 patients. All TFESIs were performed by one of the authors using classic TFESI technique. After final needle position was confirmed using biplanar fluoroscopy, 1 mL of contrast was injected after negative blood or cerebrospinal fluid aspiration. Using static and real-time fluoroscopy, we assessed the incidences of intradiscal injection, blood flashback, and the presence of intravascular contrast spread. RESULTS: The incidence of intradiscal injections was 2.3% (6/251). Six intradiscal injections were observed, all among patients who had not previously undergone disc surgery. Five intradiscal injections occurred at the L4 5 level and 1 at the L5-S1 level. The incidence of overall intravascular injection was 15.5% (39/251), of which the incidence of simultaneous vascular and epidural injection was 12.7% (32/251), whereas intravascular injection only was 2.8% (7/251). The sensitivities for detecting intravascular access via aspiration or static fluoroscopic image with contrast were 20.5% and 51.2%, respectively. CONCLUSIONS: Inadvertent intradiscal injection during TFESI is not rare. Physicians who perform interventional pain procedures should increase their awareness of related potential complications. The aspiration test and static image of fluoroscope often fail to detect the intravascular injection during the TFESI. Real-time fluoroscopy should be the gold standard for confirming intravascular injection. PMID- 24141876 TI - Biological motion stimuli are attractive to medaka fish. AB - In many social fish species, visual cues play an important role in inducing shoaling behaviour. The present study is the first to examine whether and how "biological motion" depicting a moving creature by means of only a small number of isolated points induces shoaling behaviour in fish. Medaka (Oryzias latipes) were used because they are known to have high visual acuity and exhibit a strong tendency to form shoals. In experiment 1, we found that the presentation of medaka biological motion resulted in heightened shoaling behaviour when compared with that of non-biological motion (depicted by a small number of points placed at fixed distances that moved at a constant speed in a constant direction). In experiment 2, it was indicated that medaka biological motion was more effective at inducing shoaling behaviour when compared with human biological motion. In experiment 3, it was demonstrated that shoaling behaviour was largely dependent on the smoothness of the biological motion. In experiment 4, we revealed that shoaling behaviour was maximised in normal speed group and decreased in faster- and slower-than-normal speed groups. In experiment 5, it was shown that shoaling behaviour was slightly reduced when a reversed movie was presented. These results suggest that motion information extracted from conspecifics was sufficient to induce shoaling behaviour in medaka and that deviation from normal and familiar motion impeded shoaling behaviour. The naturalness of motion may be responsible for the induction of shoaling behaviour. PMID- 24141877 TI - Synergistically enhanced electrochemical (ORR) activity of graphene oxide using boronic acid as an interlayer spacer. AB - Herein, boronic acid is incorporated into a graphene oxide (GO) structure in order to synthesise a graphene organic framework (GOF) with enhanced electrochemical performance. The results obtained indicate that the GOF favours a 4e(-) reduction pathway in the oxygen reduction reaction (ORR). PMID- 24141878 TI - Structural evidence for functional lipid interactions in the betaine transporter BetP. AB - Bilayer lipids contribute to the stability of membrane transporters and are crucially involved in their proper functioning. However, the molecular knowledge of how surrounding lipids affect membrane transport is surprisingly limited and despite its general importance is rarely considered in the molecular description of a transport mechanism. One reason is that only few atomic resolution structures of channels or transporters reveal a functional interaction with lipids, which are difficult to detect in X-ray structures per se. Overcoming these difficulties, we report here on a new structure of the osmotic stress regulated betaine transporter BetP in complex with anionic lipids. This lipid associated BetP structure is important in the molecular understanding of osmoregulation due to the strong dependence of activity regulation in BetP on the presence of negatively charged lipids. We detected eight resolved palmitoyl oleoyl phosphatidyl glycerol (PG) lipids mimicking parts of the membrane leaflets and interacting with key residues in transport and regulation. The lipid-protein interactions observed here in structural detail in BetP provide molecular insights into the role of lipids in osmoregulated secondary transport. PMID- 24141879 TI - Symbiotic lactobacilli stimulate gut epithelial proliferation via Nox-mediated generation of reactive oxygen species. AB - The resident prokaryotic microbiota of the metazoan gut elicits profound effects on the growth and development of the intestine. However, the molecular mechanisms of symbiotic prokaryotic-eukaryotic cross-talk in the gut are largely unknown. It is increasingly recognized that physiologically generated reactive oxygen species (ROS) function as signalling secondary messengers that influence cellular proliferation and differentiation in a variety of biological systems. Here, we report that commensal bacteria, particularly members of the genus Lactobacillus, can stimulate NADPH oxidase 1 (Nox1)-dependent ROS generation and consequent cellular proliferation in intestinal stem cells upon initial ingestion into the murine or Drosophila intestine. Our data identify and highlight a highly conserved mechanism that symbiotic microorganisms utilize in eukaryotic growth and development. Additionally, the work suggests that specific redox-mediated functions may be assigned to specific bacterial taxa and may contribute to the identification of microbes with probiotic potential. PMID- 24141880 TI - A small RNA activates CFA synthase by isoform-specific mRNA stabilization. AB - Small RNAs use a diversity of well-characterized mechanisms to repress mRNAs, but how they activate gene expression at the mRNA level remains not well understood. The predominant activation mechanism of Hfq-associated small RNAs has been translational control whereby base pairing with the target prevents the formation of an intrinsic inhibitory structure in the mRNA and promotes translation initiation. Here, we report a translation-independent mechanism whereby the small RNA RydC selectively activates the longer of two isoforms of cfa mRNA (encoding cyclopropane fatty acid synthase) in Salmonella enterica. Target activation is achieved through seed pairing of the pseudoknot-exposed, conserved 5' end of RydC to an upstream region of the cfa mRNA. The seed pairing stabilizes the messenger, likely by interfering directly with RNase E-mediated decay in the 5' untranslated region. Intriguingly, this mechanism is generic such that the activation is equally achieved by seed pairing of unrelated small RNAs, suggesting that this mechanism may be utilized in the design of RNA-controlled synthetic circuits. Physiologically, RydC is the first small RNA known to regulate membrane stability. PMID- 24141882 TI - A randomized controlled trial of preinsertion ultrasound guidance for spinal anaesthesia in pregnancy: outcomes among obese and lean parturients: ultrasound for spinal anesthesia in pregnancy. AB - PURPOSE: The present study was conducted to examine if preinsertion lumbar ultrasound scanning helps with performance of spinal puncture, as a tool for decreasing the number of puncture attempts and spinal procedure time and increasing the success rate. We hypothesized that ultrasound can facilitate neuraxial blockade, particularly in pregnant women with difficult topographic anatomy. METHODS: One hundred (50 lean, BMI <30 kg/m(2), and 50 obese, BMI >=30 kg/m(2)) parturients scheduled for cesarean delivery were divided into ultrasound and control groups. Subarachnoid block was performed with prepuncture ultrasound examination in lean parturients (group 1, n = 25) and in obese parturients (group 2, n = 25), and subarachnoid block was performed without prepuncture ultrasound examination in lean parturients (group 3, n = 25) and in obese parturients (group 4, n = 25). The number of puncture attempts and puncture levels were recorded. RESULTS: A lower number of puncture attempts and fewer puncture levels were detected in ultrasound (US) groups (p < 0.001). First attempt success rate under US guidance was 92 % in comparison to 44 % using a conventional technique in obese parturients (p < 0.001). In 52 % of the lean patients and in 54.2 % of the obese patients, the intercristal line was at the L3-L4 and at the L2-L3 interspace, respectively. The duration of spinal procedure was shorter in US groups (22 vs. 52 s, p = 0.031). We found a high correlation between ultrasound and needle depth (r = 0.709, p < 0.001). CONCLUSIONS: We found a high level of success in the prepuncture ultrasound-determined insertion point. The ultrasound imaging technique can be a reliable guide to facilitate spinal anesthesia, especially in obese parturients. PMID- 24141881 TI - Pds5B is required for cohesion establishment and Aurora B accumulation at centromeres. AB - Cohesin mediates sister chromatid cohesion and contributes to the organization of interphase chromatin through DNA looping. In vertebrate somatic cells, cohesin consists of Smc1, Smc3, Rad21, and either SA1 or SA2. Three additional factors Pds5, Wapl, and Sororin bind to cohesin and modulate its dynamic association with chromatin. There are two Pds5 proteins in vertebrates, Pds5A and Pds5B, but their functional specificity remains unclear. Here, we demonstrate that Pds5 proteins are essential for cohesion establishment by allowing Smc3 acetylation by the cohesin acetyl transferases (CoATs) Esco1/2 and binding of Sororin. While both proteins contribute to telomere and arm cohesion, Pds5B is specifically required for centromeric cohesion. Furthermore, reduced accumulation of Aurora B at the inner centromere region in cells lacking Pds5B impairs its error correction function, promoting chromosome mis-segregation and aneuploidy. Our work supports a model in which the composition and function of cohesin complexes differs between different chromosomal regions. PMID- 24141883 TI - Is preoperative period associated with severity and unexpected death of injured patients needing emergency trauma surgery? AB - PURPOSE: Early operative control of hemorrhage is the key to saving the lives of severe trauma patients. We investigated whether emergency room (ER) stay time [time from the ER to the operating room (OR)] is associated with trauma severity and unexpected trauma death [Trauma and Injury Severity Score (TRISS) method based probability of survival (Ps) >=0.5 but died] of injured patients needing emergency trauma surgery. METHODS: We performed a retrospective review of all trauma patients requiring emergency surgery and all patients with pelvic fractures requiring transcatheter arterial embolization at our hospital from January 2002 to December 2012. We analyzed the relationships among injury severity on ER admission [Injury Severity Score (ISS); Revised Trauma Score (RTS); Ps; Shock Index (SI); American Society of Anesthesiologists Physical Status (ASA-PS)]; mortality rate; unexpected trauma death rate; and ER stay time. RESULTS: ER stay times were significantly shorter for patients with life threatening conditions [RTS <6.0 (p < 0.01), Ps <0.5 (p < 0.001), SI >=1.0 (p < 0.01), and ASA-PS >=4E (p < 0.001)]. In particular, ER stay time was inversely related to injury severity up to 120 min. The risk of unexpected trauma death significantly increased as ER stay time increased over 90 min (p < 0.01). CONCLUSIONS: Our results suggest that all medical staff should work together effectively on high-risk patients in the ER, bringing them immediately to the OR according to their level of risk. If injured patients need emergency trauma surgery, ER stay times should be kept as short as possible to reduce unexpected trauma death. PMID- 24141884 TI - Molecular tectonics: enantiomerically pure 1D stair-type mercury coordination networks based on rigid bismonodentate C2-chiral organic tectons. AB - Combinations of three enantiomerically pure organic chiral linear tectons bearing two divergently oriented pyridyl units as coordinating poles with HgCl2 as a two connecting V-shape metallatecton offering two free coordination sites lead to the formation of stair-type 1D enantiomerically pure mercury coordination networks. PMID- 24141885 TI - The 50th anniversary of the Declaration of Helsinki: progress but many remaining challenges. PMID- 24141886 TI - Leprosy and the rhetoric of elimination. PMID- 24141887 TI - Hospital merger is blocked because of failure to prove patient benefits. PMID- 24141888 TI - US government reopens as Republican effort to derail health act collapses. PMID- 24141890 TI - Scalp EEG is not a blur: it can see high frequency oscillations although their generators are small. AB - High frequency oscillations (HFOs) are emerging as biomarkers of epileptogenicity. They have been shown to originate from small brain regions. Surprisingly, spontaneous HFOs can be recorded from the scalp. To understand how is it possible to observe these small events on the scalp, one avenue is the analysis of the cortical correlates at the time of scalp HFOs. Using simultaneous scalp and intracranial recordings of 11 patients, we studied the spatial distribution of scalp events on the cortical surface. For typical interictal epileptiform discharges the subdural distributions were, as expected, spatially extended. On the contrary, for scalp HFOs the subdural maps corresponded to focal sources, consisting of one or a few small spatial extent activations. These topographies suggest that small cortical areas generated the HFOs seen on the scalp. Similar scalp distributions corresponded to distinct distributions on a standard 1 cm subdural grid and averaging similar scalp HFOs resulted in focal subdural maps. The assumption that a subdural grid "sees" everything that contributes to the potential of nearby scalp contacts was not valid for HFOs. The results suggest that these small extent events are spatially undersampled with standard scalp and grid inter-electrode distances. High-density scalp electrode distributions seem necessary to obtain a solid sampling of HFOs on the scalp. A better understanding of the influence of spatial sampling on the observation of high frequency brain activity on the scalp is important for their clinical use as biomarkers of epilepsy. PMID- 24141889 TI - 18F-fluorocholine PET/CT compared with extended pelvic lymph node dissection in high-risk prostate cancer. AB - PURPOSE: To compare (18)F-fluorocholine positron-emission tomography/computed tomography (PET/CT) with extended pelvic lymph node dissection (ePLND) for the detection of lymph node metastases in a large cohort of patients with high-risk prostate cancer. MATERIALS AND METHODS: Patients with prostate-specific antigen levels between 20 and 99 ng/mL and/or Gleason score 8-10 cancers, planned for treatment with curative intent following a negative or inconclusive standard bone scan, were investigated with (18)F-fluorocholine PET/CT followed by an ePLND. None of the patients received hormonal therapy prior to these staging procedures. Results for PET/CT were compared on a per-patient basis with histopathology from ePLND. Sensitivity, specificity, positive and negative predictive values were calculated. RESULTS: PET/CT detected a total of 76 suspected lymph node metastases and four suspected bone metastases in 33 (29 %) of the 112 included patients. Of these, 35 suspected lymph node metastases, only within the anatomical template area of an ePLND, were found in 21 of the patients. Histopathology of the ePLND specimens detected 117 lymph node metastases in 48 (43 %) of the 112 patients. Per-patient sensitivity, specificity, positive and negative predictive values for (18)F-fluorocholine PET/CT for lymph node metastases within the ePLND template were 0.33, 0.92, 0.76 and 0.65, respectively. Only 11 patients had lymph nodes larger than 10 mm that would have been reported by CT alone. CONCLUSIONS: (18)F-fluorocholine PET/CT detects lymph node metastases in a significant proportion of patients with high-risk prostate cancer with a high specificity, but low sensitivity. PMID- 24141891 TI - The evaluation of patient-specific factors associated with meniscal and chondral injuries accompanying ACL rupture in young adult patients. AB - PURPOSE: To evaluate patient-specific factors, including the mechanism of injury, time from the injury, activity level after the initial trauma, re-injury and body mass index (BMI), as risk factors for meniscal and chondral injuries accompanying anterior cruciate ligament (ACL) rupture. METHODS: A retrospective review of young adult patients with complete ACL rupture was performed between 2007 and 2011. The presence of meniscal tears and/or chondral injury, and the mechanism of injury, time from the injury, activity level after the initial trauma, re-injury and BMI were recorded. The data were analysed for associations between patient specific factors and the prevalence of meniscal and chondral injuries. RESULTS: A total of 293 patients were included. Increasing time from the injury, active daily life and re-injury were risk factors associated with meniscal injuries (p < 0.05). Independent risk factors associated with meniscal injuries included active daily life (OR = 4.66, 95 % CI 2.21-9.86, p < 0.0001) and re-injury (OR = 7.68, 95 % CI 3.24-18.22, p < 0.0001). Contact injury, increasing time from the injury, active daily life and re-injury were risk factors associated with chondral injuries (p < 0.05). Independent risk factors associated with chondral injuries included contact injury (OR = 2.54, 95 % CI 1.27-5.10, p < 0.01), active daily life (OR = 2.62, 95 % CI 1.35-5.08, p < 0.01) and re-injury (OR = 4.18, 95 % CI 2.09-8.35, p < 0.001). The incidence of re-injury was associated with the activity level (p < 0.001) and increased with increasing time from the injury (r = -0.698, p < 0.001). CONCLUSIONS: An increased risk of meniscal tear (especially medial meniscus) was strongly associated with an active daily life and re-injury. The combination of contact injury, active daily life and re-injury substantially increased the risk of cartilage injury. Patients with increasing time from the injury and active daily life exhibited a higher risk of re-injury, implying a higher prevalence of intra-articular damage. PMID- 24141892 TI - Synovial cytokine expression in ankle osteoarthritis depends on age and stage. AB - PURPOSE: Aim of the study was the analysis of cytokine expression in ankle osteoarthritis (OA) hypothesizing age-dependent regulation patterns. METHODS: Forty-nine patients undergoing an arthroscopy of the ankle with different stages of chronic OA were prospectively included in a clinical trial comparing the group <18 years (n = 9, O15.1 +/- 2.0 years) with the older patients (>=18 years, n = 40, O36.5 +/- 11.9). Lavage fluids were analysed by ELISA for levels of aggrecan, BMP-2/7, IGF-1/R, bFGF, CD105, MMP-13, and IL-1beta. Additionally, clinical parameters and scores (FFI, CFSS, AOFAS) were evaluated and supplemented by radiographic scores [Kellgren-Lawrence Score (KLS) for conventional X-rays, Ankle Osteoarthritis Scoring System (AOSS) for MRI]. RESULTS: In contrast to distribution of gender and BMI (p < 0.005), parameters characterizing the cartilage defect as ICRS grading, size, and duration of symptoms were not dependent on age. The incidence of osteochondritis dissecans (OCD) was higher in the group <18 years (p < 0.006), but the average degree of OCD grading was not different. KLS and AOSS were significantly higher in the group >=18 years (p < 0.02). Correlating with the higher degree of OA in the elderly, clinical function measured by FFI and AOFAS was statistically significantly worse (p < 0.05). Intra articular concentrations of aggrecan (3.1-fold), bFGF (8.7-fold), BMP-7 (2.7 fold), and CD105 (1.5-fold) were statistically significantly higher in the group >=18 years (p < 0.03). CONCLUSIONS: Confirming the hypothesis, increased synovial levels of aggrecan, bFGF, BMP-7, and CD105 were found in patients over 18 years. This correlated with a higher stage of OA determined by radiographic changes or deteriorated function and may offer starting points for new diagnostics and interventional strategies. LEVEL OF EVIDENCE: II. PMID- 24141893 TI - Safety and tolerability of targeted therapies for pulmonary hypertension in children. AB - The objective of this study is to evaluate the safety and tolerability of the pharmacological treatment of pulmonary hypertension in pediatric patients. It is a retrospective, longitudinal, observational study on pediatric patients undergoing treatment with pulmonary targeted therapies. 63 patients were included (51% male), with a median age of 3.4 years (IQR, 3.6 months-10 years) and a median weight 13 kg (IQR, 6-30 kg). Congenital heart disease was the etiology of pulmonary hypertension in the majority of cases (n = 33) and 28 patients were in NYHA functional class III-IV. The most commonly used drug was sildenafil (n = 79, 56%), followed by bosentan (n = 27, 23%), and a combination of both (n = 14, 41%). 34 patients had adverse reactions (54%) with an incidence rate of 1.02 per patient per year. The most commonly reported reactions were gastrointestinal symptoms (22%) and spontaneous erections (22%) in males. Nine severe adverse reactions (10%) occurred, requiring eight treatment withdrawal and one hospital admission. Treatment with targeted therapies for pulmonary hypertension is safe in the pediatric population. Severe ADRs were uncommon both in monotherapy and in combination therapy. Combination therapy was associated with a higher rate of ADRs. We observed similar survival rates in children receiving sildenafil doses according to the European Medicines Agency (EMA) recommendations or higher. PMID- 24141894 TI - Assessing the evidence base for behavioral health services: introduction to the series. AB - The current policy environment provides the opportunity for federal and state agencies to work with private and nonprofit sectors to transform the American health care system through development of a comprehensive set of community-based, recovery-oriented, and evidence-based services for people with mental and substance use disorders. This Assessing the Evidence Base Series (AEB Series) provides science-supported information about selected mental health and substance abuse services for health care leaders. Series authors conducted reviews of research on 14 behavioral health services: behavioral management for children and adolescents, trauma-focused cognitive-behavioral therapy for children and adolescents, recovery housing, residential treatment for individuals with substance use disorders, peer support services for individuals with serious mental illnesses, peer recovery support for individuals with substance use disorders, permanent supportive housing, supported employment, substance abuse intensive outpatient programs, skill building, intensive case management, consumer and family psychoeducation, medication-assisted treatment with methadone, and medication-assisted treatment with buprenorphine. The goal of the AEB Series is to provide a framework for decision makers to build a modern addictions and mental health service system for the people who use these services and the people who provide them. The framework is intended to support decisions about the services that are likely to be most effective. This introduction to the AEB Series explains the methods used to conduct the reviews, rate the research evidence, and describe the effectiveness of the services. The rationale underlying recommendations for implementation of the services is also discussed, and suggestions are offered for future research. PMID- 24141895 TI - Neuroprotective effect of calcitriol on ischemic/reperfusion injury through the NR3A/CREB pathways in the rat hippocampus. AB - Calcitriol has been demonstrated to provide neuroprotection against ischemia/reperfusion (I/R) injury. However, the exact mechanism of this protection remains unknown. In the present study, the neuroprotective effect of calcitriol was investigated in rats exposed to cerebral I/R injury induced by middle cerebral artery occlusion (MCAO). In addition, the involvement of NR3A, extracellular signal-regulated kinase 1/2 (ERK1/2), and phosphorylated cAMP/Ca2+ response element binding protein (p-CREB) in this protective action was determined in the hippocampal neurons. Western blot analysis was conducted to analyze the protein levels of NR3A, mitogen-activated protein kinase kinase (MEK) and p-CREB. The immunoreactivity of p-CREB and NR3A were measured by quantum dot based immunofluorescence analysis. Results showed that MCAO rats exhibited large cortical infarct volumes. By contrast, intraperitoneal administration of calcitriol significantly reduced infarct volumes seven days following reperfusion, and these results were accompanied by elevated NR3A and p-CREB activity in the hippocampal neurons. The inhibition of MEK by the addition of PD98059 led to attenuation of the neuroprotective effects of calcitriol and a correlated decrease in CREB activity. The results also demonstrated that calcitriol protected the brain from I/R injury through the NR3A-MEK/ERK-CREB pathway. PMID- 24141896 TI - Is there a role for routine screening MRI in women with LCIS? AB - Women with lobular carcinoma in situ (LCIS) have an elevated breast cancer risk, yet the benefit of MRI screening is unclear. We examined cancer detection rates with mammography alone versus mammography plus MRI in this high-risk population. From a prospectively maintained, single-institution database, we identified 776 patients diagnosed with LCIS after the adoption of screening MRI in April 1999. In addition to annual mammography and breast exam, MRI was used at the discretion of the physician and patient. Kaplan-Meier methods and landmark analyses at 1, 2, and 3 years following LCIS diagnosis were performed to compare rates of cancer detection with or without MRI. MRI screening was performed in 455 (59 %) patients (median, 3/patient). Median time from LCIS diagnosis to first MRI was 9 months (range 0.3-137 months). Patients undergoing MRI were younger (p < 0.0001), premenopausal (p < 0.0001), and more likely to have >=1 first-degree relative with breast cancer (p = 0.009). At a median follow-up of 58 months, 98/776 (13 %) patients developed cancer. The crude cancer detection rate in both screening groups was 13 %. MRI was not associated with earlier stage, smaller size, or node negativity. Landmark analyses at 1, 2, and 3 years after LCIS diagnosis failed to demonstrate increased cancer detection rates among women having MRI (p = 0.23, 0.26, and 0.13, respectively). Although a diagnosis of LCIS remains a significant risk factor for breast cancer, the routine use of MRI does not result in increased cancer detection rates (short-term), nor does it result in earlier stage at diagnosis, illustrating the importance of defining optimal screening strategies for high-risk patients based on tumor biology rather than numerical risk. PMID- 24141898 TI - Engineering microstructure and redox properties in the mixed conductor Ce(0.9)Pr(0.1)O(2-delta) + Co 2 mol%. AB - 10% Praseodymium doped ceria exhibits a combination of mixed ionic and electronic conductivity, redox catalytic properties and chemical compatibility with water and carbon dioxide at high temperatures. Minor additions of cobalt oxide have been demonstrated to act as a sintering aid as well as an effective promoter of the electronic conduction. However, an excess of sintering temperature causes cobalt aggregation into the grain boundaries as inferred from FE-SEM/EDX and TEM analysis. The redox behaviour of the materials was studied by means of temperature programmed desorption (TPD) and reduction (TPR). This work shows the systematic study of sintering conditions in order to understand the evolution of the material microstructure, grain boundaries and the role of cobalt in this complex system. The final purpose of the work is to improve both electronic and oxygen ion transport properties for their potential application as oxygen transport membranes and solid oxide fuel cell components. The sample sintered at 1000 degrees C exhibited the highest total conductivity at high temperatures, which is principally related to the improvement in the electronic conductivity through the grain boundary network. PMID- 24141897 TI - Favorable modulation of benign breast tissue and serum risk biomarkers is associated with > 10 % weight loss in postmenopausal women. AB - We conducted a phase II feasibility study of a 6-month behavioral weight loss intervention in postmenopausal overweight and obese women at increased risk for breast cancer and the effects of weight loss on anthropomorphic, blood, and benign breast tissue biomarkers. 67 women were screened by random peri-areolar fine-needle aspiration, 27 were registered and 24 participated in the interventional phase. The 24 biomarker evaluable women had a median baseline BMI of 34.2 kg/m(2) and lost a median of 11 % of their initial weight. Significant tissue biomarker modulation after the 6-month intervention was noted for Ki-67 (if restricted to the 15 women with any Ki-67 at baseline, p = 0.041), adiponectin to leptin ratio (p = 0.003); and cyclin B1 (p = 0.001), phosphorylated retinoblastoma (p = 0.005), and ribosomal S6 (p = 0.004) proteins. Favorable modulation for serum markers was observed for sex hormone-binding globulin (p < 0.001), bioavailable estradiol (p < 0.001), bioavailable testosterone (p = 0.033), insulin (p = 0.018), adiponectin (p = 0.001), leptin (p < 0.001), the adiponectin to leptin ratio (p < 0.001), C-reactive protein (p = 0.002), and hepatocyte growth factor (p = 0.011). When subdivided by <10 or >10 % weight loss, change in percent total body and android (visceral) fat, physical activity, and the majority of the serum and tissue biomarkers were significantly modulated only for women with >10 % weight loss from baseline. Some factors such as serum PAI-1 and breast tissue pS2 (estrogen-inducible gene) mRNA were not significantly modulated overall but were when considering only those with >10 % weight loss. In conclusion, a median weight loss of 11 % over 6 months resulted in favorable modulation of a number of anthropomorphic, breast tissue and serum risk and mechanistic markers. Weight loss of 10 % or more should likely be the goal for breast cancer risk reduction studies in obese women. PMID- 24141899 TI - Infrared evidence of a Slater metal-insulator transition in NaOsO3. AB - The magnetically driven metal-insulator transition (MIT) was predicted by Slater in the fifties. Here a long-range antiferromagnetic (AF) order can open up a gap at the Brillouin electronic band boundary regardless of the Coulomb repulsion magnitude. However, while many low-dimensional organic conductors display evidence for an AF driven MIT, in three-dimensional (3D) systems the Slater MIT still remains elusive. We employ terahertz and infrared spectroscopy to investigate the MIT in the NaOsO3 3D antiferromagnet. From the optical conductivity analysis we find evidence for a continuous opening of the energy gap, whose temperature dependence can be well described in terms of a second order phase transition. The comparison between the experimental Drude spectral weight and the one calculated through Local Density Approximation (LDA) shows that electronic correlations play a limited role in the MIT. All the experimental evidence demonstrates that NaOsO3 is the first known 3D Slater insulator. PMID- 24141900 TI - Association between apolipoprotein E gene polymorphism and the risk of recurrent pregnancy loss: a meta-analysis. AB - PURPOSE: The association between apolipoprotein E (ApoE) gene polymorphism and the risk of recurrent pregnancy loss (RPL) remains controversial. The present meta-analysis was performed to derive a precise estimate of the relationship. METHOD(S): We searched the PubMed, Embase, and Web of Science data- bases for studies related to the association between the ApoE genotype and the risk of RPL. We estimated the summary odds ratio (OR) with 95% confidence interval (CI) to assess the association. RESULT(S): Seven studies, including 2,090 RPL cases and 742 control samples, were identified. The results showed a significant association between ApoE E4 mutation and RPL risk (for E4 allele: OR =1.98, 95 %CI =1.14-3.43, P=0.499; for E2E3 vs. E3E3: OR =1.33, 95%CI =1.12-1.42, P=0.008; for E2E4 vs. E3E3: OR =1.26, 95 % CI =1.07-1.49, P=0.005). CONCLUSION(S): The meta-analysis suggests an association between ApoE E4 mutation and increased risk of RPL. PMID- 24141901 TI - The rise and fall of the thiazolidinediones: impact of clinical evidence publication and formulary change on the prescription incidence of thiazolidinediones. AB - BACKGROUND: Numerous factors affect drug utilization including clinical trials, promotional activity, drug safety signals and funding practices. We sought to investigate the impact of cardiovascular safety concerns and public drug formulary restrictions on the use of the thiazolidinediones (TZDs): rosiglitazone and pioglitazone. METHODS: We conducted a population-based cross-sectional time series analysis among more than 1.6 million older residents of Ontario, Canada using administrative healthcare claims databases from January 2000 to September 2010 to examine the impact of two events on the rate of initiation of TZDs among those aged 66 years and older: 1) the publication of a prominent meta-analysis suggesting cardiovascular harm for rosiglitazone, and 2) the introduction of prescribing restrictions for TZDs on the public formulary. RESULTS: Incident rosiglitazone prescribing decreased significantly from 5.32 to 0.44 prescriptions per 1,000 patients in the quarter following the publication of a meta-analysis, suggesting safety concerns for rosiglitazone (p<0.01). Similarly, incident pioglitazone prescribing continued to decline from 1.89 just prior to the publication of the meta-analysis to 0.53 prescriptions per 1,000 patients just prior to the policy implementation (p<0.01). Following the implementation of formulary restrictions for TZDs in Q2 of 2009, the rate of incident prescriptions for rosiglitazone fell further, from 0.20 prescriptions per 1,000 patients in the preceding quarter to 0.03 prescriptions per 1,000 patients in the subsequent quarter (Q3 of 2009; p<0.01). The rate of prescriptions dispensed for pioglitazone also decreased from 0.53 in Q1of 2009 to 0.11 prescriptions per 1,000 patients in Q3 of 2009 (p <0.01). CONCLUSION: Both the publication of clinical evidence and drug policy changes can significantly influence the utilization of the TZDs. PMID- 24141902 TI - DDX6 localizes to nuage structures and the annulus of mammalian spermatogenic cells. AB - The localization of DEAD (Asp-Glu-Ala-Asp) box helicase 6 (DDX6) in spermatogenic cells from the mouse, rat, and guinea pig was studied by immunofluorescence (IF) and immunoelectron microscopy (IEM). Spermatogenic cells from these species yielded similar DDX6 localization pattern. IF microscopy results showed that DDX6 localizes to both the nucleus and cytoplasm. In the cytoplasm of spermatogenic cells, diffuse cytosolic and discrete granular staining was observed, with the staining pattern changing during cell differentiation. IEM revealed that DDX6 localized to the five different types of nuage structures and non-nuage structures, including small granule aggregate and late spermatid annuli. Nuclear labeling was strongest in leptotene and zygotene spermatocytes and moderately strong in the nuclear pocket of late spermatids. DDX6 also localized to the surface of outer dense fibers, which comprise of flagella. The results show that DDX6 is present in nuage and non-nuage structures as well as nuclei, suggesting that DDX6 has diverse functions in spermatogenic cells. PMID- 24141903 TI - Disability and deviance: Dario Argento's Phenomena and the maintenance of abledness as a critical framework. AB - This exploration of disability directly applies Campbell's understanding of "abledness" to the film Phenomena by Italian director Dario Argento. Phenomena (1985) explores, through the diegetic response to protagonist Jennifer Corvino's ability to communicate with insects, the shifting cultural association between disability and deviance. The film begins with the traditional response to disability, what education psychologist Kaoru Yamamoto considers the cultural importance of classifying and interpreting disabled bodies by fitting them into a narrative of deviance for surveillance and control. Throughout Argento's film, characters attempt to classify Jennifer; scientists seek to diagnose her "affliction" through the medical model of disability, while Jennifer's schoolmistresses interpret Jennifer's behavior as a disciplinary problem based in environmental factors. This represents the structural model of disability, but in each instance, the attempt to classify Jennifer fails to diagnose or discipline the supposed "deviant, disabled body." Through this failure, the film dramatizes contemporary critiques of traditional models that examine disability, moving beyond to explore what Fiona Kumari Campbell has called "the maintenance of abledness" in sexed, raced, and modified bodies. By normalizing Jennifer's ability, then, Phenomena offers a framework for examining the process through which elements of "abledness" become normalized, a concept which many theorists now argue should maintain the focus of disability studies. PMID- 24141904 TI - Comparison of intravitreal ranibizumab in phakic and pseudophakic neovascular age related macular degeneration patients with good baseline visual acuity. AB - PURPOSE: To compare the efficacy of intravitreal ranibizumab for the treatment of neovascular age-related macular degeneration between phakic and pseudophakic eyes with visual acuity >=0.5 Snellen equivalent. METHODS: This was a retrospective, interventional, comparative study. The newly diagnosed neovascular age-related macular degeneration patients with visual acuity of >=0.5 Snellen equivalent were included in the study. The patients were divided into two subgroups: phakic group and pseudophakic. All patients received three consecutive monthly intravitreal ranibizumab injections, and then, reinjection was performed as needed. Patients were examined monthly, and the data at the baseline, at Months 3, 6, 9, and 12 were evaluated. The changes in visual acuity, central retinal thickness, and the number of injections were compared between the groups. RESULTS: The study included 96 eyes of 96 patients (56 phakic and 40 pseudophakic). Mean Snellen visual acuity at the baseline, at Months 3, 6, 9, and 12 was 0.56 +/- 0.09, 0.64 +/- 0.15, 0.62 +/- 0.21, 0.60 +/- 0.22, and 0.61 +/- 0.20 for the phakic group; and 0.55 +/- 0.08, 0.63 +/- 0.14, 0.60 +/- 0.13, 0.58 +/- 0.14, and 0.59 +/- 0.13 for the pseudophakic group, respectively. The change in mean visual acuity and central retinal thickness at the study visits was not statistically significant between the 2 groups (P > 0.05 for all). Mean injection number at Month 12 was 4.5 and 4.3 in the phakic and pseudophakic group, respectively (P = 0.5). CONCLUSION: Intravitreal ranibizumab treatment on an as-needed treatment regimen is effective in preserving vision and improving central retinal thickness in both the phakic and pseudophakic group of neovascular age-related macular degeneration patients with good baseline visual acuity. PMID- 24141905 TI - No difference in in vivo polyethylene wear particles between oxidized zirconium and cobalt-chromium femoral component in total knee arthroplasty. AB - PURPOSE: Polyethylene wear particle generation is one of the most important factors affecting mid- to long-term results of total knee arthroplasties. Oxidized zirconium was introduced as a material for femoral components to reduce polyethylene wear generation. However, an in vivo advantage of oxidized zirconium on polyethylene wear particle generation is still controversial. The purpose of this study was to compare in vivo polyethylene wear particles between oxidized zirconium total knee prosthesis and conventional cobalt-chromium (Co-Cr) total knee prosthesis. METHODS: Synovial fluid was obtained from the knees of 6 patients with oxidized zirconium total knee prosthesis and from 6 patients with conventional cobalt-chromium (Co-Cr) total knee prosthesis 12 months after the operation. Polyethylene particles were isolated and examined using a scanning electron microscope and image analyser. RESULTS: Total number of particles in each knee was 3.3 +/- 1.3 * 10(7) in the case of oxidized zirconium (mean +/- SD) and 3.4 +/- 1.2 * 10(7) in that of Co-Cr (n.s.). The particle size (equivalent circle diameter) was 0.8 +/- 0.3 MUm in the case of oxidized zirconium and 0.6 +/ 0.1 MUm in that of Co-Cr (n.s.). The particle shape (aspect ratio) was 1.4 +/- 0.0 in the case of oxidized zirconium and 1.4 +/- 0.0 in that of metal Co-Cr (n.s). CONCLUSIONS: Although newly introduced oxidized zirconium femoral component did not reduce the in vivo polyethylene wear particles in early clinical stage, there was no adverse effect of newly introduced material. At this moment, there is no need to abandon oxidized zirconium femoral component. However, further follow-up of polyethylene wear particle generation should be performed to confirm the advantage of the oxidized zirconium femoral component. LEVEL OF EVIDENCE: Therapeutic study, Level III. PMID- 24141906 TI - Mycorrhizal fungal growth responds to soil characteristics, but not host plant identity, during a primary lacustrine dune succession. AB - Soil factors and host plant identity can both affect the growth and functioning of mycorrhizal fungi. Both components change during primary succession, but it is unknown if their relative importance to mycorrhizas also changes. This research tested how soil type and host plant differences among primary successional stages determine the growth and plant effects of arbuscular mycorrhizal (AM) fungal communities. Mycorrhizal fungal community, plant identity, and soil conditions were manipulated among three stages of a lacustrine sand dune successional series in a fully factorial greenhouse experiment. Late succession AM fungi produced more arbuscules and soil hyphae when grown in late succession soils, although the community was from the same narrow phylogenetic group as those in intermediate succession. AM fungal growth did not differ between host species, and plant growth was similarly unaffected by different AM fungal communities. These results indicate that though ecological filtering and/or adaptation of AM fungi occurs during this primary dune succession, it more strongly reflects matching between fungi and soils, rather than interactions between fungi and host plants. Thus, AM fungal performance during this succession may not depend directly on the sequence of plant community succession. PMID- 24141907 TI - Rab11b mediates melanin transfer between donor melanocytes and acceptor keratinocytes via coupled exo/endocytosis. AB - The transfer of melanin from melanocytes to keratinocytes is a crucial process underlying maintenance of skin pigmentation and photoprotection against UV damage. Here, we present evidence supporting coupled exocytosis of the melanin core, or melanocore, by melanocytes and subsequent endocytosis by keratinocytes as a predominant mechanism of melanin transfer. Electron microscopy analysis of human skin samples revealed three lines of evidence supporting this: (1) the presence of melanocores in the extracellular space; (2) within keratinocytes, melanin was surrounded by a single membrane; and (3) this membrane lacked the melanosomal membrane protein tyrosinase-related protein 1 (TYRP1). Moreover, co culture of melanocytes and keratinocytes suggests that melanin exocytosis is specifically induced by keratinocytes. Furthermore, depletion of Rab11b, but not Rab27a, caused a marked decrease in both keratinocyte-stimulated melanin exocytosis and transfer to keratinocytes. Thus, we propose that the predominant mechanism of melanin transfer is keratinocyte-induced exocytosis, mediated by Rab11b through remodeling of the melanosome membrane, followed by subsequent endocytosis by keratinocytes. PMID- 24141909 TI - Chest ultrasound in children: critical appraisal. AB - We analyze the potential use of ultrasound in the study of the thorax in children. The physical limitations imposed on sonography by the ventilated lung and thoracic cage are well known. We want to discuss new US applications based on the clinical and methodological experience gained in adults as outlined by emergency and critical care specialists. These specialists take information from physical acoustic phenomena that is not directly convertible into images of the human body, starting with the interpretation and handling of artifacts. We give a critical assessment from a radiologic viewpoint that is both necessary and important. PMID- 24141911 TI - Recovery housing: assessing the evidence. AB - OBJECTIVE: Recovery housing is a direct service with multiple components that provides supervised, short-term housing to individuals with substance use disorders or co-occurring mental and substance use disorders. It commonly is used after inpatient or residential treatment. This article describes recovery housing and assesses the evidence base for the service. METHODS: Authors searched PubMed, PsycINFO, Applied Social Sciences Index and Abstracts, Sociological Abstracts, and Social Services Abstracts. They identified six individual articles from 1995 through 2012 that reported on randomized controlled trials or quasi-experimental studies; no reviews or meta-analyses were found. They chose from three levels of evidence (high, moderate, or low) based on benchmarks for the number of studies and quality of their methodology. They also described the evidence of service effectiveness. RESULTS: The level of evidence for recovery housing was moderate. Studies consistently showed positive outcomes, but the results were tempered by research design limitations, such as lack of consistency in defining the program elements and outcome measures, small samples, and single-site evaluations, and by the limited number of studies. Results on the effectiveness of recovery housing suggested positive substance use outcomes and improvements in functioning, including employment and criminal activity. CONCLUSIONS: Recovery housing appears to be an important component in the continuum of care for some individuals. However, replication of study findings with greater specificity and in more settings is needed. PMID- 24141912 TI - Porous MnO2 for use in a high performance supercapacitor: replication of a 3D graphene network as a reactive template. AB - Graphene oxide hydrogel is used as a reactive template to prepare nanoporous materials with a 3D microstructure. The as-prepared porous MnO2 shows a capacitance retention of ~70.6% at a current density as high as 15 A g(-1), resulting from the 3D interconnected ion transport channel replicated from the graphene oxide hydrogel. PMID- 24141913 TI - Editor's note. PMID- 24141914 TI - Malaria as a disease and as a cultural perspective in Carlos Chagas' and Mario de Andrade's travels to the Amazon. AB - Two journeys have had an important bearing on social thought regarding the Amazon: Carlos Chagas', from 1912 to 1913, and Mario de Andrade's, in 1927. The article examines how their travel experiences influenced these two men's views and interpretations of the relation between malaria and the project to bring civilization to the tropics. In Chagas' texts, wonderment is the category that organizes his perception of the Amazon region, evinced in the idea that the pathology of the tropics challenges established knowledge of the disease. Empathy, on the other hand, is the explanatory key to understanding Mario de Andrade's critical outlook, which entails the valorization of forms of sociability, beliefs, and popular manifestations in the region, including those related to malaria. PMID- 24141915 TI - Between the Carlo R. and the Orleannais: public health and maritime prophylaxis in the description of two cases of ships transporting immigrants arriving in the port of Rio de Janeiro, 1893-1907. AB - We address the changes in Brazilian maritime prophylaxis by studying two cases of immigrant ships arriving at the port of Rio de Janeiro with epidemics onboard. The objective is to understand the etiology, means of prevention and methods used to combat the three diseases subject to international port regulations: yellow fever, bubonic plague and cholera. Until the late nineteenth century, quarantines were one of the main disease prevention practices. In the early twentieth century, microbiology and the concept of vectors in ports sanitation services emerged. Quarantines, which were already being criticized as antiquated and ineffective, were limited to a few cases, and new hygiene methods and technologies began to be applied in port sanitary defense. PMID- 24141916 TI - Radiological protection in the Spanish nuclear industry under Franco, 1939-1975. AB - In debates about nuclear controversy, the issue of occupational safety in radioactive facilities is rarely foregrounded; it has historically been relegated to second place compared to the attention given to potential harm to the general population. Aiming for, at least, partially filling this historiographical gap, this article deals with the development of occupational radiological protection in Spain under the dictatorship of General Franco (1939-1975). It covers the rise of radiological protection measures on an international level and the subsequent development of legislation in the case of Spain, a process that paralleled the growth of the nation's nuclear program. Finally, it explores the main evidence of the impact of ionizing radiation on Spain's working population. PMID- 24141917 TI - Natural history and temporalization: reflections on Buffon's Natural history. AB - This article presents a rereading of Buffon's Natural History in the light of the concepts of temporal reversibility and irreversibility. The goal is to determine to what extent Buffon introduces a transformationist concept of natural forms in this work. To that effect, the main points of classical natural history and the doctrine of preformed germs are analyzed. Subsequently, Buffon's use of the temporal variable is considered. This examination shows that despite his rejection of the theory of preformationism and the scholastic classification system, Buffon continued to use categories based on a reversible temporal matrix. PMID- 24141918 TI - [Quetelet, the average man and medical knowledge]. AB - Using two books by Adolphe Quetelet, I analyze his theory of the 'average man', which associates biological and social normality with the frequency with which certain characteristics appear in a population. The books are Sur l'homme et le developpement de ses facultes and Du systeme social et des lois qui le regissent. Both reveal that Quetelet's ideas are permeated by explanatory strategies drawn from physics and astronomy, and also by discursive strategies drawn from theology and religion. The stability of the mean as opposed to the dispersion of individual characteristics and events provided the basis for the use of statistics in social sciences and medicine. PMID- 24141919 TI - [Adolphe Quetelet and biopolitics as secularized theology]. AB - The article recaptures the work of an author who has been forgotten by the contemporary social sciences, that is, the Belgium polymath Adolphe Quetelet. Focusing on his main work, Sur l'homme et le developpement de ses facultes, ou Essai de physique sociale, the study underscores how the secularization of theological principles within the realm of science was important to the construction of Quetelet's work. His dual engagement in science and politics is pertinent here, as he was the main nineteenth-century force behind the incorporation of statistics as a science essential to the State's ability to govern its people. He also played a relevant role in the realization of the hegemonic political project of modernity, biopolitics, and its influence in the field of biomedicine in the nineteenth and twentieth centuries. PMID- 24141920 TI - [Paul Deshayes (1796-1875) and the Geological Commission of the Kingdom: a collaboration with the Portuguese state]. AB - Carlos Ribeiro, one of the directors of the Geological Commission of Portugal, voyaged in 1858 to many countries of Europe to acquire publications, equipment and comparator collections. In Paris he met Paul Deshayes, a well-known conchologist, who gave him access to his personal collections of Tertiary deposits from France and helped him to classify Portuguese fossils. The outcome of the joint work can be seen in the Ribeiro List, which is preserved in the historic archives of the National Energy and Geology Laboratory (Alfragide, Portugal). These classifications served as a basis for a monograph published by Pereira da Costa, Ribeiro's colleague on the Geological Commission, and the definition of the stratigraphy of Portugal's Tertiary deposits. PMID- 24141921 TI - [Geraldo Horacio de Paula Souza, China and Chinese medicine, 1928-1943]. AB - This essay is on the writings of sanitary doctor Geraldo Horacio de Paula Souza in Eugenia e Imigracao (1928) and, after an official trip to the Orient, in Digressoes sobre a medicina chinesa classica (1942) and A sabedoria chinesa diante da ciencia ocidental e a Escola Medica de Pequim (1943). The documents, analyzed according to the conceptual approach of Carlo Ginzburg, indicate a change in his view of the Chinese. Trained according to the Rockefeller Foundation's model of experimental medicine, Geraldo de Paula Souza was guided in his work by scientific rigor and record imagery. In his youth he was of the opinion that the Chinese civilization was stagnated, but this view changed after his visit, when he perceived the Chinese republic's capacity to modernize. PMID- 24141922 TI - [For the sacrifice of isolation: leprosy and philanthropy in Argentina and Brazil, 1930-1946]. AB - Patronato de Leprosos, in Argentina, and Federacao das Sociedades de Assistencia aos Lazaros e Defesa Contra a Lepra, in Brazil, were created as institutions designed to help people with leprosy and their families. Headed by women from the ruling classes, these entities took very similar actions, despite the different national contexts in which they operated, both supplementing leprosy healthcare policies in their respective countries. This article aims to demonstrate the similarities in the strategies adopted by both philanthropic institutions, which, in the 1930s and 1940s, acted in harmony with the physicians who supported compulsory isolation. PMID- 24141923 TI - [The smallpox epidemic and fear of the vaccine in Goias]. AB - An analysis is made of two aspects of smallpox in the Brazilian state of Goias. One is a historical reconstruction of the main outbreaks in the state in the nineteenth century and the first three decades of the twentieth century, focusing on the increased number of epidemics of the disease as transportation was modernized and the population grew. The other concerns the people's resistance in the nineteenth century to the smallpox vaccine, which may be understood in a broader context of resistance to the modernizations introduced by the State in Goias. According to the methodology used, smallpox is regarded as a hermeneutic event within the broader efforts to standardize public health made by the public authorities, which ran counter to the local people's values and attitudes. PMID- 24141924 TI - [The hospital dynamics at Maternidade Dr. Joao Moreira, Fortaleza, in the early decades of the twentieth century]. AB - Maternidade Dr. Joao Moreira, the first women's hospital in the Brazilian city of Fortaleza, was founded in March 1915. It was created with the goal of reducing infant mortality during childbirth and made the female body an object of medical practice in the city. Its wards were used not just by the city's womenfolk, but also for midwife training courses. In this study, we analyze the dynamics inside the institution: its spatial organization, its healing and disciplinary methods, its relationship with its patients, its medical staff, etc. Statistical records and clinical case studies produced by doctors were important sources of research in this, one of the first initiatives in the development of obstetrics in the state of Ceara. PMID- 24141925 TI - [On different scales: the architecture of Hospital-Colonia Rovisco Pais from the perspective of doctor Fernando Bissaya Barreto]. AB - In 1938, Portuguese physician Fernando Bissaya Barreto spearheaded the creation of a 'nursing home for lepers' in the center of Portugal, away from big towns and cities, but still accessible from any part of the country. Opened in 1947, Hospital-Colonia Rovisco Pais followed the model of a colony/hospital/hospice, and was divided symmetrically into buildings of equal features and numbers for both sexes. According to a disciplinary, non-exclusionary rationale, the urban design, building design and furniture and fittings were conceived, under the direct influence of Bissaya Barreto, as instruments for intervention in the physical and moral bodies of the patients, and also, on a different scale, for the control and modification of Portuguese society as a whole. PMID- 24141926 TI - [Literature and suffering: a medical perspective on 'life']. AB - The aesthetic approach of Ranulpho Prata, a Brazilian writer and doctor born in the state of Sergipe, emphasizes figurations about life in the catholic approach to suffering during the First Republic (1889-1930). The article problematizes the idea of resigned suffering, which, combined with the political perspective of the catholic thought of the Dom Vital Center, was recommended for the poorer strata of Brazilian society. They were identified in Prata's work as migrants from the north to the federal capital and inhabitants of the countryside. PMID- 24141927 TI - [Contributions of the thought of Didier Fassin to a critical analysis of healthcare policies for vulnerable population groups]. AB - This is a reflection on the contributions made over the last 14 years by Didier Fassin, in his analysis of issues raised by the phenomenon of migration in contemporary times, especially in France. He regards it as fundamental to comprehend the political uses behind the advent of 'humanitarian reason' and the 'empire of trauma', which underpin society today, in order to understand the suffering caused by large and small crises and the way social forces related to them act. Drawing on Foucault's concepts of biopolitics and biopower, Fassin makes a critical appraisal of the aid and assistance provided for society's 'unwanted' and their lifestyles, marked by social inclusion and exclusion via the body and trauma. PMID- 24141928 TI - [Discontinuities and reappearances: between the normal and the pathological in the theory of social control]. AB - This text highlights ambiguities and gaps in the distinction between pathology and normality in the social and individual ambits dating back to the late nineteenth century and reemerging in another guise in contemporary times. In the last decades of the nineteenth century, many authors adopted the theory of atavic criminality defended by Italian criminal anthropologists led by Lombroso. The French school criticized Italian biological determinism and left to the 'psi' sciences the aspects it deemed to be the individual dimension of criminality. Taking advantage of this space, psychiatry created the 'psychopath', inheritor in many ways of the 'innate criminal', and today accepted as a psychopathological category. In this context, the article focuses on social control involving the distinction between pathology and normality in the social and individual spheres. PMID- 24141929 TI - [Scientists and their archives]. PMID- 24141931 TI - [Making bodies in motion]. PMID- 24141930 TI - [Is the reduction of maternal mortality no more than a technical problem of cultural adaptation?]. PMID- 24141932 TI - [Living and eating in the 'rustic metropolis': the daily life of workers in the city of Sao Paulo from 1920 to 1960]. PMID- 24141933 TI - [In defense ofSaude e historia]. PMID- 24141934 TI - Water dynamics: relation between hydrogen bond bifurcations, molecular jumps, local density & hydrophobicity. AB - Structure and dynamics of water remain a challenge. Resolving the properties of hydrogen bonding lies at the heart of this puzzle. We employ ab initio Molecular Dynamics (AIMD) simulations over a wide temperature range. The total simulation time was ~ 2 ns. Both bulk water and water in the presence of a small hydrophobic molecule were simulated. We show that large-angle jumps and bond bifurcations are fundamental properties of water dynamics and that they are intimately coupled to both local density and hydrogen bond strength oscillations in scales from about 60 to a few hundred femtoseconds: Local density differences are the driving force for bond bifurcations and the consequent large-angle jumps. The jumps are intimately connected to the recently predicted hydrogen bond energy asymmetry. Our analysis also appears to confirm the existence of the so-called negativity track provided by the lone pairs of electrons on the oxygen atom to enable water rotation. PMID- 24141935 TI - Peroxisome proliferator-activated receptor gamma2 Pro12Ala (rs1801282) polymorphism and breast cancer susceptibility: a meta-analysis. AB - Several studies have investigated the correlation between the peroxisome proliferator-activated receptor gamma2 (PPAR-gamma2) Pro12Ala (rs1801282) polymorphism and the risk of breast cancer, with inconsistent results. For this reason, a meta-analysis was conducted to identify the potential correlation after pooling data from eligible case-control studies. Search strategies were conducted in PubMed, EMBASE and the COCHRANE Library in English and from VIP, CNKI and Sinomed in Chinese (all the papers were published before November 11, 2012) using appropriate terms. A total of 2,279 cases and 2,360 controls from four related case-control studies were included in this meta-analysis. According to the three eligible populations, the odds ratios (ORs) and 95% confidence intervals (CIs) on the risk of breast cancer for the CG versus CC and GG versus CC genotypes and the G versus C allele were 0.84 and 0.72-0.98, 0.92 and 0.32-2.61, and 0.98 and 0.84 1.13, respectively. The OR and 95% CI for CG+GG versus CC from the four study populations were 0.85 and 0.73-0.98, respectively. This meta-analysis supported the fact that the G allele of PPAR-gamma2 Pro12Ala (rs1801282) modestly affects the risk of breast cancer. Nevertheless, further studies are required to enrich the evidence of this correlation. PMID- 24141936 TI - Ultra-endurance sports have no negative impact on indices of arterial stiffness. AB - PURPOSE: Marathon running has been linked with higher arterial stiffness. Blood pressure is a major contributor to pulse wave velocity (PWV). We examined indices of arterial stiffness with a blood pressure-independent method in marathon runners and ultra-endurance athletes. METHODS: Male normotensive amateur runners were allocated to three groups according to former participation in competitions: group I (recreational athletes), group II (marathon runners) and group III (ultra endurance athletes). Indices of arterial stiffness were measured with a non invasive device (VaSera VS-1500N, Fukuda Denshi, Japan) to determine the cardio ankle vascular index (CAVI, primary endpoint) and brachial-ankle PWV (baPWV). Lifetime training hours were calculated. Cumulative competitions were expressed as marathon equivalents. Linear regression analysis was performed to determine predictors for CAVI and baPWV. RESULTS: Measurements of arterial stiffness were performed in 51 subjects (mean age 44.6 +/- 1.2 years): group I (n = 16), group II (n = 19) and group III (n = 16). No between-group differences existed in age, anthropometric characteristics and resting BP. CAVI and baPWV were comparable between all groups (P = 0.604 and P = 0.947, respectively). In linear regression analysis, age was the only independent predictor for CAVI (R(2) = 0.239, beta = 0.455, P = 0.001). Systolic BP was significantly associated with baPWV (R(2) = 0.225, beta = 0.403, P = 0.004). CONCLUSIONS: In middle-aged normotensive athletes marathon running and ultra-endurance sports had no negative impact on arterial stiffness. PMID- 24141938 TI - Functional patterns of microbial communities of rhizospheric soils across the development stages of a young mangrove in French Guiana. AB - The functional patterns of microbial communities (microbial respiration, enzyme activities, functional diversity) and the relevant physico-chemical characteristics of rhizospheric soils were studied during the process of mudflat colonization by mangrove. The study site is a fringe mangrove stand located in Montabo Bay at Cayenne (French Guiana). It is characterized by different vegetation development stages dominated by an assemblage of Avicennia germinans and Laguncularia racemosa. Rhizospheric and surface soils were collected from three stations based on successional stages of mangrove colonization: pioneer (P), coppice (C), and young forest (F). The microbial functional patterns showed significant progressive shifts along the mangrove vegetation profile. The P stages, those most influenced by tide currents, were macroscopically characterized by hydro-sedimentary instability and micro-phytobenthic colonization of mudflat. This stage, characterized by low total organic carbon (TOC) content and quality, showed the lowest extracellular enzymatic activities and the highest functional metabolic diversities. TOC quality analyses by (13)C CPMAS NMR provided evidence of progressive TOC enrichment and an increasing imprint of aboveground vegetation on C quality as succession occurs. These differences in the origin, amount, and quality of soil organic matter (SOM) of older stages exerted both a quantitative and qualitative control over microbial functional responses. This indicated the enhancement of aboveground-belowground functional linkages, leading to the expression of high decomposition activities and a functional loss and specialization of rhizospheric microbial communities. PMID- 24141939 TI - Differential expression of a sodium-phosphate cotransporter among Vibrio vulnificus strains. AB - Vibrio vulnificus is an estuarine bacterium with pathogenic potential. Its three known biotypes differ in host distribution. We have found the nptA gene for a sodium-phosphate cotransporter, which is rare in bacteria, in each biotype. nptA transcript abundance differed significantly among biotypes, leading to the hypothesis that transcript levels differ under environmental conditions associated with estuarine and host environments. nptA transcript abundance was assessed in V. vulnificus biotypes 1 (C and E genotypes), 2 and 3 strains under varied salinity, phosphate concentration, and pH. Differences in transcript abundance separated strains into two groups. Type C and biotype 3 strains formed Group 1, while type E and biotype 2 strains formed Group 2. Group 2 strains had significantly greater nptA RNA transcript abundance than Group 1. Transcript abundance in the two groups also responded differently to pH and salinity, suggesting differential regulation of nptA in response to environmental conditions. Comparison of the deduced amino acid sequences of NptA among strains resulted in strain grouping similar to that based on transcript abundance. Variation in transcript abundance between groups may affect the ability of V. vulnificus strains to colonize hosts and/or to compete as free-living bacteria in various habitats. PMID- 24141940 TI - Genotypic and phenotypic diversity of cyanobacteria in biological soil crusts of the Succulent Karoo and Nama Karoo of southern Africa. AB - Biological soil crusts (BSCs) are communities of cryptogamic organisms, occurring in arid and semiarid regions all over the world. Based on both morphological identification and genetic analyses, we established a first cyanobacterial inventory using the biphasic approach for BSCs within two major biomes of southern Africa. The samples were collected at two different sites in the Succulent Karoo and one in the Nama Karoo. After cultivation and morphological identification, the 16S rRNA gene was sequenced from the cyanobacterial cultures. From the soil samples, the DNA was extracted, and the 16S rRNA gene sequenced. All the sequences of the clone libraries from soil and cultures were compared with those of the public databases. Forty-five different species were morphologically identified in the samples of the Succulent Karoo (observatories of Soebatsfontein and Goedehoop). Based on the genetic analyses, 60 operational taxonomic units (OTUs) were identified for the Succulent Karoo and 43 for the Nama Karoo (based on 95% sequence similarity). The cloned sequences corresponded well with the morphologically described taxa in cultures and sequences in the public databases. Besides known species of typical crust-forming cyanobacterial genera (Microcoleus, Phormidium, Tolypothrix and Scytonema), we found sequences of so far undescribed species of the genera Leptolyngbya, Pseudanabaena, Phormidium, Oscillatoria, Schizothrix and Microcoleus. Most OTUs were restricted to distinct sites. Grazed soils showed lower taxa numbers than undisturbed soils, implying the presence of early successional crust types and reduced soil surface protection. Our combined approach of morphological identification and genetic analyses allowed both a taxa inventory and the analysis of species occurring under specific habitat conditions. PMID- 24141941 TI - Functional diversity of bacterioplankton in three North Florida freshwater lakes over an annual cycle. AB - The phylogenetic diversity of freshwater bacterioplankton is widely known; however, there is minimal information on the functional diversity of the bacterial communities in these systems. Understanding the functional diversity of freshwater bacterial communities is important because heterotrophic bacteria can be impacted by anthropogenic perturbation, which in turn can alter biogeochemical cycling. The objective of this study was to use Biolog EcoPlates to acquire spatial and temporal community-level physiological profiles (CLPPs) for three freshwater lakes of different trophic levels and to assess the phylogenetic affiliation of the bacteria responsible for utilizing the various carbon guilds within them by denaturing gradient gel electrophoresis (DGGE). CLPP results showed that bacterial communities utilized the carbon guilds similarly between sites within the three lakes. However, when the metabolic profile of each lake was compared, Lake Bradford and Moore Lake were more similar to one another than to Lake Munson, the eutrophic lake. Additionally, although the bacteria that utilized the five carbon guilds included representatives from the classes alpha-, beta-, gamma-Proteobacteria, Flavobacteria and Sphingobacteria, Lake Munson had the largest number of Flavobacteria and gamma-Proteobacteria in comparison to Moore Lake and Lake Bradford. Overall, Biolog analysis was useful in identifying differences in the functional diversity of bacterial communities between lakes of different trophic statuses and can be used as a tool to assess ecosystem health. PMID- 24141942 TI - Effects of fungal inocula and habitat conditions on alder and eucalyptus leaf litter decomposition in streams of northern Spain. AB - We investigated how fungal decomposer (aquatic hyphomycetes) communities colonizing alder and eucalyptus leaf litter respond to changes in habitat characteristics (transplantation experiment). We examined the breakdown of leaf materials and the associated fungal communities at two contrasting sites, a headwater stream (H) and a midreach (M). Agroforestry increased from headwater to midreach. One month after the start of experiments at both sites, some leaf samples from the midreach site were transplanted to the headwater site (M-H treatment). Although both sites showed similar dissolved inorganic nutrient concentrations, eucalyptus leaves initially incubated at the midreach site (M, M H) increased their breakdown rate compared to those incubated along the experiment at the headwater site (H). Alder breakdown rate was not enhanced, suggesting that their consumption was not limited by nutrient availability. Sporulation rates clearly differed between leaf types (alder > eucalyptus) and streams (H > M), but no transplantation effect was detected. When comparing conidial assemblages after transplantation, an inoculum effect (persistence of early colonizing species) was clear in both leaf species. Substrate preference and shifts in the relative importance of some fungal species along the process were also observed. Overall, our results support the determining role of the initial conditioning phase on the whole litter breakdown process, highlighting the importance of intrinsic leaf characteristics and those of the incubation habitat. PMID- 24141943 TI - The possible role of cyanobacterial filaments in coral black band disease pathology. AB - Black band disease (BBD), characterized by a black mat or line that migrates across a coral colony leaving behind it a bare skeleton, is a persistent disease affecting massive corals worldwide. Previous microscopic and molecular examination of this disease in faviid corals from the Gulf of Eilat revealed a number of possible pathogens with the most prominent being a cyanobacterium identified as Pseudoscillatoria coralii. We examined diseased coral colonies using histopathological and molecular methods in order to further assess the possible role of this cyanobacterium, its mode of entry, and pathological effects on the coral host tissues. Affected areas of colonies with BBD were sampled for examination using both light and transmission electron microscopies. Results showed that this dominant cyanobacterium was found on the coral surface, at the coral-skeletal interface, and invading the polyp tissues and gastrovascular cavity. Although tissues surrounding the invasive cyanobacterial filaments did not show gross morphological alterations, microscopic examination revealed that the coral cells surrounding the lesion were dissociated, necrotic, and highly vacuolated. No amoebocytes were evident in the mesoglea of affected tissues suggesting a possible repression of the coral immune response. Morphological and molecular similarity of the previously isolated BBD-associated cyanobacterium P. coralii to the current samples strengthens the premise that this species is involved in the disease in this coral. These results indicate that the cyanobacteria may play a pivotal role in this disease and that the mode of entry may be via ingestion, penetrating the coral via the gastrodermis, as well as through the skeletal-tissue interface. PMID- 24141944 TI - Influence of land use intensity on the diversity of ammonia oxidizing bacteria and archaea in soils from grassland ecosystems. AB - In the present study, the influence of the land use intensity on the diversity of ammonia oxidizing bacteria (AOB) and archaea (AOA) in soils from different grassland ecosystems has been investigated in spring and summer of the season (April and July). Diversity of AOA and AOB was studied by TRFLP fingerprinting of amoA amplicons. The diversity from AOB was low and dominated by a peak that could be assigned to Nitrosospira. The obtained profiles for AOB were very stable and neither influenced by the land use intensity nor by the time point of sampling. In contrast, the obtained patterns for AOA were more complex although one peak that could be assigned to Nitrosopumilus was dominating all profiles independent from the land use intensity and the sampling time point. Overall, the AOA profiles were much more dynamic than those of AOB and responded clearly to the land use intensity. An influence of the sampling time point was again not visible. Whereas AOB profiles were clearly linked to potential nitrification rates in soil, major TRFs from AOA were negatively correlated to DOC and ammonium availability and not related to potential nitrification rates. PMID- 24141945 TI - Both PKMzeta and KIBRA are closely related to reference memory but not working memory in a T-maze task in rats. AB - Protein kinase M zeta (PKMzeta) and the kidney and brain protein (KIBRA) play important roles in various forms of memories. However, whether they are involved in performing the T-maze task is still unknown. In this study, the delayed nonmatch-to-sample (DNMS) task in a T-maze was given to rats. The percentage of correct choices denoting the performance accuracy was calculated and the protein levels of PKMzeta and KIBRA in rat's prefrontal cortex were measured. The results showed significantly increased performance accuracy after the training phase, which was maintained on the next day in groups with a delay of 10 s but not 30 s, indicating that 30 s is too long for rats to maintain working memory. As for the expressions of PKMzeta and KIBRA, significant increases were observed 1 day after the training phase, indicating that the formation of reference memory accompanies an increase in PKMzeta and KIBRA. No significant difference was found among groups with various delay intervals, indicating that the expressions of PKMzeta and KIBRA exert no effects on the performance of working memory. These results provide the first evidence that KIBRA as well as PKMzeta is closely related to reference memory but not working memory in rats. PMID- 24141946 TI - A canonical to non-canonical Wnt signalling switch in haematopoietic stem-cell ageing. AB - Many organs with a high cell turnover (for example, skin, intestine and blood) are composed of short-lived cells that require continuous replenishment by somatic stem cells. Ageing results in the inability of these tissues to maintain homeostasis and it is believed that somatic stem-cell ageing is one underlying cause of tissue attrition with age or age-related diseases. Ageing of haematopoietic stem cells (HSCs) is associated with impaired haematopoiesis in the elderly. Despite a large amount of data describing the decline of HSC function on ageing, the molecular mechanisms of this process remain largely unknown, which precludes rational approaches to attenuate stem-cell ageing. Here we report an unexpected shift from canonical to non-canonical Wnt signalling in mice due to elevated expression of Wnt5a in aged HSCs, which causes stem-cell ageing. Wnt5a treatment of young HSCs induces ageing-associated stem-cell apolarity, reduction of regenerative capacity and an ageing-like myeloid-lymphoid differentiation skewing via activation of the small Rho GTPase Cdc42. Conversely, Wnt5a haploinsufficiency attenuates HSC ageing, whereas stem-cell-intrinsic reduction of Wnt5a expression results in functionally rejuvenated aged HSCs. Our data demonstrate a critical role for stem-cell-intrinsic non-canonical Wnt5a signalling in HSC ageing. PMID- 24141947 TI - Structural basis for ligase-specific conjugation of linear ubiquitin chains by HOIP. AB - Linear ubiquitin chains are important regulators of cellular signalling pathways that control innate immunity and inflammation through nuclear factor (NF)-kappaB activation and protection against tumour necrosis factor-alpha-induced apoptosis. They are synthesized by HOIP, which belongs to the RBR (RING-between-RING) family of E3 ligases and is the catalytic component of LUBAC (linear ubiquitin chain assembly complex), a multisubunit E3 ligase. RBR family members act as RING/HECT hybrids, employing RING1 to recognize ubiquitin-loaded E2 while a conserved cysteine in RING2 subsequently forms a thioester intermediate with the transferred or 'donor' ubiquitin. Here we report the crystal structure of the catalytic core of HOIP in its apo form and in complex with ubiquitin. The carboxy terminal portion of HOIP adopts a novel fold that, together with a zinc-finger, forms a ubiquitin-binding platform that orients the acceptor ubiquitin and positions its alpha-amino group for nucleophilic attack on the E3~ubiquitin thioester. The C-terminal tail of a second ubiquitin molecule is located in close proximity to the catalytic cysteine, providing a unique snapshot of the ubiquitin transfer complex containing both donor and acceptor ubiquitin. These interactions are required for activation of the NF-kappaB pathway in vivo, and they explain the determinants of linear ubiquitin chain specificity by LUBAC. PMID- 24141948 TI - Antigen-specific B-cell receptor sensitizes B cells to infection by influenza virus. AB - Influenza A virus-specific B lymphocytes and the antibodies they produce protect against infection. However, the outcome of interactions between an influenza haemagglutinin-specific B cell via its receptor (BCR) and virus is unclear. Through somatic cell nuclear transfer we generated mice that harbour B cells with a BCR specific for the haemagglutinin of influenza A/WSN/33 virus (FluBI mice). Their B cells secrete an immunoglobulin gamma 2b that neutralizes infectious virus. Whereas B cells from FluBI and control mice bind equivalent amounts of virus through interaction of haemagglutinin with surface-disposed sialic acids, the A/WSN/33 virus infects only the haemagglutinin-specific B cells. Mere binding of virus is not sufficient for infection of B cells: this requires interactions of the BCR with haemagglutinin, causing both disruption of antibody secretion and FluBI B-cell death within 18 h. In mice infected with A/WSN/33, lung-resident FluBI B cells are infected by the virus, thus delaying the onset of protective antibody release into the lungs, whereas FluBI cells in the draining lymph node are not infected and proliferate. We propose that influenza targets and kills influenza-specific B cells in the lung, thus allowing the virus to gain purchase before the initiation of an effective adaptive response. PMID- 24141949 TI - Colloidal assembly directed by virtual magnetic moulds. AB - Interest in assemblies of colloidal particles has long been motivated by their applications in photonics, electronics, sensors and microlenses. Existing assembly schemes can position colloids of one type relatively flexibly into a range of desired structures, but it remains challenging to produce multicomponent lattices, clusters with precisely controlled symmetries and three-dimensional assemblies. A few schemes can efficiently produce complex colloidal structures, but they require system-specific procedures. Here we show that magnetic field microgradients established in a paramagnetic fluid can serve as 'virtual moulds' to act as templates for the assembly of large numbers (~10(8)) of both non magnetic and magnetic colloidal particles with micrometre precision and typical yields of 80 to 90 per cent. We illustrate the versatility of this approach by producing single-component and multicomponent colloidal arrays, complex three dimensional structures and a variety of colloidal molecules from polymeric particles, silica particles and live bacteria and by showing that all of these structures can be made permanent. In addition, although our magnetic moulds currently resemble optical traps in that they are limited to the manipulation of micrometre-sized objects, they are massively parallel and can manipulate non magnetic and magnetic objects simultaneously in two and three dimensions. PMID- 24141950 TI - A high-resolution map of the three-dimensional chromatin interactome in human cells. AB - A large number of cis-regulatory sequences have been annotated in the human genome, but defining their target genes remains a challenge. One strategy is to identify the long-range looping interactions at these elements with the use of chromosome conformation capture (3C)-based techniques. However, previous studies lack either the resolution or coverage to permit a whole-genome, unbiased view of chromatin interactions. Here we report a comprehensive chromatin interaction map generated in human fibroblasts using a genome-wide 3C analysis method (Hi-C). We determined over one million long-range chromatin interactions at 5-10-kb resolution, and uncovered general principles of chromatin organization at different types of genomic features. We also characterized the dynamics of promoter-enhancer contacts after TNF-alpha signalling in these cells. Unexpectedly, we found that TNF-alpha-responsive enhancers are already in contact with their target promoters before signalling. Such pre-existing chromatin looping, which also exists in other cell types with different extracellular signalling, is a strong predictor of gene induction. Our observations suggest that the three-dimensional chromatin landscape, once established in a particular cell type, is relatively stable and could influence the selection or activation of target genes by a ubiquitous transcription activator in a cell-specific manner. PMID- 24141952 TI - A rat model for chronic spinal nerve root compression. AB - OBJECTIVES: The pathophysiology of radiculopathy associated with lumbar spinal stenosis and lumbar disc herniation is incompletely understood. The goal of the present study was to establish a chronic spinal nerve root compression model that can mimic lumbar disc herniation or spinal stenosis using silicone tube compression. We also try to link the pathology changes of damaged nerve root with the reaction of microglia in spinal cord in same rat at different time points. METHODS: Thirty rats were used in this study. The L5 nerve roots (dorsal and ventral) were exposed by hemilaminectomy; the diameter of the L5 nerve root was measured at the 2 mm proximal from the dorsal root ganglia. The dorsal and ventral nerve roots of L5 were compressed using a silicone tube, and the sham group was only exposed dorsal and ventral roots of L5. Five rats from the sham group were perfused at 8 days after surgery, and 25 rats from the model groups were perfused at 3, 8, 12, 45 days, and 5 months after surgery, each model group was composed of 5 rats according to the time point. The L5 spinal cord segments and nerve root that compressed by silicone tube were harvested from the same rat. Microglia and neuron in the spinal cord were stained by immunohistochemistry, and the nerve root was shown by electron microscope. RESULTS: In sham-operated rat, the arrangement of axon and myelin sheath is normal, the ventral root is mainly composed of large axon (>6 MUm) and it is composed of 46.3 % of all the axons of the ventral root; the average myelin thickness of large axon is 1.86 MUm; the dorsal root is mainly composed of medium (2-3.9 or 4-5.9 MUm) axons and they are composed of 79.1 % of all the axons of the dorsal root; the average myelin thickness of this category is 0.94 or 1.55 MUm. The average myelin thickness of large axon in ventral root reduced to 0.97 and 1.19 MUm from more than 1.86 MUm after compression for 3 and 8 days separately. Most of myelin sheath disappeared after 12 days of compression; the myelin sheath was partly restored at 45 days after compression which the myelin sheath thickness of large axons in ventral root was 0.47 MUm. The medium category in dorsal root reduced to 0.59 or 0.72 MUm from 0.94 MUm, and 1.55 MUm after compression for 3 days (p < 0.05 to p < 0.0001). The medium category axon in dorsal root is also 0.47 MUm after compression for 45 days (p <= 0.0001). The myelin sheath was almost totally restored at the 5 months of compression; the myelin sheath thickness returned to normal and the axons were intact in structure under EM. The number of Iba1 positive microglia increased by 18.69, 40.44, and 18.49 % after compression for 3, 8, and 12 days separately in the ipsilateral dorsal horn and 21.26, 32.15, 22.87 % in ventral horns, and the activation of microglia was also prominent in contralateral sides of the dorsal and ventral horn at 8 days time point. The microglia cell reconverted to resting status after compression for 45 days or 5 months. CONCLUSION: The chronic spinal nerve root compression with silicone tube produces a recoverable damage to nerve root, which produces recoverable microglial activation in the spinal cord. These results demonstrated that the chronic spinal nerve root compression with silicone tube could mimic the pathological changes of lumbar spinal stenosis or lumbar disc herniation. PMID- 24141953 TI - Treatment of cervical disc herniation through percutaneous minimally invasive techniques. AB - PURPOSE: The goal of this study is to compare the therapeutic effectiveness of percutaneous cervical discectomy, percutaneous cervical disc nucleoplasty, and a combination of the two for the treatment of cervical disc herniation and the effective stabilization of the cervical vertebral column. METHODS: A retrospective study was performed from February 2003 to April 2011. One hundred and seventy-one cervical disc herniation patients with a mean age of 47.8 years (ranging from 21 to 74 years) participated in the study and were treated with the three types of percutaneous minimally invasive techniques: percutaneous cervical discectomy (PCD, 97 cases), percutaneous cervical disc nucleoplasty (PCN, 50 cases), and a combination of the two (PCDN, 24 cases). After treatment, the postoperative clinical results and the stability of the cervical vertebral columns of these three groups were evaluated and compared. RESULTS: Patients in the PCD group received follow-up care for approximately 4.1 years (ranging from 0.2 to 8.5 years), while those in the PCN group received only an average of 2.6 years (ranging from 0.3 to 7.8 years), and the PCDN group received an average of 3.3 years (ranging from 0.2 to 8 years of follow-up). According to the Japanese Orthopedic Association scoring system, the functional scores (JOA scores) differed significantly between the pre- and postoperative patients within the three groups (PCD t = 21.849, P = <0.05; PCN t = 14.503, P < 0.05; PCDN t = 8.555, P < 0.05). All patients had been successfully operated on by the same spinal surgeon team. According to the Odom criterion, the clinical outcomes were not significantly different for any of the three groups (the recovery rate using the JOA standard evaluation, F = 2.19, P = 0.116, P > 0.05). The percentages of each procedure that received either an excellent or a good rating were PCD at 81.35 %, PCN at 82.44 % and PCDN at 83.19 %. In addition, the clinical success rates among the three were not significantly different (P > 0.05). Notably, there was no postoperative instability of the cervical vertebral column in any of the patients (P > 0.05), and there was no difference in the pre- or postoperative stability of the cervical vertebral columns in each group. CONCLUSIONS: Each group achieved good clinical outcomes with this safe, minimally invasive spinal surgery for the treatment of cervical disc herniation. In addition, no postoperative risk of cervical instability was found. PMID- 24141954 TI - Detection of the pandemic norovirus variant GII.4 Sydney 2012 in Rio Branco, state of Acre, northern Brazil. AB - Noroviruses (NoVs) are important cause of gastroenteritis in humans worldwide. Genotype GII.4 is responsible for the majority of outbreaks reported to date. This study describes, for the first time in Brazil, the circulation of NoV GII.4 variant Sydney 2012 in faecal samples collected from children aged less than or equal to eight years in Rio Branco, state of Acre, northern Brazil, during July September 2012. PMID- 24141955 TI - Prevalence and genetic characterisation of HTLV-1 and 2 dual infections in patients with pulmonary tuberculosis in Central-West Brazil. AB - Human T-cell lymphotropic virus (HTLV) may impact the clinical course of tuberculosis (TB). Both infections are highly endemic in Brazil. The aim of this study was to assess the prevalence of HTLV-1/2 in TB patients in Central-West Brazil and to perform a genetic characterisation of the respective isolates. Of the 402 patients, six (1.49%) were positive for anti-HTLV and five (1.24%; 95% confidence interval: 0.46-3.05) were infected with HTLV-1/2. Genetic characterisation demonstrated that the four HTLV-1 isolates belonged to the Transcontinental subgroup A of the Cosmopolitan subtype a and that the HTLV-2 isolate belonged to subtype a (HTLV-2a/c). The prevalence of HTLV infection observed in this study is higher than that observed in local blood donors and the HTLV-1 and 2 subtypes identified are consistent with those circulating in Brazil. PMID- 24141956 TI - The sandfly fauna (Diptera: Psychodidae: Phlebotominae) of the Parque Estadual da Serra da Tiririca, Rio de Janeiro, Brazil. AB - Cutaneous leishmaniasis (CL) in the state of Rio de Janeiro is sporadic and can be characterised as a peridomestic transmission that occurs in modified natural environments. The aim of this work was to study the fauna and ecological characteristics of sandflies in an environmentally protected area (the State Park of Serra da Tiririca) within the remnants of the Atlantic Forest in the municipalities of Niteroi and Marica and their possible relationship with leishmaniasis. Captures were performed using light traps during the night once a month for one year in both sylvatic environments and areas surrounding homes near the park. A total of 1,037 sandflies were captured, belonging to nine genera and 12 species: Evandromyia tupynambai (34.1%), Migonemyia migonei (20.6%), Brumptomyia cunhai (13.8%), Micropygomyia schreiberi (9.7%), Psathyromyia lanei (6.5%), Brumptomyia nitzulescui (5.7%), Evandromyia edwardsi (5.4%), Nyssomyia intermedia (2.8%), Evandromyia cortelezzii (0.6%), Pintomyia bianchigalatiae (0.5%), Lutzomyia longipalpis (0.2%) and Sciopemyia microps (0.1%). Both Mg. migonei and Ny. intermedia may be acting as vectors of CL in this area. PMID- 24141957 TI - Molecular identification of Sporothrix species involved in the first familial outbreak of sporotrichosis in the state of Espirito Santo, southeastern Brazil. AB - Sporotrichosis is a widespread subcutaneous mycosis caused by the dimorphic fungi now known as the Sporothrix schenckii complex. This complex is comprised of at least six species, including Sporothrix albicans, Sporothrix brasiliensis, Sporothrix globosa, Sporothrix luriei, Sporothrix mexicana and S. schenckii. Cases of sporotrichosis have significantly increased in Brazil over the past decade, especially in the state of Rio de Janeiro (RJ), where an epidemic among cat owners has been observed. The zoonotic transmission from cats to humans suggests a common source of infection and indicates that animals can act as vectors. We performed a molecular characterisation of samples collected during the first outbreak of familial sporotrichosis caused by S. brasiliensis in the state of Espirito Santo, Brazil. These results represent the first description of such an outbreak outside the endemic area of zoonotic sporotrichosis in RJ. PMID- 24141959 TI - Vascular endothelial growth factor-A enhances indoleamine 2,3-dioxygenase expression by dendritic cells and subsequently impacts lymphocyte proliferation. AB - Dendritic cells (DCs) are antigen (Ag)-presenting cells that activate and stimulate effective immune responses by T cells, but can also act as negative regulators of these responses and thus play important roles in immune regulation. Pro-angiogenic vascular endothelial growth factor (VEGF) has been shown to cause defective DC differentiation and maturation. Previous studies have demonstrated that the addition of VEGF to DC cultures renders these cells weak stimulators of Ag-specific T cells due to the inhibitory effects mediated by VEGF receptor 1 (VEGFR1) and/or VEGFR2 signalling. As the enzyme indoleamine 2,3-dioxygenase (IDO) is recognised as an important negative regulator of immune responses, this study aimed to investigate whether VEGF affects the expression of IDO by DCs and whether VEGF-matured DCs acquire a suppressor phenotype. Our results are the first to demonstrate that VEGF increases the expression and activity of IDO in DCs, which has a suppressive effect on Ag-specific and mitogen-stimulated lymphocyte proliferation. These mechanisms have broad implications for the study of immunological responses and tolerance under conditions as diverse as cancer, graft rejection and autoimmunity. PMID- 24141960 TI - Performance of diagnostic biomarkers in predicting liver fibrosis among hepatitis C virus-infected Egyptian children. AB - The aim of the present study was to identify specific markers that mirror liver fibrosis progression as an alternative to biopsy when biopsy is contraindicated, especially in children. After liver biopsies were performed, serum samples from 30 hepatitis C virus (HCV) paediatric patients (8-14 years) were analysed and compared with samples from 30 healthy subjects. All subjects were tested for the presence of serum anti-HCV antibodies. Direct biomarkers for liver fibrosis, including transforming growth factor-beta1, tissue inhibitor of matrix metalloproteinase-1 (TIMP-1), hyaluronic acid (HA), procollagen type III amino terminal peptide (PIIINP) and osteopontin (OPN), were measured. The indirect biomarkers aspartate and alanine aminotransferases, albumin and bilirubin were also tested. The results revealed a significant increase in the serum marker levels in HCV-infected children compared with the healthy group, whereas albumin levels exhibited a significant decrease. Significantly higher levels of PIIINP, TIMP-1, OPN and HA were detected in HCV-infected children with moderate to severe fibrosis compared with children with mild fibrosis (p < 0.05). The diagnostic accuracy of these direct biomarkers, represented by sensitivity, specificity and positive predictive value, emphasises the utility of PIIINP, TIMP-1, OPN and HA as indicators of liver fibrosis among HCV-infected children. PMID- 24141961 TI - Demographic fitness of Belminus ferroae (Hemiptera: Triatominae) on three different hosts under laboratory conditions. AB - Triatominae are widely recognised for their role as vectors of Trypanosoma cruzi. One of the main biological characteristics of this subfamily is their obligate haematophagous condition. However, previous studies on Belminus herreri and Belminus ferroae suggested that cockroaches are their principal hosts in domiciles. Due to this peculiar behaviour, the aim of this study was to analyse several demographic and reproductive parameters of B. ferroae fed on three different hosts (mice, cockroaches and Rhodnius prolixus) and relate B. ferroae fitness to these alternative hosts. The cohorts were reared under constant conditions. The egg hatching rate was similar for cohorts fed on cockroaches (69.4%) and R. prolixus (63.8%), but was much lower for the cohort fed on mice (16%). The development time from the nymph to adult stage and the average age of first reproduction (alpha) presented lower values in the cohort fed on cockroaches, which is consistent with the higher population growth rate associated with this host. Demographic parameters [intrinsic rate of natural increase, finite rate of population growth, net reproductive rate and damping ratio] showed statistically significant differences between the cohorts. Analysis of the life history of B. ferroae revealed a higher fitness related to the cockroach. The implications of these results for the origin of the subfamily are discussed. PMID- 24141963 TI - Oviposition behaviour of Phlebotomus argentipes--a laboratory-based study. AB - The breeding habitat of sandflies is a little studied and poorly understood phenomenon. More importantly, oviposition behaviour is a largely neglected aspect of sandfly biology and this knowledge gap further undermines our understanding of the biology of sandflies. Pheromones released by the eggs play an important role in identifying good sites for oviposition by female insects. Several recent studies have examined the oviposition pheromone. The present study provides a preliminary report on the oviposition behaviour of Phlebotomus argentipes, the only vector of kala-azar (or visceral leishmaniasis) on the Indian sub-continent. Sandflies prefer to oviposit their eggs on surfaces that contain organic substances, especially substances with an odour of decaying animal products and the remains of conspecific eggs. The results presented here suggest that the odour released by the organic substances of old sandfly colony remains that contain dead flies, old unhatched eggs, larval food containing vertebrate faeces, frass and other organic matter serves as an attractant for the ovipositing females of P. argentipes and hence greatly increases the number of oviposited eggs compared to eggs deposited in controlled oviposition pots. This result will be helpful in maintaining an efficient colony of P. argentipes and may be a promising tool for monitoring and controlling the target insect as part of a synergistic approach. PMID- 24141962 TI - Decreased memory T-cell response and function in human immunodeficiency virus infected patients with tegumentary leishmaniasis. AB - The effects of human immunodeficiency virus (HIV) on the immune response in patients with cutaneous leishmaniasis have not yet been fully delineated. This study quantified and evaluated the function of memory T-cell subsets in response to soluble Leishmania antigens (SLA) from patients coinfected with HIV and Leishmania with tegumentary leishmaniasis (TL). Eight TL/HIV coinfected subjects and 10 HIV seronegative subjects with TL were evaluated. The proliferative response of CD4+and CD8+T-cells and naive, central memory (CM) and effector memory (EM) CD4+T-cells in response to SLA were quantified using flow cytometry. The median cell division indices for CD4+and CD8+T-cells of coinfected patients in response to SLA were significantly lower than those in patients with Leishmania monoinfection (p < 0.05). The proportions of CM and EM CD4+T-cells in response to SLA were similar between the coinfected patients and patients with Leishmania monoinfection. However, the median CM and EM CD4+T-cell counts from coinfected patients were significantly lower (p < 0.05). The reduction in the lymphoproliferative response to Leishmania antigens coincides with the decrease in the absolute numbers of both EM and CM CD4+T-cells in response to Leishmania antigens in patients coinfected with HIV/Leishmania. PMID- 24141964 TI - A new species of phlebotomine, Trichophoromyia adelsonsouzai (Diptera: Psychodidae) of Brazilian Amazonia. AB - The phlebotomine sandfly Trichophoromyia adelsonsouzai sp. nov. is described and illustrated based on the male and female morphological characteristics of specimens collected at Km 27 of the Trans-Amazonian Highway, municipality of Vitoria do Xingu, state of Para, Brazilian Amazonia. This is an area subject to the direct influence of Belo Monte hydroelectric system. With the description of this new species the number of Trichophoromyia sandflies recorded in Brazil is increased to 20. PMID- 24141965 TI - Phlebotomus (Legeromyia) multihamatus subg. nov., sp. nov. from Gabon (Diptera: Psychodidae). AB - During a research project aimed at the study of the Culicinae fauna of Gabon and carried out in the National Park of La Lope, we captured an unknown sandfly male specimen (genus Phlebotomus) by CDC miniature light trap belonging to a new species for Science. Furthermore, the originality of his genitalia does not allow us to include this species in one of the existing subgenus, thus in this paper we propose the creation of a new subgenus, as Phlebotomus (Legeromyia) multihamatus sp. nov., subg. nov. described from the National Park of La Lope, through one male captured with CDC miniature light trap. A new species and a new subgenus of sandfly is characterised by a short style with three spines, a paramere wearing a basal hook as well as a basal pouch and the absence of basal lobe on the coxite. The originality of the genitalia of the male gives way to discussion about potential primary homologies between P. multihamatus sp. nov. and Phlebotomus (Abonnencius) fortunatarum, Phlebotomus (Anaphlebotomus) stantoni and Phlebotomus (Euphlebotomus) argentipes, which should be verified for future studies. The discovery of this new species in Gabon must encourage the study of sandflies in this country. PMID- 24141966 TI - New records of Mansonella ozzardi: a parasite that is spreading from the state of Amazonas to previously uninfected areas of the state of Acre in the Purus River region. AB - Mansonella ozzardi infections are common in the riverside communities along the Solimoes, Negro and Purus Rivers in the state of Amazonas (AM). However, little is known about the presence of this parasite in communities located in regions bordering AM and the state of Acre. The prevalence rate of M. ozzardi infections was determined in blood samples from volunteers according to the Knott method. A total of 355 volunteers from six riverine communities were enrolled in the study and 65 (18.3%) were found to be infected with M. ozzardi. As expected, most of the infections (25%) occurred in individuals involved in agriculture, cattle rearing and fishing and an age/sex group analysis revealed that the prevalence increased beginning in the 40-50-years-of-age group and reached 33% in both sexes in individuals over 50 years of age. Based on the described symptomatology, articular pain and headache were found to be significantly higher among infected individuals (56 and 65% prevalence, respectively, p < 0.05). Sera from volunteers were subjected to ELISA using a cocktail of recombinant proteins from Onchocerca volvulus to evaluate the specificity of the test in an endemic M. ozzardi region. No cross-reactions between M. ozzardi-infected individuals and recombinant O. volvulus proteins were detected, thus providing information on the secure use of this particular cocktail in areas where these parasites are sympatric. PMID- 24141967 TI - A new survey of the serology of human Trypanosoma cruzi infection in the Rio Negro microregion, Brazilian Amazon: a critical analysis. AB - The serology of human Trypanosoma cruzi infection in the Rio Negro microregion is very complex because of the large numbers of false-positive cases that result from low antibody titres and cross-reactions with other infections. In the present study, we collected 4,880 blood samples on filter paper; of these, indirect immunofluorescence (IIF) was strongly reactive in 221 (4.5%), which were considered to be positive (IIF strongly reactive; high intensity of fluorescence) and weakly reactive in 302 (6.2%), which were considered to be doubtful (IIF weakly reactive; low intensity of fluorescence). The confirmatory test on the serum using at least two of three techniques (IIF, conventional ELISA and recombinant ELISA) on 137 samples that were positive in the screening test only confirmed 33 cases (24.1%). Of the 178 samples that were considered doubtful in the screening test, only 10 (5.6%) were considered to be positive in the confirmatory test. Finally, we recommend that the serological diagnosis of T. cruzi infection in the Amazon region be made using at least two different techniques, for example immunofluorescence and ELISA and confirmed by Western blot analysis when possible. PMID- 24141968 TI - Coagulase-negative staphylococci strains resistant to oxacillin isolated from neonatal blood cultures. AB - Coagulase-negative staphylococci (CoNS) are the microorganisms most frequently isolated from clinical samples and are commonly found in neonatal blood cultures. Oxacillin is an alternative treatment of choice for CoNS infections; however, resistance to oxacillin can have a substantial impact on healthcare by adversely affecting morbidity and mortality. The objective of this study was to detect and characterise oxacillin-resistant CoNS strains in blood cultures of newborns hospitalised at the neonatal ward of the University Hospital of the Faculty of Medicine of Botucatu. One hundred CoNS strains were isolated and the mecA gene was detected in 69 of the CoNS strains, including 73.2% of Staphylococcus epidermidis strains, 85.7% of Staphylococcus haemolyticus strains, 28.6% of Staphylococcus hominis strains and 50% of Staphylococcus lugdunensis strains. Among these oxacillin-resistant CoNS strains, staphylococcal cassette chromosome mec (SCCmec) type I was identified in 24.6%, type II in 4.3%, type III in 56.5% and type IV in 14.5% of the strains. The data revealed an increase in the percentage of CoNS strains isolated from blood cultures from 1991-2009. Furthermore, a predominant SCCmec profile of the oxacillin-resistant CoNS strains isolated from neonatal intensive care units was identified with a prevalence of SCCmec types found in hospital-acquired strains. PMID- 24141969 TI - Multicomponent intervention to reduce daily sedentary time: a randomised controlled trial. AB - OBJECTIVES: To test the efficacy of a multicomponent technology intervention for reducing daily sedentary time and improving cardiometabolic disease risk among sedentary, overweight university employees. DESIGN: Blinded, randomised controlled trial. SETTING: A large south-eastern university in the USA. PARTICIPANTS: 49 middle-aged, primarily female, sedentary and overweight adults working in sedentary jobs enrolled in the study. A total of 40 participants completed the study. INTERVENTIONS: Participants were randomised to either: (1) an intervention group (N=23; 47.6+9.9 years; 94.1% female; 33.2+4.5 kg/m(2)); (2) or wait-list control group (N=17; 42.6+8.9 years; 86.9% female; 31.7+4.9 kg/m(2)). The intervention group received a theory-based, internet-delivered programme, a portable pedal machine at work and a pedometer for 12 weeks. The wait-list control group maintained their behaviours for 12 weeks. OUTCOME MEASURES: Primary (sedentary and physical activity behaviour measured objectively through StepWatch) and secondary (heart rate, blood pressure, height, weight, waist circumference, per cent body fat, cardiorespiratory fitness, fasting lipids) outcomes were measured at baseline and postintervention (12 weeks). Exploratory outcomes including intervention compliance and process evaluation measures were also assessed postintervention. RESULTS: Compared to controls, the intervention group reduced daily sedentary time (mean change (95%CI): -58.7 min/day (-118.4 to 0.99; p<0.01)) after adjusting for baseline values and monitor wear time. Intervention participants logged on to the website 71.3% of all intervention days, used the pedal machine 37.7% of all working intervention days and pedalled an average of 31.1 min/day. CONCLUSIONS: These findings suggest that the intervention was engaging and resulted in reductions in daily sedentary time among full-time sedentary employees. These findings hold public health significance due to the growing number of sedentary jobs and the potential of these technologies in large-scale worksite programmes. TRIAL REGISTRATION: ClinicalTrials.gov #NCT01371084. PMID- 24141970 TI - Continuation rates of oral hormonal contraceptives in a cohort of first-time users: a population-based registry study, Sweden 2005-2010. AB - OBJECTIVE: To investigate if continuation rates in first-time users of oral hormonal contraceptives differed between different formulations and to measure if the rates were related to the prescribing categories, that is, physicians and midwives. DESIGN: A longitudinal national population-based registry study. SETTING: The Swedish prescribed drug register. PARTICIPANTS: All women born between 1977 and 1994 defined as first-time users of hormonal contraceptives from 2007 to 2009 (n=226 211). MAIN OUTCOME MEASURES: A tendency to switch the type of hormonal contraceptive within 6 months use and repeated dispensation identical to the first were estimated as percentages and relative risks (RRs). Physicians' and midwives' prescription patterns concerning the women's continuation rates of oral hormonal contraceptive type. RESULTS: In Sweden, there were 782 375 women born between 1977 and 1994 at the time of the study. Of these, 226 211 women were identified as first-time users of hormonal contraceptives. Ethinylestradiol+levonorgestrel, desogestrel-only and ethinylestradiol+drospirenone were the hormonal contraceptives most commonly dispensed to first-time users at rates of 43.3%, 24.4% and 11.1%, respectively. The overall rate of switching contraceptive types in the first 6 months was 11.3%, which was highest for desogestrel-only (14.3%) and lowest for ethinylestradiol+drospirenone (6.6%). The switching rate for all three products was highest in the 16-year to 19-year age group. Having a repeated dispensation identical to the initial dispensation was highest for users of ethinylestradiol either combined with levonorgestrel or drospirenone, 81.4% and 81.2%, respectively, whereas this rate for the initial desogestrel-only users was 71.5%. The RR of switching of contraceptive type within the first 6 months was 1.35 (95% CI 1.32 to 1.39) for desogestrel-only and 0.63 (0.59 to 0.66) for ethinylestradiol+drospirenone compared with ethinylestradiol+levonorgestrel as the reference category. There were no differences in the women's continuation rates depending on the prescriber categories. CONCLUSIONS: Desogestrel-only users conferred the highest switcher rate to another hormonal contraceptive within a 6 month period. Users of ethinylestradiol+levonorgestrel were more prone to switch to another product within 6 months than women using ethinylestradiol+drospirenone. These findings may be of clinical importance when tailoring hormonal contraceptives on an individual basis. PMID- 24141971 TI - Exploring the relationship between baseline physical activity levels and mortality reduction associated with increases in physical activity: a modelling study. AB - BACKGROUND: Increasing physical activity (PA) levels among the general adult population of developed nations is important for reducing premature mortality and the burdens of preventable illness. Assessing how effective PA interventions are as health interventions often involves categorising participants as either 'active' or 'sedentary' after the interventions. A model was developed showing that doing this could significantly misestimate the health effect of PA interventions. METHODS: A life table model was constructed combining evidence on baseline PA levels with evidence indicating the non-linear relationship between PA levels and all-cause mortality risks. PA intervention scenarios were modelled which had the same mean increase in PA but different levels of take-up by people who were more active or more sedentary to begin with. RESULTS: The model simulations indicated that, compared with a scenario where already-active people did most of the additional PA, a scenario where the least active did the most additional PA was around a third more effective in preventing deaths between the ages of 50 and 60 years. The relationship between distribution of PA take-up and health effect was explored systematically and appeared non-linear. CONCLUSIONS: As the health gains of a given PA increase are greatest among people who are most sedentary, smaller increases in PA in the least active may have the same health benefits as much larger PA increases in the most active. To help such health effects to be assessed, PA studies should report changes in the distribution of PA level between the start and end of the study. PMID- 24141972 TI - The tipping point of the inert pair effect: experimental and computational comparison of In(I) and Sn(II) bis(imino)pyridine complexes. AB - The autoionization reaction of neutral bis(imino)pyridine and SnX2 led to three compounds [{ArN[double bond, length as m-dash]CPh}2(NC5H3)]SnX(+)SnX3(-) (Ar = 2,6-(2,5-(t)Bu2C6H3), X = Cl, Br; Ar = 2,6-(2,6-Me2C6H3), X = Cl) which display, within the same species, cations and anions possessing Sn(ii) centers. Computational analysis compared the ligated Sn(ii) cations with bis(imino)pyridine In(i) complexes that showed unprecedented weak metal-ligand covalent interactions, consistent with the In(i) 5s(2) electrons remaining as an inert nonbonding pair. Analysis of the metal-ligand bonding indicates that the chloride ligand of the Sn(ii) complex induces promotion of the metal 5s(2) electron pair to a stereochemically active hybridized orbital, which, in turn, allows strong coordination of the bis(imino)pyridine to Sn. PMID- 24141973 TI - Highlights of 38th annual IUGA meeting with the Continence Foundation of Ireland, Dublin, Ireland, 2013. PMID- 24141974 TI - Physician performance measurement: the importance of understanding physician behavior. PMID- 24141975 TI - The pathogenicity of the Streptococcus genus. AB - Streptococcus infections are still one of the important problems facing contemporary medicine. As the World Health Organization (WHO) warns, Streptococcus pneumoniae is responsible for the highest number of pneumonia cases all over the world. Despite an increasing number of pneumococcal vaccinations, incidences of disease connected to this pathogen's infection stay at the same level, which is related to a constantly increasing number of infections caused by nonvaccinal serotypes. Unfortunately, the pathogenicity of bacteria of the Streptococcus genus is also connected to species considered to be physiological flora in humans or animals and, additionally, new species exhibiting pathogenic potential have been discovered. This paper presents an opinion concerning the epidemiology of streptococci infections based on case studies and other publications devoted to this problem. It also sheds new light based on recent reports on the prevention of protective vaccinations application in the case of streptococci infections. PMID- 24141977 TI - Mitochondria-specific phosphorescent imaging and tracking in living cells with an AIPE-active iridium(III) complex. AB - An AIPE-active iridium(III) complex was found to possess high specificity for mitochondria, superior photostability, low cytotoxicity, and high resistance to the loss of mitochondrial membrane potential. Thus, this complex can be used for mitochondrial imaging and tracking in living cells. PMID- 24141976 TI - Cryptococcosis: epidemiology, fungal resistance, and new alternatives for treatment. AB - Cryptococcosis is an important systemic mycosis and the third most prevalent disease in human immunodeficiency virus (HIV)-positive individuals. The incidence of cryptococcosis is high among the 25 million people with HIV/acquired immunodeficiency syndrome (AIDS), with recent estimates indicating that there are one million cases of cryptococcal meningitis globally per year in AIDS patients. In Cryptococcus neoformans, resistance to azoles may be associated with alterations in the target enzyme encoded by the gene ERG11, lanosterol 14alpha demethylase. These alterations are obtained through mutations, or by overexpressing the gene encoding. In addition, C. gattii and C. neoformans present a heteroresistance phenotype, which may be related to increased virulence. Other species beyond C. neoformans and C. gattii, such as C. laurentii, have been diagnosed mainly in patients with immunosuppression. Infections of C. albidus have been isolated in cats and marine mammals. Recent evidence suggests that the majority of infections produced by this pathogen are associated with biofilm growth, which is also related with increased resistance to antifungal agents. Therefore, there is a great need to search for alternative antifungal agents for these fungi. The search for new molecules is currently occurring from nanoparticle drugs of plant peptide origin. This article presents a brief review of the literature regarding the epidemiology of cryptococcosis, as well as fungal resistance and new alternatives for treatment. PMID- 24141978 TI - A subset of gastric cancers with EGFR amplification and overexpression respond to cetuximab therapy. AB - A preclinical trial identified 4 of 20 (20%) gastric cancer (GC) patient-derived xenografts responded to cetuximab. Genome-wide profiling and additional investigations revealed that high EGFR mRNA expression and immunohistochemistry score (3+) are associated with tumor growth inhibition. Furthermore, EGFR amplification were observed in 2/4 (50%) responders with average copy number 5.8 and >15 respectively. Our data suggest that a GC subtype with EGFR amplification and overexpression benefit from cetuximab treatment. PMID- 24141979 TI - Efficacy of influenza vaccination of elderly rhesus macaques is dramatically improved by addition of a cationic lipid/DNA adjuvant. AB - BACKGROUND: The decreased immune response among elderly individuals results in reduced influenza vaccine efficacy. Strategies to improve vaccine efficacy in elderly individuals are needed. The goal of this study was to determine whether a cationic lipid/DNA complex (CLDC) can improve the efficacy of the trivalent inactivated influenza vaccine Fluzone in elderly nonhuman primates. METHODS: Elderly (age, >18 years) rhesus macaques were vaccinated with Fluzone, with or without CLDC, and challenged with a human seasonal influenza virus isolate, A/Memphis/7/2001(H1N1). RESULTS: We found that elderly macaques have significantly lower levels of circulating naive CD4(+) T cells, naive CD8(+) T cells, and B cells as compared to juvenile monkeys. Furthermore, on the day of challenge, recipients of Fluzone/CLDC had significantly higher plasma anti influenza virus immunoglobulin G (P < .001) and immunoglobulin A (P < .001) titers than recipients of Fluzone alone. After virus challenge, only the Fluzone/CLDC-vaccinated animals had a significantly lower level of virus replication (P < .01) relative to the unvaccinated control animals. CONCLUSIONS: These results demonstrate that CLDC can enhance the immunogenicity and efficacy of a licensed TIV in immunosenescent elderly monkeys. PMID- 24141980 TI - Yellow fever vaccine attenuation revealed: loss of diversity. PMID- 24141981 TI - Toward improved influenza vaccines. PMID- 24141982 TI - Comparison of the live attenuated yellow fever vaccine 17D-204 strain to its virulent parental strain Asibi by deep sequencing. AB - BACKGROUND: The first comparison of a live RNA viral vaccine strain to its wild type parental strain by deep sequencing is presented using as a model the yellow fever virus (YFV) live vaccine strain 17D-204 and its wild-type parental strain, Asibi. METHODS: The YFV 17D-204 vaccine genome was compared to that of the parental strain Asibi by massively parallel methods. Variability was compared on multiple scales of the viral genomes. A modeled exploration of small-frequency variants was performed to reconstruct plausible regions of mutational plasticity. RESULTS: Overt quasispecies diversity is a feature of the parental strain, whereas the live vaccine strain lacks diversity according to multiple independent measurements. A lack of attenuating mutations in the Asibi population relative to that of 17D-204 was observed, demonstrating that the vaccine strain was derived by discrete mutation of Asibi and not by selection of genomes in the wild-type population. CONCLUSIONS: Relative quasispecies structure is a plausible correlate of attenuation for live viral vaccines. Analyses such as these of attenuated viruses improve our understanding of the molecular basis of vaccine attenuation and provide critical information on the stability of live vaccines and the risk of reversion to virulence. PMID- 24141983 TI - Gastrointestinal manifestations, diagnosis, and management of hereditary angioedema. AB - Abdominal pain is one of the most common conditions in clinical practice and yet a challenging complaint to accurately diagnose due to the vast number of possible etiologies. When other health care providers cannot identify the cause of abdominal pain, gastroenterologists are often looked upon to help solve the diagnostic dilemma. Consequently, it is incumbent upon gastroenterologists to be well versed in the diagnosis and management of not only common but also rare causes of abdominal pain. One such uncommon but well-described cause of abdominal pain is angioedema of the intestinal tract due to hereditary angioedema. Acute onset, recurrent abdominal pain of varying severity is its most common presenting symptom, and misdiagnosis can not only lead to unnecessary surgical procedures but also death. The purpose of this review is to raise awareness among gastroenterologists about hereditary angioedema as a potential cause of recurrent, unexplained abdominal pain. PMID- 24141984 TI - The prevalence and clinical importance of incidental soft-tissue findings in cervical CT scans of trauma population. AB - OBJECTIVES: To define the age-related prevalence of incidental soft-tissue findings in cervical CT scans of a trauma population and to investigate their clinical importance. METHODS: The original diagnostic radiology reports and the CT images of the 357 patients with cervical trauma were retrospectively evaluated. Incidental soft-tissue findings were investigated. All findings were grouped according to age. The findings were classified based on their clinical importance into three categories: Category 1: no clinical importance, Category 2: possible clinical importance requiring further investigation and Category 3: obvious clinical importance. In addition, the medical records of the patients were investigated. The follow-up ratio of the pathologies mentioned in the original radiology report was recorded. RESULTS: The most frequently encountered findings in Categories 2 and 3 were carotid artery calcification (n = 89, 24.9%) and tonsillolith (n = 115, 32.2%), respectively. The reporting ratio in the original reports of Categories 1, 2 and 3 findings was 1.1% (n = 4), 9% (n = 27) and 34.5% (n = 64), respectively. No further investigations and follow-up was accomplished for Category 1 lesions, whereas 11.1% of Category 2 and 35.9% of Category 3 lesions were subjected to further investigations and follow-up. CONCLUSIONS: The cervical CT scans of trauma patients reveal many clinically important soft-tissue incidental findings. Cervical region incidental findings may be followed up on an outpatient basis, rarely being of life-threatening value. The ratio of reporting and follow-up of incidental findings increases parallel to the clinical importance of the lesions. PMID- 24141985 TI - Cytoprotective effect of bioactive sea buckthorn extract on paraquat-exposed A549 cells via induction of Nrf2 and its downstream genes. AB - The extract of sea buckthorn (SBT) [Hippophae rhamnoides L. (Elaeagnaceae)], is used as a food supplement and traditional medicine in numerous countries. This study investigated the protective effects of the functional extract of SBT against paraquat (PQ)-induced toxicity via antioxidant mechanisms in A549 cells. The methanol extract of SBT (25-200 ug/ml) was used to protect cells against PQ (200 uM)-induced cell death. A viability assay was conducted using 3-(4,5 dimethylthioazol-2-ly)-2,5-diphenyltetrazolium bromide and lactate dehydrogenase (LDH). Total intracellular reactive oxygen species (ROS) were measured and plotted. For validation of the SBT-induced expression of nuclear factor-E2 related factor 2 (Nrf2) and its target genes, western blot analysis and qPCR were performed. The present study showed that pretreatment of A549 cells with SBT extract significantly attenuated PQ (200 uM)-induced cellular toxicity. The maximum cytoprotective effect was identified using 200 ug/ml SBT extract; it began 24 h following exposure and was sustained up to 120 h (P<0.05). SBT extract significantly reduced LDH activity by 35.63% and ROS levels by 30.90% (P<0.05). Pretreatment with SBT extract activated Nrf2 mRNA and protein expression and its nuclear translocation. The SBT extract effectively induced Nrf2 target genes, such as NAD(P)H dehydrogenase quinone 1, glutathione peroxidase 1, glutathione reductase and catalase following treatment with PQ. Based on these results, it was hypothesized that SBT extract may be used as a potential therapeutic agent for the treatment of various oxidative stress-related diseases. PMID- 24141986 TI - Estimation of influential points in any data set from coefficient of determination and its leave-one-out cross-validated counterpart. AB - Coefficient of determination (R (2)) and its leave-one-out cross-validated analogue (denoted by Q (2) or R cv (2) ) are the most frequantly published values to characterize the predictive performance of models. In this article we use R (2) and Q (2) in a reversed aspect to determine uncommon points, i.e. influential points in any data sets. The term (1 - Q (2))/(1 - R (2)) corresponds to the ratio of predictive residual sum of squares and the residual sum of squares. The ratio correlates to the number of influential points in experimental and random data sets. We propose an (approximate) F test on (1 - Q (2))/(1 - R (2)) term to quickly pre-estimate the presence of influential points in training sets of models. The test is founded upon the routinely calculated Q (2) and R (2) values and warns the model builders to verify the training set, to perform influence analysis or even to change to robust modeling. PMID- 24141987 TI - Pancreatoduodenectomy--current status of surgical and perioperative techniques in Germany. AB - BACKGROUND: Pancreatoduodenectomy in Germany is performed by a broad range of hospitals. A diversity of operative techniques is employed as no guidelines exist for intra- and perioperative management. We carried out a national survey to determine the de facto German standards for pancreatoduodenectomy, assess quality assurance measures, and identify relevant issues for further investigation. METHODS: A questionnaire evaluating major outcome variables, case load, preferred surgical procedures, and perioperative management during pancreatoduodenectomy was developed and sent to 211 German hospitals performing >12 pancreatoduodenectomies per year (requirement for certification as a pancreas center). Statistical analysis was carried out using the Fisher Exact, Mann Whitney U, and Spearman tests. RESULTS: The final response rate was 86 % (182/211). The preferred technique and de facto German standard for pancreatoduodenectomy was pylorus-preserving pancreatoduodenectomy with pancreatojejunostomy carried out via duct-to-mucosa anastomosis with interrupted sutures using PDS 4.0. The minority of German pancreas centers were certified (18 48 %). The certification rate increased with higher capacity levels and case load (P < 0.05); however, significant correlations between the fistula rate and hospital case load, hospital capacity level, or hospital certification status were not seen. CONCLUSION: This study revealed a distinct variety of management strategies for pancreatic surgery and available evidence-based data was not necessarily translated into clinical practice. The limited certification rate represented a shortcoming of quality assurance. The data emphasize the need for further trials to answer the questions whether hospital certifications and omission of drains improve outcome after pancreatoduodenectomy and for the establishment of guidelines for pancreatoduodenectomy. PMID- 24141988 TI - Clinical and imaging predictors of 1-year and long-term mortality in light chain (AL) amyloidosis: a 5-year follow-up study. AB - Light chain amyloidosis (AL) involves multiorgan failure induced by amyloidogenic light chain proteins, and is associated with high mortality. We aimed to identify clinical, laboratory, and imaging parameters that would predict 1-year and long term AL mortality. Forty-four biopsy-proven AL patients (61.5 +/- 12 years, 20 females) underwent clinical evaluation including laboratory assays, echocardiography, and contrast cardiac magnetic resonance imaging (CMR, n = 31) prior to chemotherapy. Patients were prospectively followed for median duration of 62.7 months (interquartile range 35.5 months). Clinical and laboratory parameters were compared between 1-year survivors and nonsurvivors. Univariate Kaplan-Meier survival plots were calculated followed by stepwise logistic regression analysis to assess independent predictors of long-term survival. Eighteen (40.9 %) patients died within 1 year and an additional 10 subjects died during long-term follow-up. Patients who expired within 1 year presented with more advanced class of heart failure, higher alkaline phosphatase and uric acid, lower limb lead voltage on electrocardiography, shorter left ventricular ejection time (ET) on echocardiography, and a higher proportion of late gadolinium enhancement on CMR. On multivariable analysis, only ET <=240 ms on echocardiography (hazard ratio (HR) 5.07, 95 % confidence interval (CI) 1.83 14.1, P = 0.002) and New York Heart Association functional class II-IV presentation (HR 1.0058, 95 % CI 1.0014-1.0103, P = 0.01) were independent predictors of AL mortality. In conclusion, AL amyloidosis is associated with high 1-year and long-term mortality. Among clinical, laboratory, and imaging parameters tested, an echocardiographic finding of ET <=240 ms has independent and additive prognostic value to clinical heart failure evaluation in determining long-term survival of AL patients. This result may be important in the early identification of patients at risk. PMID- 24141989 TI - Cardioprotective effects of adipokine apelin on myocardial infarction. AB - Angiogenesis plays an important role in myocardial infarction. Apelin and its natural receptor (angiotensin II receptor-like 1, AGTRL-1 or APLNR) induce sprouting of endothelial cells in an autocrine or paracrine manner. The aim of this study is to investigate whether apelin can improve the cardiac function after myocardial infarction by increasing angiogenesis in infarcted myocardium. Left ventricular end-diastolic pressure (LVEDP), left ventricular end systolic pressure (LVESP), left ventricular developed pressure (LVDP), maximal left ventricular pressure development (+/-LVdp/dtmax), infarct size, and angiogenesis were evaluated to analyze the cardioprotective effects of apelin on ischemic myocardium. Assays of 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide, 5-bromo-2'-deoxyuridine incorporation, wound healing, transwells, and tube formation were used to detect the effects of apelin on proliferation, migration, and chemotaxis of cardiac microvascular endothelial cells. Fluorescein isothiocyanate-labeled bovine serum albumin penetrating through monolayered cardiac microvascular endothelial cells was measured to evaluate the effects of apelin on permeability of microvascular endothelial cells. In vivo results showed that apelin increased +/-LV dp/dtmax and LVESP values, decreased LVEDP values (all p < 0.05), and promoted angiogenesis in rat heart after ligation of the left anterior descending coronary artery. In vitro results showed that apelin dose dependently enhanced proliferation, migration, chemotaxis, and tube formation, but not permeability of cardiac microvascular endothelial cells. Apelin also increased the expression of vascular endothelial growth factor receptors-2 (VEGFR2) and the endothelium-specific receptor tyrosine kinase (Tie-2) in cardiac microvascular endothelial cells. These results indicated that apelin played a protective role in myocardial infarction through promoting angiogenesis and decreasing permeability of microvascular endothelial cells via upregulating the expression of VEGFR2 and Tie-2 in cardiac microvascular endothelial cells. PMID- 24141990 TI - Reduction of inorganic phosphate-induced human smooth muscle cells calcification by inhibition of protein kinase A and p38 mitogen-activated protein kinase. AB - High levels of serum phosphate are associated with calcification of human smooth muscle cells (HSMCs). We investigated whether inhibition of protein kinase A (PKA) and mitogen-activated protein kinase (MAPK) signals [p38, extracellular signal-regulated kinase (ERK), and c-Jun N-terminal kinase (JNK)] can reduce inorganic phosphate (Pi)-induced HSMC calcification. Inhibition of PKA or p38 MAPK by inhibitors or small interfering RNAs (siRNAs) reduced Ca levels and alkaline phosphatase activities in HSMCs treated with high Pi, but inhibition of ERK1/2 and JNK showed no significant changes. Moreover, there were no significant changes in cell viability on adding siRNAs and three inhibitors (PKA, p38, and MEK1/2), but JNK inhibitor slightly reduced cell viability. These results show that PKA and p38 MAPK are involved in the Pi-induced calcification of HSMCs, and may be good targets for reducing vascular calcification. PMID- 24141991 TI - cDNA cloning, characterization and expression analysis of peroxiredoxin 5 gene in the ridgetail white prawn Exopalaemon carinicauda. AB - Peroxiredoxin is a superfamily of antioxidative proteins that play important roles in protecting organisms against the toxicity of reactive oxygen species. In this study, a full-length of peroxiredoxin 5 (designated EcPrx5) cDNA was cloned from the ridgetail white prawn Exopalaemon carinicauda by using rapid amplification of cDNA ends (RACE) approaches. The full-length cDNA of the EcPrx5 was of 827 bp, containing a 5' untranslated region (UTR) of 14 bp, a 3' UTR of 228 bp with a poly (A) tail, and an open reading frame of 585 bp encoding a polypeptide of 194 amino acids with the predicted molecular weight of 20.83 kDa and estimated isoelectric point of 7.62. BLAST analysis revealed that amino acids of EcPrx5 shared 89, 68, 66, 65, 53 and 51 % identity with that of Macrobrachium rosenbergii, Megachile rotundata, Harpegnathos saltator, Acromyrmex echinatior, Danio rerio, and Homo sapiens counterparts, respectively. The conserved Prx domain and the signature of peroxiredoxin catalytic center identified in EcPrx5 suggested that EcPrx5 belonged to the atypical 2-Cys Prx subgroup. Real time quantitative RT-PCR analysis indicated that EcPrx5 could be detected in all the tested tissues with highest expression level in hepatopancreas. As time progressed, the expression level of EcPrx5 both in hemocytes and hepatopancreas increased in the first 6 h after Vibrio anguillarum and white spot syndrome virus challenge, and showed different expression profiles. The results indicated that EcPrx5 involved in immune response against bacterial and viral infection in E. carinicauda. PMID- 24141992 TI - In memoriam: William H. Daughaday, MD, 1918-2013. PMID- 24141993 TI - Shedding heat on oxytocin. PMID- 24141994 TI - Is vitamin D a key factor in muscle health? PMID- 24141995 TI - Modulation of beta-cell fate and function by TGFbeta ligands: a superfamily with many powers. PMID- 24141996 TI - p27 Stands-up-to-cancer: UPS nuclear service stops. PMID- 24141997 TI - Characterization of population exposure to organochlorines: a cluster analysis application. AB - This study aimed to show the results from a cluster analysis application in the characterization of population exposure to organochlorines through variables related to time and exposure dose. Characteristics of 354 subjects in a population exposed to organochlorine pesticides residues related to time and exposure dose were subjected to cluster analysis to separate them into subgroups. We performed hierarchical cluster analysis. To evaluate the classification accuracy, compared to intra-group and inter-group variability by ANOVA for each dimension. The aggregation strategy was accomplished by the method of Ward. It was, for the creation of clusters, variables associated with exposure and routes of contamination. The information on the estimated intake doses of compound were used to weight the values of exposure time at each of the routes, so as to obtain values proxy exposure intensity. The results showed three clusters: cluster 1 (n = 45), characteristics of greatest exposure, the cluster 2 (n = 103), intermediate exposure, and cluster 3 (n = 206), less exposure. The bivariate analyzes performed with groups that are groups showed a statistically significant difference. This study demonstrated the applicability of cluster analysis to categorize populations exposed to organochlorines and also points to the relevance of typological studies that may contribute to a better classification of subjects exposed to chemical agents, which is typical of environmental epidemiology studies to a wider understanding of etiological, preventive and therapeutic contamination. PMID- 24141998 TI - The ocurrence of dengue and weather changes in Brazil: a systematic review. AB - INTRODUCTION: Dengue is configures in recent decades as an important cause of morbidity and mortality in Brazil and around the world reaching the tropical and subtropical areas. OBJECTIVE: To review the scientific literature on the occurrence of dengue in Brazil and its relationship with meteorological variables. METHOD: A systematic review of studies published in databases (SciELO, PubMed, MEDLINE, Lilacs) using descriptors related to weather variations and dengue fever in Brazil, published between 1991 to 2010. It was selected 31 articles that had the study area nationwide. RESULTS: Most epidemiological studies use ecological design, the studies make use of entomological trapping, are common also series of studies of the disease and spatial analysis. It is evident relationship between dengue incidence with temperature and rainfall, the association is more significant from the second to fourth months of the year. Comparative studies of drought and rain show seasonal behavior of the disease. There are difficulties in establishing unique pattern of seasonality of disease incidence and weather variables for the country. CONCLUSION: Dengue is strongly related to meteorological variables. The seasonal variation in temperature and rainfall influences the dynamics of the vector and the incidence of the disease throughout the country, regardless of the climate category. PMID- 24141999 TI - Energy density in the diet of workers from Sao Paulo, Brazil, and associated socio-demographic factors. AB - OBJECTIVE: This paper aims at analyzing the energy density (ED) of the diet of workers from the city of Sao Paulo, Southeastern Brazil, and the way this is associated with socio-demographic characteristics, as well as evaluating the relationship between ED and nutrient intake. METHODS: A cross-sectional study evaluated the diet of 852 workers using the 24-hour dietary recall; one recall was applied to all individuals and a second one was applied to a sub-sample in order to adjust intrapersonal variability. The ED of the diet was calculated using three methods: inclusion of all solid foods and beverages, excluding water (ED 1); inclusion of all solid foods and beverages containing at least 5 kcal/100g (ED 2); and inclusion of all solid foods, excluding all beverages (ED 3). Linear regression was used to analyze the relationship between ED and socio demographic variables and the relationship between ED and nutrients was evaluated using Pearson coefficient correlation. RESULTS: Considering the workers' diet, the ED values observed were 1.18 kcal/g, 1.22 kcal/g and 1.73 kcal/g for the ED 1, ED 2, ED 3 methods, respectively. In the multiple regression models, only the age variable was maintained in the final model and showed an inverse association with all ED methods. ED 3 showed an increase in energy density for non-white individuals. Of all studied nutrients, protein was the only one that was not significantly correlated with ED 3 (p = 0.899). CONCLUSION: The young adults studied had a higher energy-density diet, representing a priority group for nutrition interventions. Regardless of the calculation method used, there is a correlation between ED and nutrients. PMID- 24142000 TI - Social inequalities and vaccination coverage in the city of Salvador, Bahia. AB - OBJECTIVE: To estimate the vaccination coverage in children born in the city of Salvador, analyzing these coverages by socioeconomic conditions. METHOD: A household survey on vaccination coverage was conducted with children born in 2005, in Salvador, Bahia, northeastern Brazil, who were aged between 18 to 36 months at the time of this study. Cluster sampling was performed in multiple stages. Census tracts were stratified using data from the national census conducted in 2000. Data was collected on socio-economic households. The sample size was defined by a specific methodology developed for immunization coverage surveys. The questionnaire was based upon the information contained in the vaccination cards. The estimated vaccination coverage in the various strata considered the sampling complex plan, weighting the observations according to the sampling fraction, the losses and the design effect. RESULTS: There was inequality in the socioeconomic strata analyzed, where the coverage rate was directly proportional to socioeconomic status. Strata D and E showed statistically significant differences when compared to stratum A. Regarding to the complete scheme, children living in strata D and E have significantly less coverage than those residing in strata B. For vaccines not included in the basic scheme, the differences are very marked, showing less than 3% in stratum D and E. CONCLUSIONS: Vaccination coverage for the complete schedule at the end of 18 months of age with valid doses, was unsatisfactory and shows significant differences among the socio-economic strata with poor coverage in the poorest groups. PMID- 24142001 TI - HIV rapid test counseling among parturient. AB - INTRODUCTION: The pre and post-HIV test counseling is recommended by the Ministry of Health, and is a tool for reflection and joint decision-making. OBJECTIVES: To determine the proportion of women receiving counseling for submission to the HIV rapid test and to assess factors associated to not receiving counseling for this test. METHOD: A cross-sectional study was conducted in five "Baby-Friendly Hospitals" from the High Risk Pregnancy System in Rio de Janeiro City, Southeast Brazil. The study population were 955 rooming-in parturients, undergoing the HIV rapid test, between September 11thand December 11th, 2006. Semi-standardized questionnaires were applied to the mothers, and data were also obtained from laboratory and health archives. Binomial regression was performed in order to analyze the variables associated with non-counseling. RESULTS: Were submitted to the HIV rapid test 28.5% of the parturients, and only 26.9% of them were counseled. Factors associated with non-counseling were: maternal education below 8 years of school (PR = 1.36; 95% CI: 1.15-1.62), 0 to 3 prenatal visits (RP = 0.73; IC 95%: 0.59-0.90) and hospitals with less than 50% of the parturients submitted to the HIV rapid test (PR = 1.65; 95% CI: 1.40-1.96). CONCLUSION: Socially underprivileged women were not a target of counseling, and only the low number of prenatal visits proved to be a protective factor against non counseling. Counseling was seldom practiced for HIV rapid testing, indicating that this test has been performed without the consent of women, in an imperative way. PMID- 24142002 TI - Family and community violence of schoolchildren from the city of Sao Goncalo, Rio de Janeiro, Brazil. AB - This descriptive study aimed to investigate the association between violence in the family, school and community experienced by school children/adolescents of the city of Sao Goncalo (RJ), Brazil. Questionnaires were administered to the mothers/guardians to assess violence in the family and school and to children to check their perceptions of community violence. Multiple correspondence analysis and cluster analysis, two exploratory descriptive techniques, were employed. Data from 280 schoolchildren were analyzed. A total of 43.9% of mothers reported that their children had been physically abused in their homes. With regard to children's/adolescents' perception of community violence, 93.2% said they had experienced or witnessed these events in their communities. For both sexes there was the formation of a cluster of categories with the presence of violence among siblings, presence of severe physical assault and verbal assault committed by parents. Among girls, the presence of violence in the school formed a cluster with the highest category of violence in the community. In conclusion, it should be emphasized that public policies aimed at dealing with violence should expand their scope to the various forms of violence affecting children. PMID- 24142003 TI - Prevalence of self-reported medical diagnosis of uterine leiomyomas in a Brazilian population: demographic and socioeconomic patterns in the Pro-Saude Study. AB - INTRODUCTION: Uterine leiomyomas (UL) are considered the most common tumors of the female reproductive system. However, there are few epidemiological studies about this condition in Brazil. AIM: To estimate the prevalence of self-reported history of UL according to demographic and socioeconomic characteristics, and to markers of access to health care. METHODS: We analyzed data from 1,733 university employees who participated at the baseline waves of the Pro-Saude Study (1999 2001), in relation to three outcomes: (1) self-reported medical diagnosis of UL, (2) UL with symptoms prior to diagnosis, and (3) cases with hysterectomy due to UL. Prevalence and 95% confidence intervals (95% CI) were estimated in relation to strata of variables related to demographic (age, color/race) and socioeconomic characteristics (education, income) and of markers of access to health care (Pap smear, breast clinical exam and private health insurance status). RESULTS: The prevalence of medically-diagnosed UL was 23.3% (95% CI - 21.3, 25.2), the UL with symptoms prior to diagnosis of 13.3% (95% CI - 11.7, 15.0) and hysterectomy due to UL, 8.4% (95% CI - 7.5, 10.3). Among participants younger than 45 years old, higher prevalence was observed among women with worse socioeconomic conditions and of black color/race. Among those with 45 years or more, there was higher prevalence among women with better access to health care. CONCLUSION: In this study population of Brazilian women, UL is a relevant health problem, and its prevalence and associated socio-demographic gradients are similar to those observed in other countries. PMID- 24142004 TI - Day-surgery and surgical waiting time. AB - Surgical waiting time remains an important issue regarding access to health care provision. It is considered to be excessive in most OEDC countries (over twelve weeks or ninety days). The development of day surgery has been one of the strategies that proved effective in reducing surgical waiting time. This study aims to establish a correlation between surgical waiting time and the percentage of day-surgery cases, in hospitals with surgical services, in the Portuguese National Health Services, during 2006. METHODOLOGY: An observational, analytical and ecological study was conducted to establish the correlations existing between surgical waiting time and the percentage of day-surgery procedures realized, as well as associations with other variables, through multivariate and correlation analysis. RESULTS: A negative, statistically significant Spearman's correlation was observed between the percentage of day-surgery cases and the waiting surgical time for eletive procedures. PMID- 24142005 TI - Comparison of two assessment instruments of quality of life in older adults. AB - OBJECTIVE: To investigate if there is convergent validity between the dimensions of the World Health Organization Quality of Life Questionnaire-Brief Version (WHOQOL-Bref) and the Oral Health Impact Profile-14 (OHIP-14) questionnaire. METHODS: In this cross-sectional study, a random sample of 872 elderly Southern Brazilians was evaluated. Questionnaires assessing socio-demographic data and quality of life in general (WHOQOL-Bref) and oral health-related quality of life (OHIP-14) were used. Analysis of the WHOQOL-Bref and OHIP-14 questionnaires used descriptive statistics. The dimensions of the WHOQOL-Bref and OHIP-14 questionnaires were correlated by affinity. The convergence between WHOQOL-Bref and OHIP-14 dimensions was analyzed by Spearman's correlation coefficients. RESULTS: The social relations dimension of the WHOQOL-Bref presented the greatest mean (18.24 +/- 2.30). The physical pain dimension of the OHIP-14 presented a median of 1.0 (0.0 - 3.0). All correlations between the WHOQOL-Bref and OHIP-14 dimensions were significant, negative and associated with a low magnitude. The correlation between WHOQOL-physical and OHIP-functional limitation, OHIP-physical pain, OHIP-physical disability and OHIP-handicap were - 0.164, - 0.262, - 0.196 and - 0.125 respectively. WHOQOL-psychological was associated with OHIP psychological discomfort and OHIP-psychological disability, and WHOQOL-social showed an association with OHIP-social disability. CONCLUSIONS: All correlations analyzed had a positive association of low magnitude. Despite the fact that the WHOQOL-Bref and OHIP-14 instruments have related dimensions, they measure physical, psychological and social relations differently. PMID- 24142006 TI - Assessment of urinary infection management during prenatal care in pregnant women attending public health care units in the city of Rio de Janeiro, Brazil. AB - The aim of this study was to assess the sociodemographic risk factors for urinary tract infection and the inadequacy of antenatal care, according to the Kotelchuck index, in pregnant women in the city of Rio de Janeiro. A cross-sectional study was conducted with 1,091 pregnant women, 501 with urinary tract infection, in the public health antenatal care units in Rio de Janeiro, Brazil, in 2007-2008. Demographic and socioeconomic data, obstetric history and adequacy of antenatal care were collected by interviews and antenatal care card. Inadequacy management of urinary tract infection was evaluated by professional performance, health services and women dimensions. Chi-square and multivariate logistic regression were used to compare groups and to identify associated factors with management of urinary tract infection. Pregnant teenagers, anemic and diabetic pregnant women and quality of prenatal partially adequate or inadequate were those with higher odds of urinary tract infection. In the overall assessment, 72% had inadequate management of urinary tract infection. Inadequate management of urinary tract infection was associated with brown skin color compared to white skin color. In the assessment of health professional performance, inadequacy management of urinary tract infection was more common in pregnant women with low weight and overweight and obesity. According to pregnant women evaluation, primiparous women have lower odds of inadequacy management of urinary tract infection compared to those with one or more children. PMID- 24142007 TI - Validity, reliability and understanding of the EORTC-C30 and EORTC-BR23, quality of life questionnaires specific for breast cancer. AB - OBJECTIVE: To validate and assess reliability and understanding of the EORTC-C30 quality of life questionnaire and its breast cancer specific module, the EORTC BR23. METHODS: This study was conducted at the AC Camargo Cancer Hospital, Sao Paulo, Brazil. A total of 100 women diagnosed with breast cancer were interviewed. Internal consistency, confirmatory factorial analysis, convergent validity, construct validity and degree of understanding were examined. Reliability was assessed by comparison of means at times 1 and 2, inter-class coefficient and Bland-Altman graphics. RESULTS: Cronbach's alpha ranged from 0.72 to 0.86 for the EORTC-C30 and from 0.78 to 0.83 for the EORTC-BR23 questionnaire. Most questions were confirmed in the confirmatory factorial analysis. In the construct validity analysis, the questionnaires were capable of differentiating patients with or without lymphedema, apart from the symptom scales of both questionnaires. Both questionnaires presented a significant correlation in most domains of the SF-36, in the convergent validity analysis. Only a few criticisms were reported concerning questions, and the mean grade of understanding was high (C30 = 4.91 and BR23 = 4.89). The questionnaires presented good rates of reliability, with the exception of the functional scale of the C30 and the symptom scale of the BR23. CONCLUSIONS: The EORTC-C30 and EORTC-BR23 quality of life questionnaires were validated, presented good rates of reliability and are easily understood, allowing them to be used in Brazil to assess quality of life among women with breast cancer. PMID- 24142008 TI - Health professionals in the process of vaccination against hepatitis B in two basic units of Belo Horizonte: a qualitative evaluation. AB - According to the Vaccine Coverage Survey, performed in 2007, the immunization coverage against hepatitis B in Belo Horizonte, for infants under one year old, was below the level proposed by the Brazilian National Program of Immunization. This vaccine was used as basis for evaluating the involvement of health professionals in the process of vaccination in two Basic Health Units (UBS, acronym in Portuguese) in the city. This study is qualitative and uses the notions of Social Representations Theory and the method of Structural Analysis of Narrative to carry out the interviews and data analysis. The results show flaws related to controlling and use of the mirror card and the parent orientation, and also the monitoring of vaccination coverage (VC) and use of VC data as input for planning health actions. It was observed that the working process in the UBS is focused on routine tasks, with low creativity of the professionals, which includes representations that maintain strong tendency to value activities focused on the health of individuals to the detriment of public health actions. In conclusion, the vaccination process fault can be overcome with a greater appreciation of everyday actions and with a much better use of local information about vaccination, and some necessary adjustments within the UBS to improve public health actions. PMID- 24142009 TI - Suicide and attempts suicide by exogenous intoxication in Rio de Janeiro: analysis of data from official health information systems, 2006-2008. AB - OBJECTIVE: To describe the profile of suicide and attempts suicide by exogenous intoxication and completeness of data from the Center for Poisoning Control in Niteroi City (CCIn), Information System for Notifiable Diseases (Sinan), and Mortality Information System (SIM) for Rio de Janeiro state (RJ). METHODS: It was verified the frequency of suicide attempts and mortality in Rio de Janeiro state, period 2006-2008. The variables analyzed were sex, area of occurrence, circumstance, evolution, age, toxic agents and cause (ICD-10: X60-X69). The percentage of unknown information/blank was classified as excellent (<= 10%), good (10 to 29.9%) and poor (>= 30%). SPSS was used for statistical analysis. RESULTS: Nine hundred and forty records of attempts (CCIn) and 470 (Sinan) were analysed. The female and the age group of 20-39 years predominated, as well as use of toxic agents like medicines and pesticides. About suicide, were identified 33 records (CCIn), 23 (Sinan) and 180 (SIM). In CCIn were more frequent female and age group of 15-29 years, through Sinan and SIM from 40-59 years. For both events, psychotropic drugs accounted for more than 70% of drugs. The Sinan system has shown the worst performance for toxic agents. CONCLUSIONS: Despite advances in improving the quality of information generated by the systems, problems regarding the coverage and data completeness remain committing the analysis of the magnitude of injuries. The study points out to the needs of systems compatibility and the improvement of the quality of information that are generated. PMID- 24142010 TI - Retinol binding protein 4 and incident diabetes--the Atherosclerosis Risk in Communities Study (ARIC Study). AB - BACKGROUND: Retinol binding protein 4 (RBP4) has been described as a link between impaired glucose uptake in adipocytes and systemic insulin sensitivity. OBJECTIVE: To determine whether RBP4 fasting levels predict the development of type 2 diabetes. METHODS: Using a case-cohort design, we followed 543 middle-aged individuals who developed diabetes and 537 who did not over ~9 years within the population-based Atherosclerosis Risk in Communities Study. Weighted Cox proportional hazards analyses permitted statistical inference of the RBP4 - incident diabetes associations to the entire cohort. RESULTS: Women in the highest tertile of RBP4 presented greater risk of developing diabetes (HR = 1.74; 95%CI 1.03 - 2.94) in analyses adjusted for age, ethnicity, study center, parental history of diabetes, hypertension, glomerular filtration rate, body mass index, waist-hip ratio, nonesterified fatty acids, adiponectin, leptin, triglycerides and HDL-C. When additionally adjusted for fasting insulin, this association's significance became borderline (HR = 1.68; 95%CI 1.00 - 2.82). No association between RBP4 levels and incident diabetes was found in men. CONCLUSION: These findings suggest that RBP4 levels may be directly involved in the pathogenesis of type 2 diabetes in women. PMID- 24142011 TI - Clustering of risk factors for non communicable diseases in adults from Florianopolis, SC. AB - OBJECTIVE: To investigate clustering patterns of health risk behaviors for non communicable diseases and its associated factors. METHODS: a Random telephone survey with 1,996 adults from Florianopolis, SC, was conducted in 2005. Tobacco use, high alcoholic intake episodes, fruit consumption and physical inactivity were investigated. Clustering was examined by the ratio between observed and expected prevalence of each of the 16 possible combinations. These clustered risk factors comprised the main outcome and binomial and multinomial logistic regression was conducted to examine socio-demographic correlates. RESULTS: 43% of men and 36.6% of women clustered at least two health risk factors. Three (19.2%; CI 95% 16.7 - 21.7) and five (9.8%; CI 95% 8.0 - 11.6) specific combinations exceed the expected prevalence, respectively, in men and women. Women with low schooling level and older were more likely to cluster health risk behaviors. CONCLUSION: although men showed higher prevalence of single health risk behavior and its combinations, women presented more specific combinations that clustered above the expected. Knowledge on the clustering pattern of these health risk behaviors may guide the design of more effective health promotion initiatives. PMID- 24142012 TI - Prescriptions for uncomplicated malaria treatment among pregnant women in the Brazilian Amazon: evidences from the Mafalda Project. AB - AIM: To evaluate antimalarial prescriptions according to quality indicators and to describe adverse events reports among pregnant women with uncomplicated malaria. METHODS: Descriptive study of medical files of pregnant women 15 years and older, residents in high-risk municipalities in the Brazilian Amazon. Antimalarial medicines were characterized by frequency of prescription, type of plasmodium and health care facilities where prescribing took place, and by possible adverse events. Variables were compared by Pearson's chi-square. RESULTS: A total of 262 medical files were evaluated. Most patients were diagnosed for Plasmodium vivax 71,2%. Chloroquine was the commonest prescribed antimalarial (65.6%). Of P. vivax prescriptions, 9.0%, and 16.2% of P. falciparum prescriptions presented antimalarials not recommended in the official protocol. Prescriptions for P. falciparum , in significantly higher proportion, did not adhere to the official protocol in regard to type of antimalarial and dose/duration of treatment (p = 0,001). They also lacked information on dose and dosing interval (p = 0,004). There were no significant differences among reference centers and basic health care units in respect to the prescribed antimalarials, to prescriptions containing antimalarials not recommended in the official protocol or in respect to lack of dosing information. Chloroquine was the antimalarial most related to the occurrence of adverse events. CONCLUSION: THE findings indicate that there are flaws in antimalarial prescribing for pregnant women, especially in respect to their adequacy to the official protocol. PMID- 24142013 TI - HIV/AIDS transmission knowledge among adolescents aged 11 years from Southern Brazil. AB - OBJECTIVE: To investigate the effect of demographic, socioeconomic, educational and family variables on HIV/AIDS knowledge among adolescents aged 11 years. METHODS: 3,949 adolescents born in Pelotas (Brazil). HIV/AIDS knowledge was assessed through a self-administered questionnaire and measured through five questions about HIV transmission: heterosexual intercourse, homosexual intercourse, needle sharing, open-mouth kissing and hugging someone with AIDS. All the analyses were adjusted based on a hierarchical model, using Poisson regression with robust adjustment of variance. RESULTS: Prevalence of wrong answers to the examined questions were 17.2% for heterosexual transmission, 44.1% for homosexual intercourse, 34.9% for needle sharing, 25.6% for kiss on the mouth and 16.2% for hugging someone with AIDS. In adjusted analysis, lower knowledge levels were more prevalent among boys, adolescents with lower socioeconomic status and with less maternal education level, among those who had not talked about sex with mother and without sexual education lessons at school. Knowledge was not associated with school type (public or private), skin color or talk about sex with father. CONCLUSION: Providing information to adolescents is essential to improve knowledge about HIV and other sexually transmitted infections, especially among young males, with lower socioeconomic status and with lower maternal education level. Public policies aimed to reducing HIV infection should consider maternal and school relevance to improve knowledge on adolescents. PMID- 24142014 TI - Prevalence and socioeconomic factors associated with smoking in people living with HIV by sex, in Recife, Brazil. AB - INTRODUCTION: Smoking is the leading cause of preventable death in the world. The prevalence of smoking is higher in people infected with HIV than in the general population. Although it is biologically plausible that smoking increases the morbidity and mortality of people living with HIV/AIDS, few studies in developing countries have analyzed the determinants and consequences of smoking in HIV infected people. OBJECTIVE: To estimate the prevalence of smoking and identify the socioeconomic factors associated with smoking and smoking cessation in patients with HIV by sex. METHODS: A cross-sectional study was conducted with baseline data, obtained from an ongoing prospective cohort study of patients with HIV attending two referral centers in Recife, Northeast Region of Brazil, between July 2007 and October 2009. RESULTS: The prevalence of current smoking was 28.9%. For both sexes, smoking was independently associated with heavy alcohol drinking and marijuana use. Among women, smoking was associated with living alone, not being married and illiteracy; and among men, being 40 years or older, low income and using crack. Compared with ex-smokers, current smokers were younger and more likely to be unmarried, heavy drinkers and marijuana users. CONCLUSIONS: It is important to incorporate smoking cessation interventions for the treatment of heavy alcohol drinkers and marijuana users with HIV/AIDS, which may increase life expectancy and quality of life, as smoking is related to risk of death, relapse of tuberculosis, and non communicable diseases. PMID- 24142015 TI - Sexual dysfunction symptoms in men age 40 or older: prevalence and associated factors. AB - OBJECTIVE: This study aimed to identify factors associated with sexual symptoms of aging male's in a representative sample of men aged 40 or older from Pelotas, southern Brazil. METHODS: We performed a population-based cross-sectional study including 421 men who lived in urban area. To evaluate the sexual symptoms of aging male's was used the sexual dimension of the AMS scale - The Aging Male's Symptoms Scale. RESULTS: The prevalence of sexual symptoms of male aging was 64.3% (95% CI: 59.3%-69.1%). Multivariable analysis identified direct association with age and inverse association with health self-rated. CONCLUSION: We conclude that the prevalence of sexual symptoms in older males is high and important. Public health policies coupled with increased healthy lifestyle habits could minimize the prevalence and provide better quality of life for middle-age and older men. PMID- 24142016 TI - Deaths from external causes in Cuiaba, 0 a 24 years: Profile of victims and families according to intentionality. AB - In view of the importance of knowing the circumstances associated with external causes (accidents and violence), this study analyzes the profile of the victims and their families as to the intentionality of the event (intentional or accidental). Cross-sectional study, which population comprise children, adolescents, and young people (age 0 to 24) who lived in Cuiaba, MT, and died from external causes in 2009. The data, processed by the Epi-Info software, were taken from the Declarations of Death and interviews with the families of the victims. The nonparametric chi-square test showed statistically significant differences between accidental and intentional deaths by sex and the type of accident or violence, the occurrence of the previous event external cause, parental education, family type, income, responsible for supporting the house, mother's age and caregiver. Among the victims, male participation (88.7 %) stands out compared to female (11.3 %). 50.0% of the deaths of females were accidental and 50.0% intentional; 68.2% of the deaths of males were intentional, 29.1% accidental and 2.7% from undetermined intent. Among the intentional deaths, 72.5% of the victims had already suffered violence. As the degree of instruction of the parents increases, intentional deaths decrease. The proportion of reconstituted/fragmented families is higher for fatal accidents. Intentional causes increase as family income decreases and the age of the parents increases. The agglomeration of people in the homes is higher for intentional deaths. Analizing the profiles of families and victims as to the intentionality of the event allows directing local prevention and control policies. PMID- 24142017 TI - Circumstances and consequences of falls among the older adults in Florianopolis. Epi Floripa Aging 2009. AB - The objective was to investigate the cir-cumstances and consequences of falling and risk factors associated with limitations in performing activities after falling. The study is part of the cross-sectional population based survey, conducted in 2009/2010, which involved 1,705 older adults (60 years and older) living in Florianopolis, SC. From the affirmative answer to the question of whether any falls occurred in the 12 months preceding the study, we investigated the circumstances and consequences of falls through a structured questionnaire. Descriptive analysis and binary logistic regression were used, with significance level of 5%. The prevalence of fall was 19% (14.3% for men and 21.5% for women). Most older adults fell while walking, 43.2% inside their homes. The main cause of falling was stumbling due to irregularities on the ground. 71% of those who fell reported injury, and 14.8% reported limitations in performing activities after the fall. There was a significant association between limitations in performing activities after the occurrence of falls and fractures. Preventing falls should be a public health concern, given that relatively easy changes can reduce the risk of falls. PMID- 24142018 TI - Profile of victims and treatment of injuries by external causes according to attendance by the Municipal Rehabilitation Center of Uberlandia, MG - external causes and physiotherapy. AB - In Brazil, external causes are responsible for many disabilities. Most research has emphasized the mortality and the demand for hospital treatment, and little is known about the evolution of non-fatal injuries. The objective of this study was to identify the profile of victims and the characteristics of injuries from external causes, physical therapy and functional evolution of patients treated in a public rehabilitation center. Data were prospectively collected by interviews with patients who entered the Municipal Rehabilitation Center (CEREM) of Uberlandia, from January to July 2005. Most patients were male and predominated those from 20 to 59 years old, with low income and education. The main causes of injury were falls and traffic accidents, almost half of the events occurred on public roads, and fractures were common, especially in upper limbs. The resources most frequently used were physiotherapeutic kinesiotherapy, electrotherapy and thermotherapy by addition, and most treatments started was completed. The profile of patients that seeking CEREM due to injuries from external causes may reflect, above all, that people who suffer such injuries. Simple physiotherapy resources showed to be enough for a good outcome. PMID- 24142019 TI - Variation in dietary intake and physical activity pattern as predictors of change in body mass index (BMI) Z-score among Brazilian adolescents. AB - OBJECTIVE: To assess whether changes in dietary intake and physical activity pattern are associated with the annual body mass index (BMI) z-score change among adolescents. METHODS: The study was conducted in public schools in the city of Piracicaba, Sao Paulo, Brazil, with a probabilistic sample of 431 adolescents participating in wave I (2004) (hereafter, baseline) and 299 in wave II (2005) (hereafter, follow-up). BMI, usual food intake, physical activity, screen time, sexual maturation and demographic variables were assessed twice. The association between annual change in food intake, physical activity, screen time, and annual BMI z-score changes were assessed by multiple regression. RESULTS: The study showed a positive variation in BMI z-score over one-year. Among variables related to physical activity pattern only playing videogame and using computer increased over the year. The intake of fruits and vegetables and sugar-sweetened beverages increased over one year, while the others variables showed a reduction. An increased consumption of fatty foods (beta = 0.04, p = 0.04) and sweetened natural fruit juices (beta = 0.05, p = 0.03) was positively associated with the rise in BMI z-score. CONCLUSIONS: Unhealthy dietary habits can predict the BMI z score gain more than the physical activity pattern. The intake of fatty foods and sweetened fruit juices is associated with the BMI z-score over one year. PMID- 24142020 TI - Factors associated with nutritional status in infants attending public daycare centers in the municipality of Recife, PE, Brazil. AB - OBJECTIVE: To evaluate the nutritional status of infants attending daycare centers in the Municipality of Recife and to verify its association with potential determinant factors. METHODS: This is a cross sectional study conducted with 321 infants in the age group of 6 to 30 months from August to October 2004. The nutritional status was assessed through length-for-age, weight-for-age, weight-for-length and body mass index-for-age using as reference pattern that of the World Health Organization. Multivariable linear regression analysis assessed the effect of maternal socioeconomic and demographical indicators, and child related variables on infant length-for-age. RESULTS: The percentages of malnutrition (Z score < -2) were found in 13.4%, 2.8%, 0.6% and 0.6% for length for-age, weight-for-age, weight-for-length and body mass index-for-age, respectively. The final model of the linear multivariable regression analysis showed that the socioeconomic (type of roof and water supply) and child biological conditions (birthweight, age and hemoglobin concentration) were the variables that significantly influenced the variation of length-for-age, explaining 3.8% and 12.8%, respectively. CONCLUSION: Among the studied variables, child biological factors had a higher influence in the variation of length-for age than the socioeconomic ones. PMID- 24142021 TI - Seasonal variation of food intake of adults from Niteroi, Rio de Janeiro, Brazil. AB - The measurement of usual food intake (FI) is necessary to accurately establish the relationship between diet and disease. In most studies data are collected at one particular time of the year, which may influence the interpretation of the results. The purpose of this study was to investigate the effect of seasonality on FI in a sample of adults from Niteroi, RJ, Brazil. A total of 102 healthy subjects (69 women) aged between 20 and 69 years were interviewed to obtain six 24-hour dietary recalls, three in summer and three in winter. In both seasons, the intake of energy (EI) and 23 nutrients was determined and the percent of subjects who met the recommendations for the nutrients were computed. The data of FI were deattenuated considering the within-person variability and adjusted for energy. The intake of energy and some nutrients were significantly different between men and women. EI did not differ between seasons, for both sexes, but the intake of macro and micronutrients was different. The results of this study suggest that the seasonality in the measurement of FI should be considered in order to improve the methods and instruments used in population dietary surveys. PMID- 24142022 TI - Assessment of factors that interfere on breastfeeding within the first hour of life. AB - OBJECTIVE: To investigate how the 4thStep of the Baby-Friendly Hospital Initiative was applied, assess the prevalence of breastfeeding (BF) within the first hour after birth and analyze factors associated with non-BF in this period of life. METHODS: Cross-sectional study conducted in a high-risk maternity hospital in Rio de Janeiro City, Brazil, with interview to a sample of 403 rooming-in mothers. The prevalence ratio with its respective 95% confidence interval was estimated by the use of SPSS 15(r) from a model with complementary log log link function. RESULTS: The prevalence of BF in the first hour of life was 43.9%. Multivariate analysis showed that were protected against non-BF in the first hour after birth non-black women (PR = 0.62, 95% CI: 0.42-0.90), multiparous women (PR = 0.66, 95% CI: 0.47-0.93), prenatal care (PR = 0.23, 95% CI: 0.08-0.67), vaginal delivery (PR =0 .41, 95% CI: 0.28-0.60), newborn with birthweight >= 2,500g (PR = 0.31, 95% CI: 0.11-0.86) and women who received help from the health team to BF in the delivery room (PR = 0.51, 95% CI: 0.36-0.72). CONCLUSION: Help provided by the health team to breastfeeding at birth, Step 4 of the Baby-Friendly Hospital Initiative, as well as non black women, multiparous women, receiving pre-natal care, vaginal delivery and appropriate birthweight contributed to breastfeeding in the first hour of life. PMID- 24142023 TI - Hemoglobin levels and prevalence of anemia in pregnant women assisted in primary health care services, before and after fortification of flour. AB - We evaluated hemoglobin-Hb levels and prevalence of anemia in pregnant women before and after fortification of flour. It was developed a study to evaluate intervention, of the type before and after, with independent population samples. Study was conducted in primary health care services in Maringa, PR. We assessed 366 and 419 medical records, Before and After implementation of fortification. Pregnant women with Hb < 11g/dL were considered anemic. Data were submitted to multiple linear regression analysis. There was low prevalence of anemia affecting 12.3% and 9.4% pregnant women Before and After fortification (p > 0.05), but the Group After the fortification had higher Hb levels (p < 0.05). Hb levels associated with Group, gestational age, previous pregnancy number, employment and marital status (p < 0.05). Although the fortification of flour may have had role in increasing the mean hemoglobin, we need consider the contribution of other variables not investigated. PMID- 24142024 TI - Factors related to the use of dental services among adolescents from Gravatai, RS, Brazil, in 2005. AB - INTRODUCTION: Access to health services, including those for oral health, depends upon socioeconomic, environmental and individual factors. Moreover, cultural and lifestyle differences also influence the degree to which services are sought. OBJECTIVE: This study aimed to assess factors associated with the use of dental services among adolescents in the 7th grade of public primary schools from the city of Gravatai, RS, Brazil, in 2005. METHODS: A cross-sectional survey was carried out. Data were collected in schools through self-administered questionnaires evaluating demographic, socioeconomic and psychosocial factors, lifestyle, oral health habits and behaviors of 1,170 adolescents, using the Global School-Based Student Health Survey, International Physical Activity Questionnaire and Body Shape Questionnaire. Data analysis was carried out by means of Cox regression modified for cross-sectional studies, using the STATA 6.0 software. Univariate and multivariate analyses were performed from a hierarchical conceptual model supported by the literature on hierarchical models. RESULTS: The use of dental services was less frequent among those who reported concern with body image and involvement in fights; those whose parents did not know where they were in their leisure time, those who brushed their teeth less than twice a day, those who did not use dental floss daily, those who reported seeking dental services for curative treatment and those with a lower socioeconomic status. CONCLUSIONS: The results suggest that the use of dental services by adolescents depends upon the interaction of psychosocial and individual factors as well as the family context. PMID- 24142025 TI - Medialogy diagram construction on dengue fever. PMID- 24142026 TI - State of the art of Lewis acid-containing zeolites: lessons from fine chemistry to new biomass transformation processes. AB - The former synthesis of TS-1 opened new catalytic opportunities for zeolites, especially for their application as selective redox catalysts in several fine chemistry processes. Interestingly, isolated Ti species in the framework positions of hydrophobic zeolites, such as high silica zeolites, offer unique Lewis acid sites even in the presence of protic polar solvents (such as water). Following this discovery, other transition metals (such as Sn, Zr, V, Nb, among others) have been introduced in the framework positions of different hydrophobic zeolitic structures, allowing their application in new fine chemistry processes as very active and selective redox catalysts. Recently, these hydrophobic metallozeolites have been successfully applied as efficient catalysts for several biomass-transformation processes in bulk water. The acquired knowledge from the former catalytic descriptions in fine chemistry processes using hydrophobic Lewis acid-containing zeolites has been essential for their application in these novel biomass transformations. In the present review, I will describe the recent advances in the synthesis of new transition metal-containing zeolites presenting Lewis acid character, and their unique catalytic applications in both fine chemistry and novel biomass-transformations. PMID- 24142028 TI - Older persons' use of the European Court of Human Rights. AB - One of the most significant human rights tribunals in Europe is the European Court of Human Rights (ECtHR). Up to day, no study has attempted to explore the cases brought before the ECtHR that discuss and rule on issues concerning the rights of older persons. To descriptively analyze the ECtHR cases that deal with older persons and elder rights issues. Quantitative and descriptive analysis of 226 randomly selected publicly-open ECtHR cases dealing with elder-rights between the years 2000-2010. On average, 11.9 % of the ECtHR case load included rulings that concern older persons' rights. In the majority of the cases (91 %, 205 judgments), the ECtHR found a violation of at least one human right concerning older persons. Despite the fact that rights of older persons do not appear as such in the European Convention on Human Rights, older persons do find their way to the ECtHR. PMID- 24142027 TI - Radiolabelled leucocyte scintigraphy versus conventional radiological imaging for the management of late, low-grade vascular prosthesis infections. AB - PURPOSE: In this study we evaluated the diagnostic performance of (99m)Tc-HMPAO leucocyte ((99m)Tc-HMPAO-WBC) scintigraphy in a consecutive series of 55 patients (46 men and 9 women, mean age 71 +/- 9 years, range 50 - 88 years) with a suspected late or a low-grade late vascular prosthesis infection (VPI), also comparing the diagnostic accuracy of WBC with that of other radiological imaging methods. METHODS: All patients suspected of having VPI underwent clinical examination, blood tests, microbiology, US and CT, and were classified according to the Fitzgerald criteria. A final diagnosis of VPI was established in 47 of the 55 patients, with microbiological confirmation after surgical removal of the prosthesis in 36 of the 47. In the 11 patients with major contraindications to surgery, the final diagnosis was based on microbiology and clinical follow-up of at least 18 months. RESULTS: (99m)Tc-HMPAO-WBC planar, SPECT and SPECT/CT imaging identified VPI in 43 of 47 patients (20 of these also showed infection at extra prosthetic sites). In the remaining eight patients without VPI, different sites of infections were found. The use of SPECT/CT images led to a significant reduction in the number of false-positive findings in 37% of patients (sensitivity and specificity 100 %, versus 85.1% and 62.5% for stand-alone SPECT). Sensitivity and specificity were 34% and 75% for US, 48.9% and 83.3% for CT, and 68.1% and 62.5% for the FitzGerald classification. Perioperative mortality was 5.5%, mid-term mortality 12%, and long-term mortality 27%. Survival rates were similar in patients treated with surgery and antimicrobial therapy compared to patients treated with antimicrobial therapy alone (61% versus 63%, respectively), while infection eradication at 12 months was significantly higher following surgery (83.3% versus 45.5%). CONCLUSION: (99m)Tc-HMPAO-WBC SPECT/CT is useful for detecting, localizing and defining the extent of graft infection in patients with late and low-grade late VPI with inconclusive radiological findings. (99m)Tc-HMPAO-WBC SPECT/CT might be used to optimize patient management. PMID- 24142032 TI - A comparison of outcomes between OKT3 and antithymocyte globulin for treatment of steroid-resistant rejection in hepatitis C liver transplant recipients. AB - BACKGROUND: The treatment of steroid-resistant rejection (SRR) is associated with severe recurrent hepatitis C virus (HCV) infection after liver transplantation (LTx). After OKT3 was recently withdrawn from the market, thymoglobulin (TG) became the principal treatment for SRR. METHODS: A retrospective analysis of 32 HCV patients who were treated for SRR with OKT3 (n=15) or TG (n=17) using yearly protocol liver biopsies. Mean follow-up was 4.3 years (OKT3) and 3.2 years (TG). We compared both groups for patient survival, graft loss, and severity of HCV recurrence, manifested as the mean stage of fibrosis (MSF). RESULTS: Patient survival at 1, 2, and 5 years after LTx was 80%, 73%, and 67% in the OKT3 group and 82%, 77%, and 64% in the TG group, respectively. At 2 years after LTx, the graft losses were 3 versus 4 in the OKT3 and TG groups, respectively. At years 1 and 2, the MSF in the OKT3 group was 1.9 and 2.3 versus 2.4 and 2.8 in the TG group, respectively. None of the differences between both groups was statistically significant. CONCLUSION: There was no significant difference in patient survival, graft loss, or severity of recurrent HCV, measured as MSF, between both groups. PMID- 24142033 TI - Anti-CD200R2, anti-IL-9, anti-IL-35, or anti-TGF-beta abolishes increased graft survival and Treg induction induced in cromolyn-treated CD200R1KO.CD200tg mice. AB - BACKGROUND: Rejection is associated with early degranulation (>=80%) of graft infiltrating CD200R1 receptor-positive mast cells (MCs). Survival is increased, and MC degranulation is decreased, in CD200 mice but not in CD200R1KO mice. CD200 engagement of CD200R2 (not present on MCs) alters dendritic cell differentiation and enhances induction of Foxp3 regulatory T cells (Tregs). We investigated whether attenuation of MC degranulation by sodium cromoglycate allowed CD200 to increase survival in CD200R1KO mice. METHODS: C57BL/6 control, CD200R1KO, CD200, or CD200R1KO.CD200 mice received BALB/c grafts with or without treatment with cromoglycate. Survival was monitored daily from day 10, with mixed lymphocyte culture responses measured on day 14 or 21 and graft immunohistology performed on day 14. RESULTS: Decreased MC degranulation and increased graft Foxp3 Treg infiltration/survival occurred in CD200 mice and in CD200-treated control mice or CD200R1KO.CD200 mice receiving cromoglycate. Neutralizing anti-CD200 or anti CD200R1/R2 monoclonal antibody caused graft rejection, as did anti-interleukin (IL)-9, anti-IL-35, or anti-transforming growth factor-beta antibodies, with the latter also decreasing graft-infiltrating Tregs. CONCLUSION: These data imply a coordinated effect of MCs and Tregs on increased graft survival induced by CD200, with a critical role for IL-9, IL-35, and transforming growth factor-beta in the development/function of Tregs. PMID- 24142034 TI - Liver transplantation versus liver resection in the treatment of hepatocellular carcinoma: a meta-analysis of observational studies. AB - BACKGROUND: A number of cohort studies have compared the outcomes of liver transplantation (LT) and liver resection (LR) in hepatocellular carcinoma (HCC) patients. However, the effects of LT versus LR remain unclear. We searched electronic databases and reference lists for relevant articles published before February 2013. METHODS: The primary endpoints were pooled using random-effects models to model potential heterogeneity, including overall survival (OS), disease free survival, and recurrence rate. RESULTS: We found similar 1-year OS (odds ratio [OR], 1.08; 95% confidence interval [CI], 0.81-1.43; P=0.61) yet significantly better 3-year OS (OR, 1.47; 95% CI, 1.18-1.84; P<0.001) and 5-year OS (OR, 1.77; 95% CI, 1.45-2.16; P<0.001) after LT compared with LR with relative risk differences of 9% (P<0.001) and 14% (P<0.001), respectively. The 1-, 3-, and 5-year difference-free survival were 13%, 29%, and 39% higher (P<0.001 in all) in LT recipients than LR patients. Additionally, recurrence rate was 30% less (P<0.001) in LT than LR. Furthermore, better 5-year difference-free survival (P<0.001) and recurrence rates (P<0.05) were yielded after LT when patients from the entire HCC population were included. CONCLUSIONS: When including all the 62 previous studies comparing LT and resection, LT provides increased survival and lower recurrence rates than LR for HCC patients. These results of disease-free survival and recurrence rate are similar among early HCC patients with Child Turcotte-Pugh class A cirrhosis. However, summary ORs and risk differences cannot be interpreted as causal effects of LT versus LR. PMID- 24142035 TI - Brain death-induced inflammatory activity in human pancreatic tissue: a case control study. AB - BACKGROUND: Long-term insulin independence after islet transplantation depends on engraftment of a large number of islets. However, the yield of pancreatic islets from brain-dead donors is negatively affected by the up-regulation of inflammatory mediators. Brain death is also believed to increase tissue factor (TF) expression, contributing to a low rate of engraftment. METHODS: We conducted a case-control study to assess brain death-induced inflammatory effects in human pancreas. Seventeen brain-dead patients and 20 control patients undergoing pancreatectomy were studied. Serum tumor necrosis factor (TNF), interleukin (IL) 6, IL-1beta, interferon (IFN) gamma, and TF were measured using enzyme-linked immunosorbent assay kits. Gene expressions of these cytokines and TF were evaluated by reverse transcriptase quantitative polymerase chain reaction. Protein quantification was performed by immunohistochemistry in paraffin-embedded pancreas sections. RESULTS: Brain-dead patients had higher serum concentrations of TNF and IL-6 and increased TNF protein levels compared to controls. The groups had similar TNF, IL-6, IL-1beta, and IFN-gamma messenger RNA levels in pancreatic tissue. Reverse transcriptase quantitative polymerase chain reaction revealed TF messenger RNA up-regulation in controls. Immunohistochemical analyses showed that brain-dead patients had increased TNF protein levels compared to controls. CONCLUSIONS: Brain death induces inflammation evidenced by the up-regulation of TNF in serum and pancreatic tissue. Blocking the expression of key inflammatory mediators in brain-dead donors should be evaluated as a new approach to improve the outcomes of islet transplantation. PMID- 24142036 TI - Short-course isoniazid plus rifapentine directly observed therapy for latent tuberculosis in solid-organ transplant candidates. AB - BACKGROUND: Short-course directly observed isoniazid plus rifapentine (INH/RPT) combination could have potential advantages over a standard 9-month INH regimen for the treatment of latent tuberculosis infection in solid-organ transplant (SOT) candidates. METHODS: We prospectively assessed the safety and tolerability of 12 weeks of INH/RPT given directly observed therapy in 17 consecutive SOT candidates with latent tuberculosis infection. RESULTS: The median age was 57 years and 82% were men. Of the 17 patients, 13 (76%) successfully completed therapy and 4 (24%) eventually underwent SOT. Treatment was prematurely discontinued in four patients. One of these patients underwent a kidney transplant. The overall dose compliance was 83% (169/204 scheduled doses), and 12 (71%) of 17 patients received 100% of scheduled doses. No patient developed transaminase elevations greater than twice baseline or greater than four times the upper limit of normal or clinical hepatotoxicity. No cases of TB developed during 20.4 months after transplant among INH/RPT-treated recipients. CONCLUSIONS: For carefully selected SOT candidates, combination INH/RPT weekly given as directly observed therapy seems to be reasonably well tolerated and is associated with a relatively high completion rate. Future larger prospective studies to confirm the safety and high completion rates reported here and to identify the most appropriate SOT candidates for this regimen are warranted. PMID- 24142037 TI - Highlights from the Indo-US workshop "Cyanobacteria: molecular networks to biofuels" held at Lonavala, India during December 16-20, 2012. AB - An Indo-US workshop on "Cyanobacteria: molecular networks to biofuels" was held December 16-20, 2012 at Lagoona Resort, Lonavala, India. The workshop was jointly organized by two of the authors, PPW, a chemical engineer and LAS, a biologist, thereby ensuring a broad and cross-disciplinary participation. The main objective of the workshop was to bring researchers from academia and industry of the two countries together with common interests in cyanobacteria or microalgae and derived biofuels. An exchange of ideas resulted from a series of oral and poster presentations and, importantly, through one-on-one discussions during tea breaks and meals. Another key objective was to introduce young researchers of India to the exciting field of cyanobacterial physiology, modeling, and biofuels. PhD students and early stage researchers were especially encouraged to participate and about half of the 75 participants belonged to this category. The rest were comprised of senior researchers, including 13-15 invited speakers from each country. Overall, twenty-four institutes from 12 states of India were represented. The deliberations, which are being compiled in the present special issue, revolved mainly around molecular aspects of cyanobacterial biofuels including metabolic engineering, networks, genetic regulation, circadian rhythms, and stress responses. Representatives of some key funding agencies and industry provided a perspective and opportunities in the field and for bilateral collaboration. This article summarizes deliberations that took place at the meeting and provides a bird's eye view of the ongoing research in the field in the two countries. PMID- 24142038 TI - Analysis of carbohydrate storage granules in the diazotrophic cyanobacterium Cyanothece sp. PCC 7822. AB - The unicellular diazotrophic cyanobacteria of the genus Cyanothece demonstrate oscillations in nitrogenase activity and H2 production when grown under 12 h light-12 h dark cycles. We established that Cyanothece sp. PCC 7822 allows for the construction of knock-out mutants and our objective was to improve the growth characteristics of this strain and to identify the nature of the intracellular storage granules. We report the physiological and morphological effects of reduction in nitrate and phosphate concentrations in BG-11 media on this strain. We developed a series of BG-11-derived growth media and monitored batch culture growth, nitrogenase activity and nitrogenase-mediated hydrogen production, culture synchronicity, and intracellular storage content. Reduction in NaNO3 and K2HPO4 concentrations from 17.6 and 0.23 to 4.41 and 0.06 mM, respectively, improved growth characteristics such as cell size and uniformity, and enhanced the rate of cell division. Cells grown in this low NP BG-11 were less complex, a parameter that related to the composition of the intracellular storage granules. Cells grown in low NP BG-11 had less polyphosphate, fewer polyhydroxybutyrate granules and many smaller granules became evident. Biochemical analysis and transmission electron microscopy using the histocytochemical PATO technique demonstrated that these small granules contained glycogen. The glycogen levels and the number of granules per cell correlated nicely with a 2.3 to 3.3-fold change from the minimum at L0 to the maximum at D0. The differences in granule morphology and enzymes between Cyanothece ATCC 51142 and Cyanothece PCC 7822 provide insights into the formation of large starch-like granules in some cyanobacteria. PMID- 24142039 TI - Flux balance analysis of Chlorella sp. FC2 IITG under photoautotrophic and heterotrophic growth conditions. AB - Quantification of carbon flux distribution in the metabolic network of microalgae remains important to understand the complex interplay between energy metabolism, carbon fixation, and assimilation pathways. This is even more relevant with respect to cyclic metabolism of microalgae under light-dark cycle. In the present study, flux balance analysis (FBA) was carried out for an indigenous isolate Chlorella sp. FC2 IITG under photoautotrophic and heterotrophic growth conditions. A shift in intracellular flux distribution was predicted during transition from nutrient sufficient phase to nutrient starvation phase of growth. Further, dynamic flux analysis (dFBA) was carried out to capture light-dark metabolism over discretized pseudo steady state time intervals. Our key findings include the following: (i) unlike heterotrophic condition, oxidative pentose phosphate (PP) pathway, and Krebs cycle were relatively inactive under photoautotrophic growth; (ii) in both growth conditions, while transhydrogenation reaction was highly active, glyoxalate shunt was found to be nonoperative; (iii) flux distribution during transition period was marked with up regulation of carbon flux toward nongrowth associated (NGA) maintenance energy, oxidative phosphorylation, and photophosphorylation; (iv) redirection of carbon flux from polysaccharide and neutral lipid resulted in up regulation of Krebs cycle flux in the dark phase; (v) elevated glycolytic and acetyl-CoA flux were coupled with induction of neutral lipid during light cycle of the growth; (vi) significantly active photophosphorylation in the light phase was able to satisfy cellular energy requirement without need of oxidative PP pathway; and (vi) unlike static FBA, dFBA predicted an unaltered NGA maintenance energy of 1.5 mmol g(-1) DCW h( 1). PMID- 24142040 TI - A novel photodegradable hyperbranched polymeric photoresist. AB - We report the first synthesis of a photodegradable hyperbranched polyacetal, wherein every repeat unit carries a photo-labile 2-nitrobenzyloxy moiety. The pristine HBP serves as a positive photoresist to create micron-size patterns; furthermore, by changing the terminal groups to dipropargyl acetal, clickable photo-patterned substrates can be generated. PMID- 24142041 TI - Association between peripheral muscle strength and daily physical activity in patients with COPD: a systematic literature review and meta-analysis. AB - BACKGROUND: Patients with chronic obstructive pulmonary disease have skeletal muscle dysfunction and reduced daily physical activity (PA). Whether the reduction in quadriceps strength (QS) is directly linked to physical inactivity remains to be elucidated. METHODS: A systematic review and a meta-analysis were conducted to determine the potential relationship between QS and the level of PA. The overall estimate of the correlation coefficient (r*) was calculated, and a subgroup analysis was conducted to analyze the association between QS and indices of PA separately. RESULTS: A total of 8 studies were included in the meta analysis. The overall association between QS and PA was low but highly significant (r * = 0.288, 95% CI = 0.180-0.389; P < .001). In the subgroup analysis, the association between QS and the number of steps per day was low (r = 0.260; 95% CI = 0.060-0.440) and the association between QS and the time spent walking was moderate (r = 0.418; 95% CI = 0.229-0.576). CONCLUSIONS: Peripheral muscle strength is associated with PA as assessed by the number of steps per day and the time spent walking in patients with chronic obstructive pulmonary disease. The overall association between QS and PA was low to moderate and highly significant. PMID- 24142042 TI - Cardiac rehabilitation enrollment among referred patients: patient and organizational factors. AB - PURPOSE: Cardiac rehabilitation (CR) is underutilized despite well-documented benefits for patients with coronary heart disease. The purpose of this study was to identify organizational and patient factors associated with CR enrollment. METHODS: Facilities of the Wisconsin Cardiac Rehabilitation Outcomes Registry (N = 38) were surveyed, and the records of referred patients were analyzed. Generalized estimating equations were used to account for clustering of patients within facilities. RESULTS: Of the 6874 patients referred to the 38 facilities, 67.6% (n = 4,644) enrolled in CR. Patients receiving coronary artery bypass grafting (adjusted odds ratio [OR], 1.72; 95% CI: 1.36-2.19) and those who possessed health insurance (OR, 3.04; 95% CI: 2.00-4.63) were more likely to enroll. Enrollment was also positively impacted by organizational factors, including promotion of CR program (OR, 2.35; 95% CI: 1.39-4.00), certification by the American Association of Cardiovascular Pulmonary Rehabilitation (OR, 2.63; 95% CI: 1.32-5.35), and a rural location (OR, 3.30; 95% CI: 2.35-4.64). Patients aged >=65 years (OR, 0.81; 95% CI: 0.74-0.90) and patients with heart failure (OR, 0.40; 95% CI: 0.22-0.72), diabetes (OR, 0.58; 95% CI: 0.37-0.89), myocardial infarction without a cardiac procedure (OR, 0.78; 95% CI: 0.67-0.90), previous coronary artery bypass grafting (OR, 0.72; 95% CI: 0.56-0.92), depression (OR, 0.56; 95% CI: 0.36-0.88), or current smoking (OR, 0.59; 95% CI: 0.44-0.78) were less likely to enroll. CONCLUSIONS: Predictors of patient enrollment in CR following referral included both organizational and personal factors. Modifiable organizational factors that were associated either positively or negatively with enrollment in CR may help directors of CR programs improve enrollment. PMID- 24142043 TI - The relationship between spinopelvic parameters and clinical symptoms of severe isthmic spondylolisthesis: a prospective study of 64 patients. AB - PURPOSE: To investigate the relationship between spinopelvic parameters and clinical symptoms for patients with severe isthmic spondylolisthesis. METHODS: A series of spinopelvic parameters were measured in 64 patients with L5 severe isthmic spondylolisthesis. The patients were divided into two groups according to Oswestry score obtained preoperatively, i.e. mild or severe low back pain group. T test was used to compare parameters between two groups, and multiple linear regression analysis was employed to investigate the association between parameters and Oswestry score. RESULTS: Compared with two group patients, parameters of spondylolisthesis grade, pelvic tilt (PT), lumbar lordosis (LL), T9 tilting angle (T9TA), sacro-femoral horizontal distance (SFHD), distance between perpendicular line through C7 and sacrum (SC7D), pelvic tilt/sacral slope (PT/SS), sacro-femoral horizontal distance/vertical distance (SFHD/SFVD), and lumbar lordosis/thoracic kyphosis (LL/TK) were significantly increased in severe low back pain group, while SS and SFVD were significantly decreased, and no significant difference was found for pelvic incidence (PI) and TK. The statistical analysis showed that spondylolisthesis grade, PT, SC7D, LL, SFHD, PT/SS, SFHD/SFVD, and LL/TK had a significant positive correlation with Oswestry score, with an order of spondylolisthesis grade > PT/SS > SC7D > PT > SFHD/SFVD > SFHD > LL/TK > LL. No significant correlation was found for PI, TK, T9TA with Oswestry score, while SS and SFVD had a significant negative correlation with Oswestry score, with an order of SS > SFVD. CONCLUSIONS: The spinopelvic parameters (spondylolisthesis grade, SS, PT, SC7D, LL, SFVD, SFHD, PT/SS, SFHD/SFVD, LL/TK) are significantly correlated with clinical symptoms of severe isthmic spondylolisthesis in patients. The association of the exacerbation of low back pain with SS (correlation coefficient -0.981, strong) and SFVD (correlation coefficient -0.802, strong) is the most significant correlation. PMID- 24142044 TI - The characteristics of spinopelvic sagittal alignment in patients with lumbar disc degenerative diseases. AB - PURPOSE: A comparative study of the spinopelvic sagittal alignment in patients with lumbar disc degeneration or herniation (LDD/LDH) in normal population was designed to analyse the role of sagittal anatomical parameter (pelvic incidence, PI) and positional parameters in the pathogenesis and development of the disease. Several comparative studies of these patients with asymptomatic controls have been done. However, in previous studies without lumbar MRI, a certain number of asymptomatic LDD patients should have been included in the control group and then impacted on the results. METHODS: Based on MRI findings, we divided 60 LDD or LDH patients and 110 asymptomatic volunteers into the normal group (NG) and the degeneration group (DG), which was further subdivided into the symptomatic (SDG) and asymptomatic (ADG) subgroups according to patients' symptoms. Standing full spine radiographs were used to measure sagittal parameters, including PI, sacral slope (SS), pelvic tilt (PT), lumbar lordosis (LL), thoracic kyphosis (TK), sagittal vertical axis (SVA), and sacrum-bicoxofemoral distance (SFD). RESULTS: The PI, SS and LL in DG were significantly lower than NG, while the SVA and SFD were significantly greater (P < 0.05). PI correlated well with the SS and LL in all subjects. However, the trend lines of SS or LL over PI were downward in DG. PI was similar in SDG and ADG (P = 0.716) but SS and LL were significantly lower and SVA was significantly greater (P < 0.05). CONCLUSIONS: PI may play a predisposing role in the pathogenesis of lumbar disc degenerative diseases. The secondary structural and compensatory factors would lead to a straighter spine after disc degenerative change. PMID- 24142045 TI - A new Monte Carlo program for simulating light transport through Port Wine Stain skin. AB - A new Monte Carlo program is presented for simulating light transport through clinically normal skin and skin containing Port Wine Stain (PWS) vessels. The program consists of an eight-layer mathematical skin model constructed from optical coefficients described previously. A simulation including diffuse illumination at the surface and subsequent light transport through the model is carried out using a radiative transfer theory ray-tracing technique. Total reflectance values over 39 wavelengths are scored by the addition of simulated light returning to the surface within a specified region and surface reflections (calculated using Fresnel's equations). These reflectance values are compared to measurements from individual participants, and characteristics of the model are adjusted until adequate agreement is produced between simulated and measured skin reflectance curves. The absorption and scattering coefficients of the epidermis are adjusted through changes in the simulated concentrations and mean diameters of epidermal melanosomes to reproduce non-lesional skin colour. Pseudo cylindrical horizontal vessels are added to the skin model, and their simulated mean depths, diameters and number densities are adjusted to reproduce measured PWS skin colour. Accurate reproductions of colour measurement data are produced by the program, resulting in realistic predictions of melanin and PWS blood vessel parameters. Using a modest personal computer, the simulation currently requires an average of five and a half days to complete. PMID- 24142046 TI - Shear bond strength of metal brackets to feldspathic porcelain treated by Nd:YAG laser and hydrofluoric acid. AB - Adult orthodontic treatment requires bonding orthodontic attachment to dental restorations. Ceramics are commonly used as esthetic restorative materials for the crowns and bridges. The present study evaluated the shear bond strength of metal orthodontic brackets to the feldspathic porcelain surfaces following conditioning by different powers of neodymium-doped yttrium aluminum garnet (Nd:YAG) laser and hydrofluoric acid as a conventional method. Seventy-two glazed porcelain samples were prepared and randomly attributed to six equal groups of 12. In the conventional hydrofluoric (HF) group, the specimens were etched by 9.6% hydrofluoric acid for 4 min. In laser groups, samples were conditioned by 0.75-, 1-, 1.25-, 1.5-, and 2-W Nd:YAG laser for 10 s. Metal brackets were bonded to porcelain samples and after being stored in distilled water for 24 h, they were subjected to thermocycling for 500 cycles. The debonding was carried out by a Zwick testing machine. The data were statistically analyzed by ANOVA and Tamhane multiple comparisons tests. The mean +/- SD of the shear bond strength in the laser group 0.75, 1, 1.25, 1.5, and 2 W and HF group was 2.2 +/- 0.9, 4.2 +/- 1.1, 4.9 +/- 2.4, 7 +/- 1.7, 9.6 +/- 2.7, and 9.4 +/- 2.5, respectively. Together with the increased power of laser, the mean shear bond strength was increased continuously and no significant differences were found between the HF group and the laser groups with power of 1.5 or 2 W. Also, there was no significant difference between all test groups in ARI scores. There was no significant difference between bond strength of laser groups with power of 1.5 and 2 W and HF etched group. So, Nd:YAG laser with appropriate parameters can be used as an alternative method for porcelain etching. PMID- 24142047 TI - In vivo assessment of caries excavation with a fluorescence camera compared to direct bacteriological sampling and quantitative analysis using flow cytometry. AB - The aim of this study was to assess the performance of the fluorescence camera device VistaCam iX (VC) for the control of caries excavation compared to visual assessment and bacteriological evaluation. Twenty-three patients with 32 dentinal carious lesions were included in the study. The lesions were classified using the International Caries Detection and Assessment System. Fluorescence images were taken at the surface of each lesion using the VC before excavation (stage 1), during (stage 2) and after excavation (stage 3). At each stage, dentine samples were collected. All cavities were closed after excavation using permanent fillings. Bacteria were counted within each dentine sample using flow cytometry. Significant moderate correlation between the fluorescence readings and the bacteria count was found at stage 3 (Spearman correlation coefficient rs = 0.40, p = 0.027). Area under the ROC curve (AUC) was calculated for fluorescence readings and bacteria count using the clinical status at stage 3 as a reference. AUC was 0.954 for the VC readings and 0.797 for bacteria count. Using the median bacteria count at stage 3 as a reference, the AUC for the fluorescence readings was 0.753. The results indicate that the fluorescence camera appears to be a useful supplementary tool in assessing the endpoint of caries excavation with the advantage of enabling data to be digitally visualized and stored. When an experienced dental clinician determined the excavation endpoint, the performance with respect to remaining bacteria count was good. PMID- 24142048 TI - Effect of systematic ergonomic hazard identification and control implementation on musculoskeletal disorder and injury risk. AB - OBJECTIVES: This study aimed to examine the effect of an ergonomic hazard control (HC) initiative, undertaken as part of a company ergonomics standard, on worker injury risk. METHODS: Using the company's ergonomic hazards database to identify jobs with and without ergonomic HC implementation and linking to individual job and injury histories, injury risk among person-jobs with HC implementation (the HC group) was compared to those without HC (NoHC group) using random coefficient models. Further analysis of the HC group was conducted to determine the effect of additional ergonomic hazards controlled on injury risk. RESULTS: Among 123 jobs at 17 plant locations, 347 ergonomic hazards were quantitatively identified during the study period. HC were implemented for 204 quantified ergonomic hazards in 84 jobs, impacting 10 385 persons (12 967 person-jobs). No HC were implemented for quantified ergonomic hazards in the remaining 39 jobs affecting 4155 persons (5046 person-jobs). Adjusting for age, sex, plant origin, and year to control for any temporal trend in injury risk, the relative risk (RR) for musculoskeletal disorder (MSD) was 0.85 and the RR for any injury or MSD was 0.92 in the HC compared to NoHC group. Among the HC group, each ergonomic hazard controlled was associated with risk reduction for MSD and acute injury outcomes (RR 0.93). CONCLUSION: Systematic ergonomic HC through participatory ergonomics, as part of a mandatory company ergonomics standard, is associated with MSD and injury risk reduction among workers in jobs with HC implemented. PMID- 24142049 TI - Development and validation of a clinical cancer genomic profiling test based on massively parallel DNA sequencing. AB - As more clinically relevant cancer genes are identified, comprehensive diagnostic approaches are needed to match patients to therapies, raising the challenge of optimization and analytical validation of assays that interrogate millions of bases of cancer genomes altered by multiple mechanisms. Here we describe a test based on massively parallel DNA sequencing to characterize base substitutions, short insertions and deletions (indels), copy number alterations and selected fusions across 287 cancer-related genes from routine formalin-fixed and paraffin embedded (FFPE) clinical specimens. We implemented a practical validation strategy with reference samples of pooled cell lines that model key determinants of accuracy, including mutant allele frequency, indel length and amplitude of copy change. Test sensitivity achieved was 95-99% across alteration types, with high specificity (positive predictive value >99%). We confirmed accuracy using 249 FFPE cancer specimens characterized by established assays. Application of the test to 2,221 clinical cases revealed clinically actionable alterations in 76% of tumors, three times the number of actionable alterations detected by current diagnostic tests. PMID- 24142050 TI - Engineering dynamic pathway regulation using stress-response promoters. AB - Heterologous pathways used in metabolic engineering may produce intermediates toxic to the cell. Dynamic control of pathway enzymes could prevent the accumulation of these metabolites, but such a strategy requires sensors, which are largely unknown, that can detect and respond to the metabolite. Here we applied whole-genome transcript arrays to identify promoters that respond to the accumulation of toxic intermediates, and then used these promoters to control accumulation of the intermediate and improve the final titers of a desired product. We apply this approach to regulate farnesyl pyrophosphate (FPP) production in the isoprenoid biosynthetic pathway in Escherichia coli. This strategy improved production of amorphadiene, the final product, by twofold over that from inducible or constitutive promoters, eliminated the need for expensive inducers, reduced acetate accumulation and improved growth. We extended this approach to another toxic intermediate to demonstrate the broad utility of identifying novel sensor-regulator systems for dynamic regulation. PMID- 24142052 TI - Surgical management of pelvic organ prolapse: articles from the ICUD book. PMID- 24142053 TI - ICI 2012: pelvic organ prolapse surgery. PMID- 24142051 TI - Reassessing target antigens for adoptive T-cell therapy. AB - Adoptive T-cell therapy can target and kill widespread malignant cells thereby inducing durable clinical responses in melanoma and selected other malignances. However, many commonly targeted tumor antigens are also expressed by healthy tissues, and T cells do not distinguish between benign and malignant tissues if both express the target antigen. Autoimmune toxicity from T cell-mediated destruction of normal tissue has limited the development and adoption of this otherwise promising type of cancer therapy. A review of the unique biology of T cell therapy and of recent clinical experience compels a reassessment of target antigens that traditionally have been viewed from the perspective of weaker immunotherapeutic modalities. It is important that target antigens chosen for adoptive T-cell therapy are expressed by tumors and not by essential healthy tissues. The risk of adverse autoimmune events can be further mitigated by generating antigen receptors using strategies that reduce the chance of cross reactivity against epitopes in unintended targets. In general, a circumspect approach to target selection and thoughtful preclinical and clinical studies are pivotal to the ongoing advancement of these promising treatments. PMID- 24142054 TI - Epidemiology and outcome assessment of pelvic organ prolapse. AB - INTRODUCTION AND HYPOTHESIS: The aim was to determine the incidence and prevalence of pelvic organ prolapse surgery and describe how outcomes are reported. METHODS: Every 4 years and as part of the Fifth International Collaboration on Incontinence we reviewed the English-language scientific literature after searching PubMed, Medline, Cochrane library and Cochrane database of systematic reviews, published up to January 2012. Publications were classified as level 1 evidence (randomised controlled trials [RCT] or systematic reviews, level 2 (poor quality RCT, prospective cohort studies), level 3 (case series or retrospective studies) and level 4 (case reports). The highest level of evidence was utilised by the committee to make evidence-based recommendations based upon the Oxford grading system. A grade A recommendation usually depends on consistent level 1 evidence. A grade B recommendation usually depends on consistent level 2 and/or 3 studies, or "majority evidence" from RCTs. A grade C recommendation usually depends on level 4 studies or "majority evidence" from level 2/3 studies or Delphi processed expert opinion. A grade D "no recommendation possible" would be used where the evidence is inadequate or conflicting and when expert opinion is delivered without a formal analytical process, such as by Delphi . RESULTS: Pelvic organ prolapse (POP) when defined by symptoms has a prevalence of 3-6% and up to 50% when based upon vaginal examination. Surgery for prolapse is performed twice as commonly as continence surgery and prevalence varies widely from 6 to 18%. The incidence of POP surgery ranges from 1.5 to 1.8 per 1,000 women years and peaks in women aged 60-69. When reporting outcomes of the surgical management of prolapse, authors should include a variety of standardised anatomical and functional outcomes. Anatomical outcomes reported should include all POP-Q points and staging, utilising a traditional definition of success with the hymen as the threshold for success. Assessment should be prospective and assessors blinded as to the surgical intervention performed if possible and without any conflict of interest related to the assessment undertaken (grade C). Subjective success postoperatively should be defined as the absence of a vaginal bulge (grade C). Functional outcomes are best reported using valid, reliable and responsive symptom questionnaires and condition-specific HRQOL instruments (grade C). Sexual function is best reported utilising validated condition-specific HRQOL that assess sexual function or validated sexual function questionnaires such as the Pelvic Organ Prolapse/Incontinence Sexual Questionnaire (PISQ) or the Female Sexual Function Index (FSFI). The sexual activity status of all study participants should be reported pre- and postoperatively under the following categories: sexually active without pain, sexually active with pain or not sexually active (grade C). Prolapse surgery should be defined as primary surgery, and repeat surgery sub classified as primary surgery different site, repeat surgery, complications related to surgery and surgery for non-prolapse-related conditions (grade C). CONCLUSION: Significant variation exists in the prevalence and incidence of pelvic organ prolapse surgery and how the outcomes are reported. Much of the variation may be improved by standardisation of definitions and outcomes of reporting on pelvic organ prolapse surgery. PMID- 24142055 TI - Anterior vaginal compartment surgery. AB - AIM: To review the safety and efficacy of anterior vaginal compartment pelvic organ prolapse surgery. METHODS: Every 4 years and as part of the Fifth International Collaboration on Incontinence we reviewed the English-language scientific literature after searching PubMed, Medline, Cochrane library and the Cochrane database of systematic reviews, published up to January 2012. Publications were classified as level 1 evidence (randomised controlled trials [RCT] or systematic reviews), level 2 (poor quality RCT, prospective cohort studies), level 3 (case series or retrospective studies) and level 4 case reports. The highest level of evidence was utilised by the committee to make evidence-based recommendations based upon the Oxford grading system. A grade A recommendation usually depends on consistent level 1 evidence. A grade B recommendation usually depends on consistent level 2 and/or 3 studies, or "majority evidence" from RCTs. A grade C recommendation usually depends on level studies or "majority evidence" from level 2/3 studies or Delphi processed expert opinion. A grade D "no recommendation possible" would be used where the evidence is inadequate or conflicting and when expert opinion is delivered without a formal analytical process, such as by Delphi. RESULTS: Absorbable mesh augmentation of anterior compartment native tissue repair improves the anatomical outcome compared with native tissue repair alone with no increased complication rate in meta-analysis of 2 RCTS (grade B). Biological grafts in meta-analysis have improved anatomical outcomes with no change in subjective outcomes compared with native tissue repairs (grade B). There is conflicting level 1 evidence to support porcine dermis and a single RCT to support small intestine submucosa as graft agents in anterior compartment prolapse surgery (grade B). Consistent level 1 data support a superior anatomical outcome for polypropylene mesh compared with a biological graft in the anterior compartment. Mesh exposure rate was significantly higher in the polypropylene mesh group (grade A). Consistent level 1 evidence demonstrates superior subjective and objective outcomes following anterior transvaginal polypropylene mesh as compared to anterior colporrhaphy (grade A). These outcomes did not translate into improved functional results using validated questionnaires or a lower reoperation rate for prolapse. The mesh group was also associated with longer operating time, greater blood loss and apical or posterior compartment prolapse as compared with anterior repair. Anterior polypropylene mesh had a mesh extrusion rate of 10.4% with 6.3% requiring a surgical correction (grade B). Single level 3 evidence does not support the use of transvaginal polypropylene mesh for recurrent anterior vaginal wall prolapse (grade C). CONCLUSION: Polypropylene anterior compartment mesh offers improved objective and subjective outcomes compared with native tissue repair; however, these benefits must be considered in the context of increased morbidity associated with anterior polypropylene transvaginal mesh. PMID- 24142056 TI - Uterine-preserving POP surgery. AB - INTRODUCTION AND HYPOTHESIS: To review the safety and efficacy of uterine preservation surgery. METHODS: Every four years and as part of the Fifth International Collaboration on Incontinence we reviewed the English-language scientific literature after searching PubMed, Medline, Cochrane library and Cochrane database of systematic reviews, published up to January 2012. Publications were classified as level 1 evidence (randomised controlled trials [RCT] or systematic reviews), level 2 (poor quality RCT, prospective cohort studies), level 3 (case series or retrospective studies) and level 4 case reports. The highest level of evidence was utilised by the committee to make evidence-based recommendations based upon the Oxford grading system. Grade A recommendation usually depends on consistent level 1 evidence. Grade B recommendation usually depends on consistent level 2 and/or 3 studies, or "majority evidence" from RCTs. Grade C recommendation usually depends on level 4 studies or "majority evidence" from level 2/3 studies or Delphi processed expert opinion. Grade D "no recommendation possible" would be used where the evidence is inadequate or conflicting and when expert opinion is delivered without a formal analytical process, such as by Delphi. RESULTS: A wide variety of surgical options remain for women presenting with uterine prolapse without contraindications to uterine preservation. However, long-term data are limited and the need for subsequent hysterectomy unknown (grade C). Sacrospinous hysteropexy is as effective as vaginal hysterectomy and repair in retrospective comparative studies and in a meta-analysis with reduced operating time, blood loss and recovery time. However, in a single RCT there was a higher recurrence rate associated with sacrospinous hysteropexy compared with vaginal hysterectomy (grade D). Severe prolapse increases the risk of recurrent prolapse after sacrospinous hysteropexy. In consistent level 2 evidence sacrospinous hysteropexy with mesh augmentation of the anterior compartment was as effective as hysterectomy and mesh augmentation with no significant difference in the rate of mesh exposure between the groups (grade B). Level 1 evidence from a single RCT suggests that vaginal hysterectomy and uterosacral suspension were superior to sacral hysteropexy based on reoperation rates, despite similar anatomical and symptomatic improvement (grade C). Consistent level 2 and 3 evidence suggests that sacral hysteropexy (open or laparoscopic) was as effective as sacral colpopexy and hysterectomy in anatomical outcomes; however, the sacral colpopexy and hysterectomy were associated with a five times higher rate of mesh exposure compared with sacral hysteropexy (grade B). Performing hysterectomy at sacral colpopexy was associated with a four times higher risk of mesh exposure compared with sacral colpopexy without hysterectomy (grade B). CONCLUSION: While uterine preservation is a viable option for the surgical management of uterine prolapse the evidence on safety and efficacy is currently lacking. PMID- 24142058 TI - Surgery for posterior vaginal wall prolapse. AB - INTRODUCTION AND HYPOTHESIS: The aim was to review the safety and efficacy of surgery for posterior vaginal wall prolapse. METHODS: Every 4 years and as part of the Fifth International Collaboration on Incontinence we reviewed the English language scientific literature after searching PubMed, Medline, Cochrane library and Cochrane database of systematic reviews, published up to January 2012. Publications were classified as level 1 evidence (randomised controlled trials [RCT] or systematic reviews), level 2 (poor quality RCT, prospective cohort studies), level 3 (case series or retrospective studies) and level 4 (case reports). The highest level of evidence was utilised by the committee to make evidence-based recommendations based upon the Oxford grading system. Grade A recommendation usually depends on consistent level 1 evidence. Grade B recommendation usually depends on consistent level 2 and/or 3 studies, or "majority evidence" from RCTs. Grade C recommendation usually depends on level 4 studies or "majority evidence from level 2/3 studies or Delphi processed expert opinion. Grade D "no recommendation possible" would be used where the evidence is inadequate or conflicting and when expert opinion is delivered without a formal analytical process, such as by Delphi. RESULTS: Level 1 and 2 evidence suggest that midline plication posterior repair without levatorplasty might have superior objective outcomes compared with site-specific posterior reopair (grade B). Higher dyspareunia rates are reported when levatorplasty is employed (grade C). The transvaginal approach is superior to the transanal approach for repair of posterior wall prolapse (grade A). To date, no studies have shown any benefit of mesh overlay or augmentation of a suture repair for posterior vaginal wall prolapse (grade B). While modified abdominal sacrocolpopexy results have been reported, data on how these results would compare with traditional transvaginal repair of posterior vaginal wall prolapse are lacking. CONCLUSION: Midline fascial plication without levatorplasty is the procedure of choice for posterior compartment prolapse. No evidence supports the use of polypropylene mesh or biological graft in posterior vaginal compartment prolapse surgery. PMID- 24142057 TI - Apical prolapse. AB - INTRODUCTION AND HYPOTHESIS: The aim was to review the safety and efficacy of pelvic organ prolapse surgery for vaginal apical prolapse. METHODS: Every 4 years and as part of the Fifth International Collaboration on Incontinence we reviewed the English-language scientific literature after searching PubMed, Medline, Cochrane library and Cochrane database of systematic reviews, published up to January 2012. Publications were classified as level 1 evidence (randomised controlled trials (RCT) or systematic reviews), level 2 (poor quality RCT, prospective cohort studies), level 3 (case series or retrospective studies) and level 4 case reports. The highest level of evidence was utilised by the committee to make evidence-based recommendations based upon the Oxford grading system. Grade A recommendation usually depends on consistent level 1 evidence. Grade B recommendation usually depends on consistent level 2 and or 3 studies, or "majority evidence" from RCTs. Grade C recommendation usually depends on level 4 studies or "majority evidence from level 2/3 studies or Delphi processed expert opinion. Grade D "no recommendation possible" would be used where the evidence is inadequate or conflicting and when expert opinion is delivered without a formal analytical process, such as by Delphi. RESULTS: Abdominal sacral colpopexy (ASC) has a higher success rate than sacrospinous colpopexy with less SUI and postoperative dyspareunia for vault prolapse. ASC had greater morbidity including operating time, inpatient stay, slower return to activities of daily living and higher cost (grade A). ASC has the lowest inpatient costs compared with laparoscopic sacral colpopexy (LSC) and robotic sacral colpopexy (RSC). LSC has lower inpatient costs than RSC (grade B).In single RCTs the RSC had longer operating time than both ASC and LSC (grade B). In small trials objective outcomes appear similar although postoperative pain was greater in RSC. LSC is as effective as ASC with reduced blood loss and admission time (grade C). The data relating to operating time are conflicting. ASC performed with polypropylene mesh has superior outcomes to fascia lata (level I), porcine dermis and small intestine submucosa (level 3; grade B). In a single RCT, LSC had a superior objective and subjective success rate and lower reoperation rate compared with polypropylene transvaginal mesh for vault prolapse (grade B).Level 3 evidence suggests that vaginal uterosacral ligament suspension, McCall culdoplasty, iliococcygeus fixation and colpocleisis are relatively safe and effective interventions (grade C). CONCLUSION: Sacral colpopexy is an effective procedure for vault prolapse and further data are required on the route of performance and efficacy of this surgery for uterine prolapse. Polypropylene mesh is the preferred graft at ASC. Vaginal procedures for vault prolapse are well described and are suitable alternatives for those not suitable for sacral colpopexy. PMID- 24142059 TI - Pelvic organ prolapse surgery and bladder function. AB - INTRODUCTION AND HYPOTHESIS: The aim was to determine the impact of pelvic organ prolapse surgery on bladder function. METHODS: Every 4 years, and as part of the Fifth International Collaboration on Incontinence we reviewed the English langauage scientific literature after searching PubMed, Medline, Cochrane library and Cochrane database of systematic reviews, published up to January 2012. Publications were classified as level 1 evidence (randomised controlled trials [RCT] or systematic reviews), level 2 (poor quality RCT, prospective cohort studies), level 3 (case series or retrospective studies and level 4 case reports. The highest level of evidence was utilised by the committee to make evidence based recommendations based upon the Oxford grading system. Grade A recommendation usually depends on consistent level 1 evidence. Grade B recommendation usually depends on consistent level 2 and/or 3 studies, or "majority evidence" from RCTs. Grade C recommendation usually depends on level 4 studies or "majority evidence" from level 2/3 studies or Delphi processed expert opinion. Grade D "no recommendation possible" would be used where the evidence is inadequate or conflicting and when expert opinion is delivered without a formal analytical process, such as by Delphi. RESULTS: Continent women undergoing anterior compartment prolapse surgery have a lower rate of de novo stress urinary incontinence (SUI) after anterior repair than armed mesh procedures (grade A). Data are conflicting on whether colposuspension should be performed prophylactically in continent women undergoing sacral colpopexy (grade C). No clear conclusion can be made regarding the management of continent women undergoing prolapse surgery without occult SUI. In continent women undergoing POP surgery with occult SUI the addition of continence surgery reduces the rate of postoperative SUI (grade A). In women with prolapse and SUI symptoms prolapse procedures alone (transobturator mesh and anterior repair) are associated with low success rates for SUI. Concomitant continence procedures reduce the risk of postoperative SUI (grade B). Preoperative bladder overactivity may resolve in 40% undergoing POP surgery and de novo bladder overactivity occurs in 12%. No valid conclusions regarding voiding dysfunction following POP surgery can be drawn from the available data. CONCLUSION: SUI and occult stress urinary incontinence should be treated at the time of prolapse surgery. PMID- 24142060 TI - Pelvic organ prolapse and sexual function. AB - INTRODUCTION AND HYPOTHESIS: The aim was to review the impact of pelvic organ prolapse surgery on sexual function. METHODS: Every 4 years and as part of the Fifth International Collaboration on Incontinence we reviewed the English language scientific literature after searching PubMed, Medline, Cochrane library and Cochrane database of systematic reviews, published up to January 2012. Publications were classified as level 1 evidence (randomised controlled trials [RCT] systematic reviews), level 2 (poor quality RCT, prospective cohort studies), level 3 (case series or retrospective studies) and level 4 (case reports). The highest level of evidence was utilised by the committee to make evidence based recommendations based upon the Oxford grading system. Grade A recommendation usually depends on consistent level 1 evidence. Grade B recommendation usually depends on consistent level 2 and/or 3 studies, or "majority evidence" from RCTs. Grade C recommendation usually depends on level 4 studies or "majority evidence" from level 2/3 studies or Delphi process expert opinion. Grade D "no recommendation possible" would be used where the evidence is inadequate or conflicting and when expert opinion is delivered without formal analytical process, such as by Delphi. RESULTS: With regard to the anterior compartment, the use of mesh is associated with neither a worsening in sexual function nor an increase in de novo dyspareunia compared with traditional anterior colporrhaphy (grade B). There is insufficient information to provide evidence-based recommendations on sexual function after vaginal mesh in the posterior compartment or after new lightweight or absorbable meshes (grade D). CONCLUSION: There is a paucity of data on the impact of prolapse surgery on sexual function. Sexual function and dyspareunia rates are similar after anterior polypropylene mesh and anterior colporrhaphy (grade B). We recommend using validated questionnaires measuring sexual function in women before and after prolapse surgery and reporting sexual activity and dyspareunia rates pre- and post-intervention in all patients. PMID- 24142062 TI - Economics of pelvic organ prolapse surgery. AB - INTRODUCTION AND HYPOTHESIS: The aim was to review the economic costs associated with pelvic organ prolapse surgery. METHODS: Every 4 years and as part of the Fifth International Collaboration on Incontinence we reviewed the English language scientific literature after searching PubMed, Medline, Cochrane library and Cochrane database of systematic reviews, published up to January 2012. Publications were classified as level 1 evidence (randomised controlled trials [RCT] or systematic reviews), level 2 (poor quality RCT, prospective cohort studies), level 3 (case series or retrospective studies) and level 4 (case reports). The highest level of evidence was utilised by the committee to make evidence based recommendations based upon the Oxford grading system. Grade A recommendation usually depends on consistent level 1 evidence. Grade B recommendation usually depends on consistent level 2 and/or 3 studies, or "majority evidence" from RCTs. Grade C recommendation usually depends on level 4 studies or "majority evidence" from level 2/3 studies or Delphi processed expert opinion. Grade D "no recommendation possible" would be used where the evidence is inadequate or conflicting and when expert opinion is delivered without a formal analytical process, such as by Delphi. RESULTS: The annual economic costs of pelvic organ prolapse surgeries are significant and over the next decades will grow at twice the rate of population growth because of our aging population. In a single institution study vaginal reconstructive surgery and pessary use were more cost-effective than expectant management, traditional abdominal sacral colpopexy (ASC) or robot-assisted sacral colpopexy (RSC; grade C). Two studies have demonstrated that ASC incurs lower inpatient costs than LSC or RSC (grade C). Data from a single RCT demonstrated the LSC to incur lower inpatient costs than RSC specifically relating to shorter operating times in the LSC group (grade B). Data from a single RCT demonstrated LSC to be a more effective cost-minimising surgery than total vaginal mesh for vaginal vault prolapse (grade B). Data from a meta-analysis of anterior vaginal compartment prolapse operations demonstrated that commercial mesh kits for anterior repair are less cost-effective than non kit mesh and anterior colporrhaphy (grade B). CONCLUSIONS: There is a paucity of good economic data relating to pelvic organ prolapse surgery. Transvaginal mesh surgeries have not been proven to be cost-effective. It is recommended that all randomised controlled trials relating to prolapse surgery include a formal cost analysis. PMID- 24142061 TI - Complications of pelvic organ prolapse surgery and methods of prevention. AB - INTRODUCTION AND HYPOTHESIS: The aim was to review complications associated with pelvic organ prolapse surgery. METHODS: Every 4 years and as part of the Fifth International Collaboration on Incontinence we reviewed the English-language scientific literature after searching PubMed, Medline, Cochrane library and Cochrane database of systematic reviews, published up to January 2012. Publications were classified as level 1 evidence (randomised controlled trials [RCT] or systematic reviews), level 2 (poor quality RCT, prospective cohort studies), level 3 (case series or retrospective studies) and level 4 (case reports). The highest level of evidence was utilised by the committee to make evidence-based recommendations based upon the Oxford grading system. Grade A recommendation usually depends on consistent level 1 evidence. Grade B recommendation usually depends on consistent level 2 and/or 3 studies, or "majority evidence" from RCTs. Grade C recommendation usually depends on level 4 studies or "majority evidence from level 2/3 studies or Delphi processed expert opinion. Grade D "no recommendation possible" would be used where the evidence is inadequate or conflicting and when expert opinion is delivered without a formal analytical process, such as by Delphi. RESULTS AND CONCLUSIONS: Transvaginal mesh has a higher re-operation rate than native tissue vaginal repairs (grade A). If a synthetic mesh is placed via the vaginal route, it is recommended that a macroporous polypropylene monofilament mesh should be used. At sacral colpopexy mesh should not be introduced or sutured via the vaginal route and silicone coated polyester, porcine dermis, fascia lata and polytetrafluoroethylene meshes are not recommended as grafts. Hysterectomy should also be avoided (grade B). There is no evidence to recommend routine local or systemic oestrogen therapy before or after prolapse surgery using mesh. The first cases should be undertaken with the guidance of an experienced surgeon in the relevant technique (grade C). Expert opinion suggests that by whatever the surgical route pre-operative urinary tract infections are treated, smoking is ceased and antibiotic prophylaxis is undertaken. It is recommended that a non-absorbable synthetic mesh should not be inserted into the rectovaginal septum when a rectal injury occurs. The placement of a non-absorbable synthetic mesh into the vesicovaginal septum may be considered after a bladder injury has been repaired, if the repair is considered to be satisfactory. It is possible to perform a hysterectomy in association with the introduction of a non-absorbable synthetic mesh inserted vaginally, but this is not recommended routinely. PMID- 24142064 TI - Pharmacokinetics of ethanol in the maternal-fetal unit. AB - Due to its wide range of deleterious effects on the unborn baby, knowledge on the disposition of ethanol in the maternal-fetal unit is critical. This review summarizes and updates the existing evidence on ethanol disposition in the mother, the placenta and the fetus, and relates them to their potential fetal effects. PMID- 24142063 TI - Capsaicin induces apoptosis in MG63 human osteosarcoma cells via the caspase cascade and the antioxidant enzyme system. AB - Osteosarcoma is the most common malignant bone tumor in children and adolescents. This aggressive cancer mostly occurs in the long bones. Therefore, novel therapeutic approaches, such as biological therapies and gene therapy, are required to efficiently treat osteosarcoma. Capsaicin (trans-8-methyl-N-vanillyl 6-nonenamide) has been demonstrated to inhibit the growth of several types of cancer cells and a number of studies have shown that osteosarcoma may be vulnerable to biological therapies. However, little is known regarding the therapeutic effects of capsaicin on osteosarcoma. This study investigated the effects of capsaicin on MG63 human osteosarcoma cells, in addition to elucidating the regulatory signaling pathways underlying the effects of capsaicin, the caspase cascade and the antioxidant enzyme system. The MG63 cell line was treated with various concentrations of capsaicin. Cells were analyzed using MTT and flow cytometry, and the presence of DNA fragmentation was evaluated using TUNEL assay. Results showed capsaicin induced apoptosis in MG63 cells. Thus, capsaicin exhibited an anticancer effect in osteosarcoma cells. PMID- 24142065 TI - Common polymorphism (81Val>Ile) and rare mutations (257Arg>Ser and 335Ile>Ser) of the MC3R gene in obese Polish children and adolescents. AB - The predisposing role to human obesity of the MC3R gene polymorphism is controversial. In this report we present the first study focused on the search for the MC3R polymorphism in the Polish population. Altogether 257 obese children and adolescents (RBMI>120) and 94 adults, who were never obese or overweight (BMI<25), were studied. For all subjects the entire coding sequence was analyzed by direct DNA sequencing. One common polymorphism (81Val>Ile) and two rare mutations (257Arg>Ser and 335Ile>Ser) were identified. The common polymorphism was widely distributed in the obese and control cohorts, while the mutations were identified in four obese subjects only. In case of the 335Ile>Ser substitution a three-generation family, consisting of 20 members, was also analyzed. It was found that all carriers of the 335Ser mutation were obese, but among non-carriers obese subjects also were found. Our study suggests that the predisposing effect to obesity of the 81Ile polymorphic variant is rather unlikely. With regard to the studied rare mutations we suggest that the 335Ser allele may have a small predisposing effect. PMID- 24142066 TI - LPS-induced systemic inflammation is more severe in P2Y12 null mice. AB - Thienopyridines are a class of antiplatelet drugs that are metabolized in the liver to several metabolites, of which only one active metabolite can irreversibly antagonize the platelet P2Y12 receptor. Possible effects of these drugs and the role of activated platelets in inflammatory responses have also been investigated in a variety of animal models, demonstrating that thienopyridines could alter inflammation. However, it is not clear whether it is caused only by the P2Y12 antagonism or whether off-target effects of other metabolites also intervene. To address this question, we investigated P2Y12 KO mice during a LPS-induced model of systemic inflammation, and we treated these KO mice with a thienopyridine drug (clopidogrel). Contrary to the reported effects of clopidogrel, numbers of circulating WBCs and plasma levels of cytokines were increased in LPS-exposed KO mice compared with WT in this inflammation model. Moreover, both spleen and bone marrow show an increase in cell content, suggesting a role for P2Y12 in regulation of bone marrow and spleen cellular composition. Finally, the injury was more severe in the lungs of KO mice compared with WT. Interestingly, clopidogrel treatments also exerted protective effects in KO mice, suggesting off-target effects for this drug. In conclusion, the P2Y12 receptor plays an important role during LPS-induced inflammation, and this signaling pathway may be involved in regulating cell content in spleen and bone marrow during LPS systemic inflammation. Furthermore, clopidogrel may have effects that are independent of P2Y12 receptor blockade. PMID- 24142067 TI - Hyperglycemia, acute insulin resistance, and renal dysfunction in the early phase of ST-elevation myocardial infarction without previously known diabetes: impact on long-term prognosis. AB - We evaluated the relationship between admission renal function (as assessed by estimated glomerular filtration rate (eGFR)), hyperglycemia, and acute insulin resistance, indicated by the homeostatic model assessment (HOMA) index, and their impact on long-term prognosis in 825 consecutive patients with ST-elevation myocardial infarction (STEMI) without previously known diabetes who underwent primary percutaneous coronary intervention (PCI). Admission eGFR showed a significant indirect correlation with admission glycemia (Spearman's rho -0.23, P < 0.001) and insulin values (Spearman's rho -0.11, P = 0.002). The incidence of patients with admission glycemia >=140 mg/dl was significantly higher in patients with eGFR <60 ml/min/m(2) (P < 0.001) as well as the incidence of HOMA positivity (P = 0.002). According to our data, a relationship between renal function and glucose values and acute insulin resistance in the early phase of STEMI was detectable, since a significant, indirect correlation between eGFR, insulin values, and glycemia was observed. Patients with renal dysfunction (eGFR <60 ml/min/1.73 m(2)) exhibited higher glucose values and a higher incidence of acute insulin resistance (as assessed by HOMA index) than those with normal renal function (eGFR >=60 ml/min/1.73 m(2)). The prognostic role of glucose values for 1-year mortality was confined to patients with eGFR >=60 ml/min/m(2), who represent the large part of our population and are thought to be at lower risk. In these patients, an independent relationship between 1-year mortality and glucose values was detectable not only for admission glycemia but also for glucose values measured at discharge. PMID- 24142068 TI - Prognostic impact of lipid contents on the target lesion in patients with drug eluting stent implantation. AB - We sought to determine the morphologic predictors of major adverse cardiac events (MACEs) after successful percutaneous coronary intervention (PCI) with drug eluting stents (DES), using integrated backscatter intravascular ultrasound (IB IVUS). Conventional IVUS and IB-IVUS were performed in 260 consecutive patients who underwent PCI with DES. Three-dimensional analyses were performed to determine plaque volume and the volume of each plaque component (lipid, fibrous, and calcification). Patients were divided into two groups according to the median lipid volume (LV) in the target lesion. MACEs were defined as death, nonfatal myocardial infarction, and any repeat revascularization. The median follow-up interval was 1285 days. MACEs were observed in 64 patients (24.6 %). Patients having a larger LV compared with their counterparts had worse long-term clinical outcomes regarding mortality (3.8 vs. 0 %, P = 0.02) and MACEs (31.5 vs. 17.7 %, P = 0.008) by log-rank test. After adjustment for confounders, large LV (odds ratio 1.95, 95 % confidence interval 1.14-3.33, P = 0.02) was significantly and independently associated with MACEs. The assessment of coronary plaque characteristics in the target lesion may be useful to predict long-term outcome following successful coronary intervention. PMID- 24142070 TI - Risk factors for complications of percutaneous endoscopic gastrostomy. AB - BACKGROUND: Percutaneous endoscopic gastrostomy (PEG) is a commonly performed procedure for patients with severe dysphagia leading to malnutrition. Improved knowledge of risk factors for PEG-related complications might decrease patient discomfort and healthcare costs. AIM: The aim of the present study was to investigate factors associated with complications after PEG. METHODS: A retrospective review was performed for all patients referred for PEG placement from December 2002 to December 2012 in single-tertiary care center. PEG-related complications and risk factors were evaluated through chart reviews, endoscopic reports, and endoscopic and radiologic images. RESULTS: Among a total of 245 consecutive individuals (146 male, mean age 59.2 +/- 12.6 years) enrolled, 43 major complications had developed. Multivariate analysis revealed that patients with an internal bolster of a PEG tube in the upper body of stomach were at significant risk for early [OR 6.127 (95 % CI 1.447-26.046)] and late complications [OR 6.710 (95 % CI 1.692-26.603)]. Abnormal leukocyte counts [OR 3.198 (95 % CI 1.174-8.716)], stroke as an indication for PEG [OR 3.047 (95 % CI 1.174-8.882)], and PEG tube placement by an inexperienced endoscopist [OR 3.401 (95 % CI 1.073-10.779)] were significantly associated with early complications. CONCLUSIONS: A PEG tube should not be inserted into the upper body of stomach to reduce complication risk, and PEG procedures should be performed by skilled endoscopists to prevent early complications. An abnormal leukocyte count can be a predictor of early complication, and care is needed when PEG is performed for patients with stroke. PMID- 24142071 TI - Synthesis and characterization of a novel o-tolyltelluronic trimethyltin ester and its cytotoxic assessment in vitro. AB - A new arenetelluronic triorganotin ester, namely (Me3Sn)4[o-Me-PhTe(MU O)(OH)O2)]2 (1) has been prepared by the reaction of o-tolyltelluronic acid and Me3SnCl in the presence of potassium hydroxide. The complex was fully characterized by elemental analysis, FT-IR, NMR ((1)H, (13)C, (119)Sn) spectroscopy and X-ray crystallography. Structure analysis revealed that the complex crystallized as Sn4Te2 units and a 1D linear chain was formed by intermolecular C-HO interactions. Cytotoxic assessments showed that the complex can induce apoptotic cell death via accumulation of ROS, collapse of the MMP and activating caspase-3. The results indicated that ROS is crucial to the cytotoxicity induced by the complex. PMID- 24142073 TI - Wound care does dermatology's job. PMID- 24142069 TI - New perspectives in cyclic nucleotide-mediated functions in the CNS: the emerging role of cyclic nucleotide-gated (CNG) channels. AB - Cyclic nucleotides play fundamental roles in the central nervous system (CNS) under both physiological and pathological conditions. The impact of cAMP and cGMP signaling on neuronal and glial cell functions has been thoroughly characterized. Most of their effects have been related to cyclic nucleotide-dependent protein kinase activity. However, cyclic nucleotide-gated (CNG) channels, first described as key mediators of sensory transduction in retinal and olfactory receptors, have been receiving increasing attention as possible targets of cyclic nucleotides in the CNS. In the last 15 years, consistent evidence has emerged for their expression in neurons and astrocytes of the rodent brain. Far less is known, however, about the functional role of CNG channels in these cells, although several of their features, such as Ca(2+) permeability and prolonged activation in the presence of cyclic nucleotides, make them ideal candidates for mediators of physiological functions in the CNS. Here, we review literature suggesting the involvement of CNG channels in a number of CNS cellular functions (e.g., regulation of membrane potential, neuronal excitability, and neurotransmitter release) as well as in more complex phenomena, like brain plasticity, adult neurogenesis, and pain sensitivity. The emerging picture is that functional and dysfunctional cyclic nucleotide signaling in the CNS has to be reconsidered including CNG channels among possible targets. However, concerted efforts and multidisciplinary approaches are still needed to get more in-depth knowledge in this field. PMID- 24142072 TI - The relationships between obsessive-compulsive symptom dimensions and cognitions in obsessive-compulsive disorder. AB - Several studies have linked obsessive-compulsive symptoms to specific obsessive compulsive cognitions, however methodologies have varied, and no study has determined obsessive-compulsive symptoms using the most widely used clinician rating scale, the Yale-Brown Obsessive-Compulsive Scale (Y-BOCS). Considering that almost all studies that used factor analysis to ascertain OCD symptom dimensions were based on the Y-BOCS and that self-report instruments assessing obsessive-compulsive symptoms correlate poorly with the Y-BOCS, there is a need to use the Y-BOCS to examine the relationship between obsessive-compulsive cognitions and obsessive-compulsive symptom dimensions. This study examined the relationship between five Y-BOCS-derived obsessive-compulsive symptom dimensions and the three obsessive-compulsive cognitive domains identified by the obsessive beliefs questionnaire (OBQ). The symmetry/ordering symptom dimension was associated with increased perfectionism/intolerance of uncertainty, the unacceptable/taboo thoughts symptom dimension was associated with increased importance/control of thoughts and the doubt/checking symptom dimension was associated with increased responsibility/threat estimation. There was no statistical evidence of an association between any OBQ belief sub-scale and the hoarding symptom dimension nor the contamination/cleaning symptom dimension. The findings encourage symptom-based approaches to cognitive-behavioural therapy for some OCD symptoms and call for further research on cognitions associated with contamination/cleaning symptoms and hoarding. PMID- 24142074 TI - Electrical stimulation as adjuvant treatment for chronic leg ulcers of different aetiology: an RCT. AB - OBJECTIVE: To investigate the effectiveness of an innovative electrical stimulation (ES) therapy as adjuvant treatment for chronic wounds of various aetiology, in terms of pain and ulcer healing. METHOD: Patients with chronic limb ulcers were enrolled for the study and randomised into the intervention or control group. The intervention group received conventional treatment plus ES therapy (FREMS; Lorenz Lifetech) while the control group received only conventional treatment. Each ES treatment cycle consisted of 12 sessions performed in 4 weeks (three sessions/week). All patients were treated until full wound healing occurred, or for a maximum of 9 ES cycles, with a 2-week rest between each cycle. RESULTS: A total of 60 patients were enrolled in the study and randomised into the two groups: the intervention group (n=30) and the control group (n=30). During follow-up, some patients terminated the protocol because they reached the ulcer closure before the maximum of 9 cycles. The analysis of the effect of ES on pain and ulcer healing was performed on all patients who underwent at least two consecutive clinical evaluations (two cycles), in order to reach a compatible sample size with the primary objective (one patient withdrew). In both groups, there was a significant reduction of pain compared with baseline (p < 0.05), starting from T6 visit in the first cycle. In particular, there was a significant reduction of pain in the intervention group compared with the control group after 14 days, and this reduction continued until the end of the second cycle. Similarly, there was a significant reduction of PUSH tool score in the intervention group compared with the control group after 14 days, and this reduction continued until the end of the second cycle. CONCLUSION: Data collected in this study support data in the literature. Analysis of longitudinal data analysed by simple models and complex models suggest that the ES therapy had a positive and significant effect on pain reduction (VAS) and on the improvement of ulcer healing process in terms of the PUSH tool total index compared with conventional treatment, and may have induced a significant acceleration of the wound-healing process. PMID- 24142075 TI - Nurse-patient consultations in primary care: do patients disclose their concerns? AB - OBJECTIVE: To quantify the extent to which patients disclose their concerns to community nurses during wound care consultations. METHOD: Using an 'observation checklist' based on themes and subthemes that were identified in a previous study of the same patients, 20 wound care consultations were observed. The non participant observer completed the checklist and made field notes regarding the context and nature of interactions. RESULTS: Patient participants had 160 opportunities to raise concerns regarding previously-identified pain, exudate and odour, yet they did not do so on 64 (40%) occasions. They had 28, 32 and 84 opportunities to raise emotional, wound care and daily living issues, respectively, and they did not on 16 (56%), 3 (9%) and 32 (38%) occasions. Overall, patients did not raise 38% of their concerns. Of the concerns that were raised, 8% were either not acknowledged or were disregarded by their community nurse. CONCLUSION: If these data are representative, this has profound implications for person-centred care and shared decision-making models of care, which are predicated on patients articulating their needs. They also have implications for the development of practitioners' communication and consulting skills. PMID- 24142076 TI - Meeting the challenges of wound care in Danish home care. AB - OBJECTIVE: To evaluate a community-based educational intervention to improve wound-care practice, and thereby reduce the costs of care, in four communities in Denmark. METHOD: Annual wound care audits recorded patients' ages, the number and types of wounds being treated, wound duration (days unhealed), frequency of dressing changes and nurse time per dressing change. Data were available at year 1 and year 3 post-intervention. A statistical analysis was performed, testing for changes in a range of variables between these years. RESULTS: In the post intervention period, significant reductions were found in the proportion of chronic wounds, the proportion of wounds requiring a daily dressing change, mean frequency of dressing change, mean nurse time spent in wound care per week, and the total cost of wound care per week. CONCLUSION: These results suggest that it is possible to improve wound-care practice and reduce the resource costs of wound care through a systematic programme of education and training, tailored to suit the needs of local communities. PMID- 24142077 TI - Negative pressure wound therapy: improving the patient experience. Part 1 of 3. AB - Negative pressure wound therapy (NPWT) is an effective treatment for healing wounds, which may have additional benefits, such as reduced time spent in hospital and fewer dressing changes. However, as with most wound treatments, NPWT can be painful for some patients. Research has shown that the pain and accompanying stress of wound care can impair patient quality of life and delay the healing process, highlighting the need to explore ways in which the patient experience of NPWT might be improved. This article presents part one of three studies which aimed to investigate the above. In the present study, an online survey was used to explore the views of wound care clinicians worldwide (n = 221) on NPWT and levels of pain, stress and skin trauma in patients during the different stages of treatment. Findings suggest that, in the opinion of clinicians, patients' pain levels vary during the different stages of NPWT and that removal of the wound fillers and dressings or covering films are the most painful stages. PMID- 24142078 TI - The impact of compression therapy with Unna's boot on the functional status of VLU patients. AB - OBJECTIVE: To assess disability in patients with venous leg ulcers treated with compression therapy with Unna's boot. METHOD: A descriptive analytic case control study was conducted from June 2010 to May 2011 in an outpatient wound care clinic in interior Brazil. Fifty patients of both sexes, aged 18 years or above, who had had a venous leg ulcer for more than 1 year and a Doppler ankle-brachial index of 0.8-1.0 were selected for the study. Patients were treated with wound dressings and Unna's boot. Disability was assessed using the 20-item Stanford Health Assessment Disability Scale (HAQ-20). Statistical analysis was performed using the Student's t-test, the Kruskal-Wallis test and the chi-square test of independence, all at a significance level of 0.05 (p < 0.05). RESULTS: The mean overall HAQ score at inclusion (baseline) was 2.98, indicating impaired functional capacity. After 8 and 12 months of compression treatment with Unna's boot, the mean overall HAQ scores were 1.35 and 1.0, respectively, indicating good functional capacity. CONCLUSION: Patients with venous leg ulcer reported severe difficulty or serious disability in their daily functioning at baseline; after 8 months of treatment with Unna's boot, these patients were able to perform activities of daily living. PMID- 24142079 TI - Difficulties in panic studies. PMID- 24142080 TI - Why we should use long-acting injectable antipsychotics more frequently. PMID- 24142081 TI - Familial idiopathic basal ganglia calcification: rediscovering an old challenge in organic psychiatric disorders. PMID- 24142082 TI - Psychological distress among postpartum mothers of preterm infants and associated factors: a neglected public health problem. AB - OBJECTIVE: The aim of the present study was to determine the prevalence of psychological distress, depression, anxiety, and stress among postpartum Arab mothers of preterm or low birth weight (LBW) infants and to identify maternal characteristics that can predict psychological distress among mothers of preterm infants. METHODS: A hospital-based study was conducted. A representative sample of 2,091 postpartum mothers was surveyed and 1,659 women (79.3%) gave their consent to participate in the study. The study was based on a face-to-face interview with a designed questionnaire covering sociodemographic characteristics, anthropometric measures, medical history, and maternal characteristics. Depression, anxiety, and stress were measured using the Depression Anxiety Stress Scale (DASS-21). RESULTS: In the study sample, 10.2% of the postpartum mothers had preterm/LBW infants. Depression (29.4 vs. 17.3%) and anxiety (26.5 vs. 11.6%) were significantly more common among mothers of preterm births compared to mothers of full term infants (p < 0.001). The risk of depression in mothers of preterm/LBW infants was two times the risk in mothers of full term infants, while the risk of anxiety was 2.7 times in mothers of preterm/LBW infants than in mothers of full term infants. Young mothers and those who had less than secondary education (42.0 vs. 21.7%; p = 0.007) and lower monthly household income (72.0 vs. 53.3%; p = 0.024) were more depressed and anxious after the preterm birth when compared with mothers of full term infants. Psychological distress was higher in mothers with history of preterm birth (30.0 vs. 21.7%) and delivery complications (52.0 vs. 33.3%). CONCLUSIONS: We found a greater risk of depression and anxiety in mothers of preterm births than in mothers of full term infants. Our analysis revealed that depressed and anxious women of preterm infants were younger, less educated, had a lower body weight and low household income than non-depressed and non-anxious women. PMID- 24142083 TI - Disordered eating behaviors and body image in male athletes. AB - OBJECTIVE: To identify disordered eating behaviors and body image dissatisfaction, as well as their relationship to body fat (BF), among male athletes in high risk sports for eating disorders. METHODS: One hundred and fifty six male athletes were divided into the following categories: weight-class sports, sports where leanness improves performance, and sports with aesthetic ideals. BF was assessed and three questionnaires were used: the Eating Attitudes Test; the Bulimic Investigatory Test, Edinburgh; the Body Shape Questionnaire. RESULTS: Disordered eating behaviors and body image dissatisfaction were found in 43 (27.6%) and 23 athletes (14.7%), respectively, and an association was detected between the two variables (p < 0.001). Athletes with and without disordered eating behaviors did not differ in %BF (11.0 +/- 5.2% and 9.8 +/- 4.0%, respectively; p = 0.106). However, athletes with body image dissatisfaction had higher %BF than those who were satisfied (12.6 +/- 5.9% and 9.7 +/- 3.9%, respectively; p = 0.034). There were no differences in BF, frequency of disordered eating behaviors, and body image dissatisfaction between sports categories. CONCLUSION: Nearly one-quarter of athletes showed disordered eating behaviors, which was associated with body image dissatisfaction. Athletes with higher %BF were more likely to be dissatisfied with body image. There was no difference in eating behavior and body image between athletes from different sports categories. PMID- 24142084 TI - Changing core beliefs with trial-based cognitive therapy may improve quality of life in social phobia: a randomized study. AB - OBJECTIVE: To determine whether there are differences in quality of life (QoL) improvement after treatment with the trial-based thought record (TBTR) versus conventional cognitive therapy (CCT) in patients with social anxiety disorder (SAD). METHOD: A randomized trial comparing TBTR with a set of CCT techniques, which included the standard 7-column dysfunctional thought record (DTR) and the positive data log (PDL) in patients with SAD, generalized type. RESULTS: Repeated measures analysis of variance (ANOVA) revealed a significant time effect in the general health, vitality, social functioning, and mental health domains of the Short Form 36. It also indicated significant treatment effects on the bodily pain, social functioning, role-emotional, and mental health domains, with higher scores in the TBTR group. One-way analysis of covariance (ANCOVA), using pretreatment values as covariates, showed that TBTR was associated with significantly better QoL post-treatment (bodily pain, social functioning and role emotional) and at follow-up (role-emotional). A significant treatment effect on the role-emotional domain at 12-month follow-up denoted a sustained effect of TBTR relative to CCT. CONCLUSION: This study provided preliminary evidence that TBTR is at least as effective as CCT in improving several domains of QoL in SAD, specifically when the standard 7-column DTR and the PDL are used. PMID- 24142085 TI - Human experimental anxiety: actual public speaking induces more intense physiological responses than simulated public speaking. AB - OBJECTIVES: a) To perform a systematic and meta-analytic review to verify whether the Simulated Public Speaking Task (SPST) leads to a greater increase in self rated anxiety than in physiological correlates of anxiety; and b) to compare the results obtained with the SPST with an actual public speaking task involving healthy volunteers. METHODS: a) The PubMed and ISI Web of Knowledge databases were searched for studies involving the SPST prior to 2012. Eleven publications were eligible and provided data from 143 healthy volunteers for meta-analysis; b) 48 university students without somatic or psychiatric disorders were divided into three experimental groups of 16 subjects to undergo one of the following: SPST, real-world public speaking task (real-world), and control situation (control). RESULTS: The meta-analysis showed that the SPST induced a significant increase in the Visual Analogue Mood Scale (VAMS) anxiety factor, but no significant increases in systolic blood pressure or heart rate. The empirical study showed that the real-world public speaking task increased heart rate, systolic blood pressure and diastolic blood pressure significantly more than the control and SPST conditions. CONCLUSIONS: These results suggest that real public speaking might be better than SPST in inducing experimental anxiety. PMID- 24142086 TI - Efficacy of the telephone-based Brief Motivational Intervention for alcohol problems in Brazil. AB - BACKGROUND: The Brief Motivational Intervention (BMI) is an effective treatment for alcohol misuse but has not been adequately tested for use in helplines for alcoholics. The main objective of this study was to evaluate the efficacy of a telephone-based BMI for Brazilians seeking help with alcohol use cessation. METHODS: A randomized, controlled trial was performed with Brazilian subjects. Participants were randomly assigned to either the minimal intervention group (i.e., given reference materials) or the BMI group. Alcohol abstinence was evaluated in a 6-month follow-up telephone counseling session. The analysis was based on the intention to treat (ITT). RESULTS: Of the 5,896 drug users who called the helpline, 700 (12%) used alcohol, 637 of whom enrolled in this study. At 6-month follow-up, 70% of the BMI group had stopped consuming alcohol compared to 41% in the control group (odds ratio = 1.5; 95% confidence interval = 1.2-1.9; p = 0.001). CONCLUSIONS: A helpline-based BMI helps alcohol users achieve abstinence. PMID- 24142087 TI - Ketamine alters behavior and decreases BDNF levels in the rat brain as a function of time after drug administration. AB - OBJECTIVE: To evaluate behavioral changes and brain-derived neurotrophic factor (BDNF) levels in rats subjected to ketamine administration (25 mg/kg) for 7 days. METHOD: Behavioral evaluation was undertaken at 1 and 6 hours after the last injection. RESULTS: We observed hyperlocomotion 1 hour after the last injection and a decrease in locomotion after 6 hours. Immobility time was decreased and climbing time was increased 6 hours after the last injection. BDNF levels were decreased in the prefrontal cortex and amygdala when rats were killed 6 hours after the last injection, compared to the saline group and to rats killed 1 hour after the last injection. BDNF levels in the striatum were decreased in rats killed 6 hours after the last ketamine injection, and BDNF levels in the hippocampus were decreased in the groups that were killed 1 and 6 hours after the last injection. CONCLUSION: These results suggest that the effects of ketamine on behavior and BDNF levels are related to the time at which they were evaluated after administration of the drug. PMID- 24142088 TI - Lack of association of S100beta and neuron-specific enolase with mortality in critically ill patients. AB - OBJECTIVE: To evaluate the relationship between brain damage biomarkers and mortality in the intensive care unit (ICU). METHODS: The sample comprised 70 patients admitted to an ICU. Blood samples were collected from all patients on ICU admission, and levels of S100beta and neuron-specific enolase (NSE) were determined by ELISA. RESULTS: Acute Physiologic and Chronic Health Evaluation (APACHE II) score was associated with mortality, but NSE and S100beta were not associated with this outcome. In contrast, S100beta levels were significantly higher in delirious and non-delirious patients who required mechanical ventilation during ICU stay. CONCLUSION: Levels of brain biomarkers at the time of ICU admission did not predict mortality in critically ill patients. PMID- 24142089 TI - The Crack Use Relapse Scale (CURS): development and psychometric validation. AB - OBJECTIVE: To report the development and validation of the Crack Use Relapse Scale (CURS) in an inpatient population. METHODS: A pilot study with 30 male crack users was conducted to generate 35 sentences related to the construct of interest. A five-point Likert scale including 25 items and, initially, nine theoretical factors was generated and utilized in a cross-sectional study with a sample of 333 hospitalized male crack users. RESULTS: Overall Cronbach's alpha was alpha = 0.86. The exploratory factor analysis (EFA) with oblimin rotation kept the 25 items (factor loadings > 0.40) and six definitive factors, which explained 62.1% of the total variance. CONCLUSIONS: The six-factor model yielded by the EFA of the CURS reflects the various dimensions of the construct, assigning satisfactory values and demonstrating good psychometric properties, including validity and reliability. PMID- 24142090 TI - Higher proportion of inactive Gsk3beta in platelets of elderly patients with bipolar disorder: an effect of treatment? AB - OBJECTIVE: It has been postulated that mood stabilizers inhibit glycogen synthase kinase 3-beta (Gsk3beta) activity, mainly through its phosphorylation on serine-9 (Ser9). However, in vivo studies addressing Gsk3beta activity in patients with bipolar disorder are scarce. Here, we compare Gsk3beta inactivation (as indicated by Ser9-phosphorylation) in platelets of elderly patients with bipolar disorder undergoing clinical treatment and healthy elderly adults not taking medication. METHODS: Platelet samples were obtained from 37 elderly adults (bipolar disorder = 19, controls = 18). Relative changes in Gsk3beta inactivation was estimated by comparing the ratios of phosphorylated Gsk3beta to total Gsk3beta (p-Gsk3beta Ser9/Gsk3beta) between the disease and control groups. RESULTS: Phosphorylated Gsk3beta (p < 0.001) and the p-Gsk3beta Ser9/Gsk3beta ratio (p = 0.006) were elevated in bipolar patients. In the bipolar disorder group, p-Gsk3beta Ser9/Gsk3beta was positively correlated with serum lithium levels (r = 0.478, p = 0.039). CONCLUSIONS: Gsk3beta inactivation is higher in this group of elderly adults undergoing treatment for bipolar disorder. However, whether the treatment or the disease causes Gsk3beta inactivation was confounded by the lack of an unmedicated, bipolar control group and the non-uniform treatment regimens of the bipolar disorder group. Thus, further studies should help distinguish whether Gsk3beta inactivation is an effect of drug treatment or an intrinsic characteristic of bipolar disorder. PMID- 24142091 TI - The impacts of cognitive-behavioral therapy on the treatment of phobic disorders measured by functional neuroimaging techniques: a systematic review. AB - OBJECTIVE: Functional neuroimaging techniques represent fundamental tools in the context of translational research integrating neurobiology, psychopathology, neuropsychology, and therapeutics. In addition, cognitive-behavioral therapy (CBT) has proven its efficacy in the treatment of anxiety disorders and may be useful in phobias. The literature has shown that feelings and behaviors are mediated by specific brain circuits, and changes in patterns of interaction should be associated with cerebral alterations. Based on these concepts, a systematic review was conducted aiming to evaluate the impact of CBT on phobic disorders measured by functional neuroimaging techniques. METHODS: A systematic review of the literature was conducted including studies published between January 1980 and April 2012. Studies written in English, Spanish or Portuguese evaluating changes in the pattern of functional neuroimaging before and after CBT in patients with phobic disorders were included. RESULTS: The initial search strategy retrieved 45 studies. Six of these studies met all inclusion criteria. Significant deactivations in the amygdala, insula, thalamus and hippocampus, as well as activation of the medial orbitofrontal cortex, were observed after CBT in phobic patients when compared with controls. CONCLUSION: In spite of their technical limitations, neuroimaging techniques provide neurobiological support for the efficacy of CBT in the treatment of phobic disorders. Further studies are needed to confirm this conclusion. PMID- 24142092 TI - Mild cognitive impairment. Part 2: Biological markers for diagnosis and prediction of dementia in Alzheimer's disease. AB - OBJECTIVE: To present a critical review of publications reporting on the rationale and clinical implications of the use of biomarkers for the early diagnosis of Alzheimer's disease (AD). METHODS: We conducted a systematic search of the PubMed and Web of Science electronic databases, limited to articles published in English between 1999 and 2012, and based on the following terms: mild cognitive impairment, Alzheimer's disease OR dementia, biomarkers. We retrieved 1,130 articles, of which 175 were reviews. Overall, 955 original articles were eligible. RESULTS: The following points were considered relevant for the present review: a) rationale for biomarkers research in AD and mild cognitive impairment (MCI); b) usefulness of distinct biomarkers for the diagnosis and prediction of AD; c) the role of multimodality biomarkers for the diagnosis and prediction of AD; d) the role of biomarkers in clinical trials of patients with AD and MCI; and e) current limitations to the widespread use of biomarkers in research and clinical settings. CONCLUSION: Different biomarkers are useful for the early diagnosis and prediction of AD in at-risk subjects. Nonetheless, important methodological limitations need to be overcome for widespread use of biomarkers in research and clinical settings. PMID- 24142093 TI - Recent evidence and potential mechanisms underlying weight gain and insulin resistance due to atypical antipsychotics. AB - OBJECTIVE: Atypical antipsychotics (AAPs) promote obesity and insulin resistance. In this regard, the main objective of this study was to present potential mechanisms and evidence concerning side effects of atypical antipsychotics in humans and rodents. METHOD: A systematic review of the literature was performed using the MEDLINE database. We checked the references of selected articles, review articles, and books on the subject. RESULTS: This review provides consistent results concerning the side effects of olanzapine (OL) and clozapine (CLZ), whereas we found conflicting results related to other AAPs. Most studies involving humans describe the effects on body weight, adiposity, lipid profile, and blood glucose levels. However, it seems difficult to identify an animal model replicating the wide range of changes observed in humans. Animal lineage, route of administration, dose, and duration of treatment should be carefully chosen for the replication of the findings in humans. CONCLUSIONS: Patients undergoing treatment with AAPs are at higher risk of developing adverse metabolic changes. This increased risk must be taken into account when making decisions about treatment. The influence of AAPs on multiple systems is certainly the cause of such effects. Specifically, muscarinic and histaminergic pathways seem to play important roles. PMID- 24142094 TI - Pharmacogenetics in schizophrenia: a review of clozapine studies. AB - OBJECTIVES: Clozapine is quite effective to treat schizophrenia, but its use is complicated by several factors. Although many patients respond to antipsychotic therapy, about 50% of them exhibit inadequate response, and ineffective medication trials may entail weeks of unremitted illness, potential adverse drug reactions, and treatment nonadherence. This review of the literature sought to describe the main pharmacogenetic studies of clozapine and the genes that potentially influence response to treatment with this medication in schizophrenics. METHODS: We searched the PubMed database for studies published in English in the last 20 years using keywords related to the topic. RESULTS AND CONCLUSIONS: Our search yielded 145 studies that met the search and selection criteria. Of these, 21 review articles were excluded. The 124 studies included for analysis showed controversial results. Therefore, efforts to identify key gene mechanisms that will be useful in predicting clozapine response and side effects have not been fully successful. Further studies with new analysis approaches and larger sample sizes are still required. PMID- 24142095 TI - The carbon dioxide challenge test in panic disorder: a systematic review of preclinical and clinical research. AB - This systematic review assesses the current state of clinical and preclinical research on panic disorder (PD) in which the carbon dioxide (CO2) challenge was used as a trigger for panic attacks (PAs). A total of 95 articles published from 1984 to 2012 were selected for inclusion. Some hypotheses for PD evolved greatly due to the reproducibility of PAs in a controlled environment using the safe and noninvasive CO2 test. The 35% CO2 protocol was the method chosen by the majority of studies. Results of the test report specific sensitivity to hypercapnia in PD patients of the respiratory PD subtype. The CO2 challenge helped assess the antipanic effects of medication and non-pharmaceutical approaches such as physical exercise and cognitive behavioral therapy. The test was also used in studies about the genetic component of PD, in which twins and relatives of PD patients were analyzed. PMID- 24142098 TI - Importance of web-based intervention in minimizing depressive symptoms and associated stigma in depressed medical students. PMID- 24142099 TI - Spirituality in psychiatric consultation: health benefits and ethical aspects. PMID- 24142100 TI - A low-radiation exposure protocol for 3D QCT of the spine. AB - SUMMARY: Cadaver and phantom measurements and simulations confirmed that radiation exposure in 3D QCT of the spine can be reduced if 80 kV instead of 120 kV protocols are used; 120 mAs and slice thicknesses of 1-1.3 mm should be usable but obese patient will require higher milliampere-second settings. PURPOSE: To develop a low-radiation exposure CT acquisition protocol for 3D QCT of the thoracolumbar spine. METHODS: Twenty-six cadavers were scanned with a standard protocol of 120 kV, 100 mAs and with a low-dose protocol using 90 kV, 150 mAs. The scan range included the vertebrae T6 to L4. Each vertebra was segmented and the integral volume and BMD of the total vertebral body were determined. Effective dose values were estimated. The impact of milliampere-second reduction on image quality was simulated by adding noise. RESULTS: One hundred ninety-six vertebrae were analyzed. Integral volume as well as integral BMD correlated significantly (p < 0.001) between standard and low-dose protocols (volume, r (2) = 0.991, residual root mean square (RMS) error, 0.77 cm(3); BMD, r (2) = 0.985, RMS error, 4.21 mg/cm(3)). The slope significantly differed from 1 for integral BMD but not for volume hinting at residual field inhomogeneity differences between the two voltage settings that could be corrected by cross-calibration. Compared to the standard protocol, effective dose was reduced by over 50 % in the low-dose protocol. Adding noise in the 90 kV images to simulate a reduction from 150 to 100 mAs did not affect the results for integral volume or BMD. CONCLUSIONS: For 3D QCT of the spine, depending on scanner type, 80 or 90 kV instead of 120 kV protocols may be considered as an important option to reduce radiation exposure; 120 mAs and slice thicknesses of 1-1.5 mm are usable if segmentation is robust to noise. In obese patients, higher milliampere-second settings will be required. PMID- 24142101 TI - Early discontinuation of adjuvant hormone therapy is associated with a poor prognosis in Japanese breast cancer patients. AB - PURPOSE: It is important for patients to complete the planned hormone therapy to reduce both the recurrence and mortality rates of hormone receptor-positive breast cancer. We investigated the rates and factors related to the early discontinuation of adjuvant hormone therapy at our institution. METHODS: We identified 145 females prescribed adjuvant hormone therapy who were followed up for longer than 5 years. The rate of completing the planned hormone therapy and factors related to early discontinuation were examined. The relapse-free survival rate was examined between the completion group and the discontinuation group. RESULTS: The completion rate was 90.6 %. The primary reason for discontinuing hormone therapy within 5 years was side effects, such as arthritic pain. The primary factor related to early discontinuation was a significantly younger age. The relapse-free survival rate was significantly lower in the discontinuation group (p = 0.025). CONCLUSIONS: More than 90 % of the patients completed the planned adjuvant hormone therapy, and early discontinuation was related to a shorter RFS. To improve the rate of the successful completion of adjuvant hormone therapy, it is important to provide supportive care to reduce the occurrence of side effects and to care for young females with a desire to become pregnant. PMID- 24142102 TI - Pattern electroretinogram (PERG) in the early diagnosis of normal-tension preperimetric glaucoma: a case report. AB - INTRODUCTION: The purpose of this case is to present the use of pattern electroretinogram (PERG) in the early diagnosis of normal-tension preperimetric glaucoma in 56 years old woman. METHODS AND RESULTS: At baseline the results were as follows: distance-corrected visual acuity in the right eye (RE) and left eye (LE) 1.0 and 0.7, respectively (Snellen table), normal anterior segments in both eyes, normal fundus in the RE and abnormal cup to disc ratio (0.6) in the LE. Intraocular pressure (IOP) was within normal limits in both eyes: RE-14 mmHg, LE 18 mmHg (Goldmann tonometer). Results of standard automated perimetry (SAP), short wavelength automated perimetry (SWAP) and nerve fiber analyzer (GDx) were normal in both eyes. PERG result was normal in the RE but in the LE reduced amplitudes of P50 and N95 waves were observed. After topical treatment (Xalacom to the LE), a reduction of IOP to 13 mmHg was achieved and was accompanied by amplitudes increase of PERG waves. After discontinuation of the therapy, IOP increased to 18 mmHg and P50 and N95 amplitudes decreased to the values before treatment, suggesting the influence of IOP lowering therapy on electrical function of retinal ganglion cells. After 4 years from the baseline, static perimetry results were still normal, but abnormalities in retinal nerve fiber layer thickness were detected in GDx. CONCLUSIONS: PERG was a useful test not only for the early diagnosis of normal-tension preperimetric glaucoma, but also in evaluating the effectiveness of antiglaucomatous treatment. PMID- 24142103 TI - An excitable signal integrator couples to an idling cytoskeletal oscillator to drive cell migration. AB - It is generally believed that cytoskeletal activities drive random cell migration, whereas signal transduction events initiated by receptors regulate the cytoskeleton to guide cells. However, we find that the cytoskeletal network, involving SCAR/WAVE, Arp 2/3 and actin-binding proteins, is capable of generating only rapid oscillations and undulations of the cell boundary. The signal transduction network, comprising multiple pathways that include Ras GTPases, PI(3)K and Rac GTPases, is required to generate the sustained protrusions of migrating cells. The signal transduction network is excitable, exhibiting wave propagation, refractoriness and maximal response to suprathreshold stimuli, even in the absence of the cytoskeleton. We suggest that cell motility results from coupling of 'pacemaker' signal transduction and 'idling motor' cytoskeletal networks, and various guidance cues that modulate the threshold for triggering signal transduction events are integrated to control the mode and direction of migration. PMID- 24142104 TI - The microcephaly protein Asp regulates neuroepithelium morphogenesis by controlling the spatial distribution of myosin II. AB - Mutations in ASPM are the most frequent cause of microcephaly, a disorder characterized by reduced brain size at birth. ASPM is recognized as a major regulator of brain size, yet its role during neural development remains poorly understood. Moreover, the role of ASPM proteins in invertebrate brain morphogenesis has never been investigated. Here, we characterized the function of the Drosophila ASPM orthologue, Asp, and found that asp mutants present severe defects in brain size and neuroepithelium morphogenesis. We show that size reduction depends on the mitotic function of Asp, whereas regulation of tissue shape depends on an uncharacterized function. Asp interacts with myosin II regulating its polarized distribution along the apico-basal axis. In the absence of Asp, mislocalization of myosin II results in interkinetic nuclear migration and tissue architecture defects. We propose that Asp regulates neuroepithelium morphogenesis through myosin-II-mediated structural and mechanical processes to maintain force balance and tissue cohesiveness. PMID- 24142105 TI - Binding and transcriptional regulation by 14-3-3 (Bmh) proteins requires residues outside of the canonical motif. AB - Evolutionarily conserved 14-3-3 proteins have important functions as dimers in numerous cellular signaling processes, including regulation of transcription. Yeast 14-3-3 proteins, known as Bmh, inhibit a post-DNA binding step in transcription activation by Adr1, a glucose-regulated transcription factor, by binding to its regulatory domain, residues 226 to 240. The domain was originally defined by regulatory mutations, ADR1(c) alleles that alter activator-dependent gene expression. Here, we report that ADR1(c) alleles and other mutations in the regulatory domain impair Bmh binding and abolish Bmh-dependent regulation both directly and indirectly. The indirect effect is caused by mutations that inhibit phosphorylation of Ser230 and thus inhibit Bmh binding, which requires phosphorylated Ser230. However, several mutations inhibit Bmh binding without inhibiting phosphorylation and thus define residues that provide important interaction sites between Adr1 and Bmh. Our proposed model of the Adr1 regulatory domain bound to Bmh suggests that residues Ser238 and Tyr239 could provide cross dimer contacts to stabilize the complex and that this might explain the failure of a dimerization-deficient Bmh mutant to bind Adr1 and to inhibit its activity. A bioinformatics analysis of Bmh-interacting proteins suggests that residues outside the canonical 14-3-3 motif might be a general property of Bmh target proteins and might help explain the ability of 14-3-3 to distinguish target and nontarget proteins. Bmh binding to the Adr1 regulatory domain, and its failure to bind when mutations are present, explains at a molecular level the transcriptional phenotype of ADR1(c) mutants. PMID- 24142106 TI - Characterization of two mitochondrial flavin adenine dinucleotide-dependent glycerol-3-phosphate dehydrogenases in Trypanosoma brucei. AB - Glycerol-3-phosphate dehydrogenases (G3PDHs) constitute a shuttle that serves for regeneration of NAD(+) reduced during glycolysis. This NAD-dependent enzyme is employed in glycolysis and produces glycerol-3-phosphate from dihydroxyacetone phosphate, while its flavin adenine dinucleotide (FAD)-dependent homologue catalyzes a reverse reaction coupled to the respiratory chain. Trypanosoma brucei possesses two FAD-dependent G3PDHs. While one of them (mitochondrial G3PDH [mtG3PDH]) has been attributed to the mitochondrion and seems to be directly involved in G3PDH shuttle reactions, the function of the other enzyme (putative G3PDH [putG3PDH]) remains unknown. In this work, we used RNA interference and protein overexpression and tagging to shed light on the relative contributions of both FAD-G3PDHs to overall cellular metabolism. Our results indicate that mtG3PDH is essential for the bloodstream stage of T. brucei, while in the procyclic stage the enzyme is dispensable. Expressed putG3PDH-V5 was localized to the mitochondrion, and the data obtained by digitonin permeabilization, Western blot analysis, and immunofluorescence indicate that putG3PDH is located within the mitochondrion. PMID- 24142107 TI - Continued use of low-dose aspirin does not increase the risk of bleeding during or after endoscopic submucosal dissection for early gastric cancer. AB - BACKGROUND: Although recent guidelines for endoscopic submucosal dissection (ESD) as treatment for early gastric cancer (EGC) recommend noninterruption of low-dose aspirin (LDA) perioperatively, this strategy is controversial. It was our practice to interrupt LDA therapy 5-7 days before to ESD until December 2010, when we instituted the new guidelines and performed ESD without interrupting LDA therapy. Our purpose in this study was to confirm the validity of noninterrupted use of LDA in patients undergoing ESD for EGC. METHODS: We studied 78 consecutive patients with 94 EGCs who were routinely taking LDA and were treated by ESD at Hiroshima University Hospital between April 2005 and June 2012. The patients were of two groups: those in whom LDA was interrupted perioperatively (53 patients with 66 EGCs) and those in whom LDA was continued perioperatively (25 patients with 28 EGCs). RESULTS: The complete resection rate was 92.4 % (61/66) in the LDA interrupted group and 100 % (28/28) in the LDA-continued group. Incidences of poor bleeding control during the procedure and bleeding after procedure were 10.6 % (7/66) and 4.8 % (3/66), respectively, in the LDA-interrupted group and 7.1 % (2/28) and 3.6 % (1/28) in the LDA-continued group. Two patients in the interrupted-LDA group suffered cerebrovascular infarction before ESD, and 2 patients in this group suffered acute myocardial infarction after ESD. CONCLUSIONS: Our data suggest that continued use of LDA does not increase the risk of bleeding during or after ESD for EGC and does decrease the risk of ischemic events. PMID- 24142108 TI - FTY720 protects neuronal cells from damage induced by human prion protein by inactivating the JNK pathway. AB - Prion diseases affect the central nervous system (CNS) in humans and animals, and are associated with the conversion of the cellular prion protein (PrPC) to the misfolded isoform (PrPSc). FTY720, an immune modulator and synthetic analogue of sphingosine-1-phosphate (S1P), activates S1P receptors and has been shown to be effective in experimental models of transplantation and autoimmunity, including multiple sclerosis. Whereas the immune modulatory functions of FTY720 have been extensively investigated, the other functions of FTY720 are not yet well understood. In this study, we investigated the effects of FTY720 phosphate (FTY720-p) on prion protein-mediated neuronal cell death, as well as its effects on intracellular apoptotic pathways. Treatment with FTY720-p protected neuronal cells from synthetic human prion protein peptide [PrP (106-126)]-mediated damage and prevented mitochondrial dysfunction by inhibiting the activation of c-jun N terminal kinase. Moreover, FTY720-p prevented the PrP (106-126)-induced reduction in mitochondrial potential, the translocation of Bax to the mitochondria and the release of cytochrome c. To the best of our knowledge, this study is the first to demonstrate the effects of FTY720 on prion protein-mediated neurotoxicity and to suggest that FTY720 has therapeutic potential in prion diseases. PMID- 24142109 TI - Photoresponse of the protonated Schiff-base retinal chromophore in the gas phase. AB - The fragmentation, initiated by photoexcitation as well as collisionally-induced excitation, of several retinal chromophores was studied in the gas phase. The chromophore in the protonated Schiff-base form (RPSB), essential for mammalian vision, shows a remarkably selective photoresponse. The selectivity of the gas phase chromophore is triggered by a series of fast trans to cis isomerizations followed by a Diels-Alder cyclization with subsequent slow statistical fragmentation, leading to one specific fragment ion. The pattern of the final statistical fragmentation may be altered by chemical modifications of the chromophore. We propose that isomerizations play an important role in the photoresponse of gas-phase retinal chromophores and guide internal conversion through conical intersections. The role of protein interactions is then to control the specificity of the photoisomerization in the primary step of vision and possibly to diminish thermal noise by suppressing spontaneous isomerization by heat. PMID- 24142110 TI - Key intestinal genes involved in lipoprotein metabolism are downregulated in dyslipidemic men with insulin resistance. AB - Insulin resistance (IR) is associated with elevated plasma levels of triglyceride rich lipoproteins (TRLs) of intestinal origin. However, the mechanisms underlying the overaccumulation of apolipoprotein (apo)B-48-containing TRLs in individuals with IR are not yet fully understood. This study examined the relationships between apoB-48-containing TRL kinetics and the expression of key intestinal genes and proteins involved in lipid/lipoprotein metabolism in 14 obese nondiabetic men with IR compared with 10 insulin-sensitive (IS) men matched for waist circumference. The in vivo kinetics of TRL apoB-48 were assessed using a primed-constant infusion of L-[5,5,5-D3]leucine for 12 h with the participants in a constantly fed state. The expression of key intestinal genes and proteins involved in lipid/lipoprotein metabolism was assessed by performing real-time PCR quantification and LC-MS/MS on duodenal biopsy specimens. The TRL apoB-48 pool size and production rate were 102% (P < 0.0001) and 87% (P = 0.01) greater, respectively, in the men with IR versus the IS men. On the other hand, intestinal mRNA levels of sterol regulatory element binding factor-2, hepatocyte nuclear factor-4alpha, and microsomal triglyceride transfer protein were significantly lower in the men with IR than in the IS men. These data indicate that IR is associated with intestinal overproduction of lipoproteins and significant downregulation of key intestinal genes involved in lipid/lipoprotein metabolism. PMID- 24142111 TI - Two rice plasma membrane intrinsic proteins, OsPIP2;4 and OsPIP2;7, are involved in transport and providing tolerance to boron toxicity. AB - Boron (B) toxicity is responsible for low cereal crop production in a number of regions worldwide. In this report, we characterized two rice genes, OsPIP2;4 and OsPIP2;7, for their involvement in B permeability and tolerance. Transcript analysis demonstrated that the expression of OsPIP2;4 and OsPIP2;7 were downregulated in shoots and strongly upregulated in rice roots by high B treatment. Expression of both OsPIP2;4 and OsPIP2;7 in yeast HD9 strain lacking Fps1, ACR3, and Ycf1 resulted in an increased B sensitivity. Furthermore, yeast HD9 strain expressing OsPIP2;4 and OsPIP2;7 accumulated significantly higher B as compared to empty vector control, which suggests their involvement in B transport. Overexpression of OsPIP2;4 and OsPIP2;7 in Arabidopsis imparted higher tolerance under B toxicity. Arabidopsis lines overexpressing OsPIP2;4 and OsPIP2;7 showed significantly higher biomass production and greater root length, however there was no difference in B accumulation in long term uptake assay. Short-term uptake assay using tracer B (10B) in shoots and roots demonstrated increased 10B accumulation in Arabidopsis lines expressing OsPIP2;4 and OsPIP2;7, compare to wild type control plants. Efflux assay of B in the roots showed that 10B was effluxed from the Arabidopsis transgenic plants overexpressing OsPIP2;4 or OsPIP2;7 during the initial 1-h of assay. These data indicate that OsPIP2;4 and OsPIP2;7 are involved in mediating B transport in rice and provide tolerance via efflux of excess B from roots and shoot tissues. These genes will be highly useful in developing B tolerant crops for enhanced yield in the areas affected by high B toxicity. PMID- 24142112 TI - Involvement of facultative apomixis in inheritance of EPSPS gene amplification in glyphosate-resistant Amaranthus palmeri. AB - The inheritance of glyphosate resistance in two Amaranthus palmeri populations (R1 and R2) was examined in reciprocal crosses (RC) and second reciprocal crosses (2RC) between glyphosate-resistant (R) and -susceptible (S) parents of this dioecious species. R populations and Female-R * Male-S crosses contain higher 5 enolpyruvylshikimate-3-phosphate synthase (EPSPS) gene copy numbers than the S population. EPSPS expression, EPSPS enzyme activity, EPSPS protein quantity, and level of resistance to glyphosate correlated positively with genomic EPSPS relative copy number. Transfer of resistance was more influenced by the female than the male parent in spite of the fact that the multiple copies of EPSPS are amplified in the nuclear genome. This led us to hypothesize that this perplexing pattern of inheritance may result from apomictic seed production in A. palmeri. We confirmed that reproductively isolated R and S female plants produced seeds, indicating that A. palmeri can produce seeds both sexually and apomictically (facultative apomixis). This apomictic trait accounts for the low copy number inheritance in the Female-S * Male-R offsprings. Apomixis may also enhance the stability of the glyphosate resistance trait in the R populations in the absence of reproductive partners. PMID- 24142113 TI - The lipo-facelift: merging the face-lift and liposculpture: eight years experience and a preliminary observational study. AB - BACKGROUND: Since the introduction of the classic submucosal aponeurotic system (SMAS) face-lift, the surgical approach to improve the changes of an aging face has evolved, and significant technical improvements have been made. However, several problems still have not been solved satisfactorily. These problems include facial lipodystrophy and changes in skin and skin texture. METHODS: The Lipo-Facelift procedure consists of facial liposculpturing performed simultaneously with a biplanar, bivectorial SMAS face-lift procedure. The authors analyzed pre- and postsurgical photographs of 12 patients with a Lipo-Facelift after 3 and 12 months and analyzed their charts for complications. Furthermore, O2C measurement was performed to assess improved microcirculation. The longest follow-up period was 8 years. RESULTS: The Lipo-Facelift demonstrated very satisfying results. Initial swelling and bruising were seen as well as two cases of wound-healing disorders, but no surgical intervention or revision was needed. The findings show lasting improvement of skin quality and a youthful appearance. CONCLUSION: The Lipo-Facelift corrects age-related skin and SMAS changes as well as age-related lipodystrophy, improves skin circulation and skin revitalization, and provides a lasting and natural result. The skin quality resulting from simultaneous lipofilling can be explained by improved angiogenesis due to transferred growth factors in the lipoaspirate. Also, differentiation of progenitor cells to fibroblasts and increased production of collagen contribute to firmer skin. LEVEL OF EVIDENCE IV: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 . PMID- 24142114 TI - Surgical management of digital calcinosis in CREST syndrome. AB - As a limited form of sclerodermy, CREST syndrome is characterized by calcinosis, Raynaud's phenomenon, esophageal dysmotility, sclerodactyly, and telangiectasia, which determine the acronym CREST. Calcinosis is a particularly difficult entity to treat given the paucity of effective options described in the literature. Treatment of finger calcinosis has a wide range of possibilities depending on the extent of calcifications and the involvement of deep structures. From a surgical point of view, whereas simple removal is adequate in minor outpatient cases, a radical debridement in the major and more painful cases seems required. A cover flap is needed particularly in the thumb due to its great functional importance, also if the fingertip is not involved. The authors recommend the kite flap for the dimensions, the tissue quality, and the possibility of giving sensation to the reconstructed area. With this surgical option, the transferred skin is soft, sensate, and the right fit. Usually, no further operations are needed for flap remodeling. The time required for sensory integration is about 2 years, often related to the age of the patient. Debridement and flap reconstruction usually give total resolution of pain, with complete recovery of thumb motion and the thumb-index finger grip. PMID- 24142115 TI - Gliding mentoplasty: a new technique. AB - BACKGROUND: The goal of mentoplasty is to improve chin projection. Traditionally, this is accomplished by either mandibular osteotomy or alloplastic implants. However, these procedures are not free of complications. This report describes gliding mentoplasty, a novel, simple technique for chin projection. METHODS: The 12 patients in this study underwent gliding mentoplasty. By means of a 2-cm intraoral incision, a subcutaneous dissection was made in the caudal direction. The dissection then proceeded in the subperiosteal plane, leaving a 1-cm cuff of muscle attached to the bone, and advanced toward the lower border of the chin. Subsequently, the dissection was extended laterally, and the whole mental area was dissected from the surrounding tissue. Three 2-0 monofilament nylon sutures were placed in the submandibular periosteum and connected through the remaining muscle cuff to the periosteum. These key sutures allowed the submandibular region to slide forward, project the subcutaneous tissue and mentalis muscle, define the labiomental fold, and improve the pogonion projection. RESULTS: Gliding mentoplasty resulted in a symmetric projection of the chin in all cases. In two patients, a submandibular dimple developed, which spontaneously resolved in 1 month. No revision surgery was performed, and no tissue relapse was noted. The mean follow-up period was 24.7 +/- 5.17 months (range 19-33 months). All the patients were satisfied with the result. CONCLUSION: Gliding mentoplasty is a simple, easy-to-perform, rapid surgical technique of chin projection that produces low pain, rapid recovery, and excellent cosmetic results. LEVEL OF EVIDENCE IV: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 . PMID- 24142116 TI - The labial aging process: a surface analysis-based three-dimensional evaluation. AB - BACKGROUND: With increasing age, the smile becomes elongated and less appealing. Currently, several methods are proposed for analysis of lip morphology including lateral cephalograms, profile and frontal photographs, video images, and three dimensional systems. Despite several descriptions of morphologic and histologic age-related changes in the literature, no scientific well-supported model of the labial aging process is reported. METHODS: For this study, 33 healthy volunteers were selected and divided into two groups according to age: a youthful group (ages 21-34 years) and an aged group (ages 45-65 years). Their dental and labial stone casts were obtained, digitized, and virtually reproduced using a computerized electromechanical digitizer and applying nonuniform rational B spline geometry. To obtain a synthetic parameter describing local surface deformation, average curvature and curvature variability indexes were computed and compared. RESULTS: No significant age- or sex-related differences in the average curvature were detected. In contrast, the curvature variability was significantly greater in the young than in the aged subjects. CONCLUSIONS: The labial arch surface remains macroscopically constant between the third and the sixth decades of life, but with local modifications that influence the standard deviation of its curvature. A high standard deviation described the protruding labial appearance of the young subjects, whereas a reduced one described the flat lips of the aged subjects. LEVEL OF EVIDENCE IV: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 . PMID- 24142117 TI - The infragluteal sulcus: a histologic and ultrasonographic study. AB - The buttocks are a major component of sexual attraction, and they have their place in the concept of beauty in most cultures and ethnic groups. The infragluteal sulcus, an important part of the gluteal region, determines the attractiveness of the buttocks. For that reason, any small change in the infragluteal sulcus makes a major cosmetic difference in the morphology of the buttock. In recent years, some flaps such as the infragluteal flap, the transverse upper gracilis flap, and the transverse musculocutaneous gracilis flap have become popular because of reduced donor area morbidity and their availability for hiding incision scars. In these cases, there may be distortion of the gluteal morphology and infragluteal sulcus. In this study, the anatomic and histologic features of the tissues that form the infragluteal sulcus were analyzed for their contribution to successful reconstruction of the infragluteal sulcus. LEVEL OF EVIDENCE IV: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 . PMID- 24142118 TI - Capsule commentary on Wee et al., sex, race, and consideration of bariatric surgery among primary care patients with moderate to severe obesity. PMID- 24142121 TI - Auxetic oesophageal stents: structure and mechanical properties. AB - Oesophageal cancer is the ninth leading cause of malignant cancer death and its prognosis remains poor, ranking as the sixth most frequent cause of death in the world. This research work aims to adopt an Auxetic (rotating-squares) geometry device, that had previously been examined theoretically and analysed by Grima and Evans (J Mater Sci Lett 19(17):1563-1565, 2000), to produce a novel Auxetic oesophageal stent and stent-grafts relevant to the palliative treatment of oesophageal cancer and also for the prevention of dysphagia. This paper discusses the manufacture of a small diameter Auxetic oesophageal stent and stent-graft. The oral deployment of such an Auxetic stent would be simplest if a commercial balloon dilatational catheter was used as this obviates the need for an expensive dedicated delivery system. A novel manufacturing route was employed in this research to develop both Auxetic films and Auxetic oesophageal stents, which ranged from conventional subtractive techniques to a new additive manufacturing method. Polyurethane was selected as a material for the fabrication of Auxetic films and Auxetic oesophageal stents because of its good biocompatibility and non toxicological properties. The Auxetic films were later used for the fabrication of seamed Auxetic oesophageal stents. The flexible polyurethane tubular grafts were also attached to the inner luminal side of the seamless Auxetic oesophageal stents, in order to prevent tumour in-growth. Scanning electron microscopy was used to conduct surface morphology study by using different Auxetic specimens developed from different conventional and new additive manufacturing techniques. Tensile testing of the Auxetic films was performed to characterise their mechanical properties. The stent expansion tests of the Auxetic stents were done to analyse the longitudinal extension and radial expansion of the Auxetic stent at a range of radial pressures applied by the balloon catheter, and to also identify the pressure values where the Auxetic stent fails. Finite element models of both Auxetic film and Auxetic stent were developed, and the results were compared with experimental results with a good agreement. The tensile testing of the Auxetic polyurethane films revealed that the Poisson's ratio of the sample ranged between -0.87 and -0.963 at different uniaxial tensile load values. From the stent expansion test, it was found that the Auxetic oesophageal stent radially expanded from 0.5 to 5.73 mm and longitudinally extended from 0.15 to 1.83 mm at a range of applied pressure increments (0.5-2.7 bar) from the balloon catheter. PMID- 24142119 TI - Chronic opioid therapy risk reduction initiative: impact on urine drug testing rates and results. AB - BACKGROUND: In response to epidemic levels of prescription opioid overdose, abuse, and diversion, routine urine drug tests (UDTs) are recommended for patients receiving chronic opioid therapy (COT) for chronic pain. However, UDT ordering for COT patients is inconsistent in primary care, and little is known about how to increase UDT ordering or the impact of increased testing on rates of aberrant results. OBJECTIVE: To compare rates and results of UDTs for COT patients before versus after implementation of an opioid risk reduction initiative in a large healthcare system. DESIGN: Pre-post observational study. PATIENTS: Group Health patients on COT October 2008-September 2009 (N = 4,821), October 2009-September 2010 (N = 5,081), and October 2010-September 2011 (N = 5,498). INTERVENTION: Multi-faceted opioid risk reduction initiative. MAIN MEASURES: Annual rates of UDTs and UDT results. KEY RESULTS: Half of COT patients received at least one UDT in the year after the initiative was implemented, compared to only 7 % 2 years prior. The adjusted odds of COT patients having at least one UDT in the first year of the opioid initiative were almost 16 times (adjusted OR = 15.79; 95 % CI: 13.96-17.87) those 2 years prior. The annual rate of UDT detection of marijuana and illicit drugs did not change (12.6 % after initiative implementation), and largely reflected marijuana use (detected in 11.1 % of all UDTs in the year after initiative implementation). In the year after initiative implementation, 10.7 % of UDTs were negative for opioids. CONCLUSIONS: The initiative appeared to dramatically increase urine drug testing of COT patients in the healthcare system without impacting rates of aberrant results. The large majority of aberrant results reflected marijuana use or absence of opioids in the urine. The utility of increased urine drug testing for COT patient safety and prevention of diversion remains uncertain. PMID- 24142122 TI - Pediatric anxiety disorders: from neuroscience to evidence-based clinical practice. AB - The objective of this narrative review of the literature is to describe the epidemiology, etiology, pathophysiology, diagnosis, and treatment of pediatric anxiety disorders. We aim to guide clinicians in understanding the biology of anxiety disorders and to provide general guidelines for the proper diagnoses and treatment of these conditions early in life. Anxiety disorders are prevalent, associated with a number of negative life outcomes, and currently under recognized and under-treated. The etiology involves both genes and environmental influences modifying the neural substrate in a complex interplay. Research on pathophysiology is still in its infancy, but some brain regions, such as the amygdala and the prefrontal cortex, have been implicated in fear and anxiety. Current practice is to establish diagnosis based purely on clinical features, derived from clinical interviews with the child, parents, and teachers. Treatment is effective using medication, cognitive behavioral therapy, or a combination of both. An introduction to the neuroscience behind anxiety disorders combined with an evidence-based approach may help clinicians to understand these disorders and treat them properly in childhood. PMID- 24142123 TI - Advances and perspectives in child and adolescent psychiatry. PMID- 24142124 TI - Perspectives on child and adolescent psychiatry from Brazil. PMID- 24142125 TI - Mood disorders in childhood and adolescence. AB - The identification and treatment of mood disorders in children and adolescents has grown over the last decades. Major depression is one of the most common and debilitating disorders worldwide, imposing a massive burden to the youth population. Bipolar disorder is being increasingly recognized as having its roots early in life, and its presentation during childhood and adolescence has been submitted to extensive research. This review aims to highlight clinical aspects of the current knowledge on mood disorders in the pediatric population, presenting updated information on epidemiology, diagnostic procedures, and management strategies. Limitations of available evidence and future directions of research in the field are also discussed. PMID- 24142127 TI - Developments and challenges in the diagnosis and treatment of ADHD. AB - Attention-deficit/hyperactivity disorder (ADHD) is a prevalent neurodevelopmental disorder, often associated with other psychiatric comorbidities, functional impairments, and poor long-term outcomes. The objective of this selected review is to describe current advances and challenges in the diagnosis and treatment of ADHD. The disorder is associated with neurobiological underpinnings and is highly heterogeneous in various aspects, such as symptom profiles, cognitive impairments, and neurobiological and genetic features. The efficacy and safety of short-term pharmacological treatments across the life cycle is well studied, but further research investigating long-term treatment, impact of treatment in preschoolers, and non-pharmacological interventions is needed. Future research is also needed to better characterize the neurodevelopmental pathways of the disorder, linking clinical and neurobiological information, less investigated populations, and new interventions. PMID- 24142126 TI - Irritability in children and adolescents: past concepts, current debates, and future opportunities. AB - Irritability is defined as a low threshold to experience anger in response to frustration. It is one of the most common symptoms in youth and is part of the clinical presentation of several disorders. Irritability can present early in life and is a predictor of long-term psychopathology; yet, the diagnostic status of irritability is a matter of intense debate. In the present article, we address two main components of the debate regarding irritability in youth: the misdiagnosis of chronic irritability as pediatric bipolar disorder, and the proposal of a new diagnosis in the DSM-5, disruptive mood dysregulation disorder, whose defining symptoms are chronic irritability and temper outbursts. PMID- 24142128 TI - Use of psychoactive substances by adolescents: current panorama. AB - Adolescence is a period of vulnerability to substance use disorders (SUDs). Epidemiological studies indicate that about 23% of Brazilian adolescents use drugs, with alcohol being the most widely consumed substance. The etiology of SUDs is complex, influenced by an interaction of genetic risk, individual development, environmental factors, context of use, and substance used. Clinicians should consider diagnostic criteria and be aware of behavioral changes that may indicate drug use and its consequences in various aspects of adolescent life. Identification and treatment of comorbid conditions is critical to the management of SUDs in this age group. Interventions should restrict access to drugs and facilitate prompt recognition of initial use, preventing progression to serious patterns of abuse or dependence. Intervention should be broad, including academic and occupational activities as well as social relationships and leisure, which are critical to the reestablishment of normal adolescent development. PMID- 24142129 TI - Autism spectrum disorders: an overview on diagnosis and treatment. AB - Pervasive developmental disorders are now commonly referred to as autism spectrum disorders (ASDs). ASDs present with a range of severity and impairments, and often are a cause of severe disability, representing a major public health concern. The diagnostic criteria require delays or abnormal functioning in social interaction, language, and/or imaginative play within the first 3 years of life, resulting in a deviation from the developmental pattern expected for the age. Because establishing a diagnosis of ASD is possible as early as 18-24 months of age, clinicians should strive to identify and begin intervention in children with ASD as soon as signs are manifest. Increasing efforts are underway to make ASD screening universal in pediatric healthcare. Given the crucial importance of early identification and multiple modalities of treatment for ASD, this review will summarize the diagnostic criteria, key areas for assessment by clinicians, specific scales and instruments for assessment, and discussion of evidence-based treatment programs and the role of specific drug therapies for symptom management. PMID- 24142130 TI - Phosphines with N-heterocyclic boranyl substituents. AB - A lithio-diazaborole reacted with diamino-chlorophosphines via metathesis to yield previously unavailable phosphinoboranes bearing amino substituents at both the phosphorus and boron atoms, and with Ph2PCl and Mes*PCl2via chloride transfer and reductive PP coupling to give a chloro-diazaborole and the corresponding diphosphine or diphosphene, respectively. Diazaboroles with phenylphosphino- and PH2-substituents were nonetheless accessible via inverse metathesis upon treatment of a bromoborane precursor with phosphides PhnPH2-nM (n = 0-2, M = Li, K). The products were characterised by spectroscopic data and in most cases by single-crystal X-ray diffraction studies which show the molecules to exhibit strongly pyramidal coordination at the phosphorus atom and long BP bonds of 1.93 1.95 A. The insensitivity of the BP distance towards substituent effects and the tolerance of large sterically induced torsional twists along the BP bond axis suggest the presence of pure single bonds without any contribution from P->B dative pi-interactions. This view was confirmed by DFT studies which indicate further that the molecules lack a significant electrophilic character at boron but may act as potential sigma-donor/pi-acceptor ligands through the phosphorus atom. PMID- 24142131 TI - Physical, chemical, and antioxidant activity characterization of pitaya (Stenocereus pruinosus) fruits. AB - Fruits with red and orange flesh of the columnar cactus pitaya (Stenocereus pruinosus) were studied to evaluate physical characteristics, total soluble solids, betalains and soluble phenols content, and antioxidant activity. Fruits had, in average, weight of 179.0 g, 9.8 degrees Brix, 9.4 % carbohydrates, 1.25 % protein, 0.11 % ethereal extract, 0.60 % crude fiber, and 0.62 % ash. Also, fruits resulted rich in Fe (22.8-27.8 mg/kg). Hue angle and contents of betacyanins, betaxanthins (MUg/g dry sample), and total soluble phenols (mg GAE/g fresh sample) were 19.8 degrees , 2860.0, 3210.0, and 1.6 in the red material, and 28.9 degrees , 470.0, 2670.0, and 1.2, respectively, in the orange fruit. The antioxidant capacity was higher in the red material, since the ABTS (2,2'-azino bis(3-ethylbenzothiazoline-6-sulphonic acid)) technique reported 1090.6 and 735.4 MUmol of Trolox equivalents/g fresh flesh in red and orange fruits, respectively, while the oxygen radical absorbance capacity (ORAC) assay reported 7.84 and 5.16 MUmol of Trolox equivalents/g fresh flesh, respectively. The chromatographic profile showed five betalains in red fruits, but only four of them were observed in those orange fleshed. PMID- 24142132 TI - Integration of sediment contamination with multi-biomarker responses in a novel potential bioindicator (Sepia officinalis) for risk assessment in impacted estuaries. AB - For the purpose of biomonitoring, species that combine ecological and commercial importance may provide a link between ecological and human health risk. The common cuttlefish, Sepia officinalis, holds both characteristics in south-western Europe, albeit remaining unsurveyed in ecotoxicological studies. Cuttlefish collected from an impacted estuary in SW Portugal and a reference location off the coast were analysed for a battery of biomarker responses in the digestive gland and gills. The contrast to reference animals revealed that biomarker responses, especially those related to oxidative stress, were consistent with sediment contamination by PAHs, even in a situation that combines complex toxicant mixtures, moderate levels of contamination and high ecotoxicological diversity. However, environmental parameters related to the differences between shore and estuarine habitats should not be overruled. Also, digestive gland metallothionein retained significant specificity to metals even though previous studies in the area with clams and fish failed to trigger a conclusive response. The highest net differences in biomarker responses were detected in the gills, likely indicating higher sensitivity to environmental stressors. Still, the digestive gland responses were overall the most consistent with sediment contamination and effectively differentiated between estuarine industrial- and rural-impacted sites. The results indicate that S. officinalis may be a candidate to meet the European Union's requirements for efficient biomonitoring programmes, with the additional importance of being cosmopolitan, abundant, commercially valuable and combining the molluscan biology that has been granting bivalves their high value for biomonitoring with foraging behaviour, thus better able to reflect anthropogenic stressors impacting a wider area than sedentary organisms. Nevertheless, further investigations in unpolluted sites are needed to better evaluate the background levels of biomarker responses in the species. PMID- 24142133 TI - Study on the interactions between transplanted bone marrow-derived mesenchymal stem cells and regulatory T cells for the treatment of experimental colitis. AB - Accumulating evidence has established the use of mesenchymal stem cells (MSCs) as candidate cells for immunosuppressive therapy. Experimental studies have suggested that MSCs exert their immunomodulatory effects through the induction of regulatory T cells (Tregs) in vitro and in vivo. However, the interactions between MSCs and Tregs in inflammatory bowel disease (IBD) and whether MSCs can be used for the treatment of IBD remains to be elucidated. In this study, we aimed to investigate whether MSCs can be used for the treatment of IBD through the induction of Tregs. MSCs were isolated and identified by flow cytometry. The MSCs were transduced with a replication-defective recombinant lentiviral vector carrying GFP in order to be able to trace the injected cells in vivo. Prepared MSCs (1x106) were injected into rats with 2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced colitis via the tail vein; the control rats received phosphate buffered saline (PBS) alone. Two weeks after the intravenous infusion, the frequency of CD4+CD25+Foxp3 cells in the peripheral blood was examined by flow cytometry. The colon was sectioned and analyzed for histopathological changes. Foxp3 mRNA expression was determined by real-time reverse-transcription polymerase chain reaction (qRT-PCR). In our study, the systemic infusion of MSCs significantly ameliorated the clinical and histopathologic severity of TNBS induced colitis in contrast to the controls. There was an inverse regulation of mucosal and peripheral Foxp3 expression, suggesting that the MSCs redistributed the Tregs from the mucosa to the blood. Thus, MSCs exhibit immunomodulatory functions and may be used to ameliorate or treat IBD by redistributing regulatory T cells. Therefore, the interactions between transplanted bone marrow-derived MSCs and Tregs should be further investigated; MSCs have tremendous potential for use in the treatment of IBD. PMID- 24142134 TI - The in vitro research of bacterial invasion of prosthetic vascular grafts: comparison of elastomer-sealed and gelatin-coated Dacron vascular grafts. AB - PURPOSE: To investigate the process of bacterial invasion from the surface to inside prosthetic vascular grafts. METHODS: Elastomer-sealed Dacron vascular grafts (ESDVGs) and gelatin-coated Dacron vascular grafts (GCDVGs) were cut into 6-cm segments and placed in a U-shaped configuration on culture plates. Physiological saline was poured inside the grafts and a suspension of Pseudomonas aeruginosa was added to the outside. Samples taken from inside the grafts at nine time points for up to 60 h were spread on agar. Bacterial colonies were then analyzed. The grafts were also examined using scanning electron microscopy (SEM). RESULTS: Contaminated vascular graft models were produced in 18 ESDVGs (group T) and 12 GCDVGs (group G). The bacterial counts inside the vascular grafts in both groups increased over time. Bacterial colonies were confirmed in all samples from group G by 30 h, whereas bacteria appeared inside the grafts from group T at various times between 0 and 60 h. Bacteria were undetectable in one model from group T throughout the study. SEM revealed that the elastomeric membrane in the ESDVG was uneven. CONCLUSION: Bacterial invasion of vascular grafts does not always occur immediately after contamination. ESDVGs may be more resistant to bacterial invasion as they have a thicker and evenly enriched elastomeric membrane. PMID- 24142135 TI - Autologous skin cells: a new technique for skin regeneration in diabetic and vascular ulcers. AB - Diabetic foot ulcers are often difficult to treat due to concurrent infection, neuropathy and vascular compromise. Healing adjuncts, such as negative pressure wound therapy and skin grafts, have been used with good results but eventual healing is often frustrated by slow epithelialisation. Here, we describe a novel therapeutic method to aid epithelial regeneration using autologous skin cells (ReCell; Avita Medical) to aid skin regeneration. We suggest this may provide an alternative to more established therapies used in this patient group. PMID- 24142136 TI - Salvage of shoulder joint through simplification of wound management. AB - Infection is a common sequela of open dislocation of the shoulder joint. This typically leads to joint surface and humeral head necrosis, resulting in severe limitation of motion. Few cases of open and infected glenohumeral joints have been reported, and none had a good functional outcome with pain-free, near-full range of motion. Here we report the case of a 24-year-old man, who sustained a severe degloving injury of his left shoulder with an open glenohumeral joint, in a road traffic accident. We describe a treatment plan that salvaged near-full range of shoulder motion and resulted in pain-free active and passive movements. PMID- 24142137 TI - Percutaneous foam sclerotherapy for venous leg ulcers. AB - The technique of foam sclerotherapy directed at the distal most vessels, draining the ulcer bed was first described in 2010, with excellent penetration into the underlying venous network possible with this technique. Thirty-five patients have now been treated with this technique as the initial treatment at Midwest Vein Laser, USA. There have been no complications with this technique and rapid healing occurred within 4-8 weeks after the initial treatment in 90% of the patients, and all ulcers were healed at 4 months. Here we present the representative case of a 67-year-old man treated with a modified technique that used a percutaneous approach via reticular or spider veins at the margin of the ulcer bed. PMID- 24142138 TI - Cutaneous foetal injuries related to amniocentesis. AB - Amniocentesis is one of the most important prenatal diagnostic procedures available to assess congenital abnormalities. It is performed worldwide due to its simplicity of execution and lack of risk. The most frequent known accidents in amniocentesis are abortion, oligohydramnios, amniositis and placental abruption, while direct fetal injuries produced by contact with the needle are rarely seen. The injuries produced are extremely variable in severity, but the most frequent is skin wounds, which usually heal as small, round depressed scars. The cases we describe concern the occurrence of iatrogenic cutaneous wound lesions to a fetus during amniocentesis. The medical-legal analysis of the cases required dermatological expertise in order to exclude a different pathogenesis for the skin injuries to the child and were assigned by the court, in order to assess the administrative compensation due to the parents of the child as a result of medical malpractice. PMID- 24142139 TI - Venous ulceration contaminated by multi-resistant organisms: larval therapy and debridement. AB - A 72-year-old female with venous insufficiency presented to a hospital-based multidisciplinary wound clinic after 20 years of recurrent episodes of venous leg ulcers. Examination showed bilateral leg ulcers with no evidence of arterial insufficiency, but complicated by considerable devitalised tissue, abnormally high bacterial load and the presence of multi-resistant organisms. The ulcers were initially treated with larvae to aid debridement and reduce the bacterial load, prior to skin grafting. Although ulcer free for a period of 4 months, further debridement was required when the skin condition deteriorated. Surgical intervention was chosen as the preferred method by the surgeons for a second acute care admission using hydrosugery, along with supplementary skin grafts and compression. Ongoing management, consisting of regular debridement, skin care and compression therapy, continues. PMID- 24142140 TI - Dear readers. PMID- 24142141 TI - Single-use NPWT for the treatment of complex orthopaedic surgical and trauma wounds. AB - Orthopaedic limb reconstruction patients often have wounds that are difficult to heal either due to the underlying problems, their surgery, underlying comorbidities or a combination of these factors. Negative pressure wound therapy (NPWT) is a useful tool with which to manage these wounds; however, many systems are not ideal for use in the patient's home, due in part to size and complexity. There are also staff training issues if transferring patients to an area which does not routinely use negative pressure systems. This paper reports the outcomes for some of the patients who were treated with a novel, single-use NPWT device in a orthopaedic trauma/limb reconstruction unit. PMID- 24142142 TI - Sun exposure, sunbeds and sunscreens and melanoma. What are the controversies? AB - The association between various measures of sun exposure and melanoma risk is quite complex to dissect as many case-control studies of melanoma included different subtypes of melanomas which are likely to be biologically different, so interpretation of the data is difficult. Screening bias in countries with high levels of sun exposure is also an issue. Now that progress is being made in the genetic subclassification of melanoma tumours, it is apparent that melanomas have different somatic changes according to body sites/histological subtypes and that UV exposure may be relevant for some but not all types of melanomas. Melanoma behaviour also points to non-sun-related risk factors, and complex gene environment interactions are likely. As UV exposure is the only environmental factor ever linked to melanoma, it is still prudent to avoid excessive sun exposure and sunburn especially in poor tanners. However, the impact of strict sun avoidance, which should not be recommended, may take years to be apparent as vitamin D deficiency is a now a common health issue in Caucasian populations, with a significant impact on health in general. PMID- 24142143 TI - Respiratory syncytial virus prophylaxis reduces chronic respiratory morbidity in prematurely born infants. PMID- 24142144 TI - Connected speech as a marker of disease progression in autopsy-proven Alzheimer's disease. AB - Although an insidious history of episodic memory difficulty is a typical presenting symptom of Alzheimer's disease, detailed neuropsychological profiling frequently demonstrates deficits in other cognitive domains, including language. Previous studies from our group have shown that language changes may be reflected in connected speech production in the earliest stages of typical Alzheimer's disease. The aim of the present study was to identify features of connected speech that could be used to examine longitudinal profiles of impairment in Alzheimer's disease. Samples of connected speech were obtained from 15 former participants in a longitudinal cohort study of ageing and dementia, in whom Alzheimer's disease was diagnosed during life and confirmed at post-mortem. All patients met clinical and neuropsychological criteria for mild cognitive impairment between 6 and 18 months before converting to a status of probable Alzheimer's disease. In a subset of these patients neuropsychological data were available, both at the point of conversion to Alzheimer's disease, and after disease severity had progressed from the mild to moderate stage. Connected speech samples from these patients were examined at later disease stages. Spoken language samples were obtained using the Cookie Theft picture description task. Samples were analysed using measures of syntactic complexity, lexical content, speech production, fluency and semantic content. Individual case analysis revealed that subtle changes in language were evident during the prodromal stages of Alzheimer's disease, with two-thirds of patients with mild cognitive impairment showing significant but heterogeneous changes in connected speech. However, impairments at the mild cognitive impairment stage did not necessarily entail deficits at mild or moderate stages of disease, suggesting non-language influences on some aspects of performance. Subsequent examination of these measures revealed significant linear trends over the three stages of disease in syntactic complexity, semantic and lexical content. The findings suggest, first, that there is a progressive disruption in language integrity, detectable from the prodromal stage in a subset of patients with Alzheimer's disease, and secondly that measures of semantic and lexical content and syntactic complexity best capture the global progression of linguistic impairment through the successive clinical stages of disease. The identification of disease-specific language impairment in prodromal Alzheimer's disease could enhance clinicians' ability to distinguish probable Alzheimer's disease from changes attributable to ageing, while longitudinal assessment could provide a simple approach to disease monitoring in therapeutic trials. PMID- 24142145 TI - Beneficial effects of bumetanide in a CaV1.1-R528H mouse model of hypokalaemic periodic paralysis. AB - Transient attacks of weakness in hypokalaemic periodic paralysis are caused by reduced fibre excitability from paradoxical depolarization of the resting potential in low potassium. Mutations of calcium channel and sodium channel genes have been identified as the underlying molecular defects that cause instability of the resting potential. Despite these scientific advances, therapeutic options remain limited. In a mouse model of hypokalaemic periodic paralysis from a sodium channel mutation (NaV1.4-R669H), we recently showed that inhibition of chloride influx with bumetanide reduced the susceptibility to attacks of weakness, in vitro. The R528H mutation in the calcium channel gene (CACNA1S encoding CaV1.1) is the most common cause of hypokalaemic periodic paralysis. We developed a CaV1.1-R528H knock-in mouse model of hypokalaemic periodic paralysis and show herein that bumetanide protects against both muscle weakness from low K+ challenge in vitro and loss of muscle excitability in vivo from a glucose plus insulin infusion. This work demonstrates the critical role of the chloride gradient in modulating the susceptibility to ictal weakness and establishes bumetanide as a potential therapy for hypokalaemic periodic paralysis arising from either NaV1.4 or CaV1.1 mutations. PMID- 24142146 TI - Clinical and polysomnographic course of childhood narcolepsy with cataplexy. AB - Our aim was to investigate the natural evolution of cataplexy and polysomnographic features in untreated children with narcolepsy with cataplexy. To this end, clinical, polysomnographic, and cataplexy-video assessments were performed at diagnosis (mean age of 10 +/- 3 and disease duration of 1 +/- 1 years) and after a median follow-up of 3 years from symptom onset (mean age of 12 +/- 4 years) in 21 children with narcolepsy with cataplexy and hypocretin 1 deficiency (tested in 19 subjects). Video assessment was also performed in two control groups matched for age and sex at first evaluation and follow-up and was blindly scored for presence of hypotonic (negative) and active movements. Patients' data at diagnosis and at follow-up were contrasted, compared with controls, and related with age and disease duration. At diagnosis children with narcolepsy with cataplexy showed an increase of sleep time during the 24 h; at follow-up sleep time and nocturnal sleep latency shortened, in the absence of other polysomnographic or clinical (including body mass index) changes. Hypotonic phenomena and selected facial movements decreased over time and, tested against disease duration and age, appeared as age-dependent. At onset, childhood narcolepsy with cataplexy is characterized by an abrupt increase of total sleep over the 24 h, generalized hypotonia and motor overactivity. With time, the picture of cataplexy evolves into classic presentation (i.e., brief muscle weakness episodes triggered by emotions), whereas total sleep time across the 24 h decreases, returning to more age-appropriate levels. PMID- 24142148 TI - Freezing of gait in Parkinson's disease is associated with functional decoupling between the cognitive control network and the basal ganglia. AB - Recent neuroimaging evidence has led to the proposal that freezing of gait in Parkinson's disease is due to dysfunctional interactions between frontoparietal cortical regions and subcortical structures, such as the striatum. However, to date, no study has employed task-based functional connectivity analyses to explore this hypothesis. In this study, we used a data-driven multivariate approach to explore the impaired communication between distributed neuronal networks in 10 patients with Parkinson's disease and freezing of gait, and 10 matched patients with no clinical history of freezing behaviour. Patients performed a virtual reality gait task on two separate occasions (once ON and once OFF their regular dopaminergic medication) while functional magnetic resonance imaging data were collected. Group-level independent component analysis was used to extract the subject-specific time courses associated with five well-known neuronal networks: the motor network, the right- and left cognitive control networks, the ventral attention network and the basal ganglia network. We subsequently analysed both the activation and connectivity of these neuronal networks between the two groups with respect to dopaminergic state and cognitive load while performing the virtual reality gait task. During task performance, all patients used the left cognitive control network and the ventral attention network and in addition, showed increased connectivity between the bilateral cognitive control networks. However, patients with freezing demonstrated functional decoupling between the basal ganglia network and the cognitive control network in each hemisphere. This decoupling was also associated with paroxysmal motor arrests. These results support the hypothesis that freezing behaviour in Parkinson's disease is because of impaired communication between complimentary yet competing neural networks. PMID- 24142147 TI - Sex as a determinant of relapse incidence and progressive course of multiple sclerosis. AB - The aim of this work was to evaluate sex differences in the incidence of multiple sclerosis relapses; assess the relationship between sex and primary progressive disease course; and compare effects of age and disease duration on relapse incidence. Annualized relapse rates were calculated using the MSBase registry. Patients with incomplete data or <1 year of follow-up were excluded. Patients with primary progressive multiple sclerosis were only included in the sex ratio analysis. Relapse incidences over 40 years of multiple sclerosis or 70 years of age were compared between females and males with Andersen-Gill and Tweedie models. Female-to-male ratios stratified by annual relapse count were evaluated across disease duration and patient age and compared between relapse-onset and primary progressive multiple sclerosis. The study cohort consisted of 11 570 eligible patients with relapse-onset and 881 patients with primary progressive multiple sclerosis. Among the relapse-onset patients (82 552 patient-years), 48,362 relapses were recorded. Relapse frequency was 17.7% higher in females compared with males. Within the initial 5 years, the female-to-male ratio increased from 2.3:1 to 3.3:1 in patients with 0 versus >=4 relapses per year, respectively. The magnitude of this sex effect increased at longer disease duration and older age (P < 10(-12)). However, the female-to-male ratio in patients with relapse-onset multiple sclerosis and zero relapses in any given year was double that of the patients with primary progressive multiple sclerosis. Patient age was a more important determinant of decline in relapse incidence than disease duration (P < 10(-12)). Females are predisposed to higher relapse activity than males. However, this difference does not explain the markedly lower female-to-male sex ratio in primary progressive multiple sclerosis. Decline in relapse activity over time is more closely related to patient age than disease duration. PMID- 24142149 TI - Heat-related thermal sensation, comfort and symptoms in a northern population: the National FINRISK 2007 study. AB - BACKGROUND: The occurrence of subjective symptoms related to heat strain in the general population is unknown. The present study aimed to describe the temperatures considered to be comfortable or hot and the prevalence of heat related complaints and symptoms in the Finnish population. METHODS: Four thousand and seven men and women aged 25-74 years, participants of the National FINRISK 2007 study, answered a questionnaire inquiring about the ambient temperatures considered to be hot and the upper limit of comfortable and about heat-related complaints and symptoms. The age trends in threshold temperatures and symptom prevalence were examined in 1-year groups by gender after smoothing with loess regression. The prevalence estimates were also adjusted for age. RESULTS: The temperature considered as hot averaged 26 degrees C and the upper limit for thermal comfort was 22 degrees C. Both temperatures declined with age (from 25 to 74 years) by 1-5 degrees C. Approximately 80% of the subjects reported signs or symptoms of heat strain in warm weather, mostly thirst (68%), drying of mouth (43%), impaired endurance (43%) and sleep disturbances (32%). Cardiac and respiratory symptoms were reported by 6 and 7%, respectively, and their prevalence increased up to the age of 75 years. The exception was thirst, whose prevalence declined with age. Most symptoms and complaints were more prevalent in women than men. CONCLUSIONS: A large percentage of this northern European population suffers from heat-related complaints. Information on these is an aid in assessing the burden of summer heat on population health and is a prerequisite for any rational planning of pre-emptive measures. PMID- 24142150 TI - miR-331-3p regulates expression of neuropilin-2 in glioblastoma. AB - Aberrant expression of microRNAs (miRNAs), a class of small non-coding regulatory RNAs, has been implicated in the development and progression of high-grade gliomas. However, the precise mechanistic role of many miRNAs in this disease remains unclear. Here, we investigate the functional role of miR-331-3p in glioblastoma multiforme (GBM). We found that miR-331-3p expression in GBM cell lines is significantly lower than in normal brain, and that transient overexpression of miR-331-3p inhibits GBM cell line proliferation and clonogenic growth, suggesting a possible tumor suppressor role for miR-331-3p in this system. Bioinformatics analysis identified neuropilin-2 (NRP-2) as a putative target of miR-331-3p. Using transfection studies, we validated NRP-2 mRNA as a target of miR-331-3p in GBM cell lines, and show that NRP-2 expression is regulated by miR-331-3p. RNA interference (RNAi) to inhibit NRP-2 expression in vitro decreased the growth and clonogenic growth of GBM cell lines, providing further support for an oncogenic role for NRP-2 in high-grade gliomas. We also show that miR-331-3p inhibits GBM cell migration, an effect due in part to reduced NRP-2 expression. Finally, we identified a significant inverse correlation between miR-331-3p and NRP-2 expression in The Cancer Genome Atlas GBM cohort of 491 patients. Together, our results suggest that a loss of miR-331 3p expression contributes to GBM development and progression, at least in part via upregulating NRP-2 expression and increasing cell proliferation and clonogenic growth. PMID- 24142151 TI - Functional pathways altered after silencing Pnpla6 (the codifying gene of neuropathy target esterase) in mouse embryonic stem cells under differentiation. AB - Neuropathy target esterase (NTE) is involved in several disorders in adult organisms and embryos. A relationship between NTE and nervous system integrity and maintenance in adult systems has been suggested. NTE-related motor neuron disease is associated with the expression of a mutant form of NTE and the inhibition and further modification of NTE by organophosphorus compounds is the trigger of a delayed neurodegenerative neuropathy. Homozygotic NTE knockout mice embryos are not viable, while heterozygotic NTE knockout mice embryos yields mice with neurological disorders, which suggest that this protein plays a critical role in embryonic development. The present study used D3 mouse embryonic stem cells with the aim of gaining mechanistic insights on the role of Pnpla6 (NTE gene encoding) in the developmental process. D3 cells were silenced by lipofectamine transfection with a specific interference RNA for Pnpla6. Silencing Pnpla6 in D3 monolayer cultures reduced NTE enzymatic activity to 50% 20 h post treatment, while the maximum loss of Pnpla6 expression reached 80% 48 h postsilencing. Pnpla6 was silenced in embryoid bodies and 545 genes were differentially expressed regarding the control 96 h after silencing, which revealed alterations in multiple genetic pathways, such as cell motion and cell migration, vesicle regulation, and cell adhesion. These findings also allow considering that these altered pathways would impair the formation of respiratory, neural, and vascular tubes causing the deficiencies observed in the in vivo development of nervous and vascular systems. Our findings, therefore, support the previous observations made in vivo concerning lack of viability of mice embryos not expressing NTE and help to understand the biology of several neurological and developmental disorders in which NTE is involved. PMID- 24142152 TI - Isolation, culture, and characterization of primordial germ cells in Mongolian sheep. AB - This study was performed to culture and preliminarily identify the primordial germ cells (PGCs) isolated from the genital ridge of the Mongolian sheep fetus. The growth characteristics of the sheep PGCs were detected in different culture systems such as culture media, resources, and state and passages of feeder cells. The obtained embryonic germ (EG) cells were identified by morphology, enzymology, and immunofluorescence. The results showed that the sheep EG cell colonies were ridgy, typically nest like, and compact, and had regular edges. Alkaline phosphatase staining reaction was weakly positive. EG cells expressed Kit, Rex-1, Nanog, and Oct-4. Immunofluorescence detection was weakly positive for Oct3/4, whereas positive for SSEA-1, SSEA-3, SSEA-4, TRA-1-61, and TRA-1-80. PMID- 24142153 TI - Ovalbumin enhances YKL-40, IL-5, GM-CSF, and eotaxin expression simultaneously in primarily cultured mouse tracheal epithelial cells. AB - Epithelial inflammation and eosinophil infiltration are crucial for the pathogenesis of asthma. Many inflammatory mediators, such as YKL-40, interleukin 5 (IL-5), granulocyte-macrophage colony-stimulating factor (GM-CSF), and eotaxin, are important for the development of allergic airway inflammation. This study is aimed at investigating the impact of treatment with ovalbumin (OVA) on the levels of those inflammatory mediators in primarily cultured mouse tracheal epithelial cells. Mouse tracheal epithelial cells were isolated and identified by immunofluorescent staining; the isolated mouse tracheal epithelial cells expressed cytokeratins. Treatment with OVA for 24 or 48 h significantly increased the relative levels of YKL-40, IL-5, GM-CSF, and eotaxin mRNA transcripts and YKL 40, IL-5, GM-CSF, and eotaxin proteins secreted in the supernatants of cultured cells, as compared with that in the untreated control cells (P < 0.01, P < 0.05, respectively). The levels of YKL-40 expression were correlated positively with the levels of IL-5, GM-CSF, and eotaxin expression in the OVA-treated cells. These data indicated that treatment with OVA simultaneously enhanced YKL-40, IL 5, GM-CSF, and eotaxin expression in the cultured mouse tracheal epithelial cells in vitro. These inflammatory mediators may synergistically contribute to the pathogenesis of allergic inflammation, and this study may help to understand the role of YKL-40 in the pathogenesis of asthma. PMID- 24142154 TI - Personal wilderness relationships: building on a transactional approach. AB - Wilderness managers are charged with the challenging goal of balancing resource protection and experience quality across a broad, value-laden landscape. While research has provided insight into visitors' motivations and their meanings for wilderness, a struggle exists to implement experiential concepts within current management frameworks. This research posits the human experience of wilderness to be an evolving, enduring relationship, and that research needs can be addressed by conceptualizing and investigating an individuals' personal wilderness relationship. The purpose of this study was to explore wilderness relationships of visitors to the Boundary Waters Canoe Area Wilderness. A predictive model was proposed to investigate the internal dimensions of a visitor's wilderness relationship. A mail-back questionnaire was distributed during the summer of 2007, resulting in a sample of 564 respondents. Data were analyzed using confirmatory factor analysis and structural equation modeling. Results from testing several relationship models provided support for a multidimensional structure consisting of five factors with a single overarching relationship factor. The preferred relationship model indicated the importance of identities and attachment in place relationships. Trust and commitment toward management were also important considerations. This research provided the preliminary evidence for a multidimensional wilderness relationship model and complements a perspective of wilderness experiences as wilderness. Findings may help to reframe decision-making and public-input processes that guide management actions to increased wilderness character protection and facilitate quality wilderness experiences. PMID- 24142156 TI - On the prevalence of KRAS mutations in GISTs. PMID- 24142158 TI - Dinuclear gold(I) dithio- and diselenophosph(in)ate complexes forming mononuclear gold(III) oxidative addition complexes and reversible chemical reductive elimination products. AB - Dinuclear gold(i) dithio- and diselenophosph(in)ate complexes were prepared to serve as precursors for subsequent oxidative addition (OA) chemistry following reaction with mild oxidant iodine, I2. The new OA products circumvented the formation of the expected dinuclear Au(ii) complexes, but instead formed novel chelating mononuclear square-planar gold(iii) products of the type [AuI2{E2PR2}] (R = (CH2)2Ph; E = S, 2; E = Se, 3) and [AuI2{Se2P(OR)2}] (R = Et, 4; (i)Pr, 5) directly. We further demonstrate that this process is chemically reversible as all the Au(iii) complexes undergo chemical reductive elimination to the starting dinuclear Au(i) complexes in the presence of SnI2 as determined by (119)Sn and (31)P NMR. The complexes (2-5) were all prepared from the reaction between I2 and the corresponding dinuclear gold(i) precursor material. All new complexes were characterized by (1)H, (31)P, (77)Se (for E = Se) NMR, infrared spectroscopy, elemental analysis and single crystal X-ray diffraction. PMID- 24142157 TI - Nephrogenic adenoma of the urinary tract: clinical, histological, and immunohistochemical characteristics. AB - Nephrogenic adenoma is a benign condition of the urinary tract resulting from the displacement and seeding of renal tubular cells from the renal pelvis to the urethra. A retrospective series of 134 cases collected from four hospitals in three different countries was analyzed in this study. Recorded clinical data included age and sex, topography, urological antecedents, coexistent lesions, and follow-up. Cytonuclear and architectural features were reviewed, and PAX-8, p63, PSMA, S100A1, CEA, EMA, CD117, cannabinoid receptor CB1, AMACR, E-cadherin, and CD10 antibodies were included in an immunohistochemical panel. Males predominated (105 M/29 F) with an average age of 66 years (range, 14-96). Urothelial carcinoma was the most frequent clinical antecedent (43.2 %) and also the most common coexisting lesion (14 %). Tubular architecture was the most frequent pattern detected (40 %) although most cases showed a mixed pattern (45.5 %). Deep infiltrative growth into the muscularis propria occurred in two cases. EMA and PAX-8 were expressed in 100 % of nephrogenic adenomas, while E-cadherin reactivity was observed in 66.6 % of cases, cannabinoid receptor CB1 in 25 %, CD10 in 13.6 %, CD117 in 4.1 %, and AMACR in 2.7 %. For the rest of the antigens, no reactivity was found. The average time lapse between the pathological antecedent and the discovery of a nephrogenic adenoma was 32 months. We conclude that nephrogenic adenoma displays a broad spectrum of histological features that may mimic malignancy. In our experience, CB1 immunostaining adds a further argument in favor of a renal origin of this lesion. The combination of PAX-8+, p63-, and EMA + distinguishes nephrogenic adenoma from urothelial and prostate carcinoma, its most frequent malignant look-alikes. PMID- 24142159 TI - Pseudomonas oryzae sp. nov. isolated from a paddy soil in South China. AB - A Gram-staining-negative, rod-shaped and motile with several polar flagellums bacterium, designated WM-3(T), was isolated from a rice paddy soil in South China. Growth occurred with 0-3.0 % (w/v) NaCl (optimum 2.0 %), at pH 5.5-9.0 (optimum pH 7.0) and at 25-42 degrees C (optimum 30-37 degrees C) in liquid Reasoner's 2A medium. Analysis of the 16S rRNA gene and gyrB gene sequences revealed that strain WM-3(T) was most closely related to the type strains of the species Pseudomonas linyingensis and Pseudomonas sagittaria. Its sequence similarities with P. linyingensis CGMCC 1.10701(T) and P. sagittaria JCM 18195(T) were 97.4 and 97.3 %, respectively, for 16S rRNA gene, and were 94.1 and 94.2 %, respectively, for gyrB gene. DNA-DNA hybridization between strain WM-3(T) and these two type strains showed relatedness of 35.6 and 30.9 %, respectively. G+C content of genomic DNA was 69.4 mol%. The whole-cell fatty acids mainly consisted of C16:0 (30.0 %), C16:1 omega6c and/or C16:1 omega7c (19.3 %) and C18:1 omega6c and/or C18:1 omega7c (16.3 %). The results of phenotypic, chemotaxonomic and genotypic analyses clearly indicated that strain WM-3(T) belongs to genus Pseudomonas but represents a novel species, for which the name Pseudomonas oryzae sp. nov. is proposed. The type strain is WM-3(T) (=KCTC 32247(T) =CGMCC 1.12417(T)). PMID- 24142161 TI - Monitoring of parasitic cysts in the brains of a flock of sheep in Egypt. AB - Cerebral parasitic cysts constitute a major problem for livestock. Among these, coenurosis and toxoplasmosis are predominant. Here, a total number of 60 sheep obtained from a private farm in Suez province, Egypt, were examined postmortem to detect visible parasitic cysts, and microscopically to detect small-sized entities. Necropsy revealed bladder-like cysts measuring 0.5-6.5 cm in diameter that were filled with a translucent fluid containing a large number of protoscolices. Accordingly, the cysts were identified as the metacestode Coenurus cerebralis. Among the sheep examined, 11 animals (7 males and 4 females) (18.3%) were infected. Most of the cysts were located in the cerebral hemispheres, with numbers ranging from one to three per infected animal. The effect of the presence of cysts in the brain tissue was evaluated. Histopathologically, pseudocysts of the apicomplexan Toxoplasma gondii were found in two animals with no detectable inflammatory cell reactions. In conclusion, coenurosis and toxoplasmosis are serious parasitic problems that play a significant role in sheep management in Egypt, as a result of close contact between livestock and dogs and cats, which play a critical role in the life cycle of these parasites. PMID- 24142162 TI - Metazoan endoparasites of Pygocentrus nattereri (Characiformes: Serrasalminae) in the Negro River, Pantanal, Brazil. AB - In the period of October 2007 to August 2008, 152 specimens of Pygocentrus nattereri were caught in the Negro River in the Nhecolandia region, central Pantanal wetland, State of Mato Grosso do Sul, Brazil. The specimens were necropsied and a total of 4,212 metazoan endoparasites were recovered, belonging to 10 taxons: Procamallanus (Spirocamallanus) inopinatus, Philometridae gen. sp., Eustrongylides sp., Brevimulticaecum sp., Contracaecum sp. (Nematoda), Echinorhynchus paranensis (Acanthocephala), Leiperia gracile, Sebekia oxycephala, Subtriquetra sp. 1 and Subtriquetra sp. 2 (Pentastomida). This is the first record of two parasite species from P. nattereri: E. paranensis and L. gracile. PMID- 24142163 TI - Ovary histology and quantification of hemolymph proteins of Rhipicephalus (Boophilus) microplus treated with Melia azedarach. AB - This study aimed to analyze ovary histology and quantify total protein in the hemolymph of Rhipicephalus (Boophilus) microplus females treated with hexane extracts from green fruits of Melia azedarach. Eight engorged females were immersed in the extract at 0.25% concentration, and eight in water containing 5% acetone (control). The females were dissected 72 hours after treatment, and the ovaries were weighed and subjected to standard histological techniques. The total protein concentration was measured in the hemolymph of 200 females, of which 100 were treated as described above and 100 served as a control. In the treated group, ovary weight reduction and predominance of immature oocytes were observed. In addition, there were decreases in the diameters of the cytoplasm and germ vesicle of the oocytes in the treated group, compared with the controls. The protein concentration in the hemolymph was higher in the treated group than in the controls. The morphological changes observed in the treated ovaries included: presence of vacuolization; alteration of oocyte morphology, which changed from rounded to elongated; deformation of the chorion; and disorganization of the yolk granules. These results demonstrate the action of M. azedarach fruit extracts on R. (B.) microplus oogenesis. PMID- 24142164 TI - Quantification of Leishmania infantum DNA in the bone marrow, lymph node and spleen of dogs. AB - The aim of the present study was to quantify the parasite load of Leishmania infantum in dogs using real-time PCR (qPCR). Bone marrow, lymph node and spleen samples were taken from 24 dogs serologically positive for L. infantum that had been put down by the official epidemiological surveillance service. According to the clinical signs the dogs were classified as asymptomatic or symptomatic. After DNA extraction, the samples were subjected to qPCR to detect and quantify L. infantum DNA. Out of the 24 dogs, 12.5% (3/24) were classified as asymptomatic and 87.5% (21/24) as symptomatic. Real-time PCR detected L. infantum DNA in all the animals, in at least one biological sample. In particular, 100% of bone marrow and lymph node scored positive, whereas in spleen, the presence of DNA was detected in 95.9% (23/24). In addition, out of 24 animals, 15 were microscopically positive to amastigote forms of L. infantum in bone marrow. No statistical significant difference was found in the overall mean quantity of DNA among the different biological samples (P = 0.518). Considering each organ separately, there was 100% positivity in bone marrow and lymph nodes, while among the spleen samples, 95.9% (23/24) were positive. Regarding the different clinical groups, the overall mean parasite load varied significantly (P = 0.022). According to the results obtained, it was not possible determine which biological sample was most suitable tissue for the diagnosis, based only on the parasite load. Therefore, other characteristics such as convenience and easily of obtaining samples should be taken into consideration. PMID- 24142165 TI - Seasonal distribution of gastrointestinal nematode infections in sheep in a semiarid region, northeastern Brazil. AB - The objective of this study was to determine the seasonal distribution and gastrointestinal nematode parasite load in crossbred Santa Ines tracer lambs, and to correlate the rainfall during the study period with occurrences of parasitic infections. Sixty-four male tracer lambs between the ages of four and eight months were used in the study. Two tracer lambs were inserted into the herd every 28 days to determine the pattern of infective larvae available in the environment. Variation in the fecal egg count (FEC) of nematodes was observed at the study site, with many samples containing undetectable parasite loads during the dry season. The larvae identified in coprocultures were Haemonchus sp., Trichostrongylus sp., Cooperia sp., Strongyloides sp. and Oesophagostomum sp. The nematodes recovered at necropsy were Haemonchus contortus, Trichostrongylus colubriformis, Cooperia punctata, C. pectinata, Trichuris sp., Oesophagostomum sp. and Skrajabinema ovis. The total number of larvae and the total number of immature and adult forms recovered from the tracers showed seasonal distributions that significantly correlated with the amount of rainfall received that month (p value ? 0.000 in all cases ). The species H. contortus was predominant in the herd and should be considered to be main pathogenic nematode species in these hosts under these conditions. PMID- 24142166 TI - Molecular detection of Ehrlichia canis and Anaplasma platys in dogs in Southern Brazil. AB - The aims of this study were to determine the occurrence of Anaplasma platys and Ehrlichia canis infection in dogs in Porto Alegre, Southern Brazil; and to investigate their association with hematological abnormalities. Serum samples from 196 dogs were first tested using dot-ELISA for antibodies against Anaplasma spp. and Ehrlichia canis. Peripheral blood samples from 199 dogs were subjected to 16S rRNA nested PCR (nPCR) for A. platys and E. canis, followed by DNA sequencing to ensure pathogen identity. A total of 19/196 samples (9.69%) were positive for Anaplasma spp. using ELISA and 28/199 (14.07%) samples were positive for A. platys by nested PCR. All the dog samples were negative for E. canis, both in anti-E. canis antibody tests and in nested PCR. There were no significant differences in hematological parameters between A. platys-PCR positive and negative dogs and Anaplasma spp. serologically positive dogs, except for basophil counts, which were higher in nPCR-positive dogs. This is the first report showing A. platys presence in dogs in Southern Brazil. In conclusion, hematological parameters may not be sufficient to diagnose A. platys infection in dogs in Southern Brazil, probably due either to low pathogenicity or to chronic infection. On the other hand, E. canis may either have very low occurrence or be absent in dogs in Porto Alegre. PMID- 24142167 TI - Environmental infestation and rickettsial infection in ticks in an area endemic for Brazilian spotted fever. AB - Brazilian spotted fever (BSF), caused by Rickettsia rickettsii, is endemic in the municipality of Americana, southeastern Brazil, where the disease is transmitted by the tick Amblyomma cajennense. This study evaluated the tick fauna and rickettsial infection in free-living ticks that were captured monthly using dry ice traps in areas endemic for BSF in Americana, from July 2009 to June 2010. Two tick species were captured: A. cajennense (6,122 larvae; 4,265 nymphs; 2,355 adults) and Amblyomma dubitatum (7,814 larvae; 3,364 nymphs; 1,193 adults). The immature stages of A. cajennense and A. dubitatum had similar distribution through the 12-month period, with larvae of both species collected in highest numbers between April and July, and nymphs between June and October. The highest numbers of A. cajennense adults were collected between October and December, whereas A. dubitatum adults were collected in relatively similar numbers throughout the 12-month period. Rickettsial infection was evaluated by means of PCR in 1,157 A. cajennense and 1,040 A. dubitatum ticks; only 41 (3.9%) A. dubitatum were found to be infected by Rickettsia bellii. The present study showed that the areas of Americana that are endemic for BSF are characterized by high environmental burdens of A. cajennense and A. dubitatum. PMID- 24142168 TI - Relationship between clinical and pathological signs and severity of canine leishmaniasis. AB - Canine visceral leishmaniasis (CVL) is a zoonotic disease that presents variable clinical and laboratory aspects. The aims of this study were to identify the main biochemical/hematological status of dogs naturally infected with Leishmania (Leishmania) infantum and to associate theses parameters with clinical forms of CVL. Blood samples were analyzed from 51 dogs, 15 uninfected (control group) and 36 infected, which were classified clinically in three groups: asymptomatic (n=12), oligosymptomatic (n=12) and symptomatic (n=12). All the infected dogs showed lower albumin/globulin ratios (A-G ratio) than the limit of reference. The mean values of total protein, urea, alpha-globulin 2, globulin and A-G ratio of infected dogs were outside the reference interval and differed significantly from those of the controls. Anemia was detected only in groups that showed clinical signs of the disease, and a statistical analysis indicated a significantly higher frequency of lower eritrogram in these groups than in the asymptomatic group. In addition, a significant association was observed between anemia and the presence of the symptoms, with dogs displaying higher erythrogram values showing better clinical conditions. These results provide additional evidence that the clinical forms of CVL may reflect on the erythrogram status. PMID- 24142169 TI - Characterization of the pyrethroid resistance profile of Rhipicephalus (Boophilus) microplus populations from the states of Rio Grande do Sul and Mato Grosso do Sul, Brazil. AB - Cattle ticks Rhipicephalus (Boophilus) microplus are mainly controlled in Brazil by means of acaricide products, without any official policies in this regard. Acaricides continue to be sold indiscriminately, and this has contributed towards making the problem of resistance widespread, thus making diagnosis and monitoring of tick resistance essential. Here, bioassays (larval packet test) were performed on tick populations from the states of Rio Grande do Sul and Mato Grosso do Sul regarding their susceptibility to cypermethrin, deltamethrin and flumethrin. All the tick samples tested showed resistance to cypermethrin (10) (resistance factor (RF) ranging from 5.6 to 80.3) and deltamethrin (10) (RF ranging from 2.4 to 83.1). Six out of eight populations were resistant to flumethrin (RF ranging from 3.8 to 8.2). PCR molecular analyses did not show any T2134A mutations in the voltage-gated sodium channel gene, in any of the sampled populations. The results from this study highlight the critical status of resistance of the cattle tick to synthetic pyrethroids in the regions studied. Further studies are needed to identify the mechanisms responsible for the resistant phenotypes observed in the bioassays. This was the first detection of flumethrin resistance in Brazil. PMID- 24142170 TI - Molecular detection of feline arthropod-borne pathogens in cats in Cuiaba, state of Mato Grosso, central-western region of Brazil. AB - Hemotrophic mycoplasmas (hemoplasmas), Bartonella sp., Hepatozoon sp. and Cytauxzoon felis are prominent pathogens that circulate between cats and invertebrate hosts. The present study aimed to detect the presence of DNA from hemoplasmas, Bartonella sp., Hepatozoon sp. and Cytauxzoon felis, and then confirm it by means of sequencing, in blood samples from cats in Cuiaba, MT, Brazil. From February 2009 to February 2011, blood samples with added EDTA were collected from 163 cats that were being housed in four different animal shelters in the city of Cuiaba, state of Mato Grosso, Brazil and from 15 cats that were admitted to the veterinary hospital of the Federal University of Mato Grosso (UFMT). Out of the 178 cats sampled, 15 (8.4%) were positive for hemoplasmas: four (2.2%) for Mycoplasma haemofelis, 12 (6.7%) for 'Candidatus M. haemominutum' and one (0.5%) for 'Candidatus M. turicensis'. One cat (0.5%), a patient that was attended at the veterinary hospital, was coinfected with M. haemofelis, 'Candidatus M. haemominutum' and 'Candidatus M. turicensis', based on sequencing confirmation. Four cats were positive for Bartonella spp.: three (1.7%) for B. henselae and one (0.5%) for B. clarridgeiae. None of the animals showed Cytauxzoon sp. or Hepatozoon sp. DNA in their blood samples. This study showed that cats housed in animal shelters in the city of Cuiaba, state of Mato Grosso, are exposed to hemoplasmas and Bartonella species. PMID- 24142171 TI - Helminths of wild hybrid marmosets (Callithrix sp.) living in an environment with high human activity. AB - The objective of this study was to identify the helminth fauna in hybrid, non native marmosets, through analysis of fecal samples. The study involved 51 marmosets (genus Callithrix) from five groups living in places with levels of human impact in Vicosa-MG. The marmosets were caught using a multiple-entrance trap and were anaesthetized. Feces were collected, refrigerated and analyzed by means of the sedimentation technique (Hoffmann-Pons-Janner). Eggs and parasites were identified, but not counted. Most of the marmosets (86%) were parasitized by at least one genus of helminths. Among the infected marmosets, 37% presented co infection. The intestinal helminths comprised four different taxa: Primasubulura jacchi, Ancylostomatidae, Prosthenorchis sp. and Dilepididae. P. jacchi and Ancylostomatidae had higher prevalences (> 80% and > 40%, respectively) and were found in all marmoset groups. Dilepididae species were found in almost all the groups, but only accounted for around 30% of the marmosets. Prosthenorchis sp. showed a relatively low prevalence (< 10%) and was only found in one group. Although two parasites are commonly found in marmosets and other primates (P. jacchi and Prosthenorchis sp.), our study is the first record for Ancylostomatidae and Dilepididae. Factors like marmosets' feeding behavior and their contact with humans and other species of nonhuman primates seem to be determinants of infection among marmosets. PMID- 24142172 TI - Gobioides broussonnetii (Gobiidae): a new host for Pterobothrium crassicolle (Trypanorhyncha) on Marajo Island, northern Brazil. AB - In the present study, the cestoid Pterobothrium crassicolle Diesing, 1850 (Trypanorhyncha), was observed parasitizing specimens of the violet goby (Gobioides broussonnetii Lacepede, 1800) collected from the estuary of the Paracauari River on Marajo Island in the north of the Brazilian state of Para, between January 2009 and December 2010. Tissue samples were analyzed, which led to identification of blastocysts containing plerocercoid larvae. These larvae were processed for scanning electron microscopy. Sixty G. broussonnetii specimens were dissected, and P. crassicolle was found in 48 (80%) of them. The violet goby, G. broussonnetii, is a new host for P. crassicolle. PMID- 24142173 TI - Hematological changes in Eleginops maclovinus during an experimental Caligus rogercresseyi infestation. AB - Eleginops maclovinus has been an important fishery resource in Chile since 1957. Caligus rogercresseyi is one of the most prevalent ectoparasite species found on E. maclovinus. Hematocrit, hemoglobin level, red blood cell count (RBC), white blood cell count (WBC), mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH), mean corpuscular hemoglobin concentration (MCHC) and differential white blood cell count were determined before and after an experimental infestation with C. rogercresseyi. We found significant differences in the hemoglobin level, WBC, MCV, MCH, MCHC, hematocrit level and RBC between infested and uninfested fish. Furthermore correlations between number of C. rogercresseyi with hematocrit, MCHC, neutrophil, eosinophil and lymphocyte counts were found. Hematological reference ranges of E. maclovinus in captivity conditions were also established. PMID- 24142174 TI - Parasitic infections of Piaractus mesopotamicus and hybrid (P. mesopotamicus x Piaractus brachypomus) cultured in Brazil. AB - This study evaluated the occurrence of parasitic infections in the "pacu" fish Piaractus mesopotamicus and the "patinga" hybrid (P. mesopotamicus x Piaractus brachypomus) in the northwest of Sao Paulo State, Brazil. Fish from the following three fish farms were evaluated every two months: A, a hatchery and larviculture farm (n = 16 pacu / n = 19 patinga), B, a growout farm (n = 35 patinga) and C, a fee-fishing property (n = 28 pacu / n = 7 patinga). Thirty-five fish from each property were collected from February 2010 to February 2011 and subjected to parasitological analysis. The parasites found were the following: Mymarothecium viatorum, Anacanthorus penilabiatus, Notozothecium janauachensis (Dactylogyridae, Monogenea), Trichodina spp., Ichthyophthirius multifiliis, Chilodonella sp. (Protozoa), Myxobolus spp., Henneguya spp. (Myxozoa), Rondonia rondoni, Contracaecum sp. (Nematoda), and Dolops carvalhoi (Crustacea). Of the fish examined, 62.9% from "A" and 100% from "B" and "C" were infested with at least one parasite species. Pacu fish (n = 44) showed a higher susceptibility to Anacanthorus penilabiatus infestations, whereas patinga (n = 61) were more susceptible to Mymarothecium viatorum (p < 0.05). Appropriate fish handling (nutrition, transport and storage), in conjunction with monitoring of water quality, can reduce the stress to which the farmed fish are exposed and is essential for pathogen control. PMID- 24142175 TI - Occurrence of gastrointestinal and renal helminths in Zenaida auriculata (Des Murs, 1847) trap-captured from Brazil. AB - This study aimed to determine the prevalence of gastrointestinal and renal helminths from naturally infected Zenaida auriculata captured in Londrina, Parana State. Two hundred and one Eared doves were trapped and the gastrointestinal and renal helminths were collected and identified according to morphological structures. One hundred and sixteen (57.71%) doves were parasitized by helminths with specific prevalences for Ornithostrongylus quadriradiatus in 50 doves (24.88%), Ascaridia columbae in 47 (23.38%), Paratanaisia bragai and P. confusa in 34 (16.92%), Tetrameres fissispina in 17 (8.46%), Synhimantus nasuta in 14 (6.47%), Brachylaima mazzantii in 4 (1.99%) and Raillietina allomyodes in 2 doves (1.00%). Seventy four/201 (37.00%) birds were infected with only one species, and 96/201 (48.00%) pigeons were infected with nematodes. The association between different classes of helminths occurred in 40/201 (20.00%) animals. The results showed statistically differences between the presence of nematode (p = 0.00001) and trematode species (p <= 0.05) in the doves, and there was an association between the local of capture and the presence of trematodes and A. columbae (p <= 0.05). This study is the first to report the infection of Z. auriculata from Brazil with O. quadriradiatus, A. columbae, T. fissispina, S. nasuta, R. allomyodes, P. bragai and P. confusa. PMID- 24142176 TI - Histological changes and immunolabeling of Leishmania infantum in kidneys and urinary bladder of dogs. AB - The aim of this study was to assess histological alterations and perform immunolabeling of Leishmania infantum in the kidneys and urinary bladder of naturally infected dogs. Twenty-five urinary bladder and kidney samples of serologically positive animals (ELISA S7(r) Biogene and IFAT >= 1:40 - Biomanguinhos/Fiocruz) were analyzed by means of immunohistochemical and histological techniques. Cystitis was found in 44% (11/25) of the bladder samples and membranoproliferative glomerulonephritis in 92% (23/25) of the kidney samples. Immunolabeling of the parasite revealed that 32% (8/25) of the bladders and 8% (2/25) of the kidneys were positive. In conclusion, the immunohistochemical technique is a useful tool for detecting amastigote forms of L. infantum in organs of infected dogs. In addition, this was the first report of detection of amastigote forms of L. infantum in the bladders of dogs. PMID- 24142177 TI - First autochthonous case of canine visceral leishmaniasis in Volta Redonda, Rio de Janeiro, Brazil. AB - In Brazil, American visceral leishmaniasis (AVL) is caused by Leishmania (Leishmania) chagasi and its main vector is Lutzomyia longipalpis. Cases of canine visceral leishmaniasis (CVL) in non-endemic areas have been reported over the last few years throughout the country. The objective of this research note is to describe an autochthonous case of CVL that occurred in the municipality of Volta Redonda, state of Rio de Janeiro, an area where the disease is not endemic, alerting veterinarians and the scientific community to the expansion of this important zoonosis and advising veterinary practitioners on how to deal with a suspicion of CVL. Canine visceral leishmaniasis can be misdiagnosed within a broad spectrum of canine diseases based on clinical and laboratory findings. Therefore, knowledge of its clinical manifestations, specific and sensitive laboratory diagnostic tests and parasitological procedures are of the utmost importance for rapid confirmation and notification of a case, thus contributing directly to the control of a focus. PMID- 24142178 TI - Petasiger dietz, 1909 (Trematoda: Echinostomatidae) in birds and mollusks from Brazil. AB - Species of Petasiger Dietz, 1909 are intestinal trematodes of aquatic birds. Despite the diversity of described species in Europe and North America, only two South American species are known and no species have been previously reported in birds from Brazil. During a study of helminths recovered from the Least Grebe, Tachybaptus dominicus (Linnaeus, 1766), from the state of Minas Gerais, Brazil, adult trematodes identified as Petasiger novemdecim Lutz, 1928 were found. The prevalence of infection was 55% (5/9), and the mean intensity of infection was 8 (1-32) parasites. Additionally, Biomphalaria straminea (Dunker, 1848) and Biomphalaria tenagophila (d'Orbigny, 1835) obtained from aquatic collections in the same state were found to harbor two species of echinostome cercariae of the Magnacauda group. These cercariae developed into metacercariae in experimentally infected Poecilia reticulata Peters, 1859. Attempts to obtain adult parasites in vertebrate host models (mice, chickens, ducks and canaries) were unsuccessful. The present study is the first report of Petasiger in Brazilian birds and the first morphological description of larvae of these parasites in Brazilian mollusks. Taxonomic aspects related to South American species of Petasiger are discussed. It is suggested that, based on significant morphological differences observed in larval stages (i.e., larval dimensions) and adult parasites (i.e., disposition of the testes), Petasiger caribbensis Nassi, 1980 should be reconsidered as a distinct species from P. novemdecim. PMID- 24142179 TI - Parasitic helminths of the digestive system of wild boars bred in captivity. AB - This study aimed to identify the parasites that inhabit the digestive system of Sus scrofa scrofa from a commercial breeding facility in southern Brazil, and reports the first occurrence of Trichostrongylus colubriformis in wild boars. The gastrointestinal tracts of 40 wild boars from a commercial breeding facility were collected and individualized during slaughter in a cold-storage slaughterhouse. Out of this total, 87.5% were parasitized by the helminths Ascaris suum, Trichostrongylus colubriformis, Oesophagostomum dentatum and Trichuris suis. T. colubriformis presented a prevalence of 45%, mean intensity of 28.4 and mean abundance of 12.8. The data from this study showed that T. colubriformis not only has a capacity to develop in the small intestines of wild boars, but also adapts well to animals raised in captivity, thus representing a possible cause of economic loss in commercial wild boar farming. PMID- 24142180 TI - Occurrence of antibodies to Toxoplasma gondii in rheas (Rhea americana) and ostriches (Struthio camelus) from farms of different Brazilian regions. AB - This study aimed to verify the occurrence of antibodies against Toxoplasma gondii in rheas (Rhea americana) and ostriches (Struthio camelus) commercially breeding in Brazil. Blood samples from 20 rheas and 46 ostriches (young and adults) were serologically tested using a technique known as modified agglutination test (MAT) at an initial titration of 1:16 for ostriches and 1:25 for rheas. Antibodies against T. gondii were found in 50% (10/20) of the rheas, with titers ranging from 1:25 to 1:6,400. The incidence of antibodies against T. gondii in ostriches was 17.4% (8/46) with titers ranging from 1:16 to 1:256. Birds showing titers higher than 1:200 for T. gondii were mainly the young ones. Therefore, rheas and ostriches may be parasitized by T. gondii, showing high levels of antibodies against this parasite. PMID- 24142181 TI - Video otoscopy as a diagnostic tool for canine otoacariasis. AB - Canine otoacariasis, or otodectic mange, is a common parasitic disorder of dogs' ear canals caused by the mite Otodectes cynotis. Infestation can be detected through diverse protocols of varying sensitivity. We evaluated the use of video otoscopy in comparison with conventional otoscopy and cerumen examination under a microscope for diagnosing O. cynotis in dogs. Thirty-five dogs were evaluated bilaterally for the presence of ear mites, using a veterinary otoscope (Gowlands(r)), a video otoscope (Welch Allyn(r)) and the gold-standard technique of examination of swab-collected cerumen under a microscope. Each ear was considered to represent one sample, and 69 ears were examined, since one dog presented with one completely stenotic ear canal. Ear mites were diagnosed in 59.42% (41/69) through video otoscopy. The same 41 infested ear canals were detected by means of cerumen examination under a microscope, whereas conventional otoscopy was able to diagnose mites in only 39.13% (27/69). This difference was statistically significant (p < 0.001). Video otoscopy proved to be superior to conventional otoscopy, and equivalent to the gold standard for detection of O. cynotis in canine ear canals, and should be recommended for controlled trials on drug efficacy for treatment of canine otoacariasis. PMID- 24142182 TI - Therapeutic drug monitoring to assess clinical response to sedative medications in the intensive care unit: a case report and discussion. AB - We describe the pharmacological evaluation of a 60 year old female admitted to the intensive care unit with severe necrotizing fasciitis not responding to excessive dosages of intravenous sedatives and analgesics. This evaluation revealed the first to be reported midazolam-ketamine drug interaction in the medical literature and explains how we were able to answer a relevant clinical question using pharmacokinetics and pharmacodynamics analysis of serum drug levels. PMID- 24142183 TI - Role of fibulin-3 in lung cancer: in vivo and in vitro analyses. AB - Lung cancer was the most commonly diagnosed cancer in 2008 worldwide. The level of fibulin-3 expression was found to be decreased in many cancer types due to aberrant promoter methylation and is correlated with poor survival of patients. However, the role of fibulin-3 and which form of fibulin-3 is expressed in lung cancer cells remain unclear. Therefore, pathologic and functional studies were carried out to determine the role of fibulin-3 in suppressing lung cancer both in vivo and in vitro. In the present study, we found that the levels of fibulin-3 mRNA and protein were lower in cancer tissues than in normal tissues. Downregulation of fibulin-3 mRNA in tumor tissues was associated with an increase in fibulin-3 promoter methylation. Circulating fibulin-3 was significantly associated with tumor progression, survival rate of lung cancer patients, and the number of circulating tumor cells (CTCs). To examine the effects of exogenous expression of fibulin-3 in vitro, lung cancer A549 cells were transfected with the pEGFP-C1-fibulin-3 expression vector. Relative to the untreated cells, fibulin-3-expressing cells exhibited lower proliferation and mobility as determined by MTT and Transwell assays, respectively. To conclude, our results suggest that fibulin-3 negatively modulates the invasiveness of lung cancer cells via regulation of p38-MAPK and MMP-2/9. PMID- 24142184 TI - Violence against women and gastroschisis: a case-control study. AB - BACKGROUND: Gastroschisis, a birth defect characterized by herniated fetal abdominal wall, occurs more commonly in infants born to teenage and young mothers. Ischemia of the vascular vitelline vessels is the likely mechanism of pathogenesis. Given that chronic stress and violence against women are risk factors for cardiovascular disease we explored whether these may represent risk factors for gastroschisis, when they occur during pregnancy. A case-control study was conducted, with 15 incident cases of children born with gastroschisis in the Region of Murcia, Spain, from December 2007 to June 2013. Forty concurrent controls were recruited at gestation weeks 20-24 or post-partum. All mothers of cases and controls completed a comprehensive, in-person, 'green sheet' questionnaire on environmental exposures. RESULTS: Mothers of children with gastroschisis were younger, smoked more cigarettes per week relative to controls, were exposed to higher amounts of illegal drugs, and suffered from domestic violence more frequently than the controls. Multivariable logistic regression analysis highlights periconceptional 'gender-related violence' (OR: 16.6, 95% CI 2.7 to 101.7) and younger maternal age (OR 1.1, 95% CI 1.0-1.3). CONCLUSIONS: Violence against pregnant women is associated with birth defects, and should be studied in more depth as a cause-effect teratogenic. Psychosocial risk factors, including gender-based violence, are important for insuring the health and safety of the pregnant mother and the fetus. PMID- 24142185 TI - Patients' acceptance towards a web-based personal health record system: an empirical study in Taiwan. AB - The health care sector has become increasingly interested in developing personal health record (PHR) systems as an Internet-based telehealthcare implementation to improve the quality and decrease the cost of care. However, the factors that influence patients' intention to use PHR systems remain unclear. Based on physicians' therapeutic expertise, we implemented a web-based infertile PHR system and proposed an extended Technology Acceptance Model (TAM) that integrates the physician-patient relationship (PPR) construct into TAM's original perceived ease of use (PEOU) and perceived usefulness (PU) constructs to explore which factors will influence the behavioral intentions (BI) of infertile patients to use the PHR. From ninety participants from a medical center, 50 valid responses to a self-rating questionnaire were collected, yielding a response rate of 55.56%. The partial least squares (PLS) technique was used to assess the causal relationships that were hypothesized in the extended model. The results indicate that infertile patients expressed a moderately high intention to use the PHR system. The PPR and PU of patients had significant effects on their BI to use PHR, whereas the PEOU indirectly affected the patients' BI through the PU. This investigation confirms that PPR can have a critical role in shaping patients' perceptions of the use of healthcare information technologies. Hence, we suggest that hospitals should promote the potential usefulness of PHR and improve the quality of the physician-patient relationship to increase patients' intention of using PHR. PMID- 24142186 TI - Identification and assessment of water pollution as a consequence of a leachate plume migration from a municipal landfill site (Tucuman, Argentina). AB - Landfills constitute potential sources of different pollutants that could generate human health and environmental problems. While some landfills currently work under the protection of a bottom liner with leachate collection, it was demonstrated that migration could take place even yet with these cautions. The purpose of this paper is to assess the pollution caused by a leachate plume from a municipal landfill that is affecting both groundwater and surface waters. The research was carried out at Pacara Pintado landfill in northwestern Argentina. Analysis of water samples indicates that leachate is affecting groundwater under the landfill area and an abandoned river channel hydraulically connected. In the center of the landfill area, the plume is anoxic and sulfate, nitrate, iron and manganese reduction zones were identified. Leachate plume presented high concentration of organic matter, Fe, Mn, NH(4)(+), Cl(-) and Cr reaching an extension of 900 m. The presence of a leachate plume in a landfill site with a single liner system implies that the use of this groundwater pollution control method alone is not enough especially if permeable sediments are present below. PMID- 24142187 TI - Financial motivation undermines potential enjoyment in an intensive diet and activity intervention. AB - The use of material incentives in healthy lifestyle interventions is becoming widespread. However, self-determination theory (SDT) posits that when material incentives are perceived as controlling, they undermine intrinsic motivation. We analyzed data from the Make Better Choices trial-a trial testing strategies for improving four risk behaviors: low fruit-vegetable intake, high saturated fat intake, low physical activity, and high sedentary activity. At baseline, participants reported the degree to which financial incentives were an important motivator (financial motivation); self-reported enjoyment of each behavior was assessed before and after the 3-week incentivization phase. Consistent with SDT, after controlling for general motivation and group assignment, lower financial motivation predicted more adaptive changes in enjoyment. Whereas participants low in financial motivation experienced adaptive changes, adaptive changes were suppressed among those high in financial motivation. PMID- 24142190 TI - Validation of a Quality of Life Questionnaire for Bronchiectasis: psychometric analyses of the Spanish QOL-B-V3.0. AB - PURPOSE: Bronchiectasis is a chronic disease, leading to worsening of health related quality of life. This study evaluated the psychometric properties of a new patient-reported outcome for non-cystic fibrosis bronchiectasis, the Quality of Life Questionnaire Bronchiectasis, translated into Spanish (QOL-B-Sp-V3.0). METHODS: This prospective study recruited clinically stable patients with non cystic fibrosis bronchiectasis at 4 Spanish centers. Health status was assessed with multiple indicators (dyspnea, exacerbations, bronchorrhea, etc.), microbiological, radiological, spirometric, and anthropometric parameters plus St George Respiratory Questionnaire (SGRQ). Psychometric analyses included internal consistency, test-retest reliability, convergent validity, predictive validity, and responsivity to change. RESULTS: The 207 stable patients (mean age 57.2 years) had a Bhalla score of 11.53 +/- 7.39 and FEV1% of 68.3 +/- 22.2 %. One hundred and sixty-one stable patients repeated the test 2 weeks later, and 80 patients who had an exacerbation within 6 months of the assessment also repeated it. Internal consistency was high across all scales (Cronbach's alpha >0.70). Thirty-six of 37 items correlated more strongly with their assigned scale than a competing scale. Test-retest coefficients were strong (intraclass correlations r = 0.68-0.88). All scales, except Treatment Burden, discriminated significantly between patients with mild, moderate, and severe disease according to FEV1% and other respiratory parameters. Strong convergence was found between the QOL-B-Sp V3.0 and SGRQ. Significant correlations were found between QOL-B-Sp-V3.0 and various clinical, spirometric, radiological, and anthropometric variables. Significant differences were found on all QOL-B-Sp-V3.0 scales, except emotional functioning, between the baseline responses and onset of an exacerbation; robust sensitivity to change was observed on the Respiratory Symptoms scale. CONCLUSIONS: The QOL-B-Sp-V3.0 questionnaire demonstrated strong reliability and validity. Scores were reproducible after 2 weeks, and it discriminated between patients who varied in severity and was responsive to changes related to exacerbation. PMID- 24142188 TI - Pharmacotherapy for stimulant-related disorders. AB - Stimulant-related disorders (SRD) continue to be an important public health problem for which there are presently no approved pharmacotherapies. Although behavioral interventions provide some benefit response varies. The development of novel and effective pharmacotherapies continues to be a research priority. Understanding neural mechanisms critical to the action of stimulants has helped reveal several potential pharmacotherapies that have already shown promise in controlled clinical trials. Common to some of these medications is the ability to reverse neural deficits in individuals with SRD. Results from thoroughly conducted clinical trials continue to broaden our knowledge increasing the possibility of soon developing effective pharmacotherapies for SRD. PMID- 24142191 TI - [Recovery of knee function after total knee arthroplasty: different outcomes in patients with osteoarthritis and rheumatoid arthritis]. AB - INTRODUCTION: Following total knee arthroplasty (TKA), no investigations have been published to assess possible differences between rheumatoid arthritic (RA) and osteoarthritic (OA) patients with respect to patient-reported outcome measures of knee function. PATIENTS AND METHODS: A cohort of 128 consecutively operated patients (OA: n = 92, RA: n = 36) treated with bicondylar TKA was included in this prospective, clinical study. Knee function was assessed preoperatively and at 6 and 12 months after TKA, using the Knee Injury and Osteoarthritis Outcome Score (KOOS) and Oxford Knee Score (OKS). RESULTS: Both OKS and KOOS revealed a statistically significant improvement for OA and RA patients at 6 and 12 months after surgery, as compared to the preoperative status. The results of the OKS at 6 and 12 months did not show a further improvement for either group. The KOOS, however, revealed an additional improvement between 6 and 12 months for the osteoarthritis group, regarding the total score and all subscores, but not for the RA subgroup. CONCLUSION: Functional recovery after TKA improves in the second 6 months after surgery in OA patients, but not in RA patients, when knee function is exclusively assessed with patient-reported outcome measures. PMID- 24142192 TI - Palmitate induces autophagy in pancreatic beta-cells via endoplasmic reticulum stress and its downstream JNK pathway. AB - Endoplasmic reticulum (ER) stress and autophagy have both been reported to be associated with lipotoxicity in beta-cells, yet the relationship between them has not been fully clarified. In the present study, we tested the hypothesis that the ER stress-autophagic pathway in beta-cells is a downstream pathway activated following saturated fatty acid treatment. Mouse insulinoma (MIN6) beta-cells were treated with either palmitate or thapsigargin (TG) with or without various inhibitors. The results indicated that palmitate strongly enhanced the protein expression of microtubule-associated protein 1 light chain 3 (LC3)-II. Furthermore, the expression levels of ER stress markers, BiP and CHOP, and phosphorylation levels of JNK were increased after palmitate treatment. In addition, palmitate-induced autophagy was blocked by 500 uM of the ER stress inhibitor tauroursodeoxycholic acid (TUDCA) or 20 uM JNK inhibitor SP600125. In turn, the phosphorylation of Akt (Ser473) was also downregulated by palmitate, while the levels of insulin receptor beta (IRbeta) were not reduced. A further increase in LC3-II levels was observed in cells treated with both palmitate and 50 uM PI3K/Akt inhibitor LY294002 compared with cells treated with palmitate alone. Palmitate-induced phospho-Akt (Ser473) downregulation was also inhibited by TUDCA or SP600125. Pretreatment with the autophagy inhibitor 3-methyladenine (3-MA, 5 mM) for 1 h increased the expression of ER stress markers, and enhanced cell injuries caused by 0.1 uM TG, including decreased cell viability and insulin secretion. Palmitate induces autophagy in pancreatic beta-cells possibly through activation of ER stress and its downstream JNK pathway. Palmitate-induced autophagy may protect beta-cells against cell injuries caused by ER stress. PMID- 24142193 TI - Industrial natural product chemistry for drug discovery and development. AB - Covering: up to March 2013. In addition to their prominent role in basic biological and chemical research, natural products are a rich source of commercial products for the pharmaceutical and other industries. Industrial natural product chemistry is of fundamental importance for successful product development, as the vast majority (ca. 80%) of commercial drugs derived from natural products require synthetic efforts, either to enable economical access to bulk material, and/or to optimize drug properties through structural modifications. This review aims to illustrate issues on the pathway from lead to product, and how they have been successfully addressed by modern natural product chemistry. It is focused on natural products of current relevance that are, or are intended to be, used as pharmaceuticals. PMID- 24142194 TI - Exploring the potential influence of climate change and particulate organic carbon scenarios on the fate of neutral organic contaminants in the Arctic environment. AB - The main objective of this study is to explore the potential influence of climate change and particulate organic carbon scenarios on the fate of organic chemicals in the Arctic marine environment using an evaluative modeling approach. Particulate organic carbon scenarios are included to represent changes such as enhanced primary production and terrestrial inputs. Simulations are conducted for a set of hypothetical chemicals covering a wide range of partitioning property combinations using a 40-year emission scenario. Differences in model output between the default simulations (i.e. contemporary conditions) and future scenarios during the primary emission phase are limited in magnitude (typically within a factor of two), consistent with other modeling studies. The changes to particulate organic carbon levels in the Arctic Ocean assumed in the simulations exert a relatively important influence for hydrophobic organic chemicals during the primary emission phase, mitigating the potential for exposure via the pelagic food web by reducing freely-dissolved concentrations in the water column. The changes to particulate organic carbon levels are also influential in the secondary emission/depuration phase. The model results illustrate the potential importance of changes to organic carbon levels in the Arctic Ocean and support efforts to improve the understanding of organic carbon cycling and links to climate change. PMID- 24142195 TI - The protective effects of fucosterol against skin damage in UVB-irradiated human dermal fibroblasts. AB - Exposure to ultraviolet (UV) light causes matrix metalloproteinase (MMP) overexpression and extracellular matrix depletion, leading to skin photoaging. The activation of MMP is related to increased interlukin-6 (IL-6) and type I procollagen production, which is regulated by transforming growth factor-beta1 (TGF-beta1). Activator protein-1 (AP-1) activation induces MMP-1 production and reduces type I procollagen secretion. Fucosterol, which is extracted and purified from the brown algae Hizikia fusiformis, is a phytosterol. We assessed the effects of fucosterol on photodamage and investigated its molecular mechanism of action in UVB-irradiated normal human dermal fibroblasts by using enzyme-linked immunosorbent assay, Western blot analysis, and reverse transcription-polymerase chain reaction. Our results showed that fucosterol significantly decreased the UVB-induced expression of MMP-1, IL-6, p-c-Jun, and p-c-Fos. Additionally, fucosterol markedly increased the UVB-induced production of type I procollagen and TGF-beta1. Our results indicate that fucosterol regulates MMP-1 and type I procollagen expression by modulating AP-1 and TGF-beta1 signaling and that MMP-1 activation is correlated with IL-6. These data suggest that fucosterol is a promising botanical agent to protect against skin photodamage. PMID- 24142196 TI - Accuracy of 3D fluoroscopy in cranial stereotactic surgery: a comparative study in phantoms and patients. AB - BACKGROUND: To assess the precision and accuracy of 3D fluoroscopy (XT) in phantoms and patients compared to computed tomography (CT) in localizing stereotactic probes. METHODS: Approval was obtained from the institutional research ethics board. The prospective phantom study was compared to a retrospective patient cohort. Accuracy was assessed by the mean error and precision by the mean dispersion between XT and CT with a cubic or a skull phantom containing metallic spheres installed on plates or along trajectories. Significance was assessed by Friedman's and Levene's test. Secondary endpoints were Euclidean error, other influences e.g. installed frame and radiation exposure. RESULTS: A total of 3,342 distances were assessed in 17 XT and 13 CT phantom scans. The cubic phantom showed mean distance errors of 0.33 mm (SD + 0.46 mm) for XT compared to 0.19 mm (SD + -0.83 mm) for CT scans (p = 0.0004) and a dispersion of 0.22 mm (XT) and 0.70 mm (CT). The dispersion was 0.36 mm with and 0.63 mm without a stereotactic frame (p < 0.0001). The mean Euclidean error was 0.72 mm (SD + -0.59 mm) in the skull phantom and 1.34 mm (SD + -0.82 mm) in the patient cohort. The effective dose was 0.65 mSv for the XT and 1.12 mSv for the CT. CONCLUSIONS: The accuracy of XT imaging in phantoms revealed a slightly lower accuracy but higher precision than the CT. The overall accuracy of XT was higher than that of the stereotactic frame allowing stereotactic localization with about half of the effective dose of a CT-scan. PMID- 24142197 TI - Frontobasal interhemispheric approach for large superasellar craniopharyngiomas: do the benefits outweigh the risks? AB - OBJECTIVE: Large suprasellar craniopharyngiomas are surgically challenging. The aim of our study was to explore the therapeutic efficacy of the frontobasal interhemispheric approach for these lesions. METHODS: Twenty-nine consecutive adult patients with large suprasellar craniopharyngiomas (diameter >4 cm) who underwent the frontobasal interhemispheric approach were retrospectively evaluated. Surgical and clinical outcomes were analyzed. RESULTS: Gross total removal was achieved in 23 cases (79.3%) and subtotal removal in 6 cases (20.7%). The mean follow-up period was 76.5 +/- 33.2 months (range, 12-132 months). Twenty four patients (82.7%) had improvement of the visual impairment score (VIS) after surgery. VIS was unchanged in five patients (17.3%), and no patients experienced visual deterioration. Among 23 patients who had preoperative hypopituitarism, 8 (34.8%) had an improvement. Postoperative new or aggravated hypopituitarism was observed in four patients (13.8%). Permanent diabetes insipidus was observed in ten patients (34.4%). Postoperative anosmia occurred in two earlier cases (6.9%). There was no intracranial infection or cerebrospinal fluid fistula. At last follow-up, >9% BMI gain was observed in 34.5% of patients, and 65.5% of patients returned to work. Four patients (13.8%) suffered recurrence. CONCLUSION: Although the frontobasal interhemispheric approach has some disadvantages, it provides ideal access to the suprasellar region and the third ventricle with limited brain retraction. The surgically visible angle is adequate; thus, vital structures can be better protected. For large suprasellar craniopharyngiomas, the benefits of this approach can outweigh its potential risks. PMID- 24142198 TI - HIV-1 progression links with viral genetic variability and subtype, and patient's HLA type: analysis of a Nairobi-Kenyan cohort. AB - In a Nairobi-Kenyan cohort of 50 HIV-1 positive patients, we analysed the prevalence of HIV-1 subtypes and human leucocyte antigen (HLA) alleles. From this cohort, 33 patients were selected for the analysis of HIV-1 infection progression markers (i.e. CD4 cell counts and viral loads) and their association with HIV-1 genetic variability and subtype, and patient's HLA type. HIV-1 gag genetic variability, analysed using bioinformatics tools, showed an inverse relationship with CD4 cell count whereas with viral load that relationship was direct. Certain HLA types and viral subtypes were also found to associate with patients' viral load. Associations between disease parameters and the genetic makeup of the host and virus may be crucial in determining the outcome of HIV-1 infection. PMID- 24142199 TI - Systematic review of the literature on clinical and experimental trials on the antitumor effects of cannabinoids in gliomas. AB - To evaluate, through a systematic review of the literature, the antitumoral effects of cannabinoids on gliomas. Research included the following electronic databases: PUBMED, EMBASE, LILACS and The Cochrane Collaboration Controlled Trials Register. All published studies involving the antitumoral effects (cellular and molecular mechanisms) of cannabinoids were considered for this review. The bibliography search strategy included all publications of each of these databases until December 31, 2012. From 2,260 initially identified articles, 35 fulfilled the inclusion criteria for this review. All the studies included in this systematic review were experimental (in vivo and/or in vitro), except for one pilot clinical trial phase I/II involving humans. In all experimental studies included, cannabinoids exerted antitumoral activity in vitro and/or antitumoral evidence in vivo in several models of tumor cells and tumors. The antitumor activity included: antiproliferative effects (cell cycle arrest), decreased viability and cell death by toxicity, apoptosis, necrosis, autophagy, as well as antiangiogenic and antimigratory effects. Antitumoral evidence included: reduction in tumor size, antiangiogenic, and antimetastatic effects. Additionally, most of the studies described that the canabinnoids exercised selective antitumoral action in several distinct tumor models. Thereby, normal cells used as controls were not affected. The safety factor in the cannabinoids' administration has also been demonstrated in vivo. The various cannabinoids tested in multiple tumor models showed antitumoral effects both in vitro and in vivo. These findings indicate that cannabinoids are promising compounds for the treatment of gliomas. PMID- 24142200 TI - Single institution experience treating 104 vestibular schwannomas with fractionated stereotactic radiation therapy or stereotactic radiosurgery. AB - The pupose of this study is to assess the long-term outcome and toxicity of fractionated stereotactic radiation therapy (FSRT) and stereotactic radiosurgery (SRS) for 100 vestibular schwannomas treated at a single institution. From 1993 to 2007, 104 patients underwent were treated with radiation therapy for vestibular schwannoma. Forty-eight patients received SRS, with a median prescription dose of 12.5 Gy for SRS (range 9.7-16 Gy). For FSRT, two different fraction schedules were employed: a conventional schedule (ConFSRT) of 1.8 Gy per fraction (Gy/F) for 25 or 28 fractions to a total dose of 45 or 50.4 Gy (n = 19); and a once weekly hypofractionated course (HypoFSRT) consisting of 4 Gy/F for 5 fractions to a total dose of 20 Gy (n = 37). Patients treated with FSRT had better baseline hearing, facial, and trigeminal nerve function, and were more likely to have a diagnosis of NF2. The 5-year progression free rate (PFR) was 97.0 after SRS, 90.5% after HypoFSRT, and 100.0% after ConFSRT (p = NS). Univariate analysis demonstrated that NF2 and larger tumor size (greater than the median) correlated with poorer local control, but prior surgical resection did not. Serviceable hearing was preserved in 60.0% of SRS patients, 63.2% of HypoFSRT patients, and 44.4% of ConFSRT patients (p = 0.6). Similarly, there were no significant differences in 5-year rates of trigeminal toxicity facial nerve toxicity, vestibular dysfunction, or tinnitus. CONCLUSIONS: Equivalent 5-year PFR and toxicity rates are shown for patients with vestibular schwanoma selected for SRS, HypoFSRT, and ConFSRT after multidisciplinary evaluation. Factors correlating with tumor progression included NF2 and larger tumor size. PMID- 24142201 TI - Indigenous studies speaks to environmental management. AB - This article describes the increasing connections between the fields of Indigenous studies and environmental management and examines some of the ways that an Indigenous studies perspective can guide thinking about environmental management. Indigenous groups have been involved in the management of environmental and natural resources on their lands since time immemorial. Indigenous groups have also become increasingly involved in Western practices of environmental management with the advent of co-management institutions, subsistence boards, traditional ecological knowledge forums, and environmental issues affecting Indigenous resources. Thus, it is an important time for scholarship that explores how Indigenous groups are both shaping and being affected by processes of environmental management. This article summarizes key findings and themes from eight papers situated at the intersection of these two fields of study and identify means by which environmental managers can better accommodate Indigenous rights and perspectives. It is the authors' hope that increased dialog between Indigenous studies and environmental management can contribute to the building of sustainable and socially just environmental management practices. PMID- 24142202 TI - The effect of acute tryptophan depletion on mood and impulsivity in polydrug ecstasy users. AB - RATIONALE: Several studies suggest users of 3,4-methylenedioxymethamphetamine (ecstasy) have low levels of serotonin. Low serotonin may make them susceptible to lowered mood. OBJECTIVE: This work aims to study the acute effects on mood and impulsivity of lowering serotonin levels with acute tryptophan depletion in polydrug ecstasy users and to determine whether effects were different in men and women. METHODS: In a double-blind cross-over study, participants who had used ecstasy at least 25 times (n = 13) and nonuser controls (n = 17) received a tryptophan-deficient amino acid mixture and a control amino acid mixture containing tryptophan, at least 1 week apart. Mood was measured using the profile of mood states, and impulsivity was measured with the Go/No-Go task. RESULTS: The main result shows that a lowering of mood after acute tryptophan depletion occurred only in female polydrug ecstasy users (n = 7), relative to controls (n = 9). Results from the Go/No-Go task suggested that impulsivity was not increased by acute tryptophan depletion in polydrug ecstasy users. LIMITATION: The group sizes were small, when males and females were considered separately. CONCLUSIONS: Women polydrug ecstasy users appear to be more susceptible than men to the effects of lowered serotonin levels. If use of ecstasy alone or in conjunction with other drugs causes progressive damage of serotonin neurons, women polydrug ecstasy users may become susceptible to clinical depression. PMID- 24142206 TI - Odanacatib does not influence the single dose pharmacokinetics and pharmacodynamics of warfarin. AB - BACKGROUND: Warfarin is an anticoagulant with a narrow therapeutic index that is involved in a number of drug-drug interactions. OBJECTIVES: This study evaluates the potential effect of odanacatib (a cathepsin K inhibitor in development for the treatment of osteoporosis) on the pharmacokinetics and pharmacodynamics of warfarin. METHODS: In a randomized, open-label, two-period fixed-sequence design, 13 healthy, postmenopausal female subjects received two different treatments (Treatment A: a single dose of 30 mg warfarin; Treatment B: 3 once-weekly doses of 50 mg odanacatib with 30 mg warfarin co-administered with the last dose). Warfarin R(+) and S(-) enantiomer concentrations and prothrombin time were measured at pre-dose and at specified time points over 168 hours in each treatment period. Statistical analysis was performed using linear mixed effects model. RESULTS: Odanacatib was generally well tolerated when co-administered with warfarin in this study. The GMRs (95% confidence intervals [CI]) for plasma AUC0 infinity of warfarin+odanacatib/warfarin alone were 0.99 (0.94, 1.03) for warfarin R(+) and 1.00 (0.97, 1.03) for warfarin S(-), consistent with a lack of interaction between odanacatib and warfarin; results for Cmax, Tmax, and terminal t1/2 provided also demonstrated no interaction. The GMR (warfarin + odancacatib/warfarin alone) and 95% CI for the statistical comparison of INR AUC(0-168 hr) was 1.01 (0.98, 1.04). CONCLUSIONS: The single dose pharmacokinetics and pharmacodynamics of orally administered warfarin were not meaningfully affected by multiple dose administration of odanacatib, indicating that odanacatib is not a clinically important inhibitor of CYPs 2C9, 3A4, 2C19, or 1A2. PMID- 24142203 TI - Behavioral and neurochemical pharmacology of six psychoactive substituted phenethylamines: mouse locomotion, rat drug discrimination and in vitro receptor and transporter binding and function. AB - RATIONALE: Psychoactive-substituted phenethylamines 2,5-dimethoxy-4 chlorophenethylamine (2C-C); 2,5-dimethoxy-4-methylphenethylamine (2C-D); 2,5 dimethoxy-4-ethylphenethylamine (2C-E); 2,5-dimethoxy-4-iodophenethylamine (2C I); 2,5-dimethoxy-4-ethylthiophenethylamine (2C-T-2); and 2,5-dimethoxy-4 chloroamphetamine (DOC) are used recreationally and may have deleterious side effects. OBJECTIVES: This study compares the behavioral effects and the mechanisms of action of these substituted phenethylamines with those of hallucinogens and a stimulant. METHODS: The effects of these compounds on mouse locomotor activity and in rats trained to discriminate dimethyltryptamine, (-) DOM, (+)-LSD, (+/-)-MDMA, and S(+)-methamphetamine were assessed. Binding and functional activity of the phenethylamines at 5-HT1A, 5-HT2A, 5-HT2C receptors and monoamine transporters were assessed using cells heterologously expressing these proteins. RESULTS: The phenethylamines depressed mouse locomotor activity, although 2C-D and 2C-E stimulated activity at low doses. The phenethylamines except 2C-T-2 fully substituted for at least one hallucinogenic training compound, but none fully substituted for (+)-methamphetamine. At 5-HT1A receptors, only 2C-T-2 and 2C-I were partial-to-full very low potency agonists. In 5-HT2A arachidonic acid release assays, the phenethylamines were partial to full agonists except 2C-I which was an antagonist. All compounds were full agonists at 5-HT2A and 5-HT2C receptor inositol phosphate assays. Only 2C-I had moderate affinity for, and very low potency at, the serotonin transporter. CONCLUSIONS: The discriminative stimulus effects of 2C-C, 2C-D, 2C-E, 2C-I, and DOC were similar to those of several hallucinogens, but not methamphetamine. Additionally, the substituted phenethylamines were full agonists at 5-HT2A and 5 HT2C receptors, but for 2C-T-2, this was not sufficient to produce hallucinogen like discriminative stimulus effects. Additionally, the 5-HT2A inositol phosphate pathway may be important in 2C-I's psychoactive properties. PMID- 24142207 TI - Chronic conditions and the challenges for knowledge production in health. PMID- 24142208 TI - Characterization of salt consumption among hypertensives according to socio demographic and clinical factors. AB - OBJECTIVE: To evaluate the relationship between the behaviors of salt consumption and socio-demographic and clinical variables. METHOD: Sodium consumption was evaluated using the methods: self-reporting (considering 3 different behaviors related to salt consumption), 24- hr dietary recall, discretionary salt, food frequency questionnaire, estimation of total sodium intake and 24-hr urinary excretion of sodium (n=108). RESULTS: Elevated salt intake according to the different measurements of consumption of the nutrient was associated with the variables: male sex, low level of schooling and monthly income, being Caucasian, and being professionally inactive; and with the clinical variables: elevated Body Mass Index, tensional levels, ventricular hypertrophy and the number of medications used. CONCLUSION: The data obtained shows a heterogenous association between the different behaviors related to salt consumption and the socio demographic and clinical variables. This data can be used to optimize the directing of educational activities with a view to reducing salt consumption among hypertensives. PMID- 24142209 TI - The experience of the illness and of the treatment for the person with systemic arterial hypertension: an ethnographic study. AB - OBJECTIVE: To interpret the meanings of the experience of the condition and of the treatment among people with arterial hypertension. METHOD: The authors adopted the frames of reference of interpretive and medical anthropology and of the ethnographic method. 22 people with arterial hypertension, and 10 Family Health Strategy health workers, all from Minas Gerais, participated. The authors used interviews, participant observation, focus groups, field diaries and analysis of medical records. Ethical precepts were respected. RESULTS: Two nuclei of meaning emerged: "The condition as an expression of way of living", and "The perspective of the cure of the condition". Nervous problems represent the nosological and symptomatic categories, caused by the urban way of living. The participants are supported by the belief of the curing of the problem. The family, spirituality and religion constitute social support networks. The therapeutic routes interpenetrate for the cure of the problem. The 'folk' health subsystem constitutes an important route because it provides better well-being and remission of the symptoms. CONCLUSION: The gaps evidenced between the points of view of the health professionals and the interviewees allow one to re-think the praxis so as to provide comprehensive, contextualized and humanized care, which encourages the people's potential for living, for empowerment, and for self care. PMID- 24142210 TI - Knowledge, attitudes and practices of nurses and doctors about the vertical transmission of hepatitis B. AB - OBJECTIVE: To identify knowledge, attitudes and practices of physicians and nurses of the Family Health Strategy and a maternity hospital unit about vertical transmission of hepatitis B. METHOD: A cross-sectional study with a self administered questionnaire applied to professionals. The data were analyzed according to professional category and site of action, whose differences were tested by chi2 and significance <5%. RESULTS: Professionals recognize viral hepatitis as a disease of compulsory notification; however, not everyone knows its mechanisms of transmission. A large portion of professionals requested serological tests, specifying the marker, especially physicians. The majority of family health nurses did not indicate hepatitis B vaccine for pregnant women, although they knew the immunization schedule. The majority of physicians on the maternity unit had proper knowledge about prevention of vertical transmission. CONCLUSION: The differences in the knowledge, attitudes and practices about vertical transmission of hepatitis B revealed that the population is at risk, since not all the professionals involved know or properly perform control strategies for vertical transmission of hepatitis B. Nurses dominated vaccination aspects and physicians dominated aspects related to the management of cases with positive serology. PMID- 24142211 TI - Social organization and control of tuberculosis: the experience of a Brazilian town. AB - OBJECTIVE: This study was aimed at analyzing the participation of a committee formed by representatives of the community in tuberculosis control based on a participatory management model. METHOD: This is a Case Study involving a tuberculosis committee with data collected through semi-structured interviews conducted with nine individuals. The data, organized through the Association of Ideas Map technique, were analyzed based on the Social Constructionism perspective. RESULTS: The participation of the Tuberculosis Committee studied was shown to be effective and associated with aspects articulated according to the measures taken by the social parties involved in the committee, culminating with assistances inserted into certain parts of the town's co-management. CONCLUSION: It was concluded that the reality of this case study shows that relationships among civil society can guide the management model in the search for effective processes of tuberculosis control. PMID- 24142212 TI - Retrospective study of the implementation of the nursing process in a health area. AB - OBJECTIVES: To analyze when the nursing process began to be used in the public and private healthcare centers of Gipuzkoa (Basque Country), and when both NANDA I nursing diagnoses and the NIC-NOC terminologies were incorporated into this process. METHOD: A retrospective study was conducted, based on the analysis of nursing records that were used in the 158 studied centers. RESULTS: The specific data provided showed that in Gipuzkoa, the nursing process began to be used in the 1990s. As for NANDA-I nursing diagnoses, they have been used since 1996, and the NIC-NOC terminologies has been used since 2004. CONCLUSION: It was concluded that public centers are the ones which, generally speaking, first began with the nursing methodology, and that in comparison to the United States and Canada, the nursing process started to be used about 20 years later, NANDA-I nursing diagnoses around 15 years later, and the NIC-NOC terminologies, around six years later. PMID- 24142213 TI - Efficiency of Calatonia on clinical parameters in the immediate post-surgery period: a clinical study. AB - OBJECTIVE: To assess the efficiency of the Calatonia technique about clinical parameters and pain in the immediate post-surgical phase. METHOD: A randomised study was carried out with 116 patients subjected to a cholecystectomy, by laparoscopy, divided into an experimental group (58 patients) and a placebo group (58 patients). The experimental group received the Calatonia technique, while the placebo was only subjected to non-intentional touches. RESULTS: The placebo group and the experimental group were considered homogeneous in terms of the variables: sex, age, physical status classification, duration of surgical procedures and also the time spent recovering in the Post-Anaesthetic Recovery Room. The only variable to show a statistically significant difference was the axillary temperature of the body. In relation to pain, the experimental group showed significant results, and hence it is possible to deduce that the relaxation caused by the Calatonia technique brought some relief of the general situation of pain. CONCLUSION: The application of Calatonia can take up the function of a resource complementary to assistance in the period immediately after surgery. Brazilian Register of Clinical Trials, UTN U1111-1129-9629. PMID- 24142214 TI - Perinatal mortality and socio-spatial inequalities. AB - OBJECTIVE: To analyze the social inequalities in the distribution of perinatal mortality in Belo Horizonte. MATERIAL AND METHODS: The perinatal deaths of residents in Belo Horizonte in the period 2003 to 2007 were studied on the basis of the Information Systems on Mortality and Newborns. The space analysis and the Health Vulnerability Index were used to identify existing inequalities in the sanitary districts regarding coverage and risk, determined by the Odds Ratio and a value p<0.05. The multivariate analysis was used to describe a model for perinatal mortality. RESULTS: There was a proved variation in the numbers of perinatal mortality per one thousand total births in the sanitary districts (12.5 to 19.4), coverage areas (5.3 to 49.4) and areas of risk (13.2 to 20.7). The mortality rate diminished as the maternal schooling increased. The death rates deriving from asphyxia/hypoxia and non-specified fetal death grew with the increase of risk in the area. CONCLUSION: It was verified that the perinatal deaths are distributed in a differentiated form in relation to the space and the social vulnerabilities. The confrontation of this complex problem requires the establishment of intersecting partnerships. PMID- 24142215 TI - Effectiveness of the Comprehensive Childhood Protection System for vulnerable mothers and children. AB - OBJECTIVES: To establish the effectiveness of the public benefits and services of the "Chile Grows with You" and "Protect Network" programs for socially vulnerable women and children in an urban community in the Metropolitan Region of Chile. METHOD: Descriptive study employing a questionnaire. The sample consisted of 132 mothers and their 133 infants, all grouped according to social vulnerability. Primary data were collected via a structured interview of the mothers and were complemented with institutional (secondary) data. Descriptive and associative analyses were performed. RESULTS: The perception of social vulnerability by the professionals was low at the time of admission into the program. The effectiveness of the universal and specific benefits was low, with better results for the children than for the mothers. However, no significant differences were observed according to vulnerability. Another finding was the low access to specific benefits for children with psychosocial risk and psychomotor delay, especially in the most vulnerable group. CONCLUSION: The results revealed a gap in the access to the benefits guaranteed by law. To overcome this situation, nurses must strengthen their skills in contextualized health practices and the comprehensive administration of interdisciplinary and intersectoral networks. PMID- 24142216 TI - Safe pediatric surgery: development and validation of preoperative interventions checklist. AB - OBJECTIVES: This study was aimed at developing and validating a checklist of preoperative pediatric interventions related to the safety of surgical patients. METHOD: Methodological study concerning the construction and validation of an instrument with safe preoperative care indicators. The checklist was subject to validation through the Delphi technique, establishing a consensus level of 80%. RESULTS: Five professional specialists in the area conducted the validation and a consensus on the content and the construct was reached after two applications of the Delphi technique. CONCLUSION: The "Safe Pediatric Surgery Checklist", simulating the preoperative trajectory of children, is an instrument capable of contributing to the preparation and promotion of safe surgery, as it identifies the presence or absence of measures required to promote patient safety. PMID- 24142217 TI - Classification of family risk in a Family Health Center. AB - OBJECTIVE: To identify and classify the degree of family risk in a Family Health Center by means of a multidimensional evaluation instrument. METHOD: A cross sectional study, with a quantitative and descriptive design, which evaluated 927 families registered in the center, which covers five micro-areas. The Coelho and Savassi Scale was applied, this consisting of 13 sentinels of evaluation of the social risk, using secondary data available in the File A of the families' medical records, in the last trimester of 2011. The data was analyzed using the SPSS (Statistical Package for the Social Sciences) for Windows software, version 18.0. RESULTS: Among the families studied, 68.5% were classified as not being at risk. It was ascertained that the smallest proportion of at-risk families (8.2%) was found in micro-area 1, and that micro-area 4 had the highest proportion (55.9%). The most-prevalent risk situations were poor conditions of basic sanitation, systemic arterial hypertension, diabetes mellitus and drug addiction. CONCLUSION: This study's results make it possible to create support for the planning of home visits, to implement health surveillance actions, and for health professionals to better understand the vulnerabilities of the families attended. PMID- 24142218 TI - The association between the functional incapacity of the older adult and the family caregiver's burden. AB - OBJECTIVE: To identify the association between the older adult's functional capacity and the caregiver's burden. METHOD: A cross-sectional, quantitative study, undertaken in a municipality in the north of the Brazilian state of Parana, with 178 older adults with functional incapacity, and their caregivers. The Functional Independence Measure was used for evaluating the older adults' functional capacity, and the Zarit Burden Interview was used for evaluating the caregiver burden, with the results being analyzed quantitatively. The majority of the older adults were females, widowed, with a mean age of 79.9 years old, and needing assistance for up to 50% of the daily living tasks. The majority of the caregivers were females, daughters, married, and had a mean age of 56.7 years old. RESULT: The majority of the caregivers reported moderate burden; the men presented higher probabilities of lower burden than the women; and the more independent the older adult was, the higher the probabilities of the caregiver having low burden. CONCLUSION: Encouraging actions directed at the promotion of active and healthy ageing centered on the maintenance of functional capacity and the older adult's autonomy, and implanting strategies for the organizing of care in the home which include the caregiver's health, can contribute to minimizing the effects of burden and improve quality of life. PMID- 24142219 TI - Working hours and health behaviour among nurses at public hospitals. AB - OBJECTIVE: To analyse the differences between genders in the description in the professional, domestic and total work hours and assess its association with health-related behaviour among nurses. METHODS: This is a transversal study carried out in 18 different public hospitals in the municipality of Rio de Janeiro. The data collection procedure was based on questionnaires. All nurses working with assistance were considered eligible (n=2,279). RESULTS: Men and women showed significant differences in relation to working hours. The female group showed longer domestic and total work hours when compared to the group of men. In contrast, the number of hours spent on professional work was higher among men. For the women, both the professional hours and total work hours were often associated with excessive consumption of fried food and also coffee, lack of physical exercise and also the greater occurrence of overweight and obesity. CONCLUSION: Both the professional hours and the domestic work hours need to be taken into account in studies about health, self-care and also the care provided within the context of nursing workers, particularly among women. The results add weight to the need for actions for health promotion in this occupational group and the importance of assessing the impact of long working hours on the health of workers. PMID- 24142220 TI - Transcultural adaptation and validation of the Conditions of Work Effectiveness Questionnaire-II instrument. AB - OBJECTIVE: This study aims at translating and validating the content of the instrument Conditions of Work Effectiveness-Questionnaire-II CWEQ-II), developed by Laschinger, Finegan, Shamian and Wilk, modified from the original CWEQ for the Brazilian culture. METHOD: The methodological procedure consisted of the stages of translation of the instrument into the Portuguese language; back-translation; semantic, idiomatic and cultural equivalence and tests of the final version. The instrument in the Portuguese version was applied to a group of 40 nurses in two hospitals. RESULTS: The data resulted in a Cronbach's Alpha of 0.86 for the first hospital and 0.88 for the second one. The results of the factorial analysis are considered sufficiently satisfactory. CONCLUSION: It is to conclude that the instrument can be used in Brazil. PMID- 24142221 TI - Relation between workplace accidents and the levels of carboxyhemoglobin in motorcycle taxi drivers. AB - OBJECTIVE: To investigate the relation between workplace accidents and the levels of carboxyhemoglobin found in motorcycle taxi drivers. METHOD: Correlational, quantitative study involving 111 workers and data obtained in July 2012 through a questionnaire to characterize the participants and blood collection to measure carboxyhemoglobin levels. RESULT: 28.8% had suffered workplace accidents; 27.6% had fractured the lower limbs and significant symptoms of carbon monoxide exposure were verified in smokers. The carboxyhemoglobin levels were higher among smokers and victims of workplace accidents. CONCLUSION: Motorcycle taxi drivers had increased levels of carboxyhemoglobin, possibly due to the exposure to carbon monoxide; these levels are also increased among smokers and victims of workplace accidents. The study provides advances in the knowledge about occupational health and environmental science, and also shows that carboxyhemoglobin can be an indicator of exposure to environmental pollutants for those working outdoors, which can be related to workplace accidents. PMID- 24142222 TI - Women in nursing teams: organizational identification and experiences of pleasure and suffering. AB - OBJECTIVE: To analyze the degree of influence of the organizational identification on the experiences of pleasure and suffering of women who are members of the nursing staff of two general hospitals in Belo Horizonte. METHOD: A quantitative study was conducted with 97 nurses and 414 nursing technicians chosen by convenience in their workplaces. We used a self-administered questionnaire containing four Likert-type scales: self and hetero-perceptions; identification with the organization; and experiences of pleasure and pain at work. RESULTS: The structural relations explained a small percentage of the variability of organizational identification, showing that the self and hetero perception are presented as relevant factors in professional identification with the organization. When considering how much the self and the hetero-perception and organizational identification all together impact in the experiences of pleasure and pain, a higher explanatory power is observed for: professional exhaustion, lack of recognition, freedom of expression and professional achievement. PMID- 24142223 TI - Identification of the support needs of individuals with severe mental illness using the Supports Intensity Scale. AB - OBJECTIVE: To characterize the intensity of the support needs of individuals with severe mental illness. METHODS: Quantitative and descriptive study that applied the Supports Intensity Scale to a sample comprising 182 individuals. RESULTS: The supports intensity profile identifies groups, individuals, and areas with different needs of support relative to the domains of home living, health, community living, learning, employment, and social living. As a whole, the intensity level of support needs found was low, and the domains with greater needs were employment and social. CONCLUSIONS: Identification of the intensity of support needs is helpful in planning integral care and detecting professional training needs. The support provision-centered approach, associated with the person-related outcomes perspective, has been sparsely applied to individuals with mental illness, and this represents the main contribution of the present study. In addition, this study introduces novel approaches to assessment that are both concordant and an innovation in nursing because they might provide a tool for understanding other disabilities. PMID- 24142224 TI - Alcohol consumption in young people between 18 and 24 years according to sociodemographic characteristics. AB - OBJECTIVE: To identify alcohol consumption in young people between 18 and 24 years of age in the province of Cordoba who participated in the National Survey of Risk Factors, according to sociodemographic characteristics. METHOD: A quantitative, analytic and cross-sectional study was undertaken in a sample of 240 young people. The alcohol consumption and sociodemographic characteristics were analyzed using bivariate analysis, risk ratio and confidence intervals. RESULTS: The lifetime prevalence of alcohol consumption corresponded to 79.17%, the one-year prevalence to 72.91% and the one-month prevalence to 57.08%, while episodic abuse and regular hazardous consumption corresponded to 25.55% and 24.19%. Consumption levels in the last month were higher among males (p=0.0028), single people (p=0.0001), with a secondary education degree (p=0.0306). CONCLUSION: In the province of Cordoba, drugs use, including alcohol, has not been an area of research interest in recent years, although alcohol abuse is associated with other risk factors, like accidents and violence, and is a factor of comorbidity and early mortality. Therefore, alcohol consumption in young people represents an area of concern and, once characterized, preventive actions should be adopted. PMID- 24142225 TI - Study of lipid profile in a population of university students. AB - OBJECTIVE: To evaluate the lipid profile in a population of university students. METHODS: Cross-sectional study with 702 students, of both genders enrolled in various courses at a public university in Fortaleza-CE. The demographic data and data on lifestyle habits were collected through a self-administered questionnaire. The blood collection was performed in a clinical laboratory. RESULTS: Showed a predominantly young population, with a mean age of 21.5 years with more females (62.7%). High levels of triglycerides, total cholesterol and cholesterol associated with low density lipoprotein (LDL-c) were found in 23.0%, 9.7% and 5.9% of students, respectively. The cholesterol associated with high density lipoprotein (HDL-c) was at reduced values in 12.0% of subjects and was significantly associated with smoking (p=0.0231) and physical inactivity (p=0.0357). CONCLUSION: Changes in lipid profile are present in the young population and intervention studies should be encouraged in order to reduce the prevalence of cardiovascular disease in adulthood. PMID- 24142226 TI - Record of hospitalizations for ambulatory care sensitive conditions: validation of the hospital information system. AB - OBJECTIVE: To estimate the sensitivity, specificity and positive and negative predictive values of the Unified Health System's Hospital Information System for the appropriate recording of hospitalizations for ambulatory care-sensitive conditions. METHOD: The hospital information system records for conditions which are sensitive to ambulatory care, and for those which are not, were considered for analysis, taking the medical records as the gold standard. Through simple random sampling, a sample of 816 medical records was defined and selected by means of a list of random numbers using the Statistical Package for Social Sciences. RESULT: The sensitivity was 81.89%, specificity was 95.19%, the positive predictive value was 77.61% and the negative predictive value was 96.27%. In the study setting, the Hospital Information System (SIH) was more specific than sensitive, with nearly 20% of care sensitive conditions not detected. CONCLUSION: There are no validation studies in Brazil of the Hospital Information System records for the hospitalizations which are sensitive to primary health care. These results are relevant when one considers that this system is one of the bases for assessment of the effectiveness of primary health care. PMID- 24142227 TI - Best practice of nurse managers in risk management. AB - OBJECTIVE: To identify the actions, undertaken by nurse managers in a risk management program, considered as best practice. METHOD: A case study undertaken in a private hospital in the south of Brazil. A risk manager and nurse managers working in a risk management program participated in this study. The data was collected between May and September 2011 through analysis of documents, semi structured interviews and non-participant observation. Based on the triangulation, the data was analyzed through practical measures. RESULTS: Educational actions, the critical analysis of the context, and the multiple dimensions of the management were evidenced as best practice. CONCLUSIONS: The broadening of understanding regarding risk management best practice offers further support for nurse managers to achieve excellence in their actions and thus provide safe and quality care. PMID- 24142228 TI - Motivations, contradictions and ambiguities in the leadership of nurses in management positions in a university hospital. AB - OBJECTIVE: To analyze the contradictions and ambiguities which permeate nurses' motivation for exercising leadership in management positions, in a university hospital. METHOD: This study has a qualitative approach and is exploratory and descriptive, and used a total of 33 semi-structured interviews which were submitted to thematic analysis. RESULTS: The information converged on five categories: Motivation to take on a management position; The view of nursing managers on the exercising of leadership; The emblematic aspect of working with people; Leadership in nursing--mediatory and conciliatory; Time: a dilemma between managing and caring. CONCLUSION: Leading people can be both a great encouragement, and an impeding aspect, bearing in mind the nuances of teamwork and the complexity of the context in which this process is constructed. In addition to this, conciliatory and mediatory attitudes are shown to be fundamental for a healthy and productive organizational atmosphere; however, the lack of time was indicated as a dilemma between managing and caring. PMID- 24142229 TI - Welcoming with risk classification in teaching hospitals: assessment of structure, process and result. AB - OBJECTIVE: To assess, from the worker's viewpoint, the structure, the process and the results of the Emergency Hospital Services that have taken up the guideline of "Welcoming with Risk Classification" in two teaching hospitals of the state of Parana. METHOD: Quantitative and descriptive research, exploratory and prospective, using random sampling stratified by professional category, comprising a universe of 216 professional people. RESULTS: They found some points of agreement regarding the promotion of a welcoming and humane environment; privacy and security; welcome and shelter of the companion and also the sheltering and classification of all patients; however, there was disagreement about the comfort of the environment, reference system and counter-reference, prioritisation of seriously ill patients in post-classification service, communication between the members of the multi-professional team and reassessment of the guideline. CONCLUSION: The workers assess the development of the guideline as being precarious, due mainly to the lack of physical structure, due to the lack of physical structure and shortcomings in the service process. PMID- 24142230 TI - Celiac disease resolution after allogeneic bone marrow transplantation is associated with absence of gliadin-specific memory response by donor-derived intestinal T-cells. AB - PURPOSE: To elucidate the relative role of the immune system and intestinal epithelium in the ethiopatogenesis of Celiac disease (CD). METHODS: A patient with childhood CD who underwent allogeneic bone marrow transplantation (BMT) for chronic myelogenous leukemia was followed for 5 years after resumption of gluten containing diet. Immunological memory to gliadin epitopes was assessed in the index patient and in 5 newly diagnosed CD patients by standard serology testing and by CFSE-based proliferation assays of peripheral blood CD4+ cells and of intestinal LPL towards gliadin-TTG antigens. Intestinal lymphocytes' origin was determined by combined immuno-histochemistry and fluorescent in-situ hybridiazation (FISH). RESULTS: Over 5 years of follow-up after receiving BMT from a HLA-matched woman and cessation of gluten-free diet, the patient has remained well, with negative periodic antibodies assays and unremarkable serial duodenal biopsies. In vitro proliferation assays showed lack of a memory response of the patient's peripheral blood and lamina propria CD4+ T-cells towards TTG, gliadin or TTG-treated gliadin, whereas memory responses were evident in the newly diagnosed CD patients. Immuno-FISH of post-BMT duodenal mucosa showed that the chromosomal phenotype of all the epithelial cells was XY. In contrast, CD45+ lymphocytic lineage cells were all donor-derived XX cells, presumably originating in the transplanted bone marrow and re-populating the intestinal wall. CONCLUSIONS: CD resolution following allogeneic BMT is associated with absent gliadin-specific memory response, and with a dichotomous lymphocyte-epithelial chimeric intestine. These observations suggest that the pathogenesis of CD is critically dependent upon the immune system rather than the epithelial compartment. PMID- 24142231 TI - Complete factor I deficiency due to dysfunctional factor I with recurrent aseptic meningo-encephalitis. AB - PURPOSE: Complement regulators control the activated complement system. Defects in this homeostasis can result in tissue damage and autoimmune diseases with a heterogeneity in clinical presentation. Complement factor I (FI), a serine protease, is an important regulator of alternative pathway activation. We report a diagnostic work-up of a patient with relapsing inflammatory mediated meningo encephalitis. Our work-up revealed a rare genetic factor I (FI) deficiency. So far, all cases of reported complete factor I deficiency have absent serum levels of FI. We present here a unique case of a complete factor I deficiency based on a functional FI defect. METHODS: Complement assays and measurement of FI activity were performed in the patient, her family, factor H-deficient patients, a patient with C3-nephritic factor and 11 healthy controls. Genetic sequencing of the FI coding regions in the patient and her parents was performed. RESULTS: The patient had absent alternative pathway activity with low levels of C3 and normal serum level of FI. The patient's plasma FI did not degrade C3b, with normalisation of C3b degradation after adding purified FI. Mutation analysis of the complement factor I gene revealed two heterozygous mutations (I322T and D506V). CONCLUSION: To our knowledge, this paper describes a complete FI deficiency caused by a defect of FI activity for the first time. Normal FI concentration does not exclude a complete FI defect, additional functional analysis of FI is required in any patient with a defect of complement activation. Recurrent aseptic meningo encephalitis is a rare clinical presentation of complete FI deficiency. PMID- 24142233 TI - Lymph node involvement and metastatic lymph node ratio influence the survival of malignant pleural mesothelioma: a French multicenter retrospective study. AB - Malignant pleural mesothelioma (MPM) is a rare tumor with disastrous evolution. The prognostic value of nodal involvement is still debated. We analyzed the impact of nodal involvement on overall survival (OS) in patients treated by multimodal therapy including extra pleural pneumonectomy (EPP). We evaluated the role, as a prognostic factor, of the metastatic lymph node ratio (LNR), corresponding to the number of involved nodes out of the total number of removed nodes. In this retrospective multicentric study, we reviewed the data of 99 MPM patients. Information regarding lymph node involvement was assessed from the final pathology reports. N1-N3 patients were pooled as N+ group. The OS, calculated by the Kaplan-Meier method, was compared using the log-rank test. A multivariate Cox proportional hazards model was used to identify independent prognostic factors. For the whole cohort, median OS was 18.3 months and 5-year survival was 17.5%. N+ status reduced significantly the median survival (22.4 months for N0 patients vs 12.7 months for N+ patients, P=0.002). A lower metastatic LNR (<=13%) was associated with a significantly improved median survival (19.9 vs. 11.7 months, P=0.01). OS was not related to the number of involved or total removed lymph nodes. In multivariate analysis, only adjuvant radiotherapy (P=0.001) was identified as an independent positive prognostic factor. Metastatic LNR is a more reliable prognostic factor than the number of involved lymph nodes or the total number of removed nodes. However, it could not be identified as an independent prognostic factor. PMID- 24142232 TI - A randomized, controlled dose-finding Phase II study of the M72/AS01 candidate tuberculosis vaccine in healthy PPD-positive adults. AB - PURPOSE: In this dose-finding Phase II study (NCT00621322), we evaluated the safety and immunogenicity of different formulations of the candidate tuberculosis vaccine containing the M72 antigen (10/20/40 MUg doses) and the liposome-based AS01 Adjuvant System. We aimed to select the lowest-dose combination of M72 and AS01 that was clinically well tolerated with immunogenicity comparable to that of the previously tested M72/AS01B (40 MUg) candidate vaccine. METHODS: Healthy PPD positive (induration 3-10 mm) adults (18-45 years) in The Philippines were randomized (4:4:4:4:1:1) to receive 2 injections, 1 month apart, of M72/AS01B (40 MUg), M72/AS01E (10 MUg), M72/AS01E (20 MUg), M72/AS02D (10 MUg), M72/Saline (40 MUg) or AS01B alone, and were followed up for 6 months. AS01E and AS02D contain half the quantities of the immunostimulants present in AS01B. AS02D is an oil-in water emulsion. Vaccine selection was based on the CD4(+) T-cell responses at 1 month post vaccination. RESULTS: All formulations had a clinically acceptable safety profile with no vaccine-related serious adverse events reported. Two vaccinations of each adjuvanted M72 vaccine induced M72-specific CD4(+) T-cell and humoral responses persisting at 6 months post vaccination. No responses were observed with AS01B alone. One month post second vaccination, CD4(+) T-cell responses induced by each of the three M72/AS01 vaccine formulations were of comparable magnitudes, and all were significantly higher than those induced by M72/AS02D (10 MUg) and M72/Saline. CONCLUSIONS: The formulation with the lowest antigen and adjuvant dose, M72/AS01E (10 MUg), fulfilled our pre-defined selection criteria and has been selected for further clinical development. PMID- 24142234 TI - Responsibility practices and unmanned military technologies. AB - The prospect of increasingly autonomous military robots has raised concerns about the obfuscation of human responsibility. This papers argues that whether or not and to what extent human actors are and will be considered to be responsible for the behavior of robotic systems is and will be the outcome of ongoing negotiations between the various human actors involved. These negotiations are about what technologies should do and mean, but they are also about how responsibility should be interpreted and how it can be best assigned or ascribed. The notion of responsibility practices, as the paper shows, provides a conceptual tool to examine these negotiations as well as the interplay between technological development and the ascription of responsibility. To illustrate the dynamics of responsibility practices the paper explores how the introduction of unmanned aerial vehicles has led to (re)negotiations about responsibility practices, focusing particularly on negotiations within the US Armed Forces. PMID- 24142235 TI - Systemic therapy for colorectal cancer: patterns of chemotherapy and biologic therapy use in nationally representative US claims database. AB - BACKGROUND: Treatment strategies for colorectal cancer (CRC) are highly variable. The aim of this study is to examine the patterns of chemotherapy and biologic therapy use for CRC patients in a national medical claims database. METHODS: A retrospective and observational analysis was performed using the i3 Innovus claims database to identify healthcare services consumed by patients aged 18 years and older, diagnosed with CRC between 1 January 2005 and 30 June 2009 in commercial health plans. RESULTS: Of 9,876 subjects diagnosed with CRC, fluorouracil (23.5 %) and capecitabine (10.0 %) were the dominant first-line monotherapies, followed by bevacizumab (3.2 %) and oxaliplatin (2.9 %). The most common combination regimen at first line and first and second line was FOLFOX (fluorouracil, leucovorin, and oxaliplatin; more than 25 %). The combinations FOLFIRI (fluorouracil, leucovorin, and irinotecan) plus bevacizumab (14.2 %) and FOLFOX plus bevacizumab (13.9 %) were significantly more frequent in third and successive lines of CRC therapy than other regimens (chi(2) = 191.2; P < 0.01). Additionally, the average annualized cost of CRC treatment for all patients was $US66,452, and the adjusted analysis demonstrated that patients receiving FOLFOX A (FOLFOX + avastin) or FOLFIRI-A (FOLFIRI + avastin) had higher costs for CRC treatment. CONCLUSIONS: With the exception of a sizeable portion of patients on monotherapy, the treatment patterns for CRC were largely consistent with National Comprehensive Cancer Network (NCCN) guidelines. PMID- 24142236 TI - Psychometric properties of the Dutch Short Musculoskeletal Function Assessment (SMFA) questionnaire in patients with a fracture of the upper or lower extremity. AB - PURPOSE: This prospective study examined the psychometric properties of the adapted Dutch translation of the Short Musculoskeletal Function Assessment (SMFA) questionnaire in patients with isolated unilateral lower fracture (LEF) or upper extremity fracture (UEF). METHODS: Patients (N = 458) completed the SMFA, WHOQOL BREF, and the RAND-36 at time of diagnosis (i.e. pre-injury status), 1, and 2 weeks post-fracture. Principal axis factoring was performed, and Cronbach's alpha coefficients (alpha) and intra-class correlation coefficients (ICC) were calculated. Furthermore, Pearson's product-moment correlations (r), paired t tests, and standardized response means (SRM) were calculated. RESULTS: A three factor structure was found: Lower extremity dysfunction, Upper extremity dysfunction, and Daily life consequences. This structure was different for patients with LEF versus UEF. ICCs ranged from .68 to .90, and alpha varied from .81 to .95. The correlations between the SMFA and, respectively, the RAND-36 and WHOQOL-BREF were small to large depending on the SMFA factor combined with fracture location. Responsiveness was confirmed (p < .0001; SRM ranging from .28 to 1.71). CONCLUSIONS: The SMFA has good psychometric properties in patients with fractures. Patients with UEF and LEF could not be regarded as a homogenous group. The development of separate SMFA modules should be considered. PMID- 24142237 TI - Item reduction of the Wisconsin Upper Respiratory Symptom Survey (WURSS-21) leads to the WURSS-11. AB - PURPOSE: To develop a shorter version of the Wisconsin Upper Respiratory Symptom Survey (WURSS-21), a self-report questionnaire for evaluating daily symptoms and functional impairments during acute respiratory illness (ARI). METHODS: WURSS-21 data were retrieved from 4 studies (n = 1167) spanning the years 2002-2010. Similar methodologies were employed among these studies. Degree of missingness, ceiling/floor effects, and exploratory (EFA) and confirmatory (CFA) factor analyses were investigated and used to guide item retention. Stability of the reduced WURSS was evaluated across the first 3 days of ARI. RESULTS: Degree of missingness was <1 % and appeared to be completely at random. Seven WURSS items with >30 % of ratings of zero (floor effects) were eliminated. Cross-loading items (head congestion, sleep well and breathe easily) were excluded following EFA on subset-1. Subsequent CFA using subset-2 showed satisfactory indices of fit. The reduced WURSS-11 instrument demonstrated 3 dimensions of 3 items each and was stable across 3 days of illness. The indicated dimensions (items) include nasal (runny nose, plugged nose, sneezing), throat (cough, sore throat, scratchy throat), and quality of life (feeling tired, think clearly, accomplish daily activities). CONCLUSION: The WURSS-11 has similar dimensional structure as the WURSS-21. This shorter version may reduce the time and burden required for completing the survey. PMID- 24142238 TI - Education influences the role of genetics in myopia. AB - Myopia is a complex inherited ocular trait resulting from an interplay of genes and environmental factors, most of which are currently unknown. In two independent population-based cohorts consisting of 5,256 and 3,938 individuals from European descent, we tested for biological interaction between genetic predisposition and level of education on the risk of myopia. A genetic risk score was calculated based on 26 myopia-associated single nucleotide polymorphisms recently discovered by the Consortium for Refractive Error and Myopia. Educational level was obtained by questionnaire and categorized into primary, intermediate, and higher education. Refractive error was measured during a standardized ophthalmological examination. Biological interaction was assessed by calculation of the synergy index. Individuals at high genetic risk in combination with university-level education had a remarkably high risk of myopia (OR 51.3; 95 % CI 18.5-142.6), while those at high genetic risk with only primary schooling were at a much lower increased risk of myopia (OR 7.2, 95 % CI 3.1-17.0). The combined effect of genetic predisposition and education on the risk of myopia was far higher than the sum of these two effects (synergy index 4.2, 95 % CI 1.9 9.5). This epidemiological study provides evidence of a gene-environment interaction in which an individual's genetic risk of myopia is significantly affected by his or her educational level. PMID- 24142239 TI - The fat mass index: why its height exponent should be 3 and not 2. PMID- 24142240 TI - Reply to RF Burton. PMID- 24142241 TI - Primate fructose study misses mark due to preventable design flaws. PMID- 24142242 TI - Reply to JS White. PMID- 24142245 TI - Protective effects of garlic extract on cardiac function, heart rate variability, and cardiac mitochondria in obese insulin-resistant rats. AB - PURPOSE: Garlic has been shown to exhibit antioxidant effects and cardioprotective properties. However, the effects of garlic extract on the heart in insulin resistance induced by long-term high-fat-diet consumption are not well defined. Therefore, we sought to determine the effects of garlic extract in the obese insulin-resistant rats. METHODS: Male Wistar rats (180-200 g) were divided into two groups: normal-diet or high-fat-diet (n = 24/group) fed for 12 weeks. Rats in each groups were divided into three subgroups (n = 8 each): vehicle or garlic extract (250 or 500 mg/kg/day, respectively) treated for 28 days. At the end of the treatment, the metabolic parameters, heart rate variability (HRV), cardiac function, and cardiac mitochondrial function were determined. RESULTS: Rats that received a high-fat-diet for 12 weeks had increased body weight, visceral fat, plasma insulin levels, total cholesterol, oxidative stress levels, depressed HRV, and cardiac mitochondrial dysfunction. Garlic extract at both concentrations significantly decreased the plasma insulin, total cholesterol, homeostasis model assessment index, and oxidative stress levels. Furthermore, garlic extract at both doses restored the HRV, cardiac function, and cardiac mitochondrial function. CONCLUSION: We concluded that garlic extract at both concentrations exerted cardioprotective effects against cardiac dysfunction and mitochondrial dysfunction in obese insulin-resistant rats. PMID- 24142246 TI - ExsA and LcrF recognize similar consensus binding sites, but differences in their oligomeric state influence interactions with promoter DNA. AB - ExsA activates type III secretion system (T3SS) gene expression in Pseudomonas aeruginosa and is a member of the AraC family of transcriptional regulators. AraC proteins contain two helix-turn-helix (HTH) DNA binding motifs. One helix from each HTH motif inserts into the major groove of the DNA to make base-specific contacts with the promoter region. The amino acids that comprise the HTH motifs of ExsA are nearly identical to those in LcrF/VirF, the activators of T3SS gene expression in the pathogenic yersiniae. In this study, we tested the hypothesis that ExsA/LcrF/VirF recognize a common nucleotide sequence. We report that Yersinia pestis LcrF binds to and activates transcription of ExsA-dependent promoters in P. aeruginosa and that plasmid-expressed ExsA complements a Y. pestis lcrF mutant for T3SS gene expression. Mutations that disrupt the ExsA consensus binding sites in both P. aeruginosa and Y. pestis T3SS promoters prevent activation by ExsA and LcrF. Our combined data demonstrate that ExsA and LcrF recognize a common nucleotide sequence. Nevertheless, the DNA binding properties of ExsA and LcrF are distinct. Whereas two ExsA monomers are sequentially recruited to the promoter region, LcrF binds to promoter DNA as a preformed dimer and has a higher capacity to bend DNA. An LcrF mutant defective for dimerization bound promoter DNA with properties similar to ExsA. Finally, we demonstrate that the activators of T3SS gene expression from Photorhabdus luminescens, Aeromonas hydrophila, and Vibrio parahaemolyticus are also sensitive to mutations that disrupt the ExsA consensus binding site. PMID- 24142247 TI - Functional conservation of the capacity for ent-kaurene biosynthesis and an associated operon in certain rhizobia. AB - Bacterial interactions with plants are accompanied by complex signal exchange processes. Previously, the nitrogen-fixing symbiotic (rhizo)bacterium Bradyrhizobium japonicum was found to carry adjacent genes encoding two sequentially acting diterpene cyclases that together transform geranylgeranyl diphosphate to ent-kaurene, the olefin precursor to the gibberellin plant hormones. Species from the three other major genera of rhizobia were found to have homologous terpene synthase genes. Cloning and functional characterization of a representative set of these enzymes confirmed the capacity of each genus to produce ent-kaurene. Moreover, comparison of their genomic context revealed that these diterpene synthases are found in a conserved operon which includes an adjacent isoprenyl diphosphate synthase, shown here to produce the geranylgeranyl diphosphate precursor, providing a critical link to central metabolism. In addition, the rest of the operon consists of enzymatic genes that presumably lead to a more elaborated diterpenoid, although the production of gibberellins was not observed. Nevertheless, it has previously been shown that the operon is selectively expressed during nodulation, and the scattered distribution of the operon via independent horizontal gene transfer within the symbiotic plasmid or genomic island shown here suggests that such diterpenoid production may modulate the interaction of these particular symbionts with their host plants. PMID- 24142248 TI - Corynebacterium glutamicum ArnR controls expression of nitrate reductase operon narKGHJI and nitric oxide (NO)-detoxifying enzyme gene hmp in an NO-responsive manner. AB - Corynebacterium glutamicum ArnR is a novel transcriptional regulator that represses expression of the nitrate reductase operon narKGHJI and the nitric oxide (NO)-detoxifying flavohemoglobin gene hmp under aerobic conditions. In a previous study, we showed that ArnR-mediated repression is relieved during anaerobic nitrate respiration, but we could not pinpoint the specific signal that ArnR senses. In this study, we show that in the absence of nitrate, ArnR-mediated repression is maintained under anaerobic conditions. The derepression in response to nitrate is eliminated by disruption of narG, suggesting that ArnR senses nitrate derivatives generated during nitrate respiration. Specifically, the hmp gene is upregulated in the presence of nitrite or nitric oxide (NO) in an ArnR dependent manner, although the response of narK appears to be greatly affected by ArnR-independent regulation. In vitro binding of ArnR to the narK and hmp promoter regions is more strongly inhibited by NO than by nitrite. We previously showed that the UV-visible spectrum of ArnR is typical of a Fe-S cluster containing protein. Site-directed mutagenesis of each of three cysteine residues, which are possibly involved in coordination of the cofactor in the ArnR protein, results in loss of the binding of this protein to its target promoters in vitro and eliminates the repression of the target genes in vivo under aerobic conditions. These observations suggest that the cofactor coordinated by these three cysteine residues in the ArnR protein plays a critical role in the NO responsive expression of the narKGHJI operon and the hmp gene. PMID- 24142249 TI - A replication-inhibited unsegregated nucleoid at mid-cell blocks Z-ring formation and cell division independently of SOS and the SlmA nucleoid occlusion protein in Escherichia coli. AB - Chromosome replication and cell division of Escherichia coli are coordinated with growth such that wild-type cells divide once and only once after each replication cycle. To investigate the nature of this coordination, the effects of inhibiting replication on Z-ring formation and cell division were tested in both synchronized and exponentially growing cells with only one replicating chromosome. When replication elongation was blocked by hydroxyurea or nalidixic acid, arrested cells contained one partially replicated, compact nucleoid located mid-cell. Cell division was strongly inhibited at or before the level of Z-ring formation. DNA cross-linking by mitomycin C delayed segregation, and the accumulation of about two chromosome equivalents at mid-cell also blocked Z-ring formation and cell division. Z-ring inhibition occurred independently of SOS, SlmA-mediated nucleoid occlusion, and MinCDE proteins and did not result from a decreased FtsZ protein concentration. We propose that the presence of a compact, incompletely replicated nucleoid or unsegregated chromosome masses at the normal mid-cell division site inhibits Z-ring formation and that the SOS system, SlmA, and MinC are not required for this inhibition. PMID- 24142250 TI - Identification of crucial amino acids of bacterial Peptide deformylases affecting enzymatic activity in response to oxidative stress. AB - Peptide deformylase (PDF) is an essential bacterial metalloprotease involved in deformylation of N-formyl group from nascent polypeptide chains during protein synthesis. Iron-containing variants of this enzyme from Salmonella enterica serovar Typhimurium (sPDF) and Mycobacterium tuberculosis (mPDF), although inhibited by oxidizing agents like H2O2, exhibited strikingly different 50% inhibitory concentrations (IC50s) that ranged from nanomolar (sPDF) to millimolar (mPDF) levels. Furthermore, the metal dissociation rate was higher in sPDF than mPDF. We hypothesized that a restriction in entry of environmental oxygen or oxidizing agents into the active site of mPDF might be the cause for such discrepancies between two enzymes. Since the active-site residues of the two proteins are similar, we evaluated the role of the oxidation-prone noncatalytic residue(s) in the process. Amino acid sequence analysis revealed that Cys-130 of sPDF corresponds to Met-145 of mPDF and that they are away from the active sites. Swapping methionine with cysteine in mPDF, the M145C protein displayed a drastic decrease in the IC50 for H2O2 and an increased metal dissociation rate compared to the wild type. Matrix-assisted laser desorption ionization (MALDI) analysis of a trypsin-digested fragment containing Cys-145 of the M145C protein also indicated its increased susceptibility to oxidation. To incorporate residues identical to those of mPDF, we created a double mutant of sPDF (C130M-V63C) that showed increased IC50 for H2O2 compared to the wild type. Interestingly, the oxidation state of cysteines in C130M-V63C was unaffected during H2O2 treatment. Taken together, our results unambiguously established the critical role of noncatalytic cysteine/methionine for enzymatic sensitivity to H2O2 and, thus, for conferring behavioral distinction of bacterial PDFs under oxidative stress conditions. PMID- 24142251 TI - Purification and functional reconstitution of a seven-subunit mrp-type na+/h+ antiporter. AB - Mrp antiporters and their homologues in the cation/proton antiporter 3 family of the Membrane Transporter Database are widely distributed in bacteria. They have major roles in supporting cation and cytoplasmic pH homeostasis in many environmental, extremophilic, and pathogenic bacteria. These antiporters require six or seven hydrophobic proteins that form hetero-oligomeric complexes, while most other cation/proton antiporters require only one membrane protein for their activity. The resemblance of three Mrp subunits to membrane-embedded subunits of the NADH:quinone oxidoreductase of respiratory chains and to subunits of several hydrogenases has raised interest in the evolutionary path and commonalities of their proton-translocating domains. In order to move toward a greater mechanistic understanding of these unusual antiporters and to rigorously demonstrate that they function as secondary antiporters, powered by an imposed proton motive force, we established a method for purification and functional reconstitution of the seven-subunit Mrp antiporter from alkaliphilic Bacillus pseudofirmus OF4. Na(+)/H(+) antiporter activity was demonstrated by a fluorescence-based assay with proteoliposomes in which the Mrp complex was coreconstituted with a bacterial FoF1-ATPase. Proton pumping by the ATPase upon addition of ATP generated a proton motive force across the membranes that powered antiporter activity upon subsequent addition of Na(+). PMID- 24142252 TI - The gamma-aminobutyrate permease GabP serves as the third proline transporter of Bacillus subtilis. AB - PutP and OpuE serve as proline transporters when this imino acid is used by Bacillus subtilis as a nutrient or as an osmostress protectant, respectively. The simultaneous inactivation of the PutP and OpuE systems still allows the utilization of proline as a nutrient. This growth phenotype pointed to the presence of a third proline transport system in B. subtilis. We took advantage of the sensitivity of a putP opuE double mutant to the toxic proline analog 3,4 dehydro-dl-proline (DHP) to identify this additional proline uptake system. DHP resistant mutants were selected and found to be defective in the use of proline as a nutrient. Whole-genome resequencing of one of these strains provided the lead that the inactivation of the gamma-aminobutyrate (GABA) transporter GabP was responsible for these phenotypes. DNA sequencing of the gabP gene in 14 additionally analyzed DHP-resistant strains confirmed this finding. Consistently, each of the DHP-resistant mutants was defective not only in the use of proline as a nutrient but also in the use of GABA as a nitrogen source. The same phenotype resulted from the targeted deletion of the gabP gene in a putP opuE mutant strain. Hence, the GabP carrier not only serves as an uptake system for GABA but also functions as the third proline transporter of B. subtilis. Uptake studies with radiolabeled GABA and proline confirmed this conclusion and provided information on the kinetic parameters of the GabP carrier for both of these substrates. PMID- 24142253 TI - ubiJ, a new gene required for aerobic growth and proliferation in macrophage, is involved in coenzyme Q biosynthesis in Escherichia coli and Salmonella enterica serovar Typhimurium. AB - Ubiquinone (coenzyme Q or Q8) is a redox active lipid which functions in the respiratory electron transport chain and plays a crucial role in energy generating processes. In both Escherichia coli and Salmonella enterica serovar Typhimurium, the yigP gene is located between ubiE and ubiB, all three being likely to constitute an operon. In this work, we showed that the uncharacterized yigP gene was involved in Q8 biosynthesis in both strains, and we have renamed it ubiJ. Under aerobic conditions, an ubiJ mutant was found to be impaired for Q8 biosynthesis and for growth in rich medium but did not present any defect anaerobically. Surprisingly, the C-terminal 50 amino acids, predicted to interact with lipids, were sufficient to restore Q8 biosynthesis and growth of the ubiJ mutant. Salmonella ubiE and ubiB mutants were impaired in Q8 biosynthesis and in respiration using different electron acceptors. Moreover, ubiE, ubiJ, and ubiB mutants were all impaired for Salmonella intracellular proliferation in macrophages. Taken together, our data establish an important role for UbiJ in Q8 biosynthesis and reveal an unexpected link between Q8 and virulence. They also emphasize that Salmonella organisms in an intracellular lifestyle rely on aerobic respiration to survive and proliferate within macrophages. PMID- 24142254 TI - A new addition to the cell plan of anammox bacteria: "Candidatus Kuenenia stuttgartiensis" has a protein surface layer as the outermost layer of the cell. AB - Anammox bacteria perform anaerobic ammonium oxidation (anammox) and have a unique compartmentalized cell consisting of three membrane-bound compartments (from inside outwards): the anammoxosome, riboplasm, and paryphoplasm. The cell envelope of anammox bacteria has been proposed to deviate from typical bacterial cell envelopes by lacking both peptidoglycan and a typical outer membrane. However, the composition of the anammox cell envelope is presently unknown. Here, we investigated the outermost layer of the anammox cell and identified a proteinaceous surface layer (S-layer) (a crystalline array of protein subunits) as the outermost component of the cell envelope of the anammox bacterium "Candidatus Kuenenia stuttgartiensis." This is the first description of an S layer in the phylum of the Planctomycetes and a new addition to the cell plan of anammox bacteria. This S-layer showed hexagonal symmetry with a unit cell consisting of six protein subunits. The enrichment of the S-layer from the cell led to a 160-kDa candidate protein, Kustd1514, which has no homology to any known protein. This protein is present in a glycosylated form. Antibodies were generated against the glycoprotein and used for immunogold localization. The antiserum localized Kustd1514 to the S-layer and thus verified that this protein forms the "Ca. Kuenenia stuttgartiensis" S-layer. PMID- 24142256 TI - Bacterial secretins form constitutively open pores akin to general porins. AB - Proteins called secretins form large multimeric complexes that are essential for macromolecular transit across the outer membrane of Gram-negative bacteria. Evidence suggests that the channels formed by some secretin complexes are not tightly closed, but their permeability properties have not been well characterized. Here, we used cell-free synthesis coupled with spontaneous insertion into liposomes to investigate the permeability of the secretin PulD. Leakage assays using preloaded liposomes indicated that PulD allows the efflux of small fluorescent molecules with a permeation cutoff similar to that of general porins. Other secretins were also found to form similar pores. To define the polypeptide region involved in determining the pore size, we analyzed a collection of PulD variants and studied the roles of gates 1 and 2, which were previously reported to affect the pore size of filamentous phage f1 secretin pIV, in assembly and pore formation. Liposome leakage and a novel in vivo assay showed that replacement of the conserved proline residue at position 443 in PulD by leucine increased the apparent size of the pore. The in vitro approach described here could be used to study the pore properties of membrane proteins whose production in vivo is toxic. PMID- 24142255 TI - Moraxella catarrhalis expresses a cardiolipin synthase that impacts adherence to human epithelial cells. AB - The major phospholipid constituents of Moraxella catarrhalis membranes are phosphatidylglycerol, phosphatidylethanolamine, and cardiolipin (CL). However, very little is known regarding the synthesis and function of these phospholipids in M. catarrhalis. In this study, we discovered that M. catarrhalis expresses a cardiolipin synthase (CLS), termed MclS, that is responsible for the synthesis of CL within the bacterium. The nucleotide sequence of mclS is highly conserved among M. catarrhalis isolates and is predicted to encode a protein with significant amino acid similarity to the recently characterized YmdC/ClsC protein of Escherichia coli. Isogenic mclS mutant strains were generated in M. catarrhalis isolates O35E, O12E, and McGHS1 and contained no observable levels of CL. Site-directed mutagenesis of a highly conserved HKD motif of MclS also resulted in a CL-deficient strain. Moraxella catarrhalis, which depends on adherence to epithelial cells for colonization of the human host, displays significantly reduced levels of adherence to HEp-2 and A549 cell lines in the mclS mutant strains compared to wild-type bacteria. The reduction in adherence appears to be attributed to the absence of CL. These findings mark the first instance in which a CLS has been related to a virulence-associated trait. PMID- 24142257 TI - SMU.746-SMU.747, a putative membrane permease complex, is involved in aciduricity, acidogenesis, and biofilm formation in Streptococcus mutans. AB - Dental caries induced by Streptococcus mutans is one of the most prevalent chronic infectious diseases worldwide. The pathogenicity of S. mutans relies on the bacterium's ability to colonize tooth surfaces and survive a strongly acidic environment. We performed an ISS1 transposon mutagenesis to screen for acid sensitive mutants of S. mutans and identified an SMU.746-SMU.747 gene cluster that is needed for aciduricity. SMU.746 and SMU.747 appear to be organized in an operon and encode a putative membrane-associated permease. SMU.746- and SMU.747 deficient mutants showed a reduced ability to grow in acidified medium. However, the short-term or long-term acid survival capacity and F1F0 ATPase activity remained unaffected in the mutants. Furthermore, deletion of both genes did not change cell membrane permeability and the oxidative and heat stress responses. Growth was severely affected even with slight acidification of the defined medium (pH 6.5). The ability of the mutant strain to acidify the defined medium during growth in the presence of glucose and sucrose was significantly reduced, although the glycolysis rate was only slightly affected. Surprisingly, deletion of the SMU.746-SMU.747 genes triggered increased biofilm formation in low-pH medium. The observed effects were more striking in a chemically defined medium. We speculate that the SMU.746-SMU.747 complex is responsible for amino acid transport, and we discuss its possible role in colonization and survival in the oral environment. PMID- 24142258 TI - Role of the twin arginine protein transport pathway in the assembly of the Streptomyces coelicolor cytochrome bc1 complex. AB - The cytochrome bc1-cytochrome aa3 complexes together comprise one of the major branches of the bacterial aerobic respiratory chain. In actinobacteria, the cytochrome bc1 complex shows a number of unusual features in comparison to other cytochrome bc1 complexes. In particular, the Rieske iron-sulfur protein component of this complex, QcrA, is a polytopic rather than a monotopic membrane protein. Bacterial Rieske proteins are usually integrated into the membrane in a folded conformation by the twin arginine protein transport (Tat) pathway. In this study, we show that the activity of the Streptomyces coelicolor M145 cytochrome bc1 complex is dependent upon an active Tat pathway. However, the polytopic Rieske protein is still integrated into the membrane in a DeltatatC mutant strain, indicating that a second protein translocation machinery also participates in its assembly. Difference spectroscopy indicated that the cytochrome c component of the complex was correctly assembled in the absence of the Tat machinery. We show that the intact cytochrome bc1 complex can be isolated from S. coelicolor M145 membranes by affinity chromatography. Surprisingly, a stable cytochrome bc1 complex containing the Rieske protein can be isolated from membranes even when the Tat system is inactive. These findings strongly suggest that the additional transmembrane segments of the S. coelicolor Rieske protein mediate hydrophobic interactions with one or both of the cytochrome subunits. PMID- 24142260 TI - Comparison of protective effects of safflor injection and extract of Ginkgo biloba on lung ischemia/reperfusion injury in rabbits. AB - OBJECTIVE: To observe the protective effects of safflor Injection (SI) and extract of Ginkgo biloba (EGB) on lung ischemia-reperfusion injury (LIRI) and investigate its mechanism. METHODS: In vivo rabbit model of LIRI was reconstructed. Forty rabbits were randomly and equally divided into four groups: sham-operation group (sham group), ischemia-reperfusion group (model group), ischemia-reperfusion plus SI group (safflor group) and ischemia-reperfusion plus EGB injection group (EGB group). Malondialdehyde (MDA) content, superoxide dismutase (SOD) and xanthine oxidase (XO) activity in serum were measured. The wet/dry weight ratio (W/D) of the lung tissue and activity of myeloperoxidase (MPO) were also tested. Ultrastructure change of the lung tissue was observed by the electron microscope. The expression of intercellular adhesion molecule-1 (ICAM-1) was measured by immunohistochemistry (IHC). RESULTS: In the model group, MDA and XO increased and SOD decreased in serum compared with the sham group (P<0.01). The values of W/D, MPO and ICAM-1 of the model group were higher than those of the sham group (P<0.01), but those of the safflor group and EGB group were significantly lower than those of the model group (P<0.01). The IHC demonstrated that ICAM-1 expression in lung tissue of the model group was significantly higher than those of the safflor group (P<0.01). Compared with safflor group, in the EGB group MDA, XO, MPO decreased, SOD and ICAM-1 expression increased (P<0.05), but the change of W/D was not statistically significant (P>0.05). CONCLUSIONS: SI and EGB may attenuate LIRI through antioxidation, inhibition of neutrophil aggregation and down-regulation of ICAM-1 expression. But EGB had more effect on the antioxidation, while SI did better on regulating ICAM-1 expression. PMID- 24142261 TI - A hierarchically structured graphene foam and its potential as a large-scale strain-gauge sensor. AB - A hierarchically structured thermal-reduced graphene (ReG) foam with 0.5 S cm(-1) electrical conductivity is fabricated from a well-dispersed graphene oxide suspension via a directional freezing method followed by high-temperature thermal treatment. The as-prepared three-dimensional ReG foam has an ordered macroporous honeycomb-like structure with straight and parallel voids in the range of 30 MUm to 75 MUm separated by cell walls of several tens of nanometers thick. Despite its ultra-low density, the ReG foam has an excellent compression recovery along its in-plane direction. This property of the ReG foam can be attributed to its hierarchically porous structure, as demonstrated by the compression test. The excellent compression recovery and high conductivity provide the ReG foam with exceptional piezoresistive capabilities. The electrical resistance of the ReG foam shows a linearly decreasing trend with compressive strain increments of up to 60%, which cannot be observed in conventional rigid material-based sensors and carbon nanotube-based polymer sensors. Such intriguing linear strain-responsive behavior, along with the fast response time and high thermal stability, makes the ReG foam a promising candidate for strain sensing. We demonstrated that it could be used as a wearable device for real-time monitoring of human health. PMID- 24142262 TI - ASNC president's page (2013) : ASNC's past, present, and future at 20 years: reflections from the 1st and 20th presidents. PMID- 24142263 TI - Naproxen with or without an antiemetic for acute migraine headaches in adults. AB - BACKGROUND: Migraine is a common, disabling condition and a burden for the individual, health services, and society. Many sufferers choose not to, or are unable to, seek professional help and rely on over-the-counter analgesics. Naproxen is a non-steroidal anti-inflammatory drug (NSAID); its efficacy in acute migraine has not been established by systematic reviews. Co-therapy with an antiemetic should help to reduce the nausea and vomiting commonly associated with migraine headaches. OBJECTIVES: To determine the efficacy and tolerability of naproxen, alone or in combination with an antiemetic, compared with placebo and other active interventions in the treatment of acute migraine headaches in adults. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL) on The Cochrane Library, MEDLINE, EMBASE, and the Oxford Pain Relief Database, together with two online databases (www.gsk clinicalstudyregister.com and www.clinicaltrials.gov) and reference lists, for studies to 22 May 2013. SELECTION CRITERIA: We included randomised, double-blind, placebo- or active-controlled studies, with at least 10 participants per treatment arm, using naproxen alone or with an antiemetic to treat a migraine headache episode. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed trial quality and extracted data. We used numbers of participants achieving each outcome to calculate risk ratios and numbers needed to treat (NNT) or harm (NNH) compared with placebo or a different active treatment. MAIN RESULTS: We included six studies using naproxen 275 mg, 500 mg, or 825 mg to treat attacks of moderate or severe pain intensity. Overall, 1241 participants took naproxen (275 mg to 825 mg), 229 took sumatriptan 50 mg, 173 took naratriptan 2.5 mg, and 1092 took placebo. No studies combined naproxen with an antiemetic. Studies using naproxen 275 mg provided no useable data for analysis.Naproxen (500 mg and 825 mg) was better than placebo for pain-free response and headache relief. At two hours, the NNT for pain-free response was 11 (17% response with naproxen, 8% with placebo; risk ratio 2.0 (95% CI 1.6 to 2.6), moderate quality) and for headache relief was 6.0 (45% response with naproxen, 29% with placebo; risk ratio 1.6 (1.4 to 1.8), moderate quality). The NNT for sustained pain-free response during the 24 hours post dose was 19 (12% response with naproxen, 6.7% with placebo), and for sustained headache relief during the 24 hours post dose was 8.3 (30% response with naproxen, 18% with placebo). Analysing only the lower dose of 500 mg of naproxen did not significantly change the results. Adverse events, which were mostly mild or moderate in severity and rarely led to withdrawal, were more common with naproxen than with placebo when the 500 mg and 825 mg doses were considered together, but not when the 500 mg dose was analysed alone.There were insufficient data for analysis of naproxen compared with sumatriptan, and no data suitable for analysis of naproxen compared with naratriptan. AUTHORS' CONCLUSIONS: Naproxen is statistically superior to placebo in the treatment of acute migraine, but the NNT of 11 for pain-free response at two hours suggests that it is not a clinically useful treatment. Cochrane reviews examining other commonly used analgesics for acute migraine have reported better (lower) NNT results for the same outcome. Naproxen is not clinically useful as a stand-alone analgesic in acute migraine, as it is effective in fewer than 2 people in 10. PMID- 24142264 TI - Incorporation of an introduced weed into the diet of a native butterfly: consequences for preference, performance and chemical defense. AB - The introduction of exotic plants, animals, and pathogens into non-native ecosystems can have profound effects on native organisms. Plantago lanceolata, narrow-leaf or ribwort plantain (Plantaginaceae), is a weed that was introduced to North America from Eurasia approximately 200 years ago and that has been incorporated into the diet of a variety of native North American herbivores. Plantain contains two iridoid glycosides, aucubin and catalpol, that can be toxic or deterrent to non-specialized herbivores or herbivores that have recently incorporated this species into their diet. Anartia jatrophae (Nymphalidae), the white peacock, feeds on plants in five families including the Plantaginaceae, and was recently observed feeding on plantain; however, the effects of feeding on this novel host plant are unknown. In this study, we performed a series of experiments to assess larval preference and performance on the introduced P. lanceolata and on a native host plant that does not contain iridoid glycosides, water hyssop, Bacopa monnieri (Plantaginaceae). We also tested whether or not white peacocks were able to sequester iridoid glycosides and compared this ability with an iridoid specialist, the buckeye, Junonia coenia (Nymphalidae). White peacocks successfully developed to the adult stage on plantain; larvae grew more slowly but pupae were heavier when compared with larvae and pupae reared on the native host plant. Larvae showed induced feeding preferences for the host plant on which they were reared. Furthermore, larvae sequestered small amounts of iridoids that were also retained in pupae and adults. These results suggest that incorporation of the introduced weed, plantain, into the diet of the white peacock may have important consequences for larval performance and preference, as well as for interactions with natural enemies. PMID- 24142265 TI - Computed tomography of blunt and penetrating diaphragmatic injury: sensitivity and inter-observer agreement of CT Signs. AB - Diaphragmatic injury is an uncommon but clinically important entity in the setting of trauma. Computed tomography (CT) is widely used to evaluate hemodynamically stable trauma patients. While prior studies have identified CT signs of diaphragm injury in blunt or penetrating trauma, no study has directly compared signs across these two types of injuries. We identified patients with surgically proven diaphragm injuries who underwent CT at presentation. Three reviewers examined each for 12 signs of diaphragm injury, as well as for an overall impression of diaphragm injury. We reviewed a total of 84 patients (37 % blunt trauma, 63 % penetrating). The initial interpreting radiologists discovered 77 % of blunt and 47 % of penetrating injuries (p = 0.01). We found that the majority of signs of diaphragmatic injury were split between those common in blunt trauma and those common in penetrating trauma, with minimal overlap. The presence of at least one blunt injury sign has 90 % sensitivity for diaphragm injury in blunt trauma; the presence of a wound tract traversing the diaphragm has 92 % sensitivity in penetrating trauma. Inter-observer reliability of these signs is also high (kappa > 0.65). Penetrating diaphragm injuries present a different spectrum of imaging findings from those in blunt trauma and are underdiagnosed at CT; looking for a wound tract traversing the diaphragm is highly sensitive for diaphragm injury in these cases. Signs of organ or diaphragm fragment displacement are sensitive for blunt diaphragm injuries, consistent with these injuries being caused by increased intra-abdominal pressure. PMID- 24142266 TI - Mycotic aneurysms: a critical diagnosis in the emergency setting. AB - This pictorial essay reviews the pathophysiology and causes of mycotic aneurysms, their typical imaging appearances, mimics of mycotic aneurysms on CT, and treatment options. Correctly diagnosing mycotic aneurysms is critical for patient morbidity and mortality, as infected aneurysms are at extremely high risk of rapid growth and sudden rupture. The presence of a constellation of suggestive imaging features, as well as concerning patient symptomatology, should raise the possibility of a mycotic aneurysm. PMID- 24142267 TI - Unemployment and stillbirth risk among foreign-born and Spanish pregnant women in Spain, 2007-2010: a multilevel analysis study. AB - We describe stillbirth and unemployment rates by autonomous region in Spain and analyse whether women who gave birth in regions with high unemployment rates were more likely to have a stillborn. We designed a multilevel population-based observational study of births from 2007 to 2010. We defined stillbirth as the outcome, individual maternal socioeconomic and pregnancy-related characteristics as covariates, and maternal autonomous region of residence as the contextual covariate. We used mixed-logistic regression models to account for differences across regions. In total, 1,920,235 singleton births and 5,560 stillbirths were included in the study. Women residing in autonomous regions with the highest rates of unemployment had a two-times-greater chance of delivering a stillborn (adjusted OR 2.60; 95 % CI 2.08-3.21). The region where women resided explained 14 % of the total individual differences in the risk of delivering a stillborn. The odds of stillbirth were 1.82 (95 % CI 1.62-2.05) times higher for African born women than for Spanish-born women and 1.90 (95 % CI 1.68-2.15) times higher for women with low educational attainment than for women with higher education. In conclusion, regional disparities in stillbirth rates in Spain in the period 2007-2010 were mainly associated with mothers who had low levels of education, were African-born, and lived in regions with higher unemployment. PMID- 24142268 TI - Determination and analysis of the complete genome sequence of Paralichthys olivaceus rhabdovirus (PORV). AB - Paralichthys olivaceus rhabdovirus (PORV), which is associated with high mortality rates in flounder, was isolated in China in 2005. Here, we provide an annotated sequence record of PORV, the genome of which comprises 11,182 nucleotides and contains six genes in the order 3'-N-P-M-G-NV-L-5'. Phylogenetic analysis based on glycoprotein sequences of PORV and other rhabdoviruses showed that PORV clusters with viral haemorrhagic septicemia virus (VHSV), genus Novirhabdovirus, family Rhabdoviridae. Further phylogenetic analysis of the combined amino acid sequences of six proteins of PORV and VHSV strains showed that PORV clusters with Korean strains and is closely related to Asian strains, all of which were isolated from flounder. In a comparison in which the sequences of the six proteins were combined, PORV shared the highest identity (98.3 %) with VHSV strain KJ2008 from Korea. PMID- 24142269 TI - Lettuce necrotic leaf curl virus, a new plant virus infecting lettuce and a proposed member of the genus Torradovirus. AB - A new virus was isolated from a lettuce plant grown in an open field in the Netherlands in 2011. This plant was showing conspicuous symptoms that consisted of necrosis and moderate leaf curling. The virus was mechanically transferred to indicator plants, and a total RNA extract of one of these indicator plants was used for next-generation sequencing. Analysis of the sequences that were obtained and further biological studies showed that the virus was related to, but clearly distinct from, viruses belonging to the genus Torradovirus. The name "lettuce necrotic leaf curl virus" (LNLCV) is proposed for this new torradovirus. PMID- 24142270 TI - Molecular variability of cowpea mild mottle virus infecting soybean in Brazil. AB - Molecular variability was assessed for 18 isolates of cowpea mild mottle virus (CPMMV, genus Carlavirus, family Betaflexiviridae) found infecting soybean in various Brazilian states (Bahia, Goias, Maranhao, Mato Grosso, Minas Gerais, Para) in 2001 and 2010. A variety of symptoms was expressed in soybean cv. CD206, ranging from mild (crinkle/blistering leaves, mosaic and vein clearing) to severe (bud blight, dwarfing, leaf and stem necrosis). Recombination analysis revealed only one CPMMV isolate to be recombinant. Pairwise comparisons and phylogenetic analysis were performed for partial genomes (ORF 2 to the 3' terminus) and for each ORF individually (ORFs 2 to 6), showing the isolates to be distinct. The topology of the phylogenetic tree could be related to symptoms, but not to the year of collection or geographical origin. Additionally, the phylogenetic analysis supported the existence of two distinct strains of the virus, designated CPMMV-BR1 and CPMMV-BR2, with molecular variations between them. PMID- 24142271 TI - Inhibitory effect of doxycycline against dengue virus replication in vitro. AB - Doxycycline is an antibiotic derived from tetracycline that possesses antimicrobial and anti-inflammatory activities. Antiviral activity of doxycycline against dengue virus has been reported previously; however, its anti-dengue properties need further investigation. This study was conducted to determine the potential activity of doxycycline against dengue virus replication in vitro. Doxycycline inhibited the dengue virus serine protease (DENV2 NS2B-NS3pro) with an IC50 value of 52.3 +/- 6.2 MUM at 37 degrees C (normal human temperature) and 26.7 +/- 5.3 MUM at 40 degrees C (high fever temperature). The antiviral activity of doxycycline was first tested at different concentrations against DENV2 using a plaque-formation assay. The virus titter decreased significantly after applying doxycycline at levels lower than its 50 % cytotoxic concentration (CC50, 100 MUM), showing concentration-dependent inhibition with a 50 % effective concentration (EC50) of approximately 50 MUM. Doxycycline significantly inhibited viral entry and post-infection replication of the four dengue serotypes, with serotype-specific inhibition (high activity against DENV2 and DENV4 compared to DENV1 and DENV3). Collectively, these findings underline the need for further experimental and clinical studies on doxycycline, utilizing its anti-dengue and anti-inflammatory activities to attenuate the clinical symptoms of dengue virus infection. PMID- 24142272 TI - An NA-deficient 2009 pandemic H1N1 influenza virus mutant can efficiently replicate in cultured cells. AB - We identified a novel neuraminidase (NA)-deficient virus that was a 2009 pandemic influenza H1N1 virus mutant. The mutant virus had a deletion of 1,009 nt in the NA gene and lacked an enzymatic domain. Although the yield of the NA-deficient virus was limited, it formed large plaques when applied to MDCK cell cultures, indicating that the virus was able to spread to adjacent cells. Furthermore, the NA-deficient virus was eluted from chicken erythrocytes at 37 degrees C, even in the presence of the antiviral drug peramivir. Spread of this NA-deficient virus may pose a potential threat to anti-influenza therapies. PMID- 24142273 TI - Trends of drug-resistance-associated mutations in the reverse transcriptase gene of HIV type 1 isolates from North India. AB - A major cause of failure of antiretroviral therapy (ART) is the presence of drug resistance-associated mutations in the polymerase gene of HIV-1. The paucity of data regarding potential drug resistance to reverse transcriptase inhibitors (RTIs) prompted us to carry out this study. This information will shed light on the extent of drug resistance already present in HIV strains and will give future directions in patient treatment and in drug design. Drug resistance genotyping of a partial reverse transcriptase gene was done in 103 HIV-1-infected patients, including the ART-naive and ART-experienced population. The drug resistance pattern was analyzed using the Stanford HIV-DR database, the IAS-USA mutation list and the REGA algorithm-v8.0. Subtyping was done using the REGA HIV-1 subtyping tool-v2.01. The majority of our sequences (96 %) were found to be subtype C, and four (3.8 %) were subtype A1. Significant prevalence of DR mutations (28 %) was observed in the RT gene. Major amino acid substitutions were seen at positions 41, 90, 98, 103, 106, 108, 138, 181, 184, 190, 215, and 219, which confer high/intermediate levels of resistance to most RTIs, independently or together. Our results show that there is an urgent need to tailor ART drug regimens to the individual to achieve optimum therapeutic outcome in North India. PMID- 24142274 TI - Yellow tailflower mild mottle virus: a new tobamovirus described from Anthocercis littorea (Solanaceae) in Western Australia. AB - The complete genome sequence of a tobamovirus was determined from a wild plant of yellow tailflower (Anthocercis littorea, family Solanaceae) that exhibited mild mottling and chlorosis on the leaves. The virus induced severe symptoms including systemic necrosis when inoculated to plants of three other solanaceous species. The viral genome was resequenced after passage in Nicotiana benthamiana. The two genomes were 6379 nucleotides in length, and they differed by three nucleotides. Phylogenetic analysis and the deduced architecture of the genome place the virus, provisionally named yellow tailflower mild mottle virus, with other tobamoviruses that infect solanaceous hosts. PMID- 24142275 TI - Lathosterolosis: a disorder of cholesterol biosynthesis resembling smith-lemli opitz syndrome. AB - Lathosterolosis is an inborn error of cholesterol biosynthesis due to deficiency of the enzyme 3-beta-hydroxysteroid-delta-5-desaturase (or sterol-C5-desaturase or SC5D). This leads to a block in conversion of lathosterol into 7 dehydrocholesterol. Only three patients with lathosterolosis have been reported in literature, of which one survived. We report a patient with dysmorphism, multiple congenital anomalies, and developmental delay, initially suspected to have Smith-Lemli-Opitz syndrome, who was later found to have elevated levels of lathosterol in both plasma and fibroblasts. Genetic study confirmed a compound heterozygous mutation in the sterol-C5-desaturase-like (SC5DL) gene on chromosome 11q23. Simvastatin was started as a treatment therapy and it resulted in normalization of blood lathosterol level and improvement in the neurodevelopmental profile. However, additional patients are needed for better delineation of the clinical spectrum, genotype-phenotype correlation, and potential efficacy of simvastatin treatment in this rare disorder. If the presence of distinctive facial features and limb anomalies raise the suspicion of a cholesterol biosynthesis defect, testing of full sterol profile is warranted as normal cholesterol or 7-dehydrocholesterol levels cannot rule out the diagnosis of cholesterol synthesis defect like lathosterolosis. PMID- 24142276 TI - Liver engraftment and repopulation by in vitro expanded adult derived human liver stem cells in a child with ornithine carbamoyltransferase deficiency. AB - A 3-year-old girl suffering from ornithine carbamoyltransferase (OTC) deficiency was poorly equilibrated under conventional diet and scavenger treatment. Following unsuccessful cryopreserved hepatocyte transplantation, she received two infusions of Adult Derived Human Liver Stem/Progenitor Cells (ADHLSCs) expanded in vitro under GMP settings, the quantity being equivalent to 0.75% of her calculated liver mass. Using FISH immunostaining for the Y chromosome, the initial biopsy did not detect any male nuclei in the recipient liver. Two liver biopsies taken 100 days after ADHLSC transplantation showed 3% and 5% of male donor cells in the recipient liver, thus suggesting repopulation by donor cells. Although limited follow-up did not allow us to draw conclusions on long-term improvement, these results provide a promising proof of concept that this therapy is feasible in an OTC patient. PMID- 24142277 TI - Distribution and Severity of Neuropathology in beta-Mannosidase-Deficient Mice is Strain Dependent. AB - Neurological dysfunction is common in humans and animals with lysosomal storage diseases. beta-Mannosidosis, an autosomal recessive inherited disorder of glycoprotein catabolism caused by deficiency of the lysosomal enzyme beta mannosidase, is characterized by intracellular accumulation of small oligosaccharides in selected cell types. In ruminants, clinical manifestation is severe, and neuropathology includes extensive intracellular vacuolation and dysmyelination. In human cases of beta-mannosidosis, the clinical symptoms, including intellectual disability, are variable and can be relatively mild. A beta-mannosidosis knockout mouse was previously characterized and showed normal growth, appearance, and lifespan. Neuropathology between 1 and 9 months of age included selective, variable neuronal vacuolation with no hypomyelination. This study characterized distribution of brain pathology in older mutant mice, investigating the effects of two strain backgrounds. Morphological analysis indicated a severe consistent pattern of neuronal vacuolation and disintegrative degeneration in all five 129X1/SvJ mice. However, the mice with a mixed genetic background showed substantial variability in the severity of pathology. In the severely affected animals, neuronal vacuolation was prominent in specific layers of piriform area, retrosplenial area, anterior cingulate area, selected regions of isocortex, and in hippocampus CA3. Silver degeneration reaction product was prominent in regions including specific cortical layers and cerebellar molecular layer. The very consistent pattern of neuropathology suggests metabolic differences among neuronal populations that are not yet understood and will serve as a basis for future comparison with human neuropathological analysis. The variation in severity of pathology in different mouse strains implicates genetic modifiers in the variable phenotypic expression in humans. PMID- 24142278 TI - Pregnancy and lactation outcomes in a Turkish patient with lysinuric protein intolerance. AB - Maternal lysinuric protein intolerance (LPI) is associated with increased risk of anemia, toxemia, and retarded growth in fetus during pregnancy, and bleeding complications during delivery. There has been limited number of reports about pregnancy and outcomes of lactation in LPI. Here we present pregnancy and lactation outcomes in a Turkish patient with LPI. In the pregnancy and delivery period, her metabolic status was stable with protein-restricted diet and citrulline. Pathological examination of the placenta revealed multifocal placental infarcts. A successful outcome was achieved with well-controlled anemia, thrombocytopenia despite hemophagocytosis in bone marrow, and placental infarcts during pregnancy. The baby was exclusively breastfed for 6 months. His growth and development was normal. Mild proteinuria started at the fourth month of the delivery. Our case report showed the importance of follow-up of these patients in terms of placental pathologies during pregnancy and for other complications during lactation period. PMID- 24142279 TI - Vestibular and Saccadic Abnormalities in Gaucher's Disease. AB - Gaucher's disease (GD) is a hereditary lysosomal storage disease characterized by abnormal deposition of glucocerebroside due to the enzyme glucocerebrosidase deficiency, resulting in multi-organ pathology. GD type III has a progressive neurological involvement. We studied the vestibular and saccadic abnormalities in GD type III to determine if these parameters may be useful for assessing neurological involvement. We evaluated the vestibular and saccadic responses of two siblings with genetically identified GD type III on enzyme replacement therapy. Vestibular functions were assessed with the head impulse test (HIT), vestibular evoked myogenic potentials (VEMPs), and electrical vestibular stimulation (EVS). Saccadic functions were investigated with volitional horizontal and vertical saccades to +/-20 degrees . Three-dimensional head and eye movements were recorded with dual-search coils and VEMP with surface electrodes. HIT showed impaired individual semicircular canal function with halved angular vestibulo-ocular reflex (VOR) gains and absent horizontal refixation saccade. Ocular and cervical VEMPs to air-conducted clicks were absent in the older sibling, and only cervical VEMP was present in the younger sibling indicating otolithic dysfunction. EVS showed prolonged onset latency and attenuated tonic and phasic responses suggesting impaired neural conduction and vestibular function. Horizontal saccadic velocity was miniscule (<30 degrees /s) and multiple back-to-back saccades with saccade-vergence interaction were utilized to minimize eye position error in the older sibling. Vertical saccades were slightly abnormal, but vergence and smooth pursuit were normal in both siblings. Our findings suggest that GD affected the vestibular nuclei in addition to the paramedian pontine reticular formation. These vestibular and saccadic abnormalities may be useful biomarkers to monitor neurological deterioration. PMID- 24142280 TI - Multiple Acyl-CoA Dehydrogenation Deficiency (Glutaric Aciduria Type II) with a Novel Mutation of Electron Transfer Flavoprotein-Dehydrogenase in a Cat. AB - Multiple acyl-CoA dehydrogenation deficiency (MADD; also known as glutaric aciduria type II) is a human autosomal recessive disease classified as one of the mitochondrial fatty-acid oxidation disorders. MADD is caused by a defect in the electron transfer flavoprotein (ETF) or ETF dehydrogenase (ETFDH) molecule, but as yet, inherited MADD has not been reported in animals. Here we present the first report of MADD in a cat. The affected animal presented with symptoms characteristic of MADD including hypoglycemia, hyperammonemia, vomiting, diagnostic organic aciduria, and accumulation of medium- and long-chain fatty acids in plasma. Treatment with riboflavin and L-carnitine ameliorated the symptoms. To detect the gene mutation responsible for MADD in this case, we determined the complete cDNA sequences of feline ETFalpha, ETFbeta, and ETFDH. Finally, we identified the feline patient-specific mutation, c.692T>G (p.F231C) in ETFDH. The affected animal only carries mutant alleles of ETFDH. p.F231 in feline ETFDH is completely conserved in eukaryotes, and is located on the apical surface of ETFDH, receiving electrons from ETF. This study thus identified the mutation strongly suspected to have been the cause of MADD in this cat. PMID- 24142281 TI - Severe hypertriglyceridemia in a newborn with monogenic lipoprotein lipase deficiency: an unconventional therapeutic approach with exchange transfusion. AB - Severe hypertriglyceridemia (sHTG) (plasma triglyceride level > 10 mmol/L) due to lipoprotein lipase (LPL) deficiency is a known risk factor for acute pancreatitis. A 23-day-old male with sHTG was admitted to the Neonatal Intensive Care Unit for plasmapheresis being at high risk for acute pancreatitis. Given the potential hazard of an extracorporeal technique in a very young infant, we decided to perform an exchange transfusion (ET), a procedure widely used by neonatologists and less invasive than plasmapheresis. ET led to a dramatic reduction in plasma triglyceride level, from 93.2 to 3.8 mmol/L at the end of the procedure, without adverse events. The subsequent administration of a special formula low in fat and high in medium-chain triglycerides was effective in keeping fasting plasma triglyceride level below 5.6 mmol/L during the first 5 months of life. The sequence of LPL gene revealed that the patient was apparently homozygous for a novel nucleotide deletion (c.840delG) in exon 6 leading to a premature termination codon (p.N281Mfs*23). However, family studies revealed that while the patient's mother was heterozygous for this mutation, the father was heterozygous for a novel deletion eliminating the whole LPL gene. The patient therefore turned out to be a compound heterozygous for two LPL gene mutations predicted to abolish LPL activity. This is the first case of sHTG treated with ET in a neonate reported in the literature. ET appears to be a safe procedure, alternative to plasmapheresis, to prevent acute pancreatitis in young infants with sHTG due to LPL deficiency. PMID- 24142282 TI - Obituary for M. Richard Koenigsberger, MD. PMID- 24142284 TI - Are fish paratenic natural hosts of the caiman haemoparasite Hepatozoon caimani? AB - The susceptibility of two fish and four mosquito species to the Caiman yacare haemoparasite Hepatozoon caimani was experimentally investigated. Mosquitoes belonging to four species (Aedes fluviatilis, Aedes albopictus, Aedes aegypti and Culex quinquefasciatus) were blood-fed on two naturally infected C. yacare from the Central-West Region of Brazil that exhibited distinct levels of parasitaemia: caimans A (11.05%) and B (1.25%). None of the engorged A. fluviatilis, A. albopictus or A. aegypti mosquitoes fed on caiman A survived for the duration of the sporogonic cycle; the great majority of the engorged mosquitoes died within 48 h of the blood meal. All A. aegypti fed on caiman B were negative, whereas 91.3% of dissected C. quinquefasciatus fed on the same caiman contained oocysts. Characid fish-Metynnis sp. and Astyanax sp.-were individually fed with C. quinquefasciatus females previously engorged (21-23 days) on caiman B. No parasite was found in the Astyanax fish. By contrast, 100% of the Metynnis fish depicted numerous cysts harbouring cystozoites identical to those of H. caimani, even more than 8 months after the ingestion of the infected mosquitoes. The cysts were located near the veins of the liver and, in some cases, close to the tunica intima of these vessels. No inflammatory reaction was observed. Gametocytes were observed in the blood smears of juvenile caimans that had ingested infected fish 9-12 weeks earlier. The potential role of fish as paratenic vertebrate hosts of H. caimani in nature is discussed. PMID- 24142286 TI - Oviposition deterrent activity of three mosquito repellents diethyl phenyl acetamide (DEPA), diethyl m toluamide (DEET), and diethyl benzamide (DEB) on Aedes aegypti, Aedes albopictus, and Culex quinquefasciatus. AB - Oviposition deterrent activity of three mosquito repellents namely diethyl phenyl acetamide (DEPA), diethyl benzamide (DEB) along with diethyl toluamide (DEET) was studied in the laboratory against Aedes aegypti, A. albopictus, and Culex quinquefasciatus mosquitoes. All the repellents evaluated at three log concentrations 0.1, 0.01, and 0.001% in comparison with control by dual choice method. The oviposition response and oviposition activity index (OAI) was estimated by counting number of eggs laid in both the treatment and control. Mean OAI determined for A. aegypti was in the range of -0.23 to +0.22, -0.3 to +0.27, and +0.04 to +0.33 for DEPA, DEET, and DEB, respectively, whereas it was -0.77 to -0.035, -0.92 to +0.001, and -0.77 to -0.07 for A. albopictus and -0.927 to 0.251, -1 to -0.41, and -0.94 to -0.17 for C. quinquefasciatus. The oviposition deterrent activity was observed in the order of DEET > DEPA > DEB. Similarly, the response of species toward the repellents as oviposition deterrent was in the trend of C. quinquefasciatus > A. albopictus > A. aegypti. The finding suggests potential role of mosquito repellents as oviposition deterrent. PMID- 24142285 TI - Dynamic expression of miR-132, miR-212, and miR-146 in the brain of different hosts infected with Angiostrongylus cantonensis. AB - Increasing evidence shows that microRNAs (miRNAs) are a family of regulatory molecules involved in many physiological processes, including the inflammation in central nervous system (CNS) and neurological disorders. Angiostrongylus cantonensis (A. cantonensis) is the major cause of human infectious eosinophilic meningitis and can induce CNS injury. In the present study, we investigated the expression of miRNAs involved in neuronal functions such as miR-132-3p/212-3p, and miR-146a-5p, inflammation-related miRNA, in the modulation of inflammation of CNS of mice and rats induced by A. cantonensis. The functions of differentially expressed miRNAs were analyzed through bioinformatics methods, and the expression of chosen target genes were investigated by quantitative reverse transcription polymerase chain reaction. The results showed that miR-146a-5p upregulated in the brain of rats after 21 days; A. cantonensis infection and the expression of miR 132-3p and miR-146a-5p upregulated in the brain of mice model infected by A. cantonensis. The expression of the target genes of mmu-miR-146a-5p such as Irak1 and Traf6 downregulated in 14 days and 21 days after A. cantonensis infection. Our results supply more information about the involvement of the miRNAs in the regulation of inflammation of CNS induced by A. cantonensis. PMID- 24142287 TI - Effect of Moringa oleifera lectins on survival and enzyme activities of Aedes aegypti larvae susceptible and resistant to organophosphate. AB - The indiscriminate use of synthetic insecticides to control Aedes aegypti has led to emergence of resistant populations. Moringa oleifera seeds contain the lectins WSMoL and cMoL. WSMoL has larvicidal activity on fourth-stage of A. aegypti organophosphate-susceptible larvae (Rockefeller L4). This study reports on the effects of cMoL on the survival of Rockefeller L4 as well as of WSMoL and cMoL on L4 from an organophosphate-resistant population (Rec-R). The effects of lectins on digestive (amylase, trypsin, and protease) and detoxifying (superoxide dismutase (SOD), alpha- and beta-esterases) enzymes from larvae were also determined. cMoL (0.1-0.8 mg/ml) did not kill Rockefeller L4 as well as WSMoL and cMoL (0.1-0.8 mg/ml) were not larvicidal for Rec-R L4. WSMoL stimulated protease, trypsin-like, and alpha-amylase from Rockefeller L4 while cMoL inhibited these enzymes. WSMoL had no effect on trypsin-like activity from Rec-R L4 but inhibited protease and alpha-amylase. Among digestive enzymes of Rec-R L4, cMoL inhibited only trypsin-like activity. cMoL inhibited SOD activities from Rockefeller and Rec-R L4 in a higher level than WSMoL while beta-esterase from Rockefeller L4 was more inhibited by WSMoL. The lectins promoted low stimulation or inhibition of alpha-esterase activities from both populations. In conclusion, Rockefeller and Rec-R larvae were distinctly affected by M. oleifera lectins, and larvicidal mechanism of WSMoL on Rockefeller L4 may involve deregulation of digestive enzymes. cMoL interfered mainly on SOD activity and thus it can be investigated as a synergistic agent for controlling populations whose resistance is linked to an increased detoxifying process mediated by this enzyme. PMID- 24142288 TI - Evaluation of biological and chemical insect repellents and their potential adverse effects. AB - Plant extracts, particularly plant oils, had been used and were still in use as repellents against mosquitoes. Some of them (e.g., lavender, geraniol, and citriodiol) have been notified by the European Commission as active substances to be used in repellents, which are categorized as biocides in product type 19. In the literature, it is known that these substances must be added to repellent products in high concentrations (e.g., 20% and more) in order to reach repellent efficacy. Therefore, the question arose whether they also have repellent effects if they were added as fragrances at low concentrations of 0.25 or 1% to registered active substances in order to obtain a better scent of this product. In the present study, the repellent effects of 0.25 and 1% additions of 15 plant extracts (citronellol, cinerol, citral, menthol, linalyl acetate, Eucalyptus citriodora, Eucalyptus globulus, Cymbopogon nardus, lilac, sandalwood, Vitex agnus castus, rosewood, lavender, geraniol, and paramenthan diol) when exposed on skin to hungry Aedes aegypti mosquitoes. These experiments showed that there was no repellent effect in any of these compounds even when the test was done already 10 min after distributing any of the compounds onto the hands of volunteers. These experiments have proven that these 15 compounds do not produce repellent effects as long as they are used in low concentrations of 0.25 or 1% as fragrances to ameliorate the odor of a notified repellent that is brought onto the skin. PMID- 24142289 TI - [Cold-minded thinking? The role of emotional intelligence and emotional stability in Machiavellian decision-making]. AB - Previous studies clearly show that Machiavellians' thinking and behavior are characterized by some kind of cold attitude, a tendency to be detached from the emotional features of a particular situation. However, very little is known what this cold-minded attitude means, and the presence or the absence of what abilities can lead to emotional detachment. Surprisingly, our study has shown that Machiavellians - contrary to what others believe - happen to exhibit more emotional instability than others. They experience more negative emotions, lose their peace of mind faster, and have a hard time tolerating psychological distress. However, they try to conceal their emotional worries in two different ways. On the one hand, they cannot express their emotions as subtly and precisely as others, and on the other, they are much worse at identifying and differentiating their own emotional states. Maybe it is just the deficit in evaluating and expressing emotions that enables them to implement the strategy to enforce their self-interest successfully. The weak ability to identify and comprehend their own emotions may help them stay detached from the emotional temperature of a situation, while the difficulties in expressing their emotions enable them to disguise their true intentions from their partners. PMID- 24142290 TI - [Teachers' knowledge about suicide and its connection to burn-out and avoidant coping]. AB - INTRODUCTION: Priority of suicide prevention is so-called "gatekeepers" ("helper professionals'") training on suicidology. Teachers' knowledge concerning suicide was examined mainly in search for the answer to the question whether poor knowledge of suicidology is just a result of lack of information. Assuming that the extent of suicidology knowledge is a complex issue, ignorance might be related to burnout and avoidant coping. METHODS: Teachers participating in compulsory postgradual training were tested (N = 102). Hungarian version of the short form of Hubbard McIntosh's suicide questionnaire, Maslach's burnout questionnaire for teachers and Coping Inventory for Stressful Situations (CISS 48) were used. RESULTS: Our results show that teachers' knowledge concerning suicide is somewhat worse than that of helpers, but better than the that of the average population. Avoidant coping style was more typical of teachers having poorer knowledge about suicide; and education professionals with less task oriented coping style reported greater knowledge of this subject. Authors therefore suggest a link between avoidant coping and the extent of knowledge concerning suicide. Relationship of avoidant coping with burnout was not confirmed, but a mediational model could be set up regarding male participants. CONCLUSION: Suicide prevention trainings are definitely of high importance and utility among teachers. Based on our results it seems equally important to help them overcome the cultural taboos related to the topic, to provide them with psychological support and to enable them to discuss their own suicide-related experiences and personal involvement in professional-led groups. PMID- 24142291 TI - [The Dying Horse: the contradictoriness of the Self in a dream of Raskolnikov and in the breakdown of Nietzsche]. AB - The author deals with the curious and uncanny parallel between a dream recounted in Dostoevsky's Crime and Punishment and the famous Turin incident from Nietzsche's life shortly before his psychotic breakdown. The psychoanalytic interpretation focuses on the articulation of the contradictoriness and multiplicity of the Self. PMID- 24142292 TI - [Aggressive and prosocial behavior in childhood psychopathology]. AB - Aggressive/attacking and helpful/emphatic/prosocial behaviors are extremely important in human relationships. Both high levels of aggression and deficits of prosociality play important role in the development and conservation of mental disorders. We review the measurement options and clinical importance of aggressive and prosocial behavior. The typical developmental pathways and the genetic and environmental background of these behaviors are presented. The clinical tools used in the measurement of aggression and prosociality are summarized in the present paper, with specific attention on questionnaires applied in Hungarian practice. The connections between diagnostic categories (conduct disorder, oppositional-defiant disorder, attention deficit and hyperactive disorder, autism spectrum disorders) and the two behaviors are evaluated. In the end, we present those additional research projects that explore the cognitive-emotional background of aggressive or prosocial behavior with clinical relevance either in the diagnosis or in the treatment of child psychiatric diseases. PMID- 24142293 TI - [The Hungarian version of the Problem Gambling Severity Index (PGSI-HU)]. AB - BACKGROUND AND AIMS: The growing availability of gambling is accompanied by the increased level of gambling related problems. As result, reliable and valid measurement tools that could quickly identify problem/pathological gambling are necessary. The goal of the study was the psychometric evaluation of the Hungarian version of Problem Gambling Severity Index (PGSI-HU) as well as the presentation of the first data gained by this instrument. METHODS: The administration of the instrument was conducted in Budapest on an adult sample. The sample (N=777) was recruited in lottery stores and other gambling venues. The sample consisted of 466 males and 311 females. The structural validation of the instrument was executed by confirmatory factor analysis and the concurrent validation was tested with the South Oaks Gambling Screen. RESULTS: The instrument's psychometric properties are appropriate. The majority of the sample (61.6%) is considered as non-problem gambler; 20.2 % of the sample is in the low-problem group; 11.8% is in the moderate level problem gambler category and 6.3% could be considered as pathological gambler. The results of the assessment of the concurrent validity indicate strong significant correlation among the PGSI and SOGS (r=0.802; p<0.001). CONCLUSIONS: The PGSI-HU is a valid and reliable instrument to identify problem and pathological gambling. The measure is recommended to be used both in clinical and research settings due to its appropriate properties. PMID- 24142294 TI - [Sleep disorders and physical abuse: a nation-wide representative study in Hungary]. AB - OBJECTIVES: Violence against women has been declared a major public health concern. The relationship between physical abuse and physical and psychological symptoms is well-known, however data regarding the association between physical abuse and sleep disorders are limited. Our aim is to document the prevalence of reported abuse and investigate the association between physical abuse and insomnia among females. METHODS: Cross-sectional analyses were conducted on the female sample (N=6987) of the Hungarostudy 2002, a nationwide representative survey. The survey contained sociodemographic questions and a Hungarian version of Athen Insomnia Scale (AIS). RESULTS: We found higher (>10) AIS scores and all of the items of AIS reported higher prevalence among abused women's group than non-abused women. Physical abuse was found to be associated with sleep disturbances (OR=1,707), problems with staying asleep (OR=1,552) and decrease of daytime performance (OR=2,024) after controlling the potential risk factors. CONCLUSION: Women experiencing physical abuse have a significantly higher risk of sleep disorders. The relationship between physical abuse and insomnia deserves further investigation in order to determine the possible pathways of this association. PMID- 24142295 TI - [Life paths and motifs. Meeting points of hypnotherapy and music therapy]. AB - Effects both of hypnotherapy and music therapy are originated from an attunement as supposed by the author. Either to a hypnotherapist's suggestions or to a piece of music one is able to be tuned in them. On one hand, the hypnotherapist's prosody, which can be called as melodic declamation seen as a musical phenomenon transmitting emotions. On the other hand, music has got emotional and visceral impacts. As a meeting points of these two methods four possibilities are shown by the author: 1. musical analogies of vitality affects ; 2. paternal and maternal archetypes in music; 3. analogies of copings in music; 4. corrections of psychological deficits by virtue of hypno- and music therapy with parallel used energy healing method. Finally, the author suggests, that hypnosis is regarded as an inductive method expressing its effect from outside to inside; music, however is likely to be employed as a deductive therapeutic tool, effecting from inside to outside. PMID- 24142296 TI - Spatiotemporal patterns and essential role of MSK1 expression after rat spinal cord injury. AB - Mitogen and stress activated protein kinase (MSK1) protein was initially identified as a particularly interesting protein of mitogen activated protein kinase. It was reported to enhance Bad's phosphorylation to protect cell death, suggesting that MSK1 represents a new type of anti-cell death gene. Moreover, recent study has shown that MSK1 is involved in negative feedback pathways that are crucial to prevent uncontrolled inflammation. However, its function and expression in the central nervous system lesion are not been understood very well. In this study, we performed an acute spinal cord injury (SCI) model in adult rats and studied the dynamic changes of MSK1 expression in spinal cord. Western blot and immunohistochemistry analysis revealed that MSK1 was present in normal spinal cord. It gradually decreased, reached a peak at 3 days after SCI, and then increased during the following days. Immunofluorescence double labeling revealed that MSK1 was co-expressed with NeuN and GFAP, respectively. Interesting, after injury, MSK1 expression was decreased predominantly in astrocytes, which highly expressed proliferating cell nuclear antigen, a marker for proliferating cells. In conclusion, this is the first description of MSK1 expression in spinal cord. Our data suggested that MSK1 might play important roles in CNS pathophysiology after SCI. PMID- 24142297 TI - Control of body weight versus tumorigenesis by concerted action of leptin and estrogen. AB - Improper body weight control is most critical to the development of morbid obesity, which is often associated with alternation in leptin (Ob) signaling in the central nervous system. Leptin acts to control fat mass through the regulation of both food intake and energy expenditure. In addition to the primary action in metabolic signaling, leptin has also been found to play a role in reproduction and even in breast tumorigenesis in obese patients. Interestingly, estrogen, a sex hormone, has also been recognized as another crucial factor for energy balance and breast tumorigenesis in obese subjects. Obesity in postmenopausal women has been associated with higher risk of breast cancer. There are substantial data in the literature on the connection of estrogen and leptin pathways in development of obesity and breast cancer. In this review, we discuss the cross-talk of leptin and estrogen signaling pathways in body weight control and breast cancer development. PMID- 24142298 TI - Flavones derived from nature attenuate the immediate and late-phase asthmatic responses to aerosolized-ovalbumin exposure in conscious guinea pigs. AB - OBJECTIVE: Asthma is an inflammatory disease of the lung that is characterized by airway hyperresponsiveness and the increase of inflammatory cell infiltration into the airways. Naturally occurring flavones have potent anti-inflammatory effects, but their effects on asthmatic responses are still relatively unknown. METHODS: We evaluated the inhibitory effects of flavone derivatives having the chromone moiety on the immediate-phase asthmatic response (IAR) and the late phase asthmatic response (LAR) to aerosolized-ovalbumin (OA) exposure in conscious OA-sensitized guinea pigs. RESULTS: Luteolin and apigenin (30 mg/kg, p.o.) significantly (P < 0.05) decreased not only the specific airway resistance (sRaw) in IAR and LAR, but also the recruitment of leukocytes and the release of histamine and activities of phospholipase A2 (PLA2) and eosinophil peroxide (EPO) in bronchoalveolar lavage fluid (BALF), compared to control. However, their anti asthmatic activities were less than those of cromolyn sodium and dexamethasone. CONCLUSIONS: These results indicate that flavones containing more hydroxyl radicals have a greater anti-asthmatic effect. The potencies of flavone anti asthmatic activities are, in order: luteolin >= apigenin > baicalein > chrysin > flavone. PMID- 24142299 TI - Effect of food on rilpivirine/emtricitabine/tenofovir disoproxil fumarate, an antiretroviral single-tablet regimen for the treatment of HIV infection. AB - The effect of food on rilpivirine/emtricitabine/tenofovir disoproxil fumarate single-tablet regimen (STR) was evaluated in healthy subjects. Subjects (N = 24) received rilpivirine/emtricitabine/tenofovir disoproxil fumarate (25/200/300 mg) under fasted or fed conditions (light [390 kcal, 12 g fat]; standard [540 kcal, 21 g fat]) followed by pharmacokinetic (PK) sampling. The 90% confidence interval (CI) of the geometric mean ratio for rilpivirine, emtricitabine, tenofovir exposure was estimated for fed versus fasted dosing and light versus standard meal, with equivalence boundaries of 80 - 125%. Safety was assessed throughout study. Twenty-three subjects completed the study; one discontinued due to protocol violation. Adverse events were mild to moderate. Emtricitabine PK was unaffected. Tenofovir AUCinf was 38% and 28% higher, respectively, with standard and light meal versus fasted. Rilpivirine AUCinf and Cmax were 16% and 26% higher with a standard, and 9% and 34% with a light meal, respectively, versus fasted. Compared to standard meal, the lower limit of rilpivirine AUClast and AUCinf when taken with the light meal were narrowly below the equivalence bounds (79.9 and 79.2, respectively), rilpivirine Cmax was narrowly above (129). Rilpivirine/emtricitabine/tenofovir disoproxil fumarate should be administered with food, which can be a standard or light meal. PMID- 24142300 TI - Is regional anesthesia associated with reduced PACU length of stay?: A retrospective analysis from a tertiary medical center. AB - BACKGROUND: Postanesthesia care is a costly component of overall surgical care. In the ambulatory setting, regional anesthesia has been shown for multiple surgical procedures to either decrease postanesthesia care unit (PACU) length of stay (LOS) or completely bypass it altogether. This has not been demonstrated in a large hospital setting with a complex surgical case mix. QUESTIONS/PURPOSES: We therefore determined whether regional anesthesia was associated with a reduced PACU LOS among patients undergoing inpatient and outpatient surgery in a large tertiary-care teaching hospital. Secondary study questions included risk factors for longer PACU LOS and any possible interaction between regional and general anesthesia as it might have affected PACU LOS. METHODS: We performed a matched retrospective study on patients who had surgery at our institution and were admitted to the PACU immediately after leaving the operating room. We analyzed between January 1, 2005, and January 1, 2013, with one cohort receiving regional anesthesia, with or without general anesthesia, and the other receiving no regional anesthesia. We measured the association between regional anesthesia and time to successful PACU discharge using a Cox multivariate proportional-hazards model. RESULTS: After controlling for potentially confounding variables, including patient age, American Society of Anesthesiologists' physical classification, and duration of surgery (using multivariate analysis), there was no difference in the time to successful PACU discharge between patients who received regional anesthesia and those who did not. However, when compared to those who received general anesthesia, regional anesthesia was associated with decreased PACU LOS. Further, there was significant effect modification between regional and general anesthesia; patients who received both regional and general were more likely to be successfully discharged faster from the PACU than patients who received only general anesthesia (hazard ratio = 1.50, 95% CI = 1.46-1.55, p < 0.001). CONCLUSIONS: We demonstrated that independently, regional anesthesia is not associated with a reduced PACU LOS in an unselected population at a large tertiary-care hospital, but regional is favored when compared to general anesthesia. Whether the differences are clinically important, and in what procedures they are most pronounced, would be reasonable questions for future prospective comparative trials. LEVEL OF EVIDENCE: Level III, therapeutic study. See Instructions for Authors for a complete description of levels of evidence. PMID- 24142301 TI - Not the last word: Harvard beats Yale and other fallacies. PMID- 24142303 TI - Nearly monodisperse graphene quantum dots fabricated by amine-assisted cutting and ultrafiltration. AB - We report a novel procedure involving polyethylenimine-assisted hydrothermal cutting and subsequent ultrafiltration for fabricating nearly monodisperse graphene quantum dots with a uniform lateral size and confined layer number. The isolated monolayer quantum dots exhibit a sharp band-edge absorption feature and strong photoluminescence (quantum yield of 21%) independent of excitation wavelength and pH. Their preliminary application in bioimaging has been demonstrated. PMID- 24142302 TI - Industrially prefabricated cement spacers: do vancomycin- and gentamicin impregnated spacers offer any advantage? AB - BACKGROUND: Industrially preformed antibiotic-loaded cement spacers are useful to facilitate the second stage of two-stage exchange arthroplasty for infected THAs and TKAs. However, whether gentamicin alone or a combination of antibiotics (such as vancomycin and gentamicin) is more effective is not known. QUESTIONS/PURPOSES: We therefore sought to compare industrially prefabricated spacers containing either gentamicin or gentamicin and vancomycin with respect to (1) infection control, (2) complications, and (3) quality of life, pain, and patient satisfaction. METHODS: We performed a review of 51 patients with chronic infections treated at one center using either gentamicin or vancomycin and gentamicin-prefabricated spacers. The former were used exclusively from January 2006 until May 2009, and the latter from June 2009 until July 2011, and there was no overlap. We collected data on demographics, immunologic status (McPherson classification), prosthetic joint infection location, type of prosthesis, microbiologic results, and time between stages. We evaluated the primary outcome of infection control or recurrence after at least 12 months followup. We also recorded complications. Each patient completed a quality-of-life survey, VAS, and a self-administered satisfaction scale. RESULTS: The overall infection control rate was 83% after a mean followup of 35 months (range, 12.4-64.7 months). There were no differences between gentamicin and vancomycin and gentamicin spacers in terms of infection eradication (80 % versus 85 %, respectively; p = 0.73), nor in terms of complications, quality of life, pain, or satisfaction scores. CONCLUSIONS: Prefabricated, antibiotic-loaded cement spacers has been proven effective for infection control in TKAs and THAs but with the numbers available, we did not find any differences between a gentamicin or vancomycin and gentamicin prefabricated spacer, and therefore, we are unable to validate the superiority of the combination of vancomycin and gentamicin over gentamicin alone. Because of the higher costs involved with vancomycin and gentamicin spacers, and the potential risks of unselective use of vancomycin, further comparative studies are necessary to evaluate their role in the treatment of infected THAs or TKAs. LEVEL OF EVIDENCE: Level III, therapeutic study. See the Instructions for Authors for a complete description of levels of evidence. PMID- 24142304 TI - Excited Charge Transfer States in Donor-Acceptor Fluorescent Phenanthroimidazole Derivatives. AB - Solvent-dependent electronic structure of the selected donor (D) acceptor (A) derivatives of phenanthroimidazole derivatives containing fluoro substituent as an electron acceptor fragment in the fluorescent charge transfer (CT) states has been investigated. The mechanism of the radiative charge recombination CT -> S0 is discussed in terms of the Mulliken-Murrell model of the CT complexes and the Marcus theory of photoinduced electron transfer (ET). Solvatochromic effects on the spectral position and profile of the stationary fluorescence spectra clearly indicate the CT character of the emitting singlet states of all of the compounds studied both in a polar and a non polar environment. An analysis of the CT fluorescence leads to the quantities relevant for the electron transfer in the Marcus inverted region. The values of the fluorescence rate constants (k r ) and corresponding transition dipole moments (M) and their solvent polarity dependence indicate that the electronic coupling between the emitting (1)CT state and the ground state is a governing factor of the radiative transitions. The relatively large values of M indicate a nonorthogonal geometry of the donor and acceptor subunits in the fluorescent states. It is shown that Marcus theory can be applied for the quantitative description of the radiationless charge recombination processes in the cases when an intersystem crossing to the excited triplet states can be neglected. PMID- 24142305 TI - Prognostic factors of improvement in health-related quality of life in atomoxetine-treated children and adolescents with attention-deficit/hyperactivity disorder, based on a pooled analysis. AB - The objective of this study is to identify prognostic factors of treatment response to atomoxetine in improvement of health-related quality of life (HR QoL), measured by the Child Health and Illness Profile-Child Edition Parent Report Form (CHIP-CE PRF) Achievement and Risk Avoidance domains, in children and adolescents with attention-deficit/hyperactivity disorder (ADHD). Pooled data from 3 placebo-controlled trials and separate data from 3 open-label trials of atomoxetine in children and adolescents with ADHD were analyzed using logistic regression methods. Based on baseline impairment in the Achievement and/or Risk Avoidance domains (CHIP-CE PRF < 40 points), 2 subsamples of subjects were included. Treatment outcome was categorized as <5 points or >=5 points increase in the CHIP-CE PRF Achievement and Risk Avoidance domains. Data of 190 and 183 subjects from the pooled sample, and 422 and 355 subjects from the open-label trials were included in the analysis of Achievement and Risk Avoidance domains. Baseline CHIP-CE subdomain scores proved to be the most robust prognostic factors for treatment outcome in both domains, based on data from the pooled sample of double-blind studies and from the individual open-label studies (odds ratios [OR] 0.74-1.56, p < 0.05; OR < 1, indicating a worse baseline score associated with worse odds of responding). Initial treatment response (>=25 % reduction in ADHD Rating Scale scores in the first 4-6 weeks) was another robust prognostic factor, based on data from the open-label studies (OR 2.99-6.19, p < 0.05). Baseline impairment in HR-QoL and initial treatment response can be early prognostic factors of atomoxetine treatment outcome in HR-QoL in children and adolescents with ADHD. PMID- 24142307 TI - The researchers and the scientifc production in Pediatrics: what is its value? PMID- 24142306 TI - Neuroimaging and genetic risk for Alzheimer's disease and addiction-related degenerative brain disorders. AB - Neuroimaging offers a powerful means to assess the trajectory of brain degeneration in a variety of disorders, including Alzheimer's disease (AD). Here we describe how multi-modal imaging can be used to study the changing brain during the different stages of AD. We integrate findings from a range of studies using magnetic resonance imaging (MRI), positron emission tomography (PET), functional MRI (fMRI) and diffusion weighted imaging (DWI). Neuroimaging reveals how risk genes for degenerative disorders affect the brain, including several recently discovered genetic variants that may disrupt brain connectivity. We review some recent neuroimaging studies of genetic polymorphisms associated with increased risk for late-onset Alzheimer's disease (LOAD). Some genetic variants that increase risk for drug addiction may overlap with those associated with degenerative brain disorders. These common associations offer new insight into mechanisms underlying neurodegeneration and addictive behaviors, and may offer new leads for treating them before severe and irreversible neurological symptoms appear. PMID- 24142308 TI - Profile and scientific production of Brazilian National Council of Technological and Scientific Development researchers in Pediatrics. AB - OBJECTIVE: To evaluate the profile and the scientific production of researchers in Pediatrics with scholarship from the National Counsel of Technological and Scientific Development. METHODS: The Lattes curricula of 34 researchers in Pediatrics with active scholarships, from 2006 to 2008 were included in the analysis. The variables of interest were: gender, affiliation, time since PHD, tutoring of undergraduate students, mentorship of masters and doctors, scientific production and the papers' impact. RESULTS: In a total of 411 researchers in Medicine, 34 (8%) belonged to Pediatrics. Males (77%) and scholars in the category 2 of productivity (62%) prevailed. Three states of Brazil were responsible for approximately 90% of the researchers: Sao Paulo (53%), Minas Gerais (21%), and Rio Grande do Sul (15%). During their academic career, the Pediatrics researchers have published 3,122 articles with a median of 89 articles per researcher (interquartile range - IQ=51-119). Of the total, 40 and 59% articles were indexed in the Web of Science and Scopus databases, respectively. The Pediatrics researchers have published papers in 599 journals with a median impact factor of 2.35 (IQ=1.37-3.73) for the 323 indexed journals. CONCLUSIONS: The Pediatrics researchers have a relevant scientific output from the quantity point of the view, but there is a need to improve quality. PMID- 24142309 TI - Reduction of exposure to blood donors in preterm infants submitted to red blood cell transfusions using pediatric satellite packs. AB - OBJECTIVE: In preterm newborn infants transfused with erythrocytes stored up to 28 days, to compare the reduction of blood donor exposure in two groups of infants classified according to birth weight. METHODS: A prospective study was conducted with preterm infants with birth weight <1000 g (Group 1) and 1000-1499 g (Group 2), born between April, 2008 and December, 2009. Neonates submitted to exchange transfusions, emergency erythrocyte transfusion, or those who died in the first 24 hours of life were excluded. Transfusions were indicated according to the local guideline using pediatric transfusion satellite bags. Demographic and clinical data, besides number of transfusions and donors were assessed. . Logistic regression analysis was performed to determine factors associated with multiple transfusions. RESULTS: 30 and 48 neonates were included in Groups 1 and 2, respectively. The percentage of newborns with more than one erythrocyte transfusion (90 versus 11%), the median number of transfusions (3 versus 1) and the median of blood donors (2 versus 1) were higher in Group 1 (p<0.001), compared to Group 2. Among those with multiple transfusions, 14 (82%) and one (50%) presented 50% reduction in the number of blood donors, respectively in Groups 1 and 2. Factors associated with multiple transfusions were: birth weight <1000 g (OR 11.91; 95%CI 2.14-66.27) and presence of arterial umbilical catheter (OR 8.59; 95%CI 1.94-38.13), adjusted for confounders. CONCLUSIONS: The efficacy of pediatrics satellites bags on blood donor reduction was higher in preterm infants with birth weight <1000 g. PMID- 24142310 TI - Craniofacial abnormalities among patients with Edwards Syndrome. AB - OBJECTIVE To determine the frequency and types of craniofacial abnormalities observed in patients with trisomy 18 or Edwards syndrome (ES). METHODS This descriptive and retrospective study of a case series included all patients diagnosed with ES in a Clinical Genetics Service of a reference hospital in Southern Brazil from 1975 to 2008. The results of the karyotypic analysis, along with clinical data, were collected from medical records. RESULTS: The sample consisted of 50 patients, of which 66% were female. The median age at first evaluation was 14 days. Regarding the karyotypes, full trisomy of chromosome 18 was the main alteration (90%). Mosaicism was observed in 10%. The main craniofacial abnormalities were: microretrognathia (76%), abnormalities of the ear helix/dysplastic ears (70%), prominent occiput (52%), posteriorly rotated (46%) and low set ears (44%), and short palpebral fissures/blepharophimosis (46%). Other uncommon - but relevant - abnormalities included: microtia (18%), orofacial clefts (12%), preauricular tags (10%), facial palsy (4%), encephalocele (4%), absence of external auditory canal (2%) and asymmetric face (2%). One patient had an initial suspicion of oculo-auriculo-vertebral spectrum (OAVS) or Goldenhar syndrome. CONCLUSIONS: Despite the literature description of a characteristic clinical presentation for ES, craniofacial alterations may be variable among these patients. The OAVS findings in this sample are noteworthy. The association of ES with OAVS has been reported once in the literature. PMID- 24142311 TI - Risk factors and prevalence of newborn hearing loss in a private health care system of Porto Velho, Northern Brazil. AB - OBJECTIVE: To determine the prevalence of hearing loss and to analyze the results of newborn hearing screening and audiological diagnosis in private health care systems. METHODS Cross-sectional and retrospective study in a database of newborn hearing screening performed by a private clinic in neonates born in private hospitals of Porto Velho, Rondonia, Northern Brazil. The screening results, the risk for hearing loss, the risk indicators for hearing loss and the diagnosis were descriptively analyzed. Newborns cared in rooming in with their mothers were compared to those admitted to the Intensive Care Unit regarding risk factors for hearing loss. RESULTS: Among 1,146 (100%) enrolled newborns, 1,064 (92.8%) passed and 82 (7.2%) failed the hearing screening. Among all screened neonates, 1,063 (92.8%) were cared in rooming and 83 (7.2%) needed intensive care; 986 (86.0%) were considered at low risk and 160 (14.0%) at high risk for hearing problems. Of the 160 patients identified as having high risk for hearing loss, 83 (37.7%) were admitted to an hospitalized in the Intensive Care Unit, 76 (34.5%) used ototoxic drugs and 38 (17.2%) had a family history of hearing loss in childhood. Hearing loss was diagnosed in two patients (0.2% of the screened sample). CONCLUSIONS: The prevalence of hearing loss in newborns from private hospitals was two cases per 1,000 evaluated patients. The use of ototoxic drugs, admission to Intensive Care Unit and family history of hearing loss were the most common risk factors for hearing loss in the studied population. PMID- 24142312 TI - Analysis models for variables associated with breastfeeding duration. AB - OBJECTIVE To analyze the factors associated with breastfeeding duration by two statistical models. METHODS A population-based cohort study was conducted with 86 mothers and newborns from two areas primary covered by the National Health System, with high rates of infant mortality in Vitoria, Espirito Santo, Brazil. During 30 months, 67 (78%) children and mothers were visited seven times at home by trained interviewers, who filled out survey forms. Data on food and sucking habits, socioeconomic and maternal characteristics were collected. Variables were analyzed by Cox regression models, considering duration of breastfeeding as the dependent variable, and logistic regression (dependent variables, was the presence of a breastfeeding child in different post-natal ages). RESULTS In the logistic regression model, the pacifier sucking (adjusted Odds Ratio: 3.4; 95%CI 1.2-9.55) and bottle feeding (adjusted Odds Ratio: 4.4; 95%CI 1.6-12.1) increased the chance of weaning a child before one year of age. Variables associated to breastfeeding duration in the Cox regression model were: pacifier sucking (adjusted Hazard Ratio 2.0; 95%CI 1.2-3.3) and bottle feeding (adjusted Hazard Ratio 2.0; 95%CI 1.2-3.5). However, protective factors (maternal age and family income) differed between both models. CONCLUSIONS Risk and protective factors associated with cessation of breastfeeding may be analyzed by different models of statistical regression. Cox Regression Models are adequate to analyze such factors in longitudinal studies. PMID- 24142313 TI - Coverage and adequacy of ferrous sulfate supplementation in the prevention of anemia among children treated at health centers of Florianopolis, Santa Catarina. AB - OBJECTIVE To evaluate the National Program of Iron Supplementation (PNSF) coverage, the compliance with the directions for of using of this supplementation and the association with sociodemographic factors in children aged six to 18 months old and registered in 35 public health centers of Florinopolis (Southern Brazil). METHODS Cross-sectional study using secondary data obtained from the health information system of the Health Department of Florianopolis, Santa Catarina, Brazil (Infosaude). Data on ferrous sulfate supplementation and sociodemographic variables were obtained of all children registered in PNSF in Florianopolis in 2010. STATA 11.0 software was used in the analyses. RESULTS The PNSF covered 6.3% (95%CI 5.9-6.7) of the children; the compliance with the directions regarding age at the onset of supplementation and its frequency was adequate only in 2.4% of the cases (95%CI 1.5-3.7). There was no association with the child's gender, maternal education level and ethnicity or the distance from home to the health center. CONCLUSIONS This study showed low coverage and inadequate compliance with the PNSF directions. Measures to improve this strategy are urgent. PMID- 24142314 TI - School feeding programs' role in forming eating habits. AB - OBJECTIVE To identify teaching managers' perceptions regarding the relationship of school feeding and the promotion of healthy eating habits among students. METHODS A descriptive study with a qualitative approach was developed in the city of Guarulhos (Southeast Brazil). Key informants from municipal public schools were interviewed. Public schools were selected (n=13) and classified as to the level of social exclusion, size and economic activity of the region where the school was located. Pedagogic coordinators and school principals were individually interviewed with semi-structured questions. RESULTS From school principals and pedagogical coordinators' perceptions, three categories were identified: Food in the school context; School feeding program's role and the Concept of food and nutrition security, which indicate that they considered meals as part of school routine in order to attain physiological needs of energy and nutrients. Their answers also indicated that they did not consider school meals as a pedagogical action related to their specific responsibilities. CONCLUSIONS The relationship between the school feeding and the formation of eating habits is not a topic usually discussed between the different professionals involved with health and education. The implementation of health promoting policies will only be possible after a debate about how schools and their pedagogical team adopt the program guidelines and how the professionals decode these strategies in daily activities. PMID- 24142315 TI - C-reactive protein and its relation to high blood pressure in overweight or obese children and adolescents. AB - OBJECTIVE To investigate the association between C-reactive protein (CRP) and high blood pressure (BP) in overweight or obese children and adolescents. METHODS Cross-sectional study with 184 overweight or obese children and adolescents aged from two to 18 years old, from April, 2009 to April, 2010. The classification of nutritional status used the body mass index (BMI). Based on the Centers for Disease Control and Prevention curve, individuals were classified as: overweight (BMI between the 85th-95th percentiles), obesity (BMI between 95th-97th percentiles) and severe obesity (BMI >97th percentile). Abnormal values were considered for systolic BP (SBP) and/or diastolic (DBP) if >= 90th percentile of the BP curve recommended for children and adolescents in the V Brazilian Guidelines on Hypertension, for waist circumference (WC) if >= 90th percentile of the curve established by the National Cholesterol Education Program, and for high sensitive CRP (hs-CRP) if >3mg/dL. To evaluate the association of inadequate values of CRP and the studied groups, chi-square test and analysis of variance were applied, using the Statistical Package for the Social Sciences version 17.0 and adopting a significance level of 5%. RESULTS Among the evaluated sample, 66.3% were female, 63.5%, non-white, 64.1% had severe obesity, 78.3% had altered WC and 70.6% presented high BP. There was a significant association of CRP high levels with altered WC and BMI >= 97 th percentile. In adolescents, high CRP was related to high SBP. CRP mean values were higher in individuals with elevated SBP. CONCLUSIONS Inadequate values of hs-CRP were associated with severe obesity and high SBP in the studied population. These markers can be used to identify children and adolescents at higher risk for developing atherosclerosis. PMID- 24142316 TI - Reasons for non-adherence to obesity treatment in children and adolescents. AB - OBJECTIVE To analyze the reasons for non-adherence to follow-up at a specialized outpatient clinic for obese children and adolescents. METHODS Descriptive study of 41 patients, including information from medical records and phone recorded questionnaires which included two open questions and eight closed ones: reason for abandonment, financial and structural difficulties (distance and transport costs), relationship with professionals, obesity evolution, treatment continuity, knowledge of difficulties and obesity complications. RESULTS Among the interviewees, 29.3% reported that adherence to the program spent too much time and it was difficult to adjust consultations to patients' and parents' schedules. Other reasons were: children's(tm)s refusal to follow treatment (29.3%), dissatisfaction with the result (17.0%), treatment in another health service (12.2%), difficulty in schedule return (7.3%) and delay in attendance (4.9%). All denied any relationship problems with professionals. Among the respondents, 85.4% said they are still overweight. They reported hurdles to appropriate nutrition and physical activity (financial difficulty, lack of parents' time, physical limitation and insecure neighborhood). Among the 33 respondents that reported difficulties with obesity, 78.8% had emotional disorders such as bullying, anxiety and irritability; 24.2% presented fatigue, 15.1% had difficulty in dressing up and 15.1% referred pain. The knowledge of the following complications prevailed: cardicac (97.6%), aesthetic (90.2%), psychological (90.2%), presence of obesity in adulthood (90.2%), diabetes (85.4%) and cancer (31.4%). CONCLUSIONS According to the results, it is possible to create weight control public programs that are easier to access, encouraging appropriate nutrition and physical activities in order to achieve obesity prevention. PMID- 24142317 TI - Food pattern and nutritional status of children with cerebral palsy. AB - OBJECTIVES To assess the food intake pattern and the nutritional status of children with cerebral palsy. METHODS Cross-sectional study with 90 children from two to 12.8 years with cerebral palsy in the following forms: hemiplegia, diplegia, and tetraplegia. Nutritional status was assessed by weight, height, and age data. Food intake was verified by the 24-hour recall and food frequency questionnaire. The ability to chew and/or swallowing, intestinal habits, and physical activity were also evaluated. RESULTS For 2-3 year-old age group, the mean energy intake followed the recommended range; in 4-6 year-old age group with hemiplegia and tetraplegia, energy intake was below the recommended limits. All children presented low intake of carbohydrates, adequate intake of proteins and high intake of lipids. The tetraplegia group had a higher prevalence of chewing (41%) and swallowing (12.8%) difficulties compared to 14.5 and 6.6% of children with hemiplegia, respectively. Most children of all groups had a daily intestinal habit. All children presented mild physical activity, while moderate activity was not practiced by any child of the tetraplegia group, which had a significantly lower height/age Z score than those with hemiplegia (-2.14 versus -1.05; p=0.003). CONCLUSIONS The children with cerebral palsy presented inadequate dietary pattern and impaired nutritional status, with special compromise of height. Tetraplegia imposes difficulties regarding chewing/swallowing and moderate physical activity practice. PMID- 24142318 TI - Cross-cultural analysis of the motor development of Brazilian, Greek and Canadian infants assessed with the Alberta Infant Motor Scale. AB - OBJECTIVE: To compare the motor development of infants from three population samples (Brazil, Canada and Greece), to investigate differences in the percentile curves of motor development in these samples, and to investigate the prevalence of motor delays in Brazilian children. METHODS: Observational, descriptive and cross-sectional study with 795 Brazilian infants from zero to 18 months of age, assessed by the Alberta Infant Motor Scale (AIMS) at day care centers, nurseries, basic health units and at home. The Brazilian infants' motor scores were compared to the results of two population samples from Greece (424 infants) and Canada (2,400 infants). Descriptive statistics was used, with one-sample t-test and binomial tests, being significant p <= 0.05. RESULTS: 65.4% of Brazilian children showed typical motor development, although with lower mean scores. In the beginning of the second year of life, the differences in the motor development among Brazilian, Canadian and Greek infants were milder; at 15 months of age, the motor development became similar in the three groups. A non-linear motor development trend was observed. CONCLUSIONS: The lowest motor percentiles of the Brazilian sample emphasized the need for national norms in order to correctly categorize the infant motor development. The different ways of motor development may be a consequence of cultural differences in infant care. PMID- 24142319 TI - Evaluation of the Pediatric Symptom Checklist as a screening tool for the identification of emotional and psychosocial problems. AB - OBJECTIVE To investigate the Brazilian version of Pediatric Symptom Checklist (PSC) as a screening tool to identify psychosocial and emotional problems in schoolchildren from six to 12 years old. METHODS Diagnostic test conducted in a public school of Curitiba, Parana (Southern Brazil), to evaluate the PSC accuracy and consistency, considering the Child Behavior Checklist (CBCL) as the gold standard. Among 415 parents invited for the study, 145 responded to both PSC and CBCL. The results of the two instruments were compared. PSC and CBCL were considered positive if scores >= 28 and >70 respectively. RESULTS Among the 145 cases, 49 (33.8%) were positive for both PSC and CBCL. The ROC curve showed the PSC score of 21 as the best cutoff point for screening psychosocial and emotional problems, with a sensitivity of 96.8% and a specificity of 86.7%. Regarding the reference cutoff (score >= 28 points), the sensitivity was 64.5% and the specificity, 100.0%, similar to those found in the original version of the tool. CONCLUSIONS The Portuguese version of PSC was effective for early identification of emotional and/or psychosocial problems in a schoolchildren group and may be useful for pediatricians. PMID- 24142320 TI - Contribution of the Activities Diary to the pediatric teaching. AB - OBJECTIVE To describe the fifth-year medical students' self-evaluation based on the reflexive discourse of the Activities Diaries (portfolio) from the Pediatric Internship I and Child Care Rotations. METHODS Cross sectional, qualitative and descriptive study using the collective subject discourse of the diaries used during the internship of the Medical School, in Catanduva, Sao Paulo, from January to November, 2011. The registered students' testimonials in the portfolio sections called self-assessment and students' impression were assessed according to their central ideas (discipline organization, breastfeeding outpatient clinic, number of admissions in the pediatric hospital ward and satisfaction with the Child Health training ), related to the teaching of Pediatrics and Child Care. The portfolios with incomplete registers were excluded. RESULTS The testimonials of 47 interns (75% of the students) were analyzed, and 21.3% of them expressed satisfaction with the discipline organization and 27.7% praised the inclusion of the breastfeeding outpatient clinics in the course. For 25.5% of the academics, the number of admissions in the pediatric wards was insufficient for an ideal learning; however, 70.2% were satisfied with the Child Health training. CONCLUSIONS This critical analysis allowed a summary of the reflections, suggestions and critics registered by the interns and can be used as a tool for improvement of the professional cycle. PMID- 24142321 TI - Effect of concurrent training on risk factors and hepatic steatosis in obese adolescents. AB - OBJECTIVE To analyze the effects of a 20-week concurrent training on the variables of body composition, lipid profile, and fatty liver diagnosis in obese adolescents. METHODS An open clinical trial was carried out with 34 obese adolescents aged between 12 and 15 years. Total body fat, trunk fat mass, total cholesterol and its fractions (HDL, LDL and VLDL), and triglycerides were analyzed; an upper abdominal ultrasound was performed in order to diagnose fatty liver. The participants underwent concurrent training (association of weight training with aerobic training) three times per week, lasting one hour for 20 weeks. Statistical analysis included paired Student's(tm)s t-test and frequency analysis in order to verify the relative and absolute reductions of fatty liver diagnosis, being significant p<0.05. RESULTS The studied adolescents showed statistically significant improvement in body composition, with a decrease of total body fat percentage, total fat mass, trunk fat, and an a increase in the lean body mass. They also presented reduced size of liver lobes, decrease in total cholesterol and in LDL-cholesterol, with a lower prevalence of fatty liver. CONCLUSIONS The concurrent training was effective for promoting significant improvements in body fat composition and lipid profile variables, besides reducing fatty liver prevalence rate. PMID- 24142322 TI - Timed "Up & Go" test in children and adolescents. AB - OBJECTIVE To evaluate, by a literature review, the Timed "Up & Go" (TUG) test use and its main methodological aspects in children and adolescents. DATA SOURCES The searches were performed in the following databases: PubMed, CINAHL, Web of Science, SciELO and Cochrane Library, from April to July 2012. Studies published from 1990 to 2012 using the terms in Portuguese and English "Timed "Up & Go", "test", "balance", "child", and "adolescent" were selected. The results were divided into categories: general characteristics of the studies, population, test implementation METHODS, interpretation of results and associations with other measurements. DATA SYNTHESIS 27 studies were analyzed in this review and most of them used the TUG test along with other outcome measures to assess functional mobility or balance. Three studies evaluated the TUG test in significant samples of children and adolescents with typical development, and the most studied specific diagnoses were cerebral palsy and traumatic brain injury. The absence of methodological standardization was noted, but one study proposed adaptations to the pediatric population. In children and adolescents with specific clinical diagnoses, the coefficient of within-session reliability was found to be high in most studies, as well as the intra and inter-examiner reliability, which characterizes the good reproducibility of the test. CONCLUSIONS The TUG test was shown to be a good tool to assess functional mobility in the pediatric population, presenting a good reproducibility and correlation with other assessment tools. PMID- 24142323 TI - Imperfect twinning: a clinical and ethical dilemma. AB - OBJECTIVE To review the history, epidemiology, etiology, gestational aspects, diagnosis and prognosis of imperfect twinning. DATA SOURCES Scientific articles were searched in PubMed, SciELO and Lilacs databases, using the descriptors "conjoined twins", "multiple pregnancy", "ultrasound", "magnetic resonance imaging" and "prognosis". The research was not delimited to a specific period of time and was supplemented with bibliographic data from books. DATA SYNTHESIS: The description of conjoined twins is legendary. The estimated frequency is 1/45,000 200,000 births. These twins are monozygotic, monochorionic and usually monoamniotic. They can be classified by the most prominent fusion site, by the symmetry between the conjoined twins or by the sharing structure. The diagnosis can be performed in the prenatal period or after birth by different techniques, such as ultrasound, magnetic resonance imaging and echocardiography. These tests are of paramount importance for understanding the anatomy of both fetuses/children, as well as for prognosis and surgical plan determination. CONCLUSIONS Although imperfect twinning is a rare condition, the prenatal diagnosis is very important in order to evaluate the fusion site and its complexity. Hence, the evaluation of these children should be multidisciplinary, involving mainly obstetricians, pediatricians and pediatric surgeons. However, some decisions may constitute real ethical dilemmas, in which different points should be discussed and analyzed with the health team and the family. PMID- 24142324 TI - Effects of maternal nicotine on breastfeeding infants. AB - OBJECTIVE To assess scientific evidence about the effects of maternal nicotine on infant by an integrative review. DATA SOURCES Studies published in Portuguese, English and Spanish, from 1990 to 2009, with abstracts available in the Latin American Health Sciences Literature (Lilacs) and Medical Literature Analysis and Retrieval System On-Line (Medline) databases. The descriptors were: "breastfeeding", "lactation" and "smoking". DATA SYNTHESIS The main identified effects of nicotine on infants were: changes in sleep and wakefulness patterns; reduction of iodine supply; hystopathological damage on liver and lung; intracellular oxidative damage; reduction of pancreatic beta cells; and decreased glucose tolerance. CONCLUSIONS It is recommended to inform mothers about harmful chemicals contained in cigarettes that can be secreted into breast milk. They should be strongly encouraged to stop smoking during lactation. PMID- 24142325 TI - Methodological and ethical aspects of the sexual maturation assessment in adolescents. AB - OBJECTIVE To analyze methodological and ethical aspects in the sexual maturation assessment of adolescents. DATA SOURCES Books and theses, articles and legislations on the Medline, SciELO, Science Direct databases, besides institutional documents of the World Health Organization and the Pediatric Societies of Brazil and Sao Paulo, considering the period from 1962 to 2012. The following keywords were used in Portuguese and English: "sexual maturation", "self-assessment", "ethics", "OBJECTIVE assessment of sexual maturation", "puberty", "adolescent", and "adolescentdevelopment". DATA SYNTHESIS The sexual maturation assessment is used in populatinal studies and in clinical daily care. The direct evaluation is performed by a specialized physician, whereas the self assessment is carried out by the adolescent. This evaluation should be carefully performed in the appropriate place, taking into account the ethical aspects. The patient should not be constrained and the physician must respect the privacy and the confidentiality. Before this evaluation and independently of the used method, the adolescent should receive information and explanation about the procedure and the tools that will be applied. Furthermore, the patient has the right to want or not an adult close to him. CONCLUSIONS Validation studies showed that self assessment is inferior to clinical assessment and should, therefore, be performed only when the direct examination by physicians is not possible. PMID- 24142326 TI - Congenital esophageal stenosis owing to tracheobronchial remnants. AB - OBJECTIVE To emphasize the need of an accurate diagnosis of congenital esophageal stenosis due to tracheobronchial remnants, since its treatment differs from other types of congenital narrowing. CASE DESCRIPTION Four cases of lower congenital esophageal stenosis due to tracheobronchial remnants, whose definitive diagnosis was made by histopathology. Except for the last case, in which a concomitant anti reflux surgery was not performed, all had a favorable outcome after resection and anastomosis of the esophagus. COMMENTS The congenital esophageal stenosis is an intrinsic narrowing of the organ's wall associated with its structural malformation. The condition can be caused by tracheobronchial remnants, fibromuscular stenosis or membranous diaphragm and the first symptom is dysphagia after the introduction of solid food in the diet. The first-choice treatment to tracheobronchial remnants cases is the surgical resection and end-to-end anastomosis of the esophagus. PMID- 24142327 TI - Reexpansion pulmonary edema in children. AB - OBJECTIVE To present a case of a patient with clinical and radiological features of reexpansion pulmonary edema, a rare and potentially fatal disease. CASE DESCRIPTION An 11-year-old boy presenting fever, clinical signs and radiological features of large pleural effusion initially treated as a parapneumonic process. Due to clinical deterioration he underwent tube thoracostomy, with evacuation of 3,000 mL of fluid; he shortly presented acute respiratory insufficiency and needed mechanical ventilation. He had an atypical evolution (extubated twice with no satisfactory response). Computerized tomography findings matched those of reexpansion edema. He recovered satisfactorily after intensive care, and pleural tuberculosis was diagnosed afterwards. COMMENTS Despite its rareness in the pediatric population (only five case reports gathered), the knowledge of this pathology and its prevention is very important, due to high mortality rates. It is recommended, among other measures, slow evacuation of the pleural effusion, not removing more than 1,500 mL of fluid at once. PMID- 24142328 TI - Comparison between preconsultation ultrasonography and office surgeon-performed ultrasound in patients with thyroid cancer. AB - BACKGROUND: Cervical ultrasonography (US) is mandatory before surgery for thyroid cancer and recommended for thyroid nodule evaluation. Therefore, most patients undergo thyroid ultrasound before surgical evaluation. Several US findings are critical for adequate surgical planning but they are often not mentioned on preconsultation US. The goal of this study is to compare the preconsultation US findings with surgeon-performed US (SUS) and describe the changes in management as a consequence of SUS findings in patients with thyroid cancer. METHODS: The charts of 194 consecutive patients with thyroid cancer (2007-2013) from a single institution were reviewed. Preconsultation US and SUS reports were available for 136 patients. Mention of nodes, local invasion, thyroid nodule features/location, and presence of intrathoracic extension was recorded and changes in preoperative and/or operative management based on SUS findings were described. RESULTS: From 136 patients with the diagnosis of thyroid cancer, SUS changed the management of 61 (45 %) patients by identifying preoperatively central and/or lateral node metastasis, indicating preoperative biopsy of suspicious thyroid lesions/nodes, and pointing out thyroid intrathoracic extension. When compared to SUS, the preconsultation US failed to mention node status in 101 (74 %) patients, suspicious nodule features in 60/111 (54 %) patients with suspicious lesions, bilateral thyroid lesions in 19/88 (22 %) patients with bilateral nodules, local invasion in 5/5 (100 %), and intrathoracic extension in 5/5 (100 %) cases. CONCLUSION: Surgeon-performed US changed the operative management of patients with thyroid cancer by demonstrating additional and distinct information compared to preconsultation US in almost half of the patients. Ultrasound is more accurate and critical in the evaluation of patients with thyroid cancer when performed by the surgeon. PMID- 24142329 TI - Epsilon-aminocaproic acid improves postrecirculation hemodynamics by reducing intraliver activated protein C consumption in orthotopic liver transplantation. AB - BACKGROUND: Activated protein C (APC) is related to regulating the inflammatory response and hemodynamic stability upon reperfusion in cardiac operations and orthotopic liver transplantation (OLT). Epsilon-aminocaproic acid (EACA) is frequently used to treat fibrinolysis during OLT. It also has inhibitory effects related to the inflammatory response. However, it remains to be determined whether EACA can attenuate intraliver APC consumption and improve hemodynamic stability after reperfusion during OLT. METHODS: Fifty-nine recipients were randomized to receive either EACA (150 mg kg(-1) given intravenously prior to incision, followed by 15 mg kg(-1) h(-1) infusion until 2 h after the graft reperfusion) or the same volume of saline. Blood samples to assess plasma APC and protein C were obtained immediately before and after reperfusion from the inferior caval effluent or the portal veins for calculation of transliver differences (Delta). Hemodynamics and vasoactive medication use during the reperfusion period were observed in both groups. RESULTS: No transhepatic changes in protein C were found in either group. Immediately after reperfusion, a marked intraliver consumption of APC was noted in all recipients (P < 0.001), and intraliver consumption of APC in the control group was greater than that in the EACA-treated group (P < 0.05). Fewer requirements for vasoactive medication use after reperfusion and better initial graft function were noted in the EACA treated group (P < 0.05). CONCLUSIONS: EACA can attenuate intraliver APC consumption and improve hemodynamic stability after reperfusion and initial graft function during OLT. PMID- 24142330 TI - Improvement of sleep disturbance and insomnia following parathyroidectomy for primary hyperparathyroidism. AB - BACKGROUND: The aim of the present study was to investigate the incidence of sleep disturbance and insomnia in patients with primary hyperparathyroidism (PHPT), and to evaluate the effect of parathyroidectomy. METHODS: A questionnaire was prospectively administered to adult patients with PHPT who underwent curative parathyroidectomy over an 11-month period. The questionnaire, administered preoperatively and 6 months postoperatively, included the Insomnia Severity Index (ISI) and eight additional questions regarding sleep pattern. Total ISI scores range from 0 to 28, with >7 signifying sleep difficulties and scores >14 indicating clinical insomnia. RESULTS: Of 197 eligible patients undergoing parathyroidectomy for PHPT, 115 (58.3 %) completed the preoperative and postoperative questionnaires. The mean age was 60.0 +/- 1.2 years and 80.0 % were women. Preoperatively, 72 patients (62.6 %) had sleep difficulties, and 29 patients (25.2 %) met the criteria for clinical insomnia. Clinicopathologic variables were not predictive of clinical insomnia. There was a significant reduction in mean ISI score after parathyroidectomy (10.3 +/- 0.6 vs 6.2 +/- 0.5, p < 0.0001). Postoperatively, 79 patients (68.7 %) had an improved ISI score. Of the 29 patients with preoperative clinical insomnia, 21 (72.4 %) had resolution after parathyroidectomy. Preoperative insomnia patients had an increase in total hours slept after parathyroidectomy (5.4 +/- 0.3 vs 6.1 +/- 0.3 h, p = 0.02), whereas both insomnia patients and non-insomnia patients had a decrease in the number of awakenings (3.7 +/- 0.4 vs 1.9 +/- 0.2 times, p = 0.0001). CONCLUSIONS: Sleep disturbances and insomnia are common in patients with PHPT, and the majority of patients will improve after curative parathyroidectomy. PMID- 24142331 TI - Laparoscopy-assisted hybrid left-side donor hepatectomy: is it truly less invasive for living donors? PMID- 24142332 TI - Mandatory resection of strangulation marks in small bowel obstruction? PMID- 24142333 TI - Understanding WHO surgical checklist implementation: tricks and pitfalls. An observational study. AB - BACKGROUND: The purpose of the present study was to assess the reliability of implementation data regarding the surgical safety checklist (SSC) and to identify which factors influence actual implementation. METHODS: The study was a retrospective record-based evaluation in a regional network of nine Spanish hospitals, combined with a complementary direct-observation study that included a survey of the surgical teams' attitudes. SSC compliance and associated factors were assessed and compared in a retrospective sample of 280 operations and a concurrent sample of another 85 surgical interventions. RESULTS: In the retrospective evaluation the SSC was present in 83.1 % of cases, fully completed in 28.4 %, with 69.3 % of all possible items checked. The concurrent direct observation study showed that recorded compliance was unreliable (kappa < 0.13 for all items) and significantly higher (p < 0.001) than actual compliance. Over registration occurred across hospitals and surgical specialties. Factors associated with recorded compliance included hospital size, surgical specialty, and the use of an electronic format. In actual (direct-observation) compliance, a positive attitude on the part of the surgeon is an overriding significant factor (OR 12.8), along with using the electronic format, which is consistently and positively associated with recorded compliance but negatively related to actual compliance. CONCLUSIONS: Recorded SSC compliance may be widely unreliable and higher than actual compliance, particularly when recording is facilitated by using an electronic format. A positive attitude on the part of the surgical team, particularly surgeons, is associated with actual compliance. Effective use of the SSC is a far more complex adaptive process than the usual mandatory strategy. PMID- 24142334 TI - Small bowel obstruction in patients with a prior history of cancer: predictive findings of malignant origins. AB - BACKGROUND: Determining the cause of acute small bowel obstruction (SBO) in patients previously treated for cancer is necessary for adequate management, especially to avoid incorrectly classing the patient as palliative. We aimed to identify predictive factors for a malignant or a benign origin of SBO. METHODS: We retrospectively studied data for all patients with a prior history of cancer who had undergone operations for SBO between January 2002 and December 2011. Of the 124 patients included, 36 patients had a known cancer recurrence before surgery for SBO, whereas 88 had none. RESULTS: Causes of SBO were benign (post operative adhesions, post-irradiation strictures) in 68 patients (54.8 %) and malignant in 56 (45.2 %). Incomplete obstruction, acute clinical onset, non permanent abdominal pain, a shorter period between primary cancer surgery and the first episode of obstruction, and a known cancer recurrence were significant predictors of a malignant SBO. Benign causes of SBO were observed in 72.8 % of patients who had no known cancer recurrence, but were observed in only 11.1 % of patients whose recurrences were known. In patients with cancer recurrence-related SBO, post-operative mortality was 28.6 %, with a median overall survival of 120 days. 1 month after surgery, 38 (67.8 %) of these patients tolerated oral intake. CONCLUSION: A benign cause of SBO was observed in half of the patients with a prior history of cancer and in two-thirds of those without known recurrence. Even in the absence of bowel strangulation, surgery must be considered soon after failure of medical management to treat a possible adhesion-related SBO. PMID- 24142335 TI - Small bowel obstruction in patients with a prior history of cancer: predictive findings of malignant origins. PMID- 24142336 TI - Prospecting genomes for lasso peptides. AB - Genome mining has unlocked a veritable treasure chest of natural compounds. However, each family of natural products requires a genome-mining approach tailored to its unique features to be successful. Lasso peptides are ribosomally synthesized and posttranslationally modified products with a unique three dimensional structure. Advances in the understanding of these molecules have informed the design of strategies to identify new members of the class in sequenced genomes. This review presents the bioinformatic methods used to discover novel lasso peptides and describes how such analyses have afforded insights into the biosynthesis and evolution of this peptide class. PMID- 24142338 TI - Heating and microwave assisted SPPS of C-terminal acid peptides on trityl resin: the truth behind the yield. AB - Despite correct purity of crude peptides prepared on trityl resin by Fmoc/tBu microwave assisted solid phase peptide synthesis, surprisingly, lower yields than those expected were obtained while preparing C-terminal acid peptides. This could be explained by cyclization/cleavage through diketopiperazine formation during the second amino acid deprotection and third amino acid coupling. However, we provide here evidence that this is not the case and that this yield loss was due to high temperature promoted hydrolysis of the 2-chlorotrityl ester, yielding premature cleavage of the C-terminal acid peptides. PMID- 24142337 TI - Lessons learned from the transformation of natural product discovery to a genome driven endeavor. AB - Natural product discovery is currently undergoing a transformation from a phenotype-driven field to a genotype-driven one. The increasing availability of genome sequences, coupled with improved techniques for identifying biosynthetic gene clusters, has revealed that secondary metabolomes are strikingly vaster than previously thought. New approaches to correlate biosynthetic gene clusters with the compounds they produce have facilitated the production and isolation of a rapidly growing collection of what we refer to as "reverse-discovered" natural products, in analogy to reverse genetics. In this review, we present an extensive list of reverse-discovered natural products and discuss seven important lessons for natural product discovery by genome-guided methods: structure prediction, accurate annotation, continued study of model organisms, avoiding genome-size bias, genetic manipulation, heterologous expression, and potential engineering of natural product analogs. PMID- 24142339 TI - Comparison of nestin-expressing multipotent stem cells in the tongue fungiform papilla and vibrissa hair follicle. AB - We have previously reported that hair follicles contain multipotent stem cells, which express nestin and participate in follicle growth at anagen as well as in the extension of the follicle sensory nerve. The nestin-driven green fluorescent protein (ND-GFP) transgenic mouse labels all nestin-expressing cells with GFP. The hair follicle nestin-GFP cells can differentiate into neurons, Schwann cells, and other cell types. In this study, we describe nestin-expressing multipotent stem cells in the fungiform papilla in the tongue. The nestin-expressing multipotent stem cells in the fungiform papilla are located around a peripheral sensory nerve immediately below the taste bud and co-express the neural crest cell marker p75(NTR) . The fungiform papilla cells formed spheres in suspension culture in DMEM-F12 medium supplemented with basic fibroblast growth factor (bFGF). The spheres consisted of nestin-expressing cells that co-expressed the neural crest marker p75(NTR) and which developed expression of the stem cell marker CD34. P75(NTR), CD34 and nestin co-expression suggested that nestin expressing cells comprising the fungiform papilla spheres were in a relatively undifferentiated state. The nestin-expressing cells of these spheres acquired the following markers: beta III tubulin typical of nerve cells; GFAP typical of glial cells; K15 typical of keratinocytes; and smooth-muscle antigen (SMA), after transfer to RPMI 1640 medium with 10% fetal bovine serum (FBS), suggesting they differentiated into multiple cell types. The results of the current study indicate nestin-expressing fungiform papilla cells and the nestin-expressing hair follicle stem cells have common features of cell morphology and ability to differentiate into multiple cell types, suggesting their remarkable similarity. PMID- 24142340 TI - Genetic characterization of congenital tufting enteropathy: epcam associated phenotype and involvement of SPINT2 in the syndromic form. AB - Congenital tufting enteropathy (CTE) is a rare and severe enteropathy recently ascribed to mutations in the epcam gene. Here we establish SPINT2, previously ascribed to congenital sodium diarrhea, as a second gene associated with CTE and report molecular and immunohistochemistry data in 57 CTE patients. Inclusion criteria were early onset diarrhea and intestinal insufficiency with the typical histological CTE abnormalities. The clinical phenotype was registered, the entire coding regions of epcam and SPINT2 sequenced, and immunostaining of EpCAM and SPINT2 performed on intestinal biopsies. An epcam mutation was involved in 41 patients (73 %) who mainly displayed isolated digestive symptoms. Mutations severely affected gene expression since the EpCAM signal on intestinal tissues was either undetectable or low and irregular. Twelve other patients (21 %) carried mutations in SPINT2, and were phenotypically characterized by systematic association with keratitis (p < 10(-4)) and, for half of them, with choanal atresia (p < 10(-4)). Dependency on parenteral nutrition (PN) was comparable in patients with epcam or SPINT2 mutations, but the frequent epcam mutation c.556 14A>G (abnormal splicing) was significantly associated with a better outcome (p = 0.032) with milder PN dependency to weaning in some cases. Finally, four patients (7 %) with isolated digestive symptoms had no detectable epcam or SPINT2 mutation. Two candidate genes, Elf3 and Claudin7, were excluded from this population. Our study allows us to separate CTE patients into at least three genetic classes, each with specific phenotypes. The genetics approach raises the question of the distinction between two congenital enteropathies. Our findings should help improve the diagnosis of CTE, guide toward strategies of long-term PN management, and limit indications for intestinal transplantation to life threatening PN complications. PMID- 24142342 TI - Maternal mortality due to pandemic influenza A H1N1 2009 virus in Colombia. PMID- 24142341 TI - Patient customized engineering for smart cardiovascular therapy. PMID- 24142343 TI - Molecular profiling of tumor cells in cerebrospinal fluid and matched primary tumors from metastatic breast cancer patients with leptomeningeal carcinomatosis. AB - Although leptomeningeal carcinomatosis is a well-established clinical syndrome, virtually nothing is known about the tumor cells responsible for this particularly aggressive metastatic process. To isolate cerebrospinal fluid derived tumor cells (CSFTC) from 15 patients with metastatic breast cancer diagnosed with leptomeningeal carcinomatosis, CSF samples were subjected to a two step method involving immunomagnetic enrichment and fluorescence-activated cell sorting (IE/FACS), a technique previously used for isolating circulating tumor cells (CTC) from blood. CSFTCs were subjected to genome-wide copy number analysis by array comparative genomic hybridization. Genomic profiling was successfully performed for 13 of 15 patients (87%). Copy number analysis in CSFTCs revealed genomic alterations commonly observed in primary breast cancer and CTCs, indicating their malignant origin. Interestingly, 12 (92%) harbored high-level gains on the 8q24 locus, which includes the MYC oncogene. Comparison of CSFTCs against corresponding archival primary tumors in six patients revealed clonal relationships with some divergence. Good concordance among serial samples attested to the reproducibility of the assay. Our approach for isolation and molecular analysis of CSFTCs yielded new insights into the molecular nature of these cells. Further genomic and functional analyses may help elucidate mechanisms by which tumor cells metastasize to the central nervous system. PMID- 24142344 TI - ALDH1-positive cancer stem cells predict engraftment of primary breast tumors and are governed by a common stem cell program. AB - Cancer stem-like cells (CSC) have been widely studied, but their clinical relevance has yet to be established in breast cancer. Here, we report the establishment of primary breast tumor-derived xenografts (PDX) that encompass the main diversity of human breast cancer and retain the major clinicopathologic features of primary tumors. Successful engraftment was correlated with the presence of ALDH1-positive CSCs, which predicted prognosis in patients. The xenografts we developed showed a hierarchical cell organization of breast cancer with the ALDH1-positive CSCs constituting the tumorigenic cell population. Analysis of gene expression from functionally validated CSCs yielded a breast CSC signature and identified a core transcriptional program of 19 genes shared with murine embryonic, hematopoietic, and neural stem cells. This generalized stem cell program allowed the identification of potential CSC regulators, which were related mainly to metabolic processes. Using an siRNA genetic screen designed to target the 19 genes, we validated the functional role of this stem cell program in the regulation of breast CSC biology. Our work offers a proof of the functional importance of CSCs in breast cancer, and it establishes the reliability of PDXs for use in developing personalized CSC therapies for patients with breast cancer. PMID- 24142346 TI - Targeting mitochondria by alpha-tocopheryl succinate overcomes hypoxia-mediated tumor cell resistance to treatment. AB - Rapidly proliferating tumor cells easily become hypoxic. This results in acquired stability towards treatment with anticancer drugs. Here, we show that cells grown at 0.1 % oxygen are more resistant towards treatment with the conventionally used anticancer drugs doxorubicin and cisplatin. The stimulation of apoptosis, as assessed by the number of cells in the SubG1 fraction of the cell cycle, release of cytochrome c into the cytosol, activation of caspase-3, and cleavage of PARP, was markedly suppressed under low oxygen content or when hypoxia was mimicked by deferoxamine. Hypoxia or deferoxamine treatment was accompanied by stabilization of the hypoxia-inducible factor (HIF-1). The downregulation of HIF-1 using siRNA technique restored cell sensitivity to treatment under hypoxic conditions to the levels detected under normoxic conditions. In contrast to cisplatin or doxorubicin, alpha-tocopheryl succinate (alpha-TOS), a compound that targets mitochondria, stimulated cell death irrespective of the oxygen concentration. Moreover, under hypoxic condition cell death induced by alpha-TOS was even enhanced. Thus, alpha-TOS can successfully overcome resistance to treatment caused by hypoxia, which makes alpha-TOS an attractive candidate for antitumor therapy via mitochondrial targeting. PMID- 24142348 TI - In vivo myofibre architecture in the systemic right ventricle. PMID- 24142349 TI - Inequalities in heart failure in older men: prospective associations between socioeconomic measures and heart failure incidence in a 10-year follow-up study. AB - AIMS: Socioeconomic position has been linked to incident heart failure (HF), but the underlying mechanisms are unclear. We examined the association of socioeconomic measures with incident HF in older adults and examined possible underlying pathways. METHODS AND RESULTS: A socially representative cohort of men aged 60-79 years in 1998-2000 from 24 British towns was followed-up for 10 years for incident HF. Adult socioeconomic position was based on a cumulative score, including occupation, education, housing tenure, pension, and amenities. Childhood socioeconomic measures included father's occupational social class and household amenities. Prevalent myocardial infarction and HF cases were excluded. Among 3836 men, 229 incident cases of HF occurred over 10 years. Heart failure risk increased with an increasing score of adverse adult socioeconomic measures (P for trend = < 0.0001). Compared with men with a score of 0, the hazard ratio for men with a score of >= 4 was 2.19 (95% confidence interval, CI, 1.34-3.55), which was attenuated to 1.87 (95% CI 1.12-3.11) after adjusting for systolic blood pressure, body mass index, smoking, HDL-cholesterol, diabetes, and lung function. Adjustment for left ventricular hypertrophy, atrial fibrillation, heart rate, and renal function made little difference. Further adjustment for C reactive protein, von Willebrand Factor, N-terminal pro-brain natriuretic peptide, and plasma vitamin C also made little difference to the hazard ratio [1.89 (95% CI 1.10-3.24)]. Heart failure risk did not vary by childhood socioeconomic measures. CONCLUSION: Heart failure risk in older men was greater in the most deprived socioeconomic groups, which was only partly explained by established risk factors for HF. Novel risk factors contribute little to the associated risk. PMID- 24142350 TI - Protective effects of zonisamide against rotenone-induced neurotoxicity. AB - Zonisamide (ZNS), an antiepileptic drug having beneficial effects also against Parkinson's disease symptoms, has proven to display an antioxidant effects in different experimental models. In the present study, the effects of ZNS on rotenone-induced cell injury were investigated in human neuroblastoma SH-SY5Y cells differentiated towards a neuronal phenotype. Cell cultures were exposed for 24 h to 500 nM rotenone with or without pre-treatment with 10-100 MUM ZNS. Then, the following parameters were analyzed: (a) cell viability; (b) intracellular reactive oxygen species production; (c) mitochondrial transmembrane potential; (d) cell necrosis and apoptosis; (e) caspase-3 activity. ZNS dose-dependently suppressed rotenone-induced cell damage through a decrease in intracellular ROS production, and restoring mitochondrial membrane potential. Similarly to ZNS effects, the treatment with N-acetyl-cysteine (100 MUM) displayed significant protective effects against rotenone-induced ROS production and Deltapsim at 4 and 12 h respectively, reaching the maximal extent at 24 h. Additionally, ZNS displayed antiapoptotic effects, as demonstrated by flow cytometric analysis of annexin V/propidium iodide double staining, and significant attenuated rotenone increased caspase 3 activity. On the whole, these findings suggest that ZNS preserves mitochondrial functions and counteracts apoptotic signalling mechanisms mainly by an antioxidant action. Thus, ZNS might have beneficial effect against neuronal cell degeneration in different experimental models involving mitochondrial dysfunction. PMID- 24142351 TI - Harnessing indigenous plant seed oil for the production of bio-fuel by an oleaginous fungus, Cunninghamella blakesleeana- JSK2, isolated from tropical soil. AB - Cunninghamella blakesleeana- JSK2, a gamma-linolenic acid (GLA) producing tropical fungal isolate, was utilized as a tool to evaluate the influence of various plant seed oils on biomass, oleagenicity and bio-fuel production. The fungus accumulated 26 % total lipid of their dry biomass (2 g/l) and 13 % of GLA in its total fatty acid. Among the various plant seed oils tested as carbon sources for biotransformation studies, watermelon oil had an effect on biomass and total lipid increasing up to 9.24 g/l and 34 % respectively. Sunflower, pumpkin, and onion oil increased GLA content between 15-18 %. Interestingly, an indigenous biodiesel commodity, Pongamia pinnata oil showed tremendous effect on fatty acid profile in C. blakesleeana- JSK2, when used as a sole source of carbon. There was complete inhibition of GLA from 13 to 0 % and increase in oleic acid content, one of the key components of biodiesel to 70 % (from 20 % in control). Our results suggest the potential application of indigenous plant seed oils, particularly P. pinnata oil, for the production of economically valuable bio-fuel in oleaginous fungi in general, and C. blakesleeana- JSK2, in particular. PMID- 24142347 TI - Focus on molecular events in the anterior chamber leading to glaucoma. AB - Primary open-angle glaucoma is a multifactorial disease that affects the retinal ganglion cells, but currently its therapy is to lower the eye pressure. This indicates a definite involvement of the trabecular meshwork, key region in the pathogenesis of glaucoma. This is the first target of glaucoma, and its functional complexity is a real challenge to search. Its functions are those to allow the outflow of aqueous humor and not the reflux. This article describes the morphological and functional changes that happen in anterior chamber. The "primus movens" is oxidative stress that affects trabecular meshwork, particularly its endothelial cells. In these develops a real mitochondriopaty. This leads to functional impotence, the trabecular meshwork altering both motility and cytoarchitecture. Its cells die by apoptosis, losing barrier functions and altering the aqueous humor outflow. All the morphological alterations occur that can be observed under a microscope. Intraocular pressure rises and the malfunctioning trabecular meshwork endotelial cells express proteins that completely alter the aqueous humor. This is a liquid whose functional proteomics complies with the conditions of the trabecular meshwork. Indeed, in glaucoma, it is possible detect the presence of proteins which testify to what occurs in the anterior chamber. There are six classes of proteins which confirm the vascular endothelium nature of the anterior chamber and are the result of the morphofunctional trabecular meshwork decay. It is possible that, all or in part, these proteins can be used as a signal to the posterior pole. PMID- 24142352 TI - A feruloyl esterase (FAE) characterized by relatively high thermostability from the edible mushroom Russula virescens. AB - A monomeric feruloyl esterase (FAE) with a molecular mass of 62 kDa was acquired from fresh fruiting bodies of the edible mushroom Russula virescens. The isolation procedure involved ion exchange chromatography on CM-cellulose, Q Sepharose, and SP-Sepharose and finally fast protein liquid chromatography-gel filtration on Superdex 75. Two amino acid sequences were obtained after tryptic digestion, and they both showed some homology with the esterase of some fungi. Maximal activity was observed at pH 5.0 and at 50 degrees C. The enzyme displayed relatively high thermostability as evidenced by over 70 % residual activity at 70 degrees C and about 34 % residual activity at 80 degrees C. The K m and V max for this enzyme on methyl ferulate were 0.19 mM and 1.65 U/mg proteins, respectively. The purified FAE prefers methyl ferulate over methyl caffeate and is least active on methyl p-coumarate. The FAE activity was not significantly affected by the presence of cations such as Mn(2+), Ca(2+), Cd(2+), Zn(2+), Mg(2+), Cu(2+), and K(+) ions but inhibited by Al(3+), Hg(2+), Fe(2+), and Pb(2+) ions at a tested concentration of 2. 5 mM. PMID- 24142353 TI - Depletion of the xynB2 gene upregulates beta-xylosidase expression in C. crescentus. AB - Caulobacter crescentus is able to express several enzymes involved in the utilization of lignocellulosic biomasses. Five genes, xynB1-5, that encode beta xylosidases are present in the genome of this bacterium. In this study, the xynB2 gene, which encodes beta-xylosidase II (CCNA_02442), was cloned under the control of the PxylX promoter to generate the O-xynB2 strain, which overexpresses the enzyme in the presence of xylose. In addition, a null mutant strain, Delta-xynB2, was created by two homologous recombination events where the chromosomal xynB2 gene was replaced by a copy that was disrupted by the spectinomycin-resistant cassette. We demonstrated that C. crescentus cells lacking beta-xylosidase II upregulates the xynB genes inducing beta-xylosidase activity. Transcriptional analysis revealed that xynB1 (RT-PCR analysis) and xynB2 (lacZ transcription fusion) gene expression was induced in the Delta-xynB2 cells, and high beta xylosidase activity was observed in the presence of different agro-industrial residues in the null mutant strain, a characteristic that can be explored and applied in biotechnological processes. In contrast, overexpression of the xynB2 gene caused downregulation of the expression and activity of the beta-xylosidase. For example, the beta-xylosidase activity that was obtained in the presence of sugarcane bagasse was 7-fold and 16-fold higher than the activity measured in the C. crescentus parental and O-xynB2 cells, respectively. Our results suggest that beta-xylosidase II may have a role in controlling the expression of the xynB1 and xynB2 genes in C. crescentus. PMID- 24142354 TI - Microstructural and potential dependence studies of urease-immobilized gold nanoparticles-polypyrrole composite film for urea detection. AB - Gold nanoparticle-polypyrrole nanocomposite film was electrochemically deposited in a single-step polymerization of pyrrole in the presence of 3-mercaptopropionic acid (MPA)-capped gold nanoparticles (GNPs) and p-toluenesulfonic acid (pTSA) on the surface of an indium tin oxide (ITO)-coated glass plate. The carboxyl functional groups surrounding the GNPs within the polymer matrix were utilized for the immobilization of urease enzyme through carbodiimide coupling reaction for the construction of a Urs/GNP(MPA)-PPy/ITO-glass bioelectrode for urea detection in Tris-HCl buffer. The resulting bioelectrode film was characterized by atomic force microscopy (AFM), high-resolution transmission electron microscopy (HRTEM), contact angle measurement, Fourier transform infrared spectroscopy (FTIR), and electrochemical techniques. The potentiometric response of the bioelectrode made of polymer nanocomposite films of two different thicknesses prepared at 100 and 250 mC cm(-2) charge densities, respectively, was studied towards the urea concentration in Tris-HCl buffer (pH 7.4). The thin polymer nanocomposite film-based bioelectrode prepared at 100 mC cm(-2) charge density exhibited a comparatively good potentiometric response than a thick 250 mC cm(-2) charge density film with a linear range of urea detection from 0.01 to 10 mM with a sensitivity of 29.7 mV per decade. PMID- 24142355 TI - A new near-infrared neutral pH fluorescent probe for monitoring minor pH changes and its application in imaging of HepG2 cells. AB - A new near-neutral pH near-infrared (NIR) fluorescent probe utilizing a fluorophore-receptor molecular framework that can modulate the fluorescence emission intensity through a fast photoinduced electron transfer process was developed. Our strategy was to choose tricarbocyanine (Cy), a NIR fluorescent dye with high extinction coefficients, as a fluorophore, and N-methylpiperazine (MP) as a receptor. The pH titration indicated that MP-Cy can monitor the minor physiological pH fluctuations with a pKa of ~7.10 near physiological pH, which is valuable for intracellular pH researches. The probe responds linearly and rapidly to minor pH fluctuations within the range of 3.05-7.10 and exhibits strong dependence on pH changes. As expected, the real-time imaging of cellular pH and the detection of pH in situ was achieved successfully in living HepG2 cells by this probe. It is shown that the probe effectively avoids the influence of autofluorescence and native cellular species in biological systems and meanwhile exhibits high sensitivity, good photostability, and excellent cell membrane permeability. PMID- 24142356 TI - Simultaneous detection of influenza viruses A, B, and swine origin influenza A using multiplex one-step real-time RT-PCR assay. AB - Every year, seasonal epidemics of influenza viruses are causing considerable morbidity and mortality worldwide. Also infrequent novel and rearranged strains of influenza viruses have caused quick, acute universal pandemics resulting in millions of mortalities. The usage of efficient and accurate detection is superior for infection control, effective treatment, and epidemiological supervision. Therefore, evaluation of useful real-time PCR molecular tests for the detection of pandemic viruses is important before the next wave of the pandemic. A novel quantitative real-time reverse-transcription polymerase chain reaction (qRT-PCR) assay with specific primers was used successfully for detection and monitoring of the influenza A, B, and swine influenza. The newly designed primers target highly conserved regions in influenza viruses. Our qRT PCR assay is highly specific for detecting influenza A, B, and swine influenza viruses. The cutoff CT value was determined <38 for domestic human diagnostic test, under conditions of FDA emergency, and the reaction efficiency of the InfA, swInfA, and InfB assays were thereby estimated to be 97.9 % (R2 = 0.998), 98.3 % (R2 = 0.986), and 99.5 % (R2 = 0.995), respectively. Interestingly, based on our finding, there is no cross reactivity of detecting other viruses. PMID- 24142357 TI - Fungal cellulase/xylanase production and corresponding hydrolysis using pretreated corn stover as substrates. AB - Three pretreated corn stover (ammonia fiber expansion, dilute acid, and dilute alkali) were used as carbon source to culture Trichoderma reesei Rut C-30 for cellulase and xylanase production. The results indicated that the cultures on ammonia fiber expansion and alkali pretreated corn stover had better enzyme production than the acid pretreated ones. The consequent enzymatic hydrolysis was performed applying fungal enzymes on pretreated corn stover samples. Tukey's statistical comparisons exhibited that there were significant differences on enzymatic hydrolysis among different combination of fungal enzymes and pretreated corn stover. The higher sugar yields were achieved by the enzymatic hydrolysis of dilute alkali pretreated corn stover. PMID- 24142358 TI - Investigation of growth conditions for the expansion of porcine mesenchymal stem cells on microcarriers in stirred cultures. AB - The extensive use of mesenchymal stem cells (MCS) in tissue engineering and cell therapy increases the necessity to improve their expansion. Among these, porcine MCS are valuable models for tissue engineering and are classically expanded in static T-flasks. In this work, different processes of stirred cultures were evaluated and compared. First, the effect of glucose, glutamine, antioxidant, and growth factors concentrations on porcine MSC expansion were analyzed in a suitable medium by performing kinetic studies. Results showed that a lower glucose concentration (5.5 mM) enabled to increase maximal cell concentration by 40 % compared with a higher one (25 mM), while addition of 2 to 6 mM of glutamine increased maximal cell concentration by more than 25 % compared with no glutamine supplementation. Moreover, supplementation with 1 MUM thioctic acid increased maximal cell concentration by 40 % compared with no supplementation. Using this adapted medium, microcarriers cultures were performed and compared with T-flasks expansion. Porcine MSC were shown to be able to proliferate on the five types of microcarriers tested. Moreover, cultures on Cytodex 1, Cytopore 2, and Cultispher G exhibited a MSC growth rate more than 40 % higher compared with expansion in T flasks, while MSC metabolism was similar. PMID- 24142359 TI - Sensitive electrochemical aptasensor for thrombin detection based on graphene served as platform and graphene oxide as enhancer. AB - A sensitive electrochemical aptasensor was developed with conductive graphene served as platform and inert graphene oxide (GO) as enhancer. An electrodeposited nano-Au layer was firstly formed on conductive graphene modified glass carbon electrode surface for further immobilizing of electrochemical redox probe hexacyanoferrates nanoparticles (NiHCFNPs). Subsequently, another nano-Au layer was formed for immobilizing of thrombin aptamer (TBA). In the presence of thrombin, the TBA on the electrode surface could bind with thrombin, which made a barrier for electrons and inhibited the electro-transfer, resulting in the decreased electrochemical signals of NiHCFNPs. Owing to the non-conductivity property of graphene oxide, further decreased electrochemical signals of NiHCFNPs could be obtained via the sandwich reaction with GO-labeled TBA. According to the signal changes before the thrombin recognition and after sandwich reaction, trace detection of thrombin could be achieved. As a result, the proposed approach showed a high sensitivity and a wider linearity to thrombin in the range from 0.005 nM to 50 nM with a detection limit of 1 pM. PMID- 24142360 TI - The study of ascorbate peroxidase, catalase and peroxidase during in vitro regeneration of Argyrolobium roseum. AB - Here, we demonstrate the micropropagation protocol of Argyrolobium roseum (Camb.), an endangered herb exhibiting anti-diabetic and immune-suppressant properties, and antioxidant enzymes pattern is evaluated. Maximum callogenic response (60 %) was observed from leaf explant at 1.0 mg L(-1) 1-nephthalene acetic acid (NAA) and 0.5 mg L(-1) 6-benzyl aminopurine (BA) in Murashige and Skoog (MS) medium using hypocotyl and root explants (48 % each). Addition of AgNO3 and PVP in the culture medium led to an increase in callogenic response up to 86 % from leaf explant and 72 % from hypocotyl and root explants. The best shooting response was observed in the presence of NAA, while maximum shoot length and number of shoots were achieved based on BA-supplemented MS medium. The regenerated shoots were rooted and successfully acclimatized under greenhouse conditions. Catalase and peroxidase enzymes showed ascending pattern during in vitro plant development from seed while ascorbate peroxidase showed descending pattern. Totally reverse response of these enzymes was observed during callus induction from three different explants. During shoot induction, catalase and peroxidase increased at high rate while there was a mild reduction in ascorbate peroxidase activity. Catalase and peroxidase continuously increased; on the other hand, ascorbate peroxidase activity decreased during root development and acclimatization states. The protocol described here can be employed for the mass propagation and genetic transformation of this rare herb. This study also highlights the importance and role of ascorbate peroxidase, catalase, and peroxidase in the establishment of A. roseum in vitro culture through callogenesis and organogenesis. PMID- 24142361 TI - Central mechanisms of obesity and related metabolic diseases. PMID- 24142362 TI - High mobility graphene ion-sensitive field-effect transistors by noncovalent functionalization. AB - Noncovalent functionalization is a well-known nondestructive process for property engineering of carbon nanostructures, including carbon nanotubes and graphene. However, it is not clear to what extend the extraordinary electrical properties of these carbon materials can be preserved during the process. Here, we demonstrated that noncovalent functionalization can indeed delivery graphene field-effect transistors (FET) with fully preserved mobility. In addition, these high-mobility graphene transistors can serve as a promising platform for biochemical sensing applications. PMID- 24142363 TI - Snakebite cases in the municipalities of the State of Paraiba, Brazil. AB - INTRODUCTION: This study investigated the epidemiological and clinical profile of snakebite cases reported from 2007 to 2012 in the municipalities of the Curimatau region, State of Paraiba, in northeastern Brazil. METHODS: Data were collected from the Health Department of the State of Paraiba using the Injury Notification Information System data banks of the Health Ministry. RESULTS: A total of 304 snakebite cases were studied. The cases occurred most frequently from April to June. The genera Bothrops, Crotalus, and Micrurus were responsible for 74.6%, 6.2%, and 1.3% of cases, respectively. Snakebite cases predominated in males living in rural areas and between 10 and 19 years old. The highest incidence of bites occurred on the feet. The majority of the victims received medical assistance within 1 to 3h after being bitten. With regard to severity, 48% of the cases were classified as mild, 26% as moderate, and 2.6% as severe. Successful cures predominated, and no deaths were reported. The average antivenom ampoule dose used for the treatment in some snakebite cases was lower than that recommended by the Health Ministry. CONCLUSIONS: Although our results show that Paraiba has a good level of medical care, there are serious deficiencies in recording snakebite information. These data indicate the need to improve the recording process for snakebite cases. Further training for health professionals seems to be necessary to optimize their skills in treating snakebite victims. PMID- 24142365 TI - Susceptibility of Argentinean Biomphalaria tenagophila and Biomphalaria straminea to infection by Schistosoma mansoni and the possibility of geographic expansion of mansoni schistosomiasis. AB - INTRODUCTION: Human migration and the presence of natural vectors (mollusks) of Schistosoma mansoni are the primary causes of the expansion of mansoni schistosomiasis into southern areas of South America. Water conditions are favorable for the expansion of this disease because of the extensive hydrographic network, which includes the basins of the Parana and Uruguay rivers and favors mollusk reproduction. These rivers also aid agriculture and tourism in the area. Despite these favorable conditions, natural infection by S. mansoni has not yet been reported in Argentina, Uruguay, or Paraguay. METHODS: Two species of planorbid from Argentina, Biomphalaria straminea and B. tenagophila, were exposed to the miracidia of five Brazilian strains of S. mansoni. RESULTS: Biomphalaria tenagophila (Atalaya, Buenos Aires province) was infected with the SJS strain (infection rate 3.3%), confirming the experimental susceptibility of this Argentinian species. Biomphalaria straminea (Rio Santa Lucia, Corrientes province) was susceptible to two Brazilian strains: SJS (infection rate 6.7%) and Sergipe (infection rate 6.7%). CONCLUSIONS: These results demonstrate that species from Argentina have the potential to be natural hosts of S. mansoni and that the appearance of foci of mansoni schistosomiasis in Argentina is possible. PMID- 24142366 TI - Molecular characterization of Candida spp. isolates from patients with bloodstream infections. AB - INTRODUCTION: The aim of this study was to conduct an epidemiological study comparing the genetic similarity of yeasts isolated from blood cultures. METHODS: Random amplification of polymorphic DNA (RAPD) techniques were used for the Candida samples obtained from patients at the Hospital Universitario da Universidade Federal do Mato Grosso do Sul (HU/UFMS) in Campo Grande, State of Mato Grosso do Sul, Brazil, from 1998-2000. RESULTS: The most frequently isolated species was Candida albicans (45.8%). DNA amplification from genomic yeast isolates indicated a genetic similarity of over 90%. CONCLUSIONS: The RAPD profiles obtained were able to differentiate between the isolated Candida species, thereby suggesting that the method might be useful in epidemiological studies. PMID- 24142367 TI - Ecological aspects of mosquitoes (Diptera: Culicidae) in the gallery forest of Brasilia National Park, Brazil, with an emphasis on potential vectors of yellow fever. AB - INTRODUCTION: We analyzed the vertical and monthly distributions of culicid species in the gallery forest of Brasilia National Park, with an emphasis on the potential vectors of yellow fever (YF). METHODS: Between September 2010 and August 2011, mosquitoes were captured on the ground and in the canopy of the forest for five consecutive days per month, from nine to 15 hours. The mosquitoes were examined to verify natural infection with flaviviruses by isolation in Aedes albopictus Skuse, 1864 cells followed by indirect immunofluorescence. RESULTS: We identified 2,677 culicids distributed in 29 species. Most of the mosquitoes were captured at ground level (69%) during the rainy season (86%). The most abundant species were Sabethes (Sabethes) albiprivus Theobald, 1903; Limatus durhamii Theobald, 1901; Haemagogus (Conopostegus) leucocelaenus Dyar & Shannon, 1924; Haemagogus (Haemagogus) janthinomys Dyar, 1921; Aedes (Ochlerotatus) scapularis Rondani, 1848; Psorophora (Janthinosoma) ferox Von Humboldt, 1819; and Aedes (Ochlerotatus) serratus Theobald, 1901. Limatus durhamii, Limatus durhamii, Psorophora ferox, Aedes scapularis and Aedes serratus showed significant differences (p<0.05) in their habitat use. Limatus durhamii was found more often in the canopy, unlike the other species. During the rainy season, the most abundant species were Sa. albiprivus, Haemagogus leucocelaenus and Limatus durhamii. During the dry season, the potential YF vectors exhibited a very low frequency and abundance, except Aedes scapularis and Aedes serratus. No flavivirus was detected in the 2,677 examined mosquitoes. CONCLUSIONS: We recommend continued and systematic entomological monitoring in areas vulnerable to the transmission of YF in the Federal District of Brazil. PMID- 24142368 TI - The reversible part of cognitive impairment in chronic kidney disease: can mice help men break the TEMPOLimit? PMID- 24142370 TI - [Collection and processing of personal data to evaluate cancer screening programmes - results of a survey of the German population in light of the bill 'early detection of cancer and cancer registries']. AB - In a representative German sample, 62.1% of participants of cancer screening interventions indicated willingness to provide personal data for data-linkage with cancer registries. An agreement of over 90% is deemed necessary to conduct a meaningful population-based evaluation. The 'early detection of cancer and cancer regis-tries' bill proposed a procedure based on the use of pseudonyms only. This way personal consent is not required but participants are granted the right to object. PMID- 24142369 TI - Psychosis prediction: stratification of risk estimation with information processing and premorbid functioning variables. AB - BACKGROUND: The period preceding the first psychotic episode is regarded as a promising period for intervention. We aimed to develop an optimized prediction model of a first psychosis, considering different sources of information. The outcome of this model may be used for individualized risk estimation. METHODS: Sixty-one subjects clinically at high risk (CHR), participating in the Dutch Prediction of Psychosis Study, were assessed at baseline with instruments yielding data on neuropsychology, symptomatology, environmental factors, premorbid adjustment, and neurophysiology. The follow-up period was 36 months. RESULTS: At 36 months, 18 participants (29.5%) had made a transition to psychosis. Premorbid adjustment (P = .001, hazard ratio [HR] = 2.13, 95% CI = 1.39/3.28) and parietal P300 amplitude (P = .004, HR = 1.27, 95% CI = 1.08/1.45) remained as predictors in the Cox proportional hazard model. The resulting prognostic score (PS) showed a sensitivity of 88.9% and a specificity of 82.5%. The area under the curve of the PS was 0.91 (95% CI = 0.83-0.98, cross validation: 0.86), indicating an outstanding ability of the model to discriminate between transition and nontransition. The PS was further stratified into 3 risk classes establishing a prognostic index. In the class with the worst social personal adjustment and lowest P300 amplitudes, 74% of the subjects made a transition to psychosis. Furthermore, transition emerged on average more than 17 months earlier than in the lowest risk class. CONCLUSIONS: Our results suggest that predicting a first psychotic episode in CHR subjects could be improved with a model including premorbid adjustment and information-processing variables in a multistep algorithm combining risk detection and stratification. PMID- 24142371 TI - [Anxiety and depressive symptoms and exposition towards violence in the general older population (between 60 and 84 years) in Germany - results from a cross sectional study]. AB - BACKGROUND: Depression and anxiety are important public health challenges in the general older population in Germany. Exposition towards violence/abuse in old age has been widely neglected as a risk factor for anxiety and depression among the older population. METHODS: The ABUEL study ("Abuse of the Elderly in Europe") is a cross-sectional study of people between 60 and 84 years living in Stuttgart. Anxiety and depression are assessed with the "Hospital Anxiety and Depression Scale" (HADS). We assessed 1) socio-demographic variables and 2) exposition towards violence in the past 12 months as independent variables. RESULTS: The results indicate that violence exposition in the past 12 months is a risk factor for anxiety (OR: 2.25, 95% CI: 1.32-3.84) and depression (OR: 2.27, 95% CI: 1.27 4.04) among the elderly population in Germany. Anxiety is associated with female gender (OR: 3.18, 95% CI: 1.62-6.25). Anxiety and depression are associated with times of unemployment in the life course. CONCLUSION: Our data suggest that exposure to violence in old age should be assessed to allow targeted prevention and intervention programmes. PMID- 24142372 TI - ["Hereditary and racial welfare" in public health services: support and selection]. AB - The long-term aim for the German public health service during National Socialism was a hereditary and racial welfare. Several following legal regulations contributed to the implementation of a specific national socialist population policy on the basis of racial hygiene and gave immense power to health officers. Especially with the Law for the Prevention of Hereditarily Sick Offspring, compulsory sterilisation was legalised and caused about 400,000 victims up to 1945. The central force in this new system was the public health office. The work of two health officers in neighbouring offices in upper Bavaria is compared. Results show that health officers had a large flexibility in their individual estimation. The restrictive interpretation of their duties did not necessarily cause any sanctions by the superior authority. PMID- 24142373 TI - [Extreme types - a comparison of public health systems in Thuringia and the Warthegau]. AB - Special policing measures in Nazi Germany required centralisation in the public health service which was mainly achieved through the Law for the Unification of Municipal and State Health Administration in 1934. The long-term aim for public health officers was now hereditary and racial welfare. Several following legal regulations contributed to the implementation of a specific national-socialist health and social policy on the basis of racial hygiene and gave immense power to the health officers. Especially with the Law for the Prevention of Hereditarily Sick Offspring, compulsory sterilisation was legalised and resulted in about 400,000 victims up to 1945. The central force in this new system was the public health office. The most extreme variation of public health administration was launched in Thuringia, where professional powers and state authority implemented an extensive institutional machinery which managed to reinforce Nazi population policy almost to perfection. After the invasion of western Poland the Germans built up an inhumane regime in the annexed and occupied regions, persecuted and murdered the Polish population and tried to exterminate the Jewish people. Here the health officers of the Warthegau could promote a rigorously racial dominated population policy of segregation. PMID- 24142374 TI - Age- and gender-related regional variations of human brain cortical thickness, complexity, and gradient in the third decade. AB - Brain functional and cytoarchitectural maturation continue until adulthood, but little is known about the evolution of the regional pattern of cortical thickness (CT), complexity (CC), and intensity or gradient (CG) in young adults. We attempted to detect global and regional age- and gender-related variations of brain CT, CC, and CG, in 28 healthy young adults (19-33 years) using a three dimensional T1 -weighted magnetic resonance imaging sequence and surface-based methods. Whole brain interindividual variations of CT and CG were similar to that in the literature. As a new finding, age- and gender-related variations significantly affected brain complexity (P < 0.01) on posterior cingulate and middle temporal cortices (age), and the fronto-orbital cortex (gender), all in the right hemisphere. Regions of interest analyses showed age and gender significant interaction (P < 0.05) on the temporopolar, inferior, and middle temporal-entorrhinal cortices bilaterally, as well as left inferior parietal. In addition, we found significant inverse correlations between CT and CC and between CT and CG over the whole brain and markedly in precentral and occipital areas. Our findings differ in details from previous reports and may correlate with late brain maturation and learning plasticity in young adults' brain in the third decade. PMID- 24142375 TI - Massive subcutaneous and mediastinal emphysema with little pneumothorax treated by surgery after pulmonary radiofrequency ablation. PMID- 24142376 TI - Differences in knowledge, attitudes, beliefs, and perceived risks regarding colorectal cancer screening among Chinese, Korean, and Vietnamese sub-groups. AB - Asian ethnic subgroups are often treated as a single demographic group in studies looking at cancer screening and health disparities. To evaluate knowledge and health beliefs associated with colorectal cancer (CRC) and CRC screening among Chinese, Korean, and Vietnamese subgroups, a survey assessed participants' demographic characteristics, healthcare utilization, knowledge, beliefs, attitudes associated with CRC and CRC screening. Exploratory factor analysis identified six factors accounting >60 % of the total variance in beliefs and attitudes. Cronbach's alpha coefficients assessed internal consistency. Differences among Asian subgroups were assessed using a Chi square, Fisher's exact, or Kruskal-Wallis test. Pearson's correlation coefficient assessed an association among factors. 654 participants enrolled: 238 Chinese, 217 Korean, and 199 Vietnamese. Statistically significant differences existed in demographic and health care provider characteristics, knowledge, and attitude/belief variables regarding CRC. These included knowledge of CRC screening modalities, reluctance to discuss cancer, belief that cancer is preventable by diet and lifestyle, and intention to undergo CRC screening. Chinese subjects were more likely to use Eastern medicine (52 % Chinese, 25 % Korean, 27 % Vietnamese; p < 0.001); Korean subjects were less likely to see herbs as a form of cancer prevention (34 % Chinese, 20 % Korean, 35 % Vietnamese; p < 0.001). Vietnamese subjects were less likely to consider CRC screening (95 % Chinese, 95 % Korean, 80 % Vietnamese; p < 0.0001). Important differences exist in knowledge, attitudes, and health beliefs among Asian subgroups. Understanding these differences will enable clinicians to deliver tailored, effective health messages to improve CRC screening and other health behaviors. PMID- 24142377 TI - Theoretical studies on the mechanism of activation of phosphoprotein phosphatases and purple acid phosphatases suggest an evolutionary strategy to survive in acidic environments. AB - Dephosphorylation reactions of phosphoprotein phosphatases (PPPs) share a common catalytic cycle. In one stage of the cycle, the active site is regenerated through formation of a new nucleophilic MU-hydroxy moiety and reprotonation of the proton donor, His125 (numbered according to the protein phosphatase 1 sequence). To date the exact details of the mechanism of this step remain uncertain. On the basis of recurring observations in several crystal structures, we propose an activation mechanism in which dephosphorylation of PPPs proceeds mainly through proton transfer from the water molecule that bridges the metal ions to His125, which is mediated by another water molecule. Our calculations using hybrid density functional theory and B3LYP functionals support this activation mechanism. We also propose that Asp95 facilitates proton transfer by eliminating the energy barrier and the backbone carbonyl oxygen atom of His248 acts mainly to orient and stabilize the MU-hydroxo (or water molecule) through hydrogen bonding. Furthermore, on the basis of the structural similarities of the active sites of purple acid phosphatases (PAPs) and PPPs, we speculate that PAPs are activated by a dual proton transfer mediated by one water molecule. Our calculations support this hypothesis and indicate that the active site of PAPs can still be active in an acidic environment (in agreement with the acid phosphatase activity of PAPs). Therefore, the variant of the activation mechanism from PPPs to PAPs implies an evolutionary adaptation to acidic environments. PMID- 24142378 TI - An investigation on patient dose in screen-film diagnostic radiology in Lhasa City, Xizang Autonomous Region, China. AB - This study aimed to investigate patient dose in diagnostic screen-film radiographic examinations in the city of Lhasa, China. Seven out of the twenty six hospitals registered with the Lhasa Health Bureau were included in the investigation. The entrance surface air Kerma (ESAK) of seven conventional screen film radiology X-ray equipment in these hospitals was measured with a QA dosimeter in September 2012. The X-ray examinations were divided into three categories: PA (posterior-anterior) chest, upper/lower limb, and AP (anterior posterior) lumbar spine. For each category, ESAKs were calculated and analyzed. The mean ESAK was 0.6 mGy for PA chest, 0.3 mGy for upper/lower limb, and 1.8 mGy for AP lumbar spine. In addition, the mean ESAK value recorded for PA chest X-ray examinations exceeded the corresponding value recommended by the International Atomic Energy Agency (0.4 mGy). PMID- 24142379 TI - Characterization of gibberellin-signalling elements during plum fruit ontogeny defines the essentiality of gibberellin in fruit development. AB - Fruit growth is a coordinated, complex interaction of cell division, differentiation and expansion. Gibberellin (GA) involvement in the reproductive events is an important aspect of GA effects. Perennial fruit-trees such as plum (Prunus salicina L.) have distinct features that are economically important and provide opportunities to dissect specific GA mechanisms. Currently, very little is known on the molecular mechanism(s) mediating GA effects on fruit development. Determination of bioactive GA content during plum fruit ontogeny revealed that GA1 and GA4 are critical for fruit growth and development. Further, characterization of several genes involved in GA-signalling showed that their transcriptional regulation are generally GA-dependent, confirming their involvement in GA-signalling. Based on these results, a model is presented elucidating how the potential association between GA and other hormones may contribute to fruit development. PslGID1 proteins structure, Y2H and BiFC assays indicated that plum GA-receptors can form a complex with AtDELLA-repressors in a GA-dependent manner. Moreover, phenotypical-, molecular- and GA-analyses of various Arabidopsis backgrounds ectopically expressing PslGID1 sequences provide evidence on their role as active GA-signalling components that mediate GA responsiveness. Our findings support the critical contribution of GA alone or in association with other hormones in mediating plum fruit growth and development. PMID- 24142380 TI - An improved chemically inducible gene switch that functions in the monocotyledonous plant sugar cane. AB - Chemically inducible gene switches can provide precise control over gene expression, enabling more specific analyses of gene function and expanding the plant biotechnology toolkit beyond traditional constitutive expression systems. The alc gene expression system is one of the most promising chemically inducible gene switches in plants because of its potential in both fundamental research and commercial biotechnology applications. However, there are no published reports demonstrating that this versatile gene switch is functional in transgenic monocotyledonous plants, which include some of the most important agricultural crops. We found that the original alc gene switch was ineffective in the monocotyledonous plant sugar cane, and describe a modified alc system that is functional in this globally significant crop. A promoter consisting of tandem copies of the ethanol receptor inverted repeat binding site, in combination with a minimal promoter sequence, was sufficient to give enhanced sensitivity and significantly higher levels of ethanol inducible gene expression. A longer CaMV 35S minimal promoter than was used in the original alc gene switch also substantially improved ethanol inducibility. Treating the roots with ethanol effectively induced the modified alc system in sugar cane leaves and stem, while an aerial spray was relatively ineffective. The extension of this chemically inducible gene expression system to sugar cane opens the door to new opportunities for basic research and crop biotechnology. PMID- 24142381 TI - Evidence for phosphorylation of the major seed storage protein of the common bean and its phosphorylation-dependent degradation during germination. AB - Phaseolin is the major seed storage protein of common bean, Phaseolus vulgaris L., accounting for up to 50 % of the total seed proteome. The regulatory mechanisms responsible for the synthesis, accumulation and degradation of phaseolin in the common bean seed are not yet sufficiently known. Here, we report on a systematic study in dormant and 4-day germinating bean seeds from cultivars Sanilac (S) and Tendergreen (T) to explore the presence and dynamics of phosphorylated phaseolin isoforms. High-resolution two-dimensional electrophoresis in combination with the phosphoprotein-specific Pro-Q Diamond phosphoprotein fluorescent stain and chemical dephosphorylation by hydrogen fluoride-pyridine enabled us to identify differentially phosphorylated phaseolin polypeptides in dormant and germinating seeds from cultivars S and T. Phosphorylated forms of the two subunits of type alpha and beta that compose the phaseolin were identified by matrix-assisted laser desorption/ionization time-of flight (MALDI-TOF) mass spectrometry (MS) and MALDI-TOF/TOF tandem MS. In addition, we found that the levels of phosphorylation of the phaseolin changed remarkably in the seed transition from dormancy to early germination stage. Temporal changes in the extent of phosphorylation in response to physiological and metabolic variations suggest that phosphorylated phaseolin isoforms have functional significance. In particular, this prospective study supports the hypothesis that mobilization of the phaseolin in germinating seeds occurs through the degradation of highly phosphorylated isoforms. Taken together, our results indicate that post-translational phaseolin modifications through phosphorylations need to be taken into consideration for a better understanding of the molecular mechanisms underlying its regulation. PMID- 24142382 TI - Expression of Terpenoids 1, a glandular trichome-specific transcription factor from tomato that activates the terpene synthase 5 promoter. AB - Terpene biosynthesis in tomato glandular trichomes has been well studied, with most if not all terpene synthases (TPSs) being identified. However, transcription factors (TFs) that regulate TPSs have not yet been discovered from tomato. In order to unravel the transcriptional regulation of the Solanum lycopersicum linalool synthase (SlMTS1, recently renamed SlTPS5) gene in glandular trichomes, we functionally dissected its promoter. A 207 bp fragment containing the minimal promoter and the 5'UTR appeared to be sufficient for trichome-specific expression in transgenic plants. Yeast-one-hybrid screens with this fragment identified a glandular trichome-specific transcription factor, designated Expression of Terpenoids 1 (SlEOT1). SlEOT1 is a member of a conserved family of TFs that includes the Arabidopsis Stylish 1 (AtSTY1) and Short Internode (AtSHI) genes. The EOT1 protein localized to the nucleus and specifically transactivated the SlTPS5 promoter in Nicotiana benthamiana leaves. PMID- 24142384 TI - Mineralization and kinetics of Reactive Brilliant Red X-3B by a combined anaerobic-aerobic bioprocess inoculated with the coculture of fungus and bacterium. AB - Mineralization of Reactive Brilliant Red X-3B by a combined anaerobic-aerobic process which was inoculated with the co-culture of Penicillium sp. QQ and Exiguobacterium sp. TL was studied. The optimal conditions of decolorization were investigated by response surface methodology as follows: 132.67 g/L of strain QQ wet spores, 1.09 g/L of strain TL wet cells, 2.25 g/L of glucose, 2.10 g/L of yeast extract, the initial dye concentration of 235.14 mg/L, pH 6.5, and 33 degrees C. The maximal decolorization rate was about 96 % within 12 h under the above conditions. According to the Haldane kinetic equation, the maximal specific decolorization rate was 89.629 mg/gh. It was suggested that in the anaerobic aerobic combined process, decolorization occurred in the anaerobic unit and chemical oxygen demand (COD) was mainly removed in the aerobic one. Inoculation of fungus QQ in the anaerobic unit was important for mineralization of X-3B. Besides, the divided anaerobic-aerobic process showed better performance of COD removal than the integrated one. It was suggested that the combined anaerobic aerobic process which was inoculated with co-culture was potentially useful for the field application. PMID- 24142383 TI - A barley Engulfment and Motility domain containing protein modulates Rho GTPase activating protein HvMAGAP1 function in the barley powdery mildew interaction. AB - Engulfment and Motility (ELMO) proteins are involved in the regulation of small GTPase activity in eukaryotic organisms, but little is known about ELMO proteins in plants. We isolated the barley ELMO Domain Containing Protein, HvELMOD_C, in a yeast two hybrid screen for proteins interacting with HvMAGAP1 (Microtubule Associated ROP-GTPase Activating Protein 1). HvMAGAP1 is considered as an antagonist of barley RACB, a member of the RHO of plant (ROP) family GTPases, which functions as a susceptibility factor in the interaction of barley with the barley powdery mildew fungus Blumeria graminis f.sp. hordei. HvELMOD_C interacts with the central RHO-GAP domain of HvMAGAP1. Cytoplasmic HvELMOD_C translocates to microtubules on co-expression of HvMAGAP1 but not on co-expression of HvMAGAP1 R185G, a mutant of the catalytically active arginine R185 in the RHO-GAP domain. HvELMOD_C, when simultaneously expressed with HvMAGAP1, abolished the resistance inducing effect of HvMAGAP1 to B. graminis f.sp. hordei. Therefore, HvELMOD_C might function as a new modulator of HvMAGAP1 and thus ROP activity in barley. PMID- 24142385 TI - Cultivation of Chlorella vulgaris in dairy wastewater pretreated by UV irradiation and sodium hypochlorite. AB - There is potential in the utilization of microalgae for the purification of wastewater as well as recycling the resource in the wastewater to produce biodiesel. The large-scale cultivation of microalgae requires pretreatment of the wastewater to eliminate bacteria and protozoa. This procedure is costly and complex. In this study, two methods of pretreatment, UV irradiation, and sodium hypochlorite (NaClO), in various doses and concentrations, were tested in the dairy wastewater. Combining the efficiency of biodiesel production, we proposed to treat the dairy wastewater with NaClO in the concentration of 30 ppm. In this condition, The highest biomass productivity and lipid productivity of Chlorella vulgaris reached 0.450 g L(-1) day(-1) and 51 mg L(-1) day(-1) after a 4-day cultivation in the dairy wastewater, respectively. PMID- 24142386 TI - Antifungal activity of Microgramma vacciniifolia rhizome lectin on genetically distinct Fusarium oxysporum f. sp. lycopersici races. AB - Fusarium oxysporum f. sp. lycopersici races 1, 2, and 3 deteriorate tomato crops since they cause a vascular wilt. Lectins are carbohydrate-binding proteins with hemagglutinating and antifungal activities. This work reports that Microgramma vacciniifolia rhizome lectin (MvRL) inhibits F. oxysporum f. sp. lycopersici race 3 growth (61 %) more intensely than of races 1 (55 %) and 2 (45 %). The hemagglutinating activity of MvRL was inhibited by glycoprotein preparations from mycelia of races 1, 2, and 3, and these data indicate that lectin carbohydrate binding sites recognized glycosylated molecules from races. Inter-simple sequence repeat (ISSR) marker system showed that race 3 is genetically distinct from races 1 and 2, and thus the highest sensitiveness of F. oxysporum f. sp. lycopersici race 3 to MvRL may be due to molecular characteristics of this race. PMID- 24142387 TI - Comparative analysis of different biofactories for the production of a major diabetes autoantigen. AB - The 65-kDa isoform of human glutamic acid decarboxylase (hGAD65) is a major diabetes autoantigen that can be used for the diagnosis and (more recently) the treatment of autoimmune diabetes. We previously reported that a catalytically inactive version (hGAD65mut) accumulated to tenfold higher levels than its active counterpart in transgenic tobacco plants, providing a safe and less expensive source of the protein compared to mammalian production platforms. Here we show that hGAD65mut is also produced at higher levels than hGAD65 by transient expression in Nicotiana benthamiana (using either the pK7WG2 or MagnICON vectors), in insect cells using baculovirus vectors, and in bacterial cells using an inducible-expression system, although the latter system is unsuitable because hGAD65mut accumulates within inclusion bodies. The most productive of these platforms was the MagnICON system, which achieved yields of 78.8 MUg/g fresh leaf weight (FLW) but this was substantially less than the best-performing elite transgenic tobacco plants, which reached 114.3 MUg/g FLW after six generations of self-crossing. The transgenic system was found to be the most productive and cost effective although the breeding process took 3 years to complete. The MagnICON system was less productive overall, but generated large amounts of protein in a few days. Both plant-based systems were therefore advantageous over the baculovirus-based production platform in our hands. PMID- 24142388 TI - Modelling the sitagliptin effect on dipeptidyl peptidase-4 activity in adults with haematological malignancies after umbilical cord blood haematopoietic cell transplantation. AB - BACKGROUND AND OBJECTIVES: Dipeptidyl peptidase-4 (DPP4) inhibition is a potential strategy to increase the engraftment rate of haematopoietic stem/progenitor cells. A recent clinical trial using sitagliptin, a DPP4 inhibitor approved for type 2 diabetes mellitus, has been shown to be a promising approach in adults with haematological malignancies after umbilical cord blood (UCB) haematopoietic cell transplantation (HCT). On the basis of data from this clinical trial, a semi-mechanistic model was developed to simultaneously describe DPP4 activity after multiple doses of sitagliptin in subjects with haematological malignancies after a single-unit UCB HCT. METHODS: The clinical study included 24 patients who received myeloablative conditioning followed by oral sitagliptin with single-unit UCB HCT. Using a nonlinear mixed-effects approach, a semi mechanistic pharmacokinetic-pharmacodynamic model was developed to describe DPP4 activity from these trial data, using NONMEM version 7.2 software. The model was used to drive Monte Carlo simulations to probe the various dosage schedules and the attendant DPP4 response. RESULTS: The disposition of sitagliptin in plasma was best described by a two-compartment model. The relationship between sitagliptin concentrations and DPP4 activity was best described by an indirect response model with a negative feedback loop. Simulations showed that twice daily or three times daily dosage schedules were superior to a once daily schedule for maximal DPP4 inhibition at the lowest sitagliptin exposure. CONCLUSION: This study provides the first pharmacokinetic-pharmacodynamic model of sitagliptin in the context of HCT, and provides a valuable tool for exploration of optimal dosing regimens, which are critical for improving the time to engraftment in patients after UCB HCT. PMID- 24142390 TI - Transjugular intrahepatic portosystemic shunts in liver transplant recipients. AB - The insertion of a transjugular intrahepatic portosystemic shunt (TIPS) is a minimally invasive procedure used to relieve the signs and symptoms of portal hypertension in patients with liver disease. The most common indications for placement are refractory ascites and variceal hemorrhage. In properly selected candidates, TIPS placement can serve as a bridge to liver transplantation. Expertise in TIPS placement after transplantation has significantly increased, which has allowed the procedure to become a viable option for retransplant candidates suffering the consequences of recurrent portal hypertension due to portal vein thrombosis, recurrent liver disease, or hepatic venous outflow obstruction (HVOO). However, TIPSs in liver transplant recipients are associated with a lower clinical response rate and a higher rate of complications in comparison with patients with native liver disease, and they are, therefore, generally reserved for patients with a Model for End-Stage Liver Disease (MELD) score <= 15 and <= 12 in patients with HCV. The role of TIPS placement in nonliver transplant recipients has been well studied in large trials, and it translates well into clinical applicability to candidates for orthotopic liver transplantation (OLT). However, the experience with OLT recipients is heterogeneous and restricted to small series. Thus, we focus here on reviewing the current literature and discussing the proper use of TIPSs in liver transplant recipients. PMID- 24142389 TI - Male-specific genetic effect on hypertension and metabolic disorders. AB - Genetic risk factors for hypertension may have age or gender specificity and pleiotropic effects. This study aims to measure the risk of genetic and non genetic factors in the occurrence of hypertension and related diseases, with consideration of potential confounding factors and age-gender stratification. A discovery set of 352,228 genotyped plus 1.8 million imputed single-nucleotide polymorphisms were analyzed for 2,886 hypertensive cases and 3,440 healthy controls obtained from two community-based cohorts in Korea, and selected gene variants were replicated in the Health Examinee cohort (665 cases and 1,285 controls). Genome-wide association analyses were conducted in 12 groups stratified by age and gender after adjusting for potential covariates under three genetic models. Age, rural area residence, body mass index, family history of hypertension, male gender, current alcohol drinking status, and current smoking status were significantly associated with hypertension (P = 4 * 10(-151) to 0.011). Five gene variants, rs11066280 (C12orf51), rs12229654 and rs3782889 (MYL2), rs2072134 (OAS3), rs2093395 (TREML2), and rs17249754 (ATP2B1), were found to be associated with hypertension mostly in men (P = 4.76 * 10(-14) to 4.46 * 10(-7) in the joint analysis); three SNPs (rs11066280, rs12229654, and rs3782889) remained significant after Bonferroni correction in an independent population. Three gene variants, rs12229654, rs17249754, and rs11066280, were significantly associated with metabolic disorders such as hyperlipidemia and diabetes (P = 0.00071 to 0.0097, respectively). Careful consideration of the potential confounding effects in future genome-wide association studies is necessary to uncover the genetic underpinnings of complex diseases. PMID- 24142391 TI - Evaluation of MR safety for a new liquid embolic device. AB - BACKGROUND: As an alternative to conventional treatments, a new liquid embolic device (Neucrylate) may be used to treat aneurysms or arteriovenous malformation (AVMs). Because this device contains metal for opacification, an investigation was performed to evaluate MRI issues for this liquid embolic device. METHODS: The liquid embolic device was evaluated for magnetic field interactions (translational attraction and torque) at 3 T, MRI-related heating at 1.5 T/64 MHz and 3 T/128 MHz and artifacts at 3 T using standardized techniques. In each case, MRI-related heating was assessed with the liquid embolic device in a gelled saline-filled phantom and MRI was performed using relatively high levels of radiofrequency energy. Artifacts were characterized using T1-weighted spin echo and gradient echo pulse sequences. Additionally, conductivity (ie, electrical resistance) measurements were recorded. RESULTS: The liquid embolic device exhibited no magnetic field interactions. Heating was at the same level as background temperature rises (ie, the temperatures recorded without the liquid embolic device present in the phantom) under 1.5 T/64 MHz (highest temperature change 1.4 degrees C) and 3 T/128 MHz (highest temperature change 1.8 degrees C) MRI conditions. Artifacts were small in relation to the size and shape of the liquid embolic device. The device was found to pose no risks with regard to the conductivity of the material. CONCLUSIONS: These findings demonstrate that it is acceptable for a patient with this new liquid embolic device to undergo MRI at <=3 T. Notably, the associated artifacts are unlikely to create issues for diagnostic MRI examinations. PMID- 24142392 TI - microRNA biogenesis and senescence. PMID- 24142393 TI - A systematic review and meta-analysis of clinical variables used in Huntington disease research. AB - Treatment effect in Huntington disease (HD) clinical trials has relied on primary outcome measures such as total motor score or functional rating scales. However, these measures have limited sensitivity, particularly in pre- to early stages of the disease. We performed a systematic review of HD clinical studies to identify endpoints that correlate with disease severity. Using standard HD keywords and terms, we identified 749 published studies from 1993 to 2011 based on the availability of demographic, biochemical, and clinical measures. The average and variability of each measure was abstracted and stratified according to pre-far, pre-close, early, mild, moderate, and severe HD stages. A fixed-effect meta analysis on selected variables was conducted at various disease stages. A total of 1,801 different clinical variables and treatment outcomes were identified. Unified Huntington Disease Rating Scale (UHDRS) Motor, UHDRS Independence, and Trail B showed a trend toward separation between HD stages. Other measures, such as UHDRS Apathy, Verbal Fluency, and Symbol Digit, could only distinguish between pre- and early stages of disease and later stages, whereas other measures showed little correlation with increasing HD stages. Using cross-sectional data from published HD clinical trials, we have identified potential endpoints that could be used to track HD disease progression and treatment effect. Longitudinal studies, such as TRACK-HD, are critical for assessing the value of potential markers of disease progression for use in future HD therapeutic trials. A list of variables, references used in this meta-analysis, and database is available at http://www.cmmt.ubc.ca/research/investigators/leavitt/publications. PMID- 24142394 TI - Assessing the detection of human papillomavirus late mRNA in liquid base cytology samples for risk stratification of cervical disease. AB - Molecular human papillomavirus (HPV) testing is an important and developing tool for cervical disease management. However there is a requirement to develop new HPV tests that can differentiate between clinically significant and benign, clinically insignificant infection. Evidence would indicate that clinically significant infection is linked to an abortive HPV replication cycle. In particular the later stages of the replication cycle (i.e., production of late messenger (m) RNAs and proteins) appear compromised. Compared to current DNA based tests which indicate only presence or absence of virus, detecting virus mRNAs by reverse transcriptase PCR (RT-PCR) may give a more refined insight into viral activity and by implication, clinical relevance. A novel quantitative (q)RT PCR assay was developed for the detection of mRNAs produced late in the viral replication cycle. Initially this was validated on HPV-containing cell lines before being applied to a panel of 223 clinical cervical samples representing the cervical disease spectrum (normal to high grade). Samples were also tested by a commercial assay which detects expression of early HPV E6/E7 oncoprotein mRNAs. Late mRNAs were found in samples associated with no, low and high grade disease and did not risk-stratify HPV infection. The data reveal hidden complexities within the virus replication cycle and associated lesion development. This suggests that future mRNA tests for cervical disease may require quantitative detection of specific novel viral mRNAs. PMID- 24142395 TI - Analysis of risk factors for recurrence after curative resection of well differentiated pancreatic neuroendocrine tumors based on the new grading classification. AB - BACKGROUND: It is difficult to predict the malignant potential of pancreatic neuroendocrine tumors (PNETs) precisely. This study investigated the validity of a new grading system adopted by the World Health Organization 2010 classification to determine risk factors for recurrence of PNETs. METHODS: Data of 70 patients with PNETs who underwent curative resection were retrospectively examined by uni- and multivariate analyses. Histopathological findings were re-reviewed by experienced pathologists. NET G1 was defined as mitotic count <2 per 10 high power fields (HPF) and/or <=2% Ki67 index, and NET G2 as 2-20 mitosis per 10 HPF and/or 3-20% Ki67 index. RESULTS: There were 58 patients with NET G1 and 12 with NET G2. Incidence of recurrence was 11.4%. Univariate analysis demonstrated significant risk factors for recurrence including NET G2 of histological grade (P = 0.0089), male gender (P = 0.0333), tumor size >= 20 mm (P = 0.0117), lymph node metastasis (P = 0.0004), liver metastasis (P < 0.0001), lymphatic invasion (P = 0.046), and neural invasion (P = 0.0002). By multivariate analysis, histological grade (hazard ratio; 59.76, P = 0.0022) and neural invasion (hazard ratio; 147.49, P = 0.0016) were significantly associated with recurrence of PNETs. CONCLUSIONS: This study confirmed the prognostic relevance of the new grading classification and that evaluation of perineural invasion and histological grade should be considered as prognostic predictors in well-differentiated PNETs (NET G1 and G2). PMID- 24142396 TI - Depression among Mexican men on the migration frontier: the role of family separation and other structural and situational stressors. AB - This study documents the mental health of Mexican migrant men in a new non traditional settlement in the Rocky Mountain West and examines the role of family separation and other structural and situational stressors in relation to depressive symptoms. Using a community-based participatory research approach, we conducted interviewer-assisted surveys with 134 Mexican migrant men. Findings revealed that, overall, 46 % of participants reported depressive symptoms in the range for clinical concern and that single and married men who were separated from their families were particularly vulnerable to poor mental health. Best predictors of depression included both structural stressors (family separation, sending remittances to Mexico) and situational stressors (fearfulness, worry about police confrontation, treatment by non-Latinos, and lack of support). These findings highlight the need for complex and contextually-sensitive mental health interventions designed to protect this vulnerable population on the migration frontier and to promote their mental health. PMID- 24142397 TI - Ultraviolet Light Inactivation of Murine Norovirus and Human Norovirus GII: PCR May Overestimate the Persistence of Noroviruses Even When Combined with Pre-PCR Treatments. AB - Transmission of gastroenteritis-causing noroviruses may be significant via contaminated surfaces. Measures for control, e.g. disinfection with ultraviolet irradiation (UV), are therefore necessary for interrupting this transmission. Human norovirus (HuNoV) GII.4 and Murine norovirus (MuNoV) were used to study the efficacy of UV for virus inactivation on dry glass surfaces. MuNoV inactivation was measured using viability assay and the reduction in viral RNA levels for both viruses using reverse transcription quantitative PCR (RT-QPCR). For each UV dose, two parallel sample groups were detected using RT-QPCR: one group was enzymatically pre-PCR treated with Pronase and RNAse enzymes, while the other was not treated enzymatically. In the viability assay, loss of infectivity and a 4 log reduction of MuNoV were observed when the viruses on glass slides were treated with a UV dose of 60 mJ/cm(2) or higher. In the RT-QPCR assay, a steady 2 log decline of MuNoV and HuNoV RNA levels was observed when UV doses were raised from 0 to 150 mJ/cm(2). A distinct difference in RNA levels of pretreated and non pretreated samples was observed with UV doses of 450-1.8 * 10(3) mJ/cm(2): the RNA levels of untreated samples remained over 1.0 * 10(3) PCR units (pcr-u), while the RNA levels of enzyme-treated samples declined below 100 pcr-u. However, the data show a prominent difference between the persistence of MuNoV observed with the infectivity assay and that of viral RNA detected using RT-QPCR. Methods based on genome detection may overestimate norovirus persistence even when samples are pretreated before genome detection. PMID- 24142398 TI - Influence of environmental factors in the in vitro dehydration of hydrogel and silicone hydrogel contact lenses. AB - PURPOSE: To analyze in vitro the influence of different environmental conditions on the dehydration pattern of seven currently marketed hydrogel (Hy) and silicone hydrogel (Si-Hy) contact lenses (CL). METHODS: Three Hy and four Si-Hy CLs were evaluated. CLs were exposed to four different relative humidity (RH) conditions (5%, 30%, 50%, and 70%) and two air flow (AF) rates (0 and 2.75 m/seg) within an environmental chamber. Dehydration was assessed using the gravimetric method. Data were taken at baseline, 5, 10, 15, 20, 30, 45, 60, 90, and 120 minutes of exposure. Dehydration rate (DR), valid dehydration (VD) and stabilization time were calculated. RESULTS: The interaction between RH, AF and the type of the CL material had a significant effect (p <= 0.03) on DR up to 60 minutes. The maximum differences in VD values among CL occurred around 15 minutes exposure varying from 25.16% to 42.75%. Stabilization time was quicker under the 5%RH with AF condition than under 70% RH without AF one for most CLs. CONCLUSIONS: Lower RH seems to increase CL dehydration being further accelerated with the AF presence. The dehydration pattern is material dependent, thus current marketed CLs behave differently under several controlled environmental conditions. Future in vivo studies should confirm these outcomes. PMID- 24142399 TI - Pharmacological treatment for pain in Guillain-Barre syndrome. AB - BACKGROUND: Pain in Guillain-Barre syndrome (GBS) is common, yet it is often under recognised and poorly managed. In recent years, a variety of pharmacological treatment options have been investigated in clinical trials for people with GBS-associated pain. OBJECTIVES: To assess the efficacy and safety of pharmacological treatments for various pain symptoms associated with GBS, during both the acute and convalescent (three months or more after onset) phases of GBS. SEARCH METHODS: On 27 August 2012, we searched the Cochrane Neuromuscular Disease Group Specialized Register, CENTRAL (2012, Issue 8) in The Cochrane Library, MEDLINE (January 1966 to August 2012) and EMBASE (January 1980 to August 2012). In addition, we searched ClinicalTrials.gov and the World Health Organization (WHO) International Clinical Trials Registry Platform. SELECTION CRITERIA: We included randomised controlled trials (RCTs) and quasi-RCTs in participants with confirmed GBS, with pain assessment as either the primary or secondary outcome. For cross-over trials, an adequate washout period between phases was required for inclusion. DATA COLLECTION AND ANALYSIS: Two review authors independently screened the titles and abstracts of identified records, selected studies for inclusion, extracted eligible data, cross-checked the data for accuracy and assessed the risk of bias of each study. MAIN RESULTS: Three short-term RCTs, which enrolled 277 randomised participants with acute phase GBS, were included. Risk of bias in the included studies was generally unclear due to insufficient information. None of the included studies reported the primary outcome selected for this review, which was number of patients with self reported pain relief of 50% or greater. One small study investigated seven-day regimens of gabapentin versus placebo. Pain was rated on a scale from 0 (no pain) to 10 (maximum pain). Amongst the 18 participants, significantly lower mean pain scores were found at the endpoint (day 7) in the gabapentin phase compared to the endpoint of the placebo phase (mean difference -3.61, 95% CI -4.12 to -3.10) (very low quality evidence). For adverse events, no significant differences were found in the incidence of nausea (risk ratio (RR) 0.50, 95% CI 0.05 to 5.04) or constipation (RR 0.14, 95% CI 0.01 to 2.54). A second study enrolling 36 participants compared gabapentin, carbamazepine and placebo, all administered over seven days. Participants in the gabapentin group had significantly lower median pain scores on all treatment days in comparison to the placebo and carbamazepine groups (P < 0.05). There were no statistically significant differences in the median pain scores between the carbamazepine and placebo groups from day 1 to day 3, but from day 4 until the end of the study significantly lower median pain scores were noted in the carbamazepine group (P < 0.05) (very low quality evidence). There were no adverse effects of gabapentin or carbamazepine reported other than sedation. One large RCT (223 participants, all also treated with intravenous immunoglobulin), compared a five-day course of methylprednisolone with placebo and found no statistically significant differences in number of participants developing pain (RR 0.89, 95% CI 0.68 to 1.16), number of participants with decreased pain (RR 0.95, 95% CI 0.63 to 1.42) or number of participants with increased pain (RR 0.85, 95% CI 0.52 to 1.41) (low quality evidence). The study did not report whether there were any adverse events. AUTHORS' CONCLUSIONS: While management of pain in GBS is essential and pharmacotherapy is widely accepted as being an important component of treatment, this review does not provide sufficient evidence to support the use of any pharmacological intervention in people with pain in GBS. Although reductions in pain severity were found when comparing gabapentin and carbamazepine with placebo, the evidence was limited and its quality very low. Larger, well-designed RCTs are required to further investigate the efficacy and safety of potential interventions for patients with pain in GBS. Additionally, interventions for pain in the convalescent phase of GBS should be investigated. PMID- 24142400 TI - The cardiovascular risk marker asymmetric dimethylarginine is elevated in asymptomatic, untreated HIV-1 infection and correlates with markers of immune activation and disease progression. AB - BACKGROUND: As lifespan in HIV infection increases, cardiovascular disease has emerged as a cause of morbidity and mortality. Asymmetric dimethylarginine is an established marker of endothelial dysfunction and predicts cardiovascular events. The role of asymmetric dimethylarginine in HIV-related cardiovascular disease has not been established. Our aim was to determine whether asymmetric dimethylarginine concentrations were elevated in treatment naive, HIV-infected subjects and to correlate these with markers of immune activation and disease progression. METHODS: Serum samples were collected from HIV-positive and negative subjects attending a primary health care clinic over a 12-month period. Asymmetric dimethylarginine concentrations were measured and correlated with CD4 count, viral load, hsCRP, IL-6, IgG, adenosine deaminase and CD8/38 T lymphocytes. RESULTS: Sixty HIV-positive participants (mean age 32.0 years) and 20 HIV-negative controls (mean age 32.4 years) were studied. All were of black ethnicity. The mean asymmetric dimethylarginine concentration in the infected group measured 0.67 umol/L (95% CI 0.62-0.72 umol/L) which was significantly higher than in the control group of 0.48 umol/L (95% CI 0.40-0.56 umol/L). Asymmetric dimethylarginine correlated inversely with CD4 counts and positively with IgG, adenosine deaminase and CD8/38 T lymphocytes. No significant correlation was found with hsCRP, IL-6, or viral load. CONCLUSION: We demonstrated that asymmetric dimethylarginine is elevated in HIV infection, in patients with relatively well-preserved CD4 counts not yet on anti-retroviral treatment. We showed significant correlations of asymmetric dimethylarginine with CD8/38 T lymphocytes, IgG and adenosine deaminase, suggesting that T-cell activation and the adaptive immune response underlie asymmetric dimethylarginine elevation in this population. PMID- 24142401 TI - Combined subaortic membrane and aortic valve stenosis: additive value of three dimensional echocardiography. PMID- 24142402 TI - Symptomatic charcoal heart. PMID- 24142403 TI - Combined anatomical and functional CT imaging for the detection of coronary artery disease. PMID- 24142404 TI - Acute myocardial injury from carbon monoxide poisoning by cardiac magnetic resonance imaging. PMID- 24142405 TI - Delayed heart failure due to mitral valve perforation after stab chest. PMID- 24142406 TI - Pyk2 and Src mediate signaling to CCL18-induced breast cancer metastasis. AB - Pyk2 and Src phosphorylation is initiated by CCL18, which promotes breast cancer metastasis via its functional G protein-coupled receptor PITPNM3. However, the function of Pyk2 and Src in CCL18-induced breast cancer metastasis is poorly understood. Quantitative reverse-transcription polymerase chain reactions (qRT PCRs), Western blot, boyden chamber assay, and adherence assay were performed to delineate the consequences of Pyk2/Src in CCL18-induced breast cancer cells. Co immunoprecipitation and immunofluorescence were performed to analyze the interaction of proteins. Upon the binding of CCL18 to PITPNM3, Pyk2 translocates from the cytoplasm to the plasma membrane to form a stable complex with PITPNM3, subsequently activating Src kinase. Moreover, upon stimulation with CCL18, Pyk2 and Src become essential for integrin alpha5/beta1 clustering-dependent adherence, migration, and invasion. Pyk2 and Src are important in CCL18-induced breast cancer metastasis. PMID- 24142407 TI - Circulation of intergenotype recombinant noroviruses GII.9/GII.6 from 2006 to 2011 in central Greece. AB - Noroviruses (NoVs) are members of the Caliciviridae family and are recognized as a worldwide cause of acute nonbacterial gastroenteritis. Based on the genetic analysis of the RdRp and capsid regions, human NoVs are divided into three genogroups (Gs), GI, GII, and GIV, which further segregate into distinct lineages called genotypes. In this study, in an attempt to discern the circulation of an intergenotypic recombinant GII.9/GII.6, which was previously reported by our group in central Greece, we investigated NoVs in raw sewages from 2006 to 2011 and compared the results with the viruses detected from clinical samples in the same area and in the same time period. Two specific primer pairs for NoVs were designed which amplified in a single PCR fragment from polymerase to capsid gene covering the widespread recombination point in ORF1/ORF2 junction. Based on the genetic analysis, recombinant NoV strains GII.9/GII.6 were identified. Fourteen out of 15 environmental and eight out of ten clinical samples that were used in the present study were positive, with both primer pairs, confirming that the intergenotypic recombinant GII.9/GII.6 was circulating in the population of central Greece from 2006 to 2011. The crossover point was identified to be within the overlapping region of ORF1/ORF2 (GII.9/GII.6, respectively) and was determined by Simplot at nucleotide position 5,032 bp. PMID- 24142408 TI - Comparison of fiber gene sequences of inclusion body hepatitis (IBH) and non-IBH strains of serotype 8 and 11 fowl adenoviruses. AB - Fowl adenoviruses (FAdVs) are common in broiler operations, and the most frequently isolated FAdVs belong to serotypes 1, 8, and 11. Serotype 1 viruses are considered nonpathogenic. While some serotype 8 and 11 viruses cause inclusion body hepatitis (IBH), these virus serotypes can also be isolated from non-IBH cases. The fiber protein is one of the major constituents of the adenoviral capsid, involved in virus entry, and it has been implicated in the variation of virulence of FAdVs. The fiber gene sequences of four FAdV-8 and four FAdV-11 isolates from both IBH and non-IBH cases were determined and analyzed for a possible association of the fiber gene sequence in virulence. The fiber protein can be divided into tail, shaft, and head domains comprising some specific features. The conserved "RKRP" sequence motif (aa 17-aa 20) fit the consensus sequence predicted for the nuclear localization signal, while the "VYPF" motif (aa 53-aa 56), involved in the penton base interaction, was also found. Similar to mammalian adenoviruses, 17 pseudo-repeats with an average length of 16 aa were detected in the FAdV-8 fiber shaft region, while 20 pseudo-repeats with an average length of 18 aa were found in FAdV-11 fibers. There was a 144-147 nt difference between the fiber genes of the two FAdV serotypes. In the shaft region, the TLWT motif that marks the beginning of the fiber head domain of the mastadenovirus was not evident among examined FAdVs. The FAdV-11 isolates had 99.1 % aa sequence identity and 99.3 % similarity to each other, and there was no conserved aa substitution within the fibers. The FAdV-8 fiber proteins showed an overall lower, 89 % aa sequence identity and 93.4 % similarity, to each other and 22 nonsynonymous mutations were detected. Virulence markers were not detected in the analyzed fiber gene sequences of the different pathotypes of the two FAdV serotypes. PMID- 24142410 TI - Neural correlates of successful semantic processing during propofol sedation. AB - Sedation has a graded effect on brain responses to auditory stimuli: perceptual processing persists at sedation levels that attenuate more complex processing. We used fMRI in healthy volunteers sedated with propofol to assess changes in neural responses to spoken stimuli. Volunteers were scanned awake, sedated, and during recovery, while making perceptual or semantic decisions about nonspeech sounds or spoken words respectively. Sedation caused increased error rates and response times, and differentially affected responses to words in the left inferior frontal gyrus (LIFG) and the left inferior temporal gyrus (LITG). Activity in LIFG regions putatively associated with semantic processing, was significantly reduced by sedation despite sedated volunteers continuing to make accurate semantic decisions. Instead, LITG activity was preserved for words greater than nonspeech sounds and may therefore be associated with persistent semantic processing during the deepest levels of sedation. These results suggest functionally distinct contributions of frontal and temporal regions to semantic decision making. These results have implications for functional imaging studies of language, for understanding mechanisms of impaired speech comprehension in postoperative patients with residual levels of anesthetic, and may contribute to the development of frameworks against which EEG based monitors could be calibrated to detect awareness under anesthesia. PMID- 24142411 TI - Effects of feeding selenium-enriched alfalfa hay on immunity and health of weaned beef calves. AB - Previously, we reported that feeding selenium (Se)-enriched forage improves antibody titers in mature beef cows, and whole-blood Se concentrations and growth rates in weaned beef calves. Our current objective was to test whether beef calves fed Se-enriched alfalfa hay during the transition period between weaning and movement to a feedlot also have improved immune responses and slaughter weights. Recently weaned beef calves (n = 60) were fed an alfalfa-hay-based diet for 7 weeks, which was harvested from fields fertilized with sodium selenate at 0, 22.5, 45.0, or 89.9 g Se/ha. All calves were immunized with J-5 Escherichia coli bacterin. Serum was collected for antibody titers 2 weeks after the third immunization. Whole-blood neutrophils collected at 6 or 7 weeks were evaluated for total antioxidant potential, bacterial killing activity, and expression of genes associated with selenoproteins and innate immunity. Calves fed the highest versus the lowest level of Se-enriched alfalfa hay had higher antibody titers (P = 0.02), thioredoxin reductase-2 mRNA levels (P = 0.07), and a greater neutrophil total antioxidant potential (P = 0.10), whereas mRNA levels of interleukin-8 receptor (P = 0.02), L-selectin (P = 0.07), and thioredoxin reductase-1 (P = 0.07) were lower. In the feedlot, calves previously fed the highest-Se forage had lower mortality (P = 0.04) and greater slaughter weights (P = 0.02). Our results suggest that, in areas with low-forage Se concentrations, feeding beef calves Se enriched alfalfa hay during the weaning transition period improves vaccination responses and subsequent growth and survival in the feedlot. PMID- 24142412 TI - Defining and characterizing severe hypoxemia after liver transplantation in hepatopulmonary syndrome. AB - Hepatopulmonary syndrome is defined as a triad of liver disease, intrapulmonary vascular dilatations, and abnormal gas exchange, and it carries a poor prognosis. Liver transplantation is the only known cure for this syndrome. Severe hypoxemia in the early postoperative period has been reported to be a major complication and often leads to death in this population, but it has been poorly characterized. We sought to propose an objective definition for this complication and to describe its risk factors, incidence, and outcomes. We performed a systematic literature search and reviewed our single-center experience to characterize this complication. On the basis of the most commonly applied definition in 27 identified studies, we objectively defined severe postoperative hypoxemia as hypoxemia requiring a 100% fraction of inhaled oxygen to maintain a saturation >= 85% and out of proportion to any concurrent lung process. Nineteen of the 27 reports (70%) fulfilled this definition, as did 4 of the 21 patients (19%) at our center. We determined the prevalence and mortality of this complication from reports including 10 or more consecutive patients and providing sufficient postoperative details to determine whether this complication had occurred. In these reports, the prevalence of this complication was 12% (25/209). For the 11 cases with reported outcomes, the posttransplant mortality rate was 45% (5/11). There was a trend toward an increased risk of developing this complication in patients with very severe preoperative hypoxemia, defined as a partial pressure of arterial oxygen <= 50 mm Hg (8/41 with very severe hypoxemia versus 3/49 without severe hypoxemia, P = 0.053), and there was a significantly increased risk for patients with anatomic shunting >= 20% (7/25 with anatomic shunting >= 20% versus 1/25 without anatomic shunting >= 20%, P = 0.049). In conclusion, increased preoperative vigilance for this common complication is required among high-risk patients, and further research is required to identify the best management strategies. PMID- 24142409 TI - Immunosuppression and allograft rejection following lung transplantation: evidence to date. AB - The enduring success of lung transplantation is built on the use of immunosuppressive drugs to stop the immune system from rejecting the newly transplanted lung allograft. Most patients receive a triple-drug maintenance immunosuppressive regimen consisting of a calcineurin inhibitor, an antiproliferative and corticosteroids. Induction therapy with either an antilymphocyte monoclonal or an interleukin-2 receptor antagonist are prescribed by many centres aiming to achieve rapid inhibition of recently activated and potentially alloreactive T lymphocytes. Despite this generic approach acute rejection episodes remain common, mandating further fine-tuning and augmentation of the immunosuppressive regimen. While there has been a trend away from cyclosporine and azathioprine towards a preference for tacrolimus and mycophenolate mofetil, this has not translated into significant protection from the development of chronic lung allograft dysfunction, the main barrier to the long-term success of lung transplantation. This article reviews the problem of lung allograft rejection and the evidence for immunosuppressive regimens used both in the short- and long-term in patients undergoing lung transplantation. PMID- 24142414 TI - [Extensions of the outpatient psychotherapy: a study about patient, therapist, treatment, and therapy course characteristics]. AB - Due to the treatment costs, extensions of the standard therapy duration are a matter of critical examination. This study investigates which factors characterize patients with treatment extensions in the German health system and how effective these extensions are for a reduction of the patients' symptoms. We analysed a disorder heterogeneous sample of 810 patients. We found that therapy extensions are more common among with more severe mental disorders, when the therapeutic relationship is positive, and little therapy success has been achieved during the standard duration. Overall, the findings suggest that outpatient psychotherapy is mainly extended for patients with a low symptom reduction after the standard therapy duration and that therapy extension allows a symptom reduction that could not have been achieved otherwise. PMID- 24142413 TI - Reduced BDNF attenuates inflammation and angiogenesis to improve survival and cardiac function following myocardial infarction in mice. AB - Brain-derived neurotrophic factor (BDNF) increases in failing hearts, but BDNF roles in cardiac remodeling following myocardial infarction (MI) are unclear. Male BDNF(+/+) [wild-type (WT)] and BDNF(+/-) heterozygous (HET) mice at 6-9 mo of age were subjected to MI and evaluated at days 1, 3, 5, 7, or 28 post-MI. At day 28 post-MI, 76% of HET versus 40% of WT survived, whereas fractional shortening improved and neovascularization levels were reduced in the HET (all, P < 0.05). At day 1, post-MI, matrix metalloproteinase-9, and myeloperoxidase (MPO) increased in WT, but not in HET. Concomitantly, monocyte chemotactic protein-1 and -5 levels increased and vascular endothelial growth factor (VEGF)-A decreased in HET. Neutrophil infiltration peaked at days 1-3 in WT mice, and this increase was blunted in HET. To determine if MPO administration could rescue the HET phenotype, MPO was injected at 3 h post-MI. MPO restored VEGF-A levels without altering matrix metalloproteinase-9 or neutrophil content. In conclusion, reduced BDNF levels modulated the early inflammatory and neovascularization responses, leading to improved survival and reduced cardiac remodeling at day 28 post-MI. Thus reduced BDNF attenuates early inflammation following MI by modulating MPO and angiogenic response through VEGF-A. PMID- 24142415 TI - [A validation study of the German version of the Hypersexual Behavior Inventory (HBI)]. AB - Hypersexuality is characterized by recurrent and intense sexual fantasies, sexual urges, or sexual behaviors resulting in clinically significant personal distress or impairment in social, occupa-tional, or other important areas of functioning. The Hypersexual Behavior Inventory (HBI, Reid et al., 2011) is a 3-factor measure (coping, control and consequences) developed to assess hypersexual behaviour. The aim of the present study was to investigate the psychometric properties of the German version of the HBI. In a sample consisting of 1 749 men and women the questionnaire was used as part of an online survey. The questionnaire showed good reliability and validity. A confirmatory factor analysis supported the 3-factor structure of the original English version. The results and potential benefit of the HBI in research and clinical practice are discussed. PMID- 24142416 TI - [Coping with nightmares in the General population: an online study]. AB - The present study elicited a variety of coping strategies for nightmares in the general population and asked whether these coping strategies were helpful. A large-scale online survey (N=2 872, mean age: 43 years) was carried out. About 11.5% of the participants reported nightmares once a week or more often. The results indicate that sharing of nightmares was the most prevalent coping strategy, followed by re-writing the nightmare and reading about nightmares. Seeking professional help was rarely listed, even by persons with frequent nightmares and for the majority without benefit. The findings clearly show that there is a lot of work ahead providing adequate help for persons suffering from nightmares. PMID- 24142417 TI - A novel presentation of DYT 16: acute onset in infancy and association with MRI abnormalities. PMID- 24142418 TI - Risk factors and treatments for hepatic arterial complications in pediatric living donor liver transplantation. AB - BACKGROUND: Hepatic artery complications (HAC) are a serious complication in pediatric liver transplant recipients because its incidence is high and it can occasionally lead to graft liver failure. We herein present a retrospective analysis of our 10-year experience with pediatric living donor liver transplantation (LDLT) focusing on the risk factors and treatments for HAC. METHODS: Between May 2001 and November 2011, 209 LDLTs were performed for 203 pediatric recipients. We performed the multivariate analyses to identify the factors associated with HAC and showed the therapeutic strategy and outcome for HAC. RESULTS: The overall incidence of HAC was 7.2%, and the graft survival of recipients with HAC was 73.3%. The multivariate analysis showed that the pediatric end-stage liver disease score (>=20), post-transplant laparotomy except for HAC treatment and extra-anatomical hepatic artery reconstruction were independent risk factors for HAC (P = 0.020, P = 0.015 and P = 0.002, respectively). Eleven surgical interventions and 13 endovascular interventions were performed for 15 recipients with HAC. The serum aspartate aminotransferase levels pre- and post-treatment for HAC were significantly higher in the surgical group than in the endovascular group (P = 0.016 and P = 0.022, respectively). CONCLUSIONS: It is important for recipients with risk factors to maintain strict post-transplant management to help prevent HAC and detect it in earlier stages. Endovascular intervention can be a less invasive method for treating HAC than surgical intervention, and can be performed as an early treatment. PMID- 24142419 TI - Preliminary study of the genetic diversity of eastern Assamese macaques (Macaca assamensis assamensis) in Thailand based on mitochondrial DNA and microsatellite markers. AB - Human overpopulation, deforestation, invasion of agricultural areas, and livestock are the primary causes for population fragmentation of wildlife. The distribution range of species of the genus Macaca is constantly decreasing and becoming increasingly fragmented due to forest deterioration. Assamese macaques (M. assamensis) are classified as near threatened in the International Union for Conservation of Nature (IUCN) Red List of Threatened Animals (2008) and have been declared a protected wildlife animal according to Wildlife Preservation and Protection Act, B.E.2535 (1992) of Thailand. As studies of the population history and genetic diversity of Assamese macaques in Thailand are currently lacking, we aimed at a first investigation of their genetic diversity based on mitochondrial DNA [hypervariable regions 1 and 2 (HV1, HV2) and cytochrome B (CYTB) regions], as well as 15 microsatellite markers of five sampling sites distributed across Thailand. Our results indicate that Assamese macaques in Thailand are diverse, with eight maternal haplotypes and a low inbreeding coefficient in the Phu Khieo Wildlife Sanctuary (PKWS) population. Moreover, our phylogenetic and median joining network analysis based on mitochondrial (mt)DNA suggests a population distribution in accordance with the evolutionary scenario proposed for M. sinica. Today, the population of Assamese macaques is fragmented, and conservation strategies are needed to ensure the maintenance of genetic diversity of this primate species. PMID- 24142421 TI - Repression of GH signaling: one extended life to live! PMID- 24142420 TI - Myotonic Dystrophy Health Index: initial evaluation of a disease-specific outcome measure. AB - INTRODUCTION: In preparation for clinical trials we examine the validity, reliability, and patient understanding of the Myotonic Dystrophy Health Index (MDHI). METHODS: Initially we partnered with 278 myotonic dystrophy type-1 (DM1) patients and identified the most relevant questions for the MDHI. Next, we used factor analysis, patient interviews, and test-retest reliability assessments to refine and evaluate the instrument. Lastly, we determined the capability of the MDHI to differentiate between known groups of DM1 participants. RESULTS: Questions in the final MDHI represent 17 areas of DM1 health. The internal consistency was acceptable in all subscales. The MDHI had a high test-retest reliability (ICC = 0.95) and differentiated between DM1 patient groups with different disease severities. CONCLUSIONS: Initial evaluation of the MDHI provides evidence that it is valid and reliable as an outcome measure for assessing patient-reported health. These results suggest that important aspects of DM1 health may be measured effectively using the MDHI. PMID- 24142422 TI - Favorable changes in arterial elasticity, left ventricular mass, and diastolic function after significant weight loss following laparoscopic sleeve gastrectomy in obese individuals. AB - BACKGROUND: Obesity is accompanied by increased arterial stiffness, left ventricular (LV) hypertrophy, and diastolic dysfunction, all associated with a negative prognosis. The evolution of LV mass, function, and arterial elasticity after laparoscopic sleeve gastrectomy (LSG) was unknown, and this is what we have investigated. METHODS: Thirty-four consecutive obese subjects (mean age, 39 +/- 11 years; 35.2 % men), scheduled for LSG, were studied before, at 6 and 12 months after surgery. RESULTS: The body mass index (BMI) decreased from 43.6 +/- 11.9 to 32.1 +/- 7.4 and to 28.9 +/- 5.8 kg/m(2) at 6 and 12 months after surgery (all p < 0.05). The baseline LV mass index was correlated with age, BMI, waist circumference, blood glucose level, systemic hypertension stage, and with aortic distensibility, strain, and stiffness index (all p < 0.05). Aortic distensibility increased by 110 %, aortic strain by 58 %, and aortic stiffness index decreased by 88 % at 6 months after LSG (all p(6 months-baseline) < 0.05) and all the parameters had similar values at 12 months postoperatively (all p(12-6 months) = NS). LV hypertrophy prevalence decreased from 61.8 to 47.1 % and to 32.3 % at 6 and 12 months after surgery (all p < 0.05). The proportion of patients with LV diastolic dysfunction decreased from 52.9 to 23.5 % at 6 months (p(6 months baseline) < 0.01) and to 20.6 % at 12 months postoperatively (p(12 -6 months)= 0.7). CONCLUSIONS: Significant improvements of aortic elasticity and of LV diastolic function were recorded at 6 months, and they were maintained at 12 months after LSG. The LV hypertrophy showed also a favorable evolution: it has been slightly improved 6 months after surgery and further ameliorated 1 year postoperatively. PMID- 24142423 TI - An unconventional role of BMP-Smad1 signaling in DNA damage response: a mechanism for tumor suppression. AB - The genome is under constant attack by self-produced reactive oxygen species and genotoxic reagents in the environment. Cells have evolved a DNA damage response (DDR) system to sense DNA damage, to halt cell cycle progression and repair the lesions, or to induce apoptosis if encountering irreparable damage. The best studied DDR pathways are the PIKK-p53 and PIKK-Chk1/2. Mutations in these genes encoding DDR molecules usually lead to genome instability and tumorigenesis. It is worth noting that there exist unconventional pathways that facilitate the canonical pathways or take over in the absence of the canonical pathways in DDR. This review will summarize on several unconventional pathways that participate in DDR with an emphasis on the BMP-Smad1 pathway, a known regulator of mouse development and bone remodeling. PMID- 24142424 TI - CT morphology of the normal human adult coccyx. PMID- 24142425 TI - Three-dimensional collagen scaffold enhances the human adenoid cystic carcinoma cancer stem cell and epithelial-mesenchymal transition properties. AB - Three-dimensional (3D) cell culture may provide the architectures similar to the in vivo natural extracellular matrix condition for in vitro cultured cells. In this work, a 3D collagen scaffold was used to culture the adenoid cystic carcinoma (ACC) cells. The results showed that the 3D scaffold not only induced the diversification of cell morphologies but also increased the cell proliferation. The transcription of matrix metalloproteinase and epithelial mesenchymal transition were significantly increased in the cells cultured in 3D collagen scaffolds. In addition, the expression of cancer stem cell (CSC) markers of Sox2 and Oct4 were higher than that in 2D cultured cells. The 3D cultured ACC 83 cells showed more resistance to chemotherapeutic drugs. Thus, the 3D collagen scaffold could provide a useful model for CSCs study and anticancer therapeutics research in vitro. PMID- 24142426 TI - Immobilized Sclerotinia sclerotiorum invertase to produce invert sugar syrup from industrial beet molasses by-product. AB - The fungus Sclerotinia sclerotiorum produces invertase activity during cultivation on many agroindustrial residues. The molasses induced invertase was purified by DEAE-cellulose chromatography. The molecular mass of the purified enzyme was estimated at 48 kDa. Optimal temperature was determined at 60 degrees C and thermal stability up to 65 degrees C. The enzyme was stable between pH 2.0 and 8.0; optimum pH was about 5.5. Apparent K(m) and V(max) for sucrose were estimated to be respectively 5.8 mM and 0.11 MUmol/min. The invertase was activated by beta-mercaptoethanol. Free enzyme exhibited 80 % of its original activity after two month's storage at 4 degrees C and 50 % after 1 week at 25 degrees C. In order to investigate an industrial application, the enzyme was immobilized on alginate and examined for invert sugar production by molasses hydrolysis in a continuous bioreactor. The yield of immobilized invertase was about 78 % and the activity yield was 59 %. Interestingly the immobilized enzyme hydrolyzed beet molasses consuming nearly all sucrose. It retained all of its initial activity after being used for 4 cycles and about 65 % at the sixth cycle. Regarding productivity; 20 g/l of molasses by-product gave the best invert sugar production 46.21 g/day/100 g substrate related to optimal sucrose conversion of 41.6 %. PMID- 24142427 TI - The trehalose utilization gene thuA ortholog in Mesorhizobium loti does not influence competitiveness for nodulation on Lotus spp. AB - Competitiveness for nodulation is a desirable trait in rhizobia strains used as inoculant. In Sinorhizobium meliloti 1021 mutation in either of the trehalose utilization genes thuA or thuB influences its competitiveness for root colonization and nodule occupancy depending on the interacting host. We have therefore investigated whether mutation in the thuA ortholog in Mesorhizobium loti MAFF303099 also leads to a similar competitive phenotype on its hosts. The results show that M. loti thuA mutant Ml7023 was symbiotically effective and was as competitive as the wild type in colonization and nodule occupancy on Lotus corniculatus and Lotus japonicus. The thuA gene in M. loti was not induced during root colonization or in the infection threads unlike in S. meliloti, despite its induction by trehalose and high osmolarity in in vitro assays. PMID- 24142428 TI - Ruminant feces harbor diverse uncultured symbiotic actinobacteria. AB - To isolate actinobacteria from ruminant feces and elucidate their correlations with ruminants, the actinobacterial community in sheep (Ovis aries) and cattle (Bos taurus) feces was determined by cultivation and clone library methods. Most of actinobacteria isolated belonged to Streptomyces, Amycolatopsis, Micromonospora, and Cellulosimicrobium genera. The strains showed above 99 % similarity with the type strains, respectively. All the strains isolated could grow on media containing pectin, cellulose, or xylan as the sole carbon sources. However, most antibacterial and antifungal activities were found in Streptomyces species. Clone library analysis revealed that the genera Mycobacterium, Aeromicrobium, Rhodococcus, Cellulomonas were present in cattle and sheep feces. In contrast, the 16S rRNA genes showed less than 98 % similarity with the type strains. The analysis of actinobacterial community in ruminant feces by clone library and cultivation yielded a total of 10 actinobacterial genera and three uncultured actinobacterial taxa. The ruminant feces harbored diverse actinobacterial community. Ruminants may represent an underexplored reservoir of novel actinomycetes of potential interest for probiotics and drug discovery. PMID- 24142429 TI - Atrial supply-demand balance in healthy adult pigs: coronary blood flow, oxygen extraction, and lactate production during acute atrial fibrillation. AB - AIMS: Little is known about how atrial oxygen supply responds to increased demand, and under which conditions it falls short (supply-demand mismatch). Here, we have investigated the vasodilator response, oxygen extraction, and lactate production of the left atrium (LA) and left ventricle (LV) in response to atrial pacing and atrial fibrillation (AF). METHODS AND RESULTS: Series A (n = 9 Dutch landrace pigs) was instrumented to measure LA and LV vascular conductance in branches of the circumflex artery. Coronary conductance reserve (CCR) was calculated as the ratio between conductance during adenosine infusion and baseline. Series B (n = 7) was instrumented with sampling catheters in LA and LV veins for determination of blood gases and lactate levels. LA CCR (1.76 +/- 0.14) was significantly lower than LV CCR (3.16 +/- 0.27, P = 0.002). However, basal oxygen extraction was lower in LA (27 +/- 3%) than that in the LV (58 +/- 6%, P = 0.0006), indicating a larger extraction reserve in the LA than that in the LV (4.68 +/- 0.84 vs. 1.88 +/- 0.26, P = 0.01). Atrial pacing caused an increase in LA conductance (Series A) and oxygen extraction (Series B). AF increased LA vascular conductance to 177 +/- 14% at 1 min, 168 +/- 14 at 5 min, and 164 +/- 31% at 10 min of AF (P < 0.05 vs. baseline). Atrial oxygen extraction also increased from 26 +/- 3% at baseline to 63 +/- 5% (P < 0.01) at 5 min and 60 +/- 11% (P < 0.01) at 10 min of AF. Arterio-venous lactate difference increased significantly (P = 0.02) during AF. CONCLUSIONS: In healthy pigs, the LA has a lower CCR, but a higher extraction reserve compared with the LV. Although both reserves were recruited during AF, atrial lactate production increased significantly. PMID- 24142430 TI - Prevention of VEGF-mediated microvascular permeability by C-peptide in diabetic mice. AB - AIMS: Human C-peptide has a beneficial effect on the prevention of diabetic neuropathy, nephropathy, and vascular complications; however, its role in protection against increased vascular permeability in diabetes remains unclear. Our purpose was to explore the potential protective role of C-peptide against microvascular permeability mediated by vascular endothelial growth factor (VEGF) induced reactive oxygen species (ROS) generation in diabetes. METHODS AND RESULTS: Generation of intracellular ROS, real-time changes in intracellular Ca(2+), ROS-dependent stress fibre formation, and the disassembly of the adherens junctions were studied by a confocal microscopy in human umbilical vein endothelial cells (HUVECs). VEGF-induced vascular leakage was investigated in the skin of diabetic mice using a Miles vascular permeability assay. Microvascular leakage in the retina of streptozotocin diabetic mice was investigated using a confocal microscopy after left ventricle injection of fluorescein isothiocyanate (FITC)-dextran. C-peptide inhibited the VEGF-induced ROS generation, stress fibre formation, disassembly of vascular endothelial cadherin, and endothelial permeability in HUVECs. Intradermal injection of C-peptide prevented VEGF-induced vascular leakage. Consistent with this, intravitreal injection of C-peptide prevented the extravasation of FITC-dextran in the retinas of diabetic mice, which was also prevented by anti-VEGF antibody and ROS scavengers in diabetic mice. Conclusions/interpretation C-peptide prevents VEGF-induced microvascular permeability by inhibiting ROS-mediated intracellular events in diabetic mice, suggesting that C-peptide replacement is a promising therapeutic strategy to prevent diabetic retinopathy. PMID- 24142431 TI - Sumatriptan plus naproxen for acute migraine attacks in adults. AB - BACKGROUND: Migraine is a common disabling condition and a burden for the individual, health services, and society. Effective abortive treatments include the triptan and non-steroidal anti-inflammatory classes of drugs. These drugs have different mechanisms of action and combining them may provide better relief. Sumatriptan plus naproxen is now available in combination form for the acute treatment of migraine. OBJECTIVES: To determine the efficacy and tolerability of sumatriptan plus naproxen (administered together as separate tablets or taken as a fixed-dose combination tablet) compared with placebo and other active interventions for the acute treatment of migraine headaches in adults. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL) on The Cochrane Library, MEDLINE, and EMBASE, together with two online databases (www.gsk-clinicalstudyregister.com and www.clinicaltrials.gov) for studies to 2 August 2013. We also searched the reference list of included studies and relevant reviews. SELECTION CRITERIA: We included randomised, double-blind, placebo- or active-controlled studies, with at least 10 participants per treatment arm, using sumatriptan plus naproxen to treat a migraine headache episode. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed trial quality and extracted data. We used numbers of participants achieving each outcome to calculate risk ratio and numbers needed to treat to benefit (NNT) or harm (NNH) compared with placebo or a different active treatment. MAIN RESULTS: We included 12 studies using sumatriptan 85 mg or 50 mg plus naproxen 500 mg to treat attacks of mild, moderate, or severe pain intensity: 3663 participants received combination treatment, 3682 placebo, 964 sumatriptan, and 982 naproxen. No studies were considered to be at high risk of bias for any of the criteria evaluated.Overall, the combination was better than placebo for pain-free and headache relief responses. At two hours, the NNT for pain-free response was 3.1 when the baseline pain was mild (50% response with sumatriptan plus naproxen compared with 18% with placebo), and 4.9 when baseline pain was moderate or severe (28% with sumatriptan plus naproxen compared with 8% with placebo) (RR 3.65 (95% CI 3.0 to 4.5); high quality evidence). Using 50 mg of sumatriptan, rather than 85 mg, in the combination did not significantly change the result. Treating early, when pain was still mild, was significantly better than treating once pain was moderate or severe for pain-free responses at two hours and during the 24 hours post dose. Adverse events were mostly mild or moderate in severity and rarely led to withdrawal; they were more common with the combination than with placebo.Where the data allowed direct comparison, combination treatment was superior to either monotherapy, but adverse events were less frequent with naproxen than sumatriptan. AUTHORS' CONCLUSIONS: Combination treatment was effective in the acute treatment of migraine headaches. The effect was greater than for the same dose of either sumatriptan or naproxen alone, but additional benefits over sumatriptan alone are not large. More participants achieved good relief when medication was taken early in the attack, when pain was still mild. Adverse events were more common with the combination and sumatriptan alone than with placebo or naproxen alone. PMID- 24142432 TI - Dynamic causal modeling of load-dependent modulation of effective connectivity within the verbal working memory network. AB - Neuroimaging studies have consistently shown that working memory (WM) tasks engage a distributed neural network that primarily includes the dorsolateral prefrontal cortex, the parietal cortex, and the anterior cingulate cortex. The current challenge is to provide a mechanistic account of the changes observed in regional activity. To achieve this, we characterized neuroplastic responses in effective connectivity between these regions at increasing WM loads using dynamic causal modeling of functional magnetic resonance imaging data obtained from healthy individuals during a verbal n-back task. Our data demonstrate that increasing memory load was associated with (a) right-hemisphere dominance, (b) increasing forward (i.e., posterior to anterior) effective connectivity within the WM network, and (c) reduction in individual variability in WM network architecture resulting in the right-hemisphere forward model reaching an exceedance probability of 99% in the most demanding condition. Our results provide direct empirical support that task difficulty, in our case WM load, is a significant moderator of short-term plasticity, complementing existing theories of task-related reduction in variability in neural networks. PMID- 24142433 TI - [The proliferative myositis in the psoas muscle -- a rare pseudosarcoma in an unusual localization]. PMID- 24142434 TI - [Bromidine poisoning due to psychotropic drug abuse - a rare cause of generalized hyperdense vessels in CCT]. PMID- 24142435 TI - [Postoperative subphrenic evidence of liquid with gas bubbles -- not always an abscess]. PMID- 24142436 TI - Monitoring of gadolinium-BOPTA uptake into the vessel wall during magnetic resonance (MR)-guided angioplasty of the peripheral arteries with a paclitaxel/gadolinium-BOPTA-coated balloon: an experimental study at 3 Tesla. AB - PURPOSE: The success of paclitaxel distribution within the vessel wall during paclitaxel-coated balloon angioplasty to prevent restenosis cannot be monitored under X-ray guidance. The aim of this pilot study was to demonstrate the feasibility of monitoring Gadolinium-BOPTA delivery within the vessel wall during magnetic resonance (MR)-guided paclitaxel/Gadolinium-BOPTA-coated balloon angioplasty of the peripheral arteries. MATERIALS AND METHODS: 6 pigs (47 +/- 2 kg) were investigated. All experiments were performed using a 3 Tesla MR scanner. MR-guided bilateral angioplasty of the iliac arteries was performed using a paclitaxel/MR contrast agent-coated balloon catheter. The feasibility of monitoring the delivery of Gadolinium-BOPTA to the vessel wall was assessed in 4 animals. In two additional animals, bilateral stenosis was surgically induced in the iliac arteries. Delivery of paclitaxel to the vessel wall was monitored using a 3 D T1-weighted gradient echo (GE) sequence for delineation of the vessel wall. Normalized signal intensity (SI) of the vessel wall was measured before and repeatedly after the intervention for 45 min. in all animals. RESULTS: Paclitaxel/gadolinium-BOPTA-coated balloon angioplasty was successfully accomplished in all iliac arteries (n = 12). In animals with stenosis MR angiography demonstrated successful dilatation (n = 4). The normalized SI of the vessel wall on T1-weighted GE images significantly increased after the intervention in all animals with and without stenosis for more than 45 min. (p < 0.001). CONCLUSION: Monitoring of Gadolinium-BOPTA into the vessel wall during MR guided coated balloon angioplasty is feasible. This is a first step towards providing a tool for the online control of homogenous drug delivery after paclitaxel-coated balloon angioplasty. KEY POINTS: * Monitoring of gadolinium BOPTA uptake into the vessel wall during MR-guided coated balloon angioplasty is feasible.* Endovascular MR-guided interventions on a 3 Tesla MR scanner are feasible.* This is a first step towards providing a tool for online control of homogenous drug delivery after paclitaxel-coated balloon angioplasty. PMID- 24142437 TI - Single-phase percutaneous recanalization of malignant bile duct obstructions with a covered stent graft. AB - PURPOSE: The aim of this study was to evaluate the benefit of a percutaneous transhepatic biliary drainage (PTCD) endoprothesis in the case of patients with malignant occlusion of the common bile duct (CBD). MATERIALS AND METHODS: 32 patients (mean age 72 +/- 13 years) were treated with an endoprosthesis (VIABIL; M. L. GORE & ASSOCIATES, INC., USA) due to failed attempts of endoscopic retrograde cholangiopancreatography (ERCP) in the case of malignant occlusion of the CBD. RESULTS: The technical success rate was 96.9 %. In one patient the probing of an intrahepatic bile duct was impossible. Two major complications (bleeding, liver abscess) were successfully treated with appropriate measures. The bilirubin level did not significantly decrease immediately after intervention (13.2 +/- 6.5 mg/dl; p > 0.05). However, the follow-up displayed a highly significant decrease of bilirubin to 6.0 +/- 7.4 mg/dl; p < 0.05). The endoprosthesis was extended with bare metal NITINOL stents in 9 patients. The mean survival time of the patient group was 64 +/- 28 days (range 2 - 250 days). CONCLUSION: The implantation of an endoprosthesis proved to be an option with high technical success, a low complication rate and good benefit in our patients with malignant bile duct obstruction in palliative therapy situations. KEY POINTS: * The primary objective in the case of malignant bile duct obstruction is the treatment of jaundice.* After failed endoscopic recanalization of the bile ducts, transhepatic biliary drainage is desirable.* An ePTFE-FEP covered endoprothesis is a good treatment option in palliative situations.* A single stage procedure shortens hospitalization time. PMID- 24142438 TI - Accuracy of MRI-compatible contrast media injectors. AB - PURPOSE: To analyze the exactness of MRI-compatible contrast media (CM) injectors in an experimental setup and clinical use. MATERIALS AND METHODS: Ejected fluid volumes and amounts of CM were quantified for single and double piston injections. The focus was on small volumes, as used in pediatric examination and test-bolus measurements. Samples were collected before and after clinical MRI scans and amounts of CM were measured. RESULTS: For single piston injections the volume differences were minimal (mean difference 0.01 ml). For double piston injections the volume of the first injection was decreased (mean 20.74 ml, target 21.00 ml, p < 0.01). After a position change of the Y-piece of the injection system, the amount of CM differed significantly from the target value (mean 1.23 mmol and 0.83 mmol at 1 ml/s flow rate, target 1.00 mmol, p < 0.01), independently of the wait time. The clinical samples confirmed these findings. CONCLUSION: The pistons of modern CM injectors work exactly. However, for small CM volumes the injected amount of CM can differ significantly from the target value in both directions. Influence factors are an incomplete elimination of air and exchange processes between the CM and saline chaser in the injection system. KEY POINTS: * In MRI examinations of children and test-bolus measurements, small amounts of CM are used. * The accuracy of single piston injections is high. * In double piston injections the injected amount of CM can differ significantly from the target value. PMID- 24142439 TI - Osseofix(r) system for percutaneous stabilization of osteoporotic and tumorous vertebral compression fractures - clinical and radiological results after 12 months. AB - PURPOSE: Determining whether implantation of an expandable titanium mesh cage (Osseofix(r) system) is a successful and safe minimally invasive therapy for osteoporotic and tumorous vertebral compression fractures (VCFs). MATERIALS AND METHODS: 32 patients (25 women, 7 men, mean age 71) with 46 osteoporotic or tumorous VCFs (T6 to L4) from June 2010 to January 2012 were included. All of them were stabilized with the Osseofix(r) system. Preinterventionally we performed X-ray, MRI, and bone density measurements (DXA). The clinical and radiological results were evaluated preop, postop and 12 months postop based on the visual analog scale (VAS) and the Oswestry Disability Index (ODI), X-ray (Beck Index, Cobb angle) and CT. RESULTS: There was a significant improvement in pain intensity (VAS) (7.8 to 1.6) as well as a significant reduction in the mean ODI (71.36 % to 30.4 %) after 12 months. The mean kyphotic angle according to Cobb showed significant improvements (12.3 degrees to 10.8 degrees ) after 12 months. Postinterventional imaging showed one case of loss of height in a stabilized lumbar vertebral body (2.2 %) in osteoporosis and one case with adjacent fracture (2.2 %) in osteoporosis. We saw no changes in the posterior vertebral wall. Except for one pronounced postoperative hematoma, we saw no surgical complications including no cement leakage. CONCLUSION: The clinical mid term results are good at a low complication rate. The stabilization of symptomatic osteoporotic and tumorous VCFs with the Osseofix(r) system is a safe and effective procedure, even in fractures with posterior wall involvement. The Osseofix(r) system is an interesting alternative to the established procedures of cement augmentation. KEY POINTS: * The Osseofix(r) system is well suited for stabilizing osteoporotic and tumorous VCFs.* It is a safe and effective procedure without cement leakage and with a low complication rate.* The procedure is an interesting alternative to established cement augmentation procedures. PMID- 24142440 TI - Special issue on oxidative stress in health and disease. PMID- 24142441 TI - Bystander's willingness to report theft, physical assault, and sexual assault: the impact of gender, anonymity, and relationship with the offender. AB - This research examines bystander willingness to report three different crimes to the police or campus authorities among a college student sample (n = 295). Twelve original vignettes varied anonymity when reporting, bystander's relationship with the offender (friend or stranger), and crime type. A factorial analysis of variance showed that main effects were found for crime type, bystander's gender, and bystander's relationship with the offender; anonymity was not significant. The physical assault was the most likely to be reported (4.47), followed by theft (3.26), and sexual assault (2.36). Women were more likely than men to report each crime type, and bystanders who were good friends of the offender were less likely to report than strangers. No two- or three-way interactions were significant, but a significant four-way interaction indicated that anonymity, relationship with the offender, and bystander's gender predicted willingness to report for the sexual assault scenario. PMID- 24142442 TI - Decrease in domestic violence during pregnancy: a study from Turkey. AB - Our aim is to evaluate the prevalence of domestic violence (DV) among pregnant women and find out whether several factors were associated with DV or not. A total of 317 pregnant women applied at Sanliurfa Obstetrics Hospital and Harran University obstetrics and gynecology department outpatient clinic were interviewed using the modified form of Abuse Assessment Screen questionnaire. Several clinical and sociodemographic data were also obtained from the participants. Mean pregnancy number per woman (gravida) was 3.62 +/- 0.13. 47.3% of women had experienced DV before pregnancy. However, the rate of DV exposure significantly decreased to 10.3% during pregnancy (p < .001). Participants with positive family history of DV (mother's exposure) had significantly higher DV rates (p < .001). Those who were exposed to DV, visited their parents less (p = .002). The mean body mass index of DV exposed women was significantly lower (p = .011) than non-DV exposed women. DV exposed women had fewer social interactions and their weight gain may affected by violence. Pregnancy appears to decrease DV in Sanliurfa. PMID- 24142443 TI - The nature of violence: a multilevel analysis of gun use and victim injury in violent interpersonal encounters. AB - A large number of studies have examined predictors of crime quantities yet considerably less attention has been directed toward exploring patterns in the nature or quality of violence within and across communities. The current study adds to the literature on qualitative variations in violence by assessing the incident and contextual-level predictors of offender gun use and physical injuries sustained by victims of robbery and aggravated assault. Specifically, we examine incident-level data from the National Incident Based Reporting System in conjunction with contextual-level data on the cities in which the incidents occurred. We use hierarchical linear and nonlinear modeling techniques to explore variations in predictors of offender gun use and extent of victim injury. Supporting cultural effects explicated by Anderson, results reveal certain individual-level predictors are conditioned by community characteristics. PMID- 24142444 TI - Evaluation of a gender-based violence prevention program for student athletes in Mumbai, India. AB - Gender-based violence, which includes sexual and intimate partner violence against women, is prevalent worldwide, prompting calls for primary prevention programs which engage men and boys in changing social norms that condone violence against women. Bystander intervention efforts which encourage males to say something to stop peers from enacting disrespectful and abusive behaviors toward females are a promising strategy for promoting non-violent, gender-equitable attitudes and behaviors. An evaluation of "Parivartan"--a U.S. program called "Coaching Boys Into Men" adapted for urban India cricket teams--was conducted in Mumbai, India. Baseline and 12 month follow-up surveys were administered to 309 male cricket athletes aged 10 to 16 years in 46 urban middle schools in Mumbai, India (27 intervention, 19 control). Athletes whose coaches were trained in the program demonstrated greater improvements in gender-equitable attitudes compared to athletes whose coaches provided standard coaching only. Marginally significant improvements were seen in reduction of negative bystander behavior. Violence prevention programs which utilize coaches as positive messengers for respect and non-violence may be a useful addition to global prevention efforts to reduce violence against women. PMID- 24142445 TI - Intimate partner violence reported by two samples of deaf adults via a computerized American sign language survey. AB - A computerized sign language survey was administered to two large samples of deaf adults. Six questions regarding intimate partner violence (IPV) were included, querying lifetime and past-year experiences of emotional abuse, physical abuse, and forced sex. Comparison data were available from a telephone survey of local households. Deaf respondents reported high rates of emotional abuse and much higher rates of forced sex than general population respondents. Physical abuse rates were comparable between groups. More men than women in both deaf samples reported past-year physical and sexual abuse. Past-year IPV was associated with higher utilization of hospital emergency services. Implications for IPV research, education, and intervention in the Deaf community are discussed. PMID- 24142446 TI - "He said they'd deport me": factors influencing domestic violence help-seeking practices among Latina immigrants. AB - Significant developments have been made in research on domestic violence experienced by women as well as on the practical front of the services women seek and receive when living with partner abuse. Yet, most of the studies that explore the experiences of victims of partner abuse in the United States have focused on nonimmigrant White women. The current study aims to contribute to the literature by exploring Latina immigrant victims' experiences with domestic violence service outreach in the Midwest. This exploratory study used one-on-one interviews and a focus group to identify the challenges faced by 10 Latina victims of partner abuse who had previously contacted an antiviolence organization in Iowa and had used its services. Findings demonstrate that immigration status and the inability to understand domestic violence within given cultural norms are major barriers keeping Latina victims from seeking help from formal advocacy agencies. Other impediments include feeling shame, isolation, along with the lack of bilingual service providers in mainstream institutions and, the lack of knowledge about resources among newcomers. We end with recommendations for research and practice. PMID- 24142447 TI - The effects of police contact on trajectories of violence: a group-based, propensity score matching analysis. AB - This study uses a life course framework to investigate how police contacts may serve as a potential turning point in a violent crime trajectory. Drawing on the central ideas from deterrence and labeling theories, we determine whether individuals on different violent offending trajectories increase or decrease their offending following a police contact. Analyzing nine waves of data from the Rochester Youth Development Study, an integrated propensity score matching and latent class growth model was used. First, three violent trajectory groups emerged including high offenders, non-offenders, and low offenders. Second, after accounting for selection bias using propensity score matching procedures, experiencing a police contact increased the likelihood of future violent offending for the entire sample and for those who were on a low violent-offending trajectory specifically. These findings are interpreted as partial support for labeling theory. Limitations of the study and directions for future research are discussed. PMID- 24142448 TI - Examining the genetic and environmental influences on self-control and delinquency: results from a genetically informative analysis of sibling pairs. AB - The Child and Young Adult Supplement of the National Longitudinal Survey of Youth (CNLSY) has been used extensively within criminology. A significant amount of criminological research, for example, has explored various issues related to the correlates, causes, and consequences associated with levels of self-control and delinquent involvement. The overwhelming majority of these CNLSY studies, however, have not accounted for the potential effects of genetic factors on these two widely studied criminological variables and thus the findings generated from previous empirical work may be inaccurate due to genetic confounding. The current study partially addresses this possibility by analyzing a sample of kinship pairs nested within the CNLSY. Analyses of these data revealed that genetic factors accounted for between 51% and 92% of the variance in levels of self-control and between 30% and 41% of the variance in delinquency. We discuss the implications of these results for interpreting findings from the large body of existing research using the CNLSY. PMID- 24142449 TI - Donor hemodynamic profile presages graft survival in donation after cardiac death liver transplantation. AB - Obligatory exposure to a period of warm ischemia is the defining feature of liver allografts from donation after cardiac death (DCD) donors. We explored novel methods for characterizing the dynamic aspects of donor warm ischemia that might be useful in assessing organ quality. The hemodynamic profile during donor warm ischemia was retrospectively studied for 110 Maastricht category III DCD donors. Three methods were used to summarize the hemodynamic changes after extubation: (1) the area under the systolic blood pressure curve (AUCSBP), (2) the slope of the systolic blood pressure regressed onto the time from extubation until cross clamping, and (3) the slope of the systolic blood pressure regressed onto the time from extubation but calculated with only the values during the first 10 minutes after extubation (SBP10). Stepwise multivariate Cox models were created to study the association of these measures with graft survival. The duration of the donor warm ischemia time (23.6 +/- 8.5 minutes) was not associated with graft survival (P = 0.35), although AUCSBP and SBP10 demonstrated significant associations (P = 0.02 and P = 0.05, respectively) in a univariate analysis. Multivariate regression models incorporating donor and recipient covariates indicated that among all covariates, SBP10 had the closest association with graft survival (hazard ratio = 1.08, P = 0.01). This association was even stronger when SBP10 was dichotomized into values above or below the median (-7.2 mm Hg/minute). Patients with SBP10s steeper than the median had an estimated 5-year graft survival rate of 76%, whereas patients with slopes less than the median had a 5 year survival rate of 45% (P < 0.007). In conclusion, the incorporation of novel methods for characterizing the donor warm ischemia time may help in selecting DCD liver allografts with favorable outcomes. PMID- 24142450 TI - Prefrontal seizures manifesting as motor stereotypies. AB - BACKGROUND: The definition of stereotypies traditionally does not include "epileptic automatisms." However repetitive, sometimes rhythmic behaviors can occur during frontal lobe seizures in a reproducible pattern for a given patient. Thus, the concept of a frontostriatal "motor loop" could be relevant to repetitive ictal behaviors. METHODS: We describe 17 patients with frontal lobe epilepsy who presented with motor and/or verbal stereotypies and who were explored using depth electrodes (stereoelectroencephalography [SEEG]) in the context of epilepsy presurgical evaluation. RESULTS: Motor patterns were typically reproducible between seizures for a given patient. Distal motor stereotypies were associated with anterior prefrontal localization, and proximal stereotypies were associated with posterior prefrontal localization. CONCLUSIONS: "Stereotypy" is a useful term to describe ictal repetitive behaviors produced by prefrontal seizure discharge. The expression of distal and proximal stereotypies follows a rostrocaudal gradient within the frontal lobes. Exploration of the cortical compartment of frontostriatal networks in epileptic patients offers a unique opportunity to study the mechanisms of stereotypies in vivo. PMID- 24142451 TI - Adapting cognitive interviewing for nursing research. AB - Cognitive interviewing (CI) has been used by instrument developers to examine how well an instrument generates the intended data when tested with prospective respondents. In using CI to test a new instrument to measure patients' perceptions of the quality of nursing care, the authors found challenges in applying a theory-based traditional CI approach derived from experimental psychology to more clinically oriented nursing research. The purposes of this article are to describe these challenges and the modifications of CI to capture the nursing care perspectives of hospitalized participants, and to present interpretive phenomenology as a theoretical orientation for clinically situated CI. PMID- 24142452 TI - Adenosine receptor inhibition attenuates the decrease in cutaneous vascular conductance during whole-body cooling from hyperthermia. AB - Adenosine has both vasodilatory and vasoconstrictive properties, yet its influence on cutaneous vascular conductance (CVC) during whole-body cooling remains unknown. The present study evaluated the influence of adenosine on reflex cutaneous vasoconstriction. Four microdialysis probes were inserted into the dorsal forearm skin of eight subjects and infused with the following solutions: (i) lactated Ringer solution (CON); (ii) 4 mm theophylline (Theo), a non selective adenosine receptor antagonist; (iii) 10 mm l-NAME, an inhibitor of nitric oxide synthase; and (iv) combined 4 mm theophylline and 10 mm l-NAME (Theo + l-NAME). Subjects subsequently donned a water-perfusion garment. Following a thermoneutral baseline period, the suit was perfused with water at 10 degrees C for 20 min (Cooling 1). The suit was then perfused with water at 49 degrees C for 45 min (Heating), followed by a second cooling period of 20 min using 10 degrees C water (Cooling 2). Cutaneous blood flow (laser-Doppler) was measured over each microdialysis probe and used to calculate CVC as a percentage of the maximum determined by sodium nitroprusside infusion and local heating. Cutaneous vascular conductance was significantly elevated at the Theo site relative to CON following Cooling 1 (18 +/- 6 versus 8 +/- 2%; P = 0.01) and Cooling 2 (27 +/- 11 versus 14 +/- 5%; P = 0.022). Likewise, CVC at the Theo + l-NAME site remained greater compared with l-NAME after Cooling 1 (13 +/- 4 versus 7 +/- 3%; P = 0.030) and Cooling 2 (15 +/- 3 versus 9 +/- 2%; P = 0.009). The present findings demonstrate that non-selective antagonism of adenosine receptors attenuates the decrease in cutaneous vascular conductance during whole-body cooling from hyperthermia. PMID- 24142453 TI - Centrally administered angiotensin-(1-7) increases the survival of stroke-prone spontaneously hypertensive rats. AB - NEW FINDINGS: What is the central question of this study? Activation of angiotensin-converting enzyme 2, resulting in production of angiotensin-(1-7) and stimulation of its receptor, Mas, exerts beneficial actions in a number cardiovascular diseases, including ischaemic stroke. A potential beneficial role for angiotensin-(1-7) in haemorrhagic stroke has not previously been reported. What is the main finding and its importance? Central administration of angiotensin-(1-7) into stroke-prone spontaneously hypertensive rats, a model of haemorrhagic stroke, increases lifespan and improves the neurological status of these rats, as well as decreasing microglial numbers in the striatum (implying attenuation of cerebral inflammation). These actions of angiotensin-(1-7) have not previously been reported and identify this peptide as a potential new therapeutic target in haemorrhagic stroke. Angiotensin-(1-7) [Ang-(1-7)] exerts cerebroprotective effects in ischaemic stroke, and this action is associated with a blunting of intracerebral inflammatory processes and microglial activation. Given that intracerebral inflammation and microglial activation play key roles in the mechanism of injury and brain damage in both ischaemic and haemorrhagic stroke, we have investigated the potential beneficial actions of Ang-(1-7) in stroke-prone spontaneously hypertensive rats (spSHRs), an established animal model of hypertension-induced haemorrhagic stroke. Angiotensin-(1-7) was administered by continuous infusion via the intracerebroventricular route for 6 weeks into spSHRs fed a high-sodium (4%) diet, starting at 49 days of age. This treatment resulted in a significant increase in survival of the spSHRs. Median survival was 108 days in control, artificial cerebrospinal fluid-infused spSHRs and 154 days in Ang-(1-7)-treated spSHRs. This effect was partly reversed by intracerebroventricular infusion of the Mas receptor blocker, A779. This Ang-(1 7) treatment also decreased the number of haemorrhages in the striatum, improved neurological status (reduced lethargy), decreased the number of microglia in the striatum and tended to increase neuron survival at the same site. Importantly, infusions of Ang-(1-7) had no effect on kidney pathology, heart pathology, body weight, serum corticosterone levels or blood pressure. This study is the first to demonstrate the cerebroprotective actions of Ang-(1-7), including increased survival time, in spSHRs. As such, these data reveal a potential therapeutic target for haemorrhagic stroke. PMID- 24142454 TI - Chronic depression of hypothalamic paraventricular neuronal activity produces sustained hypotension in hypertensive rats. AB - Changes in the sympathetic nervous system are responsible for the initiation, development and maintenance of hypertension. An important central sympathoexcitatory region is the paraventricular nucleus (PVN) of the hypothalamus, which may become more active in hypertensive conditions, as shown in acute studies previously. Our objective was to depress PVN neuronal activity chronically by the overexpression of an inwardly rectifying potassium channel (hKir2.1), while evaluating the consequences on blood pressure (BP) and its reflex regulation. In spontaneously hypertensive rats (SHRs) and Wistar rats (WKY) lentiviral vectors (LVV-hKir2.1; LV-TREtight-Kir-cIRES-GFP5 4 * 10(9) IU and LV-Syn-Eff-G4BS-Syn-Tetoff 6.2 * 10(9) IU in a ratio 1:4) were stereotaxically microinjected bilaterally into the PVN. Sham-treated SHRs and WKY received bilateral PVN microinjections of LVV-eGFP (LV-Syn-Eff-G4BS-Syn-Tetoff 6.2 * 10(9) IU and LV-TREtight-GFP 5.7 * 10(9) IU in a ratio 1:4). Blood pressure was monitored continuously by radio-telemetry and evaluated over 75 days. Baroreflex gain was evaluated using phenylephrine (25 MUg ml(-1), i.v.), whereas lobeline (25 MUg ml(-1), i.v.) was used to stimulate peripheral chemoreceptors. In SHRs but not normotensive WKY rats, LVV-hKir2.1 expression in the PVN produced time-dependent and significant decreases in systolic (from 158 +/- 3 to 132 +/- 6 mmHg; P < 0.05) and diastolic BP (from 135 +/- 4 to 113 +/- 5 mmHg; P < 0.05). The systolic BP low-frequency band was reduced (from 0.79 +/- 0.13 to 0.42 +/- 0.09 mmHg(2); P < 0.05), suggesting reduced sympathetic vasomotor tone. Baroreflex gain was increased and peripheral chemoreflex depressed after PVN microinjection of LVV-hKir2.1. We conclude that the PVN plays a major role in long-term control of BP and sympathetic nervous system activity in SHRs. This is associated with reductions in both peripheral chemosensitivity and respiratory induced sympathetic modulation and an improvement in baroreflex sensitivity. Our results support the PVN as a powerful site to control BP in neurogenic hypertension. PMID- 24142456 TI - Exercise training effects on hypoxic and hypercapnic ventilatory responses in mice selected for increased voluntary wheel running. AB - NEW FINDINGS: What is the central question of this study? We used experimental evolution to determine how selective breeding for high voluntary wheel running and exercise training (7-11 weeks) affect ventilatory chemoreflexes of laboratory mice at rest. What is the main finding and its importance? Selective breeding, although significantly affecting some traits, did not systematically alter ventilation across gas concentrations. As with most human studies, our findings support the idea that endurance training attenuates resting ventilation. However, little evidence was found for a correlation between ventilatory chemoreflexes and the amount of individual voluntary wheel running. We conclude that exercise 'training' alters respiratory behaviours, but these changes may not be necessary to achieve high levels of wheel running. Ventilatory control is affected by genetics, the environment and gene-environment and gene-gene interactions. Here, we used an experimental evolution approach to test whether 37 generations of selective breeding for high voluntary wheel running (genetic effects) and/or long term (7-11 weeks) wheel access (training effects) alter acute respiratory behaviour of mice resting in normoxic, hypoxic and hypercapnic conditions. As the four replicate high-runner (HR) lines run much more than the four non-selected control (C) lines, we also examined whether the amount of exercise among individual mice was a quantitative predictor of ventilatory chemoreflexes at rest. Selective breeding and/or wheel access significantly affected several traits. In normoxia, HR mice tended to have lower mass-adjusted rates of oxygen consumption and carbon dioxide production. Chronic wheel access increased oxygen consumption and carbon dioxide production in both HR and C mice during hypercapnia. Breathing frequency and minute ventilation were significantly reduced by chronic wheel access in both HR and C mice during hypoxia. Selection history, while significantly affecting some traits, did not systematically alter ventilation across all gas concentrations. As with most human studies, our findings support the idea that endurance training (access to wheel running) attenuates resting ventilation. However, little evidence was found for a correlation at the level of the individual variation between ventilatory chemoreflexes and performance (amount of individual voluntary wheel running). We tentatively conclude that exercise 'training' alters respiratory behaviours, but these changes may not be necessary to achieve high levels of wheel running. PMID- 24142457 TI - A hidden echocardiographic pitfall: the Gerbode defect. PMID- 24142455 TI - Exogenously applied muscle metabolites synergistically evoke sensations of muscle fatigue and pain in human subjects. AB - NEW FINDINGS: What is the central question of this study? Can physiological concentrations of metabolite combinations evoke sensations of fatigue and pain when injected into skeletal muscle? If so, what sensations are evoked? What is the main finding and its importance? Low concentrations of protons, lactate and ATP evoked sensations related to fatigue. Higher concentrations of these metabolites evoked pain. Single metabolites evoked no sensations. This suggests that the combination of an ASIC receptor and a purinergic P2X receptor is required for signalling fatigue and pain. The results also suggest that two types of sensory neurons encode metabolites; one detects low concentrations of metabolites and signals sensations of fatigue, whereas the other detects higher levels of metabolites and signals ache and hot. The perception of fatigue is common in many disease states; however, the mechanisms of sensory muscle fatigue are not understood. In mice, rats and cats, muscle afferents signal metabolite production in skeletal muscle using a complex of ASIC, P2X and TRPV1 receptors. Endogenous muscle agonists for these receptors are combinations of protons, lactate and ATP. Here we applied physiological concentrations of these agonists to muscle interstitium in human subjects to determine whether this combination could activate sensations and, if so, to determine how the subjects described these sensations. Ten volunteers received infusions (0.2 ml over 30 s) containing protons, lactate and ATP under the fascia of a thumb muscle, abductor pollicis brevis. Infusion of individual metabolites at maximal amounts evoked no fatigue or pain. Metabolite combinations found in resting muscles (pH 7.4 + 300 nm ATP + 1 mm lactate) also evoked no sensation. The infusion of a metabolite combination found in muscle during moderate endurance exercise (pH 7.3 + 400 nm ATP + 5 mm lactate) produced significant fatigue sensations. Infusion of a metabolite combination associated with vigorous exercise (pH 7.2 + 500 nm ATP + 10 mm lactate) produced stronger sensations of fatigue and some ache. Higher levels of metabolites (as found with ischaemic exercise) caused more ache but no additional fatigue sensation. Thus, in a dose-dependent manner, intramuscular infusion of combinations of protons, lactate and ATP leads to fatigue sensation and eventually pain, probably through activation of ASIC, P2X and TRPV1 receptors. This is the first demonstration in humans that metabolites normally produced by exercise act in combination to activate sensory neurons that signal sensations of fatigue and muscle pain. PMID- 24142458 TI - Relating pore size variation of poly (E-caprolactone) scaffolds to molecular weight of porogen and evaluation of scaffold properties after degradation. AB - The major challenge in designing a scaffold for fabricating tissue engineered blood vessels is optimization of its microstructure for supporting uniform cellular in-growth with good mechanical integrity and degradation kinetics suitable for long-term implantation. In this study, we have investigated the feasibility of varying the pore size of poly(E-caprolactone) (PCL) scaffold by altering the molecular weight of porogen and studied the effect of degradation on morphological characteristics and mechanical properties of scaffolds by correlating to the extent of degradation. Scaffolds with two different pore sizes were prepared by solvent casting and particulate leaching where poly(ethylene glycol) (PEG) porogens having two molecular weights (3400 and 8000) were used and subjected to in vitro degradation in phosphate buffered saline (PBS) upto six months. Microcomputed tomography studies of scaffolds revealed narrower pore size distribution when PEG-3400 was used as porogen and had 78% pores in the 12-24 u range, whereas incorporation of PEG-8000 resulted in broader distribution with only 65% pores in the same range. Degradation resulted in scaffolds with narrower pore size distribution to have better retention of morphological and mechanical characteristics compared to scaffolds with broader distribution. Gravimetric and molecular weight studies also showed that scaffold degradation in both cases was only in initial stages after 6 months and PCL scaffolds had potential to be recommended for vascular tissue engineering applications. PMID- 24142459 TI - The mechanism of neurogenic pulmonary edema in epilepsy. AB - Neurogenic pulmonary edema (NPE) is found in many epilepsy patients at autopsy. It is a life-threatening complication, known for almost 100 years, but its etiopathogenesis is still not completely understood. In this study, we used the tremor rat (TRM: tm/tm) as an animal model of epilepsy to investigate the potential mechanisms of NPE under epileptic conditions. We performed reverse phase high-pressure liquid chromatography assay, H&E and Masson staining, TUNEL assay, and Western blot experiments to determine the role of seizures in NPE. We found the level of catecholamine was higher in TRM rats. Also the occurrence of alveolar cell apoptosis was increased. Moreover, pulmonary vascular remodeling including the deposition of collagen and medial thickening was also found in TRM rats. Further study showed that cell apoptosis was mediated by increasing Bax, decreasing Bcl-2, and activating caspase-3. In addition, the protein level of phosphorylated ERK (p-ERK) was found to be decreased while phosphorylated JNK and phosphorylated p38 were upregulated in TRM rats. Thus, these findings suggest that pulmonary vascular remodeling and alveolar cell apoptosis might be involved in epilepsy-induced NPE and that the mitogen-activated protein kinase signal pathway was involved. PMID- 24142460 TI - Antihistamine induced blood oxygenation level dependent response changes related to visual processes during sensori-motor performance. AB - The histaminergic involvement in selective processes underlying its role in human sensori-motor performance is largely unknown. Recently, selective effects of central H1-inverse agonism on sensory visual processes were observed in electrophysiological--but not behavioral data; a discrepancy suggested to result from speeded response-choice related processes. This study attempts to establish the effects on visual processes and identify putative compensatory mechanisms related to increased visual and response-choice task demands by assessing H1 inverse agonism induced changes in blood oxygenation level dependent (BOLD) response. Twelve participants received oral doses of dexchlorpheniramine 4 mg, lorazepam 1 mg, and placebo in a three-way crossover designed study. Brain activity was assessed for choice reaction time task performance in a 3 T magnetic resonance scanner 2 h after drug administration. Participants responded with their left or right hand and index or middle finger as indicated by the laterality of stimulus presentation and identity of the stimulus, respectively. Stimuli were intact or visually degraded and responses were compatible or incompatible with the laterality of stimulus presentation. Both dexchlorpheniramine and lorazepam affected the BOLD response in the occipital cortex indicating affected visual information processing. Dexchlorpheniramine decreased BOLD response in the dorsal precuneus and left precentral gyrus as part of a motor network, which however might not be interpreted as a compensatory mechanism, but may be the upstream consequence of impaired visual processing. PMID- 24142461 TI - Increased parasitism of limpets by a trematode metacercaria in fisheries management areas of central Chile: effects on host growth and reproduction : management areas and parasitism. AB - The rapid increase in body size and abundance of most species inside Management and Exploitations Areas for Benthic Resources (MEABRs) has led to the proposal of these areas as a good complement for achieving the conservation objectives of Marine Protected Areas (MPAs). However, when evaluating MEABRs and MPAs as conservation and/or management tools, their impact upon parasite populations has rarely been considered, despite the fact that epidemiological theory suggests an increased susceptibility to parasitism under high population abundance. We evaluated the effects of MEABRs on the parasite abundance of Proctoeces lintoni and its impact on the growth of the host limpet Fissurella crassa in central Chile. Parasitic magnitude was higher inside MEABRs than in Open-Access Areas, and parasitized limpets showed a greater shell length, muscular foot biomass, and gonadosomatic index compared to non-parasitized limpets of the same age. Our results suggest that the life cycle of P. lintoni and, consequently, its trophic links have been strengthened inside MEABRs. The increased growth rate could reduce the time required to reach the minimum catch size and increase the reproductive and muscular output of the host population. Thus, parasitism should be considered in the conservation and management of economically important mollusk hosts. PMID- 24142462 TI - Forest fragmentation and risk of giardiasis in New York State. AB - In the United States, giardiasis is endemic in northern and northeastern states, but its ecology and epidemiology remain elusive. The underlying physical landscape may play a role in shaping points of contact between humans, animals, and Giardia cysts. This study examined 11 years of surveillance data in New York State to measure the relationship between forest fragmentation and the incidence of giardiasis. Adjusted Poisson models showed that increasing points of contact between forested land and developed land, as measured by their shared edges [incident rate ratio (IRR) = 1.003; P < 0.001] and by the perimeter length of forested patches (IRR = 1.31; P = 0.01), were associated with higher incidence of giardiasis cases, whereas increasing forest density was associated with a lower incidence (IRR = 0.97; P < 0.001). These associations were independent of both temperature and surface water area. While these results are only suggestive due to the county-level aggregated data, the findings do identify a potentially important signal in the landscape epidemiology of giardiasis and highlight the need for better, more targeted, field studies on individual water sources for household consumption, inter-species contact in ecotones, surface water contamination, and human giardiasis cases. PMID- 24142465 TI - Opioids for the management of breakthrough pain in cancer patients. AB - BACKGROUND: This review is an update of a previously published review in the Cochrane Database of Systematic Reviews (Issue 1, 2006). Breakthrough pain is a transient exacerbation of pain that occurs either spontaneously or in relation to a specific predictable or unpredictable trigger despite relative stable and adequately controlled background pain. Breakthrough pain usually related to background pain and is typically of rapid onset, severe in intensity and generally self limiting with a mean duration of 30 minutes. Breakthrough pain has traditionally been managed by the administration of supplemental oral analgesia (rescue medication) at a dose proportional to the total around-the-clock (ATC) opioid dose. OBJECTIVES: To determine the efficacy of opioid analgesics given by any route, used for the management of breakthrough pain in patients with cancer, and to identify and quantify, if data permitted, any adverse effects of this treatment. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE and trial registries in January 2005 for the original review, and again on 6 February 2013 for this update. SELECTION CRITERIA: We included randomised controlled trials (RCTs) of opioids used as rescue medication against active or placebo comparator in patients with cancer pain. Outcome measures sought were reduction in pain intensity measured by an appropriate scale, adverse effects, attrition, patient satisfaction and quality of life. We applied no language restrictions. DATA COLLECTION AND ANALYSIS: Two review authors independently selected and examined eligible studies. We retrieved full text if any uncertainty about eligibility remained. We screened non-English texts. We conducted quality assessment and data extraction using standardised data forms. We compared drug and placebo dose, titration, route and formulation and recorded details of all outcome measures (if available). MAIN RESULTS: The original review included four studies (393 participants), all concerned with the use of oral transmucosal fentanyl citrate (OTFC) in the management of breakthrough pain. Two studies examined the titration of OTFC, one study compared OTFC versus normal-release morphine and one study compared OTFC versus placebo.Fifteen studies (1699 participants) met the inclusion criteria for this update. All studies reported on the utility of seven different transmucosal fentanyl formulations, five of which were administered orally and two nasally. Eight studies compared the transmucosal fentanyl formulations versus placebo, four studies compared them with another opioid, one study was a comparison of different doses of the same formulation and two were randomised titration studies. Oral and nasal transmucosal fentanyl formulations were an effective treatment for breakthrough pain. When compared with placebo or oral morphine, participants gave lower pain intensity and higher pain relief scores for transmucosal fentanyl formulations at all time points. Global assessment scores also favoured transmucosal fentanyl preparations. One study compared intravenous with the transmucosal route and both were effective. AUTHORS' CONCLUSIONS: Oral and nasal transmucosal fentanyl is an effective treatment in the management of breakthrough pain. The RCT literature for the management of breakthrough pain is relatively small. Given the importance of this subject, more trials, including head-to-head comparisons of the available transmucosal fentanyl formulations are required. PMID- 24142466 TI - Widespread cranial nerve palsies while on cyclophosphamide therapy: a very rare manifestation of Wegener's granulomatosis (granulomatosis with polyangitis). PMID- 24142467 TI - Nitric oxide donors augment interleukin-1beta-induced vascular endothelial growth factor in airway smooth muscle cells. AB - Angiogenesis and microvascular leakage are features of chronic inflammatory diseases of which molecular mechanisms are poorly understood. We investigated the effects of interleukin-1beta (IL-1beta) on the expression and secretion of vascular endothelial growth factor (VEGF) and placenta growth factor (PlGF) in porcine airway smooth muscle cells (PASMC) in relation to a nitric oxide (NO) pathway. Serum-deprived (48 h) PASMC were stimulated with IL-1beta alone or with NO donor, L-arginine and/or NO synthase inhibitor L-NAME for 4 and 24 h. IL-1beta did not affect PlGF release, but augmented VEGF release (2.4-fold) after 24 h. VEGF release was inhibited by L-NAME (531.8 +/- 52 pg/ml), but restored and further elevated by L-arginine (1,529 +/- 287 pg/ml). IL-1beta up-regulated VEGF mRNA (1.8-fold) and this response was attenuated by L-NAME (1.1-fold) and augmented by L-arginine (3.8-fold) at 4 h. Restoration of a NO pathway by L arginine in L-NAME-treated cells resulted in elevated VEGF mRNA levels (2.2 fold). [(3)H]Thymidine incorporation assay revealed enhanced porcine pulmonary artery endothelial cell proliferation in response to IL-1beta, VEGF and PlGF, and this mitogenic effect was not influenced via the NO pathway. Our results suggest that a NO pathway modulates VEGF synthesis during inflammation contributing to bronchial angiogenesis and vascular leakage. PMID- 24142468 TI - T-bet or not T-bet: taking the last bow on the autoimmunity stage. AB - The search for the encephalitogenic factor driving pathogenic T cells in autoimmune diseases such as rheumatoid arthritis, multiple sclerosis (MS), and psoriasis has proven to be a long and difficult mission, which is not yet completed. In this issue of the European Journal of Immunology, the importance of the transcription factor T-bet, previously shown to be essential for the induction of autoimmune disease in mice, is challenged. Two independent groups, O'Connor et al. [Eur. J. Immunol. 2013. 43:2818-2823] report] and Grifka-Walk et al. [Eur. J. Immunol. 2013. 43:2824-2831], report that T-bet is not mandatory for T cells to cause experimental autoimmune encephalomyelitis (EAE), which serves as a paradigmatic T-cell-mediated autoimmune disease. Both groups found that T-bet KO mice were fully susceptible to develop EAE, both after immunization with self antigen and after adoptive transfer of IL-23-polarized autoaggressive T cells. T bet deficiency mediated the loss of IFN-gamma expression but retained or even enhanced GM-CSF and IL-17 production by central nervous system (CNS)-infiltrating T cells. These findings indicate that we have lost the last transcriptional regulator previously held to be required for the generation of autoimmune pathogenic T cells. PMID- 24142469 TI - Recombinant xylanase from Streptomyces coelicolor Ac-738: characterization and the effect on xylan-containing products. AB - A xylanase gene was isolated from the genomic DNA of Streptomyces coelicolor Ac 738. The 723-bp full-length gene encoded a 241-amino acid peptide consisting of a 49-residue putative TAT signal peptide and a glycoside hydrolase family-11 domain. The mature enzyme called XSC738 was expressed in Escherichia coli M15[pREP4]. The electrophoretically homogeneous protein with a specific activity of 167 U/mg for beechwood xylan was purified. The pH optimum of XSC738 was at pH 6; a high activity was retained within a pH range of 4.5-8.5. The enzyme was thermostable at 50-60 degrees C and retained an activity at pH 3.0-7.0. Xylanase XSC738 was activated by Mn2+, Co2+ and largely inhibited by Cd2+, SDS and EDTA. The products of xylan hydrolysis were mainly xylobiose, xylotriose, xylopentaose and xylohexose. Xylotetraose appeared as a minor product. Processing of such agricultural xylan-containing products as wheat, oats, soy flour and wheat bran by xylanase resulted in an increased content of sugars. PMID- 24142470 TI - In vitro plant development and root colonization of Coleus forskohlii by Piriformospora indica. AB - The present study was conducted for optimization of in vitro substrates under aseptic conditions for interaction of Piriformospora indica with the medicinal plant Coleus forskohlii. It aims to test the effects of different substrates on P. indica colonization as well as growth parameters of the in vitro raised C. forskohlii. Interaction of in vitro C. forskohlii with root endophyte P. indica under aseptic condition resulted in increase in growth parameters in fungus colonized plants. It was observed that P. indica promoted the plant's growth in all irrespective of substrates used for co-culture study. The growth was found inferior in liquid compared to semisolid medium as well as there was problem of hyperhydricity in liquid medium. P. indica treated in vitro plantlets were better adapted for establishment under green house compared to the non treated plants due to fungal intervention. PMID- 24142471 TI - Oral mucosal health in liver transplant recipients and controls. AB - Immunosuppressive drugs and other medications may predispose patients to oral diseases. Data on oral mucosal health in recipients of liver transplantation (LT) are limited. We, therefore, recruited 84 LT recipients (64 with chronic liver disease and 20 with acute liver failure) for clinical oral examinations in a cross-sectional, case-control study. Their oral health had been clinically examined before transplantation. The prevalence of oral mucosal lesions (OMLs) was assessed in groups with different etiologies of liver disease and in groups with different immunosuppressive medications, and these groups were compared to controls selected from a nationwide survey in Finland (n = 252). Risk factors for OMLs were evaluated with logistic regression. OMLs were more frequent in LT recipients versus controls (43% versus 15%, P < 0.001), and the use of steroids raised the prevalence to 53%. Drug-induced gingival overgrowth was the single most common type of lesion, and its prevalence was significantly higher for patients using cyclosporine A (CSA; 29%) versus patients using tacrolimus (TAC; 5%, P = 0.007); the prevalence was even higher with the simultaneous use of calcium channel blockers and CSA (47%) or TAC (8%, P = 0.002). Lesions with malignant potential such as drug-induced lichenoid reactions, oral lichen planus like lesions, leukoplakias, and ulcers occurred in 13% of the patients with chronic liver disease and in 6% of the controls. Every third patient with chronic liver disease had reduced salivary flow, and more than half of all patients were positive for Candida; this risk was higher with steroids. In conclusion, the high frequency of OMLs among LT recipients can be explained not only by immunosuppressive drugs but also by other medications. Because dry mouth affects oral health and OMLs may have the potential for malignant transformation, annual oral examinations are indicated. PMID- 24142472 TI - Exclusion-Based Capture and Enumeration of CD4+ T Cells from Whole Blood for Low Resource Settings. AB - In developing countries, demand exists for a cost-effective method to evaluate human immunodeficiency virus patients' CD4(+) T-helper cell count. The TH (CD4) cell count is the current marker used to identify when an HIV patient has progressed to acquired immunodeficiency syndrome, which results when the immune system can no longer prevent certain opportunistic infections. A system to perform TH count that obviates the use of costly flow cytometry will enable physicians to more closely follow patients' disease progression and response to therapy in areas where such advanced equipment is unavailable. Our system of two serially-operated immiscible phase exclusion-based cell isolations coupled with a rapid fluorescent readout enables exclusion-based isolation and accurate counting of T-helper cells at lower cost and from a smaller volume of blood than previous methods. TH cell isolation via immiscible filtration assisted by surface tension (IFAST) compares well against the established Dynal T4 Quant Kit and is sensitive at CD4 counts representative of immunocompromised patients (less than 200 TH cells per microliter of blood). Our technique retains use of open, simple-to operate devices that enable IFAST as a high-throughput, automatable sample preparation method, improving throughput over previous low-resource methods. PMID- 24142473 TI - The safety of besifloxacin ophthalmic suspension 0.6 % used three times daily for 7 days in the treatment of bacterial conjunctivitis. AB - BACKGROUND: Besifloxacin ophthalmic suspension 0.6 % (Besivance((r)); Bausch & Lomb, Rochester, NY, USA) was approved by the FDA in 2009 for the treatment of bacterial conjunctivitis, with a recommended 7-day dosing regimen. OBJECTIVE: The objective of this study was to compare the safety of besifloxacin ophthalmic suspension 0.6 %, administered three times a day for 7 days, with that of its vehicle. METHODS: This randomized, multicenter, double-masked, vehicle controlled, parallel-group study involved 518 patients >=1 year of age with a clinical diagnosis of bacterial conjunctivitis. Patients were randomized 2:1 to treatment with besifloxacin 0.6 % ophthalmic suspension or vehicle, one drop in the infected eye(s) TID for 7 days. Main outcomes included the incidence and types of adverse events reported by the subject or observed by the investigator at each study visit. RESULTS: Thirty-one ocular treatment-emergent adverse events (TEAEs) were reported by 28 subjects in the study eye; 19 occurred in 17/344 (4.9 %) besifloxacin patients, and 12 occurred in 11/170 (6.5 %) vehicle patients (p = 0.5362). Only two ocular events (mild instillation site reaction, one case in each group) were considered "definitely related" to study treatment. One event of self-limited dysgeusia in the besifloxacin group was considered definitely related to treatment; there were no other nonocular TEAEs considered related to treatment. There were no serious adverse events, and other safety outcomes (visual acuity, biomicroscopy, ophthalmoscopy) were unremarkable. CONCLUSION: These findings indicate that besifloxacin ophthalmic suspension 0.6 % is safe in patients aged 1 year and older when used TID for 7 days. PMID- 24142474 TI - Classification and pathology of primary progressive aphasia. AB - OBJECTIVE: We aimed to determine the extent to which patients with progressive language impairment conform to 2011 primary progressive aphasia (PPA) classification and to examine clinicopathologic correlations within PPA variants. METHODS: Sixty-two consecutive patients with pathologically confirmed dementia who presented clinically with aphasia were identified. Patients with insufficient clinical information were excluded. PPA classifications were applied to anonymized clinical data taken from patients' initial assessment by raters who were blinded to clinical and pathologic diagnosis. RESULTS: The final cohort comprised 52 patients, 30 of whom met basic PPA criteria. Twenty-five patients met one of the 3 PPA classifications (13 logopenic, 8 nonfluent/agrammatic, and 4 semantic). Five patients did not meet the criteria for any of the PPA variants. All patients who met semantic variant PPA and 75% of patients who met nonfluent/agrammatic variant PPA classifications had frontotemporal lobar degeneration spectrum pathology. Pathologies were heterogeneous in patients who met logopenic variant PPA criteria (46% Alzheimer disease [AD], 8% AD mixed with dementia with Lewy bodies, 23% frontotemporal lobar degeneration, and 23% other). CONCLUSION: The 2011 PPA recommendations classify a large proportion of patients who meet basic PPA criteria. However, some patients had aphasic syndromes that could not be classified, suggesting that the 2011 recommendations do not cover the full range of PPA variants. Classification of semantic variant PPA provides a good prediction of underlying pathology. Classification of logopenic variant does not successfully differentiate PPA due to AD from PPA due to other pathologies. PMID- 24142475 TI - Patterns of subregional mesiotemporal disease progression in temporal lobe epilepsy. AB - OBJECTIVE: Evidence for disease progression in the mesiotemporal lobe is mainly derived from global volumetry of the hippocampus. In this study, we tracked progressive structural changes in the hippocampus, amygdala, and entorhinal cortex in drug-resistant temporal lobe epilepsy at a subregional level. Furthermore, we evaluated the relation between disease progression and surgical outcome. METHODS: We combined cross-sectional modeling of disease duration in a large cohort of patients (n = 134) and longitudinal analysis in a subset that delayed surgery (n = 31). To track subregional pathology, we applied surface shape analysis techniques on manual mesiotemporal labels. RESULTS: Longitudinal and cross-sectional designs showed consistent patterns of progressive atrophy in hippocampal CA1, anterolateral entorhinal, and the amygdalar laterobasal group bilaterally. These regions also exhibited more marked age-related volume loss in patients compared with controls. We found a faster progression of hippocampal atrophy in patients with a seizure frequency >=6 per month. High rates of contralateral entorhinal cortex atrophy predicted postsurgical seizure relapse. CONCLUSION: We observed progressive atrophy in hippocampal, amygdalar, and entorhinal subregions that frequently display neuronal loss on histology. The bilateral character of cumulative atrophy highlights the importance of early surgery. In patients who nevertheless delay this procedure, serial scanning may provide markers of surgical outcome. PMID- 24142476 TI - Anterior nucleus of the thalamus: functional organization and clinical implications. AB - The anterior nucleus of thalamus (ANT) is a key component of the hippocampal system for episodic memory. The ANT consist of 3 subnuclei with distinct connectivity with the subicular cortex, retrosplenial cortex, and mammillary bodies. Via its connections with the anterior cingulate and orbitomedial prefrontal cortex, the ANT may also contribute to reciprocal hippocampal prefrontal interactions involved in emotional and executive functions. As in other thalamic nuclei, neurons of the ANT have 2 different state-dependent patterns of discharge, tonic and burst-firing; some ANT neurons also contribute to propagation of the theta rhythm, which is important for mechanisms of synaptic plasticity of the hippocampal circuit. Clinical and experimental evidence indicate that damage of the ANT or its inputs from the mammillary bodies are primarily responsible for the episodic memory deficit observed in Wernicke Korsakoff syndrome and thalamic stroke. Experimental models also indicate that the ANT may have a role in the propagation of seizure activity both in absence and in focal seizures. Because of its central connectivity and possible role in propagation of seizure activity, the ANT has become an attractive target for deep brain stimulation (DBS) for treatment of medically refractory epilepsy. The ANT is one of the nuclei preferentially affected in prion disorders, such as fatal familial insomnia, but the relationship between ANT involvement and the clinical manifestations of these disorders remains unclear. The connectivity patterns and electrophysiology of the ANT have been the subject of several reviews.(1-4.) PMID- 24142477 TI - Fibroblast growth factor 21 is a sensitive biomarker of mitochondrial disease. AB - OBJECTIVE: To prospectively determine the reliability and validity of serum fibroblast growth factor 21 (FGF-21) as a biomarker for mitochondrial disease in a cross-sectional cohort of adults with mitochondrial disease from a specialist primary care and tertiary referral clinic. METHODS: We recruited 140 subjects, including 54 adults with mitochondrial disease, 20 patients with nonmitochondrial neuromuscular disease, and 66 control subjects, between November 2011 and October 2012. We compared serum FGF-21 concentrations to classical biomarkers, serum creatine kinase, lactate, pyruvate, and lactate to pyruvate ratio, to determine its validity and reliability as a biomarker of mitochondrial disease. We determined the sensitivity, odds ratio (OR), and overall reliability of FGF-21 as a marker of mitochondrial disease using statistical analyses. RESULTS: Median serum FGF-21 concentrations were significantly elevated in patients with mitochondrial disease and differed significantly between all experimental groups. FGF-21 showed a markedly higher diagnostic OR (45.7 [95% confidence interval = 12.6-166.5], p < 0.0001) when compared to other biomarkers and was the best predictor of disease according to sensitivity and receiver operating characteristic curve analysis. After multivariate logistic regression analysis controlling for potential confounders, FGF-21 was the only measured parameter capable of predicting mitochondrial disease. CONCLUSION: This prospective study establishes serum FGF-21 levels as a sensitive biomarker of mitochondrial disease and demonstrates that they are the best predictor of this disorder when compared to serum levels of classical indicators: creatine kinase, lactate, pyruvate, and the lactate to pyruvate ratio. PMID- 24142478 TI - Fibroblast growth factor 21, a biomarker for mitochondrial muscle disease. PMID- 24142479 TI - Impact of lifestyle changes on stress in a modernizing rural population in Hainan Island, China. AB - OBJECTIVE: Little is known about inter-individual variation in psychological stress in modernizing rural populations in developing countries. The objective of this study was to investigate the association between Epstein-Barr virus (EBV) antibody titer, a biomarker of psychological stress, and lifestyle parameters in rural communities in Hainan Island, China. METHODS: EBV antibody titer was measured in dried blood spot (DBS) samples collected from 240 adults living in rural communities in Hainan Island. Measures of two major lifestyle changes in rural areas of Hainan Island, i.e., diet and commercial goods possession, were examined by using information on the weekly frequency of pork consumption and monthly mobile phone fees. Both parameters were standardized to create two composite scores: a total affluence index (TAI--the sum of these scores), and an investment tendency index (ITI--the difference between them). Least-squares regression analysis was used to investigate the association between EBV antibody titer and these lifestyle parameters. RESULTS: A positive association was found between the frequency f pork consumption and EBV antibody titer (P = 0.040), whereas a negative association was found between mobile phone fees and EBV antibody titer (P = 0.028). A negative association was also observed between ITI and EBV antibody titer (P = 0.002) after adjusting for the effect of TAI. CONCLUSION: Psychological stress among local residents was linked to the type of lifestyle changes they had experienced, where the adoption of a more market oriented lifestyle, irrespective of current affluence, was associated with less psychological stress. PMID- 24142480 TI - Hippocampal BOLD response during category learning predicts subsequent performance on transfer generalization. AB - To test a prediction of our previous computational model of cortico-hippocampal interaction (Gluck and Myers [1993, 2001]) for characterizing individual differences in category learning, we studied young healthy subjects using an fMRI adapted category-learning task that has two phases, an initial phase in which associations are learned through trial-and-error feedback followed by a generalization phase in which previously learned rules can be applied to novel associations (Myers et al. [2003]). As expected by our model, we found a negative correlation between learning-related hippocampal responses and accuracy during transfer, demonstrating that hippocampal adaptation during learning is associated with better behavioral scores during transfer generalization. In addition, we found an inverse relationship between Blood Oxygenation Level Dependent (BOLD) activity in the striatum and that in the hippocampal formation and the orbitofrontal cortex during the initial learning phase. Conversely, activity in the dorsolateral prefrontal cortex, orbitofrontal cortex and parietal lobes dominated over that of the hippocampal formation during the generalization phase. These findings provide evidence in support of theories of the neural substrates of category learning which argue that the hippocampal region plays a critical role during learning for appropriately encoding and representing newly learned information so that that this learning can be successfully applied and generalized to subsequent novel task demands. PMID- 24142481 TI - Supervised exercise for acute coronary patients in primary care: a randomized clinical trial. AB - BACKGROUND: Functional capacity is a prognostic factor for coronary patients; accordingly, they are recommended to walk. OBJECTIVE: To assess whether an exercise program supervised in primary care increases their functional capacity more than unsupervised walking. METHODS: A randomized clinical trial was carried out at eight primary care centres of the Spanish Health Service and involving 97 incident cases of low-risk acute coronary patients, <80 years old, randomly assigned to either an unsupervised walking program (UW group; n = 51) or a 6 month cycle ergometer exercise program with gradually increasing frequency and workload intensity supervised by primary care nurses (SE group; n = 46). The two groups received the same common components of secondary prevention care. Changes in functional capacity were assessed in terms of peak oxygen consumption (VO2peak) during exercise testing measured at baseline and at 7 months by cardiologists blinded to group assignment. RESULTS: Overall, 76% of participants completed the study, 30 in the SE and 44 in the UW. Both groups increased baseline-adjusted VO2peak: 5.56ml/kg per minute in the SE (95% confidence interval [CI] 3.38-7.74) and 1.64ml/kg per minute in the UW (95% CI -0.15 to 3.45). The multivariate-adjusted difference between groups was 4.30ml/kg per minute (95% CI 1.82-6.79; P = 0.001) when analyzing completers and 2.83ml/kg per minute (95% CI 0.61-5.05; P = 0.01) in the intention-to-treat analysis, including all participants with baseline values carried forward for those lost to follow up. CONCLUSIONS: A cycle ergometer exercise program supervised by primary care nurses increased the functional capacity of coronary patients more than unsupervised walking with a clinically relevant difference. PMID- 24142482 TI - Identification of a novel peptide that blocks basic fibroblast growth factor mediated cell proliferation. AB - Basic fibroblast growth factor (bFGF) has been implicated in tumor growth via interactions with its receptors (FGFRs) on the cell surface and therefore, bFGF/FGFRs are considered essential targets for cancer therapy. Herein, a consensus heptapeptide (LSPPRYP) was identified for the first time from a phage display heptapeptide library after three sequential rounds of biopanning against FGFR-expressing cells with competitive displacement of phage by bFGF, followed by subtraction of non-specific binding by FGFR-deficient cells. Phage bearing LSPPRYP showed high levels of binding to Balb/c 3T3 cells expressing high affinity bFGF-binding FGFR (bFGFR), but not to the cells that do not express bFGFR (Cos-7), or express a very low affinity bFGFR (HaCat). The selected-phage derived peptide synthesized by solid phase method using a rapid and practical Fmoc strategy was found to specifically compete with bFGF for binding to its receptors, inhibit bFGF-stimulated cell proliferation by inducing cell cycle arrest, and block bFGF-induced activation of Erk1 and Erk2 kinase in B16-F10 melanoma cells. Importantly, treatment of melanoma-bearing mice with the synthetic peptide significantly suppressed tumor growth. The results demonstrate a strong anticancer activity of the isolated bFGFR-binding peptide (and its future derivatives), which may have great potential for cancer therapy. PMID- 24142483 TI - The potential role of genetically-modified pig mesenchymal stromal cells in xenotransplantation. AB - Mesenchymal stromal cells (MSCs) are known to have regenerative, anti inflammatory, and immunodulatory effects. There are extensive indications that pig MSCs function satisfactorily across species barriers. Pig MSCs might have considerable therapeutic potential, particularly in xenotransplantation, where they have several potential advantages. (i) pMSCs can be obtained from the specific organ- or cell-source donor pig or from an identical (cloned) pig. (ii) They are easy to obtain in large numbers, negating the need for prolonged ex vivo expansion. (iii) They can be obtained from genetically-engineered pigs, and the genetic modification can be related to the therapeutic goal of the MSCs. We have reviewed our own studies on MSCs from genetically-engineered pigs, and summarize them here. We have successfully harvested and cultured MSCs from wild-type and genetically-engineered pig bone marrow and adipose tissue. We have identified several pig (p)MSC surface markers (positive for CD29, CD44, CD73, CD105, CD166, and negative for CD31, CD45), have demonstrated their proliferation and differentiation (into adipocytes, osteoblasts, and chondroblasts), and evaluated their antigenicity and immune suppressive effects on human peripheral blood mononuclear cells and CD4(+)T cells. They have identical or very similar characteristics to MSCs from other mammals. Genetically-modified pMSCs are significantly less immunogenic than wild-type pMSCs, and downregulate the human T cell response to pig antigens as efficiently as do human MSCs. We hypothesized that pMSCs can immunomodulate human T cells through induction of apoptosis or anergy, or cause T cell phenotype switching with induction of regulatory T cells, but we could find no evidence for these mechanisms. However, pMSCs upregulated the expression of CD69 on human CD4(+) and CD8(+) T cells, the relevance of which is currently under investigation. We conclude that MSCs from genetically engineered pigs should continue to be investigated for their immunomodulatory (and regenerative and anti-inflammatory) effects in pig-to-nonhuman primate organ and cell transplantation models. PMID- 24142484 TI - Coupling to a glioblastoma-directed antibody potentiates antitumor activity of curcumin. AB - Current therapies for glioblastoma are largely palliative, involving surgical resection followed by chemotherapy and radiation therapy, which yield serious side effects and very rarely produce complete recovery. Curcumin, a food component, blocked brain tumor formation but failed to eliminate established brain tumors in vivo, probably because of its poor bioavailability. In the glioblastoma GL261 cells, it suppressed the tumor-promoting proteins NF-kappaB, P Akt1, vascular endothelial growth factor, cyclin D1 and BClXL and triggered cell death. Expression of exogenous p50 and p65 subunits of NF-kappaB conferred partial protection on transfected GL261 cells against curcumin insult, indicating that NF-kappaB played a key role in protecting glioblastoma cells. To enhance delivery, we coupled curcumin to the glioblastoma-specific CD68 antibody in a releasable form. This resulted in a 120-fold increase in its efficacy to eliminate GL261 cells. A very similar dose response was also obtained with human glioblastoma lines T98G and U87MG. GL261-implanted mice receiving intratumor infusions of the curcumin-CD68 adduct followed by tail-vein injections of solubilized curcumin displayed a fourfold to fivefold reduction in brain tumor load, survived longer, and about 10% of them lived beyond 100 days. Hematoxylin eosin staining of brain sections revealed a small scar tissue mass in the rescued mice, indicating adduct-mediated elimination of glioblastoma tumor. The tumor cells were strongly CD68+ and some cells in the tumor periphery were strongly positive for microglial Iba1, but weakly positive for CD68. This strategy of antibody targeting of curcumin to tumor comes with the promise of yielding a highly effective therapy for glioblastoma brain tumors. PMID- 24142485 TI - Methodology of fibroblast and mesenchymal stem cell coating of surgical meshes: a pilot analysis. AB - Coating of various synthetic, absorbable, and biologic meshes with mesenchymal stem cells (MSCs) and fibroblasts was analyzed qualitatively and quantitatively. Five hernia meshes-light weight monofilament polypropylene (Soft Mesh), polyester (Parietex-TET), polylactide composite (TIGR), heavy weight monofilament polypropylene (Marlex), and porcine dermal collagen (Strattice)-were coated with three cell lines: human dermal fibroblasts (HFs), rat kidney fibroblasts (NRKs), and rat MSCs. Cell densities were determined at different time points. Samples also underwent histology and transmission electron microscopic (TEM) analyses. It required HFs 3 weeks to cover the entire mesh, while only 2 weeks for NRKs and MSCs to do so. MSCs had no preference for any of the meshes and produced the highest cell densities on Parietex and TIGR. Substrate-preference accounted for the significantly lower fibroblast densities on TIGR than Parietex. Fibroblasts failed to coat Marlex. Strattice, which had the least surface area, generated comparable cell densities to Parietex. Both histology and TEM confirmed cell coating of mesh surface. Various prosthetics can be coated by certain cell strains. Both mesh composition and cell preference dramatically influence the coating process. This methodology provides foundation for novel avenues of modulation of host response to various modern synthetic and biologic meshes. PMID- 24142486 TI - The anatomy of the clavicle: a three-dimensional cadaveric study. AB - The clavicle has a complex osteologic structure that makes morphological analysis extremely difficult. A three-dimensional study was conducted to examine the anatomical variations and characteristics of the bone. Sixty-eight human cadaver clavicles were dissected, CAT-scanned, and reconstructed. An automated parameterization and correspondence shape analysis system was developed. A new length, designated as centerline (CL) length, was defined and measured. This length represents the true length of the clavicle. The endpoint length was measured as the distance between two endpoints. The width and curvature were measured in the axial (AX) and frontal (FR) plane and defined along the CL. Next gender and side characteristics and variations were examined. The mean CL length was 159.0 +/- 11.0 mm. The mean endpoint length was 149.4 +/- 10.3 mm, which was statistically significantly shorter than the CL. The male clavicle was significantly longer (166.8 +/- 7.3 mm vs. 151.0 +/- 8.2 mm), wider (14.6 +/- 1.5 mm vs. 12.7 +/- 1.3 mm lateral FR plane, 25.9 +/- 4.1 mm vs. 23.5 +/- 3.0 mm lateral AX plane and 24.7 +/- 2.8 mm vs. 22.8 +/- 2.8 mm medial AX plane), and more curved (10.8 +/- 2.8 mm vs. 8.6 +/- 2.3 mm medial and 10.5 +/- 3.3 mm vs. 9.1 +/- 2.5 mm lateral) than the female one. Left clavicles were significant longer (159.8 +/- 10.9 mm vs. 158.0 +/- 11.2 mm) than right clavicles. A novel three-dimensional system was developed, used and tested in order to explore the anatomical variations and characteristics of the human clavicle. This information, together with the automated system, can be applied to future clavicle populations and to the design of fixation plates for clavicle fractures. PMID- 24142487 TI - A case of carotid artery dissection after surgical repair of aortic dissection successfully treated with endovascular therapy using intravascular ultrasound. AB - A 71-year-old woman developed the dissection from right brachiocephalic trunk (BCT) to internal carotid artery 6 days after the operation of ascending aortic dissection. Since no improvement of symptoms was observed despite conservative therapy, we performed endovascular therapy (EVT). Although a balloon-expandable stent was implanted in the BCT to seal the entry point of the dissection, the true lumen of the carotid artery was still compressed. Thus, we covered the dissected lesion completely with multiple stents, and her neurological findings improved. This case demonstrates that EVT using multiple stents is an effective strategy to manage dissection of supra-aortic branches. PMID- 24142488 TI - Total bowel ischemia after carbon dioxide angiography in a patient with inferior mesenteric artery occlusion. AB - A 70-year-old man with a history of hypertension and chronic renal failure experienced claudication in his left leg. He was treated by endovascular stenting in his left leg. We used CO2 angiography to prevent contrast-induced nephropathy. After the procedure, livedo vasculitis and lactic acidosis developed. We diagnosed the patient with CO2-induced ischemic colitis, after which we changed his position and administered conservative therapy. Contrast-enhanced computed tomography showed total bowel ischemia and total occlusion at the ostium of the inferior mesenteric artery. This rare complication after CO2 angiography might be related to the atherosclerotic occlusion of the inferior mesenteric artery. PMID- 24142489 TI - Source, distribution, and health risk assessment of polycyclic aromatic hydrocarbons in urban street dust from Tianjin, China. AB - To better assess and understand potential health risk of urban residents exposed to urban street dust, the total concentration, sources, and distribution of 16 polycyclic aromatic hydrocarbons (PAHs) in 87 urban street dust samples from Tianjin as a Chinese megacity that has undergone rapid urbanization were investigated. In the meantime, potential sources of PAHs were identified using the principal component analysis (PCA), and the risk of residents' exposure to PAHs via urban street dust was calculated using the Incremental Lifetime Cancer Risk (ILCR) model. The results showed that the total PAHs (?PAHs) in urban street dust from Tianjin ranged from 538 MUg kg(-1) to 34.3 mg kg(-1), averaging 7.99 mg kg(-1). According to PCA, the two to three- and four to six-ring PAHs contributed 10.3 and 89.7 % of ?PAHs, respectively. The ratio of the sum of major combustion specific compounds (SigmaCOMB) / ?PAHs varied from 0.57 to 0.79, averaging 0.64. The ratio of Ant/(Ant + Phe) varied from 0.05 to 0.41, averaging 0.10; Fla/(Fla + Pyr) from 0.40 to 0.68, averaging 0.60; BaA/(BaA + Chry) from 0.29 to 0.51, averaging 0.38; and IcdP/(IcdP + BghiP) from 0.07 to 0.37, averaging 0.22. The biomass combustion, coal combustion, and traffic emission were the main sources of PAHs in urban street dust with the similar proportion. According to the ILCR model, the total cancer risk for children and adults was up to 2.55 * 10(-5) and 9.33 * 10(-5), respectively. PMID- 24142490 TI - A review of strategies to monitor water and sediment quality for a sustainability assessment of marine environment. AB - The basic aim of this work is (1) to review and present practically operational requirements for a sustainability assessment of marine environment, such as describing the monitoring process, research approaches, objectives, guidelines, and indicators and (2) to illustrate how physico-chemical and biological indicators can be practically applied, to assess water and sediment quality in marine and coastal environment. These indicators should meet defined criteria for practical usefulness, e.g. they should be simple to understand and apply to managers and scientists with different educational backgrounds. This review aimed to encapsulate that variability, recognizing that meaningful guidance should be flexible enough to accommodate the widely differing characteristics of marine ecosystems. PMID- 24142491 TI - The relevance of physicochemical and biological parameters for setting emission limit values for plants treating complex industrial wastewaters. AB - The influents of plants treating complex industrial wastewaters from third parties may contain a large variety of often unknown or unidentified potentially harmful substances. The conventional approach of assessing and regulating the effluents of these plants is to set emission limit values for a limited set of physicochemical parameters, such as heavy metals, biological oxygen demand, chemical oxygen demand and adsorbable organic halogen compounds. The objective of this study was to evaluate the relevance of physicochemical parameters for setting emission limit values for such plants based on a comparison of effluent analyses by physicochemical and biological assessment tools. The results show that physicochemical parameters alone are not sufficient to evaluate the effectiveness of the water treatment plants for removing hazardous compounds and to protect the environment. The introduction of toxicity limits and limits for the total bioaccumulation potential should be considered to supplement generic parameters such as chemical oxygen demand and adsorbable organic halogens. A recommendation is made to include toxicity screening as a technique to consider in the determination of best available techniques (BAT) during the upcoming revision of the BAT reference document for the waste treatment industries to provide a more rational basis in decisions on additional treatment steps. PMID- 24142493 TI - Autumn. PMID- 24142492 TI - Physical fitness training for stroke patients. AB - BACKGROUND: Levels of physical fitness are low after stroke. It is unknown whether improving physical fitness after stroke reduces disability. OBJECTIVES: To determine whether fitness training after stroke reduces death, dependence, and disability. The secondary aims were to determine the effects of training on physical fitness, mobility, physical function, quality of life, mood, and incidence of adverse events. SEARCH METHODS: We searched the Cochrane Stroke Group Trials Register (last searched January 2013), the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2012, Issue 12: searched January 2013), MEDLINE (1966 to January 2013), EMBASE (1980 to January 2013), CINAHL (1982 to January 2013), SPORTDiscus (1949 to January 2013), and five additional databases (January 2013). We also searched ongoing trials registers, handsearched relevant journals and conference proceedings, screened reference lists, and contacted experts in the field. SELECTION CRITERIA: Randomised trials comparing either cardiorespiratory training or resistance training, or both, with no intervention, a non-exercise intervention, or usual care in stroke survivors. DATA COLLECTION AND ANALYSIS: Two review authors independently selected trials, assessed quality, and extracted data. We analysed data using random-effects meta analyses. Diverse outcome measures limited the intended analyses. MAIN RESULTS: We included 45 trials, involving 2188 participants, which comprised cardiorespiratory (22 trials, 995 participants), resistance (eight trials, 275 participants), and mixed training interventions (15 trials, 918 participants). Nine deaths occurred before the end of the intervention and a further seven at the end of follow-up. No dependence data were reported. Diverse outcome measures made data pooling difficult. Global indices of disability show a tendency to improve after cardiorespiratory training (standardised mean difference (SMD) 0.37, 95% confidence interval (CI) 0.10 to 0.64; P = 0.007); benefits at follow up and after mixed training were unclear. There were insufficient data to assess the effects of resistance training.Cardiorespiratory training involving walking improved maximum walking speed (mean difference (MD) 7.37 metres per minute, 95% CI 3.70 to 11.03), preferred gait speed (MD 4.63 metres per minute, 95% CI 1.84 to 7.43), walking capacity (MD 26.99 metres per six minutes, 95% CI 9.13 to 44.84), and Berg Balance scores (MD 3.14, 95% CI 0.56 to 5.73) at the end of the intervention. Mixed training, involving walking, increased preferred walking speed (MD 4.54 metres per minute, 95% CI 0.95 to 8.14), walking capacity (MD 41.60 metres per six minutes, 95% CI 25.25 to 57.95), and also pooled balance scores but the evidence is weaker (SMD 0.26 95% CI 0.04 to, 0.49). Some mobility benefits also persisted at the end of follow-up. The variability and trial quality hampered the assessment of the reliability and generalisability of the observed results. AUTHORS' CONCLUSIONS: The effects of training on death and dependence after stroke are unclear. Cardiorespiratory training reduces disability after stroke and this may be mediated by improved mobility and balance. There is sufficient evidence to incorporate cardiorespiratory and mixed training, involving walking, within post-stroke rehabilitation programs to improve the speed and tolerance of walking; improvement in balance may also occur. There is insufficient evidence to support the use of resistance training. Further well-designed trials are needed to determine the optimal content of the exercise prescription and identify long-term benefits. PMID- 24142494 TI - Swiss society. PMID- 24142495 TI - How illness affects family members: a qualitative interview survey. AB - OBJECTIVE: Spillover effects of illness on family members can be substantial. The objective of this study was to identify the domains of family members' health and well-being that are affected when a relative has a chronic health condition. METHODS: Semi-structured telephone interviews were conducted in February 2012 with 49 individuals whose relatives had any of five chronic health conditions (arthritis, cancer, Alzheimer's disease/dementia, cerebral palsy, and depression), purposively sampled to include different relationships with the ill relative (parent, child, spouse). Subjects were queried on whether and how having an ill relative affected their health and well-being; they were also asked about their caregiving responsibilities and the relative's health. Interview data were analyzed using thematic analysis. RESULTS: Family members in our sample reported experiencing psychological and non-health effects from having an ill relative, and secondarily somatic effects. Effects on emotional health were most commonly reported as psychological spillover; non-health effects frequently included changes in daily activities and provision of caregiving. Spouses of patients reported the broadest range of spillover domains affected and adolescents of ill parents the fewest. Family members reported experiencing effects that were perceived as both positive and negative. CONCLUSIONS: Spillover of illness onto family members encompasses a wide range of domains of health and well-being, extending beyond those included in many existing health-related quality of life measures. Outcomes measurement efforts should be expanded to adequately capture these health and well-being outcomes for analysis, to ensure that the benefits of interventions are accurately estimated and conclusions are valid. PMID- 24142496 TI - New therapeutic alternatives for the management of dyslipidemia. AB - Hypercholesterolemia affects over 34 million adults in the United States and is a major cause of coronary heart disease (CHD). Conventional therapies, such as statins, have demonstrated their ability to improve clinical end points and decrease morbidity and mortality in patients with CHD. Lomitapide (Juxtapid((r))), mipomersen (Kynamro((r))), and icosapent (Vascepa((r))) are 3 novel agents approved by the US Food and Drug Administration in the past 2 years, which offer new lipid-lowering treatment options with unique pharmacology. PMID- 24142497 TI - Birth defects surveillance: epidemiology, health services research, public health, and prevention. PMID- 24142498 TI - Racial/ethnic disparities in timing of death during childhood among children with congenital heart defects. AB - BACKGROUND: Infants with congenital heart defects (CHD) have increased risk of morbidity and mortality. Little is known about racial/ethnic differences in timing of death during childhood. Our intent was to investigate racial/ethnic differences in mortality for CHDs during specific time periods in childhood. METHODS: Texas Birth Defect Registry data were used for a retrospective cohort study with 30,015 singleton infants with a CHD, born January 1, 1999, to December 31, 2007, to non-Hispanic (NH) white, NH-black, or Hispanic women. Texas Birth Defect Registry data were linked to Texas death records to ascertain death. Kaplan-Meier survival probabilities and multivariable Cox-proportional hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated. RESULTS: NH blacks and Hispanics with specific CHDs had increased mortality during the postneonatal period and early childhood. NH-blacks had increased postneonatal mortality compared with NH-whites for transposition of the great arteries (HR = 2.4; 95% CI, 1.5-4.0), pulmonary valve atresia without ventricular septal defect (HR = 4.1; 95% CI, 1.7-9.7), Ebstein's anomaly (HR = 8.6; 95 CI, 1.2-61.1), hypoplastic left heart syndrome (HR = 2.1; 95% CI, 1.2-3.7), coarctation of the aorta (HR = 2.1; 95% CI, 1.2-3.5), ventricular septal defect (HR = 2.1; 95% CI, 1.6-2.8), and atrial septal defect (HR = 1.4; 95% CI, 1.1-1.8). Hispanics had increased postneonatal mortality risk for tetralogy of Fallot (HR = 2.0; 95% CI, 1.1-3.5). Racial/ethnic increases in mortality risk were also observed during infancy and childhood. CONCLUSION: Racial/ethnic differences in mortality were most notably observed during the postneonatal period and early childhood. Future studies should assess factors associated with this disparity in mortality risk for infants with CHDs. PMID- 24142499 TI - Estimate of the potential impact of folic acid fortification of corn masa flour on the prevention of neural tube defects. AB - BACKGROUND: Hispanics in the US have a higher prevalence of neural tube defect (NTD) -affected pregnancies than non-Hispanic whites, and lower median total folic acid (FA) intake. FA fortification of corn masa flour (CMF) is a policy level intervention for NTD prevention; however, the impact on NTD prevalence has not been estimated. METHODS: We developed a model to estimate the percentage reduction in prevalence of spina bifida and anencephaly (NTDs) that could occur with FA fortification of CMF. Model inputs included estimates of the percentage reduction in United States NTD prevalence attributed to FA fortification of enriched cereal grain products (1995-1996 vs. 1998-2002), the increase in median FA intake after enriched cereal grain product fortification, and the estimated increase in median FA intake that could occur with CMF fortification at the same level as enriched cereal grain products (140 MUg/100 g). We used Monte Carlo simulation to quantify uncertainty. We stratified analyses by racial/ethnic group and rounded results to the nearest 10. RESULTS: We estimated CMF fortification could prevent 30 Hispanic infants from having spina bifida (95% uncertainty interval: 0, 80) and 10 infants from having anencephaly (95% uncertainty interval: 0, 40) annually. The estimated impact among non-Hispanic whites and blacks was smaller. CONCLUSION: CMF fortification with FA could prevent from 0 to 120 infants, with the most likely value of approximately 40, from having spina bifida or anencephaly among Hispanics, the population most likely to benefit from the proposed intervention. While this estimated reduction is unlikely to be discernible using current birth defect surveillance methods, it still suggests an important benefit to the target population. PMID- 24142500 TI - Too much of a good thing: evolutionary perspectives on infant formula fortification in the United States and its effects on infant health. AB - Recently, there has been considerable debate regarding the appropriate amount of iron fortification for commercial infant formula. Globally, there is considerable variation in formula iron content, from 4 to 12 mg iron/L. However, how much fortification is necessary is unclear. Human milk is low in iron (0.2-0.5 mg/L), with the majority of infant iron stores accumulated during gestation. Over the first few months of life, these stores are depleted in breastfeeding infants. This decline has been previously largely perceived as pathological; it may be instead an adaptive mechanism to minimize iron availability to pathogens coinciding with complementary feeding. Many of the pathogens involved in infantile illnesses require iron for growth and replication. By reducing infant iron stores at the onset of complementary feeding, infant physiology may limit its availability to these pathogens, decreasing frequency and severity of infection. This adaptive strategy for iron regulation during development is undermined by the excess dietary iron commonly found in infant formula, both the iron that can be incorporated into the body and the excess iron that will be excreted in feces. Some of this excess iron may promote the growth of pathogenic, iron requiring bacteria disrupting synergistic microflora commonly found in breastfed infants. Evolutionarily, mothers who produced milk with less iron and infants who had decreased iron stores at the time of weaning may have been more likely to survive the transition to solid foods by having limited iron available for pathogens. Contemporary fortification practices may undermine these adaptive mechanisms and increase infant illness risk. PMID- 24142501 TI - Second trimester fetal neurosonography: reconstructing cerebral midline anatomy and anomalies using a novel three-dimensional ultrasound technique. AB - OBJECTIVE: To describe the application of a novel 3D ultrasound reconstructing technique (OMNIVIEW) that may facilitate the evaluation of cerebral midline structures at the second trimester anatomy scan. METHODS: Fetal cerebral midline structures from 300 consecutive normal low-risk pregnant women were studied prospectively by 2D and 3D ultrasound between 19-23 weeks of gestation. All the newborn infants underwent pediatric follow-up and were considered normal up to 2 years of life. In addition, five confirmed pathologic cases were evaluated and the abnormal features using this technique are described in this clinical series. RESULTS: Off-line volume data sets displaying the corpus callosum and the cerebellar vermis anatomy were accurately reconstructed in 98.5% and 96% of cases from sagittal and axial planes, respectively. For pathological cases, an agreement rate of 0.96 and 0.91 for midsagittal and axial planes, respectively, was observed. CONCLUSIONS: This study demonstrates the feasibility of including 3D ultrasound as an adjunct technique for the evaluation of cerebral midline structures in the second trimester fetus. Future prospective studies will be necessary to evaluate if the application of this novel 3D reconstructing technique as a step forward following 2D second trimester screening scan will improve the prenatal detection of cerebral midline anomalies in the low-risk pregnant population. PMID- 24142502 TI - An alternative approach in endocrine pathology research: MALDI-IMS in papillary thyroid carcinoma. PMID- 24142503 TI - The FAK scaffold inhibitor C4 disrupts FAK-VEGFR-3 signaling and inhibits pancreatic cancer growth. AB - Even with successful surgical resection and perioperative chemotherapy and radiation, pancreatic ductal adenocarcinoma (PDA) has a high incidence of recurrence. Tumor cell survival depends on activation of signaling pathways that suppress the apoptotic stimuli of invasion and metastasis. Focal adhesion kinase (FAK) is a critical signaling molecule that has been implicated in tumor cell survival, invasion and metastasis. We have previously shown that FAK and vascular endothelial growth factor receptor 3 (VEGFR-3) are overexpressed in cancer cells and physically interact to confer a significant survival advantage. We subsequently identified a novel small molecule inhibitor C4 that targeted the VEGFR-3-FAK site of interaction. In this study, we have shown that C4 disrupted the FAK-VEGFR-3 complexes in PDA cells. C4 treatment caused dose-dependent dephosphorylation and inactivation of the VEGFR-3 and FAK, reduction in cell viability and proliferation, cell cycle arrest and apoptosis in PDA cells. C4 increased the sensitivity of tumor cells to gemcitabine chemotherapy in vitro that lead to apoptosis at nanomolar concentrations of both drugs. C4 reduced tumor growth in vivo in subcutaneous and orthotopic murine models of PDA. The drug alone at low dose, decreased tumor growth; however, concomitant administration with low dose of gemcitabine had significant synergistic effect and led to 70% tumor reduction. Combination of C4 with gemcitabine had a prolonged cytostatic effect on tumor growth after treatment withdrawal. Finally, we report an anecdotal case of stage IV pancreatic cancer treated with gemcitabine in combination with C4 that showed a significant clinical response in primary tumor and complete clinical response in liver metastasis over an eight month period. Taken together, these results demonstrate that targeting the scaffolding function of FAK with a small-molecule FAK-VEGFR-3 inhibitor can be an effective therapeutic strategy against PDA. PMID- 24142504 TI - Progression of carcinogen-induced fibrosarcomas is associated with the accumulation of naive CD4+ T cells via blood vessels and lymphatics. AB - The tumor microenvironment comprises newly formed blood and lymphatic vessels which shape the influx, retention and departure of lymphocytes within the tumor mass. Thus, by influencing the intratumoral composition of lymphocytes, these vessels affect the manner in which the adaptive immune system responds to the tumor, either promoting or impairing effective antitumor immunity. In our study, we utilized a mouse model of carcinogen-induced fibrosarcoma to examine the composition of tumor-infiltrating lymphocytes during tumor progression. In particular, we sought to determine whether CD4(+) Foxp3(+) regulatory T cells (Tregs) became enriched during tumor progression thereby contributing to tumor driven immunosuppression. This was not the case as the proportion of Tregs and effector CD4(+) T cells actually declined within the tumor owing to the unexpected accumulation of naive T cells. However, we found no evidence for antigen-driven migration of these T cells or for their participation in an antitumor immune response. Our data support the notion that lymphocytes can enter tumors via aberrantly formed blood and lymphatic vessels. Such findings suggest that targeting both the tumor vasculature and lymphatics will alter the balance of lymphocyte subpopulations that enter the tumor mass. A consideration of this aspect of tumor immunology may be critical to the success of solid cancer immunotherapies. PMID- 24142513 TI - Informational needs of patients with metastatic breast cancer: what questions do they ask, and are physicians answering them? AB - In the setting of breast oncology consultations, we sought to understand communication patterns between patients with advanced breast cancer and their oncologists during visits with Decision Support Services. This is a descriptive study analyzing themes and their frequencies of premeditated question lists of patients with metastatic breast cancer. We identified topics physicians most commonly discussed among themes previously found, documenting questions patients with metastatic breast cancer prepare for physician consultations and oncologists' response. Inclusion criteria were as follows: diagnosis of metastatic breast cancer, completion of a question list before meeting with an oncologist, and receipt of a summary of the consultation. We identified 59 women with metastatic breast cancer who received both documents. We reviewed the question lists and consultation summaries of these patients. Of the 59 patients whose documents we reviewed, patients most often asked about prognosis (38), symptom management (31), clinical trials (43), and quality of life (38). Physicians answered questions about prognosis infrequently (37% of the time); other questions that were answered more than commonly are the following: symptom management (81%), clinical trials (79%), and quality of life (66%). Breast cancer patients have many questions regarding their disease, its treatment, and symptoms, which were facilitated in this setting by Decision Support Services. Question lists may be insufficient to bridge the divide between physicians and patient information needs in the setting of metastatic breast cancer, particularly regarding prognosis. Patients may need additional assistance defining question lists, and physicians may benefit from training in communication, particularly regarding discussions of prognosis and end of life. PMID- 24142505 TI - Bridging the gap between functional and anatomical features of cortico-cerebellar circuits using meta-analytic connectivity modeling. AB - Theories positing that the cerebellum contributes to cognitive as well as motor control are driven by two sources of information: (1) studies highlighting connections between the cerebellum and both prefrontal and motor territories, (2) functional neuroimaging studies demonstrating cerebellar activations evoked during the performance of both cognitive and motor tasks. However, almost no studies to date have combined these two sources of information and investigated cortico-cerebellar connectivity during task performance. Through the use of a novel neuroimaging tool (Meta-Analytic Connectivity Modelling) we demonstrate for the first time that cortico-cerebellar connectivity patterns seen in anatomical studies and resting fMRI are also present during task performance. Consistent with human and nonhuman primate anatomical studies cerebellar lobules Crus I and II were significantly coactivated with prefrontal and parietal cortices during task performance, whilst lobules HV, HVI, HVIIb, and HVIII were significantly coactivated with the pre- and postcentral gyrus. An analysis of the behavioral domains showed that these circuits were driven by distinct tasks. Prefrontal parietal-cerebellar circuits were more active during cognitive and emotion tasks whilst motor-cerebellar circuits were more active during action execution tasks. These results highlight the separation of prefrontal and motor cortico-cerebellar loops during task performance, and further demonstrate that activity within these circuits relates to distinct functions. PMID- 24142514 TI - Applications of modern sensors and wireless technology in effective wound management. AB - The management of chronic wounds has emerged as a major health care challenge during the 21st century consuming, significant portions of health care budgets. Chronic wounds such as diabetic foot ulcers, leg ulcers, and pressure sores have a significant negative impact on the quality of life of affected individuals. Covering wounds with suitable dressings facilitates the healing process and is common practice in wound management plans. However, standard dressings do not provide insights into the status of the wound underneath. Parameters such as moisture, pressure, temperature and pH inside the dressings are indicative of the healing rate, infection, and wound healing phase. But owing to the lack of information available from within the dressings, these are often changed to inspect the wound, disturbing the normal healing process of wounds in addition to causing pain to the patient. Sensors embedded in the dressing would provide clinicians and nurses with important information that would aid in wound care decision making, improve patient comfort, and reduce the frequency of dressing changes. The potential benefits of this enabling technology would be seen in terms of a reduction in hospitalization time and health care cost. Modern sensing technology along with wireless radio frequency communication technology is poised to make significant advances in wound management. This review discusses issues related to the design and implementation of sensor technology and telemetry systems both incorporated in wound dressings to devise an automated wound monitoring technology, and also surveys the literature available on current sensor and wireless telemetry systems. PMID- 24142515 TI - Disruption of N-linked glycosylation promotes proteasomal degradation of the human ATP-binding cassette transporter ABCA3. AB - The lipid transport protein, ABCA3, expressed in alveolar type 2 (AT2) cells, is critical for surfactant homeostasis. The first luminal loop of ABCA3 contains three putative N-linked glycosylation sites at residues 53, 124, and 140. A common cotranslational modification, N-linked glycosylation, is critical for the proper expression of glycoproteins by enhancing folding, trafficking, and stability through augmentation of the endoplasmic reticulum (ER) folding cycle. To understand its role in ABCA3 biosynthesis, we utilized EGFP-tagged fusion constructs with either wild-type or mutant ABCA3 cDNAs that contained glutamine for asparagine substitutions at the putative glycosylation motifs. In A549 cells, inhibition of glycosylation by tunicamycin increased the electrophoretic mobility (Mr) and reduced the expression level of wild-type ABCA3 in a dose-dependent manner. Fluorescence imaging of transiently transfected A549 or primary human AT2 cells showed that although single motif mutants exhibited a vesicular distribution pattern similar to wild-type ABCA3, mutation of N124 and N140 residues resulted in a shift toward an ER-predominant distribution. By immunoblotting, the N53 mutation exhibited no effect on either the Mr or ABCA3 expression level. In contrast, substitutions at N124 or N140, as well a N124/N140 double mutation, resulted in increased electrophoretic mobility indicative of a glycosylation deficiency accompanied by reduced overall expression levels. Diminished steady-state levels of glycan-deficient ABCA3 isoforms were rescued by treatment with the proteasome inhibitor MG132. These results suggest that cotranslational N-linked glycosylation at N124 and N140 is critical for ABCA3 stability, and its disruption results in protein destabilization and proteasomal degradation. PMID- 24142516 TI - TACE in perinatal mouse lung epithelial cells promotes lung saccular formation. AB - Tumor necrosis factor-alpha converting enzyme (TACE) is a cell membrane sheddase, expressed in both developmental lung epithelia and mesenchyme. Global abrogation of TACE results in neonatal lethality and multiple organ developmental abnormalities, including dysplastic lung. To further define the roles of TACE in regulating lung development, lung epithelial and/or mesenchymal specific TACE conditional knockout mice were generated. Blockade of TACE function in developing lung epithelial cells caused reduced saccular formation, decreased cell proliferation, and reduced mid-distal lung epithelial cell differentiation. In contrast, mesenchymal TACE knockout did not have any phenotypic change in developing lung. Simultaneous abrogation of TACE in both lung epithelial and mesenchymal cells did not result in a more severe lung abnormality. Interestingly, these lung-specific TACE conditional knockout mice were not neonatal lethal, and their lung structures were essentially normal after alveolarization. In addition, TACE conditional knockout in developing cardiomyocytes resulted in noncompaction of ventricular myocardium, as seen in TACE conventional knockout mice. However, these mice were also not neonatal lethal. In conclusion, lung epithelial TACE is essential for promoting fetal lung saccular formation, but not postnatal lung alveolarization in mice. Because the developmental abnormality of either lung or heart induced by TACE deficiency does not directly lead to neonatal lethality, the neonatal death of TACE conventional knockout mice is likely a result of synergistic effects of multiple organ abnormalities. PMID- 24142518 TI - Methemoglobin-induced signaling and chemokine responses in human alveolar epithelial cells. AB - Diffuse alveolar hemorrhage is characterized by the presence of red blood cells and free hemoglobin in the alveoli and complicates a number of serious medical and surgical lung conditions including the pulmonary vasculitides and acute respiratory distress syndrome. In this study we investigated the hypothesis that exposure of human alveolar epithelial cells to hemoglobin and its breakdown products regulates chemokine release via iron- and oxidant-mediated activation of the transcription factor NF-kappaB. Methemoglobin alone stimulated the release of IL-8 and MCP-1 from A549 cells via activation of the NF-kappaB pathway; additionally, IL-8 required ERK activation and MCP-1 required JNK activation. Neither antioxidants nor iron chelators and knockdown of ferritin heavy and light chains affected these responses, indicating that iron and reactive oxygen species are not involved in the response of alveolar epithelial cells to methemoglobin. Incubation of primary cultures of human alveolar type 2 cells with methemoglobin resulted in a similar pattern of chemokine release and signaling pathway activation. In summary, we have shown for the first time that methemoglobin induced chemokine release from human lung epithelial cells independent of iron- and redox-mediated signaling involving the activation of the NF-kappaB and MAPK pathways. Decompartmentalization of hemoglobin may be a significant proinflammatory stimulus in a variety of lung diseases. PMID- 24142519 TI - The Witschi Hypothesis revisited after 35 years: genetic proof from SP-C BRICHOS domain mutations. AB - Over 35 years ago, Wanda Haschek and Hanspeter Witschi published a theory for the pathogenesis of lung fibrosis that dared to challenge the longstanding view of lung fibrosis as an "inflammatory disease." On the basis of considerable experimental evidence, they proposed that lung fibrosis was initiated and propagated by microfoci of epithelial damage that, if unrepaired, upset the normal epithelial-fibroblast balance to create profibrotic microenvironments, without any obligatory contribution of "inflammatory" cells. Unfortunately, this theory was largely overlooked for many years. In the meantime, the repeated failure of attempts to treat idiopathic pulmonary fibrosis with anti-inflammatory regimens has led some investigators to revive the theory referred to, in decades past, as "The Witschi Hypothesis." This manuscript briefly reviews more recent evidence in support of the "Severity of Epithelial Injury" Hypothesis proposed by Haschek and Witschi. More important, it offers the updated viewpoint that mutations in the BRICHOS domain of surfactant protein C, which cause interstitial lung disease and induce cell death specifically in lung epithelial cells, in effect provide genetic proof that the Witschi Hypothesis is indeed the correct theory to explain the pathogenesis of fibrosis in the lungs. PMID- 24142520 TI - Endothelial progenitor cells in patients with chronic obstructive pulmonary disease. AB - The pathogenesis of chronic obstructive pulmonary disease is not fully understood. The objective of this study was to compare circulating endothelial progenitor cells in patients with chronic obstructive pulmonary disease to age, sex, and cigarette smoking matched healthy controls. Patients with chronic obstructive pulmonary disease (n = 37) and healthy controls (n = 19) were matched by age, sex, and smoking status. Circulating hematopoietic progenitor cells (CD34(+) or CD133(+) mononuclear cells) and endothelial progenitor cells (CD34(+)KDR(+) or CD34(+)CD133(+)KDR(+) mononuclear cells) were quantified by flow cytometry. Endothelial cell-colony forming units from peripheral blood mononuclear cells were quantified in vitro and phenotypic analysis carried out using immunocytochemistry. Patients with chronic obstructive pulmonary disease had more circulating mononuclear cells compared with controls (8.4 +/- 0.6 vs. 5.9 +/- 0.4 * 10(9) cells/l; P = 0.02). CD34(+) hematopoietic progenitor cells were reduced as a proportion of mononuclear cells in patients compared with controls (0.99 +/- 0.12 vs. 1.9 +/- 0.12%; P = 0.02); however, there were no differences in the absolute number of CD34(+), CD34(+)KDR(+), or CD34(+)CD133(+)KDR(+) cells (P > 0.05 for all). Endothelial cell-colony forming units were increased in patients with chronic obstructive pulmonary disease compared with controls (13.7 +/- 5.2 vs. 2.7 +/- 0.9 colonies; P = 0.048). In contrast to previous studies, the number of circulating progenitor cells was not reduced in patients with chronic obstructive pulmonary disease compared with carefully matched controls. It seems unlikely that circulating endothelial progenitor cells or failure of angiogenesis plays a central role in the development of emphysema. PMID- 24142521 TI - Pegylated liposomal doxorubicin for first-line treatment of epithelial ovarian cancer. AB - BACKGROUND: Epithelial ovarian cancer (EOC) is often diagnosed at an advanced stage, requiring primary cytoreductive surgery and combination chemotherapy for its first-line management. Currently, the recommended standard first-line chemotherapy is platinum-based, usually consisting of carboplatin and paclitaxel (PAC/carbo). Pegylated liposomal doxorubicin (PLD) is an improved formulation of doxorubicin that is associated with fewer and less severe side effects than are seen with non-modified doxorubicin. In combination with carboplatin, PLD has recently been shown to improve progression-free survival compared with PAC/carbo in women with relapsed, platinum-sensitive EOC. It is therefore important to know whether any survival benefit can be attributed to PLD when it is used in the first-line setting. OBJECTIVES: To evaluate the role of PLD, alone or in combination, in first-line chemotherapy for women with EOC. SEARCH METHODS: We searched The Cochrane Gynaecological Cancer Group's Trial Register, the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE and EMBASE from January 1990 to February 2013. In addition, we searched online trial registries for ongoing trials and abstracts of studies presented at relevant scientific meetings from 2000 onwards. SELECTION CRITERIA: We included all randomised controlled trials (RCTs) that compared PLD alone or in combination with other agent/s (e.g. carboplatin) versus other agent/s for first-line chemotherapy in women with EOC who may or may not have undergone primary cytoreductive surgery. DATA COLLECTION AND ANALYSIS: Two review authors independently selected trials, extracted data and assessed the risk of bias for each included trial. We obtained updated trial data when possible. MAIN RESULTS: We included two large trials. One trial compared three-weekly PLD and carboplatin (PLD/carbo) with PAC/carbo. The other trial included four experimental arms, one of which was PLD plus PAC/carbo, that were compared with the standard PAC/carbo regimen. We did not combine results of these two trials in the meta-analysis. We considered the two studies to be at low risk of bias.For the comparison PLD/carbo versus PAC/carbo (820 women; stages Ic to IV), no statistically significant differences in progression-free survival (PFS) (hazard ratio [HR] 1.01, 95% confidence interval [CI] 0.85 to 1.19) or overall survival (OS) (HR 0.94, 95% CI 0.78 to 1.13) were noted between study arms. Severe anaemia (risk ratio [RR] 2.74, 95% CI 1.54 to 4.88) and thrombocytopenia (RR 8.09, 95% CI 3.93 to 16.67) were significantly more common with PLD/carbo, whereas alopecia (RR 0.09, 95% CI 0.06 to 0.14) and severe neurotoxicity (RR 0.09, 95% CI 0.01 to 0.66) were significantly more common with PAC/carbo. Quality of life scores were not significantly different.For the comparison PLD/PAC/carbo versus PAC/carbo (1726 women; stage III/IV), it is important to note that PLD was given for alternate cycles only (i.e. every 6 weeks). No statistically significant difference in PFS (HR 0.98, 95% CI 0.88 to 1.09) or OS (HR 0.95, 95% CI 0.84 to 1.08) between these two treatment arms was reported. However, women in the triplet arm experienced significantly more severe haematological adverse events (anaemia, thrombocytopenia, neutropenia and febrile neutropenia) compared with those given standard treatment.No RCTs evaluated single-agent PLD for first-line treatment of EOC. AUTHORS' CONCLUSIONS: PLD/carbo is a reasonable alternative to PAC/carbo for the first-line treatment of EOC. Although three-weekly PLD/carbo may be associated with increased dose delays and discontinuations compared with the standard PAC/carbo regimen, it might be more acceptable to women who wish to avoid alopecia or those at high risk of neurotoxicity. No survival benefits appear to be associated with the alternating triplet regimen, and the additional toxicity associated with adding PLD to PAC/carbo limits further investigation. Further studies are needed to establish the safest, most effective PLD/carbo regimen for newly diagnosed disease. PMID- 24142522 TI - Abstracts of the 2013 Annual Scientific Meeting of the Irish Thoracic Society (ITS). November 15-16, 2013. Derry, Ireland. PMID- 24142523 TI - Adherence to preventive exercises and self-reported swallowing outcomes in post radiation head and neck cancer patients. AB - BACKGROUND: To reduce the risk of long-term swallowing complications after radiation, swallowing exercises may be helpful. Both the rate of adherence to swallowing exercises and its impact on future swallowing function are unknown. METHODS: In all, 109 patients with oropharyngeal cancer beginning radiation were tracked for 2 years to determine adherence to swallowing exercises. Participants completed the MD Anderson Dysphagia Inventory (MDADI) 1-2 years after treatment, to assess self-reported swallowing function. Adherence, demographics, tumor, and treatment variables were multivariably regressed onto the MDADI physical subscale score. RESULTS: In accord with speech pathologist documentation, 13% of the participants were fully adherent and 32% were partially adherent. Adherence was associated with the Physical MDADI Subscale score in the multivariate model (p = .01). CONCLUSIONS: The majority of patients with head and neck cancer are nonadherent to swallowing exercise regimens and may benefit from supportive care strategies to optimize their adherence. PMID- 24142517 TI - Airway smooth muscle in airway reactivity and remodeling: what have we learned? AB - It is now established that airway smooth muscle (ASM) has roles in determining airway structure and function, well beyond that as the major contractile element. Indeed, changes in ASM function are central to the manifestation of allergic, inflammatory, and fibrotic airway diseases in both children and adults, as well as to airway responses to local and environmental exposures. Emerging evidence points to novel signaling mechanisms within ASM cells of different species that serve to control diverse features, including 1) [Ca(2+)]i contractility and relaxation, 2) cell proliferation and apoptosis, 3) production and modulation of extracellular components, and 4) release of pro- vs. anti-inflammatory mediators and factors that regulate immunity as well as the function of other airway cell types, such as epithelium, fibroblasts, and nerves. These diverse effects of ASM "activity" result in modulation of bronchoconstriction vs. bronchodilation relevant to airway hyperresponsiveness, airway thickening, and fibrosis that influence compliance. This perspective highlights recent discoveries that reveal the central role of ASM in this regard and helps set the stage for future research toward understanding the pathways regulating ASM and, in turn, the influence of ASM on airway structure and function. Such exploration is key to development of novel therapeutic strategies that influence the pathophysiology of diseases such as asthma, chronic obstructive pulmonary disease, and pulmonary fibrosis. PMID- 24142525 TI - Penile pearls: a westward traveling phenomenon. PMID- 24142524 TI - Activation of sirtuin 1 attenuates cerebral ventricular streptozotocin-induced tau hyperphosphorylation and cognitive injuries in rat hippocampi. AB - Patients with diabetes in the aging population are at high risk of Alzheimer's disease (AD), and reduction of sirtuin 1 (SIRT1) activity occurs simultaneously with the accumulation of hyperphosphorylated tau in the AD-affected brain. It is not clear, however, whether SIRT1 is a suitable molecular target for the treatment of AD. Here, we employed a rat model of brain insulin resistance with intracerebroventricular injection of streptozotocin (ICV-STZ; 3 mg/kg, twice with an interval of 48 h). The ICV-STZ-treated rats were administrated with resveratrol (RSV; SIRT1-specific activator) or a vehicle via intraperitoneal injection for 8 weeks (30 mg/kg, once per day). In ICV-STZ-treated rats, the levels of phosphorylated tau and phosphorylated extracellular signal-regulated kinases 1 and 2 (ERK1/2) at the hippocampi were increased significantly, whereas SIRT1 activity was decreased without change of its expression level. The capacity of spatial memory was also significantly lower in ICV-STZ-treated rats compared with age-matched control. RSV, a specific activator of SIRT1, which reversed the ICV-STZ-induced decrease in SIRT1 activity, increases in ERK1/2 phosphorylation, tau phosphorylation, and impairment of cognitive capability in rats. In conclusion, SIRT1 protects hippocampus neurons from tau hyperphosphorylation and prevents cognitive impairment induced by ICV-STZ brain insulin resistance with decreased hippocampus ERK1/2 activity. PMID- 24142527 TI - Association between tumor necrosis factor-alpha rs1800629 polymorphism and risk of gastric cancer: a meta-analysis. AB - Gastric cancer is mainly initiated by inflammation and chronic superficial gastritis, and tumor necrosis factor-alpha (TNF-alpha) is an inflammatory cytokine which plays an important role in the inflammation. TNF-alpha rs1800629 G/A polymorphism was proposed to be associated with gastric cancer risk, but previous studies on Caucasians reported conflicting results. We performed a meta analysis to comprehensively assess the association between TNF-alpha rs1800629 polymorphism and gastric cancer risk in Caucasians. The pooled odds ratio (OR) with 95% confidence interval (95% CI) was calculated to assess the association. Eleven case-control studies with 7,427 subjects were finally included into the meta-analysis. Overall, TNF-alpha rs1800629 polymorphism was significantly associated with the increased risk of gastric cancer under four genetic comparison models (A versus G: OR = 1.32, 95% CI 1.12-1.56, P = 0.001; AA versus GG: OR = 1.76, 95% CI 1.37-2.26, P < 0.001; AA versus GG/GA: OR = 1.62, 95% CI 1.27-2.07, P < 0.001; AA/GA versus GG: OR = 1.35, 95% CI 1.14-1.60, P = 0.001). Meta-analysis of those studies with high quality showed that TNF-alpha rs1800629 polymorphism was still significantly associated with the increased risk of gastric cancer under four genetic comparison models. There was no risk of publication bias in the meta-analysis. The meta-analysis suggests that TNF-alpha rs1800629 polymorphism is associated with the increased risk of gastric cancer in Caucasians. PMID- 24142528 TI - Meta-analysis of the association between NQO1 Pro187Ser polymorphism and colorectal cancer in Asians. AB - There were a number of studies performed to assess the association between NQO1 Pro187Ser polymorphism and colorectal cancer risk in Asians, but no consensus was available up to now. We conducted a meta-analysis to assess the association between NQO1 Pro187Ser polymorphism and colorectal cancer risk in Asians. Case control studies investigating the association between NQO1 Pro187Ser polymorphism and colorectal cancer risk in Asians were searched in Pubmed and Wanfang databases. Pooled odds ratio (OR) and 95% confidence interval (95% CI) was calculated. Finally, seven studies involving a total of 2,051 cases and 2,798 controls met the inclusion criteria and were included into the meta-analysis. Overall, there was an obvious association between NQO1 Pro187Ser polymorphism and colorectal cancer risk in Asians (Ser versus Pro: OR = 1.42, 95% CI 1.08-1.87, P = 0.013; SerSer versus ProPro: OR = 1.86, 95% CI 1.08-3.19, P = 0.024; SerSer/ProSer versus ProPro: OR = 1.61, 95% CI 1.10-2.35, P = 0.014; SerSer versus ProPro/ProSer: OR = 1.46, 95% CI 1.02-2.10, P = 0.041). There was low risk of publication bias in the meta-analysis. This meta-analysis suggests that there is an obvious association between NQO1 Pro187Ser polymorphism and colorectal cancer risk in Asians. PMID- 24142529 TI - NQO1 C609T polymorphism is associated with esophageal cancer risk among Chinese: a meta-analysis. AB - NAD(P)H: quinone oxidoreductase 1 (NQO1) C609T gene polymorphism has been reported to influence the risk for esophageal cancer (EC) in many studies; however, the results remain controversial and ambiguous. We therefore carried out a meta-analysis of published case-control studies to investigate the association between NQO1 C609T polymorphism and EC susceptibility. Electronic searches were conducted on links between this variant and EC in several databases. Odds ratios (ORs) and 95% confidence intervals (CIs) for homozygous, dominant model, recessive model and allele were calculated to estimate the strength of associations in fixed and random effect models. Heterogeneity and publication bias were also assessed. A total of 11 case-control studies were identified, including1,619 cases and 2,101 controls. C allele was associated with a decreased susceptibility risk of EC compared with the T allele among Chinese (OR = 0.70; 95% CI = 0.59-0.84). The contrast of homozygotes and the recessive and dominant models produced the same pattern of results as the allele contrast. Our pooled data suggest a significant association exists between NQO1 C609T polymorphism and EC among Chinese. PMID- 24142530 TI - High expression of APAF-1 elevates erythroid apoptosis in iron overload myelodysplastic syndrome. AB - Apoptotic protease-activating factor 1 (APAF-1) is a central component of the intrinsic pathway of apoptosis. Our study aims at searching the role of APAF-1 in iron overload myelodysplastic syndrome (MDS). Erythroid apoptosis rate, mRNA expression levels of APAF-1, and caspase-9 activity were determined by flow cytometry, quantitative real-time PCR, and colorimetric assay in MDS patients, respectively. In addition, K562 and MDS-L cell lines were incubated with different concentrations of ferric ammonium citrate (FAC) or ferric ammonium citrate + desferrioxamine (FAC + DFO) in vitro to observe the alteration in erythrocyte apoptosis rate, APAF-1 mRNA, and protein expression levels. Moreover, as control, erythroid apoptosis rate and APAF-1 mRNA expression were detected after silencing APAF-1 expression by endoribonuclease-prepared small interfering RNAs (esiRNAs) in K562 and MDS-L cell lines. Both erythroid apoptosis rate and APAF-1 mRNA expression of the iron overload (IO) group were significantly higher than those of the non-IO group (P < 0.001 and P < 0.001). There is a significant difference of caspase-9 activity between the IO group and the non-IO group (P < 0.001). Erythroid apoptosis rate and APAF-1 mRNA expression of K562 and MDS-L cell lines significantly elevated after FAC incubation in different concentrations (P < 0.001 and P < 0.001 for K562; P < 0.001 and P < 0.001 for MDS L), while erythroid apoptosis rate and APAF-1 mRNA expression in the FAC + DFO group declined (P < 0.001 and P < 0.001 for K562; P < 0.001 and P < 0.001 for MDS L). After silencing of APAF-1 expression with specific esiRNAs, erythroid apoptosis rate and APAF-1 mRNA expression of K562 and MDS-L cell lines markedly decreased (P < 0.001 and P < 0.001 for K562; P < 0.001 and P < 0.001 for MDS-L). APAF-1 plays an important role in iron-induced erythroid apoptosis increase in MDS. PMID- 24142531 TI - Efficacy of nimotuzumab plus gemcitabine usage as first-line treatment in patients with advanced pancreatic cancer. AB - Advanced pancreatic cancer patients have poor prognosis and scarcely respond to conventional therapies. Clinical trials support the use of molecular-targeted therapy against epidermal growth factor receptor (EGFR) signaling. The objective of the current study was to evaluate the contribution of a monoclonal antibody against EGFR, nimotuzumab, to standard gemcitabine therapy. Patients with unresectable locally advanced or metastatic pancreatic adenocarcinoma were assigned to receive gemcitabine plus nimotuzumab. The primary end point was overall survival, whereas the secondary end points included progression-free survival, objective response, and adverse side effects. A total of 18 eligible patients were accrued between December 2007 and July 2010. The disease control rate, calculated as the sum of complete response, partial response, and stable disease, was 55.6%. The median overall survival time was 9.29 months (95% CI, 5.499 to 13.072). The median progression-free survival was 3.71 months (95% CI, 2.526 to 4.902), and the 1-year survival rate was 38.9%. Of all the patients, 88.8% had at least one adverse side effect; however, no grade 4 adverse side effect was reported. Nimotuzumab as a high-purity humanized monoclonal antibody with favorable safety profile, its value in the treatment of pancreatic cancer along with gemcitabine, particularly in the comprehensive treatment of advanced pancreatic cancer, is appealing for further prospective randomized large-scale clinical trials. PMID- 24142532 TI - Clinical significance of serum hepatocyte growth factor (HGF) levels in hepatocellular carcinoma. AB - Hepatocellular carcinoma (HCC) is the commonest primary malignant cancer of the liver in the world. This study was conducted to investigate the serum levels of hepatocyte growth factor (HGF)in HCC patients and the relationship with tumor progression and known prognostic parameters. Fifty-four patients with HCC were investigated. Pretreatment HGF levels were employed the quantitative sandwich enzyme immunoassay technique (ELISA). Age and sex matched 20 healthy controls were included in the analysis. The median age of the patients was 60 years (range 36-77 years); where males consistituted of majority of the group (88.8%). All of patients had cirrhotic history. Fourty-six percent (n = 25) of patients had Child Pugh Score A, 30% (n = 16) had Score B or C. All of the patients were treated with local therapies but none of them received sorafenib. The baseline serum HGF levels were significantly higher in patients with HCC than in the control group (p < 0.001). Male patients had higher serum HGF levels compared with female patients (p = 0.01). Serum HGF levels were significantly higher in the patients with elevated serum ALT levels than others with normal serum ALT levels (p = 0.05). Poor performance status (p < 0.001), viral etiology of cirrhosis (p = 0.03), larger tumor size (p = 0.01), lower serum hemogloblin levels (p = 0.03), and not be treated for HCC (p = 0.001) related to worse survival. However, serum HGF did not have significantly adverse effect on survival (p = 0.58). Despite serum HGF levels were found diagnostic value, serum HGF levels had no prognostic value in patients with HCC. PMID- 24142533 TI - Reconfigurable topography for rapid solution processing of transparent conductors. AB - Cost-effective materials for transparent conducting electrodes are essential for many devices used in clean energy production and consumer electronics. Here we report a technique for non-lithographic patterning of silver nanowires on flexible substrates from solution via microcontact transfer printing using donor substrates with reconfigurable topography. This approach is a highly scalable fabrication strategy for high performance transparent conductors. PMID- 24142534 TI - Human perceptual decision making: disentangling task onset and stimulus onset. AB - The left dorsolateral prefrontal cortex (ldlPFC) has been highlighted as a key actor in human perceptual decision-making (PDM): It is theorized to support decision-formation independently of stimulus type or motor response. PDM studies however generally confound stimulus onset and task onset: when the to-be recognized stimulus is presented, subjects know that a stimulus is shown and can set up processing resources-even when they do not know which stimulus is shown. We hypothesized that the ldlPFC might be involved in task preparation rather than decision-formation. To test this, we asked participants to report whether sequences of noisy images contained a face or a house within an experimental design that decorrelates stimulus and task onset. Decision-related processes should yield a sustained response during the task, whereas preparation-related areas should yield transient responses at its beginning. The results show that the brain activation pattern at task onset is strikingly similar to that observed in previous PDM studies. In particular, they contradict the idea that ldlPFC forms an abstract decision and suggest instead that its activation reflects preparation for the upcoming task. We further investigated the role of the fusiform face areas and parahippocampal place areas which are thought to be face and house detectors, respectively, that feed their signals to higher level decision areas. The response patterns within these areas suggest that this interpretation is unlikely and that the decisions about the presence of a face or a house in a noisy image might instead already be computed within these areas without requiring higher-order areas. PMID- 24142535 TI - Non-genomic estrogen/estrogen receptor alpha promotes cellular malignancy of immature ovarian teratoma in vitro. AB - Malignant immature ovarian teratomas (IOTs) most often occur in women of reproductive age. It is unclear, however, what roles estrogenic signaling plays in the development of IOT. In this study, we examined whether estrogen receptors (ERalpha and beta) promote the cellular malignancy of IOT. Estradiol (E2), PPT (propylpyrazole), and DPN (diarylpropionitrile) (ERalpha- and beta-specific agonists, respectively), as well as ERalpha- or ERbeta-specific short hairpin (sh)RNA were applied to PA-1 cells, a well-characterized IOT cell line. Cellular tumorigenic characteristics, for example, cell migration/invasion, expression of the cancer stem/progenitor cell marker CD133, and evidence for epithelial mesenchymal transition (EMT) were examined. In PA-1 cells that expressed ERalpha and ERbeta, we found that ERalpha promoted cell migration and invasion. We also found that E2/ERalpha signaling altered cell behavior through non-classical transactivation function. Our data show non-genomic E2/ERalpha activations of focal adhesion kinase-Ras homolog gene family member A (FAK-RhoA) and ERK governed cell mobility capacity. Moreover, E2/ERalpha signaling induces EMT and overexpression of CD133 through upregulation micro-RNA 21 (miR21; IOT stem/progenitor promoter), and ERK phosphorylations. Furthermore, E2/ERalpha signaling triggers a positive feedback regulatory loop within miR21 and ERK. At last, expression levels of ERalpha, CD133, and EMT markers in IOT tissue samples were examined by immunohistochemistry. We found that cytosolic ERalpha was co expressed with CD133 and mesenchymal cell markers but not epithelial cell markers. In conclusion, estrogenic signals exert malignant transformation capacity of cancer cells, exclusively through non-genomic regulation in female germ cell tumors. PMID- 24142536 TI - FOXO in aging: did evolutionary diversification of FOXO function distract it from prolonging life? AB - In this paper we contrast the simple role of FOXO in the seemingly non-aging Hydra with its more diversified function in multicellular eukaryotes that manifest aging and limited life spans. From this comparison we develop the concept that, whilst once devoted to life-prolonging cell-renewal (in Hydra), evolutionary accumulation of coupled functionality in FOXO has since 'distracted' it from this role. Seen in this light, aging may not be the direct cost of competing functions, such as reproduction or growth, but the result of a shift in emphasis in a protein, which is accompanied by advantages such as greater organismal complexity and adaptability, but also disadvantages such as reduced regeneration capacity. Studying the role of FOXO in non-aging organisms might, therefore, illuminate the path to extend life span in aging organisms. PMID- 24142537 TI - Trepanation in South-Central Peru during the early late intermediate period (ca. AD 1000-1250). AB - This study evaluates trepanations from five well-contextualized prehistoric sites in the south-central highlands of Andahuaylas, Peru. The emergence of trepanation in this region coincides with the collapse of the Wari Empire, ca. ad 1000. Thirty-two individuals from Andahuaylas, AMS radiocarbon dated to the early Late Intermediate Period (ca. ad 1000-1250), were found to have 45 total trepanations. Various surgical techniques were being employed concurrently throughout the region. Scraping trepanations evinced the highest survival rate; circular grooving, drilling and boring, and linear cutting were far less successful. Evidence of perioperative procedures like hair shaving, poultice application, and possible cranioplasty use aimed to ensure the survival of a trepanation recipient. Postmortem trepanations, also present in Andahuaylas, were likely executed on corpses as a means of better understanding cranial anatomy and improving techniques. Similarities in trepanation patterns throughout the region attest to common motivations to engage in surgery. Although moderate physical head trauma seems to be the impetus for intervention in many cases of trepanation, other motivations included physiological and possibly psychosomatic factors. Nevertheless, treatment was not for everyone. In Andahuaylas, trepanations were withheld from subadults, females, and those individuals who practiced cranial modification. PMID- 24142538 TI - Micro-CT and PET analysis of bone regeneration induced by biodegradable scaffolds as carriers for dental pulp stem cells in a rat model of calvarial "critical size" defect: Preliminary data. AB - Bone regeneration strategies in dentistry utilize biodegradable scaffolds seeded with stem cells able to induce bone formation. However, data on regeneration capacity of these tissue engineering constructs are still deficient. In this study micro-Computed tomography (micro-CT) and positron emission tomography (PET) analyses were used to investigate bone regeneration induced by two scaffolds [Granular deproteinized bovine bone (GDPB) and Beta-tricalcium phosphate (beta TCP)] used alone or in combination with dental pulp stem cells (DPSC) in a tissue engineered construct implanted in a rat critical calvarial defect. Bone mineral density (BMD) and standard uptake value (SUV) of tracer incorporation were measured after 2, 4, 8, and 12 weeks post-implant. The results showed that: (1) GDPB implants were mostly well positioned, as compared to beta-TCP; (2) GDPB induced higher BMD and SUV values within the cranial defect as compared to beta TCP, either alone or in combination with stem cells; (3) addition of DPSC to the grafts did not significantly induce an increase in BMD and SUV values as compared to the scaffolds grafted alone, although a small tendency to increase was observed. Thus our study demonstrates that GDPB, when used to fill critical calvarial defects, induces a greater percentage of bone formation as compared to beta-TCP. Moreover, this study shows that addition of DPSC to pre-wetted scaffolds has the potential to ameliorate bone regeneration process, although the set of optimal conditions requires further investigation. PMID- 24142539 TI - Pre-pregnancy care and pregnancy outcomes in type 1 diabetes mellitus: a comparison of continuous subcutaneous insulin infusion and multiple daily injection therapy. AB - BACKGROUND: Pre-pregnancy care improves pregnancy outcomes in type 1 diabetes mellitus (T1DM). Continuous subcutaneous insulin infusion (CSII) therapy and multiple daily injection (MDI) therapy can both be used to achieve glycaemic targets, but few data are available to compare their efficacy in pre-pregnancy care. AIM: To compare MDI and CSII in pre-pregnancy care in T1DM. METHODS: Retrospective database review of women with T1DM attending the Dublin Diabetes in Pregnancy Centre. RESULTS: 464 women with T1DM (40 treated with CSII) were included. Women attending for pre-pregnancy care had lower HbA1c levels at booking to antenatal services [52 +/- 10 mmol/mol (6.9 +/- 0.9 %) vs. 62 +/- 16 mmol/mol (7.8 +/- 1.5 %), p < 0.001], and booked at an earlier gestation (6 +/- 2 vs. 8 +/- 6 weeks, p < 0.001). In those who attended for pre-pregnancy care, the CSII group had lower HbA1c levels at booking than those using MDI [48 +/- 8 mmol/mol (6.5 +/- 0.7 %) vs. 53 +/- 10 mmol/mol (7.0 +/- 0.9 %), p = 0.03]. Gestational age at delivery and birth weight did not differ between groups. Caesarean section rates were associated with CSII use (p < 0.001), duration of diabetes (p = 0.002), and parity (p = 0.006). Nulliparous women using CSII with a longer history of diabetes were more likely to deliver by Caesarean section. There was no perinatal mortality. CONCLUSIONS: Pre-pregnancy care delivered by a specialist multi-disciplinary team effectively reduces HbA1c levels peri conception. CSII use results in lower HbA1c levels in pre-pregnancy care in selected individuals and should be considered in women with T1DM planning pregnancy. PMID- 24142540 TI - Echographic risk index and cerebral ischemic brain lesions in patients randomized to stenting versus endarterectomy for symptomatic carotid artery stenosis. AB - PURPOSE: It remains to be determined whether the impact of plaque characteristics on procedural risks differs between carotid artery stenting (CAS) and endarterectomy (CEA). We studied whether quantitative assessment of carotid plaque echolucency on ultrasound predicts the risk of embolism during CAS or CEA. MATERIALS AND METHODS: In 50 consecutive patients with symptomatic carotid stenosis randomized to CAS (n = 26) or CEA (n = 24) in the International Carotid Stenting Study (ICSS), semi-automated grayscale measurement of carotid plaques on baseline ultrasound was performed. We determined the grayscale median (GSM), percentage of echolucent plaque area, and a previously defined echographic risk index (ERI) calculated with the echolucent area and degree of stenosis. Brain MRI including diffusion-weighted imaging (DWI) was performed within 7 days before and 3 days after treatment. The primary outcome was the presence of at least 1 new hyperintense DWI lesion (DWI+) after treatment. RESULTS: In the CAS group, DWI+ patients (n = 18) had a significantly higher ERI at baseline (mean 0.11 +/- 0.12) than patients without new lesions (n = 8; mean 0.03 +/- 0.01; p = 0.012). GSM (mean 26.7 +/- 18.7 versus 34.3 +/- 8.0, p = 0.16) and echolucent plaque area (mean 42.8 +/- 21.1 versus 31.2 +/- 8.2, p = 0.054) did not differ significantly. In the CEA group, there were no differences in plaque echogenity measurements between patients with (n = 2) and without DWI lesions (n = 22). CONCLUSION: Patients with echolucent plaques causing severe narrowing are at increased risk for cerebral embolism during CAS. Quantitative ultrasound plaque analysis, with ERI in particular, may add to clinical variables in identifying patients at risk for procedural stroke with CAS, but larger studies with clinical endpoints are needed. PMID- 24142541 TI - On/Off-switchable zipper-like bioelectronics on a graphene interface. AB - An on/off-switchable graphene-based zipper-like interface is architectured for efficient bioelectrocatalysis. The graphene interface transduces a temperature input signal into structural changes of the membrane, resulting in the amplification of electrochemical signals and their transformation into the gated transport of molecules through the membrane. PMID- 24142542 TI - Expression of MT2 receptor in patients with gastric adenocarcinoma and its relationship with clinicopathological features. AB - BACKGROUND: Gastric cancer accounts 8% of the total cancer cases and 10% of total cancer deaths worldwide. The indoleamine N-acetyl-5-methoxytryptamine, better known as melatonin, is the principal hormone produced by the pineal gland. Recently, it has shown some anticancer role in some malignancies such as breast and colon cancer; also, some of its protective roles in the GI tract are as free radical scavenger and as antimitogenic and apoptotic agents. Based on the anticancer effects of melatonin and wide distribution of this neurohormone in the GI tract and some proposed physiologic and pharmacologic roles for this neurohormone, this study is initially scheduled to determine the expression of melatonin receptor MT2 in tissue samples of adenocarcinoma cancer patients. METHODS: For this aim, a total of 30 gastric adenocarcinoma patients and 30 normal individuals were selected and examined for MT2 gene expression by real time PCR. RESULTS: Our results have shown interestingly high expression for MT2 receptor in cancer and marginal cancer tissues compared with normal people. CONCLUSIONS: According to our results, it is concluded that for the first time, the expression of MT2 receptor in gastric adenocarcinoma tissues which was in parallel with breast and colon cancer studies and high expression of this receptor in the marginal tissues indicate refractory mechanism which shows the defending role of melatonin in the GI system. Our experiments has not shown any relationship between MT2 receptor expression and grade and clinicopathological features of gastric tumor, so we cannot conclude any relationship between this receptor expression and progression of the tumor, although this expression can be considered as an etiology. PMID- 24142543 TI - Inhibitory effect of chemical constituents from Artemisia scoparia Waldst. et Kit. on triglyceride accumulation in 3T3-L1 cells and nitric oxide production in RAW 264.7 cells. AB - We investigated the anti-obesity effect of the aerial part of Artemisia scoparia Waldst. et Kit. (Compositae). An 80 % aqueous EtOH extract of the aerial part inhibited triglyceride (TG) accumulation and the nitric oxide (NO) production activity. A new chromane derivative was isolated from the aerial part of A. scoparia Waldst. et Kit. along with 18 known compounds. The structure of the new chromane, scopariachromane (1), was elucidated by spectroscopic analyses. The inhibitory effects of the compounds on TG accumulation activity were examined. Among these, cirsiliol (11) inhibited TG accumulation in 3T3-L1 preadipocytes. Jaceosidin (12) inhibited NO production in a murine macrophage-like cell line (RAW 264.7). These results indicate that the 80 % aqueous EtOH extract and compounds isolated from the aerial part of A. scoparia Waldst. et Kit. may improve obesity-related insulin resistance. PMID- 24142544 TI - Linking the solution viscosity of an IgG2 monoclonal antibody to its structure as a function of pH and temperature. AB - Although the viscosity of concentrated antibody solutions has been the focus of many recent studies, less attention has been concentrated on how changes in protein structure impact viscosity. This study examines viscosity profiles of an immunoglobulin G (IgG) 2 monoclonal antibody at 150 mg/mL as a function of temperature and pH. Although the structure of the antibody at pH 4.0-7.0 was comparable at lower temperatures as measured by second derivative UV absorbance and Fourier transform infrared spectroscopy, differences in 8-anilino-1 naphthalene sulfonate (ANS) fluorescence intensity indicated small structural alterations as a function of pH. Below the structural transition onset temperature, the viscosity profiles were pH dependent and linearly correlated with fluorescence intensity, and followed semilogarithmic behavior as a function of temperature. The transitions of the viscosity profiles correlated well with the major structure transitions at a protein concentration of 150 mg/mL. The viscosity correlated particularly well with ANS fluorescence intensity at 0.2 mg/mL below and above the structural transition temperatures. These results suggest: (1) ANS can be an important measure of the overall structure and (2) hydrophobic interactions and charge-charge interactions are the two major physical factors that contribute collectively to the high viscosity of concentrated IgG solutions. PMID- 24142545 TI - Evaluation of the TMPRSS2:ERG fusion for the detection of prostate cancer: a systematic review and meta-analysis. AB - The diagnostic value of TMPRSS2:ERG detection in patients with prostate cancer is controversial. We performed a meta-analysis to consolidate current evidence regarding the use of TMPRSS2:ERG detection assays to diagnose prostate cancers. PubMed, Web of knowledge and other databases were searched for relevant original articles published until July 30, 2013. Methodological quality was assessed using the Quality Assessment of Diagnostic Accuracy Studies (QUADAS) tool. Studies that investigated the presence of TMPRSS2:ERG in the body fluid, needle biopsy and prostatectomy tissue of patients with prostate cancer were identified and reviewed. Sensitivities, specificities, and positive likelihood ratios (LR+) and negative likelihood ratios (LR-) of TMPRSS2:ERG detection in individual studies were calculated and meta-analyzed by random effects model. Thirty-two studies met the inclusion criteria for the meta-analysis. Overall sensitivity of TMPRSS2:ERG detection assays was 47.4% (95% CI, 45.5-49.3%); specificity, LR+, and LR- was 92.6% (95% CI, 91.5-93.7%), 8.94 (95% CI, 5.65-14.13) and 0.49 (95% CI, 0.43 0.55). The pooled sensitivity and specificity in the body fluid subgroup was 44.7% (95% CI, 41.5-47.9 %) and 85.8% (95% CI, 83.5-87.8%), respectively. The pooled sensitivity and specificity based on the reverse transcripts PCR was 49.0% (95% CI, 45.9-52.1%) and 90.2% (95% CI, 88.2-92.0%), respectively. TMPRSS2:ERG may not be used as first-line screening test. However, due to the high specificity, TMPRSS2: ERG detection maybe can serve as a quick and noninvasive method for confirming prostate cancer diagnosis. PMID- 24142546 TI - Association of MDR1 G2677T polymorphism and leukemia risk: evidence from a meta analysis. AB - In the light of the relationship between the MDR1 G2677T polymorphism and the risk of leukemia remains inclusive or controversial. For better understanding of the effect of MDR1 G2677T polymorphism on leukemia risk, we performed a meta analysis. Eligible studies were identified through a search of electronic databases such as PubMed, Excerpta Medica Database (Embase), Cochrane Library, and Chinese Biomedical Literature Database (CBM). The association between the MDR1 G2677T polymorphism and leukemia risk was conducted by odds ratios (ORs) and 95% confidence intervals (95% CI). A total of seven publications including eight studies with 1,229 cases and 1,097 controls were included in the meta-analysis. There was no association between MDR1 G2677T polymorphism and leukemia risk in all of five models in overall populations (T vs. G: OR = 1.00, 95% CI = 0.88 1.12, P = 0.914; TT vs. GG: OR = 0.97, 95% CI = 0.75-1.26, P = 0.812; TG vs. GG: OR = 1.00, 95% CI = 0.92-1.08, P = 0.939; TT vs. TG/GG: OR = 0.98, 95% CI = 0.67 1.43, P = 0.906; TT/TG vs. GG: OR = 1.00, 95% CI = 0.95-1.06, P = 0.994). However, the significant association was found in others (Table 2) under the homozygote model (TT vs. GG: OR = 0.68, 95% CI = 0.48-0.94, P = 0.020) and recessive model (TT vs. TG/GG: OR = 0.63, 95% CI = 0.43-0.92, P = 0.016). In the subgroup analysis, according to the type of leukemia, significant association was found between MDR1 G2677T polymorphism and myeloid leukemia but not lymphoblastic leukemia (TT vs. GG: OR = 0.66, 95% CI = 0.46-0.95, P = 0.026; TT vs. TG/GG: OR = 0.56, 95% CI = 0.38-0.84, P = 0.005). The results suggested that there was no association between MDR1 G2677T polymorphism and leukemia risk in overall populations, but significant association was found in others populations (Asians and Africans), and myeloid leukemia indicated that G2677T polymorphism might be a protective factor in the susceptibility of myeloid leukemia and in Asians and Africans. PMID- 24142547 TI - Developmental changes in resting and functional cerebral blood flow and their relationship to the BOLD response. AB - Our understanding of cerebral blood flow (CBF) in the healthy developing brain has been limited due to the invasiveness of methods historically available for CBF measurement. Clinically based studies using radioactive tracers with children have focused on resting state CBF. Yet potential age-related changes in flow during stimulation may affect the blood oxygenation level dependent (BOLD) response used to investigate cognitive neurodevelopment. This study used noninvasive arterial spin labeling magnetic resonance imaging to compare resting state and stimulus-driven CBF between typically developing children 8 years of age, 12 years of age, and adults. Further, we acquired functional CBF and BOLD images simultaneously to examine their relationship during sensory stimulation. Analyses revealed age-related CBF differences during rest; the youngest group showed greater CBF than 12-year-olds or adults. During stimulation of the auditory cortex, younger children also showed a greater absolute increase in CBF than adults. However, the magnitude of CBF response above baseline was comparable between groups. Similarly, the amplitude of the BOLD response was stable across age. The combination of the 8 year olds' elevated CBF, both at rest and in response to stimulation, without elevation in the BOLD response suggests that additional physiological factors that also play a role in the BOLD effect, such as metabolic processes that are also elevated in this period, may offset the increased CBF in these children. Thus, CBF measurements reveal maturational differences in the hemodynamics underlying the BOLD effect in children despite the resemblance of the BOLD response between children and adults. PMID- 24142548 TI - Functional analysis of NPHS1 mutations in Japanese patients. AB - BACKGROUND: Many mutations in the NPHS1 gene were detected among patients with congenital nephrotic syndrome. Functional analysis of those mutations was done with a stable-expression cell line. Nevertheless, establishing such a cell line is time-consuming. METHODS AND RESULTS: We established an easier method using automatic counting software for functional analysis with transient-transfection cells rather than a stable-expression cell line. We demonstrated maltrafficking to the plasma membrane of abnormal nephrin for immunostaining on transient expression cells by comparison without Triton X (detecting proteins on the cell membrane only) and with Triton X (detecting proteins both on the cell membrane and inside the cell cytoplasm). We obtained relevant results with data obtained previously using a stable-expression cell line. Furthermore, we conducted functional analysis of NPHS1 mutations in Japanese patients with congenital nephrotic syndrome using this simple method, which revealed that all pathogenic mutations impaired trafficking to the protein plasma membrane. CONCLUSIONS: Functional analysis using transient-expression cells with automatic counting software was useful to demonstrate maltrafficking to the plasma membrane of a protein. All pathogenic mutations detected in Japanese patients impaired trafficking to the protein plasma membrane. PMID- 24142549 TI - MSN anti-cancer nanomedicines: chemotherapy enhancement, overcoming of drug resistance, and metastasis inhibition. AB - In the anti-cancer war, there are three main obstacles resulting in high mortality and recurrence rate of cancers: the severe toxic side effect of anti cancer drugs to normal tissues due to the lack of tumor-selectivity, the multi drug resistance (MDR) to free chemotherapeutic drugs and the deadly metastases of cancer cells. The development of state-of-art nanomedicines based on mesoporous silica nanoparticles (MSNs) is expected to overcome the above three main obstacles. In the view of the fast development of anti-cancer strategy, this review highlights the most recent advances of MSN anti-cancer nanomedicines in enhancing chemotherapeutic efficacy, overcoming the MDR and inhibiting metastasis. Furthermore, we give an outlook of the future development of MSNs based anti-cancer nanomedicines, and propose several innovative and forward looking anti-cancer strategies, including tumor tissue-cell-nuclear successionally targeted drug delivery strategy, tumor cell-selective nuclear targeted drug delivery strategy, multi-targeting and multi-drug strategy, chemo /radio-/photodynamic-/ultrasound-/thermo-combined multi-modal therapy by virtue of functionalized hollow/rattle-structured MSNs. PMID- 24142553 TI - Abstracts of the 64th Annual Meeting of the American Association for the Study of Liver Diseases: the Liver Meeting 2013. November 1-2, 2013. Washington, D.C., USA. PMID- 24142550 TI - Pharmacology of antiplatelet agents. AB - Pharmacotherapies with agents that inhibit platelet function have proven to be effective in the treatment of acute coronary syndromes, and in the prevention of complications during and after percutaneous coronary intervention. Because of multiple synergetic pathways of platelet activation and their close interplay with coagulation, current treatment strategies are based not only on platelet inhibition, but also on the attenuation of procoagulant activity, inhibition of thrombin generation, and enhancement of clot dissolution. Current strategies can be broadly categorized as anticoagulants, antiplatelet agents, and fibrinolytics. This review focuses on the pharmacology of current antiplatelet therapy primarily targeting the inhibition of the enzyme cyclooxygenase 1, the P2Y12 receptor, the glycoprotein IIb/IIIa receptor, and protease-activated receptor 1. PMID- 24142560 TI - Decreased apoptosis and persistence of the common nephric duct during the development of an aberrant vesicoureteral junction in Dlg1 gene-targeted mice. AB - Congenital anomalies of the kidney and urinary tract occur at a frequency of 1 in 500 live births in humans. Mutant mice null for Dlg1 (Dlg1(-/-) mice), a membrane associated guanylate kinase containing PDZ domains, exhibit various urogenital malformations, including hypoplasia of the kidney and ureter, megaureter, hydronephrosis, and aplasia of the seminal vesicle and the vagina. The common nephric duct (CND) is a distal part of the Wolffian duct between the ureteric branch and the opening to the urogenital sinus, and normally disappears by embryonic day (E) 12.5 by a downward shift of the ureteric branch. Although retardation of the disappearance of the CND is apparent during urogenital development in Dlg1(-/-) mice, its pathogenesis and prognosis are unclear. In the present study, we found a decrease in apoptotic cells in the CND epithelium in Dlg1(-/-) mice at E11.5. Cell proliferation did not change. Additionally, histological observation of the development of the ureteral orifice indicated that the CND remained at E15.5 and was widely open to the vesical lumen in Dlg1( /-) mice, in contrast to the complete disappearance of the CND and a narrow ureteric orifice in control mice. The dilatation of the vesicoureteral junction remained at E18.5. Opening of the vesicoureteral junction is known to cause vesicoureteral reflux and subsequent megaureter and hydronephrosis. Therefore, our present observation demonstrates that lack of the Dlg1 gene induces a decrease in apoptotic epithelial cell death and the persistence of the CND, which result in a dysfunctional vesicoureteral junction and cause megaureter or hydronephrosis through vesicoureteral reflux. PMID- 24142561 TI - Determinants of vascular and cardiac baroreflex sensitivity values in a random population sample. AB - The arterial baroreflex regulates blood pressure by modifying heart rate and systemic vascular resistance. Baroreflex sensitivity is expressed as the relation between changes in blood pressure and the resulting changes in reciprocal values of heart rate (cardBRS) and in reciprocal values of vascular resistance (vascBRS). This study investigated determinants of vascBRS and cardBRS and their relationship in a random population sample. Continuous noninvasive arterial pressure was analyzed in 105 adults (43 males) with a median age of 45 (range 18 95) years and body mass index of 24.5 (range 18.1-39.1) kg m-2. Systolic and diastolic blood pressures were 130 (range 95-205) and 80 (range 47-141) mmHg, and heart rate was 66 (range 42-109) beats min-1. Pulse contour (CO-trek)-determined vascular resistance was 1.37 (range 0.60-7.75) mmHg s ml-1. The results of vascBRS and cardBRS were log-transformed; linear regression analysis revealed that age, resistance-1, systolic and diastolic blood pressures were major determinants of log(vascBRS) explaining 30.5 % of the variance. Determinants of log(cardBRS) were age, body mass index, heart rate, systolic and diastolic blood pressures, explaining 70.4 % of the variance. Thus, some established determinants of cardBRS were not correlated with vascBRS. There was no correlation between log(cardBRS) and log(vascBRS) after correction for age, supporting that vascBRS is an independent description of baroreflex regulation. These findings suggest that vascBRS and cardBRS report different modalities of cardiovascular autonomic function. PMID- 24142562 TI - The effect of precordial lead displacement on ECG morphology. AB - Inaccurate electrode placement and differences in inter-individual human anatomies can lead to misinterpretation of ECG examination. The aim of the study was to investigate the effect of precordial electrodes displacement on morphology of the ECG signal in a group of 60 patients with diagnosed cardiac disease. Shapes of ECG signals recorded from precordial leads were compared with signals interpolated at the points located at a distance up to 5 cm from lead location. Shape differences of the QRS and ST-T-U complexes were quantified using the distribution function method, correlation coefficient, root-mean-square error (RMSE), and normalized RMSE. The relative variability (RV) index was calculated to quantify inter-individual variability. ECG morphology changes were prominent in all shape parameters beyond 2 cm distance to precordial leads. Lead V2 was the most sensitive to displacement errors, followed by leads V3, V1, and V4, for which the direction of electrodes displacement plays a key role. No visible changes in ECG morphology were observed in leads V5 and V6, only scaling effect of signal amplitude. The RV ranged from 0.639 to 0.989. Distortions in ECG tracings increase with the distance from precordial lead, which are specific to chosen electrode, direction of displacement, and for ECG segment selected for calculations. PMID- 24142563 TI - School nurse intention to pursue higher education. AB - In 2011, the Institute of Medicine recommended that 80% of the nurses possess a minimum of a bachelor of science in nursing by 2020 and double the number of doctorally prepared nurses. This has prompted a significant number of registered nurses to advance their educational level. School nurses in Louisiana are not required to have a bachelor's degree. In many states, the bachelor's degree is required for all school nurses, and many school nurses are prepared at the masters' and doctoral levels. The purpose of this study was to examine the intention of Louisiana school nurses to pursue higher education in nursing. A survey was distributed to all members of the Louisiana School Nurses Organization, and results indicated that 65% of the participants were motivated to return to school. Incentives and barriers to pursuing higher education were identified, and strategies for overcoming these barriers were proposed. PMID- 24142564 TI - Association of parental awareness of using schoolbags with musculoskeletal symptoms and carrying habits of schoolchildren. AB - The association between parental awareness of using schoolbags and the occurrence of musculoskeletal symptoms and carrying habits of children was investigated in a cross-sectional study in Tabriz, Iran. Data on 454 students aged 11-14 years and their parents (n = 358) were analyzed. The awareness of the recommended weight limit, appropriate method of carrying schoolbags, and schoolbag strap adjustments was generally low among the respondents. A higher parental awareness of the schoolbag weight was associated with a lower prevalence of upper back and shoulder complaints among children and carrying loads less than 10% of their body weight. The findings suggest that parental awareness should have a more prominent role in changing the schoolbag carrying habits of children and particularly in reducing the weight of loads carried by them. This highlights the need to incorporate guidelines and recommendations into practice to ensure that the health and safety of schoolchildren are not compromised when using schoolbags. PMID- 24142565 TI - Hospitalist experiences, practice, opinions, and knowledge regarding peripherally inserted central catheters: results of a national survey. AB - BACKGROUND: A Michigan survey found variation in hospitalist-reported experience, practice, opinions, and knowledge related to peripherally inserted central catheters (PICCs). Whether these findings reflect a national trend is unknown. OBJECTIVE: To investigate self-reported PICC practice among adult hospitalists in the United States. METHODS: Society of Hospital Medicine-administered, anonymous, Web-based survey of practicing, adult, non-Michigan hospitalists. RESULTS: Of the 2112 hospitalists who were sent an electronic invitation, 381 completed the online survey (18%). Eighty-six percent of hospitalists reported having placed a PICC solely for venous access (vs specific indications such as long-term antibiotics or parenteral nutrition). Eighty-two percent reported having cared for a patient who specifically requested a PICC. Only 25% of hospitalists reported examining PICCs for evidence of external problems, whereas 57% admitted to having, at least once, forgotten about the presence of a PICC. Only 9% of respondents knew that PICC tip verification was performed primarily to prevent venous thromboembolism. Finally, 42% of participants indicated that 10% to 25% of PICCs placed in their hospitals might be inappropriately placed and/or avoidable. CONCLUSIONS: This national survey highlights several potential opportunities to improve hospitalist PICC practices. A research agenda dedicated to this issue is necessary to improve patient safety and hospital-based practice. PMID- 24142566 TI - When water does not clear the smut from the smoke. AB - Water-pipe (shisha) smoking is increasingly popular among young people in Europe and North America. The proponents claim that smoking water-pipe is much 'cleaner' than cigarettes. Although, a recent analysis of toxicant yields during 1-2 h water-pipe smoking resulted comparable to 100-200 cigarettes. We report a case of a 25-year-old patient with elevated haemoglobin, impaired concentration and reduced physical performance. Molecular investigations for JAK2 mutations and BCR ABL fusion transcripts were negative and the arterial blood gas analysis revealed an elevated carboxyhaemoglobin of 6.1%. In a follow-up visit, the patient disclosed excessive shisha smoking. Secondary polycythaemia was diagnosed caused by chronic carbon monoxide poisoning. After cessation of shisha smoking all blood values returned to normal ranges within 6 weeks. Owing to the increasing popularity of water-pipe smoking and the anticipated health risks, our report should help to enhance awareness and advocate more information in tobacco prevention programmes on its potential toxicities. PMID- 24142567 TI - MEN2B syndrome presenting as an acute respiratory emergency. AB - An 18-year-old girl presented to the emergency department with a history of noisy breathing and breathlessness progressively increasing for few days. The patient had stridor and tachypnoea. She was tall with a long thin face, wrist sign and high-arched palate suggestive of marfanoid features. X-ray of the neck revealed critical tracheal narrowing. Emergency tracheostomy was performed as a lifesaving procedure. Non-contrast CT neck revealed extratracheal compression by a mass surrounding it. Contrast-enhanced CT scan of the neck revealed heterogeneous mass arising from the right lobe of the thyroid and tracheal deviation with narrowing. Fine-needle aspiration cytology of the mass revealed medullary carcinoma of the thyroid, positive for calcitonin. Calcitonin levels were raised. Apart from the marfanoid features she had localised swellings over the lips, lower eyelid and the lateral aspects of the tongue, clinically suggestive of neuromas. A clinical diagnosis of multiple endocrine neoplasia type 2B syndrome was made. The patient underwent total thyroidectomy with central lymphnode dissection. This case highlights an unusual presentation of a rare disease. PMID- 24142568 TI - Massive breast necrosis after extravasation of a full anthracycline cycle. AB - A 57-year-old woman with invasive breast cancer was referred for adjuvant chemotherapy after undergoing breast conservative therapy and axillary dissection. A port was inserted in the contralateral subclavian vein and epirubicin, cyclophosphamide and 5-fluorouracil was the treatment of choice. After the first cycle, the patient was sent home. The following day, she reported rapidly developing redness and pain in the right breast and diagnosis of epirubicin extravasation was made. She was hospitalised, the port was surgically removed and approximately two-thirds of the breast underwent tissue necrosis. The necrotic tissue was resected and a skin graft was harvested from the thigh. She was offered DIEP-flap reconstruction 8 months later. There were no complications, except for marginal necrosis of the flap. Necrosectomy was performed and resolved through an advancement flap. PMID- 24142569 TI - Sudden collapse in a middle-aged male: giant ACOM aneurysm. PMID- 24142570 TI - Heat shock protein 27 attenuates neointima formation and accelerates reendothelialization after arterial injury and stent implantation: importance of vascular endothelial growth factor up-regulation. AB - Elevated serum heat shock protein 27 (HSP27) levels are atheroprotective; however, the role of HSP27 after arterial injury is unknown. Human endothelial progenitor cells (EPCs) were treated with recombinant (r)HSP27 (50 MUg/ml) or its inactive C1 terminus, and gene expression was characterized before functional studies were performed in vitro and in vivo. Vascular endothelial growth factor (VEGF) was markedly up-regulated by rHSP27 (10- and 6-fold increases in mRNA and secretion, respectively). Pretreatment of EPCs with rHSP27 resulted in a 60% reduction in reendothelialization (RE) time in a scratch assay, an effect that was blocked with VEGF-neutralizing antibodies. Mice overexpressing HSP27 demonstrated more robust mobilization of EPCs at the time of arterial injury, as well as a 67% increase in RE and a 45% reduction in neointima (NI) formation at 28 d. Implantation of rHSP27-eluting stents in rabbit carotid arteries resulted in a marked improvement in RE at 7 and 28 d and transient attenuation of NI formation by 42% at 7 d. Hence, extracellular HSP27 up-regulated VEGF and improved EPC migration in vitro. Augmented systemic or local levels of HSP27 markedly improved RE after vascular injury, an effect that is of particular relevance to the safety profile of vascular stents. PMID- 24142571 TI - Development and validation of a biotic ligand model for predicting chronic toxicity of lead to Ceriodaphnia dubia. AB - While it is increasingly being recognized that biotic ligand models (BLMs) are valuable in the risk assessment of metals in aquatic systems, the development of chronic BLMs has been less advanced for lead than for other metals. The authors investigated the univariate effects of Ca and pH on the chronic reproductive toxicity of Pb to Ceriodaphnia dubia at 4 levels. Calcium influenced chronic Pb toxicity to C. dubia only to a relatively small extent, whereas a high pH (8.2) provided strong protection against Pb toxicity (compared with lower pH levels). Based on this data set, a chronic Pb BLM for C. dubia was developed. The effect of pH was modeled as a single biotic ligand site competition by H(+) with a log stability constant for binding of H(+) to the biotic ligand (K(HBL)) of 7.6, while no other competitive constants were needed. The developed BLM was shown, in an independent validation with 3 other data sets, to be capable of predicting chronic Pb toxicity to different clones of C. dubia by an error of less than a factor of 2 in most synthetic and natural waters considered. The results add to the growing evidence that BLM-based risk assessment or water-quality criteria for Pb are likely to be more appropriate relative to hardness-based assessments or criteria. PMID- 24142572 TI - A single dose of pirfenidone attenuates neuronal loss and reduces lipid peroxidation after kainic acid-induced excitotoxicity in the pubescent rat hippocampus. AB - Systemic administration of kainic acid (KA) in rodents triggers limbic seizures following selective neuronal loss in the hippocampus attributed to the excitotoxic process. Lipid peroxidation products, such as 4-hydroxynonenal, are produced by oxidative stress and are present on the hippocampus, which contribute to neuronal death in the KA excitotoxicity model. Several antioxidants are neuroprotective agents. The aim of the present study was to analyse whether pirfenidone (PFD, 5-methyl-1-phenyl-2-(1H)-pyridone), an antioxidant drug, protects the neurons in the hippocampus of pubescent rats administered with KA. We evaluated the neuroprotective effect of PFD by quantifying the surviving neurons under hematoxilin-eosin staining after using three different doses of 100, 250, and 325 mg/kg administered via an orogastric tube 90 min after KA intraperitoneal injection (12 mg/kg). Only 325 mg/kg of PFD-attenuated neuronal loss in the hippocampal areas cornu ammonis field 1 (CA1) and cornu ammonis field 3 (CA3c) was observed; therefore, this dose was used in our subsequent studies. Later, we established that PFD reduces neuronal degeneration using Fluoro-Jade B stain in the CA3c but not in the CA1, and PFD reduces the presence of 4 hydroxynonenal, a lipid peroxidation product, in the CA3 by tissue immunohistochemistry. We concluded that only a single 325 mg/kg PFD dose had a neuroprotective effect after KA brain injury. This treatment may be advantageous because adequate pharmacological therapy with PFD can be developed to protect the neuron even after an acute neuronal disorder such as seizures or hypoxic/ischemic damage. PMID- 24142573 TI - Molybdenum effect on the structure of SiO2-CaO-P2O5 bioactive xerogels and on their interface processes with simulated biofluids. AB - The study is focused on synthesis, investigation of the structural and morphological changes induced by MoO3 addition, and thermal treatment, as well as in vitro characterization of a new sol-gel derived SiO2-CaO-P2O5 bioactive materials. The obtained systems are composite materials consisting of nanocrystalline apatite, bioactive glass and CaMoO4 nanoparticles, which are of interest for both regenerative medicine and specific medical applications of the releasable molybdenum ions. The changes induced by the thermal treatments and MoO3 addition with respect to the structure and morphology were completed using differential thermal analysis?thermogravimetric analysis, X-ray diffraction (XRD), scanning electron microscopy (SEM), energy dispersive X-ray (EDX), X-ray photoelectron spectroscopy (XPS), Fourier transform infrared (FTIR) spectroscopy, electron paramagnetic resonance, and Brunauer-Emmett-Teller. The biological performance of these materials was evaluated in vitro by performing bioactivity and biocompatibility tests. The bioactive properties in terms of hydroxyapatite layer formation on the biomaterial surface after simulated body fluid immersion were studied by XRD and SEM. To establish their biocompatibility, the biomaterials surface was functionalized with protein and the resulted sample was investigated using SEM, FTIR, and XPS. The obtained results suggest that the addition of molybdenum oxide in proper concentration improves the biocompatibility in terms of enhancement of protein adherence on Si-Ca-P surface due to CaMoO4 crystalline phase development and does not inhibit bioactivity. PMID- 24142574 TI - Polymorphisms of ERBB2 and breast cancer risk: a meta-analysis of 26 studies involving 35,088 subjects. PMID- 24142575 TI - Prognostic impact of p300 expression in patients with colorectal cancer. AB - BACKGROUND: This study evaluated the expression of p300 in colorectal cancer, its relationship with clinicopathological characteristics, and its potential prognostic significance. METHODS: The expression of p300 was measured using immunohistochemistry in tumors and surrounding normal mucosa from 199 patients with primary colorectal cancer. The patients were followed for a median period of 83 months. RESULTS: Nuclear p300 expression was significantly associated with histology (P = 0.031) and lymph node involvement (P = 0.019). When the low and high p300 groups were subdivided according to tumor location, the disease-free survival rate differed only for the patients with colon cancer (P = 0.008). In addition, the disease-free survival significantly differed with p300 expression for stage II disease (P = 0.038), but not for stage III disease. Multivariate analysis revealed that lymph node involvement (P = 0.014) and p300 expression (P = 0.032) were independent predictors of overall survival in adenocarcinomas. CONCLUSION: The overexpression of p300 may be an independent favorable prognostic factor for disease-free survival in patients with colorectal cancer. PMID- 24142576 TI - Management of peritoneal metastasis from neuroendocrine tumors. PMID- 24142578 TI - Robust superhydrophobicity in large-area nanostructured surfaces defined by block copolymer self assembly. AB - Robust, large area, superhydrophobic surfaces with feature sizes approaching 10 nm are fabricated by block-copolymer-based thin-film patterning. We show that tuning the nanostructure shape and aspect ratio dramatically influences the surface wetting properties, with proper control crucial for achieving superhydrophobicity. PMID- 24142577 TI - Sodium Glucose Co-transporter Type 2 (SGLT2) Inhibitors: Targeting the Kidney to Improve Glycemic Control in Diabetes Mellitus. AB - Although hyperglycemia is a key therapeutic focus in the management of patients with type 2 diabetes mellitus (T2DM), many patients experience sub-optimal glycemic control. Current glucose-lowering agents involve the targeting of various body organs. Sodium glucose co-transporter type 2 (SGLT2) inhibitors target the kidney, reduce renal glucose reabsorption, and increase urinary glucose elimination, thus lowering glucose blood levels. This review examines some of the key efficacy and safety data from clinical trials of the main SGLT2 inhibitors approved or currently in development, and provides a rationale for the use of SGLT2 inhibitors in the treatment of T2DM. PMID- 24142579 TI - Acute hypertensive response management in patients with acute stroke. AB - Acute elevation in blood pressure (acute hypertensive response) is commonly observed in the early period of both ischemic and hemorrhagic stroke. The management of acute hypertensive response depends upon the underlying intracranial pathology. Management of acute hypertensive response has been the focus of many trials and studies such as the SCAST trial, CHHIPS trial, COSSACS trial, INTERACT, and ATACH trial, which are discussed here. However, there were many limitations to these trials including time of presentation, different pathophysiology of ischemic strokes versus hemorrhagic strokes, and patient related factors. Ongoing clinical trials which take these limitations into account include ENCHANTED trial, ATACH II trial, INTERACT 2 trial, and ENOS trial. The results of these trials are expected to modify current guidelines of acute stroke, both ischemic and hemorrhagic, and potentially improve clinical outcomes and quality of life. PMID- 24142580 TI - Oleic acid increases hepatic sex hormone binding globulin production in men. AB - SCOPE: Low circulating sex hormone-binding globulin (SHBG) is an independent risk factor for cardiovascular disease. Mediterranean diet has been associated with a decreased risk of cardiovascular disease. We aimed to test the hypothesis that the increase of circulating MUFA associated with olive oil consumption (primary fat source in Mediterranean diet) increases SHBG serum levels. METHODS AND RESULTS: A total of 315 men were included. In these patients, nutrition data and plasma samples for SHBG assessment were obtained. In vitro studies to examine the effects of oleic and linoleic acid on SHBG production using HepG2 cells were performed. We provided evidence that SHBG serum levels were significantly higher in subjects using olive oil for cooking in comparison with subjects using sunflower oil. The SHBG levels correlated positively with MUFA (p < 0.001) and negatively with saturated fatty acids (p = 0.003). In the multiple regression analysis, MUFA were independently associated with SHBG levels and accounted for the 20.4% of SHBG variance. In vitro studies revealed that oleoyl-CoA increases SHBG production by downregulating PPAR-gamma levels in HepG2 cells. CONCLUSION: Olive oil consumption is associated with elevated SHBG serum levels. PPAR-gamma downregulation induced by oleoyl-CoA is an important underlying mechanism of such regulation. PMID- 24142581 TI - Quantification of primary motor pathways using diffusion MRI tractography and its application to predict postoperative motor deficits in children with focal epilepsy. AB - As a new tool to quantify primary motor pathways and predict postoperative motor deficits in children with focal epilepsy, the present study utilized a maximum a posteriori probability (MAP) classification of diffusion weighted imaging (DWI) tractography combined with Kalman filter. DWI was performed in 31 children with intractable focal epilepsy who underwent epilepsy surgery. Three primary motor pathways associated with "finger," "leg," and "face" were classified using DWI MAP classifier and compared with the results of invasive electrical stimulation mapping (ESM) via receiver operating characteristic (ROC) curve analysis. The Kalman filter analysis was performed to generate a model to determine the probability of postoperative motor deficits as a function of the proximity between the resection margin and the finger motor pathway. The ROC curve analysis showed that the DWI-MAP achieves high accuracy up to 89% (finger), 88% (leg), 89% (face), in detecting the three motor areas within 20 mm, compared with ESM. Moreover, postoperative reduction of the fiber count of finger pathway was associated with postoperative motor deficits involving the hand. The prediction model revealed an accuracy of 92% in avoiding postoperative deficits if the distance between the resection margin and the finger motor pathway seen on preoperative DWI tractography was 19.5 mm. This study provides evidence that the DWI-MAP combined with Kalman filter can effectively identify the locations of cortical motor areas even in patients whose motor areas are difficult to identify using ESM, and also can serve as a reliable predictor for motor deficits following epilepsy surgery. PMID- 24142582 TI - Morphological and immunohistochemical evaluation of ganglion cysts. Cross sectional study of 354 cases. AB - The aim of this study was to characterize the morphology and immunophenotype of ganglion cysts (GCs) and explore their histogenetic origin. MATERIAL AND METHODS: A cross-sectional morphological and immunohistochemical study of 354 GCs used the following antibody panel: vimentin, specific actin, beta-actin, smooth-muscle actin, smoothelin, h-caldesmon, beta-catenin, desmin, calponin, podoplanin, keratins 5/6, E-cadherin, cyclooxygenase 2 (COX-2), lysozyme, CD10, CD31, CD33, CD34, CD68, Ki-67, and PCNA. Double-blind semi-quantitative analyses were conducted to evaluate the immunopositivity on a 4-point scale. Samples from 10 synovial membranes and 10 scapholunate ligaments were compared. GCs showed a hyalinized wall with mesenchymal spindle cells and were intensely positive for vimentin, actins, h-caldesmon, calponin in all cases and for podoplanin in 53% of cases, suggesting features of early muscle differentiation, without ruling out a myofibroblastic origin. Focal cavity lining of non-synovial flat or raised cells (CD34/CD31/CD10/E-cadherin-negative and podoplanin-positive in 34% of cases) was detected in 93% of cases, showing differential expression with synovial membrane and scapholunate ligament cells. Nuclear positivity for proliferative markers was observed in GC wall cells (258.1+/-255; 1019.3+/-316 positive cells/mm2, Ki-67 and PCNA, respectively) but positivity for these markers was significantly lower (p?0.001 Mann Whitney U-test) in scapholunate ligament samples. CONCLUSION: In this first immunohistochemical study of GCs, focal cellular lining of the cavity was observed in almost all cases, and the immunophenotype was identical to that of GC wall cells. These cells are immunohistochemically different from synoviocytes and scapholunate ligament cells and show characteristics of myofibroblasts or mesenchymal cells undergoing early muscle differentiation. PMID- 24142583 TI - Central nervous system manifestations of neonatal lupus: a systematic review. AB - Neonatal lupus is a rare and acquired autoimmune disease. Central nervous system abnormalities are potential manifestations in neonatal lupus. Through a systematic literature review, we analyzed the clinical features of previously reported neonatal lupus cases where central nervous system abnormalities had been identified. Most reported neonatal lupus patients with central nervous system involvement were neuroimaging-determined and asymptomatic. Only seven neonatal lupus cases were identified as having a symptomatic central nervous system abnormality which caused physical disability or required neurosurgery. A high percentage of these neurosymptomatic neonatal lupus patients had experienced a transient cutaneous skin rash and had no maternal history of autoimmune disease before pregnancy. PMID- 24142584 TI - Dextromethorphan/levomethorphan issues in a case of opiate overdose. PMID- 24142586 TI - Longitudinal determinants of substance use disorders. AB - Substance use and substance use disorders (SUDs) have been linked with marital discord. Relatively little is known, however, about the antecedents of SUDs, the mediators of these factors over time, or their associations with the spousal/partner relationship among urban adults. A better understanding of the longitudinal pathways to marital conflict and to SUDs should help prevention and intervention programs target their precursors within the developmental period in which they occur. The present study, therefore, examined the longitudinal predictors of an unsupportive spousal/partner relationship and SUDs among a community sample of urban African American and Puerto Rican adults from East Harlem, NY. Participants (N = 816) completed structured questionnaires at five time waves, from adolescence to adulthood (mean ages = 14, 19, 24, 29, and 32 years). Structural equation modeling examined the effects of earlier environmental and social stressors and intrapersonal and interpersonal factors on later SUDs in adulthood. There was a good fit of the structural equation model (CFI = 0.91; RMSEA = 0.06; and SRMR = 0.06), which revealed three main pathways from adolescence to the spousal/partner relationship and SUDs in adulthood. One pathway linked a weak parent-adolescent attachment relationship with the participant's psychological symptoms in emerging adulthood (p < 0.01), which in turn were related to affiliation with deviant and drug-using peers, also in emerging adulthood (p < 0.001). Peer deviance and drug use were associated with the participant's substance use in young adulthood (p < 0.001), which predicted both an unsupportive spousal/partner relationship (p < 0.05) and SUDs (p < 0.001) later in adulthood. Other pathways highlighted the continuity of psychological symptoms as related to both substance use in young adulthood (p < 0.001) and an unsupportive spousal/partner relationship in adulthood (p < 0.001). Findings showed that the associations of both distal stressors and the parent-adolescent relationship with more proximal intra- and interpersonal problems predicted unsupportive spousal/partner relationships and SUDs among urban adults. Several aspects of the individual's life, at different developmental stages, provide opportunities for interventions to prevent or reduce unsupportive spousal/partner relationships and SUDs. PMID- 24142587 TI - Sphingomyelin and phosphatidylcholine contrarily affect the induction of apoptosis in intestinal epithelial cells. AB - SCOPE: The major alimentary sources for the plasma membrane lipid sphingomyelin (SM) are dairy products, eggs, and meat. We recently reported that the SM metabolite ceramide induces cathepsin D mediated apoptosis in murine intestinal epithelial cells (IECs) and increases inflammation in acute colitis. We investigated the impact of SM and phosphatidylcholine on apoptosis in human IECs and point out BH3-interacting death agonist (BID) as link between cathepsin D and apoptosis. METHODS AND RESULTS: HT-29 and isolated human IECs were stimulated with SM or phosphatidylcholine. SM treatment resulted in increased apoptosis. Phosphatidylcholine showed contrary effects. Western revealed higher amounts of cathepsin D and BID activation upon lipid stimulation. Western blotting revealed BID activation through SM in both an induced and a spontaneous mouse model of colitis. CONCLUSION: Dietary phospholipids may induce or abolish apoptosis in IECs and seem to play a role in the pathogenesis of inflammatory bowel diseases. This nutritional factor might be considered when evaluating the pathogenesis of inflammatory bowel diseases. Effects of SMase- and SM treatment on inflammation in dextran sulfate sodium induced animal models of colitis and in vitro experiments are discussed as controversial. Variable sources of SM, feeding techniques, and mouse strains might play a role. PMID- 24142588 TI - Preparation of cardiac extracellular matrix scaffolds by decellularization of human myocardium. AB - Extracellular matrix (ECM) derived by tissue decellularization has applications as a tissue engineering scaffold and for support of cellular regeneration. Myocardial ECM from animals has been produced by whole-organ perfusion or immersion processes, but methods for preparation of human myocardial ECM for therapy and research have not been compared in detail, yet. We analyzed the impact of decellularization processes on human myocardial ECM, and tested its ability to serve as a scaffold for cell seeding. Sodium dodecyl sulfate (SDS) based decellularization, but not treatments based on Triton X-100, deoxycholate or hypo/hypertonic incubations, removed cells satisfactorily, and incubation with fetal bovine serum (FBS) eliminated residual DNA. ECM architecture was best preserved by a protocol consisting of 2 h lysis, 6 h SDS, and 3 h FBS, but age and pathology of the donor tissue are highly important for producing reproducible, high-quality scaffolds. We also studied ECM repopulation with mesenchymal stem cells (CB-MSC), cardiomyocytes derived from induced pluripotent stem cells (iPS-CM), and na?ive neonatal mouse cardiomyocytes. Cells attached to the matrix and proliferated and displayed higher viability than in standard culture. We conclude that human cardiac ECM sheets may be suitable scaffold for cell-matrix interaction studies and as a biomaterial for tissue regeneration and engineering. PMID- 24142589 TI - The treatment of tremor. AB - Tremor is a hyperkinetic movement disorder characterized by rhythmic oscillations of one or more body parts. It can be disabling and may impair quality of life. Various etiological subtypes of tremor are recognized, with essential tremor (ET) and Parkinsonian tremor being the most common. Here we review the current literature on tremor treatment regarding ET and head and voice tremor, as well as dystonic tremor, orthostatic tremor, tremor due to multiple sclerosis (MS) or lesions in the brainstem or thalamus, neuropathic tremor, and functional (psychogenic) tremor, and summarize main findings. Most studies are available for ET and only few studies specifically focused on other tremor forms. Controlled trials outside ET are rare and hence most of the recommendations are based on a low level of evidence. For ET, propranolol and primidone are considered drugs of first choice with a mean effect size of approximately 50 % tremor reduction. The efficacy of topiramate is also supported by a large double-blind placebo controlled trial, while other drugs have less supporting evidence. With a mean effect size of about 90 % deep brain stimulation in the nucleus ventralis intermedius or the subthalamic nucleus may be the most potent treatment; however, there are no controlled trials and it is reserved for severely affected patients. Dystonic limb tremor may respond to anticholinergics. Botulinum toxin improves head and voice tremor. Gabapentin and clonazepam are often recommended for orthostatic tremor. MS tremor responds only poorly to drug treatment. For patients with severe MS tremor, thalamic deep brain stimulation has been recommended. Patients with functional tremor may benefit from antidepressants and are best be treated in a multidisciplinary setting. Several tremor syndromes can already be treated with success. But new drugs specifically designed for tremor treatment are needed. ET is most likely covering different entities and their delineation may also improve treatment. Modern study designs and long-term studies are needed. PMID- 24142590 TI - Treatment of dystonia. AB - Selecting the appropriate treatment for dystonia begins with proper classification of disease based on age, distribution, and underlying etiology. The therapies available for dystonia include oral medications, botulinum toxin, and surgical procedures. Oral medications are generally reserved for generalized and segmental dystonia. Botulinum toxin revolutionized the treatment of focal dystonia when it was introduced for therapeutic purposes in the 1980s. Surgical procedures are available for medication-refractory dystonia, markedly affecting an individual's quality of life. PMID- 24142591 TI - Panax notoginseng attenuates experimental colitis in the azoxymethane/dextran sulfate sodium mouse model. AB - Patients suffering from inflammatory bowel disease are at a high risk of developing colorectal cancer. To assess the anticancer potential of botanicals, in this study, we evaluated the effects of Panax notoginseng on azoxymethane/dextran sulfate sodium (DSS)-induced colitis. One week after A/J mice received azoxymethane, the animals received DSS for 8 days or were supplemented with P. notoginseng extract, at 30 or 90 mg/kg. DSS-induced colitis was scored with the disease activity index. The severity of the inflammatory lesions was evaluated by a colon tissue histological assessment. The expression of inducible nitric oxide synthase and cyclooxygenase-2 (COX-2) were also explored. We observed that the effects of P. notoginseng on the reduction of colon inflammation, expressed in disease activity index score, were in a dose related manner (p < 0.01). P. notoginseng inhibited the reduction of the colon length and the loss of bodyweight in dose-related manner (all p < 0.05). The histological assessment of the colitis and inflammatory-related immunohistochemical data also supported the pharmacological observations. Our data suggest that P. notoginseng is a promising candidate in preventing and treating colitis and inflammation-associated colon carcinogenesis. PMID- 24142593 TI - Mindfulness-based supportive therapy (MBST): proposing a palliative psychotherapy from a conceptual perspective to address suffering in palliative care. AB - OBJECTIVE: To develop a mindfulness-based palliative psychotherapy to address psychoexistential suffering in palliative care. CONCEPTUALIZATION: First, a theory of suffering was formulated by merging 2 models of suffering from 2 thematic analyses of 20 palliative care patients and 15 informal caregivers. Second, the results from a secondary thematic analysis of suffering caused by health care interactions were conceptualized into a psychotherapy framework. Third, principles of mindfulness were incorporated into the framework to form a mindfulness-based psychotherapy. RESULTS: Mindfulness-based supportive therapy (MBST) was developed with the following 5 components of presence, listening, empathy, compassion, and boundary awareness. CONCLUSION: We believe that MBST is a potentially useful psychological intervention in palliative care, specifically designed to address psychoexistential suffering of terminally ill patients. PMID- 24142592 TI - Moving on from GWAS: functional studies on the G6PC2 gene implicated in the regulation of fasting blood glucose. AB - Genome-wide association studies (GWAS) have shown that single-nucleotide polymorphisms (SNPs) in G6PC2 are the most important common determinants of variations in fasting blood glucose (FBG) levels. Molecular studies examining the functional impact of these SNPs on G6PC2 gene transcription and splicing suggest that they affect FBG by directly modulating G6PC2 expression. This conclusion is supported by studies on G6pc2 knockout (KO) mice showing that G6pc2 represents a negative regulator of basal glucose-stimulated insulin secretion that acts by hydrolyzing glucose-6-phosphate, thereby reducing glycolytic flux and opposing the action of glucokinase. Suppression of G6PC2 activity might, therefore, represent a novel therapy for lowering FBG and the risk of cardiovascular associated mortality. GWAS and G6pc2 KO mouse studies also suggest that G6PC2 affects other aspects of beta cell function. The evolutionary benefit conferred by G6PC2 remains unclear, but it is unlikely to be related to its ability to modulate FBG. PMID- 24142594 TI - Cancer-related insomnia. AB - Insomnia increases cancer symptom burden and impairs quality of life. The lack of standard definitions and treatment guidelines makes management difficult. Insomnia is common in most cancers but appears particularly so in lung, breast, and head and neck tumors. Older women seem most susceptible. Insomnia not only affects patients with cancer but also caregivers and families. Systematic screening is important. Few validated assessment scales are available. Nonpharmacologic therapies like cognitive behavioral therapy may help. New nonbenzodiazepine hypnotics may have some therapeutic advantages over older agents. Management of associated or contributory symptoms like fatigue, pain, and hot flashes with appropriate symptom-specific agents is important. Successful management may have a significant positive impact on global quality of life. PMID- 24142595 TI - The care of the actively dying in an academic medical center: a survey of registered nurses' professional capability and comfort. AB - BACKGROUND: Care of the dying is a significant component of nursing practice particularly in hospitals. Nurses who work in certain areas like oncology, intensive care unit (ICU) face the care of the dying, more so than other units. OBJECTIVES: The survey was conducted to assess nurses' self-perception of their professional capability and comfort in the care of the actively dying. Determine if professional capability and comfort was associated with any of the six demographics characteristics (age, gender, clinical experience, education level, nursing unit, continuing education). Identify areas of clinical challenge to promote educational initiatives to stimulate best nursing practice in the actively dying. DESIGN: The survey comprised of two parts: Part I with demographic characteristics and a single open-ended question, Part II with twenty questions on the domains recommended by the NCP. RESULTS: Older age and greater clinical experience were associated with greater levels of capability/comfort. Most nurses felt professionally capable and comfortable in domains such as knowledge, physical and psychosocial care but bioethics, communication, cultural, spiritual and bereavement issues challenged >= 40%. CONCLUSIONS: Nurses self perceived professional capability and comfort levels in caring for the dying were positively influenced by older age, greater clinical experience and extensive continuing education. Bioethics, communication and grief impacted nurses personally and emotionally. Continuing education, organized debriefing, grief counseling, and preceptors support should be routine for nurses who work in units with predictable high mortality. PMID- 24142596 TI - Hematopoietic stem cell transplant candidate and designated proxy distress levels prior to hematopoietic stem cell transplantation. AB - Hematopoietic stem cell transplantation (HCT) is associated with a high risk of morbidity, making advance care planning (ACP) essential. The purpose of this study was to assess and compare proxy and HCT candidate distress levels (Distress Thermometer) before (T1) and after (T2) ACP question completion. 79 participants (40 HCT candidates, 39 proxies) rated their distress. The T1, T2 mean distress scores (SD) for HCT candidates were 3.13(2.27), 2.96(2.10); 43% and 38% endorsed clinically significant distress (>=4). Proxies reported 4.21(2.48), 4.33 (2.46); 62% endorsed significant distress at T1, T2. The majority of proxies endorsed distress levels that were clinically significant and comparatively higher (T1 (p = 0.047) and T2 (p = 0.009)) than their paired HCT recipients. Responding to questions about ACP did not increase overall distress ratings. PMID- 24142597 TI - The rhizotoxicity of metal cations is related to their strength of binding to hard ligands. AB - Mechanisms whereby metal cations are toxic to plant roots remain largely unknown. Aluminum, for example, has been recognized as rhizotoxic for approximately 100 yr, but there is no consensus on its mode of action. The authors contend that the primary mechanism of rhizotoxicity of many metal cations is nonspecific and that the magnitude of toxic effects is positively related to the strength with which they bind to hard ligands, especially carboxylate ligands of the cell-wall pectic matrix. Specifically, the authors propose that metal cations have a common toxic mechanism through inhibiting the controlled relaxation of the cell wall as required for elongation. Metal cations such as Al(3+) and Hg(2+), which bind strongly to hard ligands, are toxic at relatively low concentrations because they bind strongly to the walls of cells in the rhizodermis and outer cortex of the root elongation zone with little movement into the inner tissues. In contrast, metal cations such as Ca(2+), Na(+), Mn(2+), and Zn(2+) , which bind weakly to hard ligands, bind only weakly to the cell wall and move farther into the root cylinder. Only at high concentrations is their weak binding sufficient to inhibit the relaxation of the cell wall. Finally, different mechanisms would explain why certain metal cations (for example, Tl(+), Ag(+), Cs(+), and Cu(2+)) are sometimes more toxic than expected through binding to hard ligands. The data presented in the present study demonstrate the importance of strength of binding to hard ligands in influencing a range of important physiological processes within roots through nonspecific mechanisms. PMID- 24142598 TI - Extensively ossifying oral leiomyoma: a rare histologic finding. AB - Oral leiomyoma are rare neoplasms of the oral cavity. Ossification within leiomyoma is not unusual but is mostly reported in leiomyoma of the deep soft tissue. Ossifying leiomyoma is extremely rare in the head and neck. We identified a total of three cases of extensively ossified leiomyoma in the head and neck in the literature including lesions in the lateral pterygoid muscle and orbit. To the best of our knowledge, only one case of extensively calcified leiomyoma has been reported in the oral cavity. We present two such rare cases of oral leiomyoma with extensive intratumoral calcifications and ossification. Ossified leiomyoma should be considered in the differential diagnosis of calcified or hard/firm soft tissue masses in the oral cavity. PMID- 24142599 TI - Body composition phenotype: Italian Mediterranean Diet and C677T MTHFR gene polymorphism interaction. AB - OBJECTIVES: Strategies to improve weight maintenance are focused on considering the genetic makeup and its interaction with dietary intake, with the aim to identify vulnerable individuals that will benefit from a variety of more personalized dietary recommendations. The aim of the study was to examine the impact of the C677T MTHFR gene Polymorphism on body composition changes induced by a balanced hypocaloric Italian Mediterannean diet (IMD). SUBJECTS AND METHODS: Participation in the study included a complete screening of anthropometry and body composition by Dual-energy X-ray absorptiometry (DXA), and a genotyping for the C677T MTHFR polymorphism. 70 Italian Caucasian obese were enrolled and 56 of them completed the screening at baseline and 12 weeks after the nutritional intervention. RESULTS: T(+) carriers had a higher content of Total Body Fat (TBFat), and Lean (TBLean), reflecting on higher weight and BMI, than T(-) carriers. After IMD, the 28.6% and 71.4% of total subjects decreased weight and TBFat (Kg), respectively. The relative changes were: delta % = -9.09+/-3.85 for weight; delta % = -15.79+/-8.51 for TBFat; delta % = -3.80+/-5.60 for TBLean. The 5.3% of subjects who reached the end point of intervention, and the 8.9% who reduced TBFat (%) below the cut-off of preobesity, were T(-) carriers. A loss of TBLean (Kg) was observed in the 5.1% and 23.5% of T(-) and T(+) carriers. CONCLUSIONS: MTHFR genetic variations analysis would be an innovative tool for the nutritional assessment, in order to predict the therapeutic response of obese subjects, in terms of fat and lean mass loss. PMID- 24142600 TI - A meta-analysis of clinical therapeutic effect of insulin glargine and insulin detemir for patients with type 2 diabetes mellitus. AB - BACKGROUND: Insulin have been recommended to decrease glycosylated hemoglobin (HbA1c) level in type 2 diabetes mellitus (T2DM) patients whose blood glucose control are unsatisfactory by using oral hypoglycemic drugs. AIM: To systematically estimate the therapeutic effect and security of insulin glargine and insulin detemir for treatment of type 2 diabetes mellitus. MATERIALS AND METHODS: We searched the Cochrane library, PubMed, EMBASE, etc databases. Quality evaluation of all randomized control tests (RCT) enrolled was conducted according to Cochrane manual, and meta-analysis was performed by using RevMan5.0 software. RESULTS: Both insulin glargine and insulin detemir can effectively control T2DM patient's blood glucose. CONCLUSIONS: Insulin detemir has evident superiority on reducing body weight than insulin glargine. As the doses are concerned, daily insulin dose of insulin detemir is higher than insulin glargine. PMID- 24142601 TI - The effects of dimethyl sulfoxide on the acute phase of experimental acid and alkali corrosive esophageal burns. AB - BACKGROUND, AIM: The aim of this study was to investigate the effects of dimethyl sulfoxide (DMSO) on the acute phase of experimental corrosive esophageal burns. MATERIALS AND METHODS: Fifty male rats were allocated into five groups (control, acid burn, alkali burn, acid burn + DMSO and alkali burn + DMSO) of ten rats each. Acid and alkali burns were creating by burning the distal esophagus with 1 N hydrochloric acid and 50% sodium hydroxide solution, respectively. DMSO was applied intraperitoneally at 15 minutes after burn creation and then every 12 hours for four days. All animals were sacrificed at the end of the 7th day. Histopathological changes in esophageal tissue were scored by a single investigator who was blind to the burn group. RESULTS: Application of DMSO resulted in a significant decrease in the severity of acute tissue damage as measured by macroscopic and microscopic assessments in both the acidic and alkaline esophagitis groups. The increased immunohistochemical Ki-67 proliferation index was significantly suppressed in the DMSO-treated alkaline esophagitis group, p < 0.05. Furthermore, the immunoreactivity of nuclear factor kappa B (NF-kB) was significantly reduced in both the acid and alkali DMSO treated groups, p < 0.05. CONCLUSIONS: DMSO reduced the acute phase symptoms and decreased the severity of tissue damage in both acidic and alkaline corrosive esophagitis. PMID- 24142602 TI - Curcumin decreases oleic acid-induced lipid accumulation via AMPK phosphorylation in hepatocarcinoma cells. AB - BACKGROUND AND OBJECTIVES: Non-alcoholic fatty liver disease (NAFLD) is one of the most common metabolic syndromes and is characterized by the accumulation of hepatic triglycerides (TG), which result from an imbalance between uptake, synthesis, export, and oxidation of fatty acids. Curcumin is a polyphenol derived from the herbal remedy and dietary spice turmeric, was found to prevent obesity and diabetes in mouse models. However, a hypolipidemic effect of curcumin in oleic acid- induced hepatocarcinoma cells has not been reported. In this study, we examined the effect of curcumin on reducing lipid accumulation in hepatic cells. MATERIALS AND METHODS: Hepatocytes were treated with oleic acid (OA) containing with or without curcumin to observe the lipid accumulation by Oil Red O stain. We also tested the effects of curcumin on triglycerides (TG) and total cholesterol (TC) in HepG2 cells. Western blot and reverse transcription polymerase chain reaction (RT-PCR) was used to measure sterol regulatory element binding proteins-1 (SREBP-1), fatty acid synthase (FAS), peroxisome proliferator activated receptor (PPAR)-alpha, and adenosine 5'-monophosphate (AMP)-activated protein kinase (AMPK) expression. RESULTS: Curcumin suppressed OA-induced lipid accumulation and TG and TC levels. Also, curcumin decreased hepatic lipogenesis such as SREBP-1, and FAS. Besides, we also found out the antioxidative effect of curcumin by increasing the expression of PPARalpha. Curcumin increased AMPK phosphorylation in hepatocytes. CONCLUSIONS: These results indicated that curcumin has the same ability to activate AMPK and then reduce SREBP-1, and FAS expression, finally leading to inhibit hepatic lipogenesis and hepatic antioxidative ability. In this report, we found curcumin exerted a regulatory effect on lipid accumulation by decreasing lipogenesis in hepatocyte. Therefore, curcumin extract may be active in the prevention of fatty liver. PMID- 24142603 TI - The effect of different suture materials on the safety of colon anastomosis in an experimental peritonitis model. AB - BACKGROUND: The aim of this experimental study was to compare the safety of different suture materials in a left colonic anastomosis in the presence of peritonitis. MATERIALS AND METHODS: Twenty-one male Wistar albino rats were randomly divided into three groups. First, left colonic injuries were created in all groups for the peritonitis model. After 24 hours, coated polyglactin 910 and silk suture were used in Group I rats, polydioxanone and silk suture were used in Group II rats, and coated polyglactin 910 plus antibacterial suture and silk suture were used in Group III rats during colonic anastomosis. Tissue hydroxyproline, anastomotic bursting pressure, and histopathologic findings on the anastomosis line were evaluated on the 10th postoperative day by performing a relaparatomy. RESULTS: The mean bursting pressure values were 198 +/- 11.37, 220 +/- 17.7, and 244 +/- 9.52 in Groups I, II, and III, respectively (Group I vs. II, p < 0.035; I vs III, p < 0.002; and II vs III, p < 0.021). The mean hydroxyproline levels were 1.21 +/- 0.58, 1.47 +/- 0.44, and 2.11 +/- 0.32 in Groups I, II, and III, respectively (Group I vs II, p < 0.338; I vs III, p < 0.011; and II vs III, p < 0.025). When histopathologic findings of the groups were compared, the healing score of the intestinal tissue was higher in Group III than in Group I (p < 0.015), whereas there were no statistically significant differences among Groups I vs II and II vs III (p < 0.081 and p < 0.095, respectively). CONCLUSION: Antibacterial suture usage increased anastomosis safety in the presence of peritonitis in resection and primary anastomosis. PMID- 24142604 TI - Evaluation of treatment with hydrocortisone on oxidant/antioxidant system in preterm infants with BPD. AB - AIM: Evidence that oxidative stress plays a role in the development of bronchopulmonary dysplasia (BPD). There is a close relationship between oxidative stress and inflammation. In this study, it is aimed to investigate influences of hydrocortisone used in the treatment of BPD on anti-oxidant system in preterm infants with BPD. PATIENTS AND METHODS: The study enrolled 33 infants with severe BPD who were undergone inpatient treatment in neonatal intensive care unit (NICU) of our Hospital and received therapy with hydrocortisone. Total oxidant status (TOS) and total anti-oxidant capacity (TAC) levels of infants enrolled to the study before and one week after the hydrocortisone therapy were studies and oxidative stress index levels were calculated. Pre- and post-treatment TOS, TAC and OSI index levels were statistically compared. RESULTS: In preterm infants with BPD, who were enrolled into the study, TOS and OSI index were found high, whereas TAC values were low. Following the treatment with hydrocortisone, statistically significant decrease in TOS and OSI index and statistically significant elevation in TAC levels were found in comparison with pre-treatment levels. CONCLUSIONS: The treatment with hydrocortisone, which is used for BPD, improves anti-oxidant system and reduces oxidative stress in infants with BPD. There is need for further studies in order to clarify the physio-pathogenesis. PMID- 24142605 TI - High sensitive C-reactive protein: a new marker for urinary tract infection, VUR and renal scar. AB - BACKGROUND: Accurate diagnosis and early treatment of urinary tract infections (UTI) are important because of its association with renal scarring (RS). AIMS: To investigate the serum levels of fibronectin, high sensitive CRP (Hs-CRP), urinary fibronectin, and beta-2 microglobulin (beta2MG) levels in patients with UTI and relationship of these parameters with VUR (vesicoureteral reflex) and RS. PATIENTS AND METHODS: 72 patients were included in study and divided into three groups: Group I (20 patients with first UTI); Group II (16 patients with recurrent UTI with VUR); Group III (16 patients without UTI with VUR). RESULTS: Serum and urine fibronectin levels were similar in all study groups and controls. Urinary beta2MG levels were higher in Group II (302+/-179 ng/ml) than in the Group I (134+/-90 ng/ml) (p < 0.001). Moreover, beta2MG levels were similar in Group II (302+/-179 ng/ml) and group III (218+/-147 ng/ml). By contrast, beta2MG levels were higher in Group III (218+/-147 ng/ml) than in the controls (64+/-32 ng/ml) (p < 0.001). Hs-CRP levels were higher in Group I (1.8+/-2.7 mg/L), Group II (23.1+/-32 mg/L), and III (0.4+/-0.1 mg/L) than the controls (0.2+/-0.08 mg/L) (p < 0.001). Hs-CRP levels were higher in Group II (23.1+/-31.9 mg/L) than in the Group I (1.8+/-2.7 mg/L) (p < 0.001). Hs-CRP levels were higher in Group I (1.8+/ 2.7 mg/L) and Group II (23.1+/-31.9 mg/L) than in the Group III (0.4+/-0.1 mg/L) (p < 0.001). Hs-CRP levels were higher in group III (0.37+/-0.17 mg/L) than in the controls (0.2+/-0.08 mg/L) (p < 0.001). Hs-CRP (18.8+/-25 mg/L) and beta2MG levels (349.4+/-128.5 ng/ml) were different in UTI with RS from the controls (0.2+/-0.08 mg/L and 64+/-32 ng/ml respectively, p < 0.001). Fibronectin levels were similar in patients with and without RS. CONCLUSIONS: Increased urinary beta2MG and Hs-CRP were observed in initial UTI and recurrent UTI with VUR. Fibronectin levels were not useful for detection of first and recurrent UTI with VUR and RS. Elevated Hs-CRP levels can help us predetermine the patients with VUR prone to proceed to clinical chronic renal failure. PMID- 24142606 TI - External quality assessment of prenatal diagnosis of a rare and subtle chromosomal structural abnormality. AB - PURPOSE OF THE STUDY: To explore the misdiagnosis probability of subtle chromosomal structural abnormalities and find proper strategy to improve the accuracy of prenatal genetic diagnosis, we carried out a preliminary external quality assessment of prenatal detection of a rare case. PATIENTS AND METHODS: Three karyograms of a rare case of cri du chat syndrome associated with t(11;22) translocation [46,XY, del(5)(p15.2), t(11;22)(q23;q11.2)] were chosen. The patient's information and karyograms were emailed to 21 laboratories simulating the scenarios of prenatal diagnosis. The laboratories were required to provide a report using current nomenclature. RESULTS: Seven laboratories sent results for evaluation (response rate: 33.33%). For t(11;22), Two labs incorrectly reported that chromosome 22 was deletion. 5 of 7 labs reported t(11;22) translocation consistent with the actual karyotype. Among them, lab 6 suspected the abnormal 5q and lab 7 incorrectly considered chromosome 22 was deletion or reduplication. All laboratories missed to report the karyotype of del(5). CONCLUSIONS: Conventional cytogenetic analysis couldn't always detect subtle chromosomal structure abnormalities correctly during prenatal diagnosis. To improve the quality of prenatal genetic diagnosis, an excellent external quality assessment (EQA) scheme is currently imperative in China. PMID- 24142607 TI - Antidepressant activity of Hibiscus esculentus L. AB - OBJECTIVES: Hibiscus (H.) esculentus L. (Okra) is distributed from Africa to Asia, Southern European and America and widely used as food. The aim of present study was to investigate antidepressant activity of Okra seeds and leaves. MATERIALS AND METHODS: Antidepressant activity of methanolic extracts were evaluated by forced swimming test (FST) and tail suspension tests (TST). Also, total phenol and flavonoid contents were measured by Folin Ciocalteau and AlCl3 assays, respectively. RESULTS: Phenol and flavonoid contents of extracts were determined as gallic acid and quercetin equivalents from a calibration curve, respectively. Extracts showed good antidepressant activity in both FST and TST. The extracts shortened remarkably the immobility period in FST and TST and exhibited a dose dependent activity. Seeds extract in 250, 500 and 750 mg kg-1 showed significant activity as compared to control (p < 0.001). Both extracts at 750 mg kg-1 showed similar activity as imipramine 15 mg kg-1 (p > 0.05) in TST. Extracts contained high amount of phenol and flavonoids. No mortality has been observed up to 2 g kg-1 for seeds and 2.5 g kg-1 for leaves. CONCLUSIONS: These results introduced H. esculentus seeds and leaves as an easily accessible and edible source of natural antidepressant. PMID- 24142608 TI - High-dose immunosuppressive therapy combined with cord blood infusion and non myeloablative peripheral blood stem cell transplantation for patients with severe aplastic anemia. AB - OBJECTIVES: The aim of this study was to compare the clinical effective rates of high-dose immunosuppressive therapy combined with cord blood infusion (IS + CBI) and non-myeloablative peripheral blood stem cell transplantation (NSCT) for severe aplastic anemia (SAA). PATIENTS AND METHODS: Human leukocyte antigen (HLA) mismatched patients received immunosuppressive therapy combined with IS + CBI, whereas those with HLA matches received NSCT. Clinical effective rates, hematopoietic recovery, and prevalence of complications were compared between the two groups. RESULTS: No significant difference in total effective rate or 2 years long-term survival was observed between the two groups. The total effective treatment in the NSCT, IS + CBI group was 80%, 68.75%, and the 2 years long-term survival rate in two groups was 2 years 76.66%, 68.75%, respectively. The median times of WBC > 1.0*109/L in the NSCT group was faster than that of IS + CBI group (13 vs 19 days) (p = 0.027). The median recovery times of PLT and Hb in the NSCT group was significantly faster than that of IS + CBI group (19 vs 50 days) (p = 0.00), (27 vs 57 days) (p = 0.001). The SAA group and the very SAA (VSAA) group did not show a significant difference in effective rate (76.74% vs 68.42%) (p = 0.490). In the NSCT group, two preparative regimens did not show a significant difference in effect (70.59% vs 92.31%) (p = 0.141). CONCLUSIONS: IS + CBI is applicable to HLA-mismatched patients with SAA. NSCT is the treatment of choice for patients with HLA matching alleles. Both treatment methods are effective on VSAA. PMID- 24142609 TI - Ang II receptor expression and effect of Ang II receptor blockade in thyrotoxic rat myocardium. AB - AIM: To investigate the relationship between expression of the angiotensin II (Ang II) receptors and thyroid hormones in the myocardium of rats with thyrotoxicosis. MATERIALS AND METHODS: Forty-four adult male Sprague-Dawley rats were divided into four groups: control group (saline), losartan group (10 mg/kg), thyrotoxicosis group (0.5 mg/kg L-thyroid hormone sodium) and thyrotoxicosis-plus losartan group (0.5 mg/kg L-thyroid hormone plus 10 mg/kg losartan) and treated intragastrically daily for four weeks. The heart weight (HW), body weight (BW) and HW/BW ratios were determined. The Ang II protein contents in cardiac homogenates and serum were determined by ELISA. The serum concentrations of levothyroxine (T3), trilodothyronine (T4) and thyroid stimulating hormone (TSH) were measured by radioimmunoassay. The expression of angiotensin II type 1 receptor (AT1R) and angiotensin II type 2 receptor (AT2R) were quantified by real time PCR and Western blotting. RESULTS: The thyrotoxicosis group had an increased BW/HW and higher cardiac AT1R and AT2R expression compared to controls. AT1R and AT2R expressions significantly reduced in the thyrotoxicosis-plus-losartan group, compared to the thyrotoxicosis group. CONCLUSIONS: Thyroid hormone upregulated cardiac AT1R and AT2R, leading to cardiac remodeling, which was reversed by losartan. Cardiac damage in thyrotoxic rats may be related to upregulation of the Ang II receptors. PMID- 24142610 TI - Clinical outcome of coronary artery bypass grafting (CABG) in hemodialysis dependent patients and comparison with non-renal failure patients. AB - BACKGROUND: Coronary artery bypass grafting (CABG) is a revascularization technique that has been reported as having satisfactory survival rates in Hemodialysis (HD) dependent patients. AIM: The aim of this study was to determine morbidity and mortality of isolated CABG in HD-dependent patients and compare with non- renal failure (RF) patients. PATIENTS AND METHODS: We performed a retrospective analysis of data related to all patients who underwent first time, on-pump, isolated CABG surgery between May 23, 2004 to September 22, 2012, we selected 32 CRF patients with history of chronic hemodialysis (group HD) and 32 non renal failure patients (group non-HD). The preoperative data of two groups were matched completely. We collected all data of intraoperative and postoperative. Data were analyzed by SPSS version 16. RESULTS: the mean age of HD group and non-HD group were 52.46+/-3.24 and 52.12+/-3.54 years (p = 0.68). Low cardiac output syndrome was occurred in 4 patients (12.5%) of HD group and one patient (3.12%) of non-HD group (p = 0.16). 96.87% of patients in HD group and 81.25% of patient in non-HD group (p = 0.045) needed infusion of packed cell. 31.25% in HD group and 6.25% in non-HD group needed platelets infusion (p = 0.010). Infection was observed in 9.37% of HD group and 3.12% of non-HD group patients (p = 0.30). The hospital stay in HD group was 15.21+/-2.63 days and in non-HD group was 5.93+/-0.94 days (p = 0.000). Finally, we have 2 death (6.25%) in HD-dependent patients. CONCLUSIONS: Isolated on-pump CABG in HD patients compared with non-HD patients was associated with high rate of morbidity and longer hospitalization. PMID- 24142611 TI - Regulatory functions of docosahexaenoic acid on ion channels in rat ventricular myocytes. AB - OBJECTIVE: The aim of this study was to study the regulatory functions of docosahexaenoic acid (DHA) on resting potential (RP), action potential duration (APD), delayed rectifier potassium current (Ik), and inwardly rectifier potassium current (Ik1) in rat ventricular myocytes, and analyze the related anti arrhythmia mechanism. MATERIALS AND METHODS: Rat ventricular myocytes were isolated by enzyme digestion method. RP, APD, Ik and Ik1 in individual ventricular myocytes were recorded by patch-clamp technique with whole-cell configuration. Effects of DHA with various concentrations (0, 20, 40, 60, 80, 100 and 120 mmol/L, respectively) on RP, AP, Ik and Ik1 were investigated. RESULTS: There was no statistical difference of RP with different DHA concentrations (p > 0.05, n = 20), and the 25%, 50% and 90% of APD (APD25, APD50, and APD90) were gradually prolonged with increase of DHA concentration, respectively (p < 0.05, n = 20). IK gradually blocked and the I-V curve was downward shifted, according to increase of DHA concentration (p < 0.05, n = 20). The DHA half effect concentration (EC50) was 47.52 +/- 2.32 umol/L. With increasing DHA concentration, the steady-state inactivation curve shifted to left, and the recovery curve shifted to right. DHA had no significant effect on IK1 (p > 0.05, n = 20). CONCLUSIONS: DHA has regulatory functions on RP, APD, Ik and Ik1 in rat ventricular myocytes, which may be one of the related antiarrhythmic mechanisms. PMID- 24142612 TI - Clinical significance of mild inferolateral wall ischemia of the left ventricle on 99mTc-MIBI myocardial perfusion single photon emission computed tomography (SPECT). AB - INTRODUCTION: Mild ischemia in the inferolateral wall on myocardial perfusion imaging is seen frequently in practice. The aim of this study is to assess the importance of the above issue on myocardial perfusion SPECT with coronary angiography. PATIENTS AND METHODS: All patients enrolled in this study exhibited mild ischemia of the inferolateral wall on myocardial single photon emission computed tomography (SPECT) with 99mTc-MIBI, using the 20 left ventricular segments model. Each patient completed a questionnaire, including type of chest pain, risk factors, and previous examinations, and all cases were followed up for one year. Luminal stenosis of >50% was classified as significant stenosis on coronary angiography. A p value < 0.05 was considered statistically significant. RESULTS: During investigation, 105 cases had mild ischemia on myocardial perfusion imaging (MPI) of which 36 subjects (22 male and 14 female) underwent coronary angiography. The mean age was 56.62+/-10.23 years old (age range: 36-73 years). The inferolateral wall was compared to the left circumflex (LCX) territory. Nineteen out of 36 (52.7%) cases had stenosis in the LCX. Twenty-three of 105 (21.90%) underwent revascularization during the one year follow up. In multiple logistic regressions, with LCX stenosis on angiography as the dependent variable, only abnormal MPI was independently associated significantly. CONCLUSIONS: The findings of the study may indicate that even a mild perfusion defect in the inferolateral wall should be carefully managed, especially in high risk subjects for coronary artery disease. PMID- 24142613 TI - Comparison of extracts from cooked and raw lentil in antagonizing angiotensin II induced hypertension and cardiac hypertrophy. AB - AIM: The objective of this study is to examine effects of extracts from cooked lentils on angiotensin II (Ang II)-induced hypertension, cardiac hypertrophy and fibrosis in normotensive rats. MATERIALS AND METHODS: Animals were divided into four groups (n=5 each group): control group, Ang II group, Ang II plus cooked lentil extract (Ang II+CLE) group, and Ang II plus raw lentil extract (Ang II+RLE) group. The telemetry blood pressure transducers were implanted into all rats. A telemetry BP probe was positioned intra-abdominally and secured to the ventral abdominal muscle with the catheter inserted into the lower abdominal aorta. Heart wall thickness, cross-sectional area of cardiomyocytes, diameter of the arterial cross-sections, and perivascular fibrosis in heart and kidney were measured. The surface area of positive-staining cardiomyocytes was analyzed using image analysis software. Reactive oxygen species (ROS) generation was determined using an oxidant-sensitive fluorogenic probe. RESULTS: Rats that received cooked or raw lentil extracts (oral administration, 8 weeks) show significantly attenuated Ang II-induced elevation in blood pressure, cardiac hypertrophy, perivascular fibrosis. Results demonstrated that pretreatment of cardiomyocytes with cooked or raw lentil extract significantly attenuated the Ang II-induced increase in the size of cells (16.0+/-1.7% and 21.2+/-2.9%, respectively, n=5, p < 0.05), and cooked or raw lentil extracts also attenuated the Ang II-induced increase in the reactive oxygen species levels in cardiomyocytes (19.8+/-2.2% & 26.6+/-3.1%, respectively, n=5, p < 0.05). CONCLUSIONS: This study showed that extracts from cooked lentils could prevent Ang II-induced elevation in blood pressure, cardiac hypertrophy, small arterial remodeling and perivascular fibrosis, and heating process does not have any significant affect on these protective effects. PMID- 24142614 TI - The influence of angiotensin-converting enzyme 2 gene polymorphisms on type 2 diabetes mellitus and coronary heart disease. AB - BACKGROUND: Diabetes mellitus is a chronic metabolic disorder that results from various genetic and environmental factors, and type 2 diabetes mellitus (T2DM) combined with coronary heart disease (CHD) is one of the most common chronic complications in diabetes. AIM: To explore the correlation between the polymorphism of angiotensin-converting enzyme 2 (ACE2) and T2DM combined with CHD. PATIENTS AND METHODS: A total of 120 patients with T2DM and 93 patients with T2DM and CHD were selected to participate in this study. And polymerase chain reaction -restriction fragment length polymorphism (PCR-RFLP) was used to analyze the polymorphism of G8790A in ACE2 gene. Meanwhile, the clinical, biochemical and echocardiographic data were also analyzed. RESULTS: There was no significant difference between T2DM group and T2DM combined with CHD group in genotype and allele frequencies (p > 0.05). And for different genotypes, both groups had no significant difference in the age, BMI, blood lipid, fasting blood glucose, EF ratio, E/A ration, LVPWTd and LVEDd (p > 0.05). But for male patients in T2DM combined with CHD group, the IVSTd, LVPWTd and urine protein level of allele G were significantly higher than that of allele A with p values less than 0.01, 0.05 and 0.05, respectively. CONCLUSIONS: Genetic polymorphism of G8790A in ACE2 gene plays an important role on the pathogenesis of male patients with T2DM and CHD by changing the levels of IVSTd, LVPWTd and urine protein. Therefore, our results reveal the role of ACE2 polymorphism in the pathogenesis of T2DM with CHD and identify several potential biomarkers for this disease. PMID- 24142615 TI - Kidney disease in HIV-infected patients. AB - The introduction of highly active antiretroviral therapy (HAART) has reduced mortality and improved life expectancy of HIV-positive patients. However, increased survival is associated with increased prevalence of comorbidities, such as cardiovascular disease, hepatic and renal disease. Kidney disease, including HIV-associated nephropathy, acute renal failure and chronic kidney disease, represents one of the main causes of morbidity and mortality, especially if associated to other risk factors, i.e. hypertension, diabetes, older age, black race and hepatitis C coinfection. Careful evaluation of renal function may help identifying kidney disease in its early stages. In addition, proper management of hypertension and diabetes is recommended. Even if HAART has changed the natural course of HIV-associated nephropathy, reducing the risk of End-stage Renal Disease (ERDS), some antiretroviral regimens have been related with the development of acute or chronic kidney disease. Further studies are needed to optimize the management of renal disease among HIV-infected patients. PMID- 24142616 TI - Efficacy of a Dermoxen(r) lenitiva for pruritus genitalis in a randomized, double blind trial. AB - BACKGROUND: Pruritus can be defined as an unpleasant cutaneous sensation associated with the immediate desire to scratch. In particular external intimate zone could be hit by pruritus genitalis because of several reasons (bacterial infection, fungal infection, stress, bad intimate behavior, synthetic intimate clothes). AIM: The aim of the study was to compare the efficacy of Dermoxen(r) Lenitiva cream versus a methylprednisolone aceponate 0.1% based cream in treating pruritus of the external genitalia. PATIENTS AND METHODS: Independent, randomized, double-blind, controlled trial in two University affiliated Italian Hospitals. 80 women, affected by aspecific pruritus genitalis with negative vaginal swab for bacterial or fungal infections or other pathogenic causes of itching, were selected and blindly treated by Dermoxen(r) Lenitiva cream or methylprednisolone aceponate 0.1% based cream. The main outcome measures were: the reduction of sensation of pruritus, evaluated by a visual analog scale (VAS) pain score, and improvement of intimate wellness sensation, and comfort during sexual intercourse, frequency and severity of adverse reactions. RESULTS: Significant reduction of itching sensation was verified for each treatment. CONCLUSIONS: Based on our results, DermoXen(r) Lenitiva vaginal cream showed efficacy so as methylprednisolone aceponate 0.1% based cream for itching treatment on external female genitalia and improved intimate comfort and comfort in sexual intercourse. PMID- 24142617 TI - Congenital idiopathic talipes equinovarus: an evaluation in infants treated by the Ponseti method. AB - BACKGROUND: Congenital talipes equinovarus (CTEV) is a common but still not fully understood disorder of the lower limb. It is usually defined as a fixation of the foot in adduction, supination, and varus. Different treatment options exist including the Ponseti method. AIM: We report here the results obtained in infants with CTEV treated by the Ponseti method. PATIENTS AND METHODS: Eighty two patients (114 clubfeet) were enrolled at the Orthopaedic Clinic of Catania University during the period of March 2004 to January 2010 and followed prospectively up to February 2011: 56 patients (68.29%) were male, the anomaly was bilateral in 32 (39%) cases, unilateral in 50 (60.9%) in the right side in 28 (56%). The mean age at initiation of treatment was 14 days (range 3-81 days), severity of the club foot deformity by the Pirani Severity score was 5.56 points (range 4.3-6 points). Total numbers of Ponseti casts before tenotomy, details of tenotomy, and compliance with CTEV brace were recorded. Clinical evaluation was performed using the functional Ponseti Scoring System. Mean follow up was 4 years: range 13-83 months. RESULTS: An average of 6.6 casts was necessary before performing the tenotomy. Tenotomy was performed by a single surgeon (V.P.) in a total of 68 patients (82.93%) always in an operating room under general anaesthesia by a percutaneous approach at a mean age of 106 days (range 45-213 days). Compliance with CTEV brace was satisfactory in 79 patients (96.3%). Functional Ponseti Scores were good/excellent in 79 (96.34%) patients (109 clubfeet; 95.61%). Only 3 patients; 3.7% (5 clubfeet; 4.4%) suffered relapse. Poor compliance with the Denis Browne splint was thought to be the main cause of failure. CONCLUSIONS: The Ponseti method provides an excellent outcome at follow up in the treatment of congenital idiopathic clubfoot. PMID- 24142618 TI - Evaluation of patients with nasal polyps about the possible association of desmosomal junctions, RORA and PDE4D gene. AB - OBJECTIVES: Nasal polyposis is chronic inflammatory disease of the nasal mucosa of the nose and sinuses, often associated with chronic non-allergic rhinitis, aspirin intolerance and non-allergic asthma. The etiology of nasal polyposis is unknown. Multiple factors contribute to the development of nasal polyps including genetic predisposition. PATIENTS AND METHODS: This study was conducted on patients applied due to nasal polyps. Blood samples were collected peripheral vein and stored at 4 degrees C until analysis for DNA extraction. Genomic DNA was extracted from peripheral blood by a standard method, samples were studied in real time PCR. All patients were evaluated about the possible association of DSG1 (rs7236477-G, 96 rxn), DSG3 (rs1941184-C, 96 rxn), PDE4D (rs1588265) and RORA (rs11071559) gene. RESULTS: 32 patients (17 male, 15 female) with nasal polyposis were included to the study. The mean age was 34.9 +/- 17.7 years, ranging between 18 and 55 years. Control group was consisted with 50 healthy volunteers without a history of nasal polyp. DSG1, DSG3 and RORA values of the study group were not statistically different from control group (p > 0.05). PDE4D values of the study group were significantly different from control group (p < 0.05). CONCLUSIONS: Multiple factors contribute to the pathogenesis of nasal polyps including genetic predisposition. The PDE4D family has gained interest in the complex pathogenesis of nasal polyposis. This is likely linked to the mucosal inflammatory response. PMID- 24142619 TI - Investigation of prevalence and characteristics of mesiodens in a non-syndromic 11256 dental outpatients. AB - AIM: To investigate the prevalence of mesiodens in a sample of Turkish dental patients and their distribution among genders. PATIENTS AND METHODS: A retrospective study was performed using panoramic radiography of 11256 patients, who ranged in age from 15 to 55 years old. All data (age, sex and or syndrome) were obtained from the patient files and analyzed for mesiodens. Statistical evaluation of the presence of mesiodens related to gender was performed by the Pearson chi-squared test. RESULTS: Mesiodens was detected in 15 subjects (0.13%). The prevalence of mesiodens for females and males was 0.20% and 0.057%, respectively (p = 0.037). The most commonly observed mesiodens was maxillary canine-like type (60%). Most of the mesiodens (67%) were found in the vertical position, followed by horizontal position (33%). The age and sex distribution, number of mesiodens per patient, shape, direction, size, and effect on permanent maxillary incisors are also presented in this study. The most common complication caused by mesiodens was midline of the permanent incisors. CONCLUSIONS: Mesiodens is an uncommon developmental anomaly in Turkish dental patients. Early diagnosis allows the most appropriate treatment, often reducing the extent of surgery, orthodontic treatment and possible complications. PMID- 24142620 TI - A new walker with upper trunk suspension system for severely disabled patients. AB - We have recently designed a new type of walker for those severely disabled patients who cannot walk with commonly used medical walkers. A drawing and the description of this new walker is reported in order to permit the worldwide companies as well as artisans to develop and produce it for the people affected from severe motor problems. This walker supposes the patient wearing either a modified climbing harness or equipped clothes and being suspended to the walking frame. It consists in two series of bands suspending the patient from the frame; the upper one suspends him for the upper part of his trunk, the lower one by his pelvis. This walker is suggested for patients belonging to three principal groups: (1) Persons who have no trunk control (e.g.: patients affected by severe stroke or ataxias). (2) Persons whose walk is allowed only if they achieve a significant reduction (up to 30-40%) of the their body weight charging on trunk, spine, and lower limbs. (3) Persons who need a differentiated reduction of the body weight either among anterior and posterior side or among their right and left part of the body (hemiparesis, Parkinson disease, scoliosis, kyphosis). Creating this walker is easy; producing costs are low; there are no maintenance costs. PMID- 24142621 TI - Platelet indices should not be considered a stand-alone test for monitoring the disease progression. PMID- 24142622 TI - Evaluation of admission glucose profile and glycosylated hemoglobin: factors associated with glucose metabolism should be assessed. PMID- 24142623 TI - The atrial electromechanical coupling time: what does it predict in patients with paroxysmal atrial fibrillation? PMID- 24142624 TI - Antenatal steroid exposure and outcomes of very premature infants: a regional cohort study. AB - OBJECTIVE: To compare mortality, short-term morbidity and long-term neurodevelopmental outcomes of <29 week premature infants with antenatal steroid exposure (none, incomplete and complete). PATIENTS AND METHODS: Multicentre retrospective cohort study, within a geographically defined area in Australia served by a network of 10 neonatal intensive care units (NICUs), of infants <29 weeks gestational age, admitted to NICUs between 1998 and 2004. Outcome measures included hospital survival, perinatal complications and functional disability at 2-3 years follow-up. RESULTS: 2549 neonates were included; 319 (12.5%) received no exposure to steroids. Hospital mortality (OR 0.59, 95% CI 0.45 to 0.76, p<0.001, intraventricular haemorrhage (IVH) (OR 0.58, 95% CI 0.42 to 0.81, p=0.001) and necrotising entercolitis (NEC) (OR 0.62, 95% CI 0.42 to 0.91, p=0.018) was less likely in infants with any steroid exposure. Any steroid exposure was associated with less need for surfactant (OR 0.41, 95% CI 0.30 to 0.57, p<0.001) and mechanical ventilation (OR 0.30, 95% CI 0.17 to 0.52, p<0.001). Subgroup analyses demonstrated differences in outcomes only with complete steroid coverage and not with incomplete coverage. Survival benefit and reduction in the incidence of severe IVH was evident from 24 to 28 weeks. Long term neurodevelopmental data available for 1473 survivors showed no significant difference in outcomes with steroid exposure after multivariate analysis. CONCLUSIONS: Exposure to a complete course of antenatal steroids is associated with higher infant survival rates, lower rates of severe IVH and NEC compared to an incomplete course or no exposure. Any exposure to steroids reduces the risk of moderate cerebral palsy, however, long-term neurodevelopmental outcome may not be affected by steroid exposure. PMID- 24142625 TI - Asymptotic number of hairpins of saturated RNA secondary structures. AB - In the absence of chaperone molecules, RNA folding is believed to depend on the distribution of kinetic traps in the energy landscape of all secondary structures. Kinetic traps in the Nussinov energy model are precisely those secondary structures that are saturated, meaning that no base pair can be added without introducing either a pseudoknot or base triple. In this paper, we compute the asymptotic expected number of hairpins in saturated structures. For instance, if every hairpin is required to contain at least theta=3 unpaired bases and the probability that any two positions can base-pair is p=3/8, then the asymptotic number of saturated structures is 1.34685[Symbol: see text]n (-3/2)[Symbol: see text]1.62178 (n) , and the asymptotic expected number of hairpins follows a normal distribution with mean [Formula: see text]. Similar results are given for values theta=1,3, and p=1,1/2,3/8; for instance, when theta=1 and p=1, the asymptotic expected number of hairpins in saturated secondary structures is 0.123194[Symbol: see text]n, a value greater than the asymptotic expected number 0.105573[Symbol: see text]n of hairpins over all secondary structures. Since RNA binding targets are often found in hairpin regions, it follows that saturated structures present potentially more binding targets than nonsaturated structures, on average. Next, we describe a novel algorithm to compute the hairpin profile of a given RNA sequence: given RNA sequence a 1,...,a n , for each integer k, we compute that secondary structure S k having minimum energy in the Nussinov energy model, taken over all secondary structures having k hairpins. We expect that an extension of our algorithm to the Turner energy model may provide more accurate structure prediction for particular RNAs, such as tRNAs and purine riboswitches, known to have a particular number of hairpins. Mathematica(TM) computations, C and Python source code, and additional supplementary information are available at the website http://bioinformatics.bc.edu/clotelab/RNAhairpinProfile/ . PMID- 24142627 TI - Application of an electronic nose in the diagnosis of head and neck cancer. AB - OBJECTIVES/HYPOTHESIS: Electronic nose (E-nose) technology has various applications such as the monitoring of air quality and the detection of explosive and chemical agents. We studied the diagnostic accuracy of volatile organic compounds (VOC) pattern analysis in exhaled breath by means of an E-nose in patients with head and neck squamous cell carcinoma (HNSCC). STUDY DESIGN: Cohort study. Exhaled breath samples from patients with HNSCC were analyzed by using an E-Nose. METHODS: Thirty-six patients diagnosed with HNSCC exhaled into a 5-litre Tedlar bag. The control group consisted of 23 patients visiting the outpatient clinic for other (benign) conditions. Air samples were analyzed using an E-nose. RESULTS: Logistic regression showed a significant difference (P < 0.05) in VOC resistance patterns between patients diagnosed with HNSCC and the control group, with a sensitivity of 90% and a corresponding specificity of 80%. CONCLUSIONS: E nose application holds a promising potential for application in the diagnosis of HNSCC due to its rapid, simple, and noninvasive nature. LEVEL OF EVIDENCE: 3b. PMID- 24142626 TI - Upregulation of the ATR-CHEK1 pathway in oral squamous cell carcinomas. AB - The ATR-CHEK1 pathway is upregulated and overactivated in Ataxia Telangiectasia (AT) cells, which lack functional ATM protein. Loss of ATM in AT confers radiosensitivity, although ATR-CHEK1 pathway overactivation compensates, leads to prolonged G(2) arrest after treatment with ionizing radiation (IR), and partially reverses the radiosensitivity. We observed similar upregulation of the ATR-CHEK1 pathway in a subset of oral squamous cell carcinoma (OSCC) cell lines with ATM loss. In the present study, we report copy number gain, amplification, or translocation of the ATR gene in 8 of 20 OSCC cell lines by FISH; whereas the CHEK1 gene showed copy number loss in 12 of 20 cell lines by FISH. Quantitative PCR showed overexpression of both ATR and CHEK1 in 7 of 11 representative OSCC cell lines. Inhibition of ATR or CHEK1 with their respective siRNAs resulted in increased sensitivity of OSCC cell lines to IR by the colony survival assay. siRNA-mediated ATR or CHEK1 knockdown led to loss of G(2) cell cycle accumulation and an increased sub-G(0) apoptotic cell population by flow cytometric analysis. In conclusion, the ATR-CHEK1 pathway is upregulated in a subset of OSCC with distal 11q loss and loss of the G(1) phase cell cycle checkpoint. The upregulated ATR-CHEK1 pathway appears to protect OSCC cells from mitotic catastrophe by enhancing the G(2) checkpoint. Knockdown of ATR and/or CHEK1 increases the sensitivity of OSCC cells to IR. These findings suggest that inhibition of the upregulated ATR-CHEK1 pathway may enhance the efficacy of ionizing radiation treatment of OSCC. PMID- 24142628 TI - Spectroscopy imaging in intraoperative MR suite: tissue characterization and optimization of tumor resection. AB - BACKGROUND: MR spectroscopy (MRS) measurements are common practice in the preoperative diagnostic regimen, but no evidence exists concerning their value in intraoperative MRI (iMRI) setting. We sought to examine the feasibility of intraoperative MRS and to assess the clinical value of the method in optimizing the gliomas resection. METHODS: Forty-five patients with low- and high-grade gliomas underwent iMRI-assisted surgery, including pre- and intraoperative MRS measurements. During the intraoperative control scan, MRS was performed at the resection margin. Peak areas under the major metabolites (N-acetyl-aspartate: NAA; choline: Cho; and creatine: Cr) resonances were estimated, and their ratios entered in the statistical analysis. RESULTS: Concerning preoperative MRS imaging, mean Cho/NAA and Cho/Cr ratios in low-grade gliomas were 2.3 and 1.2, respectively. The average Cho/NAA and Cho/Cr ratios in the high-grade gliomas were 3.9 and 2.3, respectively. In 12 out of 20 cases with low-grade gliomas, intraoperative conventional MR imaging showed suspected tumor remnant and MRS diagnosed correctly the tissue signal alterations in 10 out of those 12 cases. MRS could characterize gadolinium-enhancing or non-enhancing tumor remnants in all cases with high-grade tumors. Thus, it could help achieve total tumor resection unless the latter was contraindicated due to increased risk of neurological complications. CONCLUSIONS: MR spectroscopy (MRS) in an iMRI setting is feasible, facilitating preoperative glioma staging as well as satisfactory characterization of suspected tumor remnants. Thus, it may be helpful tool for an extended tumor resection. PMID- 24142629 TI - Interconnected, microporous hollow fibers for tissue engineering: commercially relevant, industry standard scale-up manufacturing. AB - Significant progress has been achieved in the field of tissue engineering to create functional tissue using biomimetic three-dimensional scaffolds that support cell growth, proliferation, and extracellular matrix production. However, many of these constructs are severely limited by poor nutrient diffusion throughout the tissue-engineered construct, resulting in cell death and tissue necrosis at the core. Nutrient transport can be improved by creation and use of scaffolds with hollow and microporous fibers, significantly improving permeability and nutrient diffusion. The purpose of this review is to highlight current technological advances in the fabrication of hollow fibers with interconnected pores throughout the fiber walls, with specific emphasis on developing hollow porous nonwoven fabrics for use as tissue engineering constructs via industry standard processing technologies: Spunbond processing and polymer melt extrusion. We outline current methodologies to create hollow and microporous scaffolds with the aim of translating that knowledge to the production of such fibers into nonwoven tissue engineering scaffolds via spunbond technology, a commercially relevant and viable melt extrusion manufacturing approach that allows for facile scale-up. PMID- 24142630 TI - Visual and semi-quantitative analyses of dual-phase breast-specific gamma imaging with Tc-99m-sestamibi in detecting primary breast cancer. AB - OBJECTIVES: Breast cancer is the most common malignancy for females worldwide. This study was to evaluate the application of dual-phase breast-specific gamma imaging (BSGI) in detecting primary breast cancer. METHODS: Seventy-six patients with indeterminate breast lesions that underwent dual-phase BSGI enrolled in this study. All included lesions were confirmed by pathology. BSGI was evaluated based on the visual interpretation and dual-phase semi-quantitative indices of lesion to non-lesion ratio (L/N), which were compared with pathological results. The optimal visual analysis and L/N for double-phase were calculated through receiver operating characteristic curve analysis. RESULTS: Among 76 patients, 92 lesions were finally confirmed by the surgery and pathology, with 54 malignant and 38 benign lesions. Both early and delayed L/N of malignant breast diseases were significantly higher than those of benign (3.18+/-1.57 vs 1.53+/-0.59, and 2.91+/ 1.91 vs 1.46+/-0.54, P<0.05). The optimal visual interpretation is over grade 3, and cut-off L/N was 2.06 and 1.77 for early and delayed imaging, respectively. Compared with visual analysis over grade 3 (77.8 and 81.6%), optimal early L/N (81.5 and 92.1%) or delayed L/N (79.5 and 89.5%) alone, the sensitivity and specificity of visual combined with early-phase L/N in diagnosing primary breast cancer are higher, which were 85.2 and 92.2%, respectively. CONCLUSIONS: The combination of visual and semi-quantitative analysis could improve the sensitivity and specificity of BSGI in detecting primary breast cancer. In addition, the potential value of delayed BSGI in diagnosing primary breast cancer should be further investigated in large samples. PMID- 24142631 TI - The impact of high sensitivity C-reactive protein level on coronary artery spasm as assessed by intracoronary acetylcholine provocation test. AB - PURPOSE: High sensitive C-reactive protein (hs CRP) is well known as a strong risk factor of cardiovascular disease (CVD). The aim of this study is to evaluate the impact of elevated hs CRP on coronary artery spasm (CAS) as assessed by intracoronary acetylcholine (ACh) provocation test. MATERIALS AND METHODS: A total of 1729 consecutive patients without significant CVD who underwent coronary angiography and intracoronary ACh test between November 2004 and August 2010 were analyzed. The patients were divided into five groups according to quintiles of hs CRP levels. RESULTS: At baseline, the prevalence of elderly, hypertension, diabetes mellitus, current smoking, and lipid levels were higher in patients with higher hs CRP. During ACh test, the incidences of significant CAS, ischemic electrocardiography (EKG) change, multivessel, and diffuse CAS were higher in patients with higher hs CRP. Multivariate analysis showed that the old age (OR=1.01, CI; 1.0-1.02, p=0.0226), myocardial bridge (OR=3.34, CI; 2.16-5.17, p<0.001), and highest quintile hs CRP (OR=1.54, CI; 1.12-2.18, p=0.008) were independent predictors of ACh induced CAS. However, there was no difference in clinical outcomes up to 12 months. CONCLUSION: In conclusion, higher hs CRP was associated with higher incidence of CAS, worse angiographic characteristics and ischemic EKG change, but was not associated with clinical outcomes. PMID- 24142632 TI - Association between CDH13 variants and cardiometabolic and vascular phenotypes in a Korean population. AB - PURPOSE: Although some CDH13 single nucleotide polymorphisms (SNPs) have been shown to be determinants of blood adiponectin levels, the clinical implications of CDH13 variants are not yet completely understood. The purpose of this study was to evaluate the effects of SNPs of CDH13 on metabolic and vascular phenotypes. MATERIALS AND METHODS: We included 238 hypertensive subjects and 260 age- and sex-matched controls. Seven tagging-SNPs were identified in the CDH13 gene by whole gene sequencing. The association between these SNP variants and the risk of hypertension, metabolic traits, and carotid intima-media thickness (IMT) was examined. RESULTS: Minor allele carriers of rs12444338 had a lower risk of hypertension, but the association turned out just marginal after adjusting confoudners. Blood glucose levels were higher in the minor allele carriers of c.1407C>T (p=0.01), whereas low-density lipoprotein-cholesterol levels were greater in those of rs6565105 (p=0.02). The minor allele of rs1048612 was associated with a higher body mass index (p=0.01). In addition, the mean carotid IMT was significantly associated with rs12444338 (p=0.02) and rs1048612 (p=0.02). CONCLUSION: These results provide evidence that CDH13 variants are associated with metabolic traits and carotid atherosclerosis in Koreans. This study shows the multifaceted effects of CDH13 variants on cardiometabolic risk. PMID- 24142634 TI - Osteoporosis risk prediction for bone mineral density assessment of postmenopausal women using machine learning. AB - PURPOSE: A number of clinical decision tools for osteoporosis risk assessment have been developed to select postmenopausal women for the measurement of bone mineral density. We developed and validated machine learning models with the aim of more accurately identifying the risk of osteoporosis in postmenopausal women compared to the ability of conventional clinical decision tools. MATERIALS AND METHODS: We collected medical records from Korean postmenopausal women based on the Korea National Health and Nutrition Examination Surveys. The training data set was used to construct models based on popular machine learning algorithms such as support vector machines (SVM), random forests, artificial neural networks (ANN), and logistic regression (LR) based on simple surveys. The machine learning models were compared to four conventional clinical decision tools: osteoporosis self-assessment tool (OST), osteoporosis risk assessment instrument (ORAI), simple calculated osteoporosis risk estimation (SCORE), and osteoporosis index of risk (OSIRIS). RESULTS: SVM had significantly better area under the curve (AUC) of the receiver operating characteristic than ANN, LR, OST, ORAI, SCORE, and OSIRIS for the training set. SVM predicted osteoporosis risk with an AUC of 0.827, accuracy of 76.7%, sensitivity of 77.8%, and specificity of 76.0% at total hip, femoral neck, or lumbar spine for the testing set. The significant factors selected by SVM were age, height, weight, body mass index, duration of menopause, duration of breast feeding, estrogen therapy, hyperlipidemia, hypertension, osteoarthritis, and diabetes mellitus. CONCLUSION: Considering various predictors associated with low bone density, the machine learning methods may be effective tools for identifying postmenopausal women at high risk for osteoporosis. PMID- 24142633 TI - Effects of low dose pioglitazone on restenosis and coronary atherosclerosis in diabetic patients undergoing drug eluting stent implantation. AB - PURPOSE: Thiazolidinediones are insulin-sensitizing agents that reduce neointimal proliferation and the adverse clinical outcomes associated with percutaneous coronary intervention (PCI) in patients with diabetes mellitus (DM). There is little data on whether or not low dose pioglitazone reduces adverse clinical outcomes. MATERIALS AND METHODS: The study population included 121 DM patients with coronary artery disease and they were randomly assigned to 60 patients taking 15 mg of pioglitazone daily in addition to their diabetic medications and 61 patients with placebo after the index procedure with drug-eluting stents (DESs). The primary end points were rate of in-stent restenosis (ISR) and change in atheroma volume and in-stent neointimal volume. The secondary end points were all-cause death, myocardial infarction (MI), stent thrombosis and re-PCI. RESULTS: There were no statistical differences in the clinical outcomes and the rate of ISR between the two groups [all-cause death; n=0 (0%) in the pioglitazone group vs. n=1 (1.6%) in the control group, p=0.504, MI; n=2 (3.3%) vs. n=1 (1.6%), p=0.465, re-PCI; n=6 (10.0%) vs. n=6 (9.8%), p=0.652, ISR; n=4 (9.3%) vs. n=4 (7.5%), p=1.000, respectively]. There were no differences in changes in neointimal volume, percent neointimal volume, total plaque volume and percent plaque volume between the two groups on intravascular ultrasonography (IVUS) study. CONCLUSION: Our study demonstrated that low dose pioglitazone does not reduce rate of ISR, neointimal volume nor atheroma volume in DM patients who have undergone PCI with DESs, despite the limitations of the study. PMID- 24142635 TI - Effect of testosterone replacement therapy on bone mineral density in patients with Klinefelter syndrome. AB - PURPOSE: Klinefelter syndrome (KS) is related to testicular insufficiency, which causes low testosterone levels in serum. Generally, sex hormone levels and bone mineral density (BMD) are lower in patients with KS than normal. We investigated the effects of testosterone replacement on serum testosterone levels and BMD in KS patients. MATERIALS AND METHODS: From December 2005 to March 2008, 18 KS patients with a 47, XXY karyotype were treated with initial intramuscular injections of long-acting testosterone undecanoate (Nebido(r), 1000 mg/4 mL) at baseline and second injections after six weeks. An additional four injections were administered at intervals of 12 weeks after the second injection. BMD was measured at the lumbar spine (L2-4), the left femoral neck and Ward's triangle, using dual energy X-ray absorptiometry. Medical histories, physical examinations and prostate specific antigen, hematology and serum chemistry were conducted for each patient. In addition, total testosterone and sex hormone-binding globulin levels were measured. RESULTS: Following testosterone replacement, mean serum total testosterone increased significantly from baseline (0.90 vs. 4.51 ng/mL, p<0.001), and total testosterone rose to normal levels after replacement in all patients. The mean BMD of the lumbar spine increased significantly (0.91 vs. 0.97 g/cm2, p<0.001). Similar increases of BMD were also observed at the femoral neck, but this increase was not significant. CONCLUSION: These findings suggest that testosterone replacement therapy may be effective in treating BMD deficiency in men with testosterone deficiency, especially those with Klinefelter syndrome. PMID- 24142636 TI - Inflammatory responses in the muscle coat of stomach and small bowel in the postoperative ileus model of guinea pig. AB - PURPOSE: Small intestinal function returns first after surgery, and then the function of the stomach returns to normal after postoperative ileus (POI). The aim of this study was to investigate inflammatory responses in the muscle coat of stomach and small intestine in guinea pig POI model. MATERIALS AND METHODS: The distance of charcoal migration from pylorus to the distal intestine was measured. Hematoxylin and eosin (H&E) and immunohistochemical stain for calprotectin were done from the histologic sections of stomach, jejunum and ileum obtained at 3 and 6 hour after operation. Data were compared between sham operation and POI groups. RESULTS: The distance of charcoal migration was significantly reduced in the 3 and 6 hour POI groups compared with sham operated groups (p<0.05). On H&E staining, the degree of inflammation was significantly higher in the stomach of 3 hour POI groups compared with jejunum and ileum of POI groups or sham operated groups (p<0.05). Calprotectin positive cells were significantly increased in the muscle coat of stomach of 3 hour POI groups compared with jejunum and ileum of POI groups or sham operated groups (p<0.05). There was strong association between the degree of inflammation and calprotectin positive cells in stomach. CONCLUSION: Postoperative ileus induced by cecal manipulation significantly increased the degree of inflammation and calprotectin positive cells in the muscle coat of stomach as a remote organ. The relevance of degree of inflammation and the recovery time of ileus should be pursued in the future research. PMID- 24142637 TI - Gastric autoantigenic proteins in Helicobacter pylori infection. AB - PURPOSE: This study tried to identify novel gastric autoimmune antigens that might be involved in aggravating the atrophic gastritis among patients with Helicobacter pylori infection using two-dimensional immunoblotting analysis. MATERIALS AND METHODS: Proteins from gastric mucosal antrectomy specimens and AGS cells (gastric adenocarcinoma cell lines derived from a Caucasian patient who had received no prior therapy) were 2-dimensionally immunoblotted separately with a pool of 300 sera from H. pylroi-infected patients at Gyeongsang National University Hospital. RESULTS: Thirty-eight autoantigenic proteins including alcohol dehydrogenase [NADP+], alpha enolase, gastrokine-1, gastric triacylglycerol lipase, heat shock 70 kDa protein 1, and peroxiredoxin-2 were identified in the gastric mucosal tissue. Fourteen autoantigenic proteins including programmed cell death 6-interacting protein, serum albumin and T complex protein 1 subunit gamma were identified in the AGS cells. Albumin, alpha enolase, annexin A3, cytoplasmic actin 1, heat shock cognate 71 kDa protein and leukocyte elastase inhibitor were commonly observed autoantigenic proteins in both gastric mucosal tissue and AGS cells. Alpha-enolase, glutathione S transferase P, heat shock cognate 71 kDa protein, heat shock 70 kDa protein 1, human mitochondrial adenosine triphosphate synthase (ATP) subunit beta, mitochondrial 60 kDa heat shock protein, peroxiredoxin-2, 78 kDa glucose regulated protein precursor, tyrosine-protein phosphatase non-receptor type 11 and Tryptophan-Aspartic acid (WD) repeat-containing protein 1 showed 60% or higher amino acid positivity. CONCLUSION: These newly identified gastric autoimmune antigens might be useful in the control and prevention of gastroduodenal disorders, and might be valuable in breaking the vicious circle that exists in gastroduodenal disorders if their pathophysiological roles could be understood in the progress of chronic atrophic gastritis, gastroduodenal ulcers, intestinal metaplasia, and gastric carcinogenesis. PMID- 24142638 TI - Cyclooxygenase-2 polymorphisms and susceptibility to colorectal cancer: a meta analysis. AB - PURPOSE: Four polymorphisms, -765G>C, -1195G>A, 8473T>C, and Val511Ala, in the cyclooxygenase-2 (COX-2) gene were identified to be associated with colorectal cancer (CRC) risk. However, the results are inconsistent. The objective of this meta-analysis was to evaluate the association between these four polymorphisms and the risk of CRC. MATERIALS AND METHODS: All eligible case-control studies published up to December 2012 on the association between the four polymorphisms of COX-2 and CRC risk were identified by searching PubMed and Web of Science. The CRC risk associated with the four polymorphisms of the COX-2 gene was estimated for each study by odds ratio (OR) together with its 95% confidence interval (CI), respectively. RESULTS: A total of 15 case-control studies were included. Overall, no evidence has indicated that the -1195A allele, -765C allele, 8473C allele, and 511Ala allele are associated with susceptibility to CRC (-1195G>A: OR=1.11, 95% CI: 0.82-1.51, p=0.78; -765G>C: OR=1.08, 95% CI: 0.96-1.21, p=0.07; 8473T>C: OR=1.03, 95% CI: 0.89-1.18, p=0.91; Val511Ala: OR=0.71, 95% CI: 0.46-1.09, p=0.94). However, stratified analysis with ethnicity indicated that individuals with -765GC or GC/CC genotypes had an increased risk of CRC among Asian populations (GC vs. GG: OR=1.05, 95% CI: 0.87-1.28, p=0.03; GC+CC vs. GG: OR=1.08, 95% CI: 0.96-1.21, p=0.07). CONCLUSION: This meta-analysis indicated that -765G>C polymorphism was significantly associated with susceptibility to CRC in Asian populations. PMID- 24142639 TI - Dipeptidyl peptidase 10, a novel prognostic marker in colorectal cancer. AB - PURPOSE: The dipeptidyl peptidase IV (DPPIV) gene family exhibits multiple functions and is involved in the pathogenesis of various diseases. It has attracted pharmaceutical interest in the areas of metabolic disorders as well as cancer. However, clinicopathologic significance of DPPIV family in colorectal cancer is not fully understood. MATERIALS AND METHODS: The clinical relevance of DPPIV and DPP10 expression was determined by immunohistochemical staining, and by assessing its clinicopathologic correlation in 383 colorectal cancer patients with known clinical outcomes. RESULTS: DPPIV was not expressed in normal colon mucosa, but it showed luminal expression in 52 of the 383 colorectal cancers (13.5%). DPPIV expression in tumors was associated with right-sided location of the colon (p=0.010) and more advanced tumor stage (p=0.045). DPP10 was expressed in normal colonic mucosa, but its expression varied in primary colorectal cancer tissues. Loss of DPP10 expression was found in 11 colorectal cancers (CRCs) (2.9%), and multivariate analysis showed that loss of DPP10 expression was an independent factor for poor patient prognosis (p=0.008). CONCLUSION: DPP10 may play a role in disease progression of colorectal cancer and loss of DPP10 expression in primary CRC is significantly associated with poor survival outcomes. PMID- 24142640 TI - Perioperative nutritional status changes in gastrointestinal cancer patients. AB - PURPOSE: The presence of gastrointestinal (GI) cancer and its treatment might aggravate patient nutritional status. Malnutrition is one of the major factors affecting the postoperative course. We evaluated changes in perioperative nutritional status and risk factors of postoperative severe malnutrition in the GI cancer patients. MATERIALS AND METHODS: Nutritional status was prospectively evaluated using patient-generated subjective global assessment (PG-SGA) perioperatively between May and September 2011. RESULTS: A total of 435 patients were enrolled. Among them, 279 patients had been diagnosed with gastric cancer and 156 with colorectal cancer. Minimal invasive surgery was performed in 225 patients. PG-SGA score increased from 4.5 preoperatively to 10.6 postoperatively (p<0.001). Ten patients (2.3%) were severely malnourished preoperatively, increasing to 115 patients (26.3%) postoperatively. In gastric cancer patients, postoperative severe malnourishment increased significantly (p<0.006). In univariate analysis, old age (>60, p<0.001), male sex (p=0.020), preoperative weight loss (p=0.008), gastric cancer (p<0.001), and open surgery (p<0.001) were indicated as risk factors of postoperative severe malnutrition. In multivariate analysis, old age, preoperative weight loss, gastric cancer, and open surgery remained significant as risk factors of severe malnutrition. CONCLUSION: The prevalence of severe malnutrition among GI cancer patients in this study increased from 2.3% preoperatively to 26.3% after an operation. Old age, preoperative weight loss, gastric cancer, and open surgery were shown to be risk factors of postoperative severe malnutrition. In patients at high risk of postoperative severe malnutrition, adequate nutritional support should be considered. PMID- 24142641 TI - Prognostic value of 18F-fluorodeoxyglucose positron emission tomography in patients with resectable pancreatic cancer. AB - PURPOSE: We evaluated the prognostic value of (18)F-2-fluoro-2-deoxyglucose positron emission tomography (FDG PET) in patients with resectable pancreatic cancer. MATERIALS AND METHODS: We retrospectively reviewed the medical records of pancreatic cancer patients who underwent curative resection, which included 64 consecutive patients who had preoperative FDG PET scans. For statistical analysis, the maximal standardized uptake value (SUVmax) of primary pancreatic cancer was measured. Survival time was estimated by the Kaplan-Meier method, and Cox's proportional hazard model was used to determine whether SUVmax added new predictive information concerning survival together with known prognostic factors. p<0.05 indicated statistical significance. RESULTS: Overall survival (OS) and disease- free survival (DFS) were respectively 42.9 months (27.6-58.2; 95% CI) and 14.9 months (10.1-19.7; 95% CI). When subjects were divided into two groups according to SUVmax with a cutoff value of 3.5, the high SUVmax group (n=32; SUVmax >3.5) showed significantly shorter OS and DFS than the low SUVmax group. Multivariate analysis of OS and DFS showed that both high SUVmax and poor tumor differentiation were independent poor prognostic factors. CONCLUSION: Our study showed that degree of FDG uptake was an independent prognostic factor in pancreatic cancer patients who underwent curative resection. PMID- 24142642 TI - Influence of methylenetetrahydrofolate reductase C677T polymorphism on the risk of lung cancer and the clinical response to platinum-based chemotherapy for advanced non-small cell lung cancer: an updated meta-analysis. AB - PURPOSE: Methylenetetrahydrofolate reductase (MTHFR) has been implicated in lung cancer risk and response to platinum-based chemotherapy in advanced non-small cell lung cancer (NSCLC). However, the results are controversial. We performed meta-analysis to investigate the effect of MTHFR C677T polymorphism on lung cancer risk and response to platinum-based chemotherapy in advanced NSCLC. MATERIALS AND METHODS: The databases of PubMed, Ovid, Wanfang and Chinese Biomedicine were searched for eligible studies. Nineteen studies on MTHFR C677T polymorphism and lung cancer risk and three articles on C677T polymorphism and response to platinum-based chemotherapy in advanced NSCLC, were identified. RESULTS: The results indicated that the allelic contrast, homozygous contrast and recessive model of the MTHFR C677T polymorphism were associated significantly with increased lung cancer risk. In the subgroup analysis, the C677T polymorphism was significantly correlated with an increased risk of NSCLC, with the exception of the recessive model. The dominant model and the variant T allele showed a significant association with lung cancer susceptibility of ever smokers. Male TT homozygote carriers had a higher susceptibility, but the allelic contrast and homozygote model had a protective effect in females. No relationship was observed for SCLC in any comparison model. In addition, MTHFR 677TT homozygote carriers had a better response to platinum-based chemotherapy in advanced NSCLC in the recessive model. CONCLUSION: The MTHFR C677T polymorphism might be a genetic marker for lung cancer risk or response to platinum- based chemotherapy in advanced NSCLC. However, our results require further verification. PMID- 24142643 TI - Relationships of coagulation factor XIII activity with cell-type and stage of non small cell lung cancer. AB - PURPOSE: Factor XIII (FXIII), a thrombin-activated plasma transglutaminase zymogen, is involved in cancer development and progression through a triggered coagulation pathway. The aim of this study was to examine whether FXIII activity levels differed in non-small cell lung cancer (NSCLC) patients according to histological types and TNM stage when compared with healthy subjects. MATERIALS AND METHODS: Twenty-eight NSCLC patients and 28 normal controls who had been individually age-, gender-, body mass index-, smoking status-, and smoking amount matched were enrolled: 13 adenocarcinomas, 11 squamous cell carcinomas, and four undifferentiated NSCLCs; four stage I, two stage II, 12 stage III, and 10 stage IV NSCLCs. FXIII activity was measured using fluorescence- based protein arrays. RESULTS: The median FXIII activity level of the NSCLC group [24.2 Loewy U/mL, interquartile range (IQR) 14.9-40.4 Loewy U/mL] was significantly higher than that of the healthy group (17.5 Loewy U/mL, IQR 12.6-26.4 Loewy U/mL) (p=0.01). There were no differences in FXIII activity between adenocarcinoma (median 18.6 Loewy U/mL) and squamous cell carcinoma (median 28.7 Loewy U/mL). NSCLC stage significantly influenced FXIII activity (p=0.02). The FXIII activity of patients with stage III NSCLC (median 27.3 Loewy U/mL, IQR 19.3-40.5 Loewy U/mL) was significantly higher than those of patients with stage I or II (median 14.0 Loewy U/mL, IQR 13.1-23.1 Loewy U/mL, p=0.04). FXIII activity was negatively correlated with aPTT in NSCLC patients (r=-0.38, p=0.04). CONCLUSION: Patients with advanced stage NSCLC exhibited higher coagulation FXIII activity than healthy controls and early-stage NSCLC patients. PMID- 24142644 TI - Anaplastic thyroid cancer: ultrasonographic findings and the role of ultrasonography-guided fine needle aspiration biopsy. AB - PURPOSE: To investigate the ultrasonographic (US) features of anaplastic thyroid cancer (ATC) and the diagnostic performance of US-guided fine needle aspiration biopsy (FNAB) therein. MATERIALS AND METHODS: Eighteen cases of ATC diagnosed between January 2001 and May 2011 were included. FNAB was performed in all cases. Initial FNAB results were divided into three groups: 1) the cytological ATC group, cytological diagnosis of ATC; 2) the underestimated group, cytological diagnoses of malignancy other than ATC; and 3) the false negative group, cytological diagnoses of atypical, benign and non-diagnostic lesions. We retrospectively reviewed US findings and compared treatment modalities between each group. RESULTS: Among the 18 patients, there were nine in the initially cytological ATC group, four in the underestimated group and five in the false negative group. The most common US features of ATC were a solid (64.7%) and irregular shaped (88.2%) mass with lymph node involvement (76.4%). However, except for lymph node involvement (p=0.003), US findings for each group were not statistically different. The initial cytological diagnostic accuracy of ATC was 50% (9/18). Surgery was performed less in the ATC group (11%) and the false negative group (20%) than the underestimated group (75%). CONCLUSION: The US features of ATC were not especially different from other types of aggressive thyroid cancer. A correct diagnosis of ATC by initial US-FNAB was made in 50% of the patients, which is significant in that therapeutic surgery can be undertaken in lower numbers if correctly diagnosed. PMID- 24142645 TI - Human leptin protein induces proliferation of A549 cells via inhibition of PKR like ER kinase and activating transcription factor-6 mediated apoptosis. AB - PURPOSE: To investigate the anti-apoptotic mechanism of leptin in non-small cell lung cancer. MATERIALS AND METHODS: The influences of leptin on apoptosis were investigated, analyzing the mechanism that triggers growth of A549 cells. The effects of leptin on cell proliferation were examined by XTT analysis. Leptin, C/EBP homologous protein (CHOP), phosphorylated-PKR-like ER kinase (p-Perk), inositol requiring proteins-1, spliced X-box transcription factor-1 (XBP1), cleaved activating transcription factor-6 (ATF6), eukaryotic translation initiation factor-2alpha, caspase-12 and CHOP protein were detected in four groups by western blot, and endoplasmic reticulum (ER) stress related mRNA were detected by reverse transcription PCR. RESULTS: The expression of leptin in A549 and leptin transfected cells inhibited cisplatin activated ER stress-associated mRNA transcription and protein activation. Two ER stress unfolded protein response pathways, PERK and ATF6, were involved, and XBP1 and tumor necrosis factor receptor-associated factor 2 (TRAF2) were increased significantly when treated with cisplatin in A549-siRNA against leptin cells. Furthermore, CHOP expression was inhibited upon leptin expression in A549, LPT-PeP and LPT-EX cells. CONCLUSION: Leptin serves as an important factor that promotes the growth of A549 cells through blocking ER stress-mediated pathways. This blocking is triggered by p-Perk and ATF6 via inhibition of CHOP expression. PMID- 24142646 TI - Usefulness of endobronchial ultrasound-guided transbronchial needle aspiration for diagnosis of sarcoidosis. AB - PURPOSE: Endobronchial ultrasound-guided transbronchial needle aspiration (EBUS TBNA) is an accurate and minimally invasive technique used routinely for investigation of mediastinal and hilar lymphadenopathy. However, few studies have addressed its role in comparison to the traditional diagnostic approaches of transbronchial lung biopsy (TBLB), endobronchial biopsy (EBB), and bronchoalveolar lavage (BAL) in the diagnosis of sarcoidosis. We evaluated the usefulness of EBUS-TBNA in the diagnosis of sarcoidosis compared to TBLB, EBB, and BAL. MATERIALS AND METHODS: Consecutive patients with suspected sarcoidosis (stage I and II) on chest radiography and chest computed tomography were included. All 33 patients underwent EBUS-TBNA, TBLB, EBB, and BAL during the same session between July 2009 and June 2011. EBUS-TBNA was performed at 71 lymph node stations. RESULTS: Twenty-nine of 33 patients, were diagnosed with histologically proven sarcoidosis; two patients were compatible with a clinical diagnosis of sarcoidosis during follow-up; and two patients were diagnosed with metastatic carcinoma and reactive lymphadenopathy, respectively. Among 29 patients with histologically proven sarcoidosis in combination with EBUS-TBNA, TBLB, and EBB, only EBUS-TBNA and TBLB revealed noncaseating granuloma in 18 patients and one patient, respectively. The overall diagnostic sensitivities of EBUS-TBNA, TBLB, EBB, and BAL (CD4/CD8 >=3.5) were 90%, 35%, 6%, and 71%, respectively (p<0.001). The combined diagnostic sensitivity of EBUS-TBNA, TBLB, and EBB was 94%. CONCLUSION: EBUS-TBNA was the most sensitive method for diagnosing stage I and II sarcoidosis compared with conventional bronchoscopic procedures. EBUS-TBNA should be considered first for the histopathologic diagnosis of stage I and II sarcoidosis. PMID- 24142647 TI - Decreased expression of surfactant protein genes is associated with an increased expression of Forkhead box M1 gene in the fetal lung tissues of premature rabbits. AB - PURPOSE: Recently, Forkhead box M1 (FoxM1) was reported to be correlated with lung maturation and expression of surfactant proteins (SPs) in mice models. However, no study has been conducted in rabbit lungs despite their high homology with human lungs. Thus, we attempted to investigate serial changes in the expressions of FoxM1 and SP-A/B throughout lung maturation in rabbit fetuses. MATERIALS AND METHODS: Pregnant New Zealand White rabbits were grouped according to gestational age from 5 days before to 2 days after the day of expected full term delivery (F5, F4, F3, F2, F1, F0, P1, and P2). A total of 64 fetuses were enrolled after Cesarean sections. The expressions of mRNA and proteins of FoxM1 and SP-A/B in fetal lung tissue were tested by quantitative reverse-transcriptase real-time PCR and Western blot. Furthermore, their correlations were analyzed. RESULTS: The mRNA expression of SP-A/B showed an increasing tendency positively correlated with gestational age, while the expression of FoxM1 mRNA and protein decreased from F5 to F0. A significant negative correlation was found between the expression levels of FoxM1 and SP-A/B (SP-A: R=-0.517, p=0.001; SP-B: R=-0.615, p<0.001). CONCLUSION: Preterm rabbits demonstrated high expression of FoxM1 mRNA and protein in the lungs compared to full term rabbits. Also, the expression of SP-A/B was inversely related with serial changes in FoxM1 expression. This is the first report to suggest an association between FoxM1 and expression of SP-A/B and lung maturation in preterm rabbits. PMID- 24142648 TI - Effects of diet-induced mild obesity on airway hyperreactivity and lung inflammation in mice. AB - PURPOSE: Obesity has been suggested to be linked to asthma. However, it is not yet known whether obesity directly leads to airway hyperreactivity (AHR) or obesity-induced airway inflammation associated with asthma. We investigated obesity- related changes in adipokines, AHR, and lung inflammation in a murine model of asthma and obesity. MATERIALS AND METHODS: We developed mouse models of chronic asthma via ovalbumin (OVA)-challenge and of obesity by feeding a high-fat diet, and then performed the methacholine bronchial provocation test, and real time PCR for leptin, leptin receptor, adiponectin, adiponectin receptor (adipor1 and 2), vascular endothelial growth factor (VEGF), transforming growth factor (TGF) beta, and tumor necrosis factor (TNF) alpha in lung tissue. We also measured cell counts in bronchoalveolar lavage fluid. RESULTS: Both obese and lean mice chronically exposed to OVA developed eosinophilic lung inflammation and AHR to methacholine. However, obese mice without OVA challenge did not develop AHR or eosinophilic inflammation in lung tissue. In obese mice, lung mRNA expressions of leptin, leptin receptor, VEGF, TGF, and TNF were enhanced, and adipor1 and 2 expressions were decreased compared to mice in the control group. On the other hand, there were no differences between obese mice with or without OVA challenge. CONCLUSION: Diet-induced mild obesity may not augment AHR or eosinophilic lung inflammation in asthma. PMID- 24142650 TI - Relationship between cognitive impairment and depression in dialysis patients. AB - PURPOSE: Patients with chronic kidney disease frequently show cognitive dysfunction. The association of depression and cognitive function is not well known in maintenance dialysis patients. We evaluated cognitive impairment and depression, as well as their relationship in regards to methods of dialysis, maintenance hemodialysis (MHD) and chronic peritoneal dialysis (CPD). MATERIALS AND METHODS: Fifty-six maintenance dialysis patients were recruited and their clinical and laboratory data were collected. The Korean version of the mini mental state exam (K-MMSE) was applied to screen the patient's cognitive function, while the Korean version of the Beck Depression Inventory (K-BDI) was used for depression screening. RESULTS: The average age of the participants was 54.2+/-10.2 years; 29 (51.8%) were female. The average dialysis vintage was 4.2+/ 3.8 years. The CPD group showed significantly higher K-MMSE score (27.8+/-2.9 vs. 26.1+/-3.1, p=0.010) and lower K-BDI score (12.0+/-8.4 vs. 20.2+/-10.4, p=0.003) compared with the MHD group. The percentage of patients with depression symptoms was higher in the MHD group (51.7% vs. 18.5%). There was a negative correlation between cognitive function and prevalence of depressive symptoms. Depression and education level were shown to be independent predictors for cognitive impairment in multivariate analysis. CONCLUSION: Cognitive impairment was closely correlated with depression. It is important to detect cognitive impairment and depression early in maintenance dialysis patients with simple bedside screening tools. PMID- 24142649 TI - Iodinated contrast media can induce long-lasting oxidative stress in hemodialysis patients. AB - PURPOSE: Due to their comorbidities, dialysis patients have many chances to undergo radiologic procedures using iodinated contrast media. We aimed to assess time-sequenced blood oxidative stress level after contrast exposure in hemodialysis (HD) patients compared to those in the non-dialysis population. MATERIALS AND METHODS: We included 21 anuric HD patients [HD-coronary angiography (CAG) group] and 23 persons with normal renal function (nonHD-CAG group) scheduled for CAG, and assessed 4 oxidative stress markers [advanced oxidation protein products (AOPP); catalase; 8-hydroxydeoxyguanosine; and malondialdehyde] before and after CAG, and subsequently up to 28 days. RESULTS: In the nonHD-CAG group, only AOPP increased immediately after CAG and returned to baseline within one day. However, in the HD-CAG group, all four oxidative stress markers were significantly increased starting one day after CAG, and remained elevated longer than those in the nonHD-CAG group. Especially, AOPP level remained elevated for a month after contrast exposure. CONCLUSION: Our study showed that iodinated contrast media induces severe and prolonged oxidative stress in HD patients. PMID- 24142651 TI - Factors associated with treatment outcomes in mindfulness-based cognitive therapy for panic disorder. AB - PURPOSE: Although the effectiveness of Mindfulness-Based Cognitive Therapy (MBCT) for panic disorder (PD) has been studied previously, data on the predictors of treatment outcomes in MBCT for PD are scarce. MATERIALS AND METHODS: Eighty patients with PD were screened to analyze treatment outcomes such as MBCT completion, treatment response, and remission after undergoing MBCT for PD. Sociodemographic characteristics, comorbid personality disorders, and baseline medication doses were examined. The study administered the Panic Disorder Severity Scale, Hamilton Anxiety Rating Scale, Hamilton Depression Rating Scale and Anxiety Sensitivity Inventory-Revised to patients at baseline and at eight weeks. RESULTS: Sixty-five participants were enrolled in the present study. Comorbid personality disorder was significantly associated with MBCT non completion. We found that anxiety sensitivity (AS) improvement after an eight week MBCT program was a statistically significant factor associated with treatment response. Using logistic regression analysis, AS improvement after MBCT showed significant association with PD remission after MBCT. CONCLUSION: Comorbid personality disorders of participants could be a potential predictor of MBCT non completion. Furthermore, AS improvement after MBCT may predict treatment response and remission after MBCT for PD. However, better designed studies with a larger number of patients are needed to confirm our findings. PMID- 24142652 TI - Array-based comparative genomic hybridization in 190 Korean patients with developmental delay and/or intellectual disability: a single tertiary care university center study. AB - PURPOSE: This study analyzed and evaluated the demographic, clinical, and cytogenetic data [G-banded karyotyping and array-based comparative genomic hybridization (array CGH)] of patients with unexplained developmental delay or intellectual disability at a single Korean institution. MATERIALS AND METHODS: We collected clinical and cytogenetic data based on retrospective charts at Ajou University Medical Center, Suwon, Korea from April 2008 to March 2012. RESULTS: A total of 190 patients were identified. Mean age was 5.1+/-1.87 years. Array CGH yielded abnormal results in 26 of 190 patients (13.7%). Copy number losses were about two-fold more frequent than gains. A total of 61.5% of all patients had copy number losses. The most common deletion disorders included 22q11.2 deletion syndrome, 15q11.2q12 deletion and 18q deletion syndrome. Copy number gains were identified in 34.6% of patients, and common diseases among these included Potocki Lupski syndrome, 15q11-13 duplication syndrome and duplication 22q. Abnormal karyotype with normal array CGH results was exhibited in 2.6% of patients; theses included balanced translocation (n=2), inversion (n=2) and low-level mosaicism (n=1). Facial abnormalities (p<0.001) and failure to thrive were (p<0.001) also more frequent in the group of patients with abnormal CGH findings. CONCLUSION: Array CGH is a useful diagnostic tool in clinical settings in patients with developmental delay or intellectual disability combined with facial abnormalities or failure to thrive. PMID- 24142653 TI - Single-fulcrum laparoscopic cholecystectomy in uncomplicated gallbladder diseases: a retrospective comparative analysis with conventional laparoscopic cholecystectomy. AB - PURPOSE: Single-fulcrum laparoscopic cholecystectomy (SFLC) is a variant type of single incision and multi-port technique that does not use specialized one-port devices or articulating instruments. We retrospectively compared perioperative outcomes of SFLC with those of conventional laparoscopic cholecystectomy (CLC). MATERIALS AND METHODS: Between March 2009 and December 2010, SFLC was performed in 130 patients. Among them, 105 patients with uncomplicated gallbladder disease (no inflammation or no clinical symptoms) and another 105 patients who underwent CLC were selected for this study. RESULTS: There was no open conversion. In comparison with CLC, SFLC was performed more often in young (46.4+/-12.2 years vs. 52.5+/-13.6 years, p=0.001) female patients (80/25 vs. 62/43, p=0.008). The total operation time was longer in SFLC (56.7+/-14.1 min vs. 47.5+/-17.1 min, p<0.001), but pain scores immediately after operation and at discharge time were lower for SFLC than for CLC (3.1+/-1.3 vs. 4.0+/-1.9, p<0.001, 2.0+/-0.9 vs. 2.4+/-0.8, p=0.002). Total cost was lower for SFLC than for CLC (US $ 1801+/ 289.9 vs. US $ 2003+/-617.4, p=0.004). There were no differences in hospital stay or complication rates. CONCLUSION: SFLC showed greater technical feasibility and cost benefits in treating uncomplicated benign gallbladder disease than CLC. PMID- 24142654 TI - Feasibility of a laparoscopic approach for generalized peritonitis from perforated appendicitis in children. AB - PURPOSE: This study evaluated the feasibility of a laparoscopic approach in children with generalized peritonitis secondary to perforated appendicitis. MATERIALS AND METHODS: We retrospectively analyzed the medical records of patients who underwent laparoscopic appendectomy with drainage for generalized peritonitis secondary to perforated appendicitis at our hospital between September 2001 and April 2012. Laparoscopic outcomes were compared with outcomes of an open method for perforated appendicitis. RESULTS: Ninety-nine patients underwent laparoscopic appendectomy (LA) for generalized peritonitis from perforated appendicitis, and 87 patients underwent open appendectomy (OA) for perforated appendicitis. Wound infection was more common in the OA group (12.6%) than in the LA group (4.0%; p=0.032). The incidence of intestinal obstruction during long-term follow-up was significantly higher in the OA group (4.6% vs. 0.0% in the LA group; p=0.046). LA was possible in most patients for whom LA was attempted, with a conversion rate of 10.8%. Conversion to OA was affected by the preoperative duration of symptoms and the occurrence of intraoperative complications. CONCLUSION: LA is feasible for use in children with generalized peritonitis from perforated appendicitis, with reasonable open conversion and perioperative complication rates comparable to those of the OA group. PMID- 24142655 TI - The relation between inferior mesenteric vein ligation and collateral vessels to splenic flexure: anatomical landmarks, technical precautions and clinical significance. AB - PURPOSE: Our aim to assess clinical significance of the relation between inferior mesenteric vein ligation and collateral blood supply (meandering mesenteric artery) to the splenic flexure with elaboration more in anatomical landmarks and technical tips. MATERIALS AND METHODS: We review the literature regarding the significance of the collateral vessels around inferior mesenteric vein (IMV) root and provide our prospective operative findings, anatomical landmarks and technical tips. We analyzed the incidence and pattern of anatomic variation of collateral vessels around the IMV. RESULTS: A total of 30 consecutive patients have been prospectively observed in a period between June 25-2012 and September 7 2012. Nineteen males and eleven females with mean age of 63 years. Major colorectal procedures were included. There were three anatomical types proposed, based on the relation between IMV and the collateral vessel. Type A and B in which either the collateral vessel crosses or runs close to the IMV with incidence of 43.3% and 13.3%, respectively, whereas type C is present in 43.3%. There was no definitive relation between the artery and vein. No intra or postoperative ischemic events were reported. CONCLUSION: During IMV ligation, inadvertent ligation of Arc of Riolan or meandering mesenteric artery around the IMV root "in type A&B" might result in compromised blood supply to the left colon, congestion, ischemia and different level of colitis or anastomotic dehiscence. Therefore, careful dissection and skeletonization at the IMV root "before ligation if necessary" is mandatory to preserve the collateral vessel for the watershed area and to avoid further injury. PMID- 24142656 TI - Comparative study for preventive effects of intra-abdominal adhesion using cyclo oxygenase-2 enzyme (COX-2) inhibitor, low molecular weight heparin (LMWH), and synthetic barrier. AB - PURPOSE: Postoperative adhesion is the most frequent complication of abdominal surgery. Therefore, we investigated the individual effects of synthetic barrier [hyaluronic acid/carboxymethylcellulose (HA/CMC)] and pharmacologic agents [low molecular weight heparin (LMWH) cyclo-oxygenase-2 inhibitor (COX-2 inhibitor)] using animal model of intra-abdominal adhesion. MATERIALS AND METHODS: The cecum was rubbed with sterile alcohol wet gauze until subserosal haemorrhage and punctate bleeding developed under the general anesthesia. Five animal groups were prepared using the film HA/CMC, gel HA/CMC, LMWH and COX-2 inhibitor. RESULTS: The grade of adhesion by modified Leach method for group I (control), II (film type HA/CMC), III (gel type HA/CMC), IV (LMWH) and V (COX-2 inhibitor) were 5.35+/-1.8, 6.15+/-1.3, 4.23+/-2.6, 5.05+/-0.7 and 5.50+/-0.9, respectively. Group III showed the least grade of adhesion and it is statistically significant in adhesion formation (p=0.028). The numbers of lymphocytes were significantly low in group III and group V compared to the control group (lymphocyte: p=0.004). The mast cell counts were generally low except for the control group (I: 1.05, II: 0.35, III: 0.38, IV: 0.20, V: 0.37), however, it was not statistically significant (p=0.066). CONCLUSION: The gel barriers were shown to be partly efficient in inhibiting the formation of postoperative adhesions and might provide an option for abdominal surgery to reduce postoperative adhesions. The LMWH and COX-2 inhibitor had been known for their inhibitor effect of fibrin formation and anti-angiogenic/ anti-fibroblastic activity, respectively. However, their preventive effects of adhesion and fibrosis were found to be obscure. PMID- 24142657 TI - Changes in spinal canal diameter and vertebral body height with age. AB - PURPOSE: All structures of the spine, including the spinal canal, change continuously with age. The purpose of this study was to determine how the spinal canal of the lumbar spine changes with age. The L4/5 is the most common site of spinal stenosis and has the largest flexion-extension motion, whereas the T5/6 has the least motion. Therefore, we measured the spinal canal diameter and vertebral body height at T5, T6, L4, and L5 with age. MATERIALS AND METHODS: This was a retrospective study of aged 40 to 77 years. We reviewed whole spine sagittal MRIs of 370 patients with lumbar spinal stenosis (LSS) (Group 2) and 166 herniated cervical disc (HCD) (Group 1). Each group was divided into four age groups, and demographic parameters (age, gender, height, weight, BMI), the mid spinal canal diameter, and mid-vertebrae height at T5, T6, L4, L5 were compared. Within- and between-group comparisons were made to evaluate changes by age and correlations were carried out to evaluate the relationships between all parameters. RESULTS: Height, weight, and all radiologic parameters were significantly lower in Group 2 than Group 1. Group 1 did not show any differences, when based on age, but in Group 2, height, weight, and T6, L4, and L5 height were significantly decreased in patients in their 70's than patients in their 40's, except for spinal canal diameter. Age was associated with all parameters except spinal canal diameter. CONCLUSION: Vertebral height decreased with age, but spinal canal diameter did not change in patients with either LSS or HCD. Mid-spinal canal diameter was not affected by aging. PMID- 24142658 TI - Easy identification of mechanical axis during total knee arthroplasty. AB - PURPOSE: We devised an intraoperatively identifiable mechanical axis (IIMA) as a reference of alignment in total knee arthroplasty (TKA). MATERIALS AND METHODS: Between February 2010 and January 2011, primary TKAs were consecutively performed on 672 patients (1007 knees) using an IIMA as a reference in the coronal plane. RESULTS: The alignment of the lower extremity improved from a mean of 11.4+/-6.7 degrees (-10.3-34.4 degrees ) of varus preop. to 0.7+/-3.5 degrees (-5.2-8.6 degrees ) immediately after surgery. Mean alignment of the femoral component in the coronal plane was 89.3+/-2.3 degrees (83.4-97.2 degrees ) postop. and mean alignment of the tibial component was 90.4+/-2.2 degrees (85.1-94.2 degrees ) postop. CONCLUSION: This study showed that IIMA could be of considerable value as a new guider of alignment that is easily accessible and highly effective during total knee arthroplasty. PMID- 24142659 TI - Is there relationship between brain atrophy and higher incidence of hip fracture in old age?--A preliminary study. AB - PURPOSE: The studies on the correlation between incidence of fall and brain atrophy have been going on to find out the cause of fall and its prevention. The purpose of this study was to explore the relationship between incidence of hip fracture and brain volume, measured by magnetic resonance image. MATERIALS AND METHODS: A total of 14 subjects with similar conditions (age, height, weight, and past history) were selected for this study. Fracture group (FG) was consisted of 5 subjects with intertrochanteric fracture. Control group (CG) had 9 subjects without intertrochanteric fracture. MRI-based brain volumetry was done in FG and CG with imaging software. Total brain (tBV), absolute cerebellar volumes (aCV) and relative cerebellar volumes (rCV) were compared between two groups. Student t test was used to statistically analyze the results. RESULTS: In FG, average tBV, aCV and rCV were 1034.676+/-38.80, 108.648+/-76.80 and 10.50+/-0.72 cm3, respectively. In CG, average tBV, aCV and rCV were found to be 1106.459+/-89.15, 114.899+/-98.06 and 10.39+/-0.53 cm3, respectively, having no statistically significant difference (p>0.05). CONCLUSION: There was no significant difference between the fracture and control groups. Patients with neurologic disease such as cerebellar ataxia definitely have high incidence of fall that causes fractures and have brain changes as well. However, FG without neurologic disease did not have brain volume change. We consider that high risk of fall with hip fracture might decrease brain function which is not obvious to pickup on MRI. PMID- 24142660 TI - Autologous platelet-poor plasma gel for injection laryngoplasty. AB - PURPOSE: To overcome the potential disadvantages of the use of foreign materials and autologous fat or collagen, we introduce here an autologous plasma gel for injection laryngoplasty. The purpose of this study was to present a new injection material, a plasma gel, and to discuss its clinical effectiveness. MATERIALS AND METHODS: From 2 mL of blood, the platelet poor serum layer was collected and heated at 100 degrees C for 12 min to form a plasma gel. The plasma gel was then injected into a targeted site; the safety and efficacy thereof were evaluated in 30 rats. We also conducted a phase I/II clinical study of plasma gel injection laryngoplasty in 11 unilateral vocal fold paralysis patients. RESULTS: The plasma gel was semi-solid and an easily injectable material. Of note, plasma gel maintains the same consistency for up to 1 year in a sealed bottle. However, exposure to room air causes the plasma gel to disappear within 1 month. In our animal study, the autologous plasma gel remained in situ for 6 months in animals with minimal inflammation. Clinical study showed that vocal cord palsy was well compensated for with the plasma gel in all patients at two months after injection with no significant complications. Jitter, shimmer, maximum, maximum phonation time (MPT) and mean voice handicap index (VHI) also improved significantly after plasma gel injection. However, because the injected plasma gel was gradually absorbed, 6 patients needed another injection, while the gel remained in place in 2 patients. CONCLUSION: Injection laryngoplasty with autologous plasma gel may be a useful and safe treatment option for temporary vocal cord palsy. PMID- 24142661 TI - Lipid emulsions enhance the norepinephrine-mediated reversal of local anesthetic induced vasodilation at toxic doses. AB - PURPOSE: Intravenous lipid emulsions have been used to treat the systemic toxicity of local anesthetics. The goal of this in vitro study was to examine the effects of lipid emulsions on the norepinephrine-mediated reversal of vasodilation induced by high doses of levobupivacaine, ropivacaine, and mepivacaine in isolated endothelium-denuded rat aorta, and to determine whether such effects are associated with the lipid solubility of local anesthetics. MATERIALS AND METHODS: The effects of lipid emulsions (0.30, 0.49, 1.40, and 2.61%) on norepinephrine concentration-responses in high-dose local anesthetic (6*10(-4) M levobupivacaine, 2*10(-3) M ropivacaine, and 7*10(-3) M mepivacaine) induced vasodilation of isolated aorta precontracted with 60 mM KCl were assessed. The effects of lipid emulsions on local anesthetic- and diltiazem induced vasodilation in isolated aorta precontracted with phenylephrine were also assessed. RESULTS: Lipid emulsions (0.30%) enhanced norepinephrine-induced contraction in levobupivacaine-induced vasodilation, whereas 1.40 and 2.61% lipid emulsions enhanced norepinephrine-induced contraction in both ropivacaine- and mepivacaine-induced vasodilation, respectively. Lipid emulsions (0.20, 0.49 and 1.40%) inhibited vasodilation induced by levobupivacaine and ropivacaine, whereas 1.40 and 2.61% lipid emulsions slightly attenuated mepivacaine (3*10(-3) M) induced vasodilation. In addition, lipid emulsions attenuated diltiazem-induced vasodilation. Lipid emulsions enhanced norepinephrine-induced contraction in endothelium-denuded aorta without pretreatment with local anesthetics. CONCLUSION: Taken together, these results suggest that lipid emulsions enhance the norepinephrine-mediated reversal of local anesthetic-induced vasodilation at toxic anesthetic doses and inhibit local anesthetic-induced vasodilation in a manner correlated with the lipid solubility of a particular local anesthetic. PMID- 24142662 TI - Use of animated cartoons with children's songs to increase compliance with ultrasonography in young children. AB - PURPOSE: To evaluate the effect of animated cartoons with children's songs to increase compliance with ultrasonography (US) examination in young children. MATERIALS AND METHODS: Animated cartoons with children's songs viewed on a cell phone were played just before the start of US examination when pediatric patients were agitated or irritable. The effect of this method was evaluated for initial responses and sustained responses (grade 0, no response; 1, partial response; and 2, good response). Site of US examination, scan duration, and the helpfulness of this method (0, useless; 1, partially helpful; and 2, very helpful) were also recorded. RESULTS: Among 464 pediatric patients who underwent US during the study period, 88 children (19%) needed to be calmed (67 abdominal and 21 other parts of the body). All subjects were less than five years of age (mean 1.5 years), except for four patients with mental retardation. Scan duration was less than 5 minutes in almost all examinations. Five children refused to watch the cartoon. Initial responses were good in 75 and partial in eight children. Sustained responses were good in 70 and partial in 12 children. The cartoons were very helpful in 73 (83%) and partially helpful in nine (10%) children. The effect of watching the cartoon did not change with sex, age (less or more than one year), or site of examination. CONCLUSION: Animated cartoons with children's songs viewed on a cell phone were helpful (93%) in increasing compliance with US examination in young children of both the abdomen and other parts. PMID- 24142663 TI - A case of cerebellar infarction caused by acute subclavian thrombus following minor trauma. AB - Subclavian steal syndrome caused by an acute thrombus is very rare. We present a case of cerebellar infarction with proximal subclavian artery thrombosis. A 56 year-old woman was admitted for sudden vertigo. One day prior to admission, she received a shoulder massage comprised of chiropractic manipulation. On examination, her left hand was pale and radial pulses were absent. Blood pressure was weak in the left arm. Downbeat nystagmus and a right falling tendency were observed. Brain MRI showed multiple acute infarctions in the left cerebellum. The findings of Doppler ultrasonography in the left vertebral artery were compatible with a partial subclavian artery steal phenomenon. Digital subtraction angiography demonstrated a large thrombus in the left subclavian artery. After heparin infusion, thrombus size markedly decreased. Cerebellar infarction caused by acute subclavian thrombosis following minor trauma is rare, but the thrombus can be successfully resolved with anticoagulation. PMID- 24142664 TI - A proposal to prevent the "Mephisto sign" side effect of botulinum toxin type A injection in chronic migraine. AB - Botulinum toxin type A (BoNT-A) has been reported as an effective treatment for chronic migraine. When BoNT-A is injected on the frontalis muscle for chronic migraine, an unexpected clinical side effect called the "Mephisto sign" may occur. The aim of this article is to propose a method to eliminate or prevent the Mephisto sign side effect. A 25-year-old female patient visited the hospital and was diagnosed with chronic migraine. A total of 155 U of BoNT-A was injected into 31 sites. 2-weeks later, and the patient developed the Mephisto sign. An additional 2-U dose was administered bilaterally to the lateral-most point of the frontalis muscles, and the eyebrow morphology returned to normal within 2-3 weeks. We propose that the development of the Mephisto sign may be prevented with an additional BoNT-A injection of 2-4 U bilaterally to the lateral most point of the frontalis muscles during the primary injection process. PMID- 24142665 TI - Successful azathioprine treatment with metabolite monitoring in a pediatric inflammatory bowel disease patient homozygous for TPMT*3C. AB - Thiopurine S-methyltransferase (TPMT) methylates purine analogues, showing TPMT activity in inverse relation to concentrations of active metabolites such as 6 thioguanine nucleotide (6-TGN). With conventional dosing of thiopurines, patients with homozygous variant TPMT alleles consistently suffer from severe myelosuppression. Here, we report a patient with TPMT*3C/*3C who managed successfully with monitoring of thiopurine metabolites. The patient was an 18 year-old male diagnosed with Crohn's disease. The standard dose of azathioprine (AZA) (1.8 mg/kg/day) with mesalazine (55.6 mg/kg/day) was prescribed. Two weeks after starting AZA treatment, the patient developed leukopenia. The DNA sequence analysis of TPMT identified a homozygous missense variation (NM_000367.2: c.719A>G; p.Tyr240Cys), TPMT*3C/*3C. He was treated with adjusted doses of azathioprine (0.1-0.2 mg/kg/day) and his metabolites were closely monitored. Leukopenia did not reoccur during the follow-up period of 24 months. To our knowledge, this is the first case of a patient homozygous for TPMT*3C successfully treated with azathioprine in Korea. While a TPMT genotyping test may be helpful to determine a safe starting dose, it may not completely prevent myelosuppression. Monitoring metabolites as well as routine laboratory tests can contribute to assessing drug metabolism and optimizing drug dosing with minimized drug-induced toxicity. PMID- 24142666 TI - Ceramic head fracture in ceramic-on-polyethylene total hip arthroplasty. AB - Revision rates of total hip arthroplasty have decreased after introducing total hip arthroplasty (THA) using ceramic component, since ceramic components could reduce components wear and osteolysis. The fracture of a ceramic component is a rare but potentially serious event. Thus, ceramic on polyethylene articulation is gradually spotlighted to reduce ceramic component fracture. There are a few recent reports of ceramic head fracture with polyethylene liner. Herein, we describe a case of a ceramic head component fracture with polyethylene liner. The fractured ceramic head was 28 mm short neck with conventional polyethylene liner. We treated the patient by total revision arthroplasty using 4th generation ceramic on ceramic components. PMID- 24142667 TI - Extensive tuberculous lymphadenitis mimicking distant lymph node metastasis on F 18FDG PET/CT in a patient with a history of malignant melanoma. AB - 18-Fluoredeoxyglucose position emission tomography and computed tomography (F 18FDG PET/CT) scanning has been useful in the evaluation of malignant disorders and has been extensively used in cancer screening. However, F-18FDG uptake was not found to be specific for cancer diagnosis. Here, we describe increased F 18FDG uptake on PET/CT caused by extensive tuberculous lymphadenitis in a 62-year old woman with malignant melanoma. PMID- 24142670 TI - Revascularization in heart failure in the post-STICH era. AB - Left ventricular (LV) dysfunction caused by ischemia secondary to coronary artery disease results not only from cardiac myocyte death but also from stunning and hibernation, which are potentially reversible phenomena. Myocardial viability testing is often used in patients with ischemic cardiomyopathy to predict recovery of contractile function after revascularization. Although several observational studies have supported the use of viability testing, the Surgical Treatment for Ischemic Heart failure (STICH) viability substudy challenged its role in clinical decision-making, as viability testing in this study did not predict differential outcomes based on treatment type, and there was a trend toward increased survival in patients with no viability who underwent revascularization. However, the results of the STICH trial have caused controversy because of limitations in study design and implementation. Randomized controlled trials using high-resolution modalities such as positron emission tomography or delayed hyperenhancement cardiac magnetic resonance are needed to determine the incremental benefits that revascularization may afford based on myocardial viability. PMID- 24142672 TI - Bandgap tuning by using a lattice distortion induced by two symmetries that coexist in a quantum dot. AB - Among the interests in the application of quantum dots (QDs), the bandgap tuning is of key importance in controlling their material properties. The bandgap of a QD can be adjusted by adopting a variety of different physicochemical methods. Herein, a novel way of the bandgap tuning is developed in an Ag2S-based QD system by suitably quenching the transformation from monoclinic Ag2S to cubic Ag and by subsequently inducing a lattice-distorted region of ~1-nm-scale in a QD. The two distinct crystalline phases of Ag2S and Ag coexisting with the lattice-distorted region are experimentally demonstrated by visually showing this remarkable coexistence in a QD. A new approach is presented to the bandgap tuning (2.51 to 1.64 eV) and enhancing optical properties by suitably tailoring the degree of the lattice-distorted region in a QD. This conceptual method could pave a new way to utilizing quantum effects in various QD applications. PMID- 24142671 TI - The emerging role of Galectin-3 and ST2 in heart failure: practical considerations and pitfalls using novel biomarkers. AB - Heart failure (HF) is a leading cause of morbidity and mortality worldwide and, despite recent advances in therapy HF hospitalization rates remains unacceptably high. Prompt identification and optimal management of HF can affect long-term outcome. A valuable tool with diagnostic, prognostic, and treatment-guiding properties in this respect will be very useful, as exemplified by natriuretic peptides. However, natriuretic peptide levels show biological variation and are dependent on age, renal function, and body mass index. Recent advances in the field of molecular biology and HF pathophysiology have led to the discovery of other novel biomarkers that may have advantages. Among others, Galectin-3 (GAL3) and sST2 are 2 promising biomarkers that have been recently developed and can be used alone or in combination with natriuretic peptides in clinical practice. In the current paper, we review the existing data regarding GAL3 and sST2 in HF. PMID- 24142673 TI - Self-insertion of a nasogastric tube for home enteral nutrition: a pilot study. AB - BACKGROUND: Enteral tube feeding can be a source of discomfort and reluctance from patients. We evaluated for the first time the tolerability of self-insertion of a nasogastric (NG) tube for home enteral nutrition (EN). MATERIALS AND METHODS: All patients requiring enteral tube feeding for chronic diseases were enrolled in a therapeutic patient education (TPE) program at Nancy University Hospital. RESULTS: In our department, between November 2008 and August 2012, 66 patients received EN with an NG tube. Twenty-nine of 66 had self-insertion of the NG tube (median age, 44 years), 17 had an anatomical contraindication, and 20 were excluded because of cognitive disability or language barrier or refusal. Twenty-eight of 29 patients completed the TPE program. One patient died of pancreatic cancer in palliative care during the study. Median follow-up was 20 months (interquartile range [IQR], 4-31). Median gain weight was 3.1 kg (IQR, 1.8 6.0) (P = .0002). Median duration of self-insertion of the NG tube was 3 months (IQR, 2-5), and it was well tolerated by all 29 patients. Two patients described minor adverse events: abdominal pain and nausea for 1 patient and epistaxis leading to temporary discontinuation of EN for another patient. A group of 10 consecutive patients previously had a long-term NG tube for EN. If they had the choice between a self-inserted NG tube and a long-term NG tube, all 10 patients reported they would prefer to start again with the self-inserted NG tube. CONCLUSION: This pilot study suggests that self-insertion of an NG tube may be efficacious and well tolerated in patients receiving EN for chronic conditions. PMID- 24142674 TI - Microvolt T-wave alternans in adults with complex congenital heart diseases. AB - BACKGROUND: Sudden cardiac death (SCD) mostly resulting from ventricular arrhythmia remains a cause of mortality in 19-30% of adults with congenital heart defects. Indications for implantable cardioverter-defibrillators in primary prophylaxis are still under research. MicrovoltT wave alternans (MTWA) is one of the SCD risk stratification methods. We determined the incidence of MTWA in these patients and its coincidence with ventricular arrhythmia, as well as risk factors of ventricular arrhythmia/SCD. METHODS: 204 patients with complex congenital heart anomalies and 45 healthy volunteers underwent ambulatory ECG monitoring, a cardiopulmonary test, B-type natriuretic peptide assessment, echocardiography and an MTWA test. After excluding technically inadequate traces, the remaining 179 patients and 43 controls were classified into MTWA positive (+), negative (-) and indeterminate (ind) subgroups. Additionally, MTWA (+) and MTWA (ind) formed an 'abnormal' group, labeled MTWA (non-). RESULTS: Abnormal MTWA was observed more frequently in the study group compared to controls (59 [33.0%] vs. 1 [2.3%], p = 0.000001). The MTWA (non-) group compared to MTWA (-) presented a higher number of males (61.0% vs. 37.5%, p = 0.005), predominance of patients with NYHA > I (44.1% vs. 25.0%, p = 0.007), pulmonary hypertension (16.9% vs. 0.8%, p = 0.00007), lower blood saturation (97% [73-100] vs. 99% [69-100], p = 0.0003), higher incidence of malignant arrhythmia (9 [15.2%] vs. 3 [2.5%], p = 0.003), lower peak oxygen consumption VO2 [mL/kg/min] (23.1 +/- 5.9 vs. 26.3 +/- 6.7, p = 0.002), higher VE//VCO2 slope (36.0 [25-74] vs. 31.0 [21-58], p = 0.01). Multivariate logistic regression analysis proved that pulmonary hypertension (OR = 13.7, p = 0.03), male gender (OR = 10.4,p = 0.00002), VE/VCO2 slope (OR = 1.07, p = 0.045) and VO2 (OR = 0.89, p = 0.04) increase the probability of MTWA (non-). CONCLUSIONS: Abnormal MTWA is more frequent in adults with congenital heart diseases than in the healthy population. Its probability increases in patients demonstrating clinical findings conducive to lethal arrhythmia like heart failure and pulmonary hypertension. PMID- 24142675 TI - Brugada syndrome and p.E61X_RANGRF. AB - BACKGROUND: Brugada syndrome is an inherited cardiac condition transmitted with an autosomal dominant pattern which can lead to sudden cardiac death from malignant ventricular arrhythmias. The RANGRF gene has recently been proposed to be associated with Brugada syndrome. This gene encodes the MOG1 protein, a co factor required for the full functioning of the cardiac sodium channel Nav1.5. The nonsense p.E61X genetic variation in the RANGRF gene has been postulated as responsible for Brugada syndrome although no clear association has been established. METHODS: We clinically and genetically evaluated a Spanish family diagnosed with Brugada syndrome. A comprehensive genetic analysis of all genes to date responsible for Brugada syndrome was performed in the index case. RESULTS: The index case was clinically diagnosed with Brugada syndrome after flecainide test. We identified a nonsense variation (p.E61X) in the index case and in other five family members. All of them showed a normal electrocardiogram in basal conditions. Flecainide test unmasked a type 1 Brugada syndrome electrocardiogram only in two of the relatives. CONCLUSIONS: We suggest that p.E61X_RANGRF is a rare genetic variation with an uncertain role in Brugada Syndrome. Further studies must be performed to elucidate the potential pathogenic role of p.E61X_RANGRF in Brugada Syndrome. PMID- 24142676 TI - Is metabolic syndrome related with coronary artery disease severity and complexity: An observational study about IDF and AHA/NHLBI metabolic syndrome definitions. AB - BACKGROUND: The aim of the present study was to assess the relation between metabolic syndrome (MS) and coronary artery disease (CAD) complexity, assessed by Syntax score (SS), and severity in non-diabetic patients with stable CAD who underwent coronary angiography, and to evaluate whether the MS defined by different definitions, including International Diabetes Federation (IDF) and American Heart Association/National Heart Lung Blood Institute (AHA/NHLBI) guidelines, similarly correlated with SS. METHODS: The present study is cross sectional and observational with prospective inclusion of 248 consecutive patients (157 male) who underwent coronary angiography due to stable CAD. RESULTS: The prevalence of MS was 54.4% according to IDF definition and 50.4% according to AHA/NHLBI definition. MS score according to IDF definitions (r = 0.446, p < 0.001), MS score according to AHA/NHLBI definitions (r = 0.341, p < 0.001) were moderately correlated with SS. In Fisher r to z transformation test the correlations of the presence of MS according to IDF and AHA/NHLBI definitions with SS were not statistically significant (p = 0.168, z = -1.38). The systolic blood pressure (p < 0.001, B = 0.354, 95% CI = -0.308 to 0.228), diastolic blood pressure (p = 0.006, B = -0.194, 95% CI = -0.333 to -0.056), age (p = 0.014, B = 0.147, 95% CI = 0.029 to 0.264), left ventricular ejection fraction (p = 0.031, B = -0.150, 95% CI= -0.286 to -0.014), waist/hip circumference (p < 0.001, B = 45.713, 95% CI = 23.235 to 68.1919) and log10 high density lipoprotein (p < 0.001, B = -22.209, 95% CI = -33.298 to-11.119) were the independent predictors of SS in linear regression analysis. CONCLUSIONS: MS is associated with the presence and complexity of CAD. Besides the presence of discrepancy in the limits of waist circumference, both IDF and AHA/NHLBI criteria were similarly correlated with CAD complexity. PMID- 24142677 TI - Bezafibrate treatment is associated with a reduced rate of re-hospitalization in smokers after acute coronary syndrome. AB - BACKGROUND: Significantly increased rate of hospitalizations in current smokers is a major smoking-related problem which is associated with a heavy economic burden, whereas cardiovascular disease accounted for nearly half of hospitalizations. The effect of bezafibrate on the rate of re-hospitalization in smokers already treated with statin immediately post-acute coronary syndrome (ACS) is unknown. The aim of this study was to investigate 30-day rate of re hospitalization in current smokers participating in the ACS Israeli Surveys (ACSIS) and who were treated on discharge with a bezafibrate/statin combination vs. statin alone. METHODS: The study population comprised 3392 patients with confirmed current smoking status from the ACSIS 2000, 2002, 2004, 2006, 2008 and 2010 enrollment waves who were alive on discharge and received statin. Of these, 3189 (94%) were discharged with statin alone, 203 (6%) with a combination of a statin and bezafibrate. RESULTS: Thirty-day re-hospitalization rate was significantly lower in patients from the combination group than in their counterparts from the statin monotherapy group: 12.8% vs. 19%, p = 0.028. Multivariable analysis identified the combined bezafibrate/statin treatment as an independent predictor of reduced risk of 30-day re-hospitalization rate with odds ratio (OR) 0.53 (95% confidence interval [CI] 0.31-0.91), and it corresponded to 47% risk reduction. Other significant variables in our model associated with independent risk of 30-day re-hospitalization rate during the follow-up were female gender (OR 1.43, CI 1.05-1.95, p = 0.03) and age > 65 years (OR 1.49, CI 1.13-1.95, p = 0.004). CONCLUSIONS: Adding bezafibrate to statin in smokers was associated with a significantly reduced 30-day rate of re-hospitalization after ACS. PMID- 24142678 TI - The long-term incidence and predictors of radial artery occlusion following a transradial coronary procedure. AB - BACKGROUND: Radial artery occlusion (RAO) is an infrequent complication of transradial coronary procedures (TRA). To our knowledge, there is no satisfactory data regarding the late term incidence and predictors of RAO in the literature. Our aim was to establish the long-term incidence of radial artery occlusion and investigate its predictors. METHODS: This was a single center prospective study. A total number of 409 consecutive patients undergoing their first TRA were recruited. Clinical and procedural data were all recorded. Doppler ultrasound examination was performed at 6-15 months following the intervention. RESULTS: RAO was detected in 67 patients and 342 patients maintained radial artery patency. The overall RAO incidence was 16.4% at late term. Patients with RAO were younger than the patients with patent radial arteries (55.9 +/- 9.7 vs. 59.1 +/- 9.4 years, p = 0.014). The incidence of RAO in hypertensive patients (9.8%) was lower (p < 0.001) than the observed incidence (23%) in non-hypertensive patients. RAO group had higher rate (28%, p = 0.027) of post--procedural access site pain. Regression analysis revealed that hypertension was negative while post-procedural access site pain was positive independent predictors for RAO. In addition, the relative risk for RAO also increased significantly (p < 0.001) when the ratio of sheath/artery diameter (S/A) was > 1. CONCLUSIONS: The present study reveals that the long-term incidence of RAO is 16.4%. Hypertension, post-procedural access site pain and S/A ratio > 1 are independent predictors of RAO at late term. PMID- 24142679 TI - Association between time to reperfusion and echocardiography assessed left ventricular filling pressure in patients with first ST-segment elevation myocardial infarction undergoing primary coronary intervention. AB - BACKGROUND: Diastolic dysfunction and elevated left ventricular (LV) filling pressure following acute myocardial infarction are associated with adverse outcomes. Although time to reperfusion is a powerful prognostic marker following acute myocardial infarction, little is known about its impact on diastolic function and LV filling pressure. We hypothesized that delayed time to reperfusion will be associated with worse diastolic function. METHODS: This study included 180 consecutive patients with first ST elevation myocardial infarction (STEMI) treated by primary percutaneous coronary intervention (PCI). They presented of chest pain within 24 h and underwent echocardiography within 3 days of primary PCI. RESULTS: Median time to reperfusion, defined as the time from symptom onset to reperfusion at the end of primary PCI, was 185 min (interquartile range 120-660). Patients with reperfusion time > 185 min (n = 92) had a significantly higher E/septal e' (13.3 +/- 5.0 vs. 9.7 +/- 2.3, p < 0.001) and E/lateral e' (9.8 +/- 3.5 vs. 7.8 +/- 2.2, p < 0.001) ratios, and more advanced diastolic grade (p < 0.001) compared to those having early reperfusion (n = 88). There were no significant differences in LV ejection fraction and left atrial volume between the two groups. Time to reperfusion was an independent predictor of early E/average e' ratio. The adverse effect of late reperfusion on diastolic dysfunction was more prominent in patients with anterior myocardial infarction. CONCLUSIONS: Longer time to reperfusion is associated with early elevated LV diastolic pressure in primary PCI-treated patients with STEMI. PMID- 24142680 TI - The effectiveness of transvenous leads extractions implanted more than 10 years before. AB - BACKGROUND: The increasing number of patients with cardiac implantable electronic devices (CIEDs) causes a rise in the absolute percentage of individuals qualifying for a transvenous lead extraction (TLE) due to infectious, vascular or lead failure related indications. As the survival time prolongs, TLE procedures more and more often concern the electrodes of long- -term functioning. Authors provide a retrospective analysis of the effectiveness and safety of TLE performed on leads implanted at least 10 years before the extraction. METHODS: Between 2008 and 2012 we performed TLE of 364 electrodes in 217 patients. Out of these, 66 (18.1%) leads in 43 (19.8%) patients had been implanted for at least 10 years. The mean dwelling time for electrodes was 161 months (120 to 330). In 62% of cases CIED-related infection was an indication for TLE. The following extracting techniques were used: manual direct traction, device traction, mechanical telescopic sheaths, autorotational cutting sheaths and femoral approach. RESULTS: Fifty-eight pacemakers and 8 defibrillating leads were extracted. Sixty-three (95%) completely, in the remaining 3 cases the clinical success was achieved with the small portion of the lead left into the vascular space. No major procedure complications were observed; minor complications were found in 3 (6%) patients. CONCLUSIONS: TLE with the use of various endovascular techniques is an effective and safe method for treating infectious, vascular and mechanical complications of long-lasting CIEDs therapy. PMID- 24142681 TI - Does a blanking period after pulmonary vein isolation impact long-term results? Results after 55 months of follow-up. AB - BACKGROUND: The aims of the study are 1) to assess antiarrhythmic prophylaxis efficacy during the first 2 months after radiofrequency ablation (ARF) due to AF; 2) to define risk factors for early AF recurrence (EAFR) after ARF; 3) to determine the long-term follow-up results and risk factors for late AF recurrence (LAFR). METHODS: A total number of 210 consecutive patients who had undergone ARF due to AF were analyzed. Patients were randomized into three groups: Group 1 (G1), without any anti-arrhythmic drug (AAD); Group 2 (G2), with amiodarone or sotalol; Group 3 (G3), with last ineffective AAD. The study was designed to analyze two periods: short-term observation, the first 2 months after ARF; and at least 2 years of long-term follow-up. RESULTS: After 2 months, clinical data were collected from 171 patients (123 males, mean age of 50.3 years; persistent AF in 19.8%; lone AF in 36.6%). Sinus rhythm (SR) was maintained in 84 (49.1%) patients; 35 (20.4%) patients presented with a single episode of AF, 39 (23%) patients experienced a reduction in number of AF episodes, and 13 (7.5%) patients showed no improvement. No predisposing factor for early recurrence was found. After a mean follow-up of 55 months, clinical data were collected in 137 patients, of which 47 (34%) maintained SR. Those more likely to sustain SR were: males (82.9% vs. 62.2%; p = 0.018), younger patients (44.8 +/- 12.7 vs. 52.5 +/- 9.9; p = 0.0001), patients with smaller left atrium diameter (4.05 +/- +/- 0.49 cm vs. 4.25 +/- 0.51 cm; p = 0.04), and those without any AF recurrence during the first 2 months after ARF (78.7% vs. 35.6%; p < 0.0001). In the multivariable analysis, the independent risk factors for LAFR were hypertension (p < 0.001) and persistent AF (p = 0.014). CONCLUSIONS: Antiarrhythmic prophylaxis does not affect the number of AF recurrences during the first 2 months after ablation. SR maintenance during a blanking period after AF ablation is a positive prognostic factor in long-term follow-up. Persistent AF and hypertension are independent risk factors for late AF recurrence after pulmonary vein isolation. PMID- 24142682 TI - Long-term follow-up after pacemaker implantation via persistent left superior vena cava. AB - BACKGROUND: The persistent left superior vena cava (PLSVC) is a relatively common con-genital venous return anomaly. It may have serious clinical implications especially in case of pacemaker/cardioverter-defibrillator implantation, venous catheter insertion, radio-frequency ablation and cardiac surgery. There is also some evidence that PLSVC may be accompanied by arrhythmias. The aim of this report is to present the effectiveness and safety of cardiac pacing via PLSVC, clinical outcome and appearance of arrhythmias in a long-term follow-up. METHODS AND RESULTS: Four cases of pacing electrodes implanted via PLSVC in patients without any other cardiac congenital heart anomalies were observed for at least 6 years. There was 1 patient with AAI, 2 patients with VVI, and 1 with DDD pacemaker. Atrial electrodes were implanted on the free right atrial wall, 2 ventricular electrodes were implanted in right ventricular outflow tract, 1 in postero-lateral cardiac vein. During the mean 110 months of observation, pacing was efficient. One patient underwent an upgrade from AAI to biatrial pac-ing due to progressive interatrial conduction delay during the follow-up. No other intervention or pacemaker related events were noticed except for battery replacement. CONCLUSIONS: The presence of PSVC may complicate implantation, but it does not influence the long-term follow-up of pacing parameters. PMID- 24142683 TI - Antithrombotic therapy in patients with atrial fibrillation and acute coronary syndrome in the real world: Data from the Berlin AFibACS Registry. AB - BACKGROUND: Guidelines for the management of atrial fibrillation (AFib) recommend antithromboembolic treatment strategies for patients with AFib and acute coronary syndrome (AFibACS). Our study assessed how current guidelines are implemented in the metropolitan area of Berlin and which therapeutic options were chosen in light of stroke and bleeding riskin everyday practice. METHODS AND RESULTS: Between April 2008 and January 2012, we included 1,295 AFibACS patients in the AFibACS Registry, as part of the Berlin Myocardial Infarction Registry. Meanage of the patients was 76 years with numerous comorbidities (15.4% former stroke, 35.0% renal failure, 43.5% diabetes, 92.8% hypertension). Of all the patients, 888 were treated with stent implantation, 91 with balloon angioplasty, and 316 conservatively. Overall mortality was 11.6%, and 8.3% in stented patients. At hospital discharge, triple therapy was administered to 49.9% of stented cases. After adjustment, odds of receiving triple therapy were lower within creasing age and renal failure. Odds were higher after stent implantation, with a higher CHA2DS2-VASc score, and with any AFib category compared to initially diagnosed AFib. Between 2008 and 2011, triple therapy increased from 33.3% to 49.8% for stented patients and did not change significantly for those treated conservatively or with balloon angioplasty. CONCLUSIONS: These data suggest that in AFibACS patients, antithrombotic treatment focused on dual antiplatelet therapy for ACS, rather than on anticoagulation therapy for stroke prevention. Factors influencing therapy at discharge were age, renal failure, stent implantation, AFib category, and CHA2DS2-VASc score. During the study period, triple therapy increased for stented patients. PMID- 24142684 TI - Resting heart rate at hospital admission and its relation to hospital outcome in patients with heart failure. AB - BACKGROUND: Resting heart rate (HR) has been proven to influence long-term prognosis in patients with chronic heart failure (HF). The aim of this study was to assess the relationship between resting HR at hospital admission and hospital outcome in patients with HF. METHODS: The study included Polish patients admitted to hospital due to HF who agreed to participate in Heart Failure Pilot Survey of the European Society of Cardiology. RESULTS: The final analysis included 598 patients. Median HR at hospital admission was 80 bpm. In univariate analyses, higher HR at admission was associated with more frequent use of inotropic support (p = 0.0462) and diuretics (p = 0.0426), worse clinical (New York Heart Association - NYHA) status at discharge (p = 0.0483), longer hospital stay (p = 0.0303) and higher in-hospital mortality (p = 0.003). Compared to patients who survived, patients who died during hospitalization (n = 21; 3.5%) were older, more often had a history of stroke or transient ischemic attack and were characterized by higher NYHA class, higher HR at admission, lower systolic and diastolic blood pressure at admission, lower ejection fraction, lower glomerular filtration rate, and lower natrium and hemoglobin concentrations at hospital admission. In multivariate analysis, higher HR at admission (OR 1.594 [per 10 bpm]; 95% CI 1.061-2.395; p = 0.0248) and lower natrium concentration at admission (OR 0.767 [per 1 mmol/L]; 95% CI 0.618-0.952; p = 0.0162) were the only independent predictors of in-hospital mortality. CONCLUSIONS: In patients with HF, higher resting HR at hospital admission is associated with increased in hospital mortality. PMID- 24142685 TI - Neutrophil to lymphocyte ratio predicts short- and long-term mortality following revascularization therapy for ST elevation myocardial infarction. AB - BACKGROUND: Several inflammation biomarkers have been implicated in the pathogenesis and prognosis of acute coronary syndromes. However, the prognostic role of the neutrophil-lymphocyte white cell interactive response to myocardial injury in predicting short- and long-term mortality after ST elevation myocardial infarction (STEMI) remains poorly defined. METHODS: We evaluated 250 consecutive STEMI patients presenting acutely for revascularization to our tertiary care center over 1 year. Patients with acute sepsis, trauma, recent surgery, autoimmune diseases, or underlying malignancy were excluded. Data gathered included demographics, clinical presentation, leukocyte markers, electrocardiograms, evaluations, therapy,major adverse cardiac events, and all cause mortality. RESULTS: Mean age was 62 +/- 15 years, 70.4% of subjects were males while majority (49.4%) were Caucasians. Mean duration of follow-up was 571 +/- 291 days (median 730 days). Univariate analysis of several inflammatory biomarkers including C-reactive protein, revealed white cell count (OR = 1.09, p < 0.001) and neutrophil to lymphocyte ratio (NLR) (OR = 1.05, p = 0.011) as predictors of short- and long-term mortality; but not mean neutrophil count (OR = 1.04, p = 0.055) or lymphocyte count alone (OR = 0.96, p = 0.551). Multivariate analysis using backward stepwise regression revealed NLR (OR = 2.64, p = 0.026), female gender (OR = 5.35, p < 0.001), cerebrovascular accident history (OR = 3.36, p = 0.023), low glomerular filtration rate (OR = 0.98, p = 0.012) and cardiac arrest on admission (OR = 17.43, p < 0.001) as robust independent predictors of long-term mortality. NLR was divided into two sub-groups based on an optimal cut off value of 7.4. This provided the best discriminatory cut off point for predicting adverse mortality outcome. Both short-term (<= 30 days) and long-term (<= 2 years) mortality were predicted with Kaplan-Meier survival curve separation best stratified by a NLR cut off value of 7.4. CONCLUSIONS: NLR based on an optimal cut off value of 7.4, was an excellent predictor of short- and long term survival in patients with revascularized STEMI and warrants larger scale multi-center prospective evaluation, as a prognostic indicator. NLR offers improved prognostic capacity when combined with conventional clinical scoring systems, such as the Thrombolysis In Myocardial Infarction risk score. PMID- 24142686 TI - Evaluation of beta-blockers on left ventricular dyssynchrony and reverse remodeling in idiopathic dilated cardiomyopathy: A randomized trial of carvedilol and metoprolol. AB - BACKGROUND: The effect of b-blockage on cardiac dyssynchrony in idiopathic dilated cardio-myopathy (IDC) is unknown. This study evaluated the impact of carvedilol and metoprolol succinate on left ventricular (LV) dyssynchrony and reverse remodeling in IDC. METHODS: In this small, prospective, double-blind study, we randomly assigned 81 IDC patients to receive carvedilol or metoprolol succinate. Echocardiographic measurements (dyssynchrony, LV volumes and ejection fraction [EF]) and N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels were obtained at baseline and at first and sixth month of therapy. RESULTS: A total of 74 (91%) patients completed all investigations at sixth month (38 and 36 taking carvedilol and metoprolol succinate, respectively). In the carvedilol group, reduction in LV end diastolic volume (D LVEDV at 6 months, 50 +/- 15 mL to 40 +/- 17 mL, p = 0.03) and increase in LVEF (D LVEF, 7 +/- 2% to 5 +/- 3%, p = 0.02) was higher compared to the metoprolol group. Also improvement in inter ventricular dyssynchrony achieved with carvedilol was higher than metoprolol (D interventricular delay at 6 months, 11 +/- 8 ms to 6 +/- 7 ms, p = 0.03). However, improvement in intraventricular dyssynchrony was similar in the two groups (D intraventricular delay, 9 +/- 7 ms to 9 +/- 6 ms, p = 0.91). Improvements in LV mechanical dyssynchrony and reverse remodeling achieved with both drugs were accompanied by reduction in NT-proBNP levels in both carvedilol and metoprolol groups (1614 +/- 685 pg/mL to 654 +/- +/- 488 pg/mL and 1686 +/- 730 pg/mL to 583 +/- 396 pg/mL, respectively, p < 0.001 for both). CONCLUSIONS: Although reduction in LVEDV and increase in LVEF was higher with carvedilol, improvement in intraventricular dyssynchrony was similar in carvedilol and metoprolol groups. PMID- 24142687 TI - Effect of carvedilol on silent anthracycline-induced cardiotoxicity assessed by strain imaging: A prospective randomized controlled study with six-month follow up. AB - BACKGROUND: The use of antracycline (ANT) in breast cancer has been associated with adverse cardiac events. Two-dimensional (2D) strain imaging (SI) can provide a more sensitive measure of altered left ventricular (LV) systolic function. We aimed to evaluate the preventive effect of carvedilol administration assessed by SI in a patient with breast cancer treated with ANT. METHODS: Patients receiving ANT were randomly assigned to the carvedilol- or placebo-receiving group. Each received an echocardiographic examination with conventional 2D echocardiography, pulsed tissue Doppler, and 2D SI prior to and 6 months post ANT treatment. RESULTS: During the 6-month follow-up period there were no patient deaths or interrupted chemotherapy treatments due to doxorubicin-induced cardiotoxicity. Both left ventricular ejection fraction (LVEF) and fractional shortening (FS) were within normal limits for all patients before and after ANT therapy. EF, FS and LV dimensions were measured using M-mode echocardiography and found to be similar in both groups before and after ANT therapy. The mean EF, FS, and LV echocardiograph baseline and control dimensions were similar in both groups after 6 months. Though baseline SI parameters were similar between the groups, there was a significant decrease in LV basal septal and basal lateral peak systolic strain in the control group compared to the carvedilol group. CONCLUSIONS: These results indicate that carvedilol has a protective effect against the cardiotoxicity induced by ANT. PMID- 24142688 TI - Cell layers and neuropil: contrast-enhanced MRI of mouse brain in vivo. AB - Contrast-enhanced T1- and T2-weighted MRI at 9.4 T and in-plane resolutions of 25 and 30 um has been demonstrated to differentiate between neural tissues in mouse brain in vivo, including granule cell layers, principal cell layers, general neuropil, specialized neuropil and white matter. In T1-weighted MRI of the olfactory bulb, hippocampus and cerebellum, contrast obtained by the intracranial administration of gadopentetate dimeglumine (Gd-DTPA) reflects the extra- and intracellular spaces of gray matter in agreement with histological data. General neuropil areas are highlighted, whereas other tissues present with lower signal intensities. The induced contrast is similar to that in plain T2-weighted MRI, but offers a 16-30-fold higher contrast-to-noise ratio. Systemic administration of manganese chloride increases the signal-to-noise ratio in T1-weighted MRI to a significantly greater extent in principal cell layers and specialized neuropil than in granule cell layers, whereas gadolinium-enhanced MRI indicates no larger intracellular spaces in these tissues. Granule cell layers are enhanced no more than general neuropil by manganese, whereas gadolinium-enhanced MRI indicates significantly larger intracellular spaces in the cell layers. These discrepancies suggest that the signal increase after manganese administration reflects cellular activity which is disproportionate to the intracellular space. As a result, principal cell layers and specialized neuropil become highlighted, whereas granule cell layers, general neuropil and white matter present with lower signal intensities. PMID- 24142689 TI - Buffalo alpha S1-casein gene 5'-flanking region and its interspecies comparison. AB - The expression of milk protein genes is tightly regulated in a spatio-temporal manner through the combinatorial interaction of lactogenic hormones and a set of transcription factors mediating developmental and tissue-specific gene expression. The recruitment of a unique set of transcription factors is determined by the cis-regulatory motifs present in the gene promoter region. Here, we report the isolation, sequencing, structural analysis and interspecies comparison of the 5'cis-regulatory region of the buffalo alpha S1 (alphaS1) casein gene. The proximal promoter region of the buffalo alphaS1-casein gene harbored the insertion of a 72-bp fragment of long interspersed nuclear element of the L1_BT retrotransposon family. Among the core and vertebrate-specific promoter elements, the motifs for the binding of Brn POU domain factors (BRNF), Lim homeodomain factors (LHXF), NK6 homeobox transcription factors (NKX6), nuclear factor kappa B/c-rel (NFKB), AT-rich interactive domain factor (ARID), Brn POU domain factor 5 (BRN5), pancreatic and intestinal homeodomain transcription factor (PDX1), Distal-less homeodomain transcription factors (DLXF), T-cell factor/lymphoid enhancer-binding factor-1 (LEFF) and GHF-1 pituitary-specific POU domain transcription factor (PIT1) were over-represented in the alphaS1-casein gene regulatory region (Z score >4.0). The Multiple EM for Motif elicitation predicted three motifs which consisted of the sequences known to bind mammary gland factor/signal transducer and activator of transcription 5 (MGF/STAT5), estrogen receptor-related alpha (ERalpha), steroidogenic factor 1 (SF1) and glucocorticoid receptor (GR), indicating their potential role in the mammary gland-specific gene expression. The interspecies comparison of the proximal promoter region revealed conserved sequences for TATA boxes and MGF/STAT5 in all species, whereas activator protein 1 (AP1), pregnancy-specific mammary nuclear factor (PMF), CCAAT/enhancer binding protein (C/EBP), double stranded and single-stranded DNA-binding protein 1 (DS1 and SS), ying and yang factor 1 (YY1), and GR half-sites were among ruminants. The functional significance of the L1_BT retrotransposon insertion on the buffalo alphaS1-casein gene expression needs to be experimentally validated. PMID- 24142690 TI - Defect of mitotic vimentin phosphorylation causes microophthalmia and cataract via aneuploidy and senescence in lens epithelial cells. AB - Vimentin, a type III intermediate filament (IF) protein, is phosphorylated predominantly in mitosis. The expression of a phosphorylation-compromised vimentin mutant in T24 cultured cells leads to cytokinetic failure, resulting in binucleation (multinucleation). The physiological significance of intermediate filament phosphorylation during mitosis for organogenesis and tissue homeostasis was uncertain. Here, we generated knock-in mice expressing vimentin that have had the serine sites phosphorylated during mitosis substituted by alanine residues. Homozygotic mice (VIM(SA/SA)) presented with microophthalmia and cataracts in the lens, whereas heterozygotic mice (VIM(WT/SA)) were indistinguishable from WT (VIM(WT/WT)) mice. In VIM(SA/SA) mice, lens epithelial cell number was not only reduced but the cells also exhibited chromosomal instability, including binucleation and aneuploidy. Electron microscopy revealed fiber membranes that were disorganized in the lenses of VIM(SA/SA), reminiscent of similar characteristic changes seen in age-related cataracts. Because the mRNA level of the senescence (aging)-related gene was significantly elevated in samples from VIM(SA/SA), the lens phenotype suggests a possible causal relationship between chromosomal instability and premature aging. PMID- 24142691 TI - [Ca2+]i elevation and oxidative stress induce KCNQ1 protein translocation from the cytosol to the cell surface and increase slow delayed rectifier (IKs) in cardiac myocytes. AB - Our goals are to simultaneously determine the three-dimensional distribution patterns of KCNQ1 and KCNE1 in cardiac myocytes and to study the mechanism and functional implications for variations in KCNQ1/KCNE1 colocalization in myocytes. We monitored the distribution patterns of KCNQ1, KCNE1, and markers for subcellular compartments/organelles using immunofluorescence/confocal microscopy and confirmed the findings in ventricular myocytes by directly observing fluorescently tagged KCNQ1-GFP and KCNE1-dsRed expressed in these cells. We also monitored the effects of stress on KCNQ1-GFP and endoplasmic reticulum (ER) remodeling during live cell imaging. The data showed that 1) KCNE1 maintained a stable cell surface localization, whereas KCNQ1 exhibited variations in the cytosolic compartment (striations versus vesicles) and the degree of presence on the cell surface; 2) the degree of cell surface KCNQ1/KCNE1 colocalization was positively correlated with slow delayed rectifier (IKs) current density; 3) KCNQ1 and calnexin (an ER marker) shared a cytosolic compartment; and 4) in response to stress ([Ca(2+)]i elevation, oxidative overload, or AT1R stimulation), KCNQ1 exited the cytosolic compartment and trafficked to the cell periphery in vesicles. This was accompanied by partial ER fragmentation. We conclude that the cellular milieu regulates KCNQ1 distribution in cardiac myocytes and that stressful conditions can increase IKs by inducing KCNQ1 movement to the cell surface. This represents a hitherto unrecognized mechanism by which IKs fulfills its function as a repolarization reserve in ventricular myocytes. PMID- 24142692 TI - The Ets transcription factor EHF as a regulator of cornea epithelial cell identity. AB - The cornea is the clear, outermost portion of the eye composed of three layers: an epithelium that provides a protective barrier while allowing transmission of light into the eye, a collagen-rich stroma, and an endothelium monolayer. How cornea development and aging is controlled is poorly understood. Here we characterize the mouse cornea transcriptome from early embryogenesis through aging and compare it with transcriptomes of other epithelial tissues, identifying cornea-enriched genes, pathways, and transcriptional regulators. Additionally, we profiled cornea epithelium and stroma, defining genes enriched in these layers. Over 10,000 genes are differentially regulated in the mouse cornea across the time course, showing dynamic expression during development and modest expression changes in fewer genes during aging. A striking transition time point for gene expression between postnatal days 14 and 28 corresponds with completion of cornea development at the transcriptional level. Clustering classifies co-expressed, and potentially co-regulated, genes into biologically informative categories, including groups that exhibit epithelial or stromal enriched expression. Based on these findings, and through loss of function studies and ChIP-seq, we show that the Ets transcription factor EHF promotes cornea epithelial fate through complementary gene activating and repressing activities. Furthermore, we identify potential interactions between EHF, KLF4, and KLF5 in promoting cornea epithelial differentiation. These data provide insights into the mechanisms underlying epithelial development and aging, identifying EHF as a regulator of cornea epithelial identity and pointing to interactions between Ets and KLF factors in promoting epithelial fate. Furthermore, this comprehensive gene expression data set for the cornea is a powerful tool for discovery of novel cornea regulators and pathways. PMID- 24142693 TI - The growth factor receptor ERBB2 regulates mitochondrial activity on a signaling time scale. AB - Overexpression of the ERBB2 receptor tyrosine kinase and the mitochondrial inner membrane protein UCP2 occurs frequently in aggressive cancers with dysfunctional mitochondria. Overexpressed ERBB2 signals constitutively and elevated UCP2 can uncouple mitochondria and alleviate oxidative stress. However, the physiological contributions of UCP2 and ERBB2 at the low expression levels that are typical of most tissues, as well as the path to oncogenic deregulation, are poorly understood. We now show that ERBB2 directly controls UCP2 levels, both at low physiological levels and oncogenic overexpression. At low levels of receptor and UCP2, ligand stimulation creates a distinct temporal response pattern driven by the opposing forces of translational suppression of the exceptionally short lived UCP2 protein and a time delayed transcriptional up-regulation. The latter becomes dominant through constitutive signaling by overexpressed ERBB2, resulting in high levels of UCP2 that contribute mitochondrial uncoupling. By contrast, ligand stimulation of non-overexpressed ERBB2 transiently removes UCP2 and paradoxically reduces the mitochondrial membrane potential, oxygen consumption, and OXPHOS on a signaling time scale. However, neither the transporter activity nor down regulation of already low UCP2 levels drive this reduction in mitochondrial activity. Instead, UCP2 is required to establish mitochondria that are capable of responding to ligand. UCP2 knockdown impairs proliferation at high glucose but its absence specifically impairs ligand-induced growth when glucose levels fluctuate. These findings demonstrate the ability of growth factor signaling to control oxidative phosphorylation on a signaling time scale and point toward a non-transporter role for low levels of UCP2 in establishing dynamic response capability. PMID- 24142694 TI - Allosteric control of betaII-tryptase by a redox active disulfide bond. AB - The S1A serine proteases function in many key biological processes such as development, immunity, and blood coagulation. S1A proteases contain a highly conserved disulfide bond (Cys(191)-Cys(220) in chymotrypsin numbering) that links two beta-loop structures that define the rim of the active site pocket. Mast cell betaII-tryptase is a S1A protease that is associated with pathological inflammation. In this study, we have found that the conserved disulfide bond (Cys(220)-Cys(248) in betaII-tryptase) exists in oxidized and reduced states in the enzyme stored and secreted by mast cells. The disulfide bond has a standard redox potential of -301 mV and is stoichiometrically reduced by the inflammatory mediator, thioredoxin, with a rate constant of 350 m(-1) s(-1). The oxidized and reduced enzymes have different substrate specificity and catalytic efficiency for hydrolysis of both small and macromolecular substrates. These observations indicate that betaII-tryptase activity is post-translationally regulated by an allosteric disulfide bond. It is likely that other S1A serine proteases are similarly regulated. PMID- 24142695 TI - Mechanisms of transient signaling via short and long prolactin receptor isoforms in female and male sensory neurons. AB - Prolactin (PRL) regulates activity of nociceptors and causes hyperalgesia in pain conditions. PRL enhances nociceptive responses by rapidly modulating channels in nociceptors. The molecular mechanisms underlying PRL-induced transient signaling in neurons are not well understood. Here we use a variety of cell biology and pharmacological approaches to show that PRL transiently enhanced capsaicin-evoked responses involve protein kinase C epsilon (PKCepsilon) or phosphatidylinositol 3 kinase (PI3K) pathways in female rat trigeminal (TG) neurons. We next reconstituted PRL-induced signaling in a heterologous expression system and TG neurons from PRL receptor (PRLR)-null mutant mice by expressing rat PRLR-long isoform (PRLR-L), PRLR-short isoform (PRLR-S), or a mix of both. Results show that PRLR-S, but not PRLR-L, is capable of mediating PRL-induced transient enhancement of capsaicin responses in both male and female TG neurons. However, co-expression of PRLR-L with PRLR-S (1:1 ratio) leads to the inhibition of the transient PRL actions. Co-expression of PRLR-L deletion mutants with PRLR-S indicated that the cytoplasmic site adjacent to the trans-membrane domain of PRLR L was responsible for inhibitory effects of PRLR-L. Furthermore, in situ hybridization and immunohistochemistry data indicate that in normal conditions, PRLR-L is expressed mainly in glia with little expression in rat sensory neurons (3-5%) and human nerves. The predominant PRLR form in TG neurons/nerves from rats and humans is PRLR-S. Altogether, PRL-induced transient signaling in sensory neurons is governed by PI3K or PKCepsilon, mediated via the PRLR-S isoform, and transient effects mediated by PRLR-S are inhibited by presence of PRLR-L in these cells. PMID- 24142696 TI - Independent contribution of extracellular proton binding sites to ASIC1a activation. AB - Acid-sensing ion channels (ASICs) are a group of trimeric cation permeable channels gated by extracellular protons that are mainly expressed in the nervous system. Despite the structural information available for ASIC1, there is limited understanding of the molecular mechanism that allows these channels to sense and respond to drops in extracellular pH. In this report, we employed the substituted cysteine accessibility method and site-directed mutagenesis to examine the mechanism of activation of ASIC1a by extracellular protons. We found that the modification of E238C and D345C channels by MTSET reduced proton apparent affinity for activation. Furthermore, the introduction of positively charged residues at position 345 rendered shifted biphasic proton activation curves. Likewise, channels bearing mutations at positions 79 and 416 in the palm domain of the channel showed reduced proton apparent affinity and biphasic proton activation curves. Of significance, the effect of the mutations at positions 79 and 345 on channel activation was additive. E79K-D345K required a change to a pH lower than 2 for maximal activation. In summary, this study provides direct evidence for the presence of two distinct proton coordination sites in the extracellular region of ASIC1a, which jointly facilitate pore opening in response to extracellular acidification. PMID- 24142697 TI - Cysteine racemization on IgG heavy and light chains. AB - Under basic pH conditions, the heavy chain 220-light chain 214 (H220-L214) disulfide bond, found in the flexible hinge region of an IgG1, can convert to a thioether. Similar conditions also result in racemization of the H220 cysteine. Here, we report that racemization occurs on both H220 and L214 on an IgG1 with a lambda light chain (IgG1lambda) but almost entirely on H220 of an IgGl with a kappa light chain (IgG1kappa) under similar conditions. Likewise, racemization was detected at significant levels on H220 and L214 on endogenous human IgG1lambda but only at the H220 position on IgG1kappa. Low but measurable levels of D-cysteines were found on IgG2 cysteines in the hinge region, both with monoclonal antibodies incubated under basic pH conditions and on antibodies isolated from human serum. A simplified reaction mechanism involving reversible beta-elimination on the cysteine is presented that accounts for both base catalyzed racemization and thioether formation at the hinge disulfide. PMID- 24142698 TI - Proviral insertion in murine lymphomas 2 (PIM2) oncogene phosphorylates pyruvate kinase M2 (PKM2) and promotes glycolysis in cancer cells. AB - Pyruvate kinase M2 (PKM2) is a key player in the Warburg effect of cancer cells. However, the mechanisms of regulating PKM2 are not fully elucidated. Here, we identified the protein-serine/threonine kinase PIM2, a known oncogene, as a novel binding partner of PKM2. The interaction between PIM2 and PKM2 was confirmed by multiple biochemical approaches in vitro and in cultured cells. Importantly, we found that PIM2 could directly phosphorylate PKM2 on the Thr-454 residue, resulting in an increase of PKM2 protein levels. Compared with wild type, PKM2 with the phosphorylation-defective mutation displayed a reduced effect on glycolysis, co-activating HIF-1alpha and beta-catenin, and cell proliferation, while enhancing mitochondrial respiration of cancer cells. These findings demonstrate that PIM2-dependent phosphorylation of PKM2 is critical for regulating the Warburg effect in cancer, highlighting PIM2 as a potential therapeutic target. PMID- 24142699 TI - Deficiency of a glycogen synthase-associated protein, Epm2aip1, causes decreased glycogen synthesis and hepatic insulin resistance. AB - Glycogen synthesis is a major component of the insulin response, and defective glycogen synthesis is a major portion of insulin resistance. Insulin regulates glycogen synthase (GS) through incompletely defined pathways that activate the enzyme through dephosphorylation and, more potently, allosteric activation. We identify Epm2aip1 as a GS-associated protein. We show that the absence of Epm2aip1 in mice impairs allosteric activation of GS by glucose 6-phosphate, decreases hepatic glycogen synthesis, increases liver fat, causes hepatic insulin resistance, and protects against age-related obesity. Our work identifies a novel GS-associated GS activity-modulating component of insulin resistance. PMID- 24142700 TI - Co-translational processing of glycoprotein 3 from equine arteritis virus: N glycosylation adjacent to the signal peptide prevents cleavage. AB - Signal peptide cleavage and N-glycosylation of proteins are co-translational processes, but little is known about their interplay if they compete for adjacent sites. Here we report two unique findings for processing of glycoprotein 3 of equine arteritis virus. Glycoprotein 3 (Gp3) contains an N-terminal signal peptide, which is not removed, although bioinformatics predicts cleavage with high probability. There is an overlapping sequon, NNTT, adjacent to the signal peptide that we show to be glycosylated at both asparagines. Exchanging the overlapping sequon and blocking glycosylation allows signal peptide cleavage, indicating that carbohydrate attachment inhibits processing of a potentially cleavable signal peptide. Bioinformatics analyses suggest that a similar processing scheme may exist for some cellular proteins. Membrane fractionation and secretion experiments revealed that the signal peptide of Gp3 does not act as a membrane anchor, indicating that it is completely translocated into the lumen of the endoplasmic reticulum. Membrane attachment is caused by the hydrophobic C terminus of Gp3, which, however, does not span the membrane but rather attaches the protein peripherally to endoplasmic reticulum membranes. PMID- 24142701 TI - Evidence for central regulation of glucose metabolism. AB - Evidence for central regulation of glucose homeostasis is accumulating from both animal and human studies. Central nutrient and hormone sensing in the hypothalamus appears to coordinate regulation of whole body metabolism. Central signals activate ATP-sensitive potassium (KATP) channels, thereby down-regulating glucose production, likely through vagal efferent signals. Recent human studies are consistent with this hypothesis. The contributions of direct and central inputs to metabolic regulation are likely of comparable magnitude, with somewhat delayed central effects and more rapid peripheral effects. Understanding central regulation of glucose metabolism could promote the development of novel therapeutic approaches for such metabolic conditions as diabetes mellitus. PMID- 24142702 TI - Mutations in the polybasic juxtamembrane sequence of both plasma membrane- and endoplasmic reticulum-localized epidermal growth factor receptors confer ligand independent cell transformation. AB - Deregulation of ErbB receptor-tyrosine kinases is a hallmark of many human cancers. Conserved in the ErbB family is a cluster of basic amino acid residues in the cytoplasmic juxtamembrane region. We found that charge-silencing mutagenesis within this juxtamembrane region of the epidermal growth factor receptor (EGFR) results in the generation of a mutant receptor (EGFR Mut R1-6) that spontaneously transforms NIH 3T3 cells in a ligand-independent manner. A similar mutant with one additional basic residue, EGFR Mut R1-5, fails to exhibit ligand-independent transformation. The capacity of EGFR Mut R1-6 to mediate this transformation is maintained when this mutant is retained in the endoplasmic reticulum via a single point mutation, L393H, which we describe. We show that EGFR Mut R1-6 with or without L393H exhibits enhanced basal tyrosine phosphorylation when ectopically expressed, and the ligand-independent transforming activity of EGFR Mut R1-6 is sensitive to inhibition of EGFR kinase activity and is particularly dependent on PI3K and mTOR activity. Similar to EGFR Mut R1-6/L393H in NIH 3T3 cells, EGFR variant type III, a highly oncogenic mutant form of EGFR linked to human brain cancers, confers transforming activity while it is wholly endoplasmic reticulum-retained in U87 cells. Our findings highlight the importance of the polybasic juxtamembrane sequence in regulating the oncogenic potential of EGFR signaling. PMID- 24142704 TI - Evaluation of urinary symptoms in patients with post-prostatectomy urinary incontinence treated with the male sling TOMS. AB - AIMS: To evaluate stress urinary incontinence (SUI), overactive bladder (OAB), and obstructive symptoms in patients with post-radical prostatectomy urinary incontinence (pRP-UI) treated with the bulbar compressive sling TOMS, and investigate the effect of each urinary symptom on urinary bother. MATERIALS AND METHODS: We prospectively followed 40 patients with pRP-UI before, and 6 and 12 months (T6 and T12, respectively) after implantation of the TOMS sling. Urinary symptoms were evaluated using the following questionnaires: USP, ICIQ, UCLA-PCI (urinary bother domain), PGI-I, and daily pad use. Success was defined as patients wearing no pads or using one security pad. RESULTS: Significant improvement of mean USP-SUI (6.97/9, 3.35, 3.02, P < 0.001) and USP-OAB domains (8.1/21, 5.74, 5.71, P < 0.001), ICIQ (15.15/21, 8.17/21, 8.35/21, P < 0.01), urinary bother (92.5/100, 42.5, 41.87, P < 0.001), and pad number (2.78, 1.01, 1.03, P < 0.001) were noted between baseline, T6, and T12. At baseline, 32 (80%) patients reported urge incontinence. Urinary bother strongly correlated with UPS SUI but not with UPS-OAB score. At T12, 22 (55%) patients with pad use were considered cured, and 13 (32.5%) patients reported a greatly improved urinary tract condition (PGI-I). Improvement of USP-SUI and USP-OAB scores correlated with improvement of ICIQ and PGI scores. The USP-obstructive domain remained unchanged. CONCLUSION: The TOMS sling improves SUI and OAB symptoms without generating obstructive symptoms. OAB symptoms including urge incontinence reported by most patients were not a major concern at baseline; however, improvement of these symptoms was associated with improvement of continence and PGI-I scores. PMID- 24142703 TI - Kch1 family proteins mediate essential responses to endoplasmic reticulum stresses in the yeasts Saccharomyces cerevisiae and Candida albicans. AB - The activation of a high affinity Ca(2+) influx system (HACS) in the plasma membrane is required for survival of yeast cells exposed to natural or synthetic inhibitors of essential processes (secretory protein folding or sterol biosynthesis) in the endoplasmic reticulum (ER). The mechanisms linking ER stress to HACS activation are not known. Here we show that Kch1, a recently identified low affinity K(+) transporter in the plasma membrane of Saccharomyces cerevisiae, is up-regulated in response to several ER stressors and necessary for HACS activation. The activation of HACS required extracellular K(+) and was also dependent on the high affinity K(+) transporters Trk1 and Trk2. However, a paralog of Kch1 termed Kch2 was not expressed and not necessary for HACS activation in these conditions. The pathogenic yeast Candida albicans carries only one homolog of Kch1/Kch2, and homozygous knock-out mutants were similarly deficient in the activation of HACS during the responses to tunicamycin. However, the Kch1 homolog was not necessary for HACS activation or cell survival in response to several clinical antifungals (azoles, allylamines, echinocandins) that target the ER or cell wall. Thus, Kch1 family proteins represent a conserved linkage between HACS and only certain classes of ER stress in these yeasts. PMID- 24142705 TI - Role of hypoxia-inducible factor-1alpha expression in regulatory T cells on nasal polypogenesis. AB - OBJECTIVES/HYPOTHESIS: Hypoxia-inducible factor-1alpha (HIF-1alpha) is considered as a key molecule in regulating Th17:regulatory T-cells (Tregs) balance. The aims of this study were to investigate whether HIF-1alpha is associated with the RORgamma (RAR-related orphan receptor gamma) expression of Tregs in nasal polyps and to verify whether Staphylococcus enterotoxin B (SEB) is involved in this process. STUDY DESIGN: Clinical experimental study. METHODS: Forty patients with chronic rhinosinusitis with nasal polyposis were enrolled and divided into eosinophilic nasal polyps (EPs) and noneosinophilic nasal polyps (NEPs) according to the proportion of eosinophils. Fifteen subjects who were undergoing septoplasty were enrolled as control subjects. Expression of HIF-1alpha in the tissue was measured using reverse transcriptase-polymerase chain reaction (RT PCR), Western blot, and flow cytometry. The mRNA expression of RORC (RAR-related orphan receptor C) and HIF-1alpha in Tregs separated from tissues were measured by RT-PCR. Double immunofluorescent staining for RORC/FOXP3 and HIF-1alpha/FOXP3 were conducted on the tissues. Expression of RORC and HIF-1alpha in Tregs from peripheral blood mononuclear cells (PBMCs) was measured using flow cytometry after stimulation with SEB. RESULTS: Expression of RORC and HIF-1alpha in Tregs was significantly higher in EPs and NEPs compared with control mucosa, and there was a significant correlation between RORC and HIF-1alpha expression in Tregs. Expression of RORC and HIF-1alpha mRNA in Tregs separated from the tissues was also significantly higher in nasal polyps compared with control mucosa. Expression of RORC and HIF-1alpha in Tregs were increased after 24-hour stimulation with SEB in the PBMCs. CONCLUSIONS: HIF-1alpha-induced RORC expression in Tregs may play a key role in the pathogenesis of nasal polyps. PMID- 24142707 TI - Materials-based strategies for multi-enzyme immobilization and co-localization: A review. AB - Immobilized enzymes as biocatalysts have great potential both scientifically and industrially because of their technological and economic importance. Their highly efficient catalytic mechanisms and reusability have made them excellent candidates for green and sustainable applications. Previous studies have primarily focused on single enzyme immobilization. However, there are many situations where a single enzyme cannot completely catalyze reactions and multiple enzymes working together in a cascade are needed. It is very challenging to efficiently drive the multi-step reaction toward the desired direction, which is especially true when reactive intermediates are present. Nature overcomes this limitation through the use of multi-enzyme complexes (MECs) to promote the overall catalytic efficiency, which has inspired researchers to synthesize artificial MECs to controllably enhance the production of the desired compounds in multi-step reaction cascades in vitro. The most common approaches to synthesize artificial MECs are to use genetic engineering techniques to create fusion proteins or to co-localize multiple enzymes on suitable carriers. This review focuses on the latter with a particular emphasis on materials-based approaches to enzyme co-localization, which builds on techniques developed for single enzyme immobilization. The attachment techniques used in single enzyme immobilization are also effective in multiple enzyme co-localization, which has a direct impact on the overall enzyme orientation and activity. For carrier-based strategies, the platforms developed for single enzyme immobilization are also appropriate for attaching and co-localizing multiple enzymes. However, the involvement of multiple components in co-localization brings many challenges. The properties of different enzymes makes co-localization complicated when selecting attachment techniques and platforms to preserve enzymatic activity, because the structure and function of each component enzyme needs to be taken into consideration to preserve the overall enzyme activity. In addition, the relative position of the multiple enzymes in a confined space plays a significant role in the interactions between different enzymes, which makes spatial control important for co-localization. This review focuses on the potential of materials-based approaches for multiple enzyme co-localization for the design of sustainable multi-enzyme biocatalysts. A critical analysis of the attachment techniques and carriers platforms that have been used in enzyme immobilization and multi-enzyme co-localization in vitro is provided. PMID- 24142706 TI - Oxidized alginate hydrogels as niche environments for corneal epithelial cells. AB - Chemical and biochemical modification of hydrogels is one strategy to create physiological constructs that maintain cell function. The aim of this study was to apply oxidised alginate hydrogels as a basis for development of a biomimetic niche for limbal epithelial stem cells that may be applied to treating corneal dysfunction. The stem phenotype of bovine limbal epithelial cells (LEC) and the viability of corneal epithelial cells (CEC) were examined in oxidised alginate gels containing collagen IV over a 3-day culture period. Oxidation increased cell viability (P <= 0.05) and this improved further with addition of collagen IV (P <= 0.01). Oxidised gels presented larger internal pores (diameter: 0.2-0.8 um) than unmodified gels (pore diameter: 0.05-0.1 um) and were significantly less stiff (P <= 0.001), indicating that an increase in pore size and a decrease in stiffness contributed to improved cell viability. The diffusion of collagen IV from oxidised alginate gels was similar to that of unmodified gels suggesting that oxidation may not affect the retention of extracellular matrix proteins in alginate gels. These data demonstrate that oxidised alginate gels containing corneal extracellular matrix proteins can influence corneal epithelial cell function in a manner that may impact beneficially on corneal wound healing therapy. PMID- 24142708 TI - Inhibitory effects of suppressor of cytokine signaling 3 on inflammatory cytokine expression and migration and proliferation of IL-6/IFN-gamma-induced vascular smooth muscle cells. AB - The main pathogenesis of saphenous vein graft neointimal hyperplasia after coronary artery bypass grafting (CABG) is inflammation-caused migration and proliferation of vascular smooth muscle cells (VSMCs). Janus kinase 2/signal transducer and activators of transcription 3 (JAK2/STAT3) pathway is an important signaling pathway through which VSMCs phenotype conversion occurs. Suppressor of cytokine signaling 3 (SOCS3) is the classic negative feedback inhibitor of JAK2/STAT3 pathway. Growing studies show that SOCS3 plays an important anti inflammatory role in numerous autoimmune diseases, inflammatory diseases and inflammation-related tumors. However, the effect and mechanism of SOCS3 on vein graft disease is unclear. The purpose of this study was to investigate the effects of SOCS3 on the inflammation, migration and proliferation of VSMCs in vitro and the mechanism. The small interference RNA plasmid targeting rat SOCS3 (SiRNA-rSOCS3) and the recombinant adenovirus vector carrying rat SOCS3 gene (pYrAd-rSOCS3) were constructed, and the empty plamid (SiRNA-control) and vector (pYrAd-GFP) only carrying GFP reported gene were constructed as control. The rat VSMCs were cultured. There were two large groups of A (SOCS3 up-regulated): control group, IL-6/IFN-gamma group, IL-6/IFN-gamma+pYrAd-rSOCS3 group, IL-6/IFN gamma(+)pYrAd-GFP group; and B (SOCS3 down-regulated): control group, IL-6/IFN gamma group, IL-6/IFN-gamma+SiRNA-rSOCS3 group and IL-6/ IFN -gamma+SiRNA-control group. The pYrAd-rSOCS3 and SiRNA-rSOCS3 were transfected into VSMCs induced by IL-6/IFN-gamma. After 24 h, real-time reverse transcription polymerase chain reaction (RT-PCR) and Western blotting were used to detect the mRNA and protein expression of SOCS3, STAT3 (only by Western blotting), P-STAT3 (only by Western blotting), IL-1beta, IL-6, TNF-alpha, MCP-1 and ICAM-1. The MTT, Transwell assay and flow cytometry were used to examine VSMCs proliferation, migration and cell cycle progression, respectively. As compared with control group, the mRNA and protein expression of SOCS3, STAT3, P-STAT3, IL-1beta, IL-6, TNF-alpha, MCP-1 and ICAM-1 was significantly up-regulated in VSMCs stimulated by IL-6/IFN-gamma. However, in VSMCs transfected with pYrAd-rSOCS3 before stimulation with IL-6/IFN gamma, the expression of SOCS3 mRNA and protein was further up-regulated, and that of STAT3, P-STAT3, IL-1beta, IL-6, TNF-alpha, MCP-1 and ICAM-1 was significantly down-regulated as compared with IL-6/IFN-gamma group and IL-6/IFN gamma+pYrAd-GFP group. The expression of those related-cytokines in IL-6/IFN gamma+SiRNA-rSOCS3 group was markedly increased as compared with IL-6/IFN-gamma group and IL-6/IFN-gamma+SiRNA-control group. The absorbance (A) values, the number of cells migrating to the lower chamber, and percentage of cells in the G2/M+S phase were increased in VSMCs stimulated by IL-6/IFN-gamma. In VSMCs incubated with pYrAd-rSOCS3 or SiRNA-rSOCS3 before IL-6/IFN-gamma stimulation, the A values, the number of cells migrating to the lower chamber, and the percentage of cells in the G2/M+S phase were significantly decreased, and increased respectively. These results imply that IL-6/IFN-gamma, strong inflammatory stimulators, can promote transformation of VSMCs phenotype form a quiescent contractile state to a synthetic state by activating JAK2/STAT3 pathway. Over-expresssed SOCS3 might inhibit pro-inflammatory effect, migration and growth of VSMCs by blocking STAT3 activation and phosphorylation. These data in vitro confirm that SOCS3 may play a negatively regulatory role in development and progression of vein graft failure. These conclusions can provide a novel strategy for clinical treatment of vein graft diseases and a new theoretic clue for related drug development. PMID- 24142709 TI - Electrical stimulation therapy improves sleep respiratory parameters in obstructive sleep apnea syndrome: a meta-analysis. AB - Recent clinical trials have shown that electrical stimulation has beneficial effects in obstructive sleep apnea syndrome (OSAS). The purpose of this study was to evaluate the efficacy of electrical stimulation therapy for OSAS with a meta analysis. The meta-analysis of all relative studies was performed through searching international literature, including PUBMED, CNKI, and EMBASE databases. This literature analysis compared all patients undergoing electrical stimulation therapy with respect to the respiratory disturbance index (RDI) and changes in sleep structure. Six studies were selected involving a total of 91 patients. The meta-analysis indicated that electrical stimulation therapy reduced RDI, longest apnea time, and improved the minimum SaO2. Based on the evidence found, electrical stimulation may be a potential therapy for OSAS, warranting further clinical trials. PMID- 24142710 TI - Inhibitory effect of dexamethasone on expression of cysteine-rich 61 protein in airway epithelial cells of allergic mouse models. AB - In order to study whether cysteine-rich 61 protein (cyr61) is involved in the pathogenesis of asthma and its relation to airway inflammation, the effect of dexamethasone (Dxm) on the expression of cyr61 in the lung tissues of asthmatic mice was investigated. Forty BALB/c mice were divided into asthma group (n=15), control group (n=10) and Dxm group (n=15). The asthma group was sensitized and challenged by ovalbumin (OVA). The mice in Dxm group were intraperitoneally administered with Dxm after OVA challenge. The expression of cyr61 in the lung tissues was detected by using immunohistochemistry, and that of eotaxin protein in the bronchoalveolar lavage fluid (BALF) by using enzyme-linked immunosorbent assay (ELISA). The number of inflammatory cells in BALF was also analyzed. The results showed that the cyr61 expression was highest in asthma group (P<0.05), followed by Dxm group (P<0.05) and control group. The cyr61 had a positive correlation with the total nucleated cells (r=0.867, P<0.05), especially eosinophils (r=0.856, P<0.05), and eotaxin level (r=0.983, P<0.05) in the BALF. Our findings suggested that cyr61 is expressed in airway epithelial cells and has a positive correlation with eotaxin and number of airway infiltrating eosinophils. PMID- 24142711 TI - Suppression of amino acid transporter LAT3 expression on proliferation of K562 cells. AB - The activity of the mTOR pathway is frequently increased in acute myeloid leukemia, and is tightly related with cellular proliferation. Leucine is tightly linked to the mTOR pathway and can activate it, thereby stimulating cellular proliferation. LAT3 is a major transporter for leucine, and suppression of its expression can reduce cell proliferation. Here, we show that suppression of LAT3 expression can reduce proliferation of the acute leukemia cell line, K562. We investigated the mRNA and protein expression of LAT3 in several leukemia cell lines and normal peripheral blood mononuclear cells (PBMNCs) using RT-PCR and Western blotting. We also evaluated cell viability using a methyl thiazolyl tetrazolium (MTT) assay after blocking LAT3 expression with either shRNA targeted to LAT3 or a small molecular inhibitor BCH (2-aminobicyclo-(2,2,1)-heptane-2 carboxylic acid). LAT3 mRNA and protein expression was detected in leukemia cell lines, but not in normal PBMNCs. Using K562 cells, it was found that cellular proliferation and mTOR pathway activity were significantly reduced when LAT3 was blocked with either shRNA or BCH. Our results suggest that leukemia cell proliferation can be significantly suppressed by blocking LAT3. This finding may lead to a new strategy to develop clinical therapy for the treatment of acute myeloid leukemia. PMID- 24142712 TI - KN-93, A CaMKII inhibitor, suppresses ventricular arrhythmia induced by LQT2 without decreasing TDR. AB - Abnormal enhanced transmural dispersion of repolarization (TDR) plays an important role in the maintaining of the severe ventricular arrhythmias such as torsades de pointes (TDP) which can be induced in long-QT (LQT) syndrome. Taking advantage of an in vitro rabbit model of LQT2, we detected the effects of KN-93, a CaM-dependent kinase (CaMK) II inhibitor on repolarization heterogeneity of ventricular myocardium. Using the monophasic action potential recording technique, the action potentials of epicardium and endocardium were recorded in rabbit cardiac wedge infused with hypokalemic, hypomagnesaemic Tyrode's solution. At a basic length (BCL) of 2000 ms, LQT2 model was successfully mimicked with the perfusion of 0.5 MUmol/L E-4031, QT intervals and the interval from the peak of T wave to the end of T wave (Tp-e) were prolonged, and Tp-e/QT increased. Besides, TDR was increased and the occurrence rate of arrhythmias like EAD, R-on-T extrasystole, and TDP increased under the above condition. Pretreatment with KN 93 (0.5 MUmol/L) could inhibit EAD, R-on-T extrasystole, and TDP induced by E 4031 without affecting QT interval, Tp-e, and Tp-e/QT. This study demonstrated KN 93, a CaMKII inhibitor, can inhibit EADs which are the triggers of TDP, resulting in the suppression of TDP induced by LQT2 without affecting TDR. PMID- 24142713 TI - Role of (pro)rennin receptor in cardiomyocytes of heart failure rat model. AB - The role of (pro)rennin receptor (PRR) in cardiomyocytes of a heart failure (HF) rat model was studied. Spontaneously hypertensive rats (SHR) with HF (SHR-HF) or not were identified by two-dimensional (2-D) ultrasound. Age-matched Wistar Kyoto normotensive (WKY) rats were used as controls. PRR short hair RNA (sh-RNA) was injected into the heart of SHR-HF. Simultaneously SHR and controls received the same shRNA injection into the heart. Scramble shRNA was injected into the heart as controls. The expression of PRR mRNA and protein in cardiomyocytes was detected by using real-time PCR and Western blotting respectively. The heart function was evaluated by 2-D ultrasound, including eject fraction (EF%), fractional shortening (FS%), left ventricle thickness (LV), and inter-ventricular septal thickness (IVS). The number of apoptotic cardiomyocytes was counted by using flow cytometry. The results showed that the mRNA and protein expression levels of PRR were significantly higher in cardiomyocytes of SHR-HF group than in those of SHR group or control group. The apoptosis of myocytes in SHR-HF group was increased as compared with SHR group or control group. After knock-down of PRR with shRNA in SHR-HF group, the apoptosis of myocytes was reduced, resulting in the improved heart function. It was suggested that down-regulation of PRR might protect the heart from development of HF in SHR-HF by inhibiting the apoptosis of cardiomyocytes. PMID- 24142714 TI - Role of voltage-gated potassium channels in pathogenesis of chronic pulmonary heart disease. AB - The influence of hypoxia on the activity of voltage-gated potassium channel in pulmonary artery smooth muscle cells (PASMCs) of rats and its roles in the pathogenesis of chronic pulmonary heart disease were investigated. Eighty male Sprague-Dawley rats were randomly allocated into control group (n=10), acute hypoxic group (n=10), and chronic hypoxic groups (n=60). The chronic hypoxic groups were randomly divided into 6 subgroups (n=10 each) according to the chronic hypoxic periods. The rats in the control group were kept in room air and those in acute hypoxic group in hypoxia environmental chamber for 8 h. The rats in chronic hypoxic subgroups were kept in hypoxia environmental chamber for 8 h per day for 5, 10, 15, 20, 25, and 30 days, respectively. The mean pulmonary arterial pressure (mPAP), right ventricular hypertrophy index (RVHI), and the current of voltage-gated potassium channel (I K) in PASMCs were measured. Results showed that both acute and chronic hypoxia could decrease the I K in PASMCs of rats and the I-V relationship downward shifted to the right. And the peak I K density at +60mV decreased with prolongation of hypoxia exposure. No significant difference was noted in the density of I K (at +60 mV) and I-V relationship between control group and chronic hypoxic subgroup exposed to hypoxia for 5 days (P>0.05), but there was a significant difference between control group and chronic hypoxic subgroup exposed to hypoxia for 10 days (P<0.05). Significant differences were noted in the I K density (at +60 mV) and I-V relationships between control group and chronic hypoxic subgroups exposed to hypoxia for 20 days and 30 days (P<0.01). Compared with control rats, the mPAP and RVHI were significantly increased after chronic exposure to hypoxia for 10 days (P<0.05), which were further increased with prolongation of hypoxia exposure, and there were significant differences between control group and chronic hypoxic subgroups exposed to hypoxia for 20 days and 30 days (P<0.01). Both the mPAP and the RVHI were negatively correlated with the density of I K (r=-0.89769 and -0.94476, respectively, both P<0.01). It is concluded that exposure to hypoxia may cause decreased activity of voltage-gated potassium channel, leading to hypoxia pulmonary vasoconstriction (HPV). Sustained HPV may result in chronic pulmonary hypertension, even chronic pulmonary heart disease, contributing to the pathogenesis of chronic pulmonary heart disease. PMID- 24142715 TI - Re-evaluation of transvenous lead extraction with modified standard technique: a prospective study in 229 patients. AB - As new-type powered sheaths are expensive and unavailable, the standard lead extraction techniques remain the mainstay in clinical applications in many countries. The purpose of this study was to re-evaluate the clinical application of the standard lead extraction techniques and equipment, and make some procedural modifications and innovations. In our center, between January 2006 and May 2012, 229 patients (median, 66 years) who underwent lead extraction due to infection and lead malfunction were registered and followed up prospectively with respect to clinical features, reasons for lead extraction, technical characteristics, and clinical prognosis. A total of 440 leads had to be extracted transvenously by using special tools from 229 patients (male, 72.1%). Vegetations >=1 cm were detected in six patients. Locking Stylets were applied for 398 (90.5%) leads. Telescoping dilator polypropylene sheaths and counter traction technique were used for 202 (45.9%) leads due to lead adhesion, and the mean implant duration of the 202 leads was longer than the other 238 leads (48.9+/ 22.6 vs. 26.6+/-17.8 months; P <0.01). In addition, modified isolation and snare techniques were used for 56 leads (12.7%). Minor and major procedure-related complications occurred in three (1.3%) and four (1.7%) cases respectively, including one death (0.4%). Severe lead residue occurred in one case. Complete procedural success rate was 96.1% (423/440), and clinical success rate was 98.9% (435/440). The median follow-up period was 18 (1-76) months. No infection- and procedure-related death occurred in our series. Our data demonstrated that high clinical success rate of transvenous lead extraction can be guaranteed by making full use of the standard lead extraction techniques and equipment with individualized modifications. PMID- 24142716 TI - Analysis of seizure risk factors after allogeneic hematopoietic stem cell transplantation: a 8 case report and literature review. AB - The clinical characteristics of patients with seizures after allogeneic hematopoietic stem cell transplantation (allo-HSCT) were analyzed. A total of 8 cases of seizures after allo-HSCT were investigated. Clinical data of these cases were studied retrospectively. Of 159 cases subjected to allo-HSCT, seizure occurred in 8 cases during 29-760 days after transplantation, median survival time was 46 days, and there were 6 cases of tonic-clonic seizure. The incidence of seizure after matched unrelated HSCT was higher than that after related HSCT (P=0.017). Of 7 cases treated with cyclosporine A (CsA), 4 cases obtained high blood levels of CsA. In addition, hyponatremia was diagnosed in 5 cases. Abnormal electroencephalogram and brain MRI findings were found in some cases. During 20 days after seizure, 2 cases died due to infection and graft-versus-host disease (GVHD), respectively. It was suggested that multiple factors are associated with seizures after allo-HSCT. Rapid identification and correction of the causative factors are very important to prevent permanent central nervous system damage and reduce the mortality. PMID- 24142717 TI - Impact of probiotics on toll-like receptor 4 expression in an experimental model of ulcerative colitis. AB - Toll-like receptors (TLRs) are key components of the innate immune system which trigger antimicrobial host defense responses. This study aimed to investigate the impact of probiotics (Lactobacillus, Bifidobacterium) on the expression of TLR4 and tumor necrosis factor-alpha (TNF-alpha) in the colon mucosa of rat experimental ulcerative colitis model induced by trinitrobenzene sulfonic acid (TNBS)/ethanol and immune complexes. The gross and histological changes of the colonic mucosa were observed and assessed by the means-standard deviation and independent samples t-test. The protein expression levels of TLR4 and TNF-alpha were detected by using immunohistochemistry and Western blotting, respectively. It was revealed that there was visible infiltration of inflammatory cells, formation of crypt abscess, and the reduction of goblet cells in the colon tissue of experimental models. As compared with the control group, the levels of TLR4 and TNF-alpha protein were significantly increased in the model group (P<0.01 for both). No significant difference was found in the expression of TLR4 and TNF alpha between the two-week probiotics treatment group and the model group (P>0.05), whereas significant reductions were shown in rats which were treated with probiotics for four weeks as compared with the model group (P<0.01). There was no significant difference between two probiotics-treated groups. Our results implied that probiotics were likely to play a key role in protecting ulcerative colitis by reducing the inflammatory factor TNF-alpha expression through inhibiting the TLR4 expression in the colon tissue of experimental models. PMID- 24142718 TI - Downregulation of p38 MAPK involved in inhibition of LDL-induced proliferation of mesangial cells and matrix by curcumin. AB - Curcumin, as a main pharmacological component in the traditional Chinese medicine turmeric, has shown anti-inflammatory, anti-oxidation, anti-tumor and anti fibrotic effects. This study aimed to investigate the possible underlying signaling pathway which was involved in the inhibition of LDL-induced proliferation of mesangial cells and matrix by curcumin. Rat mesangial cells in vitro were incubated with low-density lipoprotein (LDL) and different concentrations of curcumin (0, 6.25, 12.5, 25.0 MUmol/L) or p38 MAPK inhibitor, SB203580 (10 MUmol/L). Under LDL incubation, mesangial cells proliferated, the expression of MMP-2 mRNA and protein was decreased, the expression of COX-2 mRNA and protein was increased, reactive oxygen species (ROS) generation was increased and p38 MAPK was activated significantly (P<0.05). When LDL-induced cells were treated with curcumin in the concentration of 12.5 or 25.0 MUmol/L, LDL-induced proliferation of mesangial cells was suppressed, the expression of MMP-2 mRNA and protein increased, the expression of COX-2 mRNA and protein downregulated, the production of ROS inhibited and p38 MAPK inactivated (P<0.05). In conclusion, curcumin can inhibit the LDL-induced proliferation of mesangial cells and up regulate the expression of MMP-2, which may be related with the inhibitory effect of curcumin on COX-2 expression, ROS production and p38 MAPK. PMID- 24142720 TI - Protective effects of erythropoietin on endotoxin-related organ injury in rats. AB - The protective effect of erythropoietin (EPO) on tissues following ischemia and reperfusion injuries remains poorly understood. We aimed to investigate the effect of EPO in preventing endotoxin-induced organ damage. Rat model of multiple organ failure (MOF) was established by tail vein injection of 10 mg/kg lipopolysaccharide (LPS). Recombinant human EPO treatment (5000 U/kg) was administered by tail vein injection at 30 min after LPS challenge. Twenty-four h after EPO treatment, changes in serum enzyme levels, including aspartate aminotransferase (AST), alanine transaminase (ALT), blood urea nitrogen (BUN) and creatinine (Cr), were evaluated by biochemical analysis. Serum levels of tumor necrosis factor-alpha (TNF-alpha) were determined by using immunoradiometric assay. Histological examination of tissue sections was carried out by hematoxylin and eosin staining, while ultrastructure evaluation of organ tissues was assessed by transmission electron microscopy. Protein expression levels were detected by using Western blotting. EPO treatment showed a modest effect in preventing LPS induced elevation of AST, ALT, BUN, Cr, and TNF-alpha levels, and in protecting against LPS-induced tissue degeneration and injured ultrastructure in the lung, liver, and kidney. Moreover, LPS promoted phosphorylation of alanine aminotransferase (AKT) and increased nuclear factor-kappaB (NF-kappaB) activation in the lung, liver, and kidney (P<0.05 vs. control). However, EPO treatment significantly decreased the LPS-induced pAKT up-regulation in these tissues (P<0.05 vs. LPS treatment alone). The present study demonstrates that EPO may play a protective role against LPS-induced MOF by reducing the inflammatory response and tissue degeneration, possibly via the phosphatidylinositol 3 kinase/AKT and NF-kappaB signaling pathways. PMID- 24142719 TI - Erbin interacts with Sema4C and inhibits Sema4C-induced epithelial-mesenchymal transition in HK2 cells. AB - Erbin, a member of Leucine-rich repeat and PDZ-containing protein family, was found to inhibit TGF-beta-induced epithelial-mesenchymal transition (EMT) in our previous study. However, the mechanism of Erbin in regulating EMT is unclear. Semaphorin protein Sema4C, with PDZ binding site at C-terminal has been recognized as a positive regulator of EMT. Here, we aimed to examine the interaction between Erbin and Sema4C. HK2 cells were treated with TGF-beta1, or transfected with Erbin and (or) Sema4C. Interaction of Erbin and Sema4C was identified by immunoprecipitation. RT-PCR was used to detect the expression of Erbin and Sema4C at mRNA level after transfection. The expression levels of Erbin, Sema4C, and markers of EMT were measured by using Western blotting or ELISA. After HK2 cells were stimulated with 10 ng/mL TGF-beta1 for 72 h, the protein expression levels of Erbin and Sema4C were both up-regulated, and immunoprecipitation results showed Erbin interacted with Sema4C in HK2 cells both at endogenous and exogenous levels. Furthermore, overexpression of Sema4C suppressed E-cadherin, induced vimentin and promoted fibronectin secretion, indicating Sema4C promotes the process of EMT. However, HK2 cells overexpressing Erbin were resistant to Sema4C-induced EMT. In contrast, Erbin specific siRNA promoted EMT induced by Sema4C. Taken together, these results suggest that Erbin can interact with Sema4C, and co-expression of Erbin blocks the process of Sema4C induced EMT. PMID- 24142721 TI - "Total arterial devascularization first" technique for resection of pancreatic head cancer during pancreaticoduodenectomy. AB - Integrated resection of the pancreatic head is the most difficult step in radical pancreaticoduodenectomy (RPD) in patients with the portal vein (PV) and superior mesenteric vein (SMV) invasion or oppression by the tumor. This study introduced a new idea and skill named the "total arterial devascularization first" (TADF) technique and its applications in RPD. Three arterial blood supplies of pancreatic head were obstructed before dissection of veins. The critical steps included exposure of the anterior surface of the abdominal aorta (AA) by completely transecting neural and connective tissue between superior mesenteric artery (SMA) and pancreatic mesounsinate, and transection of the mesounsinate from the origin of SMA to the root of the celiac trunk. From January 2012 through May 2013, a total of 58 patients with PV/SMV invasion or oppression underwent RPD using this technique. The median operative time was 5.1 h (ranging 4.5-8.1 h). The median intraoperative blood loss was 450 mL (ranging 200-900 mL). No intraoperative and postoperative bleeding of pancreatic head region occurred. Among the 58 patients, 21 were subjected to vessel lateral wall angiectomy or angiorrhaphy, and 10 to angiectomy and end-to-end anastomosis. The incidence of postoperative bleeding, postoperative pancreatic fistula and biliary fistula was 5.2%, 6.8%, and 1.7%, respectively. No patients died 3 months after operation. The TADF technique is a new method for intricate RPD and could improve the security of surgery and reduce intraoperative bleeding, which is expected to become standardized surgical approach for RPD. PMID- 24142722 TI - Promotion of chondrogenesis of marrow stromal stem cells by TGF-beta3 fusion protein in vivo. [corrected]. AB - The purpose of this study was to investigate the repair of the osteoarthritis(OA) induced cartilage injury by transfecting the new TGF-beta3 fusion protein (LAP MMP-mTGF-beta3) with targeted therapy function into the bone marrow-derived mesenchymal stem cells (MSCs) in rats. The recombinant of pIRES-EGFP-MMP was constructed by combination of DNA encoding MMP enzyme cutting site and eukaryotic expression vector pIRES-EGFP. LAP and mTGF-beta3 fragments were obtained from rat embryos by RT-PCR and inserted into the upstream and downstream of MMP from pIRES EGFP-MMP respectively, so as to construct the recombinant plasmid of pIRES-EGFP LAP-MMP-mTGF-beta3. pIRES-EGFP-LAP-MMP-mTGF-beta3 was transfected into rat MSCs. The genetically modified MSCs were cultured in medium with MMP-1 or not. The transfected MSCs were transplanted in the rat OA models. The OA animal models were surgically induced by anterior cruciate ligament transaction (ACLT). The pathological changes were observed under a microscope by HE staining, Alcian blue, Safranin-fast Green and graded by Mankin's scale. pIRES-EGFP-LAP-MMP-mTGF beta3 was successfully constructed by means of enzyme cutting and sequencing, and the mTGF-beta3 fusion protein (39 kD) was certified by Western blotting. Those genetically modified MSCs could differentiate into chondrocytes induced by MMP and secrete the relevant-matrix. The transfected MSCs could promote chondrogenesis and matrix production in rat OA models in vivo. It was concluded that a new fusion protein LAP-MMP-mTGF-beta3 was constructed successfully by gene engineering, and could be used to repair the OA-induced cartilage injury. PMID- 24142723 TI - Construction of self-assembled cartilage tissue from bone marrow mesenchymal stem cells induced by hypoxia combined with GDF-5. AB - It is widely known that hypoxia can promote chondrogenesis of human bone marrow derived mesenchymal stem cells (hMSCs) in monolayer cultures. However, the direct impact of oxygen tension on hMSC differentiation in three-dimensional cultures is still unknown. This research was designed to observe the direct impact of oxygen tension on the ability of hMSCs to "self assemble" into tissue-engineered cartilage constructs. hMSCs were cultured in chondrogenic medium (CM) containing 100 ng/mL growth differentiation factor 5 (GDF-5) at 5% (hypoxia) and 21% (normoxia) O2 levels in monolayer cultures for 3 weeks. After differentiation, the cells were digested and employed in a self-assembly process to produce tissue engineered constructs under hypoxic and normoxic conditions in vitro. The aggrecan and type II collagen expression, and type X collagen in the self assembled constructs were assessed by using immunofluorescent and immunochemical staining respectively. The methods of dimethylmethylene blue (DMMB), hydroxyproline and PicoGreen were used to measure the total collagen content, glycosaminoglycan (GAG) content and the number of viable cells in each construct, respectively. The expression of type II collagen and aggrecan under hypoxic conditions was increased significantly as compared with that under normoxic conditions. In contrast, type X collagen expression was down-regulated in the hypoxic group. Moreover, the constructs in hypoxic group showed more significantly increased total collagen and GAG than in normoxic group, which were more close to those of the natural cartilage. These findings demonstrated that hypoxia enhanced chondrogenesis of in vitro, scaffold-free, tissue-engineered constructs generated using hMSCs induced by GDF-5. In hypoxic environments, the self-assembled constructs have a Thistological appearance and biochemical parameters similar to those of the natural cartilage. PMID- 24142724 TI - Single-level lumbar pyogenic spondylodiscitis treated with minimally invasive anterior debridement and fusion combined with posterior fixation via Wiltse approach. AB - The effect and safety of anterior debridement and fusion with a minimally invasive approach combined with posterior fixation via the Wiltse approach were assessed in the single-level lumbar pyogenic spondylodiscitis. Seventeen patients from 2007 to 2009 underwent anterior debridement and fusion with a minimally invasive approach combined with posterior fixation via the Wiltse approach. Postoperative follow-up time was 24-41 months. Data included the patients' general information, microbiology, operative time, intraoperative blood loss, postoperative complications, intervertebral fusion rate, and preoperative and final follow-up scores for American Spinal Injury Association (ASIA) impairment, visual analogue scale (VAS), and Oswestry Disability Index (ODI). Ten patients had undergone a prior spinal invasive procedure, and 7 had hematogenous infection. The infected segments included L1-2, L2-3, L3-4, and L4-5 in 1, 2, 5, and 9 cases, respectively. Thirteen bacterial cultures were positive for Staphylococcus aureus (5 cases), Staphylococcus epidermidis (4), Streptococcus (3), and Escherichia coli (1). The operative time was 213.8+/-45.6 min, and the intraoperative blood loss was 180.6+/-88.1 mL. Postoperative complications consisted of urinary retention (2 cases), constipation (3), and deep vein thrombosis (2). On the final follow-up, VAS scores and ODIs were significantly lower than those of preoperation, while the ASIA grades improved. All the cases achieved good intervertebral bony fusion. Anterior debridement and fusion with a minimally invasive approach combined with posterior fixation via the Wiltse approach can successfully treat single-level lumbar pyogenic spondylodiscitis, with less trauma and reliable immobilization. It is a viable option for clinical application. PMID- 24142725 TI - Treatment of scaphoid nonunion: pedicled vascularized bone graft vs. traditional bone graft. AB - The clinical results of the application of pedicled vascularized bone graft (VBG) from Lister's tubercle vs. traditional bone graft (TBG) were evaluated and compared. Thirteen cases of symptomatic scaphoid nonunion were treated between January 2011 and December 2012, including 7 cases subject to VBG and the rest 6 cases to TBG, respectively. Outcomes were assessed by modified Mayo wrist score system. All cases were followed up for an average period of 3.5 months after operation. The results showed that total scores in VBG group were 86.4+/-9.4 after operation with excellent result in 4 cases, good in 2 and acceptable in one, and those in TBG group were 71.7+/-9.3 after operation with good result in 2 cases, acceptable in 3 and disappointing in one. Total score of wrist function was significantly improved in VBG group as compared with TBG group (P<0.05). Our study suggests that VBG method is more effective for treating scaphoid nonunion than TBG method. PMID- 24142726 TI - Fucoidan induces G1 phase arrest and apoptosis through caspases-dependent pathway and ROS induction in human breast cancer MCF-7 cells. AB - Fucoidan is an active component of seaweed, which inhibits proliferation and induces apoptosis of several tumor cells while the detailed mechanisms underlying this process are still not clear. In this study, the effect of Fucoidan on the proliferation and apoptosis of human breast cancer MCF-7 cells and the molecular mechanism of Fucoidan action were investigated. Viable cell number of MCF-7 cells was decreased by Fucoidan treatment in a dose-dependent manner as measured by MTT assay. Fucoidan treatment resulted in G1 phase arrest of MCF-7 cells as revealed by flow cytometry, which was associated with the decrease in the gene expression of cyclin D1 and CDK-4. Annexin V/PI staining results showed that the number of apoptotic cells was associated with regulation of cytochrome C, caspase-8, Bax and Bcl-2 at transcriptional and translational levels. Both morphologic observation and Hoechst 33258 assay results confirmed the pro-apoptotic effect of Fucoidan. Meanwhile, the ROS production was also increased by Fucoidan treatment, which suggested that Fucoidan induced oxidative damage in MCF-7 cells. The results of present study demonstrated that Fucoidan could induce G1 phase arrest and apoptosis in MCF-7 cells through regulating the cell cycle and apoptosis related genes or proteins expression, and ROS generation is also involved in these processes. PMID- 24142727 TI - Assessment of the number and function of macrophages in the placenta of gestational diabetes mellitus patients. AB - In order to assess the number and function of macrophages in the placenta of pregnancy complicated with gestational diabetes mellitus (GDM) as well as those of normal pregnancies, placenta samples were collected from 15 GDM patients (GDM group) and 10 normal pregnant women (control group). The expression levels of macrophage markers (CD68/CD14) and inflammatory cytokines (IL-6/TNF-alpha) in placenta were detected using immunohistochemistry and PCR. The results showed that the number of CD68+ or CD14+ cells in the GMD group was remarkably higher than that in the control group (P<0.05), indicating that the number of macrophages in the GDM group was significantly greater than that in the control group. The mRNA expression levels of CD68+, IL-6 and TNF-alpha were higher in the GMD group than in the control group. In conclusion, more macrophages accumulate in placenta of pregnancy complicated with GDM, and the expression levels of pro inflammation factors are also increased in GDM pregnancies, suggesting that macrophages and inflammatory mediators (IL-6 and TNF-alpha) may play an important role in GDM. PMID- 24142728 TI - Role of progesterone in TLR4-MyD88-dependent signaling pathway in pre-eclampsia. AB - The role of progesterone in the Toll-like receptor 4 (TLR4)-MyD88-dependent signaling pathway in pre-eclampsia was studied. Peripheral blood mononuclear cells (PBMCs) from pre-eclampsia (PE) patients were subjected to primary culture, and stimulated with different concentrations of progesterone (0, 10(-8), 10(-6), and 10(-4) mol/L). The mRNA expression of TLR4, MyD88 and nuclear factor-kappaB (NF-kappaB) was detected by using real-time PCR. The Ikappa-B protein expression was detected by using Western blotting. The expression of tumor necrosis factor alpha (TNF-alpha) and interleukin-6 (IL-6) in the supernatant was determined by using ELISA. With the concentrations of progesterone increasing, the mRNA expression levels of TLR4, MyD88 and NF-kappaB in 2(-DeltaDeltaCT) value were significantly decreased, and the IkappaB protein expression levels were significantly increased. The TNF-alpha and IL-6 expression showed a downward trend when the progesterone concentration increased, and there were significant differences among all of the groups (P<0.05). It was suggested that progesterone can inhibit the TLR4-MyD88-dependent signaling pathway in PE significantly and benefit for the pregnancy. PMID- 24142729 TI - HPV16 E5 peptide vaccine in treatment of cervical cancer in vitro and in vivo. AB - Human papillomavirus (HPV)-induced cervical cancer is the second most common cancer among women worldwide. Despite the encouraging development of the preventive vaccine for HPV, a vaccine for both prevention and therapy or pre cancerous lesions remains in high priority. Thus far, most of the HPV therapeutic vaccines are focused on HPV E6 and E7 oncogene. However these vaccines could not completely eradicate the lesions. Recently, HPV E5, which is considered as an oncogene, is getting more and more attention. In this study, we predicted the epitopes of HPV16 E5 by bioinformatics as candidate peptide, then, evaluated the efficacy and chose an effective one to do the further test. To evaluate the effect of vaccine, rTC-1 (TC-1 cells infected by rAAV-HPV16E5) served as cell tumor model and rTC-1 loading mice as an ectopic tumor model. We prepared vaccine by muscle injection. The vaccine effects were determined by evaluating the function of tumor-specific T cells by cell proliferation assay and ELISPOT, calculating the tumor volume in mice and estimating the survival time of mice. Our in vitro and in vivo studies revealed that injection of E5 peptide+CpG resulted in strong cell-mediated immunity (CMI) and protected mice from tumor growth, meanwhile, prolonged the survival time after tumor cell loading. This study provides new insights into HPV16 E5 as a possible target on the therapeutic strategies about cervical cancer. PMID- 24142730 TI - Clinical efficacy and safety of chelation treatment with typical penicillamine in cross combination with DMPS repeatedly for Wilson's disease. AB - The aim of this study was to assess the clinical efficacy and safety of chelation treatment with penicillamine (PCA) in cross combination with sodium 2, 3 dimercapto-1-propane sulfonate (DMPS) repeatedly in patients with Wilson's disease (WD). Thirty-five patients with WD were enrolled. They were administrated intravenous DMPS in cross combination with oral PCA alternately which was practiced repeatedly, all with Zinc in the meantime. During the treatment, clinical observations and 24-h urine copper excretion as well as adverse effects of medicines were recorded and analyzed. Although the incidence of adverse effects was not significantly different after either intravenous DMPS or oral PCA treatment, levels of 24-h urine copper tended to be higher after short-term intravenous DMPS than that of oral PCA. Adverse effects in the course of intravenous DMPS were mainly neutropenia, thrombocytopenia, allergic reaction and bleeding tendency. As compared with oral PCA alone or intravenous DMPS alone, such repeated cross combination treatment could as much as possible avoid continued drug adverse effects or poor curative effect and had less chance to stop treatment in WD patients. Improved or recovered liver function in 71% of the patients, alleviated neurologic symptoms in 50% of the patients, and disappeared hematuria in 70% of the patients could be observed during the follow-up period of 6 months to 5 years after such combined chelation regimen. Chelation treatment repeatedly with oral penicillamine in cross combination with intravenous DMPS alternately could be more beneficial for WD patients to relieve symptoms, avoid continued drug adverse effects and maintain lifelong therapy. PMID- 24142731 TI - 40 Hz auditory steady state response to linguistic features of stimuli during auditory hallucinations. AB - The auditory steady state response (ASSR) may reflect activity from different regions of the brain, depending on the modulation frequency used. In general, responses induced by low rates (<=40 Hz) emanate mostly from central structures of the brain, and responses from high rates (>=80 Hz) emanate mostly from the peripheral auditory nerve or brainstem structures. Besides, it was reported that the gamma band ASSR (30-90 Hz) played an important role in working memory, speech understanding and recognition. This paper investigated the 40 Hz ASSR evoked by modulated speech and reversed speech. The speech was Chinese phrase voice, and the noise-like reversed speech was obtained by temporally reversing the speech. Both auditory stimuli were modulated with a frequency of 40 Hz. Ten healthy subjects and 5 patients with hallucination symptom participated in the experiment. Results showed reduction in left auditory cortex response when healthy subjects listened to the reversed speech compared with the speech. In contrast, when the patients who experienced auditory hallucinations listened to the reversed speech, the auditory cortex of left hemispheric responded more actively. The ASSR results were consistent with the behavior results of patients. Therefore, the gamma band ASSR is expected to be helpful for rapid and objective diagnosis of hallucination in clinic. PMID- 24142732 TI - Optimization of parameters for preparation of docetaxel-loaded PLGA nanoparticles by nanoprecipitation method. AB - The purpose of this study was to develop docetaxel-poly (lactide-co-glycolide) (PLGA) loaded nanoparticles by using nanoprecipitation method and optimize the relative parameters to obtain nanoparticles with higher encapsulation efficiency and smaller size. The physicochemical characteristics of nanoparticles were studied. The optimized parameters were as follows: the oil phase was mixture of acetone and ethanol, concentration of tocopheryl polyethylene glycol succinate (TPGS) was 0.2%, the ratio of oil phase to water phase was 1:5, and the theoretical drug concentration was 5%. The optimized nanoparticles were spherical with size between 130 and 150 nm. The encapsulation efficiency was (40.83+/ 2.1)%. The in vitro release exhibited biphasic pattern. The results indicate that docetaxel-PLGA nanoparticles were successfully fabricated and may be used as the novel vehicles for docetaxel, which would replace Taxotere(r) and play great roles in future. PMID- 24142733 TI - Comparison of dosiology between three dimensional conformal and intensity modulated radiotherapies (5 and 7 fields) in gastric cancer post-surgery. AB - The purpose of this study was to compare the dose distribution of intensity modulated radiotherapy (IMRT) in 7 and 5 fields as well as 3-D conformal radiotherapy (3D-CRT) plans for gastric cancer using dosimetric analysis. In 15 patients with gastric cancer after D1 resection, dosimetric parameters for IMRT (7 and 5 fields) and 3D-CRT were calculated with a total dose of 45 Gy (1.8 Gy/day). These parameters included the conformal index (CI), homogeneity index (HI), maximum dose spot for the planned target volume (PTV), dose-volume histogram (DVH) and dose distribution in the organs at risk (OAR), mean dose (Dmean), maximal dose (Dmax) in the spinal cord, percentage of the normal liver volume receiving more than 30 Gy (V30) and percentage of the normal kidney volume receiving more than 20 Gy (V20). IMRT (7 and 5 fields) and 3D-CRT achieved the PTV coverage. However, IMRT presented significantly higher CI and HI values and lower maximum dose spot distribution than 3D-CRT (P=0.001). For dose distribution of OAR, IMRT had a significantly lower Dmean and Dmax in spinal cord than 3D-CRT (P=0.009). There was no obvious difference in V30 of liver and V20 of kidney between IMRT and 3D-CRT, but 5-field IMRT showed lower Dmean in the normal liver than other two plans (P=0.001). IMRT revealed favorable tumor coverage as compared to 3D-CRT and IMRT plans. Specifically, 5-field IMRT plan was superior to 3D-CRT in protecting the spinal cord and liver, but this superiority was not observed in the kidney. Further studies are needed to compare differences among the three approaches. PMID- 24142734 TI - Left ventricular systolic strain of the cardiac allograft evaluated with three dimensional speckle tracking echocardiography. AB - Three-dimensional speckle tracking echocardiography was employed to evaluate the changes of left ventricular systolic strain in 23 heart transplant recipients at 1st, 3rd, 6th and 12th month after heart transplantation, and 23 healthy subjects served as controls. The three-dimensional full-volume echocardiographic images of left ventricle were recorded and then were analyzed using EchoPAC software. The strain curves and peak systolic strain values for each segment and overall left ventricular wall were obtained. Left ventricular global peak longitudinal strain (GPSL), global peak radial strain (GPSR), global peak circumferential strain (GPSC) and global peak area strain (GPSA) were measured and then statistically analyzed. There were no significant differences in left ventricular ejection fraction (LVEF) and cardiac output (CO) between heart transplant recipients and controls. The GPSL in heart transplant recipients at 1st month after surgery was significantly lower than that in controls, but close to the normal value at 3rd month after surgery and later. The GPSC, GPSA and GPSR were significantly lower in heart transplant recipients at 1st, 3rd, 6th and 12th month after surgery than those in controls. It is suggested that three-dimensional speckle tracking echocardiography can be used for monitoring changes of left ventricular systolic strains and evaluating left ventricular systolic function in cardiac allograft. PMID- 24142735 TI - Suppression of low-dose hyper-radiosensitivity in human lung cancer cell line A549 by radiation-induced autophagy. AB - This study explored the role of radiation-induced autophagy in low-dose hyperradiosensitivity (HRS) in the human lung cancer cell line A549. A549 cells, either treated with an autophagic inhibitor 3-methyladenine (3-MA), or with a vehicle control, were irradiated at different low doses (<=0.5 Gy). The generation of autophagy was examined by laser scanning confocal microscopy. Western blotting was used to detect the expression of microtubule-associated protein l light chain 3B II (LC3B-II). Flow cytometry (FCM) and clonogenic assays were used to measure the fraction of surviving cells at the low irradiation doses. Our results showed that there was a greater inhibition of autophagic activity, but a higher degree of low-dose HRS in A549 cells treated with 3-MA than in control group. Our data demonstrated that radiation-induced autophagy is correlated with HRS in A549 cells, and is probably one of the mechanisms underlying HRS. PMID- 24142736 TI - Three-dimensional finite element modeling of a maxillary premolar tooth based on the micro-CT scanning: a detailed description. AB - This study describes the details of how to construct a three-dimensional (3D) finite element model of a maxillary first premolar tooth based on micro-CT data acquisition technique, MIMICS software and ANSYS software. The tooth was scanned by micro-CT, in which 1295 slices were obtained and then 648 slices were selected for modeling. The 3D surface mesh models of enamel and dentin were created by MIMICS (STL file). The solid mesh model was constructed by ANSYS. After the material properties and boundary conditions were set, a loading analysis was performed to demonstrate the applicableness of the resulting model. The first and third principal stresses were then evaluated. The results showed that the number of nodes and elements of the finite element model were 56 618 and 311801, respectively. The geometric form of the model was highly consistent with that of the true tooth, and the deviation between them was -0.28%. The loading analysis revealed the typical stress patterns in the contour map. The maximum compressive stress existed in the contact points and the maximum tensile stress existed in the deep fissure between the two cusps. It is concluded that by using the micro CT and highly integrated software, construction of the 3D finite element model with high quality will not be difficult for clinical researchers. PMID- 24142737 TI - Intrusion of overerupted maxillary molars with miniscrew implant anchorage: a radiographic evaluation. AB - The aim of this retrospective study was to quantitatively evaluate the treatment effects of intrusion of overerupted maxillary molars using miniscrew implant anchorage and to investigate the apical root resorption after molar intrusion. The subjects included 30 patients whose average ages were 35.5+/-9.0 years. All patients had received intrusion treatments for overerupted maxillary molars with miniscrew anchorage. There were 38 maxillary first molars and 26 maxillary second molars to be intruded. Two miniscrews were inserted in the buccal and palatal alveolar bone mesial to the overerupted molar. Force of 100-150 g was applied by the elastic chains between screw head and attachment on each side. Lateral cephalograms and panoramic radiographs taken before and after intrusion were used to evaluate dental changes and root resorption of molars. Only 6 of the 128 miniscrews failed. The first and second molars were significantly intruded by averages of 3.4 mm and 3.1 mm respectively (P<0.001). The average intrusion time was more than 6 months. The crown of the molars mesially tilted by averages of 3.1 degrees and 3.3 degrees (P<0.001) for first and second molars. The amounts of root resorption were 0.2-0.4 mm on average. The intrusion treatment of overerupted molars with miniscrew anchorages could be used as an efficient and reliable method to recover lost restoration space for prosthesis. Radiographically speaking, root resorption of molars was not clinically significant after application of intrusive forces of 200 to 300 g. PMID- 24142738 TI - Pharmacokinetic and pharmacodynamic properties of batifiban coadministered with antithrombin agents in Chinese healthy volunteers. AB - The combined use of batifiban, a synthetic platelet GPII b/ IIIa receptor antagonist, and antithrombin agents is an attractive option for the treatment of patients with non-ST-segment elevation (NSTE) acute coronary syndrome (ACS) and those scheduled for percutaneous coronary intervention. To observe whether antithrombin agents affect the pharmacokinetic and pharmacodynamic properties of batifiban in combination therapy and optimize clinical administration dosage of batifiban, an open-label and parallel study was conducted. Thirty healthy subjects were randomly divided into three groups, which were sequentially treated with batifiban alone, or oral coadministration of clopidogrel, aspirin and UFH, or batifiban coadministered with these antithrombin agents. Blood samples were collected at pre-specified time points. The evaluation index included the inhibition of platelet aggregation and pharmacokinetic parameters. The pharmacokinetic parameters of batifiban and batifiban coadministered with antithrombin agents showed no significant differences. The mean inhibition rate of platelet aggregation (%) suggested that neither batifiban alone nor antithrombin agents alone could provide such potent inhibition rate (>80%) to obtain the best clinical efficacy, but they had a synergistic effect on platelet inhibition. No serious adverse effects were observed. The results in these healthy subjects suggest that batifiban coadministrated with antithrombin agents could achieve optimum clinical treatment effect for patients with NSTE ACS, and also those scheduled for percutaneous coronary intervention. PMID- 24142739 TI - Transpedal access after failed anterograde recanalization of complex below-the knee and femoropoliteal occlusions in critical limb ischemia. AB - BACKGROUND: Successful angioplasty is one of the main factor of limb salvage during critical limb ischemia. In complex femoropopliteal to infrapopliteal occlusions, an anterograde recanalization attempt can fail in up to 20% of the cases. The purpose of this dual center pilot study was to evaluate the acute success and clinical impact of retrograde transpedal access for retrograde below the-knee and femoropopliteal chronic total occlusions after failed anterograde attempt and to access the late complications at the puncture site. METHODS: The clinical and angiographic data of 51 consecutive patients with CLI treated by retrograde transpedal recanalization between 2010 and 2011 were evaluated in a pilot study. We have examined the 2-month and 1 year major adverse events (MAEs) and clinical success. In all cases after failure of the anterograde recanalization of occluded below-the-knee segments due to unsuccessful penetration or failed re-entry, the anterior tibial or posterior tibial artery was punctured under fluoroscopic guidance and retrograde recanalization was performed. Direct revascularization was tried firstly following the angiographic zones, but in failed cases indirect revascularization was carried out with increasing the collateral flow to the wound. RESULTS: Successful direct retrograde revascularization was achieved successfully in 40 patients (78.4%) and indirect revascularization was done in 10 patients (19.6%). Revascularization was failed in one patient (2%). MAE at 2 and 12 months follow-up was 6 (11.7%) and 11 (24%). Limb salvage at 2 and 12 months was 93% and 82.3%, respectively. Balloon angioplasty was performed in all interventions and provisional stenting was done in 34 patients (66.7%). One major and three minor vascular complications occurred after the procedure. The mean basal and control creatinine level was 120.9 +/- 133.4 and 123.8 +/- 131.3 MUmol/L (P = 0.83) after the procedure. CONCLUSION: Failed antegrade attempts to recanalize CTO-s of femoropopliteal and infrapopliteal vessels can be salvaged using a retrograde transpedal access, with a low acute and late complication rate. This technique could be valuable for patients with critical limb ischemia due to femoropopliteal and infrapopliteal occlusions. PMID- 24142740 TI - CLTC-ALK fusion as a primary event in congenital blastic plasmacytoid dendritic cell neoplasm. AB - Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a subtype of acute myeloid leukemia, affecting mainly the elderly. It is thought to be derived from plasmacytoid dendritic cell precursors, which frequently present as cutaneous lesions. We have made a detailed analysis of an infant with BPDCN, who manifested with hemophagocytic lymphohistiocytosis. The peripheral blood leukocytes revealed the t(2;17;8)(p23;q23;p23) translocation and a CLTC-ALK fusion gene, which have never been reported in BPDCN or in any myeloid malignancies thus far. Neonatal blood spots on the patient's Guthrie card were analyzed for the presence of the CLTC-ALK fusion gene, identifying the in utero origin of the leukemic cell. Although the leukemic cells were positive for CD4, CD56, CD123, and CD303, indicating a plasmacytoid dendritic cell phenotype, detailed analysis of the lineage distribution of CLTC-ALK revealed that part of monocytes, neutrophils, and T cells possessed the fusion gene and were involved in the leukemic clone. These results indicated that leukemic cells with CLTC-ALK originated in a multipotent hematopoietic progenitor in utero. This is the first report of the CLTC-ALK fusion gene being associated with a myeloid malignancy, which may give us an important clue to the origin of this rare neoplasm. PMID- 24142741 TI - A 21-year retrospective outcome study of New South Wales forensic patients granted conditional and unconditional release. AB - AIM: To retrospectively examine the outcomes of forensic patients found not guilty by reason of mental illness (NGMI) in New South Wales (NSW) and subsequently released into the community, as measured by reoffending, conditional release revocation and psychiatric hospital readmission. METHOD: Data were collected from the NSW Mental Health Review Tribunal (MHRT) files for all patients who received an NGMI verdict between January 1990 and December 2010, and who were released into the community during this period. The outcome measures of conditional release revocation and psychiatric hospital readmission were extracted from these files. Information about subsequent criminal charges, convictions and penalties were obtained from the Bureau of Crime Statistics and Research's reoffending database. RESULTS: During the 21-year period studied, 364 offenders received an NGMI verdict and were placed under the supervision of the MHRT. Of these, 197 were released into the community, including 85 who were granted unconditional release. Over a follow-up period averaging 8.4 years, 18% of conditionally released patients reoffended, 11.8% were convicted of a further offence, 8.7% were charged with a violent offence, 3.1% were convicted of a violent offence and 3.7% were sentenced to a term of imprisonment. Five (3.1%) conditionally released forensic patients received a further NGMI verdict. One quarter of the conditionally released patients had their conditional release revoked and half were readmitted to hospital. Of the forensic patients granted unconditional release, 12.5% were charged with an offence, 9.4% received convictions for an offence, 6.3% were charged with a violent offence and 4.7% were convicted of a violent offence, in a mean follow-up period of 7.6 years. None committed a further serious offence resulting in a term of imprisonment, nor a second NGMI verdict. CONCLUSIONS: The results of this study suggest that the treatment and rehabilitation of forensic patients in NSW, together with the decision-making procedures of the MHRT, is effective in protecting the community from further offending by forensic patients. PMID- 24142742 TI - A study on job postures and musculoskeletal illnesses in dentists. AB - OBJECTIVES: Musculoskeletal disorders (MSDs) compose a large part of occupational diseases in dental professionals, prevention of which is dependent on assessment and improvement of job postures by means of ergonomic interventions. This study was aimed at evaluation of ergonomic conditions of the profession of dentists and also at assessing the relationship between MSDs and conditions of work. MATERIALS AND METHODS: This cross-sectional study was performed among 65 dentists using the method of Rapid Entire Body Assessment (REBA). The prevalence of MSDs was obtained by the use of the Nordic Musculoskeletal Questionnaire (NMQ). RESULTS: In this investigation, the prevalence of MSDs for different body parts was: 75.9% for the neck, 58.6% for the shoulders, 56.9% for the upper back, 48.3% for the lower back and 44.8% for the wrist. Job analysis by the use of REBA showed that 89.6% of limbs in group A and 79.3% of limbs in group B had a score > 4. Only neck and lower back pain have significant relationship with the risk levels obtained using the REBA method. CONCLUSIONS: It can be concluded that work postures of dentists need to be improved. In addition to education, work station design, rest period during work and regular physical activities should be taken into account. PMID- 24142743 TI - Effects of polybrominated diphenyl ethers on thyroid hormone, neurodevelopment and fertility in rodents and humans. AB - Polybrominated diphenyl ethers (PBDEs) are used as flame retardants. Due to their widespread use in many consumer products, PBDEs can be found in food as well as in the environment. Their presence has also been found in the human serum, human adipose tissue and human breast milk. Results of experimental studies suggest that the presence of PBDE in the environment is not neutral to our health. In rats and mice exposed to PBDE disturbances in thyroid hormone homeostasis and reproductive system such as changes in reproductive organs weight and disorders in sperm motility and motion were found. In rodents, pre- and postnatal exposure to PBDE can cause neurobehavioral effects. Also in humans disturbances in thyroid hormone system, weight of reproductive organs and concentrations of sex hormones associated with PBDEs serum concentrations were found. Exposure to PBDEs during pregnancy may lead to slower mental and psychomotor development in infants. In this paper the results of previous animal and human studies are reviewed. PMID- 24142744 TI - Pre-hypertension: rationale for pharmacotherapy. AB - Pre-hypertension, defined as blood pressure 120-139/80-89 mmHg, affects ~70 million people in the US. Blood pressures in the upper half of the pre hypertensive range are linked with roughly threefold greater risk of incident hypertension than normal blood pressure <120/<80 mmHg, with an incidence rate of 8-20 % annually. Blood pressures in the upper half of the pre-hypertensive range also roughly double risk for cardiovascular events, even in the absence of progression to hypertension. Despite excess risk, guidelines recommend lifestyle interventions only for people with pre-hypertension in the absence of diabetes mellitus or clinical cardiovascular or chronic kidney disease. While efficacious, lifestyle changes have limited population effectiveness as Americans are heavier and their nutritional patterns less DASH-like than before DASH was published. Prevalent hypertension is higher in African Americans than Caucasians, but prevalent pre-hypertension is similar. African Americans experience a more rapid transition from pre-hypertension to hypertension than Caucasians with pre hypertension. Interventions that normalize racial differences in incident hypertension could, over time, improve racial equity in prevalent hypertension and related clinical complications. Individuals with pre-hypertension can be safely treated with antihypertensive medications to significantly reduce incident hypertension. Given the evidence, practical clinical trials in African Americans with pre-hypertension to reduce and eliminate racial disparities in incident hypertension have merit. The results of these trials could provide the foundation for clinical guidelines to reduce racial disparities in prevalent hypertension and associated clinical cardiovascular and renal diseases. PMID- 24142745 TI - Heparin-induced thrombocytopenia and thrombosis as an under-diagnosed cause of flap failure in heparin-naive patients: a case report and systematic review of the literature. AB - BACKGROUND: Heparin-induced thrombocytopenia and thrombosis (HITT) is an immune complex mediated and potentially devastating cause of flap loss in microvascular surgery. HITT may be an under-reported cause of early-flap failure due to subclinical manifestations at the time of flap loss. A case report of a patient presenting with HITT-related flap failure and the results of a systematic literature review of the clinical presentation of HITT in microsurgery are presented here. CASE REPORT: A patient suffering from a chronic wound on the right medial malleolus was treated with an ALT flap, which was compromised by thrombosis. Multiple attempts to rescue the flap including thrombolysis, popliteal AV loop, and a second free flap were all unsuccessful. Six days following the initial procedure, a diagnosis of HITT was made following a positive HITT-antibody test as the cause of flap failure. METHODS: PubMed, MEDLINE, and EMBASE searches yielded 113 results, of which 6 met our criteria for manuscripts describing HITT in microsurgical procedures. RESULTS: Evaluation of the peer-reviewed literature describing HITT in microsurgery suggests that HITT related flap failure occurs rapidly, more frequently in heparin-naive patients, and in advance of systemic thrombosis and thrombocytopenia. CONCLUSIONS: Due to the rapid and unpredictable onset of HITT during microsurgery, we recommend maintaining an index of suspicion for HITT in flaps with otherwise unexplained early thrombosis. We also encourage hematology consultation, discontinuing heparin use and initiating alternate thromboprophylaxis in order to inhibit the potential for subsequent life-threatening systemic complications as well as improving the potential for delayed reconstructive success. PMID- 24142746 TI - 1H NMR detects different metabolic profiles in glioblastoma stem-like cells. AB - The metabolic profiles of glioblastoma stem-like cells (GSCs) growing in neurospheres were examined by (1)H NMR spectroscopy. Spectra of two GSC lines, labelled 1 and 83, from tumours close to the subventricular zone of the temporal lobe were studied in detail and compared with those of neural stem/progenitor cells from the adult olfactory bulb (OB-NPCs) and of the T98G glioblastoma cell line. In both GSCs, signals from myoinositol (Myo-I), UDP-hexosamines (UDP-Hex) and glycine indicated an astrocyte/glioma metabolism. For line 1, the presence of signals from N-acetyl aspartate, GABA and creatine pointed to a neuronal fingerprint. These metabolites were almost absent from line 83 spectra, whereas lipid signals, absent from normal neural lineages, were intense in line 83 spectra and remained low in those of line 1, irrespective of apoptotic fate. Spectra of OB-NPC cells displayed strong similarities with those from line 1, with low lipid signals and clearly detectable neuronal signals. In contrast, the spectral profile of line 83 was more similar to that of T98G, displaying high lipids and nearly complete absence of the neuronal markers. A mixed neural astrocyte metabolic phenotype with a strong neuronal fingerprint was therefore found in line 1, while an astrocytic/glioma-like metabolism prevailed in line 83. We found a signal assigned to the amide proton of N-acetyl galactosamine in GSC lines and in OB-NPC spectra, whereas it was absent from those of T98G cells. This signal may be related to a stem-cell-specific protein glycosylation pattern and is therefore suggested as a marker of cell multipotency. Other GSC lines from patients with different clinical outcomes were then examined. Unsupervised analysis of spectral data from 13 lines yielded two clusters, with six lines resembling spectral features of line 1 and seven resembling those of line 83, suggesting that distinct metabolic phenotypes may be present in GSC lines. PMID- 24142747 TI - Initial TIMI flow >= 2 and pre-angiography total ST-segment resolution predict an aborted myocardial infarction in patients undergoing primary percutaneous coronary intervention. AB - BACKGROUND: Studies on the treatment of patients with an acute ST-segment elevation myocardial infarction (STEMI) with primary percutaneous coronary intervention (PCI) have shown a high rate of aborted MI despite a relatively long delay from the onset of symptoms to reperfusion. AIM: To assess predictors of aborted MI in patients undergoing primary PCI. METHODS: 310 STEMI patients referred for primary PCI within 12 h of symptom onset were included into a prospective study. Relationships between incidence of aborted MI, clinical, electrocardiographic and angiographic factors were analysed. RESULTS: Aborted MI was diagnosed in 29 (9.8%) patients. Patients with aborted MI did not differ with respect to age(59.4 +/- 10.1 vs. 60.5 +/- 11.2 years; p = 0.88), male sex (75.9% vs. 76.0%; p = 0.83), hypertension (51.7% vs. 48.3%;p = 0.87) or total ischaemic time (215.9 +/- 104.6 vs. 241.9 +/- 134.3 min; p = 0.44) except for the frequency of diabetes mellitus (34.5% vs. 16.1%; p = 0.02) when compared to a group with true MI. TIMI flow >= 2 prior to PCI (86.2% vs. 27.7%; p < 0.001), total ST segment resolution (STSR), both pre-angiography (65.5% vs. 19.5%; p < 0.001) and post-PCI (89.7%vs. 69.2%; p = 0.018) and myocardial blush grade 3 (89.7% vs. 60.0%; p = 0.001) were significantly more frequent in patients with aborted MI. A logistic regression model confirmed TIMI flow >= 2 prior to PCI (OR 10.7; CI 3.1 37.8; p = 0.0002), pre-angiography total STSR (OR 3.6; CI 1.2-10.5; p = 0.02) and a history of previous diabetes mellitus (OR 8.6; CI 2.6-27.6; p = 0.0003) as predictors of aborted MI. CONCLUSIONS: 1. Aborted MI was observed in 9.8% of STEMI patients undergoing PCI. 2. TIMI flow >= 2 and total STSR priorto PCI were identified as major angiographic and electrocardiographic predictors of aborted MI. PMID- 24142748 TI - Apelin in ST segment elevation and non-ST segment elevation acute coronary syndromes: a novel finding. AB - BACKGROUND: Apelin is a novel endogenous peptide with inotropic and vasodilatory properties. AIM: To investigate the role of apelin in the prognosis of acute coronary syndromes (ACS) and to assess the relationship between apelin and other diagnostic and prognostic markers. METHODS: Seventy-six patients with ACS (mean age 62.1 +/- 10 years) were evaluated in terms of their plasma apelin-36 concentrations, ejection fraction (EF), high sensitivity C-reactive protein (hsCRP), creatine kinase (CK), CK-MB and troponin I levels. The study group consisted of 35 ST elevation myocardial infarction (STEMI) and 41 non-ST elevation (NSTE) ACS patients. Patients were followed up for one year for cardiovascular outcomes. RESULTS: There was no significant relationship between apelin and TIMI, GRACE, GENSINI scores, hsCRP and EF in STEMI and NSTE-ACS groups (p > 0.05). Apelin showed positive correlations with CK, CK-MB and troponin I in patients with NSTE-ACS, but a negative correlation in patients with STEMI (p < 0.05). There were no statistically significant differences between patients reaching the composite end point at one year with regard to apelin levels. CONCLUSIONS: Apelin was positively correlated with cardiac biomarkers in patients with NSTE-ACS but negatively correlated in patients with STEMI. In STEMI, generally larger amounts of myocardial cells are subjected to infarction compared to NSTE-ACS, which may explain why apelin levels decrease with increasing CK, CK MB and troponin levels in STEMI patients. PMID- 24142749 TI - Long-term follow-up of mesh-covered stent implantation in patients with ST segment elevation myocardial infarction. AB - BACKGROUND: The MGuard stent (a bare-metal stent wrapped externally in a polymer mesh sleeve) was introduced to reduce the risk of distal embolisation and no reflow phenomenon during percutaneous coronary intervention (PCI) in thrombus containing lesions, including ST-segment elevation myocardial infarction (STEMI). However, data on the long-term performance of the MGuard stent is limited. AIM: To assess the long-term safety and efficacy of MGuard stent implantation during primary PCI for STEMI. METHODS AND RESULTS: In this multicentre study, a total of 60 patients with STEMI <=12 h treated with the MGuard stent were enrolled. Angiographic success of PCI was achieved in 96.7%, with the final TIMI grade 3 flow in 90.0% of patients. At six months, the overall rate of major adverse cardiac and cerebrovascular events (MACCE; composite of cardiac death, nonfatal target vessel reinfarction, target lesion revascularisation, and stroke) was 1.7%. A long-term follow-up of the study was successfully performed in 57 patients (mean follow-up of 38.7 +/- 3.1 months). The long-term cardiac mortality was 7.0%, with a MACCE rate of 8.8%. There was no decrease in the left ventricular ejection fraction and no enlargement of the left ventriclebetween index and long-term follow-up echocardiogram. CONCLUSIONS: The early safety and efficacy of the MGuard stent was maintained during the long-term follow-up. However, comparative data from ongoing randomised clinical trials are still required to confirm the long-term efficacy of MGuard stent implantation in patients with STEMI. PMID- 24142750 TI - Prognostic value of septal E/(E'*S') ratio in predicting cardiac death in patients with heart failure. AB - BACKGROUND: A new tissue Doppler index, E/(E'*S'), including the early diastolic transmitral/mitral annular velocity (E/E') ratio and systolic mitral annular velocity (S'), has a good accuracy in predicting left ventricular filling pressure. AIM: To investigate the value of E/(E'*S') measured at different sites of the mitral annulus to predict cardiac death in patientswith heart failure (HF). METHODS: Echocardiography was performed in 342 consecutive hospitalised patients with HF, in sinus rhythm, at hospital discharge and after one month. Velocities were determined at septal and lateral mitral annular sites, and average values obtained. E/(E'*S') worsening was defined as a value greater than the value determined at discharge. The end point was cardiac death. RESULTS: During the follow-up period (35 +/- 8.8 months), cardiac death occurred in 52 (15.2%) patients. Septal E/(E'*S') at hospital discharge presented the largest area under receiver operating characteristic (ROC) curve to predict cardiac death (0.85,95% CI 0.79-0.90, p < 0.001). A statistical comparison of the ROC curves demonstrated no significant differences between septal and average E/(E'*S') (p = 0.54), but the accuracy of septal E/(E'*S') was better compared to the other analysed echocardiographic parameters [E/(E'*S'), E/E', S', etc., all p < 0.05]. The optimal septal E/(E'*S') cut-off was 3.03 (75% sensitivity,83% specificity). Before discharge, 96 (28.1%) patients presented septal E/(E'*S') > 3.03. Cardiac death was significantly higher in patients with E/(E'*S') > 3.03 (39 deaths, 40.2% vs. 13 deaths, 5.3%, p < 0.001). Patients with septal E/(E'*S') > 3.03 at discharge and worsening after one month presented the worst prognosis in the overall population. CONCLUSIONS: Septal E/(E'*S') is a powerful predictor of cardiac death in patients with HF. PMID- 24142751 TI - The impact of renal insufficiency on in-hospital outcome in patients with ST segment elevation myocardial infarction undergoing primary percutaneous coronary interventions. AB - BACKGROUND: Chronic renal disease (CRD) is a well-known risk factor for bleeding complications in acute coronary syndrome patients. AIM: To determine the impact of CRD with ST segment elevation myocardial infarction (STEMI) treated with primary percutaneous coronary intervention (pPCI) on periprocedural complications. METHODS: 103 patients with STEMI treated with pPCI were prospectively observed for in-hospital complications and analysed according to kidney function status. Endpoints included clinical and periprocedural outcomes. Major and minor bleedings were reported according to TIMI, REPLACE2 and EASY classifications. RESULTS: Patients with CRD were at greater risk of major bleeding defined by RAPLACE-2 (20.0% vs. 2.7%; p = 0.007) and TIMI(13.3% vs. 1.3%, p = 0.018) classifications and had more grade 2 EASY scale haematomas (20.0% vs. 2.7%; p = 0.007). Vascular access crossover during PCI occurred eight fold more often among CRD patients (33.3% vs. 4.0%, p < 0.001). Grade 3 TIMI flow was achieved less frequently in CRD patients (60% vs. 89.3%, p = 0.004). CRD predisposed to contrast-induced nephropathy (35.7% vs. 5.7%; p < 0.001) and ischaemic stroke (14.3% vs. 0.0%; p = 0.004). CONCLUSIONS: CRD in STEMI patients undergoing pPCI is a risk factor for major and minor bleeding complications including major bleeding, moderate haematomas, contrast-induced nephropathy and ischaemic stroke. Treatment and diagnostic measures should be taken in CRD patients to reduce the severity of periprocedural complications. PMID- 24142752 TI - Comparison between hybrid and standard centre-based cardiac rehabilitation in female patients after myocardial infarction: a pilot study. AB - BACKGROUND: Despite the known benefits of cardiac rehabilitation (CR) for patients with stable coronary artery disease, it is neglected, especially in women. Home-based programmes may increase adherence to CR. AIM: To compare the effectiveness of centre-based CR with a hybrid model of training, partly out patient and partly home-based and tele-monitored, in terms of physical capacity and adherence in post-myocardial infarction (MI) women with preserved left ventricular function. METHODS: 53 post-MI female patients, aged 51.3 +/- 7.6 years underwent an eight-week training programme (TP) consisting of 24 interval trainings. The first ten trainings were performed in a hospital, then 33 patients (Gruop A) continued them in the centre, the remaining 20 (Group B) did tele monitored walking training at home (hybrid model). Before and after completing CR, all patients underwent a symptom-limited treadmill exercise stress test during which the analysis included: workload (METs), duration (min), heart rate (HR, bpm), double product (mm Hg/min) at rest and during effort, and HR recovery in the first minute after test. Adherence was reported as the number of trainings completed and the number of dropouts in two CR models. RESULTS: After CR, only workload (Group A: 6.5 +/- 1.1 vs. 7.0 +/- 1.4, p < 0.05; Group B: 7.4 +/- 1.1 vs. 8.3 +/- 1.4, p < 0.01) and duration (Group A: 4.7 +/- 1.1 vs. 5.1 +/- 1.2, p < 0.01; Group B: 8.1 +/- 3.9 vs. 9.3 +/- 4.2, p < 0.01) improved significantly in both groups. Comparing CR effects between both groups, no significant differences were observed. All patients completed TP. CONCLUSIONS: In post-MI women, a hybrid model of training improved physical capacity and was a similarly effective form of CR as a centre-based approach. A home-based tele-monitored programme facilitated our patients' adherence to CR. PMID- 24142753 TI - Clinical characteristics, aetiology and occurrence of type 2 acute myocardial infarction. AB - BACKGROUND: Cardiovascular diseases are the leading cause of death worldwide. One of the most important diseases in this group is myocardial infarction (MI). According to the universal definition developed by the European Society of Cardiology (ESC), MI is divided into five main types based on its cause. Type 2 MI is secondary to ischaemia due to either increased demand or decreased supply of oxygen (for example due to coronary artery spasm, anaemia, arrhythmia, coronary embolism, hypertension, or hypotension). AIM: To assess the occurrence and aetiology of type 2 acute MI (AMI), and to describe the clinical characteristics and prognosis of study patients. METHODS: Into a retrospective study, we enrolled 2,882 patients in the Cardiology Department with an initial diagnosis of AMI between 2009 and 2012. Diagnosis of AMI was made based on ESC criteria. In all patients, coronary angiography was performed in order to exclude haemodynamically significant coronary lesions. RESULTS: Among 2,882 patients hospitalised in the described time period, 58 (2%) patients were diagnosed with type 2 AMI.The mean age of the study group was 67.3 +/- 13.2 years; and the majority of the study group, 60.3%, were women. Out of them, 23 (39.6%) patients experienced AMI due to coronary artery spasm, 15 (25.9%) due to arrhythmias, 11 (19%) due to severe anaemia, and nine (15.5%) due to hypertension, without significant coronary artery disease. 42 (72.4%) patients, were diagnosed as non ST-segment elevation MI, 14 (24.1%) as ST-segment elevation MI, and two (3.5%) as AMI in the presence of ventricular paced rhythm. History of classical cardiovascular risk factors including hypertension, diabetes, dyslipidaemia, family history of heart diseases, and smoking was reported in 42 (72.4%), 14 (24.1%), 23 (39.7%), 24 (41.4%), and 16 (27.6%) cases, respectively. All-cause 30 day mortality rate was 5.2%, and six-month was 6.9%. CONCLUSIONS: Type 2 AMI patients were more often female, and they were more often diagnosed as non-ST segment elevation MI. The prevalence of classical cardiovascular risk factors in this subgroup of patients was very high. The leading cause of AMI was coronary artery spasm. PMID- 24142754 TI - Characteristics, management and five-year outcomes of patients with high risk, stable multivessel coronary heart disease. AB - BACKGROUND: Multivessel coronary artery disease (MCAD) is a common manifestation of advanced coronary atherosclerosis. AIM: To determine the clinical characteristics and long term follow up prognostic factors in patients with high risk, stable MCAD from a single institution. METHODS: We included in the final analysis 270 patients with stable MCAD. Patients were followed for the occurrence of death, stroke and myocardial infarction (MI). We defined a cumulative major adverse cardiac and cerebrovascular event (MACCE) asa composite of death, stroke, MI and urgent revascularisation. Median follow up was 5 years (4-5.5 years). 176 (65%) patients were treated surgically (coronary artery bypass grafting, CABG), 19 (7%) patients were treated percutaneously, while 75 (28%) patients were treated medically; this meant that 94 (35%) patients were treated non-surgically. RESULTS: Predictors of MACCE in the study group of patients revealed by univariate logistic regression analysis were: diabetes mellitus (p = 0.04), kidney failure (p = 0.05), total cholesterol (p = 0.05), LDL-cholesterol (p = 0.02), chest pain symptoms in CCS III class (p = 0.05), heart rate (p = 0,02), NT proBNP (p = 0.01), left ventricular diastolic (p = 0.003) and systolic diameter (p = 0.003), left ventricular ejection fraction (p = 0.001), Gensini score (p = 0.05) and CABG treatment strategy (p = 0.001). In Cox logistic regression analysis, non CABG treatment strategy (b = 0.06), heart rate (b = 0.02), and LDL cholesterol level (b = 0.006) were independent predictors of MACCE (p = 0.01). CONCLUSIONS: Our study showed that patients with advanced MCAD who are qualified for complete surgical revascularisation benefitted more with regard to several primary end points at five-year follow-up than those who were not qualified for surgery and who were treated with medical therapy supplemented in selected cases with incomplete percutaneous revascularisation. PMID- 24142755 TI - Aspirin resistance in patients with impaired renal functions. AB - BACKGROUND: Cardiovascular diseases (CVD) are the leading cause of death in patients with chronic kidney diseases (CKD). Aspirin resistance (AR) worsens prognosis in CVD. AIM: The aim of this study was to detect AR prevalence in this patient group. METHODS: The 203 patients (mean age 61.84 +/- 11.51 years, 128 [63.1%] male) with stable coronary artery disease included in the study were grouped into four study groups according to their estimated glomerular filtration rate (eGFR) values. Multiplate test was used to determine AR. Platelet aggregation results were presented as aggregation unit (AU) * min and values over 300 AU * min were accepted as AR. RESULTS: 61 (30.04%) patients in the whole study population were found to have AR. Differences were detected between AR ratios and multiplate values of the patient groups (p = 0.006 and p = 0.002). AR ratio was highest in patient group 4 (eGFR < 30 mL/min/1.73 m2) and/or on chronic haemodialysis therapy, whereas there was little difference among the other three groups. In multivariate analysis, while AR status was independently related to female sex (OR = 2.31,CI 1.14-4.65, p = 0.019) and mean platelet volume (MPV) (OR = 1.68, CI 1.21-2.33, p = 0.002), multiplate test results were independently related to MPV (b = 0.265, p < 0.0001) and eGFR (b = -0.165, p = 0.025). CONCLUSIONS: The AR ratio was found to be high in severe CKD patients, especially haemodialysis patients, but not in mild and moderate CKD patients. This increased AR ratio in severe CKD patients may affect the prognosis in patients who already have an increased risk for cardiovascular complications. PMID- 24142756 TI - The effect of rosuvastatin and atorvastatin on erectile dysfunction in hypercholesterolaemic patients. AB - BACKGROUND AND AIM: The aim of this study was to evaluate the effect of atorvastatin and rosuvastatin on erectile dysfunction in hypercholesterolaemic patients. METHODS: Ninety consecutive male hypercholesterolaemic patients (mean age 50.4 +/- 7.9 years) who were otherwise healthy were included into the study prospectively. None of the patients had any cardiovascular risk factors except hypercholesterolaemia.The patients were divided into two groups. One group received atorvastatin while the other group was given rosuvastatin. All patients were followed for six months and International Index of Erectile Function-5 (IIEF 5) score and blood samples were re-evaluated. RESULTS: Patients were in similar ages in both groups. There were also no statistical differences in terms of blood glucose levels, total cholesterol, low density lipoprotein, high density lipoprotein, triglyceride and mean IIEF score in both groups at the beginning. After six months, no IIEF score changes were observed in the rosuvastatin group after the medication. However, the IIEF score was significantly lower in the atorvastatin group (p = 0.019). CONCLUSIONS: Rosuvastatin showed no effect on erectile dysfunction, while we observed increased erectile dysfunction with atorvastatin. Our study reveals that different statin types may have different effects on erectile dysfunction. PMID- 24142757 TI - Racial and ethnic disparities in breast cancer: experts gain new clues about differences in mortality rates among racial groups. PMID- 24142758 TI - Survival difference between African American and white women with breast cancer remains steady. PMID- 24142759 TI - Big ten universities launch cancer consortium. PMID- 24142760 TI - Rural women with breast cancer less likely to receive radiotherapy. PMID- 24142761 TI - Hospice support and the transition to adult services and adulthood for young people with life-limiting conditions and their families: a qualitative study. AB - BACKGROUND: Transition to adult services and adulthood is now a prospect for young people with life-limiting conditions requiring palliative care. Little is known about their transition experiences or how children's hospices can support a young adult population during/following transition. AIMS: (1) To examine how young people with life-limiting conditions and their parents experience transition. (2) To identify families' and hospice staff's perceptions of family support needs during transition. (3) To identify the implications for children's hospices. DESIGN: Qualitative study using in-depth, semi-structured interviews. Analysis used a grounded theory approach. SETTING/PARTICIPANTS: A total of 39 participants recruited from one children's hospice in the United Kingdom. RESULTS: Transition planning was absent or poorly coordinated; for most families, there were no equivalent adult health/social services. Consequently, it was a time of uncertainty and anxiety for families. Moving to a young adult unit was a positive experience for young people as the building/support model recognised their adult status. However, they had unmet needs for emotional support and accessing information/services to realise their aspirations. Parents had unmet emotional needs and were unclear of support available once their children reached adulthood. Staff identified training needs in relation to working with adults, providing emotional support and acting as an advocate/key worker. CONCLUSIONS: Providing an appropriate building is only one aspect of developing support for young adults. A different model of support is needed, one which promotes young people's independence and provides emotional support while continuing to support parents and siblings. Hospices could play a role in transition support and coordination. PMID- 24142762 TI - Are water precautions necessary after tympanostomy tube placement? PMID- 24142765 TI - Clinical significance of Treg cell frequency in acute myeloid leukemia. AB - This study was designed to investigate the clinical significance of peripheral blood CD4(+) CD25(+) CD127 low-regulatory T (T(reg)) cells in acute myeloid leukemia (AML) patients. T(reg) cells in the peripheral blood of 80 AML patients and 35 age-matched healthy controls were counted by flow cytometry. Correlations between the frequency of circulating T(reg) cells and disease status, treatment outcome, or prognosis were evaluated. The percentages of T(reg) cells in patients at diagnosis and during refractory/relapse were significantly higher than that in healthy controls. There was no significant difference in the percentages of T(reg) cells between patients in remission and healthy controls. After six cycles of chemotherapy, the percentage of T(reg) cells in patients who achieved complete remission was significantly lower than that in patients at diagnosis, but there was no difference in T(reg) frequency between refractory/relapse patients and patients at diagnosis. T(reg) cells in the peripheral blood of AML patients may play a suppressive role in host antitumor immune response. The frequency of T(reg) cells in peripheral blood may thus be used as a biomarker for predicting sensitivity to chemotherapy and prognosis of AML patients. Additionally, T(reg) number in peripheral blood could be used to monitor disease status and evaluate disease progression. PMID- 24142767 TI - Methylation of serum insulin-like growth factor-binding protein 7 promoter in hepatitis B virus-associated hepatocellular carcinoma. AB - Methylation of gene promoter CpG islands is an important early event in hepatocellular carcinoma (HCC), and detection of cell-free tumor-specific DNA methylation is becoming a useful noninvasive method for HCC. This study was aimed at determining the diagnostic value of serum insulin-like growth factor-binding protein 7 (IGFBP7) promoter methylation in hepatitis B virus-associated HCC. A total of 217 subjects, including 136 HCC patients, 46 patients with chronic hepatitis B (CHB), and 35 healthy controls (HCs), were included. The methylation status of the serum IGFBP7 gene promoter was determined using methylation specific PCR. The frequency of serum IGFBP7 promoter methylation in HCC patients (89/136, 65%) was significantly higher than that in CHB patients (8/46, 17%; X(2) = 31.883, P < 0.001) and HCs (5/35, 14%; X(2) = 29.429, P < 0.001). Moreover, elevated IGFBP7 methylation frequency was also observed in HCC patients with vascular invasion compared with those without vascular invasion (84 versus 60%, X(2) = 6.633, P = 0.010). The sensitivities of serum IGFBP7 methylation and alpha fetoprotein (AFP) in detecting HCC were 65 and 57%, respectively. Of note, the combination of IGFBP7 methylation and AFP showed 85% for sensitivity. These results suggest that methylation of the serum IGFBP7 gene promoter may serve as a useful noninvasive biomarker for HCC diagnosis. PMID- 24142766 TI - Cardiovascular differentiation of imatinib and bosutinib in the rat. AB - Imatinib and bosutinib were administered to rats for up to 6 months at clinically relevant exposures to investigate the effects on the cardiovascular system. Imatinib treatment resulted in increased volume, wall thickness and mass suggesting a hypertrophic heart in male and female rats at one and fivefold clinical exposures, respectively. Bosutinib treatment resulted in milder cardiac hypertrophy in female rats only at fivefold clinical exposures. Analysis of excised hearts and cultured myocytes demonstrated increased expression of hypertrophic genes with imatinib or analogs, but not bosutinib or c-Abl RNAi treatment. The current dataset suggests that cardiovascular liability of imatinib and bosutinib are differentiated preclinically and c-Abl independent. PMID- 24142768 TI - A specific groove design for individualized healing in a canine partial sternal defect model by a polycaprolactone/hydroxyapatite scaffold coated with bone marrow stromal cells. AB - The reconstruction of sternal defects remains clinically challenging for thoracic surgeons. Here we aimed to explore the individualized reconstruction of partial sternal defects with new biodegradable material in a large animal model. We used the fused deposition modeling (FDM) technique to manufacture polycaprolactone/hydroxyapatite (PCL/HA) tissue scaffolds with individualized grooves to repair the sternal defect. The defects were surgically created in a sternocostal joint of eighteen Beagle dogs. The animals were separated into three groups (n = 6): Blank group, PCL/HA group, and PCL/HA/BMSCs group. Radiographic examination, histological, and histomorphometric analyses were performed to evaluate the result. In the blank group, the defect site couldn't maintain its original integrity due to no bone union. In the PCL/HA group and PCL/HA/BMSCs group, it was observed that the scaffolds retained their shapes without significant degradation at 12 weeks. Both groups could observe new bone-union by radiographic and histological examination. And PCL/HA/BMSCs would be more mineralized tissue area at implant sites (p < 0.05). These results reveal that using the FDM technique to manufacture the PCL/HA scaffolds with specific grooves could repair the sternal defect satisfactorily. Furthermore the scaffolds with BMSCs-seeded could enhance the amount of bone ingrowth and seemed to be more promising. PMID- 24142770 TI - A new device for fibular osteotomy in mandibular reconstruction. PMID- 24142769 TI - Prevalence and management of coronary chronic total occlusions in a tertiary Veterans Affairs hospital. AB - OBJECTIVES: We sought to determine the contemporary prevalence and management of coronary chronic total occlusions (CTO) in a veteran population. BACKGROUND: The prevalence and management of CTOs in various populations has received limited study. METHODS: We collected clinical and angiographic data in consecutive patients that underwent coronary angiography at our institution between January 2011 and December 2012. Coronary artery disease (CAD) was defined as >=50% diameter stenosis in >=1 coronary artery. CTO was defined as total coronary artery occlusion of >=3 month duration. RESULTS: Among 1,699 patients who underwent angiography during the study period, 20% did not have CAD, 20% had CAD and prior coronary artery bypass graft surgery (CABG), and 60% had CAD but no prior CABG. The prevalence of CTO among CAD patients with and without prior CABG was 89 and 31%, respectively. Compared to patients without CTO, CTO patients had more co-morbidities, more extensive CAD and were more frequently referred for CABG. Percutaneous coronary intervention (PCI) to any vessel was performed with similar frequency in patients with and without CTO (50% vs. 53%). CTO PCI was performed in 30% of patients without and 15% of patients with prior CABG with high technical (82 and 75%, respectively) and procedural success rates (80 and 73%, respectively). CONCLUSIONS: In a contemporary veteran population, coronary CTOs are highly prevalent and are associated with more extensive co-morbidities and higher likelihood for CABG referral. PCI was equally likely to be performed in patients with and without CTO. PMID- 24142771 TI - Current issues in transplant infectious diseases. PMID- 24142772 TI - The Metamorphosis of HIV-Associated Neurocognitive Disorders. PMID- 24142773 TI - Community DSPD pilot services in South London: rates of reconviction and impact of supported housing on reducing recidivism. AB - BACKGROUND: The effectiveness of community services in reducing recidivism by men in the 'dangerous and severe personality disorder' framework--with personality disorder and at high risk of recidivism--is unknown. AIMS: To conduct a preliminary examination of the characteristics and reconviction rates of male offenders with personality disorder accessing two South London community dangerous and severe personality disorder pilot outpatient services and to evaluate the role of supported housing for them. METHODS: Reoffending outcomes of 107 high risk offenders with personality disorder were assessed using a cross sectional cohort study design. Participants were allocated to outpatient only (non-residential) or outpatient with supported housing groups. Self-reported, collateral and criminal justice data and Offender Group Reconviction Scale III predictors of reoffending were used to describe the samples. RESULTS: The overall reconviction rate over the entire study period was 11%. At 12 months following acceptance to the service, reoffending for the entire sample was significantly lower (5%) than mean Offender Group Reconviction Scale III scores predicted (51%). Multivariate analyses confirmed that those also in receipt of supportive housing were significantly less likely to reoffend than those without. Although there was no difference between groups in violent reconviction specifically, only five men in total reoffended violently. CONCLUSIONS: Although findings appear promising, this was a naturalistic study. The sample size was small, but represented all men accepted into the two pilot services. Further evaluation of the role of supported housing and perhaps other details of community supervision should follow. PMID- 24142774 TI - Working memory biasing of visual perception without awareness. AB - Previous research has demonstrated that the contents of visual working memory can bias visual processing in favor of matching stimuli in the scene. However, the extent to which such top-down, memory-driven biasing of visual perception is contingent on conscious awareness remains unknown. Here we showed that conscious awareness of critical visual cues is dispensable for working memory to bias perceptual selection mechanisms. Using the procedure of continuous flash suppression, we demonstrated that "unseen" visual stimuli during interocular suppression can gain preferential access to awareness if they match the contents of visual working memory. Strikingly, the very same effect occurred even when the visual cue to be held in memory was rendered nonconscious by masking. Control experiments ruled out the alternative accounts of repetition priming and different detection criteria. We conclude that working memory biases of visual perception can operate in the absence of conscious awareness. PMID- 24142775 TI - Radiotherapy influences local control in patients with desmoplastic melanoma. AB - BACKGROUND: Desmoplastic melanoma may have a high risk of local recurrence after wide excision. The authors hypothesized that adjuvant radiotherapy (RT) would improve local control in patients with desmoplastic melanoma, resulting in at least a 10% absolute decrease in local recurrence rate. METHODS: A total of 277 patients from 1989 through 2010 who were treated for nonmetastatic desmoplastic melanoma by surgery with or without adjuvant RT were reviewed. Clinicopathologic and treatment variables were assessed with regard to their role in local control. RESULTS: A total of 113 patients (40.8%) received adjuvant RT. After a median follow-up of 43.1 months, adjuvant RT was found to be independently associated with improved local control on multivariable analysis (hazards ratio, 0.15; 95% confidence interval, 0.06-0.39 [P<.001]). Among 35 patients with positive resection margins, 14% who received RT developed a local recurrence versus 54% who did not (P=.004). In patients with negative resection margins, there was a trend (P=.09) toward improved local control with RT. In patients with negative resection margins and traditionally high-risk features, including a head and neck tumor location, a Breslow depth >4 mm, or a Clark level V tumor, RT was found to significantly improve local control (P< .05). The data from the current study would suggest that patients who would be good candidates for omitting RT included those with negative resection margins, a Breslow depth <= 4 mm, and either no perineural invasion present or a non-head and neck tumor location. CONCLUSIONS: RT for desmoplastic melanoma was independently associated with improved local control. Patients with positive resection margins or deeper tumors appeared to benefit the most from RT, whereas selected low-risk patients can safely omit RT. PMID- 24142776 TI - Steroids in aminoglycoside-containing ear drops: do they reduce cochlear toxicity? AB - OBJECTIVES/HYPOTHESIS: To determine whether betamethasone (BM) reduces the cochlear toxicity of otic gentamicin (GM) if given together. STUDY DESIGN: Controlled animal study. METHODS: Thirty-four mice were assigned at random to receive intratympanic injections of either 0.1 % BM (11 mice), 0.3% GM (13 mice), or a combination of both (GM/BM) with benzalkonium chloride (10 mice) in the left ear (treated) and saline on the right (untreated). Six injections were given on alternate days. Auditory brainstem response thresholds were assessed at 1 month, 2 months, and >2 months. RESULTS: There was a significantly greater degree of hearing loss in the BM-treated ears compared to the untreated ears (6.48 dB hearing loss, P = .007) and in the GM-treated ears compared to untreated ears (6.59 dB hearing loss, P = .010,). However, otic GM/BM and benzalkonium chloride did not cause significant additional hearing loss compared with the untreated ears (3.56 dB hearing loss, P = .242). CONCLUSIONS: Our data suggest that hearing loss caused by GM otic drops may be reduced by the inclusion of BM and benzalkonium chloride. Our finding that BM alone was associated with hearing loss suggests that the benzalkonium chloride may be the protective agent in combination otic drops. PMID- 24142777 TI - [Lung function assessment in the elderly]. PMID- 24142778 TI - [Tuberculosis and HIV in the world, in Europe and in Poland]. PMID- 24142779 TI - Incidence of tuberculosis and mycobacteriosis among HIV-infected patients- clinical and epidemiological analysis of patients from north-eastern Poland. AB - INTRODUCTION: According to WHO data, among patients infected with HIV, tuberculosis occurs in about 30% of patients and causes approximately 25% of deaths due to AIDS worldwide. The incidence rate of tuberculosis in the Polish population was 22.2/100,000 in 2011, while the average in European Union countries in 2011 was 14/100,000. Since 1985 to 30 April 2013 HIV infection in Poland was confirmed in 16,588 patients, while the number of reported tuberculosis cases in HIV-infected individuals in 2011 was 26. The aim of this study was to assess the prevalence and clinical course of tuberculosis and mycobacterial disease in HIV-infected patients treated in the Department of Infectious Diseases and Hepatology in Bialystok. MATERIAL AND METHODS: We analysed documentation of 577 HIV-infected patients, their demographic data, epidemiological status, degree of immunosuppression (T CD4 and CD8 numbers) and stage of HIV infection. RESULTS: Complete follow-up was possible in 389 patients, of whom 265 (68%) were male. Tuberculosis (TB) was diagnosed in 41 patients (10.5%) and mycobacteriosis in 4 patients (1.03%). In 19 patients (42%) HIV and TB or mycobacteriosis were diagnosed simultaneously. The median CD4 T lymphocyte count was lower in patients with a simultaneous diagnosis of HIV and tuberculosis or mycobacteriosis compared to the group in whom TB/mycobacteriosis was diagnosed later. The number of CD4 T-cells less than 50 cells/MUL was found in 63.2% (12/19) of patients when HIV and TB or mycobacteriosis were diagnosed simultaneously and in 38.5% (10/26) of patients who were diagnosed with TB or mycobacteriosis later than the HIV infection (p = 0.14). The median HIV viral load in patients in whom HIV infection and tuberculosis or mycobacteriosis were diagnosed at the same time was higher than in other patients and this difference was statistically significant. Pulmonary tuberculosis was the most common form of clinical disease and accounted for 60% of all cases. Among the analysed cases with HIV and tuberculosis or mycobacteriosis coinfection, tuberculosis or mycobacteriosis was the cause of death in 8 patients, and 9 died of other causes. CONCLUSION: In our material of 389 HIV-infected patients, tuberculosis was diagnosed in 41 (10.5%) and mycobacterial diseases in 4 (1.03%). In 42% of co infected patients (HIV+TB or mycobacteriosis) the diagnosis of both diseases was made at the same time. In these patients, a deep deficit of cellular immunity (CD4 < 50 cells/MUL) was observed more frequently than in patients diagnosed with TB or mycobacteriosis in the later course of HIV. HIV RNA viral load was significantly higher in the group diagnosed simultaneously than in the remaining patients with HIV and TB or mycobacteriosis coinfection. PMID- 24142780 TI - Quality of spirometry in the elderly. AB - INTRODUCTION: Spirometry is the basic method used to diagnose and monitor obstructive diseases. Spirometric tests are performed in more and more people of advanced age (more than 65 years old). The objective of the study was to assess the quality of spirometry (measurement of the flow-volume curve) in subjects of the aforementioned age group, with reference to applicable quality criteria specified in guidelines ERS/ATS 2005 and PTChP 2006. MATERIAL AND METHODS: The study was of a retrospective nature. The authors analysed the results of spirometry performed in 1271 subjects who were 65 to 94 years old and who underwent spirometric tests in the Respiratory Physiopathology Laboratory of Kujawy-Pomorze Regional Centre of Pulmonology in Bydgoszcz over a period of 6 months. This group included 759 males (average age 73.2 +/- 5.9 years) and 512 females (average age 73.2 +/- 5.7 years). The quality of the spirometry was assessed according to error codes assigned to individual spirometric sessions by the software JLab 5.31 installed in the measuring system MasterScreen (CareFusion). RESULTS: Twenty-nine (2.3%) of the 1271 subjects failed to perform spirometric measurements. For the remaining 1242 subjects the following spirometry quality was determined: correctly performed spirometric test in 415 (33.4%) subjects; one error in 673 (54.2%) subjects; 2 errors in 136 (11%) subjects; 3 errors in 15 (1.2%) subjects and 4 errors in 3 (0.2%) subjects. The analysis of individual errors revealed that the lack of a plateau at the end of exhalation was found in 747 (60.1%) subjects (including only 25 (2%) subjects with FET < 6 s); increased BEV value in 7 (0.6%) subjects; abruptly finished exhalation in 36 (2.9%) subjects; and no FVC and FEV1 repeatability in 43 (3.5%) and 169 (13.6%) subjects, respectively. CONCLUSIONS: The most common error was the lack of a plateau at the end of exhalation. Therefore, paying particular attention to the final phase of exhalation during spirometry should, as a result, increase the percentage of correctly performed spirometric tests in the elderly. PMID- 24142781 TI - The application of MDCT in the diagnosis of chest trauma. AB - INTRODUCTION: Traumas are the third most common cause of death worldwide, after cardiovascular diseases and neoplasms, and the main cause of death of patients under 40 years of age. Contemporary image diagnosis of chest trauma uses chest X ray (CXR), multidetector computed tomography (MDCT), transthoracic and transoesophageal ultrasound (USG), X-ray angiography and magnetic resonance. The aim of the present study was to evaluate MDCT results in the examination of posttraumatic chest injuries and to compare the results of CXR and MDCT in chosen chest traumatic injuries. MATERIAL AND METHODS: The sixty patients with chest trauma included in the study were diagnosed at the Department of Radiology of the Institute of Tuberculosis and Lung Diseases between May 2004 and October 2007. MDCT was performed in all patients. Two groups with different types of injury (blunt or penetrating chest trauma) were distinguished. The analysis of injuries in both groups was conducted depending on the mechanism of trauma. The detection of 20 selected injuries at CXR and MDCT was compared. Moreover, the compatibility of MDCT with the results of intraoperative assessment and bronchoscopy was analysed. The influence of MDCT on the treatment modality was also assessed. RESULTS: History of blunt chest trauma was found in 51 patients (group 1) and of penetrating trauma in 9 patients (group 2). The most frequent injuries among group 1 were lung contusion and rib fractures, and among group 2 it was pericardial hematoma. Compared to MDCT, the sensitivity and specificity of CXR were 66.7 and 58%, respectively. Change of treatment modality was observed after MDCT in 83% of patients. The sensitivity and specificity of MDCT in diagnosing tracheobronchial injury, compared to bronchoscopy, were 72.7% and 100%, respectively. Compatibility of MDCT results and intraoperative assessment was observed in 43% of patients, and the main reason for discrepancy was underdiagnosis of diaphragm injury in MDCT. CONCLUSIONS: MDCT was a valuable diagnostic method in recognition of chest trauma, characterized by high sensitivity and specificity in the assessment of life-threatening injures and for depicting tracheal and bronchial injuries. The diagnostic value of CXR was low. The compatibility of MCTD and intraoperative assessment was confirmed, with the exception of diaphragm injures and lung laceration. Change of treatment modality was certified after MDCT in 83% of patients. PMID- 24142782 TI - Efficacy and safety of a 12-week therapy with a new formulation of fluticasone propionate at doses of 125 and 250 MUg administered through a new generation cyclohaler twice daily, in comparison to fluticasone propionate 500 MUg dry powder inhaler twice daily in patients with moderate asthma. AB - INTRODUCTION: Inhaled fluticasone is used in the treatment of chronic bronchial asthma. Its high efficacy and good safety profile have been proven by clinical trials and observations. Its unique pharmacokinetic properties make it distinguishable from other drugs from this group. In vitro tests run on an artificial model of the airways and pharmacokinetic studies conducted on healthy volunteers have shown that the new formulation of this drug is outstanding due a twofold better lung deposition, compared to the reference medicine. The aim of this study was to evaluate the efficacy and safety of the new formulation of fluticasone propionate administered through new generation cyclohaler (CNG), compared to original fluticasone administered through dry powder inhaler (DPI) in patients with chronic moderate asthma. MATERIAL END METHODS: The study included 457 patients. 376 subjects were randomized to one out of the three groups: 127 subjects--to the group treated with the new formulation of fluticasone at a dose of 125 MUg BID, 125 subjects--to the group treated with new formulation of fluticasone at a dose of 250 MUg BID, and 124 subjects--to the group treated with the reference drug--fluticasone DPI 500 MUg BID. At the beginning of the study, the groups did not differ in demographical or clinical aspects. Active therapy lasted 12 weeks. The primary endpoint was a mean change in morning PEF during a 12-week course of therapy (DeltamPEF of 15 L/min was considered as statistically significant). Additionally, other functional parameters of the respiratory system -clinical symptoms and the use of rescue drugs were studied. During the whole study the safety of patients was monitored by recording adverse events; in addition, a systemic exposure to fluticasone was evaluated by testing the changes of cortisol in serum and in a 24-hour collection of urine in a subgroup consisting of 45 patients. Statistical analysis was conducted on both groups: intention-to-treat (ITT) and per protocol (PP). RESULTS: In PP as well as in ITT analysis, a mean change in morning PEF at the end of the therapy in comparison with the initial period was statistically significant in all therapeutic groups. The efficacy of the treatment with fluticasone at doses of 125 MUg BID and 250 MUg and the reference medicines did not differ statistically significantly after a 12-week course of therapy or during the whole period of treatment. During the study, significant improvement in the range of other functional parameters such as evening PEF, FEV1, clinical symptoms and the use of rescue drugs was observed in all therapeutic groups, without significant differences in efficacy between the study groups. The comparison of efficacy of fluticasone at a dose of 125 MUg BID with the generic product at a dose of 250 MUg BID showed a weak dose-response relationship concerning the change in morning PEF, which arises from the almost flat dose-response curve in the range of medium and high doses for this drug. No significant quantitative or qualitative differences were shown between the groups in the recorded adverse events, qualified as related to treatment with fluticasone. There were no significant changes revealed in cortisol concentration in serum or in a 24-hour collection of urine between the initial level and the final visit in any of the groups. CONCLUSIONS: Fluticasone administered through the new generation cyclohaler, compared to original fluticasone DPI, allows a twofold reduction in drug dose, retaining in new formulation clinical efficacy that corresponds to the reference drug at twice the dose. New formulation of fluticasone administered through the new generation cyclohaler has a safety profile clinically comparable to the reference drug. PMID- 24142783 TI - Transthyretin amyloidosis with pulmonary involvement in a patient with monoclonal gammapathy. AB - Pulmonary involvement in the course of systemic senile amyloidosis caused by non mutated transthyretin is rarely described. We report on concomitant monoclonal gammapathy of undermined significance (MGUS) and amyloidosis with non-mutated transthyretin with diffuse lesions in lung parenchyma. A female patient, 67 years old, was admitted with dyspnoea, malaise, weight loss, and disseminated radiological lesions in the lungs. On lung HRCT, signs of pulmonary hypertension, alveolar and interstitial involvement, with thickening of septal lines were found. Echocardiography revealed severe pulmonary hypertension, and electromyography revealed sensoromotoric polyneuropathy with axon and myelin damage. Pathological assessment of lung specimens revealed nodular deposits of amyloid in the bronchial walls and lung parenchyma Congo red staining was positive. Specimens of colon mucosa confirmed amyloidosis. Stainings for AA, AL and beta2-microglobulin were negative but were positive for transthyretin. Bone marrow trepanobiopsy indicated monoclonal gammapathy of MGUS type; Congo red staining was positive. Transthyretin amyloidosis with vascular involvement, particularly of arteriovenous anastomoses, including pulmonary vessels and an insignificant amount of AL protein (perhaps secondary imbibition with AL protein from serum) was diagnosed in amyloid deposits. No mutations of the transthyretin gene (exon 1,2,3,4) were found. The patient was treated with methylprednisolone, melphalan and then with cyclophosphamide. Radiological examinations performed 1 and 2 month/s after initiation of therapy showed progression of pulmonary lesions. The patient died one month later; an autopsy was not performed. PMID- 24142784 TI - Fatal clinical outcome in a patient with sarcoidosis-lymphoma syndrome. AB - A 62-year-old female suspected of malignant disease underwent a splenectomy that revealed noncaseating granulomas in the histological specimen. Chest X-ray (CXR) and lung CT scans suggested sarcoidosis stage II. TBLB showed noncaseating granulomas. A diagnosis of sarcoidosis was made. Initially no treatment was needed as partial remission on CXR and normal lung function were observed. During the follow up she underwent open lung biopsy and axillary lymph node biopsy because of radiological progression with presence of CXR opacities imitating metastases and recurrent lymphadenopathy. No malignant cells were found. Spontaneous partial resolution of disseminated changes on the CXR was observed. Because of progressive deterioration in lung function and the clinical course of the disease strongly suggesting the progression of systemic sarcoidosis, the patient was given steroid treatment, which initially resulted in partial remission of pulmonary disseminated changes, peripheral lymphadenopathy and improvement in lung function test. Eight months later severe deterioration in general condition, anaemia, leukocytosis, hypoxemia, massive hepatomegaly and recurrence of general lymphadenopathy along with progression of disseminated changes were found. She died before the final diagnosis was established. Post mortem examination showed a nodal marginal zone B-cell lymphoma with monocytoid B cells, according to WHO classification. The malignant cells were found in the jugular, mediastinal, paratracheal, paragastric, paraintestinal and retroperitoneal lymph nodes and they infiltrated the lungs, pleura, liver, thyroid gland and pancreas. No sarcoid granulomas were found in the autopsy. PMID- 24142785 TI - [A surprising diagnosis in a male with a tumour of the chest wall--not always lung cancer]. AB - Lung cancer is the most frequent malignant tumour in men. Advanced disease may produce metastatic tumours in subcutaneous tissue and also infiltrate the chest wall. We present a history of a man referred to our department suspected of lung tumour infiltrating the chest wall. Additionally, bone metastatic disease was diagnosed (ribs, vertebral bodies and skull). Thanks to a wide diagnostic approach, ductal cancer of the breast was finally diagnosed, a neoplasm that is extremely rare in male patients, usually presenting as a definite nodule in the nipple area of the breast. This case shows the importance of careful histological evaluation of the chest wall tumour. PMID- 24142786 TI - [Interstitial lung disease in patients with polymyositis and dermatomyositis- report of three cases]. AB - Polymyositis (PM) and dermatomyositis (DM) are connective tissue diseases (CTD) characterized by proximal muscle weakness along with changes in various internal organs, with the lungs most frequently involved. Presentation of the disease in the lungs comprises diffuse alveolar haemorrhage due to vasculitis and interstitial lung disease (ILD), which is the most frequent manifestation of CTD in the lungs and worsens the outcome and prognosis. The mechanisms involved in the ILD are not fully known, but the role of autoimmune response is unquestioned. No relationship between the severity of CTD and the changes in the lungs was observed. ILD may present at any time in the course of CTD, sometimes before the signs and symptoms of myositis occur. The more accurate imaging methods are, the more frequently changes in the lungs are detected. High resolution computed tomography (HRCT) is a gold standard in ILD imaging. Treatment of PM/DM-related ILD relays on systemic glucocorticosteroids as the first choice drugs. We present three cases of PM/DM-related ILD in middle-aged men, with a different clinical and radiological presentation. In all cases, apart from imaging (plain X-ray and HRCT of the chest) and pulmonary function tests, histological evaluation of lung changes was performed. In two cases non-specific interstitial pneumonitis (NSIP) was diagnosed, and in the third--organizing pneumonia along with sarcoid changes in the lymph nodes. Because of decreased pulmonary function all patients were treated with systemic corticosteroids and two of them additionally with azathioprine or cyclophosphamide, and the outcome was good in all of them. PMID- 24142787 TI - [Ischaemic heart disease and hypertension in patients with chronic obstructive pulmonary disease and obstructive sleep apnoea]. AB - Chronic obstructive pulmonary disease (COPD) affects almost 10% of the adult population of our country; obstructive sleep apnoea is increasingly being recognized and concerns, according to accepted criteria, 2-9% of females and 4 24% of men. The greatest mortality in chronic obstructive pulmonary disease is not caused by respiratory failure, but cardiovascular complications, including ischaemic heart disease. Obstructive sleep apnoea in half the cases is complicated by hypertension, often refractory to antihypertensive therapy. The paper discusses the pathogenesis of ischaemic heart disease in patients with COPD with particular attention to the inflammation that occurs in these two diseases. The pathogenesis of hypertension in the course of obstructive sleep apnoea is also presented with particular emphasis on hypoxia and sympathetic stimulation. Prevention of coronary heart disease should be a priority of the procedure in chronic obstructive pulmonary disease. The paper also discusses the treatment of ischaemic heart disease, paying attention to the modification of treatment in patients with chronic obstructive pulmonary disease, and discussing the influence of drugs used in COPD on the progression of ischaemic heart disease. Hypertension in the course of obstructive sleep apnoea is often resistant to therapy despite the use of continuous positive airway pressure devices, and often decrease after the use of aldosterone antagonists. Attention is drawn to the anti-inflammatory action of statins and trials of their use in the prevention of exacerbations of chronic obstructive pulmonary disease. PMID- 24142788 TI - [Thromboprophylaxis in patients with lung disease]. PMID- 24142789 TI - [Advancess in bronchoscopic techniques]. PMID- 24142791 TI - NRH:quinone oxidoreductase 2 (NQO2) protein competes with the 20 S proteasome to stabilize transcription factor CCAAT enhancer-binding protein alpha (C/EBPalpha), leading to protection against gamma radiation-induced myeloproliferative disease. AB - NRH:quinone oxidoreductase 2 (NQO2) is a flavoprotein that protects cells against radiation and chemical-induced oxidative stress. Disruption of the NQO2 gene in mice leads to gamma radiation-induced myeloproliferative diseases. In this report, we showed that the 20 S proteasome and NQO2 both interact with myeloid differentiation factor CCAAT-enhancer-binding protein alpha (C/EBPalpha). The interaction of the 20 S proteasome with C/EBPalpha led to the degradation of C/EBPalpha. NQO2, in the presence of its cofactor NRH, protected C/EBPalpha against 20 S degradation. Deletion and site-directed mutagenesis demonstrated that NQO2 and 20 S competed for the same binding region of S(268)GAGAGKAKKSV(279) in C/EBPalpha. Exposure of mice and HL-60 cells to gamma radiation enhanced the levels of NQO2, which led to an increased NQO2 interaction with C/EBPalpha and decreased 20 S interaction with C/EBPalpha. NQO2 stabilization of C/EBPalpha was independent of NQO1, even though both interacted with the same C/EBPalpha domain. NQO2(-/-) mice, deficient in NQO2, failed to stabilize C/EBPalpha. This contributed to the development of gamma radiation-induced myeloproliferative disease in NQO2(-/-) mice. PMID- 24142790 TI - Meclizine inhibits mitochondrial respiration through direct targeting of cytosolic phosphoethanolamine metabolism. AB - We recently identified meclizine, an over-the-counter drug, as an inhibitor of mitochondrial respiration. Curiously, meclizine blunted respiration in intact cells but not in isolated mitochondria, suggesting an unorthodox mechanism. Using a metabolic profiling approach, we now show that treatment with meclizine leads to a sharp elevation of cellular phosphoethanolamine, an intermediate in the ethanolamine branch of the Kennedy pathway of phosphatidylethanolamine biosynthesis. Metabolic labeling and in vitro enzyme assays confirmed direct inhibition of the cytosolic enzyme CTP:phosphoethanolamine cytidylyltransferase (PCYT2). Inhibition of PCYT2 by meclizine led to rapid accumulation of its substrate, phosphoethanolamine, which is itself an inhibitor of mitochondrial respiration. Our work identifies the first pharmacologic inhibitor of the Kennedy pathway, demonstrates that its biosynthetic intermediate is an endogenous inhibitor of respiration, and provides key mechanistic insights that may facilitate repurposing meclizine for disorders of energy metabolism. PMID- 24142792 TI - Multiresistance of Staphylococcus xylosus and Staphylococcus equorum from Slovak Bryndza cheese. AB - Staphylococcus xylosus, Staphylococcus equorum, and Staphylococcus epidermidis strains were isolated from Bryndza cheese and identified using PCR method. The antimicrobial susceptibility of these strains was assessed using disc diffusion method and broth microdilution method. The highest percentage of resistance was detected for ampicillin and oxacillin, and in contrary, isolates were susceptible or intermediate resistant to ciprofloxacin and chloramphenicol. Fourteen of the S. xylosus isolates (45%) and eleven of the S. equorum isolates (41%) exhibited multidrug resistance. None of the S. epidermidis isolate was multiresistant. The phenotypic resistance to oxacillin was verified by PCR amplification of the gene mecA. PMID- 24142793 TI - A novel germline JAK2 mutation in familial myeloproliferative neoplasms. PMID- 24142794 TI - Reverse flow first dorsal metacarpal artery flap for covering the defect of distal thumb. AB - Reconstruction of distal thumb injuries still remains a challenge for hand surgeons. Surgical treatment includes the use of local, regional, and free flaps. The purpose of this report is to present the results of the use of a sensitive reverse flow first dorsal metacarpal artery (FDMA) flap. The skin flap was designed on the radial side of the proximal phalanx of the index finger based on the ulnar and radial branch of the FDMA and a sensory branch of the superficial radial nerve. This neurovascular flap was used in five patients to cover distal soft-tissue thumb defects. All flaps achieved primary healing except for one patient in whom superficial partial necrosis of the flap occurred, and the defect healed by second intention. All patients maintained the thumb original length and were able to return to their previous daily activities. The reverse flow FDMA flap is a reliable option to cover immediate and delayed defects of distal thumb, offering acceptable functional and cosmetic outcomes in respect to sensibility, durability, and skin-match. PMID- 24142795 TI - Carers' experiences of being exposed to challenging behaviour in services for autism spectrum disorders. AB - Previous studies have demonstrated that being exposed to challenging behaviour in services of care can have a negative impact on staff. Recently, challenging behaviour has been linked to people with autism spectrum disorders; however, little research has been aimed at exploring staff's experiences of facing such behaviour in services for autism spectrum disorders in particular. A qualitative study using interpretative phenomenological analysis was conducted. This method involves thorough exploration of experiences revealed by individuals. A purposive sample (N = 10) was used. Participants were involved in semi-structured interviews which were later analysed according to the guidelines by Smith and Osborn. Four themes were discovered: intense mental and physical engagement, importance of adaptive coping, ambiguous experience of failure and achievement and destructive emotional reactions. Being exposed to challenging behaviour in services for autism spectrum disorders is a complex multi-component experience. The present results allow some insight into personal worlds of staff and might be useful for improving their working environment as well as ensuring a higher quality of care for service users. PMID- 24142797 TI - Media use among adolescents with autism spectrum disorder. AB - This study explores how adolescents with autism spectrum disorder (ASD) use media, and the factors associated with their media use. A total of 91 adolescents with ASD and their parents completed mail-based surveys. In all, 78% of the adolescents with ASD watched television (approximately 2 h/day), and 98% used computers (approximately 5 h/day) on any given day. They most frequently watched cartoons, played computer or video games that involved shooting, and visited websites that contained information on video games. Adolescents with ASD who watched television with parents reported more positive parent-child relationships. Adolescents with ASD who visited social networking websites or received emails from friends reported more positive friendships. The findings help us understand media-use habits of adolescents with ASD and suggest areas for future research. PMID- 24142796 TI - Outcomes of an acceptance and commitment therapy-based skills training group for students with high-functioning autism spectrum disorder: a quasi-experimental pilot study. AB - Autism spectrum disorder is characterized by social impairments and behavioural inflexibility. In this pilot study, the feasibility and outcomes of a 6-week acceptance and commitment therapy-based skills training group were evaluated in a special school setting using a quasi-experimental design (acceptance and commitment therapy/school classes as usual). A total of 28 high-functioning students with autism spectrum disorder (aged 13-21 years) were assessed using self- and teacher-ratings at pre- and post-assessment and 2-month follow-up. All participants completed the skills training, and treatment satisfaction was high. Levels of stress, hyperactivity and emotional distress were reduced in the treatment group. The acceptance and commitment therapy group also reported increased prosocial behaviour. These changes were stable or further improved at the 2-month follow-up. Larger studies are needed to further evaluate the benefits of acceptance and commitment therapy for autism spectrum disorder. PMID- 24142798 TI - Polymeric cryogels are biocompatible, and their biodegradation is independent of oxidative radicals. AB - Biocompatibility and in vivo degradation are two important characteristics of cell scaffolds. We evaluated these properties for four different polymeric macroporous cryogels, polyvinylcaprolactam, polyvinyl alcohol-alginate-bioactive glass composite, polyhydroxyethylmethacrylate-gelatin (pHEMA-gelatin), and chitosan-agarose-gelatin in mice. All the cryogels were synthesized at subzero temperature and were implanted subcutaneously in C57Bl/10.Q inbred mice. Both local and systemic toxicities were negligible as determined by serum tumor necrosis factor alpha analysis and histology of surrounding tissues nearby the implants. Complete integration of cryogels into the surrounding tissues with neovascular formation was evident in all the mice. At the implantation site, massive infiltration of macrophages and few dendritic cells were observed but neutrophils and mast cells were clearly absent. Macrophage infiltrations were observed even inside the pores of cryogel implants. To ascertain whether oxidative radicals are involved in the cryogel degradation, we implanted these gels in mice deficient for reactive oxygen species (ROS) production. Rapid gel degradation was observed in the absence of ROS, and there was no significant difference in the biodegradation of these cryogels between ROS sufficient and deficient mice thereby excluding any major role for ROS in this process. Thus, we demonstrate the biocompatibility and ROS-independent biodegradable properties of cryogels that could be useful for tissue-specific tissue engineering applications. PMID- 24142799 TI - Retrospective revaluation of associative retroactive cue interference. AB - Two fear-conditioning experiments with rats assessed whether retrospective revaluation, which has been observed in cue competition (i.e., when compounded cues are followed with an outcome), can also be observed in retroactive cue interference (i.e., when different cues are reinforced in separate phases with the same outcome). Experiment 1 found that after inducing retroactive cue interference (i.e., X-outcome followed by A-outcome), nonreinforced presentations of the interfering cue (A) decreases interference with responding to the target cue (X), just as has been observed in retrospective revaluation experiments in cue competition. Using the opposite manipulation (i.e., adding reinforced presentations of A), Experiment 2 demonstrated that after inducing retroactive cue interference, additional reinforced presentations of the interfering cue (A) increases interference with responding to the target cue (X); alternatively stated, the amount of interference increases with the amount of training with the interfering cue. Thus, both types of retrospective revaluation occur in retroactive cue competition. The results are discussed in terms of the possibility that similar associative mechanisms underlie cue competition and cue interference. PMID- 24142800 TI - Proactive interference of open field on consummatory successive negative contrast. AB - Reactivity to a reward is affected by prior experience with the different reinforcer values of that reward, a phenomenon known as incentive relativity, which can be studied using the consummatory succesive negative contrast (cSNC) paradigm, in which the performance of animals that receive a 4 % sucrose solution after trials on which they were exposed to 32 % sucrose is compared with that of subjects that always receive the 4 % sucrose solution. The exploration of a novel open field can enhance or block the acquisition of associative and nonassociative memories. The effect of open field on cSNC has not yet been explored. The main result of the present study was that open-field exposure significantly modified the expression of cSNC. Exposure to an open field 1 h but not immediately before the downshift interfered with the expression of cSNC. These animals drank more of the downshifted reward than did controls that were not exposed to the apparatus, and this behavior persisted for up to three recovery trials. This phenomenon was observed even when the animals were given a more protracted preshift phase and when the discrepancy between the preshift and shift incentive values of sucrose were increased. An open field also interfered with incentive downshift when open field exposure occurred 6 h before the downshift, and repeated exposure to the apparatus did not deteriorate this effect. The present study adds to a growing body of literature that indicates that open-field exploration can interfere with memory formation. PMID- 24142801 TI - Organ Transplantation in HIV Patients: Current Status and New Directions. AB - Combination antiretroviral therapy has resulted in longer life expectancies in persons living with HIV; however, end organ disease and death from organ failure have become growing issues for this population. With effective therapies for viral suppression, HIV is no longer considered an absolute contraindication to organ transplantation. Over the past decade, studies of transplantation in patients with HIV have had encouraging results such that patients with organ failure are pursuing transplantation. This review focuses on the current status of organ transplantation for HIV-infected persons. PMID- 24142802 TI - An observational study examining the effect of comorbidity on the rates of persistence and adherence to newly initiated oral anti-hyperglycaemic agents. AB - PURPOSE: To examine whether the type of comorbid condition affects medication persistence and adherence in patients initiating oral anti-hyperglycaemic (OAH) therapy. METHODS: The Irish Health Services Executive pharmacy claims database was used to identify a cohort of incident OAH therapy users (anatomical therapeutic chemical A10B), >=25 years, between June 2009 and December 2010. Persistence and adherence were examined at 6 and 12 months post-therapy initiation. Comorbidity was ascertained using modified versions of the RxRisk and RxRisk-V indices and classified as either concordant or discordant with diabetes. Adjusted odds ratios (ORs) and 95% confidence intervals (95%CIs) were determined in relation to comorbidity using logistic regression analysis, adjusting for age, gender and type of OAH prescribed. RESULTS: In the study cohort (n = 21 280), persistence was 74.0% and 62.6% and adherence was 70.0% and 66.7% for all OAHs at 6 and 12 months, respectively. Patients with only concordant comorbidity were significantly more likely to be persistent at 6 (OR 1.45, 95%CI 1.28, 1.65) and 12 months (OR 1.22, 95%CI 1.09, 1.38). Patients with only discordant comorbidity were significantly less likely to be persistent at 6 (OR 0.40, 95%CI 0.35, 0.46) and 12 months (OR 0.43 95%CI 0.38, 0.50) (p < 0.0001). Results were similar for adherence. CONCLUSION: The study suggests that the persistence and adherence of OAH therapy in incident users are affected by the type of comorbidity present; this may help in identifying effective interventions aimed at optimising medication use. PMID- 24142803 TI - The role of adjuvant radiotherapy in the local management of desmoplastic melanoma. AB - BACKGROUND: In the current study, the authors sought to evaluate outcomes, specifically with respect to adjuvant radiotherapy (RT), for patients with desmoplastic melanoma. METHODS: The records of 130 consecutive patients who presented between 1985 and 2009 with nonmetastatic desmoplastic melanoma and were treated curatively with either surgery alone (59 patients; 45%) or surgery and postoperative RT (71 patients; 55%) were retrospectively reviewed. Ages ranged from 21 years to 97 years (median age, 66 years). The location of the primary tumor was in the head and neck region in 62% of patients. Only 5 patients (4%) had lymph node involvement at the time of presentation. RESULTS: The median follow-up was 6.6 years (range, 11 months-24 years). Overall survival rates at 5 years and 10 years were 69% and 53%, respectively. Disease-specific survival rates were 84% and 80%, respectively, at 5 years and 10 years. The actuarial rate of local recurrence was 17% at 5 years and beyond. Of the patients who underwent surgery without receiving postoperative RT, 14 (24%) experienced local recurrence. Of the 71 patients treated with surgery and postoperative RT, 5 (7%) experienced local recurrence. In a Cox multivariate regression model, improved local control was significantly associated with the receipt of postoperative RT (P= .009). CONCLUSIONS: Surgery followed by postoperative RT appears to provide superior local control compared with surgery alone for patients with desmoplastic melanoma. PMID- 24142804 TI - Double-blind parallel placebo-controlled study to evaluate the effect of molsidomine on the endothelial dysfunction in patients with stable angina pectoris undergoing percutaneous coronary intervention: the MEDCOR Trial. AB - The effects of molsidomine (a direct nitric oxide donor) on the endothelial dysfunction have never been evaluated using reactive hyperemia peripheral arterial tonometry (RH-PAT). The objective of the MEDCOR double-blind trial will be to demonstrate the superiority of molsidomine (Coruno(r) 16 mg, once daily) over placebo, on improving the endothelial function (Endoscore by RH-PAT) after 12 months of treatment in stable angina patients undergoing elective percutaneous coronary intervention (PCI). Study design will take care of the real-life situation, in which patients are being offered PCI and stent placement (drug eluting or bare metal), but also gold standard medical therapy (beta-blockers, statins, angiotensin-converting enzyme inhibitors (ACEIs), and/or calcium antagonists). Demonstrating clinical and statistical superiority of the study drug over placebo will be a real challenge. Therefore, a sequential approach has been designed with a pilot phase aiming at recruiting 50 patients. Upon evaluation of the results by an independent data steering committee, a larger sample size phase will eventually be considered. PMID- 24142805 TI - Dietary intake and ovarian cancer risk: a systematic review. AB - Ovarian cancer is a leading cause of gynecological cancer death. There is a need to identify modifiable dietary risk factors for this disease. To evaluate the role of diet in ovarian cancer risk, we performed a PRISMA-directed systematic review that included prospective cohort studies with >200 cases (n = 24). Higher risk for ovarian cancer was shown for total, animal, and dairy fat (five of nine studies), as well as total nitrate and possibly total vitamin C. No associations were demonstrated for red meat, fiber, vitamin A, vitamin E, beta-carotene, or folate. Vegetables were associated with lower risk in one of three studies; fruit showed no association, although risk estimates were all greater than 1.0. Isoflavones and flavonoids were associated with modestly lower risk in two studies and tea intake was associated with lower risk in one of two studies. This review suggests that no specific dietary factors are consistently associated with ovarian cancer risk. Data by tumor subtypes are limited, but suggest that differential associations by tumor subtype may exist and should be evaluated. Studies of ample sample size, varied exposure, which can better control for dietary measurement error, are needed to fully define dietary recommendations for ovarian cancer prevention. PMID- 24142809 TI - Full implementation of the genetic code by tryptophanyl-tRNA synthetase requires intermodular coupling. AB - Tryptophanyl-tRNA Synthetase (TrpRS) Urzyme (fragments A and C), a 130-residue construct containing only secondary structures positioning the HIGH and KMSKS active site signatures and the specificity helix, accelerates tRNA(Trp) aminoacylation with ~10-fold specificity toward tryptophan, relative to structurally related tyrosine. We proposed that including the 76-residue connecting peptide 1 insertion (Fragment B) might enhance tryptophan affinity and hence amino acid specificity, because that subdomain constrains the orientation of the specificity helix. We test that hypothesis by characterizing two new constructs: the catalytic domain (fragments A-C) and the Urzyme supplemented with the anticodon-binding domain (fragments A, C, and D). The three constructs, together with the full-length enzyme (fragments A-D), comprise a factorial experiment from which we deduce individual and combined contributions of the two modules to the steady-state kinetics parameters for tryptophan-dependent (32)PPi exchange, specificity for tryptophan versus tyrosine, and aminoacylation of tRNA(Trp). Factorial design directly measures the energetic coupling between the two more recent modules in the contemporary enzyme and demonstrates its functionality. Combining the TrpRS Urzyme individually in cis with each module affords an analysis of long term evolution of amino acid specificity and tRNA aminoacylation, both essential for expanding the genetic code. Either module significantly enhances tryptophan activation but unexpectedly eliminates amino acid specificity for tryptophan, relative to tyrosine, and significantly reduces tRNA aminoacylation. Exclusive dependence of both enhanced functionalities of full-length TrpRS on interdomain coupling energies between the two new modules argues that independent recruitment of connecting peptide 1 and the anticodon binding domain during evolutionary development of Urzymes would have entailed significant losses of fitness. PMID- 24142810 TI - 'Third wave' cognitive and behavioural therapies versus treatment as usual for depression. AB - BACKGROUND: So-called 'third wave' cognitive and behavioural therapies represent a new generation of psychological therapies that are increasingly being used in the treatment of psychological problems. However, the effectiveness and acceptability of third-wave cognitive and behavioural therapy (CBT) approaches as treatment for acute depression remain unclear. OBJECTIVES: 1. To examine the effects of all third wave CBT approaches compared with treatment as usual/waiting list/attention placebo/psychological placebo control conditions for acute depression.2. To examine the effects of different third wave CBT approaches (ACT, compassionate mind training, functional analytic psychotherapy, dialectical behaviour therapy, MBCT, extended behavioural activation and metacognitive therapy) compared with treatment as usual/waiting list/attention placebo/psychological placebo control conditions for acute depression.3. To examine the effects of all third wave CBT approaches compared with different types of comparators (treatment as usual, no treatment, waiting list, attention placebo, psychological placebo) for acute depression. SEARCH METHODS: We searched the Cochrane Depression Anxiety and Neurosis Group Trials Specialised Register (CCDANCTR to 01/01/12), which includes relevant randomised controlled trials from The Cochrane Library (all years), EMBASE, (1974-), MEDLINE (1950-) and PsycINFO (1967-). We also searched CINAHL (May 2010) and PSYNDEX (June 2010) and reference lists of the included studies and relevant reviews for additional published and unpublished studies. An updated search of CCDANCTR restricted to search terms relevant to third wave CBT therapies was conducted in March 2013 (CCDANCTR to 01/02/13). SELECTION CRITERIA: Randomised controlled trials that compared third wave CBT therapies with control conditions for acute depression in adults. DATA COLLECTION AND ANALYSIS: Two review authors independently identified studies, assessed trial quality and extracted data. Study authors were contacted for additional information when required. We rated the quality of evidence using GRADE methods. MAIN RESULTS: Four small studies (224 participants) were included in the review. Little information was provided about the process of allocating participants to groups. None of the studies used independent outcome assessors, and evidence suggested researcher allegiance towards the active treatments. The four studies examined a diversity of third wave CBT approaches (extended behavioural activation, acceptance and commitment therapy and competitive memory training) and control conditions. None of the studies conducted follow-up assessments. The results showed a significant difference in clinical response rates in favour of third wave CBT when compared with treatment as usual (TAU) conditions (three studies, 170 participants, risk ratio (RR) 0.51, 95% confidence interval (CI) 0.27 to 0.95; very low quality). No significant difference in treatment acceptability based on dropout rates was found between third wave CBT approaches and TAU (four studies, 224 participants, RR 1.01, 95% CI 0.08 to 12.30; very low quality). Both analyses showed substantial statistical heterogeneity. AUTHORS' CONCLUSIONS: Very low quality evidence suggests that third wave CBT approaches appear to be more effective than treatment as usual in the treatment of acute depression. The very small number of available studies and the diverse types of interventions and control comparators, together with methodological limitations, limit the ability to draw any conclusions on their effect in the short term or over a longer term. The increasing popularity of third wave CBT approaches in clinical practice underscores the importance of completing further studies of third wave CBT approaches in the treatment of acute depression, on a short- and long-term basis, to provide evidence of their effectiveness to policy-makers, clinicians and users of services. PMID- 24142811 TI - Application of liquid chromatographic method with fluorescence detection for the determination of triclabendazole in tablets and biological fluids. AB - A simple and rapid liquid chromatographic method was developed and validated for the determination of triclabendazole with high accuracy and precision within 6 min. Good chromatographic separation was achieved using a CLC Shim-pack C8 (250 * 4.6 mm, 5 um particle size) using the mobile phase containing a mixture of 0.02 m phosphate buffer and methanol with a ratio of (20 : 80 v/v) at pH 4.0 was pumped at a flow rate of 1.2 mL/min with fluorescence detection for the first time at 338 nm after excitation at 298 nm. Losartan potassium was used as an internal standard. The method showed good linearity in the ranges of 0.05-2.0 ug/mL with limits of detection and quantification of 14.1 and 42.6 ng/mL, respectively. The suggested method was successfully applied for the analysis of triclabendazole in tablets. The high sensitivity of the method enabled the determination of the studied drug in spiked human plasma with mean percentage of recoveries of 99.79 +/- 5.09. Statistical evaluation of the data was performed according to ICH Guidelines. PMID- 24142812 TI - When left is not right: handedness effects on learning object-manipulation words using pictures with left- or right-handed first-person perspectives. AB - According to the body-specificity hypothesis, hearing action words creates body specific mental simulations of the actions. Handedness should, therefore, affect mental simulations. Given that pictures of actions also evoke mental simulations and often accompany words to be learned, would pictures that mismatch the mental simulation of words negatively affect learning? We investigated effects of pictures with a left-handed, right-handed, or bimanual perspective on left- and right-handers' learning of object-manipulation words in an artificial language. Right-handers recalled fewer definitions of words learned with a corresponding left-handed-perspective picture than with a right-handed-perspective picture. For left-handers, there was no effect of perspective. These findings suggest that mismatches between pictures and mental simulations evoked by hearing action words can negatively affect right-handers' learning. Left-handers, who encounter the right-handed perspective frequently, could presumably overcome the lack of motor experience with visual experience and, therefore, not be influenced by picture perspective. PMID- 24142813 TI - Personality maturation around the world: a cross-cultural examination of social investment theory. AB - During early adulthood, individuals from different cultures across the world tend to become more agreeable, more conscientious, and less neurotic. Two leading theories offer different explanations for these pervasive age trends: Five-factor theory proposes that personality maturation is largely determined by genetic factors, whereas social-investment theory proposes that personality maturation in early adulthood is largely the result of normative life transitions to adult roles. In the research reported here, we conducted the first systematic cross cultural test of these theories using data from a large Internet-based sample of young adults from 62 nations (N = 884,328). We found strong evidence for universal personality maturation from early to middle adulthood, yet there were significant cultural differences in age effects on personality traits. Consistent with social-investment theory, results showed that cultures with an earlier onset of adult-role responsibilities were marked by earlier personality maturation. PMID- 24142814 TI - Self-induced attentional blink: a cause of errors in multiple-target search. AB - Satisfaction of search (which we refer to as subsequent search misses)-a decrease in accuracy at detecting a second target after a first target has been found in a visual search-underlies real-world search errors (e.g., tumors may be missed in an X-ray if another tumor already has been found), but little is known about this phenomenon's cognitive underpinnings. In the present study, we examined subsequent search misses in terms of another, more extensively studied phenomenon: the attentional blink, a decrease in accuracy when a second target appears 200 to 500 ms after a first target is detected in a temporal stream. Participants searched for T-shaped targets among L-shaped distractors in a spatial visual search, and despite large methodological differences between self paced spatial visual searches and attentional blink tasks, an attentional-blink like effect accounted for subsequent-search-miss errors. This finding provides evidence that accuracy is negatively affected shortly after a first target is fixated in a self-paced, self-guided visual search. PMID- 24142815 TI - Passive sampling in contaminated sediment assessment: building consensus to improve decision making. AB - Contaminated sediments pose an ongoing, pervasive, global challenge to environmental managers, because sediments can reflect a legacy of pollution that can impair the beneficial uses of water bodies. A formidable challenge in assessing the risks of contaminated sediments has been the elucidation and measurement of contaminant bioavailability, expressed as the freely dissolved concentration (Cfree ) in interstitial water, which serves as a surrogate measure of the substances' chemical activity. Recent advances in passive sampling methods (PSMs) enable Cfree of sediment-associated contaminants to be quantified at trace levels, thereby overcoming current limitations of predictive models. As a result, PSMs afford the opportunity for a paradigm shift from traditional practice that can effectively reduce uncertainty in risk assessment and bolster confidence in the science used to support management of contaminated sediments. This paper provides a brief overview of the 5 subsequent papers in this series that review literature on PSM use in sediments for both organic and metal(loid) contaminants, outline the technical rationale for using PSMs as a preferred basis for risk assessment over conventional chemical analyses, describe practical considerations for and uncertainties associated with laboratory and field deployment of PSMs, discuss management application of PSMs, including illustrative case studies in which PSMs have been used in decision making, and highlight future research and communication needs. PMID- 24142816 TI - Can rotational thromboelastometry predict thrombotic complications in reconstructive microsurgery? AB - Thrombotic occlusion of the microvascular pedicle is the major reason for flap loss. Thus, identifying patients who are at risk for such events is paramount. Rotational thromboelastometry (RTE) is widely used to detect coagulopathy and hypercoagulable states. The aim of our study was to assess its diagnostic value in reconstructive microsurgery. In all 181 patients undergoing free tissue transfer at our department between February 2010 and November 2011 preoperative RTE was performed. In addition, coagulation values as well as patient's demographic data, cause and localization of defect, type of flap and surgical revisions were recorded. The majority of patients was male (59.6%) with traumatic (59.7%) defects located on the lower extremity (60.3%). ALT was the most often used flap (35.9%). Preoperatively, 36.5% of patients had a hypercoagulable RTE (higher than physiological RTE values; intrinsic (ICPT) or extrinsic (ECPT) mean clot firmness (MCF) >72mm or functional fibrinogen (ICF) MCF >25mm). A total of 28 primary thrombosis of the microvascular pedicle occurred, 11 of those in patients with a hypercoagulable state. Total flap loss rate because ofthrombosis was 7.7% (n = 14). Both a hypercoagulable RTE assay and a functional fibrinogen to platelet ratio (FPR) of >43 (MCF value of ICF divided by the MCF value of ICPT) were significant predictors of thrombotic flap loss when performing multivariate binary logistic regression, co-factoring for age, sex, and comorbidities (p = 0.036 and 0.003, respectively). RTE seems to be able to identify patients that are prone to thrombotic complications and might be used as a screening tool. PMID- 24142818 TI - Moving forward with myeloid growth factors. PMID- 24142817 TI - Association of the body adiposity index (BAI) with metabolic risk factors in young and older overweight and obese women. AB - PURPOSE: Body adiposity index (BAI) is a novel index for the assessment of percentage fat mass (FM%). We tested the association between BAI and metabolic outcomes in overweight and obese women of different ages. METHODS: 260 young women (24.7 +/- 5.3 years, 31.0 +/- 5.0 kg/m(2)) and 328 older women (66.9 +/- 4.6 years, 34.8 +/- 4.7 kg/m(2)) were recruited. BAI was calculated using hip circumference and height. Bioimpedance analysis was used to measure FM%. Metabolic risk was assessed using a composite z score integrating standardised measurements of fasting glucose, total cholesterol, liver enzymes and triglycerides. RESULTS: The association between BAI and FM% was modest in both young (r = 0.56, p < 0.001) and older (r = 0.49, p < 0.001) groups. BAI was directly associated with metabolic risk in young women (r = 0.29, p < 0.001), whereas it showed a weak, inverse association in the older group (r = -0.14, p = 0.01). CONCLUSIONS: BAI validity needs to be re-assessed in older individuals for better definition of its predictive accuracy. PMID- 24142819 TI - Imatinib-induced bone edema: case report and review of literature. AB - Imatinib mesylate represents a revolution in the management of patients with metastatic gastrointestinal stromal tumors (GISTs). More recently, postoperative imatinib has been shown to improve both disease-free and overall survivals in patients with a high risk of recurrence. This article presents a well-documented case of a patient with painful and reversible bone edema related to imatinib. PMID- 24142820 TI - Barriers to treatment in patients with locally advanced breast cancer. AB - Delays between presentation and treatment could have a significant effect on breast cancer mortality. The authors hypothesized that patient, physician, and system barriers are all responsible for treatment delays. Therefore, a study was conducted to define prevalent barriers to treatment from the patient's perspective. A modified 43-item Likert-scale questionnaire was administered to patients with clinical stage III locally advanced breast cancer (LABC) who had experienced a delay in treatment of 3 months or more. Between October 2008 and January 2010, 153 patients presented with LABC; 43 patients (28.1%) met eligibility, and 40 completed the questionnaire. Among the patient barriers reported, 38% of patients delayed care for fear of losing their breast and 47% awaited previously scheduled routine appointments instead of seeking care. Among the physician barriers reported, 20% of physicians of initial contact did not believe the breast lump/symptom was related to cancer and 15% did not believe it needed a biopsy. Among the system barriers reported, the most prevalent were delays in performing diagnostic tests and obtaining insurance authorization for tests, treatment, or physician visits. Substantial delays were seen in 28.1% of patients from presentation to when they sought therapy at City of Hope Comprehensive Cancer Center. The high prevalence of patient barriers versus physician/system barriers suggests that increased educational efforts for patients and health care professionals are needed. PMID- 24142822 TI - Computer/Online-mediated social support for cancer-related fatigue. AB - Fatigue is a pervasive symptom in individuals with cancer that is often underrecognized and undertreated by health care providers. Contrasted with the sparse data in support of pharmacologic interventions for the management of cancer-related fatigue, the literature for nonpharmacologic interventions is vast. In particular, support groups have proven beneficial. Limited access, transportation issues, and unwillingness to share in a public forum represent just a few of the barriers to more widespread participation in face-to-face support groups. Millions of people with cancer rely on the Internet to gain information regarding their diagnosis and to validate their cancer experience. Tapping into this wealth of online information is an obvious avenue for patients with cancer-related fatigue to seek support. This article explores online- and computer-mediated support groups for fatigue. PMID- 24142821 TI - Ovarian cancer, version 2.2013. AB - These NCCN Guidelines Insights focus on the major updates to the 2013 NCCN Guidelines for Ovarian Cancer. Four updates were selected based on recent important updates in the guidelines and on debate among panel members about recent clinical trials. The topics include 1) intraperitoneal chemotherapy, 2) CA 125 monitoring for ovarian cancer recurrence, 3) surveillance recommendations for less common ovarian histopathologies, and 4) recent changes in therapy for recurrent epithelial ovarian cancer. These NCCN Guidelines Insights also discuss why some recommendations were not made. PMID- 24142823 TI - Adolescent and young adult colorectal cancer. AB - Although the overall incidence of colorectal cancer (CRC) in adolescents and young adults (AYAs) is low, it has seen an increase over the past 2 to 3 decades, which contrasts with the trend of decreased incidence in the older population. This phenomenon is conceivably caused by a lack of routine CRC screening in the young population and lifestyle issues, including the obesity epidemic and dietary factors. Hereditary genetic syndromes (eg, familial adenomatous polyposis and hereditary nonpolyposis colorectal cancer syndrome) and known predisposing medical conditions (eg, inflammatory bowel disease) account for only a minority of CRC cases in AYA. Younger patients with CRC commonly present with more advanced disease at diagnosis and exhibit specific molecular and clinical characteristics associated with a distinct biologic phenotype of CRC compared with older individuals. Matched for stage, however, the prognosis of patients with young-onset CRC is similar to or better than that for older patients. A surprising paucity of data exists on outcomes associated with modern systemic cytotoxic and biologic therapy specifically in young patients with CRC. The toxicity pattern of these treatments, however, differs between young and older patients, partly because of the lower rate of pertinent comorbidities in younger adults. Issues regarding surgical management in the setting of hereditary syndromes and fertility preservation while on therapy are of particular importance to the younger patient population. Future studies should seek to increase understanding of the distinct tumor biology of AYA patients with CRC and the consequences of treatment interventions to optimize outcomes for this population. PMID- 24142824 TI - Hematopoietic stem cell transplantation for older patients with myelodysplastic syndromes. AB - Myelodysplastic syndrome is primarily a disease of older age, and hematopoietic cell transplantation is the only treatment modality that offers the potential of cure and long-term survival to a substantial proportion of patients. Transplantation is used with increasing frequency in older patients, and patients in the seventh or even eighth decade of life have been transplanted successfully. However, transplant outcome strongly depends on the disease characteristics and comorbid conditions, which tend to be common in older individuals and profoundly affect nonrelapse mortality. This is a major reason why in patients older than 60 years, typically only conditioning regimens of reduced intensity are used. However, although these regimens are associated with little acute toxicity, the probability of relapse tends to be higher than with high-intensity regimens. In addition, chronic graft-versus-host disease occurs in as many as 50% to 60% of patients. Manifestations are mild in a proportion of patients; others require long-term treatment, generally with glucocorticoids, which often are not well tolerated in older individuals. Although considerable progress has been made over the past decade, more work is needed, particularly to reduce the incidence of severe graft-versus-host disease and prevent posttransplant relapse. PMID- 24142825 TI - Targeting angiogenesis in advanced non-small cell lung cancer. AB - Lung cancer is the leading cause of cancer-related mortality in the United States. Over the past 40 years, treatments with standard chemotherapy agents have not resulted in substantial improvements in long-term survival for patients with advanced lung cancer. Therefore, new targets have been sought, and angiogenesis is a promising target for non-small cell lung cancer (NSCLC). Bevacizumab, a monoclonal antibody targeted against the vascular endothelial growth factor, is the only antiangiogenic agent currently recommended by NCCN for the treatment of advanced NSCLC. However, several antibody-based therapies and multitargeted tyrosine kinase inhibitors are currently under investigation for the treatment of patients with NSCLC. This article summarizes the available clinical trial data on the efficacy and safety of these agents in patients with advanced lung cancer. PMID- 24142826 TI - Implementing routine screening for distress, the sixth vital sign, for patients with head and neck and neurologic cancers. AB - This study examined the benefits of incorporating screening for distress as a routine part of care for patients with head and neck and neurologic cancers in a tertiary cancer center. Using a comparative 2-cohort pre-post implementation sequential design, consecutive outpatients with head and neck and neurologic cancers were recruited into 2 separate cohorts. Cohort 1 included patients attending clinics during April 2010, before the implementation of the screening program. The program was then implemented and patients completed the Screening for Distress Minimum Dataset (the Edmonton Symptom Assessment System [ESAS] and the Canadian Problem Checklist [CPC]) at each clinic visit. Cohort 2 included patients attending clinics during March 2011. Consenting patients completed screening and outcome measures (ESAS, CPC, and either the Functional Assessment of Cancer Therapy-Brain or the Functional Assessment of Cancer Therapy-Head and Neck). A total of 146 patients (78 head and neck and 68 neurologic) provided data for Cohort 1, and 143 (81 head and neck and 62 neurologic) provided data for Cohort 2. Compared with Cohort 1, patients with neurologic cancers in Cohort 2 reported significantly higher scores on the Functional Assessment of Cancer Therapy: General total and emotional quality of life subscale; fewer high scores (>= 4) on the ESAS breathlessness item; and fewer problems with fears/worries, frustration/anger, finding meaning in life, and worry about friends/family. Head and neck patients in Cohort 2 reported significantly higher emotional quality of life and fewer problems with eating and weight than those in Cohort 1. Although no definitive causal attributions can be made, patients exposed to routine screening for distress reported better well-being and fewer emotional, physical, and practical problems than historical controls. PMID- 24142827 TI - Myeloid growth factors. AB - Febrile neutropenia, a common side effect of myelosuppressive chemotherapy in patients with cancer, can result in prolonged hospitalization and broad-spectrum antibiotic use, often prompting treatment delays or dose reductions of drug regimens. Prophylactic use of myeloid growth factors (mainly the colony stimulating factors filgrastim and pegfilgrastim) in patients of heightened risk can reduce the severity and duration of febrile neutropenia. The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Myeloid Growth Factors provide recommendations on the use of these agents mainly in the oncology setting based on clinical evidence and expert consensus. This version includes revisions surrounding the issue of timing of pegfilgrastim administration. It also includes new sections on tbo-filgrastim, a recently approved agent that is biologically similar to filgrastim, and the role of myeloid growth factors in the hematopoietic cell transplant setting. PMID- 24142828 TI - Will biosimilars gain momentum? AB - Biosimilars, also known as follow-on biologics, continue to be an area of great interest in oncology because of the potential cost savings and improved access related to their use, yet significant confusion remains regarding their introduction in the United States. The regulatory and legal hurdles remain poorly defined, and companies producing branded products have been battling their introduction. The European Union provided a pathway for approval in 2004, with various agents reaching the market since that time. It is important to understand the nuances of the discussion and experiences and for clinicians and policy makers to take an active part in defining the role of biosimilars. Several outstanding questions remain, including the degree to which physiochemical, biologic, quality, and clinical end points must be demonstrated in clinical trials compared with the use of analytic data for approval; whether off-label indications should be embraced; and the regulatory rules around areas such as marketing and interchangeability. This article highlights tbo-filgrastim, an agent currently marketed as a biosimilar in Europe, because its pending introduction in the US market provides insights into the potential of these agents. PMID- 24142829 TI - Perspectives on surveillance and survivorship: when to make the transition. PMID- 24142832 TI - Early adversity, RSA, and inhibitory control: evidence of children's neurobiological sensitivity to social context. AB - This study examined parasympathetic physiology as a moderator of the effects of early adversity (i.e., child abuse and neglect) on children's inhibitory control. Children's respiratory sinus arrhythmia (RSA) was assessed during a resting baseline, two joint challenge tasks with mother, and an individual frustration task. RSA assessed during each of the joint parent-child challenge tasks moderated the effects of child maltreatment (CM) status on children's independently-assessed inhibitory control. No moderation effect was found for RSA assessed at baseline or in the child-alone challenge task. Among CM-exposed children, lower RSA levels during the joint task predicted the lowest inhibitory control, whereas higher joint task RSA was linked to higher inhibitory control scores that were indistinguishable from those of non-CM children. Results are discussed with regard to the importance of considering context specificity (i.e., individual and caregiver contexts) in how biomarkers inform our understanding of individual differences in vulnerability among at-risk children. PMID- 24142833 TI - The relation of platelet-lymphocyte ratio and coronary collateral circulation in patients with stable angina pectoris and chronic total occlusion. AB - OBJECTIVES: We aimed to investigate the relationship between the platelet lymphocyte ratio (PLR) and coronary collateral circulation (CCC) in patients with stable angina pectoris (SAP) and chronic total occlusion (CTO). METHODS: A total of 294 patients with both SAP and CTO were classified according to their Rentrop collateral grades as either poor (Rentrop grades/0-1) or good (Rentrop grades/2 3). RESULTS: The PLR values were significantly higher in patients with poor CCC than in those with good CCC (156.8 + 30.7 vs 132.1 + 24.4, P < 0.001). In regression analysis, PLR (unit = 10) [odds ratio 1.48, 95% confidence interval (CI) 1.33 -1.65; P < 0.001] and high-sensitivity C-reactive protein were found to be the independent predictors of poor CCC. In receiver operator characteristic curve analysis, optimal cut-off value of PLR to predict poor CCC was found as 138.1, with 76% sensitivity and 65% specificity. CONCLUSION: PLR may be an important, simple, and cost effective tool predicting the degree of collateralization in patients with SAP and CTO. PMID- 24142834 TI - Expyriment: a Python library for cognitive and neuroscientific experiments. AB - Expyriment is an open-source and platform-independent lightweight Python library for designing and conducting timing-critical behavioral and neuroimaging experiments. The major goal is to provide a well-structured Python library for script-based experiment development, with a high priority being the readability of the resulting program code. Expyriment has been tested extensively under Linux and Windows and is an all-in-one solution, as it handles stimulus presentation, the recording of input/output events, communication with other devices, and the collection and preprocessing of data. Furthermore, it offers a hierarchical design structure, which allows for an intuitive transition from the experimental design to a running program. It is therefore also suited for students, as well as for experimental psychologists and neuroscientists with little programming experience. PMID- 24142835 TI - AMAB: automated measurement and analysis of body motion. AB - Technologies that measure human nonverbal behavior have existed for some time, and their use in the analysis of social behavior has become more popular following the development of sensor technologies that record full-body movement. However, a standardized methodology to efficiently represent and analyze full body motion is absent. In this article, we present automated measurement and analysis of body motion (AMAB), a methodology for examining individual and interpersonal nonverbal behavior from the output of full-body motion tracking systems. We address the recording, screening, and normalization of the data, providing methods for standardizing the data across recording condition and across subject body sizes. We then propose a series of dependent measures to operationalize common research questions in psychological research. We present practical examples from several application areas to demonstrate the efficacy of our proposed method for full-body measurements and comparisons across time, space, body parts, and subjects. PMID- 24142836 TI - A latent variable model approach to estimating systematic bias in the oversampling method. AB - The method of oversampling data from a preselected range of a variable's distribution is often applied by researchers who wish to study rare outcomes without substantially increasing sample size. Despite frequent use, however, it is not known whether this method introduces statistical bias due to disproportionate representation of a particular range of data. The present study employed simulated data sets to examine how oversampling introduces systematic bias in effect size estimates (of the relationship between oversampled predictor variables and the outcome variable), as compared with estimates based on a random sample. In general, results indicated that increased oversampling was associated with a decrease in the absolute value of effect size estimates. Critically, however, the actual magnitude of this decrease in effect size estimates was nominal. This finding thus provides the first evidence that the use of the oversampling method does not systematically bias results to a degree that would typically impact results in behavioral research. Examining the effect of sample size on oversampling yielded an additional important finding: For smaller samples, the use of oversampling may be necessary to avoid spuriously inflated effect sizes, which can arise when the number of predictor variables and rare outcomes is comparable. PMID- 24142837 TI - Concreteness ratings for 40 thousand generally known English word lemmas. AB - Concreteness ratings are presented for 37,058 English words and 2,896 two-word expressions (such as zebra crossing and zoom in), obtained from over 4,000 participants by means of a norming study using Internet crowdsourcing for data collection. Although the instructions stressed that the assessment of word concreteness would be based on experiences involving all senses and motor responses, a comparison with the existing concreteness norms indicates that participants, as before, largely focused on visual and haptic experiences. The reported data set is a subset of a comprehensive list of English lemmas and contains all lemmas known by at least 85 % of the raters. It can be used in future research as a reference list of generally known English lemmas. PMID- 24142838 TI - Current misuses of multiple regression for investigating bivariate hypotheses: an example from the organizational domain. AB - By definition, multiple regression (MR) considers more than one predictor variable, and each variable's beta will depend on both its correlation with the criterion and its correlation with the other predictor(s). Despite ad nauseam coverage of this characteristic in organizational psychology and statistical texts, researchers' applications of MR in bivariate hypothesis testing has been the subject of recent and renewed interest. Accordingly, we conducted a targeted survey of the literature by coding articles, covering a five-year span from two top-tier organizational journals, that employed MR for testing bivariate relations. The results suggest that MR coefficients, rather than correlation coefficients, were most common for testing hypotheses of bivariate relations, yet supporting theoretical rationales were rarely offered. Regarding the potential impact on scientific advancement, in almost half of the articles reviewed (44 %), at least one conclusion of each study (i.e., that the hypothesis was or was not supported) would have been different, depending on the author's use of correlation or beta to test the bivariate hypothesis. It follows that inappropriate decisions to interpret the correlation versus the beta will affect the accumulation of consistent and replicable scientific evidence. We conclude with recommendations for improving bivariate hypothesis testing. PMID- 24142839 TI - Post-clearcut dynamics of carbon, water and energy exchanges in a midlatitude temperate, deciduous broadleaf forest environment. AB - Clearcutting and other forest disturbances perturb carbon, water, and energy balances in significant ways, with corresponding influences on Earth's climate system through biogeochemical and biogeophysical effects. Observations are needed to quantify the precise changes in these balances as they vary across diverse disturbances of different types, severities, and in various climate and ecosystem type settings. This study combines eddy covariance and micrometeorological measurements of surface-atmosphere exchanges with vegetation inventories and chamber-based estimates of soil respiration to quantify how carbon, water, and energy fluxes changed during the first 3 years following forest clearing in a temperate forest environment of the northeastern US. We observed rapid recovery with sustained increases in gross ecosystem productivity (GEP) over the first three growing seasons post-clearing, coincident with large and relatively stable net emission of CO2 because of overwhelmingly large ecosystem respiration. The rise in GEP was attributed to vegetation changes not environmental conditions (e.g., weather), but attribution to the expansion of leaf area vs. changes in vegetation composition remains unclear. Soil respiration was estimated to contribute 44% of total ecosystem respiration during summer months and coarse woody debris accounted for another 18%. Evapotranspiration also recovered rapidly and continued to rise across years with a corresponding decrease in sensible heat flux. Gross short-wave and long-wave radiative fluxes were stable across years except for strong wintertime dependence on snow covered conditions and corresponding variation in albedo. Overall, these findings underscore the highly dynamic nature of carbon and water exchanges and vegetation composition during the regrowth following a severe forest disturbance, and sheds light on both the magnitude of such changes and the underlying mechanisms with a unique example from a temperate, deciduous broadleaf forest. PMID- 24142840 TI - Characteristics and trends of low-dose quetiapine use in two western state Medicaid programs. AB - PURPOSE: Medicaid programs are concerned about inappropriate, potentially hazardous, and costly off-label use of second-generation antipsychotics (SGAs). Several states are exploring policies aimed at managing low-dose quetiapine, commonly prescribed for off-label conditions. This study aimed to characterize longitudinal trends and patient characteristics associated with low-dose quetiapine in two state Medicaid programs. We further aimed to quantify changes in the use of quetiapine associated with a legal settlement that curtailed off label promotion of this product. METHODS: Using administrative data from two state Medicaid programs, Oregon and Colorado, we identified SGA initiators and determined patient level factors associated with receipt of low-dose SGAs. We evaluated changes in low-dose quetiapine initiation during and after a period in which quetiapine was being promoted illegally for off-label purposes. RESULTS: We identified 14,763 new SGA starts during the study period. Low-dose (versus therapeutic dose) SGA use was common in both states, representing 53% to 56% of initiators. Quetiapine was the most commonly used SGA in both states and both dose ranges. Diagnoses of schizophrenia, bipolar disorder, posttraumatic stress disorder, anxiety disorder, and use of newer sedative hypnotics were associated with lower likelihood of initiating low-dose quetiapine. Initiation of low-dose quetiapine as a proportion of all SGA initiation and of all quetiapine initiation significantly declined in Oregon following suspension of off-label promotional activities. CONCLUSIONS: Low-dose SGA and specifically low-dose quetiapine use remains common. Medicaid programs must set policies carefully to maximize the net safety of prescription use while optimizing disease management considering the potential for substitution effects. PMID- 24142841 TI - Neurological Complications in Controlled HIV Infection. AB - In recent years, there have been great advances in therapies for human immunodeficiency virus (HIV) that have allowed suppression of the virus and its effects on the body. Despite this progress, neurological complications persist in HIV-infected individuals. In this review we consider the possible ways that HIV might cause neurotoxicity and neuroinflammation. We discuss the spectrum of neurological disorders caused by HIV and its treatment, with a particular focus on both HIV-associated neurocognitive disorders and peripheral neuropathies. Since there has been a shift to HIV being a chronic illness, we also review the increasing prevalence of cerebrovascular disease and neurodegenerative disorders. PMID- 24142842 TI - Frontal-parietal and limbic-striatal activity underlies information sampling in the best choice problem. AB - Best choice problems have a long mathematical history, but their neural underpinnings remain unknown. Best choice tasks are optimal stopping problem that require subjects to view a list of options one at a time and decide whether to take or decline each option. The goal is to find a high ranking option in the list, under the restriction that declined options cannot be chosen in the future. Conceptually, the decision to take or decline an option is related to threshold crossing in drift diffusion models, when this process is thought of as a value comparison. We studied this task in healthy volunteers using fMRI, and used a Markov decision process to quantify the value of continuing to search versus committing to the current option. Decisions to take versus decline an option engaged parietal and dorsolateral prefrontal cortices, as well ventral striatum, anterior insula, and anterior cingulate. Therefore, brain regions previously implicated in evidence integration and reward representation encode threshold crossings that trigger decisions to commit to a choice. PMID- 24142843 TI - HLA associations in schizophrenia: are we re-discovering the wheel? AB - Associations between human leukocyte antigen (HLA) polymorphisms on chromosome 6p and schizophrenia (SZ) risk have been evaluated for over five decades. Numerous case-control studies from the candidate gene era analyzed moderately sized samples and reported nominally significant associations with several loci in the HLA region (sample sizes, n = 100-400). The risk conferred by individual alleles was modest (odds ratios < 2.0). The basis for the associations could not be determined, though connections with known immune and auto-immune abnormalities in SZ were postulated. Interest in the HLA associations has re-emerged following several recent genome-wide association studies (GWAS); which utilized 10- to 100 fold larger samples and also identified associations on the short arm of chromosome 6. Unlike the earlier candidate gene studies, the associations are statistically significant following correction for multiple comparisons. Like the earlier studies; they have modest effect sizes, raising questions about their utility in risk prediction or pathogenesis research. In this review, we summarize the GWAS and reflect on possible bases for the associations. Suggestions for future research are discussed. We favor, in particular; efforts to evaluate local population sub-structure as well as further evaluation of immune-related variables in future studies. PMID- 24142844 TI - 'Third wave' cognitive and behavioural therapies versus other psychological therapies for depression. AB - BACKGROUND: So-called 'third wave' cognitive and behavioural therapies represents a new generation of psychological therapies that are increasingly being used in the treatment of psychological problems. However, the effectiveness and acceptability of third wave cognitive and behavioural therapy (CBT) approaches as a treatment for depression compared with other psychological therapies remain unclear. OBJECTIVES: 1. To examine the effects of all third wave CBT approaches compared with all other psychological therapy approaches for acute depression.2. To examine the effects of different third wave CBT approaches (ACT, compassionate mind training, functional analytic psychotherapy, extended behavioural activation and metacognitive therapy) compared with all other psychological therapy approaches for acute depression.3. To examine the effects of all third wave CBT approaches compared with different psychological therapy approaches (psychodynamic, behavioural, humanistic, integrative, cognitive-behavioural) for acute depression. SEARCH METHODS: We searched the Cochrane Depression, Anxiety and Neurosis Group Specialised Register (CCDANCTR to 01/01/12), which includes relevant randomised controlled trials from The Cochrane Library (all years), EMBASE (1974-), MEDLINE (1950-) and PsycINFO (1967-). We also searched CINAHL (May 2010) and PSYNDEX (June 2010) and reference lists of the included studies and relevant reviews for additional published and unpublished studies. An updated search of CCDANCTR restricted to search terms relevant to third wave CBT was conducted in March 2013 (CCDANCTR to 01/02/13). SELECTION CRITERIA: Randomised controlled trials that compared various third wave CBT with other psychological therapies for acute depression in adults. DATA COLLECTION AND ANALYSIS: Two review authors independently identified studies, assessed trial quality and extracted data. Study authors were contacted for additional information where required. We rated the quality of evidence using GRADE methods. MAIN RESULTS: A total of three studies involving 144 eligible participants were included in the review. Two of the studies (56 participants) compared an early version of acceptance and commitment therapy (ACT) with CBT, and one study (88 eligible participants) compared extended behavioural activation with CBT. No other studies of third wave CBT were identified. The two ACT studies were assessed as being at high risk of performance bias and researcher allegiance. Post-treatment results, which were based on dropout rates, showed no evidence of any difference between third wave CBT and other psychological therapies for the primary outcomes of efficacy (risk ratio (RR) of clinical response 1.14, 95% confidence interval (CI) 0.79 to 1.64; very low quality) and acceptability. Results at two-month follow-up showed no evidence of any difference between third wave CBT and other psychological therapies for clinical response (2 studies, 56 participants, RR 0.22, 95% CI 0.04 to 1.15). Moderate statistical heterogeneity was indicated in the acceptability analyses (I(2) = 41%). AUTHORS' CONCLUSIONS: Very low quality evidence suggests that third wave CBT and CBT approaches are equally effective and acceptable in the treatment of acute depression. Evidence is limited in quantity, quality and breadth of available studies, precluding us from drawing any conclusions as to their short- or longer-term equivalence. The increasing popularity of third wave CBT approaches in clinical practice underscores the importance of completing further studies to compare various third wave CBT approaches with other psychological therapy approaches to inform clinicians and policymakers on the most effective forms of psychological therapy in treating depression. PMID- 24142846 TI - The effect of paternal age on outcome in assisted reproductive technology using the ovum donation model. AB - OBJECTIVE: To determine the effect of paternal age (PA) on implantation and live birth rates in an ovum donation program. DESIGN: Retrospective study. METHODS: A total of 237 ovum donor cycles were reviewed. All donors were stimulated with gonadotrophin-releasing hormone agonist (GnRHa) downregulation and human menopausal gonadotropin. Recipients were prepared with GnRHa downregulation and estradiol/progesterone replacement. Embryo transfers were done at blastocyst stage under ultrasound guidance. The effect of PA on outcome was analyzed controlling for number and grade of embryos transferred. Outcome was not pregnant (NP), spontaneous abortion (SAb), and live births (LBs). RESULTS: Of the 237 cycles, 36 resulted in NP (15.2%), 39 in SAb (16.5%), and 162 in LB (68.4%). The mean PA (MPA) was significantly different between the 3 groups, and implantation rates also declined with increasing MPA (P =.01). Overall, the mean number and grade of embryos transferred were 2.1 +/- 0.4 and 1.3 +/- 0.4, respectively. The NP couples had more embryos of poorer grade than SAb and LB couples (P <.05), but there were no differences between SAb and NP couples (P >.85). Logistic regression analysis demonstrated a 26% lower odds of live birth rate with each 5 year increase in PA (P =.01). CONCLUSIONS: Advanced PA has an adverse impact on assisted reproductive technology (ART) outcome. After adjusting for number and embryo grades transferred, a younger PA has a more favorable ART outcome. PMID- 24142845 TI - Golden-angle radial sparse parallel MRI: combination of compressed sensing, parallel imaging, and golden-angle radial sampling for fast and flexible dynamic volumetric MRI. AB - PURPOSE: To develop a fast and flexible free-breathing dynamic volumetric MRI technique, iterative Golden-angle RAdial Sparse Parallel MRI (iGRASP), that combines compressed sensing, parallel imaging, and golden-angle radial sampling. METHODS: Radial k-space data are acquired continuously using the golden-angle scheme and sorted into time series by grouping an arbitrary number of consecutive spokes into temporal frames. An iterative reconstruction procedure is then performed on the undersampled time series where joint multicoil sparsity is enforced by applying a total-variation constraint along the temporal dimension. Required coil-sensitivity profiles are obtained from the time-averaged data. RESULTS: iGRASP achieved higher acceleration capability than either parallel imaging or coil-by-coil compressed sensing alone. It enabled dynamic volumetric imaging with high spatial and temporal resolution for various clinical applications, including free-breathing dynamic contrast-enhanced imaging in the abdomen of both adult and pediatric patients, and in the breast and neck of adult patients. CONCLUSION: The high performance and flexibility provided by iGRASP can improve clinical studies that require robustness to motion and simultaneous high spatial and temporal resolution. Magn Reson Med 72:707-717, 2014. (c) 2013 Wiley Periodicals, Inc. PMID- 24142847 TI - Nursing care received by older patients in Italian medical units: findings from an explorative study. AB - BACKGROUND: According to available evidence, when the nurse-to-patient ratio is insufficient the occurrence of accidental falls, pressure sores, malnutrition, hospital-acquired dependency in activities of daily living, infections associated with nursing practice and errors in administration of medication as well as mortality all increase. However, while several countries have established a body of evidence and policies concerning the minimum nurse-to-patient ratio, the amount of nursing care offered in Italian medical units remains under-studied. METHODS: Evaluating variability in the nurse-to-patient ratio and in the skill mix offered, 12 medical units willing to participate were evaluated with a face to-face interview performed by a researcher to the nurse manager of the unit. The role of the unit at the hospital level, the nurse-to-patient ratio available on a daily basis, the skill-mix and the strategies enacted in the case of patient overcrowding or understaffing were collected. RESULTS: The mission of the medical units is devoted mainly towards elderly people. The bed occupancy is high and the strategies adopted in case of patient overcrowding determine unstable environments both for medical units (extra beds) and other units (patients temporarily hosted). In the medical units, nurses attend to 5-13 patients in the morning, 7.6-14.6 in the afternoon, and 12.3-30.5 during the night. The skill-mix ranges from 43.5 % (more nursing aides than nurses are available on the ward) to 81.2 % (more nurses than nursing aides are available). CONCLUSIONS: This assessment exercise indicates that nursing care in medical units faces high workloads. Establishing national minimum standards of nursing care to be delivered towards older people admitted in Italian medical units is recommended. PMID- 24142848 TI - Pediatric hemiplegic migraine: role of multiple MRI techniques in evaluation of reversible hypoperfusion. AB - BACKGROUND: Hemiplegic migraine (HM) is a rare type of migraine with aura that involves motor weakness. Data on conventional and advanced neuroimaging findings during prolonged attacks of HM are limited, particularly in children. CASE: A 13 year-old-female with a history of migraine had a typical attack of HM characterized by right-sided hemiplegia, deterioration of vigilance and paraphasia. MRI performed 3 hours after hemiplegia onset revealed normal diffusion tensor imaging (DTI) sequences, but perfusion weighted imaging (PWI) showed a large area of hypoperfusion within the left cerebral hemisphere and susceptibility weighted imaging (SWI) demonstrated a matching area with prominent, hypointense draining sulcal veins. Magnetic resonance angiography (MRA) revealed subtle narrowing of the left middle cerebral artery. The neuroimaging abnormalities completely resolved 24 hours after the attack onset. CONCLUSION: Multiple conventional and advanced MRI techniques including SWI play a key role in an HM attack to (1) exclude acute arterial ischemic stroke and (2) further understand the pathophysiology of HM. PMID- 24142849 TI - Misdiagnosis of multiple sclerosis: frequency, causes, effects, and prevention. AB - A diagnosis of multiple sclerosis is heavily influenced by clinical judgment. Misdiagnosis of multiple sclerosis is common and has important consequences for patients and the cost of healthcare. Although rigorous data about the frequency and causes of misdiagnosis are lacking, misinterpretation and misapplication of clinical and radiographic diagnostic criteria and terminology are likely important factors. Appropriate and stringent application of diagnostic criteria and continued vigilance for "red flags" suggesting alternative diagnoses are strategies critical for prevention of misdiagnosis. PMID- 24142850 TI - Imaging of neuroinflammation in parkinsonian syndromes with positron emission tomography. AB - Microglial activation is a key aspect of the neuroinflammatory process in neurodegenerative disorders including idiopathic and atypical parkinsonian disorders. Using positron emission tomography, it has become possible to image this phenomenon in vivo and over the last years patterns of microglia activation corresponding well known distribution of neuropathologic changes in these disorders have successfully been demonstrated using this technique. It has also been possible to measure the effects of interventions aimed at suppressing microglia activation as part interventional trials. Current research aims at evaluating positron emission tomography tracers for microglial activation with more favorable properties than the prototypical [(11)C]-(R)-PK11195, as well as developing tracers targeting additional parameters of the neuroinflammatory process like astroglial function or the cannabinoid receptor type 2. PMID- 24142851 TI - Newly characterized forms of neurodegeneration with brain iron accumulation. AB - Neurodegeneration with brain iron accumulation (NBIA) comprises a group of brain iron deposition syndromes that lead to mixed extrapyramidal features and progressive dementia. Historically, there has not been a clearly identifiable molecular cause for many patients with clinical and radiologic features of NBIA. Recent discoveries have shown that mutations in C19orf12 or WDR45 can lead to NBIA. C19orf12 mutations are inherited in an autosomal recessive manner, and lead to a syndrome similar to that caused by mutations in PANK2 or PLA2G6. In contrast, WDR45 mutations lead to a distinct form of NBIA characterized by spasticity and intellectual disability in childhood followed by the subacute onset of dystonia-parkinsonism in adulthood. WDR45 mutations act in an X-linked dominant manner. Although the function of C19orf12 is largely unknown, WDR45 plays a key role in autophagy. Each of these new forms of NBIA thus leads to a distinct clinical syndrome, and together they implicate new cellular pathways in the pathogenesis of these disorders. PMID- 24142852 TI - Update on herpes virus infections of the nervous system. AB - Herpes simplex viruses types 1 and 2 (HSV-1 and HSV-2) are human neurotropic viruses that establish latent infection in dorsal root ganglia (DRG) for the entire life of the host. From the DRG they can reactivate to cause human morbidity and mortality. Although they vary, in part, in the clinical disorders they cause, and in their molecular structure, they share several features that govern the biology of their infection of the human nervous system. HSV-1 is the causative agent of encephalitis, corneal blindness, and several peripheral nervous system disorders; HSV-2 is responsible for meningoencephalitis in neonates and meningitis in adults. The biology of their ability to establish latency, maintain it for the entire life of the host, reactivate, and cause primary and recurrent disease is being studied in animal models and in humans. This review covers recent advances in understanding the biology and pathogenesis of HSV-related disease. PMID- 24142853 TI - Acute heart failure volume control multicenter randomized (AVCMA) trial: comparison of tolvaptan and carperitide. AB - BACKGROUND: [corrected] Acute decompensated heart failure (ADHF) is a common and highly morbid cardiovascular disorder. Diuresis is a major therapy for the reduction of congestive symptoms. However, most diuretics cause hyponatremia, which is a worsening factor of ADHF patients prognosis. The purpose of this study was to examine the efficacy and safety of tolvaptan, which is a selective vasopressin V2 receptor antagonist and produces water excretion without changes in sodium excretion, compared with carperitide. METHODS AND RESULTS: One hundred and nine hospitalized ADHF patients were enrolled and randomly assigned to tolvaptan or carperitide treatment groups. Subjective symptoms and plasma BNP level were similarly improved by treatment in both groups. Urine volume was significantly higher in the tolvaptan group (P < .05), but volume of water intake was also higher in the tolvaptan group (P < .05). Blood pressure was significantly lower in the carperitide group than in the tolvaptan group after treatment (P < .05). Less adverse events such as worsening heart failure and hypotension requiring drug discontinuation were observed in the tolvaptan group (P = .027). The average drug cost of tolvaptan was lower than that of carperitide (P < .001). CONCLUSIONS: Tolvaptan might be a novel promising agent for ADHF in terms of efficacy and safety compared to carperitide. PMID- 24142857 TI - Genomic approaches for studying craniofacial disorders. AB - Fast developing technologies in genomics have driven genetic studies of human diseases from classical candidate approaches toward hypothesis-free and genome wide screening methods. Compared to the low-resolution cytogenetic techniques that were the only available methods to visualize genomic changes at the chromosomal level until some 15 years ago, genome-wide studies including analyses of copy number variation (CNV), genome-wide association and linkage studies, and exome sequencing (ES) provide more accurate information for unraveling the genetic causes of diseases. Moreover, genome sequencing (GS) which interrogates the genome of a single individual at the nucleotide resolution has also been applied in genetic studies. Here we review genomic approaches in craniofacial disorders, with the emphasis on orofacial clefts, and discuss the applications, advantages, limitations, challenges, and future perspectives. PMID- 24142858 TI - Legionella pneumophila pneumonia during telaprevir-based triple therapy for HCV chronic hepatitis. PMID- 24142863 TI - Oscillating gradient spin-echo (OGSE) diffusion tensor imaging of the human brain. AB - PURPOSE: The dependence of diffusion tensor imaging (DTI) eigenvalues and fractional anisotropy (FA) on short diffusion times was investigated using oscillating gradient spin echo (OGSE) and pulsed gradient spin echo (PGSE) DTI in the human brain in vivo. THEORY AND METHODS: DTI was performed in seven healthy volunteers at 4.7 Tesla (T) with b = 300 s/mm(2) and diffusion times of 4.1 ms (OGSE 50 Hz), 7.4 ms (OGSE 25 Hz), 20 ms (PGSE), and 40 ms (PGSE). Eigenvalues and FA were compared in the corpus callosum body, splenium and genu, and the corticospinal, cingulum, inferior fronto-occipital, superior and inferior longitudinal fasciculi using tractography, and the thalamus and putamen using region-of-interest. RESULTS: Relative to 40 ms, the 4.1 ms diffusion time led to significant increases in DTI eigenvalues in seven white matter tracts (6% to 20% parallel, 13% to 40% perpendicular) and both deep gray matter regions (16% parallel, 18% to 26% perpendicular), and reductions of FA (-9% to -12%) in four tracts. CONCLUSION: DTI eigenvalues and FA depend on diffusion time in both white and gray matter in the human brain. The ability to target different length scales by means of the diffusion time may improve sensitivity to changes in tissue microstructure associated with pathology. PMID- 24142864 TI - Kupffer cell structure in the juvenile Nile crocodile, Crocodylus niloticus. AB - The morphology of Kupffer cells was examined in the liver of the juvenile Nile crocodile using light microscopy and transmission electron microscopy. Pleomorphic Kupffer cells were located in the sinusoids, in the space of Disse, in the hepatic parenchyma and often connected adjacent sinusoids. The cell surfaces were irregular due to the presence of filopodia and lamelliapodia with phagocytosis of white blood cells, red blood cells and thrombocytes being evident. The cells were in close contact with endothelial cells and pit cells in the sinusoidal lumen and with stellate cells in the space of Disse. The cytoplasm contained large phagosomes comprising a combination of ceroid pigment, melanosomes and siderosomes. The nuclei were often indented and eccentrically placed due to the presence of the phagosomes. Conspicuous clusters of membrane bound tubular organelles with a filamentous or crystalline interior were observed in the cytoplasm. The clusters were sometimes separated into smaller groups around phagosomes. A clear zone existed between the limiting membrane and the interior of these tubular organelles with the electron-dense interior profiles being, respectively, circular, angular or divided. The tubular organelles have not previously been described in Kupffer cells and possibly represent lysosomes with specialized functions. Mitochondria, microtubules, Golgi profiles, granular and smooth endoplasmic reticulum, and a few cytoplasmic lipid droplets were also present. The presence of the tubular organelles and the occurrence of the Kupffer cells in different locations in the liver of the juvenile Nile crocodile are indicative of particularly active and mobile cells. PMID- 24142862 TI - Cdk5 phosphorylation of ErbB4 is required for tangential migration of cortical interneurons. AB - Interneuron dysfunction in humans is often associated with neurological and psychiatric disorders, such as epilepsy, schizophrenia, and autism. Some of these disorders are believed to emerge during brain formation, at the time of interneuron specification, migration, and synapse formation. Here, using a mouse model and a host of histological and molecular biological techniques, we report that the signaling molecule cyclin-dependent kinase 5 (Cdk5), and its activator p35, control the tangential migration of interneurons toward and within the cerebral cortex by modulating the critical neurodevelopmental signaling pathway, ErbB4/phosphatidylinositol 3-kinase, that has been repeatedly linked to schizophrenia. This finding identifies Cdk5 as a crucial signaling factor in cortical interneuron development in mammals. PMID- 24142865 TI - WITHDRAWN: Opioid switching to improve pain relief and drug tolerability. PMID- 24142866 TI - Behavioral and electrophysiological correlates of sleep and sleep homeostasis. AB - The definition of what sleep is depends on the method that is applied to record sleep. Behavioral and (electro)-physiological measures of sleep clearly overlap in mammals and birds , but it is often unclear how these two relate in other vertebrates and invertebrates. Homeostatic regulation of sleep, where the amount of sleep depends on the amount of previous waking, can be observed in physiology and behavior in all animals this was tested in. In mammals and birds, sleep is generally subdivided into two states, non-rapid eye movement (NREM) sleep and REM sleep. In mammals the combination of behavioral sleep and the changes in the slow wave range of the NREM sleep electroencephalogram (EEG) can explain and predict the occurrence and depth of sleep in great detail. For REM sleep this is far less clear. Finally, the discovery that slow-waves in the NREM sleep EEG are influenced locally on the cortex depending on prior waking behavior is an interesting new development that asks for an adaptation of the concept of homeostatic regulation of sleep. Incorporating local sleep into models of sleep regulation is needed to obtain a comprehensive picture. PMID- 24142867 TI - Increasing the donor pool: consideration of prehospital cardiac arrest in controlled donation after circulatory death for liver transplantation. AB - Donor warm ischemia has implications for outcomes after liver transplantation (LT) using organs from donation after circulatory death (DCD) donors. Prehospital cardiac arrest (PHCA) before donation may generate a further ischemic insult. The aim of this single-center study of 108 consecutive DCD LT procedures was to compare the outcomes of PHCA and non-PHCA cohorts. A review of a prospectively collected database of all DCD grafts transplanted between January 2007 and October 2011 was undertaken to identify donors who had sustained PHCA. The unit policy was to consider such donors when transaminase levels were <=4 times the normal range and had an improving trend. Twenty-six of the 108 DCD transplants were from DCD donors with PHCA, and 82 were in the non-PHCA cohort. A comparative analysis of the PHCA and non-PHCA cohorts showed better short-term results (a low incidence of acute kidney injury) for the PHCA group but satisfactory long-term results for both groups with no significant differences in graft or patient survival between them. In conclusion, a careful donor selection policy for including PHCA DCD donors with normalized liver function tests or transaminase levels <= 4 times the norm resulted in successful transplantation and could boost the donor pool with no adverse outcomes. PMID- 24142868 TI - Formaldehyde exposure induces autophagy in testicular tissues of adult male rats. AB - Formaldehyde, a ubiquitous environmental pollutant, has long been suspected of causing adverse male reproductive effects. However, the molecular and cellular mechanisms underlying this phenomenon remain elusive. The overall aim of this study is to clarify the role of autophagy in male reproductive injuries induced by formaldehyde exposure, by which we can further understand the molecular mechanism of spermatogenesis and develop new targets for prevention and treatment of male infertility. In this study, electron microscopy, Western blot, and RT-PCR analysis were used to detect autophagy in testicular tissues. Moreover, testicular weights, histopathology, and morphometry were used to evaluate the reproductive injuries of formaldehyde exposure. We found that formaldehyde exposure-induced autophagy in testicular tissues was dose dependent. Increasing autophagosomes in spermatogenetic cells was observed by electron microscopy in formaldehyde exposure group. In addition, RT-PCR and Western blot analysis showed the transcription levels of the LC3-II, as well as the conversion from LC3-I to LC3-II, an indicator of autophagy, significantly increased in testicular tissue of formaldehyde exposure group in a dose dependent manner when compared with those in control group. Furthermore, the alterations of autophage were basically consistent with the changes in testicular weight and morphologic findings. In summary, formaldehyde exposure triggered autophagy, and autophagy may be a scathing factor responsible for male reproductive impairment induced by formaldehyde. PMID- 24142869 TI - Population pharmacogenetic-based pharmacokinetic modeling of efavirenz, 7-hydroxy and 8-hydroxyefavirenz. AB - The purpose of this study was to determine the demographic and pharmacogenetic covariates that influence the disposition of efavirenz (EFV) and its major metabolites. A population pharmacokinetic (PK) model was developed from a randomized, cross-over, drug-interaction study in healthy male Korean subjects (n = 17). Plasma concentrations of EFV and its hydroxy-metabolites (0-120 hours) were measured by LC/MS/MS. Genomic DNA was genotyped for variants in the cytochrome P450 (CYP) 2A6, 2B6, 3A5, and MDR1 genes. A PK model was built in a stepwise procedure using nonlinear mixed effect modeling in NONMEM 7. The covariate model was built using the generalized additive modeling and forward selection-backward elimination. Model-based simulations were performed to predict EFV steady-state concentrations following 200, 400, and 600 mg daily oral dose among different CYP2B6 genotypes. The final model included only CYP2B6 genotype as a covariate that predicts EFV clearance through the formation of 8-OH EFV that represented 65% to 80% of EFV clearance. The total clearance of EFV in CYP2B6*6/*6 genotype was ~30% lower than CYP2B6*1/*1 or CYP2B6*1/*6 alleles (P < .001). Clopidogrel reduced both formation and elimination clearances of 8-OH EFV by 22% and 19%, respectively (P = .033 and .041). Other demographics and genotype of accessory CYP pathways did not predict EFV or metabolites PK. CYP2B6 genotype was the only significant predictor of EFV disposition. The developed model may serve as the foundation for further exploration of pharmacogenetic-based dosing of EFV. PMID- 24142870 TI - Perspectives and challenges in advancing research into craniofacial anomalies. AB - Development of the craniofacial region is a remarkably complex and tightly orchestrated process. It is therefore not surprising that genetic and environmental insults frequently result in craniofacial anomalies. Nonetheless, our knowledge of their etiology and pathogenesis is still scarce, limiting our efforts at prevention. Furthermore, few standardized protocols have been developed to guide clinical and surgical interventions. In this Issue of the Seminars, reviews on the most recent research advances on craniofacial conditions, from genomics and epigenetics to ontology and medical care are discussed with emphasis on the most common anomalies of the craniofacial region: orofacial clefts, craniosynostosis, craniofacial microsomia, facial dysostosis, Robin sequence, jaw and dentition anomalies, and anterior neural tube defects. Phenotypic variability and the importance of detailed characterization using standardized terminology to better distinguish between phenotypes, new technologies (and their limitations) for genetic diagnosis, and the use of mouse models to study these conditions in both their complex phenotypic and genetic aspects are highlighted. PMID- 24142871 TI - The emerging role of the Nrf2-Keap1 signaling pathway in cancer. AB - The Nrf2 (nuclear factor erythroid 2 [NF-E2]-related factor 2 [Nrf2])-Keap1 (Kelch-like erythroid cell-derived protein with CNC homology [ECH]-associated protein 1) signaling pathway is one of the most important cell defense and survival pathways. Nrf2 can protect cells and tissues from a variety of toxicants and carcinogens by increasing the expression of a number of cytoprotective genes. As a result, several Nrf2 activators are currently being tested as chemopreventive compounds in clinical trials. Just as Nrf2 protects normal cells, studies have shown that Nrf2 may also protect cancer cells from chemotherapeutic agents and facilitate cancer progression. Nrf2 is aberrantly accumulated in many types of cancer, and its expression is associated with a poor prognosis in patients. In addition, Nrf2 expression is induced during the course of drug resistance. Collectively, these studies suggest that Nrf2 contributes to both intrinsic and acquired chemoresistance. This discovery has opened up a broad spectrum of research geared toward a better understanding of the role of Nrf2 in cancer. This review provides an overview of (1) the Nrf2-Keap1 signaling pathway, (2) the dual role of Nrf2 in cancer, (3) the molecular basis of Nrf2 activation in cancer cells, and (4) the challenges in the development of Nrf2-based drugs for chemoprevention and chemotherapy. PMID- 24142872 TI - Epithelial-mesenchymal plasticity in carcinoma metastasis. AB - Tumor metastasis is a multistep process by which tumor cells disseminate from their primary site and form secondary tumors at a distant site. Metastasis occurs through a series of steps: local invasion, intravasation, transport, extravasation, and colonization. A developmental program termed epithelial mesenchymal transition (EMT) has been shown to play a critical role in promoting metastasis in epithelium-derived carcinoma. Recent experimental and clinical studies have improved our knowledge of this dynamic program and implicated EMT and its reverse program, mesenchymal-epithelial transition (MET), in the metastatic process. Here, we review the functional requirement of EMT and/or MET during the individual steps of tumor metastasis and discuss the potential of targeting this program when treating metastatic diseases. PMID- 24142874 TI - LIN28B promotes growth and tumorigenesis of the intestinal epithelium via Let-7. AB - The RNA-binding proteins LIN28A and LIN28B have diverse functions in embryonic stem cells, cellular reprogramming, growth, and oncogenesis. Many of these effects occur via direct inhibition of Let-7 microRNAs (miRNAs), although Let-7 independent effects have been surmised. We report that intestine targeted expression of LIN28B causes intestinal hypertrophy, crypt expansion, and Paneth cell loss. Furthermore, LIN28B fosters intestinal polyp and adenocarcinoma formation. To examine potential Let-7-independent functions of LIN28B, we pursued ribonucleoprotein cross-linking, immunoprecipitation, and high-throughput sequencing (CLIP-seq) to identify direct RNA targets. This revealed that LIN28B bound a substantial number of mRNAs and modestly augmented protein levels of these target mRNAs in vivo. Conversely, Let-7 had a profound effect; modulation of Let-7 levels via deletion of the mirLet7c2/mirLet7b genes recapitulated effects of Lin28b overexpression. Furthermore, intestine-specific Let-7 expression could reverse hypertrophy and Paneth cell depletion caused by Lin28b. This was independent of effects on insulin-PI3K-mTOR signaling. Our study reveals that Let-7 miRNAs are critical for repressing intestinal tissue growth and promoting Paneth cell differentiation. Let-7-dependent effects of LIN28B may supersede Let-7-independent effects on intestinal tissue growth. In summary, LIN28B can definitively act as an oncogene in the absence of canonical genetic alterations. PMID- 24142873 TI - Regulation of PCP by the Fat signaling pathway. AB - Planar cell polarity (PCP) in epithelia, orthogonal to the apical-basal axis, is essential for numerous developmental events and physiological functions. Drosophila model systems have been at the forefront of studies revealing insights into mechanisms regulating PCP and have revealed distinct signaling modules. One of these, involving the atypical cadherins Fat and Dachsous and the ectokinase Four-jointed, appears to link the direction of cell polarization to the tissue axes. We discuss models for the function of this signaling module as well as several unanswered questions that may guide future investigations. PMID- 24142875 TI - Glycogen synthase kinase 3 promotes p53 mRNA translation via phosphorylation of RNPC1. AB - The RNPC1 RNA-binding protein, also called Rbm38, is a target of p53 and a repressor of p53 mRNA translation. Thus, the p53-RNPC1 loop is critical for modulating p53 tumor suppression, but it is not clear how the loop is regulated. Here, we showed that RNPC1 is phosphorylated at Ser195 by glycogen synthase kinase 3 (GSK3). We also showed that GSK3 promotes p53 mRNA translation through phosphorylation of RNPC1. Interestingly, we found that the phosphor-mimetic mutant S195D and the deletion mutant Delta189-204, which lacks the GSK3 phosphorylation site, are unable to repress p53 mRNA translation due to loss of interaction with eukaryotic translation factor eIF4E on p53 mRNA. Additionally, we found that phosphorylated RNPC1, RNPC1-S195D, and RNPC1(Delta189-204) promote p53 mRNA translation through interaction with eukaryotic translation factor eIF4G, which then facilitates the assembly of the eIF4F complex on p53 mRNA. Furthermore, we showed that upon inhibition of the phosphatidylinositol 3-kinase (PI3K)-Akt pathway, GSK3 is activated, leading to increased RNPC1 phosphorylation and increased p53 expression in a RNPC1-dependent manner. Together, we postulate that the p53-RNPC1 loop can be explored to increase or decrease p53 activity for cancer therapy. PMID- 24142876 TI - RNF4 and PLK1 are required for replication fork collapse in ATR-deficient cells. AB - The ATR-CHK1 axis stabilizes stalled replication forks and prevents their collapse into DNA double-strand breaks (DSBs). Here, we show that fork collapse in Atr-deleted cells is mediated through the combined effects the sumo targeted E3-ubiquitin ligase RNF4 and activation of the AURKA-PLK1 pathway. As indicated previously, Atr-deleted cells exhibited a decreased ability to restart DNA replication following fork stalling in comparison with control cells. However, suppression of RNF4, AURKA, or PLK1 returned the reinitiation of replication in Atr-deleted cells to near wild-type levels. In RNF4-depleted cells, this rescue directly correlated with the persistence of sumoylation of chromatin-bound factors. Notably, RNF4 repression substantially suppressed the accumulation of DSBs in ATR-deficient cells, and this decrease in breaks was enhanced by concomitant inhibition of PLK1. DSBs resulting from ATR inhibition were also observed to be dependent on the endonuclease scaffold protein SLX4, suggesting that RNF4 and PLK1 either help activate the SLX4 complex or make DNA replication fork structures accessible for subsequent SLX4-dependent cleavage. Thus, replication fork collapse following ATR inhibition is a multistep process that disrupts replisome function and permits cleavage of the replication fork. PMID- 24142879 TI - Essential facets of competence that enable trust in medical graduates: a ranking study among physician educators in two countries. AB - One way to operationalize the assessment of trainees in a competency-based context is to determine whether they can be entrusted with critical activities. To determine which facets of competence (FOCs) are most informative for such decisions, we performed a Delphi study among Dutch educators. In the current study, the resulting list of facets of competence was evaluated among experienced Dutch and German clinical educators to determine which facets appear most relevant and to evaluate the agreement among experts in different countries as a support for their external validity. Eight Dutch and eight German experts scored each FOC on a five-point scale for relevance. A rank-order comparison showed that there was almost full agreement about the top 10 FOCs, among which 'Scientific and empirical grounded method of working', 'Knowing and maintaining own personal bounds and possibilities', 'Active professional development', 'Teamwork and collegiality', 'Active listening to patients', and 'Verbal communication with colleagues and supervisors'. We conclude that these facets of competence may be used in a training for educators who need to make entrustment decisions about trainees. PMID- 24142877 TI - Physiological modulation of endogenous BRCA1 p220 abundance suppresses DNA damage during the cell cycle. AB - Endogenous BRCA1 p220 expression peaks in S and G2 when it is activated, and the protein participates in certain key DNA damage responses. In contrast, its expression is markedly reduced in G0/G1. While variations in transcription represent a significant part of p220 expression control, there is at least one other relevant process. We found that a microRNA, miR-545, that is expressed throughout the cell cycle down-modulates endogenous p220 mRNA and protein abundance directly in both G0/G1 and S/G2. When miR-545 function was inhibited by a specific antagomir, endogenous p220 expression increased in G0/G1, and aberrant p220-associated DNA damage responses and de novo DNA strand breaks accumulated. Analogous results were observed upon inhibition of miR-545 function in S/G2. Both sets of antagomir effects were mimicked by infecting cells with a p220 cDNA encoding adenoviral vector. Thus, strand breaks were a product of p220 overexpression, and their prevention by miR-545 depends on its modulation of p220 expression. Breaks were also dependent on aberrant, overexpressed p220-driven recruitment of RAD51 to either spontaneously arising or mutagen-based DNA damage sites. Hence, when its level is not physiologically maintained, endogenous p220 aberrantly directs at least one DNA repair protein, RAD51, to damage sites, where their action contributes to the development of de novo DNA damage. Thus, like its loss, a surfeit of endogenous p220 function represents a threat to genome integrity. PMID- 24142880 TI - An essential role for decorin in bladder cancer invasiveness. AB - Muscle-invasive forms of urothelial carcinomas are responsible for most mortality in bladder cancer. Finding new treatments for invasive bladder tumours requires adequate animal models to decipher the mechanisms of progression, in particular the way tumours interact with their microenvironment. Herein, using the murine bladder tumour cell line MB49 and its more aggressive variant MB49-I, we demonstrate that the adaptive immune system efficiently limits progression of MB49, whereas MB49-I has lost tumour antigens and is insensitive to adaptive immune responses. Furthermore, we unravel a parallel mechanism developed by MB49 I to subvert its environment: de novo secretion of the proteoglycan decorin. We show that decorin overexpression in the MB49/MB49-I model is required for efficient progression, by promoting angiogenesis and tumour cell invasiveness. Finally, we show that these results are relevant to muscle-invasive human bladder carcinomas, which overexpress decorin together with angiogenesis- and adhesion/migration-related genes, and that decorin overexpression in the human bladder carcinoma cell line TCCSUP is required for efficient invasiveness in vitro. We thus propose decorin as a new therapeutic target for these aggressive tumours. PMID- 24142881 TI - Improve myocardial T1 measurement in rats with a new regression model: application to myocardial infarction and beyond. AB - PURPOSE: To improve myocardial and blood T1 measurements with a multi-variable T1 fitting model specifically modified for a segmented multi-shot FLASH sequence. METHODS: The proposed method was first evaluated in a series of phantoms simulating realistic tissues, and then in healthy rats (n = 8) and rats with acute myocardial infarction (MI) induced by coronary artery ligation (n = 8). RESULTS: By taking into account the saturation effect caused by sampling alpha train pulses, and the longitudinal magnetization recovery between readouts, our model provided more accurate T1 estimate than the conventional three-parameter fit in phantoms under realistic gating procedures (error of -0.42 +/- 1.73% versus -3.40 +/- 1.46%, respectively, when using the measured inversion efficiency, beta). The baseline myocardial T1 values in healthy rats was 1636.3 +/- 23.4 ms at 7 Tesla. One day postligation, the T1 values in the remote and proximal myocardial areas were 1637.5 +/- 62.6 ms and 1740.3 +/- 70.5 ms, respectively. In rats with acute MI, regional differences in myocardial T1 values were observed both before and after the administration of gadolinium. CONCLUSION: The proposed method has improved T1 estimate as validated in phantoms and could advance applications in rodents using quantitative myocardial T1 mapping. PMID- 24142882 TI - Pelvic girdle shape predicts locomotion and phylogeny in batoids. AB - In terrestrial vertebrates, the pelvic girdle can reliably predict locomotor mode. Because of the diminished gravitational effects on positively buoyant bony fish, the same relationship does not appear to exist. However, within the negatively buoyant elasmobranch fishes, benthic batoids employ pelvic fin bottom walking and punting as primary or supplementary forms of locomotion. Therefore, in this study, we employed geometric and linear morphometrics to investigate if their pelvic girdles exhibit shape characteristics similar to those of sprawling terrestrial vertebrates. We tested for correlates of pelvic girdle shape with 1) Order, 2) Family, 3) Swim Mode, and/or 4) Punt Mode. Landmarks and semilandmarks were placed along outlines of dorsal views of 61 batoid pelvic girdles (3/3 orders, 10/13 families, 35/72 genera). The first three relative warps explained 88.45% of the variation among individuals (P < 0.01%). Only Order and Punt Mode contained groups that were all significantly different from each other (P < 0.01%). Discriminant function analyses indicated that the majority of variation within each category was due to differences in extension of lateral and prepelvic processes and puboischiac bar angle. Over 60% of the original specimens and 55% of the cross-validated specimens were correctly classified. The neutral angle of the propterygium, which articulates with the pelvic girdle, was significantly different among punt modes, whereas only pectoral fin oscillators had differently shaped pelvic girdles when compared with batoids that perform other swimming modes (P < 0.01). Pelvic girdles of batoids vary greatly, and therefore, likely function in ways not previously described in teleost fishes. This study illustrates that pelvic girdle shape is a good predictor of punt mode, some forms of swimming mode, and a species' Order. Such correlation between locomotor style and pelvic girdle shape provides evidence for the convergent evolution of morphological features that support both sprawled-gait terrestrial walking and aquatic bottom-walking. PMID- 24142883 TI - Multimodal therapy including liver transplantation for hepatic undifferentiated embryonal sarcoma. AB - The outcomes of hepatic undifferentiated embryonal sarcoma (HUES) have historically been limited by persistent, unresectable disease and the subsequent development of disease resistance and dissemination. We present our institutional experience with HUES and assess current treatment trends and outcomes in the era of liver transplantation. We conducted a retrospective chart review of cases presenting with HUES at our institution over the past 10 years. The collected data included age, sex, presenting symptoms, imaging and the associated Pretreatment Extent of Disease (PRETEXT) score, pathology, chemotherapy, surgical interventions, and outcomes. Approval was obtained from the institutional review board of the Cincinnati Children's Hospital Medical Center. HUES was identified in 6 patients (4 males and 2 females) with a median age at diagnosis of 11 years (range = 7-13 years). Initial imaging was available for all but 1 patient. The PRETEXT stage for these patients ranged from II to III. One patient was diagnosed with lung metastases. Two patients underwent upfront resection, and 1 patient received neoadjuvant therapy and then conventional resection. Three patients were treated with orthotopic liver transplantation (OLT) after neoadjuvant chemotherapy (primary OLT in 2 cases and salvage OLT for local recurrence in 1 case). Two patients received posttransplant adjuvant chemotherapy. All 6 patients remained in clinical remission with a mean follow-up of 35 months (range = 12-84 months). In conclusion, OLT has rarely been reported as a treatment option for HUES. The addition of liver transplantation as a surgical option for treating patients with HUES can result in improved survival for patients whose tumors are initially unresectable or recur. PMID- 24142884 TI - Molecular mechanism of oxidative damage of lung in mice following exposure to lanthanum chloride. AB - Exposure to lanthanoids (Ln) elicits an adverse response such as oxidative injury of lung in animals and human. The molecular targets of Ln remain unclear. In the present study, the function and signal pathway of nuclear factor erythroid 2 related factor 2 (Nrf2) in LaCl3 -induced oxidative stress in mouse lung were investigated. Mice were exposed to 2, 5, and 10 mg/kg body weight by nasal administration for 6 consecutive months. With increased doses, La was markedly accumulated and promoted the reactive oxygen species (ROS) production in the lung, which in turn resulted in peroxidation of lipids, proteins and DNA, and severe pulmonary damages. Furthermore, LaCl3 exposure could significantly increase levels of Nrf2, heme oxygenase 1 (HO-1) and glutamate-cysteine ligase catalytic subunit (GCLC) expressions in the LaCl3 -exposed lung. These findings imply that the induction of Nrf2 expression is an adaptive intracellular response to LaCl3 -induced oxidative stress in mouse lung, and that Nrf2 may regulate the LaCl3 -induced pulmonary damages. PMID- 24142885 TI - Absence of an effect of T89 on the steady-state pharmacokinetics and pharmacodynamics of warfarin in healthy volunteers. AB - This open-label, multi-dose, single-center, sequential, inpatient study evaluated the effects of a two herb combination drug (T89, Danshen plus Sanqi) on the steady-state pharmacodynamics (PD) and pharmacokinetics (PK) of warfarin in 24 healthy volunteers. Twenty-three subjects attained a stable international normalized ratio (INR) by taking warfarin alone prior to 1-week of added-on use of T89. INR was not increased after the addition of T89 for 7 days (P > .05). The 90% confidence interval (CI) of the geometric mean ratio for maximum plasma concentrations (Cmax) and area under curve (AUClast ) of both R- and S-warfarin when warfarin was administered with or without T89 was within the 0.80 to 1.25 equivalence ratio. These results indicate that T89 has no effect on the steady state PD and PK of warfarin. Warfarin and T89 dose adjustments are not required when these two drugs are co-administrated in clinical practice. PMID- 24142886 TI - Enhanced care by generalists for functional somatic symptoms and disorders in primary care. AB - BACKGROUND: Patients with medically unexplained or functional somatic symptoms are common in primary care. Previous reviews have reported benefit from specialised interventions such as cognitive behavioural therapy and consultation letters, but there is a need for treatment models which can be applied within the primary care setting. Primary care studies of enhanced care, which includes techniques of reattribution or cognitive behavioural therapy, or both, have shown changes in healthcare professionals' attitudes and behaviour. However, studies of patient outcome have shown variable results and the value of enhanced care on patient outcome remains unclear. OBJECTIVES: We aimed to assess the clinical effectiveness of enhanced care interventions for adults with functional somatic symptoms in primary care. The intervention should be delivered by professionals providing first contact care and be compared to treatment as usual. The review focused on patient outcomes only. SEARCH METHODS: We searched the Cochrane Depression, Anxiety and Neurosis Review Group Specialised Register (CCDANCTR Studies and CCDANCTR-References) (all years to August 2012), together with Ovid searches (to September 2012) on MEDLINE (1950 - ), EMBASE (1980 - ) and PsycINFO (1806 - ). Earlier searches of the Database of Abstracts of Reviews of Effectiveness (DARE), CINAHL, PSYNDEX, SIGLE, and LILACS were conducted in April 2010, and the Cochrane Central Register of Controlled Trials (CENTRAL) in October 2009. No language restrictions were applied. Electronic searches were supplemented by handsearches of relevant conference proceedings (2004 to 2012), reference lists (2011) and contact with authors of included studies and experts in the field (2011). SELECTION CRITERIA: We limited our literature search to randomised controlled trials (RCTs), primary care, and adults with functional somatic symptoms. Subsequently we selected studies including all of the following: 1) a trial arm with treatment as usual; 2) an intervention using a structured treatment model which draws on explanations for symptoms in broad bio psycho-social terms or encourages patients to develop additional strategies for dealing with their physical symptoms, or both; 3) delivery of the intervention by primary care professionals providing first contact care; and 4) assessment of patient outcome. DATA COLLECTION AND ANALYSIS: Two authors independently screened identified study abstracts. Disagreements about trial selections were resolved by a third review author. Data from selected publications were independently extracted and risk of bias assessed by two of three authors, avoiding investigators reviewing their own studies. We contacted authors from included studies to obtain missing information. We used continuous outcomes converted to standardised mean differences (SMDs) and based analyses on changes from baseline to follow-up, adjusted for clustering. MAIN RESULTS: We included seven studies from the literature search, but only six provided sufficient data for analyses. Included studies were European, cluster RCTs with adult participants seeing their usual doctor (in total 233 general practitioners and 1787 participants). Methodological quality was only moderate as studies had no blinding of healthcare professionals and several studies had a risk of recruitment and attrition bias. Studies were heterogeneous with regard to selection of patient populations and intensity of interventions. Outcomes relating to physical or general health (physical symptoms, quality of life) showed substantial heterogeneity between studies (I(2) > 70%) and post hoc analysis suggested that benefit was confined to more intensive interventions; thus we did not calculate a pooled effect. Outcomes relating to mental health showed less heterogeneity and we conducted meta analyses, which found non-significant overall effect sizes with SMDs for changes at 6 to 24 months follow-up: mental health (3 studies) SMD -0.04 (95% CI -0.18 to 0.10), illness worry (3 studies) SMD 0.09 (95% CI -0.04 to 0.22), depression (4 studies) SMD 0.07 (95% CI -0.05 to 0.20) and anxiety (2 studies) SMD -0.07 (95% CI -0.38 to 0.25). Effects on sick leave could not be estimated. Three studies of patient satisfaction with care all showed positive but non-significant effects, and measures were too heterogeneous to allow meta-analysis. Results on healthcare utilisation were inconclusive. We analysed study discontinuation and found that both short term and long term discontinuation occurred more often in patients allocated to the intervention group, RR of 1.25 (95% CI 1.08 to 1.46) at 12 to 24 months. AUTHORS' CONCLUSIONS: Current evidence does not answer the question whether enhanced care delivered by front line primary care professionals has an effect or not on the outcome of patients with functional somatic symptoms. Enhanced care may have an effect when delivered per protocol to well-defined groups of patients with functional disorders, but this needs further investigation. Attention should be paid to difficulties including limited consultation time, lack of skills, the need for a degree of diagnostic openness, and patient resistance towards psychosomatic attributions. There is some indication from this and other reviews that more intensive interventions are more successful in changing patient outcomes. PMID- 24142888 TI - Synergistic effect of static magnetic field and HA-Fe3O4 magnetic composites on viability of S. aureus and E. coli bacteria. AB - In addressing the issue of prosthetic infection, this work demonstrated the synergistic effect of the application of static magnetic field (SMF) and ferrimagnetic substrate properties on the bactericidal property in vitro. This aspect was studied using hydroxyapatite (HA)-xFe3 O4 (x=10, 20, and 40 wt.%) substrates, which have different saturation magnetization properties. During bacteria culture experiments, 100 mT SMF was applied to growth medium (with HA xFe3 O4 substrate) in vitro for 30, 120, and 240 min. A combination of MTT assay, membrane rupture assays, live/dead assay, and fluorescence microscopic analysis showed that the bactericidal effect of SMF increases with the exposure duration as well as increasing Fe3 O4 content in biomaterial substrates. Importantly, the synergistic bactericidal effect was found to be independent of bacterial cell type, as similar qualitative trend is measured with both gram negative Escherichia coli (E. coli) and gram positive Staphylococcus aureus (S. aureus) strains. The reduction in E. coli viability was 83% higher on HA-40 Wt % Fe3 O4 composite after 4 h exposure to SMF as compared to nonexposed control. Interestingly, any statistically significant difference in ROS was not observed in bacterial growth medium after magnetic field exposure, indicating the absence of ROS enhancement due to magnetic field. Overall, this study illustrates significant role being played by magnetic substrate compositions towards bactericidal property than by magnetic field exposure alone. PMID- 24142887 TI - CCR2(+) monocytes infiltrate atrophic lesions in age-related macular disease and mediate photoreceptor degeneration in experimental subretinal inflammation in Cx3cr1 deficient mice. AB - Atrophic age-related macular degeneration (AMD) is associated with the subretinal accumulation of mononuclear phagocytes (MPs). Their role in promoting or inhibiting retinal degeneration is unknown. We here show that atrophic AMD is associated with increased intraocular CCL2 levels and subretinal CCR2(+) inflammatory monocyte infiltration in patients. Using age- and light-induced subretinal inflammation and photoreceptor degeneration in Cx3cr1 knockout mice, we show that subretinal Cx3cr1 deficient MPs overexpress CCL2 and that both the genetic deletion of CCL2 or CCR2 and the pharmacological inhibition of CCR2 prevent inflammatory monocyte recruitment, MP accumulation and photoreceptor degeneration in vivo. Our study shows that contrary to CCR2 and CCL2, CX3CR1 is constitutively expressed in the retina where it represses the expression of CCL2 and the recruitment of neurotoxic inflammatory CCR2(+) monocytes. CCL2/CCR2 inhibition might represent a powerful tool for controlling inflammation and neurodegeneration in AMD. PMID- 24142889 TI - Use of hepatitis B surface antigen-positive grafts in liver transplantation: a matched analysis of the US National database. AB - The scarcity of available donor organs is the key challenge in orthotopic liver transplantation (OLT). A viable way of expanding the donor pool is the use of liver grafts from hepatitis B surface antigen (HBsAg)-positive donors. The present study used the US Scientific Registry of Transplant Recipients database (1987-2010), and each of the 78 patients who underwent OLT with HBsAg-positive grafts was matched with 4 patients who received HBsAg-negative grafts by urgent status, donor sex, recipient sex, donor age, recipient age, transplant date, Model for End-Stage Liver Disease score, and warm ischemia time. The overall graft and patient survival rates were similar for recipients of HBsAg-positive grafts and matched controls: the 5-year graft survival rates were 66% and 64%, respectively (P = 0.95), and the 5-year patient survival rates were 71% and 71%, respectively (P = 0.87). A Cox proportional hazards regression analysis that was adjusted for other variables showed no impact of the donor HBsAg status on graft or patient survival. The use of hepatitis B immunoglobulin (HBIG) was independently associated with better posttransplant graft survival [hazard ratio (HR) = 0.23, 95% confidence interval (CI) = 0.06-0.81] and patient survival (HR = 0.16, 95% CI = 0.04-0.75) for recipients of HBsAg-positive grafts. In conclusion, the use of HBsAg-positive liver grafts did not reduce posttransplant graft or patient survival. Moreover, matching these donors to recipients treated with HBIG may improve safety. PMID- 24142890 TI - Ultrastructure of spermatogenesis in the short-tailed fruit bat, Carollia perspicillata (Chiroptera: Phyllostomidae: Carollinae). AB - Among species of the Chiroptera, spermatogenesis and the fully differentiated spermatozoa differ in morphological and ultrastructural detail. This study therefore aimed to ultrastructurally characterize the spermatogenesis and the spermatozoa of Carollia perspicillata (Phyllostomidae) and compare the process with other species of bats and mammals. The differentiation of spermatogonia is similar to other bats and to Primates, with three main spermatogonia types: Ad, Ap, and B. Meiotic divisions proceed similarly to those of most mammals and spermiogenesis is clearly divided into 12 steps, in the middle of the range of developmental steps for bats (9-16 steps). The process of acrosome formation is similar to that found in Platyrrhinus lineatus, with the acrosome formed by two different types of proacrosomal vesicles. The ultrastructure of the spermatozoon is similar to other bats already described and resembles the typical mammalian sperm model; however, its morphology differs from other mammals such as marsupials and rodents, on account of a simpler spermatozoon head morphology, which indicates a pattern that is more closely related to the sperm cells of humans and other primates. Our data demonstrated that spermatogenesis in C. perspicillata presents great ultrastructural similarities to P. lineatus. This pattern is not surprising, because both species belong to the same family (Phyllostomidae); however, it is observed that C. perspicillata presents some characteristics that are more closely related to phylogenetically distant species, such as Myotis nigricans (Vespertilionidae), which is a fact that deserves attention. PMID- 24142891 TI - Microcystin-LR-caused ROS generation involved in p38 activation and tau hyperphosphorylation in neuroendocrine (PC12) cells. AB - Microcystin-LR (MC-LR), a potent specific hepatotoxin produced by cyanobacteria, has recently been reported to show neurotoxicity. Our previous study demonstrated that MC-LR caused the reorganization of cytoskeleton architectures and hyperphosphorylation of the cytoskeletal-associated proteins tau and HSP27 in neuroendocrine PC12 cell line by direct PP2A inhibition and indirect p38 mitogen activated protein kinase (MAPK) activation. It has been shown that oxidative stress is extensively associated with MC-LR toxicity, mainly resulting from an excessive production of reactive oxygen species (ROS). However, the mechanisms by which ROS mediates the cytotoxic action of MC-LR are unclear. In the present study, we investigated whether ROS might play a critical role in MC-LR-induced hyperphosphorylation of microtubule-associated protein tau and the activation of the MAPKs in PC12 cell line. The results showed that MC-LR had time- and concentration-dependent effects on ROS generation, p38-MAPK activation and tau phosphorylation. The time-course studies indicated similar biphasic changes in ROS generation and tau hyperphosphorylation, which started to increase within 1 h and reached the maximum level at 3 h followed by a decrease after prolonged treatment. Furthermore, pretreatment with the antioxidants, N-acetylcysteine and vitamin C, significantly decreased MC-LR-induced ROS generation and effectively attenuated p38-MAPK activation as well as tau hyperphosphorylation. Taken together, these findings suggest that ROS generation triggered by MC-LR is a key intracellular event that contributes to an induction of p38-MAPK activation and tau phosphorylation, and that blockade of this ROS-mediated redox-sensitive signal cascades may attenuate the toxic effects of MC-LR. PMID- 24142893 TI - Risks of PSA screening now better understood. PMID- 24142895 TI - Pregnancy options expand for women with cancer. PMID- 24142896 TI - Robust estimates of divergence times and selection with a poisson random field model: a case study of comparative phylogeographic data. AB - Mutation frequencies can be modeled as a Poisson random field (PRF) to estimate speciation times and the degree of selection on newly arisen mutations. This approach provides a quantitative theory for comparing intraspecific polymorphism with interspecific divergence in the presence of selection and can be used to estimate population genetic parameters. Although the original PRF model has been extended to more general biological settings to make statistical inference about selection and divergence among model organisms, it has not been incorporated into phylogeographic studies that focus on estimating population genetic parameters for nonmodel organisms. Here, we modified a recently developed time-dependent PRF model to independently estimate genetic parameters from a nuclear and mitochondrial DNA data set of 22 sister pairs of birds that have diverged across a biogeographic barrier. We found that species that inhabit humid habitats had more recent divergence times and larger effective population sizes than those that inhabit drier habitats, and divergence time estimated from the PRF model were similar to estimates from a coalescent species-tree approach. Selection coefficients were higher in sister pairs that inhabited drier habitats than in those in humid habitats, but overall the mitochondrial DNA was under weak selection. Our study indicates that PRF models are useful for estimating various population genetic parameters and serve as a framework for incorporating estimates of selection into comparative phylogeographic studies. PMID- 24142898 TI - Robotic single-site cholecystectomy. AB - BACKGROUND: Minimally invasive approaches for cholecystectomy are evolving in a surge for the best possible clinical outcome for the patients. As one of the most recent developments, a robotic set of instrumentation to be used with the da Vinci Si Surgical System has been developed to overcome some of the technical challenges of manual single incision laparoscopy. METHODS: From February 2011 to February 2013, all consecutive robotic single site cholecystectomies (RSSC) were prospectively collected in a dedicated database. Demographic, intra- and postoperative data of all patients that underwent RSSC at our institution were analyzed. Data were evaluated for the overall patient cohort as well as after stratification according to patient BMI (body mass index) and surgeon's experience. RESULTS: During the study period, 82 patients underwent robotic single site cholecystectomy at our institution. The dominating preoperative diagnosis was cholelithiasis. Mean overall operative time was 91 min. Intraoperative complications occurred in 2.4% of cases. One conversion to open surgery due to the intraoperative finding of a gallbladder carcinoma was observed and two patients needed an additional laparoscopic trocar. The rate of postoperative complications was 4.9% with a mean length of stay of 2.4 days. No significant differences were observed when comparing results between robotic novices and robotic experts. Patients with higher BMI trended towards longer surgical console and overall operative time, but resulted in similar rates of conversions and complications when compared to normal weight patients. CONCLUSIONS: Robotic Single-Site cholecystectomy can be performed safely and effectively with low rates of complications and conversions in patients with differing BMI and by surgeons with varying levels of experience. PMID- 24142897 TI - Regulation of aggression by obesity-linked genes TfAP-2 and Twz through octopamine signaling in Drosophila. AB - In Drosophila, the monoamine octopamine, through mechanisms that are not completely understood, regulates both aggression and mating behavior. Interestingly, our study demonstrates that the Drosophila obesity-linked homologs Transcription factor AP-2 (TfAP-2; TFAP2B in humans) and Tiwaz (Twz; KCTD15 in humans) interact to modify male behavior by controlling the expression of Tyramine beta-hydroxylase and Vesicular monanime transporter, genes necessary for octopamine production and secretion. Furthermore, we reveal that octopamine in turn regulates aggression through the Drosophila cholecystokinin satiation hormone homolog Drosulfakinin (Dsk). Finally, we establish that TfAP-2 is expressed in octopaminergic neurons known to control aggressive behavior and that TfAP-2 requires functional Twz for its activity. We conclude that genetically manipulating the obesity-linked homologs TfAP-2 and Twz is sufficient to affect octopamine signaling, which in turn modulates Drosophila male behavior through the regulation of the satiation hormone Dsk. PMID- 24142899 TI - Cytocompatible and water-stable camelina protein films for tissue engineering. AB - In this research, films with compressive strength and aqueous stability were developed from camelina protein (CP) for tissue engineering. Protein based scaffolds have poor mechanical properties and aqueous stability and generally require chemical or physical modifications to make them applicable for medical applications. However, these modifications such as crosslinking could reduce biocompatibility and/or degradability of the scaffolds. Using proteins that are inherently water-stable could avoid modifications and provide scaffolds with the desired properties. CP with a high degree of disulfide cross-linkage has the potential to provide water-stable biomaterials, but it is difficult to dissolve CP and develop scaffolds. In this study, a new method of dissolving highly cross linked proteins that results in limited hydrolysis and preserves the protein backbone was developed to produce water-stable films from CP without any modification. Only 12 % weight loss of camelina films was observed after 7 days in phosphate buffer saline (PBS) at 37 degrees C. NIH 3T3 fibroblasts could attach and proliferate better on camelina films than on citric acid cross-linked collagen films. Therefore, CP films have the potential to be used for tissue engineering, and this extraction-dissolution method can be used for developing biomedical materials from various water-stable plant proteins. PMID- 24142900 TI - Ectocranial suture fusion in primates: pattern and phylogeny. AB - Patterns of ectocranial suture fusion among Primates are subject to species specific variation. In this study, we used Guttman Scaling to compare modal progression of ectocranial suture fusion among Hominidae (Homo, Pan, Gorilla, and Pongo), Hylobates, and Cercopithecidae (Macaca and Papio) groups. Our hypothesis is that suture fusion patterns should reflect their evolutionary relationship. For the lateral-anterior suture sites there appear to be three major patterns of fusion, one shared by Homo-Pan-Gorilla, anterior to posterior; one shared by Pongo and Hylobates, superior to inferior; and one shared by Cercopithecidae, posterior to anterior. For the vault suture pattern, the Hominidae groups reflect the known phylogeny. The data for Hylobates and Cercopithecidae groups is less clear. The vault suture site termination pattern of Papio is similar to that reported for Gorilla and Pongo. Thus, it may be that some suture sites are under larger genetic influence for patterns of fusion, while others are influenced by environmental/biomechanic influences. PMID- 24142903 TI - The lateral line receptor array of cyprinids from different habitats. AB - The lateral line system of teleost fishes consists of an array of superficial and canal neuromasts (CN). Number and distribution of neuromasts and the morphology of the lateral line canals vary across species. We investigated the morphology of the lateral line system in four diurnal European cyprinids, the limnophilic bitterling (Rhodeus sericeus), the indifferent gudgeon (Gobio gobio), and ide (Leuciscus idus), and the rheophilic minnow (Phoxinus phoxinus). All fish had lateral line canals on head and trunk. The total number of both, CN and superficial neuromasts (SN), was comparable in minnow and ide but was greater than in gudgeon and bitterling. The ratio of SNs to CNs for the head was comparable in minnow and bitterling but was greater in gudgeon and ide. The SN-to CN ratio for the trunk was greatest in bitterling. Polarization of hair cells in CNs was in the direction of the canal. Polarization of hair cells in SNs depended on body area. In cephalic SNs, hair cell polarization was dorso-ventral or rostro caudal. In trunk SNs, it was rostro-caudal on lateral line scales and dorso ventral on other trunk scales. On the caudal fin, hair cell polarization was rostro-caudal. The data show that, in the four species studied here, number, distribution, and orientation of CNs and SNs cannot be unequivocally related to habitat. PMID- 24142905 TI - Change for the better. PMID- 24142904 TI - The beneficial effect of encapsulated human adipose-derived stem cells in alginate hydrogel on neural differentiation. AB - Tissue engineering employs combination of biomaterials and cell therapy to develop new therapeutic strategies for neurodegenerative diseases, spinal cord, and traumatic brain injuries. Alginate is a biocompatible hydrogel, which has been used broadly to encapsulate many types of cells. Human adipose-derived stem cells (hADSCs) have appropriate property to differentiate into neuron-like cells. Therefore, the aim of this study was to evaluate the effect of alginate hydrogel on the viability and neural differentiation potential of induced hADSCs. After neural induction of isolated hADSCs and encapsulated in alginate hydrogel, the cell viability using MTT assay and their neural differentiation potential by immunocytochemical and real time RT-PCR analysis for neural markers (Nestin, GFAP, and MAP2) were evaluated. Expression of Nestin, GFAP, and MAP2 markers was significantly increased compare to monolayer induced cells (p<0.001), but we did not found any significant effect on viability of induced cells relative to monolayer induced cells. Although neural differentiation of encapsulated cells was increased relative to monolayer induced cells, the viability of these cells was not significantly different in alginate hydrogel as compared with monolayer induced cells. PMID- 24142906 TI - The John A. Hartford Foundation Hartford gerontological nursing leaders: improving care for older adults across the health care continuum. PMID- 24142909 TI - Synthesis and antimicrobial activity of some new heterocycles incorporating the pyrazolopyridine moiety. AB - 2-Cyano-N-(4,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-3-yl)acetamide (2) was utilized as key intermediate for the synthesis of some new coumarin 3, pyridine 4, pyrrole 5, thiazole 8, pyrido[2',3':3,4]-pyrazolo-[5,1-c]triazine 7, and aminopyrazolo 10 compounds. 2-Cyano-N-(4,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-3-yl)-3 (dimethylamino)acrylamide (11) was synthesized and allowed to react with hydroxylamine, hydrazine, and guanidine to afford regioselectively the isoxazole 13, pyrazole 15, and pyrimidine 17 derivatives, respectively. The reaction of 11 with thiourea and/or with ethyl glycinate in basic medium afforded the regioisomeric pyrimidinethione 18 and 3,5-dioxo-1,4-diazepine-6-carbonitrile 23. All the synthesized products were tested and evaluated as antimicrobial agents. PMID- 24142910 TI - Design, synthesis and biological evaluation of some 2-azetidinone derivatives as potential antihyperlipidemic agents. AB - In an effort to develop new molecules with improved antihyperlipidemic activity, eight new 2-azetidinone analogs (4a-4h) of ezetimibe were designed through in silico docking experiments with the crystal structure of the Niemann-Pick C1-like 1 protein (NPC1L1). Synthesis and further antihyperlipdemic evaluation of this series in the Triton WR 1339 induced hyperlipidemic rat model showed some of the molecules to exhibit significant lipid-lowering effects comparable to ezetimibe. Correlation between the observed biological activity and the in silico molecular docking scores of the compounds was observed. PMID- 24142911 TI - Psychometric evaluation of the Symptoms of Acute Coronary Syndromes Inventory in Chinese patients with acute coronary syndromes. AB - BACKGROUND: A systematic method of symptom assessment in patients with acute coronary syndromes is important for disease recognition and initiation of early treatment. However, such assessment in Chinese people is hindered by the lack of a psychometrically sound instrument. AIMS: To develop the Chinese version of the Symptoms of Acute Coronary Syndromes Inventory (SACSI-C) and to evaluate its psychometric properties for Chinese patients. METHODS: SACSI was translated from English into Chinese according to Brislin's model. Its content validity and face validity were evaluated. A sample of 114 acute coronary syndromes patients was recruited from the cardiac units of two hospitals in Hong Kong. The reliability was assessed by one-day test-retest reliability. The known-groups validity was evaluated by its ability to differentiate patients with typical versus atypical symptom presentation in older (>=75 years) and younger (<75 years) groups. RESULTS: The Item-Content Validity Index of the SACSI-C was computed as 0.88 1.00. The Scale-Content Validity Index was computed as 0.99. The intraclass correlation coefficients of all items of the symptom subscale were above 0.75, except for item 16. The kappa values of all items in the symptom location and quality subscales were above 0.663. The test-retest reliability was good. The known-groups validity was evident, as demonstrated by the results of Chi-square test (p=0.007) and logistic regression analysis (odds ratio=2.9, p=0.039), showing that older patients were significantly more likely to have atypical symptom presentation. CONCLUSION: The psychometric properties of the SACSI-C are satisfactory and could be used to assess acute coronary syndromes symptomatology in Chinese. PMID- 24142912 TI - Pharmacologic inhibition of the renal outer medullary potassium channel causes diuresis and natriuresis in the absence of kaliuresis. AB - The renal outer medullary potassium (ROMK) channel, which is located at the apical membrane of epithelial cells lining the thick ascending loop of Henle and cortical collecting duct, plays an important role in kidney physiology by regulating salt reabsorption. Loss-of-function mutations in the human ROMK channel are associated with antenatal type II Bartter's syndrome, an autosomal recessive life-threatening salt-wasting disorder with mild hypokalemia. Similar observations have been reported from studies with ROMK knockout mice and rats. It is noteworthy that heterozygous carriers of Kir1.1 mutations associated with antenatal Bartter's syndrome have reduced blood pressure and a decreased risk of developing hypertension by age 60. Although selective ROMK inhibitors would be expected to represent a new class of diuretics, this hypothesis has not been pharmacologically tested. Compound A [5-(2-(4-(2-(4-(1H-tetrazol-1 yl)phenyl)acetyl)piperazin-1-yl)ethyl)isobenzofuran-1(3H)-one)], a potent ROMK inhibitor with appropriate selectivity and characteristics for in vivo testing, has been identified. Compound A accesses the channel through the cytoplasmic side and binds to residues lining the pore within the transmembrane region below the selectivity filter. In normotensive rats and dogs, short-term oral administration of compound A caused concentration-dependent diuresis and natriuresis that were comparable to hydrochlorothiazide. Unlike hydrochlorothiazide, however, compound A did not cause any significant urinary potassium losses or changes in plasma electrolyte levels. These data indicate that pharmacologic inhibition of ROMK has the potential for affording diuretic/natriuretic efficacy similar to that of clinically used diuretics but without the dose-limiting hypokalemia associated with the use of loop and thiazide-like diuretics. PMID- 24142913 TI - The pathway to diagnosis of dementia for francophones living in a minority situation. AB - PURPOSE OF THE STUDY: As the prevalence of dementia increases, the pressure to make early diagnoses also increases. Although patients must be able to identify the symptoms to access appropriate services, they may not be equally accessible to all citizens in a multicultural society. Health care professionals and patients may lack a common "first language." This study explores the experience of francophone persons with dementia (PWD) and their caregivers during the peri diagnostic period. DESIGN AND METHODS: Individual interviews were undertaken to elicit information regarding symptoms, the role of the family and friends, and the access to formal services. Seven PWD and their caregivers who spoke French as their primary language but who lived in a primarily English-speaking region completed the interviews. RESULTS AND IMPLICATIONS: No single symptom seemed sufficient to alert participants that dementia might be present. Participants communicated that there was a dire need to inform the public about the signs of dementia; they spoke of the role of the family physician and the importance of having a long-standing relationship with a health professional. For some, having similar personal characteristics, such as language and culture, might accentuate the strength of the relationship and facilitate the process of diagnosis. PMID- 24142907 TI - Morphological and molecular analyses of fungal endophytes of achlorophyllous gametophytes of Diphasiastrum alpinum (Lycopodiaceae). AB - PREMISE OF THE STUDY: To understand the early evolution of mycorrhizal symbioses, it is important to know the fungal partners of gametophytes and sporophytes for basal lineages of vascular plants. Subterranean mycotrophic gametophytes of the clubmoss Diphasiastrum alpinum found at three localities gave an opportunity to study their morphology and anatomy and to identify and describe their hitherto unknown fungal endophytes. In addition, sporophytes were screened for fungal partners. METHODS: Gametophytes with attached young sporophytes were excavated, and their anatomy and their associated fungi were studied by light microscopy. DNA was isolated and amplified with both universal and group-specific fungal primers for the ITS region, the large subunit and small subunit of the nuclear rDNA, respectively, to identify the fungal partner. KEY RESULTS: Gametophytes were uniformly colonized by a fungus with septate hyphae forming coils and vesicles. Its morphology resembles that of the sebacinoid genus Piriformospora. Both ITS and LSU sequences were identified as Sebacinales group B, a basal clade of the Agaricomycetes (Basidiomycota). This fungus was detected in 11 gametophytes from two localities and in rootlets of adjacent Calluna vulgaris (Ericaceae) plants, but was absent in roots of sporophytes. In addition, several ascomycetes and glomeromycetes were found by DNA sequencing. CONCLUSIONS: Our study suggests a fungus belonging to Sebacinales group B as the main fungal host of the D. alpinum gametophytes. However, Sebacinales group B fungi occur as well in adjacent Ericaceae plants; therefore, we assume the mycoheterotrophic gametophyte to be epiparasitic on Ericaceae, which would explain the steady association of these plants. PMID- 24142914 TI - The convoy model: explaining social relations from a multidisciplinary perspective. AB - PURPOSE OF THE STUDY: Social relations are a key aspect of aging and the life course. In this paper, we trace the scientific origins of the study of social relations, focusing in particular on research grounded in the convoy model. DESIGN AND METHODS: We first briefly review and critique influential historical studies to illustrate how the scientific study of social relations developed. Next, we highlight early and current findings grounded in the convoy model that have provided key insights into theory, method, policy, and practice in the study of aging. RESULTS: Early social relations research, while influential, lacked the combined approach of theoretical grounding and methodological rigor. Nevertheless, previous research findings, especially from anthropology, suggested the importance of social relations in the achievement of positive outcomes. Considering both life span and life course perspectives and grounded in a multidisciplinary perspective, the convoy model was developed to unify and consolidate scattered evidence while at the same time directing future empirical and applied research. Early findings are summarized, current evidence presented, and future directions projected. IMPLICATIONS: The convoy model has provided a useful framework in the study of aging, especially for understanding predictors and consequences of social relations across the life course. PMID- 24142915 TI - Estimated rate of reactivation of latent tuberculosis infection in the United States, overall and by population subgroup. AB - We estimated the rate of reactivation tuberculosis (TB) in the United States, overall and by population subgroup, using data on TB cases and Mycobacterium tuberculosis isolate genotyping reported to the Centers for Disease Control and Prevention during 2006-2008. The rate of reactivation TB was defined as the number of non-genotypically clustered TB cases divided by the number of person years at risk for reactivation due to prevalent latent TB infection (LTBI). LTBI was ascertained from tuberculin skin tests given during the 1999-2000 National Health and Nutrition Examination Survey. Clustering of TB cases was determined using TB genotyping data collected by the Centers for Disease Control and Prevention and analyzed via spatial scan statistic. Of the 39,920 TB cases reported during 2006-2008, 79.7% were attributed to reactivation. The overall rate of reactivation TB among persons with LTBI was estimated as 0.084 (95% confidence interval (CI): 0.083, 0.085) cases per 100 person-years. Rates among persons with and without human immunodeficiency virus coinfection were 1.82 (95% CI: 1.74, 1.89) and 0.073 (95% CI: 0.070, 0.075) cases per 100 person-years, respectively. The rate of reactivation TB among persons with LTBI was higher among foreign-born persons (0.098 cases/100 person-years; 95% CI: 0.096, 0.10) than among persons born in the United States (0.082 cases/100 person-years; 95% CI: 0.080, 0.083). Differences in rates of TB reactivation across subgroups support current recommendations for targeted testing and treatment of LTBI. PMID- 24142916 TI - Parkinson's disease and cancer: A register-based family study. AB - We wanted to compare cancer incidence rates between Parkinson's disease (PD) patients and persons without PD, as well as between siblings of these groups. We conducted a family-based matched cohort study based on nationwide Swedish health registries and the Swedish Multi-Generation Register. We assessed risk of incident cancer in PD patients (n = 11,786) during 1964-2009 versus a matched cohort of PD-free individuals (n = 58,930) and in siblings of PD patients (n = 16,841) versus siblings of PD-free individuals (n = 84,205). Hazard ratios with 95% confidence intervals were estimated using Cox proportional hazards regression. Cancer occurrence was slightly higher in PD patients than in PD-free individuals (hazard ratio (HR) = 1.05, 95% confidence interval (CI): 1.00, 1.10), largely because of cancers arising within 1 year before or after the index date for PD, but risk of smoking-related cancers was lower (HR = 0.87, 95% CI: 0.79, 0.96). PD patients had a higher risk of melanoma both up to 1 year before the PD index date (HR = 1.53, 95% CI: 1.23, 1.91) and from 1 year after the index date onward (HR = 1.46, 95% CI: 1.01, 2.10). In the sibling comparison, cancer occurrence was largely similar. These results indicate that melanoma risk is higher among PD patients and that mechanisms other than familial ones explain the association. PMID- 24142917 TI - Prenatal diethylstilbestrol exposure and risk of uterine leiomyomata in the Nurses' Health Study II. AB - Previous studies evaluating the association of prenatal exposure to diethylstilbestrol (DES), a potent endocrine disruptor, with incidence of uterine leiomyomata (UL) have had conflicting results. We evaluated the association between prenatal DES exposure and incident UL in women in the Nurses' Health Study II from 1989 to 2009. Women were aged 25-42 years at enrollment and had a prenatal exposure window corresponding to DES use. The analytical sample was larger than previous studies and included 102,164 premenopausal women with intact uteri, no prior history of UL or cancer, and prenatal DES exposure. Multivariable adjusted Cox proportional hazard models were used to estimate the relationship between DES exposure and UL risk. During 1,273,342 person-years of follow-up, there were 11,831 incident cases of UL. Women with prenatal exposure to DES had a higher incidence of UL compared with unexposed women, with an adjusted hazard ratio of 1.12 (95% confidence interval: 0.98, 1.27). Risk was strongest for women exposed to DES in the first trimester, when exposure corresponds to early stages of fetal Mullerian development (adjusted hazard ratio = 1.21, 95% confidence interval: 1.02, 1.43). These results suggest that first-trimester DES exposure may be associated with an increased risk of UL, but they must be interpreted with concern for detection and recall biases. PMID- 24142918 TI - Association between unprotected ultraviolet radiation exposure and recurrence of ocular herpes simplex virus. AB - Studies have suggested that exposure to ultraviolet (UV) light may increase risk of herpes simplex virus (HSV) recurrence. Between 1993 and 1997, the Herpetic Eye Disease Study (HEDS) randomized 703 participants with ocular HSV to receipt of acyclovir or placebo for prevention of ocular HSV recurrence. Of these, 308 HEDS participants (48% female and 85% white; median age, 49 years) were included in a nested study of exposures thought to cause recurrence and were followed for up to 15 months. We matched weekly UV index values from the National Oceanic and Atmospheric Administration to each participant's study center and used marginal structural Cox models to account for time-varying psychological stress and contact lens use and selection bias from dropout. There were 44 recurrences of ocular HSV, yielding an incidence of 4.3 events per 1,000 person-weeks. Weighted hazard ratios comparing persons with >=8 hours of time outdoors to those with less exposure were 0.84 (95% confidence interval (CI): 0.27, 2.63) and 3.10 (95% CI: 1.14, 8.48) for weeks with a UV index of <4 and >=4, respectively (ratio of hazard ratios = 3.68, 95% CI: 0.43, 31.4). Though results were imprecise, when the UV index was higher (i.e., >=4), spending 8 or more hours per week outdoors was associated with increased risk of ocular HSV recurrence. PMID- 24142919 TI - Evolutionary history of the Afro-Madagascan Ixora species (Rubiaceae): species diversification and distribution of key morphological traits inferred from dated molecular phylogenetic trees. AB - BACKGROUND AND AIMS: Previous work on the pantropical genus Ixora has revealed an Afro-Madagascan clade, but as yet no study has focused in detail on the evolutionary history and morphological trends in this group. Here the evolutionary history of Afro-Madagascan Ixora spp. (a clade of approx. 80 taxa) is investigated and the phylogenetic trees compared with several key morphological traits in taxa occurring in Madagascar. METHODS: Phylogenetic relationships of Afro-Madagascan Ixora are assessed using sequence data from four plastid regions (petD, rps16, rpoB-trnC and trnL-trnF) and nuclear ribosomal external transcribed spacer (ETS) and internal transcribed spacer (ITS) regions. The phylogenetic distribution of key morphological characters is assessed. Bayesian inference (implemented in BEAST) is used to estimate the temporal origin of Ixora based on fossil evidence. KEY RESULTS: Two separate lineages of Madagascan taxa are recovered, one of which is nested in a group of East African taxa. Divergence in Ixora is estimated to have commenced during the mid Miocene, with extensive cladogenesis occurring in the Afro-Madagascan clade during the Pliocene onwards. CONCLUSIONS: Both lineages of Madagascan Ixora exhibit morphological innovations that are rare throughout the rest of the genus, including a trend towards pauciflorous inflorescences and a trend towards extreme corolla tube length, suggesting that the same ecological and selective pressures are acting upon taxa from both Madagascan lineages. Novel ecological opportunities resulting from climate-induced habitat fragmentation and corolla tube length diversification are likely to have facilitated species radiation on Madagascar. PMID- 24142920 TI - Corolla morphology influences diversification rates in bifid toadflaxes (Linaria sect. Versicolores). AB - BACKGROUND AND AIMS: The role of flower specialization in plant speciation and evolution remains controversial. In this study the evolution of flower traits restricting access to pollinators was analysed in the bifid toadflaxes (Linaria sect. Versicolores), a monophyletic group of ~30 species and subspecies with highly specialized corollas. METHODS: A time-calibrated phylogeny based on both nuclear and plastid DNA sequences was obtained using a coalescent-based method, and flower morphology was characterized by means of morphometric analyses. Directional trends in flower shape evolution and trait-dependent diversification rates were jointly analysed using recently developed methods, and morphological shifts were reconstructed along the phylogeny. Pollinator surveys were conducted for a representative sample of species. KEY RESULTS: A restrictive character state (narrow corolla tube) was reconstructed in the most recent common ancestor of Linaria sect. Versicolores. After its early loss in the most species-rich clade, this character state has been convergently reacquired in multiple lineages of this clade in recent times, yet it seems to have exerted a negative influence on diversification rates. Comparative analyses and pollinator surveys suggest that the narrow- and broad-tubed flowers are evolutionary optima representing divergent strategies of pollen placement on nectar-feeding insects. CONCLUSIONS: The results confirm that different forms of floral specialization can lead to dissimilar evolutionary success in terms of diversification. It is additionally suggested that opposing individual-level and species-level selection pressures may have driven the evolution of pollinator-restrictive traits in bifid toadflaxes. PMID- 24142921 TI - Identification and characterization of FGF2-dependent mRNA: microRNA networks during lens fiber cell differentiation. AB - MicroRNAs (miRNAs) and fibroblast growth factor (FGF) signaling regulate a wide range of cellular functions, including cell specification, proliferation, migration, differentiation, and survival. In lens, both these systems control lens fiber cell differentiation; however, a possible link between these processes remains to be examined. Herein, the functional requirement for miRNAs in differentiating lens fiber cells was demonstrated via conditional inactivation of Dicer1 in mouse (Mus musculus) lens. To dissect the miRNA-dependent pathways during lens differentiation, we used a rat (Rattus norvegicus) lens epithelial explant system, induced by FGF2 to differentiate, followed by mRNA and miRNA expression profiling. Transcriptome and miRNome analysis identified extensive FGF2-regulated cellular responses that were both independent and dependent on miRNAs. We identified 131 FGF2-regulated miRNAs. Seventy-six of these miRNAs had at least two in silico predicted and inversely regulated target mRNAs. Genes modulated by the greatest number of FGF-regulated miRNAs include DNA-binding transcription factors Nfib, Nfat5/OREBP, c-Maf, Ets1, and N-Myc. Activated FGF signaling influenced bone morphogenetic factor/transforming growth factor-beta, Notch, and Wnt signaling cascades implicated earlier in lens differentiation. Specific miRNA:mRNA interaction networks were predicted for c-Maf, N-Myc, and Nfib (DNA-binding transcription factors); Cnot6, Cpsf6, Dicer1, and Tnrc6b (RNA to miRNA processing); and Ash1l, Med1/PBP, and Kdm5b/Jarid1b/Plu1 (chromatin remodeling). Three miRNAs, including miR-143, miR-155, and miR-301a, down regulated expression of c-Maf in the 3'-UTR luciferase reporter assays. These present studies demonstrate for the first time global impact of activated FGF signaling in lens cell culture system and predicted novel gene regulatory networks connected by multiple miRNAs that regulate lens differentiation. PMID- 24142923 TI - Saccharomyces cerevisiae genes involved in survival of heat shock. AB - The heat-shock response in cells, involving increased transcription of a specific set of genes in response to a sudden increase in temperature, is a highly conserved biological response occurring in all organisms. Despite considerable attention to the processes activated during heat shock, less is known about the role of genes in survival of a sudden temperature increase. Saccharomyces cerevisiae genes involved in the maintenance of heat-shock resistance in exponential and stationary phase were identified by screening the homozygous diploid deletants in nonessential genes and the heterozygous diploid mutants in essential genes for survival after a sudden shift in temperature from 30 to 50 degrees . More than a thousand genes were identified that led to altered sensitivity to heat shock, with little overlap between them and those previously identified to affect thermotolerance. There was also little overlap with genes that are activated or repressed during heat-shock, with only 5% of them regulated by the heat-shock transcription factor. The target of rapamycin and protein kinase A pathways, lipid metabolism, vacuolar H(+)-ATPase, vacuolar protein sorting, and mitochondrial genome maintenance/translation were critical to maintenance of resistance. Mutants affected in l-tryptophan metabolism were heat shock resistant in both growth phases; those affected in cytoplasmic ribosome biogenesis and DNA double-strand break repair were resistant in stationary phase, and in mRNA catabolic processes in exponential phase. Mutations affecting mitochondrial genome maintenance were highly represented in sensitive mutants. The cell division transcription factor Swi6p and Hac1p involved in the unfolded protein response also play roles in maintenance of heat-shock resistance. PMID- 24142922 TI - Immune-related functions of the Hivep gene family in East African cichlid fishes. AB - Immune-related genes are often characterized by adaptive protein evolution. Selection on immune genes can be particularly strong when hosts encounter novel parasites, for instance, after the colonization of a new habitat or upon the exploitation of vacant ecological niches in an adaptive radiation. We examined a set of new candidate immune genes in East African cichlid fishes. More specifically, we studied the signatures of selection in five paralogs of the human immunodeficiency virus type I enhancer-binding protein (Hivep) gene family, tested their involvement in the immune defense, and related our results to explosive speciation and adaptive radiation events in cichlids. We found signatures of long-term positive selection in four Hivep paralogs and lineage specific positive selection in Hivep3b in two radiating cichlid lineages. Exposure of the cichlid Astatotilapia burtoni to a vaccination with Vibrio anguillarum bacteria resulted in a positive correlation between immune response parameters and expression levels of three Hivep loci. This work provides the first evidence for a role of Hivep paralogs in teleost immune defense and links the signatures of positive selection to host-pathogen interactions within an adaptive radiation. PMID- 24142924 TI - Genome of Drosophila suzukii, the spotted wing drosophila. AB - Drosophila suzukii Matsumura (spotted wing drosophila) has recently become a serious pest of a wide variety of fruit crops in the United States as well as in Europe, leading to substantial yearly crop losses. To enable basic and applied research of this important pest, we sequenced the D. suzukii genome to obtain a high-quality reference sequence. Here, we discuss the basic properties of the genome and transcriptome and describe patterns of genome evolution in D. suzukii and its close relatives. Our analyses and genome annotations are presented in a web portal, SpottedWingFlyBase, to facilitate public access. PMID- 24142925 TI - Divergence of iron metabolism in wild Malaysian yeast. AB - Comparative genomic studies have reported widespread variation in levels of gene expression within and between species. Using these data to infer organism-level trait divergence has proven to be a key challenge in the field. We have used a wild Malaysian population of S. cerevisiae as a test bed in the search to predict and validate trait differences based on observations of regulatory variation. Malaysian yeast, when cultured in standard medium, activated regulatory programs that protect cells from the toxic effects of high iron. Malaysian yeast also showed a hyperactive regulatory response during culture in the presence of excess iron and had a unique growth defect in conditions of high iron. Molecular validation experiments pinpointed the iron metabolism factors AFT1, CCC1, and YAP5 as contributors to these molecular and cellular phenotypes; in genome-scale sequence analyses, a suite of iron toxicity response genes showed evidence for rapid protein evolution in Malaysian yeast. Our findings support a model in which iron metabolism has diverged in Malaysian yeast as a consequence of a change in selective pressure, with Malaysian alleles shifting the dynamic range of iron response to low-iron concentrations and weakening resistance to extreme iron toxicity. By dissecting the iron scarcity specialist behavior of Malaysian yeast, our work highlights the power of expression divergence as a signpost for biologically and evolutionarily relevant variation at the organismal level. Interpreting the phenotypic relevance of gene expression variation is one of the primary challenges of modern genomics. PMID- 24142926 TI - Genotype to phenotype maps: multiple input abiotic signals combine to produce growth effects via attenuating signaling interactions in maize. AB - The complexity of allele interactions constrains crop improvement and the prediction of disease susceptibility. Additive allele effects are the foundation for selection in animal and plant breeding, and complex genetic and environmental interactions contribute to inefficient detection of desirable loci. Manipulation and modeling of other sources of variation, such as environmental variables, have the potential to improve our prediction of phenotype from genotype. As an example of our approach to analysis of the network linking environmental input to alleles, we mapped the genetic architecture of single and combined abiotic stress responses in two maize mapping populations and compared the observed genetic architecture patterns to simple theoretical predictions. Comparisons of single and combined stress effects on growth and biomass traits exhibit patterns of allele effects that suggest attenuating interactions among physiological signaling steps in drought and ultraviolet radiation stress responses. The presence of attenuating interactions implies that shared QTL found in sets of environments could be used to group environment types and identify underlying environmental similarities, and that patterns of stress-dependent genetic architecture should be studied as a way to prioritize prebreeding populations. A better understanding of whole-plant interactor pathways and genetic architecture of multiple-input environmental signaling has the potential to improve the prediction of genomic value in plant breeding and crop modeling. PMID- 24142927 TI - STAT3 targets suggest mechanisms of aggressive tumorigenesis in diffuse large B cell lymphoma. AB - The signal transducer and activator of transcription 3 (STAT3) is a transcription factor that, when dysregulated, becomes a powerful oncogene found in many human cancers, including diffuse large B-cell lymphoma. Diffuse large B-cell lymphoma is the most common form of non-Hodgkin's lymphoma and has two major subtypes: germinal center B-cell-like and activated B-cell-like. Compared with the germinal center B-cell-like form, activated B-cell-like lymphomas respond much more poorly to current therapies and often exhibit overexpression or overactivation of STAT3. To investigate how STAT3 might contribute to this aggressive phenotype, we have integrated genome-wide studies of STAT3 DNA binding using chromatin immunoprecipitation-sequencing with whole-transcriptome profiling using RNA sequencing. STAT3 binding sites are present near almost a third of all genes that differ in expression between the two subtypes, and examination of the affected genes identified previously undetected and clinically significant pathways downstream of STAT3 that drive oncogenesis. Novel treatments aimed at these pathways may increase the survivability of activated B-cell-like diffuse large B cell lymphoma. PMID- 24142928 TI - Regulation of gene expression in Neurospora crassa with a copper responsive promoter. AB - Precise control of gene expression is a powerful method to elucidate biological function, and protein overexpression is an important tool for industry and biochemistry. Expression of the Neurospora crassa tcu-1 gene (NCU00830), encoding a high-affinity copper transporter, is tightly controlled by copper availability. Excess copper represses, and copper depletion, via the use of a copper chelator, activates expression. The kinetics of induction and repression of tcu-1 are rapid, and the effects are long lived. We constructed a plasmid carrying the bar gene (for glufosinate selection) fused to the tcu-1 promoter. This plasmid permits the generation of DNA fragments that can direct integration of Ptcu-1 into any desired locus. We use this strategy to integrate Ptcu-1 in front of wc 1, a circadian oscillator and photoreceptor gene. The addition of excess copper to the Ptcu-1::wc-1 strain phenocopies a Deltawc-1 strain, and the addition of the copper chelator, bathocuproinedisulfonic acid, phenocopies a wc-1 overexpression strain. To test whether copper repression can recapitulate the loss of viability that an essential gene knockout causes, we placed Ptcu-1 upstream of the essential gene, hpt-1. The addition of excess copper drastically reduced the growth rate as expected. Thus, this strategy will be useful to probe the biological function of any N. crassa gene through controlled expression. PMID- 24142929 TI - Mated progeny production is a biomarker of aging in Caenorhabditis elegans. AB - The relationships between reproduction and aging are important for understanding the mechanisms of aging and evaluating evolutionary theories of aging. To investigate the effects of progeny production on reproductive and somatic aging, we conducted longitudinal studies of Caenorhabditis elegans hermaphrodites. For mated wild-type animals that were not sperm limited and survived past the end of the reproductive period, high levels of cross-progeny production were positively correlated with delayed reproductive and somatic aging. In this group of animals, individuals that generated more cross progeny also reproduced and lived longer than individuals that generated fewer cross progeny. These results indicate that progeny production does not accelerate reproductive or somatic aging. This longitudinal study demonstrated that cumulative cross progeny production through day four is an early-stage biomarker that is a positive predictor of longevity. Furthermore, in mated animals, high levels of early cross progeny production were positively correlated with high levels of late cross progeny production, indicating that early progeny production does not accelerate reproductive aging. The relationships between progeny production and aging were further evaluated by comparing self-fertile hermaphrodites that generated relatively few self progeny with mated hermaphrodites that generated many cross progeny. The timing of age related somatic degeneration was similar in these groups, suggesting progeny production does not accelerate somatic aging. These studies rigorously define relationships between progeny production, reproductive aging, and somatic aging and identify new biomarkers of C. elegans aging. These results indicate that some mechanisms or pathways control age-related degeneration of both reproductive and somatic tissues in C. elegans. PMID- 24142930 TI - Manufactured nano-objects: an occupational survey in five industries in France. AB - Manufactured nano-objects (MNO) are being increasingly used in industry, and, given their particular properties, it is therefore necessary to assess the risks linked to their production and use in industrial settings. We describe a survey conducted in France, in five industries concerned with the production of inks, paints, plastics, and the production of raw nano materials. In 2009, a questionnaire was posted to each of the 993 French establishments in these industries. Of the 464 (47%) establishments that responded, 87 indicated that they were producing or using MNO at that time. The results reveal that in the five industries, MNO are generally produced in large quantities by a small number of establishments but are used in smaller amounts by a greater number of establishments. The population of workers exposed to MNO in user establishments is estimated to be ~3000 in the industries surveyed. The protective measures implemented in establishments producing or using MNO differ according to the scale of production and/or use and are sometimes inadequate given the nature of the potential risks. It is therefore necessary to inform users of the presence of MNO in raw materials (through labelling and material safety data sheets MSDS) and to make recommendations as to the collective protective measures that should be implemented. PMID- 24142932 TI - Local responses to trauma: symptom, affect, and healing. AB - This article provides an introduction to the thematic issue of Transcultural Psychiatry on local responses to trauma. To illustrate how local responses to trauma may be therapeutic, we consider the multiple dimensions or domains that may be targeted by healing rituals and interventions. We then outline a theoretical model of the generation of trauma-related symptoms and distress. We present the multiplex model of symptom generation which posits multiple cognitive, social, and physiological mechanisms by which various triggers can lead to severe distress among trauma victims in acute episodes, and which may be targeted in treatment. More persistent forms of distress can be explained in terms of the effects of persistent mood states and associated modes of cognitive processing and behavior that render individuals vulnerable to chronic symptoms and acute exacerbations. The beneficial effects of healing rituals and interventions may occur, in part, by inducing positive affective states associated with a flexible mind-set. We conclude by summarizing some of the contributions of the papers in this issue to understanding local therapeutic processes of healing. PMID- 24142933 TI - Children enacting idioms of witchcraft and spirit possession as a response to trauma: therapeutically beneficial, and for whom? AB - This article examines children's enactment of spirit possession idioms and witchcraft in Africa including the meanings such idioms provide and the local healing resources they mobilize. Idioms of haunting spirits in Northern Uganda and witch-children elsewhere in Africa can be interpreted as manifestations of social crises and mass traumatic stress. On the other hand, such idioms also allow children to articulate, reflect upon, and communicate the complex feelings resulting from their precarious positions within families and communities under duress. With the help of Dow's transactional model of symbolic healing, this article explores obstacles to the effectivity of the rich variety of symbolic healing available for haunting spirits in Uganda and points to the generational gap between children and their families and communities. Elsewhere, witchcraft idioms may act as a healing resource at the group level, but at the expense of the accused child. The idioms of evil spirits and witchcraft speak of these children's navigation of the moral universe of their postconflict communities. Given that children's appraisal of their experiences through these notions may also exacerbate their anxiety, interdisciplinary research examining the microprocesses that lead to children being haunted or accused, including emotional and physiological levels effects, is urgently needed. PMID- 24142934 TI - Perspectives on trauma and healing from anthropology and social and affective neuroscience. PMID- 24142935 TI - Back from the edge of existence: a critical anthropology of trauma. PMID- 24142936 TI - Asthma complicated by severe subcutaneous emphysema. PMID- 24142937 TI - Accurate data on all injury deaths is vital for monitoring suicide prevention. PMID- 24142938 TI - Technology transfer from biomedical research to clinical practice: measuring innovation performance. AB - Studies documented 17 years of transfer time from clinical trials to practice of care. Launched in 2002, the National Institutes of Health (NIH) translational research initiative needs to develop metrics for impact assessment. A recent White House report highlighted that research and development productivity is declining as a result of increased research spending while the new drugs output is flat. The goal of this study was to develop an expanded model of research based innovation and performance thresholds of transfer from research to practice. Models for transfer of research to practice have been collected and reviewed. Subsequently, innovation pathways have been specified based on common characteristics. An integrated, intellectual property transfer model is described. The central but often disregarded role of research innovation disclosure is highlighted. Measures of research transfer and milestones of progress have been identified based on the Association of University Technology Managers 2012 performance reports. Numeric milestones of technology transfer are recommended at threshold (top 50%), target (top 25%), and stretch goal (top 10%) performance levels. Transfer measures and corresponding target levels include research spending to disclosure (<$1.88 million), disclosure to patents (>0.81), patents to start-up (>0.1), patents to licenses (>2.25), and average per license income (>$48,000). Several limitations of measurement are described. Academic institutions should take strategic steps to bring innovation to the center of scholarly discussions. Research on research, particularly on pathways to disclosures, is needed to improve R&D productivity. Researchers should be informed about the technology transfer performance of their institution and regulations should better support innovators. PMID- 24142941 TI - The Health Committee produces a pearler. PMID- 24142942 TI - Towards evidence-based emergency medicine: best BETs from the Manchester Royal Infirmary. BET 1: excited delirium syndrome and sudden death. AB - A short-cut review was carried out to establish whether morbidity and mortality from excited delirium syndrome (EXDS) can be predicted in the emergency department (ED). Seventy-three papers were found of which 11 presented the best evidence to answer the clinical question. The author, date and country of publication, patient group studied, study type, relevant outcomes, results and study weaknesses of these best papers are shown in table 1. The clinical bottom line is that the early recognition of EXDS remains paramount as patients may have sudden cardiovascular collapse with little warning. Several authors do describe laboured respiratory efforts before death, so prompt airway and haemodynamic control may be necessary. Patients may benefit from chemical rather than physical restraint. Acidosis and hyperthermia should also be aggressively managed. Law enforcement and prehospital personnel should also be educated regarding potential complications of EXDS. PMID- 24142944 TI - Towards evidence-based emergency medicine: best BETs from the Manchester Royal Infirmary. BET 2: do parents of children with allergic reactions know how to use adrenaline autoinjectors appropriately? AB - A short-cut review was carried out to establish whether the parents of children with anaphylaxis are proficient in the use of autoinjectors. Seven hundred and three papers were found of which nine presented the best evidence to answer the clinical question. The author, date and country of publication, patient group studied, study type, relevant outcomes, results and study weaknesses of these best papers are shown in table 2. The clinical bottom line is that competence varies widely and that further efforts are required to train and monitor training outcomes. PMID- 24142945 TI - Towards evidence-based emergency medicine: best BETs from the Manchester Royal Infirmary. BET 3: do doctors know how to use adrenaline autoinjectors correctly? AB - A short-cut review was carried out to establish whether doctors know how to use autoinjectors (for anaphylaxis). Three hundred and twenty-four papers were found of which five presented the best evidence to answer the clinical question. The author, date and country of publication, patient group studied, study type, relevant outcomes, results and study weaknesses of these best papers are shown in table 3. The clinical bottom line is that the majority of doctors studied are unable to use autoinjectors correctly and may therefore be unable to teach patients or parents effectively. PMID- 24142946 TI - Towards evidence-based emergency medicine: best BETs from the Manchester Royal Infirmary. BET 4: does size matter? Chest drains in haemothorax following trauma. AB - A short-cut review was carried out to establish whether the size of chest drain inserted is important in haemothoraces. Forty-nine papers were found of which four presented the best evidence to answer the clinical question. The author, date and country of publication, patient group studied, study type, relevant outcomes, results and study weaknesses of these best papers are shown in table 4. The clinical bottom line is that while the available evidence suggests that small bore drains may be as effective as large bore drains in resolving traumatic haemothoraces without additional complications, there is insufficient evidence currently available to recommend a change to standard practice (ie, large bore drains). PMID- 24142947 TI - Guidelines in Emergency Medicine Network (GEMNet): guideline for the use of thromboprophylaxis in ambulatory trauma patients requiring temporary limb immobilisation. AB - The Guidelines in Emergency Medicine Network (GEMNet) has been created to promote best medical practice in a range of conditions presenting to emergency departments (EDs) in the UK. This guideline presents a summary of the best available evidence to guide the use of thromboprophylaxis in adult ambulatory outpatients who present to the ED following acute limb trauma and require temporary immobilisation. The document has been developed following discussion among emergency physicians and collegiate fellows to decide which topics would benefit from the development of clinical guidelines. The document is intended as a guideline for use in the ED by emergency physicians and is based on the review of the best existing evidence for treatments used in this setting. The document is summarised as a Clinical Decision Support Guideline that has been presented as an easy to follow algorithm. The intention is for each guideline to be updated and reviewed as further evidence becomes available. The formal revision date has been set at 5 years from publication, though the guideline is subject to continuous informal review. PMID- 24142949 TI - Staged calcaneus osteocutaneous filet flap for salvage of transtibial amputation. PMID- 24142950 TI - PEAR: a fast and accurate Illumina Paired-End reAd mergeR. AB - MOTIVATION: The Illumina paired-end sequencing technology can generate reads from both ends of target DNA fragments, which can subsequently be merged to increase the overall read length. There already exist tools for merging these paired-end reads when the target fragments are equally long. However, when fragment lengths vary and, in particular, when either the fragment size is shorter than a single end read, or longer than twice the size of a single-end read, most state-of-the art mergers fail to generate reliable results. Therefore, a robust tool is needed to merge paired-end reads that exhibit varying overlap lengths because of varying target fragment lengths. RESULTS: We present the PEAR software for merging raw Illumina paired-end reads from target fragments of varying length. The program evaluates all possible paired-end read overlaps and does not require the target fragment size as input. It also implements a statistical test for minimizing false-positive results. Tests on simulated and empirical data show that PEAR consistently generates highly accurate merged paired-end reads. A highly optimized implementation allows for merging millions of paired-end reads within a few minutes on a standard desktop computer. On multi-core architectures, the parallel version of PEAR shows linear speedups compared with the sequential version of PEAR. AVAILABILITY AND IMPLEMENTATION: PEAR is implemented in C and uses POSIX threads. It is freely available at http://www.exelixis lab.org/web/software/pear. PMID- 24142951 TI - Rape myth acceptance impacts the reporting of rape to the police: a study of incarcerated women. AB - We examined the association between rape myth acceptance (RMA) and reporting rapes to the police. Situational characteristics of the rape (e.g., stranger attack, injury) are known predictors of reporting, but no existing studies have examined the association between beliefs about rape and reporting. In addition, most studies of RMA do not assess victimization history. Incarcerated women experience high rates of sexual assaults prior to incarceration. We recruited 74 rape survivors from a northwestern state prison. Results suggest that women who endorsed higher levels of RMA were less likely to report their rapes to police; however, participants endorsed few rape myths. PMID- 24142952 TI - The impact of offenders leaving the scene on the police decision to arrest in cases of intimate partner violence. AB - In this article, the authors examine an issue that has not been studied in depth by prior research: the impact that fleeing the scene has on the likelihood of arrest in intimate partner violence cases. Using police data obtained from 25 police departments in four states, and controlling for a variety of incident, offender, victim, and jurisdictional characteristics, the authors find that an offender who flees the scene of the incident is more than 5 times less likely to be arrested than one who remains at the scene. The policy implications of the findings are discussed. PMID- 24142953 TI - Drawing the line: how African, Caribbean and White British women live out psychologically abusive experiences. AB - This study explores how African, Caribbean and White British women worked to hide psychological partner abuse as they experienced it, "do gender," and appear competent in social roles. They prioritized negotiated competencies as "good partners," actively setting socially and culturally embedded boundaries to their abuser's behaviors: an inner boundary encompassing normal behaviors and an outer one of "acceptable" behaviors projected as normal through remedial work. Behaviors breaching the outer boundary (e.g., if the women narrowed the bounds of the "acceptable") compromised the women's competence. This sometimes led them to actively use support services. Appropriate advice and support may change the boundaries. PMID- 24142954 TI - Frequency of intimate partner violence and rural women's mental health in four Indian states. AB - This study examines the association between self-reported frequency of verbal, physical, and sexual intimate partner violence (IPV) and mental health among 6,303 rural married women (age 15-49), in four Indian states: Bihar, Jharkhand, Maharashtra, and Tamil Nadu. Data are taken from the 2002-2003 National Family Health Survey-2 Follow-Up Survey. The results indicate that experiencing physical, verbal, or sexual IPV is associated with an increased risk of adverse mental health outcomes. Our results provide support for the importance of screening for IPV in mental health settings, especially in resource-poor settings where both IPV and mental health are often overlooked. PMID- 24142955 TI - Intimate partner violence and the relation between help-seeking behavior and the severity and frequency of physical violence among women in Turkey. AB - This study explores the severity and frequency of physical violence from an intimate partner experienced by 15- to 59-year-old women and their help-seeking behavior by using data from the "National Research on Domestic Violence Against Women in Turkey." Chi-square tests and logistic regression analyses were conducted to compare the relationship between severity and frequency of violence and women's characteristics. Of all ever-partnered women, 36% have been exposed to partner violence; almost half of these experienced severe types of violence. Women used informal strategies to manage the violence instead of seeking help from formal institutions. Help-seeking behavior increases with increased severity and frequency of violence. PMID- 24142956 TI - "Relationships so loving and so hurtful": the constructed duality of sexual and racial/ethnic intimacy in the context of violence in Asian and Pacific Islander lesbian and queer women's relationships. AB - Intimate partner violence (IPV) in Asian, Pacific Islander, and Native Hawaiian (APINH) queer women's and lesbian relationships was examined through interviews with 24 APINH respondents. Seven major themes were uncovered in the dynamics of intimate violence: (a) control, intimidation, and instilling fear; (b) "deep" emotional intimacy; (c) first, early, or rebound relationships; (d) sexual jealousy and possessiveness; (e) shame as a barrier; (f) limited social and potential partner networks; and (g) crossing/intersecting gender in the "butch" as victim. Study implications include expanding research on same-sex IPV focusing on the intersection of ethnicity, gender, and sexual identity. PMID- 24142957 TI - Open repair of inflammatory abdominal aortic aneurysm and aortocaval fistula using retrograde balloon occlusion. AB - PURPOSE: The purpose of this report is to describe a novel endovascular technique used to minimize blood loss during the open repair of an aortocaval fistula (ACF) in the context of an inflammatory abdominal aortic aneurysm (AAA). CASE REPORT: We describe a patient who presented to our hospital with a symptomatic infrarenal AAA which was discovered intraoperatively to contain a large ACF. The patient underwent successful transperitoneal open repair of the AAA with balloon occlusion of the inferior vena cava to obtain distal control of the vessel. CONCLUSIONS: Retrograde balloon occlusion of the inferior vena cava can be used to control hemorrhage during the open repair of an ACF, especially in the challenging setting of an inflammatory AAA. PMID- 24142958 TI - Assessing the perioperative safety of common femoral endarterectomy in the endovascular era. AB - INTRODUCTION: Common femoral endarterectomy (CFE) has historically been the preferred treatment for atherosclerotic lesions involving the common femoral artery. The objectives of this study are to delineate the safety of this open procedure in the endovascular era, establish contemporary benchmarks for morbidity and mortality after CFE, and identify the subgroup of patients at increased risk of postoperative adverse events. METHODS: Patients undergoing elective CFE in the 2007 to 2010 National Surgical Quality Improvement Project database were examined. Univariate analyses were used to identify the factors associated with major morbidity and mortality. Significant variables by univariate analysis were used to create multivariate logistic regression models for morbidity and mortality. RESULTS: A total of 1513 patients underwent elective CFE. The 30-day mortality rate was 1.5%. Postoperative morbidities included cardiac (1.0%), pulmonary (1.9%), renal (0.4%), urinary tract infection (1.7%), thromboembolic (0.5%), neurologic (0.4%), sepsis (2.7%), superficial (6.3%), and deep surgical site complications (2.0%). At least 1 complication, including major and minor, was seen in 7.9% of the patients. By multivariate analysis, partial- and total-dependent functional status (odds ratio [OR] 9.0, 95% confidence interval [CI] 2.8-28.4 and OR 21.3, 95% CI 3.3-139.4) and dyspnea at rest (OR 8.2, 95% 1.2-58.8) predicted mortality. Independent predictors of morbidity include steroid use (OR 2.4, 95% 1.4-4.1), diabetes (OR 1.8, 95% CI 1.3-2.4), and obesity (OR 1.6, 95% CI 1.1-2.4). DISCUSSION: Overall, CFE is tolerated well by the majority of patients with peripheral arterial disease. These results affirm the safety of CFE and can still be used as standard first-line therapy in most patients. Long-term results for endovascular interventions need to be studied to see whether high-risk patients that we identified for CFE would benefit more from an endovascular approach. PMID- 24142960 TI - Let's talk about culture! Experiencing a disco funeral in Western Kenya. PMID- 24142961 TI - Protein engineering of alpha2,3/2,6-sialyltransferase to improve the yield and productivity of in vitro sialyllactose synthesis. AB - In the large-quantity production of alpha2,3- and alpha2,6-sialyllactose (Neu5Ac(alpha2,3)Galbeta1,4Glc (3'-SL) and Neu5Ac(alpha2,6)Galbeta1,4Glc (6'-SL)) using sialyltransferases (STs), there are major hurdles to overcome for further improvement in yield and productivity of the enzyme reactions. Specifically, Pasteurella multocida alpha2,3-sialyltransferase (alpha2,3PST) forms a by-product to a certain extent, owing to its multifunctional activity at pH below 7.0, and Photobacterium damselae alpha2,6-sialyltransferase (alpha2,6PdST) shows relatively low ST activity. In this study, alpha2,3PST and alpha2,6PdST were successfully engineered using a hybrid approach that combines rational design with site-saturation mutagenesis. Narrowly focused on the substrate-binding pocket of the STs, putative functional residues were selected by multiple sequence alignment and alanine scanning, and subsequently subjected to site saturation mutagenesis. In the case of alpha2,3PST, R313N single mutation improved its activity slightly (by a factor of 1.5), and further improvement was obtained by making the double mutants (R313N/T265S and R313H/T265S) resulting in an overall 2-fold improvement in its specific alpha2,3 ST activity, which is mainly caused by the increase in kcat. It was revealed that the R313 mutations to N, D, Y, H or T greatly reduced the alpha2,6 ST side-reaction activity of alpha2,3PST at below pH 7.0. In the case of alpha2,6PdST, single-mutation L433S/T and double-mutation I411T/L433T exhibited 3- and 5-fold enhancement of the alpha2,6 ST-specific activity compared with the wild-type, respectively, via increase in kcat values. Our results show a very good model system for enhancing ST activity and demonstrate that the generated mutants could be used efficiently for the mass production of 3'-SL and 6'-SL with enhanced productivity and yield. PMID- 24142962 TI - The Bellamy challenge: it's about time. AB - In 1984, Col. Ronald Bellamy launched a worldwide challenge to develop a new resuscitation fluid to aid survival after catastrophic blood loss on the battlefield. In 1996, after careful compromise among need, cube weight and efficacy, the US military and later coalition forces adopted 6% hetastarch (HES) fluids for early resuscitation. In the intervening years, evidence has amassed indicating that the HES fluids may not be safe, and in June 2013 the US Food and Drug Administration issued a warning that HES solutions should not be used to treat patients with hypovolaemia or the critically ill. We review the unique challenges of early battlefield resuscitation, why the 'Bellamy challenge' remains open and discuss a number of forward-looking strategies that may help to solve the problem. The first two pillars of resuscitation that we believe have not been adequately addressed are rescuing and stabilising the heart (and brain) and the vascular system. The 'ideal' resuscitation fluid needs to nurture the heart and body slowly back to health, and not 'shock' it a second time with unnatural colloids or large volumes of unphysiological saline-based solutions. PMID- 24142964 TI - Chemokines in colitis: microRNA control. PMID- 24142965 TI - Interaction between preprandial and postprandial rectal sensory and motor abnormalities in IBS. AB - BACKGROUND AND AIMS: Rectal sensory and motor interactions in patients with IBS have not been studied in detail. The aim of this study was to evaluate fasting and postprandial rectal sensorimotor characteristics and their interactions in IBS compared with healthy controls. DESIGN: We included 274 patients with IBS and 34 controls. All subjects underwent a rectal barostat study before and 60 min after a standardised liquid meal (800 kcal; 60% fat). Sensory thresholds, intensity of sensations, viscerosomatic referral and compliance were measured. During 15 min before the first distension sequence and until 50 min after meal intake, rectal balloon volumes were registered in 5 min intervals at operating pressure to quantify rectal tone. Mixed models were used to analyse the rectal tone response over time. RESULTS: Rectal sensory thresholds and compliance were decreased and viscerosomatic referral areas increased in patients with IBS compared with controls. Meal intake increased rectal sensitivity, compliance and referral areas in patients and controls and the same proportions of patients were hypersensitive to distension before and after meal intake. There was a higher basal rectal tone in IBS and a significantly different rectal tone response after meal intake in patients with IBS compared with controls and, interestingly, also in IBS with rectal hypersensitivity (defined in the preprandial state), compared with normosensitive patients. CONCLUSIONS: Meal intake affects rectal sensorimotor function in IBS and health. Importantly, the rectal tone responses to a high-caloric meal are different between patients with IBS and controls, as well as between hypersensitive and normosensitive patients with IBS. PMID- 24142966 TI - Linac-based stereotactic radiosurgery and fractionated stereotactic radiotherapy for vestibular schwannomas: comparative observations of 139 patients treated at a single institution. AB - Stereotactic radiosurgery (SRS) and fractionated stereotactic radiotherapy (SRT) have been recognized as an alternative to surgery for small to medium sized vestibular schwannoma (VS). This study analysed and compared the outcomes of VS treated with the first Thailand installation of a dedicated Linac-based stereotactic radiation machine using single-fraction radiosurgery (SRS), hypofraction stereotactic radiotherapy (HSRT) and conventional fraction stereotactic radiotherapy (CSRT). From 1997 to 2010, a total of 139 consecutive patients with 146 lesions of VS were treated with X-Knife at Ramathibodi hospital, Bangkok, Thailand. SRS was selected for 39 lesions (in patients with small tumors <=3 cm and non-serviceable hearing function), whereas HSRT (79 lesions) and CSRT (28 lesions) were given for the remaining lesions that were not suitable for SRS. With a median follow-up time of 61 months (range, 12-143), the 5-year local control rate was 95, 100 and 95% in the SRS, HSRT and CSRT groups, respectively. Hearing preservation was observed after SRS in 75%, after HSRT in 87% and after CSRT in 63% of the patients. Cranial nerve complications were low in all groups. There were no statistically significant differences in local control, hearing preservation or complication between the treatment schedules. In view of our results, it may be preferable to use HSRT over CSRT for patients with serviceable hearing because of the shorter duration of treatment. PMID- 24142967 TI - A serial 4DCT study to quantify range variations in charged particle radiotherapy of thoracic cancers. AB - Weekly serial 4DCT scans were acquired under free breathing conditions to assess water-equivalent path length (WEL) variations due to both intrafractional and interfractional changes in tissue thickness and density and to calculate proton dose distributions resulting from anatomical variations observed in serial 4DCT. A template of region of interests (ROIs) was defined on the anterior-posterior (AP) beam's eye view, and WEL measurements were made over these ROIs to quantify chest wall thickness variations. Interfractional proton dose distributions were calculated to assess changes in the expected dose distributions caused by range variations. Mean intrafractional chest wall WEL changes during respiration varied by: -4.1 mm (<-10.2 mm), -3.6 mm (<-7.1 mm), -3.2 mm (<-5.6 mm) and -2.5 mm (< 5.1 mm) during respiration in the ITV, upper, middle and lower lung regions, respectively. The mean interfractional chest wall WEL variation at Week 6 decreased by -4.0 mm (<-8.6 mm), -9.1 mm (<-17.9 mm), -9.4 mm (<-25.3 mm) and 4.5 mm (<-15.6 mm) in the ITV, upper, middle and lower lung regions, respectively. The variations were decomposed into anterior and posterior chest wall thickness changes. Dose overshoot beyond the target was observed when the initial boli was applied throughout the treatment course. This overshoot is due to chest wall thickness variations and target positional variations. The radiological path length can vary significantly during respiration as well as over the course of several weeks of charged particle therapy. Intrafractional/interfractional chest wall thickness changes can be a significant source of range variation in treatment of lung tumors with charged particle beams, resulting in dose distribution perturbations from the initial plan. Consideration of these range variations should be made in choosing the therapeutic charged particle beam range. PMID- 24142968 TI - Development of a simple and rapid method of precisely identifying the position of 10B atoms in tissue: an improvement in standard alpha autoradiography. AB - Boron neutron capture therapy (BNCT) can be utilized to selectively kill cancer cells using a boron compound that accumulates only in cancer cells and not in normal cells. Tumor-bearing animals treated by BNCT are routinely used to evaluate long-term antitumor effects of new boron compounds. Alpha autoradiography is one of the methods employed in the evaluation of antitumor effects. However, a standard alpha-autoradiography cannot detect the microdistribution of (10)B because of the difficulty associated with the superposition of a tissue sample image and etched pits on a track detector with the etching process. In order to observe the microdistribution of (10)B, some special methods of alpha-autoradiography have been developed that make use of a special track detector, or the atomic force microscope combined with X-ray and UV light irradiation. In contrast, we propose, herein, a simple and rapid method of precisely identifying the position of (10)B using the imaging process and the shape of etched pits, such as their circularity, without the need to use special track detectors or a microscope. A brief description of this method and its verification test are presented in this article. We have established a method of detecting the microdistribution of (10)B with submicron deviation between the position of etched pits and the position of reaction in a tissue sample, for a given circularity of etched pits. PMID- 24142969 TI - Research into 'night shift work' and cancer: on the evolution of 'exposure' classification. PMID- 24142971 TI - Cholangiocarcinoma among workers in the printing industry. PMID- 24142970 TI - Air pollution and childhood leukaemia: a nationwide case-control study in Italy. AB - OBJECTIVES: Leukaemia is the most common cancer in children, but its aetiology is still poorly understood. We tested the hypothesis that traffic-related air pollution is associated with paediatric leukaemia because of chronic exposure to several potential carcinogens. METHODS: The Italian SETIL study (Study on the aetiology of lymphohematopoietic malignancies in children) was conducted in 14 Italian regions. All incident cases of leukaemia in children aged <=10 years from these regions (period 1998-2001) were eligible for enrolment. Two controls per case, matched on birth date, gender and region of residence were randomly selected from the local population registries. Exposure assessment at birth residence included traffic indicators (distance to main roads and length of main roads within 100 m) and estimates of pollutants concentrations (particulate matter -PM2.5 and PM10- and gases -NO2 and O3-) from national dispersion model and land use regression models. The association between the exposure variables and leukaemia was assessed by logistic regression analyses. RESULTS: Participation rates were 91.4% among cases and 69.2% in controls; 620 cases (544 acute lymphocytic and 76 acute non-lymphocytic leukaemia) and 957 controls were included. Overall, when considering the residence at birth, 35.6% of cases and 42.4% of controls lived along busy roads, and the mean annual PM10 levels were 33.3 (SD=6.3) and 33.4 ug/m(3) (SD=6.5), respectively. No association was found, and all ORs, independent of the method of assessment and the exposure windows, were close to the null value. CONCLUSIONS: Using various exposure assessment strategies, air pollution appears not to affect the incidence of childhood leukaemia. PMID- 24142972 TI - Comparison of exposure assessment methods in a lung cancer case-control study: performance of a lifelong task-based questionnaire for asbestos and PAHs. AB - OBJECTIVE: To describe the performance of a lifelong task-based questionnaire (TBQ) in estimating exposures compared with other approaches in the context of a case-control study. METHODS: A sample of 93 subjects was randomly selected from a lung cancer case-control study corresponding to 497 jobs. For each job, exposure assessments for asbestos and polycyclic aromatic hydrocarbons (PAHs) were obtained by expertise (TBQ expertise) and by algorithm using the TBQ (TBQ algorithm) as well as by expert appraisals based on all available occupational data (REFERENCE expertise) considered to be the gold standard. Additionally, a Job Exposure Matrix (JEM)-based evaluation for asbestos was also obtained. On the 497 jobs, the various evaluations were contrasted using Cohen's kappa coefficient of agreement. Additionally, on the total case-control population, the asbestos dose-response relationship based on the TBQ algorithm was compared with the JEM based assessment. RESULTS: Regarding asbestos, the TBQ-exposure estimates agreed well with the REFERENCE estimate (TBQ expertise: level-weighted kappa (lwk)=0.68; TBQ algorithm: lwk=0.61) but less so with the JEM estimate (TBQ expertise: lwk=0.31; TBQ algorithm: lwk=0.26). Regarding PAHs, the agreements between REFERENCE expertise and TBQ were less good (TBQ expertise: lwk=0.43; TBQ algorithm: lwk=0.36). In the case-control study analysis, the dose-response relationship between lung cancer and cumulative asbestos based on the JEM is less steep than with the TBQ-algorithm exposure assessment and statistically non significant. CONCLUSIONS: Asbestos-exposure estimates based on the TBQ were consistent with the REFERENCE expertise and yielded a steeper dose-response relationship than the JEM. For PAHs, results were less clear. PMID- 24142973 TI - Carving of non-asbestiform tremolite and the risk of lung cancer: a follow-up mortality study in a historical nephrite processing cohort. AB - OBJECTIVES: The health risks associated with exposure to non-asbestiform asbestos minerals, including nephrite, are unclear. In 1965 nephrite processing began in the town of Fengtian in Taiwan, and the majority of inhabitants were involved in the industry from 1970 until 1980. The objectives of this study were to examine lung cancer deaths and assess the carcinogenic effects of nephrite carving. METHODS: We studied mortality due to lung cancer (ICD-9 code 162 for cancers of the trachea, bronchus and lung) from 1979 to 2011. We calculated the standardised mortality ratio (SMR) for lung cancer using the age- and sex-specific cancer mortality rates in eastern Taiwan as the standard rates. Air samples, bulk samples and a surface sample were analysed. RESULTS: Nephrite is a non asbestiform asbestos mineral composed of microcrystalline tremolite. During nephrite processing, in personal air samples the average concentration of elongated mineral particles with the morphological characteristics of asbestos fibres was 1.4 f/cm(3), with rough grinding generating the highest concentrations (4.7 f/cm(3)). Transmission electron microscopy (TEM) confirmed that the air samples contained intact asbestiform tremolite fibres. The ambient air samples and the wipe sample indicated paraoccupational contamination. The crude mortality rates for lung cancer were higher in Fengtian than in Taiwan for all age groups and both genders. The SMR for lung cancer was 1.28 (95% CI 1.12 to 1.45). CONCLUSIONS: Nephrite carving may increase the risk of lung cancer. Appropriate medical monitoring is warranted for workers who are exposed to similar materials. PMID- 24142975 TI - Are all-cause and diagnosis-specific sickness absence, and sick-leave duration risk indicators for suicidal behaviour? A nationwide register-based cohort study of 4.9 million inhabitants of Sweden. AB - OBJECTIVES: Recent studies have found an increased risk of suicide in people on sickness absence, but less is known about to what extent diagnosis-specific sickness absence is a risk indicator for suicidal behaviour. This study aimed to examine all-cause and diagnosis-specific sickness absence and sick-leave duration as risk indicators for suicide attempt and suicide. METHODS: This is a population based prospective cohort study. All non-retired adults (n = 4 923 404) who lived in Sweden as on 31 December 2004 were followed-up for 6 years regarding suicide attempt and suicide (2005-2010). HRs and 95% CIs for suicidal behaviour were calculated, using people with no sick-leave spells in 2005 as reference. RESULTS: In analyses adjusted for sociodemographic factors and previous mental healthcare, suicide attempt and current antidepressants prescription, sickness absence predicted suicide attempt (HR 2.37; 95% CI 2.25 to 2.50 for women; HR 2.69; 95% CI 2.53 to 2.86 for men) and suicide (HR 1.91; 95% CI 1.60 to 2.29 for women; HR 1.92; 95% CI 1.71 to 2.14 for men), particularly mental sickness absence (range of HR: 2.74-3.64). The risks were also increased for somatic sickness absence, for example, musculoskeletal and digestive diseases and injury/poisoning (range of HR: 1.57-3.77). Moreover, the risks increased with sick-leave duration. CONCLUSIONS: Sickness absence was a clear risk indicator for suicidal behaviour, irrespective of sick-leave diagnoses, among women and men. Awareness of such risks is recommended when monitoring sickness certification. Further studies are warranted in order to gain more detailed knowledge on these associations. PMID- 24142976 TI - Silica dust, radon and death from non-malignant respiratory diseases in German uranium miners. AB - OBJECTIVE: To quantify the relationship between death from non-malignant respiratory diseases (NMRD) and exposure to silica dust or radon in a cohort of 58,690 former German uranium miners. METHODS: In the follow-up period from 1946 to 2008, a total of 2336 underlying deaths from NMRDs occurred, including 715 deaths from chronic obstructive pulmonary diseases (COPD) and 975 deaths from silicosis or other pneumoconiosis. Exposure to respirable crystalline silica and radon was individually assessed by means of a comprehensive job-exposure matrix. Risk analyses were based on a linear Poisson regression model with the baseline stratified by age, calendar year and duration of employment. RESULTS: There was no increase in risk of death from COPDs or any other NMRDs in relation to cumulative exposure to silica (mean=5.9, max=56 mg/m(3)-years), except in the group of deaths from silicosis or other pneumoconiosis. Here, a strong non-linear increase in risk was observed. Cumulative radon exposure (mean=280; max=3224 Working Level Months) was not related to death from COPDs or any other NMRDs. CONCLUSIONS: The present findings do not indicate a relationship between mortality from COPD with silica dust or radon. However, validity of cause of death and lack of control for smoking remain potential sources of bias. PMID- 24142974 TI - Mortality and cancer incidence in a pooled cohort of US firefighters from San Francisco, Chicago and Philadelphia (1950-2009). AB - OBJECTIVES: To examine mortality patterns and cancer incidence in a pooled cohort of 29 993 US career firefighters employed since 1950 and followed through 2009. METHODS: Mortality and cancer incidence were evaluated by life table methods with the US population referent. Standardised mortality (SMR) and incidence (SIR) ratios were determined for 92 causes of death and 41 cancer incidence groupings. Analyses focused on 15 outcomes of a priori interest. Sensitivity analyses were conducted to examine the potential for significant bias. RESULTS: Person-years at risk totalled 858 938 and 403 152 for mortality and incidence analyses, respectively. All-cause mortality was at expectation (SMR=0.99, 95% CI 0.97 to 1.01, n=12 028). There was excess cancer mortality (SMR=1.14, 95% CI 1.10 to 1.18, n=3285) and incidence (SIR=1.09, 95% CI 1.06 to 1.12, n=4461) comprised mainly of digestive (SMR=1.26, 95% CI 1.18 to 1.34, n=928; SIR=1.17, 95% CI 1.10 to 1.25, n=930) and respiratory (SMR=1.10, 95% CI 1.04 to 1.17, n=1096; SIR=1.16, 95% CI 1.08 to 1.24, n=813) cancers. Consistent with previous reports, modest elevations were observed in several solid cancers; however, evidence of excess lymphatic or haematopoietic cancers was lacking. This study is the first to report excess malignant mesothelioma (SMR=2.00, 95% CI 1.03 to 3.49, n=12; SIR=2.29, 95% CI 1.60 to 3.19, n=35) among US firefighters. Results appeared robust under differing assumptions and analytic techniques. CONCLUSIONS: Our results provide evidence of a relation between firefighting and cancer. The new finding of excess malignant mesothelioma is noteworthy, given that asbestos exposure is a known hazard of firefighting. PMID- 24142977 TI - Contribution of health status and prevalent chronic disease to individual risk for workplace injury in the manufacturing environment. AB - OBJECTIVES: An 'information gap' has been identified regarding the effects of chronic disease on occupational injury risk. We investigated the association of ischaemic heart disease, hypertension, diabetes, depression and asthma with acute occupational injury in a cohort of manufacturing workers from 1 January 1997 through 31 December 2007. METHODS: We used administrative data on real-time injury, medical claims, workplace characteristics and demographics to examine this association. We employed a piecewise exponential model within an Andersen Gill framework with a frailty term at the employee level to account for inclusion of multiple injuries for each employee, random effects at the employee level due to correlation among jobs held by an employee, and experience on the job as a covariate. RESULTS: One-third of employees had at least one of the diseases during the study period. After adjusting for potential confounders, presence of these diseases was associated with increased hazard of injury: heart disease (HR 1.23, 95% CI 1.11 to 1.36), diabetes (HR 1.17, 95% CI 1.08 to 1.27), depression (HR 1.25, 95% CI 1.12 to 1.38) and asthma (HR 1.14, 95% CI 1.02 to 1.287). Hypertension was not significantly associated with hazard of injury. Associations of chronic disease with injury risk were less evident for more serious reportable injuries; only depression and a summary health metric derived from claims remained significantly positive in this subset. CONCLUSIONS: Our results suggest that chronic heart disease, diabetes and depression confer an increased risk for acute occupational injury. PMID- 24142978 TI - Head injuries and Parkinson's disease in a case-control study. AB - BACKGROUND: Head injury is a hypothesised risk factor for Parkinson's disease, but there is a knowledge gap concerning the potential effect of injury circumstances (eg, work-related injuries) on risk. The objective of this study is to address this gap while addressing issues of recall bias and potential for reverse causation by prediagnosis symptoms. METHODS: We conducted a population based case-control study of Parkinson's disease in British Columbia, Canada (403 cases, 405 controls). Interviews queried injury history; whether injuries occurred at work, in a motor vehicle accident or during sports. Participants were also asked to report their suspicions about the causes of Parkinson's disease to provide an indicator of potential recall bias. Associations were estimated with logistic regression, adjusted for age, sex and smoking history. RESULTS: Associations were strongest for injuries involving concussion (OR: 2.08, 95% CI 1.30 to 3.33) and unconsciousness (OR: 2.64, 95% CI 1.39 to 5.03). Effects remained for injuries that occurred long before diagnosis and after adjustment for suspicion of head injury as a cause of Parkinson's disease. Injuries that occurred at work were consistently associated with stronger ORs, although small numbers meant that estimates were not statistically significant. CONCLUSIONS: This study adds to the body of literature suggesting a link between head injury and Parkinson's disease and indicates further scrutiny of workplace incurred head injuries is warranted. PMID- 24142979 TI - Is hypertension associated with job strain? A meta-analysis of observational studies. AB - Job strain results from a combination of high workload and few decision-making opportunities in the workplace. There is inconsistent evidence regarding the association between job strain and hypertension, and methodological shortcomings preclude firm conclusions. Thus, a meta-analysis of observational studies on hypertension among occupational groups was conducted to determine whether job strain was associated with hypertension. In January 2012, we carried out a comprehensive, topic-specific electronic literature search of the Ovid MEDLINE, EMBASE and PsychoINFO databases complemented by individual help from non communicable disease experts. Experimental/interventional studies and studies on personality disorders were excluded. Nine of 894 identified studies met the eligibility criteria and were included in the meta-analysis. The pooled OR of the nine studies was 1.29 (95% CI 1.14 to 1.47; p<0.001), of case-control studies 2.88 (95% CI 1.63 to 5.09; p<0.001) and of cohort studies 1.24 (95% CI1.09 to 1.41; p<0.001), all of which indicated statistically significant positive associations between job strain and hypertension [corrected]. In a subgroup analysis, cohort studies of good methodological quality showed significant associations between job strain and hypertension, while those of poor methodological quality showed no association or subgroup differences. We conclude that despite methodological differences, case-control and cohort studies of good methodological quality showed positive associations between hypertension and job strain. PMID- 24142980 TI - Food poisoned with pesticide in Bihar, India: new disaster, same story. PMID- 24142981 TI - Occupational asbestos exposure is associated with pharyngeal squamous cell carcinoma in men from the greater Boston area. AB - OBJECTIVES: Asbestos is the name given to a group of naturally occurring silicate mineral fibres that were widely used in industry during the 20th century due to their desirable physical properties. Although use in the USA has fallen over the last three decades, significant exposure in the developing world continues and the burden of disease is considerable. Asbestos is a known risk factor for several malignant diseases, including lung cancer and mesothelioma, and has more recently been implicated in pharyngeal and laryngeal cancer. However, studies of asbestos and cancers of the larynx or pharynx with adequate sample size that control for major head and neck squamous cell carcinoma (HNSCC) risk factors remain relatively sparse. METHODS: We report findings from a case-control study of 674 incident male HNSCC cases from the greater Boston region and 857 population-based male controls, matched on age (+/-3 years), sex, and town or neighbourhood of residence. Multivariable logistic regression was used to assess the association between occupational asbestos exposure and HNSCC by primary tumour site. RESULTS: 190 cases (28.2%) and 203 controls (23.7%) reported occupational exposure to asbestos. Occupational asbestos exposure was associated with elevated risk of pharyngeal carcinoma in men (OR 1.41, 95% CI 1.01 to 1.97), adjusted for age, race, smoking, alcohol consumption, education, income and HPV16 serology, with borderline increasing risk for each decade in the exposed occupation (OR 1.10, 95% CI 0.99 to 1.23). CONCLUSIONS: These observations are consistent with mounting evidence that asbestos is a risk factor for pharyngeal cancer. PMID- 24142983 TI - Long-term effects of aluminium dust inhalation. AB - OBJECTIVES: During the 1950s and 1960s, aluminium dust inhalation was used as a potential prophylaxis against silicosis in underground miners, including in Australia. We investigated the association between aluminium dust inhalation and cardiovascular, cerebrovascular and Alzheimer's diseases in a cohort of Australian male underground gold miners. We additionally looked at pneumoconiosis mortality to estimate the effect of the aluminium therapy. METHODS: SMRs and 95% CI were calculated to compare mortality of the cohort members with that of the Western Australian male population (1961-2009). Internal comparisons on duration of aluminium dust inhalation were examined using Cox regression. RESULTS: Aluminium dust inhalation was reported for 647 out of 1894 underground gold miners. During 42 780 person-years of follow-up, 1577 deaths were observed. An indication of increased mortality of Alzheimer's disease among miners ever exposed to aluminium dust was found (SMR=1.38), although it was not statistically significant (95% CI 0.69 to 2.75). Rates for cardiovascular and cerebrovascular death were above population levels, but were similar for subjects with or without a history of aluminium dust inhalation. HRs suggested an increasing risk of cardiovascular disease with duration of aluminium dust inhalation (HR=1.02, 95% CI 1.00 to 1.04, per year of exposure). No difference in the association between duration of work underground and pneumoconiosis was observed between the groups with or without aluminium dust exposure. CONCLUSIONS: No protective effect against silicosis was observed from aluminium dust inhalation. Conversely, exposure to aluminium dust may possibly increase the risk of cardiovascular disease and dementia of the Alzheimer's type. PMID- 24142984 TI - Shift work and breast cancer: do we need more evidence and what should this be? PMID- 24142982 TI - Genes involved in innate immunity associated with asbestos-related fibrotic changes. AB - OBJECTIVES: To determine whether genetic polymorphisms in several candidate genes related to innate immunity and protease-antiprotease balance modify individual susceptibility to develop asbestos-related fibrotic pleuropulmonary changes. METHODS: Sixteen polymorphisms from nine genes (NLRP3, CARD8, TNF, TGFB1, GC, MMP1, MMP9, MMP12 and TIMP2) were genotyped from 951 Finnish asbestos-exposed workers. The genotype/haplotype data were compared to signs of fibrosis and pleural thickenings using linear and logistic regression analysis adjusted for potential confounders. RESULTS: A functional polymorphism (Q705K; rs35829419) in the NLRP3 gene was associated with interstitial lung fibrosis (p=0.013), and the TGFB1 rs2241718 SNP with visceral pleural fibrosis (VPF) (p=0.044). In stratified analysis, the carriage of at least one NLRP3 variant allele conferred a 2.5-fold increased risk for pathological interstitial lung fibrosis (OR 2.44, 95% CI 0.97 to 6.14). Conversely, the carriage of at least one TGFB1 rs2241718 variant allele protected against VPF (OR 0.62, 95% CI 0.39 to 0.98). The TIMP2 rs2277698 SNP and a haplotype consisting of the TGFB1 rs1800469 and rs1800470 SNPs were associated with the degree of pleural thickening calcification (p=0.037 and p=0.035), and the CARD8 rs2043211 SNP with the greatest thickness of pleural plaques (p=0.015). CONCLUSIONS: Our results support the hypothesis that the NLRP3 inflammasome is important in the development of fibrotic lung disease by associating the NLRP3 rs35829419 variant allele with increased risk of asbestos-related interstitial lung fibrosis, and the TGFB1 rs2241718 variant allele with decreased risk of asbestos-related VPF. Polymorphisms in CARD8 and TIMP2 are proposed to modify the development and/or calcification of pleural thickenings. PMID- 24142985 TI - Pesticides and other occupational exposures are associated with airway obstruction: the LifeLines cohort study. AB - OBJECTIVES: Occupational exposures are important and possibly modifiable contributors to the global burden of chronic obstructive pulmonary disease (COPD). Exposure to vapours, gases, dusts and fumes (VGDF) has been associated with a two- to threefold higher COPD risk. Less is known about effects of occupational exposure to pesticides and solvents. In the current study, we assessed if VGDF, pesticides and solvents are associated with the level of lung function and the prevalence of airway obstruction in the general population. METHODS: We included 11 851 subjects aged 18-89 years from the LifeLines cohort study. Regression models assessing associations between occupational exposures (no/low/high), level of lung function (prebronchodilator FEV(1), FEV(1)/FVC) and mild and moderate/severe airway obstruction were adjusted for sex, age, height, weight, current/ex-smoking and packyears. Additionally, we stratified by smoking status and gender and tested for interaction. A second general population cohort (n=2364) was used to verify our initial findings. RESULTS: Occupational exposure to VGDF and pesticides was associated with a lower level of FEV(1) and FEV(1)/FVC and with a higher prevalence of mild and moderate/severe airway obstruction in the two general populations investigated. There were no associations with exposure to solvents. CONCLUSIONS: Occupational exposure to both VGDF and pesticides is associated with airway obstruction in the general population. PMID- 24142986 TI - First-time decisions regarding work injury annuity due to occupational disease: a gender perspective. AB - OBJECTIVES: This study presents an investigation of first-time decisions regarding work injury annuity due to occupational disease. Focus is a number of potential underlying factors behind the gender gap, where women are disadvantaged, in the granting of work injury annuity. METHODS: All 99 subjects (80 men and 19 women) who met the conditions of long-lasting reduction of work ability due to occupational disease (not occupational accident) in the Swedish Work Injury Insurance Act and were granted work injury annuity in 2010, together with a random sample of 118 subjects (55 men and 63 women) who were denied annuity in the same year, were selected for analysis. Each subject's case file from the Social Insurance Agency was examined with regards to cause of disease, diagnosis and the Social Insurance Agency's management and decision making of claims. The data were analysed by logistic regression analysis. RESULTS: Men had a higher probability of being granted work injury annuity than women for musculoskeletal disorders (OR 4.16), mental disorders (OR 7.93) and diseases in other diagnostic chapters (OR 3.65). After adjustment for age, country of birth, diagnosis, work exposure factors and decision support factors, the higher probability for men of being granted work injury annuity remained (full model: OR 2.67, 95% CI 1.20 to 5.94). CONCLUSIONS: Actions are necessary in order to establish equitable and gender-neutral treatment of work injury insurance claims. There is a need for more detailed knowledge of exposures in female-dominated jobs and the relationship between these exposures and occupational disease. PMID- 24142987 TI - Associations between arrhythmia episodes and temporally and spatially resolved black carbon and particulate matter in elderly patients. AB - OBJECTIVES: Ambient air pollution has been associated with sudden deaths, some of which are likely due to ventricular arrhythmias. Defibrillator discharge studies have examined the association of air pollution with arrhythmias in sensitive populations. No studies have assessed this association using residence-specific estimates of air pollution exposure. METHODS: In the Normative Aging Study, we investigated the association between temporally resolved and spatially resolved black carbon (BC) and PM2.5 and arrhythmia episodes (bigeminy, trigeminy or couplets episodes) measured as ventricular ectopy (VE) by 4 min ECG monitoring in repeated measures of 701 subjects, during the years 2000-2010. We used a binomial distribution (having or not a VE episode) in a mixed effect model with a random intercept for subject, controlling for seasonality, temperature, day of the week, medication use, smoking, having diabetes, body mass index and age. We also examined whether these associations were modified by genotype or phenotype. RESULTS: We found significant increases in VE with both pollutants and lags; for the estimated concentration averaged over the 3 days prior to the health assessment, we found increases in the odds of having VE with an OR of 1.52 (95% CI 1.19 to 1.94) for an IQR (0.30 MUg/m(3)) increase in BC and an OR of 1.39 (95% CI 1.12 to 1.71) for an IQR (5.63 MUg/m(3)) increase in PM2.5. We also found higher effects in subjects with the glutathione S-transferase theta-1 and glutathione S-transferase mu-1 variants and in obese (p<0.05). CONCLUSIONS: Increased levels of short-term traffic-related pollutants may increase the risk of ventricular arrhythmia in elderly subjects. PMID- 24142988 TI - Effects of an exercise programme on preventing neck pain among office workers: a 12-month cluster-randomised controlled trial. AB - OBJECTIVES: This study aimed to evaluate the effects of an exercise programme focusing on muscle stretching and endurance training on the 12-month incidence of neck pain in office workers. METHODS: A 12-month prospective cluster-randomised controlled trial was conducted in healthy office workers with lower-than-normal neck flexion movement or neck flexor endurance. Participants were recruited from 12 large-scale enterprises. A total of 567 healthy office workers were randomly assigned at the cluster level into either intervention (n=285) or control (n=282) groups. Participants in the intervention group received an exercise programme that included daily stretching exercise and twice-a-week muscle endurance training. Those in the control group received no intervention. The primary outcome measure was the 12-month incidence of neck pain, and the secondary outcome measures were pain intensity, disability level, and quality of life and health status. Analyses were performed using the Cox proportional hazard models. RESULTS: Over the 12-month follow-up, 12.1% of participants in the intervention group and 26.7% in the control group developed incident neck pain. Hazard rate ratios showed a protective effect of the exercise programme for neck pain (HR=0.45, 95% CI 0.28 to 0.71) after adjusting for biopsychosocial factors. There was no significant difference in pain intensity, disability and quality of life and health status between those who reported incident neck pain in the intervention and control groups. CONCLUSIONS: The exercise programme reduced incident neck pain and increased neck flexion movement for office workers with lower-than-normal neck flexion movement. PMID- 24142989 TI - An extensive epidemiological investigation of a kidney cancer cluster in a chemical plant: what have we learned? AB - OBJECTIVES: In 2003, a cluster of renal cell carcinoma (RCC) cases was reported among men working at a French chemical plant using a proprietary process to produce vitamin A. The 10 index cases yielded a standardised incidence ratio of 13.1 for 1994-2002. Nine of these 10 cases were diagnosed by a plant-specific abdominal ultrasonography screening programme that targeted exposure to an intermediate chemical, 4-chloro-1,1-dimethoxy-3-methyl-2-butene, commonly named 'chloracetal C5', suspected as the cause by some experts. Epidemiological investigations sought to examine the relations between occupational exposures and RCC. METHODS: A retrospective cohort mortality study and a nested case--control study were conducted. The cohort study included all workers who had been employed at the plant for at least 6 months between 1960 and 2003. The case--control study included an extensive search within the region for other kidney cancer cases among the cohort members. Industrial hygienists assessed occupational exposure. RESULTS: From 1968 to 2006, no significant excess mortality was observed for all causes of death or for all cancers. We found excess mortality for kidney cancer only among women. The nested case--control study showed a dose--response relation for cumulative exposure to chloracetal C5: the OR rose from 2.5 in the low exposure category to 10.5 in the high-exposure group. Adjustment for screening attenuated this relation. CONCLUSIONS: The results of the case--control study were consistent with the positive results of in vivo genotoxic tests and suggest that chloracetal C5 can have a causal role in RCC. PMID- 24142990 TI - Air pollution from livestock farms, and asthma, allergic rhinitis and COPD among neighbouring residents. AB - OBJECTIVES: There is an ongoing debate regarding environmental health risks of exposures to dust and microbial agents from livestock farming in the Netherlands. The aims of the study were (1) to investigate associations between indicators of air pollution from livestock farms and asthma, allergic rhinitis and chronic obstructive pulmonary disease (COPD) among neighbouring residents; and (2) to assess associations between farm exposures and endotoxin levels in participants' homes. METHODS: Electronic medical records of all 92 548 patients of 27 general practices in a rural area with a high density of animal farms were analysed, followed up by a case-control component using a subsample of the full population. Distance between livestock farms and home address, presence of livestock within 500 m, and particulate matter (PM)10 emissions from farms within 500 m were computed as proxies for farm exposure. Potential confounding was investigated through a case-control questionnaire study in 269 adult patients with asthma and 546 controls. Endotoxin levels were assessed in 493 homes. RESULTS: Modelled PM10 emission was inversely associated with asthma, allergic rhinitis and COPD (p<0.05). A smaller distance to the nearest farm, and the presence of swine, goat and sheep farms were also inversely related to respiratory morbidity, whereas mink farms showed positive associations with asthma and allergic rhinitis. Adjustment for confounding in the case-control study did not change results. Farm exposures were not associated with endotoxin levels in neighbouring residents' homes. CONCLUSIONS: In conclusion, indicators of air pollution from livestock farms were inversely associated with respiratory morbidity among neighbouring residents. PMID- 24142991 TI - Cholangiocarcinoma among workers in the printing industry: using the NOCCA database to elucidate the generalisability of a cluster report from Japan. AB - OBJECTIVES: A cluster of 11 cases of cholangiocarcinoma (CC) was observed in a small Japanese printing firm. To elucidate whether the identified cluster is indicative of an elevated risk of CC among workers in the printing industry at large, we explored the risk of cancer of the liver and CC among individuals employed in the printing industry in a large cohort set-up in four Nordic countries (Finland, Iceland, Norway and Sweden) over a period of 45 years. METHODS: The cohort was set-up by linking occupational information from censuses to national cancer registry data utilising personal identity codes in use in all Nordic countries. We calculated standardised incidence ratios (SIRs) for men and women working in the printing industry, and stratified by occupational category (typographers, printers, lithographers, bookbinders). RESULTS: Among men, we observed elevated SIRs for cancer of the liver (1.35, 95% CI 1.14 to 1.60; 142 cases), specifically intrahepatic CC (2.34, 95% CI 1.45 to 3.57; 21 cases). SIRs for liver cancer were especially elevated among printers and lithographers, and SIRs for intrahepatic CC among typographers and printers. SIRs for extrahepatic CC were not elevated. SIRs for women followed a similar pattern but the number of cases was low. CONCLUSIONS: Our study supports the notion that the finding of excess CC risk among workers in a small Japanese printing firm possibly extends beyond this specific firm and country. Further studies should focus on the specific exposures that occur in the printing industry. PMID- 24142992 TI - Psychosocial job strain and risk of adverse birth outcomes: a study within the Danish national birth cohort. AB - OBJECTIVE: A number of studies examined the effects of prenatal stress on birth outcomes with diverging and inconclusive results. We aimed to examine if working with high job strain during pregnancy measured in week 16 was associated with risk of giving birth to a child born preterm or small/large for gestational age (SGA/LGA), and second, if social support affected any associations. DESIGN: Study population was 48 890 pregnancies from the Danish National Birth Cohort. Multinomial logistic regression estimated ORs. Covariates included: maternal age, BMI, parity, exercise, smoking, alcohol and coffee consumption, manual work, serious maternal disease, parental height and gestational age at interview. In accordance with Good Epidemiological Practice, a protocol outlined the study design before analyses were initiated. RESULTS: High job strain was associated with significantly lower odds of being born LGA (OR=0.81, CI 0.70 to 0.92) when compared to low-strain jobs, but no associations between high strain and preterm birth or SGA were found. Stratification by social support showed a non statistically significant tendency of higher odds of preterm birth when exposed to high strain and low social support. CONCLUSIONS: In spite of the high statistical precision, we did not find any clear association between job strain and preterm birth nor between job strain and SGA. PMID- 24142993 TI - Peptide level immunoaffinity enrichment enhances ubiquitination site identification on individual proteins. AB - Ubiquitination is a process that involves the covalent attachment of the 76 residue ubiquitin protein through its C-terminal di-glycine (GG) to lysine (K) residues on substrate proteins. This post-translational modification elicits a wide range of functional consequences including targeting proteins for proteasomal degradation, altering subcellular trafficking events, and facilitating protein-protein interactions. A number of methods exist for identifying the sites of ubiquitination on proteins of interest, including site directed mutagenesis and affinity-purification mass spectrometry (AP-MS). Recent publications have also highlighted the use of peptide-level immunoaffinity enrichment of K-GG modified peptides from whole cell lysates for global characterization of ubiquitination sites. Here we investigated the utility of this technique for focused mapping of ubiquitination sites on individual proteins. For a series of membrane-associated and cytoplasmic substrates including erbB-2 (HER2), Dishevelled-2 (DVL2), and T cell receptor alpha (TCRalpha), we observed that K-GG peptide immunoaffinity enrichment consistently yielded additional ubiquitination sites beyond those identified in protein level AP-MS experiments. To assess this quantitatively, SILAC-labeled lysates were prepared and used to compare the abundances of individual K-GG peptides from samples prepared in parallel. Consistently, K-GG peptide immunoaffinity enrichment yielded greater than fourfold higher levels of modified peptides than AP-MS approaches. Using this approach, we went on to characterize inducible ubiquitination on multiple members of the T-cell receptor complex that are functionally affected by endoplasmic reticulum (ER) stress. Together, these data demonstrate the utility of immunoaffinity peptide enrichment for single protein ubiquitination site analysis and provide insights into the ubiquitination of HER2, DVL2, and proteins in the T-cell receptor complex. PMID- 24142994 TI - An automated proteogenomic method uses mass spectrometry to reveal novel genes in Zea mays. AB - New technologies in genomics and proteomics have influenced the emergence of proteogenomics, a field at the confluence of genomics, transcriptomics, and proteomics. First generation proteogenomic toolkits employ peptide mass spectrometry to identify novel protein coding regions. We extend first generation proteogenomic tools to achieve greater accuracy and enable the analysis of large, complex genomes. We apply our pipeline to Zea mays, which has a genome comparable in size to human. Our pipeline begins with the comparison of mass spectra to a putative translation of the genome. We select novel peptides, those that match a region of the genome that was not previously known to be protein coding, for grouping into refinement events. We present a novel, probabilistic framework for evaluating the accuracy of each event. Our calculated event probability, or eventProb, considers the number of supporting peptides and spectra, and the quality of each supporting peptide-spectrum match. Our pipeline predicts 165 novel protein-coding genes and proposes updated models for 741 additional genes. PMID- 24142995 TI - High pre-transplant serum nitrate levels predict risk of acute steroid-refractory graft-versus-host disease in the absence of statin therapy. AB - Steroid-refractory graft-versus-host disease is a life-threatening complication after allogeneic stem cell transplantation. Evidence is accumulating that steroid refractory graft-versus-host disease is associated with endothelial distress. Endothelial cell homeostasis is regulated by nitric oxide, and serum nitrates are derived from nitric oxide synthase activity or dietary sources. In this retrospective study based on 417 patients allografted at our institution we investigated whether quantification of serum nitrates could predict steroid refractory graft-versus-host disease. Elevated pre-transplant levels of serum nitrates (>26.5 MUM) predicted steroid-refractory graft-versus-host disease (P=0.026) and non-relapse mortality (P=0.028), particularly in combination with high pre-transplant angiopoietin-2 levels (P=0.0007 and P=0.021, respectively). Multivariate analyses confirmed serum nitrates as independent predictors of steroid-refractory graft-versus-host disease and non-relapse mortality. Differences in serum nitrate levels did not correlate with serum levels of tumor necrosis factor or C-reactive protein or expression of inducible nitric oxide synthase in blood cells. Patients with high pre-transplant nitrate levels had significantly reduced rates of refractory graft-versus-host disease (P=0.031) when pravastatin was taken. In summary, patients at high risk of developing steroid-refractory graft-versus-host disease could be identified prior to transplantation by serum markers linked to endothelial cell function. Retrospectively, statin medication was associated with a reduced incidence of refractory graft-versus-host disease in this endothelial high-risk cohort. PMID- 24142996 TI - Gemtuzumab ozogamicin in combination with vorinostat and azacitidine in older patients with relapsed or refractory acute myeloid leukemia: a phase I/II study. AB - Epigenetic therapeutics such as the histone deacetylase inhibitor, vorinostat, and the DNA methyltransferase I inhibitor, azacitidine, enhance gemtuzumab ozogamicin efficacy in vitro. We therefore investigated vorinostat/azacitidine/gemtuzumab ozogamicin in 52 adults aged 50 years or over with acute myeloid leukemia requiring therapy for first relapse (remission duration <= 12 months) or primary refractory disease in a phase I/II trial. Vorinostat and gemtuzumab ozogamicin were escalated step-wise during the phase I portion of the trial. Vorinostat (400 mg/day orally from Days 1-9), azacitidine (75 mg/m(2)/day intravenously or subcutaneously from Days 1-7), and gemtuzumab ozogamicin (3 mg/m(2)/day intravenously on Days 4 and 8) were identified as the maximum tolerated dose. Among the 43 patients treated at this dose, 10 achieved a complete remission and 8 achieved a complete remission with incomplete blood count recovery, for an overall response rate of 41.9% (exact 95% confidence interval (CI): 27.0-57.9%). Four of these 18 patients (2 with complete remission and 2 with complete remission with incomplete blood count recovery) had persistence of minimal residual disease by flow cytometry at the time of best response. Four patients died within 28 days of treatment initiation. Median overall survival for the 18 patients achieving complete remission/complete remission with incomplete blood count recovery was significantly longer than for those 21 patients who failed therapy but lived at least 29 days after treatment initiation (224.5 days (range 70-798) vs. 95 days (range 36-900); P=0.0023). These data indicate that vorinostat/azacitidine/gemtuzumab ozogamicin has activity in this difficult-to-treat acute myeloid leukemia patient subset. (ClinicalTrials.gov: identifier 00895934). PMID- 24142997 TI - Next-generation sequencing-based multigene mutational screening for acute myeloid leukemia using MiSeq: applicability for diagnostics and disease monitoring. AB - Routine molecular testing in acute myeloid leukemia involves screening several genes of therapeutic and prognostic significance for mutations. A comprehensive analysis using single-gene assays requires large amounts of DNA, is cumbersome and timely consolidation of results for clinical reporting is challenging. High throughput, next-generation sequencing platforms widely used in research have not been tested vigorously for clinical application. Here we describe the clinical application of MiSeq, a next-generation sequencing platform to screen mutational hotspots in 54 cancer-related genes including genes relevant in acute myeloid leukemia (NRAS, KRAS, FLT3, NPM1, DNMT3A, IDH1/2, JAK2, KIT and EZH2). We sequenced 63 samples from patients with acute myeloid leukemia/myelodysplastic syndrome using MiSeq and compared the results with those obtained using another next-generation sequencing platform, Ion-Torrent Personal Genome Machine and other conventional testing platforms. MiSeq detected a total of 100 single nucleotide variants and 23 NPM1 insertions that were confirmed by Ion Torrent or conventional platforms, indicating complete concordance. FLT3-internal tandem duplications (n=10) were not detected; however, re-analysis of the MiSeq output by Pindel, an indel detection algorithm, did detect them. Dilution studies of cancer cell-line DNA showed that the quantitative accuracy of mutation detection was up to an allelic frequency of 1.5% with a high level of inter- and intra-run assay reproducibility, suggesting potential utility for monitoring response to therapy, clonal heterogeneity and evolution. Examples demonstrating the advantages of MiSeq over conventional platforms for disease monitoring are provided. Easy work-flow, high throughput multiplexing capability, 4-day turnaround time and simultaneous assessment of routinely tested and emerging markers make MiSeq highly applicable for clinical molecular testing in acute myeloid leukemia. PMID- 24142998 TI - Hemophagocytic syndrome in patients with acute myeloid leukemia undergoing intensive chemotherapy. AB - Hemophagocytic lymphohistiocytosis is a condition of immune dysregulation characterized by severe organ damage induced by a hyperinflammatory response and uncontrolled T-cell and macrophage activation. Secondary hemophagocytic lymphohistiocytosis typically occurs in association with severe infections or malignancies. Patients with acute myeloid leukemia may be prone to develop hemophagocytic lymphohistiocytosis because of an impaired immune response and a high susceptibility to severe infections. In a series of 343 patients treated by intensive chemotherapy over a 5-year period in our center, we identified 32 patients (9.3%) with fever, very high ferritin levels, and marrow hemophagocytosis (i.e. patients with hemophagocytic lymphohistiocytosis). Compared to patients without hemophagocytic lymphohistiocytosis, these 32 patients had hepatomegaly, pulmonary or neurological symptoms, liver abnormalities, lower platelet count and higher levels of C-reactive protein as well as prolonged pancytopenia. A microbial etiology for the hemophagocytosis was documented in 24 patients: 14 bacterial infections, 9 Herpesviridae infections and 11 fungal infections. The treatment of hemophagocytic lymphohistiocytosis consisted of corticosteroids and/or intravenous immunoglobulins along with adapted antimicrobial therapy. Patients with hemophagocytic lymphohistiocytosis had a median overall survival of 14.9 months, which was significantly shorter than that of patients without hemophagocytic lymphohistiocytosis (22.1 months) (P=0.0016). Hemophagocytic lymphohistiocytosis was significantly associated with a higher rate of induction failure, mainly due to deaths in aplasia. Hemophagocytic lymphohistiocytosis can be diagnosed in up to 10% of patients with acute myeloid leukemia undergoing intensive chemotherapy and is associated with early mortality. Fever, very high ferritin levels and marrow hemophagocytosis represent the cornerstone of the diagnosis. Further biological studies are needed to better characterize and recognize this syndrome in patients with acute myeloid leukemia. PMID- 24142999 TI - The synergism of MCL1 and glycolysis on pediatric acute lymphoblastic leukemia cell survival and prednisolone resistance. AB - In vitro and in vivo resistance to prednisolone are predictive for an adverse prognosis in pediatric precursor B-acute lymphoblastic leukemia. Causes of resistance are still poorly understood. In this study, we observed that prednisolone exposure of prednisolone-sensitive patients' leukemic cells decreased anti-apoptotic MCL1 protein levels by 2.9-fold, while MCL1 protein expression in prednisolone-resistant leukemic patients' cells was unaffected (P<0.01). Locked nucleic acid oligonucleotides directed against MCL1 reduced MCL1 protein levels by 82+/-16% (P<0.05) in leukemic cells, decreased proliferation by 9-fold and sensitized to prednisolone up to 80.8-fold, compared to a non silencing-control locked nucleic acid (P<0.05). Remarkably, we discovered that MCL1-silencing up-regulated the glucose consumption of leukemic cells by 2.5-fold (P<0.05), suggesting a potential rescue mechanism mediated by glycolysis. Targeting glycolysis by 2-deoxyglucose synergistically inhibited leukemic survival by 23.2-fold in MCL1-silenced cells (P<0.05). Moreover, 2-deoxyglucose and MCL1 locked nucleic acid concomitantly sensitized leukemic cells to prednisolone compared to MCL1 locked nucleic acid or 2-deoxyglucose alone (P<0.05). In conclusion, these results indicate the need to target both MCL1 and glycolysis simultaneously to inhibit leukemic survival and sensitize acute leukemia patients towards prednisolone. PMID- 24143000 TI - Cost-effectiveness and clinical outcomes of double versus single cord blood transplantation in adults with acute leukemia in France. AB - Double cord blood transplantation extends the use of cord blood to adults for whom a single unit is not available, but the procedure is limited by its cost. To evaluate outcomes and cost-effectiveness of double compared to single cord blood transplantation, we analyzed 134 transplants in adults with acute leukemia in first remission. Transplants were performed in France with reduced intensity or myeloablative conditioning regimens. Costs were estimated from donor search to 1 year after transplantation. A Markov decision analysis model was used to calculate quality-adjusted life-years and cost-effectiveness ratio within 4 years. The overall survival at 2 years after single and double cord blood transplants was 42% versus 62%, respectively (P=0.03), while the leukemia-free survival was 33% versus 53%, respectively (P=0.03). The relapse rate was 21% after double transplants and 42% after a single transplant (P=0.006). No difference was observed for non-relapse mortality or chronic graft-versus-host disease. The estimated costs up to 1 year after reduced intensity conditioning for single and double cord blood transplantation were ? 165,253 and ?191,827, respectively. The corresponding costs after myeloablative conditioning were ? 192,566 and ? 213,050, respectively. Compared to single transplants, double cord blood transplantation was associated with supplementary costs of ? 21,302 and ? 32,420 up to 4 years, but with increases in quality-adjusted life-years of 0.616 and 0.484, respectively, and incremental cost-effectiveness ratios of ? 34,581 and ?66,983 in the myeloablative and reduced intensity conditioning settings, respectively. Our results showed that for adults with acute leukemia in first complete remission in France, double cord transplantation is more cost-effective than single cord blood transplantation, with better outcomes, including quality adjusted life-years. PMID- 24143001 TI - Primary cold agglutinin-associated lymphoproliferative disease: a B-cell lymphoma of the bone marrow distinct from lymphoplasmacytic lymphoma. AB - Primary chronic cold agglutinin disease is a rare hemolytic disease mediated by monoclonal IGHV4-34-encoded cold agglutinins with a predominant specificity for the blood group antigen I. Bone marrow from 54 patients was studied to type the underlying lymphoproliferative disorder better. Bone marrow biopsies showed circumscribed intra-parenchymatous nodules with small monotonous monoclonal B cells in 40/54 patients (median infiltration: 10% of marrow cells) with a CD20(+), IgMs(+), IgDs(+), CD27(+), CD5(-/+), CD11c(-), CD23(-), CD38(-) immunophenotype. Neither plasmacytoid cytological features nor expression of plasma cell differentiation-associated transcription factors MUM1, XBP1 and BLIMP1 were noted in these B cells. However, a limited number of mature monoclonal IgM(+), IgD(-) plasma cells were present outside the lymphoid nodules and were diffusely scattered throughout the marrow. Of interest, the MYD88 L265P mutation, typical of lymphoplasmacytic lymphoma, was not detected (17/17 cases). Somatically mutated monoclonal IGHV4-34 gene rearrangement was demonstrated in eight patients with frozen samples (mean sequence homology 95.4%). However, mutations of BCL6 intron 1 were not demonstrated, except in one patient, suggesting that the lymphoma cells had not matured in the germinal center. In conclusion, cold agglutinin-associated lymphoproliferative disease displays homogeneous histological and immunophenotypic features. The absence of plasmacytoid cells, the presence of plasma cells predominantly outside the nodular lymphoid infiltrates, IGHV4-34 restriction and absence of MYD88 L265P mutation strongly suggest that cold agglutinin-associated lymphoproliferative disease is a distinct entity that is different from lymphoplasmacytic lymphoma. PMID- 24143002 TI - The one hour yeast proteome. AB - We describe the comprehensive analysis of the yeast proteome in just over one hour of optimized analysis. We achieve this expedited proteome characterization with improved sample preparation, chromatographic separations, and by using a new Orbitrap hybrid mass spectrometer equipped with a mass filter, a collision cell, a high-field Orbitrap analyzer, and, finally, a dual cell linear ion trap analyzer (Q-OT-qIT, Orbitrap Fusion). This system offers high MS(2) acquisition speed of 20 Hz and detects up to 19 peptide sequences within a single second of operation. Over a 1.3 h chromatographic method, the Q-OT-qIT hybrid collected an average of 13,447 MS(1) and 80,460 MS(2) scans (per run) to produce 43,400 (x) peptide spectral matches and 34,255 (x) peptides with unique amino acid sequences (1% false discovery rate (FDR)). On average, each one hour analysis achieved detection of 3,977 proteins (1% FDR). We conclude that further improvements in mass spectrometer scan rate could render comprehensive analysis of the human proteome within a few hours. PMID- 24143003 TI - The relationship between leadership support, workplace health promotion and employee wellbeing in South Africa. AB - Leadership support has been identified as an essential component of successful workplace health promotion (WHP) programs. However, there is little research in this area and even less theoretical conceptualization on ways in which leadership support for WHP is related to improved employee wellbeing. In this paper, we developed and tested a model of leadership support for WHP and employee wellbeing outcomes using employer and employee data gathered from 71 South African organizations. A theoretical model based on social exchange theory was developed. It was hypothesized that perceptions of company commitment to health promotion mediates the relationship between leadership support, the provision of WHP facilities and employee wellbeing. A hierarchical structural equation modeling technique was used to test the model. We determined that leaders' support for WHP was important insofar as they also provided health promotion facilities to their employees. No direct relationship was found between leadership support alone and employee wellbeing. PMID- 24143004 TI - On the random distribution of scarce doses of vaccine in response to the threat of an influenza pandemic: a response to Wardrope. AB - Wardrope argues against my proposed non-consequentialist policy for the distribution of scarce influenza vaccine in the face of a pandemic. According to him, even if one accepts what he calls my deontological ethical theory, it does not follow that we are required to agree with my proposed randomised allocation of doses of vaccine by means of a lottery. He argues in particular that I fail to consider fully the prophylactic role of vaccination whereby it serves to protect from infection more people than are vaccinated. He concludes that: 'The benefits and burdens of vaccination are provided impartially and far more effectively by targeted vaccination than impartial lotteries.' He has shown convincingly that this conclusion can be established in the case of his particular envisaged scenario. However, Wardrope gives no reason to suppose that, in the circumstances that we actually face, targeted vaccination would constitute impartial treatment of citizens in the UK. I readily agree with Wardrope that if it should treat its citizens justly and impartially, it does not necessarily follow that the state should distribute vaccinations of the basis of a lottery. That will be a reasonable thing to do only if certain assumptions are made. These assumptions will not always be reasonable. However, they are reasonable ones to make in the actual circumstances that currently apply. PMID- 24143005 TI - And there we go again: the ethics of placebo-controlled RCT in case of catastrophic illness. PMID- 24143006 TI - Performance of an indigenous beta-mercaptoethanol-modified antigen in comparison with a commercial reference in direct agglutination test for detection of canine visceral leishmaniasis. AB - We compared the performance of a locally produced beta-mercaptoethanol-modified promastigote antigen (beta-ME-Ag) of an indigenous Leishmania infantum strain against that of a trypsinized Leishmania donovani reference (REF-Ag) in the direct agglutination test (DAT) for detection of canine visceral leishmaniasis (CVL). One hundred and fifty-one serum samples collected from dogs belonging to four groups with different conditions were included. At a DAT titre of 1 : 320, statistically determined as optimal cut-off value for beta-ME-Ag, and 1 : 160 for REF-Ag, a sensitivity and a specificity of 100 % were estimated for beta-ME-Ag in comparison with 96.6 % and 100 %, respectively, for REF-Ag. Overall, levels of agglutination titres recorded for the two antigens were highly concordant (Cohen's kappa = 0.879) in both the CVL and non-CVL groups. Based on current results, and ease experienced in processing the antigen and reading the test outcome, we recommend incorporation of beta-ME-Ag in DAT for confirmation or exclusion of suspected CVL in dogs. PMID- 24143007 TI - Primary cutaneous nocardiosis caused by Nocardia nova in a kidney transplant recipient. AB - Nocardia nova is a rare aetiological pathogen for cutaneous nocardiosis. To the best of our knowledge, this is the first case of N. nova primary cutaneous infection in a kidney transplant recipient. Identification was performed using 16S rRNA and secA1 gene sequence analyses. The patient was not treated successfully by antibiotics alone. Surgical debridement was required for successful treatment. PMID- 24143008 TI - Characterization of a novel beta-L-arabinofuranosidase in Bifidobacterium longum. Functional elucidation of a DUF1680 family member. PMID- 24143010 TI - Positive and negative modulation of vitamin D receptor function by transforming growth factor-beta signaling through Smad proteins. PMID- 24143011 TI - Ligand type-specific interactions of peroxisome proliferator-activated receptor gamma with transcriptional coactivators. PMID- 24143012 TI - The tamoxifen-responsive estrogen receptor alpha mutant D351Y shows reduced tamoxifen-dependent interaction with corepressor complexes. PMID- 24143013 TI - An hGCN5/TRRAP histone acetyltransferase complex co-activates BRCA1 transactivation function through histone modification. PMID- 24143014 TI - Phosphorylation of Williams syndrome transcription factor by MAPK induces a switching between two distinct chromatin remodeling complexes. PMID- 24143015 TI - Changing of the guard at Occupational and Environmental Medicine. PMID- 24143016 TI - Disinfection by-products in drinking water and reproductive health. PMID- 24143018 TI - Arsenic in drinking water and renal cancers in rural Bangladesh. AB - OBJECTIVES: Data on the role of arsenic in renal cancer are suggestive but inconclusive. The present analysis aimed to determine whether renal cancers were more likely in Bangladeshi villagers exposed to high arsenic concentration in well water and, if so, whether this excess was limited to transitional cell cancers (TCC) or occurred also for renal cell cancers (RCC). METHODS: Histology/cytology results from renal biopsies carried out at a single clinic in Dhaka, Bangladesh, from January 2008 to October 2011 were classified into four groups: RCC, TCC, other malignancy and benign. Patients aged >=18 years using hand-pumped well water were identified by questionnaire, blind to diagnosis. Arsenic concentration was estimated from British Geological Survey reports for administrative area (thana) of residence. In a case-referent design (with benign results as referents), ORs were calculated by multilevel logistic regression adjusted for confounding. Time since well installation and smoking were examined by stratification. RESULTS: Among 1489 cases included, 896 were RCC, 90 TCC and 503 benign. Arsenic concentration was estimated for 301 thanas with 63% of cases and 40% referents with arsenic concentration >=50 ug/L (p<0.001). Risk increased monotonically with arsenic concentration >=50 ug/L for both cell types (RCC and TCC). Risk estimates were greater in thana with early well installation where risk was increased for RCC in exposure stratum 10<50 ug/L (OR=2.47 95% CI 1.52 to 4.01). Stratification by 'ever smoked' confirmed the presence of risk in non smokers. CONCLUSIONS: The relationship between arsenic concentration and both RCC and TCC suggests that arsenic is a causal factor in renal cancer. PMID- 24143017 TI - Endotoxin in concentrated coarse and fine ambient particles induces acute systemic inflammation in controlled human exposures. AB - BACKGROUND: Knowledge of the inhalable particulate matter components responsible for health effects is important for developing targeted regulation. OBJECTIVES: In a double-blind randomised cross-over trial of controlled human exposures to concentrated ambient particles (CAPs) and their endotoxin and (1->3)-beta-D glucan components, we evaluated acute inflammatory responses. METHODS: 35 healthy adults were exposed to five 130-min exposures at rest: (1) fine CAPs (~250 ug/m(3)); (2) coarse CAPs (200 ug/m(3)); (3) second coarse CAPs (~200 ug/m(3)); (4) filtered air; and (5) medical air. Induced sputum cell counts were measured at screening and 24 h postexposure. Venous blood total leucocytes, neutrophils, interleukin-6 and high-sensitivity C reactive protein (CRP) were measured pre exposure, 3 and 24 h postexposure. RESULTS: Relative to filtered air, an increase in blood leucocytes 24 h (but not 3 h) postexposure was significantly associated with coarse (estimate=0.44*10(9) cells/L (95% CI 0.01 to 0.88); n=132) and fine CAPs (0.68*10(9) cells /L (95% CI 0.19 to 1.17); n=132), but not medical air. Similar associations were found with neutrophil responses. An interquartile increase in endotoxin (5.4 ng/m(3)) was significantly associated with increased blood leucocytes 3 h postexposure (0.27*10(9) cells/L (95% CI 0.03 to 0.51); n=98) and 24 h postexposure (0.37*10(9) cells/L (95% CI 0.12 to 0.63); n=98). This endotoxin effect did not differ by particle size. There were no associations with glucan concentrations or interleukin-6, CRP or sputum responses. CONCLUSIONS: In healthy adults, controlled coarse and fine ambient particle exposures independently induced acute systemic inflammatory responses. Endotoxin contributes to the inflammatory role of particle air pollution. PMID- 24143019 TI - Multicentre study for the evaluation of mutagenic/carcinogenic risk in nurses exposed to antineoplastic drugs: assessment of DNA damage. AB - OBJECTIVES: People who handle antineoplastic drugs, many of which classified as human carcinogens by International Agency for Research on Cancer, are exposed to low doses in comparison with patients; however, the long duration of exposure could lead to health effects. The aim of this work was to evaluate DNA damage in white blood cells from 63 nurses who handle antineoplastic drugs in five Italian hospitals and 74 control participants, using different versions of the Comet assay. METHODS: Primary DNA damage was assessed by using the alkaline version of the assay on leucocytes, whereas to detect DNA oxidative damage and cryptic lesions specifically, the Comet/ENDO III assay and the Comet/araC assay were performed on leucocytes and lymphocytes, respectively. RESULTS: In the present study, no significant DNA damage was correlated with the work shift. The exposed population did not differ significantly from the reference group with respect to DNA primary and oxidative damage in leucocytes. Strikingly, in isolated lymphocytes treated with araC, lower data dispersion as well as a significantly lower mean value for the percentage of DNA in the comet tail was observed in exposed participants as compared with the control group (p<0.05), suggesting a potential chronic exposure to crosslinking antineoplastic drugs. CONCLUSIONS: Although stringent rules were adopted at national and international levels to prevent occupational exposure to antineoplastic drugs, data reported in this study support the idea that a more efficient survey on long-lasting exposures at very low concentrations is needed. PMID- 24143020 TI - Psychosocial work environment and ambulatory blood pressure: independent and combined effect of demand-control and effort-reward imbalance models. AB - BACKGROUND: Two main theoretical models have been used to assess the impact of psychosocial work factors on blood pressure (BP): the demand-control model (DC) and the effort-reward imbalance (ERI) model. Little is known about their independent and combined effect. OBJECTIVE: To examine the independent and combined effect of the DC and ERI models on ambulatory BP (ABP). METHOD: Data were collected three times over 7 years from 3395 white-collar women and men using a repeated cross-sectional design. On each occasion, psychosocial work factors were measured using validated scales. ABP was measured every 15 min during a working day. Systolic and diastolic ABP means were examined in relation to contemporaneous and past exposure. Both models were mutually adjusted. A combined exposure variable was computed. RESULTS: In men, high strain, and active, passive and ERI exposure were associated with ABP using contemporaneous exposure. However, the high strain/ABP association was not significant after adjustment for ERI. In women, no association was found with the DC model, while women exposed to ERI had higher ABP. Use of past exposure showed a stronger association between ABP and active exposure in men, while ERI associations were attenuated. Combined exposure to active jobs and to ERI was associated with ABP in both genders. CONCLUSIONS: In men, associations with the DC model were mixed. Associations between high job strain and ABP were not independent of ERI exposure while both DC intermediate groups were independently associated with ABP. In women, no association was found with the DC model. ERI exposure was independently associated with ABP using contemporaneous exposure, but not using past exposure. Combined active and ERI exposure was also associated with ABP. PMID- 24143021 TI - Letter commentary on Tai et al: dioxin exposure in breast milk and infant neurodevelopment in Vietnam. PMID- 24143022 TI - Characterization of the peripheral structures of archaeal RNase P RNA from Pyrococcus horikoshii OT3. AB - Ribonuclease P (RNase P) is a ubiquitous trans-acting ribozyme that processes the 5' leader sequence of precursor tRNA (pre-tRNA). The secondary structure of RNase P RNA (PhopRNA) in the hyperthermophilic archaeon Pyrococcus horikoshii OT3 has several peripheral stem-loops. In order to investigate their functional role, we prepared six mutants, DeltaP1, DeltaP3, DeltaP8, DeltaP9, DeltaP12 and DeltaP15, in which the stem-loops including helices P1, P3, P8, P9, P12/12.1/12.2 and P15/16 in PhopRNA were individually deleted, respectively, and characterized them with respect to pre-tRNA cleavage activity in the presence of five proteins and also to the ability to form a complex with the proteins. The reconstituted particles containing DeltaP3, DeltaP8 or DeltaP9 retained considerable levels of activity (35-65%), while those containing DeltaP1, DeltaP12 or DeltaP15 had markedly reduced activity (13%). It was further found that the reconstituted particles comprising DeltaP3 or DeltaP15 lacked PhoPop5 and PhoRpp30, whereas those containing DeltaP1, DeltaP8, DeltaP9 or DeltaP12 bound to all five proteins. Since it is known that PhoPop5 functions in a complex with PhoRpp30, the present result suggests that the peripheral stem-loops containing P3 or P15/16 are involved in the structural formation of a catalytic site by interacting with the protein complex PhoPop5-PhoRpp30. PMID- 24143023 TI - Matrix-assisted laser desorption ionisation time-of-flight mass spectrometry for identification of clinically significant bacteria that are difficult to identify in clinical laboratories. AB - AIMS: Although the revolutionary matrix-assisted laser desorption ionisation time of-flight mass spectrometry (MALDI-TOF MS) has been evaluated for identification of various groups of bacteria, its application in bacteria that are 'difficult-to identify' by phenotypic tests has been less well studied. We aim to evaluate the usefulness of MALDI-TOF MS for identification of 'difficult-to-identify' bacterial isolates. METHODS: We evaluated the performance of the Bruker MALDI-TOF MS system for a collection of 67 diverse clinically important bacterial isolates that were less commonly encountered, possessed ambiguous biochemical profiles or belonged to newly discovered species. The results were compared with 16S rRNA gene sequencing as a reference method for species identification. RESULTS: Using 16S rRNA gene sequencing as the reference method, 30 (45%) isolates were identified correctly to species level (score >=2.0), 20 (30%) were only identified to genus level (score >=1.7), four (6%) were misidentified (incorrect species with score >=2.0 or incorrect genus with score >=1.7) and 13 (19%) showed 'no identification' (score <1.7). Aerobic Gram-positive bacteria showed the highest percentage of correct species identification, followed by aerobic Gram negative, anaerobic Gram-positive and anaerobic Gram-negative bacteria. Sixteen isolates identified to genus level actually showed the correct species but with scores below the threshold for species identification. Most isolates which showed 'no identification' were due to the absence of the corresponding species in the Bruker database. CONCLUSIONS: Expansion of commercial databases to include reference spectra of less commonly encountered and newly discovered species and to increase available spectra for each species is required to improve the accuracy of MALDI-TOF MS for identifying 'difficult-to-identify' bacteria. PMID- 24143024 TI - The World Bank and global health: time for a renewed focus on health policy. PMID- 24143025 TI - Allometry of skull morphology, gape size and ingestion performance in the banded watersnake (Nerodia fasciata) feeding on two types of prey. AB - Small body size imposes limitations on the feeding capabilities of juveniles, particularly in species that consume their prey whole. It has been hypothesized that juveniles exhibit exceptional performance measures to compensate for their small size. However, few studies have examined whether juveniles have better feeding performance relative to adults and investigations of snake feeding ontogeny have not shown enhanced performance in smaller snakes. I tested the hypothesis that juvenile snakes have better feeding performance by comparing maximum gape circumference and ingestion performance (time and number of pterygoid protractions) in a series of banded watersnakes (Nerodia fasciata) of different sizes fed fish and frogs. I also measured several external and osteological dimensions of the head and used Akaike's information criterion to determine which morphological measurements were the strongest predictors of relative gape. All skull measurements and maximum gape circumference showed negative allometry relative to snout-vent length (SVL). Given the available models, Akaike information criterion (AIC) analysis indicated that both skull length and mandible length were the strongest predictors of gape circumference for both external and osteological measurements. Multiple regression analysis of ingestion performance indicated SVL was negatively correlated with the time and number of pterygoid protractions required to consume fish or frogs, indicating that juveniles do not have a higher ingestion performance than adults. While exaggerated morphology in juvenile snakes does not appear to improve ingestion performance, a larger gape should increase the ability of juvenile snakes to consume a wide range of encountered prey shapes and sizes. PMID- 24143026 TI - Hearing pathways in the Yangtze finless porpoise, Neophocaena asiaeorientalis asiaeorientalis. AB - How an animal receives sound may influence its use of sound. While 'jaw hearing' is well supported for odontocetes, work examining how sound is received across the head has been limited to a few representative species. The substantial variation in jaw and head morphology among odontocetes suggests variation in sound reception. Here, we address how a divergent subspecies, the Yangtze finless porpoise (Neophocaena asiaeorientalis asiaeorientalis) hears low-, mid- and high frequency tones, as well as broadband clicks, comparing sounds presented at different locations across the head. Hearing was measured using auditory evoked potentials (AEPs). Click and tone stimuli (8, 54 and 120 kHz) were presented at nine locations on the head and body using a suction-cup transducer. Threshold differences were compared between frequencies and locations, and referenced to the underlying anatomy using computed tomography (CT) imaging of deceased animals of the same subspecies. The best hearing locations with minimum thresholds were found adjacent to a mandibular fat pad and overlaying the auditory bulla. Mean thresholds were not substantially different at locations from the rostrum tip to the ear (11.6 dB). This contrasts with tests with bottlenose dolphins and beluga whales, in which 30-40 dB threshold differences were found across the animals' heads. Response latencies increased with decreasing response amplitudes, which suggests that latency and sensitivity are interrelated when considering sound reception across the odontocete head. The results suggest that there are differences among odontocetes in the anatomy related to receiving sound, and porpoises may have relatively less acoustic 'shadowing'. PMID- 24143027 TI - Insights into differential activity patterns of drosophilids under semi-natural conditions. AB - We showed recently that Drosophila ananassae, a closely related and sympatric species of the commonly studied fruitfly D. melanogaster, shows distinctly deviant patterns in circadian activity/rest rhythm from the latter under a variety of laboratory conditions. To examine whether such differences extend to more natural conditions where a variety of time cues and similar environmental pressures might force different species to adopt similar temporal patterns, we examined these two species under semi-natural conditions over a span of 1.5 years. Furthermore, we asked to what extent features of activity/rest rhythm of flies are conserved across species under changing environmental conditions encountered across seasons, and to do so, we studied two more drosophilid species. We found that while each species exhibits seasonality in activity patterns, this seasonality is marked by interesting inter-specific differences. Similar to laboratory studies, D. ananassae showed activity mostly during the day, while D. melanogaster and D. malerkotliana exhibited almost similar activity patterns across seasons, with predominantly two peaks of activity, one in the morning and another in the evening. Throughout the year, Zaprionus indianus displayed very low levels of activity compared with D. melanogaster, yet, compared with those seen in standard laboratory assays, this species exhibited more robust rhythms under semi-natural conditions. We hypothesise that different ecological factors may have influenced these species to adopt different temporal niches. PMID- 24143028 TI - Pharmacological characterization of NMDA-like receptors in the single-celled organism Paramecium primaurelia. AB - Paramecium primaurelia is a unicellular eukaryote that moves in freshwater by ciliary beating and responds to environmental stimuli by altering motile behaviour. The movements of the cilia are controlled by the electrical changes of the cell membrane: when the intraciliary Ca(2+) concentration associated with plasma membrane depolarization increases, the ciliary beating reverses its direction, and consequently the swimming direction changes. The ciliary reversal duration is correlated with the amount of Ca(2+) influx. Here, we evaluated the effects due to the activation or blockade of N-methyl-d-aspartic acid (NMDA) receptors on swimming behaviour in Paramecium. Paramecia normally swim forward, drawing almost linear tracks. We observed that the simultaneous administration of NMDA and glycine induced a partial ciliary reversal (PaCR) leading to a continuous spiral-like swim. Furthermore, the duration of continuous ciliary reversal (CCR), triggered by high external KCl concentrations, was longer in NMDA+glycine-treated cells. NMDA action required the presence of Ca(2+), as the normal forward swimming was restored when the ion was omitted from the extracellular milieu. The PaCR and the enhancement of CCR duration significantly decreased when the antagonists of the glutamate site D-AP5 or CGS19755, the NMDA channel blocker MK-801 or the glycine site antagonist DCKA was added. The action of NMDA+glycine was also abolished by Zn(2+) or ifenprodil, the GluN2A and the GluN2B NMDA-containing subunit blockers, respectively. Searches of the Paramecium genome database currently available indicate that the NMDA-like receptor with ligand-binding characteristics of an NMDA receptor-like complex, purified from rat brain synaptic membranes and found in some metazoan genomes, is also present in Paramecium. These results provide evidence that functional NMDA receptors similar to those typical of mammalian neuronal cells are present in the single celled organism Paramecium and thus suggest that the glutamatergic NMDA system is a phylogenetically old behaviour-controlling mechanism. PMID- 24143029 TI - Nitric oxide metabolites during anoxia and reoxygenation in the anoxia-tolerant vertebrate Trachemys scripta. AB - Moderate elevations of nitrite and nitric oxide (NO) protect mammalian tissues against ischemia (anoxia)-reperfusion damage by inhibiting mitochondrial electron transport complexes and reducing the formation of reactive oxygen species (ROS) upon reoxygenation. Crucian carp appear to exploit this mechanism by upregulating nitrite and other nitrite/NO metabolites (S-nitroso and iron-nitrosyl compounds) in several tissues when exposed to anoxia. We investigated whether this is a common strategy amongst anoxia-tolerant vertebrates by evaluating NO metabolites in red-eared slider turtles during long-term (9 days) anoxia and subsequent reoxygenation at low temperature, a situation naturally encountered by turtles in ice-covered ponds. We also measured glutathione in selected tissues and assessed the impact of anoxia on electrolyte status. Anoxia induced major increases in [nitrite] in the heart, pectoral muscle and red blood cells, while [nitrite] was maintained unaltered in brain and liver. Concomitantly, the concentrations of S nitroso and iron-nitrosyl compounds increased, showing that nitrite was used to produce NO and to S-nitrosate cellular molecules during anoxia. The changes were gradually reversed during reoxygenation (1 h and 24 h), testifying that the processes were reversible. The increased NO bioavailability occurred in the absence of NO synthase activity (due to global anoxia) and may involve mobilization of internal/external nitrite reservoirs. Our data support the theory that anoxic upregulation of nitrite and other NO metabolites could be a general cytoprotective strategy amongst anoxia-tolerant vertebrates. The possible mechanisms of nitrite-derived NO and S-nitrosation in protecting cells from destructive Ca(2+) influx during anoxia and in limiting ROS formation during reoxygenation are discussed. PMID- 24143030 TI - Mechanical output in jumps of marmosets (Callithrix jacchus). AB - In this study we determined the mechanical output of common marmosets (Callithrix jacchus) during jumping. Vertical ground reaction forces were measured in 18 animals while they jumped from an instrumented crossbar to a crossbar located 70 cm higher. From the vertical force time histories, we calculated the rate of change of mechanical energy of the centre of mass (dE/dt). The mean value of dE/dt during the push-off amounted to 51.8+/-6.2 W kg(-1) body mass, and the peak value to 116.4+/-17.6 W kg(-1) body mass. We used these values in combination with masses of leg muscles, determined in two specimens, to estimate mean and peak values of dE/dt of 430 and 970 W kg(-1) muscle, respectively. These values are higher than values reported in the literature for jumps of humans and bonobos, but smaller than those of jumps of bushbabies. Surprisingly, the mean value of dE/dt of 430 W kg(-1) muscle was close to the maximal power output of 516 W kg(-1) muscle reported in the literature for isokinetic contractions of rat medial gastrocnemius, one of the fastest mammalian muscles. Further study of the force-velocity relationship of muscle tissue of small primates is indicated. PMID- 24143032 TI - Corrections to PCBs and OH-PCBs in Serum from Children and Mothers in Urban and Rural U.S. Communities. PMID- 24143031 TI - Kinship-based management strategies for captive breeding programs when pedigrees are unknown or uncertain. AB - Zoo-based captive breeding programs typically rely on accurate pedigrees to maintain long-term population genetic diversity and prevent close inbreeding. For many mixed-sex captive populations, it is difficult to assign parentage of offspring with certainty without conducting DNA-based parentage analyses. Using the demographic parameters of a North American captive population of Arabian oryx (Oryx leucoryx), 2 kinship-based breeding-pair selection strategies were modeled for their performance in handling pedigrees with varying degrees of parentage uncertainty. We also compared these strategies with 2 nonkinship-based methods. Pedigrees simulated under different management strategies were compared for their long-term ability to maintain gene diversity (GD) and avoid inbreeding. For the Arabian oryx, results indicate that recording multiple possible parents instead of removing the unknown genomic portion of the pedigree can more efficiently utilize all animals available for breeding without compromising GD and inbreeding avoidance. Both kinship-based breeding-pair selection strategies significantly outperformed the nonkinship-based strategies. PMID- 24143033 TI - Characterization of full set material constants of piezoelectric materials based on ultrasonic method and inverse impedance spectroscopy using only one sample. AB - The most difficult task in the characterization of complete set material properties for piezoelectric materials is self-consistency. Because there are many independent elastic, dielectric, and piezoelectric constants, several samples are needed to obtain the full set constants. Property variation from sample to sample often makes the obtained data set lack of self-consistency. Here, we present a method, based on pulse-echo ultrasound and inverse impedance spectroscopy, to precisely determine the full set physical properties of piezoelectric materials using only one small sample, which eliminated the sample to sample variation problem to guarantee self-consistency. The method has been applied to characterize the [001]C poled Mn modified 0.27Pb(In1/2Nb1/2)O3 0.46Pb(Mg1/3Nb2/3)O3-0.27PbTiO3 single crystal and the validity of the measured data is confirmed by a previously established method. For the inverse calculations using impedance spectrum, the stability of reconstructed results is analyzed by fluctuation analysis of input data. In contrast to conventional regression methods, our method here takes the full advantage of both ultrasonic and inverse impedance spectroscopy methods to extract all constants from only one small sample. The method provides a powerful tool for assisting novel piezoelectric materials of small size and for generating needed input data sets for device designs using finite element simulations. PMID- 24143034 TI - SUPERACID-PROMOTED HYDROXYALKYLATION OF 1,2-INDANDIONES. AB - 1,2-Indandione reacts efficiently with arenes to give 2,2-diaryl-1-indanones by the hydroxyalkylation reaction. The Bronsted superacid CF3SO3H (triflic acid) is an effective catalyst for these condensation reactions. The requisite 1,2 indandiones were prepared from the 1-indanones. PMID- 24143035 TI - Ring closing and opening reactions leading to aza-polycyclic aromatic compounds. AB - A series of functionalized aza-polycyclic aromatic compounds were prepared by a superacid-promoted ring closing and opening reaction cascade. A reaction mechanism is proposed, which involves reactive dicationic intermediates. A key step in the conversions involves ipso protonation of an aryl group and elimination of an alkyl phenyl group. PMID- 24143036 TI - Cyclizations of phenylethyl-substituted pyridinecarboxaldehydes. AB - Several phenylethyl-substituted pyridinecarboxaldehydes were prepared from 2 bromo-3-pyridinecarboxaldehyde and these substances are found to undergo cyclization reactions in acidic media. In the absence of added nucleophile, acid promoted cyclization and oxidation (MnO2) provides an efficient route to 10,11 dihydro-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-ones. Arene nucleophiles may also be added to the acidic mixture to provide good yields of triarylmethane products. Mechanisms are proposed involving dicationic superelectrophilic intermediates. PMID- 24143037 TI - Understanding and comparisons of different sampling approaches for the Fourier Amplitudes Sensitivity Test (FAST). AB - Fourier Amplitude Sensitivity Test (FAST) is one of the most popular uncertainty and sensitivity analysis techniques. It uses a periodic sampling approach and a Fourier transformation to decompose the variance of a model output into partial variances contributed by different model parameters. Until now, the FAST analysis is mainly confined to the estimation of partial variances contributed by the main effects of model parameters, but does not allow for those contributed by specific interactions among parameters. In this paper, we theoretically show that FAST analysis can be used to estimate partial variances contributed by both main effects and interaction effects of model parameters using different sampling approaches (i.e., traditional search-curve based sampling, simple random sampling and random balance design sampling). We also analytically calculate the potential errors and biases in the estimation of partial variances. Hypothesis tests are constructed to reduce the effect of sampling errors on the estimation of partial variances. Our results show that compared to simple random sampling and random balance design sampling, sensitivity indices (ratios of partial variances to variance of a specific model output) estimated by search-curve based sampling generally have higher precision but larger underestimations. Compared to simple random sampling, random balance design sampling generally provides higher estimation precision for partial variances contributed by the main effects of parameters. The theoretical derivation of partial variances contributed by higher order interactions and the calculation of their corresponding estimation errors in different sampling schemes can help us better understand the FAST method and provide a fundamental basis for FAST applications and further improvements. PMID- 24143038 TI - Benzophenones from Hypericum elegans with antioxidant and acetylcholinesterase inhibitory potential. AB - BACKGROUND: Hypericum elegans is used in Bulgarian folk medicine for treatment of wounds, depression, gastrointestinal and bacterial diseases. OBJECTIVE: RECENTLY, NEW NATURAL BENZOPHENONES: Elegaphenone and O-glycosides: Hypericophenonoside, Neoannulatophenonoside and Elegaphenonoside as well as already known 7 Epiclusianone were isolated from the titled species. The aim of the present study was to evaluate the antioxidant and acetyl cholinesterase inhibitory potential of the isolated compounds. MATERIALS AND METHODS: 1,1-diphenyl-2-picrylhydrazyl (DPPH) and 2,2'-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) di-ammonium salt (ABTS) free radicals, ferric reducing antioxidant power (FRAP) assay as well as inhibition of lipid peroxidation in linoleic acid system were used for determination of antioxidant activity. Modified Ellman's colorimetric method was carried out to assess the acetyl cholinesterase inhibition potential. Hyperoside and Galantamine hydrobromide were used as positive controls. RESULTS: Hypericophenonoside was found to possess the strongest DPPH radical scavenging activity (IC50 = 181.85 +/- 6.82 MUM), while Neoannulatophenonoside showed the highest ABTS (IC50 = 0.25 +/- 0.005 MUM) and lipid peroxidation inhibitor activity. FRAP activity was demonstrated only by prenylated aglycones - Elegaphenone [942.16 +/- 4.03 MUM Trolox Equivalent (TE)] and 7-Epiclusianone (642.95 +/- 3.95 MUM TE) and was stronger compared to the control Hyperoside (421.75 +/- 9.29 MUM TE). Elegaphenone and 7-Epiclusianone were found to possess moderate acetyl cholinesterase inhibitory potential with IC50 values of 192.19 +/ 3.54 MUM and 142.97 +/- 4.62 MUM, respectively. CONCLUSION: The results obtained revealed that H. elegans is a potential natural source of bioactive compounds and benzophenones could be useful in therapy of free radical pathologies and neurodegenerative disorders. PMID- 24143039 TI - beta-cyclodextrin assistant flavonoid glycosides enzymatic hydrolysis. AB - BACKGROUND: The content of icaritin and genistein in herba is very low, preparation with relatively large quantities is an important issue for extensive pharmacological studies. OBJECTIVE: This study focuses on preparing and enzymic hydrolysis of flavonoid glycosides /beta-cyclodextrin inclusion complex to increase the hydrolysis rate. MATERIALS AND METHODS: The physical property of newly prepared inclusion complex was tested by differential scanning calorimetry (DSC). The conditions of enzymatic hydrolysis were optimized for the bioconversion of flavonoid glycosides /beta-cyclodextrin inclusion complex by mono-factor experimental design. The experiments are using the icariin and genistein as the model drugs. RESULTS: The solubility of icariin and genistein were increased almost 17 times from 29.2 MUg/ml to 513.5 MUg/ml at 60 degrees C and 28 times from 7.78 MUg/ml to 221.46 MUg/ml at 50 degrees C, respectively, demonstrating that the inclusion complex could significantly increase the solubility of flavonoid glycosides. Under the optimal conditions, the reaction time of icariin and genistin decreased by 68% and 145%, when compared with that without beta-CD inclusion. By using this enzymatic condition, 473 mg icaritin (with the purity of 99.34%) and 567 mg genistein(with the purity of 99.46%), which was finally determined by melt point, ESI-MS, UV, IR, (1)H NMR and (13)C NMR, was obtained eventually by transforming the inclusion complex(contains 1.0 g substrates). CONCLUSION: This study can clearly indicate a new attempt to improve the speed of enzyme-hydrolysis of poorly water-soluble flavonoid glycosides and find a more superior condition which is used to prepare icaritin and genistein. PMID- 24143040 TI - Determination of oleanolic acid and ursolic acid in Chinese medicinal plants using HPLC with PAH polymeric C18. AB - BACKGROUND: The RP-HPLC resolution of two triterpenic acid isomers was unstable. OBJECTIVE: To separate the oleanolic acid (OA) and ursolic acid (UA) simply within RP-HPLC. MATERIALS AND METHODS: The separation ability of five stationary phases was studied with the retention effect of their carbon loads. Also the resolution effects of mobile phase composition and different column temperatures were systematically investigated by using Drylab((r)) (Rheodyne LLC.) after evaluating chromatograms automatically. RESULTS: The best available resolution of two bioactive isomers was achieved (r = 3.4) via using PAH (polycyclic aromatic hydrocarbons) polymeric C18 bonded phase column. The chromatographic system was applied to the quantification in ten Chinese medicinal plants and the validation was carried out and the precision (RSD <=1.34%), the linearity (r >= 0.9998) and the recovery (range from 92.1% to 102.6%) were acceptable. CONCLUSION: It is clear that the method was simple, rapid and reliable for the quantification of two compounds in new HPLC method within PAH polymeric C18. PMID- 24143041 TI - Bioassay- and liquid chromatography/mass spectrometry-guided acetylcholinesterase inhibitors from Picriafel-terrae. AB - BACKGROUND: Picria fel-terrae is a traditional Chinese medicine. MATERIALS AND METHODS: A new approach to the search for acetylcholinesterase (AChE) inhibitors from Picria fel-terrae is presented. RESULTS: Bioassay- and LC-MS-guided fractionation of the ethyl acetate extract was from traditional Chinese medicine P.fel-terrae. Following primary extraction, the ethyl acetate extracts fraction of P.fel-terrae showed strong AChE inhibitory activities. So the sample was separated using highperformance liquid chromatography (HPLC). The effluent was split towards two identical 96-well fraction collectors, and the presence of the biologically interesting portion and chromatographic fractions could be readily detected by analyzing selected ion chromatograms through an electrophoresis electrospray ionization mass spectrometry (ESIMS) system for accurate mass measurement. One 96-well plate was used for a bioassay (AChE-inhibitory assay) and detected the bioactivity and position of the relevant peak in the chromatogram. The positive well in the second 96-well plate was used for identification by LC-(+) ESIMS. CONCLUSION: As abovementioned, the AChE inhibitory constituents from P.fel-terrae by LC-bioassay-ESIMS were rapid identified. Liquid chromatography/ mass spectrometry (LC-MS) screening detected the presence of six active compounds, identified as picfeltarraenin IA (1), picfeltarraenin IB (2), picfeltarraenin IV (3), picfeltarraenin X (4), picfeltarraenin XI (5), and one unknown compound. The structures were further determined by 13C NMR. The six compounds expressed stronger AChE inhibition than the known AChE inhibitorTacrine. Above all, the value of this LC-bioassay-ESIMS methodology is highlighted by the finding and structure elucidation of the active constituents from many other structural families of natural products. PMID- 24143042 TI - Optimization of enzyme-assisted extraction and characterization of collagen from Chinese sturgeon (Acipenser sturio Linnaeus) skin. AB - BACKGROUND: Sturgeon (Acipenser sturio Linnaeus) skin contains high amount of nutrients including unsaturated fatty acids and collagen. A pepsin-assisted extraction procedure was developed and optimized for the extraction of collagen from Chinese sturgeon (Acipenser sturio Linnaeus) skins. OBJECTIVE: To determine the optimum conditions with the maximum yield of the pepsin-soluble collagen (PSC) extraction. MATERIALS AND METHODS: The conditions of the extraction were optimized using response surface methodology. The Box-Behnken design was used to evaluate the effects of the three independent variables (extraction time, enzyme concentration, and solid-liquid ratio) on the PSC yield of the sturgeon skin. RESULTS: THE OPTIMAL CONDITIONS WERE: solid-liquid ratio of 1:11.88, enzyme concentration of 2.42%, and extraction time of 6.45 h. The maximum yield of 86.69% of PSC was obtained under the optimal conditions. This value was not significantly different from the predicted value (87.4%) of the RSM (P < 0.05). CONCLUSION: The results of this study indicated that the production of PSC from sturgeon skin is feasible and beneficial. The patterns of sodium dodecyl sulfate polyacrylamide gel electrophoretic patterns (SDS-PAGE) indicated that the sturgeon skin contains type I collagen, which is made of alpha-chain and beta chain. The infrared spectra of the collagens also indicated that pepsin hydrolysis does not affect the secondary structure of collagen, especially triple helical structure. PMID- 24143043 TI - The ginsenosides and carbohydrate profiles of ginseng cultivated under mountainous forest. AB - BACKGROUND: Ginseng cultivated under mountainous forest, called "Lin-Xia-Shan Shen" (LXSS) in China's Pharmacopoeia. In recent years, it has been quickly propelled to plant at a large scale. OBJECTIVE: To study the profiles of ginsenosides and carbohydrate profiles of LXSS. MATERIALS AND METHODS: The contents of ginsenosides and carbohydrates, such as soluble sugar, polysaccharide, pectin, and starch in LXSS, were determined. All the above components were profiled, and the correlations between them were analyzed. RESULTS: The results indicated that the contents of total ginsenoside, protopanaxadiol, protopanaxatriol, Rg1, Re, Rb1, Rc, Rb2, Rd, starch, and pectin were negatively correlated with the growing years within 17 years. Among them, the content of starch was positively correlated with that of pectin. The total ginsenosides was positively correlated with starch and pectin, which cannot be found in garden ginseng, maybe resulting of fertilizer and other manual intervention in process of cultivation of garden ginseng. DISCUSSION AND CONCLUSIONS: The accumulation of ginsenosides and carbohydrate, especially starch and pectin, was different in garden ginseng and LXSS. This research may provide the scientific basis for germplasm evaluation, the cultivation and utilization of ginseng cultivated under mountainous forest. PMID- 24143044 TI - Modulation of drug efflux by aloe materials: An In Vitro investigation across rat intestinal tissue. AB - BACKGROUND: Clinically, significant herb-drug interactions have been previously documented and can be pharmacodynamic and/or pharmacokinetic in nature. Pharmacokinetic interactions have been attributed to induction or inhibition of either metabolic enzymes or efflux transporters. OBJECTIVE: The effect of gel and whole leaf materials from 3 different aloe species namely Aloe ferox, Aloe marlothii, and Aloe vera as well as polysaccharides precipitated from the A. vera materials on the bi-directional transport of cimetidine across rat intestinal tissue was investigated. MATERIALS AND METHODS: Cimetidine transport studies were performed across excised rat intestinal tissue mounted in Sweetana-Grass diffusion chambers in both the apical-to-basolateral and basolateral-to-apical directions. RESULTS: While A. vera gel and whole leaf materials did not inhibit the efflux of cimetidine, the polysaccharides precipitated from them did show a reduction of cimetidine efflux. On the other hand, both A. ferox and A. marlothii gel and whole leaf materials exhibited an inhibition effect on cimetidine efflux. CONCLUSIONS: This study identified a modulation effect of efflux transporters by certain aloe materials. This may cause herb-drug pharmacokinetic interactions when drugs that are substrates for these efflux transporters are taken simultaneously with aloe materials. On the other hand, these aloe materials may be used for drug absorption enhancement for drugs with low bioavailability due to extensive efflux. PMID- 24143045 TI - In vitro and in vivo studies of an aqueous extract of Matricaria recutita (German chamomile) on the radiolabeling of blood constituents, on the morphology of red blood cells and on the biodistribution of the radiopharmaceutical sodium pertechnetate. AB - BACKGROUND: Natural products might alter the labeling of blood constituents with technetium-99m ((99m)Tc) and these results may be correlated with modifications of the shape of the red blood cells (RBC). The biodistribution of radiopharmaceuticals can be also altered. OBJECTIVE: This investigation aimed to determine biological effects of an aqueous extract of chamomile (CE). MATERIALS AND METHODS: To study the effect of the CE on the labeling of blood constituents with (99m)Tc, in vitro and in vivo assays were performed. The effect of the CE on the morphology of RBC was observed under light microscope. The images were acquired, processed, and the perimeter/area ratio of the RBC determined. To analyze the effect of the CE on biodistribution of the sodium pertechnetate (Na(99m)TcO4) in Wistar rats, these animals were treated or not with a CE. Na(99m)TcO4 was injected, the rats were sacrificed, the organs were removed, weighted and percentage of radioactivity/gram calculated. RESULT: In the in vitro experiment, the radioactivity on blood cells compartment and on insoluble fractions of plasma was diminished. The shape and the perimeter/area ratio of the RBC were altered in in vitro assays. An increase of the percentage of radioactivity of Na(99m)TcO4 was observed in stomach after in vivo treatment. CONCLUSION: These results could be due to substances of the CE or by the products of the metabolism of this extract in the animal organism. These findings are examples of drug interaction with a radiopharmaceutical, which could lead to misdiagnosis in clinical practice with unexpected consequences. PMID- 24143046 TI - Diverse role of fast growing rhizobia in growth promotion and enhancement of psoralen content in Psoralea corylifolia L. AB - BACKGROUND: Psoralea corylifolia (Bakuchi), a weed, which possesses a highly potent and medicinally important compound psoralen. P. corylifolia has been widely exploited since ages for its biological potential. MATERIALS AND METHODS: Fifteen root nodulating bacteria as pure culture collection (PCC) were isolated from P. corylifolia in India. Further, these strains were evaluated for their effect on the psoralen content in P. corylifolia. High performance liquid chromatography (HPLC) method was used for the estimation of psoralen in P. corylifolia seed extracts. The effectiveness of these rhizobial strains was assessed on the basis of screening of various plant growth promoting attributes. RESULTS: The 16S ribosomal RNA sequencing analysis revealed the identity of two most effective rhizobial isolates PCC2 and PCC7 as Rhizobium leguminosarum and Sinorhizobium meliloti, respectively. The R. leguminosarum PCC2 (JN546144) and Ensifer meliloti PCC7 (JN546145) strains showed solubilization of insoluble inorganic phosphate, secreted indole acetic acid (IAA), produced siderophore, showed ACC deaminase activity, and were positive for nodulation and nitrogen fixing genes. Seeds of P. corylifolia were bacterized with combination of R. leguminosarum PCC2 and Ensifer meliloti PCC7 along with their individual application that resulted in enhancement of various early vegetative and late reproduction parameters of plants in two consecutive field trials in the year 2009 and 2010. The psoralen content in the seeds of P. corylifolia was observed to be increased in the field trials where the combination of rhizobial strains PCC2 and PCC7 was used (2.79%) compared to control (1.91%). CONCLUSION: These findings indicate that rhizobial strains PCC2 and PCC7 showing good plant growth promoting attributes can be effective for increasing the psoralen content in the seeds of P. corylifolia to a certain level. PMID- 24143047 TI - Formulation development, optimization and evaluation of aloe vera gel for wound healing. AB - PURPOSE: To formulate and optimize a herbal gel of Aloe vera extract containing Carbopol 934 as gelling agent and to investigate the effects of topical application of Carbopol 934 gel containing Aloe vera extract on the healing of skin wounds surgically induced in Wistar rats. MATERIALS AND METHODS: Different concentrations of viscosity enhancer Carbopol 934 were tried and finally gel that showed good spreadability and consistency was selected for wound healing property of herbal gel of Aloe vera. Excision wound model was used for the study. RESULTS: The optimized gel was evaluated for different physicochemical properties and wound healing property. Differences in wound healing were observed between the various treatments when compared to the control group. Tissue hyperplasia was lower in the control group compared to the other treated groups. In animals group treated with gel, 80.14% healing was observed up to 14(th) day. While in untreated group I (control) animals showed 52.68% healing of wounds on 14(th) day. On the other hand, control group animals also showed inflammation and pus formation up to 5(th) day of study, while treated animals did not showed any observable inflammation and pus formation. CONCLUSION: Results shows prepared gel has promising effect on the wound healing process. PMID- 24143048 TI - Mitigation of starch and glucose-induced postprandial glycemic excursion in rats by antioxidant-rich green-leafy vegetables' juice. AB - OBJECTIVE: Consumption of green-leafy vegetables is being advocated beneficial for type 2 diabetes mellitus individuals possibly because they are cost effective source of potent biological antioxidants. This research analyzed various phytochemicals, free radicals scavenging antioxidant potentials and starch digesting enzymes inhibitory activities in fresh juice of nine green-leafy vegetables. Furthermore, this study also investigated influence of these vegetables juice on starch and glucose induced postprandial glycemic load. MATERIALS AND METHODS: Phytochemical constituents, in vitro free radicals scavenging antioxidant and enzymes inhibitory activities were evaluated applying various reported methods. Post-prandial glycemic excursion was induced in rats pretreated with vegetables juice by oral administration of starch and glucose. RESULTS: All the leafy vegetables juice displayed potent free radicals scavenging activities. Juice of amaranthus, rumex, palak and raphanus displayed potential anti-oxidative property by reducing H2O2 induced hemolysis in rats red blood cells RBCs. Ajwain and rumex juice showed pancreatic alpha-amylase inhibitory activity. Alternanthera, ajwain, methi, amaranthus and sowa leaves juice displayed intestinal alpha-glucosidase inhibitory activity. Juice of raphanus, ajwain and sowa significantly mitigated starch-induced postprandial glycemic load. Amaranthus leaves juice potently mitigated glucose-induced postprandial glycemic load and also reduced hemoglobin glycation induced by glucose in vitro. CONCLUSIONS: This investigation finds that juice of leafy vegetables is potent source of biological antioxidants. In addition, juice of raphanus, ajwain and sowa leaves possess capacity to mitigate starch induced postprandial glycemic burden and amaranthus leaves' juice can reduce glucose induced postprandial glycemic excursion. PMID- 24143049 TI - in-silico characterization of beta-(1, 3)-endoglucanase (ENGL1) from Aspergillus fumigatus by homology modeling and docking studies. AB - During the past few years a significant rise in aspergillosis caused by filamentous fungus Aspergillus fumigatus has been recorded particularly in immunocompromised patients. At present, there are limited numbers of antifungal agents to combat these infections and the situation has become more complex due to emergence of antifungal resistance and side-effects of antifungal drugs. These situations have increased the demand for novel drug targets. Recent studies have revealed that the beta-1,3-endoglucanase (ENGL1) plays an essential role in cell wall remodeling that is absolutely required during growth and morphogenesis of filamentous fungi and thus is a promising target for the development of antifungal agents. Unfortunately no structural information of fungal beta- glucanases has yet been available in the Protein Databank (PDB). Therefore in the present study, 3D structure of beta-(1,3)- endoglucanase (ENGL1) was modeled by using I-TASSER server and validated with PROCHECK and VERIFY 3D. The best model was selected, energy minimized and used to analyze structure function relationship with substrate beta-(1,3)-glucan by C-DOCKER (Accelrys DS 2.0). The results indicated that amino acids (GLU 380, GLN 383, ASP 384, TYR 395, SER 712, and ARG 713) present in beta-1,3-endoglucanase receptor are of core importance for binding activities and these residues are having strong hydrogen bond interactions with beta-(1,3)-glucan. The predicted model and docking studies permits initial inferences about the unexplored 3D structure of the beta-(1,3) endoglucanase and may be promote in relational designing of molecules for structure-function studies. PMID- 24143050 TI - Homology modeling and structural validation of tissue factor pathway inhibitor. AB - Blood coagulation is a cascade of complex enzymatic reactions which involves specific proteins and cellular components to interact and prevent blood loss. The coagulation process begins by either "Tissue Dependent Pathway" (also known as extrinsic pathway) or by "contact activation pathway" (also known as intrinsic pathway). TFPI is an endogenous multivalent Kunitz type protease inhibitor which inhibits Tissue factor dependent pathway by inhibiting Tissue Factor:Factor VIIa (TF:FVIIa) complex and Factor Xa. TFPI is one of the most studied coagulation pathway inhibitor which has various clinical and potential therapeutic applications, however, its exact mechanism of inhibition is still unknown. Structure based mechanism elucidation is commonly employed technique in such cases. Therefore, in the current study the generated a complete TFPI structural model so as to understand the mechanistic details of it's functioning. The model was checked for stereochemical quality by PROCHECK-NMR, WHATIF, ProSA, and QMEAN servers. The model was selected, energy minimized and simulated for 1.5ns. The result of the study may be a guiding point for further investigations on TFPI and its role in coagulation mechanism. PMID- 24143051 TI - Molecular docking study of Beta-glucosidase with cellobiose, cellotetraose and cellotetriose. AB - Beta-glucosidase (3.2.1.21) plays an essential role in the removal of non reducing terminal glucosyl residues from glycosides. Recently, beta-glucosidase has been of interest for biomass conversion that acts in synergy with two other enzymes, endoglucanase and exo-glucanase. However, there is not much information available on the catalytic interactions of beta-glucosidase with its substrates. Thus, this study reports on the binding modes between beta-glucosidase from glycoside hydrolase family 1 namely BglB with cellobiose, cellotetraose and cellotetriose via molecular docking simulation. From the results, the binding affinities of BglB-cellobiose, BglB-cellotetraose, and BglB-cellotetriose complexes were reported to be -6.2kJ/mol , -5.68 kJ/mol and -5.63 kJ/mol, respectively. The detail interactions were also been investigated that revealed the key residues involved in forming hydrogen bonds (h-bond) with the substrates. These findings may provide valuable insigths in designing beta-glucosidase with higher cellobiose-hydrolyzing efficiency. PMID- 24143052 TI - Morphological redescription and molecular characterization of three species of Travassosinematidae (Nematoda: Oxyurida: Thelastomatoidea) from Gryllotalpa africana Beauv (Orthoptera: Gryllotalpidae). AB - Binema mirzaia (Basir, 1942a) Basir, 1956, Cameronia nisari (Parveen and Jairajpuri, 1985) Adamson and Van Waerebeke, 1992a and Mirzaiella meerutensis Singh and Malti, 2003 are redescribed morphologically along with molecular identification from the intestine of mole cricket Gryllotalpa africana. Molecular characterization was carried out using the D2-D3 expansion domains of the 18S ribosomal DNA region. This study first time presents molecular data for the above three nematode species. PMID- 24143053 TI - Feature Selection for high Dimensional DNA Microarray data using hybrid approaches. AB - Feature selection from DNA microarray data is a major challenge due to high dimensionality in expression data. The number of samples in the microarray data set is much smaller compared to the number of genes. Hence the data is improper to be used as the training set of a classifier. Therefore it is important to select features prior to training the classifier. It should be noted that only a small subset of genes from the data set exhibits a strong correlation with the class. This is because finding the relevant genes from the data set is often non trivial. Thus there is a need to develop robust yet reliable methods for gene finding in expression data. We describe the use of several hybrid feature selection approaches for gene finding in expression data. These approaches include filtering (filter out the best genes from the data set) and wrapper (best subset of genes from the data set) phases. The methods use information gain (IG) and Pearson Product Moment Correlation (PPMC) as the filtering parameters and biogeography based optimization (BBO) as the wrapper approach. K nearest neighbour algorithm (KNN) and back propagation neural network are used for evaluating the fitness of gene subsets during feature selection. Our analysis shows that an impressive performance is provided by the IG-BBO-KNN combination in different data sets with high accuracy (>90%) and low error rate. PMID- 24143054 TI - Insights from the computational analysis of CD271 glycation in mescenchymal stem cells in diabetes mellitus as a predisposition to latent tuberculosis. AB - Diabetes mellitus is considered as a predisposition factor for active tuberculosis and is known to activate the latent form of tuberculosis. However, the causative association of latent tuberculosis with diabetes is not conclusively established. Therefore, it is of interest to relate their predisposition. We describe the glycation pattern of mescenchymal stem cell surface markers as CD271+/CD45-mescenchymal stem cell is known to be associated with latent tuberculosis. We show that the lysine residues important for function of CD271 death domain are predicted to be and glycated. These observations help to discuss the role of CD271 and glycation to modulate the genesis of latent tuberculosis in chronic diabetic mellitus. PMID- 24143055 TI - A comprehensive analysis of LACK (Leishmania homologue of receptors for activated C kinase) in the context of Visceral Leishmaniasis. AB - The Leishmania homologue of activated C kinase (LACK) a known T cell epitope from soluble Leishmania antigens (SLA) that confers protection against Leishmania challenge. This antigen has been found to be highly conserved among Leishmania strains. LACK has been shown to be protective against L. donovani challenge. A comprehensive analysis of several LACK sequences was completed. The analysis shows a high level of conservation, lower variability and higher antigenicity in specific portions of the LACK protein. This information provides insights for the potential consideration of LACK as a putative candidate in the context of visceral Leishmaniasis vaccine target. PMID- 24143056 TI - MAGICdb - Mango Genetic stocks Identification and Characterisation database. AB - MAGICdb is a unique database that integrates the morphological, fruit quality and the marker data of most popular and widely cultivated commercially important mango cultivars. The main objective of MAGICdb is to provide the end users with an integrated dataset of each mango variety cultivated widely in Tamil Nadu. MAGICdb structure is categorized in to three domains namely Morphological Data Search, Fruit Quality Search and Marker Search which in further contains details on Tree Character, Bearing Habit, Season of fruiting, Number of inflorescence/Sq.m, Percentage of hermaphrodite flower(%), Fruit set percentage(%), Number of fruits/ tree, Fruit weight (g) and, Yield (Kg/ tree). This database is equipped with a user friendly interface enabling the users to retrieve the information with ease. Database is available at http://www.tnaugenomics.com/mango/index.php. PMID- 24143057 TI - AutoAssemblyD: a graphical user interface system for several genome assemblers. AB - Next-generation sequencing technologies have increased the amount of biological data generated. Thus, bioinformatics has become important because new methods and algorithms are necessary to manipulate and process such data. However, certain challenges have emerged, such as genome assembly using short reads and high throughput platforms. In this context, several algorithms have been developed, such as Velvet, Abyss, Euler-SR, Mira, Edna, Maq, SHRiMP, Newbler, ALLPATHS, Bowtie and BWA. However, most such assemblers do not have a graphical interface, which makes their use difficult for users without computing experience given the complexity of the assembler syntax. Thus, to make the operation of such assemblers accessible to users without a computing background, we developed AutoAssemblyD, which is a graphical tool for genome assembly submission and remote management by multiple assemblers through XML templates. AVAILABILITY: AssemblyD is freely available at https://sourceforge.net/projects/autoassemblyd. It requires Sun jdk 6 or higher. PMID- 24143058 TI - OPTSDNA: Performance evaluation of an efficient distributed bioinformatics system for DNA sequence analysis. AB - Storage of sequence data is a big concern as the amount of data generated is exponential in nature at several locations. Therefore, there is a need to develop techniques to store data using compression algorithm. Here we describe optimal storage algorithm (OPTSDNA) for storing large amount of DNA sequences of varying length. This paper provides performance analysis of optimal storage algorithm (OPTSDNA) of a distributed bioinformatics computing system for analysis of DNA sequences. OPTSDNA algorithm is used for storing various sizes of DNA sequences into database. DNA sequences of different lengths were stored by using this algorithm. These input DNA sequences are varied in size from very small to very large. Storage size is calculated by this algorithm. Response time is also calculated in this work. The efficiency and performance of the algorithm is high (in size calculation with percentage) when compared with other known with sequential approach. PMID- 24143059 TI - Nonlinear optical properties of free standing films of PbS quantum dots in the nonresonant femtosecond regime. AB - Devices based on optical technology for high speed communication networks require materials with large nonlinear optical response in the ultrafast regime. Nonlinear optical materials have also attracted wide attention as potential candidates for the protection of optical sensors and eyes while handling lasers. Optical limiters have a constant transmittance at low input influence and a decrease in transmittance at higher fluences and are based on a variety of mechanisms such as nonlinear refraction, nonlinear scattering, multiphoton absorption and free carrier absorption. As we go from bulk to nanosized materials especially in the strong quantum confinement regime where radius of the nanoparticle is less than the bulk exciton Bohr radius, the optical nonlinearity is enhanced due to quantum confinement effect. This paper is on the ultrafast nonresonant nonlinearity in free standing films of PbS quantum dots stabilized in a synthetic glue matrix by a simple chemical route which provides flexibility of processing in a variety of physical forms. Optical absorption spectrum shows significant blue shift from the bulk absorption onset indicating strong quantum confinement. PbS quantumdots of mean size 3.3nm are characterized by X-ray diffraction and transmission electron microscopy. The mechanism of nonlinear absorption giving rise to optical limiting is probed using open z-scan technique with laser pulses of 150 fs pulse duration at 780 nm and the results are presented in the nonresonant femtosecond regime. Irradiance dependence on nonlinear absorption are discussed. PMID- 24143060 TI - Dynamic Network Logistic Regression: A Logistic Choice Analysis of Inter- and Intra-Group Blog Citation Dynamics in the 2004 US Presidential Election. AB - Methods for analysis of network dynamics have seen great progress in the past decade. This article shows how Dynamic Network Logistic Regression techniques (a special case of the Temporal Exponential Random Graph Models) can be used to implement decision theoretic models for network dynamics in a panel data context. We also provide practical heuristics for model building and assessment. We illustrate the power of these techniques by applying them to a dynamic blog network sampled during the 2004 US presidential election cycle. This is a particularly interesting case because it marks the debut of Internet-based media such as blogs and social networking web sites as institutionally recognized features of the American political landscape. Using a longitudinal sample of all Democratic National Convention/Republican National Convention-designated blog citation networks, we are able to test the influence of various strategic, institutional, and balance-theoretic mechanisms as well as exogenous factors such as seasonality and political events on the propensity of blogs to cite one another over time. Using a combination of deviance-based model selection criteria and simulation-based model adequacy tests, we identify the combination of processes that best characterizes the choice behavior of the contending blogs. PMID- 24143061 TI - Blocking for Sequential Political Experiments. AB - In typical political experiments, researchers randomize a set of households, precincts, or individuals to treatments all at once, and characteristics of all units are known at the time of randomization. However, in many other experiments, subjects "trickle in" to be randomized to treatment conditions, usually via complete randomization. To take advantage of the rich background data that researchers often have (but underutilize) in these experiments, we develop methods that use continuous covariates to assign treatments sequentially. We build on biased coin and minimization procedures for discrete covariates and demonstrate that our methods outperform complete randomization, producing better covariate balance in simulated data. We then describe how we selected and deployed a sequential blocking method in a clinical trial and demonstrate the advantages of our having done so. Further, we show how that method would have performed in two larger sequential political trials. Finally, we compare causal effect estimates from differences in means, augmented inverse propensity weighted estimators, and randomization test inversion. PMID- 24143062 TI - A Transdiagnostic Approach to Pain and Emotion. AB - Emotion and pain are known to be intimately related, but treating co-occurring problems is still in its infancy mainly because we lack a clear theoretical understanding of the underlying mechanisms involved. This lack of understanding is problematic because treatment has proved challenging and co-occurring pain and emotional problems are associated with poor outcome, relapse, and greater sick absenteeism. Transdiagnostics has emerged as one way of focusing on the shared underlying mechanisms that drive comorbid problems. This approach has not been thoroughly examined for pain and emotion. Hence, the purpose of this review is to describe a transdiagnostic approach to pain and emotion and its clinical implications. To this end, the transdiagnostic approach is applied to pain and emotion in a narrative review of the literature. A focus on the function of emotion and pain relative to the context is underscored as a way to understand the relationship better. Avoidance, catastrophic worry, and thought suppression are put forward as three examples of potential transdiagnostic mechanisms that may underlie a co-occurring emotion and pain problem. The approach is readily translated to the clinic where assessment and treatment should focus on identifying transdiagnostic mechanisms. However, additional exploration is needed and therefore suggestions for future research are presented. PMID- 24143063 TI - Extension Educators' Perceptions of Community Readiness, Knowledge of Prevention Science, and Experience with Collaboration. AB - This investigation compared Extension educators' perceptions of community readiness, knowledge of prevention science, and experience with community collaborations with the perceptions of community human service professionals. First, Cooperative Extension System (CES) educators and human service professionals were found to hold similar perceptions of community readiness for prevention programs. Second, CES educators demonstrated less awareness of prevention programs in the community, but a greater knowledge of research-based community risk and protective factors than the human service professionals. Third, CES educators and human service professionals were similar in terms of community collaborative involvement, success, and personal effectiveness. PMID- 24143064 TI - Comparative visual performance with monofocal and multifocal intraocular lenses. AB - BACKGROUND: To compare near, intermediate, and distance vision, and quality of vision using appropriate subjective questionnaires, when monofocal or apodized diffractive multifocal intraocular lenses (IOLs) are binocularly implanted. METHODS: Patients with different binocular IOLs implanted were recruited after surgery and had their visual acuity tested, and quality of vision evaluated, at a single diagnostic visit between 3 and 8 months after second-eye surgery. Lenses tested included an aspheric monofocal and two apodized diffractive multifocal IOLs with slightly different design parameters. A total of 94 patients were evaluated. RESULTS: Subjects with the ReSTOR(r) +2.5 D IOL had better near and intermediate vision than those subjects with a monofocal IOL. Intermediate vision was similar to, and near vision slightly lower than, that of subjects with a ReSTOR(r) +3.0 D IOL implanted. The preferred reading distance was slightly farther out for the +2.5 D relative to the +3.0 D lens, and farthest for the monofocal. Visual acuity at the preferred reading distance was equal with the two multifocal IOLs and significantly worse with the monofocal IOL. Quality of vision measures were highest with the monofocal IOL and similar between the two multifocal IOLs. CONCLUSION: The data indicate that the ReSTOR +2.5 D IOL provided good intermediate and functional near vision for patients who did not want to accept a higher potential for visual disturbances associated with the ReSTOR +3.0 D IOL, but wanted more near vision than a monofocal IOL generally provides. Quality of vision was not significantly different between the multifocal IOLs, but patient self-selection for each lens type may have been a factor. PMID- 24143065 TI - A pharmacogenetics study to predict outcome in patients receiving anti-VEGF therapy in age related macular degeneration. AB - PURPOSE: To ascertain whether single nucleotide polymorphisms (SNPs) in the Vascular Endothelial Growth factor (VEGFA), Complement Factor H (CFH), and LOC387715 genes could predict outcome to anti-VEGF therapy for patients with age related macular degeneration (AMD). METHODS: Patients with "wet" AMD were identified by chart review. Baseline optical coherence tomography (OCT) and visual acuity (VA) data, and at least 6 months of clinical follow up after 3 initial monthly injections of bevacizumab or ranibizumab were required for inclusion. Based on OCT and VA, patients were categorized into two possible clinical outcomes: (a) responders and (b) non-responders. DNA was extracted from saliva and genotyped for candidate SNPs in the VEGFA, LOC387715, and CFH genes. Clinical outcomes were statistically compared to patient genotypes. RESULTS: 101 patients were recruited, and one eye from each patient was included in the analysis. 97% of samples were successfully genotyped for all SNPs. We found a statistically significant association between the LOC387715 A69S TT genotype and outcome based on OCT. CONCLUSION: Genetic variation may be associated with outcome in patients receiving anti-VEGF therapy. PMID- 24143066 TI - A case of presumed choroidal metastasis from carcinoid tumor treated by photodynamic therapy with verteporfin. AB - We report a case of metastatic choroidal carcinoid tumor with favorable outcome after photodynamic therapy. A 75-year-old woman was presumptively diagnosed with bilateral choroidal metastases from carcinoid tumor. Although the tumor in the right eye showed a tendency toward rapid expansion and required aggressive treatment to preserve vision, the size was still small and we hesitated to use external-beam radiotherapy because of the risk of radiation retinopathy. Consequently, photodynamic therapy was performed on the right eye, resulting in drastic reduction of the size and height of the choroidal tumor. Good visual acuity was maintained after photodynamic therapy. Photodynamic therapy may be an effective treatment for choroidal metastasis from carcinoid tumor. PMID- 24143067 TI - Pattern of corneal pathologies in children seen at Yaounde Gynaeco-Obstetric and Paediatric Hospital, Cameroon. AB - PURPOSE: To describe the different corneal pathologies and determine the prevalence of corneal blindness amongst children aged 0-15 years, seen at the ophthalmology unit of a tertiary hospital in Cameroon. PATIENTS AND METHODS: The medical records of all patients who presented to the Ophthalmic Unit between 2002 and 2010 were reviewed, retrospectively. The records of children aged 0-15 years, presenting with corneal pathologies, were further reviewed. Data collected included age, sex, past medical history, initial visual acuity, type of corneal lesion, and visual acuity at last follow-up. RESULTS: Of the 7,922 children seen over the study period, 168 had corneal pathologies: a prevalence of 2.1%. Males were more affected than females (male to female ratio: 1.4:1; P = 0.008). The age range was from 2 weeks to 15 years (mean age: 7.1 years; standard deviation: 4.4 years). The leading etiologies were trauma (48.2%; n = 81) and infection (28.0%; n = 47). Amongst those with available follow-up data, visual impairment and blindness occurred in 50% of the cases (n = 12), with one case being bilateral. CONCLUSION: Trauma is the most frequent cause of corneal blindness in children. PMID- 24143068 TI - Improvement of visual acuity in diabetic and nondiabetic patients after Nd:YAG laser capsulotomy. AB - PURPOSE: The aim of the study reported here was to compare the improvement of visual acuity (VA) of diabetic and nondiabetic patients after neodymium-doped yttrium-aluminum-garnet (Nd:YAG) laser capsulotomy. METHODS: In this prospective cohort study, 50 age- and sex-matched patients, comprising 25 nondiabetics and 25 diabetics (referred to as Group A and B, respectively), with posterior chamber poly(methyl methacrylate) non-foldable intraocular lens implants attending our clinic at Karachi for capsulotomy had pre- and postoperative measures of VA, posterior pole visibility, and grading of posterior capsular opacity as seen on slit-lamp examination. VA was recorded before and after performing standard capsulotomy. RESULTS: The postoperative (mean) VA in nondiabetics was 0.25, 0.23, and 0.21 logMAR as compared with 0.25, 0.25, and 0.24 logMAR in diabetics at 1 week, 1 month, and 6 months, respectively. P-values of 0.47, 0.47, and 0.24, respectively, were determined, which were not significant. Preoperative VA improvement was recorded in 92% of diabetics in Group B and 96% of nondiabetics in Group A. Two (8%) diabetic patients developed glaucoma and did not participate in the study further. CONCLUSION: Remarkable improvement in VA was achieved in both Group A and B, but the Group A nondiabetics showed more improvement in best corrected VA after Nd:YAG laser capsulotomy. PMID- 24143070 TI - Scattered depressions with temporal preponderance in visual field test coexisting with optic disc temporal atrophy in cerebral arteriovenous malformation. AB - In this article, the unusual association of optic disc temporal atrophy associated with scattered depressions with temporal preponderance in visual field test resembling incomplete bitemporal hemianopsia is reported. A 22-year-old man with cerebral arteriovenous malformation (AVM), which was located adjacent to the inferomedial portion of the posterior limb of the right internal capsule at the level of lateral ventricle, revealed interesting and unexpected ophthalmological findings. Possible mechanisms including anatomical variant, previously larger AVM, and retrograde optic neuropathy were mentioned. This case also highlighted that the usual complaint of visual disturbance might associate with unusual visual field defect in cerebral AVMs. PMID- 24143069 TI - Keratoconus: current perspectives. AB - Keratoconus is characterized by progressive corneal protrusion and thinning, leading to irregular astigmatism and impairment in visual function. The etiology and pathogenesis of the condition are not fully understood. However, significant strides have been made in early clinical detection of the disease, as well as towards providing optimal optical and surgical correction for improving the quality of vision in affected patients. The past two decades, in particular, have seen exciting new developments promising to alter the natural history of keratoconus in a favorable way for the first time. This comprehensive review focuses on analyzing the role of advanced imaging techniques in the diagnosis and treatment of keratoconus and evaluating the evidence supporting or refuting the efficacy of therapeutic advances for keratoconus, such as newer contact lens designs, collagen crosslinking, deep anterior lamellar keratoplasty, intracorneal ring segments, photorefractive keratectomy, and phakic intraocular lenses. PMID- 24143071 TI - A meta-analysis of studies on cosmetically tinted soft contact lenses. AB - BACKGROUND: Concerns regarding the safety of cosmetically tinted contact lenses have been reported in the literature. The purpose of this paper is to evaluate the safety of cosmetically tinted contact lenses in a large number of patients across six clinical trials that varied from 1 week to 3 months in duration. METHODS: LENSES TESTED INCLUDED: Naturelle limbal ring daily disposable, Lacelle limbal ring daily disposable, Lacelle colored cosmetic daily disposable, Lacelle limbal ring planned replacement at 2 weeks, and Alamode traditional/annual colored cosmetic lens. The primary safety outcome was slit-lamp examination, including epithelial edema, epithelial microcysts, corneal staining, bulbar injection, limbal injection, upper lid tarsal conjunctival abnormalities, corneal neovascularization, and corneal infiltrates. High contrast logMAR visual acuity with lenses, and lens wearing time, movement, and centration, are also presented. RESULTS: A total of 871 subjects (1,742 eyes) and 23 clinical investigators participated in the six studies, with an average completion rate of 96.4% across all studies. The mean age of the patients was 26.8 +/- 6.6 years, and 86.7% of participants were female. The total number of slit-lamp examinations across the six studies was 2,456 visits by eye (1,228 visits by patient). There were no slit lamp signs > grade 2 for any finding, with the exception of corneal staining in one study. In this study, grade 3 corneal staining was noted in one eye (0.1%) at follow-up visit 1 and four (0.6%) of all eligible dispensed eyes at follow-up visit 2, with no eyes requiring medical treatment. No adverse events were reported during any of the trials. CONCLUSION: The cosmetically tinted lenses evaluated in this meta-analysis appear to be safe when properly prescribed by an eye care professional and used in a compliant manner. PMID- 24143072 TI - Anatomic and functional outcomes of 25-gauge vitrectomy for repair of eyes with rhegmatogenous retinal detachment complicated by proliferative vitreoretinopathy. AB - BACKGROUND: The purpose of this study was to evaluate the outcome of 25-gauge vitrectomy for repair of rhegmatogenous retinal detachment (RRD) complicated by proliferative vitreoretinopathy (PVR). METHODS: Twenty-seven eyes of 27 patients who had undergone 25-gauge vitrectomy for grade C PVR were investigated retrospectively. The surgical procedures, anatomic success, and best-corrected visual acuity were assessed. RESULTS: The mean number of operations was 1.4 (range 1-4). During the 25-gauge vitrectomy, 20-gauge instruments were needed in eleven eyes (40.7%) to remove resilient fibrous preretinal membranes, to extract subretinal proliferations, or to remove or infuse silicone oil. The retina was reattached in 21 eyes (77.8%) after the initial vitrectomy and in 25 eyes (92.6%) at the final examination. The mean best-corrected visual acuity in logarithm of the minimal angle of resolution units was 1.36 +/- 0.81 before vitrectomy and 0.79 +/- 0.71 at one month, 0.73 +/- 0.72 at 3 months, 0.73 +/- 0.75 at 6 months, and 0.75 +/- 0.78 at 12 months after vitrectomy. The best-corrected visual acuities were significantly improved compared with the preoperative ones at all postoperative assessments (P<0.001). CONCLUSION: Twenty-five gauge vitrectomy is a relatively safe and efficacious method of treating RRD with PVR, although combined use of 20-gauge instruments may be needed for certain surgical procedures. PMID- 24143073 TI - Meta-analysis of the ocular biocompatibility of a new multipurpose lens care system. AB - BACKGROUND: The purpose of this paper is to evaluate the biocompatibility of a novel multipurpose solution (MPS) with a dual disinfectant system containing polyaminopropyl biguanide and polyquaternium-1 (Biotrue(r)) by analysis of biomicroscopy signs and adverse events in six large clinical trials. METHODS: Data from six consecutive, prospective clinical trials conducted from February 2008 to March 2010 were combined for meta-analysis. Subjects used the new MPS daily for periods of 2 weeks to 6 months. Slit-lamp signs were graded at each follow-up visit using an ordinal scale (0, one; 1, trace; 2, mild; 3, moderate; 4, severe). Analysis for biocompatibility included tracking of greater than grade 2 slit-lamp findings and number of adverse events. RESULTS: A total of 1,567 subjects (3,134 eyes) and 81 clinical investigators participated in the six studies, with 1,499 subjects completing the studies. Based on subject days in the studies, there were 72,904 exposures to the MPS and 7,212 biomicroscopy examinations. The completion rate for the studies was 96.3%. Per observation incidence of any finding greater than grade 2 at the follow-up visits were: corneal staining 0.08%, limbal injection 0.04%, bulbar injection 0.04%, tarsal conjunctiva abnormality 0.09%, and neovascularization 0.01%. There were no other slit-lamp signs greater than grade 2 and no statistically significant difference between hydrogels and silicone hydrogels for any finding. There were no reports of adverse events during the trials. CONCLUSION: Analysis of over 72,000 daily exposures and 7,212 eye examinations showed that the novel MPS exhibited excellent biocompatibility in subjects using daily wear hydrogel or silicone hydrogel lenses. PMID- 24143074 TI - Everolimus in the treatment of subependymal giant cell astrocytomas, angiomyolipomas, and pulmonary and skin lesions associated with tuberous sclerosis complex. AB - Tuberous sclerosis complex (TSC) is an autosomal dominant genetic disorder caused by inactivating mutations in either the TSC1 or TSC2 genes. It is characterized by the development of multiple, benign tumors in several organs throughout the body. Lesions occur in the brain, kidneys, heart, liver, lungs, and skin and result in seizures and epilepsy, mental retardation, autism, and renal and pulmonary organ system dysfunction, as well as other complications. Elucidation of the molecular pathways and etiological factors responsible for causing TSC has led to a paradigm shift in the management and treatment of the disease. TSC1 or TSC2 mutations lead to constitutive upregulation of the mammalian target of rapamycin pathway, which affects many cellular processes involved in tumor growth. By targeting mammalian target of rapamycin with everolimus, an orally active rapamycin derivative, clinically meaningful and statistically significant reductions in tumor burden have been achieved for the main brain (subependymal giant cell astrocytoma) and renal manifestations (angiomyolipoma) associated with TSC. This review provides an overview of TSC, everolimus, and the clinical trials that led to its approval for the treatment of TSC-associated subependymal giant cell astrocytoma and renal angiomyolipoma. PMID- 24143075 TI - Review of daclizumab and its therapeutic potential in the treatment of relapsing remitting multiple sclerosis. AB - Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease of the central nervous system. It can present in several forms, with the relapsing remitting pattern being the most common. Since the approval of the first disease modifying therapy and the initiation of appropriate treatments from the early stages of the disease, there seem to be positive impacts on the long-term outcomes and disability associated with MS. Currently, there are ten approved drugs for the treatment of MS, and several more are in various stages of development. These medications each have their unique profile in terms of efficacy, dose, routes of administration, tolerability, and adverse effects. Daclizumab is a humanized monoclonal antibody that is being explored for the treatment of MS. It is currently approved for use in allograft renal transplantation. Given its modulatory effects on the immune system, daclizumab's potential for use in MS was tested in extensive Phase II trials. With continued demonstration of its efficacy, it is currently in a Phase III trial for relapsing remitting MS. While daclizumab has demonstrated beneficial effects in controlling disease activity in MS, there were also some safety and tolerability concerns that were raised. Further information from the ongoing Phase III trial, and from open-label studies, will shed light on the benefit and risk profile of this drug and its potential for use in MS. PMID- 24143076 TI - A comparative study of internal laser-assisted and conventional liposuction: a look at the influence of drugs and major surgery on laboratory postoperative values. AB - BACKGROUND: Liposuction is a type of aesthetic surgery that has been performed on humans for decades. There is not much literature addressing the subject matter of pre- and post-surgery blood parameters, although this information is rather interesting. Documentation on patients who received laser-assisted liposuction treatment is particularly scarce. Until now, there has been no literature showing values of platelets, lymphocytes, and neutrophils after liposuction. PURPOSE: The aim of the work is to analyze and interpret values of platelets, lymphocytes and neutrophils in patient blood before and after liposuction, a surgery in which an extraordinarily large amount of potent drugs are used. Moreover, the aim is to compare values changes in patients of conventional and laser-assisted liposuction. MATERIAL AND METHODS: We evaluated standard blood samples in patients prior to and after liposuction. This paper covers the number of platelets, lymphocytes, and neutrophils. A total of 54 patients were examined. Moreover, we compared the change in postoperative values in laser-assisted liposuction patients with the change of values in conventional liposuction patients. A paired two-sided Student's t-test was used for statistical evaluation. P < 0.005 was acknowledged to be statistically significant. RESULTS: Values of platelets were raised both in conventional and in laser-assisted liposuction patients, but this difference was statistically non-significant and levels of platelets were still normal and within the range of blood levels in healthy patients. Values of neutrophils rose by up to 79.49% +/- 7.74% standard deviation (SD) and values of lymphocytes dropped by up to 12.68% +/- 5.61% SD. The before/after variances of conventional tumescent local anesthesia liposuction and variations in laser-assisted liposuction were similar for all measured parameters; they also showed no statistically significant differences between before and after surgery. The mean value of total operation time without laser assistance was 3 hours 42 minutes (+/- 57 minutes SD, range 2 hours 50 minutes to 5 hours 10 minutes). Surgeries with laser-assistance were on average 16 minutes shorter with a mean duration of 3 hours 26 minutes (+/- 45 minutes SD, range 2 hours 40 minutes to 4 hours 10 minutes). The difference was not statistically significant (P < 0.06). The mean value of aspirate volume for liposuctions performed without laser support was 2,618 mL (+/- 633.7 SD, range 700 mL to 3,500 mL). Mean aspirate volume for liposuctions with laser assistance was increased by up to 61 mL (2,677 mL +/- 499.5 SD, range 1,800 mL to 3,500 mL). The difference was not statistically significant (P < 0.71). CONCLUSION: We conclude that conventional liposuction and laser-assisted liposuction have a similar influence on platelets, lymphocytes, and neutrophils in patients. Moreover, laser-assisted liposuction seems to be less time consuming than conventional liposuction. PMID- 24143077 TI - New developments in the combination treatment of COPD: focus on umeclidinium/vilanterol. AB - An increasing body of evidence suggests that the long-acting muscarinic antagonist (LAMA)/long-acting beta2-agonist (LABA) combination appears to play an important role in maximizing bronchodilation, with studies to date indicating that combining different classes of bronchodilators may result in significantly greater improvements in lung function compared to the use of a single drug, and that these combinations are well tolerated in patients with moderate-to-severe chronic obstructive pulmonary disease (COPD). An inhaled, fixed-dose combination of two 24-hour bronchodilators, the LAMA umeclidinium and the LABA vilanterol, is under development as a once-daily treatment for COPD. The efficacy of both mono components has already been demonstrated. The information currently available suggests that umeclidinium/vilanterol is an effective once-daily dual bronchodilator fixed-dose combination in the treatment of COPD. However, it remains to be seen if it compares favorably with current therapies. Moreover, the question remains whether umeclidinium/vilanterol fixed-dose combination, which significantly improves FEV1, is also associated with improvements in other outcome measures that are important to COPD patients. PMID- 24143079 TI - Determinants and consequences of insulin initiation for type 2 diabetes in France: analysis of the National Health and Wellness Survey. AB - BACKGROUND: The aim of the study was to identify the intrinsic patient characteristics and extrinsic environmental factors predicting prescription and use and, more specifically, early initiation (up to 5 years of disease duration) of insulin for type 2 diabetes in France. A secondary objective was to evaluate the impact of insulin therapy on mental and physical quality of life and patient adherence. METHODS: The data used in this study were derived from the 2008, 2010, and 2011 France National Health and Wellness Survey. This survey is an annual, cross-sectional, self-administered, Internet-based questionnaire among a nationwide representative sample of adults (aged 18 years or older). Of the total of 45,958 persons recruited in France, 1,933 respondents (deduped) were identified as diagnosed with type 2 diabetes. All unique respondents from the three waves, currently using insulin or oral bitherapy or tritherapy at the time of assessment, were included in this analysis. RESULTS: Early (versus late) initiation of insulin therapy was 9.9 times more likely to be prescribed by an endocrinologist or diabetologist than by a primary care physician (P < 0.0001). Younger age at diagnosis and current smoking habits were significant predictors of early (versus late) insulin initiation (odds ratio [OR] 1.031, 95% confidence interval [CI] 1.005-1.059, P = 0.0196, and OR 2.537, 95% CI 1.165-5.524, P = 0.0191, respectively). Patients with a yearly income >=?50,000 were less likely to be put on insulin early (P = 0.0399). A link between insulin prescription and complications was shown only in univariate analysis. Mental quality of life was lower in patients on early (versus late) insulin, but only in patients with diabetes-related complications. Insulin users (versus oral bitherapy or tritherapy users) had 3.0 times greater odds of being adherent than uncontrolled oral bitherapy or tritherapy users (OR 2.983, 95% CI 1.37-6.495, P = 0.0059). CONCLUSION: This study confirms the role of specialists in early initiation of insulin, and the data presented herein reflect the fact that early initiation is more frequent in younger patients, patients with diabetes-related complications, and current smokers, and less frequent in patients with a higher income. Moreover, we observed that being treated with insulin was not associated with deterioration in quality of life, and insulin-treated patients were more often adherent than uncontrolled oral bitherapy or tritherapy users. These data suggest that doctors' concerns about patient adherence and detrimental effects on quality of life should not be a barrier to their decision regarding early initiation of insulin therapy. Due to the nature of this cross-sectional survey (eg, inability to assess treatment flow), further research is needed to confirm its findings. PMID- 24143081 TI - Erratum: Adherence to antidepressant medications: an evaluation of community pharmacists' counseling practices [Corrigendum]. AB - [This corrects the article on p. 813 in vol. 7, PMID: 23986631.]. PMID- 24143080 TI - Should treatment for depression be based more on patient preference? AB - Patient treatment preferences are of growing interest to researchers, clinicians, and patients. In this review, an overview of the most commonly recommended treatments for depression is provided, along with a brief review of the evidence supporting their efficacy. Studies examining the effect of patient treatment preferences on treatment course and outcome are summarized. Existing literature on what treatment options patients tend to prefer and believe to be helpful, and what factors may affect these preferences, is also reviewed. Finally, clinical implications of research findings on patient preferences for depression management are discussed. In summary, although our knowledge of the impact of patient preferences on treatment course and outcome is limited, knowing and considering those preferences may be clinically important and worthy of greater study for evidence-based practice. PMID- 24143082 TI - Effectiveness of exercise and protein supplementation intervention on body composition, functional fitness, and oxidative stress among elderly Malays with sarcopenia. AB - Sarcopenia, characterized as muscle loss that occurs with aging, is a major health problem in an aging population, due to its implications on mobility, quality of life, and fall risk. Protein supplementation could improve the physical fitness by increasing protein anabolism, and exercise has a documented evidence of positive effect on functional status among the elderly. However, the combined effect of both protein supplementation and exercise has not been investigated among sarcopenic elderly in the Asian population. Thus, this study aimed to determine the effectiveness of exercise intervention and protein supplementation either alone or in combination for 12 weeks, on body composition, functional fitness, and oxidative stress among elderly Malays with sarcopenia. Sixty five sarcopenic elderly Malays aged 60-74 years were assigned to the control group, exercise group (ExG), protein supplementation group (PrG), or the combination of exercise and protein supplementation group. A significant interaction effect between body weight and body mass index (BMI) was observed, with the PrG (-2.1% body weight, -1.8% BMI) showing the highest reductions. Further, there was a decrease in % body fat (-4.5%) and an increase in fat-free mass (kg) (+5.7%) in the ExG after 12 weeks (P < 0.05). The highest increments in lower and upper body strength were observed in the PrG (73.2%) and ExG (47.6%), respectively. In addition, the ExG showed a reduction in superoxide dismutase (SOD) levels, and both interventions did not alter either lipid or protein oxidation. In conclusion, the exercise program was found to improve muscle strength and body composition, while protein supplementation reduced body weight and increased upper body strength, among sarcopenic elderly in Malaysia. PMID- 24143078 TI - Current and future G protein-coupled receptor signaling targets for heart failure therapy. AB - Although there have been significant advances in the therapy of heart failure in recent decades, such as the introduction of beta-blockers and antagonists of the renin-angiotensin-aldosterone system, this devastating disease still carries tremendous morbidity and mortality in the western world. G protein-coupled receptors, such as beta-adrenergic and angiotensin II receptors, located in the membranes of all three major cardiac cell types, ie, myocytes, fibroblasts, and endothelial cells, play crucial roles in regulation of cardiac function in health and disease. Their importance is reflected by the fact that, collectively, they represent the direct targets of over one-third of the currently approved cardiovascular drugs used in clinical practice. Over the past few decades, advances in elucidation of the signaling pathways they elicit, specifically in the heart, have led to identification of an increasing number of new molecular targets for heart failure therapy. Here, we review these possible targets for heart failure therapy that have emerged from studies of cardiac G protein-coupled receptor signaling in health and disease, with a particular focus on the main cardiac G protein-coupled receptor types, ie, the beta-adrenergic and the angiotensin II type 1 receptors. We also highlight key issues that need to be addressed to improve the chances of success of novel therapies directed against these targets. PMID- 24143083 TI - Decreased functional capacity and muscle strength in elderly women with metabolic syndrome. AB - PURPOSE: To compare the metabolic parameters, flexibility, muscle strength, functional capacity, and lower limb muscle power of elderly women with and without the metabolic syndrome (MetS). METHODS: This cross-sectional study included 28 older women divided into two groups: with the MetS (n = 14; 67.3 +/- 5.5 years; 67.5 +/- 16.7 kg; 1.45 +/- 0.35 m; 28.0 +/- 7.6 kg/m(2)), and without the MetS (n = 14; 68.7 +/- 5.3 years; 58.2 +/- 9.9 kg; 1.55 +/- 0.10 m; 24.3 +/- 3.8 kg/m(2)). Body composition was evaluated by dual-energy X-ray absorptiometry and dynamic muscle strength was assessed by one-maximum repetition (1RM) tests in leg press, bench press and biceps curl exercises. Six-minute walk test, Timed Up and Go (TUG); 30-second sitting-rising; arm curl using a 2-kg dumbbell, sit-and reach (flexibility), and vertical jump tests were performed. RESULTS: There was no difference between groups regarding age (P = 0.49), height (P = 0.46), body fat (%) (P = 0.19), systolic (P = 0.64), diastolic (P = 0.41) and mean blood pressure (P = 0.86), 30-second sitting-rising (P = 0.57), 30-s arm curl (P = 0.73), leg press 1RM (P = 0.51), bench press 1RM (P = 0.77), and biceps curl 1RM (P = 0.85). However, women without the MetS presented lower body mass (P = 0.001), body mass index (BMI) (P = 0.0001), waist circumference (P = 0.02), waist to-height ratio (P = 0.02), fat body mass (kg) (P = 0.05), lean body mass (kg) (P = 0.02), blood glucose (P = 0.05), triglycerides (P = 0.03), Z-score for the MetS (P = 0.05), higher high-density lipoprotein-cholesterol (HDL-C) (P = 0.002), better performance on TUG (P = 0.01), flexibility (P = 0.03), six-minute walk test (P = 0.04), vertical jump (P = 0.05) and relative muscle strength for leg press (P = 0.03), bench press (P = 0.04) and biceps curl (P = 0.002) exercises as compared to women with the MetS. CONCLUSION: Elderly women with the MetS have higher metabolic risk profile and lower functional capacity, muscle strength, lower limb power and flexibility as compared to women without the MetS. The evaluation of functional capacity may help to determine the degree of physical decline in older persons with the MetS, while exercise interventions should be encouraged. PMID- 24143084 TI - Is the Chronic Kidney Disease Epidemiology Collaboration creatinine-cystatin C equation useful for glomerular filtration rate estimation in the elderly? AB - BACKGROUND: We aimed to evaluate the performance of the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) creatinine-cystatin C equation in a cohort of elderly Chinese participants. MATERIALS AND METHODS: Glomerular filtration rate (GFR) was measured in 431 elderly Chinese participants by the technetium-99m diethylene-triamine-penta-acetic acid ((99m)Tc-DTPA) renal dynamic imaging method, and was calibrated equally to the dual plasma sample (99m)Tc-DTPA-GFR. Performance of the CKD-EPI creatinine-cystatin C equation was compared with the Cockcroft-Gault equation, the re-expressed 4-variable Modification of Diet in Renal Disease (MDRD) equation, and the CKD-EPI creatinine equation. RESULTS: Although the bias of the CKD-EPI creatinine-cystatin C equation was greater than with the other equations (median difference, 5.7 mL/minute/1.73 m(2) versus a range from 0.4-2.5 mL/minute/1.73 m(2); P<0.001 for all), the precision was improved with the CKD-EPI creatinine-cystatin C equation (interquartile range for the difference, 19.5 mL/minute/1.73 m(2) versus a range from 23.0-23.6 mL/minute/1.73 m(2); P<0.001 for all comparisons), leading to slight improvement in accuracy (median absolute difference, 10.5 mL/minute/1.73 m(2) versus 12.2 and 11.4 mL/minute/1.73 m(2) for the Cockcroft-Gault equation and the re-expressed 4 variable MDRD equation, P=0.04 for both; 11.6 mL/minute/1.73 m(2) for the CKD-EPI creatinine equation, P=0.11), as the optimal scores of performance (6.0 versus a range from 1.0-2.0 for the other equations). Higher GFR category and diabetes were independent factors that negatively correlated with the accuracy of the CKD EPI creatinine-cystatin C equation (beta=-0.184 and -0.113, P<0.001 and P=0.02, respectively). CONCLUSION: Compared with the creatinine-based equations, the CKD EPI creatinine-cystatin C equation is more suitable for the elderly Chinese population. However, the cost-effectiveness of the CKD-EPI creatinine-cystatin C equation for clinical use should be considered. PMID- 24143085 TI - COPD management: role of symptom assessment in routine clinical practice. AB - Patients with chronic obstructive pulmonary disease (COPD) present with a variety of symptoms that significantly impair health-related quality of life. Despite this, COPD treatment and its management are mainly based on lung function assessments. There is increasing evidence that conventional lung function measures alone do not correlate well with COPD symptoms and their associated impact on patients' everyday lives. Instead, symptoms should be assessed routinely, preferably by using patient-centered questionnaires that provide a more accurate guide to the actual burden of COPD. Numerous questionnaires have been developed in an attempt to find a simple and reliable tool to use in everyday clinical practice. In this paper, we review three such patient-reported questionnaires recommended by the latest Global Initiative for Chronic Obstructive Lung Disease guidelines, ie, the modified Medical Research Council questionnaire, the clinical COPD questionnaire, and the COPD Assessment Test, as well as other symptom-specific questionnaires that are currently being developed. PMID- 24143086 TI - Development and validation of a model to predict the risk of exacerbations in chronic obstructive pulmonary disease. AB - PURPOSE: Prediction models for exacerbations in patients with chronic obstructive pulmonary disease (COPD) are scarce. Our aim was to develop and validate a new model to predict exacerbations in patients with COPD. PATIENTS AND METHODS: The derivation cohort consisted of patients aged 65 years or over, with a COPD diagnosis, who were followed up over 24 months. The external validation cohort consisted of another cohort of COPD patients, aged 50 years or over. Exacerbations of COPD were defined as symptomatic deterioration requiring pulsed oral steroid use or hospitalization. Logistic regression analysis including backward selection and shrinkage were used to develop the final model and to adjust for overfitting. The adjusted regression coefficients were applied in the validation cohort to assess calibration of the predictions and calculate changes in discrimination applying C-statistics. RESULTS: The derivation and validation cohort consisted of 240 and 793 patients with COPD, of whom 29% and 28%, respectively, experienced an exacerbation during follow-up. The final model included four easily assessable variables: exacerbations in the previous year, pack years of smoking, level of obstruction, and history of vascular disease, with a C-statistic of 0.75 (95% confidence interval [CI]: 0.69-0.82). Predictions were well calibrated in the validation cohort, with a small loss in discrimination potential (C-statistic 0.66 [95% CI 0.61-0.71]). CONCLUSION: Our newly developed prediction model can help clinicians to predict the risk of future exacerbations in individual patients with COPD, including those with mild disease. PMID- 24143088 TI - Mesoporous silica nanoparticles synthesized from liquid crystal display manufacturing extracts as a potential candidate for a drug delivery carrier: evaluation of their safety and biocompatibility. AB - Mesoporous silica nanoparticles (MSNs) were synthesized as a promising drug delivery carrier due to the large surface area and porous characteristics. Our previous study successfully recycled wastes from the liquid crystal display (LCD) industry as the silica precursor. In this study, we substantiated the possibility of applying this material as a drug carrier. MSNs synthesized from the extraction of wastes from the manufacture of LCD panels were characterized as having an average diameter of 100 nm, a surface area of 788 m(2)/g, a uniform pore size distribution of 3.8 nm, and a pore volume of up to 1.04 cm(3)/g. Methotrexate and camptothecin were entrapped in MSNs at about 33.88% and 75.12%, respectively. The cell viability assay demonstrated that MSNs at 1 MUg/mL had no significant influence on human lung fibroblast (WI-38) cells or ovarian cancer (ES-2) cells. A lactate dehydrogenase assay also indicated no inflammation occurred. Moreover, a hemolytic erythrocyte test indicated that the dose range of <100 MUg/mL showed that 5% of erythrocytes were affected. After exposure to biofluids, the ordered structure was slightly degraded. The results revealed that MSNs synthesized from extraction of wastes from the manufacture of LCD panels had a good entrapment capacity for hydrophobic drugs and controllable safety conditions; they may be applied as a drug delivery carrier. PMID- 24143087 TI - Photodynamic therapy with conventional and PEGylated liposomal formulations of mTHPC (temoporfin): comparison of treatment efficacy and distribution characteristics in vivo. AB - A major challenge in the application of a nanoparticle-based drug delivery system for anticancer agents is the knowledge of the critical properties that influence their in vivo behavior and the therapeutic performance of the drug. The effect of a liposomal formulation, as an example of a widely-used delivery system, on all aspects of the drug delivery process, including the drug's behavior in blood and in the tumor, has to be considered when optimizing treatment with liposomal drugs, but that is rarely done. This article presents a comparison of conventional (Foslip(r)) and polyethylene glycosylated (Fospeg(r)) liposomal formulations of temoporfin (meta-tetra[hydroxyphenyl]chlorin) in tumor-grafted mice, with a set of comparison parameters not reported before in one model. Foslip(r) and Fospeg(r) pharmacokinetics, drug release, liposome stability, tumor uptake, and intratumoral distribution are evaluated, and their influence on the efficacy of the photodynamic treatment at different light-drug intervals is discussed. The use of whole-tumor multiphoton fluorescence macroscopy imaging is reported for visualization of the in vivo intratumoral distribution of the photosensitizer. The combination of enhanced permeability and retention-based tumor accumulation, stability in the circulation, and release properties leads to a higher efficacy of the treatment with Fospeg(r) compared to Foslip(r). A significant advantage of Fospeg(r) lies in a major decrease in the light-drug interval, while preserving treatment efficacy. PMID- 24143089 TI - A novel application of maleimide for advanced drug delivery: in vitro and in vivo evaluation of maleimide-modified pH-sensitive liposomes. AB - Maleimide is a stable and easy-to-handle moiety that rapidly and covalently conjugates thiol groups of cysteine residues in proteins or peptides. Herein, we use maleimide to modify the surface of liposomes in order to obtain an advanced drug delivery system. Employing a small amount (0.3 mol%) of maleimide polyethylene glycol (PEG) to modify the surface of the liposomes M-GGLG liposomes, composed of 1,5-dihexadecyl N,N-diglutamyl-lysyl-L-glutamate (GGLG)/cholesterol/poly(ethylene glycol) 1,2-distearoyl-sn-glycero-3 phosphoethanolamine (PEG5000-DSPE)/maleimide-PEG5000-Glu2C18 at a molar ratio of 5:5:0.03:0.03, drug delivery efficiency was remarkably improved both in vitro and in vivo compared to unmodified liposomes (GGLG-liposomes, composed of GGLG/cholesterol/PEG5000-DSPE/PEG5000-Glu2C18 at a molar ratio of 5:5:0.03:0.03). Moreover, this modification did not elicit any detectable increase in cytotoxicity. The maleimide-modification did not alter the physical characteristics of the liposomes such as size, zeta potential, pH sensitivity, dispersibility and drug encapsulation efficiency. However, M-GGLG-liposomes were more rapidly (>=2-fold) internalized into HeLa, HCC1954, and MDA-MB-468 cells compared to GGLG-liposomes. In vivo, M-GGLG-liposomes encapsulating doxorubicin (M-GGLG-DOX-liposomes) also showed a more potent antitumor effect than GGLG-DOX liposomes and the widely used 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC) DOX-liposomes after two subcutaneous injections around breast cancer tissue in mice. The biodistribution of liposomes in this model was observed using an in vivo imaging system, which showed that M-GGLG-liposomes were present for significantly longer at the injection site compared to GGLG-liposomes. The outstanding biological functions of the maleimide-modified liposomes as a novel drug delivery system make them ideally suited to a wide range of applications. PMID- 24143090 TI - New procedure to synthesize silver nanoparticles and their interaction with local anesthetics. AB - Silver nanoparticles (AgNPs) were prepared in aqueous colloid dispersions by the reduction of Ag(+) with glucose in alkaline medium. Tetraethyl orthosilicate and L-asparagine were added as stabilizers of NPs. The AgNPs were characterized, and their interaction with three local anesthetics (procaine, dibucaine, or tetracaine) was investigated. Optical spectra show the characteristic absorption band of AgNPs, due to surface plasmon resonance. Modifications in the position and shape of this band reflect the self-assembly of metal NPs mediated by anesthetic molecules and the progress in time of the aggregation process. Zeta potential measuring was applied in order to characterize the electrostatic stability of the NPs. The size and shape of the AgNPs, as well as the features of the assemblies formed by their association in the presence of anesthetics, were evidenced by transmission electron microscopy images. Atomic force microscopy images showed the characteristics of the films of AgNPs deposited on glass support. The effect of the anesthetics could be described in terms of electrostatic forces between the negatively charged AgNPs and the anesthetic molecules, existing also in their cationic form at the working pH. But also hydrophobic and hydrogen bonding interactions between the coated nanoparticles and anesthetics molecular species should be considered. PMID- 24143091 TI - Microwave-assisted synthesis of SnO2 nanorods for oxygen gas sensing at room temperature. AB - High-quality single-crystalline SnO2 nanorods were synthesized using a microwave assisted solution method. The nanorods were characterized using X-ray diffraction (XRD), field-emission scanning electron microscopy (FE-SEM), transmission electron microscopy (TEM), ultraviolet-visible and Raman spectroscopy, Brunauer Emmett-Teller (BET), and electrical resistance measurements. The XRD pattern indicated the formation of single-phase SnO2 nanorods with rutile structure. FE SEM and TEM images revealed tetragonal nanorods of about 450-500 nm in length and 60-80 nm in diameter. The nanorods showed a higher BET surface area of 288 m2/g, much higher than that of previously reported work. The Raman scattering spectra indicated a typical rutile phase of the SnO2. The absorption spectrum showed an absorption peak centered at 340 nm, and the band-gap value was found to be 3.64 eV. The gas-sensing properties of the SnO2 nanorods for oxygen gas with different concentrations were measured at room temperature. It was found that the value of resistance increased with the increase in oxygen gas concentration in the test chamber. The SnO2 nanorods exhibited high sensitivity and rapid response-recovery characteristics to oxygen gas, and could detect oxygen concentration as low as 1, 3, 5, and 10 ppm. PMID- 24143092 TI - Bioengineering in the oral cavity: our experience. AB - BACKGROUND: To date, there are no studies reported in the literature on the possible use of bovine collagen, oxidized regenerated cellulose, or synthetic hyaluronic acid medications in the oral cavity. The aim of this paper is to report the use of bovine collagen, oxidized regenerated cellulose, and synthetic hyaluronic acid medications to improve wound healing in the oral cavity by stimulating granulomatous tissue. METHODS: From 2007 to 2011, 80 patients (median age 67 years) suffering from oral mucosal lesions participated in this double blind study. The patients were divided into two groups, each consisting of 40 patients. One group received conventional medications, while the other group of patients were treated with the advanced medications. RESULTS: Advanced medications allowed re-epithelialization of the wound margin in 2-20 days, whereas patients receiving conventional medication showed a median healing duration of 45 days. CONCLUSION: The results of this study demonstrate that treating oral mucosal wounds with advanced medication has an advantage with regard to wound healing time, allowing patients to have a rapid, functional, and esthetic recovery. PMID- 24143093 TI - Does the extracorporeal circulation worsen anemia in hemodialysis patients? Investigation with advanced microscopes of red blood cells drawn at the beginning and end of dialysis. AB - BACKGROUND: In hemodialysis (HD) patients, anemia relates to three main factors: insufficient production of erythropoietin; impaired management of iron; and decreased lifespan of red blood cells (RBCs). The third factor can relate to structural deterioration of RBCs due to extrinsic (extracorporeal circuit; biochemical activation and/or mechanical stress during dialysis) and intrinsic (uremic milieu; biochemical interference of the RBC membrane constituents with toxins) mechanisms. Herein, we evaluate information accessed with advanced imaging techniques at the cellular level. METHODS: Atomic force and scanning electron microscopes were employed to survey intact RBCs (iRBCs) of seven HD patients in comparison to seven healthy donors. The extrinsic factor was investigated by contrasting pre- and post-HD samples. The intrinsic environment was investigated by comparing the microscopy data with the clinical ones. RESULTS: The iRBC membranes of the enrolled HD patients were overpopulated with orifice-like (high incidence; typical size within 100-1,000 nm) and crevice-like (low incidence; typical size within 500-4,000 nm) defects that exhibited a statistically significant (P < 0.05) relative increase (+55% and +350%, respectively) in respect to healthy donors. The relative variation of the orifice and crevice indices (mean population of orifices and crevices per top membrane surface) between pre- and post-HD was not statistically significant (-3.3% and +4.5%, respectively). The orifice index correlates with the concentrations of urea, calcium, and phosphorus, but not, however, with that of creatinine. CONCLUSION: Extracorporeal circulation is not detrimental to the structural integrity of RBC membranes. Uremic milieu is a candidate cause of RBC membrane deterioration, which possibly worsens anemia. PMID- 24143094 TI - Local delivery of controlled-release simvastatin/PLGA/HAp microspheres enhances bone repair. AB - Statins are used clinically for reduction of cholesterol synthesis to prevent cardiovascular disease. Previous in vitro and in vivo studies have shown that statins stimulate bone formation. However, orally administered statins may be degraded during first-pass metabolism in the liver. This study aimed to prevent this degradation by developing a locally administered formulation of simvastatin that is encapsulated in poly(lactic-co-glycolic acid)/hydroxyapatite (SIM/PLGA/HAp) microspheres with controlled-release properties. The effect of this formulation of simvastatin on bone repair was tested using a mouse model of gap fracture bridging with a graft of necrotic bone. The simvastatin released over 12 days from 3 mg and 5 mg of SIM/PLGA/HAp was 0.03-1.6 MUg/day and 0.05-2.6 MUg/day, respectively. SIM/PLGA/HAp significantly stimulated callus formation around the repaired area and increased neovascularization and cell ingrowth in the grafted necrotic bone at week 2 after surgery. At week 4, both 3 mg and 5 mg of SIM/PLGA/HAp increased neovascularization, but only 5 mg SIM/PLGA/HAp enhanced cell ingrowth into the necrotic bone. The low dose of simvastatin released from SIM/PLGA/HAp enhanced initial callus formation, neovascularization, and cell ingrowth in the grafted bone, indicating that SIM/PLGA/HAp facilitates bone regeneration. We suggest that SIM/PLGA/HAp should be developed as an osteoinductive agent to treat osteonecrosis or in combination with an osteoconductive scaffold to treat severe bone defects. PMID- 24143095 TI - Targeting miRNA-based medicines to cystic fibrosis airway epithelial cells using nanotechnology. AB - Cystic fibrosis (CF) is an inherited disorder characterized by chronic airway inflammation. microRNAs (miRNAs) are endogenous small RNAs which act on messenger (m) RNA at a post transcriptional level, and there is a growing understanding that altered expression of miRNA is involved in the CF phenotype. Modulation of miRNA by replacement using miRNA mimics (premiRs) presents a new therapeutic paradigm for CF, but effective and safe methods of delivery to the CF epithelium are limiting clinical translation. Herein, polymeric nanoparticles are investigated for delivery of miRNA mimics into CF airway epithelial cells, using miR-126 as a proof-of-concept premiR cargo to determine efficiency. Two polymers, polyethyleneimine (PEI) and chitosan, were used to prepare miRNA nanomedicines, characterized for their size, surface (zeta) potential, and RNA complexation efficiency, and screened for delivery and cytotoxicity in CFBE41o- (human F508del cystic fibrosis transmembrane conductance regulator bronchial epithelial) cells using a novel high content analysis method. RNA extraction was carried out 24 hours post transfection, and miR-126 and TOM1 (target of Myb1) expression (a validated miR-126 target) was assessed. Manufacture was optimized to produce small nanoparticles that effectively complexed miRNA. Using high content analysis, PEI-based nanoparticles were more effective than chitosan-based nanoparticles in facilitating uptake of miRNA into CFBE41o- cells and this was confirmed in miR-126 assays. PEI-premiR-126 nanoparticles at low nitrogen/phosphate (N/P) ratios resulted in significant knockdown of TOM1 in CFBE41o- cells, with the most significant reduction of 66% in TOM1 expression elicited at an N/P ratio of 1:1 while chitosan-based miR-126 nanomedicines failed to facilitate statistically significant knockdown of TOM1 and both nanoparticles appeared relatively nontoxic. miRNA nanomedicine uptake can be qualitatively and quantitatively assessed rapidly by high content analysis and is highly polymer dependent but, interestingly, there is not a direct correlation between the levels of miRNA uptake and the downstream gene knockdown. Polymeric nanoparticles can deliver premiRs effectively to CFBEs in order to modulate gene expression but must be tailored specifically for miRNA delivery. PMID- 24143096 TI - Nanoscale bacteriophage biosensors beyond phage display. AB - Bacteriophages are traditionally used for the development of phage display technology. Recently, their nanosized dimensions and ease with which genetic modifications can be made to their structure and function have put them in the spotlight towards their use in a variety of biosensors. In particular, the expression of any protein or peptide on the extraluminal surface of bacteriophages is possible by genetically engineering the genome. In addition, the relatively short replication time of bacteriophages offers researchers the ability to generate mass quantities of any given bacteriophage-based biosensor. Coupled with the emergence of various biomarkers in the clinic as a means to determine pathophysiological states, the development of current and novel technologies for their detection and quantification is imperative. In this review, we categorize bacteriophages by their morphology into M13-based filamentous bacteriophages and T4- or T7-based icosahedral bacteriophages, and examine how such advantages are utilized across a variety of biosensors. In essence, we take a comprehensive approach towards recent trends in bacteriophage based biosensor applications and discuss their outlook with regards to the field of biotechnology. PMID- 24143097 TI - A novel preparation method for drug nanocrystals and characterization by ultrasonic spray-assisted electrostatic adsorption. AB - PURPOSE: The purpose of this study was to develop a novel and continuous method for preparing a nanosized particle of drug crystals and to characterize its properties. MATERIALS AND METHODS: A new apparatus was introduced to crystallize nanosized drug crystals of amitriptyline hydrochloride as a model drug. The samples were prepared in the pure state by ultrasonic spray, and elaborated deposition was completed via electrostatic adsorption. Scanning electron microscopy, X-ray powder diffraction, and atomic force microscopy were used to characterize the size of the particles; this was subsequently followed by differential scanning calorimetry. RESULTS AND DISCUSSION: Nanoparticles of drug crystals were successfully prepared. The size of the drug crystals ranged from 20 nm to 400 nm; the particle size of amitriptyline hydrochloride was approximately 71 nm. The particles were spherical and rectangular in shape. Moreover, the melting point of the nanoparticles decreased from 198.2 degrees C to 196.3 degrees C when compared to raw particle crystals. Furthermore, the agglomeration effect was also attenuated as a result of electrostatic repulsion among each particle when absorbed, and depositing on the inner wall of the gathering unit occurred under the electrostatic effect. CONCLUSION: Ultrasonic spray-assisted electrostatic adsorption is a very effective and continuous method to produce drug nanocrystals. This method can be applied to poorly water-soluble drugs, and it can also be a very effective alternative for industrial production. Once the working parameters are given, drug nanocrystals will be produced continuously. PMID- 24143098 TI - Histologic and apoptotic changes induced by titanium dioxide nanoparticles in the livers of rats. AB - Titanium dioxide (TiO2) nanoparticles are among the top five nanoparticles used in consumer products, paints, and pharmaceutical preparations. Given that exposure to such nanoparticles is mainly via the skin and inhalation, the present study was conducted in male Wistar albino rats (Rattus norvegicus). Our aim was to investigate the effect of TiO2 nanoparticles on hepatic tissue in an attempt to understand their toxicity and the potential effect of their therapeutic and diagnostic use. To investigate the effects of TiO2 nanoparticles on liver tissue, 30 healthy male Wistar albino rats were exposed to TiO2 nanoparticles at doses of 63 mg, 126 mg, and 252 mg per animal for 24 and 48 hours. Serum glutamate oxaloacetate transaminase and alkaline phosphatase activity was altered. Changes in hepatocytes can be summarized as hydropic degeneration, cloudy swelling, fatty degeneration, portal and lobular infiltration by chronic inflammatory cells, and congested dilated central veins. The histologic alterations observed might be an indication of hepatocyte injury due to the toxicity of TiO2 nanoparticles, resulting in an inability to deal with accumulated residues from the metabolic and structural disturbances caused by these nanoparticles. The appearance of cytoplasmic degeneration and destruction of nuclei in hepatocytes suggests that TiO2 nanoparticles interact with proteins and enzymes in hepatic tissue, interfering with antioxidant defense mechanisms and leading to generation of reactive oxygen species which, in turn, may induce stress in hepatocytes, promoting atrophy, apoptosis, and necrosis. More immunohistochemical and ultrastructural investigations are needed in relation to TiO2 nanoparticles and their potential effects when used as therapeutic and diagnostic tools. PMID- 24143100 TI - Adherence ability of Staphylococcus epidermidis on prosthetic biomaterials: an in vitro study. AB - Bacterial adhesion to the surface of biomaterials is an essential step in the pathogenesis of implant-related infections. In this in vitro research, we evaluated the ability of Staphylococcus epidermidis to adhere to the surface of solid biomaterials, including oxidized zirconium-niobium alloy (Oxinium), cobalt chromium-molybdenum alloy, titanium alloy, commercially pure titanium, and stainless steel, and performed a biomaterial-to-biomaterial comparison. The test specimens were physically analyzed to quantitatively determine the viable adherent density of the S. epidermidis strain RP62A (American Type Culture Collection [ATCC] 35984). Field emission scanning electron microscope and laser microscope examination revealed a featureless, smooth surface in all specimens (average roughness <10 nm). The amounts of S. epidermidis that adhered to the biomaterial were significantly lower for Oxinium and the cobalt-chromium molybdenum alloy than for commercially pure titanium. These results suggest that Oxinium and cobalt-chromium-molybdenum alloy are less susceptible to bacterial adherence and are less inclined to infection than other materials of a similar degree of smoothness. PMID- 24143099 TI - Gold nanoparticles as physiological markers of urine internalization into urothelial cells in vivo. AB - BACKGROUND: Urothelial bladder is the reservoir of urine and the urothelium minimizes the exchange of urine constituents with this tissue. Our aim was to test 1.9 nm biocompatible gold nanoparticles as a novel marker of internalization into the urothelial cells under physiological conditions in vivo. METHODS: We compared normal and neoplastic mice urothelium. Neoplastic lesions were induced by 0.05% N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN) in drinking water for 10 weeks. Nanoparticles, intravenously injected into normal and BBN-treated mice, were filtered through the kidneys and became constituents of the urine within 90 minutes after injection. RESULTS: Gold nanoparticles were densely accumulated in the urine, while their internalization into urothelial cells depended on the cell differentiation stage. In the terminally differentiated superficial urothelial cells of normal animals, nanoparticles were occasionally found in the endosomes, but not in the fusiform vesicles. Regions of exfoliated cells were occasionally found in the normal urothelium. Superficial urothelial cells located next to exfoliated regions contained gold nanoparticles in the endosomes and in the cytosol beneath the apical plasma membrane. The urothelium of BBN-treated animals developed fat hyperplasia with moderate dysplasia. The superficial cells of BBN treated animals were partially differentiated as demonstrated by the lack of fusiform vesicles. These cells contained the gold nanoparticles distributed in the endosomes and throughout their cytosol. CONCLUSION: Gold nanoparticles are a valuable marker to study urine internalization into urothelial cells in vivo. Moreover, they can be used as a sensitive marker of differentiation and functionality of urothelial cells. PMID- 24143101 TI - Lurasidone as a potential therapy for bipolar disorder. AB - Lurasidone is a benzisothiazol derivative and an atypical antipsychotic approved by the US Food and Drug Administration for the acute treatment of adults with schizophrenia (October 2010) and bipolar 1 depression (June 2013). Lurasidone has a strong antagonistic property at the D2, serotonin (5-HT)2A, and 5-HT7 receptors, and partial agonistic property at the 5-HT1A receptor. Lurasidone also has lower binding affinity for the alpha2C and 5-HT2C receptor. Lurasidone is rapidly absorbed (time to maximum plasma concentration: 1-3 hours), metabolized mainly by CYP3A4 and eliminated by hepatic metabolism. In two large, well designed, 6-week trials in adult patients with bipolar 1 depression, lurasidone monotherapy and adjunctive therapy with mood stabilizers were significantly more effective than placebo at improving depressive symptoms assessed using the Montgomery-Asberg Depression Rating Scale total score. In both trials, lurasidone also reduced the Clinical Global Impression-Bipolar Severity depression score to a greater extent than placebo. In these two trials, discontinuation rates due to adverse events in the lurasidone group were small (<7%) and were not different from those of the placebo group. The most common adverse events in the lurasidone group were headache, nausea, somnolence, and akathisia. The changes in lipid profiles, weight, and parameters of glycemic control were minimal, and these findings were in line with those observed in schizophrenia trials. Further active comparator trials and long-term tolerability and safety data in bipolar patients are required. Lurasidone may be an option for the management of depressive symptoms in patients with bipolar 1 disorder, and it may be considered as a treatment alternative for patients who are at high risk for metabolic abnormalities. PMID- 24143102 TI - Detection of subclinical atherosclerosis and diastolic dysfunction in patients with schizophrenia. AB - BACKGROUND: Patients with schizophrenia have a higher risk for cardiovascular diseases, which is associated with early mortality compared with the nonschizophrenic population. Early diagnosis of cardiovascular diseases in asymptomatic periods in patients with schizophrenia would enhance their quality of life and reduce mortality. Echocardiography, carotid ultrasonography, and ankle brachial index (ABI) measurement are known to be beneficial methods of detecting subclinical cardiovascular diseases and of risk stratification. The present study investigated carotid intima media thickness (CIMT) and ABI and echocardiographic parameters measured via conventional and tissue Doppler echocardiography in patients with schizophrenia in comparison with a control group. METHODS: The present case-control study included 116 patients with schizophrenia and 88 healthy patients. Participants with any current comorbid psychiatric disorder, current or lifetime neurological and medical problems, current coronary artery disease, diabetes, hypertension, hypothyroidism, or hyperthyroidism or who were using antihypertensives, antidiabetic agents, or antiobesity drugs were excluded. High-resolution B-mode ultrasound images were used to measure CIMT. Conventional and tissue Doppler measurements were performed according to the recommendations of the American Society of Echocardiography. RESULTS: Low ABI, mitral ratio of the early (E) to late (A) ventricular filling velocities, septal E', septal S', lateral E', lateral S', septal E'/septal A', lateral E'/lateral A', and high septal A', mitral E/septal E', mitral E/lateral E', and CIMT values were observed in the schizophrenia group compared with the control group. CONCLUSION: Doppler parameters supported the hypothesis that patients with schizophrenia are at high risk for cardiovascular diseases. PMID- 24143103 TI - Reduced serum paraoxonase 1 (PON1) activity in patients with schizophrenia treated with olanzapine but not quetiapine. AB - BACKGROUND: Second generation antipsychotics (SGAs) are currently the most prescribed drugs in the treatment of schizophrenia. Despite their advantages, which include greater improvement in negative symptoms, cognitive function, prevention of deterioration, quality of life, and fewer extrapyramidal symptoms, the concern regarding metabolic abnormalities which might cause cardiovascular diseases during treatment with SGAs have been rising. Paraoxonase 1 (PON1) is an enzyme mostly located on high-density lipoprotein particles, and has been shown to protect or inhibit lipoprotein oxidation. Growing evidence suggests that PON1 plays a key role in the pathophysiology of atherosclerosis. METHODS: In the present study, we measured serum PON1 activity and serum levels of total cholesterol (TC), triglyceride, high-density lipoprotein cholesterol (HDL-C), and low-density lipoprotein cholesterol (LDL-C) in patients with schizophrenia, who had been treated with either olanzapine or quetiapine, and in healthy controls. Thirty five patients who had been treated with olanzapine, 29 patients who had been treated with quetiapine, and 32 age, sex, and smoking status-matched healthy control (HC) participants were enrolled. Serum PON1 activity and serum levels of TC, triglyceride, HDL-C, and LDL-C were measured. RESULTS: Serum PON1 activity in the olanzapine group was significantly lower than that of HC and quetiapine groups. Furthermore, serum levels of TC and LDL-C in the olanzapine group were significantly higher than those of quetiapine and HC groups. Interestingly, there was a positive correlation between PON1 activity and HDL-C levels in the olanzapine group. CONCLUSION: These findings suggest that serum PON1 activity in patients treated with olanzapine was lower than that of HC and quetiapine groups, and that PON1 may play a role in the metabolic side effects associated with olanzapine treatment. A further study to examine the relationship between serum PON1 activity and cardiovascular and metabolic side effects during treatment with SGAs will be of great interest. PMID- 24143104 TI - An open-label study of algorithm-based treatment versus treatment-as-usual for patients with schizophrenia. AB - OBJECTIVE: The use of an algorithm may facilitate measurement-based treatment and result in more rational therapy. We conducted a 1-year, open-label study to compare various outcomes of algorithm-based treatment (ALGO) for schizophrenia versus treatment-as-usual (TAU), for which evidence has been very scarce. METHODS: In ALGO, patients with schizophrenia (Diagnostic and Statistical Manual of Mental Disorders, fourth edition) were treated with an algorithm consisting of a series of antipsychotic monotherapies that was guided by the total scores in the positive and negative syndrome scale (PANSS). When posttreatment PANSS total scores were above 70% of those at baseline in the first and second stages, or above 80% in the 3rd stage, patients proceeded to the next treatment stage with different antipsychotics. In contrast, TAU represented the best clinical judgment by treating psychiatrists. RESULTS: Forty-two patients (21 females, 39.0 +/- 10.9 years-old) participated in this study. The baseline PANSS total score indicated the presence of severe psychopathology and was significantly higher in the ALGO group (n = 25; 106.9 +/- 20.0) than in the TAU group (n = 17; 92.2 +/- 18.3) (P = 0.021). As a result of treatment, there were no significant differences in the PANSS reduction rates, premature attrition rates, as well as in a variety of other clinical measures between the groups. Despite an effort to make each group unique in pharmacologic treatment, it was found that pharmacotherapy in the TAU group eventually became similar in quality to that of the ALGO group. CONCLUSION: While the results need to be carefully interpreted in light of a hard-to distinguish treatment manner between the two groups and more studies are necessary, algorithm-based antipsychotic treatments for schizophrenia compared well to treatment-as-usual in this study. PMID- 24143105 TI - Is quetiapine suitable for treatment of acute schizophrenia with catatonic stupor? A case series of 39 patients. AB - PURPOSE: We aimed to determine which antipsychotic is most effective for the treatment of acute schizophrenia with catatonic stupor. PATIENTS AND METHODS: Data were obtained from the medical records of 450 patients with the diagnosis of schizophrenia, who had received acute psychiatric inpatient treatment between January 2008 and December 2010 at our hospital. Among them, 39 patients (8.7%) met the definition of catatonic stupor during hospitalization. The diagnoses of schizophrenia in all 39 patients were reconfirmed during the maintenance phase. We retrospectively reviewed the medical records of these 39 patients to investigate which antipsychotics were chosen for treatment during the period from admission to recovery from catatonia, at the time of discharge, and 12 and 30 months after discharge. RESULTS: As compared to other antipsychotics, it was found out that use of quetiapine had better outcomes and hence was used more often. A total of 61.5% of patients were on quetiapine at the time of recovery from catatonia and 51.3% of patients were on quetiapine at the time of discharge as compared to only 17.9% of patients on quetiapine on admission. However, at 12 and 30 months after discharge, the rates had decreased to 38.4% and 25.6%. Similarly, of 29 patients who were not administered electroconvulsive therapy, quetiapine was used at significantly higher rates at the time of recovery from catatonia (48.3%) than at the time of admission (17.2%). All 39 patients had received an antipsychotic as the first-line treatment and some antipsychotics might have contributed to the development of catatonia. CONCLUSION: This study suggests that quetiapine is a promising agent for the treatment of schizophrenia with catatonic stupor during the acute phase. PMID- 24143106 TI - Evidence for single nucleotide polymorphisms and their association with bipolar disorder. AB - Bipolar disorder (BD) is a complex disorder with a number of susceptibility genes and environmental risk factors involved in its pathogenesis. In recent years, huge progress has been made in molecular techniques for genetic studies, which have enabled identification of numerous genomic regions and genetic variants implicated in BD across populations. Despite the abundance of genetic findings, the results have often been inconsistent and not replicated for many candidate genes/single nucleotide polymorphisms (SNPs). Therefore, the aim of the review presented here is to summarize the most important data reported so far in candidate gene and genome-wide association studies. Taking into account the abundance of association data, this review focuses on the most extensively studied genes and polymorphisms reported so far for BD to present the most promising genomic regions/SNPs involved in BD. The review of association data reveals evidence for several genes (SLC6A4/5-HTT [serotonin transporter gene], BDNF [brain-derived neurotrophic factor], DAOA [D-amino acid oxidase activator], DTNBP1 [dysbindin], NRG1 [neuregulin 1], DISC1 [disrupted in schizophrenia 1]) to be crucial candidates in BD, whereas numerous genome-wide association studies conducted in BD indicate polymorphisms in two genes (CACNA1C [calcium channel, voltage-dependent, L type, alpha 1C subunit], ANK3 [ankyrin 3]) replicated for association with BD in most of these studies. Nevertheless, further studies focusing on interactions between multiple candidate genes/SNPs, as well as systems biology and pathway analyses are necessary to integrate and improve the way we analyze the currently available association data. PMID- 24143107 TI - A 6-year experience of CPR outcomes in an emergency department in Thailand. AB - PURPOSE: Sudden cardiac arrest is a common emergency condition found in the emergency department of the hospital. The survival rate of out-of-hospital cardiac arrest patients is 2.0%-10.0% and 7.4%-27.0% percent for in-hospital cardiac arrest patients. The factors for survival outcome are divided into three main groups: patient characteristics, pre-hospital factors, and resuscitated information. The objective of this study was to evaluate the related factors, outcome, and survival rate in patients with cardiac arrest who received cardiopulmonary resuscitation (CPR) at Ramathibodi Emergency Medicine Department. There are limited data for this issue in Thailand and other Asian countries. METHODS: This retrospective study included all patients who were older than 15 years with sudden cardiac arrest and who were resuscitated in the emergency room between January 2005 and December 2010. Descriptive analytic statistics and logistic regressions were used to analyze factors that related to the sustained return of spontaneous circulation (ROSC) and survival at discharge. RESULTS: There were 181 patients enrolled. The overall sustained ROSC rate was 34.8% and the survival rate at discharge was 11.1%. There were 145 out-of-hospital cardiac arrest patients, in whom the survival rate was 52.4% and the survival to discharge rate was 7.6%. For inhospital cardiac arrest, there were 36 patients with a survival rate of 86.1% and the survival to discharge rate was 25.0%. Statistically significant factors related to sustained ROSC were good and moderate cerebral performance, in-hospital cardiac arrest, beginning of CPR in less than 30 minutes, and cardiopulmonary cause of arrest. The factors influencing survival to discharge were cardiopulmonary causes of cardiac arrest. CONCLUSION: Factors associated with sustained ROSC were functional status before cardiac arrest, location of cardiac arrest, duration of CPR, and cause of cardiac arrest. Survival rate was related to the cause of cardiac arrest. PMID- 24143108 TI - Obesity detection rate among primary school students in the People's Republic of China: a meta-analysis. AB - BACKGROUND: Obesity has become a major public health problem worldwide. The prevalence of obesity is rising alarmingly among children and adolescents in the People's Republic of China, with an estimated 120 million now in the obese range. It is estimated that 8% of children in the People's Republic of China are obese and 12% are overweight. METHODS: Eligible papers on the prevalence of obesity among primary school students in the People's Republic of China and published between 2006 and 2011 were retrieved from PubMed and from online Chinese periodicals, ie, the full-text databases of VIP, the Chinese National Knowledge Infrastructure, and Wan Fang. Meta-Analyst software was used to collate and analyze the detection rates cited in the papers retrieved. RESULTS: After evaluation of the quality of the papers, 25 were finally included, giving a total sample population size for investigation of obesity of 219,763, in which 28,121 cases were detected. Meta-analysis showed that the combined obesity detection rate was 10.4% (95% confidence interval 8.6-12.6) among primary school students in the People's Republic of China, with a higher detection rate in boys (12.6%) than in girls (7.2%). The prevalence of obesity was higher in the north (11.8%) than in the south (9.5%), east (11.6%), and mid-west (8.0%) regions. Obesity defined according to the World Health Organization weight-for-height standard (14.3%) was higher than that using age-specific and gender-specific cutoff points for body mass index (9.0%). CONCLUSION: Our meta-analysis found an obesity prevalence rate of 10.4%, which does not seem as high as previous reports of childhood obesity rates in other countries. However, the prevalence of childhood obesity in the People's Republic of China is still worrisome, and is likely to rise even further if we fail to take effective and practical measures now. PMID- 24143109 TI - Cardiovascular outcomes during treatment with dabigatran: comprehensive analysis of individual subject data by treatment. AB - BACKGROUND: Dabigatran 150 mg twice daily was shown to be superior to warfarin in preventing stroke in subjects with nonvalvular atrial fibrillation (SPAF) in the RE-LY (Randomized Evaluation of Long-term anticoagulation therapY) trial. Numerically, more myocardial infarctions occurred in patients receiving dabigatran compared with well-controlled warfarin. This observation prompted a comprehensive analysis of cardiovascular outcomes, including myocardial infarction, in all completed Phase II and III trials of dabigatran etexilate. METHODS: The analysis included comparisons of dabigatran with warfarin, enoxaparin, and placebo. Data were analyzed for the occurrence of cardiovascular events from 14 comparative trials (n = 42,484) in five different indications. Individual study data were evaluated, as well as pooled subject-level data grouped by comparator. RESULTS: In the pooled analysis of individual patient data comparing dabigatran with warfarin (SPAF and venous thromboembolism treatment indications), myocardial infarction occurrence favored warfarin (odds ratio [OR] 1.30, 95% confidence interval [CI] 0.96-1.76 for dabigatran 110 mg twice daily and OR 1.42, 95% CI 1.07-1.88 for dabigatran 150 mg twice daily). The clinically relevant composite endpoint of myocardial infarction, total stroke, and vascular death demonstrated numerically fewer events in dabigatran 150 mg patients (OR 0.87, 95% CI 0.77-1.00), but was similar for dabigatran 110 mg (OR 0.99, 95% CI 0.87-1.13). Dabigatran had similar myocardial infarction rates when compared with enoxaparin or placebo. CONCLUSION: These analyses suggest a more protective effect of well-controlled warfarin, but not enoxaparin, compared with dabigatran in preventing myocardial infarction in multiple clinical settings. Dabigatran showed an overall positive benefit-risk ratio for multiple clinically important cardiovascular composite endpoints in all evaluated clinical indications. In conclusion, these data suggest that myocardial infarction is not an adverse drug reaction associated with use of dabigatran. PMID- 24143110 TI - Do structured arrangements for multidisciplinary peer group supervision make a difference for allied health professional outcomes? AB - Peer group supervision, particularly in multidisciplinary formats, presents a potential means of providing professional support, and specifically clinical supervision, for allied health professionals. Debate exists regarding the extent to which the activities of these groups should be formalized. Results drawn from an evaluation of a large-scale peer group supervision initiative are described. Analysis of 192 responses from professionals involved in peer groups indicates that participants in groups that used formal documentation - which adopted the tools provided in training, and particularly those that used formal evaluation of their groups - rated their groups as having better processes and greater impact. Interestingly, multidisciplinary peer groups were rated as having similar impacts, processes, and purposes as the more homogenous single-discipline groups. It is concluded that the implementation of formal arrangements enhances the processes and outcomes of peer groups implemented for professional support and clinical supervision. Multidisciplinary membership of such groups is perceived as equally beneficial as single-discipline groups. PMID- 24143111 TI - Predicting intention to use voluntary HIV counseling and testing services among health professionals in Jimma, Ethiopia, using the theory of planned behavior. AB - BACKGROUND: To endorse involvement in voluntary HIV counseling and testing (VCT), it is essential to recognize factors that influence people in deciding whether to access VCT services and their underlying route factors. Theory of planned behavior (TPB) constitutes a proficient framework for predicting behaviors and intentions. OBJECTIVE: The aim of the study reported here was to assess the predicting ability of TPB in determining the intended use of VCT services among health professionals in Jimma, southwest Ethiopia. METHODS: This was an institution-based cross-sectional quantitative study of a sample of 336 health professionals in 12 selected districts of Jimma, southwest Ethiopia between February 5 to March 28, 2012. Data were collected using structured questionnaire self-administered by the study participants. A hierarchal multivariable linear regression model was used to predict the role of TPB constructs that can influence the intention to use VCT services. RESULTS: The constructs of TPB explained the variability in intention to use VCT by 27% (R (2) adjusted = 0.27). The standardized regression coefficients showed that the strongest predictor of intention to use VCT was subjective norms (beta = 0.32, P < 0.0005) followed by attitude (beta = 0.21, P < 0.002). Perceived behavioral control was not a significant predictor of intention to use VCT among the study group (P = 0.12). CONCLUSION: The study revealed the possibility of describing the intention to use VCT among health professionals using TPB, with perceived social pressure being the leading predictor. In light of this, health intervention programs should be designed to develop health professionals' ability to resist norms that oppose the use of VCT and to change community-held norms against VCT use, provided they help individuals develop a positive attitude toward the services. PMID- 24143112 TI - Fludarabine-based versus CHOP-like regimens with or without rituximab in patients with previously untreated indolent lymphoma: a retrospective analysis of safety and efficacy. AB - Fludarabine-based regimens and CHOP (doxorubicin, cyclophosphamide, vincristine, prednisone)-like regimens with or without rituximab are the most common treatment modalities for indolent lymphoma. However, there is no clear evidence to date about which chemotherapy regimen should be the proper initial treatment of indolent lymphoma. More recently, the use of fludarabine has raised concerns due to its high number of toxicities, especially hematological toxicity and infectious complications. The present study aimed to retrospectively evaluate both the efficacy and the potential toxicities of the two main regimens (fludarabine-based and CHOP-like regimens) in patients with previously untreated indolent lymphoma. Among a total of 107 patients assessed, 54 patients received fludarabine-based regimens (FLU arm) and 53 received CHOP or CHOPE (doxorubicin, cyclophosphamide, vincristine, prednisone, or plus etoposide) regimens (CHOP arm). The results demonstrated that fludarabine-based regimens could induce significantly improved progression-free survival (PFS) compared with CHOP-like regimens. However, the FLU arm showed overall survival, complete response, and overall response rates similar to those of the CHOP arm. Grade 3-4 neutropenia occurred in 42.6% of the FLU arm and 7.5% of the CHOP arm (P < 0.000). Moreover, the FLU arm also had a higher occurrence of infection than the CHOP arm (27.8% vs 8.5%; P = 0.034). Multi-factor regression of infection revealed that only age (>60 years) and presentation of grade 3-4 myelosuppression were the independent factors to infection, and the FLU arm had significantly higher myelosuppression. In conclusion, the present study revealed that the use of fludarabine-based regimens could induce high rates of myelosuppression over CHOP-like regimens, in spite of significant increases in PFS. PMID- 24143113 TI - Dynamin 3: a new candidate tumor suppressor gene in hepatocellular carcinoma detected by triple combination array analysis. AB - BACKGROUND: To identify genes associated with hepatocellular carcinoma (HCC) pathogenesis, we developed a triple combination array strategy comprising methylation, gene expression, and single nucleotide polymorphism (SNP) array analysis. METHODS: Surgical specimens obtained from a 68-year-old female HCC patient were analyzed by triple combination array, and identified Dynamin 3 (DNM3) as a candidate tumor suppressor gene in HCC. Subsequently, samples from 48 HCC patients were evaluated for DNM3 methylation and expression status using methylation specific polymerase chain reaction (PCR; MSP) and semi-quantitative reverse transcriptase (RT)-PCR, respectively. The relationship between clinicopathological factors and DNM3 methylation status was also investigated. RESULTS: DNM3 was shown to be hypermethylated (methylation value 0.879, range 0 1.0) in cancer tissue compared with adjacent normal tissue (0.213) by methylation array in the 68-year-old female patient. Expression arrays revealed decreased expression of DNM3 in cancerous tissue. SNP arrays revealed that the copy number of chromosome 1q24.3, in which DNM3 resides, was normal. MSP revealed hypermethylation of the DNM3 promoter region in 33 of 48 tumor samples. A trend toward decreased DNM3 expression was observed in patients with DNM3 promoter methylation (P = 0.189). Furthermore, patients with reduced expression of DNM3 in tumor tissues exhibited worse prognosis with decreased disease specific survival compared to patients without decreased expression (P = 0.014). CONCLUSION: The present study indicates that a triple combination array strategy is an effective method to detect novel genes related to HCC. We propose that DNM3 is a tumor suppressor gene in HCC. PMID- 24143115 TI - Whole-genome sequencing in bacteriology: state of the art. AB - Over the last ten years, genome sequencing capabilities have expanded exponentially. There have been tremendous advances in sequencing technology, DNA sample preparation, genome assembly, and data analysis. This has led to advances in a number of facets of bacterial genomics, including metagenomics, clinical medicine, bacterial archaeology, and bacterial evolution. This review examines the strengths and weaknesses of techniques in bacterial genome sequencing, upcoming technologies, and assembly techniques, as well as highlighting recent studies that highlight new applications for bacterial genomics. PMID- 24143117 TI - Evaluation of the maximum beyond-use-date stability of regular human insulin extemporaneously prepared in 0.9% sodium chloride in a polyvinyl chloride bag. AB - BACKGROUND: Regular human insulin 100 units added to a sufficient quantity of 0.9% sodium chloride, to yield a total volume of 100 mL within a polyvinylchloride bag, is accepted to be stable for 24 hours due to physical denaturation and chemical modification. The objective of this study was to evaluate the extended stability of such extemporaneously prepared regular human insulin, stored under refrigeration, to the maximum beyond-use-date allowed by United States Pharmacopeia chapter 797. METHODS: At time "0" three admixtures of regular human insulin were prepared by withdrawing 1 mL of regular human insulin with a concentration of 100 units/mL and adding it to a sufficient quantity of 0.9% sodium chloride for injection in a polyvinylchloride bag to yield a total volume of 100 mL. The three admixtures were stored under refrigeration (2 degrees C-8 degrees C [36 degrees F-46 degrees F]), and one sample of each admixture was withdrawn and tested in duplicate at 0, 6, 24, 48, 72, 144, 168, 192, 216, 240, 312, and 336 hours. Utilizing high performance liquid chromatography, each sample underwent immediate testing. The time points were stable if the mean concentration of the samples exceeded 90% of the equilibrium concentration at 6 hours. RESULTS: The equilibrium concentration was 0.89 units/mL. Time points were stable if the mean concentration was at least 0.80 units/mL. All time points retained at least 90% of the equilibrium concentration, with the exception of hour 168 (0.79 +/- 0.03 units/mL). At 192 hours the mean concentration was 0.88 +/- 0.03 units/mL. At 336 hours the mean concentration was 0.91 +/- 0.02 units/mL. CONCLUSION: Based on these results, regular human insulin 100 units added to 0.9% sodium chloride for injection in a polyvinylchloride bag to yield a total volume of 100 mL is stable for up to 336 hours when stored at 2 degrees C-8 degrees C (36 degrees F-46 degrees F). PMID- 24143116 TI - Hepatic function and the cardiometabolic syndrome. AB - Despite skeletal muscle being considered by many as the source of insulin resistance, physiology tells us that the liver is a central and cardinal regulator of glucose homeostasis. This is sometimes underestimated because, in contrast with muscle, investigations of liver function are technically very difficult. Nevertheless, recent experimental and clinical research has demonstrated clearly that, due in part to its anatomic position, the liver is exquisitely sensitive to insulin and other hormonal and neural factors, either by direct intrahepatic mechanisms or indirectly by organ cross-talk with muscle or adipose tissue. Because the liver receives absorbed nutrients, these have a direct impact on liver function, whether via a caloric excess or via the nature of food components (eg, fructose, many lipids, and trans fatty acids). An emerging observation with a possibly great future is the increase in intestinal permeability observed as a consequence of high fat intake or bacterial modifications in microbiota, whereby substances normally not crossing the gut gain access to the liver, where inflammation, oxidative stress, and lipid accumulation leads to fatty liver, a situation observed very early in the development of diabetes. The visceral adipose tissue located nearby is another main source of inflammatory substances and oxidative stress, and also acts on hepatocytes and Kupffer cells, resulting in stimulation of macrophages. Liberation of these substances, in particular triglycerides and inflammation factors, into the circulation leads to ectopic fat deposition and vascular damage. Therefore, the liver is directly involved in the development of the prediabetic cardiometabolic syndrome. Treatments are mainly metformin, and possibly statins and vitamin D. A very promising avenue is treatment of the leaky gut, which appears increasingly to be an important causal factor in hepatic insulin resistance and steatosis. PMID- 24143118 TI - The effect of very low-calorie diets on renal and hepatic outcomes: a systematic review. AB - Very low-calorie diets (VLCDs) are an effective means by which to induce clinically significant weight loss. However, their acceptance by health care practitioners and the public is generally lower than that for other nonsurgical weight loss methods. Whilst there is currently little evidence to suggest they have any detrimental effect on hepatic and renal health, data assessing these factors remain limited. We carried out a systematic review of the literature on randomized controlled trials that had a VLCD component and that reported outcomes for hepatic and renal health, published between January 1980 and December 2012. Cochrane criteria were followed, and eight out of 196 potential articles met the inclusion criteria. A total of 548 participants were recruited across the eight studies. All eight studies reported significant weight loss following the VLCD. Changes in hepatic and renal outcomes were variable but generally led to either no change or improvements in either of these. Due to the heterogeneity in the quality and methodology of the studies included, the effect of VLCDs on hepatic and renal outcomes remains unclear at this stage. Further standardized research is therefore required to fully assess the impact of VLCDs on these outcome measures, to better guide clinical practice. PMID- 24143114 TI - Targeting hedgehog signaling in cancer: research and clinical developments. AB - Since its first description in Drosophila by Drs Nusslein-Volhard and Wieschaus in 1980, hedgehog (Hh) signaling has been implicated in regulation of cell differentiation, proliferation, tissue polarity, stem cell maintenance, and carcinogenesis. The first link of Hh signaling to cancer was established through studies of Gorlin syndrome in 1996 by two independent teams. Later, it was shown that Hh signaling may be involved in many types of cancer, including skin, leukemia, lung, brain, and gastrointestinal cancers. In early 2012, the US Food and Drug Administration approved the clinical use of Hh inhibitor Erivedge/vismodegib for treatment of locally advanced and metastatic basal cell carcinomas. With further investigation, it is possible to see more clinical applications of Hh signaling inhibitors. In this review, we will summarize major advances in the last 3 years in our understanding of Hh signaling activation in human cancer, and recent developments in preclinical and clinical studies using Hh signaling inhibitors. PMID- 24143119 TI - Renoprotective effects of telmisartan after unilateral renal ablation in rats. AB - PURPOSE: The renoprotective function of the angiotensin II type 1 receptor blocker (ARB) is well-known in various studies, including the animal model of renal failure. However, detailed temporal changes of pathological and molecular findings after unilateral nephrectomy are not fully understood. The main purpose of this study was to clarify the renoprotective effects and pathological changes induced by the ARB in rat-remnant kidney (RK) tissues after unilateral nephrectomy, but not after a 5/6 nephrectomy. METHODS: Telmisartan, which is structurally and functionally unique among ARB, was used in this study. Three rat groups were examined: A) no ARB administrated (RK, n=21); B) continuous subcutaneous infusion of an ARB administrated (RK-ARB, n=21); and C) a sham operated group (Sham). Renal function was evaluated by blood urea nitrogen (BUN) levels and creatinine clearance (Ccr). Fibrosis was evaluated by hydroxyproline levels and Masson's trichrome staining. Expressions of angiotensin II type 1 receptor (AT1R) and transforming growth factor beta (TGF-beta) were investigated by real-time polymerase chain reaction and Western blotting. RESULTS: There was no significant difference regarding body and kidney weight or pathological features evaluated by hematoxylin and eosin staining between the RK and RK-ARB groups. The Ccr in the RK group was significantly lower than that in the Sham group (P<0.01), but no significant difference was found between the RK-ARB and Sham groups. The fibrotic area increased significantly with time after nephrectomy in the RK group. Although a similar trend was found in the RK-ARB group, the percentage of fibrous area in the RK-ARB group was significantly lower than that in the RK group at each time point (P<0.01). AT1R mRNA levels in the RK group were regulated immediately compared with those in the RK-ARB group. Although expressions of the AT1R and TGF-beta were significantly higher in the RK ARB group than in the Sham group, no significant differences were found between the RK-ARB and Sham group. CONCLUSION: The ARB had renoprotective effects after unilateral nephrectomy. The ARB effectively maintained Ccr. Our results also showed the possibility that fibrotic changes mediated by AT1R and TGF-beta play an important role in renal protection. Moreover, this is the first report on changes of AT1R expression after using the ARB telmisartan in kidney tissues after unilateral nephrectomy. Finally, our results suggest that ARB may be useful to prevent renal failure in patients treated with nephrectomy. PMID- 24143120 TI - Hemodialysis catheter implantation in the axillary vein by ultrasound guidance versus palpation or anatomical reference. AB - BACKGROUND: WE COMPARED THE RESULTS OF FOUR DIFFERENT METHODS OF HEMODIALYSIS CATHETER INSERTION IN THE MEDIAL SEGMENT OF THE AXILLARY VEIN: ultrasound guidance, palpation, anatomical reference, and prior transient catheter. METHODS: All patients that required acute or chronic hemodialysis and for whom it was determined impossible or not recommended either to place a catheter in the internal jugular vein (for instance, those patients with a tracheostomy), or to practice arteriovenous fistula or graft; it was then essential to obtain an alternative vascular access. When the procedure of axillary vein catheter insertion was performed in the Renal Care Facility (RCF), ultrasound guidance was used, but in the intensive care unit (ICU), this resource was unavailable, so the palpation or anatomical reference technique was used. RESULTS: Two nephrologists with experience in the technique performed 83 procedures during a period lasting 15 years and 8 months (from January 1997-August 2012): 41 by ultrasound guidance; 19 by anatomical references; 15 by palpation of the contiguous axillary artery; and 8 through a temporary axillary catheter previously placed. The ultrasound guided patients had fewer punctures than other groups, but the value was not statistically significant. Arterial punctures were infrequent in all techniques. Analyzing all the procedure-related complications, such as hematoma, pneumothorax, brachial-plexus injury, as well as the reasons for catheter removal, no differences were observed among the groups. The functioning time was longer in the ultrasound-guided and previous catheter groups. In 15 years and 8 months of surveillance, no clinical or image evidence for axillary vein stenosis was found. CONCLUSION: The ultrasound guide makes the procedure of inserting catheters in the axillary veins easier, but knowledge of the anatomy of the midaxillary region and the ability to feel the axillary artery pulse (for the palpation method) also allow relatively easy successful implant of catheters in the axillary veins. PMID- 24143121 TI - Comparison of once daily versus twice daily olmesartan in patients with chronic kidney disease. AB - BACKGROUND: The effects of olmesartan (OLM) on blood pressure and kidney function in Japanese patients with chronic kidney disease (CKD) were compared between 20 mg twice daily (BID) and 40 mg once daily (QD) treatments. METHODS: The subjects were Japanese CKD patients with concurrent hypertension who had been treated with OLM 20 mg BID for at least 3 months on an outpatient basis (n=39). After a change in the treatment regimen to 40 mg OLM QD (after breakfast), blood pressure (BP) (n=39), morning home BP (n=13), estimated glomerular filtration rate (n=39), and urinary albumin-to-creatinine ratio (n=17) were monitored for 2 months. RESULTS: No significant change in office (mean +/- standard deviation [SD] [mmHg], 143.9 +/- 18.8/75.7 +/- 12.0 to 141.6 +/- 16.1/74.7 +/- 11.7, not significant [ns]) or early morning home (mean +/- SD [mmHg], 133.8 +/- 15.9/71.2 +/- 11.5 to 133.8 +/- 13.9/74.5 +/- 10.5, ns) BP was observed 2 months after the change in dose. The estimated glomerular filtration rate increased significantly (mean +/- SD, 49.0 +/- 28.0 to 51.8 +/- 27.0, P<0.05), whereas urinary albumin-to-creatinine ratio did not change significantly (mean +/- SD, 0.551 +/- 0.445 to 0.364 +/- 0.5194, ns). CONCLUSION: High-dose OLM administered BID and QD had similar effects on outpatient and early morning home BP in CKD patients, suggesting that the BID regimen can be safely changed to a QD regimen. For CKD patients with hypertension requiring continuous long-term treatment, the possibility that the QD regimen might bring a greater therapeutic effect was suggested. However, recognizing the best blood pressure control level for a CKD patient is still a matter of debate, and should ideally be personalized. PMID- 24143122 TI - Benefit risk assessment and update on the use of docetaxel in the management of breast cancer. AB - The objective of this paper is to review the data supporting the use of docetaxel in the treatment of breast cancer, focusing on pharmacokinetics, efficacy in adjuvant and metastatic trials alone and in combination with chemotherapeutic and targeted agents, and the toxicity of docetaxel in comparison to paclitaxel. Docetaxel is a semisynthetic product derived from the European yew tree Taxus baccata L. It promotes the assembly of microtubules, stabilizes them, and thereby prevents their depolymerization. Docetaxel has been incorporated into neo adjuvant chemotherapy regimens, both with and without anthracyclines. The inclusion of taxanes such as docetaxel in polychemotherapy regimens in early breast cancer is associated with a statistically significant reduction in mortality. As a single agent, docetaxel is highly active in the treatment of metastatic breast cancer. In first-line treatment of metastatic breast cancer, the combination of docetaxel and capecitabine was associated with an improvement in overall survival; however, toxicity was higher. The toxicity profile of docetaxel has been well documented and is predictable; the most frequent adverse effects are neutropenia and febrile neutropenia. Taxane-specific adverse effects, such as peripheral neuropathy, are also expected but are manageable with appropriate dosing and scheduling. PMID- 24143123 TI - Does marriage protect against hospitalization with pneumonia? A population-based case-control study. AB - BACKGROUND: To reduce the increasing burden of pneumonia hospitalizations, we need to understand their determinants. Being married may decrease the risk of severe infections, due to better social support and healthier lifestyle. PATIENTS AND METHODS: In this population-based case-control study, we identified all adult patients with a first-time pneumonia-related hospitalization between 1994 and 2008 in Northern Denmark. For each case, ten sex- and age-matched population controls were selected from Denmark's Civil Registration System. We performed conditional logistic regression analysis to estimate the odds ratios (ORs) for pneumonia hospitalization among persons who were divorced, widowed, or never married, as compared with married persons, adjusting for age, sex, 19 different comorbidities, alcoholism-related conditions, immunosuppressant use, urbanization, and living with small children. RESULTS: The study included 67,162 patients with a pneumonia-related hospitalization and 671,620 matched population controls. Compared with controls, the pneumonia patients were more likely to be divorced (10% versus 7%) or never married (13% versus 11%). Divorced and never married patients were much more likely to have previous diagnoses of alcoholism related conditions (18% and 11%, respectively) compared with married (3%) and widowed (6%) patients. The adjusted OR for pneumonia-related hospitalization was increased, at 1.29 (95% confidence interval [CI]: 1.25-1.33) among divorced; 1.15 (95% CI: 1.12-1.17) among widowed; and 1.33 (95% CI: 1.29-1.37) among never married individuals as compared with those who were married. CONCLUSION: Married individuals have a decreased risk of being hospitalized with pneumonia compared with never-married, divorced, and widowed patients. PMID- 24143124 TI - Barriers to use of modern contraceptives among women in an inner city area of Osogbo metropolis, Osun state, Nigeria. AB - OBJECTIVES: To determine the knowledge and attitudes on modern contraceptive use of women living in an inner city area of Osogbo. MATERIALS AND METHODS: Three hundred and fifty nine women of childbearing age were studied utilizing a community-based, descriptive, cross-sectional study design. A multistage random sampling technique was used in recruiting respondents to the study. A four-part questionnaire was applied dually, by interviewers and by respondents' self administration, and the data was analyzed using the SPSS software version 17.0. RESULTS: The mean age of respondents was 28.6 +/- 6.65 years. The majority (90.3%) of respondents were aware of modern methods of family planning (FP), 76.0% claimed awareness of where to obtain FP services, and 74.9% knew of at least five methods. However, only 30.6% had ever used contraceptives, while only 13.1% were current users. The most frequently used method was the male condom. The commonly perceived barriers accounting for low use of FP methods were fear of perceived side effects (44.0%), ignorance (32.6%), misinformation (25.1%), superstition (22.0%), and culture (20.3%). Some reasons were proffered for respondents' nonuse of modern contraception. Predictors of use of modern contraceptives include the awareness of a place of FP service provision, respondents' approval of the use of contraceptives, higher education status, and being married. CONCLUSION: Most of the barriers reported appeared preventable and removable and may be responsible for the reported low point prevalence of use of contraceptives. It is recommended that community-based behavioral-change communication programs be instituted, aimed at improving the perceptions of women with respect to bridging knowledge gaps about contraceptive methods and to changing deep-seated negative beliefs related to contraceptive use in Nigeria. PMID- 24143125 TI - Optimal management of severe nausea and vomiting in migraine: improving patient outcomes. AB - Migraine is a common and potentially disabling disorder for patients, with wide reaching implications for health care services, society, and the economy. Nausea and vomiting during migraine attacks are common symptoms that affect at least 60% of patients suffering from migraines. These symptoms are often more disabling than the headache itself, causing a great burden on the patient's life. Nausea and vomiting may delay the use of oral abortive medication or interfere with oral drug absorption. Therefore, they can hinder significantly the management and treatment of migraine (which is usually given orally). The main treatment of pain associated symptoms of migraine (such as nausea and vomiting) is to stop the migraine attack itself as soon as possible, with the effective drugs at the effective doses, seeking if necessary alternative routes of administration. In some cases, intravenous antiemetic drugs are able to relieve a migraine attack and associated symptoms like nausea and vomiting. We performed an exhaustive PubMed search of the English literature to find studies about management of migraine and its associated symptoms. Search terms were migraine, nausea, and vomiting. We did not limit our search to a specific time period. We focused on clinical efficacy and tolerance of the various drugs and procedures based on data from human studies. We included the best available studies for each discussed drug or procedure. These ranged from randomized controlled trials for some treatments to small case series for others. Recently updated books and manuals on neurology and headache were also consulted. We herein review the efficacy of the different approaches in order to manage nausea and vomiting for migraine patents. PMID- 24143127 TI - Scientific institutions and effective governance: a case study of Chinese stem cell research. AB - In terms of stem cell research, China appears both as a "powerhouse" armed with state-of-the-art facilities, internationally trained personnel and permissive regulation and as a "bit player," with its capability for conducting high quality research still in question. The gap between China's assiduous endeavors and the observed outcome is due to a number of factors. Based on interviews with 48 key stakeholders active in Chinese stem cell research, this article examines how the structure of scientific institutions has affected effective governance in China. It is demonstrated that despite China's recent efforts to attract highly competent researchers and to launch new regulatory initiatives, the effects of these attempts have been diminished by an absence of middle-layer positions within research teams and by the uncoordinated administrative structures among regulatory bodies. PMID- 24143126 TI - Atmospheric Prebiotic Chemistry and Organic Hazes. AB - Earth's atmospheric composition at the time of the origin of life is not known, but it has often been suggested that chemical transformation of reactive species in the atmosphere was a significant source of prebiotic organic molecules. Experimental and theoretical studies over the past half century have shown that atmospheric synthesis can yield molecules such as amino acids and nucleobases, but these processes are very sensitive to gas composition and energy source. Abiotic synthesis of organic molecules is more productive in reduced atmospheres, yet the primitive Earth may not have been as reducing as earlier workers assumed, and recent research has reflected this shift in thinking. This work provides a survey of the range of chemical products that can be produced given a set of atmospheric conditions, with a particular focus on recent reports. Intertwined with the discussion of atmospheric synthesis is the consideration of an organic haze layer, which has been suggested as a possible ultraviolet shield on the anoxic early Earth. Since such a haze layer - if formed - would serve as a reservoir for organic molecules, the chemical composition of the aerosol should be closely examined. The results highlighted here show that a variety of products can be formed in mildly reducing or even neutral atmospheres, demonstrating that contributions of atmospheric synthesis to the organic inventory on early Earth should not be discounted. This review intends to bridge current knowledge of the range of possible atmospheric conditions in the prebiotic environment and pathways for synthesis under such conditions by examining the possible products of organic chemistry in the early atmosphere. PMID- 24143128 TI - Non-specialist health worker interventions for mental health care in low- and middle- income countries. AB - : This is the protocol for a review and there is no abstract. The objectives are as follows: OVERALL OBJECTIVE: In order to assess the impact of delivery by non specialist health workers (NSHWs) and other professionals with health roles (OPHRs) on the effectiveness of mental healthcare interventions in low- and middle- income countries (LMICs), we will specifically analyse the effectiveness of NSHWs and OPHRS in delivering acute mental health interventions; as well as the effectiveness of NSHWs and OPHRs in delivering long term follow-up and rehabilitation for people with mental disorders; and the effect of the detection of mental disorders by NSHWs and OPHRs on patient and health delivery outcomes. For each of these objectives we will examine the current evidence for the impact of delivery by NSHWs and OPHRs on the resource use and costs associated with mental healthcare provision in LMICs. PMID- 24143129 TI - Does Powerlessness Explain Elevated HIV Risk Amongst Tajik Labor Migrants? An Ethnographic Study. AB - To investigate the role of powerlessness in elevated HIV risk among labor migrants, we compared internal verses external male migrant workers from Tajikistan using minimally structured interviews and focused field observations. The sample included 30 male labor migrants who traveled to work in Regar, Tajikistan (internal labor migrants), and 30 who traveled to work in Moscow, Russia (external labor migrants). Though powerlessness did not appear to account for whether labor migrants engaged in more HIV risk behaviors, the harsh living and working conditions of external labor migration impacted how the migrants manifested these HIV risks by amplifying group masculine norms and behaviors. Progress in preventing HIV infection amid the difficult social conditions of labor migration is contingent upon adequate conceptualization of how such conditions impact HIV risk behaviors. PMID- 24143130 TI - Security and Interoperable Medical Device Systems: Part 1. PMID- 24143131 TI - Security and Interoperable Medical Device Systems, Part 2: Failures, Consequences and Classifications. PMID- 24143133 TI - Deciphering the structural basis of eukaryotic protein kinase regulation. AB - Eukaryotic protein kinases (EPKs) regulate numerous signaling processes by phosphorylating targeted substrates through the highly conserved catalytic domain. Our previous computational studies proposed a model stating that a properly assembled nonlinear motif termed the Regulatory (R) spine is essential for catalytic activity of EPKs. Here we define the required intramolecular interactions and biochemical properties of the R-spine and the newly identified "Shell" that surrounds the R-spine using site-directed mutagenesis and various in vitro phosphoryl transfer assays using cyclic AMP-dependent protein kinase as a representative of the entire kinome. Analysis of the 172 available Apo EPK structures in the protein data bank (PDB) revealed four unique structural conformations of the R-spine that correspond with catalytic inactivation of various EPKs. Elucidating the molecular entities required for the catalytic activation of EPKs and the identification of these inactive conformations opens new avenues for the design of efficient therapeutic EPK inhibitors. PMID- 24143134 TI - Confirming the importance of the R-spine: new insights into protein kinase regulation. PMID- 24143132 TI - eIF4EBP3L acts as a gatekeeper of TORC1 in activity-dependent muscle growth by specifically regulating Mef2ca translational initiation. AB - Muscle fiber size is activity-dependent and clinically important in ageing, bed rest, and cachexia, where muscle weakening leads to disability, prolonged recovery times, and increased costs. Inactivity causes muscle wasting by triggering protein degradation and may simultaneously prevent protein synthesis. During development, muscle tissue grows by several mechanisms, including hypertrophy of existing fibers. As in other tissues, the TOR pathway plays a key role in promoting muscle protein synthesis by inhibition of eIF4EBPs (eukaryotic Initiation Factor 4E Binding Proteins), regulators of the translational initiation. Here, we tested the role of TOR-eIF4EBP in a novel zebrafish muscle inactivity model. Inactivity triggered up-regulation of eIF4EBP3L (a zebrafish homolog of eIF4EBP3) and diminished myosin and actin content, myofibrilogenesis, and fiber growth. The changes were accompanied by preferential reduction of the muscle transcription factor Mef2c, relative to Myod and Vinculin. Polysomal fractionation showed that Mef2c decrease was due to reduced translation of mef2ca mRNA. Loss of Mef2ca function reduced normal muscle growth and diminished the reduction in growth caused by inactivity. We identify eIF4EBP3L as a key regulator of Mef2c translation and protein level following inactivity; blocking eIF4EBP3L function increased Mef2ca translation. Such blockade also prevented the decline in mef2ca translation and level of Mef2c and slow myosin heavy chain proteins caused by inactivity. Conversely, overexpression of active eIF4EBP3L mimicked inactivity by decreasing the proportion of mef2ca mRNA in polysomes, the levels of Mef2c and slow myosin heavy chain, and myofibril content. Inhibiting the TOR pathway without the increase in eIF4EBP3L had a lesser effect on myofibrilogenesis and muscle size. These findings identify eIF4EBP3L as a key TOR dependent regulator of muscle fiber size in response to activity. We suggest that by selectively inhibiting translational initiation of mef2ca and other mRNAs, eIF4EBP3L reprograms the translational profile of muscle, enabling it to adjust to new environmental conditions. PMID- 24143136 TI - A sea of change. PMID- 24143135 TI - Biotic and human vulnerability to projected changes in ocean biogeochemistry over the 21st century. AB - Ongoing greenhouse gas emissions can modify climate processes and induce shifts in ocean temperature, pH, oxygen concentration, and productivity, which in turn could alter biological and social systems. Here, we provide a synoptic global assessment of the simultaneous changes in future ocean biogeochemical variables over marine biota and their broader implications for people. We analyzed modern Earth System Models forced by greenhouse gas concentration pathways until 2100 and showed that the entire world's ocean surface will be simultaneously impacted by varying intensities of ocean warming, acidification, oxygen depletion, or shortfalls in productivity. In contrast, only a small fraction of the world's ocean surface, mostly in polar regions, will experience increased oxygenation and productivity, while almost nowhere will there be ocean cooling or pH elevation. We compiled the global distribution of 32 marine habitats and biodiversity hotspots and found that they would all experience simultaneous exposure to changes in multiple biogeochemical variables. This superposition highlights the high risk for synergistic ecosystem responses, the suite of physiological adaptations needed to cope with future climate change, and the potential for reorganization of global biodiversity patterns. If co-occurring biogeochemical changes influence the delivery of ocean goods and services, then they could also have a considerable effect on human welfare. Approximately 470 to 870 million of the poorest people in the world rely heavily on the ocean for food, jobs, and revenues and live in countries that will be most affected by simultaneous changes in ocean biogeochemistry. These results highlight the high risk of degradation of marine ecosystems and associated human hardship expected in a future following current trends in anthropogenic greenhouse gas emissions. PMID- 24143137 TI - A new approach to psychiatric drug approval in Europe. AB - Corrado Barbui and Irene Bighelli question the current rules governing registration of new medicines in Europe, using the example of psychiatric drugs, and argue that the concept of absolute efficacy should be replaced by the concept of added value whereby evidence from studies comparing a new product with an active comparator should guide the drug approval process. Please see later in the article for the Editors' Summary. PMID- 24143139 TI - The 2003 Iraq War and avoidable death toll. AB - Salman Rawaf discusses the implications of the most recent estimate of excess deaths associated with the Iraq war and subsequent occupation in the context of the current situation in Iraq. Please see later in the article for the Editors' Summary. PMID- 24143138 TI - Use of expert panels to define the reference standard in diagnostic research: a systematic review of published methods and reporting. AB - BACKGROUND: In diagnostic studies, a single and error-free test that can be used as the reference (gold) standard often does not exist. One solution is the use of panel diagnosis, i.e., a group of experts who assess the results from multiple tests to reach a final diagnosis in each patient. Although panel diagnosis, also known as consensus or expert diagnosis, is frequently used as the reference standard, guidance on preferred methodology is lacking. The aim of this study is to provide an overview of methods used in panel diagnoses and to provide initial guidance on the use and reporting of panel diagnosis as reference standard. METHODS AND FINDINGS: PubMed was systematically searched for diagnostic studies applying a panel diagnosis as reference standard published up to May 31, 2012. We included diagnostic studies in which the final diagnosis was made by two or more persons based on results from multiple tests. General study characteristics and details of panel methodology were extracted. Eighty-one studies were included, of which most reported on psychiatry (37%) and cardiovascular (21%) diseases. Data extraction was hampered by incomplete reporting; one or more pieces of critical information about panel reference standard methodology was missing in 83% of studies. In most studies (75%), the panel consisted of three or fewer members. Panel members were blinded to the results of the index test results in 31% of studies. Reproducibility of the decision process was assessed in 17 (21%) studies. Reported details on panel constitution, information for diagnosis and methods of decision making varied considerably between studies. CONCLUSIONS: Methods of panel diagnosis varied substantially across studies and many aspects of the procedure were either unclear or not reported. On the basis of our review, we identified areas for improvement and developed a checklist and flow chart for initial guidance for researchers conducting and reporting of studies involving panel diagnosis. Please see later in the article for the Editors' Summary. PMID- 24143140 TI - Mortality in Iraq associated with the 2003-2011 war and occupation: findings from a national cluster sample survey by the university collaborative Iraq Mortality Study. AB - BACKGROUND: Previous estimates of mortality in Iraq attributable to the 2003 invasion have been heterogeneous and controversial, and none were produced after 2006. The purpose of this research was to estimate direct and indirect deaths attributable to the war in Iraq between 2003 and 2011. METHODS AND FINDINGS: We conducted a survey of 2,000 randomly selected households throughout Iraq, using a two-stage cluster sampling method to ensure the sample of households was nationally representative. We asked every household head about births and deaths since 2001, and all household adults about mortality among their siblings. We used secondary data sources to correct for out-migration. From March 1, 2003, to June 30, 2011, the crude death rate in Iraq was 4.55 per 1,000 person-years (95% uncertainty interval 3.74-5.27), more than 0.5 times higher than the death rate during the 26-mo period preceding the war, resulting in approximately 405,000 (95% uncertainty interval 48,000-751,000) excess deaths attributable to the conflict. Among adults, the risk of death rose 0.7 times higher for women and 2.9 times higher for men between the pre-war period (January 1, 2001, to February 28, 2003) and the peak of the war (2005-2006). We estimate that more than 60% of excess deaths were directly attributable to violence, with the rest associated with the collapse of infrastructure and other indirect, but war-related, causes. We used secondary sources to estimate rates of death among emigrants. Those estimates suggest we missed at least 55,000 deaths that would have been reported by households had the households remained behind in Iraq, but which instead had migrated away. Only 24 households refused to participate in the study. An additional five households were not interviewed because of hostile or threatening behavior, for a 98.55% response rate. The reliance on outdated census data and the long recall period required of participants are limitations of our study. CONCLUSIONS: Beyond expected rates, most mortality increases in Iraq can be attributed to direct violence, but about a third are attributable to indirect causes (such as from failures of health, sanitation, transportation, communication, and other systems). Approximately a half million deaths in Iraq could be attributable to the war. Please see later in the article for the Editors' Summary. PMID- 24143142 TI - A Novel Semisynthetic Anion Receptor: Synthesis and Ion Recognition of (1-H pyrrol-2-yl)-4-oxo-perezone. AB - We describe the synthesis of the novel 2-(1,5-dimethyl-4-oxo-hexyl)-3-hydroxy-5 methyl-6-pyrrolyl-1,4-benzoquinone 2 from the natural product perezone 1. The anion-guest properties of the new compound were evaluated in the presence of fluoride, chloride, bromide and iodide tetrabutylammonium salts using 1H NMR titration techniques in deuterated dichloromethane or dimethylformamide. The title compound showed interesting colorimetric behavior in the presence of inorganic salts. PMID- 24143144 TI - Permanent prostate brachytherapy extracapsular radiation dose distributions: analysis of a multi-institutional database. AB - PURPOSE: Periprostatic brachytherapy doses impact biochemical control. In this study, we evaluate extracapsular volumetric dosimetry following permanent prostate brachytherapy in patients entered in a multi-institutional community database. MATERIAL AND METHODS: In the database, 4547 patients underwent brachytherapy (3094 - (125)I, 1437 - (103)Pd and 16 - (131)Cs). Using the originally determined prostate volume, a 5 mm, 3-dimensional peri-prostatic anulus was constructed around the prostate (except for a 2 mm posterior margin), and evaluated in its entirety and in 90 degrees segments. Prostate dosimetric parameters consisted of a V100 and D90 while the annular dosimetry was reported as a V100. RESULTS: The intraprostatic V100 and D90 for (103)Pd, and (125)I were statistically comparable when stratified by isotope and/or monotherapy vs. boost. The overall mean V100 for the periprostatic annulus was 62.8%. The mean V100 at the base (51.6%) was substantially less than the apex (73.5%) and midgland (65.9%). In addition, for all patients, the anterior V100 (45.7%) was less than the lateral (68.8%) and the posterior (75.0%). The geometric V100 annular differences were consistent when evaluated by isotope. Overall, the V100 was higher in the (125)I cohort. CONCLUSIONS: The optimal extracapsular brachytherapy dose and radial extent remains unknown, but will prove increasingly important with reductions and/or elimination of supplemental external beam radiation therapy. The large multi-institutional community database demonstrates periprostatic annular doses that are not as robust as those in selected high volume brachytherapy centers, and may be inadequate for optimal biochemical control following monotherapeutic brachytherapy, especially in higher risk patients. PMID- 24143143 TI - The genetic basis for survivorship in coronary artery disease. AB - Survivorship is a trait characterized by endurance and virility in the face of hardship. It is largely considered a psychosocial attribute developed during fatal conditions, rather than a biological trait for robustness in the context of complex, age-dependent diseases like coronary artery disease (CAD). The purpose of this paper is to present the novel phenotype, survivorship in CAD as an observed survival advantage concurrent with clinically significant CAD. We present a model for characterizing survivorship in CAD and its relationships with overlapping time- and clinically-related phenotypes. We offer an optimal measurement interval for investigating survivorship in CAD. We hypothesize genetic contributions to this construct and review the literature for evidence of genetic contribution to overlapping phenotypes in support of our hypothesis. We also present preliminary evidence of genetic effects on survival in people with clinically significant CAD from a primary case-control study of symptomatic coronary disease. Identifying gene variants that confer improved survival in the context of clinically appreciable CAD may improve our understanding of cardioprotective mechanisms acting at the gene level and potentially impact patients clinically in the future. Further, characterizing other survival-variant genetic effects may improve signal-to-noise ratio in detecting gene associations for CAD. PMID- 24143145 TI - Dosimetric effects of prone and supine positions on post-implant assessments for prostate brachytherapy. AB - PURPOSE: Post-implant dosimetric assessment is essential for optimal care of patients receiving prostate brachytherapy. In most institutions, post-implant computed tomography (CT) is performed in the supine position. This study aimed to assess variability in dosimetric parameters with postural changes during acquisition of post-implant CT scans. MATERIAL AND METHODS: In total, 85 consecutive patients were enrolled in this study. Fifty-three patients underwent seed implantation alone, and the remaining 32 received a combination of seed implantation and external beam radiotherapy. For post-implant analyses, CT scans were obtained in two patient positions, supine and prone. To evaluate differences in dosimetric parameters associated with postural change, the dosimetric data obtained in the supine position were defined as the standard. RESULTS: The median prostate volume was 22.4 ml in the supine and 22.5 ml in the prone position (p = 0.51). The median prostate D90 was 120.1% in the supine and 120.3% in the prone position, not significantly different. The mean prostate V100 was 97.1% in the supine and 97.0% in the prone position, again not significantly different. Median rectal V100 in supine and prone positions were 0.42 ml and 0.33 ml, respectively (p < 0.01). Rectal D2cc was also significantly decreased in the prone as compared with the supine position (median, 59.1% vs. 63.6%; p < 0.01). A larger post implant prostate volume was associated with decreased rectal doses in the prone position. CONCLUSIONS: Though there were no significant differences among prostate D90 assessments according to postural changes, our results suggest that post-implant rectal doses decreased in the prone position. PMID- 24143146 TI - Predictors of distant metastasis after combined HDR brachytherapy and external beam radiation for prostate cancer. AB - PURPOSE: To determine predictors of distant metastases (DM) in prostate cancer patients treated with high dose rate brachytherapy boost (HDR-B) and external beam radiation therapy (EBRT). MATERIAL AND METHODS: From 1991 to 2002, 768 men with localized prostate cancer were treated with HDR-B and EBRT. The mean EBRT dose was 37.5 Gy (range: 30.6-45 Gy), and the HDR-B was 22 or 24 Gy delivered in 4 fractions. Univariate and multivariate analyses using a Cox proportional hazards model including age at diagnosis, T stage, Gleason score (GS), pretreatment PSA, biologically equivalent dose (BED), and use of androgen deprivation therapy (ADT) was used to determine predictors of developing distant metastases. RESULTS: The median follow-up time for the entire patient population was 4.2 years (range: 1-11.2 years). Distant metastases were identified in 22/768 (3%) of patients at a median of 4.1 years. PSA failure according to the Phoenix definition developed in 3%, 5%, and 14% of men with low, intermediate, and high risk disease with a median time to failure of 3.8 years. Prostate cancer specific mortality was observed in 2% of cases. T stage, GS, and use of ADT were significantly associated with developing DM on univariate analysis. GS, and use of ADT were the only factors significantly associated with developing DM on multivariate analysis (p < 0.01). Patients who received ADT had significantly higher risk features suggesting patient selection bias for higher DM in this group of patients rather than a negative interaction between HDR-B and EBRT. CONCLUSIONS: In men treated with HDR-B and EBRT, GS is a significant factor on multivariate analysis for developing distant metastasis. PMID- 24143147 TI - Can we improve the dose distribution for single or multi-lumen breast balloons used for Accelerated Partial Breast Irradiation? AB - PURPOSE: The aim of the study was to verify dose distribution parameters for multi-lumen, and artificially created single-lumen balloon applicator used for the same patient with two optimization algorithms: inverse planning simulated annealing (IPSA) and dose point optimization with distance option. MATERIAL AND METHODS: Group of 24 patients with multi-lumen balloon applied were investigated. Each patient received 10 fractions of 3.4 Gy (2 fractions daily). For every patient, four treatment plans were prepared. Firstly, for five-lumen balloon optimized with IPSA algorithm and optimization parameters adjusted for each case. Secondly, for the same applicator optimized with dose point optimization and distant option. Two other plans were prepared for single-lumen applicator, created by removing four peripheral lumens, optimized with both algorithms. RESULTS: The highest D95 parameter was obtained for plans optimized with IPSA algorithm, mean value 99.3 percent of prescribed dose, and it was significantly higher than plans optimized with dose point algorithm (mean = 83.50%, p < 0.0001), IPSA single-lumen balloon plan (mean = 83.50%, p = 0.0037) and optimized to dose point single-lumen balloon (mean = 85.51%, p < 0.0001). There were no statistically significant differences concerning maximum doses distributed to skin surface for neither application nor optimization method. Volumes receiving 200% of prescribed dose in PTV were higher for multi-lumen balloon dose point optimized plans (mean = 8.78%), than for other plans (IPSA multi-lumen balloon plan: mean = 7.37%, p < 0.0001, single-lumen IPSA: mean = 7.20%, p < 0.0001, single-lumen dose point: mean = 7.19%, p < 0.0001). CONCLUSIONS: Basing on performed survey, better dose distribution parameters are obtained for patients with multi-lumen balloon applied and optimized using IPSA algorithm with individualized optimization parameters. PMID- 24143148 TI - Racial and socioeconomic disparities in the selection of prostate brachytherapy. AB - PURPOSE: To utilize the surveillance, epidemiology, and end results database to analyze whether there are racial or socioeconomic disparities associated with the selection of prostate brachytherapy. MATERIAL AND METHODS: We selected patients who were diagnosed with localized prostate cancer between 2004-2006 and who underwent treatment with radiation. Data regarding race and estimates of socioeconomic status were also obtained by analyzing the average reported cost of living adjusted income in the SEER county from which the patient was treated, and dividing these results into quartiles. Multivariate logistic regression analysis was used to determine whether there were any disparities associated with brachytherapy use. RESULTS: A total of 38 704 patients were included in the analysis. Most patients (57%) received EBRT alone, while the remaining 43% of patients had brachytherapy as a component of their treatment, either alone (30.2%) or in combination with EBRT (12.2%). On multivariate logistic regression, prostate brachytherapy use was less likely in African American patients with an odds ratio of 0.89 (95% CI: 0.84-0.95, p < 0.001), and was more likely to be used in those with higher socioeconomic status. Regarding socioeconomic status, the odds ratio for receiving brachytherapy was 1.65 (95% CI: 1.55-1.75) for the 25 50% quartile, 1.92 (95% CI: 1.81-2.04) for the 50-75% quartile, and 2.05 (95% CI: 1.93-2.18) for the 75-100% quartile, respectively (p < 0.001). CONCLUSIONS: There do appear to be socioeconomic and racial disparities in the selection of prostate brachytherapy. These findings may have both significant equality of care as well as cost of care implications. PMID- 24143149 TI - Pulsed dose rate brachytherapy of lip cancer. AB - PURPOSE: PURPOSE: To present our experience with pulsed dose rate brachytherapy (PDR BT) of lip cancer. MATERIAL AND METHODS: The study group included 32 T1 4N0M0 lip cancer patients with a median age of 71 years (ranged 41-87 years), treated with interstitial PDR BT to the planned total dose of 60-70 Gy; 1 Gy/pulse, pulses repeated every hour a day. There were 26 untreated patients, and six patients after previous surgery including five implanted at the time of cancer relapse. RESULTS: PDR BT was delivered over few days and was well tolerated. After therapy, all patients experienced temporary, usually mild, acute mucositis. Late severe (Grade 3) mucositis of oral vestibule mucosa occurred in one case. Among 31 patients who completed the therapy, local control was achieved in 29 (93.5%). One patient with reccurrent upper lip T2 tumor was susccessfully salvaged surgically, another one died due to persisted T3 lip tumor with lymph node metastases. Overall, four patients developed neck nodal cancer relapse and two - distant metastases. The 5-year local control, and all-cause overall survival probabilities are 94% and 73%, respectively. Good/excellent cosmetic and functional outcome was obtained in all but two patients. CONCLUSIONS: PDR at the dose of 1 Gy/pulse is effective and well tolerated BT technique in treating lip cancer patients. PMID- 24143150 TI - EGSnrc Monte Carlo-aided dosimetric studies of the new BEBIG (60)Co HDR brachytherapy source. AB - PURPOSE: The purpose of this study is to obtain the dosimetric parameters of the new BEBIG (60)Co brachytherapy source following by TG-43U1 recommendation with appropriate electron cutoff energy (0.521 MeV). MATERIAL AND METHODS: The new BEBIG (60)Co brachytherapy source is used to calculate the TG-43U1 parameters. EGSnrc-based Monte Carlo simulation code has been used to calculate the radial dose functions and anisotropy functions. 2D dose rate table is obtained with Cartesian coordinate system for surrounding the source. RESULTS: The radial dose functions are calculated for the distance of 0.06 cm to 100 cm from the source center with different cutoff energies and compared. The anisotropy functions values are calculated with the range of 1 degrees to 179 degrees , and apart from 0.2 cm to 20 cm of radial distances. The along-away dose rate data are calculated for quality assurance purposes. The calculated values are compared with the consensus data set and previous published results. CONCLUSIONS: The radial dose function values from 0.06 cm to 0.16 cm are low, and these values gradually increased up to 0.3 cm radial distance. The radial dose function values are compared with the values of consensus data set using EGSnrc code system, and it is in good agreement with the published data range. The data for < 0.1 cm is not available in consensus data set, and extrapolated value is included for 0 distances which is the same as the value of 0.1 cm. In this study, the obtained values are strictly fall-off to < 0.1 cm distances. Good agreement with the published data was observed, except the values less than 40 degrees angle at 0.5 cm distance for anisotropy function values. PMID- 24143151 TI - Brachytherapy as a treatment for malignant melanoma of the nasal cavity and nasopharynx - case report. AB - PURPOSE: Primary malignant melanoma of the nasal cavity and nasopharynx is rarely seen. Clinically, most patients display initial nonspecific symptoms of unilateral nasal obstruction or epistaxis. The prognosis is generally poor, with a mean survival time of 3.5 years. MATERIAL AND METHODS: In this paper, we have reported the case of malignant melanoma of the nasal cavity and nasopharynx. 79 years old man had presented with the swelling of the nose, nasal blockage and epistaxis during the six months before diagnosis. Functional endoscopic sinus surgery was performed to excised the nasal cavity tumor. Using positron emission tomography/computed tomography examination with 18-fluorodeoxyglucose, the patient was diagnosed with residual nasopharyngeal tumor after surgery. RESULTS: Following the diagnosis, intracavitary brachytherapy for nasopharynx was administered. Solitary cervical nodal involvement occurred 6 months after the diagnosis when had been completely removed. After that, external beam radiotherapy was performed on the submandibular area on the right side. Thereafter, the patient was given follow-up care in the Department of Radiation Oncology until the time of distant progression of the disease. CONCLUSIONS: We have chosen to discuss this condition, because of its rarity and the possibility of using radiotherapy, even though the malignant melanoma had been regarded as a radioresistant disease, and also to emphasize the importance of a multidisciplinary approach to treatment of such patients. PMID- 24143152 TI - Vaginal cuff dehiscence after vaginal cuff brachytherapy for uterine cancer. A case report. AB - Vaginal cuff dehiscence is a rare, but potentially serious complication after total hysterectomy. We report a case of vaginal cuff dehiscence after vaginal cuff brachytherapy. A 62 year old female underwent a robotic-assisted laparoscopic hysterectomy with bilateral salpingo-oophorectomy, and was found to have International Federation of Gynecology and Obstetrics (FIGO) 2009 stage IB endometrioid adenocarcinoma of the uterus. The patient was referred for adjuvant vaginal cuff brachytherapy. During the radiation treatment simulation, a computerized tomography (CT) of the pelvis showed abnormal position of the vaginal cylinder. She was found to have vaginal cuff dehiscence that required immediate surgical repair. Vaginal cuff dehiscence triggered by vaginal cuff brachytherapy is very rare with only one case report in the literature. PMID- 24143153 TI - The organization of scientists and its relation to scientific productivity: Perceptions of Chinese stem cell researchers. AB - Chinese government funding of R&D ranks third in the world. Yet China ranks only 17th in terms of scientific productivity per unit of investment. The author recently conducted fieldwork on the team structure of 22 Chinese stem cell research groups. Interview data suggest that although Chinese research groups closely resemble their international counter-parts in many respects, there are also significant differences which are perceived by interviewees to affect levels of scientific productivity. One characteristic of Chinese research teams is a common deficiency in middle-layer positions. This shortage of experienced professionals is perceived by scientists participating in this study to have led to two consequences. First, inexperienced student researchers often form the backbone of scientific teams in China, which leads to frequent interruptions of research and extended laboratory training. Second, research teams consist of a relatively small number of personnel. These structural features are seen to create excessive social boundaries, which impede the exchange of information and further worsens the segmentation of resources. This article engages the question of the extent to which interviewees' local 'embedded' understandings of these difficulties may make a productive contribution to the analysis of the structural, and infra-structural, organization of Chinese professional bioscience teams. PMID- 24143154 TI - Rhabdomyosarcoma of prostate presenting as bladder outlet obstruction in a young adult. AB - A 19-year-old boy presented with bladder outlet obstruction and on evaluation was found to have prostatomegaly, which on biopsy was diagnostic of embryonal rhabdomyosarcoma (RMS). He had pulmonary metastasis and received chemotherapy with cyclophosphamide, doxorubicin, vincristine, actinomycin D, and radical radiotherapy. At one year, his prostatic tumour has resolved completely. Embryonal RMS of prostate occurs more commonly in infancy and childhood, so occurrence in young adults is rare, and a high index of suspicion is essential for early diagnosis and treatment. PMID- 24143155 TI - Real-world experience with colorectal cancer chemotherapies: patient web forum analysis. AB - BACKGROUND: In contrast to clinical trials, patient web forums provide a unique opportunity for patients to spontaneously post their experiences and thoughts about diseases and treatments. This study explored the impact of colorectal cancer (CRC) treatments in these forums. METHODS: This was a systematic cross sectional qualitative analysis. Two active CRC web forums were identified based on four criteria: active for >=five years, >12,000 total posts, >20 individuals currently browsing, and >=10 new posts/day. All relevant threads (set of messages focusing on a topic) relating to treatment posted in July and December 2010 and February to March 2011 were reviewed and coded using MaxQDA software. A content analysis was performed identifying key themes. RESULTS: The threads included 1522 posts by 264 individuals. Demographics were identified for 83% of the posters. Of these, 83% were CRC patients and 17% were family members; 76% were females, and the mean patient age was 49 years. The majority had advanced cancer (44% stage IV or metastatic, 40% stage III). The most common themes were side effects (62.3% of posts), treatment response (13%), and impact on personal, social, and work lives, and emotional distress (23.9%). The posters came to the online forums to have an emotional outlet, share experience, and seek advice. The emotional impacts primarily exemplified resilience and positive coping strategies. Formal knowledge regarding the likelihood of treatment response, magnitude of benefit, or side effects was lacking, which lead to uncertainty and anxiety. However, patients expressed appreciation for the availability of treatment options and the hope they provide. CONCLUSION: Online CRC communities provide patients with convenient and valuable emotional support and disease information. CRC and treatments may have profound impacts beyond efficacy and toxicity. Systematic information and decision tools may help to minimise uncertainties and help patients manage expectations and emotional distress. PMID- 24143156 TI - A conceptual framework for analysing and measuring land-use intensity. AB - Large knowledge gaps currently exist that limit our ability to understand and characterise dynamics and patterns of land-use intensity: in particular, a comprehensive conceptual framework and a system of measurement are lacking. This situation hampers the development of a sound understanding of the mechanisms, determinants, and constraints underlying changes in land-use intensity. On the basis of a review of approaches for studying land-use intensity, we propose a conceptual framework to quantify and analyse land-use intensity. This framework integrates three dimensions: (a) input intensity, (b) output intensity, and (c) the associated system-level impacts of land-based production (e.g. changes in carbon storage or biodiversity). The systematic development of indicators across these dimensions would provide opportunities for the systematic analyses of the trade-offs, synergies and opportunity costs of land-use intensification strategies. PMID- 24143157 TI - Challenges and opportunities in mapping land use intensity globally. AB - Future increases in land-based production will need to focus more on sustainably intensifying existing production systems. Unfortunately, our understanding of the global patterns of land use intensity is weak, partly because land use intensity is a complex, multidimensional term, and partly because we lack appropriate datasets to assess land use intensity across broad geographic extents. Here, we review the state of the art regarding approaches for mapping land use intensity and provide a comprehensive overview of available global-scale datasets on land use intensity. We also outline major challenges and opportunities for mapping land use intensity for cropland, grazing, and forestry systems, and identify key issues for future research. PMID- 24143158 TI - Land system change and food security: towards multi-scale land system solutions. AB - Land system changes are central to the food security challenge. Land system science can contribute to sustainable solutions by an integrated analysis of land availability and the assessment of the tradeoffs associated with agricultural expansion and land use intensification. A land system perspective requires local studies of production systems to be contextualised in a regional and global context, while global assessments should be confronted with local realities. Understanding of land governance structures will help to support the development of land use policies and tenure systems that assist in designing more sustainable ways of intensification. Novel land systems should be designed that are adapted to the local context and framed within the global socio-ecological system. Such land systems should explicitly account for the role of land governance as a primary driver of land system change and food production. PMID- 24143159 TI - Optimizing chronic disease management in the community (outpatient) setting (OCDM): an evidentiary framework. PMID- 24143160 TI - Hand-powered microfluidics: A membrane pump with a patient-to-chip syringe interface. AB - In this paper, we present an on-chip hand-powered membrane pump using a robust patient-to-chip syringe interface. This approach enables safe sample collection, sample containment, integrated sharps disposal, high sample volume capacity, and controlled downstream flow with no electrical power requirements. Sample is manually injected into the device via a syringe and needle. The membrane pump inflates upon injection and subsequently deflates, delivering fluid to downstream components in a controlled manner. The device is fabricated from poly(methyl methacrylate) (PMMA) and silicone, using CO2 laser micromachining, with a total material cost of ~0.20 USD/device. We experimentally demonstrate pump performance for both deionized (DI) water and undiluted, anticoagulated mouse whole blood, and characterize the behavior with reference to a resistor-capacitor electrical circuit analogy. Downstream output of the membrane pump is regulated, and scaled, by connecting multiple pumps in parallel. In contrast to existing on-chip pumping mechanisms that typically have low volume capacity (~5 MUL) and sample volume throughput (~1-10 MUl/min), the membrane pump offers high volume capacity (up to 240 MUl) and sample volume throughput (up to 125 MUl/min). PMID- 24143166 TI - Heterogeneity among orf virus isolates from goats in Fujian Province, Southern China. AB - Orf virus is a parapoxvirus that causes recurring contagious ecthyma or orf disease in goat, sheep and other wild and domestic ruminants. Infected animals show signs of pustular lesions on the mouth and muzzle and develop scabs over the lesions. Although the infection is usually cleared within 1-2 months, delayed growth and associated secondary infections could still impact the herds. Orf virus can also infect humans, causing lesions similar to the animals in pathological histology. Prior infection of orf virus apparently offers little protective immunity against future infections. Several gene products of orf virus have been identified as responsible for immunomodulatory functions. In our recent study of orf virus isolates from an area along the Minjiang River in northern Fujian Province, we found a high heterogeneity among isolates from 10 farms within a 120-kilometer distance. Only two isolates from locations within 1 km to each other had same viral genes. There is no correlation between the geographical distance between the corresponding collection sites and the phylogenetic distance in ORFV011 or ORV059 genes for any two isolates. This finding suggests that there are diverse populations of orf virus present in the environment. This may in part contribute to the phenomenon of recurring outbreaks and heighten the need for better surveillance. PMID- 24143167 TI - MUC1 regulates expression of multiple microRNAs involved in pancreatic tumor progression, including the miR-200c/141 cluster. AB - MUC1 is a transmembrane glycoprotein that modulates transcription via its cytoplasmic domain. We evaluated the capacity of MUC1 to regulate the global transcription of microRNAs in pancreatic cancer cells expressing MUC1. Results indicated that MUC1 regulated expression of at least 103 microRNAs. We evaluated further regulation of the microRNA transcript cluster miR-200c/141, which was among the most highly regulated microRNAs. We found that MUC1 directly interacted with ZEB1, a known transcriptional repressor of the miR-200c/141 cluster, at the promoter of miR-200c/141, and further reduced transcript production. These data indicate that signaling through MUC1 influences cancer progression by regulating transcription of microRNAs that are associated with the process of metastasis. PMID- 24143168 TI - Molecular phylogeny of a RING E3 ubiquitin ligase, conserved in eukaryotic cells and dominated by homologous components, the muskelin/RanBPM/CTLH complex. AB - Ubiquitination is an essential post-translational modification that regulates signalling and protein turnover in eukaryotic cells. Specificity of ubiquitination is driven by ubiquitin E3 ligases, many of which remain poorly understood. One such is the mammalian muskelin/RanBP9/CTLH complex that includes eight proteins, five of which (RanBP9/RanBPM, TWA1, MAEA, Rmnd5 and muskelin), share striking similarities of domain architecture and have been implicated in regulation of cell organisation. In budding yeast, the homologous GID complex acts to down-regulate gluconeogenesis. In both complexes, Rmnd5/GID2 corresponds to a RING ubiquitin ligase. To better understand this E3 ligase system, we conducted molecular phylogenetic and sequence analyses of the related components. TWA1, Rmnd5, MAEA and WDR26 are conserved throughout all eukaryotic supergroups, albeit WDR26 was not identified in Rhizaria. RanBPM is absent from Excavates and from some sub-lineages. Armc8 and c17orf39 were represented across unikonts but in bikonts were identified only in Viridiplantae and in O. trifallax within alveolates. Muskelin is present only in Opisthokonts. Phylogenetic and sequence analyses of the shared LisH and CTLH domains of RanBPM, TWA1, MAEA and Rmnd5 revealed closer relationships and profiles of conserved residues between, respectively, Rmnd5 and MAEA, and RanBPM and TWA1. Rmnd5 and MAEA are also related by the presence of conserved, variant RING domains. Examination of how N- or C-terminal domain deletions alter the sub-cellular localisation of each protein in mammalian cells identified distinct contributions of the LisH domains to protein localisation or folding/stability. In conclusion, all components except muskelin are inferred to have been present in the last eukaryotic common ancestor. Diversification of this ligase complex in different eukaryotic lineages may result from the apparently fast evolution of RanBPM, differing requirements for WDR26, Armc8 or c17orf39, and the origin of muskelin in opisthokonts as a RanBPM-binding protein. PMID- 24143170 TI - Can inferred provenance and its visualisation be used to detect erroneous annotation? A case study using UniProtKB. AB - A constant influx of new data poses a challenge in keeping the annotation in biological databases current. Most biological databases contain significant quantities of textual annotation, which often contains the richest source of knowledge. Many databases reuse existing knowledge; during the curation process annotations are often propagated between entries. However, this is often not made explicit. Therefore, it can be hard, potentially impossible, for a reader to identify where an annotation originated from. Within this work we attempt to identify annotation provenance and track its subsequent propagation. Specifically, we exploit annotation reuse within the UniProt Knowledgebase (UniProtKB), at the level of individual sentences. We describe a visualisation approach for the provenance and propagation of sentences in UniProtKB which enables a large-scale statistical analysis. Initially levels of sentence reuse within UniProtKB were analysed, showing that reuse is heavily prevalent, which enables the tracking of provenance and propagation. By analysing sentences throughout UniProtKB, a number of interesting propagation patterns were identified, covering over [Formula: see text] sentences. Over [Formula: see text] sentences remain in the database after they have been removed from the entries where they originally occurred. Analysing a subset of these sentences suggest that approximately [Formula: see text] are erroneous, whilst [Formula: see text] appear to be inconsistent. These results suggest that being able to visualise sentence propagation and provenance can aid in the determination of the accuracy and quality of textual annotation. Source code and supplementary data are available from the authors website at http://homepages.cs.ncl.ac.uk/m.j.bell1/sentence_analysis/. PMID- 24143169 TI - Indian signatures in the westernmost edge of the European Romani diaspora: new insight from mitogenomes. AB - In agreement with historical documentation, several genetic studies have revealed ancestral links between the European Romani and India. The entire mitochondrial DNA (mtDNA) of 27 Spanish Romani was sequenced in order to shed further light on the origins of this population. The data were analyzed together with a large published dataset (mainly hypervariable region I [HVS-I] haplotypes) of Romani (N=1,353) and non-Romani worldwide populations (N>150,000). Analysis of mitogenomes allowed the characterization of various Romani-specific clades. M5a1b1a1 is the most distinctive European Romani haplogroup; it is present in all Romani groups at variable frequencies (with only sporadic findings in non-Romani) and represents 18% of their mtDNA pool. Its phylogeographic features indicate that M5a1b1a1 originated 1.5 thousand years ago (kya; 95% CI: 1.3-1.8) in a proto Romani population living in Northwest India. U3 represents the most characteristic Romani haplogroup of European/Near Eastern origin (12.4%); it appears at dissimilar frequencies across the continent (Iberia: ~ 31%; Eastern/Central Europe: ~ 13%). All U3 mitogenomes of our Iberian Romani sample fall within a new sub-clade, U3b1c, which can be dated to 0.5 kya (95% CI: 0.3 0.7); therefore, signaling a lower bound for the founder event that followed admixture in Europe/Near East. Other minor European/Near Eastern haplogroups (e.g. H24, H88a) were also assimilated into the Romani by introgression with neighboring populations during their diaspora into Europe; yet some show a differentiation from the phylogenetically closest non-Romani counterpart. The phylogeny of Romani mitogenomes shows clear signatures of low effective population sizes and founder effects. Overall, these results are in good agreement with historical documentation, suggesting that cultural identity and relative isolation have allowed the Romani to preserve a distinctive mtDNA heritage, with some features linking them unequivocally to their ancestral Indian homeland. PMID- 24143171 TI - Role of alternative polyadenylation during adipogenic differentiation: an in silico approach. AB - Post-transcriptional regulation of stem cell differentiation is far from being completely understood. Changes in protein levels are not fully correlated with corresponding changes in mRNAs; the observed differences might be partially explained by post-transcriptional regulation mechanisms, such as alternative polyadenylation. This would involve changes in protein binding, transcript usage, miRNAs and other non-coding RNAs. In the present work we analyzed the distribution of alternative transcripts during adipogenic differentiation and the potential role of miRNAs in post-transcriptional regulation. Our in silico analysis suggests a modest, consistent, bias in 3'UTR lengths during differentiation enabling a fine-tuned transcript regulation via small non-coding RNAs. Including these effects in the analyses partially accounts for the observed discrepancies in relative abundance of protein and mRNA. PMID- 24143172 TI - Recombinant AAV-mediated BEST1 transfer to the retinal pigment epithelium: analysis of serotype-dependent retinal effects. AB - Mutations in the BEST1 gene constitute an underlying cause of juvenile macular dystrophies, a group of retinal disorders commonly referred to as bestrophinopathies and usually diagnosed in early childhood or adolescence. The disease primarily affects macular and paramacular regions of the eye leading to major declines in central vision later in life. Currently, there is no cure or surgical management for BEST1-associated disorders. The recently characterized human disease counterpart, canine multifocal retinopathy (cmr), recapitulates a full spectrum of clinical and molecular features observed in human bestrophinopathies and offers a valuable model system for development and testing of therapeutic strategies. In this study, the specificity, efficiency and safety of rAAV-mediated transgene expression driven by the human VMD2 promoter were assessed in wild-type canine retinae. While the subretinal delivery of rAAV2/1 vector serotype was associated with cone damage in the retina when BEST1 and GFP were co-expressed, the rAAV2/2 vector serotype carrying either GFP reporter or BEST1 transgene under control of human VMD2 promoter was safe, and enabled specific transduction of the RPE cell monolayer that was stable for up to 6 months post injection. These encouraging studies with the rAAV2/2 vector lay the groundwork for development of gene augmentation therapy for human bestrophinopathies. PMID- 24143173 TI - Conserving biodiversity in a human-dominated world: degradation of marine sessile communities within a protected area with conflicting human uses. AB - Conservation research aims at understanding whether present protection schemes are adequate for the maintenance of ecosystems structure and function across time. We evaluated long-term variation in rocky reef communities by comparing sites surveyed in 1993 and again in 2008. This research took place in Tigullio Gulf, an emblematic case study where various conservation measures, including a marine protected area, have been implemented to manage multiple human uses. Contrary to our prediction that protection should have favored ecosystem stability, we found that communities subjected to conservation measures (especially within the marine protected area) exhibited the greatest variation toward architectural complexity loss. Between 1993 and 2008, chronic anthropogenic pressures (especially organic load) that had already altered unprotected sites in 1993 expanded their influence into protected areas. This expansion of human pressure likely explains our observed changes in the benthic communities. Our results suggest that adaptive ecosystem-based management (EBM), that is management taking into account human interactions, informed by continuous monitoring, is needed in order to attempt reversing the current trend towards less architecturally complex communities. Protected areas are not sufficient to stop ecosystem alteration by pressures coming from outside. Monitoring, and consequent management actions, should therefore extend to cover the relevant scales of those pressures. PMID- 24143174 TI - Singular value decomposition of the radial distribution function for hard sphere and square well potentials. AB - We compute the singular value decomposition of the radial distribution function g(r) for hard sphere, and square well solutions. We find that g(r) decomposes into a small set of basis vectors allowing for an extremely accurate representation at all interpolated densities and potential strengths. In addition, we find that the coefficient vectors describing the magnitude of each basis vector are well described by a low-order polynomial. We provide a program to calculate g(r) in this compact representation for the investigated parameter range. PMID- 24143175 TI - Effects of heat shock on resistance to parasitoids and on life history traits in an aphid/endosymbiont system. AB - Temperature variation is an important factor determining the outcomes of interspecific interactions, including those involving hosts and parasites. This can apply to variation in average temperature or to relatively short but intense bouts of extreme temperature. We investigated the effect of heat shock on the ability of aphids (Aphis fabae) harbouring protective facultative endosymbionts (Hamiltonella defensa) to resist parasitism by Hymenopteran parasitoids (Lysiphlebus fabarum). Furthermore, we investigated whether heat shocks can modify previously observed genotype-by-genotype (G x G) interactions between different endosymbiont isolates and parasitoid genotypes. Lines of genetically identical aphids possessing different isolates of H. defensa were exposed to one of two heat shock regimes (35 degrees C and 39 degrees C) or to a control temperature (20 degrees C) before exposure to three different asexual lines of the parasitoids. We observed strong G x G interactions on parasitism rates, reflecting the known genetic specificity of symbiont-conferred resistance, and we observed a significant G x G x E interaction induced by heat shocks. However, this three-way interaction was mainly driven by the more extreme heat shock (39 degrees C), which had devastating effects on aphid lifespan and reproduction. Restricting the analysis to the more realistic heat shock of 35 degrees C, the G x G x E interaction was weaker (albeit still significant), and it did not lead to any reversals of the aphid lines' susceptibility rankings to different parasitoids. Thus, under conditions feasibly encountered in the field, the relative fitness of different parasitoid genotypes on hosts protected by particular symbiont strains remains mostly uncomplicated by heat stress, which should simplify biological control programs dealing with this system. PMID- 24143176 TI - Downregulation of microRNA-9 in iPSC-derived neurons of FTD/ALS patients with TDP 43 mutations. AB - Transactive response DNA-binding protein 43 (TDP-43) is a major pathological protein in frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). There are many disease-associated mutations in TDP-43, and several cellular and animal models with ectopic overexpression of mutant TDP-43 have been established. Here we sought to study altered molecular events in FTD and ALS by using induced pluripotent stem cell (iPSC) derived patient neurons. We generated multiple iPSC lines from an FTD/ALS patient with the TARDBP A90V mutation and from an unaffected family member who lacked the mutation. After extensive characterization, two to three iPSC lines from each subject were selected, differentiated into postmitotic neurons, and screened for relevant cell autonomous phenotypes. Patient-derived neurons were more sensitive than control neurons to 100 nM straurosporine but not to other inducers of cellular stress. Three disease-relevant cellular phenotypes were revealed under staurosporine induced stress. First, TDP-43 was localized in the cytoplasm of a higher percentage of patient neurons than control neurons. Second, the total TDP-43 level was lower in patient neurons with the A90V mutation. Third, the levels of microRNA-9 (miR-9) and its precursor pri-miR-9-2 decreased in patient neurons but not in control neurons. The latter is likely because of reduced TDP-43, as shRNA mediated TDP-43 knockdown in rodent primary neurons also decreased the pri-miR-9 2 level. The reduction in miR-9 expression was confirmed in human neurons derived from iPSC lines containing the more pathogenic TARDBP M337V mutation, suggesting miR-9 downregulation might be a common pathogenic event in FTD/ALS. These results show that iPSC models of FTD/ALS are useful for revealing stress-dependent cellular defects of human patient neurons containing rare TDP-43 mutations in their native genetic contexts. PMID- 24143177 TI - Identification of Mur34 as the novel negative regulator responsible for the biosynthesis of muraymycin in Streptomyces sp. NRRL30471. AB - BACKGROUND: Muraymycin, a potent translocase I (MraY) inhibitor, is produced by Streptomyces sp. NRRL30471. The muraymycin gene cluster (mur) was recently cloned, and bioinformatic analysis of mur34 revealed its encoding product exhibits high homology to a large family of proteins, including KanI and RacI in individual biosynthetic pathway of kanamycin and ribostamycin. However, the precise role of these proteins remains unknown. PRINCIPAL FINDINGS: Here we report the identification of Mur34 as the novel negative regulator involved in muraymycin biosynthesis. Independent disruption of mur34 on chromosome and cosmid directly resulted in significant improvement of muraymycin production by at least 10 folds, thereof confirming the negative function of Mur34 during muraymycin biosynthesis and realizing the engineered production of muraymycin in heterologous host. Gene expression analysis indicated that the transcription level of the mur genes in mur34 mutant (DM-5) was dramatically enhanced by ca. 30 folds. Electrophoretic mobility shift assay (EMSA) showed that Mur34 specifically bound to the promoter region of mur33. Further experiments showed that a 28-bp region downstream of the transcription start point (TSP) was protected by His6Mur34, and the -10 region is essential for the activity of mur33 promoter. CONCLUSIONS: Mur34 plays an unambiguously negative role in muraymycin biosynthesis via binding to the upstream of mur33. More importantly, Mur34 represents a novel family of regulators acting in negative manner to regulate the secondary metabolites biosynthesis in bacteria. PMID- 24143178 TI - Metaproteome analysis of endodontic infections in association with different clinical conditions. AB - Analysis of the metaproteome of microbial communities is important to provide an insight of community physiology and pathogenicity. This study evaluated the metaproteome of endodontic infections associated with acute apical abscesses and asymptomatic apical periodontitis lesions. Proteins persisting or expressed after root canal treatment were also evaluated. Finally, human proteins associated with these infections were identified. Samples were taken from root canals of teeth with asymptomatic apical periodontitis before and after chemomechanical treatment using either NaOCl or chlorhexidine as the irrigant. Samples from abscesses were taken by aspiration of the purulent exudate. Clinical samples were processed for analysis of the exoproteome by using two complementary mass spectrometry platforms: nanoflow liquid chromatography coupled with linear ion trap quadrupole Velos Orbitrap and liquid chromatography-quadrupole time-of-flight. A total of 308 proteins of microbial origin were identified. The number of proteins in abscesses was higher than in asymptomatic cases. In canals irrigated with chlorhexidine, the number of identified proteins decreased substantially, while in the NaOCl group the number of proteins increased. The large majority of microbial proteins found in endodontic samples were related to metabolic and housekeeping processes, including protein synthesis, energy metabolism and DNA processes. Moreover, several other proteins related to pathogenicity and resistance/survival were found, including proteins involved with adhesion, biofilm formation and antibiotic resistance, stress proteins, exotoxins, invasins, proteases and endopeptidases (mostly in abscesses), and an archaeal protein linked to methane production. The majority of human proteins detected were related to cellular processes and metabolism, as well as immune defense. Interrogation of the metaproteome of endodontic microbial communities provides information on the physiology and pathogenicity of the community at the time of sampling. There is a growing need for expanded and more curated protein databases that permit more accurate identifications of proteins in metaproteomic studies. PMID- 24143179 TI - High-throughput sequencing reveals differential expression of miRNAs in intestine from sea cucumber during aestivation. AB - The regulatory role of miRNA in gene expression is an emerging hot new topic in the control of hypometabolism. Sea cucumber aestivation is a complicated physiological process that includes obvious hypometabolism as evidenced by a decrease in the rates of oxygen consumption and ammonia nitrogen excretion, as well as a serious degeneration of the intestine into a very tiny filament. To determine whether miRNAs play regulatory roles in this process, the present study analyzed profiles of miRNA expression in the intestine of the sea cucumber (Apostichopus japonicus), using Solexa deep sequencing technology. We identified 308 sea cucumber miRNAs, including 18 novel miRNAs specific to sea cucumber. Animals sampled during deep aestivation (DA) after at least 15 days of continuous torpor, were compared with animals from a non-aestivation (NA) state (animals that had passed through aestivation and returned to the active state). We identified 42 differentially expressed miRNAs [RPM (reads per million) >10, |FC| (|fold change|) >= 1, FDR (false discovery rate) <0.01] during aestivation, which were validated by two other miRNA profiling methods: miRNA microarray and real time PCR. Among the most prominent miRNA species, miR-200-3p, miR-2004, miR-2010, miR-22, miR-252a, miR-252a-3p and miR-92 were significantly over-expressed during deep aestivation compared with non-aestivation animals. Preliminary analyses of their putative target genes and GO analysis suggest that these miRNAs could play important roles in global transcriptional depression and cell differentiation during aestivation. High-throughput sequencing data and microarray data have been submitted to GEO database. PMID- 24143180 TI - Long-term occupancy trends in a data-poor dugong population in the Andaman and Nicobar archipelago. AB - Prioritizing efforts for conserving rare and threatened species with limited past data and lacking population estimates is predicated on robust assessments of their occupancy rates. This is particularly challenging for elusive, long-lived and wide-ranging marine mammals. In this paper we estimate trends in long-term (over 50 years) occupancy, persistence and extinction of a vulnerable and data poor dugong (Dugong dugon) population across multiple seagrass meadows in the Andaman and Nicobar archipelago (India). For this we use hierarchical Bayesian dynamic occupancy models accounting for false negatives (detection probability<1), persistence and extinction, to two datasets: a) fragmentary long term occurrence records from multiple sources (1959-2004, n = 40 locations), and b) systematic detection/non-detection data from current surveys (2010-2012, n = 57). Dugong occupancy across the archipelago declined by 60% (from 0.45 to 0.18) over the last 20 years and present distribution was largely restricted to sheltered bays and channels with seagrass meadows dominated by Halophila and Halodule sp. Dugongs were not found in patchy meadows with low seagrass cover. In general, seagrass habitat availability was not limiting for dugong occupancy, suggesting that anthropogenic factors such as entanglement in gillnets and direct hunting may have led to local extinction of dugongs from locations where extensive seagrass meadows still thrive. Effective management of these remnant dugong populations will require a multi-pronged approach, involving 1) protection of areas where dugongs still persist, 2) monitoring of seagrass habitats that dugongs could recolonize, 3) reducing gillnet use in areas used by dugongs, and 4) engaging with indigenous/settler communities to reduce impacts of hunting. PMID- 24143181 TI - City-scale expansion of human thermoregulatory costs. AB - The physiological maintenance of a stable internal temperature by mammals and birds - the phenomenon termed homeothermy - is well known to be energetically expensive. The annual energy requirements of free-living mammals and birds are estimated to be 15-30 times higher than those of similar-size ectothermic vertebrates like lizards. Contemporary humans also use energy to accomplish thermoregulation. They are unique, however, in having shifted thermoregulatory control from the body to the occupied environment, with most people living in cities in dwellings that are temperature-regulated by furnaces and air conditioners powered by exogenous energy sources. The energetic implications of this strategy remain poorly defined. Here we comparatively quantify energy costs in cities, dwellings, and individual human bodies. Thermoregulation persists as a major driver of energy expenditure across these three scales, resulting in energy versus-ambient-temperature relationships remarkably similar in shape. Incredibly, despite the many and diversified uses of network-delivered energy in modern societies, the energy requirements of six North American cities are as temperature-dependent as the energy requirements of isolated, individual homeotherms. However, the annual per-person energy cost of exogenously powered thermoregulation in cities and dwellings is 9-28 times higher than the cost of endogenous, metabolic thermoregulation of the human body. Shifting the locus of thermoregulatory control from the body to the dwelling achieves climate independent thermal comfort. However, in an era of amplifying climate change driven by the carbon footprint of humanity, we must acknowledge the energetic extravagance of contemporary, city-scale thermoregulation, which prioritizes heat production over heat conservation. PMID- 24143182 TI - Differential expression of tomato spotted wilt virus-derived viral small RNAs in infected commercial and experimental host plants. AB - BACKGROUND: Viral small RNAs (vsiRNAs) in the infected host can be generated from viral double-stranded RNA replicative intermediates, self-complementary regions of the viral genome or from the action of host RNA-dependent RNA polymerases on viral templates. The vsiRNA abundance and profile as well as the endogenous small RNA population can vary between different hosts infected by the same virus influencing viral pathogenicity and host response. There are no reports on the analysis of vsiRNAs of Tomato spotted wilt virus (TSWV), a segmented negative stranded RNA virus in the family Bunyaviridae, with two of its gene segments showing ambisense gene arrangement. The virus causes significant economic losses to numerous field and horticultural crops worldwide. PRINCIPAL FINDINGS: Tomato spotted wilt virus (TSWV)-specific vsiRNAs were characterized by deep sequencing in virus-infected experimental host Nicotiana benthamiana and a commercial, susceptible host tomato. The total small (s) RNA reads in TSWV-infected tomato sample showed relatively equal distribution of 21, 22 and 24 nt, whereas N. benthamiana sample was dominated by 24 nt total sRNAs. The number of vsiRNA reads detected in tomato was many a magnitude (~350:1) higher than those found in N. benthamiana, however the profile of vsiRNAs in terms of relative abundance 21, 22 and 24 nt class size was similar in both the hosts. Maximum vsiRNA reads were obtained for the M RNA segment of TSWV while the largest L RNA segment had the least number of vsiRNAs in both tomato and N. benthamiana. Only the silencing suppressor, NSs, of TSWV recorded higher antisense vsiRNA with respect to the coding frame among all the genes of TSWV. SIGNIFICANCE: Details of the origin, distribution and abundance of TSWV vsiRNAs could be useful in designing efficient targets for exploiting RNA interference for virus resistance. It also has major implications toward our understanding of the differential processing of vsiRNAs in antiviral defense and viral pathogenicity. PMID- 24143183 TI - Identification of genes potentially regulated by human polynucleotide phosphorylase (hPNPase old-35) using melanoma as a model. AB - Human Polynucleotide Phosphorylase (hPNPase(old-35) or PNPT1) is an evolutionarily conserved 3'-> 5' exoribonuclease implicated in the regulation of numerous physiological processes including maintenance of mitochondrial homeostasis, mtRNA import and aging-associated inflammation. From an RNase perspective, little is known about the RNA or miRNA species it targets for degradation or whose expression it regulates; except for c-myc and miR-221. To further elucidate the functional implications of hPNPase(old-35) in cellular physiology, we knocked-down and overexpressed hPNPase(old-35) in human melanoma cells and performed gene expression analyses to identify differentially expressed transcripts. Ingenuity Pathway Analysis indicated that knockdown of hPNPase(old 35) resulted in significant gene expression changes associated with mitochondrial dysfunction and cholesterol biosynthesis; whereas overexpression of hPNPase(old 35) caused global changes in cell-cycle related functions. Additionally, comparative gene expression analyses between our hPNPase(old-35) knockdown and overexpression datasets allowed us to identify 77 potential "direct" and 61 potential "indirect" targets of hPNPase(old-35) which formed correlated networks enriched for cell-cycle and wound healing functional association, respectively. These results provide a comprehensive database of genes responsive to hPNPase(old 35) expression levels; along with the identification new potential candidate genes offering fresh insight into cellular pathways regulated by PNPT1 and which may be used in the future for possible therapeutic intervention in mitochondrial- or inflammation-associated disease phenotypes. PMID- 24143184 TI - Mixing effects of understory plant litter on decomposition and nutrient release of tree litter in two plantations in Northeast China. AB - Understory vegetation plays a crucial role in carbon and nutrient cycling in forest ecosystems; however, it is not clear how understory species affect tree litter decomposition and nutrient dynamics. In this study, we examined the impacts of understory litter on the decomposition and nutrient release of tree litter both in a pine (Pinus sylvestris var. mongolica) and a poplar (Populus * xiaozhuanica) plantation in Northeast China. Leaf litter of tree species, and senesced aboveground materials from two dominant understory species, Artemisia scoparia and Setaria viridis in the pine stand and Elymus villifer and A. sieversiana in the poplar stand, were collected. Mass loss and N and P fluxes of single-species litter and three-species mixtures in each of the two forests were quantified. Data from single-species litterbags were used to generate predicted mass loss and N and P fluxes for the mixed-species litterbags. In the mixture from the pine stand, the observed mass loss and N release did not differ from the predicted value, whereas the observed P release was greater than the predicted value. However, the presence of understory litter decelerated the mass loss and did not affect N and P releases from the pine litter. In the poplar stand, litter mixture presented a positive non-additive effect on litter mass loss and P release, but an addition effect on N release. The presence of understory species accelerated only N release of poplar litter. Moreover, the responses of mass loss and N and P releases of understory litter in the mixtures varied with species in both pine and poplar plantations. Our results suggest that the effects of understory species on tree litter decomposition vary with tree species, and also highlight the importance of understory species in litter decomposition and nutrient cycles in forest ecosystems. PMID- 24143185 TI - bfb, a novel ENU-induced blebs mutant resulting from a missense mutation in Fras1. AB - Fras1 is an extracellular matrix associated protein with essential roles in adhesion of epithelia and mesenchyme during early embryonic development. The adhesive function of Fras1 is achieved through interaction with a group of related proteins, Frem 1-3, and a cytoplasmic adaptor protein Grip1. Mutation of each of these proteins results in characteristic epithelial blistering and have therefore become known as "blebs" proteins. Human Fraser syndrome presents with a similar phenotype and the blebs mice have been instrumental in identification of the genetic basis of Fraser syndrome. We have identified a new ENU-induced blebs allele resulting from a novel missense mutation in Fras1. The resulting mouse strain, blood filled blisters (bfb), presents with a classic blebs phenotype but does not exhibit embryonic lethality typical of other blebs mutants and in addition, we report novel palate and sternal defects. Analysis of the bfb phenotype confirms the presence of epithelial-mesenchymal adhesion defects but also supports the emerging role of blebs proteins in regulating signalling during organogenesis. The bfb strain provides new opportunities to investigate the role of Fras1 in development. PMID- 24143186 TI - Characterizing brain structures and remodeling after TBI based on information content, diffusion entropy. AB - BACKGROUND: To overcome the limitations of conventional diffusion tensor magnetic resonance imaging resulting from the assumption of a Gaussian diffusion model for characterizing voxels containing multiple axonal orientations, Shannon's entropy was employed to evaluate white matter structure in human brain and in brain remodeling after traumatic brain injury (TBI) in a rat. METHODS: Thirteen healthy subjects were investigated using a Q-ball based DTI data sampling scheme. FA and entropy values were measured in white matter bundles, white matter fiber crossing areas, different gray matter (GM) regions and cerebrospinal fluid (CSF). Axonal densities' from the same regions of interest (ROIs) were evaluated in Bielschowsky and Luxol fast blue stained autopsy (n = 30) brain sections by light microscopy. As a case demonstration, a Wistar rat subjected to TBI and treated with bone marrow stromal cells (MSC) 1 week after TBI was employed to illustrate the superior ability of entropy over FA in detecting reorganized crossing axonal bundles as confirmed by histological analysis with Bielschowsky and Luxol fast blue staining. RESULTS: Unlike FA, entropy was less affected by axonal orientation and more affected by axonal density. A significant agreement (r = 0.91) was detected between entropy values from in vivo human brain and histologically measured axonal density from post mortum from the same brain structures. The MSC treated TBI rat demonstrated that the entropy approach is superior to FA in detecting axonal remodeling after injury. Compared with FA, entropy detected new axonal remodeling regions with crossing axons, confirmed with immunohistological staining. CONCLUSIONS: Entropy measurement is more effective in distinguishing axonal remodeling after injury, when compared with FA. Entropy is also more sensitive to axonal density than axonal orientation, and thus may provide a more accurate reflection of axonal changes that occur in neurological injury and disease. PMID- 24143187 TI - Effects of the deletion of early region 4 (E4) open reading frame 1 (orf1), orf1 2, orf1-3 and orf1-4 on virus-host cell interaction, transgene expression, and immunogenicity of replicating adenovirus HIV vaccine vectors. AB - The global health burden engendered by human immunodeficiency virus (HIV)-induced acquired immunodeficiency syndrome (AIDS) is a sobering reminder of the pressing need for a preventative vaccine. In non-human primate models replicating adenovirus (Ad)-HIV/SIV recombinant vaccine vectors have been shown to stimulate potent immune responses culminating in protection against challenge exposures. Nonetheless, an increase in the transgene carrying capacity of these Ad vectors, currently limited to approximately 3000 base pairs, would greatly enhance their utility. Using a replicating, E3-deleted Ad type 5 host range mutant (Ad5 hr) encoding full-length single-chain HIVBaLgp120 linked to the D1 and D2 domains of rhesus macaque CD4 (rhFLSC) we systematically deleted the genes encoding early region 4 open reading frame 1 (E4orf1) through E4orf4. All the Ad-rhFLSC vectors produced similar levels of viral progeny. Cell cycle analysis of infected human and monkey cells revealed no differences in virus-host interaction. The parental and E4-deleted viruses expressed comparable levels of the transgene with kinetics similar to Ad late proteins. Similar levels of cellular immune responses and transgene-specific antibodies were elicited in vaccinated mice. However, differences in recognition of Ad proteins and induced antibody subtypes were observed, suggesting that the E4 gene products might modulate antibody responses by as yet unknown mechanisms. In short, we have improved the transgene carrying capacity by one thousand base pairs while preserving the replicability, levels of transgene expression, and immunogenicity critical to these vaccine vectors. This additional space allows for flexibility in vaccine design that could not be obtained with the current vector and as such should facilitate the goal of improving vaccine efficacy. To the best of our knowledge, this is the first report describing the effects of these E4 deletions on transgene expression and immunogenicity in a replicating Ad vector. PMID- 24143188 TI - Physiological, behavioral and maternal factors that contribute to size variation in larval amphibian populations. AB - Size variance among similarly aged individuals within populations is a pattern common to many organisms that is a result of interactions between intrinsic and extrinsic traits of individuals. While genetic and maternal effects, as well as physiological and behavioral traits have been shown to contribute to size variation in animal populations, teasing apart the influence of such factors on individual growth rates remain a challenge. Furthermore, tracing the effects of these interactions across life stages and in shaping adult phenotypes also requires further exploration. In this study we investigated the relationship between genetics, hatching patterns, behaviors, neuroendocrine stress axis activity and variance in growth and metamorphosis among same-aged larval amphibians. Through parallel experiments we found that in the absence of conspecific interactions, hatch time and to a lesser extent egg clutch identity (i.e. genetics and maternal effects) influenced the propensity for growth and development in individual tadpoles and determined metamorphic traits. Within experimental groups we found that variance in growth rates was associated with size-dependent foraging behaviors and responses to food restriction. We also found an inverse relationship between glucocorticoid (GC) hormone levels and body mass and developmental stage among group-reared tadpoles, which suggests that GC expression plays a role in regulating differing within-population growth trajectories in response to density-dependent conditions. Taken together these findings suggest that factors that influence hatching conditions can have long term effects on growth and development. These results also raise compelling questions regarding the extent to which maternal and genetic factors influence physiological and behavioral profiles in amphibians. PMID- 24143190 TI - Genome-wide association study of breast cancer in the Japanese population. AB - Breast cancer is the most common malignancy among women in worldwide including Japan. Several studies have identified common genetic variants to be associated with the risk of breast cancer. Due to the complex linkage disequilibrium structure and various environmental exposures in different populations, it is essential to identify variants associated with breast cancer in each population, which subsequently facilitate the better understanding of mammary carcinogenesis. In this study, we conducted a genome-wide association study (GWAS) as well as whole-genome imputation with 2,642 cases and 2,099 unaffected female controls. We further examined 13 suggestive loci (P<1.0 * 10(-5)) using an independent sample set of 2,885 cases and 3,395 controls and successfully validated two previously reported loci, rs2981578 (combined P-value of 1.31 * 10(-12), OR = 1.23; 95% CI = 1.16-.30) on chromosome 10q26 (FGFR2), rs3803662 (combined P-value of 2.79 * 10( 11), OR = 1.21; 95% CI = 1.15-.28) and rs12922061 (combined P-value of 3.97 * 10( 10), OR = 1.23; 95% CI = 1.15-.31) on chromosome 16q12 (TOX3-LOC643714). Weighted genetic risk score on the basis of three significantly associated variants and two previously reported breast cancer associated loci in East Asian population revealed that individuals who carry the most risk alleles in category 5 have 2.2 times higher risk of developing breast cancer in the Japanese population than those who carry the least risk alleles in reference category 1. Although we could not identify additional loci associated with breast cancer, our study utilized one of the largest sample sizes reported to date, and provided genetic status that represent the Japanese population. Further local and international collaborative study is essential to identify additional genetic variants that could lead to a better, accurate prediction for breast cancer. PMID- 24143189 TI - Long-term functional outcomes and correlation with regional brain connectivity by MRI diffusion tractography metrics in a near-term rabbit model of intrauterine growth restriction. AB - BACKGROUND: Intrauterine growth restriction (IUGR) affects 5-10% of all newborns and is associated with increased risk of memory, attention and anxiety problems in late childhood and adolescence. The neurostructural correlates of long-term abnormal neurodevelopment associated with IUGR are unknown. Thus, the aim of this study was to provide a comprehensive description of the long-term functional and neurostructural correlates of abnormal neurodevelopment associated with IUGR in a near-term rabbit model (delivered at 30 days of gestation) and evaluate the development of quantitative imaging biomarkers of abnormal neurodevelopment based on diffusion magnetic resonance imaging (MRI) parameters and connectivity. METHODOLOGY: At +70 postnatal days, 10 cases and 11 controls were functionally evaluated with the Open Field Behavioral Test which evaluates anxiety and attention and the Object Recognition Task that evaluates short-term memory and attention. Subsequently, brains were collected, fixed and a high resolution MRI was performed. Differences in diffusion parameters were analyzed by means of voxel-based and connectivity analysis measuring the number of fibers reconstructed within anxiety, attention and short-term memory networks over the total fibers. PRINCIPAL FINDINGS: The results of the neurobehavioral and cognitive assessment showed a significant higher degree of anxiety, attention and memory problems in cases compared to controls in most of the variables explored. Voxel-based analysis (VBA) revealed significant differences between groups in multiple brain regions mainly in grey matter structures, whereas connectivity analysis demonstrated lower ratios of fibers within the networks in cases, reaching the statistical significance only in the left hemisphere for both networks. Finally, VBA and connectivity results were also correlated with functional outcome. CONCLUSIONS: The rabbit model used reproduced long-term functional impairments and their neurostructural correlates of abnormal neurodevelopment associated with IUGR. The description of the pattern of microstructural changes underlying functional defects may help to develop biomarkers based in diffusion MRI and connectivity analysis. PMID- 24143191 TI - Genomic instability: a stronger prognostic marker than proliferation for early stage luminal breast carcinomas. AB - BACKGROUND: The accurate prognosis definition to tailor treatment for early luminal invasive breast carcinoma patients remains challenging. MATERIALS AND METHODS: Two hundred fourteen early luminal breast carcinomas were genotyped with single nucleotide polymorphisms (SNPs) array to determine the number of chromosomal breakpoints as a marker of genomic instability. Proliferation was assessed by KI67 (immunohistochemistry) and genomic grade index (transcriptomic analysis). IHC3 (IHC4 score for HER2 negative tumors) was also determined. RESULTS: In the training set (109 cases), the optimal cut-off was 34 breakpoints with a specificity of 0.94 and a sensitivity of 0.57 (Area under the curve (AUC): 0.81[0.71; 0.91]). In the validation set (105 cases), the outcome of patients with > 34 breakpoints (11 events / 22 patients) was poorer (logrank test p < 0.001; Relative Risk (RR): 3.7 [1.73; 7.92]), than that of patients with < 34 breakpoints (19 events / 83 patients).Whereas genomic grade and KI67 had a significant prognostic value in univariate analysis in contrast to IHC3 that failed to have a statistical significant prognostic value in this series, the number of breakpoints remained the only significant parameter predictive of outcome (RR: 3.47, Confidence Interval (CI [1.29; 9.31], p = 0.014)) in multivariate analysis . CONCLUSION: Genomic instability, defined herein as a high number of chromosomal breakpoints, in early stage luminal breast carcinoma is a stronger prognostic marker than proliferation. PMID- 24143192 TI - Assessment of preparation methods for organic phosphorus analysis in phosphorus polluted Fe/Al-rich Haihe river sediments using solution 31P-NMR. AB - Fe/Al-rich river sediments that were highly polluted with phosphorus (P) were used in tests to determine the optimum preparation techniques for measuring organic P (Po) using solution (31)P nuclear magnetic resonance spectroscopy ((31)P-NMR). The optimum pre-treatment, extraction time, sediment to solution ratio and sodium hydroxide-ethylenediaminetetraacetic acid (NaOH-EDTA) extractant solution composition were determined. The total P and Po recovery rates were higher from freeze- and air-dried samples than from fresh samples. An extraction time of 16 h was adequate for extracting Po, and a shorter or longer extraction time led to lower recoveries of total P and Po, or led to the degradation of Po. An ideal P recovery rate and good-quality NMR spectra were obtained at a sediment:solution ratio of 1:10, showing that this ratio is ideal for extracting Po. An extractant solution of 0.25 M NaOH and 50 mM EDTA was found to be more appropriate than either NaOH on its own, or a more concentrated NaOH-EDTA mixture for (31)P-NMR analysis, as this combination minimized interference from paramagnetic ions and was appropriate for the detected range of Po concentrations. The most appropriate preparation method for Po analysis, therefore, was to extract the freeze-dried and ground sediment sample with a 0.25 M NaOH and 50 mM EDTA solution at a sediment:solution ratio of 1:10, for 16 h, by shaking. As lyophilization of the NaOH-EDTA extracts proved to be an optimal pre concentration method for Po analysis in the river sediment, the extract was lyophilized as soon as possible, and analyzed by (31)P-NMR. PMID- 24143193 TI - Differences in mismatch responses to vowels and musical intervals: MEG evidence. AB - We investigated the electrophysiological response to matched two-formant vowels and two-note musical intervals, with the goal of examining whether music is processed differently from language in early cortical responses. Using magnetoencephalography (MEG), we compared the mismatch-response (MMN/MMF, an early, pre-attentive difference-detector occurring approximately 200 ms post onset) to musical intervals and vowels composed of matched frequencies. Participants heard blocks of two stimuli in a passive oddball paradigm in one of three conditions: sine waves, piano tones and vowels. In each condition, participants heard two-formant vowels or musical intervals whose frequencies were 11, 12, or 24 semitones apart. In music, 12 semitones and 24 semitones are perceived as highly similar intervals (one and two octaves, respectively), while in speech 12 semitones and 11 semitones formant separations are perceived as highly similar (both variants of the vowel in 'cut'). Our results indicate that the MMN response mirrors the perceptual one: larger MMNs were elicited for the 12 11 pairing in the music conditions than in the language condition; conversely, larger MMNs were elicited to the 12-24 pairing in the language condition that in the music conditions, suggesting that within 250 ms of hearing complex auditory stimuli, the neural computation of similarity, just as the behavioral one, differs significantly depending on whether the context is music or speech. PMID- 24143194 TI - Assessment of paclitaxel induced sensory polyneuropathy with "Catwalk" automated gait analysis in mice. AB - Neuropathic pain as a symptom of sensory nerve damage is a frequent side effect of chemotherapy. The most common behavioral observation in animal models of chemotherapy induced polyneuropathy is the development of mechanical allodynia, which is quantified with von Frey filaments. The data from one study, however, cannot be easily compared with other studies owing to influences of environmental factors, inter-rater variability and differences in test paradigms. To overcome these limitations, automated quantitative gait analysis was proposed as an alternative, but its usefulness for assessing animals suffering from polyneuropathy has remained unclear. In the present study, we used a novel mouse model of paclitaxel induced polyneuropathy to compare results from electrophysiology and the von Frey method to gait alterations measured with the Catwalk test. To mimic recently improved clinical treatment strategies of gynecological malignancies, we established a mouse model of dose-dense paclitaxel therapy on the common C57Bl/6 background. In this model paclitaxel treated animals developed mechanical allodynia as well as reduced caudal sensory nerve action potential amplitudes indicative of a sensory polyneuropathy. Gait analysis with the Catwalk method detected distinct alterations of gait parameters in animals suffering from sensory neuropathy, revealing a minimized contact of the hind paws with the floor. Treatment of mechanical allodynia with gabapentin improved altered dynamic gait parameters. This study establishes a novel mouse model for investigating the side effects of dose-dense paclitaxel therapy and underlines the usefulness of automated gait analysis as an additional easy-to-use objective test for evaluating painful sensory polyneuropathy. PMID- 24143195 TI - Event-related potential measures of a violation of an expected increase and decrease in intensity. AB - Unexpected physical increases in the intensity of a frequently occurring "standard" auditory stimulus are experienced as obtrusive. This could either be because of a physical change, the increase in intensity of the "deviant" stimulus, or a psychological change, the violation of the expectancy for the occurrence of the lower intensity standard stimulus. Two experiments were run in which event-related potentials (ERPs) were recorded to determine whether "psychological" increments (violation of an expectancy for a lower intensity) would be processed differently than psychological decrements (violation of an expectancy for a higher intensity). Event-related potentials (ERPs) were recorded while subjects were presented with auditory tones that alternated between low and high intensity. The subjects ignored the auditory stimuli while watching a video. Deviants were created by repeating the same stimulus. In the first experiment, pairs of stimuli alternating in intensity, were presented in separate increment (H-L...H-L...H-H...H-L, in which H = 80 dB SPL and L = 60 dB SPL) and decrement conditions (L-H...L-H...L-L... L-H, in which H = 90 dB SPL and L = 80 dB SPL). The paradigm employed in the second experiment consisted of an alternating intensity pattern (H-L-H-L-H-H-H-L) or (H-L-H-L-L-L-H-L). Importantly, the stimulus prior to the deviant (the standard) and the actual deviants in both increment and decrement conditions in both experiments were physically identical (80 dB SPL tones). The repetition of the lower intensity tone therefore acted as a psychological rather than a physical decrement (a higher intensity tone was expected) while the repetition of the higher intensity tone acted as a psychological increment (a lower intensity tone was expected). The psychological increments in both experiments elicited a larger amplitude mismatch negativity (MMN) than the decrements. Thus, regardless of whether an acoustic change signals a physical increase in intensity or violates an expected decrease in intensity, a large MMN will be elicited. PMID- 24143196 TI - Association of 5-methylcytosine and 5-hydroxymethylcytosine with mitochondrial DNA content and clinical and biochemical parameters in hepatocellular carcinoma. AB - Increasing epidemiological evidence has indicated that inherited variations of mitochondrial DNA (mtDNA) copy number affect the genetic susceptibility of many malignancies in a tumour-specific manner and that DNA methylation also plays an important role in controlling gene expression during the differentiation and development of hepatocellular carcinoma (HCC). Our previous study demonstrated that HCC tissues showed a lower 5-hydroxymethylcytosine (5-hmC) content when compared to tumour-adjacent tissues, but the relationship among 5-hmC, 5 methylcytosine (5-mC) and mtDNA content in HCC patients is still unknown. This study aimed to clarify the correlation among mtDNA content, 5-mC and 5-hmC by quantitative real-time PCR and liquid chromatography tandem mass spectrometry analysis. We demonstrated that 5-hmC correlated with tumour size [odds ratio (OR) 0.847, 95% confidence interval (CI) 0.746-0.962, P = 0.011], and HCC patients with a tumour size >= 5.0 cm showed a lower 5-hmC content and higher levels of fasting plasma aspartate aminotransferase, the ratio of alanine aminotransferase to aspartate aminotransferase, gamma-glutamyltransferase, alpha-fetoprotein than those with a tumour size <5 cm (all P<0.05). We further revealed that the mtDNA content of HCC tumour tissues was 225.97(105.42, 430.54) [median (25th Percentile, 75th Percentile)] and was negatively correlated with 5-mC content (P = 0.035), but not 5-hmC content, in genomic DNA from HCC tumour tissues. PMID- 24143197 TI - A familial Cri-du-Chat/5p deletion syndrome resulted from rare maternal complex chromosomal rearrangements (CCRs) and/or possible chromosome 5p chromothripsis. AB - Cri-du-Chat syndrome (MIM 123450) is a chromosomal syndrome characterized by the characteristic features, including cat-like cry and chromosome 5p deletions. We report a family with five individuals showing chromosomal rearrangements involving 5p, resulting from rare maternal complex chromosomal rearrangements (CCRs), diagnosed post- and pre-natally by comprehensive molecular and cytogenetic analyses. Two probands, including a 41/2-year-old brother and his 21/2-year- old sister, showed no diagnostic cat cry during infancy, but presented with developmental delay, dysmorphic and autistic features. Both patients had an interstitial deletion del(5)(p13.3p15.33) spanning ~ 26.22 Mb. The phenotypically normal mother had de novo CCRs involving 11 breakpoints and three chromosomes: ins(11;5) (q23;p14.1p15.31),ins(21;5)(q21;p13.3p14.1),ins(21;5)(q21;p15.31p15.33),inv(7)(p2 q32)dn. In addition to these two children, she had three first-trimester miscarriages, two terminations due to the identification of the 5p deletion and one delivery of a phenotypically normal daughter. The unaffected daughter had the maternal ins(11;5) identified prenatally and an identical maternal allele haplotype of 5p. Array CGH did not detect any copy number changes in the mother, and revealed three interstitial deletions within 5p15.33-p13.3, in the unaffected daughter, likely products of the maternal insertions ins(21;5). Chromothripsis has been recently reported as a mechanism drives germline CCRs in pediatric patients with congenital defects. We postulate that the unique CCRs in the phenotypically normal mother could resulted from chromosome 5p chromothripsis, that further resulted in the interstitial 5p deletions in the unaffected daughter. Further high resolution sequencing based analysis is needed to determine whether chromothripsis is also present as a germline structural variation in phenotypically normal individuals in this family. PMID- 24143198 TI - The first phylogeographic population structure and analysis of transmission dynamics of M. africanum West African 1--combining molecular data from Benin, Nigeria and Sierra Leone. AB - Mycobacterium africanum is an important cause of tuberculosis (TB) in West Africa. So far, two lineages called M. africanum West African 1 (MAF1) and M. africanum West African 2 (MAF2) have been defined. Although several molecular studies on MAF2 have been conducted to date, little is known about MAF1. As MAF1 is mainly present in countries around the Gulf of Guinea we aimed to estimate its prevalence in Cotonou, the biggest city in Benin. Between 2005-06 we collected strains in Cotonou/Benin and genotyped them using spoligo- and 12-loci-MIRU-VNTR typing. Analyzing 194 isolates, we found that 31% and 6% were MAF1 and MAF2, respectively. Therefore Benin is one of the countries with the highest prevalence (37%) of M. africanum in general and MAF1 in particular. Moreover, we combined our data from Benin with publicly available genotyping information from Nigeria and Sierra Leone, and determined the phylogeographic population structure and genotypic clustering of MAF1. Within the MAF1 lineage, we identified an unexpected great genetic variability with the presence of at least 10 sub lineages. Interestingly, 8 out of 10 of the discovered sub-lineages not only clustered genetically but also geographically. Besides showing a remarkable local restriction to certain regions in Benin and Nigeria, the sub-lineages differed dramatically in their capacity to transmit within the human host population. While identifying Benin as one of the countries with the highest overall prevalence of M. africanum, this study also contains the first detailed description of the transmission dynamics and phylogenetic composition of the MAF1 lineage. PMID- 24143199 TI - Characterization of lung cancer by amide proton transfer (APT) imaging: an in vivo study in an orthotopic mouse model. AB - Amide proton transfer (APT) imaging is one of the chemical exchange saturation transfer (CEST) imaging methods which images the exchange between protons of free tissue water and the amide groups (-NH) of endogenous mobile proteins and peptides. Previous work suggested the ability of APT imaging for characterization of the tumoral grade in the brain tumor. In this study, we tested the feasibility of in-vivo APT imaging of lung tumor and investigated whether the method could differentiate the tumoral types on orthotopic tumor xenografts from two malignant lung cancer cell lines. The results revealed that APT imaging is feasible to quantify lung tumors in the moving lung. The measured APT effect was higher in the tumor which exhibited more active proliferation than the other. The present study demonstrates that APT imaging has the potential to provide a characterization test to differentiate types or grade of lung cancer noninvasively, which may eventually reduce the need invasive needle biopsy or resection for lung cancer. PMID- 24143200 TI - Development of suitable solvent system for downstream processing of biopolymer pullulan using response surface methodology. AB - Downstream processing is an important aspect of all biotechnological processes and has significant implications on quality and yield of the final product. Several solvents were examined for their efficacy on pullulan precipitation from fermentation broth. Interactions among four selected solvents and their effect on pullulan yield were studied using response surface methodology. A polynomial model was developed using D-optimal design and three contour plots were generated by performing 20 different experiments and the model was validated by performing optimization experiments. The results indicated that lower concentration of ethanol in combination with the other three solvents has resulted in higher yield of polymer from fermentation broth and the optimized solvent system was able to recover 1.44 times more pullulan as compared to the conventional ethanolic precipitation method. These observations may help in enhancing efficiency of pullulan recovery from fermentation broth and also result in reduced cost of production for the final product. PMID- 24143201 TI - The beneficial effect of suramin on monocrotaline-induced pulmonary hypertension in rats. AB - BACKGROUND: Pulmonary hypertension (PH) is a progressive disorder characterized by an increase in pulmonary artery pressure and structural changes in the pulmonary vasculature. Several observations indicate that growth factors play a key role in PH by modulating pulmonary artery smooth muscle cell (PA-SMC) function. In rats, established monocrotaline-induced PH (MCT-PH) can be reversed by blocking platelet-derived growth factor receptors (PDGF-R), epidermal growth factor receptors (EGF-R), or fibroblast growth factor receptors (FGF-R). All these receptors belong to the receptor tyrosine kinase (RTK) family. METHODS AND RESULTS: We evaluated whether RTK blockade by the nonspecific growth factor inhibitor, suramin, reversed advanced MCT-PH in rats via its effects on growth factor signaling pathways. We found that suramin inhibited RTK and ERK1/2 phosphorylation in cultured human PA-SMCs. Suramin inhibited PA-SMC proliferation induced by serum, PDGF, FGF2, or EGF in vitro and ex vivo. Treatment with suramin from day 1 to day 21 after monocrotaline injection attenuated PH development, as shown by lower values for pulmonary artery pressure, right ventricular hypertrophy, and distal vessel muscularization on day 21 compared to control rats. Treatment with suramin from day 21 to day 42 after monocrotaline injection reversed established PH, thereby normalizing the pulmonary artery pressure values and vessel structure. Suramin treatment suppressed PA-SMC proliferation and attenuated both the inflammatory response and the deposition of collagen. CONCLUSIONS: RTK blockade by suramin can prevent MCT-PH and reverse established MCT-PH in rats. This study suggests that an anti-RTK strategy that targets multiple RTKs could be useful in the treatment of pulmonary hypertension. PMID- 24143202 TI - beta-Propeller blades as ancestral peptides in protein evolution. AB - Proteins of the beta-propeller fold are ubiquitous in nature and widely used as structural scaffolds for ligand binding and enzymatic activity. This fold comprises between four and twelve four-stranded beta-meanders, the so called blades that are arranged circularly around a central funnel-shaped pore. Despite the large size range of beta-propellers, their blades frequently show sequence similarity indicative of a common ancestry and it has been proposed that the majority of beta-propellers arose divergently by amplification and diversification of an ancestral blade. Given the structural versatility of beta propellers and the hypothesis that the first folded proteins evolved from a simpler set of peptides, we investigated whether this blade may have given rise to other folds as well. Using sequence comparisons, we identified proteins of four other folds as potential homologs of beta-propellers: the luminal domain of inositol-requiring enzyme 1 (IRE1-LD), type II beta-prisms, beta-pinwheels, and WW domains. Because, with increasing evolutionary distance and decreasing sequence length, the statistical significance of sequence comparisons becomes progressively harder to distinguish from the background of convergent similarities, we complemented our analyses with a new method that evaluates possible homology based on the correlation between sequence and structure similarity. Our results indicate a homologous relationship of IRE1-LD and type II beta-prisms with beta-propellers, and an analogous one for beta-pinwheels and WW domains. Whereas IRE1-LD most likely originated by fold-changing mutations from a fully formed PQQ motif beta-propeller, type II beta-prisms originated by amplification and differentiation of a single blade, possibly also of the PQQ type. We conclude that both beta-propellers and type II beta-prisms arose by independent amplification of a blade-sized fragment, which represents a remnant of an ancient peptide world. PMID- 24143203 TI - Engagement with HIV prevention treatment and care among female sex workers in Zimbabwe: a respondent driven sampling survey. AB - OBJECTIVES: To determine the HIV prevalence and extent of engagement with HIV prevention and care among a representative sample of Zimbabwean sex workers working in Victoria Falls, Hwange and Mutare. DESIGN: Respondent driven sampling (RDS) surveys conducted at each site. METHODS: Sex workers were recruited using respondent driven sampling with each respondent limited to recruiting 2 peers. Participants completed an interviewer-administered questionnaire and provided a finger prick blood sample for HIV antibody testing. Statistical analysis took account of sampling method. RESULTS: 870 women were recruited from the three sites. HIV prevalence was between 50 and 70%. Around half of those confirmed HIV positive were aware of their HIV status and of those 50-70% reported being enrolled in HIV care programmes. Overall only 25-35% of those with laboratory confirmed HIV were accessing antiretroviral therapy. Among those reporting they were HIV negative, 21-28% reported having an HIV test in the last 6 months. Of those tested HIV negative, most (65-82%) were unaware of their status. Around two thirds of sex workers reported consistent condom use with their clients. As in other settings, sex workers reported high rates of gender based violence and police harassment. CONCLUSIONS: This survey suggests that prevalence of HIV is high among sex workers in Zimbabwe and that their engagement with prevention, treatment and care is sub-optimal. Intensifying prevention and care interventions for sex workers has the potential to markedly reduce HIV and social risks for sex workers, their clients and the general population in Zimbabwe and elsewhere in the region. PMID- 24143204 TI - Autophagy in retinal ganglion cells in a rhesus monkey chronic hypertensive glaucoma model. AB - Primary open angle glaucoma (POAG) is a neurodegenerative disease characterized by physiological intraocular hypertension that causes damage to the retinal ganglion cells (RGCs). In the past, RGC damage in POAG was suggested to have been attributed to RGC apoptosis. However, in the present study, we applied a model closer to human POAG through the use of a chronic hypertensive glaucoma model in rhesus monkeys to investigate whether another mode of progressive cell death, autophagy, was activated in the glaucomatous retinas. First, in the glaucomatous retinas, the levels of LC3B-II, LC3B-II/LC3B-I and Beclin 1 increased as demonstrated by Western blot analyses, whereas early or initial autophagic vacuoles (AVi) and late or degraded autophagic vacuoles (AVd) accumulated in the ganglion cell layer (GCL) and in the inner plexiform layer (IPL) as determined by transmission electron microscopy (TEM) analysis. Second, lysosome activity and autophagosome-lysosomal fusion increased in the RGCs of the glaucomatous retinas, as demonstrated by Western blotting against lysosome associated membrane protein 1 (LAMP1) and double labeling against LC3B and LAMP1. Third, apoptosis was activated in the glaucomatous eyes with increased levels of caspase-3 and cleaved caspase-3 and an increased number of TUNEL-positive RGCs. Our results suggested that autophagy was activated in RGCs in the chronic hypertensive glaucoma model of rhesus monkeys and that autophagy may have potential as a new target for intervention in glaucoma treatment. PMID- 24143205 TI - Recent patterns in population-based HIV prevalence in Swaziland. AB - BACKGROUND: The 2011 Swaziland HIV Incidence Measurement Survey (SHIMS) was conducted as part of a national study to evaluate the scale up of key HIV prevention programs. METHODS: From a randomly selected sample of all Swazi households, all women and men aged 18-49 were considered eligible, and all consenting adults were enrolled and received HIV testing and counseling. In this analysis, population-based measures of HIV prevalence were produced and compared against similarly measured HIV prevalence estimates from the 2006-7 Swaziland Demographic and Health. Also, measures of HIV service utilization in both HIV infected and uninfected populations were documented and discussed. RESULTS: HIV prevalence among adults aged 18-49 has remained unchanged between 2006-2011 at 31 32%, with substantial differences in current prevalence between women (39%) and men (24%). In both men and women, between since 2006-7 and 2011, prevalence has fallen in the young age groups and risen in the older age groups. Over a third (38%) of the HIV-infected population was unaware of their infection status, and this differed markedly between men (50%) and women (31%). Of those aware of their HIV-positive status, a higher percentage of men (63%) than women (49%) reported ART use. CONCLUSIONS: While overall HIV prevalence remains roughly constant, age specific changes strongly suggest both improved survival of the HIV-infected and a reduction in new HIV infections. Awareness of HIV status and entry into ART services has improved in recent years but remains too low. This study identifies opportunities to improve both HIV preventive and care services in Swaziland. PMID- 24143206 TI - The association of alternate VEGF ligands with resistance to anti-VEGF therapy in metastatic colorectal cancer. AB - BACKGROUND: Circulating angiogenic factors are altered in patients with mCRC receiving bevacizumab. Evaluation of alterations in levels of VEGF ligands may provide insights into possible resistance mechanisms. METHODS: PlGF, VEGF-A, VEGF C, and VEGF-D were measured from two cohorts of patients. Sequential plasma samples were obtained from a discovery cohort of 42 patients treated with chemotherapy and bevacizumab. A validation cohort included plasma samples from a cross-sectional of 403 patients prior to chemotherapy, or after progression on a regimen with or without bevacizumab. RESULTS: In the discovery cohort, VEGF-C was increased prior to progression and at progression (+49% and +95%, respectively, p<0.01), consistent with previously reported elevations in PlGF. Levels of VEGF-D were increased (+23%) at progression (p=0.05). In the validation cohort, samples obtained from patients after progression on a regimen with bevacizumab had higher levels of PlGF and VEGF-D (+43% and +6%, p=0.02, p=0.01, respectively) compared to untreated patients, but failed to validate the increase in VEGF-C seen in the first cohort. Patients who progressed on chemotherapy with bevacizumab had significantly elevated levels of PlGF (+88%) but not VEGF-C and VEGF-D compared to patients treated with chemotherapy alone. Elevations of PlGF and VEGF-D appeared transient and returned to baseline with a half-life of 6 weeks. CONCLUSIONS: Increases in PlGF and VEGF-D were observed after progression on chemotherapy with bevacizumab. These changes appear to be reversible after discontinuing therapy. These ligands are associated with resistance to bevacizumab-containing chemotherapy in mCRC, but causation remains to be established. PMID- 24143207 TI - Urinary fetuin-A is a novel marker for diabetic nephropathy in type 2 diabetes identified by lectin microarray. AB - We analyzed the urine samples of patients with type 2 diabetes at various stages of diabetic nephropathy by lectin microarray to identify a biomarker to predict the progression of diabetic nephropathy. Japanese patients with type 2 diabetes at various stages of nephropathy were enrolled and we performed lectin microarray analyses (n = 17) and measured urinary excretion of fetuin-A (n = 85). The increased signals of urine samples were observed in Siaalpha2-6Gal/GalNAc-binding lectins (SNA, SSA, TJA-I) during the progression of diabetic nephropathy. We next isolated sialylated glycoproteins by using SSA-lectin affinity chromatography and identified fetuin-A by liquid chromatography-tandem mass spectrometer. Urinary excretion of fetuin-A significantly increased during the progression of albuminuria (A1, 0.40 +/- 0.43; A2, 0.60 +/- 0.53; A3 1.57 +/- 1.13 ng/gCr; p = 7.29 * 10(-8)) and of GFR stages (G1, 0.39 +/- 0.39; G2, 0.49 +/- 0.45; G3, 1.25 +/- 1.18; G4, 1.34 +/- 0.80 ng/gCr; p = 3.89 * 10(-4)). Multivariate logistic regression analysis was employed to assess fetuin-A as a risk for diabetic nephropathy with microalbuminuria or GFR<60 mL/min. Fetuin-A is demonstrated as a risk factor for both microalbuminuria and reduction of GFR in diabetic nephropathy with the odds ratio of 4.721 (1.881-11.844) and 3.739 (1.785-7.841), respectively. Collectively, the glycan profiling analysis is useful method to identify the urine biomarkers and fetuin-A is a candidate to predict the progression of diabetic nephropathy. PMID- 24143208 TI - Drought responses of foliar metabolites in three maize hybrids differing in water stress tolerance. AB - Maize (Zea mays L.) hybrids varying in drought tolerance were treated with water stress in controlled environments. Experiments were performed during vegetative growth and water was withheld for 19 days beginning 17 days after sowing. Genotypic comparisons used measured changes of leaf water potential or results were expressed by time of treatment. Total dry matter of the drought tolerant hybrid on the final harvest was 53% less than that of the intermediate and susceptible maize hybrids when plants were water sufficient. This showed that maize hybrids selected for extreme drought tolerance possessed a dwarf phenotype that affected soil water contents and leaf water potentials. Changes of shoot and root growth, leaf water potential, net photosynthesis and stomatal conductance in response to the time of water stress treatment were diminished when comparing the drought tolerant to the intermediate or susceptible maize hybrids. Genotypic differences were observed in 26 of 40 total foliar metabolites during water stress treatments. Hierarchical clustering revealed that the tolerant maize hybrid initiated the accumulation of stress related metabolites at higher leaf water potentials than either the susceptible or intermediate hybrids. Opposite results occurred when changes of metabolites in maize leaves were expressed temporally. The above results demonstrated that genotypic differences were readily observed by comparing maize hybrids differing in drought tolerance based on either time of treatment or measured leaf water potential. Current findings provided new and potentially important insights into the mechanisms of drought tolerance in maize. PMID- 24143209 TI - Identification of N-glycosylation in hepatocellular carcinoma patients' serum with a comparative proteomic approach. AB - AIM: This study is to explore the different expressions of serum N-glycoproteins and glycosylation sites between hepatocellular carcinoma (HCC) patients and healthy controls. METHOD: We combined high abundant proteins depletion and hydrophilic affinity method to enrich the glycoproteins. Through liquid chromatography-tandem mass spectrometry (LC-MS/MS), we extensively surveyed different expressions of glycosylation sites and glycoproteins between the two groups. RESULT: This approach identified 152 glycosylation sites and 54 glycoproteins expressed differently between HCC patients and healthy controls. With the absolute values of Pearson coefficients of at least 0.8, eight proteins were identified significantly up or down regulated in HCC serum. Those proteins are supposed to be involved in several biological processes, cellular components and molecular functions of hepatocarcinogenesis. Several of them had been reported abnormally regulated in several kinds of malignant tumors, and may be promising biomarkers of HCC. CONCLUSION: Our work provides a systematic and quantitative method of glycoproteomics and demonstrates some key changes in clinical HCC serum. These proteomic signatures may help to unveil the underlying mechanisms of hepatocarcinogenesis and may be useful for the exploration of candidate biomarkers. PMID- 24143210 TI - Periatrial epicardial fat is associated with markers of endothelial dysfunction in patients with atrial fibrillation. AB - BACKGROUND: Epicardial adipose tissue (EAT) is associated to atrial fibrillation (AF) burden and outcome after AF ablation. We intended to determine whether global or local EAT is associated with systemic and/or left atrial (LA) inflammation and markers of endothelial dysfunction in AF patients. METHODS AND RESULTS: Total, atrial, and ventricular EAT volume (EAT total, EAT atrial, EAT ventricular) were measured by multislice cardiac CT in 49 patients with paroxysmal (PAF, n=25) or persistent AF (PeF, n=24). Periatrial epicardial fat thickness at the esophagus (LA-ESO) and thoracic aorta (LA-ThA) were also measured. Vascular endothelial growth factor (VEGF), interleukin-8 (IL-8), soluble intercellular adhesion molecule 1 (sICAM-1), transforming growth factor beta1 (TGF-beta1), and von Willebrand Factor (vWF) levels were measured in peripheral and LA blood samples obtained during catheterization during AF ablation. Patients with PeF had higher EAT atrial (P<0.05) and LA-ESO (P=0.04) than patients with PAF. VEGF, IL-8, and TGF-beta1 were not associated with EAT. In contrast, after adjusting for LA volume and body mass index, higher LA-ThA was significantly associated with higher sICAM-1 and vWF levels, both in peripheral blood (P<0.05) and in LA (P<0.05). Similar results were found with LA-ESO. Body mass index, EAT total and EAT ventricular were not associated with sICAM-1 and vWF. CONCLUSIONS: Periatrial epicardial fat showed a significant positive association with increased levels of sICAM-1 and vWF, which are biomarkers of endothelial dysfunction. No such associations were found when considering body mass index or EAT total. These results suggest that local EAT rather than regional or total adiposity may modulate endothelial dysfunction in patients with AF. PMID- 24143211 TI - Optimizing exchange transfusion for severe unconjugated hyperbilirubinemia: studies in the Gunn rat. AB - BACKGROUND: Severe unconjugated hyperbilirubinemia carries the risk of neurotoxicity. Phototherapy (PT) and exchange transfusion (ET) are cornerstones in the treatment of unconjugated hyperbilirubinemia. Studies to improve ET efficacy have been hampered by the low application of ET in humans and by the lack of an in vivo model. The absence of an appropriate animal model has also prevented to determine the efficacy of adjunct or alternative treatment options such as albumin (Alb) administration. AIM: To establish an in vivo model for ET and to determine the most effective treatment (combination) of ET, PT and Alb administration. METHODS: Gunn rats received either PT, PT+Alb, ET, ET+PT, ET+PT+Alb or sham operation (each n = 7). ET was performed via the right jugular vein in ~ 20 min. PT (18 uW/cm(2)/nm) was started after ET or at T0. Albumin i.p. injections (2.5 g/kg) were given after ET or before starting PT. Plasma unconjugated bilirubin (UCB), plasma free bilirubin (Bf), and brain bilirubin concentrations were determined. RESULTS: We performed ET in 21 Gunn rats with 100% survival. At T1, ET was profoundly more effective in decreasing both UCB 44%, p<0.01) and Bf -81%, p<0.05) than either PT or PT+Alb. After 48 h, the combination of ET+PT+Alb showed the strongest hypobilirubinemic effect (-54% compared to ET). CONCLUSIONS: We optimized ET for severe unconjugated hyperbilirubinemia in the Gunn rat model. Our data indicate that ET is the most effective treatment option, in the acute as well as the follow-up situation. PMID- 24143212 TI - NADPH oxidase deficient mice develop colitis and bacteremia upon infection with normally avirulent, TTSS-1- and TTSS-2-deficient Salmonella Typhimurium. AB - Infections, microbe sampling and occasional leakage of commensal microbiota and their products across the intestinal epithelial cell layer represent a permanent challenge to the intestinal immune system. The production of reactive oxygen species by NADPH oxidase is thought to be a key element of defense. Patients suffering from chronic granulomatous disease are deficient in one of the subunits of NADPH oxidase. They display a high incidence of Crohn's disease-like intestinal inflammation and are hyper-susceptible to infection with fungi and bacteria, including a 10-fold increased risk of Salmonellosis. It is not completely understood which steps of the infection process are affected by the NADPH oxidase deficiency. We employed a mouse model for Salmonella diarrhea to study how NADPH oxidase deficiency (Cybb (-/-)) affects microbe handling by the large intestinal mucosa. In this animal model, wild type S. Typhimurium causes pronounced enteropathy in wild type mice. In contrast, an avirulent S. Typhimurium mutant (S.Tm(avir); invGsseD), which lacks virulence factors boosting trans-epithelial penetration and growth in the lamina propria, cannot cause enteropathy in wild type mice. We found that Cybb (-/-) mice are efficiently infected by S.Tm(avir) and develop enteropathy by day 4 post infection. Cell depletion experiments and infections in Cybb (-/-) Myd88 (-/-) mice indicated that the S.Tm(avir)-inflicted disease in Cybb (-/-) mice hinges on CD11c(+)CX3CR1(+) monocytic phagocytes mediating colonization of the cecal lamina propria and on Myd88-dependent proinflammatory immune responses. Interestingly, in mixed bone marrow chimeras a partial reconstitution of Cybb-proficiency in the bone marrow derived compartment was sufficient to ameliorate disease severity. Our data indicate that NADPH oxidase expression is of key importance for restricting the growth of S.Tm(avir) in the mucosal lamina propria. This provides important insights into microbe handling by the large intestinal mucosa and the role of NADPH oxidase in maintaining microbe-host mutualism at this exposed body surface. PMID- 24143213 TI - SLCO1B1 and SLC19A1 gene variants and irinotecan-induced rapid response and survival: a prospective multicenter pharmacogenetics study of metastatic colorectal cancer. AB - BACKGROUND: Rapid response to chemotherapy in metastatic colorectal cancer (mCRC) patients (response within 12 weeks of chemotherapy) may increase the chance of complete resection and improved survival. Few molecular markers predict irinotecan-induced rapid response and survival. Single-nucleotide polymorphisms (SNPs) in solute carrier genes are reported to correlate with the variable pharmacokinetics of irinotecan and folate in cancer patients. This study aims to evaluate the predictive role of 3 SNPs in mCRC patients treated with irinotecan and fluoropyrimidine-containing regimens. MATERIALS AND METHODS: Three SNPs were selected and genotyped in 137 mCRC patients from a Chinese prospective multicenter trial (NCT01282658). The chi-squared test, univariate and multivariable logistic regression model, and receiver operating characteristic analysis were used to evaluate correlations between the genotypes and rapid response. Kaplan-Meier survival analysis and Cox proportional hazard models were used to evaluate the associations between genotypes and survival outcomes. Benjamini and Hochberg False Discovery Rate correction was used in multiple testing. RESULTS: Genotype GA/AA of SNP rs2306283 of the gene SLCO1B1 and genotype GG of SNP rs1051266 of the gene SLC19A1 were associated with a higher rapid response rate (odds ratio [OR] =3.583 and 3.521, 95%CI =1.301-9.871 and 1.271-9.804, p=0.011 and p=0.013, respectively). The response rate was 70% in patients with both genotypes, compared with only 19.7% in the remaining patients (OR = 9.489, 95%CI = 2.191-41.093, Fisher's exact test p=0.002). Their significances were all maintained even after multiple testing (all p c < 0.05). The rs2306283 GA/AA genotype was also an independent prognostic factor of longer progression-free survival (PFS) (hazard ratio = 0.402, 95%CI = 0.171-0.945, p=0.037). None of the SNPs predicted overall survival. CONCLUSIONS: Polymorphisms of solute carriers' may be useful to predict rapid response to irinotecan plus fluoropyrimidine and PFS in mCRC patients. PMID- 24143214 TI - The 'Antiretrovirals, Sexual Transmission Risk and Attitudes' (ASTRA) study. Design, methods and participant characteristics. AB - Life expectancy for people diagnosed with HIV has improved dramatically however the number of new infections in the UK remains high. Understanding patterns of sexual behaviour among people living with diagnosed HIV, and the factors associated with having condom-less sex, is important for informing HIV prevention strategies and clinical care. In addition, in view of the current interest in a policy of early antiretroviral treatment (ART) for all people diagnosed with HIV in the UK, it is of particular importance to assess whether ART use is associated with increased levels of condom-less sex. In this context the ASTRA study was designed to investigate current sexual activity, and attitudes to HIV transmission risk, in a large unselected sample of HIV-infected patients under care in the UK. The study also gathered background information on demographic, socio-economic, lifestyle and disease-related characteristics, and physical and psychological symptoms, in order to identify other key factors impacting on HIV patients and the behaviours which underpin transmission. In this paper we describe the study rationale, design, methods, response rate and the demographic characteristics of the participants. People diagnosed with HIV infection attending 8 UK HIV out-patient clinics in 2011-2012 were invited to participate in the study. Those who agreed to participate completed a confidential, self administered pen-and-paper questionnaire, and their latest CD4 count and viral load test results were recorded. During the study period, 5112 eligible patients were invited to take part in the study and 3258 completed questionnaires were obtained, representing a response rate of 64% of eligible patients. The study includes 2248 men who have sex with men (MSM), 373 heterosexual men and 637 women. Future results from ASTRA will be a key resource for understanding HIV transmission within the UK, targeting prevention efforts, and informing clinical care of individuals living with HIV. PMID- 24143215 TI - Identification of microRNAs that regulate TLR2-mediated trophoblast apoptosis and inhibition of IL-6 mRNA. AB - While infection-induced placental inflammation is a common mechanism of adverse pregnancy outcome, some pathogens can also trigger placental apoptosis, and Toll like receptors (TLRs) mediate this response. Treatment of human first trimester trophoblast cells with bacterial peptidoglycan (PDG) reduces their constitutive secretion of IL-6 protein and induces apoptosis. This apoptotic response is dependent upon the cell's expression of TLR1, TLR2 and TLR10, and their lack of TLR6, such that ectopic expression of TLR6 prevents PDG-induced apoptosis and restores IL-6 production. In this current study we have identified three microRNAs (miRs) that regulate TLR2-mediated responses in the human trophoblast. Herein we report that miR-329 plays a pivotal role in mediating PDG-induced trophoblast apoptosis and inhibition of IL-6 mRNA expression by targeting the NF kappaB subunit, p65. TLR2 activation by PDG upregulates miR-329 expression and inhibits NF-kappaB p65 and IL-6 mRNA, and this is reversed by the presence of TLR6. Moreover, inhibition of miR-329 prevents PDG-induced inhibition of NF kappaB p65 and IL-6 mRNA expression, and restores cell survival. In addition, we have found miR-23a and let-7c to directly regulate PDG-mediated inhibition of IL 6 mRNA. TLR2 activation by PDG upregulates miR23a and let-7c expression and this is reversed by the presence of TLR6. Furthermore, inhibition of both miR23a and let-7c prevents PDG-inhibition of trophoblast IL-6 mRNA expression. Together, our findings suggest that multiple miRs are involved in the molecular regulation of TLR2-mediated responses in the trophoblast towards gram-positive bacterial components. PMID- 24143216 TI - The Scutellaria baicalensis R2R3-MYB transcription factors modulates flavonoid biosynthesis by regulating GA metabolism in transgenic tobacco plants. AB - R2R3-MYB proteins play role in plant development, response to biotic and abiotic stress, and regulation of primary and secondary metabolism. Little is known about the R2R3-MYB proteins in Scutellaria baicalensis which is an important Chinese medical plant. In this paper, nineteen putative SbMYB genes were identified from a S. baicalensis cDNA library, and eleven R2R3-MYBs were clustered into 5 subgroups according to phylogenetic reconstruction. In the S. baicalensis leaves which were sprayed with GA3, SbMYB2 and SbMYB7 had similar expression pattern with SbPALs, indicating that SbMYB2 and SbMYB7 might be involved in the flavonoid metabolism. Transactivation assay results showed that SbMYB2 and SbMYB7 can function as transcriptional activator. The expression of several flavonoid biosynthesis-related genes were induced or suppressed by overexpression of SbMYB2 or SbMYB7 in transgenic tobacco plants. Consistent with the change of the expression of NtDH29 and NtCHI, the contents of dicaffeoylspermidine and quercetin-3,7-O-diglucoside in SbMYB2-overexpressing or SbMYB7-overexpressing transgenic tobacco plants were decreased. The transcriptional level of NtUFGT in transgenic tobacco overexpressing SbMYB7 and the transcriptional level of NtHCT in SbMYB2-overexpressing tobacco plants were increased; however the application of GA3 inhibited the transcriptional level of these two genes. These results suggest that SbMYB2 and SbMYB7 might regulate the flavonoid biosynthesis through GA metabolism. PMID- 24143217 TI - Pax6 downregulation mediates abnormal lineage commitment of the ocular surface epithelium in aqueous-deficient dry eye disease. AB - Keratinizing squamous metaplasia (SQM) of the ocular surface is a blinding consequence of systemic autoimmune disease and there is no cure. Ocular SQM is traditionally viewed as an adaptive tissue response during chronic keratoconjunctivitis sicca (KCS) that provokes pathological keratinization of the corneal epithelium and fibrosis of the corneal stroma. Recently, we established the autoimmune regulator-knockout (Aire KO) mouse as a model of autoimmune KCS and identified an essential role for autoreactive CD4+ T cells in SQM pathogenesis. In subsequent studies, we noted the down-regulation of paired box gene 6 (Pax6) in both human patients with chronic KCS associated with Sjogren's syndrome and Aire KO mice. Pax6 encodes a pleiotropic transcription factor guiding eye morphogenesis during development. While the postnatal function of Pax6 is largely unknown, we hypothesized that its role in maintaining ocular surface homeostasis was disrupted in the inflamed eye and that loss of Pax6 played a functional role in the initiation and progression of SQM. Adoptive transfer of autoreactive T cells from Aire KO mice to immunodeficient recipients confirmed CD4+ T cells as the principal downstream effectors promoting Pax6 downregulation in Aire KO mice. CD4+ T cells required local signaling via Interleukin-1 receptor (IL-1R1) to provoke Pax6 loss, which prompted a switch from corneal-specific cytokeratin, CK12, to epidermal-specific CK10. The functional role of Pax6 loss in SQM pathogenesis was indicated by the reversal of SQM and restoration of ocular surface homeostasis following forced expression of Pax6 in corneal epithelial cells using adenovirus. Thus, tissue-restricted restoration of Pax6 prevented aberrant epidermal-lineage commitment suggesting adjuvant Pax6 gene therapy may represent a novel therapeutic approach to prevent SQM in patients with chronic inflammatory diseases of the ocular surface. PMID- 24143218 TI - NOTCH3 is a prognostic factor that promotes glioma cell proliferation, migration and invasion via activation of CCND1 and EGFR. AB - Using a GWA analysis of a comprehensive glioma specimen population, we identified whole gain of chromosome 19 as one of the major chromosomal aberrations that correlates to patients' outcomes. Our analysis of significant loci revealed for the first time NOTCH3 as one of the most significant amplification. NOTCH3 amplification is associated with worse outcome compared to tumors with non amplified locus. NOTCH receptors (NOTCH1-4) are key positive regulators of cell cell interactions, angiogenesis, cell adhesion and stem cell niche development which have been shown to play critical roles in several human cancers. Our objective is to determine the molecular roles of NOTCH3 in glioma pathogenesis and aggressiveness. Here we show for the first time that NOTCH3 plays a major role in glioma cell proliferation, cell migration, invasion and apoptosis. Therefore, our study uncovers the prognostic value and the oncogenic function of NOTCH3 in gliomagenesis and supports NOTCH3 as a promising target of therapy in high grade glioma. Our studies allowed the identification of a subset of population that may benefit from GSI- or anti-NOTCH3- based therapies. This may lead to the design of novel strategies to improve therapeutic outcome of patients with glioma by establishing medical and scientific basis for personalized chemotherapies. PMID- 24143219 TI - Short-term consequences of angiographically-confirmed coronary stent thrombosis. AB - OBJECTIVES: To conduct a meta-analysis to quantify the real-world incidence of in hospital or 30-day death or myocardial infarction (MI), and angiographically confirmed ST-related treatment costs. BACKGROUND: The short-term clinical and economic consequences of coronary stent thrombosis (ST) are thought to be significant. METHODS: We searched MEDLINE, Embase and Scopus from January 2000 July 2012 to identify observational/registry studies that evaluated a cohort of >= 25 patients experiencing angiographically-confirmed thrombosis of a drug eluting or bare-metal stent, required the use of dual-antiplatelet therapy for guideline-recommended durations, and reported incidences of in-hospital or 30-day death or MI and/or ST-related treatment costs. Incidences and costs from each study were pooled using random-effects meta-analysis. RESULTS: Twenty-three studies were included. Of the 13 studies reporting in-hospital outcomes, 12 (N=8,832 STs) reported mortality data, with the pooled incidence rate estimated to be 7.9%, 95%CI=5.4%-11.3%, I(2)=86%. Ten studies (N=1,294 STs) reported 30-day death, with a pooled incidence of 11.6%, 95%CI=8.8%-15.1%, I(2)=55%. Patients experiencing early ST (within 30-days of implant) had higher in-hospital and 30 day mortality than those experiencing very-late ST (interaction p<0.04 for both). Stent type had no significant effect on in-hospital or 30-day mortality. In the 5 studies (N=542 STs) and 3 studies (N=180 STs) reporting in-hospital and 30-day MI, respectively, the pooled incidence rates were 6.1%, 95%CI=2.1%-16.2%, I(2)=88% and 9.5%, 95%CI=3.8%-22.0%, I(2)=65%. One study reported costs associated with ST, estimating the median/patient cost of hospitalization to treat early ST at $11,134 (in 2000US$). CONCLUSIONS: Regardless of stent type used, the short-term consequences of coronary ST appear significant. PMID- 24143221 TI - Algal bioremediation of waste waters from land-based aquaculture using ulva: selecting target species and strains. AB - The optimised reduction of dissolved nutrient loads in aquaculture effluents through bioremediation requires selection of appropriate algal species and strains. The objective of the current study was to identify target species and strains from the macroalgal genus Ulva for bioremediation of land-based aquaculture facilities in Eastern Australia. We surveyed land-based aquaculture facilities and natural coastal environments across three geographic locations in Eastern Australia to determine which species of Ulva occur naturally in this region and conducted growth trials at three temperature treatments on a subset of samples from each location to determine whether local strains had superior performance under local environmental conditions. DNA barcoding using the markers ITS and tufA identified six species of Ulva, with U. ohnoi being the most common blade species and U. sp. 3 the most common filamentous species. Both species occurred at multiple land-based aquaculture facilities in Townsville and Brisbane and multiple strains of each species grew well in culture. Specific growth rates of U. ohnoi and U. sp. 3 were high (over 9% and 15% day(-1) respectively) across temperature treatments. Within species, strains of U. ohnoi had higher growth in temperatures corresponding to local conditions, suggesting that strains may be locally adapted. However, across all temperature treatments Townsville strains had the highest growth rates (11.2-20.4% day(-1)) and Sydney strains had the lowest growth rates (2.5-8.3% day(-1)). We also found significant differences in growth between strains of U. ohnoi collected from the same geographic location, highlighting the potential to isolate and cultivate fast growing strains. In contrast, there was no clearly identifiable competitive strain of filamentous Ulva, with multiple species and strains having variable performance. The fast growth rates and broad geographical distribution of U. ohnoi make this an ideal species to target for bioremediation activities at land-based aquaculture facilities in Eastern Australia. PMID- 24143222 TI - Niche conservatism and the future potential range of Epipactis helleborine (Orchidaceae). AB - The aim of the present study was to evaluate the current distribution of suitable niches for the invasive orchid species, Epipactis helleborine, and to estimate the possibility of its further expansion. Moreover, niche modeling tools were used to explain its rapid expansion in North America and to test the niche conservatism of the species. The maximum entropy method was used to create models of the suitable niche distribution. A database of E. helleborine localities was prepared based on the examination of herbarium specimens, information from electronic databases as well as data gathered during field works. The differences between the niches occupied by native and invasive populations were evaluated using the niche overlap and niche identity test indexes. Moreover, the coverage of the most suitable habitats for the species was measured for three future scenarios as well as for the present time model. Populations of E. helleborine occupy North American west coast habitats very similar to those preferred by native, Eurasian populations, while the expansion in the east coast is related to the niche shift. The created models of suitable niche distribution indicate that the species does not realize its potential niche in the native range. The total surface of the habitats potentially available for E. helleborine will decrease in all climate change scenarios created for 2080. PMID- 24143220 TI - Global expression of molecular transporters in the human vaginal tract: implications for HIV chemoprophylaxis. AB - BACKGROUND: Pre-exposure chemoprophylaxis (PrECP) using antiretroviral agents is a promising strategy for the prevention of sexual HIV transmission in women. Molecular transporters in the human vaginal tract (VT) may play a pivotal role in determining drug disposition and, consequently, pharmacodynamic outcomes in these efforts. Little is known, however, on the expression of these transporters in vaginal tissues, representing a critical knowledge gap. METHODOLOGY/PRINCIPAL FINDINGS: Our study analyzed the genome-wide transcriptome in 44 vaginal tissue samples from 6 reproductive-age women undergoing gynecologic surgeries. The analysis revealed that, unexpectedly, a large number (43%) of gene isoforms corresponding to membrane transporters were over-expressed (above the median expression level) in all samples. A subset of 12 highly expressed membrane transporters was identified and contained 10 members (83%) of the solute carrier superfamily. The largest difference in membrane transporter gene expression was observed across subjects, but more subtle differential expression also was found along the anterior-posterior axis of the VT. Cross-validation of the microarray analyses with measurements RT-qPCR demonstrated high concordance between these data sets. Immunofluorescence labeling of membrane transporter proteins in vaginal tissues was highly dependent on tissue/cell types. CONCLUSIONS/SIGNIFICANCE: Antiretroviral PrECP drugs currently under evaluation are substrates for molecular transporters that were commonly expressed, but fell into both over- or under-expressed categories in all samples, suggesting a complex role for carrier-mediated processes in determining the disposition of these xenobiotics in vaginal tissues. These findings hold important implications for the successful development of products, either oral or intravaginal, for female-controlled HIV PrECP. PMID- 24143223 TI - Helicobacter pylori cag pathogenicity island (cagPAI) involved in bacterial internalization and IL-8 induced responses via NOD1- and MyD88-dependent mechanisms in human biliary epithelial cells. AB - Helicobacter pylori infection has been proposed to be associated with various diseases of the hepatobiliary tract, including cancer of the bile duct epithelial cells (cholangiocarcinoma, CCA). The ability of H. pylori bacteria to cause pathogenic effects in these cells has, however, yet to be investigated. Given that the cag pathogenicity island (cagPAI) is required for H. pylori pathogenesis in gastric epithelial cells, we investigated wild-type and cag mutant strains for their ability to adhere, be internalized and induce pro-inflammatory responses in two bile duct epithelial cell lines derived from cases of CCA. The findings from these experiments were compared to results obtained with the well-characterized AGS gastric cancer cell line. We showed that the cagPAI encodes factors involved in H. pylori internalization in CCA cells, but not for adhesion to these cells. Consistent with previous studies in hepatocytes, actin polymerization and alpha5beta1 integrin may be involved in H. pylori internalization in CCA cells. As for AGS cells, we observed significantly reduced levels of NF-kappaB activation and IL-8 production in CCA cells stimulated with either cagA, cagL or cagPAI bacteria, when compared with wild-type bacteria. Importantly, these IL-8 responses could be inhibited via either pre-treatment of cells with antibodies to alpha5beta1 integrins, or via siRNA-mediated knockdown of the innate immune signaling molecules, nucleotide oligomerization domain 1 (NOD1) and myeloid differentiation response gene 88 (MyD88). Taken together, the data demonstrate that the cagPAI is critical for H. pylori pathogenesis in bile duct cells, thus providing a potential causal link for H. pylori in biliary tract disease. PMID- 24143224 TI - Structural and mechanistic insight into DNA unwinding by Deinococcus radiodurans UvrD. AB - DNA helicases are responsible for unwinding the duplex DNA, a key step in many biological processes. UvrD is a DNA helicase involved in several DNA repair pathways. We report here crystal structures of Deinococcus radiodurans UvrD (drUvrD) in complex with DNA in different nucleotide-free and bound states. These structures provide us with three distinct snapshots of drUvrD in action and for the first time trap a DNA helicase undergoing a large-scale spiral movement around duplexed DNA. Our structural data also improve our understanding of the molecular mechanisms that regulate DNA unwinding by Superfamily 1A (SF1A) helicases. Our biochemical data reveal that drUvrD is a DNA-stimulated ATPase, can translocate along ssDNA in the 3'-5' direction and shows ATP-dependent 3'-5', and surprisingly also, 5'-3' helicase activity. Interestingly, we find that these translocase and helicase activities of drUvrD are modulated by the ssDNA binding protein. Analysis of drUvrD mutants indicate that the conserved beta-hairpin structure of drUvrD that functions as a separation pin is critical for both drUvrD's 3'-5' and 5'-3' helicase activities, whereas the GIG motif of drUvrD involved in binding to the DNA duplex is essential for the 5'-3' helicase activity only. These special features of drUvrD may reflect its involvement in a wide range of DNA repair processes in vivo. PMID- 24143225 TI - TIMP-1 promotes accumulation of cancer associated fibroblasts and cancer progression. AB - Treatment options for late stage prostate and colon cancer are limited and there is an urgent need to develop more effective and targeted novel therapies, which starts with identification and validation of novel therapeutic targets. Recent clinical studies have demonstrated that tissue inhibitor matrix metalloproteinase 1 (TIMP-1) levels are elevated in cancer patient plasma and elevated TIMP-1 levels are associated with worse clinical outcomes. However, it is unknown whether TIMP-1 serves merely as a biomarker of cancer progression or has a functional role in promoting cancer progression and can serve as a cancer therapeutic target, which is the main objective of this study. Here, we show that stroma of human prostate and colon cancer express higher levels of TIMP-1 compared to their normal counterparts and increased expression of TIMP-1 promotes in vivo growth of both cancer types. We demonstrate for the first time that increased TIMP-1 expression stimulates accumulation of cancer associated fibroblasts (CAFs) within prostate and colon cancer tissues and that TIMP-1 enhances prostate CAF proliferation and migration in vitro and promotes ERK1/2 kinase activation in these CAF cells. Our results establish the novel promotive effects of TIMP-1 on cancer progression and on accumulation of CAFs that in turn provides a pro-tumor microenvironment. Together, these results establish the potential of TIMP-1 as a novel target for cancer therapy and the mechanism underlying the pro-tumor activity of TIMP-1. PMID- 24143226 TI - Decreased chronic morbidity but elevated HIV associated cytokine levels in HIV infected older adults receiving HIV treatment: benefit of enhanced access to care? AB - BACKGROUND: The association of HIV with chronic morbidity and inflammatory markers (cytokines) in older adults (50+years) is potentially relevant for clinical care, but data from African populations is scarce. OBJECTIVE: To examine levels of chronic morbidity by HIV and ART status in older adults (50+years) and subsequent associations with selected pro-inflammatory cytokines and body mass index. METHODS: Ordinary, ordered and generalized ordered logistic regression techniques were employed to compare chronic morbidity (heart disease (angina), arthritis, stroke, hypertension, asthma and diabetes) and cytokines (Interleukins 1 and -6, C-Reactive Protein and Tumor Necrosis Factor-alpha) by HIV and ART status on a cross-sectional random sample of 422 older adults nested within a defined rural South African population based demographic surveillance. RESULTS: Using a composite measure of all morbidities, controlling for age, gender, BMI, smoking and wealth quintile, HIV-infected individuals on ART had 51% decreased odds (95% CI:0.26-0.92) of current morbidity compared to HIV-uninfected. In adjusted regression, compared to HIV-uninfected, the proportional odds (aPOR) of having elevated inflammation markers of IL6 (>1.56 pg/mL) was nearly doubled in HIV-infected individuals on (aPOR 1.84; 95%CI: 1.05-3.21) and not on (aPOR 1.94; 95%CI: 1.11-3.41) ART. Compared to HIV-uninfected, HIV-infected individuals on ART had >twice partial proportional odds (apPOR=2.30;p=0.004) of having non clinically significant raised hsCRP levels(>1 ug/mL); ART-naive HIV-infected individuals had >double apPOR of having hsCRP levels indicative of increased heart disease risk(>3.9 ug/mL;p=0.008). CONCLUSIONS: Although HIV status was associated with increased inflammatory markers, our results highlight reduced morbidity in those receiving ART and underscore the need of pro-actively extending these services to HIV-uninfected older adults, beyond mere provision at fixed clinics. Providing health services through regular community chronic disease screening would ensure health care reaches all older adults in need. PMID- 24143227 TI - Heat shock protein B1-deficient mice display impaired wound healing. AB - There is large literature describing in vitro experiments on heat shock protein (hsp)B1 but understanding of its function in vivo is limited to studies in mice overexpressing human hspB1 protein. Experiments in cells have shown that hspB1 has chaperone activity, a cytoprotective role, regulates inflammatory gene expression, and drives cell proliferation. To investigate the function of the protein in vivo we generated hspB1-deficient mice. HspB1-deficient fibroblasts display increased expression of the pro-inflammatory cytokine, interleukin-6, compared to wild-type cells, but reduced proliferation. HspB1-deficient fibroblasts exhibit reduced entry into S phase and increased expression of cyclin dependent kinase inhibitors p27(kip1) and p21(waf1). The expression of hspB1 protein and mRNA is also controlled by the cell cycle. To investigate the physiological function of hspB1 in regulating inflammation and cell proliferation we used an excisional cutaneous wound healing model. There was a significant impairment in the rate of healing of wounds in hspB1-deficient mice, characterised by reduced re-epithelialisation and collagen deposition but also increased inflammation. HspB1 deficiency augments neutrophil infiltration in wounds, driven by increased chemokine (C-X-C motif) ligand 1 expression. This appears to be a general mechanism as similar results were obtained in the air pouch and peritonitis models of acute inflammation. PMID- 24143228 TI - Choline plasmalogens isolated from swine liver inhibit hepatoma cell proliferation associated with caveolin-1/Akt signaling. AB - Plasmalogens play multiple roles in the structures of biological membranes, cell membrane lipid homeostasis and human diseases. We report the isolation and identification of choline plasmalogens (ChoPlas) from swine liver by high performance thin layer chromatography (HPTLC) and high performance liquid chromatography (HPLC)/MS. The growth and viability of hepatoma cells (CBRH7919, HepG2 and SMMC7721) was determined following ChoPlas treatment comparing with that of human normal immortal cell lines (HL7702). Result indicated that ChoPlas inhibited hepatoma cell proliferation with an optimal concentration and time of 25 MUmol/L and 24 h. To better understand the mechanism of the ChoPlas-induced inhibition of hepatoma cell proliferation, Caveolin-1 and PI3K/Akt pathway signals, including total Akt, phospho-Akt(pAkt) and Bcl-2 expression in CBRH7919 cells, were determined by western blot. ChoPlas treatment increased Caveolin-1 expression and reduced the expression of phospho-Akt (pAkt) and Bcl-2, downstream targets of the PI3K/Akt pathway. Further cell cycle analysis showed that ChoPlas treatment induced G1 and G1/S phase transition cell cycle arrest. The expression of essential cell cycle regulatory proteins involved in the G1 and G1/S phase transitions, cyclin D, CDK4, cyclin E and CDK2, were also analyzed by western blot. ChoPlas reduced CDK4, cyclin E and CDK2 expression. Taken together, the results indicate that swine liver-derived natural ChoPlas inhibits hepatoma cell proliferation associated with Caveolin-1 and PI3K/Akt signals. PMID- 24143229 TI - Generation of monoclonal antibody MS17-57 targeting secreted alkaline phosphatase ectopically expressed on the surface of gastrointestinal cancer cells. AB - BACKGROUND: Therapeutic antibody development is one of the fastest growing areas of the pharmaceutical industry. Generating high-quality monoclonal antibodies against a given therapeutic target is crucial for successful drug development. However, due to immune tolerance, making it difficult to generate antibodies using conventional approaches. METHODOLOGY/FINDINGS: Mixed four human gastric cancer (GC) cell lines were used as the immunogen in A/J mice; sixteen highly positive hybridoma colonies were selected via fluorescence-activated cell sorting high throughput screening (FACS-HTS) using a total of 20,000 colonies in sixty seven 96-well plates against live cells (mixed human GC cells versus human PBMC controls). MS17-57 and control commercial Alkaline Phosphatase (ALP) mAbs were used to confirm the target antigens (Ags), which were identified as ALPs expressed on the GC cell surface through a combination of western blot, immunoprecipitation and mass spectrometry (MS). MS identified the Ags recognized by MS17-57 to be two variants of a secreted ALP, PALP and IALP (Placental and intestinal ALP). These proteins belong to a hydrolase enzyme family responsible for removing phosphate groups from many types of molecules. Immunofluorescence staining using MS17-57 demonstrated higher staining of gastrointestinal (GI) cancer tissues compared to normal GI tissues (P<0.03), and confirmed binding of MS17-57 to be restricted to a functional epitope expressed on the cancer cell surface. Proliferation assays using the PALP/IALP-expressing GC cell lines demonstrated that MS17-57 inhibited cell growth by 32 +/- 8%. Transwell cell migration assays documented that MS17-57 can inhibit PALP/IALP-expressing GI cancer cell migration by 25 +/- 5%. MS17-57 mAb inhibited tumor growth in nude mice. CONCLUSIONS: Our findings indicate that PALP and IALP can be ectopically expressed on extracellular matrix of GI cancers, and that MS17-57 directed against PALP/IALP can inhibit GI cancer cells growth and migration in vitro and in vivo. This investigation provides an example of identification of cancer biomarkers representing promising therapeutic targets using mAb generated through a novel HTS technology. PMID- 24143230 TI - Changes of cytokines during a spaceflight analog--a 45-day head-down bed rest. AB - Spaceflight is associated with deregulation in the immune system. Head-down bed rest (HDBR) at -6 degrees is believed to be the most practical model for examining multi-system responses to microgravity in humans during spaceflight. In the present study, a 45-day HDBR was performed to investigate the alterations in human immune cell distributions and their functions in response to various stimuli. The effect of countermeasure, Rhodiola rosea (RR) treatment, was also examined. A significant decrease of interferon-gamma (IFN-gamma) and interleukin 17 (IL-17) productions by activated T cells, increase of IL-1beta and IL-18 by activated B and myeloid cells were observed during HDBR. The upregulation of serum cortisol was correlated with the changes of IL-1 family cytokines. In addition, a significant increase of memory T and B cell and regulatory T cells (Treg) were also detected. The uptake of RR further decreased IFN-gamma level and slowed down the upregulation of IL-1 family cytokines. These data suggest that for prolonged HDBR and spaceflight, the decreased protective T cell immunity and enhanced proinflammatory cytokines should be closely monitored. The treatment with RR may play an important role in suppressing proinflammatory cytokines but not in boosting protective T cell immunity. PMID- 24143231 TI - Longitudinal lung function growth of Mexican children compared with international studies. AB - INTRODUCTION: Our aim was to compare the longitudinal lung function growth of Mexican children and adolescents with the collated spirometric reference proposed for international use and with that of Mexican-Americans from the National Health State Examination Survey III (NHANES) III study. MATERIALS AND METHODS: A cohort of Mexican children in third year of primary school was followed with spirometry twice a year through secondary school. Multilevel mixed-effects lineal models separated by gender were fit for the spirometric variables of 2,641 respiratory healthy Mexican children expressed as Z-scores of tested reference equations. Impact of adjustment by sitting height on differences with Mexican-American children was observed in a subsample of 1,987 children. RESULTS: At same gender, age, and height, Mexican children had increasingly higher forced expiratory volume in 1 s (FEV1) and Forced vital capacity (FVC) than the children from the collated reference study (mean Z-score, 0.68 for FEV1 and 0.51 for FVC) and than Mexican-American children (Z-score, 0.23 for FEV1 and 0.21 for FVC) respectively. Differences with Mexican-Americans were not reduced by adjusting by sitting height. CONCLUSIONS: For reasons that remain unclear, the gender-, age-, and height-adjusted lung function of children from Mexico City is higher than that reported by several international studies. PMID- 24143232 TI - Minnelide: a novel therapeutic that promotes apoptosis in non-small cell lung carcinoma in vivo. AB - BACKGROUND: Minnelide, a pro-drug of triptolide, has recently emerged as a potent anticancer agent. The precise mechanisms of its cytotoxic effects remain unclear. METHODS: Cell viability was studied using CCK8 assay. Cell proliferation was measured real-time on cultured cells using Electric Cell Substrate Impedence Sensing (ECIS). Apoptosis was assayed by Caspase activity on cultured lung cancer cells and TUNEL staining on tissue sections. Expression of pro-survival and anti apoptotic genes (HSP70, BIRC5, BIRC4, BIRC2, UACA, APAF-1) was estimated by qRTPCR. Effect of Minnelide on proliferative cells in the tissue was estimated by Ki-67 staining of animal tissue sections. RESULTS: In this study, we investigated in vitro and in vivo antitumor effects of triptolide/Minnelide in non-small cell lung carcinoma (NSCLC). Triptolide/Minnelide exhibited anti-proliferative effects and induced apoptosis in NSCLC cell lines and NSCLC mouse models. Triptolide/Minnelide significantly down-regulated the expression of pro-survival and anti-apoptotic genes (HSP70, BIRC5, BIRC4, BIRC2, UACA) and up-regulated pro apoptotic APAF-1 gene, in part, via attenuating the NF-kappaB signaling activity. CONCLUSION: In conclusion, our results provide supporting mechanistic evidence for Minnelide as a potential in NSCLC. PMID- 24143233 TI - Activation associated ERK1/2 signaling impairments in CD8+ T cells co-localize with blunted polyclonal and HIV-1 specific effector functions in early untreated HIV-1 infection. AB - We recently observed that a large proportion of activated (CD38(+)HLA-DR(+)) CD8(+) T cells from recently HIV-1-infected adults are refractory to phosphorylation of ERK1/2 kinases (p-ERK1/2-refractory). Given that the ERK1/2 pathway mediates intracellular signaling critical for multiple T cell functions, including key effector functions, the loss of ERK1/2 responsiveness may have broad consequences for CD8(+) T cell function. In the current study, we hypothesized that the p-ERK1/2-refractory population, localized largely within the activated CD38(+)HLA-DR(+) CD8(+) T cell population, would display impairments in CD8(+) T cell effector functions, such as cytokine production and degranulation, compared to CD8(+) p-ERK1/2-responsive cells. We further hypothesized that the p-ERK1/2-refractory phenotype is persistent over time during untreated infection, and would correlate with poorer virologic control, in a manner independent of CD8(+) T cell activation level. We performed single-cell resolution, flow cytometric assays of phospho-kinase responses paired to intracellular cytokine staining in one assay to examine IFN-gamma, perforin and CD107alpha responses in CD8(+) T cells by ERK1/2 signaling profile. On a per cell basis, p-ERK1/2-refractory cells, which fall predominantly within the activated CD8(+) T cell compartment, produced less IFN-gamma in response to polyclonal or HIV-1 antigen-specific stimulation, and expressed lower levels of perforin and CD107alpha. The p-ERK1/2 refractory cell population displayed minimal overlap with the PD-1 and Tim-3 inhibitory exhaustion markers and predicted high viral load independent of activation, suggesting that ERK1/2 may be a unique marker and point of intervention for improving CD8(+) T cell function. Blunted effector functions, secondary to ERK1/2 signaling deficits concentrated within activated CD8(+) T cells, may contribute to immunodeficiency and underlie the predictive capacity of CD8(+) T cell activation on HIV-1 disease progression. (270/300). PMID- 24143234 TI - Global metabolomic profiling reveals an association of metal fume exposure and plasma unsaturated fatty acids. AB - BACKGROUND: Welding-associated air pollutants negatively affect the health of exposed workers; however, their molecular mechanisms in causing disease remain largely unclear. Few studies have systematically investigated the systemic toxic effects of welding fumes on humans. OBJECTIVES: To explore the effects of welding fumes on the plasma metabolome, and to identify biomarkers for risk assessment of welding fume exposure. METHODS: The two-stage, self-controlled exploratory study included 11 boilermakers from a 2011 discovery panel and 8 boilermakers from a 2012 validation panel. Plasma samples were collected pre- and post-welding fume exposure and analyzed by chromatography/mass spectrometry. RESULTS: Eicosapentaenoic or docosapentaenoic acid metabolic changes post-welding were significantly associated with particulate (PM2.5) exposure (p<0.05). The combined analysis by linear mixed-effects model showed that exposure was associated with a statistically significant decline in metabolite change of eicosapentaenoic acid [beta(95% CI) = -0.013(-0.022 ~ -0.004); p = 0.005], docosapentaenoic acid n3 [beta(95% CI) = -0.010(-0.018 ~ -0.002); p = 0.017], and docosapentaenoic acid n6 [beta(95% CI) = -0.007(-0.013 ~ -0.001); p = 0.021]. Pathway analysis identified an association of the unsaturated fatty acid pathway with exposure (p Study-2011 = 0.025; p Study-2012 = 0.021; p Combined = 0.009). The functional network built by these fatty acids and their interactive genes contained significant enrichment of genes associated with various diseases, including neoplasms, cardiovascular diseases, and lipid metabolism disorders. CONCLUSIONS: High-dose exposure of metal welding fumes decreases unsaturated fatty acids with an exposure-response relationship. This alteration in fatty acids is a potential biological mediator and biomarker for exposure-related health disorders. PMID- 24143235 TI - Differential activation of Wnt-beta-catenin pathway in triple negative breast cancer increases MMP7 in a PTEN dependent manner. AB - Mutations of genes in tumor cells of Triple Negative subset of Breast Cancer (TNBC) deregulate pathways of signal transduction. The loss of tumor suppressor gene PTEN is the most common first event associated with basal-like subtype (Martins, De, Almendro, Gonen, and Park, 2012). Here we report for the first time that the functional upregulation of secreted-MMP7, a transcriptional target of Wnt-beta-catenin signature pathway in TNBC is associated to the loss of PTEN. We identified differential expression of mRNAs in several key-components genes, and transcriptional target genes of the Wnt-beta-catenin pathway (WP), including beta catenin, FZD7, DVL1, MMP7, c-MYC, BIRC5, CD44, PPARD, c-MET, and NOTCH1 in FFPE tumors samples from TNBC patients of two independent cohorts. A similar differential upregulation of mRNA/protein for beta-catenin, the functional readout of WP, and for MMP7, a transcriptional target gene of beta-catenin was observed in TNBC cell line models. Genetic or pharmacological attenuation of beta catenin by SiRNA or WP modulators (XAV939 and sulindac sulfide) and pharmacological mimicking of PTEN following LY294002 treatment downregulated MMP7 levels as well as enzymatic function of the secreted MMP7 in MMP7 positive PTEN null TNBC cells. Patient data revealed that MMP7 mRNA was high in only a subpopulation of TNBC, and this subpopulation was characterized by a concurrent low expression of PTEN mRNA. In cell lines, a high expression of casein-zymograph positive MMP7 was distinguished by an absence of functional PTEN. A similar inverse relationship between MMP7 and PTEN mRNA levels was observed in the PAM50 data set (a correlation coefficient of -0.54). The PAM50 subtype and outcome data revealed that the high MMP7 group had low pCR (25%) and High Rd (74%) in clinical stage T3 pathologic response in contrast to the high pCR (40%) and low residual disease (RD) (60%) of the low MMP7 group. PMID- 24143236 TI - Biomass accumulation and carbon sequestration in four different aged Casuarina equisetifolia coastal shelterbelt plantations in South China. AB - Thousands of kilometers of shelterbelt plantations of Casuarina equisetifolia have been planted to protect the southeast coastline of China. These plantations also play an important role in the regional carbon (C) cycling. In this study, we examined plant biomass increment and C accumulation in four different aged C. equisetifolia plantations in sandy beaches in South China. The C accumulated in the C. equisetifolia plant biomass increased markedly with stand age. The annual rate of C accumulation in the C. equisetifolia plant biomass during 0-3, 3-6, 6 13 and 13-18 years stage was 2.9, 8.2, 4.2 and 1.0 Mg C ha(-1) yr(-1), respectively. Soil organic C (SOC) at the top 1 m soil layer in these plantations was 17.74, 5.14, 6.93, and 11.87 Mg C ha(-1), respectively, with SOC density decreasing with increasing soil depth. Total C storage in the plantation ecosystem averaged 26.57, 38.50, 69.78, and 79.79 Mg C ha(-1) in the 3, 6, 13 and 18- yrs plantation, with most of the C accumulated in the aboveground biomass rather than in the belowground root biomass and soil organic C. Though our results suggest that C. equisetifolia plantations have the characteristics of fast growth, high biomass accumulation, and the potential of high C sequestration despite planting in poor soil conditions, the interactive effects of soil condition, natural disturbance, and human policies on the ecosystem health of the plantation need to be further studied to fully realize the ecological and social benefits of the C equisetifolia shelterbelt forests in South China. PMID- 24143237 TI - Imaging the L-type amino acid transporter-1 (LAT1) with Zr-89 immunoPET. AB - The L-type amino acid transporter-1 (LAT1, SLC7A5) is upregulated in a wide range of human cancers, positively correlated with the biological aggressiveness of tumors, and a promising target for both imaging and therapy. Radiolabeled amino acids such as O-(2-[(18)F]fluoroethyl)-L-tyrosine (FET) that are transport substrates for system L amino acid transporters including LAT1 have met limited success for oncologic imaging outside of the brain, and thus new strategies are needed for imaging LAT1 in systemic cancers. Here, we describe the development and biological evaluation of a novel zirconium-89 labeled antibody, [(89)Zr]DFO Ab2, targeting the extracellular domain of LAT1 in a preclinical model of colorectal cancer. This tracer demonstrated specificity for LAT1 in vitro and in vivo with excellent tumor imaging properties in mice with xenograft tumors. PET imaging studies showed high tumor uptake, with optimal tumor-to-non target contrast achieved at 7 days post administration. Biodistribution studies demonstrated tumor uptake of 10.5 +/- 1.8 percent injected dose per gram (%ID/g) at 7 days with a tumor to muscle ratio of 13 to 1. In contrast, the peak tumor uptake of the radiolabeled amino acid [(18)F]FET was 4.4 +/- 0.5 %ID/g at 30 min after injection with a tumor to muscle ratio of 1.4 to 1. Blocking studies with unlabeled anti-LAT1 antibody demonstrated a 55% reduction of [(89)Zr]DFO-Ab2 accumulation in the tumor at 7 days. These results are the first report of direct PET imaging of LAT1 and demonstrate the potential of immunoPET agents for imaging specific amino acid transporters. PMID- 24143238 TI - Control of diapause by acidic pH and ammonium accumulation in the hemolymph of Antarctic copepods. AB - Life-cycles of polar herbivorous copepods are characterised by seasonal/ontogenetic vertical migrations and diapause to survive periods of food shortage during the long winter season. However, the triggers of vertical migration and diapause are still far from being understood. In this study, we test the hypothesis that acidic pH and the accumulation of ammonium (NH4 (+)) in the hemolymph contribute to the control of diapause in certain Antarctic copepod species. In a recent study, it was already hypothesized that the replacement of heavy ions by ammonium is necessary for diapausing copepods to achieve neutral buoyancy at overwintering depth. The current article extends the hypothesis of ammonium-aided buoyancy by highlighting recent findings of low pH values in the hemolymph of diapausing copepods with elevated ammonium concentrations. Since ammonia (NH3) is toxic to most organisms, a low hemolymph pH is required to maintain ammonium in the less toxic ionized form (NH4 (+)). Recognizing that low pH values are a relevant factor reducing metabolic rate in other marine invertebrates, the low pH values found in overwintering copepods might not only be a precondition for ammonium accumulation, but in addition, it may insure metabolic depression throughout diapause. PMID- 24143239 TI - Inhibition of human MCF-7 breast cancer cells and HT-29 colon cancer cells by rice-produced recombinant human insulin-like growth binding protein-3 (rhIGFBP 3). AB - BACKGROUND: Insulin-like growth factor binding protein-3 (IGFBP-3) is a multifunctional molecule which is closely related to cell growth, apoptosis, angiogenesis, metabolism and senescence. It combines with insulin-like growth factor-I (IGF-I) to form a complex (IGF-I/IGFBP-3) that can treat growth hormone insensitivity syndrome (GHIS) and reduce insulin requirement in patients with diabetes. IGFBP-3 alone has been shown to have anti-proliferation effect on numerous cancer cells. METHODOLOGY/PRINCIPAL FINDINGS: We reported here an expression method to produce functional recombinant human IGFBP-3 (rhIGFBP-3) in transgenic rice grains. Protein sorting sequences, signal peptide and endoplasmic reticulum retention tetrapeptide (KDEL) were included in constructs for enhancing rhIGFBP-3 expression. Western blot analysis showed that only the constructs with signal peptide were successfully expressed in transgenic rice grains. Both rhIGFBP-3 proteins, with or without KDEL sorting sequence inhibited the growth of MCF-7 human breast cancer cells (65.76 +/- 1.72% vs 45.00 +/- 0.86%, p < 0.05; 50.84 +/- 1.97% vs 45.00 +/- 0.86%, p < 0.01 respectively) and HT-29 colon cancer cells (65.14 +/- 3.84% vs 18.01 +/- 13.81%, p < 0.05 and 54.7 +/- 9.44% vs 18.01 +/- 13.81%, p < 0.05 respectively) when compared with wild type rice. CONCLUSION/SIGNIFICANCE: These findings demonstrated the feasibility of producing biological active rhIGFBP-3 in rice using a transgenic approach, which will definitely encourage more research on the therapeutic use of hIGFBP-3 in future. PMID- 24143240 TI - Allatotropin: an ancestral myotropic neuropeptide involved in feeding. AB - BACKGROUND: Cell-cell interactions are a basic principle for the organization of tissues and organs allowing them to perform integrated functions and to organize themselves spatially and temporally. Peptidic molecules secreted by neurons and epithelial cells play fundamental roles in cell-cell interactions, acting as local neuromodulators, neurohormones, as well as endocrine and paracrine messengers. Allatotropin (AT) is a neuropeptide originally described as a regulator of Juvenile Hormone synthesis, which plays multiple neural, endocrine and myoactive roles in insects and other organisms. METHODS: A combination of immunohistochemistry using AT-antibodies and AT-Qdot nanocrystal conjugates was used to identify immunoreactive nerve cells containing the peptide and epithelial muscular cells targeted by AT in Hydra plagiodesmica. Physiological assays using AT and AT- antibodies revealed that while AT stimulated the extrusion of the hypostome in a dose-response fashion in starved hydroids, the activity of hypostome in hydroids challenged with food was blocked by treatments with different doses of AT-antibodies. CONCLUSIONS: AT antibodies immunolabeled nerve cells in the stalk, pedal disc, tentacles and hypostome. AT-Qdot conjugates recognized epithelial-muscular cell in the same tissues, suggesting the existence of anatomical and functional relationships between these two cell populations. Physiological assays indicated that the AT-like peptide is facilitating food ingestion. SIGNIFICANCE: Immunochemical, physiological and bioinformatics evidence advocates that AT is an ancestral neuropeptide involved in myoregulatory activities associated with meal ingestion and digestion. PMID- 24143241 TI - Using a hazard quotient to evaluate pesticide residues detected in pollen trapped from honey bees (Apis mellifera) in Connecticut. AB - Analysis of pollen trapped from honey bees as they return to their hives provides a method of monitoring fluctuations in one route of pesticide exposure over location and time. We collected pollen from apiaries in five locations in Connecticut, including urban, rural, and mixed agricultural sites, for periods from two to five years. Pollen was analyzed for pesticide residues using a standard extraction method widely used for pesticides (QuEChERS) and liquid chromatography/mass spectrometric analysis. Sixty pesticides or metabolites were detected. Because the dose lethal to 50% of adult worker honey bees (LD50) is the only toxicity parameter available for a wide range of pesticides, and among our pesticides there were contact LD50 values ranging from 0.006 to >1000 MUg per bee (range 166,000X), and even among insecticides LD50 values ranged from 0.006 to 59.8 MUg/bee (10,000X); therefore we propose that in studies of honey bee exposure to pesticides that concentrations be reported as Hazard Quotients as well as in standard concentrations such as parts per billion. We used both contact and oral LD50 values to calculate Pollen Hazard Quotients (PHQ = concentration in ppb / LD50 as MUg/bee) when both were available. In this study, pesticide Pollen Hazard Quotients ranged from over 75,000 to 0.01. The pesticides with the greatest Pollen Hazard Quotients at the maximum concentrations found in our study were (in descending order): phosmet, Imidacloprid, indoxacarb, chlorpyrifos, fipronil, thiamethoxam, azinphos-methyl, and fenthion, all with at least one Pollen Hazard Quotient (using contact or oral LD50) over 500. At the maximum rate of pollen consumption by nurse bees, a Pollen Hazard Quotient of 500 would be approximately equivalent to consuming 0.5% of the LD50 per day. We also present an example of a Nectar Hazard Quotient and the percentage of LD50 per day at the maximum nectar consumption rate. PMID- 24143242 TI - Reaching the ball or missing the flight? Collective dispersal in the two-spotted spider mite Tetranychus urticae. AB - The two-spotted spider mite is a worldwide phytophagous pest displaying a peculiar dispersal. At high density, when plants are exhausted, individuals gather at the plant apex to form a collective silk-ball. This structure can be dispersed by wind or phoresy. Individuals initiating the ball are enclosed in the centre and have a high risk to die. For the first time, the ultimate and proximate mechanisms leading to this group dispersal are examined. To explore if a particular mite genotype was involved in the ball formation, plants were infested with individuals of different genetic background. After the silk-ball formation, the mites in the ball and those remaining on the plant were collected and genotyped. The balls were harvested after 4h and 24h to determine the role of timing between the formation and dispersal on the mortality of mites. Mites do not segregate according to their degree of relatedness, stage, or sex. Mites parallel humans using public transportation: they climb up in the ball whatever their genetic background. Silk-balls composed of unrelated individuals may help avoiding inbreeding when colonizing a new plant. Our results also emphasize the importance of an adequate timing for efficient dispersal between the time spent between ball formation and dispersal. PMID- 24143244 TI - Blueberry and mulberry juice prevent obesity development in C57BL/6 mice. AB - OBJECTIVES: To establish whether blueberry (Vaccinium ashei) and mulberry (Morus australis Poir) juice, anthocyanin rich fruit juice, may help counteract obesity. DESIGN: And Methods: Four-week-old C57BL/6 mice were fed a high-fat diet (HFD) with or without blueberry and mulberry juice for 12 weeks. Body weight, serum and hepatic lipids, liver and adipose tissues morphology, insulin and leptin were assessed. RESULTS: Mice fed HFD exhibited increased body weight, insulin resistance, serum and hepatic lipids. In comparison, blueberry and mulberry juice inhibited body weight gain, decreased the serum cholesterol, reduced the resistance to insulin, attenuated lipid accumulation and decreased the leptin secretin. CONCLUSION: These results indicate that blueberry and mulberry juice may help counteract obesity. PMID- 24143243 TI - High malnutrition rate in Venezuelan Yanomami compared to Warao Amerindians and Creoles: significant associations with intestinal parasites and anemia. AB - BACKGROUND: Children in rural areas experience the interrelated problems of poor growth, anemia and parasitic infections. We investigated the prevalence of and associations between intestinal helminth and protozoan infections, malnutrition and anemia in school-age Venezuelan children. METHODS: This cross-sectional study was conducted in 390 children aged 4-16 years from three rural areas of Venezuela: the Amazon Region, Orinoco Delta and Carabobo State. Stool samples were collected for direct parasitic examinations. Anthropometric indicators of chronic (height-for-age Z score) and acute (weight-for-height and Body Mass Index (BMI)-for-age Z score in respectively children under 5 years of age and children aged 5 years and above) malnutrition were calculated. Multivariate linear and logistic regression models were built to determine factors associated with nutritional status and polyparasitism. RESULTS: Hookworm and Strongyloides stercoralis prevalences were highest in children from the Amazon rainforest (respectively 72% and 18%) while children from the Orinoco Delta and Carabobo State showed higher rates of Ascaris lumbricoides (respectively 28% and 37%) and Trichuris trichiura (40% in both regions). The prevalence of Giardia lamblia infection was not significantly different between regions (average: 18%). Anemia prevalence was highest in the Amazon Region (24%). Hemoglobin levels were significantly decreased in children with a hookworm infection. Malnutrition was present in respectively 84%, 30% and 13% of children from the Amazon Region, Orinoco Delta and Carabobo State. In multivariate analysis including all regions, G. lamblia and helminth infections were significantly and negatively associated with respectively height-for-age and weight-for-height/BMI-for-age Z scores. Furthermore, hemoglobin levels were positively associated with the height-for-age Z score (0.11, 95% CI 0.02 - 0.20). CONCLUSIONS: In rural populations in Venezuela helminthiasis and giardiasis were associated with acute and chronic nutritional status respectively. These data highlight the need for an integrated approach to control transmission of parasites and improve the health status of rural Venezuelan children. PMID- 24143245 TI - 'Clustering' SIRPalpha into the plasma membrane lipid microdomains is required for activated monocytes and macrophages to mediate effective cell surface interactions with CD47. AB - SIRPalpha, an ITIMs-containing signaling receptor, negatively regulates leukocyte responses through extracellular interactions with CD47. However, the dynamics of SIRPalpha-CD47 interactions on the cell surface and the governing mechanisms remain unclear. Here we report that while the purified SIRPalpha binds to CD47 and that SIRPalpha is expressed on monocytes and monocytic THP-1 or U937, these SIRPalpha are ineffective to mediate cell binding to immobilized CD47. However, cell binding to CD47 is significantly enhanced when monocytes transmigrating across endothelia, or being differentiated into macrophages. Cell surface labeling reveals SIRPalpha to be diffused on naive monocytes but highly clustered on transmigrated monocytes and macrophages. Protein crosslink and equilibrium centrifugation confirm that SIRPalpha in the latter cells forms oligomerized complexes resulting in increased avidity for CD47 binding. Furthermore, formation of SIRPalpha complexes/clusters requires the plasma membrane 'lipid rafts' and the activity of Src family kinase during macrophage differentiation. These results together suggest that 'clustering' SIRPalpha into plasma membrane microdomains is essential for activated monocytes and macrophages to effectively interact with CD47 and initiate intracellular signaling. PMID- 24143246 TI - Sleep improves prospective remembering by facilitating spontaneous-associative retrieval processes. AB - Memories are of the past but for the future, enabling individuals to implement intended plans and actions at the appropriate time. Prospective memory is the specific ability to remember and execute an intended behavior at some designated point in the future. Although sleep is well-known to benefit the consolidation of memories for past events, its role for prospective memory is still not well understood. Here, we show that sleep as compared to wakefulness after prospective memory instruction enhanced the successful execution of prospective memories two days later. We further show that sleep benefited both components of prospective memory, i.e. to remember that something has to be done (prospective component) and to remember what has to be done (retrospective component). Finally, sleep enhanced prospective remembering particularly when attentional resources were reduced during task execution, suggesting that subjects after sleep were able to recruit additional spontaneous-associative retrieval processes to remember intentions successfully. Our findings indicate that sleep supports the maintenance of prospective memory over time by strengthening intentional memory representations, thus favoring the spontaneous retrieval of the intended action at the appropriate time. PMID- 24143247 TI - A plant kavalactone desmethoxyyangonin prevents inflammation and fulminant hepatitis in mice. AB - Alpinia pricei Hayata is a Formosan plant which has been popularly used as nutraceutical or folk medicine for inflammation and various disorders. An active compound of the plant rhizomes, desmethoxyyangonin (DMY), was identified in this study for its novel effect against endotoxin lipopolysaccharide (LPS)-stimulated inflammation in murine macrophages and LPS/D-galactosamine (LPS/D-GalN)-induced fulminant hepatitis in mice. DMY was observed to significantly inhibit proliferation and activation of T cells ex vivo and the activity of several pro inflammatory mediators in vitro. DMY also protected LPS/D-GalN-induced acute hepatic damages in mice through inhibiting aminotransferases activities and infiltrations of inflammatory macrophages, neutrophils and pathogenic T cells into the liver tissues. In addition, pretreatment with DMY significantly improved the survival rate of LPS/D-GalN-treated mice to 90% (9/10), compared to LPS/D GalN-treated group (40%, 4/10). UPLC/MS platform-based comparative metabolomics approach was used to explore the serum metabolic profile in fulminant hepatic failure (FHF) mice with or without the DMY pretreatment. The results showed that LPS/D-GalN-induced hepatic damage is likely through perturbing amino acid metabolism, which leads to decreased pyruvate formation via catalysis of aminotransferases, and DMY treatment can prevent to a certain degree of these alterations in metabolic network in mouse caused by LPS/D-GalN. Mechanistic investigation demonstrated that DMY protects LPS or LPS/D-GalN-induced damages in cell or liver tissues mainly through de-regulating IKK/NFkappaB and Jak2/STAT3 signaling pathways. This report provides evidence-based knowledge to support the rationale for the use of A. pricei root extract in anti-inflammation and also its new function as hepatoprotetive agent against fulminant hepatitis. PMID- 24143248 TI - Accelerated activation of SOCE current in myotubes from two mouse models of anesthetic- and heat-induced sudden death. AB - Store-operated calcium entry (SOCE) channels play an important role in Ca(2+) signaling. Recently, excessive SOCE was proposed to play a central role in the pathogenesis of malignant hyperthermia (MH), a pharmacogenic disorder of skeletal muscle. We tested this hypothesis by characterizing SOCE current (ISkCRAC) magnitude, voltage dependence, and rate of activation in myotubes derived from two mouse models of anesthetic- and heat-induced sudden death: 1) type 1 ryanodine receptor (RyR1) knock-in mice (Y524S/+) and 2) calsequestrin 1 and 2 double knock-out (dCasq-null) mice. ISkCRAC voltage dependence and magnitude at 80 mV were not significantly different in myotubes derived from wild type (WT), Y524S/+ and dCasq-null mice. However, the rate of ISkCRAC activation upon repetitive depolarization was significantly faster at room temperature in myotubes from Y524S/+ and dCasq-null mice. In addition, the maximum rate of ISkCRAC activation in dCasq-null myotubes was also faster than WT at more physiological temperatures (35-37 degrees C). Azumolene (50 uM), a more water soluble analog of dantrolene that is used to reverse MH crises, failed to alter ISkCRAC density or rate of activation. Together, these results indicate that while an increased rate of ISkCRAC activation is a common characteristic of myotubes derived from Y524S/+ and dCasq-null mice and that the protective effects of azumolene are not due to a direct inhibition of SOCE channels. PMID- 24143249 TI - High postoperative serum cortisol level is associated with increased risk of cognitive dysfunction early after coronary artery bypass graft surgery: a prospective cohort study. AB - CONTEXT: Stress response induced by surgery is proposed to play an important role in the pathogenesis of postoperative cognitive dysfunction. OBJECTIVE: To investigate the association between postoperative serum cortisol level and occurrence of cognitive dysfunction early after coronary artery bypass graft surgery. DESIGN: Prospective cohort study. SETTING: Two teaching hospitals. PATIENTS: One hundred and sixth-six adult patients who were referred to elective coronary artery bypass graft surgery from March 2008 to December 2009. INTERVENTION: None. MAIN OUTCOME MEASURES: Neuropsychological tests were completed one day before and seven days after surgery. Cognitive dysfunction was defined using the same definition as used in the ISPOCD1-study. Blood samples were obtained in the first postoperative morning for measurement of serum cortisol concentration. Multivariate Logistic regression analyses were performed to assess the relationship between serum cortisol level and occurrence of postoperative cognitive dysfunction. RESULTS: Cognitive dysfunction occurred in 39.8% (66 of 166) of patients seven days after surgery. Multivariate Logistic regression analysis showed that high serum cortisol level was significantly associated with the occurrence of postoperative cognitive dysfunction (odds ratio [OR] 2.603, 95% confidence interval [CI] 1.371-4.944, P = 0.003). Other independent predictors of early postoperative cognitive dysfunction included high preoperative New York Heart Association functional class (OR 0.402, 95% CI 0.207 0.782, P = 0.007), poor preoperative Grooved Pegboard test score of nondominant hand (OR 1.022, 95% CI 1.003-1.040, P = 0.020), use of penehyclidine as premedication (OR 2.565, 95% CI 1.109-5.933, P = 0.028), and occurrence of complications within seven days after surgery (OR 2.677, 95% CI 1.201-5.963, P = 0.016). CONCLUSIONS: High serum cortisol level in the first postoperative morning was associated with increased risk of cognitive dysfunction seven days after coronary artery bypass graft surgery. PMID- 24143250 TI - Reliability of school surveys in estimating geographic variation in malaria transmission in the western Kenyan highlands. AB - BACKGROUND: School surveys provide an operational approach to assess malaria transmission through parasite prevalence. There is limited evidence on the comparability of prevalence estimates obtained from school and community surveys carried out at the same locality. METHODS: Concurrent school and community cross sectional surveys were conducted in 46 school/community clusters in the western Kenyan highlands and households of school children were geolocated. Malaria was assessed by rapid diagnostic test (RDT) and combined seroprevalence of antibodies to bloodstage Plasmodium falciparum antigens. RESULTS: RDT prevalence in school and community populations was 25.7% (95% CI: 24.4-26.8) and 15.5% (95% CI: 14.4 16.7), respectively. Seroprevalence in the school and community populations was 51.9% (95% CI: 50.5-53.3) and 51.5% (95% CI: 49.5-52.9), respectively. RDT prevalence in schools could differentiate between low (<7%, 95% CI: 0-19%) and high (>39%, 95% CI: 25-49%) transmission areas in the community and, after a simple adjustment, were concordant with the community estimates. CONCLUSIONS: Estimates of malaria prevalence from school surveys were consistently higher than those from community surveys and were strongly correlated. School-based estimates can be used as a reliable indicator of malaria transmission intensity in the wider community and may provide a basis for identifying priority areas for malaria control. PMID- 24143251 TI - A detailed epidemiological and clinical description of 6 human cases of avian origin influenza A (H7N9) virus infection in Shanghai. AB - BACKGROUND: The world's first reported patient infected with avian influenza H7N9 was treated at the Fifth People's Hospital of Shanghai. Shortly thereafter, several other cases emerged in the local area. Here, we describe the detailed epidemiological and clinical data of 6 cases of avian influenza H7N9. METHODS AND FINDINGS: We analyzed the epidemiologic and clinical data from clustered patients infected with H7N9 in the Minhang District of Shanghai during a 2-week period. Of the 6 patients, 2 were from a single family. In addition, 3 patients had a history of contact with poultry; however, all 6 patients lived in the proximity of 2 food markets where the H7N9 virus was detected in chickens and pigeons. The main symptoms were fever, cough, and hemoptysis. At onset, a decreased lymphocyte count and elevated creatine kinase, lactate dehydrogenase, procalcitonin, and C reactive protein levels were observed. As the disease progressed, most patients developed dyspnea and hypoxemia. Imaging studies revealed lung consolidation and multiple ground-glass opacities in the early stage, rapidly extending bilaterally. All patients were treated with oseltamivir tablets beginning on days 3-8 after onset. The main complications were as follows: acute respiratory distress syndrome (ARDS; 83.3%), secondary bacterial infection (66.7%), pleural effusion (50%), left ventricular failure (33.3%), neuropsychiatric symptoms (33.3%), and rhabdomyolysis (16.7%). Of the 6 patients, 4 died of ARDS, with 2 patients recovering from the infection. CONCLUSIONS: An outbreak of H7N9 infection occurred in the Minhang District of Shanghai that easily progressed to acute respiratory distress syndrome. Two cases showed family aggregation, which led us to identify the H7N9 virus and indicated that human transmission may be involved in the spread of this infection. PMID- 24143252 TI - The use of molecular analyses in voided urine for the assessment of patients with hematuria. AB - INTRODUCTION: Patients presenting with painless hematuria form a large part of the urological patient population. In many cases, especially in younger patients, the cause of hematuria is harmless. Nonetheless, hematuria could be a symptom of malignant disease and hence most patients will be subject to cystoscopy. In this study, we aimed to develop a prediction model based on methylation markers in combination with clinical variables, in order to stratify patients with high risk for bladder cancer. MATERIAL AND METHODS: Patients (n=169) presenting with painless hematuria were included. 54 patients were diagnosed with bladder cancer. In the remaining 115 patients, the cause of hematuria was non-malignant. Urine samples were collected prior to cystoscopy. Urine DNA was analyzed for methylation of OSR1, SIM2, OTX1, MEIS1 and ONECUT2. Methylation percentages were calculated and were combined with clinical variables into a logistic regression model. RESULTS: Logistic regression analysis based on the five methylation markers, age, gender and type of hematuria resulted in an area under the curve (AUC) of 0.88 and an optimism corrected AUC of 0.84 after internal validation by bootstrapping. Using a cut-off value of 0.307 allowed stratification of patients in a low-risk and high-risk group, resulting in a sensitivity of 82% (44/54) and a specificity of 82% (94/115). Most aggressive tumors were found in patients in the high-risk group. The addition of cytology to the prediction model, improved the AUC from 0.88 to 0.89, with a sensitivity and specificity of 85% (39/46) and 87% (80/92), retrospectively. CONCLUSIONS: This newly developed prediction model could be a helpful tool in risk stratification of patients presenting with painless hematuria. Accurate risk prediction might result in less extensive examination of low risk patients and thereby, reducing patient burden and costs. Further validation in a large prospective patient cohort is necessary to prove the true clinical value of this model. PMID- 24143253 TI - MADM-ML, a mouse genetic mosaic system with increased clonal efficiency. AB - Mosaic Analysis with Double Markers (MADM) is a mouse genetic system that allows simultaneous gene knockout and fluorescent labeling of sparse, clonally-related cells within an otherwise normal mouse, thereby circumventing embryonic lethality problems and providing single-cell resolution for phenotypic analysis in vivo. The clonal efficiency of MADM is intrinsically low because it relies on Cre/loxP mediated mitotic recombination between two homologous chromosomes rather than within the same chromosome, as in the case of conditional knockout (CKO). Although sparse labeling enhances in vivo resolution, the original MADM labels too few or even no cells when a low-expressing Cre transgene is used or a small population of cells is studied. Recently, we described the usage of a new system, MADM-ML, which contains three mutually exclusive, self-recognizing loxP variant sites as opposed to a single loxP site present in the original MADM system (referred to as MADM-SL in this paper). Here we carefully compared the recombination efficiency between MADM-SL and MADM-ML using the same Cre transgene, and found that the new system labels significantly more cells than the original system does. When we established mouse medulloblastoma models with both the original and the new MADM systems, we found that, while the MADM-SL model suffered from varied tumor progression and incomplete penetrance, the MADM-ML model had consistent tumor progression and full penetrance of tumor formation. Therefore MADM-ML, with its higher recombination efficiency, will broaden the applicability of MADM for studying many biological questions including normal development and disease modeling at cellular resolution in vivo. PMID- 24143254 TI - Validation of three early ejaculation diagnostic tools: a composite measure is accurate and more adequate for diagnosis by updated diagnostic criteria. AB - PURPOSE: To validate three early ejaculation diagnostic tools, and propose a new tool for diagnosis in line with proposed changes to diagnostic criteria. Significant changes to diagnostic criteria are expected in the near future. Available screening tools do not necessarily reflect proposed changes. MATERIALS AND METHODS: Data from 148 diagnosed early ejaculation patients (M age = 42.8) and 892 controls (M age = 33.1 years) from a population-based sample were used. Participants responded to three different questionnaires (Premature Ejaculation Profile; Premature Ejaculation Diagnostic Tool; Multiple Indicators of Premature Ejaculation). Stopwatch measured ejaculation latency times were collected from a subsample of early ejaculation patients. We used two types of responses to the questionnaires depending on the treatment status of the patients 1) responses regarding the situation before starting pharmacological treatment and 2) responses regarding current situation. Logistic regressions and Receiver Operating Characteristics were used to assess ability of both the instruments and individual items to differentiate between patients and controls. RESULTS: All instruments had very good precision (Areas under the Curve ranging from .93-.98). A new five-item instrument (named CHecklist for Early Ejaculation Symptoms - CHEES) consisting of high-performance variables selected from the three instruments had validity (Nagelkerke R (2) range .51-.79 for backwards/forwards logistic regression) equal to or slightly better than any individual instrument (i.e., had slightly higher validity statistics, but these differences did not achieve statistical significance). Importantly, however, this instrument was more in line with proposed changes to diagnostic criteria. CONCLUSIONS: All three screening tools had good validity. A new 5-item diagnostic tool (CHEES) based on the three instruments had equal or somewhat more favorable validity statistics compared to the other three tools, but is more in line with recently proposed diagnostic criteria. PMID- 24143255 TI - Contributions of the complementarity determining regions to the thermal stability of a single-domain antibody. AB - Single domain antibodies (sdAbs) are the recombinantly-expressed variable domain from camelid (or shark) heavy chain only antibodies and provide rugged recognition elements. Many sdAbs possess excellent affinity and specificity; most refold and are able to bind antigen after thermal denaturation. The sdAb A3, specific for the toxin Staphylococcal enterotoxin B (SEB), shows both sub nanomolar affinity for its cognate antigen (0.14 nM) and an unusually high melting point of 85 degrees C. Understanding the source of sdAb A3's high melting temperature could provide a route for engineering improved melting temperatures into other sdAbs. The goal of this work was to determine how much of sdAb A3's stability is derived from its complementarity determining regions (CDRs) versus its framework. Towards answering this question we constructed a series of CDR swap mutants in which the CDRs from unrelated sdAbs were integrated into A3's framework and where A3's CDRs were integrated into the framework of the other sdAbs. All three CDRs from A3 were moved to the frameworks of sdAb D1 (a ricin binder that melts at 50 degrees C) and the anti-ricin sdAb C8 (melting point of 60 degrees C). Similarly, the CDRs from sdAb D1 and sdAb C8 were moved to the sdAb A3 framework. In addition individual CDRs of sdAb A3 and sdAb D1 were swapped. Melting temperature and binding ability were assessed for each of the CDR-exchange mutants. This work showed that CDR2 plays a critical role in sdAb A3's binding and stability. Overall, results from the CDR swaps indicate CDR interactions play a major role in the protein stability. PMID- 24143256 TI - OTUD5 regulates p53 stability by deubiquitinating p53. AB - BACKGROUND: The p53 tumour suppressor protein is a transcription factor that prevents oncogenic progression by activating the expression of apoptosis and cell cycle arrest genes in stressed cells. The stability of p53 is tightly regulated by ubiquitin-dependent degradation, driven mainly by its negative regulators ubiquitin ligase MDM2. PRINCIPAL FINDINGS: In this study, we have identified OTUD5 as a DUB that interacts with and deubiquitinates p53. OTUD5 forms a direct complex with p53 and controls level of ubiquitination. The function of OTUD5 is required to allow the rapid activation of p53-dependent transcription and a p53 dependent apoptosis in response to DNA damage stress. CONCLUSIONS: As a novel deubiquitinating enzyme for p53, OTUD5 is required for the stabilization and the activation of a p53 response. PMID- 24143257 TI - Combining different mRNA capture methods to analyze the transcriptome: analysis of the Xenopus laevis transcriptome. AB - mRNA sequencing (mRNA-seq) is a commonly used technique to survey gene expression from organisms with fully sequenced genomes. Successful mRNA-seq requires purification of mRNA away from the much more abundant ribosomal RNA, which is typically accomplished by oligo-dT selection. However, mRNAs with short poly-A tails are captured poorly by oligo-dT based methods. We demonstrate that combining mRNA capture via oligo-dT with mRNA capture by the 5' 7-methyl guanosine cap provides a more complete view of the transcriptome and can be used to assay changes in mRNA poly-A tail length on a genome-wide scale. We also show that using mRNA-seq reads from both capture methods as input for de novo assemblers provides a more complete reconstruction of the transcriptome than either method used alone. We apply these methods of mRNA capture and de novo assembly to the transcriptome of Xenopus laevis, a well-studied frog that currently lacks a finished sequenced genome, to discover transcript sequences for thousands of mRNAs that are currently absent from public databases. The methods we describe here will be broadly applicable to many organisms and will provide insight into the transcriptomes of organisms with sequenced and unsequenced genomes. PMID- 24143258 TI - Environmental conditions during breeding modify the strength of mass-dependent carry-over effects in a migratory bird. AB - In many animals, processes occurring in one season carry over to influence reproductive success and survival in future seasons. The strength of such carry over effects is unlikely to be uniform across years, yet our understanding of the processes that are capable of modifying their strength remains limited. Here we show that female light-bellied Brent geese with higher body mass prior to spring migration successfully reared more offspring during breeding, but only in years where environmental conditions during breeding were favourable. In years of bad weather during breeding, all birds suffered reduced reproductive output irrespective of pre-migration mass. Our results suggest that the magnitude of reproductive benefits gained by maximising body stores to fuel breeding fluctuates markedly among years in concert with conditions during the breeding season, as does the degree to which carry-over effects are capable of driving variance in reproductive success among individuals. Therefore while carry-over effects have considerable power to drive fitness asymmetries among individuals, our ability to interpret these effects in terms of their implications for population dynamics is dependent on knowledge of fitness determinants occurring in subsequent seasons. PMID- 24143259 TI - Disulfide scrambling in superoxide dismutase 1 reduces its cytotoxic effect in cultured cells and promotes protein aggregation. AB - Mutations in the gene coding for superoxide dismutase 1 (SOD1) are associated with familiar forms of the neurodegenerative disease amyotrophic lateral sclerosis (ALS). These mutations are believed to result in a "gain of toxic function", leading to neuronal degeneration. The exact mechanism is still unknown, but misfolding/aggregation events are generally acknowledged as important pathological events in this process. Recently, we observed that demetallated apoSOD1, with cysteine 6 and 111 substituted for alanine, is toxic to cultured neuroblastoma cells. This toxicity depended on an intact, high affinity Zn(2+) site. It was therefor contradictory to discover that wild-type apoSOD1 was not toxic, despite of its high affinity for Zn(2+). This inconsistency was hypothesized to originate from erroneous disulfide formation involving C6 and C111. Using high resolution non-reducing SDS-PAGE, we have in this study demonstrated that the inability of wild-type apoSOD1 to cause cell death stems from formation of non-native intra-molecular disulfides. Moreover, monomeric apoSOD1 variants capable of such disulfide scrambling aggregated into ThT positive oligomers under physiological conditions without agitation. The oligomers were stabilized by inter-molecular disulfides and morphologically resembled what has in other neurodegenerative diseases been termed protofibrils. Disulfide scrambling thus appears to be an important event for misfolding and aggregation of SOD1, but may also be significant for protein function involving cysteines, e.g. mitochondrial import and copper loading. PMID- 24143260 TI - The effect of tuberculosis treatment at combination antiretroviral therapy initiation on subsequent mortality: a systematic review and meta-analysis. AB - OBJECTIVE: We aimed to perform a systematic review and meta-analysis examining the impact of TB treatment at the time of combination antiretroviral therapy (cART) initiation on subsequent mortality. METHODS: We searched PubMed, EMBASE, and selected conference proceedings for studies that report adult mortality on cART, stratified by TB treatment status at cART initiation. Stratified random effects and meta-regression analyses were used to examine the influence of study and population characteristics. RESULTS: 22 eligible cohort studies reported data on 98,350 (range 74-15,225) adults, of whom 14,779 (15%) were receiving TB treatment at cART initiation. Studies of those receiving vs. not receiving TB treatment had an average mortality relative risk of 1.10 (95% confidence interval 0.87-1.40) at 1-3 months (based upon 8 estimates), 1.15 (0.94-1.41) at 6-12 months (11 estimates), and 1.33 (1.02-1.75) at 18-98 months (10 estimates) following cART initiation. However, there was a wide range of estimates and those at later time points were markedly heterogeneous. Meta-regression identified factors associated with elevated average risk estimates: lower median baseline CD4 counts and adjustment for baseline hemoglobin at 1-3 months; longer length of follow-up and women-only studies at 6-12 months; and not adjusting for BMI/weight at 18-98 months. CONCLUSIONS: Patients receiving TB treatment at cART initiation did not have a statistically significant estimated increase in short-term risk of all-cause mortality as compared to those not receiving TB treatment. TB treatment was significantly associated with increased mortality after about a year of cART, suggesting that patients with concurrent TB treatment at cART initiation may benefit from continued support after TB treatment completion. PMID- 24143262 TI - Experimental glomerular endothelial injury in vivo. AB - The microvascular endothelium of the kidney glomerulus is injured in Shiga-like toxigenic bacterial infection, genetic or acquired loss of complement regulatory protein function, and allo-immune responses of solid-organ or bone marrow transplantation. Existing models of diseases with glomerular endothelial cell (EC) injury, collectively grouped as thrombotic microangiopathies, are problematic, impeding investigation of the mechanisms of microvascular defense and repair. To develop a model of glomerular endothelial injury in the mouse, we conjugated the M. oreades lectin to the cytotoxin, saporin, (LS) to selectively injure the glomerular endothelium. Injury of the microvasculature was evaluated by light, immunofluorescence, and electron microscopy, and by quantitative RT-PCR of cell-type specific transcripts. Renal function was evaluated by quantitation of serum creatinine. The toxin conjugate induced apoptosis of microvascular ECs in vitro, and subtle histologic features of thrombotic microangiopathy in vivo that were enhanced by co-injection of 50 MUg/kg LPS. Among LS/LPS-treated animals, loss of glomerular EC staining correlated with decreased expression of EC-specific transcripts, and impaired kidney function. Selective injury of the glomerular microvasculature with LS toxin conjugate and LPS elicits histologic features of thrombotic microangiopathy and acute kidney failure. PMID- 24143263 TI - The lesser of two weevils: molecular-genetics of pest palm weevil populations confirm Rhynchophorus vulneratus (Panzer 1798) as a valid species distinct from R. ferrugineus (Olivier 1790), and reveal the global extent of both. AB - The red palm weevil (RPW) is a major pest of palms. It is native to southeast Asia and Melanesia, but in recent decades has vastly expanded its range as the result of multiple accidental anthropogenic introductions into the Middle East, Mediterranean Basin, Caribbean, and U.S.A. Currently regarded as a single species, Rhynchophorus ferrugineus (Olivier), RPW displays remarkable color variation across its range, and consequently has a taxonomic history littered with new species descriptions and synonymization. We compared DNA sequences of the mitochondrial cytochrome oxidase subunit I (COI) gene from RPW populations throughout the native and invaded ranges, to investigate the specific status and invasion history of this serious economic pest, and to identify possible common routes of entry. Analyses of COI haplotype data provide conclusive support, corroborated by sequences of additional nuclear gene regions, for the existence of at least two predominantly allopatric species. The true R. ferrugineus is native only to the northern and western parts of continental southeast Asia, Sri Lanka and the Philippines, and is responsible for almost all invasive populations worldwide. In contrast, the second species, which is currently synonymized under R. ferrugineus and should be resurrected under the name R. vulneratus (Panzer), has a more southern distribution across Indonesia, and is responsible for only one invasive population; that in California, U.S.A. The distribution of COI haplotypes is used to discuss the possible existence of further cryptic species, sources and routes of entry of different invasive populations, and the implications of our findings for current control methods. PMID- 24143261 TI - The mitochondrial RNA landscape of Saccharomyces cerevisiae. AB - Mitochondria are essential organelles that harbor a reduced genome, and expression of that genome requires regulated metabolism of its transcriptome by nuclear-encoded proteins. Despite extensive investigation, a comprehensive map of the yeast mitochondrial transcriptome has not been developed and all of the RNA metabolizing proteins have not been identified, both of which are prerequisites to elucidating the basic RNA biology of mitochondria. Here, we present a mitochondrial transcriptome map of the yeast S288C reference strain. Using RNAseq and bioinformatics, we show the expression level of all transcripts, revise all promoter, origin of replication, and tRNA annotations, and demonstrate for the first time the existence of alternative splicing, mirror RNAs, and a novel RNA processing site in yeast mitochondria. The transcriptome map has revealed new aspects of mitochondrial RNA biology and we expect it will serve as a valuable resource. As a complement to the map, we present our compilation of all known yeast nuclear-encoded ribonucleases (RNases), and a screen of this dataset for those that are imported into mitochondria. We sought to identify RNases that are refractory to recovery in traditional mitochondrial screens due to an essential function or eclipsed accumulation in another cellular compartment. Using this in silico approach, the essential RNase of the nuclear and cytoplasmic exosome, Dis3p, emerges as a strong candidate. Bioinformatics and in vivo analyses show that Dis3p has a conserved and functional mitochondrial-targeting signal (MTS). A clean and marker-less chromosomal deletion of the Dis3p MTS results in a defect in the decay of intron and mirror RNAs, thus revealing a role for Dis3p in mitochondrial RNA decay. PMID- 24143264 TI - Ultraviolet-B wavelengths regulate changes in UV absorption of cleaner fish Labroides dimidiatus mucus. AB - High-energy wavelengths in the ultraviolet-B (UVB, 280-315 nm) and the UVA (315 400-nm) portion of the spectrum are harmful to terrestrial and aquatic organisms. Interestingly, UVA is also involved in the repair of UV induced damage. Organisms living in shallow coral reef environments possess UV absorbing compounds, such as mycosporine-like amino acids, to protect them from UV radiation. While it has been demonstrated that exposure to UV (280-400 nm) affects the UV absorbance of fish mucus, whether the effects of UV exposure vary between UVB and UVA wavelengths is not known. Therefore, we investigated whether the UVB, UVA, or photosynthetically active radiation (PAR, 400-700 nm) portions of the spectrum affected the UV absorbance of epithelial mucus and Fulton's body condition index of the cleaner fish Labroides dimidiatus. We also compared field-measured UV absorbance with laboratory based high-performance liquid chromatography measurements of mycosporine-like amino acid concentrations. After 1 week, we found that the UV absorbance of epithelial mucus was higher in the UVB+UVA+PAR treatment compared with the UVA+PAR and PAR only treatments; after 2 and 3 weeks, however, differences between treatments were not detected. After 3 weeks, Fulton's body condition index was lower for fish in the UVB+UVA+PAR compared with PAR and UVA+PAR treatments; furthermore, all experimentally treated fish had a lower Fulton's body condition index than did freshly caught fish. Finally, we found a decrease with depth in the UV absorbance of mucus of wild-caught fish. This study suggests that the increase in UV absorbance of fish mucus in response to increased overall UV levels is a function of the UVB portion of the spectrum. This has important implications for the ability of cleaner fish and other fishes to adjust their mucus UV protection in response to variations in environmental UV exposure. PMID- 24143265 TI - Ultrastructural damage of Loligo vulgaris and Illex coindetii statocysts after low frequency sound exposure. AB - There is a considerable lack of information concerning marine invertebrate sensitivity to sound exposure. However, recent findings on cuttlefish and octopi showed that exposure to artificial noise had a direct consequence on the functionality and physiology of the statocysts, sensory organs, which are responsible for their equilibrium and movements in the water column. Owing to a lack of available data on deep diving cephalopod species, we conducted a noise exposure comparative experiment on one Mediterranean squid, Illex coindetii, and on the European squid Loligo vulgaris. Scanning electron microscopy (SEM) revealed similar injuries in the inner structure of the statocysts, as those found in cuttlefish and octopi. In addition to the ultrastructural description of the lesions, we publish here the first images of the crista-cupula system and inner statocyst cavity of I. coindetii. PMID- 24143266 TI - Three-dimensional spectral domain optical coherence tomography of retina in choroidal metastasis due to breast and lung carcinoma. PMID- 24143267 TI - Unraveling the Primary Isomerization Dynamics in Cyanobacterial Phytochrome Cph1 with Multi-pulse Manipulations. AB - The ultrafast mechanisms underlying the initial photoisomerization (Pr -> Lumi-R) in the forward reaction of the cyanobacterial photoreceptor Cph1 were explored with multipulse pump-dump-probe transient spectroscopy. A recently postulated multi-population model was used to fit the transient pump-dump-probe and dump induced depletion signals. We observed dump-induced depletion of the Lumi-R photoproduct, demonstrating that photoisomerization occurs via evolution on both the excited- and ground-state electronic surfaces. Excited-state equilibrium was not observed, as shown via the absence of a dump-induced excited-state "Le Chatelier redistribution" of excited-state populations. The importance of incorporating the inhomogeneous dynamics of Cph1 in interpreting measured transient data is discussed. PMID- 24143268 TI - Magnetic Field Effects on Triplet-Triplet Annihilation in Solutions: Modulation of Visible/NIR Luminescence. AB - Photon upconversion based on sensitized triplet-triplet annihilation (TTA) presents interest for such areas as photovoltaics and imaging. Usually energy upconversion is observed as p-type delayed fluorescence from molecules whose triplet states are populated via energy transfer from a suitable triplet donor, followed by TTA. Magnetic field effects (MFE) on delayed fluorescence in molecular crystals are well known; however, there exist only a few examples of MFE on TTA in solutions, and all of them are limited to UV-emitting materials. Here we present MFE on TTA-mediated visible and near infrared (NIR) emission, sensitized by far-red absorbing metalloporphyrins in solutions at room temperature. In addition to visible delayed fluorescence from annihilator, we also observed NIR emission from the sensitizer, occurring as a result of triplet triplet energy transfer back from annihilator, termed "delayed phosphorescence". This emission also exhibits MFE, but opposite in sign to the annihilator fluorescence. PMID- 24143269 TI - Detailed Examination of a Single Conduction Event in a Potassium Channel. AB - Although extensively studied, it has proved difficult to describe in detail how potassium ion channels conduct cations and water. We present a computational study that, by using stratified umbrella sampling, examines nearly an entire conduction event of the Kv1.2/2.1 paddle chimera and thereby identifies the expected stable configurations of ions and waters in the selectivity filter of the channel. We describe in detail the motions of the ions and waters during a conduction event, focusing on how waters and ions enter the filter, the rotation of water molecules inside the filter, and how potassium ions are coordinated as they move from a water to a protein environment. Finally, we analyze the small conformational changes undergone by the protein, showing that the stable configurations are most similar to the experimental crystal structure. PMID- 24143270 TI - Influence of losartan on the hypoglycemic activity of glimepiride in normal and diabetic rats. AB - BACKGROUND: The influence of losartan on the hypoglycemic effect of glimepiride was studied in normal and diabetic rats. METHOD: Losartan and glimepiride were studied at a dose of 4.5 and 0.09 mg/kg and in normal and diabetic rats, respectively. The blood samples were collected at 0, 1, 2, 3, 4, 6, 8, 10, 12, and 16 hours and analyzed for glucose levels using a glucometer. RESULTS: Glimepiride exhibited a maximum reduction of blood glucose levels at the 4th hour in normal and diabetic rats. The maximum hypoglycemic effect was observed at the 6th hour in normal rats treated with losartan. In normal rats, losartan did not have any significant effect on the hypoglycemic activity of glimepiride in either the single- or multiple-dose interaction study. In the case of diabetic rats, losartan did not have any significant effect on the hypoglycemic activity of glimepiride in the single-dose interaction study, but a significant change was observed in the multiple-dose study of diabetic rats. Hence, the interaction was found to be pharmacodynamic. CONCLUSIONS: The study indicates that chronic losartan pretreatment elevates the hypoglycemic effect of glimepiride by a possible rise in insulin sensitivity and improving insulin homeostasis or may be due to the inhibition of CYP2C9. The study also suggests that caution may be recommended concerning combined use of losartan and an oral hypoglycemic agent, glimepiride. PMID- 24143271 TI - The role of direct renin inhibitors in the treatment of the hypertensive diabetic patient. AB - Hypertensive patients with diabetes exhibit an increased risk for cardiovascular complications, such as acute coronary syndrome, stroke, heart failure and chronic kidney disease (CKD). These two chronic diseases are linked to a high rate of morbidity and mortality and for this reason it is important for the clinician to recognize the need for effective treatment of hypertension, which can require combination therapy to achieve blood pressure (BP) goals. Direct renin inhibitors (DRIs) may be useful in combination with angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin II receptor blockers (ARBs) as they provide a more complete blockade of the renin-angiotensin-aldosterone system (RAAS), effectively suppressing residual angiotensin II production and the counter-regulatory increase in plasma renin activity observed in patients receiving monotherapy with ACEIs or ARBs. Some questions regarding the action of aliskiren in cardiovascular and renal disorders are open. In particular, the combination therapy of aliskiren and a RAAS blocker in diabetic hypertensive patients with CKD is controversial. Several published studies demonstrated that aliskiren is suitable for once-daily administration and its antihypertensive effect is comparable or superior to that of other antihypertensive agents at recommended doses, with a good tolerability profile. At the moment the association with ACEIs and ARBs is not recommended in patients with type 2 diabetes mellitus (T2DM) and renal impairment even if a recent published open-label study of low-dose aliskiren (150 mg/daily) in association with ACEIs or ARBs has demonstrated a good tolerability profile without the adverse events found in other studies. This review provides a brief overview of RAAS blocking, in particular the rationale and clinical evidence supporting the use of the DRI aliskiren, in high-risk patients with T2DM. PMID- 24143272 TI - Fluorescently tagged Lin7c is a dynamic marker for polarity maturation in the zebrafish retinal epithelium. AB - Development of epithelial cell polarity is a highly dynamic process, and often established by the sequential recruitment of conserved protein complexes, such as the Par or the Crumbs (Crb) complex. However, detailed insights into the refinement of polarity and the formation of the complexes are still lacking. Here, we established fluorescently tagged Lin7c, a core member of the Crb complex, as an ideal tool to follow development of polarity in zebrafish epithelia. We find that in gastrula stages, RFP-Lin7c is found in the cytosol of the enveloping layer, while Pard3-GFP is already polarized at this stage. During development of the retinal epithelium, RFP-Lin7c localization is refined from being cytosolic at 14 hours post fertilization (hpf) to almost entirely apical in cells of the eye cup at 28 hpf. This apical Lin7c localization depends on the Crb complex members Oko meduzy and Nagie oko. Thus, fluorescently tagged Lin7c can be used in a broad range of epithelia to follow polarity maturation in vivo and specifically to elucidate the sequence of events determining Crb complex-mediated polarity. PMID- 24143273 TI - Insights into the osteoblast precursor differentiation towards mature osteoblasts induced by continuous BMP-2 signaling. AB - Mature osteoblasts are the cells responsible for bone formation and are derived from precursor osteoblasts. However, the mechanisms that control this differentiation are poorly understood. In fact, unlike the majority of organs in the body, which are composed of "soft" tissue from which cells can easily be isolated and studied, the "hard" mineralized tissue of bone has made it difficult to study the function of bone cells. Here, we established an in vitro model that mimics this differentiation under physiological conditions. We obtained mature osteoblasts and characterized them on the basis of the following parameters: the strong expression of osteoblastic markers, such as Runx2 and Col-I; the achievement of specific dimensions (the cell volume increases 26-fold compared to the osteoblast precursors); and the production of an abundant extracellular matrix also called osteoid. We demonstrated that the differentiation of osteoblast precursors into mature osteoblasts requires the continuous activation of Bone Morphogenetic Protein (BMP) receptors, which we established with the immobilization of a BMP-2mimetic peptide on a synthetic matrix mimicking in vivo microenvironment. Importantly, we demonstrated that the organization of the F actin network and acetylated microtubules of the cells were modified during the differentiation process. We showed that the perturbation of the F-actin cytoskeleton organization abolished the differentiation process. In addition, we demonstrated that expression of the Runx2 gene is required for this differentiation. These findings demonstrate the retro-regulation of cytoplasmic and genic components due to the continuous induction of BMP-2 and also provide more detailed insights into the correct signaling of BMPs for cell differentiation in bone tissue. PMID- 24143274 TI - A transgenic Xenopus laevis reporter model to study lymphangiogenesis. AB - The importance of the blood- and lymph vessels in the transport of essential fluids, gases, macromolecules and cells in vertebrates warrants optimal insight into the regulatory mechanisms underlying their development. Mouse and zebrafish models of lymphatic development are instrumental for gene discovery and gene characterization but are challenging for certain aspects, e.g. no direct accessibility of embryonic stages, or non-straightforward visualization of early lymphatic sprouting, respectively. We previously demonstrated that the Xenopus tadpole is a valuable model to study the processes of lymphatic development. However, a fluorescent Xenopus reporter directly visualizing the lymph vessels was lacking. Here, we created transgenic Tg(Flk1:eGFP) Xenopus laevis reporter lines expressing green fluorescent protein (GFP) in blood- and lymph vessels driven by the Flk1 (VEGFR-2) promoter. We also established a high-resolution fluorescent dye labeling technique selectively and persistently visualizing lymphatic endothelial cells, even in conditions of impaired lymph vessel formation or drainage function upon silencing of lymphangiogenic factors. Next, we applied the model to dynamically document blood and lymphatic sprouting and patterning of the initially avascular tadpole fin. Furthermore, quantifiable models of spontaneous or induced lymphatic sprouting into the tadpole fin were developed for dynamic analysis of loss-of-function and gain-of-function phenotypes using pharmacologic or genetic manipulation. Together with angiography and lymphangiography to assess functionality, Tg(Flk1:eGFP) reporter tadpoles readily allowed detailed lymphatic phenotyping of live tadpoles by fluorescence microscopy. The Tg(Flk1:eGFP) tadpoles represent a versatile model for functional lymph/angiogenomics and drug screening. PMID- 24143275 TI - Metastatic MTLn3 and non-metastatic MTC adenocarcinoma cells can be differentiated by Pseudomonas aeruginosa. AB - Cancer patients are known to be highly susceptible to Pseudomonas aeruginosa (Pa) infection, but it remains unknown whether alterations at the tumor cell level can contribute to infection. This study explored how cellular changes associated with tumor metastasis influence Pa infection using highly metastatic MTLn3 cells and non-metastatic MTC cells as cell culture models. MTLn3 cells were found to be more sensitive to Pa infection than MTC cells based on increased translocation of the type III secretion effector, ExoS, into MTLn3 cells. Subsequent studies found that higher levels of ExoS translocation into MTLn3 cells related to Pa entry and secretion of ExoS within MTLn3 cells, rather than conventional ExoS translocation by external Pa. ExoS includes both Rho GTPase activating protein (GAP) and ADP ribosyltransferase (ADPRT) enzyme activities, and differences in MTLn3 and MTC cell responsiveness to ExoS were found to relate to the targeting of ExoS-GAP activity to Rho GTPases. MTLn3 cell migration is mediated by RhoA activation at the leading edge, and inhibition of RhoA activity decreased ExoS translocation into MTLn3 cells to levels similar to those of MTC cells. The ability of Pa to be internalized and transfer ExoS more efficiently in association with Rho activation during tumor metastasis confirms that alterations in cell migration that occur in conjunction with tumor metastasis contribute to Pa infection in cancer patients. This study also raises the possibility that Pa might serve as a biological tool for dissecting or detecting cellular alterations associated with tumor metastasis. PMID- 24143276 TI - A novel method to study contact inhibition of locomotion using micropatterned substrates. AB - The concept of contact inhibition of locomotion (CIL) describes the ability of a cell to change the direction of its movement after contact with another cell. It has been shown to be responsible for physiological and developmental processes such as wound healing, macrophage dispersion and neural crest cell migration; whereas its loss facilitates cancer cell invasion and metastatic dissemination. Different assays have been developed to analyze CIL in tissue culture models. However, these methods have several caveats. Collisions happen at low frequency between freely migrating cells and the orientation of the cells at the time of contact is not predictable. Moreover, the computational analysis required by these assays is often complicated and it retains a certain degree of discretion. Here, we show that confinement of neural crest cell migration on a single dimension by using a micropatterned substrate allows standardized and predictable cell-cell collision. CIL can thus easily be quantified by direct measurement of simple cellular parameters such as the distance between nuclei after collision. We tested some of the signaling pathways previously identified as involved in CIL, such as small GTPases and non-canonical Wnt signaling, using this new method for CIL analysis. The restricted directionality of migration of cells in lines is a powerful strategy to obtain higher predictability and higher efficiency of the CIL response upon cell-cell collisions. PMID- 24143277 TI - Otx2 expression and implications for olfactory imprinting in the anemonefish, Amphiprion percula. AB - The otx2 gene encodes a transcription factor (OTX2) essential in the formation of the brain and sensory systems. Specifically, OTX2-positive cells are associated with axons in the olfactory system of mice and otx2 is upregulated in odour exposed zebrafish, indicating a possible role in olfactory imprinting. In this study, otx2 was used as a candidate gene to investigate the molecular mechanisms of olfactory imprinting to settlement cues in the coral reef anemonefish, Amphiprion percula. The A. percula otx2 (Ap-otx2) gene was elucidated, validated, and its expression tested in settlement-stage A. percula by exposing them to behaviourally relevant olfactory settlement cues in the first 24 hours post hatching, or daily throughout the larval phase. In-situ hybridisation revealed expression of Ap-otx2 throughout the olfactory epithelium with increased transcript staining in odour-exposed settlement-stage larval fish compared to no odour controls, in all scenarios. This suggests that Ap-otx2 may be involved in olfactory imprinting to behaviourally relevant settlement odours in A. percula. PMID- 24143278 TI - Myeloperoxidase modulates human platelet aggregation via actin cytoskeleton reorganization and store-operated calcium entry. AB - Myeloperoxidase (MPO) is a heme-containing enzyme released from activated leukocytes into the extracellular space during inflammation. Its main function is the production of hypohalous acids that are potent oxidants. MPO can also modulate cell signaling and inflammatory responses independently of its enzymatic activity. Because MPO is regarded as an important risk factor for cardiovascular diseases associated with increased platelet activity, we studied the effects of MPO on human platelet functional properties. Laser scanning confocal microscopy was used to reveal carbohydrate-independent MPO binding to human platelet membrane. Adding MPO to platelets did not activate their aggregation under basal conditions (without agonist). In contrast, MPO augmented agonist-induced platelet aggregation, which was not prevented by MPO enzymatic activity inhibitors. It was found that exposure of platelets to MPO leads to actin cytoskeleton reorganization and an increase in their elasticity. Furthermore, MPO evoked a rise in cytosolic Ca(2+) through enhancement of store-operated Ca(2+) entry (SOCE). Together, these findings indicate that MPO is not a direct agonist but rather a mediator that binds to human platelets, induces actin cytoskeleton reorganization and affects the mechanical stiffness of human platelets, resulting in potentiating SOCE and agonist-induced human platelet aggregation. Therefore, an increased activity of platelets in vascular disease can, at least partly, be provided by MPO elevated concentrations. PMID- 24143279 TI - Robust mitotic entry is ensured by a latching switch. AB - Cell cycle events are driven by Cyclin dependent kinases (CDKs) and by their counter-acting phosphatases. Activation of the Cdk1:Cyclin B complex during mitotic entry is controlled by the Wee1/Myt1 inhibitory kinases and by Cdc25 activatory phosphatase, which are themselves regulated by Cdk1:Cyclin B within two positive circuits. Impairing these two feedbacks with chemical inhibitors induces a transient entry into M phase referred to as mitotic collapse. The pathology of mitotic collapse reveals that the positive circuits play a significant role in maintaining the M phase state. To better understand the function of these feedback loops during G2/M transition, we propose a simple model for mitotic entry in mammalian cells including spatial control over Greatwall kinase phosphorylation. After parameter calibration, the model is able to recapture the complex and non-intuitive molecular dynamics reported by Potapova et al. (Potapova et al., 2011). Moreover, it predicts the temporal patterns of other mitotic regulators which have not yet been experimentally tested and suggests a general design principle of cell cycle control: latching switches buffer the cellular stresses which accompany cell cycle processes to ensure that the transitions are smooth and robust. PMID- 24143280 TI - Effects of testosterone on contractile properties of sexually dimorphic forelimb muscles in male bullfrogs (Rana catesbeiana, Shaw 1802). AB - This study examined the effects of testosterone (T) on the contractile properties of two sexually dimorphic forelimb muscles and one non-dimorphic muscle in male bullfrogs (Rana catesbeiana, Shaw 1802). The dimorphic muscles in castrated males with testosterone replacement (T+) achieved higher forces and lower fatigability than did castrated males without replaced testosterone (T0 males), but the magnitude of the differences was low and many of the pair-wise comparisons of each muscle property were not statistically significant. However, when taken as a whole, the means of seven contractile properties varied in the directions expected of masculine values in T+ animals in the sexually dimorphic muscles. Moreover, these data, compared with previous data on male and female bullfrogs, show that values for T+ males are similar to normal males and are significantly different from females. The T0 males tended to be intermediate in character between T+ males and females, generally retaining masculine values. This suggests that the exposure of young males to T in their first breeding season produces a masculinizing effect on the sexually dimorphic muscles that is not reversed between breeding seasons when T levels are low. The relatively minor differences in contractile properties between T+ and T0 males may indicate that as circulating T levels rise during breeding season in normal males, contractile properties can be enhanced rapidly to maximal functional levels for breeding success. PMID- 24143281 TI - Functional coupling between large-conductance potassium channels and Cav3.2 voltage-dependent calcium channels participates in prostate cancer cell growth. AB - It is strongly suspected that potassium (K(+)) channels are involved in various aspects of prostate cancer development, such as cell growth. However, the molecular nature of those K(+) channels implicated in prostate cancer cell proliferation and the mechanisms through which they control proliferation are still unknown. This study uses pharmacological, biophysical and molecular approaches to show that the main voltage-dependent K(+) current in prostate cancer LNCaP cells is carried by large-conductance BK channels. Indeed, most of the voltage-dependent current was inhibited by inhibitors of BK channels (paxillin and iberiotoxin) and by siRNA targeting BK channels. In addition, we reveal that BK channels constitute the main K(+) channel family involved in setting the resting membrane potential in LNCaP cells at around -40 mV. This consequently promotes a constitutive calcium entry through T-type Cav3.2 calcium channels. We demonstrate, using single-channel recording, confocal imaging and co immunoprecipitation approaches, that both channels form macromolecular complexes. Finally, using flow cytometry cell cycle measurements, cell survival assays and Ki67 immunofluorescent staining, we show that both BK and Cav3.2 channels participate in the proliferation of prostate cancer cells. PMID- 24143282 TI - GDNF-independent ureteric budding: role of PI3K-independent activation of AKT and FOSB/JUN/AP-1 signaling. AB - A significant fraction of mice deficient in either glial cell-derived neurotrophic factor (GDNF) or its co-receptors (Gfralpha1, Ret), undergoes ureteric bud (UB) outgrowth leading to the formation of a rudimentary kidney. Previous studies using the isolated Wolffian duct (WD) culture indicate that activation of fibroblast growth factor (FGF) receptor signaling, together with suppression of BMP/Activin signaling, is critical for GDNF-independent WD budding (Maeshima et al., 2007). By expression analysis of embryonic kidney from Ret((-/ )) mice, we found the upregulation of several FGFs, including FGF7. To examine the intracellular pathways, we then analyzed GDNF-dependent and GDNF-independent budding in the isolated WD culture. In both conditions, Akt activation was found to be important; however, whereas this occurred through PI3-kinase in GDNF dependent budding, in the case of GDNF-independent budding, Akt activation was apparently via a PI3-kinase independent mechanism. Jnk signaling and the AP-1 transcription factor complex were also implicated in GDNF-independent budding. FosB, a binding partner of c-Jun in the formation of AP-1, was the most highly upregulated gene in the ret knockout kidney (in which budding had still occurred), and we found that its siRNA-mediated knockdown in isolated WDs also blocked GDNF-independent budding. Taken together with the finding that inhibition of Jnk signaling does not block Akt activation/phosphorylation in GDNF independent budding, the data support necessary roles for both FosB/Jun/AP-1 signaling and PI3-kinase-independent activation of Akt in GDNF-independent budding. A model is proposed for signaling events that involve Akt and JNK working to regulate GDNF-independent WD budding. PMID- 24143283 TI - Central ventilatory and cardiovascular actions of trout gastrin-releasing peptide (GRP) in the unanesthetized trout. AB - Gastrin-releasing peptide (GRP), a neuropeptide initially isolated from porcine stomach, shares sequence similarity with bombesin. GRP and its receptors are present in the brains and peripheral tissues of several species of teleost fish, but little is known about the ventilatory and cardiovascular effects of this peptide in these vertebrates. The goal of this study was to compare the central and peripheral actions of picomolar doses of trout GRP on ventilatory and cardiovascular variables in the unanesthetized rainbow trout. Compared to vehicle, intracerebroventricular (ICV) injection of GRP (1-50 pmol) significantly elevated the ventilation rate (fV) and the ventilation amplitude (VAMP), and consequently the total ventilation (VTOT). The maximum hyperventilatory effect of GRP (VTOT: +225%), observed at a dose of 50 pmol, was mostly due to its stimulatory action on VAMP (+170%) rather than fV (+20%). In addition, ICV GRP (50 pmol) produced a significant increase in mean dorsal aortic blood pressure (P DA) (+35%) and in heart rate (fH) (+25%). Intra-arterial injections of GRP (5-100 pmol) were without sustained effect on the ventilatory variables but produced sporadic and transient increases in ventilatory movement at doses of 50 and 100 pmol. At these doses, GRP elevated P DA by +20% but only the 50 pmol dose significantly increased HR (+15%). In conclusion, our study suggests that endogenous GRP within the brain of the trout may act as a potent neurotransmitter and/or neuromodulator in the regulation of cardio-ventilatory functions. In the periphery, endogenous GRP may act as locally-acting and/or circulating neurohormone with an involvement in vasoregulatory mechanisms. PMID- 24143284 TI - Pocket proteins critically regulate cell cycle exit of the trabecular myocardium and the ventricular conduction system. AB - During development, the ventricular conduction system (VCS) arises from the trabecular or spongy myocardium. VCS and trabecular myocytes proliferate at a significantly slower rate than compact zone myocardial cells, establishing a transmural cell cycle gradient. The molecular determinants of VCS/trabecular myocyte cell cycle arrest are not known. Given the importance of pocket proteins (Rb, p107 and p130) in mediating G0/G1 arrest in many cell types, we examined the role of this gene family in regulating cell cycle exit of the trabecular myocardium and ventricular conduction system. Using a combinatorial knockout strategy, we found that graded loss of pocket proteins results in a spectrum of heart and lung defects. p107/p130 double knockout (dKO) hearts manifest dysregulated proliferation within the compact myocardium and trabecular bases, while the remaining trabecular region cell cycle exits normally. Consequently, dKO hearts exhibit defective cardiac compaction, septal hyperplasia and biventricular outflow tract obstruction, while the VCS appears relatively normal. Loss of all three pocket proteins (3KO) is necessary to completely disrupt the transmural cell cycle gradient. 3KO hearts exhibit massive overgrowth of the trabecular myocardium and ventricular conduction system, which leads to fetal heart failure and death. Hearts carrying a single pocket protein allele are able to maintain the transmural cell cycle gradient. These results demonstrate the exquisite sensitivity of trabecular and conduction myocytes to pocket protein function during ventricular chamber development. PMID- 24143285 TI - Erratum: transparent, a gene affecting stripe formation in Zebrafish, encodes the mitochondrial protein Mpv17 that is required for iridophore survival. AB - [This corrects the article on p. 703 in vol. 2.]. PMID- 24143286 TI - Desiring the painless urodynamic study. PMID- 24143287 TI - Development of implantable medical devices: from an engineering perspective. AB - From the first pacemaker implant in 1958, numerous engineering and medical activities for implantable medical device development have faced challenges in materials, battery power, functionality, electrical power consumption, size shrinkage, system delivery, and wireless communication. With explosive advances in scientific and engineering technology, many implantable medical devices such as the pacemaker, cochlear implant, and real-time blood pressure sensors have been developed and improved. This trend of progress in medical devices will continue because of the coming super-aged society, which will result in more consumers for the devices. The inner body is a special space filled with electrical, chemical, mechanical, and marine-salted reactions. Therefore, electrical connectivity and communication, corrosion, robustness, and hermeticity are key factors to be considered during the development stage. The main participants in the development stage are the user, the medical staff, and the engineer or technician. Thus, there are three different viewpoints in the development of implantable devices. In this review paper, considerations in the development of implantable medical devices will be presented from the viewpoint of an engineering mind. PMID- 24143288 TI - Exposure to music and noise during pregnancy influences neurogenesis and thickness in motor and somatosensory cortex of rat pups. AB - PURPOSE: Prenatal environmental conditions affect the development of the fetus. In the present study, we investigated the effects of exposure to music and noise during pregnancy on neurogenesis and thickness in the motor and somatosensory cortex of rat pups. METHODS: The pregnant rats in the music-applied group were exposed to 65 dB of comfortable music for 1 hour, once per day, from the 15th day of pregnancy until delivery. The pregnant rats in the noise-applied group were exposed to 95 dB of sound from a supersonic sound machine for 1 hour, once per day, from the 15th day of pregnancy until delivery. After birth, the offspring were left undisturbed together with their mother. The rat pups were sacrificed at 21 days after birth. RESULTS: Exposure to music during pregnancy increased neurogenesis in the motor and somatosensory cortex of rat pups. In contrast, rat pups exposed to noise during pregnancy showed decreased neurogenesis and thickness in the motor and somatosensory cortex. CONCLUSIONS: Our study suggests that music and noise during the developmental period are important factors influencing brain development and urogenital disorders. PMID- 24143289 TI - Impact of Several Types of Stresses on Short-term Memory and Apoptosis in the Hippocampus of Rats. AB - PURPOSE: Stress has a deteriorating effect on hippocampal function. It also contributes to symptom exacerbation in many disease states, including overactive bladder and interstitial cystitis/bladder pain syndrome. We investigated the effects of various types of stresses (restraint, noise, and cold) on short-term memory and apoptosis in relation with corticotropin-releasing factor (CRF) expression. METHODS: Rats in the restraint stress group were restrained in a transparent Plexiglas cylinder for 60 minutes twice daily. Rats in the noise stress group were exposed to the 120 dB supersonic machine sound for 60 minutes twice daily. Rats in the cold stress group were placed in a cold chamber at 4C for 60 minutes twice daily. Each stress was applied for 10 days. A step-down avoidance test for short-term memory, immunohistochemistry for caspase-3 expression, and western blot analysis for Bax and Bcl-2 expressions were conducted. RESULTS: Latency time was decreased and CRF expression in the hippocampal dentate gyrus and hypothalamic paraventricular nucleus were increased in all of the stress groups. The number of caspase-3-positive cells in the hippocampal dentate gyrus was increased and the expressions of Bax and Bcl2 in the hippocampus were decreased in all of the stress groups. CONCLUSIONS: All of the stress groups experienced short-term memory impairment induced by apoptosis in the hippocampus. The present results suggest the possibility that these stresses affecting the impairment of short-term memory may also induce functional lower urinary tract disorders. PMID- 24143290 TI - Factors affecting trial without catheter for first spontaneous acute urinary retention. AB - PURPOSE: To find the association of trial without catheter (TWOC) outcome for first spontaneous acute urinary retention (AUR) in benign prostatic obstruction with age, prior lower urinary tract symptoms (LUTS), retention volume at catheterization (RV), and size of prostate. METHODS: Our prospective observational analytical (interventional) study enrolled 77 cases of spontaneous AUR over 24 months. After clinical evaluation, digital rectal examination, and transabdominal ultrasonography, all patients were catheterized per urethra and their RV was recorded. TWOC was administered after 2 or 3 doses of 0.4 mg tamsulosin-oral absorption control system and after 48-72 hours had passed. A successful endpoint was defined as a maximum flow-rate, >5 mL/sec; voided volume, >100 mL; postvoid residue, <200 mL; and voiding within 6 hours of catheter removal. Data obtained from 58 patients were analyzed after excluding the cases lost to follow-up and secondary exclusion. Age, RV, duration of LUTS, and prostate volume on examination and ultrasonography (PUSG) were recorded and statistically analyzed. Prostate-specific antigen levels were obtained on follow up and cases of cancer, as seen on transrectal ultrasound-guided biopsy, were secondarily excluded. RESULTS: The patients had a mean age of 65.89+/-8.67 years. Prior LUTS was seen in 35 patients (2.07+/-2.91 months). The mean PUSG and RV were 46.81+/-20.58 mL and 854.8+/-36.26 mL, respectively. Thirty patients underwent a successful TWOC; a mean age of 63.13+/-8.58 years (mean+/-standard deviation; unpaired t-test; P=0.0053) and a PUSG of <=45 mL (Pearson chi-square test; P=0.0427) were significantly associated with a successful outcome. CONCLUSIONS: There is a significant association between TWOC outcome, age (P=0.0053), and PUSG (P=0.0427). PMID- 24143291 TI - Urinary bladder detrusor dysfunction symptoms in lyme disease. AB - PURPOSE: Symptoms of urinary bladder detrusor dysfunction have been rarely reported in Lyme disease. The aim was to carry out the first systematic study to compare the prevalence of such symptoms in a group of Lyme disease patients and a group of matched controls. METHODS: A questionnaire relating to detrusor function was administered to 17 serologically positive Lyme disease patients and to 18 control subjects. RESULTS: The two groups were matched in respect of age, sex, body mass, and mean arterial blood pressure. None of the 35 subjects was taking medication which might affect urinary function and none had undergone a previous operative procedure on the lower urinary tract. Six of the Lyme patients (35%) and none of the controls (0%) had symptoms of detrusor dysfunction (P<0.01). CONCLUSIONS: This first systematic controlled study confirms that Lyme disease is associated with urinary bladder detrusor dysfunction. Further evaluation of detrusor function is warranted in this disease. PMID- 24143292 TI - Effect of Long-term Exercise on Voiding Functions in Obese Elderly Women. AB - PURPOSE: An overactive bladder (OAB) may be defined as urgency that is a sudden, compelling, difficult to defer desire to pass urine that is usually accompanied by frequency and nocturia and possibly by incontinence. Obesity and old age are two factors in various causes of OAB. Several epidemiologic studies have identified positive associations among obesity, old age, urinary incontinence, and OAB. However, although exercise has been known to improve obesity and reduce incontinent urine loss, little research has been done in elderly women. Therefore, we investigated the effects of exercise on obesity-related metabolic factors, blood lipid factors, and OAB symptoms in elderly Korean women. METHODS: Twenty-one women aged between 69 and 72 years were recruited from the Seoul senior towers in Korea. All subjects worked out on a motorized treadmill and stationary cycle for 40 minutes, respectively, and performed resistance exercise for 30 minutes once a day for 52 weeks. Body composition, blood pressure, blood lipids, OAB symptom score, and King's health questionnaire were investigated and analyzed. RESULTS: Before performing physical exercise, all subjects showed increased OAB symptoms in association with enhanced body mass index (BMI), percentage fat, and blood lipid profiles. However, physical exercise for 52 weeks suppressed BMI, percentage fat, and blood lipid profiles and thus improved OAB symptoms. CONCLUSIONS: We suggest that long-term physical exercise can be a valuable tool for remarkable improvement of OAB. PMID- 24143293 TI - Efficacy of salvage interferential electrical stimulation therapy in patients with medication-refractory enuresis: a pilot study. AB - PURPOSE: In pediatric patients with enuresis, the protocol for salvage therapy in patients in whom first-line therapy was not successful has not yet been established. Interferential electrical stimulation (IF-ES) therapy is advantageous because it is noninvasive and shows high compliance. We aimed to investigate the efficacy and safety of IF-ES therapy on pediatric enuresis in a pilot study. METHODS: We investigated 10 patients who underwent IF-ES therapy between August 2012 and March 2013 at our clinic. Patients with a history of previous treatment with desmopressin and anticholinergic agents for at least 3 months and those in whom alarm treatment previously failed or was refused by parents were eligible. Electrical current was given starting at approximately 20 mA and was increased until the patient complained of discomfort. Treatment was performed once a week, 20 minutes per treatment, 6 times per cycle. After each cycle, an interview was performed and voiding diaries were filled. The physician in charge evaluated improvement according to the International Children's Continence Society criteria. RESULTS: A final analysis was performed in 10 patients (5 male and 5 female patients) in whom therapy for nocturnal enuresis had failed. Eight patients had nonmonosymptomatic enuresis and 2 had monosymptomatic enuresis. The mean age of the patients was 8.5+/-2.4 years, and the mean number of treatments was 10.6+/-3.6 times. A full response was observed in 1 patient (10%); a good response, in 1 patient (10%); a partial response, in 7 patients (70%); and no response, in 1 patient (10%). CONCLUSIONS: Our study demonstrated that IF-ES therapy can be a promising treatment for the future, is safe, and can benefit from appropriate clinical trials in carefully selected groups. IF-ES therapy is expected to be a safe and effective treatment modality for children with enuresis. PMID- 24143294 TI - Effectiveness of retropubic tension-free vaginal tape and transobturator inside out tape procedures in women with overactive bladder and stress urinary incontinence. AB - PURPOSE: We compared the effectiveness of the retropubic tension-free vaginal tape (TVT) and the transobturator inside-out tape (TVT-O) in treating symptoms of overactive bladder (OAB) in women with stress urinary incontinence (SUI). METHODS: Women with urodynamic SUI and OAB (mean urgency episodes >=1 and frequency >=8/24 hours on a 3-day voiding diary) were assigned to the TVT or TVT O group. Preoperative measures were based on a urodynamic study, 3-day voiding diary, the Bristol Female Lower Urinary Tract Symptoms questionnaire (BFLUTSSF), and the urgency perception scale (UPS). At 12 postoperative months, the 3-day voiding diary, symptoms questionnaire, patient satisfaction, and standing stress test were assessed. The primary endpoint was change in the number of urgency episodes/24 hours from baseline to 12 months. RESULTS: In this group of 132 women, 42 received TVT and 90 received TVT-O. The mean urgency episodes/24 hours decreased from 6.3+/-5.5 to 1.6+/-3.2 in the TVT group and from 5.1+/-4.4 to 1.8+/-3.0 in the TVT-O group. The mean percent change was significantly greater after TVT than after TVT-O (73% vs. 60%, P=0.049). All subscales of BFLUTSSF and UPS were significantly improved using either method, with significantly greater improvement seen in the quality of life (QoL) domain after TVT (P=0.002). There were no significant differences in the cure and satisfaction rates between the two groups. CONCLUSIONS: Intervention with the TVT or the TVT-O significantly improved symptoms of OAB in women with SUI and OAB. Urgency and QoL significantly improved after TVT compared with that after TVT-O. PMID- 24143295 TI - New Insights in Streptomyces Fermentations. PMID- 24143296 TI - Quantifying the test-retest reliability of cerebral blood flow measurements in a clinical model of on-going post-surgical pain: A study using pseudo-continuous arterial spin labelling. AB - Arterial spin labelling (ASL) is increasingly being applied to study the cerebral response to pain in both experimental human models and patients with persistent pain. Despite its advantages, scanning time and reliability remain important issues in the clinical applicability of ASL. Here we present the test-retest analysis of concurrent pseudo-continuous ASL (pCASL) and visual analogue scale (VAS), in a clinical model of on-going pain following third molar extraction (TME). Using ICC performance measures, we were able to quantify the reliability of the post-surgical pain state and DeltaCBF (change in CBF), both at the group and individual case level. Within-subject, the inter- and intra-session reliability of the post-surgical pain state was ranked good-to-excellent (ICC > 0.6) across both pCASL and VAS modalities. The parameter DeltaCBF (change in CBF between pre- and post-surgical states) performed reliably (ICC > 0.4), provided that a single baseline condition (or the mean of more than one baseline) was used for subtraction. Between-subjects, the pCASL measurements in the post-surgical pain state and DeltaCBF were both characterised as reliable (ICC > 0.4). However, the subjective VAS pain ratings demonstrated a significant contribution of pain state variability, which suggests diminished utility for interindividual comparisons. These analyses indicate that the pCASL imaging technique has considerable potential for the comparison of within- and between-subjects differences associated with pain-induced state changes and baseline differences in regional CBF. They also suggest that differences in baseline perfusion and functional lateralisation characteristics may play an important role in the overall reliability of the estimated changes in CBF. Repeated measures designs have the important advantage that they provide good reliability for comparing condition effects because all sources of variability between subjects are excluded from the experimental error. The ability to elicit reliable neural correlates of on-going pain using quantitative perfusion imaging may help support the conclusions derived from subjective self-report. PMID- 24143297 TI - Highlights of international digestive endoscopy network 2013. AB - Rapid advances in the technology of gastrointestinal endoscopy as well as the evolution of science have made it necessary for us to continue update in either various endoscopic techniques or state of art lectures relevant to endoscopy. International Digestive Endoscopy Network (IDEN) 2013 was held in conjunction with Korea-Japan Joint Symposium on Gastrointestinal Endoscopy (KJSGE) during June 8 to 9, 2013 at Seoul, Korea. Two days of impressive scientific program dealt with a wide variety of basic concerns from upper gastrointestine (GI), lower GI, pancreaticobiliary endoscopy to advanced knowledge including endoscopic submucosal dissection forum. IDEN seems to be an excellent opportunity to exchange advanced information of the latest issues on endoscopy with experts from around the world. In this special issue of Clinical Endoscopy, we prepared state of art review articles from contributing authors and the current highlights will skillfully deal with very hot spots of each KJSGE, upper GI, lower GI, and pancreaticobiliary sessions by associated editors of Clinical Endoscopy. PMID- 24143298 TI - Tissue acquisition in gastric epithelial tumor prior to endoscopic resection. AB - Endoscopic forceps biopsy is essential before planning an endoscopic resection of upper gastrointestinal epithelial tumors. However, forceps biopsy is limited by its superficiality and frequency of sampling errors. Histologic discrepancies between endoscopic forceps biopsies and resected specimens are frequent. Factors associated with such histologic discrepancies are tumor size, macroscopic type, surface color, and the type of medical facility. Precise targeting of biopsies is recommended to achieve an accurate diagnosis, curative endoscopic resection, and a satisfactory oncologic outcome. Multiple deep forceps biopsies can induce mucosal ulceration in early gastric cancer. Endoscopic resection for early gastric cancer with ulcerative findings is associated with piecemeal resection, incomplete resection, and a risk for procedure-related complications such as bleeding and perforation. Such active ulcers caused by forceps biopsy and following submucosal fibrosis might also be mistaken as an indication for more aggressive procedures, such as gastrectomy with D2 lymph node dissection. Proton pump inhibitors might be prescribed to facilitate the healing of biopsy-induced ulcers if an active ulcer is predicted after deep biopsy. It is unknown which time interval from biopsy to endoscopic resection is appropriate for a safe procedure and a good oncologic outcome. Further investigations are needed to conclude the appropriate time interval. PMID- 24143299 TI - Endoscopic Ultrasound-Fine Needle Aspiration versus Core Biopsy for the Diagnosis of Subepithelial Tumors. AB - Subepithelial lesions are frequently encountered and remain a diagnostic challenge. Imaging of subepithelial lesions using endoscopic ultrasound (EUS) can be helpful in narrowing the differential diagnosis of the lesion; however, definitive diagnosis typically requires tissue. Many methods for acquiring tissue exist including EUS-guided fine needle aspiration, Trucut biopsy, and fine needle biopsy. Obtaining adequate tissue is important for cytologic and histologic exams including immunohistochemical stains, thus a great deal of effort has been made to increase tissue acquisition in order to improve diagnostic yield in subepithelial lesions. PMID- 24143300 TI - Confocal microscopy in the esophagus and stomach. AB - Probe-based confocal microscopy (pCLE) is actively being investigated for applications in the esophagus and stomach. The use of pCLE allows real-time in vivo microscopy to evaluate the microarchitecture of the mucosal epithelium. pCLE appears to be particularly useful in identifying mucosal dysplasia and early malignancies that cannot be clearly distinguished using high-definition white light endoscopy, chromoendoscopy, or magnification endoscopy. In addition, the ability to detect dysplastic tissue in real-time may shift the current screening practice from random biopsy to targeted biopsy of esophageal and gastric cancers and their precursor lesions. We will review the use of pCLE for detection and surveillance of upper gastrointestinal early luminal malignancy. PMID- 24143301 TI - Endoscopic treatment for early foregut neuroendocrine tumors. AB - Foregut neuroendocrine tumors (NETs) include those arising in the esophagus, stomach, pancreas, and duodenum and seem to have a broad range of clinical behavior from benign to metastatic. Several factors including the advent of screening endoscopy may be related to increased incidence of gastrointestinal NETs; thus, many foregut NETs are diagnosed at an early stage. Early foregut NETs, such as those of the stomach and duodenum, can be managed with endoscopic treatment because of a low frequency of lymph node and distant metastases. However, controversy continues concerning the optimal management of early foregut NETs due to a lack of controlled prospective studies. Several issues such as indications, technical issues, and outcomes of endoscopic treatment for early foregut NETs are reviewed based on some published studies. PMID- 24143302 TI - Preventing and controlling bleeding in gastric endoscopic submucosal dissection. AB - Although techniques and instruments for endoscopic submucosal dissection (ESD) have improved, bleeding is still the most common complication. Minimizing the occurrence of bleeding is important because blood can interfere with subsequent procedures. Generally, ESD-related bleeding can be divided into intraprocedural and postprocedural bleedings. Postprocedural bleeding can be further classified into early post-ESD bleeding which occurs within 48 hours after ESD and late post ESD bleeding which occurs later than 48 hours after ESD. A basic principle for avoiding intraprocedural bleeding is to watch for vessels and coagulate them before cutting. Several countertraction devices have been designed to minimize intraprocedural bleeding. Methods for reducing postprocedural bleeding include administration of proton-pump inhibitors or prophylactic coagulation after ESD. Medical adhesive spray such as n-butyl-2-cyanoacrylate is also an option for preventing postprocedural bleeding. Various endoscopic treatment modalities are used for both intraprocedural and postprocedural bleeding. However, hemoclipping is infrequently used during ESD because the clips interfere with subsequent resection. Bleeding that occurs as a result of ESD can usually be managed easily. Nonetheless, more effective ways to prevent bleeding, including reliable ESD techniques, must be developed. PMID- 24143303 TI - Long-term outcome of extended endoscopic submucosal dissection for early gastric cancer with differentiated histology. AB - Endoscopic mucosal resection was introduced in the 1990s, and endoscopic submucosal dissection (ESD) in 2003. Currently, ESD is becoming the main procedure for the resection of early gastric cancer (EGC) and is leading to the development of extended indications for endoscopic resection. Many reports showed that the endoscopic and oncologic outcome of endoscopic treatment in the extended indication group was acceptable in terms of curability and safety. Especially, ESD showed better results to remove extended indication EGCs with relatively high resection rate and low local recurrence rate. However, more long-term follow-up data are needed for clinical application of the extended criteria of ESD due to the risk of lymph node metastasis. We should also keep in mind that accurate diagnosis, characterization of the lesion, and proper appreciation of technical aspects are most essential in therapeutic endoscopy. PMID- 24143304 TI - Debates on colorectal endoscopic submucosal dissection - traction for effective dissection: gravity is enough. AB - Colorectal endoscopic submucosal dissection (ESD) still remains a technically difficult procedure. The maintenance of tissue tension and good submucosal exposure during dissection is one of the most important factors for an effective and safe dissection. Although various traction methods have been developed, traction by gravity is one of the most useful method for colorectal ESD. Traction using adjunctive devices can thus be reserved for extremely difficult cases or for endoscopists in their learning periods for colorectal ESD. PMID- 24143305 TI - Endoscopic management of refractory benign colorectal strictures. AB - In colonoscopic study, benign colorectal strictures with or without symptomatic pain are not rarely encountered. Benign colorectal stricture can be caused by a number of problems, such as anastomotic stricture after surgery, inflammatory bowel disease, postendoscopic submucosal dissection, diverticular disease, ischemic colitis, and so on. There are various modalities for the management of benign colorectal stricture. Endoscopic balloon dilatation is generally considered as the primary treatment for benign colorectal stricture. In refractory benign colorectal strictures, several treatment sessions of balloon dilatation are needed for successful dilatation. The self-expandable metal stent and many combined techniques are performed at present. However, there is no specific algorithmic modality for refractory benign colorectal strictures. PMID- 24143306 TI - Lower gastrointestinal bleeding: is urgent colonoscopy necessary for all hematochezia? AB - Lower gastrointestinal bleeding (LGIB) is defined as acute or chronic abnormal blood loss distal to the ligament of Treitz. The incidence of LGIB is only one fifth of that of the upper gastrointestinal tract and is estimated to be 21 to 27 cases per 100,000 adults per year. Acute bleeding is arbitrarily defined as bleeding of <3 days' duration resulting in instability of vital signs, anemia, and/or need for blood transfusion. Chronic bleeding is defined as slow blood loss over a period of several days or longer presenting with symptoms of occult fecal blood, intermittent melena, or scant hematochezia. Bleeding means that the amounts of blood in the feces are too small to be seen but detectable by chemical tests. LGIB is usually chronic and stops spontaneously. Bleeding stop (80%), but male gender and older patients suffer from more severe LGIB. The optimal timing of colonoscopic intervention for LGIB remains uncertain. Urgent colonoscopy may serve to decrease hospital stay. However, urgent colonoscopy is difficult to control, and showed no evidence of improving clinical outcomes or lowering costs as compared with routine elective colonoscopy. PMID- 24143307 TI - Deep enteroscopy: which technique will survive? AB - The advent of deep enteroscopy (DE) has dramatically changed diagnostic and therapeutic approaches to small bowel diseases. Unlike capsule endoscopy, which is unable to obtain biopsies or treat a disease, DE techniques have diagnostic and therapeutic capabilities. Double-balloon enteroscopy (DBE) was introduced in 2001, and single-balloon enteroscopy (SBE) and spiral enteroscopy (SE) were subsequently developed for small bowel investigation. In published reports comparing these different enteroscopy techniques, most comparative parameters (depth of insertion, complications, learning curve, diagnostic yield, and therapeutic yield) were comparable among DBE, SBE, and SE. However, the procedure duration appears to be shorter for SE than for DBE and SBE. The rate of complete enteroscopy is clearly superior for DBE, compared with SE and SBE. Because these results do not indicate an increase in diagnostic or therapeutic yield, the clinical impact of complete enteroscopy remains controversial. According to previous studies, the three DE methods seem to be equally effective and safe in the clinical setting. Although larger randomized controlled trials are needed to evaluate the procedural characteristics and clinical impact, the selection of an enteroscopic technique should be based on availability and the endoscopist's experience. PMID- 24143308 TI - Refractory gastrointestinal bleeding: role of angiographic intervention. AB - Although endoscopic hemostasis remains initial treatment modality for nonvariceal gastrointestinal (GI) bleeding, severe bleeding despite endoscopic management occurs in 5% to 10% of the patients, requiring surgery or transcatheter arterial embolization (TAE). TAE is now considered the first-line therapy for massive GI bleeding refractory to endoscopic management. GI endoscopists need to be familiar with indications, principles, outcomes, and complications of TAE, as well as embolic materials available. PMID- 24143309 TI - Tips and tricks for better endoscopic treatment of colorectal tumors: usefulness of cap and band in colorectal endoscopic mucosal resection. AB - Endoscopic mucosal resection (EMR) is an endoscopic alternative to surgical resection of mucosal and submucosal neoplastic lesions. Prior to the development of knives, EMR could be performed with accessories to elevate the lesion. After the development of various knives, en bloc resection was possible without other accessories. So, recently, simple snaring without suction or endoscopic submucosal dissection using knife in the epithelial lesions such as adenoma or early mucosal cancer has been performed. However, for easy and complete resection of subepithelial lesions such as carcinoid tumor, a few accessories are needed. Complete resection of rectal carcinoid tumors is difficult to achieve with conventional endoscopic resection techniques because these tumors often extend into the submucosa. The rate of positive resection margin for tumor is lower in the group of EMR using a cap (EMR-C) or EMR with a ligation device (EMR-L) than conventional EMR group. EMR-C and EMR-L (or endoscopic submucosal resection with a ligation device) may be a superior method to conventional EMR for removing small rectal carcinoid tumors. PMID- 24143310 TI - Colonic perforation: can we manage it endoscopically? AB - Colonic perforation occurs in a variety of clinical scenarios and colonoscopy associated perforation is one of the important reasons for colonic perforation. Colonoscopy-associated perforation may be diagnosed during colonoscopy procedure by the visualization of evident colonic wall defect or, after the completion of colonoscopy, by the visualization of leaked air in the peritoneal or retroperitoneal space. Recently, the incidence of colonoscopy-associated perforation increased because of the introduction of colorectal endoscopic submucosal dissection. Traditionally, colonoscopy-associated perforation was managed surgically. However, medical management has been introduced widely and endoscopic clipping is the most important component for the medical management of colonoscopy-associated perforation. Timely administration of antibiotics is also important. Large perforations, diagnostic colonoscopy-associated perforations, large amount of pneumoperitoneum, and severe abdominal pain have been reported to be predictive of the necessity of surgery after endoscopic clipping. Surgery should be performed if patients show clinical deterioration even after the initiation of medical management. PMID- 24143311 TI - Metal versus Plastic Stent for Transmural Drainage of Pancreatic Fluid Collections. AB - The conventional management of pancreatic fluid collections (PFCs) involves surgery or percutaneous drainage. While surgery is associated with significant complications and mortality, percutaneous drainage is associated with prolonged hospitalization and oftentimes the need for other adjunctive treatment measures. Therefore, the use of endoscopy to drain PFCs is becoming increasingly popular. Randomized trials have demonstrated that endoscopic ultrasound-guided drainage is superior to conventional endoscopy in terms of technical success and potentially decreases the rates of procedural complications. While transmural drainage is usually undertaken by deployment of plastic endoprosthesis, of late, fully covered self-expandable metal stents are being placed with increasing frequency. However, the benefits of this approach are unclear and require further validation in prospective trials. PMID- 24143312 TI - Procore and flexible 19 gauge needle can replace trucut biopsy needle? AB - Endoscopic ultrasound-guided fine needle aspiration (EUS-FNA) is routinely performed for establishing tissue diagnosis in patients with gastrointestinal tumors. The concept of delivering chemotherapy based on molecular markers and the ability to establish a reliable diagnosis in lieu of an onsite cytopathologist has fuelled the recent trend in procuring core tissue by means of EUS-guided fine needle biopsy. To overcome the technical limitations induced by the rigidity of the Trucut biopsy needle, a new ProCore needle with reverse bevel technology has been developed. Recent data suggests that the newly developed flexible 19 gauge needle can also procure core tissue and has easy maneuverability when navigating the transduodenal route. Irrespective of the needles being used, the best clinical outcomes can be attained only by practicing evidence-based techniques, procuring adequate quantity of sample for ancillary studies, and processing the specimens appropriately. PMID- 24143313 TI - Pancreatic fluid collection drainage by endoscopic ultrasound: an update. AB - Endoscopic management of symptomatic pancreatic fluid collections (PFCs) is now considered to be first line therapy. Expanded use of endoscopic ultrasound (EUS) techniques has resulted in increased applicability, safety, and efficacy of endoscopic transluminal PFC drainage. Steps include EUS-guided trangastric or transduodenal fistula creation into the PFC followed by stent placement or nasocystic drain deployment in order to decompress the collection. With the remarkable improvement in the available accessories and stents and development of exchange free access device; EUS drainage techniques have become simpler and less time consuming. The use of self-expandable metal stents with modifications to drain PFC has helped in overcoming some previously encountered challenges. PFCs considered suitable for endoscopic drainage include collection present for greater than 4 weeks, possessing a well-formed wall, position accessible endoscopically and located within 1 cm of the duodenal or gastric walls. Indications for EUS-guided drainage have been increasing which include unusual location of the collection, small window of entry, nonbulging collections, coagulopathy, intervening varices, failed conventional transmural drainage, indeterminate adherence of PFC to the luminal wall or suspicion of malignancy. In this article, we present a review of literature to date and discuss the recent developments in EUS-guided PFC drainage. PMID- 24143314 TI - Functional self-expandable metal stents in biliary obstruction. AB - Biliary stents are widely used not only for palliative treatment of malignant biliary obstruction but also for benign biliary diseases. Each plastic stent or self-expandable metal stent (SEMS) has its own advantages, and a proper stent should be selected carefully for individual condition. To compensate and overcome several drawbacks of SEMS, functional self-expandable metal stent (FSEMS) has been developed with much progress so far. This article looks into the outcomes and defects of each stent type for benign biliary stricture and describes newly introduced FSEMSs according to their functional categories. PMID- 24143315 TI - Endoscopic treatments of endoscopic retrograde cholangiopancreatography-related duodenal perforations. AB - Iatrogenic duodenal perforation associated with endoscopic retrograde cholangiopancreatography (ERCP) is a very uncommon complication that is often lethal. Perforations during ERCP are caused by endoscopic sphincterotomy, placement of biliary or duodenal stents, guidewire-related causes, and endoscopy itself. In particular, perforation of the medial or lateral duodenal wall usually requires prompt diagnosis and surgical management. Perforation can follow various clinical courses, and management depends on the cause of the perforation. Cases resulting from sphincterotomy or guidewire-induced perforation can be managed by conservative treatment and biliary diversion. The current standard treatment for perforation of the duodenal free wall is early surgical repair. However, several reports of primary endoscopic closure techniques using endoclip, endoloop, or newly developed endoscopic devices have recently been described, even for use in direct perforation of the duodenal wall. PMID- 24143317 TI - The role of direct peroral cholangioscopy using an ultraslim endoscope for biliary lesions: indications, limitations, and complications. AB - Advantages of direct peroral cholangioscopy (POC) using an ultraslim endoscope include use of conventional endoscopy equipment, operation by a single endoscopist, and superior image quality of the biliary tree with easy application of enhanced endoscopy and a large working channel. The major diagnostic indications of this system are an evaluation of biliary strictures, filling defects, or unclear findings on cholangiogram or other imaging studies. Therapeutic application using a direct POC system can be broadened by a larger working channel. However, direct POC is difficult to apply in patients with a narrow diameter bile duct, far distal common bile duct lesion, or failed anchoring of the scope with accessories. An air embolism is a rare complication of direct POC but can be a fatal problem. Cholangitis can also occur during or after the procedure. Use of a CO2 system instead of room air during the POC procedure and administration of antibiotics before and after the procedure are strongly recommended. Continuous development of specialized endoscopes and accessories is expected to facilitate the diagnostic and therapeutic roles of direct POC. PMID- 24143316 TI - Percutaneous transhepatic cholangioscopy: does its role still exist? AB - Percutaneous transhepatic cholangioscopy (PTCS) is the most widely used modality for diagnosis and treatment of biliary disease. Although many other novel technologies have been developed based on recent advances in endoscopy, PTCS has its own role. In diagnostics, PTCS is used for evaluation of indeterminate biliary strictures, bile duct tumors, and postoperative biliary strictures that cannot be reached by a peroral approach. In therapeutics, the removal of bile duct stones, dilatation of bile duct strictures including postoperative anastomosis site strictures, and local tumor therapy are indications of PTCS. Especially in a therapeutic role, PTCS has the advantage of maneuverability due to a shorter endoscopic length compared to other cholangioscopic modalities. Hence, PTCS has its own indispensable diagnostic and therapeutic roles. PMID- 24143318 TI - Role of repeated endoscopic ultrasound-guided fine needle aspiration for inconclusive initial cytology result. AB - For tissue diagnosis of suspected pancreatic cancer, endoscopic ultrasound-guided fine needle aspiration (EUS-FNA) is the procedure of choice with high safety and accuracy profiles. However, about 10% of cytologic findings of EUS-FNA are inconclusive. In that situation, careful observation, surgical exploration, or alternative diagnostic tools such as bile duct brushing with endoscopic retrograde cholangiopancreatography or computed tomography-guided biopsy can be considered. However, some concerns and/or risks of these options render repeat EUS-FNA a reasonable choice. Repeated EUS-FNA may impose substantial clinical impact with low risk. PMID- 24143319 TI - Endoscopic guided biliary drainage: how can we achieve efficient biliary drainage? AB - Currently, endoscopic retrograde cholangiopancreatography (ERCP) is the preferred procedure for biliary drainage for various pancreatico-biliary disorders. ERCP is successful in 90% of the cases, but is unsuccessful in cases with altered anatomy or with tumors obstructing access to the duodenum. Due to the morbidity and mortality associated with surgical or percutaneous approaches in unsuccessful ERCP cases, biliary endoscopists have been using endoscopic ultrasound-guided biliary drainage (EUS-BD) more frequently within the last decade in different countries. As with any novel advanced endoscopic procedure that incorporates various approaches, advanced endoscopists all over the world have innovated and adopted diverse EUS-BD techniques. Indications for EUS-BD include failed conventional ERCP, altered anatomy, tumor preventing access into the biliary tree and contraindication to percutaneous access (i.e., ascites, etc.). EUS-BD utilizing EUS-guided rendezvous technique is conducted by creating a tract from either the stomach or the duodenum into the bile duct. Although EUS-BD has rapidly been gaining attraction and popularity in the endoscopic world, the indications and methods have yet to be standardized. There are several access routes and techniques that are employed by advanced endoscopists throughout the world for BD. This article reviews the indications and currently practiced EUS-BD techniques, including indications, technical details (intrahepatic or extrahepatic approach), equipment, patient selection, complications, and overall advantages and limitations. PMID- 24143321 TI - Duodenal mucosa-associated lymphoid tissue lymphomas: two cases and the evaluation of endoscopic ultrasonography. AB - Mucosa-associated lymphoid tissue lymphoma mainly arises in the stomach, with fewer than 30% arising in the small intestine. We describe here two cases of primary duodenal mucosa-associated lymphoid tissue lymphoma which were evaluated by endoscopic ultrasonography. A 52-year-old man underwent endoscopy due to abdominal pain, which demonstrated a depressed lesion on duodenal bulb. Endoscopic ultrasonographic finding was hypoechoic lesion invading the submucosa. The other case was a previously healthy 51-year-old man. Endoscopy showed a whitish granular lesion on duodenum third portion. Endoscopic ultrasonography image was similar to the first case, whereas abdominal computed tomography revealed enlargement of multiple lymph nodes. The first case was treated with eradication of Helicobacter pylori, after which the mucosal change and endoscopic ultrasound finding were normalized in 7 months. The second case was treated with cyclophosphamide, vincristine, prednisolone, and rituximab every 3 weeks. After 6 courses of chemotherapy, the patient achieved complete remission. PMID- 24143320 TI - Technical Advances in Endoscopic Ultrasound (EUS)-Guided Tissue Acquisition for Pancreatic Cancers: How Can We Get the Best Results with EUS-Guided Fine Needle Aspiration? AB - Endoscopic ultrasound-guided fine needle aspiration (EUS-FNA) is one of the least invasive and most effective modality in diagnosing pancreatic adenocarcinoma in solid pancreatic lesions, with a higher diagnostic accuracy than cystic tumors. EUS-FNA has been shown to detect tumors less than 3 mm, due to high spatial resolution allowing the detection of very small lesions and vascular invasion, particularly in the pancreatic head and neck, which may not be detected on transverse computed tomography. Furthermore, this minimally invasive procedure is often ideal in the endoscopic procurement of tissue in patients with unresectable tumors. While EUS-FNA has been increasingly used as a diagnostic tool, most studies have collectively looked at all primary pancreatic solid lesions, including lymphomas and pancreatic neuroendocrine neoplasms, whereas very few studies have examined the diagnostic utility of EUS-FNA of pancreatic ductal carcinoma only. As with any novel and advanced endoscopic procedure that may incorporate several practices and approaches, endoscopists have adopted diverse techniques to improve the tissue procurement practice and increase diagnostic accuracy. In this article, we present a review of literature to date and discuss currently practiced EUS-FNA technique, including indications, technical details, equipment, patient selection, and diagnostic accuracy. PMID- 24143322 TI - A case of gastric inverted hyperplastic polyp found with gastritis cystica profunda and early gastric cancer. AB - A gastric inverted hyperplastic polyp is a rare type of gastric polyp and is characterized by downward growth of a variety of mucosal components into the submucosa. The polyp consists of columnar cells resembling foveolar epithelium and pyloric gland epithelium and can coexist with gastritis cystica profunda. Frequently, adenocarcinoma can coexist, but the relation is not clear. A 77-year old male underwent endoscopic submucosal dissection due to early gastric cancer. A gastric inverted hyperplastic polyp was found in the removed specimen and gastric cystica profunda was also found. We report a case of gastric inverted hyperplastic polyp coexisting with gastric cystica profunda and gastric adenocarcinoma. PMID- 24143323 TI - Gastrointestinal cancers in a peutz-jeghers syndrome family: a case report. AB - A 17-year-old man was diagnosed as Peutz-Jeghers syndrome (PJS) because of pigmented lip and multiple gastrointestinal polyps. He had anemia and underwent polypectomy on the duodenum and colon. His maternal family members were patients with PJS. His mother used to be screened with endoscopy to remove large polyps. One and half years later, he underwent jejunal segmental resection due to intussusceptions. He underwent endoscopic polypectomy every 2 to 3 years. When he was 23 years old, high-grade dysplasia was found in colonic polyp and his mother underwent partial pancreatectomy due to intraductal papillary mucinous carcinoma. When he was 27 years old, diffuse gastric polyps on the greater curvature of corpus expanded and grew. Therefore, wide endoscopic polypectomy was done. Histological examination revealed focal intramucosal carcinoma and low-grade dysplasia in hamartomatous polyps. We report cases of cancers occurred in first degree relatives with PJS. PMID- 24143324 TI - Successful endoscopic mucosal resection of a low esophageal carcinoid tumor. AB - Esophageal carcinoid tumors remain some of the rarest of all carcinoid tumors, with only several cases previously reported in the literature. The endoscopic mucosal resection of selected carcinoid tumors has been shown to be a valid, safe, and effective method of treatment. Endoscopic ultrasonography is the technique of choice to select patients eligible for endoscopic resection. Here, we report successful endoscopic mucosal resection of a low esophageal carcinoid tumor and review the relevant literature. The present case is the first reported case of esophageal carcinoid tumor in Korea. PMID- 24143325 TI - Systemic amyloidosis manifested by gastric outlet obstruction. AB - Amyloidosis is characterized by extracellular deposition of insoluble protein fibrils that stain with Congo red application and appear apple green under polarized light. The presenting symptoms result from the involvement of many affected, nonspecific and generalized organ systems. Our patient was an 80-year old woman with no medical history. She presented with a 2-week history of nausea and vomiting. An esophagogastroduodenoscopy showed erythematous and edematous mucosa on the antrum with pyloric stenosis. Histopathologic examination of the biopsy specimen showed the deposition of amorphous, homogeneous, and acidophilic material in the gastric mucosa. Amyloidal protein was proven by positive Congo red stain. A serum and urine immunfixation electrophoresis showed lambda light chain band. She developed symptoms of repeated greenish color vomiting. A follow up esophagogastroduodenoscopy showed progressed antral obstruction. However, she refused further evaluation and treatment and was managed conservatively. She later died of disease progression after 34 hospital days. PMID- 24143326 TI - Gastric somatostatinoma: an extremely rare cause of upper gastrointestinal bleeding. AB - A 49-year-old woman presented with chronic abdominal discomfort, significant weight loss, and chronic intermittent diarrhea. She suddenly developed massive upper gastrointestinal bleeding and was referred for further treatment. Endoscopy indicated a large mass in the upper gastric body with antral and duodenal bulb involvement. Endosonography showed a large well-defined isoechoic gastric subepithelial mass with multiple intra-abdominal and peripancreatic lymphadenopathy, suspected to be malignant on the basis of fine needle aspiration cytology. The tumor was surgically removed, and histopathology showed typical characteristics of a neuroendocrine tumor. On the basis of immunohistochemical staining, somatostatinoma, a rare neuroendocrine tumor, was diagnosed. Gastrointestinal bleeding is a rare presentation and the stomach is an uncommon tumor location. PMID- 24143327 TI - Endoscopic resection of giant colonic lipoma: case series with partial resection. AB - Colonic lipoma, a very rare form of benign tumor, is typically detected incidentally in asymptomatic patients. The size of lipoma is reported variously from 2 mm to 30 cm, with higher likelihood of symptoms as the size is bigger. Cases with symptom or bigger lesion are surgically resected in principle; endoscopic resection, which has developed recently with groundbreaking advance of endoscopic excision technology, is being used more often but with rare report of success due to high chance of complications such as bowel perforation or bleeding. The authors report here, together with a literature review, our experiences of three cases of giant colonic lipomas showing complete remission after aggressive unroofing technique, at certain intervals, using snare catheter at the origin of the lipoma so that the remaining lipoma could be drained out of the exposed surface spontaneously, in order to reduce complications. PMID- 24143328 TI - Repetitive Colonoscopic Decompression as a Bridge Therapy before Surgery in a Pregnant Patient with Chronic Intestinal Pseudo-Obstruction. AB - Chronic intestinal pseudo-obstruction is a rare clinical syndrome which is characterized by intestinal obstruction without occluding lesions in the intestinal lumen and pregnancy is one of the important aggravating factors. Here, we report a case of a woman with intractable intestinal pseudo-obstruction that was precipitated by pregnancy. She could not make any stool passage for more than 4 weeks until a fetal gestational age of 17 weeks was reached. However, the patient could be maintained by repetitive colonoscopic decompressions and finally total colectomy could be performed successfully at a fetal gestational age of 21 weeks. PMID- 24143329 TI - Retroperitoneal cystic lymphangioma diagnosed by endoscopic ultrasound-guided fine needle aspiration. AB - Retroperitoneal cystic lymphangiomas are rare tumors of the lymphatic system. These tumors usually present in childhood and are often diagnosed incidentally with imaging procedures. Although benign, they can grow to large sizes and become symptomatic due to their compressive effects. They can cause diagnostic dilemmas with other retroperitoneal cystic tumors including those arising from the liver, kidney, and pancreas. Endoscopic ultrasound (EUS) has become an invaluable tool in the assessment of cystic lesions in the region of the pancreas. This case describes a 66-year-old female who presented with 3 months of abdominal pain. Radiographic imaging was suggestive of a cystic lesion in the region of the pancreas. EUS was performed confirming a cystic lesion adjacent to the tail of the pancreas with subsequent fine needle aspiration fluid analysis consistent with a cystic lymphangioma. PMID- 24143330 TI - Chemosensory Impairment after Traumatic Brain Injury: Assessment and Management. PMID- 24143331 TI - How I manage difficult encounters. PMID- 24143332 TI - When war follows combat veterans home. AB - While combat survivability is at an all-time high, vets return home to private struggles with depression, PTSD, traumatic brain injury, and substance abuse. Here's how to spot these patients in civilian medical practices and the steps you can take to help them. PMID- 24143333 TI - Unexplained complaints in primary care: evidence of action bias. AB - PURPOSE: Primary care physicians sometimes encounter patients with clinical complaints that do not fit into a recognized diagnostic pattern. This study was undertaken to assess the way physicians respond to patients whose symptoms are unusual or unexplained that is, what approach they take in the absence of a working hypothesis. METHODS: We surveyed 130 primary care physicians affiliated with 3 academic centers in Israel, presenting 5 clinical vignettes describing patients who had unusual complaints, no clear diagnosis, and no apparent need for urgent care. We asked physicians to provide the most likely diagnosis for each case and to rate their level of confidence in that diagnosis;respondents were also asked to provide a management strategy for each case and their level of confidence in the chosen approach. Finally, we asked the physicians to estimate how many of their own patients have presentations similar to the individuals in the clinical vignettes. RESULTS: Physicians proposed, on average, 22 diagnoses for each case. Most indicated that they would choose action (testing, consulting, sending the patient to the emergency department, or prescribing) rather than follow-up only (87% vs 13%; P<.01). Respondents' confidence in the management approach they had chosen for all the cases was higher than their confidence in the diagnoses (5.6 vs 4.3, respectively, on a scale of1-10; P<.001). Physicians estimated that 10% to 20% of the patients they see in their practice have unusual or unexplained symptoms that are difficult to diagnose. CONCLUSION: Uncertain diagnosis is a regular challenge for primary care physicians. In such cases, we found that physicians prefer a workup to follow-up, an inclination consistent with"action bias." PMID- 24143334 TI - How can we better manage difficult patient encounters? AB - These communication strategies--including 2 mnemonics and an at-a-glance guide- can help you help patients with unexplained complaints. PMID- 24143335 TI - PURLs: should you still recommend omega-3 supplements? PMID- 24143336 TI - Painful nail with longitudinal erythronychia. PMID- 24143337 TI - Clinical Inquiry: What is the best initial treatment for venous stasis ulcers? PMID- 24143338 TI - Clinical Inquiry: Does metformin prevent diabetes in at-risk adults? PMID- 24143339 TI - Clinical Inquiry: Do asymptomatic adults need screening EKGs? PMID- 24143340 TI - Would you recognize this unusual cause of acute back pain? PMID- 24143341 TI - Don't mind the noise-- they're just trying to sleep. PMID- 24143342 TI - Is fenestration really needed? PMID- 24143343 TI - Can apps reduce rates of teen pregnancy? PMID- 24143344 TI - Author response: is fenestration really needed? PMID- 24143345 TI - Diabetes: 8 strategies to put into practice. AB - In search of ways to improve the way you approach diabetes care in your practice? Consider these strategies, which have worked for us-- and have evidence to support them. PMID- 24143346 TI - A nondrug approach to dementia. AB - Nearly 9 out of 10 patients with dementia also suffer from behavioral symptoms. Several nonpharmaceutical interventions hold promise. PMID- 24143347 TI - Obstructive sleep apnea: a diagnostic and treatment guide. AB - Patients with this common sleep disorder often fit the classic profile- - but not always. Here' s help knowing what to look for and when to test, as well as how best to treat it. PMID- 24143348 TI - PURLs: ramipril for claudication? AB - This ACE inhibitor can help patients with peripheral artery disease walk longer while remaining pain free. PMID- 24143349 TI - Too little training in acute care. PMID- 24143350 TI - When to consider Mohs surgery. AB - A long-standing malignant lesion or a tumor in a cosmetically sensitive area are 2 instances in which Mohs micrographic surgery yields superior results. PMID- 24143351 TI - Peripheral neuropathy linked to obstructive sleep apnea? AB - OSA may not be the first thing that comes to mind when examining a patient with peripheral neuropathy, but treating the sleep disorder can produce surprising benefits. PMID- 24143352 TI - Large pelvic mass in a 46-year-old woman. AB - Were we dealing with a malignant tumor, or something else? PMID- 24143353 TI - Clinical Inquiry: Elevated troponin but no CVD: what's the prognosis? AB - Patients with elevated troponin levels and chronic renal disease, pulmonary hypertension, pulmonary embolism, chronic obstructive pulmonary disease, sepsis, or acute ischemic stroke have a 2- to 5-fold increased risk of death, even in the absence of known cardiovascular disease. PMID- 24143354 TI - Oral contraceptives: does formulation matter? AB - OCs come in a variety of formulations but verifiable differences between products are difficult to find. PMID- 24143358 TI - Contrasting of biological samples for X-ray synchrotron microtomography. AB - The method of contrasting with iodine ions was developed to obtain high resolution 3D images of large biological specimens using a synchrotron X-ray microtomography unit. It was shown that the samples (late mouse embryos) treated with 50% Lugol solution with addition of 25% ethanol for 48 h followed by a 48-h washout in phosphate buffered saline had maximum contrast and lowest compression artifacts. Processing of samples by this protocol allowed detecting zones of active proliferation. Incubation of brain samples for 120 h in 7.6% meglumine/sodium diatrizoate without washout ensured the best contrast during myelin identification. PMID- 24143359 TI - Cytokine levels in rat blood and brain structures after administration of lipopolysaccharide. AB - We compared cytokine profile of rat serum and brain structures after immune status modulation by LPS (30 MUg/kg intraperitoneally). The content of inflammatory (IL-1alpha, IL-1beta, IL-2, IL-6, IFN-gamma, and TNF-alpha) and anti inflammatory (IL-4 and IL-10) cytokines in biological samples of animals was measured on days 1 and 7 after antigenic stimulation. LPS administration reduced the levels of both inflammatory and anti-inflammatory cytokines in the peripheral blood of the rats, especially on the 1st day. LPS administration was also accompanied by specific changes in cytokine content in the dorsal hippocampus and anterior cingulate cortex. Antigenic stimulation increased the level of anti inflammatory cytokines IL-4 and IL-10 in the examined brain tissues, the changes were most pronounced on day 1 after LPS injection. No significant changes in the levels of proinflammatory cytokines in the brain tissue of animals were found at the above terms after LPS injection. Thus, peripheral LPS administration to rats shifts the balance between the inflammatory and anti-inflammatory cytokines in the CNS structures towards the latter. PMID- 24143360 TI - Reactivity of the immune system and activities of PPARalpha and PPARgamma in the liver under conditions of LPS-induced acute inflammatory response in hypertensive ISIAH rats. AB - The effects of LPS from E. coli on DNA-binding activities of PPARalpha and PPARgamma in the liver and immune system parameters of were studied in hypertensive ISIAH rats and normotensive WAG rats. In ISIAH rats characterized by low basal level of PPARalpha, PPARgamma, and HDL, the response of the peripheral immune system compartment to LPS was more pronounced and was not associated with decrease in DNA-binding activities of PPARalpha observed in WAG. Proinflammatory stimulus did not induce proliferative changes in the thymus of ISIAH rats, which can reflect impaired relationships between the central and peripheral organs of the immune system. The character of regulatory interactions between PPARalpha and immune cells can differ in various rat strains and depend on initial PPARalpha activity, HDL level, specific features of immune status, resistance to stress, and hormonal and metabolic background. PMID- 24143361 TI - Heart rate regulation at different levels of convulsive readiness. AB - Heart rate variability parameters and the level of convulsive readiness during pentylenetetrazole-induced kindling in rats were analyzed using telemetric ECG and EEG monitoring. Analysis of ECG recorded over many days showed that heart rate variability was equally reduced after 7 and 27 days of kindling irrespective of the level of convulsive readiness. Reduced sympathovagal index after 7 days of kindling showed the compensatory character of changes. However, compensatory mechanisms cannot prevent high risk of life-threatening arrhythmias. High convulsive readiness after 27 days of kindling was accompanied by a shift of autonomic balance towards the increase in sympathetic tone, which may lead to decompensation and transition to a prenosological state. PMID- 24143362 TI - Mechanisms of napelline action stimulating the regeneration of hemopoietic tissue in cytostatic myelosuppression. AB - Pronounced regenerative effects of alkaloid napelline extracted from Aconitum baicalense on granulocytic hemopoiesis were revealed in the model of cytostatic myelosuppression. Activation of functions of hemopoietic progenitor cells along with increased feeder capacity of the stromal elements in the hemopoiesis inducing microenvironment with decreased levels mesenchymal progenitor cells in the bone marrow are the mechanisms underlying the hemostimulating action of this substance. PMID- 24143363 TI - Effects of prenatal exposure to antibodies against brain-specific anion transporter on cognitive functions in rats. AB - We studied the effects of single intravenous injection of antibodies to brain specific transmembrane anion transporter (BSAT1; 5 mg/kg) to pregnant rats (gestation day 10) on cognitive functions and behavior of their progeny. One of major functions of BSAT1 (or Oatp1c1) is specific transport of thyroxin across the blood-brain barrier. Female rats of two control groups were injected with non specific Ig and 0.9% NaCl. The progeny of rats receiving monoclonal antibodies to BSAT1 demonstrated memory impairment in the Y-maze, novel object recognition test, passive avoidance test, and Morris water maze test in comparison with the control group. Our findings suggest that single injection of monoclonal antibodies to BSAT1 during the prenatal period was followed by cognitive impairments, which were probably related to thyroxin deficiency in the nervous tissue. PMID- 24143364 TI - Hematological parameters and redox balance of rat blood in the dynamics of immobilization. AB - Hematological and biochemical parameters were studied in rat blood in the dynamics of immobilization (0.5, 1, and 3 h). Immobilization was followed by a release of old erythrocytes in the circulation and the development of reticulocytosis. The neutrophil count significantly increased by the third hour of immobilization. Restraint stress induced changes in activities of antioxidant enzymes (SOD and catalase) in erythrocytes and plasma level of MDA. The correlation between each enzyme (SOD, glutathione peroxidase, and catalase) and MDA concentration was the highest 1 h after the beginning of immobilization. These data can reflect the tension of antioxidant systems in red blood cells. The biochemical parameters returned to the basal level by the third hour of immobilization. Correlation coefficients between the activities of antioxidant enzymes and MDA amount decreased after 3 h of stress and the correlation between glutathione peroxidase and reduced glutathione significantly increased. The redox status of the blood returned to the initial values after 3 h. PMID- 24143365 TI - Pathogenesis of neurotoxicity of acrylates acrylonitrile and acrylamide: from cell to organism. AB - The incubation of 10 mM acrylamide (in vitro) with rat brain homogenate was followed by a decrease in catalase activity by 48% as soon as 5 min after addition of acrylate to the incubation medium. Activity of this enzyme remained low 30 min after the start of the experiment. Acute poisoning with this acrylate was accompanied by LPO activation in rat brain 24 h after injection. Exposure to acrylonitrile during occupational contacts with this monomer was followed by accumulation of adducts of acrylate with erythrocytic hemoglobin in human blood. In accordance with previously observed data, modern scheme of neurotropic effects of acrylonitrile and acrylamide was proposed. This scheme explained specific features of clinical syndromes induced by acute and chronic exposure to these toxic agents. PMID- 24143366 TI - Regenerative activity of 2-(1'-hydroxy-4'-isopropenyl-1'-methylcyclohexyl-2' thio) methyl ethanoate gel. AB - We studied regenerative activity of a sulfur-containing menthane terpenoid (2-(1' hydroxy-4'-isopropenyl-1'-methylcyclohexyl-2'-thio) methyl ethanoate) in the form of gels with different concentrations in experimental superficial non-penetrating corneal wound. The examined compound significantly increased the regenerative activity by accelerating the onset and completion of epithelialization. The use of 2% and 3% gel ensured finer scarring. PMID- 24143367 TI - Study of the absolute bioavailability of citrocard, a new GABA derivative. AB - The main pharmacokinetic parameters attest to short elimination half-life and mean retention time of a single citrocard molecule. The average rate of plasma concentration decrease of the compound determined small area under the pharmacokinetic curve. Steady-state distribution volume was low and only slightly surpassed the volume of extracellular body fluids in rat, which indicated moderate capacity of citrocard to distribution and accumulation in the tissues, which is seen from low systemic clearance (Cl) despite the quick elimination of the compound. Absolute bioavailability was 64%. PMID- 24143368 TI - Antioxidant properties of pyrrolobenzimidazole derivative RU-792: experimental study. AB - We studied antioxidant activity of new derivative of pyrrolo[1,2 alpha]benzimidazole RU-792 and compared its effects on free radical processes with those of the reference antioxidant Trolox in four model free-radical systems. RU-792 had high antioxidant activity determined by its intrinsic antiradical properties. RU-792 was superior to Trolox by antioxidant activity in the models of Fe(2+)-induced chemiluminescence of lipids with 2,2-diphenyl-1 picrylhydrazyl and 2,2'-azino-bis-(3-ethylbenzothiazoline-6-sulfonic acid), but less effective in the model of luminol-dependent chemiluminescence. PMID- 24143369 TI - Mechanism of suppression of phagocytic and metabolic activity of neutrophils and production of proinflammatory cytokines during chronic poisoning with organophosphorus compounds. AB - Experiments on albino outbred rats showed that chronic poisoning with organophosphorus compounds (Russian VX, and sarin) for 30 days in a total dose of 0.3 DL50 (0.01 DL50 daily) is followed by a decrease in phagocytic and metabolic activity of neutrophils. The reduction of functional activity of monocyte phagocytic system was stipulated by the stimulation of N-cholinergic receptors of these cells. These changes were accompanied by a decrease in blood concentration of proinflammatory cytokines (TNF-alpha, IL-1beta, and IL-6). PMID- 24143370 TI - Characteristics of bacterial biofilms during long-term culturing. AB - We studied properties of bacterial biofilms during long-term culturing. The biofilms were preserved for more than 90 days under the chosen conditions. At the same time, amounts of matrix and cells underwent periodic changes. The biomass of the biofilms decreased approximately every 7 days and then returned to the previous values. PMID- 24143371 TI - Immunological parameters of the blood and monoamine content in the brain of rats during long-term overcrowding. AB - Blood immunological parameters (cytokine profile and interferon status) and the level of monoamines and their metabolites in various brain structures (amygdala, hippocampus, septum, and hypothalamus) were studied in rats kept under standard conditions or in overpopulated cages. Long-term overcrowding was associated with reduced expression of IL-4 gene, increased transcription of IL-17, and decreased production of IFN-gamma, which attested to impaired humoral and cell-mediated immunity and disturbances in IFN-gamma synthesis at the post-transcriptional level. Under these conditions, the levels of norepinephrine and dopamine decreased in the septum, but increased in the hypothalamus. The amount of dopamine metabolite dihydroxyphenylacetic acid decreased in both these structures, and the index of dopamine metabolism (dihydroxyphenylacetic acid/dopamine ratio, DOPAC/dopamine) decreased only in the hypothalamus. Overcrowding was not followed by changes in the parameters of noradrenergic and dopaminergic systems in the amygdala and hippocampus and serotoninergic system in all study structures. PMID- 24143372 TI - Dexamethasone effects on activation and proliferation of immune memory T cells. AB - Dose-dependent effects of dexamethasone on activation and proliferation of donor immune memory T cells (CD45RO(+)) were studied. Activation of memory T cells associated with IL-2 production and membrane expression of CD25 molecule was resistant to dexamethasone. Proliferative activity of memory T cells associated with membrane expression of CD71 molecule was highly sensitive to dexamethasone. Hence, glucocorticoid hormones can maintain the clonal balance in the lymphoid tissue without preventing realization of the immune memory mechanism. PMID- 24143373 TI - Pathomorphosis of experimental infection in mice, infected by Streptococcus pneumoniae, under the effect of immunotropic drugs. AB - Pathomorphological changes in the organs of animals intranasally infected with Streptococcus pneumoniae were studied under conditions of immunotropic therapy added to antibiotic therapy. The pathomorphosis in the lungs, spleen, and thymus in animals treated with likopid, tinrostim, and roncoleukin was described. A positive time course of the pathological process in experimental animals in comparison with intact animals and animals receiving no immunotropic drugs was demonstrated. PMID- 24143374 TI - Mitochondria in Lewis lung carcinoma cells under the effect of magnetosensitive nanocomplex and radiofrequency hyperthermia. AB - Electron microscopic study of Lewis lung carcinoma cell mitochondria after intravenous injection of a magnetosensitive nanocomplex based on ferric oxide (Fe3O4) nanoparticles and doxorubicin followed by radiofrequency hyperthermia showed that a common increase of the electron density of the cytoplasm was paralleled by mitochondrial edema in comparison with organelles of animals receiving doxorubicin alone. These changes were accompanied by virtually total lysis of the cristae and sharp clarification of mitochondrial matrix, which was seen from appreciable increase in mitochondria image brightness. Morphometric analysis showed lesser perimeter, area, and mean radius of the tumor cell mitochondria in animals receiving the injection of magnetosensitive nanocomplex and exposed to radiofrequency hyperthermia in comparison with those injected with doxorubicin alone. Histograms of distribution of the perimeter, area, and mean radius of the mitochondria after combined exposure to the nanocomplex and hyperthermia showed bimodal asymmetrical distribution. Injection of the magnetosensitive nanocomplex followed by radiosensitive hyperthermia led to more significant impairment of the tumor cell mitochondrial ultrastructure than doxorubicin alone. PMID- 24143375 TI - Effects of nanodispersed iron on the morphofunctional parameters of the blood system. AB - The effects of nanodispersed iron forms on the morphology and function of the blood system were studied. Maghemite and lepidocrocite caused a leukocytic shift towards segmented neutrophil forms, reduction of lymphocyte rigidity, and stimulated their compactization. In addition, the counts of small hyperchromatic erythrocytes with high rigidity increased in the blood flow. The results indicated that a single dose of nanodispersed iron-containing drugs improved the blood respiratory function and its microrheology. PMID- 24143376 TI - Organ, cellular, and subcellular localization of brain-specific anion transporter BSAT1. AB - Organ, cellular, and subcellular localization of brain-specific anion transporter BSAT1 was studied in rats using antibodies to the extracellular fragment (451-557 a.a). The antibodies were shown to recognize the antigen predominantly localized in the nervous tissue, tumors of glial origin, and primordial ovarian follicles. The absence of BSAT1 immunofluorescence signal in kidney and liver sections and accumulation of (125)I labeled antibodies to BSAT1 in these organs indicate that these antibodies do not cross-react with the most common isoforms of OATP expressed in these organs. Analysis of the cellular localization suggests that in the brain, BSAT1 is localized predominantly in astrocytes, but not in endothelial cells, as was previously reported. Laser scanning confocal microscopy with a set of relevant trackers revealed membrane localization of BSAT1. Taking into account the data on the of localization, we can conclude that antibodies to BSAT1 451-557 can be used for basic research of the transport of thyroxin and prostaglandins across the blood brain barrier and for testing the systems for targeted transport of diagnostic preparations and drugs across the blood brain barrier, e.g. to astroglial tumors. PMID- 24143377 TI - Infradian modulation of circadian rhythms of proliferative activity of the esophageal and corneal epithelium. AB - Many-day rhythms of proliferative activity of the corneal and esophageal epithelium and serum corticosterone levels were studied in adult male Wistar rats. We detected a 4-day rhythm of proliferative activity of esophageal epithelium negatively correlating with corticosterone level. A more pronounced decrease in the number of mitoses in the esophageal and corneal epithelium was recorded every 12 days. Analysis of the rhythm of mitotic activity in different experimental series carried out over 9 months showed that the acrophase of the detected 4- and 12-day periods is shifted 1 day forward every 69-73 days. The detected infradian constituents of the circadian rhythms of epithelial proliferative activity should be taken into consideration in experimental studies and in development of chronobiological approaches to the treatment of diseases caused by disorders of the proliferative activity of the epithelium. PMID- 24143378 TI - Antifibrotic effects of immobilized hyaluronidase in repeated bleomycin-induced lesions of the alveolar epithelium. AB - Antifibrotic activity of testicular hyaluronidase, immobilized on polyethylenoxide and obtained by electron beam synthesis, was studied on the model of bleomycin injuries to the alveolar epithelium (irreversible pneumofibrosis) in C57Bl/6 mice and compared to the effect of testicular hyaluronidase. Intranasal therapy with immobilized and testicular hyaluronidases prevented the deposition of fibrotic mass in the parenchyma of "bleomycin" lungs. The effect of immobilized hyaluronidase was more pronounced than that of testicular hyaluronidase. The studied compounds were virtually inessential for infiltration of the alveolar interstitium and alveolar tracts by lymphocytes, macrophages, neutrophils, and plasma cells. Unchanged histoarchitectonics of bleomycin-damaged lungs in immobilized hyaluronidase therapy was due to suppression of the progenitor fibroblast cells (CD45(-)). PMID- 24143379 TI - Morphological characteristics of the terminal villi in placental failure. AB - A comparative morphological study of the placentas in spontaneous and induced pregnancy aggravated by placental failure was carried out. Placental failure manifested by shrinkage of the terminal villi, lesser number and section areas of their capillaries, and higher expression of vascular endothelium growth factor and endothelial NO synthase in the syncytiotrophoblast and villous endotheliocytes. The changes were more pronounced in pregnancy developing after in vitro fertilization. PMID- 24143380 TI - Immunocytochemical analysis of proliferative activity of endometrial and myometrial cell populations in focal and stromal adenomyosis. AB - Immunocytochemical study has shown that Ki-67 antigen is detected in adenomyosis in both endometrial and myometrial cell populations (in the eutopic and ectopic endometrial glandular epithelium, stromal cells, smooth muscle cells, and vascular endotheliocytes of the endometrium and myometrium), the label index differing significantly in different cell populations. The highest labeled cell index is found in the endometrial gland epitheliocytes in focal adenomyosis (23.2 +/- 2.9%); in the stromal variant this index is by 2.8 times lower despite the fact that this variant is associated with endometrial glandular hyperplasia in the majority of cases. Proliferative activity of secretory epitheliocytes is significantly lower in both adenomyosis variants than in the normal eutopic endometrium. Stromal adenomyosis is characterized by 2-fold higher proliferative activity of the cytogenic stroma than that in focal adenomyosis. PMID- 24143381 TI - Plastic efficiency of different implants used for repair of soft and bone tissue defects. AB - The results of clinical and experimental morphological studies of regenerates forming after replacement of large defects of the abdominal wall and tibia with implants from different materials (polytetrafluoroethylene, reperene, prolene, titanium, and titanium nickelide) are analyzed. Study of the regenerate histology and fibroarchitectonics has shown good prospects of mesh constructions from titanium nickelide for effective surgical repair of these defects. The use of this implant seems to be theoretically well-based and promising, particularly under conditions of suppurative infection and low individual reparative regenerative potential. PMID- 24143382 TI - Express analysis of HER-2/neu status in breast cancer biopsy specimens. AB - Hyperexpression of HER-2/neu is found in tissues of 25-30% patients with primary breast cancer. Monotherapy with antitumor drug trastuzumab as second-third line therapy and its combination with cytostatics prolong the interval before disease progress and the overall survival of patients with metastatic HER-2/neu+ tumors. Trastuzumab is now prescribed after evaluation of HER-2/neu status by the immunohistochemical method and/or fluorescent in situ hybridization. We have developed a method for evaluating the HER-2/neu status of breast cancer biopsy specimens by real time reverse transcription PCR. Based on the analysis of published data, six candidate genes in the pericentromer region of chromosome 17 are selected for data normalization. Stability of these genes is verified on the cell model (MCF-7 and SK-BR-3) and on biopsy materials. The sensitivity and specificity of the method is evaluated on a collection of biopsy specimens. PMID- 24143383 TI - Long-distance effects of human subjective status on the blood physicochemical characteristics. AB - The external long-distance manifestations of the subjective status of a human being are analyzed. The subjective states of a human being can be objectively recorded at a long distance. A contact-free long-distance effect of human subjective status on the physicochemical parameters of the blood is demonstrated. The concept of the specific phenomena in the brain, which cannot exist in dead nature, is formulated. PMID- 24143384 TI - Expression and intracellular localization of ACA and TRA-1-81 in smooth muscle cell tumors. AB - We studied the expression and intracellular localization of ACA and TRA-1-81 in smooth muscle cell tumors. The study was performed on tissue specimens obtained during surgery from patients with uterine leiomyoma and leiomyosarcoma (mean age 34 and 51 years, respectively). ACA was present in leiomyoma, leiomyosarcoma, and control myometrium. Intracellular expression of ACA varied in different types of tumors and was minimum in normal myometrium and maximum in leiomyosarcoma. Membrane localization of the protein is typical of common and cellular leiomyoma, while in the growth zones of mitotically active leiomyoma and leiomyosarcoma the reaction product was primarily located in tumor cell cytoplasm. TRA was detected in some leiomyosarcoma cells. Thus, ACA dysregulation was revealed in the growth zones of leiomyomas and in leiomyosarcomas, which manifested in enhanced expression of this protein and its detachment from the plasma membrane, which leads ACA translocation into the cytoplasm and nucleus of tumor cells and potentiates their proliferative activity. PMID- 24143385 TI - A novel human glycoprotein ACA is an upstream regulator of human hematopoiesis. AB - A central issue in stem cell biology is a better understanding of the molecular mechanisms that regulate self-renewal of human hematopoietic stem cells (HSCs). Control of the specific function of HSCs like self-renewal and differentiation might be regulated by a common set of critical genes. However, the regulation among these genes is yet to be elucidated. Here, we show that activation by a novel human GPI-linked glycoprotein ACA at the surface of human peripheral blood progenitor cells induces via PI3K/Akt/mTor/PTEN upregulation of WNT, Notch1, Bmi 1 and HoxB4 genes thus, promoting self-renewal and generation of primitive HSCs. ACA-generated self-renewing cells retained their lympho-myeloid repopulating potential in NOD/SCID mouse xeno-transplantation model with long term functional capacity. We conclude that ACA is an essential regulator of the genes involved in maintaining hematopoiesis and its use in clinical praxis could overcome many of the barriers present so far in transplantation medicine. PMID- 24143386 TI - Activation by ACA induces pluripotency in human blood progenitor cells. AB - Reprogramming of human somatic cells by transcription factors to pluripotent state holds great promise for regenerative medicine. However, low efficiencies of current reprogramming methods, immunogenicity and lack of understanding regarding the molecular mechanisms responsible for their generation, limits their utilization and raises questions regarding safety for therapeutic application. Here we report that ACA signaling via PI3K/Akt/mTor induces sustained de differentiation of human blood progenitor cells leading to generation of ACA pluripotent stem cells. Blood-derived pluripotent stem cells differentiate in vitro into cell types of all three germ layers, exhibiting neuronal, liver, or endothelial characteristics. Our results reveal insight into the molecular events regulating cellular reprogramming and also indicate that pluripotency might be controlled in vivo through binding of a natural ligand(s) to ACA receptor enabling reprogramming through defined pathway(s) and providing a safe and efficient method for generation of pluripotent stem cells which could be a breakthrough in human therapeutics. PMID- 24143387 TI - Accumulation and elimination of photosens and protoporphyrin IX by different types of mesenchymal cells. AB - We studied the kinetics of accumulation and elimination of Photosens and accumulation of protoporphyrin IX in macrophages, endothelial cells, and mesenchymal stromal cells of the human adipose tissue in vitro. In all studied cells, the dynamics of Photosens accumulation was described by a multiphase curve and the maximum accumulation of the dye was observed during the second exponential phase. Elimination of Photosens did not depend on the cell function. Accumulation of protoporphyrin IX differed considerably in different cells: it was maximum in mesenchymal stromal cells was practically not detected in endothelial cells. Accumulation of the dye by macrophages depended on individual donor characteristics. PMID- 24143388 TI - The role of mesenchymal stem cells and serotonin in the development of experimental pancreatitis. AB - Pancreatitis was modeled before and after preliminary transplantation of stem cells and serotonin. It was demonstrated that transplantation of mesenchymal stem cells and activation of serotoninergic system prevent the development of pancreatitis. PMID- 24143389 TI - Effect of concentration of platelet-derived growth factor on proliferative activity of human fibroblasts. AB - Serum concentration of platelet-derived growth factor was measured in patients with trophic ulcers and proliferative activity of human fibroblasts was measured in wells with different content of added serum platelet-derived growth factor. In parallel, morphofunctional analysis of platelets from the whole blood of these patients was performed. A close correlation was found between morphofunctional parameters of blood platelets and serum concentration of platelet-derived growth factor. Platelet-derived growth factor in concentrations below 150 pg per well stimulated fibroblast proliferation and preserved their viability. Platelet derived growth factor in concentrations >200 pg per well suppressed fibroblast proliferation and impaired their viability. PMID- 24143390 TI - Biological activity of amino acids in organotypic tissue cultures. AB - We studied the effect of 20 standard L-amino acids on proliferation of the nervous, cardiovascular, urogenital, digestive, and immune system tissues from young and old animals in organotypic cultures. The effect of amino acids on tissue culture proliferation depended on their origin and animal age. PMID- 24143802 TI - Mechanisms of functional and physical genome reduction in photosynthetic and nonphotosynthetic parasitic plants of the broomrape family. AB - Nonphotosynthetic plants possess strongly reconfigured plastomes attributable to convergent losses of photosynthesis and housekeeping genes, making them excellent systems for studying genome evolution under relaxed selective pressures. We report the complete plastomes of 10 photosynthetic and nonphotosynthetic parasites plus their nonparasitic sister from the broomrape family (Orobanchaceae). By reconstructing the history of gene losses and genome reconfigurations, we find that the establishment of obligate parasitism triggers the relaxation of selective constraints. Partly because of independent losses of one inverted repeat region, Orobanchaceae plastomes vary 3.5-fold in size, with 45 kb in American squawroot (Conopholis americana) representing the smallest plastome reported from land plants. Of the 42 to 74 retained unique genes, only 16 protein genes, 15 tRNAs, and four rRNAs are commonly found. Several holoparasites retain ATP synthase genes with intact open reading frames, suggesting a prolonged function in these plants. The loss of photosynthesis alters the chromosomal architecture in that recombinogenic factors accumulate, fostering large-scale chromosomal rearrangements as functional reduction proceeds. The retention of DNA fragments is strongly influenced by both their proximity to genes under selection and the co-occurrence with those in operons, indicating complex constraints beyond gene function that determine the evolutionary survival time of plastid regions in nonphotosynthetic plants. PMID- 24143803 TI - Centromere pairing in early meiotic prophase requires active centromeres and precedes installation of the synaptonemal complex in maize. AB - Pairing of homologous chromosomes in meiosis is critical for their segregation to daughter cells. In most eukaryotes, clustering of telomeres precedes and facilitates chromosome pairing. In several species, centromeres also form pairwise associations, known as coupling, before the onset of pairing. We found that, in maize (Zea mays), centromere association begins at the leptotene stage and occurs earlier than the formation of the telomere bouquet. We established that centromere pairing requires centromere activity and the sole presence of centromeric repeats is not sufficient for pairing. In several species, homologs of the ZIP1 protein, which forms the central element of the synaptonemal complex in budding yeast (Saccharomyces cerevisiae), play essential roles in centromere coupling. However, we found that the maize ZIP1 homolog ZYP1 installs in the centromeric regions of chromosomes after centromeres form associations. Instead, we found that maize structural maintenance of chromosomes6 homolog forms a central element of the synaptonemal complex, which is required for centromere associations. These data shed light on the poorly understood mechanism of centromere interactions and suggest that this mechanism may vary somewhat in different species. PMID- 24143804 TI - Plastid genes that were lost along the road to parasitism. PMID- 24143805 TI - Laccase is necessary and nonredundant with peroxidase for lignin polymerization during vascular development in Arabidopsis. AB - The evolution of lignin biosynthesis was critical in the transition of plants from an aquatic to an upright terrestrial lifestyle. Lignin is assembled by oxidative polymerization of two major monomers, coniferyl alcohol and sinapyl alcohol. Although two recently discovered laccases, LAC4 and LAC17, have been shown to play a role in lignin polymerization in Arabidopsis thaliana, disruption of both genes only leads to a relatively small change in lignin content and only under continuous illumination. Simultaneous disruption of LAC11 along with LAC4 and LAC17 causes severe plant growth arrest, narrower root diameter, indehiscent anthers, and vascular development arrest with lack of lignification. Genome-wide transcript analysis revealed that all the putative lignin peroxidase genes are expressed at normal levels or even higher in the laccase triple mutant, suggesting that lignin laccase activity is necessary and nonredundant with peroxidase activity for monolignol polymerization during plant vascular development. Interestingly, even though lignin deposition in roots is almost completely abolished in the lac11 lac4 lac17 triple mutant, the Casparian strip, which is lignified through the activity of peroxidase, is still functional. Phylogenetic analysis revealed that lignin laccase genes have no orthologs in lower plant species, suggesting that the monolignol laccase genes diverged after the evolution of seed plants. PMID- 24143806 TI - Root systems biology: integrative modeling across scales, from gene regulatory networks to the rhizosphere. AB - Genetic and genomic approaches in model organisms have advanced our understanding of root biology over the last decade. Recently, however, systems biology and modeling have emerged as important approaches, as our understanding of root regulatory pathways has become more complex and interpreting pathway outputs has become less intuitive. To relate root genotype to phenotype, we must move beyond the examination of interactions at the genetic network scale and employ multiscale modeling approaches to predict emergent properties at the tissue, organ, organism, and rhizosphere scales. Understanding the underlying biological mechanisms and the complex interplay between systems at these different scales requires an integrative approach. Here, we describe examples of such approaches and discuss the merits of developing models to span multiple scales, from network to population levels, and to address dynamic interactions between plants and their environment. PMID- 24143807 TI - An S-domain receptor-like kinase, OsSIK2, confers abiotic stress tolerance and delays dark-induced leaf senescence in rice. AB - Receptor-like kinases play important roles in plant development and defense responses; however, their functions in other processes remain unclear. Here, we report that OsSIK2, an S-domain receptor-like kinase from rice (Oryza sativa), is involved in abiotic stress and the senescence process. OsSIK2 is a plasma membrane-localized protein with kinase activity in the presence of Mn(2+). OsSIK2 is expressed mainly in rice leaf and sheath and can be induced by NaCl, drought, cold, dark, and abscisic acid treatment. Transgenic plants overexpressing OsSIK2 and mutant sik2 exhibit enhanced and reduced tolerance to salt and drought stress, respectively, compared with the controls. Interestingly, a truncated version of OsSIK2 without most of the extracellular region confers higher salt tolerance than the full-length OsSIK2, likely through the activation of different sets of downstream genes. Moreover, seedlings of OsSIK2-overexpressing transgenic plants exhibit early leaf development and a delayed dark-induced senescence phenotype, while mutant sik2 shows the opposite phenotype. The downstream PR related genes specifically up-regulated by full-length OsSIK2 or the DREB-like genes solely enhanced by truncated OsSIK2 are all induced by salt, drought, and dark treatments. These results indicate that OsSIK2 may integrate stress signals into a developmental program for better adaptive growth under unfavorable conditions. Manipulation of OsSIK2 should facilitate the improvement of production in rice and other crops. PMID- 24143808 TI - A quorum-sensing inhibitor blocks Pseudomonas aeruginosa virulence and biofilm formation. AB - Quorum sensing is a chemical communication process that bacteria use to regulate collective behaviors. Disabling quorum-sensing circuits with small molecules has been proposed as a potential strategy to prevent bacterial pathogenicity. The human pathogen Pseudomonas aeruginosa uses quorum sensing to control virulence and biofilm formation. Here, we analyze synthetic molecules for inhibition of the two P. aeruginosa quorum-sensing receptors, LasR and RhlR. Our most effective compound, meta-bromo-thiolactone (mBTL), inhibits both the production of the virulence factor pyocyanin and biofilm formation. mBTL also protects Caenorhabditis elegans and human lung epithelial cells from killing by P. aeruginosa. Both LasR and RhlR are partially inhibited by mBTL in vivo and in vitro; however, RhlR, not LasR, is the relevant in vivo target. More potent antagonists do not exhibit superior function in impeding virulence. Because LasR and RhlR reciprocally control crucial virulence factors, appropriately tuning rather than completely inhibiting their activities appears to hold the key to blocking pathogenesis in vivo. PMID- 24143809 TI - Nuclear translation for immunosurveillance. PMID- 24143810 TI - Directing stem cell differentiation with antibodies. PMID- 24143811 TI - Live fast, die young, and win the sperm competition. PMID- 24143812 TI - Breaking the limits of artificial ubiquitination. PMID- 24143813 TI - End-of-life electrical surges. PMID- 24143814 TI - No evidence for manganese-oxidizing photosynthesis. PMID- 24143815 TI - Increases in HIV screening in primary care clinics through an electronic reminder: an interrupted time series. AB - OBJECTIVE AIM: Identify and eliminate barriers to HIV testing in primary care and to decrease the rates of patients never being tested, and limit unnecessary repeat testing. SETTING: Primary care clinics within an urban publicly funded safety net hospital and community health system in Cleveland, Ohio. Reported HIV prevalence among male Cleveland residents is 1193.5/100 000. DESIGN: A time series analysis using statistical process control was used. METHODS: Primary care encounters of patients aged 13-64 years from selected sites were reviewed throughout the initiative for HIV testing prior to the visit and associated with the visit. RESULTS: Run charts of the proportion of men and women never tested for HIV demonstrated marked improvement and special cause variation with six sequential quarters falling outside of the trend lines. Evaluation of encounters associated with a first HIV test confirmed testing occurring within primary care rather than elsewhere in the health system. CONCLUSIONS: Implementing an electronic medical record-based reminder effectively increased HIV testing among primary care patients not previously tested, while education and practice feedback alone did not. PMID- 24143816 TI - TREM2 and neurodegenerative disease. PMID- 24143817 TI - Author's reply: To PMID 22804979. PMID- 24143819 TI - Matters of significance. PMID- 24143818 TI - Author's reply: To PMID 23128542. PMID- 24143820 TI - The author file: Samie Jaffrey. PMID- 24143821 TI - Points of significance: Importance of being uncertain. PMID- 24143822 TI - Light on genome function. PMID- 24143823 TI - Cells under pressure. PMID- 24143824 TI - The influence of a host. PMID- 24143825 TI - Single-cell genetics. PMID- 24143826 TI - Strength in numbers. PMID- 24143827 TI - Calcium sensors reach new heights. PMID- 24143828 TI - Microbial planet. PMID- 24143830 TI - Highest heart failure mortality. PMID- 24143829 TI - Registry confirms transcatheter aortic valve implantation efficacy and safety in Asian patients. PMID- 24143831 TI - Current world literature. Infectious diseases. PMID- 24143832 TI - Current world literature. Critical care outcomes. PMID- 24143833 TI - Respiratory tract infection. PMID- 24143834 TI - Charles Bonnet syndrome and Terson's syndrome: good news from bad news. PMID- 24143835 TI - In response. PMID- 24143836 TI - In response. PMID- 24143837 TI - In response. PMID- 24143838 TI - In response. PMID- 24143839 TI - Proctecting patient medical data. The C-suite's role. PMID- 24143840 TI - [Prioritization of medical services as a social responsibility]. PMID- 24143841 TI - [Modern developments in neurological rehabilitation]. PMID- 24143843 TI - Monthly report on dracunculiasis cases, January - July 2013. PMID- 24143842 TI - Haemophilus influenzae type b (Hib) Vaccination Position Paper - July 2013. PMID- 24143844 TI - Percutaneous autologous bone marrow injections for delayed or non-union of bones. PMID- 24143845 TI - Author response. PMID- 24143846 TI - Achieving high reliability: other industries can help health care's safety transformation. PMID- 24143847 TI - Release of medical information. Ex parte Western Mental Health Center, So. 3d, Nos. 1011990, 1021481 (Ala. Dec. 30, 2003). PMID- 24143848 TI - Risk management information. In re Deposition of Harrington Memorial Hospital, Mass. App. Ct., N.E. 2d, No. 03-2150 (Mass. Super. Ct. Nov. 25, 2003). PMID- 24143849 TI - Peer review information. Christy v. Salem, 366 N.J. Super. 535, 841 A. 2d 937 (N.J. Super Ct. 2004). PMID- 24143850 TI - Disclosure. Schlote v. Dawson, 676 N. W. 2d 187 (Iowa 2004). PMID- 24143851 TI - The Affordable Care Act's new tools and resources to improve health and care for low-income families across the country. AB - The Commonwealth Fund Scorecard on State Health System Performance for Low-Income Populations, 2013, finds wide gaps by income in access to care, quality of care received, and health outcomes in all states, and major differences between states in health system performance for people with below-average incomes. The Affordable Care Act provides state and local leaders with unprecedented opportunity along with new tools and resources to raise the standard for everyone and to begin to close the geographic and income divide. This issue brief reviews provisions of the law that have the potential to benefit low- and modest-income individuals, including those that expand health insurance coverage; strengthen primary care and improve care coordination; bolster the capacity of providers serving low-income communities; move toward greater accountability for the quality and cost of care; and invest in public health. It concludes by highlighting some of the challenges that lie ahead. PMID- 24143852 TI - Impact of therapy options on in-hospital and three-year outcome of patients with ST-elevation myocardial infarction in Beijing. AB - OBJECTIVES: To evaluate the clinical characteristics, in-hospital and three-year outcome in ST-elevation myocardial Infraction (STEMI) patients receiving conservative treatment (CT), thrombolytic treatment (TT) and primary percutaneous coronary intervention (PCI) in Beijing. METHODS: This 12-month prospective, multicenter registry study was conducted in 19 hospitals with 808 patients with STEMI in Beijing between Jan. 2006 and Dec. 2006, 518 (64%) received PCI, 106 (16.1%) received TT and 184 (22.8%) received CT therapy. Patients were followed up for 3 years. RESULTS: At baseline, the age of patients in CT group [(64.5 +/- 13.5) years] was significantly higher than those in TT group p(57.9 +/- 11.0) years] and in PCI group [ (60.4 +/- 12.3) years, all P<0.01]; and the median time from symptom onset to hospital in CT group (207 min) was significantly longer than those in TT group (130 min) and PCI group (130 min, all P<0.01). Emergency Medical Service (EMS) use was significantly higher in PCI group (184/518, 35.5%) than in CT group (46/184, 27.3%) and TT group (29/107, 25.0%, all P<0.05). Health insurance holder was the highest in PCI group (P<0.01). PCI was performed less frequently than thrombolytic therapy [66.6% (345/518) vs. 80.2% (85/106)m P=0.02] during off-hours and more frequently performed in tertiary hospitals than in secondary hospitals[66.8%(437/651) vs. 52.6% (81/154, P<0.01)]. The in-hospital mortality and the cardiovascular mortality at 3 year after hospital discharge was significantly higher in CT group [9.2% (17/185) and 9.4% (15/159)] than in PCI group [3.5% (18/518), 4.5% (20/446)] and TT group [6.6% (7/106), 2.3% (2/86), all P<0.01]. Patients in PCI group had the highest adherence level of aspirin, beta blocker, angiotensin-converting enzyme inhibitors/angiotensin-receptor blockers or statins at 3-years follow-up (all P<0.05). Multivariable Cox proportional hazards regression analysis showed that only PCI was associated with lower risk of cardiovascular death (HR-0.40, 95% CI:0.21-0.73, P<0.01). CONCLUSIONS: Social and clinical setting may affect the physician's decision to provide reperfusion therapy in Beijing for STEMI patients. Better adherence of secondary preventive drugs and lower cardiovascular death are observed in STEMI patients receiving PCI during the 3-year follow-up PMID- 24143853 TI - Preventing unintended retained foreign objects. PMID- 24143854 TI - Rigidity and hyperCKemia as presenting signs of Hashimoto's encephalopathy. PMID- 24143855 TI - Recovery from deafness in the contralateral ear of surgery in NF 2 patient. PMID- 24143856 TI - Retraction notice to "Inosine-specific cleavage of RNA for microarray analysis of RNA A-to-I editing targets" [The Kaohsiung Journal of Medical Sciences 29/4 (April 2013) 179-86]. PMID- 24143857 TI - Membrane permeability-guided identification of neuroprotective components from Polygonum cuspidatun. AB - CONTEXT: Polygonum cuspidatum Sieb et Zucc. (Polygonaceae) possesses various pharmacological activities and has been widely using as one of the most popular and valuable Chinese herbal medicines in clinics. Its usage has increasingly attracted much of our attention and urges investigation on its bioactive components. OBJECTIVE: To establish a rapid and valid approach for screening potential neuroprotective components from P. cuspidatum. MATERIALS AND METHODS: Potential neuroprotective components from P. cuspidatum were screened utilizing liposome equilibrium dialysis followed by high-performance liquid chromatography (HPLC) analysis. Their neuroprotective effects on modulation of protein expression of alpha7 nAChR, alpha3 nAChR and synaptophysin (SPY) on SH-SY5Y human neuroblastoma cell line (SH-SY5Y) were evaluated by means of Western blotting. RESULTS: Two potential compounds, polydatin (C1) and emodin-8-O-beta-D-glucoside (C2), were detected and identified in our study. The biological tests showed that both compounds C1 and C2, respectively, at concentrations of 0.1 and 0.25 mg/mL significantly increased protein expression of alpha7 and alpha3 nicotinic acetylcholine receptors (nAChRs) in SH-SY5Y cells. Moreover, C1 and C2 at 0.1 mg/mL significantly reversed the Abeta1-42-induced decrease of alpha7 and alpha3 nAChRs protein expression in SH-SY5Y cells. In addition, C2 at 0.1 mg/mL significantly increased protein expression of SPY in SH-SY5Y cells and Abeta11-42 induced SH-SY5Y cells whereas C1 did not provide any positive effects. DISCUSSION AND CONCLUSION: In conclusion, our approach utilizing liposome equilibrium dialysis combined with HPLC analysis and cell-based assays is a prompt and useful method for screening neuroprotective agents. PMID- 24143860 TI - Inkjet-printed In(2)O(3) thin-film transistor below 200 degrees C. AB - High-performance In2O3 thin-film transistors could be prepared by an inkjet printing method below 200 degrees C with a single precursor and solvent formulation. The self-combustion reaction took place with the electrical properties of In2O3 at a low temperature of 147 degrees C, which was confirmed by X-ray photoelectron spectroacopy and thermal analysis. The electrical properties after postannealing at 200 degrees C were as follows: a mobility of 3.98 cm(2)/V.s, a threshold voltage of 1.83 V, a subthreshold slope of 0.4 V/dec, and an on-to-off current ratio of 10(8), which are the best properties by an inkjet process thus far. The positive bias stability was much improved by postannealing, and good negative bias stability was obtained. PMID- 24143859 TI - Positive association between Interleukin-8 -251A > T polymorphism and susceptibility to gastric carcinogenesis: a meta-analysis. AB - BACKGROUNDS: The associations between the polymorphisms of interleukin-8 (IL-8) gene and gastric carcinogenesis have been extensively investigated in recent years. However, the results remain conflicting rather than conclusive. METHODS: A meta-analysis of 18 eligible studies was performed to evaluate the association of IL-8 -251A > T polymorphism with risk of gastric carcinogenesis. A systematic literature search of MEDLINE, Embase, and Web of Science, CNKI databases was conducted. Statistical analysis was performed by using the Revman 5.1 software and the Stata 12.0 software. RESULTS: Of the 293 unique studies identified using our search criteria, 18 studies fulfilled our inclusion criteria and were included in the meta-analysis. These studies cumulatively reported 5,321 cases and 6,465 controls. The combined results based on all studies showed that the IL 8 -251A > T polymorphism was associated with the risk of gastric carciongenesis (A vs. T OR: 1.14 [1.02, 1.26], P = 0.02), especially gastric cancer (A vs. T OR: 1.15 [1.03, 1.29], P = 0.02), but not associated with the risk of precancerous lesion (A vs. T OR: 1.09 [0.99, 1.20], P = 0.08). Analysis stratified by ethnicity may seem that IL-8 -251A > T polymorphism was susceptible to gastric cancer in Asian population, but not in Caucasian population. CONCLUSIONS: Our meta-analysis results provide evidence that IL-8 -251A > T polymorphism is significantly associated with increased risk of gastric carcinogenesis in Asian population, particularly in gastric cancer. Further large and well-designed studies are required to confirm this conclusion. PMID- 24143858 TI - Two-wave nanotherapy to target the stroma and optimize gemcitabine delivery to a human pancreatic cancer model in mice. AB - Pancreatic ductal adenocarcinoma (PDAC) elicits a dense stromal response that blocks vascular access because of pericyte coverage of vascular fenestrations. In this way, the PDAC stroma contributes to chemotherapy resistance in addition to causing other problems. In order to improve the delivery of gemcitabine, a first line chemotherapeutic agent, a PEGylated drug-carrying liposome was developed, using a transmembrane ammonium sulfate gradient to encapsulate the protonated drug up to 20% w/w. However, because the liposome was precluded from entering the xenograft site due to the stromal interference, we developed a first-wave nanocarrier that decreases pericyte coverage of the vasculature through interference in the pericyte recruiting TGF-beta signaling pathway. This was accomplished using a polyethyleneimine (PEI)/polyethylene glycol (PEG)-coated mesoporous silica nanoparticle (MSNP) for molecular complexation to a small molecule TGF-beta inhibitor, LY364947. LY364947 contains a nitrogen atom that attaches, through H-bonding, to PEI amines with a high rate of efficiency. The copolymer coating also facilitates systemic biodistribution and retention at the tumor site. Because of the high loading capacity and pH-dependent LY364947 release from the MSNPs, we achieved rapid entry of IV-injected liposomes and MSNPs at the PDAC tumor site. This two-wave approach provided effective shrinkage of the tumor xenografts beyond 25 days, compared to the treatment with free drug or gemcitabine-loaded liposomes only. Not only does this approach overcome stromal resistance to drug delivery in PDAC, but it also introduces the concept of using a stepwise engineered approach to address a range of biological impediments that interfere in nanocancer therapy in a spectrum of cancers. PMID- 24143861 TI - TINU (tubulointerstitial nephritis uveitis) can be associated with chorioretinal scars. AB - PURPOSE: To report a case series of patients with chorioretinal lesions secondary to tubulointerstitial nephritis and uveitis (TINU). METHODS: Retrospective chart review of patients with TINU. RESULTS: We found 4 patients (3 with a possible or probable diagnosis of TINU and 1 with a definite diagnosis of TINU) and multiple chorioretinal lesions. CONCLUSION: Tubulointerstitial nephritis and uveitis usually presents with anterior uveitis, but chorioretinal lesions do occur and may facilitate the diagnosis. PMID- 24143862 TI - Copper-encapsulated vertically aligned carbon nanotube arrays. AB - A new procedure is described for the fabrication of vertically aligned carbon nanotubes (VACNTs) that are decorated, and even completely encapsulated, by a dense network of copper nanoparticles. The process involves the conformal deposition of pyrolytic carbon (Py-C) to stabilize the aligned carbon-nanotube structure during processing. The stabilized arrays are mildly functionalized using oxygen plasma treatment to improve wettability, and they are then infiltrated with an aqueous, supersaturated Cu salt solution. Once dried, the salt forms a stabilizing crystal network throughout the array. After calcination and H2 reduction, Cu nanoparticles are left decorating the CNT surfaces. Studies were carried out to determine the optimal processing parameters to maximize Cu content in the composite. These included the duration of Py-C deposition and system process pressure as well as the implementation of subsequent and multiple Cu salt solution infiltrations. The optimized procedure yielded a nanoscale hybrid material where the anisotropic alignment from the VACNT array was preserved, and the mass of the stabilized arrays was increased by over 24-fold because of the addition of Cu. The procedure has been adapted for other Cu salts and can also be used for other metal salts altogether, including Ni, Co, Fe, and Ag. The resulting composite is ideally suited for application in thermal management devices because of its low density, mechanical integrity, and potentially high thermal conductivity. Additionally, further processing of the material via pressing and sintering can yield consolidated, dense bulk composites. PMID- 24143863 TI - Fine and ultrafine particle decay rates in multiple homes. AB - Human exposure to particles depends on particle loss mechanisms such as deposition and filtration. Fine and ultrafine particles (FP and UFP) were measured continuously over seven consecutive days during summer and winter inside 74 homes in Edmonton, Canada. Daily average air exchange rates were also measured. FP were also measured outside each home and both FP and UFP were measured at a central monitoring station. A censoring algorithm was developed to identify indoor-generated concentrations, with the remainder representing particles infiltrating from outdoors. The resulting infiltration factors were employed to determine the continuously changing background of outdoor particles infiltrating the homes. Background-corrected indoor concentrations were then used to determine rates of removal of FP and UFP following peaks due to indoor sources. About 300 FP peaks and 400 UFP peaks had high-quality (median R(2) value >98%) exponential decay rates lasting from 30 min to 10 h. Median (interquartile range (IQR)) decay rates for UFP were 1.26 (0.82-1.83) h(-1); for FP 1.08 (0.62 1.75) h(-1). These total decay rates included, on average, about a 25% contribution from air exchange, suggesting that deposition and filtration accounted for the major portion of particle loss mechanisms in these homes. Models presented here identify and quantify effects of several factors on total decay rates, such as window opening behavior, home age, use of central furnace fans and kitchen and bathroom exhaust fans, use of air cleaners, use of air conditioners, and indoor-outdoor temperature differences. These findings will help identify ways to reduce exposure and risk. PMID- 24143864 TI - Synthetic remodeling of the chartreusin pathway to tune antiproliferative and antibacterial activities. AB - Natural products of the benzonaphthopyranone class, such as chartreusin, elsamicin A, gilvocarcin, and polycarcin, represent potent leads for urgently needed anticancer therapeutics and antibiotics. Since synthetic protocols for altering their architectures are limited, we harnessed enzymatic promiscuity to generate a focused library of chartreusin derivatives. Pathway engineering of the chartreusin polyketide synthase, mutational synthesis, and molecular modeling were employed to successfully tailor the structure of chartreusin. For the synthesis of the aglycones, improved synthetic avenues to substituted coumarin building blocks were established. Using an engineered mutant, in total 11 new chartreusin analogs (desmethyl, methyl, ethyl, vinyl, ethynyl, bromo, hydroxy, methoxy, and corresponding (1->2) abeo-chartreusins) were generated and fully characterized. Their biological evaluation revealed an unexpected impact of the ring substituents on antiproliferative and antibacterial activities. Irradiation of vinyl- and ethynyl-substituted derivatives with blue light resulted in an improved antiproliferative potency against a colorectal cancer cell line. In contrast, the replacement of a methyl group by hydrogen caused a drastically decreased cytotoxicity but markedly enhanced antimycobacterial activity. Furthermore, mutasynthesis of bromochartreusin led to the first crystal structure of a chartreusin derivative that is not modified in the glycoside residue. Beyond showcasing the possibility of converting diverse, fully synthetic polyphenolic aglycones into the corresponding glycosides in a whole-cell approach, this work identified new chartreusins with fine-tuned properties as promising candidates for further development as therapeutics. PMID- 24143866 TI - Prion versus doppel protein misfolding: new insights from replica-exchange molecular dynamics simulations. AB - The doppel (Dpl) and prion (PrP) proteins share a very similar fold (three helices and two short beta-strands), while they differ significantly in sequence (only 25% homologous) and in disease-related beta-rich conformations that occur for PrP only. In a previous study [Baillod, P., et al. (2012) Biochemistry 51, 9891-9899], we investigated the misfolding and rare, beta-rich folds of monomeric PrP with replica-exchange molecular dynamics (REMD) simulations. In the work presented here, we perform analogous simulations for Dpl with the aim of comparing the two systems and characterizing possible specificities of PrP for misfolding and amyloidogenesis. Our extensive simulations, which allow us to overcome high energy barriers via the REMD approach, sample several beta-rich folds, some of which are stable at room temperature, for both proteins. Per residue secondary structure propensities reveal that novel beta-sheets of Dpl and PrP are formed by amino acids belonging to the helices that are the least stable in the respective native structure, H1 for Dpl and H2 and H3 for PrP, in agreement with experimental data. Using a specific clustering method that allows discrimination against different beta-strand arrangements, seven beta-rich folds could be characterized for PrP and five for Dpl, which are clearly distinct and share only one single similar fold. A major difference between the two proteins is found in the free energy barriers leading to misfolded structures: they are approximately 3 times higher for Dpl than for PrP. This suggests that the difference in amyloidogenic behavior between PrP and Dpl might be due to kinetic reasons. PMID- 24143865 TI - Biomedical research, a tool to address the health issues that affect African populations. AB - Traditionally, biomedical research endeavors in low to middle resources countries have focused on communicable diseases. However, data collected over the past 20 years by the World Health Organization (WHO) show a significant increase in the number of people suffering from non-communicable diseases (e.g. heart disease, diabetes, cancer and pulmonary diseases). Within the coming years, WHO predicts significant decreases in communicable diseases while non-communicable diseases are expected to double in low and middle income countries in sub-Saharan Africa. The predicted increase in the non-communicable diseases population could be economically burdensome for the basic healthcare infrastructure of countries that lack resources to address this emerging disease burden. Biomedical research could stimulate development of healthcare and biomedical infrastructure. If this development is sustainable, it provides an opportunity to alleviate the burden of both communicable and non-communicable diseases through diagnosis, prevention and treatment. In this paper, we discuss how research using biomedical technology, especially genomics, has produced data that enhances the understanding and treatment of both communicable and non-communicable diseases in sub-Saharan Africa. We further discuss how scientific development can provide opportunities to pursue research areas responsive to the African populations. We limit our discussion to biomedical research in the areas of genomics due to its substantial impact on the scientific community in recent years however, we also recognize that targeted investments in other scientific disciplines could also foster further development in African countries. PMID- 24143867 TI - Galactic cosmic ray-induced radiation dose on terrestrial exoplanets. AB - This past decade has seen tremendous advancements in the study of extrasolar planets. Observations are now made with increasing sophistication from both ground- and space-based instruments, and exoplanets are characterized with increasing precision. There is a class of particularly interesting exoplanets that reside in the habitable zone, which is defined as the area around a star where the planet is capable of supporting liquid water on its surface. Planetary systems around M dwarfs are considered to be prime candidates to search for life beyond the Solar System. Such planets are likely to be tidally locked and have close-in habitable zones. Theoretical calculations also suggest that close-in exoplanets are more likely to have weaker planetary magnetic fields, especially in the case of super-Earths. Such exoplanets are subjected to a high flux of galactic cosmic rays (GCRs) due to their weak magnetic moments. GCRs are energetic particles of astrophysical origin that strike the planetary atmosphere and produce secondary particles, including muons, which are highly penetrating. Some of these particles reach the planetary surface and contribute to the radiation dose. Along with the magnetic field, another factor governing the radiation dose is the depth of the planetary atmosphere. The higher the depth of the planetary atmosphere, the lower the flux of secondary particles will be on the surface. If the secondary particles are energetic enough, and their flux is sufficiently high, the radiation from muons can also impact the subsurface regions, such as in the case of Mars. If the radiation dose is too high, the chances of sustaining a long-term biosphere on the planet are very low. We have examined the dependence of the GCR-induced radiation dose on the strength of the planetary magnetic field and its atmospheric depth, and found that the latter is the decisive factor for the protection of a planetary biosphere. PMID- 24143868 TI - Thymine and other prebiotic molecules produced from the ultraviolet photo irradiation of pyrimidine in simple astrophysical ice analogs. AB - The informational subunits of RNA or DNA consist of substituted N-heterocyclic compounds that fall into two groups: those based on purine (C5H4N4) (adenine and guanine) and those based on pyrimidine (C4H4N2) (uracil, cytosine, and thymine). Although not yet detected in the interstellar medium, N-heterocycles, including the nucleobase uracil, have been reported in carbonaceous chondrites. Recent laboratory experiments and ab initio calculations have shown that the irradiation of pyrimidine in ices containing H2O, NH3, or both leads to the abiotic production of substituted pyrimidines, including the nucleobases uracil and cytosine. In this work, we studied the methylation and oxidation of pyrimidine in CH3OH:pyrimidine, H2O:CH3OH:pyrimidine, CH4:pyrimidine, and H2O:CH4:pyrimidine ices irradiated with UV photons under astrophysically relevant conditions. The nucleobase thymine was detected in the residues from some of the mixtures. Our results suggest that the abundance of abiotic thymine produced by ice photolysis and delivered to the early Earth may have been significantly lower than that of uracil. Insofar as the delivery of extraterrestrial molecules was important for early biological chemistry on early Earth, these results suggest that there was more uracil than thymine available for emergent life, a scenario consistent with the RNA world hypothesis. PMID- 24143869 TI - Review of exchange processes on Ganymede in view of its planetary protection categorization. AB - In this paper, we provide a detailed review of Ganymede's characteristics that are germane to any consideration of its planetary protection requirements. Ganymede is the largest moon in our solar system and is the subject of one of the main science objectives of the JUICE mission to the jovian system. We explore the probability of the occurrence of potentially habitable zones within Ganymede at present, including those both within the deep liquid ocean and those in shallow liquid reservoirs. We consider the possible exchange processes between the surface and any putative habitats to set some constraints on the planetary protection approach for this moon. As a conclusion, the "remote" versus "significant" chance of contamination will be discussed, according to our current understanding of this giant icy moon. Based on the different estimates we investigate here, it appears extremely unlikely that material would be exchanged downward through the upper icy layer of Ganymede and, thus, bring material into the ocean over timescales consistent with the survival of microorganisms. PMID- 24143870 TI - Analysis of retinal ganglion cell complex thickness after brilliant blue-assisted vitrectomy for idiopathic macular holes. PMID- 24143871 TI - Analysis of maize ( Zea mays ) kernel density and volume using microcomputed tomography and single-kernel near-infrared spectroscopy. AB - Maize kernel density affects milling quality of the grain. Kernel density of bulk samples can be predicted by near-infrared reflectance (NIR) spectroscopy, but no accurate method to measure individual kernel density has been reported. This study demonstrates that individual kernel density and volume are accurately measured using X-ray microcomputed tomography (MUCT). Kernel density was significantly correlated with kernel volume, air space within the kernel, and protein content. Embryo density and volume did not influence overall kernel density. Partial least-squares (PLS) regression of MUCT traits with single-kernel NIR spectra gave stable predictive models for kernel density (R(2) = 0.78, SEP = 0.034 g/cm(3)) and volume (R(2) = 0.86, SEP = 2.88 cm(3)). Density and volume predictions were accurate for data collected over 10 months based on kernel weights calculated from predicted density and volume (R(2) = 0.83, SEP = 24.78 mg). Kernel density was significantly correlated with bulk test weight (r = 0.80), suggesting that selection of dense kernels can translate to improved agronomic performance. PMID- 24143872 TI - Temperature-regulated fluorescence and association of an oligo(ethyleneglycol)methacrylate-based copolymer with a conjugated polyelectrolyte--the effect of solution ionic strength. AB - Aqueous mixtures of a dye-labeled non-ionic thermoresponsive copolymer and a conjugated cationic polyelectrolyte are shown to exhibit characteristic changes in fluorescence properties in response to temperature and to the presence of salts, enabling a double-stimuli responsiveness. In such mixtures at room temperature, i.e., well below the lower critical solution temperature (LCST), the emission of the dye is strongly quenched due to energy transfer to the polycation, pointing to supramolecular interactions between the two macromolecules. Increasing the concentration of salts weakens the interpolymer interactions, the extent of which is simultaneously monitored from the change in the relative emission intensity of the components. When the mixture is heated above its LCST, the transfer efficiency is significantly reduced, signaling a structural reorganization process, however, surprisingly only if the mixture contains salt ions. To elucidate the reasons behind such thermo- and ion sensitive fluorescence characteristics, we investigate the effect of salts of alkali chlorides, in particular of NaCl, on the association behavior of these macromolecules before and after the polymer phase transition by a combination of UV-vis, fluorescence, and (1)H NMR spectroscopy with light scattering and small angle neutron scattering measurements. PMID- 24143873 TI - Association of Helicobacter pylori infection with diabetes mellitus and diabetic nephropathy: a meta-analysis of 39 studies involving more than 20,000 participants. AB - BACKGROUND: Helicobacter pylori infects more than half of the world's population. The aim of this study was to quantify the association between H. pylori infection and the risk of diabetes mellitus and diabetic nephropathy, and to detect at which stage the infection might have higher pathogenicity in the disease-free status-diabetes mellitus-diabetic nephropathy process. METHODS: A literature search was performed to identify studies published between 1997 and 2012 for relative risk estimates. Fixed and random effects meta-analytical techniques were conducted for diabetes mellitus and diabetic nephropathy. RESULTS: Thirty-seven case-control studies and 2 cohort studies were included. H. pylori was associated with an increased risk of each type of diabetes mellitus (odds ratio (OR) 2.00, 95% confidence interval (CI) 1.82-2.20, p for heterogeneity = 0.07). The infection was also associated with increased risks of type 1 and type 2 diabetes mellitus, separately (OR 1.99, 95% CI 1.52-2.60, p for heterogeneity = 0.15, and OR 2.15, 95% CI 1.81-2.55, p for heterogeneity = 0.24, respectively). In addition, we found a significant association between H. pylori infection and diabetic nephropathy risk (OR 1.60, 95% CI 1.10-2.33, p for heterogeneity = 0.44). CONCLUSIONS: Our meta-analyses suggest a relationship between H. pylori infection and the risk of diabetes mellitus and diabetic nephropathy. The bacterium may be able to play its pathogenic role in the whole disease process, and this action may be stronger in type 2 diabetic patients than in type 1 diabetic patients. PMID- 24143875 TI - Factors explaining the heterogeneity of effects of patient decision aids on knowledge of outcome probabilities: a systematic review sub-analysis. AB - BACKGROUND: There is considerable unexplained heterogeneity in previous meta analyses of randomized controlled trials (RCTs) evaluating the effects of patient decision aids on the accuracy of knowledge of outcome probabilities. The purpose of this review was to explore possible effect modification by three covariates: the type of control intervention, decision aid quality and patients' baseline knowledge of probabilities. METHODS: A sub-analysis of studies previously identified in the 2011 Cochrane review on decision aids for people facing treatment and screening decisions was conducted. Additional unpublished data were requested from relevant study authors to maximize the number of eligible studies. RCTs (to 2009) comparing decision aids with standardized probability information to control interventions (lacking such information) and assessing the accuracy of patient knowledge of outcome probabilities were included. The proportions of patients with accurate knowledge of outcome probabilities in each group were converted into relative effect measures. Intervention quality was assessed using the International Patient Decision Aid Standards instrument (IPDASi) probabilities domain. RESULTS: A main effects analysis of 17 eligible studies confirmed that decision aids significantly improve the accuracy of patient knowledge of outcome probabilities (relative risk = 1.80 [1.51, 2.16]), with considerable heterogeneity (87%). The type of control did not modify effects. Meta-regression suggested that the IPDASi probabilities domain score (reflecting decision aid quality) is a potential effect modifier (P = 0.037), accounting for a quarter of the variability (R2 = 0.28). Meta-regression indicated the control event rate (reflecting baseline knowledge) is a significant effect modifier (P = 0.001), with over half the variability in ln(OR) explained by the linear relationship with log-odds for the control group (R2 = 0.52); this relationship was slightly strengthened after correcting for the statistical dependence of the effect measure on the control event rate. CONCLUSIONS: Patients' baseline level of knowledge of outcome probabilities is an important variable that explains the heterogeneity of effects of decision aids on improving accuracy of this knowledge. Greater relative effects are observed when the baseline proportion of patients with accurate knowledge is lower. This may indicate that decision aids are more effective in populations with lower knowledge. PMID- 24143876 TI - Temporal arteritis in a young patient. AB - Temporal arteritis in the young is clinically and histologically different from classic giant cell arteritis of the elderly population. A male patient, aged 36 years, presented with headache and a nodule in his left temporal region. Histological examination of the nodule showed that the left temporal artery was encircled by a lymphoid tissue with prominent germinal centres. The arterial wall was infiltrated with mixed inflammatory cells, the internal elastic lamina was disrupted, and there was marked intimal hyperplasia. The patient was diagnosed with juvenile temporal arteritis. Because of persistent headache after surgical excision of the lesion, the patient was treated with prednisolone. Systemic vasculitides, classic giant cell arteritis, Kimura's disease, and angiolymphoid hyperplasia with eosinophilia should be considered in the differential diagnosis of the disease. PMID- 24143877 TI - Genome architecture changes and major gene variations of Andrias davidianus ranavirus (ADRV). AB - Ranaviruses are emerging pathogens that have led to global impact and public concern. As a rarely endangered species and the largest amphibian in the world, the Chinese giant salamander, Andrias davidianus, has recently undergone outbreaks of epidemic diseases with high mortality. In this study, we isolated and identified a novel ranavirus from the Chinese giant salamanders that exhibited systemic hemorrhage and swelling syndrome with high death rate in China during May 2011 to August 2012. The isolate, designated Andrias davidianus ranavirus (ADRV), not only could induce cytopathic effects in different fish cell lines and yield high viral titers, but also caused severely hemorrhagic lesions and resulted in 100% mortality in experimental infections of salamanders. The complete genome of ADRV was sequenced and compared with other sequenced amphibian ranaviruses. Gene content and phylogenetic analyses revealed that ADRV should belong to an amphibian subgroup in genus Ranavirus, and is more closely related to frog ranaviruses than to other salamander ranaviruses. Homologous gene comparisons show that ADRV contains 99%, 97%, 94%, 93% and 85% homologues in RGV, FV3, CMTV, TFV and ATV genomes respectively. In addition, several variable major genes, such as duplicate US22 family-like genes, viral eukaryotic translation initiation factor 2 alpha gene and novel 75L gene with both motifs of nuclear localization signal (NLS) and nuclear export signal (NES), were predicted to contribute to pathogen virulence and host susceptibility. These findings confirm the etiologic role of ADRV in epidemic diseases of Chinese giant salamanders, and broaden our understanding of evolutionary emergence of ranaviruses. PMID- 24143874 TI - Metabolic tumor profiling with pH, oxygen, and glucose chemosensors on a quantum dot scaffold. AB - Acidity, hypoxia, and glucose levels characterize the tumor microenvironment rendering pH, pO2, and pGlucose, respectively, important indicators of tumor health. To this end, understanding how these parameters change can be a powerful tool for the development of novel and effective therapeutics. We have designed optical chemosensors that feature a quantum dot and an analyte-responsive dye. These noninvasive chemosensors permit pH, oxygen, and glucose to be monitored dynamically within the tumor microenvironment by using multiphoton imaging. PMID- 24143878 TI - Dysregulation of leukocyte gene expression in women with medication-refractory depression versus healthy non-depressed controls. AB - BACKGROUND: Depressive Disorders (DD) are a great financial and social burden. Females display 70% higher rate of depression than males and more than 30% of these patients do not respond to conventional medications. Thus medication refractory female patients are a large, under-served, group where new biological targets for intervention are greatly needed. METHODS: We used real-time quantitative polymerase chain reaction (qPCR) to evaluate mRNA gene expression from peripheral blood leukocytes for 27 genes, including immune, HPA-axis, ion channels, and growth and transcription factors. Our sample included 23 females with medication refractory DD: 13 with major depressive disorder (MDD), 10 with bipolar disorder (BPD). Our comparison group was 19 healthy, non-depressed female controls. We examined differences in mRNA expression in DD vs. controls, in MDD vs. BPD, and in patients with greater vs. lesser depression severity. RESULTS: DD patients showed increased expression for IL-10, IL-6, OXTR, P2RX7, P2RY1, and TRPV1. BPD patients showed increased APP, CREB1, NFKB1, NR3C1, and SPARC and decreased TNF expression. Depression severity was related to increased IL-10, P2RY1, P2RX1, and TRPV4 expression. CONCLUSIONS: These results support prior findings of dysregulation in immune genes, and provide preliminary evidence of dysregulation in purinergic and other ion channels in females with medication refractory depression, and in transcription and growth factors in those with BPD. If replicated in future research examining protein levels as well as mRNA, these pathways could potentially be used to explore biological mechanisms of depression and to develop new drug targets. PMID- 24143879 TI - How could imaging reduce therapy-associated morbidity in rhabdomyosarcoma of the bladder or prostate? PMID- 24143880 TI - Nucleus accumbens neurons track behavioral preferences and reward outcomes during risky decision making. AB - BACKGROUND: To make appropriate decisions, organisms must evaluate the risks and benefits of action selection. The nucleus accumbens (NAc) has been shown to be critical for this processing and is necessary for appropriate risk-based decision making behavior. However, it is not clear how NAc neurons encode this information to promote appropriate behavioral responding. METHODS: Here, rats (n = 17) were trained to perform a risky decision-making task in which discrete visual cues predicted the availability to respond for a smaller certain (safer) or larger uncertain (riskier) reward. Electrophysiological recordings were made in the NAc core and shell to evaluate neural activity during task performance. RESULTS: At test, animals exhibited individual differences in risk-taking behavior; some displayed a preference for the risky option, some the safe option, and some did not have a preference. Electrophysiological analysis indicated that NAc neurons differentially encoded information related to risk versus safe outcomes. Further, during free choice trials, neural activity during reward-predictive cues reflected individual behavioral preferences. In addition, neural encoding of reward outcomes was correlated with risk-taking behavior, with safe-preferring and risk-preferring rats showing differential activity in the NAc core and shell during reward omissions. CONCLUSIONS: Consistent with previously demonstrated alterations in prospective reward value with effort and delay, NAc neurons encode information during reward-predictive cues and outcomes in a risk task that tracked the rats' preferred responses. This processing appears to contribute to subjective encoding of anticipated outcomes and thus may function to bias future risk-based decisions. PMID- 24143881 TI - Reduced cortical volume and elevated astrocyte density in rats chronically treated with antipsychotic drugs-linking magnetic resonance imaging findings to cellular pathology. AB - BACKGROUND: Increasing evidence suggests that antipsychotic drugs (APD) might affect brain structure directly, particularly the cerebral cortex. However, the precise anatomical loci of these effects and their underlying cellular basis remain unclear. METHODS: With ex vivo magnetic resonance imaging in rats treated chronically with APDs, we used automated analysis techniques to map the regions that show maximal impact of chronic (8 weeks) treatment with either haloperidol or olanzapine on the rat cortex. Guided by these imaging findings, we undertook a focused postmortem investigation with stereology. RESULTS: We identified decreases in the volume and thickness of the anterior cingulate cortex (ACC) after chronic APD treatment, regardless of the APD administered. Postmortem analysis confirmed these volumetric findings and demonstrated that chronic APD treatment had no effect on the total number of neurons or S100beta+ astrocytes in the ACC. In contrast, an increase in the density of these cells was observed. CONCLUSIONS: This study demonstrates region-specific structural effects of chronic APD treatment on the rat cortex, primarily but not exclusively localized to the ACC. At least in the rat, these changes are not due to a loss of either neurons or astrocytes and are likely to reflect a loss of neuropil. Although caution needs to be exerted when extrapolating results from animals to patients, this study highlights the power of this approach to link magnetic resonance imaging findings to their histopathological origins. PMID- 24143882 TI - Genome-wide association study of opioid dependence: multiple associations mapped to calcium and potassium pathways. AB - BACKGROUND: We report a genome-wide association study (GWAS) of two populations, African-American and European-American (AA, EA) for opioid dependence (OD) in three sets of subjects, to identify pathways, genes, and alleles important in OD risk. METHODS: The design employed three phases (on the basis of separate sample collections). Phase 1 included our discovery GWAS dataset consisting of 5697 subjects (58% AA) diagnosed with opioid and/or other substance dependence and control subjects. Subjects were genotyped with the Illumina OmniQuad microarray, yielding 890,000 single nucleotide polymorphisms (SNPs) suitable for analysis. Additional genotypes were imputed with the 1000 Genomes reference panel. Top ranked findings were further evaluated in Phase 2 by incorporating information from the publicly available Study of Addiction: Genetics and Environment dataset, with GWAS data from 4063 subjects (32% AA). In Phase 3, the most significant SNPs from Phase 2 were genotyped in 2549 independent subjects (32% AA). Analyses were performed with case-control and ordinal trait designs. RESULTS: Most significant results emerged from the AA subgroup. Genome-wide-significant associations (p < 5.0 * 10(-8)) were observed with SNPs from multiple loci-KCNG2*rs62103177 was most significant after combining results from datasets in every phase of the study. The most compelling results were obtained with genes involved in potassium signaling pathways (e.g., KCNC1 and KCNG2). Pathway analysis also implicated genes involved in calcium signaling and long-term potentiation. CONCLUSIONS: This is the first study to identify risk variants for OD with GWAS. Our results strongly implicate risk pathways and provide insights into novel therapeutic and prevention strategies and might biologically bridge OD and other non-substance dependence psychiatric traits where similar pathways have been implicated. PMID- 24143884 TI - Evaluating nurses' knowledge of chemotherapy. AB - BACKGROUND: The characteristics of the drugs that are used in chemotherapy have given rise to many issues, one of which is whether nurses are competent when working with chemotherapy. METHODS: Nurses' knowledge of chemotherapy was evaluated with a questionnaire that included 20 true-or-false questions. The questionnaire was developed from literature and expert input and validated by subject experts (content validity). A pilot study (contrasted-groups approach) was also conducted. RESULTS: A total of 203 nurses participated in the study and achieved an average overall correct answer rate of 60.9%. Most of the respondents, 63.5% (129 of 203), had a score of less than 70, and 77.3% (157 of 203) hoped to undergo more training on chemotherapy. Their knowledge of chemotherapy came mainly from consultation with colleagues (4.0 +/- 0.8) and in hospital continuing education (3.9 +/- 0.8). CONCLUSION: The evidence-based results suggested that nurses have insufficient knowledge about chemotherapy. More fundamentally, however, nurses need more education about chemotherapy in nursing school and through in-hospital continuing education. PMID- 24143883 TI - Restoration of anal sphincter function after myoblast cell therapy in incontinent rats. AB - Fecal incontinence (FI) remains a socially isolating condition with profound impact on quality of life for which autologous myoblast cell therapy represents an attractive treatment option. We developed an animal model of FI and investigated the possibility of improving sphincter function by intrasphincteric injection of syngeneic myoblasts. Several types of anal cryoinjuries were evaluated on anesthetized Fischer rats receiving analgesics. The minimal lesion yielding sustainable anal sphincter deficiency was a 90 degrees cryoinjury of the sphincter, repeated after a 24-h interval. Anal sphincter pressure was evaluated longitudinally by anorectal manometry under local electrostimulation. Myoblasts were prepared using a protocol mimicking a clinical-grade process and further transduced with a GFP-encoding lentiviral vector before intrasphincteric injection. Experimental groups were uninjured controls, cryoinjured + PBS, and cryoinjured + myoblasts (different doses or injection site). Myoblast injection was well tolerated. Transferred myoblasts expressing GFP integrated into the sphincter and differentiated in situ into dystrophin-positive mature myofibers. Posttreatment sphincter pressures increased over time. At day 60, pressures in the treated group were significantly higher than those of PBS-injected controls and not significantly different from those of normal rats. Longitudinal follow-up showed stability of the therapeutic effect on sphincter function over a period of 6 months. Intrasphincteric myoblast injections at the lesion borders were equally as effective as intralesion administration, but an injection opposite to the lesion was not. These results provide proof of principle for myoblast cell therapy to treat FI in a rat model. This strategy is currently being evaluated in humans in a randomized double-blind placebo-controlled clinical trial. PMID- 24143885 TI - Examining Taiwanese psychiatric nurses' knowledge and confidence in case management. AB - BACKGROUND: Psychiatric nurses in Taiwan are increasingly required to employ case management strategies for patients with severe mental illness. However, few studies have examined these nurses' knowledge of case management and identified their unmet educational needs. METHODS: A national cross-sectional survey was conducted to examine psychiatric nurses' knowledge of case management and confidence in their case management skills. Structured questionnaires were distributed at an arranged time and using an electronic survey tool. Overall, 424 psychiatric nurses were recruited. RESULTS: Participants' knowledge scores reflected substantial gaps (60% accuracy rate), particularly in basic concepts and case management processes. In addition, the nurses lacked confidence in applying their case management skills. The unmet educational needs of the nurses were related to the skills of assessing resource requirements, conducting referrals, collaborating with service providers, and linking patients to necessary resources. Additionally, 87% of the nurses had no previous education in case management. CONCLUSION: Strategies for enhancing continuing education in case management are required to improve nurses' knowledge of case management, address their unmet educational needs, and prepare them to serve as case managers. PMID- 24143886 TI - Applying mastery learning in a clinical skills training program for primary care nurses. AB - This article describes the application of mastery learning in the development and implementation of a clinical skills training program for primary care nurses. The objective of the training program was to equip primary care nurses with the clinical skills to triage and administer bronchodilator therapy to patients presenting to the primary care clinic with acute exacerbations of asthma or chronic obstructive pulmonary disease. The positive outcomes of this program support the idea that mastery learning is an effective competency-based training method for clinical skills acquisition. However, variations in training duration and dropout rates should be taken into consideration when planning mastery learning-based training programs. PMID- 24143887 TI - Stress modulates key psychological processes and characteristic symptoms in females with fibromyalgia. AB - OBJECTIVES: To examine how stress interacts with psychological processes and key phenotypic symptom characteristics in females with fibromyalgia. METHODS: Ninety eight women with fibromyalgia, diagnosed according to ACR 1990 criteria, and 35 female healthy controls without pain were studied. Applied questionnaires included the following: Perceived Stress scale [PSS], Fibromyalgia Impact Questionnaire [FIQ], Perceived Control of Internal States (PCOIS), Mastery scale and the Profile of Mood States scale (POMS). RESULTS: Perceived stress correlated significantly with the characteristic features of fibromyalgia including pain (p<0.05) and sleep change, fatigue and cognitive dysfunction (all p<0.001). Perceived stress correlated inversely with measures of control and positively with mood and neuroticism (all p<0.001). When controlling for stress, most of these variables were no longer significant, suggesting that stress impacts on the majority of variables associated with FM. CONCLUSIONS: Stress in females with fibromyalgia associates with both key symptoms and a range of relevant psychological variables. Stress appears to have a major role in modulating several key 'up-stream' processes in fibromyalgia. PMID- 24143888 TI - Coculture with mesenchymal stem cells results in improved viability and function of human hepatocytes. AB - Hepatocyte transplantation is becoming an accepted therapy for acute liver failure, either as a bridge to liver regeneration or to organ transplantation. Hepatocytes provide liver function in place of the failing organ. The maintenance of sufficient viability and function of the transplanted hepatocytes is a concern. There is a lot of recent interest in mesenchymal stem cells (MSCs) for the provision of structural and trophic support to hepatocytes, but few studies currently use primary human hepatocytes. The aim of this study was to investigate if coculture of human MSCs with cryopreserved human hepatocytes may improve their function and viability, thus with potential for cellular therapy of liver disease. MSCs were isolated from human umbilical cord or adipose tissue. Hepatocytes were isolated from donor organs unsuitable for transplantation. MSCs and hepatocytes were cocultured in both direct and indirect contact. Conditioned medium (CM) from cocultured MSCs and hepatocytes was also used on hepatocytes. Viability and liver-specific function were compared between test and controls. Human hepatocytes that were cocultured directly with MSCs demonstrated improved production of albumin from day 5 to day 25 of culture. This effect was most prominent at day 15. Likewise, urea production was improved in coculture from day 5 to 25. Indirect coculture demonstrated improved albumin production by day 4 (1,107 ng/ml) versus hepatocyte monoculture (940 ng/ml). Hepatocytes in CM demonstrated a nonsignificant improvement in function. The viability of cocultured hepatocytes was superior to that of monocultured cells with up to a 16% improvement. Thus, coculture of human hepatocytes with MSCs demonstrates both improved function and viability. The effect is seen mainly with direct coculture but can also be seen in indirect culture and with CM. Such coculture conditions may convey major advantages in hepatocyte survival and function for cell transplantation. PMID- 24143889 TI - Hypermobility among school children aged five to eight years: the Hospital del Mar Criteria gives higher prevalence for hypermobility than the Beighton score. AB - OBJECTIVES: The purpose was to investigate the distribution of hypermobility among school children aged five to eight years. METHODS: One hundred and twenty eight participants were assessed using the Beighton score and the Hospital del Mar criteria. RESULTS: With the Beighton score using the cut-off >=4, the prevalence was 12%, and with the Hospital del Mar criteria the prevalence was 34%. There were significantly higher scores for females on both the Beighton (p=0.01) and Hospital del Mar criteria (p<0.0001). The youngest children aged five to six years scored higher compared with the seven- and eight-year-olds (p=0.016). The knee flexion was most likely to be hypermobile (97%), followed by shoulder rotation (80%), thumb (31%), elbow (27%), metatarsal-phalangeal (16%), hip (15.5%), fingers (10%) or knee (10%), ankle (6%), trunk (4%) and patella (2%). CONCLUSIONS: Gender and probably age must be taken into account when children are assessed for hypermobility. The Hospital del Mar criteria need to be modified for some of the motions. PMID- 24143890 TI - Cognitive-reminiscence therapy and usual care for depression in young adults: study protocol for a randomized controlled trial. AB - BACKGROUND: Depression is a common affliction for young adults, and is associated with a range of adverse outcomes. Cognitive-reminiscence therapy is a brief, structured intervention that has been shown to be highly effective for reducing depressive symptoms, yet to date has not been evaluated in young adult populations. Given its basis in theory-guided reminiscence-based therapy, and incorporation of effective therapeutic techniques drawn from cognitive therapy and problem-solving frameworks, it is hypothesized to be effective in treating depression in this age group. METHODS AND DESIGN: This article presents the design of a randomized controlled trial implemented in a community-based youth mental health service to compare cognitive-reminiscence therapy with usual care for the treatment of depressive symptoms in young adults. Participants in the cognitive-reminiscence group will receive six sessions of weekly, individual psychotherapy, whilst participants in the usual-care group will receive support from the youth mental health service according to usual procedures. A between within repeated-measures design will be used to evaluate changes in self-reported outcome measures of depressive symptoms, psychological wellbeing and anxiety across baseline, three weeks into the intervention, post-intervention, one month post-intervention and three months post-intervention. Interviews will also be conducted with participants from the cognitive-reminiscence group to collect information about their experience receiving the intervention, and the process underlying any changes that occur. DISCUSSION: This study will determine whether a therapeutic approach to depression that has been shown to be effective in older adult populations is also effective for young adults. The expected outcome of this study is the validation of a brief, evidence-based, manualized treatment for young adults with depressive symptoms. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry ACTRN12613000084785. PMID- 24143891 TI - IL-13 signaling via IL-13Ralpha2 triggers TGF-beta1-dependent allograft fibrosis. AB - BACKGROUND: Allograft fibrosis still remains a critical problem in transplantation, including heart transplantation. The IL-13/TGF-beta1 interaction has previously been identified as a key pathway orchestrating fibrosis in different inflammatory immune disorders. Here we investigate if this pathway is also responsible for allograft fibrosis and if interference with the IL-13/TGF beta1 interaction prevents allograft fibrosis. METHODS: FVB or control DBA/1 donor hearts were transplanted heterotopically into DBA/1 recipient mice and hearts were explanted at day 60 and 100 post-transplantation. Cardiac tissue was examined by Masson's trichrome staining and immunohistochemistry for CD4, CD8, CD11b, IL-13, Fas ligand, matrix metalloproteinase (MMP)-1, MMP-13, beta2 microglobulin, and Gremlin-1. Graft-infiltrating cells were isolated and analyzed by flow cytometry. IL-13 and TGF-beta1 levels were determined by enzyme-linked immunosorbent assay (ELISA) and the amount of collagen was quantified using a Sircol assay; IL-13Ralpha2 expression was detected by Western blotting. In some experiments IL-13/ TGF-beta1 signaling was blocked with specific IL-13Ralpha2 siRNA. Additionally, a PCR array of RNA isolated from the allografts was performed to analyze expression of multiple genes involved in fibrosis. RESULTS: Both groups survived long-term (>100 days). The allogeneic grafts were infiltrated by significantly increased numbers of CD4+ (P <0.0001), CD8+ (P <0.0001), and CD11b+ cells (P = 0.0065) by day 100. Furthermore, elevated IL-13 levels (P = 0.0003) and numbers of infiltrating IL-13+ cells (P = 0.0037), together with an expression of IL-13Ralpha2, were detected only within allografts. The expression of IL-13 and IL-13Ralpha2 resulted in significantly increased TGF-beta1 levels (P <0.0001), higher numbers of CD11bhighGr1intermediateTGF-beta1+ cells, and elevated cardiac collagen deposition (P = 0.0094). The allograft fibrosis found in these experiments was accompanied by upregulation of multiple profibrotic genes, which was confirmed by immunohistochemical stainings of allograft tissue. Blockage of the IL-13/TGF beta1 interaction by IL-13Ralpha2 siRNA led to lower numbers of CD11bhighGr1intermediateTGF-beta1+, CD4+, CD8+, and CD11b+ cells, and prevented collagen deposition (P = 0.0018) within these allografts. CONCLUSIONS: IL-13 signaling via IL-13Ralpha2 induces TGF-beta1 and causes allograft fibrosis in a murine model of chronic transplant rejection. Blockage of this IL-13/TGF-beta1 interaction by IL-13Ralpha2 siRNA prevents cardiac allograft fibrosis. Thus, IL 13Ralpha2 may be exploitable as a future target to reduce allograft fibrosis in organ transplantation. PMID- 24143892 TI - Electroencephalographic profiles for differentiation of disorders of consciousness. AB - BACKGROUND: Electroencephalography (EEG) is best suited for long-term monitoring of brain functions in patients with disorders of consciousness (DOC). Mathematical tools are needed to facilitate efficient interpretation of long duration sleep-wake EEG recordings. METHODS: Starting with matching pursuit (MP) decomposition, we automatically detect and parametrize sleep spindles, slow wave activity, K-complexes and alpha, beta and theta waves present in EEG recordings, and automatically construct profiles of their time evolution, relevant to the assessment of residual brain function in patients with DOC. RESULTS: Above proposed EEG profiles were computed for 32 patients diagnosed as minimally conscious state (MCS, 20 patients), vegetative state/unresponsive wakefulness syndrome (VS/UWS, 11 patients) and Locked-in Syndrome (LiS, 1 patient). Their interpretation revealed significant correlations between patients' behavioral diagnosis and: (a) occurrence of sleep EEG patterns including sleep spindles, slow wave activity and light/deep sleep cycles, (b) appearance and variability across time of alpha, beta, and theta rhythms. Discrimination between MCS and VS/UWS based upon prominent features of these profiles classified correctly 87% of cases. CONCLUSIONS: Proposed EEG profiles offer user-independent, repeatable, comprehensive and continuous representation of relevant EEG characteristics, intended as an aid in differentiation between VS/UWS and MCS states and diagnostic prognosis. To enable further development of this methodology into clinically usable tests, we share user-friendly software for MP decomposition of EEG (http://braintech.pl/svarog) and scripts used for creation of the presented profiles (attached to this article). PMID- 24143893 TI - A trial of Scrambler therapy in the treatment of cancer pain syndromes and chronic chemotherapy-induced peripheral neuropathy. AB - Neuropathic pain is common among cancer patients and often difficult to treat. This study used Scrambler therapy, a patient-specific electrocutaneous nerve stimulation device, to treat cancer patients with pain. Patients received Scrambler therapy for 10 sessions (one daily) over a two-week period. The primary outcome was changed in pain numerical rating scale (NRS) at one month; secondary outcomes were changes in the Brief Pain Inventory and European Organization for Treatment and Cancer QLC-CIPN-20(EORTC CIPN-20), over time. Thirty-nine patients, mean age 56.5 yr, 16 men and 23 women, were treated over an 18-month period for an average of 9.3 days each. The "now" pain scores reduced from 6.6 before treatment to 4.5 at 14 days, 4.6, 4.8, and 4.6 at 1, 2, and 3 months, respectively (p < 0.001). Clinically important and statistically significant improvements were seen in average, least, and worst pain; BPI interference with life scores, and motor and sensory scales on the EORTC CIPN-20. No adverse effects were observed. In this single arm trial, Scrambler therapy appeared to relieve cancer-associated chronic neuropathic pain both acutely and chronically, and provided sustained improvements in many indicators of quality of life. PMID- 24143894 TI - Selective conjugation of proteins by mining active proteomes through click functionalized magnetic nanoparticles. AB - Superparamagnetic iron oxide nanoparticles (SPIONs) coated with azide groups were functionalized at the surface with biotin (biotin@SPIONs) and cysteine protease inhibitor E-64 (E-64@SPIONs) with the purpose of developing nanoparticle-based assays for identifying cysteine proteases in proteomes. Magnetite particles (ca. 6 nm) were synthesized by microwave-assisted thermal decomposition of iron acetylacetonate and subsequently functionalized following a click chemistry protocol to obtain biotin and E-64 labeled particulate systems. Successful surface modification and covalent attachment of functional groups and molecules were confirmed by FT-IR spectroscopy and thermal gravimetric analysis. The ability of the surface-grafted biotin terminal groups to specifically interact with streptavidin (either horseradish peroxidase [(HRP)-luminol-H2O2] or rhodamine) was confirmed by chemiluminescent assay. A quantitative assessment showed a capture limit of 0.55-1.65 MUg protein/100 MUg particles. Furthermore, E 64@SPIONs were successfully used to specifically label papain-like cysteine proteases from crude plant extracts. Owing to the simplicity and versatility of the technique, together with the superparamagnetic behavior of FeOx nanoparticles, the results demonstrate that click chemistry on surface anchored azide group is a viable approach toward bioconjugations that can be extended to other nanoparticles surfaces with different functional groups to target specific therapeutic and diagnostic applications. PMID- 24143895 TI - Tranilast enhances the anti-tumor effects of tamoxifen on human breast cancer cells in vitro. AB - BACKGROUND: Tamoxifen is the most widely used anti-estrogen for the treatment of breast cancer. Studies show that the combination therapy with other substances that helps the activity of tamoxifen. The objective of this study was to evaluate the effect of tamoxifen when used in combination with tranilast on human breast cancer cells. RESULTS: Two MCF-7 and MDA-MB-231 human breast cancer cell lines were treated with tamoxifen and/or tranilast. The cell viability and cytotoxicity was assessed using MTT and LDH assays; the apoptotic effects were examined by TUNEL assay, acridine orange/ethidium bromide staining and DNA laddering, also the expression levels of bax and bcl-2 genes were detected by real-time RT-PCR. The mRNA expression of TGF-beta ligands and receptors examined using real-time RT PCR and TGF-beta1 protein secretion levels were also evaluated by ELISA assay. Inhibitory effect of these drugs on invasion and metastasis were tested by wound healing and matrigel invasion assay. CONCLUSIONS: These findings indicate that tranilast, by synergistic effect, enhances the activity of tamoxifen and the TGF beta pathway is a target for this combination therapy, therefore; we propose that this combined treatment may be suitable selection in prevention of breast cancer. PMID- 24143896 TI - Long-term treatment with golimumab for severe uveitis. AB - PURPOSE: To evaluate the long-term efficacy of golimumab in patients with severe recalcitrant uveitis who had inadequate response to previous biologics. METHODS: Retrospective study (13 patients with JIA, 4 with HLA-B27-associated uveitis). Indication for treatment was active uveitis despite biologics. Golimumab dosing was 50 mg monthly/subcutaneously. MAIN OUTCOME MEASURES: uveitis activity, visual acuity improvement, reduction of systemic therapy (corticosteroids/immunosuppressants), adverse events. RESULTS: Of 17 patients (34 affected eyes), response to golimumab was seen in 14 patients; at last visit uveitis was inactive in 12 patients. Three patients were nonresponders. Mean follow-up time on golimumab was 21.9 months. Visual acuity remained stable in 26 eyes, improved in 7, and worsened in 1. Mean systemic prednisolone dose before and after golimumab was 12.5-3.5 mg/day. One patient developed pulmonary infection. CONCLUSIONS: Golimumab may be a promising new therapeutic option for severe uveitis patients who have not responded to other biologics. PMID- 24143897 TI - Use of free radicals on the surface of plasma polymer for the initiation of a polymerization reaction. AB - A novel approach to functionalize plasma polymer films (PPFs) through the grafting polymerization initiated from free radicals trapped in the film was developed in this work. 2-Ethylhexyl acrylate (EHA) was chosen as radically polymerizable monomer given the wide use of its corresponding polymer in coating and adhesive applications. The occurrence of the grafting was first confirmed by time-of-flight secondary ion mass spectrometry (ToF-SIMS) and X-ray photoelectron spectroscopy (XPS). Then grafted chains were studied in more detail. The thickness of grafted chains was quantitatively estimated by angle-resolved XPS (ARXPS), while their morphology and interfacial behavior were qualitatively investigated by atomic force microscopy (AFM), contact angle measurements, and quartz crystal microbalance (QCM). The latter technique provided additional insights regarding the swelling behavior of the grafted layer and its stability upon exposure to challenging environments. Reported scientific findings suggest to use this approach for the covalent binding of a very thin layer on the top surface of a PPF without affecting its bulk properties. PMID- 24143898 TI - Evanescent wave-based particle tracking velocimetry for nanochannel flows. AB - Understanding fluid flows in 10-1000 nm space, which we call extended nanospace, is important for novel nanofluidic devices in analytical chemistry. This study therefore developed a particle tracking velocimetry for measuring velocity distribution in nanochannel flows, by using the evanescent wave illumination. 64 nm fluorescent nanoparticles were used as flow tracer. The particle position was determined from fluorescent intensity by the evanescent wave field, with a spatial resolution smaller than light wavelengths. The time resolution of 260 MUs was achieved to make error by the Brownian diffusion of the tracer small to be neglected. An image processing by multitime particle tracking was established to detect the tracer nanoparticles of weak fluorescent intensity. Though the measurement region was affected by nonuniform particle distribution with the electrostatic interactions, pressure-driven flows of water in a nanochannel of 50 MUm width and 410 nm depth were successfully measured. The results of the velocity distribution in the depth-wise direction approximately showed agreement with the fluid dynamics with the bulk liquid properties from the macroscopic view, however, suggested slip velocities even in the hydrophilic channel. We suggest a possibility of appearance of molecular behavior in the fluid near the wall within 10 nm-order scale. PMID- 24143899 TI - A 60-year review on the changing epidemiology of measles in capital Beijing, China, 1951-2011. AB - BACKGROUND: China pledged to join the global effort to eliminate measles by 2012. To improve measles control strategy, the epidemic trend and population immunity of measles were investigated in 1951-2011 in Beijing. METHODS: The changing trend of measles since 1951 was described based on measles surveillance data from Beijing Centre of Disease Control and Prevention (CDC). The measles vaccination coverage and antibody level were assessed by routinely reported measles vaccination data and twenty-one sero-epidemiological surveys. RESULTS: The incidence of measles has decreased significantly from 593.5/100,000 in 1951 (peaked at 2721.0/100,000 in 1955), to 0.5/100,000 in 2011 due to increasing vaccination coverage of 95%-99%. Incidence rebounded from 6.6/100,000 to 24.5/100,000 since 2005 and decreased after measles vaccine (MV) supplementary immunization activities (SIAs) in 2010. Measles antibody positive rate was 85% 95% in most of years since 1981. High-risk districts were spotted in Chaoyang, Fengtai and Changping districts in recent 15 years. Age-specific incidence and proportion of measles varied over time. The most affected population were younger children of 1-4 years before 1978, older children of 5-14 years in 1978-1996, infant of <1 years and adults of >=15 years in period of aim to measles elimination. CONCLUSION: Strategies at different stages had a prevailing effect on the epidemic dynamics of measles in recent 60 years in Beijing. It will be essential to validate reported vaccination coverage, improve vaccination coverage in adults and strengthen measles surveillance in the anticipated elimination campaign for measles. PMID- 24143900 TI - Thermoregulation and stress hormone recovery after exercise dehydration: comparison of rehydration methods. AB - CONTEXT: Athletic trainers recommend and use a multitude of rehydration (REHY) methods with their patients. The REHY modality that most effectively facilitates recovery is unknown. OBJECTIVE: To compare 5 common REHY methods for thermoregulatory and stress hormone recovery after exercise dehydration (EXDE) in trained participants. DESIGN: Randomized, cross-over, controlled study. PATIENTS OR OTHER PARTICIPANTS: Twelve physically active, non-heat-acclimatized men (age = 23 +/- 4 years, height = 180 +/- 6 cm, mass = 81.3 +/- 3.7 kg, VO2max = 56.9 +/- 4.4 mL.min(-1).kg(-1), body fat = 7.9% +/- 3%) participated. INTERVENTION(S): Participants completed 20-hour fluid restriction and 2-hour EXDE; they then received no fluid (NF) or REHY (half-normal saline) via ad libitum (AL), oral (OR), intravenous (IV), or combination IV and OR (IV + OR) routes for 30 minutes; and then were observed for another 30 minutes. MAIN OUTCOME MEASURE(S): Body mass, rectal temperature, 4-site mean weighted skin temperature, plasma stress hormone concentrations, and environmental symptoms questionnaire (ESQ) score. RESULTS: Participants were hypohydrated (body mass -4.23% +/- 0.22%) post-EXDE. Rectal temperature for the NF group was significantly greater than for the IV group (P = .023) at 30 minutes after beginning REHY (REHY30) and greater than OR, IV, and IV + OR (P <= .009) but not AL (P = .068) at REHY60. Mean weighted skin temperature during AL was less than during IV + OR at REHY5 (P = .019). The AL participants demonstrated increased plasma cortisol concentrations compared with IV + OR, independent of time (P = .015). No differences existed between catecholamine concentrations across treatments (P > .05). The ESQ score was increased at REHY60 for NF, AL, OR, and IV (P < .05) but not for IV + OR (P = .217). The NF ESQ score was greater than that of IV + OR at REHY60 (P = .012). CONCLUSIONS: Combination IV + OR REHY reduced body temperature to a greater degree than OR and AL REHY when compared with NF. Future studies addressing clinical implications are needed. PMID- 24143901 TI - Trends in concussion return-to-play timelines among high school athletes from 2007 through 2009. AB - CONTEXT: Whereas guidelines about return-to-play (RTP) after concussion have been published, actual prognoses remain elusive. OBJECTIVE: To develop probability estimates for time until RTP after sport-related concussion. DESIGN: Descriptive epidemiology study. SETTING: High school. PATIENTS OR OTHER PARTICIPANTS: Injured high school varsity, junior varsity, or freshman athletes who participated in 1 of 13 interscholastic sports at 7 area high schools during the 2007-2009 academic years. INTERVENTION(S): Athletic trainers employed at each school collected concussion data. The athletic trainer or physician on site determined the presence of a concussion. Athlete-exposures for practices and games also were captured. MAIN OUTCOME MEASURE(S): Documented concussions were categorized by time missed from participation using severity outcome intervals (same-day return, 1- to 2-day return, 3- to 6-day return, 7- to 9-day return, 10- to 21-day return, >21-day return, no return [censored data]). We calculated Kaplan-Meier time-to event probabilities that included censored data to determine the probability of RTP at each of these time intervals. RESULTS: A total of 81 new concussions were documented in 478 775 athlete-exposures during the study period. After a new concussion, the probability of RTP (95% confidence interval) was 2.5% (95% confidence interval = 0.3, 6.9) for a 1- to 2-day return, 71.3% (95% confidence interval = 59.0, 82.9) for a 7- to 9-day return, and 88.8% (95% confidence interval = 72.0, 97.2) for a 10- to 21-day return. CONCLUSIONS: For high school athletes, RTP within the first 2 days after concussion was unlikely. After 1 week, the probability of return rose substantially (approximately 71%). Prognostic indicators are used to educate patients about the likely course of disease. Whereas individual symptoms and recovery times vary, prognostic time-to event probabilities allow clinicians to provide coaches, parents, and athletes with a prediction of the likelihood of RTP within certain timeframes after a concussion. PMID- 24143902 TI - Feedback in clinical education, part I: Characteristics of feedback provided by approved clinical instructors. AB - CONTEXT: Providing students with feedback is an important component of athletic training clinical education; however, little information is known about the feedback that Approved Clinical Instructors (ACIs; now known as preceptors) currently provide to athletic training students (ATSs). OBJECTIVE: To characterize the feedback provided by ACIs to ATSs during clinical education experiences. DESIGN: Qualitative study. SETTING: One National Collegiate Athletic Association Division I athletic training facility and 1 outpatient rehabilitation clinic that were clinical sites for 1 entry-level master's degree program accredited by the Commission on Accreditation of Athletic Training Education. PATIENTS OR OTHER PARTICIPANTS: A total of 4 ACIs with various experience levels and 4 second-year ATSs. DATA COLLECTION AND ANALYSIS: Extensive field observations were audio recorded, transcribed, and integrated with field notes for analysis. The constant comparative approach of open, axial, and selective coding was used to inductively analyze data and develop codes and categories. Member checking, triangulation, and peer debriefing were used to promote trustworthiness of the study. RESULTS: The ACIs gave 88 feedback statements in 45 hours and 10 minutes of observation. Characteristics of feedback categories included purpose, timing, specificity, content, form, and privacy. CONCLUSIONS: Feedback that ACIs provided included several components that made each feedback exchange unique. The ACIs in our study provided feedback that is supported by the literature, suggesting that ACIs are using current recommendations for providing feedback. Feedback needs to be investigated across multiple athletic training education programs to gain more understanding of certain areas of feedback, including frequency, privacy, and form. PMID- 24143903 TI - Frostbite in an adolescent football player: a case report. AB - OBJECTIVE: To present the case of vascular compromise of a finger from a confluent circumferential blister due to an inappropriately applied commercial cold pack in a high school athlete and to describe the mechanism of iatrogenic injury, acute surgical management, rehabilitation, and pathophysiology of frostbite and constriction injuries. BACKGROUND: A 17-year-old male football player presented with a frostbite and constriction injury to the index finger secondary to prolonged use of a cooling pack after a mild traumatic injury to the digit. He developed a prolonged sensory deficit from thermal injury, as well as acute vascular compromise requiring urgent operative intervention. DIFFERENTIAL DIAGNOSIS: Frostbite and constriction injury to the index finger. TREATMENT: Emergency surgical decompression and occupational therapy. UNIQUENESS: Frostbite injuries can occur iatrogenically because of inappropriate use of cooling devices or gel packs. Fingers are commonly injured extremities that are particularly susceptible to frostbite and compression injuries. To our knowledge, no case of vascular compromise from the blister constriction of digits has been reported. CONCLUSIONS: Patients and their caregivers must be educated about how to properly use cooling devices. Clinicians need to fully evaluate patients with iatrogenic frostbite injuries, giving particular attention to neurovascular status, and must recognize the need for surgical release of constriction syndrome to prevent substantial morbidity. PMID- 24143904 TI - Perceived levels of frustration during clinical situations in athletic training students. AB - CONTEXT: Athletic training students (ATSs) are involved in various situations during the clinical experience that may cause them to express levels of frustration. Understanding levels of frustration in ATSs is important because frustration can affect student learning, and the clinical experience is critical to their development as professionals. OBJECTIVE: To explore perceived levels of frustration in ATSs during clinical situations and to determine if those perceptions differ based on sex. DESIGN: Cross-sectional study with a survey instrument. SETTING: A total of 14 of 19 professional, undergraduate athletic training programs accredited by the Commission on Accreditation of Athletic Training Education in Pennsylvania. PATIENTS OR OTHER PARTICIPANTS: Of a possible 438 athletic training students, 318 (72.6%) completed the survey. MAIN OUTCOMES MEASURE(S): The Athletic Training Student Frustration Inventory was developed and administered. The survey gathered demographic information and included 24 Likert scale items centering on situations associated with the clinical experience. Descriptive statistics were computed on all items. The Mann-Whitney U was used to evaluate differences between male and female students. RESULTS: A higher level of frustration was perceived during the following clinical situations: lack of respect by student-athletes and coaching staffs, the demands of the clinical experience, inability of ATSs to perform or remember skills, and ATSs not having the opportunity to apply their skills daily. Higher levels of frustration were perceived in female than male ATSs in several areas. CONCLUSIONS: Understanding student frustration during clinical situations is important to better appreciate the clinical education experience. Low levels of this emotion are expected; however, when higher levels exist, learning can be affected. Whereas we cannot eliminate student frustrations, athletic training programs and preceptors need to be aware of this emotion in order to create an environment that is more conducive to learning. PMID- 24143905 TI - A multisport epidemiologic comparison of anterior cruciate ligament injuries in high school athletics. AB - BACKGROUND: The knee joint is the second most commonly injured body site after the ankle and the leading cause of sport-related surgeries. Knee injuries, especially of the anterior cruciate ligament (ACL), are among the most economically costly sport injuries, frequently requiring expensive surgery and rehabilitation. OBJECTIVE: To investigate the epidemiology of ACL injuries among high school athletes by sport and sex. DESIGN: Descriptive epidemiology study. MAIN OUTCOME MEASURE(S): Using an Internet-based data-collection tool, Reporting Information Online (RIO), certified athletic trainers from 100 nationally representative US high schools reported athlete-exposure and injury data for athletes from 9 sports during the 2007/08-2011/12 academic years. The outcome of interest in this study was ACL injuries. RESULTS: During the study period, 617 ACL injuries were reported during 9 452 180 athlete exposures (AEs), for an injury rate of 6.5 per 100 000 AEs. Nationally, in the 9 sports studied, an estimated 215 628 ACL injuries occurred during the study period. The injury rate was higher in competition (17.6) than practice (2.4; rate ratio [RR] = 7.3, 95% confidence interval [CI] = 6.08, 8.68). Girls' soccer had the highest injury rate (12.2) followed by boys' football (11.1), with boys' basketball (2.3) and boys' baseball (0.7) having the lowest rates. In sex-comparable sports, girls had a higher rate (8.9) than boys (2.6; RR = 3.4, 95% CI = 2.64, 4.47). Overall, 76.6% of ACL injuries resulted in surgery. The most common mechanisms of injury were player-to-player contact (42.8%) and no contact (37.9%). CONCLUSIONS: Anterior cruciate ligament injury rates vary by sport, sex, and type of exposure. Recognizing such differences is important when evaluating the effectiveness of evidence-based, targeted prevention efforts. PMID- 24143906 TI - Concussion-assessment and -management techniques used by athletic trainers. AB - CONTEXT: Understanding concussion-assessmment and -management practices that athletic trainers (ATs) currently use will allow clinicians to identify potential strategies for enhancing the quality of care provided to patients. OBJECTIVE: To assess current clinical concussion diagnostic and return-to-participation practices among ATs. DESIGN: Cross-sectional study. SETTING: Web-based survey. PATIENTS OR OTHER PARTICIPANTS: A link to the survey was sent randomly to a convenience sample of 3222 members of the National Athletic Trainers' Association. A total of 1053 (32.7%) certified ATs (experience as an AT = 11.2 +/ 9.1 years) responded to the survey. INTERVENTION(S): Prospective participants received electronic correspondence informing them of the purpose of the study and providing a link to the Web-based survey instrument. A reminder e-mail was sent approximately 6 weeks later, and the survey remained online for a total of 8 weeks. MAIN OUTCOME MEASURE(S): We collected information on the annual number of concussions assessed and tools employed to diagnose, manage, and safely return an athlete to participation. Descriptive statistics were computed for each variable. RESULTS: Participants reported observing 10.7 +/- 11.0 concussions per year. Clinical examination (n = 743, 70.6%) was the most commonly reported means for evaluating and diagnosing concussion. Less than half of our respondents employed the Standardized Assessment of Concussion (n = 467, 44.3%), any variation of the Romberg test (n = 461, 43.8%), and computerized neuropsychological testing (n = 459, 43.6%). Clinical examination (n = 773, 73.4%), return-to-participation guidelines (n = 713, 67.7%), physician recommendation (n = 660, 62.7%), or player self-report (n = 447, 42.5%) contributed to the return-to-participation decisions of ATs. Only 20.8% (n = 219) of ATs reported using all 3 recommended domains of the concussion battery. CONCLUSIONS: Our study demonstrated a growth in the number of ATs incorporating objective clinical measures of concussion as a part of their concussion management. Conversely, fewer ATs reported using a standard clinical examination in their concussion assessment. These findings suggest ATs must continue to increase their use of both objective concussion assessment tools and the standard clinical examination. PMID- 24143908 TI - Quantification of wheat straw lignin structure by comprehensive NMR analysis. AB - A further understanding of the structure of lignin from herbaceous crops is needed for advancing technologies of lignocellulosic biomass processing and utilization. A method was established in this study for analyzing structural motifs found in milled straw lignin (MSL) and cellulase-digested lignin (CEL) isolated from wheat straw by combining quantitative (13)C and HSQC NMR spectral analyses. The results showed that guaiacyl (G) was the predominant unit in wheat straw cell wall lignin over syringyl (S) and hydroxyphenyl (H) units. Up to 8.0 units of tricin were also detected in wheat straw lignin per 100 aromatic rings. Various interunit linkages, including beta-O-4, beta-5, beta-beta', beta-1, alpha, beta-diaryl ether, and 5-5'/4-O-beta' as well as potential lignin carbohydrate complex (LCC) bonds, were identified and quantified. These findings provide useful information for the development of biofuels and lignin-based materials. PMID- 24143907 TI - Impact of islet size on pancreatic islet transplantation and potential interventions to improve outcome. AB - Better results have been recently reported in clinical pancreatic islet transplantation (ITX) due mostly to improved isolation techniques and immunosuppression; however, some limitations still exist. It is known that following transplantation, 30% to 60% of the islets are lost. In our study, we have investigated 1) the role of size as a factor affecting islet engraftment and 2) potential procedural manipulations to increase the number of smaller functional islets that can be transplanted. C57/BL10 mice were used as donors and recipients in a syngeneic islet transplant model. Isolated islets were divided by size (large, >300 MUm; medium 150-300 MUm; small, <150 MUm). Each size was transplanted in chemically induced diabetic mice as full (600 IEQ), suboptimal (400 IEQ), and marginal mass (200 IEQ). Control animals received all size islets. Engraftment was defined as reversal of diabetes by day 7 posttransplantation. When the superiority of smaller islets was observed, strategies of overdigestion and fragmentation were adopted during islet isolation in the attempt to reduce islet size and improve engraftment. Smaller islets were significantly superior in engraftment compared to medium, large, and control (all sizes) groups. This was more evident when marginal mass data were compared. In all masses, success decreased as islet size increased. Once islets were engrafted, functionality was not affected by size. When larger islets were fragmented, a significant decrease in islet functionality was observed. On the contrary, if pancreata were slightly overdigested, although not as successful as small naive islets, an increase in engraftment was observed when compared to the control group. In conclusion, smaller islets are superior in engraftment following islet transplantation. Fragmentation has a deleterious effect on islet engraftment. Islet isolations can be performed by reducing islet size with slight overdigestion, and it can be safely adopted to improve clinical outcome. PMID- 24143909 TI - Human health impacts of biodiesel use in on-road heavy duty diesel vehicles in Canada. AB - Regulatory requirements for renewable content in diesel fuel have been adopted in Canada. Fatty acid alkyl esters, that is, biodiesel, will likely be used to meet the regulations. However, the impacts on ambient atmospheric pollutant concentrations and human health outcomes associated with the use of biodiesel fuel blends in heavy duty diesel vehicles across Canada have not been evaluated. The objective of this study was to assess the potential human health implications of the widespread use of biodiesel in Canada compared to those from ultralow sulfur diesel (ULSD). The health impacts/benefits resulting from biodiesel use were determined with the Air Quality Benefits Assessment Tool, based on output from the AURAMS air quality modeling system and the MOBILE6.2C on-road vehicle emissions model. Scenarios included runs for ULSD and biodiesel blends with 5 and 20% of biodiesel by volume, and compared their use in 2006 and 2020. Although modeling and data limitations exist, the results of this study suggested that the use of biodiesel fuel blends compared to ULSD was expected to result in very minimal changes in air quality and health benefits/costs across Canada, and these were likely to diminish over time. PMID- 24143910 TI - Human corneal epithelial cell shedding and fluorescein staining in response to silicone hydrogel lenses and contact lens disinfecting solutions. AB - PURPOSE: A pilot study was conducted to evaluate human corneal epithelial cell shedding in response to wearing a silicone hydrogel contact lens/solution combination inducing corneal staining. The nature of ex vivo collected cells staining with fluorescein was also examined. METHODS: A contralateral eye study was conducted in which up to eight participants were unilaterally exposed to a multipurpose contact lens solution/silicone hydrogel lens combination previously shown to induce corneal staining (renu(r) freshTM and balafilcon A; test eye), with the other eye using a combination of balafilcon A soaked in a hydrogen peroxide care system (Clear Care(r); control eye). Lenses were worn for 2, 4 or 6 hours. Corneal staining was graded after lens removal. The Ocular Surface Cell Collection Apparatus was used to collect cells from the cornea and the contact lens. RESULTS: In the test eye, maximum solution-induced corneal staining (SICS) was observed after 2 hours of lens wear (reducing significantly by 4 hours; p < 0.001). There were significantly more cells collected from the test eye after 4 hours of lens wear when compared to the control eye and the collection from the test eye after 2 hours (for both; n = 5; p < 0.001). The total cell yield at 4 hours was 813 +/- 333 and 455 +/- 218 for the test and control eyes, respectively (N = 5, triplicate, p = 0.003). A number of cells were observed to have taken up the fluorescein dye from the initial fluorescein instillation. Confocal microscopy of fluorescein-stained cells revealed that fluorescein was present throughout the cell cytoplasm and was retained in the cells for many hours after recovery from the corneal surface. CONCLUSION: This pilot study indicates that increased epithelial cell shedding was associated with a lens-solution combination which induces SICS. Our data provides insight into the transient nature of the SICS reaction and the nature of fluorescein staining observed in SICS. PMID- 24143911 TI - Pentoxifylline in liver ischemia and reperfusion. AB - Pentoxifylline is a methylxanthine compound which was first filed in 1973 and registered in 1974 in the United States by Sanofi-Aventis Deustchland Gmbh for the treatment of intermittent claudication for chronic occlusive arterial disease. This methylxanthine was later discovered to be a phosphodiesterase inhibitor. Furthermore, its hemorheological properties and its function as an inhibitor of inflammatory cytokines, like TNF-alpha, allowed researchers to study its effects in organ ischemia and reperfusion and transplantation. Although this drug has demonstrated beneficial effects, the mechanisms by which Pentoxifylline exerts a protective effect are not fully understood. This paper focuses on reviewing the literature to define the effect of Pentoxifylline when used in liver ischemia and reperfusion injury. Our research shows different animal models in which Pentoxifylline has been used as well as different doses and time of administration, as the ideal dose and timing have not yet been ascertained in liver ischemia and reperfusion. In conclusion, Pentoxifylline has shown positive effects in liver ischemia and reperfusion injury, and the main mechanism seems to be associated with the inhibition of TNF-alpha. PMID- 24143912 TI - Aggregation in colloidal suspensions: evaluation of the role of hydrodynamic interactions by means of numerical simulations. AB - Numerical simulations constitute a precious tool for understanding the role of key parameters influencing the colloidal arrangement in suspensions, which is crucial for many applications. The present paper investigates numerically the role of hydrodynamic interactions on the aggregation processes in colloidal suspensions. Three simulation techniques are used: Brownian dynamics without hydrodynamic interactions, Brownian dynamics including some of the hydrodynamic interactions, using the Yamakawa-Rotne-Prager tensor, and stochastic rotation dynamics coupled with molecular dynamics. A system of monodisperse colloids strongly interacting through a generalized Lennard-Jones potential is studied for a colloid volume fraction ranging from 2.5 to 20%. Interestingly, effects of the hydrodynamic interactions are shown in the details of the aggregation processes. It is observed that the hydrodynamic interactions slow down the aggregation kinetics in the initial nucleation stage, while they speed up the next cluster coalescence stage. It is shown that the latter is due to an enhanced cluster diffusion in the simulations including hydrodynamic interactions. The higher the colloid volume fraction, the more pronounced the effects on the aggregation kinetics. It is also observed that hydrodynamic interactions slow down the reorganization kinetics. It turns out that the Brownian dynamics technique using the Yamakawa-Rotne-Prager tensor tends to overestimate the effects on cluster diffusion and cluster reorganization, even if it can be a method of choice for very dilute suspensions. PMID- 24143913 TI - Synthesis, characterization, and anticancer activity of a series of ketone-N(4) substituted thiosemicarbazones and their ruthenium(II) arene complexes. AB - A series of ketone-N(4)-substituted thiosemicarbazone (TSC) compounds (L1-L9) and their corresponding [(eta(6)-p-cymene)Ru(II)(TSC)Cl](+/0) complexes (1-9) were synthesized and characterized by NMR, IR, elemental analysis, and HR-ESI-mass spectrometry. The molecular structures of L4, L9, 1-6, and 9 were determined by single-crystal X-ray diffraction analysis. The compounds were further evaluated for their in vitro antiproliferative activities against the SGC-7901 human gastric cancer, BEL-7404 human liver cancer, and HEK-293T noncancerous cell lines. Furthermore, the interactions of the compounds with DNA were followed by electrophoretic mobility spectrometry studies. PMID- 24143915 TI - Work disability in Finnish patients with rheumatoid arthritis: a 15-year follow up. AB - OBJECTIVES: To investigate long-term work disability of patients with early rheumatoid arthritis (RA) and to examine impact of early disease activity and radiological progression on the loss of final work capacity. METHODS: Work disability due to RA was studied over 15 years in 86 Finnish patients with early RA and available for the labour force at study entry. RA-related retirement was studied in relation to early disease activity defined as the 28-joint disease activity score area under curve (DAS28 AUC) during the first 12 months and the impact of early radiological progression from the baseline to year 1. RESULTS: The RA-related retirement rate was 7% after the first year, 11% after 2 years, 19% after 5 years, 33% after 10 years and 39% after 15 years. Of the patients with low disease activity (DAS28 AUC <=3.2) none were retired during the first 3 years. The retirement rate was also lower in subsequent years (10% after 5 years, 14% after 10 years, and 27% after 15 years) among these patients compared to those with DAS28 AUC >3.2 (28%, 55%, and 64%, respectively). A similar trend was evident among patients with no radiological progression (<=1 unit increase in Larsen score) and those with >1 Larsen unit of progression during the first year of RA. CONCLUSIONS: Our study suggests that low disease activity and halting of radiological progression during the first year of the disease improve possibilities to maintain work capacity in RA during the subsequent 15 years. PMID- 24143914 TI - A nanopore-nanofiber mesh biosensor to control DNA translocation. AB - Solid-state nanopores show promise as single-molecule sensors for biomedical applications, but to increase their resolution and efficiency, analyte molecules must remain longer in the nanopore sensing volume. Here we demonstrate a novel, facile, and customizable nanopore sensor modification that reduces the double stranded DNA translocation velocity by 2 orders of magnitude or more via interactions outside the nanopore. This is achieved by electrospinning a copolymer nanofiber mesh (NFM) directly onto a solid-state nanopore (NP) chip. The effect of NFMs on dsDNA translocation through an NP is highlighted using a set of NFMs of varying mesh composition that reduce the translocation speed relative to a bare pore from 1- to >100-fold. A representative NFM from this set is effective on DNA as long as 20 kbp, improves the nanopore resolution, and allows discrimination among different DNA lengths. PMID- 24143916 TI - Immunotherapy for lung cancer: ongoing clinical trials. AB - Modulation of a patient's immune system so that it acts against lung cancer cells has not been successful in the past decades. Advances in our understanding of the immune response to tumors resulted in the development of different kinds of novel immunotherapeutic agents. This has resulted in the development of two major approaches. First, antigen-specific immunotherapy or cancer vaccination, with the MAGE-A3 vaccine in resected early-stage non-small-cell lung cancer (NSCLC), the L BLP25 vaccine in locally advanced NSCLC after chemoradiotherapy and belagenpumatucel-L and the TG4010 vaccine in advanced-stage NSCLC. Second, non antigen-specific immunotherapy or cancer immunomodulation is reviewed, including how monoclonal antibodies modulate the interaction between antigen-presenting cells, T-lymphocytes and tumor cells (e.g., antibodies against CTLA-4, or against PD-1 receptor or its ligands). Recent Phase II trials with these treatments have shown promising results of efficacy and tolerability, which has led to testing in several large Phase III trials. Some of these are fully recruited, while others are still ongoing, and important results are be expected in the near future. PMID- 24143917 TI - Electro-acupuncture with different current intensities to treat functional constipation: a study protocol for a randomized controlled trial. AB - BACKGROUND: Functional constipation (FC) is highly prevalent in the general population of the world and has a substantial negative impact on the health related quality of life of individuals. Many clinical trials have indicated that acupuncture is effective in the treatment of FC. However, the sample sizes of these previous studies were too small. Furthermore, there are no reports investigating the relationship between the stimulation parameter and the therapeutic effect. We therefore designed a multicenter randomized controlled trial to address these problems and hopefully provide a more conclusive answer to these questions. METHODS: Participants will be included if they meet all of the following conditions: (1) diagnosed with functional constipation according to the Roman III standard; (2) aged between 18 and 65 years; (3) not taking any drugs that promote gastrointestinal movements at least during the 1 week prior to randomization; (3) willing to sign an informed consent form; (4) willing to return to the study site for their study visits. The participants will be randomly assigned to three groups in a 1:1:1 ratio: high current intensity group, low current intensity group, and mosapride citrate control group. The total study period is 9 weeks for each patient, 1 week for baseline, 4 weeks for treatment, and 4 weeks for follow-up. The primary outcome in this trial is the number of defecating events per week. The secondary outcomes will include the shape and properties of the stool, intensity of defecating difficulty, Patient Assessment of Constipation Quality of Life (PAC-QOL), MOS item Short Form health survey (SF 36), Self-Rating Anxiety Scale (SAS), and Self-Rating Depression Scale (SDS). DISCUSSION: This study will provide significant evidence for the application of acupuncture in FC and will identify a suitable stimulation parameter for treatment. TRIAL REGISTRATION: ClinicalTrials.gov ID: NCT01274793. PMID- 24143918 TI - Predictors of seasonal influenza vaccination in chronic asthma. AB - BACKGROUND: Guidelines advise annual influenza vaccination in chronic asthma. The aim of this study was to determine uptake of the influenza vaccine in a group of patients (n = 146) with moderate to severe chronic asthma and establish the main predictors of vaccination. METHOD: Patients attending a hospital asthma clinic were asked to complete a questionnaire in February 2012 (n = 146). These same patients were contacted a year later via telephone (n = 109 responded), and they were asked to complete the same questionnaire. RESULTS: Vaccination rate was 50.3% in winter 2011/12, and 57.8% in 2012/13. Using binary logistic regression, the predictors for vaccination in 2012 were patient advice (Odds ratio [OR] 15.37 p = 0.001), female gender (OR 2.75, p = 0.028), past side effects (OR 0.21, p = 0.001) and comorbidity (OR 0.39, p = 0.013). Stepwise regression resulted in age as predictor (T value = 3.99, p = 0.001). On analyzing the responses from the second questionnaire at one year after attendance to asthma clinic, predictors changed to compliance to medication (OR 9.52, p= 0.001) and previous exacerbations (OR 4.19, p = 0.026). Out of the 56 patients vaccinated in 2011/12, 33 reported asthma exacerbations before 2012, and 29 reported asthma exacerbations after receiving the influenza vaccine. Out of the 46 unvaccinated patients in 2012, 27 had asthma exacerbations before 2012 and 19 patients had exacerbations in 2013. Patients vaccinated in 2011/12 needed 0.59 courses of steroid/patient/year, and 1.23 visits for nebulizer/patient/year while non vaccinated patients needed 0.18 courses of steroids/patient/year (p = 0.048), and 0.65 visits for nebulized/patient/year (p = 0.012). Patients' subjective statements broadly confirmed the predictors. 16/69 (23.1%) received the vaccine in winter 2012/13 despite reporting previous side effects. CONCLUSIONS: Advice to patient, female gender and patients' age predicted vaccination, while past side effects to the influenza vaccine, and presence of comorbidities predicted non vaccination. Symptomatic asthma patients are more likely to be vaccinated. One year after the first contact, treatment compliance and previous asthma exacerbations gained statistical significance as predictors of vaccination. PMID- 24143919 TI - Bulk heterojunction nanomorphology of fluorenyl hexa-peri-hexabenzocoronene fullerene blend films. AB - In this study, the nanomorphology of fluorenyl hexa-peri-hexabenzocoronene:[6,6] phenyl C61-butyric acid methyl ester (FHBC:PC61BM) absorber layers of organic solar cells was investigated. Different electron microscopical techniques, atomic force microscopy, and grazing incidence wide-angle X-ray scattering were applied for a comprehensive nanomorphology analysis. The development of the nanomorphology upon sample annealing and the associated change of the device performance were investigated. It was shown that the annealing process enhances the phase separation and therefore the bulk heterojunction structure. Due to pi pi stacking, the FHBC molecules assemble into columnar stacks, which are already present before annealing. While the nonannealed sample consists of a mixture of homogeneously distributed PC61BM molecules and FHBC stacks with a preferential in plane stack orientation, crystalline FHBC precipitates occur in the annealed samples. These crystals, which consist of hexagonal arranged FHBC stacks, grow with increased annealing time. They are distributed homogeneously over the whole volume of the absorber layer as revealed by electron tomography. The FHBC stacks, whether in the two phase mixture or in the pure crystalline precipitates, exhibit an edge-on orientation, according to results from grazing incidence wide-angle X ray scattering (GIWAXS), dark-field transmission electron microscopy (DF TEM) imaging and selective area electron diffraction (SAED). The best solar cell efficiencies were obtained after 20 or 40 s sample annealing. These annealing times induce an optimized degree of phase separation between donor and acceptor material. PMID- 24143920 TI - Analysis of integrons and associated gene cassettes in clinical isolates of multidrug resistant Pseudomonas aeruginosa from Southwest Nigeria. AB - BACKGROUND: Multidrug resistant Pseudomonas aeruginosa harbours integrons and other mobile genetic elements such as plasmids and transposons, which easily disseminate antibiotic resistance genes among clinical strains of P. aeruginosa. METHODOLOGY: Plasmid extraction of 54 clinical isolates of P. aeruginosa was carried out by alkaline lysis method; and plasmid size estimation was done by using E. coli V517 standard plasmid marker. Fifty-four clinical strains of P. aeruginosa were isolated from 5 hospitals in 3 Southwestern states of Nigeria between March and September 2010. Plasmid extraction of isolates was carried out by alkaline lysis method; and plasmid size estimation was done by using E. coli V517 standard plasmid marker. PCR amplification for the 3 classes of resistance integrons, and gene cassette characterization were carried out using specific primers and by sequencing of PCR products. Conjugal mating of the integron positive P. aeruginosa strains with E. coli DH5alpha was performed to demonstrate transferability of integrons and gene cassettes. RESULT: Agarose gel electrophoresis of plasmid DNA revealed that all the 54 P. aeruginosa harboured 1 4 plasmids with sizes ranging from 2.2 - >58 kb. Class 1 integron was identified in 31 (57%) strains; but none of them carried class 2 and class 3 integrons. High prevalence of aadA gene conferring resistance to streptomycin/spectinomycin was detected in the strains positive for class 1 integron. Sequencing of the 1.6 kb and 1.2 kb amplified band of gene cassettes revealed the presence of aadA6-orfD and aadA13 respectively. CONCLUSION: This study demonstrates the presence of plasmids and integrons harbouring resistance gene cassettes, which may collectively constitute an efficient system for dissemination of resistance genes in P. aeruginosa. Disturbingly, the rapid and unabated spread of class 1 integron associated multidrug resistant P. aeruginosa in Southwest Nigeria may greatly hamper successful treatment of infections caused by such strains. This necessitates the establishment of functional antimicrobial resistance surveillance programmes in Nigeria. PMID- 24143921 TI - Cryptic uveitis in a patient with morning glory syndrome. AB - BACKGROUND: A 71-year-old female presented on 3 occasions with escalating pain in a congenitally blind eye. Examination revealed hypertensive uveitis with morning glory optic disc dysplasia and absence of a crystalline lens. There was no previous intraocular surgery or trauma. Intensive anti-hypertensive agents and topical steroids did not control intraocular pressure (IOP) or inflammation. RESULTS: Dilated fundus examination on the third clinical review revealed a luxated cataractous lens on the retina. Pars plana vitrectomy and fragmatome lensectomy controlled inflammation and IOP, with resolution of ocular pain. DISCUSSION: This is an exceptional case of phacogenic uveitis with secondary glaucoma occurring years after spontaneous crystalline lens luxation in a patient with morning glory syndrome. The embryological pathogenesis of morning glory syndrome and the significance of accelerated cataractogenesis and zonular weakness are discussed. Hypertensive uveitis with unexplained absence of a crystalline lens in a blind eye must prompt suspicion of delayed phacogenic uveitis following asymptomatic lens luxation. PMID- 24143923 TI - Be critical but fair. PMID- 24143922 TI - Gap junction blockers: a potential approach to attenuate morphine withdrawal symptoms. AB - BACKGROUND: The exact mechanisms of morphine-induced dependence and withdrawal symptoms remain unclear. In order to identify an agent that can prevent withdrawal syndrome, many studies have been performed. This study was aimed to evaluate the effect of gap junction blockers; carbenoxolone (CBX) or mefloquine (MFQ); on morphine withdrawal symptoms in male rat. Adult male Wistar rats (225 - 275 g) were selected randomly and divided into 10 groups. All groups underwent stereotaxic surgery and in order to induce dependency, morphine was administered subcutaneously) Sc) at an interval of 12 hours for nine continuous days. On the ninth day of the experiment, animals received vehicle or CBX (100, 400, 600 MUg/10 MUl/rat, icv) or MFQ (50, 100 and 200 MUg/10 MUl/rat, icv) after the last saline or morphine (Sc) injection. Morphine withdrawal symptoms were precipitated by naloxone hydrochloride 10 min after the treatments. The withdrawal signs including: jumping, rearing, genital grooming, abdomen writhing, wet dog shake and stool weight, were recorded for 60 minutes. RESULTS: Results showed that CBX and MFQ decreased all withdrawal signs; and the analysis indicated that they could attenuate the total withdrawal scores significantly. CONCLUSION: Taking together it is concluded that gap junction blockers prevented naloxone precipitated withdrawal symptoms. PMID- 24143925 TI - Constructing tunable nanopores and their application in drug delivery. AB - Inspired by biological cell membranes, various "smart" and efficient gating nanoporous devices have been proposed to imitate and to understand life processes. Nanodevices under development with enhanced gating efficiency could play pivotal roles in biosensing and drug delivery. In this Perspective, we highlight an important development by Willner and colleagues that is detailed in this issue of ACS Nano. They designed a new "smart" nanodevice with both "sense" and "release" functionalities for drug delivery based on a nanoporous material, mesoporous silica nanoparticles. We outline recent progress in designing intelligently gated nanoporous devices in material science and nanotechnology. We also summarize new strategies designed for drug delivery based on mesoporous materials. With continuing efforts, we expect more powerful nanodevices to be developed and used in clinical and other real-word applications. PMID- 24143926 TI - Properties of strained structures and topological defects in graphene. AB - Strain and defect engineering of graphene can modify the topological features of electronic states, leading to novel properties such as pseudomagnetism in bubbles and metallicity in extended topological defects. A consequence of graphene being a soft membrane is that it can be strain-engineered to become highly corrugated by modifying its adhesion to the substrate. Extended grain boundaries in graphene can be constructed from periodic combinations of nonhexagonal rings (5-7 pairs). However, a controlled method of producing these defects is not currently available. In this Perspective, we discuss some of the recent advances in studying the properties and formation mechanisms of strained structures and defects in graphene, extending across both physics and chemistry. PMID- 24143927 TI - Only modest long-term opioid dose escalation occurs over time in chronic nonmalignant pain management. AB - Clinical experience and the literature increasingly support differentiating chronic pain associated with malignant disease from chronic pain associated with nonmalignant conditions when defining optimal pharmacotherapy. The use of opioids for chronic nonmalignant pain has grown steadily despite the lack of a strong evidence base that can guide practice. A fundamental question is whether patients develop tolerance and need repeated dose escalations to sustain pain control. We examined opioid prescribing data from United Kingdom Clinical Practice Research Datalink longitudinal database of general practice records and tracked dose changes but not pain reports in a sample of 4035 patients who received oral or transdermal-extended release opioids for chronic nonmalignant pain. The median number of days on opioid pharmacotherapy for all patients was 311. Thirty percent of patients never changed doses during the course of treatment. In patients who never changed medications, the mean morphine equivalent 24-hour dose increased from beginning to end of opioid pharmacotherapy only by 1.4 fold, t = 25.73, Cohen's d = .427 and was independent of both age and gender. Comparison across extended release morphine, oxycodone, and fentanyl revealed that it was significantly greatest for patients using fentanyl and least for those using morphine. PMID- 24143928 TI - Quality of postoperative pain management in American versus European institutions. AB - Management of postoperative pain remains an important clinical problem throughout the world. Using the PAIN-OUT acute pain registry database to examine perioperative pain management in orthopedic surgery patients, we compared patient reported outcomes (PROs) in a pooled sample obtained from four American hospitals (N = 473) with PROs in a pooled sample of 20 European institutions (N = 8799). Most American hospitals consistently assess acute pain in surgical patients due to Joint Commission accreditation guidelines. Therefore, we hypothesized that this practice would create a climate of clinical staff sensitivity to patients' pain and a greater readiness to intervene when pain is higher than one would find in Europe as a whole. American institutions might then provide better control of postoperative pain after orthopedic surgery than European institutions. Because of the large sample sizes, our analyses focused on effect size rather than statistical significance. Evaluation of the pain PROs revealed that European patients reported much lower Worst Pain on the first day after orthopedic surgery than American patients. The mean Worst Pain (+/- SD) for Europeans was 5.4 (2.5) but for Americans the mean was 7.4 (2.7), p < .0001, a large effect size. Europeans also reported significantly less emotional discomfort, less interference of pain with activity and lower Least Pain. Nonetheless, 98.3% of American patients received opioids on the ward on the first postoperative day compared to 70.2% of European patients, and 41.1% received regional analgesia on the ward while 15.9% of European patients received regional analgesia (both small effect sizes). Overall, the results are clear in demonstrating much better pain control in the ensemble of European countries as compared to the United States. PMID- 24143929 TI - Prescriber-pharmacist collaboration: re-engineering the partnership to optimize pain patient care. AB - The Walgreen Companies recently settled a Drug Enforcement Administration (DEA) administrative action and other investigations arising in connection with a controlled substance distribution facility in Florida and several of its retail pharmacies. These DEA enforcement actions upon a national chain pharmacy have resulted in a series of policies and professional practices that appear to functionally disrupt continuity of patient care. The policy issues transcend the professions and go to the core of our responsibilities to patients. It is unfortunate that regulations intended to prevent diversion also dramatically disrupt interprofessional relations. Based on public statements of professional organizations, unification on this issue seems possible. This presents an opportunity to revisit collaboration among prescribers and pharmacists in legislative and regulatory advocacy. A uniform definition of "legitimate medical purpose" is needed to maximize patient access to needed pharmacotherapy while remaining vigilant for diversion. PMID- 24143930 TI - Cell-based galactosemia diagnosis system based on a galactose assay using a bioluminescent Escherichia coli array. AB - A new cell-based galactose assay system, which is comprised of two bioluminescent Escherichia coli strains immobilized within an agarose gel arrayed on a well plate, has been developed. For this purpose, a galT knockout strain [galT(-) cell] of E. coli was genetically constructed so that cell growth is not promoted by galactose but rather by glucose present in a sample. Another E. coli W strain (normal cell), which grows normally in the presence of either glucose or galactose, was employed. A luminescent reporter gene, which produces luminescence as cells grow, was inserted into both of the E. coli strains, so that cell growth could be monitored in a facile manner. The two strains were separately grown for 4 h on gel arrays to which test samples were individually supplied. The relative luminescence unit (RLU) values caused by cell growth were determined for each array, one of which is resulted by glucose only and the other of which is resulted by both glucose and galactose present in the sample. By employing this protocol, galactose concentrations present in the test sample are reflected in the differences between the RLU values for each array. The practical utility of the new assay system was demonstrated by its use in determining galactose levels in clinical blood spot specimens coming from newborn babies. Because it can be employed to diagnosis of galactosemia in newborn babies in a more rapid, convenient, and cost-effective manner, this cell-based solid-phase galactose assay system should become a powerful alternative to conventional methods, which require labor-intensive and time-consuming procedures and/or complicated and expensive equipment. PMID- 24143931 TI - Perceptions of HIV infected patients on the use of cell phone as a tool to support their antiretroviral adherence; a cross-sectional study in a large referral hospital in Kenya. AB - BACKGROUND: Clinical trials were conducted to assess the feasibility of using a cell phone text messaging-based system to follow up Human Immunodeficiency Virus (HIV) infected patients on antiretroviral (ARTs) and assess for improved adherence to their medication. However there is need to evaluate the perceptions of the HIV infected patients towards the use of these cell phones in an effort to better aid in the clinical management of their HIV infection. The objective of this study was therefore to determine the perceptions of HIV infected patients on the use of cell phone text messaging as a tool to support adherence to their ART medication. METHODS: A cross sectional survey was conducted among patients receiving Highly Active Anti-Retroviral Therapy (HAART) at the Kenyatta National Hospital Comprehensive Care Clinic in Nairobi between May and July, 2011. Pre tested questionnaires were used to collect the socio-demographic and perceptions data. The recruitment of the participants was done using the random probability sampling method and statistical analysis of data performed using Statistical Package for Social Sciences (SPSS) version 16.0. RESULTS: A total of 500 HIV infected patients (Male-107, Female-307) aged 19-72 years were interviewed. The majority of individuals (99%) had access to cell phones and 99% of the HIV infected patients interviewed supported the idea of cell phone use in management of their HIV infection. A large proportion (46%) claimed that they needed cell phone access for medical advice and guidance on factors that hinder their adherence to medication and only 3% of them needed it as a reminder to take their drugs. The majority (72%) preferred calling the healthcare provider with their own phones for convenience and confidential purposes with only 0.4% preferring to be called or texted by the health care provider. Most (94%), especially the older patients, had no problem with their confidentiality being infringed in the process of the conversation as per the bivariate analysis results. CONCLUSION: Cell phone communications are acceptable and in fact preferable over cell phone reminders. PMID- 24143932 TI - Prescription of antiviral drugs during the 2009 influenza pandemic: an observational study using electronic medical files of general practitioners in the Netherlands. AB - BACKGROUND: After the clinical impact of the A(H1N1) pdm09 virus was considered to be mild, treatment with antiviral drugs was recommended only to patients who were at risk for severe disease or who had a complicated course of influenza. We investigated to what extent antiviral prescriptions in primary care practices were in accordance with the recommendations, what proportion of patients diagnosed with influenza had been prescribed antiviral drugs, and to what extent prescriptions related to the stated indications for antiviral treatment. METHODS: We used data from routine electronic medical records of practices participating in the Netherlands Information Network of General Practice LINH in the period August-December 2009. We considered patient and practice characteristics, clinical diagnoses and drug prescriptions of all patients who contacted their general practitioner in the given period and who had been prescribed antiviral medication (n=351) or were diagnosed with influenza (n=3293). RESULTS: Of all antiviral prescriptions, 69% were in accordance with the recommendations. Only 5% of patients diagnosed with influenza were prescribed antiviral drugs. This percentage increased to 12% among influenza patients belonging to the designated high risk groups. On the other hand, 2.5% of influenza patients not at high risk of complications received antiviral treatment. In addition to the established high risk factors, the total number of drug prescriptions for a patient in this year was a determinant of antiviral prescriptions. Information on time since onset of symptoms and the clinical presentation of patients was not available. CONCLUSIONS: General practitioners in the Netherlands have been restrictive in prescribing antiviral drugs during the influenza pandemic, even when patients met the criteria for antiviral treatment. PMID- 24143933 TI - Steroid-induced diabetes in rheumatologic patients. AB - Glucocorticoids are widely used to suppress inflammation - especially in the acute phase - in several inflammatory and autoimmune rheumatologic diseases. Despite their efficacy, their long-term use or at high doses is associated with numerous well-characterised side effects. Hyperglycaemia or frank diabetes is one of the most common, as its prevalence is estimated between 10-20%. Its pathophysiology is mainly due to increased insulin resistance. In this review, we provide a practical guide on how to monitor patients who are started on glucocorticoids, and how to detect and manage steroid-induced hyperglycaemia or diabetes. PMID- 24143934 TI - An efficient generation of a functionalized tertiary-alkyl radical for copper catalyzed tertiary-alkylative Mizoroki-Heck type reaction. AB - alpha-Halocarbonyl compounds undergo beta-hydrogen elimination to give conjugated olefins in the presence of a transition-metal catalyst. However, a copper/triamine catalyst system can induce the alkylative Mizoroki-Heck reaction of styrenes with tertiary-alkyl halides possessing a withdrawing group under very mild conditions. This reaction provides an efficient synthetic methodology for tertiary-alkylated styrenes. PMID- 24143935 TI - Attainment vs exposure: ozone metric responses to source-specific NOx controls using adjoint sensitivity analysis. AB - We establish linkages between sources of NOx emissions and two types of national ozone metrics in Canada and the U.S. using the adjoint of an air quality model. We define an attainment-based metric using probabilistic design values (PDVs) exceeding 65 ppb to represent polluted regions and define an exposure-based metric as the premature mortality count related to short-term ozone exposure, both in Canada and the U.S. Our results reveal differences in both temporally averaged and day-specific influences of NOx emission controls across source locations. We find NOx emission reductions in California and the eastern U.S. to be most effective for reducing attainment- and exposure-based metrics, amounting to a total reduction of 6500 ppb in PDVs and 613 deaths/season nationally from a 10% reduction in NOx emissions from those source locations. While source controls in the remainder of the western U.S. are beneficial at reducing nonattainment, these reductions are less influential on ozone mortality. We also find that while exposure-based metrics are sensitive to daily emission reductions, much of the reduction in PDVs arises from controlling emissions on only a fraction of simulation days. We further illustrate the dependency of adjoint estimates of emission influences on the choice of averaging period as a follow-up to previous work. PMID- 24143936 TI - Droplet microfluidics for producing functional microparticles. AB - Isotropic microparticles prepared from a suspension that undergoes polymerization have long been used for a variety of applications. Bulk emulsification procedures produce polydisperse emulsion droplets that are transformed into spherical microparticles through chemical or physical consolidation. Recent advances in droplet microfluidics have enabled the production of monodisperse emulsions that yield highly uniform microparticles, albeit only on a drop-by-drop basis. In addition, microfluidic devices have provided a variety of means for particle functionalization through shaping, compartmentalizing, and microstructuring. These functionalized particles have significant potential for practical applications as a new class of colloidal materials. This feature article describes the current state of the art in the microfluidic-based synthesis of monodisperse functional microparticles. The three main sections of this feature article discuss the formation of isotropic microparticles, engineered microparticles, and hybrid microparticles. The complexities of the shape, compartment, and microstructure of these microparticles increase systematically from the isotropic to the hybrid types. Each section discusses the key idea underlying the design of the particles, their functionalities, and their applications. Finally, we outline the current limitations and future perspectives on microfluidic techniques used to produce microparticles. PMID- 24143937 TI - Blinking and driving: the influence of saccades and cognitive workload. AB - PURPOSE: The aim of this study was to investigate the joint influence of cognitive demands and large amplitude saccades on spontaneous blink rate. MATERIALS AND METHODS: Twenty healthy volunteers were enrolled in the study and instructed to follow a 60-minute real-life driving circuit while a video camera recorded ocular movements and blinking. Five different complexity levels were predefined in terms of driving difficulty and traffic intensity, that is, cognitive workload. Five one-minute segments were selected for each complexity level in each driving trial, whereupon spontaneous blink rate and horizontal saccades were monitored. Saccades were classified according to their amplitude and blink-saccade pairs were recorded. RESULTS: Albeit showing a high inter subject variability, spontaneous blink rate and saccades were consistent within the same complexity level. At different complexity levels, no statistically significant difference in spontaneous blink rate was encountered, with an average of 20.3 +/- 1.6 blinks/minute (mean +/- SD). The number of large amplitude gaze shifts increased with the level of complexity (F = 15.403; p < 0.001). An average of 87.5% of large amplitude saccades were accompanied by a blink, and this percentage was similar for all complexity levels, that is, the number of blink saccade pairs increased at higher complexity levels (F = 20.597; p < 0.001). CONCLUSIONS: In a complex, dynamic visual setting, spontaneous blinking accompanying large amplitude saccades may help in counteracting the reduction in blink rate associated with high cognitive demands. PMID- 24143938 TI - Basal cell adenocarcinoma of the salivary gland: a morphological and immunohistochemical comparison with basal cell adenoma with and without capsular invasion. AB - BACKGROUND: It is often difficult to diagnose salivary gland tumors that exhibit basaloid features differentially. The aim of this study was to identify additional morphological and immunohistochemical characteristics that can aid the diagnosis of basal cell adenocarcinoma (BCAC) of the salivary gland. METHODS AND RESULTS: In total, 29 basal cell neoplasms [eight BCACs, 11 basal cell adenomas (BCAs) with capsular invasion, and 10 BCAs without capsular invasion] and 10 cases of adenoid cystic carcinomas (ACCs) were subjected to histopathology and immunohistochemical analyses for CK7, CK5/6, SMA, p63, calponin, p53, c-erbB2, CD117, beta-catenin, EGFR, VEGF, Ki-67, and S100P protein expression. Compared to BCA without capsular invasion, the BCACs and BCAs with capsular invasion were more likely to be larger and have solid or cribriform patterns. Most BCACs and BCAs exhibited nuclear beta-catenin expression. In all basal cell neoplasm cases, the clinical course after surgery with or without radiotherapy was indolent. beta catenin, CK5/6, CD117, and S100P protein were helpful for differentiating basal cell neoplasms from ACC. CONCLUSIONS: BCAs with capsular invasion shared several pathological features with BCACs, including a large size and frequent cribriform patterns but the malignant potential of these tumors seems highly limited and should be reexamined. beta-catenin immunostaining may aid the differential diagnosis between basal cell neoplasms and ACCs. VIRTUAL SLIDES: The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/9637819101988153. PMID- 24143939 TI - Rethinking "posterior" tongue-tie. AB - Currently, many clinicians who help with breastfeeding problems are diagnosing "posterior" tongue-tie in infants and performing or referring for frenotomy. In this "Speaking Out" article, I argue that the diagnosis of "posterior" tongue-tie has successfully raised awareness of the importance of impaired tongue function in breastfeeding difficulty. However, the diagnosis of "posterior" tongue-tie also applies a reductionist, medicalized theoretical frame to the complex problem of impaired tongue function, risking unintended outcomes. Impaired tongue function arises out of multiple interacting and co-evolving factors, including the interplay between social behaviors concerning breastfeeding and mother-infant biology. Consideration of theoretical frames is vital if we are to build an evidence base through efficient use of the scarce resources available for clinical breastfeeding research and minimize unintended outcomes. PMID- 24143940 TI - [Metalloptysis: A new case with another cause?]. PMID- 24143941 TI - [Morgagni's hernia as a cause of acute abdomen]. PMID- 24143942 TI - [Pursuing quality in simulation-based surgical education]. PMID- 24143943 TI - Noninnocent behavior of bidentate amidophosphido [NP]2- ligands upon coordination to copper. AB - The synthesis and preliminary coordination chemistry of two new redox-active bidentate ligands containing amido and phosphido donors are described. Treatment of the [(R)NP](2-) (R = Ph, 2,4,6-trimethylphenyl) ligands with CuCl2 and PMe3 results in a dimeric copper(I) P-P coupled product via ligand oxidation. The intermediate of this reaction is proposed to involve a ligand radical generated via oxidation of the [(R)NP](2-) ligand by copper(II), and the existence of such an intermediate is probed using computational methods. Significant radical character on the phosphorus atoms of the alleged [(R)NP](*-)/copper(I) intermediate leads to P-P radical coupling. PMID- 24143944 TI - MRI biosensor for lead detection based on the DNAzyme-induced catalytic reaction. AB - A MRI biosensor for sensitive and specific detection of lead ions (Pb(2+)) was developed based on DNAzyme-induced cleavage of magnetic nanoparticles (MNPs). A low limit of detection (LOD) of 0.05 ng mL(-1) was obtained. This biosensor has the potential to serve as a general platform for the detection of heavy metal ions. PMID- 24143946 TI - Bayes plus Brass: estimating total fertility for many small areas from sparse census data. AB - Estimates of fertility in small areas are valuable for analysing demographic change, and important for local planning and population projection. In countries lacking complete vital registration, however, small-area estimates are possible only from sparse survey or census data that are potentially unreliable. In these circumstances estimation requires new methods for old problems: procedures must be automated if thousands of estimates are required; they must deal with extreme sampling variability in many areas; and they should also incorporate corrections for possible data errors. We present a two-step procedure for estimating total fertility in such circumstances and illustrate it by applying the method to data from the 2000 Brazilian Census for over 5,000 municipalities. Our proposed procedure first smoothes local age-specific rates using Empirical Bayes methods and then applies a new variant of Brass's P/F parity correction procedure that is robust to conditions of rapid fertility decline. Supplementary material at the project website ( http://schmert.net/BayesBrass ) will allow readers to replicate all the authors' results in this paper using their data and programs. PMID- 24143947 TI - Infant mortality in Kyrgyzstan before and after the break-up of the Soviet Union. AB - There is a great deal of uncertainty over the levels of, and trends in, infant mortality in the former Soviet republics of Central Asia. As a result, the impact of the break-up of the Soviet Union on infant mortality in the region is not known, and proper monitoring of mortality levels is impaired. In this paper, a variety of data sources and methods are used to assess levels of infant mortality and their trend over time in one Central Asian republic, Kyrgyzstan, between 1980 and 2010. An abrupt halt to an already established decline in infant mortality was observed to occur during the decade following the break-up of the Soviet Union, contradicting the official statistics based on vital registration. Infants of Central Asian ethnicity and those born in rural areas were also considerably more at risk of mortality than suggested by the official sources. We discuss the implications of these findings, both for health policy in this seldom studied part of the former Soviet Union and for our understanding of the health crisis which it currently faces. PMID- 24143945 TI - Pulmonary biomarkers in COPD exacerbations: a systematic review. AB - Exacerbations of COPD (ECOPD) represent a major burden for patients and health care systems. Innovative sampling techniques have led to the identification of several pulmonary biomarkers. Although some molecules are promising, their usefulness in clinical practice is not yet established. Medline and Highwire databases were used to identify studies evaluating pulmonary sampled biomarkers in ECOPD. We combined 3 terms for ECOPD, 3 for biomarkers and 6 for the sampling method. Seventy-nine studies were considered eligible for inclusion in the review and were analyzed further. Pulmonary biomarkers sampled with non-invasive, semi invasive and invasive methods were evaluated for their potential to illustrate the disease's clinical course, to correlate to clinical variables and to predict clinical outcomes, ECOPD etiology and response to treatment. According to published data several pulmonary biomarkers assessed in ECOPD have the potential to illustrate the natural history of disease through the modification of their levels. Among the clinically relevant molecules, those that have been studied the most and appear to be promising are spontaneous and induced sputum biomarkers for reflecting clinical severity and symptomatic recovery, as well as for directing towards an etiological diagnosis. Current evidence on the clinical usefulness of exhaled breath condensate and bronchoalveolar lavage biomarkers in ECOPD is limited. In conclusion, pulmonary biomarkers have the potential to provide information on the mechanisms underlying ECOPD, and several correlate with clinical variables and outcomes. However, on the basis of published evidence, no single molecule is adequately validated for wide clinical use. Clinical trials that incorporate biomarkers in decisional algorithms are required. PMID- 24143949 TI - One-pot soft-templating method to synthesize crystalline mesoporous tantalum oxide and its photocatalytic activity for overall water splitting. AB - Crystalline mesoporous Ta2O5 has been successfully synthesized by a one-pot route using P-123 as the structure directing agent (SDA). A series of crystalline mesoporous Ta2O5 samples has been prepared by changing the calcination temperature. The surface area decreased and the pore size increased with the increasing calcination temperature, which were the results of crystallite growth. At the same time, the pore volume was well maintained, which means limited shrinkage during the calcination of elevated temperature. The porous structure and crystal structure of as-synthesized mesoporous Ta2O5 were characterized by XRD, TG-DTA, SEM, TEM, and N2 sorption techniques. The photocatalytic activity of the as-synthesized mesoporous Ta2O5 with the cocatalyst NiOx for overall water splitting under ultraviolet (UV) light irradiation was systematically evaluated. The photocatalytic activity of crystalline mesoporous Ta2O5 showed about 3 times that of commercial Ta2O5 powder and 22 times that of amorphous mesoporous Ta2O5. PMID- 24143950 TI - BCR-ABL inhibitors: updates in the management of patients with chronic-phase chronic myeloid leukemia. AB - OBJECTIVES: This article reviews recent clinical experiences with first-line and second-line second-generation BCR-ABL inhibitors and discusses considerations for selection of therapy for patients with chronic-phase chronic myeloid leukemia. METHODS: We reviewed recent publications on PubMed and abstracts from major congresses relevant to the topic. RESULTS: Therapeutic options for front-line treatment have increased with the approval of two second-generation BCR-ABL inhibitors, dasatinib and nilotinib. Both agents are also treatment options for patients with resistance or intolerance to front-line imatinib. More recently, bosutinib, ponatinib, and omacetaxine have also been approved for patients with resistance or intolerance to prior therapy. DISCUSSION: Expanded treatment options coupled with rapidly changing treatment guidelines have led to numerous questions regarding the selection and monitoring of therapy. Common concerns include how to best select therapy based upon patient-specific comorbidities, monitoring and interpretation of treatment outcomes, and optimization of dosing when side effects occur. PMID- 24143951 TI - Characterization of the thermal and photoinduced reactions of photochromic spiropyrans in aqueous solution. AB - Six water-soluble spiropyran derivatives have been characterized with respect to the thermal and photoinduced reactions over a broad pH-interval. A comprehensive kinetic model was formulated including the spiro- and the merocyanine isomers, the respective protonated forms, and the hydrolysis products. The experimental studies on the hydrolysis reaction mechanism were supplemented by calculations using quantum mechanical (QM) models employing density functional theory. The results show that (1) the substitution pattern dramatically influences the pKa values of the protonated forms as well as the rates of the thermal isomerization reactions, (2) water is the nucleophile in the hydrolysis reaction around neutral pH, (3) the phenolate oxygen of the merocyanine form plays a key role in the hydrolysis reaction. Hence, the nonprotonated merocyanine isomer is susceptible to hydrolysis, whereas the corresponding protonated form is stable toward hydrolytic degradation. PMID- 24143952 TI - Giant cell arteritis presenting with uveitis. AB - Giant cell arteritis, also known as temporal arteritis, is the most common primary vasculitis affecting the nervous system. Early recognition of this treatable condition is essential to avoid potentially devastating complications. Giant cell arteritis occurs in adults older than 50 years and affects large and medium-sized arteries, especially the external and internal carotid arteries and their branches. Severe inflammation of the vessel wall may result in obstruction of the lumen and end-organ ischemia. Typical giant cell arteritis symptoms include headache, scalp tenderness, jaw claudication, and polymyalgia rheumatica. Ischemia induced by the arteritis can lead to blindness. Herein, we describe a rare case of giant cell arteritis in a patient who initially presented with uveitis, thus eluding timely diagnosis and prompt therapy. PMID- 24143954 TI - Unexpected complexity in the electro-oxidation of iodide on gold in the ionic liquid 1-ethyl-3-methylimidazolium bis(trifluoromethanesulfonyl)imide. AB - The electro-oxidation of iodide on a gold electrode in the room temperature ionic liquid 1-ethyl-3-methylimidazolium bis(trifluoromethanesulfonyl)imide has been investigated using transient cyclic voltammetry, linear-sweep semi-integral voltammetry, an electrochemical quartz crystal microbalance technique, and coulometry/electrogravimetry. Two oxidation processes are observed, with an electron stoichiometry of 1:1, compared with the well-known 2:1 electron stoichiometry observed on other commonly used electrode materials, such as platinum, glassy carbon, and boron-doped diamond, under identical conditions. Detailed mechanistic information, obtained in situ using an electrochemical quartz crystal microbalance, reveals that this unusual observation can be attributed to the dissolution of the gold electrode in the presence of iodide. Coulometric/electrogravimetric analysis suggests that the oxidation state of the soluble gold species is +1 and that diiodoaurate, [AuI2](-), is the likely intermediate. A proportionally smaller amount of triiodide intermediate is also detected by means of UV-vis spectroscopy. On this basis, it is proposed that iodide oxidation on gold occurs via two parallel pathways: predominantly via a diiodoaurate intermediate 2I(-) + Au ? [AuI2](-) + e(-) and [AuI2](-) ? I2 + Au + e(-) and to a lesser extent via a triiodide intermediate 3I(-) ? I3(-) + 2e(-) and I3(-) ? 3/2I2 + e(-). This proposed mechanism was further supported by voltammetric investigations with an authentic sample of the anionic [AuI2](-) complex. PMID- 24143953 TI - The establishment of a duplex real-time PCR assay for rapid and simultaneous detection of blaNDM and blaKPC genes in bacteria. AB - The latest threat of multidrug-resistant Gram-negative bacteria corresponds to the emergence of carbapenemase New Delhi metallo-beta-lactamase (NDM) and Klebsiella pneumoniae carbapenemase (KPC) producers. Rapid molecular detection is essential to limit their spread. In this study, a duplex real-time polymerase chain reaction (PCR) that was specific for the detection of blaNDM and blaKPC with the same limit of detection of ten plasmid copies was developed. The assay was linear over eight log dilutions for blaNDM (R2 = 0.971; slope, -3.273) and blaKPC (R2 = 0.992; slope, -2.997) with efficiencies of 102% and 115%, respectively. The assay was validated with 157 clinical isolates and showed 100% concordance with conventional PCR. The excellent performance of the duplex PCR assay makes it a powerful tool for surveillance of the carbapenemases NDM and KPC. PMID- 24143956 TI - Analysis of a beach as a time-invariant linear input/output system of marine litter. AB - The exponential decay of the amount of new litter on Wadahama Beach, Nii-jima Island, Japan revealed by 20-month mark-recapture experiments demonstrates a linear response of the beach to the input of target items. Here we show the amplitude and phase characteristics of the beach as a time-invariant linear input/output system and discuss the hydrodynamic and geomorphological factors that would determine the characteristics with the aid of a diffusion equation. The characteristics are fully determined by the residence time of the items (tau(r)=209 days) and can be described as functions of the ratio of tau(r) to the period of input variability. The decay is reproduced well by the analytical solution of the equation with a constant diffusion coefficient (D), whose order was estimated by tau(r) and the backshore width. Generally, D would depend on hydrodynamical statistics and beach geomorphology as well as the dimensions and density of the items. PMID- 24143955 TI - Spectomycin B1 as a novel SUMOylation inhibitor that directly binds to SUMO E2. AB - Conjugation of small ubiquitin-like modifier (SUMO) to protein (SUMOylation) regulates multiple biological systems by changing the functions and fates of a large number of proteins. Consequently, abnormalities in SUMOylation have been linked to multiple diseases, including breast cancer. Using an in situ cell-based screening system, we have identified spectomycin B1 and related natural products as novel SUMOylation inhibitors. Unlike known SUMOylation inhibitors such as ginkgolic acid, spectomycin B1 directly binds to E2 (Ubc9) and selectively blocks the formation of the E2-SUMO intermediate; that is, Ubc9 is the direct target of spectomycin B1. Importantly, either spectomycin B1 treatment or Ubc9 knockdown inhibited estrogen-dependent proliferation of MCF7 human breast-cancer cells. Our findings suggest that Ubc9 inhibitors such as spectomycin B1 have potential as therapeutic agents against hormone-dependent breast cancers. PMID- 24143957 TI - Polybrominated diphenyl ethers in fat samples from White-chinned Petrels (Procellaria aequinoctialis) and Spectacled Petrels (P. conspicillata) off southern Brazil. AB - Polybrominated diphenyl ethers (PBDEs) have been gaining much visibility in environmental chemical studies due to their similarity to PCBs and growing reports of harmful effects. The fact that these contaminants have not yet undergone bans or restrictions on the global level underscores the need for data on their occurrence. In the present study, fat samples from 26 White-chinned Petrels (Procellaria aequinoctialis) and 3 Spectacled Petrels (P. conspicillata) collected dead ashore or as bycatch of longline fisheries in southern Brazil were analyzed to determine concentrations of seven congeners (IUPAC #28, 47, 99, 100, 153, 154 and 183). Concentrations of SigmaPBDEs ranged from not detectable to 72.70 ng g(-1) (wet weight), comparatively lower than concentrations reported for seabird samples in northern hemisphere. The most detected congeners were 153, 154 and 183. This pattern is close to that previously reported for birds of the same group, but not those from the same region. PMID- 24143959 TI - Neurologic complication associated with intense focused ultrasound. PMID- 24143960 TI - Clinical and usability study to determine the safety and efficacy of the Silk'n Blue Device for the treatment of mild to moderate inflammatory acne vulgaris. AB - INTRODUCTION: Home devices for acne vulgaris have emerged as a way to utilize our current light based technology for the care of our patients suffering from acne vulgaris. MATERIALS AND METHODS: Patient received eight treatments with the Silk'n Blue device over a 4-week period. Follow-up visits were at 1 month and 3 months. RESULTS: Seventeen subjects were entered into this institutional review board (IRB) approved clinical research project. There was a statistically significant decrease in mean acne counts from baseline through the follow-up visits, p = 0.002. Percent reduction was also statistically significant, p = 0.041. The study also showed that 36.4% of the patients had complete clearance with the study device. 100% of the patients showed full comprehension with the label for the device. There were no adverse events. Photos were captured. DISCUSSION: The Silk'n Blue device has an array of 24 LEDs emitting a spectrum of light in the blue-violet range of light (405-460 nm). Subjects enrolled in this clinical trial clearly were able to understand the labeling for the device. CONCLUSIONS: The Silk'n Blue device is a safe efficacious at home device for the treatment of mild to moderate inflammatory acne vulgaris. PMID- 24143958 TI - Individual and environmental factors associated for overweight in urban population of Brazil. AB - BACKGROUND: Obesity is a significant global public health problem and the main cause of many chronic diseases in both developed and developing countries. The increase in obesity in different populations worldwide cannot be explained solely by metabolic and genetic factors; environmental and social factors also have a strong association with obesity. Thus, it is believed that the current obesity epidemic is the result of a complex combination of genetic factors and an obesogenic environment .The purpose of this study was to evaluate individual variables and variables within the built and social environment for their potential association with overweight and obesity in an urban Brazilian population. METHODS: Cross-sectional study was carried out in a sample of 3404 adults living in the urban area of the city. Information from the surveillance system for chronic diseases of Brazilian Ministry of Health was used and individual data was collected by telephone interviews. The database was geocoded using the Brazilian System of Postal Codes for participant residences. An updated, existing list based on the current addresses of supermarkets and hypermarkets in the city was used as an indicator variable of the availability and access to food. Georeferenced information on parks, public squares, places for practicing physical activity and the population density were also used to create data on the built environment. To characterize the social environment, we used the health vulnerability index (HVI) and georeferenced data for homicide locations. RESULTS: The prevalence was 44% for overweight, poisson regression was used to create the final model. The environment variables that independently associated with overweight were the highest population density, very high health vulnerability index and the homicide rate adjusted for individuals variables. The results of the current study illustrate and confirm some important associations between individual and environmental variables and overweight in a representative sample of adults in the Brazilian urban context. CONCLUSIONS: The social environment variables relating to the socioeconomic deprivation of the neighborhood and the built environment variables relating to higher walkability were significantly associated with overweight and obesity in Belo Horizonte. PMID- 24143961 TI - Single-crystal structure of a covalent organic framework. AB - The crystal structure of a new covalent organic framework, termed COF-320, is determined by single-crystal 3D electron diffraction using the rotation electron diffraction (RED) method for data collection. The COF crystals are prepared by an imine condensation of tetra-(4-anilyl)methane and 4,4'-biphenyldialdehyde in 1,4 dioxane at 120 degrees C to produce a highly porous 9-fold interwoven diamond net. COF-320 exhibits permanent porosity with a Langmuir surface area of 2400 m(2)/g and a methane total uptake of 15.0 wt % (176 cm(3)/cm(3)) at 25 degrees C and 80 bar. The successful determination of the structure of COF-320 directly from single-crystal samples is an important advance in the development of COF chemistry. PMID- 24143962 TI - Oxygen diffusion and nonstoichiometry in BiFeO3. AB - Leakage current is a serious problem for the use of ferroelectricity in room temperature multiferroics BiFeO3, and oxygen nonstoichiometry is considered as one of its principal origins. In order to establish a method to control oxygen content in the compound, we investigated the annealing process of stoichiometric BiFeO3 grains in air and revealed that oxygen diffusion occurs in two steps: (1) the weight of the sample decreases in a short time, which originates from the generation of oxygen deficiency near the surface of the grains; and then (2) it increases gradually and slowly, which originates from oxygen diffusion toward equilibrium in the inner part of the grains, introducing excess oxygen there. Step 1 causes the leakage current, and step 2 tends to cause inhomogeneity of oxygen content as well as the leakage current. Steps 1 and 2 are related to oxygen deficiency and excess oxygen often observed in thin films and bulk crystals, respectively. For the synthesis of homogeneous and highly insulating bulk sample, it is important to avoid these annealing processes, and it is a good way to grow a crystal with stoichiometric oxygen content by the control of atmospheric oxygen partial pressure and taking out its inner part. PMID- 24143963 TI - Diurnal variations in ocular aberrations of human eyes. AB - PURPOSE: To investigate the diurnal variations in ocular wavefront aberrations over two consecutive days in young adult subjects. MATERIALS AND METHODS: Measurements of both lower-order (sphero-cylindrical refractive powers) and higher-order (third and fourth-order aberration terms) ocular aberrations were collected for 30 young adult subjects at 10 different times over two consecutive days using a Hartmann-Shack aberrometer. Seventeen subjects were myopic and 13 were emmetropic. Five sets of measurements were collected each day at approximately 3 hourly intervals, with the first measurement taken at ~9 am and the final measurement at ~9 pm. RESULTS: Spherical equivalent refraction (p = 0.029) and spherical aberration (p = 0.043) were both found to undergo significant diurnal variation over the two measurement days. The spherical equivalent was typically found to be at a maximum (i.e. most hyperopic) at the morning measurement, with a small myopic shift of 0.37 +/- 0.15 D observed over the course of the day. The mean spherical aberration of all subjects (0.038 +/- 0.048 MUm) was found to be positive during the day and gradually became more negative into the evening, with a mean amplitude of change of 0.036 +/- 0.02 MUm. None of the other considered sphero-cylindrical refractive power components or higher-order aberrations exhibited significant diurnal variation over the two days of the experiment (p > 0.05). Except for the lower-order astigmatism at 90/180 degree (p = 0.040), there were no significant differences between myopes and emmetropes in the magnitude and timing of the observed diurnal variations (p > 0.05). CONCLUSIONS: Significant diurnal variations in spherical equivalent and spherical aberration were consistently observed over two consecutive days of measurement. Research and clinical applications requiring precise refractive error and wavefront measurements should take these diurnal changes into account when interpreting wavefront data. PMID- 24143965 TI - Adsorption of acid and polymer coated nanoparticles: a statistical thermodynamics approach. AB - A molecular theoretical description is developed to describe the adsorption of nanoparticles (NPs) that are coated with polymers and functionalized with (surface) acid groups. Results are presented for the adsorption onto both negatively and positively charged surfaces as a function of pH and salt concentration, polymer coating, and NP size. An important finding is that nanoparticles that are coated with weak charge regulating acid molecules such as citric acid develop an asymmetric charge distribution close to a charged surface, due to their finite size. Depending on the sign of the surface charge of the adsorbing surface, a nanoparticle close to the surface either gains more charge or loses charge compared to its "bulk" degree of charge. This in turn influences the amount of NPs that adsorb. The effect of adsorption of negatively charged NPs onto a positively charged surface shows a nonmonotonical variation with pH. The described charging mechanism reveals that details such as size of the NP and acid distribution on the NP need to be considered to provide an accurate understanding of the adsorption process. PMID- 24143964 TI - Expression of microRNA-497 and its prognostic significance in human breast cancer. AB - OBJECTIVE: Dysregulation of microRNAs (miRNAs) plays critical roles in tumor progression. The aim of this study was to investigate the clinicopathologic and prognostic significance of miR-497 expression in human breast cancer (BC). METHODS: Taqman qRT-PCR assay was performed to detect the expression of microRNA (miR)-497 in 30 pairs of BC tissues and corresponding noncancerous breast tissues. Additionally, the expression of this miRNA was detected in another 128 BC tissues and its correlations with clinicopathologic features of patients were analyzed. Kaplan-Meier analyses were used to assess survival of patients. Univariate and multivariate analyses were performed using the Cox proportional hazards model to analyze the prognostic significance of miR-497 expression. RESULTS: Our data indicated that the relative level of miR-497 expression in BC tissues was significantly lower than that in corresponding noncancerous breast tissues (P = 0.0046). Of 128 BC patients, 74 (57.8%) were placed in the high-miR 497 group and 54 (42.2%) were placed in the low-miR-497 group. By statistical analyses, low miR-497 expression was observed to be closely correlated with higher differentiation grade, positive HER-2 expression, higher incidence of lymph node metastasis and advanced clinical stage. Moreover, patients with high miR-497 expression had better 5-year disease-free and overall survival compared with the low miR-497 group (P = 0.0124 and 0.0018, respectively). Univariate and multivariate analyses indicated that low miR-497 expression was an independent poor prognostic factor for BC patients. CONCLUSIONS: Our data provided the first evidence that downregulation of miR-497 was correlated with BC progression, and miR-497 might be a potential molecular biomarker for predicting the prognosis of patients. VIRTUAL SLIDES: The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/2025828761093488. PMID- 24143966 TI - Carbon nanotube active-matrix backplanes for mechanically flexible visible light and X-ray imagers. AB - We report visible light and X-ray imagers on lightweight and mechanically flexible plastic substrates. The process involves solution processing of organic photodetectors on top of an active-matrix backplane consisting of carbon nanotube thin-film transistors. The system takes advantage of the high mobility of nanotube transistors for low operating voltages and efficient light absorption of organic bulk-heterojunctions for high imaging sensitivity. With this highly scalable process scheme, 18 * 18 pixel-array flexible imagers (physical size of 2 cm * 1.5 cm) with high performance are successfully demonstrated. In addition, as the absorption peak of the adopted organic photodiodes covers the green band of the light spectrum, X-ray imaging is readily demonstrated by placing a scintillator film on top of the flexible imagers. PMID- 24143967 TI - Analysis of rheumatoid factor according to various hepatitis B virus infectious statuses. AB - OBJECTIVES: Rheumatoid factor (RF) can be seen in hepatitis B virus (HBV) infection. We investigated RF positive rates according to various HBV infectious statuses and vaccination, and the relationship between RF titers and serum HBV DNA levels. METHODS: We examined 13,670 individuals who visited the Severance Hospital in Seoul, Korea, for a routine health check-up, and obtained serum samples from all individuals. RESULTS: RF was positive in 3.5% of all subjects, and HBsAg was positive in 4.3%. HBsAg was positive in 21.7% of all RF positive subjects. RF was positive in 17.5% of the HBsAg positive group, while it was positive in 2.9% of the HBsAg negative group (p<0.001). The RF positive rate was increased in positive HBsAg, female sex, and older age. The RF positive rate was lower in those who had anti-HBs after HBV vaccination than in HBsAg positive subjects (2.7% vs. 17.5%, p<0.001). Among the RF positive patients, the RF titer in HBsAg positive patients were higher than that in HBsAg negative patients (159.7+/-217.1IU/mL vs. 83.0+/-179.2 IU/mL, p=0.001). The load of HBV DNA may be closely correlated with RF titer in patients with chronic hepatitis B (r=0.508, p=0.005). CONCLUSIONS: Persistent HBV infection is an important cause for the positive RF in HBV endemic areas. Hepatitis B viral load is associated with RF titer. HBV vaccination may reduce the risk of RF formation. PMID- 24143968 TI - Chiral iminoesters derived from D-glyceraldehyde in [3 + 2] cycloaddition reactions. Asymmetric synthesis of a key intermediate in the synthesis of neuramidinase inhibitors. AB - Silver-catalyzed endo-selective and copper-catalyzed exo-selective asymmetric [3 + 2] cycloadditions of acrylates to chiral iminoesters derived from D glyceraldehyde have been investigated. The reaction diastereoselectively provides highly functionalized pyrrolidines. This approach was used to develop the first asymmetric synthesis of a key intermediate in the synthesis of pyrrolidine influenza neuramidinase inhibitors. PMID- 24143969 TI - Spatial intensity distribution analysis (SpIDA): a new tool for receptor tyrosine kinase activation and transactivation quantification. AB - This chapter presents a general approach for the application of spatial intensity distribution analysis (SpIDA) to pharmacodynamic quantification of receptor tyrosine kinase homodimerization in response to direct ligand activation or transactivation by G protein-coupled receptors. A custom graphical user interface developed for MATLAB is used to extract quantal brightness and receptor density information from intensity histograms calculated from single fluorescence microscopy images. This approach allows measurement of monomer/oligomer protein mixtures within subcellular compartments using conventional confocal laser scanning microscopy. Application of quantitative pharmacological analysis to data obtained using SpIDA provides a universal method for comparing studies between cell lines and receptor systems. In addition, because of its compatibility with conventional immunostaining approaches, SpIDA is suitable not only for use in recombinant systems but also for the characterization of mechanisms involving endogenous proteins. Therefore, SpIDA enables these biological processes to be monitored directly in their native cellular environment. PMID- 24143970 TI - Dimerization of nuclear receptors. AB - Multicellular organisms require specific intercellular communication to properly organize the complex body plan during embryogenesis and maintain its properties and functions during the entire life. While growth factors, neurotransmitters, and peptide hormones bind to membrane receptors, thereby inducing the activity of intracellular kinase cascades or the JAK-STAT signaling pathways, other small signaling compounds such as steroid hormones, certain vitamins, and metabolic intermediates enter, or are generated, within the target cells and bind to members of a large family of nuclear receptors (NRs). NRs are ligand-inducible transcription factors that control a plethora of biological phenomena, thus orchestrating complex events like development, organ homeostasis, immune function, and reproduction. NR-NR interactions are of major importance in these regulatory processes, as NRs regulate their target genes by binding to cognate DNA response elements essentially as homo- or heterodimers. A number of structural and functional studies have provided significant insights as to how combinatorial NRs rely on protein-protein contacts that discriminate geometric features of their DNA response elements, thereby allowing both binding site diversity and physiological specificity. Here, we will review our current understanding of NR-NR interactions and provide protocols for a number of experimental approaches that are useful for their study. PMID- 24143971 TI - Network analysis to uncover the structural communication in GPCRs. AB - Protein structure network (PSN) analysis is one of the graph theory-based approaches currently used to investigate the structural communication in biomolecular systems. Information on system dynamics can be provided by atomistic molecular dynamics simulations or coarse-grained Elastic Network Models paired with Normal Mode Analysis (ENM-NMA). This chapter describes the application of PSN analysis to uncover the structural communication in G protein-coupled receptors (GPCRs). Strategies to highlight changes in structural communication upon misfolding mutations, dimerization, and activation are described. Focus is put on the ENM-NMA-based strategy applied to the crystallographic structures of rhodopsin in its inactive (dark) and signaling active (meta II (MII)) states, highlighting clear changes in the PSN and the centrality of the retinal chromophore in differentiating the inactive and active states of the receptor. PMID- 24143972 TI - Simulating G protein-coupled receptors in native-like membranes: from monomers to oligomers. AB - G protein-coupled receptors (GPCRs) are one of the most relevant superfamilies of transmembrane proteins as they participate in an important variety of biological events. Recently, the scientific community is witnessing an advent of a GPCR crystallization age along with impressive improvements achieved in the field of computer simulations during the last two decades. Computer simulation techniques such as molecular dynamics (MD) simulations are now frequent tools to study the dynamic behavior of GPCRs and, more importantly, to model the complex membrane environment where these proteins spend their lifetime. Thanks to these tools, GPCRs can be simulated not only longer but also in a more "physiological" fashion. In this scenario, scientists are taking advantage of such advances to approach certain phenomena such as GPCR oligomerization occurring only at timescales not reachable until now. Thus, despite current MD simulations having important limitations today, they have become an essential tool to study key biophysical properties of GPCRs and GPCR oligomers. PMID- 24143973 TI - Structure-based molecular modeling approaches to GPCR oligomerization. AB - Classical structure-based drug design techniques using G-protein-coupled receptors (GPCRs) as targets focus nearly exclusively on binding at the orthosteric site of a single receptor. Dimerization and oligomerization of GPCRs, proposed almost 30 years ago, have, however, crucial relevance for drug design. Targeting these complexes selectively or designing small molecules that affect receptor-receptor interactions might provide new opportunities for novel drug discovery. In order to study the mechanisms and dynamics that rule GPCRs oligomerization, it is essential to understand the dynamic process of receptor receptor association and to identify regions that are suitable for selective drug binding, which may be determined with experimental methods such as Forster resonance energy transfer (FRET) or Bioluminescence resonance energy transfer (BRET) and computational sequence- and structure-based approaches. The aim of this chapter is to provide a comprehensive description of the structure-based molecular modeling methods for studying GPCR dimerization, that is, protein protein docking, molecular dynamics, normal mode analysis, and electrostatics studies. PMID- 24143974 TI - Biochemical and imaging methods to study receptor membrane organization and association with lipid rafts. AB - Lipid rafts, cell membrane domains with unique composition and properties, modulate the membrane distribution of receptors and signaling molecules facilitating the assembly of active signaling platforms. However, the underlying mechanisms that link signal transduction and lipid rafts are not fully understood, mainly because of the transient nature of these membrane assemblies. Several methods have been used to study the association of membrane receptors with lipid rafts. In the first part of this chapter, a description of how biochemical methods such as raft disruption by cholesterol depletion agents are useful in qualitatively establishing protein association with lipid rafts is presented. The second part of this chapter is dedicated to imaging techniques used to study membrane receptor organization and lipid rafts. We cover conventional approaches such as confocal microscopy to advanced imaging techniques such as homo-FRET microscopy and superresolution methods. For each technique described, their advantages and drawbacks are discussed. PMID- 24143975 TI - Serotonin type 4 receptor dimers. AB - Numerous class A G protein-coupled receptors and especially biogenic amine receptors have been reported to form homodimers. Indeed, the dimerization process might occur for all the metabotropic serotonergic receptors. Moreover, dimerization appears to be essential for the function of serotonin type 2C (5 HT2C) and type 4 (5-HT4) receptors and required to obtain full receptor activity. Several techniques have been developed to analyze dimer formation and properties. Due to our involvement in deciphering 5-HT4R transduction mechanisms, we improved and set up new procedures to study 5-HT4R dimers, by classical methods or modern tools. This chapter presents detailed protocols to detect 5-HT4R dimers by Western blotting and coimmunoprecipitation, including the optimizations that we routinely carry out. We developed an innovative method to achieve functional visualization of 5-HT4R dimers by immunofluorescence, taking advantage of the 5 HT4-RASSL (receptor activated solely by synthetic ligand) mutant that was engineered in the laboratory. Finally, we adapted the powerful time-resolved FRET technology to assess a relative quantification of dimer formation and affinity. PMID- 24143976 TI - Bioluminescence resonance energy transfer methods to study G protein-coupled receptor-receptor tyrosine kinase heteroreceptor complexes. AB - A large body of evidence indicates that G protein-coupled receptors (GPCRs) and receptor tyrosine kinases (RTKs) can form heteroreceptor complexes. In these complexes, the signaling from each interacting protomer is modulated to produce an integrated and therefore novel response upon agonist(s) activation. In the GPCR-RTK heteroreceptor complexes, GPCRs can activate RTK in the absence of added growth factor through the use of RTK signaling molecules. This integrative phenomenon is reciprocal and can place also RTK signaling downstream of GPCR. Formation of either stable or transient complexes by these two important classes of membrane receptors is involved in regulating all aspects of receptor function, from ligand binding to signal transduction, trafficking, desensitization, and downregulation among others. Functional phenomena can be modulated with conformation-specific inhibitors that stabilize defined GPCR states to abrogate both GPCR agonist- and growth factor-stimulated cell responses or by means of small interfering heteroreceptor complex interface peptides. The bioluminescence resonance energy transfer (BRET) technology has emerged as a powerful method to study the structure of heteroreceptor complexes closely associated with the study of receptor-receptor interactions in such complexes. In this chapter, we provide an overview of different BRET(2) assays that can be used to study the structure of GPCR-RTK heteroreceptor complexes and their functions. Various experimental designs for optimization of these experiments are also described. PMID- 24143977 TI - A simple method to detect allostery in GPCR dimers. AB - G protein-coupled receptors (GPCRs) represent one of the largest families of cell surface receptors as key targets for pharmacological manipulation. G proteins have long been recognized as allosteric modulators of GPCR ligand binding. More recently, small molecule allosteric modulators have now been widely characterized for a number of GPCRs, and some are now used clinically. Many studies have also underscored the importance of GPCR dimerization or higher-order oligomerization in the control of the physiological responses they modulate. Thus, allosterism can also, between monomer equivalents in the context of a dimer, oligomer, or receptor mosaic, influence signaling pathways downstream. It therefore becomes essential to characterize both small molecule allosteric ligands and allosteric interactions between receptors modulated by canonical orthosteric ligands, in a pathway-specific manner. Here, we describe a simple, radioligand-binding method, which is designed to probe for allosteric modulation mediated by any GPCR interactor, from small molecules to interacting proteins. It can also detect allosteric asymmetries within a GPCR heterodimer, via orthosteric or allosteric ligands. This assay measures time-dependent ligand occupancy of radiolabeled orthosteric or (with adaptations) allosteric ligands as modulated by either small molecules or receptor dimer partners bound or unbound with their own ligands. PMID- 24143978 TI - Fluorescence correlation spectroscopy and photon-counting histogram analysis of receptor-receptor interactions. AB - Fluorescence correlation spectroscopy (FCS) performed using a laser scanning confocal microscope is a technique with single-molecule sensitivity that is becoming more accessible to cell biologists. In this chapter, we describe the use of FCS for the analysis of diffusion coefficients and receptor-receptor interactions in live cells in culture. In particular, we describe a protocol to collect fluorescence fluctuation data from fluorescence-tagged receptors as they diffuse into an out of a small laser-illuminated observation volume using a commercially available system such as the Zeiss ConfoCor 3 or LSM-780 microscope. Autocorrelation analysis of the fluctuations in fluorescence intensity provides information about the diffusion time and number of fluorescent molecules in the observation volume. A photon-counting histogram can be used to examine the relationship between fluorescence intensity and the number of fluorescent molecules to estimate the average molecular brightness of the sample. Since molecular brightness is directly proportional to the number of fluorescent molecules, it can be used to monitor receptor-receptor interactions and to decode the number of receptor monomers present in an oligomeric complex. PMID- 24143979 TI - Monitoring receptor oligomerization by line-scan fluorescence cross-correlation spectroscopy. AB - Membrane-localized receptor proteins are involved in many signaling cascades, and diffusion and oligomerization are key processes controlling their activity. In order to study these processes in living cells, fluorescence fluctuation spectroscopy techniques have been developed that allow the quantification of concentration levels, diffusion rates, and interactions between fluorescently labeled receptor proteins at the nanomolar concentration level. This chapter presents a brief introduction to the technique and a protocol to measure and quantify the diffusion and oligomerization of human histamine1 receptor complexes in living HeLa cells using line-scanning fluorescence cross-correlation spectroscopy. PMID- 24143980 TI - Biochemical assay of G protein-coupled receptor oligomerization: adenosine A1 and thromboxane A2 receptors form the novel functional hetero-oligomer. AB - G protein-coupled receptors (GPCRs) are classified into a family of seven transmembrane receptors. Receptor oligomerization may be the key to the expression and function of these receptors, for example, ligand binding, desensitization, membrane trafficking, and signaling. The accumulation of evidence that GPCRs form an oligomerization with a functional alternation may change the strategy for the discovery of novel drugs targeting GPCRs. Identification of the oligomer is essential to elucidate GPCR oligomerization. GPCR oligomerizations have been demonstrated using various biochemical approaches, which include the coimmunoprecipitation method, fluorescence resonance energy transfer assay, and bioluminescence RET assay. Thus, various assays are useful for the study of GPCR oligomerization, and we should choose the best method to match the purpose. We previously targeted adenosine A1 and thromboxane A2 (TP) receptors to form a functionally novel hetero-oligomer, since both receptors function in the same cells. This chapter describes the methods used to detect GPCR oligomerization and alterations in the signaling pathways, principally according to our findings on oligomerization between adenosine A1 and TPalpha receptors. PMID- 24143981 TI - Oligomerization of sweet and bitter taste receptors. AB - The superfamily of G protein-coupled receptors (GPCRs) mediates numerous physiological processes, including neurotransmission, cell differentiation and metabolism, and sensory perception. In recent years, it became evident that these receptors might function not only as monomeric receptors but also as homo- or heteromeric receptor complexes. The family of TAS1R taste receptors are prominent examples of GPCR dimerization as they act as obligate functional heteromers: TAS1R1 and TAS1R3 combine to form an umami taste receptor, while the combination of TAS1R2 and TAS1R3 is a sweet taste receptor. So far, TAS2Rs, a second family of ~25 taste receptors in humans that mediates responses to bitter compounds, have been shown to function on their own, but if they do so as receptor monomers or as homomeric receptors still remains unknown. Using two different experimental approaches, we have recently shown that TAS2Rs can indeed form both homomeric and heteromeric receptor complexes. The employed techniques, coimmunoprecipitations and bioluminescence resonance energy transfer (BRET), are based on different principles and complement each other well and therefore provided compelling evidences for TAS2R oligomerization. Furthermore, we have adapted the protocols to include a number of controls and for higher throughput to accommodate the investigation of a large number of receptors and receptor combinations. Here, we present the protocols in detail. PMID- 24143982 TI - Analysis of receptor-receptor interaction by combined application of FRET and microscopy. AB - G protein-coupled receptors (GPCRs) participate in the regulation of many cellular processes and, therefore, represent key targets for pharmacological treatment. The existence of GPCR homo- and heterodimers has become generally accepted, and a growing body of evidence points to the functional importance of oligomeric complexes for the receptor trafficking, receptor activation, and G protein coupling in native tissues. Quantitative molecular microscopy is becoming more and more important to investigate such receptor-receptor interaction in their native environments. Forster resonance energy transfer (FRET) is thereby utilized to aim at investigating the interaction of molecules at distances beyond diffraction-limited spatial resolution. The exact determination of the FRET signals, which are often only fractions of the fluorescence signals, requires extensive experimental effort. Moreover, the correct interpretation of FRET measurements as well as FRET data-based modeling represents an essential challenge in microscopy and biophysics. In this chapter, we present and discuss variety of acquisition protocols and models based on "linear unmixing FRET" (lux FRET) to investigate receptor-receptor interaction in living cells with high spatial and temporal resolution. Here, we show how to apply lux-FRET in spectroscopic and different imaging devices, based either on spectral detection or on filter cubes. We focus on detailed description for FRET measurements and analyses based on sophisticated acquisition procedures according to different experimental setups and also provide several examples of biological applications. PMID- 24143983 TI - Site-specific labeling of genetically encoded azido groups for multicolor, single molecule fluorescence imaging of GPCRs. AB - Heptahelical G protein-coupled receptors (GPCRs) mediate transmembrane signal transduction to facilitate intercellular communication. GPCRs assemble in the membrane bilayer with a variety of cytoplasmic adapter and scaffold proteins to form molecular machines, or "signalosomes," which undergo complex dynamic assembly and disassembly reactions. Despite significant recent advances in structural studies of GPCRs and their associated cytoplasmic components, understanding transmembrane signaling in four dimensions with chemical precision requires new approaches. One promising approach to study allosteric effects involved in signalosome reaction pathways is to use multicolor single-molecule detection (SMD) fluorescence experiments in biochemically defined systems. We describe here the methodological foundation for automated, multicolor, single molecule fluorescence studies of the structural and compositional dynamics of macromolecular complexes involved in signal transduction. We present a general, simple, and robust method for stoichiometric, site-specific fluorescence labeling of expressed GPCRs. The method is based on bioorthogonal conjugation of a fluorescent reporter group to a genetically encoded azido group introduced into expressed GPCRs using amber codon suppression. We then present a strategy to reconstitute labeled GPCRs in native-like membranes and to tether-oriented samples onto surfaces amenable for interrogation by total internal reflectance fluorescence (TIRF) spectroscopy. We describe how to assemble an automated four color epifluorescence microscope with SMD-TIRF optics. Finally, we discuss how to adapt engineered samples for high-throughput imaging with the aim of understanding the kinetic relationships between ligand binding and the dynamic regulation of the GPCR signalosome. PMID- 24143984 TI - Analysis of EGF receptor oligomerization by homo-FRET. AB - Growth factor receptors are present in the plasma membrane of resting cells as monomers or (pre)dimers. Ligand binding results in higher-order oligomerization of ligand-receptor complexes. To study the regulation of receptor clustering, several experimental techniques have been developed in the last decades. However, many involve invasive approaches that are likely to disturb the integrity of the membrane, thereby affecting receptor interactions. In this chapter, we describe the use of a noninvasive approach to study receptor dimerization and oligomerization. This method is based upon the Forster energy transfer between identical adjacent fluorescent proteins (homo-FRET) and is determined by analyzing the change in fluorescence anisotropy. Homo-FRET takes place within a distance of 10nm, making this an excellent approach for studying receptor receptor interactions in intact cells. After excitation of monomeric GFP (mGFP) with polarized light, limiting anisotropy values (r(inf)) of the emitted light are determined, where proteins with known cluster sizes are used as references. Dimerization and oligomerization of the epidermal growth factor receptor (EGFR) in response to ligand binding is determined by using receptors that have been fused with mGFP at their C-terminus. In this chapter, we describe the involved technology and discuss the feasibility of homo-FRET experiments for the determination of cluster sizes of growth factor receptors like EGFR. PMID- 24143985 TI - Detection of G protein-coupled receptor (GPCR) dimerization by coimmunoprecipitation. AB - With 356 members in the human genome, G protein-coupled receptors (GPCRs) constitute the largest family of proteins involved in signal transduction across biological membranes. GPCRs are integral membrane proteins featuring a conserved structural topology with seven transmembrane domains. By recognizing a large diversity of hormones and neurotransmitters, GPCRs mediate signal transduction pathways through their interactions with both extracellular small-molecule ligands and intracellular G proteins to initiate appropriate cellular signaling cascades. As there is a clear link between GPCRs and several disorders, GPCRs currently constitute the largest family of proteins targeted by marketed pharmaceuticals. Therefore, a detailed understanding of the biogenesis of these receptors and of GPCR-protein complex assembly can help to answer some important questions. In this chapter, we will discuss several methods to isolate GPCRs and to study, via coimmunoprecipitation, protein-protein interactions. Special attention will be given to GPCR dimerization, which often starts already in the endoplasmic reticulum and influences the maturation of the receptor. Next, we will also explain an elegant tool to study GPCR biogenesis based on the glycosylation pattern of the receptor of interest. PMID- 24143986 TI - Lipid-dependent GPCR dimerization. AB - It has been widely demonstrated that G protein-coupled receptors (GPCRs) can form dimers both in vivo and in vitro, a process that has functional consequences. These receptor-receptor interactions take place within a phospholipid bilayer, yet, generally, little is known of the requirements for specific lipids that mediate the dimerization process. Studying this phenomenon in vivo is challenging due to difficulties in modulating the lipid content of cell membranes. Therefore, in this chapter, we describe techniques for reconstitution of GPCRs into model lipid bilayers of defined composition. The concentrations of specific lipids and sterols can be precisely controlled in these liposomes, as well as maintaining an appropriate lipid-protein ratio to avoid artifactual interactions. Receptor dimerization in this system is monitored via Forster resonance energy transfer (FRET), which requires the use of fluorescently labeled receptors. We therefore also include protocols for labeling with appropriate fluorophores and determining the apparent FRET efficiency, a measurement of the extent of receptor dimerization. Understanding the lipid dependence of GPCR dimerization will be key in understanding how this process is regulated in the dynamic heterogeneous environment of the cell membrane. PMID- 24143987 TI - Monitoring peripheral protein oligomerization on biological membranes. AB - Peripheral proteins transiently interact with cellular membranes where they regulate important cellular events such as signal transduction. A number of peripheral proteins harbor lipid-binding modules that not only bind selectively with nanomolar affinity to biological membranes but also oligomerize on the membrane surface. In some cases, specific lipid binding or specific lipid compositions can induce peripheral protein oligomerization on cellular membranes. These oligomers serve different roles in biological signaling such as regulating protein-protein interactions, induction of membrane bending, or facilitating membrane scission. A number of technologies have been employed to study protein oligomerization with fluctuation analysis of fluorescently labeled molecules recently developed for use with commercial laser-scanning microscopes. In this chapter, the approach of raster image correlation spectroscopy coupled with number and brightness (N&B) analysis to investigate protein oligomerization on cellular membranes in live cells is presented. Important considerations are discussed for designing experiments, collecting data, and performing analysis. N&B analysis provides a robust method for assessing membrane binding and assembly properties of peripheral proteins and lipid-binding modules. PMID- 24143988 TI - Single-molecule imaging of receptor-receptor interactions. AB - Single-molecule imaging is a powerful tool for the study of dynamic molecular interactions in living cell plasma membranes. Herein, we describe a single molecule imaging microscopy technique that can be used to measure lifetimes and densities of receptor dimers and oligomers. This method can be performed using a total internal reflection fluorescent microscope equipped with one or two high sensitivity cameras. For dual-color observation, two images obtained synchronously in different colors are spatially corrected and then overlaid. Receptors must be expressed at low density in cell plasma membranes because high density expression (>2 molecules/MUm(2)) creates difficulty for tracking individual fluorescent spots. In addition, the receptors should be labeled with highly photostable fluorophores at high efficiency because short photobleaching lifetimes and low labeling efficiency of receptors reduce the probability of detecting dimers and oligomers. In this chapter, we describe methods for observing and detecting colocalization of the individual fluorescent spots of receptors labeled with fluorophores via small tags and the estimation of true dimer and oligomer lifetimes after correction with photobleaching lifetimes of fluorophores. PMID- 24143989 TI - Visualization of TCR nanoclusters via immunogold labeling, freeze-etching, and surface replication. AB - T cells show high sensitivity for antigen, even though their T-cell antigen receptor (TCR) has a low affinity for its ligand, a major histocompatibility complex molecule presenting a short pathogen-derived peptide. Over the past few years, it has become clear that these paradoxical properties rely at least in part on the organization of cell surface-expressed TCRs in TCR nanoclusters. We describe a protocol, comprising immunogold labeling, cell surface replica generation, and electron microscopy (EM) analysis that allows nanoscale resolution of the distribution of TCRs and other cell surface molecules of cells grown in suspension. Unlike most of the light microscopy-based single-molecule resolution techniques, this technique permits visualization of these molecules on cell surfaces that do not adhere to an experimental support. Given the potential of adhesion-induced receptor redistributions, our technique is a relevant complement to the substrate adherence-dependent techniques. Furthermore, it does not rely on introduction of fluorescently labeled recombinant molecules and therefore allows direct analysis of nonmanipulated primary cells. PMID- 24143990 TI - Identification of multimolecular complexes and supercomplexes in compartment selective membrane microdomains. AB - Cellular membranes contain specialized microdomains that play important roles in a wide range of cellular processes. These microdomains can be found in the plasma membrane and other membranes within the cell. Initially labeled lipid rafts and defined as being resistant to extraction by nonionic detergents and enriched in cholesterol and glycosphingolipids, we now understand that these membrane microdomains are very dynamic and heterogeneous membrane structures whose composition and function can vary widely depending on their cellular location. Indeed, though they are classically associated with the plasma membrane and have been shown to facilitate a wide variety of processes, including signal transduction and membrane trafficking, specialized membrane microdomains have also been identified in other membranes including those in the mitochondria. These mitochondrial membrane microdomains are enriched in cardiolipin, the signature phospholipid of the mitochondria, and may have important implications in metabolism by facilitating optimal assembly and function of the mitochondrial respiratory chain. Furthermore, isolation of multimolecular complexes while retaining their supramolecular interactions has been critical to the study of mitochondrial respiratory supercomplexes. Here, we discuss methods to isolate various membrane microdomains, including detergent-insoluble glycosphingolipid microdomains, mitochondrial cardiolipin-enriched microdomains, and blue-native gel electrophoresis of mitochondrial membranes. PMID- 24143991 TI - G protein-coupled receptor transactivation: from molecules to mice. AB - G protein-coupled receptors (GPCRs) mediate a diverse range of physiological functions via activation of complex signaling systems. Organization of GPCRs in to dimers and oligomers provides a mechanism for both signal diversity and specificity in cellular responses, yet our understanding of the physiological significance of dimerization, particularly homodimerization, has not been forthcoming. This chapter will describe how we have investigated the physiological importance of GPCR homodimerization, using the luteinizing hormone/chorionic gonadotropin receptor as a model GPCR. Using transactivation as a mode of assessing receptor dimerization, we describe our cellular system and functional assays for assessment of transactivation in vitro and detail our strategy for generating a mouse model to assess GPCR transactivation in vivo. PMID- 24143993 TI - Methods in Cell Biology. Receptor-receptor interactions. Preface. PMID- 24143992 TI - Crystallization of G protein-coupled receptors. AB - Oligomerization is one of several mechanisms that can regulate the activity of G protein-coupled receptors (GPCRs), but little is known about the structure of GPCR oligomers. Crystallography and NMR are the only methods able to reveal the details of receptor-receptor interactions at an atomic level, and several GPCR homodimers already have been described from crystal structures. Two clusters of symmetric interfaces have been identified from these structures that concur with biochemical data, one involving helices I, II, and VIII and the other formed mainly by helices V and VI. In this chapter, we describe the protocols used in our laboratory for the crystallization of rhodopsin and the beta2-adrenergic receptor (beta2-AR). For bovine rhodopsin, we developed a new purification strategy including a (NH4)2SO4-induced phase separation that proved essential to obtain crystals of photoactivated rhodopsin containing parallel dimers. Crystallization of native bovine rhodopsin was achieved by the classic vapor diffusion technique. For beta2-AR, we developed a purification strategy based on previously published protocols employing a lipidic cubic phase to obtain diffracting crystals of a beta2-AR/T4-lysozyme chimera bound to the antagonist carazolol. PMID- 24143994 TI - Free-energy landscape for peptide amphiphile self-assembly: stepwise versus continuous assembly mechanisms. AB - The mechanism of self-assembly of 140 peptide amphiphiles (PAs) to give nanofiber structures was investigated using a coarse-grained method to quantitatively determine whether the assembly process involves discrete intermediates or is a continuous process. Two novel concepts are introduced for this analysis, a cluster analysis of the time dependence of PA assembly and use of the fraction of native contacts as reaction coordinates for characterizing thermodynamic functions during assembly. The cluster analysis of the assembly kinetics demonstrates that a pillar-like intermediate state is formed before the final cylindrical semifiber structure. We also find that head group assembly occurs on a much shorter time scale than tail group assembly. A 2D free-energy landscape with respect to the fraction of native contacts was calculated, and the pillar like intermediate structure was also found, with free energies about 1.2 kcal/mol higher than the final state. Although this intermediate state exists for only hundreds of nanoseconds, the PA self-assembly process can be recognized as involving two steps, (a) transition from the disordered state to the noncylindrical pillar-like intermediate and (b) pillar-like to final semifiber transition. These results are important to the further design of PAs as functional nanostructures. PMID- 24143995 TI - Does a 20 minute cognitive task increase concussion symptoms in concussed athletes? AB - OBJECTIVE: The purpose of the present study was to examine if concussion symptoms worsened immediately (i.e. 20 minutes) following performance on a computerized neurocognitive test. RESEARCH DESIGN: Cross-sectional study; Level of evidence, 2. METHODS AND PROCEDURES: A total of 165 athletes with a concussion participated in the study. Participants completed the Immediate Post-concussion Assessment and Cognitive Test (ImPACT) and Post-concussion Symptom Scale (PCSS) at baseline, 3 and 10 days post-concussion. Participants completed a second PCSS following the ImPACT test at 3 and 10 days post-injury. MAIN OUTCOMES AND RESULTS: Athletes with a concussion exhibited greater symptoms post-neurocognitive test 3 days post concussion on headache (p = 0.01), nausea (p = 0.03), dizziness (p = 0.03), sadness (p = 0.005), mentally foggy (p= 0.002) and visual problems (p = 0.007). Athletes with a concussion demonstrated increased symptoms on sadness (p = 0.00) and difficulty remembering (p = 0.03) at 10 days post-injury. Athletes also demonstrated neurocognitive impairments in verbal memory (p = 0.009) and slower reaction time (p = 0.01) 10 days post-concussion and visual memory (p = 0.000) and motor processing speed (p = 0.000) impairments at 3 days post-injury. CONCLUSION: The current study suggests that there may be an increase in concussion symptoms following a 20-minute cognitive task. Thus, it illustrates the need for clinicians to make sure they are symptom free with both physical and cognitive testing. PMID- 24143996 TI - The impact of silver nanoparticles on the composting of municipal solid waste. AB - The study evaluates the impact of polyvinylpyrrolidone (PVP) coated silver nanoparticles (PVP-AgNPs) on the composting of municipal solid waste. The results suggest that there was no statistically significant difference in the leachate, gas, and solid quality parameters and overall composting performance between the treatments containing the AgNPs, Ag(+), and negative control. Nonetheless, taxonomical analyses of 25 Illumina 16S rDNA barcoded libraries containing 2 393 504 sequences indicated that the bacterial communities in composted samples were highly diverse and primarily dominated by Clostridia (48.5%), Bacilli (27.9%), and beta-Proteobacteria (13.4%). Bacterial diversity studies showed that the overall bacterial community structure in the composters changed in response to the Ag-based treatments. However, the data suggest that functional performance was not significantly affected due to potential bacterial functional redundancy within the compost samples. The data also indicate that while the surface transformation of AgNPs to AgCl and Ag2S can reduce the toxicity, complexation with organic matter may also play a major role. The results of this study further suggest that at relatively low concentrations, the organically rich waste management systems' functionality may not be influenced by the presence of AgNPs. PMID- 24143998 TI - Preface. Special issue on computational cellular and biomolecular mechanics and mechanobiology. PMID- 24143997 TI - COPD symptoms in the morning: impact, evaluation and management. AB - Chronic obstructive pulmonary disease (COPD) symptoms in the morning, including dyspnea and sputum production, affect patients' quality of life and limit their ability to carry out even simple morning activities. It is now emerging that these symptoms are associated with increased risk of exacerbations and work absenteeism, suggesting that they have a more profound impact on patients than previously thought. The development of validated patient-reported outcome (PRO) questionnaires to capture patients' experience of COPD symptoms in the morning is, therefore, vital for establishing effective and comprehensive management strategies. Although it is well established that long-acting bronchodilators are effective in improving COPD symptoms, the limited available data on their impact on morning symptoms and activities have been obtained with non-validated PRO questionnaires. In this review, we discuss the impact of COPD symptoms in the morning and available tools used to evaluate them, and highlight specific gaps that need to be addressed to develop standardized instruments able to meet regulatory requirement. We also present available evidence on the effect of pharmacological therapies on morning symptoms. PMID- 24143999 TI - Quantifying the mechanical micro-environment during three-dimensional cell expansion on microbeads by means of individual cell-based modelling. AB - Controlled in vitro three-dimensional cell expansion requires culture conditions that optimise the biophysical micro-environment of the cells during proliferation. In this study, we propose an individual cell-based modelling platform for simulating the mechanics of cell expansion on microcarriers. The lattice-free, particle-based method considers cells as individual interacting particles that deform and move over time. The model quantifies how the mechanical micro-environment of individual cells changes during the time of confluency. A sensitivity analysis is performed, which shows that changes in the cell-specific properties of cell-cell adhesion and cell stiffness cause the strongest change in the mechanical micro-environment of the cells. Furthermore, the influence of the mechanical properties of cells and microbead is characterised. The mechanical micro-environment is strongly influenced by the adhesive properties and the size of the microbead. Simulations show that even in the absence of strong biological heterogeneity, a large heterogeneity in mechanical stresses can be expected purely due to geometric properties of the culture system. PMID- 24144000 TI - Cationic dendron-bearing lipids: investigating structure-activity relationships for small interfering RNA delivery. AB - A new family of cationic dendron-bearing lipids (CDLs) with poly(amidoamine) dendrons of first to third generation (named as A1, A2, and A3, respectively) was synthesized through a synthesis approach that permits facile variation of chemical structures. All CDLs could effectively bind small interfering RNA (siRNA) to form complexes confirmed by gel retardation analysis. In in vitro transfection experiments, A1/siRNA complexes exhibited significant gene silencing efficiency close to Lipofectamine 2000/siRNA complexes and much higher than A2/siRNA and A3/siRNA complexes. To reveal the underlying reason, we performed a series of experimental methods. The results suggested that the CDLs with smaller dendron sizes and higher proportion of hydrophobic segments could bind siRNA to form dendriplex aggregates with more compact structures and higher surface potentials. Therefore, they could be internalized via endocytosis more easily, which was believed to be the main reason for higher gene silencing efficiency. This paper provides an efficient CDL (A1) for siRNA delivery and indicates great potential for gene therapy. PMID- 24144001 TI - Cortisol response to psychosocial stress during a depressive episode and remission. AB - This study compared cortisol responses to a standardized psychosocial stressor during a major depressive episode (MDE) and again during remission in adolescents and young adults. Twenty-six individuals with no personal or family history of a major psychiatric disorder (NC) and 24 individuals with a diagnosis of major depressive disorder (MDD) at Time 1 participated in the study. The MDD group showed robust cortisol responses during their index episode and after recovery. In contrast, the NC group showed habituation to the repeated psychosocial stressor, as evident in a flatter cortisol response profile at Time 2. Within the MDD group, net peak cortisol during the first stress test was positively associated with the duration of the index MDE and negatively associated with the total duration of all MDEs. Whereas summary indices of cortisol responses were relatively stable across repeated stress tasks within the MDD group, this was not the case for NC. Results demonstrate that cortisol responses fail to habituate to repeated psychosocial stress during recovery from an MDE and could reflect a trait-like marker of risk for recurrence. PMID- 24144002 TI - Postnatal protein malnutrition induces neurochemical alterations leading to behavioral deficits in rats: prevention by selenium or zinc supplementation. AB - BACKGROUND/OBJECTIVES: Protein malnutrition (PM) is a worldwide problem affecting brain development in a large number of children. The present study was aimed at studying the perturbations in antioxidant defense system resulting from protein deficiency and to evaluate the preventive effect of Se and Zn on cortex and cerebellum. METHODS: Well-fed (WF) and PM rats were fed on 16 and 5% protein diet, respectively. After 10 weeks, animals were supplemented with Se and Zn at a concentration of 0.15 and 227 mg/l in drinking water for 3 weeks. RESULTS: PM rats showed significant increase in lipid peroxidation, nitrite, and protein carbonyl levels. Reduction in the activity of antioxidant enzymes, thiol levels, GSH/GSSG ratio, and neurobehavioral deficits were observed in PM groups. Se and Zn supplementation reduced the levels of lipid peroxidation, nitrite, and protein carbonyl and restored the activity of antioxidant enzymes and thiol levels in the cortex and cerebellum of PM rats along with neurobehavioral deficits. DISCUSSION: The study showed that Se and Zn supplementation might be beneficial in preventing biochemical alterations and neurobehavioral deficits in PM children. PMID- 24144003 TI - Obstructive sleep apnea among commercial motor vehicle drivers: using evidence based practice to identify risk factors. AB - Commercial motor vehicle driving is a hazardous occupation, having the third highest fatality rate among common U.S. jobs. Among the estimated 14 million U.S. commercial motor vehicle drivers, the prevalence of obstructive sleep apnea is reported to be 17% to 28%. Despite the identified increased prevalence of obstructive sleep apnea among commercial motor vehicle drivers, federal law does not require that they be screened for obstructive sleep apnea. This article presents an evidence-based practice change project; the authors developed, implemented, and evaluated a screening program to identify commercial motor vehicle drivers' risk for obstructive sleep apnea during commercial driver medical examinations. The results of this practice change indicated screening for obstructive sleep apnea during the commercial driver medical examination led to improved identification of obstructive sleep apnea risk among commercial motor vehicle drivers and should be a clinical standard in occupational health clinics. PMID- 24144004 TI - The Federal Motor Carrier Safety Administration's National Registry of Certified Medical Examiners and medical certification of interstate commercial motor vehicle drivers. AB - On April 18, 2012, the Federal Motor Carrier Safety Administration (FMCSA) announced plans to develop a National Registry of Certified Medical Examiners. The new plan requires all medical examiners who conduct physical examinations for interstate commercial motor vehicle (CMV) drivers to meet the following criteria: (1) complete specific training about FMCSA's physical qualification standards; (2) pass a test to verify understanding of those standards; and (3) maintain and demonstrate competence through periodic training and testing. By May 21, 2014, all certified medical examiners must be in the National Registry database, after which all drivers must receive a medical examination from a certified medical examiner. Health care practitioners who wish to become certified medical examiners must meet the training and testing requirements set forth by FMCSA. After training and testing requirements are met, health care practitioners are added to the National Registry. In addition, certified medical examiners must complete refresher training every 5 years and recertify every 10 years. Medical examiners who fail to meet and maintain federal standards will not be included in the National Registry. This article provides information related to U.S. Department of Transportation driver medical certification regulations. These changes impact drivers, employers, medical examiners, and occupational health nurses and safety specialists who manage the certification of drivers. PMID- 24144005 TI - Fibronectin antibody labels corneal stromal collagen fibrils in situ along their length and circumference and demonstrates distinct staining along the cell and stromal interfaces of Descemet's membrane. AB - PURPOSE/AIM OF THE STUDY: An immunoperoxidase cytochemical study of fibronectin localization in the rat corneal stroma and Descemet's membrane was conducted following organ culture to determine whether stromal swelling allowed better primary antibody penetration into the normally tough fibrous corneal stroma. MATERIALS AND METHODS: Following 24 h organ culture, corneas were fixed in 4% paraformaldehyde, washed and stained overnight at 4 degrees C in anti fibronectin followed by washing and incubation in an appropriate secondary antibody and exposure to protein A-HRP. Cytochemical processing was carried out in a DAB-containing medium followed by dehydration and Epon embedding. RESULTS: Observations of the stromal lamellae revealed the presence of a novel punctate staining pattern along the length of the collagen fibrils that extended around the fibril's circumference. Measurements on the peroxidase reaction product spacing indicated a periodicity of approximately 20.69 +/- 3.57 nm along the fibril's length. Light microscopic immunocytochemistry revealed the presence of fibronectin staining occurred within the endothelial cell layer but only along the DM/stromal interface. Electron microscopic observations however, revealed that fibronectin staining occurred in distinct linear patterns along the length of both the endothelial and stromal DM interfaces. DISCUSSION: Results indicate that organ culture mediated swelling helps facilitate the penetration of primary antibody into the corneal stroma. Observations suggest a novel association exists between fibronectin and stromal collagen fibrils that helps to mediate the arrangement and organization of the stromal extracellular matrix. Results also definitively indicate that fibronectin is deposited along both DM interfaces suggesting that it plays a role in the adhesion of both the endothelial cell layer and stroma to Descemet's membrane to help maintain the tissue architecture within this region of the cornea. PMID- 24144006 TI - Transmembrane type-2-like Cu2+ site in the P1B-3-type ATPase CopB: implications for metal selectivity. AB - Metal selectivity in P1B-type ATPase transporters is determined by conserved amino acid residues in their transmembrane helices responsible for metal binding and transport across the cellular membrane. The Cu(2+)-selective CopB from Archaeoglobus fulgidus has been investigated to explore the coordination chemistry of the transition metal binding sites in P1B-3-type ATPases. Electronic absorption, electron paramagnetic resonance, and X-ray absorption spectroscopic studies indicate the presence of a high-affinity transmembrane Type-2-like Cu(2+) center in which a single cupric ion is coordinated in a distorted square pyramidal geometry by mixed nitrogen/oxygen and sulfur ligands. PMID- 24144007 TI - Amphiphilic thiol functional linker mediated sustainable anti-biofouling ultrafiltration nanocomposite comprising a silver nanoparticles and poly(vinylidene fluoride) membrane. AB - We develop sustainable anti-biofouling ultrafiltration membrane nanocomposites by covalently immobilizing silver nanoparticles (AgNPs) onto poly(vinylidene fluoride) (PVDF) membrane mediated by a thiol-end functional amphiphilic block copolymer linker. Field emission scanning electron microscopy (FE-SEM) and energy dispersive X-ray spectroscopy (EDXS) measurements reveal that the AgNPs are highly bound and dispersed to the PVDF membrane due to the strong affinity of the AgNPs with the thiol-modified block copolymeric linkers, which have been anchored to the PVDF membrane. The membrane performs well under water permeability and particle rejection measurements, despite the high deposition of AgNPs on the surface of membrane. The Ag-PVDF membrane nanocomposite significantly inhibits the growth of bacteria on the membrane surface, resulting in enhanced anti biofouling property. Importantly, the AgNPs are not released from the membrane surface due to the robust covalent bond between the AgNPs and the thiolated PVDF membrane. The stability of the membrane nanocomposite ensures a sustainable anti biofouling activity of the membrane. PMID- 24144008 TI - Variable copy number of mitochondrial DNA (mtDNA) predicts worse prognosis in advanced gastric cancer patients. AB - BACKGROUND: Change of mitochondrial DNA (mtDNA) copy number is widely reported in various human cancers, including gastric cancer, and is considered to be an important hallmark of cancers. However, there is remarkably little consensus on the value of variable mtDNA content in the prognostic evaluation of this cancer. METHODS: Using real-time quantitative PCR approach, we examined mtDNA copy number in a cohort of gastric cancers and normal gastric tissues, and explored the association of variable mtDNA content with clinical outcomes of gastric cancer patients. RESULTS: Our data showed that the majority of gastric cancer patients had low mtDNA content as compared to control subjects although the relative mean mtDNA content was higher in the former than the latter. Moreover, we found that variable mtDNA content was strongly associated with lymph node metastasis and cancer-related death of the patients with late-stage tumors. Notably, variable mtDNA content did not affect overall survival of gastric cancer patients, however, we found that increased mtDNA content was associated with poor survival in the patients with late-stage tumors. CONCLUSION: In this study, we demonstrated that variable mtDNA content markedly increased the risk of lymph node metastasis and high mortality of the patients with late-stage tumors. Additionally, we found a strong link between increased mtDNA content and worse survival of the patients with late-stage tumors. Taken together, variable mtDNA content may be a valuable poor prognostic factor for advanced gastric cancer patients. VIRTUAL SLIDES: The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/1344721463103353. PMID- 24144009 TI - Effects of patient-reported non-severe hypoglycemia on healthcare resource use, work-time loss, and wellbeing in insulin-treated patients with diabetes in seven European countries. AB - PURPOSE: Hypoglycemia is a frequent side effect induced by insulin treatment of type 1 (T1DM) and type 2 diabetes (T2DM). Limited data exist on the associated healthcare resource use and patient impact of hypoglycemia, particularly at a country-specific level. This study investigated the effects of self-reported non severe hypoglycemic events (NSHE) on use of healthcare resources and patient wellbeing. METHODS: Patients with T1DM or insulin-treated T2DM diabetes from seven European countries were invited to complete four weekly questionnaires. Data were collected on patient demographics, NSHE occurrence in the last 7 days, hypoglycemia-related resource use, and patient impact. NSHE were defined as events with hypoglycemia symptoms, with or without blood glucose measurement, or low blood glucose measurement without symptoms, which the patient could manage without third-party assistance. RESULTS: Three thousand, nine hundred and fifty nine respondents completed at least one wave of the survey, with 57% completing all four questionnaires; 3827 respondents were used for data analyses. Overall, 2.3% and 8.9% of NSHE in patients with T1DM and T2DM, respectively, resulted in healthcare professional contact. Across countries, there was a mean increase in blood glucose test use of 3.0 tests in the week following a NSHE. Among respondents who were employed (48%), loss of work-time after the last hypoglycemic event was reported for 9.7% of NSHE. Overall, 10.2% (daytime) and 8.0% (nocturnal) NSHE led to work-time loss, with a mean loss of 84.3 (daytime) and 169.6 (nocturnal) minutes among patients reporting work-time loss. Additionally, patients reported feeling tired, irritable, and having negative feelings following hypoglycemia. LIMITATIONS: Direct comparisons between studies must be interpreted with caution because of different definitions of hypoglycemia severity, duration of the studies, and methods of data collection. CONCLUSIONS: NSHE were associated with use of extra healthcare resources and work-time loss in all countries studied, suggesting that NSHE have considerable impact on patients/society. PMID- 24144010 TI - From an open framework to a layered and a hexagonal tungsten oxide structure: controlled transformation reactions of an extended solid-state material, Cs3Ga7(SeO3)12 to Ga(OH)(SeO3) and KGa3(SeO4)2(OH)6. AB - A highly symmetric open-framework gallium selenite, Cs3Ga7(SeO3)12, containing cubic superlattices has been synthesized by a standard solid-state reaction using Cs2CO3, Ga2O3, and SeO2 as reagents. Cs3Ga7(SeO3)12 exhibits a three-dimensional open-framework structure consisting of GaO4 tetrahedra, GaO6 octahedra, and SeO3 polyhedra. Step-by-step reactions of the solid-state material in aqueous KNO3 solution at different temperatures produce Ga(OH)(SeO3) with a layered structure and KGa3(SeO4)2(OH)6 having a hexagonal tungsten oxide (HTO) topology. Novel HTO layers capped by Se(6+) cations in KGa3(SeO4)2(OH)6 led us to synthesize other alkali metal gallium selenates, NaGa3(SeO4)2(OH)6 and RbGa3(SeO4)2(OH)6, using hydrothermal reactions. Thermal analyses, infrared spectroscopy, elemental analyses, and dipole moment calculations for the reported materials are also presented. PMID- 24144011 TI - Re: acute aortic syndrome: CT findings. PMID- 24144012 TI - Re: acute aortic syndrome: CT findings. A reply. PMID- 24144013 TI - Re: Decontamination of transvaginal ultrasound probes: review of national practice and need for national guidelines. PMID- 24144014 TI - Oxidant-free conversion of primary amines to nitriles. AB - An amide-derived NNN-Ru(II) hydride complex catalyzes oxidant-free, acceptorless, and chemoselective dehydrogenation of primary and secondary amines to the corresponding nitriles and imines with liberation of dihydrogen. The catalyst system tolerates oxidizable functionality and is selective for the dehydrogenation of primary amines (-CH2NH2) in the presence of amines without alpha-CH hydrogens. PMID- 24144015 TI - Correlation between the charge of polymer particles in solution and in the gas phase investigated by zeta-potential measurements and electrospray ionization mass spectrometry. AB - The relationship between the effective charge of polymer nanoparticles (PNP) in solution and the charge states of ionized particles produced in the gas phase by electrospray ionization was investigated. Charge detection mass spectrometry was used to measure both the mass and charge of individual electrosprayed ions. The effective charges extracted from the measured zeta-potential of PNPs in solution are partially correlated with the average values of charge of PNPs in the gas phase. The correlation between the magnitude of charging of PNPs ions produced in the gas phase with the PNPs surface charge in solution demonstrates that the mass spectrometry-based analysis described in this work is an alternative and promising way for a fast and systematic characterization of charges on colloidal particles. PMID- 24144016 TI - Association between erythrocyte parameters and metabolic syndrome in urban Han Chinese: a longitudinal cohort study. AB - BACKGROUND: Although various cross-sectional studies have shown that erythrocyte parameters, including red blood cell (RBC), hemoglobin (Hb) and hematocrit (HCT), were linked with metabolic syndrome (MetS), few longitudinal studies have been used to confirm their relationship. The study, therefore, constructed a large scale longitudinal cohort in urban Chinese population to highlight and confirm the association between erythrocyte parameters and MetS/its components. METHODS: A longitudinal cohort with 6,453 participants was established based on the routine health check-up systems to follow up MetS, and Generalized Estimating Equation (GEE) model was used to detect the association between erythrocyte parameters and MetS/its components (obesity, hyperglycemia, dyslipidemia, and hypertension). RESULTS: 287 MetS occurred over the four-year follow-up, leading to a total incidence density of 14.19 per 1,000 person-years (287/20218 person years). Both RBC and Hb were strongly associated with MetS (RR/95% CI, P value; 3.016/1.525-5.967, 0.002 for RBC; 3.008/1.481-6.109, 0.002 for Hb), with their dose-response trends detected. All three erythrocyte parameters (RBC, Hb and HCT) were found to be associated with obesity, hypertension and dyslipidemia with similar dose-response trends respectively, while only Hb showed a significant association with hyperglycemia. CONCLUSIONS: Elevated erythrocyte parameters were confirmed to be associated with MetS/its components in urban Chinese population, suggesting that erythrocyte parameters might be served as a potential predictor for risk of MetS. PMID- 24144017 TI - Can ANCA differentiate eosinophilic granulomatosis with polyangiitis (Churg Strauss) from idiopathic hypereosinophilic syndrome? PMID- 24144018 TI - Local detection of nitrogen-vacancy centers in a nanodiamond monolayer. AB - Nitrogen-vacancy defect centers (NV) contained in nanodiamonds (NDs) are a promising candidate in quantum information processing and single photon sources due to the capability of controlling their assembly on various surfaces. However, their detection with traditional optical techniques becomes challenging when probing high NV densities at the nanometer scale. Here, we combine scanning probe techniques to characterize in a monolayer the structural and electronic properties of bucky-diamonds with sizes below 10 nm. We further observe by light assisted Kelvin- and scanning tunneling spectroscopy a clear signature of negatively charged subsurface NV centers in NDs at the nanoscale where conventional techniques are limited. PMID- 24144019 TI - Patterns of genetic differentiation at MHC class I genes and microsatellites identify conservation units in the giant panda. AB - BACKGROUND: Evaluating patterns of genetic variation is important to identify conservation units (i.e., evolutionarily significant units [ESUs], management units [MUs], and adaptive units [AUs]) in endangered species. While neutral markers could be used to infer population history, their application in the estimation of adaptive variation is limited. The capacity to adapt to various environments is vital for the long-term survival of endangered species. Hence, analysis of adaptive loci, such as the major histocompatibility complex (MHC) genes, is critical for conservation genetics studies. Here, we investigated 4 classical MHC class I genes (Aime-C, Aime-F, Aime-I, and Aime-L) and 8 microsatellites to infer patterns of genetic variation in the giant panda (Ailuropoda melanoleuca) and to further define conservation units. RESULTS: Overall, we identified 24 haplotypes (9 for Aime-C, 1 for Aime-F, 7 for Aime-I, and 7 for Aime-L) from 218 individuals obtained from 6 populations of giant panda. We found that the Xiaoxiangling population had the highest genetic variation at microsatellites among the 6 giant panda populations and higher genetic variation at Aime-MHC class I genes than other larger populations (Qinling, Qionglai, and Minshan populations). Differentiation index (FST)-based phylogenetic and Bayesian clustering analyses for Aime-MHC-I and microsatellite loci both supported that most populations were highly differentiated. The Qinling population was the most genetically differentiated. CONCLUSIONS: The giant panda showed a relatively higher level of genetic diversity at MHC class I genes compared with endangered felids. Using all of the loci, we found that the 6 giant panda populations fell into 2 ESUs: Qinling and non-Qinling populations. We defined 3 MUs based on microsatellites: Qinling, Minshan-Qionglai, and Daxiangling-Xiaoxiangling-Liangshan. We also recommended 3 possible AUs based on MHC loci: Qinling, Minshan-Qionglai, and Daxiangling-Xiaoxiangling-Liangshan. Furthermore, we recommend that a captive breeding program be considered for the Qinling panda population. PMID- 24144021 TI - Determination of n-alkane constituents and their phenological variation in the epicuticular wax of mature leaves of Nyctanthes arbor-tristis L. AB - The present communication is a first-time report on the analyses of n-alkane profile of epicuticular wax extracted from the mature leaves of Nyctanthes arbor tristis L. during a calender year. The composition of n-alkanes revealed hentriacontane (n-C31), tritriacontane (n-C33), tetratriacontane (n-C35) and nonacosane (n-C29) as the major constituents with tritriacontane (n-C33) being the dominant constituent. The cumulative percentage of these four odd-numbered alkanes also showed phenological variation being highest during the fruit ripening stage (average value 63.29%) followed by the flowering stage (mean value 60.74%). The values remained moderate on an average of 54.31% for the rest of the year. This study also confirms the xerophytic feature of the plant having higher proportion of longer carbon chain n-alkanes greater than C31 (dominant peaks are of C33 and C35). PMID- 24144020 TI - Accurate determination of peptide phosphorylation stoichiometry via automated diagonal capillary electrophoresis coupled with mass spectrometry: proof of principle. AB - While reversible protein phosphorylation plays an important role in many cellular processes, simple and reliable measurement of the stoichiometry of phosphorylation can be challenging. This measurement is confounded by differences in the ionization efficiency of phosphorylated and unphosphorylated sites during analysis by mass spectrometry. Here, we demonstrate diagonal capillary electrophoresis-mass spectrometry for the accurate determination of this stoichiometry. Diagonal capillary electrophoresis is a two-dimensional separation method that incorporates an immobilized alkaline phosphatase microreactor at the distal end of the first capillary and employs identical electrophoretic separation modes in both dimensions. The first dimension is used to separate a mixture of the phosphorylated and unphosphorylated forms of a peptide. Fractions are parked in the reactor where they undergo complete dephosphorylation. The products are then periodically transferred to the second capillary and analyzed by mass spectrometry (MS). Because the phosphorylated and unphosphorylated forms differ in charge, they are well resolved in the first dimension separation. Because the unphosphorylated and dephosphorylated peptides are identical, there is no bias in ionization efficiency, and phosphorylation stoichiometry can be determined by the ratio of the signal of the two forms. A calibration curve was generated from mixtures of a phosphorylated standard peptide and its unphosphorylated form, prepared in a bovine serum albumin tryptic digest. This proof of principle experiment demonstrated a linear response across nearly 2 orders of magnitude in stoichiometry. PMID- 24144022 TI - Phytochemical analysis and anticancer capacity of Shemamruthaa, a herbal formulation against DMBA- induced mammary carcinoma in rats. AB - OBJECTIVE: To investigate the bioactive constituents of Shemamruthaa (SM), a herbal combination and its therapeutic effects on the mitochondrial functions with reference to lipid peroxidation (LPO), antioxidant status, citric acid cycle enzymes and electron transport chain enzymes in mammary tissues of 7,12 dimethylbenz(a)-anthracene (DMBA) induced mammary carcinoma in rat model. METHODS: Adult female Sprague-Dawley rats were used for the study and were divided into four groups. Group I served as control and Group II rats were induced mammary carcinoma by administration of DMBA (25 mg/kg b.w.) orally. The normal and cancer-induced rats (Group III) were treated with SM (400 mg/kg b.w./day) orally by gastric incubation for 14 days. Group IV rats served as SM treated control animals. RESULTS: Cancer-induced rats showed a considerably increased level of LPO with concomitant decreased levels of antioxidants, citric acid cycle enzymes, electron transport chain enzymes and cytochrome contents in the mammary tissue. Treatment with SM brought back the aforementioned biochemical parameters to near normal. CONCLUSIONS: From the results, it can be inferred that Shemamruthaa possesses significant anticancer effect through its role in attenuation of LPO, prevention of membrane damage and restoring membrane integrity. PMID- 24144023 TI - Physical chemical and biological characterization of a new bacteriocin produced by Bacillus cereus NS02. AB - OBJECTIVE: To screen the bacteriocinogenic isolate from buffalo milk and to characterize it on physical, chemical and biological aspects for the application in biopreservation. METHODS: Bacillus cereus (B. cereus) was isolated and assessed for its baceteriocinogenic activity. Bacteriocin was produced and purified by ammonium sulphate precipitation, dialysis and gel filtration chromatography. Purified bacteriocin was used to check its antimicrobial activity against food borne bacteria. Effect and stability of bacteriocin was determined with the respect to temperature, pH, enzymes, organic solvents and chemicals. Bacteriocin was also subjected to SDS PAGE analysis to determine its molecular weight. In addition, functional groups exist in the bacteriocin was determined by FTIR analysis. RESULTS: B. cereus was identified by 16S rRNA sequence analysis. Bacteriocin showed increased activity against all the bacteria used and its activity unit was found to be 51, 200 AU/mL. It was stable to high temperature (100 degrees C) and wide range of pH (3-10), sensitive to proteolytic enzymes and resistant to nonproteolytic enzymes. It was low molecular weight (3.5 - 6 KDa) protein and FTIR study revealed the presence of amide group and NH stretching. CONCLUSIONS: Bacteriocin produced in this study possesses the highest antimicrobial activity against both gram positive and gram negative bacteria thereby it has immense application as biopreservative agent. FTIR proved its peptide nature. PMID- 24144024 TI - Study on outbreak of Neospora caninum-associated abortion in dairy cows in Tabriz (Northwest Iran) by serological, molecular and histopathologic methods. AB - OBJECTIVE: To determine Neospora caninum (N. caninum) as a cause of bovine abortion in dairy cows by ELISA, PCR and Pathological methods in Tabriz, Northwest of Iran. METHODS: For study of outbreak of neosporosis, blood samples were collected from 76 Holstein aborted dairy cows in Tabriz (Northwest Iran). Antibodies to N. caninum were assayed by using a commercially ELISA kit (IDEXX, USA). IgG against N. caninum were found in 14 (18.4%) cases. Aborted fetuses of these seropositive dams were proposed for histopathological and molecular investigations. Brains, spinal cords and placentas of the fetuses were fixed in 10% buffered formalin for histopathology. Also 5-10 g of brain tissue was sampled for DNA extraction. In 6 out of 14 (42.8%) fetuses, brain tissue was positive in PCR. All dams of these fetuses were serologically seropositive in ELISA test. RESULTS: Histopathologically, the lesions consistent with N. caninum were observed in brains, spinal cords and placenta of all fetuses. Lesions in CNS included severe congestion, perivascular and perineuronal edema, status spongiosis, perivascular cuffing, focal gliosis, nourophagy and focal necrosis. There were some Neospora-like cysts in brain. In placentas, severe congestion, perivascular infiltration of mononuclear cells, vascular thrombosis, focal placentitis and necrotic foci in cotyledons were noticed. CONCLUSIONS: The results of present study agreed the results of similar studies about serological, histopathological and molecular results of other studies about neosporosis and it seems to support the outbreak of N. caninum-associated abortion in dairy cows in Tabriz (Northwest Iran). PMID- 24144025 TI - Epidemiology of ixodid ticks in cattle population of various agro-climatic zones of Punjab, India. AB - OBJECTIVE: To determine the epidemiology of ixodid ticks in bovines of different agro-climatic zones of Punjab state, India. METHODS: A total of 4 459 cattle of all age groups and sex were examined from eighteen districts of five major agro climatic zones of Punjab state, India. RESULTS: The overall prevalence of ixodid ticks, Rhipicephalus microplus (R. microplus), Hyalomma anatolicum anatolicum (H. a. anatolicum) and mixed infestation were 58.06%, 50.16%, 11.34% and 3.45%, respectively. Among the various agro-climatic zones highest prevalence rate of R. microplus and H. a. anatolicum were recorded in submountain undulating region (79.36%) and western region (20.40%), respectively indicating that R. microplus prefers a hot and humid environment whereas, arid and semi arid conditions suit better for H. a. anatolicum. The overall prevalence of ixodid ticks was highest in monsoon season (83.74%), followed by summer (69.01%) and least in winters (31.64%) and a significant variation (P<0.01) was also observed; whereas, maximum prevalence of R. microplus and H. a. anatolicum were recorded in monsoon (72.42%) and summers (18.06%), respectively. Among the various age groups maximum tick infestation was recorded in calves <6 months of age (72.59%), followed by 6 months -1 year age group (61.74%) and least in >1year age group (55.02%) and the difference was statistically significant (P<0.01). Also a significantly higher (P<0.01) infestation rates of ixodid ticks was observed in males. CONCLUSIONS: The findings of the current study would provide a basis for evolving effective control strategy for the management of ticks in bovines of the region. PMID- 24144026 TI - Evaluation of directly observed treatment short courses at a secondary health institution in Ibadan, Oyo State, Southwestern Nigeria. AB - OBJECTIVE: To evaluate the success rate of tuberculosis intervention programme at a specialist hospital in Ibadan, Nigeria through a retrospective study as well as carry out physicochemical evaluation of anti-tuberculous agents as a way of eliminating drug-related failure. METHODS: The retrospective study involved the use of quarterly tuberculosis central register at the Government Chest Hospital, Ibadan between 1st quarter (2003) to 4th quarter (2009). Relevant data were extracted from these register with the aid of data collection forms. The basic physicochemical analyses of the drugs given to the patients were also carried out using the International Pharmacopoeia methods. RESULTS: All the drugs examined for their physicochemical properties passed the International Pharmacopeia recommended tests. A total number of 1 260 patients enrolled at the hospital were assessed through case notes. This comprises of 59.4% males of which 69.23% new cases were also males. There was a significant (P<0.05) patient enrollment across the quarters for the seven years. An overall 80.24% cure rate over the 7-period was obtained which is less than the WHO target of 85%. Cure rates were better in females than males. Failure treatment outcomes such as positive (1.51%), deaths (8.73%), defaulted (3.33%) and transferred out (5.95%) were recorded though not statistically significant (P>0.05). Failure rates in all categories were higher in males than females (P>0.05). CONCLUSIONS: More enlightenment and counseling is still required to meet up with the target for TB control. PMID- 24144027 TI - Construction and expression of retroviral vector pLEGFP-N1-TERT in preparation of seed cells for skin tissue engineering. AB - OBJECTIVE: To construct the retroviral vector pLEGFP-N1-telomerase reverse transcriptase (TERT) and to investigate the expression of TERT in neonatal mouse hypodermal cells. METHODS: The polymerase chain reaction (PCR)-amplified TERT gene was inserted into plasmid pLEGFP-N1. The positive clone was identified by restriction enzyme digestion and sequencing, then was transfected into packaging cells to produce retrovirus particles. Neonatal mouse hypodermal cells were infected with the virus to generate a stable cell line. The TERT mRNA expression level, telomerase activity, and enhanced green fluorescent protein (EGFP) expression level were analyzed. RESULTS: Retroviral vector pLEGFP-N1-TERT was constructed successfully, and a stable cell line of neonatal mouse hypodermal cells expressing EGFP was established. Western blot and immunohistochemical assay showed that the expression level of TERT was significantly elevated in the neonatal mouse hypodermal cells. CONCLUSIONS: A high titer of retrovirus pLEGFP N1-TERT mediates high-level expression of the exogenous TERT gene in the neonatal mouse hypodermal cells. This protocol has potential applications for skin tissue engineering and cell transplantation therapy. PMID- 24144028 TI - Effect of ERBB2 expression on invasiveness of glioma TJ905 cells. AB - OBJECTIVE: To investigate the influence and possible mechanism of ERBB2 expression on the invasiveness of glioma cells. METHODS: Glioma TJ905 cells were separated and cultured. ERBB2 shRNA and overexpressing vectors were constructed, which were then transfected. The ERBB2 expression was up-regulated or down regulated. Changes of invasiveness of TJ905 cells were detected by Transwell assay, and the expressions of matrix metalloprotease (MMP)-2 and MMP-9 were measured by Western blot. RESULTS: ERBB2 shRNA transfection vector could effectively inhibit expression of ERBB2; while ERBB2 overexpressing vector transfection could significantly improve the expression of ERBB2 in TJ905 cells. Transwell assay showed that when ERBB2 expression was down-regulated, the invasiveness of TJ905 cells was notably decreased; when ERBB2 expression was up regulated, the invasiveness of TJ905 cells was markedly increased. Meanwhile, Western blot indicated that down-regulating ERBB2 inhibited the expression of MMP 2 and MMP-9, while up-regulating ERBB2 enhanced their expressions. CONCLUSIONS: ERBB2 expression is closely related to the invasiveness of glioma TJ905 cells. PMID- 24144029 TI - An experimental study of preventing and treating acute radioactive enteritis with human umbilical cord mesenchymal stem cells. AB - OBJECTIVE: To test the curative effect of human umbilical cord-derived mesenchymal stem cells on rat acute radioactive enteritis and thus to provide clinical therapeutic basis for radiation sickness. METHODS: Human umbilical cord derived mesenchymal stem cells were cultivated in vitro and the model of acute radioactive enteritis of rats was established. Then, the umbilical cord mesenchymal stem cells were injected into the rats via tail vein. Visual and histopathological changes of the experimental rats were observed. RESULTS: After the injection, the rats in the prevention group and treatment group had remarkably better survival status than those in the control group. The histological observations revealed that the former also had better intestinal mucosa structure, more regenerative cells and stronger proliferation activity than the latter. CONCLUSIONS: Human umbilical cord-derived mesenchymal stem cells have a definite therapeutic effect on acute radioactive enteritis in rats. PMID- 24144030 TI - Screening of differentially expressed microRNA in ulcerative colitis related colorectal cancer. AB - OBJECTIVE: To investigate the differential expression of microRNA (miRNA) in colon between ulcerative colitis (UC) and ulcerative colitis related colorectal cancer (UCRCC). METHODS: An UC mouse model was built by dextran sodium sulfate, and an UCRCC mouse model by dextran sodium sulfate and 1,2-diformylhydrazine. RNAs were extracted from the colon, purified and hybridized with fluorescence labeled miRNA oligonucleotide gene chip. Real-time fluorescence quantitative PCR was used to verify the expression variation of miRNA. SAM was employed for the data analysis. RESULTS: The up-regulated miRNAs in colon cancer included has-miR 194, has-miR-215, has-miR-93, has-miR-192, has-miR-92a, has-miR-29b, and has-miR 20a (median false discovery rate<5%), while the down-regulated miRNAs were has miR-1231, has-miR-195, has-miR-143, and has-miR-145 (median false discovery rate<5%). CONCLUSIONS: Significant differential expression of miRNA was found between the UC mouse and UCRCC mouse, which may be related to the onset, erosion and transfer of colorectal cancer. PMID- 24144031 TI - Effect of emulsified isoflurane on apoptosis of anoxia-reoxygenation neonatal rat cardiomyocytes. AB - OBJECTIVE: To explore the effect of emulsified isoflurane (EI) on apoptosis of anoxia-reoxygenation neonatal rat cardiomyocytes and relevant protein expression. METHODS: Cardiac muscle anoxia-reoxygenation damage model was established with culture in vitro neonatal rat cardiomyocytes. The cardiomyocytes were divided into control group, model group, fat emulsion group and EI group. The cardiomyocytes apoptosis rates and lactic dehydrogenase (LDH), superoxide dismutase (SOD) and malondialdehyde (MDA) index standardization were detected after relevant treatment. The expression of apoptosis-related proteins Bel-2, Bax and Caspase-3 were detected with Western blot approach. RESULTS: After hypoxia/reoxygenation (H/R) model was treated by EI, the cells apoptosis rate decreased and was dramatically below the fat emulsion group (P<0.05). Cardiomyocytes biochemical index detection presented that, compared with the control group that the LDH activity and MDA content dramatically increased (P<0.05), while the SOD activity notably decreased (P<0.05); compared with the H/R group, the SOD activity of the fat emulsion group and EI group increased (P<0.05); while the LDH activity and MDA content decreased (P<0.05). And the change of the EI group was more remarkable than the fat emulsion group (P<0.05). The Western blot analysis presented that, compared with the control group, the Bcl-2 protein expression of the other groups significantly decreased (P<0.05), the expressions of Bax protein and Caspase-3 protein increased significantly (P<0.05); compared with H/R group, cardiomyocytes Bcl-2 protein expression of EI group increased significantly (P<0.05), the expressions of Bax protein and Caspase-3 protein decreased significantly (P<0.05), and the change of EI group was more remarkable than the fat emulsion group (P<0.05). CONCLUSIONS: EI can inhabit the apoptosis of anoxia-reoxygenation damage model cardiomyocytes, and may be related to the up-regulation of expression of Bcl-2 and down-regulation of expression of Caspase-3 protein. PMID- 24144032 TI - Effect of 5- AZn-2 '-deoxycytidine on proliferation of human lung adenocarcinoma cell line A549 in vitro. AB - OBJECTIVE: To explore effect of 5-AZn-2 '-deoxycytidine on proliferation of human lung adenocarcinoma cell line A549 in vitro. METHODS: Superoxide dismutase (SOD) activity was measured by hydroxylamine colorimetric method. Inhibition effect of 5-AZn-2' deoxycytidylic acid at different concentration and different time on growth of A549 cell was determined by MTT assay. Methylene dioxyamphetamine (MDA) was measured by thiobarbituric acid colorimetric method. Effect of 5-AZn-2' deoxycytidylic acid on apoptosis of A549 cell was determined by Hoechst 33258 dyeing detection. RESULTS: 5-AZn-2' deoxycytidylic acid had significant inhibition effect on proliferation of A549 cells in vitro, and the inhibition was notably dependent on time and dosage during 48-72 h; SOD level was significantly lower than those of control group (P<0.05, P<0.01), MDA level was significantly higher than those in the control group (P<0.05, P<0.01). A549 cells began to be in apoptosis after using 5-AZn-2'deoxycytidylic acid. CONCLUSIONS: 5- AZn-2' deoxycytidylic acid has significant inhibition effect on growth of A549 cell, and can lead the change of lipid peroxidation. It indicates that the mechanism has relationship with A549 cell cycle tissue and induction factor of apoptosis. PMID- 24144033 TI - Effect of Xinjikang on left ventricular hypertrophy remodeling in hypertensive rats. AB - OBJECTIVE: To investigate the effects of Xinjikang on the left ventricular hypertrophy remodeling and myocardial activity in hypertension. METHODS: Sixty Wistar rats were randomly divided into four groups. The pressure-loaded left ventricular hypertrophy model was established with abdominal aorta ligation method. Rats in A and B groups were intragastrically administered with physiological saline, while C and D groups were administered with Xinjikang and metoprolol, respectively. The changes in blood pressure, E/A ratio, myocardial pathological morphology, myocardial lipoperoxides and superoxide dismustase activity in four groups were observed and compared before and after treatment. RESULTS: There were statistically significant differences in E/A ratio between C group after treatment and model group (P<0.05), while no difference was observed between A and D groups (P>0.05); after treatment the myocardial lipoperoxides and superoxide dismustase contents in C and D groups were improved significantly compared with model group (P<0.05). CONCLUSIONS: Xinjikang can improve myocardial injury, restore myocardial parenchyma and myocardial interstitial remodeling functions in hypertensive rats with the left ventricular hypertrophy. PMID- 24144034 TI - Relationship between expression of COX-2, TNF-alpha, IL-6 and autoimmune-type recurrent miscarriage. AB - OBJECTIVE: To investigate the roles of COX-2, TNF-alpha, IL-6 in the pathogenesis of autoimmune-type recurrent spontaneous abortion (RSA). METHODS: RT-PCR was used to detect the mRNA of COX-2, TNF-alpha, IL-6 in the trophoblast cells of murine RSA and normal pregnant models. The COX-2, TNF-alpha, IL-6 protein expressions were determined by using immunohistochemisry staining method. The COX-2, TNF alpha, IL-6 protein expressions were determined by ELISA. RESULTS: The embryo loss rates in experiment group was significantly higher than that in normal pregnancy control group, the expression of COX-2, TNF-alpha, IL-6 in the trophoblast cells of murine RSA and normal pregnant models. The expression of COX 2 in autoimmune-type recurrent spontaneous abortion was significantly lesser than in normal pregnant models. The expression of TNF-alpha, IL-6 in autoimmune-type recurrent spontaneous abortion was significantly higher than in normal pregnant models. There was a positively correlation between TNF-alpha and IL-6. There was no relationship between COX-2, TNF-alpha and IL-6. CONCLUSIONS: The abnormal expression of COX-2, TNF-alpha and IL-6 may result in RSA. PMID- 24144035 TI - Effect of different anesthesia methods on erythrocyte immune function in mice. AB - OBJECTIVE: To explore effect of different anesthesia methods and different anesthetics on erythrocyte immune function in mice. METHODS: The mice were anesthetized by isoflurane and ether inhalation, and also under intraperitoneal anesthesia with sodium pentobarbital and chloral hydrate. Blood was collected from the ventro-cardinal vein. Automatic blood cell analyzer was used for routine blood examination, and the canthine oxidase method was used to measure the superoxide dismutase (SOD) activity. Lipid peroxidation product malondialdehyde (MDA) was measured with TBA, and glutathione peroxidase (GSH-Px) was measured with DTNB, and then the effect of different anesthesia methods and different anesthetics on erythrocyte immune function in mice was observed. RESULTS: Hct level of chloral hydrate intraperitoneal injection group was significantly higher than the other three groups (P<0.05). And the MDA levels in the pentobarbital sodium group were significantly higher than the other three groups (P<0.05). SOD and GSH-Px of the chloral hydrate and sodium pentobarbital intraperitoneal injection group were significantly lower than the other two groups; RBC-C 3bRR and RBC-ICR of the chloral hydrate and sodium pentobarbital intraperitoneal injection group were significantly lower than the other two groups. CONCLUSIONS: Different drugs can induce changes in immune function of mice at different levels. Isoflurane and ether have less damage to animal body, while chloral hydrate and sodium pentobarbital intraperitoneal injection have a certain inhibitory effect on the animal body respiratory system and can cause greater damage to the body. Therefore, the reasonable selection and control of anesthetics are very important in order to avoid the experimental errors caused by anesthesia. PMID- 24144036 TI - TGF-beta1 signal pathway in the regulation of inflammation in patients with atrial fibrillation. AB - OBJECTIVE: To observe the expression changes of inflammatory markers TGF-beta1, Smad3 and IL-6 in patients with atrial fibrillation (AF), and to explore the significance of TGF-beta1 signaling pathway in the structural remodeling of AF. METHODS: The expression of TGF-beta1, Smad3 and IL-6 in 50 cases with AF and 30 normal cases were detected by RT-PCR and ELISA. RESULTS: The TGF-beta1, Smad3 and IL-6 mRNA and protein expression levels in patients with AF were significantly higher than that in the control group (P<0.05), but there was no significantly different between the paroxysmal AF group and the persistent AF group (P>0.05). The TGF-beta1mRNA expression in the ? 50 years subgroup was significantly higher than that in the <50 years subgroups, and it was higher in the NYHA III subgroup than in the I/II grade subgroup. It was also higher in the left ventricular ejection fraction (LVEF) <50% subgroup than in LVEF ? 50% group, and it was significantly higher in the AF time ? 36 months subgroup than that in <36 months subgroup (P<0.05). The Smad3 and IL-6 expressions in the in the LVEF <50% subgroup were both high that than that in LVEF ? 50% group, and higher in the AF time ? 36 months subgroup than that in <36 months subgroup (P<0.05). There were a positive correlation between TGF-beta1, Smad3 and IL-6 (r=0.687, r=0.547). There were also a positive correlation between Smad3 and IL-6 mRNA (r=0.823). CONCLUSIONS: AF is associated with inflammation, and the inflammation is also involved in the fibrillation and sustain of AF. The TGF-beta1 signal pathway may be involved in the process of atrial structural remodeling in patients with AF, and iss related with the occurrence and maintenance of AF. PMID- 24144037 TI - Meta analysis about the efficacy and safety of anti-ocular hypertension eye drops without benzalkonium chloride. AB - OBJECTIVE: To explore the safety and efficacy of eye drops without benzalkonium chloride (BAK) in treating glaucoma and ocular hypertension. METHODS: The clinical case-control literatures about eye drops without BAK treating glaucoma and ocular hypertension were retrieved in PubMed, EMBASE, Cochrane and Chinese Biological and Medical database. Meta 5.0 software was used to analyze the literatures. RESULTS: Five clinical control studies were included. The results indicated both eye drops could lower the intraocular pressure, and the intraocular pressure-lowering difference between two eye drops was 0.07 mmHg (95% CI: 0.04, 0.19) (P>0.05). Two adverse reactions occurred more were conjunctival injection (10.78%) and allergic conjunctivitis (4.78%). The odd ratio of two eye drops occurring conjunctival injection and allergic conjunctivitis was 0.67 (95% CI, 0.25, 1.10) and 0.82 (95% CI, 0.09, 1.54), respectively (P<0.05) in fixed effect model. CONCLUSIONS: There is no difference between the eye drops with or without BAK in lowering intraocular pressure, but the latter is of higher safety. In consideration of the relatively small sample size of this research, more high quality clinical research contrasts are needed as evidence. PMID- 24144038 TI - Kinetics of circulating immunoglobulin M in sepsis: relationship with final outcome. AB - INTRODUCTION: The aim of this study was to investigate the kinetics of immunoglobulin M (IgM) during the different stages of sepsis. METHODS: In this prospective multicenter study, blood sampling for IgM measurement was done within the first 24 hours from diagnosis in 332 critically ill patients; in 83 patients this was repeated upon progression to more severe stages. Among these 83 patients, 30 patients with severe sepsis progressed into shock and IgM was monitored daily for seven consecutive days. Peripheral blood mononuclear cells (PBMCs) were isolated from 55 patients and stimulated for IgM production. RESULTS: Serum IgM was decreased in septic shock compared to patients with systemic inflammatory response syndrome (SIRS) and patients with severe sepsis. Paired comparisons at distinct time points of the sepsis course showed that IgM was decreased only when patients deteriorated from severe sepsis to septic shock. Serial measurements in these patients, beginning from the early start of vasopressors, showed that the distribution of IgM over time was significantly greater for survivors than for non-survivors. Production of IgM by PBMCs was significantly lower at all stages of sepsis compared with healthy controls. CONCLUSIONS: Specific changes of circulating IgM occur when patients with severe sepsis progress into septic shock. The distribution of IgM is lower among non survivors. PMID- 24144039 TI - Unexpected insertion of CO2 into the pentacoordinate P-N bond: Atherton-Todd-type reaction of hydrospirophosphorane with amines. AB - The Atherton-Todd-type reaction of pentacoordinate hydrospirophosphoranes with amines was investigated, and a novel CO2 insertion reaction into the pentacoordinate P-N bond under mild conditions was developed. The mechanism and stereochemistry of the CO2 insertion reaction between hydrospirophosphoranes and secondary amines were proposed via a carbon-13 labeling experiment, a (31)P NMR tracing experiment, and X-ray diffraction analysis. The chlorinated spirophosphorane intermediate was first generated with stereoretention of the configuration at phosphorus and subsequently was attacked by a carbamate anion formed from CO2 and a secondary amine. It was found that rear attack of nucleophilic substitution with stereoinversion at pentacoordinate phosphorus was the preferred route, although front attack happened for sterically hindered reactants. The configuration of the CO2 insertion product depended mainly upon the original phosphorus configuration of the hydrospirophosphoranes. PMID- 24144040 TI - Preserving catalytic activity and enhancing biochemical stability of the therapeutic enzyme asparaginase by biocompatible multilayered polyelectrolyte microcapsules. AB - The present study focuses on the formation of microcapsules containing catalytically active L-asparaginase (L-ASNase), a protein drug of high value in antileukemic therapy. We make use of the layer-by-layer (LbL) technique to coat protein-loaded calcium carbonate (CaCO3) particles with two or three poly dextran/poly-L-arginine-based bilayers. To achieve high loading efficiency, the CaCO3 template was generated by coprecipitation with the enzyme. After assembly of the polymer shell, the CaCO3 core material was dissolved under mild conditions by dialysis against 20 mM EDTA. Biochemical stability of the encapsulated L asparaginase was analyzed by treating the capsules with the proteases trypsin and thrombin, which are known to degrade and inactivate the enzyme during leukemia treatment, allowing us to test for resistance against proteolysis by physiologically relevant proteases through measurement of residual l-asparaginase activities. In addition, the thermal stability, the stability at the physiological temperature, and the long-term storage stability of the encapsulated enzyme were investigated. We show that encapsulation of l asparaginase remarkably improves both proteolytic resistance and thermal inactivation at 37 degrees C, which could considerably prolong the enzyme's in vivo half-life during application in acute lymphoblastic leukemia (ALL). Importantly, the use of low EDTA concentrations for the dissolution of CaCO3 by dialysis could be a general approach in cases where the activity of sensitive biomacromolecules is inhibited, or even irreversibly damaged, when standard protocols for fabrication of such LbL microcapsules are used. Encapsulated and free enzyme showed similar efficacies in driving leukemic cells to apoptosis. PMID- 24144041 TI - Characterization of nanoparticles from abrasive waterjet machining and electrical discharge machining processes. AB - Abrasive Waterjet Machining (AWM) and Electrical Discharge Machining (EDM) processes are found to produce nanoparticles during operation. Impacts of engineered nanoparticles released to the environment and biological system have caused much concern. Similarly, the nanoparticles unintentionally produced by the AWM and EDM can lead to comparable effects. By application of the Nanoparticle Tracking Analysis (NTA) technique, the size distribution and concentration of nanoparticles in the water used in AWM and EDM were measured. The particles generally have a peak size of 100-200 nm. The filtration systems of the AWM and EDM processes were found to remove 70% and 90% the nanoparticles present, respectively. However, the particle concentration of the filtered water from the AWM was still four times higher than that found in regular tap water. These nanoparticles are mostly agglomerated, according to the microscopy analysis. Using the electron dispersive spectroscopy (EDS) technique, the particles are confirmed to come from the debris of the materials cut with the equipment. Since AWM and EDM are widely used, the handling and disposal of used filters collected with nanoparticles, release of nanoparticles to the sewer, and potential use of higher performance filters for these processes will deserve further consideration. PMID- 24144042 TI - Regulation of stem cell self-renewal and differentiation by Wnt and Notch are conserved throughout the adenoma-carcinoma sequence in the colon. AB - BACKGROUND: Colon cancer stem cells are shown to be the self-renewing cells within a tumor that give rise to all lineages of more differentiated tumor cells. In this respect they are remarkably similar to their non-malignant counterparts that orchestrate the intestinal lining. This suggests that, despite the numerous genetic aberrations and morphological changes that have occurred during cancer initiation and progression, a remnant homeostatic regulation persists. FINDINGS: Using a number of human and mouse intestinal-derived organoid cultures from normal, adenoma and cancerous tissues, we show here that Notch signals coordinate self-renewal and lineage determination not only in normal, but also at the adenoma and carcinoma stage in both mice and humans. Moreover, the Wnt pathway, which carries activating mutations in virtually all colon cancers, is not as previously predicted constitutively active in adenomas and carcinomas, but still displays a heterogeneous activity pattern that determined stemness in all stages of disease. CONCLUSION: These data for the first time provide a comprehensive overview of Wnt and Notch-mediated signaling in the different stages of the adenoma-carcinoma sequence and demonstrates that these morphogenic pathways, despite mutations, remain crucial determinants of both architecture and hierarchy in normal and malignant intestinal tissue. PMID- 24144043 TI - Alveolar oxygen tension and angio-architecture of the distal adult lung. AB - The present study demonstrates the fine structure of pulmonary capillaries first injured and then undergoing growth in response to a change in the ambient alveolar oxygen tension. Breathing a high fraction of inspired oxygen (FiO2 0.75) triggers restriction by endothelial cell injury and effacement leading to segment narrowing and shortening and segment loss as demonstrated by a fall in density. Subsequently, breathing a relatively low fraction (FiO2 0.21) triggers capillary assembly (angiogenesis), which reverses the changes. The data underscore the structural reprogramming (reduction and restoration) of pulmonary capillaries in response to significant shifts in oxygen tension. PMID- 24144045 TI - Singlet oxygen generating activity of an electron donor connecting porphyrin photosensitizer can be controlled by DNA. AB - To control the activity of singlet oxygen ((1)O2) generation by photosensitizer through interaction with DNA, the electron- donor-connecting water-soluble porphyrin, meso-(9-anthryl)tris(N-methyl-p-pyridinio)porphyrin (AnTMPyP), was designed and synthesized. Molecular orbital calculation speculated that the photoexcited state of AnTMPyP can be deactivated via intramolecular electron transfer from the anthracene moiety to the porphyrin moiety, forming a charge transfer (CT) state. The electrostatic interaction between the cationic porphyrin and anionic DNA predicts a rise in the CT state energy, leading to the inhibition of the electron transfer quenching. AnTMPyP showed almost no fluorescence in an aqueous solution, and the fluorescence lifetime was very short (<0.04 ns). Furthermore, this porphyrin did not demonstrate (1)O2 generating activity under photoirradiation. The fluorescence intensity and lifetime of AnTMPyP were markedly increased in the presence of DNA. The photosensitized (1)O2 generation by this porphyrin was also enhanced through interaction with DNA. The estimated quantum yield of (1)O2 generation by AnTMPyP interacting with DNA without guanine sequence was 0.22. The molecular design to control the photosensitized (1)O2 generation is possible based on the regulation of electron transition and steric hindrance of photosensitizing molecule. PMID- 24144046 TI - Audiogram and cochlear implant candidacy--UK perspective. AB - OBJECTIVE AND IMPORTANCE: The candidacy for cochlear implant has changed over time and includes people with lesser degrees of hearing loss. Candidacy is based on the pure-tone audiometry thresholds and aided speech testing. The audiogram does not reflect the actual problems faced by an individual with and without hearing aids. The variability in the actual functional hearing and the pure-tone thresholds makes it difficult for the patients whose audiogram is borderline for cochlear implantation and they are not deriving enough benefit from hearing aids. CASE PRESENTATION: Retrospective report of the audiological findings of two patients whose cochlear implant funding was refused based on their audiogram. In both instances, they were not deriving benefit from hearing aids and the pure tone audiometry results were just outside the National Institute for Health and Care Excellence guidelines at 4 kHz. CONCLUSIONS: Cochlear implant candidacy should be individually based and needs to take into account other factors such as work, quality of life, and social impact rather than just adhering to the pure tone audiometry guidelines. These guidelines should not be considered as strict criteria nor used to deny the benefit of a cochlear implant at the earliest possible opportunity. PMID- 24144044 TI - Fusing dual-event data sets for Mycobacterium tuberculosis machine learning models and their evaluation. AB - The search for new tuberculosis treatments continues as we need to find molecules that can act more quickly, be accommodated in multidrug regimens, and overcome ever increasing levels of drug resistance. Multiple large scale phenotypic high throughput screens against Mycobacterium tuberculosis (Mtb) have generated dose response data, enabling the generation of machine learning models. These models also incorporated cytotoxicity data and were recently validated with a large external data set. A cheminformatics data-fusion approach followed by Bayesian machine learning, Support Vector Machine, or Recursive Partitioning model development (based on publicly available Mtb screening data) was used to compare individual data sets and subsequent combined models. A set of 1924 commercially available molecules with promising antitubercular activity (and lack of relative cytotoxicity to Vero cells) were used to evaluate the predictive nature of the models. We demonstrate that combining three data sets incorporating antitubercular and cytotoxicity data in Vero cells from our previous screens results in external validation receiver operator curve (ROC) of 0.83 (Bayesian or RP Forest). Models that do not have the highest 5-fold cross-validation ROC scores can outperform other models in a test set dependent manner. We demonstrate with predictions for a recently published set of Mtb leads from GlaxoSmithKline that no single machine learning model may be enough to identify compounds of interest. Data set fusion represents a further useful strategy for machine learning construction as illustrated with Mtb. Coverage of chemistry and Mtb target spaces may also be limiting factors for the whole-cell screening data generated to date. PMID- 24144047 TI - Role of Rho-GTPases and their regulatory proteins in glomerular podocyte function. AB - Podocytes play a critical role in maintaining glomerular permselectivity. It has been long recognized that their intricate actin-based structures are tightly associated with their normal function; however, the precise mechanisms by which podocytes form and maintain their complex structure had been poorly understood until the intensive investigations on podocyte biology began in 1998, triggered by the breakthrough discovery of nephrin. This review summarizes the recent discoveries of the molecular mechanisms by which the actin cytoskeleton is regulated in podocytes. A particular focus will be on the role of the Rho-family of small GTPases, represented by RhoA, Rac1, and Cdc42. Rho-GTPases are known for their versatile cellular functions, most importantly for the actin regulatory roles. We will also discuss the potential roles of the 3 groups of proteins known to regulate Rho-GTPases, namely GTPase-activating proteins, guanine nucleotide exchange factors, and guanine nucleotide dissociation inhibitors. PMID- 24144048 TI - The effect of bicarbonate on menadione-induced redox cycling and cytotoxicity: potential involvement of the carbonate radical. AB - We have investigated the effect of NaHCO3 on menadione redox cycling and cytotoxicity. A cell-free system utilized menadione and ascorbic acid to catalyze a redox cycle, and we utilized murine hepatoma (Hepa 1c1c7) cells for in vitro experiments. Experiments were performed using low (2 mmol/L) and physiological (25 mmol/L) levels of NaHCO3 in buffer equilibrated to physiological pH. Using oximetry, ascorbic acid oxidation, and ascorbyl radical detection, we found that menadione redox cycling was enhanced by NaHCO3. Furthermore, Hepa 1c1c7 cells treated with menadione demonstrated cytotoxicity that was significantly increased with physiological concentrations of NaHCO3 in the media, compared with low levels of NaHCO3. Interestingly, the inhibition of superoxide dismutase (SOD) with 2 different metal chelators was associated with a protective effect against menadione cytotoxicity. Using isolated protein, we found a significant increase in protein carbonyls with menadione-ascorbate-SOD with physiological NaHCO3 levels; low NaHCO3 or SOD-free reactions produced lower levels of protein carbonyls. In conclusion, these findings suggest that the hydrogen peroxide generated by menadione redox cycling together with NaHCO3-CO2 are potential substrates for SOD peroxidase activity that can lead to carbonate-radical enhanced cytotoxicity. These findings demonstrate the importance of NaHCO3 in menadione redox cycling and cytotoxicity. PMID- 24144049 TI - Celiprolol induces beta(3)-adrenoceptors-dependent relaxation in isolated porcine coronary arteries. AB - In porcine coronary arteries (PCAs), celiprolol, a selective beta(1) adrenoceptors antagonist, induces vasodilatation by an endothelium- and nitric oxide (NO)-dependent pathway. However, the mechanisms of that vascular effect have not been precisely established. beta(3)-Adrenoceptors have been shown to be involved in the relaxation per se of various vascular beds, including coronary vessels. Thus, we evaluated (i) the presence of beta(3)-adrenoceptors in the PCA and (ii) their role in celiprolol-induced vasodilatation. PCA rings were placed in organ baths and preconstricted with KCl. All experiments were performed in the presence of nadolol (a beta(1)/beta(2)-adrenoceptor antagonist). Cumulative concentration-response curves to SR 58611A and ICI 215001 (2 beta(3)-adrenoceptor agonists) and to celiprolol were constructed. We also used semiquantitative reverse transcription - polymerase chain reaction, which clearly showed the presence of beta(3)-adrenoceptor transcripts. SR 58611A, ICI 215001, and celiprolol induced concentration-dependent relaxations in PCA rings. SR 58611A induced relaxation was almost abolished after removal of endothelium or pretreatment with L-NAME (a NO synthase inhibitor). The vasorelaxations induced by SR 58611A and celiprolol were inhibited in the presence of SR 59230A and L 748337 (2 selective beta(3)-adrenoceptor antagonists). We showed (i) that PCAs possess functional beta(3)-adrenoceptors mediating endothelium- and NO-dependent relaxation, and (ii) that celiprolol exerts a beta(3)-adrenoceptor agonistic activity in this vascular bed. PMID- 24144050 TI - Investigation of the role of the NO-cGMP pathway on YC-1 and DEA/NO effects on thoracic aorta smooth muscle responses in a rat preeclampsia model. AB - The present study was designed to investigate the effects of YC-1, a nitric oxide (NO)-independent soluble guanylate cyclase (sGC) activator, and DEA/NO, a NO donor, on smooth muscle responses in the preeclampsia model with suramin-treated rats and on the levels of cyclic guanosine monophosphate (cGMP) of thoracic aorta rings isolated from term-pregnant rats. Rats of 2 groups, control group and suramin group, were given intraperitoneal injection of saline or suramin, respectively. Suramin injection caused increased blood pressure, protein in urine, and fetal growth retardation. Thoracic aorta rings were exposed to contractile and relaxant agents. KCl contraction and papaverine relaxation responses were similar. Relaxation responses of YC-1 and DEA/NO decreased in suramin group. In both groups in the presence of ODQ, a sGC inhibitor, the relaxation responses of YC-1 and DEA/NO decreased. The cGMP content was determined by radioimmunoassay technique. The content of cGMP in the suramin group decreased. In the presence of YC-1 and DEA/NO in both groups, cGMP content increased, but in ODQ-added groups, there was a significant decrease. We conclude that in preeclampsia, the decrease of relaxation responses and the decrease of cGMP content could be due to the reduction in stimulation of sGC and the decrease in cGMP levels. PMID- 24144051 TI - Involvement of cardiomyocyte apoptosis in myocardial injury of hereditary epileptic rats. AB - Many clinical cases have been reported where epilepsy profoundly influenced the pathophysiological function of the heart; however, the underlying mechanisms were not elucidated. We use the tremor (TRM) rat as an animal model of epilepsy to investigate the potential mechanisms of myocardial injury. Cardiac functions were assessed by arrhythmia score, heart rate, heart:body mass ratio, and hemodynamic parameters including left ventricular systolic pressure (LVSP), left ventricular end-diastolic pressure (LVEDP), and maximum rate of left ventricular pressure rise and fall (+dp/dtmax and -dp/dtmax). Catecholamine level was detected by HPLC. Apoptotic index was estimated by TUNEL assay. The expressions of Bcl-2, Bax, caspase-3, extracellular signal-regulated protein kinase (ERK), c-Jun NH2 terminal protein kinases (JNK), and p38 were evaluated by Western blot. The results indicated that there existed cardiac dysfunction and cardiomyocyte apoptosis, accompanied by increasing catecholamine levels in TRM rats. Further investigation revealed that apoptosis was mediated by reducing Bcl-2, upregulating Bax, and activating caspase-3. Additional experiments demonstrated that P-ERK1/2 was decreased, whereas P-JNK and P-p38 were up-regulated. Our results suggest that the sympathetic nervous system activation and cardiomyocyte apoptosis are involved in the myocardial injury of TRM rats. The mechanisms of apoptosis might be associated with the activation of the mitochondria-initiated and the mitogen-activated protein kinase pathways. PMID- 24144052 TI - Effects of vegetable oils on biochemical and biophysical properties of membrane retinal pigment epithelium cells. AB - The aim of this study was to investigate the effect of vegetable oil enrichment of retinal pigment epithelial (RPE) cells on their biochemical and biophysical properties. For this, RPE cells were incubated with 4 different vegetables oils (olive oil, corn oil, argan oil, and camelina oil). The cytotoxicity of these vegetable oils was assessed in vivo on 8-week-old mice and in vitro by using the neutral red and YO-PRO-1 tests. Membrane fluidity was evaluated by fluorescence anisotropy using the fluorescent probe diphenylhexatriene, and membrane fatty acid composition was assessed by gas chromatography. None of the oils tested displayed cytotoxic effects. In vitro, omega-3 rich oils improved membrane fluidity by 47% compared with the control cells. The omega-3 PUFA content within membranes decreased by 38% to 55% when cells were incubated separately with olive oil, corn oil, or argan oil, and increased when cells were incubated with a mixture of those oils, or with camelina oil alone (50% and 103% increase, respectively). Our results show that the fatty acids in vegetable oil incorporate into retinal cells and increase the plasma membrane fluidity. PMID- 24144053 TI - Potentiation of antioxidant effect of dietary tender cluster beans (Cyamopsis tetragonoloba) by garlic (Allium sativum) in high-cholesterol-fed rats. AB - The antioxidant role of tender cluster beans (Cyamopsis tetragonoloba, CB), a rich source of soluble fibre, was investigated in a hypercholesterolemia-induced oxidative stress situation in rats. In the context of dietary garlic (Allium sativa) potentiating the hypocholesterolemic influence of CB, we also examined if dietary garlic enhances the antioxidant potential of CB. Groups of Wistar rats were rendered hypercholesterolemic by feeding them a 0.5% cholesterol diet for 8 weeks. Dietary interventions were made by inclusion of 15% tender CB powder or 1% garlic powder or their combination in a high-cholesterol diet. Concentrations of antioxidant molecules and activities of antioxidant enzymes in blood and liver were examined. Dietary CB displayed an antioxidant influence in terms of elevating ascorbic acid and glutathione concentrations and stimulating the activities of antioxidant enzymes both in blood and liver. The antioxidant effect of dietary CB was generally potentiated by co-administration of garlic. Thus, consumption of tender CB and garlic together could form a strategy for improving the body's antioxidant status. PMID- 24144055 TI - Evaluation of a multifunctional staphylokinase variant with thrombin inhibition and antiplatelet aggregation activities produced from salt-inducible E. coli GJ1158. AB - Reocclusion is one of the major root causes for secondary complications that arise during thrombolytic therapy. A multifunctional staphylokinase variant SRH (staphylokinase (SAK) linked with tripeptide RGD and didecapeptide Hirulog) with antiplatelet and antithrombin activities in addition to clot specific thrombolytic function, was developed to address the reocclusion problem. We preferred to use Escherichia coli GJ1158 as the host in this study for economic production of SRH by osmotic (0.3 mol/L sodium chloride) induction, to overcome the problems associated with the yeast expression system. The therapeutic potential of SRH was evaluated in the murine model of vascular thrombosis. The SAK protein (1 mg/kg body mass) and SRH protein (1 mg/kg and 2 mg/kg) were administered intravenously to the different treatment groups. The results have shown a dose-dependent antithrombotic effect in carrageenan-induced mouse tail thrombosis. The thrombin time, activated partial thromboplastin time, and prothrombin time were significantly prolonged (p < 0.05) in the SRH-infused groups. Moreover, SRH inhibited platelet aggregation in a dose-dependent manner (p < 0.05), while the bleeding time was significantly (p < 0.05) prolonged. All of these results inferred that the osmotically produced multifunctional fusion protein SRH (SAK-RGD-Hirulog) is a promising thrombolytic agent, and one which sustained its multifunctionality in the animal models. PMID- 24144054 TI - Aliskiren, exendin-4, and insulin: their impact on endothelin receptor subtype(s) regulation/binding in type 1 diabetic rat hearts. AB - This study focuses on the impact of aliskiren and (or) glucagon-like peptide-1 analogue on the binding affinity/regulation of endothelin-1 (ET-1) to its receptor subtypes A (ETAR) and B (ETBR) at the level of the coronary endothelium and the cardiomyocytes in a type-1 diabetic rat model. Seven groups were used: (i) normal rats, (ii) rats with induced diabetes, (iii) rats with induced diabetes that were treated with insulin, (iv) rats with induced diabetes that were treated with exendin-4, (v) rats with induced diabetes that were treated with aliskiren, (vi) rats with induced diabetes that were co-treated with insulin plus aliskiren, and (vii) rats with induced diabetes that were co-treated with exendin-4 plus aliskiren. Heart perfusion with [(125)I]-ET-1 was employed to estimate ET-1 binding affinity (tau = 1/K-n) to ETAR and ETBR at the level of the coronary endothelium and the cardiomyocytes. Plasma ET-1 levels were measured using enzyme immunoassay, whereas densities of ETAR and ETBR were detected using Western blot. No significance differences were detected in the tau of ETAR and ETBR between normal and diabetic in cardiomyocytes and the coronary endothelium. Exendin-4 normalized the tau value for ETAR and ETBR on coronary endothelium, while aliskiren normalized it on cardiomyocytes. Furthermore, ETAR and ETBR densities were normalized with monotreatments of aliskiren and exendin-4, compared with up-regulated ETAR and down-regulated ETBR band densities in the diabetic animals. Our data indicate that aliskiren alleviates diabetes-associated hypertrophy in type 1 diabetes mellitus. PMID- 24144056 TI - 2-(4-substituted piperazin-1-yl)-1,8-naphthyridine-3-carboxylic acids: novel 5 HT3 receptor antagonists with anxiolytic-like activity in rodent behavioral models. AB - The aim of this study was to investigate the anxiolytic potential of a series of novel carboxylic acid based 1,8 naphthyridines as 5-HT3 receptor antagonists. The pA2 values of all the compounds were determined against agonist 2-methyl-5 hydroxytryptamine in longitudinal muscle myenteric plexus preparations from guinea pig ileum. Compounds with higher pA2 values, particularly those greater than ondansetron, a standard 5-HT3 receptor antagonist, and optimal log P values were screened in mice by using behavioral tests such as a light-dark (L/D) aversion test, elevated plus maze (EPM) test, and an open field test (OFT). In the L/D test, compounds 7a, 7b, 7d, 7e, and 7i (2 mg/kg body mass, intraperitoneal) significantly (P < 0.05) increased the latency time to leave the light compartment, total time spent in the light compartment, and the number of transitions between the light and dark compartments. Compounds 7a, 7d, 7f, 7h, and 7i (2 mg/kg, i.p.) significantly (P < 0.05) increased the time spent in the open arms and the number of entries into the open arms in the EPM test. In addition, compounds 7a, 7d, 7e, 7f, and 7h (2 mg/kg, i.p.) significantly (P < 0.05) increased the ambulation scores and the frequency of rearing in the OFT. PMID- 24144057 TI - Oral supplementation with glycine reduces oxidative stress in patients with metabolic syndrome, improving their systolic blood pressure. AB - Reactive oxygen species derived from abdominal fat and uncontrolled glucose metabolism are contributing factors to both oxidative stress and the development of metabolic syndrome (MetS). This study was designed to evaluate the effects of daily administration of an oral glycine supplement on antioxidant enzymes and lipid peroxidation in MetS patients. The study included 60 volunteers: 30 individuals that were supplemented with glycine (15 g/day) and 30 that were given a placebo for 3 months. We analysed thiobarbituric acid reactive substances (TBARS) and S-nitrosohemoglobin (SNO-Hb) in plasma; the enzymatic activities of glucose-6-phosphate dehydrogenase (G6PD), superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPX) in erythrocytes; and the expression of CAT, GPX, and SOD2 in leukocytes. Individuals treated with glycine showed a 25% decrease in TBARS compared with the placebo-treated group. Furthermore, there was a 20% reduction in SOD-specific activity in the glycine-treated group, which correlated with SOD2 expression. G6PD activity and SNO-Hb levels increased in the glycine-treated male group. Systolic blood pressure (SBP) also showed a significant decrease in the glycine-treated men (p = 0.043). Glycine plays an important role in balancing the redox reactions in the human body, thus protecting against oxidative damage in MetS patients. PMID- 24144058 TI - Glucocorticoids downregulate systemic nitric oxide synthesis and counteract overexpression of hepatic heme oxygenase-1 during endotoxin tolerance. AB - Heme oxygenase (HO)-1 has antioxidant and cytoprotective properties if properly expressed, whereas nitric oxide (NO) impairs tissue perfusion when greatly increased in the blood circulation. Here we hypothesized that the NO and HO-1 systems are altered during lipopolysaccharide (LPS) tolerance, and that glucocorticoids are crucial modulators of systemic NO production and hepatic HO-1 expression during this intriguing phenomenon of cellular reprogramming. Adrenalectomized (ADX) rats with or without administration of dexamethasone (DEX) were challenged with LPS for 3 consecutive days. The plasma levels of corticosterone and nitrate (NOx), and expression of HO-1 protein were assessed. During tolerance, corticosterone levels were elevated, NOx reduced, and HO-1 overexpressed. ADX rats challenged with LPS for 3 consecutive days exhibited a ~9 fold increase in NOx and a ~6-fold increase in HO-1, reverted by DEX. Our findings strongly support the fact that glucocorticoids downregulate systemic NO synthesis and counteract hepatic HO-1 overexpression during LPS tolerance. PMID- 24144059 TI - Application of flexible bronchoscopy in inhalation lung injury. AB - BACKGROUND: As acute inhalational injury is an uncommon presentation to most institutions, a standard approach to its assessment and management, especially using flexible bronchoscopy, has not received significant attention. METHODS: The objective of this study is to evaluate the value of using flexible bronchoscopy as part of the evaluation and management of patients with inhalational lung injury. Twenty-three cases of inhalational lung injury were treated in our three hospitals after a fire in a residential building. The twenty cases that underwent bronchoscopy as part of their management are included in this analysis. After admission, the first bronchoscopy was conducted within 18-72 hours post inhalational injury. G2-level patients were reexamined 24 hours after the first bronchoscopy, while G1-level patients were reexamined 72 hours later. Subsequently, all patients were re-examined every 2-3 days until recovered or until only tunica mucosa bronchi congestion was identified by bronchoscopy. RESULTS: Twenty patients had airway injury diagnosed by bronchoscopy including burns to the larynx and glottis or large airways. Bronchoscopic classification of the inhalation injury was performed, identifying 12 cases of grade G1 changes and 8 cases of grade G2. The airway injury in the 12 cases of grade G1 patients demonstrated recovery in 2-8 days, in the airway injury of the 8 cases of grade G2 patients had a prolonged recovery with airway injury improving in 6-21 days averaged. The difference in recovery time between the two groups was significant (P <0.05). CONCLUSIONS: The use of flexible bronchoscopy has great value in the diagnosis of inhalational injury without any complications. Its use should be incorporated into clinical practice. VIRTUAL SLIDES: The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/1476676925108926. PMID- 24144060 TI - Erythropoietin in amniotic fluid as a potential marker in distinction between growth restricted and constitutionally small fetuses. AB - OBJECTIVE: To determine if there is any difference in amniotic fluid erythropoietin (EPO) concentration between fetuses small for gestational age (SGA) and appropriate for gestational age (AGA), and between the constitutionally small (CSF) and growth-restricted (GRF) fetuses. METHODS: EPO concentrations in the amniotic fluid samples were determined by EpoELISA test in 38 pregnancies with SGA and 15 pregnancies with AGA fetuses. In the SGA group we measured Ponderal index (PI) and skin-fold thickness (SFT). If PI and/or SFT were below 10th percentile the neonate was GRF. If both PI and SFT were above 10th percentile the neonate was CSF. RESULTS: Higher levels of EPO were detected in the SGA in comparison to the AGA fetuses (p < 0.01). EPO concentration was higher in GRF compared to CSF (p < 0.05). The EPO cut-off level between SGA and AGA was 6.81 IU/L (sensitivity 92.3%; specificity 73.3%), and between GRF and CSF was 9.8 IU/L (sensitivity 81%; specificity 80%). CONCLUSION: The preliminary results of this study suggest that amniotic fluid erythropoietin concentration is elevated in growth-restricted fetuses and could potentially be used for distinction between growth restricted and constitutionally small fetuses. Confirmation of these results on a larger group of pregnant women is needed. PMID- 24144061 TI - [Abuse-related adverse drug reactions and abuse deterrent formulations]. PMID- 24144062 TI - Plain poly(acrylic acid) gated organic field-effect transistors on a flexible substrate. AB - We report on the use of a polyanionic proton conductor, poly(acrylic acid), to gate a poly[2,5-bis(3-tetradecylthiophen-2-yl)thieno[3,2-b]thiophene]-based organic field-effect transistor (OFET). A planar configuration of the OFET is evaluated, and the electrical performance and implementation on a flexible substrate are discussed. PMID- 24144064 TI - Wegener granulomatosis-associated optic perineuritis. AB - INTRODUNCTION: We report two patients with optic perineuritis (OPN) and hypertrophic pachymeningitis in Wegener granulomatosis (WG). CASE REPORT: Patient 1: a 74-year-old man developed blurred vision in each eye, sequentially, over a year. In the first episode, visual acuity in the right eye was reduced to no light perception, and in the second episode, the vision in the left eye fell to 20/100. Brain and orbital magnetic resonance imaging (MRI) revealed abnormal enhancement in the meninges and the ipsilateral optic nerve sheath. T2 hyperintense lesions were found along the outer rim of the ipsilateral optic nerve. Seropositive proteinase-3-antineutrophil cytoplasmic antibody (PR3-ANCA), microhematuria and multiple pulmonary nodules suggested the diagnosis of WG. Steroid therapy was initiated 3 months after the first onset, but with no clinical response. At the 2nd episode, rapid administration of steroid ameliorated visual disturbance and MRI lesions markedly. Patient 2: a 72-year-old man developed blurred vision in each eye. Visual acuity measured no light perception in OD and 6/12 in OS. Gadolinium-enhanced MRI disclosed enhancement in the meninges and both optic nerve sheaths. T2-weighted imaging displayed hyperintense lesions along the outer rims of optic nerves. Otolaryngologic examination, seropositive PR3-ANCA and pulmonary nodules supported the diagnosis of WG. Steroid and cyclophosphamide treatment improved visual dysfunction and MRI lesions in the meninges and the optic nerve sheaths. COMMENT: The morphological similarity and the anatomical continuity between the meningeal and the perioptic tissues suggest that extension of granulomatous inflammation along such tissue planes accounted for visual loss in these two patients with WG. PMID- 24144063 TI - Lipidated cyclic gamma-AApeptides display both antimicrobial and anti inflammatory activity. AB - Antimicrobial peptides (AMPs) are host-defense agents capable of both bacterial membrane disruption and immunomodulation. However, the development of natural AMPs as potential therapeutics is hampered by their moderate activity and susceptibility to protease degradation. Herein we report lipidated cyclic gamma AApeptides that have potent antibacterial activity against clinically relevant Gram-positive and Gram-negative bacteria, many of which are resistant to conventional antibiotics. We show that lipidated cyclic gamma-AApeptides mimic the bactericidal mechanism of AMPs by disrupting bacterial membranes. Interestingly, they also harness the immune response and inhibit lipopolysaccharide (LPS) activated Toll-like receptor 4 (TLR4) signaling, suggesting that lipidated cyclic gamma-AApeptides have dual roles as novel antimicrobial and anti-inflammatory agents. PMID- 24144065 TI - Impact of training of teachers on their ability, skills, and confidence to teach HIV/AIDS in classroom: a qualitative assessment. AB - BACKGROUND: Considering the significant impact of school-based HIV/AIDS education, in 2007, a curriculum on HIV/AIDS was incorporated in the national curriculum for high school students of Bangladesh through the Government's HIV prevention program. Based on the curriculum, an intervention was designed to train teachers responsible for teaching HIV/AIDS in classes. METHODS: In-depth interviews were conducted with teachers to understand their ability, skills, and confidence in conducting HIV/AIDS classes. Focus-group discussions (FGDs) were conducted with students who participated in HIV/AIDS classes. HIV/AIDS classes were also observed in randomly-selected schools. Thematic assessment was made to analyze data. RESULTS: The findings showed that the trained teachers were more comfortable in using interactive teaching methods and in explaining sensitive issues to their students in HIV/AIDS classes. They were also competent in using interactive teaching methods and could ensure the participation of students in HIV/AIDS classes. CONCLUSIONS: The findings suggest that cascading training may be scaled up as it helped increase ability, skills, and confidence of teachers to successfully conduct HIV/AIDS classes. PMID- 24144066 TI - Apraxia - the cognitive side of motor control. PMID- 24144067 TI - Template-stripped asymmetric metallic pyramids for tunable plasmonic nanofocusing. AB - We demonstrate a novel scheme for plasmonic nanofocusing with internally illuminated asymmetric metallic pyramidal tips using linearly polarized light. A wafer-scale array of sharp metallic pyramids is fabricated via template stripping with films of different thicknesses on opposing pyramid facets. This structural asymmetry is achieved through a one-step angled metal deposition that does not require any additional lithography processing and when internally illuminated enables the generation of plasmons using a Kretschmann-like coupling method on only one side of the pyramids. Plasmons traveling toward the tip on one side will converge at the apex, forming a nanoscale "hotspot." The asymmetry is necessary for these focusing effects since symmetric pyramids display destructive plasmon interference at the tip. Computer simulations confirm that internal illumination with linearly polarized light at normal incidence on these asymmetric pyramids will focus optical energy into nanoscale volumes. Far-field optical experiments demonstrate large field enhancements as well as angle-dependent spectral tuning of the reradiated light. Because of the low background light levels, wafer-scale fabrication, and a straightforward excitation scheme, these asymmetric pyramidal tips will find applications in near-field optical microscopy and array-based optical trapping. PMID- 24144068 TI - A palladium-catalyzed carbonylation approach to acid chloride synthesis. AB - We describe a new approach to acid chloride synthesis via the palladium-catalyzed carbonylation of aryl iodides. The combination of sterically encumbered phosphines (P(t)Bu3) and CO coordination has been found to facilitate the rapid carbonylation of aryl iodides into acid chlorides via reductive elimination from ((t)Bu3P)(CO)Pd(COAr)Cl. The formation of acid chlorides can also be exploited to perform traditional aminocarbonylation reactions under exceptionally mild conditions (ambient temperature and pressure), and with a range of weakly nucleophilic substrates. PMID- 24144070 TI - ... And "b" is for "balance". PMID- 24144071 TI - What are standardized clinical assessment and management plans? PMID- 24144069 TI - Lanthanide-based imaging of protein-protein interactions in live cells. AB - In order to deduce the molecular mechanisms of biological function, it is necessary to monitor changes in the subcellular location, activation, and interaction of proteins within living cells in real time. Forster resonance energy-transfer (FRET)-based biosensors that incorporate genetically encoded, fluorescent proteins permit high spatial resolution imaging of protein-protein interactions or protein conformational dynamics. However, a nonspecific fluorescence background often obscures small FRET signal changes, and intensity based biosensor measurements require careful interpretation and several control experiments. These problems can be overcome by using lanthanide [Tb(III) or Eu(III)] complexes as donors and green fluorescent protein (GFP) or other conventional fluorophores as acceptors. Essential features of this approach are the long-lifetime (approximately milliseconds) luminescence of Tb(III) complexes and time-gated luminescence microscopy. This allows pulsed excitation, followed by a brief delay, which eliminates nonspecific fluorescence before the detection of Tb(III)-to-GFP emission. The challenges of intracellular delivery, selective protein labeling, and time-gated imaging of lanthanide luminescence are presented, and recent efforts to investigate the cellular uptake of lanthanide probes are reviewed. Data are presented showing that conjugation to arginine rich, cell-penetrating peptides (CPPs) can be used as a general strategy for the cellular delivery of membrane-impermeable lanthanide complexes. A heterodimer of a luminescent Tb(III) complex, Lumi4, linked to trimethoprim and conjugated to nonaarginine via a reducible disulfide linker rapidly (~10 min) translocates into the cytoplasm of Maden Darby canine kidney cells from the culture medium. With this reagent, the intracellular interaction between GFP fused to FK506 binding protein 12 (GFP-FKBP12) and the rapamycin binding domain of mTOR fused to Escherichia coli dihydrofolate reductase (FRB-eDHFR) were imaged at high signal to-noise ratio with fast (1-3 s) image acquisition using a time-gated luminescence microscope. The data reviewed and presented here show that lanthanide biosensors enable fast, sensitive, and technically simple imaging of protein-protein interactions in live cells. PMID- 24144072 TI - Academy policy strategies to prevent type 2 diabetes. PMID- 24144074 TI - Perceived benefits and challenges for low-income mothers of having family meals with preschool-aged children: childhood memories matter. AB - Eating regular family meals is associated with a lower risk of obesity among preschool-aged children. Children in lower-income households are at higher risk for obesity, but there is little information about their mothers' perceptions of family meals, and such information could improve nutrition counseling. To identify the perceived benefits and challenges of having family meals, four focus groups were conducted with 20 mothers of preschool-aged children living in low income households in Philadelphia, PA. Three authors independently analyzed verbatim transcripts using an inductive method of open coding, and themes were established by consensus among all authors. Of the 20 mothers, 18 were black, 11 had education beyond high school, and 12 were living with an adult partner or husband. Mothers' strong childhood memories of mealtimes, both negative and positive, motivated them to have family meals because of the opportunities afforded by mealtimes to build strong relationships with their children. However, mothers also described needing help, especially from other household adults, in preparing meals and establishing calm and order with their children during mealtimes. To identify what motivates the mothers of low-income, preschool-aged children to have family meals, registered dietitians can benefit from asking about the mothers' own childhood experiences of family meals. Studies are needed to examine whether such an approach to identifying maternal motivations, when combined with practical advice about overcoming challenges with meal preparation and managing children's mealtime behavior, could lead to more frequent and nutritious family meals in this population. PMID- 24144075 TI - Cholesterol-lowering efficacy of plant sterols/stanols provided in capsule and tablet formats: results of a systematic review and meta-analysis. AB - Plant sterols/stanols-enriched foods possess well-documented low-density lipoprotein (LDL)-cholesterol-lowering effect. However, the relative efficacy of plant sterols/stanols as supplements (tablets/capsules) compared with other dietary forms still needs to be determined. Our aim was to precisely identify and quantify the LDL-cholesterol-lowering effect of plant sterols/stanols as supplements in contrast to food-based approaches. Eight eligible clinical trials published from January 1992 to April 2013 were identified from five databases. A random effect model was used to calculate weighted mean effect sizes for net differences in LDL-cholesterol concentrations. Among the included trials with the duration between 4 and 6 weeks, plant sterol/stanol dose ranged from 1.0 to 3.0 g/day administrated mainly with the main meals (2 or 3 times/day). Intake of plant sterol/stanol supplements decreased LDL-cholesterol concentrations by 12 mg/dL (0.31 mmol/L) (95% CI -0.39 to -0.23; P<0.000) compared with placebo. The test of heterogeneity was not significant (chi(2) , P=0.50, I(2)=0%). Further analysis showed no significant difference between the LDL-cholesterol-lowering action of plant sterols/stanols supplements (-12 mg/dL [-0.31 mmol/L]; 95% CI 0.39 to -0.24; P<0.0001) vs foods enriched with plant sterols/stanols (-12 mg/dL [-0.31 mmol/L]; 95% CI -0.35 to -0.27; P<0.0001). Plant sterol/stanol supplements as part of a healthy diet represent an effective means of delivering LDL cholesterol-lowering similar to plant sterols/stanols delivered in various food formats. PMID- 24144073 TI - Predictors of sustained reduction in energy and fat intake in the Diabetes Prevention Program Outcomes Study intensive lifestyle intervention. AB - BACKGROUND: Few lifestyle intervention studies examine long-term sustainability of dietary changes. OBJECTIVE: To describe sustainability of dietary changes over 9 years in the Diabetes Prevention Program and its outcomes study, the Diabetes Prevention Program Outcomes Study, among participants receiving the intensive lifestyle intervention. DESIGN: One thousand seventy-nine participants were enrolled in the intensive lifestyle intervention arm of the Diabetes Prevention Program; 910 continued participation in the Diabetes Prevention Program Outcomes Study. Fat and energy intake derived from food frequency questionnaires at baseline and post-randomization Years 1 and 9 were examined. Parsimonious models determined whether baseline characteristics and intensive lifestyle intervention session participation predicted sustainability. RESULTS: Self-reported energy intake was reduced from a median of 1,876 kcal/day (interquartile range [IQR]=1,452 to 2,549 kcal/day) at baseline to 1,520 kcal/day (IQR=1,192 to 1,986 kcal/day) at Year 1, and 1,560 kcal/day (IQR=1,223 to 2,026 kcal/day) at Year 9. Dietary fat was reduced from a median of 70.4 g (IQR=49.3 to 102.5 g) to 45 g (IQR=32.2 to 63.8 g) at Year 1 and increased to 61.0 g (IQR=44.6 to 82.7 g) at Year 9. Percent energy from fat was reduced from a median of 34.4% (IQR=29.6% to 38.5%) to 27.1% (IQR=23.1% to 31.5%) at Year 1 but increased to 35.3% (IQR=29.7% to 40.2%) at Year 9. Lower baseline energy intake and Year 1 dietary reduction predicted lower energy and fat gram intake at Year 9. Higher leisure physical activity predicted lower fat gram intake but not energy intake. CONCLUSIONS: Intensive lifestyle intervention can result in reductions in total energy intake for up to 9 years. Initial success in achieving reductions in fat and energy intake and success in attaining activity goals appear to predict long-term success at maintaining changes. PMID- 24144076 TI - The impact of social media on business and ethical practices in dietetics. PMID- 24144077 TI - What's the latest on holiday weight gain? PMID- 24144078 TI - Hydration patterns of graphene-based nanomaterials (GBNMs) play a major role in the stability of a helical protein: a molecular dynamics simulation study. AB - Graphene-based nanomaterials (GBNMs) [graphene oxide (GO), reduced graphene oxide (rGO), and graphene] have been recognized as potential candidates for various biomedical applications ranging from biosensing platform to cellular delivery of proteins and peptides. However, GBNMs induced conformational changes in proteins are the major concerns in realizing their full potential in aforementioned applications. Despite several studies, the effect of GBNMs on the conformation of proteins is still not well understood. Therefore, an attempt was made to investigate the effect of GBNMs on the adsorption and conformation of positively charged cytoplasmic protein using molecular dynamics (MD) simulations. Our study showed that the adsorption of protein on GO was highly selective and mediated through electrostatic interactions (hydrogen bond/salt bridge interactions), whereas the van der Waals and pi-pi stacking interactions were the major driving forces for the adsorption of protein on rGO and graphene. The secondary structure analysis showed the conformational stability of the protein on GO may be attributed to the extensive hydration of GO surface and the absence of tyrosine residues in pi-pi stacking with pi regions of GO. The GO surface acts as a hydrogen bond acceptor similar to the protein's natural receptor present in a physiological environment. This computational study has also explored the artificial protein receptor like potential of GO. PMID- 24144079 TI - Palladium-catalyzed synthesis of 3-acylated indoles involving oxidative cross coupling of indoles with alpha-amino carbonyl compounds. AB - A new and selective C-N bond oxidative cleavage method to 3-acylated indoles by Pd-catalyzed oxidative cross coupling of indoles with alpha-amino carbonyl compounds has been developed; moreover, one-pot synthesis of 3-acylated indoles from 2-ethynylanilines and alpha-amino carbonyl compounds has also been established. Importantly, the products 3-acylated indoles can be used to construct polyheterocyclic compound, which can be employed as efficient probes for Hg(2+) and Fe(3+). PMID- 24144080 TI - Efficient reaction based colorimetric probe for sensitive detection, quantification, and on-site analysis of nitrite ions in natural water resources. AB - We have developed a novel aza-BODIPY probe for the sensitive colorimetric detection of the nitrite ions in the aqueous medium by a simple and direct method. This probe selectively recognizes the nitrite ions through a distinct visual color change from bright blue to intense green with a sensitivity of 20 ppb. Uniquely, this probe can be coated on a glass surface to fabricate a simple solid-state dipstick device that can be used for the visual detection of the nitrite ions in the presence of other competing anions in distilled as well as natural water resources like a sea, lake, and river. Furthermore, this probe can be used for the sensitive detection of the nitrate ions when coupled to a reduction step. Our results demonstrate that this probe not only can be used for the on-site analysis and quantification but also can replace the conventional spot test carried out for the nitrite ions in the laboratory practical experiments. PMID- 24144081 TI - Bioactive metabolites isolated from Penicillium sp. YY-20, the endophytic fungus from Ginkgo biloba. AB - Six known metabolites, adenosine (1), methyl beta-D-ribofuranoside (2), adenine (3), 2'-deoxyadenosine (4), 3-methylpiperazine-2,5-dione (5) and 2'-deoxyuridine (6), were isolated from the extracts of the endophytic fungus Penicillium sp. YY 20 isolated from the root of Ginkgo biloba, and their structures were elucidated by spectroscopic methods. The antioxidant and growth-promoting activities of these compounds were first evaluated. The results indicated that compounds 1, 3 and 4 exhibited potential DPPH-scavenging activities compared with positive control. In addition, all the compounds (except 5) stimulated seed germination of Raphanus sativus, Brassica napus and Brassica chinensis but had weak stimulating effect on their root and hypocotyl growth. PMID- 24144082 TI - Comprehensive analysis of expressed sequence tags from cultivated and wild radish (Raphanus spp.). AB - BACKGROUND: Radish (Raphanus sativus L., 2n = 2* = 18) is an economically important vegetable crop worldwide. A large collection of radish expressed sequence tags (ESTs) has been generated but remains largely uncharacterized. RESULTS: In this study, approximately 315,000 ESTs derived from 22 Raphanus cDNA libraries from 18 different genotypes were analyzed, for the purpose of gene and marker discovery and to evaluate large-scale genome duplication and phylogenetic relationships among Raphanus spp. The ESTs were assembled into 85,083 unigenes, of which 90%, 65%, 89% and 89% had homologous sequences in the GenBank nr, SwissProt, TrEMBL and Arabidopsis protein databases, respectively. A total of 66,194 (78%) could be assigned at least one gene ontology (GO) term. Comparative analysis identified 5,595 gene families unique to radish that were significantly enriched with genes related to small molecule metabolism, as well as 12,899 specific to the Brassicaceae that were enriched with genes related to seed oil body biogenesis and responses to phytohormones. The analysis further indicated that the divergence of radish and Brassica rapa occurred approximately 8.9-14.9 million years ago (MYA), following a whole-genome duplication event (12.8-21.4 MYA) in their common ancestor. An additional whole-genome duplication event in radish occurred at 5.1-8.4 MYA, after its divergence from B. rapa. A total of 13,570 simple sequence repeats (SSRs) and 28,758 high-quality single nucleotide polymorphisms (SNPs) were also identified. Using a subset of SNPs, the phylogenetic relationships of eight different accessions of Raphanus was inferred. CONCLUSION: Comprehensive analysis of radish ESTs provided new insights into radish genome evolution and the phylogenetic relationships of different radish accessions. Moreover, the radish EST sequences and the associated SSR and SNP markers described in this study represent a valuable resource for radish functional genomics studies and breeding. PMID- 24144083 TI - Ovarian HMW adiponectin is associated with folliculogenesis in women with polycystic ovary syndrome. AB - BACKGROUND: Adiponectin may regulate ovarian steroidogenesis, folliculogenesis and ovulation. The alterations in the distribution of adiponectin multimers in follicular fluid (FF) and the relationship between adiponectin multimers and folliculogenesis in women with polycystic ovary syndrome (PCOS) remain unclear. In this study, we aimed to investigate the association between the levels of total and high molecular weight (HMW) adiponectin in serum and FF and folliculogenesis in women undergoing in vitro fertilisation (IVF). METHODS: This prospective study included ten Chinese women with PCOS and ten controls undergoing IVF. The levels of the total and HMW adiponectin in serum and FF were determined by ELISA. Insulin resistance (IR) was estimated using the homeostasis model assessment insulin resistance index (HOMA-IR). RESULTS: After controlling for the body mass index (BMI), the levels of the total, and the HMW adiponectin in the serum and FF were significantly lower in the women with PCOS compared with the normovulatory women undergoing IVF (P < 0.05). The levels of the HMW adiponectin were significantly lower in the FF than in the serum (P < 0.01). No significant differences were found in the total adiponectin levels in the serum and in the FF (P > 0.05). Decreased HMW adiponectin in the FF was associated with an increased number of follicles and decreased follicular diameters in the normovulatory and PCOS women, and this association was independent of the overall adiposity. A strong positive linear correlation was observed between the number of the follicles and the IR estimated by HOMA-IR (r = 0.784, P < 0.0001). We found that the larger follicular diameters had a negative relationship with the IR estimated by HOMA-IR (r = -0.445, P < 0.05). A strong negative linear correlation was observed between HOMA-IR and the HMW adiponectin levels (r = 0.726, P < 0.001) and the total adiponectin levels (r = -0.759, P < 0.001) in the FF. CONCLUSIONS: The levels of the total adiponectin and the HMW adiponectin in the FF and serum were decreased in the Chinese women with PCOS compared with the normovulatory women undergoing IVF, and the differences persisted after controlling for the BMI. Ovarian HMW adiponectin is negatively correlated to folliculogenesis. PMID- 24144084 TI - Quality of blood culture testing - a survey in intensive care units and microbiological laboratories across four European countries. AB - INTRODUCTION: Blood culture (BC) testing before initiation of antimicrobial therapy is recommended as a standard of care in international sepsis guidelines and has been shown to reduce intensive care unit (ICU) stay, antibiotic use, and costs in hospitalized patients. Whereas microbiological laboratory practice has been highly standardized, shortfalls in the preanalytic procedures in the ICU (that is indication, time-to-incubation, blood volume and numbers of BC sets) have a significant effect on the diagnostic yield. The objective of this study was to gain insights into current practices regarding BC testing in intensive care units. METHODS: Qualitative survey, data collection by 138 semi-structured telephone interviews in four European countries (Italy, UK, France and Germany) between September and November 2009 in 79 clinical microbiology laboratories (LABs) and 59 ICUs. RESULTS: Whereas BC testing is expected to remain the gold standard for sepsis diagnostics in all countries, there are substantial differences regarding preanalytic procedures. The decision to launch BC testing is carried out by physicians vs. ICU nurses in the UK in 92 vs. 8%, in France in 75 vs. 25%, in Italy in 88 vs. 12% and in Germany in 92 vs. 8%. Physicians vs. nurses collect BCs in the UK in 77 vs. 23%, in France in 0 vs. 100%, in Italy in 6 vs. 94% and in Germany in 54 vs. 46%. The mean time from blood collection to incubation in the UK is 2 h, in France 3 h, in Italy 4 h, but 20 h in German remote LABs (2 h in in-house LABs), due to the large number of remote nonresident microbiological laboratories in Germany. There were major differences between the perception of the quality of BC testing between ICUs and LABs. Among German ICU respondents, 62% reported that they have no problems with BC testing, 15% reported time constraints, 15% cost pressure, and only 8% too long time to incubation. However, the corresponding LABs of these German ICUs reported too many false positive results due to preanalytical contaminations (49%), insufficient numbers of incoming BC sets (47%), long transportation time (41%) or cost pressure (18%). CONCLUSIONS: There are considerable differences in the quality of BC testing across European countries. In Germany, time to incubation is a considerable problem due to the increasing number of remote LABs. This is a major issue of concern to physicians aiming to implement sepsis guidelines in the ICUs. PMID- 24144085 TI - Clinical approach to advanced renal function testing in dogs and cats. AB - Serum creatinine concentration is insensitive for detecting kidney injury and does not assist in differentiation between glomerular versus tubular damage. Advanced renal function tests, including glomerular filtration rate testing, determining fractional excretion of electrolytes, and assay of urine biomarkers, may allow earlier detection of reduced renal function mass, differentiation of renal from non-renal causes of azotemia, and assist with localization of damage. This article reviews the principles, indications, and limitations of these tests and describes their use in sample clinical scenarios. PMID- 24144086 TI - A laboratory diagnostic approach to hepatobiliary disease in small animals. AB - Routine biochemical tests generally include serum enzymes, proteins, and other markers useful for identifying hepatobiliary disease in dogs and cats. Obtaining results outside the reference intervals can occur with direct hepatocellular injury, enzyme induction by hepatocytes or biliary epithelium, or decreased hepatic function. However, detection of biochemical abnormalities does not necessarily indicate clinically significant disease. For a comprehensive approach to detection and treatment of hepatobiliary disease, the laboratory results must be correlated with the history and physical examination findings, diagnostic imaging results, and other assays. PMID- 24144087 TI - Diagnosis of small intestinal disorders in dogs and cats. AB - Laboratory tests are an important part of the workup of small intestinal diseases in dogs and cats. Especially in chronic cases, when extragastrointestinal causes need to be ruled out, it is important to adhere to a systematic workup. This article details the newest available data on tests to aid this diagnostic process. Once the diagnosis of a chronic enteropathy is made, there are many laboratory tests that can help in monitoring the disease and providing prognostic information. Several new tests being evaluated for clinical usefulness are discussed. PMID- 24144088 TI - Practical interpretation and application of exocrine pancreatic testing in small animals. AB - The pancreas remains a difficult organ to evaluate using laboratory methods alone. No single laboratory test is diagnostic of pancreatitis (chronic or acute) without other diagnostic modalities concurring with the diagnosis or ruling out other diseases. The diagnosis of pancreatitis is particularly difficult in cats, and pancreatitis often occurs with other diseases. The use of pancreatic cytology may be useful in diagnosing both inflammation and neoplasia. Exocrine pancreatic insufficiency (EPI) can be relatively easily diagnosed when clinically manifested by the measurement of trypsinlike immunoreactivity. Diagnosis is more difficult when EPI is subclinical. PMID- 24144089 TI - Using cardiac biomarkers in veterinary practice. AB - Blood-based assays for various cardiac biomarkers can assist in the diagnosis of heart disease in dogs and cats. The two most common markers are cardiac troponin I and N-terminal pro-B-type natriuretic peptide. Biomarker assays can assist in differentiating cardiac from noncardiac causes of respiratory signs and detection of preclinical cardiomyopathy. Increasingly, studies indicate that cardiac biomarker testing can help assess the risk of morbidity and mortality in animals with heart disease. Usage of cardiac biomarker testing in clinical practice relies on proper patient selection, correct interpretation of test results, and incorporation of biomarker testing into existing diagnostic methods. PMID- 24144090 TI - Practical acid-base in veterinary patients. AB - Acid-base abnormalities are common in critically ill veterinary patients. Rapid recognition of disturbances can be helpful in identifying the underlying cause of the patient's clinical signs, directing diagnostics, and monitoring response to therapy. If acid-base disturbances are left unidentified and untreated, severe physiologic consequences can result, including cardiovascular and neurologic dysfunction, protein and enzyme dysfunction, and electrolyte derangements. Treatment of acid-base disorders is aimed at correcting the underlying disease process. PMID- 24144091 TI - Use of lactate in small animal clinical practice. AB - Lactate is a product of anaerobic metabolism. Lactate concentration in blood is used clinically as an indicator of tissue hypoperfusion and hypoxia to determine disease severity, assess response to therapy, and predict outcome. This article reviews lactate physiology, sample collection and processing, and interpretation of lactate concentration in clinical practice. PMID- 24144092 TI - Hypocalcemia of critical illness in dogs and cats. AB - Hypocalcemia occurs in critically ill dogs and cats and is associated with medications, treatments, and underlying diseases such as acute kidney disease, pancreatitis, parathyroid disease, sepsis, and trauma. Possible underlying mechanisms include hypovitaminosis D, acquired or relative hypoparathyroidism, hypomagnesemia, and alterations in the ionized fraction of calcium caused by changes in chelated or protein-bound calcium. If severe or acute, hypocalcemia can cause obvious clinical signs related to muscle or neurologic hyperexcitability or more subtle signs of cardiovascular dysfunction. Emergency treatment with calcium gluconate administration is recommended when clinical signs are present or if there is moderate to severe ionized hypocalcemia. PMID- 24144093 TI - Diagnosis of disorders of iron metabolism in dogs and cats. AB - Iron is an essential element and is used by every cell in the body. This article summarizes iron metabolism and disorders associated with iron metabolism in dogs and cats. The diagnostic tests currently in use for assessing iron status are discussed. PMID- 24144094 TI - Making sense of lymphoma diagnostics in small animal patients. AB - This article summarizes and compares the various assays available to aid in the diagnosis and characterization of lymphoma in small animal patients. These techniques include cytology, histopathology, immunocytochemistry and immunohistochemistry, immunophenotyping by flow cytometry, and polymerase chain reaction for clonal antigen receptor gene rearrangement. PMID- 24144095 TI - Current diagnostic trends in coagulation disorders among dogs and cats. AB - The diagnostic workup to differentiate hemorrhage caused by vascular injury from a systemic hemostatic imbalance typically involves a combination of broad screening tests and specific assays. The characterization of 3 overlapping phases of primary hemostasis, secondary hemostasis, and fibrinolysis provides a simple diagnostic framework for evaluating patients with clinical signs of hemorrhage. New techniques such as flow cytometry, thrombin-generation assays, thrombelastography, and anticoagulant drug monitoring are under investigation for veterinary patients; however, their ability to improve diagnosis or treatment requires further study in clinical trials. PMID- 24144096 TI - Molecular diagnostics for infectious disease in small animal medicine: an overview from the laboratory. AB - Molecular diagnostic tests have augmented the way in which veterinary practitioners approach the diagnosis of infectious disease. The technical bases of these tests are explained in addition to the general clinical applications for which they are most aptly suited, as individual assays are best discussed in the context of their respective diseases. In this article, an emphasis is placed on validation of molecular tests so that practitioners can be educated consumers of molecular diagnostics. The relationships between disease prevalence and positive and negative predictive values are discussed. Finally, examples of the pitfalls of multiplex polymerase chain reaction testing are illustrated. PMID- 24144097 TI - Using cytology to increase small animal practice revenue. AB - Diagnostic cytology is a useful, noninvasive test with practical foundations in high-quality medicine and applications to practice building. Cytology will generate practice revenue whether assessed in-house or sent to a clinical pathologist. Thorough in-house evaluation is adequate in some cases, but expert opinion is important in many cases. Specimen slides should at least be reviewed in-house for assessment of cellularity and potential artifacts before submission to a reference laboratory. Reference laboratories also provide special stains and advanced molecular diagnostics to help further characterize many neoplastic processes, search for organisms, identify pigments, and address other important aspects of the lesion. PMID- 24144098 TI - Clinical pathology and diagnostic testing. PMID- 24144099 TI - In vivo fast equilibrium microextraction by stable and biocompatible nanofiber membrane sandwiched in microfluidic device. AB - In vivo analysis poses higher requirements about the biocompatibility, selectivity and speed of analytical method. In this study, an in vivo fast equilibrium microextraction method was developed with a biocompatible core-sheath electrospun nanofiber membrane sandwiched within a microfluidic unit. The polystyrene/collagen core-sheath nanofiber membrane was coaxially electrospun and strengthened with in situ glutaraldehyde cross-linking. This membrane not only kept high mass transfer rate, large extraction capacity and biomatrix resistance as our previously proposed membrane (Anal. Chem. 2013, 85 (12), 5924-5932), but also got much better mechanical strength and stability in water. The microfluidic device was designed to sandwich the membrane, and the blood in vivo can be introduced into it and get contact with the membrane repetitively. With this membrane and device, a 2-min equilibrium in vivo extraction method was established, validated in a simulated blood circulation system, and was used to monitor the pharmacokinetic profiles of desipramine in rabbits. The free and total concentration of desipramine in vivo was monitored with 10-min interval almost without rabbit blood consumed. The results met well with those of in vitro extraction, and a correlation factor of 0.99 was obtained. PMID- 24144101 TI - The high prevalence of metabolic syndrome in polymyositis. AB - OBJECTIVES: Metabolic syndrome (MetS) is a cluster of metabolic abnormalities that are associated with increased cardiovascular diseases (CVD). MetS has been systematically evaluated in all systemic autoimmune rheumatic diseases except for polymyositis (PM). This study aimed to evaluate the frequency of MetS in PM patients and analyse the possible association of MetS with traditional risk factors of CVD and PM-related clinical and laboratory features. METHODS: The present cross-sectional, single-centre study included 35 consecutive PM patients (Bohan and Peter, 1975) and 70 healthy controls. MetS diagnosis was determined according to the National Cholesterol Education Program Adult Treatment Panel III (NCEP ATPIII). RESULTS: The age, gender and ethnicity distributions between the PM and control groups were comparable (p>0.050). The median PM disease duration was 5 years. Compared with healthy subjects, PM patients had higher prevalence of MetS (45.7% vs. 20.0%, p=0.011). In an additional univariate analysis of PM patients with (n=26) and without (n=19) MetS revealed that patients with this complication were older (56.1+/-7.8 vs. 44.3+/-12.8 years; p=0.002) with more cumulative prednisolone doses, higher scores on the health assessment questionnaire and on the physician visual analogue scale (p<0.050). Disease duration was comparable between both groups (p>0.050). CONCLUSIONS: MetS and CVD risks are highly prevalent in PM. Monitoring for and early treatments of modifiable risk factors for CVD in PM patients are necessary. PMID- 24144102 TI - Predictions of BuChE inhibitors using support vector machine and naive Bayesian classification techniques in drug discovery. AB - Butyrylcholinesterase (BuChE, EC 3.1.1.8) is an important pharmacological target for Alzheimer's disease (AD) treatment. However, the currently available BuChE inhibitor screening assays are expensive, labor-intensive, and compound dependent. It is necessary to develop robust in silico methods to predict the activities of BuChE inhibitors for the lead identification. In this investigation, support vector machine (SVM) models and naive Bayesian models were built to discriminate BuChE inhibitors (BuChEIs) from the noninhibitors. Each molecule was initially represented in 1870 structural descriptors (1235 from ADRIANA.Code, 334 from MOE, and 301 from Discovery studio). Correlation analysis and stepwise variable selection method were applied to figure out activity related descriptors for prediction models. Additionally, structural fingerprint descriptors were added to improve the predictive ability of models, which were measured by cross-validation, a test set validation with 1001 compounds and an external test set validation with 317 diverse chemicals. The best two models gave Matthews correlation coefficient of 0.9551 and 0.9550 for the test set and 0.9132 and 0.9221 for the external test set. To demonstrate the practical applicability of the models in virtual screening, we screened an in-house data set with 3601 compounds, and 30 compounds were selected for further bioactivity assay. The assay results showed that 10 out of 30 compounds exerted significant BuChE inhibitory activities with IC50 values ranging from 0.32 to 22.22 MUM, at which three new scaffolds as BuChE inhibitors were identified for the first time. To our best knowledge, this is the first report on BuChE inhibitors using machine learning approaches. The models generated from SVM and naive Bayesian approaches successfully predicted BuChE inhibitors. The study proved the feasibility of a new method for predicting bioactivities of ligands and discovering novel lead compounds. PMID- 24144103 TI - Mechanisms of growth of a pulmonary capillary network in adult lung. AB - The present study provides new insight into structural processes remodeling pulmonary capillaries in adult lung. The data highlight mechanisms underlying the expansion and increased density of capillary segments on return to air breathing (FiO2 0.21) after injury in high oxygen (FiO2 0.75). As segments expand and increase in number, endothelial cells extend their processes to bridge the lumen and support the walls of developing interluminal structures (ILSs); endothelial epithelial surfaces infold as a single unit (sheet) into the lumen, increasing the length of each surface and subdividing segments by loop formation and by the formation of ILSs; segments further increase in number as lumen subdivision proceeds by intussusceptive microvascular growth (IMG). PMID- 24144104 TI - Secondary organic aerosol formation from photo-oxidation of unburned fuel: experimental results and implications for aerosol formation from combustion emissions. AB - We conducted photo-oxidation experiments in a smog chamber to investigate secondary organic aerosol (SOA) formation from eleven different unburned fuels: commercial gasoline, three types of jet fuel, and seven different diesel fuels. The goals were to investigate the influence of fuel composition on SOA formation and to compare SOA production from unburned fuel to that from diluted exhaust. The trends in SOA production were largely consistent with differences in carbon number and molecular structure of the fuel, i.e., fuels with higher carbon numbers and/or more aromatics formed more SOA than fuels with lower carbon numbers and/or substituted alkanes. However, SOA production from different diesel fuels did not depend strongly on aromatic content, highlighting the important contribution of large alkanes to SOA formation from mixtures of high carbon number (lower volatility) precursors. In comparison to diesels, SOA production from higher volatility fuels such as gasoline appeared to be more sensitive to aromatic content. On the basis of a comparison of SOA mass yields (SOA mass formed per mass of fuel reacted) and SOA composition (as measured by an aerosol mass spectrometer) from unburned fuels and diluted exhaust, unburned fuels may be reasonable surrogates for emissions from uncontrolled engines but not for emissions from engines with after treatment devices such as catalytic converters. PMID- 24144105 TI - Hyaluronic acid-silica nanohybrid gels. AB - Excessive water sorption and low mechanical properties are a severe drawback in some biomedical applications of hyaluronic acid (HA). A way to improve these properties is here explored through the novel concept of nanohybrid hydrogels consisting of a HA matrix including different amounts of silica-derived species. This inorganic filler phase controls the mechanical and swelling properties of HA cross-linked matrices. Below a 2 wt % of silica in the systems, nanoparticle aggregates of tens of nanometers and silica oligomers are distributed more or less homogeneously throughout the organic matrix, without percolating. This morphology of the silica phase is accompanied by an increased swelling degree of the composite when compared with pure HA. For higher silica mass ratios in the composites the inorganic counterpart coalesces, leading to a continuous inorganic silica network interpenetrated with the organic HA network, which coexists with a dispersed phase of silica-nanoparticle aggregates. Silica oligomers originating in the exposition of the nanoparticles to reactives during the composite preparation procedure contribute to the continuity of the silica network. For these compositions, swelling is reduced three times when compared with pure HA, and a significant improvement of the mechanical properties occurs. Water containing samples of these materials exhibited a glass transition, which pure dry HA does not. None of the compositions studied showed any cytotoxicity. Thus, the materials could be of use in tissue engineering applications where these properties of HA need to be modulated. PMID- 24144106 TI - Elevated concentrations of milk beta2-microglobulin are associated with increased risk of breastfeeding transmission of HIV-1 (Vertical Transmission Study). AB - There is increasing evidence to support a relationship between human immunodeficiency virus (HIV-1) transmission through breastfeeding and milk host factors. We analyzed skim milk proteome to further determine the contribution of host factors to the risk of mother-to-child transmission of HIV-1. Quantitative mass spectrometry analysis was performed on nine case-control pairs of HIV+ transmitter/nontransmitter mothers, and specific biochemical assays on two selected proteins were assessed in an independent validation set of 127 samples. 33 identified proteins were differentially expressed between HIV+ transmitter and nontransmitter mothers. Among them, beta2-microglobulin was significantly higher in the maternal transmitter than in the nontransmitter groups (p value = 0.0007), and S100A9 was significantly higher in the early maternal transmitter cases (before 4 months of age) compared with the nontransmitters (p value = 0.004). beta2-Microglobulin correlated with milk and plasma HIV viral load and CD4+ cell count, whereas S100A9 correlated with the estimated timing of infection of the infant through breastfeeding. Finally, beta2-microglobulin concentration in milk could accurately predict the risk of HIV-1 postnatal transmission by breastfeeding (p value < 0.0001, log-rank test). In conclusion, milk beta2 microglobulin and S100A9 are host factors that are found to be associated with mother-to-child transmission of HIV-1. PMID- 24144107 TI - Executive dysfunction is related with decreased frontal lobe blood flow in patients with subarachnoid haemorrhage. AB - OBJECTIVE: This study evaluated executive dysfunction in patients with subarachnoid haemorrhage (SAH) using the Behavioural Assessment of the Dysexecutive Syndrome (BADS) and correlated the occurrence of executive dysfunction with cerebral blood flow (CBF) reduction in the frontal lobe as assessed by single photon emission computed tomography (SPECT). DESIGN: Correlational study. SUBJECTS: Twenty-two patients who underwent microsurgical clipping at least 3 months after SAH. METHODS: This study evaluated the BADS and the Wechsler Adult Intelligence Scale-III (WAIS-III). In addition, it assessed activities of daily living (ADL). CBF was evaluated using SPECT. The patients were divided into the following groups according to the results of SPECT: (1) those with reduced CBF in the frontal lobe (reduced CBF group, n = 8) and (2) those with intact CBF (intact CBF group, n = 14). RESULTS: The BADS score was significantly lower in the reduced CBF group compared with that of the intact CBF group, while there was no significant difference in the WAIS-III scores and ADL scale between the two groups. CONCLUSION: Although this result was conducted with a small sample size, executive dysfunction correlates with reduced CBF in the frontal lobes of SAH patients. A detailed evaluation of executive function is suggested in SAH patients, even if the patient's intelligence test and ADL scale reveal no abnormalities. PMID- 24144109 TI - Three-dimensional orientation determination of stationary anisotropic nanoparticles with sub-degree precision under total internal reflection scattering microscopy. AB - Single-particle and single-molecule orientation determination plays a vital role in deciphering nanoscale motion in complex environments. Previous attempts to determine the absolute three-dimensional orientation of anisotropic particles rely on subjective pattern matching and are inherently plagued by high degrees of uncertainty. Herein, we describe a method utilizing total internal reflection scattering microscopy to determine the 3D orientation of gold nanorods with subdegree uncertainty. The method is then applied to the biologically relevant system of microtubule cargo loading. Finally, we demonstrate the method holds potential for identifying single particles versus proximate neighbors within the diffraction limited area. PMID- 24144108 TI - The positive correlations of apolipoprotein E with disease activity and related cytokines in systemic lupus erythematosus. AB - BACKGROUND: The aim of this study is to investigate the expression of apolipoprotein E (apoE) and the relationship between apoE and disease activity of SLE, and the possible effects of glucocorticoid on apoE and other cytokines activities in SLE patients. METHODS: Forty treatment-naive SLE patients and forty matched healthy controls were studied. All the SLE patients received prednisone 1 mg/kg/day for 28 consecutive days. The sera levels of apoE and related cytokines were evaluated by ELISA. The expression of apoE mRNA in peripheral blood mononuclear cells (PBMCs) was determined by real-time PCR. RESULTS: Compared with healthy controls, the relative expression levels of ApoE proteins and sera levels were significantly up-regulated in active SLE patients. ApoE sera concentrations positively correlated with SLEDAI, anti-dsDNA antibody and the related cytokines including IL-6, IFN-gamma and IL-10, and uncorrelated with the concentration of total cholesterol (TC) and triglyceride (TG) in SLE patients. After 4 weeks prednisone treatment, the relative mRNA expression of apoE and the serum levels of apoE and related cytokines decreased. CONCLUSIONS: ApoE correlated with disease activity and related cytokines in SLE patients. Glucocorticoid can down regulate the expressions of apoE and related cytokines. VIRTUAL SLIDE: The virtual slide(s) for this article can be found here:http://www.diagnosticpathology.diagnomx.eu/vs/1646714011077325. PMID- 24144110 TI - Combinatorial high-throughput screening for highly active Pd-Ir-Ce based ternary catalysts in electrochemical oxygen reduction reaction. AB - A combinatorial library having 66 different ternary compositions of Pd-Ir-Ce was prepared via the impregnation method to find the optimum ternary composition with the highest performance toward oxygen reduction reaction (ORR) in acid media. Its performance in ORR activity of the combinatorial array was evaluated through two different combinatorial high-throughput screening methods to gain validity: (1) multielectrode half-cell method and (2) optical screening method. From the combinatorial results, the spot at 79:12:9 for Pd-Ir-Ce (at. %) in the array showed the highest ORR activity. The electrochemical characterizations of the single catalyst demonstrates that the optimized Pd79Ir12Ce9/C catalyst shows 1.5 times the ORR activity compared to that of Pd/C catalyst at 0.85 V (vs. RHE). In the Pd-Ir-Ce based catalysts, X-ray diffraction (XRD) and X-ray photoelectron spectroscopy (XPS) results reveal that Ir and Ce are present in the form of IrO2 and CeO2, respectively, and the electron configuration of Pd is effectively modified through the decoration with IrO2 and CeO2. From the results, we suggest that the electro-modification of Pd through strong metal-metal oxide interaction with IrO2-CeO2 was a reason for the enhanced ORR activity. PMID- 24144112 TI - Computational methods for a class of network models. AB - In the following article, we provide an exposition of exact computational methods to perform parameter inference from partially observed network models. In particular, we consider the duplication attachment model that has a likelihood function that typically cannot be evaluated in any reasonable computational time. We consider a number of importance sampling (IS) and sequential Monte Carlo (SMC) methods for approximating the likelihood of the network model for a fixed parameter value. It is well-known that, for IS, the relative variance of the likelihood estimate typically grows at an exponential rate in the time parameter (here this is associated with the size of the network); we prove that, under assumptions, the SMC method will have relative variance that can grow only polynomially. In order to perform parameter estimation, we develop particle Markov chain Monte Carlo algorithms to perform Bayesian inference. Such algorithms use the aforementioned SMC algorithms within the transition dynamics. The approaches are illustrated numerically. PMID- 24144111 TI - eALPS: estimating abundance levels in pooled sequencing using available genotyping data. AB - The recent advances in high-throughput sequencing technologies bring the potential of a better characterization of the genetic variation in humans and other organisms. In many occasions, either by design or by necessity, the sequencing procedure is performed on a pool of DNA samples with different abundances, where the abundance of each sample is unknown. Such a scenario is naturally occurring in the case of metagenomics analysis where a pool of bacteria is sequenced, or in the case of population studies involving DNA pools by design. Particularly, various pooling designs were recently suggested that can identify carriers of rare alleles in large cohorts, dramatically reducing the cost of such large-scale sequencing projects. A fundamental problem with such approaches for population studies is that the uncertainty of DNA proportions from different individuals in the pools might lead to spurious associations. Fortunately, it is often the case that the genotype data of at least some of the individuals in the pool is known. Here, we propose a method (eALPS) that uses the genotype data in conjunction with the pooled sequence data in order to accurately estimate the proportions of the samples in the pool, even in cases where not all individuals in the pool were genotyped (eALPS-LD). Using real data from a sequencing pooling study of non-Hodgkin's lymphoma, we demonstrate that the estimation of the proportions is crucial, since otherwise there is a risk for false discoveries. Additionally, we demonstrate that our approach is also applicable to the problem of quantification of species in metagenomics samples (eALPS-BCR) and is particularly suitable for metagenomic quantification of closely related species. PMID- 24144113 TI - Risk factors for pulmonary tuberculosis in Croatia: a matched case-control study. AB - BACKGROUND: Mycobacterium tuberculosis is a necessary, but not sufficient, cause of tuberculosis. A number of studies have addressed the issue of risk factors for tuberculosis development. Croatia is a European country with an incidence rate of 14/100 000 which is slowly decreasing. The aim of this study is to evaluate the potential demographic, socioeconomic, behavioural and biological risk factors for tuberculosis in Croatia in comparison to other high-income, low-incidence European countries. METHODS: A total of 300 tuberculosis patients were matched for age, sex and county of residence to 300 controls randomly selected from general practitioners' registers. They were interviewed and their medical records were evaluated for variables broadly described as potential risk factors. RESULTS: In multiple logistic regression, the following factors were significant: parents born in a particular neighbouring county (Bosnia and Herzegovina) (OR = 3.90, 95% CI 2.01-7.58), the lowest level of education (OR = 3.44, 95% CI 1.39 8.50), poor household equipment (OR = 4.72, 95% CI 1.51-14.76), unemployment (OR = 2.69, 95% CI 1.18-6.16), contact with tuberculosis (OR = 2.19, 95% CI 1.27 3.77), former (OR = 2.27, 95% CI 1.19-4.33) and current smoking habits (OR = 2.35, 95% CI 1.27-4.36), diabetes (OR = 2.38, 95% CI 1.05-5.38), a malignant disease (OR = 5.79, 95% CI 1.49-22.42), being underweight in the previous year (OR = 13.57, 95% CI 1.21-152.38). CONCLUSION: In our study, the identified risk groups for tuberculosis reflect a complex interaction between socioeconomic conditions, lifestyle and non-communicable diseases. Interventions focused on poverty will undoubtedly be useful, but not sufficient. Tuberculosis control would benefit from a combination of broad public health activities aimed at the prevention and control of risky lifestyles and non-communicable diseases, interventions outside the health sector, and efforts to constantly improve the Croatian national tuberculosis programme. PMID- 24144114 TI - Bilingual skills of deaf/hard of hearing children from Spain. AB - BACKGROUND/AIMS: This study described the first language (L1) and second language (L2) skills of a group of Spanish deaf/hard of hearing (DHH) children who were bilingual. METHODS: Participants included parents of 51 DHH children from Spain. Parents completed an electronic survey that included questions on background, details on child's hearing loss, and bilingual status and L2 exposure. Parents also completed the Student Oral Language Observation Matrix, a rating scale that describes language skills. RESULTS: DHH bilingual children demonstrated L1 skills that were stronger than their monolingual DHH peers. Bilingual children demonstrated a wide range of L2 proficiency, and most were exposed to an L2 through parents and/or schooling. The majority of parents reported that their children demonstrated L2 skills that were either better than or at the level they had expected. CONCLUSION: These results correspond with earlier studies that indicate the DHH children are capable of becoming bilingual. Implications for clinical practice are discussed. PMID- 24144115 TI - [SemFYC Congress 2013: Family Medicine now more than ever]. PMID- 24144116 TI - [Advance care planning. And education revolution is needed]. PMID- 24144117 TI - MR-based measurement of spinal cord motion during flexion of the spine: implications for intradural spinal cord stimulator systems. AB - This study develops a means of delivering electrical stimuli directly to the pial surface of the spinal cord for treatment of intractable pain. This intradural implant must remain in direct contact with the cord as it moves within the spinal canal. Therefore, magnetic resonance imaging was used to measure the movement of the spinal cord between neutral and flexed-back positions in a series of volunteers (n = 16). Following flexion of the back, the mean change in the pedicle-to-spinal cord dorsal root entry zone distance at the T10-11 level was (8.5 +/- 6.0) mm, i.e. a 71% variation in the range of rostral-caudal movement of the spinal cord across all patients. There will be a large spectrum of spinal cord strains associated with this observed range of rostral-caudal motions, thus calling for suitable axial compliance within the electrode bearing portion of the intradural implant. PMID- 24144118 TI - Gene discovery, evolutionary affinity and molecular detection of Oxyspirura petrowi, an eye worm parasite of game birds. AB - BACKGROUND: Oxyspirura petrowi appears to be emerging as a nematode parasite that could negatively impact Northern Bobwhite quail individuals and populations within Texas and other regions of the United States. Despite this eye worm's potential importance in the conservation of wild quail, little is known about the general biology and genome composition of O. petrowi. To fill the knowledge gap, we performed a small scale random genome sequence survey, sequenced its 18S rRNA and the intergenic region between the 18S and 28S rRNA genes, studied its phylogenetic affinity, and developed a PCR protocol for the detection of this eye worm. RESULTS: We have generated ~240 kb of genome sequence data derived from 348 clones by a random genome survey of an O. petrowi genomic library. The eye worm genome is AT-rich (i.e., 62.2% AT-content), and contains a high number of microsatellite sequences. The discovered genes encode a wide-range of proteins including hypothetical proteins, enzymes, nematode-specific proteins. Phylogenetic analysis based on 18S rRNA sequences indicate that the Spiruroidea is paraphyletic, in which Oxyspirura and its closely related species are sisters to the filarial nematodes. We have also developed a PCR protocol based on the ITS2 sequence that allows sensitive and specific detection of eye worm DNA in feces. Using this newly developed protocol, we have determined that ~28% to 33% of the fecal samples collected from Northern Bobwhites and Scaled Quail in Texas in the spring of 2013 are O. petrowi positive. CONCLUSIONS: The O. petrowi genome is rich in microsatellite sequences that may be used in future genotyping and molecular fingerprinting analysis. This eye worm is evolutionarily close to the filarial nematodes, implying that therapeutic strategies for filariasis such as Loa loa would be referential in developing treatments for the Thelazoidea parasites. Our qPCR-based survey has confirmed that O. petrowi infection is of potential concern to quail managers in Texas. PMID- 24144119 TI - Multiple reaction monitoring mass spectrometry for the discovery and quantification of O-GlcNAc-modified proteins. AB - O-linked N-acetylglucosamine (O-GlcNAc) is a post-translational modification regulating proteins involved in a variety of cellular processes and diseases. Unfortunately, O-GlcNAc remains challenging to detect and quantify by shotgun mass spectrometry (MS) where it is time-consuming and tedious. Here, we investigate the potential of Multiple Reaction Monitoring Mass Spectrometry (MRM MS), a targeted MS method, to detect and quantify native O-GlcNAc modified peptides without extensive labeling and enrichment. We report the ability of MRM MS to detect a standard O-GlcNAcylated peptide and show that the method is robust to quantify the amount of O-GlcNAcylated peptide with a method detection limit of 3 fmol. In addition, when diluted by 100-fold in a trypsin-digested whole cell lysate, the O-GlcNAcylated peptide remains detectable. Next, we apply this strategy to study glycogen synthase kinase-3 beta (GSK-3beta), a kinase able to compete with O-GlcNAc transferase and modify identical site on proteins. We demonstrate that GSK-3beta is itself modified by O-GlcNAc in human embryonic stem cells (hESC). Indeed, by only using gel electrophoresis to grossly enrich GSK 3beta from whole cell lysate, we discover by MRM-MS a novel O-GlcNAcylated GSK 3beta peptide, bearing 3 potential O-GlcNAcylation sites. We confirm our finding by quantifying the increase of O-GlcNAcylation, following hESC treatment with an O-GlcNAc hydrolase inhibitor. This novel O-GlcNAcylation could potentially be involved in an autoinhibition mechanism. To the best of our knowledge, this is the first report utilizing MRM-MS to detect native O-GlcNAc modified peptides. This could potentially facilitate rapid discovery and quantification of new O GlcNAcylated peptides/proteins. PMID- 24144120 TI - Decoupling interfacial reactions between plasmas and liquids: charge transfer vs plasma neutral reactions. AB - Plasmas (gas discharges) formed at the surface of liquids can promote a complex mixture of reactions in solution. Here, we decouple two classes of reactions, those initiated by electrons (electrolysis) and those initiated by gaseous neutral species, by examining an atmospheric-pressure microplasma formed in different ambients at the surface of aqueous saline (NaCl) solutions. Electrolytic reactions between plasma electrons and aqueous ions yield an excess of hydroxide ions (OH(-)), making the solution more basic, while reactions between reactive neutral species formed in the plasma phase and the solution lead to nitrous acid (HNO2), nitric acid (HNO3), and hydrogen peroxide (H2O2), making the solution more acidic. The relative importance of either reaction path is quantified by pH measurements, and we find that it depends directly on the composition of the ambient background gas. With a background gas of oxygen or argon, electron transfer reactions yielding excess OH(-) dominate, while HNO2 and HNO3 formed in the plasma and by the dissolution of nitrogen oxide (NOx) species dominate in the case of air and nitrogen. For pure nitrogen (N2) gas, we observe a unique coupling between both reactions, where oxygen (O2) gas formed via water electrolysis reacts in the bulk of the plasma to form NOx, HNO2, and HNO3. PMID- 24144121 TI - Synthesis and physical properties of the conjugated dendrons bearing twisted acenes used in solution processing of organic light-emitting diodes. AB - Five novel organic conjugated derivatives containing multifraction twisted acene units have been synthesized and characterized. These compounds and the model molecule 2-methyl-5,12-diphenyl-6:7,10:11-bisbenzotetracene emit strong blue light in diluted solution with quantum yields of 0.21-0.67, while in the solid state, except for the 1,2,3,4,5,6-hexa(2-(5,12-diphenyl-6:7,10:11-bis(4'-tert butylbenzo)tetracene))benzene, green luminance is seen. The experimental results also indicate that the multifraction structure leads to a significant fluorescence enhancement (over two times) compared to the monomer, which might be attributed to the formation of delocalized excited state in multibranch structures. The quantum-chemical calculation implies that only two branches are involved in formation of the delocalized system for the multibranched derivatives. Furthermore, the organic light-emitting diode (OLED) devices using compounds 1,4-di(2-(5,12-diphenyl-6:7,10:11-bis(4'-tert butylbenzo)tetracene))benzene, 1,3-di(2-(5,12-diphenyl-6:7,10:11-bis(4'-tert butylbenzo)tetracene))benzene, and 1,3,5-tri(2-(5,12-diphenyl-6:7,10:11-bis(4' tert-butylbenzo)tetracene))benzene as emitters exhibit good electroluminescent performance. Our systematic studies might provide more chances to challenge the rational design and synthesis of new- and high-generation branched dendrimers. PMID- 24144122 TI - Bovine salmonellosis in northeast of Iran: frequency, genetic fingerprinting and antimicrobial resistance patterns of Salmonella spp. AB - OBJECTIVE: To evaluate serovar and antimicrobial resistance patterns of Salmonella spp isolated from healthy, diseased and necropsied cows and calves in this observational study. METHODS: Nineteen isolates recovered from feces and tissues of salmonellosis-affected animals of two commercial farms in north-east of Iran. In second part of the study, the two farms were sampled 4 times with an interval of 2 month. The samples included calves' feces, adult cows' feces, feeds, water, milk filters, and milk fed to calves. Five Salmonella were isolated from 332 fecal samples collected from calves and peri-parturient cows. No Salmonella was recovered from water, feed, milk filers and milk fed to calves. RESULTS: Salmonella Typhimurium was the most frequently isolate among all sero groups. S. Dublin was only accounted for 8% (two out of 24) of isolates. Isolated Salmonella strains were used for the ERIC PCR DNA fingerprinting assay. Our results grouped Salmonella isolates into 3 clusters, suggesting that specific genotypes were responsible for each sero-group of Salmonella. The results also revealed diversity among Salmonella isolates in cluster III (sero-group B). Eighteen out of 19 Salmonella spp. were resistant to oxytetracycline. Five isolates out of 19 showed more than one drug resistance. Multi-drug resistance was seen only among Salmonella Typhimurium isolates. Enrofloxacin was the most susceptible antibiotic against all isolates in this study. CONCLUSION: The emergence of multiple antibiotic-resistant strains of Salmonella Typhimurium should be of great concern to the public. No correlation between ERIC fingerprinting and resistance patterns of Salmonella isolates was found, which indicates resistance to antimicrobial agents was not related to specific genetic background. PMID- 24144123 TI - Molecular analysis of Pasteurella multocida strains isolated from fowl cholera infection in backyard chickens. AB - OBJECTIVE: To characterize Pasteurella isolated from backyard chickens using whole cell protein lysate profiles and random amplified polymorphic DNA (RAPD) techniques to show their genetic relationship because Pasteurella multocida (P. multocida) is an important cause of fatal infections in backyard chickens. METHODS: Twenty one P. multocida isolates were recovered previously from clinical cases of fowl cholera belonging to individual owners and phenotypically analyzed using biochemical tests and serotyping were used for the genetic characterization. RESULTS: Phylogenetic study based on both methods revealed that the recovered population of P. multocida isolated from backyard chickens differs markedly, constituting a well-separated cluster and appearance of 3 distinguishing lineages with greater discrimination shown by RAPD-PCR that resulted in two suclusters in cluster A and three subclusters in cluster B and were related greatly with capsular serogroups for the examined strains. The whole cell protein revealed the presence of dominant protein bands at approximately 41 and 61 kDa in all of the examined isolates that may be a virulent proteins share in the increasing of its pathogenicity. Clear distinctive bands ranged from 123 to 1554 bp. CONCLUSION: Based on the previous findings, there are three spreading clusters that may indicate the association of a small number of P. multocida variants with the majority of cases suggesting that certain clones of P. multocida are able to colonize the examined backyard chickens. Also, the ease and rapidity of RAPD-PCR support the use of this technique as alternative to the more labour-intensive SDS-PAGE system for strain differentiation and epidemiological studies of avian P. multocida. Further application of RAPD technology to the examination of avian cholera outbreaks in commercially available flocks may facilitate more effective management of this disease by providing the potential to investigate correlations of P. multocida genotypes, to identify affiliations between bird types and bacterial genotypes, and to elucidate the role of specific bird species in disease transmission. PMID- 24144124 TI - Morphological study of the asymmetrical buccal cavity of the flatfish common solea (Solea solea) and its relation to the type of feeding. AB - OBJECTIVE: To investigate the surface architecture of the asymmetrical buccal cavity of Solea solea which are considered one of the most important predators in benthic communities. METHODS: Adult Solea solea were obtained from Mediterranean Sea near Damietta. The heads were removed and processed for scanning electron microscopy. Its buccal cavity is asymmetrical and divided into roof and floor and the tongue for histological studies. RESULTS: The buccal cavity roof is formed from upper jaw, velum and the palate. The upper jaw has several wing like processes with teeth arranged in several rows which may help in cutting and pushing the food to the entrance of the digestive canal while the floor is formed from the lower jaw and the tongue. The tongue is divided into apex, body and root. There is a gradual decrease of goblet cells in the tongue from anterior to posterior. These goblet cells function in protection of the epithelium. CONCLUSIONS: Teeth in the floor of the buccal cavity and taste buds can be considered adaptive changes of the oral cavity related to the feeding habits and was a source to identify new and better methods of nutrition in aquaculture of Solea solea. PMID- 24144125 TI - Phytopharmacological evaluation of ethanol extract of Sida cordifolia L. roots. AB - OBJECTIVE: To investigate the phytochemical screening (group determination) and selected pharmacological activities (antioxidant, antimicrobial and analgesic activity) of the plant Sida cordifolia Linn (S. cordifolia). METHODS: Eighty percent concentrated ethanol extract of the roots was used. To identify the chemical constituents of plant extract standard procedures were followed. In phytochemical screening the crude extract was tested for the presence of different chemical groups like reducing sugar, tannins, saponins, steroids, flavonoids, gums, alkaloids and glycosides. The antioxidant property of ethanolic extract of S. cordifolia was assessed by DPPH free radical scavenging activity. Analgesic activity of the extract was tested using the model of acetic acid induced writhing in mice. Diclofenac sodium is used as reference standard drug for the analgesic activity test. Antibacterial activity of plant extract was carried out using disc diffusion method with five pathogenic bacteria comparison with kanamycin as a standard. RESULTS: Phytochemical analysis of the ethanolic extract of the roots of S. cordifolia indicated the presence of reducing sugar, alkaloids, steroids and saponins. In DPPH scavenging assay the IC50 value was found to be 50 MUg/mL which was not comparable to the standard ascorbic acid. The crude extract produced 44.30% inhibition of writhing at the dose of 500 mg/kg body weight which is statistically significant (P>0.001). The in vitro antimicrobial activity of the ethanol extract of the roots of S. cordifolia showed no antimicrobial activity against five types of microorganisms. The experiment was conducted only with five species of bacteria as test species, which do not at all indicate the total inactivity against micro-organisms. CONCLUSION: The obtained results provide a support for the use of this plant in traditional medicine but further pharmacological studies are required. PMID- 24144126 TI - Potential in vitro antimicrobial efficacy of Holigarna arnottiana (Hook F). AB - OBJECTIVE: To explore the in vitro antimicrobial potential of Holigarna arnottiana (H. arnottiana) against human and shrimp pathogenic bacteria and use GC-MS analysis to elucidate its antimicrobial principles. METHODS: In the present study, organic extract of H. arnottiana was examined for in vitro antimicrobial potency against five clinical human pathogens, seven species of human type culture pathogens, six pathogenic Vibrio strains isolated from moribund tiger shrimp (Penaeus monodon) and seven type cultures (Microbial Type Culture Collection, MTCC) of prominent shrimp pathogens. RESULTS: The extraction of H. arnottiana with ethyl acetate yielded bioactive crude extract that efficiently repressed the growth of all tested pathogens. Among the pathogens tested, shrimp pathogens were the most susceptible organisms while clinical pathogens were found to be a little resistant. The chemical constituents of the H. arnottiana were analysed by GC-MS which revealed the presence of major compounds such as 3,7,11,15-tetramethyl-2-hexadecen-1-o1 (42.1%), 1-lodo-2-methylundecane (34.5%) and squalene (11.1%) which might have a functional role in the chemical defence against microbial invasion. CONCLUSIONS: Based on the finding it could be inferred that H. arnottiana would be a reliable source for developing shrimp and human bio-therapeutics in future. PMID- 24144127 TI - Larvicidal efficacies and chemical composition of essential oils of Pinus sylvestris and Syzygium aromaticum against mosquitoes. AB - OBJECTIVE: To assess the chemical composition and mosquito larvicidal potentials of essential oils of locally sourced Pinus sylvestris (P. sylvestris) and Syzygium aromaticum (S. aromaticum) against Aedes aegypti (A. aegypti) and Culex quinquefasciatus (C. quinquefasciatus). METHODS: The chemical composition of the essential oils of both plants was determined using GC-MS while the larvicidal bioassay was carried out using different concentrations of the oils against the larvae of A. aegypti and C. quinquefasciatus in accordance with the standard protocol. RESULTS: The results as determined by GC-MS showed that oil of S. aromaticum has eugenol (80.5%) as its principal constituent while P. sylvestris has 3-Cyclohexene-1-methanol, .alpha., .alpha.4-trimethyl (27.1%) as its dominant constituent. Both oils achieved over 85% larval mortality within 24 h. The larvae of A. aegypti were more susceptible to the oils [LC50 (S. aromaticum)=92.56 mg/L, LC50(P. sylvestris)=100.39 mg/L] than C. quinquefasciatus [LC50(S. aromaticum)=124.42 mg/L; LC50(P. sylvestris)=128.00 mg/L]. S. aromaticum oil was more toxic to the mosquito larvae than oil of P. sylvestris but the difference in lethal concentrations was insignificant (P>0.05). CONCLUSION: The results justify the larvicidal potentials of both essential oils and the need to incorporate them in vector management and control. PMID- 24144128 TI - Pharmacognostic studies of insect gall of Quercus infectoria Olivier (Fagaceae). AB - OBJECTIVE: To study the detailed pharmacognostic profile of galls of Quercus infectoria Olivier (Q. infectoria olivier) (Fagaceae), an important medicinal plant used in the Indian system of medicine. METHODS: Samples of galls of Q. infectoria were studied by macroscopical, microscopical, physiochemical, phytochemical, fluorescence analysis and othjer methods for standardization as recommended by WHO. RESULTS: Macroscopically, the crude drug is globose with horny appearances on external surface (1.4-2.3 cm in length and 1-1.5 cm in diameter), with greyish-brown to brownish-black in colour externally and dark brown buff colored. Surface is smooth with numerous horny protuberances giving rough touch, and with unpleasant odour. Microscopically, a wide zone of radially elongated parenchyma cells between upper and lower epidermis were found. The vascular strands were present at all places and radially elongated sclerides touched the lower epidermis. In physico-chemical studies, the moisture, total ash, acid insoluble ash, alcohol soluble, water soluble, petroleum ether, chloroform extractive value and tannin content were found to be 2.790, 5.020, 0.110, 38.780, 41.210, 0.402, 1.590 and 49.200 percentage respectively. Preliminary phytochemical screening showed the presence of phenols, flavonoids, steroids, triterpenes, tannins, saponins and alkaloids. CONCLUSIONS: The results of the present study serve as a valuable source of information and provide suitable standards for identification of this medicinally important plant drug material for future investigations and applications. PMID- 24144129 TI - In vitro callus induction and plantlet regeneration of Achyranthes aspera L., a high value medicinal plant. AB - OBJECTIVE: To study callus induction from different explants (internode, leaf, root) and in vitro plantlets propagation from medicinally important plant Achyranthes aspera L. METHODS: Sterilized explants were prepared by using 0.1% HgCl2 and 0.5% Bavistin and callus was obtained when cultured onto Murashige Skoog's (MS) medium by using different concentrations and combination of 2,4-D, NAA, BAP, IAA, IBA with 3% sucrose and 0.8% agar. Induced callus was immediately transferred to MS medium containing at different concentrations of phytohormones for shootlets and rootlets induction respectively. RESULTS: Sterilization treatment of 0.1% HgCl2 for 2-3 min and Bavistin 0.5% for 10-12 min showed the highest percentage of asepsis and survival rate. Maximum induction of callus was obtained from a combination of 2.0 mg/L 2,4-D and 0.5 mg/L NAA from leaf. Highest shootlets number (4.83+/-0.17) and length (3.8+/-0.16) cm were observed on full strength MS medium when fortified with BAP 4.0 mg/L and KIN 0.5 mg/L. Concerted efforts of BAP 2.0 mg/L and NAA 0.5 mg/L on full strength MS medium showed highest leaf number (6.77+/-0.94). In vitro raised shoots were allowed to root on different strengths of MS medium fortified with IAA and IBA at different concentrations. Experimentally, 3.0 mg/L IBA was enabled to induce maximum rootlets number (10.0+/-9.82) on full strength MS medium. Afterwards, regenerated shoots with well developed roots were successfully subjected to hardening process and were acclimatized. The survived plantlets showed 66.67% survival frequency without any morphological abnormality. CONCLUSIONS: The results demonstrated that different explants were good source of callus induction, morphology analysis as well as indirect plantlets regeneration. PMID- 24144130 TI - Molecular characterization, biological forms and sporozoite rate of Anopheles stephensi in southern Iran. AB - OBJECTIVE: To identify the biological forms, sporozoite rate and molecular characterization of the Anopheles stephensi (An. stephensi) in Hormozgan and Sistan-Baluchistan provinces, the most important malarious areas in Iran. METHODS: Wild live An. stephensi samples were collected from different malarious areas in southern Iran. The biological forms were identified based on number of egg-ridges. Molecular characterization of biological forms was verified by analysis of the mitochondrial cytochrome oxidase subunit I and II (mtDNA COI/COII). The Plasmodium infection was examined in the wild female specimens by species-specific nested-PCR method. RESULTS: Results showed that all three biological forms including mysorensis, intermediate and type are present in the study areas. Molecular investigations revealed no genetic variation between mtDNA COI/COII sequences of the biological forms and no Plasmodium parasites was detected in the collected mosquito samples. CONCLUSIONS: Presence of three biological forms with identical sequences showed that the known biological forms belong to a single taxon and the various vectorial capacities reported for these forms are more likely corresponded to other epidemiological factors than to the morphotype of the populations. Lack of malaria parasite infection in An. stephensi, the most important vector of malaria, may be partly due to the success and achievement of ongoing active malaria control program in the region. PMID- 24144131 TI - Impact of dietary oils and fats on lipid peroxidation in liver and blood of albino rats. AB - OBJECTIVE: To investigate the effects of different dietary fat and oils (differing in their degree of saturation and unsaturation) on lipid peroxidation in liver and blood of rats. METHODS: The study was conducted on 50 albino rats that were randomly divided into 5 groups of 10 animals. The groups were fed on dietary butter (Group I), margarine (Group II), olive oil (Group III), sunflower oil (Group IV) and corn oil (Group V) for 7 weeks. After 12 h of diet removal, livers were excised and blood was collected to measure malondialdehyde (MDA) levels in the supernatant of liver homogenate and in blood. Blood superoxide dismutase activity (SOD), glutathione peroxidase activity (GPx), serum vitamin E and total antioxidant capacity (TAC) levels were also measured to determine the effects of fats and oils on lipid peroxidation. RESULTS: The results indicated that no significant differences were observed in SOD activity, vitamin E and TAC levels between the five groups. However, there was significant decrease of GPx activity in groups IV and V when compared with other groups. The results indicated that feeding corn oil caused significant increases in liver and blood MDA levels as compared with other oils and fats. There were positive correlations between SOD and GPx, vitamin E and TAC as well as between GPx and TAC (r: 0.743; P<0.001) and between blood MDA and liver MDA (r: 0.897; P<0.001). The results showed also negative correlations between blood MDA on one hand and SOD, GPx, vitamin E and TAC on the other hand. CONCLUSIONS: The results demonstrated that feeding oils rich in polyunsaturated fatty acids (PUFA) increases lipid peroxidation significantly and may raise the susceptibility of tissues to free radical oxidative damage. PMID- 24144132 TI - Serum uric acid level in newly diagnosed essential hypertension in a Nepalese population: a hospital based cross sectional study. AB - OBJECTIVE: To develop the missing link between hyperuricemia and hypertension. METHODS: The study was conducted in Department of Biochemistry in collaboration with Nephrology Unit of Internal Medicine Department. Hypertension was defined according to blood pressure readings by definitions of the Seventh Report of the Joint National Committee. Totally 205 newly diagnosed and untreated essential hypertensive cases and age-sex matched normotensive controls were enrolled in the study. The potential confounding factors of hyperuricemia and hypertension in both cases and controls were controlled. Uric acid levels in all participants were analyzed. RESULTS: Renal function between newly diagnosed hypertensive cases and normotensive healthy controls were adjusted. The mean serum uric acid observed in newly diagnosed hypertensive cases and in normotensive healthy controls were (290.05+/-87.05) MUmol/L and (245.24+/-99.38) MUmol/L respectively. A total of 59 (28.8%) participants of cases and 28 (13.7%) participants of controls had hyperuricemia (odds ratio 2.555 (95% CI: 1.549-4.213), P<0.001). CONCLUSIONS: The mean serum uric acid levels and number of hyperuricemic subjects were found to be significantly higher in cases when compared to controls. PMID- 24144133 TI - Prevalence of HIV infection and the correlates among homeless in Tehran, Iran. AB - OBJECTIVE: To determine the prevalence of HIV infection among homeless men and women and the related risk behaviors in Tehran, Iran. METHODS: In 2007-2008, Tehran municipality stacked up 10672 homeless men and women for assessment of HIV and began collaboration with Iranian Research Center for HIV/AIDS (IRCHA) departments to conduct HIV infection prevalence surveys in homeless populations. The results were analyzed for associations with demographic information, family support, status of drug abuse and relation with family and friends. RESULTS: Overall HIV prevalence was 1.7% (95% confidence interval 1.4-1.9). Factors independently associated with HIV infection included history of using drugs [AOR 8.15 (4.86-13.67)], older age [AOR 1.80 (1.08-2.99) for 40-55 yr], occupation [AOR 1.64 (1.19-2.24) for unemployed], and no relation with family [AOR 1.82 (1.30-2.54)]. CONCLUSIONS: This study supports the idea that injection drug use is contributing to the increased spread of HIV among Iranian homeless. Harm reduction programs should be expanded, particularly among homeless injection drug users. PMID- 24144134 TI - Toxoplasmosis among pregnant women: high seroprevalence and risk factors in Kinshasa, Democratic Republic of Congo. AB - OBJECTIVE: To determine the seroprevalence of toxoplasmosis in pregnant women, as well as the proportion of acutely infected and risk factors in the Democratic Republic of Congo. METHODS: Thirty maternities in Kinshasa were randomly selected and women attending antenatal consultation were invited to participate. They were interviewed with a structured questionnaire about known risk factors (age, meat consumption, contact with soil, and presence of cat) and a venous blood sample was taken. Sera were analysed for total immunoglobulins (Ig) by VIDAS Toxo Competition using Enzyme Linked Fluorescent Assay. IgM was determined by VIDIA Toxo IgM and IgG avidity by VIDAS Toxo IgG avidity. RESULTS: A total of 781 women were included. Median age was 28 years old (IQR: 8.5). And 627 women (80.3%; 95% CI: 77.5-83.1) were found to be positive to total Ig and 17 out of 387 (4.4%; 95% CI: 2.3-6.4) were positive to IgM. IgG avidity was low for 2 (11.8%) women, intermediate for 2 (11.8%) and high for 13 women (76.4%). There was no statistically significant association between Toxoplasma gondii infection and any risk factors assessed. CONCLUSION: In Kinshasa, toxoplasmosis endemicity is highly prevalent. One woman out of twenty five had a recent toxoplasmosis infection and 20% were not protected against primo-infection, indicating a need for measures to prevent and control toxoplasmosis during pregnancy. PMID- 24144135 TI - Coexistence of pneumothorax and Chilaiditi sign: a case report. AB - We present a case of 50 year old male patient with coexistence of Pneumothorax and Chilaiditi sign. Chilaiditi sign is an incidental radiographic finding of a usually asymptomatic condition in which a part of intestine is located between the liver and diaphragm; however, the term "Chilaiditi syndrome" is used for symptomatic hepatodiaphragmatic interposition. The patient had no symptoms of abdominal pain, constipation, diarrhea, or emesis. Incidentally, Chilaiditi sign was diagnosed on chest radiography. Pneumothorax is defined as air in the pleural space. Pneumothoraces are classified as spontaneous or traumatic. Spontaneous pneumothorax is labelled as primary when no underlying lung disease is present, or secondary, when it is associated with pre-existing lung disease. Our case is the rare in the literature indicating the coexistence of Chilaiditi sign and pneumothorax. PMID- 24144136 TI - Herbal antioxidant in clinical practice: a review. AB - Antioxidant-the word itself is magic. Using the antioxidant concept as a spearhead in proposed mechanisms for staving off so-called "free-radical" reactions, the rush is on to mine claims for the latest and most effective combination of free-radical scavenging compounds. We must acknowledge that such "radicals" have definitively been shown to damage all biochemical components such as DNA/RNA, carbohydrates, unsaturated lipids, proteins, and micronutrients such as carotenoids (alpha and beta carotene, lycopene), vitamins A, B6, B12, and folate. Defense strategies against such aggressive radical species include enzymes, antioxidants that occur naturally in the body (glutathione, uric acid, ubiquinol-10, and others) and radical scavenging nutrients, such as vitamins A, C, and E, and carotenoids. This paper will present a brief discussion of some well- and little-known herbs that may add to the optimization of antioxidant status and therefore offer added preventive values for overall health. It is important to state at the outset that antioxidants vary widely in their free radical quenching effects and each may be individually attracted to specific cell sites. Further evidence of the specialized nature of the carotenoids is demonstrated by the appearance of two carotenoids in the macula region of the retina where beta-carotene is totally absent. PMID- 24144137 TI - Contaminant adsorption on nanoscale particles: structural and theoretical characterization of Cu2+ bonding on the surface of Keggin-type polyaluminum (Al30) molecular species. AB - The adsorption of contaminants onto metal oxide surfaces with nanoscale Keggin type structural topologies has been well established, but identification of the reactive sites and the exact binding mechanism are lacking. Polyaluminum species can be utilized as geochemical model compounds to provide molecular level details of the adsorption process. An Al30 Keggin-type species with two surface-bound Cu(2+) cations (Cu2Al30-S) has been crystallized in the presence of disulfonate anions and structurally characterized by single-crystal X-ray diffraction. Density functional theory (DFT) calculations of aqueous molecular analogues for Cu2Al30-S suggest that the reactivity of Al30 toward Cu(2+) and SO4(2-) shows opposite trends in preferred adsorption site as a function of particle topology, with anions preferring the beltway and cations preferring the caps. The bonding competition was modeled using two stepwise reaction schemes that consider Cu2Al30 S formation through initial Cu(2+) or SO4(2-) adsorption. The associated DFT energetics and charge density analyses suggest that strong electrostatic interactions between SO4(2-) and the beltway of Al30 play a vital role in governing where Cu(2+) binds. The calculated electrostatic potential of Al30 provides a theoretical interpretation of the topology-dependent reactivity that is consistent with the present study as well as other results in the literature. PMID- 24144138 TI - Risk factors for intra-abdominal hypertension and abdominal compartment syndrome among adult intensive care unit patients: a systematic review and meta-analysis. AB - INTRODUCTION: Although intra-abdominal hypertension (IAH) and abdominal compartment syndrome (ACS) are associated with substantial morbidity and mortality among critically ill adults, it remains unknown if prevention or treatment of these conditions improves patient outcomes. We sought to identify evidence-based risk factors for IAH and ACS in order to guide identification of the source population for future IAH/ACS treatment trials and to stratify patients into risk groups based on prognosis. METHODS: We searched electronic bibliographic databases (MEDLINE, EMBASE, PubMed, and the Cochrane Database from 1950 until January 21, 2013) and reference lists of included articles for observational studies reporting risk factors for IAH or ACS among adult ICU patients. Identified risk factors were summarized using formal narrative synthesis techniques alongside a random effects meta-analysis. RESULTS: Among 1,224 citations identified, 14 studies enrolling 2,500 patients were included. The 38 identified risk factors for IAH and 24 for ACS could be clustered into three themes and eight subthemes. Large volume crystalloid resuscitation, the respiratory status of the patient, and shock/hypotension were common risk factors for IAH and ACS that transcended across presenting patient populations. Risk factors with pooled evidence supporting an increased risk for IAH among mixed ICU patients included obesity (four studies; odds ratio (OR) 5.10; 95% confidence interval (CI), 1.92 to 13.58), sepsis (two studies; OR 2.38; 95% CI, 1.34 to 4.23), abdominal surgery (four studies; OR 1.93; 95% CI, 1.30 to 2.85), ileus (two studies; OR 2.05; 95% CI, 1.40 to 2.98), and large volume fluid resuscitation (two studies; OR 2.17; 95% CI, 1.30 to 3.63). Among trauma and surgical patients, large volume crystalloid resuscitation and markers of shock/hypotension and metabolic derangement/organ failure were risk factors for IAH and ACS while increased disease severity scores and elevated creatinine were risk factors for ACS in severe acute pancreatitis patients. CONCLUSIONS: Although several IAH/ACS risk factors transcend across presenting patient diagnoses, some appear specific to the population under study. As our findings were somewhat limited by included study methodology, the risk factors reported in this study should be considered candidate risk factors until confirmed by a large prospective multi-centre observational study. PMID- 24144139 TI - A rapid and sensitive assay of intercellular coupling by voltage imaging of gap junction networks. AB - BACKGROUND: A variety of mechanisms that govern connexin channel gating and permeability regulate coupling in gap junction networks. Mutations in connexin genes have been linked to several pathologies, including cardiovascular anomalies, peripheral neuropathy, skin disorders, cataracts and deafness. Gap junction coupling and its patho-physiological alterations are commonly assayed by microinjection experiments with fluorescent tracers, which typically require several minutes to allow dye transfer to a limited number of cells. Comparable or longer time intervals are required by fluorescence recovery after photobleaching experiments. Paired electrophysiological recordings have excellent time resolution but provide extremely limited spatial information regarding network connectivity. RESULTS: Here, we developed a rapid and sensitive method to assay gap junction communication using a combination of single cell electrophysiology, large-scale optical recordings and a digital phase-sensitive detector to extract signals with a known frequency from Vf2.1.Cl, a novel fluorescent sensor of plasma membrane potential. Tests performed in HeLa cell cultures confirmed that suitably encoded Vf2.1.Cl signals remained confined within the network of cells visibly interconnected by fluorescently tagged gap junction channels. We used this method to visualize instantly intercellular connectivity over the whole field of view (hundreds of cells) in cochlear organotypic cultures from postnatal mice. A simple resistive network model reproduced accurately the spatial dependence of the electrical signals throughout the cellular network. Our data suggest that each pair of cochlear non-sensory cells of the lesser epithelial ridge is coupled by ~1500 gap junction channels, on average. Junctional conductance was reduced by 14% in cochlear cultures harboring the T5M mutation of connexin30, which induces a moderate hearing loss in connexin30T5M/T5M knock-in mice, and by 91% in cultures from connexin30-/- mice, which are profoundly deaf. CONCLUSIONS: Our methodology allows greater sensitivity (defined as the minimum magnitude of input signal required to produce a specified output signal having a specified signal-to-noise ratio) and better time resolution compared to classical tracer-based techniques. It permitted us to dynamically visualize intercellular connectivity down to the 10th order in non-sensory cell networks of the developing cochlea. We believe that our approach is of general interest and can be seamlessly extended to a variety of biological systems, as well as to other connexin-related disease conditions. PMID- 24144140 TI - [Scientific publications: a resource for the physician's intellectual development]. AB - The physician's professional life involves reading and analysis of scientific journals, regardless of the specialization field. The hospital and academic areas lead to the scientific-literary activity development. The aim of this editorial is to make some reflections about the way a physician reaches intellectual development, through the creation of a culture of writing and reading scientific publications. PMID- 24144141 TI - [Analysis of maternal deaths in Mexico occurred during 2009]. AB - BACKGROUND: Mexico reported 955 maternal deaths in 2011, with a ratio of 49 deaths per 100,000 live births. For 2015, the WHO commitment is to reduce the ratio to 22, equivalent to 415 maternal deaths. METHODS: it is a descriptive and retrospective study. In 1257 maternal deaths in 2009, we reviewed a sample of 173 records. Simple frequencies and percentages were calculated. RESULTS: direct causes of maternal death were preeclampsia-eclampsia, infection and obstetrical hemorrhage secondary to uterine atony, placental accreta and placenta previa. Fifteen patients died from abortion complications. Four patients died from extra uterine pregnancy, because of delayed diagnosis and treatment. Indirect causes of maternal death were neoplasms, abdominal sepsis, vascular events, metabolic problems and heart disease; twenty-five patients died of atypical pneumonia and 11 more of influenza A H1N1. CONCLUSIONS: it is feasible to reduce maternal mortality by means of an adequate prenatal care, in quantity and quality of consultations, and avoiding high risk pregnancies caused by a history of obstetric factors and associated severe diseases. Influenza A H1N1 interrupted the downward trend in maternal mortality. PMID- 24144142 TI - [Clinical improvement of diabetic neuropathy with carbamazepine or diclofenac treatment]. AB - BACKGROUND: diabetic neuropathy (DN) affects diverse aspects of a patient's life and there is not an optimal treatment. We did a comparative study of clinical improvement of DN with carbamazepine versus diclofenac. METHODS: a prospective and longitudinal study of two groups with signs and symptoms of DN was done. One group had 30 patients who used carbamazepine with an initial dose of 200 mg, every 24 hours for one week, with a gradual increase of up to 200 mg every 6 hours for 10 months. The other group had 29 patients who used diclofenac sodium 100 mg every 12 hours. Bimonthly evaluations were made to graduate the pain according to the patients' perception and laboratory studies that included glucose and lipids profile. The statistical test used was ANOVA. RESULTS: the patients who used carbamazepine presented absence of pain after 10 months compared with the diclofenac group (p < 0.01). The presence of cramps, muscular strength, pulses, perception of temperature and pressure improved significantly (p < 0.05) with the use of carbamazepine. On the other hand, muscular strength, tact and perception of temperature were deteriorated with the use of diclofenac. CONCLUSIONS: it is important to provide the appropriate treatment to diabetic patients with DN. PMID- 24144143 TI - [The lymph nodes imprint for the diagnosis of lymphoid neoplasms]. AB - BACKGROUND: lymphoma is the most frequent lymphoid neoplasm in our country. Its diagnosis is based on histopathological findings. The lymph node imprint has been used for more than 40 years. The aim was to establish the sensitivity, specificity, positive predictive value and negative predictive value of lymph node imprint and estimate the inter-observer rate. METHODS: we did an observational, retrospective, prolective study, based on the lymph node imprint obtained by excisional biopsies over a period of 6 years. RESULTS: the inclusion criteria was met on 199 samples, 27.1 % were considered as reactive (n = 54), 16.1 % Hodgkin lymphoma (n = 32), 40.2 % (n = 80) non-Hodgkin lymphoma and 16.6 % (n = 33) as metastatic carcinoma. Comparing with the final histopathology report, the sensitivity and specificity of lymph node imprint were 88 % (0.81-0.95) and 64 % (0.55-0.73) respectively, the positive predictive value was 67 % (0.59-0.76) and the negative predictive value was 86 % (0.79-0.94). The interobserver kappa index was 0.467. CONCLUSIONS: the lymph node imprint remains as a useful tool for the diagnosis of lymphoid neoplasm. The agreement between observers was acceptable. PMID- 24144144 TI - [Cost-effectiveness of two hospital care schemes for psychiatric disorders]. AB - BACKGROUND: In Mexico, six of every twenty Mexicans suffer psychiatric disorders at some time in their lives. This disease ranks fifth in the country. The objective was to determine and compare the cost-effectiveness of two models for hospital care (partial and traditional) at a psychiatric hospital of Instituto Mexicano del Seguro Social (IMSS). METHODS: a multicenter study with a prospective cohort of 374 patients was performed. We made a cost-effectiveness analysis from an institutional viewpoint with a six-month follow-up. Direct medical costs were analyzed, with quality of life gains as outcome measurement. A decision tree and a probabilistic sensitivity analysis were used. RESULTS: patient care in the partial model had a cost 50 % lower than the traditional one, with similar results in quality of life. The cost per successful unit in partial hospitalization was 3359 Mexican pesos while in the traditional it increased to 5470 Mexican pesos. CONCLUSIONS: treating patients in the partial hospitalization model is a cost-effective alternative compared with the traditional model. Therefore, the IMSS should promote the infrastructure that delivers the psychiatric services to the patient attending to who requires it. PMID- 24144145 TI - [Cost-effectiveness analysis of etanercept compared with other biologic therapies in the treatment of rheumatoid arthritis]. AB - OBJECTIVE: to conduct cost-effectiveness analysis of etanercept compared with other biologic therapies in the treatment of moderate or severe rheumatoid arthritis in patients with previous unresponse to immune selective anti inflammatory derivatives failure. METHODS: a pharmacoeconomic model based on decision analysis to assess the clinical outcome after giving etanercept, infliximab, adalimumab or tocilizumab to treat moderate or severe rheumatoid arthritis was employed. Effectiveness of medications was assessed with improvement rates of 20 % or 70 % of the parameters established by the American College of Rheumatology (ACR 20 and ACR 70). RESULTS: the model showed that etanercept had the most effective therapeutic response rate: 79.7 % for ACR 20 and 31.4 % for ACR 70, compared with the response to other treatments. Also, etanercept had the lowest cost ($149,629.10 per patient) and had the most cost effective average ($187,740.40 for clinical success for ACR 20 and $476,525.80 for clinical success for ACR 70) than the other biologic therapies. CONCLUSIONS: we demonstrated that treatment with etanercept is more effective and less expensive compared to the other drugs, thus making it more efficient therapeutic option both in terms of means and incremental cost-effectiveness ratios for the treatment of rheumatoid arthritis. PMID- 24144146 TI - [Relationship among anthropometric and gluco-metabolic parameters, bone mineral density and endometriosis]. AB - BACKGROUND: women with endometriosis may have a decreased bone mineral density (BMD). Several studies have shown that accumulation of adipose tissue profoundly affects BMD. It has also been documented that excess body fat is associated with risk of developing endometriosis. The aim was to analyze the relationship between BMD, fat mass, and the insulin-glucose axis in women with endometriosis. METHODS: thirty women with a diagnosis of endometriosis established by surgery were enrolled to participate in an observational prospective study. Anthropometry was performed to determine body mass index, and a dual X-ray densitometry to collect data on body composition and BMD. Glucose and insulin determinations were performed. Women were divided in two groups: with normal weight (n = 18) or overweight (n = 12). For the analysis of the results, we used descriptive statistics and Pearson's test. RESULTS: normal weight/overweight: mean age 32.5/35.2 years; body mass index 21.5/30.2; adiposity index: 27.7 %/36.1 %; fat mass index: 35.4/45.8 %; overweight women showed a significant value with p < 0.05. CONCLUSIONS: overweight, high values of adiposity index and fat mass index were related to endometriosis. This could support the hypothesis about a common pathogenesis among endometriosis, osteoporosis, diabetes and obesity. PMID- 24144147 TI - [Constitutional syndrome: clinical entity or a mixed bag]. AB - Fatigue, anorexia and involuntary weight loss have been included under the term constitutional syndrome. These manifestations accompany many diseases in which the diagnosis is made by specific symptoms and signs. However, these events are generally the main reason for consultation and the patient does not report other specific data. This forces us to rigorously investigate the possible causes of the disorder. Usually, three manifestations coexist: asthenia, anorexia and weight loss, but sometimes the patient has only one or two of them. The causes of constitutional symptoms are varied and can be divided into three groups: psychiatric diseases, neoplasms and non-neoplastic diseases. The etiological identification is usually done with a simple protocol, which rules out malignancy; the rest of the cases of uncertain etiology are subject to evolution. The constitutional syndrome correlates well with good prognosis or medical functional processes. Although no clinical guidelines have been developed, score scales may help for the etiological assessment. Given the myriad of different causes of the constitutional syndrome, the treatment of this illness depends primarily on the etiology. PMID- 24144148 TI - [Diagnosis and treatment of Pompe disease]. AB - Pompe disease is a rare, progressive and often fatal neuromuscular disorder. It is caused by a deficiency of the lysosomal alpha-glucosidase. Among glycogen storage disorders, it is one of the most common. Its clinical manifestations can start at any moment of life, with a very variable symptomatology. In this article, we show an extended revision of the literature in regards to the main medical aspects of Pompe disease: etiology, psychopathology, epidemiology, clinical variants, pathological diagnosis, and enzyme replacement therapy. With this information, we created a diagnostic and therapeutic guide, which is addressed to specialists and to first-level physicians, in order to let them identify both the classic and the late forms of this disease. We describe as well the best, timely, multidisciplinary treatment in use. Also, we show some suggestions to the proper functioning of health institutions, and routes to diagnosis. We conclude that Pompe disease may be properly diagnosed and treated if health care professionals follow the internationally approved recommendations. PMID- 24144149 TI - [Clinical research XVII. chi(2) test, from the expected to the observed]. AB - When you want to show if there is a statistical association or differences between categorical variables, it is recommended to use the chi(2) test. This nonparametric test is one of the most used in clinical research; it contrasts nominal or ordinal qualitative variables that are observed in clinical practice. This test calculates the p value that determines whether differences between groups are real or due to chance. The chi(2) test is the basis of other tests to analyze qualitative ordinal variables as chi(2) for linear trend, which compares three groups with two outcomes or McNemar test, which contrasts two related samples (a before and afterward comparison) or Mantel-Haenszel chi(2), which controls for potential confounding variables. When using small samples, where the expected results are less than 5, Fisher's exact test should be used. These tests are the most widely used in the medical literature; however, they do not give us the magnitude or the direction of the event and a proper interpretation that requires clinical judgment is needed. PMID- 24144150 TI - Female breast symptoms in patients attended in the family medicine practice. AB - BACKGROUND: there are few studies on breast symptoms (BS) in patients attended at primary care units in Mexico. The aim was to determine the frequency and types of BS overall and by age-group and establish which BS were related to diagnosis of breast cancer. METHODS: data from all female patients with a breast-disease related diagnosis, attended from 2006 to 2010, at the Family Medicine Unit 38, were collected. The frequencies of BS were determined by four age-groups (< 19, 20-49, 50-69, > 70 years) and likelihood ratios for breast cancer for each breast related symptom patient, with a 95 % confidence interval (CI). RESULTS: the most frequent BS in the study population were lump/mass (71.7 %) and breast pain (67.7 %) of all breast complaints, and they were more noted in women age group of 20-49 years. Overall, 120 women had breast cancer diagnosed with a median age of 53.51 + 12.7 years. Breast lump/mass had positive likelihood ratios for breast cancer 4.53 (95 % CI = 2.51-8.17) and breast pain had increased negative LR = 1.08 (95 % CI = 1.05-1.11). CONCLUSIONS: breast lump/mass was the predominant presenting complaint among females with breast symptoms in our primary care unit, and it was associated with elevated positive likelihood of breast cancer. PMID- 24144151 TI - [Gait, balance and independence rehabilitation program in elderly adults in a primary care unit]. AB - OBJECTIVE: to evaluate the effect of a supervised rehabilitation program to improve gait, balance and independence in elderly patients attending a family medicine unit. METHODS: we conducted a quasi-experimental study over a period of four weeks in a group of 72 patients older than 65 years. INTERVENTION: a supervised program regarding the risk factors for falling, and balance, gait, coordination and oculovestibular system, the modalities to be done two or three times a week in the primary care unit or at home. An analysis of both tests was performed by "up and go," Tinetti scale and the Katz index. ANALYSIS: "intention to treat" and "by protocol." RESULTS: mean age was 72 +/- 5 years, 67.8% were female and 81.9% of the patients completed the program. A significant clinical improvement with statistical level were evident for gait and balance (p = 0.001), independence showed only clinical improvement (p = 0.083). The efficacy for periodicity (two or three times/week) and performance place showed same clinical improvement and statistical level for gait and balance (p = 0.001 to 0.003) and independence showed only clinical improvement (p = 0.317 to 0.991). CONCLUSIONS: an integral rehabilitation program improved gait, balance and clinical independence significantly. The supervised program is applicable and can be reproduced at primary care unit or home for geriatric care and preventive actions. PMID- 24144152 TI - [Burnout and quality of life in medical residents]. AB - BACKGROUND: burnout and quality of life are poorly studied phenomena in postgraduate students, and its effects are unknown. The aim was to investigate the relationship between quality of life and burnout in medical residents. METHODS: a longitudinal study was performed. We included medical residents who began their postgraduate studies in 2010. The Spanish version of the Quality of Life Profile for the Chronically Ill (PLC, according to its initials in German), and the Maslach Burnout Inventory specific to physicians were applied at the beginning, and six and 12 months later. Descriptive statistics were used for nominal variables. Chi-square and ANOVA were applied to numerical variables. RESULTS: we included 45 residents, the average age was 26.9 +/- 2.93 years, 18 (40 %) were female and 27 (60 %) were male. The PLC survey found significant decrease in four of the six scales assessed in the three measurements. The Maslach Burnout Inventory found high levels of emotional exhaustion in the three tests, low levels of depersonalization and low personal gains at the beginning, rising at six and 12 months. The most affected specialty was Internal Medicine. CONCLUSIONS: burnout and impaired quality of life for residents exist in postgraduate physicians and it is maintained during the first year of residency. PMID- 24144153 TI - [An exceptional mimicker of ovarian tumors: cancer in a pelvic horseshoe kidney]. AB - BACKGROUND: although the horseshoe kidney is a frequent congenital abnormality, the likelihood of it being the cause of a malignant tumor that looks like an ovarian neoplasm has not been reported. CLINICAL CASE: a 53-year-old female came to the hospital with a pelvic tumor. The patient had a history of a simple hysterectomy due to uterine myomatosis. At abdominal physical examination we identified a rounded hypogastric tumor, 20 cm diameter, firm, and fixed. On pelvic examination the mass was easily palpated through the vaginal fornix. The diagnosis of a probable ovarian neoplasm, caused by a residual ovary syndrome was made, therefore she was admitted to the gynecology service. Computed tomography scans showed a tumor located in the right side of a deformed pelvic kidney. Hence, the gynecology service sent the patient to the surgical oncology department, where the assumption was confirmed. The analysis of the RX studies showed a possible neoplasm from a pelvic horseshoe kidney. The patient underwent an exploratory abdominal surgery, and a 19 cm tumor was excised. The pathology department reported a chromophobe cell carcinoma. CONCLUSIONS: tumors in the pelvic horseshoe kidney may simulate an ovarian neoplasms in females. PMID- 24144154 TI - [Moebius syndrome. Clinical case report]. AB - BACKGROUND: Moebius syndrome (MBS) is an infrequent disease, having an incidence of 1 in 10,000 births, mainly characterized by a congenital bilateral facial paralysis due to an agenesia of the sixth and seventh cranial nerves. In addition, orofacial and limb anomalies are frequently found in these patients. The diagnosis is fundamentally based on different clinical manifestations of the disorder. CLINICAL CASE: a female newborn with the clinical picture of Moebius syndrome is presented, and genetic or environmental aspects are discussed. Since the use of misoprostol for abortion and inducing uterine activity in combination with NSAIDs, the number of newborns with MBS associated with this drug has increased. Nowadays, either genetic or environmental factors are associated with MBS. CONCLUSIONS: it is necessary that the general and medical community be aware of the risk of teratogenic effects of misoprostol, and the usefulness of genetic counseling whenever there is a newborn with Moebius syndrome. PMID- 24144155 TI - [Myxoid liposarcoma of the lumbosacral spine. Clinical case report]. AB - BACKGROUND: liposarcoma is a malignant tumor of soft tissue and the most common sarcoma in the adult life. The myxoid liposarcoma accounts for 30 to 35 % of all liposarcomas. It is commonly seen on the thighs. Only two cases in which the liposarcoma was found in the vertebral column have been reported. CLINICAL CASE: this is a 28 year old woman with symptoms of spinal cord injury by compression (tottering gait, weakness 4/5 and decreased sensibility in right leg). The MRI showed a right paravertebral multinodular mass from L4 to S2, with solid and cystic aspects, following the S1 and S2 intervertebral foramen to the presacral space, with low signal intensity on T1 and high on T2. The diagnosis of neurofibroma was concluded. The patient was scheduled for surgery. Extra and intraspinal excision was performed and a mass was removed. Histopathologic study reported myxoid liposarcoma. CONCLUSIONS: liposarcoma is a malignant tumor of soft tissues. The spine is a rare location for this neoplasm, even for metastases. It is difficult to achieve a complete resection in this localization, so the recurrence rate is high. PMID- 24144156 TI - [Clinical practice guideline on closed tibial plateau fractures in adulthood]. AB - Closed tibiae plateau fractures are common injuries in the emergency room. The optimal treatment is not well defined or established. For this reason, there are several surgical management options: open reduction and internal fixation, closed reduction and percutaneous synthesis, external fixation, and even conservative treatment for this kind of fracture. The mechanism of production of this fracture is through large varus or valgus deformation to which is added a factor of axial load. The trauma may be direct or indirect. The degree of displacement, fragmentation and involvement of soft tissues like ligaments, menisci, vascular and nerve structures are determined by the magnitude of the force exerted. Any intra-articular fracture treatment can lead to an erroneous instability, deformity and limitation of motion with subsequent arthritic changes, leading to joint incongruity, limiting activity and significantly altering the quality of life. Open reduction and internal fixation with anatomic restitution is the method used in this type of fracture. However, the results of numerous publications can be questioned due to the inclusion in the same study of fractures treated with very different methods. PMID- 24144157 TI - Canalicular adenoma--search for the cell of origin: ultrastructural and immunohistochemical analysis of 7 cases and review of the literature. AB - Canalicular adenoma (CA) is a rare, benign epithelial neoplasm of the salivary glands. Historically considered to be a variant of basal cell adenoma, this "monomorphic" adenoma has a distinct clinical, morphologic, and immunohistochemical profile. The putative cell of origin remains a topic of debate. A combination of morphology, immunohistochemistry, and ultrastructural analyses have been employed to determine histogenesis, but the interpretations of these studies have implicated multiple different cell types along the salivary gland duct as the cell of origin. The authors sought to further characterize CA using electron microscopy, immunohistochemistry, and special and immuno-stains on 7 cases. Their morphologic, immunohistochemical, and ultrastructural findings support a cell of origin demonstrating features of both the intercalated duct cells and the striated duct luminal epithelial cells. PMID- 24144158 TI - Flavonoids with acetylated branched glycans and bioactivity of Tipuana tipu (Benth.) Kuntze leaf extract. AB - The new acetylated kaempferol tetraglycoside, kaempferol-3-O-[2"(4 acetylrhamnopyranosyl)-3"-galactopyranosyl] robinobioside (1), was isolated from the aqueous methanolic leaf extract of Tipuana tipu Benth. The known kaempferol 3 [2"-(4-acetyl-rhamnosyl)] robinobioside (2), kaempferol 3-O-2" rhamnopyranosylrutinoside (3), rutin (4), kaempferol 3-O-rutinoside (5), kaempferol 3-O-glucopyranoside (6), kaempferol 3-O-galactopyranoside (7), quarcetin 3-O-glucopyranoside (8), kaempferol (9) and quercetin (10) together with the chlorogenic acid (11) were also isolated and characterised. Structures were established on the basis of chemical and spectroscopic analysis including (1)H NMR, (13)C NMR, 2D NMR and ESI-MS. The methanol extract exhibited moderate antioxidant activity, IC50 28.96 MUg/mL, compared with ascorbic acid (1.83 MUg/mL) and tertiary-butylhydroquinone (1.92 MUg/mL). The methanol and chloroform extracts exhibited potent cytotoxic activity; the former was found to be active against larynx and liver cell lines, while the latter being active against intestine and liver cell lines. PMID- 24144159 TI - Orbital compartment syndrome following transvenous embolization of carotid cavernous fistula. AB - Superior ophthalmic vein (SOV) thrombosis is a rare complication of carotid cavernous fistula (CCF) embolization and is usually associated with a paradoxical worsening of signs followed by subsequent spontaneous resolution. We report a case in a 69-year-old female who developed orbital compartment syndrome due to SOV thrombosis following transvenous embolization of an indirect CCF. The patient was treated with an urgent lateral canthotomy and cantholysis and had good recovery. This report demonstrates that the paradoxical worsening due to SOV thrombosis in CCF may result in orbital compartment syndrome and require early recognition and prompt decompressive measures to avoid permanent visual sequelae. PMID- 24144161 TI - Advances in coal gasification, hydrogenation, and gas treating for the production of chemicals and fuels. PMID- 24144160 TI - Hyperfine coupling constants of the cyclohexadienyl radical in benzene and dilute aqueous solution. AB - The muon hyperfine coupling constant (AMU) of the muoniated cyclohexadienyl radical (C6H6Mu) has been directly measured in a 5 mM solution of benzene in water by the radio-frequency muon spin resonance (RF-MUSR) technique. The relative shift of AMU in aqueous solution compared with the value in neat benzene (DeltaAMU/AMU = +0.98(5)% at 293 K) can now be compared directly with theoretical predictions. Application of the RF-MUSR method to other dilute systems will provide extremely important information on understanding solvent effects. PMID- 24144162 TI - Vertical maxillary growth after two different surgical protocols in unilateral cleft lip and palate patients. AB - Objective : The aim of the present study was to compare vertical maxillofacial growth in patients born with unilateral cleft lip and palate (UCLP) who were treated using two different surgical protocols. Design : A retrospective cohort study. Subjects : We studied 92 patients with complete UCLP (61 male and 31 female) treated at Sahlgrenska University Hospital in Gothenburg, Sweden: 46 consecutive patients born between 1965 and 1974 who underwent surgical treatment according to the Wardill-Kilner (W-K) protocol and 46 consecutive patients born between 1982 and 1989 who underwent surgical treatment according to the Gothenburg delayed hard palate closure (DHPC) protocol. Methods : We analyzed lateral cephalograms obtained at 10 years of age. Results : Patients treated according to the Gothenburg DHPC protocol had significantly greater anterior upper facial height, anterior maxillary height, overbite, and inclination of the maxilla than those treated with the W-K protocol. Both techniques led to similar posterior upper facial height. Conclusion : The Gothenburg DHPC protocol in patients with complete UCLP results in more normal anterior maxillary vertical growth and overbite and therefore increased maxillary inclination at 10 years of age. PMID- 24144163 TI - Understanding the role of proteolytic digestion on discovery and targeted proteomic measurements using liquid chromatography tandem mass spectrometry and design of experiments. AB - Workflows in bottom-up proteomics have traditionally implemented the use of proteolysis during sample preparation; enzymatic digestion is most commonly performed using trypsin. This results in the hydrolysis of peptide bonds forming tryptic peptides, which can then be subjected to LC-MS/MS analysis. While the structure, specificity, and kinetics of trypsin are well characterized, a lack of consensus and understanding has remained regarding fundamental parameters critical to obtaining optimal data from a proteomics experiment. These include the type of trypsin used, pH during digestion, incubation temperature as well as enzyme-to-substrate ratio. Through the use of design of experiments (DOE), we optimized these parameters, resulting in deeper proteome coverage and a greater dynamic range of measurement. The knowledge gained from optimization of a discovery-based proteomics experiment was applied to targeted LC-MS/MS experiments using protein cleavage-isotope dilution mass spectrometry for absolute quantification. We demonstrated the importance of these digest parameters with respect to our limit of detection as well as our ability to acquire more accurate quantitative measurements. Additionally, we were able to quantitatively account for peptide decay observed in previous studies, caused by nonspecific activity of trypsin. The tryptic digest optimization described here has eliminated this previously observed peptide decay as well as provided a greater understanding and standardization for a common but critical sample treatment used across the field of proteomics. PMID- 24144164 TI - New two-dimensional niobium and vanadium carbides as promising materials for Li ion batteries. AB - New two-dimensional niobium and vanadium carbides have been synthesized by selective etching, at room temperature, of Al from Nb2AlC and V2AlC, respectively. These new matrials are promising electrode materials for Li-ion batteries, demonstrating good capability to handle high charge-discharge rates. Reversible capacities of 170 and 260 mA.h.g(-1) at 1 C, and 110 and 125 mA.h.g( 1) at 10 C were obtained for Nb2C and V2C-based electrodes, respectively. PMID- 24144165 TI - Biochemical and molecular heterogeneity among isolates of Yersinia ruckeri from rainbow trout (Oncorhynchus mykiss, Walbaum) in North West Germany. AB - BACKGROUND: Enteric Redmouth Disease (ERM), caused by Yersinia ruckeri, is one of the most important infectious diseases in rainbow trout (Oncorhynchus mykiss) aquaculture in Europe. More recently, non-motile vaccine resistant isolates appear to have evolved and are causing disease problems throughout Europe, including Germany. The aim of this study was to analyse the variation of biochemical and molecular characteristics of Y. ruckeri isolates collected in north west Germany as a basis for strain differentiation. The isolates originated mainly from rainbow trout and were characterised by biochemical profiling, 16S rDNA sequencing, repetitive sequence-based PCRs, including (GTG)5-PCR, BOX-PCR, ERIC-PCR and REP-PCR, and pulsed-field gel electrophoresis (PFGE). RESULTS: In total, 83 isolates were characterised, including 48 isolates collected during a field study in north west Germany. All isolates were confirmed as Y. ruckeri by the API 20E system. Five isolates were additionally confirmed as Y. ruckeri by Y. ruckeri-specific PCR and 16S rDNA sequencing. Only 17 isolates hydrolyzed Tween 80/20. Sixty-six isolates (79.5%) were non-motile. Two different patterns were obtained by REP-PCR, five patterns by ERIC-PCR, four patterns by (GTG)5-PCR and three patterns by BOX-PCR. NotI-directed PFGE resulted in 17 patterns that differed from each other by 25-29 fragments. Isolates from the field study clustered together as PFGE type C. According to the results of API 20E, repetitive sequence-based PCRs and PFGE, these isolates could be subdivided into 27 different groups. CONCLUSIONS: The detailed molecular and phenotypic characterisation scheme developed in this study could be used to help trace the dissemination of Y. ruckeri isolates, and thus may represent part of improved disease monitoring plans in the future. PMID- 24144166 TI - Enhanced lithium ion battery cycling of silicon nanowire anodes by template growth to eliminate silicon underlayer islands. AB - It is well-known that one-dimensional nanostructures reduce pulverization of silicon (Si)-based anode materials during Li ion cycling because they allow lateral relaxation. However, even with improved designs, Si nanowire-based structures still exhibit limited cycling stability for extended numbers of cycles, with the specific capacity retention with cycling not showing significant improvements over commercial carbon-based anode materials. We have found that one important reason for the lack of long cycling stability can be the presence of milli- and microscale Si islands which typically form under nanowire arrays during their growth. Stress buildup in these Si island underlayers with cycling results in cracking, and the loss of specific capacity for Si nanowire anodes, due to progressive loss of contact with current collectors. We show that the formation of these parasitic Si islands for Si nanowires grown directly on metal current collectors can be avoided by growth through anodized aluminum oxide templates containing a high density of sub-100 nm nanopores. Using this template approach we demonstrate significantly enhanced cycling stability for Si nanowire based lithium-ion battery anodes, with retentions of more than ~1000 mA.h/g discharge capacity over 1100 cycles. PMID- 24144167 TI - Thermoelectric properties and microstructure of Cu-In-O thin films. AB - Combinatorial chemistry techniques were used to study the thermoelectric properties of sputtered thin films in the system copper oxide (CuO) and indium oxide (In2O3). Seven hundred seventy thin film thermocouples or combinatorial library elements were simultaneously deposited, each with a unique spatially dependent chemistry, based on the relative position of the thermocouples to each sputtering target. The resulting thermoelectric properties of each element were determined along with electrical resistivity as a function of composition. Energy dispersive spectroscopy was used to identify the composition of each thermo element, and electron and X-ray diffraction were used to determine the degree of crystallinity and phases present. Transmission electron microscopy was used to characterize the microstructure of selected thermo-elements. A change in sign of the thermoelectric voltage was observed in the thermo-element containing 40.0 atomic percent indium, which suggests a change in the dominant carrier type occurred, from p-type to n-type. Based on this finding, the fabrication of thermoelectric p-n junctions using the same base Cu-In-O semiconductor appears feasible. PMID- 24144168 TI - Clonal diversity of Acinetobacter baumannii clinical isolates revealed by a snapshot study. AB - BACKGROUND: Acinetobacter baumannii is a notorious opportunistic pathogen mainly associated with hospital-acquired infections. Studies on the clonal relatedness of isolates could lay the foundation for effective infection control. A snapshot study was performed to investigate the clonal relatedness of A. baumannii clinical isolates in our local settings. RESULTS: Among 82 non-repetitive Acinetobacter spp. clinical isolates that were recovered during a period of four days in 13 hospitals in Sichuan, Southwest China, 67 isolates were identified as A. baumannii. Half of the 67 A. baumannii isolates were non-susceptible to carbapenems. bla(OXA-23) was the only acquired carbapenemase gene detected, present in 40 isolates including five carbapenem-susceptible ones. The isolates belonged to 62 pulsotypes determined by PFGE and 31 sequence types (ST) by multi locus sequence typing. Forty-three isolates belonged to the globally-disseminated clonal complex 92, among which ST75, ST92 and ST208 were the most common sequence types. CONCLUSIONS: Clinical isolates of A. baumannii were diverse in clonality in this snapshot study. However, most of the isolates belonged to the globally distributed clonal complex CC92. ST75, ST92 and ST208 were the most common types in our region. In particular, ST208 might be an emerging lineage carrying bla(OXA 23). PMID- 24144169 TI - Water-enabled visual detection of DNA. AB - A water-enabled visual detection strategy has been developed for the sequence specific identification of target DNA. The conceptual basis of the assay scheme, water condensation, is environmentally friendly and chemical transformation-free, thus offering significant assay advantages over conventional diagnostic systems. This label-free strategy operates on a target-driven generation of a hydrophilic structure and alteration of surface wettability and, consequently, transition of morphological state of and light propagation mode in the surface-condensed water. The chip array detection system, implemented herein with the ligase chain reaction-rolling circle amplification protocol, has allowed the achievement of high sensitivity (600 copies), high selectivity (single-base discrimination specificity), and multiplexed analysis capability. PMID- 24144170 TI - Brainstem gliomas: surgical indications and technical considerations in a series of 58 cases. AB - OBJECTIVES. To analyze the indications of surgical treatment, surgical management strategies and post-surgical outcome in patients with brainstem glioma (BSG). METHODS. In this retrospective study conducted from 1998 to 2012, 58 patients of surgically treated intrinsic BSG, meeting the inclusion criterion were enrolled. There were 40 males and 18 females, with age range varying from 3 to 55 years. The most common presentation was gait disturbances, either due to cerebellar involvement or motor weakness, followed by motor weakness, ocular involvement and headache. The posteriorly located tumors were operated by midline suboccipital approach (42 patients) and supracerebellar-infratentorial approach (4 patients). Posterolaterally located tumors were operated by retromastoid (10 patients) and all the ventrolateral tumors by subtemporal approach (4 patients). RESULTS. Above 90% patients improved in their neurological status, while 5% deteriorated. Pilocytic astrocytoma was the most common histopathology (41.4%), followed by Grade II astrocytoma (34.5%) and Grade III astrocytoma (24.1%). Overall, 19% patients had postoperative complications and three patients (5%) died in the perioperative period. CONCLUSIONS. Surgery is advocated for patients with well delineated, posteriorly, posterolaterally and ventrolaterally located tumors having slow progression and relative preservation of motor power. BSG can have excellent surgical results with surgeon's experience and modern surgical facilities. PMID- 24144171 TI - Rule-based algorithm for the classification of sitting postures in the sagittal plane from the Cardiff Body Match measurement system. AB - The purpose of this paper is to present the design and implementation of a novel rule-based algorithm for the classification of sitting postures in the sagittal plane. The research focused on individuals with severe musculoskeletal problems and, thus, specific requirements for posture and pressure management. Clients' body shapes were captured using the Cardiff Body Match system developed by the Rehabilitation Engineering Unit, Cardiff and Vale University Health Board. The algorithm consists of four main steps: the first step is the symmetry line detection, the second step involves the mathematical analysis of the curvature of the backrest profile, the third step is the sitting posture classification and the fourth step is the extraction of the geometric parameters from the curve. The results show the classification system was successful in identifying four types of curves characterizing sitting postures using local derivatives as curve descriptors with an overall accuracy of 93.9%. PMID- 24144172 TI - Multiplatform analytical methodology for metabolic fingerprinting of lung tissue. AB - Using multiplatform approaches providing wider information about the metabolome, is currently the main topic in the area of metabolomics, choosing from liquid chromatography-mass spectrometry (LC-MS), gas chromatography/mass spectrometry (GC/MS), capillary electrophoresis-mass spectrometry (CE-MS), and nuclear magnetic resonace (NMR). However, the reliability and suitability of sample treatment, data acquisition, data preprocessing, and data analysis are prerequisites for correct biological interpretation in metabolomics studies. The significance of differences between samples can only be determined when the performance characteristics of the entire method are known. This leads to performing method validation in order to assess the performance and the fitness for-purpose of a method or analytical system for metabolomics research. The present study was designed for developing a nontargeted global fingerprinting approach of lung tissue, for the first time, applying multiple complementary analytical techniques (LC-MS, GC/MS, and CE-MS) with regards to analytical method optimization (sample treatment + analytical method), characterization, and validation as well as application to real samples. An initial solvent for homogenization has been optimized, which is usually overseen in the tissue homogenization protocol. A nontargeted fingerprinting approach was applied to a pooled sample of lung tissue using these three instruments to cover a wider range of metabolites. The linearity of the validated method for all metabolites was >0.99, with good recovery and precision in all techniques. The method has been successfully applied to lung samples from rats with sepsis compared to the control samples. Only 20 mg of tissue is required for the three analytical techniques, where only one metabolite was found in common between LC-MS and CE-MS analysis as statistically significant. This proves the importance of applying a multiplatform approach in a metabolomics study as well as for biomarker discovery. PMID- 24144173 TI - Optimal ozone reduction policy design using adjoint-based NOx marginal damage information. AB - Despite substantial reductions in nitrogen oxide (NOx) emissions in the United States, the success of emission control programs in optimal ozone reduction is disputable because they do not consider the spatial and temporal differences in health and environmental damages caused by NOx emissions. This shortcoming in the current U.S. NOx control policy is explored, and various methodologies for identifying optimal NOx emission control strategies are evaluated. The proposed approach combines an optimization platform with an adjoint (or backward) sensitivity analysis model and is able to examine the environmental performance of the current cap-and-trade policy and two damage-based emissions-differentiated policies. Using the proposed methodology, a 2007 case study of 218 U.S. electricity generation units participating in the NOx trading program is examined. The results indicate that inclusion of damage information can significantly enhance public health performance of an economic instrument. The net benefit under the policy that minimizes the social cost (i.e., health costs plus abatement costs) is six times larger than that of an exchange rate cap-and trade policy. PMID- 24144174 TI - Management of patients with cochlear implants and ventriculoperitoneal shunts. AB - OBJECTIVES: The aim of this study is to provide an overview of each device, discuss conditions that may predispose to the requirement of both devices, and consider pre- and post-operative issues arising from the co-existence of advanced technologies. In addition, relevant surgical anatomy and technique in the placement of both cochlear implant (CI) after ventriculoperitoneal shunt (VPS) and VPS after CI are reviewed. METHODS: Review of literature. RESULTS: Issues relevant to CI and VPS include predisposing conditions, magnetic resonance imaging compatibility, infectious risk, surgical technique, complication management, and a host of other issues. DISCUSSION: Patients with hydrocephalus and severe-to-profound hearing loss are a unique patient population with unique pre-, intra-, and post-operative issues. Thorough understanding of the indications, radiology, anatomy, technology, and potential complications can allow for these patients to achieve the full benefit of these lifechanging surgeries. PMID- 24144175 TI - Correlation of choroidal thickness with outer and inner retinal layers. AB - BACKGROUND AND OBJECTIVE: To investigate the correlation of choroidal thickness with the outer and inner retinal layers. PATIENTS AND METHODS: A retrospective OCT scan review was conducted for healthy patients. Choroidal, outer retinal layer, and inner retinal layer thicknesses were measured at the fovea and 500 MUm, 1,000 MUm, and 1,500 MUm temporal and nasal to the fovea. Retinal thickness was also measured at the foveal center. Choroidal thickness (CT) was compared at different locations, and correlation of CT with the outer and inner retinal layers was examined. RESULTS: Mean CT was thinnest nasally, thicker in the subfoveal region, and then thinner again temporally. Correlations found between CT and outer retinal layer thicknesses at temporal points to the fovea were slightly higher than correlations between CT and inner layer thicknesses. CONCLUSION: The correlation between choroidal thickness and the outer retinal layer was very weak. Similar prospective trials are needed to assess the correlation of CT with retinal layers. PMID- 24144176 TI - Surgical technique: hand-over-hand retrieval of a posteriorly dislocated DSAEK graft in an eye with an iris reconstruction lens. AB - Descemet's stripping automated endothelial keratoplasty (DSAEK) has become the preferred surgical treatment for corneal endothelial pathologies. An intraoperative complication of DSAEK is posterior dislocation of the donor graft into the vitreous cavity. As the number of performed DSAEK procedures grows each year, the possibility of encountering a posteriorly dislocated donor graft increases. The authors report a case of intraoperative graft dislocation and a novel hand-over-hand retrieval method from the retinal surface. The hand-over hand method provides an added surgical strategy for rescuing grafts that have fallen into the vitreous cavity. PMID- 24144177 TI - Multiple evanescent white dot syndrome: multimodal imaging and correlation with proposed pathophysiology. AB - The clinical presentation of multiple evanescent white dot syndrome (MEWDS) was described nearly 30 years ago; however, our understanding of its pathophysiology continues to change, evolving with our imaging modalities. Initially, electroretinography and fluorescein angiography indicated retinal pigment epithelium (RPE) and outer retinal damage. But with indocyanine green angiography, theories shifted to a primary choroidopathy. Only spectral-domain optical coherence tomography (SD-OCT) directly demonstrated the primary effect on RPE and outer retina, although enhanced depth-imaging OCT (EDI-OCT) may further modify our understanding. The authors present a case of unilateral MEWDS with imaging including SD-OCT and EDI-OCT. PMID- 24144178 TI - Familial exudative vitreoretinopathy in a premature child. AB - Many of the clinical features associated with familial exudative vitreoretinopathy (FEVR) overlap with those commonly found in retinopathy of prematurity (ROP). Differentiating these two distinct entities may be challenging in premature infants. FEVR can be distinguished from ROP in that the former demonstrates exudates on examination and tends to recur or reactivate. The authors report the case of a premature infant diagnosed with FEVR and treated with diode laser who was subsequently lost to follow-up. Upon re-establishing care 3 years later, the patient demonstrated renewed bilateral vitreoretinopathy. This manuscript underscores the importance of accurate distinction between FEVR and ROP for the purpose of optimal patient management. PMID- 24144179 TI - Revisiting the fine structure of the triple line. AB - The fine structure of the triple line for water droplets deposited on porous polymer substrates was investigated. Substrates were obtained with the breath figures self-assembly. Water droplets demonstrated the pronounced Cassie-Baxter wetting regime. The triple line was imaged with environmental scanning electron microscopy. The roughness of a triple line was characterized with its averaged root-mean-square (rms) width w(L), and its scaling experimental dependence upon the length L of the triple line w(L) is proportional to L(zeta) was analyzed. The values of exponents in the range of 0.60-063 were established. The deduced values of zeta evidence the local nature of the triple-line elasticity and support the idea that the elastic potential of the triple line includes only even powers of the displacement. PMID- 24144180 TI - General anaesthetic considerations for haemostasis in orbital surgery. AB - Orbital surgery is often conducted in areas with limited exposure where vital structures are tightly crowded together. A bloodless field is paramount in orbital surgery for the proper identification of normal and pathologic tissue and even minimal bleeding can obscure the surgical field, making surgery more difficult and increasing the risk of complications. Surgery for highly vascular orbital lesions is an additional situation where maintaining an adequate surgical field is often challenging but paramount. The role of the anaesthetist in controlling surgical blood loss has been increasingly recognized in the last few decades. Various techniques including hypotensive anaesthesia have been described, but the control of intraoperative bleeding does not rely on a single particular technique, but a series of well-designed interventions that result in optimal conditions. An understanding of the anaesthetic considerations pertinent to haemostasis is invaluable for oculoplastic surgeons. Additionally, with the growing use of endonasal approaches to medial wall decompression and accessing the medial orbit, it has become increasingly important that orbital surgeons understand the anaesthetic requirements of their colleagues in other disciplines. PMID- 24144182 TI - The feasibility and acceptability of virtual environments in the treatment of childhood social anxiety disorder. AB - Two significant challenges for the dissemination of social skills training programs are the need to assure generalizability and provide sufficient practice opportunities. In the case of social anxiety disorder, virtual environments may provide one strategy to address these issues. This study evaluated the utility of an interactive virtual school environment for the treatment of social anxiety disorder in preadolescent children. Eleven children with a primary diagnosis of social anxiety disorder between 8 to 12 years old participated in this initial feasibility trial. All children were treated with Social Effectiveness Therapy for Children, an empirically supported treatment for children with social anxiety disorder. However, the in vivo peer generalization sessions and standard parent assisted homework assignments were substituted by practice in a virtual environment. Overall, the virtual environment programs were acceptable, feasible, and credible treatment components. Both children and clinicians were satisfied with using the virtual environment technology, and children believed it was a high-quality program overall. In addition, parents were satisfied with the virtual environment augmented treatment and indicated that they would recommend the program to family and friends. Findings indicate that the virtual environments are viewed as acceptable and credible by potential recipients. Furthermore, they are easy to implement by even novice users and appear to be useful adjunctive elements for the treatment of childhood social anxiety disorder. PMID- 24144181 TI - The Campylobacter jejuni CiaD effector protein activates MAP kinase signaling pathways and is required for the development of disease. AB - BACKGROUND: Enteric pathogens utilize a distinct set of proteins to modulate host cell signaling events that promote host cell invasion, induction of the inflammatory response, and intracellular survival. Human infection with Campylobacter jejuni, the causative agent of campylobacteriosis, is characterized by diarrhea containing blood and leukocytes. The clinical presentation of acute disease, which is consistent with cellular invasion, requires the delivery of the Campylobacter invasion antigens (Cia) to the cytosol of host cells via a flagellar Type III Secretion System (T3SS). We identified a novel T3SS effector protein, which we termed CiaD that is exported from the C. jejuni flagellum and delivered to the cytosol of host cells. RESULTS: We show that the host cell kinases p38 and Erk 1/2 are activated by CiaD, resulting in the secretion of interleukin-8 (IL-8) from host cells. Additional experiments revealed that CiaD mediated activation of p38 and Erk 1/2 are required for maximal invasion of host cells by C. jejuni. CiaD contributes to disease, as evidenced by infection of IL 10 knockout mice. Noteworthy is that CiaD contains a Mitogen-activated protein (MAP) kinase-docking site that is found within effector proteins produced by other enteric pathogens. These findings indicate that C. jejuni activates the MAP kinase signaling pathways Erk 1/2 and p38 to promote cellular invasion and the release of the IL-8 pro-inflammatory chemokine. CONCLUSIONS: The identification of a novel T3SS effector protein from C. jejuni significantly expands the knowledge of virulence proteins associated with C. jejuni pathogenesis and provides greater insight into the mechanism utilized by C. jejuni to invade host cells. PMID- 24144183 TI - Association between parity and dentition status among Japanese women: Japan public health center-based oral health study. AB - BACKGROUND: Several studies have shown that parity is associated with oral health problems such as tooth loss and dental caries. In Japan, however, no studies have examined the association. The purpose of this study was to determine whether parity is related to dentition status, including the number of teeth present, dental caries and filled teeth, and the posterior occlusion, in a Japanese population by comparing women with men. METHODS: A total of 1,211 subjects, who participated both in the Japan Public Health Center-Based (JPHC) Study Cohort I in 1990 and the dental survey in 2005, were used for the study. Information on parity or number of children was collected from a self-completed questionnaire administered in 1990 for the JPHC Study Cohort I, and health behaviors and clinical dentition status were obtained from the dental survey in 2005. The association between parity or number of children and dentition status was analyzed, by both unadjusted-for and adjusted-for socio-demographic and health behavioral factors, using a generalized linear regression model. RESULTS: Parity is significantly related to the number of teeth present and n-FTUs (Functional Tooth Units of natural teeth), regardless of socio-demographic and health behavioral factors, in female subjects. The values of these variables had a significantly decreasing trend with the rise of parity: numbers of teeth present (p for trend = 0.046) and n-FTUs (p for trend = 0.026). No relationships between the number of children and dentition status were found in male subjects. CONCLUSION: Higher-parity women are more likely to lose teeth, especially posterior occluding relations. These results suggest that measures to narrow the discrepancy by parity should be taken for promoting women's oral health. Delivery of appropriate information and messages to pregnant women as well as enlightenment of oral health professionals about dental management of pregnant women may be an effective strategy. PMID- 24144184 TI - Cyclopentasilane-fused hexasilabenzvalene. AB - Cyclopentasilane-fused hexasilabenzvalene 1 was synthesized by the reduction of tetrachlorocyclopentasilane 6 in 19% yield as a green powder. The molecular structure and properties of 1 were studied by spectroscopic and X-ray crystallographic analyses. Theoretical calculations of the model and real molecules of 1 and their structural isomers 12-16 suggest that the linkage of the central hexasilabenzvalene moiety with trisilane chains and the introduction of tert-butyl groups affect their relative energies. PMID- 24144185 TI - Methodological comparisons for antimicrobial resistance surveillance in feedlot cattle. AB - BACKGROUND: The purpose of this study was to objectively compare methodological approaches that might be utilized in designing an antimicrobial resistance (AMR) surveillance program in beef feedlot cattle. Specifically, four separate comparisons were made to investigate their potential impact on estimates for prevalence of AMR. These included investigating potential differences between 2 different susceptibility testing methods (broth microdilution and disc diffusion), between 2 different target bacteria (non-type-specific E. coli [NTSEC] and Mannheimia haemolytica), between 2 strategies for sampling feces (individual samples collected per rectum and pooled samples collected from the pen floor), and between 2 strategies for determining which cattle to sample (cattle that were culture-positive for Mannheimia haemolytica and those that were culture-negative). RESULTS: Comparing two susceptibility testing methods demonstrated differences in the likelihood of detecting resistance between automated disk diffusion (BioMIC(r)) and broth microdilution (Sensititre(r)) for both E. coli and M. haemolytica. Differences were also detected when comparing resistance between two bacterial organisms within the same cattle; there was a higher likelihood of detecting resistance in E. coli than in M. haemolytica. Differences in resistance prevalence were not detected when using individual animal or composite pen sampling strategies. No differences in resistance prevalences were detected in E. coli recovered from cattle that were culture positive for M. haemolytica compared to those that were culture-negative, suggesting that sampling strategies which targeted recovery of E. coli from M. haemolytica-positive cattle would not provide biased results. CONCLUSIONS: We found that for general purposes, the susceptibility test selected for AMR surveillance must be carefully chosen considering the purpose of the surveillance since the ability to detect resistance appears to vary between these tests depending upon the population where they are applied. Continued surveillance of AMR in M. haemolytica recovered by nasopharyngeal swab is recommended if monitoring an animal health pathogen is an objective of the surveillance program as results of surveillance using fecal E. coli cannot be extrapolated to this important respiratory pathogen. If surveillance of E. coli was pursued in the same population, study populations could target animals that were culture positive for M. haemolytica without biasing estimates for AMR in E. coli. Composite pen-floor sampling or sampling of individuals per-rectum could possibly be used interchangeably for monitoring resistance in E. coli. PMID- 24144186 TI - Precise determination of the lutetium isotopic composition in rocks and minerals using multicollector ICPMS. AB - Evidence of (176)Hf excess in select meteorites older than 4556Ma was suggested to be caused by excitation of long-lived natural radionuclide (176)Lu to its short-lived isomer (176m)Lu, due to an irradiation event during accretion in the early solar system. A result of this process would be a deficit in (176)Lu in irradiated samples by between 10/00 and 70/00. Previous measurements of the Lu isotope ratio in rock samples have not been of sufficient precision to resolve such a phenomenon. We present a new analytical technique designed to measure the (176)Lu/(175)Lu isotope ratio in rock samples to a precision of ~0.10/00 using a multicollector inductively coupled mass spectrometer (MC-ICPMS). To account for mass bias we normalized all unknowns to Ames Lu. To correct for any drift and instability associated with mass bias, all standards and samples are doped with W metal and normalized to the nominal W isotopic composition. Any instability in the mass bias is then corrected by characterizing the relationship between the fractionation factor of Lu and W, which is calculated at the start of every analytical session. After correction for isobaric interferences, in particular (176)Yb, we were able to measure (176)Lu/(175)Lu ratios in samples to a precision of ~0.10/00. However, these terrestrial standards were fractionated from Ames Lu by an average of 1.22 +/- 0.090/00. This offset in (176)Lu/(175)Lu is probably caused by isotopic fractionation of Lu during industrial processing of the Ames Lu standard. To allow more straightforward data comparison we propose the use of NIST3130a as a bracketing standard in future studies. Relative to NIST3130a, the terrestrial standards have a final weighted mean delta(176)Lu value of 0.11 +/- 0.090/00. All samples have uncertainties of better than 0.110/00; hence, our technique is fully capable of resolving any differences in delta(176)Lu of greater than 10/00. PMID- 24144187 TI - Neuroglobin modification by reactive quinone species. AB - The physiological functions of neuroglobin (Ngb), the heme protein of the globin family expressed in the nervous tissue, have not yet been clarified. Besides O2 storage and homeostasis, Ngb is thought to play a role in neuroprotection as a scavenger of toxic reactive species generated in vivo under conditions of oxidative stress. Herein, the interaction of Ngb with the quinones generated by oxidation of catecholamines (dopamine, norepinephrine) and catechol estrogens (2 hydroxyestradiol and 4-hydroxyestradiol), which have been implicated in neurodegenerative pathologies like Parkinson's and Alzheimer's diseases, has been investigated. The cytotoxicity of quinones has been ascribed to the derivatization of amino acid residues (mainly cysteine) in proteins through the formation of covalent bonds with the aromatic rings. Combined studies of tandem mass spectrometry and protein unfolding indicate the presence of quinone-promoted modifications in all of the Ngb derivatives analyzed (i.e., obtained employing either catecholamines or catechol estrogens as the source of the reactive species). Among protein residues, the highest reactivity of cysteines (Cys46, Cys55, and Cys120 in human Ngb) toward quinone species has been confirmed, and the dependence of the extent of protein modification on the method employed for catechol oxidation has been observed. When the oxidation reaction proceeds by one electron steps, the involvement of semiquinone reactivity has been observed. The whole analysis of the data of Ngb modification suggests that the catecholamine oxidation products can extensively modify proteins (likely by catecholamine oligomers, the compounds initially formed during the transformation of catecholamine to melanin). The modification mediated by catechol estrogens is less pronounced but strongly affects the interactions with the solvent as well as the protein stability. PMID- 24144188 TI - QRS complex detection based on simple robust 2-D pictorial-geometrical feature. AB - In this paper a heuristic method aimed for detecting of QRS complexes without any pre-process was developed. All the methods developed in previous studies were used pre-process, the most novelty of this study was suggesting a simple method which did not need any pre-process. Toward this objective, a new simple 2-D geometrical feature space was extracted from the original electrocardiogram (ECG) signal. In this method, a sliding window was moved sample-by-sample on the pre processed ECG signal. During each forward slide of the analysis window an artificial image was generated from the excerpted segment allocated in the window. Then, a geometrical feature extraction technique based on curve-length and angle of highest point was applied to each image for establishment of an appropriate feature space. Afterwards the K-Nearest Neighbors (KNN), Artificial Neural Network (ANN) and Adaptive Network Fuzzy Inference Systems (ANFIS) were designed and implemented to the ECG signal. The proposed methods were applied to DAY general hospital high resolution holter data. For detection of QRS complex the average values of sensitivity Se = 99.93% and positive predictivity P+ = 99.92% were obtained. PMID- 24144189 TI - Photochemical modulation of biosafe manganese nanoparticles on Vigna radiata: a detailed molecular, biochemical, and biophysical study. AB - Manganese (Mn) is an essential element for plants which intervenes mainly in photosynthesis. In this study we establish that manganese nanoparticles (MnNP) work as a better micronutrient than commercially available manganese salt, MnSO4 (MS) at recommended doses on leguminous plant mung bean (Vigna radiata) under laboratory condition. At higher doses it does not impart toxicity to the plant unlike MS. MnNP-treated chloroplasts show greater photophosphorylation, oxygen evolution with respect to control and MS-treated chloroplasts as determined by biophysical and biochemical techniques. Water splitting by an oxygen evolving complex is enhanced by MnNP in isolated chloroplast as confirmed by polarographic and spectroscopic techniques. Enhanced activity of the CP43 protein of a photosystem II (PS II) Mn4Ca complex influenced better phosphorylation in the electron transport chain in the case of MnNP-treated chloroplast, which is evaluated by sodium dodecyl sulfate polyacrylamide gel electrophoresis and corresponding Western blot analysis. To the best of our knowledge this is the first report to augment photosynthesis using MnNP and its detailed correlation with different molecular, biochemical and biophysical parameters of photosynthetic pathways. At effective dosage, MnNP is found to be biosafe both in plant and animal model systems. Therefore MnNP would be a novel potential nanomodulator of photochemistry in the agricultural sector. PMID- 24144191 TI - Improved cyclic performance of Si anodes for lithium-ion batteries by forming intermetallic interphases between Si nanoparticles and metal microparticles. AB - Silicon, an anode material with the highest capacity for lithium-ion batteries, needs to improve its cyclic performance prior to practical applications. Here, we report on a novel design of Si/metal composite anode in which Si nanoparticles are welded onto surfaces of metal particles by forming intermetallic interphases through a rapid heat treatment. Unlike pure Si materials that gradually lose electrical contact with conductors and binders upon repeated charging and discharging cycles, Si in the new Si/metal composite can maintain the electrical contact with the current collector through the intermetallic interphases, which are inactive and do not lose physical contact with the conductors and binders, resulting in significantly improved cyclic performance. Within 100 cycles, only 23.8% of the capacity of the pure Si anode is left while our Si/Ni anode obtained at 900 degrees C maintains 73.7% of its capacity. Therefore, the concept of employing intermetallic interphases between Si nanoparticles and metal particles provides a new avenue to improve the cyclic performance of Si-based anodes. PMID- 24144190 TI - Long-distance transport of Gibberellic Acid Insensitive mRNA in Nicotiana benthamiana. AB - BACKGROUND: The Gibberellic Acid (GA) signal is governed by the GAI (Gibberellic Acid Insensitive) repressor, which is characterized by a highly conserved N terminal DELLA domain. Deletion of the DELLA domain results in constitutive suppression of GA signaling. As the GAI transcript is transportable in phloem elements, a Delta-DELLA GAI (gai) transgenic stock plant can reduce the stature of a scion through transport of gai mRNA from the stock. However, little is known about the characteristics of a scion on a gai stock. RESULTS: Arabidopsis Delta DELLA GAI (gai) was fused with a T7 epitope tag and expressed under the control of a companion cell-specific expression promoter, Commelina yellow mottle virus promoter (CoYMVp), to enhance transport in the phloem. The CoYMVp:Atgai-T7 (CgT) transgenic Nicotiana benthamiana exhibited a dwarf phenotype and lower sensitivity to GA enhancement of shoot stature. A wild-type (WT) scion on a CgT stock contained both Atgai-T7 mRNA and the translated product. Microarray analysis to clarify the effect of the CgT stock on the gene expression pattern in the scion clearly revealed that the WT scions on CgT stocks had fewer genes whose expression was altered in response to GA treatment. An apple rootstock variety, Malus prunifolia, integrating CoYMVp:Atgai moderately reduced the tree height of the apple cultivar scion. CONCLUSIONS: Our results demonstrate that Atgai mRNA can move from companion cells to sieve tubes and that the translated product remains at the sites to which it is transported, resulting in attenuation of GA responses by reducing the expression of many genes. The induction of semi dwarfism in an apple cultivar on root stock harbouring Atgai suggests that long distance transport of mRNA from grafts would be applicable to horticulture crops. PMID- 24144192 TI - Expression changes and novel interaction partners of talin 1 in effector cells of autoimmune uveitis. AB - Autoimmune uveitis is characterized by crossing of blood-retinal barrier (BRB) by autoaggressive immune cells. Equine recurrent uveitis (ERU) is a valuable spontaneous model for autoimmune uveitis and analyses of differentially expressed proteins in ERU unraveled changed protein clusters in target tissues and immune system. Healthy eyes are devoid of leukocytes. In ERU, however, leukocytes enter the inner eye and subsequently destroy it. Molecular mechanisms enabling cell migration through BRB still remain elusive. Previously, we detected decreased talin 1 expression in blood-derived granulocytes of ERU cases, linking the innate immune system to ERU. Because changes in leukocyte protein expression pattern may play a role in pathological abnormalities leading to migration ability, we aimed at identifying interactors of talin 1 in leukocytes with immunoprecipitation, followed by LC-MS/MS for candidate identification. This enabled us to identify CD90 (Thy1) as novel interactor of talin 1 besides several other interactors. In blood-derived granulocytes from healthy individuals, CD90 was highly abundant and significantly reduced in ERU, especially in effector cells. Connection between talin 1 and CD90 and their expression differences in inflammation is an interesting novel finding allowing deeper insight into immune response of innate immune system and granulocyte migration ability in this organ-specific autoimmune disease. PMID- 24144193 TI - Direct composite restorations--the ugly duckling classic. PMID- 24144194 TI - Hydrogenation of carboxylic acids catalyzed by half-sandwich complexes of iridium and rhodium. AB - A series of half-sandwich Ir and Rh compounds are demonstrated to be competent catalysts for the hydrogenation of carboxylic acids under relatively mild conditions. Of the structurally diverse group of catalysts tested for activity, a Cp*Ir complex supported by an electron-releasing 2,2'-bipyridine ligand was the most active. Higher activity was achieved with employment of Bronsted or Lewis acid promoters. Mechanistic studies suggest a possible reaction pathway involving activated carboxylic acid substrates. The hydrogenation reaction was shown to be general to a variety of aliphatic acids. PMID- 24144195 TI - One-pot facile synthesis of ant-cave-structured metal oxide-carbon microballs by continuous process for use as anode materials in Li-ion batteries. AB - This paper introduces a facile one-pot method for synthesizing a new structured material, named "ant-cave microball", by continuous ultrasonic spray pyrolysis. The ant-cave-structured microballs are prepared from a colloidal spray solution with polystyrene nanobeads and sucrose. Networking between the nanovoids formed by decomposition of the polystyrene nanobeads results in the formation of nanochannels. The electrochemical properties of these ant-cave-structured MoO3-C microballs, prepared as the first target material for lithium ion batteries, are investigated. The nanochannels are uniformly distributed inside the microballs with MoO3 and carbon components uniformly distributed within the microballs. Further, the microballs have initial discharge and charge capacities of 1212 and 841 mA h g(-1), respectively, at a current density of 2 A g(-1), and the initial discharge and charge capacities based on the weight of MoO3 (disregarding carbon component) are as high as 1814 and 1259 mA h g(-1). The microballs deliver a high discharge capacity of 733 mA h g(-1) even after 300 cycles. This is although microsized MoO3 powders with a filled structure have discharge capacities of 1256 and 345 mA h g(-1) for the first and 300th cycles, respectively. PMID- 24144197 TI - Day case lumbar discectomy--viable option in the UK? AB - INTRODUCTION: The inpatient length of stay for lumbar discectomy has been steadily declining, since its original description over 80 years ago. The operation was first described as a day case procedure in 1987, but only sporadically since then, especially in the UK. We describe our initial experience in introducing this service in Manchester. METHODS: Over a 2-year period, 50 of 80 patients undergoing lumbar discectomy met the inclusion criteria for day case surgery, using standard microscopic techniques and admission via a day case unit. RESULTS: Majority (N = 48) were single level, unilateral discectomies and 36 (72%) were discharged home the same day. The remainder (28%) were discharged after an overnight stay and within 24 h. Reasons for this included post-operative back pain and hypotension. Majority (N = 47), reported improvement or resolution of pre-operative back and leg pain, which was quantified using Visual analogue scores (p < 0.01). CONCLUSIONS: Lumbar microdiscectomy as a day case procedure remains a feasible and safe option in selected patients and can help free up in patient beds with a significant economic benefit also. PMID- 24144196 TI - Levomilnacipran ER 40 mg and 80 mg in patients with major depressive disorder: a phase III, randomized, double-blind, fixed-dose, placebo-controlled study. AB - BACKGROUND: Major depressive disorder (MDD) is a global health concern. This study examined the efficacy, safety and tolerability of an extended-release (ER) formulation of levomilnacipran, an antidepressant approved for the treatment of MDD in adults. METHODS: This 10-week (1-week placebo run-in period, 8-week double blind treatment, 1-week down-taper), multicentre, double-blind, placebo controlled, parallel-group, fixed-dose study was conducted between June 2011 and March 2012. Adult outpatients (age 18-75 yr) with MDD were randomly assigned (1:1:1) to placebo or to levomilnacipran ER 40 mg/day or 80 mg/day. For primary efficacy, we analyzed the Montgomery-Asberg Depression Rating Scale (MADRS) change from baseline to week 8 using a mixed-effects model for repeated-measures approach on the intent-to-treat (ITT) population. For secondary efficacy, we used the Sheehan Disability Scale (SDS), and for safety, we examined adverse events and laboratory, vital sign/physical and electrocardiography findings. RESULTS: The ITT population consisted of 185 patients in the placebo group, 185 in the levomilnacipran ER 40 mg/day group and 187 in the levomilnacipran ER 80 mg/day group. Study completion rates were similar among the groups (76%-83%). On MADRS change from baseline the least squares mean difference (LSMD) and 95% confidence interval (CI) versus placebo was significant for levomilnacipran ER 40 mg/day ( 3.3 [-5.5 to -1.1], p = 0.003) and 80 mg/day (-3.1, [-5.3 to -1.0], p = 0.004). On SDS change from baseline the LSMD (and 95% CI) versus placebo was also significant for levomilnacipran ER 40 mg/day (-1.8, 95% [-3.6 to 0], p = 0.046) and 80 mg/day (-2.7 [-4.5 to -0.9], p = 0.003). More patients in the levomilnacipran ER than the placebo group prematurely exited the study owing to adverse events; common adverse events (>= 5% and >= double the rate of placebo) were nausea, dry mouth, increased heart rate, constipation, dizziness, hyperhidrosis, urinary hesitation and erectile dysfunction. LIMITATIONS: Limitations to our study included short treatment duration and lack of an active control arm. CONCLUSION: Levomilnacipran ER at doses of 40 mg/day and 80 mg/day demonstrated efficacy on symptomatic and functional measures of MDD and was generally well tolerated in this patient population. CLINICAL TRIAL REGISTRATION: NCT01377194. PMID- 24144198 TI - A Balanced Time Perspective in Adulthood: Well-being and Developmental Effects. AB - This article presents a study that directly replicated the recently developed Balanced Time Perspective Scale (BTPS; J.D. Webster, 2011 ) and included middle aged and older adults. Participants included 90 younger, 69 middle-aged, and 69 older adults who completed the BTPS and a measure of life satisfaction and happiness. A factor analysis replicated original findings with separate subscales for a past orientation and a future orientation obtaining simple structure (alphas = .94 and .95 respectively). A balanced time perspective predicted higher scores on both measures of well-being replicating the original J.D. Webster ( 2011 ) findings. A chi-square analysis indicated, as predicted, that the percentage of younger adults tended to be higher in the future-focused category, and the percentage of older adults tended to be higher in the past-focused category. Implications of a balanced time perspective on mental health over the life course are discussed. PMID- 24144199 TI - Anticancer activity of ferrocenylthiosemicarbazones. AB - Aliphatic and aromatic ferrocenylthiosemicarbazones were synthesized. The characterization of the new ferrocenylthiosemicarbazones was done by IR, (1)H-NMR and (13)C-NMR spectroscopy, elemental analysis and X-ray diffraction studies. The biological activity of the obtained compounds was assessed in terms of anticancer activity. Their activity against U251 (human glyoblastoma), PC-3 (human prostatic adenocarcinoma), K562 (human chronic myelogenous leukemia), HCT-15 (human colorectal adenocarcinoma), MCF-7 (human mammary adenocarcinoma) and SKLU-1 (human lung adenocarcinoma) cell lines was studied and compared with cisplatin. All tested compounds showed good activity and the aryl-chloro substituted ferrocenylthiosemicarbazones showed the best anticancer activity. PMID- 24144200 TI - A gastroretentive drug delivery system of lisinopril imbibed on isabgol-husk. AB - The gastroretentive drug delivery system is site-specific and allows the drug to remain in the stomach for a prolonged period of time so that it can be released in a controlled manner in gastrointestinal tract. The present study was carried out to develop a gastroretentive drug delivery system using isabgol as an excipient to prolong the residence time of the model drug lisinopril in the stomach. The gastroretentive ability of isabgol was increased by addition of NaHCO3 as a gas-generating agent while its mucoadhesive property was enhanced by incorporation of HPMC-K4M. The drug, NaHCO3 and HPMC-K3M were imbibed on isabgol husk as per entrapment efficiency of the isabgol-husk. After drying, the product was filled in a hard gelatin capsule and evaluated for its buoyancy, mucoadhesive properties, swelling index and in vitro drug release. The lisinopril released through isabgol was delayed by 12 hours when compared to a preparation available on the market which released the complete drug in 0.5 hours. The drug release study of lisinopril from the formulation follows first order kinetics using a diffusion controlled mechanism. The results from the present study revealed that isabgol can be used as a potential excipient for the formulation of gastroretentive drug delivery systems in the near future. PMID- 24144201 TI - Early life predictors of preschool overweight and obesity: a case-control study in Sri Lanka. AB - BACKGROUND: Childhood obesity increases the risk of obesity in adulthood and is associated with cardiovascular disease risk factors. Our aim was to assess the early life risk factors associated with overweight and obesity among preschool children. METHODS: In this case-control study, from the 1087 preschool children measured, age, sex and ethnicity matched 71 cases and 71 controls were recruited. Cases and controls were defined according to the WHO 2006 growth standards. The birth and growth characteristics were extracted from the child health development records. Infant feeding practices and maternal factors were obtained from the mother. Rapid weight gain was defined as an increase in weight-for-age Z score (WHO standards) above 0.67 SD from birth to 2 years. The magnitude and significant difference in mean values of the variables associated with overweight and obesity were evaluated using logistic regressions and paired t-test, respectively. RESULTS: Cases had significantly shorter duration (months) of breastfeeding (19.4, 24.6, p = 0.003), and smaller duration (months) of exclusive breastfeeding (3.7, 5.1, p = 0.001) compared to controls. Rapid weight gain (OR = 6.3, 95% CI = 2.04-19.49), first born status (OR = 3.6, 95% CI = 1.17-10.91) and pre-pregnancy obesity (OR = 4.0, 95% CI = 1.46-10.76) were positively associated with overweight and obesity. Breastfeeding more than 2 years (OR = 0.2, 95% CI = 0.06-0.57) was negatively associated with overweight and obesity. CONCLUSION: Rapid weight gain within first two years, first-born status and pre-pregnancy obesity of the mother contributed for preschool obesity. Our results suggest that intervention may be indicated earlier in infancy and during the toddler and preschool years to tackle the increasing prevalence of obesity. PMID- 24144202 TI - Detection of nine Mediterranean beta-thalassemia mutations in Palestinians using three restriction enzyme digest panels: a reliable method for developing countries. AB - beta-Thalassemia (beta-thal) is a public health problem in the Gaza Strip, Palestine, where about 320 patients are currently managed through blood transfusions and iron chelation. Within the restrictive environment of the Gaza Strip, no advanced molecular analysis [sequencing, real-time polymerase chain reaction (real-time PCR)] technology is currently available for developing a premarital screening protocol and providing couples at risk with prenatal diagnosis. Therefore, genetic identification of samples with indicators of beta thal is delayed for weeks before the samples can be sequenced outside the country. As nine causative mutations have been identified in the majority of beta thal cases in the Gaza Strip, a basic genetic screening strategy was designed to improve timeliness in mutation identification and reduce costs to the Palestinian health system. In the present study, we developed a reliable method for the detection of nine Mediterranean beta-thal mutations common to the Palestinian population using a panel of restriction enzyme digests. This strategy utilizes standard instrumentation (thermocycler and agarose gel electrophoresis) that would be available in any basic molecular genetics or biochemical laboratory and provides a reliable method of genetic screening and counseling for patients at risk for beta-thal. PMID- 24144203 TI - Stereocomplementary bioreduction of beta-ketonitrile without ethylated byproduct. AB - alpha-Ethylation is competing with the biocatalytic reduction of aromatic beta ketonitriles in a whole-cell system. Use of two newly mined robust and stereocomplementary carbonyl reductases in a biphasic system has completely eliminated the competing byproduct. For the first time, both enantiomers of fluoroxetine precursors were obtained at 0.5 M with >99% ee and excellent chemoselectivity, without addition of any external cofactors. PMID- 24144204 TI - Oxidation reaction of polyether-based material and its suppression in lithium rechargeable battery using 4 V class cathode, LiNi1/3Mn1/3Co1/3O2. AB - The all solid-state lithium battery with polyether-based solid polymer electrolyte (SPE) is regarded as one of next-generation lithium batteries, and has potential for sufficient safety because of the flammable-electrolyte-free system. It has been believed that polyether-based SPE is oxidized at the polymer/electrode interface with 4 V class cathodes. Therefore, it has been used for electric devices such as organic transistor, and lithium battery under 3 V. We estimated decomposition reaction of polyether used as SPE of all solid-state lithium battery. We first identified the decomposed parts of polyether-based SPE and the conservation of most main chain framework, considering the results of SPE analysis after long cycle operations. The oxidation reaction was found to occur slightly at the ether bond in the main chain with the branched side chain. Moreover, we resolved the issue by introducing a self-sacrificing buffer layer at the interface. The introduction of sodium carboxymethyl cellulose (CMC) to the 4 V class cathode surface led to the suppression of SPE decomposition at the interface as a result of the preformation of a buffer layer from CMC, which was confirmed by the irreversible exothermic reaction during the first charge, using electrochemical calorimetry. The attained 1500 cycle operation is 1 order of magnitude longer than those of previously reported polymer systems, and compatible with those of reported commercial liquid systems. The above results indicate to proceed to an intensive research toward the realization of 4 V class "safe" lithium polymer batteries without flammable liquid electrolyte. PMID- 24144205 TI - Heat-inducible gene expression system by applying alternating magnetic field to magnetic nanoparticles. AB - By combining synthetic biology with nanotechnology, we demonstrate remote controlled gene expression using a magnetic field. Magnetite nanoparticles, which generate heat under an alternating magnetic field, have been developed to label cells. Magnetite nanoparticles and heat-induced therapeutic genes were introduced into tumor xenografts. The magnetically triggered gene expression resulted in tumor growth inhibition. This system shows great potential for controlling target gene expression in a space and time selective manner and may be used for remote control of cell functions via gene expression. PMID- 24144206 TI - Photophysics and release kinetics of enzyme-activatable optical probes based on H dimerized fluorophores on self-immolative linkers. AB - A series of activatable optical probes for the model enzyme penicillin G amidase based on intramolecular formation of non-fluorescent H-dimer between two identical dyes were synthesized. The probes are based on a self-immolative linker, which allows positioning both dyes in close spatial proximity to ensure efficient quenching of probes with absorption and fluorescence emission in the near-infrared (NIR) range. A detailed photophysical investigation of the novel optical probes led to a revision of a previously anticipated quenching mechanism and revealed their potential for optimizing the performance of activatable probes based on H-dimer formation. A kinetic analysis indicated that the fluorescence progress curves can be used to qualitatively extract enzyme kinetic parameters. PMID- 24144207 TI - Crucial protein based drug targets and potential inhibitors for osteoporosis: new hope and possibilities. AB - Osteoporosis, a multifaceted bone disorder, is considered as a serious health problem throughout the world and the magnitude of diseased patients is increasing day by day. A number of successful therapeutics is available in the market for treatment. However, upon long-term administration, most of these drugs cause side effects with some limitations. Henceforth, development of new therapeutic strategies can be a way to solve this problem as well as to develop cost effective and better tolerated therapies. Detailed understanding about the mechanistic action of the drug targets can be a great aid in the drug development process. Here in this review, we discussed the existing potential protein target class and their inhibitors related to osteoporosis. We have highlighted the existing potential protein drug targets, oestrogen receptor, calcium sensing receptor, P2Y receptor, activin receptor, calcitonin receptor, therapeutic manipulation of protease class such as cathepsin K, targeting WNT/ beta-catenin signaling and targeting RANK-RANKL signaling pathway, TNF inhibition through TNF receptor. We hope this detailed report will provide a better way of understanding towards the discovery and also for development of novel therapeutics. PMID- 24144208 TI - Microneedle-based drug delivery systems for transdermal route. AB - Transdermal delivery offers an attractive, noninvasive administration route but it is limited by the skin's barrier to penetration. Minimally invasive techniques, such as the use of microneedles (MNs), bypass the stratum corneum (SC) barrier to permit the drug's direct access to the viable epidermis. These novel micro devices have been developed to puncture the skin for the transdermal delivery of hydrophilic drugs and macromolecules, including peptides, DNA and other molecules, that would otherwise have difficulty passing the outermost layer of the skin, the SC. Using the tools of the microelectronics industry, MNs have been fabricated with a range of sizes, shapes and materials. MNs have been shown to be robust enough to penetrate the skin and dramatically increase the skin permeability of several drugs. Moreover, MNs have reduced needle insertion pain and tissue trauma and provided controlled delivery across the skin. This review focuses on the current state of the art in the transdermal delivery of drugs using various types of MNs and developments in the field of microscale devices, as well as examples of their uses and clinical safety. PMID- 24144210 TI - Vestibular migraine: an emerging diagnosis. PMID- 24144211 TI - Fluorinated benzothiadiazole-based conjugated polymers for high-performance polymer solar cells without any processing additives or post-treatments. AB - Thanks to their many favorable advantages, polymer solar cells exhibit great potential for next-generation clean energy sources. Herein, we have successfully designed and synthesized a series of new fluorinated benzothiadiazole-based conjugated copolymers PBDT(TEH)-DT(H)BTff (P1), PBDT(TEH)-DT(EH)BTff (P2), and PBDT(HDO)-DT(H)BTff (P3). The power conversion efficiencies of 4.46, 6.20, and 8.30% were achieved for P1-, P2-, and P3-based devices within ~100 nm thickness active layers under AM 1.5G illumination without any processing additives or post treatments, respectively. The PCE of 8.30% for P3 is the highest value for the reported traditional single-junction polymer solar cells via a simple fabrication architecture without any additives or post-treatments. In addition, it is noteworthy that P3 also allows making high efficient polymer solar cells with high PCEs of 7.27 and 6.56% under the same condition for ~200 and ~300 nm thickness active layers, respectively. Excellent photoelectric properties and good solubility make polymer P3 become an alternative material for high performance polymer solar cells. PMID- 24144209 TI - HIF-1alpha activation results in actin cytoskeleton reorganization and modulation of Rac-1 signaling in endothelial cells. AB - BACKGROUND: Hypoxia is a major driving force in vascularization and vascular remodeling. Pharmacological inhibition of prolyl hydroxylases (PHDs) leads to an oxygen-independent and long-lasting activation of hypoxia-inducible factors (HIFs). Whereas effects of HIF-stabilization on transcriptional responses have been thoroughly investigated in endothelial cells, the molecular details of cytoskeletal changes elicited by PHD-inhibition remain largely unknown. To investigate this important aspect of PHD-inhibition, we used a spheroid-on-matrix cell culture model. RESULTS: Microvascular endothelial cells (glEND.2) were organized into spheroids. Migration of cells from the spheroids was quantified and analyzed by immunocytochemistry. The PHD inhibitor dimethyloxalyl glycine (DMOG) induced F-actin stress fiber formation in migrating cells, but only weakly affected microvascular endothelial cells firmly attached in a monolayer. Compared to control spheroids, the residual spheroids were larger upon PHD inhibition and contained more cells with tight VE-cadherin positive cell-cell contacts. Morphological alterations were dependent on stabilization of HIF-1alpha and not HIF-2alpha as shown in cells with stable knockdown of HIF-alpha isoforms. DMOG treated endothelial cells exhibited a reduction of immunoreactive Rac-1 at the migrating front, concomitant with a diminished Rac-1 activity, whereas total Rac 1 protein remained unchanged. Two chemically distinct Rac-1 inhibitors mimicked the effects of DMOG in terms of F-actin fiber formation and orientation, as well as stabilization of residual spheroids. Furthermore, phosphorylation of p21 activated kinase PAK downstream of Rac-1 was reduced by DMOG in a HIF-1alpha dependent manner. Stabilization of cell-cell contacts associated with decreased Rac-1 activity was also confirmed in human umbilical vein endothelial cells. CONCLUSIONS: Our data demonstrates that PHD inhibition induces HIF-1alpha dependent cytoskeletal remodeling in endothelial cells, which is mediated essentially by a reduction in Rac-1 signaling. PMID- 24144212 TI - Optimizing the dose of hydroxyurea therapy for patients with beta-thalassemia intermedia (Hb E-beta-thalassemia): a single center study from Eastern India. AB - Over the past 20 years, hydroxyurea (HU) has emerged as an important therapeutic agent to augment Hb F and thus total hemoglobin (Hb) in Hb E [beta26(B8)Glu->Lys; HBB: c.79G > A]-beta-thalassemia (Hb E-beta-thal), albeit used in varying doses with little consensus on its optimal dose. We report the interim analysis findings of a broader study to assess the impact of Comprehensive Thalassemia Care, of which the present report was a part. Sixty-one Hb E-beta-thal patients who were transfusion independent or requiring occasional transfusions [beta-thal intermedia (beta-TI)] were randomized to one of two groups; A (n = 32) and B (n = 29) to receive 10 and 20 mg/kg/day HU, respectively. The primary objective of the study was to assess the differences in responses to different doses of HU. Secondary end points were to see the tolerability and safety of HU in different doses. Good response (GR) was defined as a rise of Hb by > 1.0 g/dL; intermediate response (IR) as a rise in Hb by 0.6-1.0 g/dL anytime during the study period. No response (NR): rise in Hb by < 0.5 g/dL in 12 weeks or drop in Hb level from the previous value. Over a follow-up period of 24 weeks, we had 18 (56.2%) GRs, nine (28.2%) IRs and five (15.6%) NRs, while the number of GRs, IRs and NRs in group B were five (17.2%) 12 (41.4%) and 12 (41.4%), respectively. Adverse effects were more common in group B, making this dose (20 mg/kg/day) of HU more myelo suppressive than Hb F inducing. PMID- 24144213 TI - Discovery of GS-9669, a thumb site II non-nucleoside inhibitor of NS5B for the treatment of genotype 1 chronic hepatitis C infection. AB - Investigation of thiophene-2-carboxylic acid HCV NS5B site II inhibitors, guided by measurement of cell culture medium binding, revealed the structure-activity relationships for intrinsic cellular potency. The pharmacokinetic profile was enhanced through incorporation of heterocyclic ethers on the N-alkyl substituent. Hydroxyl groups were incorporated to modulate protein binding. Intrinsic potency was further improved through enantiospecific introduction of an olefin in the N acyl motif, resulting in the discovery of the phase 2 clinical candidate GS-9669. The unexpected activity of this compound against the clinically relevant NS5B M423T mutant, relative to the wild type, was shown to arise from both the N-alkyl substituent and the N-acyl group. PMID- 24144214 TI - Rapid combinatorial ERLIC-SCX solid-phase extraction for in-depth phosphoproteome analysis. AB - Protein phosphorylation is an important mechanism of cellular signaling, and many proteins are precisely regulated through the interplay of stimulatory and inhibitory phosphorylation sites. Phosphoproteomics offers great opportunities to unravel this complex interplay, generating a mechanistic understanding of vital cellular processes. However, protein phosphorylation is substoichiometric and, in particular, peptides carrying multiple phosphorylation sites are extremely difficult to detect in a highly complex mixture of abundant nonphosphorylated peptides. Chromatographic methods are employed to reduce sample complexity and thereby significantly increase the number of phosphopeptide identifications. We previously demonstrated that combinatorial strong cation exchange-electrostatic repulsion-hydrophilic interaction chromatography yields a surplus in overall identifications of phosphopeptides compared with single chromatographic approaches. Here we present a simple and rapid strategy implemented as solid phase extraction not requiring specific instrumentation such as off-line HPLC systems. It is inexpensive, adaptable for high and low amounts of starting material, and saves time by allowing multiplexed sample preparation without any carry-over problem. PMID- 24144215 TI - The efficacy of intravenous paracetamol versus dipyrone for postoperative analgesia after day-case lower abdominal surgery in children with spinal anesthesia: a prospective randomized double-blind placebo-controlled study. AB - BACKGROUND: A multimodal and preventative approach to providing postoperative analgesia is becoming increasingly popular for children and adults, with the aim of reducing reliance on opioids. We conducted a prospective, randomized double blind study to compare the analgesic efficacy of intravenous paracetamol and dipyrone in the early postoperative period in school-age children undergoing lower abdominal surgery with spinal anesthesia. METHODS: Sixty children scheduled for elective lower abdominal surgery under spinal anesthesia were randomized to receive either intravenous paracetamol 15 mg/kg, dipyrone 15 mg/kg or isotonic saline. The primary outcome measure was pain at rest, assessed by means of a visual analog scale 15 min, 30 min, 1 h, 2 h, 4 h and 6 h after surgery. If needed, pethidine 0.25 mg/kg was used as the rescue analgesic. Time to first administration of rescue analgesic, cumulative pethidine requirements, adverse effects and complications were also recorded. RESULTS: There were no significant differences in age, sex, weight, height or duration of surgery between the groups. Pain scores were significantly lower in the paracetamol group at 1 h (P = 0.030) and dipyrone group at 2 h (P = 0.010) when compared with placebo. The proportion of patients requiring rescue analgesia was significantly lower in the paracetamol and dipyrone groups than the placebo group (vs. paracetamol P = 0.037; vs. dipyrone P = 0.020). Time to first analgesic requirement appeared shorter in the placebo group but this difference was not statistically significant, nor were there significant differences in pethidine requirements, adverse effects or complications. CONCLUSION: After lower abdominal surgery conducted under spinal anesthesia in children, intravenous paracetamol appears to have similar analgesic properties to intravenous dipyrone, suggesting that it can be used as an alternative in the early postoperative period. TRIAL REGISTRATION: Clinical Trials.gov. Identifier: NCT01858402. PMID- 24144217 TI - Time, rationality, and human existence. PMID- 24144218 TI - Characteristic molecular signatures of early exposure to volatile organic compounds in rat liver. AB - OBJECTIVE: Investigation on whether the characteristic molecular signatures can discriminate individual volatile organic compounds (VOCs) and provide predictive markers for the detection of VOC exposure. METHODS: Transcriptomic analysis of liver tissues was performed 48 h after the single oral administration of three VOCs doses at LD25 or LD5 values, to Sprague-Dawley. RESULTS: Combination analysis of different multi-classifications suggested that 145 genes predicted VOC exposure. Additionally, Gene Set Enrichment Analysis of genes deregulated by VOCs revealed that T cell prolymphatic leukemia signaling was inactivated in all VOCs. CONCLUSIONS: These molecular markers could be widely implemented to assess and predict environmental exposure to VOCs. PMID- 24144219 TI - Omega-3 fatty acids regulate the interaction of the Alzheimer's abeta(25-35) peptide with lipid membranes. AB - Polyunsaturated omega-3 fatty acids are increasingly proposed as dietary supplements able to reduce the risk of development or progression of the Alzheimer's disease (AD). To date, the molecular mechanism through which these lipids act has not been yet univocally identified. In this work, we investigate whether omega-3 fatty acids could interfere with the fate of the Alzheimer related amyloid peptide by tuning the microstructural and dynamical properties of the neuronal membrane. To this aim, the influence of the omega-3 lipid, 1,2 didocosahexaenoyl-sn-glycero-3-phosphocholine [22:6(cis)PC] on the biophysical properties of lipid bilayers, and on their interaction with the amyloid peptide fragment Abeta(25-35) has been investigated by Electron Spin Resonance (ESR), using spin-labeled phospholipids. The results show that the peptide selectively interacts with bilayers enriched in cholesterol (Chol) and sphingomyelin (SM). [22:6(cis)PC] enhances the Abeta(25-35)/membrane interaction, favoring a deeper internalization of the peptide among the lipid acyl chains and, consequently, hindering its pathogenic self-aggregation. PMID- 24144220 TI - Alpha-lipoic acid-loaded nanostructured lipid carrier: sustained release and biocompatibility to HaCaT cells in vitro. AB - ALA-loaded nanostructured lipid carrier (ALA-NLC) was designed to improve physicochemical stability and water solubility, and promote sustained release of ALA as well as determine the biocompatibility of ALA-NLC. The ALA-NLC manufactured using hot high-pressure homogenization technique was investigated in terms of size, zeta potential, FTIR analysis and release behavior. In vitro cytotoxicity and biocompatibility were determined by incubating with HaCaT cells using the MTT assay, HE staining and Hoechst 33342 staining. Cell behavior and cellular division of HaCaT cells untreated and treated by ALA-NLC were investigated in real-time images gathered using time-lapse imaging system. The release investigation illustrated that only 6.9% of ALA released in 30 min from ALA-NLC formation, whereas it was 30.3% in free ALA system. ALA-NLC possessed a satisfactory release behavior of sustained release up to 72 h. It showed that ALA NLC did not exert hazardous effect on HaCaT cells up to 81.9 mg/L without morphological alterations, revealing a satisfactory biocompatibility. Evidence was provided from time-lapse imaging system that cell behavior and cellular division of ALA-NLC treated HaCaT cells were in accordance with the control. These results of this investigation demonstrated that NLC encapsulated ALA formation (ALA-NLC) can improve stability, solubility and release of ALA; ALA-NLC was biocompatible to HaCaT cells. PMID- 24144221 TI - Intersection of migration and turnover theories-What can we learn? AB - BACKGROUND: The international migration of nurses has become a major issue in the international health and workforce policy circles, but analyses are not based on a comprehensive theory. PURPOSE: The purpose of this article was to compare the concepts of an integrated nursing turnover theory with the concepts of one international migration framework. METHODS: An integrated turnover theory is compared with a frequently used migration framework using examples of each. DISCUSSION: Migration concepts relate well to turnover concepts, but the relative importance and strength of various concepts may differ. For example, identification, development, and measurement of the concept of national commitment, if it exists, is parallel to organizational commitment and may be fruitful in understanding the processes that lead to nurse migration. CONCLUSIONS: The turnover theory provides a framework for examining migration concepts and considering how these concepts could relate to each other in a future theory of migration. Ultimately, a better understanding of the relationships and strengths of these concepts could lead to more effective policy. PMID- 24144223 TI - Raised numbers of IgG4-positive plasma cells are a common histopathological finding in orbital xanthogranulomatous disease. AB - PURPOSE: To determine the relation of orbital xanthogranuloma with IgG4-related disease. METHODS: Retrospective consecutive case series over a period of 25 years. We searched our charts for histologically confirmed orbital xanthogranuloma. Patient files were reviewed for clinical and follow up data including presence or absence of systemic non-ophthalmic manifestations of IgG4 related disease. Slides were re-examined and histopathological classification was re-assessed. Sixteen cases of orbital xanthogranuloma were evaluated. Immunohistochemical stains for IgG and IgG4 were performed. Positive immunohistochemical staining required increased IgG4-positive plasma cells in the involved tissues scored as >50 per high-power field, with IgG4/IgG ratio >0.40. RESULTS: According to the criteria described above 8/16 (50%) cases showed increased numbers of IgG4-positive plasma cells in the specimens. Two of these patients may have had signs of systemic disease. CONCLUSION: Raised numbers of IgG4-positive plasma cells are a common finding in histopathological specimens of xanthogranulomatous disease of the orbit and are often not indicative for IgG4 related systemic disease. PMID- 24144222 TI - MAGNEsium Trial In Children (MAGNETIC): a randomised, placebo-controlled trial and economic evaluation of nebulised magnesium sulphate in acute severe asthma in children. AB - BACKGROUND: There are few data on the role of nebulised magnesium sulphate (MgSO4) in the management of acute asthma in children. Those studies that have been published are underpowered, and use different methods, interventions and comparisons. Thus, no firm conclusions can be drawn. OBJECTIVES: Does the use of nebulised MgSO4, when given as an adjunct to standard therapy in acute severe asthma in children, result in a clinical improvement when compared with standard treatment alone? DESIGN: Patients were randomised to receive three doses of MgSO4 or placebo, each combined with salbutamol and ipratropium bromide, for 1 hour. The Yung Asthma Severity Score (ASS) was measured at baseline, randomisation, and at 20, 40, 60 (T60), 120, 180 and 240 minutes after randomisation. SETTING: Emergency departments and children's assessment units at 30 hospitals in the UK. PARTICIPANTS: Children aged 2-15 years with acute severe asthma. INTERVENTIONS: Patients were randomised to receive nebulised salbutamol 2.5 mg (ages 2-5 years) or 5 mg (ages >= 6 years) and ipratropium bromide 0.25 mg mixed with either 2.5 ml of isotonic MgSO4 (250 mmol/l, tonicity 289 mOsm; 151 mg per dose) or 2.5 ml of isotonic saline on three occasions at approximately 20-minute intervals. MAIN OUTCOME MEASURES: The primary outcome measure was the ASS after 1 hour of treatment. Secondary measures included 'stepping down' of treatment at 1 hour, number and frequency of additional salbutamol administrations, length of stay in hospital, requirement for intravenous bronchodilator treatment, and intubation and/or admission to a paediatric intensive care unit. Data on paediatric quality of life, time off school/nursery, health-care resource usage and time off work were collected 1 month after randomisation. RESULTS: A total of 508 children were recruited into the study; 252 received MgSO4 and 256 received placebo along with the standard treatment. There were no differences in baseline characteristics. There was a small, but statistically significant difference in ASS at T60 in those children who received nebulised MgSO4 {0.25 [95% confidence interval (CI) 0.02 to 0.48]; p = 0.034} and this difference was sustained for up to 240 minutes [0.20 (95% CI 0.01 to 0.40), p = 0.042]. The clinical significance of this gain is uncertain. Assessing treatment-covariate interactions, there is evidence of a larger effect in those children with more severe asthma exacerbations ( p = 0.034) and those with a shorter duration of symptoms ( p = 0.049). There were no significant differences in the secondary outcomes measured. Adverse events (AEs) were reported in 19% of children in the magnesium group and 20% in the placebo group. There were no clinically significant serious AEs in either group. The results of the base-case economic analyses are accompanied by considerable uncertainty, but suggest that, from an NHS and Personal Social Services perspective, the addition of magnesium to standard treatment may be cost effective compared with standard treatment only. The results of economic evaluation show that the probability of magnesium being cost-effective is over 60% at cost-effectiveness thresholds of L1000 per unit decrement in ASS and L20,000 per quality-adjusted life-year (QALY) gained, respectively; it is noted that for some parameter variations this probability is much lower, reflecting the labile nature of the cost-effectiveness ratio in light of the small differences in benefits and costs shown in the trial and the relation between the main outcome measure (ASS) and preference based measures of quality of life used in cost-utility analysis (European Quality of Life-5 Dimensions; EQ-5D). CONCLUSIONS: This study supports the use of nebulised isotonic MgSO4 at the dose of 151 mg given three times in the first hour of treatment as an adjuvant to standard treatment when a child presents with an acute episode of severe asthma. No harm is done by adding magnesium to salbutamol and ipratropium bromide, and in some individuals it may be clinically helpful. The response is likely to be more marked in those children with more severe attacks and with a shorter duration of exacerbation. Although the study was not powered to demonstrate this fully, the data certainly support the hypotheses that nebulised magnesium has a greater clinical effect in children who have more severe exacerbation with shorter duration of symptoms. TRIAL REGISTRATION: Current Controlled Trials ISRCTN81456894. FUNDING: The National Institute for Health Research Health Technology Assessment programme. PMID- 24144224 TI - Surface charge controls the fate of Au nanorods in saline estuaries. AB - This work reports the distribution of negatively charged, gold core nanoparticles in a model marine estuary as a function of time. A single dose of purified polystyrene sulfonate (PSS)-coated gold nanorods was added to a series of three replicate estuarine mesocosms to emulate an abrupt nanoparticle release event to a tidal creek of a Spartina -dominated estuary. The mesocosms contained several phases that were monitored: seawater, natural sediments, mature cordgrass, juvenile northern quahog clam, mud snails, and grass shrimp. Aqueous nanorod concentrations rose rapidly upon initial dosing and then fell to stable levels over the course of approximately 50 h, after which they remained stable for the remainder of the experiment (41 days total). The concentration of nanorods rose in all other phases during the initial phase of the experiment; however, some organisms demonstrated depuration over extended periods of time (100+ h) before removal from the dosed tanks. Clams and biofilm samples were also removed from the contaminated tanks post-exposure to monitor their depuration in pristine seawater. The highest net uptake of gold (mass normalized) occurred in the biofilm phase during the first 24 h, after which it was stable (to the 95% level of confidence) throughout the remainder of the exposure experiment. The results are compared against a previous study of positively charged nanoparticles of the same size to parameterize the role of surface charge in determining nanoparticle fate in complex aquatic environments. PMID- 24144226 TI - Buyer beware! Think twice when selecting a journal (or attending a conference). PMID- 24144225 TI - Health economics perspective of fesoterodine, tolterodine or solifenacin as first time therapy for overactive bladder syndrome in the primary care setting in Spain. AB - BACKGROUND: Overactive bladder (OAB) is associated with high healthcare costs, which may be partially driven by drug treatment. There is little comparative data on antimuscarinic drugs with respect to resource use and costs. This study was conducted to address this gap and the growing need for naturalistic studies comparing health economics outcomes in adult patients with OAB syndrome initiating treatment with different antimuscarinic drugs in a primary care setting in Spain. METHODS: Medical records from the databases of primary healthcare centres in three locations in Spain were assessed retrospectively. Men and women >=18 years of age who initiated treatment with fesoterodine, tolterodine or solifenacin for OAB between 2008 and 2010 were followed for 52 weeks. Healthcare resource utilization and related costs in the Spanish National Health System were compared. Comparisons among drugs were made using multivariate general linear models adjusted for location, age, sex, time since diagnosis, Charlson comorbidity index, and medication possession ratio. RESULTS: A total of 1,971 medical records of patients (58.3% women; mean age, 70.1 [SD:10.6] years) initiating treatment with fesoterodine (n = 302), solifenacin (n = 952) or tolterodine (n = 717) were examined. Annual mean cost per patient was ?1798 (95% CI: ?1745; ?1848). Adjusted mean (95% bootstrap CI) healthcare costs were significantly lower in patients receiving fesoterodine (?1639 [1542; 1725]) compared with solifenacin (?1780 [?1699; ?1854], P = 0.022) or tolterodine (?1893 [?1815; ?1969], P = 0.001). Cost differences occurred because of significantly fewer medical visits, and less use of absorbent products and OAB-related concomitant medication in the fesoterodine group. CONCLUSIONS: Compared with solifenacin and tolterodine, fesoterodine was a cost-saving therapy for treatment of OAB in the primary care setting in Spain. PMID- 24144227 TI - Body mass and osteoarthritic pain: results from a study in general practice. AB - OBJECTIVES: To define the relationship between BMI and pain due to osteoarthritis (OA) of the hand, hip, and knee in patients seen in general practice; to evaluate if overweight is related to co-morbidity and education, and influences the prescription patterns of GPs. METHODS: 2,764 Italian GPs recruited 10 consecutive patients with symptomatic OA, diagnosed according to the ACR criteria. Pain intensity on a visual analogue scale, BMI, years of formal education, comorbidities, pharmacological and non-pharmacological interventions, and referral to specialists were recorded. RESULTS: The most painful joints were the knee in 12,827 patients (53.6%), the hip in 5,645 (23.6%), and the hand in 5,467 (22.8%). A BMI indicative of overweight or obesity was found in 74.8% of men and in 68.3% of women. Mean BMI was higher in knee OA (27.9+/-3.9), in generalised OA (27.5+/-4.2), and hip OA (27+/-3.7) than in hand OA (25.5+/-3.4). The prevalence of obesity for hip and knee OA was higher than that reported for the general Italian population. Obesity was an important risk factor for pain in all OA localisations. Co-morbidities and lower education were associated with obesity and more intense pain (p<0.0001). Obesity and overweight were less frequent in institutionalised patients. CONCLUSIONS: Our study confirms that more than two thirds of Italian patients with symptomatic OA seen by GPs are overweight or obese. Obesity is clearly associated with OA pain, a finding which is probably underestimated by GPs who are not used to modulate treatment and specialist referral according to patients' BMI. PMID- 24144229 TI - P-Stereogenic PCP pincer-Pd complexes: synthesis and application in asymmetric addition of diarylphosphines to nitroalkenes. AB - Novel P-stereogenic PCP pincer-Pd complexes were designed and prepared in short steps from optically pure tert-butylmethylphosphine-borane. These optically active Pd-complexes were successfully applied in asymmetric addition of diarylphosphines to nitroalkenes with high yields and good enantioselectivity. PMID- 24144228 TI - Layer-by-layer nanoparticles for systemic codelivery of an anticancer drug and siRNA for potential triple-negative breast cancer treatment. AB - A single nanoparticle platform has been developed through the modular and controlled layer-by-layer process to codeliver siRNA that knocks down a drug resistance pathway in tumor cells and a chemotherapy drug to challenge a highly aggressive form of triple-negative breast cancer. Layer-by-layer films were formed on nanoparticles by alternately depositing siRNA and poly-l-arginine; a single bilayer on the nanoparticle surface could effectively load up to 3500 siRNA molecules, and the resulting LbL nanoparticles exhibit an extended serum half-life of 28 h. In animal models, one dose via intravenous administration significantly reduced the target gene expression in the tumors by almost 80%. By generating the siRNA-loaded film atop a doxorubicin-loaded liposome, we identified an effective combination therapy with siRNA targeting multidrug resistance protein 1, which significantly enhanced doxorubicin efficacy by 4 fold in vitro and led to up to an 8-fold decrease in tumor volume compared to the control treatments with no observed toxicity. The results indicate that the use of layer-by-layer films to modify a simple liposomal doxorubicin delivery construct with a synergistic siRNA can lead to significant tumor reduction in the cancers that are otherwise nonresponsive to treatment with Doxil or other common chemotherapy drugs. This approach provides a potential strategy to treat aggressive and resistant cancers, and a modular platform for a broad range of controlled multidrug therapies customizable to the cancer type in a singular nanoparticle delivery system. PMID- 24144230 TI - A fingerprint pair analysis of hERG inhibition data. AB - BACKGROUND: Drugs that bind to the human Ether-a-go-go Related Gene (hERG) potassium channel and block its ion conduction can lead to Torsade de Pointes (TdP), a fatal ventricular arrhythmia. Thus, compounds are screened for hERG inhibition in the drug development process; those found to be active face a difficult road to approval. Knowing which structural transformations reduce hERG binding would be helpful in the lead optimization phase of drug discovery. RESULTS: To identify such transformations, we carried out a comprehensive analysis of all approximately 33,000 compound pairs in the Novartis internal database which have IC50 values in the dofetilide displacement assay. Most molecular transformations have only a single example in the data set; however, a few dozen transformations have sufficient numbers for statistical analysis. CONCLUSIONS: We observe that transformations which increased polarity (for example adding an oxygen, or an sp2 nitrogen), decreased lipophilicity (removing carbons), or decreased positive charge consistently reduced hERG inhibition between 3- and 10-fold. The largest observed reduction in hERG was from a transformation from imidazole to methyl tetrazole. We also observe that some changes in aromatic ring substituents (for example hydrogen to methoxy) can also reduce hERG binding in vitro. PMID- 24144231 TI - Two novel mutations (HBG1: c.-250C > T and HBG2: c.-250C > T) associated with hereditary persistence of fetal hemoglobin. AB - Mutations within the promoters of either of the gamma-globin genes [(G)gamma (HBG1) and (A)gamma (HBG2)] lead to variably increased levels of fetal hemoglobin (Hb) (Hb F, alpha2gamma2) in the syndrome of hereditary persistence of fetal Hb (HPFH). Carriers of such mutations are clinically asymptomatic and the mutations are usually detected as part of routine screening or family studies. We describe two new nondeletional HPFH mutations, both C > T substitutions at position c. 250, one in the HBG1 and the other in the HBG2 globin gene promoters. PMID- 24144232 TI - Additive insulinogenic action of Opuntia ficus-indica cladode and fruit skin extract and leucine after exercise in healthy males. AB - BACKGROUND: Oral intake of a specific extract of Opuntia ficus-indica cladode and fruit skin (OpunDiaTM) (OFI) has been shown to increase serum insulin concentration while reducing blood glucose level for a given amount of glucose ingestion after an endurance exercise bout in healthy young volunteers. However, it is unknown whether OFI-induced insulin stimulation after exercise is of the same magnitude than the stimulation by other insulinogenic agents like leucine as well as whether OFI can interact with those agents. Therefore, the aims of the present study were: 1) to compare the degree of insulin stimulation by OFI with the effect of leucine administration; 2) to determine whether OFI and leucine have an additive action on insulin stimulation post-exercise. METHODS: Eleven subjects participated in a randomized double-blind cross-over study involving four experimental sessions. In each session the subjects successively underwent a 2-h oral glucose tolerance test (OGTT) after a 30-min cycling bout at ~70% VO2max. At t0 and t60 during the OGTT, subjects ingested 75 g glucose and capsules containing either 1) a placebo; 2) 1000 mg OFI; 3) 3 g leucine; 4) 1000 mg OFI + 3 g leucine. Blood samples were collected before and at 30-min intervals during the OGTT for determination of blood glucose and serum insulin. RESULTS: Whereas no effect of leucine was measured, OFI reduced blood glucose at t90 by ~7% and the area under the glucose curve by ~15% and increased serum insulin concentration at t90 by ~35% compared to placebo (P<0.05). From t60 to the end of the OGTT, serum insulin concentration was higher in OFI+leucine than in placebo which resulted in a higher area under the insulin curve (+40%, P<0.05). CONCLUSION: Carbohydrate-induced insulin stimulation post-exercise can be further increased by the combination of OFI with leucine. OFI and leucine could be interesting ingredients to include together in recovery drinks to resynthesize muscle glycogen faster post-exercise. Still, it needs to be confirmed that such nutritional strategy effectively stimulates post-exercise muscle glycogen resynthesis. PMID- 24144233 TI - Performance of ELISA and PCR methods for the determination of allergens in food: an evaluation of six years of proficiency testing for soy (Glycine max L.) and wheat gluten (Triticum aestivum L.). AB - For the routine detection of allergens in foods, PCR and/or ELISA methods are employed. To assess the suitability of these methods, proficiency tests (PTs) could be used as a valuable instrument. It is a common practice to evaluate the results with respect to the experimentally obtained robust mean without considering the actual allergen content. In the present study, an overview is given of the results of allergen PTs for the determination of soy and gluten conducted by Dienstleistung Lebensmittel Analytik GbR (DLA). A total of 16 PTs were evaluated with respect to the comparison of PCR and ELISA performances and a new focus on the actually spiked values. The analytes were added in the ranges of 7.8-6264 mg/kg (gluten) and 184-5500 mg/kg (soy protein) in differently composed matrices such as pastry, infant food, and sausage meat. The evaluation of the PTs showed a widely reliable qualitative detection of both allergens by PCR methods. ELISA performances differed for soy and gluten. Although a high number of false negative results occurred for the detection of soy, the qualitative detection of gluten was appropriate. Quantitative results showed obvious test kit-specific differences for the ELISA methods, but the limits of quantification were suitable for gluten determination. Both ELISA and PCR methods demonstrated their valuable contribution in food allergen determination. PMID- 24144234 TI - Insight into the aging effect on enhancement of hydrogen-sensing characteristics of a zirconia-based sensor utilizing a Zn-Ta-O-based sensing electrode. AB - A significant enhancement in the hydrogen (H2) sensitivity as well as selectivity after aging for more than 40 days has been observed for a mixed-potential-type sensor using ZnO (+84 wt % Ta2O5) as the sensing electrode (SE) and yttria stabilized zirconia (YSZ) as the solid electrolyte. The effect of the aging process in enhancing the sensing characteristics of the sensor using ZnO (+84 wt % Ta2O5)-SE was studied here by investigating the changes in the morphology, crystal structure, chemical surface state, and catalytic properties of the SE material before and after aging at 500 degrees C for 80 days. X-ray diffraction measurements confirmed that the crystal structure of the SE material was found to be unaffected by aging, while the morphological change observed via scanning electron microscopy imaging indicated a decrease in the porosity and an increase in the particle size after aging. A significant change, particularly in the binding energy of Ta 4f, was also observed for the SE material after long-term aging. Although the catalytic activities toward the anodic reaction of H2 and the other examined gases were moderately stable after aging, a significant decrease in the heterogeneous catalytic activity of the gas-phase reaction (oxidation) of H2 was observed. Such a trend presumably resulted in a higher fraction of H2 reaching the triple-phase boundary, where the electrochemical reactions generate a sensing signal (mixed potential), resulting in high H2 sensitivity as well as high H2 selectivity after long-term aging of the present sensor. PMID- 24144235 TI - Theoretical study of salt effects on the Diels-Alder reaction of cyclopentadiene with methyl vinyl ketone using RISM-SCF theory. AB - Salt effects on the Diels-Alder reaction of cyclopentadiene with methyl vinyl ketone are investigated using reference interaction site model self-consistent field (RISM-SCF) theory. The rate of the reaction is accelerated by adding LiCl to the water solvent. The structures of four transition states, endo-cis, endo trans, exo-cis, exo-trans, were found by geometry optimization of the cyclopentadiene and methyl vinyl ketone complexes. The endo-trans structure shows the lowest energy in both water and LiCl solution. The activation barrier of the reaction in LiCl solution is lower than that in water, and the difference is in good agreement with that from experiments. The decrease in the activation barrier arises from destabilization of the reactant species. The salt effect of LiCl makes all species concerning the reaction unstable by the hydrophobic effect; however, the increased hydrophobic effect in the TS complexes is suppressed by making the hydrogen bond, which is stronger compared with the reactant methyl vinyl ketone. PMID- 24144236 TI - Unresectable angiosarcoma treated with bevacizumab and paclitaxel. PMID- 24144237 TI - Electron transport through a diazonium-based initiator layer to covalently attached polymer brushes of ferrocenylmethyl methacrylate. AB - A versatile method based on electrografting of aryldiazonium salts was used to introduce covalently attached initiators for atom transfer radical polymerization (ATRP) on glassy carbon surfaces. Polymer brushes of ferrocenylmethyl methacrylate were prepared from the surface-attached initiators, and these films were thoroughly analyzed using various techniques, including X-ray photoelectron spectroscopy (XPS), infrared reflection-absorption spectroscopy (IRRAS), ellipsometry, and electrochemistry. Of particular interest was the electrochemical characterization of the electron transfer through the diazonium based initiator layer to the redox centers in the polymer brush films. It was found that the apparent rate constant of electron transfer decreases exponentially with the dry-state thickness of this layer. To investigate the electron transfer in the brushes themselves, scanning electrochemical microscopy (SECM) was applied, thereby allowing the effect from the initiator layer to be excluded. The unusual transition feature of the approach curves recorded suggests that an initial fast charge transfer to the outermost-situated ferrocenyl groups is followed by a slower electron transport involving the neighboring redox units. PMID- 24144238 TI - Sexually transmitted infections and women's sexual and reproductive health. AB - Sexually transmitted infections (STIs) are widespread globally and result in a large burden of sexual and reproductive health consequences that disproportionately affect women, including pregnancy complications, cancer, infertility, and enhanced HIV transmission. A new WHO publication, available online, outlines key points of action and new and future technologies for global STI prevention and control. Highlights from the WHO publication are described in the present article. PMID- 24144239 TI - Ten years of experience in molecular prenatal diagnosis and carrier testing for spinal muscular atrophy among families from Serbia. AB - OBJECTIVE: To describe 10 years of experience of prenatal analysis of spinal muscular atrophy (SMA). METHODS: Data were retrospectively evaluated from prenatal analysis and carrier screening among parents and close relatives between January 2003 and December 2012. Screening was done before the parents were offered prenatal diagnosis. Polymerase chain reaction (PCR) and restriction fragment length polymorphism (RFLP) were used to detect the most frequent homozygous deletions in the SMN1 gene in fetal samples. A commercial MLPA kit (SALSA P060) was used to analyze SMN1 copy number for carrier status determination among healthy individuals. Bayesian calculation was used to accurately assess the risk of having a child affected with SMA. RESULTS: During the study period, 66 fetal samples from 44 Serbian families were analyzed, and 13 (19.7%) showed a homozygous deletion in the SMN1 gene. Among 28 healthy individuals, carrier status was confirmed for 16 (57.1%). For 7 couples, quantitative analyses and Bayesian calculation reduced the final risk of having a child with SMA from 1 in 200 to 1 in 2448. CONCLUSION: Owing to disease severity and lack of a curative treatment, prenatal diagnosis of SMA is the best way to prevent recurrence. Carrier detection allows accurate risk assessment and appropriate genetic counseling for all family members. PMID- 24144240 TI - Design, synthesis, and biological evaluation of 14-heteroaromatic-substituted naltrexone derivatives: pharmacological profile switch from mu opioid receptor selectivity to mu/kappa opioid receptor dual selectivity. AB - On the basis of a mu opioid receptor (MOR) homology model and the isosterism concept, three generations of 14-heteroaromatically substituted naltrexone derivatives were designed, synthesized, and evaluated as potential MOR-selective ligands. The first-generation ligands appeared to be MOR-selective, whereas the second and the third generation ones showed MOR/kappa opioid receptor (KOR) dual selectivity. Docking of ligands 2 (MOR selective) and 10 (MOR/KOR dual selective) to the three opioid receptor crystal structures revealed a nonconserved-residue facilitated hydrogen-bonding network that could be responsible for their distinctive selectivity profiles. The MOR/KOR dual-selective ligand 10 showed no agonism and acted as a potent antagonist in the tail-flick assay. It also produced less severe opioid withdrawal symptoms than naloxone in morphine dependent mice. In conclusion, ligand 10 may serve as a novel lead compound to develop MOR/KOR dual-selective ligands, which might possess unique therapeutic value for opioid addiction treatment. PMID- 24144241 TI - Angiopoietin-1 treated early endothelial outgrowth cells (eEOCs) are activated in vitro and reduce renal damage in murine acute ischemic kidney injury (iAKI). AB - BACKGROUND: Acute kidney injury (AKI) severely worsens prognosis of hospitalized patients. Early Endothelial Outgrowth Cells act protective in murine acute ischemic renal failure and renoprotective actions of eEOCs have been documented to increase after cell pretreatment with 8-O-cAMP and Melatonin. Angiopoietin-1 is critically involved in maintaining vascular integrity and regeneration. Aim of the study was to analyze the consequences of eEOC treatment with Ang-1 in murine AKI. METHODS: After 40 minutes of unilateral renal artery clamping with contralateral nephrectomy, male C57/Bl6N mice were injected with either untreated or pretreated (Ang-1) syngeneic murine eEOCs. Two days later serum creatinine levels and morphology were evaluated. Cultured, Ang-1 treated murine eEOCs were analyzed for production/release of proangiogenic and proinflammatory mediators, migratory activity, and cell survival, respectively. RESULTS: Angiopoietin-1 pretreatment of eEOCs significantly reduced serum creatinine in cell-injected mice. In vitro analysis showed increased migration of Ang-1 treated eEOCs and supernatant from Ang-1 treated eEOCs stimulated migration of cultured mature endothelial cells. In addition, Ang-1 reduced percentages of Annexin V+/PI+ eEOCs. Intrarenal numbers of eEOCs remained unaffected by Ang-1 and eEOCs did not produce more or less proangiogenic/proinflammatory mediators after being stimulated with Ang-1. CONCLUSIONS: Angiopoietin-1 pretreatment of eEOCs increases the cells' renoprotective competence in ischemic AKI. Thus, the armentarium of eEOC agonists in AKI is increasingly being expanded and the treatment of AKI with eEOCs becomes a promising future option. PMID- 24144242 TI - The role of temperament in the relationship between morningness-eveningness and mood. AB - Apart from differences in circadian phase position, individuals with different morningness-eveningness levels vary in many more characteristics. Particularly consistent relationships have been observed between morningness-eveningness and mood. Eveningness has been associated with disadvantageous mood, e.g. depressiveness in healthy individuals, and mood disorders. A concept of social jetlag suggests that evening subjects function in less advantageous environments due to discrepancies between internal and social time (societies promote morning oriented functioning), which results in their lowered mood. Individual temperament, as defined by the Regulative Theory of Temperament (RTT), refers to the capacity of the human organism to meet environmental requirements - the greater the capacity, the less negative impact of external conditions. Thus, the aim of this study is to determine which RTT traits are linked to both morningness eveningness and mood dimensions and to test whether they account for the relationship between morningness-eveningness and mood. A sample of 386 university students (267 female) aged between 19 and 47 (M = 21.15, SD = 4.23) years completed the University of Wales Institute of Science and Technology (UWIST) Mood Adjective Check List, Morningness-Eveningness Questionnaire and Formal Characteristics of Behaviour - Temperament Inventory. Analyses revealed lower endurance (EN) and higher emotional reactivity (ER) related to eveningness as well as to lower hedonic tone (HT), energetic arousal (EA) and to higher tense arousal (TA). Moreover, eveningness was associated with lower HT, EA and higher TA. Among RTT traits, EN was most strongly related to eveningness, and mediation analyses revealed that this temperamental trait fully mediated the relationship between eveningness and the three mood dimensions. The remaining RTT traits did not provide more explanation of the association between morningness-eveningness and mood than EN itself. If subjects did not differ in EN, the association between morningness-eveningness and mood was absent. EN is discussed as a protective factor against negative consequences of social jetlag and particularly lowered mood in evening individuals. PMID- 24144243 TI - A randomized controlled trial with bright light and melatonin for delayed sleep phase disorder: effects on subjective and objective sleep. AB - Delayed sleep phase disorder (DSPD) is assumed to be common amongst adolescents, with potentially severe consequences in terms of school attendance and daytime functioning. The most common treatment approaches for DSPD are based on the administration of bright light and/or exogenous melatonin with or without adjunct behavioural instructions. Much is generally known about the chronobiological effects of light and melatonin. However, placebo-controlled treatment studies for DSPD are scarce, in particular in adolescents and young adults, and no standardized guidelines exist regarding treatment. The aim of the present study was, therefore, to investigate the short- and long-term effects on sleep of a DSPD treatment protocol involving administration of timed bright light and melatonin alongside gradual advancement of rise time in adolescents and young adults with DSPD in a randomized controlled trial and an open label follow-up study. A total of 40 adolescents and young adults (age range 16-25 years) diagnosed with DSPD were recruited to participate in the study. The participants were randomized to receive treatment for two weeks in one of four treatment conditions: dim light and placebo capsules, bright light and placebo capsules, dim light and melatonin capsules or bright light and melatonin capsules. In a follow-up study, participants were re-randomized to either receive treatment with the combination of bright light and melatonin or no treatment in an open label trial for approximately three months. Light and capsules were administered alongside gradual advancement of rise times. The main end points were sleep as assessed by sleep diaries and actigraphy recordings and circadian phase as assessed by salivary dim light melatonin onset (DLMO). During the two-week intervention, the timing of sleep and DLMO was advanced in all treatment conditions as seen by about 1 h advance of bed time, 2 h advance of rise time and 2 h advance of DLMO in all four groups. Sleep duration was reduced with approximately 1 h. At three-month follow-up, only the treatment group had maintained an advanced sleep phase. Sleep duration had returned to baseline levels in both groups. In conclusion, gradual advancement of rise time produced a phase advance during the two-week intervention, irrespective of treatment condition. Termination of treatment caused relapse into delayed sleep times, whereas long-term treatment with bright light and melatonin (three months) allowed maintenance of the advanced sleep phase. PMID- 24144244 TI - Cardiovascular reactivity to stressors: effect of time of day? AB - Reduced cardiovagal baroreflex sensitivity and a peak in the incidence of cardiovascular events in the hours immediately after waking from nocturnal sleep suggest that cardiovascular control is impaired in the morning compared with other times of day. Previous research indicates that diurnal variation exists in acute blood pressure (BP) responses to exercise. However, the effect of time of day on activities such as cognitive tasks and "passive coping" physical tasks has yet to be established. Therefore, the primary aim of this study was to explore cardiovascular responses to physical and mental stressors at two times of day that have previously been associated with differing levels of cardiovascular control. In addition, the effect of the chronotype was examined to identify possible interactions between morningness/eveningness, time of day and responses to stressors. Fourteen healthy, young subjects completed a morning (08:30 h) and an afternoon (13:30 h) trial on separate days. Subjects performed a mental arithmetic task and a cold pressor test while beat-to-beat measurements of BP and heart rate were recorded continuously. Reactivity was determined using mean change scores in systolic BP, diastolic BP, mean arterial pressure, heart rate and rate-pressure product (RPP) from a period of rest recorded immediately prior to the task. There was no significant difference in cardiovascular reactivity between the morning and afternoon (p > 0.05). The time course of the responses and subsequent recovery were also consistent between the two times of day (p > 0.05). There was a significant interaction between time of day and chronotype, although this was apparent only for heart rate and RPP reactivity (p < 0.05); subjects tending towards "morningness" exhibited greater heart rate and RPP reactivity in the afternoon, and subjects tending towards "eveningness" exhibited greater heart rate and RPP reactivity in the morning. No interactions were observed between time of day and chronotype for BP reactivity (p > 0.05). Despite effects of time of day on heart rate that are dependent upon chronotype, this study suggests that BP control during mental and passive physical stress is not altered between the morning and afternoon. PMID- 24144245 TI - Clutter modulates the representation of target objects in the human occipitotemporal cortex. AB - Target objects required for goal-directed behavior are typically embedded within multiple irrelevant objects that may interfere with their encoding. Most neuroimaging studies of high-level visual cortex have examined the representation of isolated objects, and therefore, little is known about how surrounding objects influence the neural representation of target objects. To investigate the effect of different types of clutter on the distributed responses to target objects in high-level visual areas, we used fMRI and manipulated the type of clutter. Specifically, target objects (i.e., a face and a house) were presented either in isolation, in the presence of a homogeneous (identical objects from another category) clutter ("pop-out" display), or in the presence of a heterogeneous (different objects) clutter, while participants performed a target identification task. Using multivoxel pattern analysis (MVPA) we found that in the posterior fusiform object area a heterogeneous but not homogeneous clutter interfered with decoding of the target objects. Furthermore, multivoxel patterns evoked by isolated objects were more similar to multivoxel patterns evoked by homogenous compared with heterogeneous clutter in the lateral occipital and posterior fusiform object areas. Interestingly, there was no effect of clutter on the neural representation of the target objects in their category-selective areas, such as the fusiform face area and the parahippocampal place area. Our findings show that the variation among irrelevant surrounding objects influences the neural representation of target objects in the object general area, but not in object category-selective cortex, where the representation of target objects is invariant to their surroundings. PMID- 24144247 TI - Dorsolateral pFC and the representation of the incorrect use of an object: the transcranial direct current stimulation effect on N400 for visual and linguistic stimuli. AB - In this study, we explored the representation of an incongruent action (instrumentally incorrect use of an object) in comparison with sentences ending with an incongruent action word, taking into account the role of the activation of the left dorsolateral pFC (DLPFC). This activity was appositely modulated by transcranial direct current stimulation (tDCS). The effect of tDCS when participants processed congruent/incongruent object-related actions (Experiment 1) or sentences (Experiment 2) was verified by measuring changes in the ERP N400, error rates (ERs), and RTs. In Experiment 1, 30 participants performed the detection task within a dynamic context (video tapes representing a sequence of four action frames). In Experiment 2, 28 participants read sentences that represented object-related actions. The stimulation effect (a cathode applied to the DLPFC and an anode to the right supraorbital region) was analyzed by comparing the ER, RT, and ERP profiles before and after stimulation (or sham treatment). A significant reduction of the N400 was observed for incongruent stimuli in the case of cathodal (inhibitory) stimulation of the DLPFC in comparison with prestimulation conditions for Experiment 1, but not Experiment 2. Moreover, ERs were increased, and RTs were reduced in response to incongruent conditions after tDCS, but not after sham stimulation in Experiment 1. It is suggested that perturbation of the DLPFC may limit the ability to analyze a semantically anomalous action sequence as a reduced N400 ERP effect and increased random responses was observed. Finally, the contribution of the frontal area to the semantic processing of actions is discussed. PMID- 24144246 TI - Domain-general signals in the cingulo-opercular network for visuospatial attention and episodic memory. AB - We investigated the functional properties of a previously described cingulo opercular network (CON) putatively involved in cognitive control. Analyses of common fMRI task-evoked activity during perceptual and episodic memory search tasks that differently recruited the dorsal attention (DAN) and default mode network (DMN) established the generality of this network. Regions within the CON (anterior insula/frontal operculum and anterior cingulate/presupplementary cortex) displayed sustained signals during extended periods in which participants searched for behaviorally relevant information in a dynamically changing environment or from episodic memory in the absence of sensory stimulation. The CON was activated during all phases of both tasks, which involved trial initiation, target detection, decision, and response, indicating its consistent involvement in a broad range of cognitive processes. Functional connectivity analyses showed that the CON flexibly linked with the DAN or DMN regions during perceptual or memory search, respectively. Aside from the CON, only a limited number of regions, including the lateral pFC, showed evidence of domain-general sustained activity, although in some cases the common activations may have reflected the functional-anatomical variability of domain-specific regions rather than a true domain generality. These additional regions also showed task dependent functional connectivity with the DMN and DAN, suggesting that this feature is not a specific marker of cognitive control. Finally, multivariate clustering analyses separated the CON from other frontoparietal regions previously associated with cognitive control, indicating a unique fingerprint. We conclude that the CON's functional properties and interactions with other brain regions support a broad role in cognition, consistent with its characterization as a task control network. PMID- 24144249 TI - The subthalamic nucleus influences visuospatial attention in humans. AB - Spatial attention is a lateralized feature of the human brain. Whereas the role of cortical areas of the nondominant hemisphere on spatial attention has been investigated in detail, the impact of the BG, and more precisely the subthalamic nucleus, on signs and symptoms of spatial attention is not well understood. Here we used unilateral deep brain stimulation of the subthalamic nucleus to reversibly, specifically, and intraindividually modify the neuronal BG outflow and its consequences on signs and symptoms of visuospatial attention in patients suffering from Parkinson disease. We tested 13 patients with Parkinson disease and chronic deep brain stimulation in three stimulation settings: unilateral right and left deep brain stimulation of the subthalamic nucleus as well as bilateral deep brain stimulation of the subthalamic nucleus. In all three stimulation settings, the patients viewed a set of pictures while an eye-tracker system recorded eye movements. During the exploration of the visual stimuli, we analyzed the time spent in each visual hemispace, as well as the number, duration, amplitude, peak velocity, acceleration peak, and speed of saccades. In the unilateral left-sided stimulation setting, patients show a shorter ipsilateral exploration time of the extrapersonal space, whereas number, duration, and speed of saccades did not differ between the different stimulation settings. These results demonstrated reduced visuospatial attention toward the side contralateral to the right subthalamic nucleus that was not being stimulated in a unilateral left-sided stimulation. Turning on the right stimulator, the reduced visuospatial attention vanished. These results support the involvement of the subthalamic nucleus in modulating spatial attention. Therefore, the subthalamic nucleus is part of the subcortical network that subserves spatial attention. PMID- 24144248 TI - Genetic polymorphisms regulating dopamine signaling in the frontal cortex interact to affect target detection under high working memory load. AB - Frontal-dependent task performance is typically modulated by dopamine (DA) according to an inverted-U pattern, whereby intermediate levels of DA signaling optimizes performance. Numerous studies implicate trait differences in DA signaling based on differences in the catechol-O-methyltransferase (COMT) gene in executive function task performance. However, little work has investigated genetic variations in DA signaling downstream from COMT. One candidate is the DA- and cAMP-regulated phosphoprotein of molecular weight 32 kDa (DARPP-32), which mediates signaling through the D1-type DA receptor, the dominant DA receptor in the frontal cortex. Using an n-back task, we used signal detection theory to measure performance in a healthy adult population (n = 97) genotyped for single nucleotide polymorphisms in the COMT (rs4680) and DARPP-32 (rs907094) genes. Correct target detection (hits) and false alarms were used to calculate d' measures for each working memory load (0-, 2-, and 3-back). At the highest load (3-back) only, we observed a significant COMT * DARPP-32 interaction, such that the DARPP-32 T/T genotype enhanced target detection in COMT(ValVal) individuals, but impaired target detection in COMT(Met) carriers. These findings suggest that enhanced dopaminergic signaling via the DARPP-32 T allele aids target detection in individuals with presumed low frontal DA (COMT(ValVal)) but impairs target detection in those with putatively higher frontal DA levels (COMT(Met) carriers). Moreover, these data support an inverted-U model with intermediate levels of DA signaling optimizing performance on tasks requiring maintenance of mental representations in working memory. PMID- 24144251 TI - Peripheral neuropathy for dermatologists: what if not diabetic neuropathy? AB - BACKGROUND: Patients with cutaneous manifestations associated with peripheral neuropathy often present to the dermatologist's office. OBJECTIVE/METHODS: This article outlines a practical approach for obtaining the history, performing a screening physical examination, and ordering initial diagnostic testing to diagnose the cause of nondiabetic neuropathy. When to refer for neurologic consultation and principles of management of neuropathic pain and neuropathy related ulcers are also discussed. RESULTS: Cutaneous manifestations of peripheral neuropathy may be secondary to a medical condition predisposing the patient to neuropathy or a manifestation of neuropathy itself. In the latter category, skin affected by neuropathy may show characteristics of xerosis, anhidrosis, rubor, edema, callus, ulceration, muscle wasting, and foot deformity. Most often these findings occur in association with diabetic neuropathy; however, many other infectious, inflammatory, metabolic, paraneoplastic, hereditary, and medication- or toxin-related causes should be considered. The treatment of cutaneous manifestations of neuropathy includes pressure downloading, control of edema, and optimal ulcer and neuropathic pain management. CONCLUSION: It is important for dermatologists to have a basic approach to neuropathy in patients with related skin disease. Referral to Neurology is warranted when basic workup for reversible causes is negative or for any severe, rapidly progressive symptoms. PMID- 24144250 TI - Dopamine function and the efficiency of human movement. AB - To sustain successful behavior in dynamic environments, active organisms must be able to learn from the consequences of their actions and predict action outcomes. One of the most important discoveries in systems neuroscience over the last 15 years has been about the key role of the neurotransmitter dopamine in mediating such active behavior. Dopamine cell firing was found to encode differences between the expected and obtained outcomes of actions. Although activity of dopamine cells does not specify movements themselves, a recent study in humans has suggested that tonic levels of dopamine in the dorsal striatum may in part enable normal movement by encoding sensitivity to the energy cost of a movement, providing an implicit "motor motivational" signal for movement. We investigated the motivational hypothesis of dopamine by studying motor performance of patients with Parkinson disease who have marked dopamine depletion in the dorsal striatum and compared their performance with that of elderly healthy adults. All participants performed rapid sequential movements to visual targets associated with different risk and different energy costs, countered or assisted by gravity. In conditions of low energy cost, patients performed surprisingly well, similar to prescriptions of an ideal planner and healthy participants. As energy costs increased, however, performance of patients with Parkinson disease dropped markedly below the prescriptions for action by an ideal planner and below performance of healthy elderly participants. The results indicate that the ability for efficient planning depends on the energy cost of action and that the effect of energy cost on action is mediated by dopamine. PMID- 24144252 TI - Wound bed preparation 2012. AB - BACKGROUND: The concept of wound bed preparation is a holistic approach to wound diagnosis and treatment of the cause, patient-centered concerns and optimizing the components of local wound care (debridement, infection and persistent infection, moisture balance) before edge effect for healable but stalled chronic wounds. This article has introduced the concepts of healable, nonhealable and maintenance wounds. Additionally, clinical criteria (mnemonic NERDS and STONEES) are provided on the use of topical agents for critical colonization or systemic antimicrobials for deep and surrounding infection. OBJECTIVE: To present a holistic, evidence-informed approach to chronic wound care management. METHODS: This article reviews the scientific evidence base, and forms an expert consensus of key opinion leaders to the Wound Bed Preparation model. RESULTS AND CONCLUSION: This article provides clinicians with evidence-informed wound caring approaches translating the evidence base into practice. PMID- 24144253 TI - Adalimumab in treatment-resistant hidradenitis suppurativa following recurrence after extensive affected area excision: a review of biologics therapy. AB - BACKGROUND: Hidradenitis suppurativa (HS) is characterized by chronic, suppurative abscesses, sinus tracts, and fistulas affecting the axilla, groin, and perianal region resulting from hyperkeratosis and occlusion of the terminal hair follicle. OBJECTIVE: This report highlights the use of biologic agents for the treatment of recalcitrant HS. METHOD: We report on a 48-year-old male with a 15-year history of refractory perianal-inguinal-buttock HS who, despite receiving numerous surgical drainages and traditional medical treatment for HS, still had severe pain. After trialing etanercept and infliximab with methotrexate, the patient had marked improvement with adalimumab. A literature review of biologics therapy was also performed. RESULTS: After trialing many traditional therapies, we found that adalimumab appears to be the most effective treatment modality for our patient. A literature search revealed 53 articles on biologics therapy in HS. These articles are summarized. DISCUSSION: Biologic agents have been shown to have variable results in the treatment of refractory HS. Enough low-grade evidence has been accumulated to make the use of these agents suitable in HS. Until more clinical trials are performed on this topic, physicians should use clinical judgment when treating HS with biologic agents and be cautious by watching for significant adverse effects. PMID- 24144254 TI - Catastrophic wounds. AB - BACKGROUND: This article summarizes information presented at the Wound Healing Subspecialty Symposium of the Annual Conference of the Canadian Dermatology Association held in Ottawa in June 2012. OBJECTIVE: To provide continuing medical education on wound healing for dermatologists. METHODS: A review of the pertinent literature was performed by the author in order to prepare the lecture and subsequent article. RESULTS: The review found that necrotizing faciitis, hypertensive ulceration, antiphospholipid syndrome and alpha1-antitrypsin syndrome are entities that contribute to catastrophic wounds seen in wound healing clinics and in private offices. CONCLUSION: It is most important to have a high index of suspicion for these four conditions because early diagnosis can be life-saving with necrotizing faciitis, pain-relieving in ulcers caused by hypertension, and antiphospholipid syndrome, and can result in early treatment in alpha1-antitrypsin deficiency. PMID- 24144255 TI - Making necrotizing vasculitis simple. AB - BACKGROUND: Cutaneous necrotizing vasculitides (CNV) represent a heterogeneous group of inflammatory diseases affecting the skin blood vessels, characterized histologically by transmural inflammation of the blood vessel wall with fibrinoid necrosis and clinically characterized by palpable purpura, leading to ulceration. These syndromes represent a spectrum of disease from limited cutaneous small vessel vasculitis to rapidly progressive systemic vasculitis. Moreover, a number of diseases can mimic vasculitis in the skin, thereby presenting diagnostic difficulties for physicians. OBJECTIVE: We present an update of CNV and vasculopathies based on recent literature and clinical experience. We provide a dermatologic approach to the patient presenting with purpura and ischemic skin necrosis focusing on the subtle features that may help physicians discern between primary and secondary causes and the differences between vasculitis and vasculopathy. PMID- 24144256 TI - Erythema induratum: case series illustrating the utility of the interferon-gamma release assay in determining the association with tuberculosis. AB - BACKGROUND: The interferon-gamma release assay (IGRA) is a novel method for detecting previous sensitization to tuberculosis (TB). Despite having several advantages over the tuberculin skin test (TST), including higher specificity and no influence from past bacille Calmette-Guerin (BCG) exposure, there are a limited number of reports describing its application in patients with erythema induratum (EI)/nodular vasculitis (NV), which is usually but not always related to TB. OBJECTIVES: The aim of our case series was to evaluate the usefulness of the IGRA for determining a TB association in patients with EI/NV. METHODS: Retrospective chart reviews were conducted on four patients diagnosed with EI/NV at our institution in whom an IGRA had been performed. RESULTS: All four subjects had positive TST results. The IGRA was also positive and therefore supported a link with TB in two cases. One patient responded completely to anti-TB therapy, whereas the second was lost to follow-up. Both cases unrelated to TB, by virtue of negative IGRAs, demonstrated complete response to immunosuppressive therapy (methotrexate), with one individual having failed anti-TB therapy first. CONCLUSION: Our case series highlights the utility of the IGRA for establishing a TB association in patients with EI/NV. Although limited by a small sample size, we propose adjunctive use of this test at the time of EI/NV diagnosis, especially in the setting of previous BCG exposure, so that management can be tailored according to whether an underlying relationship with TB exists. PMID- 24144258 TI - Self-rated health and mortality: a follow-up study of a Spanish population. AB - OBJECTIVES: Self-rated health (SRH) is known to be a valid indicator for the prediction of health outcomes. The aims of this study were to describe and analyse the associations between SRH and health status, socio-economic and demographic characteristics; and between SRH and mortality in a Spanish population. STUDY DESIGN: Longitudinal study. METHODS: A sample of 5275 adults (age >=21 years) residing in the Valencian Community (Spanish Mediterranean region) was surveyed in 2005 and followed for four years. SRH was categorized into good and poor health. The response variable was mortality (dead/alive), obtained from the local mortality register. Logistic regression models were adjusted in order to analyse the associations between SRH and health status, socio-economic and demographic characteristics; odds ratios were calculated to measure the associations. Poisson regression models were adjusted in order to analyse the associations between mortality and explanatory variables; the relative risk of death was calculated to measure the associations. RESULTS: Poor SRH was reported by 25.9% of respondents, and the mortality rate after four years of follow-up was 3.6%. An association was found between SRH and the presence of chronic disease and disability in men and women. A perception of poor health vs good health led to a mortality risk of 3.0 in men and 2.7 in women. SRH was predictive of mortality, even after adjusting for all other variables. In men and women, the presence of disability provided additional predictive ability. CONCLUSIONS: SRH was predictive of mortality in both men and women, and acted as a mediator between socio-economic, demographic and health conditions and mortality. PMID- 24144259 TI - Neutron reflectometry elucidates density profiles of deuterated proteins adsorbed onto surfaces displaying poly(ethylene glycol) brushes: evidence for primary adsorption. AB - The concentration profile of deuterated myoglobin (Mb) adsorbed onto polystyrene substrates displaying poly(ethylene glycol) (PEG) brushes is characterized by neutron reflectometry (NR). The method allows to directly distinguish among primary adsorption at the grafting surface, ternary adsorption within the brush, and secondary adsorption at the brush outer edge. It complements depth insensitive standard techniques, such as ellipsometry, radioactive labeling, and quartz crystal microbalance. The study explores the effect of the PEG polymerization degree, N, and the grafting density, sigma, on Mb adsorption. In the studied systems there is no indication of secondary or ternary adsorption, but there is evidence of primary adsorption involving a dense inner layer at the polystyrene surface. For sparsely grafted brushes the primary adsorption involves an additional dilute outer protein layer on top of the inner layer. The amount of protein adsorbed in the inner layer is independent of N but varies with sigma, while for the outer layer it is correlated to the amount of grafted PEG and is thus sensitive to both N and sigma. The use of deuterated proteins enhances the sensitivity of NR and enables monitoring exchange between deuterated and hydrogenated species. PMID- 24144260 TI - Molecular docking study, green synthesis and pharmacological evaluation of 1,3,4 thiadiazole derivatives as potential antiepileptic agents. AB - Epilepsy is one of the commonly occurring chronic neurological disorders which involves abnormal electrical impulses in the brain. It is characterized by the sudden loss of consciousness, followed by abnormal shaking of the body. Though there are various types of antiepileptic drugs available clinically, the treatment of epilepsy still remains inadequate because of their toxicity and idiosyncratic side effects. Thus, there is unmet medical need to develop safe drugs for the treatment of epilepsy with lower side effects and improved bioavailability profiles. Considering the structural similarity between phenytoin/lamotrigine, a series of 1,3,4-thiadiazole was designed based on molecular docking study into the active site of the voltage-gated sodium channels. Antiepileptic activity of the synthesized compounds was evaluated in rats by maximal electroshock induced seizures (MES) model at different doses. Among the tested compounds, some exhibited significant anticonvulsant activity as compared to phenytoin in a dose-dependent manner. The neurotoxicity study was carried out using the rotarod test and the results of which suggests that the target compounds are safe and could be further developed as potential lead for antiepileptic drugs. PMID- 24144261 TI - Comparison of hemostatic agents used in vascular surgery. AB - INTRODUCTION: Over the past 15 years, a wide range of agents have been developed for use in surgical procedures to achieve hemostasis. These agents can be divided into three broad categories: hemostats, sealants and adhesives. They vary widely related to their mechanism of action, composition, ease of application, adherence to wet or dry tissue, immunogenicity and cost. AREAS COVERED: This article focuses on the agents used in vascular surgery to achieve hemostasis; agents involved in clinical trials are also covered. EXPERT OPINION: When surgeons achieve rapid hemostasis, potential benefits include better visualization of the surgical area, shorter operative times, decreased requirement for transfusions, better management of an anticoagulated patient, decreased wound healing time and overall improvement in patient recovery time. The need for safe and efficacious hemostatic agents that can provide a range of benefits is clearly a significant surgical issue. PMID- 24144262 TI - Fatigue in spondyloarthritis: a marker of disease activity. A cross-sectional study of 266 patients. AB - OBJECTIVES: Fatigue is an important aspect of spondyloarthritis (SpA). However the influencing factors of fatigue in SpA are unclear. The objective of this study was to explore if fatigue is related to disease activity or to patient characteristics. METHODS: This was a retroelective observational study (Cochin COSPA study) in one tertiary-referral centre. The primary outcome was fatigue, evaluated on a 0-100mm Visual Analogue Scale (VAS). The covariates were demographic characteristics, disease subtype (axial vs. peripheral) and disease related factors, e.g. Bath Disease Activity Index (BASDAI), patient global assessment (VAS), Bath Functional Index (BASFI). To explain fatigue, univariate then multivariate logistic regressions were conducted (with fatigue analysed as above or below 50 mm), as well as multiple linear regressions with the different covariates. RESULTS: Two hundred and sixty-six SpA patients were analysed. Sixty one percent were male; mean age and disease duration were 44.5+/-13.5 years and 16.8+/-11.7 years, respectively. Mean VAS fatigue was 49.3+/-32.7mm; 49.6% of patients had fatigue VAS>50mm. Logistic regression showed high fatigue was associated with disease: BASDAI and BASFI (p<0.0001), as well as female gender (p=0.025) and aerobic exercise (p=0.005), but there was no difference in the subtypes of SpA. In multivariate analysis, the single factor explaining fatigue was patient global assessment (p<0.001 and odds ratio =1.35). By linear regression, demographic variables explained 2.8% of the variance, whereas disease characteristics and activity explained 44.6%. CONCLUSIONS: Fatigue levels were high in SpA patients whatever the subtype and appeared more strongly related to the disease than to patient-related variables, thus confirming its usefulness as an outcome measure. PMID- 24144263 TI - Ocular sarcoidosis and immune thrombocytopenia: a rare association. AB - There is an association between sarcoidosis and immune thrombocytopenia, which can be severe and even fatal if left untreated. Although ocular sarcoidosis is one of the most common extrapulmonary manifestations of sarcoidosis, immune thrombocytopenia has not been reported in isolated ocular sarcoidosis. We present a patient with a remote history of immune thrombocytopenic purpura who developed a sub-conjunctival mass consistent with isolated ocular sarcoidosis. PMID- 24144264 TI - Structure of Cu(I)-bound DJ-1 reveals a biscysteinate metal binding site at the homodimer interface: insights into mutational inactivation of DJ-1 in Parkinsonism. AB - The Parkinsonism-associated protein DJ-1 has been suggested to activate the Cu-Zn superoxide dismutase (SOD1) by providing its copper cofactor. The structural and chemical means by which DJ-1 could support this function is unknown. In this study, we characterize the molecular interaction of DJ-1 with Cu(I). Mass spectrometric analysis indicates binding of one Cu(I) ion per DJ-1 homodimer. The crystal structure of DJ-1 bound to Cu(I) confirms metal coordination through a docking accessible biscysteinate site formed by juxtaposed cysteine residues at the homodimer interface. Spectroscopy in crystallo validates the identity and oxidation state of the bound metal. The measured subfemtomolar dissociation constant (Kd = 6.41 * 10(-16) M) of DJ-1 for Cu(I) supports the physiological retention of the metal ion. Our results highlight the requirement of a stable homodimer for copper binding by DJ-1. Parkinsonism-linked mutations that weaken homodimer interactions will compromise this capability. PMID- 24144265 TI - Bifunctional polymer hydrogel layers as forward osmosis draw agents for continuous production of fresh water using solar energy. AB - The feasibility of bilayer polymer hydrogels as draw agent in forward osmosis process has been investigated. The dual-functionality hydrogels consist of a water-absorptive layer (particles of a copolymer of sodium acrylate and N isopropylacrylamide) to provide osmotic pressure, and a dewatering layer (particles of N-isopropylacrylamide) to allow the ready release of the water absorbed during the FO drawing process at lower critical solution temperature (32 degrees C). The use of solar concentrated energy as the source of heat resulted in a significant increase in the dewatering rate as the temperature of dewatering layer increased to its LSCT more rapidly. Dewatering flux rose from 10 to 25 LMH when the solar concentrator increased the input energy from 0.5 to 2 kW/m(2). Thermodynamic analysis was also performed to find out the minimum energy requirement of such a bilayer hydrogel-driven FO process. This study represents a significant step forward toward the commercial implementation of hydrogel-driven FO system for continuous production of fresh water from saline water or wastewaters. PMID- 24144267 TI - Growth of Solid and Hollow Gold Particles through the Thermal Annealing of Nanoscale Patterned Thin Films. AB - Through thermally annealing well-arrayed, circular, nanoscale thin films of gold, deposited onto [111] silicon/silicon dioxide substrates, both solid and hollow gold particles of different morphologies with controllable sizes were obtained. The circular thin films formed individual particles or clusters of particles by tuning their diameter. Hollow gold particles were characterized by their diameter, typically larger than 400 nm; these dimensions and properties were confirmed by cross-section scanning electron microscopy. Hollow gold particles also exhibited plasmonic field enhancement under photoemission electron microscopy. Potential growth mechanisms for these structures were explored. PMID- 24144266 TI - Impacts of a nanosized ceria additive on diesel engine emissions of particulate and gaseous pollutants. AB - Fuel additives incorporating nanosized ceria have been increasingly used in diesel engines as combustion promoters. However, few studies have assessed the impact of these nanotechnology-based additives on pollutant emissions. Here, we systematically compare emission rates of particulate and gaseous pollutants from a single-cylinder, four-cycle diesel engine using fuel mixes containing nanoceria of varying concentrations. The test fuels were made by adding different amounts of a commercial fuel additive Envirox into an ultralow-sulfur diesel fuel at 0 (base fuel), 0.1-, 1-, and 10-fold the manufacturer-recommended concentration of 0.5 mL Envirox per liter of fuel. The addition of Envirox resulted in ceria concentration-dependent emission reductions of CO2, CO, total particulate mass, formaldehyde, acetaldehyde, acrolein, and several polycyclic aromatic hydrocarbons. These reductions at the manufacturer-recommended doping concentration, however, were accompanied by a substantial increase of certain other air pollutants, specifically the number of ultrafine particles (+32%), NO(x) (+9.3%), and the particle-phase benzo[a]pyrene toxic equivalence quotient (+35%). Increasing fuel ceria concentrations also led to decreases in the size of emitted particles. Given health concerns related to ultrafine particles and NO(x), our findings call for additional studies to further evaluate health risks associated with the use of nanoceria additives in various engines under various operating conditions. PMID- 24144268 TI - Incorporating severity and risk as factors to the Fardal cost-effectiveness model to create a cost-benefit model for periodontal treatment. AB - BACKGROUND: A previously described economic model was based on average values for patients diagnosed with chronic periodontitis (CP). However, tooth loss varies among treated patients and factors for tooth loss include CP severity and risk. The model was refined to incorporate CP severity and risk to determine the cost of treating a specific level of CP severity and risk that is associated with the benefit of tooth preservation. METHODS: A population that received and another that did not receive periodontal treatment were used to determine treatment costs and tooth loss. The number of teeth preserved was the difference of the number of teeth lost between the two populations. The cost of periodontal treatment was divided by the number of teeth preserved for combinations of CP severity and risk. RESULTS: The cost of periodontal treatment divided by the number of teeth preserved ranged from (US) $1,405 to $4,895 for high or moderate risk combined with any severity of CP and was more than $8,639 for low risk combined with mild CP. The cost of a three-unit bridge was $3,416, and the cost of a single-tooth replacement was $4,787. CONCLUSION: Periodontal treatment could be justified on the sole basis of tooth preservation when CP risk is moderate or high regardless of disease severity. PMID- 24144269 TI - Association between periodontitis needing surgical treatment and subsequent diabetes risk: a population-based cohort study. AB - BACKGROUND: It is well known that patients with diabetes have higher extent and severity of periodontitis, but the backward relationship is little investigated. The relationship between periodontitis needing dental surgery and subsequent type 2 diabetes mellitus (DMT2) in those individuals without diabetes was assessed. METHODS: This is a retrospective cohort study using data from the national health insurance system of Taiwan. The periodontitis cohort involved 22,299 patients, excluding those with diabetes already or those diagnosed with diabetes within 1 year from baseline. Each study participant was randomly frequency matched by age, sex, and index year with one individual from the general population without periodontitis. Cox proportional hazards regression analysis was used to estimate the influence of periodontitis on the risk of diabetes. RESULTS: The mean follow up period is 5.47 +/- 3.54 years. Overall, the subsequent incidence of DMT2 was 1.24-fold higher in the periodontitis cohort than in the control cohort, with an adjusted hazard ratio of 1.19 (95% confidence interval = 1.10 to 1.29) after controlling for sex, age, and comorbidities. CONCLUSIONS: This is the largest nation-based study examining the risk of diabetes in Asian patients with periodontitis. Those patients with periodontitis needing dental surgery have increased risk of future diabetes within 2 years compared with those participants with periodontitis not requiring dental surgery. PMID- 24144270 TI - Analysis of daytime variations in gingival crevicular fluid: a circadian periodicity? AB - BACKGROUND: Volumetric alterations in gingival crevicular fluid (GCF) are widely accepted to be associated with periodontal health/disease. The volume/flow of GCF was shown to be affected by an array of methodological factors. However, relatively limited information is available on whether GCF is subject to circadian rhythm. The main aim of the present study is to assess the possible presence/absence of GCF circadian rhythm. The impact of the sampling technique on daytime volumetric variations is also analyzed. METHODS: The possible daily volumetric variations of GCF with 2-hour intervals (from 08:00 to 18:00 hours) were assessed in 100 tooth sites and 600 GCF samples. Only maxillary incisors were included to eliminate any potential volumetric differences due to tooth dimensions. To analyze the potential impact of sampling technique on GCF volume and daytime variations, at one site modified intracrevicular sampling technique (MIST) was used, whereas the contralateral site was sampled with a deep intracrevicular sampling technique (DIST). Clinical periodontal parameters of the GCF sites were also recorded. RESULTS: No significant daily variations in GCF volume could be detected. Higher volumetric measures were observed in inflamed subgroups compared with healthy subgroups (P <0.05). MIST was equivalent to DIST with regard to mean GCF volumes and the possible daytime volumetric alterations. CONCLUSIONS: Within the limits of the present study, it can be suggested that daytime variations did not have significant impact on GCF volume. The sampling methodology had no apparent impact on the circadian periodicity of GCF. PMID- 24144271 TI - Microbial analysis of subgingival plaque samples compared to that of whole saliva in patients with periodontitis. AB - BACKGROUND: The detection of special bacterial species in patients with periodontitis is considered to be useful for clinical diagnosis and treatment. The collection of subgingival plaque samples is the common way for the determination of periodontopathic bacteria. However, recently, salivary analysis has been discussed as an advantageous future diagnostic method for periodontitis because it offers simple quantitative sampling and the possibility to assess various bacteria. The aim of this cross-sectional study is to investigate whether there is a correlation between the results of different bacterial species in saliva and subgingival plaque samples from individuals with aggressive periodontitis (AgP) and chronic periodontitis (CP). METHODS: Whole saliva and subgingival plaque samples from the deepest pocket of each quadrant were collected from 43 patients with CP and 33 patients with AgP. Twenty different bacterial species from both samplings were determined by the 16S ribosomal RNA based polymerase chain reaction with microarray technique. RESULTS: All bacterial species were detected in salivary and subgingival plaque samples. For Aggregatibacter actinomycetemcomitans, Porphyromonas gingivalis, Treponema denticola, and Tannerella forsythia, as well as Actinomyces viscosus, Campylobacter rectus/showae, Prevotella intermedia, Parvimonas micra, Eubacterium nodatum, and Campylobacter gracilis, a significant positive correlation between salivary and subgingival plaque samples was detected in patients with both types of periodontitis. There were no significant differences in bacteria in salivary and subgingival plaque samples between AgP and CP. CONCLUSION: Salivary analysis might be discussed as a potential alternative to subgingival plaque sampling for microbiologic analysis in both AgP and CP. PMID- 24144272 TI - Serum anticardiolipin concentrations in patients with chronic periodontitis following scaling and root planing. AB - BACKGROUND: Anticardiolipin antibodies (antiCl), present in some patients with autoimmune disease, are associated with thrombosis, fetal loss, and other conditions. A significant proportion of patients with chronic periodontitis (CP) test positive for antiCl, likely because some periodontal pathogens contain antigens homologous to the target antigen of antiCl on the serum protein beta-2 glycoprotein-I (beta2GPI) and thus can induce antiCl by molecular mimicry. The authors hypothesized that treatment of periodontitis by scaling and root planing (SRP) could therefore decrease serum titers of antiCl in patients with CP. METHODS: Thirty patients with CP received complete periodontal examinations at baseline including assessment of probing depth, attachment loss, gingival index, and plaque index. SRP was performed in two sessions at 2-week intervals. Eight weeks later, patients were reexamined. Blood samples were taken at baseline, 2 weeks after the initial therapy appointment, and 8 weeks after the completion of treatment for assessment of immunoglobulin (Ig)G and IgM antiCl levels. RESULTS: All periodontal parameters improved significantly. Consistent with previous observations, five (16.7%) of the 30 patients exhibited elevated levels of IgG or IgM antiCl at baseline. Following treatment, the concentrations of IgG and IgM antiCl remained unchanged for the entire cohort of 30 patients. However, in the five patients with elevated antiCl at baseline, IgM antiCl concentrations decreased significantly (P = 0.0008) owing to therapy, while IgG antiCl did not. CONCLUSION: The oral microflora is a likely source of antigen inducing antiCl in CP, since IgM antiCl levels can be reduced in the short term with conservative therapy. PMID- 24144273 TI - Pickering stabilized peptide gel particles as tunable microenvironments for biocatalysis. AB - We demonstrate the preparation of peptide gel microparticles that are emulsified and stabilized by SiO2 nanoparticles. The gels are composed of aromatic peptide amphiphiles 9-fluorenylmethoxycarbonyldiphenylalanine (Fmoc-FF) coassembled with Fmoc-amino acids with different functional groups (S: serine; D: aspartic acid; K: lysine; and Y: tyrosine). The gel phase provides a highly hydrated matrix, and peptide self-assembly endows the matrix with tunable chemical environments which may be exploited to support and stabilize proteins. The use of Pickering emulsion to stabilize these gel particles is advantageous through avoidance of surfactants that may denature proteins. The performance of enzyme lipase B immobilized in pickering/gel microparticles with different chemical functionalities is investigated by studying transesterification in heptane. We show that the use of Pickering particles enhances the performance of the enzyme, which is further improved in gel-phase systems, with hydrophilic environment provided by Fmoc-FF/S giving rise to the best catalytic performance. The combination of a tunable chemical environment in gel phase and Pickering stabilization described here is expected to prove useful for areas where proteins are to be exploited in technological contexts such as biocatalysis and also in other areas where protein performance and activity are important, such as biosensors and bioinspired solar fuel devices. PMID- 24144274 TI - Factors contributing to evidence-based pressure ulcer prevention. A cross sectional study. AB - BACKGROUND: Implementation of evidence-based care for pressure ulcer prevention is lacking. As the hospital organization is complex, more knowledge is needed to understand how nursing care in this area can be improved. OBJECTIVES: The present study investigated the associations between variables on different levels in the healthcare setting (patient, unit, hospital) and the documentation of (1) risk assessment and (2) skin assessment within 24h of admission, the use of (3) pressure-reducing mattresses and (4) planned repositioning in bed. DESIGN: A cross-sectional study. SETTINGS: One university hospital and one general hospital. PARTICIPANTS: Geriatric (n=8), medical (n=24) and surgical (n=19) units. All adult patients (>17 years), in total 825, were included. METHODS: A one-day prevalence study was conducted using the methodology specified by the European Pressure Ulcer Advisory Panel, together with the established methods used by the Collaborative Alliance for Nursing Outcomes. Independent variables were patient characteristics, hospital type, unit type, nurse staffing and workload. Dependent variables were documented risk and skin assessment within 24h of admission, pressure-reducing mattresses and planned repositioning in bed. The data were analysed with Logistic regression using the Generalized Estimating Equation (GEE) approach. RESULTS: Patients at risk of developing pressure ulcers (Braden<17) had higher odds of having risk assessment documented, and of receiving pressure-reducing mattresses and planned repositioning. Patients at the general hospital were less likely to have risk and skin assessment documented and to receive pressure-reducing mattresses. On the other hand, planned repositioning was more likely to be used at the general hospital. When total hours of nursing care was lower, patients had higher odds of having pressure-reducing mattresses but were less likely to have planned repositioning. CONCLUSION: Patient characteristics (high age and risk score) and hospital type were associated with pressure ulcer prevention. Surprisingly, nurse staffing played only a minor role. Leaders in healthcare organizations should establish routines on different levels that support evidence-based pressure ulcer prevention, and registered nurses need to assume responsibility for bedside care. PMID- 24144275 TI - The impact of gender, culture, and sexuality on Mauritian nursing: Nursing as a non-gendered occupational identity or masculine field? Qualitative study. AB - BACKGROUND: International studies have generally defined nursing as a female dominated occupation. The almost absence of male nurses seems universal, except as a privileged minority occupying positions within nursing specialties ('islands of masculinity'). Nursing is associated with relatively low status owing to gender and income, and is also influenced by cultural perceptions of social status, the nature of the work and sexuality. OBJECTIVE: This study aims to describe and analyse how gender and cultural perceptions influenced the development of nursing in Mauritius. This paper examines why nursing in Mauritius became gendered in different ways due to the impact of gender equivalence in the work force, the gendered segregation in clinical practice and the absence of caring feminisation in nursing. DESIGN AND SETTING: This qualitative study is based on in-depth, semi-structured interviews and convenience sampling. The sample includes nurses working at five hospitals. They all come from the central and southern part of Mauritius. The data were collected over a five-month period during 2006. PARTICIPANTS: Individual qualitative interviews were conducted with 47 nurses, both men (27) and women (20), of different grades, ages, religions and ethnic backgrounds. RESULTS: Nursing practice is gender segregated, influenced and supported by cultural traditions and perceptions of gender relations, sexuality and touch in nursing. However, the professional identity and role is considered non-gendered, implied by the title of 'nursing officer' and the presence of male nurses who constitute almost 50 percent of the work force. Male nurses do not face similar barriers deterring them from entering nursing profession. Nursing did not develop the image of women's work and a low status job in Mauritius. CONCLUSIONS: The nursing profession in Mauritius has been shaped by a different 'history of origin', social, cultural and societal conditions on the basis of the absence of gender imbalance in the work force and caring feminisation in nursing. Moreover, the increase of men's presence in nursing influenced its name, status and perception, shifting nursing into a masculine sphere with advantageous impacts on nursing. PMID- 24144276 TI - Hospital organizational factors influence work-family conflict in registered nurses: Multilevel modeling of a nation-wide cross-sectional survey in Sweden. AB - BACKGROUND: The present shortage of registered nurses (RNs) in many European countries is expected to continue and worsen, which poses a substantial threat to the maintenance of healthcare in this region. Work-family conflict is a known risk factor for turnover and sickness absence. OBJECTIVE: This paper empirically examines whether the nurse practice environment is associated with experienced work-family conflict. DESIGN: A multilevel model was fit with the individual RN at the 1st, and the hospital department at the 2nd level using cross-sectional RN survey data from the Swedish part of RN4CAST, an EU 7th framework project. The data analyzed here is based on a national sample of 8356 female and 592 male RNs from 369 hospital departments. RESULTS: We found that 6% of the variability in work-family conflict experienced by RNs was at the department level. Organizational level factors significantly accounted for most of the variability at this level with two of the work practice environment factors examined, staffing adequacy and nurse involvement in hospital affairs, significantly related to work-family conflict. Due to the design of the study, factors on ward and work group levels could not be analyzed, but are likely to account for additional variance which in the present analysis appears to be on the individual level, with private life factors likely explaining another major part. CONCLUSION: These results suggest that higher level organizational factors in health care have a significant impact on the risk of work-family conflict among RNs through their impact on the nurse practice environment. Lower level organizational factors should be investigated in future studies using hierarchical multilevel sampling. PMID- 24144277 TI - A suitable job?: A qualitative study of becoming a nurse in the context of a globalizing profession in India. AB - BACKGROUND: Research on Indian nurses has focused on their participation as global migrant workers for whom opportunities abroad act as an incentive for many to migrate overseas. However, little is known about the careers of Indian nurses, or the impact of a globalized health care market on nurses who remain and on the profession itself in India. OBJECTIVES: To explore nurses' accounts of entry into nursing in the context of the globalisation of the nursing profession in India, and the salience of 'migration' for nurses' individual careers. DESIGN: Qualitative interview study (n=56). SETTINGS AND PARTICIPANTS: The study drew on interviews with 56 nurses from six sites in Bangalore, India. These included two government hospitals, two private hospitals, a Christian mission hospital, a private outpatient clinic and two private nursing colleges. Participants were selected purposively to include nurses from Christian and Hindu backgrounds, a range of home States, ages and seniority and to deliberately over-recruit (rare) male nurses. METHODS: Interviews covered how and why nurses entered nursing, their training and career paths to date, plans for the future, their experiences of providing nursing care and attitudes towards migration. Data analysis drew on grounded theory methods. RESULTS: Nursing is traditionally seen as a viable career particularly for women from Christian communities in India, where it has created inter-generational 'nurse families'. In a globalizing India, nursing is becoming a job 'with prospects' transcending traditional caste, class and gender boundaries. Almost all nurses interviewed who intended seeking overseas employment envisaged migration as a short term option to satisfy career objectives - increased knowledge, skills and economic rewards - that could result in long-term professional and social status gains 'back home' in India. For others, migration was not part of their career plan: yet the increases in status that migration possibilities had brought were crucial to framing nursing as a 'suitable job' for a growing number of entrants. CONCLUSIONS: The possibility of migration has facilitated collective social mobility for Indian nurses. Migration possibilities were important not only for those who migrate, but for improving the status of nursing in general in India, making it a more attractive career option for a growing range of recruits. PMID- 24144278 TI - A facile approach to synthesize SiO2 . Re2O3 (Re = Y, Eu, La, Sm, Tb, Pr) hollow sphere and its application in drug release. AB - Multifunctional SiO2 . Re2O3 (Re = Y, Eu, La, Sm, Tb, Pr) hollow spheres (HSs) have been fabricated using an acidic Re3+ ion solution. Under ultraviolet radiation, functional HSs emit different colors of light according to the different rare-earth ions embedded into the shell of SiO2 hollow spheres. The as prepared hollow capsules were characterized by X-ray diffraction, transmission electron microscopy, high-resolution transmission electron microscopy, Brunauer Emmett-Teller method, scanning electron microscopy, and energy-dispersive spectrometry. Drug loading and release experiments have been carried out using SiO2 . Eu2O3 HSs that acted as drug carriers. The results demonstrate that the multifunctional HSs exhibit a high storage capacity and the ability of retaining drug stability and activity, which indicates that the as-synthesized fluorescent hollow capsules are a potential candidate as drug delivery materials. PMID- 24144279 TI - Systematic analysis of wide-field fundus autofluorescence (FAF) imaging in posterior uveitis. AB - PURPOSE: To evaluate wide-field fundus autofluorescence (FAF) in patients with uveitis with retinal or chorioretinal involvement. MATERIALS AND METHODS: We included 78 study eyes in this prospective study. Best-corrected visual acuity, a full clinical examination, wide-field green-light FAF and composite color, green and red laser separation fundus imaging with Optomap SLO were performed. In a systematic analysis, the number, extension and margins of central and peripheral retinal or chorioretinal alterations, scars and infiltrates in infectious and non infectious uveitic study eyes were evaluated. Wide-field FAF and color fundus imaging results were compared regarding their diagnostic properties. RESULTS: Nine out of 78 study eyes were diagnosed with infectious, 69 cases with non infectious uveitis. Six infectious uveitic study eyes had changes of the peripheral fundus compared with 48 of 69 non-infectious uveitic eyes. In 33 (infectious versus non-infectious: 4 versus 29) cases, wide-field FAF images revealed more retinal or chorioretinal alterations or pathologies with a farther extended demarcation than wide-field composite color fundus imaging. Eleven out of 69 non-infectious study eyes were diagnosed with vasculitis which could be more precisely evaluated with wide-field FAF than wide-field composite color, green or red light filtered fundus imaging. CONCLUSIONS: Non-invasive wide-field FAF detects more retinal or chorioretinal involvement in patients with posterior uveitis than seen in color imaging and thus is useful in diagnosis and follow-up of uveitic patients. PMID- 24144280 TI - Lamellar salt-doped hybrids with two reversible order/disorder phase transitions. AB - A lamellar bilayer hierarchically structured amide cross-linked alkyl/siloxane hybrid matrix (mono-amidosil, m-A(14)) was doped with a wide concentration range of potassium triflate (KCF3SO3), magnesium triflate (Mg(CF3SO3)2), and europium triflate (Eu(CF3SO3)3). In the K(+)-, Mg(2+)-, and Eu(3+)-based samples with n >= 5, 20, and 60 (where n is the molar ratio of amide C?O groups per cation), respectively, the original lamellar structure of m-A(14) coexists with a new lamellar phase with lower interlamellar distance. The texture of the mono amidosils doped with K(+), Mg(2+), and Eu(3+) ions mimics cabbage leaves, foliated schist, and sea sponges, respectively. In the three series of materials, the cations bond to the oxygen atoms of the amide carbonyl groups. The amide amide hydrogen-bonded array of m-A(14) is less perturbed by the inclusion of KCF3SO3 and Mg(CF3SO3)2 than by the incorporation of Eu(CF3SO3)3. The degree of ionic association is low for n >= 20. The cations coordinate to the oxygen atoms of the triflate ions, forming contact ion pairs at higher salt content. In the Mg(CF3SO3)2- and Eu(CF3SO3)3-containing materials with n = 5 and 10, respectively, crystalline salt is formed. The structural changes undergone by the alkyl chains of selected mono-amidosils in a heating/cooling cycle are reversible, are time-independent, and exhibit two distinct hysteresis domains, one associated with the order/disorder phase transition of the original lamellar bilayer structure of m-A(14) and the second one associated with the order/disorder phase transition of the new lamellar bilayer structure formed in the presence of the salts. PMID- 24144281 TI - Development of selectable marker free, insect resistant, transgenic mustard (Brassica juncea) plants using Cre/lox mediated recombination. AB - BACKGROUND: Antibiotic/ herbicide resistant marker genes have been proven to be very useful in plant transformation for the initial selection of desired transgenic events. However, presence of these genes in the genetically modified crops may render the crop less acceptable to the consumers. Among several different approaches, the effectiveness of Cre/lox mediated recombination strategy for selectable marker gene (SMG) elimination has previously been demonstrated by different groups in several plants including Brassica. In the present study exploiting Cre/lox mediated recombination strategy, attempt has been made for selectable marker gene elimination from Allium sativum leaf agglutinin (ASAL) expressing Brassica plants with hemipteran insect resistant phenotype. RESULTS: Allium sativum leaf agglutinin (ASAL) linked with lox flanked hygromycin resistant (hpt) gene was introduced in mustard. Cre recombinase gene cassette was also integrated in separate event. A Cre/lox mediated recombination using crossing strategy was adopted to remove the hpt gene from the subsequent generation of selected hybrid events. Reciprocal crosses were made between T1ASAL lox-hpt-lox and cre-bar plants. Marker gene elimination was confirmed in the resulting F1 hybrid progenies by PCR analysis, using hpt, cre and ASAL specific primers followed by Southern hybridization. In marker free plants, expression of ASAL was also confirmed by western blotting and ELISA analysis. Retention of functionality of expressed ASAL was investigated by agglutination assay using rabbit erythrocytes. Expressed ASAL was also found to be thermo-sensitive. In planta insect bioassay on F1 hybrid progenies exhibited detrimental effect on the performance of devastating target pest, Lipaphis erysimi. The F1 hybrid hpt negative, ASAL positive plants were allowed to self- fertilize to obtain F2 progeny plants. In some of these plants cre gene was found to be segregated out of the ASAL gene by genetic segregation yielding completely marker free plants. CONCLUSIONS: The present study establishes the efficient expression of the newly introduced insect resistant ASAL gene even after Cre/lox mediated recombination resulting in elimination of selectable marker gene. PMID- 24144282 TI - Determination of perfluorochemicals in fish and shellfish using liquid chromatography-tandem mass spectrometry. AB - This paper reports the validation and application of a method for determination of 10 perfluorochemicals (PFCs) in retail fish and shellfish. The analytes of interest were 7 perfluorinated carboxylates and 3 perfluorinated sulfonates. Fish and shellfish samples were digested with a basic solution of 10 mM sodium hydroxide in methanol before sonication and solid phase extraction through weak anion exchange. Analysis was performed using liquid chromatography-tandem mass spectrometry. Recoveries from spiking five different types of fish and shellfish indicate that the method performs similarly with different fish types, and recoveries were over 90% for all analytes. Forty-six retail samples, collected between 2010 and 2012, including 13 different types of fish and shellfish were analyzed for PFCs. The 13 different types included the top 10 most-consumed fish and shellfish in the United States according to data collected by the National Fisheries Institute. Two Standard Reference Materials were also analyzed. Most fish and shellfish had no detected PFCs; only 11 samples of the 46 tested had detectable concentrations of PFCs. PMID- 24144284 TI - The evolving landscape of endocrine pathology practice. PMID- 24144283 TI - Structure-guided design of potent diazobenzene inhibitors for the BET bromodomains. AB - BRD4, characterized by two acetyl-lysine binding bromodomains and an extra terminal (ET) domain, is a key chromatin organizer that directs gene activation in chromatin through transcription factor recruitment, enhancer assembly, and pause release of the RNA polymerase II complex for transcription elongation. BRD4 has been recently validated as a new epigenetic drug target for cancer and inflammation. Our current knowledge of the functional differences of the two bromodomains of BRD4, however, is limited and is hindered by the lack of selective inhibitors. Here, we report our structure-guided development of diazobenzene-based small-molecule inhibitors for the BRD4 bromodomains that have over 90% sequence identity at the acetyl-lysine binding site. Our lead compound, MS436, through a set of water-mediated interactions, exhibits low nanomolar affinity (estimated Ki of 30-50 nM), with preference for the first bromodomain over the second. We demonstrated that MS436 effectively inhibits BRD4 activity in NF-kappaB-directed production of nitric oxide and proinflammatory cytokine interleukin-6 in murine macrophages. MS436 represents a new class of bromodomain inhibitors and will facilitate further investigation of the biological functions of the two bromodomains of BRD4 in gene expression. PMID- 24144285 TI - Therapeutic implications of accurate classification of pituitary adenomas. AB - Recent data suggest that 1 of 5 individuals in the general population is affected with a pituitary adenoma. Many of these neoplasms are clinically non-functioning adenomas that may be small and clinically undetected or may present as mass lesions; others are hormonally active and cause significant morbidity due to the metabolic effects of hormone excess (e.g., acromegaly and cushing's disease). In either case, they can grow and invade adjacent anatomic structures. Tumors with similar clinical features are morphologically heterogenous and detailed comprehensive classification of pituitary adenomas is important to predict specific clinical behaviors and genetic changes that serve as targets for therapy. We provide a practical approach to clinical diagnosis and highlight the pitfalls in the classification of these common neoplasms. PMID- 24144286 TI - Pathology of the parathyroid glands in hyperparathyroidism. AB - This paper reviews the embryology, histology and pathology of the human parathyroid glands. It emphasizes those pathologic lesions which are found in the setting of clinical hyperparathyroidism. Also discussed are certain molecular features of hyperfunctioning parathyroid glands. The difficulties encountered in parathyroid FNA are reviewed and illustrated. PMID- 24144287 TI - Thyroid neoplasms of follicular cell derivation: a simplified approach. AB - Thyroid tumors of follicular cell derivation are increasing in incidence. These lesions exhibit a spectrum of morphologic and behavioral features that provide the opportunity to understand malignant transformation and progression. Molecular data suggest that the thyroid undergoes a series of genetic alterations that account for the development of the various types of thyroid carcinoma. Our understanding of these tumors has progressed dramatically over the past 50 years and the classification has become complex and cumbersome. We provide a practical approach to clinical diagnosis and propose a simplified classification of these common neoplasms. PMID- 24144288 TI - Gastroenteropancreatic neuroendocrine neoplasms: historical context and current issues. AB - The digestive organs contain a large number of neuroendocrine cells as part of the diffuse neuroendocrine system. Neuroendocrine tumors can occur in every digestive organ. It has long been recognized that this is a diverse group of tumors with very different clinical outcomes; however, well-recognized prognostic parameters had been elusive until recently. Over the years, there have been several different classification schemes, each with different strengths and weaknesses. In an effort to standardize the classification and grading criteria for gastroenteropancreatic neuroendocrine tumors, the current World Health Organization classification includes a histologic grade based on proliferative rate (mitotic rate and Ki67 index) and a TNM stage that varies from organ to organ. The prognostic value of both the grade and stage has been validated in multiple studies. However, several issues remain, including the lack of standardized methods to assess proliferative rate, potential discrepancies between the mitotic count and the Ki67 index; intratumoral heterogeneity in proliferative rate; and the need for refinement in proliferative cut-points to define the grades. More studies are needed to further improve the classification of neuroendocrine tumors, thus guiding optimal treatment for these tumors. PMID- 24144289 TI - Diagnostic and molecular aspects of adrenal cortical tumors. AB - Adrenal cortical diseases are relatively rare but tumors are the most common in diagnostic practice. This is reflected by the content of this review. By studying familial syndromes in which they occur more frequently and the pathways involved in steroidogenesis and cortical growth, the molecular genetics of these tumors is being unraveled. Genome-wide approaches have also been helpful. The emerging data may complement standard histological investigation in diagnosis and prognosis. PMID- 24144290 TI - Paragangliomas: update on differential diagnostic considerations, composite tumors, and recent genetic developments. AB - Recent developments in molecular genetics have expanded the spectrum of disorders associated with pheochromocytomas (PCCs) and extra-adrenal paragangliomas (PGLs) and have increased the roles of pathologists in helping to guide patient care. At least 30% of these tumors are now known to be hereditary, and germline mutations of at least 10 genes are known to cause the tumors to develop. Genotype-phenotype correlations have been identified, including differences in tumor distribution, catecholamine production, and risk of metastasis, and types of tumors not previously associated with PCC/PGL are now considered in the spectrum of hereditary disease. Important new findings are that mutations of succinate dehydrogenase genes SDHA, SDHB, SDHC, SDHD, and SDHAF2 (collectively "SDHx") are responsible for a large percentage of hereditary PCC/PGL and that SDHB mutations are strongly correlated with extra-adrenal tumor location, metastasis, and poor prognosis. Further, gastrointestinal stromal tumors and renal tumors are now associated with SDHx mutations. A PCC or PGL caused by any of the hereditary susceptibility genes can present as a solitary, apparently sporadic, tumor, and substantial numbers of patients presenting with apparently sporadic tumors harbor occult germline mutations of susceptibility genes. Current roles of pathologists are differential diagnosis of primary tumors and metastases, identification of clues to occult hereditary disease, and triaging of patients for optimal genetic testing by immunohistochemical staining of tumor tissue for the loss of SDHB and SDHA protein. Diagnostic pitfalls are posed by morphological variants of PCC/PGL, unusual anatomic sites of occurrence, and coexisting neuroendocrine tumors of other types in some hereditary syndromes. These pitfalls can be avoided by judicious use of appropriate immunohistochemical stains. Aside from loss of staining for SDHB, criteria for predicting risk of metastasis are still controversial, and "malignancy" is diagnosed only after metastases have occurred. All PCCs/PGLs are considered to pose some risk of metastasis, and long-term follow-up is advised. PMID- 24144291 TI - Neuroendocrine tumors of the gynecologic tract: select topics. AB - Tumors of the diffuse neuroendocrine cell system (DNES) may arise in any component of the gynecologic tract, including the vulva, vagina, cervix, endometrium, and ovary. Overall such tumors in the gynecologic tract are rare, constituting only 2% of gynecologic cancers, comprising a spectrum of tumors of variable biologic potential. Due to the rarity of such tumors, pathologists experience may be limited and these may present diagnostic challenges. Currently the nomenclature employed is still that of the pulmonary classification systems, carcinoid, atypical carcinoid, small and large cell neuroendocrine carcinoma that broadly correlates to low/grade 1, intermediate/grade 2, and high grade/grade 3 of the WHO gastroenteropancreatic neuroendocrine tumors classification. Furthermore in keeping with the lung, proliferative rate is assessed based on mitotic index rather than Ki-67 staining. In this review we cover select neuroendocrine tumors of the gynecologic tract. PMID- 24144292 TI - Neuroendocrine carcinoma of the skin--an updated review. AB - Primary neuroendocrine carcinoma of the skin, or Merkel Cell carcinoma (MCC), is a rare but aggressive tumor. Many recent advances on the morphology, immunophenotype, and pathogenesis have come to light in recent years. This review highlights the clinical features, varying histologies, histogenesis, advances in molecular pathology, prognosis, and current management of MCC. It also aims to aid in the differential diagnosis, with an emphasis on neuroendocrine tumors, and approach to the diagnosis of MCC with the use of immunohistochemistry and molecular studies. PMID- 24144293 TI - Pathology, pathophysiology, and treatment strategies of endocrine disorders and their cardiac complications. AB - The cardiovascular system is affected by a multitude of endocrine disorders, including dysfunction of the thyroid, calcium, glucocorticoids, insulin/glucose, and growth hormone axes. Since most of these changes in the cardiovascular system are reversible when treated, early diagnosis is important, as if left untreated, they may become fatal. This review focuses on the pathophysiology, clinical presentation, pathology, and treatment of patients with these endocrine diseases who present with a variety of cardiovascular manifestations. Neuroendocrine tumors presenting with the carcinoid syndrome and their cardiovascular manifestations are also discussed. PMID- 24144294 TI - Collision efficiency of water in the unimolecular reaction CH4 (+H2O) ? CH3 + H (+H2O): one-dimensional and two-dimensional solutions of the low-pressure-limit master equation. AB - The low-pressure-limit unimolecular decomposition of methane, CH4 (+M) ? CH3 + H (+M), is characterized via low-order moments of the total energy, E, and angular momentum, J, transferred due to collisions. The low-order moments are calculated using ensembles of classical trajectories, with new direct dynamics results for M = H2O and new results for M = O2 compared with previous results for several typical atomic (M = He, Ne, Ar, Kr) and diatomic (M = H2 and N2) bath gases and one polyatomic bath gas, M = CH4. The calculated moments are used to parametrize three different models of the energy transfer function, from which low-pressure limit rate coefficients for dissociation, k0, are calculated. Both one dimensional and two-dimensional collisional energy transfer models are considered. The collision efficiency for M = H2O relative to the other bath gases (defined as the ratio of low-pressure limit rate coefficients) is found to depend on temperature, with, e.g., k0(H2O)/k0(Ar) = 7 at 2000 K but only 3 at 300 K. We also consider the rotational collision efficiency of the various baths. Water is the only bath gas found to fully equilibrate rotations, and only at temperatures below 1000 K. At elevated temperatures, the kinetic effect of "weak-collider-in J" collisions is found to be small. At room temperature, however, the use of an explicitly two-dimensional master equation model that includes weak-collider-in-J effects predicts smaller rate coefficients by 50% relative to the use of a statistical model for rotations. The accuracies of several methods for predicting relative collision efficiencies that do not require solving the master equation and that are based on the calculated low-order moments are tested. Troe's weak collider efficiency, betac, includes the effect of saturation of collision outcomes above threshold and accurately predicts the relative collision efficiencies of the nine baths. Finally, a brief discussion is presented of mechanistic details of the energy transfer process, as inferred from the trajectories. PMID- 24144295 TI - [Neuroimaging follow-up of cerebral aneurysms treated with endovascular techniques]. AB - There are no specific recommendations in clinical guidelines about the best time, imaging tests, or intervals for following up patients with intracranial aneurysms treated with endovascular techniques. We reviewed the literature, using the following keywords to search in the main medical databases: cerebral aneurysm, coils, endovascular procedure, and follow-up. Within the Cerebrovascular Disease Group of the Spanish Society of Neuroradiology, we aimed to propose recommendations and an orientative protocol based on the scientific evidence for using neuroimaging to monitor intracranial aneurysms that have been treated with endovascular techniques. We aimed to specify the most appropriate neuroimaging techniques, the interval, the time of follow-up, and the best approach to defining the imaging findings, with the ultimate goal of improving clinical outcomes while optimizing and rationalizing the use of available resources. PMID- 24144297 TI - Polybromobenzene pollutants in the atmosphere of North China: levels, distribution, and sources. AB - Brominated flame retardants (BFRs) are important persistent organic pollutants. Analysis of BFRs in atmospheric samples in a previous study led us to suspect the presence of unidentified organic bromides, other than polybrominated diphenyl ethers (PBDEs), in the atmosphere. In this study, we identified and quantified polybromobenzenes, a group of organic bromides, in air samples collected through passive sampling in gridded observations in North China. We investigated their concentrations and spatial distribution, and estimated the proportion due to different sources. We detected seven species of polybromobenzenes, including hexabromobenzene (HBB), pentabromotoluene (PBT), pentabromoethylbenzene (PBEB), pentabromobenzene (PeBB), tetrabromobenzenes (TeBBs), and tribromotoluene (TrBT), in all or most of the field samples, indicating widespread occurrence of this class of pollutants. The median concentrations of each pollutant ranged from 20.0 to 144 pg/sample (or from 0.07 to 1.16 pg/m(3)), with relatively high concentrations found near e-waste recycling sites, BFR manufacturing sites, and areas of high population density. Positive matrix factorization (PMF) analysis revealed that ~70% of HBB, PBT, PBEB, and PeBB was from commercial products, while ~80% of 1,2,3,5-TeBB, 1,2,4,5-TeBB, and 2,4,5-TrBT was linked with BFR manufacturing. This study provides essential information on widespread polybromobenzene pollutants in the atmosphere, particularly TeBBs and TrBT, for which this is the first report of their presence as atmospheric pollutants. PMID- 24144298 TI - Body image and sexuality in Indonesian adults with a disorder of sex development (DSD). AB - In Indonesia, disorders of sex development (DSDs) are not well recognized and medical care for affected individuals is scarce. Consequently, many patients live with ambiguous genitalia and appearance. We compared reported outcomes on body image, sexual functioning, and sexual orientation of 39 adults with DSDs (aged 18 to 41) and 39 healthy controls matched for gender, age, and residential setting (urban, suburban, rural). Differences in gender and treatment status (treated or untreated) were also explored. On body image, adults with DSDs reported dissatisfaction with sex-related body parts. Compared to the matched controls, women with DSDs reported greater sexual distress, and men with DSDs reported lower erectile and ejaculation frequencies, and more dissatisfaction with sexual life but not with sexual desire and activities. Men with DSDs who had undergone genital surgery reported higher erectile and ejaculation frequencies than untreated men. More women than men in the DSDs group reported a nonexclusive heterosexual orientation. DSDs and infertility had a great impact on sexuality. Fear of ostracism complicated DSD acceptance. Findings were compared to those of Western studies. Based on these results, education about DSDs and their psychosexual consequences may help reduce the sexual distress and problems in adults with DSDs and improve quality of life. PMID- 24144299 TI - Directed metalation cascade to access highly functionalized thieno[2,3 f]benzofuran and exploration as building blocks for organic electronics. AB - A tandem directed metalation has been successfully applied to the preparation of thieno[2,3-f]benzofuran-4,8-dione, providing an efficient and facile approach to symmetrically and unsymmetrically functionalize the thieno[2,3-f]benzofuran core at the 2,6 positions as well as to introduce the electron-withdrawing or donating groups (EWG or EDG) at its 4,8 positions. The presence of various functional groups makes late-stage derivatization attainable. PMID- 24144301 TI - Magnetic control of protein spatial patterning to direct microtubule self assembly. AB - Living systems offer attractive strategies to generate nanoscale structures because of their innate functional properties such as the dynamic assembly of ordered nanometer fibers, the generation of mechanical forces, or the directional transport mediated by molecular motors. The design of hybrid systems, capable of interfacing artificial building blocks with biomolecules, may be a key step toward the rational design of nanoscale devices and materials. Here, we have designed a bottom-up approach to organize cytoskeletal elements in space using the self-assembly properties of magnetic nanoparticles conjugated to signaling proteins involved in microtubule nucleation. We show that magnetic nanoparticles conjugated to signaling proteins involved in microtubule nucleation can control the positioning of microtubule assembly. Under a magnetic field, a self-organized pattern of biofunctionalized nanoparticles is formed and leads to the nucleation of a periodical network of microtubules in Xenopus laevis egg extract. Our method shows how bioactive nanoparticles can generate a biochemically active pattern upon magnetic actuation, which triggers the spatial organization of nonequilibrium biological structures. PMID- 24144300 TI - Can routine clinical measures predict ultrasound-determined synovitis and remission in rheumatoid arthritis patients? AB - OBJECTIVES: The purpose of this study was to determine if routine clinical measures can predict the presence and severity of ultrasound synovitis in rheumatoid arthritis (RA) patients. METHODS: Bilateral 1-5 MCP (metacarpopharangeal) and wrist joints were examined using power Doppler (PD) ultrasound (US). Correlations between PD scores and routine clinical measures of RA - swollen joint count (SJC), tender joint count, patient's global assessment (GA), physician's GA, CRP, ESR, MMP-3, RF and anti-CCP antibody - were determined and used to identify significant predictors of PD score. Clinical measures were then compared between two groups (patients with and without PD) and analysed using multiple logistic regression, to derive a model that predicted the absence of PD signals. RESULTS: SJC was the most significant predictor of PD score (R2 = 0.4566, p value <0.0001), but was an inadequate predictor of PD signal remission. However, the combination of Steinbrocker's stage I or II (odds ratio [OR] 9.23, p=0.0049), SJC=0 in 1-5 MCP and wrist joints on both sides (OR 6.60, p=0.0039), and SDAI (or CDAI) remission (OR 5.06, p=0.0450) had a positive predictive value of 100%, predicting the absence of PD signals in all study patients meeting the 3 criteria. CONCLUSIONS: PD score and absence of PD signals can be predicted using routine clinical measures. When used in combination, Steinbrocker's stage, SJC and SDAI (or CDAI) can estimate disease activity and identify patients likely to have synovitis and requiring US. PMID- 24144302 TI - Amphiphilic conetworks and gels physically cross-linked via stereocomplexation of polylactide. AB - Amphiphilic conetworks (APCNs), consisting of hydrophilic poly[poly(ethylene glycol) methyl ester acrylate] (PPEGMEA) and hydrophobic stereocomplex of poly(L lactide) (PLLA) and poly(D-lactide) (PDLA), were prepared by free radical copolymerization of PEGMEA with acrylate macromonomer of the PLA stereocomplex. The effects of stereocomplexation and the amount of PLA stereocomplex on the rheology properties of APCNs were investigated. The results indicated that the APCNs was stronger in the presence of stereocomplexation compared with the that of nonstereocomplex system, and the strength of the APCNs increased with the increasing of the amount of PLA stereocomplex. The storage modulus of the APCNs could be easily tuned from 1200 to 4300 Pa by incorporating 2-10% of stereocomplex PLA. On the other hand, the swelling behavior of APCNs decreased with the increasing content of hydrophobic PLA cross-linker. PMID- 24144304 TI - PCSK9 acts as a chaperone for the LDL receptor in the endoplasmic reticulum. AB - PCSK9 (proprotein convertase subtilisin/kexin type 9) binds to the LDLR (low density lipoprotein receptor) at the cell surface and disrupts recycling of the LDLR. However, PCSK9 also interacts with the LDLR in the ER (endoplasmic reticulum). In the present study we have investigated the role of PCSK9 for the transport of the LDLR from the ER to the cell membrane. A truncated LDLR consisting of the ectodomain (ED-LDLR) was used for these studies to avoid PCSK9 mediated degradation of the LDLR. The amount of secreted ED-LDLR was used as a measure of the amount of ED-LDLR transported from the ER. From co-transfection experiments of various PCSK9 and ED-LDLR plasmids, PCSK9 increased the amount of WT (wild-type) ED-LDLR in the medium, but not of an ED-LDLR lacking the EGF (epidermal growth factor)-A repeat or of a Class 2a mutant ED-LDLR which fails to exit the ER. Mutant PCSK9s which failed to undergo autocatalytic cleavage or failed to exit the ER, failed to increase the amount of WT-ED-LDLR in the medium. These mutants also reduced the amount of WT-ED-LDLR intracellularly, which could partly be prevented by the proteasome inhibitor lactacystine. WT-ED-LDLR promoted autocatalytic cleavage of pro-PCSK9. The findings of the present study indicate that the binding of WT-ED-LDLR to pro-PCSK9 in the ER promotes autocatalytic cleavage of PCSK9, and autocatalytically cleaved PCSK9 acts as a chaperone to promote the exit of WT-ED-LDLR from the ER. PMID- 24144305 TI - High concentration capacity sample preparation techniques to improve the informative potential of two-dimensional comprehensive gas chromatography-mass spectrometry: application to sensomics. AB - This study reports and critically discusses the results of a systematic investigation on the effectiveness of different and complementary sampling approaches, based on either sorption and adsorption, treated as a further dimension of a two-dimensional comprehensive gas chromatography-mass spectrometry analytical platform for sensomics. The focus is on the potentials of a group of high concentration capacity (HCC) sample preparation (Solid Phase Microextraction, SPME, Stir Bar Sorptive Extraction, SBSE and Headspace Sorptive Extraction, HSSE) and Dynamic Headspace (D-HS) techniques investigated to provide information useful for fingerprinting and profiling studies of food aroma. Volatiles and semi-volatiles contributing to define whole and nonfat dry milk aroma have been successfully characterized thanks to the combination of effective and selective sampling by HCC and D-HS techniques, high separation and detection power of GC*GC-MS and suitable data elaboration (i.e., Comprehensive Template Matching Fingerprinting - CTMF). Out of the sample preparation techniques investigated, HSSE and SBSE have shown to be really effective for sensomics studies because of their high concentration factors, providing highly representative profiles as well as analyte recovery suitable for GC-Olfactometry even with high odor threshold (OT) markers or potent odorants in sub-trace amounts. PMID- 24144306 TI - Selective apoptosis induction in MCF-7 cell line by truncated minimal functional region of Apoptin. AB - BACKGROUND: Chicken Anemia Virus (CAV) VP3 protein (also known as Apoptin), a basic and proline-rich protein has a unique capability in inducing apoptosis in cancer cells but not in normal cells. Five truncated Apoptin proteins were analyzed to determine their selective ability to migrate into the nucleus of human breast adenocarcinoma MCF-7 cells for inducing apoptosis. METHODS: For identification of the minimal selective domain for apoptosis, the wild-type Apoptin gene had been reconstructed by PCR to generate segmental deletions at the N' terminal and linked with nuclear localization sites (NLS1 and NLS2). All the constructs were fused with maltose-binding protein gene and individually expressed by in vitro Rapid Translation System. Standardized dose of proteins were delivered into human breast adenocarcinoma MCF-7 cells and control human liver Chang cells by cytoplasmic microinjection, and subsequently observed for selective apoptosis effect. RESULTS: Three of the truncated Apoptin proteins with N-terminal deletions spanning amino acid 32-83 retained the cancer selective nature of wild-type Apoptin. The proteins were successfully translocated to the nucleus of MCF-7 cells initiating apoptosis, whereas non-toxic cytoplasmic retention was observed in normal Chang cells. Whilst these truncated proteins retained the tumour-specific death effector ability, the specificity for MCF-7 cells was lost in two other truncated proteins that harbor deletions at amino acid 1-31. The detection of apoptosing normal Chang cells and MCF-7 cells upon cytoplasmic microinjection of these proteins implicated a loss in Apoptin's signature targeting activity. CONCLUSIONS: Therefore, the critical stretch spanning amino acid 1-31 at the upstream of a known hydrophobic leucine-rich stretch (LRS) was strongly suggested as one of the prerequisite region in Apoptin for cancer targeting. Identification of this selective domain provides a platform for developing small targets to facilitating carrier-mediated-transport across cellular membrane, simultaneously promoting protein delivery for selective and effective breast cancer therapy. PMID- 24144308 TI - Factors that influence health-related quality of life in newly diagnosed patients with multiple myeloma aged >= 65 years treated with melphalan, prednisone and lenalidomide followed by lenalidomide maintenance: results of a randomized trial. AB - In the MM-015 trial, melphalan-prednisone-lenalidomide followed by lenalidomide maintenance (MPR-R) significantly prolonged progression-free survival versus melphalan-prednisone (MP) in newly diagnosed patients with multiple myeloma aged >= 65 years. Health-related quality of life (HRQoL), a secondary endpoint of MM 015, was also improved with MPR-R. This sub-analysis evaluated the impact of individual predictive factors on HRQoL. Patients completed HRQoL questionnaires at baseline, every third cycle and at progressive disease (PD)/treatment discontinuation. In a mixed-effects model female gender, advanced age and PD negatively affected HRQoL while better treatment responses showed positive effects. Compared to PD, HRQoL during MPR-R treatment was statistically significantly better in two of six preselected domains both of which were also clinically meaningful. HRQoL scores at end of treatment were all either improved or not statistically significantly different versus baseline. In conclusion, continuous treatment with MPR-R, which delays PD, appears to be associated with clinically meaningful improvements in HRQoL. PMID- 24144309 TI - Prognostic factors and treatment outcomes for patients with stage II extranodal nasal-type natural killer/T-cell lymphoma of the upper aerodigestive tract. AB - The prognosis and optimal therapy for high-risk early-stage extranodal nasal-type natural killer/T-cell lymphoma (NKTCL) are not well defined. This study was conducted to evaluate the prognostic factors and treatment outcomes in patients with stage II NKTCL of the upper aerodigestive tract (UADT-NKTCL). One hundred and twenty-four patients with stage II UADT-NKTCL were enrolled. Primary tumors were located in the nasal cavity (n = 53) or extranasal UADT (n = 71). Eighty four patients were treated with combined modality therapy (CMT), and 40 patients were treated with radiotherapy alone (n = 30) or chemotherapy alone (n = 10). The 5-year overall survival (OS) and progression-free survival (PFS) rates for all stage II patients were 60.1% and 47.8%, respectively. Primary location and disease extent were the important prognostic factors in univariate and multivariate analyses. CMT significantly improved survival. The 5-year OS and PFS rates were 71.2% and 56.7% for CMT, compared with 35.1% (p < 0.001) and 26.7% for single modality therapy (p < 0.001). Survival differences between CMT and single modality therapy were also observed in nasal and extranasal subgroups of UADT NKTCL. This retrospective study showed significant improvements in OS and PFS in patients who received both chemotherapy and radiotherapy for stage II NKTCL. The findings need further validation in other datasets. PMID- 24144307 TI - The histone deacetylase inhibitor SAHA sensitizes acute myeloid leukemia cells to a combination of nucleoside analogs and the DNA-alkylating agent busulfan. AB - Fludarabine (Flu), clofarabine (Clo) and busulfan (Bu) are used in allogeneic hematopoietic stem cell transplant (allo-HSCT). We reported that combining [Flu + Clo + Bu] had a synergistic cytotoxicity in AML cells. We hypothesized that combining [Flu + Clo + Bu] with the histone deacetylase inhibitor SAHA will further enhance cytotoxicity. We exposed the acute myeloid leukemia (AML) cell lines KBM3/Bu250(6) and OCI-AML3 to Flu, Clo, Bu and SAHA alone and in various combinations. [Flu + Clo + Bu + SAHA] resulted in synergistic cytotoxicity, which can be attributed to (1) activated DNA-damage response and cell cycle checkpoint activation through the ATM-CHK2-P53 (or P73) pathway or ATM-CHK2-cdc25-cdc2 pathway, (2) histone modifications and (3) activated apoptosis pathway. The [Flu + Clo + Bu + SAHA] combination causes mitochondrial outer membrane permeabilization, leakage of cytochrome c and Smac/Diablo into the cytosol with caspase activation, and release of apoptosis-inducing factor (AIF) into the nucleus resulting in nuclear fragmentation and cell death. These results provide a mechanistic basis for using SAHA in future clinical trials with double nucleoside analog-busulfan combinations in pretransplant conditioning therapy. PMID- 24144310 TI - Identification of target genes using gene expression profile of granulocytes from patients with chronic myeloid leukemia treated with tyrosine kinase inhibitors. AB - Differential gene expression analysis by suppression subtractive hybridization with correlation to the metabolic pathways involved in chronic myeloid leukemia (CML) may provide a new insight into the pathogenesis of CML. Among the overexpressed genes found in CML at diagnosis are SEPT5, RUNX1, MIER1, KPNA6 and FLT3, while PAN3, TOB1 and ITCH were decreased when compared to healthy volunteers. Some genes were identified and involved in CML for the first time, including TOB1, which showed a low expression in patients with CML during tyrosine kinase inhibitor treatment with no complete cytogenetic response. In agreement, reduced expression of TOB1 was also observed in resistant patients with CML compared to responsive patients. This might be related to the deregulation of apoptosis and the signaling pathway leading to resistance. Most of the identified genes were related to the regulation of nuclear factor kappaB (NF-kappaB), AKT, interferon and interleukin-4 (IL-4) in healthy cells. The results of this study combined with literature data show specific gene pathways that might be explored as markers to assess the evolution and prognosis of CML as well as identify new therapeutic targets. PMID- 24144311 TI - Carcinogenic risk of retained arsenic after successful treatment of acute promyelocytic leukemia with arsenic trioxide: a cause for concern? PMID- 24144312 TI - Perspective on how to approach molecular diagnostics in acute myeloid leukemia and myelodysplastic syndromes in the era of next-generation sequencing. AB - Molecular mutation information became essential for biological subclassification, risk stratification and therapeutic decisions in patients with acute myeloid leukemia (AML). In myelodysplastic syndromes (MDS), a broad spectrum of molecular biomarkers such as the spliceosome mutations has been identified in recent years. The currently established combination of various polymerase chain reaction (PCR) methods with capillary Sanger sequencing for mutation analysis in AML is time consuming and labor-intensive. The constantly increasing spectrum of molecular mutations is a tremendous challenge for hematological laboratories. The introduction of high-throughput sequencing technology, which allows the massive parallel analysis of hundreds of thousands of alleles in the shortest time, provides new options for molecular mutation analyses and for follow-up diagnostics in myeloid neoplasms. In contrast to whole-genome or exome analyses, amplicon deep-sequencing focuses on distinct genomic loci and their mutation patterns and enables a comprehensive biomarker analysis in a multitude of patients per analysis. This review summarizes thus far established common molecular diagnostic strategies and intends to outline the perspective of distinct novel amplicon deep-sequencing panels for patients with AML and MDS. It is foreseeable that clearly defined algorithms for molecular investigations will revolutionize diagnosis in patients with AML and MDS in the near future. PMID- 24144313 TI - Ten-day decitabine as initial therapy for newly diagnosed patients with acute myeloid leukemia unfit for intensive chemotherapy. AB - We retrospectively reviewed outcomes in 45 previously untreated patients with acute myeloid leukemia (AML) considered unfit for chemotherapy who were treated with 10-day courses of decitabine 20 mg/m(2) daily outside of a clinical trial, with no cut-offs for organ function or performance status (PS). Nineteen had Eastern Cooperative Group performance status (ECOG PS) >= 2, and 39 had >= 2 comorbidities. Fourteen patients (31%) achieved complete remission (CR) and five (11%) CR with incomplete count recovery, for an overall response rate of 42%, after a median of 2 (range, 1-4) courses. The only pretreatment characteristic that differed significantly between responders and non-responders was percent marrow blasts (median 42% vs. 65%; p = 0.01). Median overall survival was 9.0 months; it was 19.4 and 2.3 months for responders and non-responders, respectively (p < 0.001). Thus 10-day decitabine therapy has efficacy in patients with AML considered unfit for chemotherapy, and may serve as a backbone for the addition of other novel agents. PMID- 24144315 TI - 3D in vitro tissue models and their potential for drug screening. AB - INTRODUCTION: The development of one standard, simplified in vitro three dimensional tissue model suitable to biological and pathological investigation and drug-discovery may not yet be feasible, but standardized models for individual tissues or organs are a possibility. Tissue bioengineering, while concerned with finding methods of restoring functionality in disease, is developing technology that can be miniaturized for high throughput screening (HTS) of putative drugs. Through collaboration between biologists, physicists and engineers, cell-based assays are expanding into the realm of tissue analysis. Accordingly, three-dimensional (3D) micro-organoid systems will play an increasing role in drug testing and therapeutics over the next decade. Nevertheless, important hurdles remain before these models are fully developed for HTS. AREAS COVERED: We highlight advances in the field of tissue bioengineering aimed at enhancing the success of drug candidates through pre clinical optimization. We discuss models that are most amenable to high throughput screening with emphasis on detection platforms and data modeling. EXPERT OPINION: Modeling 3D tissues to mimic in-vivo architecture remains a major challenge. As technology advances to provide novel methods of HTS analysis, so do potential pitfalls associated with such models and methods. We remain hopeful that integration of biofabrication with HTS will significantly reduce attrition rates in drug development. PMID- 24144314 TI - Toll-like receptor 4 and 9 expression in B-chronic lymphocytic leukemia: relationship with infections, autoimmunity and disease progression. AB - Toll-like receptors (TLRs) represent major agents of innate immunity and initiators of adaptive immunity. TLR4 and TLR9 gene expression was related to the occurrence of infections, autoimmunity and disease progression in 95 patients with B-chronic lymphocytic leukemia (B-CLL), grouped according to stage, therapy and known prognostic markers, and followed prospectively (median 33.6 months, range 25-50). A retrospective analysis (median 6.8 years, range 6-26) was also performed. TLR4 gene expression was decreased and TLR9 increased in patients versus controls, the former being more pronounced in advanced and multi-treated disease, and in patients with unmutated immunoglobulin heavy chain variable (IgVH) region and unfavorable cytogenetics. Patients with reduced TLR4 had an increased risk of disease progression and development of autoimmune complications. No relationship was found between reduced TLR4 expression and infectious episodes, which were observed in advanced stages and treated patients. These findings suggest that impaired innate immunity identifies patients with B CLL with a poor prognosis and reduced ability to silence autoreactive phenomena. PMID- 24144316 TI - Effects on well-being of investing in cleaner air in India. AB - Over the past decade, India has experienced rapid economic growth along with increases in levels of air pollution. Our goal is to examine how alternative policies for air pollution abatement affect well-being there. In particular, we estimate the effects of policies to reduce the levels of ambient fine particulates (PM2.5), which are especially harmful to human health, on well being, quantified using the United Nations' human development index (HDI). Two of the three dimensions of this index are based on gross domestic product (GDP) per capita and life expectancy. Our approach allows reductions in PM2.5 to affect both of them. In particular, economic growth is affected negatively through the costs of the additional pollution control measures and positively through the increased productivity of the population. We consider three scenarios of PM2.5 abatement, corresponding to no further control, current Indian legislation, and current European legislation. The overall effect in both control scenarios is that growth in GDP is virtually unaffected relative to the case of no further controls, life expectancy is higher, and well-being, as measured by the HDI, is improved. In India, air pollution abatement investments clearly improve well being. PMID- 24144317 TI - An abscess causing a delayed optic neuropathy after decompression for thyroid eye disease. AB - A 63-year-old female with Graves' disease and chronic sinusitis presented with acute left orbital pain and proptosis five years after bilateral orbital decompression and sinus surgery. Imaging revealed bilateral frontal sinus opacification, frontoethmoidal mucoceles and left subperiosteal mass. Presence of an optic neuropathy drove emergent management with intravenous antibiotics and orbitotomy with exploration. Intra-operatively, a left orbital abscess and left frontal sinus purulence were drained. The patient regained her vision with relief of proptosis and pain. PMID- 24144319 TI - Superior CO catalytic oxidation on novel Pt/clay nanocomposites. AB - Nanostructured novel Pt/Clay nanocomposites consisting of well-defined Pt nanoparticles prepared by clay-mediated in situ reduction displays very high thermal stability, large BET surface area and superior catalytic activity for CO oxidation as compared to a model reference Pt/SiO2 catalysts. CO oxidation has attracted renewed attention because of its technological importance in the area of pollution control. The Pt/Clay system consisting of Pt nanoparticles strongly immobilized between the atomic layers of clay inhibits nanoparticle sintering and loss of catalytic activity even after prolonged heating at high temperatures. At elevated temperatures (300 degrees C), the Pt/Clay system demonstrates significant enhancement of catalytic activity, with almost 100% CO conversion in less than 5 min. Emphasis is given to the role played by the clay supporting material which is chemically and thermally stable under the catalytic conditions of exhaust purification. PMID- 24144318 TI - Transcriptional regulation and its misregulation in Alzheimer's disease. AB - Alzheimer's disease (AD) is a devastating neurodegenerative disorder characterized by loss of memory and cognitive function. A key neuropathological event in AD is the accumulation of amyloid-beta (Abeta) peptide. The production and clearance of Abeta in the brain are regulated by a large group of genes. The expression levels of these genes must be fine-tuned in the brain to keep Abeta at a balanced amount under physiological condition. Misregulation of AD genes has been found to either increase AD risk or accelerate the disease progression. In recent years, important progress has been made in uncovering the regulatory elements and transcriptional factors that guide the expression of these genes. In this review, we describe the mechanisms of transcriptional regulation for the known AD genes and the misregualtion that leads to AD susceptibility. PMID- 24144320 TI - Effect of p-tert-butyl group substitution on the quantum tunneling rate in quadruple proton rearrangement of calix[4]arene. AB - Glass-transition behaviors concerning the quadruple proton/deuteron rearrangements in the crystalline p-tert-butylcalix[4]arene-toluene (BC4A.T) host guest compound were studied by adiabatic calorimetry. The glass-transition temperatures (Tg's) of the hydrated BC4A.T-h and deuterated BC4A.T-d were found to be around 90 and 181 K, respectively. The difference of 90 K is too big to be recognized as the ordinary isotope effect, which is about 5 K in classical thermal activation processes. The temperature interval over which the enthalpy relaxation effect was observed was beyond 50 K, being too wide, in BC4A.T-h, while it was 20-30 K in BC4A.T-d; the latter is the one ordinarily observed in the classical processes. The associated equilibration rate in BC4A.T-h was evaluated from the enthalpy relaxation curve observed at 62 K to evidence the non Arrhenius nature of the temperature dependence. The relaxation effect was detected even at 20 K. These are quite the same behaviors as observed in calix[4]arene, and the quantum tunneling rate in the quadruple proton rearrangement was concluded to be only a little affected by the substitution of the tert-butyl group at the para-position of each phenol moiety. PMID- 24144296 TI - Nine loci for ocular axial length identified through genome-wide association studies, including shared loci with refractive error. AB - Refractive errors are common eye disorders of public health importance worldwide. Ocular axial length (AL) is the major determinant of refraction and thus of myopia and hyperopia. We conducted a meta-analysis of genome-wide association studies for AL, combining 12,531 Europeans and 8,216 Asians. We identified eight genome-wide significant loci for AL (RSPO1, C3orf26, LAMA2, GJD2, ZNRF3, CD55, MIP, and ALPPL2) and confirmed one previously reported AL locus (ZC3H11B). Of the nine loci, five (LAMA2, GJD2, CD55, ALPPL2, and ZC3H11B) were associated with refraction in 18 independent cohorts (n = 23,591). Differential gene expression was observed for these loci in minus-lens-induced myopia mouse experiments and human ocular tissues. Two of the AL genes, RSPO1 and ZNRF3, are involved in Wnt signaling, a pathway playing a major role in the regulation of eyeball size. This study provides evidence of shared genes between AL and refraction, but importantly also suggests that these traits may have unique pathways. PMID- 24144322 TI - Psychobiotics highlight the pathways to happiness. PMID- 24144323 TI - Glycine transporter-I inhibitors: a new class of antidepressant? PMID- 24144324 TI - Scopolamine and ketamine: evidence of convergence? PMID- 24144325 TI - Interfacial polygonal patterning via surfactant-mediated self-assembly of gold nanoparticles. AB - In this work, we explored the formation processes of interfacial polygonal patterning via surfactant-mediated self-assembly of gold nanoparticles (AuNPs). We found that a balance between DDT-capped AuNPs and PVP-passivated AuNPs is a key to making these inorganic-organic thin films. The interfacial polygonal patterning possesses many processing advantages and flexibilities, such as controllable interfacial shape and inter-AuNP distance, tuning of particle sizes, thiol population, chain lengths, and other new properties by introducing functional groups to thiol chains. In principle, self-assembly of AuNPs via well designed interfaces may be useful for fabrications of other complex architectures. PMID- 24144321 TI - From mechanosensitivity to inflammatory responses: new players in the pathology of glaucoma. AB - PURPOSE OF THE STUDY: Many blinding diseases of the inner retina are associated with degeneration and loss of retinal ganglion cells (RGCs). Recent evidence implicates several new signaling mechanisms as causal agents associated with RGC injury and remodeling of the optic nerve head. Ion channels such as Transient receptor potential vanilloid isoform 4 (TRPV4), pannexin-1 (Panx1) and P2X7 receptor are localized to RGCs and act as potential sensors and effectors of mechanical strain, ischemia and inflammatory responses. Under normal conditions, TRPV4 may function as an osmosensor and a polymodal molecular integrator of diverse mechanical and chemical stimuli, whereas P2X7R and Panx1 respond to stretch- and/or swelling-induced adenosine triphosphate release from neurons and glia. Ca(2+) influx, induced by stimulation of mechanosensitive ion channels in glaucoma, is proposed to influence dendritic and axonal remodeling that may lead to RGC death while (at least initially) sparing other classes of retinal neuron. The secondary phase of the retinal glaucoma response is associated with microglial activation and an inflammatory response involving Toll-like receptors (TLRs), cluster of differentiation 3 (CD3) immune recognition molecules associated with the T-cell antigen receptor, complement molecules and cell type specific release of neuroactive cytokines such as tumor necrosis factor-alpha (TNF-alpha) and interleukin-1beta (IL-1beta). The retinal response to mechanical stress thus involves a diversity of signaling pathways that sense and transduce mechanical strain and orchestrate both protective and destructive secondary responses. CONCLUSIONS: Mechanistic understanding of the interaction between pressure-dependent and independent pathways is only beginning to emerge. This review focuses on the molecular basis of mechanical strain transduction as a primary mechanism that can damage RGCs. The damage occurs through Ca(2+) dependent cellular remodeling and is associated with parallel activation of secondary ischemic and inflammatory signaling pathways. Molecules that mediate these mechanosensory and immune responses represent plausible targets for protecting ganglion cells in glaucoma, optic neuritis and retinal ischemia. PMID- 24144326 TI - IR spectroscopy of gas phase V(CO2)n+ clusters: solvation-induced electron transfer and activation of CO2. AB - Ion-molecule complexes of vanadium and CO2, i.e., V(CO2)n(+), produced by laser vaporization are mass selected and studied with infrared laser photodissociation spectroscopy. Vibrational bands for the smaller clusters (n < 7) are consistent with CO2 ligands bound to the metal cation via electrostatic interactions and/or attaching as inert species in the second coordination sphere. All IR bands for these complexes are consistent with intact CO2 molecules weakly perturbed by cation binding. However, multiple new IR bands occur only in larger complexes (n >= 7), indicating the formation of an intracluster reaction product whose nominal mass is the same as that of V(CO2)n(+) complexes. Computational studies and the comparison of predicted spectra for different possible reaction products allow identification of an oxalate-type C2O4 anion species in the cluster. The activation of CO2 producing this product occurs via a solvation-induced metal >ligand electron transfer reaction. PMID- 24144327 TI - Knowledge and self-reported practices regarding leptospirosis among adolescent school children in a highly endemic rural area in Sri Lanka. AB - INTRODUCTION: Leptospirosis is a zoonotic disease, which has become a major public health threat in Sri Lanka. A majority of patients are farmers in rural endemic areas. The purpose of the present study is to describe the level of knowledge and frequencies of risky practices related to leptospirosis among a sample of rural school adolescents in Galgamuwa, Kurunegala district, a highly endemic area in Sri Lanka. METHODS: A descriptive cross-sectional study was conducted among 460 adolescents studying in grades 9 and 10 of government schools. Study participants were selected using a multistage cluster sampling technique. A structured, pretested, self-administered questionnaire was used to collect data on sociodemographic characteristics, knowledge on leptospirosis, and frequency of associated risky practices related to leptospirosis. RESULTS: The response rate was 100%. Fifty-two percent of respondents had a 'good' level of knowledge of leptospirosis. In the assessment of practices, 62% were involved in rice paddy cultivation either 'frequently' or 'rarely'. Seventy percent of the fathers and 50% of the mothers of the students were involved in paddy cultivation. Thirteen percent reported that they swam, bathed, or washed in ponds of stagnant water. Of the students involved in paddy cultivation, only 18% said they usually used gloves and boots 'frequently'. Among the 9% of students who handled cattle or buffalo, 61% reported washing their hands and feet after handling the animals. Good level of knowledge was significantly associated with involvement in paddy cultivation among the adolescents (p=0.45), fathers (p<0.001), and mothers (p=0.012). The level of knowledge was not significantly associated with practicing preventive measures for leptospirosis. CONCLUSIONS: Although the respondent's overall level of knowledge regarding leptospirosis was satisfactory, the study identified several important gaps in specific areas. Those who were involved or had parents involved in paddy cultivation had better knowledge. However, this knowledge was not translated into practice of personal preventive measures. Use of protective attire in paddy farming needs to be facilitated by health authorities. PMID- 24144328 TI - Profiling polyphenols in five Brassica species microgreens by UHPLC-PDA ESI/HRMS(n.). AB - Brassica vegetables are known to contain relatively high concentrations of bioactive compounds associated with human health. A comprehensive profiling of polyphenols from five Brassica species microgreens was conducted using ultrahigh performance liquid chromatography photodiode array high-resolution multistage mass spectrometry (UHPLC-PDA-ESI/HRMS(n)). A total of 164 polyphenols including 30 anthocyanins, 105 flavonol glycosides, and 29 hydroxycinnamic acid and hydroxybenzoic acid derivatives were putatively identified.The putative identifications were based on UHPLC-HRMS(n) analysis using retention times, elution orders, UV-vis and high-resolution mass spectra, and an in-house polyphenol database as well as literature comparisons. This study showed that these five Brassica species microgreens could be considered as good sources of food polyphenols. PMID- 24144329 TI - Bifunctional PEGylated exenatide-amylinomimetic hybrids to treat metabolic disorders: an example of long-acting dual hormonal therapeutics. AB - Peptide hybrids (phybrids) comprising covalently linked peptide hormones can leverage independent biological pathways for additive or synergistic metabolic benefits. PEGylation of biologics offers enhanced stability, duration, and reduced immunogenicity. These two modalities can be combined to produce long acting therapeutics with dual pharmacology and enhanced efficacy. Compound 10 is composed of an exenatide (AC2993) analogue, AC3174, and an amylinomimetic, davalintide (AC2307), with an intervening 40 kD PEG moiety. It displayed dose dependent and prolonged efficacy for glucose control and body weight reduction in rodents with superior in vitro and in vivo activities compared to those of a side chain PEGylated phybrid 6. In diet-induced obese (DIO) rats, the weight-loss efficacy of 10 was similar to that of a combination of PEG-parents 3 and 4. A single dose of 10 elicited sustained body weight reduction in DIO rats for at least 21 days. Compound 10's terminal half-life of ~27 h should translate favorably to weekly dosing in humans. PMID- 24144330 TI - Rate constants and products of the OH reaction with isoprene-derived epoxides. AB - Recent laboratory and field work has shown that isoprene-derived epoxides (IEPOX) are crucial intermediates that can explain the existence of a variety of compounds found in ambient secondary organic aerosol (SOA). However, IEPOX species are also able to undergo gas phase oxidation, which competes with the aerosol phase processing of IEPOX. In order to better quantify the atmospheric fate of IEPOX, the gas phase OH reaction rate constants and product formation mechanisms have been determined using a flow tube chemical ionization mass spectrometry technique. The new OH rate constants are generally larger than previous estimations and some features of the product mechanism are well predicted by the Master Chemical Mechanism Version 3.2 (MCM v3.2), while other features are at odds with MCM v3.2. Using a previously proposed kinetic model for the quantitative prediction of the atmospheric fate of IEPOX, it is found that gas phase OH reaction is an even more dominant fate for chemical processing of IEPOX than previously suggested. The present results suggest that aerosol phase processing of IEPOX will be competitive with gas phase OH oxidation only under SOA conditions of high liquid water content and low pH. PMID- 24144331 TI - An explorative analysis of ERCC1-19q13 copy number aberrations in a chemonaive stage III colorectal cancer cohort. AB - BACKGROUND: Platinum-based chemotherapy has long been used in the treatment of a variety of cancers and functions by inducing DNA damage. ERCC1 and ERCC4 are involved in the removal of this damage and have previously been implicated in resistance to platinum compounds. The aim of the current investigation is to determine the presence, frequency and prognostic impact of ERCC1 or ERCC4 gene copy number alterations in colorectal cancer (CRC). METHODS: Fluorescent in situ hybridization probes directed at ERCC1 and ERCC4 with relevant reference probes were constructed. Probes were tested in a CRC cell line panel and in tumor sections from 152 stage III CRC chemonaive patients. Relationships between biomarker status and clinical endpoints (overall survival, time to recurrence, and local recurrence in rectal cancer) were analyzed by survival statistics. RESULTS: ERCC1-19q13 copy number alterations were observed in a single cell line metaphase (HT29). In patient material, ERCC1-19q13 copy number gains (ERCC1 19q13/CEN-2 >= 1.5) were detected in 27.0% of specimens, whereas ERCC1-19q13 deletions (ERCC1-19q13/CEN-2 < 0.8) were only detected in 1.3%. ERCC1-19q13 gain was significantly associated with longer survival (multivariate analysis, HR: 0.45, 95% CI: 0.20-1.00, p = 0.049) in patients with colon tumors, but not rectal tumors. No ERCC4 aberrations were detected and scoring was discontinued after 50 patients. CONCLUSIONS: ERCC1-19q13 copy number gains occur frequently in stage III CRC and influences survival in patients with colon tumors. Future studies will investigate the effect of ERCC1-19q13 aberrations in a platinum-treated patient population with the aim of developing a predictive biomarker profile for oxaliplatin sensitivity in CRC. PMID- 24144332 TI - The management of congenital superior conjunctival fornix prolapse. AB - AIM: To present the management of bilateral congenital superior fornicial prolapse and provide its up-to-date review of literature. METHODS: We present the management of congenital bilateral superior fornicial prolapse treated conservatively with topical antibiotics, lubricants and hypertonic saline. One week, 2-weeks and 1-month follow-up is presented. Results were assessed in terms of reduction of chemosis and eyelid opening. Updated current English peer reviewed literature was researched. RESULTS: The superior fornicial prolapse resolved with conservative management within 10 days, resulting in normal eyelid motility at the end of 1 month. At present 61 cases have been reported in English peer-reviewed journals. The proposed etiology is varied. Conservative management with topical medication provides relief. CONCLUSIONS: Congenital fornicial prolapse is a rare condition. Topical medication provides complete resolution of prolapse. Authors emphasise the need for awareness of condition among ophthalmologists and neonatologists, because of its gruesome appearance. PMID- 24144334 TI - Oxidative stress and hypoxia observed in the kidneys of mice after a 13-week oral administration of melamine and cyanuric acid combination. AB - Both melamine and cyanuric acid have low toxicity, but together they may cause serious lesions to the kidney, via an unknown mechanism. This study was aimed to estimate whether lesions to the kidney were relative to oxidative damage and hypoxia in the kidney after mice exposed to 1mg/kg/day, 5mg/kg/day or 25mg/kg/day of a mixture of melamine and cyanuric acid for 13 weeks. Pathological changes to the kidneys, oxidative stress and energy parameters and hypoxia-inducible factor 1alpha (HIF-1alpha) change in the kidneys were evaluated. Pathological changes were found in the distal tubules of kidneys, such as crystals, proteinaceous casts and compensatory expansion, indicating that the mixture induced toxicity to the kidney. The activities of total antioxidant capacity (TAC) and superoxide dismutase (SOD) and the concentration of glutathione (GSH) decreased, while the concentrations of lipid peroxidation (MDA) and protein carbonyl groups (PC) increased after exposure to the mixture, demonstrating that the mixture resulted in imbalance of antioxidant and reactive oxygen species (ROS) and excessive ROS induced oxidant damage to lipid and proteins in kidneys. The activities of malate dehydrogenase (MDH) and succinate dehyrogenase (SDH) decreased, however, the activity of lactic dehydrogenase (LDH) and the concentration of HIF-1alpha increased after exposure to the mixture. Accordingly, it was concluded that the mixture resulted in a hypoxic state in kidneys and that both oxidative stress and hypoxia contributed to the lesion of kidneys. The exact cause of oxidative damage and hypoxia is not clear, it might be caused by either a direct effect or by an indirect effect, which is secondary to substantial renal damage caused by tubular obstruction due to crystal formation. PMID- 24144335 TI - gEMpicker: a highly parallel GPU-accelerated particle picking tool for cryo electron microscopy. AB - BACKGROUND: Picking images of particles in cryo-electron micrographs is an important step in solving the 3D structures of large macromolecular assemblies. However, in order to achieve sub-nanometre resolution it is often necessary to capture and process many thousands or even several millions of 2D particle images. Thus, a computational bottleneck in reaching high resolution is the accurate and automatic picking of particles from raw cryo-electron micrographs. RESULTS: We have developed "gEMpicker", a highly parallel correlation-based particle picking tool. To our knowledge, gEMpicker is the first particle picking program to use multiple graphics processor units (GPUs) to accelerate the calculation. When tested on the publicly available keyhole limpet hemocyanin dataset, we find that gEMpicker gives similar results to the FindEM program. However, compared to calculating correlations on one core of a contemporary central processor unit (CPU), running gEMpicker on a modern GPU gives a speed-up of about 27 *. To achieve even higher processing speeds, the basic correlation calculations are accelerated considerably by using a hierarchy of parallel programming techniques to distribute the calculation over multiple GPUs and CPU cores attached to multiple nodes of a computer cluster. By using a theoretically optimal reduction algorithm to collect and combine the cluster calculation results, the speed of the overall calculation scales almost linearly with the number of cluster nodes available. CONCLUSIONS: The very high picking throughput that is now possible using GPU-powered workstations or computer clusters will help experimentalists to achieve higher resolution 3D reconstructions more rapidly than before. PMID- 24144333 TI - Isosteric and nonisosteric base pairs in RNA motifs: molecular dynamics and bioinformatics study of the sarcin-ricin internal loop. AB - The sarcin-ricin RNA motif (SR motif) is one of the most prominent recurrent RNA building blocks that occurs in many different RNA contexts and folds autonomously, that is, in a context-independent manner. In this study, we combined bioinformatics analysis with explicit-solvent molecular dynamics (MD) simulations to better understand the relation between the RNA sequence and the evolutionary patterns of the SR motif. A SHAPE probing experiment was also performed to confirm the fidelity of the MD simulations. We identified 57 instances of the SR motif in a nonredundant subset of the RNA X-ray structure database and analyzed their base pairing, base-phosphate, and backbone-backbone interactions. We extracted sequences aligned to these instances from large rRNA alignments to determine the frequency of occurrence for different sequence variants. We then used a simple scoring scheme based on isostericity to suggest 10 sequence variants with a highly variable expected degree of compatibility with the SR motif 3D structure. We carried out MD simulations of SR motifs with these base substitutions. Nonisosteric base substitutions led to unstable structures, but so did isosteric substitutions which were unable to make key base-phosphate interactions. The MD technique explains why some potentially isosteric SR motifs are not realized during evolution. We also found that the inability to form stable cWW geometry is an important factor in the case of the first base pair of the flexible region of the SR motif. A comparison of structural, bioinformatics, SHAPE probing, and MD simulation data reveals that explicit solvent MD simulations neatly reflect the viability of different sequence variants of the SR motif. Thus, MD simulations can efficiently complement bioinformatics tools in studies of conservation patterns of RNA motifs and provide atomistic insight into the role of their different signature interactions. PMID- 24144336 TI - Magnetic nanoparticle hyperthermia enhancement of cisplatin chemotherapy cancer treatment. AB - PURPOSE: The purpose of this study was to examine the therapeutic effect of magnetic nanoparticle hyperthermia (mNPH) combined with systemic cisplatin chemotherapy in a murine mammary adenocarcinoma model (MTGB). MATERIALS AND METHODS: An alternating magnetic field (35.8 kA/m at 165 kHz) was used to activate 110 nm hydroxyethyl starch-coated magnetic nanoparticles (mNP) to a thermal dose of 60 min at 43 degrees C. Intratumoral mNP were delivered at 7.5 mg of Fe/cm(3) of tumour (four equal tumour quadrants). Intraperitoneal cisplatin at 5 mg/kg body weight was administered 1 h prior to mNPH. Tumour regrowth delay time was used to assess the treatment efficacy. RESULTS: mNP hyperthermia, combined with cisplatin, was 1.7 times more effective than mNP hyperthermia alone and 1.4 times more effective than cisplatin alone (p < 0.05). CONCLUSIONS: Our results demonstrate that mNP hyperthermia can result in a safe and significant therapeutic enhancement for cisplatin cancer therapy. PMID- 24144338 TI - Simple recipes for separating excited-state absorption and cascading signals by polarization-sensitive measurements. AB - The dependence of four-wave mixing and six-wave mixing signals on the polarization of the laser pulses is analyzed. Assuming that the dipole moments of the electronic transitions are not all parallel, we show that the excited-state absorption signal can be separated from the total pump-probe signal by two measurements with different polarizations of the pump and probe pulses. We show, furthermore, that cascading (third-order) signals can be separated from the fifth order signal by two polarization-sensitive six-wave mixing measurements. We provide simple explicit formulas that express the excited-state absorption and cascading contributions, respectively, in terms of polarization-sensitive signals. PMID- 24144337 TI - Kinetics of myosin light chain kinase activation of smooth muscle myosin in an in vitro model system. AB - During activation of smooth muscle contraction, one myosin light chain kinase (MLCK) molecule rapidly phosphorylates many smooth muscle myosin (SMM) molecules, suggesting that muscle activation rates are influenced by the kinetics of MLCK SMM interactions. To determine the rate-limiting step underlying activation of SMM by MLCK, we measured the kinetics of calcium-calmodulin (Ca2+CaM)-MLCK mediated SMM phosphorylation and the corresponding initiation of SMM-based F actin motility in an in vitro system with SMM attached to a coverslip surface. Fitting the time course of SMM phosphorylation to a kinetic model gave an initial phosphorylation rate, kp(o), of ~1.17 heads s-1 MLCK-1. Also, we measured the dwell time of single streptavidin-coated quantum dot-labeled MLCK molecules interacting with surface-attached SMM and phosphorylated SMM using total internal reflection fluorescence microscopy. From these data, the dissociation rate constant from phosphorylated SMM was 0.80 s-1, which was similar to the kp(o) mentioned above and with rates measured in solution. This dissociation rate was essentially independent of the phosphorylation state of SMM. From calculations using our measured dissociation rates and Kd values, and estimates of SMM and MLCK concentrations in muscle, we predict that the dissociation of MLCK from phosphorylated SMM is rate-limiting and that the rate of the phosphorylation step is faster than this dissociation rate. Also, association with SMM (11-46 s-1) would be much faster than with pSMM (<0.1-0.2 s-1). This suggests that the probability of MLCK interacting with unphosphorylated versus phosphorylated SMM is 55-460 times greater. This would avoid sequestering MLCK to unproductive interactions with previously phosphorylated SMM, potentially leading to faster rates of phosphorylation in muscle. PMID- 24144339 TI - Prognostic impact of clinician-based interpretation of 18F-fluorodeoxyglucose positron emission tomography/computed tomography reports obtained in patients with newly diagnosed diffuse large B-cell lymphoma. AB - The aim of this study was to evaluate the prognostic value of clinician interpretation of positron emission tomography/computed tomography (PET/CT) reports at mid-therapy, interim PET (I-PET) and after the end of first-line therapy (E-PET) in patients with diffuse large B-cell lymphoma (DLBCL). Four hundred and thirty patients were enrolled in this study comprising a total of 617 PET reports. Each report was evaluated by three expert hematologists randomly selected from a panel of nine. Reports were labeled positive or negative if all three interpreters agreed. All others were considered indeterminate. Indeterminate reports accounted for 59% of I-PET and 49% of E-PET reports. Two year overall survival (OS) for patients with a positive, indeterminate and negative I-PET was 58%, 87% and 89% (p < 0.001), respectively. Two-year OS for patients with E-PET was 41%, 89% and 97% (p < 0.001) for positive, indeterminate and negative interpretation of PET/CT reports. Progression-free survival and OS did not differ significantly in patients with a negative and an indeterminate I PET report. The use of well-defined reporting criteria, e.g. the Deauville five point scale, is likely to reduce the number of scans perceived as indeterminate. PMID- 24144340 TI - Comprehensive assessment of hormones, phytoestrogens, and estrogenic activity in an anaerobic swine waste lagoon. AB - In this study, the distribution of steroid hormones, phytoestrogens, and estrogenic activity was thoroughly characterized within the anaerobic waste lagoon of a typical commercial swine sow operation. Three independent rounds of sampling were conducted in June 2009, April 2010, and February 2011. Thirty-seven analytes in lagoon slurry and sludge were assessed using LC/MS-MS, and yeast estrogen screen was used to determine estrogenic activity. Of the hormone analytes, steroidal estrogens were more abundant than androgens or progesterone, with estrone being the predominant estrogen species. Conjugated hormones were detected only at low levels. The isoflavone metabolite equol was by far the predominant phytoestrogen species, with daidzein, genistein, formononetin, and coumestrol present at lower levels. Phytoestrogens were often more abundant than steroidal estrogens, but contributed minimally toward total estrogenic activity. Analytes were significantly elevated in the solid phases of the lagoon; although low observed log KOC values suggest enhanced solubility in the aqueous phase, perhaps due to dissolved or colloidal organic carbon. The association with the solid phase, as well as recalcitrance of analytes to anaerobic degradation, results in a markedly elevated load of analytes and estrogenic activity within lagoon sludge. Overall, findings emphasize the importance of adsorption and transformation processes in governing the fate of these compounds in lagoon waste, which is ultimately used for broadcast application as a fertilizer. PMID- 24144341 TI - Anterior ischaemic optic neuropathy in eosinophilic granulomatosis with polyangiitis (Churg-Strauss syndrome): a case report and review of the literature. AB - We report a 62-year-old man with mild fever, headache and acute visual loss in his right eye due to anterior ischaemic optic neuropathy (AION), followed a few days later by pain in the legs and left arm associated with numbness and weakness. Giant cell arteritis complicated by AION was suspected at the beginning and high-dose oral glucocorticoids were started. However, on the basis of the past medical history of nasal polyposis, asthma, and hypereosynophilia as well as of further investigations (biopsy of the nasal mucosa showing granulomatous inflammation with a rich eosinophilic infiltrate, electromyography demonstrating, mononeuritis multiplex and positive p-ANCA), eosinophilic granulomatosis with polyangiitis (EGPA), previously known as Churg-Strauss syndrome, was diagnosed. Because visual acuity in the right eye deteriorated despite glucocorticoid therapy, pulse intravenous cyclophosphamide was started, subsequently replaced by oral azathioprine, while prednisone was slowly tapered. This treatment led to gradual improvement of the neurological symptoms, whereas the right visual impairment remained unchanged. EGPA-related AION is an uncommon lesion that is probably due to vasculitic involvement of posterior ciliary and/or chorioretinal arteries. The prognosis of established AION is poor for the affected eye, even when glucocorticoid treatment is started immediately. However, early recognition of AION and prompt aggressive treatment with high-dose glucocorticoids plus cyclophosphamide can prevent visual loss in the unaffected eye. PMID- 24144343 TI - An automated time-of-drug-addition assay to routinely determine the mode of action of HIV-1 inhibitors. AB - Cell-based high-throughput screening campaigns are widely used to identify novel antiviral compounds, for example, against human immunodeficiency virus type 1 (HIV-1). Typically, these assays enable identification of compounds that potentially target any viral or cellular factor involved in the viral replication cycle. Unraveling the mechanism of action of these active compounds is an important step to facilitate further drug development. Time-of-addition (TOA) assays are an elegant tool to achieve this goal by comparing the TOA profile of novel compounds with those of well-studied reference compounds. Downscaling to a 384-well format and automation significantly increase the capacity of the TOA assay, enabling compound handling around the clock. Mechanical liquid dispensing with optimized time points for compound addition ensures robustness (Z'>0.8) and maximal resolution in profiling novel antiviral compounds. The presented methodology has been optimized for routine use and allows for fully automated high-throughput screening to support the process in search for novel inhibitors of HIV-1. PMID- 24144345 TI - Rebuttal from the authors. PMID- 24144344 TI - Trends in surgical results of hepatic resection for hepatocellular carcinoma: 1,000 consecutive cases over 20 years in a single institution. AB - BACKGROUND: Surgical results have been reported to be improved in hepatic resections for hepatocellular carcinoma (HCC) in recent years, but the detailed trends in surgical results for HCC in a single high-volume center are still not clear. METHODS: Surgical results in 1,000 hepatic resections for HCC performed at a single medical center from 1989 to 2011 were analyzed. Patients were divided into 3 groups: those performed in the early period (1989 to 1995, n = 181), the middle period (1996 to 2004, n = 391), and the late period (2005 to 2011, n = 428). RESULTS: Hospital mortality (3.9%, 1.0%, and .5%; P = .0027) and morbidity (45%, 24%, and 15%; P < .0001) rates were significantly decreased. The overall survival rates were significantly improved (50%, 72%, and 78% at 5 years; P = .0021), but there was no significant difference in the disease-free survival (29%, 34%, and 31% at 5 years; P = .7823). CONCLUSIONS: Surgical results of hepatic resections for HCC were significantly improved, with the mortality rate nearly reaching 0%. The 5-year survival rate after hepatic resections for HCC was also improved to 78%, but the consistently high rate of HCC recurrence after hepatic remains a problem. PMID- 24144346 TI - Cytokine profiles in tears accompanying the secondary conjunctival responses induced by nasal allergy. AB - PURPOSE/AIM: Allergic conjunctivitis (AC) occurs either in a primary form, due to the allergic reaction localized in the conjunctivae or in a secondary form, induced by an allergic reaction initiated primarily in the nasal mucosa. The purpose of this study was to investigate the cytokine profiles in tears associated with the secondary conjunctival response (SCR) types. MATERIALS AND METHODS: In 47 AC patients developing 16 immediate (SICR; p < 0.01), 20 late (SLCR; p < 0.001) and 11 delayed (SDYCR; p < 0.05) responses to nasal provocation tests (NPTs) with allergens, the NPTs were repeated and combined with recording of cytokine concentrations in the tears. RESULTS: The SCRs were associated with significant concentration changes of particular cytokines in tears (p < 0.05) as follows: (1): SICRs: interleukin (IL)-3, IL-4, IL-10 and granulocyte macrophage colony-stimulating factor (GM-CSF); (2) SLCRs: IL-3, IL-4, IL-5, IL-8, IL-10, IL 12p40, GM-CSF and granulocyte colony-stimulating factor (G-CSF); and (3) SDYCRs: IL-2, IL-8, IL-10, interferon gamma, G-CSF and tumor necrosis factor alpha. No significant cytokine changes were recorded in tears during the phosphate-buffered saline controls or negative SCRs. CONCLUSIONS: Different cytokine profiles in the tears accompanying the immediate, late and delayed types of SCR, induced by nasal allergy, would indicate involvement of different hypersensitivity mechanisms in the particular SCR types. The low cytokine concentrations in tears recorded during the SCRs may suggest their origin from the nasal mucosa. These results emphasize the diagnostic value of NPTs with allergens combined with monitoring of various ocular features in patients suffering from the secondary form of AC. These results may also have an impact on the therapeutical approach to this clinical entity. PMID- 24144347 TI - Spin radical enhanced magnetocapacitance effect in intermolecular excited states. AB - This article reports the magnetocapacitance effect (MFC) based on both pristine polymer MEH-PPV and its composite system doped with spin radicals (6R-BDTSCSB). We observed that a photoexcitation leads to a significant positive MFC in the pristine MEH-PPV. Moreover, we found that a low doping of spin radicals in polymer MEH-PPV causes a significant change on the MFC signal: an amplitude increase and a line-shape narrowing under light illumination at room temperature. However, no MFC signal was observed under dark conditions in either the pristine MEH-PPV or the radical-doped MEH-PPV. Furthermore, the magnitude increase and line-shape narrowing caused by the doped spin radicals are very similar to the phenomena induced by increasing the photoexcitation intensity. Our studies suggest that the MFC is essentially originated from the intermolecular excited states, namely, intermolecular electron-hole pairs, generated by a photoexcitation in the MEH-PPV. More importantly, by comparing the effects of spin radicals and electrically polar molecules on the MFC magnitude and line shape, we concluded that the doped spin radicals can have the spin interaction with intermolecular excited states and consequently affect the internal spin exchange interaction within intermolecular excited states in the development of MFC. Clearly, our experimental results indicate that dispersing spin radicals forms a convenient method to enhance the magnetocapacitance effect in organic semiconducting materials. PMID- 24144348 TI - Impacts of select organic ligands on the colloidal stability, dissolution dynamics, and toxicity of silver nanoparticles. AB - Key understanding of potential transformations that may occur on silver nanoparticle (AgNP) surface upon interaction with naturally ubiquitous organic ligands (e.g., -SH (thoil), humic acid, or -COO (carboxylate)) is limited. Herein we investigated how dissolved organic carbon (DOC), -SH (in cysteine, a well known Ag(+) chelating agent), and -COO (in trolox, a well-known antioxidant) could alter the colloidal stability, dissolution rate, and toxicity of citrate functionalized AgNPs (citrate-AgNPs) against a keystone crustacean Daphnia magna. Cysteine, DOC, or trolox amendment of citrate-AgNPs differentially modified particle size, surface properties (charge, plasmonic spectra), and ion release dynamics, thereby attenuating (with cysteine or trolox) or promoting (with DOC) AgNP toxicity. Except with DOC amendment, the combined toxicity of AgNPs and released Ag under cysteine or trolox amendment was lower than of AgNO3 alone. The results of this study show that citrate-AgNP toxicity can be associated with oxidative stress, ion release, and the organism biology. Our evidence suggests that specific organic ligands available in the receiving waters can differentially surface modify AgNPs and alter their environmental persistence (changing dissolution dynamics) and subsequently the toxicity; hence, we caveat to generalize that surface modified nanoparticles upon environmental release may not be toxic to receptor organisms. PMID- 24144349 TI - [Comments to the article "thoracic paravertebral block plus pectoral nerve block for mastectomy in a patient with advanced amyotrophic lateral sclerosis"]. PMID- 24144350 TI - [Curricular design in anesthesiology using clinical simulation as a teaching tool]. PMID- 24144351 TI - [AnesLoc. Device invented in Spain for airway topical anesthesia and intubation in awake]. PMID- 24144352 TI - The impact of humic and fulvic acids on the dynamic properties of liposome membranes: the ESR method. AB - This paper presents the results of research on the influence of two fractions of humic substances (HS): fulvic acids (FA) and humic acids (HA), as a function of concentration, on the liposome membranes formed from egg yolk lecithin (EYL). The concentration of HS in relation to EYL changed from 0% to 10% by weight. The influence of HS on various areas of membranes: interphase water-lipid, in the lipid layer just below the polar part of the membrane and in the middle of the lipid bilayer, was investigated by different spin labels (TEMPO, DOXYL 5, DOXYL 16). The study showed that HA slightly decreased the fluidity of the analyzed membranes on the surface layer, while FA significantly liquidated the center of the lipid bilayer. The strong effect of both fractions of HS on the concentration of free radicals as a function of time was also described. PMID- 24144353 TI - TSG (2,3,4' ,5-tetrahydroxystilbene 2-O-beta-D-glucoside) suppresses induction of pro-inflammatory factors by attenuating the binding activity of nuclear factor kappaB in microglia. AB - BACKGROUND: Induction of pro-inflammatory factors is one of the characteristics of microglia activation and can be regulated by numerous active components of Chinese traditional herbs. Suppression of pro-inflammatory factors is beneficial to alleviate microglia-mediated cell injury. The present study aims to investigate the effect and possible mechanism of 2,3,4',5-tetrahydroxystilbene 2 O-beta-D-glucoside (TSG) on LPS-mediated induction of pro-inflammatory factors in microglia. METHODS: Western blot, ELISA, and Hoechst 33258 were used to measure the protein expression, TNF-alpha/IL-6 content, and apoptotic nuclei, respectively. The mRNA level was measured by real time-PCR. Nitric oxide (NO) content, lactate dehydrogenase (LDH) content, and NF-kappaB binding activity were assayed by commercial kits. RESULTS: TSG reduced iNOS protein expression as well as TNF-alpha, IL-6, and NO content in LPS-stimulated BV-2 cells. TSG attenuated the increase in apoptotic nuclei, caspase-3 cleavage, and LDH content induced by BV-2 cell-derived conditioned medium in primary hippocampal neurons. Mechanistic studies showed that TSG reduced the mRNA level of iNOS, TNF-alpha, and IL-6. TSG failed to suppress IkappaB-alpha degradation, NF-kappaB phosphorylation and nuclear translocation, and ERK1/2, JNK, and p38 phosphorylation. TSG, however, markedly reduced the binding of NF-kappaB to its DNA element. Chromatin immunoprecipitation (ChIP) assays confirmed that TSG reduced NF-kappaB binding to the iNOS promoter. These findings were ascertained in primary microglia where the LPS-induced increase in iNOS expression, NO content, apoptotic nuclei, and NF kappaB binding to its DNA element were diminished by TSG. CONCLUSIONS: These studies demonstrate that TSG attenuates LPS-mediated induction of pro inflammatory factors in microglia through reducing the binding activity of NF kappaB. This might help us to further understand the pharmacological role of TSG in inflammatory response in the central nervous system. PMID- 24144355 TI - Immune mechanisms in hypertension and vascular injury. AB - Over the last 20 years it has become recognized that low-grade inflammation plays a role in cardiovascular disease. More recently, participation of the innate and the adaptive immune response in mechanisms that contribute to inflammation in cardiovascular disease has been reported in atherosclerosis and hypertension. Different subsets of lymphocytes and their cytokines are involved in vascular remodelling in hypertension, chronic kidney disease and heart disease. Effector T cells include Th1 (interferon-gamma-producing) and Th2 (interleukin-4 producing) lymphocytes, as well as Th17 (which produce interleukin-17) and T-suppressor lymphocytes such as T(reg)-cells (regulatory T-cells), which express the transcription factor Foxp3 (forkhead box P3) and participate respectively as pro- and anti-inflammatory cells. Pro-inflammatory T-lymphocytes participate in mechanisms of cardiovascular disease in part by mediating the effects of angiotensin II and mineralocorticoids. Involvement of immune mechanisms in cardiac, vascular and renal changes in hypertension has been demonstrated in many experimental models, an example being the Dahl-salt sensitive rat and the spontaneously hypertensive rat. How activation of immunity is triggered remains unknown, but neo-antigens could be generated by elevated blood pressure through damage-associated molecular pattern receptors or other mechanisms. Once activated, Th1 cells may contribute to blood pressure elevation by affecting the kidney, vascular remodelling of blood vessels directly via the effects of the cytokines produced or through their effects on perivascular fat. T(reg)-cells protect from blood pressure elevation by acting upon similar targets. Recent data suggests that participation of these mechanisms that have been demonstrated already in murine models also occurs in humans. These novel findings may open the way for new therapeutic approaches to improve outcomes in hypertension and cardiovascular disease in humans. PMID- 24144354 TI - Recent advances in pre-clinical mouse models of COPD. AB - COPD (chronic obstructive pulmonary disease) is a major incurable global health burden and will become the third largest cause of death in the world by 2020. It is currently believed that an exaggerated inflammatory response to inhaled irritants, in particular cigarette smoke, causes progressive airflow limitation. This inflammation, where macrophages, neutrophils and T-cells are prominent, leads to oxidative stress, emphysema, small airways fibrosis and mucus hypersecretion. The mechanisms and mediators that drive the induction and progression of chronic inflammation, emphysema and altered lung function are poorly understood. Current treatments have limited efficacy in inhibiting chronic inflammation, do not reverse the pathology of disease and fail to modify the factors that initiate and drive the long-term progression of disease. Therefore there is a clear need for new therapies that can prevent the induction and progression of COPD. Animal modelling systems that accurately reflect disease pathophysiology continue to be essential to the development of new therapies. The present review highlights some of the mouse models used to define the cellular, molecular and pathological consequences of cigarette smoke exposure and whether they can be used to predict the efficacy of new therapeutics for COPD. PMID- 24144357 TI - Cyclic pi electron delocalization in fluoroborazines. AB - How does the most electronegative atom, fluorine, affect cyclic pi electron delocalization (aromaticity) of an inorganic counterpart of benzene, borazine? Previous studies have shown that N-fluorination decreases the aromatic character, whereas conclusions about the effect of B-fluorination oppose each other ( J. Phys. Chem. A 1997 , 101 , 9410 and J. Mol. Struct.: THEOCHEM 2005 , 715 , 91 ). The aim of this study is to resolve this discrepancy and also to evaluate a degree of cyclic pi electron delocalization in all possible polyfluoroborazines. This was done by employing four aromaticity indices, HOMA, NICS, ECRE, and PDI. NICS, ECRE, and PDI gave a satisfactory description of aromaticity of the studied molecules. It was found that N-monofluoroborazine, N-difluoroborazine, and N trifluoroborazine are the only fluorinated derivatives that exhibit a higher degree of aromaticity compared to borazine. This result opposes the previous ones regarding the influence of N-fluorination. PMID- 24144356 TI - Divergent structural brain abnormalities between different genetic subtypes of children with Prader-Willi syndrome. AB - BACKGROUND: Prader-Willi syndrome (PWS) is a complex neurogenetic disorder with symptoms that indicate not only hypothalamic, but also a global, central nervous system (CNS) dysfunction. However, little is known about developmental differences in brain structure in children with PWS. Thus, our aim was to investigate global brain morphology in children with PWS, including the comparison between different genetic subtypes of PWS. In addition, we performed exploratory cortical and subcortical focal analyses. METHODS: High resolution structural magnetic resonance images were acquired in 20 children with genetically confirmed PWS (11 children carrying a deletion (DEL), 9 children with maternal uniparental disomy (mUPD)), and compared with 11 age- and gender-matched typically developing siblings as controls. Brain morphology measures were obtained using the FreeSurfer software suite. RESULTS: Both children with DEL and mUPD showed smaller brainstem volume, and a trend towards smaller cortical surface area and white matter volume. Children with mUPD had enlarged lateral ventricles and larger cortical cerebrospinal fluid (CSF) volume. Further, a trend towards increased cortical thickness was found in children with mUPD. Children with DEL had a smaller cerebellum, and smaller cortical and subcortical grey matter volumes. Focal analyses revealed smaller white matter volumes in left superior and bilateral inferior frontal gyri, right cingulate cortex, and bilateral precuneus areas associated with the default mode network (DMN) in children with mUPD. CONCLUSIONS: Children with PWS show signs of impaired brain growth. Those with mUPD show signs of early brain atrophy. In contrast, children with DEL show signs of fundamentally arrested, although not deviant brain development and presented few signs of cortical atrophy. Our results of global brain measurements suggest divergent neurodevelopmental patterns in children with DEL and mUPD. PMID- 24144359 TI - Stereocomplexation of polylactide enhanced by poly(methyl methacrylate): improved processability and thermomechanical properties of stereocomplexable polylactide based materials. AB - Stereocomplexable polylactides (PLAs) with improved processability and thermomechanical properties have been prepared by one-step melt blending of high molecular-weight poly(l-lactide) (PLLA), poly(d-lactide) (PDLA), and poly(methyl methacrylate) (PMMA). Crystallization of PLA stereocomplexes occurred during cooling from the melt, and, surprisingly, PMMA enhanced the amount of stereocomplex formation, especially with the addition of 30-40 % PMMA. The prepared ternary blends were found to be miscible, and such miscibility is likely a key factor to the role of PMMA in enhancing stereocomplexation. In addition, the incorporation of PMMA during compounding substantially raised the melt viscosity at 230 degrees C. Therefore, to some extent, the use of PMMA could also overcome processing difficulties associated with low viscosities of stereocomplexable PLA-based materials. Semicrystalline miscible blends with good transparency were recovered after injection molding, and in a first approach, the thermomechanical properties could be tuned by the PMMA content. Superior storage modulus and thermal resistance to deformation were thereby found for semicrystalline ternary blends compared to binary PLLA/PMMA blends. The amount of PLA stereocomplexes could be significantly increased with an additional thermal treatment, without compromising transparency. This could result in a remarkable thermal resistance to deformation at much higher temperatures than with conventional PLA. Consequently, stereocomplex crystallization into miscible PLLA/PDLA/PMMA blends represents a relevant approach to developing transparent, heat-resistant, and partly biobased polymers using conventional injection-molding processes. PMID- 24144360 TI - Discovery and early development of TMC647055, a non-nucleoside inhibitor of the hepatitis C virus NS5B polymerase. AB - Structure-based macrocyclization of a 6-carboxylic acid indole chemotype has yielded potent and selective finger-loop inhibitors of the hepatitis C virus (HCV) NS5B polymerase. Lead optimization in conjunction with in vivo evaluation in rats identified several compounds showing (i) nanomolar potency in HCV replicon cells, (ii) limited toxicity and off-target activities, and (iii) encouraging preclinical pharmacokinetic profiles characterized by high liver distribution. This effort culminated in the identification of TMC647055 (10a), a nonzwitterionic 17-membered-ring macrocycle characterized by high affinity, long polymerase residence time, and broad genotypic coverage. In vitro results of the combination of 10a with the HCV protease inhibitor TMC435 (simeprevir) supported an evaluation of this combination in patients with regard to virus suppression and resistance emergence. In a phase 1b trial with HCV genotype 1-infected patients, 10a was considered to be safe and well-tolerated and demonstrated potent antiviral activity, which was further enhanced in a combination study with TMC435. PMID- 24144361 TI - Coumarins and lignans from Zanthoxylum schinifolium and their anticancer activities. AB - Zanthoxylum schinifolium is an aromatic shrub, and its pericarp and leaves are widely used in culinary applications in East Asian countries. It has also long been used in traditional Oriental medicine for treating the common cold, stomach ache, diarrhea, and jaundice. In this study, we identified two new compounds, zanthoxyloside (1) and schinifolisatin A (13), along with 23 known coumarins (2 12) and lignans (14-25), from a methanol extract of the stems of Z. schinifolium . The chemical structures of the compounds were determined by mass, 1D-, and 2D NMR spectroscopy. The anticancer effects of the isolated compounds were examined in three human cancer cell lines. Compounds 10-12 significantly reduced the proliferation of HL-60 human acute promyelocytic leukemia cells with IC50 values of 4.62-5.12 MUM. Treatment of PC-3 prostate cancer cells and SNU-C5 colorectal cancer cells with compound 10 resulted in potent antiproliferative activity, with IC50 values of 4.39 and 6.26 MUM, respectively. Also, compounds 10-12 induced the apoptosis of three cancer cells. Furthermore, the induction of apoptosis was accompanied by down-regulation of p-ERK1/2 MAPK, p-AKT, and c-myc levels, in a time-dependent manner. These data suggested that compounds 10-12 from Z. schinifolium have potential in cancer treatment. PMID- 24144362 TI - Salinomycin increases chemosensitivity to the effects of doxorubicin in soft tissue sarcomas. AB - BACKGROUND: Chemotherapy for soft tissue sarcomas remains unsatisfactory due to their low chemosensitivity. Even the first line chemotherapeutic agent doxorubicin only yields a response rate of 18-29%. The antibiotic salinomycin, a potassium ionophore, has recently been shown to be a potent compound to deplete chemoresistant cells like cancer stem like cells (CSC) in adenocarcinomas. Here, we evaluated the effect of salinomycin on sarcoma cell lines, whereby salinomycin mono- and combination treatment with doxorubicin regimens were analyzed. METHODS: To evaluate the effect of salinomycin on fibrosarcoma, rhabdomyosarcoma and liposarcoma cell lines, cells were drug exposed in single and combined treatments, respectively. The effects of the corresponding treatments were monitored by cell viability assays, cell cycle analysis, caspase 3/7 and 9 activity assays. Further we analyzed NF-kappaB activity; p53, p21 and PUMA transcription levels, together with p53 expression and serine 15 phosphorylation. RESULTS: The combination of salinomycin with doxorubicin enhanced caspase activation and increased the sub-G1 fraction. The combined treatment yielded higher NF-kappaB activity, and p53, p21 and PUMA transcription, whereas the salinomycin monotreatment did not cause any significant changes. CONCLUSIONS: Salinomycin increases the chemosensitivity of sarcoma cell lines - even at sub lethal concentrations - to the cytostatic drug doxorubicin. These findings support a strategy to decrease the doxorubicin concentration in combination with salinomycin in order to reduce toxic side effects. PMID- 24144364 TI - The effect of specific solvent-solute interactions on complexation of alkali metal cations by a lower-rim calix[4]arene amide derivative. AB - Complexation of alkali-metal cations with calix[4]arene secondary-amide derivative, 5,11,17,23-tetra(tert-butyl)-25,26,27,28-tetra(N hexylcarbamoylmethoxy)calix[4]arene (L), in benzonitrile (PhCN) and methanol (MeOH) was studied by means of microcalorimetry, UV and NMR spectroscopies, and in the solid state by X-ray crystallography. The inclusion of solvent molecules (including acetonitrile, MeCN) in the calixarene hydrophobic cavity was also investigated. The classical molecular dynamics (MD) simulations of the systems studied were carried out. By combining the results obtained using the mentioned experimental and computational techniques, an attempt was made to get an as detailed insight into the complexation reactions as possible. The thermodynamic parameters, that is, equilibrium constants, reaction Gibbs energies, enthalpies, and entropies, of the investigated processes were determined and discussed. The stability constants of the 1:1 (metal:ligand) complexes measured by different methods were in very good agreement. Solution Gibbs energies of the ligand and its complexes with Na(+) and K(+) in methanol and acetonitrile were determined. It was established that from the thermodynamic point of view, apart from cation solvation, the most important reason for the huge difference in the stability of these complexes in the two solvents lay in the fact that the transfer of complex species from MeOH to MeCN was quite favorable. That could be at least partly explained by a more exergonic inclusion of the solvent molecule in the complexed calixarene cone in MeCN as compared to MeOH, which was supported by MD simulations. Molecular and crystal structures of the lithium cation complex of L with the benzonitrile molecule bound in the hydrophobic calixarene cavity were determined by single-crystal X-ray diffraction. As far as we are aware, for the first time the alkali-metal cation was found to be coordinated by the solvent nitrile group in a calixarene adduct. According to the results of MD simulations, the probability of such orientation of the benzonitrile molecule included in the ligand cone was by far the largest in the case of LiL(+) complex. Because of the favorable PhCN-Li(+) interaction, L was proven to have the highest affinity toward the lithium ion in benzonitrile, which was not the case in the other solvents examined (in acetonitrile, sodium complex was the most stable, whereas in methanol, complexation of lithium was not even observed). That could serve as a remarkable example showing the importance of specific solvent-solute interactions in determining the equilibrium in solution. PMID- 24144363 TI - Human cytomegalovirus induces apoptosis in neural stem/progenitor cells derived from induced pluripotent stem cells by generating mitochondrial dysfunction and endoplasmic reticulum stress. AB - BACKGROUND: Congenital human cytomegalovirus (HCMV) infection, a leading cause of birth defects, is most often manifested as neurological disorders. The pathogenesis of HCMV-induced neurological disorders is, however, largely unresolved, primarily because of limited availability of model systems to analyze the effects of HCMV infection on neural cells. METHODS: An induced pluripotent stem cell (iPSC) line was established from the human fibroblast line MRC5 by introducing the Yamanaka's four factors and then induced to differentiate into neural stem/progenitor cells (NSPCs) by dual inhibition of the SMAD signaling pathway using Noggin and SB-431542. RESULTS: iPSC-derived NSPCs (NSPC/iPSCs) were susceptible to HCMV infection and allowed the expression of both early and late viral gene products. HCMV-infected NSPC/iPSCs underwent apoptosis with the activation of caspase-3 and -9 as well as positive staining by the terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL). Cytochrome c release from mitochondria to cytosol was observed in these cells, indicating the involvement of mitochondrial dysfunction in their apoptosis. In addition, phosphorylation of proteins involved in the unfolded protein response (UPR), such as PKR-like eukaryotic initiation factor 2a kinase (PERK), c-Jun NH2-terminal kinase (JNK), inositol-requiring enzyme 1 (IRE1), and the alpha subunit of eukaryotic initiation factor 2 (eIF2alpha) was observed in HCMV-infected NSPC/iPSCs. These results, coupled with the finding of increased expression of mRNA encoding the C/EBP-homologous protein (CHOP) and the detection of a spliced form of X-box binding protein 1 (XBP1) mRNA, suggest that endoplasmic reticulum (ER) stress is also involved in HCMV-induced apoptosis of these cells. CONCLUSIONS: iPSC-derived NSPCs are thought to be a useful model to study HCMV neuropathogenesis and to analyze the mechanisms of HCMV-induced apoptosis in neural cells. PMID- 24144365 TI - Familial multinodular goiter syndrome with papillary thyroid carcinomas: mutational analysis of the associated genes in 5 cases from 1 Chinese family. AB - BACKGROUND: Familial papillary thyroid cancer (fPTC) is recognized as a distinct entity only recently and no fPTC predisposing genes have been identified. Several potential regions and susceptibility loci for sporadic PTC have been reported. We aimed to evaluate the role of the reported susceptibility loci and potential risk genomic region in a Chinese familial multinodular goiter (fMNG) with PTC family. METHODS: We sequenced the related risk genomic regions and analyzed the known PTC susceptibility loci in the Chinese family members who consented to join the study. These loci included (1) the point mutations of the BRAF and RET; (2) the possible susceptibility loci to sporadic PTC; and (3) the suggested potential fMNG syndrome with PTC risk region. RESULTS: The members showed no mutations in the common susceptible BRAF and RET genomic region, although contained several different heterozygous alleles in the RET introns. All the members were homozygous for PTC risk alleles of rs966423 (C) at chromosome 2q35, rs2910164 (C) at chromosome 5q24 and rs2439302 (G) at chromosome 8p12; while carried no risk allele of rs4733616 (T) at chromosome 8q24, rs965513 (A) or rs1867277 (A) at chromosome 9q22 which were associated with radiation-related PTC. The frequency of the risk allele of rs944289 (T) but not that of rs116909374 (T) at chromosome 14q13 was increased in the MNG or PTC family members. CONCLUSIONS: Our work provided additional evidence to the genetic predisposition to a Chinese familial form of MNG with PTC. The family members carried quite a few risk alleles found in sporadic PTC; particularly, homozygous rs944289 (T) at chromosome 14q13 which was previously shown to be linked to a form of fMNG with PTC. Moreover, the genetic determinants of radiation-related PTC were not presented in this family. PMID- 24144366 TI - Adsorption of Gemini surfactants onto clathrate hydrates. AB - This work addresses the adsorption of two Gemini surfactants at the cyclopentane (CP) hydrate-water interface. The Gemini surfactants investigated here are Dowfax C6L and Dowfax 2A1 that have two anionic head groups and one hydrophobic tail group. The adsorption of these surfactants was quantified using adsorption isotherms and the adsorption isotherms were determined using liquid-liquid titrations. Even if the Gemini surfactant adsorption isotherms show multi-layer adsorption, they possess the first Langmuir layer with the second adsorption layer only evident in the 2A1 adsorption isotherm. Zeta potentials of CP hydrate particles in the surfactant solution of various concentrations of Dowfax C6L and Dowfax 2A1 were measured to further explain their adsorption behavior at the CP hydrate-water interface. Zeta potentials of alumina particles as a model particle system in different concentrations of sodium dodecyl sulfate (SDS), Dowfax C6L and Dowfax 2A1 were also measured to confirm the configuration of all the surfactants at the interface. The determination of the isotherms and zeta potentials provides an understanding framework for the adsorption behavior of the two Gemini surfactants at the hydrate-water interface. PMID- 24144367 TI - Salt-enhanced removal of 2-ethyl-1-hexanol from aqueous solutions by adsorption on activated carbon. AB - 2-Ethyl-1-hexanol has extensive industrial applications in solvent extraction, however, in view of its potential pollution to environment, the removal and recovery of 2-ethyl-1-hexanol is considered an essential step toward its sustainable use in the future. In this work, we report the removal of 2-ethyl-1 hexanol from aqueous solutions containing salts in high concentrations by adsorption on a coal-based activated carbon. Adsorption thermodynamics showed that the experimental isotherms were conformed well to the Langmuir equation. Also it was found that inorganic salts, i.e. MgCl2 and CaCl2 in high concentration significantly enhanced the adsorption capacity from 223 mg/g in the deionized water to 277 mg/g in a saline water. This phenomenon of adsorption enhancement could be ascribed to the salt-out effect. Kinetic analysis indicated that adsorption kinetics follows the pseudo-second-order equation and the adsorption rate constants increase with the salt concentration. The dynamic breakthrough volume and adsorbed amount of 2-ethyl-1-hexanol were significantly elevated when the salt is present in the water. The dynamic saturated adsorption amount increased from 218.3mg/g in the deionized water to 309.5mg/g in a salt lake brine. The Tomas model was well applied to predict the breakthrough curves and determine the characteristics parameters of the adsorption column. PMID- 24144368 TI - Modeling the influence of salts on the critical micelle concentration of ionic surfactants. AB - We show for the first time that a phenomenological, augmented volume-based thermodynamics (aVBT) model is capable to predict the critical micelle concentrations of ionic surfactants, including ionic liquids, with added salts. The model also adjusts for the type of salt added by including its molecular volume, which might form a connection to the Hofmeister effect. The other physico chemically relevant quantities included in the model include surface area and solvation enthalpies. PMID- 24144369 TI - Binding of cationic surfactants to a thermo-sensitive copolymer below and above its cloud point. AB - The binding interactions between cationic surfactants and a statistical thermo sensitive copolymer based on oligo(ethylene glycol) methacrylates were studied by isothermal titration calorimetry (ITC), surfactant selective electrode (SSE) and dynamic light scattering (DLS). Strong binding interactions were observed between this copolymer and cationic surfactants. The binding is driven by the hydrophobic effect, occurring on the hydrophobic backbone instead of the ethylene-glycol side chains. The surfactant saturation concentration C2 depended on the polymer concentration, but was not affected by temperature. Three types of cationic alkyltrimethylammonium bromide surfactants (RTAB with R equal to C12, C14, and C16), namely, dodecyltrimethylammonium bromide (DoTAB), tetradecyltrimethylammonium bromide (TTAB), and cetyltrimethylammonium bromide (CTAB), were examined, and the results confirmed that the binding affinity followed the sequence: CTAB>TTAB>DoTAB. PMID- 24144370 TI - Salt-free catanionic surface active ionic liquids 1-alkyl-3-methylimidazolium alkylsulfate: aggregation behavior in aqueous solution. AB - A series of salt-free catanionic surface active ionic liquids (SAILs), 1-alkyl-3 methylimidazolim alkyl sulfates (denoted as [Cnmim][CmSO4], n=6, 8, 10; m=12 and n=4; m=10, 14) were synthesized by an ion exchange reaction and their surface properties in aqueous solution were examined systematically by surface tension, fluorescence and electrical conductivity measurements. As catanionic surfactants, these SAILs exhibit notably higher surface activity, compared to the cationic or anionic analogues. Increment in both cationic and anionic alkyl chain lengths for [Cnmim][CmSO4] can both improve the amphiphilic character remarkably. This can be ascribed to cooperative interactions as formation of catanionic pairs between alkyl-substituted imidazolium cations and alkyl sulfate anions. The negative micellization Gibbs free energy values prove that the micellization of all the 1 alkyl-3-methylimidazolim alkyl sulfates investigated is a spontaneous process. Any additional CH2 group makes the micellization process easier regardless if it is on a cation or an anion. When keeping the total carbon atom number constant, we find that the [Cnmim][CmSO4] molecules with greater asymmetric alkyl chains display superior surface activity. This work indicates that the self-assembly of these imidazolium-based salt-free catanionic SAILs can be tailored by adjusting the mismatch of alkyl chains. These SAILs are expected to have potential applications in the fields of colloidal and interface and nanomaterial synthesis. PMID- 24144371 TI - One-step synthesis of Cl(-)-doped Pt(IV)/Bi2WO6 with advanced visible-light photocatalytic activity for toluene degradation in air. AB - In this study, Cl(-) doped Pt(IV)/Bi2WO6 photocatalyst was successfully synthesized via a one-step hydrothermal route by adding H2PtCl6 immediately in the reaction system. X-ray diffraction (XRD), transmission electron microscope (TEM), X-ray photoelectron spectroscopy (XPS), nitrogen adsorption-desorption isotherms and photoluminescence spectra (PL) were utilized to analyze the morphology, chemical states, surface area and optical properties of as-prepared catalysts. The addition of H2PtCl6 to the reaction system inhibited the growth of Bi2WO6 square nanoplates but facilitated the generation of irregular Bi2WO6 nanosheets with enlarged surface area and extended visible light absorption. In the resulted sample, it was observed that Pt(IV) was uniformly dispersed on the surface of Bi2WO6 irregular nanosheets and Cl(-) other than that from PtCl4 was doped into the sample by forming ionic bond with [Bi2O2](2+). Compared with pure Bi2WO6 nanosheets, Cl(-) doped Pt(IV)/Bi2WO6 showed enhanced activity in photocatalytic decomposition of toluene under visible light irradiation (420 nmPFCLA>PFC. The maximum permeate fluxes before and after backwash operation were obtained by PFC-LA, which gave the largest and most compact flocs. Coagulation suspension after breakage resulted in much more serious membrane fouling for PFC, whereas permeate flux slightly decreased when LA was used in combination with PFC. PMID- 24144373 TI - Polyacrylamide hybrid nanogels for targeted cancer chemotherapy via co-delivery of gold nanoparticles and MTX. AB - Cancer-targeting gold/polyacrylamide (Au-PAm) hybrid nanogels were successfully synthesized via water/oil microemulsion polymerization followed by in situ reduction of gold and chemical modification with methotrexate (MTX). The Au nanoparticles range from ~3 to 7 nm and the loading in the hydrogel can be easily controlled. Dynamic light scattering results showed that the hydrodynamic size distribution of these hybrid nanogels is similar to that of blank PAm nanogels (average diameter of ~30 nm), indicating that the Au nanoparticles were mostly incorporated into/onto the nanogels. MTX was used as both a targeting ligand and an anti-cancer drug for chemotherapy. The MTX-functionalized Au-PAm hybrid nanogels (Au-PAm-MTX) at a dosage of 0.5 mg/ml or higher can kill KB cells with high efficacy and suppress recovery of the cancer cells. On the other hand, the viability of macrophages showed no obvious decrease after incubation with Au-PAm MTX, indicating that such materials are not likely to initiate immune responses in the physiological environment and their circulation life time will be prolonged. Hence, such hybrid nanogels can potentially enable safe and effective cancer chemotherapy via targeted co-delivery of cytotoxic Au NPs and MTX in a single carrier to KB cells while avoiding the macrophages. PMID- 24144374 TI - The effect of superhydrophobic wetting state on corrosion protection--the AKD example. AB - Corrosion is of considerable concern whenever metal is used as construction material. In this study we address whether superhydrophobic coatings could be used as part of an environmentally friendly corrosion-protective system, and specific focus is put on how the wetting regime of a superhydrophobic coating affects corrosion inhibition. Superhydrophobic alkyl ketene dimer (AKD) wax coatings were produced, using different methods resulting in hierarchical structures, where the coatings exhibit the same surface chemistry but different wetting regimes. Contact angle measurements, ESEM, confocal Raman microscopy, open circuit potential and electrochemical impedance spectroscopy were used to evaluate the surfaces. Remarkably high impedance values of 10(10)Omega cm(2) (at 10(-2) Hz) were reached for the sample showing superhydrophobic lotus-like wetting. Simultaneous open circuit potential measurements suggest that the circuit is broken, most likely due to the formation of a thin air layer at the coating-water interface that inhibits ion transport from the electrolyte to the metal substrate. The remaining samples, showing superhydrophobic wetting in the rose state and hydrophobic Wenzel-like wetting, showed less promising corrosion protective properties. Due to the absence of air films on these surfaces the coatings were penetrated by the electrolyte, which allowed the corrosion reaction to proceed. PMID- 24144375 TI - In situ synthesis-gelation at room temperature vs. heating-cooling procedure. Fine tuning of molecular gels derived from succinic acid and L-valine. AB - HYPOTHESIS: The reaction between succinic anhydride and a diamine derived from L valine should afford efficiently a molecular gelator. Based on this reaction, it should be feasible to prepare molecular gels at room temperature, avoiding the conventional thermal treatment required for the solubilization of the gelator, by in situ, simultaneous, synthesis and gelation. The gels prepared by in situ and conventional heating-cooling protocols could present important differences relevant for potential practical applications of these materials. EXPERIMENTAL: The gelator was synthesized by reaction of succinic anhydride and a diamine derived from L-valine, affording two new amide bonds. The molecular gels were studied by IR, NMR, electron microscopy, X-ray diffraction and DSC. FINDINGS: The results indicate that different polymorphic fibrillar networks are formed depending on the gel preparation method, highlighting how the properties of molecular gels can be tuned in this way. Significant differences between thermal and in situ gels were found in properties such as thermal stability, thixotropic behavior or release of an entrapped dye. In situ synthesis-gelation has also been shown to provide gels in media such as oleic acid which cannot be jellified by conventional heating-cooling procedures. PMID- 24144376 TI - Collapsed bipolar glycolipids at the air/water interface: effect of the stereochemistry on the stretched/bent conformations. AB - This article describes a comparative study of several bipolar lipids derived from tetraether structures. The sole structural difference between the main two glycolipids is a unique stereochemical variation on a cyclopentyl ring placed in the middle of the lipids. We discuss the comparative results obtained at the air/water interface on the basis of tensiometry and ellipsometry. Langmuir Blodgett depositions during lipid film compressions and decompressions were also analyzed by AFM. The lactosylated tetraether (bipolar) lipid structures involved the formation of highly stable multilayers, which are still present at 10 mN m( 1) during decompression. This study suggests also that the stereochemistry of a central cyclopentyl ring dramatically drives the conformation of the corresponding bipolar lipids. Both isomers (trans and cis) adopt a U-shaped (bent) conformation at the air/water interface but the trans cyclopentyl ring induces a much more frustration within this type of conformation. Consequently, this bipolar lipid (trans-tetraether) undergoes a flip of one polar head-group (lactosyl) leading to a stretched conformation during collapse. PMID- 24144377 TI - Interferometry of surfaces with well-defined topography in the surface force apparatus. AB - We studied the multiple beam interferometry of surfaces with well-defined microscale features in the surface force apparatus (SFA). The structures investigated consist of hexagonal arrays of microscale cylindrical posts made out of the photoresist SU-8. The ability of the SFA to visualize the profile and topography of the interacting surfaces leads to the observation of discontinuities in primary fringes of equal chromatic order that are caused by the microscale structural features. The shift in wavelengths has been analyzed to extract the post height and compared to independent profilometry measurements. The analysis based on the shift in wavelength is shown to be viable only when the order of the fringe and the position of the discontinuity is precisely known and within the field of view. Analysis of the full profile of the interacting surface for two orthogonal 2-dimensional slices can be used to determine how the surface lattice is oriented within the point of closest approach. Finally, we discuss cases in which the structural features detrimentally affect the spatial resolution of the SFA. PMID- 24144378 TI - Bubble rubbing on solid surface: experimental study. AB - This is the first interferometric study in the literature on wetting film entrapped between bubble and moving solid substrate. Unique experimental setup was specially designed for monitoring the thickness profiles of wetting film, intercalated between the bubble and moving solid surface. For this reason, special procedure developed for this study was applied for determination of 3D film thickness profiles. This allowed us to determine 3D profiles of the disjoining, the lift pressures as well as the viscous stress tensor as a function of the velocity of the solid surface. Thus, one can see that a strong linear dependence between the average film thickness and the speed of motion of the solid surface exists until a certain critical speed of motion, beyond which the dependence becomes weaker but keeps its linear trend. Similar is the propensity with the average lift pressure. Moreover, one can observe how the inhomogeinity of the film surfaces changes upon increasing the speed of motion of the solid surface. The proposed technique reveals new possibilities for investigation of bubbles and solid surfaces on deeper level when they are in relative motion towards each other. Thus, one can conduct detailed tribological studies on bubbles moving in close proximity to solid surfaces. PMID- 24144379 TI - The ability of single-chain surfactants to emulsify an aqueous-based liquid crystal oscillates with odd-even parity of alkyl-chain length. AB - The physical properties of many organic molecules often oscillate when the number of carbons in their aliphatic chains changes from odd to even. This odd-even effect for single-chain surfactants in solution is rarely observed. Here, we report the ability of single-chain surfactants to emulsify a class of non amphiphilic organic salts, disodium cromoglycate (5'DSCG) oscillates as a function of the odd or even number of the aliphatic carbons. This system provides a water-in-oil-in-water emulsion, in which aqueous droplets of 5'DSCG in liquid crystal phases are coated with single-chain surfactants in a bulk carrying aqueous solution. For both surfactants of [Formula: see text] and CH3(CH2)nCOO( )Na(+), the ability to emulsify 5'DSCG molecules in water is stronger for surfactants with an odd number of sp(3)-hybridized carbon atoms in the aliphatic chains than those with an even number. This observed odd-even effect is consistent with the notion that conventional micelles possess a core of randomly arranged surfactant hydrocarbon tails. However, this water-in-oil-in-water resembles a vesicle system in which the surfactants assemble in a highly ordered structure that separates two aqueous systems. These new self-assembled phases have potential application in the formulation and design of new organic soft materials. PMID- 24144380 TI - Platelet-like nickel hydroxide: synthesis and the transferring to nickel oxide as a gas sensor. AB - Free-standing Ni(OH)2 platelet-like nanostructures with average width of 124 nm and thickness of 19 nm were successfully prepared through a simple one-pot polymer assisted process. The preparation involves the assistance of poly (sodium 4-styrene sulfonate) (PSS) and is easy to perform. The influence of pH value on the structure of the Ni(OH)2 product was investigated and it was found that pH value plays an important role for the formation of free-standing Ni(OH)2 nanoplatelets. A possible formation mechanism is proposed. In addition, from the obtained Ni(OH)2 nanoplatelets, a NiO sensor was fabricated and tested, which exhibits a 5 ppm sensing sensitivity to ethanol and propanol. PMID- 24144381 TI - Light-responsive viscoelastic fluids based on anionic wormlike micelles. AB - A new class of light-responsive viscoelastic fluids based on anionic wormlike micelles is reported. The key components are sodium oleate (NaOA) and a cationic azobenzene dye, 1-[2-(4-phenylazo-phenoxy)-ethyl]-3-methylimidazolium bromide (C0AZOC2IMB). These binary systems are gel-like fluids at certain concentration ratios of [C0AZOC2IMB]/[NaOA], e.g. 35/100, owing to the formation of long, entangled wormlike micelles. The viscosity of these fluids can be controlled reversibly by light due to photo isomerization between trans-C0AZOC2IMB and cis C0AZOC2IMB. For example, the zero-shear viscosity (eta0) of an originally gel like sample is high up to ~1300 Pa s when C0AZOC2IMB is in its trans from, whereas the mixture becomes a Newtonian fluid with eta0 about 0.01 Pa s after UV light irradiation. For the post-irradiated cis-C0AZOC2IMB, short cylindrical micelles form, hence accounting for the lower viscosity. Evidence for the structural transition is provided by UV-vis spectra, rheology, (1)H NMR and cryo transmission electronic microscopy measurements. PMID- 24144383 TI - Choosing the appropriate forecasting model for predictive parameter control. AB - All commonly used stochastic optimisation algorithms have to be parameterised to perform effectively. Adaptive parameter control (APC) is an effective method used for this purpose. APC repeatedly adjusts parameter values during the optimisation process for optimal algorithm performance. The assignment of parameter values for a given iteration is based on previously measured performance. In recent research, time series prediction has been proposed as a method of projecting the probabilities to use for parameter value selection. In this work, we examine the suitability of a variety of prediction methods for the projection of future parameter performance based on previous data. All considered prediction methods have assumptions the time series data has to conform to for the prediction method to provide accurate projections. Looking specifically at parameters of evolutionary algorithms (EAs), we find that all standard EA parameters with the exception of population size conform largely to the assumptions made by the considered prediction methods. Evaluating the performance of these prediction methods, we find that linear regression provides the best results by a very small and statistically insignificant margin. Regardless of the prediction method, predictive parameter control outperforms state of the art parameter control methods when the performance data adheres to the assumptions made by the prediction method. When a parameter's performance data does not adhere to the assumptions made by the forecasting method, the use of prediction does not have a notable adverse impact on the algorithm's performance. PMID- 24144384 TI - Diagnosing the severity of buccal caries lesions in governmental and private orthodontic patients at debonding, using the ICDAS-II and the DIAGNOdent Pen. AB - OBJECTIVES: To clinically evaluate the prevalence of buccal caries and white spot lesions (WSLs) at debonding in governmental and private orthodontic patients, using the International Caries Detection and Assessment System (ICDAS-II) and the DIAGNOdent Pen, and to study the correlation between the two methods. MATERIALS AND METHODS: A cross-sectional study was carried out on the nonextracted premolars and anterior teeth of 89 orthodontic patients. They were recruited into two groups based on the treatment center they attended: governmental group (G; n=45) and private group (P; n=44). Immediately after debonding, the examination of buccal caries and WSLs on premolars and anterior teeth was carried out using the ICDAS-II and the DIAGNOdent Pen. Cross-tabulation was applied to study the correlation between the ICDAS-II index and the DIAGNOdent Pen by calculating the Spearman correlation coefficient. RESULTS: The G group showed a significantly higher (P<.0001) prevalence of WSLs and/or buccal caries compared to that of the P group based on evaluation by the two methods. Based on ICDAS-II, 43% of the patients in the P group and 9% in the G group were free from any WSLs. In the G group, 22% of the patients had >=16 LESIONS, whereas there were none for the P group. The Spearman correlation coefficient between the two methods was .71. CONCLUSIONS: The prevalence of caries and/or WSLs at debonding was significantly higher in the G group compared to the P group. The clinical index (ICDAS-II) showed a good correlation with the DIAGNOdent Pen. PMID- 24144382 TI - Neuromodulation of chronic headaches: position statement from the European Headache Federation. AB - The medical treatment of patients with chronic primary headache syndromes (chronic migraine, chronic tension-type headache, chronic cluster headache, hemicrania continua) is challenging as serious side effects frequently complicate the course of medical treatment and some patients may be even medically intractable. When a definitive lack of responsiveness to conservative treatments is ascertained and medication overuse headache is excluded, neuromodulation options can be considered in selected cases. Here, the various invasive and non invasive approaches, such as hypothalamic deep brain stimulation, occipital nerve stimulation, stimulation of sphenopalatine ganglion, cervical spinal cord stimulation, vagus nerve stimulation, transcranial direct current stimulation, repetitive transcranial magnetic stimulation, and transcutaneous electrical nerve stimulation are extensively published although proper RCT-based evidence is limited. The European Headache Federation herewith provides a consensus statement on the clinical use of neuromodulation in headache, based on theoretical background, clinical data, and side effect of each method. This international consensus further gives recommendations for future studies on these new approaches. In spite of a growing field of stimulation devices in headaches treatment, further controlled studies to validate, strengthen and disseminate the use of neurostimulation are clearly warranted. Consequently, until these data are available any neurostimulation device should only be used in patients with medically intractable syndromes from tertiary headache centers either as part of a valid study or have shown to be effective in such controlled studies with an acceptable side effect profile. PMID- 24144385 TI - Primary dysmenorrhea is potentially predictive for initial orthodontic pain in female patients. AB - OBJECTIVE: To investigate the relationship between primary dysmenorrhea (PD) and orthodontic pain in female patients, and to test the hypothesis that the intensity and duration of orthodontic pain could be roughly predicted by severity of PD. MATERIALS AND METHODS: One hundred twenty college females were enrolled and put into one of three groups-mild (Mi), moderate (Mo), or severe (S) according to level of menstrual pain. Intensity of the orthodontic pain was measured by visual analog scale (VAS) on days 1, 2, 4, 7, 14, and 28 after archwire placement. RESULTS: As the intensity of orthodontic pain declined with time, the three groups demonstrated different changes during the initial week. Mi had the lowest VAS scores, whereas S possessed the highest scores. In contrast, Mo stayed in between. Significantly positive correlations were found between the severity of PD and the intensity of orthodontic pain at each time point within the first 2 weeks. In addition, though the majority of subjects reported disappearance of pain by the end of the second week in both Mi and Mo, a large proportion of females still perceived pain in S. CONCLUSION: Females with higher levels of menstrual pain tended to perceive orthodontic pain with higher intensity and more prolonged duration. Thus, PD could potentially serve as a reference to predict orthodontic pain in clinical settings. PMID- 24144387 TI - Pathologic diagnosis of achondrogenesis type 2 in a fragmented fetus: case report and evidence-based differential diagnostic approach in the early midtrimester. AB - As a group, lethal genetic skeletal disorders (GSDs) usually result in death within the perinatal period. Because lethal GSDs are often ultrasonographically detectible by early midtrimester, dilation and evacuation (D&E) is the method of choice for elective termination of pregnancy in many institutions. However, because the diagnosis of the lethal GSDs relies heavily upon radiologic examination of fetal remains, reaching an accurate diagnosis in this setting can be challenging. We report an autopsy case of a fetus delivered by D&E at 15 4/7 weeks gestation with radiologic, histologic, and genetic findings compatible with achondrogenesis type 2 and discuss an evidence-based differential diagnostic approach to lethal GSDs terminated by early midtrimester D&E. PMID- 24144386 TI - Carbon nanotube dosimetry: from workplace exposure assessment to inhalation toxicology. AB - BACKGROUND: Dosimetry for toxicology studies involving carbon nanotubes (CNT) is challenging because of a lack of detailed occupational exposure assessments. Therefore, exposure assessment findings, measuring the mass concentration of elemental carbon from personal breathing zone (PBZ) samples, from 8 U.S.-based multi-walled CNT (MWCNT) manufacturers and users were extrapolated to results of an inhalation study in mice. RESULTS: Upon analysis, an inhalable elemental carbon mass concentration arithmetic mean of 10.6 MUg/m3 (geometric mean 4.21 MUg/m3) was found among workers exposed to MWCNT. The concentration equates to a deposited dose of approximately 4.07 MUg/d in a human, equivalent to 2 ng/d in the mouse. For MWCNT inhalation, mice were exposed for 19 d with daily depositions of 1970 ng (equivalent to 1000 d of a human exposure; cumulative 76 yr), 197 ng (100 d; 7.6 yr), and 19.7 ng (10 d; 0.76 yr) and harvested at 0, 3, 28, and 84 d post-exposure to assess pulmonary toxicity. The high dose showed cytotoxicity and inflammation that persisted through 84 d after exposure. The middle dose had no polymorphonuclear cell influx with transient cytotoxicity. The low dose was associated with a low grade inflammatory response measured by changes in mRNA expression. Increased inflammatory proteins were present in the lavage fluid at the high and middle dose through 28 d post-exposure. Pathology, including epithelial hyperplasia and peribronchiolar inflammation, was only noted at the high dose. CONCLUSION: These findings showed a limited pulmonary inflammatory potential of MWCNT at levels corresponding to the average inhalable elemental carbon concentrations observed in U.S.-based CNT facilities and estimates suggest considerable years of exposure are necessary for significant pathology to occur at that level. PMID- 24144388 TI - Toward an understanding of agonist binding to human Orexin-1 and Orexin-2 receptors with G-protein-coupled receptor modeling and site-directed mutagenesis. AB - The class A G-protein-coupled receptors (GPCRs) Orexin-1 (OX1) and Orexin-2 (OX2) are located predominantly in the brain and are linked to a range of different physiological functions, including the control of feeding, energy metabolism, modulation of neuro-endocrine function, and regulation of the sleep-wake cycle. The natural agonists for OX1 and OX2 are two neuropeptides, Orexin-A and Orexin B, which have activity at both receptors. Site-directed mutagenesis (SDM) has been reported on both the receptors and the peptides and has provided important insight into key features responsible for agonist activity. However, the structural interpretation of how these data are linked together is still lacking. In this work, we produced and used SDM data, homology modeling followed by MD simulation, and ensemble-flexible docking to generate binding poses of the Orexin peptides in the OX receptors to rationalize the SDM data. We also developed a protein pairwise similarity comparing method (ProS) and a GPCR-likeness assessment score (GLAS) to explore the structural data generated within a molecular dynamics simulation and to help distinguish between different GPCR substates. The results demonstrate how these newly developed methods of structural assessment for GPCRs can be used to provide a working model of neuropeptide-Orexin receptor interaction. PMID- 24144390 TI - Hybrid photon-plasmon nanowire lasers. AB - Metallic and plasmonic nanolasers have attracted growing interest recently. Plasmonic lasers demonstrated so far operate in hybrid photon-plasmon modes in transverse dimensions, rendering it impossible to separate photonic from plasmonic components. Thus only the far-field photonic component can be measured and utilized directly. But spatially separated plasmon modes are highly desired for applications including high-efficiency coupling of single-photon emitters and ultrasensitivity optical sensing. Here, we report a nanowire (NW) laser that offers subdiffraction-limited beam size and spatially separated plasmon cavity modes. By near-field coupling a high-gain CdSe NW and a 100 nm diameter Ag NW, we demonstrate a hybrid photon-plasmon laser operating at 723 nm wavelength at room temperature, with a plasmon mode area of 0.008lambda(2). This device simultaneously provides spatially separated photonic far-field output and highly localized coherent plasmon modes, which may open up new avenues in the fields of integrated nanophotonic circuits, biosensing, and quantum information processing. PMID- 24144389 TI - Prevalence and clinical profiles of 'autoantibody-negative' systemic sclerosis subjects. AB - OBJECTIVES: To determine the prevalence of autoantibody negative systemic sclerosis (SSc) and to identify the clinical correlates thereof. METHODS: Clinical data and sera from 874 SSc subjects were collected and autoantibodies were tested in a central laboratory using 1) indirect immunofluorescence (IIF), 2) commercially available ELISA, addressable laser bead immunoassay (ALBIA), and line immunoassay (LIA), and 3) a sensitive immunoprecipitation (IP) assay. RESULTS: Fifteen (15; 1.7%) subjects were autoantibody negative by IIF, ELISA, ALBIA, LIA and IP, and 16 (1.8%) were antinuclear antibody (ANA) positive by IIF but otherwise negative by ELISA, ALBIA, LIA and IP. Thirty-seven (37; 4.2%) were ANA positive by IIF, autoantibody negative by commercially available immunoassays, but had autoantibodies identified by IP (including Th/To in 20). Autoantibody-negative subjects had generally less severe disease than positive subjects. CONCLUSIONS: Autoantibody-negative SSc is rare (<2%) and appears to be associated with a favourable prognosis. PMID- 24144391 TI - [Spontaneous thrombosis of a giant M1 aneurysm of MCA following extracranial intracranial bypass surgery]. PMID- 24144392 TI - Sucrose and oxidants. PMID- 24144393 TI - Myocardial dysfunction in pediatric septic shock. AB - OBJECTIVE: To evaluate the prevalence and significance of myocardial dysfunction in children with septic shock. STUDY DESIGN: Thirty patients with septic shock were evaluated by transthoracic echocardiography within 24 hours of admission to a pediatric critical care unit. Transthoracic echocardiography evaluation included left ventricular (LV) size and function, mitral valve inflow velocities in early and late diastole, mitral valve annular velocities in systole and early and late diastole, and LV myocardial performance index. LV systolic dysfunction was defined as an ejection fraction or shortening fraction z-score <-2, and LV diastolic dysfunction was defined as a mitral valve inflow velocity/annular velocity in early diastole ratio z-score >2. Secondary outcomes included troponin I concentration, acute kidney injury, and 28-day mechanical ventilation-free duration. RESULTS: Mortality for the 30 patients (mean age, 9.5 +/- 7 years) was 7%. The prevalence of LV systolic and/or diastolic dysfunction was 53% (16 of 30). Eleven patients (37%) had systolic dysfunction, 10 (33%) had diastolic dysfunction, and 5 (17%) had both. Systolic and/or diastolic dysfunction was significantly associated with troponin I level (P = .007) and acute kidney injury (P = .02), but not with ventilation-free duration (P = .12). Kaplan-Meier analyses for pediatric critical care unit and hospital length of stay identified no differences between patients with and those without myocardial dysfunction. CONCLUSION: Myocardial dysfunction occurs frequently in children with septic shock but might not affect hospital length of stay. PMID- 24144394 TI - Preparing for responsible sharing of clinical trial data. PMID- 24144395 TI - Access to patient-level trial data--a boon to drug developers. PMID- 24144396 TI - Effect of dietary eugenol on xenobiotic metabolism and mediation of UDP glucuronosyltransferase and cytochrome P450 1A1 expression in rat liver. AB - Xenobiotic-metabolizing enzymes (XMEs) play an important role in the elimination and detoxification of xenobiotics and drugs. A variety of natural dietary agents are known to protect against cancer by inducing XME. To elucidate the molecular mechanism of XME induction, we examined the effect of dietary eugenol (4-allyl-1 hydroxy-2-methoxybenzene) on xenobiotic metabolism. In this study, rats were administered dietary eugenol for 4 weeks to investigate the various effects of UDP-glucuronosyltransferase (UGT) and cytochrome P450 (CYP) expression. In rats administered dietary eugenol, expression levels of hepatic CYP1A 1 were reduced to 40% than of the controls, while expression of hepatic UGT1A6, UGT1A7 and UGT2B1 increased to 2-3 times than observed in the controls. Hepatic protein levels of UGT1A6 and 2B1 were also elevated in the eugenol-treated rats. These results suggest that the natural compound eugenol improves the xenobiotic metabolizing systems that suppress and induce the expression of CYP1A1 and UGT, respectively. PMID- 24144397 TI - Counterion and polythymidine loop-length-dependent folding and thermodynamic stability of DNA hairpins reveal the unusual counterion-dependent stability of tetraloop hairpins. AB - Stem-loop DNA hairpins containing a 5-base-pair (bp) stem and single-stranded polythymidine loop were investigated using thermodynamic melting analysis and stopped-flow kinetics. These studies revealed the thermodynamic stability and folding kinetics as a function of loop length and counterion concentration. Our results show the unusually high thermodynamic stability for tetraloop or 4 poly(dT) loop hairpin as compared with longer loop length hairpins. Furthermore, this exceptional stability is highly counterion-dependent. For example, in the higher counterion concentration regime of 50 mM NaCl and above, the tetraloop hairpin displays enhanced stability as compared with longer loop length hairpins. However, at lower counterion concentration of 25 mM NaCl and below, the thermal stability of tetraloop hairpin is consistent with the longer loop hairpins. The enhanced stability of tetraloop hairpins at higher counterion concentration can be explained on the basis of the combined entropic effect of loop closure as well as base stacking in the loop regions. The stability of longer loop length hairpins at all counterion concentrations as well as tetraloop hairpin at lower counterion concentration can be explained on the basis of entropic effect of loop closure alone. The thermodynamic parameters at lower and higher counterion concentrations were determined to quantify the enhanced stability of base stacking effects occurring at higher counterion concentrations. For example, for 100 mM NaCl, excess Gibbs energy and enthalpy due to base stacking within the tetraloops were measured to be -1.2 +/- 0.14 and -3.28 +/- 0.32 kcal/mol, respectively, whereas, no excess of Gibbs energy and enthalpy was observed for 0, 5, 10, and 25 mM NaCl. These findings suggest significant base-stacking interactions occurring in the loop region of the tetraloop hairpins at higher counterion concentration and less significant base-stacking interactions in the lower counterion concentration regime. We suggest that at higher counterion concentrations, hydrophobic collapse of the nucleotides in the loop may be enhanced due to the increased polarity of the solvent, thereby enhancing base stacking interactions that contribute to unusually high stability. PMID- 24144398 TI - Scleral buckling and pars plana vitrectomy for rhegmatogenous retinal detachment: an analysis of 542 eyes. AB - PURPOSE: To investigate the anatomical success rates of scleral buckling (SB) and pars plana vitrectomy (PPV) performed for rhegmatogenous retinal detachment (RRD) in a large case series and to identify prognostic factors for the primary anatomical success rates of surgical techniques. METHODS: We reviewed 542 consecutive eyes for primary RRD in this retrospective study. Follow-ups were performed for at least six months. In each of the two groups, 271 eyes were examined. The main outcome measure was the primary anatomical success rate. Multivariate analysis was also performed to determine whether independent risk factors of the preoperative parameters for redetachment exist. RESULTS: The primary anatomical success rates were 93.7% and 96.3% in the SB and PPV groups; and the final anatomical success rates were 100% in both groups (each with 271 eyes). In the SB group, eyes with macula-off had significantly lower primary anatomical success rates than those with macula-on (p = 0.002). Preoperative break location or lens status had no significant effect on primary anatomical success rates in either group. Multivariate logistic regression analysis using four variables, namely, sex, posterior vitreous detachment, macular status and preoperative visual acuity, showed that the macular status was an independent risk factor for redetachment in the SB group (p = 0.039, odds ratio 3.7). The six month follow-up visual acuity was significantly better than the preoperative visual acuity in both groups (p <= 0.001). CONCLUSIONS: Both SB and PPV gave excellent primary and final anatomical success rates. The macula-off status was associated with a lower success rate in the SB group, although break location and lens status had no significant effect on success rates in either group. PMID- 24144399 TI - A time-domain nuclear magnetic resonance study of Mediterranean scleractinian corals reveals skeletal-porosity sensitivity to environmental changes. AB - Mediterranean corals are a natural model for studying global warming, as the Mediterranean basin is expected to be one of the most affected regions and the increase in temperature is one of the greatest threats for coral survival. We have analyzed for the first time with time-domain nuclear magnetic resonance (TD NMR) the porosity and pore-space structure, important aspects of coral skeletons, of two scleractinian corals, Balanophyllia europaea (zooxanthellate) and Leptopsammia pruvoti (nonzooxanthellate), taken from three different sites on the western Italian coast along a temperature gradient. Comparisons have been made with mercury intrusion porosimetry and scanning electron microscopy images. TD NMR parameters are sensitive to changes in the pore structure of the two coral species. A parameter, related to the porosity, is larger for L. pruvoti than for B. europaea, confirming previous non-NMR results. Another parameter representing the fraction of the pore volume with pore sizes of less than 10-20 MUm is inversely related, with a high degree of statistical significance, to the mass of the specimen and, for B. europaea, to the temperature of the growing site. This effect in the zooxanthellate species, which could reduce its resistance to mechanical stresses, may depend on an inhibition of the photosynthetic process at elevated temperatures and could have particular consequences in determining the effects of global warming on these species. PMID- 24144400 TI - In situ construction of g-C3N4/g-C3N4 metal-free heterojunction for enhanced visible-light photocatalysis. AB - The photocatalytic performance of the star photocatalyst g-C3N4 was restricted by the low efficiency because of the fast charge recombination. The present work developed a facile in situ method to construct g-C3N4/g-C3N4 metal-free isotype heterojunction with molecular composite precursors with the aim to greatly promote the charge separation. Considering the fact that g-C3N4 samples prepared from urea and thiourea separately have different band structure, the molecular composite precursors of urea and thiourea were treated simultaneously under the same thermal conditions, in situ creating a novel layered g-C3N4/g-C3N4 metal free heterojunction (g-g CN heterojunction). This synthesis method is facile, economic, and environmentally benign using easily available earth-abundant green precursors. The confirmation of isotype g-g CN heterojunction was based on XRD, HRTEM, valence band XPS, ns-level PL, photocurrent, and EIS measurement. Upon visible-light irradiation, the photogenerated electrons transfer from g-C3N4 (thiourea) to g-C3N4 (urea) driven by the conduction band offset of 0.10 eV, whereas the photogenerated holes transfer from g-C3N4 (urea) to g-C3N4 (thiourea) driven by the valence band offset of 0.40 eV. The potential difference between the two g-C3N4 components in the heterojunction is the main driving force for efficient charge separation and transfer. For the removal of NO in air, the g-g CN heterojunction exhibited significantly enhanced visible light photocatalytic activity over g-C3N4 alone and physical mixture of g-C3N4 samples. The enhanced photocatalytic performance of g-g CN isotype heterojunction can be directly ascribed to efficient charge separation and transfer across the heterojunction interface as well as prolonged lifetime of charge carriers. This work demonstrated that rational design and construction of isotype heterojunction could open up a new avenue for the development of new efficient visible-light photocatalysts. PMID- 24144401 TI - Larvicidal activity of the active constituent isolated from Tabebuia avellanedae bark and structurally related derivatives against three mosquito species. AB - Mosquito larvicidal activities of active constituent isolated from Tabebuia avellanedae bark and its structurally related derivatives were examined against the fourth instar larvae of Aedes aegypti, Culex pipiens pallens, and Ochlerotatus togoi. The insecticidal constituent of T. avellanedae bark was isolated by chromatographic techniques and identified as 2-hydroxy-3-(3-methyl-2 butenyl)-1,4-naphthalenedione. On the basis of the 50% lethal concentration (LC50) values against C. pipiens pallens larvae, the most toxic compound was 1,4 naphthalenedione (1.26 mg/L), followed by 1,2-naphthalenedione (1.43 mg/L), 1,4 naphthalenediol (3.20 mg/L), 2-chloro-3-pyrrolidino-1,4-naphthalenedione (5.11 mg/L), 2-hydroxy-3-(3-methyl-2-butenyl)-1,4-naphthalenedione (8.30 mg/L), and 2 chloro-3-morpholino-1,4-naphthalenedione (12.98 mg/L). Similar results against A. aegypti and O. togoi larvae were observed for 2-hydroxy-3-(3-methyl-2-butenyl) 1,4-naphthalenedione and its derivatives. According to the LC50 values against three mosquito species, these compounds were less toxic than pirimiphos-methyl. Nonetheless, naturally occurring T. avaellenedae bark-derived materials could be useful as a natural mosquito control agent. PMID- 24144402 TI - Associations between oral contraceptive use and risks of hypertension and prehypertension in a cross-sectional study of Korean women. AB - BACKGROUND: The effect of commonly used oral contraceptives (OCs) on blood pressure is still unclear. The aim of this study was to examine the relationship between OCs use and blood pressure and the prevalence of hypertension in a population-based sample of Korean women. METHODS: A cross-sectional study was conducted using data from 3356 participants aged 35-55 years collected in the 2007-2009 Korea National Health and Nutrition Examination Surveys. OC use and demographic characteristics were obtained from participants using a questionnaire, and blood pressure was measured with a mercury sphygmomanometer. RESULTS: Longer duration of OC use was positively associated with increasing levels of systolic blood pressure and diastolic blood pressure (p for trend <0.001). After adjusting for covariates, the odds ratio (OR) of hypertension was significantly increased in longer-term (>24 months) OC users (OR 1.96; 95% confidence interval (CI) 1.03-3.73) compared with those who had never used OCs. Additionally, use of OCs >24 months was associated with increased odds of prehypertension (adjusted OR 2.23; 95% CI 1.28-3.90) and hypertension or prehypertension (adjusted OR 2.13; 95% CI 1.37-3.32). CONCLUSION: This study found a statistically significant association between OC use and blood pressure or hypertension among Korean women. PMID- 24144403 TI - Mature vessel occlusion after anti-VEGF treatment in a retinal arteriovenous malformation. AB - BACKGROUND: To report engorged vessel occlusion after repeated intravitreal injections of bevacizumab to treat the macular oedema in a case of arteriovenous malformation. CASE PRESENTATION: A 37-year-old woman presented with a sudden, painless loss of vision in her left eye. Her visual acuity was 20/200 in the left eye, and 20/20 in the right eye. Ophthalmoscopic examination revealed an abnormal tangle of vessels and enlarged draining veins. A fluorescence angiogram revealed fluorescence leakage at a turn near the fovea. Horizontally oriented optical coherence tomography revealed an increased macular thickness and an accumulation of intraretinal fluid, indicating macular oedema. After three intravitreal injections of 1.25 mg bevacizumab, her vision improved to 20/20. Ophthalmoscopic examination revealed a decreased calibre of the previously engorged draining veins and ghost vessels. Repeated horizontally oriented optical coherence tomography revealed a decreased macular thickness and the absence of an intraretinal cyst. At the 2-year follow-up visit, the vision of the patient was stable. CONCLUSION: This finding implies that certain middle-size vessels can become occluded during anti-vascular endothelium growth factor (anti-VEGF) therapy, which could induce fatal complications if it occurred in the heart or brain. Clinicians should be cautious of the potential thrombotic effects on systemic blood vessels when administering anti-VEGF treatment. PMID- 24144404 TI - 4beta-Methyl-5-(3-hydroxyphenyl)morphan opioid agonist and partial agonist derived from a 4beta-methyl-5-(3-hydroxyphenyl)morphan pure antagonist. AB - In previous studies we reported that addition of 7alpha-acylamino groups to N phenylpropyl-4beta-methyl-5-(3-hydroxyphenyl)morphan (4) led to compounds that were pure opioid receptor antagonists. In contrast to these findings we report in this study that addition of a 7alpha-amino (5a), 7alpha-alkylamino (5b-e), or 7alpha-dialkylamino (5f-h) group to 4 leads to opioid receptor ligands with varying degrees of agonist/antagonist activity. The 7alpha-amino and 7alpha methylamino analogues were full agonists at the MU and delta receptors and antagonists at the kappa receptor. The 7alpha-cyclopropylmethylamino analogue 5h was a full agonist at the MU receptor with weaker agonist activity at the delta and kappa receptors. Whereas the addition of a 7alpha-acylamino group to the pure nonselective opioid receptor antagonist N-phenylpropyl-4beta-methyl-5-(3 hydroxyphenyl)morphan (4) led to kappa selective pure opioid receptor antagonist, the addition of a 7alpha-amino, 7alpha-alkylamino, or 7alpha-dialkylamino group to 4 leads to opioid ligands that are largely MU or delta agonist with mixed agonist/antagonist properties. PMID- 24144405 TI - Hypoxia-inducible factor 1 regulates heat and cold pain sensitivity and persistence. AB - AIMS: The present study assessed the functions of the transcription factor hypoxia-inducible factor (HIF) in sensory neurons in models of acute, inflammatory, ischemic, and neuropathic pain. The alpha subunit, HIF1alpha, was specifically deleted in neurons of the dorsal root ganglia by mating HIF1alpha(fl/fl) mice with SNScre mice. RESULTS: SNS-HIF1alpha(-/-) mice were more sensitive to noxious heat and cold pain stimulation than were HIF1alpha(fl/fl) control mice. They also showed heightened first-phase nociceptive responses in the formalin and capsaicin tests with increased numbers of cFos-positive neurons in the dorsal horn, and intensified hyperalgesia in early phases after paw inflammation and hind limb ischemia/reperfusion. The behavioral cold and heat pain hypersensitivity was explained by increased calcium fluxes after transient receptor potential channel activation in primary sensory neurons of SNS-HIF1alpha(-/-) mice and lowered electrical activation thresholds of sensory fibers. SNS-HIF1alpha(-/-) mice however, developed less neuropathic pain after sciatic nerve injury, which was associated with an abrogation of HIF1 mediated gene up-regulation. INNOVATION: The results suggest that HIF1alpha is protective in terms of acute heat and cold pain but in case of ongoing activation in injured neurons, it may promote the development of neuropathic pain. CONCLUSION: The duality of HIF1 in pain regulation may have an impact on the side effects of drugs targeting HIF1, which are being developed, for example, as anticancer agents. Specifically, in patients with cancer neuropathy, however, temporary HIF1 inhibition might provide a welcome combination of growth and pain reduction. PMID- 24144406 TI - Foreword. Trypanosomatid disease drug discovery and target identification. PMID- 24144407 TI - Neutron crystallography used to identify targets to improve HIV-1 protease inhibitor. PMID- 24144408 TI - Drug discovery for the treatment of leishmaniasis, African sleeping sickness and Chagas disease. AB - The trypanosomatid protozoa Leishmania, Trypanosoma brucei and Trypanosoma cruzi are the caustive agents of the human diseases respectively, leishmaniasis, African sleeping sickness and Chagas disease. Among the 17 'neglected tropical diseases' highlighted by WHO, progress towards the treatment of these diseases has improved in recent decades, as a result of increased awareness, the emergence of public-private research partnerships and advances in drug-discovery technologies and techniques. Despite this, the current therapies for these diseases have serious shortcomings and, as such, the need to develop novel drugs, improve diagnosis and control the spread of disease is of paramount importance. Future Medicinal Chemistry invited leading experts in the field to share their thoughts and opinions on the changing face of drug discovery in the pursuit of treatments for trypanosomatid-based diseases. PMID- 24144409 TI - Identification of novel benzimidazole derivatives as anti-Trypanosoma cruzi agents: solid-phase synthesis, structure-activity relationships and molecular docking studies. AB - BACKGROUND: In this paper, we report the solid-phase synthesis of 33 novel 1,2,5 tri-substituted benzimidazole derivatives and their in vitro activity on cruzipain and Trypanosoma cruzi epimastigotes. RESULTS: Seven compounds were potent inhibitors of T. cruzi growth with IC50 values in the range 6-16 uM. Applying structure-activity relationships and principal component analysis strategies we were able to determine ring substituent effects and physicochemical properties that are important for the antichagasic activity of these novel derivatives, as well as get an insight into their possible mechanisms of action. Molecular docking studies revealed the binding orientation of the ligands in the active site of cruzipain providing new guidelines for the further design of better inhibitors. CONCLUSION: Compound 2a constitute a promising hit compound for novel anti-T. cruzi agents showing that the benzimidazole scaffold may represent an interesting therapeutic alternative for the treatment of Chagas disease. PMID- 24144410 TI - Selection and optimization of hits from a high-throughput phenotypic screen against Trypanosoma cruzi. AB - BACKGROUND: Inhibitors of Trypanosoma cruzi with novel mechanisms of action are urgently required to diversify the current clinical and preclinical pipelines. Increasing the number and diversity of hits available for assessment at the beginning of the discovery process will help to achieve this aim. RESULTS: We report the evaluation of multiple hits generated from a high-throughput screen to identify inhibitors of T. cruzi and from these studies the discovery of two novel series currently in lead optimization. Lead compounds from these series potently and selectively inhibit growth of T. cruzi in vitro and the most advanced compound is orally active in a subchronic mouse model of T. cruzi infection. CONCLUSION: High-throughput screening of novel compound collections has an important role to play in diversifying the trypanosomatid drug discovery portfolio. A new T. cruzi inhibitor series with good drug-like properties and promising in vivo efficacy has been identified through this process. PMID- 24144411 TI - Inhibitors of Trypanosoma brucei trypanothione reductase: comparative molecular field analysis modeling and structural basis for selective inhibition. AB - BACKGROUND: Sleeping sickness is a major cause of death in Africa. Since no secure treatment is available, the development of novel therapeutic agents is urgent. In this context, the enzyme trypanothione reductase (TR) is a prominent molecular target that has been investigated in drug design for sleeping sickness. RESULTS: In this study, comparative molecular field analysis models were generated for a series of Trypanosoma brucei TR inhibitors. Statistically significant results were obtained and the models were applied to predict the activity of external test sets, with good correlation between predicted and experimental results. We have also investigated the structural requirements for the selective inhibition of the parasite's enzyme over the human glutathione reductase. CONCLUSION: The quantitative structure-activity relationship models provided valuable information regarding the essential molecular requirements for the inhibitory activity upon the target protein, providing important insights into the design of more potent and selective TR inhibitors. PMID- 24144412 TI - Novel 3-nitro-1H-1,2,4-triazole-based compounds as potential anti-Chagasic drugs: in vivo studies. AB - BACKGROUND: Chagas disease is caused by the parasite Trypanosoma cruzi, is endemic in Latin America and leads to an estimated 14,000 deaths per year and around 100 million people at risk of infection. Drugs currently used in the treatment of Chagas are old, partially effective and have numerous side effects. METHODOLOGY: We have previously reported that 3-nitro-1H-1,2,4-triazole-based compounds demonstrate significant and selective activity against T. cruzi amastigotes in infected L6 cells via activation of a type I nitroreductase, specific to trypanosomatids. In the present work we evaluated in vivo 13 of these compounds based on their high in vitro potency against T. cruzi (IC50 < 1 uM) and selectivity (SI: toxicity to L6 cells/toxicity against T. cruzi amastigotes > 200). Representative compounds of different chemical classes were included. A fast luminescence assay with transgenic parasites that express luciferase, and live imaging techniques were used. A total of 11 out of 13 compounds demonstrated significant antichagasic activity when administered intraperitoneally for 5-10 days at relatively small doses. The best in vivo activity was demonstrated by amides and sulfonamide derivatives. ADMET studies were performed for specific compounds. CONCLUSION: At least three compounds were identified as effective, non toxic antichagasic agents suitable for further development. PMID- 24144413 TI - Interactions of antiparasitic alkaloids with Leishmania protein targets: a molecular docking analysis. AB - BACKGROUND: Leishmaniasis is a collection of chronic diseases caused by protozoa of the genus Leishmania. Current antileishmanial chemotherapeutics have demonstrated adverse side effects and therefore R&D into new safer alternative treatments are needed. METHODS: A molecular docking analysis has been carried out to assess possible Leishmania biochemical targets of antiparasitic alkaloids. A total of 209 antiparasitic alkaloids were docked with 24 Leishmania protein targets. RESULTS: The strongest docking alkaloid ligands were flinderoles A and B and juliflorine with Leishmania major methionyl-tRNA synthetase; juliflorine, juliprosine, prosopilosidine and prosopilosine with Leishmania mexicana glycerol 3-phosphate dehydrogenase; and ancistrogriffithine A with L. major N-myristoyl transferase. CONCLUSION: This molecular docking study has provided evidence for what classes and structural types of alkaloids may be targeting specific Leishmania protein targets. PMID- 24144414 TI - Drug discovery and human African trypanosomiasis: a disease less neglected? AB - Human African trypanosomiasis (HAT) has been neglected for a long time. The most recent drug to treat this disease, eflornithine, was approved by the US FDA in 2000. Current treatments exhibit numerous problematic side effects and are often ineffective against the debilitating CNS resident stage of the disease. Fortunately, several partnerships and initiatives have been formed over the last 20 years in an effort to eradicate HAT, along with a number of other neglected diseases. This has led to an increasing number of foundations and research institutions that are currently working on the development of new drugs for HAT and tools with which to diagnose and treat patients. New biochemical pathways as therapeutic targets are emerging, accompanied by increasing numbers of new antitrypanosomal compound classes. The future looks promising that this collaborative approach will facilitate eagerly awaited breakthroughs in the treatment of HAT. PMID- 24144415 TI - Indazoles: a new top seed structure in the search of efficient drugs against Trypanosoma cruzi. AB - For years, Chagas disease treatment has been limited to only two drugs of highly questionable and controversial use (Nifurtimox((r)) and Benznidazole((r))). In the search of effective drugs, many efforts have been made, but only a few structures have emerged as actual candidates. Heading into this, the multitarget directed approach appears as the best choice. In this framework, indazoles were shown to be potent Trypanosoma cruzi growth inhibitors, being able to lead both the formation of reactive oxygen species and the inhibition of trypanothione reductase. Herein, we discuss the main structural factors that rule the anti-T. cruzi properties of indazoles, and how they would be involved in the biological properties as well as in the action mechanisms, attempting to make parallels between the old paradigms and current evidences in order to outline what could be the next steps to follow in regard to the future drug design for Chagas disease treatment. PMID- 24144416 TI - Structural insights into the enzymes of the trypanothione pathway: targets for antileishmaniasis drugs. AB - Leishmaniasis is a neglected disease that kills 60,000 people worldwide, and which is caused by the protozoa Leishmania. The enzymes of the trypanothione pathway: trypanothione synthetase-amidase, trypanothione reductase (TR) and tryparedoxin-dependent peroxidase are absent in human hosts, and are essential for parasite survival and druggable. The most promising target is trypanothione synthetase-amidase, which has been also chemically validated. However, the structural data presented in this review show that TR also should be considered as a good target. Indeed, it is strongly inhibited by silver- and gold-containing compounds, which are active against Leishmania parasites and can be used for the development of novel antileishmanial agents. Moreover, TR trypanothione-binding site is not featureless but contains a sub-pocket where inhibitors bind, potentially useful for the design of new lead compounds. PMID- 24144417 TI - Drug resistance in leishmaniasis: current drug-delivery systems and future perspectives. AB - Leishmaniasis is a complex of diseases with numerous clinical manifestations for instance harshness from skin lesions to severe disfigurement and chronic systemic infection in the liver and spleen. So far, the most classical leishmaniasis therapy, despite its documented toxicities, remains pentavalent antimonial compounds. The arvailable therapeutic modalities for leishmaniasis are overwhelmed with resistance to leishmaniasis therapy. Mechanisms of classical drug resistance are often related with the lower drug uptake, increased efflux, the faster drug metabolism, drug target modifications and over-expression of drug transporters. The high prevalence of leishmaniasis and the appearance of resistance to classical drugs reveal the demand to develop and explore novel, less toxic, low cost and more promising therapeutic modalities. The review describes the mechanisms of classical drug resistance and potential drug targets in Leishmania infection. Moreover, current drug-delivery systems and future perspectives towards Leishmaniasis treatment are also covered. PMID- 24144418 TI - Trypanosoma cruzi trans-sialidase as a drug target against Chagas disease (American trypanosomiasis). AB - Chagas disease (or American trypanosomiasis) is a deadly tropical disease that affects millions of people worldwide, primarily in rural regions of South America. Trypanosoma cruzi, the parasitic cause of Chagas disease, possesses a membrane-anchored trans-sialidase enzyme that transfers sialic acids from the host cell surface to the parasitic cell surface, allowing T. cruzi to effectively evade the host's immune system. This enzyme has no analogous human counterpart and thus has become an interesting drug target to combat the parasite. Recent computational efforts have improved our knowledge about the enzyme's structure, dynamics and catalyzed reaction. Many compounds have been tested against trans sialidase activity, but no strong inhibitors have been identified yet. The current lack of drugs for Chagas disease necessitates more R&D into the design and discovery of strong inhibitors of T. cruzi trans-sialidase. PMID- 24144421 TI - Becoming sustainable: human determinants of change. AB - The author is a natural scientist and philosopher who has been involved in the global experience industry for more than 25 years. During this period of time he has developed a coherent, interdisciplinary body of knowledge that appears to be of essential interest as related to the transition towards a sustainable society: the Experience Science (Frank, 2011, 2012). Important scientific inputs come from underlying disciplines like cybernetics, system theory, psychology, and cognitive science. One of the key findings of the Experience Science is the innate structure of human experiencing. Any human experience includes 5 different experiential domains that influence and regulate each other: the emotional domain (feeling); the mental imagery domain (mental narrating); the sensorimotor domain (acting & perceiving); the linguistic domain (rational reasoning); the communicational domain (conversing). In the light of the Experience Science the dilemma of the current transition process towards a sustainable society becomes clearly visible. Any relevant attempt reduces the existing problems to more or less exclusively the linguistic, rational domain. Although ever evolving rational knowledge indeed is an indispensable prerequisite for a sustainable future this is not enough. Societal change towards a sustainable life-style can only happen if the whole experiential system gets a chance to reorganize itself. This leads to the following logical consequence. Any rational knowledge is embedded in a both emotional and narrative knowledge system that underlies and frames human reasoning. As long as human learning restricts itself to an exclusively rational attempt the underlying emotional and narrative program remains untouched. The learner hence continues orienting her attention into the direction determined by the underlying emotional and narrative paradigm. The paper delineates the experiential determinants of change and analyzes their specific, constitutive interrelations. From this a holistic choreography of change learning is outlined that pays tribute to the intrinsic transition principles represented by the human learner. PMID- 24144420 TI - Surface coatings of ZnO nanoparticles mitigate differentially a host of transcriptional, protein and signalling responses in primary human olfactory cells. AB - BACKGROUND: Inhaled nanoparticles have been reported in some instances to translocate from the nostril to the olfactory bulb in exposed rats. In close proximity to the olfactory bulb is the olfactory mucosa, within which resides a niche of multipotent cells. Cells isolated from this area may provide a relevant in vitro system to investigate potential effects of workplace exposure to inhaled zinc oxide nanoparticles. METHODS: Four types of commercially-available zinc oxide (ZnO) nanoparticles, two coated and two uncoated, were examined for their effects on primary human cells cultured from the olfactory mucosa. Human olfactory neurosphere-derived (hONS) cells from healthy adult donors were analyzed for modulation of cytokine levels, activation of intracellular signalling pathways, changes in gene-expression patterns across the whole genome, and compromised cellular function over a 24 h period following exposure to the nanoparticles suspended in cell culture medium. RESULTS: ZnO nanoparticle toxicity in hONS cells was mediated through a battery of mechanisms largely related to cell stress, inflammatory response and apoptosis, but not activation of mechanisms that repair damaged DNA. Surface coatings on the ZnO nanoparticles mitigated these cellular responses to varying degrees. CONCLUSIONS: The results indicate that care should be taken in the workplace to minimize generation of, and exposure to, aerosols of uncoated ZnO nanoparticles, given the adverse responses reported here using multipotent cells derived from the olfactory mucosa. PMID- 24144422 TI - A new synthetic pathway to the second and third generation of superbasic bisphosphazene proton sponges: the run for the best chelating ligand for a proton. AB - We present the up to now strongest chelating neutral pincer ligand for the simplest electrophile of chemistry, the proton. Two novel bisphosphazene proton sponges, 1,8-bis(trispyrrolidinophosphazenyl)naphthalene (TPPN) and its higher homologue P2-TPPN, were obtained via a Staudinger reaction and investigated concerning their structural features and basic properties by experimental and computational means. They exhibit experimental pK(BH)(+) values in acetonitrile of 32.3 and 42.1, respectively, exceeding the existing basicitiy record for proton sponges by more than 10 orders of magnitude. We show that Schwesinger's concept of homologization of phosphazene bases and Alder's concept of proton chelation in a constrained geometry regime of basic centers can be combined in the design of highly basic nonionic superbases of pincer type. PMID- 24144423 TI - Reliability of the craniocervical posture assessment: visual and angular measurements using photographs and radiographs. AB - OBJECTIVE: The purposes of this study were to determine the intrarater and interrater reliability of the craniocervical posture in a sagittal view using quantitative measurements on photographs and radiographs and to determine the agreement of the visual assessment of posture between raters. METHODS: One photograph and 1 radiograph of the sagittal craniocervical posture were simultaneously taken from 39 healthy female subjects. Three angles were measured on the photographs and 10 angles on the radiographs of 22 subjects using Alcimage software (Alcimage; Uberlandia, MG, Brazil). Two repeated measurements were performed by 2 raters. The measurements were compared within and between raters to test the intrarater and interrater reliability, respectively. Intraclass correlation coefficient and SEM were used. kappa Agreement was calculated for the visual assessment of 39 subjects using photographs and radiographs between 2 raters. RESULTS: Good to excellent intrarater and interrater intraclass correlation coefficient values were found on both photographs and radiographs. Interrater SEM was large and clinically significant for cervical lordosis photogrammetry and for 1 angle measuring cervical lordosis on radiographs. Interrater kappa agreement for the visual assessment using photographs was poor (kappa = 0.37). CONCLUSION: The raters were reliable to measure angles in photographs and radiographs to quantify craniocervical posture with exception of 2 angles measuring lordosis of the cervical spine when compared between raters. The visual assessment of posture between raters was not reliable. PMID- 24144424 TI - Association of postural balance and isometric muscle strength in early- and middle-school-age boys. AB - OBJECTIVE: The purpose of this study was to evaluate the isometric muscle strength (IMS) and dynamic balance in early- and middle-school-age boys and to assess the strength of association between the dynamic balance scores and 6 different IMS indexes. METHODS: This is a cross-sectional study of a convenience sample of 94 boys who were 6 to 10 years of age and classified into an early school age (6-8 years) group (n = 50) and a middle school age (8-10 years) group (n = 44). Balance was tested using a Biodex Balance System. Anteroposterior Stability Index, Mediolateral Stability Index, and Overall Stability Index were recorded. IMS of 11 muscle groups was measured with a handheld dynamometer and categorized into 6 different muscle strength indices. RESULTS: The mean (SD) values of anteroposterior, mediolateral, and overall stability indexes observed for all study boys were 1.9 +/- 1.0, 1.2 +/- 0.7, and 2.5 +/- 1.2 respectively. In the middle school age group, strong positive relationships were detected between the overall stability index and trunk, lower limb, anti-gravity, pro gravity, and total strength indexes (r = -0.86/P < .001, r = -0.91/P < .001, r = 0.88/P < .001, r = -0.83/P < .001, and r = -0.84/P < .001 respectively), while no significant relationship was detected with the upper limb strength index (r = 0.159/P = .303). In the early school age group, moderate positive relationships were detected between the overall stability index and anti-gravity, lower limb, and total strength indexes (r = -0.404/P = .004, r = -0.356/P = .011, and r = 0.350/P = .013 respectively). CONCLUSION: Dynamic balance did not appear to be mature by the age of 10 years. Better balance skills were recorded in the mediolateral direction than in the anteroposterior direction. In the middle school age group, the overall stability index had positive relationships with almost all examined muscle strength indexes excepting the upper limb strength index. PMID- 24144425 TI - Chiropractic use and changes in health among older medicare beneficiaries: a comparative effectiveness observational study. AB - OBJECTIVE: The purpose of this study was to investigate the effect of chiropractic on 5 outcomes among Medicare beneficiaries: increased difficulties performing activities of daily living (ADLs), instrumental ADLs (IADLs), and lower body functions, as well as lower self-rated health and increased depressive symptoms. METHODS: Among all beneficiaries, we estimated the effect of chiropractic use on changes in health outcomes among those who used chiropractic compared with those who did not, and among beneficiaries with back conditions, we estimated the effect of chiropractic use relative to medical care, both during a 2- to 15-year period. Two analytic approaches were used--one assumed no selection bias, whereas the other adjusted for potential selection bias using propensity score methods. RESULTS: Among all beneficiaries, propensity score analyses indicated that chiropractic use led to comparable outcomes for ADLs, IADLs, and depressive symptoms, although there were increased risks associated with chiropractic for declines in lower body function and self-rated health. Propensity score analyses among beneficiaries with back conditions indicated that chiropractic use led to comparable outcomes for ADLs, IADLs, lower body function, and depressive symptoms, although there was an increased risk associated with chiropractic use for declines in self-rated health. CONCLUSION: The evidence in this study suggests that chiropractic treatment has comparable effects on functional outcomes when compared with medical treatment for all Medicare beneficiaries, but increased risk for declines in self-rated health among beneficiaries with back conditions. PMID- 24144426 TI - An intact parathyroid hormone-based protocol for the prevention and treatment of symptomatic hypocalcemia after thyroidectomy. AB - BACKGROUND: Symptomatic (SX) hypocalcemia after thyroidectomy is a barrier to same day surgery and the cause of emergency room visits. A standard protocol of calcium and vitamin D supplementation, dependent on intact parathyroid hormone (iPTH) levels, can address this issue. How effective is it? When does it fail? METHODS: We performed a retrospective review of the prospective Thyroid database from January 2006 to December 2010. Six hundred twenty patients underwent completion thyroidectomy or total thyroidectomy and followed our postoperative protocol of calcium carbonate administration for iPTH levels >=10 pg/mL and calcium carbonate and 0.25 MUg calcitriol twice a day for iPTH <10 pg/mL. Calcium and iPTH values, pathology, and medication were compared to evaluate protocol efficacy. A P value <0.05 was considered statistically significant. RESULTS: Using the protocol, sixty-one (10.2%) patients were chemically hypocalcemic but never developed symptoms and 24 (3.9%) patients developed breakthrough SX hypocalcemia. The SX and asymptomatic groups were similar with regard to gender, cancer diagnosis, and preoperative calcium and iPTH. The SX group was significantly younger (39.6 +/- 2.8 versus 49 +/- 0.6 y, P = 0.01), with lower postoperative iPTH levels. Thirty-three percent (n = 8) of SX patients had an iPTH <=5 pg/mL versus only 6% (n = 37) of ASX patients. Although the majority of patients with a iPTH <=5 pg/mL were asymptomatic, 62.5% (n = 5) of SX patients with iPTH levels <=5 pg/mL required an increase in calcitriol dose to achieve both biochemical correction and symptom relief. CONCLUSIONS: Prophylactic calcium and vitamin D supplementation based on postoperative iPTH levels can minimize SX hypocalcemia after thyroidectomy. An iPTH <=5 pg/mL may warrant higher initial doses of calcitriol to prevent symptoms. PMID- 24144427 TI - An intensely luminescent metal-organic framework based on a highly light harvesting dyclo-metalated iridium(III) unit showing effective detection of explosives. AB - An intense visible yellow-orange emission with long lifetime and enhanced quantum yield has been achieved for a metal-organic framework based on a highly light harvesting dyclo-metalated iridium(III) unit, which shows effective detection of nitroaromatic explosives on the ppm scale. PMID- 24144428 TI - D-psicose increases energy expenditure and decreases body fat accumulation in rats fed a high-sucrose diet. AB - We investigated the anti-obesity effects of D-psicose by increasing energy expenditure in rats pair-fed the high-sucrose diet (HSD). Wistar rats were divided into two dietary groups: HSD containing 5% cellulose (C) and 5% d-psicose (P). The C dietary group was further subdivided into two groups: rats fed the C diet ad libitum (C-AD) and pair-fed the C diet along with those in the P group (C PF). Resting energy expenditure during darkness and lipoprotein lipase activity in the soleus muscle were significantly higher in the P group than in the C-PF group. Serum levels of glucose, leptin and adiponectin; glucose-6-phosphate dehydrogenase activities in the liver and perirenal adipose tissue; and body fat accumulation were all significantly lower in the P group than in the C-PF group. The anti-obesity effects of D-psicose could be induced not only by suppressing lipogenic enzyme activity but also by increasing EE in rats. PMID- 24144429 TI - Nanovascularization of polymer matrix: generation of nanochannels and nanotubes by sacrificial electrospun fibers. AB - Several methods for creating vascular structures, made of either discrete or interconnected channels have been developed. The currently employed methods enable the formation of channels with diameters in the millimetric and micrometric scale. However, the formation of an interconnected three-dimensional (3D) vasculature by using a rapid and scalable process is a challenge and largely limits the fields of applicability of these innovative materials. Here, we propose the use of electrospun nonwoven mats as sacrificial fibers to easily generate 3D macroscale vascularized composites containing interconnected networks with channels and tubes having submicrometric and nanometric diameters. The novel approach has the potentialities to give rise to a novel generation of composites potentially displaying new and enhanced functionalities thanks to the nanoscale features of the cavities. PMID- 24144430 TI - A novel mutation in the CIAS1/NLRP3 gene associated with an unexpected phenotype of cryopyrin-associated periodic syndromes. AB - OBJECTIVES: Cryopyrin-associated periodic syndromes (CAPS) comprise a spectrum of distinct, rare, autosomal dominant autoinflammatory disorders of increasing severity caused by NLRP3 gene mutations. METHODS: We describe a 13-year-old female who presented, in the initial phase of the disease, recurrent episodes of high fever, pericarditis, arthralgia, arthritis of the knees, abdominal pain and marked increase in inflammatory markers. In the subsequent months she developed recurrent episodes of chest pain, skin rash and swelling of the subcutaneous tissue, without fever, and with spontaneous resolution. RESULTS: Molecular analysis of the CIAS1 gene revealed the presence of the Q703K variant and also a c.1105C>A mutation in the heterozygous state, that predicts a L369M amino acid substitution. The latter variant has never been reported. The L369M mutation was predicted to significantly affect protein structure (scoring as 'dangerous' and 'deleterious') by the Variant Effect Predictor tool. Therapy with anakinra was started with rapid disappearance of clinical symptoms and normalization of CRP levels in 24 hours. CONCLUSIONS: The rapid response to IL-1 inhibition suggests that the disease of this patient is driven by IL-1 and supports the conclusion that this novel mutation is pathogenic and may be associated with a new CAPS phenotype. The role played by the concomitant presence of the mutation Q703K remains to be clarified. PMID- 24144431 TI - Cyclophosphamide-associated cardiotoxicity in a child after stem cell transplantation for beta-thalassemia major: case report and review of the literature. AB - We present a clinicopathologic study of the youngest reported child with lethal cyclophosphamide-induced cardiotoxicity after hematopoietic stem cell transplantation for beta-thalassemia major and the 1st pediatric report of the use of extracorporeal membrane oxygenation as a therapeutic modality to bridge the patient to myocardial recovery. Despite improvement in myocardial function while on extracorporeal membrane oxygenation, at autopsy 11 days after the onset of cardiac dysfunction, epicardial hemorrhage and extensive myocardial hemorrhagic infarction were revealed. Histopathologic and ultrastructural examination of the myocardium revealed extensive coagulative necrosis of cardiomyocytes, endothelial damage, fibrin thrombi, and subendothelial and interstitial fibrin. We review the literature on cyclophosphamide-induced cardiotoxicity and describe its clinicopathologic characteristics. Our findings point to endothelial damage leading to thrombotic microangiopathy and ischemic tissue injury as the most likely pathogenesis. PMID- 24144432 TI - Bacillus Calmette-Guerin failure in patients with non-muscle-invasive urothelial carcinoma of the bladder may be due to the urologist's failure to detect urothelial carcinoma of the upper urinary tract and urethra. AB - BACKGROUND: Various reasons exist for so-called bacillus Calmette-Guerin (BCG) failure in patients with non-muscle-invasive urothelial bladder carcinoma (NMIBC). OBJECTIVE: To explore whether urothelial carcinoma of the upper urinary tract (UUT) and/or prostatic urethra may be a cause for BCG failure. DESIGN, SETTING, AND PARTICIPANTS: Retrospective analysis of 110 patients with high-risk NMIBC repeatedly treated with intravesical BCG, diagnosed with disease recurrence, and followed for a median time of 9.1 yr. INTERVENTION: Two or more intravesical BCG induction courses without maintenance. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Primary outcome was pattern of disease recurrence (BCG failure) within the urinary tract categorised into UUT and/or urethral carcinoma (with or without intravesical recurrence), and intravesical recurrence alone. Secondary outcome was survival. Predictors of UUT and/or urethral carcinoma and the effect of pattern of disease recurrence on cancer-specific survival were assessed with multivariable Cox regression analysis adjusting for multiple clinical and tumour characteristics. RESULTS AND LIMITATIONS: Of the 110 patients, 57 (52%) had UUT and/or urethral carcinoma (with or without intravesical recurrence), and 53 (48%) had intravesical recurrence alone. In patients with UUT and/or urethral carcinoma, bladder carcinoma in situ (Tis) before the first and second BCG course was present in 42 of 57 (74%) and 47 of 57 (82%) patients, respectively. On multivariable analysis, bladder Tis before the first and/or second BCG course was the only independent predictor of UUT and/or urethral carcinoma. Of the 110 patients, 69 (63%) were alive at last follow-up visit, 18 (16%) had died due to metastatic urothelial carcinoma, and 23 (21%) had died of other causes. Pattern of disease recurrence within the urinary tract was not an independent predictor of cancer-specific survival. Main study limitations were retrospective design and limited power for survival analysis. CONCLUSIONS: In our patients with high-risk NMIBC failing after two or more courses of intravesical BCG, UUT and/or urethral carcinoma was detected in >50% of the cases during follow-up. The vast majority of these patients had bladder Tis before the first and/or second BCG course. In patients experiencing the so-called BCG failure, a diagnostic work-up of UUT and prostatic urethra should always be performed to exclude urothelial carcinoma before additional intravesical therapy or even a radical cystectomy is considered. PMID- 24144433 TI - Biomass density and filament length synergistically affect activated sludge settling: systematic quantification and modeling. AB - Settling of the biomass produced during biological treatment of wastewater is a critical and often problematic process. Filamentous bacteria content is the best known factor affecting biomass settleability in activated sludge wastewater treatment systems, and varying biomass density has recently been shown to play an important role as well. The objective of this study was to systematically determine how filament content and biomass density combine to affect microbial biomass settling, with a focus on density variations over the range found in full scale systems. A laboratory-scale bioreactor system was operated to produce biomass with a range of filamentous bacterium contents. Biomass density was systematically varied in samples from this system by addition of synthetic microspheres to allow separation of filament content and density effects on settleability. Fluorescent in-situ hybridization indicated that the culture was dominated by Sphaerotilus natans, a common contributor to poor settling in full scale systems. A simple, image-based metric of filament content (filament length per floc area) was linearly correlated with the more commonly used filament length per dry biomass measurement. A non-linear, semi-empirical model of settleability as a function of filament content and density was developed and evaluated, providing a better understanding of how these two parameters combine to affect settleability. Filament content (length per dry biomass weight) was nearly linearly related to sludge volume index (SVI) values, with a slightly decreasing differential, and biomass density exhibited an asymptotic relationship with SVI. The filament content associated with bulking was shown to be a function of biomass density. The marginal effect of filament content on settleability increased with decreasing biomass density (low density biomass was more sensitive to changes in filament content than was high density biomass), indicating a synergistic relationship between these factors. Consideration of both biomass density and filament content, as by the methods and model described herein, should improve operation and troubleshooting of settling processes for biological solids. PMID- 24144435 TI - Metabolic differentiation of diamondback moth ( Plutella xylostella (L.)) resistance in cabbage ( Brassica oleracea L. ssp. capitata). AB - The diamondback moth, Plutella xylostella (L.), is a major pest responsible for destroying cabbage and other Brassica vegetable crops. A diamondback moth resistant cabbage line was studied by comparing its metabolite profiles with those of a susceptible cabbage. Fourier transform infrared spectroscopy analysis revealed that carbohydrates, aromatic compounds, and amides were the major factors that distinguished the resistant and susceptible genotypes. Gas chromatography-time-of-flight mass spectrometry profiled 46 metabolites, including 19 amino acids, 15 organic acids, 8 sugars, 3 sugar alcohols, and 1 amine in two genotypes and F1 hybrid cabbages. The levels of glycolic acid, quinic acid, inositol, fumaric acid, glyceric acid, trehalose, shikimic acid, and aspartic acid were found to be very significantly different between the resistant and susceptible genotypes with a P value of <0.0001. These results will provide a foundation for further studies on diamondback moth resistance in cabbage breeding and for the development of other herbivore-resistant crops. PMID- 24144434 TI - The N-terminal zinc finger and flanking basic domains represent the minimal region of the human immunodeficiency virus type-1 nucleocapsid protein for targeting chaperone function. AB - The human immunodeficiency virus type-1 (HIV-1) nucleocapsid (NC) protein is a chaperone that facilitates nucleic acid conformational changes to produce the most thermodynamically stable arrangement. The critical role of NC in many steps of the viral life cycle makes it an attractive therapeutic target. The chaperone activity of NC depends on its nucleic acid aggregating ability, duplex destabilizing activity, and rapid on-off binding kinetics. During the minus strand transfer step of reverse transcription, NC chaperones the annealing of highly structured transactivation response region (TAR) RNA to the complementary TAR DNA. In this work, the role of different functional domains of NC in facilitating 59-nucleotide TAR RNA-DNA annealing was probed by using chemically synthesized peptides derived from full-length (55 amino acids) HIV-1 NC: NC(1 14), NC(15-35), NC(1-28), NC(1-35), NC(29-55), NC(36-55), and NC(11-55). Most of these peptides displayed significantly reduced annealing kinetics, even when present at concentrations much higher than that of wild-type (WT) NC. In addition, these truncated NC constructs generally bind more weakly to single stranded DNA and are less effective nucleic acid aggregating agents than full length NC, consistent with the loss of both electrostatic and hydrophobic contacts. However, NC(1-35) displayed annealing kinetics, nucleic acid binding, and aggregation activity that were very similar to those of WT NC. Thus, we conclude that the N-terminal zinc finger, flanked by the N-terminus and linker domains, represents the minimal sequence that is necessary and sufficient for chaperone function in vitro. In addition, covalent continuity of the 35 N terminal amino acids of NC is critical for full activity. Thus, although the hydrophobic pocket formed by residues proximal to the C-terminal zinc finger has been a major focus of recent anti-NC therapeutic strategies, NC(1-35) represents an alternative target for therapeutics aimed at disrupting NC's chaperone function. PMID- 24144436 TI - Ab initio and all-atom modeling of detergent organization around Aquaporin-0 based on SAXS data. AB - A necessary initial step for the application of small angle X-ray scattering (SAXS) as an analytical probe for structural investigations of membrane proteins in solution is the precise knowledge of the structure of spontaneously formed detergent assemblies around the protein. Following our recent article (Berthaud et al. J. Am. Chem. Soc. 2012, 134, 10080-10088) on the study of the n-dodecyl beta-D-maltopyranoside (dDM) corona surrounding Aquaporin-0 tetramers in solution, we aimed at the development of more elaborate models, exploiting the information content of the scattering data. Two additional approaches are developed here for the fit of SAXS experimental data, one based on a generalized ab initio algorithm for the construction of a coarse-grained representation of the detergent assemblies, and a second based on atomistic molecular dynamics. Accordingly, we are able to fit the SAXS experimental data and obtain a better insight concerning the structure of the detergent corona around the hydrophobic part of the Aquaporin-0 surface. The present analysis scheme represents an additional step toward future conformational studies of transmembrane proteins in solution. PMID- 24144437 TI - How to prepare the brightest luminescent coatings? AB - We address here the question of studying the parameters affecting the brightness of luminescent nanoparticulate coatings, among which are the absorption rate, the internal quantum yield of the phosphor nanoparticles, and the extraction factor of the emitted light in a solid angle perpendicular to the substrate. Experimental investigations are achieved on spray-deposited YVO4:Eu particles, a system whose synthesis and properties are well documented so that particles of different sizes and microstructure can be considered. This allows a quantitative evaluation of the factors affecting film brightness. Considering a film made from raw colloidal particles, this work shows that its brightness is limited by a factor of 5 due to altered quantum yield of nanoparticles, a factor of 1.75 by dielectric effects and a factor of 2.4 by light extraction issues. This investigation, through providing quantitative evaluations of these different parameters, opens the way toward a possible rational design of inorganic luminescent coatings, with a possible improvement of brightness that could reach a factor of 30 as compared to simple films made directly from colloidal suspensions. PMID- 24144438 TI - Improvement of care for the physical health of patients with severe mental illness: a qualitative study assessing the view of patients and families. AB - BACKGROUND: Patients with severe mental illness (SMI) experience more physical comorbidity than the general population. Multiple factors, including inadequate seeking of healthcare and health care related factors such as lack of collaboration, underlie this undesirable situation. To improve this situation, the logistics of physical health care for patients with SMI need to be changed. We asked both patients and their families about their views on the current organization of care, and how this care could be improved. METHODS: Group and individual interviews were conducted with patients and family of patients to explore their needs and preferences concerning the care for the physical health of patients with SMI, and to explore the shortcomings they had experienced. Using thematic analysis, responses were firstly divided into common topics, after which these topics were grouped into themes. RESULTS: Three major themes for the improvement of the physical care of patients with SMI were found. Firstly, the reduced ability of patients with SMI to survey their own physical health interests requires health care that is tailored to these needs. Secondly, the lack of collaboration amongst mental health care professionals and general practitioners (GPs) hinders optimal care. Thirdly, concerns were expressed regarding the implementation of monitoring and supporting a healthy lifestyle. Patients with SMI welcome this implementation, but the logistics of providing this care can be improved. CONCLUSIONS: An optimal approach for caring for the physical health of patients with SMI requires a professional approach, which is different to the routine care provided to the general public. This approach can and should be accomplished within the usual organizational structure. However, this requires tailoring of the health care to the needs of patients with SMI, as well as structural collaboration between mental health care professionals and GPs. PMID- 24144439 TI - Characteristic expression of major histocompatibility complex and immune privilege genes in human pluripotent stem cells and their derivatives. AB - Pluripotent stem cells, including human embryonic stem cells (hESCs) and induced pluripotent stem cells (hiPSCs), have been regarded as useful sources for cell based transplantation therapy. However, immunogenicity of the cells remains the major determinant for successful clinical application. We report the examination of several hESC lines (NTU1 and H9), hiPSC lines, and their derivatives (including stem cell-derived hepatocytes) for the expression of major histocompatibility complex (MHC), natural killer (NK) cell receptor (NKp30, NKp44, NKp46) ligand, immune-related genes, human leukocyte antigen (HLA) haplotyping, and the effects in functional mixed lymphocyte reaction (MLR). Flow cytometry showed lower levels (percentages and fluorescence intensities) of MHC class I (MHC-I) molecules, beta2-microglobulin, and HLA-E in undifferentiated stem cells. The levels were increased after cotreatment with interferon-gamma and/or in vitro differentiation. Antigen-presenting cell markers (CD11c, CD80, and CD86) and MHC-II (HLA-DP, -DQ, and -DR) remained low throughout the treatments. Recognition of stem cells/derivatives by NK lysis receptors were lower or absent. Activation of responder lymphocytes was significantly lower by undifferentiated stem cells than by allogeneic lymphocytes in MLR, but differentiated NTU1 hESCs induced a cell number-dependent lymphocyte proliferation comparable with that by allogeneic lymphocytes. Interestingly, activation of lymphocytes by differentiated hiPSCs or H9 cells became blunted at higher cell numbers. Real-time reverse transcriptase PCR (RT-PCR) showed significant differential expression of immune privilege genes (TGF-beta2, Arginase 2, Indole 1, GATA3, POMC, VIP, CALCA, CALCB, IL-1RN, CD95L, CR1L, Serpine 1, HMOX1, IL6, LGALS3, HEBP1, THBS1, CD59, and LGALS1) in pluripotent stem cells/derivatives when compared to somatic cells. It was concluded that pluripotent stem cells/derivatives are predicted to be immunogenic, though evidence suggests some level of potential immune privilege. In addition, differential immunogenicity may exist between different pluripotent stem cell lines and their derivatives. PMID- 24144440 TI - Effect of parental age on treatment response in adolescents with schizophrenia. AB - BACKGROUND: Advanced paternal age (APA) is associated with increased risk for schizophrenia, but its effect on treatment response has not been longitudinally studied. METHODS: Association of parental ages at the time of the child's birth with age of onset, initial symptom severity and treatment response (to placebo and three different weight-based doses of paliperidone ER) in adolescents with schizophrenia was assessed in a post-hoc analysis using data from a 6-week double blind study, the primary results of which are published (NCT00518323). RESULTS: The mean (SD) paternal age was 29.2 (6.2) years, range (16-50) and maternal age was 26.8 (5.7) years, range (17-42) at childbirth for the 201 adolescents (ages 12-17 years) included in the analysis. While parental ages were uncorrelated with age of onset or initial symptom severity, both maternal and paternal ages showed significant effects on treatment response (p<0.03) of all paliperidone ER arms versus placebo. Paternal age was significantly correlated to improvement in positive symptoms and maternal age significantly related to negative symptoms, although only paternal age remained significantly associated with the treatment response in analyses that included both parents' ages. CONCLUSIONS: APA was associated with greater treatment response to both paliperidone ER and placebo, but not to age of onset or initial symptom severity in adolescents with schizophrenia. The results support the contention that APA-related schizophrenia has distinct underpinnings from other cases. Further studies are required to explore the role of genetic and environmental factors, and their interactions, in treatment response in this complex disorder. PMID- 24144441 TI - Reduced subicular subdivisions of the hippocampal formation and verbal declarative memory impairments in young relatives at risk for schizophrenia. AB - INTRODUCTION: Smaller hippocampal volumes similar to those found in schizophrenia (SZ) are frequently observed to a lesser extent in non-psychotic first-degree relatives of patients with the illness, compared to control subjects. In this study, subdivisions of the hippocampal formation and their association with verbal and visual learning and memory were assessed in persons at familial high risk (FHR) for SZ. METHODS: MRI scans were acquired using a 3T Siemens scanner of young adult (ages 19-32) FHR subjects (N=46) and controls with no family history of illness (i.e., at low genetic risk LRC; N=31) were processed using FreeSurfer 5.0. Subfields of the hippocampal formation were evaluated using the van Leemput method (Van Leemput et al., 2010). Learning and memory measures were collected by standardized neurocognitive tests. RESULTS: Controlling intracranial volume, significantly reduced left (p<0.025), and right hippocampus (p<0.024) volumes were observed in FHR subjects. Among the subfields, the left (p<0.01) and right subicula (p<0.005) were significantly reduced in the FHR group. Immediate verbal recall of stories was significantly impaired and was significantly correlated with the left and right subicula within the FHR group. CONCLUSIONS: Reduced subiculum volume and its association with verbal memory refines further the association with left and right hippocampus reported in previous FHR studies of schizophrenia. Further research is needed to determine the specific genetic and environmental risk factors that may be related to hippocampal subfield alterations. PMID- 24144442 TI - Identification of a rare off-ladder allele of the D13S325 locus during paternity testing. AB - This study demonstrates an unusual rare allele of D13S325 that was falsely categorized as an allele of D12S391 under the STRtyperTM-10F/G system. The parentage cases with these rare alleles were analyzed using the SinofilerTM system and singleplex amplification system, and the alleles of D13S325 extracted from the electrophoresis gel were sequenced. 5 Cases with the rare alleles misread as allele 20 of D12S391 were identified in total 2618 cases (including 3200 unrelated parents). This rare allele was designated as allele 5.1 of D13S325 based on its DNA sequence. Its frequency in the Chinese population was 1.6*10( 3). Because the rare allele 5.1 of D13S325 locus tends to be incorrectly labeled in the STRtyperTM-10F/G system, particular attention should be paid when the system is used in paternity testing, personal identification, and DNA database comparisons. PMID- 24144443 TI - Impact of organic coating on optical growth of ammonium sulfate particles. AB - Light extinction by particles in Earth's atmosphere is strongly dependent on particle size, chemical composition, hygroscopic growth properties, and particle mixing state. Here, the influence of an organic coating on particle optical growth was studied. The particle optical growth factor, fRHext, was measured using cavity ring-down aerosol extinction spectroscopy at 532 nm. The particles were composed of ammonium sulfate (AS), 1,2,6-hexanetriol, and mixed particles containing a wet or dry ammonium sulfate core and a 1,2,6-hexanetriol coating. Dry, coated particles were generated by atomization followed by drying. Wet, coated particles were formed via liquid-liquid phase separation (LLPS). LLPS was achieved by deliquescing and then drying the particles to a relative humidity (RH) between the phase separation RH and the efflorescence RH. For the LLPS particles, the fRHext at each RH was between the fRHext of ammonium sulfate and that of 1,2,6-hexanetriol. In contrast, for the mixed dry, coated particles, the fRHext was the same as 1,2,6-hexanetriol particles. At room temperature, the water uptake properties of AS coated with 1,2,6-hexanetriol are largely dictated by the phase of the AS. Thus, the total water uptake depends on the RH history of the particle and the resulting phase of AS. PMID- 24144444 TI - Ligand bioactive conformation plays a critical role in the design of drugs that target the hepatitis C virus NS3 protease. AB - A ligand-focused strategy employed NMR, X-ray, modeling, and medicinal chemistry to expose the critical role that bioactive conformation played in the design of a variety of drugs that target the HCV protease. The bioactive conformation (bound states) were determined for key inhibitors identified along our drug discovery pathway from the hit to clinical compounds. All adopt similar bioactive conformations for the common core derived from the hit peptide DDIVPC. A carefully designed SAR analysis, based on the advanced inhibitor 1 in which the P1 to P3 side chains and the N-terminal Boc were sequentially truncated, revealed a correlation between affinity and the relative predominance of the bioactive conformation in the free state. Interestingly, synergistic conformation effects on potency were also noted. Comparisons with clinical and recently marketed drugs from the pharmaceutical industry showed that all have the same core and similar bioactive conformations. This suggested that the variety of appendages discovered for these compounds also properly satisfy the bioactive conformation requirements and allowed for a large variety of HCV protease drug candidates to be designed. PMID- 24144445 TI - Renal failure as a risk factor for venous thromboembolism in critically Ill patients: a cohort study. AB - RATIONALE: The relationship between kidney function and venous thromboembolism (VTE) in critically ill patients is not well studied. The main objective of this study was to evaluate this relationship in patients admitted to a medical surgical intensive care unit (ICU). METHODS: This was a retrospective study of 798 patients admitted to a tertiary-care ICU and prospectively followed for the development of clinically suspected and radiologically diagnosed deep venous thrombosis or pulmonary embolism. Patients were divided based on admission creatinine and dialysis history into five groups: normal kidney function, RIFLE classes R, I and F (combined=acute kidney injury [AKI]) and endstage renal disease (ESRD). We compared VTE prophylaxis practices and VTE incidence in these groups and evaluated renal failure as a VTE risk factor using multivariate Cox regression analysis. RESULTS: Of the 798 patients, 27.2% had AKI and 10.1% had ESRD. Unfractionated heparin use was similar in the five groups but enoxaparin use was less frequent in AKI (13.4%) and ESRD (3.8%) patients compared with patients with normal kidney function (39.0%). VTE occurred in 7.6% of patients with normal renal function, 7.8% AKI patients and 2.5% ESRD patients (p=0.22). The adjusted hazard ratios for VTE compared to patients with normal kidney function were 0.35 (95% confidence interval [CI], 0.08-1.47) for RIFLE class R, 1.19 (95% CI, 0.83-1.70) for RIFLE class I, 0.82 (95% CI, 0.59-1.14) for RIFLE class F and 0.71 (95% CI, 0.49-1.02, p=0.06) for ESRD. CONCLUSIONS: Neither AKI nor ESRD was an independent risk factors for critically ill patients. PMID- 24144446 TI - Oxidized low-density lipoprotein-induced CD147 expression and its inhibition by high-density lipoprotein on platelets in vitro. AB - INTRODUCTION: Matrix metalloproteinases (MMPs) are believed to progressively degrade the collagenous components of the protective fibrous cap, leading to atherosclerotic plaque rupture or destabilization. Oxidized low-density lipoprotein (ox-LDL) enhances the release of CD147, known as the extracellular MMP inducer, from coronary smooth muscle cells. However, whether ox-LDL can induce platelet CD147 expression is unknown. Therefore, we investigated the influence of ox-LDL and high-density lipoprotein (HDL) on CD147 expression on human platelets. MATERIALS AND METHODS: Washed platelets were incubated with ox LDL (or native LDL) and HDL or anti-LOX-1 monoclonal antibody prior to incubation with ox-LDL. In parallel, buffer (PBS) was added to washed platelets as a control. The expression levels of CD147, CD62P, CD63 and Annexin V were assessed by flow cytometry, and soluble CD147 from the platelets was assessed by an enzyme linked immunosorbent assay. Laser scanning microscopy (LSM) and transmission electron microscopy (TEM) were used to visualize the morphological changes and granule release, respectively, from the platelets. RESULTS: Platelets treated with ox-LDL exhibited a significant increase in the expression of CD147 (or Annexin V), followed by increases in CD62P and CD63, compared with the control group. In contrast, HDL or anti-LOX-1 monoclonal antibody decreased these effects. The expression of soluble CD147 increased as the concentration of ox-LDL used to treat the platelets increased. After exposure to ox-LDL, morphological changes and granule release in the platelets were visualized by LSM and TEM. Additionally, the TEM revealed that HDL inhibits alpha-granule release. CONCLUSIONS: In platelets, ox-LDL stimulates the release of CD147 via binding to LOX-1, whereas HDL inhibits this effect. This finding could provide new insights concerning the influence of ox-LDL and HDL on plaque stability by the up regulation of CD147 on platelets. PMID- 24144447 TI - Detection of occult vertebral fractures by quantitative assessment of bone marrow attenuation values at MDCT. AB - OBJECTIVES: To determine a cut-off value of Hounsfield attenuation units (HU) at multidetector computed tomography (MDCT) for valid and reliable detection of bone marrow oedema (BME) related to occult vertebral fractures. METHODS: 36 patients underwent both MDCT and Magnetic Resonance Imaging (MRI) for evaluation of vertebral fractures of the thoracolumbar spine and were included in this retrospective study. Two readers independently assessed HU values at MDCT in a total of 196 vertebrae. Reliability was assessed by intraclass correlation coefficient and Bland-Altman analysis. For each patient we determined the vertebra with the lowest HU value and calculated the HU-difference to each other vertebral body. HU-differences were subjected to receiver operating characteristic (ROC) curve analysis to determine the diagnostic accuracy for detection of BME as determined by MRI, which served as the reference standard. Results of HU-measurements were compared with standard visual evaluation of MDCT. RESULTS: HU measurements demonstrated a high interrater reliability (ICC=0.984). ROC curve analysis (AUC=0.978) exhibited an ideal cut-off value of 29.6 HU for detection of BME associated with vertebral fractures with an accuracy of 97.4% as compared to 93.4% accuracy of visual evaluation. Particularly, HU-measurements increased the sensitivity for detection of vertebral fractures from 78.0% to 92.7% due to the detection of 7 of 9 occult fractures that were missed by visual evaluation alone. CONCLUSIONS: Assessing bone marrow density by HU measurements using the cut-off of 29.6 HU is a valid and reliable tool for detection of BME related to occult vertebral fractures in MDCT. The introduced technique may allow more accurate treatment decisions and may make further diagnostic work-up with MRI unnecessary. PMID- 24144448 TI - Influences of point-spread function and time-of-flight reconstructions on standardized uptake value of lymph node metastases in FDG-PET. AB - PURPOSE: The purpose of this study was to investigate the effects of point-spread function (PSF) and time-of-flight (TOF) on the standardized uptake value (SUV) of lymph node metastasis in FDG-PET/CT. MATERIALS AND METHODS: This study evaluated 41 lymph node metastases in 15 patients who had undergone (18)F-FDG PET/CT. The lesion diameters were 2.5 cm or less. The mean short-axis diameter of the lymph nodes was 10.5 +/- 3.7 mm (range 4.6-22.8mm). The PET data were reconstructed with baseline OSEM algorithm, with OSEM+PSF, with OSEM+TOF and with OSEM+PSF+TOF. A semi-quantitative analysis was performed using the maximum and mean SUV of lymph node metastases (SUVmax and SUVmean) and mean SUV of normal lung tissue (SUVlung). We also evaluated image quality using the signal-to-noise ratio in the liver (SNRliver). RESULTS: Both PSF and TOF increased the SUV of lymph node metastases. The combination of PSF and TOF increased the SUVmax by 43.3% and the SUVmean by 31.6% compared with conventional OSEM. By contrast, the SUVlung was not influenced by PSF and TOF. TOF significantly improved the SNRliver. CONCLUSION: PSF and TOF both increased the SUV of lymph node metastases. Although PSF and TOF are considered to improve small-lesion detectability, it is important to be aware that PSF and TOF influence the accuracy of quantitative measurements. PMID- 24144449 TI - Uveal lymphoma: clinical features, diagnostic studies, treatment selection, and outcomes. AB - OBJECTIVE: To describe the clinical features, ancillary diagnostic studies, and treatment selection in a cohort of patients with uveal lymphoma. DESIGN: Retrospective clinical review. PARTICIPANTS: A total of 22 patients (34 affected eyes) diagnosed with uveal lymphoma between 1997 and 2013. METHODS: Data were collected regarding patient characteristics, clinical features on ophthalmic examination, ancillary imaging studies, and primary treatment selection. MAIN OUTCOME MEASURES: Relapse defined as lymphoma recurrence in the initial site of presentation, the contralateral eye, or other systemic site and overall survival. RESULTS: Fifteen patients were male (68.2%). Median age at diagnosis was 68.0 years. The choroid was involved in 21 cases (95.5%), and 1 case (4.5%) was ciliochoroidal. Other ocular adnexal structures were affected in 13 patients (59.1%), including the conjunctiva in 4 (18.2%), the orbit in 7 (31.8%), and both the conjunctiva and orbit in 2 (9.1%). Bilateral disease was present in 12 patients (54.5%). The most common presenting symptom was decreased vision in 15 patients (68.2%). The median delay in diagnosis was 4.0 months. Yellow-white choroidal infiltrates were observed on fundus examination in 34 eyes (100.0%) with corresponding hypofluorescence in 100% of cases when indocyanine green angiography was performed. Infiltrates were located anterior to the arcades (67.6%), most commonly in a diffuse (32.4%) or superotemporal (32.4%) distribution. B-scan ultrasonography detected extrascleral extension in 22 patients (75.9%) with a pattern of crescentic thickening in 19 (86.4%). Extranodal marginal zone lymphoma was the predominant (76.2%) histologic subtype. External beam radiotherapy (72.7%) was most commonly chosen for primary treatment. Systemic imaging at the time of diagnosis revealed that the majority of cases (77.3%) were localized to the eye; none of the patients developed new systemic disease (median follow-up, 30.3 months). CONCLUSIONS: Uveal lymphoma has distinctive clinical features. Overlap with ocular adnexal structures is common, and ancillary imaging is essential for evaluating the full extent of ocular disease and presence of systemic involvement. PMID- 24144450 TI - Intravitreal aflibercept for treatment-resistant neovascular age-related macular degeneration. AB - OBJECTIVE: To assess the effectiveness of intravitreal aflibercept in patients with neovascular age-related macular degeneration (AMD) previously resistant to treatment with other anti-vascular endothelial growth factor agents. DESIGN: Prospective, open-label, noncontrolled, registered clinical trial. PARTICIPANTS: Forty-nine patients with treatment-resistant neovascular AMD. INTERVENTION: A dose of 2 mg intravitreal aflibercept was administered as 3 initial loading doses every 4 weeks (week 0, week 4, and week 8), followed by further injections every 8 weeks (weeks 16 and 24) across a 24-week period in total. All patients underwent a complete ophthalmic examination, including measurement of Early Treatment Diabetic Retinopathy Study (ETDRS) best-corrected visual acuity (BCVA), intraocular pressure assessment, adverse event monitoring, and spectral-domain optical coherence tomography at every visit. Baseline fluorescein angiography and indocyanine green angiography also were performed. MAIN OUTCOME MEASURES: Outcomes assessed included proportions of patients with a gain or loss of more than 5 ETDRS letters and a decrease or increase in central retinal thickness (CRT) of more than 150 MUm at week 24 compared with baseline, change in mean BCVA and CRT between baseline and week 24, and descriptive safety data. RESULTS: The BCVA improved and CRT was reduced significantly at all follow-up visits compared with baseline (P < 0.001), with a mean improvement of 6.9 letters of BCVA and a decrease of 89.4 MUm in CRT at week 24. Spacing of injections from every 4 weeks to 8 weeks resulted in an increase of 37.4 MUm in CRT (P < 0.001); however, this was not correlated with a significant change in vision. There was 1 (2%) patient who lost more than 5 ETDRS letters, and 27 (55%) patients who gained more than 5 letters. Two (4%) patients had a more than 150 MUm increase in CRT at week 24, and 10 (20%) patients showed a decrease in CRT of more than 150 MUm. CONCLUSIONS: Intravitreal aflibercept is effective in previously treatment-resistant neovascular AMD. Further follow-up is required to determine whether these improvements can be maintained. PMID- 24144451 TI - Involvement of LCA5 in Leber congenital amaurosis and retinitis pigmentosa in the Spanish population. AB - OBJECTIVE: We aimed to identify novel genetic defects in the LCA5 gene underlying Leber congenital amaurosis (LCA) in the Spanish population and to describe the associated phenotype. DESIGN: Case series. PARTICIPANTS: A cohort of 217 unrelated Spanish families affected by autosomal recessive or isolated retinal dystrophy, that is, 79 families with LCA and 138 families with early-onset retinitis pigmentosa (EORP). A total of 100 healthy, unrelated Spanish individuals were screened as controls. METHODS: High-resolution homozygosity mapping was performed in 44 patients with LCA using genome-wide single nucleotide polymorphism (SNP) microarrays. Direct sequencing of the LCA5 gene was performed in 5 patients who showed homozygous regions at chromosome 6 and in 173 unrelated individuals with LCA or EORP. The ophthalmic history of 8 patients carrying LCA5 mutations was reviewed and additional examinations were performed, including electroretinography (ERG), optical coherence tomography (OCT), and fundus photography. MAIN OUTCOME MEASURES: Single nucleotide polymorphism genotyping, identity-by-descent (IBD) regions, LCA5 mutations, best-corrected visual acuity, visual field assessments, fundus appearance, ERG, and OCT findings. RESULTS: Four novel and 2 previously reported LCA5 mutations have been identified in 6 unrelated families with LCA by homozygosity mapping or Sanger sequencing. Thus, LCA5 mutations have a frequency of 7.6% in the Spanish population. However, no LCA5 mutations were found in 138 patients with EORP. Although most of the identified LCA5 mutations led to a truncated protein, a likely pathogenic missense variant was identified for the first time as a cause of LCA, segregating in 2 families. We also have characterized a novel splicing site mutation at the RNA level, demonstrating that the mutant LCA5 transcript was absent in a patient. All patients carrying LCA5 mutations presented nystagmus, night blindness, and progressive loss of visual acuity and visual field leading to blindness toward the third decade of life. Fundoscopy showed fundus features of pigmentary retinopathy with atrophic macular lesions. CONCLUSIONS: This work reveals a higher frequency of LCA5 mutations in a Spanish LCA cohort than in other populations. This study established gene-specific frequencies and the underlying phenotype of LCA5 mutations in the Spanish population. PMID- 24144452 TI - Defects of the lamina cribrosa in eyes with localized retinal nerve fiber layer loss. AB - OBJECTIVE: To determine whether focal abnormalities of the lamina cribrosa (LC) are present in glaucomatous eyes with localized retinal nerve fiber layer (RNFL) defects. DESIGN: Cross-sectional, observational study. PARTICIPANTS: We analyzed 20 eyes of 14 subjects with localized RNFL defects detected by masked grading of stereophotographs and 40 eyes of 25 age-matched healthy subjects recruited from the Diagnostic Innovations in Glaucoma Study at the University of California, San Diego. METHODS: All eyes had stereoscopic optic disc photography and in vivo LC imaging using enhanced depth imaging optical coherence tomography (EDI-OCT). Two masked graders identified focal LC defects defined by a standardized protocol using 48 radial scan EDI-OCT images. The kappa coefficient was calculated as a measure of the reliability of interobserver agreement. MAIN OUTCOME MEASURES: The number of focal LC defects and the relationship between the location of LC defects and the location of localized RNFL defects. RESULTS: Of 20 eyes with a localized RNFL defect, 15 (75%) had >=1 LC defect compared with only 1 of 40 healthy eyes (3%). There were 13 eyes with localized RNFL defects that had 1 LC defect, 1 eye with 2 LC defects, and 1eye with 3 LC defects. The largest area LC defect was present in a radial line EDI-OCT scan corresponding with a localized RNFL defect in 13 of 15 eyes (87%). There was good agreement between graders as to whether an eye had an LC defect (kappa = 0.87; 95% confidence interval [CI], 0.73-1.00; P<0.001) and the location of the largest defect (kappa = 0.72; 95% CI, 0.44-1.00; P<0.001). CONCLUSIONS: Focal defects of the LC were frequently visible in glaucomatous eyes with localized RNFL defects. Focal abnormalities of the LC may be associated with focal retinal nerve fiber damage. PMID- 24144454 TI - Successful transplantation of in vitro expanded human cadaver corneal endothelial precursor cells on to a cadaver bovine's eye using a nanocomposite gel sheet. AB - PURPOSE: In vitro expansion of human corneal endothelial precursor (HCEP) cells has been reported via production of cell aggregated spheres. However, to translate this procedure in human patients warrants maintaining the position of the eyeballs facing down for 36 h, which is not feasible. In this study, we report a method using a nanocomposite (NC) gel sheet to accomplish the integration of HCEP cells to the endothelium of cadaver bovine's eyes. MATERIALS AND METHODS: HCEP cells were isolated from the corneal endothelium of a cadaver human eye and then expanded using a thermoreversible gelation polymer (TGP) as reported earlier. For the study, three cadaver bovine eyes were used. The NC gel sheets were inserted into the bovine eyes', aligned and suture-fixed in position under the host endothelium. HCEP cells previously expanded in the TGP were harvested and injected using a 26-gauge syringe between the endothelium and the NC gel sheet. The eyes were left undisturbed for three hours following which the NC gel sheets were gently removed. The corneas were harvested and subjected to histopathological studies. RESULTS: Histopathological studies showed that all the three corneas used for NC gel sheet implantation showed the presence of engrafted HCEP cells, seen as multi-layered cells over the native endothelium of the bovine cornea. Examination of the NC gel sheets used for implantation showed that only very few corneal endothelial cells remained on the sheets amounting to what could be considered negligible. CONCLUSION: The use of the NC gel sheet makes HCEP cell transplantation feasible for human patients. Further in vitro basic studies followed by translational studies are necessary to bring this method for clinical application in appropriate indications. PMID- 24144453 TI - The role of topical antibiotic prophylaxis to prevent endophthalmitis after intravitreal injection. AB - OBJECTIVE: To compare the incidence of endophthalmitis after intravitreal injection with and without topical postinjection antibiotic prophylaxis. DESIGN: Retrospective case-control study. PARTICIPANTS: All patients treated with intravitreal injection of ranibizumab, bevacizumab, or aflibercept for a variety of retinal vascular diseases at a single, large retina practice between January 1, 2009, and October 1, 2012, were included. METHODS: The total numbers of patients and injections were determined from a review of billing code and practice management records. Endophthalmitis cases were determined from billing records and from an infection log. All cases of endophthalmitis were confirmed with chart review. A 28-month period when topical antibiotics were prescribed after intravitreal injection was compared with a 9-month period when topical antibiotics were not prescribed. Patients treated during an 8-month transition period were excluded to allow for the conversion of antibiotic prescription practices. MAIN OUTCOME MEASURES: Incidence of endophthalmitis, visual acuity outcomes, and microbial spectrum. RESULTS: During the study period, a total of 117 171 intravitreal injections were performed (57 654 injections during the topical antibiotic period, 24 617 during the transition period, and 34 900 during the no-antibiotic period), with a total of 44 cases of suspected endophthalmitis (0.038%; 1 in 2663 injections), 17 of which showed culture-positive results (0.015%; 1 in 6892 injections). During the 28-month topical antibiotic period, there were 28 cases of suspected endophthalmitis (0.049%; 1 in 2059 injections), 10 of which showed culture-positive results (0.017%; 1 in 5765 injections). During the 9-month no-antibiotic period, there were 11 cases of suspected endophthalmitis (0.032%; 1 in 3173 injections), 4 of which showed culture positive results (0.011%; 1 in 8725 injections). Topical antibiotic use was associated with a trend toward increased risk of suspected endophthalmitis (odds ratio [OR], 1.54; 95% confidence interval [CI], 0.77-3.10) and culture-positive endophthalmitis (OR, 1.51; 95% CI, 0.47-4.83). CONCLUSIONS: The incidence of endophthalmitis after intravitreal injection is low. Using postinjection topical antibiotic drops does not reduce the risk of endophthalmitis developing and is associated with a trend toward higher incidence of endophthalmitis. PMID- 24144455 TI - Hollow carbon-nanotube/carbon-nanofiber hybrid anodes for Li-ion batteries. AB - By a novel in situ chemical vapor deposition, activated N-doped hollow carbon nanotube/carbon-nanofiber composites are prepared having a superhigh specific Brunauer-Emmett-Teller (BET) surface area of 1840 m(2) g(-1) and a total pore volume of 1.21 m(3) g(-1). As an anode, this material has a reversible capacity of ~1150 mAh g(-1) at 0.1 A g(-1) (0.27 C) after 70 cycles. At 8 A g(-1) (21.5 C), a capacity of ~320 mAh g(-1) fades less than 20% after 3500 cycles, which makes it a superior anode material for a Li-ion battery. PMID- 24144456 TI - Associations between TRAF1-C5 gene polymorphisms and rheumatoid arthritis: a meta analysis. AB - OBJECTIVE: The aim of this study is to determine whether tumor necrosis factor receptor-associated factor 1-complement 5 (TRAF1-C5) polymorphisms are associated with susceptibility to rheumatoid arthritis (RA) in different populations. METHODS: We conducted a meta-analysis of associations between the TRAF1-C5 polymorphisms and RA susceptibility. RESULTS: A total of 24 comparative studies were included in this meta-analysis, including 22,682 patients with RA and 23,493 controls. The meta-analysis showed an association between the second allele of rs10818488 and RA in Europeans, but not in Asians (OR 1.229, 95% CI 1.094-1.381, p = 0.001; OR 1.060, 95% CI 0.930-1.335, p = 0.092). The meta-analysis also indicated an association between the second allele of rs3761847 and RA in Europeans, but not in Asians (OR 1.156, 95% CI 1.006-1.327, p = 0.041; OR 1.049, 95% CI 0.952-1.156, p = 0.333). The meta-analysis revealed an association between the second allele of the rs2900180 and rs10760130 polymorphisms and RA risk in Europeans (OR 1.224, 95% CI 1.065-1.405, p = 0.004; OR 1.072, 95% CI 1.002-1.147, p = 0.042). CONCLUSIONS: This meta-analysis confirms that the TRAF1-C5 rs10818488, rs3761847, rs2900180 and rs10760130 polymorphisms are associated with RA susceptibility in Europeans. PMID- 24144457 TI - Complex 5d magnetism in a novel S = 1/2 trimer system, the 12L hexagonal perovskite Ba4BiIr3O12. AB - The 12L hexagonal perovskite Ba4BiIr3O12 has been synthesized for the first time and characterized using high-resolution neutron and synchrotron X-ray diffraction as well as physical properties measurements. The structure contains Ir3O12 linear face-sharing octahedral trimer units, bridged by corner-sharing BiO6 octahedra. The average electronic configurations of Ir and Bi are shown to be +4(d(5)) and +4(s(1)), respectively, the same as for the S = 1/2 dimer system Ba3BiIr2O9, which undergoes a spin-gap opening with a strong magnetoelastic effect at T* = 74 K. Anomalies in magnetic susceptibility, heat capacity, electrical resistivity, and unit cell parameters indeed reveal an analogous effect at T* ~ 215 K in Ba4BiIr3O12. However, the transition is not accompanied by the opening of a gap in spin excitation spectrum, because antiferromagnetic coupling among S = 1/2 Ir(4+) (d(5)) cations leads to the formation of a S = 1/2 doublet within the trimers, vs S = 0 singlets within dimers. The change in magnetic state of the trimers at T* leads to a structural distortion, the energy of which is overcompensated for by the formation of S = 1/2 doublets. Extending this insight to the dimer system Ba3BiIr2O9 sheds new light on the more pronounced low temperature anomalies observed for that compound. PMID- 24144458 TI - The role of abdominal ultrasound in the diagnosis of typhoid fever: an observational study. AB - OBJECTIVES: To study the usefulness of abdominal ultrasound in the diagnosis of typhoid fever and to determine the common ultrasound findings early in the course of the disease. METHODS: Abdominal ultrasound examination was performed within the first week of initiation of symptoms in 350 cases with clinical diagnosis of typhoid fever. Subsequent ultrasound follow-up examination was done 15 days later (beginning of the third week). All the patients proved to have positive Widal test and Sallmonella culture. The study was performed in Erbil-Iraq from the period January 1993 to October 2010. RESULTS: The following ultrasound findings were reported: hepatomegaly (31.4%), prominent intrahepatic bile ducts (64.85%), splenomegaly (100%), mesenteric lymphadenopathy (42.85%), bowel wall thickening (35.71%), acalculous cholecystitis (16.28%), perforations (1.14%), and ascites in (3.4%). CONCLUSION: The current study showed that the findings are typical enough to justify initiation of treatment for typhoid fever when serology is equivocal and culture is negative, and is fairly safe to say that normal ultrasound examination early in the course of febrile illness rules out typhoid fever. PMID- 24144459 TI - Sex and time to diagnosis in systemic sclerosis: an updated analysis of 1,129 patients from the Canadian scleroderma research group registry. AB - OBJECTIVES: A previous study found that time to diagnosis was significantly longer from onset of Raynaud's phenomenon for women compared to men with diffuse systemic sclerosis (SSc) and that, in limited SSc, it was more than twice as long for women than men. That study was limited, however, by the small number of men in disease subtype subgroups. The objective of the present study was to investigate the association of sex with time to diagnosis of SSc using a substantially larger patient sample. METHODS: Association between sex and time to diagnosis was assessed overall and stratified based on diffuse versus limited disease using Kaplan-Meier curves and Cox proportional hazards models. RESULTS: There were 1,129 patients in the study (median age=56.0 years; 978 [86.6%] women). Time to diagnosis was significantly longer for women (median=1.1 years) than men (median 0.8= years; p=0.037) with diffuse SSc following onset of Raynaud's phenomenon. There were no significant or substantive sex differences in time to diagnosis after Raynaud's onset in limited SSc or from onset of first non Raynaud's disease manifestation in diffuse or limited SSc. CONCLUSIONS: Time to diagnosis was significantly longer for women compared to men with diffuse SSc following onset of Raynaud's phenomenon, but the difference was small and unlikely to be clinically significant. There were no differences in time to diagnosis following Raynaud's onset in limited disease or following onset of first non-Raynaud's disease manifestation in diffuse or limited disease. Overall, sex does not appear to influence time to diagnosis meaningfully. PMID- 24144460 TI - Correlation of Nav1.8 and Nav1.9 sodium channel expression with neuropathic pain in human subjects with lingual nerve neuromas. AB - BACKGROUND: Voltage-gated sodium channels Nav1.8 and Nav1.9 are expressed preferentially in small diameter sensory neurons, and are thought to play a role in the generation of ectopic activity in neuronal cell bodies and/or their axons following peripheral nerve injury. The expression of Nav1.8 and Nav1.9 has been quantified in human lingual nerves that have been previously injured inadvertently during lower third molar removal, and any correlation between the expression of these ion channels and the presence or absence of dysaesthesia investigated. RESULTS: Immunohistochemical processing and quantitative image analysis revealed that Nav1.8 and Nav1.9 were expressed in human lingual nerve neuromas from patients with or without symptoms of dysaesthesia. The level of Nav1.8 expression was significantly higher in patients reporting pain compared with no pain, and a significant positive correlation was observed between levels of Nav1.8 expression and VAS scores for the symptom of tingling. No significant differences were recorded in the level of expression of Nav1.9 between patients with or without pain. CONCLUSIONS: These results demonstrate that Nav1.8 and Nav1.9 are present in human lingual nerve neuromas, with significant correlations between the level of expression of Nav1.8 and symptoms of pain. These data provide further evidence that changes in expression of Nav1.8 are important in the development and/or maintenance of nerve injury-induced pain, and suggest that Nav1.8 may be a potential therapeutic target. PMID- 24144461 TI - Reinventing the technique of tongue-lip adhesion in Pierre Robin sequence. PMID- 24144462 TI - Factors influencing on the bioaccessibility of polybrominated diphenyl ethers in size-specific dust from air conditioner filters. AB - Size-specific concentrations and bioaccessibility of polybrominated diphenyl ethers (PBDEs) in dust from air conditioner filters were measured, and the factors influencing the PBDE bioaccessibility were determined. Generally, the PBDE concentrations increased with decreasing dust particle size, and BDE209 (deca-BDE) was generally the predominant congener. The bioaccessibility ranged from 20.3% to 50.8% for tri- to hepta-BDEs, and from 5.1% to 13.9% for BDE209 in dust fractions of varied particle size. The bioaccessibility of most PBDE congeners decreased with increasing dust particle size. The way of being of PBDE (adsorbed to dust surface or incorporated into polymers) in dust significantly influenced the bioaccessibility. There was a significant negative correlation between the tri- to hepta-BDE bioaccessibility and organic matter (OM) contents in dust. Furthermore, tri- to hepta-BDE bioaccessibility increased with increasing polarity of OMs, while with decreasing aromaticity of OMs. The tri- to hepta-BDE bioaccessibility significantly positively correlated with the surface areas and pore volumes of dust. Using multiple linear regression analysis, it was found that the OM contents and pore volumes of dust were the most important factors to influence the tri- to hepta-BDE bioaccessibility and they could be used to estimate the bioaccessibility of tri- to hepta-BDEs according to the following equation: bioaccessibility (%)=45.05-0.49 * OM%+1.79 * pore volume. However, BDE209 bioaccessibility did not correlate to any of these factors. PMID- 24144463 TI - Photoelectrocatalytic degradation of carbamazepine using Ti/TiO2 nanostructured electrodes deposited by means of a pulsed laser deposition process. AB - The objective of the present work is to evaluate the potential of photoelectrocatalytic oxidation (PECO) process using Ti/TiO2 for the degradation of carbamazepine (CBZ). Ti/TiO2 prepared by pulsed laser deposition (PLD) has been used as a photo-catalyst in a photoelectrocatalytic cell. The PLD TiO2 coatings were found to be of anatase structure consisting of nanocrystallites of approximately 15nm in diameter. Factorial and central and extreme composite design methodologies were successively employed to define the optimal operating conditions for CBZ degradation. Several factors such as current intensity, treatment time, pollutant concentration and cathode material were investigated. Using a 2(4) factorial matrix, the best performance for CBZ degradation (53.5%) was obtained at a current intensity of 0.1 A during 120min of treatment time and when the vitreous carbon (VC) was used at the cathode in the presence of 10mgL( 1) of CBZ. Treatment time and pollutant concentration were found to be very meaningful for CBZ removal. The PECO process applied under optimal conditions (at current intensity of 0.3A during 120min in the presence of 10mgL(-1) of CBZ with VC at the cathode) is able to oxidize around 73.5% +/-2.8% of CBZ and to ensure 21.2%+/-7.7% of mineralization. During PECO process, CBZ was mainly transformed to acridine and anthranilic acid. Microtox biotests (Vibrio fisheri) showed that the treated - effluent was not toxic. The pseudo-second order kinetic model (k2=6*10(-4)Lmg(-1)min(-1)) described very well the oxidation of CBZ. PMID- 24144464 TI - Soil stabilisation using AMD sludge, compost and lignite: TCLP leachability and continuous acid leaching. AB - Utilising locally available industrial by-products for in situ metal stabilisation presents a low-cost remediation approach for contaminated soil. This study explored the potential use of inorganic (acid mine drainage (AMD) sludge and zero-valent iron) and carbonaceous materials (green waste compost, manure compost, and lignite) for minimising the environmental risks of As and Cu at a timber treatment site. After 9-month soil incubation, significant sequestration of As and Cu in soil solution was accomplished by AMD sludge, on which adsorption and co-precipitation could take place. The efficacy of AMD sludge was comparable to that of zero-valent iron. There was marginal benefit of adding carbonaceous materials. However, in a moderately aggressive environment (Toxicity Characteristic Leaching Procedure), AMD sludge only suppressed the leachability of As but not Cu. Therefore, the provision of compost and lignite augmented the simultaneous reduction of Cu leachability, probably via surface complexation with oxygen-containing functional groups. Under continuous acid leaching in column experiments, combined application of AMD sludge with compost proved more effective than AMD sludge with lignite. This was possibly attributed to the larger amount of dissolved organic matter with aromatic moieties from lignite, which may enhance Cu and As mobility. Nevertheless, care should be taken to mitigate ecological impact associated with short-term substantial Ca release and continuous release of Al at a moderate level under acid leaching. This study also articulated the engineering implications and provided recommendations for field deployment, material processing, and assessment framework to ensure an environmentally sound application of reactive materials. PMID- 24144465 TI - Consequences of using pooled versus individual samples for designing environmental monitoring sampling strategies. AB - Choosing an appropriate sampling strategy for chemical analysis within environmental monitoring includes the important decision of whether to sample and store individual or pooled samples. This choice impacts on future analyses from Environmental Specimen Bank samples. A number of advantages exist to support using either individual or pooled samples for temporal trend studies. However, it is important to know the total and analytical variance to be able to design the best sampling strategy. Statistical power in temporal or spatial studies is determined by the random/unexplained sample variation. The relationship between chemical analytical error and other sources of variation, as well as the cost for collection, preparation of samples and chemical analysis, will determine the number of individuals in each pool, and the number of pools that should be analysed to achieve high cost efficiency and good statistical power. Various scenarios of different numbers of individual samples, different numbers of pooled samples containing various numbers of individual specimens, the relationships between chemical analytical error and other sources of sample variance, have been compared by simulating random sampling from computer generated populations using realistic measures of variation from ongoing monitoring activities. These results offer guidance in the design of a cost-efficient, statistically sound sampling strategy. PMID- 24144466 TI - PBDEs, PCBs and organochlorine pesticides distribution in edible fish from Negro River basin, Argentinean Patagonia. AB - DDTs, endosulfans, HCHs, chlordanes, PCBs and PBDEs levels were determined in different tissues of patagonian silverside (Odontesthes hatcheri) from the Upper (UV), Middle (MV) and Lower (LV) valleys of the Negro River, Argentina. Results showed a direct relation between pollutant levels in fish and land uses along the basin. All tissues showed decreasing levels from headwaters (UV) to downstream (LV). A significant predominance of organochlorine pesticides (306-3,449 ng g(-1) lipid) followed by SigmaPCBs (65-3,102 ng g(-1) lipid) and SigmaPBDEs (22-870 ng g(-1) lipid) was observed in all tissues and valleys, suggesting agriculture as the main source of pollutants in this basin. Pesticides were dominated by DDTs (90% pp'-DDE) followed by endosulfan (alpha->beta->sulfate), gamma-HCH and gamma chlordane showing the prevalence of legacy compounds. Endosulfan levels point out the current use of technical endosulfan in the surrounding areas. The highest PCBs and PBDEs concentrations observed in fish from UV were associated to hydroelectric power plants and industries established upstream. PCB fingerprint presented a prevailing contribution of hexa-CBs (66 +/- 7%) and penta-CBs (27 +/- 9%), with a similar composition to Aroclor 1254-1260. The predominance of BDE-47 (69 +/- 17%) among PBDEs, followed by BDE-100 and BDE-99, suggests possible debromination processes. These results were similar to worldwide trends found in fishes and environmental compartments. PCBs levels in silverside muscles along the Negro River exceeded the maximum limits for safe consumption, suggesting a possible human health risk related to silverside ingest. Therefore, a continued long-term monitoring of organic contaminants in fishes is needed in order to assess the potential risk for human health. PMID- 24144467 TI - Tinbergen's four questions: an appreciation and an update. AB - This year is the 50th anniversary of Tinbergen's (1963) article 'On aims and methods of ethology', where he first outlined the four 'major problems of biology'. The classification of the four problems, or questions, is one of Tinbergen's most enduring legacies, and it remains as valuable today as 50 years ago in highlighting the value of a comprehensive, multifaceted understanding of a characteristic, with answers to each question providing complementary insights. Nonetheless, much has changed in the intervening years, and new data call for a more nuanced application of Tinbergen's framework. The anniversary would seem a suitable opportunity to reflect on the four questions and evaluate the scientific work that they encourage. PMID- 24144468 TI - Preparation of self assembled sodium oleate monolayer on mild steel and its corrosion inhibition behavior in saline water. AB - A self assembled monolayer (SAM) of sodium oleate was generated on mild steel by the dip coating method. Formation of the SAM on mild steel was examined using Infrared Reflection Absorption Spectroscopy (IRRAS) and contact angle measurements. The chemical and anticorrosive properties of the SAM were analyzed using different techniques. IRRAS and water contact angle data revealed the crystallinity and chemical stability of the SAM modified mild steel. The electrochemical measurements showed that the mild steel with the sodium oleate derived SAM exhibited better corrosion resistance in saline water. The effect of temperature and pH on the SAM formation and its anti corrosion ability was explored. PMID- 24144469 TI - Effectiveness of 2+1 PCV7 vaccination schedules in children under 2 years: a meta analysis of impact studies. AB - Although a case control study suggested high effectiveness of the 2+1 PCV-7 vaccination, schedule against invasive pneumococcal disease (IPD) in children the results of impact studies in, different countries yield considerable differences in the magnitude of the effects. A systematic, literature review was conducted to identify all relevant studies on IPD incidence reduction after onset, of PCV7 vaccination programmes in children younger than 2 years of age given in the 2+1 schedule. The incidence rate ratio between IPI incidences for vaccine serotypes before and after beginning of the, vaccination programme was calculated for each study. Heterogeneity was assessed and attempts to, identify causes for heterogeneity were made. In the literature search 4 studies which fulfilled inclusion, criteria were identified. The summary estimates yielded an IRR 0.10 [0.04; 0.30] suggesting a 90%, incidence reduction. Heterogeneity was high with I(2)=93%. Heterogeneity might be explained by, differences in vaccination rates, the way vaccination rates were assessed, matching of the periods of, vaccination and case ascertainment, time between onset of the vaccination programme and onset of, case ascertainment during the vaccination period and the length of the observation period after onset, of the vaccination programme. A study which started 3 years after onset of the vaccination programme, with vaccination rates >=80% throughout the ascertainment period of the incidence rates reported a, 98% reduction in the incidence rates. A meta-analysis on IRR studies on reductions of the IPD, incidence in children <2 years of age suggested high effectiveness of the 2+1 vaccination schedule for PCV 7. PMID- 24144470 TI - Use of near-real-time medical claims data to generate timely vaccine coverage estimates in the US: the dynamics of PCV13 vaccine uptake. AB - BACKGROUND: Vaccine coverage estimates lag by years in the US. Commercially available medical claims databases contain timely records of childhood vaccinations given in physician offices. We used such data to track the replacement of the 7-valent pneumococcal conjugate vaccine (PCV7) by PCV13, a new vaccine active against 6 additional serotypes, starting in March 2010. METHODS: We developed an age cohort model to compute vaccination coverage over time. We used age-stratified, national projections of monthly PCV7 and PCV13 doses administered to children <5 years based on physicians' office claims, January 2008-May 2012. We assumed doses were given on schedule, and tracked cumulative numbers of doses given to aging monthly cohorts to estimate the percentage of children fully PCV13-immunized. To account for children uninsured or in the Vaccines for Children program, estimates were projected using National Immunization Survey coverage data. RESULTS: PCV7 was phased out by June 2010. By March 2012, 82% of children 6-23 months were fully immunized with PCV13 and 42% of toddlers aged 15-59 months had received a catch-up PCV13 dose. For children aged 6-59 months, protective PCV13 coverage levels reached 33% and 56% by March 2011 and 2012, respectively, and were projected to reach 88% by March 2014. Our estimates for children aged 0-59 and 24-59 months are consistent with CDC's Immunization Information System sentinel sites data for 2011-2012. CONCLUSIONS: By using a simple analytic approach to compute vaccine coverage in aging cohorts from claims data, we show that PCV13 coverage rose rapidly as the PCV7 program was replaced. These estimates, validated against a CDC sentinel surveillance system in 8 states, should enable early documentation of the PCV13 impact on pneumococcal disease in the US. Moreover, they demonstrate the feasibility of tracking uptake patterns in near real-time even with simple summary counts of medical claims data. PMID- 24144471 TI - Characterization of W-Beijing isolates of Mycobacterium tuberculosis from the Western Cape. AB - The purpose of this simple study was to characterize a panel of clinical isolates of Mycobacterium tuberculosis obtained from the Western Cape region of South Africa where new clinical vaccine trials are beginning, in the low dose aerosol guinea pig infection model. Most of the strains tested grew well in the lungs and other organs of these animals, and in most cases gave rise to moderate to very severe lung damage. We further observed that the current BCG vaccine was highly protective against two randomly selected strains, giving rise to significantly prolonged survival. PMID- 24144472 TI - Safety and immunogenicity of an adjuvanted protein therapeutic HIV-1 vaccine in subjects with HIV-1 infection: a randomised placebo-controlled study. AB - The human immunodeficiency virus type-1 (HIV-1) vaccine candidate F4/AS01 has previously been shown to induce potent and persistent polyfunctional CD4(+) T cell responses in HIV-1-seronegative volunteers. This placebo-controlled study evaluated two doses of F4/AS01 1-month apart in antiretroviral treatment (ART) experienced and ART-naive HIV-1-infected subjects (1:1 randomisation in each cohort). Safety, HIV-1-specific CD4(+) and CD8(+) T-cell responses, absolute CD4(+) T-cell counts and HIV-1 viral load were monitored for 12 months post vaccination. Reactogenicity was clinically acceptable and no vaccine-related serious adverse events were reported. The frequency of HIV-1-specific CD4(+) T cells 2 weeks post-dose 2 was significantly higher in the vaccine group than in the placebo group in both cohorts (p<0.05). Vaccine-induced HIV-1-specific CD4(+) T-cells exhibited a polyfunctional phenotype, expressing at least CD40L and IL-2. No increase in HIV-1-specific CD8(+) T-cells or change in CD8(+) T-cell activation marker expression profile was detected. Absolute CD4(+) T-cell counts were variable over time in both cohorts. Viral load remained suppressed in ART experienced subjects. In ART-naive subjects, a transient reduction in viral load from baseline was observed 2 weeks after the second F4/AS01 dose, which was concurrent with a higher frequency of HIV-1-specific CD4(+) T-cells expressing at least IL-2 in this cohort. In conclusion, F4/AS01 showed a clinically acceptable reactogenicity and safety profile, and induced polyfunctional HIV-1-specific CD4(+) T-cell responses in ART-experienced and ART-naive subjects. These findings support further clinical investigation of F4/AS01 as a potential HIV-1 vaccine for therapeutic use in individuals with HIV-1 infection. PMID- 24144473 TI - Increased risk of anaphylaxis following administration of 2009 AS03-adjuvanted monovalent pandemic A/H1N1 (H1N1pdm09) vaccine. AB - BACKGROUND: Anaphylaxis after trivalent influenza vaccination is typically reported at a rate of <1 per million doses. In Quebec, Canada, anaphylaxis following administration of the monovalent AS03-adjuvanted H1N1pdm09 vaccine was reported through passive surveillance at a rate of 8 per million doses administered. This was 20 times higher than the reporting rate for non-adjuvanted trivalent vaccines administered during the six previous seasons. However, adequate estimation of the incidence of anaphylaxis is hindered by wide variations in definitions and diagnosis. METHODS: Using the Brighton collaboration case definition of anaphylaxis, all cases with allergic symptoms (AS) reported to public health were reviewed to estimate the incidence of anaphylaxis following AS03-adjuvanted H1N1pdm09 vaccine. RESULTS: Among 752 reports of allergic symptoms, 33 were initially reported as anaphylaxis of which 20/33 (60%) met the Brighton definition (19/20 with certainty levels 1 or 2). A total of 38 additional cases with onset within 1h of vaccination also met the Brighton definition of anaphylaxis (27 (71%) with certainty levels 1 or 2). The 58 cases meeting Brighton Level 1 or 2 criteria for anaphylaxis represent a 75% increase over the 33 passively reported and an incidence of 13 per million doses administered. CONCLUSION: A substantial number of patients with early-onset allergic symptoms met the most specific levels of the Brighton case definition but were not reported as anaphylaxis. Based on this specific case definition, the incidence of anaphylaxis after AS03-adjuvanted H1N1pdm09 vaccine substantially exceeded that reported with seasonal influenza vaccines, a signal that warrants better understanding. PMID- 24144474 TI - Recombinant duck enteritis virus expressing the HA gene from goose H5 subtype avian influenza virus. AB - The duck enteritis virus (DEV) may be a promising candidate viral vector for an aquatic poultry vaccination that can protect against multiple pathogens because it has a very large genome and a narrow host range. Recently, we described two DEV recombinants that contained deletions of the viral US2 or gIgE genes. The hemagglutinin (HA) gene of an H5N1-type highly pathogenic avian influenza virus (HPAIV) of goose origin was inserted into the deletion sites to construct two rDEVs expressing the AIV HA antigen. The resulting rDEV-DeltagIgE-HA or rDEV DeltaUS2-HA recombinant DEV viruses were used to infect duck embryo fibroblasts. Reverse transcription PCR, immunofluorescence and western blot analysis results indicated that rDEV-DeltagIgE-HA and rDEV-DeltaUS2-HA were successfully expressed in duck embryo fibroblasts (DEFs). To investigate whether the HA gene could be stably maintained in the recombinant viruses, the viruses were passaged in DEFs 18 times. The HA gene in both recombinants could be detected by PCR amplification. The immunized four-week-old ducks induced specific antibodies against DEV and AIV HA and were protected against challenge infections with DEV AV1221 viruses. PMID- 24144475 TI - Recombinant Ehrlichia P29 protein induces a protective immune response in a mouse model of ehrlichiosis. AB - Ehrlichioses are emerging tick-borne bacterial diseases of humans and animals for which no vaccines are available. The diseases are caused by obligately intracellular bacteria belonging to the genus Ehrlichia. Several immunoreactive proteins of ehrlichiae have been identified based on their reactivity with immune sera from human patients and animals. These include the major outer membrane proteins, ankyrin repeat proteins and tandem repeat proteins (TRP). Polyclonal antibodies directed against the tandem repeats (TRs) of Ehrlichia chaffeensis TRP32, TRP47 and TRP120 have been shown to provide protection in mice. In the present study, we evaluated E. muris P29, which is the ortholog of E. chaffeensis TRP47 and E. canis TRP36, as a subunit vaccine in a mouse model of ehrlichiosis. Our study indicated that unlike E. chaffeensis TRP47 and E. canis TRP36, orthologs of E. muris (P29) and E. muris-like agent (EMLA) do not contain tandem repeats. Immunization of mice with recombinant E. muris P29 induced significant protection against a challenge infection. The protection induced by E. muris P29 was associated with induction of strong antibody responses. In contrast to development of P29-specific IgG antibodies following immunization, development of P29-specific IgG antibodies, but not IgM antibodies, was impaired during persistent E. muris infection. Furthermore, our study indicated that CD4+ T cells target P29 during E. muris infection and differentiate into IFN-gamma-producing Th1 effector/memory cells. In conclusion, our study indicated that orthologs of E. muris P29 showed considerable variation in the central tandem repeat region among different species, induction of P29-specific IgG antibody response was impaired during persistent E. muris infection, and rP29 induced protective immune responses. PMID- 24144476 TI - DNA vaccine expressing the non-structural proteins of hepatitis C virus diminishes the expression of HCV proteins in a mouse model. AB - Most of the people infected with hepatitis C virus (HCV) develop chronic hepatitis, which in some cases progresses to cirrhosis and ultimately to hepatocellular carcinoma. Although various immunotherapies against the progressive disease status of HCV infection have been studied, a preventive or therapeutic vaccine against this pathogen is still not available. In this study, we constructed a DNA vaccine expressing an HCV structural protein (CN2), non structural protein (N25) or the empty plasmid DNA as a control and evaluated their efficacy as a candidate HCV vaccine in C57BL/6 and novel genetically modified HCV infection model (HCV-Tg) mice. Strong cellular immune responses to several HCV structural and non-structural proteins, characterized by cytotoxicity and interferon-gamma (IFN-gamma) production, were observed in CN2 or N25 DNA vaccine-immunized C57BL/6 mice but not in empty plasmid DNA-administered mice. The therapeutic effects of these DNA vaccines were also examined in HCV-Tg mice that conditionally express HCV proteins in their liver. Though a reduction in cellular immune responses was observed in HCV-Tg mice, there was a significant decrease in the expression of HCV protein in mice administered the N25 DNA vaccine but not in mice administered the empty plasmid DNA. Moreover, both CD8(+) and CD4(+) T cells were required for the decrease of HCV protein in the liver. We found that the N25 DNA vaccine improved pathological changes in the liver compared to the empty plasmid DNA. Thus, these DNA vaccines, especially that expressing the non-structural protein gene, may be an alternative approach for treatment of individuals chronically infected with HCV. PMID- 24144477 TI - Comparison of the immune responses induced by soluble and particulate Plasmodium vivax circumsporozoite vaccine candidates formulated in AS01 in rhesus macaques. AB - We have designed a pre-erythrocytic vaccine candidate based on the Plasmodium vivax circumsporozoite (CSV) protein, which includes its N- and C-terminal parts and a truncated region containing repeat sequences from both the VK210 and the VK247 P. vivax subtypes. Two versions of this vaccine candidate were made: a soluble recombinant protein expressed in Escherichia coli, designated VMP001 and a particulate antigen expressed in Saccharomyces cerevisiae, designated CSV-S,S. The latter is composed of CSV-S, a fusion protein between VMP001 and hepatitis B surface antigen (HBsAg), and free HBsAg co-expressed in yeast and self-assembling into mixed particles. Both antigen versions, adjuvanted with AS01, were shown to be immunogenic in rhesus monkeys. CSV-S,S/AS01 induced higher levels of VMP001 specific antibodies than did VMP001/AS01. Antibody responses against the N- and C terminal regions of CSV and the VK210 repeat motif were of a similar magnitude following immunization with either the soluble or the particulate antigen. However, antibodies against the AGDR region, a potentially protective B cell epitope, were only detected after immunization with CSV-S,S. Analysis of the induced CD4(+) T cells highlighted different cytokine profiles depending on the antigen form. These results warrant further clinical evaluation of these two vaccine candidates to assess the added value of a particulate versus soluble form of CSV, in terms of both immunogenicity and protective efficacy. PMID- 24144478 TI - A replication-incompetent influenza virus bearing the HN glycoprotein of human parainfluenza virus as a bivalent vaccine. AB - Influenza virus and human parainfluenza virus (HPIV) are major etiologic agents of acute respiratory illness in young children. Inactivated and live attenuated influenza vaccines are approved in several countries, yet no vaccine is licensed for HPIV. We previously showed that a replication-incompetent PB2-knockout (PB2 KO) virus that possesses a reporter gene in the coding region of the PB2 segment can serve as a platform for a bivalent vaccine. To develop a bivalent vaccine against influenza and parainfluenza virus, here, we generated a PB2-KO virus possessing the hemagglutinin-neuraminidase (HN) glycoprotein of HPIV type 3 (HPIV3), a major surface antigen of HPIV, in its PB2 segment. We confirmed that this virus replicated only in PB2-expressing cells and expressed HN. We then examined the efficacy of this virus as a bivalent vaccine in a hamster model. High levels of virus-specific IgG antibodies in sera and IgA, IgG, and IgM antibodies in bronchoalveolar lavage fluids against both influenza virus and HPIV3 were detected from hamsters immunized with this virus. The neutralizing capability of these serum antibodies was also confirmed. Moreover, the immunized hamsters were completely protected from virus challenge with influenza virus or HPIV3. These results indicate that PB2-KO virus expressing the HN of HPIV3 has the potential to be a novel bivalent vaccine against influenza and human parainfluenza viruses. PMID- 24144479 TI - Bilateral intralobar sequestration of the lung with a bridging isthmus: pathologic and radiologic findings. AB - A 4-year-old boy presented with pneumonia. Computed tomography demonstrated a multicystic mass at the posteromedial bilateral lower lobe segments, which were connected by a bronchus behind the heart. Enhanced computed tomography revealed that an anomalous artery arose from the left gastric artery and inserted into the left sequestrated lung and branched to the right one. The diagnosis of bilateral intralobar sequestration (ILS) with a bridging isthmus was made. After removal of the bilateral ILS, radiologic and pathologic approaches were undertaken to reconstruct the vascular and bronchial architectures. The following observations were made: (1) histologically, the region near the anomalous artery insertion site contained bronchial structures, which looked like an ectopic pulmonary hilus. This bronchial structure was continuously observed in the isthmus and its opening of the right sequestrated lung; (2) radiologically, the shape and course of the bronchi within the ILS indicated a distinct bronchial origin that arose from the pulmonary hilus-like structure, and the anomalous artery that ran along with those bronchi, resembled a pulmonary artery. These features suggested that this bilateral ILS might have originated from an accessory lung tissue. PMID- 24144480 TI - Correction to Neocosmospora sp.-Derived Resorcylic Acid Lactones with in Vitro Binding Affinity for Human Opioid and Cannabinoid Receptors. PMID- 24144481 TI - Lead exposure results in hearing loss and disruption of the cochlear blood labyrinth barrier and the protective role of iron supplement. AB - This study was designed to investigate the impact of lead (Pb(2+)) on the auditory system and its molecular mechanisms. Pb(AC)2 was administrated to male SD rats aged 21-22 d for 8 weeks at a dose of 300ppm. Male guinea pigs were also administrated with 50mg/kg Pb(AC)2 two times a week for 8 weeks. The auditory nerve-brainstem evoked responses (ABR) was recorded and the morphological changes of the outer hair cells (OHCs) were observed with Phallodin-FITC staining. In addition, the integrity of the blood-labyrinth barrier was observed by TEM and the expression of tight junction proteins (TJPs) in the cochlear stria vascularis was determined by immunofluorescence. Our results showed that Pb(2+) exposure resulted in increased ABR threshold in both rats and guinea pigs. Abnormal shapes and loss of OHCs were found in the cochlear basilar membrane following the Pb(2+) exposure. TEM study showed that the tight junctions between the endothelial cells and the border cells were lost and disrupted. Down-regulation of the occludin, ZO 1 and claudin-5 in the stria vascularis suggested that the increased permeability of the blood-labyrinth barrier may attribute to the Pb(2+)-induced decrease of TJPs' expression. Additionally, Fe(2+) supplement partly reversed the Pb(2+) induced hearing loss and down-regulation of TJPs. Taken together, these data indicate that the disruption of blood-labyrinth barrier by down-regulating the expression of TJPs plays a role in the Pb(2+)-induced hearing loss, and Fe(2+) supplement protects the auditory system against Pb(2+)-induced toxicity and may have significant clinical implications. PMID- 24144482 TI - Ultrasound assisted synthesis of {[Cu2(BDC)2(dabco)].2DMF.2H2O} nanostructures in the presence of modulator; new precursor to prepare nano copper oxides. AB - As a new precursor to prepare nano copper oxide, nanostructures of porous metal organic framework (MOF) {[Cu2(BDC)2(dabco)].2DMF.2H2O} (1) have been synthesized in the presence of acetic acid as a modulator via sonochemical method. Different concentrations of metal ion, organic linkers, modulator reagent and also different sonication times were held to improve the quality of nanostructures. Ultrasound irradiation helps nucleation step of the oriented attachment of modulation method and nanoparticles with a few nanorods has been prepared. As prepared MOF was calcinated at 500 degrees C to prepare nano CuO and Cu2O. Compound 1, CuO and Cu2O nanostructures were characterized by scanning electron microscopy (SEM), transmission electron microscopy (TEM) and X-ray powder diffraction (XRD). PMID- 24144483 TI - A multi-dose serological assay suitable to quantify the potency of inactivated rabies vaccines for veterinary use. AB - The mouse vaccination-challenge test, which is the most widely used method for determining the potency of inactivated rabies vaccines, is imprecise, time consuming, and causes severe distress to the test animals. An alternative single dose serological method has been implemented in the European Pharmacopoeia Monograph 0451 to replace the mouse challenge test for batch release. This single dose limit method provides semi-quantitative results, but is not suitable for quantifying potency. We have now extended this serological method to a multi-dose format which allows a quantification of vaccine potency. In studies including all rabies vaccine strains relevant for Europe, we found dose-dependency for all vaccines and standard preparations. We have demonstrated that the multi-dose serological approach provides reliable quantitative potency results and is more precise than the mouse vaccination-challenge test. We have shown that adjuvanted vaccines can be calibrated against non-adjuvanted material, and that reference material can be calibrated against the International Standard. The method is therefore capable of assigning potency with the additional advantage of requiring fewer animals and reducing distress. Once the applicability of the method has been further verified in a collaborative study, it can complement the single-dose assay and eventually eliminate the need for the mouse challenge test. PMID- 24144484 TI - Correlation between DNA interactions and cytotoxic activity of four new ternary compounds of copper(II) with N-donor heterocyclic ligands. AB - Four new ternary complexes of copper(II) were synthesized and characterized: [Cu(hyd)(bpy)(acn)(ClO4)](ClO4)] (1), [Cu(hyd)(phen)(acn)(ClO4)](ClO4)] (2), [Cu(Shyd)(bpy)(acn)(ClO4)](ClO4)] (3) and [Cu(Shyd)(phen)(acn)(ClO4)](ClO4)] (4), in which acn=acetonitrile; hyd=2-furoic acid hydrazide, bpy=2,2-bipyridine; phen=1,10-phenanthroline and Shyd=2-thiophenecarboxylic acid hydrazide. The cytotoxic activity of the complexes in a chronic myelogenous leukemia cell line was investigated. All complexes are able to enter cells and inhibit cellular growth in a concentration-dependent manner, with an activity higher than that of the corresponding free ligands. The substitution of Shyd for hyd increases the activity, while the substitution of bpy for phen renders the complex less active. Therefore, the most potent complex is 4 with an IC50 value of 1.5+/-0.2MUM. The intracellular copper concentration needed to inhibit 50% of cell growth is approximately 7*10(-15)mol/cell. It is worth notifying that a correlation between cytotoxic activity, DNA binding affinity and DNA cleavage was found: 1<3<2<4. PMID- 24144485 TI - An autoradiographic study of neurotensin receptors in the human hypothalamus. AB - The aim of the present investigation was to determine a detailed mapping of neurotensin (NT) in the human hypothalamus, the brain region involved in neuroendocrine control. For this, we investigated the presence and the distribution of neurotensin binding sites in the human hypothalamus, using an in vitro quantitative autoradiography technique and the selective radioligand monoiodo-Tyr3-neurotensin (2000Ci/mM). This study was performed on nine adult human postmortem hypothalami. We first determined the biochemical kinetics of the binding and found that binding affinity constants were of high affinity and do not differ significantly between all cases investigated. Our analysis of the autoradiographic distribution shows that NT binding sites are widely distributed throughout the rostrocaudal extent of the hypothalamus. However, the distribution of NT binding sites is not homogenous and regional variations exist. In general, the highest densities are mainly present in the anterior hypothalamic level, particularly in the preoptic region and the anterior boarding limit (i.e. the diagonal band of Broca). Important NT binding site densities are also present at the mediobasal hypothalamic level, particularly in the paraventricular, parafornical and dorsomedial nuclei. At the posterior level, relatively moderate densities could be observed in the mammillary complex subdivisions, apart from the supramammillary nucleus and the posterior hypothalamic area. In conclusion, the present study demonstrates the occurrence of high concentrations of NT binding sites in various structures in many regions in the human adult hypothalamus, involved in the control of neuroendocrine and/or neurovegetative functions. PMID- 24144486 TI - Serum tissue polypeptide-specific antigen is an independent predictor in breast cancer. AB - Tissue polypeptide-specific antigen (TPS) is a tumor proliferative marker associated with cytokeratin 18. The aim of the study was to investigate the potential relationship between the preoperative serum TPS levels and the outcome in Chinese breast cancer patients. 975 consecutive female patients, affected by invasive breast cancer under investigation from January 2005 to December 2011, had their TPS levels measured with a one-step solid phase radiometric sandwich assay detecting the M3 epitope on cytokeratin 18 fragments. The cut-off value was 80U/L. The average age diagnosed with breast cancer was 48, ranging from 23 to 71. About 19% (185) patients displayed an elevated preoperative TPS level (>80U/L) associated with older age (>45), advanced cancer stage, larger tumor size (>2cm), axillary lymph node metastasis, negative progesterone receptor status, and positive HER2 status. In addition, preoperative TPS levels were also significantly connected with recurrence (p<0.05), particularly distant metastasis and visceral metastasis. The mean preoperative TPS level was 68.4+/-116.43U/L (range 0-1839U/L). In multivariate analysis, high preoperative TPS level was recognized as an independent prognostic factor for disease-free survival (p<0.001 and overall survival (p=0.023). From these results we conclude that the serum preoperative TPS level may be a valuable and independent marker for breast cancer. PMID- 24144487 TI - TAMRA- and Cy5-labeled probe for efficient kinetic characterization of caspase-3. AB - Our objective was to create a novel fluorogenic substrate for efficient in vitro kinetic assays on caspase-3. We designed a TAMRA (5'-tetramethylrhodamine-5(6) carboxamide)- and Cy5 (cyanine 5)-labeled probe that allowed us to evaluate the caspase-3 activity via the changes in fluorescence intensity and wavelength. The prepared probe was found to be an efficient and selective substrate of caspase-3, with V(max) of 41.4+/-3.3 nM/min and K(M) of 1.60+/-0.23 MUM. The strategy used in the design of this fluorogenic substrate can be applied in future endeavors to development of substrates for caspase-3 inhibitor screening assays or for real time detection of apoptosis in living cells. PMID- 24144488 TI - A new, sensitive ecto-5'-nucleotidase assay for compound screening. AB - Ecto-5'-nucleotidase (eN) is a membrane-bound enzyme that hydrolyzes extracellular nucleoside-5'-monophosphates yielding the respective nucleoside and phosphate. Increased levels of eN expression have been observed in many cancer cells. By increasing extracellular adenosine concentrations, they contribute to their proliferative, angiogenic, metastatic, and immunosuppressive effects. Therefore, eN is of considerable interest as a novel drug target for the treatment of cancer as well as of inflammatory diseases. In this study, we developed, optimized, and applied a highly sensitive radiometric assay using [3H]adenosine-5'-monophosphate (AMP) as a substrate. The reaction product [3H]adenosine was separated from [3H]AMP by precipitation of the latter with lanthanum chloride and subsequent filtration through glass fiber filters. Conditions were optimized to reproducibly collect the [3H]adenosine-containing filtrate used for quantitative determination. Validation of the assay yielded a mean Z' factor of 0.73, which demonstrates its suitability for high-throughput screening. The new assay shows a limit of detection that is at least 30-fold lower than those of common colorimetric methods (e.g., optimized malachite green assay and capillary electrophoresis-based assay procedures), and it is also superior to a recently developed luciferase-based assay. PMID- 24144489 TI - Functionalized bis-cyclometalated alkynylgold(III) complexes: synthesis, characterization, electrochemistry, photophysics, photochemistry, and electroluminescence studies. AB - A series of luminescent alkynylgold(III) complexes containing various tridentate bis-cyclometalating ligands derived from 2,6-diphenylpyridine (R-C(^)N(^)C), [Au(R-C(^)N(^)C)(C=C-C6H4-R')] has been successfully synthesized and characterized. Complexes 1 and 6 have been determined by X-ray crystallography. Electrochemical studies show a ligand-centered reduction that originated from the tridentate R-C(^)N(^)C pincer ligands and an alkynyl-centered oxidation. The photophysical properties of the complexes have been studied in detail by electronic absorption and emission studies. Tunable photoluminescence behaviors have been observed, with the emission maxima spanning through the visible region from 476 to 669 nm in dichloromethane at room temperature, and the complexes were also found to be emissive in various media at both room and low temperatures. Transient absorption studies have been conducted to investigate the excited state properties of the complexes. Furthermore, selected complexes have been incorporated into the emissive layer (EML) of organic light-emitting devices (OLEDs) and have demonstrated interesting electroluminescence. PMID- 24144490 TI - Variable expansin expression in Arabidopsis leads to different growth responses. AB - Expansins have long been implicated in the control of cell wall extensibility. However, despite ample evidence supporting a role for these proteins in the endogenous mechanism of plant growth, there are also examples in the literature where the outcome of altered expansin gene expression is difficult to reconcile with a simplistic causal linkage to growth promotion. To investigate this problem, we report on the analysis of transgenic Arabidopsis plants in which a heterologous cucumber expansin can be inducibly overexpressed. Our results indicate that the effects of expansin expression on growth depend on the degree of induction of expansin expression and the developmental pattern of organ growth. They support the role of expansin in directional cell expansion. They are also consistent with the idea that excess expansin might itself impede normal activities of cell wall modifications, culminating in both growth promotion and repression depending on the degree of expression. PMID- 24144491 TI - Impact of visual impairment on vision-specific quality of life among older adults living in nursing home. AB - BACKGROUND: Visual impairment (VI) has a significant negative impact on quality of life (QoL) amongst older people living in nursing homes. The purpose of this study was to determine the prevalence of VI and blindness and to explore the association between severity of VI and vision-specific QoL among older people living in nursing homes of Kathmandu, Nepal. METHODS: This cross-sectional study involved 158 residents aged 60 years or older residing in seven nursing homes of Kathmandu Valley, Nepal. Near acuity, presenting and the best corrected distance visual acuity (VA) were assessed in each eye and considered in the better eye after adequate refraction. A complete anterior and posterior segment examination was carried out. Face-to-face interviews were conducted using a 57-item Nursing Home Vision-Targeted Health-Related Quality of Life (NHVQoL) questionnaire. RESULTS: The mean age of residents was 75.60 +/- 7.12 years and the majority were female (66.46%). The prevalence of VI and blindness was 45.57% and its leading cause was cataract, which was followed by age-related macular degeneration, corneal opacity, glaucoma and macular scar. The mean composite score of NHVQoL questionnaire was 52.22 +/- 12.49. There was a consistent overall deterioration in the mean composite score as well as each subscale score of NHVQoL questionnaire with a worsening of VA. CONCLUSION: VI and blindness are highly prevalent among older people living in nursing homes. VI has a significant negative impact on vision-specific QoL. Vision-specific QoL is reduced, and the reduction in the QoL bears a positive association with severity of VI among older people living in nursing homes. PMID- 24144492 TI - Prolactin administration during early postnatal life decreases hippocampal and olfactory bulb neurogenesis and results in depressive-like behavior in adulthood. AB - Tight regulation of hormone and neurochemical milieu during developmental periods is critical for adequate physiological functions. For instance, activation of peptide systems during early life stress induces morphological changes in the brain resulting in depression and anxiety disorders. Prolactin (PRL) exerts different actions within the brain; it regulates neurogenesis and modulates neuroendocrine functions in the adult. However, PRL effects during early postnatal life are hardly known. Therefore, we examined whether neonatal administration of PRL influences cell survival in the hippocampal dentate gyrus (DG) and in the olfactory bulb (OB) and whether such influence results in behavioral consequences in adulthood. PRL-treated rat pups (13 mg/kg; PND1 to PND14), injected with BrdU at postnatal day 5 (PND5), showed a decrease in the density of DG BrdU/DCX and BrdU/NeuN-positive cells that survive at PND15. Similarly, PRL treatment decreased the density of BrdU+ cells in the OB compared with VEH. Fluorojade B analysis showed no significant changes in the amount of cell death in the DG between the groups. Postnatal PRL administration induced a passive coping strategy in the forced swimming test in male and female adult rats when compared with control and vehicle groups. Corticosterone endogenous levels at PND12 were not affected by PRL or VEH treatment. Altogether, these results suggest that opposed to its effects in the adult, postnatal PRL treatment affects neurogenesis and results in psychopathology later in life. High PRL levels, as observed in neonates under several pathological states, might contribute to detrimental effects on the developing brain. PMID- 24144494 TI - Safety of the Las Vegas left-turn display. AB - This paper provides a safety evaluation of a special protected/permitted left turn signal control (Las Vegas LT Display) that has been implemented in the urbanized area of Las Vegas, Nevada. The Las Vegas LT Display eliminates the yellow trap condition for leading approach in lead/lag operation. It provides protected only left turns during certain times of day by suppressing the permitted green ball and yellow ball displays. Before and after studies were conducted using the crash data from 10 intersections. Results from the analyses indicated that no obvious safety concerns due to use of the special display. PMID- 24144493 TI - Pulmonary MRI contrast using Surface Quadrupolar Relaxation (SQUARE) of hyperpolarized (83)Kr. AB - Hyperpolarized (83)Kr has previously been demonstrated to enable MRI contrast that is sensitive to the chemical composition of the surface in a porous model system. Methodological advances have lead to a substantial increase in the (83)Kr hyperpolarization and the resulting signal intensity. Using the improved methodology for spin exchange optical pumping of isotopically enriched (83)Kr, internal anatomical details of ex vivo rodent lung were resolved with hyperpolarized (83)Kr MRI after krypton inhalation. Different (83)Kr relaxation times were found between the main bronchi and the parenchymal regions in ex vivo rat lungs. The T1 weighted hyperpolarized (83)Kr MRI provided a first demonstration of surface quadrupolar relaxation (SQUARE) pulmonary MRI contrast. PMID- 24144495 TI - Internal validation of near-crashes in naturalistic driving studies: a continuous and multivariate approach. AB - Large naturalistic driving studies give extremely detailed insight into how traffic accidents happen and what causes them. However, even in very large studies there are only relatively few crashes. Hence one additionally selects and studies crash surrogates, so called "near-crashes", i.e. situations when a crash almost happened. The selection procedures invariably entail severe risks of causing bias. In this paper we use extreme value statistics to develop two methods to study the extent and form of this bias. The methods are applied to a large naturalistic driving study, the 100-car study. Both methods identified a severe discrepancy between the rear-striking near-crashes and the rear-striking crashes. Perhaps surprisingly, one conclusion is that, for rear-striking and in this study, the crashes have little relevance for increasing traffic safety. We believe substantial efforts should be made to develop statistical methods for using near-crashes and crashes in future large naturalistic driving studies (such as the SHRP2 study). PMID- 24144496 TI - EEG alpha spindles and prolonged brake reaction times during auditory distraction in an on-road driving study. AB - Driver distraction is responsible for a substantial number of traffic accidents. This paper describes the impact of an auditory secondary task on drivers' mental states during a primary driving task. N=20 participants performed the test procedure in a car following task with repeated forced braking on a non-public test track. Performance measures (provoked reaction time to brake lights) and brain activity (EEG alpha spindles) were analyzed to describe distracted drivers. Further, a classification approach was used to investigate whether alpha spindles can predict drivers' mental states. Results show that reaction times and alpha spindle rate increased with time-on-task. Moreover, brake reaction times and alpha spindle rate were significantly higher while driving with auditory secondary task opposed to driving only. In single-trial classification, a combination of spindle parameters yielded a median classification error of about 8% in discriminating the distracted from the alert driving. Reduced driving performance (i.e., prolonged brake reaction times) during increased cognitive load is assumed to be indicated by EEG alpha spindles, enabling the quantification of driver distraction in experiments on public roads without verbally assessing the drivers' mental states. PMID- 24144497 TI - Near-miss narratives from the fire service: a Bayesian analysis. AB - BACKGROUND: In occupational safety research, narrative text analysis has been combined with coded surveillance, data to improve identification and understanding of injuries and their circumstances. Injury data give, information about incidence and the direct cause of an injury, while near-miss data enable the, identification of various hazards within an organization or industry. Further, near-miss data provide an, opportunity for surveillance and risk reduction. The National Firefighter Near-Miss Reporting System, (NFFNMRS) is a voluntary reporting system that collects narrative text data on near-miss and injurious, events within the fire and emergency services industry. In recent research, autocoding techniques, using Bayesian models have been used to categorize/code injury narratives with up to 90% accuracy, thereby reducing the amount of human effort required to manually code large datasets. Autocoding, techniques have not yet been applied to near-miss narrative data. METHODS: We manually assigned mechanism of injury codes to previously un-coded narratives from the, NFFNMRS and used this as a training set to develop two Bayesian autocoding models, Fuzzy and Naive. We calculated sensitivity, specificity and positive predictive value for both models. We also evaluated, the effect of training set size on prediction sensitivity and compared the models' predictive ability as, related to injury outcome. We cross-validated a subset of the prediction set for accuracy of the model, predictions. RESULTS: Overall, the Fuzzy model performed better than Naive, with a sensitivity of 0.74 compared to 0.678., Where Fuzzy and Naive shared the same prediction, the cross-validation showed a sensitivity of 0.602., As the number of records in the training set increased, the models performed at a higher sensitivity, suggesting that both the Fuzzy and Naive models were essentially "learning". Injury records were, predicted with greater sensitivity than near-miss records. CONCLUSION: We conclude that the application of Bayesian autocoding methods can successfully code both near misses, and injuries in longer-than-average narratives with non specific prompts regarding injury. Such, coding allowed for the creation of two new quantitative data elements for injury outcome and injury, mechanism. PMID- 24144498 TI - Assessing factors causing severe injuries in crashes of high-deck buses in long distance driving on freeways. AB - High-deck buses that have a higher center of gravity traveling at an excessive speed have a higher likelihood of causing serious and fatal accidents when drivers lose control of the vehicle. In addition, drivers who suffer from fatigue in long-distance driving increase the likelihood of serious accident. This paper examines the effects of risk factors contributing to severe crashes associated with high-deck buses used for long-distance driving on freeways. An ordered logit and latent class models are used to examine significant factors on the severity of injuries in crashes related to high-deck buses. Driver fatigue, drivers or passengers not wearing a seat belt, reckless driving, drunk driving, crashes occurred between midnight and dawn, and crashes occurred at interchange ramps were found to significantly affect the severity of injuries in crashes involving high-deck buses. Safety policies to prevent severe injuries in crashes involving high deck buses used for long-distance runs on freeways include: (1) restricting drivers from exceeding the limit of daily driving hours and mandating sufficient rest breaks; (2) installing an automatic sleep-warning device in the vehicle; (3) drivers with obstructive sleep apnea syndrome or sleep disorders should be tested and treated before they are allowed to perform long hours of driving tasks; (4) educating the public or even amending the seatbelt legislation to require all passengers to wear a seat belt and thus reduce the chance of ejection from a high deck bus and prevent serious injuries in a crash while traveling at a higher speed on freeways. PMID- 24144499 TI - Relative fatality risk curve to describe the effect of change in the impact speed on fatality risk of pedestrians struck by a motor vehicle. AB - Models describing the relation between impact speed and fatality risk for pedestrians struck by a motor vehicle have frequently been used by practitioners and scientists in applying an S curve to visualize the importance of speed for the chance of survival. Recent studies have suggested that these risk curves are biased and do not give representative risk values. These studies present new fatality risk curves that show much lower risks of fatality than before, which has caused confusion and misconceptions about how these new curves should be interpreted, and how this should affect speed management policy. The aim here is to deepen the understanding of the implications this new knowledge has for urban speed policies by analyzing (1) what the most reliable knowledge is for this relation today and what limitations it has, (2) how these risk curves are interpreted today, and what limitations this interpretation has and (3) what the risk curves say about the importance of speed and speed changes. This paper proposes an additional tool, the relative fatality risk curve, to help prevent misconceptions. The proposed relative risk ratios and curves show that, even though the most recent results indicate that the risk is lower than assumed by the older models, the fatality risk is still as sensitive to speed changes as before. PMID- 24144500 TI - Physical activity levels among children attending family day care. AB - OBJECTIVE: To objectively measure the physical activity (PA) levels of children attending family day care programs. METHODS: A total of 114 children from 47 family day care centers wore an accelerometer for the duration of their time in care. Time in moderate-to-vigorous PA (MVPA) and total PA was calculated using previously validated cut points. RESULTS: Children accumulated 5.8 +/- 3.2 minutes of MVPA and 10.4 +/- 4.4 minutes of total PA per hour of attendance. Boys exhibited significantly higher levels of PA than girls. Among healthy weight children, 4- and 5-year-olds exhibited significantly higher levels of PA than 2- and 3-year-olds. Overweight and obese 4- and 5-year-olds exhibited significantly lower levels of PA than their healthy weight counterparts. CONCLUSIONS AND IMPLICATIONS: Children attending family day care participate in low levels of PA during the child care day. The results highlight the need for effective programs to promote PA in family day care. PMID- 24144501 TI - Stable microRNA expression enhances therapeutic antibody productivity of Chinese hamster ovary cells. AB - MicroRNAs (miRNAs) are short non-coding RNAs that post-transcriptionally regulate the expression of different target genes and, thus, enable engineered gene networks to achieve complex phenotypic changes in mammalian cells. We hypothesized that exploiting this feature of miRNAs could improve therapeutic protein production processes by increasing viable cell densities and/or productivity of the mammalian cells used for manufacturing. To identify miRNAs that increase the productivity of producer cells, we performed a genome wide functional miRNA screen by transient transfection of Chinese hamster ovary (CHO) cells stably expressing an IgG1 antibody (CHO-IgG1). Using this approach, we identified nine human miRNAs that improved the productivities not only of the CHO IgG1 cells but also of CHO cells expressing recombinant human serum albumin (HSA), demonstrating that the miRNAs act in a product-independent manner. We selected two miRNAs (miR-557 and miR-1287) positively impacting the viable cell density and the specific productivity, respectively, and then stably co-expressed them in IgG1 expressing CHO cells. In these cells, higher IgG1 titers were observed in fed-batch cultures whilst product quality was conserved, demonstrating that miRNA-based cell line engineering provides an attractive approach toward the genetic optimization of CHO producer cells for industrial applications. PMID- 24144502 TI - Fatal aspiration of foreign bodies in infants and children. AB - PURPOSE: To investigate the frequency, circumstances, demographics and autopsy findings of infants and children dying as a result of foreign body aspiration. METHODS: Retrospective review of autopsy cases in children aged between seven days and 18 years, at one specialist centre over a 16-year period, in which death was the result of aspiration of a foreign body. RESULTS: Ten cases were identified out of a total autopsy population of 2165. Only one individual had an underlying diagnosis potentially contributing to aspiration. All but one case involved aspiration of food, with grapes being a feature of four cases. In cases with a prolonged survival interval, autopsy demonstrated bronchopneumonia and hypoxic-ischaemic encephalopathy. In the remaining cases autopsy findings were non-specific. CONCLUSIONS: Fatal aspiration of a foreign body is rare in this population. The cases involve normal children who aspirate food, particularly grapes. There are typically minimal, non-specific findings at autopsy. PMID- 24144503 TI - Age-related cortical thickness differences in adolescents with early-onset schizophrenia compared with healthy adolescents. AB - The aim of the present study was to investigate the influence of age on cerebral cortical thickness in adolescents with early-onset schizophrenia (EOS) (n=22, aged 12-18 years), as compared to an age-matched healthy control group (n=32). All participants were scanned with magnetic resonance imaging. Whereas in the healthy control group there was a negative association between increasing age and cortical thickness measures in widespread brain regions, including frontal and parietal cortices, the patient group showed no significant effects of age when the groups were studied separately. There was a trend towards an age-by-group effect in the left supramarginal gyrus and the right pre- and postcentral gyri. The between-group statistical analysis indicated similar cortical thickness in the patients as in the healthy controls. There were no significant effects of medication on cortical thickness, nor was there any significant sex-by-group interaction. The results suggest that patients with EOS have a deficiency of the expected cortical thinning to occur during adolescence development. The findings are discussed in context of neurobiological processes known to be involved in brain maturation, including synaptic reorganization, pruning and myelination. PMID- 24144504 TI - The efficiency of functional brain networks does not differ between smokers and non-smokers. AB - Acute nicotine consumption in smokers impacts on functional brain network topology indicating an increase in the efficiency of information transfer and attentional task performance. The effects of chronic nicotine consumption on functional brain network topology are unknown. We here investigated the effects of chronic smoking-behaviour on functional brain network topology. Minimally deprived smokers (N=18) and non-smokers (N=17) were measured within an fMRI scanner during a resting state condition. Graph-theoretical metrics of functional network integration (global efficiency and clustering) that have been shown to be affected by acute nicotine administration were compared between both groups. Our results revealed that smoking status did not significantly change functional network integration. Additional tests for non-inferiority confirmed the similarity of regional or nodal network properties. Brain regions such as the left insular and middle frontal gyrus, in which acute nicotine consumption affected network topology, did not reveal any decrease in functional network efficiency following chronic nicotine consumption. Within the limitation of the investigated sample size, our data suggest that the integration of functional brain networks is not altered in minimally-deprived smokers. Our findings are of relevance for clinical studies showing changes in network topology between psychiatric patients with high prevalence of smoking and healthy control subjects. PMID- 24144505 TI - Resting state functional connectivity and treatment response in late-life depression. AB - Indices of functional connectivity in the default mode network (DMN) are promising neural markers of treatment response in late-life depression. We examined the differences in DMN functional connectivity between treatment responsive and treatment-resistant depressed older adults. Forty-seven depressed older adults underwent MRI scanning pre- and post-pharmacotherapy. Forty-six never depressed older adults underwent MR scanning as comparison subjects. Treatment response was defined as achieving a Hamilton Depression Rating Scale of 10 or less post-treatment. We analyzed resting state functional connectivity using the posterior cingulate cortex as the seed region-of-interest. The resulting correlation maps were employed to investigate between-group differences. Additionally we examined the association between white matter hyperintensity burden and functional connectivity results. Comparison of pre- and post-treatment scans of depressed participants revealed greater post-treatment functional connectivity in the frontal precentral gyrus. Relative to treatment responsive participants, treatment-resistant participants had increased functional connectivity in the left striatum. When adjusting for white matter hyperintensity burden, the observed differences lost significance for the PCC prefrontal functional connectivity, but not for the PCC-striatum functional connectivity. The post-treatment "frontalization" of the DMN connectivity suggests a normalizing effect of antidepressant treatment. Moreover, our study confirms the central role of white matter lesions in disrupting brain functional connectivity. PMID- 24144506 TI - White matter metabolism differentiates schizophrenia and bipolar disorder: a preliminary PET study. AB - Fluorodeoxyglucose-F18 positron emission tomography studies (FDG-PET) have shown similar corticolimbic metabolic dysregulation in bipolar disorder and schizophrenia, with hypoactive prefrontal cortex coupled with hyperactive anterior limbic areas. However, it is not clear whether white matter metabolism connecting these regions is differently affected in the two disorders. Twenty-six patients with schizophrenia (mean age +/- S.D.=30.23 +/- 9.7 year-old; 19 males; mean weight +/- S.D.=71 +/- 3 kg) and 26 patients with bipolar disorder (mean age +/- S.D.=48.73 +/- 13 year-old; 18 males; mean weight +/- S.D.=75 +/- 15 kg) underwent an FDG-PET scan. Normalized datasets the two groups of patients were compared on a voxel-by-voxel basis using a two-sample t statistic test as implemented in SPM8, and adding age as covariate. Group differences were assessed applying a threshold of p<0.0005. White matter metabolic rates significantly differed between schizophrenia and bipolar disorder, whereas no differences were shown for cortical activity. This is the first FDG-PET, to our best knowledge, directly comparing subjects with schizophrenia to those with bipolar disorder. It reports decreased activity in the center of large fronto-temporal and cerebellar white matter tracts in patients with schizophrenia in respect to those with bipolar disorder. This feature may characterize and differentiate the regional brain metabolism of the two illnesses. PMID- 24144507 TI - An altered neural response to reward may contribute to alcohol problems among late adolescents with an evening chronotype. AB - Evening chronotypes not only differ from morning-types in their sleep and circadian timing, but they are prone to problematic outcomes involving reward function, including affective disturbance, sensation seeking, and substance involvement. We explored the neural mechanisms underlying these chronotype differences by comparing the neural response to reward in morning- and evening types. Using a monetary reward fMRI paradigm, we compared the neural response to reward in 13 morning-types and 21 evening-types (all 20 y/o males). Region-of interest (ROI) analyses focused on the medial prefrontal cortex (mPFC) and ventral striatum (VS), comparing the chronotype groups in these ROIs during anticipation and outcome conditions, and adjusting for time of scan. Chronotype groups were also compared on measures of sensation-seeking, substance involvement, and sleep quality. Evening-types reported significantly greater levels of alcohol dependence and worse sleep quality. Furthermore, evening-types showed an altered neural response to reward relative to morning-types, specifically, reduced mPFC reactivity during reward anticipation and increased VS reactivity during win outcome. In turn, less activation in the mPFC region in response to reward was associated with greater alcohol consumption, while increased activation in the VS in response to reward was associated with more symptoms of alcohol dependence. Increased reward-related problems among evening types may be accompanied by altered neural responses to reward. PMID- 24144508 TI - Longitudinal cerebral diffusion changes reflect progressive decline of language and cognition. AB - Language deficits are regularly found in cortical neurodegenerative diseases. The progression of language deficits shows a considerable inter-individual variability even within one diagnostic group. We aimed at detecting patterns of altered diffusion as well as atrophy of cerebral gray and white matter which underlie ongoing language-related deterioration in patients with cortical neurodegenerative diseases. Diffusion tensor imaging and T1-weighted MRI data of 26 patients with clinically diagnosed neurodegenerative disorders were acquired at baseline and 14 months later in this prospective study. Language functions were assessed with a confrontation naming test and the Token Test. Diffusion and voxel-based morphometric measures were calculated and correlates of language performance were evaluated. Across all patients, the naming impairment was related to diffusion (false discovery rate-corrected P<0.05 at baseline) and atrophy abnormalities (family-wise error (FWE)-corrected P<0.05 at follow-up) primarily in the left temporal lobe. Deficits in the Token Test were correlated with predominantly left frontal MRI abnormalities (FWE-corrected P<0.05). The Token Test performance decline over 14 months was accompanied by further increasing abnormalities in the frontal cortex, left caudate, parietal cortex (all FWE-corrected P<0.05), and posterior callosal body (FWE-corrected P=0.055). Both diffusion and structural MRI were apt to elucidate the underpinnings of inter-individual differences in language-related deficits and to detect longitudinal changes that accompanied ongoing cognition and language decline, with mean diffusivity appearing most sensitive. This might indicate the usefulness of diffusion measures as markers for successful intervention in therapy studies. PMID- 24144509 TI - Characterizing white matter health and organization in atherosclerotic vascular disease: a diffusion tensor imaging study. AB - Atherosclerotic vascular disease (AVD) is endemic to the developed world, with known negative outcomes for cognition and brain health. The effects of AVD on the white matter fibers of the brain have not yet been studied using diffusion tensor imaging (DTI). This study examined differences in fractional anisotropy (FA) between AVD and healthy comparison (HC) participants, and described the regional patterns of FA in each group. AVD participants were hypothesized to have lower FA than HC participants, indicating abnormalities in white matter health or organization. 1.5 T diffusion tensor imaging was performed in 35 AVD and 22 HC participants. Mean FA measures were calculated for the white matter of the whole brain, as well for individual lobes. Globally and in every brain region measured except the temporal lobes, there were significant effects of group where AVD participants had lower FA values than their HC counterparts. Group differences in FA remained significant when controlled for white matter hyperintensity (WMH) volume, suggesting that FA detects white matter abnormality above and beyond what is measurable using the older WMH technique. These findings suggest a likely neural substrate underlying the changes in cognition and mood reported in atherosclerotic vascular disease patients. PMID- 24144510 TI - Altered relationships between age and functional brain activation in adolescents at clinical high risk for psychosis. AB - Schizophrenia is considered a neurodevelopmental disorder, but whether the adolescent period, proximal to onset, is associated with aberrant development in individuals at clinical high risk (CHR) for psychosis is incompletely understood. While abnormal gray and white matter development has been observed, alterations in functional neuroimaging (fMRI) parameters during adolescence as related to conversion to psychosis have not yet been investigated. Twenty CHR individuals and 19 typically developing controls (TDC), (ages 14-21), were recruited from the Center for Assessment and Prevention of Prodromal States (CAPPS) at UCLA. Participants performed a Sternberg-style verbal working memory (WMem) task during fMRI and data were analyzed using a cross-sectional design to test the hypothesis that there is a deviant developmental trajectory in WMem associated neural circuitry in those at risk for psychosis. Eight of the CHR adolescents converted to psychosis within 2 years of initial assessment. A voxel-wise regression examining the relationship between age and activation revealed a significant group-by-age interaction. TDC showed a negative association between age and functional activation in the WMem circuitry while CHR adolescents showed a positive association. Moreover, CHR patients who later converted to overt psychosis showed a distinct pattern of abnormal age-associated activation in the frontal cortex relative to controls, while non-converters showed a more diffuse posterior pattern. Finding that age related variation in baseline patterns of neural activity differentiate individuals who subsequently convert to psychosis from healthy subjects suggests that these differences are likely to be clinically relevant. PMID- 24144511 TI - Bactericidal evaluation of N-halamine-functionalized silica nanoparticles based on barbituric acid. AB - Novel N-halamine-functionalized silica nanoparticles (NHFS NPs) were facilely fabricated from the 5-allylbarbituric acid (ABBA) by a seeded copolymerization using colloidal silica nanoparticles as support and ABBA-based N-halamine copolymers as shell. The NHFS NPs with spherical morphology and legible core shell structure have the average diameter of 538.5 nm and the average shell thickness of 19.8 nm. The NHFS NPs possessed improved antimicrobial activity against both Gram-positive and Gram-negative bacteria compared with their bulk powder counterparts. The structural effect of N-halamine on bactericidal activity was clarified through the comparison between barbituric acid-based NHFS NPs and hydantoin-structural NHFS NPs. Effects of colloidal silica support and comonomer methyl methacrylate on particles morphology and the corresponding antimicrobial activity were comparatively investigated as well. Antibacterial tests revealed that N-halamine nanomaterials originated from barbituric acid derivative displayed powerful antibacterial performance and long-term stability. PMID- 24144512 TI - Construction of a measurement system for simultaneity judgment using odor and taste stimuli. AB - BACKGROUND: The modalities examined in previous simultaneity judgment (SJ) were limited to vision, audition, and touch. By contrast, olfaction and gustation have not been addressed to date in SJ. NEW METHOD: In this study, we constructed a measurement system for performing SJ with three cross-modal, combinations of odor, taste, and light stimuli. Odor and taste stimulators were able to stimulate to only the receptors corresponding to the modalities of each stimulus, without inducing tactile sensation. Furthermore, in order to precisely calculate the time points at which stimulus reached receptors in each trial, we monitored the presented stimuli in real time. After we calculated the actual values of stimulus onset asynchrony (SOA) between standard and comparison stimuli on the basis of the records of real-time monitoring, we evaluated the temporal distributions of simultaneous response rates in each cross-modal combination. RESULTS: When we fitted a Gaussian distribution to these temporal distributions, we observed low error rates in all cross-modal combinations, as demonstrated in SJ using visual, audio, and tactile stimuli. COMPARISON WITH EXISTING METHOD(S): SJ using chemical stimuli and SJ using physical stimuli exhibit the same degree of measurement accuracy. CONCLUSIONS: We succeeded in development a high accurate measurement system for SJ using chemical stimuli. We attribute this success to the use of strict real-time monitoring of stimulus presentation. PMID- 24144513 TI - The effects of head movement and walking speed on gait parameters in patients with chronic neck pain. AB - It has been documented that neck pain can influence sensorimotor function. However, little is known about the effects of head movement and walking speed on gait characteristics in patients with neck pain. The aim of this study was to determine gait characteristics of patients with neck pain during walking with different head movements and gait speeds as compared to a control group without neck pain. Twenty women aged between 18 and 59 years with chronic neck pain (>3 months) and 20 healthy controls of similar age, weight and height were recruited into the study. Participants with neck pain completed the Neck Disability Index and Visual Analogue Pain Scale. The experiment consisted of two walking sessions. The first session included walking with head straight, head up-down, and head turns from side to side. The second session included walking at comfortable and maximum speeds. Each trial was performed twice. Gait parameters measured using GAITRite walkway system were step length, stride length, step time, stride time, step width, cadence and gait speed. Patients with chronic neck pain demonstrated a narrower step width, a shorter step length and a slower gait speed during walking with the head movements and at maximum speed compared to the control group (all p < 0.05). Maximum gait speed was moderately correlated with pain intensity and disability (p < 0.01). The results suggest that patients with chronic neck pain have gait disturbances. This supports the notion that assessment of gait should be addressed in patients with persistent neck pain. PMID- 24144514 TI - Raman microspectroscopy: shining a new light on reproductive medicine. AB - BACKGROUND The last 20 years have seen an enormous upsurge in the number of publications reporting findings obtained by Raman spectroscopy, a non-invasive, non-destructive method which uses the inelastic scattering of light to provide a 'fingerprint' of the sample's chemical composition and constituents. Long neglected because of practical difficulties, the technique has been transformed by recent technological advances into a powerful analytical tool capable of opening avenues of investigation that were previously out of the reach of biomedical scientists. Beyond introducing the approach and describing its relative merits and weaknesses, the aim of this review is to provide a spur for discussion of what may become an invaluable tool for biomedical investigations. METHODS A comprehensive review of the literature was conducted searching PubMed and Ovid databases using numerous MeSH terms associated with reproductive medicine. Furthermore, the reference lists of all reported literature were explored. The searches were restricted to English language articles published in the last 50 years. RESULTS Beginning with simple characterizations of biologically and medically important substances, aided by increasing technological sophistication, the use of Raman spectroscopy in biomedicine has quickly expanded to the investigation of complex biochemical interactions, the assessment of organelles and now the evaluation of living cells and tissue. The first Raman investigations of reproductive organs were primarily oncological in nature; however, the past few years have seen an increase in the application of the technique for the assessment and evaluation of both male and female gametes. In particular, progress has been made in the characterization, identification and localization of sperm nuclear DNA damage. CONCLUSIONS The use of Raman spectroscopy has already provided many tantalizing glimpses into the potential that the technique has to answer many of the unresolved issues in investigative and therapeutic reproductive medicine. However, without stringent assessment and the clear representation of the methods' findings, their true meaning cannot be revealed nor should any conclusions be hastily derived. For the potential of Raman microspectroscopy to be truly realized, the dependability and reliability of the technique and its results can only be ascertained by multidisciplinary collaborations that undertake carefully conducted, controlled and analysed studies. PMID- 24144515 TI - Reduced efficacy of moxidectin and abamectin in young red deer (Cervus elaphus) after 20 years of moxidectin pour-on use on a New Zealand deer farm. AB - A study was undertaken on weaned 4-5 month old farmed red deer to test the efficacy of moxidectin and abamectin anthelmintics, given by three different routes of administration, compared with an untreated control. Faecal samples were collected on days 0, 7 and 14 for a faecal egg count reduction test (FECRT), blood samples were collected on days 0, 0.5, 1, 2, 3, 5, 7, 10 and 14 for pharmacokinetics, and the deer were killed on days 14 or 15 for total nematode count. The control group averaged 1264 adult Ostertagia-type nematode parasite species and treatment efficacy was 77.4% for moxidectin injection, 26% for oral moxidectin and 27.6% for pour-on moxidectin, while the treatment efficacy was 72.4% for abamectin injection, 70.1% for oral abamectin (Hi-Mineral) and 34.1% for pour-on abamectin. Both moxidectin and abamectin injections were significantly more efficacious than their equivalent pour-ons. There was a significant difference in efficacy between oral abamectin (Hi-Mineral) and oral moxidectin (P<0.01). The control group averaged 2956 adult lungworm (Dictyocaulus eckerti) and 50 Oesophagostomum venulosum in the large intestine and treatment efficacy against these nematodes was 100% for all treatments. There were negligible numbers of other gastro-intestinal nematodes. At slaughter, there was a significant correlation (P=0.02) between FEC and Ostertagia-type nematodes in the untreated controls. Relatively few eggs were found in faeces from treated animals at 7 and 14 days post-treatment despite significant worm burdens in all six treatment groups, suggesting egg-laying suppression in resistant nematodes, and all three different FECRT calculations tended to overestimate the efficacy of the treatments compared with actual nematode counts. Peak plasma concentrations (Cmax) for both actives were measured 12h after treatment for injection and oral and at 5 days for pour-on. Cmax (ng/ml) for moxidectin injection, oral and pour on were 71.8, 8.3 and 0.4, respectively, and for abamectin injection, oral and pour-on were 62.1, 30.3 and 10.0, respectively. Area under the curve (AUC) estimates for moxidectin injection, oral and pour-on were 106.6, 12.9 and 6.1, respectively, and for abamectin injection, oral and pour-on were 162.7, 57.5 and 74.3, respectively. The results demonstrate that significant anthelmintic resistance to moxidectin and abamectin is present on this deer farm. However, the injection was the most effective route of administration in young deer for both anthelmintics, although <80% efficacious. We conclude that the FECRT is unreliable in deer when anthelmintic resistance is present. PMID- 24144516 TI - Efficacy of Milbemax (milbemycin oxime + praziquantel) in the treatment of dogs experimentally infected with Crenosoma vulpis. AB - Crenosoma vulpis, the fox lungworm, infects wild and domestic canids and is a cause of chronic respiratory disease in dogs in North America and Europe. The objective of this study was to determine the efficacy of milbemycin oxime (0.5mg/kg)/praziquantel (5mg/kg) (Milbemax; Novartis Animal Health, Inc.) against C. vulpis infection in a randomized, blinded, placebo-controlled study using experimentally infected dogs. Sixteen beagles (8 males, 8 females) were each given 100 infective third-stage larvae of C. vulpis. Fecal samples were examined for first-stage larvae by quantitative Baermann examination pre-exposure and at days 21, 28, 35, 42 and 49 post-infection (PI). All of the dogs were shedding larvae in the feces at 21 days PI. The dogs were randomly assigned to one of two groups. At 28 days PI, Group 1 (4 males, 4 females) received placebo only while Group 2 (4 males, 4 females) received a single treatment of milbemycin oxime (0.5mg/kg) and praziquantel (5mg/kg). The 16 dogs were euthanized and necropsied at 49 days PI. Lungs were removed, assessed for gross lesions (graded on a subjective scale 0-3 with 0 being normal) and C. vulpis were collected by lung flush and counted. Samples of lung tissue were preserved for evaluation of histopathology and the lesions graded on a subjective scale (0-3 with 0 being normal). Gross and histopathology lesions were detected in all 8 untreated Group 1 dogs with mean subjective lesion scores of 1.8 +/- 0.7 (range 1-3) and 3.0 +/- 0.0 (range 3), respectively. Gross lesions were observed in 3/8 and histopathology lesions in all 8 of the treated Group 2 dogs with mean subjective lesion scores of 0.4 +/- 0.5 (range 0-1) and 1.3 +/- 0.4 (range 1-2), respectively. The mean (geometric) number for adult C. vulpis recovered in untreated dogs was 48.3 (range 25-70) compared with 0.65 (range 0-2) in animals treated with Milbemax. The resulting efficacy against C. vulpis was 98.7%. The number of C. vulpis was significantly lower for treated dogs than the burden in the untreated group (p=0.0002). A single dose of Milbemax (milbemycin oxime 0.5mg/kg+praziquantel 5mg/kg) was highly effective for the treatment of patent C. vulpis infection in dogs. A dosing interval for the prevention of clinical disease in dogs exposed to natural infections has not been established. PMID- 24144517 TI - Pregnancy screening strategies for potentially challenging patients before diagnostic nuclear medicine procedures: qualitative survey analysis. AB - Because of the ionizing radiation used in diagnostic nuclear medicine procedures, it is recommended that all female patients of childbearing age be questioned about their pregnancy status before the procedure begins. Several patient groups have been identified as potentially difficult to question: teenagers, unconscious or sedated patients, patients with language or cultural barriers, and patients with mental disability. Our aim was to capture the thoughts and opinions of nuclear medicine personnel in Australia and New Zealand regarding pregnancy screening strategies before diagnostic imaging procedures. METHODS: Members of the Australian and New Zealand Society of Nuclear Medicine were invited to complete an online survey. Section 4 consisted of open-response questions asking participants to describe the strategies they use to question a patient about pregnancy status in 4 potentially difficult clinical scenarios. The content of the responses was analyzed. RESULTS: For each question, 232 responses were recorded. The most commonly used strategies included questioning teenage girls away from their parents, referring to medical notes for unconscious patients, using an interpreter and visual aids for patients with language barriers, and asking a caregiver or relative of mentally disabled patients. Pregnancy testing was used when there was doubt about the patient's pregnancy status. Personal questions about menstrual and sexual history were often asked to determine the risk of pregnancy. CONCLUSION: The study revealed that a variety of strategies are used by nuclear medicine personnel in Australia and New Zealand to determine the pregnancy status of patients. A standardized practice guideline may be useful to ensure a consistent approach to questioning that would optimize the accuracy of pregnancy assessment and reduce the possibility of fetal irradiation. PMID- 24144518 TI - Osteoblastoma is a metabolically active benign bone tumor on 18F-FDG PET imaging. AB - We describe a case of a 9-y-old girl who on (18)F-FDG PET imaging was found to have a highly metabolically active sacral tumor with an average standarized uptake value of 6.2. The tumor was proven to be osteoblastoma by pathologic examination. Osteoblastoma is a relatively rare benign primary bone tumor and occurs predominantly in patients younger than 20 y. The most common area of involvement is the spine. Osteoblastoma has been reported to be metabolically active on (18)F-FDG PET imaging, with an average standarized uptake value of 3.2, which renders (18)F-FDG PET imaging unable to differentiate benign from malignant primary bone tumors. To our knowledge, only 5 cases of osteoblastoma evaluated by (18)F-FDG PET imaging have been reported in the literature; all were metabolically active on (18)F-FDG PET imaging. The objective of this case report is to show that a metabolically active primary bone tumor on (18)F-FDG PET imaging might be benign and not necessarily malignant. PMID- 24144520 TI - Fiber-reinforced composite anterior bridge in pediatric traumatology: clinical considerations. AB - This article describes the protocol for creation of a fiber-reinforced composite bridge for temporary treatment of traumatic tooth loss affecting young adult dentition. This non-invasive solution is justified by the time lapse between the end of orthodontic treatment and the moment when the state of maturity of the various tissues makes it possible to install a conventional or implant-based prosthesis. PMID- 24144521 TI - The prevalence of bipolar disorder in general primary care samples: a systematic review. AB - OBJECTIVE: To obtain an estimate of the prevalence of bipolar disorder in primary care. METHODS: We used the Preferred Reporting Items for Systematic Reviews and Meta-Analyses method to conduct a systematic review in January 2013. We searched seven databases with a comprehensive list of search terms. Included articles had a sample size of 200 patients or more and assessed bipolar disorder using a structured clinical interview or bipolar screening questionnaire in random adult primary care patients. Risk of bias in each study was also assessed. RESULTS: We found 5595 unique records in our search. Fifteen studies met our inclusion criteria. The percentage of patients with bipolar disorder found on structured psychiatric interviews in 10 of 12 studies ranged from 0.5% to 4.3%, and a positive screen for bipolar disorder using a bipolar disorder questionnaire was found in 7.6% to 9.8% of patients. CONCLUSION: In 10 of 12 studies using a structured psychiatric interview, approximately 0.5% to 4.3% of primary care patients were found to have bipolar disorder, with as many as 9.3% having bipolar spectrum illness in some settings. Prevalence estimates from studies using screening measures that have been found to have low positive predictive value were generally higher than those found using structured interviews. PMID- 24144522 TI - [Ocular involvement in familial amyloid polyneuropathy]. AB - Familial amyloid polyneuropathy (FAP) or transthyretin (TTR) amyloid polyneuropathy is a progressive sensorimotor and autonomic neuropathy of adult onset, which is transmitted as an autosomal dominant trait. In addition to neurologic symptoms, FAP may be associated with weight loss, cardiac and renal failure and ocular complications. FAP is a devastating disease, causing death within 10years after the first symptoms. The TTR Val30Met mutation is the most common of more than 100 amyloidogenic mutations identified worldwide. Liver transplantation (LT) is currently the only treatment for preventing synthesis of the amyloidogenic variants of TTR. LT can halt progression of the neuropathy in up to 70% of cases and doubles the overall median survival of young Val30Met patients. Oral administration of tafamidis, which prevents deposition of mutated TTR, is now available to delay neurologic complications in early stages of the disease. Ocular manifestations of FAP are frequent and mainly include keratoconjunctivitis sicca, secondary glaucoma, vitreous deposits and pupillary abnormalities. Retinal and choroidal vascular abnormalities are more rare. Since ocular TTR is synthesized, at least in part, in the retinal pigment epithelium, LT does not influence the course of ocular involvement. The effects of tafamidis on the latter are still unknown. Because LT and symptomatic treatments greatly improve life expectancy of patients with FAP, ocular involvement is becoming a more frequent challenge to address. This review summarizes the pathophysiology, clinical findings and possible treatments of ocular manifestations of FAP. PMID- 24144523 TI - [Diagnostic value of multidisciplinary meetings on orbital inflammatory pathologies discussed in Nantes University Medical Center]. AB - INTRODUCTION: Observational study of the diagnoses and the treatment modalities used for orbital inflammatory pathologies discussed in multidisciplinary meetings (MDM) in Nantes University Medical Center over 4 years. MATERIAL AND METHOD: A multidisciplinary meeting to discuss eyelid and orbital pathologies (excluding cancer) has been held in Nantes three times per year since October 2008. This retrospective study focuses on the cases of orbital inflammatory pathologies discussed at this meeting from October 2008 to October 2012 (49 cases included). RESULTS: Twenty-eight (57%) patients were diagnosed with orbital inflammation, 16 (33%) cases with isolated myositis and 5 (10%) with dacryoadenitis. In the diagnostic work-up, orbital biopsy was performed in 64% of orbital inflammation cases, 38% of myositis cases and 80% of dacryoadenitis cases. These specimens led to the diagnosis of 9 lymphomas, 2 histiocytoses and 1 metastasis. The internal medicine work-up allowed for the diagnosis of 3 granulomatoses with polyangiitis, one patient with sarcoidosis, and one patient with tuberculosis. Despite work-up, there remained 14 (29%) idiopathic orbital inflammatory syndromes (IOIS). DISCUSSION: The MDM of orbital pathology allows for the collective approach to the most difficult cases of management and is not concerned with stable orbitopathies or those presenting no diagnostic dilemma. Despite a multidisciplinary, rational etiologic work-up (frequently involving a biopsy), we find a higher rate of IOIS than reported in the literature. CONCLUSION: A multidisciplinary approach appears to be useful in improving management of orbital disease. PMID- 24144524 TI - [Optimizing the financial impact of transitioning to transconjunctival vitrectomy and microincisional phacoemulsification]. AB - OBJECTIVES: To report the financial impact of using modern lens and vitreoretinal surgical techniques. MATERIALS AND METHOD: Bottom-up sterilization and consumables costs for new surgical techniques (microincisional coaxial phacoemulsification and transconjunctival sutureless vitrectomy) and the corresponding former techniques (phacoemulsification with 3.2-mm incision and 20G vitrectomy) were determined. These costs were compared to each other and to the target costs of the Diagnosis Related Groups for public hospitals (Groupes Homogenes de Sejours [GHS]) concerned, extracted from the analytic accounting data of the French National Cost Study (Etude Nationale des Couts [ENC]) for 2009 (target=sum of sterilization costs posted under medical logistics, consumables, implantable medical devices, and special pharmaceuticals posted as direct expenses). RESULTS: For outpatient lens surgery with or without vitrectomy (GHS code: 02C05J): the ENC's target cost for 2009 was 339? out of a total of 1432?. The cost detailed in this study was 4 % higher than the target cost when the procedure was performed using the former technique (3.2mm sutured incision) and 12 % lower when the procedure was performed using the new technique (1.8mm sutureless) after removing now unnecessary consumables and optimization of the technique. For level I retinal detachment surgeries (GHS code: 02C021): the ENC's 2009 target cost was 641? out of a total of 3091?. The cost specified in this study was 1 % lower than the target cost when the procedure was done using the former technique (20-G vitrectomy) and 16 % less when the procedure was performed using the new technique (transconjunctival vitrectomy) after removal of now unnecessary consumables and optimization of the technique. DISCUSSION AND CONCLUSIONS: Contrary to generally accepted ideas, implementing modern techniques in ocular surgery can result in direct cost and sterilization savings when the operator takes advantage of the possibilities these techniques offer in terms of simplification of the procedures to do away with consumables that are no longer necessary. PMID- 24144525 TI - Enzymology of the carotenoid cleavage dioxygenases: reaction mechanisms, inhibition and biochemical roles. AB - Carotenoid cleavage dioxygenases (CCDs) are a large family of non-heme iron (II) dependent enzymes. CCDs catalyse the selective oxidative cleavage of carotenoids to produce apocarotenoids. Apocarotenoid derived molecules form important signalling molecules in plants in the form of abscisic acid and strigolactone and in mammals in the form of retinal. Very little is known biochemically about the CCDs and only a handful of CCDs have been biochemically characterised. Mechanistically, debate surrounds whether CCDs utilise a mono or dioxygenase mechanism. Here, we review the biochemical roles of CCDs, discuss the mechanisms by which CCD cleavage is proposed to occur, and discuss recent reports of selective CCD enzyme inhibitors. PMID- 24144527 TI - Making drug development visible--and viable. PMID- 24144526 TI - MauG, a diheme enzyme that catalyzes tryptophan tryptophylquinone biosynthesis by remote catalysis. AB - MauG contains two c-type hemes with atypical physical and catalytic properties. While most c-type cytochromes function simply as electron transfer mediators, MauG catalyzes the completion of tryptophan tryptophylquinone (TTQ)(1) biosynthesis within a precursor protein of methylamine dehydrogenase. This posttranslational modification is a six-electron oxidation that requires crosslinking of two Trp residues, oxygenation of a Trp residue and oxidation of the resulting quinol to TTQ. These reactions proceed via a bis-Fe(IV) state in which one heme is present as Fe(IV)O and the other is Fe(IV) with axial heme ligands provided by His and Tyr side chains. Catalysis does not involve direct contact between the protein substrate and either heme of MauG. Instead it is accomplished by remote catalysis using a hole hopping mechanism of electron transfer in which Trp residues of MauG are reversibly oxidized. In this process, long range electron transfer is coupled to the radical mediated chemical reactions that are required for TTQ biosynthesis. PMID- 24144528 TI - Comparison of clinical outcomes and toxicity in endometrial cancer patients treated with adjuvant intensity-modulated radiation therapy or conventional radiotherapy. AB - PURPOSE: To evaluate the treatment outcomes and toxicity in endometrial cancer patients treated with hysterectomy and adjuvant intensity-modulated radiation therapy (IMRT) or conventional radiotherapy (CRT). METHODS: There were 101 patients with stage IA-IIIC2 endometrial carcinoma treated with hysterectomy and adjuvant radiotherapy. In total, 36 patients received adjuvant CRT and 65 were treated with adjuvant IMRT. The endpoints were overall survival, local failure free survival, and disease-free survival. Patients were assessed for acute toxicity weekly according to the Common Terminology Criteria for Adverse Events version 3.0. Late toxicity was evaluated according to the Radiation Therapy Oncology Group and the European Organization for Research and Treatment of Cancer Late Radiation Morbidity Scoring Schema. RESULTS: The 5-year overall survival, local failure-free survival, and disease-free survival for the CRT group and the IMRT group were 82.9% versus 93.5% (p = 0.26), 93.7% versus 89.3% (p = 0.68), and 88.0% versus 82.8% (p = 0.83), respectively. Four (11.1%) patients had Grade 3 or greater acute gastrointestinal (GI) toxicity and three (8.3%) patients had Grade 3 or greater acute genitourinary (GU) toxicity in the CRT group, whereas four (6.2%) patients had Grade 3 or greater acute GI toxicity in the IMRT group and no patient had severe GU toxicity. There was one (2.8%) patient who had Grade 3 or greater late GI toxicity and one (2.8%) patient had Grade 3 or greater late GU toxicity in the CRT group, whereas no patient had severe GI or GU toxicity in the IMRT group. CONCLUSION: Adjuvant IMRT for endometrial cancer patients had comparable clinical outcomes with CRT and had less acute and late toxicity. PMID- 24144529 TI - Oral tongue melanoma. PMID- 24144530 TI - Sleep disorders in perinatal women. AB - Insufficient sleep is common in the general population, and can result from environmental and psychosocial factors, medical and psychiatric disorders, and sleep disorders, such as insomnia, circadian rhythm disorders, sleep apnoea and restless legs. Women are particularly at risk for sleep disorders, and complaints of sleep disturbance are more prevalent among women than men across the life span. During the perinatal period, many common sleep disorders, such as obstructive sleep apnoea or restless legs may be exacerbated, or in the case of insomnia or narcolepsy, treatment options may change. In addition, the role of circadian rhythms in fertility and perinatal health is just beginning to be appreciated. In this chapter, we provide an overview of the current knowledge of the unique aspects of diagnosis and treatment of sleep disorders during the perinatal period. PMID- 24144531 TI - High-intensity interval training in patients with lifestyle-induced cardiometabolic disease: a systematic review and meta-analysis. AB - BACKGROUND/AIM: Cardiorespiratory fitness (CRF) is a strong determinant of morbidity and mortality. In athletes and the general population, it is established that high-intensity interval training (HIIT) is superior to moderate intensity continuous training (MICT) in improving CRF. This is a systematic review and meta-analysis to quantify the efficacy and safety of HIIT compared to MICT in individuals with chronic cardiometabolic lifestyle diseases. METHODS: The included studies were required to have a population sample of chronic disease, where poor lifestyle is considered as a main contributor to the disease. The procedural quality of the studies was assessed by use of a modified Physiotherapy Evidence Base Database (PEDro) scale. A meta-analysis compared the mean difference (MD) of preintervention versus postintervention CRF (VO2peak) between HIIT and MICT. RESULTS: 10 studies with 273 patients were included in the meta analysis. Participants had coronary artery disease, heart failure, hypertension, metabolic syndrome and obesity. There was a significantly higher increase in the VO2peak after HIIT compared to MICT (MD 3.03 mL/kg/min, 95% CI 2.00 to 4.07), equivalent to 9.1%. CONCLUSIONS: HIIT significantly increases CRF by almost double that of MICT in patients with lifestyle-induced chronic diseases. PMID- 24144532 TI - Sedentary behaviour and physical inactivity assessment in primary care: the Rapid Assessment Disuse Index (RADI) study. AB - BACKGROUND: The emerging evidence of the effects of sedentary time on health outcomes suggests a need to better measure this exposure. Healthcare settings, however, are not equipped with a tool that can quickly assess the sedentary habits of their patient population. The purpose of this study was to validate a tool for rapidly quantifying and tracking the sedentary time and low levels of daily lifestyle physical activity among primary care patients. METHODS: The study examined the test-retest reliability and validity of the rapid assessment disuse index (RADI) among adult patients from a large primary care clinic. Patients completed RADI (comprised of 3 items: sitting, moving and stair climbing) twice, followed by accelerometer monitoring. Test-retest reliability was computed, and the correlation between survey responses and accelerometry was determined. A receiver operating characteristic curve was constructed and the area under the curve (AUC) was calculated. RESULTS: RADI was temporally stable (intraclass correlation coefficients 0.79), and a higher score was significantly correlated with greater sedentary time (rho=0.40; p<0.01), fewer sedentary to active transitions (rho=-0.42; p<0.01), and less light-intensity physical activity (rho= 0.40; p<0.01). The ability of RADI to detect patients with high levels of sedentary time was fair (AUC=0.72). CONCLUSIONS: This brief assessment tool, designed to quickly identify patients with high levels of sitting and low daily physical activity, exhibits good reliability and moderate validity. RADI can assist in providing recommendations at the point of care pertaining to modifying sedentary behaviour. PMID- 24144533 TI - Sensory and motor deficits exist on the non-injured side of patients with unilateral tendon pain and disability--implications for central nervous system involvement: a systematic review with meta-analysis. AB - INTRODUCTION: Tendinopathy manifests as activity-related tendon pain with associated motor and sensory impairments. Tendon tissue changes in animals present in injured as well as contralateral non-injured tendon. This review investigated evidence for bilateral sensory and motor system involvement in unilateral tendinopathy in humans. METHODS: A comprehensive search of electronic databases, and reference lists using keywords relating to bilateral outcomes in unilateral tendinopathy was undertaken. Study quality was rated with the Epidemiological Appraisal Instrument and meta-analyses carried out where appropriate. Analysis focused on comparison of measures in the non-symptomatic side of patients against pain-free controls. RESULTS: The search revealed 5791 studies, of which 20 were included (117 detailed reviews, 25 met criteria). There were 17 studies of lateral epicondylalgia (LE) and one each for patellar, Achilles and rotator cuff tendinopathy. Studies of LE were available for meta analysis revealing the following weighted pooled mean deficits: pressure pain thresholds (-144.3 kPa; 95% CI -169.2 to -119.2 p<0.001), heat pain thresholds ( 1.2 degrees C; 95% CI -2.1 to -0.2, p<0.001), cold pain thresholds (3.1 degrees C; 95% CI 1.8 to 4.4, p<0.001) and reaction time (37.8 ms; 95% CI 24.8 to 50.7, p<0.001). DISCUSSION: Deficits in sensory and motor systems present bilaterally in unilateral tendinopathy. This implies potential central nervous system involvement. This indicates that rehabilitation should consider the contralateral side of patients. Research of unilateral tendinopathy needs to consider comparison against pain-free controls in addition to the contralateral side to gain a complete understanding of sensory and motor features. PMID- 24144534 TI - Gender equity in dental academics: gains and unmet challenges. PMID- 24144535 TI - MHC-NP: predicting peptides naturally processed by the MHC. AB - We present MHC-NP, a tool for predicting peptides naturally processed by the MHC pathway. The method was part of the 2nd Machine Learning Competition in Immunology and yielded state-of-the-art accuracy for the prediction of peptides eluted from human HLA-A*02:01, HLA-B*07:02, HLA-B*35:01, HLA-B*44:03, HLA B*53:01, HLA-B*57:01 and mouse H2-D(b) and H2-K(b) MHC molecules. We briefly explain the theory and motivations that have led to developing this tool. General applicability in the field of immunology and specifically epitope-based vaccine are expected. Our tool is freely available online and hosted by the Immune Epitope Database at http://tools.immuneepitope.org/mhcnp/. PMID- 24144536 TI - Percutaneous vertebroplasty combined with zoledronic acid for the treatment of painful osteolytic spinal metastases in patients with breast cancer. AB - PURPOSE: To assess retrospectively the efficacy and safety of percutaneous vertebroplasty (PVP) combined with zoledronic acid (ZA) for the treatment of painful osteolytic spinal metastases from breast cancer. MATERIALS AND METHODS: PVP was performed in 43 patients with breast cancer and painful osteolytic spinal metastases; 126 vertebrae were treated. The patients subsequently received 4 mg ZA via a 15-minute intravenous infusion every 4 weeks for 12 months. Pain and quality of life (QoL) were assessed using a visual analog scale (VAS) and Karnofsky performance scale (KPS), respectively, 24 hours before PVP and 24 hours, 1 month, 3 months, 6 months, and 12 months after PVP. Skeletal-related events (SREs) were assessed for 12 months following the intervention. RESULTS: The mean VAS scores decreased significantly from 7.6 +/- 1.9 at 24 hours before PVP to 3.6 +/- 1.4 at 24 hours, 2.0 +/- 1.5 at 1 month, 2.8 +/- 1.6 at 3 months, 3.1 +/- 0.8 at 6 months, and 2.5 +/- 0.9 at 12 months after the intervention (P < .05). KPS scores increased significantly after the combination treatment (P < .05). Compared with previous studies without PVP or ZA treatment, this patient group had a lower incidence of SREs. No major complications were observed. CONCLUSIONS: PVP combined with ZA was shown to be a highly effective and safe combination therapy to relieve pain and improve QoL in patients with osteolytic spinal metastases from breast cancer. The combination therapy also prevented the occurrence of SREs. PMID- 24144537 TI - Morphologic outcome after endovascular treatment of complicated type B aortic dissection. AB - PURPOSE: To investigate the long-term morphologic changes of the aorta after thoracic endovascular aortic repair (TEVAR) for acute complicated type B aortic dissection and to analyze whether these changes differed between DeBakey class IIIa and IIIb dissections. MATERIALS AND METHODS: During the period 1999-2009, 58 patients with acute complicated type B aortic dissection were treated with TEVAR. Seven patients lacked follow-up data, leaving 51 patients-17 patients with DeBakey IIIa aortic dissection and 34 patients with DeBakey IIIa aortic dissection IIIb-for inclusion in the study. Computed tomography scans performed before and after TEVAR were evaluated. Maximum thoracic and abdominal aortic diameters and diameters of the true lumen and false lumen at the level of the maximum aortic diameter in the thorax and abdomen were analyzed as well as degree of thrombosis of the false lumen. RESULTS: There was an overall significant reduction of the thoracic aortic diameter, increased true lumen diameter, and reduced false lumen diameter (P < .05). Total thrombosis of the false lumen, with or without reintervention, was seen in 53% of all patients, in 41% primarily and in 12% after reintervention. The IIIa group had a higher degree of total false lumen thrombosis. All patients in the IIIb group had total thrombosis of the false lumen along the stent graft. CONCLUSIONS: Long-term follow-up showed favorable aortic remodeling after TEVAR for acute complicated type B aortic dissection. Total thrombosis of the false lumen occurred more often in patients with DeBakey IIIa aortic dissection compared with patients with DeBakey IIIb aortic dissection. PMID- 24144539 TI - In vitro and in vivo models to study human listeriosis: mind the gap. AB - Listeria monocytogenes (Lm) is the etiological agent of listeriosis, one of the deadliest human foodborne infections. Lm is able to cross the intestinal, placental and blood-brain barriers, leading to septicemia, fetoplacental infection, meningitis and encephalitis. The intracellular life cycle of this facultative intracellular bacterium has been studied in detail in in vitro cell culture systems. Lm enters in non-phagocytic cells in an InlA-Ecad and/or InB-Met dependent manner. Lm then escapes from its internalization vacuole via the action of the pore forming toxin LLO and spreads from cell to cell in an ActA-dependent manner. In vivo studies in "humanized" mouse models and human epidemiological data have led to the deciphering of the mechanisms underlying Lm crossing of intestinal and placental barriers. As illustrated in this review, in vivo outcomes could not be deduced directly from in vitro observations, and led to revisit the intracellular fate of Lm during infection. PMID- 24144538 TI - Percutaneous intraportal application of adipose tissue-derived mesenchymal stem cells using a balloon occlusion catheter in a porcine model of liver fibrosis. AB - PURPOSE: To investigate the safety and effectiveness of a novel endovascular approach for therapeutic cell delivery using a balloon occlusion catheter in a large animal model of liver fibrosis. MATERIALS AND METHODS: Transcatheter arterial embolization with ethiodized oil (Ethiodol) and ethanol was used to induce liver damage in 11 pigs. Mesenchymal stem cells (MSCs) were harvested from adipose tissue and engineered to express green fluorescent protein (GFP). A balloon occlusion catheter was positioned in the bilateral first-order portal vein branches 2 weeks after embolization to allow intraportal application of MSCs in six experimental animals. MSCs were allowed to dwell for 10 minutes using prolonged balloon inflation. Five control animals received a sham injection of normal saline in a similar fashion. Hepatic venous pressure gradient (HVPG) was measured immediately before necropsy. Specimens from all accessible lobes were obtained with ultrasound-guided percutaneous 18-gauge biopsy 2 hours after cell application. All animals were euthanized within 4 weeks. Fluorescent microscopy was used to assess the presence and distribution of cells. RESULTS: Liver injury and fibrosis were successfully induced in all animals. MSCs (6-10 * 10(7)) were successfully delivered into the portal vein in the six experimental animals. Cell application was not associated with vascular complications. HVPG showed no instances of portal hypertension. GFP-expressing MSCs were visualized in biopsy specimens and were distributed primarily within the sinusoidal spaces; however, 4 weeks after implantation, MSCs could not be identified in histologic specimens. CONCLUSIONS: A percutaneous endovascular approach for cell delivery using a balloon occlusion catheter proved safe for intraportal MSC application in a large animal model of liver fibrosis. PMID- 24144540 TI - Acute kidney injuries induced by various irrigation pressures in rat models of mild and severe hydronephrosis. AB - OBJECTIVE: To clarify whether tolerance to irrigation pressure could be modified over varying degrees of kidney obstruction during the endoscopic treatment of kidney stones in a rat model. METHODS: A total of 126 rats were randomly allocated into 2 experimental groups and a control group. The experimental groups underwent a surgical procedure to induce mild (group M, n = 60) or severe (group S, n = 60) hydronephrosis. In each group, the rats were then randomly allocated into 4 subgroups (M0 to M3 and S0 to S3) of respectively 6, 18, 18, and 18 rats. Groups 0 to 3 were respectively perfused with 0 (no irrigation), 20, 60, and 100 mm Hg pressure fluid. The control group underwent no surgical procedures and was only perfused with 100 mm Hg pressure fluid. Acute kidney injuries were assessed by analyzing the kidney microstructure, tubular cell apoptosis, kidney injury molecule-1, and cysteine-rich 61 (Cyr61/CCN1) expression using immunohistochemistry. RESULTS: No abnormalities were observed for the control group, groups 0, or 1. In group 2, abnormalities were observed only in the S group, whereas all kidneys in group 3 suffered acute kidneys injuries, along with occurrence of tubular cells necrosis, increased apoptosis, and increased expression of kidney injury molecule-1 and Cyr61. CONCLUSION: Rats with severely obstructed kidneys were more likely to suffer acute kidney injuries than those with less obstructed kidneys when exposed to higher kidney irrigation pressures. This suggests that the pressure should be controlled and reduced when performing endourologic procedures in the context of kidney obstruction. PMID- 24144541 TI - Investigating the interaction between peptides of the amphipathic helix of Hcf106 and the phospholipid bilayer by solid-state NMR spectroscopy. AB - The chloroplast twin arginine translocation (cpTat) system transports highly folded precursor proteins into the thylakoid lumen using the protonmotive force as its only energy source. Hcf106, as one of the core components of the cpTat system, is part of the precursor receptor complex and functions in the initial precursor-binding step. Hcf106 is predicted to contain a single amino terminal transmembrane domain followed by a Pro-Gly hinge, a predicted amphipathic alpha helix (APH), and a loosely structured carboxy terminus. Hcf106 has been shown biochemically to insert spontaneously into thylakoid membranes. To better understand the membrane active capabilities of Hcf106, we used solid-state NMR spectroscopy to investigate those properties of the APH. In this study, synthesized peptides of the predicted Hcf106 APH (amino acids 28-65) were incorporated at increasing mol.% into 1-palmitoyl-2-oleoyl-sn-glycero phosphocholine (POPC) and POPC/MGDG (monogalactosyldiacylglycerol; mole ratio 85:15) multilamellar vesicles (MLVs) to probe the peptide-lipid interaction. Solid-state (31)P NMR and (2)H NMR spectroscopic experiments revealed that the peptide perturbs the headgroup and the acyl chain regions of phospholipids as indicated by changes in spectral lineshape, chemical shift anisotropy (CSA) line width, and (2)H order SCD parameters. In addition, the comparison between POPC MLVs and POPC/MGDG MLVs indicated that the lipid bilayer composition affected peptide perturbation of the lipids, and such perturbation appeared to be more intense in a system more closely mimicking a thylakoid membrane. PMID- 24144542 TI - Lipid bilayers containing sphingomyelins and ceramides of varying N-acyl lengths: a glimpse into sphingolipid complexity. AB - The thermotropic properties of aqueous dispersions of sphingomyelins (SM) and ceramides (Cer) with N-acyl chains varying from C6:0 to C24:1, either pure or in binary mixtures, have been examined by differential scanning calorimetry. Even in the pure state, Cer and particularly SM exhibited complex endotherms, and their thermal properties did not vary in a predictable way with changes in structure. In some cases, e.g. C18:0 SM, atomic force microscopy revealed coexisting lamellar domains made of a single lipid. Partial chain interdigitation and metastable crystalline states were deemed responsible for the complex behavior. SM:Cer mixtures (90:10mol ratio) gave rise to bilayers containing separate SM rich and Cer-rich domains. In vesicles made of more complex mixtures (SM:PE:Chol, 2:1:1), it is known that sphingomyelinase degradation of SM to Cer is accompanied by vesicle aggregation and release of aqueous contents. These vesicles did not reveal observable domain separation by confocal microscopy. Vesicle aggregation occurred at a faster rate for those bilayers that appeared to be more fluid according to differential scanning calorimetry. Content efflux rates measured by fluorescence spectroscopy were highest with C18:0 and C18:1 SM, and in general those rates did not vary regularly with other physical properties of SM or Cer. In general the individual SM and Cer appear to have particular thermotropic properties, often unrelated to the changes in N-acyl chain. PMID- 24144543 TI - Electroporation of heterogeneous lipid membranes. AB - Electroporation is the basis for the transfection of genetic material and for drug delivery to cells, including electrochemotherapy for cancer. By means of molecular dynamics many aspects of membrane electroporation have been unveiled at the molecular detail in simple, homogeneous, lipid bilayers. However, the correspondence of these findings ?with the process happening in cell membranes requires, at least, the consideration of laterally structured membranes. Here, I present a systematic molecular dynamics study of bilayers composed of different liquid-ordered and liquid-disordered lipid phases subjected to a transversal electric field. The simulations reveal two significant results. First, the electric field mainly affects the properties of the disordered phases, so that electroporation takes place in these membrane regions. Second, the smaller the disordered domains are, the faster they become electroporated. These findings may have a relevant significance in the experimental application of cell electroporation in vivo since it implies that electro-induced and pore-mediated transport processes occur in particularly small disordered domains of the plasma membrane, thus locally affecting only specific regions of the cell. PMID- 24144544 TI - Impaired executive function following ischemic stroke in the rat medial prefrontal cortex. AB - Small (lacunar) infarcts frequently arise in frontal and midline thalamic regions in the absence of major stroke. Damage to these areas often leads to impairment of executive function likely as a result of interrupting connections of the prefrontal cortex. Thus, patients experience frontal-like symptoms such as impaired ability to shift ongoing behavior and attention. In contrast, executive dysfunction has not been demonstrated in rodent models of stroke, thereby limiting the development of potential therapies for human executive dysfunction. Male Sprague-Dawley rats (n=40) underwent either sham surgery or bilateral endothelin-1 injections in the mediodorsal nucleus of the thalamus or in the medial prefrontal cortex. Executive function was assessed using a rodent attention set shifting test that requires animals to shift attention to stimuli in different stimulus dimensions. Medial prefrontal cortex ischemia impaired attention shift performance between different stimulus dimensions while sparing stimulus discrimination and attention shifts within a stimulus dimension, indicating a selective attention set-shift deficit. Rats with mediodorsal thalamic lacunar damage did not exhibit a cognitive impairment relative to sham controls. The selective attention set shift impairment observed in this study is consistent with clinical data demonstrating selective executive disorders following stroke within specific sub-regions of frontal cortex. These data contribute to the development and validation of a preclinical animal model of executive dysfunction, that can be employed to identify potential therapies for ameliorating cognitive deficits following stroke. PMID- 24144545 TI - Corticotropin-releasing factor receptor type-2 is involved in the cocaine-primed reinstatement of cocaine conditioned place preference in rats. AB - Here we explored the in vivo role of brain corticotropin-releasing factor receptor type-2 (CRFR2) in cocaine-primed reinstatement of drug seeking. Conditioned place preference (CPP) procedure was used to assess the acquisition, extinction and reinstatement of cocaine-seeking behavior in rats. First, expressions of CRFR2 were shown to be affected in a brain region-specific manner within cocaine-induced CPP and cocaine-extinct CPP models. Bilateral blockade of CRFR2 in the dorsal portion of the medial prefrontal cortex (mPFC), or hippocampus (HP) was partially inhibited, but in the dorsal striatum (DS) did not affect, the cocaine-primed reinstatement of cocaine CPP. PMID- 24144546 TI - Spatial learning, monoamines and oxidative stress in rats exposed to 900 MHz electromagnetic field in combination with iron overload. AB - The increasing use of mobile phone technology over the last decade raises concerns about the impact of high frequency electromagnetic fields (EMF) on health. More recently, a link between EMF, iron overload in the brain and neurodegenerative disorders including Parkinson's and Alzheimer's diseases has been suggested. Co-exposure to EMF and brain iron overload may have a greater impact on brain tissues and cognitive processes than each treatment by itself. To examine this hypothesis, Long-Evans rats submitted to 900 MHz exposure or combined 900 MHz EMF and iron overload treatments were tested in various spatial learning tasks (navigation task in the Morris water maze, working memory task in the radial-arm maze, and object exploration task involving spatial and non spatial processing). Biogenic monoamines and metabolites (dopamine, serotonin) and oxidative stress were measured. Rats exposed to EMF were impaired in the object exploration task but not in the navigation and working memory tasks. They also showed alterations of monoamine content in several brain areas but mainly in the hippocampus. Rats that received combined treatment did not show greater behavioral and neurochemical deficits than EMF-exposed rats. None of the two treatments produced global oxidative stress. These results show that there is an impact of EMF on the brain and cognitive processes but this impact is revealed only in a task exploiting spontaneous exploratory activity. In contrast, there are no synergistic effects between EMF and a high content of iron in the brain. PMID- 24144547 TI - Regional and subtype-specific loss of GnRH neurons is associated with diminished mating behavior in middle-aged male rats. AB - The current study was to examine the relationship between the number of gonadotropin-releasing hormone (GnRH) neurons and male sexual behavior in middle aged rats. Based on their sexual performance, middle-aged male rats (18-19 months) were assigned to three groups: (i) Group MIE (showing mounts, intromissions, and ejaculation), (ii) Group MI (displaying mounts and intromissions, but no ejaculation), and (iii) Group NC (showing no copulatory behavior). The brains of these middle-aged animals and of sexually active, young controls were collected and then examined for immunohistochemical localization of GnRH neurons. The numbers of two subtypes of GnRH neurons, smooth (s-GnRH) and irregular (i-GnRH), in the medial septum (MS), organum vasculosum of the lamina terminalis (OVLT), preoptic area (POA), and anterior hypothalamus (AH), were determined under a light microscope. As compared to young controls, an age related decrease in the number of s-GnRH neurons was found in the MS of MIE rats. Among three groups of middle-aged rats, Groups MIE and MI had more s-GnRH neurons in the POA and i-GnRH neurons in the OVLT and POA than Group NC. In addition, loss of s-GnRH and i-GnRH neurons in the MS was observed in Groups MI and NC and Group NC, respectively. Our results suggest that a decrease in GnRH neuron subtypes occurring in different brain regions might be critical for the loss of specific components of male rat sexual behavior during aging. PMID- 24144548 TI - Interindividual synchronization of brain activity during live verbal communication. AB - Verbal social interaction plays an important role both in the etiology and treatment of psychiatric disorders. However, the neural basis of social interaction has primarily been studied in the individual brain, neglecting the inter-individual perspective. Here, we show inter-individual neuronal coupling of brain activity during live verbal interaction, by investigating 11 pairs of good female friends who were instructed to speak about autobiographical life events during simultaneous fMRI acquisition. The analysis revealed that the time course of neural activity in areas associated with speech production was coupled with the time course of neural activity in the interlocutor's auditory cortex. This shows the feasibility of the new methodology, which may help elucidate basic reciprocal mechanisms of social interaction and the underpinnings of disordered communication. In particular, it may serve to study the process of psychotherapy on a neuronal level. PMID- 24144549 TI - The anteroventral third ventricle region is critical for the behavioral desensitization caused by repeated injections of angiotensin II. AB - A single central injection of angiotensin II (AngII) potently increases water intake; however, a growing body of research suggests that repeated, acute intracerebroventricular injections of AngII cause a reduction in the dipsogenic response to subsequent AngII. This AngII-induced behavioral desensitization is specific to the effects of angiotensin and mediated by the angiotensin type-1 (AT1) receptor. The neuroanatomical substrate for this phenomenon, however, remains unknown. The anteroventral third ventricle (AV3V) region is an important site for the behavioral and physiological actions of AngII. Therefore, we hypothesized that this region also mediates the effects of repeated central AngII administration. In support of this hypothesis, we found that repeated injections of AngII into the AV3V reduced water intake stimulated by a test injection of AngII given into this region. Moreover, repeated AngII injections in the AV3V reduced water intake after AngII was injected into the lateral ventricle. These studies also demonstrate that activation of the AT1 receptor within the AV3V is required for AngII-induced behavioral desensitization because direct injection of the AT1 receptor antagonist, losartan, into the AV3V blocked the desensitizing effect of repeated AngII injections into the lateral ventricle. These findings provide additional support for a role of the AV3V in the dipsogenic actions of AngII, and suggest that this region is critical for the desensitization that occurs after acute repeated central injections of AngII. PMID- 24144550 TI - Bizarre behaviors and risk assessment in 3xTg-AD mice at early stages of the disease. AB - Bizarre behaviors (stereotyped stretching, stereotyped rearing, backward movements and jumps) were conspicuously elicited in classical unconditioned tests with different levels of anxiogenic conditions. They were characterized for the first time as early-BPSD-like symptoms in 6 month-old male and female 3xTg-AD mice. The pattern of these behaviors differed from that exhibited by their age- and gender-matched NTg counterparts. Confrontation of an open and illuminated field was the best trigger of such behaviors as compared to mild neophobia in the corner test or the choice between two compartments in the dark-light box. Here we also report that increased freezing, delayed thigmotaxis and enhancement of emotional behaviors were early BPSD-like symptoms indicative of their response to low-stressful environments. Independently of the genotype, consistent gender effects pointed toward the relevance of female gender to study bizarre behaviors and risk assessment. The identification of items of behavior and its gender component were relevant to find out bidirectional and selective behavioral long lasting effects of postnatal handling. This early life treatment reduced freezing and most of the bizarre behaviors whereas potentiated risk assessment and the horizontal locomotor activity. In contrast, vertical exploratory activity was not modified by the treatment. The results also talk in favor of the beneficence of early-life interventions on the behavioral outcome in adulthood in both healthy and disease conditions. As shown, the consideration of bizarre behaviors and risk assessment may become an additional tool for evaluating BPSD-like symptoms in relation to preventive and/or therapeutical strategies targeted at AD. It may also have a role in the evaluation of the potential risk factors for the disease. PMID- 24144551 TI - Orthokeratology for slowing myopic progression in a pair of identical twins. AB - PURPOSE: To compare the axial length elongation and change in refractive errors in a pair of identical twins wearing orthokeratology (ortho-k) and single vision lenses (SVLs), respectively. CASE REPORT: Identical Twin A and B, who were 8 years of age, with the same amount of near activities, were assigned to wear ortho-k and SVLs randomly and they were monitored for two years for myopic progression. Twin A and B were assigned to wear ortho-k and SVLs, respectively. Myopic progression was evaluated by the change in axial length and in refractive errors. A faster axial length elongation was observed in each eye of Twin B during the two-year study period. The overall change in axial length was 0.52mm (OD) and 0.70 (OS) in Twin A and 0.77mm (OD) and 0.82mm (OS) in Twin B. In terms of cycloplegic refractive errors (SER), one month after ceasing lens wear (after completion of the two-year study), the increase (from baseline) were 11% (OD) and 48% (OS) in Twin A and 87% (OD) and 67% (OS) in Twin B. CONCLUSIONS: Ortho-k is more effective in controlling myopic progression in terms of axial elongation than wearing SVLs in this pair of identical twins. PMID- 24144552 TI - Clinical relevance of mupirocin resistance in Staphylococcus aureus. AB - Mupirocin is a topical antibiotic used for decolonization of meticillin susceptible S. aureus (MSSA) and meticillin-resistant S. aureus (MRSA), both in patients and in healthcare personnel, and for treatment of local skin and soft tissue infections caused by S. aureus and streptococcal species. Mupirocin prevents bacterial protein synthesis by inhibiting the bacterial isoleucyl-tRNA synthetase (IleRS). Low-level resistance against mupirocin, defined as minimum inhibitory concentration (MIC) of 8-256mg/L, results from a point mutation in the native IleRS, and high-level resistance (MIC >=512mg/L) is mediated by the mupA (ileS-2) gene, located on mobile genetic elements decoding for an alternate IleRS. EUCAST and BSAC clinical thresholds for S. aureus are <=1mg/L for susceptible and >256mg/L for resistant, placing the susceptible threshold at the epidemiological cut-off value (ECOFF). Isolates with MICs above the wild type (ECOFF 1mg/L) but without a recognized resistance mechanism (MIC <=4mg/L) will thus be reported intermediate. Resistance to mupirocin, both high- and low-level, reduces the effectiveness of decolonizing strategies for S. aureus or MRSA. Low level resistant isolates may initially be eradicated as effectively as susceptible isolates, but recolonization appears to be more usual. Increased use of mupirocin has been associated with emergence of resistance through enhanced selective pressure and cross-transmission. Unrestricted over-the-counter use and treatment of wounds and pressure sores with mupirocin are especially strongly associated with resistance. Yet emergence of mupirocin resistance following increased use has not been reported consistently, and an integrated understanding of all factors underlying the dynamics of mupirocin resistance in hospitals and communities is lacking. PMID- 24144553 TI - Reducing pathogen transmission in a hospital setting. Handshake versus fist bump: a pilot study. AB - Handshaking is a known vector for bacterial transmission between individuals. Handwashing has become a major initiative throughout healthcare systems to reduce transmission rates, but as many as 80% of individuals retain some disease-causing bacteria after washing. The fist bump is an alternative to the handshake that has become popular. We have determined that implementing the fist bump in the healthcare setting may further reduce bacterial transmission between healthcare providers by reducing contact time and total surface area exposed when compared with the standard handshake. PMID- 24144554 TI - Detection of lead(II) ions with a DNAzyme and isothermal strand displacement signal amplification. AB - A DNAzyme based method for the sensitive and selective quantification of lead(II) ions has been developed. A DNAzyme that requires Pb(2+) for activation was selected. An RNA containing DNA substrate was cleaved by the DNAzyme in the presence of Pb(2+). The 2',3'-cyclic phosphate of the cleaved 5'-part of the substrate was efficiently removed by Exonuclease III. The remaining part of the single stranded DNA (9 or 13 base long) was subsequently used as the primer for the strand displacement amplification reaction (SDAR). The method is highly sensitive, 200 pM lead(II) could be easily detected. A number of interference ions were tested, and the sensor showed good selectivity. Underground water samples were also tested, which demonstrated the feasibility of the current approach for real sample applications. It is feasible that our method could be used for DNAzyme or aptazyme based new sensing method developments for the quantification of other target analytes with high sensitivity and selectivity. PMID- 24144555 TI - Fabrication of 2D ordered mesoporous carbon nitride and its use as electrochemical sensing platform for H2O2, nitrobenzene, and NADH detection. AB - Two-dimensional ordered mesoporous carbon nitride (OMCN) has been successfully prepared for the first time using SBA-15 mesoporous silica and melamine as template and precursor respectively, by a nano hard-templating approach. A series of OMCN-x samples with different pyrolysis temperatures have been reported. The formation of these composite materials was verified by detailed characterization (e.g., Fourier transform infrared spectroscopy, X-ray photoelectron spectroscopy, N2 adsorption, X-ray diffraction, scanning electron microscopy, and transmission electron microscopy). The results showed that the materials were structurally well ordered with two-dimensional porous structure, high surface area and large pore volume. The influence of BET surface area and different amounts of N-bonding configurations formed at different pyrolysis temperatures of OMCN-x for the electrocatalysis towards hydrogen peroxide, nitrobenzene, and nicotinamide adenine dinucleotide were investigated in detail. Results indicated that OMCN treated at 800 degrees C with largest BET surface area and highest amounts of pyrindinic N showed improved electrocatalytic activity for H2O2, nitrobenzene, and NADH in neutral solution. PMID- 24144556 TI - Aptamer-based array electrodes for quantitative interferon-gamma detection. AB - Present work describes the methylene blue tagged thiolated aptamer-modified gold micro-array based biosensor for specific detection of IFN-gamma. The microchips with the microelectrode array were fabricated using standard silicon microfabrication technologies, and modified with methylene blue tagged aptamer using standard gold thiol chemistry. Electrodes were characterized and tested using Cyclic Voltammetric (CV) and Square Wave Voltammetry (SQW) measurements in a standard three-electrode format at room temperature. On an aptamer modified electrode, aptamer density was estimated to be about 4.4 * 10(12)molecules/cm(2). In IFN-gamma studies, oxidation peak currents were found to decrease and more than 50% signal suppression was achieved at 500 ng/ml. Further, the magnitude of signal suppression was found to be logarithmically proportional to the IFN-gamma in the concentration range of 1-500 ng/ml, with a detection limit of 1.3 ng/ml (i.e. 0.8 fmol in used sample volume of 10 ul). Biosensor showed negligible signal changes (5%) in a very high non-specific protein background, while still able to differentiate target protein IFN-gamma at 5 ng/ml. The results indicated that our sensor binds selectively to target molecules, and the non-specific binding where adsorption of BSA protein molecules may be effectively omitted from consideration. PMID- 24144557 TI - On-line protein capture on magnetic beads for ultrasensitive microfluidic immunoassays of cancer biomarkers. AB - Accurate, sensitive, multiplexed detection of biomarker proteins holds significant promise for personalized cancer diagnostics. Here we describe the incorporation of a novel on-line chamber to capture cancer biomarker proteins on magnetic beads derivatized with 300,000 enzyme labels and 40,000 antibodies into a modular microfluidic immunoarray. Capture and detection chambers are produced from PDMS on machined molds and do not require lithography. Protein analytes are captured from serum or other biological samples in the stirred capture chamber on the beads held in place magnetically. The beads are subsequently washed free of sample components, and wash solutions sent to waste. Removal of the magnet and valve switching sends the magnetic bead-protein bioconjugates into a detection chamber where they are captured on 8 antibody-decorated gold nanoparticle-film sensors and detected amperometrically. Most steps in the immunoassay including protein capture, washing and measurement are incorporated into the device. In simultaneous assays, the microfluidic system gave ultralow detection limits of 5 fg mL(-1) for interleukin-6 (IL-6) and 7 fg mL(-1) for IL-8 in serum. Accuracy was demonstrated by measuring IL-6 and IL-8 in conditioned media from oral cancer cell lines and showing good correlations with standard ELISAs. The on-line capture chamber facilitates rapid, sensitive, repetitive protein separation and measurement in 30 min in a semi-automated system adaptable to multiplexed protein detection. PMID- 24144558 TI - Unsubstituted phenothiazine as a superior water-insoluble mediator for oxidases. AB - The mediation of oxidases glucose oxidase (GOx), lactate oxidase (LOx) and cholesterol oxidase (ChOx) by a new electron shuttling mediator, unsubstituted phenothiazine (PTZ), was studied. Cyclic voltammetry and rotating-disk electrode measurements in nonaqueous media were used to determine the diffusion characteristics of the mediator and the kinetics of its reaction with GOx, giving a second-order rate constant of 7.6 * 10(3)-2.1 * 10(4)M(-1)s(-1) for water acetonitrile solutions containing 5-15% water. These values are in the range reported for commonly used azine-type mediators, indicating that PTZ is able to function as an efficient mediator. PTZ and GOx, LOx and ChOx were successfully co immobilised in sol-gel membrane on a screen-printed electrode to construct glucose, lactate and cholesterol biosensors, respectively, which were then optimised in terms of stability and sensitivity. The electrocatalytic oxidation responses showed a dependence on substrate concentration ranging from 0.6 to 32 mM for glucose, from 19 to 565 mM for lactate and from 0.015 to 1.0mM for cholesterol detection. Oxidation of substrates on the surface of electrodes modified with PTZ and enzyme membrane was investigated with double-step chronoamperometry and the results showed that the PTZ displays excellent electrochemical catalytic activities even when immobilised on the surface of the electrode. PMID- 24144559 TI - Continuous monitoring of Naproxen by a cytochrome P450-based electrochemical sensor. AB - This paper reports the characterization of an electrochemical biosensor for the continuous monitoring of Naproxen based on cytochrome P450. The electrochemical biosensor is based on the drop-casting of multi-walled carbon-nanotubes (MWCNTs) and microsomal cytochrome P4501A2 (msCYP1A2) on a graphite screen-printed electrode (SPE). The proposed biosensor was employed to monitor Naproxen (NAP), a well-known anti-inflammatory compound, through cyclic voltammetry. The dynamic linear range for the amperometric detection of NAP had an upper limit of 300 uM with a corresponding limit of detection (LOD) of 16 +/- 1 uM (S/N=3), which is included in NAP physiological range (9-300 uM). The MWCNT/msCYP1A2-SPE sensor was also calibrated for NAP detection in mouse serum that was previously extracted from mice, showing a slightly higher LOD (33 +/- 18 uM). The stability of the msCYP1A2-based biosensor was assessed by longtime continuous cyclic voltammetric measurements. The ability of the sensor to monitor drug delivery was investigated by using a commercial micro-osmotic pump. Results show that the MWCNT/msCYP1A2 SPE sensor is capable of precisely monitoring the real-time delivery of NAP for 16 h. This work proves that the proposed electrochemical sensor might represent an innovative point-of-care solution for the personalization of drug therapies, as well as for pharmacokinetic studies in both animals and humans. PMID- 24144560 TI - Intimate violence, family, and femininity: women's narratives on their construction of violence and self. AB - In the context of a high threshold for violence in everyday living and the cultural value of the institution of family, this article looks at women's narratives from counseling settings in India to comment on the cultural processes of explaining and rationalizing domestic violence that silence women. Definitions of femininity, marriage, and motherhood in India that are hinged on women's responsibility toward holding a family together have obstructed an understanding of women's individual rights and of violations of these rights. There is need to address both the public and professionals on the specific nature of domestic violence, and its ideological and structural context for creating recognition of the issue as a major social problem. PMID- 24144561 TI - Learning from each other: the Special Cell and domestic violence activist responses in different contexts across the world. AB - Designed to act possibly as an anchor for other contributions, this article responds to the preceding article on the Special Cell for Women and Children in Mumbai, and offers a broad, brush-stroke overview of a selection of criminal justice-focused activist responses to violence against women in India, the United Kingdom, and other countries. It reflects on the work of the Special Cell in the context of other women's support projects in police stations across the world, including Domestic Violence Matters, London, UK; the Family Consultant Service, London, Canada; and the women's police stations in Brazil. The article goes on to discuss the different activist responses in India and the United Kingdom, and both the contradictions around, and recent developments in, the activist provision of shelters worldwide. PMID- 24144562 TI - Computerized provider order entry improves compliance of vancomycin dosing guidelines in the emergency department. PMID- 24144563 TI - Prognostic utility of 90Y radioembolization dosimetry based on fusion 99mTc macroaggregated albumin-99mTc-sulfur colloid SPECT. AB - Planning hepatic (90)Y radioembolization activity requires balancing toxicity with efficacy. We developed a dual-tracer SPECT fusion imaging protocol that merges data on radioactivity distribution with physiologic liver mapping. METHODS: Twenty-five patients with colorectal carcinoma and bilobar liver metastases received whole-liver radioembolization with resin microspheres prescribed as per convention (mean administered activity, 1.69 GBq). As part of standard treatment planning, all patients underwent SPECT imaging after intraarterial injection of 37 MBq of (99m)Tc-macroaggregated albumin ((99m)Tc MAA) to simulate subsequent (90)Y distribution. Immediately afterward, patients received 185 MBq of labeled sulfur colloid ((99m)Tc-SC) intravenously as a biomarker for normal hepatic reticuloendothelial function and SPECT was repeated. The SPECT images were coregistered and fused. A region-based method was used to predict the (90)Y radiation absorbed dose to functional liver tissue (DFL) by calculation of (99m)Tc-MAA activity in regions with (99m)Tc-SC uptake. Similarly, the absorbed dose to tumor (DT) was predicted by calculation of (99m)Tc-MAA activity in voxels without (99m)Tc-SC uptake. Laboratory data and radiographic response were measured for 3 mo, and the survival of patients was recorded. SPECT based DT and DFL were correlated with parameters of toxicity and efficacy. RESULTS: Toxicity, as measured by increase in serum liver enzymes, correlated significantly with SPECT-based calculation of DFL at all time points (P < 0.05) (mean DFL, 27.9 Gy). Broad biochemical toxicity (>50% increase in all liver enzymes) occurred at a DFL of 24.5 Gy and above. In addition, in uni- and multivariate analysis, SPECT-based calculation of DT (mean DT, 44.2 Gy) correlated with radiographic response (P < 0.001), decrease in serum carcinoembryonic antigen (P < 0.05), and overall survival (P < 0.01). The cutoff value of DT for prediction of 1-y survival was 55 Gy (area under the receiver operating-characteristic curve = 0.86; P < 0.01). Patients who received a DT of more than 55 Gy had a median survival of 32.8 mo, compared with 7.2 mo in patients who received less (P < 0.05). CONCLUSION: Dual-tracer (99m)Tc-MAA (99m)Tc-SC fusion SPECT offers a physiology-based imaging tool with significant prognostic power that may lead to improved personalized activity planning. PMID- 24144564 TI - Attenuation correction maps for SPECT myocardial perfusion imaging from contrast enhanced coronary CT angiography: gemstone spectral imaging with single-source dual energy and material decomposition. AB - The aim of this study was to explore the feasibility of attenuation correction (AC) of myocardial perfusion imaging (MPI) with a virtual unenhanced cardiac CT scan synthesized from contrast-enhanced single-source dual-energy coronary CT angiography. METHODS: Segmental myocardial percentage uptake values obtained with AC were analyzed by use of correlation analysis and Bland-Altman limits of agreement (20-segment model), and clinical agreement was evaluated in 30 patients. RESULTS: The 2 methods showed an excellent correlation for segmental myocardial percentage uptake at stress (r = 0.93; P < 0.001; low dose) and at rest (r = 0.90; P < 0.001; high dose) with narrow Bland-Altman limits of agreement (-6.8% to 7.8% and -7.8% to 7.4%, respectively). The levels of clinical agreement of SPECT MPI corrected with standard versus virtual unenhanced CT AC were 99% per coronary territory and 97% per patient. CONCLUSION: Our results suggest that AC of SPECT MPI with a virtual unenhanced CT scan synthesized from contrast-enhanced coronary CT angiography is feasible and reliable. PMID- 24144565 TI - Depletion of casein kinase I leads to a NAD(P)(+)/NAD(P)H balance-dependent metabolic adaptation as determined by NMR spectroscopy-metabolomic profile in Kluyveromyces lactis. AB - BACKGROUND: In the Crabtree-negative Kluyveromyces lactis yeast the rag8 mutant is one of nineteen complementation groups constituting the fermentative-deficient model equivalent to the Saccharomyces cerevisiae respiratory petite mutants. These mutants display pleiotropic defects in membrane fatty acids and/or cell walls, osmo-sensitivity and the inability to grow under strictly anaerobic conditions (Rag(-) phenotype). RAG8 is an essential gene coding for the casein kinase I, an evolutionary conserved activity involved in a wide range of cellular processes coordinating morphogenesis and glycolytic flux with glucose/oxygen sensing. METHODS: A metabolomic approach was performed by NMR spectroscopy to investigate how the broad physiological roles of Rag8, taken as a model for all rag mutants, coordinate cellular responses. RESULTS: Statistical analysis of metabolomic data showed a significant increase in the level of metabolites in reactions directly involved in the reoxidation of the NAD(P)H in rag8 mutant samples with respect to the wild type ones. We also observed an increased de novo synthesis of nicotinamide adenine dinucleotide. On the contrary, the production of metabolites in pathways leading to the reduction of the cofactors was reduced. CONCLUSIONS: The changes in metabolite levels in rag8 showed a metabolic adaptation that is determined by the intracellular NAD(P)(+)/NAD(P)H redox balance state. GENERAL SIGNIFICANCE: The inadequate glycolytic flux of the mutant leads to a reduced/asymmetric distribution of acetyl-CoA to the different cellular compartments with loss of the fatty acid dynamic respiratory/fermentative adaptive balance response. PMID- 24144566 TI - Acute exposure of beta-cells to troglitazone decreases insulin hypersecretion via activating AMPK. AB - BACKGROUND: It has been recognized that insulin hypersecretion can lead to the development of insulin resistance and type 2 diabetes mellitus. There is substantial evidence demonstrating that thiazolidinediones are able to delay and prevent the progression of pancreatic beta-cell dysfunction. However, the mechanism underlying the protective effect of thiazolidinediones on beta-cell function remains elusive. METHODS: We synchronously detected the effects of troglitazone on insulin secretion and AMP-activated protein kinase (AMPK) activity under various conditions in isolated rat islets and MIN6 cells. RESULTS: Long-term exposure to high glucose stimulated insulin hypersecretion and inhibited AMPK activity in rat islets. Troglitazone-suppressed insulin hypersecretion was closely related to the activation of AMPK. This action was most prominent at the moderate concentration of glucose. Glucose-stimulated insulin secretion was decreased by long-term troglitazone treatment, but significantly increased after the drug withdrawal. Compound C, an AMPK inhibitor, reversed troglitazone-suppressed insulin secretion in MIN6 cells and rat islets. Knockdown of AMPKalpha2 showed a similar result. In MIN6 cells, troglitazone blocked high glucose-closed ATP-sensitive K(+) (KATP) channel and decreased membrane potential, along with increased voltage-dependent potassium channel currents. Troglitazone suppressed intracellular Ca(2+) response to high glucose, which was abolished by treatment with compound C. CONCLUSION: Our results suggest that troglitazone provides beta-cell "a rest" through activating AMPK and inhibiting insulin hypersecretion, and thus restores its response to glucose. GENERAL SIGNIFICANCE: These data support that AMPK activation may be an important mechanism for thiazolidinediones preserving beta-cell function. PMID- 24144567 TI - Decreased solute adsorption onto cracked surfaces of mechanically injured articular cartilage: towards the design of cartilage-specific functional contrast agents. AB - BACKGROUND: Currently available methods for contrast agent-based magnetic resonance imaging (MRI) and computed tomography (CT) of articular cartilage can only detect cartilage degradation after biochemical changes have occurred within the tissue volume. Differential adsorption of solutes to damaged and intact surfaces of cartilage may be used as a potential mechanism for detection of injuries before biochemical changes in the tissue volume occur. METHODS: Adsorption of four fluorescent macromolecules to surfaces of injured and sliced cartilage explants was studied. Solutes included native dextran, dextrans modified with aldehyde groups or a chondroitin sulfate (CS)-binding peptide and the peptide alone. RESULTS: Adsorption of solutes to fissures was significantly less than to intact surfaces of injured and sliced explants. Moreover, solute adsorption at intact surfaces of injured and sliced explants was less reversible than at surfaces of uninjured explants. Modification of dextrans with aldehyde or the peptide enhanced adsorption with the same level of differential adsorption to cracked and intact surfaces. However, aldehyde-dextran exhibited irreversible adsorption. Equilibration of explants in solutes did not decrease the viability of chondrocytes. CONCLUSIONS AND GENERAL SIGNIFICANCE: Studied solutes showed promising potential for detection of surface injuries based on differential interactions with cracked and intact surfaces. Additionally, altered adsorption properties at surfaces of damaged cartilage which visually look healthy can be used to detect micro-damage or biochemical changes in these regions. Studied solutes can be used in in vivo fluorescence imaging methods or conjugated with MRI or CT contrast agents to develop functional imaging agents. PMID- 24144568 TI - A retrospective analysis of urethral rupture in 63 cats. AB - The aim of this study was to investigate the short- and long-term morbidity and mortality associated with urethral rupture in cats. Medical records were reviewed from four veterinary hospitals. Diagnosis was made from retrograde urethrography or direct visualisation during surgery. Location of rupture was categorised as pre-, intra- or post-pelvic. Follow-up data were collected from referring veterinarians. Sixty-three cats were included in the study of which, males predominated (88.9%). Trauma was the most common cause (n = 35; 55.6%) with the remainder due to iatrogenic injury. Forty-eight cats (88.9%) were treated surgically and six (11.1%) managed conservatively. Significant differences between cats suffering traumatic versus iatrogenic injury included the presence of musculoskeletal injuries (P <0.001); the location of rupture (P <0.001); the degree of rupture (P <0.001); definitive management (P <0.001) and short-term complications (P = 0.026). Short-term complications were significantly associated with the following: musculoskeletal injuries (P = 0.012); uroabdomen/uroretroperitoneum (P = 0.004); azotaemia (P = 0.021); postoperative urinary diversion (P = 0.036) and >1 surgery performed (P = 0.006). Forty-seven cats (74.6%) survived to discharge. Prognostic factors associated with survival to discharge included the presence of musculoskeletal injuries (P = 0.017); cause of rupture (P = 0.017); location of rupture (P = 0.039) and definitive management (P = 0.020). Twenty-four cats (57.1%) suffered short-term complications and 10 (27.0%) suffered long-term complications. Of those cats surviving to discharge 30 (71.4%) had a good outcome. Median follow-up was 16 months. Outcome was significantly associated with cause of rupture (P = 0.04); short-term complications (P = 0.03) and long-term complications (P <0.001). In conclusion, a significantly greater proportion of cats with iatrogenic injuries survived to discharge and had a good outcome compared with those that suffered trauma. PMID- 24144570 TI - Prevalence of post-mastectomy pain syndrome and associated risk factors: a cross sectional cohort study. AB - This study was designed to determine the prevalence of post-mastectomy pain and its associated risk factors in women submitted to surgical treatment for breast cancer. A cross-sectional cohort study was conducted involving 250 women treated surgically for breast cancer. The variables evaluated were (a) post-mastectomy pain syndrome (PMPS) (as a dependent variable or outcome) and (b) the patients' social characteristics (schooling, marital status), biological characteristics (body mass index, skin color, age), prior history of headache and dysmenorrhea, occurrence of acute postoperative pain, and type of surgery (mastectomy or quadrantectomy) (as independent or predictive variables). The prevalence ratios (PR) and their respective 95% confidence intervals (95% CI) were calculated as a measure of the risk of PMPS. Multivariate analysis was performed using a hierarchical model of stepwise logistic regression that included possible explanatory variables, calculating the adjusted risk of PMPS from the odds ratio (OR) and the 95% CI at a significance level of 5%. PMPS was found in 44.4% of patients. The variables that remained strongly associated with PMPS following multiple logistic regression analysis were quadrantectomy with axillary lymphadenectomy (OR = 2.83; 95% CI: 1.60-5.02), prior history of headache (OR = 1.92; 95% CI: 1.10-3.34), and age <50 years (OR = 4.37; 95% CI: 2.43-7.86). PMPS is a common condition, particularly in women submitted to quadrantectomy with axillary lymphadenectomy, those under 50 years of age, and those with a prior history of headache. Attention should be paid to these factors at preoperative evaluation and counseling, and they should be taken into consideration in postoperative management. PMID- 24144569 TI - Meeting the public health challenge of pain in later life: what role can senior centers play? AB - Interest in nonpharmacologic approaches for managing pain continues to grow. The aim of this study was to determine the types of pain-relevant programs offered by senior centers and whether the programs varied by clients' race/ethnicity status and center size. A telephone survey was conducted. Respondents were presented with a list of 15 programs and the option to choose "other" and asked (1) whether the activity was offered and, if so, how often; (2) if they believed the programs had value for seniors with pain; and (3) whether the classes were advertised as a means of achieving pain relief. Of 204 center staff contacted, 195 (95.6%) participated. The most common programs offered were movement-based, including exercise (by 91.8% of the centers), dance (72.3%), walking clubs (71.8%), yoga (65.6%), and Tai Chi (53.3%) classes. Creative arts programs were also frequently offered, including music (58.5%) and fine arts (47.7%). Programs such as stress management (27%) and relaxation (26%) classes were less commonly offered. Most respondents identified movement-based programs as helpful for seniors with pain, but few identified creative arts classes as potentially beneficial. The programs/classes offered were infrequently advertised as a means of helping seniors manage pain and varied by clients' race/ethnicity status and center size. Programs that have potential utility for older adults with pain are commonly offered by senior centers. Future research should determine optimal strategies for engaging older adults in these programs in the senior center setting. PMID- 24144571 TI - The relationship between chronic pain pattern, interference with life and health related quality of life in a nationwide community sample. AB - To establish the scope of the problem of chronic pain in the population, we need to extend the focus on prevalence, the most frequently studied factor. Among other important factors is the complex relationship between the temporal characteristics of pain and their impact on peoples' lives. The purpose of the present study was to describe the characteristics of chronic pain, including pattern, severity, location, spread, and duration, in a population-based sample and to investigate the relationships between pain pattern and impact on the individual's life measured by interference with life and health-related quality of life (HRQoL). In this cross-sectional study, a postal questionnaire measuring pain characteristics, life interference (Brief Pain Inventory), and HRQoL (Short Form 36 Health Survey), was sent to a sample of 4,500 individuals, randomly drawn from the Icelandic National Register. The total response rate was 36.9% and was significantly higher among native Icelanders (40.6%) than individuals of non Icelandic origin (8.6%).The prevalence of chronic pain (>=3 months) was 47.5% with mean duration of 9.3 years, and 31.9% reported constant pain. Participants with constant pain reported higher life interference scores and less HRQoL than participants with intermittent or periodic pain. Hierarchical stepwise regression analyses showed that pain pattern and severity accounted for 44.4% variance for life interference. The range of the variances for these variables for the five domains of HRQoL was from 7.3% (mental health) to 53.3% (bodily pain). Pain pattern and severity are the most significant predictors of the impact of chronic pain on individual's daily life. PMID- 24144572 TI - Acupoint stimulation to improve analgesia quality for lumbar spine surgical patients. AB - Lumbar spine surgery has a high incidence of postoperative pain, but this pain is treatable through many methods, including patient-controlled analgesia (PCA). Acupoint stimulation could be considered an adjunct to PCA, improving the effectiveness of analgesia for patients recovering from lumbar spine surgery. The current study aimed to examine the effect of acupoint stimulation with PCA on improving analgesia quality after lumbar spine surgery. A single-blinded, sham controlled design was used for the experimental, not control, groups. Data collection for the control group was completed first, followed by data collection for the other 2 groups. Participants were randomly assigned to the acupoint stimulation (AS) (n = 45) or sham group (n = 45). All participants received structural PCA multimedia information before lumbar surgery. The AS group received auricular acupressure combined with transcutaneuos electric acupoint stimulation (TEAS) at the true acupoint; the sham group received acupoint stimulation in the same manner but at a sham acupoint and without embedding seeds; and the control group received no acupoint stimulations. The analgesia quality, analgesic consumption, and postoperative nausea and vomiting (PONV) were used as measure of effects for the interventions. Significant differences were found between the AS and control groups in pain intensity but not in the belief and satisfaction subscales of analgesia quality. Also found a significant difference among the 3 groups in analgesic consumption and the severity of PONV in the first 72 hours after surgery. The current study shows that the combination of auricular acupressure and TEAS reduced pain intensity, morphine consumption, and PONV severity. Acupoint stimulation could be considered a multimodal analgesia method and an adjunct to PCA for lumbar spine surgery patients. PMID- 24144573 TI - A psychometric evaluation of three pain rating scales for people with moderate to severe dementia. AB - Little comparative information exists regarding the reliability and validity of pain rating scales for nurses to assess pain in people with moderate to severe dementia in residential aged care facilities. The objective of this study was to evaluate the relative psychometric merits of the Abbey Pain Scale, the DOLOPLUS-2 Scale, and the Checklist of Nonverbal Pain Indicators Scale, three well-known pain rating scales that have previously been used to assess pain in nonverbal people with dementia. An observational study design was used. Nurses (n = 26) independently rated a cross-section of people with moderate to severe dementia (n = 126) on two occasions. The Abbey Pain Scale and the DOLOPLUS-2 Scale showed good psychometric qualities in terms of reliability and validity, including resistance to the influence of rater characteristics. The Checklist of Nonverbal Pain Indicators Scale also had reasonable results but was not as psychometrically strong as the Abbey Pain Scale and DOLOPLUS-2 Scale. This study has provided comparative evidence for the reliability and validity of three pain rating scales in a single sample. These scales are strong, objective adjuncts in making comprehensive assessments of pain in people who are unable to self-report pain due to moderate to severe dementia, with each having their own strengths and weaknesses. The DOLOPLUS-2 Scale provides more reliable measurement, and the Abbey Pain Scale may be better suited than the other two scales for use by nurse raters who only occasionally use pain rating scales or who have lower level nursing qualifications. PMID- 24144574 TI - Mtx toxins from Lysinibacillus sphaericus enhance mosquitocidal cry-toxin activity and suppress cry-resistance in Culex quinquefasciatus. AB - The interaction of Mtx toxins from Lysinibacillus sphaericus (formerly Bacillus sphaericus) with Bacillus thuringiensis subsp. israelensis Cry toxins and the influence of such interactions on Cry-resistance were evaluated in susceptible and Cry-resistant Culex quinquefasciatus larvae. Mtx-1 and Mtx-2 were observed to be active against both susceptible and resistant mosquitoes; however varying levels of cross-resistance toward Mtx toxins were observed in the resistant mosquitoes. A 1:1 mixture of either Mtx-1 or Mtx-2 with different Cry toxins generally showed moderate synergism, but some combinations were highly toxic to resistant larvae and suppressed resistance. Toxin synergy has been demonstrated to be a powerful tool for enhancing activity and managing Cry-resistance in mosquitoes, thus Mtx toxins may be useful as components of engineered bacterial larvicides. PMID- 24144575 TI - Anaphylaxis in America: the prevalence and characteristics of anaphylaxis in the United States. AB - BACKGROUND: Although anaphylaxis is recognized as an important life-threatening condition, data are limited regarding its prevalence and characteristics in the general population. OBJECTIVE: We sought to estimate the lifetime prevalence and overall characteristics of anaphylaxis. METHODS: Two nationwide, cross-sectional random-digit-dial surveys were conducted. The public survey included unselected adults, whereas the patient survey captured information from household members reporting a prior reaction to medications, foods, insect stings, or latex and idiopathic reactions in the previous 10 years. In both surveys standardized questionnaires queried anaphylaxis symptoms, treatments, knowledge, and behaviors. RESULTS: The public survey included 1,000 adults, of whom 7.7% (95% CI, 5.7% to 9.7%) reported a prior anaphylactic reaction. Using increasingly stringent criteria, we estimate that 5.1% (95% CI, 3.4% to 6.8%) and 1.6% (95% CI, 0.8% to 2.4%) had probable and very likely anaphylaxis, respectively. The patient survey included 1,059 respondents, of whom 344 reported a history of anaphylaxis. The most common triggers reported were medications (34%), foods (31%), and insect stings (20%). Forty-two percent sought treatment within 15 minutes of onset, 34% went to the hospital, 27% self-treated with antihistamines, 10% called 911, 11% self-administered epinephrine, and 6.4% received no treatment. Although most respondents with anaphylaxis reported 2 or more prior episodes (19% reporting >=5 episodes), 52% had never received a self-injectable epinephrine prescription, and 60% did not currently have epinephrine available. CONCLUSIONS: The prevalence of anaphylaxis in the general population is at least 1.6% and probably higher. Patients do not appear adequately equipped to deal with future episodes, indicating the need for public health initiatives to improve anaphylaxis recognition and treatment. PMID- 24144576 TI - Identification and characterization of an alternative splice variant of Mpl with a high affinity for TPO and its activation of ERK1/2 signaling. AB - The thrombopoietin receptor is a crucial element in thrombopoietin-initiated signaling pathways, which stimulates the differentiation of normal hematopoietic progenitor cells, the maturation of megakaryocytes, and the generation of platelets. In this study, we identified a novel activating variant of thrombopoietin receptor, termed Mpl-D, in human megakaryoblastic leukemia Dami cells and demonstrated that the binding affinity of the Mpl-D receptor for thrombopoietin is enhanced. Cell cycle analysis revealed that in the presence of thrombopoietin, most Mpl-D expressing NIH3T3 (NIH3T3/Mpl-D) cells were prevalent in G1 phase while the S and G2/M populations were less frequently observed. Unexpectedly, thrombopoietin induced strong and prolonged ERK1/2 signaling in NIH3T3/Mpl-D cells compared with its receptor wild-type expressing NIH3T3 (NIH3T3/Mpl-F) cells. Further analysis of the mRNA levels of cyclin D1/D2 in NIH3T3/Mpl-D cells demonstrated markedly down-regulated expression compared to NIH3T3/Mpl-F cells in the presence of thrombopoietin. Thus, the prolonged activation of ERK1/2 by Mpl-D might lead to G1 cell cycle arrest through a profound reduction of cyclin D1/D2 in order to support cell survival without proliferation. We also provided tertiary structural basis for the Mpl-D and thrombopoietin interaction, which might provide insights into how Mpl-D effectively increases binding to thrombopoietin and significantly contributes to its specific signaling pathway. These results suggest a new paradigm for the regulation of cytokine receptor expression and function through the alternative splicing variant of Mpl in Dami cells, which may play a role in the pathogenesis of megakaryoblastic leukemia. PMID- 24144577 TI - The molecular basis for the immunomodulatory activities of unconjugated bilirubin. AB - Nearly a century ago, jaundiced patients were observed to have surprising and spontaneous remissions from incurable immunologic diseases including rheumatoid arthritis, allergy, and asthma. The mystery of why this phenomenon occurred remains unresolved to this day. Bilirubin has traditionally been considered an excretory product resulting from heme metabolism with little benefit to human physiology. In the past few decades, however, the salutary role of this byproduct as a potent antioxidant has been repeatedly noted. Most recently, the molecule has been found to possess immunomodulatory properties that rival its redox capacity, possibly explaining its ability to suppress inflammation. In this review, we specifically examine unconjugated bilirubin (UCB) as an immunomodulator and explore the molecular basis for its immunosuppressive effects. PMID- 24144578 TI - H-3, a new lectin from the marine sponge Haliclona caerulea: purification and mass spectrometric characterization. AB - A new lectin from the marine sponge Haliclona caerulea (H-3) was isolated using a combination of hydrophobic interaction chromatography and ion-exchange chromatography. H-3 is a protein with three distinct bands on SDS-PAGE: 9 kDa, 16 kDa and 18 kDa. Nevertheless, on gel filtration and N-PAGE, H-3 showed a symmetrical peak and a unique band, respectively. Hemagglutinating activity of H 3 was stable at neutral pH and temperatures up to 60 degrees C. N Acetylgalactosamine and porcine stomach mucin were the most potent inhibitors of H-3. Primary structure of the lectin was determined using tandem mass spectrometry, and it showed no similarity to any members of the animal lectin families. Top down fragmentation revealed some posttranslational modifications in H-3, including glycosylation. The glycan composition of H-3 was determined, and its structure was predicted. Furthermore, H-3 is a blue protein, binding to a chromophore(-597) by weak interactions, and this is the first time that the interaction between one lectin and a natural chromophore has been shown. PMID- 24144579 TI - Physical activity and depressive symptoms in older adults. AB - OBJECTIVES: Depressive symptoms are prevalent in older adults, and physical activity (PA) may have beneficial effects on depression. The purpose of this study was to explore the association between physical activity and depressive symptoms, taking into account demographic factors, and the associations between selected demographic factors and physical activity levels in community-dwelling older adults (age >= 60 years). METHODS: Data were drawn from the National Health and Nutrition Examination Survey 2005-2006. Descriptive statistics and logistic models were used in data analysis. RESULTS: Four percent of participants reported moderate depressive symptoms, and 24% of subjects exhibited sedentary PA. Factors associated with increased risk of moderate depression included age, sedentary PA, and chronic medical conditions (ps < 0.05). Sedentary PA was significantly associated with age, race, education, BMI, smoking status, alcohol use, and taking psychotropics (ps < 0.05). DISCUSSION: PA is a protective factor for depression in older adults, and clinical implications to encourage PA are discussed. PMID- 24144580 TI - Depressed adolescents as young adults - predictors of suicide attempt and non suicidal self-injury during an 8-year follow-up. AB - BACKGROUND: Clinically derived follow-up studies examining the predictors of suicide attempts (SA) and non-suicidal self-injury (NSSI) among adolescents are scarce. The aims were to study SA and NSSI as predictors of future NSSI and SA, and to study the role of other risk and protective factors, especially alcohol use, and perceived social support from family and peers during a 1-year follow-up and between the 1-year and 8-year follow-ups among consecutively referred depressed adolescent outpatients. METHODS: The Adolescent Depression Study (ADS) is a longitudinal study of depressed adolescent outpatients (mean age at baseline 16.5 years, 81.8% females). The subjects of the present study (n=139, 63.8% of the original study population) were assessed at baseline, at 1-year and 8-year follow-ups using semi-structured diagnostic interviews (K-SADS-PL) for DSM-IV diagnoses, and structured self-report scales for clinical risk factors. RESULTS: In multivariate comparisons, SAs were predicted both in the 1-year follow-up and in the period between the 1- and 8-year follow-ups by alcohol use and low perceived peer support. NSSI in the 1-year of follow-up was predicted by baseline NSSI, younger age and alcohol use, whereas the only significant predictor for NSSI between the 1- and 8-year follow-ups was NSSI. LIMITATIONS: A large majority of the sample were females, limiting the possibility to analyze gender differences. CONCLUSIONS: Among depressed outpatients NSSI is a strong predictor of suicidal behavior, and other factors beyond depression, such as alcohol use and availability of social support, must also be addressed to prevent the recurrence of suicidal behavior. PMID- 24144581 TI - Mixed-state bipolar I and II depression: time to remission and clinical characteristics. AB - BACKGROUND: We compared the time to achieve remission and the clinical characteristics of patients with bipolar depressive mixed state and those with bipolar depressive non-mixed state. METHODS: The subjects (N=131) were inpatients diagnosed between 2006 and 2012 with bipolar I or II disorder, depression and were classified into the following three groups: "pure depressive state" (PD, n=70), "sub-threshold mixed state" (SMX, n=38), and "depressive mixed state" (DMX, n=23). Diagnosis of a DMX was in accordance with Benazzi's definition: three or more manic symptoms in a depressive episode. The subjects' charts were retrospectively reviewed to ascertain the time to achieve remission from the index episode and to identify other factors, such as demographic and clinical characteristics, specific manic symptoms, and pharmacological treatment, that may have contributed to remission. RESULTS: The time to achieve remission was significantly longer in the DMX (p=0.022) and SMX (p=0.035) groups than in the PD group. Adjustment for covariates using a Cox proportional hazards model did not change these results. Clinically, subjects with a DMX were more likely to have manic symptoms in the index episode, especially inflated self-esteem and psychomotor agitation than those in the PD. LIMITATIONS: We investigated only inpatients and therefore could not comment on outpatients. CONCLUSIONS: These findings showed that sub-syndromal manic symptoms in bipolar depression had different clinical characteristics and a more severe illness course, including a longer time to achieve remission, than did a pure depressive state. PMID- 24144582 TI - Performance anxiety in Brazilian musicians: prevalence and association with psychopathology indicators. AB - BACKGROUND: Musical performance anxiety (MPA) refers to persistent and distressing apprehension associated with performing to an audience. Our objective was to assess the presence of MPA and other psychopathologies in musicians and find correlations between socio-demographic and clinical variables. METHODS: We assessed 230 musicians using self-rated instruments whose results were statistically compared. The logistic regression was used to check for predictors of MPA. RESULTS: 24% of musicians had MPA indicators, 19% had indicators of social anxiety, and 20% of depression. These figures were even higher in the comparison between professional and amateur musicians, where the rates were doubled. In the logistic regression, gender and professional status did not predict MPA, but did predict social anxiety (OD=3.22; p=0.006) and depression (OD=3.87; p=0.003). CONCLUSIONS: We conclude that there is a high rate of psychiatric indicators among musicians, who have been dealing not only with difficulties inherent to their occupation, but also with under-recognized comorbidities with the potential to affect their personal and professional life in specific, poorly investigated ways. LIMITATIONS: It should be noted that our results must be interpreted with caution as we used screening and not diagnostic instruments, and because of the fact that our sample was restricted to the Brazilian context. Also, the role of temperamental features that could have a positive association with the condition of musician-and therefore minimize performance anxiety-could have been explored in order to provide a deeper understanding of the topic. PMID- 24144583 TI - Re-examining the risk for switch from unipolar to bipolar major depressive disorder in youth with ADHD: a long term prospective longitudinal controlled study. AB - BACKGROUND: Recent studies have identified subthreshold forms of bipolar (BP)-I disorder and deficits in emotional regulation as risk factors for bipolar disorder in youth. The primary aim of this study was to investigate whether emotional dysregulation and subthreshold forms of BP-I disorder increase the risk for BP switches in ADHD youth with non-bipolar MDD. METHODS: We used data from two large controlled longitudinal family studies of boys and girls with and without ADHD. Subjects (N=522) were followed prospectively and blindly over an average follow up period of 11.4 years. Comparisons were made between ADHD youth with unipolar major depression (MDD) who did (N=24) and did not (N=79) switch to BP-I disorder at follow-up. RESULTS: The rate of conversion to BP-I disorder at follow up was higher in MDD subjects with subthreshold BP-I disorder at baseline compared to those without (57% vs. 21%; OR=9.57, 95% CI=1.62-56.56, p=0.013) and in MDD subjects with deficient emotional self-regulation (OR=3.54, 95% CI=1.08 11.60, p=0.037). LIMITATIONS: The sample was largely Caucasian, so these results may not generalize to minority groups. The sample of youth with SED was small, which limited the statistical power for some analyses. CONCLUSIONS: Switches from unipolar MDD to BP-I disorder in children with ADHD and MDD were predicted by baseline subthreshold BP-I disorder symptoms and baseline deficits in emotional regulation. More work is needed to assess whether these risk factors are operant outside the context of ADHD. PMID- 24144584 TI - Does comorbid subthreshold anxiety predict treatment response in depression? Results from a naturalistic cohort study (the CRESCEND study). AB - OBJECTIVE: To investigate whether the anxious depression defined as depression with clinically significant anxiety but not comorbid anxiety disorder predicts poor outcomes of depression treatment in naturalistic clinical setting. METHOD: From nationwide sample of 18 hospitals, 674 patients with moderate to severe depression who completed the DSM-IV-based Structured Clinical Interview (SCID) were recruited. Anxious depression was defined as not having comorbid anxiety disorder by SCID and having a Hamilton Rating Scale for Anxiety (HAM-A) total score >= 20. Participants were classified into three groups: anxious depression (N=259), non-anxious depression (N=351), or comorbid anxiety disorder (N=64). Rates of and time to remission and response and changes in scale scores were compared between these groups during 12 weeks treatment with antidepressant interventions freely determined by clinicians. RESULTS: No significant differences were observed in the Hamilton Rating Scale for Depression (HAM-D) remission rate and the time to achieve HAM-D remission between anxious and non anxious depression after adjustment for variables is not equally distributed at baseline. There were also no significant differences in HAM-D and HAM-A response rate and time to responses between two groups. Patients with comorbid anxiety disorder showed less improvement on HAM-D and HAM-A score than did those with anxious depression despite similar baseline symptom severity. LIMITATION: This study was observational, and the treatment modality was naturalistic. CONCLUSIONS: Anxious depression did not predict worse outcome to antidepressants treatment. This finding might result from exclusion of comorbid anxiety disorder from anxious depression population and allowance of broad treatment modality. PMID- 24144585 TI - Guidance on the conversion of the Chinese versions of the Quick Inventory of Depressive Symptomatology-Self-Report (C-QIDS-SR) and the Montgomery-Asberg Scale (C-MADRS) in Chinese patients with major depression. AB - BACKGROUND: The 16-item Quick Inventory of Depressive Symptomatology-Self-Report (QIDS-SR) is a newly introduced screening tool, while the Montgomery-Asberg Scale (MADRS) is commonly used in research and clinical practice in China. Converting the total scores between the two instruments could facilitate the comparison of different studies. METHODS: This study included 1164 patients with major depressive disorder (MDD). The diagnosis was established using the Mini International Neuropsychiatric Interview (MINI). The severity of depressive symptoms was assessed with the Chinese versions of MADRS (C-MADRS) and QIDS-SR (C QIDS-SR) at baseline and 6 weeks later (exit point). Total scores of both scales were converted using Item Response Theory (IRT) analysis. RESULTS: At baseline, the C-MADRS and C-QIDS-SR were not unifactorial, therefore the conversion between them could not be performed. At exit, the C-MADRS and C-QIDS-SR were unifactorial, meeting the unidimensionality assumption of the IRT approach. Depression severity thresholds for the QIDS-SR are suggested as 6-10 for mild, 11 15 for moderate, 16-20 for severe, 21+ for very severe depression and <= 5 for remission (www.ids-qids.org). Based on the results of this study, the corresponding C-MADRS thresholds are 9-17 for mild, 18-24 for moderate, 25-33 for severe, 34+ for very severe depression and <= 7 or 8 (7.5) for remission. CONCLUSIONS: The conversion of C-QIDS-SR and C-MADRS total scores would help researchers understand findings across different studies using these scales. PMID- 24144586 TI - Towards understanding the molecular mechanism of the endocytosis-like process in the bacterium Gemmata obscuriglobus. AB - An endocytosis-like process of protein uptake in the planctomycete Gemmata obscuriglobus is a recently discovered process unprecedented in the bacterial world. The molecular mechanisms underlying this process are not yet characterized. A homolog of the MC (membrane-coating) proteins of eukaryotes has been proposed to be involved in the mechanism of this process, but its relationship to eukaryote proteins is controversial. However, a number of other proteins of G. obscuriglobus with domains homologous to those involved in endocytosis in eukaryotes can also be identified. Here we critically evaluate current bioinformatic knowledge, and suggest practical experimental steps to overcome the limits of bioinformatics in elucidating the molecular mechanism of endocytosis in bacteria. This article is part of a Special Issue entitled: Protein trafficking and secretion in bacteria. Guest Editors: Anastassios Economou and Ross Dalbey. PMID- 24144587 TI - Examining the relationships between posttraumatic stress disorder symptoms, positive smoking outcome expectancies, and cigarette smoking in people with substance use disorders: a multiple mediator model. AB - Cigarette smoking is highly prevalent in people with substance use disorders (SUDs) and is associated with significant physical health problems. Posttraumatic stress disorder (PTSD) is also highly associated with both SUDs and cigarette smoking and may serve as a barrier to smoking cessation efforts. In addition, people with PTSD are more likely to hold positive smoking outcome expectancies (i.e., beliefs that smoking cigarettes results in positive outcomes); these beliefs may contribute to cigarette smoking in people with SUDs experiencing PTSD symptoms. The present study examined the relationship between PTSD symptoms and typical daily cigarette smoking/cigarette dependence symptoms in a sample of 227 trauma-exposed current smokers with SUDs (59.9% male, 89.4% Caucasian) seeking detoxification treatment services. Additionally, the indirect effects of multiple types of positive smoking outcome expectancies on these relationships were examined. Participants completed questionnaires assessing PTSD symptoms, positive smoking outcome expectancies, cigarette consumption, and cigarette dependence symptoms. Results indicated that PTSD symptoms were not directly related to cigarette consumption or cigarette dependence symptoms. However, negative affect reduction outcome expectancies were shown to have a significant indirect effect between PTSD symptoms and cigarette consumption, while negative affect reduction, boredom reduction, and taste-sensorimotor manipulation outcome expectancies were all found to have significant indirect effects between PTSD symptoms and cigarette dependence symptoms. The indirect effect involving negative affect reduction outcome expectancies was statistically larger than that of taste sensorimotor manipulation outcome expectancies, while negative affect reduction and boredom reduction outcome expectancies were comparable in magnitude. These results suggest that expectancies that smoking can manage negative affective experiences are related to cigarette smoking in people with SUDs experiencing PTSD symptoms and suggest that effective smoking cessation treatments should take into account these expectancies. PMID- 24144588 TI - Psychometric properties of the Chinese version of the gambling related cognitions scale in Chinese mainland sample. AB - The English items of Gambling Related Cognitions Scale (GRCS) were first developed and validated by community-based population in 2004. The scale is now becoming a validated and reliable instrument to assess gambling related cognitions in the gambling literature of the West. The present study recruited 730 general adult Chinese individuals to validate the Chinese version of Gambling Related Cognitions Scale (GRCS-C). The results of a confirmatory factor analysis of the Chinese data supported the second-order model with five major factors proposed by Oei and Raylu (2006). The overall scale and five factors demonstrated satisfactory internal consistency and test-retest reliability. Construct validity and concurrent validity of GRCS-C was also sound suggesting that the GRCS-C is a valid and reliable instrument for assessing gambling related cognition among non clinical Chinese individuals. PMID- 24144589 TI - Parents' beliefs and children's marijuana use: evidence for a self-fulfilling prophecy effect. AB - Parents' beliefs about their children's involvement in aberrant behaviors are variable and sometimes inaccurate, but they may be influential. This study is concerned with inconsistencies between parents' estimates and their children's reports of marijuana use, and children's subsequent usage one year later. The self-fulfilling prophecy hypothesis suggests that discrepancies between parents' beliefs and children's behaviors could have detrimental or beneficial outcomes, depending on the inconsistency. This possibility was investigated with data from a panel survey of a nationally representative sample of parents and their adolescent children (N=3131). Marijuana-abstinent adolescents in the first year (T1) of the survey were significantly more likely to initiate use over the next year if they were characterized by parents as users at T1; conversely, adolescent marijuana users at T1 were significantly less likely to continue usage in the second year if they were labeled by parents as abstinent at T1 (both p<.001). Odds that abstinent children whose parents believed they used marijuana would initiate use a year later (T2) were 4.4 times greater than those of abstinent respondents whose parents judged them abstinent. Odds of self-reported users quitting by T2 were 2.7 greater if parents believed they had not used at T1. PMID- 24144590 TI - Computer-based programmes for the prevention and management of illicit recreational drug use: a systematic review. AB - The last few decades have seen increasing use of computer-based programmes to address illicit recreational drug use but knowledge about their effectiveness is limited. We conducted a systematic review to examine evidence on these programmes. Eight electronic databases were searched to identify primary research studies evaluating computer-based programmes to prevent or reduce use of illicit recreational drugs. From an initial 3413 extracted studies, 10 were identified for inclusion, covering a range of intervention types, target groups and settings. Universal drug prevention programmes were effective in reducing the frequency of recreational drug use in the mid-term (<12 months), but not immediately post intervention. Programmes targeting recreational drug users showed more inconsistent results but were generally effective in reducing use of drugs both immediately and in the mid-term. Computer-based programmes have the potential for use in addressing recreational drug use when targeted both universally and at illicit drug users, at least in the mid-term. However, longer term evaluations are needed to better understand the duration of effects. Given the benefits that computer-based programmes can have over traditional delivery methods, research is needed to better understand the value of human contact in health interventions and help inform whether, and how much, professional contact should be involved in computer-based programmes. PMID- 24144591 TI - miR-137 suppresses cell growth in ovarian cancer by targeting AEG-1. AB - Astrocyte elevated gene-1 (AEG-1) is an oncogene overexpressed in multiple types of human cancers including ovarian cancer (OC). However, the underlying mechanism of AEG-1 up-regulation in OC is not well understood. In this study, we showed that miR-137 downregulated AEG-1 expression through interaction with its 3' untranslated region (3'UTR) and that miR-137 expression was inversely correlated with AEG-1 levels in OC specimens. Similar to the downregulation of AEG-1, overexpression of miR-137 in OC cell lines decreased in vitro cell growth, clonogenicity, and also induced G1 arrest. Importantly, miR-137 overexpression suppressed in vivo tumor growth in nude mice models. Furthermore, we found that restoring the AEG-1 (without the 3'UTR) significantly rescued miR-137-induced cell growth inhibition and cell-cycle arrest. Taken together, these findings indicate that miR-137 functions as a tumor suppressor by inhibition of AEG-1. These molecules might be targets for prevention or treatment of OC. PMID- 24144592 TI - Brain response characteristics associated with subclavian steal phenomenon. AB - BACKGROUND: Chronic, repetitive, and sublethal hypoperfusion by intra- or extracranial artery stenosis promotes collateral development and conditions the brain toward preventing subsequent lethal ischemia, although these latent properties have rarely been demonstrated in the clinical setting. This study assessed the previously unexplored role of subclavian steal syndrome (SSS) on inciting and protecting brain damage. METHODS: We enrolled patients diagnosed with SSS associated with subclavian artery stenosis. Subclavian steal was determined by transcranial Doppler and/or digital subtraction angiography. We analyzed the prevalences and predictors of posterior ischemic symptoms and infarcts in SSS patients and also investigated individual cases to demonstrate a clinical evidence of brain conditioning, focusing on cytotoxic and vasogenic edema. RESULTS: Of 54 SSS patients, 36 (66.7%) had been asymptomatic and incidentally diagnosed with SSS, whereas 18 (33.3%) patients had presented with posterior ischemic symptoms. Symptoms and infarcts including old silent lesions occurred more frequently as unstable hemodynamics of the anterior circulation were combined. Of 18 symptomatic patients, 13 patients (72.2%) had transient ischemic attack and 5 (27.8%) patients had an infarct in the posterior circulation territory. Four patients with cytotoxic edema had mild neurologic deficits and rapid and complete recovery, whereas 1 patient had prolonged, severe vasogenic edema after acute hypertension. CONCLUSIONS: Although we noted low rates of disabling or fatal strokes in patients with SSS, a variety of vascular and neural factors beyond severity of subclavian steal could influence the likelihood of brain damage. PMID- 24144594 TI - Stroke and cardiac papillary fibroelastoma: mechanical thrombectomy after thrombolytic therapy. AB - We describe a case of a 34-year-old man with a sudden development of right hemiparesis and aphasia because of infarction of the left middle cerebral artery that was submitted to intravenous (IV) recombinant tissue plasminogen activator and mechanical thrombectomy. Transesophageal echocardiogram showed a small mass on the anterior leaflet of the mitral valve. Cardiac surgery was performed, and histological examination of the removed material was consistent with cardiac papillary fibroelastoma (CPF). Experience in using IV thrombolysis for the treatment of embolic stroke because of CPF is limited. To the best of our knowledge, only 3 patients are reported in literature in whom acute ischemic stroke and associated CPF were treated with thrombolytic therapy. A discussion of the efficacy of IV thrombolysis and the possible superiority of mechanical thrombectomy is included. PMID- 24144593 TI - Correlates of post-traumatic stress disorder in stroke survivors. AB - BACKGROUND: Post-traumatic stress disorder (PTSD) can occur after life threatening events, including illness, but correlates of PTSD after stroke or transient ischemic attack (TIA) have not been well described. METHODS: We measured the prevalence of stroke-induced PTSD with the PTSD Checklist Specific for stroke (PCL-S) in adults who had a stroke or TIA within 5 years. A PCL-S score of 50 or more indicated likely PTSD. We tested for potential predictors of stroke-associated PTSD, including demographics, stroke history, disability, medical comorbidities, depression, and emotional support and then examined the association between poststroke PTSD and measures of physical and mental health. RESULTS: Of 535 participants, 95 (18%) had a PCL-S score of 50 or more; the mean score was 35.4 +/- 13.7 (range 17-80 of 85). In logistic regression analysis, low income (odds ratio [OR] 1.98, 95% confidence interval [CI] 1.01-3.61), recurrent stroke or TIA (OR 1.86, 1.10-3.16), more disability (OR 1.79, 1.43-2.23), and increased comorbidities (OR 1.90, 1.05-3.45) were independently associated with PTSD. Older age (OR .93, .90-.95), marriage or partnership (OR .52, .28-.98), and having emotional support (OR .25, .11-.54) were protective against developing PTSD. Participants with likely PTSD had worse physical and mental health. CONCLUSIONS: In this racially and ethnically diverse cohort of stroke and TIA survivors, stroke-induced PTSD was associated with younger age, recurrent strokes, greater disability, and comorbidities. PTSD was associated with a substantially increased physical, mental, and quality of life burden in this already vulnerable population. Having social support was protective, suggesting a potential target for intervention. PMID- 24144595 TI - Incidence, epidemiology, and treatment of aneurysmal subarachnoid hemorrhage in 12 midwest communities. AB - Only 8 studies have investigated the incidence and epidemiology of aneurysmal subarachnoid hemorrhage (aSAH) in the United States. This is the first investigation in Indiana, which has some of the highest rates of tobacco smoking and obesity in the nation. The authors prospectively identified 441 consecutive patients with aSAH from 2005 to 2010 at 2 hospitals where the majority of cases are treated. Incidence calculations were based on US Census populations. Epidemiologic variables included demography; risk factors; Hunt and Hess scale; Fisher grade; number, location, and size of aneurysms; treatment type; and complications. Overall incidence was 21.8 per 100,000 population. Incidence was higher in women, increased with age, and did not vary by race. One third to half of patients were hypertensive and/or smoked cigarettes at the time of ictus. Variations by count were partially explained by Health Factor and Morbidity Rankings. Complications varied by treatment. These findings deviate from estimates that 6-16 per 100,000 people in the United States will develop aSAH and are double the incidence in a Minnesota population between 1945 and 1974. The results also deviate from the worldwide estimate of 9.0 aSAHs per 100,000 person years. The predictive value of variations in Health Factor and Morbidity Rankings implicates the importance of future research on multivariate biopsychosocial causation of aSAH. PMID- 24144596 TI - Clinical spectrum of artery of Percheron infarct: clinical-radiological correlations. AB - BACKGROUND: The occlusion of the artery of Percheron results in bilateral thalamic and mesencephalic infarctions. In this series, we attempted to classify the subtypes of clinical presentations and long-term prognosis with regards to radiological patterns. METHODS: We sought the clinical and radiological findings of 15 (8 men and 7 women; mean age 48 years) consecutive patients with Percheron artery infarct over 10 years. We classified the clinical symptoms according to the presence of a mental status disturbance (MSD), behavioral amnesic impairment (BAI), aphasia/dysarthria, ocular movement disorders (OMDs), motor deficit, cerebellar signs, and others. The Percheron artery infarct images were classified as bilateral paramedian thalamic with rostral midbrain infarction (BPTRMI), bilateral paramedian thalamic without midbrain infarction (BPTWMI), bilateral paramedian and anterior thalamic with midbrain infarction (BPATMI), and bilateral paramedian and anterior thalamic without midbrain infarction. The outcome was evaluated using a modified Rankin Scale (mRS). RESULTS: OMD and MSD were the most common clinical manifestations in patients with BPTRMI (n = 8). BAI and MSD were the main clinical findings in patients with BPTWMI (n = 6). A patient with BPATMI had a combination of clinical manifestations. After a mean follow-up of 55 months, a good outcome (mRS score <= 2) was present in 25% of the patients with BPTRMI, 67% of the patients with BPTWMI, and in 1 patient with BPATMI. CONCLUSIONS: Our findings suggest that it is possible to identify clinical and radiological subgroups of Percheron artery infarct. The long-term follow-up outcome is generally good, except in cases with midbrain involvement. PMID- 24144598 TI - Feasibility of iron loaded 'okara' for biosorption of phosphorous in aqueous solutions. AB - This study investigated the feasibility of using soybean milk by-products (okara) as a sustainable biosorbent for phosphate removal in water and wastewater. The results show that raw okara could hardly decontaminate phosphate from aqueous solutions. Hence, in this work, okara was modified by being cationized using FeCl3 0.25 M (namely iron loaded okara, ILO) to enhance the phosphorus adsorption capacity. The phosphate sorption onto ILO was well achieved under the conditions of pH 3, initial phosphorous concentration of 25 mg/L, biosorbent dose of 20 mg/L and contact time of 7 h. Based on Langmuir model, the maximum adsorption capacity of phosphate by ILO was 4.785 mg/g. The effects of interfering anions were in the order of CO3(2-)>SO4(2-)>NO3(-). It was also observed that Fe(III) was detached during operation. This problem can hinder the sustainable usability of ILO. Thus, further research would be necessary for improving the modification method. PMID- 24144597 TI - Features of patients with transient monocular blindness: a multicenter retrospective study in Japan. AB - BACKGROUND: Transient monocular blindness (TMB) is associated with a transient ischemic attack (TIA). The purpose of this study was to investigate the features of TMB in the Japanese population using data from a multicenter retrospective study of TIA. METHODS: The subjects were consecutive TIA patients admitted to 13 stroke centers within 7 days after symptom onset. We compared clinical characteristics of patients with TMB and those without TMB who had other symptoms of cerebral TIA. RESULTS: A total of 464 patients were registered between January 2008 and December 2009, and 444 patients (283 men, mean age: 68.5 years) were included in the analysis. Thirteen patients (2.9%) presented with TMB. Patients with TMB were less likely to arrive at the specialized stroke center quickly than those without TMB (P = .013). Stenotic lesions in the extracranial internal carotid artery were more common in patients with TMB (33.3% versus 9.1%, P = .022). CONCLUSIONS: TMB was not common in our TIA inpatients. This study suggests that patients with TMB should immediately undergo a diagnostic workup, including brain and vessel imaging, and cardiac evaluation, as is performed in patients with other cerebral TIA symptoms. A larger, prospective cohort is needed to confirm the risks and outcomes of patients with TMB in the Japanese population. PMID- 24144599 TI - In situ self-catalyzed reactive extraction of germinated oilseed with short chained dialkyl carbonates for biodiesel production. AB - In order to eliminate the expense associated with solvent extraction and oil cleanup, and reduce the processing steps in biodiesel production, reactive extraction has become a focus of research in recent years. In this study, germinated castor seed was used as substrate and catalyst, dimethyl carbonate (DMC) was used as acyl acceptor and oil extractant to produce biodiesel. The optimum conditions were as follows: the germination time of castor seed was 72 h, DMC/germinated seed ratio was 12.5 ml/g, reaction temperature was 35 degrees C, and water content was 2.11%. The biodiesel yield could reach as much as 87.41% under the optimized conditions. This germinated oilseed self-catalyzed reactive extraction can be a promising route for biodiesel production. PMID- 24144600 TI - A home for interprofessional medical education at Dalhousie. PMID- 24144603 TI - Emergency department problems raised at Sinclair inquest. PMID- 24144601 TI - Concordance of effects of medical interventions on hospital admission and readmission rates with effects on mortality. AB - BACKGROUND: Many clinical trials examine a composite outcome of admission to hospital and death, or infer a relationship between hospital admission and survival benefit. This assumes concordance of the outcomes "hospital admission" and "death." However, whether the effects of a treatment on hospital admissions and readmissions correlate to its effect on serious outcomes such as death is unknown. We aimed to assess the correlation and concordance of effects of medical interventions on admission rates and mortality. METHODS: We searched the Cochrane Database of Systematic Reviews from its inception to January 2012 (issue 1, 2012) for systematic reviews of treatment comparisons that included meta-analyses for both admission and mortality outcomes. For each meta-analysis, we synthesized treatment effects on admissions and death, from respective randomized trials reporting those outcomes, using random-effects models. We then measured the concordance of directions of effect sizes and the correlation of summary estimates for the 2 outcomes. RESULTS: We identified 61 meta-analyses including 398 trials reporting mortality and 182 trials reporting admission rates; 125 trials reported both outcomes. In 27.9% of comparisons, the point estimates of treatment effects for the 2 outcomes were in opposite directions; in 8.2% of trials, the 95% confidence intervals did not overlap. We found no significant correlation between effect sizes for admission and death (Pearson r = 0.07, p = 0.6). Our results were similar when we limited our analysis to trials reporting both outcomes. INTERPRETATION: In this metaepidemiological study, admission and mortality outcomes did not correlate, and discordances occurred in about one third of the treatment comparisons included in our analyses. Both outcomes convey useful information and should be reported separately, but extrapolating the benefits of admission to survival is unreliable and should be avoided. PMID- 24144605 TI - Community partnerships fill mental health gaps. PMID- 24144604 TI - Surgical management of hip osteoarthritis. PMID- 24144606 TI - National cord blood bank opens first sites in Ottawa. PMID- 24144607 TI - Traffic-related air pollution and health in Canada. PMID- 24144609 TI - Revisiting medication use in a frail 93-year-old man experiencing possible adverse effects. PMID- 24144611 TI - Patients with Crohn's disease on anti-tumor necrosis factor therapy are at significant risk of inadequate response to the 23-valent pneumococcal polysaccharide vaccine. AB - BACKGROUND/AIMS: The effect of immunosuppressants on the efficacy of a variety of vaccines is a controversial issue in patients with inflammatory bowel disease (IBD). In this study we determined whether specific immunosuppressants impair the serological response to the standard 23-valent pneumococcal polysaccharide vaccine (PPSV23) in a large cohort of patients with Crohn's disease (CD). METHODS: This was a multi-center, prospective observational study of adult patients with CD at 15 academic teaching hospitals in Korea. The study population received one intramuscular injection of PPSV23. Anti-pneumococcal IgG antibody titers were measured by immunoassay prior to and 4weeks after vaccination. All vaccination-related adverse events and the effect of the vaccine on disease activity were also evaluated. RESULTS: The overall serological response rate was 67.5% (133/197). The serological response rate was significantly lower in patients on anti-tumor necrosis factor (anti-TNF) therapy (50.0% on anti-TNF alone; 58.0% on anti-TNF combined with an immunomodulator, IM) than patients on 5 aminosalicylate (78.4%; all P-values vs. 5-aminosalicylate<0.05); 45.6% (41/90) of patients on anti-TNF therapy were not protected against PPSV23. IM did not affect the immunologic response to the vaccine. Female gender and anti-TNF therapy were significant predictors of non-response to the vaccine (odds ratio [OR] 2.316, P=0.015; OR 2.582, P=0.048, respectively). Vaccination was generally safe and tolerated by all patients. CONCLUSIONS: Patients with CD on anti-TNF therapy are at significant risk of an inadequate response to PPSV23. The pneumococcal vaccination strategy should be optimized for patients with CD on anti-TNF therapy. PMID- 24144612 TI - Plant growth promotion in cereal and leguminous agricultural important plants: from microorganism capacities to crop production. AB - Plant growth-promoting rhizobacteria (PGPR) are free-living bacteria which actively colonize plant roots, exerting beneficial effects on plant development. The PGPR may (i) promote the plant growth either by using their own metabolism (solubilizing phosphates, producing hormones or fixing nitrogen) or directly affecting the plant metabolism (increasing the uptake of water and minerals), enhancing root development, increasing the enzymatic activity of the plant or "helping" other beneficial microorganisms to enhance their action on the plants; (ii) or may promote the plant growth by suppressing plant pathogens. These abilities are of great agriculture importance in terms of improving soil fertility and crop yield, thus reducing the negative impact of chemical fertilizers on the environment. The progress in the last decade in using PGPR in a variety of plants (maize, rice, wheat, soybean and bean) along with their mechanism of action are summarized and discussed here. PMID- 24144613 TI - Acute gastric volvulus in a six-year-old: a case report and review of the literature. AB - BACKGROUND: First described in the pediatric population in 1899 by Oltmann, pediatric gastric volvulus is a rare disease, but carries a high mortality rate. Due to vague signs and symptoms it can easily be mistaken for gastroenteritis or appendicitis, but unique radiographic findings can help illuminate the diagnosis. The pathophysiology of gastric volvulus is related to an abnormality in the attachment of at least one of the gastric ligaments, which can occur either primarily or secondarily. The abnormality in these ligaments allows the stomach to freely rotate, eventually causing an obstruction. We describe a unique case occurring in a 6-year-old with no pre-exiting medical conditions as well as the associated radiographic images. OBJECTIVES: Our aim is to discuss the presentation and management of a potentially lethal intra-abdominal process that mimics far more benign disease entities and to highlight the pertinent radiographic findings. CASE REPORT: A previously healthy 6-year-old female presented to the emergency department in the middle of the night after sudden onset of vomiting and abdominal pain. On exam her heart rate was mildly elevated but all other vital signs were within normal limits. She was assessed with an abdominal x-ray and given ondansetron. After settling with her parents and having no further bouts of emesis she was sent home. She returned that afternoon febrile with increasing abdominal pain and emesis. Abdominal x-ray revealed a massively distended stomach and left diaphragmatic eventration. She underwent operative intervention and improved over the course of the following week. CONCLUSION: Acute gastric volvulus presents a diagnostic challenge. In patients with vague abdominal complaints knowledge of the typical x-ray findings is essential in early identification and treatment. PMID- 24144614 TI - Extension block pinning using a small external fixator for mallet finger fractures. AB - PURPOSE: To describe surgical outcomes of a series of patients with bony mallet fingers treated by a modified extension blocking technique with external fixation. METHODS: We developed an external fixator that was attached to the extension block pin. Dorsal rotation of the dorsal fragment during reduction was prevented with 1 or 2 additional pins abutted on the fragment through the fixator. We reviewed 12 consecutive patients with mallet finger fractures who were treated surgically with the external fixator. The mean age of the patients was 33 years (range, 15-60 y). RESULTS: Rotation of the fragment during reduction was well controlled in all patients. All fractures united at an average of 5 weeks after surgery. Average extension lag was 2 degrees and active flexion was 74 degrees . No patient reported pain at a final follow-up of 4 months (range, 3 8 mo). According to the Crawford rating scale, 10 patients were classified as excellent and 2 were good. CONCLUSIONS: Our modification of the extension block method prevented dorsal rotation of the fragment during reduction and resulted in early union. TYPE OF STUDY/LEVEL OF EVIDENCE: Therapeutic IV. PMID- 24144616 TI - Calculations of stopping powers and inelastic mean free paths for 20 eV-20 keV electrons in 11 types of human tissue. AB - Systematic calculations are performed for determining the stopping powers (SP) and inelastic mean free paths (IMFP) for 20 eV-20 keV electrons in 11 types of human tissue. The calculations are based on a dielectric model, including the Born-Ochkur exchange correction. The optical energy loss functions (OELF) are empirically evaluated, because of the lack of available experimental optical data for the 11 tissues under consideration. The evaluated OELFs are examined by the f sum rule expected from the dielectric response theory, and by calculation of the mean excitation energy. The calculated SPs are compared with those for PMMA (polymethylmethacrylate, a tissue equivalent material) and liquid water. The SP and IMFP data presented here are the results for the 11 human tissues over the energy range of 20 eV-20 keV, and are of importance in radiotherapy planning and for studies of various radiation effects on human tissues. PMID- 24144615 TI - A cluster analysis of tic symptoms in children and adults with Tourette syndrome: clinical correlates and treatment outcome. AB - Cluster analytic methods have examined the symptom presentation of chronic tic disorders (CTDs), with limited agreement across studies. The present study investigated patterns, clinical correlates, and treatment outcome of tic symptoms. 239 youth and adults with CTDs completed a battery of assessments at baseline to determine diagnoses, tic severity, and clinical characteristics. Participants were randomly assigned to receive either a comprehensive behavioral intervention for tics (CBIT) or psychoeducation and supportive therapy (PST). A cluster analysis was conducted on the baseline Yale Global Tic Severity Scale (YGTSS) symptom checklist to identify the constellations of tic symptoms. Four tic clusters were identified: Impulse Control and Complex Phonic Tics; Complex Motor Tics; Simple Head Motor/Vocal Tics; and Primarily Simple Motor Tics. Frequencies of tic symptoms showed few differences across youth and adults. Tic clusters had small associations with clinical characteristics and showed no associations to the presence of coexisting psychiatric conditions. Cluster membership scores did not predict treatment response to CBIT or tic severity reductions. Tic symptoms distinctly cluster with little difference across youth and adults, or coexisting conditions. This study, which is the first to examine tic clusters and response to treatment, suggested that tic symptom profiles respond equally well to CBIT. Clinical trials.gov. identifiers: NCT00218777; NCT00231985. PMID- 24144617 TI - Accurate determination of 41Ca concentrations in spent resins from the nuclear industry by accelerator mass spectrometry. AB - The radiological characterisation of nuclear waste is essential for managing storage sites. Determining the concentration of Long-Lived RadioNuclides (LLRN) is fundamental for their long-term management. This paper focuses on the measurement of low (41)Ca concentrations in ions exchange resins used for primary fluid purification in Pressurised Water Reactors (PWR). (41)Ca concentrations were successfully measured by Accelerator Mass Spectrometry (AMS) after the acid digestion of resin samples, followed by radioactive decontamination and isobaric suppression through successive hydroxide, carbonate, nitrate and final CaF2 precipitations. Measured (41)Ca concentrations ranged from 0.02 to 0.03 ng/g, i.e. from 0.06 to 0.09 Bq/g. The (41)Ca/(60)Co activity ratios obtained were remarkably reproducible and in good agreement with the current ratio used for resins management. PMID- 24144618 TI - Early life stress in epilepsy: a seizure precipitant and risk factor for epileptogenesis. AB - Stress can influence epilepsy in multiple ways. A relation between stress and seizures is often experienced by patients with epilepsy. Numerous questionnaire and diary studies have shown that stress is the most often reported seizure precipitating factor in epilepsy. Acute stress can provoke epileptic seizures, and chronic stress increases seizure frequency. In addition to its effects on seizure susceptibility in patients with epilepsy, stress might also increase the risk of epilepsy development, especially when the stressors are severe, prolonged, or experienced early in life. Although the latter has not been fully resolved in humans, various preclinical epilepsy models have shown increased seizure susceptibility in naive rodents after prenatal and early postnatal stress exposure. In the current review, we first provide an overview of the effects of stress on the brain. Thereafter, we discuss human as well as preclinical studies evaluating the relation between stress, epileptic seizures, and epileptogenesis, focusing on the epileptogenic effects of early life stress. Increased knowledge on the interaction between early life stress, seizures, and epileptogenesis could improve patient care and provide a basis for new treatment strategies for epilepsy. PMID- 24144619 TI - An iron-sulfur cluster in the polymerase domain of yeast DNA polymerase epsilon. AB - DNA polymerase epsilon (Polepsilon) is a multi-subunit polymerase that contributes to genomic stability via its roles in leading strand replication and the repair of damaged DNA. Polepsilon from Saccharomyces cerevisiae is composed of four subunits--Pol2, Dpb2, Dpb3, and Dpb4. Here, we report the presence of a [Fe-S] cluster directly within the active polymerase domain of Pol2 (residues 1 1187). We show that binding of the [Fe-S] cluster is mediated by cysteines in an insertion (Pol2(ins)) that is conserved in Pol2 orthologs but is absent in the polymerase domains of Polalpha, Poldelta, and Polzeta. We also show that the [Fe S] cluster is required for Pol2 polymerase activity but not for its exonuclease activity. Collectively, our work suggests that Polepsilon is perhaps more sensitive than other DNA polymerases to changes in oxidative stress in eukaryotic cells. PMID- 24144620 TI - Amino acid profiles in first trimester amniotic fluids of healthy bovine cloned pregnancies are similar to those of IVF pregnancies, but not nonviable cloned pregnancies. AB - Somatic cell nuclear transfer (SCNT), or cloning, is one of the assisted reproductive technologies currently used in agriculture. Commercial applications of SCNT are presently limited to the production of animals of high genetic merit or the production of the most elite show cattle owing to its relatively low efficiency. In current practice, 20% to 40% of SCNT pregnancies do not result in viable offspring. In an effort to better understand some of the anomalies associated with SCNT pregnancies, we investigated amino acid compositions of first trimester amniotic fluid. In this retrospective study, amniotic fluids were collected from SCNT and control IVF pregnancies at Day 75 of gestation and grouped according to the pregnancy results: control IVF (IVF), viable SCNT pregnancies that resulted in live healthy calves (SCNT-HL), nonviable SCNT pregnancies that were aborted before Day 150 (SCNT-ED), and nonviable SCNT pregnancies that were aborted after Day 150 or produced deceased calves (SCNT LD). High-performance liquid chromatography (HPLC) was used to analyze the concentrations of 22 amino acids (AAs) in the amniotic fluid samples. There were no differences in average AA concentrations between IVF and SCNT-HL groups, whereas SCNT-LD and SCNT-ED had higher levels of total AA concentrations. Concentrations of asparagine, citruline, arginine, and valine were significantly higher in the SCNT-LD group. Both SCNT-LD and SCNT-ED groups had relatively large intragroup variances in AA concentrations. Urea concentration was also measured in the SCNT amniotic fluid samples. No correlations between urea concentrations and arginine concentrations or pregnancy outcomes were found. The findings in this study not only deepen the understanding on SCNT pregnancy anomalies, but also provide a potentially useful screening tool for assessing viable and nonviable SCNT pregnancies. PMID- 24144621 TI - Traumatic inter-condylar dislocation of the patella: report of two cases. AB - Traumatic patellar dislocation usually occurs in the lateral direction. In a few cases, however, the patella rotates around its horizontal axis and becomes wedged between the femoral condyles. We report two cases of traumatic inter-condylar patellar dislocation that required surgical management. PMID- 24144622 TI - Chromatin regulators of neural development. AB - During all stages of neural development-from the fate switches of neural precursor/progenitor cells to activity-dependent synapse maturation-chromatin level modifications are important regulators of the gene expression that control developmental programs. Such modifications, including both alterations of histone tails and cytosine residues in the DNA, as well as changes in the chromatin structure, act dynamically throughout development and work together to determine the chromatin state at each time point. While many studies have shown localized action of chromatin modifiers at relevant gene loci, recent reports have also indicated that some chromatin modifications work on a more global scale, altering many loci throughout the genome. Here we review recent papers that describe the roles of chromatin-level regulation, at both the local and global scale, in the development of the mouse brain. PMID- 24144623 TI - Inhibition of mitochondrial fission attenuates Abeta-induced microglia apoptosis. AB - Mitochondrial division inhibitor 1 (mdivi-1), a selective inhibitor of mitochondrial fission protein dynamin-related protein 1 (Drp1), has been reported to display neuroprotective properties in different animal models. In the present study, we investigated the protective effect of mdivi-1 on beta-amyloid protein (Abeta)-induced cytotoxicity and its potential mechanisms in BV-2 and primary microglial cells. We found that mitochondrial fission was increased in Abeta treatment and inhibition of mitochondrial fission by mdivi-1 significantly reduced Abeta-induced expression of CD11b (a marker of microglial activation), viability loss and apoptotic rate increase in BV-2 and primary microglial cells. Moreover, we also found that mdivi-1 treatment markedly reversed mitochondrial membrane potential loss, cytochrome c (CytC) release and caspase-3 activation. Altogether, our data suggested that mdivi-1 exerts neuroprotective effects against Abeta-induced microglial apoptosis, and the underlying mechanism may be through inhibiting mitochondrial membrane potential loss, CytC release and suppression of the mitochondrial apoptosis pathway. PMID- 24144625 TI - Arm sway holds sway: locomotor-like modulation of leg reflexes when arms swing in alternation. AB - It has been argued that arm movements are important during human gait because they affect leg activity due to neural coupling between arms and legs. Consequently, one would expect that locomotor-like alternating arm swing is more effective than in-phase swing in affecting the legs' motor output. Other alternating movements such as trunk rotation associated to arm swing could also affect leg reflexes. Here, we assessed how locomotor-like movement patterns would affect soleus H-reflexes in 13 subjects performing arm swing in the sagittal plane (ipsilateral, contralateral and bilateral in-phase versus locomotor-like anti-phase arm movements) and trunk rotation with the legs stationary, and leg stepping with the arms stationary. Findings revealed that soleus H-reflexes were suppressed for all arm, trunk or leg movements. However, a marked reflex modulation occurred during locomotor-like anti-phase arm swing, as was also the case during leg stepping, and this modulation flattened out during in-phase arm swing. This modulation had a peculiar bell shape and showed maximum suppression at a moment where the heel-strike would occur during a normal walking cycle. Furthermore, this modulation was independent from electromyographic activity, suggesting a spinal processing at premotoneuronal level. Therefore, trunk movement can affect legs' output, and a special neural coupling occurs between arms and legs when arms move in alternation. This may have implications for gait rehabilitation. PMID- 24144624 TI - Glutamate dysregulation in the trigeminal ganglion: a novel mechanism for peripheral sensitization of the craniofacial region. AB - In the trigeminal ganglion (TG), satellite glial cells (SGCs) form a functional unit with neurons. It has been proposed that SGCs participate in regulating extracellular glutamate levels and that dysfunction of this SGC capacity can impact nociceptive transmission in craniofacial pain conditions. This study investigated whether SGCs release glutamate and whether elevation of TG glutamate concentration alters response properties of trigeminal afferent fibers. Immunohistochemistry was used to assess glutamate content and the expression of excitatory amino acid transporter (EAAT)1 and EAAT2 in TG sections. SGCs contained glutamate and expressed EAAT1 and EAAT2. Potassium chloride (10 mM) was used to evoke glutamate release from cultured rat SGCs treated with the EAAT1/2 inhibitor (3S)-3-[[3-[[4-(trifluoromethyl)ben zoyl]amino]phenyl]methoxy]-L aspartic acid (TFB-TBOA) or control. Treatment with TFB-TBOA (1 and 10 MUM) significantly reduced the glutamate concentration from 10.6 +/- 1.1 to 5.8 +/- 1.4 MUM and 3.0 +/- 0.8 MUM, respectively (p<0.05). Electrophysiology experiments were conducted in anaesthetized rats to determine the effect of intraganglionic injections of glutamate on the response properties of ganglion neurons that innervated either the temporalis or masseter muscle. Intraganglionic injection of glutamate (500 mM, 3 MUl) evoked afferent discharge and significantly reduced muscle afferent mechanical threshold. Glutamate-evoked discharge was attenuated bythe N-methyl-D-aspartate receptor antagonist 2-amino-5-phosphonovalerate (APV) and increased by TFB-TBOA, whereas mechanical sensitization was only sensitive to APV. Antidromic invasion of muscle afferent fibers by electrical stimulation of the caudal brainstem (10 Hz) or local anesthesia of the brainstem with lidocaine did not alter glutamate-induced mechanical sensitization. These findings provide a novel mechanism whereby dysfunctional trigeminal SGCs could contribute to cranial muscle tenderness in craniofacial pain conditions such as migraine headache. PMID- 24144626 TI - Light adaptation increases response latency of alpha ganglion cells via a threshold-like nonlinearity. AB - Adaptation is an important process of sensory systems to adjust sensitivity to ensure the appropriate information encoding. Sensitivity and kinetics of retinal ganglion cell (RGC) responses have been studied extensively using a brief flash superimposed on different but steady backgrounds. However, it is still unclear if light adaptation exerts any effect on more complex response properties, such as response nonlinearity. In this study, we found that the latency of spike responses to a repeated flashing spot stimulation increased by 30 ms in the mouse ON alpha RGCs (An ON-type RGC is excited when a spot is turned on in the center of its receptive field). A single dimming event preceding the test flash on a steady adapting background could also produce similar effect in increasing latency of light responses. A simple computational model with a linear transformation of the light stimulus and a threshold-like nonlinearity could account for the experimental data. Moreover, the strength of the measured nonlinearity and the response latency were affected by the duration of light adaptation. The possible biological processes underlying this nonlinearity were explored. Voltage clamp recording revealed the presence of the increase in latency and threshold-like nonlinearity in the excitatory input of RGCs. However, no comparable nonlinearity was observed in the light responses of the ON cone bipolar cells. We further excluded GABAergic and glycinergic inhibition, N-methyl D-aspartate receptor rectification and voltage-gated Na(+) channels as potential sources of this nonlinearity by pharmacological experiments. Our results indicate the bipolar cell terminals as the potential site of nonlinearity. Computational modeling constrained by experimental data supports that conclusion and suggests the voltage-sensitive Ca(++) channels and Ca(++)-dependent vesicle release in the bipolar cell terminals as mechanistic basis. PMID- 24144627 TI - Intravenous GLP-1 (7-36) amide for prevention of hyperglycemia during cardiac surgery: a randomized, double-blind, placebo-controlled study. AB - OBJECTIVE: The authors sought to evaluate the efficacy of an intravenous glucagon like peptide-1 (GLP-1) infusion, compared with placebo, to mitigate intraoperative hyperglycemia. DESIGN: Prospective, double-blinded, randomized, placebo-controlled. SETTING: University hospital. PARTICIPANTS: Diabetic (non insulin dependent) and non-diabetic patients undergoing elective cardiac surgery with cardiopulmonary bypass. INTERVENTIONS: Patients were randomized in a 1:1 fashion to GLP-1 (7-36) amide infusion (1.5 pmol/kg/min) or placebo. Insulin was administered intraoperatively to both groups per a standardized protocol. MEASUREMENTS AND MAIN RESULTS: A total of 77 patients were included for analysis (GLP-1, n = 37; placebo, n = 40). Mean blood glucose during cardiopulmonary bypass was 127.5 mg/dL and 142.5 mg/dL (p = 0.002) in the GLP-1 and placebo groups, respectively. Mean blood glucose values during the entire intraoperative course were 12.2 mg/dL lower for subjects given GLP-1 (95% CI 2.3, 22, p = 0.015), independent of time. During the period of cardiopulmonary bypass, mean blood glucose values in subjects given GLP-1 were 14.1 mg/dL lower than those who received placebo (95% CI 3.5, 24.8, p = 0.009), independent of time. The incidence of hypoglycemia did not differ significantly between the 2 groups. CONCLUSIONS: Administration of intravenous GLP-1 (7-36) amide to patients undergoing cardiac surgery significantly reduced their plasma glucose levels intraoperatively and may represent a novel therapeutic strategy to prevent perioperative hyperglycemia. PMID- 24144628 TI - Comparison of a waxy maize and a potato starch-based balanced hydroxyethyl starch for priming in patients undergoing coronary artery bypass grafting. AB - OBJECTIVE: Concerns have been raised about differences in the safety profile of potato- versus waxy maize-derived hydroxyethyl starch (HES). The objective of this study was to compare 2 HES solutions derived from 2 different source materials (potato versus waxy maize) for their dose-related effects on hemostasis and organ function when used to prime the cardiopulmonary bypass circuit (CPB). DESIGN: A prospective, randomized, controlled study. SETTING: Tertiary care center. PARTICIPANTS: Eighty patients undergoing coronary artery bypass grafting (CABG) on CPB. INTERVENTIONS: For priming the CPB circuit, the HESPRL group received 1000 mL of potato-derived balanced 6% HES 130/0.42 along with 500 mL of Ringer's lactate; the HESP group received 1,500 mL of potato-derived balanced 6% HES 130/0.42; the HESMRL group received 1000 mL of waxy maize-derived balanced 6% HES 130/0.4 along with 500 mL of Ringer's lactate, and the HESM group received 1500 mL of waxy maize-derived balanced 6% HES 130/0.4. MEASUREMENTS AND MAIN RESULTS: There were no significant differences in 24-hour mediastinal drainage, rate of re-exploration, blood product usage, coagulation parameters, and measures of pulmonary, renal, and hepatic function with respect to plant source of HES, when equivalent doses were used. Sonoclot activated clotting time (SonACT) was significantly higher and clot rate (CR) significantly lower at end of surgery (T1) and 24 hours after surgery (T2) in the HESP and HESM groups compared with the HESPRL and HESMRL groups. Compared with baseline, CR and platelet function were significantly lower at T1, PaO2/FIO2 ratio decreased significantly at T1 and T2, and serum bilirubin and transaminases increased significantly at T2 in all 4 groups. CONCLUSIONS: There was no significant difference in cumulative 24-hour mediastinal drainage when potato-derived balanced 6% HES 130/0.42 or waxy maize derived balanced 6% HES 130/0.4 was used to prime the CPB circuit in patients undergoing CABG. In equal doses, both starches exerted the same effect on blood coagulation and pulmonary, renal, and hepatic function. PMID- 24144629 TI - Robotic mitral valve repair: a review of anesthetic management of the first 200 patients. AB - OBJECTIVE: The aim of this study was to describe the evolution in anesthetic technique used for the first 200 patients undergoing robotic mitral valve surgery. DESIGN: A retrospective review. SETTING: A single tertiary referral academic hospital. PARTICIPANTS: Two hundred consecutive patients undergoing robotic mitral valve surgery using the da Vinci Surgical System (Intuitive Surgical, Inc., Sunnyvale, CA) at Mayo Clinic Rochester. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: After obtaining institutional review board approval, surgical and anesthetic data were recorded. For analysis, patients were placed in 4 groups, each containing 50 consecutive patients, labeled Quartiles 1 to 4. Over time, there were statistically significant decreases in cardiopulmonary bypass and aortic cross-clamp times. Significant differences in the anesthetic management were shown, with a reduction of intraoperative fentanyl and midazolam doses, and the introduction of paravertebral blockade in Quartile 2. There was a reduction of time between incision closure and extubation, and nearly 90% of patients were extubated in the operating room in Quartiles 3 and 4. Despite changes to the intraoperative analgesic management, and focus on earlier extubation, there were no differences seen in visual analog scale (VAS) pain scores over the 4 quartiles. Reductions were seen in total intensive care unit and hospital length of stay during the study period. CONCLUSIONS: Changes to the practice, including efforts to limit intraoperative opioid administration and the addition of preoperative paravertebral blockade, helped facilitate earlier extubation. In the second half of the study period, close to 90% of patients were extubated in the operating room safely and without delaying patient transition to the intensive care unit. PMID- 24144630 TI - Anti-fibrotic and anti-inflammatory properties of melatonin on human gingival fibroblasts in vitro. AB - Melatonin (MEL) has been proposed as a therapeutic agent for the oral cavity, due to its antioxidant and anti-inflammatory effects since periodontal diseases are aggravated by free radicals, and by disproportionate immunological response to plaque microorganism. In addition, MEL promotes bone formation. This study aimed to investigate the effects of MEL and 5-methoxytryptophol (5-MTX), an indole derivative related to MEL, on the growth rate of Staphylococcus epidermidis and on human gingival fibroblasts (HGF) for potential use in periodontal applications. HGF were treated with MEL and 5-MTX and the effects were evaluated on cell viability, gene expression, collagen production, wound healing and matrix metalloproteinase-1/tissue inhibitor of metalloproteinases-1 (MMP1/TIMP1) production. MEL showed the most promising biological effects in relation to periodontal applications. Thus, MEL was not toxic for HGF, increased collagen IIIalpha1, decorin and IL10, it down-regulated the expression of pro-fibrotic markers during wound healing, decreased the MMP1/TIMP1protein ratio. These results suggest that MEL could contribute to protect and recover the integrity of gingival tissues, thus, displaying a potential use for periodontal disease treatment or to functionalize dental implant abutments to improve soft tissue integration. PMID- 24144631 TI - Stilbene 5c, a microtubule poison with vascular disrupting properties that induces multiple modes of growth arrest and cell death. AB - The stilbene derivative, cis-3,4',5-trimethoxy-3'-aminostilbene (stilbene 5c), is a potentially potent antitumor agent that acts via binding to the colchicine binding site in tubulin. The current studies were designed to investigate the effectiveness of stilbene 5c against the HCT-116 human colon cancer cell line and B16/F10 melanoma cells as well as human endothelial cell tube formation and tumor perfusion. Stilbene 5c produced a time-dependent decrease in cell viability in both cell lines and the capacity of the cells to proliferate was not restored upon removal of the drug. Treatment with stilbene 5c also promoted both senescence and autophagy in both cell lines. TUNEL and annexin 5 staining indicated that apoptosis also occurs in stilbene 5c-treated HCT-116 cells, but not in B16/F10 melanoma cells. DAPI staining revealed morphological changes in the cell nuclei (binucleated and micronucleated cells) indicative of mitotic catastrophe in HCT-116 cells but not in the B16/F10 melanoma cells. p53-null HCT 116 cells demonstrated a similar growth arrest/cell death response to stilbene as p53-wild type HCT-116 cells. Stilbene 5c also completely inhibited human endothelial cell tube formation on Matrigel, consistent with potential anti angiogenic actions. Using a new method developed for monitoring the pharmacodynamic effects of stilbene 5c in vivo, we found that a single injection of stilbene 5c reduced tumor perfusion by 65% at 4h, returning to baseline by 24h, while subsequent daily injections of stilbene 5c produced progressively larger reductions and smaller rebounds. This work indicates that stilbene 5c could potentially be effective against melanoma and colon cancer through the promotion of multiple modes of growth arrest and cell death coupled with anti angiogenic and antivascular actions. PMID- 24144633 TI - Uncoupling of eNOS contributes to redox-sensitive leukocyte recruitment and microvascular leakage elicited by methylglyoxal. AB - Elevated levels of the glycolysis metabolite methylglyoxal (MG) have been implicated in impaired leukocyte-endothelial interactions and vascular complications in diabetes, putative mechanisms of which remain elusive. Uncoupling of endothelial nitric oxide synthase (eNOS) was shown to be involved in endothelial dysfunction in diabetes. Whether MG contributes to these effects has not been elucidated. By using intravital microscopy in vivo, we demonstrate that MG-triggered reduction in leukocyte rolling velocity and increases in rolling flux, adhesion, emigration and microvascular permeability were significantly abated by scavenging reactive oxygen species (ROS). In murine cremaster muscle, MG treatment reduced tetrahydrobiopterin (BH4)/total biopterin ratio, increased arginase expression and stimulated ROS and superoxide production. The latter was significantly blunted by ROS scavengers Tempol (300MUM) or MnTBAP (300MUM), by BH4 supplementation (100MUM) or by NOS inhibitor N(G)-nitro-L-arginine methyl ester (L-NAME; 20MUM). In these tissues and cultured murine and human primary endothelial cells, MG increased eNOS monomerization and decreased BH4/total biopterin ratio, effects that were significantly mitigated by supplementation of BH4 or its precursor sepiapterin but not by L-NAME or tetrahydroneopterin, indicative of MG-triggered eNOS uncoupling. MG treatment further decreased the expression of guanosine triphosphate cyclohydrolase I in murine primary endothelial cells. MG-induced leukocyte recruitment was significantly attenuated by supplementation of BH4 or sepiapterin or suppression of superoxide by L-NAME confirming the role of eNOS uncoupling in MG-elicited leukocyte recruitment. Together, our study uncovers eNOS uncoupling as a pivotal mechanism in MG-induced oxidative stress, microvascular hyperpermeability and leukocyte recruitment in vivo. PMID- 24144632 TI - JAK2-targeted anti-inflammatory effect of a resveratrol derivative 2,4-dihydroxy N-(4-hydroxyphenyl)benzamide. AB - Chemical derivatization of resveratrol has been widely conducted in an effort to overcome its chemical instability and therapeutic potential. In the present study, we examined the anti-inflammatory effects of resveratrol derivatives containing an amide functionality using in vitro macrophage models that were stimulated by Toll-like receptor (TLR) ligands, and using several animal inflammatory disease models. Of the resveratrol derivatives tested, compound 8 (2,4-dihydroxy-N-(4-hydroxyphenyl)benzamide) most strongly inhibited the production of nitric oxide (NO), tumor necrosis factor (TNF)-alpha, and prostaglandin E2 (PGE2), as well as the mRNA expression of inducible NO synthase (iNOS), TNF-alpha, and cyclooxygenase (COX)-2 in lipopolysaccharide (LPS) activated RAW264.7 cells, differentiated U937 cells, and peritoneal macrophages. The inhibitory activity of compound 8 was apparently mediated by suppressing the phosphorylation of signal transducer and activator of transcription (STAT)-1, STAT-3, STAT-5, and interferon regulatory factor (IRF)-3. The direct target of compound 8 was revealed to be Janus kinase 2 (JAK2) but not TANK-binding kinase (TBK) 1 using the direct kinase assay and analyses of complex formation with these molecules. Additionally, upstream kinase of TBK1 seems to be also inhibited by compound 8. This compound also strongly ameliorated mouse inflammatory symptoms seen in arachidonic acid-induced ear edema, dextran sodium sulfate (DSS) treated colitis, EtOH/HCl-induced gastritis, collagen type II-triggered arthritis, and acetic acid-induced writhing. Therefore, of the resveratrol derivatives that we tested, compound 8 was determined to have the strongest anti inflammatory activities in vitro and in vivo and may potentially be developed for use as a novel anti-inflammatory drug. PMID- 24144634 TI - Mobile EEG: towards brain activity monitoring during natural action and cognition. PMID- 24144635 TI - Towards the measurement of event-related EEG activity in real-life working environments. AB - In applied contexts, psychophysiological measures have a long tradition to evaluate the user state. EEG correlates that indicate mechanisms of information processing, however, are hardly accessible since discrete time stamps that are necessary for this approach are commonly not available in natural situations. However, eye blinks may close this gap. Eye blinks are assumed to mark distinct points in information processing, necessary to segment the incoming data stream. By using mobile EEG in a simulated working situation we demonstrate that eye blink-related potentials provide reliable information about cognitive processing in distinct working environments. During cognitive tasks, an increase in the fronto-central N2 component as well as evoked theta activity can be shown, both indices of enhanced cognitive control. The posterior P3 is reduced during physical tasks (sorting of boxes), probably reflecting the more continuous nature of this task. The data are discussed within a model of dopaminergic modulation of blink activity that involves both task specific aspects like executive control and modulating influences of motivation or fatigue. PMID- 24144637 TI - Mobile EEG and its potential to promote the theory and application of imagery based motor rehabilitation. AB - Studying the brain in its natural state remains a major challenge for neuroscience. Solving this challenge would not only enable the refinement of cognitive theory, but also provide a better understanding of cognitive function in the type of complex and unpredictable situations that constitute daily life, and which are often disturbed in clinical populations. With mobile EEG, researchers now have access to a tool that can help address these issues. In this paper we present an overview of technical advancements in mobile EEG systems and associated analysis tools, and explore the benefits of this new technology. Using the example of motor imagery (MI) we will examine the translational potential of MI-based neurofeedback training for neurological rehabilitation and applied research. PMID- 24144636 TI - Emotional expressions modulate low alpha and beta oscillations in a cortically blind patient. AB - Studies of cortical blindness have suggested that some residual visual function may persist without perceptual awareness, a condition known as blindsight. To investigate electrophysiological evidence of unconscious processing of emotional stimuli, we examined the event-related oscillations (EROs) in a 62year-old male patient (TN) with affective blindsight during random stimulation of three facial expressions (fearful, happy and neutral). Spectral power analysis in response to the different emotions revealed significant differences between fearful and happy faces over the right frontal regions at 7-8Hz (low alpha), and between emotional and neutral faces over the left frontal sites at 12-13Hz (low beta) in a time period between 100-400ms after visual stimulus onset. These results demonstrate that emotional face processing occurs very early in time in the absence of any functional striate cortex, and further reveals the existence of specific oscillatory frequencies that reflect unconscious processing of facial expressions in affective blindsight. PMID- 24144638 TI - Event-related synchronization of delta and beta oscillations reflects developmental changes in the processing of affective pictures during adolescence. AB - Recent research has determined that affective pictures modulate event-related delta and beta oscillations in adults. However, it is unclear whether these brain oscillations reflect developmental changes in the processing of affective information during adolescence. EEG data were collected from 51 adolescents and 18 undergraduates as they viewed a total of 90 pictures. In the range of fast wave activities, event-related synchronization (ERS) in the beta band varied with emotional valence, indicating that beta ERS is indicative of early bottom-up processing of visual emotional stimuli. Adolescents at the age of 12years exhibited more positive beta ERS amplitudes over posterior brain regions for positive versus neutral pictures compared to adolescents at the ages 14years, 16years and in young adults; however, no age-related differences were found for negative versus neutral pictures. In the range of slow wave activities, delta ERSs and late positive potential (LPP) amplitudes exhibited affective modulation and decreased over anterior brain regions from between the age of 12years and early adulthood. These slow wave activities (delta and LPPs) reflected top-down attention to the motivational relevance of the emotional stimuli. Taken together, these observations suggest that adolescents exhibit dissociable ERS patterns in the delta and beta bands during affective processing. Furthermore, adolescents undergo age-dependent changes in oscillatory brain reorganization. Our results should be useful to researchers interested in affective processing during adolescence. PMID- 24144639 TI - Characteristics of Sexually Transmitted Infections among High-Risk HIV-Positive Patients Attending an Urban Clinic in Uganda. AB - BACKGROUND: Sexually transmitted infections (STIs) significantly increase HIV transmission. Sexually transmitted infections may be asymptomatic and therefore remain undiagnosed in HIV-positive persons. Routine screening and treatment of STIs in HIV-positive high-risk populations in sub-Saharan Africa have not been described previously. METHODS: We reviewed data from an HIV-positive high-risk population at the Infectious Diseases Institute, Makerere University, a large urban HIV clinic, between July 2011 and April 2012. Our high-risk population cohort included female sex workers, long-distance drivers, barmaids, taxi drivers, commercial motorcycle "boda-boda" riders, soldiers, police officers, prison officers, security guards, prisoners, and fishermen. RESULTS: Of 355 participants enrolled in the high-risk population's program, 21.4% were diagnosed with an STI either clinically or microbiologically. The STIs diagnosed in this population were syphilis, hepatitis B, genital herpes, human papilloma virus infection (condylomata acuminata), nongonococcal urethritis (NGU), and gonorrhea. Rates of syphilis, hepatitis B, genital herpes, condylomata acuminata, NGU, and gonorrhea were 8.5%, 7.0%, 5.4%, 1.4%, 1.4%, and 0.3%, respectively. CONCLUSION: Clinical and microbiologically diagnosed STIs were diagnosed in nearly one-fourth of the HIV-positive high-risk population. HIV care programs should note our high rates of STIs among HIV-positive high-risk populations and consider routine screening and treatment algorithms for these populations in their own settings. PMID- 24144640 TI - Allogeneic hematopoietic stem cell transplantation in Fanconi anemia: the European Group for Blood and Marrow Transplantation experience. AB - Although allogeneic hematopoietic stem cell transplantation (HSCT) remains the only curative treatment for patients with Fanconi anemia (FA), published series mostly refer to single-center experience with limited numbers of patients. We analyzed results in 795 patients with FA who underwent first HSCT between May 1972 and January 2010. With a 6-year median follow-up, overall survival was 49% at 20 years (95% confidence interval, 38-65 years). Better outcome was observed for patients transplanted before the age of 10 years, before clonal evolution (ie, myelodysplastic syndrome or acute myeloid leukemia), from a matched family donor, after a conditioning regimen without irradiation, the latter including fludarabine. Chronic graft-versus-host disease and secondary malignancy were deleterious when considered as time-dependent covariates. Age more than 10 years at time of HSCT, clonal evolution as an indication for transplantation, peripheral blood as source of stem cells, and chronic graft-versus-host disease were found to be independently associated with the risk for secondary malignancy. Changes in transplant protocols have significantly improved the outcome of patients with FA, who should be transplanted at a young age, with bone marrow as the source of stem cells. PMID- 24144641 TI - Smoldering multiple myeloma requiring treatment: time for a new definition? AB - Smoldering multiple myeloma (SMM) bridges the gap between monoclonal gammopathy of undetermined significance (a mostly premalignant disorder) and active multiple myeloma (MM). Until recently, no interventional study in patients with SMM showed improved overall survival (OS) with therapy as compared with observation. A report from the PETHEMA-GEM (Programa Espanol de Tratamientos en Hematologica) group described both fewer myeloma-related events and better OS among patients with high-risk SMM who were treated with lenalidomide and dexamethasone. This unique study prompted us to review current knowledge about SMM and address the following questions: (1) Are there patients currently defined as SMM who should be treated routinely? (2) Should the definitions of SMM and MM be reconsidered? (3) Has the time come when not treating is more dangerous than treating? (4) Could unintended medical harm result from overzealous intervention? Our conclusion is that those patients with the highest-risk SMM (extreme bone marrow plasmacytosis, extremely abnormal serum immunoglobulin free light chain ratio, and multiple bone lesions detected only by modern imaging) should be reclassified as active MM so that they can receive MM-appropriate therapy and the paradigm of careful observation for patients with SMM can be preserved. PMID- 24144642 TI - SCID patients with ARTEMIS vs RAG deficiencies following HCT: increased risk of late toxicity in ARTEMIS-deficient SCID. AB - A subgroup of severe combined immunodeficiencies (SCID) is characterized by lack of T and B cells and is caused by defects in genes required for T- and B-cell receptor gene rearrangement. Several of these genes are also involved in nonhomologous end joining of DNA double-strand break repair, the largest subgroup consisting of patients with T(-)B(-)NK(+)SCID due to DCLRE1C/ARTEMIS defects. We postulated that in patients with ARTEMIS deficiency, early and late complications following hematopoietic cell transplantation might be more prominent compared with patients with T(-)B(-)NK(+)SCID caused by recombination activating gene 1/2 (RAG1/2) deficiencies. We analyzed 69 patients with ARTEMIS and 76 patients with RAG1/2 deficiencies who received transplants from either HLA-identical donors without conditioning or from HLA-nonidentical donors without or with conditioning. There was no difference in survival or in the incidence or severity of acute graft-versus-host disease regardless of exposure to alkylating agents. Secondary malignancies were not observed. Immune reconstitution was comparable in both groups, however, ARTEMIS-deficient patients had a significantly higher occurrence of infections in long-term follow-up. There is a highly significant association between poor growth in ARTEMIS deficiency and use of alkylating agents. Furthermore, abnormalities in dental development and endocrine late effects were associated with alkylation therapy in ARTEMIS deficiency. PMID- 24144644 TI - Preterm birth and hypertension risk: the oxidative stress paradigm. PMID- 24144643 TI - Clinical, genomic, and imaging predictors of myeloma progression from asymptomatic monoclonal gammopathies (SWOG S0120). AB - All cases of clinical myeloma (CMM) are preceded by an asymptomatic monoclonal gammopathy (AMG), classified as either monoclonal gammopathy of undetermined significance (MGUS) or asymptomatic multiple myeloma (AMM). We analyzed data from AMG patients (n = 331) enrolled in a prospective, observational clinical trial (S0120). Baseline data from clinical variables, gene expression profiles (GEP) of purified tumor cells, and findings of magnetic resonance imaging (MRI) were correlated with the risk of progression to CMM requiring therapy. GEP of purified tumor cells revealed that all molecular subtypes of CMM are also represented in the AMG phase. An increased risk score (>-0.26) (based on a 70-gene signature, GEP70) was an independent predictor of the risk of progression to CMM. Combination of elevated serum free light chain, M-spike, and GEP70 risk score identified a subset with high risk (67% at 2 years) of progression to CMM requiring therapy. Importantly, absence of these factors in AMM patients predicted low risk similar to MGUS. Detection of multiple (>1) focal lesions by MRI also conferred an increased risk of progression. These data demonstrate that signatures associated with high-risk CMM impact disease risk and support inclusion of genomic analysis in the clinical management of AMGs. PMID- 24144645 TI - Importance of pressure pulse amplification in the association of resting heart rate and arterial stiffness. PMID- 24144646 TI - Association between ambulatory systolic blood pressure during the day and asymptomatic intracranial arterial stenosis. AB - It is unclear at what time-window of the day blood pressure (BP) is most closely associated with cerebrovascular damage. In this cross-sectional study, we examined the strength of association between intracranial arterial stenosis (ICAS) and systolic BP (SBP) across different time-windows using 24-hour ambulatory BP monitoring in 757 consecutively recruited patients with hypertension. ICAS was diagnosed with computerized tomographic angiography in 127 (16.8%) patients, of whom 64 (50.4%) had stenosis >=50% and 82 (64.6%) had ICAS in >=2 vessels. Patients with ICAS (142 mm Hg), especially of multiple vessels (145 mm Hg), compared with patients without ICAS (126 mm Hg), had significantly (P<0.001) higher early morning (05:00-07:59 am) SBP. The differences remained significant (P<=0.015) after adjustment for cardiovascular risk factors and SBPs at other time-windows of the day. Multivariate regression analysis showed that consecutive 3-hourly mean SBPs during the day were significantly associated with ICAS (odds ratio for each 10-mm Hg increase, 1.28-1.38; P<=0.001). However, only mean SBP obtained between 05:00 am and 07:59 am remained significant for ICAS (odds ratio, 1.30; P=0.019) when all consecutive 3-hourly mean SBPs were forced into a single multivariate model. In conclusion, the present study showed a significant association between early morning SBP and asymptomatic ICAS in patients with hypertension after accounting for conventional cardiovascular risk factors. Our findings highlight the importance of morning SBP as a cardiovascular risk factor and should be validated in prospective studies. PMID- 24144647 TI - Classical transient receptor potential 1 and 6 contribute to hypoxic pulmonary hypertension through differential regulation of pulmonary vascular functions. AB - Hypoxic pulmonary hypertension is characterized by increased vascular tone, altered vasoreactivity, and vascular remodeling, which are associated with alterations in Ca(2+) homeostasis in pulmonary arterial smooth muscle cells. We have previously shown that classical transient receptor potential 1 and 6 (TRPC1 and TRPC6) are upregulated in pulmonary arteries (PAs) of chronic hypoxic rats, but it is unclear whether these channels are essential for the development of pulmonary hypertension. Here we found that pulmonary hypertension was suppressed in TRPC1 and TRPC6 knockout (Trpc1(-/-) and Trpc6(-/-)) mice compared with wild type after exposure to 10% O(2) for 1 and 3 weeks. Muscularization of pulmonary microvessels was inhibited, but rarefaction was unaltered in hypoxic Trpc1(-/-) and Trpc6(-/-) mice. Small PAs of normoxic wild-type mice exhibited vasomotor tone, which was significantly enhanced by chronic hypoxia. Similar vasomotor tone was found in normoxic Trpc1(-/-) PAs, but the hypoxia-induced enhancement was blunted. In contrast, there was minimal vascular tone in normoxic Trpc6(-/-) PAs, but the hypoxia-enhanced tone was preserved. Chronic hypoxia caused significant increase in serotonin-induced vasoconstriction; the augmented vasoreactivity was attenuated in Trpc1(-/-) and eliminated in Trpc6(-/-) PAs. Moreover, the effects of 3-week hypoxia on pulmonary arterial pressure, right ventricular hypertrophy, and muscularization of microvessels were further suppressed in TRPC1-TRPC6 double knockout mice. Our results, therefore, provide clear evidence that TRPC1 and TRPC6 participate differentially in various pathophysiological processes, and that the presence of TRPC1 and TRPC6 is essential for the full development of hypoxic pulmonary hypertension in the mouse model. PMID- 24144648 TI - Spiral artery remodeling in preeclampsia revisited. PMID- 24144649 TI - Interferon regulatory factor 9 protects against cardiac hypertrophy by targeting myocardin. AB - Pathological cardiac hypertrophy is a major risk factor for heart failure. In this study, we identified interferon regulatory factor 9 (IRF9), a member of the IRF family, as a previously unidentified negative regulator of cardiac hypertrophy. The level of IRF9 expression was remarkably elevated in the hearts from animals with aortic banding-induced cardiac hypertrophy. IRF9-deficient mice exhibited pronounced cardiac hypertrophy after pressure overload, as demonstrated by increased cardiomyocyte size, extensive fibrosis, reduced cardiac function, and enhanced expression of hypertrophy markers, whereas transgenic mice with cardiac-specific overexpression of murine IRF9 exhibited a significant reduction in the hypertrophic response. Mechanistically, IRF9 competes with p300 for binding to the transcription activation domain of myocardin, a coactivator of serum response factor (SRF). This interaction markedly suppresses the transcriptional activity of myocardin because IRF9 overexpression strongly inhibits the ability of myocardin to activate CArG box-dependent reporters. These results provide compelling evidence that IRF9 inhibits the development of cardiac hypertrophy by suppressing the transcriptional activity of myocardin in the heart. PMID- 24144650 TI - Reduced heart rate variability is associated with worse cognitive performance in elderly Mexican Americans. AB - Reduced heart rate variability is a strong predictor of cardiovascular risk factors, cardiovascular events, and mortality and thus may be associated with cognitive neurodegeneration. Yet, this has been relatively unexplored, particularly in minority populations with high cardiovascular burden. We used data from the Sacramento Area Latino Study on Aging to examine the cross sectional association of reduced heart rate variability with cognitive function among elderly Mexican Americans. A total of 869 participants (mean age, 75 years; 59% women) had their 6-minute heart rate variability measured using an ECG monitor and respiration pacer in response to deep breathing. We used the mean circular resultant, known as R bar, as a measure of heart rate variability and categorized it into quartiles (Q1 to Q4 of R bar: reduced to high heart rate variability). Cognitive function was assessed using the modified Mini-Mental State Examination, a 100-point test of global cognitive function, and the Spanish and English verbal learning test, a 15-point test of verbal memory recall. In fully adjusted linear regression models, participants in quartile 1 had a 4-point lower modified Mini-Mental State Examination score (P<0.01), those in quartile 2 had a 2-point lower score (P=0.04), and those in quartile 3 had a 1-point lower score (P=0.35) compared with those in the highest quartile of R bar. Reduced R bar was not associated with verbal memory. Our results suggest that reduced heart rate variability is associated with worse performance on the test of global cognitive function, above and beyond traditional cardiovascular risk factors. PMID- 24144651 TI - Nonlaboratory-based risk assessment algorithm for undiagnosed type 2 diabetes developed on a nation-wide diabetes survey. AB - OBJECTIVE: To develop a New Chinese Diabetes Risk Score for screening undiagnosed type 2 diabetes in China. RESEARCH DESIGN AND METHODS: Data from the China National Diabetes and Metabolic Disorders Study conducted from June 2007 to May 2008 comprising 16,525 men and 25,284 women aged 20-74 years were analyzed. Undiagnosed type 2 diabetes was detected based on fasting plasma glucose >=7.0 mmol/L or 2-h plasma glucose >=11.1 mmol/L in people without a prior history of diabetes. beta-Coefficients derived from a multiple logistic regression model predicting the presence of undiagnosed type 2 diabetes were used to calculate the New Chinese Diabetes Risk Score. The performance of the New Chinese Diabetes Risk Score was externally validated in two studies in Qingdao: one is prospective with follow-up from 2006 to 2009 (validation 1) and another cross-sectional conducted in 2009 (validation 2). RESULTS: The New Chinese Diabetes Risk Score includes age, sex, waist circumference, BMI, systolic blood pressure, and family history of diabetes. The score ranges from 0 to 51. The area under the receiver operating curve of the score for undiagnosed type 2 diabetes was 0.748 (0.739-0.756) in the exploratory population, 0.725 (0.683-0.767) in validation 1, and 0.702 (0.680 0.724) in validation 2. At the optimal cutoff value of 25, the sensitivity and specificity of the score for predicting undiagnosed type 2 diabetes were 92.3 and 35.5%, respectively, in validation 1 and 86.8 and 38.8% in validation 2. CONCLUSIONS: The New Chinese Diabetes Risk Score based on nonlaboratory data appears to be a reliable screening tool to detect undiagnosed type 2 diabetes in Chinese population. PMID- 24144652 TI - Peripheral neuropathy in adolescents and young adults with type 1 and type 2 diabetes from the SEARCH for Diabetes in Youth follow-up cohort: a pilot study. AB - OBJECTIVE: To estimate the prevalence of and risk factors for diabetic peripheral neuropathy (DPN) in a pilot study among youth participating in the SEARCH for Diabetes in Youth study. RESEARCH DESIGN AND METHODS: DPN was assessed using the Michigan Neuropathy Screening Instrument (MNSI) (examination for foot abnormalities, distal vibration perception, and ankle reflexes). An MNSI exam (MNSIE) score >2 is diagnostic for DPN. RESULTS: The MNSIE was completed in 399 subjects, including 329 youth with type 1 diabetes (mean age 15.7 +/- 4.3 years, duration 6.2 +/- 0.9 years) and 70 with type 2 diabetes (mean age 21.6 +/- 4.1 years, duration 7.6 +/- 1.8 years). Glycated hemoglobin (A1C) was similar in both groups (8.8 +/- 1.8% for type 1 vs. 8.5 +/- 2.9% for type 2). The prevalence of DPN was significantly higher in youth with type 2 compared with those with type 1 diabetes (25.7 vs. 8.2%; P < 0.0001). In unadjusted analyses, diabetes type, older age, longer duration of diabetes, increased waist circumference, elevated blood pressure, lower HDL cholesterol, and presence of microalbuminuria (urinary albumin-to-creatinine ratio >30 mg/g) were associated with DPN. The association between diabetes type and DPN remained significant after adjustment for age and sex (odds ratio 2.29 [95% CI 1.05-5.02], P = 0.03). CONCLUSIONS: DPN prevalence among youth with type 2 diabetes approached rates reported in adult populations with diabetes. Our findings suggest not only that youth with diabetes are at risk for DPN but also that many already show measurable signs of DPN. PMID- 24144653 TI - Effects of naltrexone sustained-release/bupropion sustained-release combination therapy on body weight and glycemic parameters in overweight and obese patients with type 2 diabetes. AB - OBJECTIVE: To assess the efficacy and safety of 32 mg naltrexone sustained release (SR)/360 mg bupropion SR (NB) in overweight/obese individuals with type 2 diabetes with or without background oral antidiabetes drugs. RESEARCH DESIGN AND METHODS: This was a 56-week, double-blind, placebo-controlled study in which 505 patients received standardized lifestyle intervention and were randomized 2:1 to NB or placebo. Coprimary end points were percent weight change and achievement of >=5% weight loss. Secondary end points included achievement of HbA1c <7% (53 mmol/mol), achievement of weight loss >=10%, and change in HbA1c, waist circumference, fasting blood glucose, and lipids. RESULTS: In the modified intent to-treat population (54% female, 80% Caucasian, and mean age 54 years, weight 106 kg, BMI 37 kg/m(2), and HbA1c 8.0% [64 mmol/mol]), NB resulted in significantly greater weight reduction (-5.0 vs. -1.8%; P < 0.001) and proportion of patients achieving >=5% weight loss (44.5 vs. 18.9%, P < 0.001) compared with placebo. NB also resulted in significantly greater HbA1c reduction (-0.6 vs. -0.1% [6.6 vs. 1.1 mmol/mol]; P < 0.001), percent of patients achieving HbA1c <7% (53 mmol/mol) (44.1 vs. 26.3%; P < 0.001), and improvement in triglycerides and HDL cholesterol compared with placebo. NB was associated with higher incidence of nausea (42.3 vs. 7.1%), constipation (17.7 vs. 7.1%), and vomiting (18.3 vs. 3.6%). No difference was observed between groups in the incidence of depression, suicidal ideation, or hypoglycemia. CONCLUSIONS: NB therapy in overweight/obese patients with type 2 diabetes induced weight loss, which was associated with improvements in glycemic control and select cardiovascular risk factors and was generally well tolerated with a safety profile similar to that in patients without diabetes. PMID- 24144655 TI - A novel model for metabolic syndrome risk quantification based on areal similarity degree. AB - Metabolic syndrome (MS) refers to a clustering of specific cardiovascular disease (CVD) risk factors whose underlying pathology is thought to be related to insulin resistance. The risk factors include insulin resistance, obesity, dyslipidemia, and hypertension and it is known to increase the risk for CVD and type II diabetes. Since MS helps to identify individuals at high risk for both CVD and type II diabetes, it has become a major public healthcare issue in many countries. There has been much effort to establish diagnostic criteria for MS, but the current diagnostic criteria of MS have weaknesses, such as binary decision based on diagnostic criteria, equal weight among risk factors, and difficulty in estimating the temporal progress of the risk factors. To resolve these problems, this paper proposes a risk quantification model for MS, which is based on areal similarity degree analysis between weighted radar charts comprising MS diagnostic criteria and examination results of risk factors. The clinical effectiveness of the proposed model is extensively evaluated by using data of a large number of subjects obtained from the third Korea National Health and Nutrition Examination Survey. The evaluation results show that the proposed model can quantify the risk of MS and effectively identify a group of subjects who might be classified into a potential risk group for having MS in the future. PMID- 24144656 TI - Measuring time-varying information flow in scalp EEG signals: orthogonalized partial directed coherence. AB - This study aimed to develop a time-frequency method for measuring directional interactions over time and frequency from scalp-recorded electroencephalographic (EEG) signals in a way that is less affected by volume conduction and amplitude scaling. We modified the time-varying generalized partial directed coherence (tv gPDC) method, by orthogonalization of the strictly causal multivariate autoregressive model coefficients, to minimize the effect of mutual sources. The novel measure, generalized orthogonalized PDC (gOPDC), was tested first using two simulated models with feature dimensions relevant to EEG activities. We then used the method for assessing event-related directional information flow from flash evoked responses in neonatal EEG. For testing statistical significance of the findings, we followed a thresholding procedure driven by baseline periods in the same EEG activity. The results suggest that the gOPDC method 1) is able to remove common components akin to volume conduction effect in the scalp EEG, 2) handles the potential challenge with different amplitude scaling within multichannel signals, and 3) can detect directed information flow within a subsecond time scale in nonstationary multichannel EEG datasets. This method holds promise for estimating directed interactions between scalp EEG channels that are commonly affected by the confounding impact of mutual cortical sources. PMID- 24144657 TI - Nonrigid registration of volumetric images using ranked order statistics. AB - Nonrigid image registration techniques using intensity based similarity measures are widely used in medical imaging applications. Due to high computational complexities of these techniques, particularly for volumetric images, finding appropriate registration methods to both reduce the computation burden and increase the registration accuracy has become an intensive area of research. In this paper, we propose a fast and accurate nonrigid registration method for intra modality volumetric images. Our approach exploits the information provided by an order statistics based segmentation method, to find the important regions for registration and use an appropriate sampling scheme to target those areas and reduce the registration computation time. A unique advantage of the proposed method is its ability to identify the point of diminishing returns and stop the registration process. Our experiments on registration of end-inhale to end-exhale lung CT scan pairs, with expert annotated landmarks, show that the new method is both faster and more accurate than the state of the art sampling based techniques, particularly for registration of images with large deformations. PMID- 24144654 TI - Dapagliflozin is effective as add-on therapy to sitagliptin with or without metformin: a 24-week, multicenter, randomized, double-blind, placebo-controlled study. AB - OBJECTIVE: To assess the efficacy and safety of dapagliflozin as add-on therapy in patients with type 2 diabetes who were inadequately controlled with a dipeptidyl peptidase-4 inhibitor with or without metformin. RESEARCH DESIGN AND METHODS: In this 24-week, multicenter, randomized, double-blind, placebo controlled, parallel-group, phase 3 study with a 24-week blinded extension period, 432 patients were randomized to receive dapagliflozin 10 mg/day or placebo added to sitagliptin (100 mg/day) +/- metformin (>=1,500 mg/day). RESULTS: Baseline HbA1c and FPG levels were 7.9% (63.0 mmol/mol) and 162.2 mg/dL (9.0 mmol/L) for the dapagliflozin group and 8.0% (64.0 mmol/mol) and 163 mg/dL (9.0 mmol/L) for placebo. At week 24, dapagliflozin significantly reduced mean HbA1c levels (-0.5% [-4.9 mmol/mol]) versus placebo (0.0% [+0.4 mmol/mol]). Dapagliflozin reduced body weight versus placebo (-2.1 and -0.3 kg) and reduced HbA1c levels in patients with baseline values >=8.0% (-0.8% [8.7 mmol/mol] and 0.0% [0.3 mmol/mol]) and fasting plasma glucose levels (-24.1 mg/dL [-1.3 mmol/L] and 3.8 mg/dL [0.2 mmol/L]). Similar results were observed when data were stratified by background therapy. Glycemic and weight benefits observed at week 24 were maintained through week 48. Changes from baseline in systolic blood pressure at week 8 were not significantly different between treatment groups. Over 48 weeks, fewer patients receiving dapagliflozin were discontinued or rescued for failing to achieve glycemic targets compared with placebo. Adverse events were balanced between groups, and discontinuation rates were low. At week 48, signs and symptoms suggestive of genital infection were more frequent with dapagliflozin (9.8%) than with placebo (0.4%). Signs and symptoms suggestive of urinary tract infection were balanced between dapagliflozin (6.7%) and placebo (6.2%). CONCLUSIONS: These results suggest that in patients with type 2 diabetes, inadequately controlled on sitagliptin with or without metformin, add-on treatment with dapagliflozin provides additional clinical benefit and is well tolerated. PMID- 24144658 TI - Model-based optoacoustic image reconstruction of large three-dimensional tomographic datasets acquired with an array of directional detectors. AB - Image quality in 3-D optoacoustic (photoacoustic) tomography is greatly influenced by both the measurement system, in particular the number and spatial arrangement of ultrasound sensors, and the ability to account for the spatio temporal response of the sensor element(s) in the reconstruction algorithm. Herein we present a reconstruction procedure based on the inversion of a time domain forward model incorporating the spatial impulse response due to the shape of the transducer, which is subsequently applied in a tomographic system based on a translation-rotation scan of a linear detector array. The proposed method was also adapted to cope with the data-intensive requirements of high-resolution volumetric optoacoustic imaging. The processing of 2 . 10 (4) individual signals resulted in well-resolved images of both ~ 200 MUm absorbers in phantoms and complex vascular structures in biological tissue. The results reported herein demonstrate that the introduced model-based methodology exhibits a better contrast and resolution than standard back-projection and model-based algorithms that assume point detectors. Moreover, the capability of handling large datasets anticipates that model-based methods incorporating the sensor properties can become standard practice in volumetric opto acoustic image formation. PMID- 24144659 TI - Motion-related resource allocation in dynamic wireless visual sensor network environments. AB - This paper investigates quality-driven cross-layer optimization for resource allocation in direct sequence code division multiple access wireless visual sensor networks. We consider a single-hop network topology, where each sensor transmits directly to a centralized control unit (CCU) that manages the available network resources. Our aim is to enable the CCU to jointly allocate the transmission power and source-channel coding rates for each node, under four different quality-driven criteria that take into consideration the varying motion characteristics of each recorded video. For this purpose, we studied two approaches with a different tradeoff of quality and complexity. The first one allocates the resources individually for each sensor, whereas the second clusters them according to the recorded level of motion. In order to address the dynamic nature of the recorded scenery and re-allocate the resources whenever it is dictated by the changes in the amount of motion in the scenery, we propose a mechanism based on the particle swarm optimization algorithm, combined with two restarting schemes that either exploit the previously determined resource allocation or conduct a rough estimation of it. Experimental simulations demonstrate the efficiency of the proposed approaches. PMID- 24144660 TI - [Symbol: see text]2 Optimized predictive image coding with [Symbol: see text]infinity bound. AB - In many scientific, medical, and defense applications of image/video compression, an [Symbol: see text]infinity error bound is required. However, pure[Symbol: see text]infinity-optimized image coding, colloquially known as near-lossless image coding, is prone to structured errors such as contours and speckles if the bit rate is not sufficiently high; moreover, most of the previous [Symbol: see text]infinity-based image coding methods suffer from poor rate control. In contrast, the [Symbol: see text]2 error metric aims for average fidelity and hence preserves the subtlety of smooth waveforms better than the infinity error metric and it offers fine granularity in rate control, but pure [Symbol: see text]2-based image coding methods (e.g., JPEG 2000) cannot bound individual errors as the [Symbol: see text]infinity-based methods can. This paper presents a new compression approach to retain the benefits and circumvent the pitfalls of the two error metrics. A common approach of near-lossless image coding is to embed into a DPCM prediction loop a uniform scalar quantizer of residual errors. The said uniform scalar quantizer is replaced, in the proposed new approach, by a set of context-based [Symbol: see text]2-optimized quantizers. The optimization criterion is to minimize a weighted sum of the [Symbol: see text]2 distortion and the entropy while maintaining a strict [Symbol: see text]infinity error bound. The resulting method obtains good rate-distortion performance in both [Symbol: see text]2 and [Symbol: see text]infinity metrics and also increases the rate granularity. Compared with JPEG 2000, the new method not only guarantees lower [Symbol: see text]infinity error for all bit rates, but also it achieves higher PSNR for relatively high bit rates. PMID- 24144661 TI - A bit allocation method for sparse source coding. AB - In this paper, we develop an efficient bit allocation strategy for subband-based image coding systems. More specifically, our objective is to design a new optimization algorithm based on a rate-distortion optimality criterion. To this end, we consider the uniform scalar quantization of a class of mixed distributed sources following a Bernoulli-generalized Gaussian distribution. This model appears to be particularly well-adapted for image data, which have a sparse representation in a wavelet basis. In this paper, we propose new approximations of the entropy and the distortion functions using piecewise affine and exponential forms, respectively. Because of these approximations, bit allocation is reformulated as a convex optimization problem. Solving the resulting problem allows us to derive the optimal quantization step for each subband. Experimental results show the benefits that can be drawn from the proposed bit allocation method in a typical transform-based coding application. PMID- 24144662 TI - Harmonic active contours. AB - We propose a segmentation method based on the geometric representation of images as 2-D manifolds embedded in a higher dimensional space. The segmentation is formulated as a minimization problem, where the contours are described by a level set function and the objective functional corresponds to the surface of the image manifold. In this geometric framework, both data-fidelity and regularity terms of the segmentation are represented by a single functional that intrinsically aligns the gradients of the level set function with the gradients of the image and results in a segmentation criterion that exploits the directional information of image gradients to overcome image inhomogeneities and fragmented contours. The proposed formulation combines this robust alignment of gradients with attractive properties of previous methods developed in the same geometric framework: 1) the natural coupling of image channels proposed for anisotropic diffusion and 2) the ability of subjective surfaces to detect weak edges and close fragmented boundaries. The potential of such a geometric approach lies in the general definition of Riemannian manifolds, which naturally generalizes existing segmentation methods (the geodesic active contours, the active contours without edges, and the robust edge integrator) to higher dimensional spaces, non-flat images, and feature spaces. Our experiments show that the proposed technique improves the segmentation of multi-channel images, images subject to inhomogeneities, and images characterized by geometric structures like ridges or valleys. PMID- 24144663 TI - Multi-illuminant estimation with conditional random fields. AB - Most existing color constancy algorithms assume uniform illumination. However, in real-world scenes, this is not often the case. Thus, we propose a novel framework for estimating the colors of multiple illuminants and their spatial distribution in the scene. We formulate this problem as an energy minimization task within a conditional random field over a set of local illuminant estimates. In order to quantitatively evaluate the proposed method, we created a novel data set of two dominant-illuminant images comprised of laboratory, indoor, and outdoor scenes. Unlike prior work, our database includes accurate pixel-wise ground truth illuminant information. The performance of our method is evaluated on multiple data sets. Experimental results show that our framework clearly outperforms single illuminant estimators as well as a recently proposed multi-illuminant estimation approach. PMID- 24144664 TI - Parametric blur estimation for blind restoration of natural images: linear motion and out-of-focus. AB - This paper presents a new method to estimate the parameters of two types of blurs, linear uniform motion (approximated by a line characterized by angle and length) and out-of-focus (modeled as a uniform disk characterized by its radius), for blind restoration of natural images. The method is based on the spectrum of the blurred images and is supported on a weak assumption, which is valid for the most natural images: the power-spectrum is approximately isotropic and has a power-law decay with the spatial frequency. We introduce two modifications to the radon transform, which allow the identification of the blur spectrum pattern of the two types of blurs above mentioned. The blur parameters are identified by fitting an appropriate function that accounts separately for the natural image spectrum and the blur frequency response. The accuracy of the proposed method is validated by simulations, and the effectiveness of the proposed method is assessed by testing the algorithm on real natural blurred images and comparing it with state-of-the-art blind deconvolution methods. PMID- 24144666 TI - A compact, low input capacitance neural recording amplifier. AB - Conventional capacitively coupled neural recording amplifiers often present a large input load capacitance to the neural signal source and hence take up large circuit area. They suffer due to the unavoidable trade-off between the input capacitance and chip area versus the amplifier gain. In this work, this trade-off is relaxed by replacing the single feedback capacitor with a clamped T-capacitor network. With this simple modification, the proposed amplifier can achieve the same mid-band gain with less input capacitance, resulting in a higher input impedance and a smaller silicon area. Prototype neural recording amplifiers based on this proposal were fabricated in 0.35 MUm CMOS, and their performance is reported. The amplifiers occupy smaller area and have lower input loading capacitance compared to conventional neural amplifiers. One of the proposed amplifiers occupies merely 0.056 mm(2). It achieves 38.1-dB mid-band gain with 1.6 pF input capacitance, and hence has an effective feedback capacitance of 20 fF. Consuming 6 MUW, it has an input referred noise of 13.3 MUVrms over 8.5 kHz bandwidth and NEF of 7.87. In-vivo recordings from animal experiments are also demonstrated. PMID- 24144665 TI - Angular pattern and binary angular pattern for shape retrieval. AB - In this paper, we propose two novel shape descriptors, angular pattern (AP) and binary angular pattern (BAP), and a multiscale integration of them for shape retrieval. Both AP and BAP are intrinsically invariant to scale and rotation. More importantly, being global shape descriptors, the proposed shape descriptors are computationally very efficient, while possessing similar discriminability as state-of-the-art local descriptors. As a result, the proposed approach is attractive for real world shape retrieval applications. The experiments on the widely used MPEG-7 and TARI-1000 data sets demonstrate the effectiveness of the proposed method in comparison with existing methods. PMID- 24144667 TI - Massively-parallel neuromonitoring and neurostimulation rodent headset with nanotextured flexible microelectrodes. AB - We present a compact wireless headset for simultaneous multi-site neuromonitoring and neurostimulation in the rodent brain. The system comprises flexible-shaft microelectrodes, neural amplifiers, neurostimulators, a digital time-division multiplexer (TDM), a micro-controller and a ZigBee wireless transceiver. The system is built by parallelizing up to four 0.35 MUm CMOS integrated circuits (each having 256 neural amplifiers and 64 neurostimulators) to provide a total maximum of 1024 neural amplifiers and 256 neurostimulators. Each bipolar neural amplifier features 54 dB-72 dB adjustable gain, 1 Hz-5 kHz adjustable bandwidth with an input-referred noise of 7.99 MUVrms and dissipates 12.9 MUW. Each current mode bipolar neurostimulator generates programmable arbitrary-waveform biphasic current in the range of 20-250 MUA and dissipates 2.6 MUW in the stand-by mode. Reconfigurability is provided by stacking a set of dedicated mini-PCBs that share a common signaling bus within as small as 22 * 30 * 15 mm3 volume. The system features flexible polyimide-based microelectrode array design that is not brittle and increases pad packing density. Pad nanotexturing by electrodeposition reduces the electrode-tissue interface impedance from an average of 2 MOmega to 30 kOmega at 100 Hz. The rodent headset and the microelectrode array have been experimentally validated in vivo in freely moving rats for two months. We demonstrate 92.8 percent seizure rate reduction by responsive neurostimulation in an acute epilepsy rat model. PMID- 24144668 TI - Opto- MUECoG array: a hybrid neural interface with transparent MUECoG electrode array and integrated LEDs for optogenetics. AB - Electrocorticogram (ECoG) recordings, taken from electrodes placed on the surface of the cortex, have been successfully implemented for control of brain machine interfaces (BMIs). Optogenetics, direct optical stimulation of neurons in brain tissue genetically modified to express channelrhodopsin-2 (ChR2), enables targeting of specific types of neurons with sub-millisecond temporal precision. In this work, we developed a BMI device, called an Opto- MUECoG array, which combines ECoG recording and optogenetics-based stimulation to enable multichannel, bi-directional interactions with neurons. The Opto- MUECoG array comprises two sub-arrays, each containing a 4 * 4 distribution of micro-epidural transparent electrodes ( ~ 200 MUm diameter) and embedded light-emitting diodes (LEDs) for optical neural stimulation on a 2.5 * 2.5 mm2 footprint to match the bilateral hemispherical area of the visual cortex in a rat. The transparent electrodes were fabricated with indium tin oxide (ITO). Parylene-C served as the main structural and packaging material for flexibility and biocompatibility. Optical, electrical, and thermal characteristics of the fabricated device were investigated and in vivo experiments were performed to evaluate the efficacy of the device. PMID- 24144669 TI - Neuron array with plastic synapses and programmable dendrites. AB - We describe a novel neuromorphic chip architecture that models neurons for efficient computation. Traditional architectures of neuron array chips consist of large scale systems that are interfaced with AER for implementing intra- or inter chip connectivity. We present a chip that uses AER for inter-chip communication but uses fast, reconfigurable FPGA-style routing with local memory for intra-chip connectivity. We model neurons with biologically realistic channel models, synapses and dendrites. This chip is suitable for small-scale network simulations and can also be used for sequence detection, utilizing directional selectivity properties of dendrites, ultimately for use in word recognition. PMID- 24144670 TI - Changes in oscillatory impedance and nitrogen washout with combination fluticasone/salmeterol therapy in COPD. AB - INTRODUCTION: Combination inhaled corticosteroid/long-acting bronchodilator (ICS/LABA) therapy reduces the exacerbation rate and improves spirometry and quality of life in COPD. We hypothesized that ICS/LABA therapy also improves small airway function measured by FOT. METHODS: 14 subjects with COPD were commenced on combination fluticasone propionate/salmeterol therapy for 3 months. At baseline, subjects completed the St George Respiratory Questionnaire (SGRQ) and underwent standard pulmonary function tests as well as forced oscillation technique (FOT) and single and multiple breath nitrogen washouts. All tests were repeated at the completion of 3 months of therapy. RESULTS: Subjects were of mean (SD) age 65.9 years (8.4), BMI 30.0 (5.6), pack years 51.4 (21.1), post bronchodilator FEV1% predicted 62.7 (20). At baseline, mean SGRQ total was 39.0 (17.7) and FRC% predicted 125.4 (31.3). From FOT, Rrs-total was 5.69 (1.29) cmH2O/L/s, Xrs-total -3.48 (2.16) cmH2O/L/s, EFL Index 3.51 (2.45) cmH2O/L/s. After 3 months of therapy, there were significant improvements in SGRQ score ( 13.81, p < 0.0001) despite no change in FEV1 (+40 mL, p = 0.14). From FOT, total resistance (-0.63 cmH2O/L/s, p = 0.0004), reactance (+1.2 cmH2O/L/s, p = 0.013), and expiratory flow limitation (-1.21 cmH2O/L/s, p = 0.02) also improved. There were no significant changes in ventilation heterogeneity indices. CONCLUSION: Combination therapy is associated with improvements in small airways function in COPD, despite an absence of change in FEV1. FOT may be a clinically useful marker of small airway function in COPD that is responsive to treatment. PMID- 24144671 TI - Discriminative power of chemically sensitive silicon nanowire field effect transistors to volatile organic compounds. AB - We report on the sensing of different polar and nonpolar volatile organic compounds (VOCs) in an atmosphere with background humidity (relative humidity: 40%), using molecularly modified silicon nanowire field effect transistors (SiNW FETs). In this endeavor, a systematic comparative analysis is performed with: (i) SiNW FETs that were functionalized with a series of molecules having different electron-withdrawing and electron-donating end groups; and (ii) SiNW FETs that are functionalized with a series of molecules having similar functional groups but different backbone lengths. The analysis of the sensing signals are focused on three main FET parameters: (i) changes in the threshold voltage, (ii) changes in the carrier mobility, and (iii) changes in the on-current, compared to the baseline values under vacuum. Using discriminant factor analysis, the performance of the molecularly modified SiNW FETs is further analyzed as sensors array. The combination of sensors having the best discriminative power between the various VOCs are identified and discussed in terms of their constituent surface modifications. PMID- 24144672 TI - Dengue specific IgM seropositivity correlates with severe clinical outcome. PMID- 24144673 TI - High incidence of reassortant G9P[4] rotavirus strain in Bangladesh: fully heterotypic from vaccine strains. PMID- 24144674 TI - Comparative analysis of the neurovascular injury and functional outcomes in experimental stroke models in diabetic Goto-Kakizaki rats. AB - Diabetes worsens functional outcome and is associated with greater hemorrhagic transformation (HT) after ischemic stroke. We have shown that diabetic Goto Kakizaki (GK) rats develop greater HT and neurological deficit despite smaller infarcts after transient middle cerebral artery occlusion (MCAO) with the suture model. However, the impact of (1) the duration of ischemia/reperfusion (I/R); (2) the method of ischemia; and (3) acute glycemic control on neurovascular injury and functional outcome in diabetic stroke remained unanswered. Wistar and GK rats were subjected to variable MCAO by suture or embolus occlusion. A group of GK rats were treated with insulin or metformin before stroke with suture occlusion. In all groups, infarct size, edema, HT occurrence and severity, and functional outcome were measured. Infarct size at 24h was smaller in GK rats with both suture and embolic MCAO, but expanded with longer reperfusion period. Edema and HT were increased in GK rats after 90min and 3h occlusion with the suture model, but not in the embolic MCAO. Neurological deficit was greater in diabetic rats. These findings suggest that diabetes accelerates the development of HT and amplifies vascular damage in the suture model where blood flow is rapidly reestablished. Acute metformin treatment worsened the infarct size, HT, and behavior outcome, whereas insulin treatment showed a protective effect. These results suggest that the impact of ischemia/reperfusion on neurovascular injury and functional outcome especially in disease models needs to be fully characterized using different models of stroke to model the human condition. PMID- 24144676 TI - Rock paper scissors. PMID- 24144675 TI - Head start for target language in bilingual listening. AB - In this study we investigated the availability of non-target language semantic features in bilingual speech processing. We recorded EEG from Dutch-English bilinguals who listened to spoken sentences in their L2 (English) or L1 (Dutch). In Experiments 1 and 3 the sentences contained an interlingual homophone. The sentence context was either biased towards the target language meaning of the homophone (target biased), the non-target language meaning (non-target biased), or neither meaning of the homophone (fully incongruent). These conditions were each compared to a semantically congruent control condition. In L2 sentences we observed an N400 in the non-target biased condition that had an earlier offset than the N400 to fully incongruent homophones. In the target biased condition, a negativity emerged that was later than the N400 to fully incongruent homophones. In L1 contexts, neither target biased nor non-target biased homophones yielded significant N400 effects (compared to the control condition). In Experiments 2 and 4 the sentences contained a language switch to a non-target language word that could be semantically congruent or incongruent. Semantically incongruent words (switched, and non-switched) elicited an N400 effect. The N400 to semantically congruent language-switched words had an earlier offset than the N400 to incongruent words. Both congruent and incongruent language switches elicited a Late Positive Component (LPC). These findings show that bilinguals activate both meanings of interlingual homophones irrespective of their contextual fit. In L2 contexts, the target-language meaning of the homophone has a head start over the non-target language meaning. The target-language head start is also evident for language switches from both L2-to-L1 and L1-to-L2. PMID- 24144677 TI - Automated estimation of fetal cardiac timing events from Doppler ultrasound signal using hybrid models. AB - In this paper, a new noninvasive method is proposed for automated estimation of fetal cardiac intervals from Doppler Ultrasound (DUS) signal. This method is based on a novel combination of empirical mode decomposition (EMD) and hybrid support vector machines-hidden Markov models (SVM/HMM). EMD was used for feature extraction by decomposing the DUS signal into different components (IMFs), one of which is linked to the cardiac valve motions, i.e. opening (o) and closing (c) of the Aortic (A) and Mitral (M) valves. The noninvasive fetal electrocardiogram (fECG) was used as a reference for the segmentation of the IMF into cardiac cycles. The hybrid SVM/HMM was then applied to identify the cardiac events, based on the amplitude and timing of the IMF peaks as well as the sequence of the events. The estimated timings were verified using pulsed doppler images. Results show that this automated method can continuously evaluate beat-to-beat valve motion timings and identify more than 91% of total events which is higher than previous methods. Moreover, the changes of the cardiac intervals were analyzed for three fetal age groups: 16-29, 30-35, and 36-41 weeks. The time intervals from Q-wave of fECG to Ac (Systolic Time Interval, STI), Ac to Mo (Isovolumic Relaxation Time, IRT), Q-wave to Ao (Preejection Period, PEP) and Ao to Ac (Ventricular Ejection Time, VET) were found to change significantly ( ) across these age groups. In particular, STI, IRT, and PEP of the fetuses with 36-41 week were significantly ( ) different from other age groups. These findings can be used as sensitive markers for evaluating the fetal cardiac performance. PMID- 24144678 TI - Enabling smart personalized healthcare: a hybrid mobile-cloud approach for ECG telemonitoring. AB - The severe challenges of the skyrocketing healthcare expenditure and the fast aging population highlight the needs for innovative solutions supporting more accurate, affordable, flexible, and personalized medical diagnosis and treatment. Recent advances of mobile technologies have made mobile devices a promising tool to manage patients' own health status through services like telemedicine. However, the inherent limitations of mobile devices make them less effective in computation- or data-intensive tasks such as medical monitoring. In this study, we propose a new hybrid mobile-cloud computational solution to enable more effective personalized medical monitoring. To demonstrate the efficacy and efficiency of the proposed approach, we present a case study of mobile-cloud based electrocardiograph monitoring and analysis and develop a mobile-cloud prototype. The experimental results show that the proposed approach can significantly enhance the conventional mobile-based medical monitoring in terms of diagnostic accuracy, execution efficiency, and energy efficiency, and holds the potential in addressing future large-scale data analysis in personalized healthcare. PMID- 24144679 TI - [Pressure support ventilation and proportional assist ventilation during weaning from mechanical ventilation]. AB - OBJECTIVES: To compare tolerance, duration of mechanical ventilation (MV) and clinical outcomes during weaning from MV in patients subjected to either pressure support ventilation (PSV) or proportional assist ventilation (PAV). DESIGN: A prospective, observational study was carried out. SETTING: Intensive Care Unit. PATIENTS: A total of 40 consecutive subjects were allocated to either the PSV or the PAV group until each group contained 20 patients. Patients were included in the study when they met the criteria to begin weaning and the attending physician decided to initiate the weaning process. The physician selected the modality and set the ventilatory parameters. INTERVENTIONS: None. VARIABLES OF INTEREST: Demographic data, respiratory mechanics, ventilatory parameters, duration of MV, and clinical outcomes (reintubation, tracheostomy, mortality). RESULTS: Baseline characteristics were similar in both groups. No significant differences were observed between the PSV and PAV groups in terms of the total duration of MV (10 [5-18] vs. 9 [7-19] days; P=.85), reintubation (5 [31%] vs. 3 [19%]; P=.69), or mortality (4 [20%] vs. 5 [25%] deaths; P=1). Eight patients (40%) in the PSV group and 6 patients (30%) in the PAV group (P=.74) required a return to volume assist-control ventilation due to clinical deterioration. CONCLUSIONS: Tolerance, duration of MV and clinical outcomes during weaning from mechanical ventilation were similar in PSV and PAV. PMID- 24144680 TI - TLR2-TLR4/CD14 polymorphisms and predisposition to severe invasive infections by Neisseria meningitidis and Streptococcus pneumoniae. AB - PURPOSE: Streptococcus pneumoniae and Neisseria meningitidis are major causes of severe invasive bacterial infections in some individuals. Apparently the genetic is a major susceptibility determinant to these infectious diseases. We study if the functional polymorphisms within genes of the innate immune system (TLR2-TLR4 and CD14) are related to the predisposition to severe invasive infections caused by S. pneumoniae and N. meningitidis. MATERIAL AND METHODS: Prospective descriptive study. Sixty-six Caucasian healthy children and 173 consecutive Caucasian children with invasive bacterial infections by N. meningitidis (n=59) and S. pneumoniae (n=114) were enrolled between January 1, 2008 and December 31, 2010. All blood samples were genotyped with description of the coding polymorphisms in p.R753Q of TLR2 gene and p.D299G of TLR4 gene as well as the promotor polymorphism c.-159C>T of the CD14 gene. RESULTS: Compared to the controls the p.753Q allele of TLR2 and the allele c.-159T of CD14 were more frequent in patients with S. pneumoniae (p<0.0001 and p=0.0167) and meningococcal infections (p=0.0003 and p=0.0276 respectively). CONCLUSIONS: Genetical variations in the innate immune system by polymorphisms in the TLR2 and CD14, could be related with an increases susceptibility to severe invasive infections by S. pneumoniae and N. meningitidis. PMID- 24144681 TI - Production of canine soluble CD40 ligand to induce maturation of monocyte derived dendritic cells for cancer immunotherapy. AB - CD40 ligand (CD40L) expressed by activated T cells is shown to induce maturation of immature dendritic cells (DCs) and this maturation is a vital part in DC based tumor immunotherapy. We constructed an expression vector by cloning the extracellular domain of canine CD40L fused to the signal sequence of canine IL 12p40. When PBMCs were incubated with canine granulocyte-macrophage (GM) -CSF and IL-4, expression of CD86 was significantly elevated, but the majority of cells displayed the morphology of immature DCs. Following addition of the expressed canine soluble CD40L (csCD40L) to the DC-inducing culture, the cell morphology shifted to that of mature DCs, and expression of CD80, CD86, MHC class II and CD1a was significantly enhanced. This morphological change and enhancement of expression was observed even when the csCD40L was present only in the second half period of the culture. Furthermore, the csCD40L caused a significant increase in IL-12 production from DCs. These results show that the csCD40L significantly promotes the maturation and activation of canine monocyte derived DCs. PMID- 24144682 TI - Inhibition of virus replication and induction of human tetherin gene expression by equine IFN-alpha1. AB - Type I interferons (IFNs) play important roles in the defense of host cells against viral infection by inducing the expression of a diverse range of antiviral factors. IFNs from different animals likely share similar features with human IFNs, and some of them have cross-species activities. Equine IFN-alpha was proved effective in both equine and human cells. However, the previous studies mostly focused on the inhibition of virus induced cytopathic effects. In this study, we used virus-specific assays to demonstrate the antiviral activities of equine IFN-alpha1 in both equine and human cells. Equine IFN-alpha1 inhibited the expression of viral structural proteins and the production of virions of equine infectious anemia virus (EIAV) and equine arteritis virus (EAV) in equine cells. In addition, equine IFN-alpha1 inhibited the production of EIAV virus-like particles (VLP) from human 293T cells. An IFN-inducible human gene, tetherin, was induced in 293T cells by equine IFN-alpha1. Its induction correlated with the inhibition of VLP release from the cell membrane. This result indicates that equine IFN-alpha1 shares a similar mechanism of action with human IFN-alpha in regulating antiviral genes expression in human cells. PMID- 24144683 TI - Immunopathology of granulomas produced by Mycobacterium bovis in naturally infected wild boar. AB - Limited information has been published on the wild boar immune response against bovine tuberculosis (bTB) and the immunopathogenesis of the pathological hallmark (granuloma) in this species. The main objectives of this study were, on the one hand, to characterize the histopathological features (number of acid-fast bacilli (AFB) and multinucleated giant cells (MNGCs) and the immunohistochemical distribution of different cell subsets (CD3+, CD79a+ and MAC387+) and chemical mediators (iNOS and IFN-gamma) in the different developmental stages of granulomas produced by the natural infection of Mycobacterium bovis (M. bovis) in wild boar. On the other hand, the study also aimed to analyze the mechanisms underlying the marked differences in the typical lesional patterns observed in M. bovis infections of wild boar (contained, not generalized) and those previously described in fallow deer (poorly contained, generalized). The majority of granulomas analyzed (95.3%) did not show any AFB with the ZN stain and a low number of MNGCs were identified in the different granuloma stages. The immunohistochemical analysis showed that MAC387 was the only immune marker that produced decreasing positivity by granuloma stage, being statistically significantly lower in stages III and IV when compared to stage I and II. Immune markers for lymphocyte cells (CD3 and CD79a) showed a slight rise in the positivity (which was not statistically significant) in the advanced granuloma stages. In keeping with the presence of large numbers of T cells and macrophages, there was a consistently high level of expression of IFN-gamma at all stages of granuloma development without a statistical significant decrease in advanced stages. Also related with the higher presence of macrophages in stage I and II, the expression of iNOS was higher in early stages and sustained until stage III, showing a non statistical significant decrease in stage IV. The macrophage and iNOS activity are more intense and sustained along the granuloma development than those described in fallow deer. Immunohistochemical protocols with a panel of markers for wild boar different cells subsets (CD3+, CD79a+ and MAC387+) and chemical mediators (iNOS and IFN-gamma), and their use to further investigate the immune response in this species are provided. PMID- 24144684 TI - Towards a better understanding of salivary and meat juice acute phase proteins determination in pigs: an expression study. AB - Acute phase proteins (APPs) determination in different fluids like serum, saliva and meat juice measured with ultrasensitive assays can be used to evaluate the disease status of porcine populations under field conditions. Liver is the main production site of serum APPs, but the origin of APPs that can be determined in body fluids different from blood remains unknown. The objective of this study was to clarify the origin of three APPs: C-reactive protein (CRP), serum amyloid A (SAA) and haptoglobin (Hp) in saliva and meat juice. The mRNA expression of these proteins was measured in liver, salivary gland and diaphragmatic muscle by quantitative PCR and compared with the protein levels in serum, saliva and meat juice, respectively in healthy and naturally diseased animals. As expected, concentrations of all APP were significantly higher in all body fluids from diseased animals. Levels of all APPs mRNA were very low in diaphragmatic muscle tissue, and the expression was independent of the disease status. In contrast, we found higher expression levels of SAA and Hp mRNA in the salivary gland of diseased animals, while CRP mRNA was not detected. Our data indicate that the APP present in meat juice derived predominantly from serum. This assumption is also supported by the good correlation of the levels of both proteins in meat juice with those in serum. Further, the lower variability of the APP levels within the two groups of animals, suggests meat juice as an alternate sampling material. The APP levels that are determined in saliva, however, appear to result from an increased local production except for CRP, indicating that the salivary gland responds to disease. These findings are relevant for the establishment of saliva as the preferred diagnostic sample for health monitoring programmes, due to the technical and ethical advantages of the collection. PMID- 24144685 TI - Regional variation in quality of prostate cancer care. AB - PURPOSE: Despite the endorsement of several quality measures for prostate cancer by the National Quality Forum and the Physician Consortium for Performance Improvement, how consistently physicians adhere to these measures has not been examined. We evaluated regional variation in adherence to these quality measures to identify targets for future quality improvement. MATERIALS AND METHODS: For this retrospective cohort study we used SEER (Surveillance, Epidemiology, and End Results)-Medicare data for 2001 to 2007 to identify 53,614 patients with newly diagnosed prostate cancer. Patients were assigned to 661 regions (Hospital Service Areas). Hierarchical generalized linear models were used to examine reliability adjusted regional adherence to the endorsed quality measures. RESULTS: Adherence at the patient level was highly variable, ranging from 33% for treatment by a high volume provider to 76% for receipt of adjuvant androgen deprivation therapy while undergoing radiotherapy for high risk cancer. In addition, there was considerable regional variation in adherence to several measures, including pretreatment counseling by a urologist and radiation oncologist (range 9% to 89%, p <0.001), avoiding overuse of bone scans in low risk cancer (range 16% to 96%, p <0.001), treatment by a high volume provider (range 1% to 90%, p <0.001) and followup with radiation oncologists (range 14% to 86%, p <0.001). CONCLUSIONS: We found low adherence rates for most established prostate cancer quality of care measures. Within most measures regional variation in adherence was pronounced. Measures with low adherence and a large amount of regional variation may be important low hanging targets for quality improvement. PMID- 24144686 TI - Low methodological and reporting quality of randomized, controlled trials of devices to treat urolithiasis. AB - PURPOSE: We assessed the methodological and reporting quality of randomized, controlled trials of stone disease management and determined whether the reporting quality of randomized, controlled trials improved with time. MATERIALS AND METHODS: We systematically searched the literature for randomized, controlled trials of urolithiasis treatment. We developed and pilot tested a data extraction checklist based on CONSORT (Consolidated Standards of Reporting Trials) criteria as well as a clinical checklist relevant to urolithiasis, each scored as 0 to 25. Our primary outcome measures were the mean differences in CONSORT and clinical summary scores with time. We performed statistical hypothesis testing using the Student t-test with 2-sided alpha = 0.05 to compare scores between 2002 to 2006 and 2007 to 2011. RESULTS: A total of 104 randomized, controlled trials met study inclusion criteria. The most common procedure types studied were percutaneous nephrolithotomy (41.3%), ureteral stenting (28.8%) and shock wave lithotripsy (25.0%). Mean +/- SE CONSORT summary scores were 11.4 +/- 0.4 and 12.1 +/- 0.3 in 2002 to 2006 and 2007 to 2011, respectively, with a mean difference of 0.7 (95% CI -0.3-1.6, p = 0.167). Mean clinical summary scores were 7.4 +/- 0.5 and 9.3 +/ 0.4 in 2002 to 2006 and 2007 to 2011, respectively, with a mean difference of 1.8 (95% CI 0.6-3.1, p = 0.004). CONCLUSIONS: While the number of randomized, controlled trials of urological devices used to treat stone disease substantially increased with time, methodological and clinical reporting quality remains suboptimal. This compromises their credibility and warrants efforts to promote appropriate performance of future endourological studies. PMID- 24144689 TI - Synthesis, characterization, DNA interaction, antioxidant and anticancer activity of new ruthenium(II) complexes of thiosemicarbazone/semicarbazone bearing 9,10 phenanthrenequinone. AB - A new series of octahedral ruthenium(II) complexes supported by tridentate ligands derived from phenanthrenequinone and derivatives of thiosemicarbazide/semicarbazide and other co-ligands have been synthesized and characterized. DNA binding experiments indicated that ruthenium(II) complexes can interact with DNA through non-intercalation and the apparent binding constant value (Kb) of [RuCl(CO)(PPh3)(L3)] (3) at room temperature was calculated to be 2.27 * 10(3)M(-1). The DNA cleavage studies showed that the complexes have better cleavage of pBR 322 DNA. Antioxidative activity proved that the complexes have significant radical scavenging activity against free radicals. Cytotoxic activities showed that the ruthenium(II) complexes exhibited more effective cytotoxic activity against selected cancer cells. PMID- 24144690 TI - Structural Laplacian Eigenmaps for modeling sets of multivariate sequences. AB - A novel embedding-based dimensionality reduction approach, called structural Laplacian Eigenmaps, is proposed to learn models representing any concept that can be defined by a set of multivariate sequences. This approach relies on the expression of the intrinsic structure of the multivariate sequences in the form of structural constraints, which are imposed on dimensionality reduction process to generate a compact and data-driven manifold in a low dimensional space. This manifold is a mathematical representation of the intrinsic nature of the concept of interest regardless of the stylistic variability found in its instances. In addition, this approach is extended to model jointly several related concepts within a unified representation creating a continuous space between concept manifolds. Since a generated manifold encodes the unique characteristic of the concept of interest, it can be employed for classification of unknown instances of concepts. Exhaustive experimental evaluation on different datasets confirms the superiority of the proposed methodology to other state-of-the-art dimensionality reduction methods. Finally, the practical value of this novel dimensionality reduction method is demonstrated in three challenging computer vision applications, i.e., view-dependent and view-independent action recognition as well as human-human interaction classification. PMID- 24144687 TI - Anti-3-[(18)F]FACBC positron emission tomography-computerized tomography and (111)In-capromab pendetide single photon emission computerized tomography computerized tomography for recurrent prostate carcinoma: results of a prospective clinical trial. AB - PURPOSE: We prospectively evaluated the amino acid analogue positron emission tomography radiotracer anti-3-[(18)F]FACBC compared to ProstaScint(r) ((111)In capromab pendetide) single photon emission computerized tomography-computerized tomography to detect recurrent prostate carcinoma. MATERIALS AND METHODS: A total of 93 patients met study inclusion criteria who underwent anti-3-[(18)F]FACBC positron emission tomography-computerized tomography plus (111)In-capromab pendetide single photon emission computerized tomography-computerized tomography for suspected recurrent prostate carcinoma within 90 days. Reference standards were applied by a multidisciplinary board. We calculated diagnostic performance for detecting disease. RESULTS: In the 91 of 93 patients with sufficient data for a consensus on the presence or absence of prostate/bed disease anti-3 [(18)F]FACBC had 90.2% sensitivity, 40.0% specificity, 73.6% accuracy, 75.3% positive predictive value and 66.7% negative predictive value compared to (111)In capromab pendetide with 67.2%, 56.7%, 63.7%, 75.9% and 45.9%, respectively. In the 70 of 93 patients with a consensus on the presence or absence of extraprostatic disease anti-3-[(18)F]FACBC had 55.0% sensitivity, 96.7% specificity, 72.9% accuracy, 95.7% positive predictive value and 61.7% negative predictive value compared to (111)In-capromab pendetide with 10.0%, 86.7%, 42.9%, 50.0% and 41.9%, respectively. Of 77 index lesions used to prove positivity histological proof was obtained in 74 (96.1%). Anti-3-[(18)F]FACBC identified 14 more positive prostate bed recurrences (55 vs 41) and 18 more patients with extraprostatic involvement (22 vs 4). Anti-3-[(18)F]FACBC positron emission tomography-computerized tomography correctly up-staged 18 of 70 cases (25.7%) in which there was a consensus on the presence or absence of extraprostatic involvement. CONCLUSIONS: Better diagnostic performance was noted for anti-3 [(18)F]FACBC positron emission tomography-computerized tomography than for (111)In-capromab pendetide single photon emission computerized tomography computerized tomography for prostate carcinoma recurrence. The former method detected significantly more prostatic and extraprostatic disease. PMID- 24144691 TI - Efficacy of combined anteroposterior fusion with no plate versus anterior fusion alone with cage and plate for multilevel degenerative cervical disease. AB - BACKGROUND CONTEXT: Many studies have reported that anterior fusion alone has high rates of complications, such as pseudoarthrosis, graft subsidence, and graft dislodgement, with multisegmental constructs. No previous studies have compared the outcomes of combined anteroposterior fusion with no plate and anterior fusion alone with a cage and plate. PURPOSE: To compare the efficacy of combined anteroposterior fusion with that of anterior fusion alone for the treatment of multisegmental degenerative cervical disorder. STUDY DESIGN: Retrospective study. PATIENT SAMPLE: Sixty-two consecutive patients who underwent anterior fusion alone with a cage and plate or combined anteroposterior fusion with no plate for multisegmental (three or more segments) degenerative cervical disease. OUTCOME MEASURE: Radiological and clinical outcome measures. METHODS: Patients in group A (n=36) underwent anterior fusion with a cage and plate construct (AFA); patients in group B (n=26) underwent combined anterior fusion with a cage and posterior fusion with a rod/screw construct (CAPF). The degree and maintenance of the correction angle, fusion rates, and adjacent level degeneration were assessed with radiographs. Clinical outcomes were assessed with a visual analog scale (VAS) and Neck Disability Index (NDI) scores, operative time, blood loss, and rates of complications. RESULTS: The mean correction angle did not differ significantly between groups, but the loss of correction at final follow-up was greater in group A than group B (p=.001). Compared with group B, group A had a higher incidence of pseudarthrosis (p=.035), cage subsidence (p=.005), hardware related complications (p=.032), and dysphagia (p=.012). The mean VAS score for arm pain and the mean NDI score were better for group B than group A (p=.0461, .0360), but the mean VAS score for posterior neck pain was better for group A than group B (p=.0352). Group B had greater blood loss and a longer operative time than group A (blood loss: p=.037; operative time: p=.0001). CONCLUSIONS: Although combined anterior/posterior fusion is associated with a longer operative time and greater blood loss than anterior fusion alone, the combined approach provides better maintenance of sagittal alignment, a higher rate of fusion, a lower incidence of cage subsidence and adjacent level disease, and better VAS and NDI scores. PMID- 24144692 TI - The influence of cervical spine position on the three anterior endoscopic approaches to the craniovertebral junction: an imaging study. AB - BACKGROUND CONTEXT: Three endoscopic anterior approaches, the transnasal, transoral, and transcervical approaches, are used for ventral lesions of the craniovertebral junction and have been compared regarding surgical working distances and approach angles. However, how the position of the cervical spine influences the depths of surgical corridors and approach angles for the three approaches has not been evaluated. PURPOSE: To evaluate the depths of surgical corridors and the approach angles for the three endoscopic approaches, taking the influence of cervical spine position into account. STUDY DESIGN: A radiographic study comparing three anterior endoscopic approaches to the craniovertebral junction. PATIENT SAMPLE: Cervical extension and flexion radiographs for 34 patients and cross-sectional computed tomography scans for 30 additional patients were assessed. OUTCOME MEASURES: The depths of the surgical corridors and the approach angles for the three endoscopic approaches in the midsagittal planes. METHODS: We determined the mean angles of the surgical trajectories for the endoscopic transoral and transcervical approaches on cervical extension and flexion radiographs. In addition, we measured the depths of the surgical corridors and the approach angles for the three approaches in the midsagittal plane. RESULTS: The average depths of surgical corridors were as follows: endonasal, 93.65 mm; transoral, 85.27 mm; transcervical, 62.97 mm (in extension). The average approach angles were as follows: endonasal, 31.22 degrees ; transoral, 30.87 degrees ; transcervical, 36.58 degrees (in extension). CONCLUSIONS: The position of the cervical spine does not influence the surgical convenience of the endoscopic transnasal approach, but it can influence the endoscopic transoral and transcervical approaches, especially the latter. The endoscopic transcervical approach offers several advantages over the endoscopic transoral and endonasal approaches. PMID- 24144693 TI - [Spontaneous renal forniceal rupture with suspicious ovarian mass]. AB - Extravasation of urine following rupture of the renal fornix is a rare complication mostly caused by obstruction secondary to distal ureteric stones. This 35-year-old woman was referred with back pain. Her CT scan revealed rupture of the renal fornix secondary to a pelvic mass. Laparoscopy subsequently confirmed this to be an ovarian abscess. We report the first case of spontaneous renal forniceal rupture secondary to pelvic inflammatory disease. PMID- 24144694 TI - Plant leaf senescence and death - regulation by multiple layers of control and implications for aging in general. AB - How do organisms, organs, tissues and cells change their fate when they age towards senescence and death? Plant leaves provide a unique window to explore this question because they show reproducible life history and are readily accessible for experimental assays. Throughout their lifespan, leaves undergo a series of developmental, physiological and metabolic transitions that culminate in senescence and death. Leaf senescence is an 'altruistic death' that allows for the degradation of the nutrients that are produced during the growth phase of the leaf and their redistribution to developing seeds or other parts of the plant, and thus is a strategy that has evolved to maximize the fitness of the plant. During the past decade, there has been significant progress towards understanding the key molecular principles of leaf senescence using genetic and molecular studies, as well as 'omics' analyses. It is now apparent that leaf senescence is a highly complex genetic program that is tightly controlled by multiple layers of regulation, including at the level of chromatin and transcription, as well as by post-transcriptional, translational and post-translational regulation. This Commentary discusses the latest understandings and insights into the underlying molecular mechanisms, and presents the perspectives necessary to enable our system-level understanding of leaf senescence, together with their possible implications for aging in general. PMID- 24144695 TI - Modulation of integrin activation and signaling by alpha1/alpha1'-helix unbending at the junction. AB - How conformational signals initiated from one end of the integrin are transmitted to the other end remains elusive. At the ligand-binding betaI domain, the alpha1/alpha1'-helix changes from a bent to a straightened alpha-helical conformation upon integrin headpiece opening. We demonstrated that a conserved glycine at the alpha1/alpha1' junction is crucial for maintaining the bent conformation of the alpha1/alpha1'-helix in the resting state. Mutations that facilitate alpha1/alpha1'-helix unbending rendered integrin constitutively active; however, mutations that block the alpha1/alpha1'-helix unbending abolished soluble ligand binding upon either outside or inside stimuli. Such mutations also blocked ligand-induced integrin extension from outside the cell, but had no effect on talin-induced integrin extension from inside the cell. In addition, integrin-mediated cell spreading, F-actin stress fiber and focal adhesion formation, and focal adhesion kinase activation were also defective in these mutant integrins, although the cells still adhered to immobilized ligands at a reduced level. Our data establish the structural role of the alpha1/alpha1' junction that allows relaxation of the alpha1/alpha1'-helix in the resting state and transmission of bidirectional conformational signals by helix unbending upon integrin activation. PMID- 24144696 TI - Keratin 8 modulates beta-cell stress responses and normoglycaemia. AB - Keratin intermediate filament (IF) proteins are epithelial cell cytoskeletal components that provide structural stability and protection from cell stress, among other cellular and tissue-specific functions. Numerous human diseases are associated with IF gene mutations, but the function of keratins in the endocrine pancreas and their potential significance for glycaemic control are unknown. The impact of keratins on beta-cell organisation and systemic glucose control was assessed using keratin 8 (K8) wild-type (K8(+/+)) and K8 knockout (K8(-/-)) mice. Islet beta-cell keratins were characterised under basal conditions, in streptozotocin (STZ)-induced diabetes and in non-obese diabetic (NOD) mice. STZ induced diabetes incidence and islet damage was assessed in K8(+/+) and K8(-/-) mice. K8 and K18 were the predominant keratins in islet beta-cells and K8(-/-) mice expressed only remnant K18 and K7. K8 deletion resulted in lower fasting glucose levels, increased glucose tolerance and insulin sensitivity, reduced glucose-stimulated insulin secretion and decreased pancreatic insulin content. GLUT2 localisation and insulin vesicle morphology were disrupted in K8(-/-) beta cells. The increased levels of cytoplasmic GLUT2 correlated with resistance to high-dose STZ-induced injury in K8(-/-) mice. However, K8 deletion conferred no long-term protection from STZ-induced diabetes and prolonged STZ-induced stress caused increased exocrine damage in K8(-/-) mice. beta-cell keratin upregulation occurred 2 weeks after treatments with low-dose STZ in K8(+/+) mice and in diabetic NOD mice, suggesting a role for keratins, particularly in non-acute islet stress responses. These results demonstrate previously unrecognised functions for keratins in beta-cell intracellular organisation, as well as for systemic blood glucose control under basal conditions and in diabetes-induced stress. PMID- 24144698 TI - A non-canonical di-acidic signal at the C-terminus of Kv1.3 determines anterograde trafficking and surface expression. AB - Impairment of Kv1.3 expression at the cell membrane in leukocytes and sensory neuron contributes to the pathophysiology of autoimmune diseases and sensory syndromes. Molecular mechanisms underlying Kv1.3 channel trafficking to the plasma membrane remain elusive. We report a novel non-canonical di-acidic signal (E483/484) at the C-terminus of Kv1.3 essential for anterograde transport and surface expression. Notably, homologous motifs are conserved in neuronal Kv1 and Shaker channels. Biochemical analysis revealed interactions with the Sec24 subunit of the coat protein complex II. Disruption of this complex retains the channel at the endoplasmic reticulum. A molecular model of the Kv1.3-Sec24a complex suggests salt-bridges between the di-acidic E483/484 motif in Kv1.3 and the di-basic R750/752 sequence in Sec24. These findings identify a previously unrecognized motif of Kv channels essential for their expression on the cell surface. Our results contribute to our understanding of how Kv1 channels target to the cell membrane, and provide new therapeutic strategies for the treatment of pathological conditions. PMID- 24144697 TI - TAK1 regulates SOX9 expression in chondrocytes and is essential for postnatal development of the growth plate and articular cartilages. AB - TAK1 is a MAP3K that mediates non-canonical TGF-beta and BMP signaling. During the embryonic period, TAK1 is essential for cartilage and joint development as deletion of Tak1 in chondro-osteo progenitor cells leads to severe chondrodysplasia with defects in both chondrocyte proliferation and maturation. We have investigated the role of TAK1 in committed chondrocytes during early postnatal development. Using the Col2a1-CreER(T2); Tak1(f/f) mouse model, we induced deletion of Tak1 at postnatal day 7 and characterized the skeletal phenotypes of these mice at 1 and 3 months of age. Mice with chondrocyte-specific Tak1 deletion exhibited severe growth retardation and reduced proteoglycan and type II collagen content in the extracellular matrix of the articular cartilage. We found reduced Col2a1 and Acan expression, but increased Mmp13 and Adamts5 expression, in Tak1-deficient chondrocytes along with reduced expression of the SOX trio of transcription factors, SOX9, SOX5 and SOX6. In vitro, BMP2 stimulated Sox9 gene expression and Sox9 promoter activity. These effects were reduced; however, following Tak1 deletion or treatment with a TAK1 kinase inhibitor. TAK1 affects both canonical and non-canonical BMP signal transduction and we found that both of these pathways contribute to BMP2-mediated Sox9 promoter activation. Additionally, we found that ATF2 directly binds the Sox9 promoter in response to BMP signaling and that this effect is dependent upon TAK1 kinase activity. These novel findings establish that TAK1 contributes to BMP2-mediated Sox9 gene expression and is essential for the postnatal development of normal growth plate and articular cartilages. PMID- 24144699 TI - Interaction of 4.1G and cGMP-gated channels in rod photoreceptor outer segments. AB - In photoreceptors, the assembly of signaling molecules into macromolecular complexes is important for phototransduction and maintaining the structural integrity of rod outer segments (ROSs). However, the molecular composition and formation of these complexes are poorly understood. Using immunoprecipitation and mass spectrometry, 4.1G was identified as a new interacting partner for the cyclic-nucleotide gated (CNG) channels in ROSs. 4.1G is a widely expressed multifunctional protein that plays a role in the assembly and stability of membrane protein complexes. Multiple splice variants of 4.1G were cloned from bovine retina. A smaller splice variant of 4.1G selectively interacted with CNG channels not associated with peripherin-2-CNG channel complex. A combination of truncation studies and domain-binding assays demonstrated that CNG channels selectively interacted with 4.1G through their FERM and CTD domains. Using immunofluorescence, labeling of 4.1G was seen to be punctate and partially colocalized with CNG channels in the ROS. Our studies indicate that 4.1G interacts with a subset of CNG channels in the ROS and implicate this protein protein interaction in organizing the spatial arrangement of CNG channels in the plasma membrane of outer segments. PMID- 24144701 TI - Entry into the nuclear pore complex is controlled by a cytoplasmic exclusion zone containing dynamic GLFG-repeat nucleoporin domains. AB - Nuclear pore complexes (NPCs) mediate nucleocytoplasmic movement. The central channel contains proteins with phenylalanine-glycine (FG) repeats, or variations (GLFG, glycine-leucine-phenylalanine-glycine). These are 'intrinsically disordered' and often represent weak interaction sites that become ordered upon interaction. We investigated this possibility during nuclear transport. Using electron microscopy of S. cerevisiae, we show that NPC cytoplasmic filaments form a dome-shaped structure enclosing GLFG domains. GLFG domains extend out of this structure and are part of an 'exclusion zone' that might act as a partial barrier to entry of transport-inert proteins. The anchor domain of a GLFG nucleoporin locates exclusively to the central channel. By contrast, the localisation of the GLFG domains varied between NPCs and could be cytoplasmic, central or nucleoplasmic and could stretch up to 80 nm. These results suggest a dynamic exchange between ordered and disordered states. In contrast to diffusion through the NPC, transport cargoes passed through the exclusion zone and accumulated near the central plane. We also show that movement of cargo through the NPC is accompanied by relocation of GLFG domains, suggesting that binding, restructuring and movement of these domains could be part of the translocation mechanism. PMID- 24144700 TI - Activation of Rac by Asef2 promotes myosin II-dependent contractility to inhibit cell migration on type I collagen. AB - Non-muscle myosin II (MyoII) contractility is central to the regulation of numerous cellular processes, including migration. Rho is a well-characterized modulator of actomyosin contractility, but the function of other GTPases, such as Rac, in regulating contractility is currently not well understood. Here, we show that activation of Rac by the guanine nucleotide exchange factor Asef2 (also known as SPATA13) impairs migration on type I collagen through a MyoII-dependent mechanism that enhances contractility. Knockdown of endogenous Rac or treatment of cells with a Rac-specific inhibitor decreases the amount of active MyoII, as determined by serine 19 (S19) phosphorylation, and negates the Asef2-promoted increase in contractility. Moreover, treatment of cells with blebbistatin, which inhibits MyoII activity, abolishes the Asef2-mediated effect on migration. In addition, Asef2 slows the turnover of adhesions in protrusive regions of cells by promoting large mature adhesions, which has been linked to actomyosin contractility, with increased amounts of active beta1 integrin. Hence, our data reveal a new role for Rac activation, promoted by Asef2, in modulating actomyosin contractility, which is important for regulating cell migration and adhesion dynamics. PMID- 24144702 TI - Association of constipation and fecal incontinence with attention deficit/hyperactivity disorder. AB - OBJECTIVE: Functional constipation and fecal incontinence are common childhood gastrointestinal conditions. Both conditions may be associated with behavioral problems. Attention-deficit/hyperactivity disorder (ADHD) is the most common behavioral disorder of childhood, characterized by shortened attention span and hyperactivity. We hypothesize that a diagnosis of ADHD increases the risk for functional constipation and fecal incontinence. METHODS: A retrospective cohort study of children was performed by using the military health system database. Children of active-duty military personnel, aged 4 to 12 years, from October 2005 to September 2007, were included. ADHD, constipation, and fecal incontinence were identified by International Classification of Diseases, Ninth Revision, Clinical Modification diagnostic codes. Relative risks and adjusted incidence rate ratios (IRRs) were calculated. A subgroup analysis of subjects receiving medical therapy was performed. RESULTS: There were 742,939 children identified in the study, 32,773 (4.4%) of whom had ADHD. Children with ADHD had an increased prevalence of constipation (4.1% of children with ADHD vs 1.5% children without ADHD; P < .001) and fecal incontinence (0.9% of children with ADHD vs 0.15% of children without ADHD; P < .0001). Children with ADHD had more visits than those without ADHD for both constipation (IRR 3.39; 95% confidence interval 2.59-4.43) and fecal incontinence (IRR 7.74; 95% confidence interval 5.01-11.98). Children with ADHD receiving medicinal therapy did not differ significantly from children with ADHD not receiving medicinal therapy on rates of constipation visits (P = .57) or fecal incontinence visits (P = .32). CONCLUSIONS: Children with ADHD are significantly more likely to have constipation and fecal incontinence. Medical therapy for ADHD does not impact visit rates for defecation disorders. PMID- 24144703 TI - Neonatal ECMO study of temperature (NEST): a randomized controlled trial. AB - BACKGROUND: Despite evidence to support the use of extracorporeal membrane oxygenation (ECMO) in defined groups of newborn infants, rates of impairment among survivors remain high. Therapeutic hypothermia has been shown to provide neuroprotection in mature infants exposed to perinatal asphyxia. We hypothesized that therapeutic hypothermia during ECMO would reduce the proportion of infants with brain injury, and thus later impairment. METHODS: We conducted a randomized trial in the United Kingdom to compare ECMO with cooling (34 degrees C for the first 48 to 72 hours) with standard ECMO (37 degrees C). The primary outcome was the cognitive composite score of the Bayley Scales of Infant and Toddler Development, 3rd edition, at 2 years. Prespecified secondary outcomes included death, neonatal morbidity, and other neurodevelopmental and behavioral outcomes at 2 years. RESULTS: A total of 111 infants were entered into the study, 14 died before 2 years of age (16% who received ECMO with cooling vs 9% who received ECMO alone). Two infants were lost to follow-up, and 8 were unable to complete the full range of tests. For 45 evaluated infants who received ECMO with cooling, mean cognitive scores at 2 years were 88.0 (SD: 16.2) compared with 90.6 (SD: 13.1) for 48 infants receiving ECMO only (difference in means: -2.6; 95% confidence interval: -8.7 to 3.4). The various secondary outcomes were not significantly different between the groups, but most favored ECMO without cooling. CONCLUSIONS: In newborn infants treated by ECMO, the use of mild hypothermia for the first 48 to 72 hours did not result in improved outcomes up to 2 years of age. PMID- 24144704 TI - Psychotropic medication use and polypharmacy in children with autism spectrum disorders. AB - OBJECTIVE: The objectives of this study were to examine rates and predictors of psychotropic use and multiclass polypharmacy among commercially insured children with autism spectrum disorders (ASD). METHODS: This retrospective observational study used administrative medical and pharmacy claims data linked with health plan enrollment and sociodemographic information from 2001 to 2009. Children with ASD were identified by using a validated ASD case algorithm. Psychotropic polypharmacy was defined as concurrent medication fills across >= 2 classes for at least 30 days. Multinomial logistic regression was used to model 5 categories of psychotropic use and multiclass polypharmacy. RESULTS: Among 33,565 children with ASD, 64% had a filled prescription for at least 1 psychotropic medication, 35% had evidence of psychotropic polypharmacy (>= 2 classes), and 15% used medications from >= 3 classes concurrently. Among children with polypharmacy, the median length of polypharmacy was 346 days. Older children, those who had a psychiatrist visit, and those with evidence of co-occurring conditions (seizures, attention-deficit disorders, anxiety, bipolar disorder, or depression) had higher odds of psychotropic use and/or polypharmacy. CONCLUSIONS: Despite minimal evidence of the effectiveness or appropriateness of multidrug treatment of ASD, psychotropic medications are commonly used, singly and in combination, for ASD and its co-occurring conditions. Our results indicate the need to develop standards of care around the prescription of psychotropic medications to children with ASD. PMID- 24144705 TI - Opting in to online professionalism: social media and pediatrics. PMID- 24144706 TI - Policy statement on planned home birth: upholding the best interests of children and families. PMID- 24144707 TI - Planned home birth: a violation of the best interests of the child standard? PMID- 24144708 TI - Measles in children vaccinated with 2 doses of MMR. AB - OBJECTIVE: A previous measles outbreak investigation in a high school in Quebec, Canada identified 2-dose vaccine effectiveness of 94%. The risk of measles in 2 dose recipients was significantly higher (2-4 times) when measles vaccine was first administered at 12 versus >= 15 months of age, with no significant effect of the age at second dose. Generalizability of this association was also assessed in the expanded provincial data set of notified cases. METHODS: This matched case control study included only 2-dose recipients. All confirmed (laboratory or epidemiologically linked) cases in patients aged 5 to 17 years were included. Each case was matched to 5 controls. RESULTS: A total of 102 cases and 510 controls were included; 89% of cases were in patients 13 to 17 years old. When the first dose was administered at 12 to 13 months compared with >= 15 months of age, the risk of measles in participants outside the outbreak school was 6 times higher (95% confidence interval, 1.33-29.3) and was 5.2 times higher (95% confidence interval, 1.91-14.3) in the pooled estimate (participants from the outbreak school + outside that school). CONCLUSIONS: A significantly greater risk of measles among 2-dose recipients whose first dose was given at 12 to 13 months rather than >= 15 months of age is confirmed in the larger Quebec data set. The mechanism remains unknown, but vaccine failures in 2-dose recipients could have substantial implications for measles elimination efforts through 2-dose vaccination. The optimal age at first dose may warrant additional evaluation. PMID- 24144709 TI - Anticoagulant treatment with rivaroxaban in severe protein S deficiency. AB - We report a case of a 6-year-old girl with severe protein S deficiency due to a homozygous mutation and recurrent episodes of skin necrosis. She developed purpura fulminans at birth and a catheter-related venous thrombosis complicated by massive pulmonary embolism at the sixth day of life. Long-term oral anticoagulant therapy with a vitamin K-antagonist was started with a therapeutic range of the international normalized ratio of prothrombin time between 2.0 and 3.0. Unfortunately, this common range was not sufficient because recurrent episodes of warfarin-induced skin necrosis developed if the international normalized ratio was <4.0. Vitamin K antagonists decrease plasma level of vitamin K-dependent coagulation proteins, including the natural anticoagulant protein C. In our patient, the hypercoagulable state due to warfarin-induced reduction of protein C, other than severe protein S deficiency, outweighed the anticoagulant efficacy of the inhibition of procoagulant factors II, VII, IX, and X. The switch of anticoagulant therapy from warfarin to rivaroxaban, a direct inhibitor of activated factor X that does not inhibit other vitamin K-dependent proteins, resulted in the disappearance of skin necrosis at 1 year of follow-up. Rivaroxaban may be considered as a valid anticoagulant alternative in patients with severe inherited protein S deficiency and warfarin-induced skin necrosis. PMID- 24144711 TI - Health outcomes associated with transition from pediatric to adult cystic fibrosis care. AB - BACKGROUND: Almost half of individuals who have cystic fibrosis (CF) are over 18 years old, thus safely transferring patients from pediatric to adult care is a priority. The purpose of this study is to compare youth transferred from pediatric to adult CF care versus those remaining in pediatric CF care and quantify the relationship between transfer status and health outcomes. METHODS: Patients who transferred from pediatric to adult CF care were identified from the CF Foundation Patient Registry from 1997 to 2007. Transferred patients were compared with individuals who have similar baseline characteristics who remained in pediatric care throughout the same time period. The main outcome measures include pulmonary function, nutritional status, care use, and home intravenous antibiotic events per year. A propensity-matched analysis was performed. RESULTS: Fifty-eight percent of patients remained in pediatric programs throughout the study period. The mean age at transfer to adult care was 21.2 (1.3) years. In the 2 years after transfer there was a less rapid decline in percent predicted forced expiratory volume in 1 second of 0.78 percentage points per year among transfer positive patients compared with transfer-negative ones (95% confidence interval; 0.06-1.51); there were no other significant health related changes. CONCLUSIONS: The current study contradicts reports of other chronic childhood conditions, in which transfer between the pediatric and adult health system was associated with adverse health outcomes. Further research is needed to explore the long-term relationship between transition practices and health status outcomes to establish a systematic, evidence-based transition process. PMID- 24144710 TI - Using registries to identify adverse events in rheumatic diseases. AB - The proven effectiveness of biologics and other immunomodulatory products in inflammatory rheumatic diseases has resulted in their widespread use as well as reports of potential short- and long-term complications such as infection and malignancy. These complications are especially worrisome in children who often have serial exposures to multiple immunomodulatory products. Post-marketing surveillance of immunomodulatory products in juvenile idiopathic arthritis (JIA) and pediatric systemic lupus erythematosus is currently based on product-specific registries and passive surveillance, which may not accurately reflect the safety risks for children owing to low numbers, poor long-term retention, and inadequate comparators. In collaboration with the US Food and Drug Administration (FDA), patient and family advocacy groups, biopharmaceutical industry representatives and other stakeholders, the Childhood Arthritis and Rheumatology Research Alliance (CARRA) and the Duke Clinical Research Institute (DCRI) have developed a novel pharmacosurveillance model (CARRA Consolidated Safety Registry [CoRe]) based on a multicenter longitudinal pediatric rheumatic diseases registry with over 8000 participants. The existing CARRA infrastructure provides access to much larger numbers of subjects than is feasible in single-product registries. Enrollment regardless of medication exposure allows more accurate detection and evaluation of safety signals. Flexibility built into the model allows the addition of specific data elements and safety outcomes, and designation of appropriate disease comparator groups relevant to each product, fulfilling post marketing requirements and commitments. The proposed model can be applied to other pediatric and adult diseases, potentially transforming the paradigm of pharmacosurveillance in response to the growing public mandate for rigorous post marketing safety monitoring. PMID- 24144712 TI - Active versus passive cooling during neonatal transport. AB - BACKGROUND AND OBJECTIVE: Therapeutic hypothermia is now the standard of care for hypoxic-ischemic encephalopathy. Treatment should be started early, and it is often necessary to transfer the infant to a regional NICU for ongoing care. There are no large studies reporting outcomes from infants cooled passively compared with active (servo-controlled) cooling during transfer. Our goal was to review data from a regional transport service, comparing both methods of cooling. METHODS: This was a retrospective observational study of 143 infants referred to a regional NICU for ongoing therapeutic hypothermia. Of the 134 infants transferred, the first 64 were cooled passively, and 70 were subsequently cooled after purchase of a servo-controlled mattress. Key outcome measures were time to arrival at the regional unit, temperature at referral and arrival at the regional unit, and temperature stability during transfer. RESULTS: The age cooling was started was significantly shorter in the actively cooled group (46 [0-352] minutes vs 120 [0-502] minutes; P <.01). The median (range) stabilization time (153 [60-385] minutes vs 133 [45-505] minutes; P = .04) and age at arrival at the regional unit (504 [191-924] minutes vs 452 [225-1265]) minutes; P = .01) were significantly shorter in the actively cooled group. Only 39% of infants passively cooled were within the target temperature range at arrival to the regional unit compared with 100% actively cooled. CONCLUSIONS: Servo-controlled active cooling has been shown to improve temperature stability and is associated with a reduction in transfer time. PMID- 24144713 TI - Infant hospitalizations for pertussis before and after Tdap recommendations for adolescents. AB - OBJECTIVE: Recent universal vaccination efforts among children in the United States have markedly changed hospitalization patterns for many vaccine preventable diseases. Infants with pertussis often require hospitalization to monitor for potentially life-threatening respiratory failure. In 2006, tetanus diphtheria-acellular pertussis (Tdap) vaccination was recommended for universal administration to adolescents, a known source of pertussis in infants. By 2011, 78% of adolescents in the United States had received Tdap. We sought to understand if patterns of pertussis hospitalization for infants changed with adoption of Tdap vaccination among adolescents. METHODS: Infants (aged <1 year) diagnosed with pertussis were identified in the Nationwide Inpatient Sample by using diagnostic codes. We used variance-weighted least-squares regression over preimplementation years (2000-2005) to estimate pertussis hospitalization patterns if Tdap had not been available. We compared expected hospitalization rates with observed rates for 2008-2011. Two years (2006 and 2007) were excluded from analysis during early Tdap implementation. RESULTS: The incidence of hospitalization for pertussis in 2000 was 5.82 (95% confidence interval: 4.51 7.13) discharges per 10,000 infants in the US population. The rate increased during pre-Tdap years by a mean of 0.64 pertussis discharges per 10,000 infants per year (P for trend = .004). Observed hospitalization rates for pertussis among infants were significantly lower than expected in 2008, 2009, and 2011, but in 2010 the observed and expected rates of hospitalization were not significantly different. CONCLUSIONS: Adolescent Tdap vaccination appears to be partially effective in preventing pertussis hospitalizations among infants. However, broader Tdap immunization coverage may be necessary to achieve sustainable reductions in infant pertussis burden. PMID- 24144714 TI - Microbial contamination of human milk purchased via the Internet. AB - OBJECTIVE: To quantify microbial contamination of human milk purchased via the Internet as an indicator of disease risk to recipient infants. METHODS: Cross sectional sample of human milk purchased via a popular US milk-sharing Web site (2012). Individuals advertising milk were contacted to arrange purchase, and milk was shipped to a rented mailbox in Ohio. The Internet milk samples (n = 101) were compared with unpasteurized samples of milk donated to a milk bank (n = 20). RESULTS: Most (74%) Internet milk samples were colonized with Gram-negative bacteria or had >10(4) colony-forming units/mL total aerobic count. They exhibited higher mean total aerobic, total Gram-negative, coliform, and Staphylococcus sp counts than milk bank samples. Growth of most species was positively associated with days in transit (total aerobic count [log10 colony forming units/mL] beta = 0.71 [95% confidence interval: 0.38-1.05]), and negatively associated with number of months since the milk was expressed (beta = 0.36 [95% confidence interval: -0.55 to -0.16]), per simple linear regression. No samples were HIV type 1 RNA-positive; 21% of Internet samples were cytomegalovirus DNA-positive. CONCLUSIONS: Human milk purchased via the Internet exhibited high overall bacterial growth and frequent contamination with pathogenic bacteria, reflecting poor collection, storage, or shipping practices. Infants consuming this milk are at risk for negative outcomes, particularly if born preterm or are medically compromised. Increased use of lactation support services may begin to address the milk supply gap for women who want to feed their child human milk but cannot meet his or her needs. PMID- 24144716 TI - Avoiding endotracheal ventilation to prevent bronchopulmonary dysplasia: a meta analysis. AB - BACKGROUND AND OBJECTIVE: Mechanical ventilation via an endotracheal tube is a risk factor for bronchopulmonary dysplasia (BPD), one of the most common morbidities of very preterm infants. Our objective was to investigate the effect that strategies to avoid endotracheal mechanical ventilation (eMV) have on the incidence of BPD in preterm infants <30 weeks' gestational age (GA). METHODS: In February 2013, we searched the databases Medline, Embase, and the Cochrane Central Register of Controlled Trials. Study selection criteria included randomized controlled trials published in peer-reviewed journals since the year 2000 that compared preterm infants <30 weeks' GA treated by using a strategy aimed at avoiding eMV with a control group in which mechanical ventilation via an endotracheal tube was performed at an earlier stage. Data were extracted and analyzed by using the standard methods of the Cochrane Neonatal Review Group. The authors independently assessed study eligibility and risk of bias, extracted data and calculated odds ratios and 95% confidence intervals, employing RevMan version 5.1.6. RESULTS: We identified 7 trials that included a total of 3289 infants. The combined odds ratio (95% confidence interval) of death or BPD was 0.83 (0.71 0.96). The number needed to treat was 35. The study results were remarkably homogeneous. Avoiding eMV had no influence on the incidence of severe intraventricular hemorrhage. CONCLUSIONS: Strategies aimed at avoiding eMV in infants <30 weeks' GA have a small but significant beneficial impact on preventing BPD. PMID- 24144715 TI - Asymptomatic DNAemia heralds CMV-associated NEC: case report, review, and rationale for preemption. AB - Human cytomegalovirus (CMV) infection may be acquired in very low birth weight and extremely low birth weight (ELBW) infants from breast milk. The clinical relevance of such infections is uncertain. There is no consensus on whether screening breast milk for CMV, freezing/pasteurizing milk before feeding, or performing virological monitoring on at-risk infants is warranted. We describe an ELBW infant who acquired CMV postnatally from breast milk and developed CMV sepsis syndrome and clinical evidence of necrotizing enterocolitis (NEC) at ~ 5 weeks of age. The availability of serial dried blood spots from day of life (DOL) 4 to 21, coincidentally obtained for a metabolic study, provided the novel opportunity to retrospectively test for and quantify the magnitude of CMV DNAemia. DNAemia was present for several weeks before the onset of severe CMV disease, first being noted on DOL 18 and increasing in magnitude daily to 4.8 log10 genomes/mL on DOL 21, approximately 8 days before the onset of abdominal distension and 15 days before the onset of CMV sepsis syndrome and NEC. After surgical resection, supportive care, and ganciclovir therapy, the infant recovered. This case underscores the importance of including CMV infection in the differential diagnosis of sepsis and NEC in premature infants. This case also suggests the value of prospective virological monitoring in at-risk low birth weight and ELBW infants. Future studies should examine the potential utility of preemptive monitoring for, and possibly treatment of, CMV DNAemia in premature infants, which may herald the onset of serious disease. PMID- 24144717 TI - Pediatrician-led motivational interviewing to treat overweight children: an RCT. AB - OBJECTIVE: The aim of this study was to evaluate the effect of family pediatrician-led motivational interviews (MIs) on BMI of overweight (85th >= BMI percentile >= 95 th) children aged 4 to 7 years. METHODS: All the family pediatricians working in Reggio Emilia Province (Italy) were invited to participate in the study; 95% accepted. Specific training was provided. Parents were asked to participate in the trial if they recognized their child as overweight. Children were individually randomly assigned to MIs or usual care. All children were invited for a baseline and a 12-month visit to assess BMI and lifestyle behaviors. The usual care group received an information leaflet, and the intervention group received 5 MI family meetings. The primary outcome was the individual variation of BMI, assessed by pediatricians unblinded to treatment groups. RESULTS: Of 419 eligible families, 372 (89%) participated; 187 children were randomized to MIs and 185 to the usual care group. Ninety-five percent of the children attended the 12-month visit. The average BMI increased by 0.49 and 0.79 during the intervention in the MI and control groups, respectively (difference: -0.30; P = .007). MI had no effect in boys or in children whose mothers had a low educational level. Positive changes in parent-reported lifestyle behaviors occurred more frequently in the MI group than in the control group. CONCLUSIONS: The pediatrician-led MI was overall effective in controlling BMI in these overweight children aged 4 to 7 years, even though no effect was observed in male children or when the mother's education level was low. PMID- 24144718 TI - Spanking and child development across the first decade of life. AB - OBJECTIVE: To examine the prevalence of maternal and paternal spanking of children at 3 and 5 years of age and the associations between spanking and children's externalizing behavior and receptive vocabulary through age 9. METHODS: The Fragile Families and Child Well-Being Study, a longitudinal birth cohort study of children in 20 medium to large US cities, was used. Parental reports of spanking were assessed at age 3 and 5, along with child externalizing behavior and receptive vocabulary at age 9 (N = 1933). The data set also included an extensive set of child and family controls (including earlier measures of the child outcomes). RESULTS: Overall, 57% of mothers and 40% of fathers engaged in spanking when children were age 3, and 52% of mothers and 33% of fathers engaged in spanking at age 5. Maternal spanking at age 5, even at low levels, was associated with higher levels of child externalizing behavior at age 9, even after an array of risks and earlier child behavior were controlled for. Father's high-frequency spanking at age 5 was associated with lower child receptive vocabulary scores at age 9. CONCLUSIONS: Spanking remains a typical rearing experience for American children. These results demonstrate negative effects of spanking on child behavioral and cognitive development in a longitudinal sample from birth through 9 years of age. PMID- 24144719 TI - Tissue-specific metabolism of benzo[a]pyrene in rainbow trout (Oncorhynchus mykiss): a comparison between the liver and immune organs. AB - Polycyclic aromatic hydrocarbons (PAHs) are immunotoxicants in fish. In mammals, phase I metabolites are believed to be critically involved in the immunotoxicity of PAHs. This mechanism has been suggested for fish as well. The present study investigates the capacity of immune organs (head kidney, spleen) of rainbow trout, Oncorhynchus mykiss, to metabolize the prototypic PAH, benzo[a]pyrene (BaP). To this end, we analyzed 1) the induction of enzymatic capacity measured as 7-ethoxyresorufin-O-deethylase (EROD) activity in immune organs compared with liver, 2) the organ profiles of BaP metabolites generated in vivo, and 3) rates of microsomal BaP metabolite production in vitro. All measurements were done for control fish and for fish treated with an intraperitoneal injection of 15 mg BaP/kg body weight. In exposed trout, the liver, head kidney, and spleen contained similar levels of BaP, whereas EROD induction differed significantly between the organs, with liver showing the highest induction factor (132.8*), followed by head kidney (38.4*) and spleen (1.4*). Likewise, rates of microsomal metabolite formation experienced the highest induction in the liver of BaP exposed trout, followed by the head kidney and spleen. Microsomes from control fish displayed tissue-specific differences in metabolite production. In contrast, in BaP-exposed trout, microsomes of all organs produced the potentially immunotoxic BaP-7,8-dihydrodiol as the main metabolite. The findings from this study show that PAHs, like BaP, are distributed into immune organs of fish and provide the first evidence that immune organs possess inducible PAH metabolism leading to in situ production of potentially immunotoxic PAH metabolites. PMID- 24144720 TI - Traumatic childhood experiences in the 21st century: broadening and building on the ACE studies with data from the National Child Traumatic Stress Network. AB - The study objectives were to (a) examine the association between total number of trauma types experienced and child/adolescent behavioral problems and (b) determine whether the number of trauma types experienced predicted youth behavioral problems above and beyond demographic characteristics, using a diverse set of 20 types of trauma. Data came from the National Child Traumatic Stress Network's (NCTSN) Core Data Set (CDS), which includes youth assessed and treated for trauma across the United States. Participants who experienced at least one type of trauma were included in the sample (N = 11,028; age = 1½-18 years; 52.3% girls). Random effects models were used to account for possible intraclass correlations given treatment services were provided at different NCTSN centers. Logistic regression analyses were used to investigate associations among demographic characteristics, trauma, and emotional and behavioral problems as measured by the Child Behavior Checklist (CBCL). Significant dose-response relations were found between total number of trauma types and behavior problems for all CBCL scales, except Sleep, one of the subscales only administered to 1½- to 5-year-olds. Thus, each additional trauma type endorsed significantly increased the odds for scoring above the clinical threshold. Results provide further evidence of strong associations between diverse traumatic childhood experiences and a diverse range of behavior problems, and underscore the need for a trauma-informed public health and social welfare approach to prevention, risk reduction, and early intervention for traumatized youth. PMID- 24144721 TI - My beliefs of my peers' beliefs: exploring the gendered nature of social norms in adolescent romantic relationships. AB - Dating violence in adolescent relationships is a growing social problem in the United States. A majority of adolescents have dated by the time they finish high school and these experiences have an impact on their relationship trajectories as adults. Although more and more prevention efforts are aimed at reducing teen dating violence and/or teaching adolescents about healthy relationships, very few of these efforts investigate discrepancies in descriptive and injunctive norms associated with adolescent dating. This pilot study adds to the existing literature by investigating the dating norms of early and mid-adolescents to aid in tailoring prevention efforts among this population. One hundred eighty-seven middle and high school student leaders from public schools in the Midwest completed an annual relationship survey. Findings suggest that participants did not support unhealthy relationship norms overall. However, two patterns of discrepancies emerged: one between participant attitudes (descriptive norms) and their perceptions of peer attitudes (injunctive norms), and another between perceptions participants hold about their male versus female peers' beliefs. Results imply the development of pluralistic ignorance occurs during adolescence and that perceptions of peer norms are in line with the principles of hegemonic masculinity. Implications for possible prevention initiatives and future research directions are noted. PMID- 24144722 TI - Victimization experiences and adolescent substance use: does the type and degree of victimization matter? AB - Evidence indicates an association between victimization and adolescent substance use, but the exact nature of this relationship remains unclear. Some research focuses solely on the consequences of experiencing indirect victimization (e.g., witnessing violence), others examine direct victimization (e.g., being personally victimized), and still others combine both forms of victimization without assessing the relative impact of each on substance use. Furthermore, many of these studies only assess these relationships in the short-term using cross sectional data. This study uses data from the Project on Human Development in Chicago Neighborhoods (PHDCN) to explore the impact of experiencing only indirect victimization, only direct victimization, both forms of victimization, and no victimization on substance use at two time points during adolescence. We find that of those adolescents who are victimized, the majority experience indirect victimization only, followed by experiencing both forms of victimization, and experiencing direct victimization only. Each of the victimization experiences were associated with increased contemporaneous substance use, with the strongest effects for those experiencing multiple forms of violence. For all victims, however, the impact on substance use declined over time. PMID- 24144723 TI - Over-expression of Mash1 improves the GABAergic differentiation of bone marrow mesenchymal stem cells in vitro. AB - Bone marrow mesenchymal stem cells (BMSCs) have been shown to be a promising cell type for the study of neuronal differentiation; however, few attempts had been made to differentiate these cells into inhibitory gamma-aminobutyric acid (GABA)ergic neurons. In this study, we over-expressed mammalian achaete-scute homologue-1 (Mash1), a basic helix-loop-helix (bHLH) transcription factor, in Sprague-Dawley rat BMSCs via lentiviral vectors, and then induced neuronal differentiation of these cells using conditioned medium. Our Western blot results show that, under conditions of differentiation, Mash1-overexpressing BMSCs exhibit an increased expression of neuronal markers and a greater degree of neuronal morphology compared to control, non-Mash1-overexpressing cells. Using immunocytochemistry, we observed increased expression of glutamic acid decarboxylase 67 (GAD67), as well as neuron-specific nuclear protein (NeuN) and beta3-tubulin, in Mash1-overexpressing BMSCs compared to control cells. Moreover, we also found the differentiated cells showed representative traces of action potentials in electrophysiological characterization. In conclusion, our study demonstrated that over-expression of Mash1 can improve GABAergic differentiation of BMSCs in vitro. PMID- 24144724 TI - Treatment of recurrent rectovaginal/pouch-vaginal fistulas by gracilis muscle transposition - a single center experience. AB - PURPOSE: Rectovaginal fistulas constitute a serious burden for the affected patient and a major challenge for the attending surgeon. Definitive surgical treatment of the fistula depends on the size and location of the fistula, the underlying disease, and any previous therapies. In regards to complicated recurrent rectovaginal fistulas, transposition of the gracilis muscle is one of the well-established therapeutic options with a success rate of up to 70%. MATERIAL AND METHODS: Between 01/2004 and 06/2010, ten patients diagnosed with a recurrent rectovaginal fistula were treated in the surgical department of Klinikum Oldenburg by gracilis muscle transposition; their data were collected and analyzed. Post-operative evaluation was performed using a standardized telephone interview. All patients had a protective stoma. The primary endpoint of assessment was the long-term healing of the fistula following stoma reversal, and the comparison between those who were treated successfully versus those who were not. RESULTS: Over a time span of 6years, ten women with a complicated rectovaginal fistula underwent fistula repair with the gracilis muscle transposition. Patient age ranged from 29 and 64years. There were five rectovaginal fistulas, four pouch-vaginal fistulas, and one anovaginal fistula. The underlying disease was rectal cancer in seven patients, Crohn's disease in one patient, previous complicated gynecologic surgery in one patient, and idiopathic anal fistula in one patient. All seven patients with rectal cancer underwent radiochemotherapy with 50.4Gy (n=6 neo-adjuvant, n=1 adjuvant). All ten patients had previously undergone repair by a different surgical approach while five presented with a second or third recurrence. Post-operative complications were noted in two patients (perineal wound defect, thigh hematoma). Follow-up of the patients ranged from 8 to 60months. Recurrent rectovaginal fistula occurred in four patients. Evaluation of the data failed to identify statistically significant criteria for treatment failure of rectovaginal fistula repair. CONCLUSION: Our results are similar to previous studies in this area. For the majority of the patients, the gracilis muscle transposition was a long-term effective treatment of recurrent rectovaginal fistulas, however recurrences were noted in 40% of cases. Predictive criteria for treatment failure could not be established. PMID- 24144725 TI - Effect of mature blood-stage Plasmodium parasite sequestration on pathogen biomass in mathematical and in vivo models of malaria. AB - Parasite biomass and microvasculature obstruction are strongly associated with disease severity and death in Plasmodium falciparum-infected humans. This is related to sequestration of mature, blood-stage parasites (schizonts) in peripheral tissue. The prevailing view is that schizont sequestration leads to an increase in pathogen biomass, yet direct experimental data to support this are lacking. Here, we first studied parasite population dynamics in inbred wild-type (WT) mice infected with the rodent species of malaria, Plasmodium berghei ANKA. As is commonly reported, these mice became moribund due to large numbers of parasites in multiple tissues. We then studied infection dynamics in a genetically targeted line of mice, which displayed minimal tissue accumulation of parasites. We constructed a mathematical model of parasite biomass dynamics, incorporating schizont-specific host clearance, both with and without schizont sequestration. Combined use of mathematical and in vivo modeling indicated, first, that the slowing of parasite growth in the genetically targeted mice can be attributed to specific clearance of schizonts from the circulation and, second, that persistent parasite growth in WT mice can be explained solely as a result of schizont sequestration. Our work provides evidence that schizont sequestration could be a major biological process driving rapid, early increases in parasite biomass during blood-stage Plasmodium infection. PMID- 24144728 TI - Geographic variation in commercial medical-care expenditures: a framework for decomposing price and utilization. AB - This study introduces a new framework for measuring and analyzing medical-care expenditures. The framework focuses on expenditures at the disease level that are decomposed between price and utilization. We find that both price and utilization differences are important contributors to expenditure differences across commercial markets. Further examination shows that for some diseases utilization drives variation while for others price is more important. Finally, when disease specific measures are aggregated across diseases, much of the important disease specific variation is masked, leading to much smaller measures of aggregate variation. PMID- 24144726 TI - Dormant intracellular Salmonella enterica serovar Typhimurium discriminates among Salmonella pathogenicity island 2 effectors to persist inside fibroblasts. AB - Salmonella enterica uses effector proteins delivered by type III secretion systems (TTSS) to colonize eukaryotic cells. Recent in vivo studies have shown that intracellular bacteria activate the TTSS encoded by Salmonella pathogenicity island-2 (SPI-2) to restrain growth inside phagocytes. Growth attenuation is also observed in vivo in bacteria colonizing nonphagocytic stromal cells of the intestinal lamina propria and in cultured fibroblasts. SPI-2 is required for survival of nongrowing bacteria persisting inside fibroblasts, but its induction mode and the effectors involved remain unknown. Here, we show that nongrowing dormant intracellular bacteria use the two-component system OmpR-EnvZ to induce SPI-2 expression and the PhoP-PhoQ system to regulate the time at which induction takes place, 2 h postentry. Dormant bacteria were shown to discriminate the usage of SPI-2 effectors. Among the effectors tested, SseF, SseG, and SseJ were required for survival, while others, such as SifA and SifB, were not. SifA and SifB dispensability correlated with the inability of intracellular bacteria to secrete these effectors even when overexpressed. Conversely, SseJ overproduction resulted in augmented secretion and exacerbated bacterial growth. Dormant bacteria produced other effectors, such as PipB and PipB2, that, unlike what was reported for epithelial cells, did not to traffic outside the phagosomal compartment. Therefore, permissiveness for secreting only a subset of SPI-2 effectors may be instrumental for dormancy. We propose that the S. enterica serovar Typhimurium nonproliferative intracellular lifestyle is sustained by selection of SPI-2 effectors that are produced in tightly defined amounts and delivered to phagosome-confined locations. PMID- 24144727 TI - Streptococcus pyogenes arginine and citrulline catabolism promotes infection and modulates innate immunity. AB - A bacterium's ability to acquire nutrients from its host during infection is an essential component of pathogenesis. For the Gram-positive pathogen Streptococcus pyogenes, catabolism of the amino acid arginine via the arginine deiminase (ADI) pathway supplements energy production and provides protection against acid stress in vitro. Its expression is enhanced in murine models of infection, suggesting an important role in vivo. To gain insight into the function of the ADI pathway in pathogenesis, the virulence of mutants defective in each of its enzymes was examined. Mutants unable to use arginine (DeltaArcA) or citrulline (DeltaArcB) were attenuated for carriage in a murine model of asymptomatic mucosal colonization. However, in a murine model of inflammatory infection of cutaneous tissue, the DeltaArcA mutant was attenuated but the DeltaArcB mutant was hyperattenuated, revealing an unexpected tissue-specific role for citrulline metabolism in pathogenesis. When mice defective for the arginine-dependent production of nitric oxide (iNOS(-/-)) were infected with the DeltaArcA mutant, cutaneous virulence was rescued, demonstrating that the ability of S. pyogenes to utilize arginine was dispensable in the absence of nitric oxide-mediated innate immunity. This work demonstrates the importance of arginine and citrulline catabolism and suggests a novel mechanism of virulence by which S. pyogenes uses its metabolism to modulate innate immunity through depletion of an essential host nutrient. PMID- 24144729 TI - The use of alternative preference elicitation methods in complex discrete choice experiments. AB - We analyse stated preference data over nursing jobs collected from two different discrete choice experiments: a multi-profile case best-worst scaling experiment (BWS) prompting selection of the best and worst among alternative jobs, and a profile case BWS wherein the respondents choose the best and worst job attributes. The latter allows identification of additional utility parameters and is believed to be cognitively easier. Results suggest that respondents place greater value on pecuniary over non-pecuniary gains in the multi-profile case. There is little evidence that this discrepancy is induced by the extra cognitive burden of processing several profiles at once in the multi-profile case. We offer thoughts on other likely mechanisms. PMID- 24144730 TI - Vocal learning of a communicative signal in captive chimpanzees, Pan troglodytes. AB - We hypothesized that chimpanzees could learn to produce attention-getting (AG) sounds via positive reinforcement. We conducted a vocal assessment in 76 captive chimpanzees for their use of AG sounds to acquire the attention of an otherwise inattentive human. Fourteen individuals that did not produce AG sounds during the vocal assessment were evaluated for their ability to acquire the use of an AG sound through operant conditioning and to employ these sounds in an attention getting context. Nine of the 14 chimpanzees were successfully shaped using positive reinforcement to produce an AG sound. In a post-training vocal assessment, eight of the nine individuals that were successfully trained to produce AG sounds generalized the use of these newly acquired signals to communicatively relevant situations. Chimpanzees possess the ability to acquire the use of a communicative signal via operant conditioning and can generalize the use of this newly acquired signal to appropriate communicative contexts. PMID- 24144731 TI - The role of sterol-C4-methyl oxidase in epidermal biology. AB - Deficiency of sterol C4 methyl oxidase, encoded by the SC4MOL gene, has recently been described in four patients from three different families. All of the patients presented with microcephaly, congenital cataracts, and growth delay in infancy. The first patient has suffered since the age of six years from severe, diffuse, psoriasiform dermatitis, sparing only her palms. She is now 20 years old. The second patient is a 5 year old girl who has just started to develop dry skin and hair changes. The third and fourth patients are a pair of affected siblings with a severe skin condition since infancy. Quantitative sterol analysis of plasma and skin scales from all four patients showed marked elevation of 4alpha-methyl- and 4, 4'-dimethylsterols, consistent with a deficiency in the first step of sterol C4 demethylation in cholesterol biosynthesis. Mutations in the SC4MOL have been identified in all of the patients. SC4MOL deficiency is the first autosomal recessive disorder identified in the sterol demethylation complex. Cellular studies with patient-derived fibroblasts have shown a higher mitotic rate than control cells in cholesterol-depleted medium, with increased de novo cholesterol biosynthesis and accumulation of methylsterols. Immunologic analyses of granulocytes and B cells from patients and obligate carriers in the patients' families indicated dysregulation of immune-related receptors. Inhibition of sterol C4 methyl oxidase in human transformed lymphoblasts induced activation of the cell cycle. Additional studies also demonstrated diminished EGFR signaling and disrupted vesicular trafficking in cells from the affected patients. These findings suggest that methylsterols play an important role in epidermal biology by their influence on cell proliferation, intracellular signaling, vesicular trafficking and immune response. SC4MOL is situated within the psoriasis susceptibility locus PSORS9, and may be a genetic risk factor for common skin conditions. This article is part of a Special Issue entitled The Important Role of Lipids in the Epidermis and their Role in the Formation and Maintenance of the Cutaneous Barrier. Guest Editors: Kenneth R. Feingold and Peter Elias. PMID- 24144732 TI - Preferential suppression of limbic Fos expression by intermittent hypoxia in obese diabetic mice. AB - Sleep apnea (SA) causes not only sleep disturbances, but also neurocognitive impairments and/or psychoemotional disorders. Here, we studied the effects of intermittent hypoxia (IH) on forebrain Fos expression using obese diabetic db/db mice to explore the pathophysiological alterations in neural activities and the brain regions related to SA syndrome. Male db/db mice were exposed to IH stimuli (repetitive 6-min cycles of 1min with 5% oxygen followed by 5min with 21% oxygen) for 8h (80 cycles) per day or normoxic condition (control group) for 14 days. Fos protein expression was immunohistochemically examined a day after the last IH exposure. Mapping analysis revealed a significant reduction of Fos expression by IH in limbic and paralimbic structures, including the cingulate and piriform cortices, the core part of the nucleus accumbens and most parts of the amygdala (i.e., the basolateral and basomedial amygdaloid nuclei, cortical amygdaloid area and medial amygdaloid nucleus). In the brain stem regions, Fos expression was region-specifically reduced in the ventral tegmental area while other regions including the striatum, thalamus and hypothalamus, were relatively resistant against IH. In addition, db/db mice exposed to IH showed a trend of sedative and/or depressive behavioral signs in the open field and forced swim tests. The present results illustrate that SA in the obese diabetic model causes neural suppression preferentially in the limbic and paralimbic regions, which may be related to the neuropsychological disturbances associated with SA. PMID- 24144733 TI - Neuroinflammation: the role and consequences. AB - Neuroinflammation is central to the common pathology of several acute and chronic brain diseases. This review examines the consequences of excessive and prolonged neuroinflammation, particularly its damaging effects on cellular and/or brain function, as well as its relevance to disease progression and possible interventions. The evidence gathered here indicates that neuroinflammation causes and accelerates long-term neurodegenerative disease, playing a central role in the very early development of chronic conditions including dementia. The wide scope and numerous complexities of neuroinflammation suggest that combinations of different preventative and therapeutic approaches may be efficacious. PMID- 24144734 TI - DNA vaccination against membrane-bound Kit ligand: a new approach to inhibiting tumour growth and angiogenesis. AB - A functional c-Kit/Kit ligand (KitL) signalling network is required for tumour angiogenesis and growth, and therefore the c-Kit/KitL system might well be a suitable target for the cancer immunotherapy approach. We herein describe a strategy that targets membrane-bound KitL (mbKitL) via DNA vaccination. The vaccination procedure generated antibodies which are able to detect mbKitL on human tumour endothelial cells (TECs) and on the breast cancer cell line: TSA. DNA vaccination, interferes with tumour vessel formation and transplanted tumour growth in vivo. Histological analysis demonstrates that, while tumour cell proliferation and vessel stabilisation are impaired, vessel permeability is increased in mice that produce mbKitL-targeting antibodies. We also demonstrate that vessel stabilisation and tumour growth require Akt activation in endothelial cells but not in pericytes. Moreover, we found that regulatory T cells (Treg) and tumour infiltrating inflammatory cells, involved in tumour growth and angiogenesis, were reduced in number in the tumour microenvironment of mice that generate anti-mbKitL antibodies. These data provide evidence that mbKitL targeted vaccination is an effective means of inhibiting tumour angiogenesis and growth. PMID- 24144735 TI - Sorting out measures and definitions of screening participation to improve comparability: the example of colorectal cancer. AB - Participation is a key indicator of the potential effectiveness of any population based intervention. Defining, measuring and reporting participation in cancer screening programmes has become more heterogeneous as the number and diversity of interventions have increased, and the purposes of this benchmarking parameter have broadened. This study, centred on colorectal cancer, addresses current issues that affect the increasingly complex task of comparing screening participation across settings. Reports from programmes with a defined target population and active invitation scheme, published between 2005 and 2012, were reviewed. Differences in defining and measuring participation were identified and quantified, and participation indicators were grouped by aims of measure and temporal dimensions. We found that consistent terminology, clear and complete reporting of participation definition and systematic documentation of coverage by invitation were lacking. Further, adherence to definitions proposed in the 2010 European Guidelines for Quality Assurance in Colorectal Cancer Screening was suboptimal. Ineligible individuals represented 1% to 15% of invitations, and variable criteria for ineligibility yielded differences in participation estimates that could obscure the interpretation of colorectal cancer screening participation internationally. Excluding ineligible individuals from the reference population enhances comparability of participation measures. Standardised measures of cumulative participation to compare screening protocols with different intervals and inclusion of time since invitation in definitions are urgently needed to improve international comparability of colorectal cancer screening participation. Recommendations to improve comparability of participation indicators in cancer screening interventions are made. PMID- 24144737 TI - Histone deacetylase inhibitors induce human renal cell carcinoma cell apoptosis through p-JNK activation. AB - OBJECTIVE: To study the effect of histone deacetylase inhibitors trichostatin A (TSA) and LBH589 on the growth of human renal cell carcinoma OS-RC-2 cells in vitro and explore the underlying molecular mechanism. METHODS: OS-RC-2 cells were treated with LBH589 or TSA with or without SP600125 pretreatment, and the cell viability was measured by MTT assay. The changes of cell cycle distribution and apoptosis of OS-RC-2 cells were examined by flow cytometry, and the expressions of c-Jun, p-c-Jun, Bcl-2, and Bax were quantified by Western blotting. RESULTS: TSA and LBH589 both inhibited the growth of OS-RC-2 cells in a dose- and time dependent manner. TSA at 1 unmol/L and LBH589 at 50 nmol/L caused obvious cell cycle arrest in G2/M phase and cell apoptosis, and significantly increased the protein levels of phosphorylated c-Jun. TSA treatment obviously increased Bax expression but decreased Bcl2 expression in the cells. The growth inhibitory effect of TSA was attenuated by the JNK inhibitor SP600125 in OS-RC-2 cells. TSA induced phosphorylation of c-Jun and Bax upregulation was partially counteracted by SP600125. CONCLUSION: TSA and LBH589 can cause cell cycle arrest and induce apoptosis in OS-RC-2 cells, in which process P-JNK pathway plays an important role. PMID- 24144736 TI - Statin therapy is associated with improved survival after endovascular and open aneurysm repair. AB - BACKGROUND: The relationship between numerous risk factors and perioperative mortality after cardiovascular surgery has been studied extensively. While improved perioperative survival and fewer cardiovascular events have been related to statin therapy, its effect on long-term survival after aneurysm repair remains to be elucidated. The aim of this study is to determine the effect of statin therapy on long-term survival after open and endovascular aneurysm repair and to identify other cardiovascular and patient-related risk factors in this respect. METHODS: A post-hoc analysis of a randomized trial comparing open and endovascular abdominal aortic aneurysm repair was performed. In this multicenter trial, 351 patients were randomly assigned to undergo either open abdominal aortic aneurysm repair or endovascular repair. Patients who were on lipid lowering medication at their inclusion in the trial (n = 135) were compared with those who were not (n = 216). RESULTS: During 6 years of follow-up, 118 (33.6%) patients died after randomization. Statin therapy, baseline characteristics, Society for Vascular Surgery/International Society for Cardiovascular Surgery risk factors, aneurysm size, reinterventions, antiplatelet or anticoagulant agents, and beta-blockers were used to identify prognostic factors influencing survival. After identification of significant factors in a Kaplan-Meier analysis, a multivariable Cox regression analysis was applied. Statin therapy at inclusion in the trial was independently associated with better overall survival after open or endovascular aneurysm repair (hazard ratio [HR], 0.5; 95% confidence interval [CI], 0.3-0.8; P = .004). Statins were especially associated with fewer cardiovascular deaths (HR, 0.4; 95% CI, 0.2-0.9; P = .025). Several risk factors were associated with poor survival after open and endovascular aneurysm repair: age >70 (HR, 3.4; 95% CI, 2.2-5.0; P < .001), a history of cardiac disease at baseline (HR, 1.9; 95% CI, 1.3-2.8; P = .001), and moderate/severe tobacco use (HR, 1.7; 95% CI, 1.2-2.5; P = .004). Gender, aneurysm size, the need for reintervention, pulmonary disease, renal disease, carotid disease, hypertension, diabetes mellitus, antiplatelet or anticoagulant agents, and beta-blockers were not significantly associated with impaired long-term survival (P > .05). CONCLUSIONS: Despite the limitations of a post-hoc analysis of a prospectively maintained trial, we conclude that statin therapy at the beginning of the trial is independently associated with improved long-term survival after open or endovascular aneurysm repair, while age above 70 years, a history of cardiovascular disease, and tobacco use are associated with decreased long-term survival. PMID- 24144738 TI - [Diammonium glycyrrhizinate inhibits airway smooth muscle proliferation in a murine model of chronic asthma]. AB - OBJECTIVE: To investigate the therapeutic value and possible mechanism of diammonium glycyrrhizinate (DG) in treatment of airway remodeling in a murine model of chronic asthma. METHODS: Thirty male BALB/C mice were randomly divided into control group, OVA+DG group and OVA group (n=10). HE staining was used to observe the pathological changes, and Masson's staining was used to detect and measure collagen deposition. Alpha-SMA and PPARgamma mRNA expressions were analyzed by RT-PCR, and the protein expressions of alpha-SMA and PPARgamma were measured by Western blotting. RESULTS: After 75 days of OVA sensitization and challenge, obvious pathological changes occurred in the lung tissues, which was more severe in OVA group than in OVA+DG group. Collagen deposition was significantly increased after OVA stimulation, but was obviously milder in OVA+DG group than in OVA group. OVA-induced up-regulation of alpha-SMA was notably attenuated by DG injection. The expression of PPARgamma was markedly down regulated after OVA stimulation but was substantially enhanced after DG intervention. CONCLUSION: DG can inhibit airway smooth muscle proliferation possibly through up-regulation of PPARgamma in a murine model of chronic asthma. PMID- 24144739 TI - [Tricostantin A inhibits self-renewal of breast cancer stem cells in vitro]. AB - OBJECTIVE: To investigate the effect of tricostantin A (TSA) on self-renewal of breast cancer stem cells and explore the mechanisms. METHODS: Breast cancer cell lines MDA-MB-468, MDA-MB-231, MCF-7 and SKBR3 were cultured in suspension and treated with different concentrations of TSA for 7 days, using 0.1% DMSO as the control. Secondary mammosphere formation efficiency and percentage of CD44(+)/CD24(-) sub-population in the primary mammospheres were used to evaluate the effects of TSA on self-renewal of breast cancer stem cells. The breast cancer stem cell surface marker CD44(+)/CD24(-) and the percentage of apoptosis in the primary mammospheres were assayed using flow cytometry. The mRNA expressions of Nanog, Sox2 and Oct4 in the primary mammospheres were assayed with quantitative PCR. RESULTS: TSA at both 100 and 500 nmol/L, but not at 10 nmol/L, partially inhibited the self-renewal of breast cancer stem cells from the 4 cell lines. TSA at 500 nmol/L induced cell apoptosis in the primary mammospheres. TSA down regulated the mRNA expression of Nanog and Sox2 in the primary mammospheres. CONCLUSION: TSA can partially inhibit the self-renewal of breast cancer stem cells through a mechanism involving the down-regulation of Nanog and Sox2 expression, indicating the value of combined treatments with low-dose TSA and other anticancer drugs to achieve maximum inhibition of breast cancer stem cell self-renewal. The core transcriptional factor of embryonic stem cells Nanog and Sox2 can be potential targets of anticancer therapy. PMID- 24144740 TI - [Significance of MICA antibody monitoring in management of acute and chronic rejection after renal transplantation]. AB - OBJECTIVE: To evaluate the association of major histocompatibility complex class I chain related gene A (MICA) antibodies with acute rejection (AR), chronic rejection (CR) and renal function after renal transplantation. METHODS: Serum MICA antibodies were detected with ELISA before and after transplantation with also examinations of panel reactive antibodies (PRA), serum creatinine, urine, graft ultrasound, lymphocyte subsets and the pathology of graft biopsy. The study was carried out in two parts to monitor MICA antibodies in acute and chronic rejections after renal transplantation. RESULTS: In the first part of the study 18 of the 41 recipients experienced episodes of acute rejection, and the incidence rate was markedly higher in MICA(+) group than in MICA(-) group (P<0.05). Compared with the recipients with stable renal functions, the patients with acute graft rejection showed a significantly higher positivity rate of MICA antibodies. Postoperative MICA antibody monitoring showed that MICA antibody level increased gradually 2-3 days after the occurrence of acute rejection; anti rejection treatment lowered serum creatinine to a normal level but MICA antibodies remained positive. In the second part, 21 of 40 patients had chronic graft rejection and showed significantly higher positivity rate of MICA than the patients with stable renal functions (P<0.05). In patients with chronic rejections, the serum creatinine levels were significantly higher in MICA(+) than in MICA(-) cases (P<0.05). Graft biopsy of all MICA(+) cases showed C4d deposition. CONCLUSION: The status of MICA antibodies can predict the occurrence and treatment outcomes of acute rejection, and also as one of the major causes of chronic graft rejection, they affect the long-term survival of the renal grafts. PMID- 24144741 TI - [MAPK-ERK1/2 signaling pathway regulates osteogenic gene expression in rat osteoblasts in vitro]. AB - OBJECTIVE: To investigate the effect of inhibition and activation of MAPK-ERK1/2 pathway on the expression of osteogenic genes and proliferation of rat osteoblasts in vitro. METHODS: Primarily cultured rat osteoblasts, identified by cell morphology studies and ALP staining, were exposed to 1% or 5% rat serum for 24 h or to the specific MAPK-ERK1/2 inhibitor PD0325901. The downstream molecules of MAPK-ERK1/2 pathway including p-ERK1/2 and ERK1/2, osteogenic genes such as Runx2 and Type I collagen, and proliferating cell nuclear antigen (PCNA) were detected by Western Blotting, and alkaline phosphatase activities were analyzed quantitatively. RESULTS: Compared with 1% rat serum-treated cells, exposure of the cells to a higher concentration (5%) of rat serum caused a significantly increased phosphorylation level of p-ERK1/2 (P<0.05) and obviously enhanced expressions of the osteogenic genes (Runx2, type I collagen and ALP) and PCNA (P<0.05). Inhibition of the MAPK-ERK1/2 pathway with PD0325901 resulted in suppressed expressions of the osteogenic genes and PCNA. CONCLUSION: The activation of MAPK-ERK1/2 pathway promotes the expression of osteogenic genes such as Runx2, type I collagen and ALP and enhances the proliferative activity of the osteoblasts, while inhibition of this pathway suppresses the expressions of these genes and the cell proliferation, suggesting that this pathway may potentially serve as a therapeutic target for osteoporosis. PMID- 24144742 TI - [Neurogenesis in the dentate gyrus of the hippocampus in a rat model of intracerebral hemorrhage]. AB - OBJECTIVE: To investigate whether intracerebral hemorrhage (ICH) can promote neurogenesis in the dentate gyrus (DG) of rat hippocampus. METHODS: Western blot analysis, immunohistochemical staining, and immunofluorescent double labeling combined with confocal microscope were used to detect neurogenesis in the DG of the hippocampus in rats after ICH. RESULTS: The expression of DCX protein in the ipsilateral DG of the hippocampus was enhanced in the rats 1 day after ICH (0.202?0.062) as compared with that in normal rats (0.127?0.088), reaching the peak level at 14 days (0.771?0.108, P<0.01) and beginning to decrease at 28 days (0.582?0.121, P<0.01). Meanwhile, DCX-positive cells and BrdU-positive cells, and DCX/BrdU double-labeled cells were detected in the DG of the hippocampus. Compared with those in the control group, BrdU/NeuN double-labeled cells were markedly increased in the granular cell layer of the DG at 28 days after ICH (1.808?1.020 vs 5.654?1.671, P<0.01). CONCLUSION: ICH can promote neurogenesis in the DG of rat hippocampus. PMID- 24144743 TI - [Effects of Xixin decoction on enzymes related to O-GlcNAc glycosylation of tau proteins in the brain of rats with sporadic Alzheimer's disease]. AB - OBJECTIVE: To study the effects of Xixin decoction (XXD) on O-GlcNAc transferase (OGT) and O-GlcNAc glycosidase in O-GlcNAc glycosylation of tau proteins in the brain of rats with sporadic Alzheimer's disease (SAD) and explore the possible mechanism. METHODS: Male SD rats were randomly divided into sham-operated group, model group, donepezil group, and low-, moderate-, and high-dose XXD groups. After treatment and behavioral test, the rats were sacrificed for detecting the expressions of OGT and O-GlcNAc glycosidase in the brain using immunohistochemistry and Western blotting. RESULTS: XXD significantly enhanced the expressions of OGT in the hippocampus of SAD rats and lowered the expression of O-GlcNAc glycosidase (P<0.05 or 0.01). OGT and O-GlcNAc glycosidase expressions showed no significant differences between the model group and donepezil group (P>0.05). CONCLUSION: XXD can regulate the expression of OGT and O-GlcNAc glycosidase to enhance O-GlcNAc glycosylation of tau proteins in the hippocampus of SAD rats. PMID- 24144744 TI - [Evaluation of different pathological staining methods for classifying renal amyloidosis]. AB - OBJECTIVE: To analyze the effect of special staining and immunohistochemical staining in distinguishing the types of renal amyloidosis to improve the diagnosis accuracy. METHODS: Congo red staining with different methods, and immunohistochemical staining of Kappa, Lambda and Amyloid A with different antigen retrieval methods were used for staining frozen and paraffin-embedded renal tissue sections. RESULTS: Wright's Congo red staining produced a better contrast and a higher resolution and showed a greater stability than the other 2 methods after repeated use for staining the renal tissue sections (P<0.05). Immunofluorescent staining produced better results in frozen renal tissue sections than in paraffin-embedded tissues. Immunofluorescent staining produced had better performance than immunohistochemical staining in paraffin-embedded tissues. The retrieval effect with protein kinase K was the best among the antigen retrieval methods in paraffin-embedded tissues. CONCLUSION: Wright's Congo red staining is better than the other 2 methods in diagnosing renal amyloidosis. Immunohistochemical staining of Kappa, Lambda and Amyloid A in frozen renal tissue sections is necessary to discriminate the types of renal amyloidosis. For paraffin-embedded renal tissues, antigen retrieval using protein kinase K is better than the other 2 methods. PMID- 24144745 TI - [Comparison of chemical components between Baishao and Chishao water extracts and their effects on proliferation of rat thoracic aorta smooth muscle cells]. AB - OBJECTIVE: To compare the chemical components in Baishao and Chishao water extracts and investigate their effects on the proliferation of rat thoracic aorta smooth muscle cells in vitro. METHODS: The contents and chemical structures of monomers separated from the water extracts of Baishao and Chishao were analyzed using high-performance liquid chromatography and mass spectroscopy. Rat thoracic aorta smooth muscle cell line A7r5 and its platelet-derived growth factor-BB (PDGF-BB)-induced proliferation model were exposed to different concentrations of Baishao and Chishao water extracts, and the cell viability was analyzed by mitochondrial-dependent reduction of MTT and real-time cell analyzer. RESULTS: The growth of A7r5 cells was significantly stimulated by 300 ug/ml Baishao water extract (P<0.01), but Chishao water extract produced no such effect (P>0.05). In PDGF-BB-induced cell proliferation model, the cell growth was significantly suppressed by 100-500 ug/ml Chishao water extract (P<0.01), while Baishao water extract showed no obvious effect on the cell proliferation (P>0.05). CONCLUSION: Baishao and Chishao water extracts have different chemical components and produce different biological effects. PMID- 24144746 TI - [Correlation between serum marker variations and pulmonary hypertension secondary to chronic obstructive pulmonary disease]. AB - OBJECTIVE: To examine the correlation of the changes in the serum markers (C reactive protein, endothelin-1, interleukin-6, and brain natriuretic peptide) with chronic obstructive pulmonary disease (COPD) and pulmonary hypertension secondary to COPD. METHODS: A total of 174 COPD patients with acute exacerbation, admitted between February 2011 and February, 2013, were enrolled in this study, with 43 volunteers with normal pulmonary functions as controls. Pulmonary arterial pressure was determined by Doppler echocardiograph, and the severities (mild, moderate and severe) of PH secondary to COPD was evaluated. The levels of serum markers were determined using ELISA kits. RESULTS: The levels of serum markers in patients with COPD was significantly elevated compared with those of the control subjects (P<0.05), and further increased in patients with pulmonary hypertension secondary to COPD (P<0.05). A positive correlation was found between these serum markers and pulmonary artery pressure in COPD patients with mild and moderate pulmonary hypertension. In patients with severe pulmonary hypertension, only the serum level of brain natriuretic peptide continued to increase with pulmonary artery pressure (P<0.05), and the other markers did not further increase. CONCLUSIONS: Early and combined examination of these serum markers in patients with COPD can help to identify pulmonary hypertension in early stage and estimate the severity of pulmonary hypertension. Hemodynamic monitoring of the changes of these serum markers can be of important clinical value in the treatment of pulmonary hypertension secondary to COPD and in evaluation of the prognosis of COPD. PMID- 24144747 TI - [Effects of peroxisome proliferator-activated receptors gamma on the expression of insulin receptor substrate-4 gene in rat cortical neurons and mouse brain]. AB - OBJECTIVE: To investigate the effect of peroxisome proliferator-activated receptors gamma (PPARgamma) on insulin receptor substrate-4 (IRS-4) gene expression in the brain. METHODS: Primarily cultured cortical neurons from E17-18 Sprague Dawley rats, after 1 week of plating, were exposed to 10 umol/L PPARgamma agonist rosiglitazone for 0, 1, 4 or 24 h. Adult C57BL/6J mice or conditional brain PPARgamma knock-out mice (B-PPARgamma-KO, BKO) received an intraperitoneal injection of rosiglitazone in 10% DMSO at 12 mg/kg or injection of the same volume of saline containing 10% DMSO. The effect of rosiglitazone on the survival of the neurons was examined by MTT assay. The expression of IRS-4 mRNA was analyzed by real-time quantitative PCR. RESULTS: The survival of the cortical neurons showed no significant difference between the agonist groups and the control group. The expression of IRS-4 mRNA was significantly up-regulated in the cortical tissues and neurons of the agonist groups compared with the control groups (P<0.05), but in BKO mice without treatment, IRS-4 mRNA expression was significantly down-regulated (P<0.05). CONCLUSION: PPARgamma can enhance the expression of IRS-4 mRNA in the brain. PMID- 24144748 TI - [Voiding urosonography with SonoVue and fluoroscopic voiding cystourethrography in evaluation of vesicoureteral reflux: a comparative study]. AB - OBJECTIVE: To assess the value of voiding urosonography (VUS) with SonoVue in evaluation of vesicoureteral reflux. METHODS: Thirty-six pediatric patients (72 pyeloureter units [PUUs]) suspected of vesicoureteral reflux underwent both VUS and fluoroscopic voiding cystourethrography (VCUG). The sensitivity of VUS and VCUG and their consistency in detecting vesicoureteral reflux as well as in grading vesicoureteral reflux were compared. RESULTS: Vesicoureteral reflux was detected in 26 of the 72 PUUs (36.1%) by VUS while in 21 PUUs (29.2%) by VCUG (P=0.347). The two modalities yielded the same results for 65 PUUs (kappa=0.843), showing a very good consistency between them. VUS also detected post-urethral valve in 2 patients via transperineal scans. CONCLUSION: VUS with Sonovue has at least comparable, if not better, sensitivity in detecting vesicoureteral reflux with VCUG, and therefore should serve as the primary screening and follow-up modality for vesicoureteral reflux. In addition, transperineal VUS can be helpful in evaluation of post-urethral lesions. PMID- 24144749 TI - [Effects of parthenolide on high glucose-induced cell proliferation, NF-kappaB activation and MCP-1 expression in rat mesangial cells]. AB - OBJECTIVE: To explore the effects of parthenolide (PTL) on high glucose stimulated cell proliferation, NF-kappaB activation and monocyte chemoattractant protein-1 (MCP-1) expression in rat mesangial cells (MCs). METHODS: MCs were cultured in normal glucose (5.6 mmol/L), high glucose (30 mmol/L), or high glucose with PTL. MTT assay was used to detect the cell proliferation. MCP-1 content in the supernatant was measured by ELISA, and the level of IkappaBalpha was detected by Western blotting to reflect NF-kappaB activity. EMSA method was used to measure the activation of NF-kappaB. RESULTS: MC proliferation, MCP-1 expression and NF-kappaB activation were significantly enhanced and the expression of NF-kappaB-binding protein IkappaBalpha was obviously reduced in cells cultured in high glucose. Application of PTL obviously abolished the effects of high glucose. CONCLUSION: PTL can suppress high glucose-stimulated NF kappaB activation and MCP-1 expression in rat MC. These data provide a theoretical basis for the clinical application of PTL in prevention and control of diabetic nephropathy. PMID- 24144750 TI - [Changes of fecal flora and its correlation with inflammatory indicators in patients with inflammatory bowel disease]. AB - OBJECTIVE: To investigate the changes in fecal flora and its correlation with the occurrence and progression of inflammatory bowel disease (IBD). METHODS: We collected fresh fecal specimens from 167 IBD patients (including 113 with ulcerative colitis and 54 with Crohn's disease) and 54 healthy volunteers. The fecal flora was analyzed by gradient dilution method and the data of inflammatory markers including WBC, PLT, CRP and ESR were collected to assess the association between the fecal flora and the inflammatory markers. RESULTS: The species Enterrococcus (6.60?0.23, P<0.01), Saccharomyces (2.22?0.27, P<0.05), Bacteriodes (5.57?0.28, P<0.001), Bifidobacterium (5.08?0.30, P<0.01), Peptococcus (6.22?0.25, P<0.001), Lactobacillus (6.00?0.26, P<0.001), and Clostridium (3.57?0.30, P<0.05) all increased significantly, while Eubacterium (1.56?0.24, P<0.01) reduced markedly in patients with ulcerative colitis compared with those in the control subjects. Enterrococcus (6.93?0.28, P<0.01), Saccharomyces (2.73?0.37, P<0.01), Bacteriodes (4.32?0.52, P<0.05), Bifidobacterium (4.88?0.42, P<0.05), Peptococcus (6.19?0.32, P<0.01) and Lactobacillus (4.73?0.47, P<0.001) all increased significantly and Eubacterium (1.01?0.29, P<0.01) and Clostridium (0.87?0.31, P<0.01) decreased in patients with Crohn's disease. The positivity rates of bacterial culture were consistent with the results of quantitative analysis of the fecal flora. The changes in fecal flora did not show a significant correlation with these inflammatory markers. CONCLUSION: IBD patients have fecal flora imbalance compared with the healthy controls, and this imbalance may contribute to the occurrence and progression of IBD. The decline of Eubacterium contributes to the occurrence and development of IBD. PMID- 24144751 TI - [Renal arterial spin labeling magnetic resonance imaging in normal adults: a study with a 3.0 T scanner]. AB - OBJECTIVE: To analyze the renal relative blood flow value (rBFV) and image quality in normal adults using single-shot fast spin echo, flow sensitive invention recovery (SSFSE-FAIR) magnetic resonance (MR) sequence and echo planar imaging, and flow sensitive invention recovery (EPI-FAIR) MR sequence, and assess its value for clinical application in routine renal examination. METHODS: Forty volunteers (25 male and 15 female adults, aged 30 to 62 years) with normal renal function were included in this prospective study. All the subjects underwent 3.0 Tesla MR scanning using 3 MR scan modes, namely breath-holding EPI-FAIR, breath holding SSFSE-FAIR and free breathing SSFSE-FAIR. RESULTS: SSFSE-FAIR without breath-holding was capable of differentiating the renal cortex and medulla with the corresponding rBFVs of 111.48?9.23 and 94.98?3.38, respectively. Breath holding SSFSE-FAIR and EPI-FAIR failed to distinguish the borders of the renal cortex and medulla. The EPI-FAIR rBFV of mixed cortex and medulla value was 178.50?17.17 (95%CI: 167.59, 189.41). CONCLUSION: Breath-holding SSFSE-FAIR and EPI-FAIR can not distinguish the renal cortex and medulla due to a poor spatial resolution but can be used for rough evaluation of renal blood perfusion. Free breathing SSFSE-FAIR with an improved spatial resolution allows evaluation of the status of renal perfusion of the cortex and medulla. PMID- 24144752 TI - [Screening molecular markers in early breast cancer of the same pathological types but with different prognoses using Agilent gene chip]. AB - OBJECTIVE: To screen molecular markers in early breast cancer and establish gene subtyping-based diagnostic criteria for predicting the prognosis of early breast cancers. METHODS: Tumor tissue specimens were obtained from 8 patients with early breast cancer for analysis of the differentially expressed genes using Agilent custom 8*15 000 chips in combination with the prognostic data of the patients. Another 42 tumor tissue specimens were used to validate the differential genes by real-time fluorescent quantitative PCR. RESULTS: Gene microarray analysis identified 132 differentially expressed genes between the patients with favorable and poor prognosis, and 44 of these genes were significantly up-regulated (by over two folds) and 88 down-regulated in patients with poor prognoses. CONCLUSION: The gene expression profiles differ in early breast cancer tissues of the same pathological type but with different clinical stages and prognoses, and CD44, MKI67, NTRK2, Nek2, C16orf60, TOP2A, ANCCA, and RRM2 genes can be used as the prognostic markers for early breast cancer. PMID- 24144753 TI - [Effect of mild to moderate hypothermia on casepase-3, Bcl-2 and Bax expressions in brain tissue of rats after cardiopulmonary resuscitation]. AB - OBJECTIVE: To explore the effect of mild to moderate hypothermia on the expressions of apoptosis-related genes in the brain tissue of rats after cardiopulmonary resuscitation (CPR). METHODS: CPR models were established by asphyxia in 15 male SD rats, which were randomized equally into normal temperature group, 34 degrees celsius hypothermia group and 32 degrees celsius hypothermia group. The brain tissues of the rats were obtained after treatment for 12 h to observe the pathological changes. The expression of caspase-3 in cerebral cortex neurons was determined with immunohistochemistry, and the expressions of Bcl-2 and Bax were detected by Western blotting. RESULTS: Compared with normal temperature group, the two hypothermia groups (especially 32 degrees celsius group) showed significantly decreased expression of caspase-3 in the cortical neurons (P<0.05). Bcl-2 protein expression was significantly increased in the hypothermia groups, especially in 32 degrees celsius hypothermia group (P<0.05). There was no significant difference in Bax protein expression among the 3 groups. CONCLUSION: Mild hypothermia can relieve brain injury by down regulating caspase-3 expression and up-regulating Bcl-2 protein expression to inhibit apoptosis of the brain neurons. Hypothermia at 32 degrees celsius offers better protection of the brain tissue than hypothermia at 34 degrees celsius. PMID- 24144754 TI - [Effect of Notch1 signaling pathway activation on pancreatic cancer cell proliferation in vitro]. AB - OBJECTIVE: To observe the effect of activation of Notch1 signaling pathway by Notch intracellular domain (NICD) plasmid transfection on pancreatic cancer cell proliferation and explore the underlying mechanism. METHODS: The transfection rates were observed under microscope with fluorescence stimulation, and mRNA expression levels of Hes1 were detected by real-time PCR. Cell proliferation changes were evaluated by CCK-8 after NICD and control plasmid transfection in pancreatic cancer cells. Caspase 3 activity was examined using a caspase 3 detection kit. RESULTS: The transfection rates of NICD plasmid were up to 80% by fluorescence stimulation observation. Hes1 expression was significantly increased after NICD plasmid transfection, suggesting the activation of Notch1 signaling pathway. NICD plasmid transfection significantly promoted cancer cell proliferation compared to control plasmid transfeciton. The activities of caspase 3 were obviously decreased after NICD plasmid transfection in 3 pancreatic cancer cell lines. CONCLUSION: Activation of Notch1 signaling pathway by NICD plasmid transfection can promote the proliferation of pancreatic cancer cells by inhibiting the apoptosis pathway. PMID- 24144755 TI - [Glucagon-like peptide-1 regulates lipometabolism by down-regulating adipose triglyceride lipase in 3T3-L1 adipocytes]. AB - OBJECTIVE: To investigate the effect of glucagon-like peptide-1 (GLP-1) on glycolipid metabolism in 3T3-L1 adipocytes and explore the mechanism. METHODS: 3T3-L1 adipocytes were treated with GLP-1, insulin, or both for 24 h, and Western blotting was used to analyze the expression levels of adipose triglyceride lipase (ATGL), glucose transporter type 4 (GLUT4), Akt1, Akt2 and phosphorylated Akt in the cells. Immunofluorescence was used to observe lipid content in 3T3-L1 adipocytes. RESULTS: Akt1 and Akt2 were not activated by insulin stimulation in 3T3-L1 adipocytes. Akt was phosphorylated by GLP-1 stimulation, which inhibited the expression of ATGL and increased the translocation of GLUT4 from the intracellular membranes to plasma membranes. These changes were more obvious under the synergistic effect of insulin in 3T3-L1 adipocytes. CONCLUSION: GLP-1 decreases lipolysis by inhibiting the expression of ATGL and improves insulin resistance by increasing the translocation of GLUT4 in 3T3-L1 adipocytes. PMID- 24144756 TI - [Effect of pretreatment with apoptotic donor spleen cells on spleen lymphocyte function of recipient rats after islet transplantation]. AB - OBJECTIVE: To study the effect of pretreatment with apoptotic donor spleen cells on spleen lymphocyte function of recipient rats undergoing islet transplantation to explore new approaches to prolong islet graft survival. METHODS: Apoptotic spleen cells from donor rats were obtained by exposure to gamma-ray irradiation from (60)Co. Diabetic SD rat models were randomly divided into 4 groups to receive tail vein injections with saline (group A), normal cells (group B), apoptotic donor cells (group C), or necrotic donor cells (group D). One week later, orthotopic transplantation of islets under the renal capsule was performed. Before and at 1 and 2 weeks after islet transplantation, the recipient rats were examined for proliferative activity of spleen lymphocytes with CFSE cell staining and for IL-2 and IL-10 expressions in the cells using ELISA. RESULTS: Pretreatment with donor apoptotic cells significantly suppressed the proliferative activity of recipient spleen lymphocytes before and at 1 and 2 weeks after islet transplantation as compared with the other three groups (P<0.05). The level of IL-2 was significantly decreased while IL-10 increased in apoptotic donor cell pretreatment group compared with those in the other 3 groups at each time point of observation. CONCLUSION: The effect of pretreatment with apoptotic donor cells on recipient spleen lymphocytes suggest an important role of apoptotic donor spleen cells in immune tolerance of grafts. PMID- 24144757 TI - [Association of T393C single nucleotide polymorphism of GNAS1 gene with non valvular atrial fibrillation]. AB - OBJECTIVE: To analyze the association between T393C single nucleotide polymorphism (SNP) of GNAS1 gene and non-valvular atrial fibrillation (AF) in Chinese Han patients. METHODS: Ninety patients with non-valvular AF and 90 healthy subjects were examined for T393C SNP of GNAS1 gene using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). The allele genotypes and the distribution of allele frequencies were analyzed and compared between the two groups. The relationship between allele frequency distribution characteristics and the heart rate variability (HRV) were also studied for analysis of the association between T393C SNP of GNAS1 gene and the autonomic nervous activation in non-valvular AF. RESULTS: The two groups showed a significant difference in the frequencies of genotypes of T393C SNP of GNAS1 gene and allele frequencies (P<0.01). CC genotype and T393C allele frequency were significantly increased in the case group. pNN50, LF, or LF/HF showed no significant difference between different genotypes (P<0.05). CONCLUTIONS: The T393C SNP of GNAS1 gene is closely associated with non-valvular AF in Chinese Han patients. PMID- 24144758 TI - [Human stem cells from apical papilla can regenerate dentin-pulp complex]. AB - OBJECTIVE: To regenerate dentin-pulp complex by tissue engineering with human stem cells from apical papilla cells (SCAP) as the seed cells. METHODS: SCAP was separated from from normal human impacted third molars with immature roots by outgrowth culture. The cells were then cultured in the differentiation medium for 3 weeks or in normal medium for 60 days, and analyzed for mineralization potential by Alizarin red staining. The osteo/odontogenic markers including alkaline phosphatase (ALP), bone sialoprotein (BSP), osteocalcin (OC) and dentin sialoprotein (DSP) were investigated by immunofluorescence staining and reverse transcription-polymerase chain reaction. The co-cultured mixture of SCAP and HA/TCP, or HA/TCP alone was implanted subcutaneously on the back of nude mice for 8 weeks, and the implants were collected and examined by HE and immunohistochemical staining. RESULTS: Round alizarin red-positive nodules formed in the isolated cells after cell culture in the differentiation medium for 3 weeks or in normal medium for 60 days with positive staining for osteo/odontogenic markers. SCAP with HA/TCP could regenerate pulp-dentin complex like tissue in nude mice. The cells near the dentin-like tissue were positive for DSP. No mineral tissue was found in mice receiving HA/TCP implantation. CONCLUSIONS: SCAP may serve as a promising seed cell for dentin-pulp complex tissue engineering. PMID- 24144759 TI - [Transplantation of pedicled autologous sinoatrial node tissue for treatment of complete atrioventricular block in dogs]. AB - OBJECTIVE: To observe the changes of surface ECG and cell couplings between sinoatrial node cells and myocardial cells following transplantion of pedicled autologous sinoatrial node tissue graft into the right ventricle of a canine model of complete atrioventricular block. METHODS: Ten healthy dogs were randomized into transplantation group and control group. Pedicled autologous sinoatrial node tissue grafts were transplanted into the right ventricle in the transplantation group, while the sinoatrial nodes were only excised in the control group after placement of temporary myocardial pacing wires. The changes of surface ECG were observed at 1, 2, 3 and 4 weeks postoperatively. At 4 weeks, complete atrioventricular block was induced in the dogs by radiofrequency ablation of the His bundle. The heart rate of the dogs in both groups were recorded after the injection of isoproternol (ISO) from the femoral vein, and the transplanted tissue graft was observed under optical and transmission electron microscopes. RESULTS: No significant changes occurred in the surface ECG. All the dogs showed ECG waveforms specific of complete heart block after the ablation, and the ventricular heart rates were similar between the two groups (P>0.05). The ventricular heart rate did not undergo obvious changes after ISO injection (P>0.05). The transplanted pedicled autologous sinoatrial node survived in the dogs and the sinoatrial node cells established desmosome junctions with the myocardial cells, but the number of junctions was not sufficient to support heart pacing. CONCLUSION: Desmosome junction can occur between ventricular myocardial cells and sinoatrial node cells at the edge of transplanted pedicled autologous sinoatrial node tissue. PMID- 24144760 TI - [Clinical efficacy and safety of sequential treatment with alprostadil and beraprost sodium for chronic renal failure induced by chronic glomerulonephritis]. AB - OBJECTIVE: To evaluate the clinical efficacy and safety of sequential treatment with alprostadil and beraprost sodium for chronic renal failure caused by chronic glomerulonephritis. METHODS: Sixty-three patients with chronic renal failure due to chronic glomerulonephritis, after receiving a 2-week-long conventional treatment, were randomly divided into alprostadil group (n=20, with alprostadil injection at 10 ug/d for 2 weeks), sequential treatment group (n=21, with alprostadil injection at 10 ug/d for 2 weeks and oral beraprost sodium at 20 ug three times a day for 12 weeks), and strengthened sequential treatment group (n=22, with alprostadil injection at 20 ug/d for 2 weeks and a double dose of oral beraprost sodium for 12 weeks). Urinary albumin excretion rate (UAER), cystatin C (Cys C), blood urea nitrogen, creatinine, fibrinogen, D-dimer, prothrombin time (PT), and platelets were tested before and after the treatment, and the changes in urinary albumin discharge rate, serum creatinine, and glomerular filtration rate were determined. RESULTS: The patients in strengthened sequential treatment group showed a significantly decreased change rate of urinary albumin discharge rate (P<0.01) than those in the other two groups. In the two sequential treatment groups, especially the strengthened treatment group, the change rate of glomerular filtration rate increased significantly compared with that in alprostadil group (P<0.01). Strengthened sequential treatment resulted also in significantly decreased increment of serum creatinine compared that in the other 2 groups (P<0.01). After 14 weeks of treatment, fibrinogen and D-dimer were decreased in all the 3 groups (P<0.05) to a comparable level between the 3 groups (P>0.05), and prothrombin time (PT) or platelet showed no significant changes (P>0.05). CONCLUSION: Sequential treatment with alprostadil and beraprost sodium can improve the glomerular filtration rate and decrease urine albumin excretion rate, serum creatinine increase rate, and lower blood fibrinogen and D-dimer levels, thus delaying the progression of chronic renal failure caused by chronic glomerulonephritis. This therapy shows a dose-related effect with good clinical safety. PMID- 24144761 TI - [Comparative study of glucocorticoids versus NSAIDS for treatment of partial splenic embolization syndrome]. AB - OBJECTIVE: To compare the clinical effect of glucocorticoids and NSAID in the treatment of partial splenic embolization syndrome. METHODS: Sixty patients with cirrhosis and spleen hyperactivity who developed partial splenic embolization syndrome after partial splenic embolization with Seldinger technique were randomized equally into two groups to receive treatments with intravenous dexamethasone or oral nonsteroidal anti-inflammatory drugs (NSAIDs). White blood cell counts, liver functions, fever duration, abdominal pain duration, hospital stay, and occurrence of upper gastrointestinal hemorrhage and spleen abscess were recorded and analyzed. RESULTS: In dexamethasone group, the average fever duration, abdominal pain duration, and hospitalization days was 3.36?2.31, 7.39?4.00, and 11.48?3.29 days, respectively, significantly shorter than those in NSAIDs group (5.72?3.83, 9.59?4.22, and 15.07?7.93 days, respectively, P<0.05). Seven days after the operation, white blood cell count (*10(9)=L) significantly increased from 4.23?5.09 to 8.49?3.53 in dexamethasone group (P<0.05), and from 3.21?1.33 to 6.52?2.37 in NSAIDs group (P<0.05); the increment was more obvious in dexamethasone group (P<0.05). The two groups of patients showed no significant difference in liver functions after the operation. None of the patients developed upper gastrointestinal hemorrhage or spleen abscess. CONCLUSION: Intravenous dexamethasone produces better therapeutic effect than oral NSAIDs in the management of partial splenic embolization syndrome. PMID- 24144762 TI - [Ultrasound-guided percutaneous laser ablation for benign solid thyroid nodule: a pilot study]. AB - OBJECTIVE: To evaluate the method, safety and short-term efficacy of ultrasound guided percutaneous laser ablation (PLA) for benign solid thyroid nodule (BSTN). METHODS: The treatment group consisting of 12 patients with single BSTN were treated with ultrasound-guided PLA. After treatment, the size and blood flow signals in conventional ultrasonography, the ablation extent of lesions in contrast-enhanced ultrasonography (CEUS), and the related complications and thyroid function were assessed in comparison with the the baseline. A control group including 12 untreated patients with single BSTN was followed-up in the same manner as in the treatment group. RESULTS: In the treatment group, all the 12 patients completed the treatment successfully. During the follow-up, the volume of the nodules was reduced gradually (P<0.05), and blood flow signals in the nodules disappeared. Eleven nodules were non-enhanced in CEUS immediately after the treatment, and the complete ablation rate was 91.7%. During the operation, 3 patients complained of intolerable pain, which was ameliorated or totally relieved after appropriate treatment. The thyroid function showed no significant changes after the treatment (P>0.05). The control group followed up for 6 months showed no significant changes in the nodule volume or thyroid function in comparison with the baseline (P>0.05). CONCLUSION: Ultrasound-guided PLA is a safe and effective minimally invasive treatment of BSTN without obvious adverse effect on thyroid function. PMID- 24144763 TI - [Comparison of anterior chamber depth measured by anterior segment optical coherence tomography and ultrasound biomicroscopy: a meta-analysis]. AB - OBJECTIVE: To compare the differences in the anterior chamber depth (ACD) measured by anterior segment optical coherence tomography (AS-OCT) and ultrasound biomicroscopy (UBM). METHODS: All studies pertaining to ACD measured by AS-OCT and UBM were collected from online databases. The assessment of methodological quality and data extraction from the included studies were performed independently by two reviewers for meta-analysis. RESULTS: Eight studies involving 710 eyes were included in the analysis. The difference of ACD measurements between AS-OCT and UBM was not statistically significant in the overall patients included for analysis (SMD=0.19, 95%CI [0.00, 0.39]) or in the patients with primary angle-closed glaucoma (SMD=0.02, 95%CI[-0.04,0.19]). CONCLUSIONS: The ACD measurements do not differ significantly between AS-OCT and UBM. Due to the relatively small number of the included studies and the patients involved, this conclusion needs further confirmation by high-quality studies involving larger sample sizes. PMID- 24144764 TI - [Surgical strategy for management of postoperative stenosis of ateriovenous fistula in patients with end-stage renal disease]. AB - OBJECTIVE: To explore the surgical approaches for management of postoperative stenosis of ateriovenous fistula (AVF) in patients with end-stage renal disease (ESRD). METHODS: Of the 415 patients with ESRD receiving radial-cephalic end-to side anastomosis during the last 3 years, 29 developed postoperative AVF stenosis (of type Ia in 5 cases, type Ib in 17 cases, type II in 3 cases, and type II in 2 cases). A proximal anastomosis was created between the radical artery and cephalic vein for type Ia stenosis. In the 17 cases with type I b stenosis, 5 were managed by interception of suitable segments from the accessory cephalic veins for cephalic vein reconstructions, and 12 by transposition of the accessory cephalic veins. Of 3 cases with type II stenosis, 1 was managed by interception of the accessory cephalic vein for interposing into the cephalic vein, 1 by interception of the distal great saphenous vein for interposing into the cephalic vein, and 1 by transposition of the forearm basilic vein for end-to-side anastomosis with the radial artery. The 2 cases with type III were managed by end to-side anastomosis between the forearm basilic vein and the radial artery or by conversion to AVF repair on the contralateral forearm. RESULTS: Twenty-eight of the 28 patients finally received surgical repair of AVF stenosis and the surgeries were completed successfully. Thrombosis of the outflow vein occurred 12 h after the repair in 1 case to require emergency embolectomy and anastomosis; restenosis occurred in 2 cases at 9 months postoperatively, for which progressive percutaneous transluminal angioplasty (PTA) was performed. The rate of restenosis was 7.1% (2/28). All the 28 patients undergoing AVF stenosis repair had successful HD for 12 months after the operation. CONCLUSION: Reconstructing the arteriovenous anastomosis, replacing the stenosis segment with an accessory cephalic vein or great saphenous vein graft, or altering the outflow with the forearm basilic vein can be surgical options for repairing postoperative AVF stenosis. PMID- 24144765 TI - [A training model for laparoscopic dismembered pyeloplasty]. AB - OBJECTIVE: To introduce a training model for laparoscopic dismembered pyeloplasty. METHODS: The model of ureteropelvic junction obstruction was simulated using pig kidney and chicken crop. With the model placed in a training box, 8 residents without laparoscopic experience but with basic technical training performed 10 rounds of anastomosis according to the standard operation procedures. For each resident, the operating time and quality of the operation were recorded and assessed. RESULTS: All the 8 residents successfully completed the training. The operating time decreased from 72.70?8.26 min in the first training session to 54.50?7.69 min in the last training session, and the anastomosis error score decreased from 5.60?1.35 to 2.50?1.58 min, showing significant differences between the recordings (P<0.05). CONCLUSION: This simple training model allows effective simulation of the surgical procedures of laparoscopic pyeloplasty and is suitable for training surgeons without laparoscopic experiences. PMID- 24144766 TI - [Pulmonary expression of Nr1d1 in rats with ventilation-induced lung injury]. AB - OBJECTIVE: To investigate the changes in the expression of nuclear receptor subfamily1 (Nr1d1) in the lungs of rats with ventilation-induced lung injury and explore the molecular mechanism. METHODS: Seventy-two rats were randomly divided into 4 groups for observation at 4 time points (1:00 AM, 7:00 AM, 1:00 PM and 7:00 PM), and each group was further divided into 3 subgroups (Group FB, Group LV and Group HV). After ventilation for 3 h, the rats were sacrificed and lung tissue samples were obtained for testing the expression of Nr1d1 using gene chip technology and RT-PCR. RESULTS: Nr1d1 gene expression was down-regulated in HV group as shown by gene chip RT-PCR data. Cosine analysis showed that Nr1d1 expression exhibited a rhythmicity in FB group (P<0.05). CONCLUSION: The rhythmicity of Nr1d1 expression disappears as the tidal volume the increase. Diminished Nr1d1 expression is closely correlated with ventilation-induced lung injury in rats. PMID- 24144767 TI - [Comparison of dissolution properties between Ginseng micropowder and common powder]. AB - OBJECTIVE: To compare the dissolution properties of Ginseng micropowder and common powder in vitro and investigate the effect of micronization on dissolution of Ginseng. METHODS: Five ginsenosides including Rg1, Re, Rf, Rb1, and Rb2 were determined by high performance liquid chromatography, and the dissolution curves of Ginseng micropowder and common powder were drawn. RESULTS: The dissolution rates of ginsenosides from micropowder exceeded 90% within 5 min, significantly greater than that from common powder. But when the powders were packed in tea bags, the dissolution rates of ginsenosides were higher from common powder than from micropowder. CONCLUSION: Micronization treatments can promote dissolution of ginsenosides from Ginseng. PMID- 24144768 TI - [Detection of plasma cofilin protein for diagnosis of lung cancer]. AB - OBJECTIVE: To detect serum content of cofilin protein in patients with lung cancer and investigate its clinical value. METHODS: The serum content of cofilin protein was detected in 30 cases of lung cancer and 30 healthy control subjects using enzyme-linked immunosorbent assay. RESULTS: The mean serum content of cofilin protein was 0.485?0.465 ng/ml in patients with lung cancer and 0.203?0.102 ng/ml in the control subjects, showing a significant difference between them (P<0.05). The content of cofilin protein in patients with stage III and IV lung cancer 0.744?0.584 ng/ml, significantly higher than that in stage II patients (0.257?0.126 ng/ml). CONCLUSION: Serum cofilin protein is elevated in patients with lung cancer, especially in cases in advanced stages, suggesting its relation with lung cancer staging. PMID- 24144769 TI - [Apatite-forming ability of pure titanium implant after micro-arc oxidation treatment]. AB - OBJECTIVE: To investigate the apatite forming ability of pure titanium implant after micro-arc oxidation treatment in simulated body fluid (SBF) and obtain implants with calcium phosphate (Ca-P) layers. METHODS: The implants were immersed in (SBF) after micro-arc oxidation treatment for different time lengths, and their apatite forming ability and the morphology and constituents of the Ca-P layers formed on the sample surface were analyzed using X-ray diffraction, scanning electron microscopy, X-ray photoelectron spectroscopy, and energy dispersive electron probe. RESULTS: After immersion in SBF, large quantities of Ca-P layers were induced on the surface of the samples. The Ca-P layers were composed of octacalcium phosphate and carbonated hydroxyapatite, and the crystals showed a plate-like morphology with an oriented growth. CONCLUSION: The implants with micro-arc oxidation treatment show good apatite forming ability on the surface with rich calcium and phosphorus elements. The formed layers are composed of bone-like apatite including octacalcium phosphate and carbonated hydroxyapatite. PMID- 24144770 TI - [Neonatal hyperthyroidism: a case report and literature review]. AB - OBJECTIVE: We report a case of neonatal thyrotoxicosis with concurrent respiratory failure in an infant born to a mother with Graves' disease and review the published literature describing neonatal hyperthyroidism. The male infant who was born by spontaneous delivery at 35 weeks of gestational age presented with fever, tachycardia and tachypnea at rest on day 11 after birth, and developed severe apnea on day 14. Thyroid function studies revealed hyperthyroidism in the infant, and his mother was confirmed to have Grave's disease during pregnancy. Literature review showed that among the 33 infants with similar conditions, tachycardia, tachypnea and poor weight gain were the most distinct clinical features of congenital hyperthyroidism. Accurate diagnosis of Graves' disease in the mother during pregnancy and awareness of the clinical presentations of neonatal hyperthyroidism are key to reducing missed diagnosis or misdiagnosis of neonatal hyperthyroidism. PMID- 24144771 TI - Head and pelvic movement symmetry in horses during circular motion and in rising trot. AB - Lameness examinations in horses often include lungeing and ridden exercise. To incorporate these exercises into the evidence-based decision making process aided by quantitative sensor based gait analysis, guideline values for movement asymmetry are needed. In this study, movement symmetry (MS) was quantified in horses during unridden and ridden trot on the straight and on the circle. Systematic changes in MS were expected as a result of the 'asymmetrical loading' caused by circular movement, the rising trot and the combination of the two. Out of 23 horses (age 4-20 years, height 13.3-17.2 hands), 13 presented within normal limits for head movement and 22 for pelvic movement. Inertial measurement units assessed MS of vertical head and sacral movement during trot in-hand, on the lunge and in rising trot (straight, left/right circle). Changes in MS between straight line trot and ridden exercise on the circle were more pronounced for the head than for the sacrum. The highest amount of asymmetry was observed during rising trot on the circle (symmetry index of the head: 1.23 for the left rein, 0.83 for the right rein; symmetry index of the sacrum 0.84 for the left rein, 1.15 for the right rein). Change in MS was significant between exercise conditions except for the difference between head displacement maxima. Horses had greatest asymmetry during rising trot on the circle, with MS values of comparable magnitude to mild lameness. PMID- 24144772 TI - Relationship between morphological and stabilographic variables in standing horses. AB - A stabilogram plots movements of the centre of pressure (COP) in the horizontal plane. Derived stabilographic variables quantify postural balance, but it is not known if these variables are size dependent. The aims of this study were to determine which morphological variable was most representative of size, which stabilographic variables were most representative of balance and whether size normalisation improved estimates of postural performance. Croup height (0.93-1.77 m), mass (117-666 kg), base of support (BOS) length (0.74-1.18 m) and BOS width (0.22-0.45 m) were measured in 24 horses. Stabilographic variables describing craniocaudal (CC), mediolateral (ML) and resultant amplitudes, velocities and frequencies of COP motion were measured as the horses stood stationary for 15s with fore and hind hooves on separate force plates (960 Hz). Principal component analysis identified morphological and stabilographic components. Morphological variables were consolidated into a single size component that was represented by body mass. Five stabilographic components explained 91% of the variation in sway patterns and five representative stabilographic variables were identified: CC amplitude, CC velocity, CC frequency, ML amplitude and ML frequency. Mass was correlated with CC velocity and ML frequency, with larger horses having smaller CC velocities and slower ML sway frequencies. When horses were grouped by mass (small horses <400 kg; large horses >= 400 kg), the within-group values for CC velocity and ML frequency were no longer correlated with mass. PMID- 24144773 TI - Practical use of a uterine score system for predicting effects on interval from calving to first insemination and non-return rate 56 in Danish dairy herds. AB - A detailed study of 398,237 lactations of Danish Holstein dairy cows was undertaken. The objective was to investigate the information gained by evaluating vaginal discharge in cows from 5 to 19 days post-partum (p.p.) using an ordinal scale from 0 to 9. The study focused on the interval from calving to first insemination (CFI) and the non-return rate 56 days after first insemination (NR56), adjusted for the confounders milk production and body condition score (BCS). For the analyses, BCS was evaluated on the same day that the uterine score was made. Milk production was defined as test-day milk yield in the first month p.p. The study showed that the evaluation of vaginal discharge according to this score system permitted ranking of cows according to CFI and NR56, i.e. an increasing uterine score was associated with a significantly longer time from calving to first insemination and significantly reduced the probability of success of the first insemination. Reproductive success was already affected if the uterine score had reached 4 (i.e. before the discharge smelled abnormally). The negative effect on CFI and NR56 increased as the uterine score increased, which suggested that the uterine scoring system was a useful guide to dairy producers. PMID- 24144774 TI - Synergistic anti-glioma effect of Hydroxygenkwanin and Apigenin in vitro. AB - Apigenin (AP) and Hydroxygenkwanin (HGK) are two natural flavonoid compounds. Previous studies have already demonstrated the anti-tumor capability of AP. However, it is not clear whether HGK has such property. In the current study, the anti-glioma activities of HGK and its synergistic anti-glioma effects with AP on C6 glioma cells were investigated. In addition, the possible mechanisms were also studied. MTT assay and morphologic analysis including acridine orange/ethidium bromide (AO/EB) and 4',6-diamidino-2-phenylindole (DAPI) staining were used in the research, and the results indicated that the treatment with AP or HGK could inhibit C6 glioma cell proliferation respectively. Moreover, when AP was administrated simultaneously, the anti-glioma effect of HGK was dramatically enhanced in a dose-dependent manner, which is obviously better than that of carmustine (BCNU) at the concentration 25MUM for treating of 24h. Compared with control, mitochondrial membrane potential (MPP) loss and mitochondrion damage were detected by JC-1 fluorescence probes (JC-1) and transmission electron microscopy (TEM) after treatment. Obvious DNA damage and cell cycle S phase arrest were detected by alkaline comet assay and flow cytometric analysis (FCM). Additionally, up regulation of TNF-alpha level, activations of caspase-3, -8, over expressions of BID and BAK protein and BCL-XL protein down expression were also observed after treatment by the combination of AP and HGK. The results indicate that HGK may be an effective natural product to treat glioma, and the combination of AP and HGK may be a promising method for glioma chemotherapy. PMID- 24144775 TI - Modulation of carbon tetrachloride-induced hepatic oxidative stress, injury and fibrosis by olmesartan and omega-3. AB - This study was designed to investigate the potential effects of omega-3, olmesartan and their combination on established hepatic fibrosis in the carbon tetrachloride (CCl4) rat model. Male Wistar rats received subcutaneous injections of CCl4 twice weekly for 12weeks, as well as daily oral treatments of olmesartan (1 and 3mg/kg), omega-3 (75 and 150mg/kg) and their combination during the last 4weeks of intoxication. Our results indicated that omega-3 and, to a lesser extent, olmesartan dose-dependently blunted CCl4-induced necroinflammation scoring and elevation of liver injury parameters in serum. Besides, omega-3 and, to a lesser extent, olmesartan treatments in a dose dependent manner attenuated CCl4-induced liver fibrosis, as demonstrated by hepatic histopathology scoring and 4-hydroxyproline content. The mechanisms behind these beneficial effects of both omega-3 and olmesartan were also elucidated. These include (1) counteracting hepatic oxidative stress and augmenting hepatic antioxidants; (2) preventing the activation of hepatic stellate cells (HSCs), as denoted by reducing alpha-smooth muscle actin (alpha-SMA) expression in the liver; (3) inhibiting the proliferation and chemotaxis of HSCs, as evidenced by downregulating platelet derived growth factor receptors-beta (PDGFR-beta) expression in the liver; and (4) inhibiting the fibrogenesis response of HSCs, as indicated by inhibiting the secretion of transforming growth factor-beta1 (TGF-beta1). Unexpectedly, when olmesartan was co-administered with omega-3, it interfered with the hepatoprotective and anti-fibrotic activities of omega-3. In conclusion, this study introduces the first evidence regarding the pronounced anti-fibrotic activity of omega-3 and suggests that it may be beneficial in the treatment of hepatic fibrosis in humans. PMID- 24144776 TI - The large spectrum of pulmonary complications following illicit drug use: features and mechanisms. AB - Damage to lungs may occur from systemic as well as inhalational exposure to various illegal drugs of abuse. Aspiration pneumonia probably represents the most common pulmonary complication in relation to consciousness impairment. Some pulmonary consequences may be specifically related to one given drug. Prolonged smoking of marijuana may result in respiratory symptoms suggestive of obstructive lung disease. Non-cardiogenic pulmonary edema has been attributed to heroin, despite debated mechanisms including attempted inspiration against a closed glottis, hypoxic damage to alveolar integrity, neurogenic vasoactive response to stress, and opiate-induced anaphylactoid reaction. Naloxone-related precipitated withdrawal resulting in massive sympathetic response with heart stunning has been mistakenly implicated. In crack users, acute respiratory syndromes called "crack lung" with fever, hemoptysis, dyspnea, and pulmonary infiltration on chest X-rays have been reported up-to 48h after free-base cocaine inhalation, with features of pulmonary edema, interstitial pneumonia, diffuse alveolar hemorrhage, and eosinophil infiltration. The high-temperature of volatilized cocaine and the presence of impurities, as well as cocaine-induced local vasoconstriction have been suggested to explain alveolar damage. Some other drug-related pulmonary insults result from the route of drug self-administration. In intravenous drug users, granulomatous pneumonia with multinodular patterns on thoracic imaging is due to drug contaminants like talcum. Septic embolism from right-sided endocarditis represents an alternative diagnosis in case of sepsis from pulmonary origin. Following inhalation, pneumothorax, and pneumomediastinum have been attributed to increased intrathoracic pressure in relation to vigorous coughing or repeated Valsalva maneuvers, in an attempt to absorb the maximal possible drug amount. In conclusion, pulmonary consequences of illicit drugs are various, resulting in both acute life-threatening conditions and long-term functional respiratory sequelae. A better understanding of their spectrum and the implicated mechanisms of injury should help to improve patient management. PMID- 24144777 TI - Lycopene modulates initiation of N-nitrosodiethylamine induced hepatocarcinogenesis: studies on chromosomal abnormalities, membrane fluidity and antioxidant defense system. AB - Oxidative damage due to free radicals generated during nitrosamine metabolism has been suggested as one of the major cause for the initiation of hepatocarcinogenesis. Lycopene, is a well known antioxidant and have promising preventive potentials, however the mechanism of action remain hypothetical and unclear. To investigate the involvement of lycopene extracted from tomatoes (LycT) against oxidative stress induced deleterious effect of N nitrosodiethylamine (NDEA) on cellular macromolecules, female Balb/c mice were divided in four groups: Control, NDEA (cumulative dose of 200mg NDEA/kg body weight injected intraperitoneally in 8 weeks), LycT (5mg/kg body weight given orally on alternate days, throughout the study) and LycT+NDEA (co-administration of LycT and NDEA). NDEA treatment commenced after 2 weeks of LycT administration. At the end of NDEA exposure i.e., at 10th week, enhanced activities of hepatic phase I enzymes, levels of reactive oxygen species (ROS), lipid peroxidation (LPO) was observed in NDEA group which may have contributed in chromosomal aberrations, enhanced micronucleated cell score, membrane fluidity and serum liver marker enzymes. A significant decrease in enzymatic and non-enzymatic antioxidant system could delineate the mechanism behind such NDEA insults. LycT pre-treatment to NDEA challenged group showed lower chromosomal abnormalities, micronucleated cells score, ROS, LPO levels and liver enzymes. Lycopene aids in normalizing the membrane fluidity and enhancing the activity of antioxidant enzymes and reduced glutathione which could account for the reduced oxidative damage in LycT+NDEA group. It seemed that lycopene supplementation target multiple dys-regulated pathways during initiation of carcinogenesis. Thus, dietary supplementation with lycopene can serve as an alternate measure to intervene the initiation of carcinogenesis. PMID- 24144778 TI - Curcumin induces radiosensitivity of in vitro and in vivo cancer models by modulating pre-mRNA processing factor 4 (Prp4). AB - Radiation therapy plays a central role in adjuvant strategies for the treatment of both pre- and post-operative human cancers. However, radiation therapy has low efficacy against cancer cells displaying radio-resistant phenotypes. Ionizing radiation has been shown to enhance ROS generation, which mediates apoptotic cell death. Further, concomitant use of sensitizers with radiation improves the efficiency of radiotherapy against a variety of human cancers. Here, the radio sensitizing effect of curcumin (a derivative of turmeric) was investigated against growth of HCT-15 cells and tumor induction in C57BL/6J mice. Ionizing radiation induced apoptosis through ROS generation and down-regulation of Prp4K, which was further potentiated by curcumin treatment. Flow cytometry revealed a dose-dependent response for radiation-induced cell death, which was remarkably reversed by transfection of cells with Prp4K clone. Over-expression of Prp4K resulted in a significant decrease in ROS production possibly through activation of an anti-oxidant enzyme system. To elucidate an integrated mechanism, Prp4K knockdown by siRNA ultimately restored radiation-induced ROS generation. Furthermore, B16F10 xenografts in C57BL/6J mice were established in order to investigate the radio-sensitizing effect of curcumin in vivo. Curcumin significantly enhanced the efficacy of radiation therapy and reduced tumor growth as compared to control or radiation alone. Collectively, these results suggest a novel mechanism for curcumin-mediated radio-sensitization of cancer based on ROS generation and down-regulation of Prp4K. PMID- 24144780 TI - Unusual case of paroxysmal sympathetic hyperactivity in a patient with leukemia. PMID- 24144779 TI - Blocked versus randomized presentation modes differentially modulate feedback related negativity and P3b amplitudes. AB - OBJECTIVE: Electrophysiological studies on feedback processing typically use a wide range of feedback stimuli which might not always be comparable. The current study investigated whether two indicators of feedback processing - feedback related negativity (FRN) and P3b - differ for feedback stimuli with explicit (facial expressions) or assigned valence information (symbols). In addition, we assessed whether presenting feedback in either a trial-by-trial or a block-wise fashion affected these ERPs. METHODS: EEG was recorded in three experiments while participants performed a time estimation task and received two different types of performance feedback. RESULTS: Only P3b amplitudes varied consistently in response to feedback type for both presentation types. Moreover, the blocked feedback type presentation yielded more distinct FRN peaks, higher effect sizes, and a significant relation between FRN amplitudes and behavioral task performance measures. CONCLUSION: Both stimulus type and presentation mode may provoke systematic changes in feedback-related ERPs. The current findings point at important potential confounds that need to be controlled for when designing FRN or P3b studies. SIGNIFICANCE: Studies investigating P3b amplitudes using mixed types of stimuli have to be interpreted with caution. Furthermore, we suggest implementing a blocked presentation format when presenting different feedback types within the same experiment. PMID- 24144781 TI - Inability of F waves to control for changes in the excitability of the motoneurone pool in motor control studies. PMID- 24144782 TI - Poor performers in general practice will be targeted, new inspector tells conference. PMID- 24144783 TI - Increased adhesive and inflammatory properties in blood outgrowth endothelial cells from sickle cell anemia patients. AB - The endothelium plays an important role in sickle cell anemia (SCA) pathophysiology, interacting with red cells, leukocytes and platelets during the vaso-occlusive process and undergoing activation and dysfunction as a result of intravascular hemolysis and chronic inflammation. Blood outgrowth endothelial cells (BOECs) can be isolated from adult peripheral blood and have been used in diverse studies, since they have a high proliferative capacity and a stable phenotype during in vitro culture. This study aimed to establish BOEC cultures for use as an in vitro study model for endothelial function in sickle cell anemia. Once established, BOECs from steady-state SCA individuals (SCA BOECs) were characterized for their adhesive and inflammatory properties, in comparison to BOECs from healthy control individuals (CON BOECs). Cell adhesion assays demonstrated that control individual red cells adhered significantly more to SCA BOEC than to CON BOEC. Despite these increased adhesive properties, SCA BOECs did not demonstrate significant differences in their expression of major endothelial adhesion molecules, compared to CON BOECs. SCA BOECs were also found to be pro inflammatory, producing a significantly higher quantity of the cytokine, IL-8, than CON BOECs. From the results obtained, we suggest that BOEC may be a good model for the in vitro study of SCA. Data indicate that endothelial cells of sickle cell anemia patients may have abnormal inflammatory and adhesive properties even outside of the chronic inflammatory and vaso-occlusive environment of patients. PMID- 24144784 TI - [Initial antiretroviral treatment in human immunodeficiency virus-infected patients in Spain: Decisions made in relation to particular immunovirological characteristics (PERFIL-es study)]. AB - INTRODUCTION: The purpose of Perfil-es study was to identify the proportion of patients starting ARV treatment based on NNRTIs or PI/r, and to identify the variables involved in the therapeutic decision-making in standard clinical practice. METHODS: An observational retrospective study performed in 65 Spanish hospitals. RESULTS: Was a total of 1,687 starts: 53% with NNRTI-based regimen and 42% with PI/r, and of the 642 patients analyzed, 72% had a CD4 count<350 cells/MUl. CONCLUSION: The initiation of ARV treatment is still late in Spain. NNRTIs are the more frequent choice, although PI/r plays an important role. PMID- 24144785 TI - [Genetic profiling of Giardia intestinalis by polimerase chain in human and dogs samples of Colombian Caribean Coast]. AB - INTRODUCTION: Giardia intestinalis (G. Intestinalis) is a protozoan that causes diarrheal disease and malabsorption syndrome in humans and other mammals. It presents a high genetic diversity evidenced in the recognition of 7 genotypes (A G). Genotypes A and B are commonly associated to humans and domestic animals such as dogs. The aim of this study was to conduct a preliminary genetic characterization of G. intestinalis in humans and dogs from two cities on the Caribbean coast of Colombia. METHODS: Sampling areas were selected according to the highest numbers of acute diarrheal disease. Stool samples were collected from children under 7 years old, with positive medical tests for G. intestinalis. Cysts were purified by sucrose gradient and DNA samples were isolated by extraction with organic solvents. Molecular characterization was performed by amplifying the gene triose phosphate isomerase (tpi) by using a semi-nested PCR. RESULTS: A total of 202 samples of DNA were obtained; of these, 111 were positive in coproparasitological analysis (13 dogs and 98 children). Genotype distribution in positive samples was: 5.1% belonged to genotype A and 92.3% to genotype B. Genotype B was present in humans and animals. CONCLUSIONS: The most common genotype in both human and animal samples was genotype B, suggesting a zoonotic transmission cycle. PMID- 24144786 TI - Learn and apply: using multi-sensory storytelling to gather knowledge about preferences and abilities of children with profound intellectual and multiple disabilities--three case studies. AB - Knowledge about the preferences and abilities of children with profound intellectual and multiple disabilities (PIMDs) is crucial for providing appropriate activities. Multi-sensory storytelling (MSST) can be an ideal activity for gathering such knowledge about children with PIMDs. The aim of this study was to analyse whether using MSST did lead to changes in teachers' knowledge about preferences and abilities and whether this knowledge was then applied in practice. Three dyads of children with PIMDs and their teachers read an MSST book 20 times during a 10-week period. A questionnaire designed to identify the teachers' current knowledge was filled in before the 1st and again after the 10th and 20th reading sessions. Also, the teachers were asked for their opinion about their newly gathered knowledge. In all three cases, changes in the teachers' knowledge were observed. However, teachers are insufficiently aware of their new knowledge and do not apply it in practice. PMID- 24144787 TI - Tobacco use among HIV-infected individuals in a rural community in Yunnan Province, China. AB - OBJECTIVE: To examine the prevalence and correlates of smoking versus tobacco chewing, and potential gender differences in tobacco use among HIV-infected individuals in a rural community in Yunnan Province, China. METHOD: A cross sectional design using face-to-face interviews. RESULTS: Among the participants, 301 (66.2%) were male; 79 (17.4%) were ethnic Han, 310 (68.1%) were Jingpo minority, 62 (13.6%) were Dai minority; 17.8% had no formal education and 55.6% had only primary school education; 15.4% were never married; 40% reported drinking in the past 30 days; 55.4% had ever used drugs; and 67% were currently receiving antiretroviral therapy (ART). The mean age of the study participants was 38.1 years (SD=8.8). About 62% were current cigarette smokers. Current cigarette smoking was positively associated with being male (OR=142.43, 95% CI: 35.61-569.72) and current drinking (OR=7.64, 95% CI: 2.68-21.81), as well as having ever used drugs (OR=4.03, 95% CI: 1.31-12.35). Among current smokers, 67.6% were heavy smokers (smoked at least 20 cigarettes per day). Those who were older than 46 years of age (OR=9.68, 95% CI: 1.41-66.59) and current drinkers (OR=2.75, 95% CI: 1.56-4.83) were more likely to be heavy smokers. Approximately 9% were currently used chewing tobacco. Those who were female (OR=41.29, 95% CI: 8.53-199.93) and current drinkers (OR=3.22, 95% CI: 1.02-10.16) were more likely to use chewing tobacco. All who used chewing tobacco were ethnic minorities. CONCLUSIONS: Cigarette smoking and use of chewing tobacco were highly prevalent among HIV-infected individuals in rural Yunnan, underscoring the urgent need for tobacco prevention and intervention programs tailored for this population. PMID- 24144788 TI - Apixaban vs. warfarin with concomitant aspirin in patients with atrial fibrillation: insights from the ARISTOTLE trial. AB - AIMS: We assessed the effect of concomitant aspirin use on the efficacy and safety of apixaban compared with warfarin in patients with atrial fibrillation (AF). METHODS AND RESULTS: In ARISTOTLE, 18 201 patients were randomized to apixaban 5 mg twice daily or warfarin. Concomitant aspirin use was left to the discretion of the treating physician. In this predefined analysis, simple and marginal structured models were used to adjust for baseline and time-dependent confounders associated with aspirin use. Outcome measures included stroke or systemic embolism, ischaemic stroke, myocardial infarction, mortality, major bleeding, haemorrhagic stroke, major or clinically relevant non-major bleeding, and any bleeding. On Day 1, 4434 (24%) patients were taking aspirin. Irrespective of concomitant aspirin use, apixaban reduced stroke or systemic embolism [with aspirin: apixaban 1.12% vs. warfarin 1.91%, hazard ratio (HR) 0.58, 95% confidence interval (CI) 0.39-0.85 vs. without aspirin: apixaban 1.11% vs. warfarin 1.32%, HR 0.84, 95% CI 0.66-1.07; P interaction = 0.10] and caused less major bleeding than warfarin (with aspirin: apixaban 3.10% vs. warfarin 3.92%, HR 0.77, 95% CI 0.60-0.99 vs. without aspirin: apixaban 1.82% vs. warfarin 2.78%, HR without aspirin 0.65, 95% CI 0.55-0.78; P interaction = 0.29). Similar results were seen in the subgroups of patients with and without arterial vascular disease. CONCLUSION: Apixaban had similar beneficial effects on stroke or systemic embolism and major bleeding compared with warfarin, irrespective of concomitant aspirin use. PMID- 24144789 TI - Why is intracardiac echocardiography helpful? Benefits, costs, and how to learn. AB - Current interventional procedures in structural heart disease and cardiac arrhythmias require peri-interventional echocardiographic monitoring and guidance to become as safe, expedient, and well-tolerated for patients as possible. Intracardiac echocardiography (ICE) complements and has in part replaced transoesophageal echocardiography (TEE), including real-time three-dimensional (RT-3D) imaging. The latter is still widely accepted as a method to prepare for and to guide interventional treatments. In contrast to TEE, ICE represents a purely intraprocedural guiding and imaging tool unsuitable for diagnostic purposes. Patients tolerate ICE much better, and the method does not require general anaesthesia. Accurate imaging of the particular pathology, its anatomic features, and spatial relation to the surrounding structures is critical for catheter and wire positioning, device deployment, evaluation of the result, and for ruling out complications. This review describes the peri-interventional role of ICE, outlines current limitations, and points out future implications. Two dimensional ICE has become a suitable guiding tool for a variety of percutaneous treatments in patients who are conscious or under monitored anaesthesia care, whereas RT-3DICE is still undergoing clinical testing. Continuous TEE monitoring under general anaesthesia remains a widely accepted alternative. PMID- 24144790 TI - Lignification in sugarcane: biochemical characterization, gene discovery, and expression analysis in two genotypes contrasting for lignin content. AB - Sugarcane (Saccharum spp.) is currently one of the most efficient crops in the production of first-generation biofuels. However, the bagasse represents an additional abundant lignocellulosic resource that has the potential to increase the ethanol production per plant. To achieve a more efficient conversion of bagasse into ethanol, a better understanding of the main factors affecting biomass recalcitrance is needed. Because several studies have shown a negative effect of lignin on saccharification yield, the characterization of lignin biosynthesis, structure, and deposition in sugarcane is an important goal. Here, we present, to our knowledge, the first systematic study of lignin deposition during sugarcane stem development, using histological, biochemical, and transcriptional data derived from two sugarcane genotypes with contrasting lignin contents. Lignin amount and composition were determined in rind (outer) and pith (inner) tissues throughout stem development. In addition, the phenolic metabolome was analyzed by ultra-high-performance liquid chromatography-mass spectrometry, which allowed the identification of 35 compounds related to the phenylpropanoid pathway and monolignol biosynthesis. Furthermore, the Sugarcane EST Database was extensively surveyed to identify lignin biosynthetic gene homologs, and the expression of all identified genes during stem development was determined by quantitative reverse transcription-polymerase chain reaction. Our data provide, to our knowledge, the first in-depth characterization of lignin biosynthesis in sugarcane and form the baseline for the rational metabolic engineering of sugarcane feedstock for bioenergy purposes. PMID- 24144791 TI - Seedling Lethal1, a pentatricopeptide repeat protein lacking an E/E+ or DYW domain in Arabidopsis, is involved in plastid gene expression and early chloroplast development. AB - Chloroplasts are the site of photosynthesis and the biosynthesis of essential metabolites, including amino acids, fatty acids, and secondary metabolites. It is known that many seedling-lethal mutants are impaired in chloroplast function or development, indicating the development of functional chloroplast is essential for plant growth and development. Here, we isolated a novel transfer DNA insertion mutant, dubbed sel1 (for seedling lethal1), that exhibited a pigment defective and seedling-lethal phenotype with a disrupted pentatricopeptide repeat (PPR) gene. Sequence analysis revealed that SEL1 is a member of the PLS subgroup, which is lacking known E/E(+) or DYW domains at the C terminus, in the PLS subfamily of the PPR protein family containing a putative N-terminal transit peptide and 14 putative PPR or PPR-like motifs. Confocal microscopic analysis showed that the SEL1-green fluorescent protein fusion protein is localized in chloroplasts. Transmission electron microscopic analysis revealed that the sel1 mutant is impaired in the etioplast, as well as in chloroplast development. In sel1 mutants, plastid-encoded proteins involved in photosynthesis were rarely detected due to the lack of the corresponding transcripts. Furthermore, transcript profiles of plastid genes revealed that, in sel1 mutants, the transcript levels of plastid-encoded RNA polymerase-dependent genes were greatly reduced, but those of nuclear-encoded RNA polymerase-dependent genes were increased or not changed. Additionally, the RNA editing of two editing sites of the acetyl-CoA carboxylase beta subunit gene transcripts in the sel1 mutant was compromised, though it is not directly connected with the sel1 mutant phenotype. Our results demonstrate that SEL1 is involved in the regulation of plastid gene expression required for normal chloroplast development. PMID- 24144792 TI - The F-box protein OsFBK12 targets OsSAMS1 for degradation and affects pleiotropic phenotypes, including leaf senescence, in rice. AB - Leaf senescence is related to the grain-filling rate and grain weight in cereals. Many components involved in senescence regulation at either the genetic or physiological level are known. However, less is known about molecular regulation mechanisms. Here, we report that OsFBK12 (an F-box protein containing a Kelch repeat motif) interacts with S-ADENOSYL-l-METHIONINE SYNTHETASE1 (SAMS1) to regulate leaf senescence and seed size as well as grain number in rice (Oryza sativa). Yeast two-hybrid, pull-down, and bimolecular fluorescence complementation assays indicate that OsFBK12 interacts with Oryza sativa S-PHASE KINASE-ASSOCIATED PROTEIN1-LIKE PROTEIN and with OsSAMS1. Biochemical and physiological data showed that OsFBK12 targets OsSAMS1 for degradation. OsFBK12 RNA interference lines and OsSAMS1 overexpression lines showed increased ethylene levels, while OsFBK12-OX lines and OsSAMS1-RNA interference plants exhibited decreased ethylene. Phenotypically, overexpression of OsFBK12 led to a delay in leaf senescence and germination and increased seed size, whereas knockdown lines of either OsFBK12 or OsSAMS1 promoted the senescence program. Our results suggest that OsFBK12 is involved in the 26S proteasome pathway by interacting with Oryza sativa S-PHASE KINASE-ASSOCIATED PROTEIN1-LIKE PROTEIN and that it targets the substrate OsSAMS1 for degradation, triggering changes in ethylene levels for the regulation of leaf senescence and grain size. These data have potential applications in the molecular breeding of rice. PMID- 24144793 TI - Stimulation of G protein-coupled bile acid receptor enhances vascular endothelial barrier function via activation of protein kinase A and Rac1. AB - Bile acids are end products of cholesterol metabolism, and they constantly exist at high concentrations in the blood. Since vascular endothelial cells express G protein-coupled bile acid receptor (GPBAR), bile acids potentially modulate endothelial function. Here, we investigated whether and how GPBAR agonism affects endothelial barrier function. In bovine aortic endothelial cells (BAECs), treatment with a GPBAR agonist, taurolithocholic acid (TLCA) increased the transendothelial electrical resistance. In addition, TLCA suppressed the thrombin induced dextran infiltration through the endothelial monolayer. Knockdown of GPBAR abolished the inhibitory effect of TLCA on hyperpermeability. These results indicate that stimulation of GPBAR enhances endothelial barrier function. TLCA increased intracellular cAMP production in BAECs. Inhibition of protein kinase A (PKA) or Rac1 significantly attenuated the TLCA-induced endothelial barrier protection. TLCA induced cortical actin polymerization, which was attenuated by a Rac1 inhibitor. In vivo, local administration of TLCA into the mouse ear significantly inhibited vascular leakage and edema formation induced by croton oil or vascular endothelial growth factor. These results indicate that stimulation of GPBAR enhances endothelial barrier function by cAMP/PKA/Rac1 dependent cytoskeletal rearrangement. PMID- 24144794 TI - Bradykinin contracts rat urinary bladder largely independently of phospholipase C. AB - Several receptor systems in the bladder causing detrusor smooth muscle contraction stimulate phospholipase C (PLC). PLC inhibition abolishes bladder contraction via P2Y6 but not that via M3 muscarinic receptors, indicating a receptor-dependent role of PLC. Therefore, we explored the role of PLC in rat bladder contraction by bradykinin. The PLC inhibitor U 73,122 [1-(6-[([17beta]-3 methoxyestra-1,3,5[10]-trien-17-yl)-amino]hexyl)-1H-pyrrole-2,5-dione] did not affect the bradykinin response to a significantly greater degree than its inactive analog U 73,343 [10 MUM each; 1-(6-[-([17beta]-3-methoxyestra-1,3,5[10] trien-17-yl)-amino]hexyl)-2,5-pyrrolidinedione], whereas the phospholipase D inhibitor butan-1-ol relative to its inactive control butan-2-ol caused a weak but significant inhibition (0.3% each). The cytosolic phospholipase A2 inhibitor arachidonyltrifluoromethyl ketone (300 MUM) and the cyclooxygenase inhibitor indomethacin (10 MUM) caused strong inhibition of the bradykinin response. The L type Ca(2+) channel blocker nifedipine (10-100 nM) concentration-dependently caused strong inhibition, whereas only a small but significant inhibition was seen with SK&F 96,365 [10 MUM; 1-[beta-[3-(4-methoxyphenyl)propoxy]-4 methoxyphenethyl]-1H-imidazole HCl], an inhibitor of receptor-operated Ca(2+) channels. Several protein kinase C inhibitors yielded an equivocal picture (inhibition by 10 MUM bisindolylmaleimide I and 1 MUM calphostin but not by 10 MUM chelerythrine). The rho kinase inhibitor Y 27,632 [1-10 MUM; trans-4-[(1R)-1 aminoethyl]-N-4-pyridinylcyclohexanecarboxamide] caused a strong and concentration-dependent inhibition of the bradykinin response. Our data support that not only M3 but also bradykinin receptors cause bladder contraction by a largely PLC-independent mechanism. Both responses strongly involve L-type Ca(2+) channels and rho kinase, whereas only the bradykinin response additionally involves the phospholipase A2/cyclooxygenase pathway. PMID- 24144795 TI - Nitric oxide and interleukin-1beta stimulate the proteasome-independent degradation of the retinoic acid hydroxylase CYP2C22 in primary rat hepatocytes. AB - CYP2C22 was recently described as a retinoic acid-metabolizing cytochrome P450 enzyme whose transcription is induced by all-trans-retinoic acid (atRA) in hepatoma cells (Qian L, Zolfaghari R, and Ross AC (2010) J Lipid Res 51:1781 1792). We identified CYP2C22 as a putative nitric oxide (NO)-regulated protein in a proteomic screen and raised specific polyclonal antibodies to CYP2C22 to study its protein expression. We found that CYP2C22 is a liver-specific protein that was not significantly induced by activators of the pregnane X receptor, constitutive androstane receptor, or peroxisome proliferator-activated receptor alpha, but was downregulated to <25% of control by the aryl hydrocarbon receptor agonist beta-naphthoflavone in cultured rat hepatocytes. CYP2C22 protein and its mRNA both were induced by atRA in hepatocytes, with EC50 of 100-300 nM, whereas the maximal extent of mRNA induction was twice that of the protein. CYP2C22 protein, but not its mRNA, was rapidly downregulated in hepatocytes by interleukin-1 (IL-1) or NO-donating compounds, and the downregulation by IL-1 was blocked by inhibition of NO synthases. The NO donor (Z)-1-[N-(3-aminopropyl)-N-(3 ammoniopropyl)amino]diazen-1-ium-1,2-diolate reduced the half-life of CYP2C22 from 8.7 to 3.4 hours in the presence of cycloheximide, demonstrating that NO dependent downregulation is due to stimulated proteolysis. No intermediate degradation products were detected. However, this degradation was insensitive to inhibitors of calpains or the canonical proteasomal or lysosomal pathways, indicating that NO-dependent degradation of CYP2C22 proceeds via a novel pathway. PMID- 24144796 TI - Identification of seniors at risk (ISAR) screening tool in the emergency department: implementation using the plan-do-study-act model and validation results. AB - INTRODUCTION: To better meet the needs of older adults in the emergency department, Senior Friendly care processes, such as high-risk screening are recommended. The identification of Seniors at Risk (ISAR) tool is a 6-item validated screening tool for identifying elderly patients at risk of the adverse outcomes post-ED visit. This paper describes the implementation of the tool in the Mount Sinai Hospital emergency department using a Plan-Do-Study-Act model; and demonstrates whether the tool predicts adverse outcomes. METHODS: An observational study tracked tool implementation. A retrospective chart audit was completed to collect data about elderly ED patients during 2 time periods in 2010 and 2011. Data analysis compared the characteristics of patients with positive and negative screening tool results. RESULTS: The identification of Seniors at Risk tool was completed for 51.6% of eligible patients, with 61.2% of patients having a positive result. Patients with positive screening results were more likely to be over age 79 (P = .003); be admitted to hospital (P < .001); have a longer mean ED length of stay (P < .001). For patients admitted to hospital, those with positive screening results had a longer mean inpatient stay (P = .012). DISCUSSION: Implementing the Idenfitication of Seniors at Risk tool was challenged by problematic compliance with tool completion. Strategies to address this included tool adaptation; and providing staff with knowledge of ED and inpatient geriatric resources and feedback on completion rates. Positive screening results predicted adverse outcomes in elderly Mount Sinai Hospital ED patients. PMID- 24144797 TI - New ursane-type triterpenoid saponins from the stem bark of Schefflera heptaphylla. AB - Phytochemical investigation on the stem bark of Schefflera heptaphylla led to the isolation of five new ursane-type triterpenoid saponins (1-5). Their structures were determined on the basis of spectroscopic and chemical methods. It is noteworthy in this study that the genins of all compounds are reported for the first time. All compounds isolated from this plant were evaluated for their inhibitory activities on lipopolysaccharide-induced nitric oxide production in RAW264.7 cells, and compounds 2 and 5 showed weak anti-inflammatory activities under their non-cytotoxic concentrations. PMID- 24144798 TI - Anti-inflammatory activity of sulfate-containing phenolic compounds isolated from the leaves of Myrica rubra. AB - Three sulfated phenolic compounds, juglanin B (11R)-O-sulfate (1), myricetin 3'-O sulfate (2), and ampelopsin 3'-O-sulfate (3), were isolated from the leaves of Myrica rubra. Compound 1 was a new sulfated lignan, 2 was a new sulfated flavone, and 3 was a known sulfated flavone. The structures of the new compounds (1 and 2) were determined by acid hydrolysis and spectroscopic methods, including IR, FAB MS, 1D and 2D NMR. The inhibitory activities of compounds 1-3 and their hydrolysates (1a-3a) against LPS-induced cytokine (TNF-alpha, IL-1beta, and IL-6) production in macrophage RAW 264.7 cells were evaluated. The 2 new compounds (1 and 2) and their aglycones (1a and 2a) significantly reduced LPS-induced expression of iNOS and COX-2 proteins. PMID- 24144799 TI - Inhibitory effects of celastrol on rat liver cytochrome P450 1A2, 2C11, 2D6, 2E1 and 3A2 activity. AB - The present study was the first time to investigate the effects of celastrol, derived from Trypterygium wilfordii Hook F. ("Thunder of God Vine"), a traditional Chinese medicine plant, on the metabolism of model probe substrates of CYP isoforms, CYP1A2, CYP2C11, CYP2D6, CYP2E1 and CYP3A2, which are important in the metabolism of a variety of xenobiotics. The effects of celastrol on CYP1A2 (phenacetin O-deethylase), CYP2C11 (tolbutamide 4-hydroxylase), CYP2D6 (dextromethorphan O-demethylation), CYP2E1 (chlorzoxazone 6-hydroxylase) and CYP3A2 (testosterone 6beta-hydroxylase) activities were investigated using rat liver microsomes. HPLC-DAD was used to measure the model substrates and metabolites. Inhibition of rat CYP isoforms (IC50) by celastrol in potency order was CYP2C11 (10.2 MUM)>CYP3A2 (23.2 MUM)>CYP1A2 (52.8 MUM)>CYP2E1 (74.2 MUM)>CYP2D6 (76.4 MUM). Enzyme kinetic studies showed that the celastrol was not only a competitive inhibitor of CYP1A2 and 2C11, but also a mixed-type inhibitor of CYP3A2, with Ki of 39.2 MUM, 7.05 MUM and 14.2 MUM, respectively. The data indicate that celastrol inhibited the metabolism of CYP1A2, 2C and 3A substrates in rat liver in vitro with a different mode of inhibition. These in vitro studies of celastrol with CYP isoforms may be helpful for the development and application of celastrol as a promising anti-cancer agent. Further systematic studies in humans in vitro and in vivo are needed to identify the interactions of celastrol with cytochrome P450s. PMID- 24144800 TI - Cycloartane triterpenes from Beesia calthaefolia (Maxim.). AB - Three new cycloartane triterpenoids (1-3) and two known compounds (4, 5) were isolated from the whole plant of Beesia calthaefolia. Their structures were elucidated by 1D and 2D NMR, HRESIMS and optical rotation spectral data. All isolates were investigated for their inhibitory effects on the classical pathway of the complement system. Among them, compound 4 showed stronger inhibitory activity (IC50 136.7 MUM) than positive control (Rosmarinic acid, IC50 181.8 MUM) while compounds 2 and 3 were moderately active with IC50 value of 206 MUM and 200.9 MUM. Chemical compound studied in this article: Rosmarinic acid (PubChem CID: 5281792). PMID- 24144801 TI - ProNormz--an integrated approach for human proteins and protein kinases normalization. AB - The task of recognizing and normalizing protein name mentions in biomedical literature is a challenging task and important for text mining applications such as protein-protein interactions, pathway reconstruction and many more. In this paper, we present ProNormz, an integrated approach for human proteins (HPs) tagging and normalization. In Homo sapiens, a greater number of biological processes are regulated by a large human gene family called protein kinases by post translational phosphorylation. Recognition and normalization of human protein kinases (HPKs) is considered to be important for the extraction of the underlying information on its regulatory mechanism from biomedical literature. ProNormz distinguishes HPKs from other HPs besides tagging and normalization. To our knowledge, ProNormz is the first normalization system available to distinguish HPKs from other HPs in addition to gene normalization task. ProNormz incorporates a specialized synonyms dictionary for human proteins and protein kinases, a set of 15 string matching rules and a disambiguation module to achieve the normalization. Experimental results on benchmark BioCreative II training and test datasets show that our integrated approach achieve a fairly good performance and outperforms more sophisticated semantic similarity and disambiguation systems presented in BioCreative II GN task. As a freely available web tool, ProNormz is useful to developers as extensible gene normalization implementation, to researchers as a standard for comparing their innovative techniques, and to biologists for normalization and categorization of HPs and HPKs mentions in biomedical literature. URL: http://www.biominingbu.org/pronormz. PMID- 24144802 TI - Emergency median sternotomy and cardiopulmonary bypass during ruptured abdominal aortic aneurysm repair. AB - We report the case of a patient who developed severe cardiogenic shock during the open repair of a ruptured abdominal aortic aneurysm. After controlling the bleeding from the ruptured aneurysm, the electrocardiogram exhibited ST-T elevation and bradycardia. A median sternotomy was performed, and cardiopulmonary bypass was established. Under cardiopulmonary bypass support, the patient successfully underwent a Y-shaped graft replacement. The venous and arterial cannulae were recannulated through the femoral artery and vein. The chest and abdomen were closed in the usual fashion. Five hours after admission to the intensive care unit, cardiopulmonary bypass was weaned successfully, and the patient was extubated 1 day after surgery. Postoperative coronary angiography showed severe vasospastic angina of the right coronary artery, which might have caused cardiogenic shock during the aneurysm repair. The patient had an uneventful recovery period and was discharged on the 14th postoperative day without neurological complications. PMID- 24144803 TI - A 76-year old man with a torn Freedom SOLO bioprosthesis. AB - We describe a case of a 76-year old male who presented with progressive dyspnoea. He underwent an aortic valve replacement with a Freedom SOLO bioprosthesis 6 years ago. Transthoracic echocardiography showed a moderate-to-severe leakage of the Freedom SOLO bioprosthesis. During surgical reintervention, a partial tear of the left coronary cusp was seen from the commissure of the right coronary cusp to its base. After radiographic and microscopic examination, no clear cause was found for the failure of this Freedom SOLO bioprosthesis. To our knowledge, this is the third failure of a Freedom SOLO bioprosthesis reported in the literature. When the long-term follow-up of the Freedom SOLO bioprosthesis is available, it has to be compared with other bioprosthesis for long-term durability. PMID- 24144804 TI - Isolated tricuspid valve surgery at a single centre: the 47-year Auckland experience, 1965-2011. AB - OBJECTIVES: Isolated tricuspid valve surgery is not commonly performed with few studies and limited numbers published. We reviewed the characteristics and outcomes, including survival, reoperation rates and their predictors of different types of isolated tricuspid surgery. METHODS: Patients coded for isolated tricuspid valve surgery were identified from the Green Lane Hospital database. Relevant clinical characteristics were collected from both clinical and written clinical records. Mortality was checked against the national 'Births, Deaths and Marriages' database from the Ministry of Health. RESULTS: Seventy-two consecutive patients (48 +/- 16 years; 71% women, body mass index 25 +/- 6) underwent isolated tricuspid valve surgery from 1965 to 2011. Valve repair was performed in 53 and 47% had a valve replacement. The majority of these operations were performed in the last two decades. Early mortality within 30 days of operation was 7.9% for repair and 17.6% for replacement (P = 0.29). The 1-, 5-, 10- and 25 year survival rates were 83.8, 74.5, 63.6 and 32.8% for tricuspid repair and 81.8, 68.2, 61.4 and 15.2% for tricuspid replacement, respectively. Preoperative loop diuretic dose (P = 0.0120) and preoperative haemoglobin level (P = 0.0377) were independent predictors of survival for all isolated tricuspid surgery, while preoperative creatinine level (P = 0.04) independently predicted reoperation during the follow-up. CONCLUSIONS: Both isolated tricuspid replacement and repair were associated with significant but acceptable early and late mortality with no statistically significant difference in cumulative survival. Preoperative loop diuretic dose, haemoglobin and creatinine are individually associated with survival and/or reoperation after isolated tricuspid valve surgery. PMID- 24144805 TI - Technical and early outcomes of Ivor Lewis minimally invasive oesophagectomy for gastric tube construction in the thoracic cavity. AB - OBJECTIVES: Ivor Lewis minimally invasive oesophagectomy (ILMIE) is a complex surgery aiming to remove an oesophageal tumour and to create a new gastric tube in the abdomen. The objective was to assess the technical and early outcomes of ILMIE for gastric tube construction in the thoracic cavity. METHODS: A retrospective analysis was conducted in 25 middle or lower oesophageal cancer patients treated with ILMIE between August and December 2012. A gastric tube was constructed in the thoracic cavity in all patients. The gastric tube and the oesophagus were anastomosed using a circular stapler. Clinical data (age, gender, pathological pattern and TNM stage), surgical data (operation time, intraoperative blood loss and intraoperative complications) and follow-up data (postoperative complications, length of stay, thoracic tube drainage time and time before eating) were assessed. RESULTS: The mean age was 61 +/- 8 years. Sixteen patients were male and 9 were female. Oesophageal cancer was located in the middle oesophagus in 5 cases and in the lower oesophagus in 20. No conversion to open surgery was performed. The mean operative time and intraoperative blood loss were 320 +/- 63 min and 137 +/- 95 ml, respectively. A mean of 2.4 +/- 0.5 linear stapler cartridges was used per patient. A mean of 14.6 +/- 5.4 lymph nodes was dissected per patient. Postoperative hospital stay was 13.2 +/- 2.4 days. Intraoperative and postoperative complications occurred in 12% (3 of 25) and 20% (5 of 25) of patients, respectively, including 1 case of anastomotic fistula. The patients were followed up for a mean of 3.5 +/- 1.2 months, and there was no relapse or death. CONCLUSIONS: The construction of a gastric tube through the thoracic cavity using ILMIE is feasible and safe in patients with middle or lower oesophageal cancer. However, longer follow-up and larger sample sizes are needed to evaluate the oncological efficacy. PMID- 24144806 TI - Three-dimensional surgical simulation-guided navigation in thoracic surgery: a new approach to improve results in chest wall resection and reconstruction for malignant diseases. AB - OBJECTIVES: Oncological surgery of the chest wall should be performed to achieve free margins of at least 2 cm for metastasis or 4 cm for primary tumours. When the lesion is not visible or palpable, difficulty in identification may lead to a larger incision and a resection wider than is necessary. METHODS: We report three cases of non-palpable metastatic chest wall lesions in which the preoperative surgical planning and the intraoperative identification of the tumour, and thus the subsequent chest wall reconstruction, was supported using computer-based surgery. RESULTS: The application of high-resolution three-dimensional imaging technology and navigational systems is used in preoperative surgical planning to provide virtual simulations of a patient's skeletal changes and new soft tissue profile. Intraoperatively, a mobile navigation probe was used to identify the lesion, matching surgical landmarks and the preoperative computed tomography imaging, achieving the radical resection of the tumour with correct but not excessive surgical margins. Two patients underwent partial sternectomy followed by sternal allograft reconstruction. The third patient underwent chest wall resection followed by reconstruction using titanium bars and vicryl mesh. In all cases, the postoperative period was uneventful. After a follow-up period of 13.9 and 8 months, respectively, all patients are disease free, without complications. CONCLUSIONS: Application of navigation technology in thoracic surgery should be encouraged because it is easy to use and requires a limited learning curve. PMID- 24144807 TI - Comparison of drug-eluting and bare-metal stents in patients with diabetes undergoing primary percutaneous coronary intervention: what is the evidence? AB - A best evidence topic was written according to a structured protocol. The question addressed was, should the practising interventional cardiologist use drug-eluting stents (DESs) or bare-metal stents (BMSs) when undertaking primary percutaneous coronary intervention (PCI) in diabetic patients. The relevant outcomes that were used to determine the answer to this question included: in stent restenosis, target vessel revascularization (TVR), mortality, myocardial infarction and in-stent thrombosis. The OVID Medline database was used to carry out the reported search for abstracts of relevant journal articles. Altogether 102 papers were found, of which 7 represented the best evidence to answer the clinical question. The authors, journal, date and country of publication, patient group studied, study type, relevant outcomes and results of these papers are tabulated. From the evidence available, we conclude that in-stent restenosis is less likely to occur over a follow-up of at least 6 months if a DES is used instead of a BMS. Furthermore, TVR is less likely to be required in diabetic patients who receive a DES in comparison with a BMS. Nevertheless, no significant difference in mortality between stents was detected by the studies reviewed. This included no difference in the incidence of cardiac and non-cardiac causes of death. There was evidence showing that DESs are associated with a decrease in the risk of myocardial infarction and, in particular, a decrease in non-Q-wave myocardial infarction. However, there was also conflicting evidence demonstrating no significant difference in the incidence of myocardial infarction between diabetic patients who had received a BMS or a DES. Moreover, the available evidence showed no significant difference in the risk of in-stent thrombosis for all DESs with the exception of Sirolimus eluting stents in which the evidence was not consistent. In summary, the available evidence supports the use of DESs over BMSs in diabetic patients undergoing primary PCI. PMID- 24144808 TI - Locoregional and distant recurrences after breast conserving therapy in patients with triple-negative breast cancer: a meta-analysis. AB - BACKGROUND: With higher incidence of recurrence, ongoing dispute exists on whether triple-negative breast cancer (TNBC) is a good candidate for breast conserving therapy (BCT). OBJECTIVE: We aimed to appraise the safety of BCT in treating TNBC, in comparison with modified radical mastectomy. The prognostic effect of TN phenotype in conservatively managed patients was also assessed. METHODS: A systematic search for studies regarding recurrences in patients with TNBC or treated by BCT was conducted up to March 2013. Summary relative risks (RRs) for ipsilateral locoregional recurrence (ILRR) and distant metastasis (DM) were calculated in a fixed-effects model. RESULTS: Twenty-two studies concerning 15,312 breast cancer patients were analyzed. In the cohort of TNBC, the patients receiving BCT were less likely to develop ILRR and DM in comparison with mastectomy (RR 0.75, 95% CI 0.65-0.87; RR 0.68, 95% CI 0.60-0.76). In the cohort of BCT, the TN subtype increased the risks of both ILRR and DM than non-TN subtypes (RR 1.88, 95% CI 1.58-2.22; RR 2.12, 95% CI 1.72-2.62). Further subgroup analyses of BCT cohort revealed that the luminal phenotype had the most favorable prognosis. Notably, TN subtype was less likely to develop ILRR than HER-2 subtype (RR 0.69, 95% CI 0.53-0.91), there was no difference in DM rate between them. CONCLUSIONS: BCT benefits patients with TNBC than mastectomy does. However, TN subtype predicts a poorer prognosis than non-TN subtype, suggesting more aggressive adjuvant therapy for TNBC be established in future trials. PMID- 24144809 TI - 2,3-Butanediol recovery from fermentation broth by alcohol precipitation and vacuum distillation. AB - This study presents a new and effective downstream process to recover 2,3 butanediol (2,3-BD) from fermentation broth which is produced by a recombinant Klebsiella pneumoniae strain. The ldhA-deficient K. pneumoniae strain yielded about 90 g/L of 2,3-BD, along with a number of by-products, such as organic acids and alcohols, in a 65 h fed-batch fermentation. The pH-adjusted cell-free fermentation broth was firstly concentrated until 2,3-BD reached around 500 g/L by vacuum evaporation at 50 degrees C and 50 mbar vacuum pressure. The concentrated solution was further treated using light alcohols, including methanol, ethanol, and isopropanol, for the precipitation of organic acids and inorganic salts. Isopropanol showed the highest removal efficiency, in which 92.5% and 99.8% of organic acids and inorganic salts were precipitated, respectively. At a final step, a vacuum distillation process enabled the recovery of 76.2% of the treated 2,3-BD, with 96.1% purity, indicating that fermentatively produced 2,3-BD is effectively recovered by a simple alcohol precipitation and vacuum distillation. PMID- 24144810 TI - Mammalian cardiolipin biosynthesis. AB - Cardiolipin is a major phospholipid in mitochondria and is involved in the generation of cellular energy in the form of ATP. In mammalian and eukaryotic cells it is synthesized via the cytidine-5'-diphosphate-1,2-diacyl-sn-glycerol phosphate pathway. This brief review will describe some of the more recent studies on mammalian cardiolipin biosynthesis and provide an overview of regulation of cardiolipin biosynthesis. In addition, the important role that this key phospholipid plays in disease processes including heart failure, diabetes, thyroid hormone disease and the genetic disease Barth Syndrome will be discussed. PMID- 24144811 TI - Molecular mechanism of deactivation of C. antarctica lipase B by methanol. AB - The catalytic activity of Candida antarctica lipase B upon alcoholysis of a constant concentration of 15.2% vinyl acetate (vol/vol) and varying concentrations of methanol (0.7-60%) in toluene was determined experimentally by measuring the initial reaction velocity. The molecular mechanism of the deactivation of the enzyme by methanol was investigated by fitting the experimental data to a kinetic model and by molecular dynamics simulations of C. antarctica lipase B in toluene-methanol-water mixtures. The highest catalytic activity (280 U/mg) was observed at methanol concentrations as low as 0.7% methanol (vol/vol), followed by a sharp decrease at higher methanol concentrations. For methanol concentrations above 10% (vol/vol), catalytic activity was at 30% of the maximum activity. A variation of water activity in the range 0.02-0.09 had only minor effects. These experimental observations are described by a simple kinetic model using three assumptions: (1) a ping-pong bi bi mechanism of the enzyme, (2) competitive inhibition by the substrate methanol, and (3) by describing enzyme kinetics by the thermodynamic activities of the substrates rather than by their concentrations. Two equilibrium constants of methanol (KM,MeOH=0.05 and Ki,MeOH=0.23) were derived by modeling methanol binding to the substrate binding site of the lipase in molecular dynamics simulations of protein-solvent systems at atomic resolution. Thus, the sharp maximum of catalytic activity of C. antarctica lipase B at 0.7% methanol is a direct consequence of the fact that methanol-toluene mixtures are far from ideal. Understanding the thermodynamics of solvent mixtures is prerequisite to a quantitative model of enzymatic activity in organic solvents. PMID- 24144812 TI - Depletion of blood neutrophils from patients with sepsis: treatment for the future? AB - Organ failure arising from severe sepsis accounts for nearly 6 million deaths worldwide per annum. At present there are no specific pharmacological agents available for its treatment and identifying a suitable therapeutic target is urgently needed. Neutrophils appear to be contributing directly to pulmonary damage in severe forms of lung injury and indirectly to the failure of other organs. Blood neutrophils from patients with sepsis possess a phenotype that is indicative of activation and our results show that neutrophils isolated from patients with sepsis exhibit a supranormal adherence to endothelial monolayers treated with pro-inflammatory cytokines. Additional studies reveal that the patients' cells are highly efficient at releasing IL-8. We also demonstrate that organ function is improved upon removing neutrophils from the circulation. In this article we propose that in severe sepsis there is a subpopulation of neutrophils which is actively engaged in pathological insult. The phenotypic characterisation of this subset may provide a novel therapeutic strategy for sepsis that could lead to patient benefit. PMID- 24144813 TI - Anti-invasive effects of celastrol in hypoxia-induced fibroblast-like synoviocyte through suppressing of HIF-1alpha/CXCR4 signaling pathway. AB - Rheumatoid arthritis (RA) joints are in a hypoxic condition. Hypoxia-induced migration and invasion of fibroblast-like synoviocytes (FLSs) are considered to play a critical role in the pathogenesis of RA. Among the key genes upregulated by hypoxia-inducible factor-1alpha (HIF-1alpha), CXC chemokine receptor 4 (CXCR4) plays an important role in FLS migration and invasion. Our previous studies have shown that celastrol exerts anti-arthritic effects by inhibiting FLS migration and invasion under normoxic conditions. However, the effect and molecular mechanisms underlying the effect of celastrol on hypoxia-induced FLS migration and invasion are poorly understood. In the present study, we assessed the effect of celastrol on hypoxia-induced FLS migration and invasion. Results showed that celastrol suppressed hypoxia-induced FLS migration and invasion. In addition, we also found that celastrol inhibited hypoxia-induced CXCR4 expression at both the mRNA and the protein levels in RA-FLSs. Meanwhile, it is revealed that celastrol inhibited the transcriptional activity of CXCR4 under hypoxic conditions by suppressing the binding activity of HIF-1alpha in the CXCR4 promoter, and blocked hypoxia-induced accumulation of nuclear HIF-1alpha. Furthermore, treatment with HIF-1alpha inhibitor reduced the hypoxia-induced expression and transcriptional activity of CXCR4. In conclusion, our results indicate that celastrol inhibits hypoxia-induced migration and invasion via suppression of HIF-1alpha mediated CXCR4 expression in FLSs under hypoxic conditions. These results provide a strong rationale for further testing and validation of the use of celastrol as a new alternative for using in the treatment of RA. PMID- 24144814 TI - [In honor of Prof. dr. Gyorgy Weber on his 60th birthday]. PMID- 24144815 TI - [Robotic surgery]. AB - Due to the fast spread of laparoscopic cholecystectomy, surgical procedures have been changed essentially. The new techniques applied for both abdominal and thoracic procedures provided the possibility for minimally invasive access with all its advantages. Robots - originally developed for industrial applications - were retrofitted for laparoscopic procedures. The currently prevailing robot assisted surgery is ergonomically more advantageous for the surgeon, as well as for the patient through the more precise preparative activity thanks to the regained 3D vision. The gradual decrease of costs of robotic surgical systems and development of new generations of minimally invasive devices may lead to substantial changes in routine surgical procedures. PMID- 24144816 TI - [Effectiveness and safety of total thyroidectomy in the management of benign multinodular goiters]. AB - BACKGROUND: The appropriate surgical procedure for benign multinodular goiters is debated. We report our clinical experience of performing total thyroidectomy for multinodular goiters, focusing on the outcome and complications to evaluate the efficacy and safety. MATERIAL AND METHODS: The medical records of 264 patients who underwent total thyroidectomy for multinodular goiter between 2000 and 2006 were reviewed retrospectively. We examined the indications for operation, average hospital stay, early and late postoperative complications, the results of the final pathology in particular the frequency of incidental thyroid cancers and the recurrence rates after an average 6.2 years follow-up. The results were compared to literature data. RESULTS: The indications for surgery were compression and/or dislocation of the trachea in 174 (65.9%) patients, hyperthyreodism in 74 (28%) and cosmetic problems in others. The mean hospital stay was 4 days. Thirty-one patients (11.7%) had transient hypocalcaemia, but only 1 (0.3%) was symptomatic, and only 4 (1.5%) had permanent hypocalcaemia. Other complications included hematoma 4 (1.5%), temporary unilateral recurrent laryngeal nerve palsy 7 (2.6%), permanent unilateral laryngeal nerve palsy 2 (0.75%), and seroma in 8 (3%) cases. Incidental thyroid carcinomas were found on hystology in 9 (3.5%) patients. No recurrence was observed during the follow-up. CONCLUSION: Total thyroidectomy may be the procedure of choice for the surgical management of benign multinodular goiter. PMID- 24144817 TI - [Examination of cytoprotective and anti-inflammatory effect of PACAP-38 on small bowel autotransplantation]. AB - INTRODUCTION: The small intestine is one of the most sensitive organs to ischemia reperfusion injury during transplantation. Cytoprotective effect of pituitary adenylate cyclase-activating polypeptide (PACAP) is well known. The aim of our study was to measure changes of PACAP-38-like immunoreactivities and cytokine levels in intestinal grafts stored PACAP-38 containing preservation solution. MATERIAL AND METHODS: Small-bowel autotransplantation was performed on male Wistar rats (n = 56). Grafts were stored in University of Wisconsin (UW) solution at 4 degrees C for 1 (GI), 3 (GII), and 6 hours (GIII); and in PACAP-38 containing UW solution for 1 (GIV), 3 (GV), and 6 hours (GVI). Reperfusion lasted 3 hours in each group. Intestinal PACAP-38 immunoreactivities were measured by radioimmunoassay. To measure cytokine from tissue homogenates we used rat cytokine array and Luminex Multiplex Immunoassay. RESULTS: Levels of PACAP-38 like and PACAP-27-like immunoreactivities decreased by preservation time compared to control. This decrease was significant following 6 hours cold storage (p < 0.05). Values remained significantly higher in grafts stored in PACAP-38 containing UW. Expressions of sICAM-1, L-selectin, tissue inhibitor of metalloproteinase-1 were increased in GIII and were decreased in GVI. CONCLUSION: PACAP-38 increased tissue levels of PACAP-38 and PACAP-27, and decreased cytokine expression. This indicates that PACAP-38 has anti-inflammatory and cytoprotective effects in intestinal autotransplantation model. PMID- 24144818 TI - [New possibilities in practical education of surgery]. AB - The fast spread of laparoscopic surgery in the surgical community also required introduction of new methods of surgical education of these techniques. Training boxes applied for this reason meant a considerable help. The technique of the virtual reality introduced simulation, which is a new possibility in education. For the first time in the history of surgery we can measure medical students' or residents' dexterity and one can get acquainted with a surgical procedure in the form of "serious games". By application of the up-to-date imaging methods we can plan the movements of the surgeon's hand even before the planned operation, practice and repeating can contribute to the safety of the real procedure. Open surgical procedures can be practiced on plastic phantoms mimicking human anatomy and the use of interactive touch devices and e-learning can also contribute to practical education of surgery. PMID- 24144819 TI - [The mechanism of adhesion formation and the possibilities of modeling -- a preliminary study]. AB - A huge number of factors play a significant role in the process of adhesion formation, like bleeding, the presence of foreign bodies, tissue injury, tissue destruction, ischemia and hypoxia. Adhesions are present in 95% of the cases following abdominal surgery. As a result of adhesions a large number of postoperative complications can occur, such as abdominal pain, bowel motility disturbances and infertility. Hence, it is important to know the precise mechanism of adhesion formation process and establish a suitable animal model to investigate the underlying mechanisms. Molecules which play a part in the process of adhesion formation were collected from the international literature. Male Wistar rats were used to create the adhesion model. Bleeding, implantation of foreign bodies, creation of ischemic areas and tissue destructions were carried out. Within this experiment the tiny bleeding and ischemic areas did not result in adhesion formation. The adhesion formation due to foreign body implantation depends on the type of the materials. Due to the inhibitory mechanism of adhesion formation there was no adhesion detectable due to tiny peritoneal destruction. The most reliable model was the one when gross tissue destruction of the abdominal wall was applied and the resulting bleeding initiated the adhesion formation process. It is also extremely important to know the key participants in the complex process of adhesion formation. This reliable model can help to work out the proper method of prevention. PMID- 24144820 TI - [Trocar site herniation (TSH) following laparoscopic cholecystectomy: incidence, pathogenesis, and prevention -- animal study]. AB - INTRODUCTION: In 1968 R. E. Fear first reported a trocar site hernia (TSH) in his large series on laparoscopy. Currently, the incidence of TSH is estimated to be 0.65-2.80%. Ports >=10-mm are usually closed, but ports of the 5-mm trocars are always left open, which may lead to herniation. MATERIAL AND METHODS: Authors guided teaching courses for hands-on animal laparoscopic cholecystectomy (LC) operations, where trainees performed LC-s on 60 animals. Two and four weeks following the operations the animals underwent second look laparoscopy to detect adhesion formation. RESULTS: Trocar site herniation was observed, and in 20% of the animals herniation was found. 70% of the hernias were situated in the 5-mm ports and 30% in the 10-mm ports. CONCLUSION: Port sites should be closed to prevent the formation of TSH. Attention should be payed on the closure of 5-mm trocar sites as well. PMID- 24144821 TI - [The treatment of Aspergillus empyema using open thoraco-myoplasty with the preservation of lung function -- case report]. AB - CASE REPORT: Invasive aspergillosis is a life threatening complication in immune compromised patients causing lung tissue destruction. Aspergillus empyema requires aggressive multimodality treatment. MATERIAL AND METHOD: We present a case of Aspergillus empyema treated by thoracic and plastic surgery preserving the lung function in an 18 year-old male patient suffering dermatomyositis and treated with steroids for a long time. After open window thoracostomy (OWT) we used pedicled musculus latissimus dorsi (MLD) flap and mobilised the anterior serratus muscle to close the pleural cavity. CONCLUSION: The intrathoracic use of muscle flaps after OWT in case of chronic Aspergillus empyema can preserve the underlying lung tissue. Cooperation of thoracic and plastic surgeons - as in the cases presented - provides an excellent opportunity to treat successfully of otherwise hopeless patients. PMID- 24144822 TI - [Emergency surgery: nuisance or no-nonsense]. PMID- 24144823 TI - [To the Editor-in-Chief: Contribution to the topic discussed by Harsanyi et al., "Why is the scientometric gap widening? Deterioration of the scientific parameters of surgical specialties in Hungary"]. PMID- 24144824 TI - [15th Congress of the Endoscopy Section of the Hungarian Surgical Society, Herceghalom, October 12-13, 2013 -- Abstracts]. PMID- 24144826 TI - Reinforcement of denture base resin with short vegetable fiber. AB - OBJECTIVES: Short ramie fibers were selected to investigate the effect of fiber length and volume fraction on the flexural properties of ramie fiber reinforced denture base PMMA. With the aid of measured interfacial shear strength and theoretical prediction values, experimental results were well interpreted. METHODS: Interfacial properties between denture base PMMA and ramie fibers were evaluated by single fiber pull-out test. Then, chopped ramie fibers were pre stirred with PMMA powder by a mechanical blender and then mixed with MMA liquid to fabricate composites. Two crucial influencing factors, fiber volume fraction and fiber length, were studied to clarify their effects on flexural properties of composites. RESULTS: With 1.5mm fibers addition, flexural modulus of denture base PMMA rose from 2.50 to 3.46 GPa with 10 vol.% fibers, while flexural strength declined steadily with increment of fiber content. If fiber length was 3.0mm, the modulus showed a growth to 3.5 GPa at 4 vol.% fiber content followed by a drop to 3.00 GPa at 10 vol.%, whereas fluctuation in strength was experienced. Experimental results were discussed by comparison with two theoretical models. SIGNIFICANCE: Short ramie fiber reinforced denture base PMMA had higher flexural modulus than neat resin, while strength was lowered due to the weak interfacial adhesion. The potential of vegetable fibers as reinforcing agents for denture base should be further investigated by strengthening the interface between cellulose and denture base PMMA. PMID- 24144827 TI - Cellular changes in motor neuron cell culture produced by cytotoxic cerebrospinal fluid from patients with amyotrophic lateral sclerosis. AB - INTRODUCTION: The neurotoxic effects of cerebrospinal fluid (CSF) from patients with amyotrophic lateral sclerosis (ALS) have been reported by various authors who have attributed this neurotoxicity to the glutamate in CSF-ALS. MATERIAL AND METHODS: Cultures of rat embryonic cortical neurons were exposed to CSF from ALS patients during an incubation period of 24 hours. Optical microscopy was used to compare cellular changes to those elicited by exposure to 100MUm glutamate, and confocal microscopy was used to evaluate immunohistochemistry for caspase-3, TNFalpha, and peripherin. RESULTS: In the culture exposed to CSF-ALS, we observed cells with nuclear fragmentation and scarce or null structural modifications to the cytoplasmic organelles or to plasma membrane maintenance. This did not occur in the culture exposed to glutamate. The culture exposed to CSF-ALS also demonstrated increases in caspase-3, TNFalpha, and in peripherin co-locating with caspase-3, but not with TNFalpha, suggesting that TNFalpha may play an early role in the process of apoptosis. CONCLUSIONS: CFS-ALS cytotoxicity is not related to glutamate. It initially affects the nucleus without altering the cytoplasmic membrane. It causes cytoplasmic apoptosis that involves an increase in caspase-3 co-located with peripherin, which is also overexpressed. PMID- 24144829 TI - Portal venous gas and pneumatosis intestinalis in necrotizing pancreatitis. PMID- 24144828 TI - Infantile-onset ascending hereditary spastic paralysis: a case report and brief literature review. AB - BACKGROUND: Infantile-onset ascending hereditary spastic paralysis (IAHSP) is a rare, early-onset autosomal recessive motor neuron disease associated with mutations in ALS2. AIM: We studied a 17-year-old boy who had features of IAHSP. We also reviewed the current literature on ALS2-related syndromes. METHODS: Clinical and neuroimaging studies were performed. Blood DNA analyses were combined with mRNA studies in cultured skin fibroblasts. RESULTS: Like previously described cases, the patient presented with severe spastic paraparesis and showed rapid progression of paresis to the upper limbs. He also developed bulbar involvement and severe scoliosis during childhood. In blood DNA we identified a novel splice-site homozygous mutation in ALS2 (c.3836+1G > T), producing exon skipping in fibroblast mRNA and predicting premature protein truncation. CONCLUSIONS: This case adds to the allelic heterogeneity of IAHSP. Review of the pertinent literature indicates a fairly homogeneous clinical picture in IAHSP that should facilitate molecular confirmation and prevention of long-term complications. PMID- 24144830 TI - Chelating stability of an amphoteric chelating polymer flocculant with Cu(II), Pb(II), Cd(II), and Ni(II). AB - The absorption spectra of Cu(2+), Pb(2+), Cd(2+), and Ni(2+) chelates of an amphoteric chelating polymer flocculant (ACPF) were measured by ultraviolet spectrophotometry, and their compositions and stability constants (beta) were calculated. ACPF exhibited three apparent absorption peaks at 204, 251, and 285 nm. The CSS(-) group of ACPF reacted with Cu(2+), Ni(2+), Pb(2+), and Cd(2+) to form ACPF-Cu(2+), ACPF-Ni(2+), ACPF-Pb(2+), and ACPF-Cd(2+) chelates, respectively, according to a molar ratio of 2:1. The maximum absorption peaks of ACPF-Cu(2+), ACPF-Ni(2+), ACPF-Pb(2+), and ACPF-Cd(2+) appeared at 319, 326, 310, and 313.5 nm, respectively. The maximum absorption peaks of the chelates showed significant red shifting compared with the absorption peaks of ACPF. The beta values of the ACPF-Cu(2+), ACPF-Pb(2+), ACPF-Cd(2+), and ACPF-Ni(2+) chelates were (1.37+/-0.35)*10(12), (3.26+/-0.39)*10(11), (2.05+/-0.27)*10(11), and (3.04+/-0.45)*10(10), respectively. The leaching rate of heavy metal ions from the chelating precipitates decreased with increasing pH. ACPF-Cu(2+), ACPF Ni(2+), ACPF-Pb(2+), and ACPF-Cd(2+) were very stable at pH>=5.6. Cu(2+), Ni(2+), Pb(2+), and Cd(2+) concentrations in the leaching liquors were lower than the corresponding limits specified by the Integrated Wastewater Discharge Standard of China. PMID- 24144831 TI - Highly sensitive detection of chromium (III) ions by resonance Rayleigh scattering enhanced by gold nanoparticles. AB - Simple and sensitive determination of chromium (III) ions (Cr(3+)) has potential applications for detecting trace contamination in environment. Here, the assay is based on the enhancement of resonance Rayleigh scattering (RRS) by Cr(3+)-induced aggregation of citrate-capped gold nanoparticles (AuNPs). Transmission electron microscopy (TEM) and UV-vis absorption spectroscopy were employed to characterize the nanostructures and spectroscopic properties of the Cr(3+)-AuNP system. The experiment conditions, such as reaction time, pH value, salt concentration and interfering ions, were investigated. The combination of signal amplification of Cr(3+)-citrate chelation with high sensitivity of RRS technique allow a selective assay of Cr(3+) ions with a detection limit of up to 1.0 pM. The overall assay can be carried out at room temperature within only twenty minutes, making it suitable for high-throughput routine applications in environment and food samples. PMID- 24144832 TI - Description of spatial patterns of radionuclide deposition by lognormal distribution and hot spots. AB - Spatial distributions of activity density (kBq/m(2)) and activity concentration (Bq/kg) are studied on sites with non-cultivated soils. Fitting datasets with lognormal, Weibull and normal distributions with sampling size n >= 60 showed that radionuclide deposition ((90)Sr, (137)Cs, (238)Pu, (239+240)Pu, (241)Am) due to Chernobyl fallout no more than in 10% of cases are described by Weibull distribution, and in the rest of the cases--by lognormal distribution. However asymptotics of "righthand tail" of empirical (sample) distribution quite often differs from the right-hand tail asymptotics of lognormal distribution. Thereby lognormal distribution is only an approximate statistical model of radionuclides' spatial pattern. Estimates of site surface area with "hot spots" are considered. Also distributions of (137)Cs and (134)Cs activity concentration on the territory contaminated by Fukushima fallout are reviewed. Characteristics of activity concentration for Fukushima and Chernobyl fallouts are collated. The results obtained make it possible to suggest that in both cases spatial contaminations of soil are described by approximately the same statistical models. PMID- 24144833 TI - Clinical algorithms for the diagnosis and management of urological leaks following pelvic exenteration. AB - BACKGROUND: Urine leak following pelvic exenteration for locally advanced pelvic malignancy is a major complication leading to increased mortality, morbidity and length of stay. We reviewed our experience and developed a diagnostic and management algorithm for urine leaks in this patient population. METHODS: Consecutive patients who underwent en bloc cystectomy and conduit formation as part of pelvic exenteration at a single quaternary referral centre from 1995 to 2012 were reviewed. Patients with urine leak were identified. Medical records were reviewed to extract data on diagnosis and management and a suggested clinical algorithm was developed. RESULTS: Of 325 exenterations, there were 102 conduits, of which 15 patients (15%) developed a conduit related urine leak. Most (14/15) patients were symptomatic. Diagnosis was made by drain creatinine studies (12/15) and/or imaging (15/15). Management comprised of conservative management, radiologic urinary diversion, early surgical revision and late surgical revision in 3, 11, 2 and 1 patients respectively. Important lessons from our 17 year experience include a high index of suspicion in a patient who is persistently septic despite appropriate treatment, the importance of regular drain creatinine studies, CT (computer tomography) with delayed images (CT intravenous pyelogram) when performing a CT for investigation of sepsis and early aggressive management with radiologic urinary diversion to facilitate early healing. CONCLUSION: Urine leak after pelvic exenteration is a complex problem. Conservative management usually fails and early diagnosis and intervention is the key. It is hoped that our algorithms will facilitate diagnosis and subsequent management of this group of patients. PMID- 24144834 TI - NLRP3 polymorphisms are associated with late-onset Alzheimer's disease in Han Chinese. AB - The innate immunity and inflammatory response plays an important role in AD pathogenesis. Recently, a wealth of information linking the activation of NLRP3 inflammasome to Alzheimer's disease (AD) pathogenesis has emerged. Considering the pivotal role of NLRP3 in the inflammatory process and in AD, we hypothesized that variations in NLRP3 gene may also affect susceptibility to AD. Three selected functional single-nucleotide polymorphisms (SNPs) in NLRP3 gene (rs2027432, rs10754558, rs35829419) were genotyped in 1133 late-onset AD (LOAD) patients and 1159 healthy controls in a large Northern Han Chinese population. Among them, the 5'-flanking rs2027432 polymorphism seemed to be most associated with LOAD risk even after adjusting for age, gender, and ApoE epsilon4 status. For rs10754558, the genotype frequency differed significantly only in ApoE epsilon4 carriers. On the other hand, the minor A allele of rs35829419 (Q705K) polymorphism appeared to exert a protective effect against the development of LOAD. Our data support the notion that genetic variation in NLRP3 gene may contribute to LOAD risk in Northern Han Chinese. PMID- 24144835 TI - Survey of faculty perceptions regarding a peer review system. AB - PURPOSE: Virtually all radiologists participate in peer review, but to our knowledge, this is the first detailed study of their opinions toward various aspects of the process. METHODS: The study qualified for quality assurance exemption from the institutional review board. A questionnaire sent to all radiology faculty at our institution assessed their views about peer review in general, as well as case selection and scoring, consensus section review for rating and presentation of errors, and impact on radiologist performance. RESULTS: Of 52 questionnaires sent, 50 were completed (response rate, 96.2%). Of these, 44% agreed that our RADPEER-like system is a waste of time, and 58% believed it is done merely to meet hospital/regulatory requirements. Conversely, 46% agreed that peer review improves radiologist performance, 32% agreed that it decreases medical error, and 42% believed that peer review results are valuable to protect radiologists in cases referred to the medical board. A large majority perform all peer reviews close to the deadline, and substantial minorities frequently or almost always select more than one previous examination for a single medical record number (28%), consciously select "less time intensive" cases (22%), and intentionally avoid cases requiring more time to peer review (30%). DISCUSSION: Almost one-half of respondents agreed that peer review has value, but as currently performed is a waste of time. The method for selecting cases raises serious questions regarding selection bias. A new approach is needed that stresses education of all radiologists by learning from the mistakes of others. PMID- 24144836 TI - Sorafenib as monotherapy or in association with cytarabine and clofarabine for the treatment of relapsed/refractory FLT3 ITD-positive advanced acute myeloid leukemia. PMID- 24144837 TI - Preparation of cell-embedded colloidosomes in an oil-in-water emulsion. AB - Cell encapsulation by locking the interfacial microgels in a water-in-oil Pickering emulsion has currently been attracting intensive attention because of the biofriendly reaction condition. Various kinds of functional microgels can only stabilize an oil-in-water Pickering emulsion, and it is thus difficult to encapsulate cells in the emulsion where the cells are usually dispersed in the continuous phase. Herein, we introduce a facile method for preparing cell embedded colloidosomes in an oil-in-water emulsion via polyelectrolyte complexation. Escherichia coli (E. coli) was chosen as a model cell and embedded in the thin shell of chitosan/poly(N-isopropylacrylamide-co-acrylic acid) (P(NIPAM-co-AAc)) microcapsules. This is beneficial for expressing cell function because of the little resistance of mass exchange between the embedded cells and the external environment. Cells can be used in biocatalysis or biomedicine and our product will hold great promises to improve the performance in those fields. The synthesis route presents a platform to prepare cell-embedded microcapsules in an oil-in-water Pickering emulsion in a facile and biocompatible way. First, an emulsion stabilized by P(NIPAM-co-AAc) microgels was prepared. Then, the interfacial microgels in the emulsion were locked by chitosan to form colloidosomes. The mechanism of cell encapsulation in this system was studied via fluorescent labeling. The viability of E. coli after encapsulation is ca. 90%. Encapsulated E. coli is able to metabolize glucose from solution, and exhibits a slower rate than free E. coli. This demonstrates a diffusion constraint through the colloidosome shell. PMID- 24144838 TI - AmphoraNet: the webserver implementation of the AMPHORA2 metagenomic workflow suite. AB - MOTIVATION: Metagenomics went through an astonishing development in the past few years. Today not only gene sequencing experts, but numerous laboratories of other specializations need to analyze DNA sequences gained from clinical or environmental samples. Phylogenetic analysis of the metagenomic data presents significant challenges for the biologist and the bioinformatician. The program suite AMPHORA and its workflow version are examples of publicly available software that yields reliable phylogenetic results for metagenomic data. RESULTS: Here we present AmphoraNet, an easy-to-use webserver that is capable of assigning a probability-weighted taxonomic group for each phylogenetic marker gene found in the input metagenomic sample; the webserver is based on the AMPHORA2 workflow. Since a large proportion of molecular biologists uses the BLAST program and its clones on public webservers instead of the locally installed versions, we believe that the occasional user may find it comfortable that, in this version, no time consuming installation of every component of the AMPHORA2 suite or expertise in Linux environment is required. AVAILABILITY: The webserver is freely available at http://amphoranet.pitgroup.org; no registration is required. PMID- 24144839 TI - A common polymorphism in pre-microRNA-146a is associated with lung cancer risk in a Korean population. AB - INTRODUCTION: MicroRNAs (miRs) play important roles in the development and progression of human cancers. MiR-146a down-regulates epidermal growth factor receptor and the nuclear factor-kappaB regulatory kinase interleukin-1 receptor associated kinase 1 genes that play important roles in lung carcinogenesis. This study was conducted to evaluate the association between rs2910164C>G, a functional polymorphism in the pre-miR-146a, and lung cancer risk. MATERIAL AND METHODS: The rs2910164C>G genotypes were determined in 1094 patients with lung cancer and 1100 healthy controls who were frequency matched for age and gender. RESULTS: The rs2910164 CG or GG genotype was associated with a significantly decreased risk for lung cancer compared to that of the CC genotype (adjusted odds ratio=0.80, 95% confidence interval=0.66-0.96, P=0.02). When subjects were stratified according to smoking exposure (never, light and heavy smokers), the effect of the rs2910164C>G genotype on lung cancer risk was significant only in never smokers (adjusted odds ratio=0.66, 95% confidence interval=0.45-0.96, P=0.03, under a dominant model for the C allele) and decreased as smoking exposure level increased (Ptrend<0.001). In line with this result, the level of miR-146a expression in the tumor tissues was significantly higher in the GG genotype than in the CC or CG genotype only in never-smokers (P=0.02). CONCLUSIONS: These findings suggest that the rs2910164C>G in pre-miR-146a may contribute to genetic susceptibility to lung cancer, and that miR-146a might be involved in lung cancer development. PMID- 24144840 TI - Association between JY-1 gene polymorphisms and reproductive traits in beef cattle. AB - Reproductive traits have a high economic value and it is interesting to include them in the selection objectives of an animal breeding program. These traits generally show low heritability and molecular markers may therefore be used in genetic evaluations to improve the accuracy of predictions. The JY-1 gene is expressed in the oocyte and it is associated with folliculogenesis and early embryo development. It has been suggested to affect reproductive traits. In this study, exons 1 and 2 of the JY-1 gene were studied in 385 Nellore females by PCR sequencing. Seventeen polymorphisms were identified. After analysis of linkage disequilibrium, association tests were performed between eight SNPs and the occurrence of early pregnancy, age at first calving, days to calving, and reconception of primiparous heifers. Seven SNPs were significant for three traits. The most significant was chr29:12,999 T/A (p=0.003) which was associated with the occurrence of early pregnancy. This SNP might be involved in protein translation inhibition since it affects the initial methionine codon. The JY-1, an oocyte specific gene, influences reproductive traits; further studies investigating other regions of the gene or other genes expressed in tissues of the female reproductive system would be interesting to be performed. PMID- 24144841 TI - Cloning and characterization of the promoter regions from the parent and paralogous creatine transporter genes. AB - Interconversion between phosphocreatine and creatine, catalyzed by creatine kinase is crucial in the supply of ATP to tissues with high energy demand. Creatine's importance has been established by its use as an ergogenic aid in sport, as well as the development of intellectual disability in patients with congenital creatine deficiency. Creatine biosynthesis is complemented by dietary creatine uptake. Intracellular transport of creatine is carried out by a creatine transporter protein (CT1/CRT/CRTR) encoded by the SLC6A8 gene. Most tissues express this gene, with highest levels detected in skeletal muscle and kidney. There are lower levels of the gene detected in colon, brain, heart, testis and prostate. The mechanism(s) by which this regulation occurs is still poorly understood. A duplicated unprocessed pseudogene of SLC6A8-SLC6A10P has been mapped to chromosome 16p11.2 (contains the entire SLC6A8 gene, plus 2293 bp of 5'flanking sequence and its entire 3'UTR). Expression of SLC6A10P has so far only been shown in human testis and brain. It is still unclear as to what is the function of SLC6A10P. In a patient with autism, a chromosomal breakpoint that intersects the 5'flanking region of SLC6A10P was identified; suggesting that SLC6A10P is a non-coding RNA involved in autism. Our aim was to investigate the presence of cis-acting factor(s) that regulate expression of the creatine transporter, as well as to determine if these factors are functionally conserved upstream of the creatine transporter pseudogene. Via gene-specific PCR, cloning and functional luciferase assays we identified a 1104 bp sequence proximal to the mRNA start site of the SLC6A8 gene with promoter activity in five cell types. The corresponding 5'flanking sequence (1050 bp) on the pseudogene also had promoter activity in all 5 cell lines. Surprisingly the pseudogene promoter was stronger than that of its parent gene in 4 of the cell lines tested. To the best of our knowledge, this is the first experimental evidence of a pseudogene with stronger promoter activity than its parental gene. PMID- 24144842 TI - PacBio sequencing of gene families - a case study with wheat gluten genes. AB - Amino acids in wheat (Triticum aestivum) seeds mainly accumulate in storage proteins called gliadins and glutenins. Gliadins contain alpha/beta-, gamma- and omega-types whereas glutenins contain HMW- and LMW-types. Known gliadin and glutenin sequences were largely determined through cloning and sequencing by capillary electrophoresis. This time-consuming process prevents us to intensively study the variation of each orthologous gene copy among cultivars. The throughput and sequencing length of Pacific Bioscience RS (PacBio) single molecule sequencing platform make it feasible to construct contiguous and non-chimeric RNA sequences. We assembled 424 wheat storage protein transcripts from ten wheat cultivars by using just one single-molecule-real-time cell. The protein genes from wheat cultivar Chinese Spring are comparable to known sequences from NCBI. We demonstrated real-time sequencing of gene families with high-throughput and low-cost. This method can be applied to studies of gene amplification and copy number variation among species and cultivars. PMID- 24144843 TI - Tri-allelic pattern at the TPOX locus: a familial study. AB - Alleles at the TPOX STR locus have 6-14 different numbers of a four-nucleotide (AATG) repeat motif arranged in tandem. Although tri-allelic genotypes are generally rare, the TPOX tri-allelic pattern has a higher frequency, varying widely among populations. Despite this, there are few accurate reports to disclose the nature of the TPOX third allele. In this work we present data obtained from 45 individuals belonging to the same pedigree, in which there are cases of tri-allelic TPOX genotypes. The subjects were apparently healthy with a normal biological development. We noticed six tri-allelic cases in this family, and all of them were women. Karyotype analysis showed no occurrence of partial 2p trisomy. All the tri-allelic cases had the genotype 8-10-11, probably due to three copies of the TPOX STR sequence in all cells (Type 2 tri-allelic pattern). Based on previous data we assumed the allele 10 as the TPOX third allele. The pedigree analyses show evidences that the TPOX extra-allele was the allele10, it is placed far from the main TPOX locus, and that there is a potential linkage of the TPOX extra-allele-10 with Xq. This was the first study that included a large pedigree analysis in order to understand the nature TPOX tri-allelic pattern. PMID- 24144845 TI - Universal newborn screening for haemoglobinopathies in Guadeloupe (French West Indies): a 27-year experience. AB - OBJECTIVES: In Guadeloupe, an island in the French West Indies, a universal newborn screening programme for sickle cell disease and other abnormal haemoglobins was initiated in 1984. In 1990, a comprehensive sickle cell centre was established to carry on the management programme. We here report the main results from the newborn screening programme from 1984 to 2010, and consider how the establishment of the sickle cell centre affected the programme. METHODS: All blood samples were screened for the haemoglobinopathies using two reference methods in a single reference diagnosis laboratory. DNA analyses were also performed for confirmatory tests and analysis of the globin gene status. RESULTS: Between 1 January 1984 and 31 December 2010, 178,428 newborns were screened at birth, and 585 children were diagnosed with major sickle cell syndromes (ie. an overall incidence of 1 in 304 births). Sickle cell anaemia (haemoglobin SS disease) was the most frequently observed (1 in 575 births), followed by haemoglobin SC disease (1 in 771 births) and haemoglobin Sbeta-thalassemia disease (1 in 4,243 births). Some other rare haemoglobin variants were also detected, the most common being HbD(Punjab). The establishment of a comprehensive sickle cell centre resulted in a significant improvement in the screening coverage (p < 0.001) and a significant reduction of the delay between diagnosis and the first medical visit (p < 0.001). CONCLUSION: The universal screening programme has made it possible to establish the incidence of the major sickle cell syndromes in Guadeloupe, and the management centre has improved its efficiency. PMID- 24144844 TI - Analysis of mutant frequencies and mutation spectra in hMTH1 knockdown TK6 cells exposed to UV radiation. AB - Ultraviolet radiation is a highly mutagenic agent that damages the DNA by the formation of mutagenic photoproducts at dipyrimidine sites and by oxidative DNA damages via reactive oxygen species (ROS). ROS can also give rise to mutations via oxidation of dNTPs in the nucleotide pool, e.g. 8-oxo-dGTP and 2-OH-dATP and subsequent incorporation during DNA replication. Here we show that expression of human MutT homolog 1 (hMTH1) which sanitizes the nucleotide pool by dephosphorylating oxidized dNTPs, protects against mutagenesis induced by long wave UVA light and by UVB light but not by short wave UVC light. Mutational spectra analyses of UVA-induced mutations at the endogenous Thymidine kinase gene in human lymphoblastoid cells revealed that hMTH1 mainly protects cells from transitions at GC and AT base pairs. PMID- 24144846 TI - The first five years of a preventive programme for haemoglobinopathies in Northeastern Iraq. AB - OBJECTIVE: To evaluate the feasibility and effectiveness of a preventive programme for haemoglobinopathies in a single centre in Northeastern Iraq. METHODS: Premarital screening, genetic counselling and prenatal diagnosis (PND) were implemented over a 5 year period. RESULTS: Among a total of 108,264 screened individuals (54,132 couples), beta-thalassaemia trait, deltabeta-thalassaemia trait, and sickle cell trait were diagnosed in 3.98%, 0.11% and 0.07%, respectively. Of 130 at risk couples (2.4/1000), 107 (82%) were available for follow up, with 105 couples (98.1%) proceeding with their marriage after counselling. In the 125 registered pregnancies in the latter couples, PND was performed in 85 (in 80 couples, uptake 76%). Selective termination was chosen in 10 of the 11 pregnancies with an affected fetus. Six affected babies were born among couples who declined PND. At the same time 30 already married couples with at least one thalassaemic child underwent PND, revealing three affected fetuses; all three pregnancies were terminated. CONCLUSION: The programme revealed that most at risk couples diagnosed by premarital screening chose to proceed with their marriage, with 76% seeking PND followed by selective termination of an affected fetus. A 65% reduction in number of affected births was reported over the 5 year period. This regional programme could serve as a prototype for a national haemoglobinopathy prevention programme. PMID- 24144847 TI - Uncontrolled confounding in studies of screening effectiveness: an example of colonoscopy. AB - OBJECTIVE: To estimate the expected magnitude of error produced by uncontrolled confounding from health behaviours in observational medical record-based studies evaluating effectiveness of screening colonoscopy. METHODS: We used data from the prospective National Institutes of Health American Association of Retired Persons (NIH-AARP) Diet and Health Study to assess the impact of health behaviour related factors (lifestyle, education, and use of non-steroidal anti-inflammatory drugs [NSAID]) on the association between colonoscopy and colorectal cancer (CRC) mortality. We first examined the difference between adjusted and unadjusted results within the cohort data, and then estimated a broader range of likely confounding errors based on the Breslow-Day approach that uses prevalence of confounders among persons with and without exposure, and the rate ratio reflecting the association between these confounders and the outcome of interest. As dietary factors and habits are often inter-correlated, we combined these variables (physical activity, body mass index, waist-to-hip ratio, alcohol consumption, and intakes of red meat, processed meat, fibre, milk, and calcium) into a "healthy lifestyle score" (HLS). RESULTS: The estimated error (a ratio of biased-to-true result) attributable to confounding by HLS was 0.959-0.997, indicating less than 5% departure from the true effect of colonoscopy on CRC mortality. The corresponding errors ranged from 0.970 to 0.996 for NSAID, and from 0.974 to 1.006 for education (all <=3% difference). The results for other CRC screening tests were similar. CONCLUSION: Health behaviour-related confounders, either alone or in combination, seem unlikely to strongly affect the association between colonoscopy and CRC mortality in observational studies of CRC screening. PMID- 24144848 TI - Anti-cancer evaluation of carboxamides of furano-sesquiterpene carboxylic acids from the soft coral Sinularia kavarattiensis. AB - The chemical investigation of soft coral Sinularia kavarattiensis is described. It yielded furano-sesquiterpene carboxylic acids 1 and 2 and their methyl esters 3 and 4. Semi-synthesis of furano-sesquiterpene carboxylic acid 1 gave amide derivatives 5-12. Structures of all the compounds were established by IR, NMR and mass spectral analysis. Interestingly all compounds are selectively potent on leukemia cell line. All these compounds were screened for cytotoxic activity against five human cancer cell lines (leukemia, prostate, lung, breast and cervix). Among these compounds 9 and 10 showed promising activity against leukemia and prostate cancer cell lines. PMID- 24144849 TI - Pahangensin A and B, two new antibacterial diterpenes from the rhizomes of Alpinia pahangensis Ridley. AB - The rhizomes of Alpinia pahangensis Ridley yielded a new bis-labdanic diterpene for which the name pahangensin A (1) was proposed along with a new labdane diterpene, pahangensin B (2). Their structures were elucidated by spectroscopic methods including, 1D and 2D NMR techniques and LCMS-IT-TOF analysis. Pahangensin A (1) was found to be an antibacterial agent against Staphylococcus aureus, Bacillus cereus and Bacillus subtilis with MIC values less than 100 MUg/mL, respectively. Pahangensin B (2) exhibited antibacterial activity (MIC <100 MUg/mL) against B. cereus. PMID- 24144850 TI - Design checkpoint kinase 2 inhibitors by pharmacophore modeling and virtual screening techniques. AB - Damage to DNA is caused by ionizing radiation, genotoxic chemicals or collapsed replication forks. When DNA is damaged or cells fail to respond, a mutation that is associated with breast or ovarian cancer may occur. Mammalian cells control and stabilize the genome using a cell cycle checkpoint to prevent damage to DNA or to repair damaged DNA. Checkpoint kinase 2 (Chk2) is one of the important kinases, which strongly affects DNA-damage and plays an important role in the response to the breakage of DNA double-strands and related lesions. Therefore, this study concerns Chk2. Its purpose is to find potential inhibitors using the pharmacophore hypotheses (PhModels) and virtual screening techniques. PhModels can identify inhibitors with high biological activities and virtual screening techniques are used to screen the database of the National Cancer Institute (NCI) to retrieve compounds that exhibit all of the pharmacophoric features of potential inhibitors with high interaction energy. Ten PhModels were generated using the HypoGen best algorithm. The established PhModel, Hypo01, was evaluated by performing a cost function analysis of its correlation coefficient (r), root mean square deviation (RMSD), cost difference, and configuration cost, with the values 0.955, 1.28, 192.51, and 16.07, respectively. The result of Fischer's cross-validation test for the Hypo01 model yielded a 95% confidence level, and the correlation coefficient of the testing set (rtest) had a best value of 0.81. The potential inhibitors were then chosen from the NCI database by Hypo01 model screening and molecular docking using the cdocker docking program. Finally, the selected compounds exhibited the identified pharmacophoric features and had a high interaction energy between the ligand and the receptor. Eighty-three potential inhibitors for Chk2 are retrieved for further study. PMID- 24144851 TI - The design of a novel series of muscarinic receptor antagonists leading to AZD8683, a potential inhaled treatment for COPD. AB - A novel series of muscarinic receptor antagonists was developed, with the aim of identifying a compound with high M3 receptor potency and a reduced risk of dose limiting side effects with potential for the treatment of COPD. Initial compound modifications led to a novel cycloheptyl series, which was improved by focusing on a quinuclidine sub-series. A wide range of N-substituents was evaluated to determine the optimal substituent providing a high M3 receptor potency, high intrinsic clearance and high human plasma protein binding. Compounds achieving in vitro study criteria were selected for in vivo evaluation. Pharmacokinetic half lives, inhibition of bronchoconstriction and duration of action, as well as systemic side effects, induced by the compounds were assessed in guinea-pig models. Compounds with a long duration of action and good therapeutic index were identified and AZD8683 was selected for progression to the clinic. PMID- 24144852 TI - Dual isotope labeling: conjugation of 32P-oligonucleotides with 18F aryltrifluoroborate via copper(I) catalyzed cycloaddition. AB - A one-pot-two-step labeling of an oligonucleotide with an (18)F-ArBF3( )(aryltrifluoroborate) radioprosthetic is reported herein. In order to characterize labeling in terms of radiochemistry, phosphorus-32 was also introduced to the 5'-terminus of the oligonucleotide via enzymatic phosphorylation. A pendant azide group was subsequently conjugated to the 5' phosphate of the oligonucleotide. Copper(I) catalyzed [2+3] cycloaddition was undertaken to conjugate an alkyne-bearing(18)F-ArBF3(-) to the oligonucleotide. Following polyacrylamide gel electrophoresis, this doubly-labeled bioconjugate exhibited decay properties of both the phosphorus-32 and fluorine-18, that were confirmed by autoradiography at selected lengths of time, which in turn provided concrete evidence of successful conjugation. These results are corroborated by HPLC analysis of the labeled material. Taken together this work demonstrates viable use of (18)F-ArBF3(-) prosthetics for labeling oligonucleotides for use in PET imaging. PMID- 24144853 TI - Synthesis of 3-spiromorpholinone androsterone derivatives as inhibitors of 17beta hydroxysteroid dehydrogenase type 3. AB - Spiromorpholinone derivatives were synthesized from androsterone or cyclohexanone in 6 or 3 steps, respectively, and these scaffolds were used for the introduction of a hydrophobic group via a nucleophilic substitution. Non-steroidal spiromorpholinones are not active as inhibitors of 17beta-hydroxysteroid dehydrogenase type 3 (17beta-HSD3), but steroidal morpholinones are very potent inhibitors. In fact, those with (S) stereochemistry are more active than their (R) homologues, whereas N-benzylated compounds are more active than their non substituted precursors. The target compounds exhibited strong inhibition of 17beta-HSD3 in rat testis homogenate (87-92% inhibition at 1 MUM). PMID- 24144854 TI - Schiff's base derivatives bearing nitroimidazole moiety: new class of antibacterial, anticancer agents and potential EGFR tyrosine kinase inhibitors. AB - New Schiff's base derivatives 5a-5h have been synthesized by reaction between 1 (4-bromophenyl)-2-(2-methyl-5-nitro-1H-imidazol-1-yl)ethanone 3 and various benzohydrazide 4a-4h in presence of nickel (II) nitrate as a catalyst in ethanol at room temperature in good yield (54-88%). All compounds were tested for antibacterial as well as anticancer and inhibition of EGFR. Of the compounds studied, compounds 5d, 5f and 5g in the case of antiproliferation and inhibition of EGFR as well as compounds 5b, 5c, 5e and 5h in the case of antibacterial activity were found to be most effective compounds in the series. Compound 5f shows effective inhibition (IC50=0.21+/-0.02 MUM) by binding in to the active pocket of EGFR receptor with minimum binding energy (DeltaGb=-49.4869 kcal/mol). PMID- 24144855 TI - A multidisciplinary weight of evidence approach for environmental risk assessment at the Costa Concordia wreck: Integrative indices from Mussel Watch. AB - A complex framework of chemical, biological and oceanographic activities was immediately activated after the Costa Concordia shipwreck, to assess possible contamination events and the environmental impact during both emergency and wreck removal operations. In the present paper, we describe the results obtained with caged mussels, Mytilus galloprovincialis, chosen as bioindicator organisms to detect variations of bioavailability and the early onset of molecular and cellular effects (biomarkers). Seven translocation experiments were carried out during the first year from the incident, with organisms deployed at 2 depths in 3 different sites. After 4-6 weeks, tissue concentrations were measured for the main classes of potentially released chemicals (trace metals, polycyclic aromatic hydrocarbons, volatile and aliphatic hydrocarbons, polychlorinated biphenyls, halogenated pesticides, organotin compounds, brominated flame retardants, anionic surfactants); a wide battery of biomarkers covered responses indicative of exposure, detoxification, oxidative stress, cell damage and genotoxic effects. Results excluded serious contamination events or a consistent increase of environmental pollution although some episodic spills with reversible effects were detected. Data were elaborated within a quantitative weight of evidence (WOE) model which provided synthetic hazard indices for each typology of data, before their overall integration in an environmental risk index, which generally ranged from slight to moderate. The proposed WOE model was confirmed a useful tool to summarize large datasets of complex data in integrative indices, and to simplify the interpretation for stakeholders and decision makers, thus supporting a more comprehensive process of "site-oriented" management decisions. PMID- 24144857 TI - [4th Interdisciplinary Conference of the Hungarian Medical Journal (Orvosi Hetilap), October 18-19, 2013, Budapest - Program and abstracts]. PMID- 24144856 TI - Behavioral responses of a harbor porpoise (Phocoena phocoena) to playbacks of broadband pile driving sounds. AB - The high under-water sound pressure levels (SPLs) produced during pile driving to build offshore wind turbines may affect harbor porpoises. To estimate the discomfort threshold of pile driving sounds, a porpoise in a quiet pool was exposed to playbacks (46 strikes/min) at five SPLs (6 dB steps: 130-154 dB re 1 MUPa). The spectrum of the impulsive sound resembled the spectrum of pile driving sound at tens of kilometers from the pile driving location in shallow water such as that found in the North Sea. The animal's behavior during test and baseline periods was compared. At and above a received broadband SPL of 136 dB re 1 MUPa [zero-peak sound pressure level: 151 dB re 1 MUPa; t90: 126 ms; sound exposure level of a single strike (SELss): 127 dB re 1 MUPa(2) s] the porpoise's respiration rate increased in response to the pile driving sounds. At higher levels, he also jumped out of the water more often. Wild porpoises are expected to move tens of kilometers away from offshore pile driving locations; response distances will vary with context, the sounds' source level, parameters influencing sound propagation, and background noise levels. PMID- 24144858 TI - Joint contribution to fingertip movement during a number entry task: an application of Jacobian matrix. AB - Upper extremity kinematics during keyboard use is associated with musculoskeletal health among computer users; however, specific kinematics patterns are unclear. This study aimed to determine the dynamic roles of the shoulder, elbow, wrist and metacarpophalangeal (MCP) joints during a number entry task. Six subjects typed in phone numbers using their right index finger on a stand-alone numeric keypad. The contribution of each joint of the upper extremity to the fingertip movement during the task was calculated from the joint angle trajectory and the Jacobian matrix of a nine-degree-of-freedom kinematic representation of the finger, hand, forearm and upper arm. The results indicated that in the vertical direction where the greatest fingertip movement occurred, the MCP, wrist, elbow (including forearm) and shoulder joint contributed 10.2%, 55.6%, 27.7% and 6.5%, respectively, to the downward motion of the index finger averaged across subjects. The results demonstrated that the wrist and elbow contribute the most to the fingertip vertical movement, indicating that they play a major role in the keying motion and have a dynamic load beyond maintaining posture. PMID- 24144859 TI - Low-abundance envelope protein VP12 of white spot syndrome virus interacts with envelope protein VP150 and capsid protein VP51. AB - VP12 and VP150 are two minor envelope proteins of white spot syndrome virus (WSSV). In our previous studies, VP12 was found to co-migrate with 53-kDa form of VP150 on two-dimensional Blue Native/SDS-PAGE, suggesting that there is an interaction between them. In this study, we confirmed the interaction by co immunoprecipitation assay and demonstrated that the binding region with VP12 is located between residues 207 and 803 of VP150. Further studies found that VP12 can be attached to WSSV capsids by interacting with capsid protein VP51. These findings suggest that VP12 may function as a linker protein participating in the linkage between VP12/VP150 complex and viral nucleocapsid. PMID- 24144860 TI - Genetic characterization of Duck Hepatitis A Viruses isolated in China. AB - In recent years, the spread of Duck Hepatitis A Viruses (DHAVs) has represented a serious threat and significant economic impact in duck industry of China. The sixteen reported DHAV isolates (15 DHAV-1 strains and one DHAV-3) were identified from infected ducks with clinical symptoms in China between 2009 and 2012. In the present study, the virulence of these viruses and complete sequences of the virion protein 1 (VP1) genes of the 16 DHAVs were characterized. The median embryonic lethal doses (ELD50) of the second generation duck embryo allantoic fluid of the 16 DHAV isolates were calculated on duck and chicken embryos. The results demonstrated that the various DHAV-1 strains have shown different pathogenic ability in embryos, and duck eggs were more susceptible to DHAV than chicken eggs. The histopathological examination revealed significant signs of virus infection, severe vacuolation, and hepatocyte necrosis. Phylogenetic analyses indicated that the 15 DHAV-1 viruses display significant correlation in their geographic distribution. The DHAV-1 strains isolated from Shandong Province were more evolutionarily divergent than the JX strains. There were two hypervariable regions in the VP1 protein, which may determine the virulence of DHAV-1 isolates in chicken eggs but not virulence in duck eggs. These results demonstrate the genetic and biological diversity of DHAVs in China and aid in understanding the epidemiology and evolution of DHAVs. PMID- 24144861 TI - Further characteristics of Arcanobacterium canis, a novel species of genus Arcanobacterium. AB - Comparable to previously conducted phenotypical and genotypical investigations characterizing Arcanobacterium canis, a newly described species with the type strain A. canis DSM 25104 isolated from an otitis externa of a dog, four additional A. canis strains isolated from infections of three dogs and one cat could reliably be identified by phenotypic properties, by matrix-assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOF MS) and by sequencing the genomic targets 16S rDNA, 16S-23S rDNA intergenic spacer region, 23S rDNA, and the genes rpoB and gap. All four A. canis investigated in the present study were isolated from the infected animals together with several other bacterial species indicating that the pathogenic importance of A. canis remains unclear. However, the detection of peptidic spectra by MALDI-TOF MS and the presented phenotypic and genotypic approaches might help to identify A. canis in future and might elucidate the role this species plays in infections of dogs and cats. PMID- 24144862 TI - Is the horse a reservoir or an indicator of Coxiella burnetii infection? Systematic review and biomolecular investigation. AB - The role of the horse in Coxiella burnetii infection has not been defined. Accordingly, a twofold approach was taken to further our knowledge on this topic: (1) conduct a systematic review of the literature to establish available evidence of C. burnetii infection in the horse; (2) undertake a biomolecular investigation of 122 cases of equine abortion, stillbirth and neonatal foal death, for the presence of C. burnetii using a PCR test targeting the IS1111 gene of C. burnetii. A review of the literature turned up seven studies that identified C. burnetii DNA in equine specimens, especially aborted fetuses, while an additional 34 studies sought to determine seroprevalence of the infection in the horse. A meta-analytical approach was taken to calculate a pooled mean seroprevalence in equines based on published studies. A seroprevalence of 15.8% (95% confidence interval: 9.6-23.0%) was obtained. This figure is comparable to those previously reported in other species, especially ruminants. None of the 122 cases of equine abortion, stillbirth or neonatal foal death were positive for C. burnetii DNA. C. burnetii has rarely been looked for in equine specimens in previous studies. Cases of equine abortion should be comprehensively investigated to assess the risk of abortion in a pregnant mare infected with C. burnetii. Consideration should also be given to the possible role of the horse as a source of the organism for other animal species including humans. PMID- 24144863 TI - Evaluation of the impact of standardization process on the quality of serum creatinine determination in Italian laboratories. AB - BACKGROUND: Creatinine determination in serum is a key indicator of kidney glomerular function. A reference measurement system for its standardization is available and virtually all IVD manufacturers have aligned their assays to this system. In this study, we verified the impact of these standardization efforts on the results of an Italian EQAS involving about 430 laboratories. METHOD: We considered data obtained during 2006, 2010 and 2011 schemes of EQAS Prolarit for control materials with target values assigned by a traceable method (enzymatic assay calibrated against the NIST SRM 967). RESULTS: The results showed a good alignment at concentrations ~170MUmol/L, with 2011 results - except for one method group - well inside the desirable bias (+/-4%). At higher concentrations, whereas the bias was small in 2010, for some groups using alkaline-picrate (AP) methods it became significantly negative in 2011. The performance seems to worsen when measuring physiologic concentrations, where a significant positive bias (up to ~20%) is shown by most of the AP-based analytical systems. With few exceptions, no evident improvement in individual assay bias was noted from pre- (2006) to post-standardization (2011) periods. The enzymatic method groups were the only always presenting an acceptable bias at all creatinine concentrations, also showing the lowest between-laboratory variability. CONCLUSION: Our data seem to indicate that the standardization efforts are still having effects lower than expected. Even taking into consideration that some of the bias may derive from non commutability problems, most of the current "standardized" AP-based methods, at the lower creatinine concentrations, seem to present accuracy problems. This inaccuracy can adversely impact the estimation of GFR by equations and the evaluation of kidney function in pediatrics. PMID- 24144864 TI - Validating common reference intervals in routine laboratories. AB - Common reference intervals for numerical pathology tests have been proposed for many years as an improvement over the common situation where individual laboratories establish or select and validate their own intervals. However it is important that any intervals that are developed for common use are themselves validated for use in individual laboratories. There are three main aspects to consider, the appropriateness of the interval, methodological factors and population factors. Techniques for assessing method biases are reasonably straightforward with the use of shared samples and appropriate external quality assurance schemes. Validating the local population, which also encompasses the laboratory's method, can be done using a number of healthy subjects, the more the better, or by various "data mining" techniques using the results of tests performed on routine patients. In any of these methods there is the need to consider the selection of subjects, the statistical approach and the acceptance criteria. Only if a proposed common reference interval can be shown to be appropriate in routine laboratories can it become widely adopted and become truly "common". PMID- 24144865 TI - VEGF-C in non-small cell lung cancer: meta-analysis. AB - BACKGROUND: We sought to clarify the prognostic value of vascular endothelial growth factor C (VEGF-C) in survival of patients with non-small cell lung cancer (NSCLC). METHODS: We performed a meta-analysis of relevant literature to aggregate the available survival results, using studies published in English until May 2013. Eligible studies dealt with VEGF-C assessment in NSCLC patients on primary lesions and reported survival data according to VEGF-C expression. RESULTS: We aggregated 16 trials, comprising 1988 patients, in this meta analysis. The overall combined hazard ratio (HR) was 1.65 (95% confidence interval (CI): 1.37-1.98) and was calculated using a random-effects model. It associated high VEGF-C expression with poor survival in all NSCLC patients, including those with stage I NSCLC and high VEGF-C expression (HR: 2.00; 95% CI: 1.22-3.28). However, VEGF-C expression did not significantly correlate with survival in patients with lung adenocarcinoma (ADC) (HR: 1.48; 95% CI: 1.01 2.18). CONCLUSION: Our meta-analysis shows that VEGF-C expression is associated with poor prognosis for NSCLC patients, including patients with stage I NSCLC. However, VEGF-C expression is not significantly correlated with survival for patients with lung ADC. PMID- 24144866 TI - CD2AP mRNA in urinary exosome as biomarker of kidney disease. AB - AIMS: Podocyte injury plays an important role in the pathogenesis of kidney disease. Urinary exosomes are microvesicles released by tubular epithelial cells and podocytes containing information of their originated cells. This study investigated for the first time whether podocyte related mRNA in urinary exosome could serve as novel biomarkers for kidney disease. METHODS: Urine samples were collected from 32 patients of kidney disease who underwent kidney biopsy and 7 controls. CD2AP, NPHS2 and synaptopodin were detected by real-time RT-PCR on RNA isolated from urinary exosome. RESULTS: The pellet microvesicles were positively stained with exosome and podocyte marker, AQP2, CD9 and nephrin. CD2AP mRNA was lower (p=0.008) in kidney disease patients compared with controls and decreased with the increasing severity of proteinuria (p=0.06). CD2AP correlated with serum creatinine (r=-0.373, p=0.035), BUN (r=-0.445, p=0.009) and eGFR (r=0.351, p=0.046). Neither NPHS2 nor synaptopodin correlated with parameters of renal function. CD2AP mRNA correlated negatively with 24 hour urine protein (r=-0.403, p=0.022), severity of tubulointerstitial fibrosis (r=-0.394, p=0.026) and glomerulosclerosis (r=-0.389, p=0.031) and could discriminate kidney disease from controls with AUC of 0.821 (p=0.008). CONCLUSIONS: Urinary exosome mRNA of CD2AP might be a non-invasive tool for detecting both renal function and fibrosis of kidney disease. PMID- 24144867 TI - Investigation and identification of potential biomarkers in human saliva for the early diagnosis of oral squamous cell carcinoma. AB - BACKGROUND: Oral cancer is 1 of the 6 most common human cancers, with an annual incidence of >300,000 cases worldwide. This study aimed to investigate potential biomarkers in human saliva to facilitate the early diagnosis of oral squamous cell carcinoma (OSCC). METHODS: Unstimulated whole saliva obtained from OSCC patients (n=30) and apparently healthy individuals (n=30) were assayed with ultra performance liquid chromatography-mass spectrometry (UPLC-MS) in hydrophilic interaction chromatography mode. The data were analyzed using a nonparametric Mann-Whitney U test, logistic regression, and the receiver operating characteristic (ROC) to evaluate the predictive power of each of 4 biomarkers, or combinations of biomarkers, for OSCC screening. RESULTS: Four potential salivary biomarkers demonstrated significant differences (P<0.05) in concentrations between patients at stages I-II and the healthy individuals. The area under the curve (AUC) values in control vs OSCC I-II mode based on choline, betaine, pipecolinic acid, and l-carnitine were 0.926, 0.759, 0.994, and 0.708, respectively. Four salivary biomarkers in combination yielded satisfactory accuracy (0.997), sensitivity (100%), and specificity (96.7%) in distinguishing OSCC I-II from control. CONCLUSIONS: Salivary metabolite biomarkers for the early diagnosis of OSCC were verified in this study. The proposed approach is expected to be applied as a potential technique of preclinical screening of OSCC. PMID- 24144868 TI - [Therapeutic strategy in inflammatory myopathies (polymyositis, dermatomyositis, overlap myositis, and immune-mediated necrotizing myopathy)]. AB - Inflammatory myopathies (IM) are a heterogeneous group of autoimmune muscle disorders of unknown origin that share clinical symptoms such as muscle weakness and histological features with the presence in muscle of inflammatory infiltrate. Based on clinical, histological and serological characteristics, IM can be divided into polymyositis, dermatomyositis, overlap myositis, cancer-associated myositis, immune-mediated necrotizing myopathy, and inclusion-body myositis. Because of their resistance to corticosteroids and immunosuppressive drugs, inclusion-body myositis will be treated separately in this issue. Major obstacles in conducting high quality randomized controlled trials in inflammatory myopathies include the low prevalence and the heterogeneity of these diseases as well as the lack of international consensus on the outcome measures. In the absence of adequate controlled therapeutic trials, treatment of these disorders remains largely empirical. Corticosteroids are the cornerstone therapy. Due to the chronic course of the disease, there is a frequent need to use additional immunosuppressive treatment both to improve the disease response and to reduce the side effects of corticosteroids. Intravenous immunoglobulin infusion is a costly treatment option that is reserved in the presence of refractory dermatomyositis based on a trial showing superior efficacy against control in patients with impaired swallowing or with contraindications to immunosuppressive drugs. In patients who fail second-line therapy, which usually consists of methotrexate plus corticosteroids, the diagnosis should be carefully reassessed before considering other treatment options including methotrexate plus azathioprine or biological agents such as rituximab. PMID- 24144869 TI - Including post-discharge mortality in calculation of hospital standardised mortality ratios: retrospective analysis of hospital episode statistics. AB - OBJECTIVES: To assess the consequences of applying different mortality timeframes on standardised mortality ratios of individual hospitals and, secondarily, to evaluate the association between in-hospital standardised mortality ratios and early post-discharge mortality rate, length of hospital stay, and transfer rate. DESIGN: Retrospective analysis of routinely collected hospital data to compare observed deaths in 50 diagnostic categories with deaths predicted by a case mix adjustment method. SETTING: 60 Dutch hospitals. PARTICIPANTS: 1 228 815 patients discharged in the period 2008 to 2010. MAIN OUTCOME MEASURES: In-hospital standardised mortality ratio, 30 days post-admission standardised mortality ratio, and 30 days post-discharge standardised mortality ratio. RESULTS: Compared with the in-hospital standardised mortality ratio, 33% of the hospitals were categorised differently with the 30 days post-admission standardised mortality ratio and 22% were categorised differently with the 30 days post-discharge standardised mortality ratio. A positive association was found between in hospital standardised mortality ratio and length of hospital stay (Pearson correlation coefficient 0.33; P=0.01), and an inverse association was found between in-hospital standardised mortality ratio and early post-discharge mortality (Pearson correlation coefficient -0.37; P=0.004). CONCLUSIONS: Applying different mortality timeframes resulted in differences in standardised mortality ratios and differences in judgment regarding the performance of individual hospitals. Furthermore, associations between in-hospital standardised mortality rates, length of stay, and early post-discharge mortality rates were found. Combining these findings suggests that standardised mortality ratios based on in hospital mortality are subject to so-called "discharge bias." Hence, early post discharge mortality should be included in the calculation of standardised mortality ratios. PMID- 24144870 TI - An introduction to advance care planning in practice. PMID- 24144871 TI - Diagnostic parotid sialogram. PMID- 24144872 TI - I was sexually harassed as a junior by senior doctors: it still goes on, and it needs to stop. PMID- 24144873 TI - L1m campaign aims to reduce patients' fears over sharing of personal data. PMID- 24144874 TI - Reduced axonal motor protein expression in non-lesional grey matter in multiple sclerosis. AB - BACKGROUND: Multiple sclerosis (MS) is a neurological disease characterised by central nervous system inflammation, demyelination, axonal degeneration and neuronal injury. Preventing neuronal and axon damage is of paramount importance in attempts to prevent disease progression. Intact axonal transport mechanisms are crucial to axonal integrity and evidence suggests these mechanisms are disrupted in MS. Anterograde axonal transport is mediated to a large extent through the kinesin superfamily proteins. Recently, certain kinesin superfamily proteins (KIF5A, KIF1B and KIF21B) were implicated in MS pathology. OBJECTIVES: To investigate the expression of KIF5A, KIF21B and KIF1B in MS and control post mortem grey matter. METHODS: Using both quantitative real-time polymerase chain reaction (PCR) and Immunodot-blots assays, we analysed the expression of kinesin superfamily proteins in 27 MS cases and 13 control cases not linked to neurological disease. RESULTS: We have shown significant reductions in KIF5A, KIF21B and KIF1B messenger ribonucleic acid (mRNA) expression and also KIF5A protein expression in MS grey matter, as compared to control grey matter. CONCLUSION: We have shown significant reductions in mRNA and protein levels of axonal motor proteins in the grey matter of MS cases, which may have important implications for the pathogenesis of neuronal/axonal injury in the disease. PMID- 24144875 TI - HLA-E restricted CD8+ T cell subsets are phenotypically altered in multiple sclerosis patients. AB - BACKGROUND: The importance of Qa-1 restricted CD8(+) T cells in regulating autoreactive T cell responses has been demonstrated in animal models for autoimmune disorders, including multiple sclerosis (MS). OBJECTIVE: We hypothesize that their human variant, HLA-E restricted CD8(+) T cells, fulfills a similar regulatory role in man and that these cells are of importance in MS. METHODS: A large cohort of MS patients and healthy controls was genotyped for the two known HLA-E polymorphisms. Flow cytometry was used to determine HLA-E expression kinetics and to phenotype HLA-E restricted CD8(+) T cells. Immunohistochemistry was performed to investigate HLA-E expression in the central nervous system (CNS) of MS patients. RESULTS: HLA-E is upregulated on immune cells upon in vitro activation and this upregulation is polymorphism-dependent for T and B cells. T and B cells in lesions of MS patients show enhanced HLA-E expression. Furthermore, NKG2C(+)CD8(+) T cells of MS patients have a significantly lower Foxp3 expression, while NKG2A(+)CD8(+) T cells of MS patients produce higher levels of pro-inflammatory cytokines compared to those of healthy individuals. CONCLUSION: Our study indicates that the HLA-E system is altered in MS and could play a regulatory role in disease. PMID- 24144876 TI - A randomized clinical trial of oral versus intravenous methylprednisolone for relapse of MS. AB - BACKGROUND: Steroids improve multiple sclerosis (MS) relapses but therapeutic window and dose, frequency and administration route remain uncertain. OBJECTIVE: The objective of this paper is to compare the clinical and radiologic efficacy, tolerability and safety of intravenous methylprednisolone (ivMP) vs oral methylprednisolone (oMP), at equivalent high doses, for MS relapse. METHODS: Forty-nine patients with moderate or severe relapse within the previous 15 days were randomized in a double-blind, noninferiority, multicenter trial to receive ivMP or oMP and their matching placebos. Expanded Disability Status Scale (EDSS) scores were determined at baseline and weeks 1, 4 and 12. Brain MRI were assessed at baseline and at weeks 1 and 4. Primary endpoint was a noninferiority assessment of EDSS improvement at four weeks (noninferiority margin of one point), with further key efficacy assessments of number and volume of T1 gadolinium-enhancing (Gd+), and new or enlarged T2 lesions at four weeks' post treatment initiation. Secondary outcomes were safety and tolerability. RESULTS: The study achieved the main outcome of noninferiority at four weeks for improved EDSS score. No differences were found between ivMP and oMP in the number of Gd+ lesions (0 (0-1) vs 0 (0-0.5), p = 0.630), volume of Gd+ lesions (0 (0-88.0) vs 0 (0-32.9) mm(3), p = 0.735), or new or enlarged T2 lesions (0 (0-194) vs 0 (0 123), p = 0.769). MP was well tolerated, and no serious adverse events were reported. CONCLUSIONS: This study provides confirmatory evidence that oMP is not inferior to ivMP in reducing EDSS, similar in MRI lesions at four weeks for MS relapses and is equally well tolerated and safe. TRIAL REGISTRATION: clinicaltrials.gov identifier: NCT00753792. PMID- 24144878 TI - Hydrogen sulphide inhibits Ca2+ release through InsP3 receptors and relaxes airway smooth muscle. AB - Hydrogen sulphide (H2S) is a signalling molecule that appears to regulate diverse cell physiological process in several organs and systems including vascular and airway smooth muscle cell (SMC) contraction. Decreases in endogenous H2S synthesis have been associated with the development of cardiovascular diseases and asthma. Here we investigated the mechanism of airway SMC relaxation induced by H2S in small intrapulmonary airways using mouse lung slices and confocal and phase-contrast video microscopy. Exogenous H2S donor Na2S (100 MUm) reversibly inhibited Ca(2+) release and airway contraction evoked by inositol-1,4,5 trisphosphate (InsP3) uncaging in airway SMCs. Similarly, InsP3-evoked Ca(2+) release and contraction was inhibited by endogenous H2S precursor l-cysteine (10 mm) but not by l-serine (10 mm) or either amino acid in the presence of dl propargylglycine (PPG). Consistent with the inhibition of Ca(2+) release through InsP3 receptors (InsP3Rs), Na2S reversibly inhibited acetylcholine (ACh)-induced Ca(2+) oscillations in airway SMCs. In addition, Na2S, the H2S donor GYY-4137, and l-cysteine caused relaxation of airways pre-contracted with either ACh or 5 hydroxytryptamine (5-HT). Na2S-induced airway relaxation was resistant to a guanylyl cyclase inhibitor (ODQ) and a protein kinase G inhibitor (Rp-8-pCPT cGMPS). The effects of H2S on InsP3-evoked Ca(2+) release and contraction as well as on the relaxation of agonist-contracted airways were mimicked by the thiol reducing agent dithiothreitol (DTT, 10 mm) and inhibited by the oxidizing agent diamide (30 MUm). These studies indicate that H2S causes airway SMC relaxation by inhibiting Ca(2+) release through InsP3Rs and consequent reduction of agonist induced Ca(2+) oscillations in SMCs. The results suggest a novel role for endogenously produced H2S that involves the modulation of InsP3-evoked Ca(2+) release - a cell-signalling system of critical importance for many physiological and pathophysiological processes. PMID- 24144879 TI - Motor unit recruitment by size does not provide functional advantages for motor performance. AB - It is commonly assumed that the orderly recruitment of motor units by size provides a functional advantage for the performance of movements compared with a random recruitment order. On the other hand, the excitability of a motor neuron depends on its size and this is intrinsically linked to its innervation number. A range of innervation numbers among motor neurons corresponds to a range of sizes and thus to a range of excitabilities ordered by size. Therefore, if the excitation drive is similar among motor neurons, the recruitment by size is inevitably due to the intrinsic properties of motor neurons and may not have arisen to meet functional demands. In this view, we tested the assumption that orderly recruitment is necessarily beneficial by determining if this type of recruitment produces optimal motor output. Using evolutionary algorithms and without any a priori assumptions, the parameters of neuromuscular models were optimized with respect to several criteria for motor performance. Interestingly, the optimized model parameters matched well known neuromuscular properties, but none of the optimization criteria determined a consistent recruitment order by size unless this was imposed by an association between motor neuron size and excitability. Further, when the association between size and excitability was imposed, the resultant model of recruitment did not improve the motor performance with respect to the absence of orderly recruitment. A consistent observation was that optimal solutions for a variety of criteria of motor performance always required a broad range of innervation numbers in the population of motor neurons, skewed towards the small values. These results indicate that orderly recruitment of motor units in itself does not provide substantial functional advantages for motor control. Rather, the reason for its near-universal presence in human movements is that motor functions are optimized by a broad range of innervation numbers. PMID- 24144877 TI - The developmental stages of synaptic plasticity. AB - The brain is programmed to drive behaviour by precisely wiring the appropriate neuronal circuits. Wiring and rewiring of neuronal circuits largely depends on the orchestrated changes in the strengths of synaptic contacts. Here, we review how the rules of synaptic plasticity change during development of the brain, from birth to independence. We focus on the changes that occur at the postsynaptic side of excitatory glutamatergic synapses in the rodent hippocampus and neocortex. First we summarize the current data on the structure of synapses and the developmental expression patterns of the key molecular players of synaptic plasticity, N-methyl-d-aspartate (NMDA) and alpha-amino-3-hydroxy-5-methyl-4 isoxazolepropionic acid (AMPA) receptors, as well as pivotal kinases (Ca(2+)/calmodulin-dependent protein kinase II, protein kinase A, protein kinase C) and phosphatases (PP1, PP2A, PP2B). In the second part we relate these findings to important characteristics of the emerging network. We argue that the concerted and gradual shifts in the usage of plasticity molecules comply with the changing need for (re)wiring neuronal circuits. PMID- 24144880 TI - Phase-shifting response to light in older adults. AB - Age-related changes in circadian rhythms may contribute to the sleep disruption observed in older adults. A reduction in responsiveness to photic stimuli in the circadian timing system has been hypothesized as a possible reason for the advanced circadian phase in older adults. This project compared phase-shifting responses to 2 h of broad-spectrum white light at moderate and high intensities in younger and older adults. Subjects included 29 healthy young (25.1 +/- 4.1 years; male to female ratio: 8: 21) and 16 healthy older (66.5 +/- 6.0 years; male to female ratio: 5: 11) subjects, who participated in two 4-night and 3-day laboratory stays, separated by at least 3 weeks. Subjects were randomly assigned to one of three different time-points, 8 h before (-8), 3 h before (-3) or 3 h after (+3) the core body temperature minimum (CBTmin) measured on the baseline night. For each condition, subjects were exposed in a randomized order to 2 h light pulses of two intensities (2000 lux and 8000 lux) during the two different laboratory stays. Phase shifts were analysed according to the time of melatonin midpoint on the nights before and after light exposure. Older subjects in this study showed an earlier baseline phase and lower amplitude of melatonin rhythm compared to younger subjects, but there was no evidence of age-related changes in the magnitude or direction of phase shifts of melatonin midpoint in response to 2 h of light at either 2000 lux or 8000 lux. These results indicate that the acute phase-shifting response to moderate- or high-intensity broad spectrum light is not significantly affected by age. PMID- 24144881 TI - Distribution and Ca(2+) signalling of fibroblast-like (PDGFR(+)) cells in the murine gastric fundus. AB - Platelet-derived growth factor receptor alpha positive (PDGFRalpha(+)) cells are suggested to mediate purinergic inputs in GI muscles, but the responsiveness of these cells to purines in situ has not been evaluated. We developed techniques to label and visualize PDGFRalpha(+) cells in murine gastric fundus, load cells with Ca(2+) indicators, and follow their activity via digital imaging. Immunolabelling demonstrated a high density of PDGFRalpha(+) cells in the fundus. Cells were isolated and purified by fluorescence-activated cell sorting (FACS) using endogenous expression of enhanced green fluorescent protein (eGFP) driven off the Pdgfra promoter. Quantitative PCR showed high levels of expression of purinergic P2Y1 receptors and SK3 K(+) channels in PDGFRalpha(+) cells. Ca(2+) imaging was used to characterize spontaneous Ca(2+) transients and responses to purines in PDGFRalpha(+) cells in situ. ATP, ADP, UTP and beta-NAD elicited robust Ca(2+) transients in PDGFRalpha(+) cells. Ca(2+) transients were also elicited by the P2Y1-specific agonist (N)-methanocarba-2MeSADP (MRS-2365), and inhibited by MRS 2500, a P2Y1-specific antagonist. Responses to ADP, MRS-2365 and beta-NAD were absent in PDGFRalpha(+) cells from P2ry1((-/-)) mice, but responses to ATP were retained. Purine-evoked Ca(2+) transients were mediated through Ca(2+) release mechanisms. Inhibitors of phospholipase C (U-73122), IP3 (2-APB), ryanodine receptors (Ryanodine) and SERCA pump (cyclopiazonic acid and thapsigargin) abolished Ca(2+) transients elicited by purines. This study provides a link between purine binding to P2Y1 receptors and activation of SK3 channels in PDGFRalpha(+) cells. Activation of Ca(2+) release is likely to be the signalling mechanism in PDGFRalpha(+) cells responsible for the transduction of purinergic enteric inhibitory input in gastric fundus muscles. PMID- 24144882 TI - New genetic insights highlight 'old' ideas on motor dysfunction in dystonia. AB - Primary dystonia is a poorly understood but common movement disorder. Recently, several new primary dystonia genes were identified that provide new insight into dystonia pathogenesis. The GNAL dystonia gene is central for striatal responses to dopamine (DA) and is a component of a molecular pathway already implicated in DOPA-responsive dystonia (DRD). Furthermore, this pathway is also dysfunctional and pathogenically linked to mTOR signaling in L-DOPA-induced dyskinesias (LID). These new data suggest that striatal DA responses are central to primary dystonia, even when symptoms do not benefit from DA therapies. Here we integrate these new findings with current understanding of striatal microcircuitry and other dystonia-causing insults to develop new ideas on the pathophysiology of this incapacitating movement disorder. PMID- 24144883 TI - Very early-onset lone atrial fibrillation patients have a high prevalence of rare variants in genes previously associated with atrial fibrillation. AB - BACKGROUND: Atrial fibrillation (AF) is the most common cardiac arrhythmia. Currently, 14 genes important for ion channel function, intercellular signaling, and homeostatic control have been associated with AF. OBJECTIVE: We hypothesized that rare genetic variants in genes previously associated with AF had a higher prevalence in early-onset lone AF patients than in the background population. METHODS: Sequencing results of KCNQ1, KCNH2, SCN5A, KCNA5, KCND3, KCNE1, 2, 5, KCNJ2, SCN1-3B, NPPA, and GJA5 from 192 early-onset lone AF patients were compared with data from the National Heart, Lung, and Blood Institute Exome Variant Server consisting of 6503 persons from 18 different cohort studies. RESULTS: Among the lone AF patients, 29 (7.6%) alleles harbored a novel or very rare variant (minor allele frequency <0.1 in the Exome Variant Server), a frequency that was significantly higher than what was found in the reference database (4.1%; with minor allele frequency <0.1; P = .0012). Previously published electrophysiological data showed that 96% (n = 23) of the rare variants that has been functionally investigated (n = 24) displayed significant functional changes. CONCLUSIONS: We report a much higher prevalence of rare variants in genes associated with AF in early-onset lone AF patients than in the background population. By presenting these data, we believe that we are the first to provide quantitative evidence for the role of rare variants across AF susceptibility genes as a possible pathophysiological substrate for AF. PMID- 24144884 TI - A detailed assessment of the human coronary venous system using contrast computed tomography of perfusion-fixed specimens. AB - BACKGROUND: Access to the coronary venous system is required for the delivery of several cardiac therapies including cardiac resynchronization therapy, coronary sinus ablation, and coronary drug delivery. Therefore, characterization of the coronary venous anatomy will provide insights to gain improved access to these vessels and subsequently improved therapies. For example, cardiac resynchronization therapy has a 30% nonresponder rate, partially due to suboptimal lead placement within the coronary veins. OBJECTIVE: To understand the implications of coronary venous anatomy for the development of devices deployed within these vessels. METHODS: We cannulated the coronary sinus of 121 perfusion fixed human hearts with a venogram balloon catheter and injected contrast into the venous system while obtaining computed tomographic images. For each major coronary vein, distance to the coronary sinus, branching angle, arc length, tortuosity, number of branches, and ostial diameter were assessed from the reconstructed anatomy. RESULTS: Twenty-nine percent (35/121) specimens did not have a venous branch overlying the inferolateral side of the heart large enough to fit a 5F pacing lead. No significant differences in anatomy were found between subgroups with varying cardiac medical histories. CONCLUSION: The anatomical approach employed in this study has allowed for the development of a unique database of human coronary venous anatomy that can be used for the optimization of design and delivery of cardiac devices. PMID- 24144885 TI - Implantable intravascular defibrillator: defibrillation thresholds of an intravascular cardioverter-defibrillator compared with those of a conventional ICD in humans. AB - BACKGROUND: A percutaneous intravascular cardioverter-defibrillator (PICD) has been developed with a right ventricular (RV) single-coil lead and titanium electrodes in the superior vena cava (SVC)-brachiocephalic vein (BCV) region and the inferior vena cava (IVC). OBJECTIVE: To compare defibrillation thresholds (DFTs) of the PICD with those of a conventional ICD in humans. METHODS: Ten patients with ischemic cardiomyopathy and ejection fraction <=35% were randomized to initial testing with either PICD or conventional ICD. A standard dual-coil lead was positioned in the RV apex. If randomized to PICD, the device was placed into the vasculature such that 1 titanium electrode was positioned in the SVC-BCV region and the second in the IVC. For PICD DFTs, the RV coil of the conventional ICD lead was connected to the PICD mandrel [shock vector: RV (+) to SVC-BCV (-) + IVC (-)]. When testing the conventional ICD, a subcutaneous pocket was formed in the left pectoralis region and the ICD was connected to the lead system and positioned in the pocket [shock vector: RV (+) to SVC (-) + active can (-)]. Each device was removed before testing with the other. A step-down binary search protocol determined the DFT, with the initial shock being 9 J. RESULTS: The mean PICD DFT was 7.6 +/- 3.3 J, and the conventional ICD system demonstrated a mean DFT of 9.5 +/- 4.7 J (N = 10; paired t test, P = .28). CONCLUSION: The intravascular defibrillator has DFTs similar to those of commercially available ICDs. PMID- 24144886 TI - [An exophtalmos]. PMID- 24144887 TI - [Soft swelling of the pinna]. PMID- 24144888 TI - Bioinformatics analysis of a non-specific nuclease from Yersinia enterocolitica subsp. palearctica. AB - In this paper, the physical and chemical characteristics, biological structure and function of a non-specific nuclease from Yersinia enterocolitica subsp. palearctica (Y. NSN) found in our group were studied using multiple bioinformatics approaches. The results showed that Y. NSN had 283 amino acids, a weight of 30,692.5 ku and a certain hydrophilic property. Y. NSN had a signal peptide, no transmembrane domains and disulphide bonds. Cleavage site in Y. NSN was between pos. 23 and 24. The prediction result of the secondary structure showed Y. NSN was a coil structure-based protein. The ratio of alpha-helix, beta folded and random coil were 18.73%, 16.96% and 64.31%, respectively. Active sites were pos. 124, 125, 127, 157, 165 and 169. Mg(2+) binding site was pos. 157. Substrate binding sites were pos. 124, 125 and 169. The analysis of multisequencing alignment and phylogenetic tree indicated that Y. NSN shared high similarity with the nuclease from Y. enterocolitica subsp. enterocolitica 8081. The enzyme activity results showed that Y. NSN was a nuclease with good thermostability. PMID- 24144890 TI - Is all heart failure the same around the globe? PMID- 24144889 TI - Transport of (137)Cs, (241)Am and Pu isotopes in the Curonian Lagoon and the Baltic Sea. AB - Activities of (137)Cs, (241)Am and (239,240)Pu were analyzed with special emphasis on better understanding of radionuclide transport from land via the Neman River estuaries to the Baltic Sea and behavior in the marine environment. Although activity concentrations of (137)Cs in water samples collected the Baltic Sea were almost 100 times higher as compared to the Curonian Lagoon, its activities in the bottom sediments were found to be comparable. Activity (238)Pu/(239,240)Pu and atom (240)Pu/(239)Pu ratios indicated a different contribution of the Chernobyl-originated Pu to the suspended particulate matter (SPM) and bottom sediments. The largest amount of the Chernobyl-derived Pu was found in the smallest suspended matter particles of 0.2-1 MUm in size collected in the Klaipeda Strait in 2011-2012. The decrease of characteristic activity (238)Pu/(239,240)Pu and atom (240)Pu/(239)Pu ratios towards the global fallout ones in surface soil and the corresponding increase of plutonium (Pu) ratios in the suspended particulate matter and bottom sediments have indicated that the Chernobyl-derived Pu, primarily deposited on the soil surface, was washed out and transported to the Baltic Sea. Behavior of (241)Am was found to be similar to that of Pu isotopes. PMID- 24144892 TI - Calcium-calmodulin signaling elicits mitochondrial dysfunction and the release of cytochrome c during cadmium-induced apoptosis in primary osteoblasts. AB - Cadmium (Cd) is a toxic heavy metal used in industry and is associated with adverse effects on human health following long- or short-term environmental exposure. Although Cd is known to induce apoptosis in many human organ systems, the mechanism that underlies its toxicity in primary osteoblasts (OBs) is not yet established. In the present study, we confirmed that Cd induced apoptosis in OBs isolated from the craniums of fetal Sprague-Dawley rats. We then showed that exposure to Cd transiently increased intracellular calcium ([Ca(2+)]i) levels for up to 1.5h, after which the levels returned to normal. Pretreatment with the calcium chelator BAPTA-AM was able to prevent Cd-induced apoptosis by reversing Cd-induced changes in the mitochondrial transmembrane potential (DeltaPsim). In addition, we found that the antagonist of calcium-dependent calmodulin (CaM), W 7, inhibited the conformational change of calmodulin induced by Cd. Furthermore, Cd-induced apoptosis could be inhibited by W-7 through the suppression of the mitochondrial release of cytochrome c to the cytosol and the reversal of Cd activation of caspase-3. These data indicate that activated Ca(2+)/CaM might transmit apoptotic signals to the mitochondria during Cd-induced apoptosis. Our findings provide new insights into the mechanisms underlying apoptosis in OBs following exposure to Cd. PMID- 24144893 TI - Par-4 downregulation confers cisplatin resistance in pancreatic cancer cells via PI3K/Akt pathway-dependent EMT. AB - Cisplatin (CDDP) efficiency in pancreatic cancer therapy is limited due to development of drug resistance. However, the comprehensive mechanisms remain largely unclear. In this study, we first established a CDDP-resistant pancreatic cancer cell line-BXPC-3/CDDP from its parental cell line-BXPC-3. The results showed that CDDP resistance in BXPC-3/CDDP cells correlates with changes in cellular EMT phenotypes. Prostate apoptosis response-4 (Par-4) expression at both mRNA and protein levels were reduced in CDDP-resistant BXPC-3/CDDP cells compared with that in BXPC-3 cells. Ectopic expression of Par-4 reversed EMT and CDDP resistance in BXPC-3/CDDP cells. In BXPC-3 cells, knockdown of Par-4 expression induces EMT and CDDP insensitivity, however, these effects were blocked by inhibition of PI3K/Akt pathway using LY294002. Furthermore, Par-4 knockdown could significantly stimulate PI3K/Akt signaling in BXPC-3 cells. In vivo studies, xenograft BXPC-3 tumors were sensitive to CDDP treatment. Treatment with CDDP alone had little effect on the growth of Par-4 siRNA-transfected BXPC-3 tumors in nude mice and the survival rate compared with control. Inhibition of PI3K/Akt pathway using LY294002 reversed CDDP resistance in Par-4 siRNA-transfected BXPC-3 tumors. In conclusion, these results indicate that Par-4 downregulation confers CDDP resistance via PI3K/Akt pathway-dependent EMT in BXPC-3 cells. Therefore, Par-4 may be a potential target for overcoming CDDP resistance in pancreatic cancer. PMID- 24144895 TI - Long-term safety study of fosamprenavir-containing regimens in HIV-1-infected patients. AB - BACKGROUND: Safety and efficacy of the protease inhibitor fosamprenavir (FPV) +/- ritonavir (r) was evaluated in 3 pivotal 48-week phase III studies. A follow-on study provides long-term data on FPV-based regimens. METHODS: International, multicenter, uncontrolled open-label study APV30005 provided FPV as part of combination therapy to HIV-1-infected patients aged >=13 years who had participated in previous FPV and amprenavir studies. Regimens included FPV/r 1400/200 mg once daily, FPV/r 700/100 mg twice daily, or FPV 1400 mg twice daily. Safety and efficacy were evaluated every 12 weeks, including incidence and frequency of adverse events and laboratory abnormalities, plasma HIV-1 RNA levels, CD4+ cell counts, and frequency of HIV disease progression. Because this was a nonrandomized, observational study, no significance testing was performed. RESULTS: Overall, 753 patients were enrolled. The most common reasons for premature discontinuation were lost to follow-up (88 [12%]) and insufficient viral load response (69 [9%]). The majority of patients had ?192 weeks exposure to FPV, with 53 patients exposed for more than 8 years. Drug-related grade 2-4 adverse events were reported for 250 patients (33%), with the majority reported in the first 48 weeks of the study. Most commonly reported grade 3/4 laboratory parameters were increased lipase, triglycerides, and elevated liver enzymes. The observed proportions of patients with plasma HIV-1 RNA levels <50 copies/mL remained ?70% from week 48 onwards. CONCLUSIONS: Extended treatment of up to 8 years with FPV-containing regimens revealed no new safety concerns and was associated with sustained antiviral responses. PMID- 24144894 TI - Utility of heel dual-energy X-ray absorptiometry in diagnosing osteoporosis. AB - Although peripheral dual-energy X-ray absorptiometry measurements have been found to predict fractures in population studies of white subjects, little is known about their utility in other races and in patients with greater risk of fracture. In a cross-sectional study of 874 women referred for bone mineral density (BMD) testing, we examined the utility of heel BMD in African-American (AA) compared with Caucasian (CA) women and in women using glucocorticoids. The ability of heel T-score to predict central osteoporosis was similar in AA and CA women (odds ratio [OR] per 1 unit decrease in T-score of 2.79 [95% confidence interval {CI} 2.16-3.60] and 3.15 [95% CI 2.53-3.92], respectively). The association between heel T-score and prevalent vertebral fractures was also similar in the 2 groups (OR 1.46 [95% CI 1.15-1.85] in AA and 1.42 [95% CI 1.16-1.74] in CA). In women using glucocorticoids heel T-score was better than central T-score in predicting vertebral fractures (OR 1.38 [95% CI 1.03-1.85] and 1.22 [95% CI 0.86-1.73], respectively). We conclude that in a multiracial referral population heel BMD predicts central osteoporosis and prevalent vertebral fractures equally well in AA as in CA women and may be better than central BMD in assessing fragility in glucocorticoid users. PMID- 24144896 TI - Pharmacokinetics, safety, and monotherapy antiviral activity of GSK1265744, an HIV integrase strand transfer inhibitor. AB - BACKGROUND: GSK1265744 is an HIV integrase strand transfer inhibitor selected for clinical development. OBJECTIVE: This first-time-in-human and phase IIa investigation assessed GSK1265744 antiviral activity, pharmacokinetics, safety, and tolerability in healthy and HIV-1-infected subjects. METHODS: This double blind, placebo-controlled study consisted of a dose escalation of single (part A) and multiple (part B) oral doses in 48 healthy subjects and an oral dose (part C) in 11 HIV-1-infected subjects. In part A, 2 cohorts of 9 subjects received either 5 and 25 mg or 10 and 50 mg. In part B, 3 cohorts of 10 subjects received 5, 10, or 25 mg once daily for 14 days. In part C and the phase IIa study, subjects received 5 or 30 mg once daily for 10 days. RESULTS: Dose-proportional increases in drug exposure were observed in healthy and HIV-1-infected subjects. In healthy subjects, pharmacokinetic variability was low following single or repeat dosing (coefficient of variation, 13%-34% and 15%-23%, respectively). Mean plasma half life was 31.5 hours. GSK1265744 monotherapy significantly reduced plasma HIV-1 RNA from baseline to day 11 in HIV-1-infected subjects receiving 5 or 30 mg versus placebo (P < .001); mean decrease was 2.2 to 2.3 log10 copies/mL, respectively. Study drug was generally well tolerated with no clinically relevant trends in laboratory values, vital signs, or electrocardiograms. CONCLUSIONS: GSK1265744 was well tolerated in healthy and HIV-1-infected subjects. Results demonstrate once-daily doses of 5 or 30 mg exceeded minimum target therapeutic concentrations and produced a significant reduction in plasma HIV-1 RNA viral load. PMID- 24144897 TI - Safety, efficacy, and persistence of emtricitabine/tenofovir versus other nucleoside analogues in naive subjects aged 50 years or older in Spain: the TRIP study. AB - OBJECTIVES: Current antiretroviral guidelines state that being older than 50 to 55 years of age is an indication to start antiretroviral therapy (ART), regardless of CD4 status. However, no references to the preferred combination ART (cART) for these patients have been described. Our study compares emtricitabine and tenofovir disoproxil fumarate (FTC/TDF) versus other nucleoside reverse transcriptase inhibitor (NNRTI) regimens in HIV ART-naive patients who are >=50 years. DESIGN: National, retrospective cohort analysis of patients who were >=50 years old when they began the first cART (January 1, 2006 to December 31, 2009). METHODS: We compared safety, effectiveness, and persistence of treatment in FTC/TDF versus non-FTC/TDF users. Among FTC/TDF users, we compared protease inhibitor (PI) versus NNRTI users and lopinavir/r versus efavirenz users. RESULTS: We included 161 patients: median age was 54.6 years, 83% were men, median CD4 count was 191 cells/uL, median viral load was 4.7 log, and median follow-up was 19 months (maximum, 48 months). Of these participants, 112 started with FTC/TDF and 49 with other nucleotide reverse transcriptase inhibitors (NRTIs). During follow-up, 21.9% of subjects developed at least one laboratory event >=grade 3, 5.6% interrupted cART due to adverse events,19.3% had virologic failure, and 49.1% modified cART. There were no statistically significant differences between FTC/TDF and non-FTC/TDF users for any output except for persistence: The proportion of subjects who changed cART was 71.4% for non FTC/TDF users and 38.6% for FTC/TDF users (log rank 0.001; adjusted hazard ratio, 2.10; 95% CI, 1.34-3.29). CONCLUSIONS: In a population of HIV-infected subjects who were >=50 years old, our study suggests that the use of FTC/TDF is generally safe and effective, with a longer persistence as compared to other regimens. PMID- 24144898 TI - Efficacy and safety 48 weeks after switching from efavirenz to rilpivirine using emtricitabine/tenofovir disoproxil fumarate-based single-tablet regimens. AB - BACKGROUND: Due to ongoing neuropsychiatric adverse events in some efavirenz (EFV)-treated patients, a switch to an alternative non-nucleoside reverse transcriptase inhibitor may be considered. Rilpivirine (RPV) has been coformulated as a single-tablet regimen (STR) with emtricitabine/tenofovir disoproxil fumarate (FTC/TDF), and the components have demonstrated noninferior efficacy to EFV+FTC/TDF, good tolerability profile, and high adherence. After discontinuation, EFV has an extended inductive effect on cytochrome P450 (CYP) 3A4 that, after switching, may reduce RPV exposures and adversely impact clinical outcomes. OBJECTIVE: This study examines the clinical implications of reduced RPV exposures with concomitant FTC/TDF and declining EFV exposures when patients, intolerant to EFV, switch from EFV/FTC/TDF to RPV/FTC/TDF. METHODS: This 48-week, phase 2b, open-label, multicenter study evaluated the efficacy and safety of switching from EFV/FTC/TDF (>=3 months duration) to RPV/FTC/TDF. Virologic suppression (HIV-1 RNA <50 copies/mL), safety, and EFV and RPV pharmacokinetics were assessed. RESULTS: At weeks 12 and 24, all 49 dosed subjects remained suppressed on RPV/FTC/TDF. At week 48, 46 (93.9%) subjects remained suppressed and virologic failure occurred in 2/49 (4.1%) subjects with no emergence of resistance. EFV concentrations were above the 90th percentile for inhibitory concentration (IC90) for several weeks after EFV discontinuation, and RPV exposures were in the range observed in phase 3 studies by approximately 2 weeks post switch. No subjects discontinued the study due to an adverse event. CONCLUSIONS: Switching from EFV/FTC/TDF to RPV/FTC/ TDF was a safe, efficacious option for virologically suppressed HIV-infected patients with EFV intolerance wishing to remain on an STR. PMID- 24144900 TI - Site nurse-initiated adherence and symptom support telephone calls for HIV positive individuals starting antiretroviral therapy, ACTG 5031: substudy of ACTG 384. AB - BACKGROUND: Effective and easy to implement interventions to improve adherence to antiretroviral therapy are needed. OBJECTIVE: To compare site nurse-initiated adherence and symptom support telephone calls for HIV-positive individuals starting antiretroviral therapy to the study site's standard of care. METHODS: A randomized controlled trial of site nurse-initiated adherence and symptom support telephone calls for HIV-positive individuals starting antiretroviral therapy. Subjects were randomized to receive site nurse-initiated telephone calls (intervention) or no additional calls to the site's standard of care (control). Subjects received calls 1 to 3 days after initiating antiretrovirals, on weeks 1, 2, 3, 6, 10, 14, 18, 22, and 26, and every 8 weeks thereafter. Self-reported adherence was captured during study visits. RESULTS: A total of 333 subjects starting antiretrovirals as part of ACTG 384 were co-enrolled into ACTG 5031. Subjects were followed for up to 160 weeks and were contacted for 74% of scheduled calls. There was no significant difference in proportion of patients with ?95% mean total adherence (87.9% and 91.2%; P = .34) and mean self-reported total adherence (97.9% and 98.4%) in the intervention and control groups, respectively, or in symptom distress and clinical endpoints. CONCLUSIONS: In the context of a clinical trial where self-reported adherence was exceptionally high, the site nurse-initiated telephone calls did not further improve self-reported adherence, symptom distress, or clinical outcomes. PMID- 24144901 TI - Efficacy and tolerability of darunavir/ritonavir in combination with abacavir/lamivudine: an option in selected HIV-infected patients. AB - OBJECTIVE: To evaluate the safety and efficacy of abacavir/lamivudine (ABC/3TC) plus darunavir/ritonavir (DRV-RTV) in experienced patients. METHODS: The study was conducted in Spain in 6 hospital clinics and involved HIV-positive patients who needed to change their antiretroviral treatment (ART) for several reasons. They started fixed-dose combination (FDC) ABC/3TC (600 mg/300 mg), DRV (400 mg 2 tablets qd), and RTV (100 mg) from January 2010 to April 2012. The patients were evaluated at baseline and at intervals of 3 to 6 months, and at least once at the end of the follow-up. Adverse events (AEs), concurrent medications, HIV associated conditions, and adherence were also assessed at each visit. RESULTS: Seventy-six patients were included from 6 sites (60 male). Median CD4 cell count was 479/mm3, and the median time on follow-up was 10.1 months. Thirty-eight patients (50%) have reached 48 weeks of follow-up and 32 (84.2 %) have achieved HIV RNA <50 copies/mL in this period. Immunological recovery was observed with a median CD4 count increase of 119 cells/mm3 by week 48. There were no patients who discontinued the study treatment due to AEs, and all the toxicities that lead to change ART at baseline were resolved or improved substantially. CONCLUSION: This study showed that the study regimen provided consistent antiviral and immunological responses until 48 weeks. The antiretroviral effect of the regimen was observed in subsets of patients evaluated, including those with high baseline HIV-1 RNA levels and virological failure and those with switching, with little or no difference across subgroups. PMID- 24144899 TI - Bone mineral density effects of randomized regimen and nucleoside reverse transcriptase inhibitor selection from ACTG A5142. AB - OBJECTIVE: To compare the longitudinal changes in total bone mineral density (TBMD) across antiretroviral (ARV) regimens. METHODS: A5142 was an open-label study comparing 3 ARV regimens for the initial treatment of HIV-1. Subjects were randomized equally to efavirenz (EFV) plus 2 nucleoside reverse transcriptase inhibitors (NRTIs), lopinavir/ritonavir (LPV/r) plus 2 NRTIs, or LPV/r plus EFV without NRTI. The NRTI regimen (lamivudine [3TC] plus zidovudine [ZDV], stavudine [d4T], or tenofovir [TDF]) was selected prior to randomization. TBMD was assessed via whole-body dual-energy X-ray absorptiometry (DXA) at baseline and 48 and 96 weeks. Analysis was modified intent-to-treat (ITT) ignoring regimen changes using all evaluations. RESULTS: Significant mean declines in TBMD at week 48 were observed among subjects. In repeated-measures analysis of changes (including randomized regimen, NRTI used, and time), there was a significant difference in the NRTI-containing arms in mean percentage change in TBMD at week 48 according to NRTI used (P < .001). Subjects taking ZDV had similar changes to those taking d4T (P = .970), whereas those taking TDF had larger declines (P < .001). There was a nonsignificant trend toward greater mean declines among subjects taking LPV/r versus EFV (P = .080). Overall, TDF-containing regimens demonstrated the greatest losses in TBMD, while EFV regimens without TDF had lesser TBMD reductions even compared to the NRTI-sparing arm. From week 48 to 96, all treatment groups continued to lose TBMD at similar rates. CONCLUSIONS: Among NRTI containing arms, NRTI selection, especially use of TDF, had a greater effect on TBMD change than randomized regimen. The long-term clinical significance remains to be demonstrated. PMID- 24144902 TI - Magnetic-based multi-layer microparticles for endothelial progenitor cell isolation, enrichment, and detachment. AB - Although endothelial progenitor cells (EPCs) are useful in many applications including cell-based therapies, their use is still limited due to issues associated with cell culture techniques like a low isolation efficiency, use of harmful proteolytic enzymes in cell cultures, and difficulty in ex vivo expansion. Here, we report a tool to simultaneously isolate, enrich, and detach EPCs without the use of harmful chemicals. In particular, we developed magnetic based multi-layer microparticles (MLMPs) that (1) magnetically isolate EPCs via anti-CD34 antibodies to avoid the use of Ficoll and harsh shear forces; (2) provide a 3D surface for cell attachment and growth; (3) produce sequential releases of growth factors (GFs) to enrich ex vivo expansion of cells; and (4) detach cells without using trypsin. MLMPs were successful in isolating EPCs from a cell suspension and provided a sequential release of GFs for EPC proliferation and differentiation. The cell enrichment profiles indicated steady cell growth on MLMPs in comparison to commercial Cytodex3 microbeads. Further, the cells were detached from MLMPs by lowering the temperature below 32 degrees C. Results indicate that the MLMPs have potential to be an effective tool towards efficient cell isolation, fast expansion, and non-chemical detachment. PMID- 24144903 TI - Alveolar epithelial differentiation of human induced pluripotent stem cells in a rotating bioreactor. AB - Traditional stem cell differentiation protocols make use of a variety of cytokines including growth factors (GFs) and inhibitors in an effort to provide appropriate signals for tissue specific differentiation. In this study, iPSC derived type II pneumocytes (iPSC-ATII) as well as native isolated human type II pneumocytes (hATII) were differentiated toward a type I phenotype using a unique air-liquid interface (ALI) system that relies on a rotating apparatus that mimics in vivo respiratory conditions. A relatively homogenous population of alveolar type II-like cells from iPSC was first generated (iPSC-ATII cells), which had phenotypic properties similar to mature human alveolar type II cells. iPSC-ATII cells were then cultured in a specially designed rotating culture apparatus. The effectiveness of the ALI bioreactor was compared with the effectiveness of small molecule-based differentiation of type II pneumocytes toward type 1 pneumocytes. The dynamics of differentiation were examined by quantitative reverse transcriptase polymerase chain reaction (qRT-PCR), flow cytometry and immunocytochemistry. iPSC-ATII and hATII cells cultured in the ALI bioreactor had higher levels of type I markers, including aquaporin-5(AQ5), caveolin-1, and T1alpha, at both the RNA and protein levels as compared with the flask-grown iPSC ATII and hATII that had been treated with small molecules to induce differentiation. In summary, this study demonstrates that a rotating bioreactor culture system that provides an air-liquid interface is a potent inducer of type I epithelial differentiation for both iPS-ATII cells and hATII cells, and provides a method for large-scale production of alveolar epithelium for tissue engineering and drug discovery. PMID- 24144904 TI - Sandwich-type fiber scaffolds with square arrayed microwells and nanostructured cues as microskin grafts for skin regeneration. AB - The paper reports the fabrication of sandwich-type scaffolds consisting of radially-aligned nanofibers at the bottom, nanofiber membranes with square arrayed microwells and nanostructured cues at the top, and microskin tissues in between as microskin grafts for use in skin regeneration. This class of nanofiber scaffolds was able to confine the microskin tissues in the square arrayed wells and simultaneously present nanotopographic cues to the cultured NIH 3T3 fibroblasts and primary rat skin cells, guiding and facilitating their migration in vitro. More importantly, we demonstrated that the sandwich-type transplants exhibited an even distribution of microskin grafts, greatly improved the 'take' rate of microskin tissues, and promoted re-epithelialization on wound in vivo. In addition, the void area in the scaffolds was well suitable for exudate drainage in wound. The sandwich-type scaffolds show great potential as microskin grafts for repairing extensive burn injuries and may provide a good solution for the treatment of acute skin defects and chronic wounds including diabetic ulcer, pressure ulcer, and venous stasis ulcer. PMID- 24144905 TI - Integrated platform for functional monitoring of biomimetic heart sheets derived from human pluripotent stem cells. AB - We present an integrated platform comprised of a biomimetic substrate and physiologically aligned human pluripotent stem cell-derived cardiomyocytes (CMs) with optical detection and algorithms to monitor subtle changes in cardiac properties under various conditions. In the native heart, anisotropic tissue structures facilitate important concerted mechanical contraction and electrical propagation. To recapitulate the architecture necessary for a physiologically accurate heart response, we have developed a simple way to create large areas of aligned CMs with improved functional properties using shrink-wrap film. Combined with simple bright field imaging, obviating the need for fluorescent labels or beads, we quantify and analyze key cardiac contractile parameters. To evaluate the performance capabilities of this platform, the effects of two drugs, E-4031 and isoprenaline, were examined. Cardiac cells supplemented with E-4031 exhibited an increase in contractile duration exclusively due to prolonged relaxation peak. Notably, cells aligned on the biomimetic platform responded detectably down to a dosage of 3 nM E-4031, which is lower than the IC50 in the hERG channel assay. Cells supplemented with isoprenaline exhibited increased contractile frequency and acceleration. Interestingly, cells grown on the biomimetic substrate were more responsive to isoprenaline than those grown on the two control surfaces, suggesting topography may help induce more mature ion channel development. This simple and low-cost platform could thus be a powerful tool for longitudinal assays as well as an effective tool for drug screening and basic cardiac research. PMID- 24144906 TI - Targeting the tumor-draining lymph node with adjuvanted nanoparticles reshapes the anti-tumor immune response. AB - Accumulating evidence implicates the tumor-draining lymph node (TDLN) in tumor induced immune escape, as it drains regulatory molecules and leukocytes from the tumor microenvironment. We asked whether targeted delivery of adjuvant to the TDLN, presumably already bathed in tumor antigens, could promote anti-tumor immunity and hinder tumor growth. To this end, we used 30 nm polymeric nanoparticles (NPs) that effectively target dendritic cells (DCs, CD11c(+)) within the lymph node (LN) after intradermal administration. These NPs accumulated within the TDLN when administered in the limb ipsilateral (i.l.) to the tumor or in the non-TDLN when administered in the contralateral (c.l.) limb. Incorporating the adjuvants CpG or paclitaxel into the NPs (CpG-NP and PXL-NP) induced DC maturation in vitro. When administered daily i.l. and thus targeting the TDLN of a B16-F10 melanoma, adjuvanted NPs induced DC maturation within the TDLN and reshaped the CD4(+) T cell distribution within the tumor towards a Th1 (CXCR3(+)) phenotype. Importantly, this also led to an increase in the frequency of antigen-specific CD8(+) T cells within the tumor. This correlated with slowed tumor growth, in contrast to unhindered tumor growth after c.l. delivery of adjuvanted NPs (targeting a non-TDLN) or i.l. delivery of free adjuvant. CpG-NP treatment in the i.l. limb also was associated with an increase in CD8(+)/CD4(+) T cell ratios and frequencies of activated (CD25(+)) CD8(+) T cells within the TDLN whereas PXL-NP treatment reduced the frequency of regulatory T (FoxP3(+) CD4(+)) cells in the TDLN. Together, these data implicate the TDLN as a delivery target for adjuvant therapy of solid tumors. PMID- 24144907 TI - Tuning cell-surface affinity to direct cell specific responses to patterned proteins. AB - Interactions with local extracellular cues direct cell migration. A versatile method to study cell response to a protein consists of patterning the protein cue on a substrate and quantifying the distribution of cells between patterned and non-patterned areas. Here, we define the concepts of (i) cell-surface affinity to describe cell choices, and of (ii) reference surface (RS) to clarify that the choice is made relative to a reference. Furthermore, we report a method to systematically tune the RS and show that it can dominate the experimental cell response to a protein cue. The cell response to a cue can be switched from strong preference to strong aversion by only changing the RS. Using microcontact printing, we patterned the extracellular matrix proteins fibronectin or netrin-1 adjacent to a series of RSs with different ratios of poly-D-lysine (PDL) and polyethylene glycol (PEG), which are of high affinity and of low-affinity for cells, respectively. C2C12 myoblasts or primary neurons seeded on substrates with a high affinity RS (high % PDL) did not respond to a printed protein of interest, and conversely on RSs of low affinity (high % PEG) the cells preferred the printed protein even in the absence of a specific interaction. However, when testing cell response to a standardized series of RSs varying from high to low affinity, a specific response curve was obtained that was unique to each cell type-protein pair. Importantly, for intermediate RSs with moderate affinity, the cell response to the cue was dependent on the activation of biologically relevant protein-specific biochemical signal transduction pathways. Our results establish that choices made by cells in response to a surface-bound cue must take into account, and be interpreted in the context of, the RS. The use of a series of RSs with varying cell-surface affinity reveals specific response curves of cells to a cue that can be compared quantitatively and that may help gain new insights into cellular responses to extracellular proteins. PMID- 24144908 TI - Cancer stem cell therapy using doxorubicin conjugated to gold nanoparticles via hydrazone bonds. AB - Nanoparticle-mediated delivery of chemotherapies has demonstrated enhanced anti cancer efficacy, mainly through the mechanisms of both passive and active targeting. Herein, we report other than these well-elucidated mechanisms, rationally designed nanoparticles can efficiently deliver drugs to cancer stem cells (CSCs), which in turn contributes significantly to the improved anti-cancer efficacy. We demonstrate that doxorubicin-tethered gold nanoparticles via a poly(ethylene glycol) spacer and an acid-labile hydrazone bond mediate potent doxorubicin delivery to breast CSCs, which reduces their mammosphere formation capacity and their cancer initiation activity, eliciting marked enhancement in tumor growth inhibition in murine models. The drug delivery mediated by the nanoparticles also markedly attenuates tumor growth during off-therapy stage by reducing breast CSCs in tumors, while the therapy with doxorubicin alone conversely evokes an enrichment of breast CSCs. Our findings suggest that with well-designed drug delivery system, the conventional chemotherapeutic agents are promising for cancer stem cell therapy. PMID- 24144910 TI - Use of extracorporeal membrane oxygenation in adults. AB - Since the first successful application of the heart-lung machine in 1953 by John Gibbon [1], great efforts have been made to modify the bypass techniques and devices in order to allow prolonged extracorporeal circulation in the intensive care unit (ICU), commonly referred to as extracorporeal membrane oxygenation (ECMO). ECMO uses classic cardiopulmonary bypass technology to support circulation. It provides continuous, non-pulsatile cardiac output and extracorporeal oxygenation [2]. Veno-venous ECMO (VV ECMO) provides respiratory support, while veno-arterial ECMO (VA ECMO) provides cardio-respiratory support to patients with severe but potentially reversible cardiac or respiratory deterioration refractory to standard therapeutic modalities. ECMO is a temporary form of life support providing a prolonged biventricular circulatory and pulmonary support for patients experiencing both pulmonary and cardiac failure unresponsive to conventional therapy. Despite the advent of newer ventricular assist devices that are more suitable for long term support, ECMO is simple to establish, cost-effective to operate. PMID- 24144909 TI - Probing the non-canonical interface for agonist interaction with an alpha5 containing nicotinic acetylcholine receptor. AB - Nicotinic acetylcholine receptors (nAChRs) containing the alpha5 subunit are of interest because genome-wide association studies and candidate gene studies have identified polymorphisms in the alpha5 gene that are linked to an increased risk for nicotine dependence, lung cancer, and/or alcohol addiction. To probe the functional impact of an alpha5 subunit on nAChRs, a method to prepare a homogeneous population of alpha5-containing receptors must be developed. Here we use a gain of function (9') mutation to isolate populations of alpha5-containing nAChRs for characterization by electrophysiology. We find that the alpha5 subunit modulates nAChR rectification when co-assembled with alpha4 and beta2 subunits. We also probe the alpha5-alpha4 interface for possible ligand-binding interactions. We find that mutations expected to ablate an agonist-binding site involving the alpha5 subunit have no impact on receptor function. The most straightforward interpretation of this observation is that agonists do not bind at the alpha5-alpha4 interface, in contrast to what has recently been demonstrated for the alpha4-alpha4 interface in related receptors. In addition, our mutational results suggest that the alpha5 subunit does not replace the alpha4 or beta2 subunits and is relegated to occupying only the auxiliary position of the pentameric receptor. PMID- 24144911 TI - Glutamine depletion and heat shock protein 70 (HSP70) in children with meningococcal disease. AB - BACKGROUND & AIMS: Heat shock proteins are classified into six main families, of which HSP70 is the best studied. HSP70 is postulated to modulate the immune/inflammatory response in critical illness. Glutamine promotes HSP70 release, however, little is known about the relationship between glutamine and HSP70 in paediatric critical illness. We therefore aimed to describe plasma levels of HSP70, inflammatory mediators and glutamine in critically ill children. METHODS: A clinical audit identified 143 children with severe meningococcal disease, 78 convalescent children, in addition to 35 healthy paediatric controls. Stored plasma was used to measure plasma concentrations of HSP70, inflammatory mediators and glutamine. RESULTS: HSP70 was significantly increased on admission (n = 143, mean 26.7 ng/ml; +/-SD 79.95) compared with convalescence (n = 78, mean 3.16 ng/ml; +/-SD 5.67). Glutamine levels were low (n = 132, mean 0.31 mmol/l; +/ SD 0.13), which continued in convalescence (n = 65, mean 0.40 mmol/l; +/-SD 0.14). Enteral glutamine provided only 28% of the recommendations. Glutamine was inversely correlated with length-of-stay (n = 98, r = -0.520, p < 0.001), ventilation (n = 98, r = -0.513, p < 0.001), lactate (n = 98, r = -0.41, p < 0.001) and CRP (n = 98, r = -0.51, p < 0.001). HSP70 was correlated with length of-stay (n = 99, r = 0.30, p < 0.001), ventilation (n = 99, r = 0.31, p < 0.001), lactate (n = 99, r = 0.26, p < 0.001) and CRP (n = 99, r = 0.29, p < 0.001) and inflammatory mediators. There was no relationship between glutamine and HSP70 or inflammatory mediators. CONCLUSIONS: During acute illness HSP70/inflammatory mediators are significantly increased, and glutamine is significantly depleted. However, glutamine and HSP70 were not correlated. Enteral feeds only provided a small proportion of the ASPEN/ESPEN recommendations for glutamine. PMID- 24144912 TI - Aliphatic polyamines in physiology and diseases. AB - Aliphatic polyamines are a family of polycationic molecules derived from decarboxylation of the amino acid ornithine that classically comprise three molecules: putrescine, spermidine and spermine. In-cell polyamine homeostasis is tightly controlled at key steps of cell metabolism. Polyamines are involved in an array of cellular functions from DNA stabilization, and regulation of gene expression to ion channel function and, particularly, cell proliferation. As such, aliphatic polyamines play an essential role in rapidly dividing cells such as in the immune system and digestive tract. Because of their role in cell proliferation, polyamines are also involved in carcinogenesis, prompting intensive research into polyamine metabolism as a target in cancer therapy. More recently, another aliphatic polyamine, agmatine, the decarboxylated derivative of arginine, has been identified as a neurotransmitter in mammals, and investigations have focused on its effects in the CNS, notably as a neuroprotector in brain injury. PMID- 24144913 TI - Reproducibility and comparative validity of a food frequency questionnaire for Australian adults. AB - BACKGROUND: Food frequency questionnaires (FFQ) are used in epidemiological studies to investigate the relationship between diet and disease. There is a need for a valid and reliable adult FFQ with a contemporary food list in Australia. AIMS: To evaluate the reproducibility and comparative validity of the Australian Eating Survey (AES) FFQ in adults compared to weighed food records (WFRs). METHODS: Two rounds of AES and three-day WFRs were conducted in 97 adults (31 males, median age and BMI for males of 44.9 years, 26.2 kg/m(2), females 41.3 years, 24.0 kg/m(2). Reproducibility was assessed over six months using Wilcoxon signed-rank tests and comparative validity was assessed by intraclass correlation coefficients (ICC) estimated by fitting a mixed effects model for each nutrient to account for age, sex and BMI to allow estimation of between and within person variance. RESULTS: Reproducibility was found to be good for both WFR and FFQ since there were no significant differences between round 1 and 2 administrations. For comparative validity, FFQ ICCs were at least as large as those for WFR. The ICC of the WFR-FFQ difference for total energy intake was 0.6 (95% CI 0.43, 0.77) and the median ICC for all nutrients was 0.47, with all ICCs between 0.15 (%E from saturated fat) and 0.7 (g/day sugars). CONCLUSIONS: Compared to WFR the AES FFQ is suitable for reliably estimating the dietary intakes of Australian adults across a wide range of nutrients. PMID- 24144914 TI - Novel mutations in the fukutin gene in a boy with asymptomatic hyperCKemia. AB - Mutations in the fukutin gene were first identified in Japanese patients with classic Fukuyama congenital muscular dystrophy, a severe form of congenital muscular dystrophy associated with cobblestone lissencephaly and ocular defects. Patients of different ethnicities and with milder phenotypes, including limb girdle muscular dystrophy and cardiomyopathy without brain impairment, have also been reported. The hallmark of this disorder, regardless of the clinical outcome, is moderate-to-severe hypoglycosylation of alpha-dystroglycan in muscle sections. We describe the case of a boy harboring two novel mutations in fukutin gene and presenting a five-year history of asymptomatic hyperCKemia, without overt muscle, brain or ocular involvement. Genetic investigations, guided by the presence of moderate myopathic changes on muscle biopsy with loss of immunodetectable alpha dystroglycan, led to a definitive diagnosis. Cardiac and echocardiographic examinations at follow-up disclosed low normal left ventricular function but no active cardiovascular symptoms. We suggest that fukutin mutations should be sought in asymptomatic hyperCKemia and subclinical heart dysfunction. PMID- 24144915 TI - Social-emotional delays at 2 years in extremely low gestational age survivors: correlates of impaired orientation/engagement and emotional regulation. AB - BACKGROUND: Premature infants are less socially and emotionally competent at school age than infants born at term. AIMS: To evaluate the correlates of social and emotional delays at 2 years of age among prematurely born children. STUDY DESIGN: This is a prospective cohort study. SUBJECTS: 904 children born at <28 weeks gestation during 2002-2004 and enrolled in the ELGAN study who survived until age 2 years and returned for a developmental assessment. OUTCOME MEASURES: The Bayley Behavior Rating Scale (BRS), a neurological examination, and the Bayley Scales of Infant Development II (BSID-II). RESULTS: Fully 31% of children had a non-optimal (14%) or questionable (17%) (NO/Q) BRS score for Emotional Regulation (ER), and 27% had a non-optimal (13%) or questionable (14%) score for Orientation/Engagement (O/E). Children with NO/Q scores on ER and O/E were more likely than others to have MDI and PDI scores <70 and be unable to walk. Antecedents of NO/Q OE scores included multi-fetal pregnancy, while antecedents of NO/Q scores for both ER and O/E included indicators of socioeconomic disadvantage, and male sex. CONCLUSIONS: Over 25% of children born extremely premature exhibit socio-emotional delays during developmental assessment at age 2 years. Antecedents of these delays include sociodemographic characteristics, as well as those common antecedents of other impairments commonly observed among extremely preterm infants. PMID- 24144916 TI - Folate-linked lipoplexes for short hairpin RNA targeting claudin-3 delivery in ovarian cancer xenografts. AB - Ovarian cancers highly overexpress folate receptor alpha (FRalpha) and claudin3 (CLDN3), both of which are associated with tumor progression and poor prognosis of patients. Downregulation of FRalpha and CLDN3 in ovarian cancer may suppress tumor growth and promote benign differentiation of tumor. In this study, F-P LP/CLDN3, a FRalpha targeted liposome loading with short hairpin RNA (shRNA) targeting CLDN3 was prepared and the pharmaceutical properties were characterized. Then, the antitumor effect of F-P-LP/CLDN3 was studied in an in vivo model of advanced ovarian cancer. Compared with Control, F-P-LP/CLDN3 promoted benign differentiation of tumor and achieved about 90% tumor growth inhibition. In the meantime, malignant ascites production was completely inhibited, and tumor nodule number and tumor weight were significantly reduced (p<0.001). FRalpha and CLDN3 were downregulated together in tumor tissues treated by F-P-LP/CLDN3. The antitumor mechanisms were achieved by promoting tumor cell apoptosis, inhibiting tumor cell proliferation and reducing microvessel density. Finally, safety evaluation indicated that F-P-LP/CLDN3 was a safe formulation in intraperitoneally administered cancer therapy. We come to a conclusion that F-P LP/CLDN3 is a potential targeting formulation for ovarian cancer gene therapy. PMID- 24144917 TI - Manipulating the pH response of 2,3-diaminopropionic acid rich peptides to mediate highly effective gene silencing with low-toxicity. AB - Cationic amphipathic pH responsive peptides possess high in vitro and in vivo nucleic acid delivery capabilities and function by forming a non-covalent complex with cargo, protecting it from nucleases, facilitating uptake via endocytosis and responding to endosomal acidification by being released from the complex and inserting into and disordering endosomal membranes. We have designed and synthesised peptides to show how Coulombic interactions between ionizable 2,3 diaminopropionic acid (Dap) side chains can be manipulated to tune the functional pH response of the peptides to afford optimal nucleic acid transfer and have modified the hydrogen bonding capabilities of the Dap side chains in order to reduce cytotoxicity. When compared with benchmark delivery compounds, the peptides are shown to have low toxicity and are highly effective at mediating gene silencing in adherent MCF-7 and A549 cell lines, primary human umbilical vein endothelial cells and both differentiated macrophage-like and suspension monocyte-like THP-1 cells. PMID- 24144918 TI - Poly(ethylene glycol)-poly(lactic-co-glycolic acid) based thermosensitive injectable hydrogels for biomedical applications. AB - Stimuli triggered polymers provide a variety of applications related with the biomedical fields. Among various stimuli triggered mechanisms, thermoresponsive mechanisms have been extensively investigated, as they are relatively more convenient and effective stimuli for biomedical applications. In a contemporary approach for achieving the sustained action of proteins, peptides and bioactives, injectable depots and implants have always remained the thrust areas of research. In the same series, Poloxamer based thermogelling copolymers have their own limitations regarding biodegradability. Thus, there is a need to have an alternative biomaterial for the formulation of injectable hydrogel, which must remain biocompatible along with safety and efficacy. In the same context, poly(ethylene glycol) (PEG) based copolymers play a crucial role as a biomedical material for biomedical applications, because of their biocompatibility, biodegradability, thermosensitivity and easy controlled characters. This review stresses on the physicochemical property, stability and composition prospects of smart PEG/poly(lactic-co-glycolic acid) (PLGA) based thermoresponsive injectable hydrogels, recently utilized for biomedical applications. The manuscript also highlights the synthesis scheme and stability characteristics of these copolymers, which will surely help the researchers working in the same area. We have also emphasized the applied use of these smart copolymers along with their formulation problems, which could help in understanding the possible modifications related with these, to overcome their inherent associated limitations. PMID- 24144919 TI - Photothermal therapy of tumors in lymph nodes using gold nanorods and near infrared laser light. AB - Lymph node dissection for regional nodal metastasis is a primary option, but is invasive and associated with adverse effects. The development of non-invasive therapeutic methods in preclinical experiments using mice has been restricted by the small lymph node size and the limited techniques available for non-invasive monitoring of lymph node metastasis. Here, we show that photothermal therapy (PTT) using gold nanorods (GNRs) and near-infrared (NIR) laser light shows potential as a non-invasive treatment for tumors in the proper axillary lymph nodes (proper-ALNs) of MXH10/Mo-lpr/lpr mice, which develop systemic swelling of lymph nodes (up to 13mm in diameter, similar in size to human lymph nodes). Tumor cells were inoculated into the proper-ALNs to develop a model of metastatic lesions, and any anti-tumor effects of therapy were assessed. We found that GNRs accumulated in the tumor in the proper-ALNs 24h after tail vein injection, and that irradiation with NIR laser light elevated tumor temperature. Furthermore, combining local or systemic delivery of GNRs with NIR irradiation suppressed tumor growth more than irradiation alone. We propose that PTT with GNRs and NIR laser light can serve as a new therapeutic method for lymph node metastasis, as an alternative to lymph node dissection. PMID- 24144920 TI - The zinc finger homeodomain-2 gene of Drosophila controls Notch targets and regulates apoptosis in the tarsal segments. AB - The development of the Drosophila leg is a good model to study processes of pattern formation, cell death and segmentation. Such processes require the coordinate activity of different genes and signaling pathways that progressively subdivide the leg territory into smaller domains. One of the main pathways needed for leg development is the Notch pathway, required for determining the proximo distal axis of the leg and for the formation of the joints that separate different leg segments. The mechanisms required to coordinate such events are largely unknown. We describe here that the zinc finger homeodomain-2 (zfh-2) gene is highly expressed in cells that will form the leg joints and needed to establish a correct size and pattern in the distal leg. There is an early requirement of zfh-2 to establish the correct proximo-distal axis, but zfh-2 is also needed at late third instar to form the joint between the fourth and fifth tarsal segments. The expression of zfh-2 requires Notch activity but zfh-2 is necessary, in turn, to activate Notch targets such as Enhancer of split and big brain. zfh-2 is controlled by the Drosophila activator protein 2 gene and regulates the late expression of tarsal-less. In the absence of zfh-2 many cells ectopically express the pro-apoptotic gene head involution defective, activate caspase-3 and are positive for acridine orange, indicating they undergo apoptosis. Our results demonstrate the key role of zfh-2 in the control of cell death and Notch signaling during leg development. PMID- 24144921 TI - The human constitutive androstane receptor promotes the differentiation and maturation of hepatic-like cells. AB - Expression of the constitutive androstane receptor (CAR, NR1I3) is enriched in the mature mammalian liver and increasingly recognized for its prominent role in regulating a myriad of processes including biotransformation, chemical transport, energy metabolism and lipid homeostasis. Previously, we demonstrated that CAR levels were markedly enhanced during the differentiation of hepatic-like cells derived from hESCs, prompting the hypothesis that CAR contributes a key functional role in directing human hepatogenesis. Here we demonstrate that over expression of CAR in human embryonic stem cells (ESCs), transduced by a lentiviral vector, accelerates the maturation of hepatic-like cells, with CAR over-expressing cells exhibiting a 2.5-fold increase in albumin secretion by day 20 in culture differentiation, and significantly enhanced levels of mRNA expression of several liver-selective markers, including hepatic transcription factors, plasma proteins, biotransformation enzymes, and metabolic enzymes. CAR over-expressing cells also exhibited enhanced CITCO-inducible CYP3A7 enzymatic activity. Knockdown of CAR via siRNA attenuated the differentiation-dependent expression programs. In contrast, expression levels of the pregnane X receptor (PXR), a nuclear receptor most similar to CAR in primary sequence, were negligible in human fetal liver tissues or in the differentiating hESCs, and stable over-expression of PXR in hepatic-induced hESCs failed to enhance expression of hepatic phenotype markers. Together, these results define a novel role for human CAR in hepatic lineage commitment. PMID- 24144922 TI - Selective decontamination of the oropharynx and the digestive tract, and antimicrobial resistance: a 4 year ecological study in 38 intensive care units in the Netherlands. AB - OBJECTIVES: Selective oropharyngeal decontamination (SOD) and selective decontamination of the digestive tract (SDD) are associated with improved outcomes among patients in intensive care units (ICUs), but uncertainty remains about their long-term effects on resistance levels. We determined trends in antibiotic resistance among Gram-negative bacteria in 38 Dutch ICUs using and not using SOD/SDD. METHODS: The Infectious Disease Surveillance Information System Antibiotic Resistance (ISIS-AR) was used to identify all Enterobacteriaceae, Pseudomonas aeruginosa and Acinetobacter spp. isolates from blood and respiratory tract specimens from ICUs between January 2008 and April 2012. Per patient, the last isolate per species per specimen per month was selected to determine cumulative resistance rates (per 100 beds/month) for colistin, tobramycin, ciprofloxacin, ceftazidime and cefotaxime/ceftriaxone in ICUs that continuously used or did not use SOD/SDD, and ICUs that introduced SOD/SDD. Time trends were analysed by multilevel Poisson regression. RESULTS: Seventeen ICUs continuously used SOD/SDD (859 months), 13 did not use SOD/SDD (663 months) and 8 introduced SOD/SDD (223 and 117 months before and after introduction). There were no discernible trends in antibiotic resistance among 637 blood isolates. For the 8353 respiratory isolates, resistance to cefotaxime/ceftriaxone increased in ICUs that did not use SOD/SDD (P < 0.001) and decreased in those that continuously used SOD/SDD (P = 0.04), as did resistance to ciprofloxacin (P < 0.001). The introduction of SOD/SDD was followed by statistically significant reductions in resistance rates for all antimicrobial agents. CONCLUSIONS: Continuous use of SOD/SDD was associated with decreasing trends for resistance to cefotaxime/ceftriaxone and ciprofloxacin. The introduction of SOD/SDD was associated with reductions in resistance rates for all antimicrobial agents included. PMID- 24144923 TI - Exposure of HIV-1 to a combination of two carbohydrate-binding agents markedly delays drug resistance development and selects for virus strains with compromised fitness. AB - OBJECTIVES: We investigated the effect of combining two potent carbohydrate binding agents (CBAs) with a complementary resistance profile (based on different N-glycan deletion selections in the HIV envelope glycoprotein gp120) on drug resistance development and viral fitness. METHODS: A long-term selection procedure was used to obtain virus strains resistant to the mannose-specific Hippeastrum hybrid agglutinin (HHA), the mannose-recognizing monoclonal antibody 2G12 and the combination of both compounds. The env genes of the mutant viruses were sequenced and the infectivity potential and phenotypic resistance profile of the virus strains were examined in CD4+ T lymphocyte C8166 cell cultures. RESULTS: The long-term exposure of HIV-1 to CBAs resulted in the selection of virus isolates containing deletions of several high-mannose-type N-glycans in their envelope. The generation of virus strains phenotypically resistant to the combination of both CBAs took markedly longer than the generation of virus strains resistant to the single compounds. The mutant HIV strains derived from the HHA/2G12 combination exposure showed much lower genotypic and phenotypic resistance than those isolated from the virus selection experiments with the single compounds. It was further shown that the CBA-resistant viruses had significantly decreased infectivities. CONCLUSIONS: The data revealed that CBAs are interesting anti-HIV drug candidates with an increased antiviral potential upon internal combination. PMID- 24144924 TI - Magnetic resonance imaging of the temporal lobe: normal anatomy and diseases. AB - OBJECTIVE: This pictorial essay will review the magnetic resonance imaging anatomy of the temporal lobes and describe the major pathologic processes of this complex area. CONCLUSIONS: Magnetic resonance imaging is an essential tool in the investigation of a patient with suspected temporal lobe pathology. Various conditions may affect this anatomic region, and, therefore, classification of imaging findings into specific groups may help provide a more focused differential diagnosis. PMID- 24144925 TI - The role of preoperative urodynamics in urogynecologic procedures. AB - Urodynamic studies refer to any tests that provide objective information about lower urinary tract function with the goal of evaluating bladder and urethral function. Pre-operative urodynamic testing is commonly performed prior to urogynecologic procedures for urinary incontinence and pelvic organ prolapse. Although the utility of preoperative urodynamics testing before urogynecologic procedures have been challenged in the literature, the preoperative utilization of urodynamic testing in women with complex voiding dysfunction or associated conditions such as prolapse or urethral diverticulum is still considered important for surgical planning and pre-operative counseling. PMID- 24144926 TI - Trial participation as a determinant of clinical outcome: differences between trial-participants and Every Day Clinical Care patients in the field of interventional cardiology. AB - BACKGROUND: This study examines differences in clinical outcome between trial participants and non-participants after percutaneous coronary intervention (PCI). METHODS AND RESULTS: This study compromised of 11,931 consecutive patients who underwent PCI in a high volume center, during the period 2000 - 2009. Of these patients, 1787 (15%) participated in an interventional clinical trial with a follow-up period of at least six months. The maximum follow-up duration was 11.8 years, with a median of 3.8 years (IQR: 2.6 - 6.5). Baseline and procedural characteristics differed between trial-participants and non-participants. Trial participants were more often male, were younger, had more cardiovascular risk factors and were treated more often for stable angina pectoris and single vessel disease. Overall mortality at maximum follow-up was lower for trial-participants compared to non-participants (8.1% versus 17.6%, p<0.001, adjusted HR, 0.62, 95% CI: 0.52-0.74). There was no difference in the incidence of non-fatal MI and CABG. Repeat PCI was seen more often in trial-participants (18.1% versus 30.7%, p<0.001, adjusted HR 1.91, 95%CI 1.73-2.10). Consequently, a higher incidence of the composite of mortality, repeat revascularization, and non-fatal MI was seen in the trail-participants (adjusted HR.1.36 95% CI 1.25 - 1.47), but this association was primarily driven by the occurrence of repeat PCI. CONCLUSION: Participants in clinical trials in the field of interventional cardiology with a follow-up of at least six months differed considerably from non-participants in baseline and procedural characteristics. Trial-participants had better survival than non-participants. In contrast, a two-fold higher incidence of repeat PCI was observed in trial-participants. PMID- 24144927 TI - Prospective meta-analysis of trials comparing fixed dose combination based care with usual care in individuals at high cardiovascular risk: the SPACE Collaboration. AB - BACKGROUND: An international collaboration of investigators will assess the benefits and risks of fixed dose combination (FDC) based care compared with usual care in populations at high risk of cardiovascular disease (CVD). Several trials are being conducted, as the effectiveness and economic impact of a FDC-based strategy may vary substantially between countries, given the varying influence of the health-care system within which the intervention is delivered. METHODS: Individual patient data (IPD) will be provided by participating trials for combined IPD meta-analysis. RESULTS: Primary outcomes will include self-reported current use of antiplatelet, statin, and combination (>= 2) blood pressure lowering therapies at 12 months, and change in systolic blood pressure (SBP) and LDL cholesterol from baseline to 12 months. Non-inferiority margins of 3 mm Hg for SBP and 0.3 mmol/L for LDL cholesterol have been pre-specified. Secondary outcomes will include change in cholesterol fractions, diastolic blood pressure and creatinine from baseline to 12 months, quality of life, new onset diabetes mellitus, mortality (cardiovascular, non-cardiovascular and all cause) and a composite outcome of cardiovascular events (including all coronary heart disease events, heart failure events leading to death or requiring hospital admission, cerebrovascular events and peripheral arterial events). CONCLUSION: The SPACE group of trials will assess, in a variety of healthcare settings, whether a FDC strategy for delivery of preventive medication has the potential to significantly improve prevention of cardiovascular disease in patients at high risk. PMID- 24144928 TI - Ventilatory efficiency slope correlates with functional capacity, outcomes, and disease severity in pediatric patients with pulmonary hypertension. AB - BACKGROUND: Cardiopulmonary exercise testing is widely used in a variety of cardiovascular conditions. Ventilatory efficiency slope can be derived from submaximal exercise testing. The present study sought to evaluate the relationship between ventilatory efficiency slope and functional capacity, outcomes, and disease severity in pediatric patients with pulmonary hypertension. METHODS: Seventy six children and young adults with a diagnosis of pulmonary hypertension (PH) performed 258 cardiopulmonary exercise tests from 2001 to 2011. Each individual PH test was matched to a control test. Ventilatory efficiency slope was compared to traditional measures of functional capacity and disease severity including WHO functional classification, peak oxygen consumption, and invasive measures of pulmonary arterial pressures and pulmonary vascular resistance. RESULTS: Ventilatory efficiency slope was significantly higher in patients with pulmonary arterial hypertension, with an estimated increase of 7.2 for each increase in WHO class (p<0.0001), compared with normal control subjects (38.9 vs. 30.9, p<0.001). Ventilatory efficiency slope correlated strongly with invasive measures of disease severity including pulmonary vascular resistance index (r =0.61), pulmonary artery pressure (r =0.58), mean pulmonary artery pressure/mean aortic pressure ratio (r =0.52), and peak VO2 (r=-0.58). Ventilatory efficiency slope in 12 patients with poor outcomes (9 death, 3 lung transplant), was significantly elevated compared to patients who did not (51.1 vs. 37.9, p<0.001). CONCLUSIONS: Ventilatory efficiency slope correlates well with invasive and noninvasive markers of disease severity including peak VO2, WHO functional class, and catheterization variables in pediatric patients with PH. Ventilatory efficiency slope may be a useful noninvasive marker for disease severity. PMID- 24144929 TI - Asymmetrical hemisphere activation enhances global-local processing. AB - Decades of research focusing on the neurophysiological underpinnings related to global-local processing of hierarchical stimuli have associated global processing with the right hemisphere and local processing with the left hemisphere. The current experiment sought to expand this research by testing the causal contributions of hemisphere activation to global-local processing. To manipulate hemisphere activation, participants engaged in contralateral hand contractions. Then, EEG activity and attentional scope were measured. Right-hand contractions caused greater relative left-cortical activity than left-hand contractions. Participants were more narrowly focused after left-hemisphere activation than after right-hemisphere activation. Moreover, N1 amplitudes to local targets in the left hemisphere were larger after left-hemisphere activation than after right hemisphere activation. Consistent with past research investigating hemispheric asymmetry and attentional scope, the current results suggest that manipulating left (right) hemisphere activity enhanced local (global) attentional processing. PMID- 24144930 TI - Comparative clinical and radiographic study of the lumbar spine between parachute infantry soldiers and non-parachute infantry soldiers in Japanese Ground Self Defense forces. AB - BACKGROUND: The long-term effect of repetitive trauma by military parachuting on the lumbar spine is not well investigated. Therefore, the purpose of this study was to examine the development of lumbar degenerative changes during a 30-year follow-up in Japanese Ground Self Defense Forces (JGSDF) parachute infantry soldiers with normal lumbar radiographs at entry by comparison with those with non-parachute infantry soldiers. METHODS: 79 non-parachutists and 65 parachutists were included for radiological examination and questionnaires for low back pain (LBP). All subjects were non-commissioned officers with similar socioeconomic status and life styles. The number of parachuting descent during the 30-year in the parachute group ranged from 208 to 630, with an average of 322. RESULTS: The mean age of the subjects was 18.3+/-0.5 years at entry and 48.5+/-0.3 years at follow-up. LBP had been experienced by 37% in the non-parachute group and 25% in the parachute group with no significant difference. The nature of their LBP was judged as mild. The prevalence rate of degenerative changes was similar in both groups. Disc space narrowing was detected 37 subjects (47%) in non-parachute group an 23 subjects (35%) in parachute group without significant difference. Vertebral osteophytes were detected in 52 subjects (67%) in non-parachute group and 47 subjects (72%) in parachute group without significant difference. CONCLUSIONS: This study did not identify any significant differences in the development of lumbar degenerative changes between the parachutists and non parachutists over a 30-year follow-up, suggesting that military parachuting itself does not accelerate the development of intervertebral disc degeneration. Further studies are needed using large cohorts assessed by MRI as well as plain X ray. PMID- 24144931 TI - How to operate for MRCS candidates and other surgical trainees. PMID- 24144932 TI - The upscheduling of combination analgesics containing codeine: the impact on the practice of pharmacists. AB - BACKGROUND: Prior to the 1st May 2010 some combination analgesics containing codeine (CACC) were available for sale over the counter (OTC) in Australia with no requirement for input from a pharmacist. Since then the upscheduling of these medications requires the involvement of a pharmacist in all OTC CACC sales. OBJECTIVE: To explore how the upscheduling of OTC CACC has impacted the practice of community pharmacists. METHODS: A descriptive qualitative design was used, with data collected via face-to-face semi-structured interviews that were recorded and transcribed verbatim. The data were analyzed thematically via open, axial and selective coding. RESULTS: Pharmacists were found to monitor the supply of OTC CACC by recording sales and to intervene when they felt that the medication was being used too frequently. They perceived a number of challenges surrounding the provision of OTC CACC including; supply from other pharmacies, establishing therapeutic need, managing codeine dependent people, lacking confidence in discussing misuse with people, being unsure where to refer dependent people for help and purchaser resentment towards pharmacist involvement in all sales. People who request OTC CACC tended to be stereotyped by participants as either 'genuine' or 'misusers.' CONCLUSION: A number of challenges faced by community pharmacists to ensure the safe provision of OTC CACC and to assist codeine dependent people were identified, highlighting the need for more effective ways of monitoring the use of OTC CACC and intervening in OTC codeine dependence. PMID- 24144933 TI - Current and future imaging of the peripheral nervous system. AB - Peripheral nervous system (PNS) imaging is usually carried out by ultrasound and MRI. Thanks to its wide availability and excellent spatial resolution, ultrasound is a mature investigation with clearly established indications, particularly in entrapment syndromes and tumors. MRI is generally a second-line examination, which provides decisive additional information thanks to its excellent contrast resolution and its multiplanar abilities. This review describes the current methods for imaging the PNS, concentrating on acquisition techniques, normal results and basic pathological semiology. Ongoing and future developments are described in order to underline the forthcoming changes in this very dynamic field of musculoskeletal radiology. PMID- 24144934 TI - Vertical migration of leachate pollutants in clayey soils beneath an uncontrolled landfill at Huainan, China: a field and theoretical investigation. AB - To assess the extent of leachate migration, continuous samples of clayey soils (about 9m) were obtained beneath a 17-year old uncontrolled landfill in southeastern China. The soil samples were sub sectioned and analyzed to determine the concentrations of chloride, sodium and COD in the pore water. Total nitrogen and soil organic matter content of the soil samples were also determined. Leachate-derived chloride was detected in the clayey soil to a maximum depth of 9m. Sodium and COD were found to migrate into the soils to depths of 3-4m due to the attenuation of solutes by the soil organic matter and clay minerals at the shallow soils. The estimated migration depths for the chloride are 3m in the case of pure diffusion. Advection and mechanical dispersion were found to be more important than molecular diffusion for this site with an 8m high leachate mound. By comparing the results obtained by the mathematical modeling for layered advection-dispersion problem with the measured concentration profiles, the ranges of the effective diffusion coefficient, retardation factor and dispersivity of the soils were estimated. Better fits are obtained by employing an artificial effective interface about 1m above the observed interface. The clayey soils showed a relatively high attenuation capacity for COD with the estimated retardation factor of 5. PMID- 24144935 TI - Photodegradation of antibiotics under simulated solar radiation: implications for their environmental fate. AB - Roxithromycin, erythromycin, ciprofloxacin and sulfamethoxazole are frequently detected antibiotics in environmental waters. Direct and indirect photolysis of these problematic antibiotics were investigated in pure and natural waters (fresh and salt water) under irradiation of different light sources. Fundamental photolysis parameters such as molar absorption coefficient, quantum yield and first order rate constants are reported and discussed. The antibiotics are degraded fastest under ultraviolet 254 nm, followed by 350 nm and simulated solar radiation. The composition of the matrix (pH, dissolved organic content, chloride ion concentration) played a significant role in the observed photodegradation. Under simulated solar radiation, ciprofloxacin and sulfamethoxazole degrade relatively quickly with half-lives of 0.5 and 1.5h, respectively. However, roxithromycin and erythromycin, macrolides are persistent (half-life: 2.4-10 days) under solar simulation. The transformation products (15) of the targeted antibiotics produced under irradiation experiments were identified using high resolution mass spectrometry and degradation pathways were proposed. PMID- 24144936 TI - Multivariate analysis of effects of diurnal temperature and seasonal humidity variations by tropical savanna climate on the emissions of anthropogenic volatile organic compounds. AB - Volatile organic compounds (VOCs), particularly those from anthropogenic sources, have been of substantial concern. In this study, the influences of diurnal temperature and seasonal humidity variations by tropical savanna climate on the distributions of VOCs from stationary industrial sources were investigated by analyzing the concentrations during the daytime and nighttime in the dry and wet seasons and assessing the results by principal component analysis (PCA) and cluster analysis. Kaohsiung City in Southern Taiwan, known for its severe VOC pollution, was chosen as the location to be examined. In the results, the VOC concentrations were lower during the daytime and in the wet season, possibly attributed to the stronger photochemical reactions and increasing inhibition of VOC emissions and transports by elevating humidity levels. Certain compounds became appreciably more important at higher humidity, as these compounds were saturated hydrocarbons with relatively low molecular weights. The influence of diurnal temperature variation on VOC distribution behaviors seemed to be less important than and interacted with that of seasonal humidity variation. Heavier aromatic hydrocarbons with more complex structures and some aliphatic compounds were found to be the main species accounting for the maximum variances of the data observed at high humidity, and the distinct grouping of compounds implied a pronounced inherent characteristic of each cluster in the observed VOC distributions. Under the influence of diurnal temperature variation, selected VOCs that may have stronger photochemical resistances and/or longer lifetimes in the atmosphere were clustered with each other in the cluster analysis, whereas the other groups might consist of compounds with different levels of vulnerability to sunlight or high temperatures. These findings prove the complications in the current knowledge regarding the VOC contaminations and providing insight for managing the adverse impacts of the anthropogenic VOCs on the environment and public health. PMID- 24144937 TI - Effects of environmental and physiological variables on the accumulated concentrations of trace metals in the New Zealand cockle Austrovenus stutchburyi. AB - We examined potential causes of variation in trace element accumulation in an estuarine bivalve Austrovenus stutchburyi from two estuarine systems in South Island, New Zealand which differed in their metal contamination and salinity regimes. Concentrations of Ag, As, Cd, Co, Cr, Cu, Fe, Mn, Ni, Pb, Ti, V and Zn were measured (ICP-OES) in whole body tissues of bivalves collected from 10 sites, seston collected at high tide (a potential food resource) and in the sediment at the sites. All 13 elements showed a relationship between log bioaccumulated trace element concentration (mgkg(-1) dry weight tissue) and log shell length (mm), either in the whole data set or at least one site (ANCOVA). Growth rates of cockles varied significantly amongst sites. Accumulated soft tissue concentrations of Ag, As, Co and Cr increased with age of cockle, those of Pb and Zn decreased, with no clear age-related trend for the remaining metals (ANCOVA). Shell length was generally a good proxy for age when allowing for any size effect in metal accumulation by the cockle. There was no consistent pattern between the estuarine systems, probably reflecting unidentified contaminant inputs. Following depuration, tissue concentrations decreased significantly for some elements (Fe, Mn, Ti and V), indicating high concentrations of these metals in the gut contents. Trace element concentrations in the seston generally did not correlate with the bivalve tissue concentrations. There were few (Spearman's Rank) correlations between environmental variables at the time of sampling and cockle tissue trace element concentrations. The main sources of variation in bioaccumulated trace metal concentrations in the whole tissues of the cockle are location, shell length and age. PMID- 24144938 TI - Potential health risks of heavy metals in cultivated topsoil and grain, including correlations with human primary liver, lung and gastric cancer, in Anhui province, Eastern China. AB - Environmental exposure to heavy metals is a well-known risk factor for cancers. To evaluate potential health risks of heavy metals (Cr, Cd, Pb, As and Hg) and Se in cultivated topsoil and grains, we investigated the concentrations of Hg, As and Se using atomic fluorescence spectrometry and Cr, Cd and Pb using inductive coupled plasma emission spectrometry (ICP-MS). We also analyzed human cancer tissues for heavy metals. Potential health risks for local residents were evaluated by calculating the hazard index (HI) and the total carcinogenic risk (TCR) for soil heavy metals and the target hazard quotient (THQ) and the carcinogenic risk (CR) for grain heavy metals. A bioconcentration factor (BCF) was applied to quantify the bioaccumulation of heavy metals. Our results demonstrated that the mean concentrations of heavy metals in soil were all within the safety limits set by FAO/WHO and Chinese regulations; however, the mean concentrations of Cr and Hg in grain exceeded the safety limits. HI and TCR for soil heavy metals were all within acceptable levels, but the THQ for four grain heavy metals exceeded the target value of 1 (Cr, 2.64; Pb, 1.41; As, 1.24; Hg, 1.07; Cd, 0.39). The grain CR for Cr, Pb and As exceeded the accepted risk level of 10(-6). BCF values indicated that the bioaccumulation capacity decreased in the following sequence: Hg>Se>Cd>Cr>Pb>As. We also observed statistically significant correlations of topsoil Pb concentration with human gastric cancer and grain Hg with human liver cancer. Therefore, long-term low dose exposure of heavy metals may play a key role in tumorigenesis, and it may not be necessary to accumulate a high concentration of heavy metals in the human body for those metals to induce tumorigenesis. PMID- 24144939 TI - Effects of halogenated aromatics/aliphatics and nitrogen(N)-heterocyclic aromatics on estimating the persistence of future pharmaceutical compounds using a modified QSAR model. AB - The effects of halogenated aromatics/aliphatics and nitrogen(N)-heterocyclic aromatics on estimating the persistence of future pharmaceutical compounds were investigated using a modified half life equation. The potential future pharmaceutical compounds investigated were approximately 2000 pharmaceutical drugs currently undergoing the United States Food and Drug Administration (US FDA) testing. EPI Suite (BIOWIN) model estimates the fates of compounds based on the biodegradability under aerobic conditions. While BIOWIN considered the biodegradability of a compound only, the half life equation used in this study was modified by biodegradability, sorption and cometabolic oxidation. It was possible that the potential future pharmaceutical compounds were more accurately estimated using the modified half life equation. The modified half life equation considered sorption and cometabolic oxidation of halogenated aromatic/aliphatics and nitrogen(N)-heterocyclic aromatics in the sub-surface, while EPI Suite (BIOWIN) did not. Halogenated aliphatics in chemicals were more persistent than halogenated aromatics in the sub-surface. In addition, in the sub-surface environment, the fates of organic chemicals were much more affected by halogenation in chemicals than by nitrogen(N)-heterocyclic aromatics. PMID- 24144940 TI - Effects on the mobility of metals from acidification caused by possible CO2 leakage from sub-seabed geological formations. AB - Carbon dioxide capture and storage (CCS) in submarine geological formations has been proposed as a mitigation measure for the prevention of global warming. However, leakage of CO2 to overlying sediments may occur over time, leading to various effects on ecosystems. Laboratory-scale experiments were performed, involving direct release of carbon dioxide into sediment, inside non-pressurized chambers, in order to provide data on the possible effects of CO2 leakage from geological storage sites on the fate of several metals. Marine sediments from three sites with different levels of contamination were sampled and submitted to acidification by means of CO2 injection. The experiment lasted 10 days and sediment samples were collected at the beginning and end of the experiment and pore water was extracted for metal analysis. The results revealed that mobility of metals from sediment to pore water depends on the site, metal and length of time exposed. Mobilization of the metals Al, Fe, Zn, Co, Pb and Cu increases with acidification, and this response generally increases with time of exposure to CO2 injection. The geochemical model applied suggests that acidification also influences the speciation of metals, transforming metals and metalloids, like As, into species much more toxic to biota. The data obtained from this study will be useful for calculating the potential risk of CCS activities to the marine environment. PMID- 24144941 TI - Risk assessment of an abandoned pyrite mine in Spain based on direct toxicity assays. AB - This research reports the risk assessment of an abandoned pyrite mine using direct toxicity assays of soil and groundwater samples taken at the site. The toxicity of As and heavy metals from mining soils to soil and aquatic organisms was studied using the Multispecies Soil System (MS-3) in soil columns. Ecotoxicological assessment was performed with soil samples diluted with a control soil at concentrations of 12.5, 25, 50 and 100% test soil/soil (w/w). In this way, changes in the mobility and bioavailability of soil contaminants due to changes in geochemical soil properties via soil dilution were studied. The toxicity of water samples was tested on algae and Daphnia magna. The assessment of the mining area indicated that the current presence of As and heavy metals at the site may cause injuries to soil and aquatic organisms in the entire research area. Moreover, this investigation demonstrated that changes in geochemical conditions can increase the availability of arsenic and, consequently, the environmental risk of these soils. A good correlation was not found between toxicity parameters and the concentrations of soil contaminants based on total and extracted element concentrations. This finding reinforces the usefulness of direct toxicity assays for evaluating environmental risk. PMID- 24144942 TI - Retention and loss of water extractable carbon in soils: effect of clay properties. AB - Clay sorption is important for organic carbon (C) sequestration in soils, but little is known about the effect of different clay properties on organic C sorption and release. To investigate the effect of clay content and properties on sorption, desorption and loss of water extractable organic C (WEOC), two experiments were conducted. In experiment 1, a loamy sand alone (native) or mixed with clay isolated from a surface or subsoil (78 and 96% clay) resulting in 90, 158 and 175 g clay kg(-1) soil. These soil treatments were leached with different WEOC concentrations, and then CO2 release was measured for 28 days followed by leaching with reverse osmosis water at the end of experiment. The second experiment was conducted to determine WEOC sorption and desorption of clays isolated from the loamy sand (native), surface soil and subsoil. Addition of clays isolated from surface and subsoil to sandy loam increased WEOC sorption and reduced C leaching and cumulative respiration in percentage of total organic C and WEOC added when expressed per g soil and per g clay. Compared to clays isolated from the surface and subsoil, the native clay had higher concentrations of illite and exchangeable Ca(2+), total organic C and a higher CEC but a lower extractable Fe/Al concentration. This indicates that compared to the clay isolated from the surface and the subsoil, the native clay had fewer potential WEOC binding sites because it had lower Fe/Al content thus lower number of binding sites and the existing binding sites are already occupied native organic matter. The results of this study suggest that in the soils used here, the impact of clay on WEOC sorption and loss is dependent on its indigenous organic carbon and Fe and/or Al concentrations whereas clay mineralogy, CEC, exchangeable Ca(2+) and surface area are less important. PMID- 24144943 TI - Influence of biochar amendments on the sorption-desorption of aminocyclopyrachlor, bentazone and pyraclostrobin pesticides to an agricultural soil. AB - The many advantageous properties of biochar have led to the recent interest in the use of this carbonaceous material as a soil amendment. However, there are limited studies dealing with the effect of biochar on the behavior of pesticides applied to crops. The objective of this work was to determine the effect of various biochars on the sorption-desorption of the herbicides aminocyclopyrachlor (6-amino-5-chloro-2-cyclopropyl-4-pyrimidinacarboxylic acid) and bentazone (3 isopropyl-1H-2,1,3-benzothiadiazin-4(3H)-one 2,2-dioxide) and the fungicide pyraclostrobin (methyl 2-[1-(4-chlorophenyl) pyrazol-3-yloxymethil]-N methoxycarbanilate) to a silt loam soil. Aminocyclopyrachlor and bentazone were almost completely sorbed by the soils amended with the biochars produced from wood pellets. However, lower sorption of the herbicides was observed in the soils amended with the biochar made from macadamia nut shells as compared to the unamended soil, which was attributed to the competition between dissolved organic carbon (DOC) from the biochar and the herbicides for sorption sites. Our results showed that pyraclostrobin is highly sorbed to soil, and the addition of biochars to soil did not further increase its sorption. Thus, addition of biochars to increase the retention of low mobility pesticides in soil appears to not be necessary. On the other hand, biochars with high surface areas and low DOC contents can increase the sorption of highly mobile pesticides in soil. PMID- 24144945 TI - Severe, fatal multisystem manifestations in a patient with dolichol kinase congenital disorder of glycosylation. AB - Congenital disorders of glycosylation are a group of metabolic disorders with an expansive and highly variable clinical presentation caused by abnormal glycosylation of proteins and lipids. Dolichol kinase (DOLK) catalyzes the final step in biosynthesis of dolichol phosphate (Dol-P), which is the oligosaccharide carrier required for protein N-glycosylation. Human DOLK deficiency, also known as DOLK-CDG or CDG-Im, results in a syndrome that has been reported to manifest with dilated cardiomyopathy of variable severity. A male neonate born to non consanguineous parents of Palestinian origin presented with dysmorphic features, genital abnormalities, talipes equinovarus, and severe, refractory generalized seizures. Additional multi-systemic manifestations developed including dilated cardiomyopathy, hepatomegaly, severe insulin-resistant hyperglycemia, and renal failure, which were ultimately fatal at age 9months. Electrospray ionization mass spectrometric (ESI-MS) analysis of transferrin identified a type I congenital disorder of glycosylation; next-generation sequencing demonstrated homozygous p.Q483K DOLK mutations that were confirmed in patient fibroblasts to result in severely reduced substrate binding and catalytic activity. This patient expands the phenotype of DOLK-CDG to include anatomic malformations and multi-systemic dysfunction. PMID- 24144944 TI - Elevated phenylacetic acid levels do not correlate with adverse events in patients with urea cycle disorders or hepatic encephalopathy and can be predicted based on the plasma PAA to PAGN ratio. AB - BACKGROUND: Phenylacetic acid (PAA) is the active moiety in sodium phenylbutyrate (NaPBA) and glycerol phenylbutyrate (GPB, HPN-100). Both are approved for treatment of urea cycle disorders (UCDs) - rare genetic disorders characterized by hyperammonemia. PAA is conjugated with glutamine in the liver to form phenylacetyleglutamine (PAGN), which is excreted in urine. PAA plasma levels >= 500 MUg/dL have been reported to be associated with reversible neurological adverse events (AEs) in cancer patients receiving PAA intravenously. Therefore, we have investigated the relationship between PAA levels and neurological AEs in patients treated with these PAA pro-drugs as well as approaches to identifying patients most likely to experience high PAA levels. METHODS: The relationship between nervous system AEs, PAA levels and the ratio of plasma PAA to PAGN were examined in 4683 blood samples taken serially from: [1] healthy adults [2], UCD patients of >= 2 months of age, and [3] patients with cirrhosis and hepatic encephalopathy (HE). The plasma ratio of PAA to PAGN was analyzed with respect to its utility in identifying patients at risk of high PAA values. RESULTS: Only 0.2% (11) of 4683 samples exceeded 500 MUg/ml. There was no relationship between neurological AEs and PAA levels in UCD or HE patients, but transient AEs including headache and nausea that correlated with PAA levels were observed in healthy adults. Irrespective of population, a curvilinear relationship was observed between PAA levels and the plasma PAA:PAGN ratio, and a ratio>2.5 (both in MUg/mL) in a random blood draw identified patients at risk for PAA levels>500 MUg/ml. CONCLUSIONS: The presence of a relationship between PAA levels and reversible AEs in healthy adults but not in UCD or HE patients may reflect intrinsic differences among the populations and/or metabolic adaptation with continued dosing. The plasma PAA:PAGN ratio is a functional measure of the rate of PAA metabolism and represents a useful dosing biomarker. PMID- 24144946 TI - Can a novel web-based computer test predict poor simulated driving performance? a pilot study with healthy and cognitive-impaired participants. AB - BACKGROUND: Driving a car is a complex instrumental activity of daily living and driving performance is very sensitive to cognitive impairment. The assessment of driving-relevant cognition in older drivers is challenging and requires reliable and valid tests with good sensitivity and specificity to predict safe driving. Driving simulators can be used to test fitness to drive. Several studies have found strong correlation between driving simulator performance and on-the-road driving. However, access to driving simulators is restricted to specialists and simulators are too expensive, large, and complex to allow easy access to older drivers or physicians advising them. An easily accessible, Web-based, cognitive screening test could offer a solution to this problem. The World Wide Web allows easy dissemination of the test software and implementation of the scoring algorithm on a central server, allowing generation of a dynamically growing database with normative values and ensures that all users have access to the same up-to-date normative values. OBJECTIVE: In this pilot study, we present the novel Web-based Bern Cognitive Screening Test (wBCST) and investigate whether it can predict poor simulated driving performance in healthy and cognitive-impaired participants. METHODS: The wBCST performance and simulated driving performance have been analyzed in 26 healthy younger and 44 healthy older participants as well as in 10 older participants with cognitive impairment. Correlations between the two tests were calculated. Also, simulated driving performance was used to group the participants into good performers (n=70) and poor performers (n=10). A receiver-operating characteristic analysis was calculated to determine sensitivity and specificity of the wBCST in predicting simulated driving performance. RESULTS: The mean wBCST score of the participants with poor simulated driving performance was reduced by 52%, compared to participants with good simulated driving performance (P<.001). The area under the receiver operating characteristic curve was 0.80 with a 95% confidence interval 0.68-0.92. CONCLUSIONS: When selecting a 75% test score as the cutoff, the novel test has 83% sensitivity, 70% specificity, and 81% efficiency, which are good values for a screening test. Overall, in this pilot study, the novel Web-based computer test appears to be a promising tool for supporting clinicians in fitness-to-drive assessments of older drivers. The Web-based distribution and scoring on a central computer will facilitate further evaluation of the novel test setup. We expect that in the near future, Web-based computer tests will become a valid and reliable tool for clinicians, for example, when assessing fitness to drive in older drivers. PMID- 24144947 TI - Comparative study of cytotoxic and genotoxic effects induced by herbicide S metolachlor and its commercial formulation Twin Pack Gold(r) in human hepatoma (HepG2) cells. AB - The in vitro effects of S-metolachlor and its formulation Twin Pack Gold((r)) (96% a.i.) were evaluated in human hepatoma (HepG2) cells. Cytokinesis-blocked micronucleus cytome (CBMN-cyt) and MTT assays as well as Neutral Red uptake were employed for genotoxicity and cytotoxicity evaluation. Activities were tested within the concentration range of 0.25-15 MUg/ml S-metolachlor for 24h of exposure. Both compounds rendered a minor reduction in the NDI although not reaching statistical significance. Results demonstrated that the S-metolachlor was not able to induce MNs. On the other hand, 0.5-6 MUg/ml Twin Pack Gold((r)) increased the frequency of MNs. When cytotoxicity was estimated, S-metolachlor was not able to induce either a reduction of lysosomal or mitochondrial activity. Contrarily, whereas 1-15 MUg/ml Twin Pack Gold((r)) induced a significant reduction of mitochondrial activity, all tested concentrations of the formulated product induced a significant decrease of lysosomal performance as a function of the concentration of the S-metolachlor-based formulation titrated into cultures. Genotoxicity and cytotoxicity differences obtained with pure S-metolachlor and the commercial S-metolachlor-based formulation indicate that the latter may contain additional unsafe xenobiotics and support the concept of the importance of evaluating not only the active principle but also the commercial formulation when estimating the real hazard from agrochemicals. PMID- 24144948 TI - Advanced glycation end products as an upstream molecule triggers ROS-induced sFlt 1 production in extravillous trophoblasts: a novel bridge between oxidative stress and preeclampsia. AB - Although abnormal soluble fms-like tyrosine kinase-1 (sFlt-1) production is thought to be an important factor in the pathogenesis of pre-eclampsia, the mechanisms that regulate the production of sFlt-1 during pre-eclampsia are unclear. Accumulation of advanced glycation end products (AGEs) is prevalent in obesity, advanced maternal age, diabetes mellitus, and polycystic ovary syndrome. Alterations in the regulation and signaling of angiogenic pathways have been considered as a link between these conditions and pre-eclampsia. The purpose of this study was to explore the possible effects of AGEs on sFlt-1 secretion in extravillous trophoblasts (EVT). A EVT cell line (HRT-8/SVneo) was treated with various concentrations of AGEs-BSA. The mRNA expression of sFlt-1, vascular endothelial growth factor (VEGF), and placental growth factor (PlGF) in EVT were detected with real-time polymerase chain reaction. The secretion of sFlt-1, VEGF, and PlGF protein from EVT was measured with ELISA. The levels of intracellular reactive oxygen species (ROS) production were determined by DCFH-DA. Exposure of EVT to AGEs-BSA induced increased intracellular ROS generation and overexpression of sFlt-1 at mRNA and protein levels in a dose dependent manner. Anti-RAGE immunoglobulin G or apocynin (an inhibitors of NADPH oxidase) could decrease the intracellular ROS generation and subsequently suppressed the production of sFlt-1 at mRNA and protein levels. Our data suggested that AGEs may be a new class of important mediator in the regulation of angiogenic pathways of EVT. Accumulation of AGEs might contribute to the pathogenesis of preeclampsia by promoting sFlt-1 production through activation of RAGE/NADPH oxidase dependent pathway in EVT. PMID- 24144949 TI - Biological therapies in breast cancer: common toxicities and management strategies. AB - In recent years, a number of new molecules - commonly known as biological therapies - have been approved or are in late stages of regulatory evaluation for the treatment of advanced breast cancer. These innovative compounds have improved treatment efficacy and have probably contributed to the increase in survival length observed in some breast cancer subtypes. However, these agents are not deprived of toxicity, which can impair quality of life and may occasionally be life-threatening. In this article, we reviewed the most common toxicities associated with these drugs and provided a number of practical recommendations on their optimal clinical management. PMID- 24144950 TI - Quaternary polymethacrylate-magnesium aluminum silicate films: molecular interactions, mechanical properties and tackiness. AB - The aim of this study was to investigate the impact of the addition of magnesium aluminum silicate (MAS), a natural clay, on the properties of polymeric films based on quaternary polymethacrylates (QPMs). Two commercially available aqueous QPM dispersions were studied: Eudragit((r)) RS 30D and Eudragit((r)) RL 30D (the dry copolymers containing 5 and 10% quaternary ammonium groups, respectively). The composite QPM-MAS films were prepared by casting. Importantly, QPM interacted with MAS and formed small flocculates prior to film formation. Continuous films were obtained up to MAS contents of 19% (referred to the QPM dry mass). ATR-FTIR and PXRD revealed that the positively charged quaternary ammonium groups of QPM interacted with negatively charged SiO(-) groups of MAS, creating nanocomposite materials. This interaction led to improved thermal stability of the composite films. The puncture strength and elongation at break of dry systems decreased with increasing MAS content. In contrast, the puncture strength of the wet QPM MAS films (upon exposure to acidic or neutral media) increased with increasing MAS content. Furthermore, incorporation of MAS into QPM films significantly decreased the latter's tackiness in the dry and wet state. These findings suggest that nanocomposite formation between QPM and MAS in the systems can enhance the strength of wet films and decrease their tackiness. Thus, MAS offers an interesting potential as novel anti-tacking agent for QPM coatings. PMID- 24144951 TI - Targeted gene delivery to glioblastoma using a C-end rule RGERPPR peptide functionalised polyethylenimine complex. AB - Safe and efficient systems capable of specifically targeting brain tumour cells represent a promising approach for the treatment glioblastoma multiforme. Neuropilin-1 (NRP-1) is over-expressed in U87 glioma cells. In the current study, the tumour specific peptide RGERPPR, which binds specifically to NRP-1, was used as a targeting ligand in a gene delivery strategy for glioblastoma. The RGERPPR peptide was coupled to branched polyethylenimine (PEI, 25kDa) using heterobifunctional Mal-PEG-NHS, resulting in a novel gene delivery polymer. Polymer/plasmid DNA (pDNA) complexes were formed and their sizes and zeta potentials were measured. Compared with the unmodified mPEG-PEI/pDNA complexes, the RGERPPR-PEG-PEI/pDNA complex led to a significant enhancement in intracellular gene uptake and tumour spheroid penetration. Furthermore, the RGERPPR-PEG-PEI/pDNA complex facilitated enhanced transfection efficiency levels, as well as a reduction in cytotoxicity when tested in U87 glioma cells in vitro. Most significantly of all, when complexes formed with pDsRED-N1 were injected into the tail vein of intracranial U87 tumour-bearing nude mice, the RGERPPR-PEG PEI complexes led to improved levels of red fluorescence protein expression in the brain tissue. Taken together, the results show that RGERPPR-PEG-PEI could be used as a safe and efficient gene delivery vehicle with potential applications in glioblastoma gene delivery. PMID- 24144952 TI - Quantification of the types of water in Eudragit RLPO polymer and the kinetics of water loss using FTIR. AB - Coalescence of polymer particles in polymer matrix tablets influences drug release. The literature has emphasized that coalescence occurs above the glass transition temperature (Tg) of the polymer and that water may plasticize (lower Tg) the polymer. However, we have shown previously that nonplasticizing water also influences coalescence of Eudragit RLPO; so there is a need to quantify the different types of water in Eudragit RLPO. The purpose of this study was to distinguish the types of water present in Eudragit RLPO polymer and to investigate the water loss kinetics for these different types of water. Eudragit RLPO was stored in tightly closed chambers at various relative humidities (0, 33, 56, 75, and 94%) until equilibrium was reached. Fourier transform infrared spectroscopy (FTIR)-DRIFTS was used to investigate molecular interactions between water and polymer, and water loss over time. Using a curve fitting procedure, the water region (3100-3,700 cm(-1)) of the spectra was analyzed, and used to identify water present in differing environments in the polymer and to determine the water loss kinetics upon purging the sample with dry compressed air. It was found that four environments can be differentiated (dipole interaction of water with quaternary ammonium groups, water cluster, and water indirectly and directly binding to the carbonyl groups of the polymer) but it was not possible to distinguish whether the different types of water were lost at different rates. It is suggested that water is trapped in the polymer in different forms and this should be considered when investigating coalescence of polymer matrices. PMID- 24144953 TI - Ozonated oils as functional dermatological matrices: effects on the wound healing process using SKH1 mice. AB - Wound tissue repair is a complex and dynamic process of restoring cellular structures and tissue layers. Improvement of this process is crucial for several pathologies characterized by chronic delayed wound closure such as diabetes, and the investigation of new approaches aimed to ameliorate the wound healing process is under continuous evolution. Recently, the usage of vegetable matrices in the form of ozonated oils has been proposed and several researchers have shown a positive effect in the wound, based on their bactericidal, antiviral, and antifungal properties. The present study was undertaken to compare the effect that different ozonated oils (olive, sesame and linseed) with the same level of ozonation have on wound healing rate in SKH1 mice. Several histological parameters and the level of key proteins such as VEGF and PCNA have been analyzed. Only treatment with ozonated sesame oil shows a faster wound closure in the first 7 days. This effect paralleled with the increased VEGF and PCNA levels, NFkappaB nuclear translocation and 4-HNE formation. The present study shows that not only the ozonation grade is of importance for the improvement of wound healing process but also the typical composition of the oil. PMID- 24144954 TI - An innovative matrix controlling drug delivery produced by thermal treatment of DC tablets containing polycarbophil and ethylcellulose. AB - An innovative matrix, produced by thermal treatment on direct compression (DC) tablets containing polycarbophil (POL) and ethylcellulose (EC), identified as matrix forming polymers, and able to control the release of diltiazem hydrochloride, was developed. At pH 7.2, 72 +/- 1.2% (w/w) of drug loaded was released in 25 h, mostly at constant rate. This swellable and unerodible matrix controls drug release by an anomalous transport mechanism. The modifications induced by the thermal treatment are irreversible and can be used to control and characterize the matrix. A 3-component constrained mixture design allowed the investigation of the experimental domain in which the matrix forms and the computation of a mathematical model that can be used to optimize the formulation properties. The release rate can be modulated (0.032-0.064% drug released/min) through the choice of suitable treatment conditions and tablet composition. The maximum amount of diltiazem hydrochloride released by zero-order kinetics, at the lowest release rate, occurs for POL:EC ratio in the range of 1:1-2:3 with 20-30% of diluent. The tablets are able to load up to 50% (w/w) of diltiazem hydrochloride without losing their properties. A stability study performed on a selected formulation containing DTZ showed stability for at least 2.7 years at RT conditions. PMID- 24144955 TI - The after-effects of bilingual language production. AB - We explored the temporal course of bilingual language control after-effects to shed light on the scope of language control (local vs. global) and on the way in which language control is implemented (L1 inhibition or L2 over-activation). High proficient bilinguals named objects across three blocks, first in their L1, then in their L2, and then again in their L1 (and conversely) while event-related brain potentials (ERPs) were recorded. Behaviorally we found only the L1 as being hindered by previous naming in the L2. In the ERPs we did not observe inhibitory effects in the N2 component time-window. However, the P2 component showed more positive-going deflections when the previous language slowed down naming latencies of the successive language. The P2 mean amplitude predicted naming latencies whereas the N2 did not. We conclude that in high-proficient bilinguals the P2 component is the marker of language control mechanisms other than inhibition, which are applied globally. PMID- 24144956 TI - Reading impairment in schizophrenia: dysconnectivity within the visual system. AB - Patients with schizophrenia suffer from perceptual visual deficits. It remains unclear whether those deficits result from an isolated impairment of a localized brain process or from a more diffuse long-range dysconnectivity within the visual system. We aimed to explore, with a reading paradigm, the functioning of both ventral and dorsal visual pathways and their interaction in schizophrenia. Patients with schizophrenia and control subjects were studied using event-related functional MRI (fMRI) while reading words that were progressively degraded through word rotation or letter spacing. Reading intact or minimally degraded single words involves mainly the ventral visual pathway. Conversely, reading in non-optimal conditions involves both the ventral and the dorsal pathway. The reading paradigm thus allowed us to study the functioning of both pathways and their interaction. Behaviourally, patients with schizophrenia were selectively impaired at reading highly degraded words. While fMRI activation level was not different between patients and controls, functional connectivity between the ventral and dorsal visual pathways increased with word degradation in control subjects, but not in patients. Moreover, there was a negative correlation between the patients' behavioural sensitivity to stimulus degradation and dorso-ventral connectivity. This study suggests that perceptual visual deficits in schizophrenia could be related to dysconnectivity between dorsal and ventral visual pathways. PMID- 24144957 TI - Fructose-1,6-bisphosphate induces phenotypic reversion of activated hepatic stellate cell. AB - Hepatic stellate cells (HSC) play a key role in liver fibrogenesis. Activation of PPARgamma and inhibition of fibrogenic molecules are potential strategies to block HSC activation and differentiation. Aware that the process of hepatic fibrosis involves inflammatory mediators, various anti-inflammatory substances have been studied in an attempt to revert fibrosis. The purpose of this study was to investigate the in vitro effects of fructose-1,6-bisphosphate (FBP) on HSC phenotype reversion. The results demonstrated that FBP induced quiescent phenotype in GRX cells via PPARgamma activation. Significant decrease in type I collagen mRNA expression was observed in the first 24h of treatment. These events preceded the reduction of TGF-beta1 and total collagen secretion. Thus, FBP promoted downregulation of HSC activation by its antifibrotic action. These findings demonstrate that FBP may have potential as a novel therapeutic agent for the treatment of liver fibrosis. PMID- 24144958 TI - Predicting healthy lifestyle patterns among retirement age older adults in the WELL study: a latent class analysis of sex differences. AB - OBJECTIVES: The aim of this study was to identify subgroups of retirement age older adults with respect to their lifestyle patterns of eating, drinking, smoking, physical activity and TV viewing behaviors, and to examine the association between these patterns and socio-demographic covariates. METHODS: The sample consisted of 3133 older adults aged 55-65 years from the Wellbeing, Eating and Exercise for a Long Life (WELL) study, 2010. This study used latent class analysis (stratified by sex), with a set of lifestyle indicators and including socio-demographic covariates. Statistical analyses were performed by generalized linear latent and mixed models in Stata. RESULTS: Two classes of lifestyle patterns were identified: Healthy (53% men and 72% women) and less healthy lifestyles. Physical activity, TV-viewing time, and fruit intake were good indicators distinguishing the "Healthier" class, whereas consumption of vegetables, alcohol (men) and fast food (women) could not clearly discriminate older adults in the two classes. Class membership was associated with education, body mass index, and self-rated health. CONCLUSIONS: This study contributes to the literature on lifestyle behaviors among older adults, and provides evidence that there are meaningful sex differences in lifestyle behaviors between subgroups of older adults. From a policy perspective, understanding indicators or "markers" of healthy and less healthy lifestyle patterns is important for identifying target groups for interventions. PMID- 24144960 TI - Stem cells and the reproductive system: historical perspective and future directions. AB - Recent findings in stem cell biology have presented new perspectives and opportunities for the treatment of reproductive disease. In a departure from the long held dogma of embryologically fixed numbers of oocytes, current literature suggests that human ovaries contain stem cells which form new oocytes even in adulthood and that these stem cells can be cultured in vitro to develop into mature oocytes. These findings have provided new hope and broader options for fertility preservation. Evidence of endometrial regeneration by bone marrow stem cells in endometrial tissue of women who received bone marrow transplant highlight potential for the novel treatments of uterine disorders and supports new theories for the etiology of endometriosis - ectopic transdifferentiation of stem cells. Further, endometrial derived stem cells have been demonstrated to be useful in the treatment of several chronic and often debilitating diseases, including Parkinson's Disease and Diabetes. Other cells that may present future therapeutic benefits for a myriad of disease states include placental and fetal cells which enter maternal circulation during pregnancy and can later promote parenchymal regeneration in maternal tissue. These findings highlight novel functions of the uterus and ovaries. They demonstrate that the uterus is a dynamic organ permeable to fetal stem cells capable of transdifferentiation as well as a renewable source of multipotent stem cells. While we still have much to understand about stem cells, their potential applications in reproductive biology and medicine are countless. PMID- 24144959 TI - Telephone-guided Self-Help Cognitive Behavioural Therapy for menopausal symptoms. AB - OBJECTIVES: Group and Self-Help forms of Cognitive Behavioural Therapy (CBT) are effective treatment options for women with problematic menopausal hot flushes and night sweats (HF/NS). However, some women are unable to attend face-to-face sessions. This study investigates whether Self-Help CBT for HF/NS is as effective when rolled out to women living at a distance with minimal telephone guidance. STUDY DESIGN: Forty-seven women completed a Self-Help CBT intervention (booklet and relaxation/paced breathing CD) during a 4-week period. They also received one 'guiding' telephone call from a clinical psychologist two weeks into treatment to provide support and discuss individual treatment goals. Questionnaires were collected at baseline, 6 weeks (post-treatment) and 3 months (follow-up) after the end of the intervention. MAIN OUTCOME MEASURES: HF/NS problem rating. SECONDARY OUTCOME MEASURES: HF/NS frequency, HF/NS beliefs and behaviours, sleep, anxiety and depressed mood. RESULTS: There was a significant reduction in HF/NS problem-rating following the intervention which was maintained at follow-up. Moreover, women reported less frequent HF/NS along with further improvements in sleep quality, mood and HF/NS beliefs and behaviours. CONCLUSIONS: Telephone guided Self-Help interventions might provide an effective way of widening access to CBT treatment for HF/NS. PMID- 24144961 TI - Electronic bed weighing vs daily fluid balance changes after cardiac surgery. AB - PURPOSE: The purpose of this study is to establish the validity and reliability of measuring weight in critically ill patients with electronic weighing beds. METHODS: All patients admitted to a private intensive care unit (ICU) after cardiac surgery over a 7-month period were weighed on admission and then twice daily (1200 and 2400 hours) using electronic weighing beds (Hill-Rom, Batesville, AR). For each measurement, nonremovable items were recorded, and an average value was deducted from measured weight. We compared differences in body weights (BWs) between 2 consecutive 12-hour periods with the corresponding fluid balance (FB). In addition, we compared weights obtained with electronic weighing beds with those obtained with a regular calibrated scale on ICU discharge. RESULTS: We obtained data in 103 patients for 414 (75.5%) of 548 of all possible BW measurements. On average, we identified a total of 3.5 kg (SD, 1.4) of nonremovable items on patients' beds. The correlation between 12-hourly changes in BW and FB was weak (r = 0.28; 95% confidence interval [CI], 0.17-0.39), even after correction for insensible fluid losses (r = 0.27; 95% CI, 0.15-0.38) and when only values obtained in intubated patients were taken into account (r = 0.34; 95% CI, 0.16-0.49). Similarly, limits of agreements were wide (95% CI, -3.3 to 3.5 kg). There was also poor agreement between weights obtained on electronic beds and those obtained on the regular scale on ICU discharge (95% CI, -7.6 to 7.6 kg). CONCLUSION: Body weight measured by electronic weighing beds does not seem sufficiently robust or accurate to replace daily FB in ICU. The clinical value of purchasing such beds remains uncertain. PMID- 24144962 TI - Go with the flow - membrane transport in the gut. PMID- 24144963 TI - Plasma nutrient status of patients with Alzheimer's disease: Systematic review and meta-analysis. AB - BACKGROUND: Alzheimer disease (AD) patients are at risk of nutritional insufficiencies because of physiological and psychological factors. Nutritional compounds are postulated to play a role in the pathophysiological processes that are affected in AD. We here provide the first systematic review and meta-analysis that compares plasma levels of micronutrients and fatty acids in AD patients to those in cognitively intact elderly controls. A secondary objective was to explore the presence of different plasma nutrient levels between AD and control populations that did not differ in measures of protein/energy nourishment. METHODS: We screened literature published after 1990 in the Cochrane Central Register of Controlled Trials, Medline, and Embase electronic databases using Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) guidelines for AD patients, controls, micronutrient, vitamins, and fatty acids, resulting in 3397 publications, of which 80 met all inclusion criteria. Status of protein/energy malnutrition was assessed by body mass index, mini nutritional assessment score, or plasma albumin. Meta-analysis, with correction for differences in mean age between AD patients and controls, was performed when more than five publications were retrieved for a specific nutrient. RESULTS: We identified five or more studies for folate, vitamin A, vitamin B12, vitamin C, vitamin D, vitamin E, copper, iron, and zinc but fewer than five studies for vitamins B1 and B6, long-chain omega-3 fatty acids, calcium, magnesium, manganese, and selenium (the results of the individual publications are discussed). Meta-analysis showed significantly lower plasma levels of folate and vitamin A, vitamin B12, vitamin C, and vitamin E (P < .001), whereas nonsignificantly lower levels of zinc (P = .050) and vitamin D (P = .075) were found in AD patients. No significant differences were observed for plasma levels of copper and iron. A meta-analysis that was limited to studies reporting no differences in protein/energy malnourishment between AD and control populations yielded similar significantly lower plasma levels of folate and vitamin B12, vitamin C, and vitamin E in AD. CONCLUSIONS: The lower plasma nutrient levels indicate that patients with AD have impaired systemic availability of several nutrients. This difference appears to be unrelated to the classic malnourishment that is well known to be common in AD, suggesting that compromised micronutrient status may precede protein and energy malnutrition. Contributing factors might be AD-related alterations in feeding behavior and intake, nutrient absorption, alterations in metabolism, and increased utilization of nutrients for AD pathology-related processes. Given the potential role of nutrients in the pathophysiological processes of AD, the utility of nutrition may currently be underappreciated and offer potential in AD management. PMID- 24144964 TI - Thyroid status and functional and cognitive status at baseline and survival after 3 years of follow-up: the OCTABAIX study. AB - OBJECTIVE: Subclinical thyroid disorders are common in older individuals. Health risks associated with subclinical hypothyroidism in older adults are unclear. The aim of the study is to evaluate whether thyroid status in elderly subjects correlates with physical and cognitive function at baseline and with 3-year mortality. DESIGN: A population-based, prospective cohort of the OCTABAIX study (307 inhabitants aged 85 years at baseline). METHODS: Chronic drug prescription, functional status (Barthel and Lawton indices) and cognitive status according to the Spanish version of the Mini-Mental State Examination were recorded. Quality of life was assessed using the visual analogue scale of the quality of life test. Concentrations of TSH and thyroxine were measured. Participants were classified in accordance with clinical categories of thyroid function. RESULTS: Twenty (6.5%) individuals had subclinical hypothyroidism and five (1.6%) had subclinical hyperthyroidism. Compared with euthyroid subjects (n=280; 91.8%), subclinical hypo- and hyperthyroidism subjects were not significantly associated with poor physical or cognitive function at baseline. Fifty-one (15.1%) subjects died during the 36 months of follow-up. TSH values and subclinical hypo- and hyperthyroidism were not associated with an increased overall mortality risk (hazard ratio (HR) 1.086, 95% CI 0.987-1.196 and HR 0.905, 95% CI 0.902-1.053 respectively). CONCLUSIONS: This study does not support the association of TSH or thyroid disorders with physical or cognitive function at baseline or with 3-year mortality in the oldest old subjects. PMID- 24144965 TI - Systematic screening for PRKAR1A gene rearrangement in Carney complex: identification and functional characterization of a new in-frame deletion. AB - BACKGROUND: Point mutations of the PRKAR1A gene are a genetic cause of Carney complex (CNC) and primary pigmented nodular adrenocortical disease (PPNAD), but in 30% of the patients no mutation is detected. OBJECTIVE: Set up a routine-based technique for systematic detection of large deletions or duplications of this gene and functionally characterize these mutations. METHODS: Multiplex ligation dependent probe amplification (MLPA) of the 12 exons of the PRKAR1A gene was validated and used to detect large rearrangements in 13 typical CNC and 39 confirmed or putative PPNAD without any mutations of the gene. An in-frame deletion was characterized by western blot and bioluminescence resonant energy transfer technique for its interaction with the catalytic subunit. RESULTS: MLPA allowed identification of exons 3-6 deletion in three patients of a family with typical CNC. The truncated protein is expressed, but rapidly degraded, and does not interact with the protein kinase A catalytic subunit. CONCLUSIONS: MLPA is a powerful technique that may be used following the lack of mutations detected by direct sequencing in patients with bona fide CNC or PPNAD. We report here one such new deletion, as an example. However, these gene defects are not a frequent cause of CNC or PPNAD. PMID- 24144966 TI - Refined association of TSH receptor susceptibility locus to Graves' disease in the Chinese Han population. AB - BACKGROUND: Convincing evidence has demonstrated the association of TSH receptor (TSHR) with Graves' disease (GD) in the Chinese Han population. OBJECTIVE: The aim of this study was to identify the causal variants for GD in the region encompassing TSHR by a refining association study. DESIGN AND METHODS: GD patients (1536) and 1516 sex-matched controls were recruited in the first stage, and an additional 3832 GD patients and 3426 sex-matched controls were recruited in the replication stage. Genotyping was performed using Illumina Human660-Quad BeadChips or TaqMan single nucleotide polymorphism (SNP) Genotyping Assays and the Fluidigm EP1 platform. RESULTS: When the results of regression analysis for 74 genotyped SNPs and 922 imputed SNPs in the first-stage cohort were combined, rs179243 and rs3783949 were the probable susceptibility SNPs associated with GD in TSHR. Eleven SNPs, including rs179243 and rs3783949, were selected to further refine the association in the replication study. Finally, rs12101261 and rs179243 were confirmed as independent GD susceptibility variants in the replication and combined populations. Further, we also found that the rate of persistent TSHR autoantibody positivity (pTRAb+) was significantly higher in the GD patients with the susceptible genotypes rs12101261 or rs179243 than in the GD patients carrying the protective genotypes, after the GD patients had been treated for more than 1 year. CONCLUSIONS: These findings indicate that rs12101261 and rs179243 are the possible causal SNPs for GD susceptibility in the TSHR gene and could serve as genetic markers to predict the outcome of pTRAb+ in GD patients. PMID- 24144967 TI - Management of endocrine disease: GH excess: diagnosis and medical therapy. AB - Acromegaly is predominantly caused by a pituitary adenoma, which secretes an excess of GH resulting in increased IGF1 levels. Most of the GH assays used currently measure only the levels of the 22 kDa form of GH. In theory, the diagnostic sensitivity may be lower compared with the previous assays, which have used polyclonal antibodies. Many GH-secreting adenomas are plurihormonal and may co-secrete prolactin, TSH and alpha-subunit. Hyperprolactinaemia is found in 30 40% of patients with acromegaly, and hyperprolactinaemia may occasionally be diagnosed before acromegaly is apparent. Although trans-sphenoidal surgery of a GH-secreting adenoma remains the first treatment at most centres, the role of somatostatin analogues, octreotide long-acting repeatable and lanreotide Autogel as primary therapy is still the subject of some debate. Although the normalisation of GH and IGF1 levels is the main objective in all patients with acromegaly, GH and IGF1 levels may be discordant, especially during somatostatin analogue therapy. This discordance usually takes the form of high GH levels and an IGF1 level towards the upper limit of the normal range. Pasireotide, a new somatostatin analogue, may be more efficacious in some patients, but the drug has not yet been registered for acromegaly. Papers published on pasireotide have reported an increased risk of diabetes mellitus due to a reduction in insulin levels. Pegvisomant, the GH receptor antagonist, is indicated - alone or in combination with a somatostatin analogue - in most patients who fail to enter remission on a somatostatin analogue. Dopamine-D2-agonists may be effective as monotherapy in a few patients, but it may prove necessary to apply combination therapy involving a somatostatin analogue and/or pegvisomant. PMID- 24144969 TI - Cheap doctors. PMID- 24144968 TI - Six-year follow-up of a characteristic osteolytic lesion in a patient with tumor induced osteomalacia. AB - OBJECTIVE: Tumor-induced osteomalacia is a rare paraneoplastic syndrome characterized by hypophosphatemia and inappropriately normal or low 1,25 dihydroxyvitamin D. CLINICAL CASE: Here, we report a 6-year postoperative follow up of a patient with oncogenic osteomalacia with a distinctive skeletal manifestation. The latter was characterized by an almost linear lytic lesion of a few millimeters with irregular borders, mainly involving the trabecular compartment but extending into cortical shell, located in the middle third of the right fibula. Six years after tumor resection, a sclerotic repair with a complete recovery was observed. Furthermore, we monitored a striking increase in bone mineral density throughout the observation period, reaching a peak of 73% over basal values at lumbar spine after 2 years; at total femur and radius, the peak was 47.5 and 4.6% respectively, after 4 years from tumor resection. CONCLUSIONS: We report for the first time that an osteolytic lesion may be part of the skeletal involvement in tumor-induced osteomalacia. PMID- 24144970 TI - Prescriptions for elderly people vary widely across US. PMID- 24144971 TI - High Court brings GMC into legal action over RCGP membership exam. PMID- 24144972 TI - India plans joint project with World Bank to improve safe water supply. PMID- 24144973 TI - Indian advocacy group urges Woody Allen to accept display of antismoking messages across latest film. PMID- 24144974 TI - Doctors fail to get life support withdrawn from "minimally conscious" patient. PMID- 24144978 TI - Mot1 redistributes TBP from TATA-containing to TATA-less promoters. AB - The Swi2/Snf2 family ATPase Mot1 displaces TATA-binding protein (TBP) from DNA in vitro, but the global relationship between Mot1 and TBP in vivo is unclear. In particular, how Mot1 activates transcription is poorly understood. To address these issues, we mapped the distribution of Mot1 and TBP on native chromatin at base pair resolution. Mot1 and TBP binding sites coincide throughout the genome, and depletion of TBP results in a global decrease in Mot1 binding. We find evidence that Mot1 approaches TBP from the upstream direction, consistent with its in vitro mode of action. Strikingly, inactivation of Mot1 leads to both increases and decreases in TBP-genome association. Sites of TBP gain tend to contain robust TATA boxes, while sites of TBP loss contain poly(dA-dT) tracts that may contribute to nucleosome exclusion. Sites of TBP gain are associated with increased gene expression, while decreased TBP binding is associated with reduced gene expression. We propose that the action of Mot1 is required to clear TBP from intrinsically preferred (TATA-containing) binding sites, ensuring sufficient soluble TBP to bind intrinsically disfavored (TATA-less) sites. PMID- 24144979 TI - Ubiquitination-deubiquitination by the TRIM27-USP7 complex regulates tumor necrosis factor alpha-induced apoptosis. AB - Tumor necrosis factor alpha (TNF-alpha) plays a role in apoptosis and proliferation in multiple types of cells, and defects in TNF-alpha-induced apoptosis are associated with various autoimmune diseases. Here, we show that TRIM27, a tripartite motif (TRIM) protein containing RING finger, B-box, and coiled-coil domains, positively regulates TNF-alpha-induced apoptosis. Trim27 deficient mice are resistant to TNF-alpha-d-galactosamine-induced hepatocyte apoptosis. Trim27-deficient mouse embryonic fibroblasts (MEFs) are also resistant to TNF-alpha-cycloheximide-induced apoptosis. TRIM27 forms a complex with and ubiquitinates the ubiquitin-specific protease USP7, which deubiquitinates receptor-interacting protein 1 (RIP1), resulting in the positive regulation of TNF-alpha-induced apoptosis. Our findings indicate that the ubiquitination deubiquitination cascade mediated by the TRIM27-USP7 complex plays an important role in TNF-alpha-induced apoptosis. PMID- 24144980 TI - Cdyl, a new partner of the inactive X chromosome and potential reader of H3K27me3 and H3K9me2. AB - X chromosome inactivation is a remarkable example of chromosome-wide gene silencing and facultative heterochromatin formation. Numerous histone posttranslational modifications, including H3K9me2 and H3K27me3, accompany this process, although our understanding of the enzymes that lay down these marks and the factors that bind to them is still incomplete. Here we identify Cdyl, a chromodomain-containing transcriptional corepressor, as a new chromatin associated protein partner of the inactive X chromosome (Xi). Using mouse embryonic stem cell lines with mutated histone methyltransferase activities, we show that Cdyl relies on H3K9me2 for its general association with chromatin in vivo. For its association with Xi, Cdyl requires the process of differentiation and the presence of H3K9me2 and H3K27me3, which both become chromosomally enriched following Xist RNA coating. We further show that the removal of the PRC2 component Eed and subsequent loss of H3K27me3 lead to a reduction of both Cdyl and H3K9me2 enrichment on inactive Xi. Finally, we show that Cdyl associates with the H3K9 histone methyltransferase G9a and the MGA protein, both of which are also found on Xi. We propose that the combination of H3K9me2 and H3K27me3 recruits Cdyl to Xi, and this, in turn, may facilitate propagation of the H3K9me2 mark by anchoring G9a. PMID- 24144988 TI - Evaluation of the relationship between IL28B, IL10RB and IL28RA single-nucleotide polymorphisms and susceptibility to hepatitis C virus in Chinese Han population. AB - Hepatitis C virus (HCV) infection is associated with both viral and host factors. Cytokines, such as interferon (IFN)-lambda, play a critical role in modulating the innate and adaptive immune systems. This study aims to investigate the association between single-nucleotide polymorphisms (SNPs) of interleukin (IL) 28B, IL10RB, and IL28RA genes and susceptibility to HCV infection in a population from the Liaoning Province of China. We used high resolution melt-polymerase chain reaction (HRM-PCR) analyses for genotype 6 polymorphisms in these genes in 271 chronic HCV-infected patients and in 300 healthy control subjects. The distribution of IL10RB and IL28RA genotypes among the HCV-infected and control groups did not differ significantly. However, we did find that the four IL28B variants were in complete linkage disequilibrium (r(2) = 0.831-0.922), and the frequency of rs8099917 GT genotype was significantly higher among chronic HCV infected patients than among controls (OR = 2.21, 95% CI = 1.33-3.68, P = 0.00193); the G allele was found more frequently in the chronic HCV-infected group than in the control group (OR = 2.10, 95% CI = 1.28-3.44, P = 0.00276). Haplotype analysis showed that IL28B (rs12980275, rs11881222, rs12979860 and rs8099917) haplotype AACT had a protective effect for HCV infection (OR = 0.52, 95% CI = 0.33-0.83, P = 0.00551). This study indicates that the four SNPs in IL28B are correlated with susceptibility to HCV infection. PMID- 24144981 TI - Microtubule dynamic instability controls podosome patterning in osteoclasts through EB1, cortactin, and Src. AB - In osteoclasts (OCs) podosomes are organized in a belt, a feature critical for bone resorption. Although microtubules (MTs) promote the formation and stability of the belt, the MT and/or podosome molecules that mediate the interaction of the two systems are not identified. Because the growing "plus" ends of MTs point toward the podosome belt, plus-end tracking proteins (+TIPs) might regulate podosome patterning. Among the +TIPs, EB1 increased as OCs matured and was enriched in the podosome belt, and EB1-positive MTs targeted podosomes. Suppression of MT dynamic instability, displacement of EB1 from MT ends, or EB1 depletion resulted in the loss of the podosome belt. We identified cortactin as an Src-dependent interacting partner of EB1. Cortactin-deficient OCs presented a defective MT targeting to, and patterning of, podosomes and reduced bone resorption. Suppression of MT dynamic instability or EB1 depletion increased cortactin phosphorylation, decreasing its acetylation and affecting its interaction with EB1. Thus, dynamic MTs and podosomes interact to control bone resorption. PMID- 24144989 TI - Compliance with the Swiss Society for Nutrition's dietary recommendations in the population of Geneva, Switzerland: a 10-year trend study (1999-2009). AB - The trends in compliance with the dietary recommendations of the Swiss Society for Nutrition in the Geneva population were assessed for the period from 1999 to 2009 using 10 cross-sectional, population-based surveys (Bus Sante study) with a total of 9,320 participants aged 35 to 75 years (50% women). Dietary intake was assessed using a self-administered, validated, semi-quantitative food frequency questionnaire. Trends were assessed by logistic regression adjusting for age, smoking status, education, and nationality using survey year as the independent variable. After excluding participants with extreme intakes, the percentage of participants with a cholesterol intake of <300 mg/day increased from 40.8% in 1999 to 43.6% in 2009 for men (multivariate-adjusted P for trend=0.04) and from 57.8% to 61.4% in women (multivariate-adjusted P for trend=0.06). Calcium intake >1 g/day decreased from 53.3% to 46% in men and from 47.6% to 40.7% in women (multivariate-adjusted P for trend<0.001). Adequate iron intake decreased from 68.3% to 65.3% in men and from 13.3% to 8.4% in women (multivariate-adjusted P for trend<0.001). Conversely, no significant changes were observed for carbohydrates, protein, total fat (including saturated, monounsaturated, and polyunsaturated fatty acids), fiber, and vitamins D and A. We conclude that the quality of the Swiss diet did not improve between 1999 and 2009 and that intakes deviate substantially from expert recommendations for health promotion and chronic disease risk reduction. PMID- 24144990 TI - Transitioning to new child-care nutrition policies: nutrient content of preschool menus differs by presence of vegetarian main entree. AB - Children who attend child care outside the home may be at increased risk for developing obesity. In 2012, the South Carolina ABC Child Care program issued new standards for food and nutrition. The goal of our study (conducted June to December 2012) was to examine changes that occurred at a large, Columbia, SC, preschool during the implementation of the South Carolina ABC Child Care program standards using an observational design, including a survey of parents and nutrient analysis of menus. The nutrition content of menu items before (n=15 days; six of which were vegetarian) and after (n=15 days; six of which were vegetarian) implementation of the new standards was compared. In addition, parents (N=75) were surveyed to examine opinions and support for the changes. Independent samples t tests were used to compare nutrient values before and after menu changes and analysis of variance was used to compare pre- and post-change vegetarian menus and pre- and post-change nonvegetarian menus. There were no significant differences between before and after menus with the exception of a 0.3 cup/day increase in vegetables (P<0.05). Vegetarian menus after the revisions were significantly higher in fiber (13 +/- 3 g) than postrevision nonvegetarian menus (11 +/- 3 g; P<0.05) and lower in sodium (1,068 +/- 207 mg) than postrevision nonvegetarian menus (1,656 +/- 488 mg; P<0.05). Standards that received the most parental support were serving at least two vegetables (score of 8.7 on a scale of one to nine) and two fruits per day (score of 8.6) and implementing policies against staff using food as a reward or punishment (score of 8.6). The center-specific policy of only bringing healthy foods for celebrations received the lowest support (score of 5.8). Adding more vegetarian menu items has the potential to improve the nutrient content of menus while keeping energy intake, saturated fat, sodium, and cholesterol levels at a more optimum level. PMID- 24144991 TI - Self-reported taste preference can be a proxy for daily sodium intake in middle aged Japanese adults. AB - Reducing dietary salt intake remains a challenging issue in the management of chronic disease. Taste preference is suspected to be an important proxy index of daily sodium consumption. This study examined the difference in daily sodium intake according to self-reported taste preference for miso soup as representative of homemade cooking in middle-aged urban Japanese adults. Among 896 candidates randomly selected from examinees of cancer screening provided by the National Cancer Center, Japan, 143 men and women participated in this cross sectional study. During the period from May 2007 through April 2008, participants provided a food frequency questionnaire, which included information on taste preference and dietary behaviors, a weighed food record over 4 consecutive days, a simultaneous 24-hour urine collection, and a sample of miso soup as it is usually prepared in the home. Mean 24-hour urinary sodium excretion and daily sodium intake were compared according to the self-reported taste preference for miso soup. Taste preference was significantly associated with both 24-hour urinary sodium excretion (trend P<0.01) and daily sodium intake (trend P=0.01), with a corresponding regression coefficient per 1 rank preference increment of 403 mg and 315 mg/day, respectively. The observed association between preference and urinary excretion was attenuated by further adjustment for discretionary salt related behaviors. These findings suggest that self-reported taste preference for homemade cooking is a defining feature of daily sodium intake through discretionary salt-related dietary behaviors. A reduction in daily sodium consumption per 1 rank light preference was estimated to equate to approximately 1 g salt/day. PMID- 24144992 TI - Women's perceptions and experiences of severe maternal morbidity--a synthesis of qualitative studies using a meta-ethnographic approach. AB - BACKGROUND: maternal mortality is a relatively rare event in high-income countries and some middle-income countries. There is however a rising trend in the overall rate of severe maternal morbidity in many of these countries due to the increasingly complex obstetric and medical needs of women who become pregnant. With the aim to identify how women's experiences of health services following severe maternal morbidity could be improved, we explored women's perceptions and experiences of severe maternal morbidity (defined as major obstetric haemorrhage, severe preeclampsia, eclampsia, HELLP syndrome, critical care unit admission) by synthesising evidence from qualitative studies. METHODS: a systematic search of the literature was conducted using multiple databases, including MEDLINE, PsycINFO, EMBASE, CINAHL, British Nursing Index (BNI), Web of Science and Scopus, using predetermined search strategies. Studies were selected based on pre-defined inclusion and exclusion criteria. The methodological quality of selected qualitative studies was assessed using relevant CASP appraisal tools. Evidence synthesis was undertaken using meta-ethnography. The synthesis involved three steps: (1) ascertaining how studies were related or dissimilar through comparison; (2) translating one study's findings into another and (3) synthesis of the translation. FINDINGS: 12 studies met inclusion criteria. Synthesis of these studies showed that women's experiences of severe maternal morbidity can be broadly categorised into three areas: experiencing the event of severe maternal morbidity, the immediate reaction to the event (physical experience, perception/interpretation of their situation, and emotion), and the aftermath (either a negative or positive experience), which are all interconnected. Women's experiences of severe maternal morbidity may be influenced by other factors such as the individuals' personal characteristics, pre-existing health conditions, feeling safe within the care provided, availability and accessibility of high quality health care, and their wider social support networks. Importantly, women's perceptions and experiences of severe maternal morbidity could be compounded by inadequate clinical management and care. CONCLUSIONS: an experience of severe maternal morbidity and its subsequent management are physically and emotionally distressing, conjuring negative feelings and emotions and possibly poor postnatal outcomes. Findings suggest the importance of ensuring that the safety and quality of intrapartum interventions and models of postnatal care are enhanced, to reduce or prevent subsequent implications of an acute medical event on women and their families. PMID- 24144993 TI - A retrospective analysis of clinical features of oral malignant and potentially malignant disorders with and without oral epithelial dysplasia. AB - OBJECTIVE: Clinical identification of underlying histopathology of oral mucosal lesions (OMLs) remains difficult. The study aims to identify clinical indicators of underlying histopathology of oral malignant and potentially malignant disorders. STUDY DESIGN: All clinical patient records of an oral medicine and pathology clinic over a 12-year period were manually searched. Cases of OMLs with a histopathologic diagnosis of dysplasia (n = 124) and malignancy (n = 27) and a sample of nondysplastic OMLs (n = 109) were analyzed using both univariate and multivariate analysis and odds ratios for an association with clinical characteristics. RESULTS: A nonhomogeneous clinical appearance was strongly associated with underlying dysplasia in both univariate and multivariate analysis (P < .001; odds ratio, 4.4). For lesions with homogeneous appearance, dysplasia was associated with lesion location (P = .005; odds ratio, 2.6) and smoking history (P = .04). CONCLUSIONS: These findings suggest that a nonhomogeneous mucosal lesion is a significant independent indicator for underlying oral epithelial dysplasia, with location, size, and color as additional contributing factors. PMID- 24144994 TI - Dietary alterations in patients with oral vesiculoulcerative diseases. AB - OBJECTIVE: Patients with oral vesiculoulcerative diseases experience chronic oral discomfort, which may alter their dietary intake. The prevalence of dietary changes in these patients was investigated to determine the need for additional interventions. STUDY DESIGN: Forty-eight patients completed a diet and food continuous avoidance questionnaire. A visual analog scale (VAS) of 0 to 10 assessed symptoms. The study group (n = 25; VAS >= 2) and comparison group (n = 23; VAS = 0 or 1) were compared. RESULTS: Fifty-two percent and 13% of study and comparison group patients, respectively, (P = .004) avoided citrus fruits and tomatoes, with a higher percentage of tongue involvement noted among these patients. Avoidance of hard, spicy, and sour foods and alcohol was higher in the study group. CONCLUSIONS: Patients with moderate chronic oral vesiculoulcerative diseases modify their eating habits, which may impair well-being. Professional guidance regarding maintenance of a balanced diet during periods of exacerbation may be beneficial. PMID- 24144995 TI - Deletion of circadian gene Per1 alleviates acute ethanol-induced hepatotoxicity in mice. AB - The severity of ethanol-induced liver injury is associated with oxidative stress and lipid accumulation in the liver. Core circadian clock is known to mediate antioxidative enzyme activity and lipid metabolism. However, the link between circadian clock and ethanol-induced hepatotoxicity remains unclear. Here we showed that extents of acute ethanol-induced liver injury and steatosis in mice exhibit circadian variations consistent with hepatic expression of Period (Per) genes. Mice lacking clock gene Per1 displayed less susceptible to ethanol-induced liver injury, as evidenced by lower serum transaminase activity and less severe histopathological changes. Ethanol-induced lipid peroxidation was alleviated in Per1-/- mice. However, Per1 deletion had no effect on antioxidants depletion caused by ethanol administration. Ethanol-induced triglycerides (TG) accumulation in the serum and liver was significantly decreased in Per1-/- mice compared with that in wild-type (WT) mice. Analysis of gene expression in the liver revealed peroxisome proliferators activated receptor-gamma (PPARgamma) and its target genes related to TG synthesis are remarkably down-regulated in Per1-/- mice. HepG2 cells were treated with ethanol at 150 mM for 3 days. Per1 overexpression augmented lipid accumulation after treatment with ethanol in HepG2 cells, but had no effect on ethanol-induced oxidative stress. Expression of genes related to lipogenesis, including PPARgamma and its target genes, was up-regulated in cells overexpressing Per1. In conclusion, these results indicated that circadian rhythms of ethanol-induced hepatotoxicity are controlled by clock gene Per1, and deletion of Per1 protected mice from ethanol-induced liver injury by decreasing hepatic lipid accumulation. PMID- 24144996 TI - Cancer caregivers advocate a patient- and family-centered approach to advance care planning. AB - CONTEXT: Cancer caregivers have important roles in delivering practical, emotional, and end-of-life support to patients; however, they express multiple unmet needs, particularly information on future care planning. Early regular communication and decision making may improve access to timely information, alleviate anxiety, reduce uncertainty, and improve coping strategies. OBJECTIVES: This study examines how cancer caregivers view advance care planning (ACP) to inform an ACP program in an Australian cancer center. METHODS: This study used a qualitative descriptive design with grounded theory overtones. Eighteen caregivers of patients from lung and gastrointestinal tumor streams participated in focus groups or semistructured interviews, which incorporated the vignette technique. RESULTS: Caregivers believe that, although confronting, ACP discussions can be helpful. Conversations are sometimes patient initiated, although caregivers may intend to sensitively broach conversations over time. Findings highlight the impact of caregiver hierarchies, adaptive family decision making styles, and complex cultural influences on decision making. Some caregivers may develop subsidiary care intentions, based on "knowing" or overriding patients' desires. Hindrances on caregivers supporting patients' ACPs include limited information access, patient or caregiver resistance to engage in conversations, and ACPs association in oncology with losing hope. Many caregivers wanted professional support and further opportunities to obtain information, develop subsidiary plans, and help patients engage in ACP discussions. CONCLUSION: Findings highlight the influence of cancer caregivers and family dynamics over ACP decisions and actualization of future care plans. A patient- and family-centered care approach to ACP, promoting shared decision making and caregiver support, is recommended. Given that caregivers may override and, plausibly, misinterpret patients' desires, caregivers' subsidiary planning warrants further investigation. PMID- 24144997 TI - Heavy metal contamination of overlying waters and bed sediments of Haihe Basin in China. AB - The Haihe Basin is in an area of high population density and rapid economic development, and is one of the most polluted river basins in China. Examination of heavy metals (Cd, Co, Cr, Cu, Mn, Ni, Pb and Zn) in overlying waters and surface sediments in rivers was conducted in the basin's seven watersheds. Cd concentrations of overlying river waters exceeded Chinese environmental quality standard values for surface water (>0.010 mg/L) at 90% of stations. In surface river sediments, average concentrations of Cd, Co, Cr, Cu, Mn, Ni, Pb and Zn in the basin were 0.364, 13.4, 81.9, 53.3, 435, 27.8, 20.0 and 256 mg/kg, respectively. Cd, Zn and Cu were the most anthropogenically enriched elements, as indicated by enrichment factor (EF) values>1.5; EF values were highest for these metals in the Zi Ya He (ZYH) and Zhang Wei He (ZWH) watersheds. Cd in surface river sediments showed a high potential ecological risk (PER) in the ZYH and ZWH watersheds. The comprehensive PER due to all studied metals was high at many stations, especially in the ZYH and ZWH watersheds. The results indicate that heavy metal contamination in the rivers of the Haihe Basin should be considered when developing basin management strategies for protecting the aquatic environment. PMID- 24144998 TI - Accumulation and health risk of heavy metals in vegetables from harmless and organic vegetable production systems of China. AB - Heavy metal accumulation in vegetables is a growing concern for public health. Limited studies have elucidated the heavy metal accumulation characteristics and health risk of different vegetables produced in different facilities such as greenhouses and open-air fields and under different management modes such as harmless and organic. Given the concern over the aforementioned factors related to heavy metal accumulation, this study selected four typical greenhouse vegetable production bases, short-term harmless greenhouse vegetable base (SHGVB), middle-term harmless greenhouse vegetable base (MHGVB), long-term harmless greenhouse vegetable base (LHGVB), and organic greenhouse vegetable base (OGVB), in Nanjing City, China to study heavy metal accumulation in different vegetables and their associated health risks. Results showed that soils and vegetables from SHGVB and OGVB apparently accumulated fewer certain heavy metals than those from other bases, probably due to fewer planting years and special management, respectively. Greenhouse conditions significantly increased certain soil heavy metal concentrations relative to open-air conditions. However, greenhouse conditions did not significantly increase concentrations of As, Cd, Cu, Hg, and Zn in leaf vegetables. In fact, under greenhouse conditions, Pb accumulation was effectively reduced. The main source of soil heavy metals was the application of large amounts of low-grade fertilizer. There was larger health risk for producers' children to consume vegetables from the three harmless vegetable bases than those of residents' children. The hazard index (HI) over a large area exceeded 1 for these two kinds of children in the MHGVB and LHGVB. There was also a slight risk in the SHGVB for producers' children solely. However, the HI of the whole area of the OGVB for two kinds of children was below 1, suggesting low risk of heavy metal exposure through the food chain. Notably, the contribution rate of Cu and Zn to the HI were high in the four bases, yet current Chinese standards provide no limit for the concentrations of Cu and Zn; thus a potential health risk concerning these metals exists. PMID- 24144999 TI - Lead resistant bacteria: lead resistance mechanisms, their applications in lead bioremediation and biomonitoring. AB - Lead (Pb) is non-bioessential, persistent and hazardous heavy metal pollutant of environmental concern. Bioremediation has become a potential alternative to the existing technologies for the removal and/or recovery of toxic lead from waste waters before releasing it into natural water bodies for environmental safety. To our best knowledge, this is a first review presenting different mechanisms employed by lead resistant bacteria to resist high levels of lead and their applications in cost effective and eco-friendly ways of lead bioremediation and biomonitoring. Various lead resistant mechanisms employed by lead resistant bacteria includes efflux mechanism, extracellular sequestration, biosorption, precipitation, alteration in cell morphology, enhanced siderophore production and intracellular lead bioaccumulation. PMID- 24145000 TI - Primary adenosquamous carcinoma of the prostate: a rare aggressive tumor. PMID- 24145001 TI - Tumor necrosis on magnetic resonance imaging correlates with aggressive histology and disease progression in clear cell renal cell carcinoma. AB - OBJECTIVE: The study objective was to correlate the magnetic resonance imaging (MRI) features of clear cell renal cell carcinoma (ccRCC) with the histopathologic features and disease progression. METHODS: Institutional review board approval for this retrospective study was obtained; patient consent was not required. The initial staging MRI scans of 75 patients with histologically confirmed ccRCC were retrospectively reviewed. The imaging was assessed by 2 radiologists for the presence of tumor necrosis, cystic degeneration, intracellular fat, hemorrhage, retroperitoneal collaterals, and renal vein thrombosis. Quantitative analysis for the MRI presence of intracellular lipid within tumors was performed. MRI findings were correlated with histopathologic findings of clear cell percentage, alveolar and tubular growth pattern, and disease progression. Statistical associations were evaluated with nonparametric univariable analyses and multivariable logistic regression models. RESULTS: Correlation between MRI and histopathologic features was performed in 75 patients, whereas follow-up data were available for progression analysis in 68 patients. The presence of tumor necrosis, retroperitoneal collaterals, and renal vein thrombosis on MRI was significantly associated with a low percentage of tumor cells with clear cytoplasm (P < .01) and metastatic disease at presentation or disease progression (P < .01). At multivariable analysis, necrosis remained the only feature statistically associated with disease progression (P = .03; adjusted odds ratio, 27.7; 95% confidence interval, 1.4-554.7 for reader 1 and P = .02; adjusted odds ratio, 29.3; 95% confidence interval, 1.7-520.8 for reader 2). CONCLUSIONS: Necrosis in ccRCC on MRI correlates with the histopathologic finding of lower percentage of tumor cells with clear cytoplasm and is a poor prognostic indicator irrespective of tumor size. PMID- 24145002 TI - Extracellular transport of cell-size particles and tumor cells by dendritic cells in culture. AB - Many particulate materials of sizes approximating that of a cell disseminate after being introduced into the body. While some move about within phagocytic inflammatory cells, others appear to move about outside of, but in contact with, such cells. In this report, we provide unequivocal photomicroscopic evidence that cultured, mature, human dendritic cells can transport in extracellular fashion over significant distances both polymeric beads and tumor cells. At least in the case of polymeric beads, both fibrinogen and the beta2-integrin subunit, CD18, appear to play important roles in the transport process. These discoveries may yield insight into a host of disease-related phenomena, including and especially tumor cell invasion and metastasis. PMID- 24145003 TI - A problem in an article called "Immunoregulatory effects of alpha-GalCer in a murine model of autoimmune myocarditis" published in Experimental and Molecular Pathology 91 (2011) 636-642. PMID- 24145004 TI - The liver is populated by a broad spectrum of markers for macrophages. In alcoholic hepatitis the macrophages are M1 and M2. AB - BACKGROUND: Liver cell injury in alcoholic hepatitis (AH) is in part, due to macrophage generated proinflammatory cytokines i.e., M1, M2a, M2b, and M2c might be involved in ALD. The T cell response to chemokines and cytokines differs not only when M1 and M2 macrophages are compared but even when individual M2 subtypes are profiled. PURPOSE: In AH, M1 monocytes in the blood show increased sensitivity in the TNF-alpha response to LPS. Immunohistochemistry (IHC) studies showed that the liver sinusoids in ALD are abundantly populated by CD163 expressing type 2 macrophages. In this report, we profile many of the molecules associated with M1 and M2 macrophages in livers with AH using IHC. METHODS: Using immunofluorescent antibody-labeling, we profiled the receptors, cytokines and chemokines observed in M1, M2a, M2b, and M2c macrophages in liver biopsies from patients with AH. RESULTS: The increased CD 163 expression found in previous studies was confirmed as well an additional macrophage phenotypic marker CD206, suggesting that AH pathogenesis at least partially involves M2a and M2c macrophages. TGF-beta was found to be robustly over expressed by liver sinusoidal macrophages. Macrophage expression of the phenotypic markers TLR-2, TLR-4 and TLR 8 - found in both M1 and M2 macrophages - as well as the chemokines CCL-1 and CCL 18 was found. However, IRF-4, which is related to IL-4 production and M2a polarization as well as the cytokines CCL-1 and Il-1beta and the chemokine CXCL-1 were also observed, suggesting that M2a and M2b also play a role in AH pathogenesis. CONCLUSION: Livers with AH show robust macrophage over expression of TGF-beta, a growth factor more commonly associated with M2 type macrophages and mostly known for its fibrogenetic properties. However, our immunoprofiling of macrophage over expression also shows that AH is driven by receptors, interferons, and cytokines that are commonly associated not just with M2 macrophages, but with M1 as well. Thus, a complex interplay between different types of macrophages expressing a diverse array of molecules and receptors is involved in AH. PMID- 24145005 TI - In vivo anti-inflammatory and anti-ulcerogenic activities of extracts from wild growing and in vitro plants of Castilleja tenuiflora Benth. (Orobanchaceae). AB - ETHNOPHARMACOLOGICAL RELEVANCE: Castilleja tenuiflora Benth. (Orobanchaceae) is a perennial shrub used since the 16(th) century in Mexican traditional medicine for the treatment of a number of health disorders including inflammation, stomach pain and tumors. The aim of the present study was to evaluate the cytotoxic, anti inflammatory and anti-ulcerogenic activities of ethyl acetate (EaE), methanol (ME) and aqueous extracts (AE) of Castilleja tenuiflora wild grown (CtW) and in vitro plants (CtIv). MATERIAL AND METHOD: Phytochemical analysis of the phenylethanoid glycoside (PhG) and iridoid glycoside (IG) components was carried out by chromatographic methods. In vitro cytotoxic activity of the extracts was evaluated in the following four carcinoma cell lines: colon (HF-6), breast (MCF 7), prostate (PC-3), and nasopharyngeal (KB). The topical anti-inflammatory activity was evaluated in mouse ear edema induced by 12-O-tetradecanoylphorbol-13 acetate (TPA). Anti-ulcerogenic activity was evaluated in rats using an absolute ethanol-induced acute gastric ulcer model. RESULTS: The main compounds in the extracts were isoverbascoside, verbascoside and aucubin and their concentration depended both on the solvent used and on the plant material origin. None of the extracts showed cytotoxicity against the tested cell lines. In contrast, CtWEaE, CtWAE and CtIvEaE (1.6 mg/ear) showed moderate anti-inflammatory activity similar to dexamethasone (1 mg/ear) with a 38.2, 39.3 and 49.1% decrease of inflammation, respectively. CtWEaE and CtIvEaE (100 mg/kg) showed high anti-ulcerogenic activity with 88.3 and 83.1% inhibition, respectively, compared to famotidine (20 mg/kg, 32.8% inhibition). CONCLUSION: Castilleja tenuiflora extracts provided significant gastric protection in an acute ulcer induction model and topical anti inflammatory activity in a mouse ear edema model. These activities are related to verbascoside and may explain the traditional use of Castilleja tenuiflora in the treatment of anti-inflammatory and gastrointestinal disorders. Cultured Castilleja tenuiflora plants (in vitro) exhibited pharmacological activities and also have the potential to produce bioactive compounds. PMID- 24145006 TI - Lysimachia clethroides Duby extract attenuates inflammatory response in Raw 264.7 macrophages stimulated with lipopolysaccharide and in acute lung injury mouse model. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Lysimachia clethroides Duby (LC) is a traditional medicinal herb used to treat edema, hepatitis and inflammatory diseases in China and other Asian countries. In this study, the anti-inflammatory effects of LC extract and the mechanisms underlying were explored in both in vitro cell lines and acute lung injury (ALI) animal model of inflammation in vivo. MATERIALS AND METHODS: Lipopolysaccharide (LPS)-stimulated Raw 264.7 murine macrophages were used to study the regulatory effects of LC extract on inflammatory mediators such as nitric oxide (NO) and proinflammatory cytokine expression. Western blotting or ELISA techniques were employed to estimate protein levels. RT-PCR was used for analyzing the interferon (IFN)-beta production. LPS-induced ALI mouse model in vivo was employed to study the effect of LC extract. Further high-performance liquid chromatography (HPLC) fingerprinting technique was used to evaluate the active constituents present in LC extract, compared with reference standards. RESULTS: Pre-treatment with LC extract inhibited the LPS-stimulated NO release, interleukin (IL)-1beta and IL-6 production in Raw 264.7 cells dose dependently. LC extract inhibited the LPS-stimulated IRF3 and STAT1 phosphorylation. Further, in vivo experiments revealed that LC extract suppressed the infiltration of immune cells into the lung and proinflammatory cytokine production in broncho alveolar lavage fluid (BALF) in the LPS-induced ALI mouse model. CONCLUSIONS: Our results indicate that LC extract attenuates LPS-stimulated inflammatory responses in macrophages via regulating the key inflammatory mechanisms, providing a scientific support for its traditional use in treating various inflammatory diseases. PMID- 24145007 TI - One-pot efficient synthesis of 13(R),14(R)-epoxy-17beta-methyl-20(S)-hydroxyl-18 nor-pregna-4-en-3-one via a tandem epoxidation-rearrangement-epoxidation reaction sequence. AB - One-pot synthesis of an 18-norsteroid compound, 13(R),14(R)-epoxy-17beta-methyl 20(S)-hydroxyl-18-nor-pregna-4-en-3-one has been achieved with peracetic acid/acetic acid under a mild condition, via a proved tandem epoxidation rearrangement-epoxidation sequence. Its structure was designated on the basis of NMR and X-ray crystallography data. PMID- 24145008 TI - Amides derived from heteroaromatic amines and selected steryl hemiesters. AB - The current interest of the team has been focused on investigation of novel amides with potential cytotoxicity. The presented series of compounds was synthesized from selected steryl hemiesters and heteroaromatic amines. The synthetic protocol was designed in a simple and economic way, and divided into several general methodologies applicable to the compounds synthesized. The cytotoxicity was tested on cells derived from human T-lymphoblastic leukemia, breast adenocarcinoma and cervical cancer, and compared with tests on normal human fibroblasts. Most of the lanosterol-based compounds (3-5 and 7-10) showed medium to good cytotoxicity, while only two derivatives of cholesterol (18 and 19) showed medium cytotoxicity on human T-lymphoblastic leukemia cell line. The compounds 8 and 9 displayed the reasonable cytotoxicity among this series of amides, tested on the cell lines of T-lymphoblastic leukemia [14.5+/-0.4 MUM (8) and 18.5+/-3.9 MUM (9)], breast adenocarcinoma [19.5+/-2.1 MUM (8) and 23.1+/-4.0 MUM (9)] and cervical cancer [24.8+/-5.3 MUM (8) and 29.1+/-4.7 MUM (9)]. Only the compound 8 was adequately less active on normal human fibroblasts (40.4+/ 11.1 MUM). PMID- 24145010 TI - Prognostic factors for mortality in neonatal tetanus: a systematic review and meta-analysis. AB - OBJECTIVES: To determine prognostic factors for mortality in neonates with tetanus and to assess the associations between prognostic factors and neonatal tetanus (NT) mortality. METHODS: Five databases were searched for studies on prognostic factors and NT mortality published up to April 2013 to identify studies relevant to this review. Prognostic factors of interest were birth weight, age at onset of symptoms, age at presentation, delay in presentation, and duration of hospitalization. Odds ratios (ORs) for prognostic factors and mortality were estimated by random effects models and stratified analyses for all studies. RESULTS: Sixteen studies including a total of 4535 neonates were included in the analysis: nine from Africa, five from Asia, and two from Europe. The prognostic factors identified consistently in the studies were birth weight, age at onset of symptoms, and age at presentation. Of the 16 studies, only one assessed all three prognostic factors, five studies assessed two prognostic factors, and 10 studies assessed one prognostic factor. Neonates with a low birth weight were more likely to have an increased odds of NT death (OR 2.09, 95% confidence interval (CI) 1.29-3.37) than normal weight neonates. This mortality risk was exacerbated for low birth weight neonates with age at onset<=6 days (OR 6.80, 95% CI 2.42-19.11). Age at onset<=5-7 days was associated with an increased odds of NT death. CONCLUSIONS: Low birth weight predicted an increased odds of death by NT. Age at onset<=5-7 days to diagnosis is crucial in determining survival among neonates with tetanus. PMID- 24145009 TI - Pediatric catastrophic antiphospholipid syndrome: descriptive analysis of 45 patients from the "CAPS Registry". AB - Given the lack of information about catastrophic antiphospholipid syndrome (APS) in pediatric patients, the objective of the current study was to describe the clinical characteristics, laboratory features, treatment, and outcome of pediatric patients with catastrophic APS and compare them with the adult patients with catastrophic APS. We identified patients who were under 18years of age at time of catastrophic APS diagnosis included in the international registry of patients with catastrophic APS (CAPS Registry). Their main demographic and clinical characteristics, laboratory features, treatment, and outcome were described and compared with those of adult patients with catastrophic APS. From the 446 patients included in the CAPS Registry as of May 2013, 45 (10.3%) patients developed 46 catastrophic events before 18years of age (one patient presented two episodes). Overall, 32 (71.1%) patients were female and the mean age was 11.5+/-4.6years (range, 3months-18years). A total of 31 (68.9%) patients suffered from primary APS and 13 (28.9%) from systemic lupus erythematosus (SLE). The main differences between the two groups of patients were the higher prevalence of infections as precipitating factor for catastrophic event in the pediatric population (60.9% versus 26.8% in the adult population, p<0.001) and of peripheral vessel thrombosis (52.2% versus 34.3%, p=0.017). In addition, catastrophic APS was the first manifestation of APS more frequently in pediatric patients (86.6% versus 45.2%, p<0.001). Interestingly, pediatric patients showed a trend of lower mortality, although the difference was not statistically significant (26.1% versus 40.2%; odds ratio, 1.9; 95% confidence interval, 0.96 3.79; p=0.063). No differences were found neither in the laboratory features nor in the isolated or combination treatments between groups. Catastrophic APS in pediatric patients is a rare disease. There are minimal differences in the clinical and laboratory features, treatment, and outcome of pediatric and adult catastrophic APS patients. PMID- 24145011 TI - Seroepidemiological survey of tularemia among different groups in western Iran. AB - BACKGROUND: The first human case of tularemia in Iran was reported in 1980 and there have been no subsequent reports of tularemia in the country. The aim of this study was to carry out a survey of tularemia among different groups in the province of Kurdistan in western Iran. METHODS: The following information was collected by means of an in-house questionnaire: participant demographic characteristics, exposure to risks, and use of appropriate personal protective equipment and disinfectant in their occupation. A blood sample was collected from each participant. Sera were tested using an ELISA kit (Virion?Serion) to detect specific IgG antibodies against Francisella tularensis. RESULTS: Of a total of 250 serum samples, 14.40% had anti-tularemia IgG antibodies. The highest seroprevalence was found in hunters (18%) and the lowest in health care workers (12%). Age had a significant positive association with tularemia seroprevalence (p<0.001). The seroprevalence of tularemia in people exposed to foxes (hunting or eating the meat) (25%) was significantly higher than in others (8.65%) (p = 0.01). CONCLUSIONS: According to the findings of this study, it is highly recommended that physicians and health care workers are informed about bacteria circulating in this area. By sensitizing the health system, it is expected that some cases of the clinical disease will be reported in the near future. Similar studies in other parts of the country and on domestic and wild animals will clarify the epidemiology of tularemia in Iran. PMID- 24145012 TI - Improvement of the robustness of solar photo-Fenton processes using chemometric techniques for the decolorization of azo dye mixtures. AB - The aim of this study was to propose and to evaluate a strategy based on chemometric tools to improve the robustness of photo-Fenton processes during decolorization of mixtures of sulfonated azo dyes. The strategy consisted of three stages: quantification, reagent dose selection and robustness analysis. The partial least square method was used for the simultaneous quantification of acid orange 7, acid red 151, and acid blue 113, in a mixture, by using UV-visible spectra. Then, a central composite design was applied to set the best reagent dose (Fe(2+) and H2O2) to obtain a decolorization of 97% for each dye. The application of the strategy allowed to predict the concentration of each dye and to select the best reagent dose to decolorize mixtures of sulfonated dyes. Also with the application of the developed strategy, a reduction of peroxide from 33 to 65% was obtained and the undesirable reactions were reduced. It was observed that the variation of dye concentrations do not affected the percentage of decolorization. PMID- 24145013 TI - Estimation of CO2 emission from water treatment plant--model development and application. AB - A comprehensive mathematical model developed for this study was used to compare estimates of on-site and off-site CO2 emissions, from conventional and advanced water treatment plants (WTPs). When 200,000 m(3) of raw water at 10 NTU (Nepthelometric Turbidity Unit) was treated by a conventional WTP to 0.1 NTU using aluminum sulfate as a coagulant, the total CO2 emissions were estimated to be 790 +/- 228 (on-site) and 69,596 +/- 3950 (off-site) kg CO2e/d. The emissions from an advanced WTP containing micro-filtration (MF) membrane and ozone disinfection processes; treating the same raw water to 0.005 NTU, were estimated to be 395 +/- 115 (on-site) and 38,197 +/- 2922 (off-site) kg CO2e/d. The on-site CO2 emissions from the advanced WTP were half that from the conventional WTP due to much lower use of coagulant. On the other hand, off-site CO2 emissions due to consumption of electricity were 2.14 times higher for the advanced WTP, due to the demands for operation of the MF membrane and ozone disinfection processes. However, the lower use of chemicals in the advanced WTP decreased off-site CO2 emissions related to chemical production and transportation. Overall, total CO2 emissions from the conventional WTP were 1.82 times higher than that from the advanced WTP. A sensitivity analysis was performed for the advanced WTP to suggest tactics for simultaneously reducing CO2 emissions further and enhancing water quality. PMID- 24145014 TI - Simultaneous determination of multiple amino acids in plasma in critical illness by high performance liquid chromatography with ultraviolet and fluorescence detection. AB - There is increasing recognition that the host response to critical illness includes derangement of multiple amino acid pathways, including amino acids (AAs) central to metabolism and immune, endothelial and neurological function. To characterise concentration changes of these plasma amino acid we report the development and validation of a method for the quantification of AAs in small volumes of plasma (50MUL) using HPLC with simultaneous UV and fluorescence (FL) detection. Protein precipitation and pre-column derivatization with 6 aminoquinolyl-N-hydroxysuccinimidyl carbamate (AQC) is followed by reversed phase HPLC separation. Calibration curves were built with norleucine as an internal standard. Thirty-three (including the 20 proteinogenic) AAs, were selected as standards and their corresponding concentrations in the plasma of healthy human controls and patients with severe falciparum malaria were quantified. This method enables the detection of perturbations in arginine metabolism, aromatic amino acid pathways, methionine transsulfuration and transmethylation pathways and other metabolic pathways. PMID- 24145015 TI - Profiling analysis of biogenic amines and their acidic metabolites in mouse brain tissue using gas chromatography-tandem mass spectrometry. AB - The profiling analysis of biogenic amines, including catecholamines and serotonin, and their metabolites in mouse brain tissue provides an important key to understanding their roles in the body and the possibility of simple and accurate diagnosis of neural diseases. A novel approach in the analysis of biogenic amines and their acidic metabolites in brain tissue using gas chromatography-tandem mass spectrometry (GC-MS/MS) is presented. Biogenic amines and their acidic metabolites in brain tissue were effectively separated using a mixed-cation-exchange solid-phase extraction (MCX-SPE) cartridge with a variation in the composition of the SPE elution solvents. A selective derivatization with hexamethyldisilazane (HMDS) and N-methyl-bis-heptafluorobutyramide (MBHFBA) was used to increase the detection sensitivity and to prevent the formation of any side-products. The identification and quantification of the target analytes were performed by gas chromatography triple quadrupole mass spectrometry (GC-MS/MS) using multiple ion reaction monitoring (MRM) mode. The overall recovery yields of the biogenic amines and their metabolites were above 87.5% at 10ng/g and 92.4% at 100ng/g of spiking concentration range. The isotopic-labeled internal standards were used for the precise quantification of bioamines and their metabolites. The calibration curves for the biogenic amines and their metabolites obtained through GC-MS/MS were linear (r(2)>0.995) over the concentration range of 1 (2 or 3) 200ng/mL. The present method was reproducible (relative standard deviation range 0.6-9.3%) and accurate (range 85.4-107.9%), with LLOQs of 0.71-3.69ng/mL. The developed method was successfully applied to the determination and quantification of bioamines and their metabolites in rat brain tissue samples. PMID- 24145016 TI - Development and validation of a high-performance liquid chromatography-tandem mass spectrometry assay quantifying olaparib in human plasma. AB - Olaparib is an inhibitor of poly ADP ribose polymerase 1 (PARP-1). Phase I and II trials showed promising results of olaparib against tumours in BRCA mutation carriers. Currently an increasing number of clinical trials with olaparib in combination with other compounds or radiotherapy are conducted. To support these clinical trials an LC-MS/MS method was developed and validated for the quantification of olaparib in human plasma. Human plasma samples were collected in the clinic and stored at nominally -20 degrees C. Olaparib was isolated from plasma by liquid-liquid extraction, separated on a C18 column with gradient elution and analyzed with triple quadrupole mass spectrometry in positive ion mode. A deuterated isotope was used as internal standard for the quantification. The assay, ranging from 10 to 5000ng/mL, was linear with correlation coefficients (r(2)) of 0.9994 or better. The assay was accurate and precise, with inter-assay and intra-assay accuracies within +/-7.6% of nominal and inter-assay and intra assay precision <=9.3% at the lower limit of quantification and <=5.7% at the other concentration levels tested. All results were within the acceptance criteria of the US FDA and the latest EMA guidelines for method validation. A quantitative method was developed and validated for the quantification of olaparib in human plasma. The method could successfully be applied for the pharmacokinetic quantification of olaparib in cancer patients treated with olaparib. PMID- 24145017 TI - Development of a hyphenated procedure of heat-reflux and ultrasound-assisted extraction followed by RP-HPLC separation for the determination of three flavonoids content in Scutellaria barbata D. Don. AB - A hyphenated procedure of heat-reflux and ultrasound-assisted extraction (HUAE), and an accurate high-performance liquid chromatographic (HPLC) method were developed for the determination of apigenin, baicalin and luteolin content in Scutellaria barbara D. Don. The suitable HUAE conditions for the extraction of target compounds from the herb were identified as an ultrasonic frequency of 40kHz, power of 185W, duty cycle of 75% (intermittent sonication), mean particle size of 0.355mm, extraction temperature of 50 degrees C, ratio of solvent to raw material of 12:1 (mL/g), ethanol concentration of 60% (v/v), extraction time of 30min and three cycles. Compared with a traditional heat-reflux extraction method, the proposed method reduced the extraction time, extraction temperature and solvent consumption. Also, this HUAE method achieved superior apigenin, baicalin and luteolin yields. Furthermore, the developed HUAE-HPLC method was applied successfully for the simultaneous evaluation of three bioactive compounds in five samples of S. barbara D. Don obtained from different geographical regions. These results clearly demonstrated that the combined HUAE-HPLC process is feasible in the future commercialized manufacture of this highly valuable Chinese herbal medicine. PMID- 24145018 TI - Clostridium difficile glutamate dehydrogenase is a secreted enzyme that confers resistance to H2O2. AB - Clostridium difficile produces an NAD-specific glutamate dehydrogenase (GDH), which converts l-glutamate into alpha-ketoglutarate through an irreversible reaction. The enzyme GDH is detected in the stool samples of patients with C. difficile-associated disease and serves as one of the diagnostic tools to detect C. difficile infection (CDI). We demonstrate here that supernatant fluids of C. difficile cultures contain GDH. To understand the role of GDH in the physiology of C. difficile, an isogenic insertional mutant of gluD was created in strain JIR8094. The mutant failed to produce and secrete GDH as shown by Western blot analysis. Various phenotypic assays were performed to understand the importance of GDH in C. difficile physiology. In TY (tryptose yeast extract) medium, the gluD mutant grew slower than the parent strain. Complementation of the gluD mutant with the functional gluD gene reversed the growth defect in TY medium. The presence of extracellular GDH may have a functional role in the pathogenesis of CDI. In support of this assumption we found higher sensitivity to H2O2 in the gluD mutant as compared to the parent strain. Complementation of the gluD mutant with the functional gluD gene reversed the H2O2 sensitivity. PMID- 24145020 TI - Opioid use in the US hemodialysis population. PMID- 24145021 TI - Pharmacokinetics and pharmacodynamics of imipenem and meropenem in critically ill patients treated with continuous venovenous hemodialysis. PMID- 24145022 TI - Membranoproliferative glomerulonephritis: the role for laser microdissection and mass spectrometry. AB - Monoclonal gammopathy is increasingly recognized as a common cause of membranoproliferative glomerulonephritis (MPGN); however, establishing this diagnosis can be challenging. We report the case of a 58-year-old asymptomatic woman who presented with proteinuria with protein excretion of 5,000mg/d, microscopic hematuria, and normal kidney function. Kidney biopsy was consistent with MPGN pattern of injury. Immunofluorescence studies were positive for nonspecific segmental immunoglobulin M (IgM) and C3 staining. Electron microscopy showed subendothelial, subepithelial, and mesangial electron-dense deposits. The workup excluded an infectious or autoimmune disease, but IgG kappa monoclonal protein was detected in serum at a concentration of 0.4mg/dL. Because there was a mismatch between the serum monoclonal protein (IgG kappa) and immunofluorescence staining pattern (nonspecific IgM, no light chain restriction), laser microdissection and mass spectrometry were performed on the kidney biopsy tissue. This identified the deposits as monoclonal IgG kappa, thereby leading to the diagnosis of monoclonal gammopathy-associated MPGN. Our case emphasizes the importance of searching for an underlying cause of MPGN, reviews the technique of laser microdissection-mass spectrometry, and highlights its application as a pathology tool for the evaluation of monoclonal gammopathy-related glomerulonephritis. PMID- 24145019 TI - Developing epigenetic diagnostics and therapeutics for brain disorders. AB - Perturbations in epigenetic mechanisms have emerged as cardinal features in the molecular pathology of major classes of brain disorders. We therefore highlight evidence which suggests that specific epigenetic signatures measurable in central - and possibly even in peripheral tissues - have significant value as translatable biomarkers for screening, early diagnosis, and prognostication; developing molecularly targeted medicines; and monitoring disease progression and treatment responses. We also draw attention to existing and novel therapeutic approaches directed at epigenetic factors and mechanisms, including strategies for modulating enzymes that write and erase DNA methylation and histone/chromatin marks; protein-protein interactions responsible for reading epigenetic marks; and non-coding RNA pathways. PMID- 24145026 TI - The mechanism for molecular assembly of the proteasome. AB - In eukaryotic cells, the ubiquitin proteasome system plays important roles in diverse cellular processes. The 26S proteasome is a large enzyme complex that degrades ubiquitinated proteins. It consists of 33 different subunits that form two subcomplexes, the 20S core particle and the 19S regulatory particle. Recently, several chaperones dedicated to the accurate assembly of this protease complex have been identified, but the complete mechanism of the 26S proteasome assembly is still unclear. In this review, we summarize what is known about the assembly of proteasome to date and present our group's recent findings on the role of the GET pathway in the assembly of the 26S proteasome, in addition to its role in mediating the insertion of tail-anchored (TA) proteins into the ER membrane. PMID- 24145027 TI - Presenilins regulate neurotrypsin gene expression and neurotrypsin-dependent agrin cleavage via cyclic AMP response element-binding protein (CREB) modulation. AB - Presenilins, the catalytic components of the gamma-secretase complex, are upstream regulators of multiple cellular pathways via regulation of gene transcription. However, the underlying mechanisms and the genes regulated by these pathways are poorly characterized. In this study, we identify Tequila and its mammalian ortholog Prss12 as genes negatively regulated by presenilins in Drosophila larval brains and mouse embryonic fibroblasts, respectively. Prss12 encodes the serine protease neurotrypsin, which cleaves the heparan sulfate proteoglycan agrin. Altered neurotrypsin activity causes serious synaptic and cognitive defects; despite this, the molecular processes regulating neurotrypsin expression and activity are poorly understood. Using gamma-secretase drug inhibitors and presenilin mutants in mouse embryonic fibroblasts, we found that a mature gamma-secretase complex was required to repress neurotrypsin expression and agrin cleavage. We also determined that PSEN1 endoproteolysis or processing of well known gamma-secretase substrates was not essential for this process. At the transcriptional level, PSEN1/2 removal induced cyclic AMP response element binding protein (CREB)/CREB-binding protein binding, accumulation of activating histone marks at the neurotrypsin promoter, and neurotrypsin transcriptional and functional up-regulation that was dependent on GSK3 activity. Upon PSEN1/2 reintroduction, this active epigenetic state was replaced by a methyl CpG-binding protein 2 (MeCP2)-containing repressive state and reduced neurotrypsin expression. Genome-wide analysis revealed hundreds of other mouse promoters in which CREB binding is similarly modulated by the presence/absence of presenilins. Our study thus identifies Tequila and neurotrypsin as new genes repressed by presenilins and reveals a novel mechanism used by presenilins to modulate CREB signaling based on controlling CREB recruitment. PMID- 24145028 TI - Substrate cleavage profiling suggests a distinct function of Bacteroides fragilis metalloproteinases (fragilysin and metalloproteinase II) at the microbiome inflammation-cancer interface. AB - Enterotoxigenic anaerobic Bacteroides fragilis is a significant source of inflammatory diarrheal disease and a risk factor for colorectal cancer. Two distinct metalloproteinase types (the homologous 1, 2, and 3 isoforms of fragilysin (FRA1, FRA2, and FRA3, respectively) and metalloproteinase II (MPII)) are encoded by the B. fragilis pathogenicity island. FRA was demonstrated to be important to pathogenesis, whereas MPII, also a potential virulence protein, remained completely uncharacterized. Here, we, for the first time, extensively characterized MPII in comparison with FRA3, a representative of the FRA isoforms. We employed a series of multiplexed peptide cleavage assays to determine substrate specificity and proteolytic characteristics of MPII and FRA. These results enabled implementation of an efficient assay of MPII activity using a fluorescence-quenched peptide and contributed to structural evidence for the distinct substrate cleavage preferences of MPII and FRA. Our data imply that MPII specificity mimics the dibasic Arg?Arg cleavage motif of furin-like proprotein convertases, whereas the cleavage motif of FRA (Pro-X-X-Leu-(Arg/Ala/Leu)?) resembles that of human matrix metalloproteinases. To the best of our knowledge, MPII is the first zinc metalloproteinase with the dibasic cleavage preferences, suggesting a high level of versatility of metalloproteinase proteolysis. Based on these data, we now suggest that the combined (rather than individual) activity of MPII and FRA is required for the overall B. fragilis virulence in vivo. PMID- 24145029 TI - Escherichia coli virulence protein NleH1 interaction with the v-Crk sarcoma virus CT10 oncogene-like protein (CRKL) governs NleH1 inhibition of the ribosomal protein S3 (RPS3)/nuclear factor kappaB (NF-kappaB) pathway. AB - Enterohemorrhagic Escherichia coli and other attaching/effacing bacterial pathogens cause diarrhea in humans. These pathogens use a type III secretion system to inject virulence proteins (effectors) into host cells, some of which inhibit the innate immune system. The enterohemorrhagic E. coli NleH1 effector prevents the nuclear translocation of RPS3 (ribosomal protein S3) to inhibit its participation as a nuclear "specifier" of NF-kappaB binding to target gene promoters. NleH1 binds to RPS3 and inhibits its phosphorylation on Ser-209 by IkappaB kinase-beta (IKKbeta). However, the precise mechanism of this inhibition is unclear. NleH1 possesses a Ser/Thr protein kinase activity that is essential both for its ability to inhibit the RPS3/NF-kappaB pathway and for full virulence of the attaching/effacing mouse pathogen Citrobacter rodentium. However, neither RPS3 nor IKKbeta is a substrate of NleH1 kinase activity. We therefore screened ~9,000 human proteins to identify NleH1 kinase substrates and identified CRKL (v Crk sarcoma virus CT10 oncogene-like protein), a substrate of the BCR/ABL kinase. Knockdown of CRKL abundance prevented NleH1 from inhibiting RPS3 nuclear translocation and NF-kappaB activity. CRKL residues Tyr-198 and Tyr-207 were required for interaction with NleH1. Lys-159, the kinase-active site of NleH1, was necessary for its interaction with CRKL. We also identified CRKL as an IKKbeta interaction partner, mediated by CRKL Tyr-198. We propose that the CRKL interaction with IKKbeta recruits NleH1 to the IKKbeta complex, where NleH1 then inhibits the RPS3/NF-kappaB pathway. PMID- 24145031 TI - Molecular basis for auto- and hetero-catalytic maturation of a thermostable subtilase from thermophilic Bacillus sp. WF146. AB - The proform of the WF146 protease, an extracellular subtilase produced by thermophilic Bacillus sp. WF146, matures efficiently at high temperatures. Here we report that the proform, which contains an N-terminal propeptide composed of a core domain (N*) and a linker peptide, is intrinsically able to mature via multiple pathways. One autocatalytic pathway is initiated by cis-processing of N* to generate an autoprocessed complex N*-I(WT), and this step is followed by truncation of the linker peptide and degradation of N*. Another autocatalytic pathway is initiated by trans-processing of the linker peptide followed by degradation of N*. Unlike most reported subtilases, the maturation of the WF146 protease occurs not only autocatalytically but also hetero-catalytically whereby heterogeneous proteases accelerate the maturation of the WF146 protease via trans processing of the proform and N*-I(WT). Although N* acts as an intramolecular chaperone and an inhibitor of the mature enzyme, the linker peptide is susceptible to proteolysis, allowing the trans-processing reaction to occur auto- and hetero-catalytically. These studies also demonstrate that the WF146 protease undergoes subtle structural adjustments during the maturation process and that the binding of Ca(2+) is required for routing the proform to mature properly at high temperatures. Interestingly, under Ca(2+)-free conditions, the proform is cis-processed into a unique propeptide-intermediate complex (N*-I(E)) capable of re-synthesis of the proform. Based on the basic catalytic principle of serine proteases and these experimental results, a mechanism for the cis-processing/re synthesis equilibrium of the proform and the role of the linker peptide in regulation of this equilibrium has been proposed. PMID- 24145030 TI - Ikaros sets the potential for Th17 lineage gene expression through effects on chromatin state in early T cell development. AB - Th17 cells are important effectors of immunity to extracellular pathogens, particularly at mucosal surfaces, but they can also contribute to pathologic tissue inflammation and autoimmunity. Defining the multitude of factors that influence their development is therefore of paramount importance. Our previous studies using Ikaros(-/-) CD4+ T cells implicated Ikaros in Th1 versus Th2 lineage decisions. Here we demonstrate that Ikaros also regulates Th17 differentiation through its ability to promote expression of multiple Th17 lineage-determining genes, including Ahr, Runx1, Rorc, Il17a, and Il22. Ikaros exerts its influence on the chromatin remodeling of these loci at two distinct stages in CD4+ T helper cell development. In naive cells, Ikaros is required to limit repressive chromatin modifications at these gene loci, thus maintaining the potential for expression of the Th17 gene program. Subsequently, Ikaros is essential for the acquisition of permissive histone marks in response to Th17 polarizing signals. Additionally, Ikaros represses the expression of genes that limit Th17 development, including Foxp3 and Tbx21. These data define new targets of the action of Ikaros and indicate that Ikaros plays a critical role in CD4+ T cell differentiation by integrating specific cytokine cues and directing epigenetic modifications that facilitate activation or repression of relevant genes that drive T cell lineage choice. PMID- 24145032 TI - Real-time monitoring of intermediates reveals the reaction pathway in the thiol disulfide exchange between disulfide bond formation protein A (DsbA) and B (DsbB) on a membrane-immobilized quartz crystal microbalance (QCM) system. AB - Disulfide bond formation protein B (DsbBS-S,S-S) is an inner membrane protein in Escherichia coli that has two disulfide bonds (S-S, S-S) that play a role in oxidization of a pair of cysteine residues (SH, SH) in disulfide bond formation protein A (DsbASH,SH). The oxidized DsbAS-S, with one disulfide bond (S-S), can oxidize proteins with SH groups for maturation of a folding preprotein. Here, we have described the transient kinetics of the oxidation reaction between DsbASH,SH and DsbBS-S,S-S. We immobilized DsbBS-S,S-S embedded in lipid bilayers on the surface of a 27-MHz quartz crystal microbalance (QCM) device to detect both formation and degradation of the reaction intermediate (DsbA-DsbB), formed via intermolecular disulfide bonds, as a mass change in real time. The obtained kinetic parameters (intermediate formation, reverse, and oxidation rate constants (kf, kr, and kcat, respectively) indicated that the two pairs of cysteine residues in DsbBS-S,S-S were more important for the stability of the DsbA-DsbB intermediate than ubiquinone, an electron acceptor for DsbBS-S,S-S. Our data suggested that the reaction pathway of almost all DsbASH,SH oxidation processes would proceed through this stable intermediate, avoiding the requirement for ubiquinone. PMID- 24145034 TI - Loop L5 assumes three distinct orientations during the ATPase cycle of the mitotic kinesin Eg5: a transient and time-resolved fluorescence study. AB - Members of the kinesin superfamily of molecular motors differ in several key structural domains, which probably allows these molecular motors to serve the different physiologies required of them. One of the most variable of these is a stem-loop motif referred to as L5. This loop is longest in the mitotic kinesin Eg5, and previous structural studies have shown that it can assume different conformations in different nucleotide states. However, enzymatic domains often consist of a mixture of conformations whose distribution shifts in response to substrate binding or product release, and this information is not available from the "static" images that structural studies provide. We have addressed this issue in the case of Eg5 by attaching a fluorescent probe to L5 and examining its fluorescence, using both steady state and time-resolved methods. This reveals that L5 assumes an equilibrium mixture of three orientations that differ in their local environment and segmental mobility. Combining these studies with transient state kinetics demonstrates that there is a major shift in this distribution during transitions that interconvert weak and strong microtubule binding states. Finally, in conjunction with previous cryo-EM reconstructions of Eg5.microtubule complexes, these fluorescence studies suggest a model in which L5 regulates both nucleotide and microtubule binding through a set of reversible interactions with helix alpha3. We propose that these features facilitate the production of sustained opposing force by Eg5, which underlies its role in supporting formation of a bipolar spindle in mitosis. PMID- 24145033 TI - Defective regulation of microRNA target genes in myoblasts from facioscapulohumeral dystrophy patients. AB - Facioscapulohumeral muscular dystrophy (FSHD) is an autosomal dominant hereditary neuromuscular disorder linked to the deletion of an integral number of 3.3-kb long macrosatellite repeats (D4Z4) within the subtelomeric region of chromosome 4q. Most genes identified in this region are overexpressed in FSHD myoblasts, including the double homeobox genes DUX4 and DUX4c. We have carried out a simultaneous miRNome/transcriptome analysis of FSHD and control primary myoblasts. Of 365 microRNAs (miRNAs) analyzed in this study, 29 were found to be differentially expressed between FSHD and normal myoblasts. Twenty-one microRNAs (miR-1, miR-7, miR-15a, miR-22, miR-30e, miR-32, miR-107, miR-133a, miR-133b, miR 139, miR-152, miR-206, miR-223, miR-302b, miR-331, miR-362, miR-365, miR-382, miR 496, miR-532, miR-654, and miR-660) were up-regulated, and eight were down regulated (miR-15b, miR-20b, miR-21, miR-25, miR-100, miR-155, miR-345, and miR 594). Twelve of the miRNAs up-regulated in FHSD were also up-regulated in the cells ectopically expressing DUX4c, suggesting that this gene could regulate miRNA gene transcription. The myogenic miRNAs miR-1, miR-133a, miR-133b, and miR 206 were highly expressed in FSHD myoblasts, which nonetheless did not prematurely enter myogenic differentiation. This could be accounted for by the fact that in FSHD myoblasts, functionally important target genes, including cell cycle, DNA damage, and ubiquitination-related genes, escape myogenic microRNA induced repression. PMID- 24145035 TI - WD repeat protein WDR48 in complex with deubiquitinase USP12 suppresses Akt dependent cell survival signaling by stabilizing PH domain leucine-rich repeat protein phosphatase 1 (PHLPP1). AB - PHLPP1 (PH domain leucine-rich repeat protein phosphatase 1) is a protein serine/threonine phosphatase and a negative regulator of the PI3-kinase/Akt pathway. Although its function as a suppressor of tumor cell growth has been established, the mechanism of its regulation is not completely understood. In this study, by utilizing the tandem affinity purification approach we have identified WDR48 and USP12 as novel PHLPP1-associated proteins. The WDR48.USP12 complex deubiquitinates PHLPP1 and thereby enhances its protein stability. Similar to PHLPP1 function, WDR48 and USP12 negatively regulate Akt activation and thus promote cellular apoptosis. Functionally, we show that WDR48 and USP12 suppress proliferation of tumor cells. Importantly, we found a WDR48 somatic mutation (L580F) that is defective in stabilizing PHLPP1 in colorectal cancers, supporting a WDR48 role in tumor suppression. Together, our results reveal WDR48 and USP12 as novel PHLPP1 regulators and potential suppressors of tumor cell survival. PMID- 24145036 TI - UDP-glucose dehydrogenase activity and optimal downstream cellular function require dynamic reorganization at the dimer-dimer subunit interfaces. AB - UDP-glucose dehydrogenase (UGDH) provides precursors for steroid elimination, hyaluronan production, and glycosaminoglycan synthesis. The wild-type UGDH enzyme purifies in a hexamer-dimer equilibrium and transiently undergoes dynamic motion that exposes the dimer-dimer interface during catalysis. In the current study we created and characterized point mutations that yielded exclusively dimeric species (obligate dimer, T325D), dimeric species that could be induced to form hexamers in the ternary complex with substrate and cofactor (T325A), and a previously described exclusively hexameric species (UGDHDelta132) to investigate the role of quaternary structure in regulation of the enzyme. Characterization of the purified enzymes revealed a significant decrease in the enzymatic activity of the obligate dimer and hexamer mutants. Kinetic analysis of wild-type UGDH and the inducible hexamer, T325A, showed that upon increasing enzyme concentration, which favors the hexameric species, activity was modestly decreased and exhibited cooperativity. In contrast, cooperative kinetic behavior was not observed in the obligate dimer, T325D. These observations suggest that the regulation of the quaternary assembly of the enzyme is essential for optimal activity and allosteric regulation. Comparison of kinetic and thermal stability parameters revealed structurally dependent properties consistent with a role for controlled assembly and disassembly of the hexamer in the regulation of UGDH. Finally, both T325A and T325D mutants were significantly less efficient in promoting downstream hyaluronan production by HEK293 cells. These data support a model that requires an operational dimer-hexamer equilibrium to function efficiently and preserve regulated activity in the cell. PMID- 24145037 TI - Biased agonism as a mechanism for differential signaling by chemokine receptors. AB - Chemokines display considerable promiscuity with multiple ligands and receptors shared in common, a phenomenon that is thought to underlie their biochemical "redundancy." Their receptors are part of a larger seven-transmembrane receptor superfamily, commonly referred to as G protein-coupled receptors, which have been demonstrated to be able to signal with different efficacies to their multiple downstream signaling pathways, a phenomenon referred to as biased agonism. Biased agonism has been primarily reported as a phenomenon of synthetic ligands, and the biologic prevalence and importance of such signaling are unclear. Here, to assess the presence of biased agonism that may underlie differential signaling by chemokines targeting the same receptor, we performed a detailed pharmacologic analysis of a set of chemokine receptors with multiple endogenous ligands using assays for G protein signaling, beta-arrestin recruitment, and receptor internalization. We found that chemokines targeting the same receptor can display marked differences in their efficacies for G protein- or beta-arrestin-mediated signaling or receptor internalization. This ligand bias correlates with changes in leukocyte migration, consistent with different mechanisms underlying the signaling downstream of these receptors induced by their ligands. These findings demonstrate that biased agonism is a common and likely evolutionarily conserved biological mechanism for generating qualitatively distinct patterns of signaling via the same receptor in response to different endogenous ligands. PMID- 24145038 TI - Binding of a sialic acid-recognizing lectin Siglec-9 modulates adhesion dynamics of cancer cells via calpain-mediated protein degradation. AB - Although regulatory mechanisms for immune cells with inhibitory signals via immunoreceptor tyrosine-based inhibitory motifs are well known, signals transduced via interaction between Siglecs and sialyl compounds on their counterreceptors into target cells have not been reported to date. In this study, we found that an astrocytoma cell line, AS, showed detachment from culture plates when co-cultured with Siglec-9-expressing cells and/or soluble Siglec-9. Moreover, detached AS cells regrew as co-cultured cells with Siglec-9-deficient cells. They also showed increased motility and invasiveness upon Siglec-9 binding. In immunoblotting, rapid degradation of focal adhesion kinase (FAK) and related signaling molecules such as Akt, paxillin, and p130Cas was observed immediately after the co-culture. Despite degradation of these molecules, increased p-Akt was found at the front region of the cytoplasm, probably reflecting increased cell motility. Calpain was considered to be a responsible protease for the protein degradation by the inhibition experiments. These results suggest that protein degradation of FAK and related molecules was induced by Siglec-9 binding to its counterreceptors via sialylglycoconjugates, leading to the modulation of adhesion kinetics of cancer cells. Thus, this might be a mechanism by which cancer cells utilize Siglec-9-derived signals to escape from immunosurveillance. PMID- 24145040 TI - Prognostic value of cell-free DNA in plasma of out-of-hospital cardiac arrest survivors at ICU admission and 24h post-admission. AB - Cell-free DNA has been associated with outcome in several acute conditions including two reports concerning the outcomes after cardiac arrest that found association of circulating DNA quantities at admission with mortality. The origins of cell-free DNA are primarily necrosis and apoptosis, which in cardiac arrest occur during ischaemia ("no-flow" and "low-flow" period), during reperfusion injury and as a consequence of post-arrest inflammatory response. Respecting the facts that significant cellular damage may occur during the post arrest period, and that damage might be reduced by mild therapeutic hypothermia, we investigated the prognostic value of cell free DNA at ICU admission and 24h after admission. A prospective study was conducted in three university associated intensive care units and included patients resuscitated from non-traumatic out-of hospital cardiac arrest. Patient data were collected in accordance with the Utstein protocol. Therapeutic hypothermia was performed according to ICU policies. Blood for cell-free DNA quantification was sampled at admission and at 24+/-1h after admission. Outcome measures were hospital morality and cerebral performance expressed with CPC scale at discharge. Inclusion criteria were met in 67 patients; 24-h mortality was 37.3% and hospital mortality was 71.6%. The following variables were associated with 24-h mortality in univariate analysis: asystole as the presenting rhythm, "no-flow" time, "low-flow" time and cell-free DNA at admission (median 0.081 in survivors vs. 0.160ng/MUl in non-survivors; P=0.038). Multivariate analysis that included the above variables showed that no flow time and low-flow time were independently associated with 24-h mortality. Hospital mortality was associated with the following factors: "low flow" time, coronary intervention, cell-free DNA at ICU admission and at 24h after admission (0.042 vs. 0.188ng/MUl; P=0.048). ROC curve for cell-free DNA 24h post-admission showed sensitivity of 81.0% and specificity of 78.3% for the cut-off value of 0.115ng/MUl. Multivariate analysis showed that "low-flow" time and cell-free DNA at 24h after ICU admission were independently associated with hospital mortality. Cell free DNA showed different dynamics in patients who were and who were not treated with mild therapeutic hypothermia: it decreased in treated patients and slightly increased in non-treated patients. Cell-free DNA quantity at ICU admission and 24h after admission is associated with hospital mortality. Further studies will need to additionally investigate possible practical use of this new laboratory marker in patients resuscitated from cardiac arrest. PMID- 24145039 TI - Misregulation of pre-mRNA alternative splicing in cancer. AB - Alternative splicing of mRNA precursors enables one gene to produce multiple protein isoforms with differing functions. Under normal conditions, this mechanism is tightly regulated in order for the human genome to generate proteomic diversity sufficient for the functional requirements of complex tissues. When deregulated, however, cancer cells take advantage of this mechanism to produce aberrant proteins with added, deleted, or altered functional domains that contribute to tumorigenesis. Here, we discuss aspects of alternative splicing misregulation in cancer, focusing on splicing events affected by deregulation of regulatory splicing factors and also recent studies identifying mutated components of the splicing machinery. SIGNIFICANCE: An increasing body of evidence indicates that aberrant splicing of mRNA precursors leads to production of aberrant proteins that contribute to tumorigenesis. Recent studies show that alterations in cellular concentrations of regulatory splicing factors and mutations in components of the core splicing machinery provide major mechanisms of misregulation of mRNA splicing in cancer. A better understanding of this misregulation will potentially reveal a group of novel drug targets for therapeutic intervention. PMID- 24145041 TI - An observational study of paediatric pre-hospital intubation and anaesthesia in 1933 children attended by a physician-led, pre-hospital trauma service. AB - INTRODUCTION: Trauma accounts for 16-44% of childhood deaths. The number of severely injured children who require pre-hospital advanced airway intervention is thought to be small but there is little published data detailing the epidemiology of these interventions. This study was designed to evaluate the children who received pre-hospital intubation (with or without anaesthesia) in a high volume, physician-led, pre-hospital trauma service and the circumstances surrounding the intervention. METHODS: We conducted a 12 year retrospective database analysis of paediatric patients attended by a United Kingdom, physician led, pre-hospital trauma service. All paediatric patients (<16 years of age) that were attended and received pre-hospital advanced airway intervention were included. The total number of pre-hospital intubations and the proportion that received a rapid sequence induction (RSI) were established. To illustrate the context of these interventions the ages, injury mechanisms and intervention success rates were recorded. RESULTS: Between 1 January 2000 and 31 October 2011 the service attended 1933 children. There were 315 (16.3%) pre-hospital intubations. Of those intubated, 81% received a rapid sequence induction and 19% were intubated without anaesthesia in the setting of near or actual cardiac arrest. Nearly three quarters of the patients were in the age range of 6-15 years with only 3 patients under the age of 1 year. The most common injury mechanisms that required intubation were Road Traffic Crashes (RTC) and 'falls from height'. These accounted for 79% of patients receiving intubation. Intubation success rate was 99.7% with a single failed intubation during the study period. CONCLUSION: Pre-hospital paediatric intubation is not infrequent in this high-volume trauma service. The majority of patients received a rapid sequence induction. The commonest injury mechanisms were RTCs and 'falls from height'. Pre-hospital paediatric intubation is associated with a high success rate in this physician led service. PMID- 24145042 TI - Clinical and economic assessment of diabetic foot ulcer debridement with collagenase: results of a randomized controlled study. AB - BACKGROUND: Despite significant advances, the treatment of diabetic foot ulcers (DFUs) remains a major therapeutic challenge for clinicians, surgeons, and other health care professionals. There is an urgent need for new strategies with clinically effective interventions to treat DFUs to reduce the burden of care in an efficient and cost-effective way. OBJECTIVE: This randomized trial evaluated and compared the clinical effectiveness, tolerability, and costs of clostridial collagenase ointment (CCO) debridement to that of debridement using saline moistened gauze (SMG) and selective sharp debridement for the treatment of DFUs. METHODS: Randomized, controlled, parallel group, multicenter, open-label, 12-week study of 48 patients with neuropathic DFUs randomized to 4 weeks of treatment with either CCO or SMG after baseline surgical debridement. The primary end point was the condition of the ulcer bed at the end of treatment as measured using a standardized wound assessment tool. Secondary end points were the percentage of reduction in wound area and therapeutic response rates. Adverse events were monitored for the tolerability analysis. In addition, a comparative cost effectiveness analysis was performed from the perspective of the Centers for Medicare and Medicaid Services as a payer. RESULTS: Both the CCO and SMG groups had significantly improved wound assessment scores after 4 weeks of treatment (CCO, -2.5, P = 0.007; SMG, -3.4, P = 0.006). Only CCO treatment resulted in a statistically significant decrease from baseline in the mean wound area at the end of treatment (P = 0.0164) and at the end of follow-up (P = 0.012). In addition, the CCO group exhibited a significantly better response rate at the end of follow-up compared with the SMG group (0.92 vs 0.75, P < 0.05). Reported adverse events were similar between the 2 treatment groups. None of the reported adverse events were considered to be related to treatment. The economic analysis indicated that the direct mean costs per responder in the physician office setting of care were $832 versus $1042 for the CCO group versus the SMG group, whereas the direct mean costs per responder in the hospital outpatient department setting were $1607 versus $1980. CONCLUSIONS: CCO treatment provides equivalent debridement of DFUs similar to SMG while fostering better progress toward healing as measured by decreasing wound area over time and improved response rates at the end of follow-up. In addition, CCO yields a more favorable cost-effectiveness ratio in both the physician office and hospital outpatient department settings of care. ClinicalTrials.gov identifier: NCT01056198. PMID- 24145043 TI - Pain as the fifth vital sign: exposing the vital need for pain education. AB - The push to evaluate pain in patients as exemplified by the fifth vital sign has exposed serious deficits in practitioner education and training in pain assessment and management because patient report of pain level has become commonplace in clinical practice. The rapid increase in prescription opioid medications suggests that practitioners are trying to address their patients' pain by prescribing opioids. However, the increase in prescription opioids has also been associated with an increase in prescription opioid-related unintended deaths. In clinical practice, the fifth vital sign has proven to be more complex to assess, evaluate, and manage than originally anticipated. Expanding pain education and training is critical to remedying some of the issues the routine report of pain by patients has uncovered. PMID- 24145045 TI - The effect of a short bout of practice on reaching behavior in late preterm infants at the onset of reaching: a randomized controlled trial. AB - The purpose of this study was to examine the effects of a short bout of practice on reaching behavior in late preterm infants at the onset of goal-directed reaching. The study was designed as a blind, three-arm parallel-group, randomized controlled, clinical trial. Thirty-six late preterm infants were recruited from a maternity hospital and allocated according to computer generated randomization into groups that received reaching practice based on either a blocked schedule, a serial schedule, or no practice. Practice consisted of a 4 min session of induced reaching using a toy in three activities guided by a physical therapist. The activities were elicited in separate blocks for the blocked practice group and in a pre-established order for the serial practice group. The control group stayed in the physical therapist's lap but was not stimulated to reach. The infants were assessed 3.3+/-1.4 days after the onset of goal-directed reaching in three tests: pre-test (immediately before practice), post-test (immediately after practice), and retention test (24 h after post-test). During assessments, the infants were seated in a baby chair and a toy was presented at his/her midline within reaching distance for 2 min. Changes in the number of reaches, proportions of uni/bimanual reaches and kinematic parameters of reaching were main outcome measures. From pre to post-test, the amount of reaches and bimanual reaches increased in the serial practice group, but the increase was not maintained in the retention test. Kinematic parameters were not affected by practice. Changes in the reaching behavior of late preterm infants can be triggered after the first few minutes of toy-oriented experience based on a serial practice schedule. These changes are not consolidated one day later. PMID- 24145044 TI - Longitudinal use of complementary and alternative medicine among older adults with radiographic knee osteoarthritis. AB - BACKGROUND: Osteoarthritis (OA), a chronic and often painful disease for which there is no cure, accounts for more mobility issues in older adults than any other disease. Cross-sectional studies have found that arthritis is the most common reason for older adults to use complementary and alternative medicine (CAM). Although previous research has profiled the sociodemographic and clinical characteristics of CAM users, few studies have provided information on variation in CAM use over time and most only considered use of any CAM, which was often a mixture of heterogeneous therapies. OBJECTIVES: This study sought to describe the longitudinal patterns of CAM use among older adults with knee OA and to identify correlates and predictors of different commonly used CAM therapies. METHODS: The Osteoarthritis Initiative included 1121 adults aged >=65 years with radiographic tibiofemoral OA in one or both knees at baseline. Annual surveys captured current use of conventional therapies and 25 CAM modalities (grouped into 6 categories) for joint pain or arthritis at baseline and during the 4-year follow-up. We assessed longitudinal use of CAM modalities by summing the number of visits with participants reporting use of each modality. Correlates of CAM use under consideration included sociodemographic indicators, body mass index, overall measures of mental and physical well-being, and clinical indices of knee OA. Generalized estimation equations provided adjusted odds ratio estimates and 95% CIs. RESULTS: Nearly one-third of older adults reported using >=1 CAM modality for treating OA at all assessments. With the exception of glucosamine and chondroitin (18%), few were persistent users of other CAM modalities. One in 5 of those using nonsteroidal anti-inflammatory drugs or glucosamine and/or chondroitin were using them concurrently. Adjusted models revealed the following: (1) adults aged >=75 years were less likely to use dietary supplements than those between ages 65 and 75 years; (2) persons with more severe knee pain or stiffness reported more CAM use; (3) better knee-related physical function was correlated with more use of chiropractic care or massage; and (4) older adults with more comorbidities were less likely to report use of dietary supplements. CONCLUSION: Patterns of CAM use are, to some extent, inconsistent with current guidelines for OA treatment. Evaluating the potential risks and benefits in older adults from commonly used CAM modalities, with or without combination use of conventional analgesics, is warranted. PMID- 24145046 TI - The effects of an exercise training program on hand and wrist strength, and function, and activities of daily living, in adults with severe cerebral palsy. AB - The purpose of the current study was to establish measurement reliability in adults with Cerebral Palsy (CP), and to examine the feasibility and outcomes of an upper extremity strength training program (three times per week for 90 min each time). A control group design mixed with a prospective time series design for the intervention group was completed, including a pre-test, a post-test after a 12-week intervention period, and a follow-up in the intervention group after an additional 10-week period. Seventeen adults with CP with severe motor impairment took part in the study (10 in the intervention and seven in the control group). The test battery was comprised of wrist and hand dynamometry; dominant hand upper extremity function measures (Jebsen Hand Function Test=JHFT, Minnesota Manual Dexterity Test=MMDT, and the Nine Hole Peg Test=NHPT); and activity of daily living with the Barthel Index. The results indicated that in both the control and the intervention groups, the strength tests exhibited good-to-excellent reliability during pre-test and post-test. The group comparison revealed that while in the pre-test no between-group differences existed, in the post-test the strength training group demonstrated significantly higher values in five out of eight strength measures, as well as in the MMDT. Discontinuing the program for eight weeks reversed the effects almost to baseline. In conclusion, the outcomes demonstrated the reliability of the assessments utilized in this study, as well as the feasibility of the strength training program, in adults with severe motor impairment due to CP. PMID- 24145047 TI - High fat diet and body weight have different effects on cannabinoid CB(1) receptor expression in rat nodose ganglia. AB - Energy balance is regulated, in part, by the orexigenic signaling pathways of the vagus nerve. Fasting-induced modifications in the expression of orexigenic signaling systems have been observed in vagal afferents of lean animals. Altered basal cannabinoid (CB1) receptor expression in the nodose ganglia in obesity has been reported. Whether altered body weight or a high fat diet modifies independent or additive changes in CB1 expression is unknown. We investigated the expression of CB1 and orexin 1 receptor (OX-1R) in the nodose ganglia of rats fed ad libitum or food deprived (24h), maintained on low or high fat diets (HFD), with differing body weights. Male Wistar rats were fed chow or HFD (diet-induced obese: DIO or diet-resistant: DR) or were body weight matched to the DR group but fed chow (wmDR). CB1 and OX-1R immunoreactivity were investigated and CB1 mRNA density was determined using in situ hybridization. CB1 immunoreactivity was measured in fasted rats after sulfated cholecystokinin octapeptide (CCK8s) administration. In chow rats, fasting did not modify the level of CB1 mRNA. More CB1 immunoreactive cells were measured in fed DIO, DR and wmDR rats than chow rats; levels increased after fasting in chow and wmDR rats but not in DIO or DR rats. In HFD fasted rats CCK8s did not reduce CB1 immunoreactivity. OX-1R immunoreactivity was modified by fasting only in DR rats. These data suggest that body weight contributes to the proportion of neurons expressing CB1 immunoreactivity in the nodose ganglion, while HFD blunts fasting-induced increases, and CCK-induced suppression of, CB1-immunoreactivity. PMID- 24145048 TI - Firing patterns of muscle sympathetic neurons during apnea in chronic heart failure patients and healthy controls. AB - In the present study we investigated the influence of end-expiratory breathing cessation on firing activity of muscle sympathetic fibers in 6 stable chronic heart failure (CHF) patients and in 6 healthy age and gender matched controls. Integrated multi-unit bursts, as well as action potentials (APs), were identified from multi-unit muscle sympathetic nerve activity (MSNA) recordings during baseline and during functional residual capacity (FRC) apnea. Compared with controls, CHF patients had higher burst frequency and AP firing frequency (P<0.05) at baseline. FRC apnea caused an increase in the number of APs per multi unit sympathetic burst, in the AP frequency (P<0.05) and in the number of active clusters per multi-unit sympathetic burst in both groups (controls P<0.06, CHF group P=0.1). The data suggest a comparable pattern of sympathetic activation associated with breath hold in healthy middle-aged individuals and in stable CHF patients. Thus, recruitment patterns for this stress are not affected by CHF despite their elevated sympathetic state. PMID- 24145049 TI - Afferent and efferent immunological pathways of the brain. Anatomy, function and failure. AB - Immunological privilege appears to be a product of unique lymphatic drainage systems for the brain and receptor-mediated entry of inflammatory cells through the blood-brain barrier. Most organs of the body have well-defined lymphatic vessels that carry extracellular fluid, antigen presenting cells, lymphocytes, neoplastic cells and even bacteria to regional lymph nodes. The brain has no such conventional lymphatics, but has perivascular pathways that drain interstitial fluid (ISF) from brain parenchyma and cerebrospinal fluid (CSF) from the subarachnoid space to cervical lymph nodes. ISF and solutes drain along narrow, ~100 nm-thick basement membranes within the walls of cerebral capillaries and arteries to cervical lymph nodes; this pathway does not allow traffic of lymphocytes or antigen presenting cells from brain to lymph nodes. Although CSF drains into blood through arachnoid villi, CSF also drains from the subarachnoid space through channels in the cribriform plate of the ethmoid bone into nasal lymphatics and thence to cervical lymph nodes. This pathway does allow the traffic of lymphocytes and antigen presenting cells from CSF to cervical lymph nodes. Efferent pathways by which lymphocytes enter the brain are regulated by selected integrins on lymphocytes and selective receptors on vascular endothelial cells. Here we review: (1) the structure and function of afferent lymphatic drainage of ISF and CSF, (2) mechanisms involved in the efferent pathways by which lymphocytes enter the brain and (3) the failure of lymphatic drainage of the brain parenchyma with age and the role of such failure in the pathogenesis of Alzheimer's disease. PMID- 24145050 TI - Cell-autonomous iodothyronine deiodinase expression mediates seasonal plasticity in immune function. AB - Annual rhythms in morbidity and mortality are well-documented, and host defense mechanisms undergo marked seasonal phenotypic change. Siberian hamsters (Phodopus sungorus) exhibit striking immunological plasticity following adaptation to short winter day lengths (SD), including increases in blood leukocytes and in the magnitude of T cell-mediated immune responses. Thyroid hormone (TH) signaling is rate-limited by tissue-level expression of iodothyronine deiodinase types II and III (dio2, dio3), and dio2/dio3 expression in the central nervous system gate TH dependent transduction of photoperiod information into the neuroendocrine system. THs are also potent immunomodulators, but their role in seasonal immunobiology remains unexamined. Here we report that photoperiod-driven changes in triiodothyronine (T3) signaling mediate seasonal changes in multiple aspects of immune function. Transfer from long days (LD) to SD inhibited leukocyte dio3 expression, which increased cellular T4->T3 catabolism. T3 was preferentially localized in the lymphocyte cytoplasm, consistent with a non-nuclear role of T3 in lymphoid cell differentiation and maturation. Exposure to SD upregulated leukocyte DNA methyltransferase expression and markedly increased DNA methylation in the dio3 proximal promoter region. Lastly, to bypass low endogenous T3 biosynthesis in LD lymphocytes, LD hamsters were treated with T3, which enhanced T cell-dependent delayed-type hypersensitivity inflammatory responses and blood leukocyte concentrations in a dose-dependent manner, mimicking effects of SD on these immunophenotypes. T3 signaling represents a novel mechanism by which environmental day length cues impact the immune system: changes in day length alter lymphoid cell T3-signaling via epigenetic transcriptional control of dio3 expression. PMID- 24145052 TI - Paraoxonase and arylesterase activity and total oxidative/anti-oxidative status in patients with idiopathic Parkinson's disease. AB - This study investigated serum paraoxonase (PON1) and arylesterase activity along with determination of oxidative status via measurement of total oxidant status (TOS), total anti-oxidant status (TAS) and oxidative stress index (OSI) in patients with Parkinson's disease (PD) and compared results with data from healthy controls. A total of 82 subjects, including 42 patients with idiopathic PD, newly diagnosed and untreated (24 men, 18 women, aged 47-66 years) and 40 healthy controls were enrolled in this study. We aimed to evaluate the oxidative status of PD patients via measurement of serum TOS and TAS and estimation of OSI using new automated methods. PON1 and arylesterase activities were measured spectrophotometrically. Serum total cholesterol, high density lipoprotein cholesterol, low density lipoprotein (LDL) cholesterol and triglyceride levels were measured using routine methods. TAS levels of PD patients were significantly lower than that of controls (p<0.05). TOS levels of PD patients were higher than those of controls (p<0.05). PON1 and arylesterase activities of PD were lower than those of controls (p<0.05). Serum levels of total and LDL cholesterol were significantly reduced in PD patients. In conclusion, the presence of high TOS and OSI levels together with low levels of TAS in PD patients supports the important role of oxidative stress in the pathophysiology of PD. Since oxidative stress is involved in neurodegeneration, selecting anti-oxidants, metal chelators or other compounds boosting endogenous enzymatic and non-enzymatic defense mechanisms seems to be an obvious choice as treatment for PD. PMID- 24145051 TI - Toll-like receptors 2 and 4 modulate autonomic control of heart rate and energy metabolism. AB - Toll-like receptors (TLR) are innate immune receptors typically activated by microbial-associated molecular patterns (MAMPs) during infection or damage associated molecular patterns (DAMPs) as a result of tissue injury. Recent findings suggest that TLR2 and TLR4 signaling play important roles in developmental and adult neuroplasticity, and in learning and memory. In addition, activation of TLR2 and TLR4 worsens ischemic injury to the heart and brain in animal models of myocardial infarction and stroke. TLR activation is also implicated in thermoregulation and fever in response to infection. However, it is not known whether TLRs participate in the regulation of the sympathetic and/or parasympathetic components of the autonomic nervous system (ANS). Here we provide evidence that TLR2 and TLR4 influence autonomic regulation of heart rate (HR) body temperature and energy metabolism in mice. We show that mice lacking TLR2 or TLR4 exhibit reduced basal HR, which results from an increase of parasympathetic tone. In addition, thermoregulatory responses to stress are altered in TLR2-/- and TLR4-/- mice, and brown fat-dependent thermoregulation is altered in TLR4-/- mice. Moreover, TLR2-/- and TLR4-/- mice consume less food and exhibit a greater mass compared to wild type mice. Collectively, our findings suggest important roles for TLR2 and TLR4 in the ANS regulation of cardiovascular function, thermoregulation, and energy metabolism. PMID- 24145053 TI - A replication study of 19 GWAS-validated type 2 diabetes at-risk variants in the Lebanese population. AB - AIM: Recent genome-wide association scans (GWAS) and replication studies have expanded the list of validated type 2 diabetes (T2DM) susceptibility loci. We replicated T2DM association of 19 SNPs from 15 candidate loci in Lebanese Arabs. METHODS: Case-control association study, comprising 995 T2DM patients and 1076 control participants. We genotyped by the allelic discrimination method 19 SNPs in/near ADAM30, NOTCH2, THADA, TMEFF2, COL8A1, ADAMTS9-AS2, WFS1, JAZF1, SLC30A8, KCNQ1, LOC387761, ALX4, TSPAN8, FTO, and HNF1. RESULTS: Allele frequencies of the tested SNPs were comparable with those of Caucasians. COL8A1 rs792837 (P=2.9 * 10(-9)), KCNQ1 rs2237892 (P=1.8 * 10(-18)) and rs2237895 (P=0.002), ALX4 rs729287 (Pc=7.5 * 10(-5)), and HNF1 rs4430796 (P=0.003) were significantly associated with T2DM, with similar effect sizes to those of Europeans. While FTO rs8050136 and rs17817449, ADAMTS9 rs4607103, and WFS1 rs10010131 were initially associated with T2DM, this was lost upon multiple testing correction. The remaining variants were not associated with T2DM, possibly resulting from insufficient power to detect smaller allele effects. CONCLUSION: In addition to previous findings on the association of IGF2BP2, CDKAL1, TCF7L2 variants with T2DM among Lebanese, here we extend these by validating the association of five additional loci with T2DM in Lebanese Arabs. PMID- 24145054 TI - Patient and professional delay in the referral trajectory of patients with diabetic foot ulcers. AB - AIMS: A cohort study investigated referral and treatment trajectories of patients with diabetic foot ulceration consulting podiatrists. The study aims were to quantify patient, professional and treatment (=total) delay and to identify relationships between patient- or professional-related characteristics, delays or ulcer healing time. METHODS: Ten podiatrists specialising in diabetes care included 54 consecutive adults with diabetic foot ulceration. Assessments were performed retrospectively (e.g. delays) and prospectively (12 weeks). RESULTS: Median (SD; range) patient delay was 3.0 days (50.6; 0-243), professional delay 7.0 days (63.4; 0-279) and treatment delay 20.5 days (97.3; 0-522). 57% of patients took >2 weeks before visiting a podiatrist. Ulcers healed in 67% of patients in 49.0 days (90.2; 4-408). The number of health care professionals in the referral trajectory was positively related to treatment delay (p<0.01) and to ulcer healing time (p<0.01). Professional delay and treatment delay was positively correlated with the duration of the podiatric treatment (p<0.05). Patient awareness of ulceration risk tended to decrease the healing time. CONCLUSIONS: Patients with diabetic foot ulcers presented small median delays in the referral trajectory to podiatrists specialising in diabetes. The study results suggest that reducing the number of health care professionals in the referral trajectory might decrease treatment delay and ulcer healing time. Also improving patient awareness of ulceration risk might be beneficial for the healing time. PMID- 24145056 TI - Multisite monitoring of choline using biosensor microprobe arrays in combination with CMOS circuitry. AB - A miniature device enabling parallel in vivo detection of the neurotransmitter choline in multiple brain regions of freely behaving rodents is presented. This is achieved by combining a biosensor microprobe array with a custom-developed CMOS chip. Each silicon microprobe comprises multiple platinum electrodes that are coated with an enzymatic membrane and a permselective layer for selective detection of choline. The biosensors, based on the principle of amperometric detection, exhibit a sensitivity of 157+/-35 uA mM(-1) cm(-2), a limit of detection of below 1 uM, and a response time in the range of 1 s. With on-chip digitalization and multiplexing, parallel recordings can be performed at a high signal-to-noise ratio with minimal space requirements and with substantial reduction of external signal interference. The layout of the integrated circuitry allows for versatile configuration of the current range and can, therefore, also be used for functionalization of the electrodes before use. The result is a compact, highly integrated system, very convenient for on-site measurements. PMID- 24145055 TI - Transcriptional regulation and alternative splicing cooperate in muscle fiber type specification in flies and mammals. AB - Muscles coordinate body movements throughout the animal kingdom. Each skeletal muscle is built of large, multi-nucleated cells, called myofibers, which are classified into several functionally distinct types. The typical fiber-type composition of each muscle arises during development, and in mammals is extensively adjusted in response to postnatal exercise. Understanding how functionally distinct muscle fiber-types arise is important for unraveling the molecular basis of diseases from cardiomyopathies to muscular dystrophies. In this review, we focus on recent advances in Drosophila and mammals in understanding how muscle fiber-type specification is controlled by the regulation of transcription and alternative splicing. We illustrate the cooperation of general myogenic transcription factors with muscle fiber-type specific transcriptional regulators as a basic principle for fiber-type specification, which is conserved from flies to mammals. We also examine how regulated alternative splicing of sarcomeric proteins in both flies and mammals can directly instruct the physiological and biophysical differences between fiber types. Thus, research in Drosophila can provide important mechanistic insight into muscle fiber specification, which is relevant to homologous processes in mammals and to the pathology of muscle diseases. PMID- 24145057 TI - Cytochrome P450 genetic polymorphisms of Mexican indigenous populations. AB - This review focuses on the genetic polymorphisms of the cytochrome P450 (CYP) genes in Mexican indigenous populations, who are a part of the wide ethnic diversity of this country. These native groups have a particular historical trajectory that is different from the Mexican Mestizos. This variability may be reflected in the frequency distribution of polymorphisms in the CYP genes that encode enzymes involved in the metabolism of drugs and other xenobiotics. Therefore, these polymorphisms may affect drug efficacy and safety in indigenous populations in Mexico. The present study aimed to analyze the prevalence of CYP polymorphisms in indigenous Mexicans and to compare the results with studies in Mexican Mestizos. Because the extrapolation of pharmacogenetic data from Mestizos is not applicable to the majority of indigenous groups, pharmacogenetic studies directed at indigenous populations need to be developed. The Amerindians analyzed in this study showed a low phenotypic (CYP2D6) and genotypic (CYP2D6, CYP2C9) diversity, unlike Mexican Mestizos. The frequency of polymorphisms in the CYP1A1, CYP2C19, CYP2E1, and CYP3A4 genes was more similar among the Amerindians and Mexican Mestizos, with the exception of the CYP1A2 gene, whose *1F variant frequency in Mexican Amerindians was the highest described to date. PMID- 24145058 TI - Diagnostic inconsistency of faecal immunochemical tests for haemoglobin in population screening of colorectal cancer. AB - BACKGROUND: There is currently very little data available on the consistency of quantitative and qualitative faecal immunochemical test (FIT) for colorectal cancer screening. METHODS: A representative random population (n=1889, 40-74 year olds) in Jiashan, China was invited for FIT screening in 2012. Faecal samples were collected by a single specimen collection device and simultaneously tested by a quantitative FIT (OC-SENSOR, OC) and two qualitative FITs (FIT A and FIT B with intrinsic positive haemoglobin cut-off concentrations of 20 MUg Hb/g faeces and 40 MUg Hb/g faeces, respectively). The observational criteria for a positive result of the qualitative FIT were set according to the density of the colour appearing in the test strip. The results produced by the quantitative and qualitative FIT for each sample were compared. kappa coefficient was used to measure consistency. RESULTS: A total of 1368 (72.4%) individuals returned faecal samples. Both FIT A and FIT B precisely identified all faecal samples with haemoglobin concentration above 100 MUg Hb/g faeces, but the overall consistency was poor for OC & FIT A (kappa=0.32, 95% CI 0.20-0.44) and was moderate for OC & FIT B (kappa=0.74, 95% CI 0.64-0.85). A more favourable consistency (kappa=0.64, 95% CI 0.57-0.72) was achieved when a different positive criterion was employed for FIT A. CONCLUSIONS: The diagnostic inconsistency between quantitative and qualitative FITs mainly exists in the faecal samples with low haemoglobin concentrations. Refining the criterion for a positive result may be a feasible way to improve the accuracy of qualitative FIT. PMID- 24145060 TI - Sticklebacks as model hosts in ecological and evolutionary parasitology. AB - The three-spined stickleback is a small teleost fish, native to coastal regions of the Northern Hemisphere, which has emerged as a key model organism in evolutionary biology and ecology. Sticklebacks possess a well-documented and experimentally amenable parasite fauna, and are well suited to both laboratory and field parasitological investigation. As a consequence, sticklebacks have been extensively used as model hosts in studies of host-parasite interactions, and these studies have provided considerable insight into the roles of parasites in ecology and evolutionary biology. In this review, I discuss key advances in our understanding of host-parasite interactions that have arisen from studies involving stickleback hosts, highlight areas of current research activity, and identify potentially promising areas for future research. PMID- 24145059 TI - Arsenic augments the uptake of oxidized LDL by upregulating the expression of lectin-like oxidized LDL receptor in mouse aortic endothelial cells. AB - Although chronic arsenic exposure is a well-known risk factor for cardiovascular diseases, including atherosclerosis, the molecular mechanism underlying arsenic induced atherosclerosis remains obscure. Therefore, this study aimed to elucidate this molecular mechanism. We examined changes in the mRNA level of the lectin like oxidized LDL (oxLDL) receptor (LOX-1) in a mouse aortic endothelial cell line, END-D, after sodium arsenite (SA) treatment. SA treatment significantly upregulated LOX-1 mRNA expression; this finding was also verified at the protein expression level. Flow cytometry and fluorescence microscopy analyses showed that the cellular uptake of fluorescence (Dil)-labeled oxLDL was significantly augmented with SA treatment. In addition, an anti-LOX-1 antibody completely abrogated the augmented uptake of Dil-oxLDL. We observed that SA increased the levels of the phosphorylated forms of nuclear factor of kappa light polypeptide gene enhancer in B cells (NF-kappaB)/p65. SA-induced upregulation of LOX-1 protein expression was clearly prevented by treatment with an antioxidant, N acetylcysteine (NAC), or an NF-kappaB inhibitor, caffeic acid phenethylester (CAPE). Furthermore, SA-augmented uptake of Dil-oxLDL was also prevented by treatment with NAC or CAPE. Taken together, our results indicate that arsenic upregulates LOX-1 expression through the reactive oxygen species-mediated NF kappaB signaling pathway, followed by augmented cellular oxLDL uptake, thus highlighting a critical role of the aberrant LOX-1 signaling pathway in the pathogenesis of arsenic-induced atherosclerosis. PMID- 24145061 TI - Control of cysticercosis in Madagascar: beware of the pitfalls. AB - Taenia solium cysticercosis is a zoonosis of public health importance in areas where the disease is endemic, with significant economic impacts on human health and the swine industry. Several gaps remain in the epidemiology of the parasite and the strategies of control in developing countries. We detail the key factors to consider in Madagascar in terms of the porcine husbandry system, Taenia transmission cycle, and diagnosis of cysticercosis in pigs, in order to better estimate the sanitary and economic impacts of this parasitic disease as well as to define an integrated control program. PMID- 24145062 TI - Psychiatrists, criminals, and the law: forensic psychiatry in Switzerland 1850 1950. AB - Between 1880 and 1950, Swiss psychiatrists established themselves as experts in criminal courts. In this period, the judicial authorities required psychiatric testimonies in a rising number of cases. As a result, more offenders than ever before were declared mentally deficient and, eventually, sent to psychiatric asylums. Psychiatrists also enhanced their authority as experts at the political level. From the very beginning, they got involved in the preparatory works for a nationwide criminal code. In this article, I argue that these trends toward medicalization of crime were due to incremental processes, rather than spectacular institutional changes. In fact, Swiss psychiatrists gained recognition as experts due to their daily interactions with judges, public prosecutors, and legal counsels. At the same time, the spread of medical expertise had serious repercussions on psychiatric institutions. From 1942 onwards, asylums had to deal with a growing number of "criminal psychopaths," which affected ward discipline and put psychiatry's therapeutic efficiency into question. The defensive way in which Swiss psychiatrists reacted to this predicament was crucial to the further development of forensic psychiatry. For the most part, it accounts for the subdiscipline's remarkable lack of specialization until the 1990s. PMID- 24145063 TI - Premises and evidence in the rhetoric of assisted suicide and euthanasia. AB - In debates about euthanasia and assisted suicide, it is rare to find an article that begins with an expression of neutral interest and then proceeds to examine the various arguments and data before drawing conclusions based upon the results of a scholarly investigation. Although authors frequently give the impression of being impartial in their introduction, they invariably reach their prior conclusions. Positions tend to be clearly dichotomized: either one believes that the practice of euthanasia or assisted suicide is totally acceptable or completely unacceptable in a just and moral society. Where there is some admission of a gray zone of incertitude, authors attempt to persuade us that their beliefs (preferences) are the only sensible way to resolve outstanding dilemmas. The practice of vehemently promoting a "pro" or "con" position may be useful when societies must decide to either legalize certain practices or not. Although only a handful of countries have thus far accepted the legal practice of euthanasia or assisted suicide (Belgium, Luxembourg, The Netherlands, the U.S. states of Montana, Oregon, Vermont and Washington, and Switzerland), scholarly articles in recent trends mainly promote legalization, to the point of recommending expansion of the current practices. Is this a case of the philosophers being ahead of their time in promoting and rationalizing the wave of the future? Alternatively, does the small number of countries that have legalized these practices indicate a substantial gap between the beliefs and desires of common citizens and the universe of the 'abstracted realm'? For the time being, what we do know is that more countries and states are debating legalization of euthanasia or assisted suicide, the nature of laws and legal practices vary greatly and both ethical and empirical assessments of current practices are the subject of much controversy. This article presents an examination of the premises and evidence in the rhetoric of assisted suicide and euthanasia. Inasmuch as any analysis cannot be totally impartial, we do not contend that our analysis is without influence from our experiences and philosophical affinities. Notwithstanding this caveat, we venture to propose that our scrutiny of the arguments and empirical data may offer some guidance to individuals who are attempting to reach practical conclusions based upon the available evidence, whether empirical or rationalized. PMID- 24145064 TI - The irresponsible criminal in Norwegian medico-legal discourse. AB - This article discusses discourses on criminal responsibility in Norway in the 19th and 20th centuries, in light of Michel Foucault's regimes of power and knowledge: the apparatuses of law, discipline and security. The passing of two criminal codes, in 1842 and 1902 marks a development from neo-classical law to a law influenced by positivist criminology. In these consecutive ways of thinking law, the figure of the irresponsible criminal constituted a contentious issue. From being a figure marking the limits of the law, the irresponsible criminal became an object to be disciplined and a security threat. This redefinition of criminal responsibility created or was created by new groups of experts speaking from positions increasingly close to the criminals. The most important professional group was of course the psychiatrists, that emerged in Norway as a distinct professional group in the second half of the 19th century, and whose influence in the legislative process culminated in the 1920s. PMID- 24145065 TI - New water-soluble ruthenium(II) cytotoxic complex: biological activity and cellular distribution. AB - A novel water soluble organometallic compound, [RuCp(mTPPMSNa)(2,2' bipy)][CF3SO3] (TM85, where Cp=eta(5)-cyclopentadienyl, mTPPMS=diphenylphosphane benzene-3-sulfonate and 2,2'-bipy=2,2'-bipyridine) is presented herein. Studies of interactions with relevant proteins were performed to understand the behavior and mode of action of this complex in the biological environment. Electrochemical and fluorescence studies showed that TM85 strongly binds to albumin. Studies carried out to study the formation of TM85 which adducts with ubiquitin and cytochrome c were performed by electrospray ionization mass spectrometry (ESI MS). Antitumor activity was evaluated against a variety of human cancer cell lines, namely A2780, A2780cisR, MCF7, MDAMB231, HT29, PC3 and V79 non-tumorigenic cells and compared with the reference drug cisplatin. TM85 cytotoxic effect was reduced in the presence of endocytosis modulators at low temperatures, suggesting an energy-dependent mechanism consistent with endocytosis. Ultrastructural analysis by transmission electron microscopy (TEM) revealed that TM85 targets the endomembranar system disrupting the Golgi and also affects the mitochondria. Disruption of plasma membrane observed by flow cytometry could lead to cellular damage and cell death. On the whole, the biological activity evaluated herein combined with the water solubility property suggests that complex TM85 could be a promising anticancer agent. PMID- 24145066 TI - Dual topoisomerase I and II poisoning by chiral Ru(II) complexes containing 2 thiophenylimidazo[4,5-f][1,10]phenanthroline derivatives. AB - A series of chiral Ru(II) complexes bearing thiophene ligands were synthesized and characterized. Both Ru(II) complexes Delta/Lambda-[Ru(bpy)2(pscl)](2+) (Delta/Lambda-1) and Delta/Lambda-[Ru(bpy)2(psbr)](2+) (Delta/Lambda-2) (bpy=2,2' bipyridine, pscl=2-(5-chlorothiophen-2-yl)imidazo[4,5-f][1,10]phenanthroline, psbr=2-(5-bromothiophen-2-yl)imidazo[4,5-f][1,10]phenanthroline) showed antitumor activities against A549, HepG2 and BEL-7402 tumor cell lines, especially HeLa tumor cell line. Moreover, Delta enantiomers were more active than Lambda enantiomers, accounting for the different cellular uptake. In addition, with the extension of time, these enantiomers could finally accumulate in the nucleus, suggesting that nucleic acids were the cellular target of these enantiomers. The DNA-binding behaviors of complexes were studied using spectroscopic and viscosity measurements. Results suggested that four complexes could bind to DNA in an intercalative mode but no obvious DNA-binding selectivity between the enantiomers was observed. Topoisomerase inhibition and DNA religation assay confirmed that four complexes acted as efficient dual topoisomerase I and II poisons, DNA strand breaks had also been observed from alkaline single cell gel electrophoresis (comet assay). Delta-1 and Delta-2 inhibited the growth of HeLa cells through the induction of apoptotic cell death, as evidenced by the Alexa Fluor(r) 488 annexin V staining assays and flow cytometry analysis. The results demonstrated that Delta/Lambda-1 and Delta/Lambda-2 acted as dual topoisomerase I and II poisons and caused DNA damage that could lead to cell cycle arrest by apoptosis. PMID- 24145068 TI - A prospective randomised study comparing rotating platform and fixed bearing total knee arthroplasty in a cruciate substituting design--outcomes at two year follow-up. AB - BACKGROUND: Fixed bearing (FB) total knee replacement is a well established technique against which new techniques must be compared. Mobile bearing (MB) prostheses, in theory, reduce polyethylene wear but the literature is yet to provide evidence that they are superior in terms of function or long-term survivorship. In addition there has been no comparison of patella resurfacing on the outcome of either design. The aims of this randomised prospective study were firstly to determine whether a mobile bearing prosthesis produced better clinical outcome and range of motion at two year follow-up and secondly to assess the effect of patella resurfacing on the outcomes of both types of bearing design. METHODS: Three hundred fifty-two patients were randomised into receiving either a PFC Sigma(c) cruciate sacrificing total knee arthroplasty either with a mobile bearing or a fixed bearing, with a sub-randomisation to either patella resurfacing or patella retention. All patients participated with standard clinical outcome measures and had their range of motion measured both pre operatively and at follow-up. RESULTS: The mobile bearing TKR design had no impact on range of motion; Oxford Knee Score and American Knee Society knee and function scores when compared to its fixed bearing equivalent. CONCLUSIONS: At two year follow-up there was no difference between the PFC Sigma(c) fixed and mobile bearing designs. With no clinical difference between the cohorts, we cannot recommend one design over the other. Long term benefits, particularly with regards to polyethylene wear, may yet be demonstrated. Level of evidence--1B. PMID- 24145067 TI - ENaC gamma-expressing astrocytes in the circumventricular organs, white matter, and ventral medullary surface: sites for Na+ regulation by glial cells. AB - Using a double immunofluorescence procedure, we report the discovery of a novel group of fibrous astrocytes that co-express epithelial sodium channel (ENaC) gamma-subunit protein along with glial acidic fibrillary protein (GFAP). These cells are concentrated along the borders of the sensory circumventricular organs (CVOs), embedded in the white matter (e.g., optic nerve/chiasm, anterior commissure, corpus callosum, pyramidal tract) and are components of the pia mater. In the CVOs, a compact collection of ENaC gamma-immunoreactive glial fibers form the lamina terminalis immediately rostral to the organum vasculosum of the lamina terminalis (OVLT). Astrocyte processes can be traced into the median preoptic nucleus - a region implicated in regulation of sodium homeostasis. In the subfornical organ (SFO), ENaC gamma-GFAP astrocytes lie in its lateral border, but not in the ventromedial core. In the area postrema (AP), a dense ENaC gamma-GFAP glial fibers form the interface between the AP and nucleus tractus solitarius; this area is termed the subpostremal region. Antibodies against the ENaC alpha- or beta-subunit proteins do not immunostain these regions. In contrast, the antibodies against the ENaC gamma-subunit protein react weakly with neuronal cell bodies in the CVOs. Besides affecting glial neural functions in the CVOs, the astrocytes found in the white matter may affect saltatory nerve conduction, serving as a sodium buffer. The ENaC gamma-expressing astrocytes of the ventral medulla send processes into the raphe pallidus which intermingle with the serotoninergic (5-HT) neurons found in this region as well as with the other nearby 5-HT neurons distributed along ventral medullary surface. PMID- 24145070 TI - Characterization of tradeoffs in biomolecular signaling. AB - Systems-level tradeoffs are fundamental in engineering, and recent work has highlighted an analogous role for them in biology. However, the extent of validity of these tradeoffs, especially for biomolecular systems, is generally unclear. Here, we address this issue for signaling tradeoffs that can constrain, for a fixed concentration of the signaling protein, a simultaneous enhancement of the gain and range of an amplifier or of the gain and threshold of a switch. We find that these gain-related tradeoffs persist in mathematical models of biomolecular reaction mechanisms that are at the core of large classes of signaling systems. Further, we find that these tradeoffs are also prevalent in the parametric functional forms commonly used to describe input-output curves in experimental analyses. Finally, we find that these tradeoffs can persist even in the presence of transcriptional feedback mechanisms that can change the concentration of the signaling protein. These results present a systematic characterization of these tradeoffs in biomolecular signaling systems. PMID- 24145069 TI - Role of DDL processes during electrolytic reduction of Cu(II) in a low oxygen environment. AB - Heavy metals typically accumulate in reduced bottom sediments after being discharged into waterways by industrial and municipal processes. A laboratory experiment was conducted in order to determine if abundance of clay in the bottom sediments of a Cu-contaminated aqueous ecosystem could enhance electrolytic reduction of the heavy metal. Cu(NO3)2 . 2.5H2O was added to simulate a moderately contaminated system with 650 MUg Cu/ml kaolinite clay-water slurry. A constant electrical potential of 1.0 V/cm was applied across platinum wire electrodes inserted into the continuously stirred system for four days while the system ORP(2) was monitored and periodic sub-samples were taken for analysis. The electrical as well as the chemical results indicate that the quantity of Cu(II) being reduced to Cu(I), especially within the aqueous phase, is increased within the first 48 h of experimentation by the presence of kaolinite clay up to 0.05 mg clay/l slurry. PMID- 24145071 TI - [Motivation and sociology of blood donors in Tunisia: reality and perspectives]. AB - In Tunisia, blood donation is voluntary, anonymous and non-remunerated. The aim of the study is to analyze donor motivation and sociology in the regional center of transfusion of Sfax. Between 14 May 2007 and 23 June 2007, a total of 903 Tunisian blood donors filled a questionnaire. Among the donors, 81.8% were men and have a mean age of 34.2 years and the majority of them have an age between 18 and 29 years. The middle social class was majority (77.8%) as well as the liberal profession (65.1%). Primary and secondary education were dominant (79.3%). Among the blood donors, 41.6% were new donors and 28.6% had a history of a single donation, 50.3% were voluntary and 49.7% replacement donors. The reasons motivating the voluntary donation were solidarity (69.9%), religion (21.2%), health benefit (3.6%) and insurance for the family (5.2%). The replacement donors refuse the voluntary donation for not obvious reasons (51%), lack of availability (13.3%), difficulties of accessibility of the sites of collection (7.6%), phobia of the blood and the stings (4.02%) or by refusal of blood donation (1.79%). The information and the raising awareness of the replacement donors could change in a near future their attitudes to become voluntary and regular donors. The implication of donor associations in the organization of the collections and the promotion of the blood donation would be of considerable contribution. PMID- 24145072 TI - Serotonin discovery and stepwise disclosure of 5-HT receptor complexity over four decades. Part I. General background and discovery of serotonin as a basis for 5 HT receptor identification. AB - This review contains background information on the serotonin system, furthermore the suggestion to introduce the term Contemporary Witness Report (CWR) for a novel type of review and, as the main part, an overview over the history of serotonin discovery as a basis for the identification of its receptor heterogeneity and the increase in complexity by genetic and allosteric variation. The present article conforms to CWRs in historical and autobiographical elements, in more emphasis on the author's work than in conventional reviews and in aspects neglected in previous reviews, but not in the main feature namely the work of a scientist with comprehensive expertise in a field in which, over long time, he/she continuously performed research and published. A scientist complying with these requirements is a contemporary witness in that field. His report on the scientific achievements in that period, a CWR, comprises confirmation and putative re-interpretation of data from a superior viewpoint. Identification of serotonin's vascular properties (publication year: 1912) as an "adrenaline mimicking substance" (without attempt to isolate it) by O'Connor preceded the discovery of serotonin in the gastrointestinal tract by Erspamer [1937] and in blood by Rapport [1948, 1949], who identified its structure as 5 hydroxytryptamine [1949]. Detection as a neurotransmitter in invertebrates suggested its occurrence in vertebrate CNS as well. This was verified by finding it in dog, rat and rabbit brain [1953]. The Falck-Hillarp technique [1962] visualized serotonin neurones as fluorescent structures. The neurotoxin 5,7 dihydroxytryptamine [1972] indirectly proved the involvement of 5-HT in multiple CNS functions. PMID- 24145073 TI - Research advances in basic mechanisms of seizures and antiepileptic drug action. AB - Epilepsy is a common neurological disease but the mechanism of seizure generation has been only partially unraveled. Furthermore, almost 30% of epileptic patients are resistant to pharmacological treatment. Therefore, elucidation of the basic mechanism of seizures and search for new antiepileptics in order to treat the drug-resistant form of epilepsy and to improve the efficacy of current therapies seem justified. The aim of this overview is a brief presentation of some new concepts and research directions in pathogenesis and pharmacotherapy of epilepsy. Development of ideas on the mechanisms of seizures and antiepileptic drugs reflects the progress in our understanding of the central nervous system physiology, particularly of neurotransmission. Hyperactivity of excitatory amino acid systems, insufficient GABAA receptor-mediated neurotransmission, and disturbances in intrinsic properties of neuronal membranes are still regarded as the most important mechanisms of seizures. New data add to the complexity of GABA glutamate interaction showing both excitatory and inhibitory role of GABA and glutamatergic neurons in the central nervous system. Moreover, besides synaptic NMDA and GABAA receptors, also extrasynaptic receptors for the amino acid transmitters have been recently implicated in the pathomechanism of epilepsy. Changes in expression, polymorphisms, lost- or gain-function mutations as well as cellular energetic imbalance can contribute to the disturbed function of the ligand- and voltage-dependent sodium, potassium, chloride and calcium channels, resulting in epileptiform activity. Voltage-dependent sodium and calcium channel blockers, and GABA mimetics are the most clinically useful groups of antiepileptic drugs and the newest research in this field is focused on more selective and subtle regulations of their molecular targets. Of interest is an emerging role of extrasynaptic GABAA receptors, various kinds of potassium ion channels, hyperpolarization-activated cyclic nucleotide gated (HCN) channels, acid-sensing ion channels, and gap junctions in the regulation of neuronal excitability and seizures. Iono- and metabotropic glutamate receptors used to be viewed as an attractive target for new anticonvulsants, however, opinions are now less enthusiastic, since their competitive and non-competitive antagonists possess undesired side effects. Positive or negative allosteric modulators of glutamate receptors with fewer side-effects can be more promising. The introduction of new compounds acting through novel pharmacological mechanisms gives hope that the proportion of patients with uncontrolled epilepsy will substantially decrease. However, this may be possible if molecular background of the pharmacoresistance in epilepsy is deciphered. PMID- 24145074 TI - Female ovarian steroids in epilepsy: a cause or remedy. AB - In this article, we review published preclinical and clinical studies that examine the role of female ovarian steroids (estrogen and progesterone) in epilepsy. Its effects on the reproductive and endocrine system are well known but a large and growing body of evidences indicates that the hormones also exert neuroprotective effects on the central nervous system. Estrogen crosses the blood brain barrier due to its low molecular weight and lipophilic properties and easily reaches the neuronal tissue. Estrogens and progesterone influence neuronal activity and are important for normal brain functions. It is commonly accepted that estrogens may increase neuronal excitability and thus mediate proconvulsant effects whereas in case of progesterone, various preclinical and clinical studies have proved that progesterone shows anticonvulsant effects. To concise our review we concluded that the effects of estrogens and progesterone on seizures depend on various factors, such as treatment duration and latency prior to the seizure testing, dose, hormonal status, the seizure type/model used and sex. PMID- 24145075 TI - Effects of serotonin (5-HT)1B receptor ligands on amphetamine-seeking behavior in rats. AB - BACKGROUND: Numerous studies have indicated that serotonin (5-HT)1B receptor ligands affect the behavioral effects of psychostimulants (cocaine, amphetamine), including the reinforcing activities of these drugs. METHODS: To substantiate a role for those receptors in incentive motivation for amphetamine, we used the extinction/reinstatement model to examine the effects of the 5-HT1B receptor ligands on the reinstatement of extinguished amphetamine-seeking behavior. Rats trained to self-administer amphetamine (0.06 mg/kg/infusion) subsequently underwent the extinction procedure. These rats were then tested for the amphetamine-primed or amphetamine-associated cue-induced reinstatement of extinguished amphetamine-seeking behavior. RESULTS: The 5-HT1B receptor antagonist SB 216641 (5-7.5 mg/kg) attenuated the amphetamine (1.5 mg/kg)- and the amphetamine-associated cue combined with the threshold dose of amphetamine (0.5 mg/kg)-induced reinstatement of amphetamine-seeking behavior. The 5-HT1B receptor agonist CP 94253 (1.25-5 mg/kg) also inhibited the amphetamine-seeking behavior induced by amphetamine (1.5 mg/kg) but not by the cue combined with the threshold dose of amphetamine. The inhibitory effect of CP94253 on amphetamine seeking behavior remained unaffected by the 5-HT1B receptor antagonist. CONCLUSION: Our results indicate that tonic activation of 5-HT1B receptors is involved in amphetamine- and cue-induced reinstatement of amphetamine-seeking behavior and that the inhibitory effects of 5-HT1B receptor antagonists on these phenomena are directly related to the motivational aspects of amphetamine abuse. The inhibitory effect of CP 94253 on amphetamine-seeking behavior seems to be unrelated to 5-HT1B receptor activation and may result from a general reduction of motivation. PMID- 24145076 TI - Synthesis and neuromodulatory effects of TRH-related peptides: inhibitory activity on catecholamine release in vitro. AB - BACKGROUND: A detailed comprehension of central mechanisms underlying feeding behavior holds considerable promise for the treatment of alimentary disorders. METHODS: In order to elucidate the tight interrelationships occurring at the hypothalamic neuronal endings between aminergic neurotransmitters and co localized appetite modulators, we initially studied the effects of two anorexigenic peptides structurally related to thyrotropin-releasing hormone (TRH, 1), namely cyclo(His-Pro) (CHP, 2) and pGlu-His-Gly-OH (3), on [(3)H] norepinephrine and [(3)H]-dopamine release from perfused rat hypothalamic synaptosomes. Furthermore, a number of TRH and CHP analogues were synthesized and tested for their ability to influence neurotransmitter release in the selected neuronal model. RESULTS: Peptide 3 showed only a slight inhibitory activity on norepinephrine release, whereas no effect was observed for compound 2. TRH analogue 8, metabolically stabilized by the replacement of pyroglutamate with the pyrohomocysteic acid (pHcs), was found to be inactive. Conversely, a significant inhibitory effect on dopamine and norepinephrine release was observed for the CHP related diketopiperazines cyclo(Leu-Pro) (11) and cyclo(His-Gly) (14). CONCLUSIONS: These results suggest a potential role for cyclo-dipeptides 11 and 14 in the hypothalamic modulation of appetite suppressant circuitry. PMID- 24145077 TI - Identification of Dmt-D-Lys-Phe-Phe-OH as a highly antinociceptive tetrapeptide metabolite of the opioid-neurotensin hybrid peptide PK20. AB - BACKGROUND: Recently, we presented a novel compound (PK20, Dmt-D-Lys-Phe-Phe-Lys Lys-Pro-Phe-Tle-Leu-OH) that targets single entity opioid and neurotensin pharmacophores. This endomorphin-2-like opioid peptide was introduced as a highly active analgesic because it elicited a strong dose- and time-dependent antinociceptive response when administered centrally and peripherally. Its pain relieving activity was observed as rapidly as 5 min after drug injection. Such promising results led us to perform further studies, such as determining the resistance to enzymatic degradation, which resulted in obtaining a very stable opioid pharmacore PK20 metabolite. METHODS: The synthesis of PK20 and its N terminal tetrapeptide fragment has been accomplished using solid phase peptide chemistry. The biological stability of peptides has been measured in human serum and analyzed by HPLC/MS. Peptides were pharmacologically characterized in in vitro MOP and DOP receptor binding as well as [(35)S]GTPgammaS receptor binding assays. Antinociceptive properties of compounds were measured by in vivo assays in C57Bl6 mice after intravenous or intrathecal applications. RESULTS: Dmt-D-Lys Phe-Phe-OH (PK20M), an N-terminal tetrapeptide metabolite of the opioid neurotensin hybrid peptide PK20, is characterized by a long duration of action, as demonstrated by a preserved, long-lasting analgesic effect even 2 h post injection (average % MPE = 69.33). In rat brain membranes, PK20M efficiently displaced both the MOP and DOP receptor selective radioprobes [(3)H]DAMGO and [(3)H]DIDI (pKi of 9.52 and 7.86, respectively) and potently stimulated [(35)S]GTPgammaS binding, proving full agonism at both receptor types. In the [(35)S]GTPgammaS assay, which measured the agonist-mediated G protein activation, PK20M together with PK20 and Met-enkephalin were potent stimulators of the regulatory G proteins. The relative affinities of PK20M for the MU and delta receptor subtypes revealed MU-receptor selectivity. CONCLUSION: The novel MOP receptor selective metabolite has been shown to possess opioid subtype receptor selectivity, high potency, and effective analgesic activities as measured in various bioassays. PMID- 24145078 TI - Different effects of postnatal caffeine treatment on two pentylenetetrazole induced seizure models persist into adulthood. AB - BACKGROUND: Postnatal treatment with caffeine from P7 to P11 (10 or 20 mg/kg daily) resulted in transient changes in two pentylenetetrazole (PTZ)-induced models of epileptic seizures characterized by spike-and-wave EEG rhythm in immature rats. To know if some changes persist into adulthood we studied these models in young adult Wistar rats. METHODS: Caffeine treatment at a daily dose of 10 and/or 20 mg/kg, sc was executed during postnatal days 7-11. Rhythmic metrazol activity (RMA, model of human absences) was induced in 60-day old rats by two successive doses of PTZ (20 + 20 mg/kg, ip) while for induction of minimal clonic seizures (model of human myoclonic seizures) the second dose of PTZ was 40 mg/kg. RESULTS: RMA episodes elicited by the 20 + 20 mg/kg dose of PTZ in adult rats exposed to caffeine at P7 to P11 were decreased. This effect was more pronounced in group treated with the higher dose of caffeine. In contrast, the lower dose of caffeine exacerbated minimal clonic seizures (both incidence and intensity were increased). In addition, some animals from the 20-mg/kg caffeine group exhibited transition to generalized tonic-clonic seizures. CONCLUSION: Different effects of postnatal caffeine exposure persist into adulthood; the seizure ameliorating effects in a model of absences and seizure exacerbating action in a model of myoclonic seizures are dose-specific. PMID- 24145079 TI - Differential effects of LY294002 and wortmannin on neurons and vascular endothelial cells in the rat retina. AB - BACKGROUND: Neuronal damage leads to capillary degeneration in an N-methyl-D aspartate (NMDA)-induced retinal degeneration model; however, the mechanisms underlying this phenomenon are not fully understood. The phosphatidylinositol 3 kinase (PI3K)/Akt signaling pathway has been recognized as an intracellular pro survival signaling system. Therefore, we used the PI3K inhibitors LY294002 and wortmannin to investigate the role of this pathway in neuronal and blood vessel injury in the rat retina treated with NMDA. METHODS: Male Sprague-Dawley rats weighing 220-240 g were used in this study. NMDA combined with LY294002, wortmannin, or vehicle was administered intravitreally, and histological evaluation was performed at 2 and 7 days after injection. The effects of LY294002 or wortmannin alone were also evaluated. RESULTS: The number of cells in the ganglion cell layer (GCL) was significantly reduced at 2 and 7 days after intravitreal injection of NMDA, whereas enhanced capillary degeneration was observed at 7 days. Simultaneous injection of LY294002 with NMDA significantly attenuated NMDA-induced retinal cell loss and capillary degeneration at 7 days. However, simultaneous injection of wortmannin with NMDA did not affect cell loss, but enhanced capillary degeneration. Treatment with LY294002 alone showed no effect on neuronal or vascular cells, whereas wortmannin induced capillary degeneration without significantly affecting the cell number in the GCL. CONCLUSIONS: Although both LY294002 and wortmannin are known as PI3K inhibitors, they exhibit differential effects on neurons and vascular endothelial cells in the rat retina. Therefore, the results obtained using these inhibitors should be carefully interpreted. However, our finding that LY294002 was protective against NMDA-induced retinal damage suggests that this compound may be an effective candidate for preventing the development of retinal diseases associated with glutamate-induced excitotoxicity. PMID- 24145080 TI - LPS-induced oxidative stress and inflammatory reaction in the rat striatum. AB - BACKGROUND: Inflammation-induced microglia activation and increased oxidative stress have been observed in neurodegenerative disorders, such as Parkinson's disease. The aim of our study was to determine the appropriate dose and route of LPS administration to study hydroxyl radical generation and extracellular level of dopamine (DA), glutamate (GLU) and adenosine (ADN) in the rat striatum as markers of DA neuron damage and glial cell activation. The effect of LPS administration on DA, DOPAC, HVA and hydroxyl radical tissue level was also examined. METHODS: LPS was given to rats in a single dose of 10 mg/kg ip, repeatedly for 5 days in a dose of 5 mg/kg ip and intrastriatally at doses 5, 20 and 40 MUg/4 MUl. The extracellular level of DA, hydroxyl radical, ADN and GLU were assayed in striatal dialysates using HPLC with electrochemical, fluorescence and VIS detection, respectively. RESULTS: A single ip LPS (10 mg/kg) administration increased hydroxyl radical production but did not affect extracellular DA, GLU and ADN level. Repeated ip LPS (5 * 5 mg/kg) treatment decreased extracellular level of DA, GLU, ADN and production of hydroxyl radical. LPS (5 and 10 MUg) given intrastriatally increased hydroxyl radical production, extracellular GLU and ADN level from 0 to 180 min after administration, but did not influence DA level. LPS (5, 20 and 40 MUg) decreased striatal DA and DOPAC content, but increased HVA and hydroxyl radical level 72 h after intrastriatal administration. CONCLUSIONS: Our data indicate that local intrastriatal LPS administration activates glial cells and increases production of free radicals and secretion of GLU and ADN in early phase of inflammation. The damage of DA neurons is observed 72 h after local LPS administration. PMID- 24145081 TI - Can the antiplatelet effects of cangrelor be reliably studied in mice under in vivo and in vitro conditions using flow cytometry? AB - BACKGROUND: The effects of blood platelet inhibitors are often not quite equivalent under in vivo and in vitro conditions. Amongst various models of human pathology using laboratory animals, mice offer several benefits that make them convenient tools for studying the putative therapeutic value of various compounds. However, despite its advantages, the mouse model has methodological limitations concerning the small amount of blood available and technical difficulties with its collection. Among the variety of available methods used to study blood platelet activation and/or reactivity, flow cytometry seems an attractive technique that largely minimizes the constraints of using small rodents and enables outcomes of laboratory research to be transferred successfully to clinical practice. In this study we aimed at a critical evaluation of the optimal discriminative flow cytometric protocol, useful for reliable studies of the effect of cangrelor, a P2Y12 receptor antagonist, on mouse platelets under in vitro and in vivo conditions. METHODS: Blood samples were drawn from two-month-old female BALB/c mice. Protocols differing in methods of anesthesia, blood withdrawal, anticoagulation, gating antibodies, blood preparation and fixation were tested to optimize the one best suited to discrimination between resting and activated platelets. The antiplatelet capabilities of cangrelor were tested in vitro (140 MUM in whole blood) and in vivo (7.8 mg/kg b.w. administered once, directly into the bloodstream through the vena cava of the anesthetized animal, 15 min prior to blood withdrawal). Expressions of P-selectin, activated alpha(IIb)beta3 complex and GPIba were monitored using two-color flow cytometry. RESULTS: "Washed blood" anticoagulated with low molecular weight heparin demonstrated the best discrimination between circulating (resting) platelets and upon their in vitro response to thrombin, collagen or ADP in freshly-stained unfixed cell suspensions. Cangrelor inhibited the expression of the active form of the integrin a(IIb)beta3 to approximately the same extent under in vitro and in vivo conditions (84.5 +/- 7.7% vs. 75.4 +/- 19.5% for the in vitro and in vivo approaches, respectively, n.s.). CONCLUSIONS: The agreement between the in vivo and in vitro approaches with respect to cangrelor-inhibited hallmarks of blood platelet activation and reactivity supports our proposal that flow cytometry is useful and reliable for determining the effects of antiplatelet agents on the activation of circulating platelets in the mouse model, as well as the in vitro response of platelets to agonists. PMID- 24145082 TI - Exendin-4 and GLP-1 decreases induced expression of ICAM-1, VCAM-1 and RAGE in human retinal pigment epithelial cells. AB - BACKGROUND: Advanced glycation end products (AGEs) take part in the development of diabetic retinopathy. Hyperglycemia triggers an inflammatory response in the retina. These mechanisms may lead to an enhanced expression of adhesion molecules (ICAM-1 and VCAM-1) in human retinal pigment epithelium (HRPE). Glucagon-like peptide 1 (GLP-1) functions as an incretin hormone with antidiabetogenic properties. GLP-1 also possesses vasoprotective properties. METHODS: The aim of our study was to evaluate the influence of glycated albumin (GlyAlb; 100; 500 and 1000 mg/l) and pro-inflammatory cytokine, TNF-alpha (2.5 and 10 ng/ml), on expression of RAGE, ICAM-1 and VCAM-1 and to evaluate the influence of GLP-1 (100 nM) and its analogue, exendin-4 (10 nM), on the expression of RAGE, ICAM-1 and VCAM-1 in stimulated HRPE. RESULTS: TNF-alpha increased RAGE expression in HRPE cells. The addition of GlyAlb (500 and 1000 mg/l) resulted in a decrease of RAGE expression. Both TNF-alpha and GlyAlb increased the secretion of both adhesion molecules. In cells co-treated with GLP-1 or exendin-4 both incretins decreased RAGE expression in TNF-alpha treated cells, and in GlyAlb group. The ICAM-1 expression was lowered by exendin-4 and GLP-1 in cells stimulated by TNF-alpha and GlyAlb. The similar results were obtained for VCAM-1. All observed alterations were statistically significant. CONCLUSIONS: The obtained results indicate that both GLP-1 and exendin-4 by decreasing the expression of RAGE in HRPE can make these cells more resistant to circulating AGEs, and decreased expression of circulating VCAM-1 and ICAM-1, can be the result of anti inflammatory properties of incretins and decreased expression of RAGE. PMID- 24145083 TI - Disparate effects of anti-TNF-alpha therapies on measures of disease activity and mediators of endothelial damage in ankylosing spondylitis. AB - BACKGROUND: Asymmetric dimethylarginine (ADMA) is associated with endothelial injury. Increased ADMA levels are found in rheumatoid arthritis (RA) and ankylosing spondylitis (AS). We set out to assess the ADMA and symmetric dimethylarginine (SDMA) levels in AS, RA, and healthy controls, and in the anti TNF treated patients with active AS. METHODS: In 78AS patients and 29 RA patients who were anti-TNF treatment naive at baseline, along with 23 healthy control subjects, we assessed erythrocyte sedimentation rate (ESR), high-sensitivity C reactive protein (hsCRP), ADMA, and SDMA. For AS patients, the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI), back pain VAS and patient's global activity of disease were calculated. After 6 months, we repeated the assessment in 30 out of the 78 AS patients in whom the anti-TNF treatment was initiated. RESULTS: The baseline mean (SD) plasma ADMA concentration of AS patients was 0.64 (0.19) MUmol/l and did not differ from controls (0.65 [0.19] MUmol/l, p > 0.05). In the RA group, ADMA concentration was higher than in controls (0.77 vs. 0.65 MUmol/l, p < 0.05). Both at baseline and at follow-up, ADMA levels correlated positively with BASDAI (R = 0.52, p = 0.02, and R = 0.47, p = 0.04, baseline and follow-up, respectively). Six months of anti-TNF treatment did not influence ADMA concentration (0.51 [0.12] vs. 0.51 [0.11] MUmol/l, p = 0.70). CONCLUSION: An absence of changes in plasma ADMA levels in the anti-TNF treated AS group despite the improvement in disease activity (BASDAI) and inflammation (ESR, CRP) may suggest either a lack of effect, or, even if such an effect were to take place, it needs not imply measurable changes in blood ADMA. PMID- 24145084 TI - Influence of NADPH oxidase inhibition on oxidative stress parameters in rat hearts. AB - BACKGROUND: The aim of this study was to assess whether apocynin, an nicotinamide adenine dinucleotide phosphate (NADPH) oxidase blocker, influences lipid peroxidation TBARS, hydrogen peroxide (H2O2) content, protein level, heart edema, tumor necrosis factor alpha (TNF-alpha) concentration or the glutathione redox system in heart homogenates obtained from endothelin 1 (ET-1)-induced oxidative stress rats. METHODS: Experiments were carried out on adult male Wistar-Kyoto rats. The animals were divided into 4 groups: Group I: saline-treated control; Group II: saline followed by ET-1 (3 MUg/kg b.w., iv); Group III: apocynin (5 mg/kg b.w., iv) administered half an hour before saline; Group IV: apocynin (5 mg/kg b.w., iv) administered half an hour before ET-1 (3 MUg/kg b.w., iv). RESULTS: Injection of ET-1 alone showed a significant (p < 0.001) increase in thiobarbituric acid reactive substances (TBARS) and the hydrogen peroxide level (p < 0.01) vs. control, as well as a decrease (p < 0.001) in the GSH level. Apocynin significantly decreased TBARS (p < 0.001) and H2O2 (p < 0.05) level (vs. control) as well as improved protein level (p < 0.001) in the heart. Apocynin also prevented ET-1-induced heart edema (p < 0.05). The presence of ET-1 increased the concentration of TNF-alpha (p < 0.05) while apocynin decreased it (p < 0.05). Our results indicate that ET-1 may induce oxidative stress in heart tissue by reducing the GSH/GSSG ratio, stimulating lipid peroxidation and increasing TNF-alpha concentration. Apocynin diminished these measures of oxidative stress and TNF-alpha. CONCLUSION: ET-1-induced formation of ROS in the heart is at least partially regulated via NADPH oxidase. PMID- 24145085 TI - Exposure to alcohol and tobacco smoke causes oxidative stress in rats. AB - BACKGROUND: Tobacco smoking and alcohol abuse causes oxidative stress in humans and underlay numerous chronic degenerative diseases. Liver is the main organ exposed to alcohol toxic metabolites, whereas tobacco smoke is chiefly harmful to the lungs. METHODS: The aim of the current study was the assessment and comparison of selected oxidative stress markers, reduced glutatione (GSH), glutathione S-transferase (GST), superoxide dismutase (SOD), catalase, nitrites and protein nitrosylation and DNA damage in the livers and in the lungs of alcohol-addicted rats exposed to tobacco smoke alone or in combination with a single dose of ethanol. RESULTS: The highest levels of GSH were measured in the liver of smoke only exposed animals and in the lungs of rats exposed to smoke and alcohol. In the liver of animals treated with a single dose of alcohol or with smoke and alcohol, GST was significantly higher than in the group exposed to smoke only. SOD and catalase showed the highest activities in the livers of rats receiving a single dose of alcohol. High concentration of nitrites was observed in the lungs of animals treated with smoke and alcohol in combination, which corresponded to elevated protein nitrosylation in this group, whereas in the livers of these animals relatively low level of nitrites was accompanied with the lowest concentration of nitrosylated proteins. In the liver of alcohol only treated rats the highest nitrites corresponded to the highest protein nitrosylation. In the lungs of all treatment groups the range of DNA damage was higher, than the respective values in the livers. Although alcohol is not considered a specific toxicant to the lungs it was found to cause oxidative stress in this organ. CONCLUSIONS: The obtained results suggest that in the ethanol-addicted rats combined exposure to smoke and alcohol differentially modulate endogenous antioxidant defense system and reactions to oxidative stress. PMID- 24145086 TI - Exposure to ethanol and tobacco smoke in relation to level of PCNA antigen expression in pancreatic and hepatic rat cells. AB - BACKGROUND: Previous results proved that simultaneous effect of tobacco smoke constituents and alcohol consumption may change toxicity of these substances and have a greater effect on hepatic and pancreatic disease and cancer risk. The aim of this study was to investigate hepatocyte and pancreatic cells regeneration after tobacco and/or ethanol treatment. METHODS: In the study, four groups of rats were used - alcohol non-addicted and addicted male and female rats. The animals from each group were exposed to tobacco smoke, to ethanol or tobacco smoke and ethanol. After the exposure, pancreas and liver were collected at two time-points--5 and 24 h. Biochemical methods were used to measure concentration of ethanol and cotinine in blood and plasma. Additionally, proliferating cell nuclear antigen labeling index (PCNA-LI), an S-phase marker was assessed by immunohistochemical staining and morphometric method. RESULTS: Our experimental results showed that the exposure of rats to tobacco smoke does not have influence on ethanol concentration in blood of non-addicted (male, female) and addicted (male and female) animals. The results also proved that alcohol addiction did not influence nicotine metabolism in all animals exposed to tobacco smoke. Morphological studies of tissues display significant damage in liver of addicted males, including fatty degradation, fibrosis and slight inflammatory infiltrate. Immunohistochemical studies revealed at first, significant increase of PCNA-LI and, thus, increased cell proliferation activity and damage in tissues were observed in hepatic and pancreatic cells of addicted males when compared with non addicted males. Secondly, comparison between addicted males and addicted females revealed that PCNA-LI in females is significantly lower, both in hepatic and pancreatic tissues. And finally, animals exposed only to ethanol and to tobacco smoke plus ethanol were characterized by higher percentage of PCNA positive cells in relation to animals exposed only to tobacco smoke. CONCLUSION: From the preliminary study one can conclude that the influence of ethanol and simultaneous influence of ethanol and tobacco smoke impairs liver and pancreatic functions to a greater degree than tobacco abuse. PMID- 24145087 TI - Combination of omeprazole with GLP-1 agonist therapy improves insulin sensitivity and antioxidant activity in liver in type 1 diabetic mice. AB - BACKGROUND: Combination with suitable pharmacological agents can improve the antiobesity and antidiabetic actions of glucagon like peptide-1 (GLP-1) based therapies. GLP-1 agonist exendin-4 may have insulin-independent effects on amelioration of insulin resistance and hepatic steatosis by virtue of its action on hepatic GLP-1 receptors, and these effects can be improved by combination with proton pump inhibitors. However, it was not assessed whether omeprazole can improve the peripheral actions of exendin-4 in the state of insulin deficiency. METHODS: We investigated the effects of combination of omeprazole with GLP-1 agonist exendin-4 in multiple low-dose streptozotocin (STZ)-induced diabetes in C57BL/KsJ mice, a model of type 1 diabetes. Male diabetic mice were treated with exendin-4 and/or omeprazole for a period of 4 weeks. RESULTS: Omeprazole treatment had no significant effect on lowering the blood glucose levels of diabetic mice, when compared to control, although it improved the antihyperglycemic actions of exendin-4. Similarly, serum triglycerides and total cholesterols levels were significantly lower in the combination treated mice compared to either exendin-4 and omeprazole alone. In addition, the combination treatment significantly ameliorated lipid peroxidation and hepatic triglycerides in diabetic mice compared to either exendin-4 and omeprazole alone. The improvement in hepatic insulin sensitivity, as indicated by insulin tolerance test (ITT) and pyruvate tolerance test (IPPTT), was correlated with the expression of nuclear factor erythroid-related factor 2 (Nrf2) and insulin receptor substrate-1 (IRS-1) and the combination treatment significantly improved the insulin sensitivity in comparison to vehicle control. CONCLUSION: We conclude that combination with omeprazole improves the insulin sensitizing actions of GLP 1 therapy and these effects are partially mediated through the decrease in hepatic steatosis and improvement in antioxidant status in the liver. PMID- 24145088 TI - Metabolic effects of the HIV protease inhibitor--saquinavir in differentiating human preadipocytes. AB - BACKGROUND: The iatrogenic, HIV-related lipodystrophy is associated with development of the significant metabolic and cardiovascular complications. The underlying mechanisms of antiretroviral (ARV) drugs are not completely explored. METHODS: The aim of the study was to characterize effects of the protease inhibitor (PI)--saquinavir (SQV) on metabolic functions, and gene expression during differentiation in cells (Chub-S7) culture. RESULTS: SQV in concentrations observed during antiretroviral therapy (ART) significantly decreased mitochondrial membrane potential (MMP), oxygen consumption and ATP generation. The effects were greater in already differentiated cells. This was accompanied by characteristic changes in the expression of the genes involved in endoplasmic reticulum (ER) stress, and differentiation (lipid droplet formation) process such as: WNT10a, C/EBPa, AFT4, CIDEC, ADIPOQ, LPIN1. CONCLUSIONS: The results indicate that SQV affects not only metabolic (mitochondrial) activity of adipocytes, but affects the expression of genes related to differentiation and to a lesser extent to cell apoptosis. PMID- 24145089 TI - Comparative evaluation of different doses of PPAR-gamma agonist alone and in combination with sulfasalazine in experimentally induced inflammatory bowel disease in rats. AB - BACKGROUND: Inflammatory bowel disease (IBD) is an idiopathic, chronic inflammatory condition, which affects the gastrointestinal tract and has no curative treatment. The present study aimed to investigate the effect of different doses of pioglitazone alone and in combination with sulfasalazine in TNBS (trinitrobenzenesulfonic acid)-induced inflammatory bowel disease (IBD) in rats. METHODS: A total of 36 animals were included in the study. Animals were divided into five groups (n = 6): group I--vehicle (ethanol), group II--TNBS + ethanol, group IIIA--TNBS + pioglitazone (15 mg/kg), group IIIB--TNBS + pioglitazone (30 mg/kg), group IV--TNBS + sulfasalazine (360 mg/kg), group V- TNBS + sulfasalazine (360 mg/kg) + pioglitazone (least effective dose found in group III). Group III was divided into two subgroups, namely IIIA and IIIB, on the basis of different doses of pioglitazone used. After completion of two weeks of treatment, rats were sacrificed under ether anesthesia by cervical dislocation for assessment of intestinal inflammation, histological analysis, myeloperoxidase assay, malondialdehyde assay and TNF-alpha estimation. RESULTS: All the drug treated groups showed both gross morphological and microscopic score either 1 or 2. None of them showed score of > 2 on both gross and microscopic morphological examination. Both MDA levels and MPO activity were significantly reduced in the drug-treated groups, with maximum reduction seen in the combination group. TNF alpha was reduced in pioglitazone group. It was highly reduced in sulfasalazine group (group V) as compared to TNBS group thereby indicating that pioglitazone is protective in TNBS-induced inflammatory bowel disease. CONCLUSION: The present study showed reduction in lipid peroxidation, malondialdehyde levels and TNF alpha levels in pioglitazone-treated group and hence, there was significant improvement in gross and microscopic features, too. However, combination of pioglitazone and sulfasalazine has shown greater efficacy. PMID- 24145090 TI - Effect of infliximab on metabolic disorders induced by Walker-256 tumor in rats. AB - BACKGROUND: The purpose of this study was to investigate the effect of infliximab, an anti-tumor necrosis factor alpha (TNFalpha) monoclonal antibody, on the progression of cachexia and several metabolic parameters affected by the Walker-256 tumor in rats. METHODS: Infliximab (0.5 mg/kg) was ip administered, twice a day, beginning at the day in which the Walker-256 tumor cells were inoculated. After 12 days of treatment, the tumor growth, some parameters of cachexia/anorexia, the blood levels of triacylglycerol, glucose, lactate and urea, the peripheral response to insulin and the hepatic glycolysis and gluconeogenesis were investigated. The peripheral response to insulin was evaluated by the insulin tolerance test and the glycolysis and gluconeogenesis in isolated perfused liver. RESULTS: The treatment with infliximab did not alter the growth of the Walker-256 tumor, but attenuated (p < 0.05) the reduction of body weight and prevented (p < 0.05) the loss of retroperitoneal adipose tissue induced by the tumor. Moreover, treatment with infliximab tended to minimize the loss of gastrocnemius muscle, the reduction in food intake, the peripheral response to insulin and the liver gluconeogenesis from alanine, as well as the increased blood triacylglycerol, caused by the tumor. In contrast, treatment with infliximab did not attenuate the reduction in hepatic glycolysis and glycemia, nor did it minimize the rise in blood levels of lactate and urea induced by the tumor. CONCLUSION: The treatment with infliximab ameliorated some changes associated with cachexia, such as the reduction of adipose tissue and body weight, suggesting that TNFalpha plays a significant role in mediating these changes induced by the tumor. In addition, infliximab tended to improve or had no effect on other metabolic parameters affected by the Walker-256 tumor, suggesting that other mediators or tumor-related events are involved in these disorders. PMID- 24145091 TI - Anti-nephrolithic potential of resveratrol via inhibition of ROS, MCP-1, hyaluronan and osteopontin in vitro and in vivo. AB - BACKGROUND: Though resveratrol is known to have anti-cancer, anti-diabetic, anti oxidant and anti-inflammatory activities, the inhibitory mechanism of resveratrol in kidney stone formation has not been elucidated so far. METHOD: ELISA, flow cytometry, RT-PCR, and western blotting were performed. Human renal epithelial cells (HRCs) and rats with ethylene glycol (EG)-induced kidney stones were used. RESULTS: A wound healing assay revealed that resveratrol significantly inhibited the oxalate-mediated migration of HRCs, considering oxalate mediates kidney stone formation. Also, resveratrol suppressed the mRNA expression of nicotinamide adenine dinucleotide phosphate hydrogen (NADPH) oxidase subunits such as p22(phox) and p47(phox), monocyte chemoattractant protein 1 (MCP-1) and osteopontin (OPN) in oxalate-treated HRCs. Furthermore, western blotting showed that resveratrol downregulated the expression of MCP-1-related proteins including transforming growth factor(TGF-beta1), TGFR-I or II and hyaluronan in oxalate treated HRCs. Consistently, resveratrol reduced oxalate-mediated production of reactive oxygen species (ROS) and malondialdehyde (MDA) in oxalate-treated HRCs, while the activities of anti-oxidant enzymes such as superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GPx) were enhanced by resveratrol in HRCs and EG-treated kidneys of rats. Consistently, resveratrol significantly reduced the number of urine calcium oxalate crystals and serum MDA, and attenuated the expression of OPN and hyaluroran in EG-treated rats. CONCLUSIONS: Our findings suggest that resveratrol exerts anti-nephrolithic potential via inhibition of ROS, MCP-1 hyaluronan and OPN signaling. PMID- 24145092 TI - 1,2-Diazole prevents cisplatin-induced nephrotoxicity in experimental rats. AB - BACKGROUND: Cisplatin (a platinum-compound) is a anti-neoplastic drug used in the treatment of various cancers but eventually results in severe adverse effects namely nephrotoxicity or renal disorder through generation of reactive oxygen species (ROS). This biochemical measurements and histopathology analysis investigated a possible protective effect of 1,2-diazole with regards to cisplatin-induced nephrotoxicity in experimental animals. METHODS: Animals were divided into four groups of six mice each. Group A: normal control, vehicle (1% (w/v) gum acacia in phosphate buffer saline (PBS)). Group B: cisplatin group, vehicle + cisplatin (7.5 mg/kg). Group C: 1,2-diazole (10 mg/kg) + cisplatin and Group D: silymarin (50 mg/kg) + cisplatin. Each vehicle/drug treatment was given daily via intraperitoneal (ip) injection for 10 consecutive days starting from day 1. On group B, C and D cisplatin was given in single dose only on day 5 one hour post drug administration. Animals were allowed till 10th day and on day 11 all four groups animals were anesthetized. Blood samples were collected and serum was isolated for biochemical measurements. The rats were then euthanized by cervical dislocation and their kidney was recovered and then prepared for biochemical measurements and histopathology analyses. RESULTS: Pretreatment with 1,2-diazole prevented nephrotoxicity induced by cisplatin through a protective mechanism that involved reduction of increased oxidative stress by significantly increasing the enzymatic and non enzymatic antioxidant enzymes such as glutathione peroxidase (GPx), glutathione (GSH) and diminishing the lipid peroxidation (LPO). The pretreatment with 1,2-diazole does not affect superoxide dismutase (SOD), catalase (CAT), serum urea and creatinine level during nephrotoxicity when compared to cisplatin-induced group. Moreover, the 1,2 diazole animals shown significant decrease in urine volume and kidney weight when compared with cisplatin-induced group. Histopathological findings reveals the protective efficacy of 1,2-diazole that restores histopathological changes against nephrotoxicity. CONCLUSION: These analysis will provide a critical evidence that 1,2-diazole could provide a new protective strategy against cisplatin-induced nephrotoxicity. PMID- 24145093 TI - Involvement of NMDA and AMPA receptors in the antidepressant-like activity of antidepressant drugs in the forced swim test. AB - BACKGROUND: The involvement of glutamate system (particularly the NMDA and AMPA receptors) in the mechanism of antidepressant activity was demonstrated in preclinical and clinical studies. METHODS: In the present study, we investigated the effect of NMDA and AMPA receptors' ligands (agonists and antagonists) on the antidepressant-like activity of escitalopram, milnacipran, imipramine and reboxetine in the forced swim test in mice. RESULTS: Antidepressant activity (reduction in immobility time) of escitalopram and milnacipran but not of imipramine and reboxetine was antagonized by N-methyl-D-aspartate acid. CGP37849 (antagonist of the NMDA receptor) enhanced the antidepressant activity of all examined antidepressants. On the other hand, CX614 (a potentiator/positive allosteric modulator of the AMPA receptor) enhanced the antidepressant activity of imipramine and reboxetine but not of escitalopram and milnacipran in this test. NBQX (the AMPA receptor antagonist) did not influence the antidepressant activity of all tested agents. CONCLUSIONS: The data indicate the complex interactions following the activation or blockade of the NMDA and AMPA receptors with antidepressant drugs. The general phenomenon is the enhancing effect of the NMDA receptor antagonism on the antidepressant activity. Moreover, is can be concluded that the activity of antidepressants with a serotonergic mechanism of action can be inhibited by NMDA activation, while antidepressants with a noradrenergic mechanism of action are dependent on AMPA receptor transmission. PMID- 24145094 TI - Partial agonist efficacy of EMD386088, a 5-HT6 receptor ligand, in functional in vitro assays. AB - BACKGROUND: Over recent years, the 5-hydroxytryptamine6 (5-HT6) receptor has emerged as a promising molecular target which interacts with several central nervous system acting drugs. In animal models, both agonists and antagonists of this receptor exhibit equivalent potency and efficacy as potential antidepressants, anxiolytics and anti-obesity or anti-dementia drugs. EMD386088 (5-chloro-2-methyl-3-(1,2,3,6-tetrahydro-4-pyridinyl)-1H-indole hydrochloride) has been described as a high affinity 5-HT6 receptor ligand with a full agonist activity and with moderate affinity for 5-HT3 sites. METHODS: We have extended these data by broadening its profile for other, not yet tested, monoaminergic, GABA(A), opioid MU receptors and serotonin transporter (SERT) and we have conducted functional in vitro assays; i.e., measurement of cAMP by homogeneous TR FRET immunoassay and HTRF method made by CEREP as well as aequorin-based calcium flux assay. RESULTS: In two in vitro models based on cAMP formation, maximal efficacy values for EMD386088 were 65 and 31%, for in house and CEREP experiments, respectively. In a model based on calcium response, the studied compound showed 46% of maximal serotonin (5-HT) signal. EMD386088 antagonizes 5 HT response in increasing concentrations from 10(-9) to 10(-6) M. CONCLUSIONS: The present in vitro findings confirm that EMD386088 is a selective 5-HT6 receptor ligand with moderate affinity for 5-HT3 sites only and it behaves as a potent partial agonist of 5-HT6 receptor with varying levels of agonist intrinsic activity, depending on a method employed. In view of these results, caution is recommended in the interpretation of pharmacological in vivo studies with EMD386088. PMID- 24145095 TI - Dose-depending effect of intracerebroventricularly administered bradykinin on nociception in rats. AB - BACKGROUND: The effect of small and high doses of intracerebroventricularly (icv) applied bradykinin (BK) on nociception produced by mechanical stimuli and the participation of B1 and B2 receptors in this nociception were investigated in rats. RESULTS: BK at the lowest dose (0.06 MUg) produced hyperalgesia whereas at the higher doses (6 and 12 MUg) antinociception. This effect was abolished by B1 or B2 receptor antagonists, des-Arg(10)-HOE140 and HOE140 (1 pmol icv), respectively. CONCLUSION: Depending on the dose used, BK produces pro- or anti nociceptive action. Both B1 and B2 receptors are involved in the action of icv applied BK. PMID- 24145096 TI - Enalapril enhances the anticonvulsant activity of lamotrigine in the test of maximal electroshock. AB - BACKGROUND: The aim of this study was to find out whether angiotensin-converting enzyme (ACE) inhibitors, enalapril and cilazapril, affect the anticonvulsant action of some second-generation antiepileptics, lamotrigine (LTG), topiramate (TPM) and oxcarbazepine (OXC). METHODS: The effects of ACE inhibitors on antiepileptic drugs were examined in the mouse model of maximal electroshock. RESULTS: Enalapril (30 mg/kg ip) potentiated the anticonvulsant action of LTG, decreasing its ED50 value from 5.3 to 3.6 mg/kg (p < 0.01). The anticonvulsant activity of TPM or OXC was not modified by enalapril. Cilazapril did not affect the protective activity of the studied antiepileptics. The interaction between enalapril and LTG could be pharmacodynamic in nature because enalapril did not change plasma and total brain concentrations of LTG. CONCLUSIONS: This study shows that there are no negative interactions between the studied antiepileptic drugs and enalapril or cilazapril. Enalapril even enhanced the anticonvulsant activity of LTG in the MES test in mice that is thought to be a predictive model of human generalized tonic-clonic seizures. PMID- 24145097 TI - Are anti-inflammatory properties of lipoic acid associated with the formation of hydrogen sulfide? AB - BACKGROUND: Lipoic acid (LA) was shown to possess anti-inflammatory properties. In this study, we present evidence supporting the hypothesis that the anti inflammatory properties of LA are associated with the formation of hydrogen sulfide (H2S). METHODS: The study was conducted on male albino Swiss mice. The animals were treated with carrageenan by subcutaneous (sc) injection into the right hind paw to induce acute inflammation. Animals were treated intraperitoneally (ip) with LA (30, 50 and 100 mg/kg) or indomethacin (20 mg/kg) 30 min before carrageenan administration. The control group was given ip the vehicle (1% Tween 80) 30 min before carrageenan administration. Additional experiment involved ip combined treatment of mice with glibenclamide (10 mg/kg) or glibenclamide (10 mg/kg) and LA(100 mg/kg) 30 min before carrageenan administration. LA, indomethacin and glibenclamide were suspended in 1% Tween 80. At 1, 2 and 3 h after treatment with carrageenan the degree of the paw edema was evaluated by the measurement of the paw volume using aqueous plethysmometer. RESULTS: Injection of carrageenan into the mouse hind paw increased paw volume. The increase in paw edema was completely suppressed by pretreatment with LA. The reduction of paw edema by LA was abolished by pretreatment with the K(ATP) channel antagonist, glibenclamide. CONCLUSION: Our findings demonstrate for the first time in vivo that the anti-inflammatory activity of LA might be connected with the formation of H2S. PMID- 24145098 TI - Marsanidine and 7-Me-marsanidine, the new hypotensive imidazolines augment sodium and urine excretion in rats. AB - BACKGROUND: We have recently described the synthesis and circulatory properties of two novel centrally acting imidazoline agents: marsanidine (1-[(imidazolidin-2 yl)imino]indazole) and 7-Me-marsanidine (1-[(imidazolidin-2-yl)imino]-7 methylindazole). Marsanidine has proven to be a highly selective alpha2 adrenoceptor ligand with the alpha2/I1 selectivity ratio of 3879, while 7-Me marsanidine has been shown to be a mixed a2-adrenoceptor/imidazoline I1 receptor agonist with the a2/I1 selectivity ratio of 7.2. In the same paper, we indicated that iv administration of both compounds to Wistar rats induced a decrease in blood pressure and heart rate. The hypotensive effect of the iv administered imidazolines might be mediated not only through activation of the central alpha2 and/or I1 receptors but also through subsequent decrease of the renal sympathetic nerve activity and a direct effect on peripheral receptors. The present studies were performed to determine whether the newly synthesized compounds might influence the diuresis and sodium excretion in rats. METHODS: Both compounds were infused iv to anesthetized rats in the dose of 100 MUg/kg b.w. The diuresis and sodium concentration in urine and blood samples were determined. The mean arterial blood pressure and heart rate were monitored directly throughout the experiment. RESULTS: A significant increase of diuresis and natriuresis was observed within 40 min after the administration of both marsanidine and 7-Me marsanidine, in comparison to both the control period and the control group. However, between the 20 and 40 min of the experiment the natriuretic and diuretic effect of 7-Me-marsanidine was markedly higher than that of marsanidine. CONCLUSION: Our study indicates that the new hypotensive imidazoline compounds of marsanidine and 7-Me-marsanidine increase diuresis and natriuresis in rats. However, the effect of 7-Me-marsanidine is markedly more potent, probably due to its moderate affinity to the I1-imidazoline receptor. PMID- 24145099 TI - Tissue distribution of gold nanoparticles after single intravenous administration in mice. AB - BACKGROUND: Nanoparticles (a part of matter which size is less than 100 nm) have numerous potential applications in biomedicine, due to their unique surface, electronic and optical properties. The goal of the present study was to examine the distribution of gold nanoparticles (GNPs) in mice after single intravenous administration. METHODS: Spherical GNPs were synthesized by chemical reduction of tetrachloroauric acid with ascorbic acid as a reductant. GNPs were stabilized using polyvinyl alcohol (PVA, m.w. = 67000Da) a substance approved for use in the pharmaceutical industry. The size of colloidal gold particles (diameter equals 25 +/- 8 nm) was determined using HR SEM and DLS techniques; zeta potential of GNPs was determined using Malvern Zetasizer Nano ZS and it equals -5.2 +/- 5.4 mV. An aqueous dispersion of GNPs was administered to mice in a dose of about 10 cm(3)/kg and 24 h later the amount of gold in different organs was determined using the inductively coupled plasma mass spectrometer (ICP MS). Initial concentration of GNPs equals 29.55 mg/l. RESULTS: GNPs after single intravenous administration preferentially accumulated in the liver (12.7% of the applied dose), while the other organs accumulated around 0.1% or less. CONCLUSION: Colloidal GNPs of the used size (about 25 +/- 8 nm) provide new potential route for direct delivery system to the liver, which may be important e.g., in liver cancer diagnosis. PMID- 24145100 TI - Support for translational research: exhausting all the possibilities. PMID- 24145101 TI - "No-fault" compensation for victims of medical injuries. Ten years of implementing the French model. AB - CONTEXT: For decades and in many countries, the issue of compensation for victims of medical injuries has led to lively debates. In 2002, a law set up a new model for compensation in France - based on the creation of a "no fault" compensation scheme and of an out-of-court settlement mechanism. This is one of the most recent models to have been adopted in European countries. This article analyses the choices made by the law and discusses the key figures of its ten years of implementation. METHODS: We conducted (1) a study of debates regarding compensation for victims of medical injuries in France; (2) a comparative analysis of the different models of compensation which had already been adopted in different countries; (3) a study of primary sources provided by the bodies in charge of the French new out-of-court settlement mechanism; and (4) a statistical analysis of the exhaustive list of 18,258 claims filed between 2003 and 2009. RESULTS: The article highlights the context which led to the adoption of the 2002 law on the quality of care and patients' rights. It analyses, from a comparative standpoint, the specificities of the new compensation model set up by the law. It shows how the opportunities for victims of medical injuries to be compensated had improved in France. Finally, we discuss the limits of the new model and what the next step might be to improve access to compensation for victims of medical injuries. PMID- 24145102 TI - Vestibular involvement in adults with HIV/AIDS. AB - OBJECTIVE: HIV/AIDS is responsible for widespread clinical manifestations involving the head, and neck. The prevalence and nature of vestibular involvement is still largely unknown. This study, aimed to describe and compare the occurrence and nature of vestibular involvement among a group of, adults infected with HIV compared to a control group. It also aimed to compare the vestibular function, of symptomatic and asymptomatic HIV positive adults who receive antiretroviral (ARV) therapies to, subjects not receiving ARV. METHODS: A cross sectional study was conducted on 53 adults (29 male, 24 female, aged 23-49 years, mean=38.5, SD=4.4) infected with HIV, compared to a control group of 38 HIV negative adults (18, male, 20 female, aged 20-49 years, mean=36.9, SD=8.2). A structured interview probed the subjective, perception of vestibular symptoms. Medical records were reviewed for CD4+ cell counts and the use of, ARV medication. An otologic assessment and a comprehensive vestibular assessment (bedside, assessments, vestibular evoked myogenic potentials, ocular motor and positional tests and bithermal, caloric irrigation) were conducted. RESULTS: Vestibular involvement occurred in 79.2% of subjects with HIV in all categories of disease, progression, compared to 18.4% in those without HIV. Vestibular involvement increased from 18.9% in CDC category 1 to 30.2% in category 2. Vestibular involvement was 30.1% in category 3. There were, vestibular involvement in 35.9% of symptomatic HIV positive subjects, and 41.5% in asymptomatic, HIV positive subjects. There was no significant difference in the occurrence of vestibular involvement, in subjects receiving ARV therapies compared to those not receiving ARV therapies (p=.914; chi-square, test). The odds ratio indicates that individuals with HIV have a 16.61 times higher risk of developing, vestibular involvement during their lifetime of living with the disease and that it may occur despite, being asymptomatic. CONCLUSION: Vestibular involvement was significantly more common in subjects with HIV. Primary health care providers could screen HIV positive patients to ascertain if there are symptoms of vestibular involvement. If there are any, then they may consider further vestibular assessments and subsequent vestibular rehabilitation therapy. PMID- 24145103 TI - Reduction and alkylation of peanut allergen isoforms Ara h 2 and Ara h 6; characterization of intermediate- and end products. AB - Conglutins, the major peanut allergens, Ara h 2 and Ara h 6, are highly structured proteins stabilized by multiple disulfide bridges and are stable towards heat-denaturation and digestion. We sought a way to reduce their potent allergenicity in view of the development of immunotherapy for peanut allergy. Isoforms of conglutin were purified, reduced with dithiothreitol and subsequently alkylated with iodoacetamide. The effect of this modification was assessed on protein folding and IgE-binding. We found that all disulfide bridges were reduced and alkylated. As a result, the secondary structure lost alpha-helix and gained some beta-structure content, and the tertiary structure stability was reduced. On a functional level, the modification led to a strongly decreased IgE-binding. Using conditions for limited reduction and alkylation, partially reduced and alkylated proteins were found with rearranged disulfide bridges and, in some cases, intermolecular cross-links were found. Peptide mass finger printing was applied to control progress of the modification reaction and to map novel disulfide bonds. There was no preference for the order in which disulfides were reduced, and disulfide rearrangement occurred in a non-specific way. Only minor differences in kinetics of reduction and alkylation were found between the different conglutin isoforms. We conclude that the peanut conglutins Ara h 2 and Ara h 6 can be chemically modified by reduction and alkylation, such that they substantially unfold and that their allergenic potency decreases. PMID- 24145104 TI - Structural bases for a complete myotoxic mechanism: crystal structures of two non catalytic phospholipases A2-like from Bothrops brazili venom. AB - Bothrops brazili is a snake found in the forests of the Amazonian region whose commercial therapeutic anti-bothropic serum has low efficacy for local myotoxic effects, resulting in an important public health problem in this area. Catalytically inactive phospholipases A2-like (Lys49-PLA2s) are among the main components from Bothrops genus venoms and are capable of causing drastic myonecrosis. Several studies have shown that the C-terminal region of these toxins, which includes a variable combination of positively charged and hydrophobic residues, is responsible for their activity. In this work we describe the crystal structures of two Lys49-PLA2s (BbTX-II and MTX-II) from B. brazili venom and a comprehensive structural comparison with several Lys49-PLA2s. Based on these results, two independent sites of interaction were identified between protein and membrane which leads to the proposition of a new myotoxic mechanism for bothropic Lys49-PLA2s composed of five different steps. This proposition is able to fully explain the action of these toxins and may be useful to develop efficient inhibitors to complement the conventional antivenom administration. PMID- 24145105 TI - Newborn with oculocutaneous albinism. PMID- 24145106 TI - Breast cancer lung metastases incidentally detected on bone SPECT/CT: a rare finding that might be missed on whole body scan. PMID- 24145107 TI - Surgical repair of pulmonary artery branches. AB - Surgical repair of pulmonary artery (PA) branches encompasses many different clinical scenarios and technical challenges. The most common, such as bifurcation and central PA reconstruction, are described, as well as the challenges of complex and peripheral reconstruction. PMID- 24145108 TI - Suppression of alkali-induced oxidative injury in the cornea by mesenchymal stem cells growing on nanofiber scaffolds and transferred onto the damaged corneal surface. AB - The purpose of this study was to investigate whether rabbit bone marrow-derived mesenchymal stem cells (MSCs) effectively decrease alkali-induced oxidative stress in the rabbit cornea. The alkali (0.15 N NaOH) was applied on the corneas of the right eyes and then rinsed with tap water. In the first group of rabbits the injured corneas remained untreated. In the second group MSCs were applied on the injured corneal surface immediately after the injury and eyelids sutured for two days. Then the sutures were removed. In the third group nanofiber scaffolds seeded with MSCs (and in the fourth group nanofibers alone) were transferred onto the corneas immediately after the injury and the eyelids sutured. Two days later the eyelid sutures were removed together with the nanofiber scaffolds. The rabbits were sacrificed on days four, ten or fifteen after the injury, and the corneas were examined immunohistochemically, morphologically, for the central corneal thickness (taken as an index of corneal hydration) using an ultrasonic pachymeter and by real-time PCR. Results show that in untreated injured corneas the expression of malondialdehyde (MDA) and nitrotyrosine (NT) (important markers of lipid peroxidation and oxidative stress) appeared in the epithelium. The antioxidant aldehyde dehydrogenase 3A1 (ALDH3A1) decreased in the corneal epithelium, particularly in superficial parts, where apoptotic cell death (detected by active caspase-3) was high. (In control corneal epithelium MDA and NT are absent and ALDH3A1 highly present in all layers of the epithelium. Cell apoptosis are sporadic). In injured untreated cornea further corneal disturbances developed: The expressions of matrix metalloproteinase 9 (MMP9) and proinflammatory cytokines, were high. At the end of experiment (on day 15) the injured untreated corneas were vascularized and numerous inflammatory cells were present in the corneal stroma. Vascular endothelial growth factor (VEGF) expression and number of macrophages were high. The results obtained in injured corneas covered with nanofiber scaffolds alone (without MSCs) or in injured corneas treated with MSCs only (transferred without scaffolds) did not significantly differ from the results found in untreated injured corneas. In contrast, in the injured corneas treated with MSCs on nanofiber scaffolds, ALDH3A1 expression remained high in the epithelium (as in the control cornea) and positive expression of the other immunohistochemical markers employed was very low (MMP9) or absent (NT, MDA, proinflammatory cytokines), also similarly as in the control cornea. Corneal neovascularization and the infiltration of the corneal stroma with inflammatory cells were significantly suppressed in the injured corneas treated with MSCs compared to the untreated injured ones. The increased central corneal thickness together with corneal opalescency appearing after alkali injury returned to normal levels over the course of ten days only in the injured corneas treated with MSCs on nanofiber scaffolds. The expression of genes for the proinflammatory cytokines corresponded with their immunohistochemical expression. In conclusion, MSCs on nanofiber scaffolds protected the formation of toxic peroxynitrite (detected by NT residues), lowered apoptotic cell death and decreased matrix metalloproteinase and pro-inflammatory cytokine production. This resulted in reduced corneal inflammation as well as neovascularization and significantly accelerated corneal healing. PMID- 24145109 TI - Pharmacological actions of the slow release hydrogen sulfide donor GYY4137 on phenylephrine-induced tone in isolated bovine ciliary artery. AB - Hydrogen sulfide (H2S), a colorless gas characterized by its pungent odor of rotten eggs has been reported to elicit relaxation effects on basal and pre contracted non-ocular smooth muscles of several mammalian species. In the present study, we investigated the pharmacological actions of a H2S donor, GYY4137 on isolated bovine posterior ciliary artery after contraction with the adrenergic receptor agonist, phenylephrine. Furthermore, we studied the underlying mechanism of inhibitory action of GYY4137 on the posterior ciliary arteries. Isolated bovine posterior ciliary arteries were mounted in oxygenated organ baths and changes in isometric tension were measured with a Grass FT03 transducer connected to a recorder using a Grass Polyview Software. The relaxant actions of GYY4137 on phenylephrine pre-contracted arteries were observed in the absence and presence of an inhibitor of cyclo-oxygenase, flurbiprofen. Furthermore, the inhibitory effects of GYY4137 were studied in the absence or presence of inhibitors/activators of biosynthetic enzymes for H2S and nitric oxide production, as well as specific ion channel blockers. In the concentration range, 100 nM to 100 MUM, GYY4137 elicited a concentration-dependant relaxation of phenylephrine-induced tone in isolated posterior ciliary arteries, with IC50 value of 13.4 +/- 1.9 MUM (n = 6). The cyclo-oxygenase inhibitor, flurbiprofen, significantly (p < 0.01) enhanced the relaxation induced by GYY4137 yielding IC50 value of 0.13 +/- 0.08 MUM (n = 6). Both the inhibitors of cystathionine beta synthase (aminooxyacetic acid, AOAA, 30 MUM) and cystathionine gamma-lyase (propargylglycine, PAG, 1 mM) caused significant (p < 0.05) rightward shifts in the concentration-response curve to GYY4137. Furthermore, the KATP channel antagonist, glibenclamide (100 MUM) significantly (p < 0.01) attenuated the relaxant action induced by GYY4137 on bovine ciliary artery. Conversely, the activator of cystathionine beta-synthase, SAM (100 MUM) and an inhibitor of nitric oxide synthase, L-NAME (100 MUM) had no significant effect on relaxations induced by GYY4137. We conclude that the inhibitory action of GYY4137 on isolated bovine ciliary artery is dependent upon the endogenous production of both prostanoids and H2S. Furthermore, the observed vascular smooth muscle relaxation induced by GYY4137 is mediated, at least in part, by KATP channels. PMID- 24145110 TI - Surgical informed consent in Iran--how much is it informed? AB - INTRODUCTION: Informed consent constitutes one of the most important legal, professional, and ethical principles of a surgical operation. Consent obtained from a patient is only valid when the patient has received enough information regarding the proposed treatment option. This study aims to determine how much the patients are informed before undergoing surgery, as well as the factors influencing it in hospitals affiliated with Tehran University of Medical Sciences. METHOD: This is a cross-sectional, descriptive-analytic study of 300 patients undergoing surgery in 7 teaching hospitals affiliated with Tehran University of Medical Sciences. The patients were recruited through clustered sampling. Data were collected using a questionnaire completed by interview. Data were analyzed on SPSS software using descriptive and inferential statistics. RESULT: The mean score of data provision for patients was 27.09 out of 60, indicating the level of information provided as unacceptable. Among 12 questions dealing with data provision, patients had received an intermediate level of information about nature of the disease, type of surgery, benefits and importance of the surgery, and complications of rejecting the recommended therapy. On the contrary, they had not received enough information about the surgical procedure, type of anesthesia, potential complications of surgery, potential risks of surgery, other therapy options instead of surgery, length of hospital stay for surgery, postsurgical follow-up, and expenses of the surgery. In the majority (85%) of cases, the surgeon was reported to be the information provider. Among the variables studied, level of information received was directly related to the patient's education level. DISCUSSION: The findings of this study indicate that during the process of obtaining an informed consent for surgery, patients do not receive sufficient information, and it is necessary to provide the essential information in an understandable manner adjusted for the patient's level of education. PMID- 24145111 TI - Use of social media to conduct a cross-sectional epidemiologic and quality of life survey of patients with neuroendocrine carcinoma of the cervix: a feasibility study. AB - OBJECTIVE: To determine the feasibility of using social media to perform cross sectional epidemiologic and quality-of-life research on patients with rare gynecologic tumors, we performed a survey of patients with neuroendocrine tumors of the cervix using Facebook. METHODS: After approval from our Institutional Review Board, a support group of patients with neuroendocrine tumors of the cervix was identified on Facebook. Group members were asked to complete a survey comprising 84 questions evaluating clinical presentation; treatment; recurrence; quality of life; and sexual function. RESULTS: The survey was posted for 30 days, during which 57 women responded from 8 countries across 4 continents treated at 51 centers. All respondents provided a detailed clinical and tumor history. The mean age was 38.5 years. The stage distribution was stage I, 36 patients (63%); II, 13 (23%); III, 2 (4%); and IV, 6 (11%). Forty-nine patients (86%) had small cell and 8 (14%) had large cell tumors. Forty-five of the respondents (79%) had completed primary therapy and were without evidence of disease. Five (9%) had recurrence, 3 (5%) had persistent disease after therapy, and 4 (7%) were still under treatment. Forty-one patients (72%) reported symptoms at time of presentation. Thirty-seven patients (65%) received multimodality primary therapy. Quality of life instruments demonstrated high scores for anxiety and a negative impact of anxiety and cancer on functional and emotional well-being. Sexual function scores did not differ significantly between respondents and the PROMIS reference population. CONCLUSIONS: Use of a social media network to perform epidemiologic and quality of life research on patients with rare gynecologic tumors is feasible and permits such research to be conducted efficiently and rapidly. PMID- 24145112 TI - A novel diagnostic criterion for lymph node metastasis in cervical cancer using multi-detector computed tomography. AB - OBJECTIVES: The sensitivity of the current 10mm cut-off diameter that is used to diagnose lymph node (LN) metastasis is too low. This is the first study to develop a new criterion to diagnose LN metastasis in a region-by-region manner using multi-detector computed tomography (MDCT). METHODS: 1) The short-axis diameter of the LNs in MDCT images from 1-mm slices obtained immediately prior to surgery was compared with the pathological diagnosis in 78 uterine cervical cancer patients undergoing primary surgery. For the region-by-region analysis, we divided para-aortic and pelvic spaces into 13 regions. 2) In 28 cases in which patients received neoadjuvant chemotherapy (NAC) followed by surgery, we compared MDCT images before and after NAC. RESULTS: 1) The optimal cut-off in the region by-region analysis was 5mm, yielding 71% sensitivity and 79% specificity. 2) NAC significantly decreased LN size (p<0.0001). NAC decreased the number of swollen LN regions (>5mm) from 51% (81/158) to 26% (41/158). CONCLUSIONS: The new criterion developed using MDCT could be effective for accurately assessing LN status. It also facilitates the assessment of NAC efficacy regarding the eradication of LN metastases. PMID- 24145113 TI - Genetic profiling to predict recurrence of early cervical cancer. AB - OBJECTIVE: Recurrence is the major cause of death in early cervical cancer. We compared the prediction powers for disease recurrence between the gene set prognostic model and the clinical prognostic model. MATERIALS AND METHODS: A gene set model to predict disease free survival was developed using the cDNA-mediated annealing, selection, extension, and ligation (DASL) assay data set from a cohort of early cervical cancer patients who had been treated with radical surgery with or without adjuvant therapy. A clinical prediction model was also developed using the same cohort, and the ability of predicting recurrence from each model was compared. RESULTS: Adequate DASL assay profiles were obtained from 300 patients, and we selected 12 genes for the gene set model. When patients were categorized as having a low or high risk by the prognostic score, the Kaplan-Meier curve showed significantly different recurrence rates between the two groups. The clinical model was developed using FIGO stage and post-surgical pathological findings. In multivariate Cox regression analysis of prognostic models, the gene set prognostic model showed a higher hazard ratio than that of the clinical prognostic model. CONCLUSIONS: The genetic quantitative approach may be better in predicting recurrence in early cervical cancer patients. PMID- 24145114 TI - The synthetic flavonoid WYC02-9 inhibits cervical cancer cell migration/invasion and angiogenesis via MAPK14 signaling. AB - OBJECTIVE: Development of flavonoids as potential chemotherapeutic agents for cervical cancer may open new avenues in anticancer drug design. In this study, the cytotoxic activity and anti-migration/invasion/angiogenesis efficiency of the synthetic flavonoid WYC02-9 on cervical cancer and the underlying mechanisms are explored. METHODS: XTT cell viability assay, apoptosis assays, cell cycle analysis, and immunoblotting analysis were applied to study the biologic activity of WYC02-9. Anchorage independent soft agar assay and xenograft nude mouse model were applied to study the anti-tumor effect of WYC02-9 in vivo. Wound healing assay, transwell invasion assay, and gelatin zymography analysis were applied to study the effect of WYC02-9 on cancer cell migration and invasion. Tube formation analysis, zebrafish angiogenesis model, and nude mice Matrigel plug angiogenesis assay were applied to study the effect of WYC02-9 on angiogenesis. RESULTS: WYC02 9 induced cytotoxicity on cervical cancer cells by promoting apoptosis and G2/M cell cycle arrest. WYC02-9 inhibited cervical cancer cell migration/invasion and angiogenesis in vitro and in vivo via MAPK14 pathway. CONCLUSION: WYC02-9 significantly inhibited cervical cancer cell proliferation/migration/invasion and angiogenesis in vitro and in vivo. WYC02-9 may be a promising drug candidate for cervical cancer chemotherapy. PMID- 24145115 TI - Neo-adjuvant chemotherapy in the treatment of advanced malignant germ cell tumors of ovary. AB - OBJECTIVE: In order to preserve fertility, we attempted neo-adjuvant chemotherapy (NACT) in patients of malignant ovarian germ cell tumor (MOGCT) with advance and bulky disease. PATIENTS AND METHODS: Between January 1988 and December 2009, 23 patients received NACT. Patient's median age was 19 years, ranging from 14 to 28 years. FIGO stages III - 20 and IV - 3. Histology subtypes were: dysgerminoma, n = 14, mixed GCT, n=6 and 3 had endodermal sinus tumor. Patients were planned for four cycles of BEP (bleomycin, etoposide and cisplatin) chemotherapy followed by fertility sparing surgery (unilateral salpingo-oophorectomy+omentectomy +/- lymphadenectomy). RESULTS: Following NACT - 21 patients responded; complete (CR) 16 and partial response (PR) - 5. One patient progressed and another was lost to follow-up after 2 cycles. 18 of 21 responders underwent surgery; 13/18 had pathological CR, 5/18 had residual disease and achieved CR following 2 more cycles of BEP. 3 patients refused for surgery; 2 relapsed at 9 and 12 months, and achieved second CR following salvage chemotherapy and surgery, third patient continues to be disease-free. Currently, 21 of 23 patients are alive and disease free at a median follow-up of 74 months. 18/21 patients have resumed menstruation and 10 eligible patients have delivered 13 full term healthy babies. These results are comparable to patients with advanced disease (n = 43) treated with standard approach (initial surgery and adjuvant chemotherapy) during the same period. CONCLUSION: NACT followed by fertility sparing surgery could be a reasonable option for patients of advanced MOGCT, not suitable for optimal cyto reduction. PMID- 24145116 TI - Family-specific differences in growth rate and hepatic gene expression in juvenile triploid growth hormone (GH) transgenic Atlantic salmon (Salmo salar). AB - Growth hormone transgenic (GHTg) Atlantic salmon (Salmo salar) have enhanced growth when compared to their non-transgenic counterparts, and this trait can be beneficial for aquaculture production. Biological confinement of GHTg Atlantic salmon may be achieved through the induction of triploidy (3N). The growth rates of triploid GH transgenic (3NGHTg) Atlantic salmon juveniles were found to significantly vary between families in the AquaBounty breeding program. In order to characterize gene expression associated with enhanced growth in juvenile 3NGHTg Atlantic salmon, a functional genomics approach (32K cDNA microarray hybridizations followed by QPCR) was used to identify and validate liver transcripts that were differentially expressed between two fast-growing 3NGHTg Atlantic salmon families (AS11, AS26) and a slow-growing 3NGHTg Atlantic salmon family (AS25); juvenile growth rate was evaluated over a 45-day period. Of 687 microarray-identified differentially expressed features, 143 (116 more highly expressed in fast-growing and 27 more highly expressed in slow-growing juveniles) were identified in the AS11 vs. AS25 microarray study, while 544 (442 more highly expressed in fast-growing and 102 more highly expressed in slow-growing juveniles) were identified in the AS26 vs. AS25 microarray study. Forty microarray features (39 putatively associated with fast growth and 1 putatively associated with slow growth) were present in both microarray experiment gene lists. The expression levels of 15 microarray-identified transcripts were studied using QPCR with individual RNA samples to validate microarray results and to study biological variability of transcript expression. The QPCR results agreed with the microarray results for 12 of 13 putative fast-growth associated transcripts, but QPCR did not validate the microarray results for 2 putative slow growth associated transcripts. Many of the 39 microarray-identified genes putatively associated at the transcript expression level with fast-growing 3NGHTg salmon juveniles (including APOA1, APOA4, B2M, FADSD6, FTM, and GAPDH) are involved in metabolism, iron homeostasis and oxygen transport, and immune- or stress-related responses. The results of this study increase our knowledge of family-specific impacts on growth rate and hepatic gene expression in juvenile 3NGHTg Atlantic salmon. In addition, this study provides a suite of putative rapid growth rate-associated transcripts that may contribute to the development of molecular markers [e.g. intronic, exonic or regulatory region single nucleotide polymorphisms (SNPs)] for the selection of GHTg Atlantic salmon broodstock that can be utilized to produce sterile triploids of desired growth performance for future commercial applications. PMID- 24145117 TI - Transcriptome responses in the rectal gland of fed and fasted spiny dogfish shark (Squalus acanthias) determined by suppression subtractive hybridization. AB - Prior studies of the elasmobranch rectal gland have demonstrated that feeding induces profound and rapid up regulation of the gland's ability to secrete concentrated NaCl solutions and the metabolic capacity to support this highly ATP consuming process. We undertook the current study to attempt to determine the degree to which up regulation of mRNA transcription was involved in the gland's activation. cDNA libraries were created from mRNA isolated from rectal glands of fasted (7days post-feeding) and fed (6h and 22h post-feeding) spiny dogfish sharks (Squalus acanthias), and the libraries were subjected to suppression subtractive hybridization (SSH) analysis. Quantitative real time PCR (qPCR) was also used to ascertain the mRNA expression of several genes revealed by the SSH analysis. In total the treatments changed the abundance of 170 transcripts, with 103 up regulated by feeding, and 67 up regulated by fasting. While many of the changes took place in 'expected' Gene Ontology (GO) categories (e.g., metabolism, transport, structural proteins, DNA and RNA turnover, etc.), KEGG analysis revealed a number of categories which identify oxidative stress as a topic of interest for the gland. GO analysis also revealed that branched chain essential amino acids (e.g., valine, leucine, isoleucine) are potential metabolic fuels for the rectal gland. In addition, up regulation of transcripts for many genes in the anticipated GO categories did not agree (i.e., fasting down regulated in feeding treatments) with previously observed increases in their respective proteins/enzyme activities. These results suggest an 'anticipatory' storage of selected mRNAs which presumably supports the rapid translation of proteins upon feeding activation of the gland. PMID- 24145118 TI - How should we assess the safety of IVF technologies? AB - Clinical IVF treatment was established over 30 years ago through pioneering work by Edwards and Steptoe and other teams around the world and is now considered routine treatment. However, the pace of scientific and technological advances means that IVF practitioners can now access an increasing array of new and invasive technologies. The examples are many but include: extended embryo culture, development of media to include growth factors, developments in genetic screening, use of time-lapse technology and the advent of vitrification of embryos and oocytes. In parallel, wider scientific and medical advances are raising our awareness of the potential impact of assisted reproduction technology on areas such as embryonic development, gene expression and genomic imprinting and the developmental origins of health and disease. A recently suggested paradigm for assessing new technologies in IVF includes development in animal models such as rodents and large animals, preclinical research with human gametes and embryos donated to research, prospective clinical trials in IVF and, finally, follow-up studies of IVF children. In this paper, we describe efforts to address key areas of this pathway, namely preclinical research using human gametes/embryos and long-term, follow-up studies of the health of assisted reproduction children. PMID- 24145119 TI - Selecting the 'best' embryos: prospects for improvement. AB - This review considers why and how embryos are selected for transfer and with what consequences. It concludes that: (i) current selection methods are inadequate or at least inadequately subjected to evidential scrutiny; (ii) decisions about number of embryos should be based not solely on input (numbers transferred) but on the likelihood of the transfer resulting in multiple pregnancies - out turn; and (iii) what is needed are better methods not just for selecting better embryos, but also for selecting responsible clinicians who collude less with their patients' demands but advise them more responsibly. PMID- 24145120 TI - Indoleamine-2,3-dioxygenase elevated in tumor-initiating cells is suppressed by mitocans. AB - Tumor-initiating cells (TICs) often survive therapy and give rise to second-line tumors. We tested the plausibility of sphere cultures as models of TICs. Microarray data and microRNA data analysis confirmed the validity of spheres as models of TICs for breast and prostate cancer as well as mesothelioma cell lines. Microarray data analysis revealed the Trp pathway as the only pathway upregulated significantly in all types of studied TICs, with increased levels of indoleamine 2,3-dioxygenase-1 (IDO1), the rate-limiting enzyme of Trp metabolism along the kynurenine pathway. All types of TICs also expressed higher levels of the Trp uptake system consisting of CD98 and LAT1 with functional consequences. IDO1 expression was regulated via both transcriptional and posttranscriptional mechanisms, depending on the cancer type. Serial transplantation of TICs in mice resulted in gradually increased IDO1. Mitocans, represented by alpha-tocopheryl succinate and mitochondrially targeted vitamin E succinate (MitoVES), suppressed IDO1 in TICs. MitoVES suppressed IDO1 in TICs with functional mitochondrial complex II, involving transcriptional and posttranscriptional mechanisms. IDO1 increase and its suppression by VE analogues were replicated in TICs from primary human glioblastomas. Our work indicates that IDO1 is increased in TICs and that mitocans suppress the protein. PMID- 24145121 TI - Glutathione is essential to preserve nuclear function and cell survival under oxidative stress. AB - Glutathione (GSH) is considered the most important redox buffer of the cell. To better characterize its essential function during oxidative stress conditions, we studied the physiological response of H2O2-treated yeast cells containing various amounts of GSH. We showed that the transcriptional response of GSH-depleted cells is severely impaired, despite an efficient nuclear accumulation of the transcription factor Yap1. Moreover, oxidative stress generates high genome instability in GSH-depleted cells, but does not activate the checkpoint kinase Rad53. Surprisingly, scarce amounts of intracellular GSH are sufficient to preserve cell viability under H2O2 treatment. In these cells, oxidative stress still causes the accumulation of oxidized proteins and the inactivation of the translational activity, but nuclear components and activities are protected against oxidative injury. We conclude that the essential role of GSH is to preserve nuclear function, allowing cell survival and growth resumption after oxidative stress release. We propose that cytosolic proteins are part of a protective machinery that shields the nucleus by scavenging reactive oxygen species before they can cross the nuclear membrane. PMID- 24145122 TI - The psychotic mummified hand: an unusual hand injury complication. AB - The authors report the case of a patient with psychotic symptoms secondary to a posttraumatic stress disorder following a work-related hand injury. The somatic presentation was a "mummified" hand neglected for several years in a splint without any care. The psychiatric analysis concluded that this was part of a delusion of persecution expressing a conflict against the patient's employer and insurance company. Surgical treatment was limited to a hand cleaning with hardware removal. Despite 3 years of antipsychotic medication the patient was still suffering from delusion and the hand remained neglected at the last follow up. PMID- 24145123 TI - miR-203 induces oxaliplatin resistance in colorectal cancer cells by negatively regulating ATM kinase. AB - Chemotherapy for patients with metastatic colorectal cancer (CRC) is the standard of care, but ultimately nearly all patients develop drug resistance. Understanding the mechanisms that lead to resistance to individual chemotherapeutic agents may help identify novel targets and drugs that will, in turn, improve therapy. Oxaliplatin is a common component combination therapeutic regimen for use in patients with metastatic CRC, but is also used as a component of adjuvant therapy for patients at risk for recurrent disease. In this study, unbiased microRNA array screening revealed that the miR-203 microRNA is up regulated in three of three oxaliplatin-resistant CRC cell lines, and therefore we investigated the role of miR-203 in chemoresistance. Exogenous expression of miR-203 in chemo-naive CRC cells induced oxaliplatin resistance. Knockdown of miR 203 sensitized chemoresistant CRC cells to oxaliplatin. In silico analysis identified ataxia telangiectasia mutated (ATM), a primary mediator of the DNA damage response, as a potential target of miR-203. ATM mRNA and protein levels were significantly down-regulated in CRC cells with acquired resistance to oxaliplatin. Using TCGA database, we identified a significant reverse correlation of miR-203 and ATM expression in CRC tissues. We validated ATM as a bona fide target of miR-203 in CRC cells. Mutation of the putative miR-203 binding site in the 3' untranslated region (3'UTR) of the ATM mRNA abolished the inhibitory effect of miR-203 on ATM. Furthermore, stable knockdown of ATM induced resistance to oxaliplatin in chemo-naive CRC cells. This is the first report of oxaliplatin resistance in CRC cells induced by miR-203-mediated suppression of ATM. PMID- 24145124 TI - RETRACTED: Role of mammalian sirtuin 1 (SIRT1) in lipids metabolism and cell proliferation of goose primary hepatocytes. AB - This article has been retracted: please see Elsevier Policy on Article Withdrawal (http://www.elsevier.com/locate/withdrawalpolicy).This article has been retracted at the request of the Authors.It has come to the attention of the corresponding author that there are two errors in Section 3.1 of the Results section titled "Effect of overfeeding on gene expression and enzyme activity of several genes in liver". The first error is that the article contains the wrong number of overfeeding days. The second error is that there are incorrect correlations between liver weight, lipids content in live and plasma metabolic substrates because of the wrong overfeeding days.The authors take responsibility for them and apologize to the readership of Molecular and Cellular Endocrinology. PMID- 24145125 TI - Glucose sensing mechanisms in hypothalamic cell models: glucose inhibition of AgRP synthesis and secretion. AB - Glucose-sensing neurons play a role in energy homeostasis, yet how orexigenic neurons sense glucose remains unclear. As models of glucose-inhibited (GI) neurons, mHypoE-29/1 and mHypoA-NPY/GFP cells express the essential orexigenic neuropeptide AgRP and glucose sensing machinery. Exposure to increasing concentrations of glucose or the glucose analog 2-deoxyglucose (2-DG) results in a decrease in AgRP mRNA levels. Taste receptor, Tas1R2 mRNA expression was reduced by glucose, whereas 2-DG reduced Tas1R3 mRNA levels. Increasing glucose concentrations elicited a rise in Akt and neuronal nitric oxide synthase (nNOS) phosphorylation, CaMKKbeta levels, and a reduction of AMP-kinase alpha phosphorylation. Inhibitors of NOS and the cystic fibrosis transmembrane conductance regulator (CFTR) prevented a decrease in AgRP secretion with glucose, suggesting a pivotal role for nNOS and the CFTR in glucose-sensing. These models possess the hallmark characteristics of GI neurons, and can be used to disentangle the mechanisms by which orexigenic neurons sense glucose. PMID- 24145126 TI - Embryonic development of gonadotrope cells and gonadotropic hormones--lessons from model fish. AB - Pituitary gonadotropins, follicle-stimulating hormone (FSH) and luteinizing hormone (LH), are key regulators of vertebrate reproduction. The differential regulation of these hormones, however, is poorly understood and little is known about gonadotrope embryonic development. The different cell types in the vertebrate pituitary develop from common progenitor cells just after gastrulation. Proper development and merging of the anterior and posterior pituitary is dependent upon carefully regulated cell-to-cell interactions, and a suite of signaling pathways with precisely organized temporal and spatial expression patterns, which include transcription factors and their co-activators and repressors. Among the pituitary endocrine cell types, the gonadotropes are the last to develop and become functional. Although much progress has been made during the last decade regarding details of gonadotrope development, the coordinated program for their maturation is not well described. FSH and LH form an integral part of the hypothalamo-pituitary-gonad axis, the main regulator of gonad development and reproduction. Besides regulating gonad development, pre- and early post-natal activity in this axis is thought to be essential for proper development, especially of the central nervous system in mammals. As a means to investigate early functions of FSH and LH in more detail, we have developed a stable transgenic line of medaka with the LH beta subunit gene (lhb) promoter driving green fluorescent protein (Gfp) expression to characterize development of lhb-expressing gonadotropes. The lhb gene is maternally expressed early during embryogenesis. lhb-Expressing cells are initially localized outside the primordial pituitary in the developing gut tube as early as 32 hpf. At hatching, lhb-Gfp is clearly detected in the gut epithelium and in the anterior digestive tract. lhb-Gfp expression later consolidates in the developing pituitary by 2 weeks post-fertilization. This review discusses status of knowledge regarding pituitary morphology and development, with emphasis on gonadotrope cells and gonadotropins during early development, comparing main model species like mouse, zebrafish and medaka, including possible developmental functions of the observed extra pituitary expression of lhb in medaka. PMID- 24145127 TI - MicroRNA-224 is involved in the regulation of mouse cumulus expansion by targeting Ptx3. AB - MicroRNAs (miRNAs) are indicated to regulate ovarian development in a cell- or stage-specific manner. Our previous study showed that miR-224 is involved in TGF beta1-mediated follicular granulosa cell (GC) growth and estradiol (E2) production during the transition from the preantral to early antral stage by targeting Smad4. In this study, miR-224 was found to target pentraxin 3 (Ptx3), a gene critical for cumulus expansion during ovulation. In addition, PTX3 was up regulated in mouse mural GCs and cumulus-oocyte complexes (COCs) by TGF-beta1 treatment, which was partially mediated by miR-224. The effect of miR-224 during ovulation was further examined in vitro and in vivo by construction of an adenovirus-mediated expression vector for miR-224 (Ad-miR-224). In vitro studies demonstrated that miR-224 could perturb cumulus expansion in EGF-stimulated COCs by decreasing PTX3 secretion. In vivo studies also showed that injection of Ad miR-224 into ovarian bursa decreased PTX3 expression and disrupted ovulation, which led to a decreased number of implantation sites and offspring being born. These results indicate that miR-224 may affect ovulation and subsequent embryo development by targeting Ptx3, suggesting potential roles for miRNAs in offering new treatments for ovulation disorder-associated infertility, or, conversely, designing new contraceptives. PMID- 24145128 TI - Transcriptional repression of the Ahr gene by LHCGR signaling in preovulatory granulosa cells is controlled by chromatin accessibility. AB - Recent advances in establishing the role of the aryl hydrocarbon receptor (Ahr) in normophysiology have discovered its fundamental role, amongst others, in female reproduction. Considering previous studies suggesting the hormonal modulation of Ahr, we aimed to investigate whether in murine granulosa cells (GCs) the gonadotropins regulate Ahr expression and how this is mechanistically implemented. We found that the FSH-like substance--pregnant mare serum gonadotropin--led to stimulation of Ahr expression. More importantly hCG produced relatively rapid reduction of Ahr mRNA in GCs of preovulatory follicles. We show for the first time that LHCGR signaling in regulating the Ahr message involves protein kinase A pathway and is attributable to decreased transcription rate. Finally, we found that Ahr promoter accessibility was decreased by hCG, implicating chromatin remodeling in Ahr gene regulation by LH. PMID- 24145129 TI - Regulation of male fertility by the bone-derived hormone osteocalcin. AB - Traditionally, bone has been viewed as a relatively static tissue only fulfilling mechanical and scaffolding function. In the past decade however, this classical view of the bone has considerably evolved towards a more complex picture. It is now clear that the skeleton is not only a recipient for hormonal input but it is also an endocrine organ itself. Through the secretion of an osteoblast-derived molecule, osteocalcin, the skeleton regulates glucose homeostasis and male reproductive functions. When undercarboxylated, osteocalcin acts following its binding to a G-coupled receptor, Gprc6a, on pancreatic beta cells to increase insulin secretion, on muscle and white adipose tissue to promote glucose homeostasis and on Leydig cells of the testis to favor testosterone biosynthesis. More recently, it was also shown that osteocalcin acts via a pancreas-bone-testis axis that regulates, independently of and in parallel to the hypothalamus pituitary-testis axis, male reproductive functions by promoting testosterone biosynthesis. Lastly, in trying to expand the biological relevance of osteocalcin from mouse to human, it was shown that Gprc6a is a potential new susceptibility locus for primary testicular failure in humans. Altogether, these results shed new light on the importance of the endocrine role of the skeleton and also provide credence to the search for additional endocrine functions of this organ. PMID- 24145130 TI - Progestin-inducible EDD E3 ubiquitin ligase binds to alpha4 phosphoprotein to regulate ubiquitination and degradation of protein phosphatase PP2Ac. AB - Mammalian alpha4 phosphoprotein binds to the protein phosphatase 2A catalytic subunit (PP2Ac) to regulate PP2A activity, and to poly(A)-binding protein (PABP) and progestin-inducible EDD E3 ubiquitin ligase. This study showed induction of the EDD protein by progesterone, 17beta-estradiol and prolactin in breast cancer cells. Co-immunoprecipitation analyses, using lysates of COS-1 cells transfected with alpha4-deletion constructs, showed the alpha4 N-terminus binding to endogenous PP2Ac and PABP, and the C-terminus to EDD. Monoubiquitinated alpha4 in MCF-7 cells was unaffected by EDD-targeting siRNA (siEDD) nor by non-targetting siNT, thus, EDD does not ubiquitinate alpha4. PP2Ac is polyubiquitinated, and 36 kDa PP2Ac only was detected in siEDD- or siNT-transfected cells. However, treatment with proteasomal inhibitor MG132 showed polyubiquitinated-PP2Ac molecules (~65-250kDa) abundantly in siNT controls but low in siEDD transfectants, implicating PP2Ac as an EDD substrate. Finally, progesterone induction of EDD in MCF-7 cells correlated with decreased PP2Ac levels, further implicating hormone-inducible EDD in PP2Ac turnover. PMID- 24145132 TI - Cellular mechanisms and integrative timing of neuroendocrine control of GnRH secretion by kisspeptin. AB - The hypothalamus integrates endogenous and exogenous inputs to control the pituitary-gonadal axis. The ultimate hypothalamic influence on reproductive activity is mediated through timely secretion of GnRH in the portal blood, which modulates the release of gonadotropins from the pituitary. In this context neurons expressing the RF-amide neuropeptide kisspeptin present required features to fulfill the role of the long sought-after hypothalamic integrative centre governing the stimulation of GnRH neurons. Here we focus on the intracellular signaling pathways triggered by kisspeptin through its cognate receptor KISS1R and on the potential role of proteins interacting with this receptor. We then review evidence implicating both kisspeptin and RFRP3--another RF-amide neuropeptide--in the temporal orchestration of both the pre-ovulatory LH surge in female rodents and the organization of seasonal breeding in photoperiodic species. PMID- 24145131 TI - Angiotensin II-induced activation of central AT1 receptors exerts endocannabinoid mediated gastroprotective effect in rats. AB - The aim of the present study was to analyze whether angiotensin II via the endocannabinoid system can induce gastric mucosal protection, since transactivation of cannabinoid CB1 receptors by angiotensin AT1 receptor in CHO cells was described. Experimental ulcer was induced by acidified ethanol given orally in male Wistar rats, CB1(+/+) wild type and CB1(-/-) knockout mice. The compounds were administered intracerebroventricularly. It was found, that 1. Angiotensin II inhibited the ethanol-induced gastric lesions (11.9-191pmol); the effect of angiotensin II (191pmol) was inhibited by the CB1 receptor inverse agonist AM 251 (1.8nmol) and the inhibitor of diacylglycerol lipase (DAGL), tetrahydrolipstatin (0.2nmol). 2. Angiotensin II exerted gastroprotection in wild type, but not in CB1(-/-) mice. 3. The gastroprotective effect of angiotensin II (191pmol) was reduced by atropine (1mg/kg i.v.) and bilateral cervical vagotomy. In conclusion, stimulation of central angiotensin AT1 receptors via activation of cannabinoid CB1 receptors induces gastroprotection in a DAGL-dependent and vagus mediated mechanism. PMID- 24145134 TI - Scintillation event energy measurement via a pulse model based iterative deconvolution method. AB - This work focuses on event energy measurement, a crucial task of scintillation detection systems. We modeled the scintillation detector as a linear system and treated the energy measurement as a deconvolution problem. We proposed a pulse model based iterative deconvolution (PMID) method, which can process pileup events without detection and is adaptive for different signal pulse shapes. The proposed method was compared with digital gated integrator (DGI) and digital delay-line clipping (DDLC) using real world experimental data. For singles data, the energy resolution (ER) produced by PMID matched that of DGI. For pileups, the PMID method outperformed both DGI and DDLC in ER and counts recovery. The encouraging results suggest that the PMID method has great potentials in applications like photon-counting systems and pulse height spectrometers, in which multiple-event pileups are common. PMID- 24145133 TI - TRPV1 antagonist capsazepine suppresses 4-AP-induced epileptiform activity in vitro and electrographic seizures in vivo. AB - Transient receptor potential vanilloid 1 (TRPV1) is a cation-permeable ion channel found in the peripheral and central nervous systems. The membrane surface expression of TRPV1 is known to occur in neuronal cell bodies and sensory neuron axons. TRPV1 receptors are also expressed in the hippocampus, the main epileptogenic region in the brain. Although, previous studies implicate TRPV1 channels in the generation of epilepsy, suppression of ongoing seizures by TRPV1 antagonists has not yet been attempted. Here, we evaluate the role of TRPV1 channels in the modulation of epileptiform activity as well as the anti convulsant properties of capsazepine (CZP), an established TRPV1 competitive antagonist, using in vitro and in vivo models. To this end, we used 4 aminopyridine (4-AP) to trigger seizure-like activity. We found that CZP suppressed 4-AP induced epileptiform activity in vitro (10-100MUM) and in vivo (50mg/kg s.c.). In contrast, capsaicin enhanced 4-AP induced epileptiform activity in vitro (1-100MUM) and triggered bursting activity in vivo (100MUM dialysis perfusion), which was abolished by the TRPV1 antagonist CZP. To further investigate the mechanisms of TRPV1 modulation, we studied the effect of capsaicin and CZP on evoked potentials. Capsaicin (1-100MUM) and CZP (10-100MUM) increased and decreased, respectively, the amplitude of extracellular field evoked potentials in a concentration-dependent manner. Additional in vitro studies showed that the effect of the TRPV1 blocker on evoked potentials was similar whether the response was orthodromic or antidromic, suggesting that the effect involves interference with membrane depolarization on cell bodies and axons. The fact that CZP could act directly on axons was confirmed by decreased amplitude of the compound action potential and by an increased delay of both the antidromic potentials and the axonal response. Histological studies using transgenic mice also show that, in addition to the known neural expression, TRPV1 channels are widely expressed in alvear oligodendrocytes in the hippocampus. Taken together, these results indicate that activation of TRPV1 channels leads to enhanced excitability, while their inhibition can effectively suppress ongoing electrographic seizures. These results support a role for TRPV1 channels in the suppression of convulsive activity, indicating that antagonism of TRPV1 channels particularly in axons may possibly be a novel target for effective acute suppression of seizures. PMID- 24145135 TI - Neuropsychological and neuroimaging phenotype induced by a CAMTA1 mutation. AB - BACKGROUND/AIMS: CAMTA1 mutations have recently been reported in families with intellectual disability and/or non-progressive congenital ataxias. The objective of this study was to describe the neuropsychological and neuroimaging phenotype of CAMTA1 mutation. METHODS: We performed neuropsychological examinations, MRI and FDG-PET imaging in three patients with autosomal dominant mild intellectual disabilities and ataxia induced by a CAMTA1 intragenic deletion at 1p36.31p36.23. RESULTS: Neuropsychological tests showed similar findings in two patients, with low information processing speed, slow memory consolidation, phonological disorders, working memory deficits, but mainly preserved executive function. Bilateral parietal and medial temporal abnormalities were found on brain MRI. Diffuse parieto-occipital and local left temporo-parietal decrease of FDG uptake was observed on PET images. CONCLUSION: These results suggest that CAMTA1 mutation may induce an unusual neuropsychological profile and parieto-temporal developmental abnormalities. We recommend screening for CAMTA1 mutations in patients with autosomal dominant mild intellectual disability presenting with similar a phenotype. PMID- 24145136 TI - Synthesis and biochemical evaluation of highly enantiomerically pure (R,R)- and (S,S)-alexidine. AB - Alexidine is in everyday human use as oral disinfectant and contact lens disinfectant. It is used as a mixture of stereoisomers. Since all of alexidine's known biological targets are chiral, the biological activity of any of its chiral stereoisomers could be significantly higher than that of the mixture of stereoisomers. This makes a synthetic methodology for obtaining the individual enantiomers of the chiral diastereoisomer highly desirable. Here, we describe the first synthesis of both enantiomers of alexidine in high enantiomeric purity, and demonstrate their activity against the protein-protein interaction between the anti-apoptotic protein Bcl-xL and the pro-apoptotic protein Bak. PMID- 24145138 TI - Synthesis of combretastatin A-4 O-alkyl derivatives and evaluation of their cytotoxic, antiangiogenic and antitelomerase activity. AB - We here report the synthesis and biological evaluation of several combretastatin A-4 derivatives alkylated at the phenol hydroxyl group. Some of these derivatives contain an (E)-arylalkene fragment reminiscent of that present in some natural stilbenes like resveratrol. The cytotoxicities towards one human healthy kidney embryonic and two tumoral cell lines were determined. In addition, the ability of these compounds to inhibit the production of the vascular endothelial growth factor (VEGF) was measured. Finally, the expression of genes controlling the production of telomerase was measured. Some of the compounds were found to have an activity comparable or higher than that of combretastatin A-4 in at least one of the aforementioned biological properties. The compounds with the (E) arylalkene fragment were in general terms more active than the simple O-alkyl derivatives. However, no clear structure/activity correlations were perceived when comparing the observed compound activities across the three biological properties. This points out the existence of marked differences between the mechanisms responsible for their cytotoxicity. PMID- 24145137 TI - The 3,7-diazabicyclo[3.3.1]nonane scaffold for subtype selective nicotinic acetylcholine receptor ligands. Part 2: carboxamide derivatives with different spacer motifs. AB - 3,7-Diazabicyclo[3.3.1]nonane (bispidine) based nicotinic acetylcholine receptor (nAChR) ligands have been synthesized and evaluated for nAChRs interaction. Diverse spacer motifs were incorporated between the hydrogen bond acceptor (HBA) part and a variety of substituted (hetero)aryl moieties. Bispidine carboxamides bearing spacer motifs often showed high affinity in the low nanomolar range and selectivity for the alpha4beta2(*) nAChR. Compounds 15, 25, and 47 with Ki values of about 1 nM displayed the highest affinities for alpha4beta2(*) nAChR. All evaluated compounds are partial agonists or antagonists at alpha4beta2(*), with reduced or no effects on alpha3beta4(*) with the exception of compound 15 (agonist), and reduced or no effect at alpha7 and muscle subtypes. PMID- 24145139 TI - Mycobacterium tuberculosis possesses an unusual tmRNA rescue system. AB - Trans-translation is a key process in bacteria which recycles stalled ribosomes and tags incomplete nascent proteins for degradation. This ensures the availability of ribosomes for protein synthesis and prevents the accumulation of dysfunctional proteins. The tmRNA, ssrA, is responsible for both recovering stalled ribosomes and encodes the degradation tag; ssrA associates and functions with accessory proteins such as SmpB. Although ssrA and smpB are ubiquitous in bacteria, they are not essential for the viability of many species. The Mycobacterium tuberculosis genome has homologues of both ssrA and smpB. We demonstrated that ssrA is essential in M. tuberculosis, since the chromosomal copy of the gene could only be deleted in the presence of a functional copy integrated elsewhere. However, we were able to delete the proteolytic tagging function by constructing strains carrying a mutant allele (ssrADD). This demonstrates that ribosome rescue by ssrA is the essential function in M. tuberculosis, SmpB was not required for aerobic growth, since we were able to construct a deletion strain. However, the smpBDelta strain was more sensitive to antibiotics targeting the ribosome. Strains with deletion of smpB or mutations in ssrA did not show increased sensitivity (or resistance) to pyrazinamide suggesting that this antibiotic does not directly target these components of the tmRNA tagging system. PMID- 24145141 TI - Microwave-assisted acid hydrolysis of proteins combined with peptide fractionation and mass spectrometry analysis for characterizing protein terminal sequences. AB - We report a relatively simple mass spectrometric technique for characterizing the terminal amino acid sequences of proteins. It is based on the use of microwave assisted acid hydrolysis (MAAH) with 3M HCl to hydrolyze a protein into polypeptide ladders with varying sizes of up to the molecular mass of the protein. The hydrolysate is then fractionated by isocratic reversed phase liquid chromatography (RPLC) to produce a low-mass-peptide fraction mainly consisting of the terminal peptides. This fraction is subjected to LC tandem mass spectrometry (MS/MS) analysis to generate the terminal peptide sequence information. Using bovine serum albumin as an example, it is shown that more than 10 terminal peptides of each end could be identified using as little as 0.5MUg (7.5pmol) of protein. This method was applied for the characterization of a recombinant protein (mCherry with an additional sequence tag added to the N-terminal for expression and purification) and its truncated form (mCherry treated with enterokinase to cleave off the tag). Sequence errors and unexpected by-products with different terminal sequences were determined from these two samples, illustrating that this method of HCl MAAH with peptide fractionation and LC-MS/MS analysis should be useful for detailed characterization of protein terminal sequences. BIOLOGICAL SIGNIFICANCE: Protein terminal truncation or modification plays an important role in determining the biological functions of a protein. Detailed characterization of protein terminal sequences is critical in biological studies as well as in the development and quality control of protein-based therapeutics and vaccines. In this work, we report a relatively simple method for analyzing protein terminal sequences based on microwave-assisted acid hydrolysis to generate the peptide ladder of a protein, liquid chromatography fractionation of the resultant ladder to collect the low-mass-peptide fraction which mainly contains terminal peptides, and LC-ESI MS/MS sequencing of the collected peptides. This article is part of a Special Issue entitled: Can Proteomics Fill the Gap Between Genomics and Phenotypes? PMID- 24145140 TI - mRNA expression profile of multidrug-resistant genes in acute lymphoblastic leukemia of children, a prognostic value for ABCA3 and ABCA2. AB - Multidrug resistance (MDR) is an important cause of treatment failure in acute lymphoblastic leukemia (ALL). The ABC family of membrane transporters is proposed, albeit with controversy, to be involved in this process. The present study aims to investigate the mRNA expression profile of several genes of this family, including ABCA2, ABCA3, ABCB1/MDR1, MRP1/ABCC1, MRP3/ABCC3, ABCG2/BCRP, and the intracellular transporter MVP/LRP, in childhood ALL, and to evaluate their association with response to therapy. Some genes in the present research are being studied for the first time in Iran. Using quantitative real-time PCR, we evaluated 27 children with ALL at diagnosis and 15 children with normal bone marrow. The status of response to therapy was assessed one year after the onset of therapy through investigating the IgH/TCRgamma gene rearrangements. Our findings indicate a considerable and direct relationship between mRNA expression levels of ABCA2, ABCA3, MDR1, and MRP1 genes and positive minimal residual disease (MRD) measured after one year of treatment. Statistical analysis revealed that expression of these genes higher than the cutoff point will raise the risk of MRD by 15-, 6.25-, 12-, and 9-fold, respectively. No relationship was found between of MVP/LRP, MRP3 and ABCG2 genes expression and ALL prognoses. Considering the direct and significant relationship between the increased expression of ABCA2, ABCA3, MDR1, and MRP1 genes and positive risk of MRD in children with ALL, evaluating the expression profile of these genes on diagnosis may identify high risk individuals and help plan a more efficient treatment strategy. PMID- 24145142 TI - The strategy, organization, and progress of the HUPO Human Proteome Project. AB - The Human Proteome Project is a major, comprehensive initiative of the Human Proteome Organization. This global collaborative effort aims to identify and characterize at least one protein product and many PTM, SAP, and splice variant isoforms from the 20,300 human protein-coding genes. The deliverables are an extensive parts list and an array of technology platforms, reagents, spectral libraries, and linked knowledge bases that advance the field and facilitate the use of proteomics by a much wider community of life scientists. Such enablement will help address the Grand Challenge of using proteomics to bridge major gaps between evidence of genomic variation and diverse phenotypes. BIOLOGICAL SIGNIFICANCE: The HUPO Human Proteome Project (HPP) has made an outstanding launch, including a special issue of the Journal of Proteome Research on the Chromosome-centric HPP with a total of 48 articles. This article is part of a Special Issue: Can Proteomics Fill the Gap Between Genomics and Phenotypes? PMID- 24145143 TI - The serum proteome of Atlantic salmon, Salmo salar, during pancreas disease (PD) following infection with salmonid alphavirus subtype 3 (SAV3). AB - Salmonid alphavirus is the aetological agent of pancreas disease (PD) in marine Atlantic salmon, Salmo salar, and rainbow trout, Oncorhynchus mykiss, with most outbreaks in Norway caused by SAV subtype 3 (SAV3). This atypical alphavirus is transmitted horizontally causing a significant economic impact on the aquaculture industry. This histopathological and proteomic study, using an established cohabitational experimental model, investigated the correlation between tissue damage during PD and a number of serum proteins associated with these pathologies in Atlantic salmon. The proteins were identified by two-dimensional electrophoresis, trypsin digest and peptide MS/MS fingerprinting. A number of humoral components of immunity which may act as biomarkers of the disease were also identified. For example, creatine kinase, enolase and malate dehydrogenase serum concentrations were shown to correlate with pathology during PD. In contrast, hemopexin, transferrin, and apolipoprotein, amongst others, altered during later stages of the disease and did not correlate with tissue pathologies. This approach has given new insight into not only PD but also fish disease as a whole, by characterisation of the protein response to infection, through pathological processes to tissue recovery. BIOLOGICAL SIGNIFICANCE: Salmonid alphavirus causes pancreas disease (PD) in Atlantic salmon, Salmo salar, and has a major economic impact on the aquaculture industry. A proteomic investigation of the change to the serum proteome during PD has been made with an established experimental model of the disease. Serum proteins were identified by two dimensional electrophoresis, trypsin digest and peptide MS/MS fingerprinting with 72 protein spots being shown to alter significantly over the 12week period of the infection. The concentrations of certain proteins in serum such as creatine kinase, enolase and malate dehydrogenase were shown to correlate with tissue pathology while other proteins such as hemopexin, transferrin, and apolipoprotein, altered in concentration during later stages of the disease and did not correlate with tissue pathologies. The protein response to infection may be used to monitor disease progression and enhance understanding of the pathology of PD. PMID- 24145144 TI - Proteomics boosts translational and clinical microbiology. AB - The application of proteomics to translational and clinical microbiology is one of the most advanced frontiers in the management and control of infectious diseases and in the understanding of complex microbial systems within human fluids and districts. This new approach aims at providing, by dedicated bioinformatic pipelines, a thorough description of pathogen proteomes and their interactions within the context of human host ecosystems, revolutionizing the vision of infectious diseases in biomedicine and approaching new viewpoints in both diagnostic and clinical management of the patient. Indeed, in the last few years, many laboratories have matured a series of advanced proteomic applications, aiming at providing individual proteome charts of pathogens, with respect to their morph and/or cell life stages, antimicrobial or antimycotic resistance profiling, epidemiological dispersion. Herein, we aim at reviewing the current state-of-the-art on proteomic protocols designed and set-up for translational and diagnostic microbiological purposes, from axenic pathogens' characterization to microbiota ecosystems' full description. The final goal is to describe applications of the most common MALDI-TOF MS platforms to advanced diagnostic issues related to emerging infections, increasing of fastidious bacteria, and generation of patient-tailored phylotypes. This article is part of a Special Issue entitled: Trends in Microbial Proteomics. PMID- 24145145 TI - The pore-forming bacterial effector, VopQ, halts autophagic turnover. AB - Vibrio parahemolyticus Type III effector VopQ is both necessary and sufficient to induce autophagy within one hour of infection. We demonstrated that VopQ interacts with the Vo domain of the conserved vacuolar H(+)-ATPase. Membrane associated VopQ subsequently forms pores in the membranes of acidic compartments, resulting in immediate release of protons without concomitant release of lumenal protein contents. These studies show how a bacterial pathogen can compromise host ion potentials using a gated pore-forming effector to equilibrate levels of small molecules found in endolysosomal compartments and disrupt cellular processes such as autophagy. PMID- 24145146 TI - Ultrasound indicators of persistent obstruction after submandibular sialolithotomy. AB - OBJECTIVE: To identify and describe the ultrasound indicators of persistent obstruction following transoral submandibular sialolithotomy and discuss the utility of ultrasound in the immediate postoperative period. STUDY DESIGN: We performed a prospective case series with planned data collection of patients who underwent treatment for symptomatic submandibular swelling. SETTING: A tertiary care center. SUBJECTS: Thirty-three patients of either sex with known submandibular gland sialoliths who failed endoscopic retrieval of calculi. METHODS: We performed in-office or operating room-based transoral submandibular gland sialolithotomy followed by immediate postprocedure ultrasound examination for the assessment of residual calculi. All patients underwent mandatory reexploration for suspicious findings. RESULTS: Only the appearance of hyperechogenic foci with posterior shadowing reliably predicted the presence of residual stones following transoral sialolithotomy (P < .0001). The presence of hyperechogenic foci without posterior shadowing (P = 1.00), ductal dilatation (P = .23), and intraglandular dilatation (P = 1.00) was not indicative of retained calculi. CONCLUSION: The presence of hyperechogenic foci with posterior shadowing on immediate postprocedure ultrasound is an accurate indicator of residual stones following transoral submandibular sialolithotomy. Ultrasound examination can be reliably used to identify patients at risk of symptomatic recurrence of sialoliths. PMID- 24145147 TI - Comparison of dental health of patients with head and neck cancer receiving IMRT vs conventional radiation. AB - OBJECTIVE: To analyze the dental health of patients with head and neck cancer who received comprehensive dental care after intensity-modulated radiation therapy (IMRT) compared with radiation therapy (RT). STUDY DESIGN: Historical cohort study. SETTING: Veteran Affairs (VA) hospital. SUBJECTS AND METHODS: In total, 158 patients at a single VA hospital who were treated with RT or IMRT between 2003 and 2011 were identified. A complete dental evaluation was performed prior to radiation treatment, including periodontal probing, tooth profile, cavity check, and mobility. The dental treatment plan was formulated to eliminate current and potential dental disease. The rates of dental extractions, infections, caries, mucositis, xerostomia, and osteoradionecrosis (ORN) were analyzed, and a comparison was made between patients treated with IMRT and those treated with RT. RESULTS: Of the 158 patients, 99 were treated with RT and 59 were treated with IMRT. Compared with those treated with IMRT, significantly more patients treated with RT exhibited xerostomia (46.5% vs 16.9%; P < .001; odds ratio [OR], 0.24; 95% confidence interval [CI], 0.11-0.52), mucositis (46.5% vs 16.9%; P < .001; OR, 0.24; 95% CI, 0.11-0.52), and ORN (10.1% vs 0%; P = .014; OR, 0.07; 95% CI, 0.00-1.21). However, significantly more patients treated with IMRT were edentulous by the conclusion of radiation treatment (32.2% vs 11.1%; P = .002; OR, 3.8; 95% CI, 1.65-8.73). CONCLUSION: Patients who were treated with IMRT had fewer instances of dental disease, more salivary flow, and fewer requisite posttreatment extractions compared with those treated with RT. The number of posttreatment extractions has been reduced with the advent of IMRT and more so with a complete dental evaluation prior to treatment. PMID- 24145149 TI - Recombinant soluble CD137 prevents type one diabetes in nonobese diabetic mice. AB - Nonobese diabetic (NOD) mice are genetically programmed to spontaneously develop type one diabetes (T1D). Multiple Insulin dependent diabetes (Idd) genetic loci have been identified but their functional effects are mostly poorly understood. TnfsfR9, expressing the protein product CD137, is a strong candidate gene in the Idd9.3 locus, and NOD.B10 Idd9.3 mice are significantly protected from type one diabetes (T1D). We previously showed that nonobese diabetic (NOD) mice have a deficiency in the numbers of CD137(pos) T regulatory cells, that CD137(pos) Tregs are the source of soluble CD137 (sCD137), and that NOD mice have low serum levels of sCD137. To test the hypothesis that correcting low levels of sCD137 could affect the disease, we constructed a lentiviral vector producing recombinant sCD137; this physiologic sCD137 is glycosylated and exists primarily as a dimer. NOD mice treated with the recombinant sCD137 are protected from developing T1D. Insulitis is significantly decreased, but not eliminated in the sCD137 treated mice, however insulin producing pancreatic beta cells are preserved despite residual insulitis. To begin to understand the protective immune mechanisms of sCD137, we tested sCD137 in vitro. It was previously suggested that sCD137 simply blocked the interaction between CD137 (on T cells) and CD137 ligand (on antigen presenting cells (APCs)). Here however, we use an APC independent assay and demonstrate that sCD137 can actively suppress highly purified CD4 T cells in a CD137L dependent fashion. These results support the hypothesis that sCD137 acts in a negative feedback loop to actively suppress over-zealous immune responses, and that it can be used clinically to suppress autoimmunity. sCD137 is an important Treg derived natural immunosuppressive molecule that regulates effector T cells to avert diabetes in vivo. PMID- 24145150 TI - An interface finite element model can be used to predict healing outcome of bone fractures. AB - After fractures, bone can experience different potential outcomes: successful bone consolidation, non-union and bone failure. Although, there are a lot of factors that influence fracture healing, experimental studies have shown that the interfragmentary movement (IFM) is one of the main regulators for the course of bone healing. In this sense, computational models may help to improve the development of mechanical-based treatments for bone fracture healing. Hence, based on this fact, we propose a combined repair-failure mechanistic computational model to describe bone fracture healing. Despite being a simple model, it is able to correctly estimate the time course evolution of the IFM compared to in vivo measurements under different mechanical conditions. Therefore, this mathematical approach is especially suitable for modeling the healing response of bone to fractures treated with different mechanical fixators, simulating realistic clinical conditions. This model will be a useful tool to identify factors and define targets for patient specific therapeutics interventions. PMID- 24145148 TI - Corticotropin releasing factor in neuroplasticity. AB - Stress is among the strongest signals promoting neuroplasticity: Stress signals, indicating real or perceived danger, lead to alterations of neuronal function and often structure, designed to adapt to the changed conditions and promote survival. Corticotropin releasing factor (CRF) is expressed and released in several types of neuronal populations that are involved in cognition, emotion and the regulation of autonomic and endocrine function. CRF expressing neurons undergo functional and structural plasticity during stress and, in addition, the peptide acts via specific receptors to promote plasticity of target neurons. PMID- 24145151 TI - Chemotherapy stimulates syndecan-1 shedding: a potentially negative effect of treatment that may promote tumor relapse. AB - In patients with multiple myeloma, the heparan sulfate proteoglycan syndecan-1 (CD138) is shed from the surface of tumor cells and accumulates in the serum and within the extracellular matrix of the bone marrow where it promotes tumor growth and metastasis. In the present study we discovered that commonly used anti myeloma drugs stimulate syndecan-1 shedding both in vitro and in animals bearing myeloma tumors. Enhanced shedding is accompanied by increased syndecan-1 synthesis prior to drug induced tumor cell death. Addition of a caspase inhibitor blocks the drug-induced shedding of syndecan-1 in vitro indicating that shedding is linked to the onset of apoptosis. ADAM inhibitors or siRNA targeting ADAMs blocked drug-induced shedding suggesting that upregulation or activation of ADAMs is responsible for cleaving syndecan-1 from the tumor cell surface. These results reveal that myeloma chemotherapy stimulates synthesis and shedding of syndecan-1, a potentially negative side effect that may lead to the accumulation of high levels of syndecan-1 to establish a microenvironment that nurtures relapse and promotes tumor progression. Interestingly, we also found that chemotherapeutic drugs stimulated syndecan-1 shedding from pancreatic cancer cells as well, indicating that drug-induced shedding of syndecan-1 may occur in many cancer types. Overall, our results indicate that the use of metalloproteinase inhibitors (to inhibit syndecan-1 shedding) in combination with chemotherapy may represent a novel therapeutic strategy to prevent re-establishment of a microenvironment conducive for tumor relapse. PMID- 24145152 TI - Heparan sulfate proteoglycan as a cell-surface endocytosis receptor. AB - How various macromolecules are exchanged between cells and how they gain entry into recipient cells are fundamental questions in cell biology with important implications e.g. non-viral drug delivery, infectious disease, metabolic disorders, and cancer. The role of heparan sulfate proteoglycan (HSPG) as a cell surface receptor of diverse macromolecular cargo has recently been manifested. Exosomes, cell penetrating peptides, polycation-nucleic acid complexes, viruses, lipoproteins, growth factors and morphogens among other ligands enter cells through HSPG-mediated endocytosis. Key questions that partially have been unraveled over recent years include the respective roles of HSPG core protein and HS chain structure specificity for macromolecular cargo endocytosis, the down stream intracellular signaling events involved in HSPG-dependent membrane invagination and vesicle formation, and the biological significance of the HSPG transport pathway. Here, we discuss the intriguing role of HSPGs as a major entry pathway of macromolecules in mammalian cells with emphasis on recent in vitro and in vivo data that provide compelling evidence of HSPG as an autonomous endocytosis receptor. PMID- 24145153 TI - Bone marrow-derived myofibroblasts promote colon tumorigenesis through the IL 6/JAK2/STAT3 pathway. AB - Bone marrow-derived myofibroblasts (BMFs) have been shown to promote tumor growth. Here, we found that BMFs or BMF conditioned medium (BMF-CM) induced cancer stem cell-like sphere formation of colon cancer cells. The co-cultured BMFs, but not co-cultured cancer cells, expressed higher levels of IL-6 than BMFs or cancer cells cultured alone. Anti-mouse IL-6 neutralizing antibody, JAK2 inhibitors and STAT3 knockdown in mouse cancer cells reduced BMF- and BMF-CM induced sphere formation of colon cancer cells. When co-injected, BMFs significantly enhanced tumorigenesis of colon cancer cells in mice. Our results demonstrate that BMFs promote tumorigenesis via the activation of the IL 6/JAK2/STAT3 pathway. PMID- 24145154 TI - Clinical advances and controversies. PMID- 24145155 TI - Genetic characterisation of infectious bursal disease virus isolates in Ethiopia. AB - The objective of the investigation was to characterise infectious bursal disease viruses (IBDV) circulating in commercial and breeding poultry farms in Ethiopia between 2009 and 2011. The nucleotide and deduced amino acid sequence for VP2 hypervariable region of ten IBDVs were determined by RT-PCR, sequenced and compared to well characterised IBDV isolates worldwide. IBDV genetic material was amplified directly from bursa or cell passaged material. Phylogenetically, Ethiopian IBDVs represented two genetic lineages: very virulent (vv) IBDVs or variants of the classical attenuated vaccine strain (D78). The nucleotide identity between Ethiopian vvIBDVs ranged between 0% and 2.6%. Ethiopian vvIBDVs are clustered phylogenetically with the African IBDV genetic lineage, independent of the Asian/European lineage. This report demonstrates the circulation of vvIBDV in commercial and breeding poultry farms in Ethiopia. PMID- 24145156 TI - A novel association between Rhodnius neglectus and the Livistona australis palm tree in an urban center foreshadowing the risk of Chagas disease transmission by vectorial invasions in Monte Alto City, Sao Paulo, Brazil. AB - After several public notifications of domiciliary invasions, palm trees were investigated in downtown Monte Alto City, Sao Paulo State, Brazil, in proximity to the city hall building, the main church, condominiums and marketing establishments. One hundred seventy four palm trees of 10 species were investigated, in which 72 specimens of Rhodnius neglectus, a potential Chagas disease vector, were captured via manual methods. All insects were collected from dead leaves, organic debris and bird nests in the only three Livistona australis palm trees in the central park square. This was the first record of R. neglectus colonizing this palm species. Although no Trypanosoma cruzi was found by abdominal compression followed by light microscopy, the poor nutritional status of the bugs hampered the examination of gut contents for parasite detection. Furthermore, the central crowns of the trees, which shelter bats (Chiroptera: Mammalia), could not be carefully searched for insects due to difficult access. This new finding highlights the sudden alteration in insect behavior, probably as a result of man's interference. This report aims to warn those involved in the health system about this new threat, justifying detailed research of the area to evaluate the magnitude of this emerging public health issue. PMID- 24145157 TI - "Freezing" parasites in pre-Himalayan region, Himachal Pradesh: Experience with mini-FLOTAC. AB - BACKGROUND: Helminths and protozoa infections pose a great burden especially in developing, countries, due to morbidity caused both by acute and chronic infections. Data on distribution of intestinal parasitic infections among the native and expatriates populations in Himachal Pradesh are scarce. The aim of our survey was to analyze the intestinal parasitic burden in communities from Dharamsala, Kangra district, in clinical and public health settings. We also field-tested the mini- FLOTAC, an innovative diagnostic device. METHODS: Subjects referring to the Tibetan Delek Hospital for abdominal discomfort and all children of the Tibetan Primary School in Dharamsala were screened for intestinal parasitic infections with direct smear, formol-ether concentration (FEC) method and mini-FLOTAC, their clinical history was recorded, and correlations between clinical symptoms and infections analyzed. RESULTS: 152 subjects were screened for intestinal parasites, of which 72 subjects in the outpatients department (OPD) (36 expatriates and 36 natives) and 80 in the school. 60% of schoolchildren and 57% of OPD patients were found positive for any infection, the most represented were protozoa infections (50%), whereas helminthic infections accounted only for 13% and 20% in OPD patients and schoolchildren, respectively. The most prevalent among helminths was Ascaris lumbricoides (11%). Giardia intestinalis was more present among schoolchildren than the OPD patients (20% vs 6%) and E. histolytica/dispar was more prevalent among the OPD patients (42%) than the school children (23%). Correlations were found between nausea and loose or watery stools and parasitic infections, particularly in expatriates, whereas schoolchildren, despite being as infected as adults, were completely asymptomatic. Mini-FLOTAC detected higher number of helminth infections whereas FEC method was more accurate for the diagnosis of protozoa. CONCLUSIONS: This study presents an accurate snapshot of intestinal parasitic infections in Dharamsala, and their high prevalence calls for more awareness and control measures. Mini-FLOTAC is a promising and simple technique for the diagnosis of helminth infections. PMID- 24145159 TI - Heroin or conventional opioid maintenance? The patients' perspective. AB - OBJECTIVE: This study focused on the question whether patients with conventional opioid maintenance treatment (COMT) would prefer a switch to heroin maintenance treatment (HMT). METHODS: We performed a region-wide anonymous survey of patients in the opioid maintenance program in Berlin, Germany. All 20 psychiatric hospitals and all 110 physicians' practices in Berlin licensed to offer COMT were approached to reach patients under COMT and also fulfilling the Diagnostic and Statistical Manual of Mental Disorders (Fourth Edition) criteria of opiate dependence. The anonymous questionnaire focused on the question whether patients would prefer HMT to COMT. In our study, 986 of 5032 patients (19.6%) with COMT in Berlin participated. Of them, 881 (89.4%) patients gave information whether they would prefer HMT to COMT. RESULTS: Of the participating patients, 40.9% would prefer HMT to COMT. These patients report more detoxification therapies (P < 0.001), a higher dose of methadone equivalent (P = 0.001), and more often continued use of multiple illegal drugs despite COMT (P < 0.001) than patients not preferring HMT. They also report less improvement in mental health (P < 0.001) and working abilities (P < 0.001) because of COMT than patients not preferring HMT. CONCLUSIONS: The data on the patients' perspective complement the existing clinical studies, showing that previously unresponsive opioid-addicted patients especially would switch to HMT, whereas most patients would prefer continuation of COMT. PMID- 24145158 TI - Association of comorbid generalized anxiety disorder and alcohol use disorder symptoms with health-related quality of life: results from the National Epidemiological Survey on Alcohol and Related Conditions. AB - BACKGROUND: Although prior studies have documented the co-occurrence of generalized anxiety disorder (GAD) and alcohol use disorder (AUD) disorder, there is a paucity of research assessing the patterns of alcohol involvement among individuals with GAD symptoms. This study investigated subtypes, or classes, of comorbid AUD and GAD symptoms, and assessed the association of class membership with health-related quality of life. METHODS: Using data from the Wave 1 of the National Epidemiologic Survey on Alcohol and Related Conditions, a latent class analysis was performed on the subset of individuals who were current drinkers and had reported ever experiencing a 6-month episode of feeling tense, nervous, or worried most of the time. We examined the association of these latent classes with physical and mental health-related quality of life measured by the Short Form-12, version 2. RESULTS: Latent class analysis identified a 5-class model of AUD and GAD symptoms. A significant graded relationship was observed between the ordered classes and severity of impairment on the mental health scale of the Short Form-12, version 2, but no significant relationship was found with the physical health scale. CONCLUSIONS: Mental, but not physical, health-related quality of life in this population is associated with both the number and pattern of comorbid GAD and AUD symptoms. PMID- 24145160 TI - Prospective study of QTc changes among former opiate addicts since admission to methadone maintenance treatment: benzodiazepine risk. AB - OBJECTIVES: To prospectively evaluate QTc changes among methadone maintenance treatment (MMT) patients. METHODS: All 512 opiate addicts newly admitted to 2 MMT clinics had been prospectively studied for 4.5 years. Ninety-one patients were excluded because they were admitted from other MMTs, and 26 were excluded because their first electrocardiogram was performed following 28 days in MMT; therefore, 421 were studied. QTc values were again performed either after (A) a steady methadone dose for at least 3 months and negative urine tests for opiates, cocaine, amphetamines, cannabis, benzodiazepine; or after (B) same as for (A) but with positive urine tests for cannabis and/or benzodiazepine. RESULTS: Mean QTc intervals were not related to benzodiazepine or cocaine use on admission. QTc interval was significantly prolonged from the baseline to steady methadone dose (424.5 +/- 23.2 ms and 438.6 +/- 26.6 ms, respectively) but not affected by methadone dose (<100 or >=100 mg/d) or by the time to achieve a steady methadone dose (between 3 months and >2 years). QTc prolongation was greater among patients whose urine tested positive for benzodiazepine on a steady dose (P = 0.003). No additional prolongation was observed in 49 patients who achieved a steady methadone dose less than 1 year in MMT and had additional follow-up. Two patients who were benzodiazepine abusers died for undefined reasons. CONCLUSIONS: There is significant QTc prolongation during early MMT with no apparent clinical significance. A combination of benzodiazepine and methadone should be monitored. PMID- 24145161 TI - Sexual behavior differences between amphetamine-type stimulants users and heroin users. AB - OBJECTIVES: To explore the sexual behavior of amphetamine-type stimulant (ATS) users and heroin users, and to find out the dangerous sexual behaviors, even related risk factors among them. METHODS: Four hundred thirty-eight ATS users and 524 heroin users were recruited in 10 compulsory detoxification treatment centers and voluntary detoxification centers in Beijing, Shenzhen, Guangzhou, Xi'an, and Taiyuan. Their sociodemographic characteristics, history of drug taking, and sexual behaviors were surveyed. RESULTS: Many variables of sociodemographic characteristics and sexual behaviors were significantly different between ATS users and heroin users (P < 0.05). Dangerous sexual behaviors among ATS users include sexual intercourse often or each time after taking drug (30.1%), multiple sexual intercourse (16.5%), casual sex partners (34.0%), homosexual partners (2.5%), and never or occasionally using condom with a steady sex partner (79.3%) or with casual sex partners (39.1%). The rate of ever-infecting sexually transmitted disease (STD) was high in both the groups (ATS, 20.5%; heroin, 30.9%). CONCLUSIONS: Sexual behavior is the main way to transmit STD and human immunodeficiency virus among ATS users. The study results will promote the government's awareness of the issue and take necessary steps to slow the spread of STD and human immunodeficiency virus among the ATS users. PMID- 24145162 TI - A motivational profile for smoking among adolescents. AB - OBJECTIVES: To characterize a motivational profile of reasons for smoking among teenagers. To investigate the influence of clinical and social elements on observed scores. METHODS: High school students who smoked in the past month (n = 226; age, 16.4 +/- 10 years; 46.5% male) answered a questionnaire during school time. The instrument included the University of Sao Paulo Reasons for Smoking Scale (USP-RSS), the Fagerstrom Test for Nicotine Dependence, and clinical and social information. The USP-RSS scores from 307 healthy adult smokers (67.5% male; age, 37.9 +/- 11.2 years) were also used for comparisons. RESULTS: Most of the adolescents (90.2%) exhibited low or very low levels of nicotine addiction (median Fagerstrom Test for Nicotine Dependence score 0, range 0 to 8). The mean scores of the USP-RSS subscales were as follows: Addiction, 1.9 +/- 1.1; Pleasure From Smoking, 3.0 +/- 1.3; Tension Reduction, 2.4 +/- 1.3; Stimulation, 1.9 +/- 0.9; Automatism, 1.3 +/- 0.6; Handling, 2.3 +/- 1.1; Social Smoking, 1.9 +/- 1.0; Weight Control, 1.4 +/- 1.0; and Affiliative Attachment, 1.6 +/- 0.9. In comparison with adults, teenagers exhibited lower scores for Addiction, Pleasure From Smoking, Tension Reduction, Automatism, Weight Control, and Affiliative Attachment and higher scores for Social Smoking (P < 0.05). Older age, past school failure, illicit drugs use, alcohol abuse, high levels of perceived stress, and the death of at least one parent were associated with high scores for all subscales. CONCLUSIONS: The USP-RSS subscales Addiction, Pleasure From Smoking, and Social Smoking were important factors for adolescent smoking. Comparisons with adult smokers stressed the importance of the component of Social Smoking. The identification of distinctive factors that drive teenagers to smoke might help in making decisions dealing with interventions aimed at smoking cessation and control. PMID- 24145163 TI - Physician health programs: the Maryland experience. AB - BACKGROUND: This article briefly summarizes not only the history of physician health programs, including their singular success, but also their struggle to maintain the ethical integrity of the programs, their appropriate autonomy, and the privacy of physicians enrolled in them. METHOD: We review the history of the Maryland Physicians Health Program, how it initially developed and was funded, how the program became funded by the state, how this ultimately caused serious problems, and how these were eventually resolved. RESULTS: Maryland was able to achieve a 2-program solution that protected both the voluntary participants while meeting the needs of the state licensing board for participants mandated by the state licensing board. This result has been well received by both the physician community and the state licensing board. CONCLUSIONS: How the problems were solved and the ultimate agreement provide a model for others to use. PMID- 24145164 TI - Lipid droplet breakdown requires dynamin 2 for vesiculation of autolysosomal tubules in hepatocytes. AB - Lipid droplets (LDs) are lipid storage organelles that in hepatocytes may be catabolized by autophagy for use as an energy source, but the membrane trafficking machinery regulating such a process is poorly characterized. We hypothesized that the large GTPase dynamin 2 (Dyn2), well known for its involvement in membrane deformation and cellular protein trafficking, could orchestrate autophagy-mediated LD breakdown. Accordingly, depletion or pharmacologic inhibition of Dyn2 led to a substantial accumulation of LDs in hepatocytes. Strikingly, the targeted disruption of Dyn2 induced a dramatic four- to fivefold increase in the size of autolysosomes. Chronic or acute Dyn2 inhibition combined with nutrient deprivation stimulated the excessive tubulation of these autolysosomal compartments. Importantly, Dyn2 associated with these tubules along their length, and the tubules vesiculated and fragmented in the presence of functional Dyn2. These findings provide new evidence for the participation of the autolysosome in LD metabolism and demonstrate a novel role for dynamin in the function and maturation of an autophagic compartment. PMID- 24145165 TI - Microtubules that form the stationary lattice of muscle fibers are dynamic and nucleated at Golgi elements. AB - Skeletal muscle microtubules (MTs) form a nonclassic grid-like network, which has so far been documented in static images only. We have now observed and analyzed dynamics of GFP constructs of MT and Golgi markers in single live fibers and in the whole mouse muscle in vivo. Using confocal, intravital, and superresolution microscopy, we find that muscle MTs are dynamic, growing at the typical speed of ~9 um/min, and forming small bundles that build a durable network. We also show that static Golgi elements, associated with the MT-organizing center proteins gamma-tubulin and pericentrin, are major sites of muscle MT nucleation, in addition to the previously identified sites (i.e., nuclear membranes). These data give us a framework for understanding how muscle MTs organize and how they contribute to the pathology of muscle diseases such as Duchenne muscular dystrophy. PMID- 24145166 TI - Golgi-associated RhoBTB3 targets cyclin E for ubiquitylation and promotes cell cycle progression. AB - Cyclin E regulates the cell cycle transition from G1 to S phase and is degraded before entry into G2 phase. Here we show that RhoBTB3, a Golgi-associated, Rho related ATPase, regulates the S/G2 transition of the cell cycle by targeting cyclin E for ubiquitylation. Depletion of RhoBTB3 arrested cells in S phase, triggered Golgi fragmentation, and elevated cyclin E levels. On the Golgi, RhoBTB3 bound cyclin E as part of a Cullin3 (CUL3)-dependent RING-E3 ubiquitin ligase complex comprised of RhoBTB3, CUL3, and RBX1. Golgi association of this complex was required for its ability to catalyze cyclin E ubiquitylation and allow normal cell cycle progression. These experiments reveal a novel role for a Ras superfamily member in catalyzing cyclin E turnover during S phase, as well as an unexpected, essential role for the Golgi as a ubiquitylation platform for cell cycle control. PMID- 24145167 TI - Soluble oligomers are sufficient for transmission of a yeast prion but do not confer phenotype. AB - Amyloidogenic proteins aggregate through a self-templating mechanism that likely involves oligomeric or prefibrillar intermediates. For disease-associated amyloidogenic proteins, such intermediates have been suggested to be the primary cause of cellular toxicity. However, isolation and characterization of these oligomeric intermediates has proven difficult, sparking controversy over their biological relevance in disease pathology. Here, we describe an oligomeric species of a yeast prion protein in cells that is sufficient for prion transmission and infectivity. These oligomers differ from the classic prion aggregates in that they are soluble and less resistant to SDS. We found that large, SDS-resistant aggregates were required for the prion phenotype but that soluble, more SDS-sensitive oligomers contained all the information necessary to transmit the prion conformation. Thus, we identified distinct functional requirements of two types of prion species for this endogenous epigenetic element. Furthermore, the nontoxic, self-replicating amyloid conformers of yeast prion proteins have again provided valuable insight into the mechanisms of amyloid formation and propagation in cells. PMID- 24145168 TI - Polarity, cell division, and out-of-equilibrium dynamics control the growth of epithelial structures. AB - The growth of a well-formed epithelial structure is governed by mechanical constraints, cellular apico-basal polarity, and spatially controlled cell division. Here we compared the predictions of a mathematical model of epithelial growth with the morphological analysis of 3D epithelial structures. In both in vitro cyst models and in developing epithelial structures in vivo, epithelial growth could take place close to or far from mechanical equilibrium, and was determined by the hierarchy of time-scales of cell division, cell-cell rearrangements, and lumen dynamics. Equilibrium properties could be inferred by the analysis of cell-cell contact topologies, and the nonequilibrium phenotype was altered by inhibiting ROCK activity. The occurrence of an aberrant multilumen phenotype was linked to fast nonequilibrium growth, even when geometric control of cell division was correctly enforced. We predicted and verified experimentally that slowing down cell division partially rescued a multilumen phenotype induced by altered polarity. These results improve our understanding of the development of epithelial organs and, ultimately, of carcinogenesis. PMID- 24145171 TI - Increased risk for respiratory syncytial virus-associated, community-acquired alveolar pneumonia in infants born at 31-36 weeks of gestation. AB - BACKGROUND: We compared hospitalization and pediatric intensive care unit (PICU) admission rates for community-acquired alveolar pneumonia (CAAP) and respiratory syncytial virus (RSV)-associated CAAP (RSV-CAAP) in non-RSV-immunized children <24-month-old born at 31-36 weeks gestational age (GA) versus those born at term (>36 weeks GA). METHODS: Nasopharyngeal samples for RSV were obtained prospectively (2004-2011) during RSV season, from hospitalized children with radiographic-diagnosed CAAP. Soroka University Medical Center is the only hospital in the region, enabling population-based rate calculation. Relative risks (RR) and 95% confidence intervals (95% CI) were calculated comparing RSV CAAP incidence in 31-36 weeks GA with >36 weeks GA children. RESULTS: CAAP hospitalization incidences (per 1000 population) were 23.6 and 9.4 (RR: 2.52; 95% CI: 2.13-2.68), respectively; the respective incidences of PICU admission for overall CAAP were 1.8 and 0.2 (RR: 7.88; 95% CI: 4.59-11.83). The RRs (and 95% CI) for RSV-CAAP hospitalizations and PICU admission rates were (after extrapolation) 15.2 and 5.8 (RR: 2.79; 95% CI: 2.31-3.06) and 1.1 and 0.1 (RR: 9.14; 95% CI: 4.93-16.96), respectively. In a multiregression analysis in patients with RSV-CAAP versus CAAP, 31-36 weeks GA was an independent risk factor for hospitalization (RR: 1.485; 95% CI: 1.03-2.14). CONCLUSIONS: Children <24 month-old born at 31-36 weeks GA are at increased risk for hospitalization and PICU admission for both overall CAAP and RSV-associated CAAP compared with those born at >36 weeks GA. Moreover, in late premature children, RSV represented a 50% increased risk for CAAP compared with infants born at term. PMID- 24145169 TI - The bone morphogenetic protein axis is a positive regulator of skeletal muscle mass. AB - Although the canonical transforming growth factor beta signaling pathway represses skeletal muscle growth and promotes muscle wasting, a role in muscle for the parallel bone morphogenetic protein (BMP) signaling pathway has not been defined. We report, for the first time, that the BMP pathway is a positive regulator of muscle mass. Increasing the expression of BMP7 or the activity of BMP receptors in muscles induced hypertrophy that was dependent on Smad1/5 mediated activation of mTOR signaling. In agreement, we observed that BMP signaling is augmented in models of muscle growth. Importantly, stimulation of BMP signaling is essential for conservation of muscle mass after disruption of the neuromuscular junction. Inhibiting the phosphorylation of Smad1/5 exacerbated denervation-induced muscle atrophy via an HDAC4-myogenin-dependent process, whereas increased BMP-Smad1/5 activity protected muscles from denervation-induced wasting. Our studies highlight a novel role for the BMP signaling pathway in promoting muscle growth and inhibiting muscle wasting, which may have significant implications for the development of therapeutics for neuromuscular disorders. PMID- 24145172 TI - Changes in Kawasaki disease during 2 decades at a single institution in Daejeon, Korea. AB - BACKGROUND: The goal of this study is to evaluate the changes in the epidemiologic and clinical features of Kawasaki disease (KD) in a period of 20 years. METHODS: We compared the epidemiologic features of 3 KD patient groups: those admitted from 1987 to 1990 (122 cases), from 1997 to 2000 (137 cases) and from 2007 to 2010 (102 cases). For clinical features, we reviewed the medical records of patients admitted from 1996 to 2000 (141 cases) and from 2006 to 2010 (121 cases). RESULTS: There were a total of 772 KD patients during the study period (mean age: 27.2 months; male-to-female ratio: 1.6:1). There were some variations in the mean ages (23.8, 27.8 and 30 months), in the male-to-female ratios (1.9:1, 1.3:1 and 1.8:1) and in the age distributions, including the patients of ages <6 months and >5 years, but the differences were not statistically significant across the groups. The seasonal distributions were relatively consistent with some variations. In clinical features, the preadmission and total fever durations were shorter (P < 0.001, respectively), and the proportions of incomplete KD tended to increase, and the rates of coronary artery aneurysm tended to decrease in recently admitted patients. CONCLUSIONS: There were no significant changes in the demographic and seasonal features of KD, although the evaluation of the clinical features showed shorter fever duration suggestive of improved identification and treatment of KD over time. PMID- 24145170 TI - FOXO1 promotes wound healing through the up-regulation of TGF-beta1 and prevention of oxidative stress. AB - Keratinocyte mobilization is a critical aspect of wound re-epithelialization, but the mechanisms that control its precise regulation remain poorly understood. We set out to test the hypothesis that forkhead box O1 (FOXO1) has a negative effect on healing because of its capacity to inhibit proliferation and promote apoptosis. Contrary to expectations, FOXO1 is required for keratinocyte transition to a wound-healing phenotype that involves increased migration and up regulation of transforming growth factor beta1 (TGF-beta1) and its downstream targets, integrin-alpha3 and -beta6 and MMP-3 and -9. Furthermore, we show that FOXO1 functions in keratinocytes to reduce oxidative stress, which is necessary to maintain cell migration and prevent cell death in a TGF-beta1-independent manner. Thus, our studies identify a novel function for FOXO1 in coordinating the response of keratinocytes to wounding through up-regulation of TGF-beta1 and other factors needed for keratinocyte migration and protection against oxidative stress, which together promote migration and decrease apoptosis. PMID- 24145173 TI - Inhibition of NF-kappaB signaling ablates the invasive phenotype of glioblastoma. AB - Glioblastoma multiforme, the most common primary brain tumor, is highly refractory to therapy, mainly due to its ability to form micrometastases, which are small clusters or individual cells that rapidly transverse the brain and make full surgical resection impossible. Here, it is demonstrated that the invasive phenotype of glioblastoma multiforme is orchestrated by the transcription factor NF-kappaB which, via metalloproteinases (MMP), regulates fibronectin processing. Both, cell lines and tumor stem cells from primary glioblastoma multiforme, secrete high levels of fibronectin which when cleaved by MMPs forms an extracellular substrate. Subsequently, forming and interacting with their own microenvironment, glioblastoma multiforme cells are licensed to invade their surroundings. Mechanistic study revealed that NF-kappaB inhibition, either genetically or pharmacologically, by treatment with Disulfiram, significantly abolished the invasive phenotype in the chick chorioallantoic membrane assay. Furthermore, having delineated the underlying molecular mechanism of glioblastoma multiforme invasion, the potential of a disulfiram-based therapy was revealed in a highly invasive orthotrophic glioblastoma multiforme mouse model. IMPLICATIONS: This study defines a novel therapeutic approach that inhibits micrometastases invasion and reverts lethal glioblastoma into a less aggressive disease. PMID- 24145174 TI - Preputioplasty associated with urethroplasty for correction of distal hypospadias: a prospective study and proposition of a new objective scoring system for evaluation of esthetic and functional outcome. AB - OBJECTIVE: Most surgical procedures for correction of hypospadias involve the removal of foreskin resulting in a circumcised penis. We report our experience and the medium-term results in the reconstruction of the foreskin during the correction of distal hypospadias. MATERIALS AND METHODS: Between January 2007 and December 2011, 445 patients aged between 8 and 120 months underwent surgical correction of hypospadias. In 354 out of 445 patients, we performed the reconstruction of the foreskin. Urethroplasty was performed according to either the TIPU (tubularized incised urethral plate urethroplasty; Snodgrass) technique (233/354, 66%) or MAGPI (meatal advancement glanduloplasty incorporated) procedure (121/354, 34%). In 91 out of 445 patients urethroplasty was performed using classic TIPU technique and they were circumcised. The cosmetic and functional results were evaluated using the Hypospadias Objective Penile Evaluation (HOPE) scoring system. RESULTS: At a 12 months follow-up, 300 patients (84.7%) had retractable foreskin while 54 patients (15.3%) required postoperative steroid application. We had a total complication rate of 8.7%. As for preputioplasty, 16 patients (4.5%) had partial or total dehiscence of the reconstructed foreskin, one patient was circumcised for persistent phimosis (0.2%). As for urethroplasty complications, we recorded 11 fistulas (3.1%) and three stenosis (0.9%). The complication rate of the control group of circumcised patients was of 3.3% (2 fistulas [2.1%] and 1 stenosis [1.2%]). CONCLUSIONS: Our experience shows that foreskin reconstruction can be performed successfully in selected patients with distal hypospadias. However, preputioplasty add an additional 4.7% complication rate. As for the complications of urethroplasty, it seems that preputioplasty does not increase the incidence of complications on the urethra reconstruction. We propose a new objective scoring system (modified HOPE score) for evaluation of esthetic and functional outcome. PMID- 24145175 TI - Penile length nomogram for Asian Indian prepubertal boys. AB - BACKGROUND: Penile length-for-age nomograms in prepubertal boys may aid in early recognition of endocrine and genetic disorders associated with abnormal phallic size. There are scarce data on the penile length measurements in children beyond the neonatal period and there is a lack of such a nomogram for Asian Indians. MATERIALS AND METHODS: Of the boys who were admitted in our ward or seen in the outpatient setting for genitalia-unrelated surgical problems, 20 consecutive boys were included in each of the following ten age slots (total of 200 subjects): 0 1, 1-2, 2-3, 3-4, 4-5, 5-6, 6-7, 7-8, 8-9, and 9-10 years. Their stretched penile length (SPL) measurements were used to establish the normal range (mean +/- 2 SD) of penile length-for-age in prepubertal Indian boys. Mean +/- 2.5 SD was also calculated to define the cut-offs for micropenis and macropenis, respectively, in each age group. RESULTS: A rapid increase is seen in penile length up to 4 years of age. A much slower increase is implied thereafter. CONCLUSION: This study provides reference values of penile lengths for Asian Indian boys aged 0-10 years. PMID- 24145176 TI - Commentary to 'Priapism in children: a comprehensive review and clinical guideline'. PMID- 24145177 TI - MicroRNA targets autophagy in pancreatic cancer cells during cancer therapy. AB - The therapeutic outcome of pancreatic cancer is generally poor due to the inherent or acquired resistance of cancer cells to treatment. Pancreatic cancer cells have higher basal autophagy levels than other cancer cell types, which may correlate with their nonresponsiveness to the available cancer therapy. Therefore, understanding the mechanisms behind autophagy activation in pancreatic cancer cells may ultimately improve therapeutic outcomes. Here we demonstrated that MIR23B is a potent inhibitor of autophagy. MIR23B targets the 3?UTR of the autophagy-related gene ATG12, thereby decreasing autophagic activity and ultimately promoting radiation-induced pancreatic cancer cell death. Thus, our study clarified some of the underlying molecular mechanisms of activated autophagy in response to cancer therapy in pancreatic cancer. PMID- 24145178 TI - In vivo time-serial multi-modality optical imaging in a mouse model of ovarian tumorigenesis. AB - Identification of the early microscopic changes associated with ovarian cancer may lead to development of a diagnostic test for high-risk women. In this study we use optical coherence tomography (OCT) and multiphoton microscopy (MPM) (collecting both two photon excited fluorescence [TPEF] and second harmonic generation [SHG]) to image mouse ovaries in vivo at multiple time points. We demonstrate the feasibility of imaging mouse ovaries in vivo during a long-term survival study and identify microscopic changes associated with early tumor development. These changes include alterations in tissue microstructure, as seen by OCT, alterations in cellular fluorescence and morphology, as seen by TPEF, and remodeling of collagen structure, as seen by SHG. These results suggest that a combined OCT-MPM system may be useful for early detection of ovarian cancer. PMID- 24145179 TI - A dual-plane co-RASOR technique for accurate and rapid tracking and position verification of an Ir-192 source for single fraction HDR brachytherapy. AB - Effective high-dose-rate (HDR) treatment requires accurate and independent treatment verification to ensure that the treatment proceeds as prescribed, in particular if a high dose is given, as in single fraction therapy. Contrary to CT imaging and fluoroscopy, MR imaging provides high soft tissue contrast. Conventional MR techniques, however, do not offer the temporal resolution in combination with the 3D spatial resolution required for accurate brachytherapy source localization. We have developed an MR imaging method (center-out RAdial Sampling with Off-Resonance (co-RASOR)) that generates high positive contrast in the geometrical center of field perturbing objects, such as HDR brachytherapy sources. co-RASOR generates high positive contrast in the geometric center of an Ir-192 source by applying a frequency offset to center-out encoded data. To obtain high spatial accuracy in 3D with adequate temporal resolution, two orthogonal center-out encoded 2D images are applied instead of a full 3D acquisition. Its accuracy in 3D is demonstrated by 3D MRI and CT. The 2D images show high positive contrast in the geometric center of non-radioactive Ir-192 sources, with signal intensities up to 160% of the average signal intensity in the surrounding medium. The accuracy with which the center of the Ir-192 source is located by the dual-plane MRI acquisition corresponds closely to the accuracy obtained by 3D MRI and CT imaging. The positive contrast is shown to be obtained in homogeneous and in heterogeneous tissue. The dual-plane MRI technique allows the brachytherapy source to be tracked in 3D with millimeter accuracy with a temporal resolution of approximately 4 s. PMID- 24145180 TI - Level of TNF-related apoptosis-inducing-ligand and CXCL8 correlated with 2 [18F]Fluoro-2-deoxy-D-glucose uptake in anti-VEGF treated colon cancers. AB - BACKGROUND: The changes and correlations of TRAIL (TNF-related apoptosis-inducing ligand) and CXCL8 (IL8) prior to treatment and three months following therapy as well as the corresponding Positron emission tomography (PET/CT) (SUV(max): standardized uptake maximum values) results were evaluated. MATERIAL AND METHODS: The measurements were taken before and after treatment for comparison purposes. The study population comprised 29 patients with Metastatic Colorectal cancer (MCRC), undergoing PET/CT scanning prior to treatment. RESULTS: There were significant changes prior to treatment and three months later for sTRAIL (p=0.0080) and CXCL8 (p=0.0001)values. Generally, sTRAIL values were increasing during therapy, while a decrease was observed for CXCL8. Correlation analysis was applied to the data and revealed significant correlations for the SUV(max) in the primary tumor prior to treatment and CXCL8 prior to therapy (p=0.0303). Furthermore, significant correlations were observed for the SUV(max) and sTRAIL (p=0.0237) as well as CXCL8 (p=0.0002) three months after treatment initiation. CXCL8 prior to treatment was also correlated with the SUV three months after onset of treatment (p=0.0072). A significant correlation was noted for one combination of two variables, the SUV(max) in the metastases and CXCL8 prior to treatment (p=0.0175). These results are supported when we group the SUV(max) in the metastases following treatment into two groups with SUV(max) <5 and SUV(max) >5. CONCLUSIONS: This study provides evidence that proteomics patterns of sTRAIL and CXCL8 predict tumor response und survival in MCRC patients treated with bevacizumab and within a high concordance of FDG-PET/CT findings. PMID- 24145182 TI - Doppler deterioration in intrauterine growth restriction: Unterscheider et al. AB - The article below summarizes a roundtable discussion of a study published in this issue of the Journal in light of its methodology, relevance to practice, and implications for future research. Article discussed: Unterscheider J, Daly S, Geary MP, et al. Predictable progressive Doppler deterioration in IUGR-does it really exist? Am J Obstet Gynecol 2013;209:539.e1-7. PMID- 24145183 TI - Discussion: 'Doppler deterioration in intrauterine growth restriction,' by Unterscheider et al. AB - In the roundtable that follows, clinicians discuss a study published in this issue of the Journal in light of its methodology, relevance to practice, and implications for future research. Article discussed: Unterscheider J, Daly S, Geary MP, et al. Predictable progressive Doppler deterioration in IUGR-does it really exist? Am J Obstet Gynecol 2013;209:539.e1-7. PMID- 24145184 TI - Effect of obesity on incidence of preeclampsia. PMID- 24145185 TI - Comparison of placental pathology in preterm, late-preterm, near-term, and term births. AB - OBJECTIVE: The purpose of this study was to determine whether placental pathologic condition supports the recent suggestion of subcategorizing preterm and term births into smaller gestational age subgroups with different perinatal mortality and morbidity rates. STUDY DESIGN: Twenty-seven clinical and 43 placental phenotypes were retrospectively compared in 4617 third-trimester births: 1332 preterm pregnancies (28-33 weeks' gestation), 1066 late preterm pregnancies (34-36 weeks' gestation), 940 near-term pregnancies (37-38 weeks' gestation), and 1279 term pregnancies (>=39 weeks' gestation). RESULTS: Acute inflammatory pattern of placental injury was seen mostly at both gestational sides of the third trimester; the clinical conditions linked to in utero hypoxia (preeclampsia, diabetes mellitus, fetal growth restriction) and their placental associations (atherosis, membrane chorionic microcysts, chorangiosis, intervillous thrombi) were associated statistically significantly with mid third trimester. Acute fetal distress (abnormal fetal heart tracing and clinical and histologic meconium) were increasing with gestational age and were statistically significantly most common in full-term pregnancies. CONCLUSION: Differences in placental pathologic condition among the 4 subgroups of third-trimester pregnancy not only challenge the use of an arbitrary cutoff point of 37 weeks' gestation that separates the preterm birth and term birth but also further support separation of late preterm births from preterm births and term births from near term births. Based on placental pathologic condition, chronic uteroplacental malperfusion is the dominating etiopathogenetic factor in the mid third trimester (late preterm and near-term births), and acute fetal distress is the factor in full-term births. This obscures relative frequencies of perinatal death and management modalities in the third trimester. PMID- 24145181 TI - Alpha-1-adrenergic receptors in heart failure: the adaptive arm of the cardiac response to chronic catecholamine stimulation. AB - Alpha-1-adrenergic receptors (ARs) are G protein-coupled receptors activated by catecholamines. The alpha-1A and alpha-1B subtypes are expressed in mouse and human myocardium, whereas the alpha-1D protein is found only in coronary arteries. There are far fewer alpha-1-ARs than beta-ARs in the nonfailing heart, but their abundance is maintained or increased in the setting of heart failure, which is characterized by pronounced chronic elevation of catecholamines and beta AR dysfunction. Decades of evidence from gain and loss-of-function studies in isolated cardiac myocytes and numerous animal models demonstrate important adaptive functions for cardiac alpha-1-ARs to include physiological hypertrophy, positive inotropy, ischemic preconditioning, and protection from cell death. Clinical trial data indicate that blocking alpha-1-ARs is associated with incident heart failure in patients with hypertension. Collectively, these findings suggest that alpha-1-AR activation might mitigate the well-recognized toxic effects of beta-ARs in the hyperadrenergic setting of chronic heart failure. Thus, exogenous cardioselective activation of alpha-1-ARs might represent a novel and viable approach to the treatment of heart failure. PMID- 24145186 TI - Obstetrical and neonatal outcomes from the BEST Trial: single embryo transfer with aneuploidy screening improves outcomes after in vitro fertilization without compromising delivery rates. AB - OBJECTIVE: We sought to determine whether performing elective single embryo transfer (eSET) after trophectoderm biopsy and rapid aneuploidy screening results in improved obstetrical and neonatal outcomes compared with transferring 2 untested embryos. STUDY DESIGN: The Blastocyst Euploid Selective Transfer (BEST) Trial enrolled infertile couples with a female partner up to age 42 years who were undergoing in vitro fertilization. They were randomized to receive transfer of a single euploid embryo (eSET) or to the standard of care with transfer of 2 embryos that were not biopsied for aneuploidy screening (untested 2-embryo transfer). Gestational age at delivery, birthweight, and neonatal intensive care unit (NICU) lengths of stay were compared with Mann-Whitney U. The risk of preterm delivery, low birthweight, and NICU admission were compared with chi(2). RESULTS: Among the 175 randomized patients, the delivery rates were similar (69% after euploid eSET vs 72% after untested 2-embryo transfer; P = .6) through the fresh cycle and up to 1 frozen transfer, with a dramatic difference in multiple births (1.6% vs 47%; P < .0001). The risk of preterm delivery (P = .03), low birthweight (P = .002), and NICU admission (P = .04) were significantly higher after untested 2-embryo transfer. Babies born after untested 2-embryo transfer spent >5 times as many days in the NICU (479 vs 93 days; P = .03). CONCLUSION: By enhancing embryo selection with a validated method of aneuploidy screening, a single euploid embryo with high reproductive potential can be selected for transfer. Using this approach, eSET can be performed without compromising delivery rates and improving the chance of having a healthy, term singleton delivery after in vitro fertilization. PMID- 24145187 TI - Angiomodulin is required for cardiogenesis of embryonic stem cells and is maintained by a feedback loop network of p63 and Activin-A. AB - The transcription factor p63, member of the p53 gene family, encodes for two main isoforms, TAp63 and DeltaNp63 with distinct functions on epithelial homeostasis and cancer. Recently, we discovered that TAp63 is essential for in vitro cardiogenesis and heart development in vivo. TAp63 is expressed by embryonic endoderm and acts on cardiac progenitors by a cell-non-autonomous manner. In the present study, we search for cardiogenic secreted factors that could be regulated by TAp63 and, by ChIP-seq analysis, identified Angiomodulin (AGM), also named IGFBP7 or IGFBP-rP1. We demonstrate that AGM is necessary for cardiac commitment of embryonic stem cells (ESCs) and its regulation depends on TAp63 isoform. TAp63 directly activates both AGM and Activin-A during ESC cardiogenesis while these secreted factors modulate TAp63 gene expression by a feedback loop mechanism. The molecular circuitry controlled by TAp63 on AGM/Activin-A signaling pathway and thus on cardiogenesis emphasizes the importance of p63 during early cardiac development. PMID- 24145188 TI - Direct lineage reprogramming of mouse fibroblasts to functional midbrain dopaminergic neuronal progenitors. AB - The direct lineage reprogramming of somatic cells to other lineages by defined factors has led to innovative cell-fate-change approaches for providing patient specific cells. Recent reports have demonstrated that four pluripotency factors (Oct4, Sox2, Klf4, and c-Myc) are sufficient to directly reprogram fibroblasts to other specific cells, including induced neural stem cells (iNSCs). Here, we show that mouse fibroblasts can be directly reprogrammed into midbrain dopaminergic neuronal progenitors (DPs) by temporal expression of the pluripotency factors and environment containing sonic hedgehog and fibroblast growth factor 8. Within thirteen days, self-renewing and functional induced DPs (iDPs) were generated. Interestingly, the inhibition of both Jak and Gsk3beta notably enhanced the iDP reprogramming efficiency. We confirmed the functionality of the iDPs by showing that the dopaminergic neurons generated from iDPs express midbrain markers, release dopamine, and show typical electrophysiological profiles. Our results demonstrate that the pluripotency factors-mediated direct reprogramming is an invaluable strategy for supplying functional and proliferating iDPs and may be useful for other neural progenitors required for disease modeling and cell therapies for neurodegenerative disorders. PMID- 24145189 TI - Sphingosine-1-phosphate-induced Flk-1 transactivation stimulates mouse embryonic stem cell proliferation through S1P1/S1P3-dependent beta-arrestin/c-Src pathways. AB - Although recent findings showed that the bioactive lipid metabolites can regulate the ES cell functions, the physiological relevance of interaction between sphingosine-1-phosphate (S1P) and Flk-1 and its related signaling molecules are not yet clear in ES cell proliferation. In the present study, S1P1-5 receptors were expressed in mouse ES cells and S1P increased S1P1-3 receptor expression level. S1P treatment stimulated the cellular proliferation in S1P1/3-dependent manner, located in lipid rafts. In response to S1P, beta-arrestin was recruited to S1P1/3 receptor and c-Src was activated. S1P also increased the binding of S1P1/3 receptor with Flk-1. Similar to responses for VEGF, S1P increased Flk-1 phosphorylation, which was blocked by beta-arrestin siRNA, and PP2, but not by VEGF-A164 antibody or VEGF siRNA. In addition, S1P induced VEGF expression and VEGFR2 kinase inhibitor (SU1498) blocked the S1P-induced cellular proliferation. However, VEGF-A164 antibody or VEGF siRNA partially blocked S1P-induced cellular proliferation, suggesting that both VEGF-dependent Flk-1 activation and VEGF independent Flk-1 activation are involved in S1P-induced ES cell proliferation. S1P and VEGF-induced phosphorylation of ERK and JNK were blocked by pretreatment with SU1498. Moreover, inhibition of ERK and JNK blocked S1P-induced cellular proliferation. In conclusion, S1P-elicited transactivation of Flk-1 mediated by S1P1/3-dependent beta-arrestin/c-Src pathways stimulated mouse ES cell proliferation. PMID- 24145190 TI - Maintenance of the stemness in CD44(+) HCT-15 and HCT-116 human colon cancer cells requires miR-203 suppression. AB - The purpose of this study was to isolate cancer stem cells (CSCs, also called tumor-initiating cells, TICs) from established human colorectal carcinoma (CRC) cell lines, characterize them extensively and dissect the mechanism for their stemness. Freshly isolated CD44(+) and CD44(-) cells from the HCT-15 human colon cancer cell line were subjected to various analyses. Interestingly, CD44(+) cells exhibited higher soft agar colony-forming ability and in vivo tumorigenicity than CD44(-) cells. In addition, the significant upregulation of the protein Snail and the downregulation of miR-203, a stemness inhibitor, in CD44(+) cells suggested that this population possessed higher invasion/metastasis and differentiation potential than CD44(-) cells. By manipulating the expression of CD44 in HCT-15 and HCT-116 cells, we found that the levels of several EMT activators and miR-203 were positively and negatively correlated with those of CD44, respectively. Further analyses revealed that miR-203 levels were repressed by Snail, which was shown to bind to specific E-box(es) present in the miR-203 promoter. In agreement, silencing miR-203 expression in wild-type HCT-116 human colon cancer cells also resulted in an increase of their stemness. Finally, we discovered that c-Src kinase activity was required for the downregulation of miR-203 in HCT-15 cells, which was stimulated by the interaction between hyaluronan (HA) and CD44. Taken together, CD44 is a critical molecule for modulating stemness in CSCs. More importantly, we show for the first time that the downregulation of miR-203 by HA/CD44 signaling is the main reason for stemness-maintenance in colon cancer cells. PMID- 24145191 TI - Micron-scale resolution optical tomography of entire mouse brains with confocal light sheet microscopy. AB - Understanding the architecture of mammalian brain at single-cell resolution is one of the key issues of neuroscience. However, mapping neuronal soma and projections throughout the whole brain is still challenging for imaging and data management technologies. Indeed, macroscopic volumes need to be reconstructed with high resolution and contrast in a reasonable time, producing datasets in the TeraByte range. We recently demonstrated an optical method (confocal light sheet microscopy, CLSM) capable of obtaining micron-scale reconstruction of entire mouse brains labeled with enhanced green fluorescent protein (EGFP). Combining light sheet illumination and confocal detection, CLSM allows deep imaging inside macroscopic cleared specimens with high contrast and speed. Here we describe the complete experimental pipeline to obtain comprehensive and human-readable images of entire mouse brains labeled with fluorescent proteins. The clearing and the mounting procedures are described, together with the steps to perform an optical tomography on its whole volume by acquiring many parallel adjacent stacks. We showed the usage of open-source custom-made software tools enabling stitching of the multiple stacks and multi-resolution data navigation. Finally, we illustrated some example of brain maps: the cerebellum from an L7-GFP transgenic mouse, in which all Purkinje cells are selectively labeled, and the whole brain from a thy1 GFP-M mouse, characterized by a random sparse neuronal labeling. PMID- 24145192 TI - Autophagy: friend or foe in the treatment of fusion protein-associated leukemias? AB - Both radiation and chemotherapeutic drugs induce autophagy in tumor cells, and whether this contributes to cell death or survival is debated. Although a prodeath role has been reported in certain contexts, treatment-induced autophagy often exerts a prosurvival function by preventing apoptosis and delaying necrosis. Interestingly, a more specific role of autophagy has been demonstrated in certain subtypes of leukemia. The fusion oncoproteins PML-RARA and BCR-ABL, the main oncogenic drivers of acute promyelocytic leukemia and chronic myeloid leukemia (CML), respectively, have recently been identified as autophagy substrates and their degradation by autophagy shown to contribute to treatment. However, this does not seem to be a general feature of leukemic fusion oncoproteins, as we recently found that AML1-ETO, the most frequently occurring acute myeloid leukemia (AML) fusion protein, is not an autophagy substrate. Rather we demonstrate a clear prosurvival role of autophagy in this AML subtype and that addition of autophagy inhibitors in the treatment regimen might be beneficial. PMID- 24145193 TI - Authors' response to the comments on automated platelet analyses by Dr Beyan. PMID- 24145194 TI - Feasibility of left ventricular volume measurements by three-dimensional speckle tracking echocardiography depends on image quality and degree of left ventricular enlargement: validation study with cardiac magnetic resonance imaging. AB - BACKGROUND: Novel 3-dimensional echocardiography with speckle tracking imaging (3D-STE) may have advantages in assessing left ventricular (LV) volume through a cardiac cycle. The feasibility of 3D-STE may be affected by image quality and LV morphology. METHODS AND RESULTS: We studied 64 patients (38 men, age 55+/-12 years) who underwent cardiac magnetic resonance imaging (CMRI) and 3D-STE on the same day. LV end-diastolic volume (EDV) and end-systolic volume (ESV) were measured by both modalities. Imaging qualities were quantified in each of 6 LV segments by an imaging quality score (IQS) of 1-3, and scores were averaged (mean IQS) at end-diastole and end-systole. Compared to CMRI, 3D-STE showed a tendency to underestimate LV volume measurements, but not significantly (EDV: bias=-18+/ 37ml; ESV: bias=-10+/-34ml), and measurements correlated well with those by CMRI (EDV: R=0.80, ESV: R=0.86, ejection fraction: R=0.75, p<0.001). The absolute differences of LVEDV and ESV between 3D-STE and CMRI correlated significantly with mean IQS (LVEDV, R=-0.35, p=0.005; LVESV, R=-0.30, p=0.02). Based on the medium value of LVEDV by CMRI (127ml), subjects were classified into the small (<127ml) and large LVEDV (?127ml) groups. In the large LVEDV group, mean IQS significantly correlated with the absolute differences of LVEDV (mean IQS, r= 0.45, p=0.01), despite no significant correlation in the small LVEDV group. CONCLUSION: 3D-STE could measure LV volume as well as CMRI, however, its accuracy depends on the quality of the acquired image and particularly on enlargement of the left ventricle. PMID- 24145195 TI - Survey of the current status and management of Eisenmenger syndrome: a Japanese nationwide survey. AB - BACKGROUND: The management of Eisenmenger syndrome (ES) has dramatically changed since the advent of disease-targeted therapy (DTT). However, guidelines for ES management, including DTT, have not been established. We aimed to clarify the current incidence, underlying disease, and management of ES in Japan, using a nationwide survey. METHODS: A written questionnaire was sent to members of the Japanese Society for Adult Congenital Heart Disease, through which information was obtained from 86 institutions. RESULTS: A total of 251 patients with ES (80.5% cases>=20 years of age) were followed as of February 2012; DTT was performed in 124 (49.4%) patients. Unrepaired simple anatomy was reported as an underlying condition in 165 patients (65.7%). Among patients with ES, 55 (21.9%), 128 (51%), 53 (21.1%), and 12 (4.8%) were classified into functional classes I, II, III, and IV, respectively. DTT was routinely performed at 52 (60.5%) institutions, but there were variations in the DTT therapeutic strategy at these institutions. Combined therapy was more often used than monotherapy; an endothelin receptor antagonist was the most frequently prescribed medication. There were institutional differences regarding heart failure treatment and indications for anticoagulation. Digitalis and angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers were widely used, but beta blockers were infrequently used to manage heart failure. CONCLUSIONS: This survey describes the current status, including prevalence and underlying disease, and variations in the practical management of ES in Japan. The results will help in the creation of future guidelines for ES management. PMID- 24145196 TI - Clinical impact of acute hyperglycemia on development of diabetes mellitus in non diabetic patients with acute myocardial infarction. AB - BACKGROUND: Acute hyperglycemia (AH) after the onset of acute myocardial infarction (AMI) is a manifestation of transient abnormal glucose metabolism that may reflect AMI severity, and thus be a predictor of poor prognosis. However, it remains unknown whether AH may predict development of de novo diabetes mellitus (dn-DM) in non-diabetic AMI patients. METHODS AND RESULTS: Among AMI patients registered in the Osaka Acute Coronary Insufficiency Study between 1998 and 2007, we investigated hospital records of 1493 patients who had an admission glycated hemoglobin A1c (HbA1c) level of <=6.0% and were subjected to glycometabolic profiling after survival discharge. dn-DM was defined as initiation of diabetic medication or documentation of an HbA1c level of >=6.5% during the 5-year follow up period. AH, defined as an admission serum glucose level of >=200mg/dl, was observed in 133 (8.9%) patients. dn-DM development was more frequent in post-AMI patients with AH than those without [24.8% vs 12.0%, adjusted hazard ratio (HR) 1.776, p=0.021], particularly among patients with an HbA1c of <5.6% on admission. Treatment with angiotensin-converting enzyme inhibitors or angiotensin receptor blockers was associated with a reduced incidence of dn-DM in patients with AH (adjusted HR 0.397, p=0.031). CONCLUSION: Admission AH was a predictor of dn-DM in non-diabetic post-AMI patients. Renin-angiotensin system inhibitors were associated with reduced incidence of dn-DM in post-AMI patients with AH. PMID- 24145197 TI - DeltaNp53 and aging. PMID- 24145198 TI - OCT4: dynamic DNA binding pioneers stem cell pluripotency. AB - OCT4 was discovered more than two decades ago as a transcription factor specific to early embryonic development. Early studies with OCT4 were descriptive and looked at determining the functional roles of OCT4 in the embryo as well as in pluripotent cell lines derived from embryos. Later studies showed that OCT4 was one of the transcription factors in the four-factor cocktail required for reprogramming somatic cells into induced pluripotent stem cells (iPSCs) and that it is the only factor that cannot be substituted in this process by other members of the same protein family. In recent years, OCT4 has emerged as a master regulator of the induction and maintenance of cellular pluripotency, with crucial roles in the early stages of differentiation. Currently, mechanistic studies look at elucidating the molecular details of how OCT4 contributes to establishing selective gene expression programs that define different developmental stages of pluripotent cells. OCT4 belongs to the POU family of proteins, which have two conserved DNA-binding domains connected by a variable linker region. The functions of OCT4 depend on its ability to recognize and bind to DNA regulatory regions alone or in cooperation with other transcription factors and on its capacity to recruit other factors required to regulate the expression of specific sets of genes. Undoubtedly, future iPSC-based applications in regenerative medicine will benefit from understanding how OCT4 functions. Here we provide an integrated view of OCT4 research conducted to date by reviewing the different functional roles for OCT4 and discussing the current progress in understanding their underlying molecular mechanisms. This article is part of a Special Issue entitled: Chromatin and epigenetic regulation of animal development. PMID- 24145199 TI - Evaluation and application of alternative air pollution exposure metrics in air pollution epidemiology studies. PMID- 24145200 TI - Cochrane review summary for cancer nursing: low-bacterial diet versus control diet to prevent infection in cancer patients treated with chemotherapy causing episodes of neutropenia. PMID- 24145201 TI - What will it take? PMID- 24145202 TI - Persistent smoking as a predictor of disability pension due to musculoskeletal diagnoses: a 23 year prospective study of Finnish twins. AB - OBJECTIVE: To investigate whether stability or changes in smoking predict disability pension (DP) due to low back diagnoses (LBD) and musculoskeletal diagnoses (MSD) after taking familial confounding into account using a co-twin design. METHOD: Longitudinal smoking patterns and multiple covariates in a population-based cohort of 17,451 Finnish twins (6959 complete pairs) born before 1958 were surveyed through questionnaires in 1975 and 1981. The outcome data were collected from the national pension registers until the end of 2004. Cox proportional hazards regression models were used for statistical analyses. RESULTS: Disability pension due to low back diagnoses was granted to 408 individuals and disability pension due to musculoskeletal diagnoses to 1177 individuals during the follow-up of 23 years. Being a persistent smoker (current smoker both 1975 and 1981) predicted a significantly increased risk for disability pension (hazard ratio 1.69, 95% confidence interval 1.46, 1.97) compared to those individuals who had never smoked. The association remained when several confounding factors, including familial factors, were taken into account. CONCLUSION: Persistent smoking predicts early disability pension due to musculoskeletal diagnoses and low back diagnoses independently from numerous confounding factors, including familial effects shared by the co-twins. PMID- 24145203 TI - Car ownership and the association between fruit and vegetable availability and diet. AB - OBJECTIVE: Nearly all research on the food environment and diet has not accounted for car ownership - a potential key modifying factor. This study examined the modifying effect of car ownership on the relationship between neighborhood fruit and vegetable availability and intake. METHODS: Data on respondents' (n=760) fruit and vegetable intake, car ownership, and demographics came from the 2008 New Orleans Behavioral Risk Factor Surveillance System. Shelf space data on fresh, frozen, and canned fruits and vegetables were collected in 2008 from a random sample of New Orleans stores (n=114). Availability measures were constructed by summing the amount of fruit and vegetable shelf space in all stores within defined distances from respondent households. Regression analyses controlled for demographics and were run separately for respondents with and without a car. RESULTS: Fruit and vegetable availability was positively associated with intake among non-car owners. An additional 100 m of shelf space within 2 km of a residence was predictive of a half-serving/day increase in fruit and vegetable intake. Availability was not associated with intake among car owners. CONCLUSIONS: Future research and interventions to increase neighborhood healthy food options should consider car ownership rates in their target areas as an important modifying factor. PMID- 24145204 TI - A cluster randomized trial of a multi-level intervention, delivered by service staff, to increase physical activity of children attending center-based childcare. AB - OBJECTIVE: To evaluate the impact of a multi-level intervention on the physical activity levels of 3-5 year old children attending center-based childcare services. METHOD: The trial was conducted in New South Wales Australia in 2010 in 20 centers with 459 children. The intervention, included: fundamental movement skill sessions; structured activities; staff role modelling; limiting small screen recreation and sedentary time; and anactivity promoting physical environment. Control services continued with usual routines. Physical activity during care was assessed using pedometers at baseline and at six months after baseline. Intervention implementation was assessed via observation of staff physical activity practices and audits of service environment and policy. RESULTS: Mean step counts at baseline and follow-up were 17.20 (CI 15.94-18.46) and 16.12 (CI 14.86-17.30) in the intervention group and 13.78 (CI 12.76-14.80) and 13.87 (CI 12.57-15.17) in the control group (p=0.12). Intervention services showed significantly greater increases in the total minutes that teachers led structured activities, relative to control group services (p=0.02). CONCLUSION: The intervention showed no significant effect on child step counts per minute despite increasing time that staff delivered structured activity which is likely to be attributable to difficulties experienced by service staff in delivering a number of intervention components. PMID- 24145205 TI - The impact of HIV treatment as prevention in the presence of other prevention strategies: lessons learned from a review of mathematical models set in resource rich countries. AB - OBJECTIVE: We aimed to assess the potential prevention benefits of HIV treatment as prevention (TasP) in resource-rich countries and examine the potential interactions between TasP and other prevention strategies by reviewing mathematical models of TasP. METHOD: Multiple databases were searched for mathematical models published in the previous 5 years (from July 2007 to July 2012). The nine models located were set in Canada, Australia and the United States. RESULTS: These models' predictions suggested that the impact of expanding treatment rates on expected new infections could range widely, from no decrease to a decrease of 76%, depending on the time horizon, assumptions and the form of TasP modeled. Increased testing, reducing sexually transmitted infections and reducing risky practices were also predicted to be important strategies for decreasing expected new infections. Sensitivity analysis suggests that current uncertainties such as the effectiveness of highly active antiretroviral therapy outside of heterosexual transmission, less than ideal adherence, and risk compensation, could impact on the success of TasP at the population level. CONCLUSION: The results from large scale pilots and community randomized controlled trials will be useful in demonstrating how well this prevention approach works in real world settings, and in identifying the factors that are needed to support its effectiveness. PMID- 24145206 TI - Targeting EBV-LMP1 DNAzyme enhances radiosensitivity of nasopharyngeal carcinoma cells by inhibiting telomerase activity. AB - The latent membrane protein 1 (LMP1), which is encoded by the Epstein-Barr virus (EBV), has been suggested to be one of the major oncogenic factors in nasopharyngeal carcinoma (NPC). In previous studies, we experimentally demonstrated that downregulation of LMP1 expression by targeting EBV-LMP1 DNAzyme (Dz1) could increase the radiosensitivity of NPC. However, how Dz1 contributes to the radiosensitivity in NPC is still not clear. In the present study, we confirmed that Dz1 decreases LMP1 expression and downregulates the expression of the catalytic subunit of telomerase (hTERT), both at the protein and mRNA levels (P<0.01), and therefore, consequently inhibits telomerase activity (P<0.05) in LMP1-positive NPC cells. We also observed that LMP1 mediated Akt phosphorylation is involved in the regulation of hTERT expression and phosphorylation. After LMP1 and hTERT expression was silenced by Dz1 and hTERT-targeted siRNA, respectively, the radiosensitivity increased in CNE1-LMP1 cells (P<0.05). The inhibition was more significant after Dz1 treatment was combined with siRNA (P<0.01). We concluded that hTERT expression and phosphorylation could be regulated by LMP1 through the Akt pathway, and Dz1 enhances radiosensitivity of LMP1-positive NPC cells by inhibiting telomerase activity. PMID- 24145207 TI - Persistent post-surgical pain and experimental pain sensitivity in the Tromso study: comorbid pain matters. AB - In a large survey incorporating medical examination (N=12,981), information on chronic pain and surgery was collected, and sensitivity to different pain modalities was tested. Tolerance to the cold pressor test was analysed with survival statistics for 10,486 individuals, perceived cold pressor pain intensity was calculated for 10,367 individuals, heat pain threshold was assessed for 4,054 individuals, and pressure pain sensitivity for 4,689 individuals. Persistent post surgical pain, defined by self-report, was associated with lower cold pressor tolerance (sex-adjusted hazard ratio=1.34, 95% confidence interval=1.08-1.66), but not when adjusting for other chronic pain. Other experimental pain modalities did not differentiate between individuals with or without post-surgical pain. Of the individuals with chronic pain (N=3352), 6.2% indicated surgery as a cause, although only 0.5% indicated surgery as the only cause. The associations found between persistent post-surgical pain and cold pressor tolerance is largely explained by the co-existence of chronic pain from other causes. We conclude that most cases of persistent post-surgical pain are coexistent with other chronic pain, and that, in an unselected post-surgical population, persistent post surgical pain is not significantly associated with pain sensitivity when controlling for comorbid pain from other causes. A low prevalence of self reported persistent pain from surgery attenuates statistically significant associations. We hypothesize that general chronic pain is associated with central changes in pain processing as expressed by reduced tolerance for the cold pressor test. PMID- 24145208 TI - Single intrathecal administration of the transcription factor decoy AYX1 prevents acute and chronic pain after incisional, inflammatory, or neuropathic injury. AB - The persistence of pain after surgery increases the recovery interval from surgery to a normal quality of life. AYX1 is a DNA-decoy drug candidate designed to prevent post-surgical pain following a single intrathecal injection. Tissue injury causes a transient activation of the transcription factor EGR1 in the dorsal root ganglia-dorsal horn network, which then triggers changes in gene expression that induce neuronal hypersensitivity. AYX1 is a potent, specific inhibitor of EGR1 activity that mimics the genomic EGR1-binding sequence. Administered in the peri-operative period, AYX1 dose dependently prevents mechanical hypersensitivity in models of acute incisional (plantar), inflammatory (CFA), and chronic neuropathic pain (SNI) in rats. Furthermore, in a knee surgery model evaluating functional measures of postoperative pain, AYX1 improved weight bearing incapacitance and spontaneous rearing compared to control. These data illustrate the potential clinical therapeutic benefits of AYX1 for preventing the transition of acute to chronic post-surgical pain. PMID- 24145209 TI - A CRPS-IgG-transfer-trauma model reproducing inflammatory and positive sensory signs associated with complex regional pain syndrome. AB - The aetiology of complex regional pain syndrome (CRPS), a highly painful, usually post-traumatic condition affecting the limbs, is unknown, but recent results have suggested an autoimmune contribution. To confirm a role for pathogenic autoantibodies, we established a passive-transfer trauma model. Prior to undergoing incision of hind limb plantar skin and muscle, mice were injected either with serum IgG obtained from chronic CRPS patients or matched healthy volunteers, or with saline. Unilateral hind limb plantar skin and muscle incision was performed to induce typical, mild tissue injury. Mechanical hyperalgesia, paw swelling, heat and cold sensitivity, weight-bearing ability, locomotor activity, motor coordination, paw temperature, and body weight were investigated for 8days. After sacrifice, proinflammatory sensory neuropeptides and cytokines were measured in paw tissues. CRPS patient IgG treatment significantly increased hind limb mechanical hyperalgesia and oedema in the incised paw compared with IgG from healthy subjects or saline. Plantar incision induced a remarkable elevation of substance P immunoreactivity on day 8, which was significantly increased by CRPS IgG. In this IgG-transfer-trauma model for CRPS, serum IgG from chronic CRPS patients induced clinical and laboratory features resembling the human disease. These results support the hypothesis that autoantibodies may contribute to the pathophysiology of CRPS, and that autoantibody-removing therapies may be effective treatments for long-standing CRPS. PMID- 24145210 TI - Increasing optimism abolishes pain-induced impairments in executive task performance. AB - Coping with the demands of pain diminishes self-regulatory capacity and causes self-regulatory fatigue, which then leads to deteriorated executive task performance. It has been suggested that optimism can counteract the depletion of self-regulatory capacity. This study employed a 2 (optimism/no optimism)*2 (pain/no pain) between-subjects design to explore whether (1) experimentally induced pain (cold pressor task) deteriorates subsequent executive task performance, and (2) whether an optimism induction can counteract this sustained deteriorating effect of pain on executive task performance. Results indicated that although pain led to significantly worse performance on the executive functioning task in the no optimism condition, this sustained deteriorating effect of pain on task performance was abolished in the optimism condition. This finding is imperative because it suggests that optimism may be an important factor to implement in current psychological treatment approaches to diminish the negative impact of chronic pain on the ability to function in daily life. PMID- 24145212 TI - Clinical genetics: exomes in the clinic. PMID- 24145213 TI - Small RNAs: antiviral RNAi in mammals. PMID- 24145211 TI - Incidence and predictors of neck and widespread pain after motor vehicle collision among US litigants and nonlitigants. AB - Debate continues regarding the influence of litigation on pain outcomes after motor vehicle collision (MVC). In this study we enrolled European Americans presenting to the emergency department (ED) in the hours after MVC (n=948). Six weeks later, participants were interviewed regarding pain symptoms and asked about their participation in MVC-related litigation. The incidence and predictors of neck pain and widespread pain 6weeks after MVC were compared among those engaged in litigation (litigants) and those not engaged in litigation (nonlitigants). Among the 859 of 948 (91%) participants completing 6-week follow up, 711 of 849 (83%) were nonlitigants. Compared to nonlitigants, litigants were less educated and had more severe neck pain and overall pain, and a greater extent of pain at the time of ED evaluation. Among individuals not engaged in litigation, persistent pain 6weeks after MVC was common: 199 of 711 (28%) had moderate or severe neck pain, 92 of 711 (13%) had widespread pain, and 29 of 711 (4%) had fibromyalgia-like symptoms. Incidence of all 3 outcomes was significantly higher among litigants. Initial pain severity in the ED predicted pain outcomes among both litigants and nonlitigants. Markers of socioeconomic disadvantage predicted worse pain outcomes in litigants but not nonlitigants, and individual pain and psychological symptoms were less predictive of pain outcomes among those engaged in litigation. These data demonstrate that persistent pain after MVC is common among those not engaged in litigation, and provide evidence for bidirectional influences between pain outcomes and litigation after MVC. PMID- 24145214 TI - An x-ray fluorescence imaging system for gold nanoparticle detection. AB - Gold nanoparticles (GNPs) may be used as a contrast agent to identify tumour location and can be modified to target and image specific tumour biological parameters. There are currently no imaging systems in the literature that have sufficient sensitivity to GNP concentration and distribution measurement at sufficient tissue depth for use in in vivo and in vitro studies. We have demonstrated that high detecting sensitivity of GNPs can be achieved using x-ray fluorescence; furthermore this technique enables greater depth imaging in comparison to optical modalities. Two x-ray fluorescence systems were developed and used to image a range of GNP imaging phantoms. The first system consisted of a 10 mm(2) silicon drift detector coupled to a slightly focusing polycapillary optic which allowed 2D energy resolved imaging in step and scan mode. The system has sensitivity to GNP concentrations as low as 1 ppm. GNP concentrations different by a factor of 5 could be resolved, offering potential to distinguish tumour from non-tumour. The second system was designed to avoid slow step and scan image acquisition; the feasibility of excitation of the whole specimen with a wide beam and detection of the fluorescent x-rays with a pixellated controlled drift energy resolving detector without scanning was investigated. A parallel polycapillary optic coupled to the detector was successfully used to ascertain the position where fluorescence was emitted. The tissue penetration of the technique was demonstrated to be sufficient for near-surface small-animal studies, and for imaging 3D in vitro cellular constructs. Previous work demonstrates strong potential for both imaging systems to form quantitative images of GNP concentration. PMID- 24145215 TI - Raman micro-spectroscopy tracing human lymphocyte activation. AB - The activation of lymphocytes occurs when they are exposed to viruses or other foreign antigens. The aim of this work was to verify if Raman spectroscopy can be used to screen the activation of lymphocytes during viral infection. There are distinct peaks that reveal differences between activated and intact cells. The most important marker of the lymphocyte activation process is the prominent 521 cm(-1) disulfide band which marks the immunoglobulin formation. The up shift of the S-S mode from the broad band centered at 510 cm(-1) of human normal immunoglobulin to a single band at 521 cm(-1) of human B cells indicates a selection of the optimal geometry of the disulphide bridges to bind to a foreign antigen. Polarization data is used to detect the structural alteration between domain fragments. Differences in other band intensities may be due to different protein compositions in both the investigated forms. B cell activation causes the change of the intracellular cytoplasm composition due to the secretion of immunoglobulins during the fighting of the infection. PMID- 24145216 TI - CSF1R mutations in hereditary diffuse leukoencephalopathy with spheroids are loss of function. AB - Hereditary diffuse leukoencephalopathy with spheroids (HDLS) in humans is a rare autosomal dominant disease characterized by giant neuroaxonal swellings (spheroids) within the CNS white matter. Symptoms are variable and can include personality and behavioural changes. Patients with this disease have mutations in the protein kinase domain of the colony-stimulating factor 1 receptor (CSF1R) which is a tyrosine kinase receptor essential for microglia development. We investigated the effects of these mutations on Csf1r signalling using a factor dependent cell line. Corresponding mutant forms of murine Csf1r were expressed on the cell surface at normal levels, and bound CSF1, but were not able to sustain cell proliferation. Since Csf1r signaling requires receptor dimerization initiated by CSF1 binding, the data suggest a mechanism for phenotypic dominance of the mutant allele in HDLS. PMID- 24145217 TI - Long-acting injectables and risk for rehospitalization among patients with schizophrenia in the home care program in Taiwan. AB - We aimed at evaluating the relationship between medication and treatment effectiveness in a home care setting among patients with schizophrenia. Patients with schizophrenia hospitalized between 2004 and 2009 with a primary International Classification of Diseases, Ninth Revision, Clinical Modification code of 295 were identified from Psychiatric Inpatient Medical Claims Data released by the National Health Research Institute in Taiwan. Patients who joined the home care program after discharge and were prescribed long-acting injection (LAI) (the LAI group) or oral antipsychotic medications (the oral group) were included as study subjects. The final sample for the study included 810 participants in the LAI group and 945 in the oral group. Logistic regression was performed to examine the independent effect of LAI medication on the risk for rehospitalization within the 12-month observation window after controlling for patient and hospital characteristics and propensity score quintile adjustment. The unadjusted odds ratio for rehospitalization risk was 0.80 (confidence interval, 0.65-0.98) for the LAI group compared to the oral group. The adjusted odds ratio was further reduced to 0.78 (confidence interval, 0.63-0.97). Results remained unchanged when the propensity score quintiles were entered into the regression for further adjustment. In a home care setting, patients treated with long-acting antipsychotic agents are at a significantly lower risk for psychiatric rehospitalization than those treated with oral medication. Consequently, LAI home-based treatment for the prevention of schizophrenia relapse may lead to substantial clinical and economic benefits. PMID- 24145218 TI - Clinimetric evaluation of the Simpson-Angus Scale in older adults with schizophrenia. AB - OBJECTIVE: Parkinsonism (or Parkinson's syndrome [PS]) remains common in patients exposed to antipsychotic drugs. One clinical tool used in its detection and follow-up, the Simpson-Angus Scale (SAS), has been under revision lately. We further examined the discriminative power of the SAS to detect PS and its efficacy as a measure of PS intensity in chronic schizophrenia. METHODS: Fifty six outpatients between 50 and 75 years of age, under stable antipsychotic drug therapy, provided consent to undergo an evaluation along the SAS and Unified Parkinson's Disease Rating Scale III motor subsection, split according to the presence or absence of PS defined in the UK Parkinson's Disease Society Brain Bank (UKPDSBB) criteria or Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition criteria. RESULTS: The identification rate for PS was 39.3% based on UKPDSBB criteria applied to the Unified Parkinson's Disease Rating Scale III, compared with 62.5% and 87.5% according to the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition criteria and SAS cutoff value greater than 0.3, respectively. Median SAS scores for PS and PS-free participants were comparable. The SAS yielded high sensitivity (90.9%) but low specificity (17.7%). kappa Values generally revealed only slight agreement between the group allocation provided by the SAS and the UKPDSBB criteria. Receiver operating characteristic curve for screening performance of the SAS provided poor prediction of subject status. CONCLUSIONS: The SAS lacks specificity and constitutes an imperfect detection and measurement tool for PS in older adults. Raising the cutoff score would avoid inflation in PS identification. The scale is probably best used as a measure of change relative to baseline score following an intervention, but results should be interpreted with caution. PMID- 24145219 TI - Drug attitude in adolescents: a key factor for a comprehensive assessment. AB - OBJECTIVE: Very few studies have evaluated the subjective experience (SE) in children and adolescents treated with antipsychotics. The present study aimed to evaluate the SE of antipsychotics in adolescents diagnosed with different psychiatric conditions and to identify explanatory variables of adolescents' SE and compliance with treatment. METHODS: The Drug Attitude Inventory (DAI) was used to evaluate SE in 67 adolescents in 2 different countries (Italy and United Kingdom). Compliance was measured using a Likert scale completed by both patients and parents. To evaluate other parameters correlated to the SE, the following scales were administered: Clinical Global Impression Scale, Children's Global Assessment Scale, Extrapyramidal Symptoms Rating Scale, Barnes Akathisia Rating Scale, and EuroQoL (for quality of life). Multiple and logistic regression analyses were applied. RESULTS: No significant difference in drug attitude was found between psychotic and nonpsychotic patients. Our results showed a highly significant association between DAI and compliance (Spearman index, 0.33; P = 0.005); for all other variables, DAI associated significantly only with quality of life (r = 0.25; P = 0.03). The multivariable analysis confirmed the presence of a strong association between compliance and DAI (P = <0.001). In our sample, drug attitude was the only variable found to be correlated with the compliance, whereas extrapyramidal adverse effects showed an only marginally significant association. CONCLUSIONS: Our observations provide confirmation, also in adolescents, that drug attitude is strongly correlated with treatment compliance and underline the need in clinical assessments to always consider the patient's viewpoint. PMID- 24145220 TI - The opiate antagonist, naltrexone, in the treatment of trichotillomania: results of a double-blind, placebo-controlled study. AB - Trichotillomania (TTM) is characterized by repetitive hair pulling resulting in hair loss. Data on the pharmacological treatment of TTM are limited. This study examined the opioid antagonist, naltrexone, in adults with TTM who had urges to pull their hair. Fifty-one individuals with TTM were randomized to naltrexone or placebo in an 8-week, double-blind trial. Subjects were assessed with measures of TTM severity and selected cognitive tasks. Naltrexone failed to demonstrate significantly greater reductions in hair pulling compared to placebo. Cognitive flexibility, however, significantly improved with naltrexone (P = 0.026). Subjects taking naltrexone with a family history of addiction showed a greater numerical reduction in the urges to pull, although it was not statistically significant. Future studies will have to examine whether pharmacological modulation of the opiate system may provide promise in controlling pulling behavior in a subgroup of individuals with TTM. PMID- 24145221 TI - Augmentation of clozapine with ziprasidone in refractory schizophrenia: a double blind, placebo-controlled study. AB - The present 16-week double-blind, randomized, placebo-controlled trial was aimed to explore the efficacy of ziprasidone add-on pharmacotherapy on clinical symptoms and cognitive functioning in 40 schizophrenic patients (active group, n = 20; placebo group, n = 20) with residual symptoms (Brief Psychiatric Rating Scale mean [SD] baseline total score in active group vs placebo, 40.4 [5.9] vs 37.9 [6.8]) despite receiving clozapine monotherapy at the highest tolerated dosage. The results obtained evidenced that ziprasidone augmentation of clozapine significantly reduced Positive and Negative Syndrome Scale "Negative" (P = 0.006, mean change [SD] in active group vs placebo, -2.7 [2.3] vs 1.1 [2.1], Cohen d = 1.7) and "General Psychopathology" (P = 0.009, mean change [SD] in active group vs placebo, -5.3 [3.8] vs -0.7 [2.0], Cohen d = 1.5). Regarding cognitive domains, ziprasidone was more effective than placebo in improving semantic fluency (P < 0.0001, mean change [SD] in active group vs placebo, 4.4 [3.5] vs 0.1 [4.1], Cohen d = 1.2). Ziprasidone had only a small effect on prolongation of heart-rate corrected QT interval (QTc) of the electrocardiogram, not significantly different from placebo (QTc milliseconds, mean [SD], week 16 in active group vs placebo, 408.17 [20.85] vs 405.45 [17.11], P = 0.321); within group comparison revealed that QTc prolongation induced by ziprasidone was statistically significant (baseline vs week 16, P = 0.002). Ziprasidone added to clozapine was effective on negative and cognitive symptoms, although it may be proposed as a helpful treatment in schizophrenia, mainly for those patients who partially respond to clozapine monotherapy. PMID- 24145222 TI - Epigenetic aging: insights from network biology. PMID- 24145223 TI - Using machine learning and high-throughput RNA sequencing to classify the precursors of small non-coding RNAs. AB - Recent advances in high-throughput sequencing allow researchers to examine the transcriptome in more detail than ever before. Using a method known as high throughput small RNA-sequencing, we can now profile the expression of small regulatory RNAs such as microRNAs and small interfering RNAs (siRNAs) with a great deal of sensitivity. However, there are many other types of small RNAs (<50nt) present in the cell, including fragments derived from snoRNAs (small nucleolar RNAs), snRNAs (small nuclear RNAs), scRNAs (small cytoplasmic RNAs), tRNAs (transfer RNAs), and transposon-derived RNAs. Here, we present a user's guide for CoRAL (Classification of RNAs by Analysis of Length), a computational method for discriminating between different classes of RNA using high-throughput small RNA-sequencing data. Not only can CoRAL distinguish between RNA classes with high accuracy, but it also uses features that are relevant to small RNA biogenesis pathways. By doing so, CoRAL can give biologists a glimpse into the characteristics of different RNA processing pathways and how these might differ between tissue types, biological conditions, or even different species. CoRAL is available at http://wanglab.pcbi.upenn.edu/coral/. PMID- 24145225 TI - Bunyaviral cap-snatching vs. decapping: recycling cell cycle mRNAs. PMID- 24145224 TI - Genetic polymorphisms potentially associated with response to metformin in postmenopausal diabetics suffering and not suffering with cancer. AB - Metformin is a well-known antidiabetic medication, which, besides diabetes, may be involved into modulation of other age-related pathologies, including cancer. The study concerns 12 gene polymorphisms divided into 2 groups consisting of 6 genes each. The first group was composed from so-called "standard" (S) polymorphisms, for which the connection with metabolic response to metformin is already established. The second group included polymorphisms of genes encoding proteins possibly connected with diabetes mellitus type 2 (DM2), impaired glucose tolerance or cancer and entitled here as "associated" (A). A total of 156 postmenopausal women (average age 60.7 +/- 0.7) were included, 37 of them healthy, 64 with type DM2 and concurrent treatment-naive cancer (mostly breast, endometrial or colorectal cancer), 32 with DM2 without cancer, and 23 with treatment-naive cancer and normal glucose tolerance. The leading metformin response S-marker in combined group of DM2 patients was the CC variant of OCT1 R61C polymorphism of organic cation transporter protein 1 gene. In cancer patients without DM2, this position belonged to AC and AA genotypes of OCT1_rs622342 polymorphism. Among the A-polymorphisms, GA variant of sex hormone binding globulin gene SHBG_D356N was less frequently observed in DM2 patients with or without cancer. Besides, in diabetics, the same polymorphic variant of SHBG as well as GC genotype of oxidized lipoprotein receptor OLR1_G501C and GG genotype of locus rs11065987 near BRAP gene were carried rather often in combination with "metformin-positive" variant of OCT1_R61C. In addition, carriers of OCT1_R61C and OCT1_rs622342 polymorphisms with potentially positive reaction to metformin had higher insulin resistance score (HOMA-IR) values. Received data lead to the conclusion that postmenopausal diabetics, both with and without cancer, differ in genetic stigmata of potential response to metformin less than they differ from cancer patients without DM2. As genetic polymorphisms associated with metabolic and anticancer metformin (and, possibly, phenformin) effects may be different, this subject requires further investigation. PMID- 24145226 TI - Tie2 (to) Abl: Signaling to endothelial cell survival. PMID- 24145227 TI - Epigenetic regulation of neuronal fate determination: the role of CHD7. PMID- 24145229 TI - Intragenic breakpoint: a marker of genome instability in glioblastoma. PMID- 24145228 TI - "Sister" miRNAs in cancers. PMID- 24145230 TI - Spinal pain management. The role of physical and rehabilitation medicine physicians. The European perspective based on the best evidence. A paper by the UEMS-PRM Section Professional Practice Committee. AB - One of the objectives of the Professional Practice Committee (PPC) of the Physical and Rehabilitation Medicine (PRM) Section of the Union of European Medical Specialists (UEMS) is the development of the field of competence of PRM physicians in Europe. To achieve this objective, UEMS PRM Section PPC has adopted a systematic action plan of preparing a series of papers describing the role of PRM physicians in a number of disabling health conditions, based on the evidence of effectiveness of the PRM interventions. The aim of this paper is to describe the role of PRM physicians in the management of spinal pain focusing particularly on low back pain and neck pain. These disorders are associated with significant disability that results in activity limitations and participation restrictions. A wide variety of PRM interventions including patient education, behavioural therapies, exercise, a number of physical modalities, manual techniques, and multidisciplinary rehabilitation may help patients with low back pain and cervical pain in improving their functioning. PRM physicians may address many of the problems encountered by these patients in many life areas taking the International Classification of Functioning, Disability and Health as a reference guide and may have an important role in improving the quality of their lives. PMID- 24145231 TI - Local soft tissue musculoskeletal disorders and injuries. The role of physical and rehabilitation medicine physicians. The European perspective based on the best evidence. A paper by the UEMS-PRM Section Professional Practice Committee. AB - One of the objectives of the Professional Practice Committee (PPC) of the Physical and Rehabilitation Medicine (PRM) Section of the Union of European Medical Specialists (UEMS) is the development of the field of competence of PRM physicians in Europe. To achieve this objective, UEMS PRM Section PPC has adopted a systematic action plan of preparing a series of papers describing the role of PRM physicians in a number of disabling health conditions, based on the evidence of effectiveness of PRM interventions. Soft tissue musculoskeletal disorders (MSDs) and injuries are associated with significant pain and loss of function that may lead to significant disability. The aim of this paper is to define the role of PRM physician in the management of local soft tissue MSDs and injuries with their specific focus on assessing and improving function as well as participation in the community. The training of PRM specialists make them well equipped to successfully treat MSDs including soft tissue MSDs and injuries. PRM specialists may well meet the needs of patients with soft tissue MSDs and injuries using PRM approaches including 1) assessment based on the comprehensive model of functioning, the International Classification of Functioning, Disability and Health (ICF), that enable them to identify the areas of impaired functioning in order to apply necessary measures; 2) accurate diagnosis using instrumental diagnostic procedures in addition to clinical examination; 3) outcome measurements available to them; 4) evidence-based pharmacological and nonpharmacological treatments; and finally 5) maintenance of social involvement including "return to work" based on restoration of function, all of which will eventually result in improved quality of life for patients with soft tissue MSDs and injuries. PMID- 24145232 TI - Shoulder pain management. The role of physical and rehabilitation medicine physicians. The European perspective based on the best evidence. A paper by the UEMS-PRM Section Professional Practice Committee. AB - One of the objectives of the Professional Practice Committee (PPC) of the Physical and Rehabilitation Medicine (PRM) Section of the Union of European Medical Specialists (UEMS) is the development of the field of competence of PRM physicians in Europe. To achieve this objective, UEMS PRM Section PPC has adopted a systematic action plan of preparing a series of papers describing the role of PRM physicians in a number of disabling health conditions, based on the evidence of effectiveness of the physical and rehabilitation medicine interventions. According to the PCC of the UEMS-PRM Section, the role of PRM physician in the management of shoulder pain (SP) has to be situated inside the general pain management field. SP is a common condition that can place limitations on the activity and restriction in social life participation of sufferers. A variety of shoulder problems, commonly including subacromial impingement, calcifying tendinitis, frozen shoulder, acromio-clavicular disturbances, gleno-humeral instability and gleno-humeral arthritis, can cause pain, and patients should be assessed and treated in order to relieve symptoms and reduce disability. This position paper describes the role of the PRM specialist in the management of such patients. Many assessment methods and treatment interventions are usually used in the management of patients with SP. Depending on the process, disability and patient characteristics, some intervention modalities have reported evidence in pain relief, movement and daily life activity (DLA) restoration, thus permiting a patient early recovery and social participation. Oral medications, local injections, physical therapy modalities and exercises are normally used for the management of SP. The PRM specialist should, always use this best medical evidence to decide how to efficiently and effectively reduce SP-related disability. An adequate therapeutic algorithm is also proposed in order to channelize the above mentioned evidence and reach the best results. PMID- 24145233 TI - Musculoskeletal perioperative problems. The role of physical and rehabilitation medicine physicians. The European perspective based on the best evidence. A paper by the UEMS-PRM Section Professional Practice Committee. AB - One of the objectives of the Professional Practice Committee (PPC) of the Physical and Rehabilitation Medicine (PRM) Section of the Union of European Medical Specialists (UEMS) is the development of the field of competence of PRM physicians in Europe. To achieve this objective, UEMS PRM Section PPC has adopted a systematic action plan of preparing a series of papers describing the role of PRM physicians in a number of disabling health conditions, based on the evidence of effectiveness of the physical and rehabilitation medicine interventions. According to the UEMS-PRM section, the role of PRM physician in musculoskeletal perioperative settings has to be situated inside general pain management. Musculoskeletal surgery (MSS) represents a frequent medical situation among patients suffering from musculoskeletal disorders (MSDs), in which PRM physicians need to be involved. A wide number of MSDs have to be operated in order to diminish disability and relieve symptoms, thus improving the patient's functioning and social participation: Joint replacements, spine decompressions, vertebroplasties, internal fixation of unstable fractures, arthroscopies for tendon and joint repairs, and others. This paper describes the role of the PRM physician during the perioperative period. A well-coordinated rehabilitation programme followed by a good home rehabilitation programme results in pain reduction, faster recovery with better patient participation and increased cost effectiveness. PRM physicians have to identify patients at risk of continuing activity limitation and participation restriction who will benefit from an early rehabilitation process and formulate a PRM programme of care taking into account each patient's environmental factors. PMID- 24145234 TI - Revascularization with the occipital artery to treat aneurysms in the posterior circulation. PMID- 24145235 TI - The impact of obesity on surgeon ratings and patient-reported outcome measures after degenerative cervical spine disease surgery. AB - OBJECTIVE: Obesity is a growing public health problem. A considerable number of patients undergoing cervical spine surgery are obese, but the correlation between obesity and surgical outcome is still unclear. In this study, we investigated the impact of body mass index (BMI) on patients' and surgeons' perception of spine surgery outcomes. METHODS: We analyzed a prospectively collected spine surgery registry with patient-reported outcome measures and surgeon ratings. Mixed effects linear models and linear regression models were applied to investigate the relationship between different World Health Organization obesity classifications and surgical outcome. RESULTS: A total of 88 patients had surgery for degenerative cervical spine disease, with 97.72% follow-up at 3 months and 94.31% at 6 months postoperatively. Mean BMI was 27.92 +/- 7.9 kg/m(2); 28.57% were overweight (BMI 25-29.9), and 31.57% were obese (Class I obesity, BMI 30 34.9). We found a positive correlation between BMI and VAS at 6 months (R = 0.298, P < 0.05) and between BMI and change in Neck Disability Index (R = 0.385, P < 0.01), suggesting that obese patients had less improvement and more pain 6 months postoperatively than nonobese patients. Overweight patients had worse MCS values (R = -0.275, P < 0.05) and obese patients had worse visual analog scale values 6 months after surgery (R = 0.284, P < 0.03). Interestingly, surgeon ratings matched the aforementioned results. Patients with greater BMI had worse surgeon ratings 3 and 6 months postoperatively (R = 0.555, P < 0.05), whereas normal-weight patients had better outcomes when rated from the surgeon's perspective (R = -0.536, P < 0.05). CONCLUSION: Obese patients had worse postoperative patient-reported outcome scores and less overall patient-rated improvement compared with nonobese patients. Patients with BMI >25 reported less improvement after surgery both in the patients' and in the surgeons' perspectives. PMID- 24145236 TI - Quest for level I evidence in the treatment of cervical spondylotic myelopathy. PMID- 24145237 TI - Beware of the arcuate foramen. PMID- 24145238 TI - A novel mouse model of nonalcoholic steatohepatitis with significant insulin resistance. AB - Currently available models insufficiently reflect the pathogenic alternation of nonalcoholic steatohepatitis?NASH), such as insulin resistance. The present study aimed to characterize a novel NASH model caused by feeding the diet containing conjugated linoleic acid (CLA). In this study, mice were fed a control diet or the diet containing 0.5% CLA for 8 weeks. The insulin tolerance test (ITT) and homeostasis model assessment of insulin resistance (HOMA-IR) were used to determine the extent of insulin resistance. Liver lipotoxicity and inflammation were assessed by endoplasmic reticulum (ER) stress, autolipophagy, recruitment of Kupffer cells and hepatic stellate cell (HSC) activation. We found that liver weight was markedly increased, and histopathological examination showed marked macrosteatosis with focal hepatocellular death through apoptosis, and mild pericellular fibrosis with Kupffer cell recruitment and HSC activation, as well as light chain IIIbeta-positive cells and enhanced ER stress in mice fed the CLA containing diet. Enhanced synthesis and reduced beta-oxidation of fatty acids resulted in their accumulation and lipotoxicity in hepatocytes. A biophotonic technology revealed lipid droplet accumulation in the liver from mice fed the CLA containing diet, and Raman spectroscopic analysis indicated that these lipid droplets predominantly contained saturated fatty acids. Elevated fasting insulin levels, abnormal ITT and HOMA-IR confirmed the marked insulin resistance in these mice. Decreased phosphorylation of the insulin-signaling molecule Akt was partially responsible for the significant insulin resistance. In conclusion, Mice fed the diet containing CLA-developed steatohepatitis with marked insulin resistance, which is similar to the characteristics observed in NASH patients. The further characterization of this model would be particularly useful for revealing the critical role of insulin resistance in NASH development in conditions such as metabolic syndrome, diabetes and obesity. PMID- 24145239 TI - Expression of KIAA0101 protein is associated with poor survival of esophageal cancer patients and resistance to cisplatin treatment in vitro. AB - The KIAA0101 protein is overexpressed in various human cancers, including esophageal cancer (EC). This study assessed the association of KIAA0101 protein with prognosis and resistance to chemotherapy in EC patients and then explored the role of KIAA0101 in EC cells in vitro. A total of 228 EC patients participated in the study. Tissue samples were collected for immunohistochemical analysis of KIAA0101 expression in tumor and normal tissues for association with clinicopathological and survival data. KIAA0101 cDNA or shRNA were transfected into EC cells for assessment of tumor cell viability, sensitivity to cisplatin treatment, and gene expression. Array-based comparative genomic hybridization (aCGH) was used to detect the changed copy-number alterations in cell lines expressing different levels of KIAA0101. Expression of KIAA0101 protein was upregulated in EC tissues, which was associated with pTNM stage, resistance to chemotherapy, tumor recurrence, and poor survival of EC patients. In vitro experiments showed that expression of KIAA0101 enhanced cell proliferation and upregulated cyclins A and B expression, leading to a reduced G1 phase of the cell cycle. KIAA0101 also induced resistance of EC Eca-109 and TE-1 cell lines to cisplatin treatment through a decrease in apoptosis. The aCGH data showed that levels of KIAA0101 expression altered chromosome stability, affecting genes that are associated with cancer progression. In conclusion, upregulated KIAA0101 expression is associated with EC progression, resistance to chemotherapy, and poor survival of the patients. PMID- 24145240 TI - Stem cell self-renewal factors Bmi1 and HMGA2 in head and neck squamous cell carcinoma: clues for diagnosis. AB - Head and neck squamous cell carcinoma (HNSCC) includes both morphological and functional cellular heterogeneity, as would be expected if it arose from dysregulated stem or progenitor cells as opposed to the simple clonal expansion of a mutated cell; however, stemness molecule expression levels and distribution in HNSCC remain unclear. To clarify this, stemness molecule expressions were determined in HNSCC, as well as their properties and prognosis. Two proto oncogenic chromatin regulators, Bmi-1 and high-mobility-group A2 (Hmga2), were identified in 12 pair cases of HNSCC tumor regions by comparison with their non cancerous background tissues using cDNA microarray. Both Bmi-1 and Hmga2 are known to promote stem cell self-renewal by negatively regulating the expressions of Ink4a and Arf tumor suppressors. Despite similar targets, Bmi-1 protein was expressed in an early cancerous region and HMGA2 protein was expressed in a region showing more progression. Similarly, Bmi1 expression had no significance with regard to overall survival (P=0.67), whereas HMGA2 expression was associated with decreased overall survival (P=0.05). Quantitative real-time reverse transcription polymerase chain reaction analyses also correlated with protein levels. These findings suggest that Bmi-1 is an early detection marker to distinguish cancerous from non-cancerous regions, whereas HMGA2 is presumed to be a tumor prognosis marker. Among our HNSCC analyses, these stemness molecules expressed fewer primitive rare cells in the tumor than all other cells in the tumor. HNSCC cells with high expression of stemness molecules partly behave like stem cells. PMID- 24145242 TI - Multiplexed fluorescent microarray for human salivary protein analysis using polymer microspheres and fiber-optic bundles. AB - Herein, we describe a protocol for simultaneously measuring six proteins in saliva using a fiber-optic microsphere-based antibody array. The immuno-array technology employed combines the advantages of microsphere-based suspension array fabrication with the use of fluorescence microscopy. As described in the video protocol, commercially available 4.5 MUm polymer microspheres were encoded into seven different types, differentiated by the concentration of two fluorescent dyes physically trapped inside the microspheres. The encoded microspheres containing surface carboxyl groups were modified with monoclonal capture antibodies through EDC/NHS coupling chemistry. To assemble the protein microarray, the different types of encoded and functionalized microspheres were mixed and randomly deposited in 4.5 MUm microwells, which were chemically etched at the proximal end of a fiber-optic bundle. The fiber-optic bundle was used as both a carrier and for imaging the microspheres. Once assembled, the microarray was used to capture proteins in the saliva supernatant collected from the clinic. The detection was based on a sandwich immunoassay using a mixture of biotinylated detection antibodies for different analytes with a streptavidin-conjugated fluorescent probe, R-phycoerythrin. The microarray was imaged by fluorescence microscopy in three different channels, two for microsphere registration and one for the assay signal. The fluorescence micrographs were then decoded and analyzed using a homemade algorithm in MATLAB. PMID- 24145243 TI - A new room temperature dark conglomerate mesophase formed by bent-core molecules combining 4-iodoresorcinol with azobenzene units. AB - The first bent-core molecules comprising 4-iodoresorcinol as the central core unit and incorporating azobenzene units have been synthesized. A new type of dark conglomerate phase (DC phase) is observed, which remains over a wide temperature range down to room temperature without crystallization. PMID- 24145241 TI - Stem cells and targeted approaches to melanoma cure. AB - Melanoma stem cells, also known as malignant melanoma-initiating cells, are identifiable through expression of specific biomarkers such as ABCB5 (ATP-binding cassette, sub-family B (MDR/TAP), member 5), NGFR (nerve growth factor receptor, CD271) and ALDH (aldehyde dehydrogenase), and drive melanoma initiation and progression based on prolonged self-renewal capacity, vasculogenic differentiation and immune evasion. As we will review here, specific roles of these aggressive subpopulations have been documented in tumorigenic growth, metastatic dissemination, therapeutic resistance, and malignant recurrence. Moreover, recent findings have provided pre-clinical proof-of-concept for the potential therapeutic utility of the melanoma stem cell concept. Therefore, melanoma stem cell-directed therapeutic approaches represent promising novel strategies to improve therapy of this arguably most virulent human cancer. PMID- 24145246 TI - The experiences of head and neck cancer patients requiring major surgery. AB - BACKGROUND: The prevalence of head and neck cancers is lower (3.5% of total cancers in Australia) than for a number of other cancers. Treatment for head and neck cancer is often drastic and debilitating and patient outcomes are poorer. OBJECTIVE: This qualitative study explored the experiences of cancer patients who underwent surgery for head and neck cancer. METHODS: In-depth face-to-face interviews were conducted with 12 patients 7 to 26 months after surgery. Interviews were thematically analyzed to produce a rich description of patients' experiences from diagnosis through surgery and beyond. RESULTS: Critical aspects of patients' experiences are described through the following themes: only having half the story, shocks and aftershocks, living with the aftermath, and being supported. Participants identified difficulties arising from receiving insufficient, confusing, and often untimely information. The persistent and traumatic nature of what patients endure challenges their physical, mental, and emotional coping capacity and, in some cases, their motivation to live. CONCLUSIONS: There is a need to address gaps in support and education of patients and carers. Of particular concern is the problem related to information provision and comprehension. Critical examination of current practices, together with efforts toward coordinated care tailored to individual needs, is required, along with outreach services for patients in rural areas. IMPLICATIONS FOR PRACTICE: The development and evaluation of targeted resources in a variety of forms such as DVD, Internet, and pamphlets are needed. Robust assessment strategies are required to inform supportive interventions matched to stages and significant events in patients' journeys. PMID- 24145245 TI - Comparison of resilience in adolescent survivors of brain tumors and healthy adolescents. AB - BACKGROUND: Resilience is essential for the psychological adjustment of adolescents experiencing difficulty. Comparing differences in resilience between adolescent survivors of brain tumors and healthy adolescents may help identify factors related to resilience in adolescents. OBJECTIVE: The purpose of this study was to clarify how illness impacts the normative development of adolescent survivors of brain tumors by comparing them to healthy adolescents in terms of resilience and how it is affected by various health problems. METHODS: This cross sectional, case-control study used convenience sampling to recruit 13- to 18-year old adolescent survivors of brain tumors and healthy adolescents matched by school level, gender, and living area. Data were collected by structured questionnaires. RESULTS: The sample included 60 adolescent survivors and 120 healthy adolescents. Participants in both groups were predominantly male adolescents (63.3%) and junior high school students (55%). The 2 groups did not differ significantly in resilience, but survivors without emotional problems had a higher mean resilience score than did healthy adolescents and survivors with emotional problems (F = 8.65, P < .01). CONCLUSIONS: Our results identify emotional problems as a risk factor for resilience in both adolescent survivors of brain tumors and healthy adolescents. In addition, the impact of emotional problems on resilience was more severe in brain tumor survivors than in healthy adolescents. IMPLICATIONS FOR PRACTICE: Our results suggest that pediatric oncology nurses design interdisciplinary school-based interventions to reduce the impact of emotional problems on resilience in both healthy adolescents and those who survived brain tumors. PMID- 24145247 TI - Existential anxiety and growth: an exploration of computerized drawings and perspectives of children and adolescents with cancer. AB - BACKGROUND: Until now, most existentially focused cancer research has been conducted within adult populations. Only a handful of qualitative investigations have captured the experiences of children with cancer relative to themes such as existential fear and finitude, meaning/meaninglessness, uncertainty, authenticity, and inauthenticity. OBJECTIVE: This article aimed to provide a deeper understanding of the existential challenges faced by children living with cancer. METHODS: An interpretive, descriptive qualitative research approach was used. Thirteen children (8-17 years) undergoing treatment for cancer participated. Children participated in individual open-ended interviews and also had the opportunity to journal their experiences in a computerized drawing tool. RESULTS: The 4 main themes that emerged in relation to the existential challenges experienced by children with cancer included (1) existential worry, (2) existential vacuum, (3) existential longing, and (4) existential growth. The drawing tool within the computer diary was found to be particularly beneficial in assisting children to express the existential challenges that they had previously been unable to articulate in words. CONCLUSION: Children moved between existential anxiety and existential growth within the cancer world. The expressive means of drawing pictures gave children a therapeutic space to explore and work at understanding the existential challenges experienced. IMPLICATIONS FOR PRACTICE: This research provides evidence that the active engagement of children's imaginations through the use of a computer-drawing tool may have significant therapeutic value for children with cancer. As well, the findings support the importance of nurses "being there" for young patients with cancer in their time of despair. PMID- 24145248 TI - The nurse's role in managing chemotherapy-induced nausea and vomiting: an international survey. AB - BACKGROUND: Nurses play a substantial role in the prevention and management of chemotherapy-induced nausea and vomiting (CINV). OBJECTIVES: This study set out to describe nurses' roles in the prevention and management of CINV and to identify any gaps that exist across countries. METHODS: A self-reported survey was completed by 458 registered nurses who administered chemotherapy to cancer patients in Australia, China, Hong Kong, and 9 Latin American countries. RESULTS: More than one-third of participants regarded their own knowledge of CINV as fair to poor. Most participants (>65%) agreed that chemotherapy-induced nausea and chemotherapy-induced vomiting should be considered separately (79%), but only 35% were confident in their ability to manage chemotherapy-induced nausea (53%) or chemotherapy-induced vomiting (59%). Only one-fifth reported frequent use of a standardized CINV assessment tool and only a quarter used international clinical guidelines to manage CINV. CONCLUSIONS: Participants perceived their own knowledge of CINV management to be insufficient. They recognized the need to develop and use a standardized CINV assessment tool and the importance of adopting international guidelines to inform the management of CINV. IMPLICATIONS FOR PRACTICE: Findings indicate that international guidelines should be made available to nurses in clinically relevant and easily accessible formats, that a review of chemotherapy assessment tools should be undertaken to identify reliable and valid measures amenable to use in a clinical settings, and that a CINV risk screening tool should be developed as a prompt for nurses to enable timely identification of and intervention for patients at high risk of CINV. PMID- 24145244 TI - Pubertal onset in children with perinatal HIV infection in the era of combination antiretroviral treatment. AB - OBJECTIVE: To evaluate associations of perinatal HIV infection, HIV disease severity, and combination antiretroviral treatment with age at pubertal onset. DESIGN: Analysis of data from two US longitudinal cohort studies (IMPAACT 219C and PHACS AMP), conducted during 2000-2012, including perinatally HIV-infected (PHIV) and HIV-exposed but uninfected (HEU) youth. Tanner stage assessments of pubertal status (breast and pubic hair in girls; genitalia and pubic hair in boys) were conducted annually. METHODS: We compared the timing of pubertal onset (Tanner stage >=2) between PHIV and HEU youth using interval-censored models. For PHIV youth, we evaluated associations of HIV disease severity and combination antiretroviral treatment with age at pubertal onset, adjusting for race/ethnicity and birth cohort. RESULTS: The mean age at pubertal onset was significantly later for the 2086 PHIV youth compared to the 453 HEU children (10.3 vs. 9.6, 10.5 vs. 10.0, 11.3 vs. 10.4, and 11.5 vs. 10.7 years according to female breast, female pubic hair, male genitalia, and male pubic hair staging, respectively, all P < 0.001). PHIV youth with HIV-1 RNA viral load above 10, 000 copies/ml (vs. <=10, 000 copies/ml) or CD4% below 15% (vs. >=15%) had significantly later pubertal onset (by 4-13 months). Each additional year of combination antiretroviral treatment was associated with a 0.6-1.2-month earlier mean age at pubertal onset, but this trend did not persist after adjustment for birth cohort. CONCLUSION: Pubertal onset occurs significantly later in PHIV than in HEU youth, especially among those with more severe HIV disease. However, in the current era, combination antiretroviral treatment may result in more normal timing of pubertal onset. PMID- 24145249 TI - Grief related to the experience of being the sibling of a child with cancer. AB - BACKGROUND: Few studies have described the well siblings' experience of grief when a brother or sister is treated for cancer. Knowing how sibling grief is expressed will guide clinician and family efforts to provide appropriate support. OBJECTIVE: The aim of this study was to describe siblings' reports of grief related to the experience of having a brother or sister with cancer. METHODS: A qualitative descriptive method was chosen based on open-ended interviews with 29 siblings aged 8 to 24 years. Qualitative content analysis was applied to the interview data. RESULTS: Four categories of grief were identified: anticipatory grief after receiving information about the cancer diagnosis, grief and concern about the ill sibling's loss of a normal life, grief about being unimportant and forgotten in the family, and grief that continues after the sibling's death as a kind of bond. CONCLUSION: Despite variations in age and gender among participating siblings, their thoughts were similar. Grief was experienced differently from the time of the diagnosis onward, in the form of concerns related to the illness and situation of the ill sibling. Grief related to sibling bonds remained after death. IMPLICATION FOR PRACTICE: This study recommends offering siblings realistic information about their ill sibling and support for them in their situation from diagnosis and continuously thereafter. To meet the needs of well siblings, it is necessary to ask the siblings about their thoughts and discuss with them their emotions and worries. PMID- 24145251 TI - "It's just going to a new hospital ... that's it." Or is it? An experiential perspective on moving from pediatric to adult cancer services. AB - BACKGROUND: Survivors of childhood cancer will, at some stage, move from pediatric to adult care and/or to a different model of care to continue to receive long-term follow-up. Literature relating to transitional care for childhood onset conditions exists, but little research has been undertaken into transition in a cancer context, specifically from an experiences perspective. OBJECTIVE: The aim of this study was to report how the process of transition should be considered within the context of young people's entire illness experience and how that experience can impact their transition readiness. INTERVENTION/METHODS: A qualitative, collective case study approach was adopted. Semistructured interviews were conducted with young people, parents, and healthcare professionals. Young people's oncology case notes were also reviewed. RESULTS: Data analysis generated a multidimensional and multiple-perspective understanding of the experience of the process of transition. A central orienting theme was identified: the experience of readiness in the context of transition. CONCLUSIONS: Understanding the multifaceted components of readiness is crucial; readiness should embody people's illness experiences, the numerous and associated losses intertwined with a move from pediatric to adult care, and the simultaneous developmental changes occurring in people's lives. IMPLICATIONS FOR PRACTICE: The findings provide a meaningful framework to understand the experience of transition from the perspective of young people, parents, and healthcare professionals. These findings could help with the planning and preparation of individualized transitional care pathways for survivors of childhood cancer. PMID- 24145250 TI - Predictors of stage of adoption for colorectal cancer screening among African American primary care patients. AB - BACKGROUND: Compared with other racial groups, African Americans have the highest colorectal cancer (CRC) incidence and mortality rates coupled with lower screening rates. OBJECTIVE: Our study examined the predictors of stage of adoption for fecal occult blood testing (FOBT) and colonoscopy among African American primary care patients who were nonadherent to published screening guidelines. METHODS: Baseline data (N = 815) in a randomized clinical trial were analyzed. Participants were categorized into precontemplation, contemplation, and preparation stages for FOBT and colonoscopy. Predictor variables were demographics, clinical variables, CRC health beliefs and knowledge, and social support. Hierarchical modeling was to identify significant predictors of stage of adoption. RESULTS: Older, male, Veterans Affairs participants and those with higher perceived self-efficacy, family/friend encouragement, and a provider recommendation had higher odds of being at a more advanced stage of adoption for FOBT. Patients with a history of cancer and higher perceived barriers had higher odds of being at an earlier stage of adoption for FOBT. Predictors of more advanced stage of adoption for colonoscopy included higher perceived benefits, higher perceived self-efficacy, family/friend encouragement, and a provider recommendation for colonoscopy. Higher income (>30 000 vs <15 000) was predictive of earlier stage of adoption for colonoscopy. CONCLUSIONS: Enhancing self efficacy, encouragement from family and friends, and provider recommendations are important components of interventions to promote CRC screening. IMPLICATIONS FOR PRACTICE: Nurses can use knowledge of the characteristics associated with stage of adoption to educate and motivate their African American primary care patients to complete CRC screening tests. PMID- 24145252 TI - Keeping hope possible: a grounded theory study of the hope experience of parental caregivers who have children in treatment for cancer. AB - BACKGROUND: Hope has been found to support parents as they care for their child with a life-limiting or life-threatening illness. However, very little research focuses on the nursing care of parents of pediatric oncology patients, and therefore, nurses may have difficulty in understanding and supporting parental well-being. OBJECTIVE: The purpose of this qualitative study was to gain an understanding of the experience of hope for parents who care for their child in treatment for cancer. METHODS: Using purposive theoretical sampling, 16 parents participated in this study. Thirty-three open-ended, face-to-face interviews were conducted, and 14 parent journals were collected. Analysis of the data was conducted using Charmaz's constructivist grounded theory approach. RESULTS: A developing, substantive grounded theory was constructed. Parental hope was described as an essential, powerful, deliberate, life-sustaining, dynamic, cyclical process that was anchored in time; was calming and strengthening; and provided inner guidance through the challenging experience of preparing for the worst and hoping for the best. Parents' main concern was "fearing the loss of hope," which was ameliorated by the basic social process of "keeping hope possible" through accepting reality, establishing control, restructuring hope, and purposive positive thinking. CONCLUSIONS: Parents journeyed through numerous transitions related to the treatment of cancer that caused feelings of uncertainty, anxiety, stress, and loss of control. Hope was identified as vital to parents. IMPLICATIONS FOR PRACTICE: To minimize these adverse experiences, nurses can support parents' ability to keep hope possible and thus to optimize their well-being by understanding, assessing, and supporting parental hope. PMID- 24145253 TI - DQS advisor: a visual interface and knowledge-based system to balance dose, quality, and reconstruction speed in iterative CT reconstruction with application to NLM-regularization. AB - Motivated by growing concerns with regards to the x-ray dose delivered to the patient, low-dose computed tomography (CT) has gained substantial interest in recent years. However, achieving high-quality CT reconstructions from the limited projection data collected at reduced x-ray radiation is challenging, and iterative algorithms have been shown to perform much better than conventional analytical schemes in these cases. A problem with iterative methods in general is that they require users to set many parameters, and if set incorrectly high reconstruction time and/or low image quality are likely consequences. Since the interactions among parameters can be complex and thus effective settings can be difficult to identify for a given scanning scenario, these choices are often left to a highly-experienced human expert. To help alleviate this problem, we devise a computer-based assistant for this purpose, called dose, quality and speed (DQS) advisor. It allows users to balance the three most important CT metrics--DQS--by ways of an intuitive visual interface. Using a known gold-standard, the system uses the ant-colony optimization algorithm to generate the most effective parameter settings for a comprehensive set of DQS configurations. A visual interface then presents the numerical outcome of this optimization, while a matrix display allows users to compare the corresponding images. The interface allows users to intuitively trade-off GPU-enabled reconstruction speed with quality and dose, while the system picks the associated parameter settings automatically. Further, once the knowledge has been generated, it can be used to correctly set the parameters for any new CT scan taken at similar scenarios. PMID- 24145254 TI - The association between risk factors and hypertension in perak, malaysia. AB - INTRODUCTION: Hypertension is a major public health problem in Malaysia. A survey was initiated to examine the association of modifiable and non-modifiable risk factors for hypertension in Perak, Malaysia. METHODS: A total of 2025 respondents aged 30 years and above were recruited using a multi-stage sampling method. Hypertension was defined as self-reported hypertension and/or average of two blood pressure readings at single occasion with SBP >= 140mmHg or DBP >= 90 mmHg. Body mass index (BMI) was defined using the Asian criteria and International Physical Activity Questionnaire (IPAQ) was used to evaluate physical activity. Body weight, height and blood pressure were obtained using standard procedures. Univariate analyses were conducted to examine the associations between risk factors and hypertension. Multiple logistic regression was used to examine each significant risk factor on hypertension after adjusted for confounders. RESULTS: In total, 1076 (54.9%) respondents were found to be hypertensive. Significant associations (p <0.001) with hypertension were noted for increasing age, low physical activity, obese BMI, no education background and positive family history of hypertension. After adjusting for age, sex, ethnicity, education background, family history, BMI, physical activity, smoking and diet, respondents who were obese and had positive family history had higher odds for hypertension (OR:2.34; 95% CI:1.84-3.17 and 1.96 (1.59-2.42) respectively. A significant increase (p <0.001) in risk for hypertension was noted for age. Those with moderate physical activities were 1.40 (1.04-1.78) times more of having hypertension than those active. Poor diet score and smoking were not significantly associated with increased risk for hypertension. CONCLUSION: In conclusion, modifiable risk factors such as BMI and physical activity are important risk factors to target in reducing the risk for hypertension. PMID- 24145255 TI - Indications for invasive prenatal diagnostic procedures at a dedicated fetal medicine centre: an 8 year audit 2003-2010. AB - OBJECTIVE: Analyze indications and type of prenatal diagnostic procedures performed. METHOD: This retrospective audit was conducted at a dedicated fetal medicine center in Petaling Jaya. All invasive prenatal diagnosis procedures performed from 2003 up until 2010 (amniocentesis, chorionic villous sampling and fetal blood sampling) were analyzed. RESULT: A total of 1560 invasive prenatal diagnostic procedures were performed during the 8 year period. Advanced maternal age is the leading indication for invasive prenatal diagnostic procedures followed by fetal abnormalities. The fetal loss rate was 0.2% for amniocentesis and 1.2% for CVS. CONCLUSION: Advanced maternal age is the leading indication for invasive prenatal diagnostic procedures at this centre but is on a declining trend. The fetal loss rates are comparable to auditable standards set by professional bodies, in this case, the Royal College of Obstetricians & Gynecologists of London. PMID- 24145256 TI - Prevalence of erectile dysfunction in men with ischemic heart disease in a tertiary hospital in malaysia. AB - We report a study which defined the prevalence of erectile dysfunction (ED) among men with ischaemic heart disease. We recruited 510 men with established ischemic heart disease and interviewed these men using the International Index of Erectile Dysfunction (IIEF-5) questionnaire to determine the presence and severity of ED. Presence of ED was defined as IIEF-5 score of less than 22. The mean age was 60.5 years (range 36-92 years; SD: +9.58). 461 (90.4%) men reported some degree of ED of which two third of them had moderate to severe ED. The prevalence of ED increased significantly with age. Age above 60 years was the only significant risk factor. Non-statistically significant but important risk factors included diabetes, hypertension, diuretics and oral hypoglycemic agents. ED is very common among men with ischemic heart disease. The prevalence and severity increased significantly with age above 60 years old. PMID- 24145258 TI - Knowledge of diabetes and lifestyle behaviour amongst indigenous population in Peninsular Malaysia. PMID- 24145257 TI - "Wide Skeletonization" Tubularised Incised Plate (TIP) Repair of Distal Penile Hypospadias with Narrow Urethral Plate. AB - The importance of an adequate caliber neo-meatus for success of any hypospadias repair cannot be overstated. TIP repair incorporates a midline relaxing incision thus enabling tubularization but ultimately may not result in adequate neourethral caliber to avoid fistulas or meatal stenosis when the plate was narrow or flat, respectively. Objectives of this study is to evaluate results of a modification of TIP - "wide skeletonization" tubularized incised plate (TIP) - for repair of distal penile hypospadias with narrow urethral plate (UP), with regard to meatal stenosis and urethrocutaneous fistula. MATERIALS & METHODS: Total of 108 hypospadias patients were operated upon. 26 were found to have distal penile ypospadias with narrow UP (Narrow UP defined as any plate less than 6 mm width). 22 were selected for the study; All underwent "wide skeletonization" of the UP distally ("Wide Skeletonization" implies meatal based ventral "V" shaped incisions on outer margins of UP so as to incorporate generous portions of adjoining skin thereby allowing recruitment of penile and glandular skin lateral to the urethral plate to facilitate tubularization). Urethroplasty was fashioned over 10mm circumference of native UP with adjoining skin over a urethral stent. Repair was started with meatus first (calibrated over size 10-12F bougie). Meatal stitch was followed proximally with subepithelial tubularization of the neourethra; second layer comprising of spongiosal tissue. Barrier flaps were interposed between the neourethra and overlying glans and shaft skin closure, using inner prepucial mucosal flap. RESULTS: Two patients had urethrocutaneous fistulae; one child had superficial dehiscence of glans. All three children were managed conservatively with no child requiring further surgery. All children had a good sized meatus and good stream of urine without any splaying. CONCLUSIONS: "Wide Skeletonization" of the urethral plate distally (in a "V" fashion rather than "U") gives an adequate caliber aesthetic neo-meatus especially in hypospadias children with narrow UP. It further helps in decreasing incidence of neourethral and/or meatal stenosis without increasing urethroplasty complication leading to an excellent functional outcome. Whether this leads to better long term functionality of neourethra remains to be seen. PMID- 24145259 TI - The quality of life in hearing impaired adolescents after hearing aid application. AB - Hearing impairment in adolescents is a major public health problem. According to the World Health Organization (WHO) deafness and hearing impairment are common health problems throughout the world. Hearing impairment generally impairs emotional, social, communication and educational function. The aim of this study was to determine the correlation between duration of hearing aid use and improvements in the quality of life. The cross sectional study was conducted at Jalan Peel Primary Special School and Universiti Kebangsaan Malaysia Medical Center (UKMMC) from July 2010 until June 2011. A total of 21 students with hearing impairment involved in this study with mean age of 12.57 (10 to 19 years old). The subjects were divided into 2 groups: first-time hearing aid users and long standing hearing aid users. The hearing assessment was conducted in the first group and hearing aids were fitted. After 1 month hearing aid fitting, the questionnaires were distributed to both groups. Statistical analysis had showed no relation (p>0.05) between duration of hearing aid use and the improvement in the quality of life. However, regardless of the duration of hearing aid usage, there was improvement in the quality of life as shown by the scores of the questionnaires. In conclusion there was no significant relation between duration of hearing aid use and the improvement in the quality of life. Hearing aids were beneficial for hearing loss students regardless of the duration of the hearing aid usage. PMID- 24145260 TI - Knowledge of Good Blood Culture Sampling Practice among Healthcare Staffs in An Emergency Department - Are We Getting It Right? AB - BACKGROUND: Although a vital test, blood culture is often plagued with the problem of contamination and false results, especially in a chaotic emergency department setting. The objectives of this pilot study is to find out the level of understanding among healthcare staffs in emergency department, Hospital Universiti Sains Malaysia (HUSM) regarding good blood culture sampling practice. METHODS: All healthcare staffs in emergency department, HUSM who consented to this study were given a set of selfadministered anonymous questionnaire to fill. RESULTS: More than half (53.1%) of the 64 participants are emergency medicine residents. Majority of them (75%) have been working in the emergency medicine, HUSM for more than 2 years. More than half of them were able to answer correctly the amount of blood volume needed for culture in adult and pediatric patients. When asked what are the factors required to improve the true yield as well as to reduce the risk of culture contamination, the four commonest answers given were observing proper aseptic technique during blood sampling, donning sterile glove, proper hand scrubbing as well as ensuring the sterility of the equipments. DISCUSSION AND CONCLUSION: This study suggests that there is a lack of proper knowledge of good blood culture sampling practice among our healthcare staffs in emergency department. PMID- 24145261 TI - Trends of platelet inhibition in different clopidogrel pretreatment patterns in malaysian patients undergoing elective percutaneous coronary intervention. PMID- 24145262 TI - Prevalence, awareness, treatment and control of Hypertension among the elderly: the 2006 National Health and Morbidity Survey III in Malaysia. AB - INTRODUCTION: The objective of this study was to determine the prevalence and factors associated with the awareness, treatment and control of hypertension among the elderly population in Malaysia. METHODS: Analysis of secondary data from a cross-sectional national population based survey using stratified multistage sampling conducted from April to August 2006 throughout Malaysia National Health and Morbidity Survey III(NHMS III). Adults aged 60 and older who had participated in the survey were included in the study. RESULTS: A total of 4954 respondents (14.3%) were elderly from the 34,539 respondents aged 18 years and above for hypertension module in NHMS III. A total of 4933 elderly had their blood pressure examined (giving a response rate of 99.6%). The overall prevalence of hypertension among elderly was 74.0%, more in elderly female (77.4%) than men (70.1%). Only 49.3% of them were aware of their hypertensive status, 42.4% were currently treated and 22.6% of those being treated were under control. The results of multiple logistic regression showed factors associated with higher awareness and treatment rates were similar i.e. females, young-old age group (age 60-74), urban residents, Chinese ethnic group and higher education. For those elderly who were on treatment, determinants associated with controlled hypertension were Chinese and Indians ethnic groups and higher educational level. CONCLUSIONS: There was a high prevalence of hypertension among the elderly in Malaysia but with poor awareness, treatment and control rate. Reliable information on these aspects is important for the development of patient education programs, health policies to improve disease management and overall health care resource allocation especially among the elderly in Malaysia. PMID- 24145263 TI - Optic disc topography of normal tension glaucoma patients in Malaysia. AB - There are limited data in the literature on the optic disc topography in normal tension glaucoma (NTG) patients in Asian countries, especially in Southeast Asia. This study is aimed at comparing optic disc topography in NTG patients and a control group in Malaysia, and we discuss the literature on NTG studies in other Asian populations. A comparative cross-sectional study was conducted in two hospitals with glaucoma services in Malaysia from November 2010 to February 2012. A total of 109 eyes of 109 Malay patients were included in this study: 32 NTG patients and 77 subjects in the control group. All participants underwent a thorough ocular examination, including visual acuity, subjective refraction, anterior segment and fundus examinations, Humphrey visual field 24-2, intraocular pressure measurement, gonioscopy examination and fundus photography. Optic disc topography was assessed using the Heidelberg Retinal Tomograph III by an identified masked investigator in each hospital. NTG patients had a notably larger disc area (2.65 (0.41) vs 2.19 (0.43) mm(2), respectively), larger cupping (1.54 (0.43) vs 0.63 (0.40) mm(2), respectively), smaller retinal rim areas (1.12 (0.41) vs 1.56 (0.33) mm(2), respectively), higher cup volume (0.47 (0.28) vs 0.11 (0.19) mm(3), respectively), reduced rim volume (0.23 (0.13) vs 0.41 (0.16) mm(3), respectively), higher cup to disc area ratio (0.58 (0.14) vs 0.27 (0.15), respectively), higher linear cup to disc ratio (0.76 (0.09) vs 0.49 (0.17) mm(2), respectively), higher mean cup depth (0.37 (0.09) vs 0.22 (0.09) mm, respectively), higher maximum cup depth (0.77 (0.16) vs 0.59 (0.20) mm, respectively), higher mean of cup shape measure (-0.04 (0.06) vs -0.16 (0.07), respectively), and thinner mean retinal nerve fibre layer thickness (0.15 (0.15) vs 0.24 (0.07) mm, respectively) compared to the control group (p<0.05). In conclusion, most of the optic disc parameters were significantly different in NTG patients compared to healthy individuals in Malaysia. Our findings are comparable to those reported in NTG studies in other Asian countries. PMID- 24145264 TI - Species distribution and antifungal susceptibility patterns of Candida species: Is low susceptibility to itraconazole a trend in Malaysia? AB - Resistance to antifungal agents has increased in Candida spp., especially in non albicans species. Recent findings reported a strikingly low susceptibility in Candida spp. towards itraconazole in Malaysia. In this study, a colorimetric broth dilution method was utilized to determine the susceptibility of Candida spp. isolated in Kuala Lumpur Hospital within a six month period. A total of 82 isolates from blood, peritoneal and other fluids were tested against 8 antifungal agents using the Sensititre Yeast One method. These comprised of 32 (39%) C. albicans, 17 (20.7%) C. glabrata, 15 (18.3%) C. tropicalis, 13 (15.9%) C. parapsilosis, two (2.4%) C. sake and 1 (1.2%) each of C. pelliculosa, C. rugosa and Pichia etchellsii/carsonii. Overall, susceptibility of all isolates to caspofungin was 98.8%, amphotericin B, 97.6%; 5-flucytosine, 97.6%; voriconazole, 97.6%; posaconazole, 87.8%; fluconazole, 82.9%; ketoconazole, 79.3%; and itraconazole, 56.1%. A total of 18 Candida spp. isolates (22 %) were resistant to at least one antifungal agent tested, and half of these were resistant to three or more antifungal agents. C. glabrata was the most frequently identified resistant species (10 isolates), followed by C. tropicalis (4 isolates), C. parapsilosis (3 isolates) and C. albicans (1 isolate). Resistance was highest against ketoconazole (20.9%), followed by itraconazole (13.4%). However, 30.5% of isolates were susceptible-dose dependent towards itraconazole. Long-term usage of itraconazole in Malaysia and a predominance of nonalbicans species may account for the results observed in this study. In conclusion, susceptibility to antifungal drugs is species-dependent among Candida spp.; reduced susceptibility to itraconazole is concomitant with the high number of non-albicans Candida species isolated in Malaysia. PMID- 24145265 TI - Outcomes Following Surgery for Distal Rectal Cancers: A Comparison between Laparoscopic and Open Abdomino-Perineal Resection. AB - PURPOSE: Oncologic outcomes following laparoscopic abdomino-perineal resection (APR) for distal rectal cancer are infrequently reported. This study aims to compare the long term outcomes between laparoscopic and open APR in distal rectal cancers. METHODS: A retrospective review of all patients who underwent APR for distal rectal cancer from May 2001 to November 2009 was performed. RESULTS: Forty two patients, median age 60 (24 - 86) years, formed the study group. Laparoscopic resection was attempted in 16 patients and was successful in all but one. Patients with recurrent diseases, previous abdominal operations and neoadjuvant chemoradiation were more likely to undergo open APR. There were no differences in the T-staging, number of lymph nodes harvested or the final stage of the disease between the two groups. The laparoscopic APR group had a shorter median length of hospitalization (7 vs. 10 days, p < 0.05), but longer operative duration (300 vs. 240 minutes, p > 0.05). Excluding the 9 (21.4%) patients with metastatic disease on presentation, 13 (39.4%) developed recurrence after a median follow up of 24 (4 - 107) months. Twenty (47.6%) patients died from their advanced disease subsequently while one (2.4%) died from a noncancer related cause. Analysis showed that tumour stage and circumferential resection margin positivity were associated with a poorer survival. The types of approach had no significant impact on the survival. CONCLUSION: Laparoscopic APR for distal rectal cancer yields similar oncologic outcomes as open APR. Long-term outcome is determined by the tumour stage and circumferential resection margin and not the approach. PMID- 24145266 TI - Salvage of elbow function in chronic complex elbow fracture dislocation with total elbow arthroplasty: a case report. AB - In patients with an elbow fracture dislocation the incidence of radial head fracture is 36%, where as coronoid process fractures occur in 13%, and olecranon fractures in 4% of patients. Combination of all these fractures with a 'terrible triad' is rarely reported in the literature. We describe a 40 year old lady involved in a polytrauma who had head injury, pnuemothorax and an open fracture dislocation of the left elbow. The Injury Severity Score initially on admission was 44. She presented with chronic elbow instability with pain 1 year later. A semi constrained total elbow arthroplasty (TEA) with a Coonrad-Morrey prosthesis was performed in this complex injury involving fractures of the coronoid, olecranon, proximal third of the ulna and radial head malunion with heterotrophic ossification around the elbow joint. Although the survivorship of total elbow replacements has improved, it is still a procedure reserved to older patients with low functional demand. At 1-year follow-up, the patient had full range in flexion and extension. The Mayo Elbow Performance Score (MEPS) was 100. TEA is a procedure which gains function and stability in a terrible triad elbow. PMID- 24145267 TI - Recurrent glomangiomas of the ankle: a case report. PMID- 24145268 TI - Pruritus during Pregnancy. PMID- 24145269 TI - Persistent left superior vena cava diagnosed during haemodialysis catheter placement - a case report. PMID- 24145270 TI - Case of lung perforation secondary to nasogastric tube insertion. PMID- 24145271 TI - A Case of PHACES Syndrome with Successful Treatment of Facial Haemangioma With Propranolol. PMID- 24145272 TI - Minimally invasive thoracoscopic mesh repair of diaphragmatic fenestrations for catamenial pneumothorax due to likely thoracic endometriosis: a case report. PMID- 24145273 TI - Chronic discharging ear in a child: are we missing something? AB - Chronic discharging ear, mostly due to middle or external ear infection, is one of the leading causes for seeking healthcare among the paediatric population in a developing country. However, a long-standing forgotten middle ear foreign body forms a rare cause for such presentation demanding a high index of suspicion from the clinicians. Most of them are iatrogenic or accidental, and are removed by conventional permeatal approach; need for tympanotomy is rarely documented in the recent literature. We report the first case where a large stone was introduced into the middle ear through a pre-existing tympanic membrane perforation by the child himself, and only the second documentation of removal of a middle ear foreign body by tympanotomy in a child. PMID- 24145274 TI - Pancytopenia in a Patient with Grave's Disease. AB - Pancytopenia can rarely complicate Grave's disease. It can be due to uncontrolled thyrotoxicosis or as a result of rare side effect of antithyroid medication. Pernicious anemia leading to Vitamin B12 deficiency is another rare associated cause. We report a case of a patient with Grave's disease and undiagnosed pernicious anemia whom was assumed to have antithyroid drug induced pancytopenia. Failure to recognize this rare association of pernicious anemia as a cause of pancytopenia had resulted in delay in treatment and neurological complication in our patient. PMID- 24145275 TI - Perinatal management of cardiac tumors: a case series. AB - Primary cardiac tumours in the foetuses and neonates are uncommon. Foetuses with cardiac tumour have risk for heart failure and hydrops fetalis. Therefore, an early decision for delivery should be made in the evidence of foetal compromise. Early neonatal care varies on tumour size, type, location and obstructive features. Antenatal detection of foetal cardiac tumours ensures better prenatal and postnatal management. We describe our 5- year experience in managing 5 cases of primary cardiac tumours from 1st January 2006 to 31st December 2010. PMID- 24145276 TI - A case report on the use of an acetylcholinesterase inhibitor (donepezil) in traumatic brain injury. AB - Traumatic Brain injury (TBI) is one of the most common causes of death and disability worldwide, with recent interest in the use of cholinomimetics in the treatment of TBI patients for cognitive impairments. Our patient who suffered TBI was started on a trial of an acetylcholinesterase inhibitor (Donepezil) for five weeks. Cognitive and memory testing with the Mini-Mental State Examination (MMSE) and Functional Independence Measurement (FIM) showed some degree of improvement: The three item recall component of MMSE improved and the FIM Memory score increased from 1 (Complete dependence) to 6 (Functional independence). Subjective assessment of his behaviour in the ward also showed improvement. This suggests that donepezil may help improve memory and behaviour of moderately severe traumatic brain injury patients, although more research in this direction should be undertaken. PMID- 24145277 TI - Screening for peripheral arterial disease in prospective coronary bypass surgical patients. PMID- 24145279 TI - Liver: plant sterols have a role in liver injury associated with parenteral nutrition. PMID- 24145278 TI - Adhesion and fusion efficiencies of human immunodeficiency virus type 1 (HIV-1) surface proteins. AB - In about half of patients infected with HIV-1 subtype B, viral populations shift from utilizing the transmembrane protein CCR5 to CXCR4, as well as or instead of CCR5, during late stage progression of the disease. How the relative adhesion efficiency and fusion competency of the viral Env proteins relate to infection during this transition is not well understood. Using a virus-cell fusion assay and live-cell single-molecule force spectroscopy, we compare the entry competency of viral clones to tensile strengths of the individual Env-receptor bonds of Env proteins obtained from a HIV-1 infected patient prior to and during coreceptor switching. The results suggest that the genetic determinants of viral entry were predominantly enriched in the C3, HR1 and CD regions rather than V3. Env proteins can better mediate entry into cells after coreceptor switch; this effective entry capacity does not correlate with the bond strengths between viral Env and cellular receptors. PMID- 24145280 TI - Therapy: oesophageal cancer surgery. PMID- 24145281 TI - Rectal cancer: is 'watch and wait' a safe option for rectal cancer? PMID- 24145283 TI - MRP1 overexpression determines poor prognosis in prospectively treated patients with localized high-risk soft tissue sarcoma of limbs and trunk wall: an ISG/GEIS study. AB - Patients with localized high-risk soft tissue sarcomas (STS) of the limbs and trunk wall still have a considerable metastatic recurrence rate of more than 50%, in spite of adjuvant chemotherapy. This drug-ceiling effect of chemotherapy in sarcoma setting could be explained, at least partially, by multidrug resistance (MDR) mechanisms. The aim of this study was to ascertain whether mRNA and protein expression of ABCB1 (P-glycoprotein), ABCC1 (MRP1), and GSTA1 (glutathione S transferase pi) was prognostic in localized high-risk STS. Immunohistochemistry and reverse transcriptase-PCR studies were performed from biopsies at the time of diagnosis. Patients of this series were prospectively enrolled into a phase III trial that compared three versus five cycles of epirubicin plus ifosfamide. The series of 102 patients found 41 events of recurrence and 37 of death with a median follow-up of 68 months. In univariate analysis, variables with a statistically significant relationship with relapse-free survival (RFS) were: MRP1 expression (5-year RFS rate of 23% in positive cases and 63% in negative cases, P = 0.029), histology (5-year RFS rate of 74% in undifferentiated pleomorphic sarcoma and 43% in synovial sarcoma, P = 0.028), and ABCC1 expression (5-year RFS rate of 33% in overexpression and 65% in downregulation, P = 0.012). Combined ABCC1/MRP1 was the only independent prognostic factor for both RFS (HR = 2.704, P = 0.005) and overall survival (HR = 2.208, P = 0.029). ABCC1/MRP1 expression shows robust prognostic relevance in patients with localized high-risk STS treated with anthracycline-based chemotherapy, which is the standard front line treatment in STS. This finding deserves attention as it points to a new targetable protein in STS. PMID- 24145282 TI - Antitumor effects of immunotoxins are enhanced by lowering HCK or treatment with SRC kinase inhibitors. AB - Recombinant immunotoxins (RIT) are agents being developed for cancer treatment. They are composed of an Fv that binds to a cancer cell, fused to a 38-kDa fragment of Pseudomonas exotoxin A. SS1P is a RIT that targets mesothelin, a protein expressed on mesothelioma as well as pancreatic, ovarian, lung, and other cancers. Because the protein tyrosine kinase family regulates a variety of cellular processes and pathways, we hypothesized that tyrosine kinases might regulate susceptibility to immunotoxin killing. To investigate their role, we used siRNAs to lower the level of expression of the 88 known tyrosine kinases. We identified five tyrosine kinases, INSR, HCK, SRC, PDGFRbeta, and BMX that enhance the activity of SS1P when their level of expression is lowered by siRNAs. We further investigated the Src family member HCK in this study. Knocking down of SRC slightly increased SS1P killing in A431/H9 cells, but knocking down HCK substantially enhanced killing by SS1P. We investigated the mechanism of enhancement and found that HCK knockdown enhanced SS1P cleavage by furin and lowered levels of Mcl-1 and raised Bax. We then found that Src inhibitors mimic the stimulatory effect of HCK knockdown; both SU6656 and SKI-606 (bosutinib) enhanced immunotoxin killing of mesothelin-expressing cells by SS1P and CD22 expressing cells by HA22 (moxetumomab pasudotox). SU6656 also enhanced the antitumor effects of SS1P and HA22 in mouse xenograft tumor models. Our data suggest that the combination of immunotoxin with tyrosine kinase inhibitors may be an effective way to treat some cancers. PMID- 24145284 TI - Construction and expression of an antimicrobial peptide scolopin 1 from the centipede venoms of Scolopendra subspinipes mutilans in Escherichia coli using SUMO fusion partner. AB - Antimicrobial peptide scolopin 1 (AMP-scolopin 1) is a small cationic peptide identified from centipede venoms of Scolopendra subspinipes mutilans. It has broad-spectrum activities against bacteria, fungi, and tumor cells, which may possibly be used as an antimicrobial agent. We first report here the application of small ubiquitin-related modifier (SUMO) fusion technology to the expression and purification of cationic antimicrobial peptide AMP-scolopin 1. The fusion protein expressed in a soluble form was purified to a purity of 95% by Ni-IDA chromatography. After the SUMO-scolopin 1 fusion protein was cleaved by the SUMO protease at 30 degrees C for 1 h, the cleaved sample was reapplied to a Ni-IDA. The recombinant scolopin1 had similar antimicrobial properties to the synthetic scolopin 1. Thus, we successfully established a system for purifying peptide of centipede, which could be used for further research. PMID- 24145285 TI - 1H-NMR measurements of proton mobility in nano-crystalline YSZ. AB - We report nuclear magnetic resonance (NMR) results on water saturated, dense, nano-crystalline YSZ samples (9.5 mol% yttria doped zirconia) which exhibit proton conductivity at temperatures as low as room temperature. (1)H-NMR spectra recorded under static and magic angle spinning conditions show two distinct signals. Their temperature-dependent behavior and their linewidths suggest that one can be attributed to (free) water adsorbed on the surface of the sample and the other one to mobile protons within the sample. This interpretation is supported by comparison with measurements on a single-crystalline sample. For the nano-crystalline samples motional narrowing is observed for the signal originating from protons in the sample interior. For these protons, the analysis of temperature and field dependent spin-lattice relaxation time T1 points towards diffusion in a confined two-dimensional geometry. We attribute this quasi two dimensional motion to protons that are mobile along internal interfaces or nanopores of nano-crystalline YSZ. PMID- 24145286 TI - Cytokine-induced 'bystander' senescence in DDR and immuno-surveillance. PMID- 24145287 TI - Optic Nerve Head and Retinal Nerve Fiber Layer Differences Between Caribbean Black and African American Patients as Measured by Spectral Domain OCT. AB - PURPOSE: There are well-established differences in optic nerve morphology between patients of African and European descent. Spectral domain optical coherence tomography (OCT) scanning has demonstrated these differences with respect to optic disc area (DA), average cup-disc ratio, cup volume, and nerve fiber layer thickness. However, the term "African descent" describes a heterogenous group with considerable variability. This study evaluates differences in optic nerve and retinal nerve fiber layer (RNFL) parameters as measured by Cirrus HD-OCT between Caribbean black and African American patients. DESIGN AND METHODS: A total of 25 African American subjects and 25 Caribbean black subjects with normal ocular examinations were consecutively recruited to this study. All patients received imaging of the optic nerve and nerve fiber layer with Cirrus HD-OCT. Optic nerve and RNFL parameters were evaluated for statistically significant differences using a t test. A mixed effect model for correlated data was then created to adjust outcome variables for (1) repeated measures and (2) optic nerve size. Two one-sided t tests were then utilized to determine equivalence. RESULTS: After adjustment for DA, RNFL thickness, cup volume, DA, inferior nerve fiber layer, and vertical cup-disc ratio demonstrated statistically significant equivalence between the 2 groups (P value <0.05). The superior nerve fiber layer quadrant was significantly different between the 2 groups and may merit further investigation. CONCLUSIONS: Findings of this study suggest that optic nerve and RNFL morphology is markedly similar between Caribbean blacks and African Americans once adjusted for optic nerve size but cannot be considered equivalent in all measures, particularly in the superior nerve fiber layer. PMID- 24145288 TI - Comparison of Intraocular Pressure Measurements Between Goldmann Applanation Tonometry and Reichert 7 Noncontact Tonometry. AB - PURPOSE: The aim of this study was to compare the Reichert 7 (R7) noncontact tonometry with Goldmann applanation tonometry (GAT) and to determine the influence of central corneal thickness (CCT) in these measurements in the healthy population. DESIGN: A prospective cross-sectional study. METHODS: Intraocular pressure (IOP) of the right eyes of 120 patients was measured with GAT and R7. All patients were free of glaucoma. All the measurements were carried out between 7 AM and 9 AM The measurements with the R7 were taken in the automatic mode. After 15 minutes, IOP with GAT was measured followed by pachymetry. The R7 provided a Goldmann-correlated IOP (IOPg) and a corneal-compensated IOP (IOPcc). RESULTS: The mean age of the patients was 53.9+/-19.3 (range, 26 to 85 y). The male/female ratio was 0.9/1. When R7 measurements were compared with GAT measurements, R7 measurements (both IOPcc and IOPg) were significantly higher than GAT measurements (P<=0.001). Besides that, IOPcc was significantly higher than IOPg (P<=0.001). There was a significant positive linear relationship between IOPcc and GAT (r=0.761, P<=0.001), and similar relationship between IOPg and GAT (r(2)=0.739, P<=0.001). The mean CCT was 545.9+/-33.2 MUm (range, 476 to 634 MUm). A weak correlation was observed between CCT and GAT (r=0.196, P=0.032). There was a significant correlation between CCT and IOPg (r=0.283, P=0.02). The correlation between CCT and IOPcc was not statistically significant (r=0.123, P=0.179). CONCLUSIONS: IOP values of R7 are higher than GAT values. However, IOPg was observed more coherent to the GAT values than IOPcc. IOPcc should be an evaluation factor along with GAT or IOPg in glaucoma examination. PMID- 24145289 TI - Intradevice and Interdevice Agreement Between a Rebound Tonometer, Icare PRO, and the Tonopen XL and Kowa Hand-held Applanation Tonometer When Used in the Sitting and Supine Position. AB - PURPOSE: The aim of the study was to investigate the agreement between a new portable tonometer, Icare PRO, and the Tonopen XL and Kowa hand-held applanation tonometers (HAT). METHODS: The right eyes of 127 healthy subjects were enrolled. Intraocular pressure (IOP) was measured in both sitting and supine positions using the Icare PRO, Tonopen XL, and Kowa HAT tonometers. The repeatability of the IOP measurements was evaluated by calculating intraclass correlation coefficients. Between-method agreements of tonometer measurements were evaluated using Bland-Altman analysis. RESULTS: Intradevice agreement: The intraclass correlation coefficients (sitting, supine) of Icare PRO, Tonopen XL, and Kowa HAT were (0.863, 0.656), (0.845, 0.819), and (0.957, 0.956), respectively.Interdevice agreement: The Bland-Altman analysis revealed that, in the sitting position, the mean differences between Icare PRO and Tonopen XL, and between Icare PRO and Kowa HAT were -0.43 and 0.43 mm Hg, respectively (95% limits of agreement: -6.24 to 5.34 mm Hg, -4.04 to 4.90 mm Hg). In the supine position, the corresponding mean differences were -0.88 and 0.14 mm Hg (95% limits of agreement: -5.66 to 3.91 mm Hg, -4.06 to 4.33 mm Hg). IOP differences between Icare PRO and the other tonometers were unaffected by central corneal thickness. CONCLUSIONS: The repeatability of Icare PRO was slightly lower in the supine position than in the sitting position. Although Icare PRO underestimated IOP values in eyes with higher IOP when compared with Tonopen XL and Kowa HAT in both positions, we observed good interdevice agreement between Icare PRO and both Tonopen XL and Kowa HAT. PMID- 24145290 TI - Retinal nerve fiber layer analysis of cupping in children born prematurely. AB - PURPOSE: The aim of this study was to quantitatively study the retinal nerve fiber layer (RNFL) thickness in children born prematurely with isolated optic nerve cupping. PATIENTS AND METHODS: Six otherwise healthy premature children with clinical evidence of increased cup to disc ratios were enrolled in this observational case series. RNFL thickness was measured using Cirrus optical coherence tomography (OCT) optic disc cube 200*200 protocol and compared with age matched normal controls using T test for statistical significance, with Bonferroni correction when appropriate. RESULTS: Nerve fiber layer measurements showed a statistically significant decrease in overall RNFL. Superior quadrant RNFL thinning was statistically significant and inferior, nasal, and temporal nerve fiber layer thickness was decreased, although results were not statistically significant. CONCLUSIONS: Nerve fiber layer thinning in children born prematurely showing enlarged cup to disc ratios appears more consistent with optic nerve hypoplasia than glaucoma, as reflected by the markedly decreased average nerve fiber layer thickness with no other hallmarks of congenital glaucoma. PMID- 24145291 TI - Risk factors for adverse consequences of low intraocular pressure after trabeculectomy. AB - PURPOSE: To determine the risk factors for low intraocular pressure (IOP) and its detrimental consequences after trabeculectomy. PATIENTS AND METHODS: We performed a retrospective chart review of consecutive patients aged 12 years and above undergoing trabeculectomy alone by 1 of 2 surgeons between May 2000 and October 2008 at the Wilmer Institute. RESULTS: Among 753 eyes of 596 patients, 112 eyes (14.9%) of 103 patients had an IOP of <=5 mm Hg at >=3 months postoperatively (late low IOP). Physical signs related to low IOP occurred in 61 eyes of 58 patients, and 40 eyes of 37 patients had revision surgery for low IOP. Physical signs of low IOP included 34 eyes with choroidal detachment or shallow anterior chamber, 10 with hypotony maculopathy, and 7 with both. Compared with 187 control eyes of 165 patients, risk factors for late low IOP included: surgeon 2 (P=0.0003), left eyes (P=0.03), and secondary glaucoma (P=0.05). Physical signs of low IOP were more common in phakic eyes (P=0.03), whereas need for revision surgery was associated with younger age (P=0.01). The presence of hypotony maculopathy significantly decreased the risk of choroidal detachment/shallow anterior chamber (P=0.003). Hypotony maculopathy was associated with younger age (P=0.02). CONCLUSIONS: Late low IOP was more common with techniques used by 1 of 2 surgeons and in eyes with secondary glaucoma. Clinical signs of low IOP were more common in phakic eyes. Younger age was a risk factor for hypotony maculopathy. Hypotony maculopathy and choroidal detachment tend to occur in different eyes. PMID- 24145292 TI - Corneal patch graft for the repair of late-onset hypotony or filtering bleb leak after trabeculectomy: a new surgical technique. AB - PURPOSE: Repair of leaking filtering blebs after trabeculectomy is a surgical challenge, especially when the patient presents with hypotony. Repair of the filtering bleb using only conjunctiva reconstruction often fails when deeper tissue structures do not provide sufficient outflow resistance. Here, we present a technique that uses anterior stromal lamellae left over from donor corneas used for descemet stripping automated endothelial keratoplasty procedures as patch grafts to repair the scleral tissue wound as a way to treat ocular hypotony. MATERIALS AND METHODS: We describe a new surgical technique to reconstruct the outflow resistance of melted trabeculectomy scleral flaps and present the course of 5 cases of severe hypotony treated using this technique. RESULTS: All 5 patients suffered from severe hypotony several years after trabeculectomy with antiproliferative agents. Multiple surgical and nonsurgical attempts to treat hypotony had failed. Lamellar corneal tissue was used as a patch graft to replace the weakened sclera near the site of the earlier trabeculectomy. This procedure successfully reversed hypotony in all cases. During the follow-up periods of at least 9 months, no recurrences of bleb leak or hypotony were observed. Intraocular pressure (IOP) remained controlled with topical IOP-lowering treatment in 4 cases. In 1 case, a glaucoma drainage implant was used to control IOP. CONCLUSIONS: The use of lamellar corneal donor tissue to restore scleral outflow resistance is a safe and effective treatment for severe hypotony after mitomycin C-assisted trabeculectomy with or without filtering bleb leaks. PMID- 24145293 TI - Facial Scanning With a Digital Camera: A Novel Way of Screening for Primary Angle Closure. AB - PURPOSE: We hypothesize that patients with primary angle closure (PAC) have common significant facial characteristics that set them apart from an age matched, sex-matched, and race-matched control population. The primary objective of this study was to test whether a 3-dimensional (3D) camera could pick up these differences in order to differentiate PAC patients from controls. PATIENTS: A total of 55 patients with PAC and 38 controls were included in the study. MATERIALS AND METHODS: Cases and controls had their facial photographs taken using a 3-dimensional digital camera (3dMdFace System). The facial features in the captured photographs were analyzed using a computer software (Neural Network Toolbox). A regression formula was devised to show whether these facial parameters could be used to distinguish between patients and controls. RESULTS: Thirteen facial parameters were measured, and using a regression formula and neural network classification we were able to mathematically distinguish patients from controls using this method of screening. CONCLUSIONS: PAC patients have distinct facial features that may be differentiated from those of normal individuals mathematically using 3D photography. There is potential for this 3D facial scanning technology in screening for PAC in the general population. PMID- 24145294 TI - Does the behavioral immune system prepare females to be religiously conservative and collectivistic? AB - Previous research has indicated that females are more likely than males to endorse collectivistic values and religious conservatism. The present research investigated an evolutionary explanation for these sex differences. More specifically, the sex differences in social conservatism may be due to variation in the behavioral immune system (BIS). The BIS is a set of psychological mechanisms that are proposed to be evolved solutions to disease threat. Four studies were conducted to examine this evolutionary explanation. In Study 1, BIS measures (e.g., disgust sensitivity) fully mediated sex differences in collectivism. This effect was specific to sexual disgust (Study 2). In Studies 3 and 4, the effect was extended to other forms of social conservatism (i.e., religious conservatism) and measures of the BIS. Together, these results suggest that sex differences in collectivism and religious conservatism may be explained in part by sex differences in the BIS. PMID- 24145295 TI - Mental models at work: cognitive causes and consequences of conflict in organizations. AB - This research investigated the reciprocal relationship between mental models of conflict and various forms of dysfunctional social relations in organizations, including experiences of task and relationship conflicts, interpersonal hostility, workplace ostracism, and abusive supervision. We conceptualize individual differences in conflict construals as reflecting variation in people's belief structures about conflict and explore how different elements in people's associative networks-in particular, their beliefs about their best and worst strategy in conflict-relate to their personality, shape their experiences of workplace conflict, and influence others' behavioral intentions toward them. Five studies using a variety of methods (including cross-sectional surveys, a 12-week longitudinal diary study, and an experiment) show that the best strategy beliefs relate in theoretically meaningful ways to individuals' personality, shape social interactions and relationships significantly more than the worst strategy beliefs, and are updated over time as a result of individuals' ongoing experiences of conflict. PMID- 24145296 TI - Mental contrasting and transfer of energization. AB - Mental contrasting a desired future with present reality is a self-regulation strategy that fosters energization in line with a person's expectations of successfully attaining the desired future. We investigated whether physiological energization (measured by systolic blood pressure) elicited by mental contrasting a desired future of solving a given task transfers to effort in an unrelated task. As predicted, mental contrasting a desired future of excelling in an intelligence test (Study 1) and of writing an excellent essay (Study 2) triggered changes in energization that translated into physical effort in squeezing a handgrip (Study 1) and translated into mental effort in writing a get-well letter (Study 2). Results suggest that mental contrasting of solving one task triggers energization that may fuel effort for performing an unrelated task. Implications for intervention research are discussed. PMID- 24145297 TI - Polypyrimidine tract binding protein (PTB) associates with intronic and exonic domains to squelch nuclear export of unspliced RNA. AB - Retention of unspliced pre-messenger RNA (pre-mRNA) in the nucleus is essential for cell survival. Available nuclear factors must recognize and discern between diverse export signals present in pre-mRNA to establish an export inhibitory complex. We found that polypyrimidine domains present in both intron and exon were important for export inhibition of a minigene transcript based on hepatitis B virus pregenomic RNA. Overexpression of PTB drastically reduced export and presence of RRM4 domain seemed critical. This inhibitory network overrode stimulation from an exonic export-facilitating element. We posit that binding of PTB to multiple loci on pre-mRNA regulates nuclear retention. PMID- 24145299 TI - Structural analysis of heteropolysaccharide from Saccharina japonica and its derived oligosaccharides. AB - Degraded fucoidan (F1) was desulfated by DMSO-MeOH. And anion exchange chromatography was performed to fractionate desulfated F1 (ds-F1) into five fractions. Electrospray ionization mass spectrometry (ESI-MS) showed that each fraction contained at least one set of neutral and/or sulfated fucooligosaccharides in the form of methyl glycosides. And the structures of oligomeric fragments were characterized by ESI-CID-MS/MS and ESI-CID-MS/MS/MS. In addition, more structural features were shown by NMR. Therefore, it was concluded that LF1 contained a backbone of (1->3)-linked fucopyranose residues sulfated at C-4 and branched at C-2 by fucopyranose residues and fucoglucuronomannan, fucoglucuronan, galactan and xylan were found in LF-5. Finally, it was concluded that F1 was the middle component, which contained the information of both F0.5 and F2, indicating that the differences between F1 and F0.5, F2 might be derived primarily from the different needs of algae itself. PMID- 24145298 TI - Doxorubicin in TAT peptide-modified multifunctional immunoliposomes demonstrates increased activity against both drug-sensitive and drug-resistant ovarian cancer models. AB - Multidrug resistance (MDR) is a hallmark of cancer cells and a crucial factor in chemotherapy failure, cancer reappearance, and patient deterioration. We have previously described the physicochemical characteristics and the in vitro anticancer properties of a multifunctional doxorubicin-loaded liposomal formulation. Lipodox((r)), a commercially available PEGylated liposomal doxorubicin, was made multifunctional by surface-decorating with a cell penetrating peptide, TATp, conjugated to PEG 1000-PE, to enhance liposomal cell uptake. A pH-sensitive polymer, PEG 2000-Hz-PE, with a pH-sensitive hydrazone (Hz) bond to shield the peptide in the body and expose it only at the acidic tumor cell surface, was used as well. In addition, an anti-nucleosome monoclonal antibody 2C5 attached to a long-chain polymer to target nucleosomes overexpressed on the tumor cell surface was also present. Here, we report the in vitro cell uptake and cytotoxicity of the modified multifunctional immunoliposomes as well as the in vivo studies on tumor xenografts developed subcutaneously in nude mice with MDR and drug-sensitive human ovarian cancer cells (SKOV-3). Our results show the ability of multifunctional immunoliposomes to overcome MDR by enhancing cytotoxicity in drug-resistant cells, compared with non-modified liposomes. Furthermore, in comparison with the non-modified liposomes, upon intravenous injection of these multifunctional immunoliposomes into mice with tumor xenografts, a significant reduction in tumor growth and enhanced therapeutic efficacy of the drug in both drug-resistant and drug-sensitive mice was obtained. The use of "smart" multifunctional delivery systems may provide the basis for an effective strategy to develop, improve, and overcome MDR cancers in the future. PMID- 24145300 TI - Mastoid obliteration using 3D PCL scaffold in combination with alginate and rhBMP 2. AB - Various materials, both biological and alloplastic, have been used for mastoid obliteration after canal wall-down mastoidectomy in chronic otitis media. The purpose of this study is to investigate the osteoinductive potential of PCL scaffolds in mastoid obliteration, and to test that osteoinductivity can be enhanced by coating PCL with alginate and rhBMP-2. The in vitro biocompatibilities of the scaffolds were examined using osteoblast-like cells (MG63). Cell-morphology and calcium deposition were assessed. Based on scanning electron microscope (SEM) images, the cells grew sporadically on the surfaces of the struts in the PCL scaffold, while the entire struts of the PCL/alginate/BMP-2 scaffold was covered with the cells. Furthermore, the PCL/alginate/BMP-2 scaffold showed significantly higher calcium deposition than the PCL/alginate scaffold. Micro-CT showed osteogenesis in the pores of the 3D PCL scaffold in the experimental group, compared to the control group. Confocal microscopic findings showed that the honeycomb appearance of the PCL structure remained in the control group (pure PCL), but significant amount of bone remodeling in the experimental group (PCL/alginate/BMP-2). Histomorphometric analysis showed that the experimental group demonstrated a significantly higher amount (p=0.014) of new bone formation with 50.2 +/- 6.5% (mean +/- SD), compared to 10.2 +/- 3.5% for the control group. Based on these in vitro and in vivo results, the use of the PCL/alginate/BMP-2 scaffold seemed to be a promising technique for the mastoid obliteration. PMID- 24145301 TI - Chemical analysis and antioxidant activity of polysaccharides extracted from Inonotus obliquus sclerotia. AB - Three water-soluble polysaccharide fractions (IOP40, IOP60 and IOP80) were isolated by using different concentrations of alcohol precipitation from Inonotus obliquus sclerotia. Their physicochemical properties, including total sugar content, protein content, monosaccharide composition and percentage were analyzed. And their in vitro antioxidant capacities were investigated in terms of reducing power assay and scavenging of 2,2-diphenyl-1-picrylhydrazyl (DPPH) radicals, hydroxyl radicals, superoxide anion radicals and hydrogen peroxide (H2O2). In general, three polysaccharide fractions exhibited increasing antioxidant activity with increasing concentration at the ranges of tested dosage. The orders of reducing power, DPPH-scavenging capacity, H2O2-scavenging capacity, and hydroxyl-scavenging activity were all IOP60>IOP40>IOP80. These findings demonstrated that three polysaccharide fractions extracted from I. obliquus, especially IOP60, could be employed as natural ingredients in functional food and pharmaceutical industry to alleviate the oxidative stress. PMID- 24145302 TI - X-ray texture analysis indicates downward spinning of chitin microfibrils in tubeworm tube. AB - The direction of beta-chitin deposition in the tube of tubeworm Lamellibrachia satsuma was investigated by texture analysis using X-ray diffraction. The beta chitin crystallite in the tube has planar orientation with the (110) plane perpendicular to the surface, and the c-axis is aligned parallel to the tube. The monoclinic unit cell of beta-chitin allowed determination of the sense of c-axis from the orientation of (010) and (100) planes. This means that the reducing end of beta-chitin is pointing up in the tube. This orientation can be ascribed to possible secretion mechanisms of the beta-chitin microfibrils, i.e. the chitin synthesizing enzyme complex travels unidirectionally from top to bottom when the worm body contracts in the tube. PMID- 24145303 TI - Crowded chromatin is not sufficient for heterochromatin formation and not required for its maintenance. AB - In contrast to cytoplasmic organelles, which are usually separated from the rest of the cell by phospholipid membranes, nuclear compartments are readily accessible to diffusing proteins and must rely on different mechanisms to maintain their integrity. Specific interactions between scaffolding proteins are known to have important roles for the formation and maintenance of nuclear structures. General physical mechanisms such as molecular crowding, phase separation or colloidal behavior have also been suggested, but their physiological significance remains uncertain. For macromolecular crowding, a role in the maintenance of nucleoli and promyelocytic leukemia (PML) nuclear bodies has been shown. Here, we tested whether a modulation of the compaction state of chromatin, which directly influences the local crowding state, has an impact on the formation and maintenance of densely packed heterochromatin. By osmotic perturbations, we could modify the packing state of chromatin in a controlled manner and show that chromatin compaction, which is associated with increased crowding conditions, is not, per se, sufficient to initiate the formation of new bona fide heterochromatin structures nor is it necessary to maintain already established heterochromatin domains. In consequence, if an increase in crowding induced by chromatin compaction maybe an early step in heterochromatin formation, specific protein-protein interactions are nevertheless required to make heterochromatin long lasting and independent of the crowding state. PMID- 24145304 TI - Children with nephrotic syndrome have greater bone area but similar volumetric bone mineral density to healthy controls. AB - BACKGROUND: Glucocorticoid use has been associated with an increased fracture risk and reduced bone mineral density (BMD), particularly in the trabecular compartment. However the contribution of the underlying inflammatory disease process to these outcomes is poorly understood. Childhood nephrotic syndrome (NS) typically follows a relapsing-remitting course often requiring recurrent courses of glucocorticoids, but with low systemic inflammation during remission. NS therefore represents a useful clinical model to investigate the effects of glucocorticoids on BMD and bone geometry in childhood. METHODS: Children with NS were compared to age and sex matched healthy controls. Body composition and areal BMD (whole body, lumbar spine and hip) were assessed by DXA. Peripheral quantitative computed tomography (pQCT) scans were obtained at metaphyseal (4%) and diaphyseal (66%) sites of the tibia to determine volumetric BMD and bone cross-sectional geometry. Lifetime cumulative glucocorticoid exposure was calculated from medical records. RESULTS: 29 children with NS (55% male, age 10.7+/-3.1years) were compared to 29 healthy controls (55% male, age 11.0+/ 3.0years). The children with NS were of similar height SDS to controls (p=0.28), but were heavier (0.65+/-1.28SDS vs -0.04+/-0.89SDS, p=0.022) and had greater body fat percentage SDS (0.31+/-1.01 vs -0.52+/-1.10, p=0.008). Tibial trabecular and cortical vBMD were similar between the two groups but bone cross-sectional area (CSA) was significantly greater in children with NS at both the metaphysis (954+/-234mm(2) vs 817+/-197mm(2), p=0.002) and diaphysis (534.9+/-162.7mm(2) vs 463.2+/-155.5mm(2), p=0.014). Endosteal and periosteal circumferences were greater in children with NS than controls (both p<0.01), resulting in reduced cortical thickness (2.4+/-0.7mm vs 2.8+/-0.7mm, p=0.018), but similar cortical CSA (p=0.22). The differences in cortical geometry were not statistically significant when weight was included as a confounding factor. There were no associations between cumulative steroid exposure, duration of NS or number of relapses and any bone parameter. CONCLUSIONS: Tibial bone CSA is increased in children with NS. We speculate that this is a compensatory response to increased body weight. Defects in trabecular BMD were not identified in this cohort of children with NS. PMID- 24145305 TI - Finite element analysis and CT-based structural rigidity analysis to assess failure load in bones with simulated lytic defects. AB - There is an urgent need to improve the prediction of fracture risk for cancer patients with bone metastases. Pathological fractures that result from these tumors frequently occur in the femur. It is extremely difficult to determine the fracture risk even for experienced physicians. Although evolving, fracture risk assessment is still based on inaccurate predictors estimated from previous retrospective studies. As a result, many patients are surgically over-treated, whereas other patients may fracture their bones against expectations. We mechanically tested ten pairs of human cadaveric femurs to failure, where one of each pair had an artificial defect simulating typical metastatic lesions. Prior to testing, finite element (FE) models were generated and computed tomography rigidity analysis (CTRA) was performed to obtain axial and bending rigidity measurements. We compared the two techniques on their capacity to assess femoral failure load by using linear regression techniques, Student's t-tests, the Bland Altman methodology and Kendall rank correlation coefficients. The simulated FE failure loads and CTRA predictions showed good correlation with values obtained from the experimental mechanical testing. Kendall rank correlation coefficients between the FE rankings and the CTRA rankings showed moderate to good correlations. No significant differences in prediction accuracy were found between the two methods. Non-invasive fracture risk assessment techniques currently developed both correlated well with actual failure loads in mechanical testing suggesting that both methods could be further developed into a tool that can be used in clinical practice. The results in this study showed slight differences between the methods, yet validation in prospective patient studies should confirm these preliminary findings. PMID- 24145306 TI - Localization of the gene for X-linked calvarial hyperostosis to chromosome Xq27.3 Xqter. AB - X-linked calvarial hyperostosis is a rare disorder characterized by isolated calvarial thickening. Symptoms are prominent frontoparietal bones, a flat nasal root and a short upturned nose, a high forehead with ridging of the metopic and sagittal sutures, and lateral frontal prominences. The mandible is normal, as are the clavicles, pelvis and long bones. The thickened bone in the skull appears to be softer than normal bone. Despite calvarial hyperostosis, increased intracranial pressure and cranial nerve entrapment do not occur. The major disability seems to be cosmetic. The disease segregates with an X-linked recessive mode of inheritance. Female carriers do not show any clinical symptoms. To date, only one family has been described with X-linked calvarial hyperostosis including three affected individuals. In order to localize the disease causing gene, 31 polymorphic microsatellite markers that spread across the X-chromosome were analyzed. Genotypes were combined in haplotypes to delineate the region. A chromosomal region spanning from Xq27.3 to Xqter cosegregates with the disorder. This region encompasses 23.53cM or 8.2Mb according to the deCODE map and contains 165 genes. CNV-analysis did not show small duplications or deletions in this region. Exome sequencing was performed on a male patient in this family. However, this did not reveal any putative mutation. These results indicate that a non coding regulatory sequence might be involved in the pathogenesis of this disorder. PMID- 24145308 TI - Development of an ultrahigh resolution Si-PM based PET system for small animals. AB - Since a high resolution PET system is needed for small animal imaging, especially for mouse studies, we developed a new small animal PET system that decreased the size of the scintillators to less than 1 mm. Our developed PET system used 0.5 * 0.7 * 5 mm(3) LYSO pixels arranged in an 11 * 13 matrix to form a block with a 0.1 mm BaSO4 reflector between the pixels. Two LYSO blocks were optically coupled to two optical fiber based angled image guides. These LYSO blocks and image guides were coupled to a Si-PM array (Hamamatsu MPPC S11064-050P) to form a block detector. Eight block detectors (16 LYSO blocks) were arranged in a 34 mm inner diameter ring to form a small animal PET system. The block detector showed good separation for the 22 * 13 LYSO pixels in the two-dimensional position histogram. The energy resolution was 20% full-with at half-maximum (FWHM) for 511 keV gamma photons. The transaxial resolution reconstructed by filtered backprojection was 0.71 to 0.75 mm FWHM and the axial resolution was 0.70 mm. The point source sensitivity was 0.24% at the central axial field-of-view. High resolution mouse images were obtained using our PET system. The developed ultrahigh resolution PET system showed attractive images for small animal studies and has a potential to provide new findings in molecular imaging researches. PMID- 24145307 TI - Effects of unfractionated heparin on renal osteodystrophy and vascular calcification in chronic kidney disease rats. AB - Unfractionated heparin (UFH) is the most widely used anticoagulant in hemodialysis for chronic kidney disease (CKD) patients. Many studies have verified that UFH can induce bone loss in subjects with normal bone, but few have focused on its effect on renal osteodystrophy. We therefore investigated this issue in adenine-induced CKD rats. As CKD also impairs mineral metabolism systemically, we also studied the impacts of UFH on serum markers of CKD-mineral and bone disorder (CKD-MBD) and vascular calcification. We administered low and high doses of UFH (1U/g and 2U/g body weight, respectively) to CKD rats and compared them with CKD controls. At sacrifice, the serum markers of CKD-MBD did not significantly differ among the two UFH CKD groups and the CKD control group. The mean bone mineral densities (BMDs) of the total femur and a region of interest (ROI) constituted of trabecular and cortical bone were lower in the high dose UFH (H-UFH) CKD group than in the CKD control group (P<0.05 and P<0.01, respectively). The BMD of the femoral ROI constituted of cortical bone did not differ between the H-UFH CKD group and the CKD control group. Histomorphometrical changes in the CKD rats indicated secondary hyperparathyroidism, and the femoral trabecular bone volume, but not cortical bone volume, significantly decreased with increasing UFH dose. The same decreasing trend was found in osteoblast parameters, and an increasing trend was found in osteoclast parameters; however, most differences were not significant. Moreover, no distinct statistical differences were found in the comparison of vascular calcium or phosphorus content among the CKD control group and the two UFH CKD groups. Therefore, we concluded that UFH could induce bone loss in CKD rats with secondary hyperparathyroidism, mainly by reducing the trabecular volume and had little effect on cortical bone volume. The underlying mechanism might involve inhibition of osteoblast activity and promotion of osteoclast activity by UFH. We did not find any effect of UFH on vascular calcification in CKD rats with secondary hyperparathyroidism. PMID- 24145309 TI - Early predictors of gestational hypertension in a low-risk cohort. Results of a pilot study. AB - OBJECTIVE: To determine if the clinical or biochemical markers used in pregnancy can be applied as early predictors of gestational hypertension. DESIGN: Prospective cohort study. POPULATION: 315 pregnant women referred from the Prenatal Diagnosis Unit between weeks 10-13 of pregnancy and followed up to the childbirth. METHODS: Biomarkers were measured in serum specimens in the first and second trimester of pregnancy. Blood pressure (BP) was measured in the first, second and third trimester. RESULTS: The cumulative incidence of gestational hypertension was 6.01%. In the first trimester gestational hypertension predictors were uric acid greater than 3.15 mg/dl (P=0.01), BMI greater than 24 kg/m (P=0.003) SBP at least 120 mmHg (P=0.02) and DBP at least 71 mmHg (P=0.007). After applied multivariate analysis just uric acid and SBP were statistically significant. CONCLUSION: In our cohort of healthy pregnant women uric acid above 3.15 mg/dl and SBP at least 120 mmHg are consistent predictors of gestational hypertension in the first trimester. The most important implication of our study is the possibility to identify in the first trimester women at risk to develop gestational hypertension using available markers. PMID- 24145310 TI - Ribosomes: the future of targeted therapies? PMID- 24145311 TI - Can non-polar hydrogen atoms accept hydrogen bonds? AB - We examine an unusual case where a neutral hydrogen atom acts as a hydrogen-bond acceptor. The association constant between trihexylsilane and perfluoro-tert butanol was measured as ~0.8 M(-1) in cyclohexane. Computations and experimental NMR data are consistent with a weak, but favourable Si-H...HO interaction. PMID- 24145312 TI - Rapid and long-lasting decrease of T-regulatory cells in patients with myelofibrosis treated with ruxolitinib. PMID- 24145314 TI - Pathogenic mechanisms and clinical implications of congenital neutropenia syndromes. AB - PURPOSE OF REVIEW: The purpose of this review is to summarize pathogenic mechanisms and clinical implications of the most illustrative genetic entities of congenital neutropenia syndromes. RECENT FINDINGS: Congenital neutropenia comprise monogenetic entities with or without additional immunologic and extrahaematopoietic syndromatic features. Continuous careful explorations of known entities such as ELANE, GFI1, HAX1, G6PC3 deficiency and XLN help to define principles controlling differentiation and function of neutrophil granulocytes. Furthermore, the identification of novel genetic defects associated with congenital neutropenia, such as VPS45 deficiency, broadens our understanding of neutrophil biology. Pathogenic mechanisms imply protein and vesicle mistrafficking, endoplasmic reticulum stress, the unfolded protein response, destabilization of the mitochondrial membrane potential, disturbed energy metabolism, dysglycosylation and deregulated actin polymerization. SUMMARY: Advanced genetic and biochemical techniques have helped to expand our knowledge of congenital neutropenia syndromes. Known and novel genetic entities shed light on fundamental biological processes important for the homeostatis and functioning not only of the neutrophil granulocyte but as well of the entire haematopoietic system. Furthermore, treatment decisions become more tailored and might pave the road towards personalized molecular medicine. PMID- 24145313 TI - Assays for the identification of novel antivirals against bluetongue virus. AB - To identify potential antivirals against BTV, we have developed, optimized and validated three assays presented here. The CPE-based assay was the first assay developed to evaluate whether a compound showed any antiviral efficacy and have been used to screen large compound library. Meanwhile, cytotoxicity of antivirals could also be evaluated using the CPE-based assay. The dose-response assay was designed to determine the range of efficacy for the selected antiviral, i.e. 50% inhibitory concentration (IC50) or effective concentration (EC50), as well as its range of cytotoxicity (CC50). The ToA assay was employed for the initial MoA study to determine the underlying mechanism of the novel antivirals during BTV viral lifecycle or the possible effect on host cellular machinery. These assays are vital for the evaluation of antiviral efficacy in cell culture system, and have been used for our recent researches leading to the identification of a number of novel antivirals against BTV. PMID- 24145316 TI - First principles studies on the redox ability of (Ga(1-x)Zn(x))N(1-x)O(x) solid solutions and thermal reactions for H2 and O2 production on their surfaces. AB - The (Ga1-xZnx)N1-xOx solid solution has been emerging as an effective photocatalyst for water splitting utilizing the visible solar spectrum, regarded as a host GaN bulk doped with ZnO impurities. H2 and O2 production occur simultaneously and stoichiometrically on the surface of (Ga1-xZnx)N1-xOx particles. In this work, we characterize the redox ability of (Ga1-xZnx)N1-xOx and find that a solid solution with a ZnO concentration of 0.125 < x < 0.250 is optimal for water splitting. This is consistent with the experimental finding that the maximum photocatalytic activity of (Ga1-xZnx)N1-xOx is achieved at x = 0.13. The thermal reactions of water splitting are modeled on both the GaN and an idealized (Ga1-xZnx)N1-xOx (101[combining macron]0) surface. The computed activation barriers allow us to gain some clues on the efficiency of water splitting on a specific photocatalyst surface. Our results suggest that the non polar (101[combining macron]0) and polar (0001) surfaces may play different roles in water splitting, i.e., the (101[combining macron]0) surface is responsible for O2 production, while hydroxyl groups could dissociate on the (0001) surface. PMID- 24145315 TI - Reducing and managing systemic reactions to immunotherapy. AB - PURPOSE OF REVIEW: To identify and discuss recent articles pertaining to the reduction and management of systemic reactions to allergen immunotherapy (AIT). RECENT FINDINGS: Fatal reactions to AIT may be declining. Screening asthma patients before AIT and dose adjustment during pollen season may contribute to lower systemic reaction rates. Cluster build-up protocols with multiallergen subcutaneous immunotherapy (SCIT) may lead to an increased risk of systemic reactions compared with cluster build-up protocols with single-allergen SCIT. Sublingual immunotherapy (SLIT) studies confirm the low rates of systemic reactions using this method, including for rapid build-up schedules. Studies of newer forms of AIT (intralymphatic, epicutaneous, recombinant allergens) have too few patients to form confident systemic reaction risk estimates. High-grade delayed systemic reactions to AIT may be less frequent than previously reported. SUMMARY: Recent studies increase confidence in risk estimates for systemic reactions to AIT, suggest useful strategies to predict systemic reactions to AIT, and offer strategies to prevent systemic reactions. PMID- 24145317 TI - Nanoporous gold as an active low temperature catalyst toward CO oxidation in hydrogen-rich stream. AB - Preferential CO oxidation (PROX) was investigated by using dealloyed nanoporous gold (NPG) catalyst under ambient conditions. Systematic investigations were carried out to characterize its catalytic performance by varying reaction parameters such as temperature and co-existence of CO2 and H2O, which revealed that NPG was a highly active and selective catalyst for PROX, especially at low temperature. At 20 degrees C, the exit CO concentration could be reduced to less than 2 ppm with a turnover frequency of 4.1 * 10(-2) s(-1) at a space velocity of 120,000 mL h(-1) g(-1)cat. and its high activity could retain for more than 24 hours. The presence of residual Ag species in the structure did not seem to improve the intrinsic activity of NPG for PROX; however, they contributed to the stabilization of the NPG structure and apparent catalytic activity. These results indicated that NPG might be readily applicable for hydrogen purification in fuel cell applications. PMID- 24145318 TI - A robust computational solution for automated quantification of a specific binding ratio based on [123i]fp-cit SPECT images. AB - AIM: The purpose of the current paper is to present a computational solution to accurately quantify a specific to a non-specific uptake ratio in [123I]fP-CIT single photon emission computed tomography (SPECT) images and simultaneously measure the spatial dimensions of the basal ganglia, also known as basal nuclei. A statistical analysis based on a reference dataset selected by the user is also automatically performed. METHODS: The quantification of the specific to non specific uptake ratio here is based on regions of interest defined after the registration of the image under study with a template image. The computational solution was tested on a dataset of 38 [123I]FP-CIT SPECT images: 28 images were from patients with Parkinson's disease and the remainder from normal patients, and the results of the automated quantification were compared to the ones obtained by three well-known semi-automated quantification methods. RESULTS: The results revealed a high correlation coefficient between the developed automated method and the three semi-automated methods used for comparison (r >=0.975). The solution also showed good robustness against different positions of the patient, as an almost perfect agreement between the specific to non-specific uptake ratio was found (ICC=1.000). The mean processing time was around 6 seconds per study using a common notebook PC. CONCLUSION: The solution developed can be useful for clinicians to evaluate [123I]FP-CIT SPECT images due to its accuracy, robustness and speed. Also, the comparison between case studies and the follow-up of patients can be done more accurately and proficiently since the intra- and inter observer variability of the semi-automated calculation does not exist in automated solutions. The dimensions of the basal ganglia and their automatic comparison with the values of the population selected as reference are also important for professionals in this area. PMID- 24145319 TI - Ultrastructure of autophagy in plant cells: a review. AB - Just as with yeasts and animal cells, plant cells show several types of autophagy. Microautophagy is the uptake of cellular constituents by the vacuolar membrane. Although microautophagy seems frequent in plants it is not yet fully proven to occur. Macroautophagy occurs farther away from the vacuole. In plants it is performed by autolysosomes, which are considerably different from the autophagosomes found in yeasts and animal cells, as in plants these organelles contain hydrolases from the onset of their formation. Another type of autophagy in plant cells (called mega-autophagy or mega-autolysis) is the massive degradation of the cell at the end of one type of programmed cell death (PCD). Furthermore, evidence has been found for autophagy during degradation of specific proteins, and during the internal degeneration of chloroplasts. This paper gives a brief overview of the present knowledge on the ultrastructure of autophagic processes in plants. PMID- 24145321 TI - Chronic kidney disease: Obesity in children with end-stage renal disease. AB - A recent publication by Bonthuis et al. shows a high prevalence of overweight or obesity in children with end-stage renal disease, particularly in renal transplant recipients. Underweight is more prevalent in infants than in other age groups. This study highlights the need to evaluate and implement interventional strategies in this patient population. PMID- 24145324 TI - Dialysis: Prevention of peritoneal-dialysis-related infections-antibacterial honey might not be the solution. PMID- 24145325 TI - Dialysis: Sudden cardiac death prevention? PMID- 24145326 TI - Transplantation: rituximab induction only for sensitized kidney recipients? AB - In contrast to earlier studies that showed a beneficial influence of rituximab on HLA antibody production after kidney transplantation, a recent report by Ashimine et al. questions such an effect. That previous studies included presensitized patients who are more prone to antibody development, might explain this controversy. PMID- 24145327 TI - Transplantation: Autoantibodies-epiphenomena or biological clues. AB - The potential roles for autoantibodies in renal transplantation are increasing, as illustrated by a recent report of polyreactive autoantibodies produced by B cell clones from a kidney transplant recipient that can bind apoptotic cells and activate complement. Such autoantibodies have the potential to amplify microcirculation injury caused by alloantibody in antibody-mediated transplant rejection. PMID- 24145330 TI - Tryptophan promotes interpersonal trust. PMID- 24145329 TI - CYP2J2-derived epoxyeicosatrienoic acids suppress endoplasmic reticulum stress in heart failure. AB - Prolonged endoplasmic reticulum (ER) stress causes apoptosis and is associated with heart failure. Whether CYP2J2 and its arachidonic acid metabolites [epoxyeicosatrienoic acids (EETs)] have a protective influence on ER stress and heart failure has not been studied. Assays of myocardial samples from patients with end-stage heart failure showed evidence of ER stress. Chronic infusion of isoproterenol (ISO) or angiotensin II (AngII) by osmotic mini-pump induced cardiac hypertrophy and heart failure in mice as evaluated by hemodynamic measurements and echocardiography. Interestingly, transgenic (Tr) mice with cardiomyocyte-specific CYP2J2 expression were protected against heart failure compared with wild-type mice. ISO or AngII administration induced ER stress and apoptosis, and increased levels of intracellular Ca(2+). These phenotypes were abolished by CYP2J2 overexpression in vivo or exogenous EETs treatment of cardiomyocytes in vitro. ISO or AngII reduced sarcoplasmic/endoplasmic reticulum calcium ATPase (SERCA2a) expression in hearts or isolated cardiomyocytes; however, loss of SERCA2a expression was prevented in CYP2J2 Tr hearts in vivo or in cardiomyocytes treated with EETs in vitro. The reduction of SERCA2a activity was concomitant with increased oxidation of SERCA2a. EETs reversed SERCA2a oxidation through increased expression of antioxidant enzymes and reduced reactive oxygen species levels. Tempol, a membrane-permeable radical scavenger, similarly decreased oxidized SERCA2a levels, restored SERCA2a activity, and markedly reduced ER stress response in the mice treated with ISO. In conclusion, CYP2J2-derived EETs suppress ER stress response in the heart and protect against cardiac failure by maintaining intracellular Ca(2+) homeostasis and SERCA2a expression and activity. PMID- 24145331 TI - A person-by-situation approach to emotion regulation: cognitive reappraisal can either help or hurt, depending on the context. AB - Emotion regulation is central to psychological health. For instance, cognitive reappraisal (reframing an emotional situation) is generally an adaptive emotion regulation strategy (i.e., it is associated with increased psychological health). However, a person-by-situation approach suggests that the adaptiveness of different emotion-regulation strategies depends on the context in which they are used. Specifically, reappraisal may be adaptive when stressors are uncontrollable (when the person can regulate only the self) but maladaptive when stressors can be controlled (when the person can change the situation). To test this prediction, we measured cognitive-reappraisal ability, the severity of recent life stressors, stressor controllability, and level of depression in 170 participants. For participants with uncontrollable stress, higher cognitive reappraisal ability was associated with lower levels of depression. In contrast, for participants with controllable stress, higher cognitive-reappraisal ability was associated with greater levels of depression. These findings support a theoretical model in which particular emotion-regulation strategies are not adaptive or maladaptive per se; rather, their adaptiveness depends on the context. PMID- 24145332 TI - How bad could it be? Alcohol dampens stress responses to threat of uncertain intensity. AB - Stress response dampening is an important motive for alcohol use. However, stress reduction via alcohol (alcohol SRD) is observed inconsistently in the laboratory, and this has raised questions about the precise mechanisms and boundary conditions for these effects. Emerging evidence indicates that alcohol SRD may be observed selectively during uncertain but not certain threats. In a final sample of 89 participants, we measured stress response via potentiation of defensive startle reflex in response to threat of shock in blocks with certain (low and high) and uncertain shock intensity. Our alcohol-administration procedure produced blood alcohol concentrations (BACs) across a broad range (0.00%-0.12%) across participants. Increasing BACs were associated with linearly decreasing startle potentiation and self-reported anxiety. This SRD effect was greater during uncertain than certain threat. More broadly, these results suggest that distinct mechanisms are involved in response to threats of uncertain intensity and threats of certain intensity. PMID- 24145339 TI - Locoregional failure rate after preoperative chemoradiation of esophageal adenocarcinoma and the outcomes of salvage strategies. AB - PURPOSE: The primary purpose of surveillance of patients with esophageal adenocarcinoma (EAC) and/or esophagogastric junction adenocarcinoma after local therapy (eg, chemoradiotherapy followed by surgery or trimodality therapy [TMT]) is to implement a potentially beneficial salvage therapy to overcome possible morbidity/mortality caused by locoregional failure (LRF). However, the benefits of surveillance are not well understood. We report on LRFs and salvage strategies in a large cohort. PATIENTS AND METHODS: Between 2000 and 2010, 518 patients with EAC who completed TMT were analyzed for the frequency of LRF over time and salvage therapy outcomes. Standard statistical techniques were used. RESULTS: For 518 patients, the median follow-up time was 29.3 months (range, 1 to 149 months). Distant metastases (with or without LRF) occurred in 188 patients (36%), and LRF only occurred in 27 patients (5%). Eleven of 27 patients had lumen-only LRF. Most LRFs (89%) occurred within 36 months of surgery. Twelve patients had salvage chemoradiotherapy, but only five survived more than 2 years. Four patients needed salvage surgery, and three who survived more than 2 years developed distant metastases. The median overall survival of 27 patients with LRF was 17 months, and 10 patients (37%) survived more than 2 years. Thus, only 2% of all 518 patients benefited from surveillance/salvage strategies. CONCLUSION: Our surveillance strategy, which is representative of many others currently being used, raises doubts about its effectiveness and benefits (along with concerns regarding types and times of studies and costs implications) to patients with EAC who have LRF only after TMT. Fortunately, LRFs are rare after TMT, but the salvage strategies are not highly beneficial. Our data can help develop an evidence-based surveillance strategy. PMID- 24145340 TI - Dose-limiting toxicity after hypofractionated dose-escalated radiotherapy in non small-cell lung cancer. AB - PURPOSE: Local failure rates after radiation therapy (RT) for locally advanced non-small-cell lung cancer (NSCLC) remain high. Consequently, RT dose intensification strategies continue to be explored, including hypofractionation, which allows for RT acceleration that could potentially improve outcomes. The maximum-tolerated dose (MTD) with dose-escalated hypofractionation has not been adequately defined. PATIENTS AND METHODS: Seventy-nine patients with NSCLC were enrolled on a prospective single-institution phase I trial of dose-escalated hypofractionated RT without concurrent chemotherapy. Escalation of dose per fraction was performed according to patients' stratified risk for radiation pneumonitis with total RT doses ranging from 57 to 85.5 Gy in 25 daily fractions over 5 weeks using intensity-modulated radiotherapy. The MTD was defined as the maximum dose with <= 20% risk of severe toxicity. RESULTS: No grade 3 pneumonitis was observed and an MTD for acute toxicity was not identified during patient accrual. However, with a longer follow-up period, grade 4 to 5 toxicity occurred in six patients and was correlated with total dose (P = .004). An MTD was identified at 63.25 Gy in 25 fractions. Late grade 4 to 5 toxicities were attributable to damage to central and perihilar structures and correlated with dose to the proximal bronchial tree. CONCLUSION: Although this dose-escalation model limited the rates of clinically significant pneumonitis, dose-limiting toxicity occurred and was dominated by late radiation toxicity involving central and perihilar structures. The identified dose-response for damage to the proximal bronchial tree warrants caution in future dose-intensification protocols, especially when using hypofractionation. PMID- 24145341 TI - Prediagnostic body mass index and pancreatic cancer survival. AB - PURPOSE: Although obesity is associated with increased incidence of pancreatic cancer, studies have not prospectively evaluated prediagnostic body mass index (BMI) and survival. PATIENTS AND METHODS: We analyzed survival by prediagnostic BMI assessed in 1986 among 902 patients from two large prospective cohorts diagnosed from 1988 to 2010. We estimated hazard ratios (HRs) for death using Cox proportional hazards models, with adjustment for age, sex, race/ethnicity, smoking, diagnosis year, and stage. We evaluated the temporal association of BMI with survival by grouping reported BMI by 2-year lag-time intervals before diagnosis. RESULTS: The multivariable-adjusted HR for death was 1.53 (95% CI, 1.11 to 2.09) comparing patients with BMI >= 35 kg/m(2) with those with BMI < 25 kg/m(2) (P trend = .001), which was similar after adjustment for stage. The association of BMI with survival was stronger with longer lag times between reported BMI and cancer diagnosis. Among patients with BMI collected 18 to 20 years before diagnosis, HR for death was 2.31 (95% CI, 1.48 to 3.61; P trend < .001), comparing obese with healthy-weight patients. No statistically significant differences were seen by cohort, smoking status, or stage, although the association was stronger among never-smokers (HR, 1.61; 95% CI, 1.01 to 2.57; P trend = .002) than ever-smokers (HR, 1.36; 95% CI, 0.86 to 2.15; P trend = .63), comparing BMI >= 35 kg/m(2) with BMI < 25 kg/m(2). Higher prediagnostic BMI was associated with more advanced stage at diagnosis, with 72.5% of obese patients presenting with metastatic disease versus 59.4% of healthy-weight patients (P = .02). CONCLUSION: Higher prediagnostic BMI was associated with statistically significantly decreased survival among patients with pancreatic cancer from two large prospective cohorts. PMID- 24145342 TI - Novel use of a hydrogel spacer permits reirradiation in otherwise incurable recurrent gynecologic cancers. PMID- 24145343 TI - Psychological impact of prostate biopsy: physical symptoms, anxiety, and depression. AB - PURPOSE: To investigate the psychological impact of prostate biopsy, including relationships between physical biopsy-related symptoms and anxiety and depression. PATIENTS AND METHODS: A prospective cohort of 1,147 men, nested within the Prostate Testing for Cancer and Treatment trial and recommended to receive prostate biopsy, completed questionnaires assessing physical and psychological harms after biopsy in the Prostate Biopsy Effects study. Psychological impact was measured using the Hospital Anxiety and Depression Scale, and scores were compared according to experiences of biopsy-related symptoms at biopsy, and at 7 and 35 days afterward, and in relation to biopsy results. RESULTS: A total of 1,144 men (99.7%) returned questionnaires at biopsy, with 1,090 (95.0%) and 1,016 (88.6%) responding at 7 and 35 days postbiopsy. Most men experienced biopsy-related symptoms as no problem or a minor problem, and overall levels of anxiety and depression were low and similar to normative levels. Of men receiving a negative biopsy result (n = 471), anxiety was greater in those experiencing problematic biopsy-related symptoms compared with those experiencing nonproblematic symptoms at 7 days for the following symptoms: pain (P < .001), shivers, (P = .020), hematuria (P < .001), hematochezia (P < .001), and hemoejaculate (P < .001). Anxiety was reduced, although symptoms were not, after 35 days. Overall levels of anxiety were low across all time points except at the 35-day assessment among men who had received a cancer diagnosis. CONCLUSION: Problematic postbiopsy symptoms can lead to increased anxiety, distinct from distress related to diagnosis of prostate cancer. Men and doctors need to consider these additional potential harms of biopsy when deciding whether to initiate prostate-specific antigen testing. PMID- 24145344 TI - Coexistent multiple myeloma or increased bone marrow plasma cells define equally high-risk populations in patients with immunoglobulin light chain amyloidosis. AB - PURPOSE: There is consensus that patients with light chain (AL) amyloidosis with hypercalcemia, renal failure, anemia, and lytic bone lesions attributable to clonal expansion of plasma cells (CRAB criteria) also have multiple myeloma (MM). The aim of this study was to examine the spectrum of immunoglobulin AL amyloidosis with and without MM, with a goal of defining the optimal bone marrow plasma cell (BMPC) number to qualify as AL amyloidosis with MM. PATIENTS AND METHODS: We identified 1,255 patients with AL amyloidosis seen within 90 days of diagnosis between January 1, 2000, and December 31, 2010. We defined a population of patients with coexisting MM on the basis of the existence of CRAB criteria (AL CRAB). Receiver operating characteristic analysis determined the optimal BMPC cut point to predict for 1-year mortality in patients with AL amyloidosis without CRAB to produce two additional groups: AL only (<= 10% BMPCs) and AL plasma cell MM (AL-PCMM; > 10% BMPCs). RESULTS: Among the 1,255 patients, 100 (8%) had AL CRAB, 476 (38%) had AL-PCMM, and 679 (54%) had AL only. Their respective median overall survival rates were 10.6, 16.2, and 46 months (P < .001). Because the outcomes of AL-CRAB and AL-PCMM were similar, they were pooled for univariate and multivariate analyses. On multivariate analysis, pooled AL-CRAB and AL-PCMM retained negative prognostic value independent of age, Mayo Clinic AL amyloidosis stage, prior autologous stem-cell transplantation, and difference between the involved and uninvolved free light chain. CONCLUSION: Patients with AL amyloidosis who have more than 10% BMPCs have a poor prognosis, similar to that of patients with AL-CRAB, and should therefore be considered together as AL amyloidosis with MM. PMID- 24145345 TI - Safety, efficacy, and biomarkers of nivolumab with vaccine in ipilimumab refractory or -naive melanoma. AB - PURPOSE: Nivolumab, a human immunoglobulin G4-blocking antibody against the T cell programmed death-1 checkpoint protein, has activity against metastatic melanoma. Its safety, clinical efficacy, and correlative biomarkers were assessed with or without a peptide vaccine in ipilimumab-refractory and -naive melanoma. PATIENTS AND METHODS: In this phase I study, 90 patients with unresectable stage III or IV melanoma who were ipilimumab naive and had experienced progression after at least one prior therapy (cohorts 1 to 3, 34 patients) or experienced progression after prior ipilimumab (cohorts 4 to 6, 56 patients) received nivolumab at 1, 3, or 10 mg/kg every 2 weeks for 24 weeks, then every 12 weeks for up to 2 years, with or without a multipeptide vaccine. RESULTS: Nivolumab with vaccine was well tolerated and safe at all doses. The RECIST 1.1 response rate for both ipilimumab-refractory and -naive patients was 25%. Median duration of response was not reached at a median of 8.1 months of follow-up. High pretreatment NY-ESO-1 and MART-1-specific CD8(+) T cells were associated with progression of disease. At week 12, increased peripheral-blood T regulatory cells and decreased antigen-specific T cells were associated with progression. PD-L1 tumor staining was associated with responses to nivolumab, but negative staining did not rule out a response. Patients who experienced progression after nivolumab could respond to ipilimumab. CONCLUSION: In patients with ipilimumab-refractory or -naive melanoma, nivolumab at 3 mg/kg with or without peptide vaccine was well tolerated and induced responses lasting up to 140 weeks. Responses to nivolumab in ipilimumab-refractory patients or to ipilimumab in nivolumab-refractory patients support combination or sequencing of nivolumab and ipilimumab. PMID- 24145346 TI - PointBreak: a randomized phase III study of pemetrexed plus carboplatin and bevacizumab followed by maintenance pemetrexed and bevacizumab versus paclitaxel plus carboplatin and bevacizumab followed by maintenance bevacizumab in patients with stage IIIB or IV nonsquamous non-small-cell lung cancer. AB - PURPOSE: PointBreak (A Study of Pemetrexed, Carboplatin and Bevacizumab in Patients With Nonsquamous Non-Small Cell Lung Cancer) compared the efficacy and safety of pemetrexed (Pem) plus carboplatin (C) plus bevacizumab (Bev) followed by pemetrexed plus bevacizumab (PemCBev) with paclitaxel (Pac) plus carboplatin (C) plus bevacizumab (Bev) followed by bevacizumab (PacCBev) in patients with advanced nonsquamous non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS: Patients with previously untreated stage IIIB or IV nonsquamous NSCLC and Eastern Cooperative Oncology Group performance status of 0 to 1 were randomly assigned to receive pemetrexed 500 mg/m(2) or paclitaxel 200 mg/m(2) combined with carboplatin area under the curve 6 and bevacizumab 15 mg/kg every 3 weeks for up to four cycles. Eligible patients received maintenance until disease progression: pemetrexed plus bevacizumab (for the PemCBev group) or bevacizumab (for the PacCBev group). The primary end point of this superiority study was overall survival (OS). RESULTS: Patients were randomly assigned to PemCBev (n = 472) or PacCBev (n = 467). For PemCBev versus PacCBev, OS hazard ratio (HR) was 1.00 (median OS, 12.6 v 13.4 months; P = .949); progression-free survival (PFS) HR was 0.83 (median PFS, 6.0 v 5.6 months; P = .012); overall response rate was 34.1% versus 33.0%; and disease control rate was 65.9% versus 69.8%. Significantly more study drug-related grade 3 or 4 anemia (14.5% v 2.7%), thrombocytopenia (23.3% v 5.6%), and fatigue (10.9% v 5.0%) occurred with PemCBev; significantly more grade 3 or 4 neutropenia (40.6% v 25.8%), febrile neutropenia (4.1% v 1.4%), sensory neuropathy (4.1% v 0%), and alopecia (grade 1 or 2; 36.8% v 6.6%) occurred with PacCBev. CONCLUSION: OS did not improve with the PemCBev regimen compared with the PacCBev regimen, although PFS was significantly improved with PemCBev. Toxicity profiles differed; both regimens demonstrated tolerability. PMID- 24145347 TI - Progression in smoldering myeloma is independently determined by the chromosomal abnormalities del(17p), t(4;14), gain 1q, hyperdiploidy, and tumor load. AB - PURPOSE: The aim of this study was to analyze chromosomal aberrations in terms of frequency and impact on time to progression in patients with smoldering multiple myeloma (SMM) on the background of clinical prognostic factors. PATIENTS AND METHODS: The chromosomal abnormalities 1q21, 5p15/5q35, 9q34, 13q14.3, 15q22, 17p13, t(11;14)(q13;q32), and t(4;14)(p16.3;q32) were assessed in CD138-purified myeloma cells by interphase fluorescent in situ hybridization (iFISH) alongside clinical parameters in a consecutive series of 248 patients with SMM. RESULTS: The high-risk aberrations in active myeloma (ie, del(17p13), t(4;14), and +1q21) present in 6.1%, 8.9%, and 29.8% of patients significantly confer adverse prognosis in SMM with hazard ratios (HRs) of 2.90 (95% CI, 1.56 to 5.40), 2.28 (95% CI, 1.33 to 3.91), and 1.66 (95% CI, 1.08 to 2.54), respectively. Contrary to the conditions in active myeloma, hyperdiploidy, present in 43.3% of patients, is an adverse prognostic factor (HR, 1.67; 95% CI, 1.10 to 2.54). Percentage of malignant bone marrow plasma cells assessed by iFISH and combination of M-protein and plasma cell infiltration as surrogates of tumor load significantly confer adverse prognosis with HRs of 4.37 (95% CI, 2.79 to 6.85) and 4.27 (95% CI, 2.77 to 6.56), respectively. In multivariate analysis, high-risk aberrations, hyperdiploidy, and surrogates of tumor load are independently prognostic. CONCLUSION: The high-risk chromosomal aberrations del(17p13), t(4;14), and +1q21 are adverse prognostic factors in SMM just as they are in active myeloma, independent of tumor mass. Hyperdiploidy is the first example for an adverse prognostic factor in SMM of opposite predictiveness in active myeloma. Risk association of chromosomal aberrations is not only a priori treatment dependent (predictive) but is also an intrinsic property of myeloma cells (prognostic). PMID- 24145348 TI - Oral contraceptives and risk of ovarian cancer and breast cancer among high-risk women: a systematic review and meta-analysis. AB - PURPOSE: To estimate the risks of ovarian cancer and breast cancer associated with oral contraceptive (OC) use among women at elevated risk owing to mutations in BRCA1/2 or a strong family history. METHODS: We searched PubMed, Embase, the Cochrane Database of Systematic Reviews, and ClinicalTrials.gov for studies published 2000 to 2012 that evaluated associations between OC use and breast or ovarian cancer among women who are carriers of a BRCA1/2 mutation or have a family history of breast or ovarian cancer. RESULTS: From 6,476 unique citations, we identified six studies examining ovarian cancer risk in BRCA1/2 mutation carriers and eight studies examining breast cancer risk in BRCA1/2 mutation carriers. For BRCA1/2 mutation carriers combined, meta-analysis showed an inverse association between OC use and ovarian cancer (odds ratio [OR], 0.58; 95% CI, 0.46 to 0.73) and a nonstatistically significant association with breast cancer (OR, 1.21; 95% CI, 0.93 to 1.58). Findings were similar when examining BRCA1 and BRCA2 mutation carriers separately. Data were inadequate to perform meta-analyses examining duration or timing of use. For women with a family history of ovarian or breast cancer, we identified four studies examining risk for ovarian cancer and three for breast cancer, but differences between studies precluded combining the data for meta-analyses, and no overall pattern could be discerned. CONCLUSION: Our analyses suggest that associations between ever use of OCs and ovarian and breast cancer among women who are BRCA1 or BRCA2 mutation carriers are similar to those reported for the general population. PMID- 24145349 TI - BCCIP suppresses tumor initiation but is required for tumor progression. AB - Dysfunctions of genome caretaker genes contribute to genomic instability and tumor initiation. Because many of the caretaker genes are also essential for cell viability, permanent loss of function of these genes would prohibit further tumor progression. How essential caretaker genes contribute to tumorigenesis is not fully understood. Here, we report a "hit-and-run" mode of action for an essential caretaker gene in tumorigenesis. Using a BRCA2-interacting protein BCCIP as the platform, we found that a conditional BCCIP knockdown and concomitant p53 deletion caused rapid development of medulloblastomas, which bear a wide spectrum of alterations involving the Sonic Hedgehog (Shh) pathway, consistent with a caretaker responsibility of BCCIP on genomic integrity. Surprisingly, the progressed tumors have spontaneously lost the transgenic BCCIP knockdown cassette and restored BCCIP expression. Thus, a transient downregulation of BCCIP, but not necessarily a permanent mutation, is sufficient to initiate tumorigenesis. After the malignant transformation has been accomplished and autonomous cancer growth has been established, BCCIP reverses its role from a tumor-initiation suppressor to become a requisite for progression. This exemplifies a new type of tumor suppressor, which is distinct from the classical tumor suppressors that are often permanently abrogated during tumorigenesis. It has major implications on how a nonmutagenic or transient regulation of essential caretaker gene contributes to tumorigenesis. We further suggest that BCCIP represents a paradoxical class of modulators for tumorigenesis as a suppressor for initiation but a requisite for progression (SIRP). PMID- 24145350 TI - miRNA-95 mediates radioresistance in tumors by targeting the sphingolipid phosphatase SGPP1. AB - Radiation resistance poses a major clinical challenge in cancer treatment, but little is known about how microRNA (miR) may regulate this phenomenon. In this study, we used next-generation sequencing to perform an unbiased comparison of miR expression in PC3 prostate cancer cells rendered resistant to fractionated radiation treatment. One miR candidate found to be upregulated by ionizing radiation was miR-95, the enforced expression of which promoted radiation resistance in a variety of cancer cells. miR-95 overexpression recapitulated an aggressive phenotype including increased cellular proliferation, deregulated G2-M checkpoint following ionizing radiation, and increased invasive potential. Using combined in silico prediction and microarray expression analyses, we identified and validated the sphingolipid phosphatase SGPP1, an antagonist of sphingosine-1 phosphate signaling, as a target of miR-95 that promotes radiation resistance. Consistent with this finding, cell treatment with FTY720, a clinically approved small molecule inhibitor of S1P signaling, sensitized miR-95 overexpressing cells to radiation treatment. In vivo assays extended the significance of these results, showing that miR-95 overexpression increased tumor growth and resistance to radiation treatment in tumor xenografts. Furthermore, reduced tumor necrosis and increased cellular proliferation were seen after radiation treatment of miR 95 overexpressing tumors compared with control tumors. Finally, miR-95 expression was increased in human prostate and breast cancer specimens compared with normal tissue. Together, our work reveals miR-95 expression as a critical determinant of radiation resistance in cancer cells. PMID- 24145351 TI - A novel model of dormancy for bone metastatic breast cancer cells. AB - Mortality of patients with breast cancer is due overwhelmingly to metastatic spread of the disease. Although dissemination is an early event in breast cancer, extended periods of cancer cell dormancy can result in long latency of metastasis development. Deciphering the mechanisms underlying cancer cell dormancy and subsequent growth at the metastatic site would facilitate development of strategies to interfere with these processes. A challenge in this undertaking has been the lack of models for cancer cell dormancy. We have established novel experimental systems that model the bone microenvironment of the breast cancer metastatic niche. These systems are based on 3D cocultures of breast cancer cells with cell types predominant in bone marrow. We identified conditions in which cancer cells are dormant and conditions in which they proliferate. Dormant cancer cells were able to proliferate upon transfer into supportive microenvironment or upon manipulation of signaling pathways that control dormancy. These experimental systems will be instrumental for metastasis studies, particularly the study of cellular dormancy. PMID- 24145352 TI - Silencing of the miR-17~92 cluster family inhibits medulloblastoma progression. AB - Medulloblastoma, originating in the cerebellum, is the most common malignant brain tumor in children. Medulloblastoma consists of four major groups where constitutive activation of the Sonic Hedgehog (SHH) signaling pathway is a hallmark of one group. Mouse and human SHH medulloblastomas exhibit increased expression of microRNAs encoded by the miR-17~92 and miR-106b~25 clusters compared with granule progenitors and postmitotic granule neurons. Here, we assessed the therapeutic potential of 8-mer seed-targeting locked nucleic acid (LNA)-modified anti-miR oligonucleotides, termed tiny LNAs, that inhibit microRNA seed families expressed by miR-17~92 and miR-106b~25 in two mouse models of SHH medulloblastomas. We found that tumor cells (medulloblastoma cells) passively took up 8-mer LNA-anti-miRs and specifically inhibited targeted microRNA seed sharing family members. Inhibition of miR-17 and miR-19a seed families by anti miR-17 and anti-miR-19, respectively, resulted in diminished tumor cell proliferation in vitro. Treatment of mice with systemic delivery of anti-miR-17 and anti-miR-19 reduced tumor growth in flank and brain allografts in vivo and prolonged the survival of mice with intracranial transplants, suggesting that inhibition of the miR-17~92 cluster family by 8-mer LNA-anti-miRs might be considered for the treatment of SHH medulloblastomas. PMID- 24145353 TI - Decoding the histone code: Role of H3K36me3 in mismatch repair and implications for cancer susceptibility and therapy. AB - DNA mismatch repair (MMR) maintains genome stability primarily by correcting replication-associated mismatches. Defects in MMR lead to several human cancers characterized by frequent alterations in simple repetitive DNA sequences, a phenomenon called microsatellite instability (MSI). In most MSI-positive cancers, genetic or epigenetic changes that alter the function or expression of an essential MMR protein have been identified. However, in a subset of MSI-positive cancers, epigenetic or genetic changes have not been found in known MMR genes, such that the molecular basis of the MMR defect in these cells remains unknown. A possible answer to this puzzle emerged recently when it was discovered that H3K36me3, a well-studied posttranslational histone modification or histone mark, plays a role in regulating human MMR in vivo. In this review, potential roles for this histone mark to modulate genome stability and cancer susceptibility in human cells are discussed. PMID- 24145355 TI - Real-time liquid biopsy in cancer patients: fact or fiction? AB - Distant metastases harbor unique genomic characteristics not detectable in the corresponding primary tumor of the same patient and metastases located at different sites show a considerable intrapatient heterogeneity. Thus, the mere analysis of the resected primary tumor alone (current standard practice in oncology) or, if possible, even reevaluation of tumor characteristics based on the biopsy of the most accessible metastasis may not reveal sufficient information for treatment decisions. Here, we propose that this dilemma can be solved by a new diagnostic concept: liquid biopsy, that is, analysis of therapeutic targets and drug resistance-conferring gene mutations on circulating tumor cells (CTC) and cell-free circulating tumor DNA (ctDNA) released into the peripheral blood from metastatic deposits. We discuss the current challenges and future perspectives of CTCs and ctDNA as biomarkers in clinical oncology. Both CTCs and ctDNA are interesting complementary technologies that can be used in parallel in future trials assessing new drugs or drug combinations. We postulate that the liquid biopsy concept will contribute to a better understanding and clinical management of drug resistance in patients with cancer. PMID- 24145356 TI - Renal cell carcinoma: trying but failing to improve the only curative therapy. PMID- 24145357 TI - IL-15 improves the cytotoxicity of cytokine-induced killer cells against leukemia cells by upregulating CD3+CD56+ cells and downregulating regulatory T cells as well as IL-35. AB - Cytokine-induced killer (CIK) cells are usually generated from peripheral blood mononuclear cells with the stimulation of IL-2 in vitro. Unlike the conventional IL-2-stimulated CIK cells (IL-2-CIK cells), we investigated the characteristics and potential mechanism of IL-15-stimulated CIK cells (IL-15-CIK cells) in this study. Compared with IL-2-CIK cells, the percentage of CD3CD56 cells was significantly increased in IL-15-CIK cells, but the expression of regulatory T (Treg) cells and IL-35 was significantly decreased in IL-15-CIK cells. Meanwhile, the in vitro cytotoxicity against human myeloid leukemia cells K562 of IL-15-CIK cells was significantly augmented compared with IL-2-CIK cells. These data suggest that IL-15 may improve the cytotoxicity of CIK cells against leukemia cells by upregulating CD3CD56 cells and downregulating Treg cells and IL-35. PMID- 24145358 TI - Listeria monocytogenes (Lm)-LLO immunotherapies reduce the immunosuppressive activity of myeloid-derived suppressor cells and regulatory T cells in the tumor microenvironment. AB - Myeloid-derived suppressor cells (MDSC) and regulatory T cells (Treg) are major components of the immune suppressive cells that potentially limit the effectiveness of an immunotherapy-based treatment. Both of these suppressive cell types have been shown to expand in tumor models and promote T-cell dysfunction that in turn favors tumor progression. This study demonstrates that Listeria monocytogenes (Lm)-LLO immunotherapies effect on the suppressive ability of MDSC and Treg in the tumor microenvironment (TME), resulting in a loss in the ability of these cells to suppress T cells. This alteration of immunosuppression in the TME was an inherent property of all Lm-LLO immunotherapies tested and was independent of the tumor model. The virtually total loss in the suppressive ability of these cells in the TME was linked to the reduction in the expression of arginase I in MDSC and IL-10 in Treg. The results presented here provide insight into a novel mechanism of Lm-LLO immunotherapies that potentially contributes to therapeutic antitumor responses. PMID- 24145359 TI - Immunogenicity of murine solid tumor models as a defining feature of in vivo behavior and response to immunotherapy. AB - Immune profiling has been widely used to probe mechanisms of immune escape in cancer and identify novel targets for therapy. Two emerging uses of immune signatures are to identify likely responders to immunotherapy regimens among individuals with cancer and to understand the variable responses seen among subjects with cancer in immunotherapy trials. Here, the immune profiles of 6 murine solid tumor models (CT26, 4T1, MAD109, RENCA, LLC, and B16) were correlated to tumor regression and survival in response to 2 immunotherapy regimens. Comprehensive profiles for each model were generated using quantitative reverse transcriptase polymerase chain reaction, immunohistochemistry, and flow cytometry techniques, as well as functional studies of suppressor cell populations (regulatory T cells and myeloid-derived suppressor cells), to analyze intratumoral and draining lymphoid tissues. Tumors were stratified as highly or poorly immunogenic, with highly immunogenic tumors showing a significantly greater presence of T-cell costimulatory molecules and immune suppression in the tumor microenvironment. An absence of tumor-infiltrating cytotoxic T lymphocytes and mature dendritic cells was seen across all models. Delayed tumor growth and increased survival with suppressor cell inhibition and tumor-targeted chemokine+/ dendritic cells vaccine immunotherapy were associated with high tumor immunogenicity in these models. Tumor MHC class I expression correlated with the overall tumor immunogenicity level and was a singular marker to predict immunotherapy response with these regimens. By using experimental tumor models as surrogates for human cancers, these studies demonstrate how select features of an immune profile may be utilized to identify patients most likely to respond to immunotherapy regimens. PMID- 24145361 TI - Innovations in minimally invasive hysterectomy. AB - Vaginal hysterectomy, when feasible, is the safest and most cost-effective route for hysterectomy, however, when this is not possible, minimally invasive hysterectomy is often the next best option. Laparoscopic hysterectomy has advanced significantly since 1988, when it was first introduced. Continued improvements in instrumentation, energy sources, hemostatic agents, and vaginal cuff closure techniques have expanded the use of minimally invasive hysterectomy. Variations of laparoscopy, specifically laparoendoscopic single-site surgery hysterectomy and robotic-assisted laparoscopic hysterectomy, have further expanded the role of minimally invasive hysterectomy with the goal of decreasing morbidity. As with any evolving technology, well-designed studies are needed to demonstrate safety, efficacy, and cost-effectiveness before wide-spread adoption. PMID- 24145360 TI - A phase II study of bevacizumab and high-dose interleukin-2 in patients with metastatic renal cell carcinoma: a Cytokine Working Group (CWG) study. AB - Overexpression of vascular endothelial growth factor in renal cell carcinoma (RCC) leads to angiogenesis, tumor progression, and inhibition of immune function. We conducted the first phase II study to estimate the efficacy and safety of bevacizumab with high-dose interleukin-2 (IL-2) therapy in patients with metastatic RCC. Eligible patients had predominantly clear cell metastatic RCC, measurable disease, a Karnofsky Performance Status of >=80%, and adequate end-organ function. IL-2 (600,000 IU/kg) was infused intravenously every 8 hours (maximum 28 doses) during two 5-day cycles on days 1 and 15 of each 84-day course. Bevacizumab (10 mg/kg) was infused intravenously every 2 weeks beginning 2 weeks before initiating IL-2. Fifty of 51 eligible patients from 8 centers were enrolled. Median progression-free survival (PFS) was 11.2 months (90% confidence interval, 5.7-17.7), and 2-year PFS was 18% (90% confidence interval, 8%-27%). Responses included 4 complete (8%) and 11 partial (22%) responses. Toxicities did not exceed those expected from each agent alone. Combining IL-2 plus bevacizumab is feasible, with a response rate and PFS at least as high as reported previously for the single agents. The regimen did not appear to enhance the rate of durable major responses over that of IL-2 alone. PMID- 24145362 TI - Hysterectomy for pelvic organ prolapse: indications and techniques. AB - Pelvic organ prolapse (POP) is the third most common indication for hysterectomy. Although the techniques for hysterectomy do not differ for prolapsed versus nonprolapsed uteri, there are special considerations when performing a hysterectomy for POP. It is important to remember that a hysterectomy is not sufficient treatment for POP; subsequently after the uterus is removed attention should be paid to correcting the vaginal prolapse. A midurethral sling should be considered for all patients undergoing vaginal prolapse surgery to prevent or treat urinary incontinence. PMID- 24145363 TI - Shared decision making and informed consent for hysterectomy. AB - This article provides an overview of the components of the informed consent process for surgery including the components specific to hysterectomy. Shared decision making and informed consent for hysterectomy rely on a mutual understanding by the patient and surgeon of the goals, risks, benefits, and alternatives as well as the choice of hysterectomy technique. The importance of a patient-centered approach is emphasized with an explanation of several communication methods and resources for decision aids that will help to ensure that patients have a good understanding of the items listed above and are able to provide informed consent. PMID- 24145364 TI - Gestational diabetes. Foreword. PMID- 24145365 TI - Nevirapine-raltegravir combination, an NRTI and PI/r sparing regimen, as maintenance antiretroviral therapy in virologically suppressed HIV-1-infected patients. AB - BACKGROUND: Nucleoside reverse transcriptase inhibitor (NRTI) and protease inhibitor (PI)/ritonavir sparing regimens may be useful to some HIV-infected patients. Nevirapine (NVP) and raltegravir (RAL) are both potent antiretrovirals with good long-term safety profiles. METHODS: We retrospectively identified from our electronic database all patients with HIV RNA<50 copies/ml for >6 months on an NVP-containing regimen and no prior exposure to integrase strand transfer inhibitors who were switched to RAL plus NVP. Data was collected for 36 months or until discontinuation of RAL plus NVP for any reason. RESULTS: A total of 39 patients (30 male) were included in this analysis. Median duration of prior antiretroviral therapy was 14 years (IQR 10-17) and median duration with plasma HIV-1 RNA<50 copies/ml prior to switch was 50 months (IQR 22-96). Switched regimens included mainly a boosted PI (n=24) or tenofovir disoproxil fumarate/emtricitabine (n=12). After switching, the percentages of patients with HIV-1 RNA<50 copies/ml were 87.2% (95% CI 76.7, 97.7) and 82.1% (95% CI 70.0, 94.1) at 6 and 12 months, respectively, in the intent-to-treat-exposed analysis, 97.1% (95% CI 91.6, 100) and 94.1% (95% CI 86.2, 100), respectively, in the per protocol analysis. All patients with follow-up to month 24 (n=22) or month 36 (n=14) had HIV-1 RNA<50 copies/ml. One virological failure was observed (related to archived non-nucleoside reverse transcriptase inhibitor resistance mutation). During follow-up, no patient experienced Grade 3 or 4 adverse events. Median values of serum creatinine and lipids significantly improved after switch. CONCLUSIONS: In patients with prolonged HIV-1 RNA<50 copies/ml, switching to NVP RAL combination maintained virological suppression throughout 36 months. This combination deserves further evaluation in patients unable to tolerate NRTI or PI/ritonavir agents. PMID- 24145367 TI - Multilocus analysis of intraspecific differentiation in three endemic bird species from the northern Neotropical dry forest. AB - Among-species phylogeographic concordance provides insight into the common processes driving lineage divergence in a particular region. However, identifying the processes that caused phylogeographic breaks is not always straight forward, and inferring past environmental conditions in combination with documented geologic events is sometimes necessary to explain current patterns. We searched for concordant phylogeographic patterns and investigated their causes in three bird species (Momotus mexicanus, Melanerpes chrysogenys, and Passerina leclancherii) that belong to three different avian orders and are endemic to the northernmost range of the Neotropical dry forest. We obtained mitochondrial DNA (ND2 and COI or cyt b) and nuclear DNA (20454, GAPDH, MUSK, and TGFB) sequences for at least one locus from 162 individuals across all species and defined climatically stable areas using environmental niche model projections for the last 130,000 years to have a paleoenvironmental framework for the phylogeographic results. All three species showed marked phylogeographic structure, with breaks found in roughly similar areas, such as the border between the Mexican states of Guerrero and Oaxaca, and between southern Jalisco and Michoacan. Both of these regions are known biogeographic breaks among other taxa. Patterns of genetic diversity and differentiation were partially compatible with climatically stable areas. Coalescent analyses revealed recent population growth and estimated the deeper haplogroup divergence of all three taxa to have occurred within the last 600,000 years. The phylogeographic patterns found are noteworthy because they are maintained in a relatively small area for bird species with continuous ranges, and highlight a unique situation when compared to phylogeographic patterns found in other studies of Neotropical birds that have stressed the role of geographic barriers to explain intraspecific differentiation. Our results point to a scenario of population isolation resulting in the present phylogeographic structure, likely a result of historical climate fluctuations that have fragmented and reconnected the Neotropical dry forest. This study contributes to a growing body of evidence indicating active diversification of endemic lineages in the northern Neotropical dry forest region. PMID- 24145366 TI - Rescue of recombinant Newcastle disease virus from cDNA. AB - Newcastle disease virus (NDV), the prototype member of the Avulavirus genus of the family Paramyxoviridae(1), is a non-segmented, negative-sense, single stranded, enveloped RNA virus (Figure 1) with potential applications as a vector for vaccination and treatment of human diseases. In-depth exploration of these applications has only become possible after the establishment of reverse genetics techniques to rescue recombinant viruses from plasmids encoding their complete genomes as cDNA(2-5). Viral cDNA can be conveniently modified in vitro by using standard cloning procedures to alter the genotype of the virus and/or to include new transcriptional units. Rescue of such genetically modified viruses provides a valuable tool to understand factors affecting multiple stages of infection, as well as allows for the development and improvement of vectors for the expression and delivery of antigens for vaccination and therapy. Here we describe a protocol for the rescue of recombinant NDVs. PMID- 24145368 TI - Stability of graphitic-like zinc oxide layers under carriers doping: a first principles study. AB - Although theoretical works have demonstrated that (0001) polar films of wurtzite (WZ) ZnO automatically transform into graphitic-like (GP) structures, the experimental realization of GP ZnO is limited to a thickness of several atomic layers. Here, using first-principles calculations, we demonstrated that the stability of GP ZnO is closely related to the concentration of near-free carriers. Our results show that the doped carriers, originating from the rich oxygen vacancies, can effectively screen the polar field, and stabilize the WZ structure. Thus, in order to obtain GP ZnO layers with much thicker films, it is necessary to reduce the near-free carrier concentration. PMID- 24145369 TI - Alzheimer disease: [11C]PBB3--a new PET ligand that identifies tau pathology in the brains of patients with AD. PMID- 24145370 TI - Dementia: Disclosure of results to participants in dementia research. PMID- 24145371 TI - Alzheimer disease and stroke: Cognitive and neuroimaging predictors of AD and stroke. PMID- 24145376 TI - Epistatic interaction between COMT and DTNBP1 modulates prefrontal function in mice and in humans. AB - Cognitive functions are highly heritable and the impact of complex genetic interactions, though undoubtedly important, has received little investigation. Here we show in an animal model and in a human neuroimaging experiment a consistent non-linear interaction between two genes--catechol-O-methyl transferase (COMT) and dysbindin (dys; dystrobrevin-binding protein 1 (DTNBP1))- implicated through different mechanisms in cortical dopamine signaling and prefrontal cognitive function. In mice, we found that a single genetic mutation reducing expression of either COMT or DTNBP1 alone produced working memory advantages, while, in dramatic contrast, genetic reduction of both in the same mouse produced working memory deficits. We found evidence of the same non-linear genetic interaction in prefrontal cortical function in humans. In healthy volunteers (N=176) studied with functional magnetic resonance imaging during a working memory paradigm, individuals homozygous for the COMT rs4680 Met allele that reduces COMT enzyme activity showed a relatively more efficient prefrontal engagement. In contrast, we found that the same genotype was less efficient on the background of a dys haplotype associated with decreased DTNBP1 expression. These results illustrate that epistasis can be functionally multi-directional and non-linear and that a putatively beneficial allele in one epistastic context is a relatively deleterious one in another. These data also have important implications for single-locus association analyses of complex traits. PMID- 24145380 TI - Beyond statistics: a new combinatorial approach to identifying biomarker panels for the early detection and diagnosis of Alzheimer's disease. AB - Interventions to delay or slow Alzheimer's disease (AD) progression are most effective when implemented at pre-clinical disease stages, making early diagnosis essential. For this reason, there is an increasing focus on discovery of predictive biomarkers for AD. Currently, the most reliable predictive biomarkers require either expensive (brain imaging) or invasive (cerebrospinal fluid collection) procedures, leading researchers to strive toward identifying robust biomarkers in blood. Yet promising early results from candidate blood biomarker studies are being refuted by subsequent findings in other cohorts or using different assay technologies. Recent evidence suggests that univariate blood biomarkers are not sufficiently sensitive or specific for the diagnosis of disorders as complex, multifactorial, and heterogeneous as AD. To overcome these present limitations, more consideration must be given to the development of 'biomarker panels' assessing multiple molecular entities. The selection of such panels should draw not only on traditional statistical approaches, whether parametric or non-parametric, but also on newer non-statistical approaches that have the capacity to retain and utilize information about all individual study participants rather than collapsing individual data into group summary values (e.g., mean, variance). These new approaches, facilitated by advances in computing, have the potential to preserve the context of interrelationships between different molecular entities, making them amenable to the development of panels that, as a multivariate collective, can overcome the challenge of individual variability and disease heterogeneity to accurately predict and classify AD. We argue that the AD research community should take fuller advantage of these approaches to accelerate discovery. PMID- 24145379 TI - Response to 'Predicting the diagnosis of autism spectrum disorder using gene pathway analysis'. PMID- 24145383 TI - The foundation of modern spin-crossover. AB - The first explanation of spin-crossover in iron(II) complexes was published in Chem. Commun. in 1966. This has led to nearly 50 years of research in coordination chemistry, crystal engineering, solid state chemistry and physics, and nanoscience involving this class of molecular switch. PMID- 24145382 TI - 1H NMR metabolomic signatures in five brain regions of the AbetaPPswe Tg2576 mouse model of Alzheimer's disease at four ages. AB - In the quest for biomarkers of onset and progression of Alzheimer's disease, a 1H NMR-based metabolomic study was performed on the simple single-transgenic Tg2576 mouse model. These mice develop a slow cognitive decline starting by 6 months and express amyloid plaques from 10 months of age. The metabolic profiles of extracts from five brain regions (frontal cortex, rhinal cortex, hippocampus, midbrain, and cerebellum) of Tg2576 male mice were compared to those of controls, at 1, 3, 6 and 11 months of age. The most obvious differences were due to brain regions. Age was also a discriminating parameter. Metabolic perturbations were already detected in the hippocampus and the rhinal cortex of transgenic mice as early as 1 month of age with decreased concentrations of glutamate (Glu) and N acetylaspartate (NAA) compared to those in wild-type animals. Metabolic changes were more numerous in the hippocampus and the rhinal cortex of 3 month-old transgenic mice and involved Glu, NAA, myo-inositol, creatine, phosphocholine, and gamma-aminobutyric acid (only in the hippocampus) whose concentrations decreased. A metabolic disruption characterized by an increase in the hippocampal concentrations of Glu, creatine, and taurine was detected in 6 month-old transgenic mice. At this time point, the chemical profile of the cerebellum was slightly affected. At 11 months, all the brain regions analyzed (except the frontal cortex) were metabolically altered, with mainly a marked increase in the formation of the neuroprotective metabolites creatine and taurine. Our findings demonstrate that metabolic modifications occur long before the onset of behavioral impairment. PMID- 24145381 TI - Cerebral level of vGlut1 is increased and level of glycine is decreased in TgSwDI mice. AB - Amyloid-beta (Abeta) deposition, one of the main hallmarks of Alzheimer's disease (AD), has been linked to glutamatergic dysfunction, i.e., increased stimulation of synaptic glutamate receptors that may ultimately result in neuronal loss. It was our aim to study the effect of Abeta on multiple components of the glutamatergic system, and therefore we assessed the expression of several glutamate-related proteins and amino acids in the TgSwDI mouse model for Abeta pathology. We determined that in TgSwDI mice, levels of several amino acids are altered, in particular that of glycine. Protein changes were only found in 9 month-old TgSwDI mice with extensive Abeta deposits, with the most prominent change an increased expression of vesicular glutamate transporter 1 (vGlut1). Autoradiography experiments demonstrated that, while the number of activated N methyl-D-aspartic acid (NMDA) receptors was unchanged in TgSwDI mice, binding of the NMDA receptor radioligand [3H]MDL-105,519 to the glycine-binding site of these receptors was increased. Although there are some discrepancies between our results and those found in AD patients, our results suggest that several components of the glutamatergic system might serve as meaningful markers to monitor the progression of AD. PMID- 24145384 TI - Autophagy as a broad antiviral at the placental interface. PMID- 24145385 TI - A quantum chemical perspective on (6-4) photolesion repair by photolyases. AB - (6-4)-Photolyases are fascinating enzymes which repair (6-4)-DNA photolesions utilizing light themselves. It is well known that upon initial photo-excitation of an antenna pigment an electron is transferred from an adjacent FADH(-) cofactor to the photolesion initiating repair, i.e. restoration of the original undamaged DNA bases. Concerning the molecular details of this amazing repair mechanism, the early steps of energy transfer and catalytic electron generation are well understood, the terminal repair mechanism, however, is still a matter of ongoing debate. In this perspective article, recent results of quantum chemical investigations are presented, and their meaning for the repair mechanism under natural conditions is outlined. Consequences of natural light conditions, temperature and thermal equilibration are highlighted when issues like the initial protonation state of the relevant histidines and the lesion, or the direction of electron transfer are discussed. PMID- 24145386 TI - 1,4-Metal migration in a Cp*Rh(III) complex. AB - The reaction of [Cp*RhCl(Ph)(PR3)] (R = Ph or Me) with internal alkynes in the presence of NaBAr(F)4 affords the o-vinylaryl complex with a Rh-(vinyl CH) agostic interaction by way of the alkyne insertion followed by 1,4-rhodium migration, providing the first example of the 1,4-migration of a Rh(III) center. PMID- 24145387 TI - Dual role of 2-tosylaminomethylaniline as a ligand and a nucleophile in the copper-mediated oxidation of methanol. AB - Some reactivity in the oxidation of methanol to formaldehyde has been spectroscopically detected on the methanolic mother liquors of a copper(ii) complex of a Schiff base ligand derived from the condensation of 8 hydroxyquinoline-2-carboxaldehyde and 2-tosylaminomethylaniline. An investigation has shown that 2-tosylaminomethylaniline (HA(TS)) plays a dual role in the oxidative process acting as a N-donor ligand and reacting in situ with formaldehyde, which leads to 3-tosyl-1,2,3,4-tetrahydroquinazoline (1). This was characterized by using both spectroscopic and X-ray diffraction techniques. The influence of 8-hydroxyquinoline derivatives, water and ligand stoichiometry on the yield of 1 was studied. PMID- 24145389 TI - Chromosomal abnormalities in patients with congenital heart disease. AB - BACKGROUND: Chromosomal abnormalities (CAs) are an important cause of congenital heart disease (CHD). OBJECTIVE: Determine the frequency, types and clinical characteristics of CAs identified in a sample of prospective and consecutive patients with CHD. METHOD: Our sample consisted of patients with CHD evaluated during their first hospitalization in a cardiac intensive care unit of a pediatric referral hospital in Southern Brazil. All patients underwent clinical and cytogenetic assessment through high-resolution karyotype. CHDs were classified according to Botto et al. Chi-square, Fisher exact test and odds ratio were used in the statistical analysis (p < 0.05). RESULTS: Our sample consisted of 298 patients, 53.4% males, with age ranging from 1 day to 14 years. CAs were observed in 50 patients (16.8%), and 49 of them were syndromic. As for the CAs, 44 (88%) were numeric (40 patients with +21, 2 with +18, 1 with triple X and one with 45,X) and 6 (12%) structural [2 patients with der(14,21), +21, 1 with i(21q), 1 with dup(17p), 1 with del(6p) and 1 with add(18p)]. The group of CHDs more often associated with CAs was atrioventricular septal defect. CONCLUSIONS: CAs detected through karyotyping are frequent in patients with CHD. Thus, professionals, especially those working in Pediatric Cardiology Services, must be aware of the implications that performing the karyotype can bring to the diagnosis, treatment and prognosis and for genetic counseling of patients and families. PMID- 24145390 TI - Predictors of hospitalization in patients with syncope assisted in specialized cardiology hospital. AB - BACKGROUND: Risk stratification of a syncopal episode is necessary to better differentiate patients needing hospitalization of those who can be safely set home from the emergency department. Currently there are no strict guidelines from our Brazilian medical societies to guide the cardiologist that evaluate patients in an emergency setting. OBJECTIVES: To analyze the criteria adopted for defining the need for hospitalization and compare them with the predictors of high risk for adverse outcome defined by the OESIL score that is already validated in the medical literature for assessing syncope. METHODS: A cross-sectional study of patients diagnosed with syncope during emergency department evaluation at our institution in the year 2011. RESULTS: Of the 46,476 emergency visits made in that year, 216 were due to syncope. Of the 216 patients analyzed, 39% were hospitalized. The variables associated with the need of hospital admission were - having health care insurance, previous known cardiovascular disease, no history of prior stroke, previous syncope and abnormal electrocardiograms during the presentation. In comparison with those not admitted OESIL scores of 0-1 were associated with a greater chance of emergency discharge; 2-3 scores showed greater association with the need of hospitalization. A score > 2 OESIL provided an odds ratio 7.8 times higher for hospitalization compared to score 0 (p <0.001, 95% CI:4,03-15,11). In approximately 39% no etiological cause for syncope was found and in 18% cardiac cause was identified. CONCLUSIONS: Factors such as cardiovascular disease, prior history of syncope, health insurance, no previous stroke and abnormal electrocardiograms, were the criteria used by doctors to indicate hospital admission. There was a good correlation between the clinical judgment and the OESIL criteria for high risk described in literature. PMID- 24145391 TI - Brazilian Portuguese validated version of the Cardiac Anxiety Questionnaire. AB - BACKGROUND: Cardiac Anxiety (CA) is the fear of cardiac sensations, characterized by recurrent anxiety symptoms, in patients with or without cardiovascular disease. The Cardiac Anxiety Questionnaire (CAQ) is a tool to assess CA, already adapted but not validated to Portuguese. OBJECTIVE: This paper presents the three phases of the validation studies of the Brazilian CAQ. METHODS: To extract the factor structure and assess the reliability of the CAQ (phase 1), 98 patients with coronary artery disease were recruited. The aim of phase 2 was to explore the convergent and divergent validity. Fifty-six patients completed the CAQ, along with the Body Sensations Questionnaire (BSQ) and the Social Phobia Inventory (SPIN). To determine the discriminative validity (phase 3), we compared the CAQ scores of two subgroups formed with patients from phase 1 (n = 98), according to the diagnoses of panic disorder and agoraphobia, obtained with the MINI - Mini International Neuropsychiatric Interview. RESULTS: A 2-factor solution was the most interpretable (46.4% of the variance). Subscales were named "Fear and Hypervigilance" (n=9; alpha = 0.88), and "Avoidance", (n = 5; alpha = 0.82). Significant correlation was found between factor 1 and the BSQ total score (p<0.01), but not with factor 2. SPIN factors showed significant correlations with CAQ subscales (p < 0.01). In phase 3, "Cardiac with panic" patients scored significantly higher in CAQ factor 1 (t = -3.42; p < 0.01, CI = -1.02 to -0.27), and higher, but not significantly different, in factor 2 (t = -1.98; p = 0.51, CI = -0.87 to 0.00). CONCLUSIONS: These results provide a definite Brazilian validated version of the CAQ, adequate to clinical and research settings. PMID- 24145392 TI - Coronary computed tomography angiography in the assessment of acute chest pain in the emergency room. AB - The coronary computed tomography angiography has recently emerged as an accurate diagnostic tool in the evaluation of coronary artery disease, providing diagnostic and prognostic data that correlate directly with the data provided by invasive coronary angiography. The association of recent technological developments has allowed improved temporal resolution and better spatial coverage of the cardiac volume with significant reduction in radiation dose, and with the crucial need for more effective protocols of risk stratification of patients with chest pain in the emergency room, recent evaluation of the computed tomography coronary angiography has been performed in the setting of acute chest pain, as about two thirds of invasive coronary angiographies show no significantly obstructive coronary artery disease. In daily practice, without the use of more efficient technologies, such as coronary angiography by computed tomography, safe and efficient stratification of patients with acute chest pain remains a challenge to the medical team in the emergency room. Recently, several studies, including three randomized trials, showed favorable results with the use of this technology in the emergency department for patients with low to intermediate likelihood of coronary artery disease. In this review, we show data resulting from coronary angiography by computed tomography in risk stratification of patients with chest pain in the emergency room, its diagnostic value, prognosis and cost-effectiveness and a critical analysis of recently published multicenter studies. PMID- 24145393 TI - Is conventional cardiac pacing harmful in patients with normal ventricular function? AB - BACKGROUND: Right ventricular pacing may be deleterious in patients with left ventricular dysfunction, but in patients with normal function the impact of this stimulation triggering clinically relevant ventricular dysfunction is not fully established. OBJECTIVES: To evaluate the clinical, echocardiographic findings of patients with previously normal left ventricular function underwent implantation of a pacemaker. METHODS: Observational, cross-sectional study with 20 patients, who underwent implantation of pacemaker, prospectively followed-up, with the following inclusion criteria: normal left ventricular function defined by echocardiography and ventricular pacing higher than 90%. Were evaluated functional class (FC) (New York Heart Association), 6-minute walk test (6MWT), B type natriuretic peptide (BNP), echocardiographic assessment (conventional and dyssynchrony parameters), and quality of life questionnaire (QLQ) (SF-36). The assessment was performed at ten days (t1), four months (t2), eight months (t3), 12 months (t4) and 24 months (t5). RESULTS: Conventional echocardiographic parameters and dyssynchrony parameters showed statistically significant variation over time. The 6MWT, FC, and BNP showed worsening at the end of two years. QLQ showed initial improvement and worsening at the end of two years. CONCLUSION: The implantation of conventional pacemaker was associated with worsening in functional class, worsening in walk test, increased BNP levels, increased duration of QRS, and worsening in some domains of the QLQ at the end of two years. There were no changes in echocardiography measurements (conventional and asynchrony measures). PMID- 24145395 TI - Paraneoplastic leukemoid reaction in solid tumors. AB - Leukemoid reaction is defined as leucocytosis >50,000/MUL. When it occurs in association with a malignancy, and infection or leukemia has been ruled out, it is termed as paraneoplastic leukemoid reaction. A patient presented with fatigue, generalized weakness, and abdominal distension and was incidentally noted to have a white blood cell count of 139,000/MUL. Leukemia was ruled out by peripheral smear and flow cytometry. Computed tomography-guided biopsy of thickened omentum revealed poorly differentiated metastatic carcinoma. He died 3 days after admission with a peak white blood cell count of 180,000/MUL. Previous reports and pathophysiology of paraneoplastic leukemoid reaction are reviewed. PMID- 24145394 TI - Formation and control of Turing patterns in a coherent quantum fluid. AB - Nonequilibrium patterns in open systems are ubiquitous in nature, with examples as diverse as desert sand dunes, animal coat patterns such as zebra stripes, or geographic patterns in parasitic insect populations. A theoretical foundation that explains the basic features of a large class of patterns was given by Turing in the context of chemical reactions and the biological process of morphogenesis. Analogs of Turing patterns have also been studied in optical systems where diffusion of matter is replaced by diffraction of light. The unique features of polaritons in semiconductor microcavities allow us to go one step further and to study Turing patterns in an interacting coherent quantum fluid. We demonstrate formation and control of these patterns. We also demonstrate the promise of these quantum Turing patterns for applications, such as low-intensity ultra-fast all optical switches. PMID- 24145397 TI - Prevention nearby: the influence of the presence of a potential guardian on the severity of child sexual abuse. AB - The main aim of this study was to examine the effect of a potential guardian on the severity of child sexual abuse. Using data obtained on crime events from adult child sexual offenders incarcerated in Queensland (Australia), mixed effects logistic regression analyses were conducted to examine the effect of potential guardianship on the severity of abuse. Controlling for victim and situational characteristics, the analyses showed that the presence of a potential guardian reduced the duration of sexual contact and the occurrence of penetration. Presence of a potential guardian decreased the risk of sexual penetration by 86%. The study highlights the importance of the presence of a potential guardian for reducing the severity of child sexual abuse, and suggests more broadly that guardianship may be an important protective factor in sexual offending. PMID- 24145398 TI - Earth-viewing satellite perspectives on the Chelyabinsk meteor event. AB - Large meteors (or superbolides [Ceplecha Z, et al. (1999) Meteoroids 1998:37 54]), although rare in recorded history, give sobering testimony to civilization's inherent vulnerability. A not-so-subtle reminder came on the morning of February 15, 2013, when a large meteoroid hurtled into the Earth's atmosphere, forming a superbolide near the city of Chelyabinsnk, Russia, ~1,500 km east of Moscow, Russia [Ivanova MA, et al. (2013) Abstracts of the 76th Annual Meeting of the Meteoritical Society, 5366]. The object exploded in the stratosphere, and the ensuing shock wave blasted the city of Chelyabinsk, damaging structures and injuring hundreds. Details of trajectory are important for determining its specific source, the likelihood of future events, and potential mitigation measures. Earth-viewing environmental satellites can assist in these assessments. Here we examine satellite observations of the Chelyabinsk superbolide debris trail, collected within minutes of its entry. Estimates of trajectory are derived from differential views of the significantly parallax displaced [e.g., Hasler AF (1981) Bull Am Meteor Soc 52:194-212] debris trail. The 282.7 +/- 2.3 degrees azimuth of trajectory, 18.5 +/- 3.8 degrees slope to the horizontal, and 17.7 +/- 0.5 km/s velocity derived from these satellites agree well with parameters inferred from the wealth of surface-based photographs and amateur videos. More importantly, the results demonstrate the general ability of Earth-viewing satellites to provide valuable insight on trajectory reconstruction in the more likely scenario of sparse or nonexistent surface observations. PMID- 24145400 TI - Functional traits predict relationship between plant abundance dynamic and long term climate warming. AB - Predicting climate change impact on ecosystem structure and services is one of the most important challenges in ecology. Until now, plant species response to climate change has been described at the level of fixed plant functional types, an approach limited by its inflexibility as there is much interspecific functional variation within plant functional types. Considering a plant species as a set of functional traits greatly increases our possibilities for analysis of ecosystem functioning and carbon and nutrient fluxes associated therewith. Moreover, recently assembled large-scale databases hold comprehensive per-species data on plant functional traits, allowing a detailed functional description of many plant communities on Earth. Here, we show that plant functional traits can be used as predictors of vegetation response to climate warming, accounting in our test ecosystem (the species-rich alpine belt of Caucasus mountains, Russia) for 59% of variability in the per-species abundance relation to temperature. In this mountain belt, traits that promote conservative leaf water economy (higher leaf mass per area, thicker leaves) and large investments in belowground reserves to support next year's shoot buds (root carbon content) were the best predictors of the species increase in abundance along with temperature increase. This finding demonstrates that plant functional traits constitute a highly useful concept for forecasting changes in plant communities, and their associated ecosystem services, in response to climate change. PMID- 24145399 TI - Rapidly evolving R genes in diverse grass species confer resistance to rice blast disease. AB - We show that the genomes of maize, sorghum, and brachypodium contain genes that, when transformed into rice, confer resistance to rice blast disease. The genes are resistance genes (R genes) that encode proteins with nucleotide-binding site (NBS) and leucine-rich repeat (LRR) domains (NBS-LRR proteins). By using criteria associated with rapid molecular evolution, we identified three rapidly evolving R gene families in these species as well as in rice, and transformed a randomly chosen subset of these genes into rice strains known to be sensitive to rice blast disease caused by the fungus Magnaporthe oryzae. The transformed strains were then tested for sensitivity or resistance to 12 diverse strains of M. oryzae. A total of 15 functional blast R genes were identified among 60 NBS-LRR genes cloned from maize, sorghum, and brachypodium; and 13 blast R genes were obtained from 20 NBS-LRR paralogs in rice. These results show that abundant blast R genes occur not only within species but also among species, and that the R genes in the same rapidly evolving gene family can exhibit an effector response that confers resistance to rapidly evolving fungal pathogens. Neither conventional evolutionary conservation nor conventional evolutionary convergence supplies a satisfactory explanation of our findings. We suggest a unique mechanism termed "constrained divergence," in which R genes and pathogen effectors can follow only limited evolutionary pathways to increase fitness. Our results open avenues for R-gene identification that will help to elucidate R-gene vs. effector mechanisms and may yield new sources of durable pathogen resistance. PMID- 24145401 TI - Tenascin-C is an innate broad-spectrum, HIV-1-neutralizing protein in breast milk. AB - Achieving an AIDS-free generation will require elimination of postnatal transmission of HIV-1 while maintaining the nutritional and immunologic benefits of breastfeeding for infants in developing regions. Maternal/infant antiretroviral prophylaxis can reduce postnatal HIV-1 transmission, yet toxicities and the development of drug-resistant viral strains may limit the effectiveness of this strategy. Interestingly, in the absence of antiretroviral prophylaxis, greater than 90% of infants exposed to HIV-1 via breastfeeding remain uninfected, despite daily mucosal exposure to the virus for up to 2 y. Moreover, milk of uninfected women inherently neutralizes HIV-1 and prevents virus transmission in animal models, yet the factor(s) responsible for this anti HIV activity is not well-defined. In this report, we identify a primary HIV-1 neutralizing protein in breast milk, Tenascin-C (TNC). TNC is an extracellular matrix protein important in fetal development and wound healing, yet its antimicrobial properties have not previously been established. Purified TNC captured and neutralized multiclade chronic and transmitted/founder HIV-1 variants, and depletion of TNC abolished the HIV-1-neutralizing activity of milk. TNC bound the HIV-1 Envelope protein at a site that is induced upon engagement of its primary receptor, CD4, and is blocked by V3 loop- (19B and F39F) and chemokine coreceptor binding site-directed (17B) monoclonal antibodies. Our results demonstrate the ability of an innate mucosal host protein found in milk to neutralize HIV-1 via binding to the chemokine coreceptor site, potentially explaining why the majority of HIV-1-exposed breastfed infants are protected against mucosal HIV-1 transmission. PMID- 24145402 TI - Cleavage strongly influences whether soluble HIV-1 envelope glycoprotein trimers adopt a native-like conformation. AB - We compare the antigenicity and conformation of soluble, cleaved vs. uncleaved envelope glycoprotein (Env gp)140 trimers from the subtype A HIV type 1 (HIV-1) strain BG505. The impact of gp120-gp41 cleavage on trimer structure, in the presence or absence of trimer-stabilizing modifications (i.e., a gp120-gp41 disulfide bond and an I559P gp41 change, together designated SOSIP), was assessed. Without SOSIP changes, cleaved trimers disintegrate into their gp120 and gp41-ectodomain (gp41ECTO) components; when only the disulfide bond is present, they dissociate into gp140 monomers. Uncleaved gp140s remain trimeric whether SOSIP substitutions are present or not. However, negative-stain electron microscopy reveals that only cleaved trimers form homogeneous structures resembling native Env spikes on virus particles. In contrast, uncleaved trimers are highly heterogeneous, adopting a variety of irregular shapes, many of which appear to be gp120 subunits dangling from a central core that is presumably a trimeric form of gp41ECTO. Antigenicity studies with neutralizing and nonneutralizing antibodies are consistent with the EM images; cleaved, SOSIP stabilized trimers express quaternary structure-dependent epitopes, whereas uncleaved trimers expose nonneutralizing gp120 and gp41ECTO epitopes that are occluded on cleaved trimers. These findings have adverse implications for using soluble, uncleaved trimers for structural studies, and the rationale for testing uncleaved trimers as vaccine candidates also needs to be reevaluated. PMID- 24145403 TI - B-cell malignancies in microRNA EMU-miR-17~92 transgenic mice. AB - miR-17~92 is a polycistronic microRNA (miR) cluster (consisting of miR-17, miR 18a, miR-19a, miR-19b, miR-20a, and miR-92a) which frequently is overexpressed in several solid and lymphoid malignancies. Loss- and gain-of-function studies have revealed the role of miR-17~92 in heart, lung, and B-cell development and in Myc induced B-cell lymphomas, respectively. Recent studies indicate that overexpression of this locus leads to lymphoproliferation, but no experimental proof that dysregulation of this cluster causes B-cell lymphomas or leukemias is available. To determine whether miR-17~92- overexpression induces lymphomagenesis/leukemogenesis, we generated a B-cell-specific transgenic mouse model with targeted overexpression of this cluster in B cells. The miR-17~92 overexpression was driven by the Eu-enhancer and Ig heavy-chain promoter, and a 3' GFP tag was added to the transgene to track the miR expression. Expression analysis using Northern Blot and quantitative RT-PCR confirmed 2.5- to 25-fold overexpression of all six miRs in the transgenic mice spleens as compared with spleens from wild-type mice. Eu-miR-17~92 mice developed B-cell malignancy by the age of 12-18 mo with a penetrance of ~80% (49% splenic B-cell lymphoproliferative disease, 28% lymphoma). At this stage mice exhibited severe splenomegaly with abnormal B-cell-derived white pulp expansion and enlarged lymph nodes. Interestingly, we found three classes of B-cell lymphomas/leukemias at varying grades of differentiation. These included expansion of CD19(+) and CD5(+) double positive B cells similar to the aggressive form of human B-cell chronic lymphocytic leukemia, B220(+) CD43(+) B1-cell proliferation, and a CD19(+) aggressive diffuse large B-cell lymphoma-like disease, as assessed by flow cytometry and histopathological analysis. PMID- 24145404 TI - Overexpression of calcium-activated potassium channels underlies cortical dysfunction in a model of PTEN-associated autism. AB - De novo phosphatase and tensin homolog on chromosome ten (PTEN) mutations are a cause of sporadic autism. How single-copy loss of PTEN alters neural function is not understood. Here we report that Pten haploinsufficiency increases the expression of small-conductance calcium-activated potassium channels. The resultant augmentation of this conductance increases the amplitude of the afterspike hyperpolarization, causing a decrease in intrinsic excitability. In vivo, this change in intrinsic excitability reduces evoked firing rates of cortical pyramidal neurons but does not alter receptive field tuning. The decreased in vivo firing rate is not associated with deficits in the dendritic integration of synaptic input or with changes in dendritic complexity. These findings identify calcium-activated potassium channelopathy as a cause of cortical dysfunction in the PTEN model of autism and provide potential molecular therapeutic targets. PMID- 24145405 TI - Hyperpolarization without persistent radicals for in vivo real-time metabolic imaging. AB - Hyperpolarized substrates prepared via dissolution dynamic nuclear polarization have been proposed as magnetic resonance imaging (MRI) agents for cancer or cardiac failure diagnosis and therapy monitoring through the detection of metabolic impairments in vivo. The use of potentially toxic persistent radicals to hyperpolarize substrates was hitherto required. We demonstrate that by shining UV light for an hour on a frozen pure endogenous substance, namely the glucose metabolic product pyruvic acid, it is possible to generate a concentration of photo-induced radicals that is large enough to highly enhance the (13)C polarization of the substance via dynamic nuclear polarization. These radicals recombine upon dissolution and a solution composed of purely endogenous products is obtained for performing in vivo metabolic hyperpolarized (13)C MRI with high spatial resolution. Our method opens the way to safe and straightforward preclinical and clinical applications of hyperpolarized MRI because the filtering procedure mandatory for clinical applications and the associated pharmacological tests necessary to prevent contamination are eliminated, concurrently allowing a decrease in the delay between preparation and injection of the imaging agents for improved in vivo sensitivity. PMID- 24145406 TI - Autophosphorylation and Pin1 binding coordinate DNA damage-induced HIPK2 activation and cell death. AB - Excessive genome damage activates the apoptosis response. Protein kinase HIPK2 is a key regulator of DNA damage-induced apoptosis. Here, we deciphered the molecular mechanism of HIPK2 activation and show its relevance for DNA damage induced apoptosis in cellulo and in vivo. HIPK2 autointeracts and site specifically autophosphorylates upon DNA damage at Thr880/Ser882. Autophosphorylation regulates HIPK2 activity and mutation of the phosphorylation acceptor sites deregulates p53 Ser46 phosphorylation and apoptosis in cellulo. Moreover, HIPK2 autophosphorylation is conserved between human and zebrafish and is important for DNA damage-induced apoptosis in vivo. Mechanistically, autophosphorylation creates a binding signal for the phospho-specific isomerase Pin1. Pin1 links HIPK2 activation to its stabilization by inhibiting HIPK2 polyubiquitination and modulating Siah-1-HIPK2 interaction. Concordantly, Pin1 is required for DNA damage-induced HIPK2 stabilization and p53 Ser46 phosphorylation and is essential for induction of apotosis both in cellulo and in zebrafish. Our results identify an evolutionary conserved mechanism regulating DNA damage induced apoptosis. PMID- 24145407 TI - Ultrafast folding kinetics and cooperativity of villin headpiece in single molecule force spectroscopy. AB - In this study we expand the accessible dynamic range of single-molecule force spectroscopy by optical tweezers to the microsecond range by fast sampling. We are able to investigate a single molecule for up to 15 min and with 300-kHz bandwidth as the protein undergoes tens of millions of folding/unfolding transitions. Using equilibrium analysis and autocorrelation analysis of the time traces, the full energetics as well as real-time kinetics of the ultrafast folding of villin headpiece 35 and a stable asparagine 68 alanine/lysine 70 methionine variant can be measured directly. We also performed Brownian dynamics simulations of the response of the bead-DNA system to protein-folding fluctuations. All key features of the force-dependent deflection fluctuations could be reproduced: SD, skewness, and autocorrelation function. Our measurements reveal a difference in folding pathway and cooperativity between wild-type and stable variant of headpiece 35. Autocorrelation force spectroscopy pushes the time resolution of single-molecule force spectroscopy to ~10 us thus approaching the timescales accessible for all atom molecular dynamics simulations. PMID- 24145408 TI - Critical clamp loader processing by an essential AAA+ protease in Caulobacter crescentus. AB - Chromosome replication relies on sliding clamps that are loaded by energy dependent complexes. In Escherichia coli, the ATP-binding clamp loader subunit DnaX exists as both long (tau) and short (gamma) forms generated through programmed translational frameshifting, but the need for both forms is unclear. Here, we show that in Caulobacter crescentus, DnaX isoforms are unexpectedly generated through partial proteolysis by the AAA+ protease casein lytic proteinase (Clp) XP. We find that the normally processive ClpXP protease partially degrades DnaX to produce stable fragments upon encountering a glycine rich region adjacent to a structured domain. Increasing the sequence complexity of this region prevents partial proteolysis and generates a tau-only form of DnaX in vivo that is unable to support viability on its own. Growth is restored when gamma is provided in trans, but these strains are more sensitive to DNA damage compared with strains that can generate gamma through proteolysis. Our work reveals an unexpected mode of partial processing by the ClpXP protease to generate DnaX isoforms, demonstrates that both tau and gamma forms of DnaX are required for Caulobacter viability, and identifies a role for clamp loader diversity in responding to DNA damage. The conservation of distinct DnaX isoforms throughout bacteria despite fundamentally different mechanisms for producing them suggests there may be a conserved need for alternate clamp loader complexes during DNA damaging conditions. PMID- 24145409 TI - Effects of childhood poverty and chronic stress on emotion regulatory brain function in adulthood. AB - Childhood poverty has pervasive negative physical and psychological health sequelae in adulthood. Exposure to chronic stressors may be one underlying mechanism for childhood poverty-health relations by influencing emotion regulatory systems. Animal work and human cross-sectional studies both suggest that chronic stressor exposure is associated with amygdala and prefrontal cortex regions important for emotion regulation. In this longitudinal functional magnetic resonance imaging study of 49 participants, we examined associations between childhood poverty at age 9 and adult neural circuitry activation during emotion regulation at age 24. To test developmental timing, concurrent, adult income was included as a covariate. Adults with lower family income at age 9 exhibited reduced ventrolateral and dorsolateral prefrontal cortex activity and failure to suppress amygdala activation during effortful regulation of negative emotion at age 24. In contrast to childhood income, concurrent adult income was not associated with neural activity during emotion regulation. Furthermore, chronic stressor exposure across childhood (at age 9, 13, and 17) mediated the relations between family income at age 9 and ventrolateral and dorsolateral prefrontal cortex activity at age 24. The findings demonstrate the significance of childhood chronic stress exposures in predicting neural outcomes during emotion regulation in adults who grew up in poverty. PMID- 24145410 TI - Early-life stress has persistent effects on amygdala function and development in mice and humans. AB - Relatively little is known about neurobiological changes attributable to early life stressors (e.g., orphanage rearing), even though they have been associated with a heightened risk for later psychopathology. Human neuroimaging and animal studies provide complementary insights into the neural basis of problem behaviors following stress, but too often are limited by dissimilar experimental designs. The current mouse study manipulates the type and timing of a stressor to parallel the early-life stress experience of orphanage rearing, controlling for genetic and environmental confounds inherent in human studies. The results provide evidence of both early and persistent alterations in amygdala circuitry and function following early-life stress. These effects are not reversed when the stressor is removed nor diminished with the development of prefrontal regulation regions. These neural and behavioral findings are similar to our human findings in children adopted from orphanages abroad in that even following removal from the orphanage, the ability to suppress attention toward potentially threatening information in favor of goal-directed behavior was diminished relative to never institutionalized children. Together, these findings highlight how early-life stress can lead to altered brain circuitry and emotion dysregulation that may increase the risk for psychopathology. PMID- 24145411 TI - Molecular mechanism underlying ethanol activation of G-protein-gated inwardly rectifying potassium channels. AB - Alcohol (ethanol) produces a wide range of pharmacological effects on the nervous system through its actions on ion channels. The molecular mechanism underlying ethanol modulation of ion channels is poorly understood. Here we used a unique method of alcohol-tagging to demonstrate that alcohol activation of a G-protein gated inwardly rectifying potassium (GIRK or Kir3) channel is mediated by a defined alcohol pocket through changes in affinity for the membrane phospholipid signaling molecule phosphatidylinositol 4,5-bisphosphate. Surprisingly, hydrophobicity and size, but not the canonical hydroxyl, were important determinants of alcohol-dependent activation. Altering levels of G protein Gbetagamma subunits, conversely, did not affect alcohol-dependent activation, suggesting a fundamental distinction between receptor and alcohol gating of GIRK channels. The chemical properties of the alcohol pocket revealed here might extend to other alcohol-sensitive proteins, revealing a unique protein microdomain for targeting alcohol-selective therapeutics in the treatment of alcoholism and addiction. PMID- 24145412 TI - Structural and biological studies on bacterial nitric oxide synthase inhibitors. AB - Nitric oxide (NO) produced by bacterial NOS functions as a cytoprotective agent against oxidative stress in Staphylococcus aureus, Bacillus anthracis, and Bacillus subtilis. The screening of several NOS-selective inhibitors uncovered two inhibitors with potential antimicrobial properties. These two compounds impede the growth of B. subtilis under oxidative stress, and crystal structures show that each compound exhibits a unique binding mode. Both compounds serve as excellent leads for the future development of antimicrobials against bacterial NOS-containing bacteria. PMID- 24145413 TI - Isolation and characterization of the positive-sense replicative intermediate of a negative-strand RNA virus. AB - Negative-strand RNA viruses represent a significant class of important pathogens that cause substantial morbidity and mortality in human and animal hosts worldwide. A defining feature of these viruses is that their single-stranded RNA genomes are of opposite polarity to messenger RNA and are replicated through a positive-sense intermediate. The replicative intermediate is thought to exist as a complementary ribonucleoprotein (cRNP) complex. However, isolation of such complexes from infected cells has never been accomplished. Here we report the development of an RNA-based affinity-purification strategy for the isolation of cRNPs of influenza A virus from infected cells. This technological advance enabled the structural and functional characterization of this elusive but essential component of the viral RNA replication machine. The cRNP exhibits a filamentous double-helical organization with defined termini, containing the viral RNA-dependent RNA polymerase (RdRp) at one end and a loop structure at the other end. In vitro characterization of cRNP activity yielded mechanistic insights into the workings of this RNA synthesis machine. In particular, we found that cRNPs show activity in vitro only in the presence of added RdRp. Intriguingly, a replication-inactive RdRp mutant was also able to activate cRNP templated viral RNA synthesis. We propose a model of influenza virus genome replication that relies on the trans-activation of the cRNP-associated RdRp. The described purification strategy should be applicable to other negative-strand RNA viruses and will promote studies into their replication mechanisms. PMID- 24145414 TI - Natural killer cell licensing in mice with inducible expression of MHC class I. AB - Mouse natural killer (NK) cells acquire effector function by an education process termed "licensing" mediated by inhibitory Ly49 receptors which recognize self-MHC class I. Ly49 receptors can bind to MHC class I on targets (in trans) and also to MHC class I on the NK-cell surface (in cis). Which of these interactions regulates NK-cell licensing is not yet clear. Moreover, there are no clear phenotypic differences between licensed and unlicensed NK cells, perhaps because of the previously limited ability to study NK cells with synchronized licensing. Here, we produced MHC class I-deficient mice with inducible MHC class I consisting of a single-chain trimer (SCT), ovalbumin peptide-beta2 microgloblin H2K(b) (SCT-K(b)). Only NK cells with a Ly49 receptor with specificity for SCT K(b) were licensed after MHC class I induction. NK cells were localized consistently in red pulp of the spleen during induced NK-cell licensing, and there were no differences in maturation or activation markers on recently licensed NK cells. Although MHC class I-deficient NK cells were licensed in hosts following SCT-K(b) induction, NK cells were not licensed after induced SCT-K(b) expression on NK cells themselves in MHC class I-deficient hosts. Furthermore, hematopoietic cells with induced SCT-K(b) licensed NK cells more efficiently than stromal cells. These data indicate that trans interaction with MHC class I on hematopoietic cells regulates NK-cell licensing, which is not associated with other obvious phenotypic changes. PMID- 24145415 TI - High-throughput imaging of neuronal activity in Caenorhabditis elegans. AB - Neuronal responses to sensory inputs can vary based on genotype, development, experience, or stochastic factors. Existing neuronal recording techniques examine a single animal at a time, limiting understanding of the variability and range of potential responses. To scale up neuronal recordings, we here describe a system for simultaneous wide-field imaging of neuronal calcium activity from at least 20 Caenorhabditis elegans animals under precise microfluidic chemical stimulation. This increased experimental throughput was used to perform a systematic characterization of chemosensory neuron responses to multiple odors, odor concentrations, and temporal patterns, as well as responses to pharmacological manipulation. The system allowed recordings from sensory neurons and interneurons in freely moving animals, whose neuronal responses could be correlated with behavior. Wide-field imaging provides a tool for comprehensive circuit analysis with elevated throughput in C. elegans. PMID- 24145416 TI - Plasmodium falciparum phosphoethanolamine methyltransferase is essential for malaria transmission. AB - Efficient transmission of Plasmodium species between humans and Anopheles mosquitoes is a major contributor to the global burden of malaria. Gametocytogenesis, the process by which parasites switch from asexual replication within human erythrocytes to produce male and female gametocytes, is a critical step in malaria transmission and Plasmodium genetic diversity. Nothing is known about the pathways that regulate gametocytogenesis and only few of the current drugs that inhibit asexual replication are also capable of inhibiting gametocyte development and blocking malaria transmission. Here we provide genetic and pharmacological evidence indicating that the pathway for synthesis of phosphatidylcholine in Plasmodium falciparum membranes from host serine is essential for parasite gametocytogenesis and malaria transmission. Parasites lacking the phosphoethanolamine N-methyltransferase enzyme, which catalyzes the limiting step in this pathway, are severely altered in gametocyte development, are incapable of producing mature-stage gametocytes, and are not transmitted to mosquitoes. Chemical screening identified 11 inhibitors of phosphoethanolamine N methyltransferase that block parasite intraerythrocytic asexual replication and gametocyte differentiation in the low micromolar range. Kinetic studies in vitro as well as functional complementation assays and lipid metabolic analyses in vivo on the most promising inhibitor NSC-158011 further demonstrated the specificity of inhibition. These studies set the stage for further optimization of NSC-158011 for development of a class of dual activity antimalarials to block both intraerythrocytic asexual replication and gametocytogenesis. PMID- 24145417 TI - Simulation as an engine of physical scene understanding. AB - In a glance, we can perceive whether a stack of dishes will topple, a branch will support a child's weight, a grocery bag is poorly packed and liable to tear or crush its contents, or a tool is firmly attached to a table or free to be lifted. Such rapid physical inferences are central to how people interact with the world and with each other, yet their computational underpinnings are poorly understood. We propose a model based on an "intuitive physics engine," a cognitive mechanism similar to computer engines that simulate rich physics in video games and graphics, but that uses approximate, probabilistic simulations to make robust and fast inferences in complex natural scenes where crucial information is unobserved. This single model fits data from five distinct psychophysical tasks, captures several illusions and biases, and explains core aspects of human mental models and common-sense reasoning that are instrumental to how humans understand their everyday world. PMID- 24145418 TI - Phenformin enhances the therapeutic benefit of BRAF(V600E) inhibition in melanoma. AB - Biguanides, such as the diabetes therapeutics metformin and phenformin, have demonstrated antitumor activity both in vitro and in vivo. The energy-sensing AMP activated protein kinase (AMPK) is known to be a major cellular target of biguanides. Based on our discovery of cross-talk between the AMPK and v-Raf murine sarcoma viral oncogene homolog B1 (BRAF) signaling pathways, we investigated the antitumor effects of combining phenformin with a BRAF inhibitor PLX4720 on the proliferation of BRAF-mutated melanoma cells in vitro and on BRAF driven tumor growth in vivo. Cotreatment of BRAF-mutated melanoma cell lines with phenformin and PLX4720 resulted in synergistic inhibition of cell viability, compared with the effects of the single agent alone. Moreover, treatment with phenformin significantly delayed the development of resistance to PLX4720 in cultured melanoma cells. Biochemical analyses showed that phenformin and PLX4720 exerted cooperative effects on inhibiting mTOR signaling and inducing apoptosis. Noticeably, phenformin selectively targeted subpopulations of cells expressing JARID1B, a marker for slow cycling melanoma cells, whereas PLX4720 selectively targeted JARID1B-negative cells. Finally, in contrast to their use as single agents, the combination of phenformin and PLX4720 induced tumor regression in both nude mice bearing melanoma xenografts and in a genetically engineered BRAF(V600E)/PTEN(null)-driven mouse model of melanoma. These results strongly suggest that significant therapeutic advantage may be achieved by combining AMPK activators such as phenformin with BRAF inhbitors for the treatment of melanoma. PMID- 24145419 TI - Genome duplication and mutations in ACE2 cause multicellular, fast-sedimenting phenotypes in evolved Saccharomyces cerevisiae. AB - Laboratory evolution of the yeast Saccharomyces cerevisiae in bioreactor batch cultures yielded variants that grow as multicellular, fast-sedimenting clusters. Knowledge of the molecular basis of this phenomenon may contribute to the understanding of natural evolution of multicellularity and to manipulating cell sedimentation in laboratory and industrial applications of S. cerevisiae. Multicellular, fast-sedimenting lineages obtained from a haploid S. cerevisiae strain in two independent evolution experiments were analyzed by whole genome resequencing. The two evolved cell lines showed different frameshift mutations in a stretch of eight adenosines in ACE2, which encodes a transcriptional regulator involved in cell cycle control and mother-daughter cell separation. Introduction of the two ace2 mutant alleles into the haploid parental strain led to slow sedimenting cell clusters that consisted of just a few cells, thus representing only a partial reconstruction of the evolved phenotype. In addition to single nucleotide mutations, a whole-genome duplication event had occurred in both evolved multicellular strains. Construction of a diploid reference strain with two mutant ace2 alleles led to complete reconstruction of the multicellular-fast sedimenting phenotype. This study shows that whole-genome duplication and a frameshift mutation in ACE2 are sufficient to generate a fast-sedimenting, multicellular phenotype in S. cerevisiae. The nature of the ace2 mutations and their occurrence in two independent evolution experiments encompassing fewer than 500 generations of selective growth suggest that switching between unicellular and multicellular phenotypes may be relevant for competitiveness of S. cerevisiae in natural environments. PMID- 24145420 TI - Pupil response as a predictor of blindsight in hemianopia. AB - Significantly above-chance detection of stimuli presented within the field defect of patients with postgeniculate lesions is termed "blindsight." It has been proposed that those with blindsight are more likely to benefit from visual rehabilitation by repeated stimulation, leading to increased visual sensitivity within their field defect. Establishing the incidence of blindsight and developing an objective and reliable method for its detection are of great interest. Sudden onsets of a grating pattern in the absence of any change in light flux result in a transient constriction of the pupil, termed "pupil grating response." The existence of pupil grating responses for stimuli presented within the blindfield has previously been reported in a hemianopic patient and two monkeys with removal of the primary visual cortex unilaterally. Here, we have systematically investigated the presence of a spatial channel of processing at a range of spatial frequencies using a psychophysical forced-choice technique and obtained the corresponding pupil responses in the blindfield of 19 hemianopic patients. In addition, in 13 cases we determined the pupil responses in a sighted field location that matched the blindfield eccentricities. Our findings demonstrate that blindfield pupil responses are similar to those for the sighted field, but attenuated in amplitude. Pupillometry correctly characterized the presence or absence of a significant psychophysical response and thus is worth measuring in the cortically blindfields as a predictor of intact psychophysical capacity. The incidence of blindsight where detection performance had been investigated psychophysically over a range of spatial frequencies was 70%. PMID- 24145421 TI - Structural basis for substrate specificity in the Escherichia coli maltose transport system. AB - ATP-binding cassette (ABC) transporters are molecular pumps that harness the chemical energy of ATP hydrolysis to translocate solutes across the membrane. The substrates transported by different ABC transporters are diverse, ranging from small ions to large proteins. Although crystal structures of several ABC transporters are available, a structural basis for substrate recognition is still lacking. For the Escherichia coli maltose transport system, the selectivity of sugar binding to maltose-binding protein (MBP), the periplasmic binding protein, does not fully account for the selectivity of sugar transport. To obtain a molecular understanding of this observation, we determined the crystal structures of the transporter complex MBP-MalFGK2 bound with large malto-oligosaccharide in two different conformational states. In the pretranslocation structure, we found that the transmembrane subunit MalG forms two hydrogen bonds with malto oligosaccharide at the reducing end. In the outward-facing conformation, the transmembrane subunit MalF binds three glucosyl units from the nonreducing end of the sugar. These structural features explain why modified malto-oligosaccharides are not transported by MalFGK2 despite their high binding affinity to MBP. They also show that in the transport cycle, substrate is channeled from MBP into the transmembrane pathway with a polarity such that both MBP and MalFGK2 contribute to the overall substrate selectivity of the system. PMID- 24145422 TI - Cyclic 100-ka (glacial-interglacial) migration of subseafloor redox zonation on the Peruvian shelf. AB - The coupling of subseafloor microbial life to oceanographic and atmospheric conditions is poorly understood. We examined diagenetic imprints and lipid biomarkers of past subseafloor microbial activity to evaluate its response to glacial-interglacial cycles in a sedimentary section drilled on the Peruvian shelf (Ocean Drilling Program Leg 201, Site 1229). Multiple and distinct layers of diagenetic barite and dolomite, i.e., minerals that typically form at the sulfate-methane transition (SMT), occur at much shallower burial depth than the present SMT around 30 meters below seafloor. These shallow layers co-occur with peaks of (13)C-depleted archaeol, a molecular fossil of anaerobic methane oxidizing Archaea. Present-day, non-steady state distributions of dissolved sulfate also suggest that the SMT is highly sensitive to variations in organic carbon flux to the surface shelf sediments that may lead to shoaling of the SMT. Reaction-transport modeling substantiates our hypothesis that shallow SMTs occur in response to cyclic sediment deposition with a high organic carbon flux during interglacials and a low organic carbon flux during glacial stages. Long diffusion distances expectedly dampen the response of deeply buried microbial communities to changes in sediment deposition and other oceanographic drivers over relatively short geological time scales, e.g., glacial-interglacial periods. However, our study demonstrates how dynamically sediment biogeochemistry of the Peru Margin has responded to glacial-interglacial change and how these changes are now preserved in the geological record. Such changes in subsurface biogeochemical zonation need to be taken into account to assess the role of the subseafloor biosphere in global element and redox cycling. PMID- 24145423 TI - Human genome-guided identification of memory-modulating drugs. AB - In the last decade there has been an exponential increase in knowledge about the genetic basis of complex human traits, including neuropsychiatric disorders. It is not clear, however, to what extent this knowledge can be used as a starting point for drug identification, one of the central hopes of the human genome project. The aim of the present study was to identify memory-modulating compounds through the use of human genetic information. We performed a multinational collaborative study, which included assessment of aversive memory--a trait central to posttraumatic stress disorder--and a gene-set analysis in healthy individuals. We identified 20 potential drug target genes in two genomewide corrected gene sets: the neuroactive ligand-receptor interaction and the long term depression gene set. In a subsequent double-blind, placebo-controlled study in healthy volunteers, we aimed at providing a proof of concept for the genome guided identification of memory modulating compounds. Pharmacological intervention at the neuroactive ligand-receptor interaction gene set led to significant reduction of aversive memory. The findings demonstrate that genome information, along with appropriate data mining methodology, can be used as a starting point for the identification of memory-modulating compounds. PMID- 24145424 TI - Temporal motifs reveal homophily, gender-specific patterns, and group talk in call sequences. AB - Recent studies on electronic communication records have shown that human communication has complex temporal structure. We study how communication patterns that involve multiple individuals are affected by attributes such as sex and age. To this end, we represent the communication records as a colored temporal network where node color is used to represent individuals' attributes, and identify patterns known as temporal motifs. We then construct a null model for the occurrence of temporal motifs that takes into account the interaction frequencies and connectivity between nodes of different colors. This null model allows us to detect significant patterns in call sequences that cannot be observed in a static network that uses interaction frequencies as link weights. We find sex-related differences in communication patterns in a large dataset of mobile phone records and show the existence of temporal homophily, the tendency of similar individuals to participate in communication patterns beyond what would be expected on the basis of their average interaction frequencies. We also show that temporal patterns differ between dense and sparse neighborhoods in the network. Because also this result is independent of interaction frequencies, it can be seen as an extension of Granovetter's hypothesis to temporal networks. PMID- 24145425 TI - Gate-tunable carbon nanotube-MoS2 heterojunction p-n diode. AB - The p-n junction diode and field-effect transistor are the two most ubiquitous building blocks of modern electronics and optoelectronics. In recent years, the emergence of reduced dimensionality materials has suggested that these components can be scaled down to atomic thicknesses. Although high-performance field-effect devices have been achieved from monolayered materials and their heterostructures, a p-n heterojunction diode derived from ultrathin materials is notably absent and constrains the fabrication of complex electronic and optoelectronic circuits. Here we demonstrate a gate-tunable p-n heterojunction diode using semiconducting single-walled carbon nanotubes (SWCNTs) and single-layer molybdenum disulfide as p-type and n-type semiconductors, respectively. The vertical stacking of these two direct band gap semiconductors forms a heterojunction with electrical characteristics that can be tuned with an applied gate bias to achieve a wide range of charge transport behavior ranging from insulating to rectifying with forward-to-reverse bias current ratios exceeding 10(4). This heterojunction diode also responds strongly to optical irradiation with an external quantum efficiency of 25% and fast photoresponse <15 MUs. Because SWCNTs have a diverse range of electrical properties as a function of chirality and an increasing number of atomically thin 2D nanomaterials are being isolated, the gate-tunable p-n heterojunction concept presented here should be widely generalizable to realize diverse ultrathin, high-performance electronics and optoelectronics. PMID- 24145426 TI - No known hominin species matches the expected dental morphology of the last common ancestor of Neanderthals and modern humans. AB - A central problem in paleoanthropology is the identity of the last common ancestor of Neanderthals and modern humans ([N-MH]LCA). Recently developed analytical techniques now allow this problem to be addressed using a probabilistic morphological framework. This study provides a quantitative reconstruction of the expected dental morphology of the [N-MH]LCA and an assessment of whether known fossil species are compatible with this ancestral position. We show that no known fossil species is a suitable candidate for being the [N-MH]LCA and that all late Early and Middle Pleistocene taxa from Europe have Neanderthal dental affinities, pointing to the existence of a European clade originated around 1 Ma. These results are incongruent with younger molecular divergence estimates and suggest at least one of the following must be true: (i) European fossils and the [N-MH]LCA selectively retained primitive dental traits; (ii) molecular estimates of the divergence between Neanderthals and modern humans are underestimated; or (iii) phenotypic divergence and speciation between both species were decoupled such that phenotypic differentiation, at least in dental morphology, predated speciation. PMID- 24145427 TI - Number sense in infancy predicts mathematical abilities in childhood. AB - Human infants in the first year of life possess an intuitive sense of number. This preverbal number sense may serve as a developmental building block for the uniquely human capacity for mathematics. In support of this idea, several studies have demonstrated that nonverbal number sense is correlated with mathematical abilities in children and adults. However, there has been no direct evidence that infant numerical abilities are related to mathematical abilities later in childhood. Here, we provide evidence that preverbal number sense in infancy predicts mathematical abilities in preschool-aged children. Numerical preference scores at 6 months of age correlated with both standardized math test scores and nonsymbolic number comparison scores at 3.5 years of age, suggesting that preverbal number sense facilitates the acquisition of numerical symbols and mathematical abilities. This relationship held even after controlling for general intelligence, indicating that preverbal number sense imparts a unique contribution to mathematical ability. These results validate the many prior studies purporting to show number sense in infancy and support the hypothesis that mathematics is built upon an intuitive sense of number that predates language. PMID- 24145428 TI - Long-term fate of nitrate fertilizer in agricultural soils. AB - Increasing diffuse nitrate loading of surface waters and groundwater has emerged as a major problem in many agricultural areas of the world, resulting in contamination of drinking water resources in aquifers as well as eutrophication of freshwaters and coastal marine ecosystems. Although empirical correlations between application rates of N fertilizers to agricultural soils and nitrate contamination of adjacent hydrological systems have been demonstrated, the transit times of fertilizer N in the pedosphere-hydrosphere system are poorly understood. We investigated the fate of isotopically labeled nitrogen fertilizers in a three-decade-long in situ tracer experiment that quantified not only fertilizer N uptake by plants and retention in soils, but also determined to which extent and over which time periods fertilizer N stored in soil organic matter is rereleased for either uptake in crops or export into the hydrosphere. We found that 61-65% of the applied fertilizers N were taken up by plants, whereas 12-15% of the labeled fertilizer N were still residing in the soil organic matter more than a quarter century after tracer application. Between 8 12% of the applied fertilizer had leaked toward the hydrosphere during the 30-y observation period. We predict that additional exports of (15)N-labeled nitrate from the tracer application in 1982 toward the hydrosphere will continue for at least another five decades. Therefore, attempts to reduce agricultural nitrate contamination of aquatic systems must consider the long-term legacy of past applications of synthetic fertilizers in agricultural systems and the nitrogen retention capacity of agricultural soils. PMID- 24145429 TI - Pneumatic oscillator circuits for timing and control of integrated microfluidics. AB - Frequency references are fundamental to most digital systems, providing the basis for process synchronization, timing of outputs, and waveform synthesis. Recently, there has been growing interest in digital logic systems that are constructed out of microfluidics rather than electronics, as a possible means toward fully integrated laboratory-on-a-chip systems that do not require any external control apparatus. However, the full realization of this goal has not been possible due to the lack of on-chip frequency references, thus requiring timing signals to be provided from off-chip. Although microfluidic oscillators have been demonstrated, there have been no reported efforts to characterize, model, or optimize timing accuracy, which is the fundamental metric of a clock. Here, we report pneumatic ring oscillator circuits built from microfluidic valves and channels. Further, we present a compressible-flow analysis that differs fundamentally from conventional circuit theory, and we show the utility of this physically based model for the optimization of oscillator stability. Finally, we leverage microfluidic clocks to demonstrate circuits for the generation of phase-shifted waveforms, self-driving peristaltic pumps, and frequency division. Thus, pneumatic oscillators can serve as on-chip frequency references for microfluidic digital logic circuits. On-chip clocks and pumps both constitute critical building blocks on the path toward achieving autonomous laboratory-on-a-chip devices. PMID- 24145430 TI - Plus-end tracking proteins, CLASPs, and a viral Akt mimic regulate herpesvirus induced stable microtubule formation and virus spread. AB - Although microtubules (MTs) frequently form highly dynamic networks, subsets of MTs become stabilized in response to environmental cues and function as specialized tracks for vesicle and macromolecular trafficking. MT stabilization is controlled by specialized plus-end tracking proteins (+TIPs) whose accumulation at the MT ends is facilitated by the end-binding protein, EB1, and regulated by various signaling pathways. As cargoes themselves, viruses are dependent on MTs for their intracellular movement. Although many viruses affect MT organization, the potential contribution of MT stabilization by +TIPs to infection remains unknown. Here we show that early in infection of primary human fibroblasts, herpes simplex virus type 1 (HSV-1) disrupts the centrosome, the primary MT organizing center in many cell types. As infection progresses HSV-1 induces the formation of stable MT subsets through inactivation of glycogen synthase kinase 3beta by the viral Ser/Thr kinase, Us3. Stable MT formation is reduced in cells infected with Us3 mutants and those stable MTs that form cluster around the trans-Golgi network. Downstream of glycogen synthase kinase 3beta, cytoplasmic linker-associated proteins (CLASPs), specialized host +TIPs that control MT formation at the trans-Golgi network and cortical capture, are specifically required for virus-induced MT stabilization and HSV-1 spread. Our findings demonstrate the biological importance of +TIPs to viral infection and suggest that HSV-1 has evolved to exploit the trans-Golgi network as an alternate MT organizing center to facilitate virus spread. PMID- 24145431 TI - Hyperammonemia in cirrhosis induces transcriptional regulation of myostatin by an NF-kappaB-mediated mechanism. AB - Loss of muscle mass, or sarcopenia, is nearly universal in cirrhosis and adversely affects patient outcome. The underlying cross-talk between the liver and skeletal muscle mediating sarcopenia is not well understood. Hyperammonemia is a consistent abnormality in cirrhosis due to impaired hepatic detoxification to urea. We observed elevated levels of ammonia in both plasma samples and skeletal muscle biopsies from cirrhotic patients compared with healthy controls. Furthermore, skeletal muscle from cirrhotics had increased expression of myostatin, a known inhibitor of skeletal muscle accretion and growth. In vivo studies in mice showed that hyperammonemia reduced muscle mass and strength and increased myostatin expression in wild-type compared with postdevelopmental myostatin knockout mice. We postulated that hyperammonemia is an underlying link between hepatic dysfunction in cirrhosis and skeletal muscle loss. Therefore, murine C2C12 myotubes were treated with ammonium acetate resulting in intracellular concentrations similar to those in cirrhotic muscle. In this system, we demonstrate that hyperammonemia stimulated myostatin expression in a NF-kappaB-dependent manner. This finding was also observed in primary murine muscle cell cultures. Hyperammonemia triggered activation of IkappaB kinase, NF kappaB nuclear translocation, binding of the NF-kappaB p65 subunit to specific sites within the myostatin promoter, and stimulation of myostatin gene transcription. Pharmacologic inhibition or gene silencing of NF-kappaB abolished myostatin up-regulation under conditions of hyperammonemia. Our work provides unique insights into hyperammonemia-induced myostatin expression and suggests a mechanism by which sarcopenia develops in cirrhotic patients. PMID- 24145432 TI - Regulation of onset of female mating and sex pheromone production by juvenile hormone in Drosophila melanogaster. AB - Juvenile hormone (JH) coordinates timing of female reproductive maturation in most insects. In Drosophila melanogaster, JH plays roles in both mating and egg maturation. However, very little is known about the molecular pathways associated with mating. Our behavioral analysis of females genetically lacking the corpora allata, the glands that produce JH, showed that they were courted less by males and mated later than control females. Application of the JH mimic, methoprene, to the allatectomized females just after eclosion rescued both the male courtship and the mating delay. Our studies of the null mutants of the JH receptors, Methoprene tolerant (Met) and germ cell-expressed (gce), showed that lack of Met in Met(27) females delayed the onset of mating, whereas lack of Gce had little effect. The Met(27) females were shown to be more attractive but less behaviorally receptive to copulation attempts. The behavioral but not the attractiveness phenotype was rescued by the Met genomic transgene. Analysis of the female cuticular hydrocarbon profiles showed that corpora allata ablation caused a delay in production of the major female-specific sex pheromones (the 7,11-C27 and -C29 dienes) and a change in the cuticular hydrocarbon blend. In the Met(27) null mutant, by 48 h, the major C27 diene was greatly increased relative to wild type. In contrast, the gce(2.5k) null mutant females were courted similarly to control females despite changes in certain cuticular hydrocarbons. Our findings indicate that JH acts primarily via Met to modulate the timing of onset of female sex pheromone production and mating. PMID- 24145435 TI - Making sense of big data. PMID- 24145434 TI - Recognition of synthetic glycopeptides by HIV-1 broadly neutralizing antibodies and their unmutated ancestors. AB - Current HIV-1 vaccines elicit strain-specific neutralizing antibodies. Broadly neutralizing antibodies (BnAbs) are not induced by current vaccines, but are found in plasma in ~20% of HIV-1-infected individuals after several years of infection. One strategy for induction of unfavored antibody responses is to produce homogeneous immunogens that selectively express BnAb epitopes but minimally express dominant strain-specific epitopes. Here we report that synthetic, homogeneously glycosylated peptides that bind avidly to variable loop 1/2 (V1V2) BnAbs PG9 and CH01 bind minimally to strain-specific neutralizing V2 antibodies that are targeted to the same envelope polypeptide site. Both oligomannose derivatization and conformational stabilization by disulfide-linked dimer formation of synthetic V1V2 peptides were required for strong binding of V1V2 BnAbs. An HIV-1 vaccine should target BnAb unmutated common ancestor (UCA) B cell receptors of naive B cells, but to date no HIV-1 envelope constructs have been found that bind to the UCA of V1V2 BnAb PG9. We demonstrate herein that V1V2 glycopeptide dimers bearing Man5GlcNAc2 glycan units bind with apparent nanomolar affinities to UCAs of V1V2 BnAbs PG9 and CH01 and with micromolar affinity to the UCA of a V2 strain-specific antibody. The higher-affinity binding of these V1V2 glycopeptides to BnAbs and their UCAs renders these glycopeptide constructs particularly attractive immunogens for targeting subdominant HIV-1 envelope V1V2 neutralizing antibody-producing B cells. PMID- 24145433 TI - Prediction and experimental validation of enzyme substrate specificity in protein structures. AB - Structural Genomics aims to elucidate protein structures to identify their functions. Unfortunately, the variation of just a few residues can be enough to alter activity or binding specificity and limit the functional resolution of annotations based on sequence and structure; in enzymes, substrates are especially difficult to predict. Here, large-scale controls and direct experiments show that the local similarity of five or six residues selected because they are evolutionarily important and on the protein surface can suffice to identify an enzyme activity and substrate. A motif of five residues predicted that a previously uncharacterized Silicibacter sp. protein was a carboxylesterase for short fatty acyl chains, similar to hormone-sensitive-lipase-like proteins that share less than 20% sequence identity. Assays and directed mutations confirmed this activity and showed that the motif was essential for catalysis and substrate specificity. We conclude that evolutionary and structural information may be combined on a Structural Genomics scale to create motifs of mixed catalytic and noncatalytic residues that identify enzyme activity and substrate specificity. PMID- 24145436 TI - Landscape of somatic mutations and clonal evolution in mantle cell lymphoma. AB - Mantle cell lymphoma (MCL) is an aggressive tumor, but a subset of patients may follow an indolent clinical course. To understand the mechanisms underlying this biological heterogeneity, we performed whole-genome and/or whole-exome sequencing on 29 MCL cases and their respective matched normal DNA, as well as 6 MCL cell lines. Recurrently mutated genes were investigated by targeted sequencing in an independent cohort of 172 MCL patients. We identified 25 significantly mutated genes, including known drivers such as ataxia-telangectasia mutated (ATM), cyclin D1 (CCND1), and the tumor suppressor TP53; mutated genes encoding the anti apoptotic protein BIRC3 and Toll-like receptor 2 (TLR2); and the chromatin modifiers WHSC1, MLL2, and MEF2B. We also found NOTCH2 mutations as an alternative phenomenon to NOTCH1 mutations in aggressive tumors with a dismal prognosis. Analysis of two simultaneous or subsequent MCL samples by whole genome/whole-exome (n = 8) or targeted (n = 19) sequencing revealed subclonal heterogeneity at diagnosis in samples from different topographic sites and modulation of the initial mutational profile at the progression of the disease. Some mutations were predominantly clonal or subclonal, indicating an early or late event in tumor evolution, respectively. Our study identifies molecular mechanisms contributing to MCL pathogenesis and offers potential targets for therapeutic intervention. PMID- 24145437 TI - BC-box protein domain-related mechanism for VHL protein degradation. AB - The tumor suppressor VHL (von Hippel-Lindau) protein is a substrate receptor for Ubiquitin Cullin Ring Ligase complexes (CRLs), containing a BC-box domain that associates to the adaptor Elongin B/C. VHL targets hypoxia-inducible factor 1alpha to proteasome-dependent degradation. Gam1 is an adenoviral protein, which also possesses a BC-box domain that interacts with the host Elongin B/C, thereby acting as a viral substrate receptor. Gam1 associates with both Cullin2 and Cullin5 to form CRL complexes targeting the host protein SUMO enzyme SAE1 for proteasomal degradation. We show that Gam1 protein expression induces VHL protein degradation leading to hypoxia-inducible factor 1alpha stabilization and induction of its downstream targets. We also characterize the CRL-dependent mechanism that drives VHL protein degradation via proteasome. Interestingly, expression of Suppressor of Cytokine Signaling (SOCS) domain-containing viral proteins and cellular BC-box proteins leads to VHL protein degradation, in a SOCS domain-containing manner. Our work underscores the exquisite ability of viral domains to uncover new regulatory mechanisms by hijacking key cellular proteins. PMID- 24145438 TI - GmNAC30 and GmNAC81 integrate the endoplasmic reticulum stress- and osmotic stress-induced cell death responses through a vacuolar processing enzyme. AB - Prolonged endoplasmic reticulum and osmotic stress synergistically activate the stress-induced N-rich protein-mediated signaling that transduces a cell death signal by inducing GmNAC81 (GmNAC6) in soybean. To identify novel regulators of the stress-induced programmed cell death (PCD) response, we screened a two-hybrid library for partners of GmNAC81. We discovered another member of the NAC (NAM ATAF1,2-CUC2) family, GmNAC30, which binds to GmNAC81 in the nucleus of plant cells to coordinately regulate common target promoters that harbor the core cis regulatory element TGTG[TGC]. We found that GmNAC81 and GmNAC30 can function either as transcriptional repressors or activators and cooperate to enhance the transcriptional regulation of common target promoters, suggesting that heterodimerization may be required for the full regulation of gene expression. Accordingly, GmNAC81 and GmNAC30 display overlapping expression profiles in response to multiple environmental and developmental stimuli. Consistent with a role in PCD, GmNAC81 and GmNAC30 bind in vivo to and transactivate hydrolytic enzyme promoters in soybean protoplasts. A GmNAC81/GmNAC30 binding site is located in the promoter of the caspase-1-like vacuolar processing enzyme (VPE) gene, which is involved in PCD in plants. We demonstrated that the expression of GmNAC81 and GmNAC30 fully transactivates the VPE gene in soybean protoplasts and that this transactivation was associated with an increase in caspase-1-like activity. Collectively, our results indicate that the stress-induced GmNAC30 cooperates with GmNAC81 to activate PCD through the induction of the cell death executioner VPE. PMID- 24145439 TI - Mutualists and antagonists drive among-population variation in selection and evolution of floral display in a perennial herb. AB - Spatial variation in the direction of selection drives the evolution of adaptive differentiation. However, few experimental studies have examined the relative importance of different environmental factors for variation in selection and evolutionary trajectories in natural populations. Here, we combine 8 y of observational data and field experiments to assess the relative importance of mutualistic and antagonistic interactions for spatial variation in selection and short-term evolution of a genetically based floral display dimorphism in the short-lived perennial herb Primula farinosa. Natural populations of this species include two floral morphs: long-scaped plants that present their flowers well above the ground and short-scaped plants with flowers positioned close to the ground. The direction and magnitude of selection on scape morph varied among populations, and so did the frequency of the short morph (median 19%, range 0 100%; n = 69 populations). A field experiment replicated at four sites demonstrated that variation in the strength of interactions with grazers and pollinators were responsible for among-population differences in relative fitness of the two morphs. Selection exerted by grazers favored the short-scaped morph, whereas pollinator-mediated selection favored the long-scaped morph. Moreover, variation in selection among natural populations was associated with differences in morph frequency change, and the experimental removal of grazers at nine sites significantly reduced the frequency of the short-scaped morph over 8 y. The results demonstrate that spatial variation in intensity of grazing and pollination produces a selection mosaic, and that changes in biotic interactions can trigger rapid genetic changes in natural plant populations. PMID- 24145440 TI - Cell-body rocking is a dominant mechanism for flagellar synchronization in a swimming alga. AB - The unicellular green alga Chlamydomonas swims with two flagella that can synchronize their beat. Synchronized beating is required to swim both fast and straight. A long-standing hypothesis proposes that synchronization of flagella results from hydrodynamic coupling, but the details are not understood. Here, we present realistic hydrodynamic computations and high-speed tracking experiments of swimming cells that show how a perturbation from the synchronized state causes rotational motion of the cell body. This rotation feeds back on the flagellar dynamics via hydrodynamic friction forces and rapidly restores the synchronized state in our theory. We calculate that this "cell-body rocking" provides the dominant contribution to synchronization in swimming cells, whereas direct hydrodynamic interactions between the flagella contribute negligibly. We experimentally confirmed the two-way coupling between flagellar beating and cell body rocking predicted by our theory. PMID- 24145441 TI - Microenvironmental reprogramming by three-dimensional culture enables dermal papilla cells to induce de novo human hair-follicle growth. AB - De novo organ regeneration has been observed in several lower organisms, as well as rodents; however, demonstrating these regenerative properties in human cells and tissues has been challenging. In the hair follicle, rodent hair follicle derived dermal cells can interact with local epithelia and induce de novo hair follicles in a variety of hairless recipient skin sites. However, multiple attempts to recapitulate this process in humans using human dermal papilla cells in human skin have failed, suggesting that human dermal papilla cells lose key inductive properties upon culture. Here, we performed global gene expression analysis of human dermal papilla cells in culture and discovered very rapid and profound molecular signature changes linking their transition from a 3D to a 2D environment with early loss of their hair-inducing capacity. We demonstrate that the intact dermal papilla transcriptional signature can be partially restored by growth of papilla cells in 3D spheroid cultures. This signature change translates to a partial restoration of inductive capability, and we show that human dermal papilla cells, when grown as spheroids, are capable of inducing de novo hair follicles in human skin. PMID- 24145442 TI - Therapeutic potential of proteasome inhibitors in congenital erythropoietic porphyria. AB - Congenital erythropoietic porphyria (CEP) is a rare autosomal recessive disorder characterized by uroporphyrinogen III synthase (UROS) deficiency resulting in massive porphyrin accumulation in blood cells, which is responsible for hemolytic anemia and skin photosensitivity. Among the missense mutations actually described up to now in CEP patients, the C73R and the P248Q mutations lead to a profound UROS deficiency and are usually associated with a severe clinical phenotype. We previously demonstrated that the UROS(C73R) mutant protein conserves intrinsic enzymatic activity but triggers premature degradation in cellular systems that could be prevented by proteasome inhibitors. We show evidence that the reduced kinetic stability of the UROS(P248Q) mutant is also responsible for increased protein turnover in human erythroid cells. Through the analysis of EGFP-tagged versions of UROS enzyme, we demonstrate that both UROS(C73R) and UROS(P248Q) are equally destabilized in mammalian cells and targeted to the proteasomal pathway for degradation. We show that a treatment with proteasomal inhibitors, but not with lysosomal inhibitors, could rescue the expression of both EGFP-UROS mutants. Finally, in CEP mice (Uros(P248Q/P248Q)) treated with bortezomib (Velcade), a clinically approved proteasome inhibitor, we observed reduced porphyrin accumulation in circulating RBCs and urine, as well as reversion of skin photosensitivity on bortezomib treatment. These results of medical importance pave the way for pharmacologic treatment of CEP disease by preventing certain enzymatically active UROS mutants from early degradation by using proteasome inhibitors or chemical chaperones. PMID- 24145443 TI - Increased dry-season length over southern Amazonia in recent decades and its implication for future climate projection. AB - We have observed that the dry-season length (DSL) has increased over southern Amazonia since 1979, primarily owing to a delay of its ending dates (dry-season end, DSE), and is accompanied by a prolonged fire season. A poleward shift of the subtropical jet over South America and an increase of local convective inhibition energy in austral winter (June-August) seem to cause the delay of the DSE in austral spring (September-November). These changes cannot be simply linked to the variability of the tropical Pacific and Atlantic Oceans. Although they show some resemblance to the effects of anthropogenic forcings reported in the literature, we cannot attribute them to this cause because of inadequate representation of these processes in the global climate models that were presented in the Intergovernmental Panel on Climate Change's Fifth Assessment Report. These models significantly underestimate the variability of the DSE and DSL and their controlling processes. Such biases imply that the future change of the DSE and DSL may be underestimated by the climate projections provided by the Intergovernmental Panel on Climate Change's Fifth Assessment Report models. Although it is not clear whether the observed increase of the DSL will continue in the future, were it to continue at half the rate of that observed, the long DSL and fire season that contributed to the 2005 drought would become the new norm by the late 21st century. The large uncertainty shown in this study highlights the need for a focused effort to better understand and simulate these changes over southern Amazonia. PMID- 24145444 TI - Metallofullerene and fullerene formation from condensing carbon gas under conditions of stellar outflows and implication to stardust. AB - Carbonaceous presolar grains of supernovae origin have long been isolated and are determined to be the carrier of anomalous (22)Ne in ancient meteorites. That exotic (22)Ne is, in fact, the decay isotope of relatively short-lived (22)Na formed by explosive nucleosynthesis, and therefore, a selective and rapid Na physical trapping mechanism must take place during carbon condensation in supernova ejecta. Elucidation of the processes that trap Na and produce large carbon molecules should yield insight into carbon stardust enrichment and formation. Herein, we demonstrate that Na effectively nucleates formation of Na@C60 and other metallofullerenes during carbon condensation under highly energetic conditions in oxygen- and hydrogen-rich environments. Thus, fundamental carbon chemistry that leads to trapping of Na is revealed, and should be directly applicable to gas-phase chemistry involving stellar environments, such as supernova ejecta. The results indicate that, in addition to empty fullerenes, metallofullerenes should be constituents of stellar/circumstellar and interstellar space. In addition, gas-phase reactions of fullerenes with polycyclic aromatic hydrocarbons are investigated to probe "build-up" and formation of carbon stardust, and provide insight into fullerene astrochemistry. PMID- 24145445 TI - Regulation of IL-1beta-induced NF-kappaB by hydroxylases links key hypoxic and inflammatory signaling pathways. AB - Hypoxia is a prominent feature of chronically inflamed tissues. Oxygen-sensing hydroxylases control transcriptional adaptation to hypoxia through the regulation of hypoxia-inducible factor (HIF) and nuclear factor kappaB (NF-kappaB), both of which can regulate the inflammatory response. Furthermore, pharmacologic hydroxylase inhibitors reduce inflammation in multiple animal models. However, the underlying mechanism(s) linking hydroxylase activity to inflammatory signaling remains unclear. IL-1beta, a major proinflammatory cytokine that regulates NF-kappaB, is associated with multiple inflammatory pathologies. We demonstrate that a combination of prolyl hydroxylase 1 and factor inhibiting HIF hydroxylase isoforms regulates IL-1beta-induced NF-kappaB at the level of (or downstream of) the tumor necrosis factor receptor-associated factor 6 complex. Multiple proteins of the distal IL-1beta-signaling pathway are subject to hydroxylation and form complexes with either prolyl hydroxylase 1 or factor inhibiting HIF. Thus, we hypothesize that hydroxylases regulate IL-1beta signaling and subsequent inflammatory gene expression. Furthermore, hydroxylase inhibition represents a unique approach to the inhibition of IL-1beta-dependent inflammatory signaling. PMID- 24145446 TI - Neuroprotective Sirtuin ratio reversed by ApoE4. AB - The canonical pathogenesis of Alzheimer's disease links the expression of apolipoprotein E epsilon4 allele (ApoE) to amyloid precursor protein (APP) processing and Abeta peptide accumulation by a set of mechanisms that is incompletely defined. The development of a simple system that focuses not on a single variable but on multiple factors and pathways would be valuable both for dissecting the underlying mechanisms and for identifying candidate therapeutics. Here we show that, although both ApoE3 and ApoE4 associate with APP with nanomolar affinities, only ApoE4 significantly (i) reduces the ratio of soluble amyloid precursor protein alpha (sAPPalpha) to Abeta; (ii) reduces Sirtuin T1 (SirT1) expression, resulting in markedly differing ratios of neuroprotective SirT1 to neurotoxic SirT2; (iii) triggers Tau phosphorylation and APP phosphorylation; and (iv) induces programmed cell death. We describe a subset of drug candidates that interferes with the APP-ApoE interaction and returns the parameters noted above to normal. Our data support the hypothesis that neuronal connectivity, as reflected in the ratios of critical mediators such as sAPPalpha:Abeta, SirT1:SirT2, APP:phosphorylated (p)-APP, and Tau:p-Tau, is programmatically altered by ApoE4 and offer a simple system for the identification of program mediators and therapeutic candidates. PMID- 24145447 TI - Charge-dependent secretion of an intrinsically disordered protein via the autotransporter pathway. AB - Autotransporters are a large class of virulence proteins produced by Gram negative bacteria. They contain an N-terminal extracellular ("passenger") domain that folds into a beta-helical structure and a C-terminal beta-barrel ("beta") domain that anchors the protein to the outer membrane. Because the periplasm lacks ATP, the source of energy that drives passenger domain secretion is unknown. The prevailing model postulates that vectorial folding of the beta-helix in the extracellular space facilitates unidirectional secretion of the passenger domain. In this study we used a chimeric protein composed of the 675-residue receptor-binding domain (RD) of the Bordetella pertussis adenylate cyclase toxin CyaA fused to the C terminus of the Escherichia coli O157:H7 autotransporter EspP to test this hypothesis. The RD is a highly acidic, repetitive polypeptide that is intrinsically disordered in the absence of calcium. Surprisingly, we found that the RD moiety was efficiently secreted when it remained in an unfolded conformation. Furthermore, we found that neutralizing or reversing the charge of acidic amino acid clusters stalled translocation in the vicinity of the altered residues. These results challenge the vectorial folding model and, together with the finding that naturally occurring passenger domains are predominantly acidic, provide evidence that a net negative charge plays a significant role in driving the translocation reaction. PMID- 24145448 TI - Neuronal activity regulates astrocytic Nrf2 signaling. AB - Nuclear factor erythroid 2-related factor 2 (Nrf2), the transcriptional master regulator of the stress-induced antioxidant response, plays a key role in neuronal resistance to oxidative stress and glutamate-induced excitotoxicity. Nrf2-mediated neuroprotection is primarily conferred by astrocytes both in vitro and in vivo, but little is known about physiologic signals that regulate neuronal and astrocytic Nrf2 signaling. Here, we report that activity of the Nrf2 pathway in the brain is fine-tuned through a regulatory loop between neurons and astrocytes: elevated neuronal activity leads to secretion of glutamate and other soluble factors, which activate the astrocytic Nrf2 pathway through a signaling cascade that involves group I metabotropic glutamate receptors and intracellular Ca(2+). Therefore, regulation of endogenous antioxidant signaling is one of the functions of the neuron-astrocyte tripartite synapse; by matching the astrocyte neuroprotective capacity to the degree of activity in adjacent neuronal synapses, this regulatory mechanism may limit the physiologic costs associated with Nrf2 activation. PMID- 24145449 TI - Ferrous iron-dependent drug delivery enables controlled and selective release of therapeutic agents in vivo. AB - The precise targeting of cytotoxic agents to specific cell types or cellular compartments is of significant interest in medicine, with particular relevance for infectious diseases and cancer. Here, we describe a method to exploit aberrant levels of mobile ferrous iron (Fe(II)) for selective drug delivery in vivo. This approach makes use of a 1,2,4-trioxolane moiety, which serves as an Fe(II)-sensitive "trigger," making drug release contingent on Fe(II)-promoted trioxolane fragmentation. We demonstrate in vivo validation of this approach with the Plasmodium berghei model of murine malaria. Malaria parasites produce high concentrations of mobile ferrous iron as a consequence of their catabolism of host hemoglobin in the infected erythrocyte. Using activity-based probes, we successfully demonstrate the Fe(II)-dependent and parasite-selective delivery of a potent dipeptidyl aminopeptidase inhibitor. We find that delivery of the compound in its Fe(II)-targeted form leads to more sustained target inhibition with greatly reduced off-target inhibition of mammalian cathepsins. This selective drug delivery translates into improved efficacy and tolerability. These findings demonstrate the utility of a purely chemical means to achieve selective drug targeting in vivo. This approach may find useful application in parasitic infections and more broadly in any disease state characterized by aberrant production of reactive ferrous iron. PMID- 24145450 TI - Profile of Dennis Lo. PMID- 24145451 TI - Nonequilibrium landscape theory of neural networks. AB - The brain map project aims to map out the neuron connections of the human brain. Even with all of the wirings mapped out, the global and physical understandings of the function and behavior are still challenging. Hopfield quantified the learning and memory process of symmetrically connected neural networks globally through equilibrium energy. The energy basins of attractions represent memories, and the memory retrieval dynamics is determined by the energy gradient. However, the realistic neural networks are asymmetrically connected, and oscillations cannot emerge from symmetric neural networks. Here, we developed a nonequilibrium landscape-flux theory for realistic asymmetrically connected neural networks. We uncovered the underlying potential landscape and the associated Lyapunov function for quantifying the global stability and function. We found the dynamics and oscillations in human brains responsible for cognitive processes and physiological rhythm regulations are determined not only by the landscape gradient but also by the flux. We found that the flux is closely related to the degrees of the asymmetric connections in neural networks and is the origin of the neural oscillations. The neural oscillation landscape shows a closed-ring attractor topology. The landscape gradient attracts the network down to the ring. The flux is responsible for coherent oscillations on the ring. We suggest the flux may provide the driving force for associations among memories. We applied our theory to rapid-eye movement sleep cycle. We identified the key regulation factors for function through global sensitivity analysis of landscape topography against wirings, which are in good agreements with experiments. PMID- 24145452 TI - Protein kinase and ribonuclease domains of IRE1 confer stress tolerance, vegetative growth, and reproductive development in Arabidopsis. AB - The unfolded protein response (UPR) endows plants with the capacity to perceive, respond, and protect themselves from adverse environmental conditions. The UPR signaling pathway in Arabidopsis has two "arms," one arm involving the bifunctional protein kinase (PK)/ribonuclease, IRE1, a RNA splicing enzyme, and another involving membrane-associated transcription factors, such as basic leucine zipper transcription factor 28 (bZIP28). Because of functional redundancies, single gene mutations in the plant UPR signaling pathway generally have not resulted in prominent phenotypes. In this study we generated multiple mutations in the UPR signaling pathway, such as an ire1a ire1b double mutant, which showed defects in stress tolerance and vegetative growth and development. Complementation of ire1a ire1b with constructs containing site-specific mutations in the PK or RNase domains of IRE1b demonstrated that a functional RNase domain is required for endoplasmic reticulum stress tolerance, and that both the PK and RNase domains are required for normal vegetative growth under unstressed conditions. Root growth under stress conditions was dependent on the splicing target of IRE1b, bZIP60 mRNA, and on regulated IRE1-dependent decay of target genes. However, root and shoot growth in the absence of stress was independent of bZIP60. Blocking both arms of the UPR signaling pathway in a triple ire1a ire1b bzip28 mutant was lethal, impacting pollen viability under unstressed conditions. Complementation with IRE1b constructs showed that both the PK and RNase domains are required for normal gametophyte development, but bZIP60 is not. Hence, the UPR plays a critical role in stress tolerance, and in normal vegetative growth and reproductive development in plants. PMID- 24145453 TI - Neonicotinoid clothianidin adversely affects insect immunity and promotes replication of a viral pathogen in honey bees. AB - Large-scale losses of honey bee colonies represent a poorly understood problem of global importance. Both biotic and abiotic factors are involved in this phenomenon that is often associated with high loads of parasites and pathogens. A stronger impact of pathogens in honey bees exposed to neonicotinoid insecticides has been reported, but the causal link between insecticide exposure and the possible immune alteration of honey bees remains elusive. Here, we demonstrate that the neonicotinoid insecticide clothianidin negatively modulates NF-kappaB immune signaling in insects and adversely affects honey bee antiviral defenses controlled by this transcription factor. We have identified in insects a negative modulator of NF-kappaB activation, which is a leucine-rich repeat protein. Exposure to clothianidin, by enhancing the transcription of the gene encoding this inhibitor, reduces immune defenses and promotes the replication of the deformed wing virus in honey bees bearing covert infections. This honey bee immunosuppression is similarly induced by a different neonicotinoid, imidacloprid, but not by the organophosphate chlorpyriphos, which does not affect NF-kappaB signaling. The occurrence at sublethal doses of this insecticide induced viral proliferation suggests that the studied neonicotinoids might have a negative effect at the field level. Our experiments uncover a further level of regulation of the immune response in insects and set the stage for studies on neural modulation of immunity in animals. Furthermore, this study has implications for the conservation of bees, as it will contribute to the definition of more appropriate guidelines for testing chronic or sublethal effects of pesticides used in agriculture. PMID- 24145454 TI - Nitrite produced by Mycobacterium tuberculosis in human macrophages in physiologic oxygen impacts bacterial ATP consumption and gene expression. AB - In high enough concentrations, such as produced by inducible nitric oxide synthase (iNOS), reactive nitrogen species (RNS) can kill Mycobacterium tuberculosis (Mtb). Lesional macrophages in macaques and humans with tuberculosis express iNOS, and mice need iNOS to avoid succumbing rapidly to tuberculosis. However, Mtb's own ability to produce RNS is rarely considered, perhaps because nitrate reduction to nitrite is only prominent in axenic Mtb cultures at oxygen tensions <=1%. Here we found that cultures of Mtb-infected human macrophages cultured at physiologic oxygen tensions produced copious nitrite. Surprisingly, the nitrite arose from the Mtb, not the macrophages. Mtb responded to nitrite by ceasing growth; elevating levels of ATP through reduced consumption; and altering the expression of 120 genes associated with adaptation to acid, hypoxia, nitric oxide, oxidative stress, and iron deprivation. The transcriptomic effect of endogenous nitrite was distinct from that of nitric oxide. Thus, whether or not Mtb is hypoxic, the host expresses iNOS, or hypoxia impairs the action of iNOS, Mtb in vivo is likely to encounter RNS by producing nitrite. Endogenous nitrite may slow Mtb's growth and prepare it to resist host stresses while the pathogen waits for immunopathology to promote its transmission. PMID- 24145456 TI - Mechanisms of atrial mitral regurgitation: insights using 3D transoesophageal echo. AB - AIMS: Functional mitral regurgitation (FMR) is a consequence of mitral annular enlargement, leaflet tethering and reduced co-aptation. The importance of the left atrium (LA) as a cause of mitral regurgitation (MR) is less clear. We applied a co-aptation index using three-dimensional (3D) transoesophageal echocardiography to FMR and MR secondary to LA dilatation (atrial mitral regurgitation, AMR). METHODS AND RESULTS: Seventy-two patients underwent comprehensive 3D echo studies: FMR (n = 19); AMR (n = 33); and 20 controls. We recorded: LV size and function; LA dimensions; mitral annular area (MVA); and leaflet area in early and late systole. MVA fractional change was defined: (MVA late systole - MVA early systole)/MVA late systole * 100%; the co-aptation index was defined: (leaflet area early systole - leaflet area late systole)/leaflet area early systole * 100%. Despite normal LV size and function in AMR, MVA was increased similarly to FMR (AMR 12.86 cm(2) vs. FMR 12.33 cm(2), P = ns; both P < 0.01 vs. controls 8.83 cm(2)), and MVA fractional change similarly reduced (AMR 5.1% vs. FMR 6.3%; P = ns; both P < 0.001 vs. controls 14.6%). The co-aptation index was reduced in both MR groups (FMR 6.6% vs. AMR 7.0%, P = ns; both P < 0.001 vs. controls 19.6%). After multivariate analysis, the co-aptation index (chi(2) = 41.2) and MVA fractional change (chi(2) = 22.1) remained the strongest predictors of MR (both P < 0.001 for the model). A co-aptation index of <=13% was 96% sensitive and 90% specific for the presence of MR. CONCLUSION: LA dilatation leads to MVA enlargement, reduced leaflet co-aptation and MR even without LV dilatation. A co-aptation index describes this in vivo. This work provides insights into the mechanism of AMR. PMID- 24145455 TI - Monoallelic loss of tumor suppressor GRIM-19 promotes tumorigenesis in mice. AB - Gene-associated with retinoid-interferon induced mortality-19 (GRIM-19), a STAT3 inhibitory protein, was isolated as a growth-suppressive gene product using a genome-wide expression knockdown screen. We and others have shown a loss of expression and occurrence of mutations in the GRIM-19 gene in a variety of primary human cancers, indicating its potential role as tumor suppressor. To help investigate its role in tumor development in vivo, we generated a genetically modified mouse in which Grim-19 can be conditionally inactivated. Deletion of Grim-19 in the skin significantly increased the susceptibility of mice to chemical carcinogenesis, resulting in development of squamous cell carcinomas. These tumors had high Stat3 activity and an increased expression of Stat3 responsive genes. Loss of Grim-19 also caused mitochondrial electron transport dysfunction resulting from failure to assemble electron transport chain complexes and altered the expression of several cellular genes involved in glycolysis. Surprisingly, the deletion of a single copy of the Grim-19 gene was sufficient to promote carcinogenesis and formation of invasive squamous cell carcinomas. These observations highlight the critical role of GRIM-19 as a tumor suppressor. PMID- 24145458 TI - A classic yet unusual case: the full spectrum of bicuspid aortic valve disease. PMID- 24145457 TI - Diastolic function assessed from tagged MRI predicts heart failure and atrial fibrillation over an 8-year follow-up period: the multi-ethnic study of atherosclerosis. AB - OBJECTIVES: The strain relaxation index (SRI), a novel diastolic functional parameter derived from tagged magnetic resonance imaging (MRI), is used to assess myocardial deformation during left ventricular relaxation. We investigated whether diastolic function indexed by SRI predicts heart failure (HF) and atrial fibrillation (AF) over an 8-year follow-up. METHODS: As a part of the multi ethnic study of atherosclerosis, 1544 participants free of known cardiovascular disease (CVD) underwent tagged MRI in 2000-02. Harmonic phase analysis was used to compute circumferential strain. Standard parameters, early diastolic strain rate (EDSR) and the peak torsion recoil rate were calculated. An SRI was calculated as difference between post-systolic and systolic times of the strain peaks, divided by the EDSR peak. It was normalized by the total interval of relaxation. Over an 8-year follow-up period, we defined AF (n = 57) or HF (n = 36) as combined (n = 80) end-points. Cox regression assessed the ability of SRI to predict events adjusted for risk factors and markers of subclinical disease. Integrated discrimination index (IDI) and net reclassification index (NRI) of SRI, compared with conventional indices, were also assessed. RESULTS: The hazard ratio for SRI remained significant for the combined HF and AF end-points as well as for HF alone after adjustment. For the combined end-point, IDI was 1.5% (P < 0.05) and NRI was 11.4% (P < 0.05) for SRI. Finally, SRI was more robust than all other existing cardiovascular magnetic resonance diastolic functional parameters. CONCLUSION: SRI predicts HF and AF over an 8-year follow-up period in a large population free of known CVD, independent of established risk factors and markers of subclinical CVD. PMID- 24145460 TI - Cardiovascular benefits of daily haemodialysis: peeling the onion. PMID- 24145459 TI - Anaemia management in non-dialysis chronic kidney disease (CKD) patients: a multicentre prospective study in renal clinics. AB - BACKGROUND: Knowledge on anaemia management in non-dialysis chronic kidney disease (ND-CKD) patients regularly followed in renal clinics is scarce although being essential to identifying areas of therapeutic improvement. METHODS: We prospectively evaluated anaemia management in two visits, performed 6 months apart, in 755 prevalent ND-CKD stage 3b-5 patients followed in 19 nephrology clinics from >=6 months. Anaemia was defined as severe (Hb <11 g/dL) or mild (Hb: 11-13.5 in males and 11-12 g/dL in females); iron deficiency (ID) was defined as transferrin saturation (TSAT) <20% and/or ferritin <100 ng/mL. Primary endpoint was the change of anaemia and ID prevalence between baseline and 6-month visit. Secondary endpoint was the prevalence of clinical inertia to either ESA or iron supplementation, that is, the lack of ESA or iron prescription despite Hb <11 g/dL or ID. RESULTS: Age was 69 +/- 13 years and GFR 27.5 +/- 10.0 mL/min/1.73 m(2); male gender, diabetes and prior cardiovascular disease were 57.2, 30.1 and 30.1%, respectively. Prevalence of severe and mild anaemia was 18.0 and 44.0% at baseline and remained unchanged at Month 6 (19.3 and 43.2%). ID was prevalent at both visits (60.1 and 60.9%). Clinical inertia to ESA was similar at baseline and at Month 6 (39.6 and 34.2%, respectively, P = 0.487) and it was less frequent than clinical inertia to iron therapy (75.7 and 72.0%, respectively). CONCLUSIONS: This study shows that anaemia prevalence is unexpectedly high in the setting of tertiary nephrology care. This was due to a persistent clinical inertia in the anaemia management, remarkable for iron supplementation and less critical, but still significant, for ESA treatment. PMID- 24145461 TI - Living kidney donor estimated glomerular filtration rate and recipient graft survival. AB - BACKGROUND: Kidney transplants from living donors with an estimated glomerular filtration rate (eGFR) < 80 mL/min per 1.73 m(2) may be at risk for increased graft loss compared with a recipient who receives a kidney from a living donor with a higher eGFR. METHODS: This retrospective cohort study considered 2057 living kidney donors and their recipients from July 1993 to March 2010 at five centres in Ontario, Canada, and linked them to population-based, universal healthcare databases. Recipients were divided into five groups based on their donor's baseline eGFR. The median (inter-quartile range) for the lowest eGFR group was 73 (68-77) mL/min per 1.73 m(2). Subjects were followed for a median of 6 years (IQR: 3-10 years). RESULTS: There was no significant difference in the adjusted hazard ratio (HR) for graft loss when comparing recipients in each eGFR category to the referent group (>=110 mL/min per 1.73 m(2)). The adjusted HRs (95% CI) from the lowest (<80 mL/min per 1.73 m(2)) to highest (100-109.9 mL/min per 1.73 m(2)) eGFR categories were 1.27 (0.84-1.92), 1.43 (0.96-2.14), 1.23 (0.86-1.77) and 1.23 (0.85-1.77), respectively. Similar results were observed when dichotomizing the baseline donor eGFR using a cut-point of 80 mL/min per 1.73 m(2)-adjusted HR 1.01 [95% confidence interval (95% CI) (0.76-1.44)]. CONCLUSIONS: Further research in this setting should clarify whether additional tests (i.e. measured GFR) should be performed in potential donors whose eGFR is considered borderline, whether eGFR values should be standardized to body surface area, and the outcomes for donors after nephrectomy. PMID- 24145462 TI - Approaches to increase physical activity. PMID- 24145464 TI - Implications of the implementation of the reduced dose limits for the lens of the eye: an IRPA activity. PMID- 24145463 TI - Inhibition of glycolysis attenuates 4-hydroxynonenal-dependent autophagy and exacerbates apoptosis in differentiated SH-SY5Y neuroblastoma cells. AB - How cellular metabolic activities regulate autophagy and determine the susceptibility to oxidative stress and ultimately cell death in neuronal cells is not well understood. An important example of oxidative stress is 4-hydroxynonenal (HNE), which is a lipid peroxidation product that is formed during oxidative stress, and accumulates in neurodegenerative diseases causing damage. The accumulation of toxic oxidation products such as HNE, is a prevalent feature of neurodegenerative diseases, and can promote organelle and protein damage leading to induction of autophagy. In this study, we used differentiated SH-SY5Y neuroblastoma cells to investigate the mechanisms and regulation of cellular susceptibility to HNE toxicity and the relationship to cellular metabolism. We found that autophagy is immediately stimulated by HNE at a sublethal concentration. Within the same time frame, HNE induces concentration dependent CASP3/caspase 3 activation and cell death. Interestingly, both basal and HNE activated autophagy, were regulated by glucose metabolism. Inhibition of glucose metabolism by 2-deoxyglucose (2DG), at a concentration that inhibited autophagic flux, further exacerbated CASP3 activation and cell death in response to HNE. Cell death was attenuated by the pan-caspase inhibitor Z-VAD-FMK. Specific inhibition of glycolysis using koningic acid, a GAPDH inhibitor, inhibited autophagic flux and exacerbated HNE-induced cell death similarly to 2DG. The effects of 2DG on autophagy and HNE-induced cell death could not be reversed by addition of mannose, suggesting an ER stress-independent mechanism. 2DG decreased LAMP1 and increased BCL2 levels suggesting that its effects on autophagy may be mediated by more than one mechanism. Furthermore, 2DG decreased cellular ATP, and 2DG and HNE combined treatment decreased mitochondrial membrane potential. We conclude that glucose-dependent autophagy serves as a protective mechanism in response to HNE. PMID- 24145465 TI - The optokinetic response as a quantitative measure of visual acuity in zebrafish. AB - Zebrafish are a proven model for vision research, however many of the earlier methods generally focused on larval fish or demonstrated a simple response. More recently adult visual behavior in zebrafish has become of interest, but methods to measure specific responses are new coming. To address this gap, we set out to develop a methodology to repeatedly and accurately utilize the optokinetic response (OKR) to measure visual acuity in adult zebrafish. Here we show that the adult zebrafish's visual acuity can be measured, including both binocular and monocular acuities. Because the fish is not harmed during the procedure, the visual acuity can be measured and compared over short or long periods of time. The visual acuity measurements described here can also be done quickly allowing for high throughput and for additional visual procedures if desired. This type of analysis is conducive to drug intervention studies or investigations of disease progression. PMID- 24145466 TI - The use of chemostats in microbial systems biology. AB - Cells regulate their rate of growth in response to signals from the external world. As the cell grows, diverse cellular processes must be coordinated including macromolecular synthesis, metabolism and ultimately, commitment to the cell division cycle. The chemostat, a method of experimentally controlling cell growth rate, provides a powerful means of systematically studying how growth rate impacts cellular processes - including gene expression and metabolism - and the regulatory networks that control the rate of cell growth. When maintained for hundreds of generations chemostats can be used to study adaptive evolution of microbes in environmental conditions that limit cell growth. We describe the principle of chemostat cultures, demonstrate their operation and provide examples of their various applications. Following a period of disuse after their introduction in the middle of the twentieth century, the convergence of genome scale methodologies with a renewed interest in the regulation of cell growth and the molecular basis of adaptive evolution is stimulating a renaissance in the use of chemostats in biological research. PMID- 24145467 TI - Thienylpyridine-based cyclometallated iridium(III) complexes and their use in solid state light-emitting electrochemical cells. AB - The synthesis and characterization of four iridium(iii) complexes [Ir(thpy)2(N^N)][PF6] where Hthpy = 2-(2'-thienyl)pyridine and N^N are 6-phenyl 2,2'-bipyridine (1), 4,4'-di-(t)butyl-2,2'-bipyridine (2), 4,4'-di-(t)butyl-6 phenyl-2,2'-bipyridine (3) or 4,4'-dimethylthio-2,2'-bipyridine (4) are described. The single crystal structures of ligand 4 and the complexes containing the [Ir(thpy)2(1)](+) and [Ir(thpy)2(4)](+) cations have been determined. In [Ir(thpy)2(1)](+), the pendant phenyl ring engages in an intra-cation pi-stacking interaction with one of the thienyl rings in the solid state, and undergoes hindered rotation on the NMR timescale in [Ir(thpy)2(1)](+) and [Ir(thpy)2(3)](+). The solution spectra of [Ir(thpy)2(1)][PF6] and [Ir(thpy)2(4)][PF6] show emission maxima around 640 nm and are significantly red shifted compared with [Ir(thpy)2(2)][PF6] and [Ir(thpy)2(3)][PF6] which have structured emission bands with maxima around 550 and 590 nm. In thin films, the emission spectra of the four complexes are similar with emission peaks around 550 and 590 nm and a shoulder around 640 nm that are reminiscent of the features observed in solution. In solution, quantum yields are low, but in thin films, values range from 29% for [Ir(thpy)2(1)][PF6] to 51% for [Ir(thpy)2(4)][PF6]. Density functional theory calculations rationalize the structured emission observed for the four complexes in terms of the (3)LC nature predicted for the lowest-energy triplet states that mainly involve the cyclometallated [thpy](-) ligands. Support for this theoretical result comes from the observed features of the low temperature (in frozen MeCN) photoluminescence spectra of the complexes. Photoluminescence and electroluminescence spectra of the complexes in a light emitting electrochemical cell (LEC) device configuration have been investigated. The electroluminescence spectra are similar for all [Ir(thpy)2(N^N)][PF6] complexes with emission maxima at ~600 nm, but device performances are relatively poor probably due to the poor charge-transporting properties of the complexes. PMID- 24145468 TI - Paediatric urology: first study of incontinent ileovesicostomy in children. PMID- 24145469 TI - Paediatric urology: kids with stones--data on causes and treatment safety. PMID- 24145470 TI - Prostate cancer: prediction of node-negative status after radical prostatectomy. PMID- 24145471 TI - Paediatric urology: vesicoamniotic shunting for fetal LUTO--questions linger. PMID- 24145472 TI - Prostate cancer: optimizing exercise interventions for men on ADT. PMID- 24145473 TI - Paediatric urology: is osteotomy necessary for primary exstrophy closure? PMID- 24145474 TI - Prostate cancer: does genetic score justify early prostate biopsy? PMID- 24145475 TI - Prostate cancer: patient-reported outcomes of first-line abiraterone therapy. PMID- 24145476 TI - Paediatric urology: rapid uptake of guidelines for imaging after first febrile UTI. PMID- 24145477 TI - Enantioselective synthesis of 1,2,4-triazolines catalyzed by a cinchona alkaloid derived organocatalyst. AB - An enantioselective organocatalytic process for the one-step synthesis of poly substituted 1,2,4-triazolines is reported. The heterocycle formation is believed to go through a step-wise mechanism of nucleophilic addition of an azlactone to an azodicarboxylate in the presence of an organic base catalyst, followed by a TMSCHN2 mediated heterocyclization. Both theoretical calculations and experimental evidence suggest the pre-organization of the transition state for the chirality determining step via a unique 7-membered intramolecular hydrogen bonding. PMID- 24145478 TI - The weapons effect. PMID- 24145479 TI - MicroRNA and gene networks in human Hodgkin's lymphoma. AB - There has been significant progress in gene and microRNA (miRNA) research with regard to the morbidity of Hodgkin's lymphoma (HL). However, the regulatory mechanisms of genes and miRNAs have yet to be determined. In the current study, the regulatory association between genes, miRNAs and transcription factors (TFs) was investigated to gain an understanding of the mechanisms and key pathways of HL. The association between TFs and miRNAs, miRNAs and target genes and miRNA and its host gene was examined. To show the regulatory correlation clearly, three regulatory networks were hierarchically constructed: Differentially expressed, associated and global networks. Following comparison and analysis of the similarities and differences among the three networks, a number of key pathways, which showed self-adaptation associations were identified. This included NFkappaB1 and hsa-miR-9, hsa-miR-196a-1 and its host gene HOXB7, which separately forms a self-adaptation association. The differentially expressed network illuminated the pathogenesis of HL. In addition, the associated network further described the regulatory mechanism associated with HL, including prevention, diagnosis, development and therapy. The current study systematically explains the regulatory mechanisms of HL and supplies comprehensive data associated with HL for further studies. With increasing knowledge of the occurrence, mechanism, improvement, metastasis and treatment, an increased understanding of HL may be achieved. PMID- 24145480 TI - Absolute density measurement of SD radicals in a supersonic jet at the quantum noise-limit. AB - The absolute density of SD radicals in a supersonic jet has been measured down to (1.1 +/- 0.1) * 10(5) cm(-3) in a modestly specified apparatus that uses a cross correlated combination of cavity ring-down and laser-induced fluorescence detection. Such a density corresponds to 215 +/- 21 molecules in the probe volume at any given time. The minimum detectable absorption coefficient was quantum noise-limited and measured to be (7.9 +/- 0.6) * 10(-11) cm(-1), in 200 s of acquisition time, corresponding to a noise-equivalent absorption sensitivity for the apparatus of (1.6 +/- 0.1) * 10(-9) cm(-1) Hz(-1/2). PMID- 24145481 TI - Amphiphilic peptoid transporters--synthesis and evaluation. AB - Cell-penetrating peptoids are an important class of peptidomimetics, which can replace highly biodegradable cell penetrating peptides for enhanced drug delivery. Typically, they contain positively charged amino side chains which are synthesized via their protected analogues. To avoid the use of amine protecting groups a Click-chemistry based modular synthesis of novel hydrophilic as well as amphiphilic cell penetrating peptoids was developed to generate novel structures for drug delivery in cells. PMID- 24145482 TI - Optic disc doubling or pseudo-optic disc in colobomatous retinal abnormality? PMID- 24145484 TI - The interest of amyloid PET imaging in the diagnosis of Alzheimer's disease. AB - PURPOSE OF REVIEW: This review evaluates the potential clinical utility of amyloid imaging. RECENT FINDINGS: Amyloid PET is a valid in-vivo marker of neuritic plaque load and correlates with amyloid plaque surface area. Abundant diffuse plaques, however, with scant neuritic plaques can also give rise to a positive scan, most often reported in association with Lewy body disease. Specificity of amyloid PET for discriminating Alzheimer's disease from healthy controls is higher than that of structural MRI. Sensitivity for discriminating Alzheimer's disease from healthy controls or from frontotemporal lobar degeneration is also higher than that of fluorodeoxyglucose-PET, with higher interreader reliability. Within a same center there is high concordance between dichotomization of cases based on amyloid PET versus cerebrospinal fluid Abeta42. In a tentative algorithm, we restrict clinical-diagnostic use to dementia with age of onset before 60 years, primary progressive aphasia and corticobasal syndrome, cases with objective cognitive deficits that could be due to a neurodegenerative cause but also have significant cerebrovascular or psychiatric comorbidity, and rapidly progressive dementia. SUMMARY: Empirical studies that evaluate how amyloid PET can change clinical-diagnostic thinking are starting to emerge. Key questions to be resolved are its role compared with cerebrospinal fluid markers and its impact on patient outcome. PMID- 24145485 TI - So what's next? PMID- 24145486 TI - Should extreme obesity in children be considered child abuse? PMID- 24145483 TI - Bioorthogonal chemistry: strategies and recent developments. AB - The use of covalent chemistry to track biomolecules in their native environment-a focus of bioorthogonal chemistry-has received considerable interest recently among chemical biologists and organic chemists alike. To facilitate wider adoption of bioorthogonal chemistry in biomedical research, a central effort in the last few years has been focused on the optimization of a few known bioorthogonal reactions, particularly with respect to reaction kinetics improvement, novel genetic encoding systems, and fluorogenic reactions for bioimaging. During these optimizations, three strategies have emerged, including the use of ring strain for substrate activation in the cycloaddition reactions, the discovery of new ligands and privileged substrates for accelerated metal catalysed reactions, and the design of substrates with pre-fluorophore structures for rapid "turn-on" fluorescence after selective bioorthogonal reactions. In addition, new bioorthogonal reactions based on either modified or completely unprecedented reactant pairs have been reported. Finally, increasing attention has been directed toward the development of mutually exclusive bioorthogonal reactions and their applications in multiple labeling of a biomolecule in cell culture. In this feature article, we wish to present the recent progress in bioorthogonal reactions through the selected examples that highlight the above mentioned strategies. Considering increasing sophistication in bioorthogonal chemistry development, we strive to project several exciting opportunities where bioorthogonal chemistry can make a unique contribution to biology in the near future. PMID- 24145488 TI - Evaluating venous pool technique for blood sampling in neonatal ICU. AB - PURPOSE: To evaluate venous pool technique (VPT) for obtaining neonatal blood samples as compared with the needlestick technique. METHOD AND SAMPLE: An experimental design was used with subjects enrolled in two phases: an equivalence phase (N = 10) and a comparison phase (N = 64). In the equivalence phase, subjects weighing 1,500 g or more had two needlesticks. In the comparison phase, subjects weighing 800 g or more were randomized to receive blood drawn by either needlestick method or VPT. RESULTS: Comparative results suggest that infant and maternal demographic factors, sampling attempts, and sampling failures were similar. However, for the outcome of hematoma development, the standard technique was significantly worse (t = 2.25 ; p = .029). Results suggest that the VPT method is safe and accurate for use in critically ill neonates. CLINICAL IMPLICATIONS: This study demonstrated that the VPT process is easily learned and may provide advantages over standard blood sampling methods. Nurses can use this information to evaluate this VPT technique in their institutions. PMID- 24145489 TI - Influence of motivation on the efficacy of natural family planning. AB - PURPOSE: To determine the influence of mutual motivation on unintended pregnancy rates of couples who used natural family planning (NFP) methods to avoid pregnancy. STUDY DESIGN AND METHODS: Using an online taught NFP method, 358 women and (their male partners) indicated "how much" and "how hard" they wished to avoid pregnancy on a scale of 0 to 10 before each menstrual cycle charted over 12 month of use. This motivation scale is used in the National Survey of Family Growth as a measure of motivation. All pregnancies were verified with an online pregnancy evaluation and urine-based pregnancy test. A combined motivation score was used in analysis. RESULTS: There were 28 pregnancies among the low-motivation participants (N = 60) and 16 among the high-motivation participants (N = 298). At 12 months of use, there were 75 pregnancies per 100 users for the low-motivation group and only 8 for the high-motivation group. There was an 80% greater likelihood of a pregnancy with the low-motivation group (chi = 25.5, p < .001, odds ratio = 1.80; 95% confidence interval = 1.61-1.90). CLINICAL IMPLICATIONS: High motivation to avoid pregnancy by both the female user of a behavioral method of family planning and her male partner is required for high efficacy. Assessing motivation of both the woman and her male partner before prescribing NFP methods is recommended. PMID- 24145492 TI - Strategies for neonatal hyperbilirubinemia: a literature review. AB - "Common" neonatal jaundice can lead to dangerous levels of hyperbilirubinemia, causing neurological damage and even death. This article outlines evidence-based assessment techniques, management guidelines, and treatments for neonatal hyperbilirubinemia, addressing complexities that have arisen with new technologies and research results. We also explicate the role of the nurse in both prevention and care of patients and families who are affected by hyperbilirubinemia and jaundice. PMID- 24145494 TI - Strategies to increase milk volume in mothers of VLBW infants. AB - The provision of breast milk to premature VLBW infants is associated with significant health benefits. Unfortunately, the delivery of breast milk to these vulnerable infants is often limited due to insufficient maternal milk supply. Several interventions have been investigated with respect to increasing milk volume in mothers of VLBW infants but confusion exists concerning the interventions' effectiveness. The purpose of this systematic review is to critique the evidence regarding specific milk expression strategies that aim to improve milk volume in mothers of VLBW infants.Published article references, electronic databases, dissertations and theses, and select conference proceedings were searched with the goal of finding studies that target VLBW infants and milk expression techniques in which breast milk volume was an outcome. Analysis of evidence revealed an association between increased milk volume and early initiation of expression, increased frequency of expression, and provision of kangaroo care. The use of simultaneous or sequential milk expression and duration of milk expression sessions were not found to significantly improve milk volume. These results may be used to formulate specific strategies designed to increase breast milk volume in this population. PMID- 24145495 TI - Treating ADHD with nutritional options. PMID- 24145496 TI - Crowdsourcing in healthcare. PMID- 24145497 TI - Landmark global action to reduce complications in preterm infants. PMID- 24145499 TI - Alarm fatigue. PMID- 24145500 TI - From swimming to swarming: Escherichia coli cell motility in two-dimensions. AB - Escherichia coli swarmer cells coordinate their movement when confined in thin layers of fluid on agar surfaces. The motion and dynamics of cells, pairs of cells, and packs of cells can be recapitulated and studied in polymer microfluidic systems that are designed to constrain swarmer cell movement in thin layers of fluid between no-slip surfaces. The motion of elongated, smooth swimming E. coli cells in these environments reproduces the behavior of packs of cells observed at the leading edge of swarming communities and demonstrates the delicate balance between the physical dimensions of fluids and bacterial cell behavior. PMID- 24145501 TI - Experimental evidence suggests the existence of evolutionary conserved global operation principles governing microbial metabolism. AB - The search for optimization principles in microbial metabolism, such as biomass or ATP yields or growth rate optimization, has attracted substantial research efforts in the recent years. Here we use the results of C13 labeling experiments together with genome scale metabolic networks of S cerevisiae and E coli in order to assess if there are relationships between systemic variables that are present in both organisms. Strong correlations between the total flux per unit of substrate and the ATP turnover rate per unit of substrate and between the growth rate divided by the total flux and the total flux per unit of substrate were observed for both organisms. We also observed that the common assumption of biomass yield optimization is not consistent with the experiments. PMID- 24145502 TI - High-temperature photo-induced switching and pressure-induced transition in a cooperative molecular spin-crossover material. AB - The thermal and photo-induced switching properties of the recently published molecular spin crossover complex [Fe(H4L)2](ClO4)2.H2O.2(CH3)2CO () have been investigated in detail through Raman spectroscopy. Magnetometric and single crystal X-ray diffraction kinetic studies within the hysteresis loop have proven its metastable character, which allowed establishing the shape of the true, quasi static hysteresis loop. This is related to the proximity of the temperatures of the thermal high to low spin SCO (T1/2?) to those of the relaxation of the thermally or photo-generated metastable states (T(TIESST) and T(LIESST), respectively). Green light irradiation within the hysteresis loop results in a complete low to high spin photo-switch. In addition, the SCO of at room temperature can be induced by applying pressure, as followed by Raman spectroscopy. PMID- 24145503 TI - Clinical features, outcome and prognostic factors in dogs diagnosed with non cortisol-secreting adrenal tumours without adrenalectomy: 20 cases (1994-2009). AB - The aims of this study were to describe the clinical features, the outcome and the prognostic factors of dogs with non-cortisol-secreting adrenal masses without adrenalectomy, and also to provide clinical data that can be useful for making decisions when managing dogs with these types of neoplasms. Medical records from 1994 to 2009 were reviewed and 20 dogs were included in the study. The results showed that mean age at diagnosis for dogs with non-cortisol-secreting adrenal masses was 12 years with no sex predisposition. Most dogs were asymptomatic. The most frequent clinical signs, when present, were lethargy, weakness and hypertension. Radiological evidence of metastases at diagnosis was not frequent. The maximal dorso-ventral thickness of the adrenal mass ranged from 10.0 to 45.0 mm. Right adrenal gland masses were more frequent than left-sided. Hypertension was found to be related to tumour growth during follow-up. The median survival time of dogs with non-cortisol-secreting tumours was 17.8 months. Body weight at diagnosis, tumour size and the presence of metastases at diagnosis were inversely related to survival. In conclusion, survival of dogs with non-cortisol-secreting adrenal tumours without adrenalectomy is relatively high and comparable with that of dogs treated with adrenalectomy. Dogs with metastasis and large adrenal tumours have a poorer prognosis. Hypertension is related to tumour growth, and might be used as an additional tool to assess the potential growing capacity of the tumour. PMID- 24145504 TI - Fatal epicarditis in a hen harrier (Circus cyaneus) a red-listed bird of high conservation concern in Britain associated with Cyathostoma species and Escherichia coli infection. PMID- 24145505 TI - Hader bar and clip attachment retained mandibular complete denture. AB - Bar and clip attachments significantly improve the level of satisfaction of denture-wearing patients by enhancing the retention and stability of the prosthesis. These attachments have been most commonly used for connecting the prosthesis to implants, but they can be effectively used to retain tooth supported prosthesis as well. The primary functions of bar attachments are splinting the abutments together, even distribution of forces to the abutments and supporting areas, guiding the prosthesis into place, improving the retention, stability, support and comfort of the patient. The primary requirement for the use of bar attachments is the availability of sufficient vertical and buccolingual space for the proper placement of the bar, sleeves, teeth arrangement and sufficient thickness of acrylic denture base to minimise incidence of denture fracture in the area of bar assembly. PMID- 24145506 TI - Nerve afflictions of maxillofacial region: a report of two cases. AB - Neurological disorders and conditions affecting the maxillofacial region result in disabilities that affect an individual's functioning. Sensory or motor disturbances of the nerves may be caused by trauma, infections, pressure effect or infiltration by tumours or other health conditions. Two rare cases of nerve afflictions are described here with their typical clinical features. The first case had an involvement of maxillary, mandibular and ophthalmic divisions of the trigeminal nerve (sensory) due to herpes zoster infection in a very young patient and the second case had a unilateral isolated hypoglossal nerve palsy (motor) secondary to infiltration of the nerve by carcinoma of pyriform fossa. PMID- 24145507 TI - Adrenal ganglioneuroma in a patient with polycystic ovarian disease (PCOD): a rare association. AB - Adrenal ganglioneuromas are rare, benign incidentalomas of a neural crest origin. A majority of these tumours are clinically silent and discovered on imaging for unrelated reasons. Polycystic ovarian disease (PCOD) is an endocrine disorder characterised by bilateral polycystic ovaries, anovulation leading to infertility, irregular menstrual cycles and features of androgen hormone excess. Herein we report a rare case of adrenal ganglioneuroma in a 14-year-old girl with PCOD. She was referred to us by the gynaecologist after incidental detection of adrenal mass on ultrasonography. Except for raised 24 h urinary metanephrines, rest of the hormones measured were in normal range. Transperitoneal adrenalectomy was performed and histopathology was suggestive of ganglioneuroma. Postoperative recovery was excellent and she is doing well. To our knowledge it is the first such type of case to be reported. PMID- 24145508 TI - Ischaemia-reperfusion injury in central retinal artery occlusion. AB - A 53-year-old man presented with sudden painless diminution of vision in his right eye for 3 days. His fundus examination showed diffuse whitening of the retina with a cherry red spot at the fovea with cilioretinal artery sparing. On fluorescein angiography delayed arteriovenous transit was observed. Three dimensional spectral domain optical coherence tomography was used to assess retinal nerve fibre layer thickness and average macular central subfield thickness on days 3, 7, 30 and 90. Marked retinal oedema due to ischaemia was observed on day 3 of occurrence of central retinal artery occlusion. On day 7, significant decrease in retinal nerve fibre thickness and macular thickness was noted suggestive of acute reperfusion injury. Retinal nerve fibre layer thickness and macular thickness returned to near normal on day 30 due to restoration of blood supply with wash out of stress mediators. Retinal atrophy was observed on day 90. PMID- 24145509 TI - A painful toe: botfly myiasis. PMID- 24145510 TI - CD36-specific antibodies block release of HIV-1 from infected primary macrophages and its transmission to T cells. AB - HIV-1-infected macrophages likely represent viral reservoirs, as they accumulate newly formed virions in internal virus-containing compartments (VCCs). However, the nature and biogenesis of VCCs remain poorly defined. We show that upon HIV-1 infection of primary human macrophages, Gag is recruited to preexisting compartments containing the scavenger receptor CD36, which then become VCCs. Silencing of CD36 in HIV-1-infected macrophages decreases the amount of virions released. Strikingly, soluble anti-CD36 antibodies, but not the natural ligands of CD36, inhibit release of virions from HIV-1-infected macrophages and the transmission of virus to CD4(+) T cells. The effect of the antibodies is potent, rapid, and induces the retention of virions within VCCs. Ectopic expression of CD36 in HeLa cells renders them susceptible to the inhibitory effect of the anti CD36 mAb upon HIV-1 infection. We show that the anti-CD36 mAb inhibits HIV-1 release by clustering newly formed virions at their site of budding, and that signaling via CD36 is not required. Thus, HIV-1 reservoirs in macrophages may be tackled therapeutically using anti-CD36 antibodies to prevent viral dissemination. PMID- 24145511 TI - Overexpression of TLR7 promotes cell-intrinsic expansion and autoantibody production by transitional T1 B cells. AB - Toll-like receptor (TLR), a ligand for single-stranded RNA, has been implicated in the development of pathogenic anti-RNA autoantibodies both in systemic lupus erythematous (SLE) patients and in murine models of lupus. It is still unclear, however, where and how TLR7-mediated interactions affect the development of autoreactive B cells. We found that overexpression of TLR7 in transgenic mice (TLR7.1Tg) leads to marked alterations of transitional (T1) B cells, associated with their expansion and proliferation within the splenic red pulp (RP). This phenotype was intrinsic to the T1 subset of B cells and occurred independently of type 1 IFN signals. Overexpression of RNase in TLR7.1Tg mice significantly limited the expansion and proliferation of T1 cells, indicating that endogenous RNA complexes are driving their activation. TLR7.1Tg T1 cells were hyper responsive to anti-IgM and TLR7 ligand stimulation in vitro and produced high concentrations of class-switched IgG2b and IgG2c, including anti-RNA antibodies. Our results demonstrate that initial TLR7 stimulation of B cells occurs at the T1 stage of differentiation in the splenic RP and suggest that dysregulation of TLR7 expression in T1 cells can result in production of autoantibodies. PMID- 24145512 TI - The cohesin complex regulates immunoglobulin class switch recombination. AB - Immunoglobulin (Ig) class switch recombination (CSR) is initiated by the transcription-coupled recruitment of activation-induced cytidine deaminase (AID) to switch regions and by the subsequent generation of double-stranded DNA breaks (DSBs). These DNA breaks are ultimately resolved through the nonhomologous end joining (NHEJ) pathway. We show that during CSR, AID associates with subunits of cohesin, a complex previously implicated in sister chromatid cohesion, DNA repair, and the formation of DNA loops between enhancers and promoters. Furthermore, we implicate the cohesin complex in the mechanism of CSR by showing that cohesin is dynamically recruited to the SMU-CMU region of the IgH locus during CSR and that knockdown of cohesin or its regulatory subunits results in impaired CSR and increased usage of microhomology-based end joining. PMID- 24145513 TI - A type I IFN-Flt3 ligand axis augments plasmacytoid dendritic cell development from common lymphoid progenitors. AB - During infections and inflammation, plasmacytoid dendritic cells (pDCs) are the most potent type I interferon (IFN-I)-producing cells. However, the developmental origin of pDCs and the signals dictating pDC generation remain incompletely understood. Here, we report a synergistic role for IFN-I and Flt3 ligand (FL) in pDC development from common lymphoid progenitors (CLPs). Both conventional DCs (cDCs) and pDCs were generated from CLPs in response to FL, whereas pDC generation required higher concentrations of FL and concurrent IFN-I signaling. An absence of IFN-I receptor, impairment of IFN-I signaling, or neutralization of IFN-I significantly impeded pDC development from CLPs. Furthermore, FL induced IFN-I expression in CLPs, which in turn induced Flt3 up-regulation that facilitated survival and proliferation of CLPs, as well as their differentiation into pDCs. Collectively, these results define a critical role for the FL/IFN I/Flt3 axis in pDC differentiation from CLPs. PMID- 24145514 TI - SIRPalpha polymorphisms, but not the prion protein, control phagocytosis of apoptotic cells. AB - Prnp(-/-) mice lack the prion protein PrP(C) and are resistant to prion infections, but variable phenotypes have been reported in Prnp(-/-) mice and the physiological function of PrP(C) remains poorly understood. Here we examined a cell-autonomous phenotype, inhibition of macrophage phagocytosis of apoptotic cells, previously reported in Prnp(-/-) mice. Using formal genetic, genomic, and immunological analyses, we found that the regulation of phagocytosis previously ascribed to PrP(C) is instead controlled by a linked locus encoding the signal regulatory protein alpha (Sirpa). These findings indicate that control of phagocytosis was previously misattributed to the prion protein and illustrate the requirement for stringent approaches to eliminate confounding effects of flanking genes in studies modeling human disease in gene-targeted mice. The plethora of seemingly unrelated functions attributed to PrP(C) suggests that additional phenotypes reported in Prnp(-/-) mice may actually relate to Sirpa or other genetic confounders. PMID- 24145515 TI - A regulatory role for the cohesin loader NIPBL in nonhomologous end joining during immunoglobulin class switch recombination. AB - DNA double strand breaks (DSBs) are mainly repaired via homologous recombination (HR) or nonhomologous end joining (NHEJ). These breaks pose severe threats to genome integrity but can also be necessary intermediates of normal cellular processes such as immunoglobulin class switch recombination (CSR). During CSR, DSBs are produced in the G1 phase of the cell cycle and are repaired by the classical NHEJ machinery. By studying B lymphocytes derived from patients with Cornelia de Lange Syndrome, we observed a strong correlation between heterozygous loss-of-function mutations in the gene encoding the cohesin loading protein NIPBL and a shift toward the use of an alternative, microhomology-based end joining during CSR. Furthermore, the early recruitment of 53BP1 to DSBs was reduced in the NIPBL-deficient patient cells. Association of NIPBL deficiency and impaired NHEJ was also observed in a plasmid-based end-joining assay and a yeast model system. Our results suggest that NIPBL plays an important and evolutionarily conserved role in NHEJ, in addition to its canonical function in sister chromatid cohesion and its recently suggested function in HR. PMID- 24145516 TI - Extracellular adenosine regulates naive T cell development and peripheral maintenance. AB - Adenosine produced as a byproduct of metabolic activity is present in all tissues and produces dose-dependent suppression of TCR signaling. Naive T cell maintenance depends on inhibition of TCR signals by environmental sensors, which are yet to be fully defined. We produced mice with a floxed adenosine A2A receptor (A2AR) gene, Adora2a, and show that either global A2AR deletion or cre mediated T cell deletion elicits a decline in the number of naive but not memory T cells. A2AR signaling maintains naive T cells in a quiescent state by inhibiting TCR-induced activation of the phosphatidylinositide 3-kinase (PI3K) AKT pathway, thereby reducing IL-7Ralpha down-regulation and naive T cell apoptosis. Patterns of IL-7Ralpha expression on T cells in chimeric mice reconstituted with Adora2a(+/+) and Adora2a(-/-) bone marrow cells suggest that decreased IL-7Ralpha in naive T cells is a cell-intrinsic consequence of Adora2a deletion. In addition, A2AR expression increases in early thymic T cell development and contributes to progression of double-negative thymic precursors to single-positive thymocytes with increased IL-7Ralpha expression. Therefore, A2AR signaling regulates T cell development and maintenance to sustain normal numbers of naive T cells in the periphery. PMID- 24145517 TI - Burkholderia pseudomallei isolates from Sarawak, Malaysian Borneo, are predominantly susceptible to aminoglycosides and macrolides. AB - Melioidosis is a potentially fatal disease caused by the saprophytic bacterium Burkholderia pseudomallei. Resistance to gentamicin is generally a hallmark of B. pseudomallei, and gentamicin is a selective agent in media used for diagnosis of melioidosis. In this study, we determined the prevalence and mechanism of gentamicin susceptibility found in B. pseudomallei isolates from Sarawak, Malaysian Borneo. We performed multilocus sequence typing and antibiotic susceptibility testing on 44 B. pseudomallei clinical isolates from melioidosis patients in Sarawak district hospitals. Whole-genome sequencing was used to identify the mechanism of gentamicin susceptibility. A novel allelic-specific PCR was designed to differentiate gentamicin-sensitive isolates from wild-type B. pseudomallei. A reversion assay was performed to confirm the involvement of this mechanism in gentamicin susceptibility. A substantial proportion (86%) of B. pseudomallei clinical isolates in Sarawak, Malaysian Borneo, were found to be susceptible to the aminoglycoside gentamicin, a rare occurrence in other regions where B. pseudomallei is endemic. Gentamicin sensitivity was restricted to genetically related strains belonging to sequence type 881 or its single-locus variant, sequence type 997. Whole-genome sequencing identified a novel nonsynonymous mutation within amrB, encoding an essential component of the AmrAB OprA multidrug efflux pump. We confirmed the role of this mutation in conferring aminoglycoside and macrolide sensitivity by reversion of this mutation to the wild-type sequence. Our study demonstrates that alternative B. pseudomallei selective media without gentamicin are needed for accurate melioidosis laboratory diagnosis in Sarawak. This finding may also have implications for environmental sampling of other locations to test for B. pseudomallei endemicity. PMID- 24145518 TI - Prevalence of polymorphisms in antifolate drug resistance molecular marker genes pvdhfr and pvdhps in clinical isolates of Plasmodium vivax from Kolkata, India. AB - Sulfadoxine-pyrimethamine has never been recommended for the treatment of Plasmodium vivax malaria as the parasite is intrinsically resistant to pyrimethamine. The combination was introduced as a promising agent to treat Plasmodium falciparum malaria in many countries but was withdrawn after a few years due to development and spread of resistant strains. Presently, sulfadoxine pyrimethamine is used as a partner drug of artemisinin-based combination therapy to treat uncomplicated falciparum malaria, and a combination of artesunate sulfadoxine-pyrimethamine is currently in use in India. In countries like India, where both P. vivax and P. falciparum are equally prevalent, some proportion of P. vivax bacteria is exposed to sulfadoxine-pyrimethamine due to misdiagnosis and mixed infections. As reports on the in vivo therapeutic efficacy of sulfadoxine pyrimethamine in P. vivax are rare, the study of mutations in the marker genes P. vivax dhfr (pvdhfr) and pvdhps is important for predicting drug selection pressure and sulfadoxine-pyrimethamine resistance monitoring. We studied the prevalence of point mutations and haplotypes of both the genes in 80 P. vivax isolates collected from urban Kolkata, India, by the DNA sequencing method. Point mutation rates in both the genes were low. The double mutant pvdhfr A15N50R58N117I173 (mutations are in boldface) and the single mutant pvdhps genotype S382G383K512A553V585 were more prevalent, while 35% of the isolates harbored the wild-type genotype. The triple mutant ANRNI-SGKAV was found in 29.9% isolates. No quintuple mutant genotype was recorded. The P. vivax parasites in urban Kolkata may still be susceptible to sulfadoxine-pyrimethamine. Hence, a combination of antimalarial drugs like artesunate-sulfadoxine-pyrimethamine introduced for P. falciparum infection might be effective in P. vivax infection also. Study of the therapeutic efficacy of this combination in P. vivax is thus strongly suggested. (The study protocol was registered in the Clinical Trial Registry-India [CTRI] of the Indian Council of Medical Research under registration number CTRI/2011/09/002031.). PMID- 24145519 TI - beta-Lactams enhance vancomycin activity against methicillin-resistant Staphylococcus aureus bacteremia compared to vancomycin alone. AB - Vancomycin (VAN) is often used to treat methicillin-resistant Staphylococcus aureus (MRSA) bacteremia despite a high incidence of microbiological failure. Recent in vitro analyses of beta-lactams in combination with VAN demonstrated synergistic activity against MRSA. The goal of this study was to examine the impact of combination therapy with VAN and a beta-lactam (Combo) on the microbiological eradication of MRSA bacteremia compared to VAN alone. This was a retrospective cohort study of patients with MRSA bacteremia who received Combo therapy or VAN alone. Microbiological eradication of MRSA, defined as a negative blood culture obtained after initiation of therapy, was used to evaluate the efficacy of each regimen. A total of 80 patients were included: 50 patients in the Combo group and 30 patients in the VAN-alone group. Microbiological eradication was achieved in 48 patients (96%) in the Combo group compared to 24 patients (80%) in the VAN-alone group (P = 0.021). In a multivariable model, the Combo treatment had a higher likelihood of achieving microbiological eradication (adjusted odds ratio, 11.24; 95% confidence interval, 1.7 to 144.3; P = 0.01). In patients with infective endocarditis (n = 22), 11/11 (100%) who received Combo therapy achieved microbiological eradication compared to 9/11 (81.8%) treated with VAN alone, but the difference was not statistically significant (P = 0.20). Patients with MRSA bacteremia who received Combo therapy were more likely to experience microbiological eradication of MRSA than patients who received VAN alone. PMID- 24145520 TI - Occurrence of rpoB mutations in isoniazid-resistant but rifampin-susceptible Mycobacterium tuberculosis isolates from Germany. AB - Four out of 143 phenotypically isoniazid-resistant but rifampin-susceptible Mycobacterium tuberculosis strains that were isolated from patients in Germany in 2011 had mutations in the rifampin resistance-determining region of rpoB. After performing drug susceptibility testing (DST) with two methods, the proportion method on Lowenstein-Jensen medium and using the Bactec 960 Mycobacteria Growth Indicator Tube system, we conclude that the two methods are equally reliable for phenotypic DST and MIC determination. PMID- 24145521 TI - Therapeutic efficacy of SQ641-NE against Mycobacterium tuberculosis. AB - A phospholipid-based nanoemulsion formulation of SQ641 (SQ641-NE) was active against intracellular Mycobacterium tuberculosis in J774A.1 mouse macrophages, although SQ641 by itself was not. Intravenous (i.v.) SQ641-NE was cleared from circulation and reached peak concentrations in lung and spleen in 1 h. In a murine tuberculosis (TB) model, 8 i.v. doses of SQ641-NE at 100 mg/kg of body weight over 4 weeks caused a 1.73 log10 CFU reduction of M. tuberculosis in spleen and were generally bacteriostatic in lungs. PMID- 24145522 TI - Pharmacometric characterization of efavirenz developmental pharmacokinetics and pharmacogenetics in HIV-infected children. AB - The aim of this analysis was to create a pharmacometric model of efavirenz developmental pharmacokinetics and pharmacogenetics in HIV-infected children. The data consisted of 3,172 plasma concentrations from 96 HIV-1-infected children who participated in the Pediatric AIDS Clinical Trials Group 382 (PACTG382) study. Analyses were performed using NONMEM, and the impacts of body weight, age, race, sex, formulation, liver function, and cytochrome P450 2B6 (CYP2B6)-G516T and multidrug-resistance transporter gene (MDR1)-C3435T polymorphisms were assessed. A one-compartment model using weight-based allometry on oral clearance and apparent volume of distribution adequately described the data. A sigmoid maximum effect (Emax) maturation model demonstrated an increase in oral clearance with age to reach 90% of its mature level by the age of 9 months. The liquid formulation bioavailability relative to the capsule was found to increase with age to reach 90% of its mature value by the age of 8 years. The CYP2B6-G516T polymorphism decreased oral clearance, while the MDR1-C3435T polymorphism demonstrated no effect. PMID- 24145523 TI - Distribution of hydroxychloroquine in lymphoid tissue in a rabbit model for HIV infection. AB - Hydroxychloroquine has been proposed for HIV treatment; however, little is known about its disposition in the lymphatic system, where replication takes place. Therefore, its distribution in lymphoid tissues (Peyer's patches and popliteal, submandibular, femoral, splenic, and prescapular lymph nodes) was evaluated and compared with that in blood. Results showed a high affinity of hydroxychloroquine for all of these tissues, with higher affinity for the splenic and submandibular lymph nodes, suggesting its potential use as a coadjuvant in HIV therapy. PMID- 24145524 TI - Amidate prodrugs of 9-[2-(phosphonomethoxy)ethyl]adenine as inhibitors of adenylate cyclase toxin from Bordetella pertussis. AB - Adenylate cyclase toxin (ACT) is the key virulence factor of Bordetella pertussis that facilitates its invasion into the mammalian body. 9-[2 (Phosphonomethoxy)ethyl]adenine diphosphate (PMEApp), the active metabolite of the antiviral drug bis(POM)PMEA (adefovir dipivoxil), has been shown to inhibit ACT. The objective of this study was to evaluate six novel amidate prodrugs of PMEA, both phenyloxy phosphonamidates and phosphonodiamidates, for their ability to inhibit ACT activity in the J774A.1 macrophage cell line. The two phenyloxy phosphonamidate prodrugs exhibited greater inhibitory activity (50% inhibitory concentration [IC50] = 22 and 46 nM) than the phosphonodiamidates (IC50 = 84 to 3,960 nM). The inhibitory activity of the prodrugs correlated with their lipophilicity and the degree of their hydrolysis into free PMEA in J774A.1 cells. Although the prodrugs did not inhibit ACT as effectively as bis(POM)PMEA (IC50 = 6 nM), they were significantly less cytotoxic. Moreover, they all reduced apoptotic effects of ACT and prevented an ACT-induced elevation of intracellular [Ca(2+)]i. The amidate prodrugs were less susceptible to degradation in Caco-2 cells compared to bis(POM)PMEA, while they exerted good transepithelial permeability in this assay. As a consequence, a large amount of intact amidate prodrug is expected to be available to target macrophages in vivo. This feature makes nontoxic amidate prodrugs attractive candidates for further investigation as novel antimicrobial agents. PMID- 24145525 TI - Ganciclovir-resistant cytomegalovirus infections among lung transplant recipients are associated with poor outcomes despite treatment with foscarnet-containing regimens. AB - Ganciclovir-resistant cytomegalovirus (CMV) infections are reported infrequently among lung transplant recipients receiving extended valganciclovir prophylaxis. We performed a single-center, retrospective review of ganciclovir-resistant CMV infections in a program that employed valganciclovir prophylaxis for >=6 months after lung transplant. CMV infections were diagnosed in 28% (170/607) of patients. UL97 mutations were detected in 9.4% (16/170) of CMV-infected patients at a median of 8.5 months posttransplant (range, 5 to 21) and despite prophylaxis for a median of 7 months (range, 4 to 21). UL97 mutations were canonical; 25% (4/16) of strains carried concurrent UL54 mutations. Ganciclovir-resistant CMV was more likely with breakthrough infections (75% [12/16] versus 19% [30/154]; P = 0.00001) and donor positive/recipient negative (D+/R-) serostatus (75% versus 45% [69/154]; P = 0.03). The median whole-blood CMV load was 4.13 log10 copies/cm(3) (range, 2.54 to 5.53), and 93% (14/15) of patients had low-moderate immune responses (Cylex Immunoknow). Antiviral therapy was successful, failed, or eradicated viremia followed by relapse in 12% (2/16), 31% (5/16), and 56% (9/16) of patients, respectively. Eighty-seven percent (14/16) of patients were treated with foscarnet-containing regimens; toxicity developed in 78% (11/14) of these. Median viral load half-life and time to viremia eradication among foscarnet treated patients were 2.6 and 23 days, respectively, and did not correlate with protection from relapse. Sixty-nine percent (11/16) of patients developed CMV pneumonitis, and 25% (4/16) died of it. Serum viral load was independently associated with death among foscarnet-treated patients (P = 0.04). In conclusion, ganciclovir-resistant CMV infections remained a major cause of morbidity and mortality following lung transplantation. Foscarnet-based regimens often eradicated viremia rapidly but were ineffective in the long term and limited by toxicity. PMID- 24145526 TI - Evidence for pyronaridine as a highly effective partner drug for treatment of artemisinin-resistant malaria in a rodent model. AB - The increasing prevalence in Southeast Asia of Plasmodium falciparum infections with delayed parasite clearance rates, following treatment of malaria patients with the artemisinin derivative artesunate, highlights an urgent need to identify which of the currently available artemisinin-based combination therapies (ACTs) are most suitable to treat populations with emerging artemisinin resistance. Here, we demonstrate that the rodent Plasmodium berghei SANA strain has acquired artemisinin resistance following drug pressure, as defined by reduced parasite clearance and early recrudescence following daily exposure to high doses of artesunate or the active metabolite dihydroartemisinin. Using the SANA strain and the parental drug-sensitive N strain, we have interrogated the antimalarial activity of five ACTs, namely, artemether-lumefantrine, artesunate-amodiaquine, artesunate-mefloquine, dihydroartemisinin-piperaquine, and the newest combination artesunate-pyronaridine. By monitoring parasitemia and outcome for 30 days following initiation of treatment, we found that infections with artemisinin resistant P. berghei SANA parasites can be successfully treated with artesunate pyronaridine used at doses that are curative for the parental drug-sensitive N strain. No other partner drug combination was as effective in resolving SANA infections. Of the five partner drugs tested, pyronaridine was also the most effective at suppressing the recrudescence of SANA parasites. These data support the potential benefit of implementing ACTs with pyronaridine in regions affected by artemisinin-resistant malaria. PMID- 24145527 TI - Curcumin targets cell wall integrity via calcineurin-mediated signaling in Candida albicans. AB - Curcumin (CUR) shows antifungal activity against a range of pathogenic fungi, including Candida albicans. The reported mechanisms of action of CUR include reactive oxygen species (ROS) generation, defects in the ergosterol biosynthesis pathway, decrease in hyphal development, and modulation of multidrug efflux pumps. Reportedly, each of these pathways is independently linked to the cell wall machinery in C. albicans, but surprisingly, CUR has not been previously implicated in cell wall damage. In the present study, we performed transcriptional profiling to identify the yet-unidentified targets of CUR in C. albicans. We found that, among 348 CUR-affected genes, 51 were upregulated and 297 were downregulated. Interestingly, most of the cell wall integrity pathway genes were downregulated. The possibility of the cell wall playing a critical role in the mechanism of CUR required further validation; therefore, we performed specific experiments to establish if there was any link between the two. The fractional inhibitory concentration index values of 0.24 to 0.37 show that CUR interacts synergistically with cell wall-perturbing (CWP) agents (caspofungin, calcofluor white, Congo red, and SDS). Furthermore, we could observe cell wall damage and membrane permeabilization by CUR alone, as well as synergistically with CWP agents. We also found hypersusceptibility in calcineurin and mitogen activated protein (MAP) kinase pathway mutants against CUR, which confirmed that CUR also targets cell wall biosynthesis in C. albicans. Together, these data provide strong evidence that CUR disrupts cell wall integrity in C. albicans. This new information on the mechanistic action of CUR could be employed in improving treatment strategies and in combinatorial drug therapy. PMID- 24145528 TI - Deletion of the beta-acetoacetyl synthase FabY in Pseudomonas aeruginosa induces hypoacylation of lipopolysaccharide and increases antimicrobial susceptibility. AB - The beta-acetoacetyl-acyl carrier protein synthase FabY is a key enzyme in the initiation of fatty acid biosynthesis in Pseudomonas aeruginosa. Deletion of fabY results in an increased susceptibility of P. aeruginosa in vitro to a number of antibiotics, including vancomycin and cephalosporins. Because antibiotic susceptibility can be influenced by changes in membrane lipid composition, we determined the total fatty acid profile of the DeltafabY mutant, which suggested alterations in the lipid A region of the lipopolysaccharide. The majority of lipid A species in the DeltafabY mutant lacked a single secondary lauroyl group, resulting in hypoacylated lipid A. Adding exogenous fatty acids to the growth media restored the wild-type antibiotic susceptibility profile and the wild-type lipid A fatty acid profile. We suggest that incorporation of hypoacylated lipid A species into the outer membrane contributes to the shift in the antibiotic susceptibility profile of the DeltafabY mutant. PMID- 24145529 TI - Treatment failure and miltefosine susceptibility in dermal leishmaniasis caused by Leishmania subgenus Viannia species. AB - Treatment failure and parasite drug susceptibility in dermal leishmaniasis caused by Leishmania (Viannia) species are poorly understood. Prospective evaluation of drug susceptibility of strains isolated from individual patients before drug exposure and at clinical failure allows intrinsic and acquired differences in susceptibility to be discerned and analyzed. To determine whether intrinsic susceptibility or loss of susceptibility to miltefosine contributed to treatment failure, we evaluated the miltefosine susceptibility of intracellular amastigotes and promastigotes of six Leishmania (Viannia) braziliensis and six Leishmania (Viannia) panamensis strains isolated sequentially, at diagnosis and treatment failure, from two children and four adults >=55 years old with concurrent conditions. Four patients presented only cutaneous lesions, one had mucosal disease, and one had disseminated mucocutaneous disease. Expression of the Leishmania drug transporter genes abca2, abca3, abcc2, abcc3, abcg4, abcg6, and LbMT was evaluated by quantitative reverse transcription-PCR (qRT-PCR). Intracellular amastigotes (median 50% effective concentration [EC50], 10.7 MUmol/liter) were more susceptible to miltefosine than promastigotes (median EC50, 55.3 MUmol/liter) (P < 0.0001). Loss of susceptibility at failure, demonstrated by a miltefosine EC50 of >32 MUmol/liter (the upper limit of intracellular amastigote assay), occurred in L. panamensis infection in a child and in L. braziliensis infection in an adult and was accompanied by decreased expression of the miltefosine transporter LbMT (LbMT/beta-tubulin, 0.42- to 0.26 fold [P = 0.039] and 0.70- to 0.57-fold [P = 0.009], respectively). LbMT gene polymorphisms were not associated with susceptibility phenotype. Leishmania ABCA3 transporter expression was inversely correlated with miltefosine susceptibility (r = -0.605; P = 0.037). Loss of susceptibility is one of multiple factors involved in failure of miltefosine treatment in dermal leishmaniasis. PMID- 24145530 TI - Monotherapy with fluoroquinolone or trimethoprim-sulfamethoxazole for treatment of Stenotrophomonas maltophilia infections. AB - The treatment of choice for Stenotrophomonas maltophilia is trimethoprim sulfamethoxazole (SXT). Fluoroquinolones (FQs) have in vitro activity against S. maltophilia; however, there is limited published information on their effectiveness. The purpose of this study is to compare the effectiveness of FQs and SXT for the treatment of S. maltophilia. A retrospective review of 98 patients with S. maltophilia infections who received SXT or FQ monotherapy was conducted. Patients >=18 years old with a positive culture for S. maltophilia and clinical signs of infection who received treatment for >=48 h were included. Microbiological cure and clinical response were evaluated at the end of therapy (EOT). In-hospital mortality and isolation of nonsusceptible isolates were also evaluated. Thirty-five patients received SXT, and 63 patients received FQ; 48 patients received levofloxacin, and 15 patients received ciprofloxacin. The most common infection was pulmonary. The overall microbiological cure rate at EOT was 63%. Thirteen of 20 patients (65%) who received SXT and 23 of 37 patients (62%) who received FQ had microbiological cure at EOT (P = 0.832). The overall clinical success rate was 55%, 52% for those who received FQ and 61% for those who received SXT (P = 0.451). In-hospital mortality was 24%, with similar rates in the two groups (25% for FQ versus 22% for SXT; P = 0.546). Development of resistance on repeat culture was 30% for FQ and 20% for SXT (P = 0.426). Fluoroquinolone and SXT monotherapies may be equally effective for the treatment of S. maltophilia infections. Resistance was documented in subsequent isolates of S. maltophilia in both groups. PMID- 24145531 TI - Daptomycin dosing based on ideal body weight versus actual body weight: comparison of clinical outcomes. AB - Daptomycin use at our institution changed to ideal body weight dosing based on a published analysis of pharmacokinetic-pharmacodynamic efficacy target attainment, bacterial ecology, and a desire to reduce drug toxicity. The current study compared outcomes between actual body weight and ideal body weight dosing of daptomycin before and after this intervention. In the evaluable group, 69 patients received doses based on actual body weight and 48 patients received doses based on ideal body weight. Patients were treated for documented Enterococcus species, Staphylococcus aureus, or coagulase-negative Staphylococcus infections, including bloodstream, intraabdominal, skin and soft tissue, urinary, and bone. There was no statistically significant difference in clinical success between the groups (88.9% for actual body weight compared to 89.1% for ideal body weight, P = 0.97). After we adjusted for gender, age, body mass index, concomitant 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors, infection type, and organism type, clinical success rates remained similar between groups (adjusted odds ratio of 0.68 in favor of actual body weight, 95% confidence interval [CI] of 0.13 to 3.55). Microbiological outcomes, length of stay, mortality, and adverse effects were also similar between groups. Further studies are warranted to confirm that ideal body weight dosing provides similar outcomes to actual body weight dosing for all patients and types of infections and organisms. PMID- 24145532 TI - ARG-ANNOT, a new bioinformatic tool to discover antibiotic resistance genes in bacterial genomes. AB - ARG-ANNOT (Antibiotic Resistance Gene-ANNOTation) is a new bioinformatic tool that was created to detect existing and putative new antibiotic resistance (AR) genes in bacterial genomes. ARG-ANNOT uses a local BLAST program in Bio-Edit software that allows the user to analyze sequences without a Web interface. All AR genetic determinants were collected from published works and online resources; nucleotide and protein sequences were retrieved from the NCBI GenBank database. After building a database that includes 1,689 antibiotic resistance genes, the software was tested in a blind manner using 100 random sequences selected from the database to verify that the sensitivity and specificity were at 100% even when partial sequences were queried. Notably, BLAST analysis results obtained using the rmtF gene sequence (a new aminoglycoside-modifying enzyme gene sequence that is not included in the database) as a query revealed that the tool was able to link this sequence to short sequences (17 to 40 bp) found in other genes of the rmt family with significant E values. Finally, the analysis of 178 Acinetobacter baumannii and 20 Staphylococcus aureus genomes allowed the detection of a significantly higher number of AR genes than the Resfinder gene analyzer and 11 point mutations in target genes known to be associated with AR. The average time for the analysis of a genome was 3.35 +/- 0.13 min. We have created a concise database for BLAST using a Bio-Edit interface that can detect AR genetic determinants in bacterial genomes and can rapidly and easily discover putative new AR genetic determinants. PMID- 24145534 TI - First Report of bla(IMP-8) in Raoultella planticola. AB - Two carbapenem-resistant Raoultella planticola clinical isolates were isolated from patients with pneumonia and Port-A catheter-related bacteremia, respectively, in Taiwan. These isolates remained susceptible to fluoroquinolone, aminoglycoside, and colistin. Though the two isolates had the same antibiogram, plasmidic carbapenemase blaIMP-8, class 1 integron cassette (dfrA12-orfF-aadA2), and qnrB2, they had different pulsed-field gel electrophoresis patterns, plasmid sizes, and outer membrane protein loss profiles. To our knowledge, this is the first report of blaIMP-8 found in R. planticola. Interestingly, blaIMP-8 is the most common carbapenemase found in Klebsiella pneumoniae in Taiwan. In the literature, carbapenemase genes in R. planticola in each country were also found in carbapenem-resistant Enterobacteriaceae in the same country. PMID- 24145533 TI - A novel dengue virus inhibitor, BP13944, discovered by high-throughput screening with dengue virus replicon cells selects for resistance in the viral NS2B/NS3 protease. AB - Dengue virus (DENV) causes disease globally, resulting in an estimated 25 to 100 million new infections per year. No effective DENV vaccine is available, and the current treatment is only supportive. Thus, there is an urgent need to develop therapeutic agents to cure this epidemic disease. In the present study, we identified a potential small-molecule inhibitor, BP13944, via high-throughput screening (HTS) of 60,000 compounds using a stable cell line harboring an efficient luciferase replicon of DENV serotype 2 (DENV-2). BP13944 reduced the expression of the DENV replicon reporter in cells, showing a 50% effective concentration (EC50) of 1.03 +/- 0.09 MUM. Without detectable cytotoxicity, the compound inhibited replication or viral RNA synthesis in all four serotypes of DENV but not in Japanese encephalitis virus (JEV). Sequencing analyses of several individual clones derived from BP13944-resistant RNAs purified from cells harboring the DENV-2 replicon revealed a consensus amino acid substitution (E66G) in the region of the NS3 protease domain. Introduction of E66G into the DENV replicon, an infectious DENV cDNA clone, and recombinant NS2B/NS3 protease constructs conferred 15.2-, 17.2-, and 3.1-fold resistance to BP13944, respectively. Our results identify an effective small-molecule inhibitor, BP13944, which likely targets the DENV NS3 protease. BP13944 could be considered part of a more effective treatment regime for inhibiting DENV in the future. PMID- 24145535 TI - Types and prevalence of carbapenem-resistant Acinetobacter calcoaceticus Acinetobacter baumannii complex in Northern Taiwan. AB - The frequency of the carbapenem-resistant Acinetobacter calcoaceticus Acinetobacter baumannii (CRACB) complex increases annually in our hospitals. However, the types and prevalence of carbapenemases among isolates still remain unclear. In this study, we identified and collected 672 carbapenem-resistant isolates from a medical center in Northern Taiwan between April and December of 2010. There were 577 genospecies 2 (Acinetobacter baumannii), 79 genospecies 13TU, and 16 genospecies 3 isolates. The isolates had an acquired blaOXA-24-like gene, which was confirmed by sequencing for the encoded OXA-72 carbapenemase, and were often associated with high-level carbapenem resistance. These CRACB complex isolates remained susceptible to colistin (100%). The genotyping of isolates was conducted using pulsed-field gel electrophoresis with ApaI digestion. In most clonally related groups, patients were from both branch hospitals. The results indicate that interhospital dissemination of clones occurred. This study provides updated data on the types and prevalence of the CRACB complex. In addition, it presents a warning on the emergence and spread of CRACB complex harboring blaOXA 24-like genes in northern Taiwan. PMID- 24145536 TI - Retrospective molecular analysis of DIM-1 metallo-beta-lactamase discovered in Pseudomonas stutzeri from India in 2000. AB - Among 220 clinical isolates of Gram-negative bacilli collected in India during 2000, 22 strains showing elevated imipenem MICs were evaluated for carbapenemase production. One DIM-1-producing Pseudomonas stutzeri isolate was detected, and no other carbapenemase-encoding genes were identified. This detection of a DIM-1 producing P. stutzeri isolate from India predating the finding of this gene in the index Dutch strain and the very recent detection of DIM-1 in Africa suggest an unidentified environmental source of this metallo-beta-lactamase gene. PMID- 24145537 TI - Activities of fosfomycin and rifampin on planktonic and adherent Enterococcus faecalis strains in an experimental foreign-body infection model. AB - Enterococcal implant-associated infections are difficult to treat because antibiotics generally lack activity against enterococcal biofilms. We investigated fosfomycin, rifampin, and their combinations against planktonic and adherent Enterococcus faecalis (ATCC 19433) in vitro and in a foreign-body infection model. The MIC/MBClog values were 32/>512 MUg/ml for fosfomycin, 4/>64 MUg/ml for rifampin, 1/2 MUg/ml for ampicillin, 2/>256 MUg/ml for linezolid, 16/32 MUg/ml for gentamicin, 1/>64 MUg/ml for vancomycin, and 1/5 MUg/ml for daptomycin. In time-kill studies, fosfomycin was bactericidal at 8* and 16* MIC, but regrowth of resistant strains occurred after 24 h. With the exception of gentamicin, no complete inhibition of growth-related heat production was observed with other antimicrobials on early (3 h) or mature (24 h) biofilms. In the animal model, fosfomycin alone or in combination with daptomycin reduced planktonic counts by ~4 log10 CFU/ml below the levels before treatment. Fosfomycin cleared planktonic bacteria from 74% of cage fluids (i.e., no growth in aspirated fluid) and eradicated biofilm bacteria from 43% of cages (i.e., no growth from removed cages). In combination with gentamicin, fosfomycin cleared 77% and cured 58% of cages; in combination with vancomycin, fosfomycin cleared 33% and cured 18% of cages; in combination with daptomycin, fosfomycin cleared 75% and cured 17% of cages. Rifampin showed no activity on planktonic or adherent E. faecalis, whereas in combination with daptomycin it cured 17% and with fosfomycin it cured 25% of cages. Emergence of fosfomycin resistance was not observed in vivo. In conclusion, fosfomycin showed activity against planktonic and adherent E. faecalis. Its role against enterococcal biofilms should be further investigated, especially in combination with rifampin and/or daptomycin treatment. PMID- 24145538 TI - Low-molecular-mass penicillin binding protein 6b (DacD) is required for efficient GOB-18 metallo-beta-lactamase biogenesis in Salmonella enterica and Escherichia coli. AB - Metallo-beta-lactamases (MBLs) are Zn(2+)-containing secretory enzymes of clinical relevance, whose final folding and metal ion assembly steps in Gram negative bacteria occur after secretion of the apo form to the periplasmic space. In the search of periplasmic factors assisting MBL biogenesis, we found that dacD null (DeltadacD) mutants of Salmonella enterica and Escherichia coli expressing the pre-GOB-18 MBL gene from plasmids showed significantly reduced resistance to cefotaxime and concomitant lower accumulation of GOB-18 in the periplasm. This reduced accumulation of GOB-18 resulted from increased accessibility to proteolytic attack in the periplasm, suggesting that the lack of DacD negatively affects the stability of secreted apo MBL forms. Moreover, DeltadacD mutants of S. enterica and E. coli showed an altered ability to develop biofilm growth. DacD is a widely distributed low-molecular-mass (LMM) penicillin binding protein (PBP6b) endowed with low dd-carboxypeptidase activity whose functions are still obscure. Our results indicate roles for DacD in assisting biogenesis of particular secretory macromolecules in Gram-negative bacteria and represent to our knowledge the first reported phenotypes for bacterial mutants lacking this LMM PBP. PMID- 24145539 TI - Multiple mutations lead to MexXY-OprM-dependent aminoglycoside resistance in clinical strains of Pseudomonas aeruginosa. AB - Constitutive overproduction of the pump MexXY-OprM is recognized as a major cause of resistance to aminoglycosides, fluoroquinolones, and zwitterionic cephalosporins in Pseudomonas aeruginosa. In this study, 57 clonally unrelated strains recovered from non-cystic fibrosis patients were analyzed to characterize the mutations resulting in upregulation of the mexXY operon. Forty-four (77.2%) of the strains, classified as agrZ mutants were found to harbor mutations inactivating the local repressor gene (mexZ) of the mexXY operon (n = 33; 57.9%) or introducing amino acid substitutions in its product, MexZ (n = 11; 19.3%). These sequence variations, which mapped in the dimerization domain, the DNA binding domain, or the rest of the MexZ structure, mostly affected amino acid positions conserved in TetR-like regulators. The 13 remaining MexXY-OprM strains (22.8%) contained intact mexZ genes encoding wild-type MexZ proteins. Eight (14.0%) of these isolates, classified as agrW1 mutants, overexpressed the gene PA5471, which codes for the MexZ antirepressor ArmZ [corrected], with 5 strains exhibiting growth defects at 37 degrees C and 44 degrees C, consistent with mutations impairing ribosome activity. Interestingly, one agrW1 mutant appeared to harbor a 7-bp deletion in the coding sequence of the leader peptide, PA5471.1, involved in ribosome-dependent, translational attenuation of PA5471 expression. Finally, DNA sequencing and complementation experiments revealed that 5 (8.8%) strains, classified as agrW2 mutants, harbored single amino acid variations in the sensor histidine kinase of ParRS, a two-component system known to positively control mexXY expression. Collectively, these results demonstrate that clinical strains of P. aeruginosa exploit different regulatory circuitries to mutationally overproduce the MexXY-OprM pump and become multidrug resistant, which accounts for the high prevalence of MexXY-OprM mutants in the clinical setting. PMID- 24145540 TI - Anidulafungin versus caspofungin in a mouse model of candidiasis caused by anidulafungin-susceptible Candida parapsilosis isolates with different degrees of caspofungin susceptibility. AB - Candida parapsilosis isolates occasionally display resistance in vitro to echinocandins and cause breakthrough infections to echinocandins. The degree of the in vivo cross-resistance among echinocandins and the fitness loss associated with caspofungin (CAS) resistance of C. parapsilosis are not well studied. We compared the activities of CAS and anidulafungin (ANF), each given at 2 dosing schedules (high dose or low dose) in a nonneutropenic mouse model of invasive candidiasis (IC) caused by ANF-susceptible isolates of C. parapsilosis with different degrees of susceptibility to CAS (CAS resistant [CAS-R], MIC, >16 mg/liter; CAS intermediate [CAS-I], MIC, 4 mg/liter; and CAS susceptible [CAS-S], MIC, 2 mg/liter). We analyzed tissue fungal burden, histopathology, and weight loss patterns. Increasing CAS resistance was associated with reduced virulence of C. parapsilosis isolates (mortality rates for CAS-S versus CAS-I versus CAS-R, 100% versus 11.1% versus 0%, respectively; P < 0.001). High doses of either echinocandin were active against infection with the CAS-I isolate when assessed by fungal burden reduction and weight gain. In contrast to CAS-S and CAS-I isolates, there was no reduction in fungal burden in mice infected with the CAS-R isolate following treatment with either echinocandin, each given at a high or low dose. Nevertheless, mice infected with the CAS-R isolate had reduced disease severity following echinocandin treatment, suggesting that echinocandins have activity in vivo, even against echinocandin-resistant strains. A complex interplay of residual echinocandin activity, decreased virulence, and/or fitness of isolates with altered cell wall and possible immunomodulatory effects can be encountered in vivo during infection with CAS-resistant C. parapsilosis isolates. PMID- 24145541 TI - Ribavirin inhibits in vitro hepatitis E virus replication through depletion of cellular GTP pools and is moderately synergistic with alpha interferon. AB - Hepatitis E virus (HEV) is a common cause of acute hepatitis that results in high mortality in pregnant women and may establish chronic infections in immunocompromised patients. We demonstrate for the first time that alpha interferon (IFN-alpha) and ribavirin inhibit in vitro HEV replication in both a subgenomic replicon and an infectious culture system based on a genotype 3 strain. IFN-alpha showed a moderate but significant synergism with ribavirin. These findings corroborate the reported clinical effectiveness of both drugs. In addition, the antiviral activity of ribavirin against wild-type genotype 1, 2, and 3 strains was confirmed by immunofluorescence staining. Furthermore, the in vitro activity of ribavirin depends on depletion of intracellular GTP pools, which is evident from the facts that (i) other GTP-depleting agents (5-ethynyl-1 beta-d-ribofuranosylimidazole-4-carboxamide [EICAR] and mycophenolic acid) inhibit viral replication, (ii) exogenously added guanosine reverses the antiviral effects, and (iii) a strong correlation (R(2) = 0.9998) exists between the antiviral activity and GTP depletion of ribavirin and other GTP-depleting agents. PMID- 24145542 TI - Role of Neisseria meningitidis PorA and PorB expression in antimicrobial susceptibility. PMID- 24145543 TI - Pharmacokinetics of ganciclovir during continuous venovenous hemodiafiltration in critically ill patients. AB - Ganciclovir is an antiviral agent that is frequently used in critically ill patients with cytomegalovirus (CMV) infections. Continuous venovenous hemodiafiltration (CVVHDF) is a common extracorporeal renal replacement therapy in intensive care unit patients. The aim of this study was to investigate the pharmacokinetics of ganciclovir in anuric patients undergoing CVVHDF. Population pharmacokinetic analysis was performed for nine critically ill patients with proven or suspected CMV infection who were undergoing CVVHDF. All patients received a single dose of ganciclovir at 5 mg/kg of body weight intravenously. Serum and ultradiafiltrate concentrations were assessed by high-performance liquid chromatography, and these data were used for pharmacokinetic analysis. Mean peak and trough prefilter ganciclovir concentrations were 11.8 +/- 3.5 mg/liter and 2.4 +/- 0.7 mg/liter, respectively. The pharmacokinetic parameters elimination half-life (24.2 +/- 7.6 h), volume of distribution (81.2 +/- 38.3 liters), sieving coefficient (0.76 +/- 0.1), total clearance (2.7 +/- 1.2 liters/h), and clearance of CVVHDF (1.5 +/- 0.2 liters/h) were determined. Based on population pharmacokinetic simulations with respect to a target area under the curve (AUC) of 50 mg . h/liter and a trough level of 2 mg/liter, a ganciclovir dose of 2.5 mg/kg once daily seems to be adequate for anuric critically ill patients during CVVHDF. PMID- 24145544 TI - Escherichia coli with bla(IMP-8) in Singapore. PMID- 24145545 TI - Human cytomegalovirus UL97 kinase is involved in the mechanism of action of methylenecyclopropane analogs with 6-ether and -thioether substitutions. AB - Methylenecyclopropane nucleoside (MCPN) analogs are being investigated for treatment of human cytomegalovirus (HCMV) infection because of favorable preclinical data and limited ganciclovir cross-resistance. Monohydroxymethyl MCPNs bearing ether and thioether functionalities at the purine 6 position have antiviral activity against herpes simplex virus (HSV) and varicella-zoster virus (VZV) in addition to HCMV. The role of the HCMV UL97 kinase in the mechanism of action of these derivatives was examined. When tested against a kinase-inactive UL97 K355M virus, a moderate 5- to 7-fold increase in 50% effective concentration (EC50) was observed, in comparison to a 13- to 25-fold increase for either cyclopropavir or ganciclovir. Serial propagation of HCMV under two of these compounds selected for three novel UL97 mutations encoding amino acid substitutions D456N, C480R,and Y617del. When transferred to baseline laboratory HCMV strains, these mutations individually conferred resistance to all of the tested MCPNs, ganciclovir, and maribavir. However, the engineered strains also demonstrated severe growth defects and abnormal cytopathic effects similar to the kinase-inactive mutant. Expressed and purified UL97 kinase showed in vitro phosphorylation of the newly tested MCPNs. Thus, HCMV UL97 kinase is involved in the antiviral action of these MCPNs, but the in vitro selection of UL97-defective viruses suggests that their activity against more typical ganciclovir-resistant growth-competent UL97 mutants may be relatively preserved. PMID- 24145546 TI - Novel antifungal drug discovery based on targeting pathways regulating the fungus conserved Upc2 transcription factor. AB - Infections by Candida albicans and related fungal pathogens pose a serious health problem for immunocompromised patients. Azole drugs, the most common agents used to combat infections, target the sterol biosynthetic pathway. Adaptation to azole therapy develops as drug-stressed cells compensate by upregulating several genes in the pathway, a process mediated in part by the Upc2 transcription factor. We have implemented a cell-based high-throughput screen to identify small-molecule inhibitors of Upc2-dependent induction of sterol gene expression in response to azole drug treatment. The assay is designed to identify not only Upc2 DNA binding inhibitors but also compounds impeding the activation of gene expression by Upc2. An AlphaScreen assay was developed to determine whether the compounds identified interact directly with Upc2 and inhibit DNA binding. Three compounds identified by the cell-based assay inhibited Upc2 protein level and UPC2-LacZ gene expression in response to a block in sterol biosynthesis. The compounds were growth inhibitory and attenuated antifungal-induced sterol gene expression in vivo. They did so by reducing the level of Upc2 protein and Upc2 DNA binding in the presence of drug. The mechanism by which the compounds restrict Upc2 DNA binding is not through a direct interaction, as demonstrated by a lack of DNA binding inhibitory activity using the AlphaScreen assay. Rather, they likely inhibit a novel pathway activating Upc2 in response to a block in sterol biosynthesis. We suggest that the compounds identified represent potential precursors for the synthesis of novel antifungal drugs. PMID- 24145547 TI - The fluoroquinolone levofloxacin triggers the transcriptional activation of iron transport genes that contribute to cell death in Streptococcus pneumoniae. AB - We studied the transcriptomic response of Streptococcus pneumoniae to levofloxacin (LVX) under conditions inhibiting topoisomerase IV but not gyrase. Although a complex transcriptomic response was observed, the most outstanding result was the upregulation of the genes of the fatDCEB operon, involved in iron (Fe(2+) and Fe(3+)) uptake, which were the only genes varying under every condition tested. Although the inhibition of topoisomerase IV by levofloxacin did not have a detectable effect in the level of global supercoiling, increases in general supercoiling and fatD transcription were observed after topoisomerase I inhibition, while the opposite was observed after gyrase inhibition with novobiocin. Since fatDCEB is located in a topological chromosomal domain downregulated by DNA relaxation, we studied the transcription of a copy of the 422-bp (including the Pfat promoter) region located upstream of fatDCEB fused to the cat reporter inserted into the chromosome 106 kb away from its native position: PfatfatD was upregulated in the presence of LVX in its native location, whereas no change was observed in the Pfatcat construction. Results suggest that topological changes are indeed involved in PfatfatDCE transcription. Upregulation of fatDCEB would lead to an increase of intracellular iron and, in turn, to the activation of the Fenton reaction and the increase of reactive oxygen species. In accordance, we observed an attenuation of levofloxacin lethality in iron deficient media and in a strain lacking the gene coding for SpxB, the main source of hydrogen peroxide. In addition, we observed an increase of reactive oxygen species that contributed to levofloxacin lethality. PMID- 24145548 TI - Activity of and effect of subcutaneous treatment with the broad-spectrum antiviral lectin griffithsin in two laboratory rodent models. AB - Griffithsin (GRFT) is a red-alga-derived lectin that binds the terminal mannose residues of N-linked glycans found on the surface of human immunodeficiency virus type 1 (HIV-1), HIV-2, and other enveloped viruses, including hepatitis C virus (HCV), severe acute respiratory syndrome coronavirus (SARS-CoV), and Ebola virus. GRFT displays no human T-cell mitogenic activity and does not induce production of proinflammatory cytokines in treated human cell lines. However, despite the growing evidence showing the broad-spectrum nanomolar or better antiviral activity of GRFT, no study has reported a comprehensive assessment of GRFT safety as a potential systemic antiviral treatment. The results presented in this work show that minimal toxicity was induced by a range of single and repeated daily subcutaneous doses of GRFT in two rodent species, although we noted treatment associated increases in spleen and liver mass suggestive of an antidrug immune response. The drug is systemically distributed, accumulating to high levels in the serum and plasma after subcutaneous delivery. Further, we showed that serum from GRFT-treated animals retained antiviral activity against HIV-1-enveloped pseudoviruses in a cell-based neutralization assay. Overall, our data presented here show that GRFT accumulates to relevant therapeutic concentrations which are tolerated with minimal toxicity. These studies support further development of GRFT as a systemic antiviral therapeutic agent against enveloped viruses, although deimmunizing the molecule may be necessary if it is to be used in long term treatment of chronic viral infections. PMID- 24145549 TI - Antiviral effects of artesunate on polyomavirus BK replication in primary human kidney cells. AB - Polyomavirus BK (BKV) causes polyomavirus-associated nephropathy (PyVAN) and hemorrhagic cystitis (PyVHC) in renal and bone marrow transplant patients, respectively. Antiviral drugs with targeted activity against BKV are lacking. Since the antimalarial drug artesunate was recently demonstrated to have antiviral activity, the possible effects of artesunate on BKV replication in human primary renal proximal tubular epithelial cells (RPTECs), the host cells in PyVAN, were explored. At 2 h postinfection (hpi), RPTECs were treated with artesunate at concentrations ranging from 0.3 to 80 MUM. After one viral replication cycle (approximately 72 hpi), the loads of extracellular BKV DNA, reflecting viral progeny production, were reduced in a concentration-dependent manner. Artesunate at 10 MUM reduced the extracellular BKV load by 65%; early large T antigen mRNA and protein expression by 30% and 75%, respectively; DNA replication by 73%; and late VP1 mRNA and protein expression by 47% and 64%, respectively. Importantly, the proliferation of RPTECs was also inhibited in a concentration-dependent manner. At 72 hpi, artesunate at 10 MUM reduced cellular DNA replication by 68% and total metabolic activity by 47%. Cell impedance and lactate dehydrogenase measurements indicated a cytostatic but not a cytotoxic mechanism. Flow cytometry and 5-ethynyl-2'-deoxyuridine incorporation revealed a decreased number of cells in S phase and suggested cell cycle arrest in G0 or G2 phase. Both the antiproliferative and antiviral effects of artesunate at 10 MUM were reversible. Thus, artesunate inhibits BKV replication in RPTECs in a concentration-dependent manner by inhibiting BKV gene expression and genome replication. The antiviral mechanism appears to be closely connected to cytostatic effects on the host cell, underscoring the dependence of BKV on host cell proliferative functions. PMID- 24145550 TI - Distinctive origin and spread route of pyrimethamine-resistant Plasmodium falciparum in southern China. AB - Southeast Asia (the Thailand-Cambodia border) has been considered the primal epicenter for most antimalarial drug resistance; however, numerous molecular epidemiological studies have successively reported multiple independent origins of sulfadoxine-pyrimethamine (SP) resistance-associated Plasmodium falciparum dhfr (pfdhfr) and pfdhps alleles in other areas. To better understand the origin and evolutionary pathway of the SP resistance in Southeast Asia, a total of 374 P. falciparum field isolates from the Yunnan-Burma border and Hainan Island in southern China have been collected for comprehensive investigations on the mutation patterns of the pfdhfr/pfdhps genes as well as their microsatellite haplotypes. By comparative analysis of single-nucleotide polymorphism (SNP) genotyping and flanking microsatellite haplotypes, we reveal a unique origin of pyrimethamine-resistant mutations in Pfdhfr gene in Hainan Island and an oriented spread route of the pyrimethamine resistance from the Thailand-Cambodia border into the Hainan area, which reflects the geographical traits and SP administration histories in the two geographically independent areas. Moreover, genetic linkages between the high-level SP resistance-conferring pfdhfr/pfdhps alleles have been established in the isolates from the Yunnan-Burma border, raising the concern of a genetic basis in adopting combination chemotherapies against falciparum malaria. PMID- 24145551 TI - Informed choice in cancer screening. PMID- 24145552 TI - Particles without a box: brush-first synthesis of photodegradable PEG star polymers under ambient conditions. AB - Convenient methods for the rapid, parallel synthesis of diversely functionalized nanoparticles will enable discovery of novel formulations for drug delivery, biological imaging, and supported catalysis. In this report, we demonstrate parallel synthesis of brush-arm star polymer (BASP) nanoparticles by the "brush first" method. In this method, a norbornene-terminated poly(ethylene glycol) (PEG) macromonomer (PEG-MM) is first polymerized via ring-opening metathesis polymerization (ROMP) to generate a living brush macroinitiator. Aliquots of this initiator stock solution are added to vials that contain varied amounts of a photodegradable bis-norbornene crosslinker. Exposure to crosslinker initiates a series of kinetically-controlled brush+brush and star+star coupling reactions that ultimately yields BASPs with cores comprised of the crosslinker and coronas comprised of PEG. The final BASP size depends on the amount of crosslinker added. We carry out the synthesis of three BASPs on the benchtop with no special precautions to remove air and moisture. The samples are characterized by gel permeation chromatography (GPC); results agreed closely with our previous report that utilized inert (glovebox) conditions. Key practical features, advantages, and potential disadvantages of the brush-first method are discussed. PMID- 24145554 TI - TNF-alpha gene silencing using polymerized siRNA/thiolated glycol chitosan nanoparticles for rheumatoid arthritis. AB - Among various proinflammatory cytokines involved in the pathogenesis of rheumatoid arthritis (RA), tumor necrosis factor (TNF)-alpha plays a pivotal role in the release of other cytokines and induction of chronic inflammation. Even though siRNA has the therapeutic potential, they have a challenge to be delivered into the target cells because of their poor stability in physiological fluids. Herein, we design a nanocomplex of polymerized siRNA (poly-siRNA) targeting TNF alpha with thiolated glycol chitosan (tGC) polymers for the treatment of RA. Poly siRNA is prepared through self-polymerization of thiol groups at the 5' end of sense and antisense strand of siRNA and encapsulated into tGC polymers, resulting in poly-siRNA-tGC nanoparticles (psi-tGC-NPs) with an average diameter of 370 nm. In the macrophage culture system, psi-tGC-NPs exhibit rapid cellular uptake and excellent in vitro TNF-alpha gene silencing efficacy. Importantly, psi-tGC-NPs show the high accumulation at the arthritic joint sites in collagen-induced arthritis (CIA) mice. Treatment monitoring data obtained by the matrix metalloproteinase 3-specific nanoprobe and microcomputed tomography show that intravenous injection of psi-tGC-NPs significantly inhibits inflammation and bone erosion in CIA mice, comparable to methotrexate (5 mg/kg). Therefore, the availability of psi-tGC-NP therapy that target specific cytokines may herald new era in the treatment of RA. PMID- 24145553 TI - Vascular delivery of rAAVrh74.MCK.GALGT2 to the gastrocnemius muscle of the rhesus macaque stimulates the expression of dystrophin and laminin alpha2 surrogates. AB - Overexpression of GALGT2 in skeletal muscle can stimulate the glycosylation of alpha dystroglycan and the upregulation of normally synaptic dystroglycan-binding proteins, some of which are dystrophin and laminin alpha2 surrogates known to be therapeutic for several forms of muscular dystrophy. This article describes the vascular delivery of GALGT2 gene therapy in a large animal model, the rhesus macaque. Recombinant adeno-associated virus, rhesus serotype 74 (rAAVrh74), was used to deliver GALGT2 via the femoral artery to the gastrocnemius muscle using an isolated focal limb perfusion method. GALGT2 expression averaged 44 +/- 4% of myofibers after treatment in macaques with low preexisting anti-rAAVrh74 serum antibodies, and expression was reduced to 9 +/- 4% of myofibers in macaques with high preexisting rAAVrh74 immunity (P < 0.001; n = 12 per group). This was the case regardless of the addition of immunosuppressants, including prednisolone, tacrolimus, and mycophenolate mofetil. GALGT2-treated macaque muscles showed increased glycosylation of alpha dystroglycan and increased expression of dystrophin and laminin alpha2 surrogate proteins, including utrophin, plectin1, agrin, and laminin alpha5. These experiments demonstrate successful transduction of rhesus macaque muscle with rAAVrh74.MCK.GALGT2 after vascular delivery and induction of molecular changes thought to be therapeutic in several forms of muscular dystrophy. PMID- 24145555 TI - BECN1/Beclin 1 is recruited into lipid rafts by prion to activate autophagy in response to amyloid beta 42. AB - Prion protein (PRNP) has been implicated in various types of neurodegenerative diseases. Although much is known about prion diseases, the function of cellular PRNP remains cryptic. Here, we show that PRNP mediates amyloid beta1-42 (Abeta42) induced autophagy activation through its interaction with BECN1. Treatment with Abeta42 enhanced autophagy flux in neuronal cells. Abeta42-induced autophagy activation, however, was impaired in prnp-knockout primary cortical neurons and Prnp-knockdown or prnp-knockout neuronal cells. Immunoprecipitation assays revealed that PRNP interacted with BECN1 via the BCL2-binding domain of BECN1. This interaction promoted the subcellular localization of BECN1 into lipid rafts of the plasma membrane and enhanced activity of PtdIns3K (whose catalytic subunit is termed PIK3C3, mammalian ortholog of yeast VPS34) in lipid rafts by generating PtdIns3P in response to Abeta42. Further, the levels of lipid rafts that colocalized with BECN1, decreased in the brains of aged C57BL/6 mice, as did PRNP. These results suggested that PRNP interacts with BECN1 to recruit the PIK3C3 complex into lipid rafts and thus activates autophagy in response to Abeta42, defining a novel role of PRNP in the regulation of autophagy. PMID- 24145556 TI - Evaluation of corneal biomechanical properties following penetrating keratoplasty using ocular response analyzer. AB - PURPOSE: To evaluate corneal biomechanical properties in eyes that has undergone penetrating keratoplasty (PK). MATERIALS AND METHODS: Retrospective observational study in a tertiary care centre. Data recorded included ocular response analyzer (ORA) values of normal and post-keratoplasty eyes [corneal hysteresis (CH), corneal resistance factor (CRF), Goldmann-correlated intraocular pressure (IOPg), and cornea-compensated intraocular pressure (IOPcc)], corneal topography, and central corneal thickness (CCT). Wilcoxon signed rank test was used to analyze the difference in ORA parameter between post-PK eyes and normal eyes. Correlation between parameters was evaluated with Spearman's rho correlation. RESULTS: The ORA study of 100 eyes of 50 normal subjects and 54 post-keratoplasty eyes of 51 patients showed CH of 8.340 +/- 1.85 and 9.923 +/- 1.558, CRF of 8.846 +/- 2.39 and 9.577 +/- 1.631 in post-PK eyes and normal eyes, respectively. CH and CRF did not correlate with post-keratoplasty astigmatism (P = 0.311 and 0.276, respectively) while a significant correlation was observed with IOPg (P = 0.004) and IOPcc (P < 0.001). CONCLUSION: Biomechanical profiles were significantly decreased in post-keratoplasty eyes with significant correlation with higher IOP as compared with that in normal eyes. PMID- 24145557 TI - Ophthalmomyiasis externa by Musca domestica in a case of orbital metastasis. AB - Infestation of the living tissues of the eye, ocular adnexae or orbit by larvae of flies of the order Diptera is known as ophthalmomyiasis. Ophthalmomyiasis externa is a limited superficial infestation of external ocular structures such as conjunctiva and adnexae. A case of follicular carcinoma thyroid with orbital metastasis presenting as ophthalmomyiasis externa is reported. The patient presented with foul smelling ulcers of the medial and lateral orbital walls of the right eye extending into the lids and nose, teeming with maggots. Computerized Tomography (CT) showed widespread bone destruction with extension into surrounding sinuses. Over 200 maggots were manually removed after immobilisation with turpentine oil instillation. Entomological examination showed it to be a case of accidental myiasis caused by the common housefly Musca domestica. The patient was managed conservatively and the ulcer cavities filled up with healthy granulation tissue. This case is presented on account of its rarity. PMID- 24145558 TI - Comparison of visual field test results obtained through Humphrey matrix frequency doubling technology perimetry versus standard automated perimetry in healthy children. AB - AIMS: The aim of this study was to compare the visual field test results in healthy children obtained via the Humphrey matrix 24-2 threshold program and standard automated perimetry (SAP) using the Swedish interactive threshold algorithm (SITA)-Standard 24-2 test. MATERIALS AND METHODS: This prospective study included 55 healthy children without ocular or systemic disorders who underwent both SAP and frequency doubling technology (FDT) perimetry visual field testing. Visual field test reliability indices, test duration, global indices (mean deviation [MD], and pattern standard deviation [PSD]) were compared between the 2 tests using the Wilcoxon signed-rank test and paired t-test. The performance of the Humphrey field analyzer (HFA) 24-2 SITA-standard and frequency doubling technology Matrix 24-2 tests between genders were compared with Mann Whitney U-test. RESULTS: Fifty-five healthy children with a mean age of 12.2 +/- 1.9 years (range from 8 years to 16 years) were included in this prospective study. The test durations of SAP and FDT were similar (5.2 +/- 0.5 and 5.1 +/- 0.2 min, respectively, P = 0.651). MD and the PSD values obtained via FDT Matrix were significantly higher than those obtained via SAP (P < 0.001), and fixation losses and false negative errors were significantly less with SAP (P < 0.05). A weak positive correlation between the two tests in terms of MD (r = 0.352, P = 0.008) and PSD (r = 0.329, P = 0.014) was observed. CONCLUSION: Children were able to complete both the visual test algorithms successfully within 6 min. However, SAP testing appears to be associated with less depression of the visual field indices of healthy children. FDT Matrix and SAP should not be used interchangeably in the follow-up of children. PMID- 24145559 TI - The central retinal artery occlusion in the right eye followed by a branch retinal artery occlusion in the left eye four days later. AB - A 65-year-old woman was admitted to our clinic with complaints of sudden, painless, decrease in vision, and sectoral visual field defect in the left eye and later presented to our clinic again with a history of sudden loss of vision in her right eye. In this case study we reported that the patient had branch retinal artery occlusion (BRAO) in the left eye and at the same time progressing central retinal artery occlusion (CRAO) in the right eye. PMID- 24145560 TI - Dislocation of polyfocal full-optics accommodative intraocular lens after neodymium-doped yttrium aluminum garnet capsulotomy in vitrectomized eye. AB - We report a case of dislocation of WIOL-CF(r) polyfocal full-optics intraocular lens (IOL) after neodymium-doped yttrium aluminum garnet (Nd: YAG) laser capsulotomy in the vitrectomized eye. At 22 months before the dislocation of the IOL, a 55-year-old male patient underwent phacoemulsification with WIOL-CF(r) IOL implantation in a local clinic and 10 months after the cataract surgery the patient underwent pars plana vitrectomy, endolaser photocoagulation and 14% C 3 F 8 gas tamponade for the treatment of rhegmatogenous retinal detachment. At 9 months after the vitrectomy, the patient visited our clinic for a sudden decrease of vision after Nd: YAG capsulotomy in the local clinic. On fundus examination, the dislocated IOL was identified and the Nd: YAG capsulotomy site and the larger break, which is suspected to have been a route of the dislocation were observed in the posterior capsule. PMID- 24145561 TI - Cataract surgery in juvenile xanthogranuloma: case report and a brief review of literature. AB - There is limited literature on the management of cataracts in juvenile xanthogranuloma (JXG). A 2-month-old girl presented to us with hyphema, secondary glaucoma OU and skin nodules suggestive of JXG. She developed bilateral cataracts during her follow-up and was treated successfully with cataract surgery and aphakic rehabilitation. PMID- 24145562 TI - Long-term change in central corneal thickness from a glaucoma perspective. AB - AIM: To investigate the longitudinal change in central corneal thickness (CCT) over 3 years in patients with glaucoma. MATERIALS AND METHODS: The Chennai Glaucoma Follow-up Study, an offshoot of the Chennai Glaucoma Study, was designed to evaluate the progression of glaucoma. A cohort of participants in the Chennai Glaucoma Study that were suffering from glaucoma or were at a higher risk for glaucoma underwent comprehensive ophthalmic evaluation at the base hospital at 6 month intervals during the years 2004 to 2007. The CCT (average of 10 readings) was measured between 11 am and 1 pm on any given day using an ultrasonic pachymeter. Patients with a history of ocular surgery, corneal disease and usage of topical carbonic anhydrase inhibitor were excluded. No patient was a contact lens wearer. RESULTS: One hundred and ninety-six patients (84 male, 112 female) met the inclusion criteria. We analyzed data from the right eye. The mean age of the patients was 59.97 +/- 9.06 years. Fifty-nine (30.1%) of the patients were diabetic. The mean change in CCT (CCT at first patient visit--CCT at last patient visit) was 3.46 +/- 7.63 MUm. The mean change in CCT was 0.75 MUm per year (R2 = 0.00). Age, gender, intraocular pressure at the first patient visit and diabetic status had no significant influence on the magnitude of change in CCT. CONCLUSION: A carefully obtained CCT reading by a trained examiner need not be repeated for at least 3 years as long as the ocular and systemic factors known to affect the measurement of CCT are constant. PMID- 24145563 TI - Surgically induced astigmatism after 3.0 mm temporal and nasal clear corneal incisions in bilateral cataract surgery. AB - AIMS: To compare the corneal refractive changes induced after 3.0 mm temporal and nasal corneal incisions in bilateral cataract surgery. MATERIALS AND METHODS: This prospective study comprised a consecutive case series of 60 eyes from 30 patients with bilateral phacoemulsification that were implanted with a 6.0 mm foldable intraocular lens through a 3.0 mm horizontal clear corneal incision (temporal in the right eyes, nasal in the left eyes). The outcome measures were surgically induced astigmatism (SIA) and uncorrected visual acuity (UCVA) 1 and 3 months, post-operatively. RESULTS: At 1 month, the mean SIA was 0.81 diopter (D) for the temporal incisions and 0.92 D for nasal incisions (P = 0.139). At 3 months, the mean SIA were 0.53 D for temporal incisions and 0.62 D for nasal incisions (P = 0.309). The UCVA was similar in the 2 incision groups before surgery, and at 1 and 3 months post-operatively. CONCLUSION: After bilateral cataract surgery using 3.0 mm temporal and nasal horizontal corneal incisions, the induced corneal astigmatic change was similar in both incision groups. Especially in Asian eyes, both temporal and nasal incisions (3.0 mm or less) would be favorable for astigmatism-neutral cataract surgery. PMID- 24145564 TI - Is being female a risk factor for shallow anterior chamber? The associations between anterior chamber depth and age, sex, and body height. AB - AIM OF STUDY: To analyze the association between anterior chamber depth (ACD) and age, sex, and body height (BH). MATERIALS AND METHODS: One thousand four hundred eighty eyes of 1480 adults 40 years of age and older receiving preoperative evaluation for cataract surgery were recruited consecutively from June 1, 2006, to December 31, 2010. ACD was measured with the Zeiss IOLMaster. Univariate and multivariate linear regression models were used to analyze the correlations, and receiving operator characteristic (ROC) curves and the area under the curve (AUC) were used for evaluating the predictability of an ACD less than 2.70 mm. RESULTS: ACD was negatively correlated with age and positively correlated with BH in both univariate and multivariate regression analysis (P < 0.001). Sex was associated with ACD in univariate analysis, but not after adjustment with age and BH. In predicting an ACD less than 2.70 mm, the AUCs of ROC curves for 'age and sex', 'age and BH', and 'age, sex, and BH' were 0.687, 0.689, and 0.689, respectively. CONCLUSION: Age and BH were independent associating factors of ACD; however, sex was not. Older people and shorter ones likely had shallower ACD, and therefore were predisposed to Primary angle closure glaucoma (PACG). The predictability of ACD by age and BH solely was low, and adding sex did not increase it. PMID- 24145565 TI - Analysis of prenatal and postnatal risk factors of retinopathy of prematurity in a tertiary care hospital in South India. AB - CONTEXT: Recent advances in neonatology have influenced the incidence and severity of ROP in a dichotomous fashion. AIMS: To determine the incidence of ROP and to analyse its risk factors. SETTINGS AND DESIGN: Prospective clinical case series. MATERIALS AND METHODS: 282 preterm infants with birthweight < 1500 g and/or gestational age <= 32 weeks and also those with gestational age > 32 weeks, with birthweight between 1500-2000 g, who were at risk for ROP were selected. Weight gain proportion was measured as weight at 6 weeks minus birthweight divided by birthweight. STATISTICAL ANALYSIS: Univariate and multivariate logistic regression. RESULTS: Incidence of any ROP was 21.6% while severe ROP was 6.7%. Prenatal factors like multiple gestation (P = 0.510) and antenatal steroids (P = 0.104) were not significantly associated with ROP. On multivariate analysis, postnatal factors like weight at birth < 1250 g (P = 0.01) and gestational age between 31-32 weeks (P = 0.02) were independent risk factors for any ROP, while intraventricular hemorrhage (P = 0.03) was the only independent risk factor for severe ROP. Mean birthweight of infants with severe ROP was 1056 MU 207 g (P = 0.004), which was significantly low. After logistic regression, the mean weight gain proportion at 6 weeks, of those neonates with severe ROP was 30%. CONCLUSIONS: Low birthweight and prematurity were the most important risk factors for developing any ROP, while intraventricular hemorrhage was the independent risk factor for developing severe ROP. The mean postnatal weight gain at 6 weeks was not statistically significant in neonates with severe ROP. PMID- 24145566 TI - Profile of serpiginous choroiditis in a tertiary eye care centre in eastern India. AB - PURPOSE: To study the clinical profile of serpiginous choroiditis in eastern India. MATERIALS AND METHODS: Ninety-one eyes of 54 patients with serpiginous choroiditis presenting to a tertiary care centre in eastern India between January 2006 and December 2010 were included in the study. Clinical presentation, treatment given, and visual outcome of the eyes were studied. RESULTS: Thirty five (64.8%) patients were male and 19 (35.2%) were female in the age group of 13 62 years (mean age: 34.1 MU 18.7 years). Blurring of vision (71; 78%) and floaters (36; 39.5%) were commonest symptoms. In 75 (82.4%) eyes, choroiditis started from optic nerve head and spreading centrifugally. Overall, 38 (41.75%) eyes had macular involvement at first visit. Mantoux test reading was 10 mm or more (Group A) in 12 (22.22%) patients and less than 10 mm (Group B) in 42 (77.77%) patients. Difference between Groups A and B in macular involvement at first visit (10; 50% vs. 28; 39.4%) and rate of recurrence (3; 15% vs. 14; 19.7%) was not statistically significant (P = 0.37 and 0.68). Oral steroid (51; 94.4%) was the commonest mode of treatment. Fifty-one (56%) eyes had two lines or more improvement in vision. CONCLUSIONS: The present study details the clinical presentation, treatment, and visual outcome of serpiginous choroiditis. Mantoux test reading does not affect the clinical presentation or the treatment outcome in these eyes. PMID- 24145567 TI - Corrrection of exotropia by implantable collamer lens. PMID- 24145568 TI - Mean platelet volume as a marker of branch retinal vein occlusion may be influenced by many factors. PMID- 24145569 TI - Delayed diagnosis of ocular syphilis that manifested as retinal vasculitis and acute posterior multifocal placoid epitheliopathy. AB - A 55-year-old female presented with bilateral progressive retinal vasculitis. She was on systemic and intravitreal steroids on the basis of uveitis work-up result (negative result including rapid plasma reagin), but her visual acuity continued to deteriorate to light perception only. Ocular examination showed retinal vasculitis, multiple yellow placoid lesions and severe macula edema in both eyes. Repeated work-up revealed positivity of fluorescent treponemal antibody absorption in serum and subsequently in cerebrospinal fluid. Ocular syphilis was diagnosed. And intravenous penicillin G resulted in rapid resolution of vasculitis and macular edema. To avoid delay in the diagnosis of ocular syphilis, high index of suspicion and repeating serological tests (including both treponemal and non-treponemal tests) are warranted. PMID- 24145570 TI - IIH with normal CSF pressures? AB - Idiopathic intracranial hypertension (IIH) is a condition of raised intracranial pressure (ICP) in the absence of space occupying lesions. ICP is usually measured by lumbar puncture and a cerebrospinal fluid (CSF) pressure above 250 mm H2O is one of the diagnostic criteria of IIH. Recently, we have encountered two patients who complained of headaches and exhibited disc swelling without an increased ICP. We prescribed acetazolamide and followed both patients frequently; because of the definite disc swelling with IIH related symptoms. Symptoms and signs resolved in both patients after they started taking acetazolamide. It is generally known that an elevated ICP, as measured by lumbar puncture, is the most important diagnostic sign of IIH. However, these cases caution even when CSF pressure is within the normal range, that suspicion should be raised when a patient has papilledema with related symptoms, since untreated papilledema may cause progressive and irreversible visual loss. PMID- 24145572 TI - Optical quality of hyperopic and myopic phakic intraocular lenses. AB - AIMS: To assess and compare the optical quality of the myopic and hyperopic implantable collamer lens (ICL) from its wavefront aberrations for different powers and pupil diameters. SETTINGS AND DESIGN: Prospective study. MATERIAL AND METHODS: The wavefront aberrations of two myopic (-3 and -6 diopters (D)) and two hyperopic V4b ICLs (+3 and +6D) were measured in vitro. To assess and compare the optical quality of different powers of ICLs, we analyzed the root mean square (RMS) of total higher order aberrations (HOAs), trefoil, coma, tetrafoil, secondary astigmatism, and spherical aberration at 3- and 4.5-mm pupil. In addition, the point spread functions (PSFs) of each ICL evaluated were calculated from the wavefront aberrations at 3- and 4.5-mm pupil. STATISTICAL ANALYSIS: A Student's t-test for unpaired data was used for comparison between myopic and hyperopic ICLs. RESULTS: Myopic ICLs showed negative spherical aberration, in contrast hyperopic ICLs showed positive spherical aberration, which increases when the ICL power increases, due to the innate optical properties of the lens. All ICLs evaluated had negligible amounts of other aberrations. We did not find statistical significant differences in any Zernike coefficient RMS values analyzed between myopic and hyperopic ICLs at 3- and 4.5-mm pupil (P > 0.05). CONCLUSIONS: Myopic and hyperopic ICLs provide good and comparable optical quality for low to moderate refractive error. The ICLs evaluated showed values of wavefront aberrations clinically negligible to affect the visual quality after implantation. PMID- 24145571 TI - Effect of the combination of basic fibroblast growth factor and cysteine on corneal epithelial healing after photorefractive keratectomy in patients affected by myopia. AB - BACKGROUND: This study sought to evaluate the effect of basic fibroblast growth factor eye drops and cysteine oral supplements on corneal healing in patients treated with photorefractive keratectomy (PRK). MATERIALS AND METHODS: One hundred and twenty patients treated bilaterally with PRK for myopia were enrolled at one of two eye centers (Clinica Santa Lucia, Bologna, Italy and Department of Ophthalmology, University of Magna Graecia, Catanzaro, Italy) and were treated at the former center. Sixty patients included in the study group (Group 1) were treated postoperatively with topical basic fibroblast growth factor plus oral L cysteine supplements, whereas 60 subjects included in the control group (Group 2) received basic fibroblast growth factor eye drops. We recorded the rate of corneal re-epithelialization and patients were followed-up every 30 days for 6 months. Statistical analyses were performed on the collected data. RESULTS: The eyes in Group 1 demonstrated complete re-epithelialization at Day 5, whereas the eyes in Group 2 achieved this status on Day 6. No side-effects were reported. CONCLUSIONS : Patients treated with basic fibroblast growth factor eye drops and L-cysteine oral supplements benefit from more rapid corneal re-epithelialization. In human eyes, this combination treatment appeared to be safe and effective in accelerating corneal surfacing after surgery. FINANCIAL DISCLOSURE: No author has any financial or proprietary interest in any material or method used in this study. TRIAL REGISTRATION: Current Controlled Trials ISRCTN73824458. PMID- 24145573 TI - Outcome of surgery in post-cytomegalovirus retinal detachment: experience before and in the era of highly active anti-retroviral therapy in Indian eyes. AB - PURPOSE: To evaluate the outcome of surgery for cytomegalovirus associated retinal detachment (CMVRD) in human immunodeficiency virus (HIV)-infected patients in pre-highly active antiretroviral therapy (HAART) and HAART era in Indian eyes. MATERIALS AND METHODS: Retrospective, we reviewed medical records of all consecutive HIV patients, who underwent surgical repair for CMVRD from July 1998 to June 2011. We divided patients into two groups, i.e. group 1, pre HAART era and group 2, HAART era. We compared two groups for various parameters like visual outcome, surgical success, additional procedures, follow-up, etc., RESULTS: Twenty-eight eyes of 26 patients were included; 12 eyes of the 11 patients in group 1 and 16 eyes of the 15 patients in group 2. Significant visual acuity improvement was seen in both groups. Complete anatomic success was seen in 11 eyes in group 1 and 15 eyes in group 2. One additional procedure in group 1 and 29 additional procedures were done in group 2. A mean follow-up was 16 months in group 1 and 41 months in group 2. CONCLUSION: There was no difference in outcome in pre-HAART and HAART group, except for longer follow-up and additional surgical procedures in HAART group. PMID- 24145574 TI - Rapid high throughput amylose determination in freeze dried potato tuber samples. AB - This protocol describes a high through put colorimetric method that relies on the formation of a complex between iodine and chains of glucose molecules in starch. Iodine forms complexes with both amylose and long chains within amylopectin. After the addition of iodine to a starch sample, the maximum absorption of amylose and amylopectin occurs at 620 and 550 nm, respectively. The amylose/amylopectin ratio can be estimated from the ratio of the 620 and 550 nm absorbance values and comparing them to a standard curve in which specific known concentrations are plotted against absorption values. This high throughput, inexpensive method is reliable and reproducible, allowing the evaluation of large populations of potato clones. PMID- 24145575 TI - A sulfur rich electron acceptor and its [Fe(Cp*)2]+ charge transfer salt with ferromagnetic interactions. AB - The study of a side product of the aerial dithiolene oxidation allowed the rational and efficient synthesis of a sulfur rich electron acceptor, (E)-3,3' diethyl-5,5'-bithiazolidinylidene-2,4,2',4'-tetrathione, that presents easily accessible redox states and forms with decamethylferrocene a charge transfer salt exhibiting ferromagnetic coupling. PMID- 24145576 TI - Dietary practices in isolated First Nations communities of northern Canada: combined isotopic and lipid markers provide a good qualitative assessment of store-bought vs locally harvested foods consumption. AB - OBJECTIVE: In First Nations communities of northwestern Ontario, where rates of type 2 diabetes mellitus are some of the highest in the world, ascertaining wild food dietary practices is extremely challenging owing to seasonal availability, environmental factors, life circumstances and language/cultural barriers. The purpose of this study was to determine whether analysis of isotopic and fatty acid (FA) profiles could provide more comprehensive information to discriminate between three categories of wild food consumption (that is, plants and animals) in two isolated First Nations communities of northwestern Ontario. In addition, this analysis also highlights whether wild food consumption as practiced in these two communities can increase circulating levels of polyunsaturated FAs (PUFAs), which provide a number of important metabolic benefits that could impact the prevention/treatment of T2DM. RESULTS: (13)C enrichment (in expired CO2, plasma and hair), (15)N enrichment (in hair) and FA profiles in plasma phospholipids (phospholipid fatty acid (PL-FA)) were quantified in men and in women consuming various amounts of wild food. (13)C/(12)C ratios were lower and (15)N/(14)N ratios were higher in participants consuming wild food at least once a week. In addition, FA results indicated that the relative contributions of 20:4 Omega-6 and 22:6 Omega-3 to total PL-FAs were higher and 18:2 Omega-6 lower in wild food consumers. CONCLUSION: Together, these findings confirm that isotopic and lipid markers discriminate between the different wild food categories in these two First Nations communities. Knowing the close relationship between dietary intake and the potential role of PUFA in the prevention/treatment of obesity and obesity related diseases, it is critical to accurately measure the composition of diet for individuals in their specific environments. PMID- 24145577 TI - ER stress in rodent islets of Langerhans is concomitant with obesity and beta cell compensation but not with beta-cell dysfunction and diabetes. AB - OBJECTIVE: The objective of this study was to determine whether ER stress correlates with beta-cell dysfunction in obesity-associated diabetes. METHODS: Quantitative RT-PCR and western blot analysis were used to investigate changes in the expression of markers of ER stress, the unfolded protein response (UPR) and beta-cell function in islets isolated from (1) non-diabetic Zucker obese (ZO) and obese female Zucker diabetic fatty (fZDF) rats compared with their lean littermates and from (2) high-fat-diet-fed fZDF rats (HF-fZDF), to induce diabetes, compared with age-matched non-diabetic obese fZDF rats. RESULTS: Markers of an adaptive ER stress/UPR and beta-cell function are elevated in islets isolated from ZO and fZDF rats compared with their lean littermates. In islets isolated from HF-fZDF rats, there was no significant change in the expression of markers of ER stress compared with age matched, obese, non-diabetic fZDF rats. CONCLUSIONS: These results provide evidence that obesity-induced activation of the UPR is an adaptive response for increasing the ER folding capacity to meet the increased demand for insulin. As ER stress is not exacerbated in high-fat-diet-induced diabetes, we suggest that failure of the islet to mount an effective adaptive UPR in response to an additional increase in insulin demand, rather than chronic ER stress, may ultimately lead to beta-cell failure and hence diabetes. PMID- 24145578 TI - Screening for cognitive impairment in older adults: A systematic review for the U.S. Preventive Services Task Force. AB - BACKGROUND: Earlier identification of cognitive impairment may reduce patient and caregiver morbidity. PURPOSE: To systematically review the diagnostic accuracy of brief cognitive screening instruments and the benefits and harms of pharmacologic and nonpharmacologic interventions for early cognitive impairment. DATA SOURCES: MEDLINE, PsycINFO, and the Cochrane Central Register of Controlled Trials through December 2012; systematic reviews; clinical trial registries; and experts. STUDY SELECTION: English-language studies of fair to good quality, primary care feasible screening instruments, and treatments aimed at persons with mild cognitive impairment or mild to moderate dementia. DATA EXTRACTION: Dual quality assessment and abstraction of relevant study details. DATA SYNTHESIS: The Mini Mental State Examination (k = 25) is the most thoroughly studied instrument but is not available for use without cost. Publicly available instruments with adequate test performance to detect dementia include the Clock Drawing Test (k = 7), Mini-Cog (k = 4), Memory Impairment Screen (k = 5), Abbreviated Mental Test (k = 4), Short Portable Mental Status Questionnaire (k = 4), Free and Cued Selective Reminding Test (k = 2), 7-Minute Screen (k = 2), and Informant Questionnaire on Cognitive Decline in the Elderly (k = 5). Medications approved by the U.S. Food and Drug Administration for Alzheimer disease (k = 58) and caregiver interventions (k = 59) show a small benefit of uncertain clinical importance for patients and their caregivers. Small benefits are also limited by common adverse effects of acetylcholinesterase inhibitors and limited availability of complex caregiver interventions. Although promising, cognitive stimulation (k = 6) and exercise (k = 10) have limited evidence to support their use in persons with mild to moderate dementia or mild cognitive impairment. LIMITATION: Limited studies in persons with dementia other than Alzheimer disease and sparse reporting of important health outcomes. CONCLUSION: Brief instruments to screen for cognitive impairment can adequately detect dementia, but there is no empirical evidence that screening improves decision making. Whether interventions for patients or their caregivers have a clinically significant effect in persons with earlier detected cognitive impairment is still unclear. PRIMARY FUNDING SOURCE: Agency for Healthcare Research and Quality. PMID- 24145579 TI - Icaritin reverses multidrug resistance of HepG2/ADR human hepatoma cells via downregulation of MDR1 and P-glycoprotein expression. AB - Multidrug resistance (MDR) of tumor cells is a serious obstacle encountered in cancer treatment. In the current study a multiple drug-resistant HepG2/adriamycin (HepG2/ADR) cell line was established and its MDR was characterized. Icaritin, an active ingredient isolated from the medical plant Herba Epimedium, was observed to reverse MDR in the present model. Icaritin significantly increased the intracellular accumulation of ADR and decreased the expression of the MDR1 gene in HepG2/ADR cells compared with drug-sensitive HepG2 cells. In addition, the present results showed that icaritin may significantly downregulate the expression of P-glycoprotein. These results indicate that icaritin is a novel and potent MDR reversal agent and may be a promising drug for tumor chemotherapy. PMID- 24145580 TI - Coculture system with an organotypic brain slice and 3D spheroid of carcinoma cells. AB - Patients with cerebral metastasis of carcinomas have a poor prognosis. However, the process at the metastatic site has barely been investigated, in particular the role of the resident (stromal) cells. Studies in primary carcinomas demonstrate the influence of the microenvironment on metastasis, even on prognosis(1,2). Especially the tumor associated macrophages (TAM) support migration, invasion and proliferation(3). Interestingly, the major target sites of metastasis possess tissue-specific macrophages, such as Kupffer cells in the liver or microglia in the CNS. Moreover, the metastatic sites also possess other tissue-specific cells, like astrocytes. Recently, astrocytes were demonstrated to foster proliferation and persistence of cancer cells(4,5). Therefore, functions of these tissue-specific cell types seem to be very important in the process of brain metastasis(6,7). Despite these observations, however, up to now there is no suitable in vivo/in vitro model available to directly visualize glial reactions during cerebral metastasis formation, in particular by bright field microscopy. Recent in vivo live imaging of carcinoma cells demonstrated their cerebral colonization behavior(8). However, this method is very laborious, costly and technically complex. In addition, these kinds of animal experiments are restricted to small series and come with a substantial stress for the animals (by implantation of the glass plate, injection of tumor cells, repetitive anaesthesia and long-term fixation). Furthermore, in vivo imaging is thus far limited to the visualization of the carcinoma cells, whereas interactions with resident cells have not yet been illustrated. Finally, investigations of human carcinoma cells within immunocompetent animals are impossible(8). For these reasons, we established a coculture system consisting of an organotypic mouse brain slice and epithelial cells embedded in matrigel (3D cell sphere). The 3D carcinoma cell spheres were placed directly next to the brain slice edge in order to investigate the invasion of the neighboring brain tissue. This enables us to visualize morphological changes and interactions between the glial cells and carcinoma cells by fluorescence and even by bright field microscopy. After the coculture experiment, the brain tissue or the 3D cell spheroids can be collected and used for further molecular analyses (e.g. qRT-PCR, IHC, or immunoblot) as well as for investigations by confocal microscopy. This method can be applied to monitor the events within a living brain tissue for days without deleterious effects to the brain slices. The model also allows selective suppression and replacement of resident cells by cells from a donor tissue to determine the distinct impact of a given genotype. Finally, the coculture model is a practicable alternative to in vivo approaches when testing targeted pharmacological manipulations. PMID- 24145581 TI - Enhanced photocatalytic activity of TiO2-C hybrid aerogels for methylene blue degradation. AB - Carbon-based TiO2 composites have many advantages as photocatalysts. However, they suffer from low light efficiency due to the low contrast of TiO2 with carbon. We synthesized a novel type of anatase-type TiO2-C hybrid aerogel by a one-pot sol-gel method, which shows a photocatalytic activity for methylene degradation up to 4.23 times that of P25, a commercial photocatalyst from Degussa Inc. The hybrid aerogels are prepared from TiCl4 and resorcinol-furfural, and have a tunable macropore size from 167 to 996 nm. They are formed of submicrometer particles that consist of interwoven anatase and carbon nanoparticles. The anatase nanoparticles have a size of 8-9 nm and a tunable oxygen vacancy from 7.2 to 18.0%. The extremely high activity is ascribed to the large light absorption caused by macropore scattering and oxygen vacancies in the anatase. These findings may open up a new avenue and stimulate further research to improve photocatalytic performance. PMID- 24145583 TI - Hexa-substituted polyoxometalates made of trivacant Dawson {P2W15} fragments and {Ni6} clusters under hydrothermal conditions. AB - Three novel polyoxometalates (POMs) containing [Ni6(MU3-OH)3](9-) and [P2W15O56](12-) units were first made, showing the first hexa-nuclearity transition-metal substituted POMs (TMSPs) based on monomeric lacunary Dawson fragments, which further indicates that the hydrothermal technique can offer an effective way for making new TMSPs through lacunary POM fragments incorporated with high-nuclear TM clusters. PMID- 24145584 TI - Advancing medication infusion safety through the clinical integration of technology. AB - Adverse drug events resulting from errors in prescribing or administering medications are preventable. Within a hospital system, numerous technologies are employed to address the common sources of medication error, including the use of electronic medical records, physician order entry, smart infusion pumps, and barcode medication administration systems. Infusion safety is inherently risky because of the high-risk medications administered and the lack of integration among the stand-alone systems in most institutions. Intravenous clinical integration (IVCI) is a technology that connects electronic medical records, physician order entry, smart infusion pumps, and barcode medication administration systems. It combines the safety features of an automatically programmed infusion pump (drug, concentration, infusion rate, and patient weight, all auto-programmed into the device) with software that provides visibility to real-time clinical infusion data. Our article describes the characteristics of IVCI at WellSpan Health and its impact on patient safety. The integrated infusion system has the capability of reducing medication errors, improving patient care, reducing in-facility costs, and supporting asset management. It can enhance continuous quality improvement efforts and efficiency of clinical work flow. After implementing IVCI, the institution realized a safer patient environment and a more streamlined work flow for pharmacy and nursing. PMID- 24145585 TI - Update in perioperative medicine 2013. AB - Perioperative medicine is an important and rapidly expanding area of interest across multiple specialties, including internal medicine, anesthesiology, surgery, and hospital medicine. A multi-specialty team approach that ensures best possible patient outcomes has fostered collaborative strategies across the continuum of patient care. It is difficult to keep current in this multidisciplinary field, as physicians interested in perioperative medicine would need to review multiple specialty journals on a regular basis. To facilitate this process, we performed a focused review of this literature published in 2012. In this update, we review 9 key articles that potentially impact clinical practice in various areas of perioperative medicine including preoperative testing, cardiovascular medicine, pulmonary care, anticoagulation, and medication management. PMID- 24145586 TI - Evaluation of a process-of-care model for open intravesical ureteral reimplantation in children from a contemporary health care perspective. AB - INTRODUCTION: Surgical management of patients with vesicoureteral reflux consists of both open and minimally invasive approaches. Open approaches are associated with postoperative hospitalization and stays of 2 to 3 days, dependent on the type of procedure; alternately, when endoscopic correction is performed, it is a same-day procedure. Changes in health care policy emphasize reduction in cost while maintaining and improving quality of care. We sought to evaluate the impact of a "1-night cost-saving process-of-care" model for open surgical correction of vesicoureteral reflux in children on quality of care, which was defined as a return to the emergency room (ER)/office or readmission to the hospital within 2 days of discharge. MATERIALS AND METHODS: An institutional review board-approved retrospective chart review of all open ureteral reimplantations for uncomplicated vesicoureteral reflux from January 2009 through January 2013 was performed. Children who underwent ureteral stent placement and those who did not have a caudal anesthetic were excluded from the study. Length of postoperative stay, ER records, hospitalizations, and office records were reviewed to assess for presentation to the ER/office or readmission to the hospital within 2 days of discharge. RESULTS: During the 4-year study period, 92 children (23 males, 69 females) underwent open ureteral reimplantation-there were 83 (89.1%) discharges on the first postoperative day; 9 (9.8%) on the second postoperative day; and 1 (1.1%) on the third postoperative day. One patient presented to the ER within 2 days of discharge, and 4 patients presented to the ER/office or were readmitted > 2 days after discharge. CONCLUSION: Use of a caudal anesthetic, earlier catheter removal, a knowledgeable nursing team, and parental education allowed us to decrease the length of stay to 1 night in 82 of 92 patients (89.1%). These procedural changes allowed for a decrease in hospital stay comparable with and potentially shorter than robotic-assisted laparoscopic approaches. Additionally, these changes did not seem to increase the risk of early (<= 2 days of discharge) presentation to the ER/office or readmission. PMID- 24145587 TI - Salvage combination intravesical immunotherapy with Bacillus Calmette-Guerin and interferon-alpha2B: impact on recurrence, progression, and survival. AB - BACKGROUND: The population of patients with bladder cancer who have recurrence following an initial instillation of Bacillus Calmette-Guerin (BCG) is critical to study, as treatment delay with repeated courses of intravesical therapy may yield poor prognosis in patients with disease progression. OBJECTIVE: To evaluate our institution's experience with use of BCG alone and in combination with interferon (INF)-alpha2B in regard to the rates of bladder cancer recurrence, disease progression, need for eventual cystectomy, and survival in patients with initial BCG failure. STUDY DESIGN: We identified a combined series of 139 patients who had undergone intravesical instillations of BCG alone (n = 114) or in combination with INF-alpha2B (n = 25) performed at Brigham and Women's Hospital, Boston, between 2002 and 2007. All patients previously received an initial 6-week course of BCG therapy and subsequently had BCG failure on follow up cystoscopy. Study outcome measures included: time to cancer recurrence in patients, progression of disease, eventual cystectomy, and patient mortality. RESULTS: At a median follow-up of 64.7 months from initial BCG administration, 84% of patients treated with BCG + INF-alpha2B had disease recurrence. The average time to recurrence was < 1 year, and 63% of patients had recurrence on the first post-treatment biopsy. Among patients with a positive first biopsy, 52% had disease progression on initial surveillance. Overall, disease progression was seen in 48% of patients receiving BCG + INF-alpha2B therapy, and 28% of all patients eventually underwent radical cystectomy. All outcomes occurred more frequently in patients undergoing combination intravesical therapy compared with patients given BCG monotherapy. CONCLUSIONS: Patients with bladder cancer undergoing salvage intravesical BCG + INF-alpha2B at our institution had a > 50% chance of disease recurrence and progression, and > 25% of patients eventually proceeded to radical cystectomy. Randomized trials are needed to clarify the issues present in our findings and to determine the appropriate role for concomitant INF therapy in patients when BCG monotherapy has failed. PMID- 24145588 TI - Overview of myasthenia gravis. AB - Myasthenia gravis is an antibody-mediated disorder of neuromuscular transmission that is characterized by weakness and fatigue of voluntary muscles. Weakness may be ocular, bulbar, or generalized. Diagnostic evaluation of patients consists of bedside assessment, antibody testing, and electrophysiologic studies. Various therapeutic options are available, which consist of anticholinesterase inhibitors for symptomatic management, immunosuppressive agents as maintenance therapy, and thymectomy. Plasmapheresis and intravenous immunoglobulin are used in patients in crisis or those with rapidly worsening or refractory symptoms. In our article, we elaborate on key aspects of the epidemiology, pathogenesis, diagnostic evaluation, and therapeutic options for patients with myasthenia gravis. PMID- 24145589 TI - Elderly patients with type 2 diabetes mellitus-the need for high-quality, inpatient diabetes care. AB - Elderly patients (aged > 70 years) with diabetes are at high risk of hospitalization. We provide a detailed commentary about recent international clinical guidelines and a consensus statement devoted to elderly patients with type 2 diabetes mellitus in the context of hospitalization. In emergency departments, the 4 medication agents associated with the greatest number of patient adverse drug events are warfarin, oral glucose-lowering medications, insulin, and antiplatelet agents, all of which are commonly prescribed in older patients with diabetes. Comprehensive gerontological assessment, including review and, if indicated, discontinuation of all potentially unsafe or inappropriate patient medications should be done upstream to reduce the likelihood of adverse drugs events. Severe infections and ischemic heart disease are also frequent causes of acute admission into hospital in patients aged > 75 years. These patients are also likely to be malnourished and nutritional status should be monitored. Nutritional support, combined with specific products to avoid uncontrolled hyperglycemia must be implemented in patients at risk of malnutrition. Early exercise prescription may help patients maintain physical function and prevent the risk of falling. Clinical guidelines should be applied to achieve safe and effective patient target glucose levels. Insulin should be used earlier for its anabolic properties and patients closely monitored to reduce the risk of hypoglycemia and excessive hyperglycemia. The discharge plan needs to address full medical and social needs along with suitable follow-up to ensure a high level of patient safety. PMID- 24145590 TI - Obstructive sleep apnea in adults. AB - Obstructive sleep apnea (OSA) is the most common sleep-related breathing disorder characterized by repeated episodes of obstructed (apnea) or reduced (hypopnea) airflow in the upper airway during sleep. Obstructive sleep apnea results in variable arterial oxygen desaturations and arousals leading to sleep fragmentation. Most patients with OSA first come to the attention of a clinician when they complain of daytime sleepiness or when their bed partner reports loud snoring and witnessed episodes. Obstructive sleep apnea is associated with impaired quality of life, cardiovascular disease, metabolic syndrome, and motor vehicle accidents, yet the disorder remains undiagnosed in a significant portion of the population. Overnight polysomnography, whether facility-based or portable, is required for appropriate patient diagnosis. Portable monitoring can be used in patients with a high pre-test probability for moderate-to-severe OSA, who are without significant comorbidities. Management of OSA requires a long-term multidisciplinary approach. Continuous positive airway pressure (CPAP) remains the mainstay of treatment for patients with moderate-to-severe OSA. Oral appliances may be indicated in patients with mild-to-moderate OSA who do not wish to use CPAP. Surgical therapy is generally reserved for selected patients in whom CPAP or oral appliance are not an option. PMID- 24145591 TI - A review of the pathophysiology, diagnosis, and treatment of aortic valve stenosis in elderly patients. AB - Elderly patients experiencing valvular aortic stenosis (AS) show an increased prevalence of coronary risk factors, coronary artery disease, and other atherosclerotic vascular diseases. Angina pectoris, syncope or near syncope, and congestive heart failure are the 3 classic manifestations of severe AS in patients. Prolonged duration and late peaking of an aortic systolic ejection murmur best differentiate severe AS from mild AS upon physical examination of the patient. Doppler echocardiography is used to diagnose the severity of patient AS. In the article, indications for aortic valve replacement (AVR) in patients, the use of warfarin after AVR in patients with mechanical prostheses, and the use of aspirin or warfarin after AVR in patients with bioprosthesis are discussed. Transcatheter aortic valvular replacement should be performed in non-operable patients with symptomatic severe AS to improve their survival and quality of life rather than using regular medical management of the condition. PMID- 24145592 TI - A urologic oncology roundtable discussion: the role of disease monitoring in treatment decision-making for patients with metastatic castration-resistant prostate cancer. AB - A recent Elsevier survey of 200 urologists and oncologists who treat patients with castration-resistant prostate cancer (CRPC) identified a lack of physician confidence in understanding and using current clinical practices regarding the identification, treatment, and management of patients with CRPC. In response to this knowledge gap, a urologic oncology physician roundtable discussion was convened and a companion summary article created to provide a knowledge-based perspective for optimizing the identification, monitoring, and treatment of patients with metastatic CRPC (http://prostatecancer.urologiconcology.org/). Leading urology experts were selected to discuss how CRPC is defined and monitored, and to elaborate (through the presentation of 2 different cases) on considerations of how the currently approved chemotherapeutics, immunotherapy, and oral androgen inhibition agents can be used in the treatment of metastatic CRPC. PMID- 24145593 TI - A urologic oncology roundtable discussion: issues to consider in choosing treatment for metastatic castration-resistant prostate cancer. AB - A recent Elsevier survey of 100 urologists and 100 medical oncologists who treat patients with castration-resistant prostate cancer (CRPC) identified a knowledge gap in their understanding of the recently approved therapies and what information they wanted to know concerning how and when to properly prescribe these treatments. The survey also revealed that approximately 30% of urologists had yet to prescribe one of the newly approved therapies. In response to these findings, a panel of topic experts in the fields of oncology, nursing, and specialty pharmacy convened for a roundtable discussion and to develop a companion summary article to provide a knowledge-based perspective for physicians treating patients with metastatic CRPC (http://prostatecancer.urologiconcology.org/). These participating oncology experts discussed how CRPC is defined, how the newly approved agents should be sequenced in the management of a typical patient with CRPC, and the clinical considerations regarding the role of specialty pharmacy providers and nurse practitioners as patient advocates when selecting these therapies for treating metastatic CRPC. PMID- 24145594 TI - Case report of intracranial Rosai-Dorfman disease. AB - Rosai-Dorfman disease (RDD)-sinus histiocytosis with massive lymphadenopathy represents a peculiar proliferation of histiocyte-like cells in patients. The condition was described by Rosai and Dorfman in 1969, after examining 4 cases, as an idiopathic histiocytic disorder. In 1972, they studied an additional 30 cases of patients with RDD. A histioproliferative disorder, RDD is characterized by bilateral, painless, cervical lymphadenopathy in 81% of patients. Fever, leukocytosis, elevated sedimentation rate, and polyclonal hypergammaglobulinemia may also be found. In 30% of patients, extranodal involvement is present and may include the skin, eye orbit, upper respiratory tract, or testes. Cases involving the central nervous system are rare and account for < 5% of patients with RDD. We report on a 78-year-old woman presenting with new-onset headache, dizziness, and imbalance, which had been present for a few weeks prior to admission. Magnetic resonance imaging of the brain showed 2 enhancing lesions within the right and left cerebellar hemispheres. Biopsy of the mass demonstrated a lymphohistiocytic infiltrate involving the cerebellum with foci of emperipolesis (phagocytosed lymphocytes). The adjacent cerebellum showed myelinated nerve fibers with reactive gliosis. A thorough work-up and histopathologic exam of the biopsied mass demonstrated lymphohistiocytic infiltrate with foci of emperipolesis (phagocytosed lymphocytes) consistent with RDD. Other differential considerations, such as primary or secondary neoplasms, infections, lymphoproliferative disorders, granulomatoses, Langerhans cell histiocytosis, and lymphocyte-rich meningioma were ruled out by additional histopathologic exam. PMID- 24145595 TI - Anatomic localization of motor points of wrist flexors. AB - OBJECTIVE: The aim of this study was to determine the location of the motor points and the intramuscular branches of the wrist flexors in relation to bony landmarks. DESIGN: Sixteen limbs from eight adult cadavers were anatomically dissected. The motor branch points of the flexor carpi radialis and flexor carpi ulnaris muscles and the proximal limit points and the distal limit points in relation to a reference line connecting the medial epicondyle and the pisiform bone or one connecting the medial epicondyle and the base of the second metarcarpal bone were identified. RESULTS: For the flexor carpi radialis muscles, the motor branch points were located at a distance of 27% +/- 6% of the reference line, whereas the proximal limit points and the distal limit points were located at a distance of 21% +/- 5% and 37% +/- 8% of the reference line. For the flexor carpi ulnaris muscles, the corresponding data were 32% +/- 8%, 23% +/- 6%, and 43% +/- 9%. CONCLUSIONS: The results may assist in enhancing accuracy when localizing points for neuromuscular blockade of the wrist flexors. The optimal area for flexor carpi radialis muscle injection is at a quarter point and that for flexor carpi ulnaris muscle injection is at one-third point along each reference line from the medial epicondyle. PMID- 24145596 TI - Charge transfer dynamics in squaraine-naphthalene diimide copolymers. AB - The synthesis of an alternating squaraine-naphthalene diimide donor-acceptor low band gap polymer (1.14-1.40 eV) as well as its monomolecular analogue is presented. Spectroelectrochemistry experiments and transient absorption spectroscopy in the fs-time regime reveal an ultrafast population of a charge separated state for both polymer and monomer. Local excitation of the squaraine moiety is followed by population of intermediate states, presumably charge transfer states, followed by full charge separation, which occurs within a ca. 2 ps. Charge recombination takes place within 5.2 ps, probably because the system is close to the Marcus optimal region for barrierless ET. For the polymer, measurements of the transient absorption anisotropy show that neither charge nor does energy transfer take place within the lifetime of the charge separated state, indicating that this state is essentially confined within one donor acceptor pair. PMID- 24145597 TI - Less is more: Overdiagnosis and overtreatment: evaluation of what physicians tell their patients about screening harms. PMID- 24145598 TI - Investigating Clostridium difficile. AB - Clostridium difficile is one of the leading health-care-associated infections in the UK and has a significant clinical and economic impact. Optimal laboratory testing for this pathogen is controversial and interpretation of results can lead to confusion. In the context of the clinical syndrome of C. difficile infection, this article reviews disease presentation, the diagnostic tests available, and their translation into information that can assist clinical management at the bedside. PMID- 24145599 TI - How to prepare for and present at a journal club. AB - Presenting a paper at a journal club can be a daunting prospect for a trainee and one for which undergraduate medical education may leave the trainee feeling under prepared. However, the ability to critically appraise and present an academic paper is a competency required of the trainee doctor. PMID- 24145600 TI - Thiopurine toxicity. AB - Thiopurines are a class of immunosuppressant and antineoplastic drugs developed by Gertrude Elion and George Hitchings and patented in 1953 for use to treat leukaemia, then used to prevent transplant rejection (Marx, 2005). PMID- 24145601 TI - Antiviral therapy for the treatment and prophylaxis of influenza. AB - Influenza is a seasonal, viral, respiratory tract infection, presenting as a febrile illness with associated systemic upset. It causes biannual epidemics and occasional global pandemics. Diagnosis is made clinically with the assistance of real time polymerase chain reaction of nasopharyngeal swab specimens, and treatment is primarily aimed at symptom control. PMID- 24145602 TI - Efficient cross-coupling of aryl Grignard reagents with alkyl halides by recyclable ionic iron(III) complexes bearing a bis(phenol)-functionalized benzimidazolium cation. AB - A novel bis(phenol)-functionalized benzimidazolium salt, 1,3-bis(3,5-di-tert butyl-2-hydroxybenzyl)benzimidazolium chloride (H3LCl, 1), was designed and used to prepare ionic iron(III) complexes of the type [H3L][FeX4] (X = Cl, 2; X = Br, 3). Both 2 and 3 were characterized by elemental analysis, Raman spectroscopy, electrospray ionization mass spectrometry and X-ray crystallography. The catalytic performances of 2 and 3 in cross-coupling reactions using aryl Grignard reagents with primary and secondary alkyl halides bearing beta-hydrogens were studied. This analysis shows that complex 2 has good potential for alkyl chloride mediated coupling. In comparison, complex 3 showed slightly lower catalytic activity. After decanting the product contained in the ethereal layer, complex 2 could be recycled at least eight times without significant loss of catalytic activity. PMID- 24145603 TI - A modified heterotopic swine hind limb transplant model for translational vascularized composite allotransplantation (VCA) research. AB - Vascularized Composite Allotransplantation (VCA) such as hand and face transplants represent a viable treatment option for complex musculoskeletal trauma and devastating tissue loss. Despite favorable and highly encouraging early and intermediate functional outcomes, rejection of the highly immunogenic skin component of a VCA and potential adverse effects of chronic multi-drug immunosuppression continue to hamper widespread clinical application of VCA. Therefore, research in this novel field needs to focus on translational studies related to unique immunologic features of VCA and to develop novel immunomodulatory strategies for immunomodulation and tolerance induction following VCA without the need for long term immunosuppression. This article describes a reliable and reproducible translational large animal model of VCA that is comprised of an osteomyocutaneous flap in a MHC-defined swine heterotopic hind limb allotransplantation. Briefly, a well-vascularized skin paddle is identified in the anteromedial thigh region using near infrared laser angiography. The underlying muscles, knee joint, distal femur, and proximal tibia are harvested on a femoral vascular pedicle. This allograft can be considered both a VCA and a vascularized bone marrow transplant with its unique immune privileged features. The graft is transplanted to a subcutaneous abdominal pocket in the recipient animal with a skin component exteriorized to the dorsolateral region for immune monitoring. Three surgical teams work simultaneously in a well coordinated manner to reduce anesthesia and ischemia times, thereby improving efficiency of this model and reducing potential confounders in experimental protocols. This model serves as the groundwork for future therapeutic strategies aimed at reducing and potentially eliminating the need for chronic multi-drug immunosuppression in VCA. PMID- 24145604 TI - Resveratrol attenuates vascular endothelial inflammation by inducing autophagy through the cAMP signaling pathway. AB - Inflammation participates centrally in all stages of atherosclerosis (AS), which begins with inflammatory changes in the endothelium, characterized by expression of the adhesion molecules. Resveratrol (RSV) is a naturally occurring phytoalexin that can attenuate endothelial inflammation; however, the exact mechanisms have not been thoroughly elucidated. Autophagy refers to the normal process of cell degradation of proteins and organelles, and is protective against certain inflammatory injuries. Thus, we intended to determine the role of autophagy in the antiinflammatory effects of RSV in human umbilical vein endothelial cells (HUVECs). We found that RSV pretreatment reduced tumor necrosis factor ? (TNF/TNF?)-induced inflammation and increased MAP1LC3B2 (microtubule-associated protein 1 light chain 3 ? 2) expression and SQSTM1/p62 (sequestosome 1) degradation in a concentration-dependent manner. A bafilomycin A 1 (BafA1) challenge resulted in further accumulation of MAP1LC3B2 in HUVECs. Furthermore, autophagy inhibitors 3-methyladenine (3-MA), chloroquine as well as ATG5 and BECN1 siRNA significantly attenuated RSV-induced autophagy, which, subsequently, suppressed the downregulation of RSV-induced inflammatory factors expression. RSV also increased cAMP (cyclic adenosine monophosphate) content, the expression of PRKA (protein kinase A) and SIRT1 (sirtuin 1), as well as the activity of AMPK (AMP-activated protein kinase). RSV-induced autophagy in HUVECs was abolished in the presence of inhibitors of ADCY (adenylyl cyclase, KH7), PRKA (H-89), AMPK (compound C), or SIRT1 (nicotinamide and EX-527), as well as ADCY, PRKA, AMPK, and SIRT1 siRNA transfection, indicating that the effects of RSV on autophagy induction were dependent on cAMP, PRKA, AMPK and SIRT1. In conclusion, RSV attenuates endothelial inflammation by inducing autophagy, and the autophagy in part was mediated through the activation of the cAMP-PRKA-AMPK-SIRT1 signaling pathway. PMID- 24145605 TI - Truncation of gene F5L partially masks rescue of vaccinia virus strain MVA growth on mammalian cells by restricting plaque size. AB - Modified vaccinia virus Ankara (MVA) is a candidate vaccine vector that is severely attenuated due to mutations acquired during several hundred rounds of serial passage in vitro. A previous study used marker rescue to produce a set of MVA recombinants with improved replication on mammalian cells. Here, we extended the characterization of these rescued MVA strains and identified vaccinia virus (VACV) gene F5L as a determinant of plaque morphology but not replication in vitro. F5 joins a growing group of VACV proteins that influence plaque formation more strongly than virus replication and which are disrupted in MVA. These defective genes in MVA confound the interpretation of marker rescue experiments designed to map mutations responsible for the attenuation of this important VACV strain. PMID- 24145606 TI - Downregulation of miR-130a contributes to cisplatin resistance in ovarian cancer cells by targeting X-linked inhibitor of apoptosis (XIAP) directly. AB - MicroRNAs (miRNAs) are short, highly conserved small non-coding RNA molecules, which post-transcriptionally regulate genes expression and play crucial roles in diverse biological processes. Recent studies have shown that dysregulation of miRNAs might modulate the resistance of cancer cells to chemotherapeutic agents. To investigate the possible role of miR-130a in the development of cisplatin resistance in human ovarian cancer cell line A2780, we evaluated the expression of microRNA-130a (miR-130a) in the cells by the quantitative real-time reverse transcription-polymerase chain reaction. The results showed that miR-130a was significantly down-regulated in cisplatin-resistant ovarian cancer cells. MTT assay and flow cytometry (FCM) results showed that over-expression of miR-130a regulated apoptotic activity, and thereby cisplatin chemosensitivity, in ovarian cancer cells. Furthermore, we found that miR-130a can directly target XIAP, and participate in the regulation of apoptosis. The up-regulation of miR-130a led to a significant decrease in the XIAP mRNA levels and protein levels. XIAP plays an important role in cisplatin resistance in ovarian cancer cell line A2780. Our findings suggested that miR-130a could play a role in the development of cisplatin resistance in ovarian cancer cell line A2780, at least in part by modulation of apoptosis via targeting XIAP. PMID- 24145608 TI - A young woman with a divided left atrium. PMID- 24145609 TI - Variable selection. Editorial. PMID- 24145610 TI - Understanding the metabolic fate and assessing the biosafety of MnO nanoparticles by metabonomic analysis. AB - Recently, some types of MnO nanoparticle (Mn-NP) with favorable imaging capacity have been developed to improve the biocompatible profile of the existing Mn-based MRI contrast agent Mn-DPDP; however, the overall bio-effects and potential toxicity remain largely unknown. In this study, (1)H NMR-based metabolic profiling, integrated with traditional biochemical analysis and histopathological examinations, was used to investigate the absorption, distribution, metabolism, excretion and toxicity of Mn-NPs as candidates for MRI contrast agent. The metabolic responses in biofluids (plasma and urine) and tissues (liver, spleen, kidney, lung and brain) from rats could be divided into four classes following Mn NP administration: Mn biodistribution-dependent, time-dependent, dose-dependent and complicated metabolic variations. The variations of these metabolites involved in lipid, energy, amino acid and other nutrient metabolism, which disclosed the metabolic fate and biological effects of Mn-NPs in rats. The changes of metabolic profile implied that the disturbance and impairment of biological functions induced by Mn-NP exposure were correlated with the particle size and the surface chemistry of nanoparticles. Integration of metabonomic technology with traditional methods provides a promising tool to understand the toxicological behavior of biomedical nanomaterials and will result in informed decision-making during drug development. PMID- 24145611 TI - CDC73 mutational status and loss of parafibromin in the outcome of parathyroid cancer. AB - Inactivating mutations of the CDC73 tumor suppressor gene have been reported in parathyroid carcinomas (PC), in association with the loss of nuclear expression of the encoded protein, parafibromin. The aim of this study was to further investigate the role of the CDC73 gene in PC and evaluate whether gene carrier status and/or the loss of parafibromin staining might have an effect on the outcome of the disease. We performed genetic and immunohistochemical studies in parathyroid tumor samples from 35 patients with sporadic PC. Nonsense or frameshift CDC73 mutations were detected in 13 samples suitable for DNA sequencing. Six of these mutations were germline. Loss of parafibromin expression was found in 17 samples. The presence of the CDC73 mutation as well as the loss of parafibromin predicted a high likelihood of subsequent recurrence and/or metastasis (92.3%, P=0.049 and 94.1%, P=0.0017 respectively), but only the latter was associated with a decreased overall 5- and 10-year survival rates (59%, P=0.107, and 23%, P=0.0026 respectively). The presence of both the CDC73 mutation and loss of parafibromin staining compared with their absence predicted a lower overall survival at 10- (18 vs 84%, P=0.016) but not at 5-year follow-up. In conclusion, loss of parafibromin staining, better than CDC73 mutation, predicts the clinical outcome and mortality rate. The added value of CDC73 mutational analysis is the possibility of identifying germline mutations, which will prompt the screening of other family members. PMID- 24145612 TI - Association between novel adipocytokines adiponectin, vaspin, visfatin, and thyroid: An experimental and clinical update. AB - Adipose tissue secretes a variety of active biological substances, called adipocytokines, that act in an autocrine, paracrine, and endocrine manner. They have roles in appetite control, thermogenesis, and thyroid and reproductive functions. All these molecules may lead to local and generalized inflammation, mediating obesity-associated vascular disorders including hypertension, diabetes, atherosclerosis, and insulin resistance. Thyroid dysfunction is associated with changes in body weight, thermogenesis, and energy expenditure. The connections between cardiovascular risk factors such as dyslipidemia, impaired glucose tolerance, insulin resistance, atherosclerosis, and thyroid dysfunction have been reported in several studies. The adipocytokines serve as causative or protective factors in the development of these disorders in the states of thyroid dysfunction. Abnormal levels of adipocytokines (adiponectin (ADP), leptin, resistin, vaspin, and visfatin) in hypo- and hyperthyroidism have been reported with controversial results. This review aims to update the implication of novel adipokines ADP, vaspin, and visfatin in thyroid dysfunction. PMID- 24145613 TI - PKA regulatory subunit R2B is required for murine and human adipocyte differentiation. AB - ADIPOGENESIS IS A COMPLEX PROCESS MODULATED BY SEVERAL FACTORS, INCLUDING CAMP SIGNALING. THE MAIN CAMP TARGET IS PROTEIN KINASE A (PKA), A TETRAMERIC ENZYME WITH FOUR REGULATORY SUBUNITS SHOWING TISSUE-SPECIFIC EXPRESSION AND FUNCTION: PRKAR2B is the main regulatory subunit in adipose tissue in mice and in adult humans. This study aimed to evaluate the expression of PKA regulatory subunits in human adipose tissue during fetal development and to investigate their role in the differentiation of 3T3-L1 and primary human preadipocytes. The expression of PKA regulatory subunits was evaluated in fetal adipose tissue (immunohistochemistry) and in cultured 3T3-L1 and primary human preadipocytes (western blot analysis). Cultured cells were transiently transfected with siRNA against PRKAR2B and induced to differentiate. Differentiation was evaluated by intracellular triglyceride staining (Oil Red O) and expression of molecular markers of adipocyte differentiation. In this study, we found that PRKAR2B is the main regulatory subunit in human adipose tissue during fetal development, from 12 weeks of gestation to the end of gestation, as well as in 3T3-L1 and primary human preadipocytes. The expression of PRKAR2B increases progressively during in vitro differentiation. The silencing of PRKAR2B abolishes the increase in the expression of peroxisome proliferator-activated receptor gamma (PPARgamma (PPARG)), fatty acid synthase, aP2 (FABP4), and lipoprotein lipase, as well as intracellular triglyceride accumulation, resulting in impaired adipocyte differentiation in both mouse and human cell systems. In conclusion, PRKAR2B is the key PKA regulatory subunit involved in mouse and human adipose tissue development. The physiological increase in the expression of PRKAR2B is an essential event in adipogenesis in both mice and humans, and it might represent a possible target for future strategies for obesity treatment. PMID- 24145614 TI - Are pre-miR-146a and PTTG1 associated with papillary thyroid cancer? AB - Papillary thyroid carcinoma (PTC) is the most common endocrine malignancy, with a steadily increasing incidence in the last few decades worldwide. The predisposition to developing this carcinoma by the heterozygous state of rs2910164 within the precursor of the miR-146a has been reported, but recently not confirmed. Interestingly, on the same chromosome, almost 50 kb separate the pre-miR-146a from the pituitary tumor-transforming gene 1 (PTTG1), a proto oncogene involved in several tumors, including thyroid cancers. In this study, we analyzed, using a case-control design, the genetic association between PTC and the genomic region encompassing pre-miR-146a rs2910164 and PTTG1 rs1862391 and rs2910202. We enrolled 307 affected patients and 206 healthy controls. The possible presence of thyroid nodules in controls was excluded by ultrasonography. All the cases were submitted to single-nucleotide polymorphism (SNP) genotyping of pre-miR-146a and PTTG1, and risk association analyses were carried out. The genotypic and allelic frequencies of pre-miR-146a rs2910164 were not statistically different in the patients and controls, and this SNP was not in linkage disequilibrium with the investigated PTTG1 SNPs. Consistently, meta analyses, the first including all the affected cases published to date, did not confirm the previously reported association of the heterozygous CG genotype with PTC. The PTTG1 SNPs exhibited the same allelic frequency in the patients and controls and were not associated with the disease. In conclusion, in a well selected Italian population, neither pre-miR-146a rs2910164 nor PTTG1 rs1862391 and rs2910202 were found to be associated with the risk of developing PTC. PMID- 24145615 TI - Metabolic syndrome and its components among obese (BMI >=95th) Mexican adolescents. AB - The aim of this study was to estimate the prevalence of metabolic syndrome (MS) and its components in obese Mexican adolescents and to compare the clinical, anthropometric, and biochemical characteristics between patients with and without MS by sex. We conducted a cross-sectional study with a sample of 110 obese adolescents (boys and girls) from 8 to 16 years old (BMI >=95th percentile), who were recruited in the pediatric obesity clinic of a third-level care hospital. A frequency analysis was used to estimate the prevalence of MS and its components, and the assessments were compared between the sexes and between the groups with and without MS using the Kruskal-Wallis test. The prevalence of MS was 62%. IN ORDER OF PREVALENCE, THE FOLLOWING COMPONENTS OF MS WERE OBSERVED IN THE SAMPLE: abdominal obesity (88%), high triglycerides (TG) (85%), low HDL-C (60%), hypertension (35%), and hyperglycemia (5%). In the groups with MS, hypertension (P<0.001), waist circumference (P=0.003), and TG (P=0.012) were significantly higher, and HDL-C (P<0.001) was significantly lower. In conclusion the prevalence of MS and its components is high among obese Mexican-Hispanic children. These findings show the importance of preventing and treating obesity in the early stages of life in order to decrease the incidence rates of cardiovascular disease and type 2 diabetes mellitus. PMID- 24145616 TI - Lysophosphatidic acid activates beta-catenin/T cell factor signaling, which contributes to the suppression of apoptosis in H19-7 cells. AB - Lysophosphatidic acid (LPA) is a lipid growth factor that regulates diverse cell functions, including cell proliferation, survival and apoptosis. LPA has been demonstrated to be involved in the regulation of cortical neurogenesis by increasing the survival of neural precursors. Previously, we reported that LPA stimulated the inactivation of glycogen synthase kinase 3 (GSK3) via the G protein-coupled LPA1 and LPA2 receptors, by which apoptosis is suppressed in H19 7 cells [an embryonic hippocampal progenitor cell (HPC) line]. Increasing numbers of studies have demonstrated that certain G protein-coupled receptors activate beta-catenin/T cell factor (TCF) signaling independently of Wnt, which is involved in cell fate determination, cell proliferation and cell survival. To determine whether LPA activates beta-catenin-mediated transcriptional activation pathways and whether beta-catenin/TCF signaling is involved in neurogenesis by controlling the survival of neural precursors, beta-catenin/TCF signaling cascades induced by LPA were investigated in the HPCs. Activation of beta catenin/TCF signaling was determined by the nuclear translocation of beta-catenin and the transcriptional activation of a TCF reporter gene. The activation of beta catenin/TCF signaling was blocked by pertussis toxin (PTX) and a protein kinase C (PKC) inhibitor. The expression of a constitutively active mutated form of GSK3beta activated beta-catenin/TCF signaling to comparable levels to those induced by LPA, and protected against apoptosis in differentiating H19-7 cells. These results showed that LPA activates beta-catenin/TCF signaling in a PTX- and PKC-dependent manner, which contributes to LPA-induced cell survival in the HPCs. Activation of beta-catenin/TCF signaling by LPA may be involved in neurogenesis by controlling the survival of neural precursors. PMID- 24145617 TI - Coordination programming: science of molecular superstructures towards chemical devices. PMID- 24145618 TI - Effect of a low-intensity parent-focused nutrition intervention on dietary intake of 2- to 5-year olds. AB - OBJECTIVES: Community-based nutrition interventions aimed at influencing child dietary intake are rarely evaluated. We hypothesised that providing self-directed nutrition and parenting resources to parents living in rural northern New South Wales, Australia, would positively affect the dietary patterns of children ages 2 to 5 years. METHODS: A total of 146 parent-child dyads (76 boys, ages 2.0-5.9 years) were randomly assigned to either a 12-month parent-centred intervention involving self-directed education provided in CD and DVD formats, or a participant-blinded control group who received generic nutrition and physical activity information. Data were collected at baseline, 3, and 12 months. RESULTS: Total reported energy from nutrient-dense food groups and percentage energy from energy-dense, nutrient-poor foods were high at baseline relative to estimated total energy expenditure for child age. Using random effects modelling, there were significant group-by-time effects for a reduction in mean (standard deviation) total energy intake (EI) at 12 months (-461 kJ/day (196); P = 0.04). An intervention group-by-time effect on carbohydrate intake (-17.4 g/day (10.6); P < 0.05) was largely attributable to decreased consumption of breads and cereals (-180 g/day (80); P = 0.007). Decreases in energy-dense, nutrient-poor foods were not statistically significant. CONCLUSIONS: The proportion of total EI from noncore foods in children in rural New South Wales is high and did not improve in response to a low-intensity nutrition intervention. Parents reported small changes in consumption frequency for core and noncore food intakes, leading to a reduction in total EI. Strategies to increase resource use such as prompting via e-mail are required to further explore the effectiveness of nutrition resource dissemination at a population level. PMID- 24145619 TI - Early-life factors associated with pediatric functional constipation. AB - OBJECTIVE: This multicenter prospective study aimed to establish possible risk factors for functional constipation (FC) in the first year of life. METHODS: At the infant's age of 3, 6, and 12 months, parents of all included infants completed 2 questionnaires: one about the presence of FC and the other screened the possible risk factors for FC. Parents of 465 infants completed the questionnaires at 3 and 6 months and of 402 infants at 12 months of life. RESULTS: According to the Rome III criteria, FC was found in 11.6% of the infants at 3 months, in 13.7% at 6 months, and in 10.7% at 12 months after birth. Family history of atopy was present in 38.8% and 45.3% of infants with constipation at 3 and 6 months (P = 0.04 and P = 0.02, respectively), but no significant association was found at 12 months (P = 0.80). Breast-feeding was significantly related to a normal evacuation pattern at 3 months (P = 0.05), but not at 6 and 12 months (P = 0.12 and P = 0.9, respectively). Acetaminophen and female sex appeared to be risk factors for FC at 12 months. After the adjustment for all analyzed variables, FC in infants was significantly associated with the use of acetaminophen (odds ratio 6.98, 95% confidence interval 0.82-13.50). CONCLUSIONS: Our results confirmed that breast-feeding is a protective factor for FC in the first 3 months of life and that the female sex is at risk to have FC. We found that the use of acetaminophen was associated with a higher incidence of FC in the first year of life. PMID- 24145620 TI - Autologous intestinal reconstructive surgery to reduce bowel dilatation improves intestinal adaptation in SBS. PMID- 24145621 TI - Prevalence and risk factors of iron deficiency in healthy young children in the southwestern Netherlands. AB - OBJECTIVES: Iron deficiency (ID) and iron deficiency anemia (IDA), during the first years of life, are associated with delayed motor and neurological development. Many studies evaluated iron status without an assessment of an acute phase protein to identify infection. Because most indicators of iron status are influenced by infection, these data may underestimate the ID prevalence. A food consumption survey in the Netherlands showed that the mean iron intake of children ages 2 to 3 years was below the advised adequate intake of 7 mg/day. The aim of the study was to investigate iron status in a well-defined, healthy population of young children in the southwestern region of the Netherlands and to identify risk factors for ID. METHODS: We conducted a multicenter, observational study in healthy children ages 0.5 to 3 years. We defined ID as ferritin <12 MUg/L and IDA when, in addition, hemoglobin was <110 g/L. Children with elevated C-reactive protein levels (>5 mg/L) or underlying causes for anemia were excluded. Parents filled in a questionnaire to identify risk factors for ID. RESULTS: We included 400 children in the study. ID and IDA were detected in 18.8% and 8.5% of the children, respectively. The present use of formula and the visit of preschool/day care were associated with a lower prevalence of ID, and a high intake of cow's milk was associated with a higher prevalence of ID, after adjustment for age. CONCLUSIONS: ID is present in 18.8% of healthy children ages 0.5 to 3 years and living in the southwestern region of the Netherlands. The present visit of preschool/day care and the use of formula are associated with a reduced risk of ID, whereas a high intake of cow's milk is associated with an increased risk of ID. PMID- 24145622 TI - Appendiceal neuroendocrine tumours in childhood: Italian TREP project. AB - BACKGROUND: Neuroendocrine tumours (NETs) of the appendix are slow-growing tumours and, although rare, they are the most common gastrointestinal epithelial tumours in childhood and adolescence. The treatment and the follow-up screenings have not been standardised. In addition to this, although tumour size is considered the main prognostic variable to define the aggressiveness of approach, a precise cutoff needs to be established. METHODS: A total of 113 patients younger than 18 years with a diagnosis of appendiceal NETs were registered as of January 1, 2000, until May 30, 2013, within the Rare Tumors in Pediatric Age (TREP) project, an Italian multi-institutional network dedicated to rare tumours in children and adolescents. The recommendations of the Rare Tumors in Pediatric Age study included imaging and laboratory investigations. The treatment after appendectomy was decided on the basis of histology, tumour size, and imaging; primary reexcision (PRE) was not recommended in completely excised tumours, regardless of tumour size and invasiveness. RESULTS: A total of 113 of 113 patients had a diagnosis of well-differentiated NETs; in 108 of 113 the tumour was smaller than 2 cm and in 5, larger than 2 cm. Excision margins were free in 111 of 113 patients. In 3 of 113 a PRE was performed, and in 1 residual tumour was detected. All 113 of 113 patients are alive in complete remission (median follow-up of 41 months). CONCLUSIONS: Reported data and our experience showed that no relapse or death occurred in children and adolescents affected by appendiceal NETs. Appendectomy alone should be considered curative for most patients, and a more aggressive surgical approach is warranted in the cases with incompletely excised tumours. PMID- 24145623 TI - Preparation of hydrophobic metal-organic frameworks via plasma enhanced chemical vapor deposition of perfluoroalkanes for the removal of ammonia. AB - Plasma enhanced chemical vapor deposition (PECVD) of perfluoroalkanes has long been studied for tuning the wetting properties of surfaces. For high surface area microporous materials, such as metal-organic frameworks (MOFs), unique challenges present themselves for PECVD treatments. Herein the protocol for development of a MOF that was previously unstable to humid conditions is presented. The protocol describes the synthesis of Cu-BTC (also known as HKUST-1), the treatment of Cu BTC with PECVD of perfluoroalkanes, the aging of materials under humid conditions, and the subsequent ammonia microbreakthrough experiments on milligram quantities of microporous materials. Cu-BTC has an extremely high surface area (~1,800 m(2)/g) when compared to most materials or surfaces that have been previously treated by PECVD methods. Parameters such as chamber pressure and treatment time are extremely important to ensure the perfluoroalkane plasma penetrates to and reacts with the inner MOF surfaces. Furthermore, the protocol for ammonia microbreakthrough experiments set forth here can be utilized for a variety of test gases and microporous materials. PMID- 24145625 TI - Functional data analyses for the assessment of joint power profiles during gait of stroke subjects. AB - Lower extremity kinetic data during walking of 12 people with chronic poststroke were reanalyzed, using functional analysis of variance (FANOVA). To perform the FANOVA, the whole curve is represented by a mathematical function, which spans the whole gait cycle and avoids the need to identify isolated points, as required for traditional parametric analyses of variance (ANOVA). The power variables at the ankle, knee, and hip joints, in the sagittal plane, were compared between two conditions: With and without walking sticks at comfortable and fast speeds. For the ankle joint, FANOVA demonstrated increases in plantar flexion power generation during 60-80% of the gait cycle between fast and comfortable speeds with the use of walking sticks. For the knee joint, the use of walking sticks resulted in increases in the knee extension power generation during 10-30% of the gait cycle. During both speeds, the use of walking sticks resulted in increased power generation by the hip extensors and flexors during 10-30% and 40-70% of the gait cycle, respectively. These findings demonstrated the benefits of applying the FANOVA approach to improve the knowledge regarding the effects of walking sticks on gait biomechanics and encourage its use within other clinical contexts. PMID- 24145624 TI - A genomic classifier predicting metastatic disease progression in men with biochemical recurrence after prostatectomy. AB - BACKGROUND: Due to their varied outcomes, men with biochemical recurrence (BCR) following radical prostatectomy (RP) present a management dilemma. Here, we evaluate Decipher, a genomic classifier (GC), for its ability to predict metastasis following BCR. METHODS: The study population included 85 clinically high-risk patients who developed BCR after RP. Time-dependent receiver operating characteristic (ROC) curves, weighted Cox proportional hazard models and decision curves were used to compare GC scores to Gleason score (GS), PSA doubling time (PSAdT), time to BCR (ttBCR), the Stephenson nomogram and CAPRA-S for predicting metastatic disease progression. All tests were two-sided with a type I error probability of 5%. RESULTS: GC scores stratified men with BCR into those who would or would not develop metastasis (8% of patients with low versus 40% with high scores developed metastasis, P<0.001). The area under the curve for predicting metastasis after BCR was 0.82 (95% CI, 0.76-0.86) for GC, compared to GS 0.64 (0.58-0.70), PSAdT 0.69 (0.61-0.77) and ttBCR 0.52 (0.46-0.59). Decision curve analysis showed that GC scores had a higher overall net benefit compared to models based solely on clinicopathologic features. In multivariable modeling with clinicopathologic variables, GC score was the only significant predictor of metastasis (P=0.003). CONCLUSIONS: When compared to clinicopathologic variables, GC better predicted metastatic progression among this cohort of men with BCR following RP. While confirmatory studies are needed, these results suggest that use of GC may allow for better selection of men requiring earlier initiation of treatment at the time of BCR. PMID- 24145627 TI - Inhibition of corneal neovascularization by subconjunctival and topical bevacizumab and sunitinib in a rabbit model. PMID- 24145626 TI - Superior versus inferior conjunctival autografts combined with fibrin glue in the management of primary pterygia. AB - PURPOSE: To compare the outcomes of superior versus inferior conjunctival autograft (CAU) in the prevention of recurrence after performing a pterygium surgery in patients with primary pterygia. METHODS: This was a prospective randomized study of 60 eyes of 60 patients with primary pterygium. All the eyes underwent pterygium excision and were assigned randomly to receive either superior (30 eyes) or inferior (30 eyes) CAU. All grafts were attached with fibrin glue. The patients were followed up on postoperative day 1, day 7, 1 month, 3 months, and 6 months. RESULTS: Outcome measures included rate of recurrence, mean surgical time, visual analog scale pain score, and amount of pain medication required in the first postoperative week. The mean surgical time, visual analog scale pain score, and amount of pain medication required in both groups were not statistically different. A follow-up of at least 6 months (mean 5.5 +/- 1.1 months) was achieved in 49 eyes of 49 patients (24 eyes in the superior CAU group and 25 eyes in the inferior CAU group). One eye in the superior CAU group (4.2%) and 1 eye in the inferior CAU group (4.0%) developed pterygium recurrence. There was no statistically significant difference in the recurrence rates between the 2 groups. In the inferior CAU group, mild localized donor site scarring was noted in 2 patients (8.3%). CONCLUSIONS: Pterygium excision with superior or inferior CAU secured with fibrin glue is safe and effective. There was no significant difference in surgical time, pain, and recurrence rates of pterygium after excision with superior or inferior CAU. PMID- 24145628 TI - Incidence and prevalence of episcleritis and scleritis in Northern California. AB - PURPOSE: To evaluate the incidence and prevalence of episcleritis and scleritis in a large well-defined population in Northern California. METHODS: Secondary analysis was performed on data from the Northern California Epidemiology of Uveitis Study. The patient database of a large regional health maintenance organization was searched for all patients who potentially experienced ocular inflammatory disease during the 12-month study period. Medical records were reviewed for all potential patients to confirm ocular inflammatory disease and specific diagnosis, establish the time of onset, and collect additional data. Age and sex-stratified quarterly study population data were used to calculate incidence rates and prevalence ratios. RESULTS: After reviewing 2011 possible cases, 297 new-onset cases of episcleritis, 39 prior-onset cases of episcleritis, 25 new-onset cases of scleritis, and 8 prior-onset cases of scleritis were confirmed. For episcleritis, the overall incidence was 41.0 per 100,000 person years and an annual prevalence ratio of 52.6 per 100,000. The overall incidence of scleritis was 3.4 per 100,000 person-years and an annual prevalence ratio of 5.2 per 100,000 persons. For both episcleritis and scleritis, there was a statistically significant increase in eye disease in older patients (P = 0.05 and <0.001, respectively) and for women in comparison with men (P = 0.001 and <0.001, respectively). Patients with scleritis were older than those with episcleritis (P = 0.017). CONCLUSIONS: This study found that patients with scleritis were older than those with episcleritis and that women had higher rates of both episcleritis and scleritis compared with what men had. PMID- 24145629 TI - Genotypic characterization of Staphylococcus aureus isolates from cases of keratitis and healthy conjunctival sacs. AB - PURPOSE: Staphylococcus aureus is the predominant pathogen that causes keratitis, and the rate of occurrence of drug-resistant S. aureus is increasing. However, little is known about its clinical epidemiology in Japan. This study was designed to characterize the genotypes of methicillin-susceptible S. aureus (MSSA) and methicillin-resistant S. aureus (MRSA) isolates from keratitis and healthy conjunctival sacs. METHODS: Thirty keratitis isolates (19 MSSA and 11 MRSA) and 18 healthy conjunctival sac isolates (16 MSSA and 2 MRSA) obtained before cataract surgery were used. They were characterized by multilocus sequence typing. The prevalence of Panton-Valentine leukocidin was determined. RESULTS: In multilocus sequence typing analysis, ST5 and ST764 (ST5 variant) were the most frequently identified sequence types in MRSA strains from both keratitis and healthy conjunctival sacs. ST188 was the most frequently identified sequence type in the 19 MSSA isolates from keratitis (4 isolates, 21.1%), but was only identified in 1 of the 16 commensal MSSA strains. ST8 was found to be predominant among the 16 commensal MSSA strains (5 isolates, 31.3%). None of the isolates had Panton-Valentine leukocidin genes. CONCLUSIONS: MRSA isolates from keratitis and healthy conjunctival sacs may have similar genotypic characteristics, but certain clones occur more often among MSSA isolates from keratitis than among commensal MSSA strains. These results suggest that specific MSSA lineages that possess genotypic characteristics can more effectively cause keratitis. PMID- 24145630 TI - Ocular surface squamous neoplasia: a survey of changes in the standard of care from 2003 to 2012. AB - PURPOSE: To evaluate the current standard of care of ophthalmologists who are likely to encounter ocular surface squamous neoplasia (OSSN) in their practices and to compare this with data gathered in 2003. METHODS: Invitations to a web based survey were sent to members of the Ocular Microbiology and Immunology Group. In addition, the survey was posted to the Cornea Society Listserv, Keranet. The survey contained questions regarding the surgical and medical management of OSSN and postcare follow-up. The results of this survey were compared with the results of a 2003 survey, where possible, to identify the areas of change in the standard of care. RESULTS: Eighty-one ophthalmologists participated in the survey. Seventy-nine percent of the responders thought that there was enough evidence for topical monotherapy in OSSN, but only 58% reported ever using topical agents as monotherapy. First-line topical therapy was interferon alpha2b (56%) followed by mitomycin C (MMC) (37%). A shift from surgical excision alone to excision followed by topical therapy was seen when comparing the 2012 survey to the 2003 survey. The preferred postexcision topical agent was MMC. Seventy-five percent of responders evaluate their patients every 2 to 4 months during the first 2 years. CONCLUSIONS: Topical agents were being used more in 2012, either in combination with surgical excision or as monotherapy, compared with those used in 2003. Interferon has replaced MMC as the agent most used for topical monotherapy, possibly because of a favorable safety and tolerance profile. Prospective randomized trials are needed to better define the ideal practice patterns. PMID- 24145631 TI - Functional and visual improvement with prosthetic replacement of the ocular surface ecosystem scleral lenses for irregular corneas. AB - PURPOSE: To evaluate the Doheny Eye Institute Experience with Prosthetic Replacement of the Ocular Surface Ecosystem (PROSE) scleral lenses for the management of irregular corneas with outcomes based on visual acuity (VA) and visual function. METHODS: A retrospective chart review of 58 subjects (90 eyes) with irregular corneal surfaces referred to the Doheny Eye Institute for PROSE treatment between July 2009 and December 2011 was performed. The best-corrected VA before and after PROSE fitting was recorded. A functional assessment before and after PROSE fitting was also performed using the Ocular Surface Disease Index, a 12-item questionnaire that grades the severity of ocular discomfort and vision-related function. RESULTS: Keratoconus (43%) represented the largest group, and post-PK astigmatism (31%) represented the second largest group of patients with irregular corneas who had completed the PROSE treatment. Patients with keratoconus had the greatest improvement in VA after PROSE fitting with an 88% improvement in the logarithm of the minimal angle of resolution vision. Patients with post-PK astigmatism had the greatest improvement in Ocular Surface Disease Index scores with a 79% improvement observed after PROSE fitting. CONCLUSIONS: PROSE scleral lenses offer improvements in the VA and function, and they could be an option for patients with irregular corneas who have failed conventional treatments before considering additional surgery. PMID- 24145632 TI - Immediate endothelial cell loss after penetrating keratoplasty. AB - PURPOSE: To report the pattern and the extent of corneal endothelial cell loss immediately after a penetrating keratoplasty (PK) is performed. METHODS: Ten donor corneal-scleral tissues with healthy endothelium were used to perform 10 PK surgeries on cadaver eyes. An 8.25-mm donor graft was placed into an 8.00-mm trephinated recipient bed of the cadaver eye. A 10-0 nylon suture was used with a 16-interrupted suture closure technique to secure each donor button. Viscoelastic was used to protect the endothelium in every case. The corneal donor buttons were removed and stained using trypan blue and alizarin red dyes. Digital high definition photographs were obtained to record the pattern and quantity of stain resulting from endothelial damage and cell loss. Percent endothelial loss was calculated using the digital planimetry of our previously described Adobe Photoshop technique. RESULTS: The immediate mean percent cell loss across the whole graft was 25.7% +/- 7.5% (Range, 18-39). There was a distinct pattern of loss, with 58.3% of the loss in the peripheral 0.75 mm, and 12.4% of the loss in the central 3.00 mm. CONCLUSIONS: The immediate total endothelial cell loss after the PK was performed was about 25%. The immediate cell loss after the PK was consistent with areas of trephination and suture placement. PMID- 24145633 TI - Debridement-scaling: a new procedure that increases Meibomian gland function and reduces dry eye symptoms. AB - PURPOSE: To evaluate whether a new in-office procedure, the mechanical debridement-scaling of the line of Marx (LOM) and keratinized lid margin, improves meibomian gland (MG) function and reduces dry eye symptoms. METHODS: Twenty-eight patients symptomatic for and diagnosed with evaporative dry eye (16 test patients and 12 controls), who also evidenced anteroplacement and a thickened LOM, were enrolled and consented. SYMPTOMS were evaluated with the Standard Patient Evaluation of Eye Dryness questionnaire. The MG function was evaluated with the standardized MG function evaluator. The LOM was stained with lissamine green (Odyssey Medical, TN) for evaluation. For the test group only, the stained LOM and the entire width of the keratinized lower lid margin were debrided-scaled using a stainless steel, foreign body, golf club spud (Hilco Wilson Ophthalmics, Plainville, MA). All the patients were monitored for change in symptoms and MG function approximately 1 month later. RESULTS: The mean ages of the patients were 55.9 +/- 15.0 years (test) versus 53.7 +/- 15.3 years (control). There was a significant improvement in the symptoms and MG function 1 month post-debridement-scaling in the test group. The controls evidenced no significant change in either parameter. SYMPTOMS: baseline mean pre-debridement scaling: 13.4 +/- 4.6 (test) versus 13.9 +/- 5.5 (control); 1 month post debridement-scaling: 10.5 +/- 3.8 (test, population level statistic < 0.0001) versus 14.3 +/- 7.5 (control, population level statistic > 0.05). Number of functional MGs: baseline mean pre-debridement-scaling: 2.6 +/- 1.3 (test) versus 2.7 +/- 1.5 (control); 1 month post-debridement-scaling: 3.8 +/- 1.4 (test, P = 0.0007) versus 2.4 +/- 1.1 (control, P > 0.05). Only data for the right eye are reported. CONCLUSIONS: The debridement-scaling of the LOM and lower lid margin provides statistically significant symptom relief and improvement in the MG function. The novel procedure should be considered in the management of MGD and evaporative dry eye. PMID- 24145634 TI - Repeatability of corneal epithelial thickness measurements using Fourier-domain optical coherence tomography in normal and post-LASIK eyes. AB - PURPOSE: To evaluate the repeatability of corneal epithelial thickness (ET) and corneal thickness (CT) measurements in normal eyes and laser in situ keratomileusis (LASIK)-treated eyes using optical coherence tomography (RTVue system). METHODS: In 35 right eyes of 35 normal subjects and 45 right eyes of 45 subjects who underwent a myopic LASIK, corneal ET and CT were evaluated in 17 areas: (1) 1 central zone within a 0- to 2.0-mm diameter, (2) 8 paracentral zones from a 2.0- to 5.0-mm diameter, and (3) 8 peripheral zones from a 5.0- to 6.0-mm diameter. The repeatability was assessed using within-subject standard deviation (SD), coefficient of variation, and intraclass correlation coefficient. RESULTS: At the central and paracentral zones, respectively, the SD values were 0.7 MUm and 0.6 to 0.9 MUm in normal eyes and 0.7 MUm and 0.8 to 1.7 MUm in LASIK-treated eyes for ET, and 1.0 MUm and 2.8 to 4.6 MUm in normal eyes and 1.3 MUm and 4.0 to 4.8 MUm in LASIK-treated eyes for CT. At the peripheral zones, in normal and LASIK-treated eyes, respectively, the SD values ranged from 0.8 to 1.2 MUm and 1.4 to 2.2 MUm for ET, and 4.1 to 6.4 MUm and 6.0 to 9.1 MUm for CT. The coefficient of variation values were low and intraclass correlation coefficient values were high in both groups for both ET and CT measurements. CONCLUSIONS: The Optical coherence tomography produced excellent repeatability, especially at the central and paracentral zones up to a 5-mm diameter for both corneal ET and CT measurements. PMID- 24145635 TI - Evaluation of microbial flora in eyes with a Boston type 1 Keratoprosthesis. AB - PURPOSE: To evaluate the microbial flora of eyes with a Boston Keratoprosthesis (K-Pro). METHODS: A prospective study was performed for 17 eyes of 15 patients who underwent a K-Pro implantation between September 2005 and June 2011. Preoperative diagnoses included failed corneal grafts, limbal stem cell deficiency, chemical burns, and Stevens-Johnson Syndrome. The patients used topical antibiotics after their surgery including a fluoroquinolone, polymyxin trimethoprim, vancomycin, or a combination of the 3. The conjunctiva in the study eye was swabbed and cultured. A separate culture was taken of the contralateral eye as well. If available, the bandage contact lens was removed, and half of it was placed in thioglycolate broth, and half in 5 mL of a sterile balanced salt solution. The contact lens in the balanced salt solution was sonicated using a QSonica Q125 sonicator (Newtown, CT) for 1 minute, at an amplitude of 20%. Ten microliters of fluid was subsequently cultured. RESULTS: Of the patients who underwent the K-Pro surgery during that time period, 15 patients with 17 eyes were able to participate in the data collection. Nine of the 17 eyes implanted with the K-Pro (53%) had positive cultures. Two of the 13 (15%) of the control swabs exhibited bacterial growth. Eight percent (1/12) of the sonicated lenses were positive on culture, whereas 4/12 (33%) of the lenses placed in thioglycolate broth were positive for organisms. CONCLUSIONS: Despite being on antibiotics, eyes implanted with the K-Pro were more likely to have a positive conjunctival culture in our cohort as compared with that of fellow eyes. PMID- 24145637 TI - When and how does one refer a death to the coroner? PMID- 24145636 TI - Influence of preoperative donor tissue characteristics on graft dislocation rate after Descemet stripping automated endothelial keratoplasty. AB - PURPOSE: To determine the influence of preoperative donor tissue characteristics on the graft dislocation rate after performing a Descemet stripping automated endothelial keratoplasty (DSAEK). METHODS: We retrospectively analyzed the associations between donor tissue characteristics and graft dislocation rates for consecutive DSAEK surgeries performed in a 4-year period at a single institution. RESULTS: From June 2007 to June 2011, 64 (18%) of 355 eyes underwent a procedure for graft dislocation. There were no differences in donor age, preoperative endothelial graft thickness, preprocessing endothelial cell density, change in endothelial cell density after processing, time from death to tissue processing, or time from tissue processing to surgery between eyes that experienced dislocations and those that did not (P > 0.05 for each). The graft recipient's corneal disease diagnosis, preoperative corneal thickness, preoperative visual acuity, glaucoma status, history of glaucoma surgery, and cataract surgery at the time of performing the DSAEK were not associated with an increased rate of dislocation (P > 0.05 for each). Recipients who experienced graft dislocation were significantly older (73.6 vs. 70.2 years, P = 0.03) and more likely to undergo subsequent repeat transplantation (29.7% vs. 10.7%, P < 0.0001). CONCLUSIONS: We found no correlation between any corneal donor tissue characteristic and graft dislocation after the DSAEK was performed. Graft dislocation was more common in older recipients. Patients with dislocation had a higher rate of subsequent transplantation. PMID- 24145638 TI - Interpretation of syphilis serology. PMID- 24145639 TI - Ocular trauma: classification, management and prognosis. PMID- 24145640 TI - How to improve your curriculum vitae. PMID- 24145641 TI - Multifunctional biodegradable polymer nanoparticles with uniform sizes: generation and in vitro anti-melanoma activity. AB - We present a simple, yet versatile strategy for the fabrication of uniform biodegradable polymer nanoparticles (NPs) with controllable sizes by a hand driven membrane-extrusion emulsification approach. The size and size distribution of the NPs can be easily tuned by varying the experimental parameters, including initial polymer concentration, surfactant concentration, number of extrusion passes, membrane pore size, and polymer molecular weight. Moreover, hydrophobic drugs (e.g., paclitaxel (PTX)) and inorganic NPs (e.g., quantum dots (QDs) and magnetic NPs (MNPs)) can be effectively and simultaneously encapsulated into the polymer NPs to form the multifunctional hybrid NPs through this facile route. These PTX-loaded NPs exhibit high encapsulation efficiency and drug loading density as well as excellent drug sustained release performance. As a proof of concept, the A875 cell (melanoma cell line) experiment in vitro, including cellular uptake analysis by fluorescence microscope, cytotoxicity analysis of NPs, and magnetic resonance imaging (MRI) studies, indicates that the PTX-loaded hybrid NPs produced by this technique could be potentially applied as a multifunctional delivery system for drug delivery, bio-imaging, and tumor therapy, including malignant melanoma therapy. PMID- 24145642 TI - Architectural heterogeneity and cribriform pattern predict adverse clinical outcome for Gleason grade 4 prostatic adenocarcinoma. AB - Gleason grade 4 defines a group of prostatic adenocarcinomas with a variety of architectural patterns, including poorly formed glands, fused glands, and cribriform pattern. To address the relative contribution to clinical prognosis by these distinct patterns, the histology of 241 consecutive radical prostatectomy specimens with the highest Gleason grade of 4 was reviewed. The presence of poorly formed glands, fused glands, and cribriform pattern was recorded for each case, and the types of architectural patterns present were associated with patient outcome. In this population, prostatic adenocarcinomas demonstrated architectural heterogeneity, with 17% of cases exhibiting a single Gleason grade 4 pattern, and 41% of cases exhibiting all 3 morphologic patterns. Patients exhibiting all 3 architectural patterns had lower rates of biochemical disease free survival (66% vs. 76% at 5 y; log rank P=0.006). Twenty-two of 165 patients (13.3%) with cribriform pattern adenocarcinoma developed metastasis, whereas 2 of 76 patients (2.6%) without cribriform pattern developed metastasis at a median postoperative follow-up of 10.0 years. The presence of a cribriform pattern was an independent predictor for biochemical recurrence (hazard ratio 2.41; 95% confidence interval, 1.34-4.32; P=0.003) as well as metastasis after radical prostatectomy (hazard ratio 5.62; 95% confidence interval, 1.29-24.5; P=0.02). These results suggest that the morphologic subclassification of distinct Gleason grade 4 architectural patterns provides prognostic information beyond the current Gleason classification system. PMID- 24145643 TI - GATA3: a multispecific but potentially useful marker in surgical pathology: a systematic analysis of 2500 epithelial and nonepithelial tumors. AB - GATA3 is a transcription factor important in the differentiation of breast epithelia, urothelia, and subsets of T lymphocytes. It has been suggested to be useful in the evaluation of carcinomas of mammary or urothelial origin or metastatic carcinomas, but its distribution in normal and neoplastic tissues is incompletely mapped. In this study, we examined normal developing and adult tissues and 2040 epithelial and 460 mesenchymal or neuroectodermal neoplasms for GATA3 expression to explore its diagnostic value in surgical pathology, using monoclonal antibody (clone L50-823) and Leica Bond automated immunohistochemistry. GATA3 was expressed in trophoblast, fetal and adult epidermis, adult mammary and some salivary gland and sweat gland ductal epithelia, urothelia, distal nephron in developing and adult tissues, some prostatic basal cells, and subsets of T lymphocytes. It was expressed stronger in fetal than in adult mesothelia and was absent in respiratory and gastrointestinal epithelia. In epithelial neoplasms, GATA3 was expressed in >90% of primary and metastatic ductal and lobular carcinomas of the breast, urothelial, and cutaneous basal cell carcinomas and trophoblastic and endodermal sinus tumors. In metastatic breast carcinomas, it was more sensitive than GCDFP. Among squamous cell carcinomas, the expression was highest in the skin (81%) and lower in cervical (33%), laryngeal (16%), and pulmonary tumors (12%). Common positivity was found in skin adnexal tumors (100%), mesothelioma (58%), salivary gland (43%), and pancreatic (37%) ductal carcinomas, whereas frequency of expression in adenocarcinomas of lung, stomach, colon, endometrium, ovary, and prostate was <10%. Chromophobe renal cell carcinoma was a unique renal tumor with frequent positivity (51%), whereas oncocytomas were positive in 17% of cases but other types only rarely. Among mesenchymal and neuroectodermal tumors, paragangliomas were usually positive, which sets these tumors apart from epithelial neuroendocrine tumors. Mesenchymal tumors were only sporadically positive, except epithelia of biphasic synovial sarcomas. GATA3 is a useful marker in the characterization of not only mammary and urothelial but also renal and germ cell tumors, mesotheliomas, and paragangliomas. The multiple specificities of GATA3 should be taken into account when using this marker to detect metastatic mammary or urothelial carcinomas. PMID- 24145644 TI - Malignant melanotic schwannian tumor: a clinicopathologic, immunohistochemical, and gene expression profiling study of 40 cases, with a proposal for the reclassification of "melanotic schwannoma". AB - Melanotic schwannomas (MSs), variably associated with the Carney complex, are rare tumors that usually involve spinal nerve roots but may occur in other locations. Clinicopathologic evaluation poorly predicts the behavior of MS. Fewer than 200 cases have been reported. We report a series of 40 well-characterized MSs, one of the largest series to date. The tumors were comprehensively evaluated, and clinical follow-up was obtained. Immunohistochemistry for S100 protein, Melan-A, HMB45, tyrosinase, glial fibrillary acidic protein (GFAP), EMA, SMARCB1, Ki-67 antigen, ASMTL, and the Carney complex-associated PRKAR1A gene product was performed using commercially available antibodies and the Ventana Ultraview detection system. Gene microarray study was conducted on formalin fixed, paraffin-embedded blocks from 10 MSs and the results compared with previous data from melanoma and schwannoma. Differentially expressed genes were selected at >3-fold and P<0.001. The Fisher exact test was used for statistical analysis. The tumors occurred in 18 male and 22 female patients (mean age 41 y; range, 11 to 84 y) and involved the paravertebral nerve roots (N=31), mediastinum (N=3), sacrum, cauda equina, para-aortic region, fifth cranial nerve, buttock, and cerebellum (N=1 each). Two patients had known Carney complex, and 1 patient also had a cutaneous myxoma, suggestive of Carney complex. The tumors expressed S100 protein (21/25, 84%), Melan-A (23/25, 92%), HMB45 (25/25, 100%), tyrosinase (25/25, 100%), GFAP (0/24, 0%), EMA (0/9, 0%), SMARCB1 (retained in 25/25, 100%), and ASMTL (5/19, 26%); PRKAR1A expression was lost in 7/20 cases (35%). Ki-67 labeling index was <5% in 23/25 cases (92%) and 5% to 10% in 2/25 cases (8%). Gene expression profiling showed significant differences between MS, melanoma, and conventional schwannoma. Clinical follow-up (26/40, 65%; mean 55 mo; range, 1 to 300 mo) showed local recurrences in 9/26 (35%) and metastases in 11/26 (44%) patients. Fourteen patients were alive without disease, 5 were alive with disease, and 7 had died of disease. Only a mitotic rate >2/10 HPF correlated with metastases (P=0.008). The clinicopathologic features of tumors with and without psammoma bodies were identical. We conclude that MSs are distinctive malignant tumors, rather than benign neoplasms with occasionally unpredictable behavior, and propose their reclassification as "malignant melanotic schwannian tumors." Loss of PRKAR1A expression suggests a link to Carney complex, even when this history is absent. PMID- 24145645 TI - Leiomyoma of the gastrointestinal tract with interstitial cells of Cajal: a mimic of gastrointestinal stromal tumor. AB - Leiomyomas (LMs) of the gastrointestinal tract arise within the muscularis mucosae (superficial) and muscularis propria (deep). There are isolated reports of KIT-positive cells, presumed interstitial cells of Cajal (ICCs), within gastrointestinal LMs. We have encountered esophageal LMs with a high proportion of KIT-positive and DOG1-positive spindle-shaped cells, an appearance that mimicked gastrointestinal stromal tumor. Our aim was to explore the prevalence of ICCs in LMs of the gastrointestinal tract and the etiopathogenic significance of these cells in this benign neoplasm. We identified 34 esophageal LMs (28 deep, 6 superficial), 8 gastric LMs, and 5 small-bowel LMs (all lesions in muscularis propria). We performed immunohistochemical staining studies for desmin, DOG1, and KIT on these neoplasms. We also evaluated 12 superficial colonic LMs. ICCs were distinguished from mast cells on the basis of morphology (elongated and occasionally branching spindle-shaped cells) and the presence of DOG1 reactivity. Four cases were screened for mutations in PDGFRA exons 12, 14, and 18 and KIT exons 9, 11, 13, and 17. ICCs were identified in all deep esophageal LMs and constituted an average of 20% of the lesional cells; focally, these cells comprised >50% of cells. The density of these cells was significantly higher than the background muscularis propria, and hyperplasia of ICCs was not identified in the adjacent muscle. ICCs were identified in 6 of 8 gastric LMs and 1 of 5 small bowel LMs and were entirely absent in all superficial esophageal and colonic/rectal LMs. There were no mutations in KIT or PDGFRA. ICCs are universally present in deep esophageal LMs, and thus these neoplasms could be mistaken for gastrointestinal stromal tumors, particularly on biopsy samples, an error associated with adverse clinical consequences. ICCs are also identified in gastric and intestinal LMs, albeit in a smaller proportion of cases. Colonization and hyperplasia by non-neoplastic ICCs likely account for this phenomenon. PMID- 24145646 TI - Peripheral hemangioblastoma: clinicopathologic characterization in a series of 22 cases. AB - Hemangioblastoma is a rare tumor of uncertain histotype that typically arises in the cerebellum, quite often in the setting of Von Hippel-Lindau syndrome (VHL). Exceptional cases of hemangioblastoma arising outside the central nervous system have been reported, but little is known about their clinicopathologic and immunohistochemical features. Twenty-two cases of hemangioblastoma arising at peripheral sites were identified in consultation files. Clinical, morphologic, and immunohistochemical features were evaluated. Outcome data were obtained from referring pathologists. Twelve patients were female and 10 male; the median age was 58 years (range, 27 to 79 y). All the tumors were solitary (except 1) and arose in spinal nerve roots (12), kidney (3), intestine (2), orbit (1), forearm (1), peritoneum (1), periadrenal soft tissue (1), and flank (1). Five patients had VHL; another 5 had lesions suggestive of VHL. One patient had tuberous sclerosis. The median tumor size was 4 cm (range, 1.3 to 15 cm). Most tumors were well circumscribed; 6 were poorly marginated-3 eroded the adjacent bone and 1 extended into the pleura. All tumors were composed of an admixed population of plump spindle cells and microvacuolated cells with palely eosinophilic or clear cytoplasm, which often mimicked lipoblasts or renal cell carcinoma. In 5 cases the microvacuolated cells were scant. Spindle cell nuclei were hyperchromatic or vesicular with inconspicuous nucleoli. Four tumors showed marked nuclear pleomorphism. Mitotic activity was low (range, 0 to 2/10 HPF). All tumors had a complex capillary network, with admixed larger thin-walled or thick-walled vessels in a solid and often lobular growth pattern, similar to central nervous system hemangioblastoma. In 9 cases the larger vessels showed a branching hemangiopericytoma-like pattern. No necrosis or lymphovascular invasion was identified. Tumor cells expressed inhibin in 95% (20/21), neuron-specific enolase in 79% (15/19), and S100 protein in 65% (13/20); they also expressed GLUT1 (7/10, mostly weak), SMA (4/5), epithelial membrane antigen (2/8, focal), PAX8 (1/10), and desmin (1/4). Brachyury was consistently negative (0/19), as were keratin, HMB-45, melan-A, and GFAP. CD31 and CD34 highlighted tumor vasculature. Follow-up information was available for 17 patients (range, 5 to 117 mo; median 36 mo). Three patients had locally persistent disease after incomplete resection. True local recurrence or distant metastasis has not been identified in any patient so far. One patient died of metastatic renal cell carcinoma. Peripheral hemangioblastoma is rare, often associated with VHL syndrome, and may mimic some malignant tumors. The immunohistochemical profile can aid diagnosis. Unresectable cases may be locally aggressive, but complete excision appears to be curative. Recognition of this tumor may identify patients in whom testing for VHL syndrome is warranted. PMID- 24145647 TI - Clinicopathologic analysis of choriocarcinoma as a pure or predominant component of germ cell tumor of the testis. AB - Although well recognized in the literature, the contemporary clinicopathologic data regarding choriocarcinoma (CC) as a pure or the predominant component of a testicular germ cell tumor (GCT) are limited. Herein, we present a series of pure CC and predominant CC in mixed GCT of the testis obtained from a single oncology institution. A comprehensive histologic review of 1010 orchiectomies from 1999 to 2011 yielded 6 (0.6%) pure CC and 9 (0.9%) mixed GCT cases with a predominant CC component. Patients' ages ranged from 20 to 39 years (median 29 y). All patients had markedly elevated serum beta-hCG levels (median 199,000 IU/mL) at presentation. All tumors were unilateral and involved the right (9/15) and left (6/15) testis. The mean tumor size was 6.5 cm (range, 1.5 to 8 cm). Histology was similar for pure CCs and the CC component of mixed GCTs. CC commonly showed expansile hemorrhagic nodular cysts surrounded by variable layers of neoplastic trophoblastic cells (mononucleated trophoblasts and syncytiotrophoblasts). The syncytiotrophoblasts usually covered columns of mononucleated trophoblasts and occasionally formed plexiform aggregates and pseudovillous protrusions. Immunohistochemical stains suggested a mixture of cytotrophoblasts (p63+, HPL_) and intermediate trophoblasts (p63-, HPL weak +/-) in the columns of mononucleated cells. In the 9 mixed GCTs, CC comprised 50% to 95% (7/9 were >=80% CC) of the tumor; 7 were combined with 1, and 2 were combined with 2 other GCT components. The non-CC components included teratoma (5/9), seminoma (2/9), yolk sac tumor (2/9), and embryonal carcinoma (2/9). Lymphovascular invasion, spermatic cord invasion, and tunica vaginalis invasion were present in 15/15, 5/15, and 1/12 cases, respectively. In mixed GCTs, these locally aggressive features were attributed to the CC component, except in 1 tumor in which it was also exhibited by the embryonal carcinoma component. Lymphovascular invasion was multifocal to widespread in 73% of tumors. The stages of the 15 tumors were: pT2 (10), pT3 (5); NX (1), N1 (4), N2 (5), N3 (5); and M1a (2) and M1b (13). Distant organ metastasis mostly involved the lungs (11) and liver (10). Follow-up information was available in 14 patients, all of whom received cisplatin-based chemotherapy. All 6 pure CC patients were dead of disease (range, 6 to 14 mo, median 9.5 mo). Follow-up of 8 patients with predominant CC (range, 10 to 72 mo, median 27 mo) showed that 5 died of the disease, and 1 was alive with disease and 2 were alive with no evidence of disease at 60 and 72 months of follow-up, respectively; these latter 2 patients were the only ones with M1a disease on presentation. This series confirms the proclivity for high-stage presentation including presence of distant metastasis, hematogenous spread, and poor outcome of testicular CC. Mixed GCT with a predominant CC component has similar tendency for high-stage presentation, marked elevation of serum beta-hCG levels, and aggressive behavior compared with pure CC. This study also showed that distant metastasis by CC when only involving the lungs (M1a) may not be uniformly fatal with chemotherapy. The mononucleated trophoblastic columns in testicular CC appear to be a mixture of cytotrophoblasts and intermediate trophoblasts, similar to that described in gestational CC. PMID- 24145648 TI - Assessment of SOX11 expression in routine lymphoma tissue sections: characterization of new monoclonal antibodies for diagnosis of mantle cell lymphoma. AB - The diagnosis of mantle cell lymphoma (MCL) can be difficult, especially when no t(11;14) translocation and cyclin D1 overexpression can be detected. In such cases, the transcription factor SOX11 represents an important diagnostic marker, as it is expressed in most MCLs and, in particular, in all cyclin D1-negative MCLs reported so far. A reliable anti-SOX11 antibody is therefore a very useful tool for routine diagnosis. Here, we characterize the new monoclonal anti-SOX11 antibodies, suitable for Western blot assay and immunohistochemistry (IHC) on formalin-fixed paraffin-embedded tissue; we tested them on a large series of primary lymphoid tumors and compared these results with those of other routinely used antibodies. Moreover, we show that IHC results depend on transcription levels of SOX11, which suggests that posttranscriptional and posttranslational modifications do not significantly affect cutoff levels for IHC detection of SOX11. PMID- 24145649 TI - Frequent expression of napsin A in clear cell carcinoma of the endometrium: potential diagnostic utility. AB - The histotyping of high-grade endometrial carcinomas with clear cells may be subject to significant interobserver variability, which suggests that a biomarker that can distinguish endometrial clear cell carcinoma (CCC) from its mimics would be of diagnostic utility. This study assessed the usefulness of napsin A immunohistochemistry in the diagnosis of CCC, on the basis of an analysis of 77 cases diagnosed as such at 9 institutions. After being independently reviewed by a subset of 3 pathologists, cases for which there was diagnostic consensus among all 3 reviewers in agreement with the primary contributor (n=60) were used to establish a "consensus group" that served as a gold standard relative to which napsin A performance was assessed. Duplicate, 1.0-mm-core tissue microarrays were constructed from the 54 cases in the consensus group for which requisite materials were available, as well as from 49 endometrial endometrioid carcinomas (all grades) and 17 endometrial serous carcinomas. Napsin A immunohistochemical analysis was performed on the microarrays and on the 17 cases for which there was no diagnostic consensus, with scoring based on the proportion of immunoreactive cells (0, 1+, 2+, and 3+ indicative of 0, 1% to 25%, 26% to 49%, and >=50% immunoreactive cells, respectively). The distribution of scores for the 49 CCC cases with evaluable cores was as follows: 0, n=6; 1+, n=6; 2+, n=8; 3+, n=29. Among the evaluable cases, the frequency of >=1+ napsin A immunoreactivity was significantly higher in CCCs (43/49, 88%) than in endometrial serous carcinomas (1/13, 7.7%; P<0.0001) and endometrial endometrioid carcinomas (0/49, 0%; P<0.0001). The sensitivity, specificity, negative predictive value, and positive predictive value of >=1+ napsin A expression in predicting the consensus clear cell histotype were 0.88 (95% confidence interval [CI], 0.75-0.95), 0.98 (95% CI, 0.9-1), 0.91 (95% CI, 0.86-0.96), and 0.98 (95% CI, 0.86-1), respectively. Napsin A expression was not associated with survival or clinicopathologic factors. In the group of cases without diagnostic consensus for CCC, 50% showed >=1+ napsin A expression; all napsin A-negative cases had previously been classified as non-CCC by >=2 reviewers, whereas only 37.5% of the napsin A-positive cases had been classified as CCC by 2 of the 3 reviewers. In conclusion, napsin A is a sensitive and specific biomarker of the clear cell histotype in endometrial carcinomas and accordingly may have diagnostic utility in their histotyping. PMID- 24145650 TI - A quantitative histomorphometric classifier (QuHbIC) identifies aggressive versus indolent p16-positive oropharyngeal squamous cell carcinoma. AB - Human papillomavirus-related (p16-positive) oropharyngeal squamous cell carcinoma patients develop recurrent disease, mostly distant metastasis, in approximately 10% of cases, and the remaining patients, despite cure, can have major morbidity from treatment. Identifying patients with aggressive versus indolent tumors is critical. Hematoxylin and eosin-stained slides of a microarray cohort of p16 positive oropharyngeal squamous cell carcinoma cases were digitally scanned. A novel cluster cell graph was constructed using the nuclei as vertices to characterize and measure spatial distribution and cell clustering. A series of topological features defined on each node of the subgraph were analyzed, and a random forest decision tree classifier was developed. The classifier (QuHbIC) was validated over 25 runs of 3-fold cross-validation using case subsets for independent training and testing. Nineteen (11.9%) of the 160 patients on the array developed recurrence. QuHbIC correctly predicted outcomes in 140 patients (87.5% accuracy). There were 23 positive patients, of whom 11 developed recurrence (47.8% positive predictive value), and 137 negative patients, of whom only 8 developed recurrence (94.2% negative predictive value). The best other predictive features were stage T4 (18 patients; 83.1% accuracy) and N3 nodal disease (10 patients; 88.6% accuracy). QuHbIC-positive patients had poorer overall, disease-free, and disease-specific survival (P<0.001 for each). In multivariate analysis, QuHbIC-positive patients still showed significantly poorer disease-free and disease-specific survival, independent of all other variables. In summary, using just tiny hematoxylin and eosin punches, a computer-aided histomorphometric classifier (QuHbIC) can strongly predict recurrence risk. With prospective validation, this testing may be useful to stratify patients into different treatment groups. PMID- 24145651 TI - Mammary analogue secretory carcinoma of salivary glands with high-grade transformation: report of 3 cases with the ETV6-NTRK3 gene fusion and analysis of TP53, beta-catenin, EGFR, and CCND1 genes. AB - Mammary analogue secretory carcinoma of salivary gland origin (MASC) is a recently described tumor resembling secretory carcinoma of the breast characterized by strong S-100 protein, mammaglobin, and vimentin immunoexpression and which harbors a t(12;15) (p13;q25) translocation resulting in ETV6-NTRK3 fusion product. Histologically, conventional MASC displays bland histomorphology and a lobulated growth pattern and is often composed of microcystic, tubular, and solid structures with abundant eosinophilic homogenous or bubbly secretions. Colloid-like secretory material stains positively for periodic acid-Schiff with and without diastase as well as for Alcian Blue. We present for the first time, 3 patients with MASC of the parotid gland in which high-grade (HG) transformation developed in each case characterized by an accelerated clinical course and poor outcome. The HG component revealed strong membrane staining for EGFR and beta catenin, cytoplasmic/nuclear staining for S-100 protein, and nuclear staining for cyclin-D1, whereas HER-2/neu was absent. Analysis for the presence of the ETV6 NTRK3 fusion transcript revealed positivity in both HG and low-grade component of MASC in 2 of the 3 studied cases. The tumor in case 2 was negative in both its elements for the t(12;15) translocation, but ETV6 gene rearrangement was detected in both components in all 3 cases. Analysis of TP53 and CTNNB1 gene mutations in the HG component of MASCs as well as detection of copy number aberration of EGFR and CCND1 gene did not harbor any abnormalities. All 3 patients with HG transformed MASC died of disseminated disease within 2 to 6 years after diagnosis. Recognizing HG-transformed MASC and testing for ETV6 rearrangement may be of potential value in patient treatment, because the presence of the ETV6 NTRK3 translocation may represent a therapeutic target in MASC. PMID- 24145652 TI - CD20 antigen may be expressed by reactive or lymphomatous cells of transformed mycosis fungoides: diagnostic and prognostic impact. AB - Mycosis fungoides (MF), the most common primitive cutaneous T-cell lymphoma, can undergo transformation in about 10% of cases. Transformed mycosis fungoides (T MF) is often associated with the appearance of a CD20 component. The aim of this study was to analyze whether such cells are reactive or lymphomatous and to evaluate their prognostic impact. Among 311 T-MFs from the French Cutaneous Lymphoma Study Group registry, we studied 148 cases. CD20 was expressed in 88 cases (59%). The proportion of CD20 cells among T-MF lesions was <10% for 54 cases (38%), 10% to 49% for 71 cases (81%), and >50% for 17 cases (19%). We focused the study on 23 cases that contained >50% CD20 cells. To evaluate the nature of the CD20 component, we used immunohistochemistry (2 anti-CD20 antibodies, L26 and 7D1 clones, and 2 other anti-B-cell antigen antibodies, CD22 and PAX5) and a double-stain immunofluorescence technique (anti-CD20 and anti-CD3 antibodies). The clonality of B cells was studied by polymerase chain reaction. Three profiles were observed. In 15 of the 23 cases, the CD20 cells were reactive. In 6 cases, CD20 protein was aberrantly expressed in T-MF lesions. Lastly, there were 2 composite lymphomas (T-MF infiltrate with a B-cell follicular lymphoma). In view of this series, we propose a simple algorithm to help pathologists evaluate the nature of the CD20 component associated with T-MF. Although statistically not significant, there was a trend toward a worse prognosis in the presence of >50% CD20 cells and of a nodular perifollicular pattern of this component. PMID- 24145653 TI - Lobular endocervical glandular hyperplasia is a neoplastic entity with frequent activating GNAS mutations. AB - To clarify the significance of GNAS mutations in cervical tumorigenesis, we performed mutational analyses in a total of 154 lesions and in 22 normal tissues of the uterine cervix. Activating GNAS mutations were found in 8 of the 19 lobular endocervical glandular hyperplasias (LEGH; 42%) and 4 of the 79 endocervical-type mucinous adenocarcinomas (5%) but were never seen in the normal endocervical tissue, minimal deviation adenocarcinomas, endometrioid adenocarcinomas, or squamous cell carcinomas. We further examined the presence of human papillomavirus (HPV) DNA and p16 expression to probe the relationship between GNAS mutations and HPV infection in LEGHs and carcinomas. All the GNAS mutated LEGHs were negative for HPV DNA and p16 expression, whereas all the GNAS mutated adenocarcinomas were positive for HPV DNA and/or p16 expression, implicating GNAS mutations in the development of LEGH and a minor subset of HPV related cervical adenocarcinomas. Additional mutational analyses of LEGH identified KRAS and STK11 mutations in 1 and 2 cases, respectively. The GNAS, KRAS, and STK11 mutations were mutually exclusive; thus, a total of 11 LEGHs (58%) had 1 of these genetic alterations. Although LEGH has been regarded as a metaplastic lesion, the frequent presence of genetic alterations suggests a neoplastic nature. PMID- 24145654 TI - TNF-alpha expression in tumor cells as a novel prognostic marker for diffuse large B-cell lymphoma, not otherwise specified. AB - Several cytokines promote malignant cell growth and are therefore believed to contribute to disease aggressiveness. The cytokine tumor necrosis factor-alpha (TNF-alpha) acts as a tumor-promoting factor and has been linked to all tumorigenic stages in many cancers. Here, we evaluated 62 lymphoma tissue specimens from patients having diffuse large B-cell lymphoma, not otherwise specified (DLBCL, NOS) by immunostaining with anti-TNF-alpha antibody. Cytoplasmic TNF-alpha reactivity in >=20% of the tumor cells was considered positive. Our results demonstrated that tumor specimens from DLBCL, NOS patients could be divided into 2 types-TNF-alpha positive (38 cases, 61%) and TNF-alpha negative (24 cases, 39%)--and that TNF-alpha positivity in DLBCL, NOS was correlated with poorer overall survival (OS; P=0.0005, log rank test) and progression-free survival (PFS; P=0.0330, log rank test) compared with TNF-alpha negativity. Cox regression analysis showed that TNF-alpha expression was a significant prognostic factor for OS (P<0.0001) and PFS (P=0.0323). Regarding OS and PFS, multivariate analysis showed that TNF-alpha expression in tumor cells was an independent prognostic factor for the International Prognostic Index (IPI). Therefore, TNF-alpha-positive DLBCL, NOS may constitute a unique subtype of DLBCL, NOS with an aggressive clinical course. The addition of TNF-alpha expression to the IPI may significantly improve the predictive prognostic value. The therapeutic strategy of DLBCL, NOS patients should be based on correct prognosis; therefore, patients with poor prognoses could be more accurately detected by evaluating both TNF-alpha expression levels and the IPI. PMID- 24145655 TI - Influence of histologic criteria and confounding factors in staging equivocal cases for microscopic perivesical tissue invasion (pT3a): an interobserver study among genitourinary pathologists. AB - Current oncology guidelines and clinical trials consider giving adjuvant chemotherapy to bladder cancer patients with at least microscopic perivesical tissue invasion (MPVTI) (>=pT3a) on cystectomy. The boundary of muscularis propria (MP) and perivesical tissue is commonly ill defined, and hence, when the tumor involves the interface, interpretation of MPVTI is likely to be subjective. In this study, 20 sets of static images that included 1 nontumoral bladder wall for defining MP-perivesical tissue boundary and 19 bladder cancer cases equivocal for MPVTI with confounding factors were sent to 17 expert genitourinary pathologists for review. The confounding factors were "histoanatomic," as defined by the irregular MP-perivesical tissue boundary, and "tumor related," such as fibrosis, dense inflammation, tumor cells at the edge of the outermost MP muscle bundle, and lymphovascular invasion. These equivocal cases were divided into 3 categories according to the following factors: (1) histoanatomic only (7/19), (2) histoanatomic+tumor related (7/19), and (3) tumor related only (5/19). Participating genitourinary pathologists used different criteria to assess MPVTI: (A) drawing a straight horizontal line using the outermost MP muscle bundle edge as the MP-perivesical tissue boundary reference (3/17); (B) drawing multiple straight lines interconnecting the outermost MP muscle bundle edges (9/17); (C) following the curves of every outermost MP muscle bundle edge (4/17). In category 1 cases, most pathologists who used the A criterion called for absence (6/7), whereas those who used the C criterion called for presence (5/7) of MPVTI, which resulted in disparity in 4/7 cases. There was no circumstance in which criteria A and C agreed on the presence or absence of MPVTI but was opposed by the B criterion in category 1 cases. Median pairwise agreement among all pathologists (regardless of criteria) for all cases (regardless of category) was only "fair" (kappa=0.281). However, when only the B criterion was assessed for category 1 cases, median agreement was "substantial" (kappa=0.696), and pairwise rater comparisons included 6/36 (17%) "near perfect," 13/36 (36%) "substantial," and 11/36 (31%) "moderate" agreements. When all cases with histoanatomic factors (categories 1 and 2) were combined, median pairwise agreements were: (A) kappa=0.588, (B) kappa=0.423, and (C) kappa=0.512, and the B criterion rater comparisons included 0/36 (0%) "near perfect," 6/36 (17%) "substantial," and 16/36 (44%) "moderate" agreements, which showed the confounding effect of tumor related factors. For category 3 cases, median pairwise agreement for all pathologists was "fair" (kappa=0.286), with consensus agreement in only 2/5 of these equivocal cases. Lymphovascular invasion only at the MP-perivesical tissue boundary was not staged as MPVTI by 87.5% of pathologists. In conclusion, this study showed that interpretation of equivocal cases for MPVTI can be made difficult by factors intrinsic to bladder histoanatomy, defined by an irregular MP-perivesical tissue boundary, and factors related to tumor spread. There are at least 3 different approaches to demarcating an irregular outer MP boundary, and agreement is improved on equivocal cases when a common histoanatomic criterion is used. However, inconsistent agreement of anatomic criteria may cause systematic discrepancy in assessing MPVTI. Tumor-related factors such as dense fibrosis or desmoplasia, obscuring inflammation, tumor cells at the edge of the outermost MP muscle bundle, and admixed lymphovascular invasion can also negatively influence the agreement on interpretation of MPVTI. This study highlights the need to adopt common criteria in defining the outer MP boundary. Future studies may identify the most clinically relevant histoanatomic criteria for MPVTI. PMID- 24145656 TI - Iatrogenic immunodeficiency-associated classical hodgkin lymphoma: clinicopathologic features of 54 cases reported in the literature. PMID- 24145657 TI - Physical activity profiles of overweight and obese women in rural Georgia. PMID- 24145658 TI - A gene responsible for prolyl-hydroxylation of moss-produced recombinant human erythropoietin. AB - Recombinant production of pharmaceutical proteins is crucial, not only for personalized medicine. While most biopharmaceuticals are currently produced in mammalian cell culture, plant-made pharmaceuticals gain momentum. Post translational modifications in plants are similar to those in humans, however, existing differences may affect quality, safety and efficacy of the products. A frequent modification in higher eukaryotes is prolyl-4-hydroxylase (P4H) catalysed prolyl-hydroxylation. P4H sequence recognition sites on target proteins differ between humans and plants leading to non-human posttranslational modifications of recombinant human proteins produced in plants. The resulting hydroxyprolines display the anchor for plant-specific O-glycosylation, which bears immunogenic potential for patients. Here we describe the identification of a plant gene responsible for non-human prolyl-hydroxylation of human erythropoietin (hEPO) recombinantly produced in plant (moss) bioreactors. Targeted ablation of this gene abolished undesired prolyl-hydroxylation of hEPO and thus paves the way for plant-made pharmaceuticals humanized via glyco engineering in moss bioreactors. PMID- 24145659 TI - A solid-solid phase transition in carbon dioxide at high pressures and intermediate temperatures. AB - Despite its terrestrial abundance and astrochemical significance, many aspects of the phase diagram of solid carbon dioxide remain uncertain or unknown. The observed transition pressures from cubic to orthorhombic phase range widely from 2.5 GPa at 80 K to above 18 GPa at room temperature. The vibrational Raman bands that appear at higher pressure and serve as a decisive proof of the existence of the orthorhombic phase have never been assigned. Here we introduce a general ab initio computational method that can predict the Gibbs free energies and thus phase diagrams of molecular crystals. Using this with second-order Moller-Plesset perturbation theory, we obtain the transition pressure of 13 GPa at 0 K with small temperature dependence, which is in line with many experiments. We also computationally reproduce the vibrational Raman bands and explain the pressure dependence of the structure parameters and Raman band positions of both phases quantitatively. PMID- 24145661 TI - Monte Carlo simulation of near-infrared light propagation through homogeneous mixed media. AB - ABSTRACT. Noninvasive blood analysis devices that can measure levels of small constituents of blood are of interest in the medical community. An important step in creating these devices is to understand the interaction of photons with human tissue in increasingly greater physiological detail. Models based on layered biological materials give excellent results for many applications but may not be as accurate as needed when those materials are finely intertwined to the point of resembling a homogeneous mixture. To explore the ramifications of treating materials as layers versus a mixture, we have modeled, using a Monte Carlo technique, the interaction of photons through epidermis, blood, and water arranged both in layers and in a homogeneous blend. We confirm the expected linear relation between photon attenuation and material volumetric percentage in two-layer models. However, when the materials are homogeneously mixed together and volumetric percentage is replaced with interaction volume percentage, this relationship becomes nonlinear. These nonlinearities become significant when the values of the interaction coefficient, MUt, differ by an order of magnitude or more. PMID- 24145660 TI - Autophagy is not involved in the degradation of sperm mitochondria after fertilization in mice. AB - In almost all animals, mitochondrial DNA (mtDNA) is transmitted only from the female, while the paternal mitochondria and mtDNA are thought to be eliminated during early embryogenesis. Autophagy is involved in the elimination of sperm mitochondria and mtDNA in early embryos in Caenorhabditis elegans; however, solid evidence is still lacking in mammals. Recently, we found that despite the fact that some autophagy-related proteins, such as SQSTM1 and LC3 could localize nearby sperm mitochondria before the 2-cell stage, autophagy did not participate in the elimination of sperm mitochondria and mtDNA. Instead, the pre-elimination of sperm mtDNA before fertilization and the restriction of sperm mitochondria in one blastomere before 4-cell stage embryos are the most important mechanisms of maternal mitochondrial inheritance in mice. PMID- 24145662 TI - Multiplexing-based polarization sensitive en-face optical coherence tomography. AB - We present a time-domain polarization-sensitive (PS) optical coherence tomography configuration operating at 830 nm, equipped with multichannel acousto-optic deflectors and single photodetectors. The system is used to simultaneously acquire interference information from multiple PS channels and to enable measurement and imaging of backscattered intensity to create both PS and polarization insensitive images. Our approach enables multiple channel imaging without need to divide the object signal. Here, we employ our system in order to demonstrate PS imaging of a thermally damaged muscle tissue. PMID- 24145663 TI - CO2-lased enamel microhardness after brushing and cariogenic challenge. AB - This study aimed to assess how the wear that brushing promotes affects CO2 laser irradiated enamel microhardness after cariogenic challenge in vitro. Forty fragments measuring 4 * 4 mm were randomly assigned to four groups according to the enamel surface treatment: G1-control, G2-CO2-laser irradiation, G3-brushing, and G4-CO2 laser irradiation + brushing. A laser device emitting at 10.6 MUm was used (power=0.5 W, energy per pulse=0.05 mJ, and frequency=10 kHz). Specimens belonging to groups G3 and G4 were brushed (80,000 strokes) with a brushing simulator using toothpaste. Next, the samples were challenged with acid: the specimens were immersed in demineralizing and remineralizing solutions for 8 days. The acid resistance of enamel was evaluated by cross-sectional microhardness tests. The area under the curve (KHN * MUm) was calculated. Analysis of variance (ANOVA) one-away and Fisher's test were performed for the statistical analysis (p<0.05). Group G2 specimens (31,185 +/- 4706) were statistically different from specimens belonging to groups G1 (26,723 +/- 2446), G3 (28,194 +/- 1376), and G4 (28,207 +/- 2234), which were statistically similar. The brushing time used in the present study probably wore the CO2-lased enamel, so demineralization could not be prevented in the brushed group. PMID- 24145666 TI - 268 nm photodissociation of ClN3: a femtosecond velocity-map imaging study. AB - We report the first time-resolved study of the photochemistry of chlorine azide (ClN3) by femtosecond velocity-map imaging (fs-VMI). The dissociation dynamics are initiated at 4.6 eV and the photofragments are detected by multiphoton ionization using an intense laser field centered at 803 nm. A dissociation time of 262 +/- 38 fs was measured from the rising time of the co-fragments N3 and Cl. The time dependency of the angular distribution of N3, which converges from beta2 ~ 2 to beta2 = 1.61 +/- 0.07 in 170 +/- 45 fs, reveals the parallel nature of the transition dipole moment. PMID- 24145664 TI - Parabiosis in mice: a detailed protocol. AB - Parabiosis is a surgical union of two organisms allowing sharing of the blood circulation. Attaching the skin of two animals promotes formation of microvasculature at the site of inflammation. Parabiotic partners share their circulating antigens and thus are free of adverse immune reaction. First described by Paul Bert in 1864(1), the parabiosis surgery was refined by Bunster and Meyer in 1933 to improve animal survival(2). In the current protocol, two mice are surgically joined following a modification of the Bunster and Meyer technique. Animals are connected through the elbow and knee joints followed by attachment of the skin allowing firm support that prevents strain on the sutured skin. Herein, we describe in detail the parabiotic joining of a ubiquitous GFP expressing mouse to a wild type (WT) mouse. Two weeks after the procedure, the pair is separated and GFP positive cells can be detected by flow cytometric analysis in the blood circulation of the WT mouse. The blood chimerism allows one to examine the contribution of the circulating cells from one animal in the other. PMID- 24145667 TI - Heterogeneity in Trail Making Test performance in OEF/OIF/OND veterans with mild traumatic brain injury. AB - This study used cluster analysis to examine variability in Trail Making Test (TMT) performance in a sample of Operation Enduring Freedom/Operation Iraqi Freedom/Operation New Dawn (OEF/OIF/OND) veterans referred for mild traumatic brain injury (mTBI). Three clusters were extracted, two of which were characterized by level of performance and the third with a unique performance pattern characterized by slow performance on the TMT B (Low B). Clusters did not differ on demographic or psychiatric variables. The Above Average cluster had better performance on measures of processing speed, working memory, and phonemic fluency compared with the Low B cluster. Results suggest that a subset of patients with mTBI perform poorly on TMT B, which subsequently predicts poorer cognitive functioning on several other neuropsychological measures. This subset may be vulnerable to cognitive changes in the context of mTBI and multiple comorbidities while a number of other patients remain cognitively unaffected under the same circumstances. PMID- 24145668 TI - Titanium mediated olefination of aldehydes with alpha-haloacetates: an exceptionally stereoselective and general approach to (Z)-alpha-haloacrylates. AB - An exceptionally stereoselective and general synthesis of (Z)-alpha haloacrylates, ready to undergo various synthetic transformations, has been demonstrated from alpha-haloacetates and aldehydes in a one-pot manner via the titanium-enolate based asymmetric aldol condensation. Besides being an expedient synthetic procedure, the ready availability of diverse alpha-haloacetates, exceptional stereoselectivity, and high yields make the process a versatile transformation in organic synthesis. The potential of this method in up-scaling operations has been illustrated. PMID- 24145669 TI - Lipopolysaccharide-induced apoptosis in a murine intestinal endocrine cell line by modulation of Bcl-2, Bax and caspase-3. AB - Numerous studies have focused on how to modulate the secretion of glucagon-like peptide 1 (GLP-1) due to its marked anti-diabetic function. However, few studies have investigated the apoptosis of enteroendocrine L cells, which secrete GLP-1. The aim of this study was to determine whether lipopolysaccharide (LPS), a gut bacterial product, is capable of inducing apoptosis in the intestinal endocrine cell line STC-1. We found that LPS is capable of reducing the viability of STC-1 cells in a concentration-dependent manner. annexin V/propidium iodide (PI) double staining detected by fluorescence microscopy and flow cytometry revealed a strong apoptosis-inducing ability for LPS in STC-1 cells. Furthermore, western blotting revealed that exposure to LPS significantly decreased the expression of Bcl-2 and increased the expression of Bax and caspase-3. In conclusion, LPS induced the apoptosis of STC-1 cells in a dose-dependent manner, which may be responsible for the reduced secretion of GLP-1 in diabetes. PMID- 24145671 TI - Completing cremation forms: a practical guide. AB - Before a body can be cremated doctors must complete a series of lengthy forms better known as 'crem forms'. One doctor first completes a medical certificate (Cremation Form 4, previously known as 'Part B') while a second must complete a confirmatory medical certificate (Cremation Form 5, previously 'Part C'). PMID- 24145670 TI - A degradative detour for mutant TP53. AB - Accumulation of mutant TP53 proteins in cancer cells has been recognized as an important factor that promotes cancer progression and metastasis. Thus, strategies that promote the degradation of mutant TP53 might be beneficial for the treatment of cancers. In a recent issue of Genes & Development, we demonstrated that blocking macroautophagy under nutritional stress condition leads to the degradation of mutant TP53 through activating the chaperone-mediated autophagy (CMA) pathway in nonproliferating cancer cells. We propose CMA as a new degradative mechanism for mutant TP53 and the possibility of activating CMA as a new treatment for cancers with mutant TP53. PMID- 24145672 TI - Management of medication in patients with Parkinson's disease who are nil-by mouth. AB - Parkinson's disease affects approximately 200 in every 100000 patients in London (Schrag et al, 2000). These individuals experience increased rates of emergency admissions to hospital secondary to falls, fractures, impaired mobility, infections, psychiatric disturbances and cardiovascular disease. The duration of their hospital stay is frequently prolonged compared to patients who do not have Parkinson's disease (Woodford and Walker, 2005). In addition, significant numbers of patients with Parkinson's disease are admitted for elective surgery. PMID- 24145673 TI - Hand infections. AB - Hand infections account for a significant number of attendances to the emergency department, with the NHS reporting an incidence of hand cellulitis alone as 16.4/1000 person years (Office of Population Censuses and Surveys, 1992; Masson, 2002). Prompt treatment allows a rapid return of function; however, delayed diagnosis risks significant disability and suboptimal outcomes for patients. The spectrum of clinical presentation and pathophysiology varies immensely and can be diagnostically challenging. PMID- 24145674 TI - Robust plan optimization for electromagnetic transponder guided hypo-fractionated prostate treatment using volumetric modulated arc therapy. AB - To develop an optimization algorithm for volumetric modulated arc therapy which incorporates an electromagnetic tracking (EMT) guided gating strategy and is robust to residual intra-fractional motion uncertainties. In a computer simulation, intra-fractional motion traces from prior treatments with EMT were converted to a probability distribution function (PDF), truncated using a patient specific action volume that encloses allowed deviations from the planned position, and renormalized to yield a new PDF with EMT-gated interventions. In lieu of a conventional planning target volume (PTV), multiple instances of clinical target volume (CTV) and organs at risk (OARs) were replicated and displaced to extreme positions inside the action volume representing possible delivery scenarios. When optimizing the volumetric modulated arc therapy plan, doses to the CTV and OARs were calculated as a sum of doses to the replicas weighted by the PDF to account for motion. A treatment plan meeting the clinical constraints was produced and compared to the counterpart conventional margin (PTV) plan. EMT traces from a separate testing database served to simulate motion during gated delivery. Dosimetric end points extracted from dose accumulations for each motion trace were utilized to evaluate potential clinical benefit. Five prostate cases from a hypofractionated protocol (42.5 Gy in 5 fractions) were retrospectively investigated. The patient specific gating window resulted in tight anterior and inferior action levels (~1 mm) to protect rectal wall and bladder wall, and resulted in an average of four beam interruptions per fraction in the simulation. The robust-optimized plans achieved the same average CTV D95 coverage of 40.5 Gy as the PTV-optimized plans, but with reduced patient-averaged rectum wall D1cc by 2.2 Gy (range 0.7 to 4.7 Gy) and bladder wall mean dose by 2.9 Gy (range 2.0 to 3.4 Gy). Integration of an intra-fractional motion management strategy into the robust optimization process is feasible and may yield improved OAR sparing compared to the standard margin approach. PMID- 24145675 TI - Granulocyte macrophage colony-stimulating factor auto-antibodies and disease relapse in inflammatory bowel disease. AB - OBJECTIVES: Along with others, we have reported that neutralization of granulocyte macrophage colony-stimulating factor (GM-CSF) increases intestinal permeability and bacterial translocation, and reduces neutrophil bacterial killing and anti-microbial seroreactivity. The objective was to investigate the utility of serum GM-CSF auto-antibody (Ab) as a marker for confirmation of stable remission and prediction of relapses in patients with inflammatory bowel disease (IBD). METHODS: We consecutively included 181 adults and children with Crohn's disease (CD, n=61) or ulcerative colitis (UC, n=120). Over a 3-year period, we collected 861 serum samples and 610 stool samples during regular follow-up visits. GM-CSF Abs and fecal S100 proteins were measured by an enzyme-linked immunoassay. RESULTS: Serum GM-CSF Ab levels correlated with disease activity, location, and extent. Time course analysis before and after relapse showed a clear increase of GM-CSF Ab concentrations up to 6 months before clinical relapse. At 1.7 MUg/ml (CD) and 0.5 MUg/ml (UC), the sensitivity and specificity of GM-CSF Ab for predicting relapse already 2-6 months earlier were 88% and 95% in CD and 62% and 68% in UC, respectively. A baseline GM-CSF Ab level of >1.7 MUg/ml was significantly associated with relapse of CD within 18 months. CONCLUSIONS: As GM-CSF is required for myeloid cell antimicrobial functions and homeostatic responses to tissue injury, serum GM-CSF Ab levels might reflect the degree of bowel permeability and bacterial translocation. Therefore, GM-CSF Ab might identify IBD patients at risk of disease relapse at an early stage, which makes the test a potential tool for monitoring disease activity and optimizing therapy. PMID- 24145676 TI - Opium use and risk of mortality from digestive diseases: a prospective cohort study. AB - OBJECTIVES: Opium use, particularly in low doses, is a common practice among adults in northeastern Iran. We aimed to investigate the association between opium use and subsequent mortality from disorders of the digestive tract. METHODS: We used data from the Golestan Cohort Study, a prospective cohort study in northeastern Iran, with detailed, validated data on opium use and several other exposures. A total of 50,045 adults were enrolled during a 4-year period (2004-2008) and followed annually until December 2012, with a follow-up success rate of 99%. We used Cox proportional hazard regression models to evaluate the association between opium use and outcomes of interest. RESULTS: In all, 8,487 (17%) participants reported opium use, with a mean duration of 12.7 years. During the follow-up period 474 deaths from digestive diseases were reported (387 due to gastrointestinal cancers and 87 due to nonmalignant etiologies). Opium use was associated with an increased risk of death from any digestive disease (adjusted hazard ratio (HR)=1.55, 95% confidence interval (CI)=1.24-1.93). The association was dose dependent, with a HR of 2.21 (1.57-3.31) for the highest quintile of cumulative opium use vs. no use (Ptrend=0.037). The HRs (95% CI) for the associations between opium use and malignant and nonmalignant causes of digestive mortality were 1.38 (1.07-1.76) and 2.60 (1.57-4.31), respectively. Increased risks were seen both for smoking opium and for ingestion of opium. CONCLUSIONS: Long-term opium use, even in low doses, is associated with increased risk of death from both malignant and nonmalignant digestive diseases. PMID- 24145677 TI - Clinical and endoscopic characteristics do not reliably differentiate PPI responsive esophageal eosinophilia and eosinophilic esophagitis in patients undergoing upper endoscopy: a prospective cohort study. AB - OBJECTIVES: Proton-pump inhibitor-responsive esophageal eosinophilia (PPI-REE) is a newly recognized entity that must be differentiated from eosinophilic esophagitis (EoE). Little is known about this condition. We aimed to determine the prevalence of PPI-REE and EoE in patients undergoing upper endoscopy and determine features that distinguish the two groups. METHODS: This prospective study conducted at the University of North Carolina from 2009 to 2011 enrolled consecutive adult patients undergoing outpatient upper endoscopy. Subjects had esophageal biopsies to quantify the maximum eosinophil count per high-power field (eos/hpf; hpf=0.24 mm(2)). If biopsies revealed >=15 eos/hpf, subjects were treated with twice daily PPI for 8 weeks and endoscopy was repeated. If >=15 eos/hpf persisted despite PPI therapy, EoE was diagnosed. If there were <15 eos/hpf, PPI-REE was diagnosed. The proportion of patients in each group was calculated, and patients with EoE and PPI-REE were compared. RESULTS: Of the 223 subjects enrolled, 173 had dysphagia and 50 did not. Of those with dysphagia, 66 (38%) had >=15 eos/hpf. After the PPI trial, 40 (23%) were confirmed to have EoE, and 24 (14%) had PPI-REE. Of those without dysphagia, 2 (4%) had >=15 eos/hpf, and after the PPI trial, 1 (2%) had EoE. Compared with EoE, PPI-REE patients were more likely to be older and male and less likely to have typical endoscopic findings of EoE. However, none of the individual factors was independently predictive of PPI-REE status on multivariable analysis. Similarly, although some endoscopic findings were differentially distributed between PPI-REE and EoE, none were significantly associated with disease status on multivariable analysis. CONCLUSIONS: Esophageal eosinophilia is common among patients undergoing esophagogastroduodenoscopy for dysphagia. Although EoE was seen in nearly a quarter of patients with dysphagia, PPI-REE was almost as common, and accounted for over one-third of those with >=15 eos/hpf. No clinical or endoscopic features independently distinguished PPI-REE from EoE before the PPI trial. PMID- 24145679 TI - Inpatient weekend ERCP is associated with a reduction in patient length of stay. AB - OBJECTIVES: Endoscopic retrograde cholangiopancreatography (ERCP) performed on the weekend requires significant effort from the endoscopist, nursing staff, and anesthesia services. These factors often result in delaying the procedure until the following Monday. No data exist on whether performing weekend ERCP reduces length of stay (LOS) and total cost to justify the additional physician and nursing burden. METHODS: In this single tertiary academic center, institutional review board-approved study, we retrospectively reviewed all hospitalized patients in whom an ERCP had been completed from May 2010 to September 2011. Demographic and clinical information, procedure details as well as total hospitalization charges (USD) were compared between patients who had an ERCP either on the weekend or weekday holiday (WE ERCP) or Monday (MON ERCP). Statistical comparisons were made using chi(2) and Fischer's exact test. A logistic regression model adjusted for propensity scores (PSs) was used to estimate the risk in prolonged LOS and high total charges associated with WE ERCPs vs. MON ERCPs. RESULTS: A total of 1,114 ERCP's were performed during the time period, 123 of which met inclusion criteria (52 WE, 71 MON). Mean patient age was 56.3+/-16.7 years (54.5% female, 60.2% Caucasian). There were no significant demographic differences between the two groups. The most common procedure indications were choledocholithiasis (34.9%) and elevated liver enzymes after liver transplantation (25.2%). The analysis showed a significantly decreased LOS (P=0.010) and a trend towards decreased cost (P=0.050) associated with WE ERCP. In the multivariate analysis adjusted for PS, WE ERCP had a significantly decreased odds ratio of LOS>3 days (odds ratio: 0.37 (0.16-0.85); P=0.019). CONCLUSIONS: We demonstrated a significant decrease in LOS and a trend towards decrease in charges in patients who underwent weekend ERCP compared with delaying ERCP until Monday. Thus, health-care organizations should consider removing barriers to weekend inpatient ERCPs. PMID- 24145678 TI - A randomized, open-label, non-inferiority study of intravenous iron isomaltoside 1,000 (Monofer) compared with oral iron for treatment of anemia in IBD (PROCEED). AB - OBJECTIVES: In the largest head-to-head comparison between an oral and an intravenous (IV) iron compound in patients with inflammatory bowel disease (IBD) so far, we strived to determine whether IV iron isomaltoside 1,000 is non inferior to oral iron sulfate in the treatment of iron deficiency anemia (IDA). METHODS: This prospective, randomized, comparative, open-label, non-inferiority study was conducted at 36 sites in Europe and India. Patients with known intolerance to oral iron were excluded. A total of 338 IBD patients in clinical remission or with mild disease, a hemoglobin (Hb) <12 g/dl, and a transferrin saturation (TSAT) <20% were randomized 2:1 to receive either IV iron isomaltoside 1,000 according to the Ganzoni formula (225 patients) or oral iron sulfate 200 mg daily (equivalent to 200 mg elemental iron; 113 patients). An interactive web response system method was used to randomize the eligible patient to the treatment groups. The primary end point was change in Hb from baseline to week 8. Iron isomaltoside 1,000 and iron sulfate was compared by a non-inferiority assessment with a margin of -0.5 g/dl. The secondary end points, which tested for superiority, included change in Hb from baseline to weeks 2 and 4, change in s ferritin, and TSAT to week 8, number of patients who discontinued study because of lack of response or intolerance of investigational drugs, change in total quality of life (QoL) score to weeks 4 and 8, and safety. Exploratory analyses included a responder analysis (proportion of patients with an increase in Hb >=2 g/dl after 8 weeks), the effect of regional differences and total iron dose level, and other potential predictors of the treatment response. RESULTS: Non inferiority in change of Hb to week 8 could not be demonstrated. There was a trend for oral iron sulfate being more effective in increasing Hb than iron isomaltoside 1,000. The estimated treatment effect was -0.37 (95% confidence interval (CI): -0.80, 0.06) with P=0.09 in the full analysis set (N=327) and 0.45 (95% CI: -0.88, -0.03) with P=0.04 in the per protocol analysis set (N=299). In patients treated with IV iron isomaltoside 1,000, the mean change in s ferritin concentration was higher with an estimated treatment effect of 48.7 (95% CI: 18.6, 78.8) with P=0.002, whereas the mean change in TSAT was lower with an estimated treatment effect of -4.4 (95% CI: -7.4, -1.4) with P=0.005, compared with patients treated with oral iron. No differences in changes of QoL were observed. The safety profile was similar between the groups. The proportion of responders with Hb >=2 g/dl (IV group: 67%; oral group: 61%) were comparable between the groups (P=0.32). Iron isomaltoside 1,000 was more efficacious with higher cumulative doses of >1,000 mg IV. Significant predictors of Hb response to IV iron treatment were baseline Hb and C-reactive protein (CRP). CONCLUSIONS: We could not demonstrate non-inferiority of IV iron isomaltoside 1,000 compared with oral iron in this study. Based on the dose-response relationship observed with the IV iron compound, we suggest that the true iron demand of IV iron was underestimated by the Ganzoni formula in our study. Alternative calculations including Hb and CRP should be explored to gauge iron stores in patients with IBD. PMID- 24145680 TI - A systematic review of the influence of opioids on advanced cancer patient survival. AB - PURPOSE OF REVIEW: Many health professionals still believe that opioids shorten the lifespan of patients. This situation implies that the ethical doctrine of double effect is often invoked to justify their use in extreme circumstances. The objective of this study is to revise the evidence existing in the recently published literature regarding the effect on patient survival of opioid used to control disease symptoms. RECENT FINDINGS: A review of the scientific literature regarding the effects of opioids on symptom control and survival does not provide any evidence that there is an association between these two variables. SUMMARY: The studies revised have not shown that the use of opioids for symptom control in advanced disease stages or in the last days of life has any effect on patient survival. Similarly, survival was not influenced by either the use of higher or lower doses of opioids, or by the practice of administering a double dose at night. PMID- 24145682 TI - Status of palliative care in Latin America: looking through the Latin America Atlas of Palliative Care. AB - PURPOSE OF REVIEW: Several studies have been published reporting the status of palliative care in different countries of Latin America, but no studies have been published on the status of the discipline across the whole region. This article provides a summary of the current situation as reported in the Atlas of Palliative Care recently completed by the Latin American Association for Palliative Care. The aim of this project was to collect information on the degree of palliative care development, help create a network, and influence the progress of palliative care across Latin America. RECENT FINDINGS: The Atlas provides an overview of the status of palliative care in Latin America according to the World Health Organization public health strategy for palliative care: policies, drug availability, education, and implementation of services. The results indicate that there is significant variation among countries in the region and that strategies to support and develop palliative care require tailored approaches to meet the needs of each. SUMMARY: The information in this review gives a broad notion of the current status of palliative care in Latin America. The Atlas is expected to help the progress of palliative care and serve as a driver of the field in Latin America and other regions. PMID- 24145683 TI - Mechanomyographic and electromyographic responses during fatiguing eccentric muscle actions of the leg extensors. AB - The purpose of the current study was to examine the patterns of responses for torque, mechanomyographic (MMG) amplitude, MMG frequency, electromyographic (EMG) amplitude, and EMG frequency across 30 repeated maximal eccentric muscle actions of the leg extensors. Eleven moderately trained females performed an eccentric fatigue protocol at 30 degrees /s with MMG and EMG signals recorded from the vastus lateralis. The results indicated there were significant (P<.05) decreases in MMG frequency (linear, r2=.395), EMG frequency (linear, r2=.177), and torque (linear, r2=.570; % decline=9.8+/-13.3%); increases in MMG amplitude (linear, r2=.783); and no change in EMG amplitude (r2=.003). These findings suggested that the neural strategies used to modulate torque during fatiguing eccentric muscle actions involved de-recruitment of motor units, reduced firing rates, and synchronization. In addition, the decreases in eccentric torque were more closely associated with changes in MMG frequency than EMG frequency. Thus, these findings indicated that MMG frequency, compared with EMG frequency, more accurately tracks fatigue during repeated maximal eccentric muscle actions. PMID- 24145681 TI - Clinical development of ghrelin axis-derived molecules for cancer cachexia treatment. AB - PURPOSE OF REVIEW: Cachexia is a devastating complication of cancer for which there is no approved treatment. Here we review the clinical development of ghrelin and ghrelin mimetics (also known as growth hormone secretagogues or GHS) for cancer cachexia treatment. RECENT FINDINGS: Ghrelin, a novel hormone known to increase appetite, lean and fat mass, and growth hormone secretion, is being developed as a therapeutic option for cancer anorexia-cachexia syndrome (CACS). Recent animal studies suggest that it may also decrease inflammation and that some of its effects may be independent of its only known receptor, the GHS receptor-1a.Clinical studies recently have shown that administration of ghrelin or GHS improves appetite and quality of life as assessed by questionnaires. Weight gain, increased food intake and better tolerance to chemotherapy have also been reported. This treatment appears to be safe and well tolerated. SUMMARY: Ghrelin and GHS have the potential to effectively prevent or reverse CACS. Preliminary studies show improvements in weight stabilization and appetite with short-term usage. Further studies are required to fully characterize the role of ghrelin and GHS for the treatment of CACS and to establish the safety of this approach. PMID- 24145684 TI - Surface engineered porous silicon for stable, high performance electrochemical supercapacitors. AB - Silicon materials remain unused for supercapacitors due to extreme reactivity of silicon with electrolytes. However, doped silicon materials boast a low mass density, excellent conductivity, a controllably etched nanoporous structure, and combined earth abundance and technological presence appealing to diverse energy storage frameworks. Here, we demonstrate a universal route to transform porous silicon (P-Si) into stable electrodes for electrochemical devices through growth of an ultra-thin, conformal graphene coating on the P-Si surface. This graphene coating simultaneously passivates surface charge traps and provides an ideal electrode-electrolyte electrochemical interface. This leads to 10-40X improvement in energy density, and a 2X wider electrochemical window compared to identically structured unpassivated P-Si. This work demonstrates a technique generalizable to mesoporous and nanoporous materials that decouples the engineering of electrode structure and electrochemical surface stability to engineer performance in electrochemical environments. Specifically, we demonstrate P-Si as a promising new platform for grid-scale and integrated electrochemical energy storage. PMID- 24145685 TI - Walking Index for Spinal Cord Injury version II in acute spinal cord injury: reliability and reproducibility. AB - STUDY DESIGN: Administration of the walking index for SCI (WISCI) II is recommended to assess walking in spinal cord injury (SCI) patients. Determining the reliability and reproducibility of the WISCI II in acute SCI would be invaluable. OBJECTIVES: The objective of this study is to assess the reliability and reproducibility of the WISCI II in patients with traumatic, acute SCI. DESIGN: Test-retest analysis and calculation of reliability and smallest real difference (SRD). SETTING: SCI unit of a rehabilitation hospital. METHODS: Thirty three patients, median age 44 years, median time since onset of SCI 40 days. Level: 20 cervical, 8 thoracic, 5 lumbar; ASIA (American Spinal Injury Association) impairment scale (AIS) grade: 32 D/1 C. Assessment of maximum WISCI II levels by two trained, blinded raters to evaluate interrater (IRR) and intrarater reliability. RESULTS: The intrarater reliability was 0.999 for therapists A and 0.979 for therapists B, for the maximum WISCI II level. The IRR for the maximum WISCI II score was 0.996 on day 1 and 0.975 on day 2. The SRD for the maximum WISCI II score was 1.147 for tetraplegics and 1.682 for paraplegics. These results suggest that a change of two WISCI II levels could be considered real. CONCLUSIONS: The WISCI II has high IRR and intrarater reliability and good reproducibility in the acute and subacute phase when administered by trained raters. PMID- 24145686 TI - Changes in renal function during acute spinal cord injury: implications for pharmacotherapy. PMID- 24145687 TI - The effect of steroids on the incidence of gastrointestinal hemorrhage after spinal cord injury: a case-controlled study. AB - STUDY DESIGN: Retrospective case-controlled study. OBJECTIVES: To understand the incidence of gastrointestinal hemorrhage (GIH) and subsequent mortality rate associated with steroid use after acute spinal cord injury (SCI). SETTING: Miami, Florida, USA. METHODS: This case-controlled study investigates two sequential study groups with SCI treated by a single surgeon in a level I trauma center. The first study cohort (1997-2005) received steroids according to the NASCIS II protocol and the second (2005-2012) received no steroid treatment. The groups were comparable with respect to age, sex, severity and level of injury (43 vs 45 years old/3:1 male-female/AIS scale %-43.5 vs 41.7 A, 10.6 vs 11.1 B, 20.3 vs 13.4 C, 25.4 vs 33.5 D/64.3 vs 73.8% cervical, 35.6 vs 25.7% thoracic and lumbar). The incidence and mortality from GIH were the primary outcome measures. RESULTS: A total of 350 patients were evaluated during the study period. The incidence of GIH in the SCI group receiving steroids was 6/216 (2.77%) with 2 mortalities (33.3%). No gastrointestinal (GI) complications were noted in the 134 patients that did not receive any steroids (P=0.086). All GIH cases in the steroid group were in cervical SCI patients-6/139 (4.32%; P=0.043). Average time to onset of GIH was 16 days. CONCLUSION: The use of steroids in acute SCI appears to be a key risk factor in increasing the incidence of clinically overt GI complications with a subsequent high mortality rate, particularly in patients with cervical SCI. PMID- 24145688 TI - Response to 'changes in renal function during acute spinal cord injury: implications for pharmacotherapy'. PMID- 24145689 TI - Endoplasmic reticulum stress response in the rat contusive spinal cord injury model-susceptibility in specific cell types. AB - STUDY DESIGN: Focus group study. OBJECTIVE: To investigate cell-specific endoplasmic reticulum (ER) stress reactions in contusive spinal cord by evaluating the expression of the glucose-regulated protein 78 (GRP78) and C/EBP homologous transcription factor protein (CHOP) using immunohistochemical staining. SETTING: Data were analysed at Tokai University School of Medicine in Japan. METHODS: The authors generated rat spinal cord injury (SCI) models using an IH-Impactor (100 kdyne(LI), 200 kdyne (HI)). Rats were killed at 1, 3, 5, 7 and 14 days post operation (dpo). Spinal cord sections were prepared and the expression ratio of GRP78 and CHOP was evaluated in oligodendrocyte precursor cells (OPCs) (NG2+), oligodendrocytes (OLs) (APC+), neurons (NeuN+) and astrocytes (GFAP+) using double immunohistochemical staining. We examined an area 8 mm distal from SCI-epicenter. RESULTS: Compared with the sham group, both injured groups had higher GRP78 expression ratio in contused spinal cord at 1 dpo. GRP78 expression ratio was highest in GFAP+ cells of both groups, and lowest in NG2+ cells. Although GRP78 was expressed strongly immediately after SCI in the both groups, increased CHOP expression was observed only in the HI group. The CHOP expression in NG2+ cells was significantly higher than that observed in GFAP+ cells at 5 dpo. CONCLUSION: Although the ER stress response contributes to cell survival in the low-stress SCI conditions, the ER stress response induces an apoptotic cascade in high-stress SCI conditions. The ER response varies according to cell type, with the highest observed in astrocytes, and the lowest observed in oligodendrocyte precursor cells. PMID- 24145690 TI - Sputter growth and characterization of metamagnetic B2-ordered FeRh epilayers. AB - Chemically ordered alloys are useful in a variety of magnetic nanotechnologies. They are most conveniently prepared at an industrial scale using sputtering techniques. Here we describe a method for preparing epitaxial thin films of B2 ordered FeRh by sputter deposition onto single crystal MgO substrates. Deposition at a slow rate onto a heated substrate allows time for the adatoms to both settle into a lattice with a well-defined epitaxial relationship with the substrate and also to find their proper places in the Fe and Rh sublattices of the B2 structure. The structure is conveniently characterized with X-ray reflectometry and diffraction and can be visualised directly using transmission electron micrograph cross-sections. B2-ordered FeRh exhibits an unusual metamagnetic phase transition: the ground state is antiferromagnetic but the alloy transforms into a ferromagnet on heating with a typical transition temperature of about 380 K. This is accompanied by a 1% volume expansion of the unit cell: isotropic in bulk, but laterally clamped in an epilayer. The presence of the antiferromagnetic ground state and the associated first order phase transition is very sensitive to the correct equiatomic stoichiometry and proper B2 ordering, and so is a convenient means to demonstrate the quality of the layers that can be deposited with this approach. We also give some examples of the various techniques by which the change in phase can be detected. PMID- 24145691 TI - Preliminary experience of sandwich repair technique: a new method of laparoscopic splenorraphy for high-grade splenic injuries. AB - BACKGROUND: Laparoscopic splenectomy has been used safely for patients with blunt splenic trauma and failed nonoperative management. Reports of using laparoscopic splenorraphy for spleen salvage were fewer and mainly limited to lower grades of injuries. No study has focused on the role of laparoscopic splenorraphy in the treatment of patients with high grades of splenic injuries. METHODS: Medical records of 15 patients with high grades of splenic injuries that required an operation for failed nonoperative management were retrospectively reviewed. They underwent a new technique of sandwich repair laparoscopically for spleen salvage by 3 surgeons who had adequate training in laparoscopy for trauma. Preoperative parameters, sandwich repair technique, perioperative parameters, and postoperative outcomes were evaluated. RESULTS: Fourteen of the 15 (93.3%) patients underwent the technique successfully with 1 patient converting to laparotomy. The median (interquartile range) time to reach hemostasis was 30.0 (26.0-40.0) minutes, and the median overall operation time was 135.0 (120.0 165.0) minutes. Median blood loss amount was 1300.0 (750.0-2300.0) mL. The median length of hospital stay was 8.0 (7.0-11.0) days, and the intensive care unit stay was 2.0 (0.0-4.0) days. No mortality was noted. No rebleeding, total splenic infarction, or intra-abdominal abscess was noted during 3-month follow-up after the operation. CONCLUSIONS: The preliminary results show that laparoscopic splenorraphy by the "sandwich repair technique" is feasible and safe for patients with high-grade splenic injuries. PMID- 24145692 TI - A novel registration method for computer-assisted total knee arthroplasty using a patient-specific registration guide. AB - Total knee arthroplasty (TKA) is a surgical method for replacing a degenerated or diseased knee joint that can no longer perform daily functions with an artificial knee implant. In TKA, the artificial knee implant should be inserted such that it aligns well with the mechanical axis of the leg. Thus, precise bone cutting is essential. To improve TKA outcomes, a registration process is performed to locate the predetermined bone cutting area by calculating the position and posture of the femur and tibia. In this article, we propose a patient-specific registration guide that is able to significantly reduce registration time and effort without loss of accuracy. Furthermore, the patient-specific registration guide can be implemented with real-time registration, allowing continuous surgical information to be provided without the insertion of any tracking devices. The precision and accuracy of the proposed registration guide were confirmed through animal tests with a digitizer, stereo camera, and linear motion generator. The error of our registration method, including measurement and guide attachment errors, reached a maximum of 0.321 mm for one pair of cow legs. PMID- 24145693 TI - Contemporary data about hospital strategies to reduce unplanned readmissions: what has changed? PMID- 24145694 TI - Sleep habits in mild cognitive impairment. AB - We explored the relationship between sleep disturbances and mild cognitive impairment (MCI) in community-dwelling seniors. Recent evidence suggests that sleep habits are differentially compromised in different subtypes of MCI, but the relationship between sleep disruption and MCI remains poorly understood. We gathered daily objective measures of sleep disturbance from 45 seniors, including 16 with MCI (mean age, 86.9+/-4.3 y), over a 6-month period. We also collected self-report measures of sleep disturbance. Although there were no differences between groups in any of our self-report measures, we found that amnestic MCI (aMCI) volunteers had less disturbed sleep than both nonamnestic MCI (naMCI) and cognitively intact volunteers, as measured objectively by movement in bed at night (F2,1078=4.30, P=0.05), wake after sleep onset (F2,1078=41.6, P<0.001), and number of times up at night (F2,1078=26.7, P<0.001). The groups did not differ in total sleep time. In addition, the aMCI group had less day-to-day variability in these measures than the intact and naMCI volunteers. In general, the naMCI volunteers showed a level of disturbed sleep that was intermediate to that of aMCI and intact volunteers. These differences in sleep disruption between aMCI and naMCI may be related to differences in the pathology underlying these MCI subtypes. PMID- 24145695 TI - Gene-environment interaction of body mass index and apolipoprotein E epsilon4 allele on cognitive decline. AB - Genetic variation alone may not account for common chronic disease susceptibility. Rather, an interaction between genetic and environmental factors may clarify the underlying disease mechanism. Hence, we tested whether body mass index (BMI) modified the genetic association of the apolipoprotein E epsilon4 allele with cognitive decline. The data came from a longitudinal population-based sample of 4055 participants interviewed at 3-year intervals from 1993 to 2012. Cognitive function was assessed using a standardized global cognitive score and BMI was assessed at baseline and classified as normal, overweight, and obese. There were 1374 (34%) participants with the epsilon4 allele. In normal BMI participants, cognitive decline was 0.048 units/y without the epsilon4 allele, and increased by an additional 0.031 units/y with the epsilon4 allele. In overweight participants, cognitive decline was 0.038 units/y without the epsilon4 allele, and increased by an additional 0.026 units/y with the epsilon4 allele. Finally, in obese participants, cognitive decline was 0.038 units/y without the epsilon4 allele, and increased by an additional 0.014 units/y with the epsilon4 allele. The association of epsilon4 allele with cognitive decline was significantly lower in obese participants compared with normal BMI participants (P=0.003), thereby suggesting significant gene-environment interaction on cognitive decline. PMID- 24145696 TI - The spectrum of paraneoplastic cutaneous vasculitis in a defined population: incidence and clinical features. AB - Cutaneous vasculitis may be associated with malignancies, and may behave as a paraneoplastic syndrome. This association has been reported in a variable proportion of patients depending on population selection. We conducted the current study to assess the frequency, clinical features, treatment, and outcome of paraneoplastic vasculitis in a large unselected series of 766 patients with cutaneous vasculitis diagnosed at a single university hospital. Sixteen patients (10 men and 6 women; mean age +/- standard deviation, 67.94 +/- 14.20 yr; range, 40-85 yr) presenting with cutaneous vasculitis were ultimately diagnosed as having an underlying malignancy. They constituted 3.80% of the 421 adult patients. There were 9 hematologic and 7 solid underlying malignancies. Skin lesions were the initial clinical presentation in all of them, and the median interval from the onset of cutaneous vasculitis to the diagnosis of the malignancy was 17 days (range, 8-50 d). The most frequent skin lesions were palpable purpura (15 patients). Other clinical manifestations included constitutional syndrome (10 patients) and arthralgia and/or arthritis (4 cases). Hematologic cytopenias (11 cases) as well as immature peripheral blood cells (6 cases) were frequently observed in the full blood cell count, especially in those with vasculitis associated with hematologic malignancies. Specific treatment for vasculitis was prescribed in 10 patients; nonsteroidal antiinflammatory drugs (4 patients), corticosteroids (3 patients), chloroquine (1 patient), antihistamines (1 patient), and cyclophosphamide (1 patient). Ten patients died due to the malignancy and 6 patients recovered following malignancy therapy. Patients with paraneoplastic vasculitis were older, more frequently had constitutional syndrome, and less frequently had organ damage due to the vasculitis than the remaining patients with cutaneous vasculitis. In summary, cutaneous paraneoplastic vasculitis is an entity not uncommonly encountered by clinicians. The most common underlying malignancy is generally hematologic. In these cases the presence of cytopenias and immature cells may be red flags for the diagnosis of cancer. In patients with paraneoplastic cutaneous vasculitis, the prognosis depends on the underlying neoplasia. PMID- 24145698 TI - High prevalence of prothrombotic abnormalities in multifocal osteonecrosis: description of a series and review of the literature. AB - Multifocal or multiple osteonecrosis (ON), defined by the involvement of 3 or more anatomic sites, is unusual, being observed in only 3%-10% of patients diagnosed with ON. We report the clinical characteristics of a cohort of 29 patients with multifocal ON from a single center and evaluate the prevalence of associated prothrombotic abnormalities in 26 of these patients. We conducted a retrospective study of all patients diagnosed with multifocal ON evaluated in our institution during the last 20 years. We recorded clinical manifestations and underlying diagnoses. A wide thrombophilic profile was performed, including antithrombin, protein C, protein S, lupus anticoagulant, anticardiolipin antibodies, activated protein C resistance, factor V Leiden, mutation G-20210-A of the prothrombin gene, and factor VIII. Coagulation test results were compared with those in a healthy control group and a group of patients with history of lower-extremity deep venous thrombosis. The mean age of the patients was 49.2 +/- 15 years (range, 28-81 yr). The mean number of ON localizations per patient was 5.2 +/- 2.3 (range, 3-11). Hips were the most commonly affected joint (82%), followed by knees (58%), shoulders (37%), and ankles (13%). Most patients had an underlying disease process, and 12 of 25 (48%) patients had coagulation test abnormalities. The most common alterations were high factor VIII levels and antiphospholipid antibody (aPL) positivity in 24% and 20% of cases, respectively. These abnormalities were more prevalent in patients with multifocal ON compared with patients in the control groups. Sixty-one percent of patients had a history of corticosteroid treatment. Patients with coagulation abnormalities had a higher number of ON localizations per patient (6.5 +/- 2.7 vs. 3.88 +/- 0.8; p = 0.002) and a higher prevalence of atypical ON localizations (25% vs. 0%; p = 0.05). In conclusion, in the present cohort of patients with multifocal ON, 48% of the patients had at least 1 prothrombotic factor, especially high levels of factor VIII and aPL. These findings have major implications for the diagnosis and treatment of multifocal ON and clearly indicate the need to perform a thrombophilic profile in these patients. PMID- 24145697 TI - Fusarium infection: report of 26 cases and review of 97 cases from the literature. AB - Fusarium species is a ubiquitous fungus that causes opportunistic infections. We present 26 cases of invasive fusariosis categorized according to the European Organization for Research and Treatment of Cancer/Mycoses Study Group (EORTC/MSG) criteria of fungal infections. All cases (20 proven and 6 probable) were treated from January 2000 until January 2010. We also review 97 cases reported since 2000. The most important risk factors for invasive fusariosis in our patients were compromised immune system, specifically lung transplantation (n = 6) and hematologic malignancies (n = 5), and burns (n = 7 patients with skin fusariosis), while the most commonly infected site was the skin in 11 of 26 patients. The mortality rates among our patients with disseminated, skin, and pulmonary fusariosis were 50%, 40%, and 37.5%, respectively. Fusarium solani was the most frequent species, isolated from 49% of literature cases. Blood cultures were positive in 82% of both current study and literature patients with disseminated fusariosis, while the remaining 16% had 2 noncontiguous sites of infection but negative blood cultures. Surgical removal of focal lesions was effective in both current study and literature cases. Skin lesions in immunocompromised patients should raise the suspicion for skin or disseminated fusariosis. The combination of medical monotherapy with voriconazole or amphotericin B and surgery in such cases is highly suggested. PMID- 24145699 TI - Serum creatinine may indicate risk of symptomatic intracranial hemorrhage after intravenous tissue plasminogen activator (IV tPA). AB - Symptomatic intracranial hemorrhage (sICH) is a known complication following administration of intravenous tissue plasminogen activator (IV tPA) for acute ischemic stroke. sICH results in high rates of death or long-term disability. Our ability to predict its occurrence is important in clinical decision making and when counseling families. The initial National Institute of Neurological Disorders and Stroke (NINDS) investigators developed a list of relative contraindications to IV tPA meant to decrease the risk of subsequent sICH. To date, the impact of renal impairment has not been well studied. In the current study we evaluate the potential association between renal impairment and post-tPA intracranial hemorrhage (ICH). Admission serum creatinine and estimated glomerular filtration rate (eGFR) were recorded in 224 patients presenting within 4.5 hours from symptom onset and treated with IV tPA based on NINDS criteria. Neuroimaging was obtained 1 day post-tPA and for any change in neurologic status to evaluate for ICH. Images were retrospectively evaluated for hemorrhage by a board-certified neuroradiologist and 2 reviewers blinded to the patient's neurologic status. Medical records were reviewed retrospectively for evidence of neurologic decline indicating a "symptomatic" hemorrhage. sICH was defined as subjective clinical deterioration (documented by the primary neurology team) and hemorrhage on neuroimaging that was felt to be the most likely cause. Renal impairment was evaluated using both serum creatinine and eGFR in a number of ways: 1) continuous creatinine; 2) any renal impairment by creatinine (serum creatinine >1.0 mg/dL); 3) continuous eGFR; and 4) any renal impairment by eGFR (eGFR <60 mL/min per 1.73 m2). Student paired t tests, Fisher exact tests, and multivariable logistic regression (adjusted for demographics and vascular risk factors) were used to evaluate the relationship between renal impairment and ICH. Fifty-seven (25%) of the 224 patients had some evidence of hemorrhage on neuroimaging. The majority of patients were asymptomatic. Renal impairment (defined by serum creatinine >1.0 mg/dL) was not associated with combined symptomatic and asymptomatic intracranial bleeding (p = 0.359); however, there was an adjusted 5.5-fold increased odds of sICH when creatinine was >1.0 mg/dL (95% confidence interval, 1.08-28.39), and the frequency of sICH for patients with elevated serum creatinine was 10.6% (12/113), versus 1.8% (2/111) in those with normal renal function (p = 0.010). Our study suggests that renal impairment is associated with higher risk of sICH after administration of IV tPA. As IV tPA is an important and effective treatment for acute ischemic stroke, a multicenter study is needed to determine whether the observation that renal dysfunction is associated with sICH from this retrospective study holds true in a larger prospective trial. PMID- 24145700 TI - Central nervous system involvement in Whipple disease: clinical study of 18 patients and long-term follow-up. AB - Whipple disease (WD) is a rare multisystemic infection with a protean clinical presentation. The central nervous system (CNS) is involved in 3 situations: CNS involvement in classic WD, CNS relapse in previously treated WD, and isolated CNS infection. We retrospectively analyzed clinical features, diagnostic workup, brain imaging, cerebrospinal fluid (CSF) study, treatment, and follow-up data in 18 patients with WD and CNS infection. Ten men and 8 women were included with a median age at diagnosis of 47 years (range, 30-56 yr). The median follow-up duration was 6 years (range, 1-19 yr). As categorized in the 3 subgroups, 11 patients had classic WD with CNS involvement, 4 had an isolated CNS infection, and 3 had a neurologic relapse of previously treated WD. CNS involvement occurred during prolonged trimethoprim-sulfamethoxazole (TMP-SMX) treatment in 1 patient with classic WD. The neurologic symptoms were various and always intermingled, as follows: confusion or coma (17%) related to meningo-encephalitis or status epilepticus; delirium (17%); cognitive impairment (61%) including memory loss and attention defects or typical frontal lobe syndrome; hypersomnia (17%); abnormal movements (myoclonus, choreiform movements, oculomasticatory myorhythmia) (39%); cerebellar ataxia (11%); upper motor neuron (44%) or extrapyramidal symptoms (33%); and ophthalmoplegia (17%) in conjunction or not with progressive supranuclear palsy. No specific pattern was correlated with any subgroup. Brain magnetic resonance imaging (MRI) revealed a unique focal lesion (35%), mostly as a tumorlike brain lesion, or multifocal lesions (23%) involving the medial temporal lobe, midbrain, hypothalamus, and thalamus. Periventricular diffuse leukopathy (6%), diffuse cortical atrophy (18%), and pachymeningitis (12%) were observed. The spinal cord was involved in 2 cases. MRI showed ischemic sequelae at diagnosis or during follow-up in 4 patients. Brain MRI was normal despite neurologic symptoms in 3 cases. CSF cytology was normal in 62% of patients, whereas Tropheryma whipplei polymerase chain reaction (PCR) analysis was positive in 92% of cases with tested CSF. Periodic acid-Schiff (PAS)-positive cells were identified in cerebral biopsies of 4 patients. All patients were treated with antimicrobial therapy for a mean duration of 2 years (range, 1-7 yr) with either oral monotherapy (TMP-SMX, doxycycline, third-generation cephalosporins) or a combination of antibiotics that sometimes followed parenteral treatment with beta lactams and aminoglycosides. Eight patients also received hydroxychloroquine. At the end of follow-up, the clinical outcome was favorable in 14 patients (78%), with mild to moderate sequelae in 9. Thirteen patients (72%) had stopped treatment for an average time of 4 years (range, 0.7-14 yr). Four patients had clinical worsening despite antimicrobial therapy; 2 of those died following diffuse encephalitis (n = 1) and lung infection (n = 1). In conclusion, the neurologic manifestations of WD are diverse and may mimic almost any neurologic condition. Brain involvement may occur during or after TMP-SMX treatment. CSF T. whipplei PCR analysis is a major tool for diagnosis and may be positive in the absence of meningitis. Immune reconstitution syndrome may occur in the early months of treatment. Late prognosis may be better than previously reported, as a consequence of earlier diagnosis and a better use of antimicrobial therapy, including hydroxychloroquine and doxycycline combination. PMID- 24145701 TI - Miniature optical coherence tomography-ultrasound probe for automatically coregistered three-dimensional intracoronary imaging with real-time display. AB - We have developed a novel miniature integrated optical coherence tomography (OCT) intravascular ultrasound (IVUS) probe, with a 1.5-mm-long rigid part and 0.9-mm outer diameter, for real-time intracoronary imaging of atherosclerotic plaques and guiding of interventional procedures. By placing the OCT ball lens and IVUS transducer back-to-back at the same axial position, this probe can provide automatically coregistered, coaxial OCT-IVUS imaging. To demonstrate its real time capability, three-dimensional OCT-IVUS imaging of a pig's coronary artery displaying in polar coordinates, as well as images of three major types of atherosclerotic plaques in human cadaver coronary segments, were obtained using this probe and our upgraded system. Histology validation is also presented. PMID- 24145702 TI - Flash freezing route to mesoporous polymer nanofibre networks. AB - There are increasing requirements worldwide for advanced separation materials with applications in environmental protection processes. Various mesoporous polymeric materials have been developed and they are considered as potential candidates. It is still challenging, however, to develop economically viable and durable separation materials from low-cost, mass-produced materials. Here we report the fabrication of a nanofibrous network structure from common polymers, based on a microphase separation technique from frozen polymer solutions. The resulting polymer nanofibre networks exhibit large free surface areas, exceeding 300 m(2) g(-1), as well as small pore radii as low as 1.9 nm. These mesoporous polymer materials are able to rapidly adsorb and desorb a large amount of carbon dioxide and are also capable of condensing organic vapours. Furthermore, the nanofibres made of engineering plastics with high glass transition temperatures over 200 degrees C exhibit surprisingly high, temperature-dependent adsorption of organic solvents from aqueous solution. PMID- 24145704 TI - Dielectric properties of cobalt ferrite nanoparticles in ultrathin nanocomposite films. AB - Multilayered nanocomposite films (thickness 50-90 nm) of cobalt ferrite nanoparticles (np-CoFe2O4, 18 nm) were deposited on top of interdigitated microelectrodes by the layer-by-layer technique in order to study their dielectric properties. For that purpose, two different types of nanocomposite films were prepared by assembling np-CoFe2O4 either with poly(3,4-ethylenedioxy thiophene):poly(styrene sulfonic acid) or with polyaniline and sulfonated lignin. Despite the different film architectures, the morphology of both was dominated by densely-packed layers of nanoparticles surrounded by polyelectrolytes. The dominant effect of np-CoFe2O4 was also observed after impedance spectroscopy measurements, which revealed that dielectric behavior of the nanocomposites was largely influenced by the charge transport across nanoparticle-polyelectrolyte interfaces. For example, nanocomposites containing np-CoFe2O4 exhibited a single low-frequency relaxation process, with time constants exceeding 15 ms. At 1 kHz, the dielectric constant and the dissipation factor (tan delta) of these nanocomposites were 15 and 0.15, respectively. These values are substantially inferior to those reported for pressed pellets made exclusively of similar nanoparticles. Impedance data were further fitted with equivalent circuit models from which individual contributions of particle's bulk and interfaces to the charge transport within the nanocomposites could be evaluated. The present study evidences that such nanocomposites display a dielectric behavior dissimilar from that exhibited by their individual counterparts much likely due to enlarged nanoparticle-polyelectrolyte interfaces. PMID- 24145705 TI - Palladium-catalyzed tandem N-H/C-H arylation: regioselective synthesis of N heterocycle-fused phenanthridines as versatile blue-emitting luminophores. AB - A general and highly regioselective synthetic protocol for structurally diverse N heteroaryl-fused phenanthridines has been developed. Varieties of fluorescence molecules comprising imidazole-fused, benzoimidazole-fused, indole-fused and pyrrole-fused phenanthridines were obtained by this modular approach, some of which exhibit excellent blue-emitting performance, high quantum yields, long fluorescence lifetimes, interesting electrochemical properties, and thermal stabilities. PMID- 24145706 TI - Effects of nitrous oxide on the production of cytokines and chemokines by the airway epithelium during anesthesia with sevoflurane and propofol. AB - The aim of this study was to evaluate the effects of nitrous oxide (a gaseous anesthetic) on the in vivo production of inflammatory cytokines and chemokines by the airway epithelium, when combined with sevoflurane or propofol. Subjects undergoing simple or segmental mastectomy were randomly assigned to the sevoflurane and nitrous oxide, sevoflurane and air, propofol and nitrous oxide, or propofol and air group (all n=13). Epithelial lining fluid (ELF) was obtained using the bronchoscopic microsampling method prior to and following the mastectomy to enable measurement of the pre- and post-operative levels of certain inflammatory cytokines and chemokines using a cytometric bead array system. Notably, the levels of interleukin (IL)-1beta, IL-8 and monocyte chemotactic protein-1 (MCP-1) in the ELF were significantly increased following the operations which involved the inhalation of sevoflurane and nitrous oxide, although the levels of these molecules were not significantly changed by the inhalation of sevoflurane and air. Furthermore, the IL-12p70 levels were significantly reduced in the ELF following the operations that involved the inhalation of sevoflurane and air, although the IL-12p70 levels were not significantly changed by the inhalation of nitrous oxide and sevoflurane. These observations suggest that the combination of sevoflurane and nitrous oxide induces an inflammatory response (increased production of IL-1beta, IL-8 and MCP 1) and suppresses the anti-inflammatory response (reduced production of IL-12p70) in the local milieu of the airway. Thus, the combination of these compounds should be carefully administered for anesthesia. PMID- 24145708 TI - [Abnormal liver function tests in the intensive care unit]. AB - Abnormal liver biochemical and function tests are found in the majority of critically ill patients and are associated with increased mortality. Frequent causes for elevated liver function tests in the intensive care unit (ICU) are acute hepatic dysfunction due to acute hepatitis, acute liver failure (ALF), and drug-induced liver injury (DILI). Furthermore, exacerbations of pre-existing liver diseases (acute on chronic) and secondary liver injury during critical diseases such as sepsis, right heart failure, or cardiogenic shock, resulting in ischemic or hypoxic hepatitis, need to be considered. Elevated liver enzymes may also reflect a complication of ICU treatment measures like drug-related hepatotoxicity, secondary sclerosing cholangitis in critically ill patients (SC CIP), or related to parenteral nutrition. Comprehensive diagnostic evaluation is essential to identify the underlying etiology of abnormal liver function tests and to initiate the appropriate therapeutic strategies. PMID- 24145711 TI - Metabolomics: integration of a new "omics" with clinical pharmacology. AB - The term "pharmacometabolomics" was coined in 2006 to reflect the potential of the predrug metabolomic signature to predict the postdrug response. Metabolomics can be used to examine the contribution of nongenomic factors, such as the environment, diet, or the gut microbiome, to the overall drug response. As such, the complexity of human biology afforded by metabolomics can complement genomic approaches, ultimately moving the discipline of clinical pharmacology closer to full implementation of personalized medicine. PMID- 24145709 TI - [Acute dyspnea, subfebrile temperatures and chills in a patient with multiple myeloma]. PMID- 24145714 TI - Metabolomics in drug discovery and development. AB - Metabolomics technology is being utilized across the spectrum of drug discovery and development; from the assessment of unanticipated biochemical sequelae of target engagement in transgenic models to monitoring media content to improve the efficiency of the manufacture of biologics, the impact of the technology is expanding dramatically. Applications critical for the pharmaceutical industry include translational medicine, biomarker discovery, and patient stratification. Technological innovation and cultural acceptance will be necessary to optimally use this powerful tool. PMID- 24145715 TI - Modifications of iterative schemes used for curvature correction in noninvasive biomedical imaging. AB - Iterative polynomial fitting along image rows and columns has recently been used to remove curvature bias in multispectral image sets of the human forearm and phantoms. However, this method is only applicable if foreground and background features satisfy strong separation conditions. In this method, we verify that the iterative polynomial approach converges toward bivariate polynomial fitting, and, hence, the resulting fit corresponds to low-pass filtering the image. In contrast to the iterative fitting, the bivariate polynomial fit can be performed on images with missing or excluded parts. Indeed, our observation enables us to modify the scheme and significantly weaken the required assumptions on foreground/background separation allowing a wider range of application. PMID- 24145716 TI - Atg18 lifts up from and lands on the vacuolar membrane mediated by phosphorylation of its propellers. AB - Pichia pastoris Atg18 (PpAtg18), a member of the PROPPIN family of proteins, is localized not only to the PAS (pre-autophagosomal structure or phagophore assembly site) during autophagy but also to the vacuolar membrane during vacuolar fission. Recently we reported that the localization of Atg18 was determined by its phosphorylation level. We identified two phosphorylated regions within the ? propeller structures of PpAtg18, whose modification affects its affinity toward phosphatidylinositol 3,5-bisphosphate [PtdIns(3,5)P 2]. The findings indicated that phosphoregulaton of Atg18 mediates the signal from various environmental stimuli and regulates its intracellular localization for vacuolar fission and autophagy. PMID- 24145717 TI - Laser confocal feedback tomography and nano-step height measurement. AB - A promising method for tomography and step height measurement is proposed, which combines the high sensitivity of the frequency-shifted feedback laser and the axial positioning ability of confocal microscopy. By demodulating the feedback induced intensity modulation signals, the obtained amplitude and phase information are used to respectively determine the coarse and fine measurement of the samples. Imaging the micro devices and biological samples by the demodulated amplitude, this approach is proved to be able to achieve the cross-sectional image in highly scattered mediums. And then the successful height measurement of nano-step on a glass-substrate grating by combination of both amplitude and phase information indicates its axial high resolution (better than 2 nm) in a non ambiguous range of about ten microns. PMID- 24145718 TI - Using a discrete preisach model for hysteresis in ankle joint passive moment. AB - The steady-state passive joint moment was considered as a nonlinear elasticity in the past. However, we found that it was path dependent and the estimation error could be large if the commonly used path-independent functions were adopted. The aim of this study was to develop a model to describe the movement history dependent passive moment in the steady state. The steady-state passive ankle moments of the rabbit were measured by a series of ramp-and-hold angle changes (stairway angle trajectory). A customized discrete Preisach model was constructed and a commonly adopted double-exponential function was also implemented. Two sets of data with different angle paths (major loop and inward loop trajectories) were acquired for model validation. The performance of the two models was compared. The results showed that the proposed model could accurately estimate the steady state passive moment for both sets of validation data. The estimated error of the proposed model was approximately 50% smaller than that of the double-exponential function approach. It is expected that this new approach, by reducing the error of estimating passive joint moment, may contribute to the active control of joint moments. PMID- 24145719 TI - Effects of prostaglandin E2 on p53 mRNA transcription and p53 mutagenesis during T-cell-independent human B-cell clonal expansion. AB - Within T-cell-dependent germinal centers, p53 gene transcription is repressed by Bcl-6 and is thus less vulnerable to mutation. Malignant lymphomas within inflamed extranodal sites exhibit a relatively high incidence of p53 mutations. The latter might originate from normal B-cell clones manifesting activation induced cytosine deaminase (AID) and up-regulated p53 following T-cell independent (TI) stimulation. We here examine p53 gene transcription in such TI clones, with a focus on modulatory effects of prostaglandin E2 (PGE2), and evaluate progeny for p53 mutations. Resting IgM(+)IgD(+)CD27(-) B cells from human tonsils were labeled with CFSE and stimulated in vitro with complement coated antigen surrogate, IL-4, and BAFF +/- exogenous PGE2 (50 nM) or an analog specific for the EP2 PGE2 receptor. We use flow cytometry to measure p53 and AID protein within variably divided blasts, qRT-PCR of p53 mRNA from cultures with or without actinomycin D to monitor mRNA transcription/stability, and single-cell p53 RT-PCR/sequencing to assess progeny for p53 mutations. We report that EP2 signaling triggers increased p53 gene transcriptional activity in AID(+) cycling blasts (P<0.01). Progeny exhibit p53 mutations at a frequency (8.5 * 10(-4)) greater than the baseline error rate (<0.8 * 10(-4)). We conclude that, devoid of the repressive influences of Bcl-6, dividing B lymphoblasts in inflamed tissues should display heightened p53 transcription and increased risk of p53 mutagenesis. PMID- 24145720 TI - Skeletal muscle glycoprotein 130's role in Lewis lung carcinoma-induced cachexia. AB - Chronic inflammation is associated with cachexia-induced skeletal muscle mass loss in cancer. Levels of IL-6 cytokine family members are increased during cancer-related cachexia and induce intracellular signaling through glycoprotein130 (gp130). Although muscle STAT3 and circulating IL-6 are implicated in cancer-induced muscle wasting, there is limited understanding of muscle gp130's role in this process. Therefore, we investigated the role of skeletal muscle gp130 (skm-gp130) in cancer-induced alterations in the regulation of muscle protein turnover. Lewis lung carcinoma (LLC) cells were injected into 8 wk-old skm-gp130-knockout (KO) mice or wild-type mice. Skeletal muscle loss was attenuated by 16% in gp130-KO mice, which coincided with attenuated LLC-induced phosphorylation of muscle STAT3, p38, and FOXO3. gp130 KO did not restore mTOR inhibition or alter AMP-activated protein kinase (AMPK) expression. The induction of atrogin expression and p38 phosphorylation in C2C12 myotubes exposed to LLC treated medium was attenuated by gp130 inhibition, but mTOR inhibition was not restored. STAT signaling inhibition in LLC-treated myotubes did not attenuate the induction of p38 or AMPK phosphorylation. We concluded that, during LLC-induced cachexia, skm-gp130 regulates muscle mass signaling through STAT3 and p38 for the activation of FOXO3 and atrogin, but does not directly regulate the suppression of mTOR. PMID- 24145721 TI - The 4 Notch receptors play distinct and antagonistic roles in the proliferation and hepatocytic differentiation of liver progenitors. AB - The Notch signaling pathway is involved in liver development and regeneration. Here, we investigate the role of the 4 mammalian Notch paralogs in the regulation of hepatoblast proliferation and hepatocytic differentiation. Our model is based on bipotential mouse embryonic liver (BMEL) progenitors that can differentiate into hepatocytes or cholangiocytes in vitro and in vivo. BMEL cells were subjected to Notch antagonists or agonists. Blocking Notch activation with a gamma-secretase inhibitor, at 50 MUM for 48 h, reduced cell growth by 50%. S phase entry was impaired, but no apoptosis was induced. A systematic paralog specific strategy was set using lentiviral transduction with constitutively active forms of each Notch receptor along with inhibition of endogenous Notch signaling. This assay demonstrates that proliferation of BMEL cells requires Notch2 and Notch4 activity, resulting in significant down-regulation of p27(Kip1) and p57(Kip2) cyclin-dependent kinase inhibitors. Conversely, Notch3-expressing cells proliferate less and express 3-fold higher levels of p57(Kip2). The Notch3 cells present a hepatocyte-like morphology, enhanced multinucleation, and a ploidy shift. Moreover, Notch3 activity is conducive to hepatocytic differentiation in vitro, while its paralogs impede this fate. Our study provides the first evidence of a functional diversity among the mammalian Notch homologues in the proliferation and hepatocytic-lineage commitment of liver progenitors. PMID- 24145722 TI - Effects of aerobic exercise on lipid-effector molecules of the innate immune response. AB - INTRODUCTION: Consistent, moderate-to-vigorous-intensity exercise has been associated with a lower risk of upper respiratory tract infection (URI). However, the molecular basis for this apparent protection has not yet been fully resolved. Host-derived lipids such as cholesteryl esters (CE) have emerged as important effector molecules of innate defense against infections. Here, we compared antimicrobial CE in nasal fluid before and after moderate-to-vigorous exercise between active and inactive subjects. METHODS: Nasal fluid was collected from 14 healthy, recreationally active subjects (32 +/- 11 yr, 7 men and 7 women) and 14 healthy, inactive subjects (25 +/- 3 yr, 7 men and 7 women) before and after treadmill exercise at 70% heart rate reserve. Nasal fluid was analyzed for lysozyme, cholesteryl linoleate (CL), cholesteryl arachidonate (CA), and albumin (Alb) concentrations. RESULTS: Baseline concentrations (mean +/- SEM, inactive vs active) of lysozyme (117.7 +/- 31.1 vs 122.9 +/- 15.5 MUg.mL), CL + CA (15.3 +/- 1.8 vs 26.2 +/- 10.05 MUg.mL), and Alb (156.6 +/- 54.5 vs 126.9 +/- 32.8 MUg.mL) were similar to previously reported levels and did not differ significantly between study groups. However, postexercise, CL + CA concentration was significantly lower in inactive compared with active subjects (7.8 +/- 1.5 vs 20.1 +/- 4.8 MUg.mL, P = 0.036) dropping below the antimicrobial effective range. Once adjusted to Alb concentrations, the changes were no longer significant, suggesting that plasma transudation accounted for the increased CA + CL concentration postexercise in the active group relative to the inactive group. CONCLUSIONS: Moderate-to-vigorous aerobic exercise acutely decreases the antimicrobial CE response in inactive subjects but does not modify baseline levels of CE between active and inactive subjects. This suggests that compared with active individuals, inactive individuals may be at greater risk for upper respiratory tract infection immediately postexercise. PMID- 24145723 TI - Muscle activation patterns and patellofemoral pain in cyclists. AB - INTRODUCTION: Patellofemoral pain syndrome (PFPS) is pervasive and debilitating in the sport of cycling. Currently, little is known about the underlying mechanism causing patellofemoral pain in cyclists. PURPOSE: The purpose of this study was to determine whether temporal differences in the muscle activity of the vastus medialis (VM), vastus lateralis (VL), semitendinosus (ST), and biceps femoris (BF) were correlated to patellofemoral pain in cycling. METHODS: Ten healthy cyclists (six women and four men, height = 1.74 +/- 0.10 cm, weight = 71.9 +/- 16.5 kg, cycling experience = 199.5 +/- 82 miles . wk(-1)) and seven cyclists with PFPS (one woman and six men, height = 1.84 +/- 0.08 cm, weight = 89.8 +/- 9.4 kg, cycling experience = 228 +/- 51 miles . wk(-1)) volunteered to participate in this study. Each participant completed a 10-min cycling trial during which surface EMG was recorded for the VM, VL, ST, and BF muscles. Sagittal plane knee kinematic data were recorded using an electrogoniometer. RESULTS: An ANOVA revealed no significant difference between groups for the differences in onset times of the VM and VL (P = 0.805). There were significant differences between groups for the differences in offset time of the VM and VL (P = 0.032), the differences in onset time of BF and ST (P < 0.001), and the differences in offset time of the ST and BF (P = 0.024). Root mean square values for BF activity were significantly higher in the PFPS group compared with the control (CTL) group (P < 0.01), and ST values were significantly lower in the PFPS group compared with the CTL group (P < 0.01). Root mean square values for BF were significantly greater than ST activity in the PFPS group (P < 0.01) but not in the CTL group (P > 0.05). CONCLUSION: The results of this study indicate that trained cyclists with PFPS exhibit altered temporal characteristics in muscle activation patterns compared with trained cyclists without PFPS. PMID- 24145725 TI - Repeated bouts of exercise in patients with anterior cruciate ligament reconstruction. AB - PURPOSE: Reduced quadriceps activation after anterior cruciate ligament reconstructions (ACL-R) has been reported. Patients often return to daily exercise or sport after ACL-R; however, there is little information regarding quadriceps function after exercise in this population. Therefore, the purpose of this study was to compare quadriceps strength and central activation after repeated bouts of exercise between individuals with and without a history of ACL R. METHODS: Eighteen recreationally active subjects participated in this study: 8 with unilateral ACL-R at least 6 months earlier and 10 healthy controls. All subjects performed 30 min of continuous exercise on two consecutive days. Exercise included repeated bouts of inclined treadmill walking and jumping exercises. We measured maximal isometric knee extension torque and quadriceps central activation ratio (CAR) using the superimposed burst technique before and after exercise on day 1. Subjects returned 24 h later (day 2) for a repeat testing session. RESULTS: There was a significant group-time interaction for knee extension torque. ACL-R subjects were weaker at baseline on day 1 of testing (P = 0.01) but exhibited no significant reduction in knee extension torque after exercise (P = 0.13), whereas the healthy control subjects did (P = 0.01). Knee extension torque on day 2 remained significantly lower than baseline for the controls (P = 0.03), but not the ACL-R (P = 0.73). On day 2, both groups experienced significantly reduced knee extension torque after exercise. There was no group-time interaction for CAR, but a group main effect indicated that, on average, ACL-R had significantly lower CAR bilaterally compared with healthy controls. CONCLUSIONS: The quadriceps in ACL-R knees were weaker and showed less reduction of isometric knee extension torque compared with healthy group in day 1. However, there were no group differences of quadriceps strength on day 2. PMID- 24145724 TI - Computational models predict larger muscle tissue strains at faster sprinting speeds. AB - INTRODUCTION: Proximal biceps femoris musculotendon strain injury has been well established as a common injury among athletes participating in sports that require sprinting near or at maximum speed; however, little is known about the mechanisms that make this muscle tissue more susceptible to injury at faster speeds. PURPOSE: This study aimed to quantify localized tissue strain during sprinting at a range of speeds. METHODS: Biceps femoris long head (BFlh) musculotendon dimensions of 14 athletes were measured on magnetic resonance (MR) images and used to generate a finite-element computational model. The model was first validated through comparison with previous dynamic MR experiments. After validation, muscle activation and muscle-tendon unit length change were derived from forward dynamic simulations of sprinting at 70%, 85%, and 100% maximum speed and used as input to the computational model simulations. Simulations ran from midswing to foot contact. RESULTS: The model predictions of local muscle tissue strain magnitude compared favorably with in vivo tissue strain measurements determined from dynamic MR experiments of the BFlh. For simulations of sprinting, local fiber strain was nonuniform at all speeds, with the highest muscle tissue strain where injury is often observed (proximal myotendinous junction). At faster sprinting speeds, increases were observed in fiber strain nonuniformity and peak local fiber strain (0.56, 0.67, and 0.72 for sprinting at 70%, 85%, and 100% maximum speed). A histogram of local fiber strains showed that more of the BFlh reached larger local fiber strains at faster speeds. CONCLUSIONS: At faster sprinting speeds, peak local fiber strain, fiber strain nonuniformity, and the amount of muscle undergoing larger strains are predicted to increase, likely contributing to the BFlh muscle's higher injury susceptibility at faster speeds. PMID- 24145726 TI - Plasmatic hypercoagulation in patients with breast cancer: role of heme oxygenase 1. AB - Breast cancer is an important health threat to women worldwide, and is associated with a 9-14% incidence of thrombophilia. Of interest, patients with breast cancer have been noted to have an increase in endogenous carbon monoxide production via upregulation of heme oxygenase-1 activity. Given that it has been demonstrated that carbon monoxide enhances plasmatic coagulation in vitro and in vivo, we sought to determine whether patients with breast cancer had an increase in endogenous carbon monoxide and concurrent plasmatic hypercoagulability. Breast cancer patients who were not smokers scheduled to undergo partial or complete mastectomy (n = 18) had 15 ml of whole blood collected via an indwelling intravenous catheter and anticoagulated with sodium citrate. Whole blood was centrifuged and citrated plasma assessed with a thromboelastometric method to measure coagulation kinetics and the formation of carboxyhemefibrinogen. Breast cancer patients were determined to have an abnormally increased carboxyhemoglobin concentration of 2.5 +/- 1.3%, indicative of heme oxygenase-1 upregulation. Breast cancer patient plasma on average clotted 73% more quickly and had 32% stronger thrombus strength than normal individual (n = 30) plasma. Further, 44% of breast cancer patients had plasma clot strength that exceeded the 95% confidence interval value observed in normal individuals, and 75% of this hypercoagulable subgroup had carboxyhemefibrinogen formation. Future investigation of the role played by heme oxygenase-1-derived carbon monoxide in the pathogenesis of breast cancer-related thrombophilia is warranted. PMID- 24145727 TI - Relationship between orthodontic expertise and perception of need for orthodontic treatment for mandibular protrusion in Japan. AB - The aims of this study were to investigate how the Peer Assessment Rating (PAR index) predicts the perceived need for orthodontic treatment of mandibular protrusion in Japanese subjects, and to elucidate whether the perceived need for treatment was affected by the raters' orthodontic expertise. The subjects were 110 dental students and 32 orthodontists. We showed them casts of 10 untreated mandibular protrusion cases and gave them a questionnaire in which they had to describe their perceptions of the orthodontic treatment needs using a 10-point visual analog scale (VAS). The PAR index was used for cast evaluation. The PAR index scores showed significant correlations with the VAS scores. In casts with a low PAR score, there were no differences in the VAS scores between orthodontists and students. In casts with a PAR score greater than 23, the orthodontists perceived a significantly greater treatment need than did the students;for scores of 22, 28, and 29, students who had received orthodontic treatment themselves were more likely to perceive the treatment need. The PAR index is a good clinical predictor for assessing the perceived treatment needs for mandibular protrusion. Perception of the need for orthodontic treatment for mandibular protrusion depended on the degree of orthodontic expertise in Japanese subjects. PMID- 24145728 TI - Is presence or history of extracolonic primary malignancy a risk for colorectal neoplasia? An analysis of patients who underwent colonoscopy. AB - Whether presence or history of extracolonic primary malignancy is a risk for colorectal neoplasia is not fully known. In this study, 26,452 first-time colonoscopy cases were examined using a colonoscopy database. Among the analyzed subjects, 3,026 (11%) subjects had history or concomitance of extracolonic primary malignancy, while the remaining 23,426 subjects did not. Colorectal neoplasia was observed in 39% of all the subjects. A crude comparison showed that the prevalence of any type of colorectal neoplasia was higher in subjects with extracolonic malignancy than in those without (42% vs. 39%, p=0.0012). However, after adjusting for confounding factors, the odds ratios (ORs) of subjects with extracolonic malignancy for having colorectal neoplasia, advanced neoplasia, and cancer were all less than 1.0, and all significantly different from those of subjects without extracolonic malignancy. Analysis according to the type of extracolonic malignancy revealed that gastric cancer cases had a significantly lower risk for colorectal advanced neoplasia (OR:0.81;95% CI:0.67-0.99). Among major malignancies, only esophageal squamous cell cancer cases had increased risk for colorectal neoplasia (OR:1.66;95% CI:1.20-2.29). Patients with presence or history of extracolonic malignancy did not carry a higher risk of occurrence of colorectal neoplasia. PMID- 24145729 TI - Inhibitory function and working memory in attention deficit/hyperactivity disorder and pervasive developmental disorders: does a continuous cognitive gradient explain ADHD and PDD traits? AB - To clarify the relationship between attention deficit/hyperactivity disorder (AD/HD) and pervasive developmental disorders (PDD), we investigated the common features and differences of these disorders in neuropsychological profiles. The subjects were 4 groups of Japanese boys aged 6 to 15 years, categorized by diagnosis:AD/HD (n=20), PDD with comorbid AD/HD (PDD+:n=16), PDD without comorbid AD/HD (PDD-:n=8), and typically developing (n=60). We evaluated executive function (EF) through verbal and visuospatial memory tasks, the Go/NoGo task, and the color-word matching Stroop task. We performed a categorical analysis to estimate the effects of the 3 disorders on EF and a dimensional analysis to estimate the effects of symptom scales on EF. We found that the AD/HD and PDD+ subjects had negative effects on verbal working memory and intra-individual response variability. The severity of these impairments was positively correlated with the inattentiveness score. The subjects with a PDD+ or PDD- diagnosis had poorer scores on interference control;the severity of this impairment was correlated with the PDD symptom score. Impairments in visuospatial working memory were detected in the AD/HD and PDD- groups but not in the PDD+ group. Impairments in inhibition of the pre-potent response were noted in all 3 categories. AD/HD and PDD share neuropsychological features, though each disorder has a specific impairment pattern. Our findings partially support the idea that AD/HD and PDD are on a spectrum. PMID- 24145730 TI - Double congenital fistulae with aneurysm diagnosed by combining imaging modalities. AB - Congenital coronary pulmonary artery fistula (CAF) is rare, and systemic-to pulmonary artery fistula (SPAF) is even more so. Furthermore, congenital coronary pulmonary fistula associated with congenital SPAF is extremely rare. As far as we know, CAF and SPAF connected with an aneurysm have not been described very often. We described an 83-year-old woman with an aneurysm originating from a CAF connected to an aortopulmonary artery fistula. Chest radiography revealed a shadow at the left edge of the heart line. Multi-detector-row computed tomography (MDCT) with contrast enhancement and coronary cine angiography revealed that the shadow was an aneurysm connected to a tortuous fistula at the left anterior descending coronary artery. The aneurysm was formed by congenital coronary pulmonary and aortopulmonary artery fistulae. Echocardiography revealed predominantly systolic blood flow in the fistula from the left anterior descending coronary artery (LAD). Although neither MDCT, echocardiography nor coronary angiography alone could provide a comprehensive image of the anomaly, including the hemodynamics in the fistulae and their relationship with surrounding organs and tissues, their combination could provided important facts the led to a deeper understanding of this very uncommon occurrence. PMID- 24145731 TI - Occult Compression Fracture of Metacarpal Head without Evidence of Avascular Necrosis. AB - We report a case of 4th metacarpal head collapse of a 19-year-old healthy man. MRI revealed T1 low and T2 high regions in the collapsed 4th metacarpal head, as well as in the right 3rd and left 4th metacarpal head. Our initial diagnosis was occult compression fracture due to avascular necrosis, known as Dieterich's disease. However, pathological findings of surgically resected right 4th metacarpal head were compatible with transient osteoporosis and metacarpal head fracture followed by active tissue repair. The autologous osteochondral transplants from costchondral junction survived and maintained their size and shape even at 10-year follow-up. PMID- 24145732 TI - Preparation of enteric-coated capsules of beclomethasone dipropionate for patients with intestinal graft-versus-host disease and a case study. AB - Graft-versus-host disease (GVHD) is a major concern in transplantation patients. Gut GVHD is accompanied by diarrhea, abdominal pain, and/or melena. Although oral treatment with corticosteroids (CSs) is effective in treating gut GVHD, it can cause adverse reactions that affect the entire body. Topical administration of CSs can be effective in treating diseases in which lesions are limited locally, because adverse reactions can then be alleviated. In this study, we examine and discuss an enteric-coated beclomethasone dipropionate (BDP) capsule (BDP-EC) formulated at Okayama University Hospital. The BDP-EC did not dissolve in solution 1 (pH1.2), and began disintegrating in solution 2 (pH6.8) after 5min, with a mean dissolution rate at 15min of 85%. We then used the capsule to treat a patient who developed gut GVHD after allogeneic hematopoietic stem cell transplantation. Clinically, the frequency of diarrhea decreased after BDP-EC administration. In addition, we were able to decrease the prednisolone equivalent dose. Symptoms associated with adverse reactions to BDP were not observed during the hospitalization period. These findings suggest that the administration of BDP EC in the early stages of gut GVHD may allow a reduction in the initial doses of systemic CSs. PMID- 24145733 TI - Phalloplasty with an innervated island pedicled anterolateral thigh flap in a female-to-male transsexual. AB - Since 2001, we have been performing phalloplasty with a radial forearm free flap as the flap of first choice in female-to-male transsexuals (FTMTS). In the present case, a 22-year-old FTMTS with a negative Allen test, we achieved good results by performing phalloplasty with an innervated island pedicled anterolateral thigh flap using the "tube within a tube" technique, in which the penis and urethra are constructed with a single flap. As compared to a forearm flap, use of an innervated island-pedicled flap may have the following advantages in phalloplasty:1) no need for a microsurgical technique;2) no scars at noticeable sites;3) small functional loss in the flap donor area;4) no sacrifice of major blood vessels. Thus, this technique seems to be a useful clinical alternative for phallic reconstruction. PMID- 24145734 TI - Screening for colorectal cancer in individuals at average risk: current methods and emerging issues. PMID- 24145735 TI - Isolation of primary myofibroblasts from mouse and human colon tissue. AB - The myofibroblast is a stromal cell of the gastrointestinal (GI) tract that has been gaining considerable attention for its critical role in many GI functions. While several myofibroblast cell lines are commercially available to study these cells in vitro, research results from a cell line exposed to experimental cell culture conditions have inherent limitations due to the overly reductionist nature of the work. Use of primary myofibroblasts offers a great advantage in terms of confirming experimental findings identified in a cell line. Isolation of primary myofibroblasts from an animal model allows for the study of myofibroblasts under conditions that more closely mimic the disease state being studied. Isolation of primary myofibroblasts from human colon tissue provides arguably the most relevant experimental data, since the cells come directly from patients with the underlying disease. We describe a well-established technique that can be utilized to isolate primary myofibroblasts from both mouse and human colon tissue. These isolated cells have been characterized to be alpha-smooth muscle actin and vimentin-positive, and desmin-negative, consistent with subepithelial intestinal myofibroblasts. Primary myofibroblast cells can be grown in cell culture and used for experimental purposes over a limited number of passages. PMID- 24145737 TI - Harvesting singlet fission for solar energy conversion via triplet energy transfer. AB - The efficiency of a conventional solar cell may be enhanced if one incorporates a molecular material capable of singlet fission, that is, the production of two triplet excitons from the absorption of a single photon. To implement this, we need to successfully harvest the two triplets from the singlet fission material. Here we show in the tetracene (Tc)/copper phthalocyanine (CuPc) model system that triplets produced from singlet fission in the former can transfer to the later on the timescale of 45+/-5 ps. However, the efficiency of triplet energy transfer is limited by a loss channel due to faster formation (400+/-100 fs) and recombination (2.6+/-0.5 ps) of charge transfer excitons at the interface. These findings suggest a design principle for efficient energy harvesting from singlet fission: one must reduce interfacial area between the two organic chromophores to minimize charge transfer/recombination while optimizing light absorption, singlet fission and triplet rather than singlet transfer. PMID- 24145739 TI - Hydrosoluble and solvatochromic naphthalene diimides with NIR absorption. AB - Mimicking biochromophore anions containing phenolate moieties, eight conjugated naphthalene diimides (NDIs) have been synthesized in order to develop probes, displaying charge-transfer transitions affected by the nearby environment. NIR absorption of the resulting phenolates and their solvatochromic properties in both organic solvents and water are described. PMID- 24145738 TI - Role of endothelin B receptor in oligodendroglioma proliferation and survival: In vitro and in vivo evidence. AB - In this study, the role of the endothelin B receptor (ETBR) in oligodendroglioma cell proliferation and survival was investigated in vitro and in vivo. The overexpression and knockdown of ETBR was conducted in Hs683 human oligodendroglioma cells, and cell proliferation and activation (phosphorylation) of extracellular signal-regulated kinase (ERK) were measured in vitro. An orthotopic xenograft oligodendroglioma mouse model was established. Mouse survival times and immunohistochemical Ki67 staining in the xenografts were examined. In vitro experiments demonstrated that the overexpression of ETBR significantly enhanced the proliferation of oligodendroglioma cells and the activation of ERK compared with the controls, which was eliminated by the selective ETBR inhibitor BQ788 and ERK-specific inhibitor U0126, but not selective endothelin A receptor inhibitor BQ123. By contrast, the knockdown of endogenous ETBR markedly decreased oligodendroglioma cell proliferation and the activation of ERK compared with the controls. Overexpression of ETBR significantly increased immunohistochemical Ki67 staining in the Hs683 cell orthotopic xenograft and decreased animal survival. By contrast, knockdown of ETBR significantly decreased Ki67 staining and increased mouse survival times. Intratumoral injection of BQ788, but not BQ123, significantly decreased Ki67 staining and prolonged mouse survival times. In conclusion, ETBR was demonstrated to mediate the proliferation of oligodendroglioma cells according to an ERK dependent mechanism. Using an orthotopic xenograft oligodendroglioma mouse model, it was demonstrated in vivo that ETBR promotes oligodendroglioma proliferation and that the selective ETBR antagonist effectively inhibits the proliferation of oligodendroglioma cells and prolongs survival times. This study provides a novel insight into the role of ETBR in oligodendroglioma proliferation and survival, and provides the first in vivo evidence that ETBR-specific antagonists are a potential therapeutic alternative for oligodendrogliomas. PMID- 24145740 TI - Disease location is associated with survival in patients with peripheral arterial disease. AB - BACKGROUND: We investigated whether disease location influences survival in patients with peripheral arterial disease. METHODS AND RESULTS: Patients (n = 12,731; mean age, 67.5 +/- 12.7 years; 57.4% male) who underwent outpatient noninvasive lower extremity arterial evaluation were followed up for 5.9 +/- 3.1 years for all-cause mortality. Peripheral arterial disease (n = 8930) was defined as a resting or postexercise ankle-brachial index (ABI) <= 0.90, and normal ABI (n = 3,801) was defined as a resting and postexercise ABI of 1.00 to 1.30. Presence or absence of disease at the proximal location or distal location was determined on the basis of Doppler signals in leg arteries; 42% had no PD or DD, 45% had proximal (14% postexercise PD only), 30% had distal disease, 17% had both proximal and distal disease, 28% had proximal only and 14% had distal only. We performed multivariable logistic regression to identify factors associated with disease location, and Cox proportional hazard regression to assess the respective effects of proximal or distal disease on survival. Older age, male sex, diabetes, heart failure, and critical limb ischemia were associated with distal disease, whereas female sex, smoking, hypertension, dyslipidemia, coronary heart disease, cerebrovascular disease, chronic obstructive pulmonary disease, and critical limb ischemia were associated with proximal disease. Over a mean follow-up of 5.9 +/- 3.1 years, 3039 patients (23.9%) died. After adjustment for potential confounders, the hazard ratios (HRs) of death associated with PD only and DD only were 1.3 (1.3 to 1.4) and 1.5 (1.4 to 1.6), respectively. After additional adjustment for resting ABI, there was no significant association between proximal disease and death, whereas the association of distal disease with death remained significant (HR, 1.2; 95% CI, 1.1 to 1.3). CONCLUSIONS: In patients with peripheral arterial disease, proximal and distal disease locations were associated with distinctive risk factor and comorbidity profiles. Distal disease was associated with worse survival even after adjustment for risk factors, comorbidities, and resting ABI. PMID- 24145741 TI - Myocardial ischemia during mental stress: role of coronary artery disease burden and vasomotion. AB - BACKGROUND: Mental stress-induced myocardial ischemia (MSIMI) is associated with adverse prognosis in patients with coronary artery disease (CAD), yet the mechanisms underlying this phenomenon remain unclear. We hypothesized that compared with exercise/pharmacological stress-induced myocardial ischemia (PSIMI) that is secondary to the atherosclerotic burden of CAD, MSIMI is primarily due to vasomotor changes. METHODS AND RESULTS: Patients with angiographically documented CAD underwent 99mTc-sestamibi myocardial perfusion imaging at rest and following both mental and physical stress testing, performed on separate days. The severity and extent of CAD were quantified using the Gensini and Sullivan scores. Peripheral arterial tonometry (Itamar Inc) was used to assess the digital microvascular tone during mental stress as a ratio of pulse wave amplitude during speech compared with baseline. Measurements were made in a discovery sample (n = 225) and verified in a replication sample (n = 159). In the pooled (n = 384) sample, CAD severity and extent scores were not significantly different between those with and without MSIMI, whereas they were greater in those with compared with those without PSIMI (P < 0.04 for all). The peripheral arterial tonometry ratio was lower in those with compared with those without MSIMI (0.55 +/- 0.36 versus 0.76 +/- 0.52, P = 0.009). In a multivariable analysis, the peripheral arterial tonometry ratio was the only independent predictor of MSIMI (P = 0.009), whereas angiographic severity and extent of CAD independently predicted PSIMI. CONCLUSIONS: The degree of digital microvascular constriction, and not the angiographic burden of CAD, is associated with MSIMI. Varying causes of MSIMI compared with PSIMI may require different therapeutic interventions that require further study. PMID- 24145742 TI - Plasma phospholipid omega-3 fatty acids and incidence of postoperative atrial fibrillation in the OPERA trial. AB - BACKGROUND: Long-chain polyunsaturated omega-3 fatty acids (n-3 PUFA) demonstrated antiarrhythmic potential in experimental studies. In a large multinational randomized trial (OPERA), perioperative fish oil supplementation did not reduce the risk of postoperative atrial fibrillation (PoAF) in cardiac surgery patients. However, whether presupplementation habitual plasma phospholipid n-3 PUFA, or achieved or change in n-3 PUFA level postsupplementation are associated with lower risk of PoAF is unknown. METHODS AND RESULTS: In 564 subjects undergoing cardiac surgery between August 2010 and June 2012 in 28 centers across 3 countries, plasma phospholipid levels of eicosapentaenoic acid (EPA), docosapentaenoic acid (DPA), and docosahexaenoic acid (DHA) were measured at enrollment and again on the morning of cardiac surgery following fish oil or placebo supplementation (10 g over 3 to 5 days, or 8 g over 2 days). The primary endpoint was incident PoAF lasting >= 30 seconds, centrally adjudicated, and confirmed by rhythm strip or ECG. Secondary endpoints included sustained (>= 1 hour), symptomatic, or treated PoAF; the time to first PoAF; and the number of PoAF episodes per patient. PoAF outcomes were assessed until hospital discharge or postoperative day 10, whichever occurred first. Relative to the baseline, fish oil supplementation increased phospholipid concentrations of EPA (+142%), DPA (+13%), and DHA (+22%) (P < 0.001 each). Substantial interindividual variability was observed for change in total n-3 PUFA (range = -0.7% to 7.5% after 5 days of supplementation). Neither individual nor total circulating n-3 PUFA levels at enrollment, morning of surgery, or change between these time points were associated with risk of PoAF. The multivariable adjusted OR (95% CI) across increasing quartiles of total n-3 PUFA at enrollment were 1.0, 1.06 (0.60 to 1.90), 1.35 (0.76 to 2.38), and 1.19 (0.64 to 2.20); and for changes in n-3 PUFA between enrollment and the morning of surgery were 1.0, 0.78 (0.44 to 1.39), 0.89 (0.51 to 1.55), and 1.01 (0.58 to 1.75). In stratified analysis, demographic, medication, and cardiac parameters did not significantly modify these associations. Findings were similar for secondary PoAF endpoints. CONCLUSIONS: Among patients undergoing cardiac surgery, neither higher habitual circulating n-3 PUFA levels, nor achieved levels or changes following short-term fish oil supplementation are associated with risk of PoAF. PMID- 24145743 TI - Cardiac rehabilitation patient and organizational factors: what keeps patients in programs? AB - BACKGROUND: Despite documented benefits of cardiac rehabilitation, adherence to programs is suboptimal with an average dropout rate of between 24% and 50%. The goal of this study was to identify organizational and patient factors associated with cardiac rehabilitation adherence. METHODS AND RESULTS: Facilities of the Wisconsin Cardiac Rehabilitation Outcomes Registry Project (N = 38) were surveyed and records of 4412 enrolled patients were analyzed. Generalized estimating equations were used to account for clustering of patients within facilities. The results show that organizational factors associated with significantly increased adherence were relaxation training and diet classes (group and individual formats) and group-based psychological counseling, medication counseling, and lifestyle modification, the medical director's presence in the cardiac rehabilitation activity area for >= 15 min/week, assessment of patient satisfaction, adequate space, and adequate equipment. Patient factors associated with significantly increased adherence were aged >= 65 years, the American Association of Cardiovascular and Pulmonary Rehabilitation (AACVPR) high-risk category, having received coronary artery bypass grafting, and diabetes disease. Non-white race was negatively associated with adherence. There was no significant gender difference in adherence. None of the baseline patient clinical profiles were associated with adherence including body mass index, total cholesterol, low density lipoprotein, high-density lipoprotein, triglycerides, and blood pressure. CONCLUSIONS: Factors associated with adherence to cardiac rehabilitation included both organizational and patient factors. Modifiable organizational factors may help directors of cardiac rehabilitation programs improve patient adherence to this beneficial program. PMID- 24145744 TI - Influence of natural adsorbates of magnesium oxide on its reactivity in basic catalysis. AB - Solid materials possessing basic properties are naturally covered by carbonates and hydroxyl groups. Those natural adsorbates modify their chemical reactivity. This article aims to specifically evidence the role of surface carbonates and hydroxyls in basic heterogeneous catalysis on MgO. It compares the catalytic behaviors of hydroxylated or carbonated MgO surfaces for two types of reactions: one alkene isomerization and one alcohol conversion (hept-1-ene isomerization and 2-methyl-3-butyn-2-ol conversion). Catalysis experiments showed that carbon dioxide adsorption poisons the catalyst surface and the DRIFT-DFT combination showed that the nature of active sites in the two reactions differs. On the reverse, partial hydroxylation of the surface enhances activity for both reactions. Interestingly hept-1-ene isomerization gives a volcano curve for the conversion as a function of hydroxyl coverage. Calculations of the electronic structure of magnesium oxide surfaces show that neither Lewis basicity nor Bronsted basicity of the surface defects (steps for example) are enhanced by hydroxylation. Meanwhile CO2 adsorption followed by IR spectroscopy shows that (110) and (111) unstable planes are strongly basic and are stabilized by partial surface hydroxylation. These results could explain the volcano curve obtained for the evolution of alkene isomerisation as a function of hydroxyl coverage. PMID- 24145747 TI - Pesticide removal from aqueous solutions by adding salting out agents. AB - Phase segregation in aqueous biphasic systems (ABS) composed of four hydrophilic ionic liquids (ILs): 1-butyl-3-methylimidazolium methylsulfate and 1-ethyl-3 methylimidazolium methylsulfate (C(n)C1im C1SO4, n = 2 and 4), tributylmethyl phosphonium methylsulfate (P4441 C1SO4) and methylpyridinium methylsulfate (C1Py C1SO4) and two high charge density potassium inorganic salts (K2CO3 and K2HPO4) were determined by the cloud point method at 298.15 K. The influence of the addition of the selected inorganic salts to aqueous mixtures of ILs was discussed in the light of the Hofmeister series and in terms of molar Gibbs free energy of hydration. The effect of the alkyl chain length of the cation on the methylsulfate-based ILs has been investigated. All the solubility data were satisfactorily correlated to several empirical equations. A pesticide (pentachlorophenol, PCP) extraction process based on the inorganic salt providing a greater salting out effect was tackled. The viability of the proposed process was analyzed in terms of partition coefficients and extraction efficiencies. PMID- 24145746 TI - MicroRNA-regulated pathways in hematological malignancies: how to avoid cells playing out of tune. AB - The coordinated expression and interplay among lineage specific transcription factors and microRNAs contribute to the regulation of gene expression and determination of cell specificity. In hematopoietic stem cells (HSCs), unique combinations of transcription factors largely control growth and maturation of different blood cell lineages through cooperative regulation of specific target genes. MicroRNAs provide an additional level of control beyond transcription factors. By acting as regulators of crucial lineage-specific genetic programs, microRNAs direct early multipotential progenitor cells to adopt a certain cell fate program. Thus, alteration of specific microRNA levels may affect proliferation, differentiation and genetic stability of HSCs, contributing to the onset of myeloproliferative disorders and leukemia. The major aim of this review is to highlight the critical role of microRNA-regulated pathways during the establishment and progression of hematological malignancies, with a particular attention to leukemia, lymphomas and myelodysplastic syndromes. This will give us the opportunity to discuss the potential use of microRNA-based therapeutic approaches in these diseases. MicroRNAs are indeed emerging as relevant tools to improve the efficacy of currently used therapeutic protocols. PMID- 24145748 TI - DNA damage induced MutS homologue hMSH4 acetylation. AB - Acetylation of non-histone proteins is increasingly recognized as an important post-translational modification for controlling the actions of various cellular processes including DNA repair and damage response. Here, we report that the human MutS homologue hMSH4 undergoes acetylation following DNA damage induced by ionizing radiation (IR). To determine which acetyltransferases are responsible for hMSH4 acetylation in response to DNA damage, potential interactions of hMSH4 with hTip60, hGCN5, and hMof were analyzed. The results of these experiments indicate that only hMof interacts with hMSH4 in a DNA damage-dependent manner. Intriguingly, the interplay between hMSH4 and hMof manipulates the outcomes of nonhomologous end joining (NHEJ)-mediated DNA double strand break (DSB) repair and thereby controls cell survival in response to IR. This study also shows that hMSH4 interacts with HDAC3, by which HDAC3 negatively regulates the levels of hMSH4 acetylation. Interestingly, elevated levels of HDAC3 correlate with increased NHEJ-mediated DSB repair, suggesting that hMSH4 acetylation per se may not directly affect the role of hMSH4 in DSB repair. PMID- 24145749 TI - Biofilm matrix and its regulation in Pseudomonas aeruginosa. AB - Biofilms are communities of microorganisms embedded in extracellular polymeric substances (EPS) matrix. Bacteria in biofilms demonstrate distinct features from their free-living planktonic counterparts, such as different physiology and high resistance to immune system and antibiotics that render biofilm a source of chronic and persistent infections. A deeper understanding of biofilms will ultimately provide insights into the development of alternative treatment for biofilm infections. The opportunistic pathogen Pseudomonas aeruginosa, a model bacterium for biofilm research, is notorious for its ability to cause chronic infections by its high level of drug resistance involving the formation of biofilms. In this review, we summarize recent advances in biofilm formation, focusing on the biofilm matrix and its regulation in P. aeruginosa, aiming to provide resources for the understanding and control of bacterial biofilms. PMID- 24145750 TI - Differences in the structure of the gut bacteria communities in development stages of the Chinese white pine beetle (Dendroctonus armandi). AB - The Chinese white pine beetle Dendroctonus armandi Tsai and Li, is arguably the most destructive forest insect in the Qinling Mountains in Northern China. Little is known about the structure of the bacterial communities associated with D. armandi even though this wood-boring insect plays important roles in ecosystem and biological invasion processes that result in huge economic losses in pine forests. The aim of this study was to investigate the composition of the bacterial communities present in the guts of D. armandi at different developmental stages using a culture-independent method involving PCR-denaturing gradient gel electrophoresis (DGGE). Analysis of PCR-amplified 16S rRNA gene fragments of bacteria from the guts of larvae, pupae, and male and female adults revealed bacterial communities of low complexity that differed according to the developmental stage. Citrobacter spp. and Pantoea spp. predominated in larvae and adults, whereas Methylobacterium was the dominant genus at the pupal stage. The main difference between the guts of male and female adults was the greater dominance of Citrobacter in females. Previous studies suggest that the bacterial community associated with D. armandi guts may influence insect development. The data obtained in this study regarding the phylogenetic relationships and the community structure of intestinal bacteria at different developmental stages of the D. armandi life cycle contribute to our understanding of D. armandi and could aid the development of new pest control strategies. PMID- 24145752 TI - The influence of silica nanoparticles on ionic liquid behavior: a clear difference between adsorption and confinement. AB - The phase behaviors of ionic liquids (ILs) confined in nanospace and adsorbed on outer surface of nanoparticles are expected to be different from those of the bulk. Anomalous phase behaviors of room temperature ionic liquid tributylhexadecylphosphonium bromide (P44416Br) confined in ordered mesoporous silica nanoparticles with average pore size 3.7 nm and adsorbed on outer surface of the same silica nanoparticles were reported. It was revealed that the melting points (T(m)) of confined and adsorbed ILs depressed significantly in comparison with the bulk one. The T(m) depressions for confined and adsorbed ILs are 8 degrees C and 14 degrees C, respectively. For comparison with the phase behavior of confined P44416Br, 1-butyl-3-methylimidazolium bromide (BmimBr) was entrapped within silica nanopores, we observed an enhancement of 50 degrees C in T(m) under otherwise similar conditions. The XRD analysis indicates the formation of crystalline-like phase under confinement, in contrast to the amorphous phase in adsorbed IL. It was confirmed that the behavior of IL has clear difference. Moreover, the complex pi-pi stacking and H-bonding do not exist in the newly proposed phosphonium-based IL in comparison with the widely studied imidazolium based IL. The opposite change in melting point of P44416Br@SiO2 and BmimBr@SiO2 indicates that the cationic species plays an important role in the variation of melting point. PMID- 24145753 TI - A genome-wide expression profile of salt-responsive genes in the apple rootstock Malus zumi. AB - In some areas of cultivation, a lack of salt tolerance severely affects plant productivity. Apple, Malus x domestica Borkh., is sensitive to salt, and, as a perennial woody plant the mechanism of salt stress adaption will be different from that of annual herbal model plants, such as Arabidopsis. Malus zumi is a salt tolerant apple rootstock, which survives high salinity (up to 0.6% NaCl). To examine the mechanism underlying this tolerance, a genome-wide expression analysis was performed, using a cDNA library constructed from salt-treated seedlings of Malus zumi. A total of 15,000 cDNA clones were selected for microarray analysis. In total a group of 576 cDNAs, of which expression changed more than four-fold, were sequenced and 18 genes were selected to verify their expression pattern under salt stress by semi-quantitative RT-PCR. Our genome-wide expression analysis resulted in the isolation of 50 novel Malus genes and the elucidation of a new apple-specific mechanism of salt tolerance, including the stabilization of photosynthesis under stress, involvement of phenolic compounds, and sorbitol in ROS scavenging and osmoprotection. The promoter regions of 111 genes were analyzed by PlantCARE, suggesting an intensive cross-talking of abiotic stress in Malus zumi. An interaction network of salt responsive genes was constructed and molecular regulatory pathways of apple were deduced. Our research will contribute to gene function analysis and further the understanding of salt tolerance mechanisms in fruit trees. PMID- 24145751 TI - Impaired glutathione synthesis in neurodegeneration. AB - Glutathione (GSH) was discovered in yeast cells in 1888. Studies of GSH in mammalian cells before the 1980s focused exclusively on its function for the detoxication of xenobiotics or for drug metabolism in the liver, in which GSH is present at its highest concentration in the body. Increasing evidence has demonstrated other important roles of GSH in the brain, not only for the detoxication of xenobiotics but also for antioxidant defense and the regulation of intracellular redox homeostasis. GSH also regulates cell signaling, protein function, gene expression, and cell differentiation/proliferation in the brain. Clinically, inborn errors in GSH-related enzymes are very rare, but disorders of GSH metabolism are common in major neurodegenerative diseases showing GSH depletion and increased levels of oxidative stress in the brain. GSH depletion would precipitate oxidative damage in the brain, leading to neurodegenerative diseases. This review focuses on the significance of GSH function, the synthesis of GSH and its metabolism, and clinical disorders of GSH metabolism. A potential approach to increase brain GSH levels against neurodegeneration is also discussed. PMID- 24145754 TI - Heritable gene-targeting with gRNA/Cas9 in rats. PMID- 24145755 TI - A highly fluorescent chemosensor for Zn(2+) and the recognition research on distinguishing Zn(2+) from Cd(2+). AB - A new fluorescent sensor, 2-(2-oxo-2-(quinolin-8-ylamino)ethoxy)-N-(pyridine-2 ylmethyl) benzamide (L), composed of a quinoline group as the fluorogenic unit and a pyridin-2-ylmethanamine as the binding unit for metal ions has been synthesized. The sensor shows excellent selectivity and sensitivity with a fluorescence enhancement to Zn(2+) over other cations in acetonitrile aqueous solution. The X-ray crystal structure analysis reveals that sensor L coordinates to Zn(2+)via a 1 : 1 binding mode but to Cd(2+)via a 2 : 1 binding mode, which lead to a different spatial arrangement of the fluorogenic unit in these complexes. In addition, density functional theory calculations on L, and the Zn(2+)/L and Cd(2+)/L complexes also imply that the different structures of L significantly affect the molecular orbital energy levels and electron transition, which would result in the spectral changes to distinguish Zn(2+) from Cd(2+). The absorption study results may also suggest the Cd(2+) in the complex can be displaced by Zn(2+). Furthermore, the fluorescence imaging of Zn(2+) in living cells was obtained. PMID- 24145758 TI - Origin of fasciculations in amyotrophic lateral sclerosis and benign fasciculation syndrome. AB - IMPORTANCE: Fasciculation potentials (FPs) may arise proximally or distally within the peripheral nervous system. We recorded FPs in the tibialis anterior using 2 concentric needle electrodes, ensuring by slight voluntary contraction and electrical nerve stimulation that each electrode recorded motor unit potentials innervated by different axons. OBSERVATIONS: Time-locked FPs recorded from both electrodes, suggesting a spinal origin, were most frequent in benign fasciculation syndrome (44%) (P < .001) and amyotrophic lateral sclerosis without reinnervation (27%). Fewer time-locked FPs were found (14%) in the reinnervated tibialis anterior in amyotrophic lateral sclerosis (P < .001). CONCLUSIONS AND RELEVANCE: We conclude that in chronic partial denervation FPs are more likely to arise distally and that FPs in benign fasciculation syndrome more frequently arise proximally. PMID- 24145760 TI - Histone deacetylase 10-promoted autophagy as a druggable point of interference to improve the treatment response of advanced neuroblastomas. AB - Neuroblastoma is the most common extracranial solid tumor in childhood. Despite intense multimodal therapy and many improvements through basic scientific and clinical research, the successful response of advanced-stage patients to chemotherapy remains poor. Autophagy is a cytoprotective mechanism that may help advanced cancer cells survive stressful conditions such as chemotherapy. Here we review our recent findings describing HDAC10 as a promoter of autophagy-mediated survival in neuroblastoma cells and identifying this HDAC isozyme as a druggable regulator of advanced-stage tumor cell survival. These results propose a new and promising way to considerably improve treatment response in the neuroblastoma patient subgroup with the poorest outcome. PMID- 24145756 TI - Hox genes are involved in vascular wall-resident multipotent stem cell differentiation into smooth muscle cells. AB - Human vascular wall-resident CD44+ multipotent stem cells (VW-MPSCs) within the vascular adventitia are capable to differentiate into pericytes and smooth muscle cells (SMC). This study demonstrates HOX-dependent differentiation of CD44(+) VW MPSCs into SMC that involves epigenetic modification of transgelin as a down stream regulated gene. First, HOXB7, HOXC6 and HOXC8 were identified to be differentially expressed in VW-MPSCs as compared to terminal differentiated human aortic SMC, endothelial cells and undifferentiated pluripotent embryonic stem cells. Silencing these HOX genes in VW-MPSCs significantly reduced their sprouting capacity and increased expression of the SMC markers transgelin and calponin and the histone gene histone H1. Furthermore, the methylation pattern of the TAGLN promoter was altered. In summary, our findings suggest a role for certain HOX genes in regulating differentiation of human VW-MPSC into SMCs that involves epigenetic mechanisms. This is critical for understanding VW-MPSC dependent vascular disease processes such as neointima formation and tumor vascularization. PMID- 24145761 TI - Synthesis and microdiffraction at extreme pressures and temperatures. AB - High pressure compounds and polymorphs are investigated for a broad range of purposes such as determine structures and processes of deep planetary interiors, design materials with novel properties, understand the mechanical behavior of materials exposed to very high stresses as in explosions or impacts. Synthesis and structural analysis of materials at extreme conditions of pressure and temperature entails remarkable technical challenges. In the laser heated diamond anvil cell (LH-DAC), very high pressure is generated between the tips of two opposing diamond anvils forced against each other; focused infrared laser beams, shined through the diamonds, allow to reach very high temperatures on samples absorbing the laser radiation. When the LH-DAC is installed in a synchrotron beamline that provides extremely brilliant x-ray radiation, the structure of materials under extreme conditions can be probed in situ. LH-DAC samples, although very small, can show highly variable grain size, phase and chemical composition. In order to obtain the high resolution structural analysis and the most comprehensive characterization of a sample, we collect diffraction data in 2D grids and combine powder, single crystal and multigrain diffraction techniques. Representative results obtained in the synthesis of a new iron oxide, Fe4O5 (1) will be shown. PMID- 24145763 TI - Magnetomotive optical coherence elastography for microrheology of biological tissues. AB - Optical coherence elastography (OCE) is an established paradigm for measuring biomechanical properties of tissues and cells noninvasively, in real time, and with high resolution. We present a different development of a spectral domain OCE technique that enables simultaneous measurements of multiple biomechanical parameters of biological tissues. Our approach extends the capabilities of magnetomotive OCE (MM-OCE), which utilizes iron oxide magnetic nanoparticles (MNPs) distributed and embedded in the specimens as transducers for inducing motion. Step-wise application of an external magnetic field results in displacements in the tissue specimens that are deduced from sensitive phase measurements made with the MM-OCE system. We analyzed freshly excised rabbit lung and muscle tissues. We observe that while they present some similarities, rabbit lung and muscle tissue displacements display characteristic differentiating features. Both tissue types undergo a fast initial displacement followed by a rapidly damped oscillation and the onset of creep. However, the damping is faster in muscle compared to lung tissue, while the creep is steeper in muscle. This approach has the potential to become a novel way of performing real-time measurements of biomechanical properties of tissues and to enable the development of different diagnostic and monitoring tools in biology and medicine. PMID- 24145764 TI - Use of high-sensitivity troponin for the diagnosis of acute myocardial infarction. AB - Although there is broad consensus that cardiac troponin I or T (cTn) is the preferred biomarker and complements clinical assessment and the 12-lead ECG in the early diagnosis of acute myocardial infarction, important uncertainties and questions remain on the value of high-sensitivity cTn assays, including their best clinical use. Although these assays have been introduced clinically in many countries, they still await regulatory approval in the USA. This review summarizes the recent advances and potential pitfalls in the clinical application of high-sensitivity cTn assays in the early diagnosis of acute myocardial infarction. PMID- 24145765 TI - Rivaroxaban and risk of myocardial infarction: insights from a meta-analysis and trial sequential analysis of randomized clinical trials. AB - OBJECTIVE: To evaluate the risk of myocardial infarction (MI) associated with the use of rivaroxaban. METHODS: We searched PubMed, CINAHL, Cochrane CENTRAL, Scopus, and the Web of Science for randomized controlled trials of rivaroxaban that reported on MI as clinical outcomes. We express the associations as odds ratios and their 95% confidence intervals. A trial sequential analysis was carried out to ensure validity of our findings. RESULTS: Nine trials were selected (N=53 827), including one study on stroke prophylaxis in atrial fibrillation, two in acute coronary syndrome, four of short-term prophylaxis of deep venous thrombosis, and two for treatment of deep venous thrombosis/pulmonary embolism. Control arms included warfarin, enoxaparin, or placebo administration. Rivaroxaban was associated with a significantly lower risk of MI compared with the agents used in the control group (odds ratio, 0.82; 95% confidence interval, 0.72-0.94; P=0.004). No heterogeneity was noted in the risk (I=0%; P=0.55); trial sequential analysis reinforced the validity of our findings. CONCLUSION: Rivaroxaban is associated with a significantly lower risk of MI in a broad spectrum of patients when tested against different controls. PMID- 24145766 TI - Synthesis of three 18F-labelled cyclooxygenase-2 (COX-2) inhibitors based on a pyrimidine scaffold. AB - Cyclooxygenase (COX) is the key enzyme within the complex conversion of arachidonic acid into prostaglandins (PGs). Inhibitors of this enzyme represent a particularly promising class of compounds for chemoprevention and cancer therapy. The experimental data on the involvement of COX isoform COX-2 in tumour development and progression, as well as the observed overexpression of COX-2 in a variety of human cancers provide the rationale for targeting COX-2 for molecular imaging and therapy of cancer. A series of trifluoromethyl-substituted pyrimidines was prepared as a novel class of selective COX-2 inhibitors, based on the lead structure 1a. All compounds were tested in cyclooxygenase (COX) assays in vitro to determine COX-1 and COX-2 inhibitory potency and selectivity. Molecular docking studies using the catalytic site of COX-1 and COX-2, respectively, provided complementary theoretical support for the obtained experimental biological structure-activity relationship data of three highly potent and selective fluorobenzyl-containing COX-2 inhibitors. Selected fluorobenzyl-substituted pyrimidine derivatives were further developed as (18)F labelled radiotracers ([(18)F]1a, [(18)F]2a, [(18)F]3a). Radiotracers [(18)F]1a and [(18)F]2a were radiolabelled using 4-[(18)F]fluorobenzylamine ([(18)F]FBA) as a building block. Radiotracer [(18)F]3a was radiofluorinated directly using a nucleophilic aromatic substitution reaction with no-carrier-added (n.c.a.) [(18)F]fluoride on an iodylaryl compound as a labelling precursor. PMID- 24145767 TI - Importance of promoter methylation of GATA4 gene in epithelial ovarian cancer. AB - AIMS: Ovarian cancer is the most lethal gynecological malignancy, with typically late diagnosis. Altered DNA methylation of tumor suppressor gene promoters probably plays a relevant role in ovarian carcinogenesis and frequently occurs as an early event in the development of different types of cancer including ovarian carcinoma. GATA4 methylation has been reported in a variety of human cancers. The aim of this study was to investigate promoter methylation of the GATA4 gene in ovarian cancer by comparison with that in normal ovarian tissue. METHODS: To search for promoter methylation of the GATA4 gene we used MSP (methylation specific PCR) to compare the methylation status in 67 tissue samples of ovarian cancer with that in 40 control samples. RESULTS: In our study, methylation specific PCR revealed GATA4 promoter methylation in 21 of 67 specimens with ovarian cancer (31.3%), and in none of the control ovarian tissue samples. CONCLUSION: These results confirm that methylation in the GATA4 promoter region could play an important role in ovarian carcinogenesis, and show new loci which are highly methylated only in ovarian cancer samples and which are associated predominantly with the endometrioid type of ovarian carcinoma. PMID- 24145768 TI - Chemical decellularization: a promising approach for preparation of extracellular matrix. AB - BACKGROUND: A biological scaffold from extracellular matrix can be produced by a variety of decellularization methods whose caveat consists in efficiently eliminating cells from the treated tissue. This scaffold can be used in diverse applications for tissue engineering and organ regeneration. Preservation of the extracellular matrix ultrastructure is highly desirable because of its unique architecture, contained growth factors and decreased immunological response. All of these properties provide attachment sites and adequate environment for cells colonizing this scaffold, reconstituting the decellularized organ. This review briefly describes chemical decellularization methods, evaluation of these protocols and the role of ECM in tissue engineering. CONCLUSION: Chemical decellularization is an often used method for scaffold preparation and makes possible a well-preserved three dimensional structure of extracellular matrix. PMID- 24145769 TI - Partial trisomy and tetrasomy of chromosome 21 without Down Syndrome phenotype and short overview of genotype-phenotype correlation. A case report. AB - AIMS: Trisomy of chromosome 21 is associated with Down syndrome (DS) - the commonest genetic cause of mental retardation. We report two unusual cases with partial trisomy of chromosome 21 and tetrasomy of chromosome 21 without DS phenotype. We include a short overview of the genotype-phenotype correlation studies in discussion. METHODS: Conventional chromosomal analysis, fluorescent in situ hybridisation (FISH), quantitative fluorescent PCR (QFPCR) and Nimblegen targeted chromosome 21 array were used for deciphering the genotypes. RESULTS: Conventional chromosomal analysis revealed one extra copy of derivative chromosome 21 in peripheral blood lymphocytes of the patients. FISH and QF PCR analyses identified duplicated loci (D21Z1, D21S1414, D21S1435) spanning from the centromere to band 21q21. Nimblegen targeted chromosome 21 array specified the range of duplication from the centromere to the band 21q21.3 (19 Mb) in the first case and the range of duplication and triplication resp from centromere to the bands 21q21.3 (15 Mb) and 21q11.2 (4 Mb) resp. in the second case. Additional material was of maternal origin in both cases. The different mechanisms led to the formation of the particular chromosomal imbalances. CONCLUSION: These findings confirm the conclusion of nonpresence of DS when bands 21q22.2 and 21q22.3 (Down critical region) are not duplicated. The patients had nonspecific phenotypes although some of their features such as "sandal gaps", joint hyperlaxity, hypotonia and brachycephaly are present in patients with DS. Our observation can help to narrow the region responsible for DS and to map the loci accountable for minor features of DS. PMID- 24145770 TI - Comparison of human mesenchymal stem cells derived from dental pulp, bone marrow, adipose tissue, and umbilical cord tissue by gene expression. AB - AIMS: Our aims were to characterize human mesenchymal stem cells isolated from various tissues by pluripotent stem cells gene expression profile. METHODS: Four strains of dental pulp stem cells (DP-MSCs) were isolated from dental pulp tissue fragments adhered to plastic tissue culture dishes. Mesenchymal stem cells derived from umbilical cord tissue (UBC-MSCs) were isolated with the same technique. Bone marrow derived mesenchymal stem cells (BM-MSCs) were isolated from nucleated cells of bone marrow obtained by density gradient centrifugation. Human mesenchymal stem cells from adipose tissue (AT-MSCs) were isolated by collagenase digestion. All kinds of MSCs used in this study were cultivated in low glucose DMEM containing 5% or human platelet extract. All stem cell manipulation was performed in GMP conditions. Expression of 15 pluripotent stem cells genes on the level of proteins was measured by Proteome Profiler Human Pluripotent Stem Cell Array. Induction of MSCs to in vitro differentiation to adipocytes, osteoblasts, chondroblasts was achieved by cultivation of cells in appropriate differentiation medium. RESULTS: All MSCs tested were phenotypically similar and of fibroblastoid morphology. DP-MSCs and UBC-MSCs were more proliferative than bone marrow BM-MSCs and AT-MSCs. Protein expression of 15 genes typical for pluripotent stem cells distinguished them into two groups. While the gene expression profiles of BM-MSC, AT-MSCs and UBC-MSCs were similar, DP-MSCS differed in relative gene expression on the level of their products in several genes. CONCLUSIONS: Dental pulp mesenchymal stem cells cultivated in vitro under the same conditions as MSCs from bone marrow, adipose tissue and umbilical cord tissue can be distinguished by pluripotent stem cell gene expression profile. PMID- 24145771 TI - Long-term restorative effects of bromocriptine on operant responding in the 6 hydroxydopamine-lesioned rat. AB - Despite recent recognition of the complexity of the motor and nonmotor dysfunctions that manifest in Parkinson's disease, the propensity of drugs to alleviate the dopamine-dependent symptoms in the 6-hydroxydopamine rat model is still typically being assessed using relatively simple measures of motor function. We investigated the ability of the D2 agonist, bromocriptine, to ameliorate impairments in a more complex operant task, which simultaneously assessed both motor and nonmotor deficits. Rats were trained on a lateralized choice reaction time task that has previously been found to be sensitive to dopamine depletion. One subgroup of rats was then given unilateral 6 hydroxydopamine lesions of the medial forebrain bundle. Once they exhibited stable postlesion deficits, the rats in the lesion group were administered bromocriptine (1.25 mg/kg) 120 min before testing. Bromocriptine induced a transient improvement in motor function but most notably produced a persistent improvement in the accuracy of performance in the task. The improvement in response initiation and selection persisted on testing in the absence of bromocriptine and was not reversed by the D2 antagonist, raclopride (0.2 mg/kg). These results may reflect a conditioning effect of bromocriptine on operant behaviour. PMID- 24145772 TI - L-Stepholidine, a naturally occurring dopamine D1 receptor agonist and D2 receptor antagonist, attenuates heroin self-administration and cue-induced reinstatement in rats. AB - Opiate addiction is a chronic, relapsing brain disease characterized by persistent and uncontrolled drug-seeking behavior despite negative effects. L Stepholidine (L-SPD) is an alkaloid extract of the Chinese herb Stephania intermedia with dopamine D1 receptor partial agonistic and D2 receptor antagonistic dual actions. The unique pharmacological profile of L-SPD suggests that L-SPD may be effective for the treatment of opiate addiction. The aim of this study was to characterize the effects of L-SPD on heroin self-administration on a fixed-ratio 1 schedule and cue-induced reinstatement under an extinction/reinstatement protocol. The effect of L-SPD on the locomotor activity of heroin-free rats was also tested. We found that 2.5, 5, and 10 mg/kg of L-SPD attenuated heroin self-administration and cue-induced reinstatement without affecting locomotor activity. These results showed that L-SPD, which has dual actions on dopamine D1 and D2 receptors, attenuates heroin self-administration and cue-induced reinstatement. PMID- 24145773 TI - Profiling metabolite changes in the neuronal differentiation of human striatal neural stem cells using 1H-magnetic resonance spectroscopy. AB - OBJECTIVE: Neural stem cells (NSCs) have been found to play an increasing clinical role in stroke. However, at present, it is not yet possible to noninvasively monitor their differentiation once implanted into the brain. METHODS: Here, we describe the use of high-resolution H-magnetic resonance spectroscopy (MRS) to define a metabolite profile of undifferentiated human striatal NSCs from the STROC05 cell line and their differentiation after 3-weeks of treatment with purmorphamine. RESULTS: The undifferentiated conditions were characterized by ~95% of cells expressing nestin and ~77% being Ki67(+)ve, indicating that these were still proliferating. Phosphophocholine+glycerophosphocholine (PC+GPC) as well as myo-Inositol (mI) were increased in these cells. PC+GPC and mI were markedly reduced upon differentiation, potentially serving as markers of the NSC state. Upon differentiation (~45% neurons, ~30% astrocytes, ~13% oligodendrocytes), the concentration of many metabolites decreased in absolute value. The decreasing trend of the N-acetyl-aspartate level was observed in differentiated cells when compared with NSCs. An increase in plasmalogen (enriched in myelin sheets) could potentially serve as a marker of oligodendrocytes. CONCLUSION: These metabolite characteristics of undifferentiated and differentiated NSCs provide a basis for exploration of their possible use as markers of differentiation after cell transplantation. PMID- 24145774 TI - Cerebrospinal fluid-targeted delivery of neutralizing anti-IFNgamma antibody delays motor decline in an ALS mouse model. AB - Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disorder characterized by the selective and gradual loss of motoneurons in the brain and spinal cord. A persistent inflammation, typified by the activation of astrocytes and microglia, accompanies the progressive degeneration of motoneurons. Interferon gamma (IFNgamma), a potent proinflammatory cytokine that is aberrantly present in the spinal cord of ALS mice and patients, has been proposed to contribute to motoneuron death by eliciting the activation of the lymphotoxin beta receptor (LT-betaR) through its ligand LIGHT. However, the implication of IFNgamma in the pathogenic process remains elusive. Here, we show that an antagonistic anti-IFNgamma antibody efficiently rescues motoneurons from IFNgamma induced death. When transiently delivered in the cerebrospinal fluid through a subcutaneously implanted osmotic minipump, the neutralizing anti-IFNgamma antibody significantly retarded motor function decline in a mouse model of ALS. However, this transient infusion of anti-IFNgamma antibody did not increase the life expectancy of ALS mice. Our results suggest that IFNgamma contributes to ALS pathogenesis and represents a potential therapeutic target for ALS. PMID- 24145775 TI - The challenges of administering cell-based therapies to patients with Parkinson's disease. AB - Although the concept of cell-based therapy for Parkinson's disease has been around for more than three decades with proof-of-concept studies in man having been achieved, it still remains a controversial experimental therapy. In this review, we discuss the reasons for this and the challenges that this approach generates in the treatment of Parkinson's disease in terms of adopting better strategies by which to develop this whole therapeutic area, an approach that is becoming more necessary as the era of stem cell therapies start to become a clinical reality. PMID- 24145776 TI - Inhibition of amyloid-beta production by anti-amyloid precursor protein antibodies in primary mouse cortical neurones. AB - Current therapies for Alzheimer's disease only treat the symptoms of the disease. We have previously developed a novel monoclonal antibody, 2B3, which binds to the beta-secretase cleavage site in amyloid precursor protein (APP) and reduces the production of amyloid-beta (Abeta) in human cell lines. To determine whether the antibody was likely to be effective in mouse models of amyloid pathology in vivo, we investigated whether 2B3 could also bind to APP in mouse primary cortical neurones. Primary cortical neurones were produced from E15.5-17.5 C57Bl/6 wild type and transgenic APP/V717I (London mutation) embryos. The percentage of the neuronal population was determined by immunocytochemistry. Cells were treated with 10 MUg/ml 2B3 or an irrelevant IgG for 48 h and Abeta40 levels determined by ELISA. The population of cells was found to contain over 75% neurones and 2B3 bound effectively to these cells. No differences in Abeta40 were detected between wild-type and transgenic cells. Importantly, 2B3 significantly inhibited the production of Abeta40 by 75.15+/-1.37% of the media control, whereas an irrelevant IgG only significantly reduced Abeta40 levels by 23.35+/-5.55% of the media control. The reduction in Abeta40 produced by 2B3 was significantly greater than that caused by the IgG. These data indicate that 2B3 binds to APP in mouse neurones and can inhibit Abeta40, similar to our previous findings. The antibody is probably therefore acting by steric hindrance of beta-secretase and these data suggest that it will be effective in mice in vivo and could be an alternative potential therapy for Alzheimer's disease. PMID- 24145777 TI - Sex differences in cocaine conditioned place preference in C57BL/6J mice. AB - Men and women respond differently to the subjective effects of cocaine and cocaine-associated cues, which has implications for the development and maintenance of cocaine addiction. Preclinical studies performed in rats, modeling various aspects of cocaine addiction, have largely validated these results, indicating that female rats may be more sensitive to the rewarding properties of cocaine. The molecular mechanisms leading to sex differences in cocaine reward have largely not been determined, although sex hormones are thought to play a role. The mouse is commonly used as a model organism to study the molecular and genetic factors that influence a variety of psychiatric disorders. In particular, the inbred C57BL/6 mouse strain is often used for behavioral studies related to substance abuse. To begin to understand the hormonal, molecular and genetic mechanisms that might affect cocaine reward, we directly compared male and female C57BL/6J mice in cocaine conditioned place preference (CPP), a test that examines the rewarding and cue-associated properties of drugs of abuse. We conditioned mice at three doses of cocaine and examined preference and extinction of preference. We found that the acquisition of cocaine CPP did not differ between male and female mice. However, extinction of cocaine CPP was delayed in male mice compared with females at the lowest dose of cocaine. We conclude that sex differences in cocaine CPP can be observed in C57BL/6J mice at very low doses of cocaine. PMID- 24145778 TI - No antigen-presentation defect in Unc93b1(3d/3d) (3d) mice. PMID- 24145779 TI - Respond to "No antigen-presentation defect in Unc93b1(3d/3d) (3d) mice". PMID- 24145780 TI - HIV-AIDS: much accomplished, much to do. AB - As a result of decades of research-driven breakthroughs in basic and clinical science and recent advances in the broad-scale implementation of interventions for the prevention and treatment of infection with HIV, a turning point has been reached in the global HIV-AIDS pandemic. To end the pandemic and achieve the goal of an AIDS-free generation, researchers and clinicians must follow the dual pathway of optimizing the implementation of existing prevention and treatment interventions and discovering with basic and clinical research new and effective tools in both of these arenas. PMID- 24145781 TI - ADAPted secretion of cytokines in NK cells. PMID- 24145782 TI - Polarized effector programs for innate-like thymocytes. PMID- 24145783 TI - You break it, you fix it: functions for AID downstream of deamination. PMID- 24145784 TI - Bypassing T cell 'exhaustion'. PMID- 24145792 TI - Combining ionic liquids and polyethylene glycols to boost the hydrophobic hydrophilic range of aqueous biphasic systems. AB - This work reveals, for the first time, that polymer-ionic-liquid-based aqueous biphasic systems (ABS) exhibit a much wider hydrophilic-hydrophobic range than conventional systems reported to date. Three probe dyes were used to demonstrate that either the polymer-rich or the ionic-liquid-rich layer can serve as the most hydrophobic phase. It was found that the phase polarities can be easily tuned by the choice of an appropriate ionic liquid. PMID- 24145791 TI - Effect of helminth-induced immunity on infections with microbial pathogens. AB - Helminth infections are ubiquitous worldwide and can trigger potent immune responses that differ from and potentially antagonize host protective responses to microbial pathogens. In this Review we focus on the three main killers in infectious disease-AIDS, tuberculosis and malaria-and critically assesses whether helminths adversely influence host control of these diseases. We also discuss emerging concepts for how M2 macrophages and helminth-modulated dendritic cells can potentially influence the protective immune response to concurrent infections. Finally, we present evidence advocating for more efforts to determine how and to what extent helminths interfere with the successful control of specific concurrent coinfections. PMID- 24145793 TI - Biological activity of oleanane triterpene derivatives obtained by chemical derivatization. AB - Nine new derivatives of oleanane triterpenoids isolated from Fatsia polycarpa Hayata were synthesized through chemical transformations. Acetylation was effected by reaction with acetic anhydride in pyridine to afford compounds 1-5, while compound 6 was obtained using 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC.HCl) in CH2Cl2. The others derivatives 7-9 were obtained in reactions of the corresponding triterpenoids with EDC.HCl, 4-N,N dimethylaminopyridine hydrochloride and 4-N,N-dimethylaminopyridine in CH2Cl2. The structures of 1-9 were elucidated from extensive spectroscopic and HRESIMS data, while the structure of 9 was further confirmed by X-ray diffraction analysis. The cytotoxic, anti-hepatitis B virus (HBV), antibacterial, hypoglycaemic and Wnt signaling activities of these derivatives were evaluated in vitro. PMID- 24145794 TI - Selection of a mimotope peptide of S-adenosyl-L-homocysteine and its application in immunoassays. AB - A competitive immunoassay for S-adenosyl-L-homocysteine (SAH) has been used in the clinical test for homocysteine via an enzymatic conversion reaction. Since S adenosyl-l-homocysteine is a relatively unstable compound, we have used peptide library phage display to select a new mimotope peptide that interacts with the anti-SAH antibody. By immobilizing the synthetic peptide on solid phase as a competitive surrogate for SAH, we demonstrate its utility in a competitive ELISA assay. The linear range of the assay for SAH was 0.4-6.4 uM, in good correlation to the conventional assay using an SAH-conjugated plate. Our results show that the mimotope peptide has potential to substitute for SAH in immunoassays. PMID- 24145795 TI - Synthesis and protective effect of new ligustrazine-benzoic acid derivatives against CoCl2-induced neurotoxicity in differentiated PC12 cells. AB - A series of novel ligustrazine-benzoic acid derivatives were synthesized and evaluated for their protective effect against cobalt chloride-induced neurotoxicity in differentiated PC12 cells. Combining hematoxylin and eosin staining, we found compound that (3,5,6-trimethylpyrazin-2-yl)methyl 3-methoxy-4 [(3,5,6-trimethylpyrazin-2-yl)methoxy]benzoate (4a) displayed promising protective effect on the proliferation of the injured PC12 cells (EC50 = 4.249 uM). Structure-activity relationships are briefly discussed. PMID- 24145797 TI - PARP1 orchestrates variant histone exchange in signal-mediated transcriptional activation. AB - Transcriptional activation is accompanied by multiple molecular events that remodel the local chromatin environment in promoter regions. These molecular events are often orchestrated in response to the activation of signalling pathways, as exemplified by the response of immediate early genes such as FOS to ERK MAP kinase signalling. Here, we demonstrate that inducible NFI recruitment permits PARP1 binding to the FOS promoter by a mutually reinforcing loop. PARP1 and its poly(ADP-ribosyl)ation activity are required for maintaining FOS activation kinetics. We also show that the histone variant H2A.Z associates with the FOS promoter and acts in a transcription-suppressive manner. However, in response to ERK pathway signalling, H2A.Z is replaced by H2A; PARP1 activity is required to promote this exchange. Thus, our work has revealed an additional facet of PARP1 function in promoting dynamic remodelling of promoter-associated nucleosomes to allow transcriptional activation in response to cellular signalling. PMID- 24145798 TI - Ubiquitously transcribed genes use alternative polyadenylation to achieve tissue specific expression. AB - More than half of human genes use alternative cleavage and polyadenylation (ApA) to generate mRNA transcripts that differ in the lengths of their 3' untranslated regions (UTRs), thus altering the post-transcriptional fate of the message and likely the protein output. The extent of 3' UTR variation across tissues and the functional role of ApA remain poorly understood. We developed a sequencing method called 3'-seq to quantitatively map the 3' ends of the transcriptome of diverse human tissues and isogenic transformation systems. We found that cell type specific gene expression is accomplished by two complementary programs. Tissue restricted genes tend to have single 3' UTRs, whereas a majority of ubiquitously transcribed genes generate multiple 3' UTRs. During transformation and differentiation, single-UTR genes change their mRNA abundance levels, while multi UTR genes mostly change 3' UTR isoform ratios to achieve tissue specificity. However, both regulation programs target genes that function in the same pathways and processes that characterize the new cell type. Instead of finding global shifts in 3' UTR length during transformation and differentiation, we identify tissue-specific groups of multi-UTR genes that change their 3' UTR ratios; these changes in 3' UTR length are largely independent from changes in mRNA abundance. Finally, tissue-specific usage of ApA sites appears to be a mechanism for changing the landscape targetable by ubiquitously expressed microRNAs. PMID- 24145799 TI - Genetic rescue of Muenke syndrome model hearing loss reveals prolonged FGF dependent plasticity in cochlear supporting cell fates. AB - The stereotyped arrangement of cochlear sensory and supporting cells is critical for auditory function. Our previous studies showed that Muenke syndrome model mice (Fgfr3P244R/+) have hearing loss associated with a supporting cell fate transformation of two Deiters' cells to two pillar cells. We investigated the developmental origins of this transformation and found that two prospective Deiters' cells switch to an outer pillar cell-like fate sequentially between embryonic day 17.5 (E17.5) and postnatal day 3 (P3). Unexpectedly, the Fgfr3P244R/+ hearing loss and supporting cell fate transformation are not rescued by genetically reducing fibroblast growth factor 8 (FGF8), the FGF receptor 3c (FGFR3c) ligand required for pillar cell differentiation. Rather, reducing FGF10, which normally activates FGFR2b or FGFR1b, is sufficient for rescue of cochlear form and function. Accordingly, we found that the P244R mutation changes the specificity of FGFR3b and FGFR3c such that both acquire responsiveness to FGF10. Moreover, Fgf10 heterozygosity does not block the Fgfr3P244R/+ supporting cell fate transformation but instead allows a gradual reversion of fate-switched cells toward the normal phenotype between P5 and at least P14. This study indicates that Deiters' and pillar cells can reversibly switch fates in an FGF-dependent manner over a prolonged period of time. This property might be exploited for the regulation of sensory cell regeneration from support cells. PMID- 24145800 TI - Tracheal intubation with a flexible fibreoptic scope or the McGrath videolaryngoscope in simulated difficult airway scenarios: a randomised controlled manikin study. AB - BACKGROUND: Flexible fibreoptic endoscopic (FFE) intubation is considered the 'gold-standard' when difficult airway management is anticipated. Several videolaryngoscopes have been developed to facilitate intubation by laryngoscopy. OBJECTIVE: The aim of the study was to compare the performance of the McGrath series 5 videolaryngoscope (McGrath videolaryngoscope) and the FFE for tracheal intubation in manikins with a simulated difficult airway, hypothesizing that the McGrath videolaryngoscope intubation would prove faster than FFE intubation. DESIGN: A randomised controlled study. SETTING: The Danish Institute for medical simulation between December 2009 and June 2010. PARTICIPANTS: Twenty-eight anaesthesia residents participating in the Danish mandatory 3-day airway management course. INTERVENTIONS: All participants received instructions and training in the use of the McGrath videolaryngoscope and FFE. The participants then performed tracheal intubation on a SimMan manikin once with the McGrath videolaryngoscope and once with the FFE in three difficult airway scenarios: (1) pharyngeal obstruction; (2) pharyngeal obstruction and cervical rigidity; (3) tongue oedema. MAIN OUTCOME MEASURES: We measured successful intubations, defined as intubation within 120 s, and time to tracheal intubation. RESULTS: The trachea was intubated within 120 s with the McGrath videolaryngoscope in 25 out of 27 (93%), 25 out of 28 (89%) and 18 out of 28 (64%) occasions compared with 11 out of 28 (40%), 11 out of 28 (40%) and 16 out of 28 (57%) with the FFE in scenarios (1), (2) and (3), respectively. Time to tracheal intubation was shorter with the McGrath videolaryngoscope in scenarios (1) and (2) than with the FFE (Wilcoxon signed rank sum test, P < 0.0001). CONCLUSION: The McGrath videolaryngoscope is a valuable device with higher success rate and a quicker performance in simulated difficult airways. In patients, videolaryngoscopy may have a role in difficult airway algorithms, but the optimal device has yet to be found. PMID- 24145801 TI - Anaesthesia and orphan disease: a patient with alkaptonuria. PMID- 24145802 TI - Preoperative urine-specific gravity and the incidence of complications after hip fracture surgery: A prospective, observational study. AB - BACKGROUND: Mild to moderately severe dehydration is common in the elderly, but its relationship to surgical outcome is unclear. OBJECTIVES: To study the incidence of dehydration prior to hip fracture surgery and its relationship to postoperative complications. DESIGN: Prospective observational study. SETTING: Operation department and orthopaedic ward at a regional hospital. PATIENTS: Forty five patients [median (interquartile range) age 78 (75 to 86) years] undergoing acute hip fracture surgery. INTERVENTIONS: A urine sample was taken on admission to the operating theatre. Complications were assessed 2 days postoperatively using a check-list. MAIN OUTCOME MEASURES: Dehydration was considered to be present if the urinary specific gravity was 1.020 or higher, indicating renal water conservation. The number and type of postoperative complications were recorded. RESULTS: Dehydration was present in one third of the patients. Sixty percent of these patients had at least one postoperative complication, whereas the corresponding proportion was 30% in the euhydrated patients (P < 0.01). Only one patient (3%) had more than one complication in the euhydrated group compared with six patients (40%) in the dehydrated group (P < 0.01). Euhydrated patients had a mean of 0.3 postoperative complications per surgery, whereas dehydrated patients scored 1.1 complications (P < 0.015). The higher incidence included confusion, arterial desaturation and cardiovascular events. CONCLUSION: Dehydration before surgery nearly quadrupled the number of postoperative complications after hip fracture repair. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT 01294930. PMID- 24145803 TI - Comparison of laryngeal mask airway Supreme and laryngeal mask airway Pro-Seal for controlled ventilation during general anaesthesia in adult patients: systematic review with meta-analysis. AB - BACKGROUND: Laryngeal mask airway (LMA) Supreme is a newly introduced single-use supraglottic device, which shares common features of both the LMA Pro-Seal and the intubating LMA (ILMA). Clinical studies have compared the safety and efficacy of the LMA Supreme over the 'gold standard' LMA Pro-Seal in different patient populations. However, the clinical relevance of the potential advantage which one device may offer over the other remains unclear. OBJECTIVE: To quantify the potential advantage that the LMA Supreme may offer over the LMA Pro-Seal on oropharyngeal leak pressures in adult patients. DESIGN: A systematic review and meta-analysis of randomised controlled trials. DATA SOURCE: Three authors independently searched PubMed, PubMed Central, Scopus, Central Register of Clinical Trials of the Cochrane Collaboration, Google Scholar and Directory of open access journals. ELIGIBILITY CRITERIA: Randomised trials comparing the LMA Supreme and the LMA Pro-Seal in adults in supine position, reporting on safety outcomes and published in English. RESULTS: Seven randomised controlled trials met the eligibility criteria and were included in the meta-analysis. Pooled data from 666 patients showed that the LMA Supreme provided lower oropharyngeal leak pressures than the LMA Pro-Seal [mean difference -2.48 cmH2O, 95% confidence interval (CI) -4.45 to -0.52]. First insertion success rate was higher for the LMA Supreme than for the LMA Pro-Seal when a muscle relaxant was not used [relative risk 1.17, 95% CI 1.03 to 1.35; number needed to treat (NNT) 6, 95% CI 4 to 12]. Time taken to insert the LMA was similar for the two devices. Complications associated with the use of either of the devices are infrequent and similar. CONCLUSION: Although the single-use LMA Supreme provides lower oropharyngeal leak pressures in comparison with the LMA Pro-Seal for controlled ventilation in supine adult patients, the clinical relevance of this small difference may be debatable and should be weighed against the potential risks of transmission of communicable diseases with the LMA Pro-Seal. PMID- 24145804 TI - Ultrasound guidance of needle tip position for femoral nerve blockade: an observational study. AB - BACKGROUND: The femoral nerve lies in the ilio-fascial space in a groove formed by the iliac and psoas muscles (GIPM) posteriorly, and overlaid by the iliac fascia. Recommendations for needle insertion for femoral blockade using ultrasound imaging are to insert the needle tip behind the iliac fascia at the lateral side of the femoral nerve, but this part of the nerve is poorly visualised in some patients. A more accurate location of the lateral part of the femoral nerve might be achieved by identifying the GIPM and its lateral segment. OBJECTIVES: The objectives of this study are to determine the frequency of ultrasound visibility of the lateral part of the femoral nerve and GIPM, and to note the motor response to electrostimulation of the nerve and the spread of local anaesthetic when positioning the needle tip at the lateral segment of the GIPM. DESIGN: A prospective observational (case series) study. SETTING: Department of Anaesthesiology of a University Hospital. PATIENTS: Inpatients undergoing hip or knee surgery scheduled to have femoral nerve blockade were eligible to participate. INTERVENTIONS: The ultrasound probe was positioned in the inguinal region, and direct ultrasound identification of the femoral nerve, lying on the GIPM behind the iliac fascia, was obtained. A stimulating needle, inserted in-plane and advanced lateral to medial was directed towards the femoral nerve until it made contact with the target structure defined as the lateral segment of the GIPM. MAIN OUTCOME MEASURE: Ultrasound identification of the lateral part of the femoral nerve and GIPM. RESULTS: An image compatible with the lateral part of the femoral nerve was observed in 91 out of 100 patients. In the remaining nine patients, when the lateral part of the femoral nerve was not seen, GIPM could be visualised in five (55%) patients. The iliac fascia and GIPM were clearly visualised in 68 and 85 patients respectively. In 85 cases when the needle tip was placed at the lateral segment of GIPM, a quadriceps femoris muscle motor response was obtained, and the distribution of the anaesthetic solution was observed behind the iliac fascia in all patients. In two patients, only the iliac fascia was identified, and in the two patients, none of these structures was correctly visualised. CONCLUSION: The GIPM was seen in the majority undergoing ultrasound-guided femoral nerve blockade, even when the lateral part of the femoral nerve was not visualised. Using the lateral segment of GIPM as a target for needle tip location in an in-plane lateral to medial approach of the femoral nerve deserves further investigation. PMID- 24145805 TI - Minimal incidence of chronic and neuropathic postthoracotomy pain after anteroaxillary thoracotomy with consequent systemic pain therapy. PMID- 24145806 TI - Comparison of Aintree and Fastrach techniques for low-skill fibreoptic intubation in patients at risk of secondary cervical injury: a randomised controlled trial. AB - BACKGROUND: We compared two methods of asleep fibreoptic intubation in patients at risk of secondary cervical injury: the Aintree Intubation Catheter via a classic laryngeal mask airway (cLMA) versus the Fastrach technique via the intubating laryngeal mask airway (iLMA). OBJECTIVE: To test which system has the highest rate of successful intubations in the clinical setting. DESIGN: A randomised controlled study. SETTING: Single-centre, between 2007 and 2010. PATIENTS: We randomly allocated 80 patients (30 women and 50 men) who underwent elective neurosurgery of the cervical spine to either group, placed in a neutral position and wearing a soft cervical collar. Entry criteria were ASA status 1 to 3, age 18 to 80 years and written informed consent. Exclusion criteria were patients with cervical instability, known or predicted difficult airway, BMI greater than 40 kg m-2 and symptomatic gastro-oesophageal reflux. INTERVENTIONS: Two anaesthetists who were experienced in both techniques performed all anaesthesia procedures within the study. There was a maximum of three attempts for performing each technique. MAIN OUTCOME MEASURES: The primary outcome was the rate of successful fibreoptic intubation in a neutral position. We also investigated the timing sequence for both techniques, the Brimacombe and Berry Bronchoscopy Score, and differences in technical aspects. RESULTS: All 40 patients in the Aintree group but only 31 patients in the Fastrach group were intubated successfully. Thus, fibreoptic intubation failed significantly less using the Aintree technique (P = 0.002). For secondary outcomes, the cLMA was faster (260 versus 289 s, P = 0.039) and easier (P = 0.036) to insert than the iLMA. The fibreoptic view of the glottis according to the Brimacombe and Berry Bronchoscopy Score was better (P = 0.016) and the tracheal tube was easier to insert (P = 0.010) in the Aintree group. CONCLUSION: Fibreoptic intubation using the Aintree system was more successful than the Fastrach technique in our population of patients in a neutral position wearing a soft cervical collar. The differences in the time to successful intubation between the two groups are unlikely to be clinically relevant. PMID- 24145807 TI - Propofol inhibits gap junctions by attenuating sevoflurane-induced cytotoxicity against rat liver cells in vitro. AB - BACKGROUND: Liver abnormalities are seen in a small proportion of patients following anaesthesia with sevoflurane. OBJECTIVES: To investigate whether the cytotoxicity of sevoflurane against rat liver cells was mediated by gap junction intercellular communications, and the effect of propofol on sevoflurane-induced cytotoxicity. DESIGN: Experimental study. SETTING: The study was carried out in the central laboratory of The Third Affiliated Hospital, Sun Yat-sen University. CELL LINE: BRL-3A rat liver cells. METHODS: Immortal rat liver cells BRL-3A were grown at low and high density. Colony-forming assays were performed to determine clonogenic growth of these cells. To investigate the effect of oleamide and propofol on gap junction function, we measured fluorescence transmission between cells using parachute dye-coupling assays. Immunoblotting assays were performed to determine connexin32 and connexin43 expression. RESULTS: Our colony formation assays revealed that, in low-density culture, sevoflurane caused no apparent inhibition of clonogenic growth of BRL-3A cells. In high-density culture, 2.2 to 4.4% sevoflurane markedly inhibited clonogenic growth of BRL-3A cells with 67.6 (0.34)% and 61.2 (0.17)% of the cells being viable, respectively (P = 0.003 vs. low-density culture), suggesting cell density dependency of sevoflurane-induced cytotoxicity. Our colony formation assays revealed that propofol markedly attenuated the suppression by sevoflurane of the clonogenic growth of BRL-3A cells (viability: propofol and sevoflurane, 91.5 (0.014)% vs. sevoflurane, 56.6 (0.019)%; P <0.01). Blocking gap junctions with 10 MUmol l oleamide significantly attenuated 4.4% sevoflurane-induced suppression with a viability of 83.6 +/- 0.138% (oleamide and sevoflurane vs. sevoflurane, P < 0.01). Immunoblotting assays further showed that propofol (3.2 MUg ml) markedly reduced CX32 levels and significantly inhibited gap junctional intercellular communications as revealed by parachute dye-coupling assays. Values are mean (SD). CONCLUSION: This study provides the first direct evidence that sevoflurane-induced cytotoxicity, which is mediated through gap junctions, is attenuated by propofol, possibly by its action on Cx32 homomeric or heteromeric complexes. PMID- 24145808 TI - Reply to: Ultrasound-guided transversus abdominis plane block in children. PMID- 24145809 TI - Ultrasound-guided transversus abdominis plane block in children. PMID- 24145810 TI - A simple epidural simulator: fruits and potatoes, and what kind of bananas? PMID- 24145811 TI - Venous air embolism during major liver surgery: Far more common, than we think. PMID- 24145813 TI - Free standing acetylene black mesh to capture dissolved polysulfide in lithium sulfur batteries. AB - Herein, we report a cheap and simple approach to solve the polysulfide dissolution problem in lithium sulfur batteries. It was interestingly revealed that a simple insertion of acetylene black mesh enabled us to obtain the capacity of 1491 mA h g(-1) at initial discharge and 1062 mA h g(-1) after 50 cycles. PMID- 24145814 TI - Predictors of mortality in atypical antipsychotic-treated community-dwelling elderly patients with behavioural and psychological symptoms of dementia: a prospective population-based cohort study from Italy. AB - PURPOSE: To evaluate the effect of a broad range of covariates on the survival of a real-life long-term follow-up cohort of community-dwelling patients with behavioural and psychological symptoms of dementia who were new users of atypical antipsychotic medications (APMs). METHODS: This was a prospective cohort study of 1,618 subjects aged >=65 years with dementia and BPSD ("behavioural and psychological symptoms of dementia") who were new users of atypical APMs and registered in a Dementia Evaluation Unit of Campania Region (Italy) from September 2006 to March 2010. The potential of baseline features to predict mortality was assessed with the Cox proportional hazards model. RESULTS: The average follow-up was 309 days. Of the 1,618 new users of atypical antipsychotics, 9.3 % experienced at least one adverse event, including death (5.1 %), drug therapeutic failure (3.0 %), extrapyramidal symptoms (0.5 %) and stroke (0.2 %). The crude all-cause mortality rate was 6.0 per 100 person-years [95 % confidence interval (CI) 4.8-7.4]; the rate was higher in patients aged >85 years (9.0 per 100 person-years, 95 % CI 6.4-12.7) and among male patients (7.5 per 100 person-years, 95% CI 5.3-10.6). In the multivariate analysis, only age was associated to all-cause mortality [hazard ratio (HR) 1.1; 95 % CI 1.0-1.1 and HR 1.4; 95 % CI: 0.9-2.2, respectively). In contrast, hallucination (HR 0.4; 95 % CI 0.2-0.6) and dosage change (HR 0.4; 95 % CI 0.2-0.78) were significantly associated with a lower risk of all-cause mortality. CONCLUSIONS: Among our patient cohort, the mortality rate of patients with BPSD receiving long-term treatment with atypical APMs was lower than that reported in other studies, and only age was found to be significant predictor factor of mortality. PMID- 24145815 TI - Use of exenatide and liraglutide in Denmark: a drug utilization study. AB - PURPOSE: The purpose of this study was to characterise the utilization of the glucagon-like peptide-1 (GLP-1) analogues exenatide and liraglutide in Denmark. METHODS: From the Danish National Prescription Registry, we extracted all prescriptions for either liraglutide or exenatide twice-daily in the period 1 April 2007 to 31 December 2012. Using descriptive statistics, we calculated incidence rates, prevalence proportions, daily consumption, and concomitant drug use. For a subset of users we included data from other registries and characterised the baseline characteristics of incident users of GLP-1 analogues. RESULTS: We identified 21,561 and 2,354 users of liraglutide and exenatide respectively. From market entry in 2009 liraglutide showed an increasing prevalence reaching 2.4 per thousand inhabitants in 2012. Exenatide ranged between 0.01 and 0.25 per thousand inhabitants from 2007 to 2012. Treatment intensity showed geographical variation ranging from 1.84per thousand inhabitants to 3.22 per thousand inhabitants for liraglutide. Average doses were 1.34 mg/day (liraglutide) and 16.4 MUg/day (exenatide). Treatment initiation was most often performed by a hospital physician and was not associated with any changes in concomitant treatment with antihypertensives, cholesterol-lowering drugs or anticoagulants. Of liraglutide and exenatide users, 38 % and 43 % also used insulin. Low kidney function (eGFR < 30 ml/min) was found in 10.1 % and 9.0 % of users of liraglutide and exenatide respectively. CONCLUSIONS: The preferred GLP-1 analogue in Denmark is liraglutide. Certain aspects of the utilization of GLP-1 analogues, such as large regional differences and concomitant use of GLP-1 analogues and insulin, warrant further investigation. PMID- 24145816 TI - Cluster-like headache attacks triggered by nitrofurantoin intake. PMID- 24145817 TI - Long-term neurocognitive effects of antipsychotics in schizophrenia: a network meta-analysis. AB - PURPOSE: Most schizophrenic patients have mild to moderate cognitive impairment in the early stages of schizophrenia. The aim was to compare the long-term effects of various antipsychotic drugs on overall cognition and on specific cognitive domains in patients with schizophrenia or related disorders. METHODS: We searched MEDLINE and EMBASE for randomized controlled trials in which oral formulations of second-generation antipsychotic drugs were compared head-to-head or against placebo or against haloperidol. Trials had to be of at least 6 months duration to be included. We used a network meta-analysis to combine direct and indirect comparisons of the cognitive effects between antipsychotics. RESULTS: Nine studies were eligible. The median trial duration was 52 weeks. Quetiapine, olanzapine and risperidone had better effects on global cognitive score than amisulpride (p < 0.05) and haloperidol (p < 0.05). When memory tasks were considered, ziprasidone had better effect than amisulpride (0.28 [0.02-0.54]) and haloperidol (0.32 [0.09-0.55]). Quetiapine was better than other drugs (p < 0.001) on attention and processing speed tasks, followed by ziprasidone (p < 0.05) and olanzapine (p < 0.05). The effects of quetiapine, risperidone and olanzapine were better than those of amisulpride (p < 0.05) on executive functions. CONCLUSIONS: Our results suggest differences between antipsychotics in their effect on the overall cognitive score in schizophrenia. Quetiapine and olanzapine had the most positive effects, followed by risperidone, ziprasidone, amisulpride and haloperidol in that order. Significant differences were also observed according to specific cognitive tasks. PMID- 24145818 TI - Is the quality of data in an electronic medical record sufficient for assessing the quality of primary care? AB - OBJECTIVE: Quality indicators for the treatment of type 2 diabetes are often retrieved from a chronic disease registry (CDR). This study investigates the quality of recording in a general practitioner's (GP) electronic medical record (EMR) compared to a simple, web-based CDR. METHODS: The GPs entered data directly in the CDR and in their own EMR during the study period (2011). We extracted data from 58 general practices (8235 patients) with type 2 diabetes and compared the occurrence and value of seven process indicators and 12 outcome indicators in both systems. The CDR, specifically designed for monitoring type 2 diabetes and reporting to health insurers, was used as the reference standard. For process indicators we examined the presence or absence of recordings on the patient level in both systems, for outcome indicators we examined the number of compliant or non-compliant values of recordings present in both systems. The diagnostic OR (DOR) was calculated for all indicators. RESULTS: We found less concordance for process indicators than for outcome indicators. HbA1c testing was the process indicator with the highest DOR. Blood pressure measurement, urine albumin test, BMI recorded and eye assessment showed low DOR. For outcome indicators, the highest DOR was creatinine clearance <30 mL/min or mL/min/1.73 m(2) and the lowest DOR was systolic blood pressure <140 mm Hg. CONCLUSIONS: Clinical items are not always adequately recorded in an EMR for retrieving indicators, but there is good concordance for the values of these items. If the quality of recording improves, indicators can be reported from the EMR, which will reduce the workload of GPs and enable GPs to maintain a good patient overview. PMID- 24145819 TI - Modification of the relationship of the apolipoprotein E epsilon4 allele to the risk of Alzheimer disease and neurofibrillary tangle density by sleep. AB - IMPORTANCE: The apolipoprotein E (APOE [GenBank, 348; OMIM, 107741]) epsilon4 allele is a common and well-established genetic risk factor for Alzheimer disease (AD). Sleep consolidation is also associated with AD risk, and previous work suggests that APOE genotype and sleep may interact to influence cognitive function. OBJECTIVE: To determine whether better sleep consolidation attenuates the relationship of the APOE genotype to the risk of incident AD and the burden of AD pathology. DESIGN, SETTING, AND PARTICIPANTS: A prospective longitudinal cohort study with up to 6 years of follow-up was conducted. Participants included 698 community-dwelling older adults without dementia (mean age, 81.7 years; 77% women) in the Rush Memory and Aging Project. EXPOSURES: We used up to 10 days of actigraphic recording to quantify the degree of sleep consolidation and ascertained APOE genotype. MAIN OUTCOMES AND MEASURES: Participants underwent annual evaluation for AD during a follow-up period of up to 6 years. Autopsies were performed on 201 participants who died, and beta-amyloid (Abeta) and neurofibrillary tangles were identified by immunohistochemistry and quantified. RESULTS: During the follow-up period, 98 individuals developed AD. In a series of Cox proportional hazards regression models, better sleep consolidation attenuated the effect of the epsilon4 allele on the risk of incident AD (hazard ratio, 0.67; 95% CI, 0.46-0.97; P = .04 per allele per 1-SD increase in sleep consolidation). In a series of linear mixed-effect models, better sleep consolidation also attenuated the effect of the epsilon4 allele on the annual rate of cognitive decline. In individuals who died, better sleep consolidation attenuated the effect of the epsilon4 allele on neurofibrillary tangle density (interaction estimate, -0.42; SE = 0.17; P = .02), which accounted for the effect of sleep consolidation on the association between APOE genotype and cognition proximate to death. CONCLUSIONS AND RELEVANCE: Better sleep consolidation attenuates the effect of APOE genotype on incident AD and development of neurofibrillary tangle pathology. Assessment of sleep consolidation may identify APOE+ individuals at high risk for incident AD, and interventions to enhance sleep consolidation should be studied as potentially useful means to reduce the risk of AD and development of neurofibrillary tangles in APOE epsilon4+ individuals. PMID- 24145820 TI - LAMP2A as a therapeutic target in Parkinson disease. AB - Abnormal aggregation of SNCA/?-synuclein plays a crucial role in Parkinson disease (PD) pathogenesis. SNCA levels determine its toxicity, and its accumulation, even to a small extent, may be a risk factor for neurodegeneration. One of the main pathways for SNCA degradation is chaperone-mediated autophagy (CMA), a selective form of autophagy, while aberrant SNCA may act as a CMA inhibitor. In the current punctum we summarize our recent data showing that induction of CMA, via overexpression of the protein controlling its rate-limiting step, the lysosomal receptor LAMP2A, effectively decreases SNCA levels and ameliorates SNCA-induced neurodegeneration, both in neuronal cell culture systems and in the rat brain. Such findings suggest that modulation of LAMP2A and, consequently, CMA, represents a viable therapeutic target for PD and other synucleinopathies where SNCA accumulation and aggregation plays a fundamental role. PMID- 24145821 TI - 3'-End processing of histone pre-mRNAs in Drosophila: U7 snRNP is associated with FLASH and polyadenylation factors. AB - 3'-End cleavage of animal replication-dependent histone pre-mRNAs is controlled by the U7 snRNP. Lsm11, the largest component of the U7-specific Sm ring, interacts with FLASH, and in mammalian nuclear extracts these two proteins form a platform that recruits the CPSF73 endonuclease and other polyadenylation factors to the U7 snRNP. FLASH is limiting, and the majority of the U7 snRNP in mammalian extracts exists as a core particle consisting of the U7 snRNA and the Sm ring. Here, we purified the U7 snRNP from Drosophila nuclear extracts and characterized its composition by mass spectrometry. In contrast to the mammalian U7 snRNP, a significant fraction of the Drosophila U7 snRNP contains endogenous FLASH and at least six subunits of the polyadenylation machinery: symplekin, CPSF73, CPSF100, CPSF160, WDR33, and CstF64. The same composite U7 snRNP is recruited to histone pre-mRNA for 3'-end processing. We identified a motif in Drosophila FLASH that is essential for the recruitment of the polyadenylation complex to the U7 snRNP and analyzed the role of other factors, including SLBP and Ars2, in 3'-end processing of Drosophila histone pre-mRNAs. SLBP that binds the upstream stem-loop structure likely recruits a yet-unidentified essential component(s) to the processing machinery. In contrast, Ars2, a protein previously shown to interact with FLASH in mammalian cells, is dispensable for processing in Drosophila. Our studies also demonstrate that Drosophila symplekin and three factors involved in cleavage and polyadenylation-CPSF, CstF, and CF Im-are present in Drosophila nuclear extracts in a stable supercomplex. PMID- 24145822 TI - G17-modified hammerhead ribozymes are active in vitro and in vivo. AB - Natural hammerhead ribozymes (HHRz) feature tertiary interactions between hairpin loops or bulges in two of three helices that surround the catalytic core of conserved nucleotides. Their conservation was originally established on minimal versions lacking the tertiary interactions. While those sequence requirements in general also apply to natural versions, we show here differences for the HHRz cleavage site N17. A guanosine at this position strongly impairs cleavage activity in minimal versions, whereas we observe for the G17 variants of four tertiary stabilized HHRz significant cleavage and ligation activity in vitro. Kinetic analyses of these variants revealed a reduced rate and extent of cleavage, compared with wild-type sequences, while variants with distorted tertiary interactions cleaved at a reduced rate, but to the same extent. Contrary to this, G17 variants exhibit similar in vitro ligation activity as compared with the respective wild-type motif. To also address the catalytic performance of these motifs in vivo, we have inserted HHRz cassettes in the lacZ gene and tested this beta-galactosidase reporter in Dictyostelium discoideum. In colorimetric assays, we observe differences in the enzymatic activity of beta-galactosidase, which correlate well with the activity of the different HHRz variants in vitro and which can be unambiguously attributed to ribozyme cleavage by primer extension analysis. PMID- 24145823 TI - Rational design of microRNA-siRNA chimeras for multifunctional target suppression. AB - MicroRNAs (miRNAs) are involved in a variety of human diseases by simultaneously suppressing many gene targets. Thus, the therapeutic value of miRNAs has been intensely studied. However, there are potential limitations with miRNA-based therapeutics such as a relatively moderate impact on gene target regulation and cellular phenotypic control. To address these issues, we proposed to design new chimeric small RNAs (aiRNAs) by incorporating sequences from both miRNAs and siRNAs. These aiRNAs not only inherited functions from natural miRNAs, but also gained new functions of gene knockdown in an siRNA-like fashion. The improved efficacy of multifunctional aiRNAs was demonstrated in our study by design and testing of an aiRNA that inherited the functions of both miR-200a and an AKT1 targeting siRNA for simultaneous suppression of cancer cell motility and proliferation. The general principles of aiRNA design were further validated by engineering new aiRNAs mimicking another miRNA, miR-9. By regulating multiple cellular functions, aiRNAs could be used as an improved tool over miRNAs to target disease-related genes, thus alleviating our dependency on a limited number of miRNAs for the development of RNAi-based therapeutics. PMID- 24145824 TI - LigandRNA: computational predictor of RNA-ligand interactions. AB - RNA molecules have recently become attractive as potential drug targets due to the increased awareness of their importance in key biological processes. The increase of the number of experimentally determined RNA 3D structures enabled structure-based searches for small molecules that can specifically bind to defined sites in RNA molecules, thereby blocking or otherwise modulating their function. However, as of yet, computational methods for structure-based docking of small molecule ligands to RNA molecules are not as well established as analogous methods for protein-ligand docking. This motivated us to create LigandRNA, a scoring function for the prediction of RNA-small molecule interactions. Our method employs a grid-based algorithm and a knowledge-based potential derived from ligand-binding sites in the experimentally solved RNA ligand complexes. As an input, LigandRNA takes an RNA receptor file and a file with ligand poses. As an output, it returns a ranking of the poses according to their score. The predictive power of LigandRNA favorably compares to five other publicly available methods. We found that the combination of LigandRNA and Dock6 into a "meta-predictor" leads to further improvement in the identification of near-native ligand poses. The LigandRNA program is available free of charge as a web server at http://ligandrna.genesilico.pl. PMID- 24145825 TI - A one-step extraction/clean-up method for determination of PCBs, PBDEs and HBCDs in environmental solid matrices. AB - A selective pressurized liquid extraction (S-PLE) method was developed for rapid determination of 3 classes of halogenated organic contaminants in indoor dust, soil and sediment samples. The optimised method used 3 : 2 v/v n-hexane dichloromethane for extraction of polychlorinated biphenyls (PCBs), polybrominated diphenyl ethers (PBDEs) and hexabromocyclododecanes (HBCDs). Extraction was performed at 90 degrees C for 5 min followed by 4 min static time under 1500 psi. Good recoveries of target analytes were obtained after 3 extraction cycles. In-cell cleanup was performed using 10 g of 44% H2SO4 acid silica and 5 g of florisil (secondary fat retainer), while copper powder was used to remove elemental sulfur. The method was validated using NIST SRM2585 and SRM 1941b in addition to an in-house previously characterised soil sample. Measured concentrations of target compounds showed good agreement with the certified values with RSD < 20% indicating the good accuracy and precision of the S-PLE method. Clean extracts provided low noise levels resulting in low method detection limits (<0.03 ng g(-1)) and LOQs (<0.1 ng g(-1)). The method developed was applied successfully to real environmental samples and it provided various advantages over traditional methods including reduced solvent consumption and analysis time, minimal sample contamination and high sample throughput which can be beneficial for environmental monitoring programs dealing with large numbers of samples. PMID- 24145826 TI - Can technique modification training reduce knee moments in a landing task? AB - Anterior cruciate ligament (ACL) injuries are costly. Sidestep technique training reduces knee moments that load the ACL. This study examined whether landing technique training alters knee moments. Nineteen team sport athletes completed the study. Motion analysis and ground reaction forces were recorded before and after 6 weeks of technique modification. An inverse dynamic model was used to calculate three-dimensional knee loading. Pre- and postintervention scores were compared using paired t tests. Maximal knee flexion angle during landing was increased following training. There was no change in valgus or flexion moments, but an increase in peak internal rotation moment. This increase in internal rotation moment may increase the risk of ACL injury. However, the increased angle at which the peak internal rotation moment occurred at follow up may mitigate any increase in injury risk by reducing load transmission. PMID- 24145828 TI - Culturing of human nasal epithelial cells at the air liquid interface. AB - In vitro models using human primary epithelial cells are essential in understanding key functions of the respiratory epithelium in the context of microbial infections or inhaled agents. Direct comparisons of cells obtained from diseased populations allow us to characterize different phenotypes and dissect the underlying mechanisms mediating changes in epithelial cell function. Culturing epithelial cells from the human tracheobronchial region has been well documented, but is limited by the availability of human lung tissue or invasiveness associated with obtaining the bronchial brushes biopsies. Nasal epithelial cells are obtained through much less invasive superficial nasal scrape biopsies and subjects can be biopsied multiple times with no significant side effects. Additionally, the nose is the entry point to the respiratory system and therefore one of the first sites to be exposed to any kind of air-borne stressor, such as microbial agents, pollutants, or allergens. Briefly, nasal epithelial cells obtained from human volunteers are expanded on coated tissue culture plates, and then transferred onto cell culture inserts. Upon reaching confluency, cells continue to be cultured at the air-liquid interface (ALI), for several weeks, which creates more physiologically relevant conditions. The ALI culture condition uses defined media leading to a differentiated epithelium that exhibits morphological and functional characteristics similar to the human nasal epithelium, with both ciliated and mucus producing cells. Tissue culture inserts with differentiated nasal epithelial cells can be manipulated in a variety of ways depending on the research questions (treatment with pharmacological agents, transduction with lentiviral vectors, exposure to gases, or infection with microbial agents) and analyzed for numerous different endpoints ranging from cellular and molecular pathways, functional changes, morphology, etc. In vitro models of differentiated human nasal epithelial cells will enable investigators to address novel and important research questions by using organotypic experimental models that largely mimic the nasal epithelium in vivo. PMID- 24145829 TI - The effects of racial differences on body composition and total body water measured by multifrequency bioelectrical impedance analysis influence delivered Kt/V dialysis dosing. AB - INTRODUCTION: Haemodialysis dosing is traditionally based on urea clearance (Kt/V). Aiming for the same Kt/V target, some racial groups have better survival. We investigated whether body composition differs with ethnicity and may lead to differences in Kt/V delivered. METHODS: We compared total body water (TBW) measured by multifrequency bioelectrical impedance analysis (MF-BIA) that calculated from standard anthropometric equations. RESULTS: Three hundred and seventy-one adult patients, with a mean age of 58.2 +/- 16.6 years, 60.6% of whom were male, 29.1% diabetic, 38.5% Caucasoid, 29.4% African/Afro-Caribbean, 24.8% South Asian and 5.4% East Asian, were studied. TBW measured by MF-BIA differed significantly from that predicted by anthropometric equations. Body fat of women and diabetics was greater, and muscle mass in South Asians was reduced. The difference between the TBW MF-BIA measurement and that of the equation by Watson et al. [11] was associated with % muscle mass (beta -10.8, p < 0.001), age (beta 0.23, p < 0.001), serum albumin (beta -0.24, p < 0.001), body mass index (beta 0.91, p = 0.001) and racial origin (beta -9.86, p = 0.04). CONCLUSIONS: Variation in body composition between ethnic groups potentially leads to over-estimation of delivered dose for some ethnic groups and underestimation for others when using anthropometric equations. MF-BIA assessments of body water should be evaluated as a method for dosing dialysis patients. PMID- 24145830 TI - Recovery of an injured fornix in a stroke patient. AB - OBJECTIVE: Knowledge about recovery of an injured fornix following brain injury is limited. We describe here a patient who showed recovery of an injured fornix following stroke. CASE REPORT: A 57-year-old female patient underwent coiling for a ruptured anterior communicating cerebral artery aneurysm, and conservative management for subarachnoid and intraventricular haemorrhage. The patient showed severe cognitive impairment 6 weeks after onset. However, her cognition showed continuous improvement with time; based on the Mini-Mental State Examination and the Memory Assessment Scale, her cognition was within the normal range 7 months after onset. RESULTS: Findings from diffusion tensor tractography at 6 weeks and 7 months showed discontinuations in both columns of the fornix. The proximal portion of both crus also showed discontinuation on diffusion tensor tractography at 6 weeks and 7 months; however, on 7-month diffusion tensor tractography, the end of the fornical body was shown to be connected to the splenium of the corpus callosum and then branched to the right medial temporal lobe and right thalamus. CONCLUSION: The unusual neural connection between the injured fornix and the thalamus appears to be a recovery phenomenon, which allows the injured fornix and the medial temporal lobe to obtain cholinergic innervation from cholinergic nuclei in the brainstem rather than from cholinergic nuclei in the basal forebrain. PMID- 24145831 TI - TLM-PSD model for optimization of energy and power density of vertically aligned carbon nanotube supercapacitor. AB - Electrochemical capacitors with fast charging-discharging rates are very promising for hybrid electric vehicle industries including portable electronics. Complicated pore structures have been implemented in active materials to increase energy storage capacity, which often leads to degrade dynamic response of ions. In order to understand this trade-off phenomenon, we report a theoretical model based on transmission line model which is further combined with pore size distribution function. The model successfully explained how pores length, and pore radius of active materials and electrolyte conductivity can affect capacitance and dynamic performance of different capacitors. The powerfulness of the model was confirmed by comparing with experimental results of a micro supercapacitor consisted of vertically aligned multiwalled carbon nanotubes (v MWCNTs), which revealed a linear current increase up to 600 Vs(-1) scan rate demonstrating an ultrafast dynamic behavior, superior to randomly entangled singlewalled carbon nanotube device, which is clearly explained by the theoretical model. PMID- 24145832 TI - Intraosseous lipid emulsion: an effective alternative to IV delivery in emergency situations. AB - OBJECTIVE: To determine whether intraosseous infusion of a lipid emulsion reverses cardiac pharmacotoxicity in anaesthetized rats. DESIGN: Prospective, randomized animal study. SETTING: Academic research laboratory. SUBJECTS: Adult, male Sprague-Dawley rats. INTERVENTIONS: We assigned 25 male Sprague-Dawley rats into four groups: intraosseous lipid emulsion, intraosseous saline, IV lipid emulsion, and sham/null. Rats were anesthetized with 1.5% isoflurane and 95% oxygen. The left internal carotid artery and both internal jugular veins were cannulated and a flow probe was placed on the right carotid artery. Subsequently, in animals assigned to the intraosseous groups, the greater trochanter of the left proximal femur was exposed and the intraosseous space was cannulated. After surgical recovery, bupivacaine (10 mg/kg) was injected IV over 20 seconds followed 10 seconds later by treatment with one of the following: intraosseous lipid-emulsion (10 mL/kg over 180 s), intraosseous saline (10 mL/kg over 180 s), IV lipid-emulsion (10 mL/kg over 90 s), or no treatment (sham/null). MEASUREMENTS AND MAIN RESULTS: Electrocardiogram, aortic blood pressure, and carotid blood flow were recorded continuously. Rats treated with intraosseous lipid emulsion experienced a significantly faster recovery of hemodynamic variables (return of 50% flow; median [CI]: 160 s [105-263 s]) than did rats treated with saline (471 s [283-611 s]; p < 0.05) or animals with no treatment (415 s [340-539 s], p < 0.05), but at a similar rate to animals treated with IV lipid emulsion (176 s [152-217 s], p = not significant). All groups experienced persistent negative chronotropic effects. A compensatory increase in systemic arterial pressure was observed in rats treated with lipid emulsion. CONCLUSION: These proof-of principle data indicate that intraosseous infusion of lipid emulsion rapidly reverses bupivacaine-induced cardiac toxicity in rats. Further studies are warranted to optimize this novel route of lipid emulsion injection in emergency situations when intravascular access is not secured. PMID- 24145834 TI - Consulting communities when patients cannot consent: a multicenter study of community consultation for research in emergency settings. AB - OBJECTIVES: To assess the range of responses to community consultation efforts conducted within a large network and the impact of different consultation methods on acceptance of exception from informed consent research and understanding of the proposed study. DESIGN: A cognitively pretested survey instrument was administered to 2,612 community consultation participants at 12 U.S. centers participating in a multicenter trial of treatment for acute traumatic brain injury. SETTING: Survey nested within community consultation for a phase III randomized controlled trial of treatment for acute traumatic brain injury conducted within a multicenter trial network and using exception from informed consent. SUBJECTS: Adult participants in community consultation events. INTERVENTIONS: Community consultation efforts at participating sites. MEASUREMENTS AND MAIN RESULTS: Acceptance of exception from informed consent in general, attitude toward personal exception from informed consent enrollment, and understanding of the study content were assessed. Fifty-four percent of participants agreed exception from informed consent enrollment was acceptable in general in the proposed study; 71% were accepting of personal exception from informed consent enrollment. Participants in interactive versus noninteractive community consultation events were more accepting of exception from informed consent in general (63% vs 49%) and personal exception from informed consent inclusion (77% vs 67%). Interactive community consultation participants had high level recall of study content significantly more often than noninteractive consultation participants (77% vs 67%). Participants of interactive consultation were more likely to recall possible study benefits (61% vs 45%) but less likely to recall potential risks (56% vs 69%). CONCLUSIONS: Interactive community consultation methods were associated with increased acceptance of exception from informed consent and greater overall recall of study information but lower recall of risks. There was also significant variability in exception from informed consent acceptance among different interactive consultation events. These findings have important implications for institutional review board and investigators conducting exception from informed consent research and for community engagement efforts in research more generally. PMID- 24145835 TI - Variation in diagnostic testing in ICUs: a comparison of teaching and nonteaching hospitals in a regional system. AB - OBJECTIVES: To explore variation in the use of diagnostic testing in ICUs, with emphasis on differences between teaching and nonteaching ICUs. DESIGN: Retrospective review of a prospective clinical ICU database. SETTING: Five teaching and four nonteaching ICUs in Winnipeg, Canada, during 2006-2010. PATIENTS: All adults admitted to the nine ICUs during the study period were eligible. After excluding subgroups restricted to teaching ICUs, inter-ICU transfers, prior ICU admission within 90 days, ICU length of stay less than 12 hours, and missing death dates, 10,262 patients were evaluated. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Our primary outcome variable (TotalTesting) was the cumulative number of nine common laboratory tests, three radiologic tests, and electrocardiograms performed in each ICU. We used multivariable median regression to identify factors associated with TotalTesting, including length of stay, demographics, admission details, type and severity of acute illness, and specific medical interventions. We estimated the predictive power of variables as the decline in pseudo-R2 (a goodness-of-fit measure for median regression) when omitting those variables from the model. Median (interquartile range) TotalTesting was 27 (18-49) in teaching ICUs and 20 (13-36) in nonteaching units. With multivariable adjustment, median TotalTesting was 7.1 higher (95% CI, 6.6 7.7) in teaching ICUs. The most influential variable was length of stay, accounting for almost half of the variation. ICU teaching status was the second most important factor, greater than the degree of physiologic derangement and details of medical management. CONCLUSIONS: After adjustment for confounding variables, patients in teaching ICUs had slightly but significantly more diagnostic tests done than those in nonteaching ICUs. In addition to increasing costs, prior studies have shown that excessive testing can cause harm in various ways and does not improve outcomes. Interventions to reduce testing should be directed to all caregivers with responsibility for ordering diagnostic tests, in both teaching and nonteaching institutions. PMID- 24145836 TI - Expression and role of neuroglobin in rats with sepsis-associated encephalopathy. AB - OBJECTIVES: To determine the role of neuroglobin in the pathology of sepsis associated encephalopathy and ascertain if neuroglobin has any protective effects against sepsis-associated encephalopathy. DESIGN: Randomized laboratory animal study. SETTING: Research university animal laboratory. SUBJECTS: Two hundred and forty adult male Sprague-Dawley rats. INTERVENTIONS: Rats received cecal puncture and ligation (or sham) surgery to induce sepsis, then broken up into groups based on whether or not the rat developed sepsis-associated encephalopathy as determined by electroencephalograph and evoked potential recordings. The rats were then left untreated to examine the effect of sepsis-associated encephalopathy on neuroglobin, treated with a neuroglobin antisense nucleotide to block gene expression, or given hemin, a neuroglobin inducer. MEASUREMENTS AND MAIN RESULTS: Following sepsis induction, diagnosis, and treatment, the brains were analyzed for both gross and ultrastructural morphology. Also, neuronal neuroglobin immunoreactivity and apoptosis (via terminal uridine nucleotide end labeling) were examined. Blood serum levels were then analyzed for neuroglobin, superoxide dismutase, and malondialdehyde levels. We determined that sepsis associated encephalopathy induces damage evident when examining both gross and ultrastructural morphology, as well as induces neuronal neuroglobin expression. Also, blockade of neuroglobin expression via antisense treatment will exacerbate these pathological effects, while increasing neuroglobin levels via hemin will ameliorate them. Blood analysis found that levels of superoxide dismutase and malondialdehyde mirrored the level of pathology found in the brain, while plasma neuroglobin levels reflected the amount of neuronal neuroglobin immunoreactivity. CONCLUSIONS: We conclude that neuroglobin is involved in the pathogenesis of sepsis-associated encephalopathy and has neuroprotective effects. We also determined that hemin has protective effects against sepsis-associated encephalopathy as well, most probably due to its effect on neuroglobin. PMID- 24145837 TI - Recombinant human annexin A5 inhibits proinflammatory response and improves cardiac function and survival in mice with endotoxemia. AB - OBJECTIVES: Annexin A5 is a 35-kDa protein with high affinity binding to negatively charged phospholipids. However, its effects on sepsis are not known. Our aim was to study the effects of annexin A5 on myocardial tumor necrosis factor-alpha expression, cardiac function, and animal survival in endotoxemia. DESIGN: Prospective experimental study. SETTING: University laboratory. SUBJECTS: Adult male C57BL/6 mice. INTERVENTIONS: Mice were challenged with lipopolysaccharide (4 or 20 mg/kg, i.p.) to induce endotoxemia with and without recombinant human annexin A5 treatment (5 or 10 MUg/kg, i.v.). Cytokine expression and cardiac function were assessed, and animal survival was monitored. MEASUREMENTS AND MAIN RESULTS: Treatment with annexin A5 inhibited myocardial mitogen-activated protein kinase, and nuclear factor-kappaB activation in mice with endotoxemia. Furthermore, annexin A5-treated animals showed significant reductions in myocardial and plasma levels of tumor necrosis factor-alpha and interleukin-1beta while cardiac function was significantly improved during endotoxemia. Additionally, 5-day animal survival was significantly improved by either an immediate or a 4-hour delayed annexin A5 treatment after lipopolysaccharide challenge. Importantly, annexin A5 dose-dependently inhibited lipopolysaccharide binding to a toll-like receptor-4/myeloid differentiation factor 2 fusion protein. CONCLUSIONS: Annexin A5 treatment decreases cytokine expression and improves cardiac function and survival during endotoxemia. These effects of annexin A5 are mediated by its ability to inhibit lipopolysaccharide binding to toll-like receptor-4, leading to reductions in mitogen-activated protein kinase and Akt signaling. Our study suggests that annexin A5 may have therapeutic potential in the treatment of sepsis. PMID- 24145838 TI - Melatonin receptors mediate improvements of survival in a model of polymicrobial sepsis. AB - OBJECTIVES: Melatonin has been demonstrated to improve survival after experimental sepsis via antioxidant effects. Yet, recent evidence suggests that this protective capacity may also rely on melatonin receptor activation. Therefore, the present study was designed to investigate whether selective melatonin receptor-agonist ramelteon may influence survival and immune response in a model of polymicrobial sepsis in rats, wild-type and melatonin receptor MT1/MT2 double knockout mice. DESIGN: Prospective, randomized, controlled study. SETTING: University research laboratory. SUBJECTS: Male Sprague-Dawley rats (200 250 g) and male C3H/HeN wild-type and MT1/MT2 receptor knockout mice (20-22 g). INTERVENTIONS: Animals underwent cecal ligation and incision and remained anesthetized for evaluation of survival for 12 hours (rats: n = 15 per group) or 15 hours (mice: n = 10 per group). Analysis of immune response by means of enzyme linked immunosorbent assay was performed before and 5 hours after cecal ligation and incision (rats only; n = 5 per group). After induction of sepsis, animals were treated IV with vehicle, different doses of melatonin (rats: 0.01/0.1/1.0/10 mg/kg; mice: 1.0 mg/kg), ramelteon, melatonin receptor-antagonist luzindole, ramelteon + luzindole, or melatonin + luzindole (each 1.0 mg/kg). Sham controls underwent laparotomy but not cecal ligation and incision. MEASUREMENTS AND MAIN RESULTS: Compared with vehicle, administration of ramelteon or melatonin significantly improved median survival time in rats (sepsis/melatonin [0.1 mg/kg], 554 min, [1.0 mg/kg] 570 min, [10 mg/kg] 579 min; sepsis/ramelteon, 468 min; each p < 0.001 vs sepsis/vehicle, 303 min) and wild-type mice (sepsis/melatonin, 781 min; sepsis/ramelteon, 701 min; both p < 0.001 vs sepsis/vehicle, 435 min). This effect was completely antagonized by coadministration of luzindole in all groups. Melatonin, ramelteon, or luzindole had no significant effect on survival time in knockout mice. Significantly elevated concentrations of tumor necrosis factor-alpha, interleukin-6, and interleukin-10 were observed 5 hours after cecal ligation and incision in rats (p < 0.05 vs baseline and corresponding sham); neither ramelteon nor melatonin treatment significantly affected immune response. CONCLUSIONS: Melatonin receptors mediate improvements of survival after polymicrobial sepsis in rats and mice; this effect appears to be independent from major alterations of cytokine release. PMID- 24145833 TI - Structure, process, and annual ICU mortality across 69 centers: United States Critical Illness and Injury Trials Group Critical Illness Outcomes Study. AB - OBJECTIVE: Hospital-level variations in structure and process may affect clinical outcomes in ICUs. We sought to characterize the organizational structure, processes of care, use of protocols, and standardized outcomes in a large sample of U.S. ICUs. DESIGN: We surveyed 69 ICUs about organization, size, volume, staffing, processes of care, use of protocols, and annual ICU mortality. SETTING: ICUs participating in the United States Critical Illness and Injury Trials Group Critical Illness Outcomes Study. SUBJECTS: Sixty-nine intensivists completed the survey. MEASUREMENTS AND MAIN RESULTS: We characterized structure and process variables across ICUs, investigated relationships between these variables and annual ICU mortality, and adjusted for illness severity using Acute Physiology and Chronic Health Evaluation II. Ninety-four ICU directors were invited to participate in the study and 69 ICUs (73%) were enrolled, of which 25 (36%) were medical, 24 (35%) were surgical, and 20 (29%) were of mixed type, and 64 (93%) were located in teaching hospitals with a median number of five trainees per ICU. Average annual ICU mortality was 10.8%, average Acute Physiology and Chronic Health Evaluation II score was 19.3, 58% were closed units, and 41% had a 24-hour in-house intensivist. In multivariable linear regression adjusted for Acute Physiology and Chronic Health Evaluation II and multiple ICU structure and process factors, annual ICU mortality was lower in surgical ICUs than in medical ICUs (5.6% lower [95% CI, 2.4-8.8%]) or mixed ICUs (4.5% lower [95% CI, 0.4 8.7%]). We also found a lower annual ICU mortality among ICUs that had a daily plan of care review (5.8% lower [95% CI, 1.6-10.0%]) and a lower bed-to-nurse ratio (1.8% lower when the ratio decreased from 2:1 to 1.5:1 [95% CI, 0.25 3.4%]). In contrast, 24-hour intensivist coverage (p = 0.89) and closed ICU status (p = 0.16) were not associated with a lower annual ICU mortality. CONCLUSIONS: In a sample of 69 ICUs, a daily plan of care review and a lower bed to-nurse ratio were both associated with a lower annual ICU mortality. In contrast to 24-hour intensivist staffing, improvement in team communication is a low-cost, process-targeted intervention strategy that may improve clinical outcomes in ICU patients. PMID- 24145839 TI - Adoption of ICU telemedicine in the United States. AB - OBJECTIVE: ICU telemedicine is a novel approach for providing critical care services from a distance. We sought to study the extent of use and patterns of adoption of this technology in U.S. ICUs. DESIGN: Retrospective study combining a systematic listing of ICU telemedicine installations with hospital characteristic data from the Centers for Medicare and Medicaid Services. We examined adoption over time and compared hospital characteristics between facilities that have adopted ICU telemedicine and those that have not. SETTING: U.S. ICUs. SETTING: U.S. hospitals from 2002 to 2010. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: The number of hospitals using ICU telemedicine increased from 16 (0.4% of total) to 213 (4.6% of total) between 2003 and 2010. The number of ICU beds covered by telemedicine increased from 598 (0.9% of total) to 5,799 (7.9% of total). The average annual rate of ICU bed coverage growth was 101% per year in the first four study years but slowed to 8.1% per year over the last four study years (p < 0.001 for difference in linear trend). Compared with non-adopting hospitals, hospitals adopting ICU telemedicine were more likely to be large (percentage with > 400 beds: 11.1% vs 3.7%, p < 0.001), teaching (percentage with resident coverage: 31.4% vs 21.9%, p = 0.003), and urban (percentage located in metropolitan statistical areas with more than 1 million residents: 45.3% vs 30.1%, p < 0.001). CONCLUSIONS: ICU telemedicine adoption was initially rapid but recently slowed. Efforts are needed to uncover the barriers to future growth, particularly regarding the optimal strategy for using this technology most effectively and efficiently. PMID- 24145840 TI - Inhaled isoflurane sedation during therapeutic hypothermia after cardiac arrest: a case series. AB - OBJECTIVE: Therapeutic hypothermia in the ICU requires mechanical ventilation and sedation. Hypothermia reduces the metabolism of commonly used IV sedatives. The use of long-acting sedative agents may confound neurologic assessment. Volatile anesthetics have been reported to provide protection against ischemia-reperfusion injury and have been safely used in the ICU to provide sedation in trials with shorter wake-up times. There are no clinical studies in this setting. We describe a case series and discuss potential benefits. DESIGN: Retrospective study. SETTINGS: Ten-bed ICU, university hospital. PATIENTS: Twelve patients resuscitated from cardiac arrest with Glasgow Coma Scale score less than or equal to 4. INTERVENTION: Isoflurane sedation with the AnaConDa during 24 hours therapeutic hypothermia, until rewarming. MEASUREMENTS AND MAIN RESULTS: Data were extracted from the computerized ICU chart/monitors, hospital and prehospital charts, and the national death index. Patients were 49-76 years old. Median return of spontaneous circulation was 14 minutes. Glasgow Coma Scale scores were assessed within 24 hours from reaching normal body temperature and compared with outcomes at 6 months: six patients had poor Glasgow Coma Scale scores (< 8) that remained low and all died before 6-month follow-up, whereas another six patients had high scores (> 8) and survived to 6 months with good Cerebral Performance Category. In the ICU, four of the survivors were directly extubated after rewarming while two were once more sedated due to pneumonia requiring invasive ventilator therapy. All patients required norepinephrine to maintain adequate mean arterial pressure. Isoflurane sedation was changed to midazolam in two nonsurviving patients because of hemodynamic instability, which persisted despite the change. CONCLUSIONS: Sedation with volatile anesthetics during therapeutic hypothermia may be a feasible short-acting option with potential postconditioning effects protecting vital organs from ischemia-reperfusion injury. Its measurability and insignificant drug accumulation could facilitate early neurologic assessment. Prospective clinical trials are warranted. PMID- 24145841 TI - Expanded measurements of intra-abdominal pressure do not increase the detection rate of intra-abdominal hypertension: a single-center observational study. AB - OBJECTIVE: Intra-abdominal hypertension may contribute to a poor outcome. Whether limiting intra-abdominal pressure measurements to preselected at-risk patients allows for sufficient detection of intra-abdominal hypertension is unclear. We aimed to clarify whether expanded intra-abdominal pressure monitoring results in an increased detection rate of intra-abdominal hypertension. DESIGN: Retrospective observational study. SETTING: General ICU of University Hospital. PATIENTS: Consecutive adult ICU patients from 2004 to 2011. INTERVENTIONS: Intra abdominal pressure measurements in predefined at-risk patients. MEASUREMENTS AND MAIN RESULTS: Prospectively collected data of 2,696 admissions were divided into three subgroups according to the intra-abdominal pressure measurement policy in different years: 1) 2004-2005, mechanically ventilated patients with at least one additional risk factor for intra-abdominal hypertension (multiple trauma, abdominal surgery, pancreatitis, post-cardiopulmonary resuscitation, fluid resuscitation > 5 L/24 hr, vasoactive or inotropic support, and renal replacement therapy); 2) 2006-2009, all mechanically ventilated patients expected to stay for more than or equal to 24 hours; and 3) 2010-2011, mechanically ventilated patients with a body mass index greater than 30 kg/m, positive end-expiratory pressure more than 10 cm H2O, PaO2/FIO2 less than 300, use of vasopressors/inotropes, pancreatitis, hepatic failure/cirrhosis with ascites, gastrointestinal bleeding, or postlaparotomy. In all, 2,696 patients were studied, and 1,241 patients (46.0%) underwent intra-abdominal pressure monitoring. The intra-abdominal pressure was measured in 31.7%, 55.6%, and 41.1% of patients during the first, second, and third time periods (p < 0.001), and intra-abdominal hypertension (intra-abdominal pressure >= 12 mm Hg) occurred in 19.9%, 20.3%, and 20.1% of patients, respectively (p = 0.972). The mean intra abdominal pressure at admission day was an independent predictor of mortality in patients with intra-abdominal pressure measurements started within the first 24 hours (odds ratio, 1.046 [95% CI, 1.019-1.072]). The mortality of patients with intra-abdominal hypertension was 29.8% versus 18.6% in those without intra abdominal hypertension (p < 0.001). CONCLUSIONS: Expanding the measurement of intra-abdominal pressure to more than 50% of intensive care admissions does not increase the detection rate of intra-abdominal hypertension. In patients with intra-abdominal pressure monitoring, the mean intra-abdominal pressure on the admission day is an independent predictor of mortality. PMID- 24145842 TI - Post-ICU admission fluid balance and pediatric septic shock outcomes: a risk stratified analysis. AB - OBJECTIVE: Observed associations between fluid balance and septic shock outcomes are likely confounded by initial mortality risk. We conducted a risk-stratified analysis of the association between post-ICU admission fluid balance and pediatric septic shock outcomes. DESIGN: Retrospective analysis of an ongoing multicenter pediatric septic shock clinical and biological database. SETTING: Seventeen PICUs in the United States. PATIENTS: Three hundred and seventeen children with septic shock. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: We stratified subjects into three mortality risk categories (low, intermediate, and high) using a validated biomarker-based stratification tool. Within each category, we assessed three fluid balance variables: total fluid intake/kg/d during the first 24 hours, percent positive fluid balance during the first 24 hours, and cumulative percent positive fluid balance up to 7 days. We used logistic regression to estimate the effect of fluid balance on the odds of 28-day mortality, and on complicated course, which we defined as either death within 28 days or persistence of two or more organ failures at 7 days. There were 40 deaths, and 91 subjects had a complicated course. Increased cumulative percent positive fluid balance was associated with mortality in the low-risk cohort (n = 204; odds ratio, 1.035; 95% CI, 1.004-1.066) but not in the intermediate- and high-risk cohorts. No other associations with mortality were observed. Fluid intake, percent positive fluid balance in the first 24 hours, and cumulative percent positive fluid balance were all associated with increased odds of a complicated course in the low-risk cohort but not in the intermediate- and high risk cohorts. CONCLUSIONS: When stratified for mortality risk, increased fluid intake and positive fluid balance after ICU admission are associated with worse outcomes in pediatric septic shock patients with a low initial mortality risk but not in patients at moderate or high mortality risk. PMID- 24145843 TI - Central venous catheter placement by advanced practice nurses demonstrates low procedural complication and infection rates--a report from 13 years of service*. AB - OBJECTIVES: To report procedural characteristics and outcomes from a central venous catheter placement service operated by advanced practice nurses. DESIGN: Single-center observational study. SETTING: A tertiary care university hospital in Sydney, Australia. PATIENTS: Adult patients from the general wards and from critical care areas receiving a central venous catheter, peripherally inserted central catheter, high-flow dialysis catheter, or midline catheter for parenteral therapy between November 1996 and December 2009. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Prevalence rates by indication, site, and catheter type were assessed. Nonparametric tests were used to calculate differences in outcomes for categorical data. Catheter infection rates were determined per 1,000 catheter days after derivation of the denominator. A total of 4,560 catheters were placed in 3,447 patients. The most common catheters inserted were single lumen peripherally inserted central catheters (n = 1,653; 36.3%) and single-lumen central venous catheters (n = 1,233; 27.0%). A small proportion of high-flow dialysis catheters were also inserted over the reporting period (n = 150; 3.5%). Sixty-one percent of all catheters placed were for antibiotic administration. The median device dwell time (in d) differed across cannulation sites (p < 0.001). Subclavian catheter placement had the longest dwell time with a median of 16 days (interquartile range, 8-26 d). Overall catheter dwell was reported at a cumulative 63,071 catheter days. The overall catheter-related bloodstream infection rate was 0.2 per 1,000 catheter days. The prevalence rate of pneumothorax recorded was 0.4%, and accidental arterial puncture (simple puncture with no dilation or cannulation) was 1.3% using the subclavian vein. CONCLUSIONS: This report has demonstrated low complication rates for a hospital-wide service delivered by advance practice nurses. The results suggest that a centrally based service with specifically trained operators can be beneficial by potentially improving patient safety and promoting organizational efficiencies. PMID- 24145844 TI - Prolonged therapeutic hypothermia is more effective in attenuating brain apoptosis in a Swine cardiac arrest model. AB - OBJECTIVES: To investigate whether 48 hours of therapeutic hypothermia is more effective to attenuate brain apoptosis than 24 hours and to determine whether the antiapoptotic effects of therapeutic hypothermia are associated with the suppressions of the cleavage of protein kinase C-delta, the cytosolic release of cytochrome c, and the cleavage of caspase 3 in a swine cardiac arrest model. DESIGN: Prospective laboratory study. SETTING: University laboratory. SUBJECTS: Male domestic pigs (n = 24). INTERVENTIONS: After 6 minutes of no-flow time that was induced by ventricular fibrillation, cardiopulmonary resuscitation was provided, and the return of spontaneous circulation was achieved. The animals were randomly assigned to the following groups: sham, normothermia, 24 hours of therapeutic hypothermia, or 48 hours of therapeutic hypothermia. Therapeutic hypothermia (core temperature, 32-34 degrees C) was maintained for 24 or 48 hours post return of spontaneous circulation, and the animals were rewarmed for 8 hours. At 60 hours post return of spontaneous circulation, the animals were killed, and brain tissues were harvested. MEASUREMENTS AND MAIN RESULTS: We examined cellular apoptosis and neuronal damage in the brain hippocampal cornu ammonis 1 region. We also measured the cleavage of protein kinase C-delta, the cytosolic release of cytochrome c, and the cleavage of caspase 3 in the hippocampus. The 48 hours of therapeutic hypothermia attenuated cellular apoptosis and neuronal damage when compared with normothermia. There was also a decrease in the cleavage of protein kinase C-delta, the cytosolic release of cytochrome c, and the cleavage of caspase 3. However, 24 hours of therapeutic hypothermia did not significantly attenuate cellular apoptosis or neuronal damage. CONCLUSIONS: We found that 48 hours of therapeutic hypothermia was more effective in attenuating brain apoptosis than 24 hours of therapeutic hypothermia. We also found that the antiapoptotic effects of therapeutic hypothermia were associated with the suppressions of the cleavage of protein kinase C-delta, the cytosolic release of cytochrome c, and the cleavage of caspase 3. PMID- 24145845 TI - When policy gets it right: variability in u.s. Hospitals' diagnosis of ventilator associated pneumonia*. AB - OBJECTIVE: The Centers for Disease Control has recently proposed a major change in how ventilator-associated pneumonia is defined. This has profound implications for public reporting, reimbursement, and accountability measures for ICUs. We sought to provide evidence for or against this change by quantifying limitations of the national definition of ventilator-associated pneumonia that was in place until January 2013, particularly with regard to comparisons between, and ranking of, hospitals and ICUs. DESIGN: A prospective survey of a nationally representative group of 43 hospitals, randomly selected from the American Hospital Association Guide (2009). Subjects classified six standardized vignettes of possible cases of ventilator-associated pneumonia as pneumonia or no pneumonia. SUBJECTS: Individuals responsible for ventilator-associated pneumonia surveillance at 43 U.S. hospitals. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: We measured the proportion of standardized cases classified as ventilator-associated pneumonia. Of 138 hospitals consented, 61 partially completed the survey and 43 fully completed the survey (response rate 44% and 31%, respectively). Agreement among hospitals about classification of cases as ventilator-associated pneumonia/not ventilator-associated pneumonia was nearly random (Fleiss kappa 0.13). Some hospitals rated 0% of cases as having pneumonia; others classified 100% as having pneumonia (median, 50%; interquartile range, 33 66%). Although region of the country did not predict case assignment, respondents who described their region as "rural" were more likely to judge a case to be pneumonia than respondents elsewhere (relative risk, 1.25, Kruskal-Wallis chi square, p = 0.03). CONCLUSIONS: In this nationally representative study of hospitals, assignment of ventilator-associated pneumonia is extremely variable, enough to render comparisons between hospitals worthless, even when standardized cases eliminate variability in clinical data abstraction. The magnitude of this variability highlights the limitations of using poorly performing surveillance definitions as methods of hospital evaluation and comparison, and our study provides very strong support for moving to a more objective definition of ventilator-associated complications. PMID- 24145846 TI - Rates and timing of central venous cannulation among patients with sepsis and respiratory arrest admitted by the emergency department*. AB - OBJECTIVES: Clinical guidelines for the acute management of emergency department patients with severe sepsis encourage the placement of central venous catheters. Data examining the timing of central venous catheter insertion among critically ill patients admitted from the emergency department are limited. We examined the hypothesis that prompt central venous catheter insertion during hospitalization among patients admitted from the emergency department acts as a surrogate marker for early aggressive care in the management of critically ill patients. DESIGN: Retrospective cross-sectional analysis of emergency department visits using 2003 2006 discharge data from California, State Inpatient Databases, Healthcare Cost and Utilization Project, Agency for Healthcare Research and Quality. SETTING: General medical or general surgical hospitals (n = 310). PATIENTS: Patient hospitalizations beginning in the emergency department with the two most common diagnoses associated with central venous catheter (sepsis and respiratory arrest). INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: We identified the occurrence and timing of central venous catheter using International Classification of Diseases, 9th Revision, Clinical Modifications procedure codes. The primary outcomes measured were annual central venous catheters per 1,000 hospitalizations that began in the emergency department occurring emergently (procedure day 0), urgently (procedure day 1-2), or late (procedure day 3 or later). A total of 129,288 hospital discharges had evidence of central venous catheter. In 2003, 5,759 central venous catheters were placed emergently compared with 10,469 in 2006. The rate of emergent central venous catheter/1,000 increased annually from 228 in 2003, 239 in 2004, 257 in 2005, up to 269 in 2006. Urgent and late central venous catheter rates trended down (p < 0.001). In a multilevel model, the odds of undergoing emergent central venous catheter relative to 2003 increased annually: 1.08 (95% CI, 1.03-1.12) in 2004, 1.19 (95% CI, 1.14-1.23) in 2005, and 1.28 (95% CI, 1.23-1.33) in 2006. CONCLUSIONS: Central venous catheters are inserted earlier and more frequently among critically ill patients admitted from the emergency department. Earlier central venous catheter insertion may require systematic changes to meet increasing utilization and enhanced mechanisms to measure central venous catheter outcomes. PMID- 24145847 TI - Noninvasive ventilation and breathing-swallowing interplay in chronic obstructive pulmonary disease*. AB - OBJECTIVES: To investigate breathing-swallowing interactions in patients with chronic obstructive pulmonary disease requiring noninvasive mechanical ventilation and, if needed, to develop a technical modification of the ventilator designed to eliminate ventilator insufflations during swallowing. DESIGN: We conducted a prospective, open-label, interventional study. PATIENTS: Fifteen consecutive chronic obstructive pulmonary disease patients with exacerbations requiring ICU admission and NIV. INTERVENTIONS: Swallowing performance and breathing-swallowing interactions were investigated noninvasively by chin electromyography, cervical piezoelectric sensor, and inductive respiratory plethysmography. Two water-bolus sizes (5 and 10 mL) were tested in random order. Swallowing was tested with and without noninvasive mechanical ventilation, in random order. First, a standard mechanical ventilator capable of delivering noninvasive mechanical ventilation was used. Second, a marketed device was equipped with an off-switch for use during swallowing. MEASUREMENTS AND MAIN RESULTS: Swallowing performance and breathing-swallowing interactions were investigated noninvasively by chin electromyography, cervical piezoelectric sensor, and inductive respiratory plethysmography. Two water bolus sizes (5 and 10 mL) were tested in random order. Swallowing was tested with and without noninvasive mechanical ventilation in random order. First, a standard mechanical ventilator capable of delivering noninvasive mechanical ventilation was used. Swallowing efficiency, breathing-swallowing synchronization, and Borg Scale dyspnea scores improved significantly with noninvasive mechanical ventilation. However, swallowing induced ventilator triggering followed by autotriggering. To improve patient-ventilator synchrony, a marketed device was equipped with an off switch for use during swallowing. This device completely eliminated swallowing induced ventilator triggering and postswallow autotriggering. CONCLUSION: Patients with chronic obstructive pulmonary disease admitted to the ICU for acute exacerbations had abnormal breathing-swallowing interactions and dyspnea, which improved with noninvasive mechanical ventilation. Furthermore, a ventilator device with a simple switch-off pushbutton to eliminate insufflations during swallows prevented swallowing-induced ventilator triggering and postswallow autotriggering. PMID- 24145848 TI - Cornell Assessment of Pediatric Delirium: a valid, rapid, observational tool for screening delirium in the PICU*. AB - OBJECTIVE: To determine validity and reliability of the Cornell Assessment of Pediatric Delirium, a rapid observational screening tool. DESIGN: Double-blinded assessments were performed with the Cornell Assessment of Pediatric Delirium completed by nursing staff in the PICU. These ratings were compared with an assessment by consultation liaison child psychiatrist using the Diagnostic and Statistical Manual IV criteria as the "gold standard" for diagnosis of delirium. An initial series of duplicate Cornell Assessment of Pediatric Delirium assessments were performed in blinded fashion to assess interrater reliability. Nurses recorded the time required to complete the Cornell Assessment of Pediatric Delirium screen. SETTING: Twenty-bed general PICU in a major urban academic medical center over a 10-week period, March-May 2012. PATIENTS: One hundred eleven patients stratified over ages ranging from 0 to 21 years and across developmental levels. INTERVENTION: Two hundred forty-eight paired assessments completed. MEASUREMENTS AND MAIN RESULTS: The Cornell Assessment of Pediatric Delirium had an overall sensitivity of 94.1% (95% CI, 83.8-98.8%) and specificity of 79.2% (95% CI, 73.5-84.9%). Overall Cronbach's alpha of 0.90 was observed, with a range of 0.87-0.90 for each of the eight items, indicating good internal consistency. A scoring cut point of 9 demonstrated good interrater reliability of the Cornell Assessment of Pediatric Delirium when comparing results of the screen between nurses (overall kappa = 0.94; item range kappa = 0.68-0.78). In patients without significant developmental delay, sensitivity was 92.0% (95% CI, 85.7 98.3%) and specificity was 86.5% (95% CI, 75.4-97.6%). In developmentally delayed children, the Cornell Assessment of Pediatric Delirium showed decreased specificity of 51.2% (95% CI, 24.7-77.8%) but sensitivity remained high at 96.2% (95% CI, 86.5-100%). The Cornell Assessment of Pediatric Delirium takes less than 2 minutes to complete. CONCLUSIONS: With an overall prevalence rate of 20.6% in our study population, delirium is a common problem in pediatric critical care. The Cornell Assessment of Pediatric Delirium is a valid, rapid, observational nursing screen that is urgently needed for the detection of delirium in PICU settings. PMID- 24145849 TI - The prevalence and significance of methicillin-resistant Staphylococcus aureus colonization at admission in the general ICU Setting: a meta-analysis of published studies. AB - OBJECTIVE: To estimate the prevalence and significance of nasal methicillin resistant Staphylococcus aureus colonization in the ICU and its predictive value for development of methicillin-resistant S. aureus infection. DATA SOURCES: MEDLINE and EMBASE and reference lists of all eligible articles. STUDY SELECTION: Studies providing raw data on nasal methicillin-resistant S. aureus colonization at ICU admission, published up to February 2013. Analyses were restricted in the general ICU setting. Medical, surgical, and interdisciplinary ICUs were eligible. ICU studies referring solely on highly specialized ICUs populations and reports on methicillin-resistant S. aureus outbreaks were excluded. DATA EXTRACTION: Two authors independently assessed study eligibility and extrapolated data in a blinded fashion. The two outcomes of interest were the prevalence estimate of methicillin-resistant S. aureus nasal colonization at admission in the ICU and the sensitivity/specificity of colonization in predicting methicillin-resistant S. aureus-associated infections. DATA SYNTHESIS: Meta-analysis, using a random effect model, and meta-regression were performed. Pooled data extracted from 63,740 evaluable ICU patients provided an estimated prevalence of methicillin resistant S. aureus nasal colonization at admission of 7.0% (95% CI, 5.8-8.3). Prevalence was higher for North American studies (8.9%; 95% CI, 7.1-10.7) and for patients screened using polymerase chain reaction (14.0%; 95% CI, 9.6-19). A significant per year increase in methicillin-resistant S. aureus colonization was also noted. In 17,738 evaluable patients, methicillin-resistant S. aureus infections (4.1%; 95% CI, 2.0-6.8) developed in 589 patients. The relative risk for colonized patients was 8.33 (95% CI, 3.61-19.20). Methicillin-resistant S. aureus nasal carriage had a high specificity (0.96; 95% CI, 0.90-0.98) but low sensitivity (0.32; 95% CI, 0.20-0.48) to predict methicillin-resistant S. aureus associated infections, with corresponding positive and negative predictive values at 0.25 (95% CI, 0.11-0.39) and 0.97 (95% CI, 0.83-1.00), respectively. CONCLUSIONS: Among ICU patients, 5.8-8.3% of patients are colonized by methicillin-resistant S. aureus at admission, with a significant upward trend. Methicillin-resistant S. aureus colonization is associated with a more than eight fold increase in the risk of associated infections during ICU stay, and methicillin-resistant S. aureus infection develops in one fourth of patients who are colonized with methicillin-resistant S. aureus at admission to the ICU. PMID- 24145851 TI - Tuning solid-state blue and red luminescence by the formation of solvate crystals. AB - Tuning and controlling the solid-state luminescence of molecular solids play a key role in developing multi-color displays and tunable dye laser. In this work, we report the tunable blue and red luminescence by the formation of solvate crystals of 1,4-bis(5-phenyl-2-oxazolyl)benzene (POPOP) and 4-(dicyanomethylene) 2-methyl-6-(4-dimethylaminostyryl)-4H-pyran (DCM). Upon introduction of guest solvents (chloroform and dichloromethane) into the POPOP and DCM host matrices, the obtained solvate crystals exhibit an alternated stacking arrangement, interaction fashion, and crystal symmetry compared with the pristine chromophore solids. Furthermore, the solvates of POPOP (CCl3H) and DCM (CCl2H2) present changeable luminescent properties (such as one-/two-photon emissive wavelength, fluorescence lifetime and photoluminescent quantum yield) in the blue/red regions relative to the pristine POPOP and DCM. In addition, the second harmonic generation can also be obtained for the DCM (CCl2H2) due to the transformation of the centrosymmetric to a non-centrosymmetric structure from pristine DCM. Periodic density functional theoretical calculations suggest that the guest solvents do not participate in the frontier orbital distribution within the solvate crystals. Therefore, by the combination of experimental and theoretical studies on the solvate crystals, this work not only reports the supramolecular assembly of new types of host-guest photoactive systems, but also provides a detailed understanding of the electronic structures of the solid-state luminescent materials. PMID- 24145850 TI - Transient regional hypothermia applied to a traumatic limb attenuates distant lung injury following blast limb trauma. AB - OBJECTIVES: Explosive traumatic injury to an extremity may lead to both local and distant organ injury. Regional traumatic tissue hypothermia has been reported to offer systemic protection; here we investigated the protective effects of regional limb hypothermia on local tissue trauma and the lungs. Furthermore, the optimal duration of regional traumatic limb hypothermic treatment was also evaluated. DESIGN: Prospective, controlled, animal study. SETTING: University research laboratory. SUBJECTS: Adult male Sprague-Dawley rats. INTERVENTIONS: Anesthetized rats were randomized to sham, blast limb trauma, sham and regional hypothermia for 30 minutes, and blast limb trauma and regional hypothermia for 30 minutes, 60 minutes, and 6 hours. Blast limb trauma was created using chartaceous electricity detonators. MEASUREMENTS AND MAIN RESULTS: Distant lung and local tissue injury following blast limb trauma were attenuated by regional traumatic limb hypothermic treatment for 30 minutes, 60 minutes, and 6 hours reflected by reduced lung histopathological changes and water content. Regional traumatic limb hypothermic treatment for 60 minutes and 6 hours failed to further attenuate distant lung and local tissue injury compared with regional traumatic limb hypothermic treatment for 30 minutes. Inhibition of cystathionine gamma lyase/hydrogen sulfide was reduced by regional traumatic limb hypothermic treatment for 30 minutes in blast limb trauma rats. A surrogate of neutrophil accumulation, myeloperoxidase activity, and release of tumor necrosis factor alpha and interleukin-6 were also attenuated by regional traumatic limb hypothermic treatment for 30 minutes in blast limb trauma rats. Oxidative stress was alleviated by regional traumatic limb hypothermic treatment for 30 minutes evidenced by reduction of hydrogen peroxide and malondialdehyde and an increase of superoxide dismutase and glutathione in blast limb trauma rats. CONCLUSIONS: Our data indicate that regional traumatic limb hypothermic treatment for 30 minutes offers both local protection for traumatic tissue and systemic protection for the lungs, which is likely associated with restoration of the cystathionine gamma-lyase/hydrogen sulfide pathway and inhibition of the inflammatory response and oxidative stress. PMID- 24145852 TI - Adolescent risk taking, cocaine self-administration, and striatal dopamine signaling. AB - Poor decision making and elevated risk taking, particularly during adolescence, have been strongly linked to drug use; however the causal relationships among these factors are not well understood. To address these relationships, a rat model (the Risky Decision-making Task; RDT) was used to determine whether individual differences in risk taking during adolescence predict later propensity for cocaine self-administration and/or whether cocaine self-administration causes alterations in risk taking. In addition, the RDT was used to determine how risk taking is modulated by dopamine signaling, particularly in the striatum. Results from these experiments indicated that greater risk taking during adolescence predicted greater intake of cocaine during acquisition of self-administration in adulthood, and that adult cocaine self-administration in turn caused elevated risk taking that was present following 6 weeks of abstinence. Greater adolescent risk taking was associated with lower striatal D2 receptor mRNA expression, and pharmacological activation of D2/3 receptors in the ventral, but not dorsal, striatum induced a decrease in risk taking. These findings indicate that the relationship between elevated risk taking and cocaine self-administration is bi directional, and that low striatal D2 receptor expression may represent a predisposing factor for both maladaptive decision making and cocaine use. Furthermore, these findings suggest that striatal D2 receptors represent a therapeutic target for attenuating maladaptive decision making when choices include risk of adverse consequences. PMID- 24145853 TI - A putative candidate for the recessive gall midge resistance gene gm3 in rice identified and validated. AB - KEY MESSAGE: We report here tagging and fine-mapping of gm3 gene, development of a functional marker for it and its use in marker-assisted selection. The recessive rice gall midge resistance gene, gm3 identified in the rice breeding line RP2068-18-3-5 confers resistance against five of the seven Indian biotypes of the Asian rice gall midge Orseolia oryzae. We report here tagging and fine mapping of gm3 gene, development of a functional marker for it and demonstrated its use in marker-assisted selection (MAS). A mapping population consisting of 302 F10 recombinant inbred lines derived from the cross TN1 (susceptible)/RP2068 18-3-5, was screened against gall midge biotype 4 (GMB4) and analyzed with a set of 89 polymorphic SSR markers distributed uniformly across the rice genome. Two SSR markers, RM17480 and gm3SSR4, located on chromosome 4L displayed high degree of co-segregation with the trait phenotype and flanked the gene. In silico analysis of the genomic region spanning these two markers contained 62 putatively expressed genes, including a gene encoding an NB-ARC (NBS-LRR) domain containing protein. A fragment of this gene was amplified with the designed marker, NBcloning 0.9 Kb from the two susceptible TN1, Improved Samba Mahsuri (B95-1) and two resistant cultivars, RP 2068-18-3-5 and Phalguna (with Gm2 gene). The amplicons were observed to be polymorphic between the susceptible and resistant genotypes and hence were cloned and sequenced. A new primer, gm3del3, which was designed based on sequence polymorphism, amplified fragments with distinct size polymorphism among RP2068-18-3-5, Phalguna and TN1 and B95-1 and displayed no recombination in the entire mapping population. Expression of the candidate NB ARC gene in the susceptible TN1 and the resistant RP2068-18-3-5 plants following infestation with GMB4 was analyzed, through real-time reverse transcription PCR. Results showed twofold enhanced expression in RP2068-18-3-5 plants, but not in TN1 plants, 120 h after infestation. Amino acid sequence and structure analysis of the proteins coded by different alleles of gm3 gene showed deletion of eight amino acids due to an early stop codon in RP2068-18-3-5 resulting in a change in the functional domain of the protein. The gm3del3 was used as a functional marker for introgression of gm3 gene into the genetic background of the elite bacterial blight resistant cultivar Improved Samba Mahsuri (B95-1) through MAS. PMID- 24145854 TI - Priming of T follicular helper cells by dendritic cells. AB - T follicular helper cells (Tfh) are required to generate long-lived antibody responses, which confer long-term protection to pathogens following vaccination or infection. Despite significant advances in the field, however, little is known about the early steps that drive Tfh cell differentiation. In this review, we will discuss the mechanisms by which dendritic cells promote the initial commitment of activated CD4(+) T cells to the Tfh cell differentiation pathway. PMID- 24145855 TI - The fate of CD4+ T cells under tolerance-inducing stimulation: a modeling perspective. AB - Non-depleting anti-CD4 monoclonal antibodies (MAbs) induce long-term dominant tolerance mediated by regulatory T cells in several animal models of transplantation, allergy and autoimmunity. However, despite many studies on tolerance induction following CD4 blockade, the consequences of this intervention on T-cell kinetics are still unknown. Mathematical models have been useful to understand lymphocyte dynamics, estimating rates of proliferation and cell death following an intervention. Using the same strategy, we found that CD4(+) T cells activated in vitro in the presence of non-depleting anti-CD4 MAbs are prevented from undergoing optimal proliferation and show a higher frequency of apoptosis. Although the changes are small, during the course of a proliferative response, they lead to very distinct final levels of cell numbers. The importance of these mechanisms, predicted by the mathematical model, was validated by showing that lck-driven Bcl-x(L) transgenic mice, bearing T cells resistant to apoptosis, fail to become tolerant to skin grafts following CD4-blockade. Our data show that, in addition to induction of regulatory T cells, CD4 blockade has a marked effect in the effector T-cell pool by the combined action of hindering proliferation while favoring apoptosis. It is, therefore, the combination of all those mechanisms that leads to stable tolerance. PMID- 24145856 TI - Co-expression of S. Typhi GroEL and IL-22 gene augments immune responses against Salmonella infection. AB - Recombinant DNA vaccines represent a novel method for generating in situ expression of vaccine antigens. Intramuscular injections of naked DNA are able to elicit potent humoral and cellular immune responses but still numerous factors limit the immunogenicity of DNA vaccines. Co-expression of cytokines with antigen encoding genes in DNA vectors can improve the immune responses and modify Th1/Th2 balance. In this study, the immunomodulatory effect of Interleukin 22 (IL-22) as an adjuvant was studied by DNA vaccination with S. Typhi Heat shock protein 60 (HSP60/GroEL) in mice. Further, DNA construct of IL-22 gene fused with GroEL was developed and immunization studies were carried out in mice. DNA vaccination with GroEL alone stimulated humoral and cell-mediated immune responses. Co immunization (IL-22+GroEL) further resulted in increase in T-cell proliferative responses, antibody titres (IgG, IgG1, IgG2a) and secretion of IFNgamma (Th1), IL 1beta and Th2 (IL-4, IL-6) cytokines. Co-expression (IL-22-GroEL DNA) also promoted antibody titres and cytokine levels were significantly higher as compared to co-immunized group. A reduction in bacterial load in spleen, liver and intestine was seen in all the immunized groups as compared to control, with least organ burden in fusion DNA construct group (co-expression). Improved protective efficacy (90%) against lethal challenge by Salmonella was observed with IL-22-GroEL co-expressing DNA vector as compared with plasmid encoding GroEL only (50-60%) or co-immunization group (75-80%). This study thus shows that co expression of IL-22 and GroEL genes enhances the immune responses and protective efficacy, circumventing the need of any adjuvant. PMID- 24145857 TI - Follicular T-helper cells: controlled localization and cellular interactions. AB - Affinity-matured, isotype-switched antibodies afford humoral protection against microbial infections. Cells capable of producing such antibodies are derived from the germinal center (GC) formed during a T-dependent B-cell response. Follicular T-helper (TFH) cells are a recently defined subset of CD4 T cells that are specialized in promoting the B-cell response and GC reaction. These cells exhibit a CXCR5(+)ICOS(hi)PD-1(hi) surface phenotype, express a high level of transcriptional repressor Bcl-6 and possess a unique ability to reside in the GC. Insights into how TFH cells develop and function promise to refine our strategies toward more effective antibody-based vaccines and therapies for humoral autoimmunity. In this review, we summarize the current understanding of how TFH associated molecules regulate dynamic localization and B-cell-interacting properties of these cells, as both aspects are at the core of being TFH cells. PMID- 24145858 TI - Human T follicular helper (Tfh) cells and disease. AB - The generation of protective antibodies by B cells following natural infection or vaccination requires 'help' from CD4(+) T cells. T follicular helper (Tfh) cells are the specialized CD4(+) T cell subset that has evolved the appropriate mechanisms to induce the activation and differentiation of B cells into immunoglobulin (Ig) secreting cells. As such, appropriate control of Tfh cell generation and function is essential to human health as overactivation is likely to result in autoimmunity, whereas underactivation is often associated with immunodeficiency. Furthermore, an understanding of the regulation of these cells may be invaluable to improved vaccine development strategies. Traditionally Tfh cells have been identified by their anatomical location in secondary lymphoid tissues, which has hindered the study of these cells in humans as access to these tissues is often not feasible. However, recent studies have identified the circulating counterparts to tissue Tfh cells and with this has come a wealth of knowledge gained from the study of these cells in human disease. Here we review some of the recent developments on the role of human Tfh cells in health and disease. PMID- 24145860 TI - Viability of Saccharomyces cerevisiae incorporated within silica and polysaccharide hosts monitored via time-resolved fluorescence. AB - The viability of Saccharomyces cerevisiae in biocompatible polymers under different growth conditions and studied using time-resolved fluorescence techniques is presented. Two fluorophores, the viscosity sensitive probe 4-(4 (dimethylamino)styryl)-N-methyl-pyridiniumiodine (DASPMI) and the yeast viability stain 2-chloro-4-(2,3-dihydro-3-methyl-(benzo-1,3-thiazol-2-yl)-methylidene)-1 phenylquinolinium iodide (FUN-1) are used to elucidate information on the incorporated yeast cell viability. Variations in cell viscosity, which are indicative of the cell state, were obtained using DASPMI. Prior to observing FUN 1 in yeast cells using fluorescence lifetime imaging, its photophysics in solution and heterogeneous media were investigated. Time-resolved emission spectra were measured and analysed to associate lifetimes to the spectral emission. Preliminary results show that monitoring the fluorescence lifetime of FUN-1 may give a useful insight into cellular metabolism. The results indicate that both fluorophores may be used to monitor the entrapped yeast cell viability, which is important for in vitro studies and applications, such as that in the biofuel industry, where Saccharomyces cerevisiae are required to remain active in high ethanol environments. PMID- 24145859 TI - Self-reported sleep and beta-amyloid deposition in community-dwelling older adults. AB - IMPORTANCE: Older adults commonly report disturbed sleep, and recent studies in humans and animals suggest links between sleep and Alzheimer disease biomarkers. Studies are needed that evaluate whether sleep variables are associated with neuroimaging evidence of beta-amyloid (Abeta) deposition. OBJECTIVE To determine the association between self-reported sleep variables and Abeta deposition in community-dwelling older adults. DESIGN, SETTING, AND PARTICIPANTS: Cross sectional study of 70 adults (mean age, 76 [range, 53-91] years) from the neuroimaging substudy of the Baltimore Longitudinal Study of Aging, a normative aging study. EXPOSURE Self-reported sleep variables. MAIN OUTCOMES AND MEASURES beta-Amyloid burden, measured by carbon 11-labeled Pittsburgh compound B positron emission tomography distribution volume ratios (DVRs). RESULTS: After adjustment for potential confounders, reports of shorter sleep duration were associated with greater Abeta burden, measured by mean cortical DVR (B = 0.08 [95% CI, 0.03 0.14]; P = .005) and precuneus DVR (B = 0.11 [0.03-0.18]; P = .007). Reports of lower sleep quality were associated with greater Abeta burden measured by precuneus DVR (B = 0.08 [0.01-0.15]; P = .03). CONCLUSIONS AND RELEVANCE: Among community-dwelling older adults, reports of shorter sleep duration and poorer sleep quality are associated with greater Abeta burden. Additional studies with objective sleep measures are needed to determine whether sleep disturbance causes or accelerates Alzheimer disease. PMID- 24145861 TI - P2X4 promotes interleukin-1beta production in osteoarthritis via NLRP1. AB - Interleukin-1beta (IL-1beta) has a significant role in osteoarthritis (OA). The purinergic receptor, P2X4, has previously been implicated in IL-1beta secretion. The NLRP1 inflammasome mediates the production of IL-1beta in inflammatory disorders. However, it is unknown whether P2X4 modulates NLRP1-mediated IL-1beta release. In the present study, the correlation between the P2X4 receptor and NLRP1 was investigated in OA fibroblast-like synoviocytes (OAFLS). The expression of P2X4 and NLRP1 was detected in the OAFLS. The OAFLS were stimulated with P2X4 and the levels of IL-1beta and matrix metalloproteinases (MMPs) were measured. To determine whether P2X4 is involved in NLRP1-triggered IL-1beta production, NLRP1 small interfering RNA (siRNA) was used. In the OAFLS, a markedly higher expression of P2X4 and NLRP1 was revealed compared with that in the normal FLS. OAFLS stimulated by P2X4 resulted in concentration-dependent increases in the production of IL-1beta, MMP-3 and MMP-9. Furthermore, P2X4-mediated IL-1beta production was attenuated by the NLRP1 siRNA. The results of the present study indicate that P2X4 induced IL-1beta, MMP-3 and MMP-9 production in the OAFLS. IL 1beta induced by P2X4 is mediated via NLRP1. P2X4/NLRP1 may be important in the pathogenesis of OA and may represent a novel therapeutic target. PMID- 24145863 TI - The protein invasion: a broad review on the origin of the translational system. AB - Translation, coded peptide synthesis, arguably exists at the heart of modern cellular life. By orchestrating an incredibly complex interaction between tRNAs, mRNAs, aaRSs, the ribosome, and numerous other small molecules, the translational system allows the interpretation of data in the form of DNA to create massively complex proteins which control and enact almost every cellular function. A natural question then, is how did this system evolve? Here we present a broad review of the existing theories of the last two decades on the origin of the translational system. We attempt to synthesize the wide variety of ideas as well as organize them into modular components, addressing the evolution of the peptide RNA interaction, tRNA, mRNA, the ribosome, and the first proteins separately. We hope to provide both a comprehensive overview of the literature as well as a framework for future discussions and novel theories. PMID- 24145862 TI - Molecular evolutionary analysis of vertebrate transducins: a role for amino acid variation in photoreceptor deactivation. AB - Transducin is a heterotrimeric G protein that plays a critical role in phototransduction in the rod and cone photoreceptor cells of the vertebrate retina. Rods, highly sensitive cells that recover from photoactivation slowly, underlie dim-light vision, whereas cones are less sensitive, recover more quickly, and underlie bright-light vision. Transducin deactivation is a critical step in photoreceptor recovery and may underlie the functional distinction between rods and cones. Rods and cones possess distinct transducin alpha subunits, yet they share a common deactivation mechanism, the GTPase activating protein (GAP) complex. Here, we used codon models to examine patterns of sequence evolution in rod (GNAT1) and cone (GNAT2) alpha subunits. Our results indicate that purifying selection is the dominant force shaping GNAT1 and GNAT2 evolution, but that GNAT2 has additionally been subject to positive selection operating at multiple phylogenetic scales; phylogeny-wide analysis identified several sites in the GNAT2 helical domain as having substantially elevated dN/dS estimates, and branch-site analysis identified several nearby sites as targets of strong positive selection during early vertebrate history. Examination of aligned GNAT and GAP complex crystal structures revealed steric clashes between several positively selected sites and the deactivating GAP complex. This suggests that GNAT2 sequence variation could play an important role in adaptive evolution of the vertebrate visual system via effects on photoreceptor deactivation kinetics and provides an alternative perspective to previous work that focused instead on the effect of GAP complex concentration. Our findings thus further the understanding of the molecular biology, physiology, and evolution of vertebrate visual systems. PMID- 24145864 TI - PillCam small bowel capsule endoscopy gastric passage interval association with patient's complaints and pathological findings: a prospective study. AB - BACKGROUND AND AIMS: Prolonged gastric transit interval of small bowel video capsule endoscopy (SBCE) can potentially indicate a motility disorder and disrupt whole small bowel visualization. The aim of this study was to prospectively examine the association of prolonged gastric passage interval with symptoms, anthropometric and laboratory factors, and factors related to the SBCE examination, such as indications and pathological findings. MATERIALS AND METHODS: This was a prospective single-center study that included 100 patients who underwent SBCE for any indication. Before the examination, clinical, demographic, and anthropometric data were recorded. The patients filled the Gastroparesis Cardinal Symptoms Index (GCSI) questionnaire. We assessed the difference in the study parameters between the prolonged gastric transit (>=45 min) group and the group with a normal gastric transit. RESULTS: Seventy-six patients had normal gastric passage interval and 24 patients had prolonged gastric passage interval. No significant differences were found between the groups in age, sex, prevalence of diabetes mellitus, use of antimotility drugs, indications for the exam and levels of hemoglobin, C-reactive protein, and albumin. Esophageal and small bowel transition intervals did not vary between both groups. The mean score for any GCSI item and the mean total GCSI score did not differ significantly between the normal and the prolonged gastric passage interval groups. There were no significant differences between the groups in pathological findings in the small bowel. CONCLUSION: In the study population, prolonged SBCE gastric transit interval had no clinical significance, and therefore, probably does not mandate any further gastrointestinal evaluation. PMID- 24145865 TI - Medical resource utilization and associated costs in patients with ulcerative colitis in the UK: a chart review analysis. AB - OBJECTIVE: Limited evidence is available on the economic burden of ulcerative colitis (UC) in the UK, particularly relating to the impact of relapse frequency on direct medical costs. This study identifies and assesses medical resource utilization (MRU) and associated direct costs in mild and moderate UC patients in the UK. PATIENTS AND METHODS: A retrospective chart review of patients with mild to-moderate UC diagnosed at least 1 year before the study was performed. From 33 general practitioner (GP) and 34 gastroenterologist sites, charts of the last three UC patients fulfilling the inclusion criteria were reviewed. Descriptive statistics were calculated for MRU and 2011 costs (GBL) by number of relapses. RESULTS: The study population included 201 patients with a mean age of 39.9 years; 44% were women and the mean disease duration was 7.4 years. UC-related costs of each MRU category increased with the number of relapses. Comparing patients without relapse with those with more than two relapses, the mean annual UC-related costs were L14 versus L2556 for hospitalizations; L218 versus L988 for visits (including nurse, GP, specialist, and other visits); L21 versus L1303 for procedures; L17 versus L188 for diagnostics; and L1168 versus L6660 for all-cause total costs. Age, sex, and site of data reporting (GP vs. gastroenterologist) were not associated with MRU or costs. CONCLUSION: Patients with mild-to-moderate UC incurred considerable costs that increased markedly with the number of relapses. These findings support the importance of maintenance therapies in UC that reduce or prevent relapses. Quantifying the relationship between relapse rate and costs will inform future health economic studies. PMID- 24145866 TI - Separation of spermatogenic cell types using STA-PUT velocity sedimentation. AB - Mammalian spermatogenesis is a complex differentiation process that occurs in several stages in the seminiferous tubules of the testes. Currently, there is no reliable cell culture system allowing for spermatogenic differentiation in vitro, and most biological studies of spermatogenic cells require tissue harvest from animal models like the mouse and rat. Because the testis contains numerous cell types--both non-spermatogenic (Leydig, Sertoli, myeloid, and epithelial cells) and spermatogenic (spermatogonia, spermatocytes, round spermatids, condensing spermatids and spermatozoa)--studies of the biological mechanisms involved in spermatogenesis require the isolation and enrichment of these different cell types. The STA-PUT method allows for the separation of a heterogeneous population of cells--in this case, from the testes--through a linear BSA gradient. Individual cell types sediment with different sedimentation velocity according to cell size, and fractions enriched for different cell types can be collected and utilized in further analyses. While the STA-PUT method does not result in highly pure fractions of cell types, e.g. as can be obtained with certain cell sorting methods, it does provide a much higher yield of total cells in each fraction (~1 x 10(8) cells/spermatogenic cell type from a starting population of 7-8 x 10(8) cells). This high yield method requires only specialized glassware and can be performed in any cold room or large refrigerator, making it an ideal method for labs that have limited access to specialized equipment like a fluorescence activated cell sorter (FACS) or elutriator. PMID- 24145867 TI - Association of navicular drop and selected lower-limb biomechanical measures during the stance phase of running. AB - There is evidence to suggest that navicular drop measures are associated with specific lower-extremity gait biomechanical parameters. The aim of this study was to examine the relationship between navicular drop and a) rearfoot eversion excursion, b) tibial internal rotation excursion, c) peak ankle inversion moment, and d) peak knee adduction moment during the stance phase of running. Sixteen able-bodied men having an average age of 28.1 (SD=5.30) years, weight of 81.5 (SD=10.40) kg, height of 179.1 (SD=5.42) cm volunteered and ran barefoot at 170 steps/minute over a force plate. Navicular drop measures were negatively correlated with tibial internal rotation excursion (r=-0.53, P=.01) but not with rearfoot eversion excursion (r=-0.19; P=.23). Significant positive correlations were found between navicular drop and peak knee adduction moment (r=.62, P<.01) and peak ankle inversion moment (r=.60, P<.01). These findings suggest that a low navicular drop measure could be associated with increasing tibial rotation excursion while high navicular drop measure could be associated with increased peak ankle and knee joint moments. These findings indicate that measures of navicular drop explained between 28% and 38% of the variability for measures of tibial internal rotation excursion, peak knee adduction moment and peak ankle inversion moments. PMID- 24145869 TI - THALAMIC PARCELLATION FROM MULTI-MODAL DATA USING RANDOM FOREST LEARNING. AB - The thalamus sub-cortical gray matter structure consists of contiguous nuclei, each individually responsible for communication between various cerebral cortex and midbrain regions. These nuclei are differentially affected in neurodegenerative diseases such as multiple sclerosis and Alzheimer's. However thalamic parcellation of the nuclei, manual or automatic, is difficult given the limited contrast in any particular magnetic resonance (MR) modality. Several groups have had qualitative success differentiating nuclei based on spatial location and fiber orientation information in diffusion tensor imaging (DTI). In this paper, we extend these principles by combining these discriminating dimensions with structural MR and derived information, and by building random forest learners on the resultant multi-modal features. In training, we form a multi-dimensional feature per voxel, which we associate with a nucleus classification from a manual rater. Learners are trained to differentiate thalamus from background and thalamic nuclei from other nuclei. These learners inform the external forces of a multiple object level set model. Our cross validated quantitative results on a set of twenty subjects show the efficacy and reproducibility of our results. PMID- 24145868 TI - Functional role of the flexible N-terminal extension of FKBP38 in catalysis. AB - FKBP38 regulates apoptosis through unique interactions with multiple regulators including Bcl-2. Interestingly, the peptidylprolyl isomerase activity of FKBP38 is only detectable when it binds to calcium-saturated calmodulin (CaM/Ca(2+)). This, in turn, permits the formation of a complex with Bcl-2. FKBP38 thereby provides an important link between isomerase activity and apoptotic pathways. Here, we show that the N-terminal extension (residues 1-32) preceding the catalytic domain of FKBP38 has an autoinhibitory activity. The core isomerase activity of FKBP38 is inhibited by transient interactions involving the flexible N-terminal extension that precedes the catalytic domain. Notably, CaM/Ca(2+) binds to this N-terminal extension and thereby releases the autoinhibitory contacts between the N-terminal extension and the catalytic domain, thus potentiating the isomerase activity of FKBP38. Our data demonstrate how CaM/Ca(2+) modulates the catalytic activity of FKBP38. PMID- 24145870 TI - Antioxidant and anticlastogenic capacity of prickly pear juice. AB - Plants belonging to the genus Opuntia spp. are the most abundant of the Cactaceae family, grown throughout America and the Mediterranean central area. Its fruit, known as cactus pear or prickly pear, is an oval berry grouped in different colors. Some studies have shown its antioxidant activities which may help in preventing chronic pathologies such as diabetes. The purpose of the study was to evaluate the antioxidant capacity of three varieties of prickly pear juice (red purple, white-green and yellow-orange) in five different concentrations (100, 250, 500, 750, and 1000 mg/mL) by DPPH (1,1-diphenyl-2-picrylhydrazyl radical) colorimetric method, selecting the best variety to determine its anticlastogenic potential against methyl methanesulfonate (MMS). The results indicate that the highest antioxidant was found in the juice of the prickly pear red-purple variety (PPRP), in all concentrations. Its anticlastogenic potential was therefore evaluated with a micronucleus assay. The experiment was run over two weeks. A negative control was included along with a positive control with MMS (40 mg/kg), a group of mice treated with PPRP (25 mL/kg), and three groups with PPRP (in doses of 25, 16.5 and 8.3 mL/kg) plus the mutagen. The PPRP was administered daily by oral gavage and the MMS was injected intraperitoneally five days prior to the end of the experiment. Blood samples were obtained at 0, 24, 48, 72 and 96 h in order to determine the frequency of micronucleated polychromatic erythrocytes (MNPE). The results indicated that PPRP is not a genotoxic agent, on the contrary, it may reduce the number of MNPE. In this regard, the PPRP showed an anticlastogenic effect directly proportional to its concentrations. Thus, the highest protection was obtained with a concentration of 25 mL/kg after 48 h of treatment. PMID- 24145871 TI - Health benefits of methylxanthines in cacao and chocolate. AB - One may wonder why methylxanthines are so abundant in beverages used by humans for centuries, or in cola-drinks that have been heavily consumed since their appearance. It is likely that humans have stuck to any brew containing compounds with psychoactive properties, resulting in a better daily life, i.e., more efficient thinking, exploring, hunting, etc., however, without the serious side effects of drugs of abuse. The physiological effects of methylxanthines have been known for a long time and they are mainly mediated by the so-called adenosine receptors. Caffeine and theobromine are the most abundant methylxanthines in cacao and their physiological effects are notable. Their health-promoting benefits are so remarkable that chocolate is explored as a functional food. The consequences of adenosine receptor blockade by natural compounds present in cacao/chocolate are here reviewed. Palatability and health benefits of methylxanthines, in general, and theobromine, in particular, have further contributed to sustain one of the most innocuous and pleasant habits: chocolate consumption. PMID- 24145875 TI - Is methicillin-susceptible Staphylococcus aureus (MSSA) sequence type 398 confined to Northern Manhattan? Rising prevalence of erythromycin- and clindamycin-resistant MSSA clinical isolates in the United States. PMID- 24145874 TI - Treatment-naive individuals are the major source of transmitted HIV-1 drug resistance in men who have sex with men in the Swiss HIV Cohort Study. AB - BACKGROUND: Human immunodeficiency virus type 1 (HIV-1) transmitted drug resistance (TDR) can compromise antiretroviral therapy (ART) and thus represents an important public health concern. Typically, sources of TDR remain unknown, but they can be characterized with molecular epidemiologic approaches. We used the highly representative Swiss HIV Cohort Study (SHCS) and linked drug resistance database (SHCS-DRDB) to analyze sources of TDR. METHODS: ART-naive men who have sex with men with infection date estimates between 1996 and 2009 were chosen for surveillance of TDR in HIV-1 subtype B (N = 1674), as the SHCS-DRDB contains pre ART genotypic resistance tests for >69% of this surveillance population. A phylogeny was inferred using pol sequences from surveillance patients and all subtype B sequences from the SHCS-DRDB (6934 additional patients). Potential sources of TDR were identified based on phylogenetic clustering, shared resistance mutations, genetic distance, and estimated infection dates. RESULTS: One hundred forty of 1674 (8.4%) surveillance patients carried virus with TDR; 86 of 140 (61.4%) were assigned to clusters. Potential sources of TDR were found for 50 of 86 (58.1%) of these patients. ART-naive patients constitute 56 of 66 (84.8%) potential sources and were significantly overrepresented among sources (odds ratio, 6.43 [95% confidence interval, 3.22-12.82]; P < .001). Particularly large transmission clusters were observed for the L90M mutation, and the spread of L90M continued even after the near cessation of antiretroviral use selecting for that mutation. Three clusters showed evidence of reversion of K103N or T215Y/F. CONCLUSIONS: Many individuals harboring viral TDR belonged to transmission clusters with other Swiss patients, indicating substantial domestic transmission of TDR in Switzerland. Most TDR in clusters could be linked to sources, indicating good surveillance of TDR in the SHCS-DRDB. Most TDR sources were ART naive. This, and the presence of long TDR transmission chains, suggests that resistance mutations are frequently transmitted among untreated individuals, highlighting the importance of early diagnosis and treatment. PMID- 24145876 TI - Reply to Gandra et al. PMID- 24145877 TI - How will physicians respond to the next influenza pandemic? AB - The emergence of the H7N9 virus in China is another reminder of the threat of a global influenza pandemic. Many believe we could confront a pandemic by expanding our capacity to provide timely supplies of affordable pandemic vaccines and antiviral agents. Experience in 2009 demonstrated that this cannot and will not be done. Consequently, physicians may have little more to offer their patients than they had in the 1918 pandemic. Fortunately, several modern drugs (eg, statins, angiotensin II receptor blockers, angiotensin-converting enzyme inhibitors) can modify the host response to inflammatory illness, and laboratory and clinical studies suggest they might be used to treat pandemic patients. Unfortunately, little attention has been given to the research needed to support their use in patient care. There is no guarantee these drugs will work, but physicians will never know unless those responsible for pandemic preparedness recognize and act on the extraordinary possibility that they might save lives. PMID- 24145878 TI - Resistance to HIV integrase strand transfer inhibitors among clinical specimens in the United States, 2009-2012. AB - BACKGROUND: Data on integrase inhibitor resistance come primarily from clinical trials and in vitro studies. We examined results of all clinically indicated integrase genotypic resistance tests (GRTs) performed at a US national referral lab from 2009 through 2012. METHODS: Integrase sequences and demographic data were compiled with paired protease-reverse transcriptase (PR-RT) GRT results, when available. Analyses utilized the Stanford HIV Drug Resistance Database. "Major" integrase mutations included T66AIK, E92QV, F121Y, Y143CHR, S147G, Q148HKR, and N155H; multiple accessory mutations were also assessed. RESULTS: Among 3294 sequences from 3012 patients, 471 patients had viruses with >= 1 raltegravir or elvitegravir resistance mutation (15.6%). Q148 and N155 pathways were equally represented (both n = 197); 84 had Y143 mutations. Q148 rarely occurred without accessory mutations (n = 3). Among 224 patients with serial integrase GRTs, 22 with baseline wild-type acquired a major mutation, after a median 224 days between tests (interquartile range, 148-335 days). Major mutations were observed to persist up to 462 days. Most (62%) had paired PR-RT results. Patients with integrase-resistant viruses were older and more likely to have PR-RT mutations (both P < .001). Among those with PR-RT data, 42 patients had 4-class resistance (2.3%). Sex, geographic region, and test year were not associated with integrase resistance. High-level dolutegravir resistance was predicted in 12% of patients with raltegravir- or elvitegravir-resistant viruses (2% of all patients). CONCLUSIONS: Approximately 1 in 6 US patients undergoing integrase GRT for clinical decision making harbors significant resistance, with Q148 and N155 pathways equally common. Dolutegravir is likely to have full or partial activity against most variants observed. PMID- 24145880 TI - Role of ritonavir in the drug interactions between telaprevir and ritonavir boosted atazanavir. AB - BACKGROUND: Detrimental bidirectional pharmacokinetic interactions have been observed when telaprevir (TVR) and ritonavir (RTV)-boosted human immunodeficiency virus (HIV) protease inhibitors are coadministered in healthy volunteers. Our aim was to evaluate the role of RTV in the bidirectional TVR and atazanavir (ATV) interactions. METHOD: An open-label, sequential study was carried out in hepatitis C virus (HCV)/HIV-coinfected patients on a RTV-boosted ATV-based (ATVr) antiretroviral regimen (300/100 mg every 24 hours) and triple therapy for chronic C hepatitis genotype 1 (TVR, 1125 mg every 12 hours, pegylated interferon-alpha and ribavirin). Pharmacokinetic profiles were acquired before and after switching from ATVr to unboosted ATV (200 mg every 12 hours). The plasma levels of both drugs were determined by liquid chromatography coupled with mass spectrometry. Pharmacokinetic parameters were calculated by noncompartmental analysis and compared by geometric mean ratios and their 90% confidence intervals. RESULTS: Fourteen white HCV/HIV-coinfected males were enrolled in this study. After RTV was withdrawn, the TVR AUC(0-12) (area under the concentration-time curve), maximum concentration (C(max)), and minimum concentration (C(min)) values increased by 19% (7%-30%), 12% (0.9%-29%), and 18% (2%-34%), respectively, without any changes in the TVR terminal half-life. The ATV AUC(0-12), C(max), and C(min) values were 39% (13%-66%), 19% (8%-59%), and 48% (1%-96%) higher, respectively, with a significantly shorter terminal half-life (22.6 hours vs 10.4 hours). CONCLUSIONS: RTV is responsible for the adverse interactions that occur when TVR and ATVr are administered together, possibly by influencing either the absorption phase or first-pass metabolism of TVR. The boost effect of TVR on ATV exposure is higher than on RTV, despite its shorter terminal half-life. The coadministration of TVR and unboosted ATV results in increased exposure of both drugs compared with their coadministration with RTV. CLINICAL TRIALS REGISTRATION: ClinicalTrials.gov: NCT01818856. European Medicines Agency EudraCT no. 2012-002515-25. PMID- 24145881 TI - The Dercum-Muybridge collaboration for sequential photography of neurologic disorders. AB - OBJECTIVE: To analyze the contributions of American photographer Eadweard Muybridge (1830-1904) and Philadelphia neurologist Francis Dercum (1856-1931) toward creating the first motion-picture sequences of patients with neurologic disorders. BACKGROUND: In the late 1870s and 1880s, prior to the development of movie cameras or projectors, Muybridge photographed sequential images of people and animals in motion, using arrays of sequentially triggered single-image cameras and multilens cameras. METHODS: Examination of published writings and photographic sequences by Muybridge and Dercum, and primary source documents, including letters from Dercum. RESULTS: In 1885, Philadelphia neurologist Francis Dercum (1856-1931) collaborated with Muybridge at the University of Pennsylvania to photograph sequential images of patients with various neurologic disorders involving abnormal movements. Subjects were recruited from the neurology services of the University Hospital and the Philadelphia Hospital. Muybridge and Dercum photographed patients with tabes dorsalis, hemiparesis, paraparesis, athetotic cerebral palsy, lead encephalopathy, congenital hydrocephalus with diparesis, poliomyelitis, pseudoseizures, psychogenic movement disorder, and other conditions. CONCLUSIONS: These are the first motion-picture sequences of neurologic disorders ever filmed, and provide an important visual archive and teaching resource for neurologic disorders that were prevalent in the late 19th century. PMID- 24145882 TI - Extensive striatal, cortical, and white matter brain MRI abnormalities in Wilson disease. PMID- 24145879 TI - Pharmacokinetics, safety, and 48-week efficacy of oral raltegravir in HIV-1 infected children aged 2 through 18 years. AB - BACKGROUND: IMPAACT P1066 is a phase I/II open-label multicenter trial to evaluate pharmacokinetics, safety, tolerability, and efficacy of multiple raltegravir formulations in human immunodeficiency virus (HIV)-infected youth. METHODS: Dose selection for each cohort (I: 12 to <19 years; II: 6 to <12 years; and III: 2 to <6 years) was based on review of short-term safety (4 weeks) and intensive pharmacokinetic evaluation. Safety data through weeks 24 and 48, and grade >= 3 or serious adverse events (AEs) were assessed. The primary virologic endpoint was achieving HIV RNA <400 copies/mL or >= 1 log10 reduction between baseline and week 24. RESULTS: The targeted pharmacokinetic parameters (AUC0-12h and C12h) were achieved for each cohort, allowing dose selection for 2 formulations. Of 96 final dose subjects, there were 15 subjects with grade 3 or higher clinical AEs (1 subject with drug-related [DR] psychomotor hyperactivity and insomnia); 16 subjects with grade 3 or higher laboratory AEs (1 with DR transaminase elevation); 14 subjects with serious clinical AEs (1 with DR rash); and 1 subjects with serious laboratory AEs (1 with DR transaminase increased). There were no discontinuations due to AEs and no DR deaths. Favorable virologic responses at week 48 were observed in 79.1% of patients, with a mean CD4 increase of 156 cells/uL (4.6%). CONCLUSIONS: Raltegravir as a film-coated tablet 400 mg twice daily (6 to <19 years, and >= 25 kg) and chewable tablet 6 mg/kg (maximum dose 300 mg) twice daily (2 to <12 years) was well tolerated and showed favorable virologic and immunologic responses. CLINICAL TRIALS REGISTRATION: NCT00485264. PMID- 24145883 TI - Ethical and quality pitfalls in electronic health records. PMID- 24145884 TI - Pediatric neuroenhancement: ethical, legal, social, and neurodevelopmental implications. PMID- 24145885 TI - Pearls & oy-sters: oval pupil: two observations. AB - The presence of an oval pupil usually localizes the neurologic problem to the midbrain. PMID- 24145886 TI - Teaching neuroimages: chiasmal enlargement and enhancement in Leber hereditary optic neuropathy. PMID- 24145887 TI - Teaching neuroimages: Burkitt dural lymphoma mimicking a subacute subdural hematoma. PMID- 24145888 TI - Potential increased risk of ischemic heart disease mortality with significant dose fractionation in the Canadian Fluoroscopy Cohort Study. AB - Risks of noncancer causes of death, particularly cardiovascular disease, associated with exposures to high-dose ionizing radiation, are well known. Recent studies have reported excess risk in workers who are occupationally exposed to low doses at a low dose rate, but the risks of moderately fractionated exposures, such as occur during diagnostic radiation procedures, remain unclear. The Canadian Fluoroscopy Cohort Study includes 63,707 tuberculosis patients exposed to multiple fluoroscopic procedures in 1930-1952 and followed-up for death from noncancer causes in 1950-1987. We used a Poisson regression to estimate excess relative risk (ERR) per Gy of cumulative radiation dose to the lung (mean dose = 0.79 Gy; range, 0-11.60). The risk of death from noncancer causes was significantly lower in these subjects compared with the Canadian general population (P < 0.001). We estimated small, nonsignificant increases in the risk of death from noncancer causes with dose. We estimated an ERR/Gy of 0.176 (95% confidence interval: 0.011, 0.393) (n = 5,818 deaths) for ischemic heart disease (IHD) after adjustment for dose fractionation. A significant (P = 0.022) inverse dose fractionation effect in dose trends of IHD was observed, with the highest estimate of ERR/Gy for those with the fewest fluoroscopic procedures per year. Radiation-related risks of IHD decreased significantly with increasing time since first exposure and age at first exposure (both P < 0.05). This is the largest study of patients exposed to moderately fractionated low-to-moderate doses of radiation, and it provides additional evidence of increased radiation-associated risks of death from IHD, in particular, significantly increased radiation risks from doses similar to those from diagnostic radiation procedures. The novel finding of a significant inverse dose-fractionation association in IHD mortality requires further investigation. PMID- 24145890 TI - An integrative literature review of contextual factors in perioperative information management systems. AB - Perioperative information management systems are used to generate the official documentation of patient care throughout the surgical experience. Successful implementation of perioperative information management systems requires a careful assessment of the contextual factors (ie, the social, cultural, and physical environment) that are present at the site. Failure to sufficiently assess these contextual factors is one of the leading causes of unsuccessful system implementation and can result in decreased patient safety, poor documentation quality, inefficient work processes, and wasted financial resources. Clearly defining and identifying the contextual factors are necessary to improve the performance and utilization of information management systems. The purpose of this article was to provide an integrative review of the empirical and theoretical literature on the contextual factors present in the perioperative environment to help guide future research and clinical practice. Specifically, this review addresses a gap in the literature regarding the descriptions of the contextual factors and how these factors affect implementation practices and system use. By clearly identifying these contextual factors and determining their relationship to successful system implementations, informatics specialists can tailor implementation and assessment tools to both patients and perioperative settings. PMID- 24145891 TI - A reddish brown reticulated hyperpigmented erythema on the abdomen of a girl. Erythema ab igne, also known as toasted skin syndrome, caused by a heating pad on the abdomen. PMID- 24145893 TI - Diagnosis: Accelerated diagnostic protocol for patients with chest pain assessed in a randomized clinical trial. PMID- 24145892 TI - Mechanical antithrombotic intervention by LAA occlusion in atrial fibrillation. AB - Stroke in patients with atrial fibrillation (AF) is often associated with substantial morbidity and mortality. Oral anticoagulation remains the first-line approach to stroke prevention in such individuals; however, for a considerable proportion of patients, traditional treatment using warfarin is limited by a number of factors, such as the inconvenience of frequent therapeutic monitoring and the risk of haemorrhage. The development of new oral anticoagulants with improved efficacy and safety profiles has provided viable options for oral anticoagulation therapy in patients with nonvalvular (nonrheumatic AF). Nonetheless, in patients who have an increased risk of major haemorrhage, a nonpharmacological approach to antithrombotic therapy remains an attractive alternative. The left atrial appendage (LAA) has been found to be the source of >90% of thrombi in patients with nonvalvular AF; thus, prevention of thrombus formation via transcatheter mechanical LAA occlusion is a novel therapeutic target for stroke prevention in this patient population. In this Review, we present the rationale for LAA occlusion in patients with AF, the available occlusion devices and their clinical evidence to date. We also discuss the roles of various imaging techniques in device implantation and the management strategy for associated procedural complications. PMID- 24145894 TI - Dyslipidaemia: RNAi targeting PCSK9 decreases lipid levels in a human trial. PMID- 24145895 TI - Effects of opium consumption on cardiometabolic diseases. AB - Opium is the second-most-commonly abused substance (after tobacco) in developing countries of the Middle East region, and in many Asian nations. One of the reasons for the high prevalence of opium abuse in these countries is a traditional belief among Eastern people, even including some medical staff, that opium might have beneficial effects on cardiovascular health and in the control of diabetes mellitus, hypertension, and dyslipidaemia. In this Perspectives article, we summarize the current understanding of the pharmacotoxicology of opium and its specific effects on glycaemic control, blood pressure, lipid profile, and atherosclerosis. On the basis of the available evidence, we believe not only that opium has no ameliorating effect on cardiovascular diseases, but also that the use of this drug might have adverse effects on these conditions. Therefore, people should be educated about the hazardous effects of opium consumption on cardiometabolic diseases. PMID- 24145896 TI - Infantile hemangioma of the liver in an adult: a case report and review of the literature. AB - Infantile hemangioma (IH), a representative vascular liver tumor, usually occurs in infancy or early childhood but rarely in adults. In this study, we describe a case of IH in a 47-year-old female and we also review the literature. A plain computed tomography (CT) image revealed five hypoattenuating masses in the liver. A dynamic study revealed the masses appeared to be well-enhanced in the arterial phase, and were considered to be high-flow hemangiomas. The tumors appeared as hypointense tumors on the T1-weighted images and as hyperintensities on fat suppression T2-weighted images. Following the administration of gadolinium ethoxybenzyl diethylenetriamine pentaacetic acid (Gd-EOB-DTPA), tumors appeared to be well-enhanced in the arterial phase. In the portal phase, tumors demonstrated isointensity compared with the surrounding liver parenchyma, and hypointensity in the equilibrium and hepatobiliary phases. The apparent diffusion coefficient (ADC) values ranged from 2.0 to 2.4x10(-3) mm2/sec. Microscopically, the tumors were composed of numerous capillary-like small vessels lined with plump endothelial cells, arranged in a single layer without mitoses, and small bile ducts were trapped and scattered within the tumor. These findings were considered to be characteristic of IH. To the best of our knowledge, this case is the third report on IH in adults. PMID- 24145897 TI - Bacteriochlorophyll homolog compositions in the bchU mutants of green sulfur bacteria. AB - Chlorosomes of the green sulfur bacterium Chlorobaculum limnaeum contain a large number of self-aggregated bacteriochlorophyll (BChl) e molecules. The DeltabchU mutant of this organism lacks BchU, a C20-methyltransferase, and therefore produces BChl f, which is the C20-unsubstituted form of BChl e. The BChl e homolog compositions, in terms of degrees of C8(2)-methylation, were not changed in the wild type during growth, while the BChl f homolog patterns in the mutant were significantly altered at various time periods of growth. BChl f with an isobutyl group at the C8 position was dominant at the early stage of growth, whereas the proportion of BChl f with the C8-ethyl group increased in the late exponential phase. We also constructed the DeltabchU mutant of C. tepidum which originally produces BChl c: the mutant therefore produces BChl d. BChl d homologs highly methylated at the C8(2) position also increased in the DeltabchU mutant of C. tedium compared to those in the wild type. These phenomena suggest that BchU interferes with the methylation ability of BchQ, a C8(2)-methyltransferase, and that the enzymes might compete in terms of obtaining S-adenosyl-methionine, the source of a methyl group. As a result, when grown to the late log phase, the DeltabchU mutant of C. limnaeum had similar heterogeneities of pigment homolog compositions compared to those in the wild type. Chlorosomes with a high proportion of C8-ethylated BChl homologs might be important for fine-tuning the light-harvesting or energy-transfer efficiency. Chlorosomes of the DeltabchU mutants at the various growth stages will be good materials for investigating effects of C8(2)-methylations on supramolecular structures of self-aggregated pigments. PMID- 24145898 TI - Effect of submaximal repetitive exercise on knee coactivation in young and middle aged women. AB - Coactivation of the knee extensors and flexors increases knee joint contact forces, which may lead to degradation of the articular surfaces. This study investigated the effect of neuromuscular fatigue induced by submaximal, repetitive, dynamic contractions on coactivation of knee musculature in young and middle-aged women. Data from 10 young women (24.6+/-1.8 years) and 8 middle-aged women (55.4+/-4.2 years) were analyzed. Measures included peak knee extension and flexion torques and the average amplitude of surface electromyography of rectus femoris and biceps femoris. Coactivation ratios were calculated from these activations. To induce fatigue, participants completed up to ten sets of 50 concentric knee extension and flexion contractions at 60 degrees /s. A two-factor analysis of variance was used to determine the effect of age and fatigue. The young group showed higher peak torque compared with the middle-aged group (P<.001). During flexion, biceps femoris activity increased after fatigue when both groups were considered together (P=.018). During extension, biceps femoris activity was higher in the middle-aged than young group (P=.043). Middle-aged women exhibited a trend for greater coactivation during knee extension compared with young women (P=.066). This coactivation likely contributed to extension torque decrements in middle-aged women. PMID- 24145900 TI - Spontaneous resolution of delayed epithelial ingrowth after LASIK. AB - OBJECTIVE: Epithelial ingrowth is a known complication after laser in situ keratomileusis (LASIK), with a high incidence after repeat surgery or trauma. The authors report the occurrence of epithelial ingrowth 23 months after primary LASIK and its subsequent spontaneous resolution over the following 6 months. METHODS: A 35-year-old man underwent bilateral uneventful microkeratome-assisted LASIK in June 2008. The patient presented 23 months later after noticing a "white spot" in his left eye. Examination of the left eye showed an oval patch of epithelial growth in the superonasal quadrant. Uncorrected distance visual acuity (UDVA) was 1.0 OD and 0.6 OS. Topical fluorometholone 0.1% eye drops were prescribed four times a day. Over the next 2 weeks, the UDVA improved to 1.0 and the size of the interface opacities decreased slightly. However, no further change was observed with continuation of corticosteroid eye drops over the next 2 weeks. All treatment was stopped. Three months later, the epithelial ingrowth expanded toward the visual axis. An option of surgical intervention was refused by the patient. RESULTS: Subsequent monthly follow-ups over another 3 months showed gradual decrease in the size of epithelial growth. Final slit-lamp examination showed complete clearance of the epithelial cells from the interface. The UDVA returned to 1.0 in the left eye. CONCLUSIONS: Epithelial ingrowth can occur after a long interval after primary LASIK. In our case, the epithelial cells disappeared without any surgical intervention over a period of 6 months. PMID- 24145899 TI - Biomarker-based predictive models for prognosis in amyotrophic lateral sclerosis. AB - IMPORTANCE: Although median survival in amyotrophic lateral sclerosis (ALS) is 2 to 4 years, survival ranges from months to decades, creating prognostic uncertainty. Strategies to predict prognosis would benefit clinical management and outcomes assessments of clinical trials. OBJECTIVE: To identify biomarkers in plasma and cerebrospinal fluid (CSF) of patients with ALS that can predict prognosis. DESIGN, PARTICIPANTS, AND SETTING: We conducted a retrospective study of plasma (n = 29) and CSF (n = 33) biomarkers identified in samples collected between March 16, 2005, and August 22, 2007, from patients with ALS at an academic tertiary care center. Participants included patients who were undergoing diagnostic evaluation in the neurology outpatient clinic and were eventually identified as having definite, probable, laboratory-supported probable, or possible ALS as defined by revised El-Escorial criteria. All were white and none had a family history of ALS. Clinical information extended from initial presentation to death. Genotyping for hemochromatosis (HFE) gene status was performed. Multiplex and immunoassay analysis of plasma and CSF was used to measure levels of 35 biomarkers. Statistical modeling was used to identify biomarker panels that could predict total disease duration. MAIN OUTCOMES AND MEASURES: Total disease duration, defined as the time from symptom onset to death, was the main outcome. The hypothesis being tested was formulated after data collection. RESULTS: Multivariable models for total disease duration using biomarkers from plasma, CSF, and plasma and CSF combined incorporated 7, 6, and 6 biomarkers to achieve goodness-of-fit R2 values of 0.769, 0.617, and 0.962, respectively. After classification into prognostic categories, actual and predicted values achieved moderate to good agreement, with Cohen kappa values of 0.526, 0.515, and 0.930 for plasma, CSF, and plasma and CSF combined models, respectively. Inflammatory biomarkers, including select interleukins, growth factors such as granulocyte colony-stimulating factor, and l-ferritin, had predictive value. CONCLUSIONS AND RELEVANCE: This study provides proof-of-concept for a novel multivariable modeling strategy to predict ALS prognosis. These results support unbiased biomarker discovery efforts in larger patient cohorts with detailed longitudinal follow-up. PMID- 24145901 TI - Wearing time as a measure of success of scleral lenses for patients with irregular astigmatism. AB - OBJECTIVES: To evaluate the visual correction and clinical performance with scleral contact lenses (CL) for the visual rehabilitation of irregular astigmatism and to report the effect of brief wearing breaks on the wearing time and success rate. METHODS: A retrospective review was performed on consecutive patients who were fitted with scleral CL because of irregular astigmatism following failure of other optical corrections. Visual acuity (VA) and wearing times were abstracted. RESULTS: The 97 consecutive identified patients (155 eyes) were divided according to the diagnosis: (1) keratoconus (105 eyes; 67.7%), (2) postpenetrating keratoplasty (PK) (28 eyes; 18.1%); (3) multiple diagnoses (22 eyes; 14.2%)-postradial keratotomy, keratoglobus, pellucid marginal degeneration, PK with aphakia, and iatrogenic ectasia. The mean follow-up was 34.9 +/- 18.5 months (range, 2-71 months). There was a significant increase in best VA-scleral when compared with the previous best VA-prescleral (P<0.001). The best VA-scleral was similar in the 3 groups (P>0.5). Patients who took brief breaks every 4 to 5 continuous wearing hours had a significantly higher success rate (P<0.001) among all diagnosis groups. The success rate in wearing time in the keratoconus group was significantly higher than in the PK group (P<0.001). Twenty-six patients (27%) discontinued to wear scleral lenses. CONCLUSION: Scleral lenses can be used successfully for visual rehabilitation and management of irregular astigmatism from various causative factors. The daily wearing time was significantly improved by taking brief breaks for replenishing the CL. PMID- 24145902 TI - Optical penalization with contact lenses for children with unilateral aphakia: an alternative to patching. AB - OBJECTIVES: To evaluate the efficacy of high-plus contact lenses as a form of optical penalization in children with unilateral aphakia. METHODS: An internal database review was used to identify 10 patients with unilateral aphakia after congenital cataract extraction who underwent treatment with a high-plus contact lens in their sound eye after a period of failure with traditional occlusive patching. The details surrounding the switch from patching to optical penalization with contact lens were recorded along with related changes in compliance and any demonstrable effect suggestive of an improvement in visual ability. RESULTS: After an average 15-month delay between the end of occlusive patching and the start of optical penalization with high-plus contact lenses, 6 of 10 patients achieved good compliance with high-plus contact lens therapy and most families were able to successfully administer the lenses according to the prescribed regimen. Three patients showed evidence of a fixation switch to the contact-lens-corrected aphakic eye during optical penalization of the sound eye. No safety issues were reported. CONCLUSION: Using a high-plus contact lens to optically penalize the sound eye of a unilaterally aphakic child seems to have the potential as an effective alternative to occlusive patching for those with compliance issues. A prospective study is warranted to assess long-term safety, and above all, efficacy in visual outcome. PMID- 24145903 TI - The SWI/SNF tumor suppressor complex: Regulation of promoter nucleosomes and beyond. AB - Nucleosomes, octamers of histones wrapped in 147 bp of DNA, are the basic unit of chromatin. In eukaryotic cells, the placement of nucleosomes along the genome is highly organized, and modulation of this ordered arrangement contributes to regulation of gene expression. The SWI/SNF complex utilizes the energy of ATP hydrolysis to mobilize nucleosomes and remodel chromatin structure. Recently, the complex has also been implicated in oncogenesis as genes encoding multiple SWI/SNF subunits have been found mutated at high frequency across a wide spectrum of cancers. Given that epigenetic aberrations are now characterized as a hallmark of human cancer, hypotheses have been put forth that the SWI/SNF complex inhibits tumor formation by regulating key chromatin functions. To understand how the SWI/SNF complex contributes to nucleosome organization in vivo we performed a genome-wide study in mammalian cells. We found that inactivation of SWI/SNF subunits leads to disruptions of specific nucleosome patterning and a loss of nucleosome occupancy at a large number of promoters. These findings define a direct relationship between the SWI/SNF complex, chromatin structure, and transcriptional regulation. In this extra view, we discuss our findings, their relevance to gene regulation, and possible links to the tumor suppression activities of the SWI/SNF complex. PMID- 24145904 TI - Primary adenocarcinoma of the lacrimal gland with sebaceous differentiation in a 4-year-old child. AB - Primary adenocarcinoma of the lacrimal gland with sebaceous differentiation is an extremely rare tumor. Only 11 cases have been reported in the literature, none in children. A 4-year-old girl presented with a rapidly progressing mass in the left lacrimal gland fossa. An incisional biopsy followed by partial orbital exenteration confirmed the diagnosis of adenocarcinoma with sebaceous cell differentiation. Currently, no previous reports of this malignancy in childhood have been published. This case underscores the necessity of expanding the presenting age that adenocarcinomas with sebaceous differentiation of the lacrimal gland can occur. PMID- 24145905 TI - Clinicopathologic review of epithelial tumors of the lacrimal gland. AB - OBJECTIVE: To study the clinicopathologic features of epithelial tumors of the lacrimal gland diagnosed at a tertiary care center in India during a 10-year period. METHODS: Medical records of cases with histopathologically proven epithelial tumors of the lacrimal gland were reviewed for demographic details and clinical features at the time of presentation. For histopathologic findings, slides with hemotoxylin and eosin-stained sections of the tumors were reviewed. Special stains, including histochemical and immunohistochemical stains, and additional sections were studied, whenever needed. RESULTS: Of 66 cases with epithelial tumors of the lacrimal gland identified during the study period, 50 (76%) cases were benign and 16 (24%) cases were malignant tumors. Histopathologic examination was consistent with the diagnosis of pleomorphic adenoma (PA) in all 50 cases of benign tumors. The mean age at diagnosis in PA cases was 37.7 years. Microscopic examination of PA tumors showed cystic degeneration in 18 (36%) cases, squamous metaplasia in 16 (32%) cases, calcification in 6 (12%) cases, and ossification in 1 (2%) case. Among malignant tumors, adenoid cystic carcinoma (ACC) was the most common tumor (n = 12, 18%), with an average age at diagnosis of 32.4 years. Microscopic examination of ACC revealed that most cases were grade I tumors. Solid areas were noted in 4 (33.3%) cases and perineural invasion was identified in 2 (16.7%) cases. Other malignant tumors included 1 case each of carcinoma ex-PA (1.5%), lacrimal duct carcinoma (1.5%), mucoepidermoid carcinoma (1.5%), and basal cell adenocarcinoma (1.5%). CONCLUSIONS: As far as the authors are aware, this is the largest series on clinicopathologic features of epithelial tumors of the lacrimal gland from South Asia. The incidence of PA was significantly higher in this study than reported in the Caucasian population. Among malignant tumors, ACCs were the most common, although rare tumors were also identified. PMID- 24145906 TI - Prospective audit of ptosis surgery at the Singapore National Eye Centre: two year results. AB - PURPOSE: To evaluate the demographics, presentation, and surgical outcomes of patients undergoing ptosis surgery in an Asian population in a prospective manner. METHODS: A prospective ptosis audit was conducted over a 2-year period from January 2010 to December 2011 in a tertiary eye hospital in Singapore. All patients undergoing ptosis surgery by, or under the supervision of, an oculoplastic-trained consultant in the institution were included. Institutional Review Board approval was obtained for the study. RESULTS: This study comprises 302 patients, of which 236 were acquired and 66 were congenital ptosis cases. Levator repair (77.2%) was the most commonly performed procedure, followed by levator resection (13.9%) and brow suspension (8.9%). Forty-seven (10.1%) eyes had readjustment within 2 weeks, the reasons for readjustment being eyelid height undercorrection (n = 35), eyelid height overcorrection (n = 9), and unsatisfactory eyelid contour (n = 4). Postoperatively, 93.8% of patients showed an increase in marginal reflex distance-1 (MRD1), 91.3% achieved symmetry or <1 mm of asymmetry in MRD1, 98.5% had good eyelid contour, and 74.3% had symmetric eyelid crease. On a scale of 1 to 10, 83.1% of patients gave a subjective grade of 7 or better. CONCLUSIONS: This study is the first prospective ptosis surgery audit in an Asian population and takes a leading step in assessing both subjective and objective surgical outcomes in a prospective manner. With the continuation of this audit in years to come, it will allow us to generate clinical outcomes in a robust manner and allow for more reliable benchmarking with major centers elsewhere. PMID- 24145907 TI - Extruded, partially disintegrated, poly-HEMA orbital implant (AlphaSphere). AB - A 54-year-old diabetic man underwent enucleation for endophthalmitis. Secondary implantation of a 2-hydroxyethyl methacrylate (HEMA) sphere (AlphaSphere, Addition Technology) was performed 2 weeks later. Six weeks after insertion, noninfectious disintegration of sutured tissue planes represented by Tenon's capsule, rectus muscle, and conjunctiva occurred, requiring removal of the fragmenting implant before uncontrolled extrusion occurred. Histopathologic analysis revealed an absence of infectious pathogens and no tissue necrosis, but rather breakup of the implant material that elicited a granulomatous response with sparse T-lymphocytes and almost no polymorphonuclear leukocytes. This distinctively designed poly-HEMA orbital implant incited a dramatic and irreversible host tissue response. Investigation of other cases will be necessary to determine the frequency of such a complication and should include rigorous histopathologic techniques. PMID- 24145908 TI - Reconstruction of a congenital upper eyelid coloboma using a lamellar-based technique. AB - A 17-year-old woman presented with a left upper eyelid coloboma from birth, extending from the lateral side of the punctum to the center of the eyelid as much as 10 mm in width. The posterior lamella (tarsus) was lost completely in this area, but an anterior lamella defect was limited to 1 to 2 mm in height. The area was devoid of eyelashes. Part of the medial tarsal plate was spared. The anterior and posterior lamellae of this eyelid were separately reconstructed with an anterior skin crease incision and posterior wedge excision with a good cosmetic outcome. PMID- 24145909 TI - A cyst-like foreign body reaction to porcine decellularized membrane (TarSys). AB - A 58-year-old Caucasian woman with thyroid eye disease underwent a bilateral lower eyelid blepharoplasty with porcine decellularized membrane (TarSys) eyelid spacer graft placement. Three months postoperatively, she developed unusual cyst like masses in both lower eyelids that were excised. These were found to be consistent with inflammatory cysts with a foreign body reaction. No such reaction has ever been reported. PMID- 24145910 TI - Multidetector CT of nasolacrimal canal morphology: normal variation by age, gender, and race. AB - PURPOSE: To accurately characterize anatomical age, gender, and racial differences in normal nasolacrimal canal morphology and to describe a new, accurate technique for measuring nasolacrimal canal parameters based on high resolution CT. METHODS: The CT images of 72 patients were reviewed retrospectively and grouped according to age, gender, and race. Patients with history of long-term sinusitis, facial trauma, or nasolacrimal duct pathology were excluded from study. Variations in nasolacrimal duct length, minimal and maximal diameter, and other metrics were recorded and compared across each category. All patient records were deidentified to protect privacy. RESULTS: Nasolacrimal canal length and volume were significantly greater in men than those in women. A trend was noted for greater canal cross-sectional diameter in patients older than 50 years when compared with that in younger patients. Significant differences in canal diameters were noted at the canal apex and base of older patients compared with those of younger patients. The cross-sectional area of the canal base was greater in black patients than that in Caucasian patients. CONCLUSIONS: Although some significant age, gender, and racial variations of nasolacrimal canal morphology exist, these do not fully explain the epidemiology of primary acquired nasolacrimal duct obstruction. The new method described here for measuring nasolacrimal canal metrics is straightforward and theoretically more accurate than those previously defined in the literature. PMID- 24145911 TI - Apoplastic calmodulin promotes self-incompatibility pollen tube growth by enhancing calcium influx and reactive oxygen species concentration in Pyrus pyrifolia. AB - Calmodulin (CaM) has been associated with various physiological and developmental processes in plants, including pollen tube growth. In this study, we showed that CaM regulated the pear pollen tube growth in a concentration-dependent bi-phasic response. Using a whole-cell patch-clamp configuration, we showed that apoplastic CaM induced a hyperpolarization-activated calcium ion (Ca2+) current, and anti CaM largely inhibited this type of Ca2+ current. Moreover, upon anti-CaM treatment, the reactive oxygen species (ROS) concentration decreased and actin filaments depolymerized in the pollen tube. Interestingly, CaM could partially rescue the inhibition of self-incompatible pear pollen tube growth. This phenotype could be mediated by CaM-enhanced pollen plasma membrane Ca2+ current, tip-localized ROS concentration and stabilized actin filaments. These data indicated that Ca2+, ROS and actin filaments were involved with CaM in regulating pollen tube growth and provide a potential way for overcoming pear self incompatibility. PMID- 24145912 TI - Identification and validation of sugarcane streak mosaic virus-encoded microRNAs and their targets in sugarcane. AB - Plants have developed several defense mechanisms to cope with various pathogens (bacteria, fungi, virus, and phytoplasma). Among these, RNA interference (RNAi) mediated defense against viral infection was found to be a major innate immune response. As a counter attack strategy against the host defense, viruses produce suppressors of host RNAi pathway. MicroRNAs (miRNAs) are an abundant class of short (~18-22 nucleotide) non-coding single-stranded RNAs involved in RNAi pathway leading to post-transcriptional regulation of gene expression. Sugarcane streak mosaic virus (SCSMV) is a distinct strain of Potyviridae family which has a single-stranded positive-sense RNA genome causing mosaic disease in sugarcane. In this study, we computationally predicted and experimentally validated the miRNA encoded by the SCSMV genome with detection efficiency of 99.9 % in stem loop RT-qPCR and predicted their potential gene targets in sugarcane. These sugarcane target genes considerably broaden future investigation of the SCSMV encoded miRNA function during viral pathogenesis and might be applied as a new strategy for controlling mosaic disease in sugarcane. PMID- 24145915 TI - Bioinspired TiO2 nanostructure films with special wettability and adhesion for droplets manipulation and patterning. AB - Patterned surfaces with special wettability and adhesion (sliding, sticky or patterned superoleophobic surface) can be found on many living creatures. They offer a versatile platform for microfluidic management and other biological functions. Inspired by their precise arrangement of structure and chemical component, we described a facile one-step approach to construct large scale pinecone-like anatase TiO2 particles (ATP) film. The as-prepared ATP film exhibits excellent superamphiphilic property in air, changes to underwater superoleophobicity with good dynamical stability. In addition, erasable and rewritable patterned superamphiphobic ATP films or three-dimensional (3D) Janus surfaces were constructed for a versatile platform for microfluidic management and biomedical applications. In a proof-of-concept study, robust super antiwetting feet for artificial anti-oil strider at the oil/water interface, novel superamphiphobic surface for repeatable oil/water separation, and multifunctional patterned superamphiphobic ATP template for cell, fluorecent probe and inorganic nanoparticles site-selective immobilization were demonstrated. PMID- 24145913 TI - A decellularization methodology for the production of a natural acellular intestinal matrix. AB - Successful tissue engineering involves the combination of scaffolds with appropriate cells in vitro or in vivo. Scaffolds may be synthetic, naturally derived or derived from tissues/organs. The latter are obtained using a technique called decellularization. Decellularization may involve a combination of physical, chemical, and enzymatic methods. The goal of this technique is to remove all cellular traces whilst maintaining the macro- and micro-architecture of the original tissue. Intestinal tissue engineering has thus far used relatively simple scaffolds that do not replicate the complex architecture of the native organ. The focus of this paper is to describe an efficient decellularization technique for rat small intestine. The isolation of the small intestine so as to ensure the maintenance of a vascular connection is described. The combination of chemical and enzymatic solutions to remove the cells whilst preserving the villus-crypt axis in the luminal aspect of the scaffold is also set out. Finally, assessment of produced scaffolds for appropriate characteristics is discussed. PMID- 24145916 TI - An electronic tongue designed to detect ammonium nitrate in aqueous solutions. AB - An electronic tongue has been developed to monitor the presence of ammonium nitrate in water. It is based on pulse voltammetry and consists of an array of eight working electrodes (Au; Pt; Rh; Ir; Cu; Co; Ag and Ni) encapsulated in a stainless steel cylinder. In a first step the electrochemical response of the different electrodes was studied in the presence of ammonium nitrate in water in order to further design the wave form used in the voltammetric tongue. The response of the electronic tongue was then tested in the presence of a set of 15 common inorganic salts; i.e.; NH4NO3; MgSO4; NH4Cl; NaCl; Na2CO3; (NH4)2SO4; MgCl2; Na3PO4; K2SO4; K2CO3; CaCl2; NaH2PO4; KCl; NaNO3; K2HPO4. A PCA plot showed a fairly good discrimination between ammonium nitrate and the remaining salts studied. In addition Fuzzy Art map analyses determined that the best classification was obtained using the Pt; Co; Cu and Ni electrodes. Moreover; PLS regression allowed the creation of a model to correlate the voltammetric response of the electrodes with concentrations of ammonium nitrate in the presence of potential interferents such as ammonium chloride and sodium nitrate. PMID- 24145917 TI - A wearable inertial measurement unit for long-term monitoring in the dependency care area. AB - Human movement analysis is a field of wide interest since it enables the assessment of a large variety of variables related to quality of life. Human movement can be accurately evaluated through Inertial Measurement Units (IMU), which are wearable and comfortable devices with long battery life. The IMU's movement signals might be, on the one hand, stored in a digital support, in which an analysis is performed a posteriori. On the other hand, the signal analysis might take place in the same IMU at the same time as the signal acquisition through online classifiers. The new sensor system presented in this paper is designed for both collecting movement signals and analyzing them in real-time. This system is a flexible platform useful for collecting data via a triaxial accelerometer, a gyroscope and a magnetometer, with the possibility to incorporate other information sources in real-time. A uSD card can store all inertial data and a Bluetooth module is able to send information to other external devices and receive data from other sources. The system presented is being used in the real-time detection and analysis of Parkinson's disease symptoms, in gait analysis, and in a fall detection system. PMID- 24145918 TI - Optical fiber-based MR-compatible sensors for medical applications: an overview. AB - During last decades, Magnetic Resonance (MR)--compatible sensors based on different techniques have been developed due to growing demand for application in medicine. There are several technological solutions to design MR-compatible sensors, among them, the one based on optical fibers presents several attractive features. The high elasticity and small size allow designing miniaturized fiber optic sensors (FOS) with metrological characteristics (e.g., accuracy, sensitivity, zero drift, and frequency response) adequate for most common medical applications; the immunity from electromagnetic interference and the absence of electrical connection to the patient make FOS suitable to be used in high electromagnetic field and intrinsically safer than conventional technologies. These two features further heightened the potential role of FOS in medicine making them especially attractive for application in MRI. This paper provides an overview of MR-compatible FOS, focusing on the sensors employed for measuring physical parameters in medicine (i.e., temperature, force, torque, strain, and position). The working principles of the most promising FOS are reviewed in terms of their relevant advantages and disadvantages, together with their applications in medicine. PMID- 24145920 TI - Ultrasensitive protein detection: a case for microfluidic magnetic bead-based assays. AB - We review the use of magnetic micro- and nanoparticles ('magnetic beads') in microfluidic systems for ultrasensitive protein detection. During recent years magnetic beads have been used frequently in immunoassays, either as mobile substrates on which the target antigen is captured, as detection labels, or simultaneously as substrates and labels. The major part of the reviewed work has as application the detection of antibodies or disease biomarkers in serum or of biotoxins from food samples. Several of the most sensitive assays allow protein detection down to fg mL(-1) concentrations. We benchmark the performance of these microfluidic magnetic bead-based assays with the most promising earlier work and with alternative solutions. PMID- 24145919 TI - Pandoraea sp. RB-44, a novel quorum sensing soil bacterium. AB - Proteobacteria are known to communicate via signaling molecules and this process is known as quorum sensing. The most commonly studied quorum sensing molecules are N-acylhomoserine lactones (AHLs) that consists of a homoserine lactone moiety and an N-acyl side chain with various chain lengths and degrees of saturation at the C-3 position. We have isolated a bacterium, RB-44, from a site which was formally a landfill dumping ground. Using matrix-assisted laser desorption ionization time-of-flight (MALDI-TOF) mass spectrometry analysis, this isolate was identified as a Pandoraea sp.which was then screened for AHL production using biosensors which indicated its quorum sensing properties. To identify the AHL profile of Pandoraea sp. RB-44, we used high resolution tandem mass spectrometry confirming that this isolate produced N-octanoylhomoserine lactone (C8-HSL). To the best of our knowledge, this is the first report that showed quorum sensing activity exhibited by Pandoraea sp. Our data add Pandoraea sp. to the growing number of bacteria that possess QS systems. PMID- 24145921 TI - H. pylori infection-induced MSC differentiation into CAFs promotes epithelial mesenchymal transition in gastric epithelial cells. AB - Mesenchymal stem cell (MSC) tropism to injured tissue sites in response to inflammation and wounds has been suggested. MSC activation and recruitment by Helicobacter pylori (H. pylori)-infected gastrointestinal epithelial cells has been demonstrated. As a component of the chronic gastritis microenvironment, MSCs play critical roles in the development of H. pylori-associated gastric mucosal lesions/malignancies. However, the mechanisms responsible for this process remain largely unknown. In this study, we demonstrate that H. pylori infection induces the differentiation of MSCs into cancer-associated fibroblast (CAF)-like cells. H. pylori-infected MSCs possessed an altered cytokine profile and induced epithelial-mesenchymal transition in gastric epithelial cells, leading to destroyed cell junctions, enhanced cell migration, reduced cell apoptosis and increased oncogenic potential. In conclusion, our findings indicate that H. pylori infection may cause gastric lesions/malignancies by inducing the differentiation of MSCs into CAFs and suggest a novel mechanism of action and role of MSCs in the development and progression of gastric cancer. PMID- 24145922 TI - Endocrine-disrupting effects of compounds in Danish streams. AB - Effluents from municipal wastewater-treatment plants and scattered dwellings, as well as runoff from agricultural fields, are sources of endocrine-disrupting compounds (EDCs) in the aquatic environment. The present study investigated the correlation between the occurrence of EDCs in nine Danish streams using passive samplers (polar organic integrative samplers and silicone membranes) and determined their possible biological effects as assessed by mammal cell cultures and the mussel (Unio tumidus). The passive samplers and mussels were exposed simultaneously at the study sites. The extracts from the passive samplers were used to measure the concentrations of EDCs and the biological effects on the estrogen (ER), androgen (AR), and aryl hydrocarbon (AhR)-receptor transactivation. Male mussels were investigated for biomarkers of endocrine effects, such as the levels of vitellogenin-like proteins measured as alkali labile phosphate (ALP). EDC concentrations, hormone-receptor transactivation (ER, AR, AhR), and level of ALP were greater downstream of wastewater-treatment plants compared with upstream sites and sites supposed to be relatively nonimpacted by wastewater. Furthermore, there was a significant positive correlation between in vitro AhR transactivation and frequency of ALP of male mussels. We conclude that wastewater effluent is an important source of endocrine-disrupting effects in the aquatic environment and that the combination of biological effect measurements and chemical analyses based on passive sampling is useful in the assessment of the ecological state of the aquatic environment. PMID- 24145923 TI - The role of nitrogen availability for the salt-tolerance of two different varieties of durum wheat. AB - Salt stress tolerance of durum wheat was assessed in control and 200 and 300 mM NaCl-exposed seed of two cultivars (BidiAP4 and Azizi). These salt treatments were accompanied by different levels of nitrate (Ca(NO3)2) added to the media (0.1, 3, 10 mM). The data showed that NaCl stress increased Na(+) and Cl(-) contents and lowered K(+) and NO3 (-) levels in seeds of BidiAP4 cultivar. In Azizi seeds exposed to NaCl, Na(+) and K(+) were highly accumulated while low levels of NO3 (-) and Cl(-) were detected. Those findings highlight the difference in the salt stress tolerance of these two durum wheat cultivars also depending on nitrogen (N) availability, Azizi cultivar being less sensitive to NaCl treatment than BidiAP4. These data also suggested a relationship between salt tolerance capacity and enhancement or maintenance of nitrogen and carbon metabolisms enzyme activity. PMID- 24145924 TI - Using grouper fish as bio-indicator of Cd, Cu, Pb and V in the vicinity of a single buoy mooring (SBM3) at Mina Al Fahal in the Sultanate of Oman. AB - This paper investigated metal contamination in muscle tissue of the grouper (Epinephelus coioides) in the vicinity of a single buoy mooring (SBM3) at the Sultanate of Oman. The fish samples were analyzed for cadmium (Cd), copper (Cu), lead (Pb) and vanadium (V). The mean concentrations of Cd, Cu, Pb and V in the fish samples were 0.05 +/- 0.004, 0.34 +/- 0.013, 0.20 +/- 0.018 and 0.03 +/- 0.006 mg/kg, respectively. The results were compared with the corresponding permissible concentration limits according to the Sultanate of Oman (0.05, 3.28, 0.3 and 1.4 mg/kg for Cd, Cu, Pb and V, respectively) and the European Commission (0.05 mg/kg for Cd and 0.3 mg/kg for Pb). It was found that none of the overall mean metal concentrations exceeded the corresponding Omani legislation or European Commission limits. However, the overall mean concentration of Cd was identical to the maximum permissible limit of 0.05 mg/kg that has been established by both Commissions, and the limits were exceeded for mean Cd levels in fish at two of the six sampling stations at SBM3. In general, this study indicated that the fishes at SBM3 were not highly contaminated with these metals. PMID- 24145925 TI - Dissipation and residues of difenoconazole and azoxystrobin in bananas and soil in two agro-climatic zones of China. AB - Residues of a fungicide suspension (12 % difenoconazole, 18 % azoxystrobin) in bananas and soil were studied under tropical and subtropical monsoon climates, in Hainan and Yunnan provinces, respectively. The half-lives in bananas were shorter in Hainan (difenoconazole: 8.4-10.7 days; azoxystrobin: 7.8-8.4 days) than Yunnan (difenoconazole: 11.3-13.0 days; azoxystrobin: 10.4-11.6 days), possibly because of the higher temperatures and solar radiation levels in Hainan. The half-lives in soil were shorter in Yunnan (difenoconazole: 15.5-16.7; azoxystrobin: 11.9 13.9 days) than Hainan (difenoconazole: 23.1-23.2 days; azoxystrobin: 16.0-16.1 days), possibly because the organic carbon content was higher and rainfall lower in Yunnan than Hainan. Their physico-chemical properties suggest difenoconazole and azoxystrobin should be stable in bananas and soil, but both decreased to safe concentrations by the minimum harvest time after spraying the mixture at the recommended dosage and 1.5 times that dosage, through physical, chemical, and biological processes. PMID- 24145926 TI - Satiety responsiveness and eating behavior among Chilean adolescents and the role of breastfeeding. AB - OBJECTIVE: To determine patterns of satiety responsiveness and its relationship to eating in the absence of hunger (EAH), in a cohort of adolescents. We also assessed whether sex, body mass index and duration of breastfeeding, during infancy, predicted satiety responsiveness and eating behavior at 16 years. METHODS: Adolescents (n=576) from a longitudinal cohort, which began as an iron deficiency anemia preventive trial, participated in an unlimited breakfast after an overnight fast, and reported satiety response on a visual analog scale after the meal, followed by an EAH procedure. Height, weight and body composition were measured before breakfast. Latent profile analysis generated profiles that captured individual differences in satiety responsiveness. Multivariable regressions, adjusted for potential confounders, evaluated the association between: (1) satiety responsiveness and EAH, and (2) breastfeeding in infancy, satiety responsiveness and EAH in adolescence. RESULTS: Participants were on average 16.7-year old, 48% female, 37% overweight/obese and 76% were breastfed as the sole source of milk for <6 months. We found three latent profiles of satiety responsiveness: 1: 'responsive' (49%); 2: 'not responsive' (41%); 3: 'still hungry' (10%). Participants in the 'not responsive' or 'still hungry' profile were more likely to eat during the EAH procedure (odds ratio (OR)=2.5, 95% confidence interval (CI)=1.8-3.6). Being breastfed for <6 months was related to higher odds of being in the 'not responsive' or 'still hungry' profile (OR=1.8, 95% CI=1.2-2.6) and EAH (OR=2.2, 95% CI=1.4-3.3). Satiety responsiveness was not influenced by sex and overweight/obesity. CONCLUSION: After an ad libitum meal, we found varied satiety responses, which related to EAH. Furthermore, shorter breastfeeding duration was associated with poorer satiety response and higher consumption during an EAH procedure. Understanding if breastfeeding influences the development of satiety responsiveness and eating behavior may be important in an era characterized by abundant calorie-dense foods and a plethora of environmental cues promoting consumption. PMID- 24145927 TI - Clostridium difficile carriage and serum antitoxin responses in children with inflammatory bowel disease. AB - BACKGROUND: Adults with inflammatory bowel disease (IBD) have a high prevalence of Clostridium difficile carriage, but little data exist regarding pediatric patients with IBD. Serum antibody responses to C. difficile toxins in correlation with organism carriage are not described in IBD. This study determines the prevalence of C. difficile carriage and compares serum antibody responses to C. difficile toxins in pediatric outpatients with IBD and controls. METHODS: Fecal and serum samples were prospectively collected from pediatric outpatients with IBD (n = 85) and age-matched controls (n = 78). Initial and follow-up stool samples were tested using cytotoxigenic C. difficile culture and PCR to detect the toxin B gene. Pulsed-field gel electrophoresis determined the strain type. Enzyme-linked immunosorbent assay determined serum immunoglobulin responses to C. difficile toxins. RESULTS: Asymptomatic C. difficile carriage was significantly greater in IBD (17%) versus controls (3%) (P = 0.012). IBD type, disease severity, IBD therapy, recent antibiotics, and hospitalizations were not associated with carriage. Proton pump inhibitor use was significantly higher in patients with C. difficile carriage (54% versus 25%, P < 0.05). North American pulsed-field (NAP) strain carriage varied over time in patients colonized with C. difficile. A significantly greater proportion of patients with IBD had a positive serum antibody response to toxin A (69%) compared with controls (53%) (P < 0.05). CONCLUSIONS: Asymptomatic toxigenic C. difficile carriage was increased in pediatric outpatients with IBD compared with controls. Proton pump inhibitor use was associated with increased carriage. Antibody responses to C. difficile toxins were increased in IBD, potentially promoting asymptomatic colonization. Future studies should identify the risk factors for symptomatic C. difficile in pediatric IBD. PMID- 24145928 TI - Ethnicity differences in genetic susceptibility to ulcerative colitis: a comparison of Indian asians and white northern Europeans. AB - BACKGROUND: Studies in Caucasian populations have identified a number of genetic associations with ulcerative colitis (UC), but reports from other ethnic groups have been limited. Recent studies from India have reported an association with UC and a single polymorphism (SNP) in CARD15/NOD2 (SNP5, rs2066842), which has not been reported in Caucasian UC cohorts. In addition, strong genetic associations with SNPs in the HLA region have been reported in Indian UC populations. However, there have been no reports on the frequency of HLA class II alleles in Indian populations with inflammatory bowel disease to examine whether the associations differ from other ethnic populations. METHODS: Genotyping was performed for 137 Indian UC patients for HLA class II alleles (HLA-DRB1*1502 & HLA-DRB1*0103), IL23R (rs11209026), and CARD15/NOD2 (rs2066842). The genetic data were compared with 204 healthy Indian controls and 50 white European UC patients. RESULTS: The HLA-DRB1*0103 allele was absent in all Indian UC patients and controls in contrast to white European UC patients (9/50: 18%). The HLA-DRB1*1502 allele was significantly more frequent in the Indian UC cohort (29.2%) than controls (17.6%) (P = 0.04) and the allele was absent in the white European cohort. There were no significant differences in the frequency of the CARD15/NOD2 (rs2066842) variant or IL23R (rs11209026) between the different ethnic groups. CONCLUSIONS: The HLA DRB1*0103 allele is rare or absent in the Indian Asian population but HLA DRB1*1502 is positively associated with UC. Further genetic studies in this population could provide valuable information and may help distinguish the degree of influence of genetic and environmental pathogenic factors. PMID- 24145929 TI - Contributions of mood, pain catastrophizing, and cold hyperalgesia in acute and chronic low back pain: a comparison with pain-free controls. AB - OBJECTIVES: Quantitative sensory testing (QST) has been used to elucidate the peripheral and central mechanisms that underlie changes in pain sensitivity associated with low back pain (LBP). However, it remains unclear to what degree peripheral and central changes contribute to the generation and maintenance of LBP. The aim of this study was to compare thermal pain sensitivity, measured using QST, in participants with acute LBP, chronic LBP, and pain-free controls. MATERIALS AND METHODS: Participant groups with acute LBP (N=20), chronic LBP (N=30), and pain-free controls (N=30) were assessed by thermal QST. The unique contributions of pain-related psychological and QST variables to predict membership to the acute and chronic pain groups were also determined. RESULTS: We found that participants with chronic LBP demonstrated significantly lower cold pain threshold (CPT) in the primary area of pain (low back) as well as in an area anatomically remote from the primary area of pain (forearm) when compared with controls. Participants with acute LBP did not show significantly elevated pain sensitivity. CPT at the remote site was a significant independent predictor of membership to the chronic pain group, after the adjustment for mood and pain catastrophizing. CPT explained 8% of the total variance of 46% related to group membership. DISCUSSION: We found evidence for localized and generalized cold hyperalgesia in chronic, but not acute LBP. We might speculate that hyperalgesia develops as a consequence of long-lasting LBP, but prospective studies are needed to confirm this assumption. PMID- 24145930 TI - Middle East respiratory syndrome novel corona MERS-CoV infection. Epidemiology and outcome update. AB - Middle East respiratory syndrome coronavirus MERS-CoV is a newly emerging respiratory virus with a high case fatality rate among identified cases. The virus is thought to cause a severe disease in patients with underlying comorbidities. The identification of asymptomatic patients and mild cases among family and healthcare worker contacts of confirmed cases indicates a wider spectrum of clinical manifestation of the disease. The majority of patients presented with fever 98%, fever with cough 83%, and shortness of breath 72%. Radiographic manifestations range from unilateral infiltrate 43%, to increased bronchovascular markings 17%, and diffuse reticulonodular pattern 4%. Our understanding of the epidemiology and clinical presentation of the disease is increasing overtime. It is still not known what the source of the virus is and what the best treatment modality should be. PMID- 24145931 TI - Advanced techniques in molecular genetics and its implications on genetic testing and screening in the Arabian Peninsula. AB - Molecular diagnosis of human disorders is referred to as the detection of the various pathogenic mutations in DNA and/or RNA samples in order to facilitate detection, diagnosis, sub-classification, prognosis, and monitoring response to therapy. The use of molecular biology techniques to expand scientific knowledge of the natural history of diseases, identify people who are at risk for acquiring specific diseases, and diagnose human diseases at the nucleic acid level. Molecular diagnostics combines laboratory medicine with the knowledge and technology of molecular genetics and has been enormously revolutionized over the last decades, benefiting from the discoveries in the field of molecular biology. This review will discuss in details the recent advances in molecular diagnostics and how the Arabian Peninsula can benefit from those techniques knowing for a fact the high percentages of consanguineous marriages and the tribal nature of marriages which resulted in high incidence of genetic diseases. PMID- 24145932 TI - Characterization of the ABCC8 gene mutation and phenotype in patients with congenital hyperinsulinism in western Saudi Arabia. AB - OBJECTIVE: To understand the genetic etiologies of congenital hyperinsulinism (CHI) in a population of Saudi patients, and to explore genotype-phenotype characteristics. METHODS: We retrospectively reviewed a cohort of 11 children with CHI presenting to King Abdulaziz University Hospital, Jeddah, Kingdom of Saudi Arabia between March 2007 and February 2012. Mutational analysis (ABCC8 and KCNJ11) was performed retrospectively to identify phenotype and genotype characteristics. RESULTS: Analysis revealed ABCC8 mutations in 81.8% (9/11) of patients, with 2 patients not revealing any gene mutation. All positive patients showed a homozygous mutation in the ABCC8 gene, one in exon 29, 2 in exon 1-22, 2 in exon 28, and 4 in intron 36; one patient had a heterozygous mutation. Five patients (45.4%) responded well to treatment with diazoxide not requiring subtotal pancreatectomy, while 6 patients (54.6%) required subtotal pancreatectomy despite treatment with diazoxide and octreotide. Three patients (33.3%) died while waiting for surgery due to sepsis and thrombosis. Two patients (18.1%) showed remission, one of them after subtotal pancreatectomy. CONCLUSION: Homozygous mutations in ABCC8 are the most common causes of CHI in Saudi patients. Early diagnosis and therapy for persistent hyperinsulinemic hypoglycemia of infancy are essential to prevent neurodevelopmental delay. PMID- 24145933 TI - The polymorphism of angiotensin-receptor gene A1166C in familial hypertension and its distribution in the Han Yellow race of China. AB - OBJECTIVE: To study the polymorphism of angiotensin-type 1 receptor (AT1R) gene A1166C in familial primary hypertension and its distribution in Han Yellow race of China. METHODS: One hundred and four hypertensive patients with no family history, 178 hypertensive patients with familial history, and 150 healthy adults were randomly selected to participate in a prospective clinical trial, and genetype detection by standard polymerase chain reaction methods and restriction fragment length polymorphism (PCR-RFLP) in trials. The study was carried out between October 2009 and November 2010 at Jinan Center for Cardiovascular Disease, Affiliated Hospital of Taishan Medical College, Jinan, China. RESULTS: Notable statistical significances exist in the frequency of genotype and allele of A1166C in familial hypertension group (x2=7.663, p=0.020) compared with the normal control group (x2= 8.288, p=0.004). No significant difference was found in the hypertension group (x2 = 2.186, p=0.322) compared with the normal control group (x2=1.289, p=0.256) in the frequency of genotype and allele of A1166C. No significant differences were found between various ages or genders in each of the 3 groups in genotype and allele of A1166C (p>0.05) distribution. CONCLUSION: In the Han Yellow race population of China, the frequency of genotype and allele of A1166C of patients with familial hypertension is higher than that of healthy adults. The distribution of AT1R gene polymorphisms of A1166C is not related to age or gender. PMID- 24145934 TI - Characterization, quantification, and assessment of immune protection potential of secretory immunoglobulin A in colostrum samples from Saudi women. AB - OBJECTIVE: To characterize, quantify, and assess the function of colostral secretory immunoglobulin A (sIgA) in Saudi women. METHODS: This prospective study was performed between March 2009 and February 2010 at King Khalid University Hospital, Riyadh, Saudi Arabia. Twenty milliliters of colostrum sample was collected from each of 23 healthy Saudi women (mean age 26+/-4 years) included in the study within 48 hours postpartum. Levels of sIgA and sIgM were determined by enzyme-linked immunosorbent assay (ELISA) and purification of secretory antibodies from pooled clarified sample was performed by thiophilic-gel chromatography, Jacalin-agarose chromatography, and Sephacryl S-300 gel filtration. Antibody induced respiratory burst in peripheral blood neutrophils and monocytes was assessed by chemiluminescence. RESULTS: The median concentration of sIgA1 was 0.053 mg/ml, sIgA2 0.047 mg/ml and sIgM 0.067 mg/ml with interquartile ranges of 0.308, 0.158 and 0.150. The levels of antibodies were no different. Whereas, 60% of IgA1 was present in dimeric and 30% in trimeric form; the major bulk of sIgA2 (85%) were comprised of the dimeric form. Both sIgA and serum IgA were able to induce effective and almost identical respiratory bursts in neutrophils and monocytes. CONCLUSION: Dimeric forms of sIgA were the predominant antibodies in colostrum samples and sIgA antibodies exhibited functional similarity with serum IgA. PMID- 24145935 TI - Relation between serum creatinine and postoperative results of open-heart surgery. AB - OBJECTIVE: To determine the impact of preoperative serum creatinine level in non dialyzable patients on postoperative morbidity and mortality. METHODS: This is a prospective study, where serum creatinine was used to give primary assessment on renal function status preoperatively. This study includes 1,033 patients, who underwent coronary artery bypass grafting, or valve(s) operations. The study took place at Al-Hada Military Hospital, Taif, Kingdom of Saudi between May 2008 and January 2012. Data were statistically analyzed using Chi square (x2) test and multivariable logistic regression, to evaluate the postoperative morbidity and mortality risks associated with low serum creatinine levels. RESULTS: Postoperative mortality increased with high serum creatinine level >1.8 mg/dL (p/=50 years, n=114), and group B-I (<60 years, n=215) and group B-II (>/=60 years, n=36). Serum FT concentrations were measured by using enzyme-linked immunosorbent assay technique. RESULTS: The results revealed significant negative correlation between serum FT concentrations and the age values of the studied subjects (r= -0.231, p=0.0001). The mean (+/-SEM) value of serum FT concentrations was significantly decreased in group 3 when compared with that of group 1 (p<0.009) and group 2 (p=0.031) as well as in group BII than in group BI (p=0.043). CONCLUSION: This study found significant decline in serum FT level, the gold test for andropause phenomenon, in healthy male subjects in age-related changes and the cutoff at which such significant decrease occurred is at 60 years of age and above. PMID- 24145937 TI - Retrospective review of visual outcome in operated lens subluxation. AB - OBJECTIVE: To describe the visual outcome of patients with lens subluxation (LS), including ectopia lentis (EL) due to genetic causes, who underwent surgical correction using standard selection criteria and surgical techniques in order to assess effectiveness of current LS therapy. METHODS: This is a retrospective review of 17 sequential patients with LS who underwent lens aspiration between 2000 and 2012 through an anterior (limbal) or posterior (pars plana) approach at King Abdulaziz University Hospital, Riyadh, Saudi Arabia. Snellen visual acuity was converted to the logarithm of the Minimum Angle of Resolution (logMAR) equivalent for statistical analysis. All statistical comparisons were performed by t-test. RESULTS: This series consisted of 28 eyes with causes of LS including Marfan syndrome (12 eyes), familial EL (5 eyes), homocystinuria (4 eyes), sickle cell anemia (2 eyes), and trauma (6 eyes). Mean visual acuity (VA) for the entire group increased from 20/200 before surgery to 20/70 after surgery (p>/=0.01). Post-operative VA was >/=20/60 in all eyes that did not have complicating factors such as amblyopia, retinal detachment, and/or other ocular abnormalities. Visual outcome of limbal and pars plana approaches was statistically similar (p>/=0.29). Patients with genetic causes of EL had a significantly better visual outcome than other patients (p>/=0.01); out of these, patients with Marfan syndrome had a better visual outcome than other patients with genetic abnormalities (p>/=0.02). CONCLUSION: Accepted surgical criteria and techniques improved visual outcome in patients with LS. Patients with Marfan syndrome and others genetic abnormalities without ocular complications had best visual outcomes. PMID- 24145938 TI - Rectus abdominis endometriosis. A descriptive analysis of 10 cases concerning this rare occurrence. AB - OBJECTIVE: To report 10 cases of rectus abdominis endometrioma, emphasizing the clinical presentations, imaging investigations, cytohistological findings, and surgical treatment employed. METHODS: This is a descriptive analysis of 10 surgically-proven cases of rectus abdominis muscle endometriosis, seen over a 5 year period from 2007 to 2012 at Sohag University Hospital, Sohag, Egypt and Najran Armed Forces Hospital, Najran, Saudi Arabia. All patients had undergone ultrasonography. Computerized tomography (CT) and magnetic resonance imaging (MRI) were performed in some cases. Surgical excision was the way of treatment in all patients. RESULTS: This study was carried out in 10 women with a mean age of 33.9 years. Nine cases had previous history of cesarean section (CS) while one patient had laparoscopy converted to laparotomy for ovarian cyst. All patients were presented with abdominal pain but only 3 had a palpable mass. Ten lesions within the rectus abdominis muscle were detected with automated ultrasound and MRI depicted one lesion, which was missed by ultrasound in a patient who had 2 concomitant lesions. Preoperative fine needle aspiration (FNA) was carried out in 2 patients. Wide surgical excision was performed in all cases. Histopathology was confirmatory in each instance. No complications or recurrence were recorded on follow-up (6-24 months; mean 13.2 months). CONCLUSION: This disease is not as rare as previously thought, and should be included in the differential diagnosis of abdominal wall masses in reproductive-age females. PMID- 24145939 TI - Accidental genital trauma in the female children in Jordan and the role of forensic medicine. AB - OBJECTIVE: To evaluate the frequency and the nature of genital trauma in female children in Jordan, and to stress the role of forensics. METHODS: This is a cross sectional study conducted between March 2008 and December 2011 in Jordan University Hospital, Amman, Jordan. Sixty-three female children were examined for genital trauma after immediate admission. The mechanism of injury was categorized and reported by the examiners as either straddle, non-straddle blunt, or penetrating. RESULTS: Straddle injury was the cause of injuries in 90.5% of patients, and contusions were the significant type of injury in 34% of patients, followed by abrasions in both labia majora and labia minora. Only one case suffered from non-intact hymen and 2 had hematuria. These 3 cases (4.7%) required surgical intervention and follow-up after 2 weeks. CONCLUSION: Straddle injuries were the main cause of genital trauma and rarely affect the hymen; however, due to the sensitivity of the subject and the severity of the traumas, forensic physicians should provide consultation and cooperate with gynecologists to exclude or confirm hymenal injuries, where empathy is necessary to mitigate tension associated with such injuries for the sake of the child and the parents as well, along with good management of the injury type. PMID- 24145940 TI - A comparative study between prescribed and over-the-counter antibiotics. AB - OBJECTIVE: To examine the influence of pharmacists' demographic characteristics on dispensing antibiotics purchased with and without a prescription in the community pharmacies. METHODS: This cross-sectional study was conducted in 24 randomly-selected community pharmacies located in Abu Dhabi, United Arab Emirates between March and September 2009. Data were collected through a closed-structured questionnaire and analyzed using the Statistical Package for Social Sciences Version 17. Descriptive statistics, odds ratios, significance and 95% CI and logistic regression analyses were then used to analyze the resulting data. RESULTS: Participating pharmacists conducted a total of 1645 antibiotic transactions (1211 [73.6%] dispensed with prescriptions versus and 434 [26.4%] without). Gender and socioeconomic status of the patients had a significant effect in acquiring antibiotics without prescription (p=0.012, p=0.001). Clarithromycin (91.5%), cefuroxime (91.3%), and co-amoxiclav (66.4%) were dispensed with prescription. Ceftriaxone (53.3%), amoxicillin (47.8%) and co amoxiclav (33.6%) were dispensed without prescription. Dispensing of antibiotics with prescription were frequently given a 5, 7, or 10 day regimen, while those without prescription were frequently given 3-7 days duration. Co-amoxiclav for sore throat was commonly dispensed without prescription. Ceftriaxone for sexually transmitted diseases was dispensed at a similar rate, both with and without prescription. CONCLUSION: Dispensing antibiotic without prescription is illegal and alarming. Patient interviews and interventions to improve the current prescribing pattern for both prescribers and pharmacists are highly warranted. PMID- 24145941 TI - Evidence based medicine workshop. Randomized controlled trial of the efficacy on physician's knowledge and skills. AB - OBJECTIVE: To assess the effect of evidence based medicine (EBM) workshop on knowledge and skills of physicians towards EBM use in the near future, as well as in the long run. METHODS: This is a randomized controlled trial conducted in the primary health care administration center in Dammam, Saudi Arabia between October and November 2008. Fifty-nine primary care physicians in the intervention group participated in the EBM workshops while 89 physicians from the control group attended other primary health care activities other than EBM workshop. The main outcome was to measure the change in the participants' level of awareness and competencies in EBM components (including formulation of questions, literature searching, critical thinking and appraisal) using a pre-designed questionnaire before, immediately after, and 4 months after the workshop. RESULTS: Evidence based medicine workshops improved physician's scores in all components of EBM, from 38.9%+/-20.0% at pre-test to 81.4%+/-10.6% post-test, and sustained this improvement to a lesser degree to 66.8%+/-10.0% 4 months post-intervention test (p<0.001 for the differences in all scores). CONCLUSION: Participating in EBM workshop significantly enhanced physicians' ability to formulate questions, performed literature search, critical appraisal, and applied best-evidence in clinical practice, which retained up to 4 months post-test. PMID- 24145942 TI - Analysis of health promoting lifestyle behaviors and associated factors among nurses at a university hospital in Turkey. AB - OBJECTIVE: To determine the health promotion lifestyle behaviors (HPLB) of nurses working in a university medical faculty hospital in Turkey and to investigate the factors related behaviors. METHODS: This descriptive and cross-sectional study was conducted in Ankara University Medical Faculty Hospital, Ankara, Turkey, between January 2008 and 23 January 2009. Two hundred and eighty nurses were recruited randomly out of 550 female nurses. However, 10 of them were removed from the research due to the annual leave. The study was conducted among 270 nurses. Health promotion lifestyle behaviors were evaluated using Personal Information Form and Health Promoting Lifestyle Profile (HPLP II). Data were analyzed using independent t-test and analysis of variance (ANOVA), Kruskall Wallis, Tukey test by SPSS Version 16 package with significance level of p<0.05. RESULTS: The highest sub-scale score with 26.0+/-5.00 was detected from self realization and the lowest was detected from physical activity with 13.9+/-4.50 points. Nurses' self-realization scores differed significantly by perception of health status (p=0.029). Income status differed significantly by health responsibility (p=0.049), interpersonal relations (p=0.032), stress management (p=0.027) subscales, and total score of the HPLP II (p=0.043). The physical activity subscale score of the HPLP II differed significantly by marital status (p=0.036) and situation of having a child but singles scored better than married (p=0.001). CONCLUSION: Low exercise score indicated the need for intervention programs for the nurses surveyed. New regulations aim to raise the income level of nurses should be applied. PMID- 24145943 TI - A case of pediatric gastrointestinal basidiobolomycosis mimicking Crohn's disease. A review of pediatric literature. AB - Basidiobolomycosis is a rare fungal infection caused by basidiobolus ranarum. The vast majority of gastrointestinal basidiobolomycosis cases were reported from tropical and subtropical regions. We report a Saudi pediatric patient with ileal basidiobolomycosis and initial clinical presentation mimicking acute appendicitis before being misdiagnosed as Crohn's disease. Our case is the first to report effective treatment of pediatric gastrointestinal basidiobolomycosis using voriconazole mono-therapy. In addition, we present extensive review of pediatric gastrointestinal basidiobolomycosis in medical literature. PMID- 24145944 TI - Management of an impacted maxillary central incisor with dilacerated root. AB - Dilaceration is a comparatively uncommon dental deformity generally characterized by an angulation between crown and root, and consequently causing non-eruption of the tooth. Dilaceration generally occurs following trauma to the apices of deciduous dentition, which lies close to the permanent tooth buds. As a result, surgical extraction used to be the first choice when making the treatment plan for a case with severely dilacerated teeth. This case report presents the orthodontic alignment of a permanent maxillary right central incisor in an 8-year old boy who had an impacted inverted maxillary central incisor, with distoangular root dilaceration through the crown. Following surgical exposure with the closed eruption technique and appropriate orthodontic traction, the tooth was successfully aligned into the dental arch and the root was radiologically shown to be straightened and relatively well developed. The impacted dilacerated incisor diagnosed in the early mixed dentition should be treated with the aid of orthodontic traction. PMID- 24145945 TI - Septic pulmonary embolism secondary to Staphylococcus aureus septic thrombophlebitis in a pediatric patient. AB - We present the clinical course of an 11-year-old child with septic pulmonary embolism secondary to community acquired methicillin-resistant Staphylococcus aureus (MRSA) septic deep venous thrombosis. The aim is to emphasize the non specific symptoms of septic pulmonary embolism in pediatrics, the frequent association with septic deep venous thrombosis and osteomyelitis, and to highlight that MRSA is the most frequently isolated organism. Pediatricians should consider septic pulmonary embolism in cases of septic deep venous thrombosis even in the absence of respiratory symptoms. The initial antibiotic management should include glycopeptides, as community acquired MRSA is increasingly the isolated organism in this disorder. PMID- 24145946 TI - A development model for nursing in the Kingdom of Saudi Arabia. PMID- 24145947 TI - Muscle synergies during a single-leg drop-landing in boys and girls. AB - The purpose of this study was to investigate muscle activation patterns during a landing task in boys and girls through the use of muscle synergies. Electromyographical data from six lower extremity muscles were collected from 11 boys and 16 girls while they performed single-leg drop-landings. Electromyographical data from six leg muscles were rectified, smoothed, and normalized to maximum dynamic muscle activity during landing. Data from 100 ms before to 100 ms after touchdown were submitted to factor analyses to extract muscle synergies along with the associated activation and weighing coefficients. Boys and girls both used three muscle synergies. The activation coefficients of these synergies captured muscle activity during the prelanding, touchdown, and postlanding phases of the single-leg drop-landing. Analysis of the weighing coefficients indicated that within the extracted muscle synergies the girls emphasized activation of the medial hamstring muscle during the prelanding and touchdown synergy whereas boys emphasized activation of the vastus medialis during the postlanding synergy. Although boys and girls use similar muscle synergies during single-leg drop-landings, they differed in which muscles were emphasized within these synergies. The observed differences in aspects related to the muscle synergies during landing may have implications with respect to knee injury risk. PMID- 24145948 TI - Long-term outcomes after first-generation autologous chondrocyte implantation for cartilage defects of the knee. AB - BACKGROUND: Autologous chondrocyte implantation (ACI) represents an established surgical therapy for large cartilage defects of the knee joint. Although various studies report satisfying midterm results, little is known about long-term outcomes. PURPOSE: To evaluate long-term clinical and magnetic resonance imaging (MRI) outcomes after ACI. STUDY DESIGN: Case series; Level of evidence, 4. METHODS: Between January 1997 and June 2001, a total of 86 patients were treated with ACI for isolated cartilage defects of the knee. The mean patient age at the time of surgery was 33.3 +/- 10.2 years, and the mean defect size was 6.5 +/- 4.0 cm(2). Thirty-four defects were located on the medial femoral condyle and 13 on the lateral femoral condyle, while 6 patients were treated for cartilage defects of the trochlear groove and 17 for patellar lesions. At a mean follow-up of 10.9 +/- 1.1 years, 70 patients (follow-up rate, 82%) treated for 82 full-thickness cartilage defects of the knee were available for an evaluation of knee function using standard instruments, while 59 of these patients were additionally evaluated by 1.5-T MRI to quantify the magnetic resonance observation of cartilage repair tissue (MOCART) score. Clinical function at follow-up was assessed by means of the Lysholm score, the International Knee Documentation Committee (IKDC) score, and the Knee injury and Osteoarthritis Outcome Score (KOOS). Patient activity was assessed by the Tegner score. In addition, pain on a visual analog scale (VAS) and patient satisfaction were evaluated separately. RESULTS: At follow-up, 77% reported being "satisfied" or "very satisfied." The mean IKDC score at follow-up was 74.0 +/- 17.3. The mean Lysholm score improved from 42.0 +/- 22.5 before surgery to 71.0 +/- 17.4 at follow-up (P < .01). The mean pain score on the VAS decreased from 7.2 +/- 1.9 preoperatively to 2.1 +/- 2.1 postoperatively. The mean MOCART score was 44.9 +/- 23.6. Defect-associated bone marrow edema was found in 78% of the cases. Nevertheless, no correlation between the MOCART score and clinical outcome (IKDC score) could be found (Pearson coefficient, r = 0.173). CONCLUSION: First-generation ACI leads to satisfying clinical results in terms of patient satisfaction, reduction of pain, and improvement in knee function. Nevertheless, full restoration of knee function cannot be achieved. Although MRI reveals lesions in the majority of the cases and the overall MOCART score seems moderate, this could not be correlated with long term clinical outcomes. PMID- 24145949 TI - Operative management of ulnar collateral ligament insufficiency in adolescent athletes. AB - BACKGROUND: The incidence of ulnar collateral ligament (UCL) injuries of the elbow has increased in adolescents over the past decade because of widespread participation in athletics and heightened awareness among physicians. HYPOTHESIS: Ulnar collateral ligament reconstruction using the docking technique would result in a successful return to athletic activity in this age group. STUDY DESIGN: Case series; Level of evidence, 4. METHODS: Study participants were 55 skeletally mature adolescent athletes (mean age, 17.6 years; range, 15-18 years) who underwent UCL reconstruction between 2008 and 2010. While the majority of patients were baseball players (n = 47), there were 3 gymnasts and 5 javelin throwers included in the study. Each patient underwent UCL reconstruction utilizing the docking technique after an adequate trial of nonoperative management (mean, 5.8 months). At the latest follow-up, patients were evaluated to determine their ability to return to athletic activity. Clinical outcomes were classified using the Conway scale, the Andrews-Timmerman score, and the Kerlan Jobe Orthopaedic Clinic (KJOC) score. RESULTS: At a minimum 2-year follow-up, 87% (48/55) of patients had excellent results using the Conway scale. Overall, there were only 2 poor results (3.6%) that were observed in patients with concomitant osteochondritis dissecans lesions of the capitellum. There were 4 postoperative complications in 4 patients (2 gymnasts and 2 javelin throwers) who developed ulnar neuritis after UCL reconstruction. The mean Andrews-Timmerman score was 83.6 +/- 7.2 (range, 30-100), and the mean KJOC score was 88.0 +/- 6.0 (range, 40 100). CONCLUSION: The docking technique results in favorable clinical outcomes in adolescent athletes with UCL insufficiency at a minimum of 2 years postoperatively. Patients with concomitant intra-articular lesions should be cautioned preoperatively that they might experience inferior clinical outcomes. Postoperatively, adolescent gymnasts and javelin throwers may be at an increased risk for transient paresthesia of the ulnar nerve caused by increased stress on the medial elbow. PMID- 24145950 TI - Molecular analysis of transplant rejection: marching onward. AB - Transcriptional profiling of organ transplants is increasingly defining the biological pathways responsible for graft rejection at the molecular level and identifying gene transcripts that diagnose or predict rejection. These advances hold significant promise for the treatment of organ rejection and for improving clinical outcomes after transplantation, but hurdles remain. PMID- 24145952 TI - Psychoactive substance use in truck drivers: occupational health and public health. PMID- 24145951 TI - Dynamic contrast-enhanced magnetic resonance imaging can assess vascularity within fracture non-unions and predicts good outcome. AB - OBJECTIVES: To prospectively evaluate whether dynamic contrast-enhanced (DCE) MRI can assess vascularity within non-unions and predicts clinical outcome in combination with the clinical Non-Union Scoring System (NUSS). METHODS: Fifty eight patients with non-unions of extremities on CT underwent 3-T DCE MRI. Signal intensity curves obtained from a region-of-interest analysis were subdivided into those with more intense contrast agent uptake within the non-union than in adjacent muscle (vascularised non-union) and those with similar or less contrast uptake. The pharmacokinetic parameters of the Tofts model K trans, K ep, iAUC and V e were correlated with union at CT 1 year later (n = 49). RESULTS: Despite inserted osteosynthetic material, DCE parameters could be evaluated in 57 fractures. The sensitivity/specificity of vascularised non-unions as an indicator of good outcome was 83.9%/50.0 % compared to 96.8%/33.3% using NUSS (n = 49). Logistic regression revealed a significant impact of NUSS on outcome (P = 0.04, odds ratio = 0.93). At first examination, median iAUC (initial area under the enhancement curve) for the ratio non-union/muscle was 10.28 in patients with good outcome compared with 3.77 in non-responders (P = 0.023). K trans, K ep and Ve within the non-union were not significantly different initially (n = 57) or 1 year later (n = 19). CONCLUSIONS: DCE MRI can assess vascularity in fracture non unions. A vascularised non-union correlates with good outcome. KEY POINTS: * Dynamic contrast-enhanced magnetic resonance imaging can assess vascularity within bony non-unions. * Vascularised ununited fractures appear better at 1-year CT than poorly vascularised fractures. * Non-union healing after osteosynthesis or osteoinductive drugs fundamentally requires vascularity. * DCE MRI predicts treatment outcome better than the clinical Non-Union Scoring System. * DCE MRI is clinically feasible to predict treatment outcome in bony non-unions. PMID- 24145953 TI - Psychoactive substance use by truck drivers: a systematic review. AB - The aim of this study was to summarise the scientific evidence on the prevalence of psychoactive substance use and on the factors associated with their intake among truck drivers. A systematic review was performed in the databases PubMed, Scientific Electronic Library Online, Latin American and Caribbean Health Sciences, and Cochrane and 36 cross-sectional studies were identified with quantitative results about the use of psychoactive substances by truck drivers. Out of these, 28 were carried out in countries with large land areas and 23 obtained their information through self-reporting. The most frequently studied substances were alcohol (n=25), amphetamines (n=17), marijuana (n=16) and cocaine (n=13). The prevalence of the use of these substances greatly varied: alcohol (0.1-91.0%); amphetamines (0.2-82.5%), marijuana (0.2-29.9%), cocaine (0.1-8.3%). The frequency of substance use was lower in studies that investigated the presence of these substances in biological samples than in those based on self reported use. In 12 studies that evaluated factors associated with the intake of psychoactive substances, the following stood out: younger age, higher income, longer trips, alcohol consumption, driving in the night shift, travelling interstate routes, long or short sleep, fewer hours of rest, little experience of the driver, connection with small and medium sized companies, income below levels determined by labour agreements, productivity-based earnings and prior involvement in accidents. The frequency of psychoactive substance use by truck drivers seems to be high, although that greatly varies according to the type of substance and the method of collecting the information. The use of these substances was mainly associated with indicators of poor working conditions. PMID- 24145954 TI - Prevalence of vitamin D deficiency among perinatally HIV-infected Thai adolescents receiving antiretroviral therapy. AB - We assessed the prevalence of vitamin D deficiency among 101 perinatally HIV infected Thai adolescents receiving antiretroviral therapy. Median age was 14.3 (interquartile range 13.0-15.7) years, and 90% had a HIV RNA<50 copies/mL. The median (interquartile range) 25-hydroxyvitamin D (25-OHD) level was 24.8 (6.9 46.9) ng/mL; 25 (24.7%) had vitamin D deficiency (25-OHD<20 ng/mL) and 47 (46.5%) had insufficiency (25-OHD 20-30 ng/mL). Adolescents with vitamin D deficiency had significantly higher parathyroid hormone levels (54.9 vs. 40.2 pg/mL, P<0.007). No associations between vitamin D deficiency and body mass index, bone mineral density, efavirenz use, HIV RNA, CD4 or self-reported sunlight exposure were observed. PMID- 24145955 TI - Comparing Haemophilus influenzae type b conjugate vaccine schedules: a systematic review and meta-analysis of vaccine trials. AB - BACKGROUND: The optimal schedule and the need for a booster dose are unclear for Haemophilus influenzae type b (Hib) conjugate vaccines. We systematically reviewed relative effects of Hib vaccine schedules. METHODS: We searched 21 databases to May 2010 or June 2012 and selected randomized controlled trials or quasi-randomized controlled trials that compared different Hib schedules (3 primary doses with no booster dose [3p+0], 3p+1 and 2p+1) or different intervals in primary schedules and between primary and booster schedules. Outcomes were clinical efficacy, nasopharyngeal carriage and immunological response. Results were combined in random-effects meta-analysis. RESULTS: Twenty trials from 15 countries were included; 16 used vaccines conjugated to tetanus toxoid (polyribosylribitol phosphate conjugated to tetanus toxoid). No trials assessed clinical or carriage outcomes. Twenty trials examined immunological outcomes and found few relevant differences. Comparing polyribosylribitol phosphate conjugated to tetanus toxoid 3p+0 with 2p+0, there was no difference in seropositivity at the 1.0 MUg/mL threshold by 6 months after the last primary dose (combined risk difference -0.02; 95% confidence interval: -0.10, 0.06). Only small differences were seen between schedules starting at different ages, with different intervals between primary doses, or with different intervals between primary and booster doses. Individuals receiving a booster were more likely to be seropositive than those at the same age who did not. CONCLUSIONS: There is no clear evidence from trials that any 2p+1, 3p+0 or 3p+1 schedule of Hib conjugate vaccine is likely to provide better protection against Hib disease than other schedules. Until more data become available, scheduling is likely to be determined by epidemiological and programmatic considerations in individual settings. PMID- 24145956 TI - Evaluation and treatment of mastitis in infants. AB - We reviewed cases of mastitis in infants treated at Children's Healthcare of Atlanta from 2005 to 2011. Among infants with breast cultures, Staphylococcus aureus was the most common cause. No infant with a positive breast culture had a concordant positive culture elsewhere. Our findings argue that urine, blood and spinal fluid cultures are unnecessary in well-appearing afebrile infants with mastitis. PMID- 24145957 TI - Identification of inflammatory neuronal injury and prevention of neuronal damage in multiple sclerosis: hope for novel therapies? AB - IMPORTANCE: Although multiple sclerosis (MS) has long been considered the prototype for an inflammatory, demyelinating disease of the central nervous system, modern histopathology and imaging techniques show that significant damage to neuronal structures already start occurring in the earliest stages of the disease. As the disease progresses, the extent of neuronal pathology accumulates. Therapeutic progress in terms of the prevention of increased disability has only just begun. OBJECTIVE: To review possible diagnostic improvements of neuronal compartment pathology as well as direct therapeutic interventions based on reports from the last decade and outline clinical results from studies and perspectives on the progression of MS. EVIDENCE REVIEW: Literature search focused on publications and the references contained therein, relating to neuronal compartment pathology and direct therapeutic interventions published in the last decade in well-established peer-reviewed journals. The quality of the cited works was ensured by their acceptance by peer review, participation in clinical trials, and authors' own expert assessment. FINDINGS: Current MS therapies as well as medications that are in late phase 3 trials or under approval exhibit primarily anti-inflammatory properties. However, clinical and imaging data demonstrate the potential of using novel therapies to prevent neuronal damage. Whether these exhibit effects on the neuronal compartment due to interference with the immune system or additional direct effects depends without question on the specific mechanism of action. CONCLUSIONS AND RELEVANCE: Combining anti-inflammatory and direct neuroprotective, neuroregenerative/repair therapy strategies may open up new avenues in the treatment of MS. PMID- 24145958 TI - Stabilization of metastable ferroelectric Ba1-xCaxTi2O5 by breaking Ca-site selectivity via crystallization from glass. AB - The thermal stability and dielectric and structural properties of ferroelectric Ba1-xCaxTi2O5 (0 <= x <= 0.30) prepared by crystallization from glass are investigated. The Ba1-xCaxTi2O5 compounds with x < 0.10 are thermally stable phases, while those with x >= 0.10 are metastable phases. The ferroelectric transition temperature drastically decreases from 470 to 220 degrees C with increasing x. Crystal structure analyses reveal that one of two possible Ba sites is occupied by Ca in the stable phase region, while Ca-site selectivity is broken in the metastable phase region. The Ca-site selectivity introduces local distortion and makes the crystal lattice unstable. However, the local distortion is suppressed by the occupancy of Ca into both Ba sites. Accordingly, the metastable ferroelectric phase can be obtained beyond the substitution limit of Ca by crystallization from the glassy state. The stabilization mechanism provides possible wide control of the functionality of materials by expanding the composition range. PMID- 24145959 TI - Inhibition of ZNF746 suppresses invasion and epithelial to mesenchymal transition in H460 non-small cell lung cancer cells. AB - Although ZNF746, also known as Parkin-interacting substrate (PARIS), has been reported to suppress peroxisome proliferator-activated receptor gamma coactivator 1alpha (PGC-1alpha) and its target gene NRF-1 leading to the neurodegeneration in Parkinson's disease, its function in tumorigenesis has yet to be investigated. Thus, in the present study, the role of ZNF746 in the invasion and epithelial to mesenchymal transition (EMT) in H460 non-small cell lung cancer (NSCLC) cells was investigated. Invasion assay showed that inhibition of ZNF746 using siRNA transfection inhibited the invasion of H460 NSCLC cells using Boyden chamber. Quantitative PCR (qPCR) analysis revealed that the silencing of ZNF746 attenuated the expression of matrix metalloproteinase (MMP)1, MMP2 and MMP9, but not MMP7, in H460 NSCLC cells. Immunoblotting assay revealed that the expression of E cadherin and beta-catenin of epithelial phenotype was upregulated, while Slug was downregulated in ZNF746 siRNA-transfected H460 NSCLC cells. Accordingly, the mRNA expression of E-cadherin was upregulated while vimentin or Slug, Twist, ZEB as EMT key transcriptional factors were suppressed in ZNF746 siRNA-transfected H460 NSCLC cells. Also, mRNA expression of transcriptional marker Nanog and Octamer binding transcription factor 4 (OCT4), known to enhance malignancy and metastasis in lung adenocarcinoma, was suppressed in ZNF746 siRNA-transfected H460 NSCLC cells. Notably, the endogenous expression of ZNF746 was induced in parallel with Twist at the protein level during hypoxia. Overall, our findings suggest that inhibition of ZNF746 suppresses the invasion and EMT molecules in H460 NSCLC cells and ZNF746 may be an important target molecule in lung tumorigenesis. PMID- 24145961 TI - Hierarchical structure of biological systems: a bioengineering approach. AB - A general theory of biological systems, based on few fundamental propositions, allows a generalization of both Wierner and Berthalanffy approaches to theoretical biology. Here, a biological system is defined as a set of self organized, differentiated elements that interact pair-wise through various networks and media, isolated from other sets by boundaries. Their relation to other systems can be described as a closed loop in a steady-state, which leads to a hierarchical structure and functioning of the biological system. Our thermodynamical approach of hierarchical character can be applied to biological systems of varying sizes through some general principles, based on the exchange of energy information and/or mass from and within the systems. PMID- 24145960 TI - Identification and characterization of porcine kobuvirus variant isolated from suckling piglet in Gansu province, China. AB - Kobuviruses comprise three species, the Aichivirus A, Aichivirus B, and Aichivirus C (porcine kobuvirus). Porcine kobuvirus is endemic to pig farms and is not restricted geographically but, rather, is distributed worldwide. The complete genomic sequences of four porcine kobuvirus strains isolated during a diarrhea outbreak in piglets in the Gansu province of China were determined. Two of these strains exhibited variations relative to the traditional strains. The potential 3C/3D cleavage sites of the variant strains were Q/C, which differed from the Q/S in the traditional porcine kobuvirus genome. A 90-nucleotide deletion in the 2B protein and a single nucleotide insertion in the 3'UTR were found in the variant strains. The VP1 regions of all four porcine kobuviruses in our study were highly variable (81%-86%). Ten common amino acid mutations were found specifically at certain positions within the VP1 region. Significant recombination sites were identified using SimPlot scans of whole genome sequences. Porcine kobuviruses were also detected in pig serum, indicating that the virus can escape the gastrointestinal tract and travel to the circulatory system. These findings suggest that mutations and recombination events may have contributed to the high level of genetic diversity of porcine kobuviruses and serve as a driving force in its evolution. PMID- 24145962 TI - Evidence of excited state localization and static disorder in LH2 investigated by 2D-polarization single-molecule imaging at room temperature. AB - Two-dimensional polarization fluorescence imaging of single light harvesting complexes 2 (LH2) of Rps. acidophila was carried out to investigate the polarization properties of excitation and fluorescence emission simultaneously, at room temperature. In two separate experiments we excited LH2 with a spectrally narrow laser line matched to the absorption bands of the two chromophore rings, B800 and B850, thereby indirectly and directly triggering fluorescence of the B850 exciton state. A correlation analysis of the polarization modulation depths in excitation and emission for a large number of single complexes was performed. Our results show, in comparison to B800, that the B850 ring is a more isotropic absorber due to the excitonic nature of its excited states. At the same time, we observed a strong tendency for LH2 to emit with dipolar character, from which preferential localization of the emissive exciton, stable for minutes, is inferred. We argue that the observed effects can consistently be explained by static energetic disorder and/or deformation of the complex, with possible involvement of exciton self-trapping. PMID- 24145963 TI - Oridonin exerts protective effects against hydrogen peroxide-induced damage by altering microRNA expression profiles in human dermal fibroblasts. AB - The aim of the present study was to evaluate the protective effects of oridonin on hydrogen peroxide-induced cytotoxicity in normal human dermal fibroblasts (NHDFs) using microRNA (miRNA) expression profile analysis. Oridonin was not cytotoxic at low doses (<=5 uM) in the NHDFs, and pre-treatment of the cells with oridonin significantly reduced hydrogen dioxide (H2O2)-mediated cytotoxicity and cell death. Whereas oridonin showed no free radical scavenging activity in in vitro and in vivo antioxidant assays, treatment of the NHDFs with oridonin was associated with intracellular scavenging of reactive oxygen species. High-density miRNA microarray analysis revealed alterations in the expression profiles of specific miRNAs (5 upregulated and 22 downregulated) following treatment with oridonin in the H2O2-treated NHDFs. Moreover, the use of a miRNA target-gene prediction tool and Gene Ontology analysis demonstrated that these miRNAs are functionally related to the inhibition of apoptosis and cell growth. These data provide valuable insight into the cellular responses to oridonin in H2O2-induced damage in NHDFs. PMID- 24145964 TI - Antibody staining in C. elegans using "freeze-cracking". AB - To stain C. elegans with antibodies, the relatively impermeable cuticle must be bypassed by chemical or mechanical methods. "Freeze-cracking" is one method used to physically pull the cuticle from nematodes by compressing nematodes between two adherent slides, freezing them, and pulling the slides apart. Freeze-cracking provides a simple and rapid way to gain access to the tissues without chemical treatment and can be used with a variety of fixatives. However, it leads to the loss of many of the specimens and the required compression mechanically distorts the sample. Practice is required to maximize recovery of samples with good morphology. Freeze-cracking can be optimized for specific fixation conditions, recovery of samples, or low non-specific staining, but not for all parameters at once. For antibodies that require very hard fixation conditions and tolerate the chemical treatments needed to chemically permeabilize the cuticle, treatment of intact nematodes in solution may be preferred. If the antibody requires a lighter fix or if the optimum fixation conditions are unknown, freeze-cracking provides a very useful way to rapidly assay the antibody and can yield specific subcellular and cellular localization information for the antigen of interest. PMID- 24145965 TI - [Biopsies from bone and soft tissue sarcoma : a nationwide survey in Germany]. AB - AIM OF THE STUDY: A biopsy is an essential step in the diagnostic cascade of malignant bone and soft tissue tumors. The objective is always the extraction of a representative tissue specimen in line with the approach for the definitive operation. The aim of this study therefore was to assess the diagnostic approaches regarding the biopsy of tumors in orthopedic centers in Germany. MATERIAL AND METHODS: In total 60 hospitals with an orthopedic focus on tumors were contacted and provided with a newly developed questionnaire with 13 items regarding biopsy technique, indication criteria, execution, supportive imaging and histopathological results. Evaluation of the responses was performed by means of binary systems and proportional consent to every answer possibility was calculated. RESULTS: The results of the questionnaire showed that open biopsies are performed in all centers and in 72 % of the hospitals percutaneous techniques are additionally applied. The most important criterion for an open or percutaneous procedure was the tumor location (80 %). The indications for either technique are assessed by a tumor orthopedic consultant in 68 % of the centers and special imaging is applied in 36 % of the institutions. The approach for the biopsy is defined by the orthopedic surgeon in 88 %. Percutanous biopsies are carried out by interventional radiologists in 60 % of the centers. Open biopsies are performed by residents under supervision by a tumor orthopedic consultant in 88 %. The histopathological results are discussed in 88 % of the hospitals in an interdisciplinary tumor board and in 64 % patients are informed about the diagnosis in an outpatient clinic. CONCLUSIONS: Overall, biopsy of musculoskeletal tumors is performed according to the guidelines in most institutions. Only small differences were identified regarding the definition of the surgical approach and the application of imaging techniques during biopsy. PMID- 24145966 TI - [Pedobarographic results of Girdlestone-Taylor tendon transfer in flexible small toe deformity]. AB - AIM: The aim of the study was to analyze the biomechanical effects of flexible claw toe correction by tendon transfer with the Girdlestone-Taylor approach using dynamic pedobarography. MATERIAL AND METHODS: In the study 12 patients were examined preoperatively and 12 months postoperatively. The results obtained by pedobarography 12 months postoperatively were compared with those of a healthy control group of matched age and body mass index (BMI). For clinical evaluation the American Orthopaedic Foot and Ankle Society (AOFAS) score and visual analogue pain scale (VAS) were evaluated. RESULTS: The results showed a significant increase in the average AOFAS score from 72 (range 63-79) preoperatively to 92 (84-96) points 12 months postoperatively. The pedobarography revealed significantly increased values in the force-time integral and the maximum force for the second and third toes 12 months postoperatively. Compared with preoperative measurement values a significantly increased peak pressure could be assessed for the third toe only. It is assumed that the combination of functional arthrodesis of the proximal interphalangeal (PIP) joint and the strain shift by tendon transfer causes this increase in peak pressure. CONCLUSION: Atter Girdlestone-Taylor tendon transfer reestablishment of floor contact of flexible claw toes could be demonstrated by dynamic pedobarography. PMID- 24145967 TI - Technologies for detection of circulating tumor cells: facts and vision. AB - Hematogeneous tumor cell dissemination is a key step in cancer progression. The detection of CTCs in the peripheral blood of patients with solid epithelial tumors (e.g., breast, prostate, lung and colon cancer) holds great promise, and many exciting technologies have been developed over the past years. However, the detection and molecular characterization of circulating tumor cells (CTCs) remain technically challenging. The identification and characterization of CTCs require extremely sensitive and specific analytical methods, which are usually a combination of complex enrichment and detection procedures. CTCs occur at very low concentrations of one tumor cell in the background of millions of normal blood cells and the epithelial-mesenchymal plasticity of CTCs can hamper their detection by the epithelial markers used in current CTC assays. In the present review, we summarize current methods for the enrichment and detection of CTCs and discuss the key challenges and perspectives of CTC analyses within the context of improved clinical management of cancer patients. PMID- 24145968 TI - Benign prenatal hypophosphatasia: a treatable disease not to be missed. AB - Prenatal bowing of the long bones is often associated with severe bone dysplasias. We report a child who presented marked bowing of the long bones at birth but showed a relatively benign postnatal course with spontaneous improvement of bowing. The fetal imaging showed normal skeletal mineralization and normal chest and abdominal circumferences despite the limb bowing and shortening. Decreased serum alkaline phosphatase activity and elevated urine phosphoethanolamine was biochemically evident, and compound heterozygous mutations in the tissue-nonspecific alkaline phosphatase (TNSALP) gene were identified, which confirmed the diagnosis of a benign form of prenatal hypophosphatasia. Benign prenatal hypophosphatasia should be considered in the differential diagnosis of congenital bowing of the long bones. PMID- 24145969 TI - Two alternative sutureless strategies for aortic valve replacement: a two-center experience. AB - OBJECTIVE: Important comorbid conditions in patients referred for aortic valve replacement (AVR) require less invasive strategies. We describe our initial experience with the Perceval S (Sorin Group, Saluggia, Italy) and 3f Enable (Medtronic, Minneapolis, MN USA) sutureless aortic bioprostheses. METHODS: We compared intraoperative data, postoperative clinical outcomes, and echocardiographic results from patients receiving a Perceval S (P group; n = 97) or a 3f Enable (E group; n = 32) prosthesis in two cardiac surgery departments (Nuremberg, Germany, and Massa, Italy). RESULTS: Baseline patient characteristics were similar in both groups, except for mean +/- SD body surface area (P group = 2.01 +/- 2.9 m, E group = 1.83 +/- 3.8 m; P < 0.001). Sixty-five patients (67%) in the P group and 19 patients (59.5%) in the E group (P = 0.22) underwent minimally invasive AVR with either ministernotomy or right anterior minithoracotomy approach. Concomitant procedures were performed in 37 patients (38%) in the P group and 9 patients (28%) in the E group (P = 0.56). In-hospital mortality was 2%. The mean +/- SD prosthesis diameter was 23.5 +/- 1.4 mm (P group) compared with 22.1 +/- 2 mm (E group) (P < 0.001). In isolated AVR, aortic cross-clamp time was 36 +/- 12.7 minutes in the P group and 66 +/- 18 minutes in the E group (P < 0.001). At a mean +/- SD follow-up of 8.3 +/- 4.5 months, survival was 97% (one death in the P group). In five patients (P group = 1, E group = 4), a moderate paravalvular leak was present (P = 0.013). The mean +/- SD transvalvular gradient was 9.1 +/- 3.3 mm Hg with the Perceval S and 11.2 +/- 5.2 mm Hg with the 3f Enable (P = 0.017). CONCLUSIONS: Aortic valve replacement with sutureless aortic bioprosthesis is feasible, also with a minimally invasive approach. The Perceval S showed lower operative times and moderate paravalvular leaks and lower mean transvalvular gradients than did the 3f Enable, related to the larger diameter of the Perceval S implanted. Both prostheses showed an excellent hemodynamic performance. This new technology needs long-term follow-up. PMID- 24145970 TI - Right superior mediastinal lymph node dissection in thoracoscopic surgery using a bipolar sealing device. AB - OBJECTIVE: This study investigated the use of a new bipolar sealing device (BSD) in right superior mediastinal lymph node dissection during thoracoscopic surgery. METHODS: The study population consisted of 42 consecutive patients undergoing lobectomy with right superior mediastinal lymph node dissection for primary lung cancer. Operative results were compared with those of conventional surgery in 42 background-matched controls. The primary endpoint for the present analysis was the success of right superior mediastinal lymph node dissection during thoracoscopic surgery using a BSD. The secondary endpoints included the duration of the operation, number of dissected lymph nodes, chest drainage volume and duration, postoperative hospital stay, morbidity, and mortality. RESULTS: The BSD was used successfully in 42 patients. No significant difference in duration of lymph node dissection, chest drainage volume, drainage duration, or number of dissected lymph nodes was observed between the study group and the controls. Because of a learning curve, the procedure initially took more than 20 minutes to complete, but surgical time was reduced to approximately 15 minutes after the procedure was performed in 15 patients. CONCLUSIONS: Our method is safe and in no way inferior to the conventional procedure. The tendency of the learning curve suggests that a significantly shorter duration of lymph node dissection is possible using this method. PMID- 24145971 TI - Outcomes and predictors of mortality and stroke after on-pump and off-pump coronary artery bypass surgery in octogenarians. AB - OBJECTIVE: Octogenarians, as the fastest growing stratum of the population and with the highest prevalence of coronary artery disease, are being increasingly referred for coronary artery bypass grafting (CABG). The general perception is that the presence of comorbidities and the propensity for neurological injury expose them to a higher risk for mortality and morbidity after conventional on pump CABG, and therefore, off-pump CABG should be preferentially offered to octogenarians to improve outcomes. This study evaluates the in-hospital outcomes and predictors of mortality and stroke in octogenarians undergoing on- and off pump CABG at our institution. METHODS: From January 2000 to December 2010, a total of 290 octogenarians underwent off-pump (n = 217) and on-pump (n = 73) CABG. Their data were prospectively entered into the cardiac surgery database (Patients Analysis & Tracking System; Dendrite Clinical Systems, Ltd, Oxford, England, United Kingdom) and analyzed retrospectively. Outcome measures included in-hospital mortality, major complications, and length of stay. Multivariate analysis was performed to identify predictors of combined outcome of in-hospital mortality and stroke. RESULTS: The mean +/- SD age of the patients was 82 +/- 2.0 years. Preoperative demographics were similar for the on-pump and off-pump groups. The patients who underwent off-pump CABG had a lower number of distal anastomoses performed compared with the patients who underwent on-pump CABG [mean difference, 0.2; 95% confidence interval (CI), 0.02-0.4; P = 0.03]. However, the ratio of grafts (received/needed) was the same in both groups. In-hospital mortality for the entire cohort was 7.2%, with no significant difference between the groups for death (6.0% vs 11.0%; P = 0.08), stroke (2.8% vs 2.8%; P = 1.0), other major complications, and length of hospital stay. Independent predictors of combined outcome identified from the multiple logistic model included heart failure [odds ratio (OR), 4.4; 95% CI, 1.5-13.0; P = 0.008], diabetes (OR, 2.6; 95% CI, 1.0-6.0; P = 0.046), nitrate infusion (OR, 2.9; 95% CI, 1.1-8.0; P = 0.04), postoperative renal failure requiring hemofiltration (OR, 8.6; 95% CI, 3.5 21.1; P < 0.001), and postoperative ventricular arrhythmias (OR, 7.3; 95% CI, 1.9 27.8; P = 0.009). CONCLUSIONS: Both on-pump and off-pump CABG are reasonable revascularization strategies in octogenarians. Careful patient selection and individualized treatment decisions can minimize postoperative mortality and morbidity in octogenarians undergoing on- and off-pump CABG. PMID- 24145972 TI - Performance of a novel bipolar/monopolar radiofrequency ablation device on the beating heart in an acute porcine model. AB - OBJECTIVE: Although the advent of ablation technology has simplified and shortened surgery for atrial fibrillation, only bipolar clamps have reliably been able to create transmural lesions on the beating heart. Currently, there are no devices capable of reproducibly creating the long linear lesions in the right and left atria needed to perform a Cox-Maze procedure. This study evaluated the performance of a novel suction-assisted radiofrequency device that uses both bipolar and monopolar energy to create lesions from an epicardial approach on the beating heart. METHODS: Six domestic pigs underwent median sternotomy. A dual bipolar/monopolar radiofrequency ablation device was used to create epicardial linear lesions on the superior and inferior vena cavae, the right and left atrial free walls, and the right and left atrial appendages. The heart was stained with 2,3,5-triphenyl-tetrazolium chloride, and each lesion was cross-sectioned at 5-mm intervals. Lesion depth and transmurality were determined. RESULTS: Transmurality was documented in 94% of all cross sections, and 68% of all ablation lines were transmural along their entire length. Tissue thickness was not different between the transmural and nontransmural cross sections (3.1 +/- 1.3 and 3.4 +/- 2.1, P = 0.57, respectively), nor was the anatomic location on the heart (P = 0.45 for the distribution). Of the cross sections located at the end of the ablation line, 11% (8/75) were found to be nontransmural, whereas only 4% (8/195) of the cross sections located within the line of ablation were found to be nontransmural (P = 0.04). Logistic regression analysis demonstrated that failure of the device to create transmural lesions was associated with low body temperature (P = 0.006) but not with cardiac output (P = 0.54). CONCLUSIONS: This novel device was able to consistently create transmural epicardial lesions on the beating heart, regardless of anatomic location, cardiac output, or tissue thickness. The performance of this device was improved over most devices previously tested but still falls short of ideal clinical performance. Transmurality was lower at the end of the lesions, highlighting the importance of overlapping lines of ablation in the clinical setting. PMID- 24145973 TI - Ex vivo pneumostasis evaluation of a variable-height staple design. AB - OBJECTIVE: This study examined the effect of using a variable-height staple construct containing three rows of staples with heights of 3.0, 3.5, and 4.0 mm (staple leg length, medial to lateral) versus standard three-row single-height staplers (with staple heights of either 3.5 or 4.8 mm) for pneumostasis in healthy porcine and canine lung parenchyma to determine whether a single stapler that uses variable staple heights could perform as well as, or better than, existing single-height stapling devices. The work presented here used healthy animal tissues, in lieu of diseased tissue, which is extremely difficult to obtain and quantify. METHODS: Briefly, fresh explanted porcine and canine trachea lung blocs were used for all testing. Tissue thicknesses were measured with a custom-design spring-loaded caliper before stapling with control and test articles to ensure that the tissue was of "appropriate" thickness for the stapler size (staple height) selected (per manufacturer's instructions for use). All tissue measurements were comparable across each area of lung tested, and both test and control devices were fired into the same tissue thicknesses. After stapling, the lungs were submerged in water, insufflated, checked for air leaks at four discrete (increasing) pressures, and scored using a predetermined scale. Statistical analysis was performed for n = 26 (3.5-mm staples), n = 29 (4.8-mm staples), and n = 26 or 29 (paired to the standard group) for the variable-height stapler (3.0-, 3.5-, and 4.0-mm staples). RESULTS: The results demonstrated that the test article comprising three rows of variable-height staples provided comparable pneumostasis with the standard three-row single-height staplers (with staple heights of either 3.5 or 4.8 mm) under the test conditions described. CONCLUSIONS: A novel test article containing three rows of staples with heights of 3.0, 3.5, and 4.0 mm (variable-height stapler) showed promising results when compared with standard commercially available single-height staplers, performing as well as or better than the standard single-height staplers. This work demonstrates important first steps to proving equivalent device performance, which might facilitate the use of a variable-height stapler in place of multiple single-height staplers. PMID- 24145974 TI - Assessment of a new type I endoleak repair technique using an anchoring device. AB - OBJECTIVE: Type I endoleaks are one of the most frequent and life-threatening complications of thoracic endovascular aortic repair. This study aimed to assess the use of suture-anchoring devices for repairing type I endoleaks. METHODS: The descending aortic aneurysm model (saccular type) was made by side-to-end anastomosis to a Dacron graft. A Matsui-Kitamura stent graft was deployed to create a proximal type I endoleak. Approximately 5 mm above the upper rim of the anastomosis, the aorta was punctured by the pistol of the suture-anchoring device with a T-shaped bar under fluoroscopy. Sutures were applied until angiography showed the absence of a type I endoleak. During the process, two pressure measurements were used to perform continuous assessments of aortic pressure and intra-aneurysm sac pressure. RESULTS: A mean +/- SD of 5 +/- 1 anchoring shots were used to eliminate type I endoleaks. The device performed well, and no complications were observed. The mean +/- SD intrasac pressures before stent graft deployment, during endoleak maintenance, and after repair were 118 +/- 5, 61 +/- 4, and 26 +/- 5 mm Hg, respectively. The postrepair pressure was significantly decreased (P < 0.001; Student t test). CONCLUSIONS: Despite some anatomic and clinical limitations identified during the experiments, the effectiveness of the suture-anchoring device was confirmed. Further improvement of the device will soon lead to its use as a less invasive endoleak repair procedure. PMID- 24145975 TI - Cotton-derived oxidized cellulose in minimally invasive thoracic surgery: a clinicopathological study. AB - OBJECTIVE: The aim of this study was to identify resorption, clinical performance, and safety of cotton-derived oxidized cellulose gauze applied as a hemostat in minimally invasive oncologic thoracic surgery. METHODS: This is a pilot prospective noncomparative observational human in vivo study. A piece of cotton-derived oxidized cellulose gauze measuring 5 * 20 cm was inserted into the subcarinal space of patients with potentially resectable lung carcinoma at the time of video-assisted mediastinoscopic lymphadenectomy and reexamined several days later for macroscopic and histologic evaluation at the time of subsequent lung resection. The primary endpoint was the local situation at the implantation site described by cellulose remnants, fluid collections, and adhesions. The secondary endpoint was safety, described by the number of adverse events and surgical reinterventions. RESULTS: Twenty-five consecutive eligible patients with potentially resectable lung carcinoma were included. The desired hemostatic effect was achieved in all cases. No adverse events were observed. At re exploration 10.5 (5-28) days later, the cellulose gauze was found to lose its solid structure from the fifth day on. Remnants were last detected 14 days after insertion. The implantation site exhibited no inflammatory changes and a remarkable small amount of fluid collections and adhesions. CONCLUSIONS: Mediastinal application of cotton-derived oxidized cellulose is safe and effective. A piece of gauze measuring 5 * 20 cm seems to be absorbed completely within 15 days, thus precluding any interference with oncologic restaging and follow-up. The absence of relevant adhesions facilitates further surgical procedures. Larger comparative confirmatory studies are required. For large-scale resorption studies, our clinical model should be translated into a porcine model. PMID- 24145976 TI - Somatosensory-evoked potential-guided intercostal artery reimplantation in thoracoabdominal aortic aneurysm surgery. AB - OBJECTIVE: This study was undertaken to evaluate the use of somatosensory evokedpotential (SSEP) monitoring on intercostal artery reimplantation (IAR) and spinal cord ischemia rates during thoracoabdominal ortic aneurysm repair. METHODS: Fifty-two patients had thoracoabdominal aortic aneurysm repair with IAR under SSEP guidance and 79 patients had repair with routine IAR without SSEP guidance from 1999 to 2010. RESULTS: No differences were observed between the two groups in age (63.1 +/- 11.6 vs 64.8 +/- 9.8 years), sex (57.7% vs 50.6% men), chronic dissections (40.4% vs 44.3%), renal insufficiency (11.5% vs 10.1%), and Crawford type 1 and 2 aneurysms (53.9% vs 53.9%). There was one case (1.9%) of immediate paraplegia and one case (1.9%) of delayed paraplegia in the SSEP group versus 2 cases (2.5%) of immediate paraplegia in the non-SSEP group (P = 0.92). In the SSEP group, 38 patients (73.1%) had SSEP changes, but only 15 (28.8%) required reimplantation. There were fewer IARs in the SSEP group compared with the non-SSEP group (28.8% vs. 59.5%, P = 0.004). No difference was observed in 30 day mortality between the SSEP and the non-SSEP group (3.9% vs. 7.6%, P = 0.48). CONCLUSIONS: The use of SSEP monitoring led to a significant decrease in the need for IAR without increasing the paraplegia rate. PMID- 24145977 TI - Thirty-five day Impella 5.0 support via right axillary side graft cannulation for acute cardiogenic shock. AB - We describe the use of an Impella 5.0 for mechanical support in acute cardiogenic shock after an acute myocardial infarction. A 61-year-old man with a history of severe coronary artery disease who underwent coronary artery bypass grafting with ischemic cardiomyopathy presented with cardiogenic shock after an ST-elevation myocardial infarction. An Impella Recover LP 5.0 (Abiomed, Danvers, MA USA) was inserted via a right axillary side graft, using transesophageal echocardiographic and fluoroscopic guidance. The patient remained in the intensive care unit, where he required a tracheostomy to be weaned off the ventilator. He required renal replacement therapy with subsequent complete recovery. His Impella support was weaned, and on postoperative day 35, the device was removed. The patient developed axillary thrombosis the morning after removal, requiring thrombectomy. Discharge echocardiogram showed mild left ventricular enlargement with global hypokinesis and left ventricular ejection fraction of 25%. The Impella 5.0 device can safely and effectively be used in the long-term support of cardiogenic shock. PMID- 24145978 TI - Combined totally endoscopic robotic coronary bypass and mitral valve repair via right-sided ports. AB - We present a case of combined coronary artery bypass grafting and mitral valve (MV) repair using a robotic totally endoscopic right-sided approach. A 61-year old man presented with fatigue due to significant mitral regurgitation and was found to have a tight stenosis in the mid left anterior descending artery. Using the da Vinci robotic system, the patient underwent a left internal mammary artery graft to the left anterior descending artery using the C-Port Flex A distal anastomotic device followed by a MV repair. Both procedures were performed endoscopically via right chest ports and right femorofemoral bypass successfully. The patient was discharged from the hospital 3 days postoperatively and returned to normal activity within 3 weeks after surgery. This case study shows the feasibility of using an endoscopic robotic approach in selected patients undergoing combined MV coronary artery bypass grafting surgery. PMID- 24145979 TI - Normothermic cardiopulmonary bypass with beating heart for management of renal cell carcinoma with atrial tumor thrombus. AB - Renal cell carcinoma is occasionally complicated by the formation of a neoplastic thrombus invading the inferior vena cava. Rarely, the thrombus extends into the vena cava, reaching the right atrium. In these situations, despite the advanced tumor stage, surgical resection continues to offer the best chance for effective treatment. The operation requires a complex surgical approach with mobilization of the liver and use, in most cases, of extracorporeal circulation, which allows removal of the tumor thrombus from the right atrium. Traditionally, the intervention is performed using deep hypothermic circulatory arrest or, less frequently, using moderate hypothermia, aortic cross clamping, and cardioplegic cardiac arrest. These strategies have the downside of causing increased blood loss, coagulopathy, and long operative time and can potentially have a negative impact on survival. We report a different operative approach using normothermic cardiopulmonary bypass, with the expectation of lowering the rate of blood product transfusions, hospital length of stay, and overall incidence of complications. PMID- 24145981 TI - Radiography and biomechanics of sixth and seventh cervical vertebrae segments after disc fenestration and after insertion of an intervertebral body spacer. A canine cadaveric study. AB - OBJECTIVES: To study the radiographic characteristics and the biomechanical properties of the sixth and seventh cervical (C6-C7) vertebral motion unit (VMU) with an intact disc, after disc fenestration, and after placement of an intervertebral body spacer (IVBS). METHODS: Six cadaveric C6-C7 VMU were retrieved from six Greyhound cadavers. Each VMU was loaded at 3 Nm of torque sequentially in flexion, extension, and in right and left lateral bending. The range-of-motion (ROM) was measured with a Zebris 3D(r) system. The intervertebral disc cross-sectional area was measured on lateral and ventro-dorsal radiographs. Biomechanical testing and radiographic measurements were performed with an intact disc, after disc fenestration, and after IVBS placement. Data were reported as mean+/-SD. RESULTS: The intervertebral disc cross-sectional area was significantly decreased after disc fenestration and increased after IVBS placement, but remained significantly smaller than the area of intact disc in some of the tested conditions. The ROM with an intact disc, after disc fenestration and after IVBS placement, in flexion were 11.5 degrees +/-1.0, 15.2 degrees +/-2.3, and 10.9 degrees +/-4.7, respectively, and in extension were 15.6 degrees +/-3.7, 24.7 degrees +/-6.2, 21.9 degrees +/-4.0, respectively. There was a significant increase in extension ROM after disc fenestration. Intervertebral body spacer placement significantly decreased ROM in flexion but ROM in extension was not different from disc fenestration. No significant changes in lateral bending ROM were detected. CLINICAL SIGNIFICANCE: The use of an IVBS reduced disc space collapse but did not restore stability of the VMU to normal values in extension after cervical disc fenestration. PMID- 24145982 TI - Post-translational control of cardiac hemodynamics through myosin binding protein C. AB - Cardiac myosin binding protein C (cMyBP-C) is an integral sarcomeric protein that associates with the thick, thin, and titin filament systems in the contractile apparatus. Three different isoforms of MyBP-C exist in mammalian muscle: slow skeletal (MyBPC1), fast skeletal (MyBP-C2, with several variants), and cardiac (cMyBP-C). Genetic screening studies show that mutations in MYBPC3 occur frequently and are responsible for as many as 30-35 % of identified cases of familial hypertrophic cardiomyopathy. The function of cMyBP-C is stringently regulated by its post-translational modification. In particular, the addition of phosphate groups occurs with high frequency on certain serine residues that are located in the cardiac-specific regulatory M domain. Phosphorylation of this domain has been extensively studied in vitro and in vivo. Phosphorylation of the M domain can regulate the manner in which actin and myosin interact, affecting the cross bridge cycle and ultimately, cardiac hemodynamics. PMID- 24145984 TI - A DFT/TDDFT study on the effect of CN substitution on color tuning and phosphorescence efficiency of a series of Ir(III) complexes with phosphine silanolate ligands. AB - A DFT/TDDFT investigation was performed on the electronic structures, absorption and emission spectra, as well as the phosphorescence efficiency of [(ppy)2Ir(P^SiO)] (1) and the derivatives (1a, 1b, 1c and 1d) with CN substitution at different positions in ppy ligands, as well as [(dfppy)2Ir(P^SiO)] (2) [where ppy = 2-phenylpyridine, dfppy = 2-(2,4 difluorophenyl)pyridine and (P^SiO) is an organosilanolate ancillary chelate]. The calculated results reveal that the introduction of CN leads to a significant red shift for 1a-1d in absorption spectra compared with that of 1. Moreover, the CN substitution at different positions on C^N ligands may be an efficient approach towards tuning emitting color. 1b, 1c, and 1d lead to a blue shift of emission spectra compared with 1, while an obvious red shift is observed for 1a. The high quantum yield of 1 (0.90) compared to 2 (0.59) is explained based on the S1-Tn splitting energies and energy gap between (3)MLCT/pi-pi* and (3)MC d-d states, and the evaluation of the radiative and nonradiative rate constants for all the complexes is also studied. The designed complexes 1a, 1c and 1d are expected to be potential phosphorescence emitters in OLEDs with high quantum efficiency. PMID- 24145983 TI - 5-HT2A receptor-mediated excitation on cerebellar fastigial nucleus neurons and promotion of motor behaviors in rats. AB - It has long been known that serotonergic afferent inputs are the third largest afferent population in the cerebellum after mossy fibers and climbing fibers. However, the role of serotonergic inputs in cerebellar-mediated motor behaviors is still largely unknown. Here, we show that only 5-HT2A receptors among the 5 HT2 receptor subfamily are expressed and localized in the rat cerebellar fastigial nucleus (FN), one of the ultimate outputs of the spinocerebellum precisely regulating trunk and limb movements. Remarkably, selective activation of 5-HT2A receptors evokes a postsynaptic excitatory effect on FN neurons in a concentration-dependent manner in vitro, which is in accord with the 5-HT elicited excitation on the same tested neurons. Furthermore, selective 5-HT2A receptor antagonist M100907 concentration-dependently blocks the excitatory effects of 5-HT and TCB-2, a 5-HT2A receptor agonist, on FN neurons. Consequently, microinjection of 5-HT into bilateral FNs significantly promotes rat motor performances on accelerating rota-rod and balance beam and narrows stride width rather than stride length in locomotion gait. All these motor behavioral effects are highly consistent with those of selective activation of 5 HT2A receptors in FNs, and blockage of the component of 5-HT2A receptor-mediated endogenous serotonergic inputs in FNs markedly attenuates these motor performances. All these results demonstrate that postsynaptic 5-HT2A receptors greatly contribute to the 5-HT-mediated excitatory effect on cerebellar FN neurons and promotion of the FN-related motor behaviors, suggesting that serotonergic afferent inputs may actively participate in cerebellar motor control through their direct modulation on the final output of the spinocerebellum. PMID- 24145985 TI - The validity of gait variability and fractal dynamics obtained from a single, body-fixed triaxial accelerometer. AB - A single triaxial accelerometer has the ability to collect a large amount of continuous gait data to quantitatively assess the control of gait. Unfortunately, there is limited information on the validity of gait variability and fractal dynamics obtained from this device. The purpose of this study was to test the concurrent validity of the variability and fractal dynamic measures of gait provided by a triaxial accelerometer during a continuous 10 minute walk in older adults. Forty-one healthy older adults were fitted with a single triaxial accelerometer at the waist, as well as a criterion footswitch device before completing a ten minute overground walk. The concurrent validity of six outcome measures was examined using intraclass correlation coefficients (ICC) and 95% limits of agreement. All six dependent variables measured by the accelerometer displayed excellent agreement with the footswitch device. Mean parameters displayed the highest validity, followed by measures of variability and fractal dynamics in stride times and measures of variability and fractal dynamics in step times. These findings suggest that an accelerometer is a valid and unique device that has the potential to provide clinicians with valid quantitative data for assessing their clients' gait. PMID- 24145986 TI - Lung cancer: MET-negative patients--eclipsing benefits. PMID- 24145987 TI - Latest biopsy approach for suspected metastases in patients with breast cancer. AB - Biopsy of suspected metastases in patients with breast cancer is recommended in the practice guidelines of the National Comprehensive Cancer Network, but not always performed in routine oncology practice, often because of the cost and invasiveness of the procedure. Biopsies can confirm the presence of metastatic disease, reveal unsuspected benign disease or second (non-breast) malignancies and confirm expression of biomarkers, all of which can aid the optimal management of the cancer. Image-guided biopsy has increased the accuracy and safety of the procedure. Here, we aim to provide a practical algorithm for deciding when to perform biopsy of suspected breast cancer metastases, in order to optimize clinical practice. We expect that future clinical trials and standard-of-care practice will increasingly obtain tissue from metastases to assess molecular differences (DNA, RNA, protein) between the primary tumour and metastases. Advances in targeted therapy for breast cancer will be highly dependent on the availability of metastatic tissue. In this article, we provide an up-to-date review of the current issues in biopsy of suspected metastases in patients with breast cancer, including technical details of biopsy, pathology review of biopsy specimens, and interpretation of biopsy findings. PMID- 24145988 TI - New insights into the molecular pathogenesis of intrahepatic cholangiocarcinoma. AB - Intrahepatic cholangiocarcinoma is an aggressive malignancy and is one of the most devastating cancers of the gastrointestinal tract. The molecular mechanisms contributing to the pathogenesis of these cancers are not well understood. The recognition and distinction of these cancers from other tumors such as perihilar or extrahepatic distal cholangiocarcinoma and hepatocellular carcinoma are important in defining the pathogenesis. New insights into molecular mechanisms contributing to disease pathogenesis are emerging from recent epidemiological, genome-wide profiling and laboratory based studies. These have contributed to an improved understanding of risk factors, genetic mutations and pathophysiological mechanisms that are associated with these tumors. The contribution of well established risk factors such as biliary tract inflammation and key signaling pathways involved in intrahepatic cholangiocarcinoma are being further defined. These new insights have several important implications for both molecular diagnosis and therapy of these cancers. PMID- 24145989 TI - Is real-time PCR the correct method to evaluate the incidence of human papillomavirus in prepuces of asymptomatic boys and men? AB - OBJECTIVE: To investigate the prevalence of human papillomavirus (HPV) in prepuces of asymptomatic boys and men, the present study was designed. METHODS: Two hundred and fifty male prepuce specimens who underwent circumcision due to phimosis were collected. Samples were subdivided into groups regarding their age: children (group I, 0-10 years), adolescents (group II, 11-20 years) and adults (group III, >20 years). HPV High Screen Real-TM Quant 2x kit detecting HPV 6 and 11 (low risk) as well as another kit for identification of HPV 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58 and 59 (high risk) were used. Additionally, a Taq Man assay has been designed targeting the L1 gene of HPV 6, 11, 16 and 18. RESULTS: Evaluating the number of low-risk HPV subtypes, we found HPV 6 and 11 in 5.3 % of samples (n = 12/226). Concerning high-risk HPV, we found a positivity in 4 % of samples (n = 9/224). In contrast to low-risk data where no age distribution was observed, we found an age-specific accumulation of high-risk HPV subtypes in the children group (n = 6/9). A second independent assay (Taq Man PCR assay) measuring HPV 6, 11, 16 and 18 of all positive samples confirmed only the high risk HPV subtypes of the Real-TM Quant 2x assay. CONCLUSIONS: Our study provides evidence that qPCR estimation for HPV infection obviously underestimates the incidence rate of infected prepuces in boys and men with phimosis. Contrary, an overestimation of the HPV infection rate with the in situ hybridization method of phimotic prepuces cannot be excluded. PMID- 24145990 TI - A functionally conserved Polycomb response element from mouse HoxD complex responds to heterochromatin factors. AB - Anterior-posterior body axis in all bilaterians is determined by the Hox gene clusters that are activated in a spatio-temporal order. This expression pattern of Hox genes is established and maintained by regulatory mechanisms that involve higher order chromatin structure and Polycomb group (PcG) and trithorax group (trxG) proteins. We identified earlier a Polycomb response element (PRE) in the mouse HoxD complex that is functionally conserved in flies. We analyzed the molecular and genetic interactions of mouse PRE using Drosophila melanogaster and vertebrate cell culture as the model systems. We demonstrate that the repressive activity of this PRE depends on PcG/trxG genes as well as the heterochromatin components. Our findings indicate that a wide range of factors interact with the HoxD PRE that can contribute to establishing the expression pattern of homeotic genes in the complex early during development and maintain that pattern at subsequent stages. PMID- 24145991 TI - Screening, monitoring, and treatment of stage 1 to 3 chronic kidney disease: A clinical practice guideline from the American College of Physicians. AB - DESCRIPTION: The American College of Physicians (ACP) developed this guideline to present the evidence and provide clinical recommendations on the screening, monitoring, and treatment of adults with stage 1 to 3 chronic kidney disease. METHODS: This guideline is based on a systematic evidence review evaluating the published literature on this topic from 1985 through November 2011 that was identified by using MEDLINE and the Cochrane Database of Systematic Reviews. Searches were limited to English-language publications. The clinical outcomes evaluated for this guideline included all-cause mortality, cardiovascular mortality, myocardial infarction, stroke, chronic heart failure, composite vascular outcomes, composite renal outcomes, end-stage renal disease, quality of life, physical function, and activities of daily living. This guideline grades the evidence and recommendations by using ACP's clinical practice guidelines grading system. RECOMMENDATION 1: ACP recommends against screening for chronic kidney disease in asymptomatic adults without risk factors for chronic kidney disease. (Grade: weak recommendation, low-quality evidence) RECOMMENDATION 2: ACP recommends against testing for proteinuria in adults with or without diabetes who are currently taking an angiotensin-converting enzyme inhibitor or an angiotensin II-receptor blocker. (Grade: weak recommendation, low-quality evidence) RECOMMENDATION 3: ACP recommends that clinicians select pharmacologic therapy that includes either an angiotensin-converting enzyme inhibitor (moderate-quality evidence) or an angiotensin II-receptor blocker (high-quality evidence) in patients with hypertension and stage 1 to 3 chronic kidney disease. (Grade: strong recommendation) RECOMMENDATION 4: ACP recommends that clinicians choose statin therapy to manage elevated low-density lipoprotein in patients with stage 1 to 3 chronic kidney disease. (Grade: strong recommendation, moderate-quality evidence). PMID- 24145992 TI - The 2013 Society of Surgical Oncology Susan G. Komen for the Cure Symposium: MRI in breast cancer: where are we now? AB - Magnetic resonance imaging (MRI) has been widely applied in the contemporary management of patients with breast cancer and as a screening tool for those at increased risk; however, prospective evidence that the use of breast MRI improves patient outcomes remains limited to screening of known BRCA mutation carriers or women at increased risk based on a strong family history. Despite this, the role of MRI in the routine evaluation of the newly diagnosed breast cancer patient remains a subject of much debate, with widely divergent views on the value of MRI in selecting local therapy. The application of MRI in patients undergoing neoadjuvant therapy is an area of active investigation, with several potential benefits, including predicting response to therapy. We review the current state of the literature on the topics of MRI for screening, MRI and short-term surgical outcomes, MRI and long-term surgical outcomes, and MRI and neoadjuvant chemotherapy as presented at the 2013 Society of Surgical Oncology Susan G. Komen for the Cure Symposium, 9 March 2013. PMID- 24145993 TI - Bone marrow micrometastases do not impact disease-free and overall survival in early stage sentinel lymph node-negative breast cancer patients. AB - BACKGROUND: The presence of lymph node metastases is the most important prognostic factor in early stage breast cancer. Whether bone marrow micrometastases (BMM) impact the prognosis in sentinel lymph node (SLN)-negative breast cancer patients remains a matter of debate. Therefore, the objective of this study was to assess the impact of BMM on 5-year disease-free and overall survival among those patients. METHODS: We analyzed 410 patients with early stage breast cancer (pT1 and pT2 <= 3 cm, cN0) who were prospectively enrolled into the Swiss Multicenter Sentinel Lymph Node Study in Breast Cancer between January 2000 and December 2003. All patients underwent bone marrow aspiration followed by SLN biopsy. All SLN were stained with hematoxylin and eosin and immunohistochemistry (Lu-5, CK-22). Cancer cells in the bone marrow were identified after staining with monoclonal antibodies A45-B/B3 against CK-8, -18, and -19. RESULTS: Negative SLN were found in 67.6% (277 of 410) of the enrolled patients. Of those, BMM status was negative in 75.8% (210 of 277) and positive in 24.2% (67 of 277) patients. Median follow-up was 61 (range 11-96) months. Five-year disease-free survival was 93.6% (95% confidence interval [CI] 89.1-96.0) in BMM-negative and 92.2% (95% CI 82.5-96.2) in BMM-positive patients (p = 0.50). Five-year overall survival was 92.7% (95% CI 87.9-95.8) for the BMM-negative and 92.5% (95% CI 83.4 96.2) for the BMM-positive group (p = 0.85). CONCLUSIONS: This is one of the first prospective studies to examine 5-year disease-free and overall survivals in SLN-negative patients in correlation to their BMM status. Although BMM are identified in one of four SLN-negative patients, they do not impact disease-free and overall survival. PMID- 24145994 TI - Postmastectomy radiation and recurrence patterns in breast cancer patients younger than age 35 years: a population-based cohort. AB - BACKGROUND: The utility of post mastectomy radiotherapy in very young women is understudied. The objective of this study was to evaluate the use of PMRT in very young women to determine the effect on recurrence and survival. METHODS: All women aged <=35 years diagnosed with invasive breast cancer from 1994 to 2003 were identified from the Ontario Cancer Registry. Patient, tumour, treatment and outcome data were abstracted from primary chart review. Local or regional recurrence was the primary endpoint with contralateral, distant recurrence/death treated as competing risks. Propensity score methods were incorporated into multivariable Cox proportional hazards models to evaluate the effect of radiation therapy on the time to local/regional, distant recurrence or death. RESULTS: 588 patients were identified during the study period, of which 382 were eligible for analysis. Overall, 182 (48%) of patients sustained a recurrence after a median follow-up of 2.72 years. The use of PMRT significantly reduced locoregional recurrence (HR 0.54, 95% CI 0.29-0.996) compared with those who did not receive PMRT. There was no significant effect of PMRT on contralateral, distant recurrences, or death without recurrence (HR 0.98, 95% CI 0.66-1.47). Of the patients with known node status (N = 451), isolated local recurrence occurred in 5, 2.5, and 8.5% in patients with N0, N1-3, and N4 positive nodes respectively. CONCLUSIONS: We have found a significant reduction in locoregional recurrence with PMRT but no survival benefit in very young women with breast cancer. PMID- 24145995 TI - Current paradigms for metastatic spinal disease: an evidence-based review. AB - INTRODUCTION: Management of metastatic spine disease is quite complex. Advances in research have allowed surgeons and physicians to better provide chemotherapeutic agents that have proven more efficacious. Additionally, the advancement of surgical techniques and radiosurgical implementation has altered drastically the treatment paradigm for metastatic spinal disease. Nevertheless, the physician-patient relationship, including extensive discussion with the neurosurgeon, medicine team, oncologists, radiation oncologists, and psychologists, are all critical in the evaluation process and in delivering the best possible care to our patients. The future remains bright for continued improvement in the surgical and nonsurgical management of our patients with metastatic spine disease. METHODS: We include an evidence-based review of decision making strategies when attempting to determine most efficacious treatment options. Surgical treatments discussed include conventional debulking versus en bloc resection, conventional RT, and radiosurgical techniques, and minimally invasive approaches toward treating metastatic spinal disease. CONCLUSIONS: Surgical oncology is a diverse field in medicine and has undergone a significant paradigm shift over the past few decades. This shift in both medical and surgical management of patients with primarily metastatic tumors has largely been due to the more complete understanding of tumor biology as well as due to advances in surgical approaches and instrumentation. Furthermore, radiation oncology has seen significant advances with stereotactic radiosurgery and intensity-modulated radiation therapy contributing to a decline in surgical treatment of metastatic spinal disease. We analyze the entire spectrum of treating patients with metastatic spinal disease, from methods of diagnosis to the variety of treatment options available in the published literature. PMID- 24145996 TI - Impact of Charlson comorbidity index varies by age in patients with prostate cancer treated by radical prostatectomy: a competing risk regression analysis. AB - PURPOSE: To investigate the prognostic impact of the Charlson comorbidity index (CCI) on either cancer-specific mortality (CSM) or other-cause mortality (OCM) according to age in patients with prostate cancer (PC) who underwent radical prostatectomy (RP). METHODS: Data from 336 patients who underwent RP for PC between 1992 and 2005 were analyzed. Variables, including the preoperative prostate-specific antigen (PSA), prostate volume, clinical stage, and pathologic stage, were compared across age groups (<65 or >=65 years old). Preexisting comorbidities were evaluated by the CCI, and patients were classified into two CCI score categories (0 or >=1). RESULTS: The median (interquartile range) follow up period was 96 (85-121) months. Subjects were divided into two subgroups according to age: <65 years (n = 151) or >=65 years (n = 185). There was no significant difference in PSA, biopsy Gleason sum, body mass index, pathologic stage, or CCI between the two age groups. OCM was significantly associated with the CCI score (P = 0.011). Cumulative incidence estimates obtained from competing risk regression analysis indicated that CCI was not associated with CSM (P = 0.795) or OCM (P = 0.123) in the >=65-year group. However, in men <65 years, cumulative incidence estimates for OCM were significantly associated with CCI (P = 0.036). CONCLUSIONS: CCI was independently associated with OCM after RP, but only in men <65 years old. CCI was not associated with CSM in either age group. Accordingly, a thorough evaluation of patient's comorbidities is mandatory when considering aggressive surgical treatment, especially in relatively young patients. PMID- 24145997 TI - A gene signature combining the tissue expression of three angiogenic factors is a prognostic marker in early-stage non-small cell lung cancer. AB - BACKGROUND: Angiogenesis and lymphangiogenesis are key mechanisms for tumor growth and dissemination. They are mainly regulated by the vascular endothelial growth factor (VEGF) family of ligands and receptors. The aim of this study was to analyze relative expression levels of angiogenic markers in resectable non small cell lung cancer patients in order to asses a prognostic signature that could improve characterization of patients with worse clinical outcomes. METHODS: RNA was obtained from tumor and normal lung specimens from 175 patients. Quantitative polymerase chain reaction was performed to analyze the relative expression of HIF1A, PlGF, VEGFA, VEGFA165b, VEGFB, VEGFC, VEGFD, VEGFR1, VEGFR2, VEGFR3, NRP1 and NRP2. RESULTS: Univariate analysis showed that tumor size and ECOG-PS are prognostic factors for time to progression (TTP) and overall survival (OS). This analysis in the case of angiogenic factors also revealed that PlGF, VEGFA, VEGFB and VEGFD distinguish patients with different outcomes. Taking into account the complex interplay between the different ligands of the VEGF family and to more precisely predict the outcome of the patients, we considered a new analysis combining several VEGF ligands. In order to find independent prognostic variables, we performed a multivariate Cox analysis, which showed that the subgroup of patients with higher relative expression of VEGFA plus lower VEGFB and VEGFD presented the poorest outcome for both TTP and OS. CONCLUSIONS: The relative expression of these three genes can be considered as an angiogenic gene signature whose applicability for the selection of candidates for targeted therapies needs to be further validated. PMID- 24145998 TI - BRCA1/2 and clinical outcome in a monoinstitutional cohort of women with hereditary breast cancer. AB - The clinical outcome of BRCA mutation carriers and non-carriers still remains a topic of discussion. In order to interpret controversial data, in the present study, we analyzed a large consecutive monoinstitutional series of breast cancer patients and relatives with familial features carrying or not carrying BRCA mutations. The intense research in recent years regarding the clinical genetics of patients with breast or ovarian cancer and their relatives has allowed the organization of a unique database comprising anamnestic, clinical, pathological and molecular data. Families with two or more cases of breast cancer under the age of 50 years, or with three cases at any age, were identified. From June, 2003 to June, 2010, a total of 202 patients (136 probands + 66 relatives) from 45 families were included in the analysis. A total of 136 (49 carrier and 87 non carrier) cases had a cancer diagnosis at the time of their genetic testing. Twenty and 24 events were observed in the carrier and control group, respectively. The 10-year disease-free suvival rate was 57% for patients in the control group compared with 50% for patients carrying a BRCA mutation (P=0.15 by log-rank test). Finally, 66 (32 genetic and 34 control) cases were unaffected at the time of molecular analysis, and 6 new cases of cancer were observed in the carriers, while no new cases were detected in the control cohort. Thus, at age 50, 40% of carriers had a high risk of disease (P=0.0069 by log-rank test). Our data support the hypothesis that the presence of BRCA mutations does not alter the clinical outcome for hereditary breast cancer patients. Conversely, BRCA mutations are proven to be crucial for prediction of risk in healthy relatives from carrier families. PMID- 24145999 TI - Multiscale electronic transport in Li(1+x)Ni(1/3-u)Co(1/3-v)Mn(1/3-w)O2: a broadband dielectric study from 40 Hz to 10 GHz. AB - This work is the first detailed study concerning the multiscale electronic transport and its temperature dependence in the LiNi1/3Co1/3Mn1/3O2 (NMC) family, high-capacity electrode materials for lithium ion batteries. Powders with two different mean cluster sizes (3 MUm and 10 MUm) but the same particle sizes (0.4 to 1.3 MUm) were measured. The detailed formula of the studied compound is Li1.04Ni(2+)0.235Ni(3+)0.09Mn(4+)0.315Co(3+)0.32O2. Different electrical relaxations are evidenced, resulting from the polarizations at the different scales of the powder architecture. When the frequency increases, three dielectric relaxations are detected in the following order due to: (a) space-charge polarization (low-frequency range) owing to the interface between the sample and the conductive metallic layer deposited on it; (b) polarization of NMC clusters (micronic scale) induced by the existence of resistive junctions between them; and (c) polarization of NMC particles (at sub-micronic scale) induced by resistive junctions between them. High interatomic level conductivity of about 20 S m(-1) was evidenced and attributed to the contribution of the extended states and to a Brownian motion of the charge carriers with mean free path similar to the lattice constant. The ratio between sample and local conductivity is more than 10(5). The large conductivity drop of 3 to 4 orders of magnitude is observed from the particle to the cluster scale. A very large number of charge carriers are blocked by the interparticle junctions within the clusters. The conductivity drop from the cluster to the sample scale is comparatively very small, owing to the dense architecture of the NMC sample in which the spherical clusters are very piled up on each other. PMID- 24146000 TI - Decipher beta2-microglobulin: gain- or loss-of-function (a mini-review). AB - beta2-microglobulin (beta2M) functions as a chaperon to maintain structural stability of MHC class I complex that is associated with antigen presentation to cytotoxic (CD8+) T lymphocytes. Cancerous cells in beta2M loss-of-function are thought to avoid immune surveillance. As increased level of beta2M present in tissue/serum is significantly associated with tumor status in various cancers, beta2M may become an important prognostic and survival factor in a range of malignancies. It is believed that beta2M acts as hormone-like molecule to trigger a pleiotropic signaling via a ligand-to-receptor binding mechanism. Anti- beta2M monoclonal antibodies successfully induce apoptosis in malignant cells, suggesting a surprising therapeutic approach. Of note, beta2M is largely localized in the cytoplasm of advanced oral cavity squamous cell carcinoma (OCSCC), in contrast to that in the plasma membrane of normal oral mucosa. This suggests that beta2M-derived intracellular signaling might be preceded by its accumulation in the cytoplasm of epithelial cells of tumors. Hence, translocation of beta2M from cell surface to cytoplasm in advanced tumors may shed light on the mechanism of beta2M-mediated tumorigenesis. PMID- 24146001 TI - Rapid protocol for preparation of electrocompetent Escherichia coli and Vibrio cholerae. AB - Electroporation has become a widely used method for rapidly and efficiently introducing foreign DNA into a wide range of cells. Electrotransformation has become the method of choice for introducing DNA into prokaryotes that are not naturally competent. Electroporation is a rapid, efficient, and streamlined transformation method that, in addition to purified DNA and competent bacteria, requires commercially available gene pulse controller and cuvettes. In contrast to the pulsing step, preparation of electrocompetent cells is time consuming and labor intensive involving repeated rounds of centrifugation and washes in decreasing volumes of sterile, cold water, or non-ionic buffers of large volumes of cultures grown to mid-logarithmic phase of growth. Time and effort can be saved by purchasing electrocompetent cells from commercial sources, but the selection is limited to commonly employed E. coli laboratory strains. We are hereby disseminating a rapid and efficient method for preparing electrocompetent E. coli, which has been in use by bacteriology laboratories for some time, can be adapted to V. cholerae and other prokaryotes. While we cannot ascertain whom to credit for developing the original technique, we are hereby making it available to the scientific community. PMID- 24146002 TI - Risk factors for Pseudomonas aeruginosa pneumonia in the early twenty-first century. PMID- 24146004 TI - Experiments of the Richtmyer-Meshkov instability. AB - The Richtmyer-Meshkov instability is caused by a shock interacting with a density stratified interface. The mixing of the fluids is driven by vorticity created by the interaction of the density and pressure gradients. Because the flow is shock driven, the ensuing mixing occurs rapidly, making experimental measurements difficult. Over the past 10 years, there have been significant improvements in the experimental techniques used in shock-driven mixing flows. Many of these improvements have been driven by modelling and simulation efforts, and others have been driven by technology. High-resolution measurements of turbulence quantities are needed to advance our understanding of shock-driven flows, and this paper reviews the current state of experimental diagnostics, as well as paths forward in studying shock-driven mixing and turbulence. PMID- 24146003 TI - Implementation of a multifaceted sepsis education program in an emerging country setting: clinical outcomes and cost-effectiveness in a long-term follow-up study. AB - PURPOSE: To evaluate whether a multifaceted, centrally coordinated quality improvement program in a network of hospitals can increase compliance with the resuscitation bundle and improve clinical and economic outcomes in an emerging country setting. METHODS: This was a pre- and post-intervention study in ten private hospitals (1,650 beds) in Brazil (from May 2010 to January 2012), enrolling 2,120 patients with severe sepsis or septic shock. The program used a multifaceted approach: screening strategies, multidisciplinary educational sessions, case management, and continuous performance assessment. The network administration and an external consultant provided performance feedback and benchmarking within the network. The primary outcome was compliance with the resuscitation bundle. The secondary outcomes were hospital mortality, hospital and ICU length of stay, quality-adjusted life year (QALY) gain, and cost effectiveness. RESULTS: The proportion of patients who received all the required items for the resuscitation bundle improved from 13% [95% confidence interval (CI) 8-18%] at baseline to 62% (95% CI 54-69%) in the last trimester (p < 0.001). Hospital mortality decreased from 55% (95% CI 48-62%) to 26% (95% CI 19-32%, p < 0.001). Full compliance with the resuscitation bundle was associated with lower risk of hospital mortality (propensity weighted corrected risk ratio 0.74; 95% CI 0.56-0.94, p = 0.02). There was a reduction in the total cost per patient from 29.3 (95% CI 23.9-35.4) to 17.5 (95% CI 14.3-21.1) thousand US dollars from baseline to the last 3 months (mean difference -11,815; 95% CI -18,604 to 5,338). The mean QALY increased from 2.63 (95% CI 2.15-3.14) to 4.06 (95% CI 3.58 4.57). For each QALY, the full compliance saves US$5,383. CONCLUSIONS: A multifaceted approach to severe sepsis and septic shock patients in an emerging country setting led to high compliance with the resuscitation bundle. The intervention was cost-effective and associated with a reduction in mortality. PMID- 24146005 TI - The density ratio dependence of self-similar Rayleigh-Taylor mixing. AB - Previous research on self-similar mixing caused by Rayleigh-Taylor (RT) instability is summarized and a recent series of high resolution large eddy simulations is described. Mesh sizes of approximately 2000 *1000 * 1000 are used to investigate the properties of high Reynolds number self-similar RT mixing at a range of density ratios from 1.5 : 1 to 20 : 1. In some cases, mixing evolves from 'small random perturbations'. In other cases, random long wavelength perturbations (k(-3) spectrum) are added to give self-similar mixing at an enhanced rate, more typical of that observed in experiments. The properties of the turbulent mixing zone (volume fraction distributions, turbulence kinetic energy, molecular mixing parameter, etc.) are related to the RT growth rate parameter, alpha. Comparisons are made with experimental data on the internal structure and the asymmetry of the mixing zone (spike distance/bubble distance). The main purpose of this series of simulations is to provide data for calibration of engineering models (e.g. Reynolds-averaged Navier-Stokes models). It is argued that the influence of initial conditions is likely to be significant in most applications and the implications of this for engineering modelling are discussed. PMID- 24146006 TI - New directions for Rayleigh-Taylor mixing. AB - We study the Rayleigh-Taylor (RT) mixing layer, presenting simulations in agreement with experimental data. This problem is an idealized subproblem of important scientific and engineering problems, such as gravitationally induced mixing in oceanography and performance assessment for inertial confinement fusion. Engineering codes commonly achieve correct simulations through the calibration of adjustable parameters. In this sense, they are interpolative and not predictive. As computational science moves from the interpolative to the predictive and reduces the reliance on experiment, the quality of decision making improves. The diagnosis of errors in a multi-parameter, multi-physics setting is daunting, so we address this issue in the proposed idealized setting. The validation tests presented are thus a test for engineering codes, when used for complex problems containing RT features. The RT growth rate, characterized by a dimensionless but non-universal parameter alpha, describes the outer edge of the mixing zone. Increasingly accurate front tracking/large eddy simulations reveal the non-universality of the growth rate and agreement with experimental data. Increased mesh resolution allows reduction in the role of key subgrid models. We study the effect of long-wavelength perturbations on the mixing growth rate. A self-similar power law for the initial perturbation amplitudes is here inferred from experimental data. We show a maximum +/-5% effect on the growth rate. Large (factors of 2) effects, as predicted in some models and many simulations, are inconsistent with the experimental data of Youngs and co-authors. The inconsistency of the model lies in the treatment of the dynamics of bubbles, which are the shortest-wavelength modes for this problem. An alternative theory for this shortest wavelength, based on the bubble merger model, was previously shown to be consistent with experimental data. PMID- 24146007 TI - Numerical simulations of two-fluid turbulent mixing at large density ratios and applications to the Rayleigh-Taylor instability. AB - A tentative review is presented of various approaches for numerical simulations of two-fluid gaseous mixtures at high density ratios, as they have been applied to the Rayleigh-Taylor instability (RTI). Systems exhibiting such RTI behaviour extend from atomistic sizes to scales where the continuum approximation becomes valid. Each level of description can fit into a hierarchy of theoretical models and the governing equations appropriate for each model, with their assumptions, are presented. In particular, because the compressible to incompressible limit of the Navier-Stokes equations is not unique and understanding compressibility effects in the RTI critically depends on having the appropriate basis for comparison, two relevant incompressible limits are presented. One of these limits has not been considered before. Recent results from RTI simulations, spanning the levels of description presented, are reviewed in connection to the material mixing problem. Owing to the computational limitations, most in-depth RTI results have been obtained for the incompressible case. Two such results, concerning the asymmetry of the mixing and small-scale anisotropy anomaly, as well as the possibility of a mixing transition in the RTI, are surveyed. New lines for further investigation are suggested and it is hoped that bringing together such diverse levels of description may provide new ideas and increased motivation for studying such flows. PMID- 24146008 TI - Mechanochemical mechanism for reaction of aluminium nano- and micrometre-scale particles. AB - A recently suggested melt-dispersion mechanism (MDM) for fast reaction of aluminium (Al) nano- and a few micrometre-scale particles during fast heating is reviewed. Volume expansion of 6% during Al melting produces pressure of several GPa in a core and tensile hoop stresses of 10 GPa in an oxide shell. Such stresses cause dynamic fracture and spallation of the shell. After spallation, an unloading wave propagates to the centre of the particle and creates a tensile pressure of 3-8 GPa. Such a tensile pressure exceeds the cavitation strength of liquid Al and disperses the melt into small, bare clusters (fragments) that fly at a high velocity. Reaction of the clusters is not limited by diffusion through a pre-existing oxide shell. Some theoretical and experimental results related to the MDM are presented. Various theoretical predictions based on the MDM are in good qualitative and quantitative agreement with experiments, which resolves some basic puzzles in combustion of Al particles. Methods to control and improve reactivity of Al particles are formulated, which are exactly opposite to the current trends based on diffusion mechanism. Some of these suggestions have experimental confirmation. PMID- 24146009 TI - Direct numerical simulation of turbulent mixing. AB - The results of three-dimensional numerical simulations of turbulent flows obtained by various authors are reviewed. The paper considers the turbulent mixing (TM) process caused by the development of the main types of instabilities: those due to gravitation (with either a fixed or an alternating-sign acceleration), shift and shock waves. The problem of a buoyant jet is described as an example of the mixed-type problem. Comparison is made with experimental data on the TM zone width, profiles of density, velocity and turbulent energy and degree of homogeneity. PMID- 24146010 TI - Implicit large eddy simulation of shock-driven material mixing. AB - Under-resolved computer simulations are typically unavoidable in practical turbulent flow applications exhibiting extreme geometrical complexity and a broad range of length and time scales. An important unsettled issue is whether filtered out and subgrid spatial scales can significantly alter the evolution of resolved larger scales of motion and practical flow integral measures. Predictability issues in implicit large eddy simulation of under-resolved mixing of material scalars driven by under-resolved velocity fields and initial conditions are discussed in the context of shock-driven turbulent mixing. The particular focus is on effects of resolved spectral content and interfacial morphology of initial conditions on transitional and late-time turbulent mixing in the fundamental planar shock-tube configuration. PMID- 24146011 TI - Shock interactions, turbulence and the origin of the stellar mass spectrum. AB - Supersonic turbulence is an essential element in understanding how structure within interstellar gas is created and shaped. In the context of star formation, many computational studies show that the mass spectrum of density and velocity fluctuations within dense clouds, as well as the distribution of their angular momenta, trace their origin to the statistical and physical properties of gas that is lashed with shock waves. In this paper, we review the observations, simulations and theories of how turbulent-like processes can account for the structures we see in molecular clouds. We then compare traditional ideas of supersonic turbulence with a simpler physical model involving the effects of multiple shock waves and their interactions in the interstellar medium. Planar intersecting shock waves produce dense filaments and generate vortex sheets that are essential to create the broad range of density and velocity structure in clouds. As an example, the lower-mass behaviour of the stellar initial mass function can be traced to the tendency of a collection of shock waves to build up a lognormal density distribution (or column density). Vorticity--which is essential to produce velocity structure over a very broad range of length scales in shocked clouds--can also be generated by the passage of curved shocks or intersecting planar shocks through such media. Two major additional physical forces affect the structure of star-forming gas--gravity and feedback processes from young stars. Both of these can produce power-law tails at the high-mass end of the initial mass function. PMID- 24146012 TI - Some peculiar features of hydrodynamic instability development. AB - We discuss the results of experiments that illustrate some features of a turbulent mixing zone (TMZ) structure at a gas-liquid interface (Rayleigh-Taylor instability) and at a gas-gas interface accelerated by shock waves (Richtmyer Meshkov instability). The important feature is the existence of a heavier substance concentration (density) jump at the interface between the heavy medium and the TMZ. It is found that the existence of this jump is a generic feature of any developed TMZ and is the necessary condition for its continuous development. In the case of a gas-liquid interface, the stable existence of this jump is connected with the stability of the cupola of gas bubbles penetrating into the liquid in a TMZ. The important feature of the development of interface instability accelerated by an unsteady shock is the decaying ability (up to full suppression) of the interface instability in the case when a decaying wave passes through the interface in the direction from light gas to heavy gas. PMID- 24146013 TI - Some peculiarities of turbulent mixing growth and perturbations at hydrodynamic instabilities. AB - The author presents a review of some experimental works devoted to the research of evolution of large-scale perturbations and turbulent mixing (TM) in liquid and gaseous media during the growth of hydrodynamic instabilities. In particular, it is shown that growth of perturbations and TM in gases is sensitive to the Mach number of shock wave; character of gas front penetration into liquid is not changed as the Reynolds number of flow increases from 5*10(5) to 10(7); and change of the Atwood number sign from positive to negative causes stopping of gas front penetration into liquid, but mixing zone width is expanded under inertia. PMID- 24146014 TI - What is certain and what is not so certain in our knowledge of Rayleigh-Taylor mixing? AB - Past decades significantly advanced our understanding of Rayleigh-Taylor (RT) mixing. We briefly review recent theoretical results and numerical modelling approaches and compare them with state-of-the-art experiments focusing the reader's attention on qualitative properties of RT mixing. PMID- 24146015 TI - Acceleration and turbulence in Rayleigh-Taylor mixing. AB - Past decades have significantly advanced our ability to probe turbulent mixing in Rayleigh-Taylor flows, in both experiments and simulations. Yet, our basic understanding remains elusive and requires better basis. For instance, observations do not substantiate the rudimentary dimensional arguments to the same degree of certainty as in classical three-dimensional turbulence. We provide a plausible scenario based on a momentum-driven model. The results presented are specific enough that they can be used to interpret experimental and numerical simulation data. PMID- 24146016 TI - Turbulent mixing and beyond: non-equilibrium processes from atomistic to astrophysical scales II. AB - This Introduction summarizes and provides a perspective on the papers representing one of the key themes of the 'Turbulent mixing and beyond' programme -the hydrodynamic instabilities of the Rayleigh-Taylor (RT) and Richtmyer-Meshkov (RM) type and their applications in nature and technology. The collection is intended to present the reader a balanced overview of the theoretical, experimental and numerical studies of the subject and to assess what is firm in our knowledge of the RT and RM turbulent mixing. PMID- 24146017 TI - Synthesis and in vitro characterization of ionone-based compounds as dual inhibitors of the androgen receptor and NF-kappaB. AB - Current therapeutic strategy for advanced prostate cancer is to suppress the androgen receptor (AR) signaling. However, lethal castration-resistant prostate cancer (CRPC) arises due to AR reactivation via multiple mechanisms, including mutations in the AR and cross-talk with other pathways such as NF-kappaB. We have previously identified two ionone-based antiandrogens (SC97 and SC245), which are full antagonists of the wild type and the clinically-relevant T877A, W741C and H874Y mutated ARs. Here, we discovered SC97 and SC245 also inhibit NF-kappaB. By synthesizing a series of derivatives of these two compounds, we have discovered a novel compound 3b that potently inhibits both AR and NF-kappaB signalling, including the AR F876L mutant. Compound 3b showed low micromolar antiproliferative activites in C4-2B and 22Rv1 cells, which express mutated ARs and are androgen-independent, as well as DU-145 and PC-3 cells, which exhibit constitutively activated NF-kappaB signalling. Our studies indicate 3b is effective against the CRPC cells. PMID- 24146018 TI - Copper nanoparticle-catalyzed cross-coupling of alkyl halides with Grignard reagents. AB - A cross-coupling reaction between alkyl bromides and chlorides and various Grignard reagents was carried out in the presence of commercially available copper or copper oxide nanoparticles as a catalyst and an alkyne additive. The catalytic system shows high activity, a broad scope, and good functional group tolerance. PMID- 24146020 TI - Ultrahigh-throughput sorting of microfluidic drops with flow cytometry. AB - The detection and sorting of aqueous drops is central to microfluidic workflows for high-throughput biology applications, including directed evolution, digital PCR, and antibody screening. However, high-throughput detection and sorting of drops require optical systems and microfluidic components that are complex, difficult to build, and often yield inadequate sensitivity and throughput. Here, we demonstrate a general method to harness flow cytometry, with its unmatched speed and sensitivity, for droplet-based microfluidic sorting. PMID- 24146019 TI - Neem leaf extract inhibits mammary carcinogenesis by altering cell proliferation, apoptosis, and angiogenesis. AB - Plant-based medicines are useful in the treatment of cancer. Many breast cancer patients use complementary and alternative medicine in parallel with conventional treatments. Neem is historically well known in Asia and Africa as a versatile medicinal plant with a wide spectrum of biological activities. The experiments reported herein determined whether the administration of an ethanolic fraction of Neem leaf (EFNL) inhibits progression of chemical carcinogen-induced mammary tumorigenesis in rat models. Seven-week-old female Sprague Dawley rats were given a single intraperitoneal injection of N-methyl-N-nitrosourea (MNU). Upon the appearance of palpable mammary tumors, the rats were divided into vehicle-treated control groups and EFNL-treated groups. Treatment with EFNL inhibited MNU-induced mammary tumor progression. EFNL treatment was also highly effective in reducing mammary tumor burden and in suppressing mammary tumor progression even after the cessation of treatment. Further, we found that EFNL treatment effectively upregulated proapoptotic genes and proteins such as p53, B cell lymphoma-2 protein (Bcl-2)-associated X protein (Bax), Bcl-2-associated death promoter protein (Bad) caspases, phosphatase and tensin homolog gene (PTEN), and c-Jun N terminal kinase (JNK). In contrast, EFNL treatment caused downregulation of anti apoptotic (Bcl-2), angiogenic proteins (angiopoietin and vascular endothelial growth factor A [VEGF-A]), cell cycle regulatory proteins (cyclin D1, cyclin dependent kinase 2 [Cdk2], and Cdk4), and pro-survival signals such as NFkappaB, mitogen-activated protein kinase 1 (MAPK1). The data obtained in this study demonstrate that EFNL exert a potent anticancer effect against mammary tumorigenesis by altering key signaling pathways. PMID- 24146021 TI - Intra-oral mandibular sagittal osteotomy technique to correct mandibular distocclusion and mesio-occlusion. Study in canine cadavers. AB - Skeletal malocclusions may be due to disturbances in the growth of the mandible or maxilla. In most cases, discomfort is the result of tooth-to-tooth malocclusion or tooth-to-soft-tissue contact. Currently, in veterinary medicine, these problems are treated palliatively. In humans, orthognathic surgery is indicated to correct severe skeletal malocclusions, offering aesthetic and functional benefits to the patients. This research evaluated the effects of an intra-oral mandibular sagittal split osteotomy in 20 dog cadavers with skeletal malocclusion. After sagittal osteotomy and mandibular repositioning, the osteotomies were fixed with titanium mini-plates and 1.5 mm diameter screws or 1.5 mm bicortical screws. The statistical analysis revealed a significant occlusion difference in the treated cadavers (Wilcoxon test, p<0.05). In 19/20 cadavers there was correction of the angular osteotomy while the mandibular alveolar vessels and nerve were preserved during osteotomy and fixation in all cadavers. In conclusion, intra-oral mandible sagittal osteotomy allowed correction of malocclusion in cadavers. However, it would be important to prepare a preoperative orthodontic-surgical treatment plan to obtain a satisfactory occlusion during the surgery in clinical patients. PMID- 24146022 TI - Changes in population HIV RNA levels in Mbarara, Uganda, during scale-up of HIV antiretroviral therapy access. AB - OBJECTIVE: In a rural Ugandan community scaling up antiretroviral therapy (ART), we sought to determine if population-based HIV RNA levels [population viral load (VL)] decreased from 2011 to 2012. DESIGN: Serial cross-sectional analyses (May 2011 and May 2012) of a defined study community of 6300 persons in a district with HIV prevalence of 8%. METHODS: We measured HIV-1 RNA (VL) levels on all individuals testing positive for HIV during a 5-day high-throughput multidisease community health campaign in May 2012 that recruited two-thirds of the population. We aggregated individual-level VL results into population VL metrics including the proportion of individuals with an undetectable VL and compared these VL metrics to those we previously reported for this geographic region in 2011. RESULTS: In 2012, 223 of 2179 adults were HIV-seropositive adults (10%). Overall, among 208 of 223 HIV-seropositive adults in whom VL was tested, 53% had an undetectable VL [95% confidence interval (CI): 46 to 60], up from 37% (95% CI: 30 to 45; P = 0.02) in 2011. Seven (3%) individuals had a VL of >100,000 copies/mL in 2012, down from 21 (13%) in 2011 (P = 0.0007). Mean log (VL) (geometric mean) was 3.18 log (95% CI: 3.06 to 3.29 log) in 2012, down from 3.62 log (95% CI: 3.46 to 3.78 log) in 2011 (P < 0.0001). Similar reductions in population VL were seen among men and women. CONCLUSIONS: Reductions in population VL metrics and a substantial increase in the proportion of persons with an undetectable VL were observed in a rural Ugandan community from 2011 to 2012. These findings from a resource-limited setting experiencing rapid ART scale up may reflect a population-level effectiveness of expanding ART access. PMID- 24146024 TI - An emitting Hofmann-type compound: evidence for interlayer aurophilic interactions. AB - A newly synthesized Hofmann-type bimetallic coordination polymer, [Cd(II)(3 methylpyridine)2][Au(CN)2]2, was luminescent with emission peaks at 400 nm, 440 nm, 490 nm and 550 nm (shoulder) under irradiation at 360 nm, whose multiple peak character in the emission spectrum was rationalized in terms of the vibrational structures in the interactions between the Au atoms in adjacent layers. PMID- 24146023 TI - A systems biology perspective on the role of WRKY transcription factors in drought responses in plants. AB - Drought is one of the major challenges affecting crop productivity and yield. However, water stress responses are notoriously multigenic and quantitative with strong environmental effects on phenotypes. It is also clear that water stress often does not occur alone under field conditions but rather in conjunction with other abiotic stresses such as high temperature and high light intensities. A multidisciplinary approach with successful integration of a whole range of -omics technologies will not only define the system, but also provide new gene targets for both transgenic approaches and marker-assisted selection. Transcription factors are major players in water stress signaling and some constitute major hubs in the signaling webs. The main transcription factors in this network include MYB, bHLH, bZIP, ERF, NAC, and WRKY transcription factors. The role of WRKY transcription factors in abiotic stress signaling networks is just becoming apparent and systems biology approaches are starting to define their places in the signaling network. Using systems biology approaches, there are now many transcriptomic analyses and promoter analyses that concern WRKY transcription factors. In addition, reports on nuclear proteomics have identified WRKY proteins that are up-regulated at the protein level by water stress. Interactomics has started to identify different classes of WRKY-interacting proteins. What are often lacking are connections between metabolomics, WRKY transcription factors, promoters, biosynthetic pathways, fluxes and downstream responses. As more levels of the system are characterized, a more detailed understanding of the roles of WRKY transcription factors in drought responses in crops will be obtained. PMID- 24146025 TI - SGOL1 variant B induces abnormal mitosis and resistance to taxane in non-small cell lung cancers. AB - Mitosis is the most conspicuous cell cycle phase and Shugoshin-like 1 (SGOL1) is a key protein in protecting sister chromatids from precocious separation during mitosis. We studied the role of SGOL1 and its splice variants in non-small cell lung cancer (NSCLC) using 82 frozen NSCLC tissue samples. SGOL1-B expression was prevalent in smokers, in cases with a wild-type (WT) EGFR status, and in cases with the focal copy number amplification of genes that are known to be important for defining the biological behaviors of NSCLC. The overexpression of SGOL1-B1 in an NSCLC cell line induced aberrant chromosome missegregation, precociously separated chromatids, and delayed mitotic progression. A higher level of SGOL1-B mRNA was related to taxane resistance, while the forced downregulation of SGOL1-B increased the sensitivity to taxane. These results suggest that the expression of SGOL1-B causes abnormal mitosis and taxane resistance in NSCLC cells. PMID- 24146027 TI - Reproductive endocrinology: Estrogens--not just female hormones. AB - In a carefully conducted, outstanding example of clinical research, Finkelstein et al. clearly demonstrate the physiological underpinnings for the action of testosterone and the relative roles of its androgenic and estrogenic effects on body composition and sexual function. This study has important clinical implications for testosterone replacement therapy of male hypogonadism. PMID- 24146028 TI - Bone: Strontium ranelate does not have an anabolic effect on bone. AB - Strontium ranelate, a therapeutic for osteoporosis, was thought to have a dual mode of action, simultaneously stimulating bone formation and reducing resorption. A recent study casts doubt on this explanation, suggesting instead that it has a mild suppressive effect on bone formation with little effect on bone resorption. PMID- 24146029 TI - Bone: Role for PLS3 in X-linked osteoporosis revealed. PMID- 24146035 TI - Validity and reliability of an inertial sensor for wheelchair court sports performance. AB - The purpose of the current study was to determine the validity and reliability of an inertial sensor for assessing speed specific to athletes competing in the wheelchair court sports (basketball, rugby, and tennis). A wireless inertial sensor was attached to the axle of a sports wheelchair. Over two separate sessions, the sensor was tested across a range of treadmill speeds reflective of the court sports (1.0 to 6.0 m/s). At each test speed, ten 10-second trials were recorded and were compared with the treadmill (criterion). A further session explored the dynamic validity and reliability of the sensor during a sprinting task on a wheelchair ergometer compared with high-speed video (criterion). During session one, the sensor marginally overestimated speed, whereas during session two these speeds were underestimated slightly. However, systematic bias and absolute random errors never exceeded 0.058 m/s and 0.086 m/s, respectively, across both sessions. The sensor was also shown to be a reliable device with coefficients of variation (% CV) never exceeding 0.9 at any speed. During maximal sprinting, the sensor also provided a valid representation of the peak speeds reached (1.6% CV). Slight random errors in timing led to larger random errors in the detection of deceleration values. The results of this investigation have demonstrated that an inertial sensor developed for sports wheelchair applications provided a valid and reliable assessment of the speeds typically experienced by wheelchair athletes. As such, this device will be a valuable monitoring tool for assessing aspects of linear wheelchair performance. PMID- 24146030 TI - Adipose tissue browning and metabolic health. AB - Accumulation of excess white adipose tissue (WAT) has deleterious consequences for metabolic health. The activation of brown adipose tissue (BAT), the primary organ for heat production, confers beneficial effects on adiposity, insulin resistance and hyperlipidaemia, at least in mice. As the amount of metabolically active BAT seems to be particularly low in patients with obesity or diabetes mellitus who require immediate therapy, new avenues are needed to increase the capacity for adaptive thermogenesis. In this light, we review the findings that BAT in human adults might consist of not only classic brown adipocytes but also inducible brown adipocytes (also called beige, brown-in-white, or brite adipocytes), which are phenotypically distinct from both white and brown adipocytes. Stimulating the development of beige adipocytes in WAT (so called 'browning') might reduce adverse effects of WAT and could help to improve metabolic health. This article focuses on the development and regulatory control of beige adipocytes at the transcriptional and hormonal levels. Emerging insights into the metabolic role of beige adipocytes are also discussed, along with the developments that can be expected from these promising targets for therapy of metabolic disease in the future. PMID- 24146033 TI - Energy metabolism and fertility: a balance preserved for female health. AB - In female animals, energy metabolism and fertility are tightly connected, and reciprocally regulated. However, the relative contributions of metabolic and reproductive pathways have changed over the course of evolution. In oviparous animals, metabolic factors take precedence over fertility, enabling egg production to be inhibited in a nutritionally poor environment. By contrast, in placental mammals, the opposite occurs: the need to feed a developing embryo and neonate forces metabolic pathways to adapt to these reproductive needs. This physiological necessity explains why in female mammals alterations of gonadal activity, including age-dependent cessation of ovarian functions, are associated with a disruption of metabolic homeostasis and consequent inflammatory reactions that trigger the onset of metabolic, cardiovascular, skeletal and neural pathologies. This Review discusses how metabolic homeostasis and reproductive functions interact to optimize female fertility and explains the pathogenic mechanisms underlying the disordered energy metabolism associated with human ovarian dysfunction owing to menopause, polycystic ovary syndrome and Turner syndrome. Finally, this article highlights how hormone replacement therapy might aid the restoration of metabolic homeostasis in women with ovarian dysfunction. PMID- 24146036 TI - TLR3 and TLR4 as potential clinically biomarkers of cardiovascular risk in coronary artery disease (CAD) patients. AB - Coronary artery disease (CAD), as a lipid-driven and inflammation-driven disease, has threatened thousands of patients' lives. Toll-like receptors, the most characterized innate immune receptors, have recently been demonstrated to play a key role in coronary artery disease, particularly Toll-like receptor (TLR) 3 and TLR4. We examined TLR3, TLR4, and associated inflammatory factors expression in monocytes and their signaling pathway proteins in patients with varying degrees of coronary artery atherosclerosis [group S (single diseased vessel), n = 36; group D (double diseased vessels), n = 36; group T (three diseased vessels), n = 33 compared with controls (n = 35)]. In mononuclear cells, TLR3 mRNA and protein, and IRF-3 were significantly down-regulated as the coronary arteries stenosis number increased. However, TLR4 mRNA and protein, and MyD88 were significantly increased in patients with coronary artery stenosis compared with controls, and were associated with the number of stenoses. In serum, there was significant up regulation in TNF-alpha, IL-8, and MCP-1 and obvious down-regulation in INF-beta and IP-10 with severity of CAD. This study demonstrates differential expression of TLR3 and TLR4 at both the mRNA and protein level in both mononuclear cells and downstream serum readouts of patients with CAD compared with the control. The expression of TLR4 and TLR3 closely correlated with the severity of coronary artery disease as reflected by the number of coronary artery stenoses. TLR3 and TLR4 have the potential to be a clinically useful biomarker of cardiovascular risk. PMID- 24146037 TI - Evaluation of multiwave pulse total-hemoglobinometer during general anesthesia. AB - The purpose of this prospective study was to evaluate the accuracy and trending ability of a four-wavelength pulse-total hemoglobinometer that continuously and noninvasively measures hemoglobin in surgical patients. With IRB approval and informed consent, spectrophotometric hemoglobin (SpHb) was measured with a pulse total hemoglobinometer manufactured by Nihon Kohden Corp (Tokyo, Japan) and compared to the CO-oximeter equipped with blood gas analyzer. Two hundred twenty five samples from 56 subjects underwent analysis. Bland-Altman analysis revealed that the bias +/- precision of the current technology was 0.0 +/- 1.4 g/dl and 0.2 +/- 1.3 g/dl for total samples and samples with 8 < Hb < 11 g/dl, respectively. The percentages of samples with intermediate risk of therapeutic error in error grid analysis and the concordance rate of 4-quadrant trending assay was 17 % and 77 %, respectively. The Cohen kappa statistic for Hb < 10 g/dl was 0.38, suggesting that the agreement between SpHb and CO-oximeter-derived Hb was fair. Collectively, wide limits of agreement, especially at the critical level of hemoglobin, and less than moderate agreement against CO-oximeter-derived hemoglobin preclude the use of the pulse-total hemoglobinometer as a decision making tool for transfusion. PMID- 24146038 TI - Summaries for patients. Screening, monitoring, and treatment of early stage chronic kidney disease: recommendations from the American College of Physicians. PMID- 24146039 TI - ERC/mesothelin is expressed in human gastric cancer tissues and cell lines. AB - ERC/mesothelin is expressed in mesothelioma and other malignancies. The ERC/mesothelin gene (MSLN) encodes a 71-kDa precursor protein, which is cleaved to yield 31-kDa N-terminal (N-ERC/mesothelin) and 40-kDa C-terminal (C ERC/mesothelin) proteins. N-ERC/mesothelin is a soluble protein and has been reported to be a diagnostic serum marker of mesothelioma and ovarian cancer. Gastric cancer tissue also expresses C-ERC/mesothelin, but the significance of serum N-ERC levels for diagnosing gastric cancer has not yet been studied. We examined the latter issue in the present study as well as C-ERC/mesothelin expression in human gastric cancer tissues and cell lines. We immunohistochemically examined C-ERC/mesothelin expression in tissue samples from 50 cases of gastric cancer, and we also assessed the C-ERC/mesothelin expression in 6 gastric cancer cell lines (MKN-1, MKN-7, MKN-74, NUGC-3, NUGC-4 and TMK-1) using reverse transcription-polymerase chain reaction, flow cytometry, immunohistochemistry and immunoblotting. We also examined the N-ERC/mesothelin concentrations in the supernatants of cultured cells and in the sera of gastric cancer patients using an enzyme-linked immunosorbent assay (ELISA). N ERC/mesothelin was detected in the supernatants of 3 gastric cancer cell lines (MKN-1, NUGC-4 and TMK-1) by ELISA, but its concentration in the sera of gastric cancer patients was almost same as that observed in the sera of the normal controls. In the gastric cancer tissues, C-ERC/mesothelin expression was associated with lymphatic invasion. N-ERC/mesothelin was secreted into the supernatants of gastric cancer cell lines, but does not appear to be a useful serum marker of gastric cancer. PMID- 24146040 TI - Heparan sulfate in angiogenesis: a target for therapy. AB - Heparan sulfate (HS), a long linear polysaccharide of alternating disaccharide residues, interacts with a wide variety of proteins, including many angiogenic factors. The involvement of HS in signaling of pro-angiogenic factors (e.g. vascular endothelial growth factor and fibroblast growth factor 2), as well as interaction with anti-angiogenic factors (e.g. endostatin), warrants its role as an important modifier of (tumor) angiogenesis. This review summarizes our current understanding of the role of HS in angiogenic growth factor signaling, and discusses therapeutic strategies to target HS and modulate angiogenesis. PMID- 24146041 TI - CD8+ T cell responses to lytic EBV infection: late antigen specificities as subdominant components of the total response. AB - EBV elicits primary CD8(+) T cell responses that, by T cell cloning from infectious mononucleosis (IM) patients, appear skewed toward immediate early (IE) and some early (E) lytic cycle proteins, with late (L) proteins rarely targeted. However, L Ag-specific responses have been detected regularly in polyclonal T cell cultures from long-term virus carriers. To resolve this apparent difference between responses to primary and persistent infection, 13 long-term carriers were screened in ex vivo IFN-gamma ELISPOT assays using peptides spanning the two IE, six representative E, and seven representative L proteins. This revealed memory CD8 responses to 44 new lytic cycle epitopes that straddle all three protein classes but, in terms of both frequency and size, maintain the IE > E > L hierarchy of immunodominance. Having identified the HLA restriction of 10 (including 7 L) new epitopes using memory CD8(+) T cell clones, we looked in HLA matched IM patients and found such reactivities but typically at low levels, explaining why they had gone undetected in the original IM clonal screens. Wherever tested, all CD8(+) T cell clones against these novel lytic cycle epitopes recognized lytically infected cells naturally expressing their target Ag. Surprisingly, however, clones against the most frequently recognized L Ag, the BNRF1 tegument protein, also recognized latently infected, growth-transformed cells. We infer that BNRF1 is also a latent Ag that could be targeted in T cell therapy of EBV-driven B-lymphoproliferative disease. PMID- 24146042 TI - Alternative end-joining and classical nonhomologous end-joining pathways repair different types of double-strand breaks during class-switch recombination. AB - Classical nonhomologous end-joining (C-NHEJ) and alternative end-joining (A-EJ) are the main DNA double-strand break (DSB) repair pathways when a sister chromatid is not available. However, it is not clear how one pathway is chosen over the other to process a given DSB. To address this question, we studied in mouse splenic B cells and CH12F3 cells how C-NHEJ and A-EJ repair DSBs initiated by the activation-induced deaminase during IgH (Igh) class-switch recombination (CSR). We show in this study that lowering the deamination density at the Igh locus increases DSB resolution by microhomology-mediated repair while decreasing C-NHEJ activity. This process occurs without affecting 53BP1 and gammaH2AX levels during CSR. Mechanistically, lowering deamination density increases exonuclease I recruitment and single-stranded DNA at the Igh locus and promotes C-terminal binding protein interacting protein and MSH2-dependent DSB repair during CSR. Indeed, reducing activation-induced deaminase levels increases CSR efficiency in C-NHEJ-defective cells, suggesting enhanced use of an A-EJ pathway. Our results establish a mechanism by which C-NHEJ and this C-terminal binding protein interacting protein/MSH2-dependent pathway that relies on microhomology can act concurrently but independently to repair different types of DSBs and reveal that the density of DNA lesions influences the choice of DSB repair pathway during CSR. PMID- 24146044 TI - Microglial activation milieu controls regulatory T cell responses. AB - Although mechanisms leading to brain-specific inflammation and T cell activation have been widely investigated, regulatory mechanisms of local innate immune cells in the brain are only poorly understood. In this study, to our knowledge we show for the first time that MHC class II(+)CD40(dim)CD86(dim)IL-10(+) microglia are potent inducers of Ag-specific CD4(+)Foxp3(+) regulatory T cells (Tregs) in vitro. Microglia differentially regulated MHC class II expression, costimulatory molecules, and IL-10 depending on the amount of IFN-gamma challenge and Ag dose, promoting either effector T cell or Treg induction. Microglia-induced Tregs were functionally active in vitro by inhibiting Ag-specific proliferation of effector T cells, and in vivo by attenuating experimental autoimmune encephalomyelitis disease course after adoptive transfer. These results indicate that MHC class II(+)CD40(dim)CD86(dim)IL-10(+) microglia have regulatory properties potentially influencing local immune responses in the CNS. PMID- 24146043 TI - Differential T cell responses to residual viral antigen prolong CD4+ T cell contraction following the resolution of infection. AB - The contraction phase of the T cell response is a poorly understood period after the resolution of infection when virus-specific effector cells decline in number and memory cells emerge with increased frequencies. CD8(+) T cells plummet in number and quickly reach stable levels of memory following acute lymphocytic choriomeningitis virus infection in mice. In contrast, virus-specific CD4(+) T cells gradually decrease in number and reach homeostatic levels only after many weeks. In this study, we provide evidence that MHCII-restricted viral Ag persists during the contraction phase following this prototypical acute virus infection. We evaluated whether the residual Ag affected the cell division and number of virus-specific naive and memory CD4(+) T cells and CD8(+) T cells. We found that naive CD4(+) T cells underwent cell division and accumulated in response to residual viral Ag for >2 mo after the eradication of infectious virus. Surprisingly, memory CD4(+) T cells did not undergo cell division in response to the lingering Ag, despite their heightened capacity to recognize Ag and make cytokine. In contrast to CD4(+) T cells, CD8(+) T cells did not undergo cell division in response to the residual Ag. Thus, CD8(+) T cells ceased division within days after the infection was resolved, indicating that CD8(+) T cell responses are tightly linked to endogenous processing of de novo synthesized virus protein. Our data suggest that residual viral Ag delays the contraction of CD4(+) T cell responses by recruiting new populations of CD4(+) T cells. PMID- 24146046 TI - A new hole density as a stability measure for boron fullerenes. AB - We investigate the stability of boron fullerene sets B76, B78 and B82. We evaluate the ground state energies, nucleus-independent chemical shift (NICS), the binding energies per atom and the band gap values by means of first principles methods. We construct our fullerene design by capping of pentagons and hexagons of B60 cages in such a way that the total number of atoms is preserved. In doing so, a new hole density definition is proposed such that each member of a fullerene group has a different hole density which depends on the capping process. Our analysis reveals that each boron fullerene set has its lowest-energy configuration around the same normalized hole density and the most stable cages are found in the fullerene groups which have a relatively large difference between the maximum and the minimum hole densities. The result is a new stability measure relating the cage geometry characterized by the hole density to the relative energy. PMID- 24146045 TI - Superior antimitogenic and chemosensitization activities of the combination treatment of the histone deacetylase inhibitor apicidin and proteasome inhibitors on human colorectal cancer cells. AB - Despite the effectiveness of histone deacetylase inhibitors, proteasome inhibitors and cytotoxic drugs on human cancers, none of these types of treatments by themselves has been sufficient to eradicate the disease. The combination of different modalities may hold enormous potential for eliciting therapeutic results. In the current study, we examined the effects of treatment with the histone deacetylase inhibitor (HDACI) apicidin (APC) in combination with proteasome inhibitors on human colorectal cancer cells. The molecular mechanisms of the combined treatments and their potential to sensitize colorectal cancer cells to chemotherapies were also investigated. Cancer cells were exposed to the agents alone and in combination, and cell growth inhibition was determined by MTT and colony formation assays. HDAC, proteasome and NF-kappaB activities as well as reactive oxygen species (ROS) were monitored. Cell cycle perturbation and induction of apoptosis were assessed by flow cytometry. The expression of cell cycle/apoptosis- and cytoprotective/stress-related genes was determined by quantitative PCR and EIA, respectively. The potentiation of cancer cell sensitivity to chemotherapies upon APC/PI combination treatment was also studied. The combination of APC and MG132, PI-1 or epoxomicin potently inhibited cancer cell growth, disrupted the cell cycle, induced apoptosis, decreased NF-kappaB activity and increased ROS production. These events were accompanied by the altered expression of genes associated with the cell cycle, apoptosis and cytoprotection/stress regulation. The combination treatment markedly enhanced the chemosensitivity of colorectal cancer cells (50-3.7 x 10(4)-fold) in a drug-, APC/PI combination- and colorectal cancer subtype-dependent manner. The results of this study have implications for the development of com-binatorial treatments that include HDACIs, PIs and conventional chemotherapeutic drugs, suggesting a potential therapeutic synergy with general applicability to various types of cancers. PMID- 24146047 TI - Smoking and multiple sclerosis susceptibility. AB - Smoking is one of the most established risk factors for multiple sclerosis (MS). The aim of this study was to investigate how age at smoking debut, duration, intensity and cumulative dose of smoking, and smoking cessation influence the association between smoking and MS risk. In two Swedish population-based case control studies (7,883 cases, 9,264 controls), subjects with different smoking habits were compared regarding MS risk, by calculating odds ratios with 95% confidence intervals. We observed a clear dose response association between cumulative dose of smoking and MS risk (p value for trend <10(-35)). Both duration and intensity of smoking contributed independently to the increased risk of MS. However, the detrimental effect of smoking abates a decade after smoking cessation regardless of the cumulative dose of smoking. Age at smoking debut did not affect the association between smoking and MS. Smoking increases the risk of MS in a dose response manner. However, in contrary to several other risk factors for MS that seem to affect the risk only if the exposure takes place during a specific period in life, smoking affects MS risk regardless of age at exposure, and the detrimental effect slowly abates after smoking cessation. PMID- 24146048 TI - Prevalence of restless legs syndrome among adult population in a Serbian district: a community-based study. PMID- 24146049 TI - Three-dimensional computed tomography evaluation of anterior cruciate ligament footprint for anatomic single-bundle reconstruction. AB - PURPOSE: Femoral and tibial footprint coordinates have been well studied in double-bundle anterior cruciate ligament (ACL) reconstruction. However, in a single-bundle reconstruction approach, the central coordinate of femoral and tibial footprints have not been determined. The purpose of this study was to describe the central point locations of the ACL footprints visualized by three dimensional computed tomography (3D CT) images and analysed by the quadrant method. METHODS: Eight cadaveric knees were dissected, and the central points of ACL femoral and tibial footprints were marked and analysed using 3D CT images. RESULTS: In the present study, the means (and standard deviation) of ACL femoral footprint dimensions were in the ventral-dorsal plane and in the cranial-caudal plane 9.4 +/- 0.8 and 15.6 +/- 0.9 mm, respectively. In the tibial side, the means of ACL footprint dimensions were in the anterior-posterior and in the medial-lateral 18.5 +/- 1.9 and 15.5 +/- 1.0 mm, respectively. In the tomographic analyses, the means of femoral central location coordinates in the ventral-dorsal (y) and in the cranial-caudal (x) axes were 35.3 +/- 4.5 and 30.0 +/- 1.6 %, respectively. The means of tibial central location coordinates were in the anterior-posterior (y) and in the medial-lateral (x) axes, respectively: 40.5 +/- 5.3 and 50.2 +/- 1.3 %, respectively. CONCLUSIONS: These computed tomographic coordinates might help future studies as a reference on ACL single-bundle anatomic reconstruction, with respect to the management of ACL revision surgery or in symptomatic patients after ACL reconstruction. Improvements in three dimensional image acquisition could facilitate its intraoperative applicability in the coming years. PMID- 24146050 TI - Why menisci show higher healing rate when repaired during ACL reconstruction? Growth factors release can be the explanation. AB - PURPOSE: Healing rate of meniscus repair is higher when the suture is associated with anterior cruciate ligament reconstruction. A possible explanation can be a different pattern of release of growth factors between anterior cruciate ligament reconstruction and isolated meniscus surgery. Hypothesis of this study is that the concentrations of bFGF, TGF-beta and platelet-derived growth factor (PDGF) in joint fluid, immediately after single-bundle anterior cruciate ligament reconstruction and arthroscopic partial meniscectomy, can be different. METHODS: Twenty consecutive patients underwent partial medial meniscectomy and twenty consecutive patients underwent single-bundle anterior cruciate ligament reconstruction with hamstring grafts were enrolled in the study. Thirty minutes after the end of the surgical procedure, a sample of joint fluid, as well of venous blood, was collected from all the patients. Concentrations of growth factors were determined by enzyme-linked immunosorbent assay. RESULTS: The peripheral blood concentration of TGF-beta, bFGF and PDGF was comparable between partial meniscectomy and anterior cruciate ligament reconstruction groups. No differences between the two surgical techniques were also found in term of TGF beta and bFGF joint fluid concentration, whereas joint PDGF concentration of anterior cruciate ligament reconstruction patients was significantly higher than the one found in partial meniscectomy patients. CONCLUSIONS: A significant growth factors release was detected in the knee joint during arthroscopic surgery. PDGF concentration was significantly higher in anterior cruciate ligament reconstructed knee than in the meniscectomy group. PDGF can play an important role enhancing the healing response of meniscus suture and can be one of the biological reasons of the higher meniscal healing rate in anterior cruciate ligament reconstructed knee. PMID- 24146051 TI - Use of innovative biomimetic scaffold in the treatment for large osteochondral lesions of the knee. AB - PURPOSE: Large osteochondral defects involve two different tissues characterized by different intrinsic healing capacity. Different techniques have been proposed to treat these lesions with results still under discussion. The aim of the study is to evaluate the clinical outcome of 19 patients treated with a type I collagen hydroxyapatite nanostructural biomimetic osteochondral scaffold at minimum follow up of 2 years. METHODS: Twenty lesions, 19 patients were treated with this scaffold implantation. The lesions size went from 4 to 8 cm(2) (mean size 5.2 +/- 1.6 cm(2)). All patients were clinically evaluated using the International Repair Cartilage Society score, the Tegner Score and EQ-VAS. MRI was performed at 12 and 24 months after surgery and then every 12 months and evaluated with magnetic resonance observation of cartilage repair tissue scoring scale. RESULTS: The IKDC subjective score improved from a mean score of 35.7 +/- 6.3 at the baseline evaluation to 67.7 +/- 13.4 at 12-month follow-up (p < 0.0005). A further improvement was documented from 12 to 24 months (mean score of 72.9 +/- 12.4 at 24 months) (p < 0.0005). The IKDC objective score confirmed the results. The Tegner activity score improvement was statistically significant (p < 0.0005). The EQ-VAS showed a significant improvement from 3.15 +/- 1.09 to 7.35 +/- 1.14 (p < 0.0005) at 2-year follow-up. The lesion' site seems to influence the results showing a better outcome in the patients affected in the medial femoral condyle. CONCLUSIONS: The use of the MaioRegen scaffold is a good procedure for the treatment for large osteochondral defects where other classic techniques are difficult to apply. It is an open one-step surgery with promising stable results at medium follow-up. LEVEL OF EVIDENCE: IV. PMID- 24146052 TI - Cross-cultural adaptation to Swedish and validation of the Copenhagen Hip and Groin Outcome Score (HAGOS) for pain, symptoms and physical function in patients with hip and groin disability due to femoro-acetabular impingement. AB - PURPOSE: There is a lack of standardised outcome measures in Swedish for active, young and middle-aged patients with hip and groin disability. The purpose of this study was to adapt the Danish version of the Copenhagen Hip and Groin Outcome Score (HAGOS) patient-reported outcome instrument for use in Swedish patients and evaluate the adaptation according to the Consensus-Based Standards for the Selection of Health Status Measurement Instruments checklist. METHODS: Cross cultural adaptation was performed in several steps, including translation, back translation, expert review and pretesting. The final version was evaluated for reliability, validity and responsiveness. Five hundred and two patients (337 men and 167 women, mean age 37, range 15-75) were included in the study. RESULTS: Cronbach's alpha for the six HAGOS-S subscales ranged from 0.77 to 0.89. Significant correlations were obtained with the international Hip Outcome Tool average score (r s = 0.37-0.68; p < 0.01) and a standardised instrument, the EuroQol, EQ-5D total score (r s = 0.40-0.60, p = 0.01), for use as a measurement of health outcome. Test-retest reliability (intraclass correlation coefficient) ranged from 0.81 to 0.87 for the six HAGOS-S subscales. The smallest detectable change ranged from 7.8 to 16.1 at individual level and 1.6-3.2 at group level. Factor analysis revealed that the six HAGOS-S subscales had one strong factor per subscale. Effect sizes were generally medium or large. CONCLUSION: The Swedish version of the HAGOS is a valid, reliable and responsive instrument that can be used both for research and in the clinical setting at individual and group level. PMID- 24146053 TI - Comment on "Reconstruction of posterior glenoid deficiency using distal tibial osteoarticular allograft". PMID- 24146055 TI - "Speak what we feel, not what we ought to say": moral distress and bioethics. PMID- 24146054 TI - PVA-chitosan composite hydrogel versus alginate beads as a potential mesenchymal stem cell carrier for the treatment of focal cartilage defects. AB - PURPOSE: To investigate whether mesenchymal stem cells (MSCs) seeded in novel polyvinyl alcohol (PVA)-chitosan composite hydrogel can provide comparable or even further improve cartilage repair outcomes as compared to previously established alginate-transplanted models. METHODS: Medial femoral condyle defect was created in both knees of twenty-four mature New Zealand white rabbits, and the animals were divided into four groups containing six animals each. After 3 weeks, the right knees were transplanted with PVA-chitosan-MSC, PVA-chitosan scaffold alone, alginate-MSC construct or alginate alone. The left knee was kept as untreated control. Animals were killed at the end of 6 months after transplantation, and the cartilage repair was assessed through Brittberg morphological score, histological grading by O'Driscoll score and quantitative glycosaminoglycan analysis. RESULTS: Morphological and histological analyses showed significant (p < 0.05) tissue repair when treated with PVA-chitosan-MSC or alginate MSC as compared to the scaffold only and untreated control. In addition, safranin O staining and the glycosaminoglycan (GAG) content were significantly higher (p < 0.05) in MSC treatment groups than in scaffold-only or untreated control group. No significant difference was observed between the PVA-chitosan MSC- and alginate-MSC-treated groups. CONCLUSION: PVA-chitosan hydrogel seeded with mesenchymal stem cells provides comparable treatment outcomes to that of previously established alginate-MSC construct implantation. This study supports the potential use of PVA-chitosan hydrogel seeded with MSCs for clinical use in cartilage repair such as traumatic injuries. PMID- 24146056 TI - Death's Dominion: an appreciation of Ronald Dworkin (1931-2013). PMID- 24146057 TI - A highly stable dynamic fluorescent metal-organic framework for selective sensing of nitroaromatic explosives. AB - A dynamic fluorescent metal-organic framework has been constructed using triphenylene-2,6,10-tricarboxylate and Tb(3+) as building blocks, which exhibits guest-responsive structural dynamism and selective sensing of nitroaromatic explosives. PMID- 24146058 TI - Comparison of meloxicam and a glucosamine-chondroitin supplement in management of feline osteoarthritis. A double-blind randomised, placebo-controlled, prospective trial. AB - OBJECTIVE: To compare the efficacy of meloxicam and a glucosamine-chondroitin (Glu-Ch) supplement in the management of feline osteoarthritis (OA). METHODS: Prospective, blinded, randomized clinical trial. Cats over eight years of age with clinical signs of chronic OA were assigned to one of two groups and Glu-Ch or meloxicam was administered orally for 70 days, followed by a placebo until day 98. Cats were assessed by a veterinarian on five occasions and the owner completed an assessment form at the same time. RESULTS: Data were collected from thirty cats. Pre-treatment disease scores were significantly higher in the meloxicam group for owner mobility (p=0.01) and veterinary lameness (p=0.02). Owner mobility scores at day 14 (p=0.01) and day 42 (p=0.002) were significantly improved compared to pre-treatment scores for the meloxicam group. When meloxicam and Glu-Ch were discontinued and the placebo commenced, a significant proportion of the meloxicam group showed worsening of all the owner-assessed scores between day 70 and day 98, when compared to the Glu-Ch group (mobility p=0.01; activity p=0.02; temperament p=0.04; lifestyle p=0.01). CONCLUSIONS: Treatment with meloxicam resulted in a significant improvement in mobility and activity levels of cats with OA until the placebo was introduced. A greater proportion of cats receiving meloxicam medication showed a significant worsening of owner assessment scores once the placed was introduced, when compared to the Glu-Ch group. PMID- 24146059 TI - Beyond the firstborn son: epidemiology to enlighten the pathogenesis of hypertrophic pyloric stenosis. PMID- 24146060 TI - Prooxidant-antioxidant balance in perinatal asphyxia. AB - OBJECTIVE: To determine the prooxidant-antioxidant balance (PAB) in neonatal asphyxia and compare it with values for PAB in healthy neonates. METHODS: In a prospective observational study, serum PAB of umbilical cord blood of 30 neonates with asphyxia [pH < 7.2, low Apgar score, signs of respiratory distress syndrome (RDS)] as the case group and 35 healthy neonates (without an abnormal clinical event at birth and after the first week) as the control group were compared. RESULTS: Among the 35 neonates in the control group, the average level of serum PAB was 20.00 HK units, which was significantly lower than for the 30 neonates within the case group (40.46 HK units; p = 0.019). The blood pH in the case group was significantly lower than for control group (P < 0.001). In controls, HCO3 (-) and pCO2 were 18.6 mmol/L and 38.5 mmHg respectively, whilst in the case group these values were 15.5 mmol/L and 45.7 mmHg respectively (p < 0.05). CONCLUSIONS: Determination of PAB may be useful in the early diagnosis of perinatal asphyxia and is consistent with HCO3 (-), pCO2 and Apgar score. PMID- 24146061 TI - Within-participant variance in multiplanar breast kinematics during 5 km treadmill running. AB - More and more studies are emerging reporting breast kinematics. These studies rarely present effect sizes, power, and variance in the data. Important inferences are drawn from these data, including applications to product design, breast pain assessment, sports performance effects, and more. The aim of the study was to explore the within-participant variance in breast kinematic data during a 5 km run. Multiplanar breast kinematics and within-participant variance, defined by the coefficient of variation, for 10 female participants wearing a low and high level breast support were calculated during a 5 km run. Greater within participant variance was reported in the high level (mean=15%) breast support compared with the low level (mean=12%). Within-participant variance in breast kinematics did not change over the 5 km run. Differences in the magnitude of within-participant variance in breast kinematics were reported between directions of breast movement, with greater levels in the anteroposterior direction compared with mediolateral and vertical. It is important for the progression of this research area that the presence and sources of within-participant variance in breast kinematics are quantified and acknowledged, ensuring that the margin for meaningful differences can be reported. PMID- 24146062 TI - Catechol conjugates are in vivo metabolites of Salicis cortex. AB - After oral administration of 100 mg/kg b. w. (235.8 umol/kg) salicortin to Wistar rats, peak serum concentrations of 1.43 mg/L (13.0 uM) catechol were detected after 0.5 h in addition to salicylic acid by HPLC-DAD after serum processing with beta-glucuronidase and sulphatase. Both metabolites could also be detected in the serum of healthy volunteers following oral administration of a willow bark extract (Salicis cortex, Salix spec., Salicaceae) corresponding to 240 mg of salicin after processing with both enzymes. In humans, the cmax (1.46 mg/L, 13.3 uM) of catechol was reached after 1.2 h. The predominant phase-II metabolite in humans and rats was catechol sulphate, determined by HPLC analysis of serum samples processed with only one kind of enzyme. Without serum processing with glucuronidase and sulphatase, no unconjugated catechol could be detected in human and animal serum samples. As catechol is described as an anti-inflammatory compound, these results may contribute to the elucidation of the mechanism of the action of willow bark extract. PMID- 24146064 TI - Recurrence after endoscopic mucosal resection-therapy failure? AB - PURPOSE: To evaluate the success and complication rates of endoscopic mucosal resections (EMR) for large flat adenomas and to identify risk factors for adenoma recurrence. METHODS: We evaluated all consecutive patients treated with EMR at our institution between 2003 and 2005 that fulfilled the following criteria: >10 mm diameter, Paris 0-Is and 0-IIa-c, and endoscopic follow-up. We conducted univariate analysis and multivariate analysis using a non-stratified logistic regression model to identify possible influencing factors. RESULT: In a median follow-up period of 6 years, we analyzed 177 EMR procedures, with a mean size of 21 mm. The majority of the resections were in the right colon. Recurrence occurred in 29 patients. Further treatment of patients with recurrence was endoscopic in 27 patients, whereas 1 patient was treated with transanal endoscopic microsurgery and one underwent surgery. The variables influencing the multivariate model were resection technique, immediate complication age, and histology. CONCLUSIONS: We show that EMR can achieve a long-term clearance of large flat adenomas. A recurrence after EMR does not equal to failed therapy. The possibility of recurrence has to be considered in the clinical implementation of EMR. An important part of the stratifying factors for follow-up is the procedural assessment of the effectiveness of the resection and the resection technique. PMID- 24146063 TI - A cell rolling cytometer reveals the correlation between mesenchymal stem cell dynamic adhesion and differentiation state. AB - This communication presents quantitative studies of the dynamic adhesion behavior of mesenchymal stem cells (MSCs) enabled by the combination of cell-surface receptor-ligand interactions and three-dimensional hydrodynamic control by microtopography. PMID- 24146065 TI - Rice bran oil and n-3 fatty acid-rich garden cress (Lepidium sativum) seed oil attenuate murine model of ulcerative colitis. PMID- 24146066 TI - Radon measurements and effective dose from radon inhalation estimation in the Neapolitan catacombs. AB - In this study, the indoor radon activity concentrations have been measured in the Neapolitan catacombs using LR115 detectors. The detectors were exposed for two quarters, one in the warm season and the other in the cold. This has allowed one to evaluate the seasonal variations of concentrations, while the diurnal variations were evaluated performing continuous measurements by a Radim 5 monitor. The authors found that radon concentrations were lower in winter than in summer. Based on their values, taking into consideration the working hours in the catacombs and the equilibrium factor of 0.4, the effective dose to workers was estimated. PMID- 24146067 TI - Biphasic activation of nuclear factor kappa B and expression of p65 and c-Rel after traumatic brain injury in rats. AB - BACKGROUND AND OBJECT: Nuclear factor kappa B (NF-kappaB) functions as a key regulator in the central nervous system and regulates the inflammatory pathway. There are two peaks of cerebral NF-kappaB activation after neonatal hypoxia ischemia and subarachnoid hemorrhage. Our previous studies found that NF-kappaB activity was up-regulated at an early stage and remained elevated at day 7 after traumatic brain injury (TBI). However, data are lacking regarding an overview of NF-kappaB activity and expression of NF-kappaB subunits after TBI. Hence, the current study was designed to detect the time course of NF-kappaB activation and expression of NF-kappaB p65 and c-Rel subunits around the contused cortex following TBI. METHODS: Adult Sprague-Dawley rats were randomly divided into sham and TBI groups at different time points. A TBI model was induced, and then the NF kappaB DNA-binding activity in the surrounding areas of injured brain was detected by electrophoretic mobility shift assay. Western blotting was used to measure the protein levels of p65 and c-Rel in the nucleus. The concentrations of tumor necrosis factor-alpha (TNF-alpha) and interleukin-1beta (IL-1beta) were detected by enzyme-linked immunosorbent assay. Moreover, the distribution of c Rel and p65 was examined by immunohistochemical studies. RESULTS: There were double peaks of cerebral cortical NF-kappaB activity, at 3 and 10 days post injury. Additionally, protein levels of p65 were found to be elevated and peaked at 3 days after TBI, while levels of c-Rel were elevated significantly during the later phase of injury. Furthermore, TNF-alpha and IL-1beta concentrations also showed a biphasic increase. CONCLUSIONS: Biphasic activation of NF-kappaB could be induced after experimental TBI in rats. NF-kappaB p65 and c-Rel subunits were elevated at different post-TBI time periods, leading to a hypothesis that different NF-kappaB subunits might be involved in different pathophysiological processes after TBI. PMID- 24146068 TI - Exosomes derived from Rab27a-overexpressing tumor cells elicit efficient induction of antitumor immunity. AB - Lung cancer is the leading cause of mortality worldwide. However, there is a lack of effective therapeutic strategies. Currently, tumor immunotherapy based on exosomes, which are secreted by a variety of cell types including tumor cells, has drawn particular attention and are suggested to have the potential for exploitation in tumor therapy. Nevertheless, the therapeutic efficacy mediated via tumor cell-derived exosomes is not satisfactory. Rab27a, one of the Rab family of small GTPases, has been suggested to be important in exosome secretion. Thus, the purpose of the present study was to examine whether exosomes derived from Rab27a-overexpressing cells elicited more potent antitumor immunity. A Rab27a-overexpressing line was established via transfection of a Rab27a overexpression vector into the human non-small-cell lung cancer cell line, A549. Exosomes were isolated and the typical exosomal protein markers, CD9, CD63, heat shock protein (Hsp) 70 and Hsp90, were found to be enriched in the exosomes derived from Rab27a-overexpressing cells. Subsequently, these exosomes were demonstrated to be capable of upregulating major histocompatibility complex class II molecules as well as the co-stimulatory molecules CD80 and CD86 on dendritic cells (DCs), suggesting that more potent maturation of DCs was induced. Furthermore, DCs loaded with exosomes derived from Rab27-overexpressing cells significantly promoted CD4+ T cell proliferation in vitro. In addition, in vivo immunization of exosomes derived from Rab27a-overexpressing cells inhibited tumor growth in a mouse model. It was also demonstrated that splenocytes from mice immunized with exosomes derived from Rab27-overexpressing cells expressed high levels of type I cytokines, including IL-2 and IFN-gamma, which are important in the regulation of cell-mediated antitumor immunity. Collectively, it was demonstrated that exosomes derived from Rab27a-overexpressing cancer cells elicited more potent antitumor immune effects, which may provide novel insights for the development of efficient exosome-based cancer vaccines. PMID- 24146069 TI - A new catalytic oxidation method for sensitive quantification of bromate in flours and bottled water using AgNPs. AB - In this paper, a simple and sensitive spectrophotometric method for the determination of nanomolar level of bromate, based on the catalytic effect of silver nanoparticles on the oxidation of acid red 14 by potassium bromate, is described. The reaction rate was monitored spectrophotometrically by measuring the decrease in absorbance of acid red 14 at 516 nm. The detection limit of the method was 8 ng/mL, and the linear range was between 15 and 130 ng/mL. The effects of acidity, concentration of reactants and reaction time, and external ions were also discussed. The optimum reaction conditions were fixed, and some kinetic parameters determined. The relative standard deviation for the determination of bromate at the concentration of 50 ng/mL was calculated to be 0.996 % (n = 10). The method has been successfully applied to the determination of bromate in flours and bottled waters. PMID- 24146070 TI - Parameters for sample size estimation from a group-randomized HIV prevention trial in HIV clinics in sub-Saharan Africa. AB - Sample size calculations for a group-randomized trial (GRT) require an estimate of the expected intraclass correlation coefficient (ICC). However, few ICC estimates from GRTs in HIV/AIDS research have been published, leaving investigators with little data on which to base expectations. We used data from a multi-country study to estimate ICCs for variables related to physical and mental health and HIV risk behaviors. ICCs for perceptions of physical and mental health tended to be higher than those for HIV risk behavior variables, which were higher than ICCs for CD4 count. Covariate adjustment for country and socio-demographic variables reduced most ICC estimates. For risk behavior variables, adjustment for country and socio-demographic variables reduced ICC estimates by as much as 84 %. Variability in ICC estimates has important implications for study design, as a larger ICC reduces power. ICC estimates presented in this analysis will allow more precise sample size estimates for future GRTs. PMID- 24146071 TI - Comparing operations for POP: the importance of standardization of surgical technique. PMID- 24146072 TI - Calculation of membrane tension in selected sections of the pelvic floor. AB - INTRODUCTION AND HYPOTHESIS: A mathematical model to estimate membrane tensions (Mt) at the urogenital hiatus and midpelvis in patients with and without prolapse is proposed. For that purpose the complex structures of the pelvic floor were simplified and, based on assumptions concerning geometry and loading conditions, Laplace's law was used to calculate Mt. The pelvic cavity is represented by an ellipsoid in which the midpelvic and hiatal sections are described by an ellipse. The downwards forces within the pelvis (F(in)) are in equilibrium with the support forces within its walls (F(w)). F(in) is the abdominal pressure (PABD) multiplied by the area A of the ellipse. The force inside the tissues (F(w)) is distributed along the circumference of the ellipse C. The Mt can be approximated as Mt = (PABD.A)/C (N/m). Mt-alpha accounts for the angle alpha which describes tissue orientation with respect to the anatomical section and is calculated as Mt alpha = Mt/sin(alpha). METHODS: We conducted a retrospective study on archived magnetic resonance imaging scans (n = 20) and ultrasound images in patients with (n = 50) or without prolapse (n = 50) and measured actual geometrical variables. PABD was measured in patients with and without prolapse (n = 20). RESULTS: Mt at the urogenital hiatus at rest is 0.35 N/cm. They significantly increase with the Valsalva manoeuvre, by a factor of 2.3 (without prolapse) to 3.6 (with prolapse). CONCLUSIONS: Calculated Mt are much lower than what is reported for the abdominal cavity. Prolapse patients have significantly larger Mt, which during the Valsalva manoeuvre increase more than in healthy subjects. PMID- 24146073 TI - Dynamic magnetic resonance imaging before and 6 months after laparoscopic sacrocolpopexy. AB - INTRODUCTION AND HYPOTHESIS: The objective of this study was to correlate dynamic magnetic resonance imaging (MRI) with Pelvic Organ Prolapse Quantification (POP Q) measurements and pelvic floor symptoms in order to determine the value of dynamic MRI for evaluating vaginal vault prolapse both before and 6 months after laparoscopic sacrocolpopexy. METHODS: This was a prospective, single-center cohort study in 43 patients who underwent a modified laparoscopic sacrocolpopexy/hysteropexy operation using bone-anchor fixation and synthetic mesh. The study included dynamic MRI, POP-Q staging, and validated questionnaires before and 6 months after laparoscopic sacrocolpopexy. To assess MRI data, the pubococcygeal reference line and specifically defined anatomical landmarks for the separate compartments were used. Differences between pre- and postoperative measurements were evaluated with the Wilcoxon signed-rank test, and correlations at the 0.05 level were considered to be significant (Pearson correlation, two tailed). RESULTS: At 6 months, a statistically significant improvement was seen in POP-Q staging for all compartments. Dynamic MRI measurements only revealed a significant improvement after surgery for the apical compartment. The correlation between (changes in) MRI measurements, POP-Q measurements, and validated questionnaires was poor. CONCLUSIONS: The value of dynamic MRI for evaluating and documenting changes in vaginal vault support and position after laparoscopic sacrocolpopexy is limited due to the poor correlation with both POP-Q staging and pelvic floor symptoms. PMID- 24146074 TI - Synthesis of 6a,6b,13,13a-tetrahydro-6H-5-oxa-12a-azadibenzo[a,g]fluorene derivatives via cycloaddition reactions of isoquinolinium salts with 3 nitrochromenes. AB - An efficient and diastereoselective synthetic procedure for functionalized 6a,6b,13,13a-tetrahydro-6H-5-oxa-12a-azadibenzo[a,g]fluorene derivatives was successfully developed by the cycloaddition reaction of isoquinolinium salts and 3-nitrochromenes with triethylamine as base in ethanol at room temperature. 1H NMR data and single crystal structures confirm the production and isolation of a single stereoisomer. PMID- 24146075 TI - Morphological and opto-electrical properties of a solution deposited platinum counter electrode for low cost dye sensitized solar cells. AB - Although platinum (Pt) is a rare and very expensive material, Pt counter electrodes are still very commonly used for reaching high efficiencies in dye sensitized solar cells (DSCs). The use of alternative cheaper catalyst materials did not yet yield equivalent efficiencies. In this work, we tried to understand how to reduce the amount of deposited Pt-material and simultaneously deliver higher DSC performances. We systematically compared the properties of Pt-counter electrodes prepared by simple solution deposition methods such as spray-coating, dip-coating, brushing with reference to the Pt-electrodes prepared by sputtering onto fluorine doped-tin oxides (FTOs). The morphological and structural characterizations of the deposited Pt-layers were performed by atomic force microscopy (AFM) and scanning electron microscopy (SEM). The composition of Pt material was quantified using SEM electron dispersive X-ray (EDX) mapping measurements which were further compared with optical transmission measurements. Also contact angle and sheet resistance measurements were performed. By taking Pt layers composition, morphology and structural factors into account, 9.16% efficient N3 dye based DSCs were assembled. The DSCs were subjected to various opto-electrical characterization techniques like current-voltage (I-V), external quantum efficiency (EQE), cyclic voltammetry (CV), electrochemical impedance spectroscopy (EIS) and transient photo voltage (TPV) measurements. The obtained experimental data suggest that the Pt counter electrodes prepared by solution deposition methods can also reach high DSC device performances with a consumption of very little amount of Pt material as compared with sputtered Pt-layers. This process also proves that higher DSC performances are not limited to the usage of sputtered Pt-layer as counter electrode. PMID- 24146076 TI - Ligand spheres in asymmetric hetero Diels-Alder reactions catalyzed by Cu(II) box complexes: experiment and modeling. AB - The stereoselective hetero Diels-Alder reaction between ethyl glyoxylate and cyclohexadiene catalyzed by [Cu(ii)t-Bu-(box)](OTf)2 was investigated. The reaction was performed step-by-step and the geometry of the Cu(ii) complexes formed in the course of the catalysis was analysed by EPR spectroscopy, advanced pulsed EPR methods (ENDOR, and HYSCORE) and DFT calculations. Our results show that one triflate counterion is directly coordinated to Cu(ii) during the catalytic process (axial position). This leads to penta-coordinated Cu(ii) complexes. Solvent molecules are able to alter the geometry of the Cu(ii) complexes although their coordination is weak. These findings provide an explanation for the solvent and counterion effects observed in many catalytic reactions. PMID- 24146077 TI - Production, characterization, and immunogenicity of a secreted form of Plasmodium falciparum merozoite surface protein 4 produced in Bacillus subtilis. AB - Plasmodium falciparum is the causative agent of the most serious form of malaria. Although a combination of control measures has significantly limited malaria morbidity and mortality in the last few years, it is generally agreed that sustained control or even eradication will require additional tools including an effective malaria vaccine. Merozoite surface protein 4, MSP4, which is present during the asexual stage of P. falciparum, is a recognized target that would be useful in a subunit vaccine against blood stages of malaria. Falciparum malaria is most prevalent in developing countries, and this in turn leads to a requirement for safe, low-cost vaccines. We have attempted to utilize the nonpathogenic, gram-positive organism Bacillus subtilis to produce PfMSP4. PfMSP4 was secreted into the culture medium at a yield of 4.5 mg/L. Characterization studies including SDS-PAGE, mass spectrometry, and N-terminal sequencing indicated that the B. subtilis expression system secreted a full length PfMSP4 protein compared to a truncated version in Escherichia coli. Equivalent amounts of purified B. subtilis and E. coli-derived PfMSP4 were used for immunization studies, resulting in statistically significant higher mean titer values for the B. subtilis-derived immunogen. The mouse antibodies raised against B. subtilis produced PfMSP4 that were reactive to parasite proteins as evidenced by immunoblotting on parasite lysate and indirect immunofluorescence assays of fixed parasites. The B. subtilis expression system, in contrast to E. coli, expresses higher amounts of full length PfMSP4 products, decreased levels of aggregates, and allows the development of simplified downstream processing procedures. PMID- 24146078 TI - Establishment of a CpG island microarray for analyses of genome-wide DNA methylation in Chinese hamster ovary cells. AB - Optimizing productivity and growth rates of recombinant Chinese hamster ovary (CHO) cells requires insight into the regulation of cellular processes. In this regard, the elucidation of the epigenetic process of DNA methylation, known to influence transcription by a differential occurrence in CpG islands in promoter regions, is increasingly gaining importance. However, DNA methylation has not yet been investigated on a genomic scale in CHO cells and suitable tools have not existed until now. Based on the genomic and transcriptomic CHO data currently available, we developed a customized oligonucleotide microarray covering 19598 CpG islands (89 % of total bioinformatically identified CpG islands) in the CHO genome. We applied our CHO-specific CpG island microarray to investigate the effect of butyrate treatment on differential DNA methylation in CHO cultures in a time-dependent approach. Supplementation of butyrate is known to enhance cell specific productivities in CHO cells and leads to alterations of epigenetic silencing events. Gene ontology clusters regarding, e.g., chromatin modification or DNA repair, were significantly overrepresented 24 h after butyrate addition. Functional classifications furthermore indicated that several major signaling systems such as the Wnt/beta-catenin pathway were affected by butyrate treatment. Our novel CHO-specific CpG island microarray will provide valuable information in future studies of cellular processes associated with productivity and product characteristics. PMID- 24146079 TI - Characteristics of foliar fungal endophyte assemblages and host effective components in Salvia miltiorrhiza Bunge. AB - Salvia miltiorrhiza Bunge, a well-known medicinal plant, has more than 20 effective components. The aim of this study was to comprehensively investigate foliar fungal endophyte communities of S. miltiorrhiza and explore the inside relationship between host-specific fungal endophytes and effective components accumulation. Five plant samples were collected from four geological different provinces in China. Foliar fungal endophyte communities were determined by terminal restriction fragment length polymorphism (T-RFLP) of the ITS region. Effective components were analyzed with high-performance liquid chromatography. The results showed that S. miltiorrhiza foliage harbored a large diversity of fungal endophytes. Principal component analysis revealed similar T-RFLP profiles and the characteristics of the 24 effective components among the five samples, which could be clustered into three groups. In foliar T-RFLP profiles derived from the restriction digestion by CfoI, HaeIII, MspI, or TaqI, there were identical 45, 42, 38, and 34 terminal restriction fragments (T-RFs) from the five samples. We consider these T-RFs as host-specific fungal endophytes. Correlation analysis of these T-RFs' area and 24 effective components contents revealed a significant correlationship between some host-specific fungal endophytes and foliage or root effective components accumulation. PMID- 24146080 TI - The synthesis of elemental selenium particles by Synechococcus leopoliensis. AB - Exposure of Synechococcus leopoliensis to selenite in the light resulted in orange-colored granules associated with the cells. No such particles were made in dark grown cells or when selenite was replaced by selenate. Light and scanning electron microscopy revealed that the particles formed inside the cells. Furthermore, these were easily extracted and shown to be composed of selenium as determined by energy-dispersive X-ray spectroscopy. During selenium particle synthesis there was a concurrent loss of organic pigments in the cyanobacteria. Cells also become heavier as they produced and accumulated particles which were on average 220 nm in diameter and generally spherical in shape. The decline in selenite concentration in the culture media can be accounted for by the formation of cellular elemental selenium (Se(0)) during particle formation, although synthesis of small amounts of other Se compounds cannot be entirely discounted. Photosynthetic activity is required for the formation of Se(0), implicating the involvement of thylakoids. It is possible that an intimate association between the nascent particles and the thylakoids occurred. However, Se(0) granule formation did not occur peripherally between the thylakoid and the cytoplasmic membranes, but inside the thylakoid bands towards the center of the cells. It then appears that the particles are mobilized to the periphery and expelled from the cells, causing irreparable damage to the cell walls. PMID- 24146081 TI - A role for recency of response conflict in producing the bivalency effect. AB - The bivalency effect is a block-wise response slowing that is observed during task-switching when rare stimuli that cue two tasks (bivalent stimuli) are encountered. This adjustment in response style affects all trials that follow bivalent stimuli, including those trials that do not share any features with bivalent stimuli. However, the specific stimulus and response properties that trigger the bivalency effect are not well understood. In typical bivalency effect experiments, bivalent stimuli can be congruent or incongruent with respect to the response afforded by the irrelevant stimulus feature, and this distinction has never been examined. In the present study, we show that cognitive load defined by the response incongruence on bivalent trials plays a critical role in producing the subsequent response slowing observed in the bivalency effect, as well as maintaining the magnitude of the bivalency effect across practice. We propose that the bivalency effect reflects a process involved in predicting future cognitive load based on recent cognitive load experience. This is in line with a recent proposal for a role of the ACC in monitoring ongoing changes in the environment to optimize future performance (Sheth et al., in Nature 488:218-221, 2012). PMID- 24146082 TI - Warmer outdoor temperature is associated with task-related increased BOLD activation in patients with multiple sclerosis. AB - Patients with multiple sclerosis (MS) demonstrate worse cognition on warmer days. Here, we examine the neurophysiology underlying this temperature-cognition relationship. The association between task-related BOLD fMRI activation and outdoor temperature was investigated in 28 MS patients who demonstrated worse cognitive function on warmer days. In MS patients, warmer outdoor temperature was associated with greater BOLD activation during performance of a simple sustained attention task. The brain areas that showed greater activation on warmer days (p = .01) were regions that have been shown to be more activated by MS patients during task performance: frontal, dorsolateral prefrontal, and parietal cortex. The relationship between outdoor temperature and cerebral activation was absent in healthy controls. The purpose of this study was to identify the neurophysiological basis for worse cognition among MS patients on warmer days. We show here that MS patients activate task-related brain regions more on warmer days. Increased brain activation required by MS patients on warmer days to perform a simple task may signify neural inefficiency. PMID- 24146084 TI - Role of bottle feeding in the etiology of hypertrophic pyloric stenosis. AB - IMPORTANCE Bottle feeding has been implicated in the etiology of hypertrophic pyloric stenosis (HPS). Further data are needed to define the nature of this relationship and the clinical variables that influence it. OBJECTIVE To determine if bottle feeding after birth is associated with the development of HPS in infants. We hypothesized that bottle feeding is associated with an increased risk of HPS and that this risk is modified by other risk factors. DESIGN, SETTING, AND PARTICIPANTS Population-based case-control study of births from January 1, 2003, to December 31, 2009, using Washington State birth certificates linked to hospital discharge data. Cases included all singleton infants born within the study period and subsequently admitted with both a diagnostic code for HPS and a procedure code for pyloromyotomy (n = 714). Controls were randomly chosen among singleton infants who did not develop HPS and were frequency matched to cases by birth year. EXPOSURE Feeding status (breast vs bottle) was coded on the birth certificate as the type of feeding the infant was receiving at birth discharge. MAIN OUTCOME AND MEASURE Diagnosis of HPS. RESULTS Hypertrophic pyloric stenosis incidence decreased over time, from 14 per 10,000 births in 2003 to 9 per 10,000 in 2009. Simultaneously, breastfeeding prevalence increased from 80% in 2003 to 94% in 2009. Compared with controls, cases were more likely to be bottle feeding after birth (19.5% vs 9.1%). After adjustment, bottle feeding was associated with an increased risk of HPS (odds ratio [OR], 2.31; 95% CI, 1.81-2.95). This association did not differ according to sex or maternal smoking status but was significantly modified by maternal age (<20 years OR, 0.98; 95% CI, 0.51-1.88; >=35 years OR, 6.07; 95% CI, 2.81-13.10) and parity (nulliparous OR, 1.60; 95% CI, 1.07-2.38; multiparous OR, 3.42; 95% CI, 2.23-5.24). CONCLUSIONS AND RELEVANCE Bottle feeding is associated with an increased risk of HPS, and this effect seems to be most important in older and multiparous women. These data suggest that bottle feeding may play a role in HPS etiology, and further investigations may help to elucidate the mechanisms underlying the observed effect modification by age and parity. PMID- 24146083 TI - Treatment of high-grade spondylolisthesis with Schanz recoil screws: our experience. AB - PURPOSE: Spondylolisthesis surgical treatment is often difficult with higher degree of slip and related techniques still debated. We have taken into consideration double thread recoil Schanz screws. This system should allow the best reduction of the slip, treating only the affected vertebrae. METHODS: We retrospectively analyzed 46 patients affected by grade II or higher spondylolisthesis, treated with circumferential arthrodesis using Schanz screws. Duration of surgery, complications, reduction, and rate of fusion have been recorded. RESULTS: We found that duration of surgery and complications were similar or slightly lower if compared to our standard Posterior Lumbar Interbody Fusion procedures. However, radiological results and clinical outcome appear better in cases treated with Schanz screws. CONCLUSIONS: Fixation system with Schanz screws seems to be effective in reducing the slip, treating only the affected level, in high grade of spondylolisthesis. PMID- 24146085 TI - An in vitro biomechanical investigation of an interlocking nail system developed for buffalo tibia. AB - OBJECTIVE: The objectives of the study were to determine the mechanical properties of a customized buffalo interlocking nail (BIN), intact buffalo tibia, and ostectomized tibia stabilized with BIN in different configurations, as well as to assess the convenience of interlocking nailing in buffalo tibia. MATERIALS AND METHODS: The BIN (316L stainless steel, 12 mm diameter, 250 mm long, nine hole solid nails with 10 degrees proximal bend) alone was loaded in compression and three-point bending (n=4 each); intact tibiae and ostectomized tibiae (of buffaloes aged 5-8 years, weighing 300-350 kg) stabilized with BIN using 4.9 mm standard or modified locking bolts (4 or 8) in different configurations were subjected to axial compression, cranio-caudal three-point bending and torsion (n=4 each) using a universal testing machine. Mechanical parameters were determined from load-displacement curves and compared using Kruskal-Wallis test (p<0.05). RESULTS: Intact tibiae were significantly stronger than BIN and bone BIN constructs in all testing modes. The strength of fixation constructs with eight locking bolts was significantly more than with four bolts. Overall strength of fixation with modified locking bolts was better than standard bolts. Based on technical ease and biomechanical properties, cranio-caudal insertion of bolts into the bone was found better than medio-lateral insertion. CLINICAL SIGNIFICANCE: The eight bolt BIN-bone constructs could be useful to treat tibial fractures in large ruminants, especially buffaloes. PMID- 24146086 TI - Computer-delivered social norm message increases pain tolerance. AB - BACKGROUND: Few experimental studies have been conducted on social determinants of pain tolerance. PURPOSE: This study tests a brief, computer-delivered social norm message for increasing pain tolerance. METHODS: Healthy young adults (N = 260; 44 % Caucasian; 27 % Hispanic) were randomly assigned into a 2 (social norm) * 2 (challenge) cold pressor study, stratified by gender. They received standard instructions or standard instructions plus a message that contained artificially elevated information about typical performance of others. RESULTS: Those receiving a social norm message displayed significantly higher pain tolerance, F(1, 255) = 26.95, p < .001, eta p (2) = .10 and pain threshold F(1, 244) = 9.81, p = .002, eta p (2) = .04, but comparable pain intensity, p > .05. There were no interactions between condition and gender on any outcome variables, p > .05. CONCLUSIONS: Social norms can significantly increase pain tolerance, even with a brief verbal message delivered by a video. PMID- 24146087 TI - [Medical rehabilitation preventing long-term care for the elderly: analysis based on routine data]. AB - BACKGROUND: Medical rehabilitation of statutory health insurance (SHI) in Germany aims at prevention of (increasing) disability and thus the need for long-term care. The paper examines the inpatient rehabilitation care utilization in the elderly based on claims data, taking into account the need of pre-existing long term care (LTC) in according to the German Long-Term Care Insurance and further changes (survival, LTC level). METHODS: Anonymous data from inpatient medical rehabilitation of AOK-insured patients >= 65 years (2008/2009) following different treatment pathways were evaluated: early rehabilitation while hospital treatment (FR), combined treatment with early and subsequent rehabilitation (F /AR), subsequent rehabilitation after hospital treatment (AR); rehabilitation without previous hospital treatment (SR). Survival and LTC-Level (higher level=higher care demands) were tracked for 12 months after utilization of rehabilitation. RESULTS: The extent of pre-existing levels of LTC >= 1 was in FR 44.1%, in F-/AR 19.1%, in AR 10.1% and in SR 15.9%. Above-average shares of geriatric indications and below-average shares of orthopaedic indications were observed for all 4 groups. LTC levels remained unchanged for varying percentages of patients in the treatment groups (FR 57%, F-/AR 46%, AR 85%, SR 92%). Higher LTC-Levels were observed for 42% of cases in the FR group, 54% in the F-/AR group, and only 14% and 7% in the AR and the SR group respectively. Lower LTC Levels could be found in less than 1% of the cases in all groups. Survival rates varied significantly (72% FR, F-/AR 84%, AR 92% and 96% SR). Cases with a pre existing care level had significantly reduced survival rates. The results could be confirmed after standardization for age and gender. CONCLUSION: The current application of the legal principle "rehabilitation before LTC" for older insurants is in SHI mainly segmented afterwards or integrated into hospital treatment but rarely combined intersectoral or conducted without immediately preceding hospital-treatment. PMID- 24146088 TI - Graphene-platinum nanohybrid as a robust and low-cost counter electrode for dye sensitized solar cells. AB - Dry plasma reduction (DPR) is an excellent approach for easily, continuously, uniformly and stably hybridizing platinum nanoparticles (Pt-NPs) on a graphene coated layer under atmospheric pressure without any toxic chemicals and at a low temperature. The Pt-NPs with a size of 0.5-4 nm and mostly 2 nm were stably and uniformly hybridized on the surface of reduced graphene oxide (RGO) after co reduction of Pt precursor ions and GO to Pt atoms and RGO, respectively. XPS analysis also revealed a repair of structural damage on the basal plane of the graphene as well as chemical bonding between Pt-NPs and RGO after DPR. Thus, the Pt-NPs/RGO nanohybrids applied to the counter electrode of dye-sensitized solar cells (DSCs) exhibited robust stability as well as ultrahigh electrochemical catalytic activity and conductivity using less than 1% of the Pt exploited for the Pt-sputtered counter electrodes. Thus, the Pt-NPs/RGO nanohybrid fabricated by DPR could be an excellent material for a robust and low-cost counter electrode for DSCs. PMID- 24146089 TI - Connective tissue growth factor (CTGF/CCN2): diagnostic and prognostic value in acute heart failure. AB - BACKGROUND: As a mediator of ECM homeostasis, connective tissue growth factor (CTGF) appears to be involved in adverse structural remodeling processes in the heart. However, the diagnostic and prognostic value of CTGF levels in acute heart failure (AHF) in addition to natriuretic peptide testing has not yet been evaluated. METHODS AND RESULTS: A total of 212 patients presenting with acute dyspnea and/or peripheral edema to the Emergency Department were evaluated. CTGF and NT-proBNP plasma levels were measured at the initial presentation. All patients were followed up to 1 and 5 years. The first endpoint tested was the diagnostic non-inferiority of combined CTGF plus NT-proBNP compared to NT-proBNP alone for AHF diagnosis. Afterwards, the additional diagnostic value of CTGF plus NT-proBNP was tested. CTGF levels were higher in NYHA class III/IV and AHA/ACC class C/D patients compared to lower class patients (p = 0.04). Patients with HFREF revealed highest CTGF levels (median 93.3 pg/ml, IQR 18.2-972 pg/ml, n = 48) compared to patients with a normal heart function (i.e., without HFREF and HFPEF) (median 25.9, IQR <1-82.2 pg/ml, n = 37) (p < 0.05), followed by patients with HFPEF (median 82.2 pg/ml, IQR 11.5-447 pg/ml, n = 32) as assessed by echocardiography. Finally, CTGF levels were higher in patients with AHF (median 77.3 pg/ml, IQR 22.5-1012 pg/ml, n = 66) compared to those without (p = 0.002). CTGF plus NT-proBNP was non-inferior to NT-proBNP testing alone for AHF diagnosis (AUC difference 0.01, p > 0.05). CTGF plus NT-proBNP improved the diagnostic capacity for AHF (accuracy 82 %, specificity 83 %, positive predictive value 66 %, net reclassification improvement +0.11) compared to NT-proBNP alone (p = 0.0001). CTGF levels were not able to differentiate prognostic outcomes after 1 and 5 years. CONCLUSIONS: Additional CTGF measurements might lead to a better discrimination of higher functional and structural heart failure stages and might identify patients of an increased risk for an acute cardiac decompensation. PMID- 24146090 TI - Segregation distortion caused by weak hybrid necrosis in recombinant inbred lines of common wheat. AB - Segregation distortion of molecular markers is closely related to hybrid incompatibility in progeny from intraspecific crosses. Recent reports in higher plants have demonstrated that hybrid sterility results in segregation distortion at the causal gene regions in progeny of intraspecific crosses. Ne1 and Ne2 complementary loci are known to control hybrid necrosis in intraspecific crosses of common wheat cultivars. Here, we examine the effect of a weak necrosis allele Ne1(w) on the segregation ratio of molecular markers in recombinant inbred lines (RILs) of common wheat. Some RILs showed accelerated cell death in the leaves at the heading stage due to the epistatic interaction between two quantitative trait loci (QTL) on chromosomes 5B and 2B. Chromosomal localization of these QTL corresponding to Ne1(w) and Ne2 showed distorted segregation ratios of assigned markers having oppositely biased direction. Although the Ne1(w) and Ne2 interaction had no obvious effect on seed fertility, Ne1(w) reduced completion of grain development under the Ne2-homozygous background. This reduction might be one of causes that induces segregation distortion in the 5B and 2B chromosomal regions of RILs. The present study demonstrated that weak hybrid necrosis has limited phenotypic effects; it causes segregation distortion in progeny from intraspecific crosses. PMID- 24146091 TI - Altered expression of pannexin proteins in patients with temporal lobe epilepsy. AB - The aim of the present study was to investigate the expression of the pannexin (Panx) proteins, Panx1 and Panx2, in the temporal lobe tissue of patients with temporal lobe epilepsy (TLE). Immunohistochemistry and western blotting methods were used to localize and quantify Panx1 and Panx2 in the surgically removed brain tissue of patients with TLE (n=37). The results were then compared with non epileptogenic controls (n=9). Panx1 and Panx2 expression was detected in the temporal lobe cortex of patients with TLE and in the control tissues. Panx1 and Panx2 proteins were expressed in all layers of the epileptic cortex, but predominantly in layers II and III of the cortex in the control group. Panx1 protein expression was significantly higher in the temporal lobe cortex of the patients with TLE than in the controls (P<0.05; t-test); however, no significant differences were identified in the Panx2 expression levels between the patients and the controls (P>0.05; t-test). The expression of the two Panx proteins in the tissue layers of the epileptic cortex varied in the patients and controls. The results indicate that Panx channels may be involved in the pathogenesis of TLE. PMID- 24146093 TI - Family contexts: parental experiences of discrimination and child mental health. AB - Research on the mental health correlates of discrimination traditionally has been intra-individual, focusing exclusively on the individual directly experiencing discrimination. A small number of studies have begun to consider the links between parental experiences of discrimination and child mental health, but little is known about potential underlying mechanisms. The present study tested the independent mediating effects of parent mental health and household socioeconomic status on the associations between parental experiences of discrimination (past-year perceived discrimination and perceptions of being unaccepted culturally) and child mental health (internalizing and externalizing symptoms) using a bootstrapping analytic approach. Data were drawn from racial/ethnic minority (n = 383) and White (n = 574) samples surveyed in an urban Midwestern county. For all measures of discrimination and child mental health, findings supported an association between parental experiences of discrimination and child mental health. Whereas parent mental health served as a significant mediator in all analyses, socioeconomic status did not. Mediation findings held for both the White and racial/ethnic minority samples. Results suggest that parental experiences of discrimination and mental health may contribute to child mental health concerns, thus highlighting the role of family contexts in shaping child development. PMID- 24146092 TI - The role of periostin in tissue remodeling across health and disease. AB - Periostin, also termed osteoblast-specific factor 2, is a matricellular protein with known functions in osteology, tissue repair, oncology, cardiovascular and respiratory systems, and in various inflammatory settings. However, most of the research to date has been conducted in divergent and circumscribed areas meaning that the overall understanding of this intriguing molecule remains fragmented. Here, we integrate the available evidence on periostin expression, its normal role in development, and whether it plays a similar function during pathologic repair, regeneration, and disease in order to bring together the different research fields in which periostin investigations are ongoing. In spite of the seemingly disparate roles of periostin in health and disease, tissue remodeling as a response to insult/injury is emerging as a common functional denominator of this matricellular molecule. Periostin is transiently upregulated during cell fate changes, either physiologic or pathologic. Combining observations from various conditions, a common pattern of events can be suggested, including periostin localization during development, insult and injury, epithelial mesenchymal transition, extracellular matrix restructuring, and remodeling. We propose mesenchymal remodeling as an overarching role for the matricellular protein periostin, across physiology and disease. Periostin may be seen as an important structural mediator, balancing appropriate versus inappropriate tissue adaption in response to insult/injury. PMID- 24146094 TI - Race/ethnic differences in associations between bone mineral density and fracture history in older men. AB - SUMMARY: To determine whether there are race/ethnic differences in bone mineral density (BMD) by fracture history in men aged 65 years and older, we performed cross-sectional analysis in five large independent cohorts. Low BMD was associated with a higher prevalence of fracture in all cohorts, and the magnitude of the BMD differences by fracture status was similar across groups. INTRODUCTION: We aimed to determine whether there are race/ethnic and geographic differences in bone mineral density by fracture history in men aged 65 years and older. METHOD: The datasets included the Osteoporotic Fractures in Men (MrOS) Study (5,342 White, 243 African-American, 190 Asian, and 126 Hispanic), MrOS Hong Kong (1,968 Hong Kong Chinese), Tobago Bone Health Study (641 Afro-Caribbean), Namwon Study (1,834 Korean), and Dong-gu Study (2,057 Korean). The two Korean cohorts were combined. RESULTS: The prevalence of self-reported non-traumatic fracture was US white, 17.1 %; Afro-Caribbean, 5.5 %; US African-American, 15.1 %; US Hispanic, 13.7 %; US Asian, 10.5 %; Hong Kong Chinese, 5.6 %, and Korean, 5.1 %. The mean differences in hip and lumbar spine BMD between subjects with fracture and without fracture were statistically significant in all cohorts except US African American and US Asian men. There was a significant race/ethnic interaction for lumbar spine BMD by fracture status (p for interaction = 0.02), which was driven by the small number of Hispanic men. There was no interaction for femoral neck or total hip BMD. There were no significant race/ethnic differences in the odds ratio of fracture by BMD. CONCLUSIONS: Low BMD was associated with a higher prevalence of fracture in all cohorts and the magnitude of the BMD differences by fracture status was similar across groups suggesting homogeneity in the BMD-fracture relationship among older men. PMID- 24146096 TI - Relations of osteoporosis and follow-up duration to recurrent falls in older men and women. AB - SUMMARY: There were differences in risk factors between men and women and between two follow-up time lengths. Osteoporosis was significantly associated with recurrent falls for women but not for men. The relationship of osteoporosis with falls in the past year decreased during follow-up, while those of sedatives and hypnotics remained. INTRODUCTION: A prospective study to investigate relationships between osteoporosis and recurrent falls at two follow-up lengths of 6 and 12 months in older men and women. METHODS: In total, 204 men and 447 women who visited an emergency department due to a fall were recruited. RESULTS: For men, the risk of falling was not significantly associated with osteoporosis at 6 or 12 months. Men with a fall history were 127 and 100 %, respectively, more likely to have a fall at 6 and 12 months than those without. Men who did not use walking aids were 97 % more likely to have a fall at 12 months than those who did. Women with osteoporosis were 246 and 104 %, respectively, more likely to have a fall at 6 and 12 months than those without. Women with a fall history were 129 and 66 %, respectively, more likely to have a fall at 6 and 12 months than those without. Women taking sedatives and hypnotics were 75 and 102 %, respectively, more likely to have a fall at 6 and 12 months than their counterparts. Women with depression were 138 % more likely to have a fall at 6 months and those using walking aids were 59 % more likely to have a fall at 12 months, compared to their counterparts. CONCLUSIONS: Osteoporosis is association with falls for older women but not for older men. Identifying risk factors for recurrent falls in older people may be affected by the follow-up length, as their associations are reduced over time. PMID- 24146097 TI - Exercise habits during middle age are associated with lower prevalence of sarcopenia: the ROAD study. AB - SUMMARY: The present cross-sectional study investigated the prevalence of sarcopenia and clarified its associated factors in 1,000 elderly participants of Japanese population-based cohorts. Exercise habit in middle age was associated with low prevalence of sarcopenia in older age, suggesting that it is a protective factor against sarcopenia in older age. INTRODUCTION: The present study investigated the prevalence of sarcopenia using the European Working Group on Sarcopenia in Older People (EWGSOP) definition, and clarified the association of sarcopenia with physical performance in the elderly participants of Japanese population-based cohorts of the Research on Osteoarthritis/osteoporosis Against Disability (ROAD) study. METHODS: We enrolled 1,000 participants (aged >=65 years) from the second visit of the ROAD study who had completed assessment of handgrip strength, gait speed, and skeletal muscle mass measured by bioimpedance analysis. Presence of sarcopenia was determined according to the EWGSOP algorithm. Information collected included exercise habits in middle age. RESULTS: Prevalence of sarcopenia was 13.8 % in men and 12.4 % in women, and tended to be significantly higher according to increasing age in both sexes. Factors associated with sarcopenia, as determined by logistic regression analysis, were chair stand time (odds ratio [OR], 1.09; 95 % confidence interval [CI], 1.04 1.14), one-leg standing time (OR, 0.97; 95 % CI, 0.96-0.99), and exercise habit in middle age (OR, 0.53; 95 % CI, 0.31-0.90). Exercise habit in middle age was associated with low prevalence of sarcopenia in older age. Furthermore, linear regression analysis revealed that exercise habits in middle age were significantly associated with grip strength (P < .001), gait speed (P < .001), and one-leg standing time (P = .005) in older age. CONCLUSIONS: This cross sectional study suggests that exercise habit in middle age is a protective factor against sarcopenia in older age and effective in maintaining muscle strength and physical performance in older age. PMID- 24146095 TI - Cancer-associated bone disease. AB - Bone is commonly affected in cancer. Cancer-induced bone disease results from the primary disease, or from therapies against the primary condition, causing bone fragility. Bone-modifying agents, such as bisphosphonates and denosumab, are efficacious in preventing and delaying cancer-related bone disease. With evidence based care pathways, guidelines assist physicians in clinical decision-making. Of the 57 million deaths in 2008 worldwide, almost two thirds were due to non communicable diseases, led by cardiovascular diseases and cancers. Bone is a commonly affected organ in cancer, and although the incidence of metastatic bone disease is not well defined, it is estimated that around half of patients who die from cancer in the USA each year have bone involvement. Furthermore, cancer induced bone disease can result from the primary disease itself, either due to circulating bone resorbing substances or metastatic bone disease, such as commonly occurs with breast, lung and prostate cancer, or from therapies administered to treat the primary condition thus causing bone loss and fractures. Treatment-induced osteoporosis may occur in the setting of glucocorticoid therapy or oestrogen deprivation therapy, chemotherapy-induced ovarian failure and androgen deprivation therapy. Tumour skeletal-related events include pathologic fractures, spinal cord compression, surgery and radiotherapy to bone and may or may not include hypercalcaemia of malignancy while skeletal complication refers to pain and other symptoms. Some evidence demonstrates the efficacy of various interventions including bone-modifying agents, such as bisphosphonates and denosumab, in preventing or delaying cancer-related bone disease. The latter includes treatment of patients with metastatic skeletal lesions in general, adjuvant treatment of breast and prostate cancer in particular, and the prevention of cancer-associated bone disease. This has led to the development of guidelines by several societies and working groups to assist physicians in clinical decision making, providing them with evidence-based care pathways to prevent skeletal-related events and bone loss. The goal of this paper is to put forth an IOF position paper addressing bone diseases and cancer and summarizing the position papers of other organizations. PMID- 24146099 TI - High dietary taurine inhibits myocardial apoptosis during an atherogenic diet: association with increased myocardial HSP70 and HSF-1 but not caspase 3. AB - BACKGROUND AND AIM: Apoptosis is a major cause of myocyte death, and taurine is anti-apoptotic. Heat shock protein 70 (HSP70) (which is regulated by heat shock factor-HSF-1) is also anti-apoptotic, and caspase 3 stimulates the apoptotic pathway. This study investigated whether taurine affects atherogenic diet-induced myocardial apoptosis, and whether HSP70, HSF-1 and caspase 3 are involved. METHODS: New Zealand white rabbits were divided into 3 groups for 4 weeks according to their diet. Group 1 (control) was fed a normal rabbit diet; Group 2 (MC) received a normal rabbit diet with 1% methionine plus 0.5% cholesterol. Group 3 received MC diet + 2.5% taurine (MCT). RESULTS: The atherogenic diet did not affect myocardial HSP70 or HSF-1 protein, but increased myocardial apoptotic nuclei to 40% (p < 0.01) versus 7% in con and 12% in MCT (p < 0.01). However, in MCT, myocardial HSP70 expression increased by 42.7% versus con and MC (p = 0.016), HSF-1 by 12% versus con and MC (p < 0.05), and total nuclei count increased by 37% versus MC (p < 0.05). Caspase 3 subunits remained unchanged in all groups, and HSP70 was increased approximately twofold in endothelial layer of arterioles (p = 0.01). CONCLUSION: This study shows that taurine could reduce myocardial apoptotic nuclei and thus confer myocardial cytoprotection via stimulating myocardial HSP70 via HSF-1 and caspase 3-independent mechanisms. PMID- 24146101 TI - Is the transnasal access for esophagogastroduodenoscopy in routine use equal to the transoral route? A prospective, randomized trial. AB - BACKGROUND AND STUDY AIMS: Routine esophagogastroduodenoscopy (EGD) is increasingly performed without sedation. Transoral (TO) and transnasal (TN) EGD offer different patient comfort and complications. PATIENTS AND METHODS: For a controlled, randomized, clinical trial comparing TN-EGD with TO-EGD without sedation, patients were assigned to TN-EGD using a thin endoscope (group 1, 93 patients), or TO-EGD using a standard endoscope (group 2, 90 patients). Physician rated procedural time and complications as well as patient-rated side effects and preferences were compared. In group 3, patients (118) who had previously undergone TO-EGD, now underwent TN-EGD. RESULTS: Between group 1 and 2 there was no significant difference for procedural time. Nausea (p = 0.047) and epistaxis (p < 0.001) were significantly more frequent for TN-EGD. Conversion rate from TN- to TO-EGD was low with 4.3 %. For TN-EGD, patients' tolerance was better (p < 0.001), gagging was less (p < 0.001). In case of a future EGD, patients who know both procedures (group 3), strongly vote for TN-EGD (80 %). All groups vote against sedation for future procedures (90 %/90 %/89 %). CONCLUSIONS: Epistaxis can be relevant after TN-EGD, but can mostly be managed conservatively. TN-EGD is superior to TO-EGD regarding subjective and objective gagging as well as procedural tolerance. Patients who experienced both access routes, prefer TN-EGD. TN-EGD without sedation should be aspired for patient comfort and is recommended for routine use. PMID- 24146100 TI - Study of molecular mechanism of Prostaglandin E1 in inhibiting coronary heart disease. AB - Prostaglandin E1 has been used clinically for improving heart diseases. In this study, we examined the effect of Prostaglandin E1 on blood lipid levels, heart protein and genes expression in coronary heart disease (CHD) rats. Female rats were fed either a control diet or hypercholesterolemic diet for 14 weeks. The feeding of a hypercholesterolemic diet (HCD) increased the serum TC, TG, and LDL c levels, decreased the serum HDL-c, E2, P, FSH, LH and PRL levels in CHD rats. In addition, The feeding of a HCD diet markedly increased the content of serum TXA2, TXB2, and decreased the content of serum PGI2, and PGI2/TXA2, 6-Keto PGF1a. Furthermore, the feeding of a hypercholesterolemic diet markedly increased expression levels of myocardium Fas and Caspase-3 protein and mRNA levels, vascular endothelial growth factor and basic fibroblast growth factor mRNA, and decreased RyR2 mRNA in CHD rats. The feeding of Prostaglandin E1 for 14 weeks significantly reversed these abnormal biochemical indexes in rats. These findings suggest that Prostaglandin E1 play a obvious heart protective effect. The mechanisms may be related to restraining the excessive activation of Fas and Caspase-3 protein and modulating some gene expressions associated with CHD. PMID- 24146102 TI - [Microscopic colitis--new insights relevant to clinical practice]. AB - Microscopic colitis is an increasingly recognised chronic inflammatory bowel disease associated with watery, non-bloody diarrhoea. In addition, many patients suffer from abdominal pain, nocturnal diarrhoea, urgency and incontinence. The two traditional histological subtypes are collagenous colitis and lymphocytic colitis. A novel third subgroup is the so-called incomplete microscopic colitis which is clinically indistinguishable. At present, budesonide is the only evidenced-based effective therapy, however many problems in the long-term treatment strategy are still unsolved. The present paper reviews new developments in microscopic colitis which are relevant for clinical practice. PMID- 24146103 TI - Glucose transporter-1 expression in CD133+ laryngeal carcinoma Hep-2 cells. AB - CD133 is a useful putative marker of cancer stem cells (CSCs) in human laryngeal tumors. Numerous studies have demonstrated that CD133+ CSCs possess higher clonogenicity, invasiveness and tumorigenesis compared with CD133- cells. Recently, interest in the Warburg effect in the microenvironment of CSCs has escalated. The Warburg effect dictates that cancer cells rely on glycolysis rather than oxidative phosphorylation under aerobic conditions. In numerous cancer cells, glucose is used mainly for the glycolytic pathway. Stem cells express high levels of glycolytic enzymes and rely mostly on glycolysis to meet their energy demands. Glucose is transported through cell membranes by glucose transporters (Glut). Studies of Glut-1 expression in CSCs are limited. In the present study, we investigated the proliferation of CD133+ Hep-2 cells and whether Glut-1 is expressed in laryngeal carcinoma CD133+ Hep-2 cells. Real-time reverse transcription-polymerase chain reaction (RT-PCR) demonstrated that the size of the CD133 product was 213 bp. Dissociation curve analysis demonstrated only the expected peaks at 82.1C for CD133. The mean DeltaCt of CD133 expression was 10.98. Prior to isolation, the CD133+ fraction was 1.2% by fluorescence activated cell sorting (FACS) analysis. Following isolation, the CD133+ fraction was increased to 76.1%. Successive tests also demonstrated that cells grew well following isolation. The proliferation of CD133+ and CD133- cells was not different during the first 3 days (P>0.05). From day 4, the proliferation capacity of CD133+ cells in vitro was higher than that of CD133- cells (P<0.05). The mean DeltaCt of Glut-1 mRNA expression was 1.78 for CD133+ cells and 1.00 for CD133- cells (P<0.05). The mean Glut-1 protein values in CD133+ and CD133- Hep-2 cells relative to beta-tubulin were 0.48 +/- 0.02 and 0.21 +/- 0.03 (ug/ul), respectively (P<0.05). In conclusion, CD133+ cells demonstrated higher proliferation. Glut-1 mRNA and protein levels were higher in CD133+ than in CD133 cells. Our results suggest that Glut-1 is important in the energy supply of laryngeal CD133+ Hep-2 cells and Glut-1 may represent a potential therapeutic target for the inhibition of the proliferation of laryngeal CSCs. PMID- 24146104 TI - Accuracy evaluation of a two-wire technique for osteotomy positioning in the tibial plateau levelling procedure. AB - OBJECTIVE: To evaluate a tibial plateau levelling osteotomy (TPLO) saw blade positioning technique and to retrospectively evaluate the accuracy of the osteotomy position. METHOD: Preoperative and postoperative radiographs of 72 cases that had a TPLO surgery using a two-wire technique were reviewed. Three measurements (A1, B1, C1) were obtained in preoperative planning using a computer template system (Orthoview Vet) which mapped the intended osteotomy position. The postoperative radiographs were analysed to determine the variability of these three measurements (A2, B2, C2) and therefore the accuracy of the osteotomy. RESULTS: On average the least variable measurement was B2 (5%) followed by C2 (7%) and then A2 (13%). The maximum mean difference between the intended position and achieved position was 1.5 mm. CLINICAL SIGNIFICANCE: Despite there being a significant difference between the intended and the actual position of the osteotomy, the variation between the intended and actual tibial tuberosity width was small (5%). None of the cases suffered a tibial tuberosity fracture, which also supports the clinical value of this technique. Care must be taken to avoid inadvertent cutting of the Kirschner guide wires. PMID- 24146105 TI - Flexible and high-performance paper-based biofuel cells using printed porous carbon electrodes. AB - We demonstrate a flexible paper-based biofuel cell using porous carbon inks for high power output. The power density of the fabricated biofuel cell reached 0.12 mW cm(-2) (at 0.4 V), which is the highest output power reported to date, to the best of our knowledge. PMID- 24146106 TI - First evidence for the anti-inflammatory activity of fucoxanthin in high-fat-diet induced obesity in mice and the antioxidant functions in PC12 cells. AB - Obesity, characterized as a state of low-level inflammation, is a powerful determinant influencing the development of insulin resistance and progression to type 2 diabetes. The purpose of the present study was to investigate the anti inflammatory activity of fucoxanthin in experimental high-fat-diet-induced obesity in mice and antioxidant activity in PC12 cells under oxidative stress situation. The anti-inflammatory potential of fucoxanthin in the regulation of maleic dialdehyde (MDA), polymorphonuclear cells (PMNs), interleukin-1beta (IL 1beta), inducible nitric oxide synthase (iNOS), tumor necrosis factor alpha (TNF alpha), and cyclooxygenase-2 (COX-2) was determined by ELISA. Fucoxanthin significantly inhibited obesity-induced upregulation of the production of IL 1beta, TNF-alpha, iNOS, and COX-2. Moreover, fucoxanthin suppressed MDA and infiltration of PMNs. The protective effects were associated with lack of hypertrophy and crown-like structures in mammary gland. At the same time, fucoxanthin showed an advantage of antioxidant activity in PC12 cells under oxidative stress situation. These results suggest that supplementation of fucoxanthin is a promising strategy for blocking macrophage-mediated inflammation and inflammation-induced obesity and its associated complications. PMID- 24146107 TI - Transcriptional repression of the poly(3-hydroxybutyrate) depolymerase in Ralstonia pickettii T1 by a tetR-like gene. AB - Ralstonia pickettii T1 secretes a poly(3-hydroxybutyrate) (PHB) depolymerase (PhaZ) and a 3-hydroxybutyrate (3HB)-oligomer hydrolase, and extracellularly degrades PHB to produce 3HB. However, it is not clear how the expression of phaZ is regulated. In this study, the mechanism by which phaZ expression is controlled in R. pickettii T1 was examined using a mutant made by the random insertion of a transposon, Tn5. The mutant produced a larger amount of PhaZ than the wild type in nutrient broth or a minimal salt (SM) medium supplemented with succinate. However, there was essentially no difference in the activity or amount of PhaZ in the culture supernatant between the wild type and mutant when the two were grown on 3HB. The gene disrupted by the insertion of Tn5 (epdR) was cloned and its nucleotide sequence was determined. In a BLAST search, epdR showed a high degree of similarity to genes for TetR transcriptional regulators of several bacteria. The introduction of epdR into the wild type and mutant grown on the three media described above decreased the amount of PhaZ. These results indicated EpdR to be involved in the repression of phaZ in R. pickettii T1. A quantitative RT-PCR analysis indicated that mRNA levels corresponded with the activity detected and the amounts of PhaZ in the wild type and mutant. Furthermore, the amount of epdR transcript was inversely proportional to the amount of phaZ transcript. In addition, the existence of a positive element acting on phaZ expression was suggested, because in the mutant lacking EpdR, the amount of phaZ transcript varied in cells grown in SM-3HB, SM-succinate or nutrient broth. Based on the above results, a model for the regulation of PhaZ expression in R. pickettii T1 is proposed. PMID- 24146109 TI - Covalent functionalization based heteroatom doped graphene nanosheet as a metal free electrocatalyst for oxygen reduction reaction. AB - Oxygen reduction reaction (ORR) is an important reaction in energy conversion systems such as fuel cells and metal-air batteries. Carbon nanomaterials doped with heteroatoms are highly attractive materials for use as electrocatalysts by virtue of their excellent electrocatalytic activity, high conductivity, and large surface area. This study reports the synthesis of highly efficient electrocatalysts based on heteroatom-doped graphene nanosheets prepared through covalent functionalization using various small organic molecules and a subsequent thermal treatment. A series of nitrogen-doped reduced graphene oxide (NRGOn) nanosheets exhibited varying degrees and configurations of nitrogen atoms within the graphitic framework depending on the type of precursors used. On the basis of the rotating disk electrode (RDE) and rotating ring-disk electrode (RRDE) experiments, NRGO3, with a high degree of pyridinic-N content, displayed the desired one-step, quasi-four-electron transfer pathway during ORR, similar to commercial Pt/C. We also demonstrated the potential of covalent functionalization of sulfur and boron-doped graphene nanosheets. PMID- 24146108 TI - HOXB13 is a sensitive and specific marker of prostate cells, useful in distinguishing between carcinomas of prostatic and urothelial origin. AB - The origin of a primary or metastatic carcinoma in the pelvic area is sometimes difficult to establish, in particular the distinction between those originating in the bladder and the prostate. A candidate marker is the HOXB13 gene, essential for prostate development. Some studies have shown expression of HOXB13 protein by immunohistochemistry in the nuclear compartment of benign prostate luminal epithelium and prostate carcinoma. Forty-two cases of biopsies and resection specimens of the prostate and urinary bladder, metastatic lymph nodes, and pelvic masses were retrieved from our databases. In all cases, doubt persisted regarding prostatic versus urothelial origin. All cases were stained for CK7, p63, p504s, PSA, CK20, and HOXB13. Chromogranin A, CD56, and synaptophysin were used when neuroendocrine differentiation was suspected. HOXB13 staining was negative or only weakly positive in all carcinomas of urothelial origin. Three of four carcinomas with neuroendocrine differentiation did not express HOXB13. The fourth carcinoma, in a patient with a history of prostate carcinoma, was positive. In two cases with a synchronous prostatic and urothelial carcinoma, HOXB13 was exclusively expressed in the prostatic carcinoma. Our results demonstrate that HOXB13 expression identifies prostatic origin of a carcinoma with good sensitivity (89 %) and very good specificity (100 %). HOXB13 is a specific and sensitive marker for prostate cells and a valuable diagnostic tool, especially when poorly differentiated or neuroendocrine tumors are encountered. These results justify testing of HOXB13 as a prostate-specific carcinoma marker in larger cohorts for a more thorough evaluation of its sensitivity and specificity. PMID- 24146110 TI - Prevalence and 1-year prognosis of transient heart failure following coronary revascularization. AB - The occurrence of heart failure during the whole pre-discharge course of coronary revascularization, as far as its influence on subsequent prognosis, is poorly understood. The present study examined the effect of transient heart failure (THF) developing in the acute and rehabilitative phase on survival after coronary artery bypass graft surgery (CABG) and percutaneous coronary intervention (PCI). Patients in the Italian survey on cardiac rehabilitation and secondary prevention after cardiac revascularization (ICAROS) were analyzed for THF, the latter being defined either as signs and symptoms consistent with decompensation or cardiogenic shock. ICAROS was a prospective, multicenter registry of 1,262 consecutive patients discharged from 62 cardiac rehabilitation (CR) facilities, providing data on risk factors, lifestyle habits, drug treatments, and major cardiovascular events (MACE) during a 1-year follow-up. Records were linked to the official website of the Italian Association of Cardiovascular Prevention and Rehabilitation (GICR-IACPR). The overall prevalence of pre-discharge THF was 7.6%, with 69.8% of cases in acute wards, 22.9% during CR, and 7.3% in both settings. THF affected more frequently patients with chronic cardiac condition (42.7 vs. 30.6%; p < 0.05), age >=75 years (33.3 vs. 23.1%; p < 0.005), COPD (19.8 vs. 12.3%; p < 0.05), and chronic kidney disease (17.7 vs. 7%; p < 0.001). After discharge, THF patients showed good maintenance rates of RAAS modulators (90.6%) and beta-blockers (83.3%), while statin therapy significantly decreased from 81.3 to 64.6% (p < 0.05). The pursuit of secondary prevention targets, as far as self-reported drug adherence, was not different among groups. Patients with THF had increased 1-year mortality (8.3 vs. 1.6%, p < 0.001). Moreover, THF independently predicted adverse outcome with OR for recurrent events (mainly further episodes of decompensation) of 2.4 (CI 1.4-4.3). Patients who experienced THF after coronary revascularization had increased post-discharge mortality and cardiovascular events. Hemodynamic instability, rather than recurrent myocardial ischemia, seems to be linked with worse prognosis. PMID- 24146111 TI - Molecular, cellular, and tissue impact of depleted uranium on xenobiotic metabolizing enzymes. AB - Enzymes that metabolize xenobiotics (XME) are well recognized in experimental models as representative indicators of organ detoxification functions and of exposure to toxicants. As several in vivo studies have shown, uranium can alter XME in the rat liver or kidneys after either acute or chronic exposure. To determine how length or level of exposure affects these changes in XME, we continued our investigation of chronic rat exposure to depleted uranium (DU, uranyl nitrate). The first study examined the effect of duration (1-18 months) of chronic exposure to DU, the second evaluated dose dependence, from a level close to that found in the environment near mining sites (0.2 mg/L) to a supra environmental dose (120 mg/L, 10 times the highest level naturally found in the environment), and the third was an in vitro assessment of whether DU exposure directly affects XME and, in particular, CYP3A. The experimental in vivo models used here demonstrated that CYP3A is the enzyme modified to the greatest extent: high gene expression changed after 6 and 9 months. The most substantial effects were observed in the liver of rats after 9 months of exposure to 120 mg/L of DU: CYP3A gene and protein expression and enzyme activity all decreased by more than 40 %. Nonetheless, no direct effect of DU by itself was observed after in vitro exposure of rat microsomal preparations, HepG2 cells, or human primary hepatocytes. Overall, these results probably indicate the occurrence of regulatory or adaptive mechanisms that could explain the indirect effect observed in vivo after chronic exposure. PMID- 24146112 TI - Protective effects of dioscin against alcohol-induced liver injury. AB - Our previous studies have shown that dioscin has protective effect against liver injury. However, the action of the compound against ethanol-induced liver injury is still unknown. In the present paper, ethanol-induced acute and chronic liver damage rat models were used, and the results showed that dioscin significantly alleviated liver steatosis, reduced the levels of alanine aminotransferase, aspartate aminotransferase, total triglyceride (TG), total cholesterol and malondialdehyde, and increased the levels of high-density lipoprotein, superoxide dismutase, glutathione and glutathione peroxidase. Transmission electron microscopy and terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling assays showed that dioscin prevented mitochondrial ultrastructural alterations and apoptosis caused by ethanol. In addition, dioscin significantly inhibited ethanol-induced cytochrome P450 2E1 activation, down-regulated the levels of mitogen-activated protein kinases phosphorylation, inhibited the expressions of nuclear factor kappa B, glucose regulated protein 78, activating transcription factor 6 and alpha subunit of translation initiation factor 2 to attenuate oxidative damage, decreased the expressions of tumor necrosis factor alpha and interleukin-6, and down-regulated the expressions of apoptosis-related proteins including p53, caspase-3, caspase-9, poly (ADP-ribose)-polymerase and cytokeratin-18. Further investigation indicated that dioscin markedly increased the expressions of peroxisome proliferators-activated receptor alpha and its target genes including medium-chain acyl-CoA dehydrogenase, carnitine palmitoyl CoA transferase I and acyl-CoA oxidase to advance fatty acid beta-oxidation, up regulated the expressions of acyl-CoA synthetase long-chain family member 1, acyl CoA synthetase long-chain family member 5, alpha-aminoadipic semialdehyde dehydrogenase and acyl-CoA dehydrogenase to promote fatty acid metabolism, and down-regulated the expressions of glycerol-3-phosphate acyltransferase, diacylglycerol acyltransferase 1 and diacylglycerol acyltransferase 2 to accelerate TG synthesis. However, dioscin had no effects on the expressions of sterol regulatory element-binding protein-1c, fatty acid synthase, acetyl-CoA carboxylase 1 and stearoyl-CoA desaturase 1 associated with fatty acid synthesis. In conclusion, dioscin shows excellent protective effect against ethanol-induced liver injury through ameliorating ethanol-induced oxidative stress, mitochondrial function, inflammatory cytokine production, apoptosis and liver steatosis, which should be developed as a new drug for the treatment of ethanol-induced liver injury in the future. PMID- 24146113 TI - ["Prescription upon request" or "determining demand"? On the perception of the tranquiliser-consumer in the GDR (1960-1970)]. PMID- 24146114 TI - ["In a Socialist State it Should be Possible for Activists like me to Receive Effective Medication." Psychotropic Drugs and Consumer Interests in the GDR]. PMID- 24146115 TI - [Commensalism: a fundamental concept in ecology?]. PMID- 24146116 TI - Antidepressant class, age, and the risk of deliberate self-harm: a propensity score matched cohort study of SSRI and SNRI users in the USA. AB - BACKGROUND: The US Food and Drug Administration's meta-analyses of placebo controlled antidepressant trials found approximately twice the rate of suicidal behaviors among children and adults aged 24 years and younger who were randomized to receive antidepressant medication than among those who were randomized to placebo. Rates of suicidal behavior were similar for subjects aged 25-64 years whether they received antidepressants or placebo, and subjects aged 65 years or older randomized to antidepressants were found to have lower rates of suicidal behavior. The age-stratified FDA meta-analyses did not have adequate power to investigate rates of suicidal behaviors by antidepressant drug class. OBJECTIVE: Our objective was to assess the risk of deliberate self-harm associated with the two most commonly prescribed classes of antidepressant agents. DESIGN: Propensity score matched cohort study of incident users of antidepressant agents. SETTING: Population-based healthcare utilization data of US residents. PATIENTS: US residents aged 10-64 years with a recorded diagnosis of depression who initiated use of selective serotonin reuptake inhibitors (SSRIs) or serotonin norepinephrine reuptake inhibitors (SNRIs) between 1 January 1998 and 31 December 2010. MAIN OUTCOME MEASURES: ICD-9 external cause of injury codes E950.x-E958.x (deliberate self-harm). RESULTS: A total of 102,647 patients aged between 10 and 24 years, and 338,021 aged between 25 and 64 years, initiated therapy with antidepressants. Among 10-24 year olds, prior to propensity score matching, 75,675 initiated therapy with SSRIs and 5,344 initiated SNRIs. After matching, there were 5,344 SNRI users and 10,688 SSRI users. Among the older cohort, 36,037 SNRI users were matched to 72,028 SSRI users (from an unmatched cohort of 225,952 SSRI initiators). Regardless of age cohort, patients initiating SSRIs and patients initiating SNRIs had similar rates of deliberate self-harm. Restriction to patients with no antidepressant use in the past 3 years did not alter our findings. CONCLUSIONS: Our findings of similar rates of deliberate self-harm for depressed patients who initiate treatment with either an SSRI or an SNRI suggests that physicians who have decided that their patients would benefit from initiating antidepressant therapy need not weigh differential suicide risk when deciding which class of antidepressant to prescribe. PMID- 24146117 TI - Quantitative myocardial blood flow imaging: not all flow is equal. PMID- 24146118 TI - Preparation and characterization of an advanced medical device for bone regeneration. AB - Tridimensional scaffolds can promote bone regeneration as a framework supporting the migration of cells from the surrounding tissue into the damaged tissue and as delivery systems for the controlled or prolonged release of cells, genes, and growth factors. The goal of the work was to obtain an advanced medical device for bone regeneration through coating a decellularized and deproteinized bone matrix of bovine origin with a biodegradable, biocompatible polymer, to improve the cell engraftment on the bone graft. The coating protocol was studied and set up to obtain a continuous and homogeneous polylactide-co-glycolide (PLGA) coating on the deproteinized bone matrix Orthoss(r) block without occluding pores and decreasing the scaffold porosity. The PLGA-coated scaffolds were characterized for their morphology and porosity. The effects of PLGA polymer coating on cell viability were assessed with the 3-(4,5-dimethyl-2-thiazolyl)-2,5 diphenyl-2H tetrazolium assay. The polymer solution concentration and the number of polymeric layers were the main variables affecting coating efficiency and porosity of the original decellularized bone matrix. The designed polymer coating protocol did not affect the trabecular structure of the original decellularized bone matrix. The PLGA-coated decellularized bone matrix maintained the structural features, and it improved the ability in stimulating fibroblasts attachment and proliferation. PMID- 24146119 TI - Comments on "prediction of drug solubility in lipid mixtures from the individual ingredients". PMID- 24146120 TI - First reply to: Delayed surgery in displaced paediatric supracondylar fractures: a safe approach? Results from a large UK tertiary paediatric trauma centre. PMID- 24146122 TI - ECG challenge: October 22, 2013. PMID- 24146123 TI - Out of Africa: congenital submitral aneurysm with extrinsic compression of the left anterior descending and circumflex arteries. PMID- 24146124 TI - Impact of aneurysm repair on thoracic aorta hemodynamics. PMID- 24146121 TI - Targeting interleukin-1 in heart disease. PMID- 24146125 TI - Cardiology Patient Page. Preeclampsia. PMID- 24146127 TI - Letter by Pescini et al regarding article, "Peripheral artery disease as a manifestation of cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) and practical implications". PMID- 24146128 TI - Letter by Dichgans et al regarding article, "Peripheral artery disease as a manifestation of cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) and practical implications". PMID- 24146129 TI - Response to Letters regarding article, "Peripheral artery disease as a manifestation of cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) and practical implications". PMID- 24146130 TI - Use of a peer support intervention for promoting academic engagement of students with autism in general education settings. AB - Students with autism spectrum disorder (ASD) have been shown to benefit from being educated in general education classrooms that provide interactions with typically developing peers. However, behaviors exhibited by students with ASD frequently lead to their return to segregated special education settings. Evidence-based interventions that are both cost-efficient and easy to use in general education settings are needed. The purpose of this study was to evaluate the effects of a simple peer support intervention on the minor disruptive, off task behaviors of three elementary students with high-functioning ASD in three different general education classrooms. Results indicated the peer support intervention was effective in reducing the off-task behaviors of the students with ASD in these inclusion settings. Practical implications and directions for future research are discussed. PMID- 24146132 TI - Changes in the integrity of thalamocortical connections are associated with sensorimotor deficits in children with congenital hemiplegia. AB - Preservation of thalamocortical projections to the sensorimotor cortex is related to improved hand function in children with cerebral palsy (CP). Whether CP is associated with altered microstructure of these sensorimotor projections or other thalamocortical pathways remains unclear. Forty-two children with congenital hemiplegia and fifteen typically developing children (TDC) underwent structural and diffusion-weighted imaging (high-angular-resolution diffusion imaging) using a 3T MRI. Structural T1-images were parcellated into 34 cortical regions and the thalamus per hemisphere. Thalamocortical projections were extracted using probabilistic tractography and the top tan cortical regions with the greatest number of thalamocortical streamlines for the TDC group were selected for further analysis. The thalamus was parcellated based on its cortical connections. Differences between hemispheres for thalamocortical streamline numbers to each cortical region [asymmetry index (AI)], tract volume and tract microstructure [weighted mean fractional anisotropy (FA) and mean diffusivity (MD)] were calculated. Correlations between these measures (AI, FA and MD) and sensorimotor function were performed. Thalamocortical projections showed topographical organisation based on cortical connectivity. Projections to paracentral lobule, pre-central and post-central gyri showed greater AI in CP group, which indicates reduced streamlines on the ipsilesioned hemisphere. Reduced FA, reduced tract volume and increased MD were also found for these thalamocortical projections on the ipsilesioned hemisphere in children with CP. Changes in AI and tract microstructure of these projections were associated with poorer sensorimotor function. The findings suggest CP is associated with reorganisation of thalamocortical projections to the sensorimotor cortex. Integrity in these projections may underpin deficits in sensorimotor function. PMID- 24146131 TI - DISC1 Ser704Cys impacts thalamic-prefrontal connectivity. AB - The Disrupted-in-Schizophrenia 1 (DISC1) gene has been thought as a putative susceptibility gene for various psychiatric disorders, and DISC1 Ser704Cys is associated with variations of brain morphology and function. Moreover, our recent diffusion magnetic resonance imaging (dMRI) study reported that DISC1 Ser704Cys was associated with information transfer efficiency in the brain anatomical network. However, the effects of the DISC1 gene on functional brain connectivity and networks, especially for thalamic-prefrontal circuit, which are disrupted in various psychiatric disorders, are largely unknown. Using a functional connectivity density (FCD) mapping method based on functional magnetic resonance imaging data in a large sample of healthy Han Chinese subjects, we first investigated the association between DISC1 Ser704Cys and short- and long-range FCD hubs. Compared with Ser homozygotes, Cys-allele individuals had increased long-range FCD hubs in the bilateral thalami. The functional and anatomical connectivity of the thalamus to the prefrontal cortex was further analyzed. Significantly increased thalamic-prefrontal functional connectivity and decreased thalamic-prefrontal anatomical connectivity were found in DISC1 Cys-allele carriers. Our findings provide consistent evidence that the DISC1 Ser704Cys polymorphism influences the thalamic-prefrontal circuits in humans and may provide new insights into the neural mechanisms that link DISC1 and the risk for psychiatric disorders. PMID- 24146134 TI - Measurement of the patellar tendon-tibial plateau angle and tuberosity advancement in dogs with cranial cruciate ligament rupture. Reliability of the common tangent and tibial plateau methods of measurement. AB - OBJECTIVES: To (i) compare agreement of the common tangent (CT) and tibial plateau angle (TP) methods in terms of measuring the patellar tendon angle (PTA) and required advancement and (ii) determine the intra- and inter-observer reliability of observers who measured PTA and the advancement. METHODS: Six observers were divided into three groups based on their level of experience. They measured the PTA and the required advancement on 43 radiographic images of the tibiae of dogs affected by cranial cruciate ligament rupture. Each observer repeated the measurements three times with each method. The inter-technique (interT), intra-observer (intraO), and interobserver (interO) reliabilities were evaluated, assessed by calculating the intraclass correlation coefficient (ICC), and represented by Jones plots. RESULTS: The agreement between PTA-CT and PTA-TP was low (the ICC interT values ranged from 0.11 to 0.4). The PTA-CT was associated with moderate intra-observer reliability (ICC intraO, CT = 0.61) and poor interobserver reliability (ICC interO, CT = 0.33). The PTA-TP was associated with good intra-observer reliability (ICC intraO, TP = 0.75) and moderate interobserver reliability (ICC interO, TP = 0.59). Interobserver reliability did not depend on the level of experience. The advancement measurements were associated with reliability results similar to those obtained for PTA. Jones' plots showed that the CT method consistently yielded lower PTA and advancement values than the TP method. CONCLUSION: Given its poor reliability, the CT method is not recommended. PMID- 24146133 TI - Gray and white matter structures in the midcingulate cortex region contribute to body mass index in Chinese young adults. AB - Overweight and obesity are rapidly becoming a central public health challenge around the world. Previous studies have suggested that elevated Body Mass Index (BMI) might be associated with structural changes in both gray and white matter, but this association is still not well understood. The present study aimed to investigate the relationship between BMI and brain structure with a relatively large sample of young adults (N = 336) in a small age range (20 +/- 1 years). Voxel-based morphometry results showed significant negative correlations between BMI and gray-matter volumes in the midcingulate cortex (MCC), left orbital frontal cortex, and left ventromedial prefrontal cortex. There was also a significant negative correlation between BMI and white matter integrity as indexed by fractional anisotropy in bilateral cingulum. Further tractography analysis showed a significant negative correlation between BMI and the number of fibers passing the MCC region. Regression analysis showed that gray matter and white matter in these regions both contributed to the variance of BMI. These results remained significant even when analysis was restricted to the subjects with normal weights. Finally, we found that decision-making ability (as assessed by the Iowa Gambling Task) mediated the association between the structure of the MCC (a region responsible for impulse control and decision making) and BMI. These results shed light on the structural neural basis of weight variations. PMID- 24146135 TI - Noble metal alloy clusters in the gas phase derived from protein templates: unusual recognition of palladium by gold. AB - Matrix assisted laser desorption ionization of a mixture of gold and palladium adducts of the protein lysozyme (Lyz) produces naked alloy clusters of the type Au24Pd(+) in the gas phase. While a lysozyme-Au adduct forms Au18(+), Au25(+), Au38(+) and Au102(+) ions in the gas phase, lysozyme-Pd alone does not form any analogous cluster. Addition of various transition metal ions (Ag(+), Pt(2+), Pd(2+), Cu(2+), Fe(2+), Ni(2+) and Cr(3+)) in the adducts contributes to drastic changes in the mass spectrum, but only palladium forms alloys in the gas phase. Besides alloy formation, palladium enhances the formation of specific single component clusters such as Au38(+). While other metal ions like Cu(2+) help forming Au25(+) selectively, Fe(2+) catalyzes the formation of Au25(+) over all other clusters. Gas phase cluster formation occurs from protein adducts where Au is in the 1+ state while Pd is in the 2+ state. The creation of alloys in the gas phase is not affected whether a physical mixture of Au and Pd adducts or a Au and Pd co-adduct is used as the precursor. The formation of Au cores and AuPd alloy cores of the kind comparable to monolayer protected clusters implies that naked clusters themselves may be nucleated in solution. PMID- 24146136 TI - Secondary interventions following endovascular repair of abdominal aortic aneurysm. AB - Endovascular aneurysm repair (EVAR) of the abdominal aortic aneurysms is an attractive alternative to open surgery with significantly improved perioperative outcomes. However, EVAR is accompanied by a higher rate of graft-related complications and secondary interventions. Therefore, life-long surveillance and management of secondary treatment is essential for successful EVAR. Endoleaks are one of the most crucial problems after EVAR. Persistent endoleaks are classified into five types and its management depends on the type and severity. Most persistent endoleaks are detectable by contrast-enhanced computed tomography; however, in some cases, two different endoleak types may coexist. Determining whether an endoleak requires any treatment or not is an important consideration. Most if not all type I and III endoleaks require prompt and definitive secondary treatment. While type II endoleaks are most commonly encountered during follow up, not all type II endoleaks require invasive treatment. When secondary treatment is required, it can be treated endovascularly in most cases, even if there is no endoleak. Following EVAR, due to the decompression of the sac, the integrity of the aneurysmal wall strength reduces. Therefore, sudden sac expansion/rupture may occur when an endoleak is encountered following a period of complete aneurysmal exclusion. If diagnosed promptly most late complications can be treated in a less invasive manner, but it could lead to catastrophic event if it is missed. Therefore, adequate and life-long radiographic follow-up is as important as the appropriate patient and device selection as well as the EVAR procedure itself. PMID- 24146137 TI - Reduction of the reinforcing effectiveness of cocaine by continuous D-amphetamine treatment in rats: importance of active self-administration during treatment period. AB - RATIONALE: Continuous administration of D-amphetamine has shown promise as a treatment for psychostimulant addiction. In rodent studies, constant infusion of D-amphetamine (5 mg/kg/day) has been shown to reduce cocaine-reinforced responding in the dose range of 0.19-0.75 mg/kg/inf. OBJECTIVES: The present study tested whether these effects were a reflection of pharmacological interactions between D-amphetamine and cocaine or if they resulted from associative learning mechanisms METHODS: After stable progressive ratio (PR) baselines were established, rats were implanted with subcutaneous osmotic minipumps filled with either D-amphetamine (5 mg/kg/day-groups 1 and 2) or saline (group 3). During the treatment period, groups 1 and 3 self-administered cocaine at a dose that was previously shown to produce the most robust effects in combination with D-amphetamine treatment (0.19 mg/kg/inf), while group 2 received passive cocaine infusions. RESULTS: In replication of previous studies, D amphetamine treatment resulted in a significant (35 %) decrease in breakpoints relative to saline controls. By contrast, no reductions in breakpoints were observed in animals that received passive cocaine infusions during the treatment period (group 2). CONCLUSIONS: Active self-administration of cocaine during the treatment period appears to be an important factor in reducing cocaine-reinforced breakpoints. These findings suggest learning mechanisms are involved in the therapeutic effects of continuous D-amphetamine, and pharmacological interaction mechanisms such as cross-tolerance cannot completely account for the observed decreases in cocaine seeking. PMID- 24146138 TI - Antagonism of brain insulin-like growth factor-1 receptors blocks estradiol effects on memory and levels of hippocampal synaptic proteins in ovariectomized rats. AB - RATIONALE: Treatment with estradiol, the primary estrogen produced by the ovaries, enhances hippocampus-dependent spatial memory and increases levels of hippocampal synaptic proteins in ovariectomized rats. Increasing evidence indicates that the ability of estradiol to impact the brain and behavior is dependent upon its interaction with insulin-like growth factor-1 (IGF-1). OBJECTIVE: The goal of the current experiment was to test the hypothesis that the ability of estradiol to impact hippocampus-dependent memory and levels of hippocampal synaptic proteins is dependent on its interaction with IGF-1. METHODS: Adult rats were ovariectomized and implanted with estradiol or control capsules and trained on a radial-maze spatial memory task. After training, rats were implanted with intracerebroventricular cannulae attached to osmotic minipumps (flow rate 0.15 MUl/h). Half of each hormone treatment group received continuous delivery of JB1 (300 MUg/ml), an IGF-1 receptor antagonist, and half received delivery of aCSF vehicle. Rats were tested on trials in the radial-arm maze during which delays were imposed between the fourth and fifth arm choices. Hippocampal levels of synaptic proteins were measured by western blotting. RESULTS: Estradiol treatment resulted in significantly enhanced memory. JB1 blocked that enhancement. Estradiol treatment resulted in significantly increased hippocampal levels of postsynaptic density protein 95 (PSD-95), spinophilin, and synaptophysin. JB1 blocked the estradiol-induced increase of PSD-95 and spinophilin and attenuated the increase of synaptophysin. CONCLUSIONS: Results support a role for IGF-1 receptor activity in estradiol-induced enhancement of spatial memory that may be dependent on changes in synapse structure in the hippocampus brought upon by estradiol/IGF-1 interactions. PMID- 24146139 TI - [Acute and chronic heart failure in light of the new ESC guidelines]. AB - In June 2012, the New Guidelines for the Treatment of Acute and Chronic Heart Failure of the European Society of Cardiology were published. According to the EMPHASIS-HF trial, mineralocorticoid receptor antagonists are indicated in all stages of symptomatic chronic heart failure under treatment with beta-blockers and ACE inhibitors. Based on the SHIFT trial, patients with class NYHA II-IV heart failure, an ejection fraction <35%, and sinus rhythm with a heart rate of >70/min despite pharmacological treatment including beta-blockers at the maximum tolerated dose should be treated with ivabradin. The RAFT trial justified the extended indication for CRT systems. In acute heart failure, the RELAX-AHF trial showed promising results with serelaxin. This manuscript summarizes the innovations of the new guidelines and the underlying clinical trials. PMID- 24146140 TI - [Joy and sorrow with guidelines 2013]. PMID- 24146143 TI - Insulin administration and the impacts of forgetting a dose. AB - PURPOSE: Little is known about unintentional non-adherence associated with forgetting insulin injections and dose amounts. The study objective was to qualitatively examine unintentional insulin dosing and injection irregularities due to forgetting among people with diabetes mellitus. METHODS: Seven focus group interviews and eight telephone interviews were conducted in Canada, Germany, and China. Participants were required to have diabetes, and to have experienced at least two instances in the previous 3 months of forgetting their insulin injection, forgetting the time/amount taken, or questioning if they had taken their injection. Transcripts were coded thematically, based on a grounded theoretical approach. RESULTS: Sixty-four patients participated: 34.4 % with type 1 diabetes and 65.6 % with type 2 diabetes. The mean age was 50.1 years (range, 18-72 years). The analysis included six domains: Forgetting, what people forgot; Reasons for forgetting; Realizing forgetting; Corrective actions; Consequences of forgetting; and Feelings about forgetting. Participants reported forgetting both bolus and basal insulin doses and often felt uncertain about whether, when, and how much insulin they had taken. The major reasons for forgetting were disruptions to their daily routine, distraction by social events, minor interruptions, and being busy. Participants employed a wide variety of strategies and corrective actions when they thought they had forgotten, and often worried as a result. CONCLUSIONS: Forgetting or questioning insulin dosing impacts insulin taking behavior and contributes to patient uncertainty and worry about their diabetes management. Insulin strategies that assist patients in managing memory related dosing issues may improve adherence or treatment outcomes. PMID- 24146141 TI - Glutathione depletion regulates both extrinsic and intrinsic apoptotic signaling cascades independent from multidrug resistance protein 1. AB - Glutathione (GSH) depletion is an important hallmark of apoptosis. We previously demonstrated that GSH depletion, by its efflux, regulates apoptosis by modulation of executioner caspase activity. However, both the molecular identity of the GSH transporter(s) involved and the signaling cascades regulating GSH loss remain obscure. We sought to determine the role of multidrug resistance protein 1 (MRP1) in GSH depletion and its regulatory role on extrinsic and intrinsic pathways of apoptosis. In human lymphoma cells, GSH depletion was stimulated rather than inhibited by pharmacological blockage of MRP1 with MK571. GSH loss was dependent on initiator caspases 8 and 9 activity. Genetic knock-down (>60 %) of MRP1 by stable transfection with short hairpin small interfering RNA significantly reduced MRP1 protein levels, which correlated directly with the loss of MRP1 mediated anion transport. However, GSH depletion and apoptosis induced by both extrinsic and intrinsic pathways were not affected by MRP1 knock-down. Interestingly, stimulation of GSH loss by MK571 also enhanced the initiator phase of apoptosis by stimulating initiator caspase 8 and 9 activity and pro-apoptotic BCL-2 interacting domain cleavage. Our results clearly show that caspase dependent GSH loss and apoptosis are not mediated by MRP1 proteins and that GSH depletion stimulates the initiation phase of apoptosis in lymphoid cells. PMID- 24146144 TI - Early postoperative results for females undergoing isolated coronary artery bypass surgery: comparison of the pre- and postmenopausal periods. AB - PURPOSE: In this retrospective study, we investigated the demographic data and evaluated our early postoperative results of premenopausal and postmenopausal females who underwent coronary artery bypass graft surgery (CABG). METHODS: A total of 730 female patients who underwent CABG between April 2004 and January 2012 were included in the study. Patients were divided into two groups based on whether they were pre- (group 1) or postmenopausal (group 2). The groups were compared in terms of the demographic and peri-operative parameters. RESULTS: Smoking and the preoperative hematocrit levels were higher in group 1, whereas the incidence of hypertension and obesity and the European system for cardiac operative risk evaluation values were higher in group 2 (p values <0.01; <0.01; <0.01; 0.004 and <0.01 respectively). The utilization of a left internal mammary artery graft and the postoperative drainage volumes were higher in group 1; however, the number of grafts per patient, cardiopulmonary bypass duration, number of patients who needed inotropic support, blood transfusion volumes, the duration of ventilatory support and the hospital stay were higher in group 2 (p values 0.038; 0.040; 0.026; 0.032; 0.014; 0.001; <0.01 and <0.01, respectively). CONCLUSIONS: Although the mortality rates were not significantly different, postmenopausal patients require more intensive postoperative care in comparison to premenopausal patients following CABG. PMID- 24146145 TI - Screening and management for ischemic heart disease in patients undergoing emergency surgery for a type A acute aortic dissection. AB - PURPOSE: We assessed the incidence of coronary artery disease (CAD) during hospitalization after emergency surgery for a type A acute aortic dissection. METHODS: A total of 123 patients underwent multi-slice computed tomography (MSCT) scans during an early stage after surgery. The patients were divided into two groups: group I consisted of 14 patients (11.4%) who had coronary artery stenosis of more than 75% on MSCT, and group II consisted of 109 patients (88.6%) who had no coronary lesions. RESULTS: The prevalence of diabetes, dyslipidemia and a smoking history was significantly higher in group I. Although the serum low density lipoprotein cholesterol levels were similar, the high-density lipoprotein cholesterol (HDL) level was significantly lower in group I (36.4 +/- 7.9 mg/dl) than in group II (49.6 +/- 13.5 mg/dl, P = 0.0005). The maximum carotid intima media thickness (IMT) was significantly thicker in group I (1.17 +/- 0.37 mm) compared to group II (0.96 +/- 0.33 mm, P = 0.0297). The logistic regression analysis detected that a carotid IMT over 1.1 mm (odds ratio 4.35, P = 0.0371) and HDL less than 40 mg/dl (odds ratio 3.90, P = 0.0482) were predictors for CAD. CONCLUSIONS: CAD screening should be recommended for patients with aortic dissection who have several atherosclerosis risk factors, even after emergency surgery. PMID- 24146146 TI - Decreased HPV-specific T cell responses and accumulation of immunosuppressive influences in oropharyngeal cancer patients following radical therapy. AB - Oropharyngeal cancer (OPC) is a type of squamous cell head and neck cancer that is often associated with human papillomavirus (HPV) infection, suggesting the potential for immunotherapeutic targeting of HPV antigens. This study aimed to determine the effect of radical therapy on HPV-specific T cells and other immune parameters in 20 OPC patients, as a prelude to future immunotherapy studies. HPV DNA could be detected in 9/12 available tissue samples (8/9 HPV(+) samples were also p16(+)). HPV-specific T cell responses against HPV16 E6 and E7 peptides were detected by enzyme-linked immunoSPOT in 10/13 and 8/13 evaluable patients, respectively, but did not appear to correlate with HPV status. Post-treatment, both HPV E6 and E7 T cell responses were decreased (4/13 and 2/13 patients, respectively). These reductions in T cell response could not be explained by a concurrent decrease in memory T cells whose absolute numbers were relatively unaffected by radical therapy (27,975 vs. 25,661/10(5) PBMC) despite a significant decrease in overall lymphocyte counts (1.74 vs. 0.69 * 10(9)/L). Instead, there were significant increases in regulatory T cells (3.7 vs. 6.8 %) and a population of myeloid-derived suppressor cells (CD14(-)HLA-DR(-)CD15(hi), 12.38 vs. 21.92 %). This suggests that immunosuppression may contribute to the reduction in HPV-specific T cell responses post-treatment, although study of larger patient cohorts will be required to test whether this affects clinical outcome. Overall these findings suggest that HPV-targeted immunotherapy in post therapy OPC patients will require multiple strategies to boost T cell immunity and to overcome the influence of immunosuppressive cells. PMID- 24146147 TI - External validation of preoperative nomograms predicting biochemical recurrence after radical prostatectomy. AB - OBJECTIVE: Preoperative nomograms can accurately predict the rate of biochemical recurrence after radical prostatectomy. Although these nomograms were shown to be valid in several external validation cohorts of Caucasian patients, they have not been validated in non-Caucasian patients from Asian countries. We therefore validated these preoperative nomograms in a Japanese cohort, using different cutoff values of prostate-specific antigen concentrations for biochemical recurrence. METHODS: We analyzed 637 patients who underwent radical prostatectomy for clinically localized prostate cancer at the Tokyo Medical University Hospital between February 2000 and January 2011. We evaluated two prostate-specific antigen cutoff values for biochemical recurrence, 0.2 and 0.4 ng/ml. Using c index and calibration plots, we validated the previously developed Kattan and Stephenson nomograms. RESULTS: Overall, the mean 5-year non-biochemical recurrence rate was 72 +/- 4%. Using a prostate-specific antigen cutoff values of 0.2 and 0.4 ng/ml, the c-indices for the Kattan nomogram were 0.714 and 0.733. Similarly, using a prostate-specific antigen cutoff values of 0.2 and 0.4 ng/ml, the c-indices for the Stephenson nomograms were 0.717 and 0.671. The calibration plots showed that the predictive value of the Stephenson nomogram at a prostate specific antigen cutoff of 0.2 ng/ml was close to the actual outcomes compared with other combinations of nomograms and prostate-specific antigen cutoff levels. CONCLUSIONS: Because the c-indices of both nomograms were generally high, these nomograms can be applied to our cohort. The addition of biopsy information did not markedly improve the c-index but resulted in good calibration, indicating that the Stephenson nomogram may be a better fit for our patient cohort. PMID- 24146148 TI - A simulation-based approach for evaluating and comparing the environmental footprints of beef production systems. AB - A methodology was developed and used to determine environmental footprints of beef cattle produced at the U.S. Meat Animal Research Center (MARC) in Clay Center, NE, with the goal of quantifying improvements achieved over the past 40 yr. Information for MARC operations was gathered and used to establish parameters representing their production system with the Integrated Farm System Model. The MARC farm, cow-calf, and feedlot operations were each simulated over recent historical weather to evaluate performance, environmental impact, and economics. The current farm operation included 841 ha of alfalfa and 1,160 ha of corn to produce feed predominately for the beef herd of 5,500 cows, 1,180 replacement cattle, and 3,724 cattle finished per year. Spring and fall cow-calf herds were fed on 9,713 ha of pastureland supplemented through the winter with hay and silage produced by the farm operation. Feedlot cattle were backgrounded for 3 mo on hay and silage with some grain and finished over 7 mo on a diet high in corn and wet distillers grain. For weather year 2011, simulated feed production and use, energy use, and production costs were within 1% of actual records. A 25-yr simulation of their current production system gave an average annual carbon footprint of 10.9+/-0.6 kg of CO2 equivalent units per kg BW sold, and the energy required to produce that beef (energy footprint) was 26.5+/-4.5 MJ/kg BW. The annual water required (water footprint) was 21,300+/-5,600 L/kg BW sold, and the water footprint excluding precipitation was 2,790+/-910 L/kg BW. The simulated annual cost of producing their beef was US$2.11+/-0.05/kg BW. Simulation of the production practices of 2005 indicated that the inclusion of distillers grain in animal diets has had a relatively small effect on environmental footprints except that reactive nitrogen loss has increased 10%. Compared to 1970, the carbon footprint of the beef produced has decreased 6% with no change in the energy footprint, a 3% reduction in the reactive nitrogen footprint, and a 6% reduction in the real cost of production. The water footprint, excluding precipitation, has increased 42% due to greater use of irrigated corn production. This proven methodology provides a means for developing the production data needed to support regional and national full life cycle assessments of the sustainability of beef. PMID- 24146149 TI - Methane emissions, body composition, and rumen fermentation traits of beef heifers differing in residual feed intake. AB - This study examined the relationship of residual feed intake (RFI) and performance with methane emissions, rumen fermentation, and digestion in beef heifers. Individual DMI and growth performance were measured for 22 Simmental heifers (mean initial BW 449 kg, SD = 46.2 kg) offered grass silage ad libitum for 120 d. Ultrasonically scanned muscle and fat depth, BCS, muscularity score, skeletal measurements, blood variables, rumen fermentation (via stomach tube), and total tract digestibility (indigestible marker) were measured. Methane production was estimated using the sulfur hexafluoride tracer gas technique over two 5-d periods beginning on d 20 and 75 of the RFI measurement period. Phenotypic RFI was calculated as actual DMI minus expected DMI. The residuals of the regression of DMI on ADG and midtest metabolic body weight, using all heifers, were used to compute individual RFI coefficients. Heifers were ranked by RFI and assigned to low (efficient), medium, or high (inefficient) groupings. Overall ADG and DMI were 0.58 kg (SD = 0.18) and 7.40 kg (SD = 0.72), respectively. High-RFI heifers consumed 9 and 15% more (P < 0.05) than medium- and low-RFI groups, respectively. Body weight, growth, skeletal, and composition traits did not differ (P > 0.05) between low- and high-RFI groups. High-RFI heifers had higher concentrations of plasma glucose (6%) and urea (13%) and lower concentrations of plasma creatinine (9%) than low-RFI heifers (P < 0.05). Rumen pH and apparent in vivo digestibility did not differ (P > 0.05) between RFI groups, although acetate:propionate ratio was lowest (P = 0.07) for low-RFI (3.5) and highest for high-RFI (4.6) heifers. Methane production expressed as grams per day or grams per kilogram metabolic body weight was greater (P < 0.05) for high (297 g/d and 2.9 g/kg BW0.75) compared with low (260 g/d and 2.5 g/kg BW0.75) RFI heifers, with medium (275 g/d and 2.7 g/kg BW0.75) RFI heifers being intermediate. Regression analysis indicated that a 1 kg DM/d increase in RFI was associated with a 23 g/d increase (P = 0.09) in methane emissions. Results suggest that improved RFI will reduce methane emissions without affecting productivity of growing beef cattle. PMID- 24146150 TI - Effect of social ranks and gestation housing systems on oxidative stress status, reproductive performance, and immune status of sows. AB - Ninety-six multiparous sows were randomly assigned into 2 different gestation housing systems on d 35 of gestation: individual gestational crates (n = 24) or small groups with 3 sows in gestational pens (n = 24). Sows were classified into 4 treatments based on gestation housing systems and social ranks within each gestational pen: sows housed in individual gestational crates were in control treatment (CON), and sows destined to high, middle, or low social ranks within each pen were classified into high social rank treatment (HR), middle social rank treatment (MR), and low social rank treatment (LR). The social rank of sows within a pen was determined by their winning percentage during aggressive interactions observed for a 4-d period after mixing on d 35 of gestation. Plasma samples collected from each sow on d 35, 60, 90, and 109 of gestation and d 1 and 18 of lactation were used to determine concentrations of malondialdehyde (MDA), protein carbonyls, 8-hydroxy-deoxyguanosine (8-OHdG), IgG, and IgM. Sows in HR had higher (P < 0.05) body weight during gestation and lactation, smallest (P < 0.05) litter weight at birth, increased (P < 0.05) number of stillborn than sows in MR and LR, and tended to have decreased (P = 0.073, P = 0.064) number of born alive compared with sows in CON and LR. Sows in LR had lower farrowing rate compared with sows in MR. Plasma concentration of protein carbonyl in HR was higher (P < 0.05) than that in MR on d 3 of lactation. Plasma concentrations of 8 OHdG in LR was greater (P < 0.05) than that in HR on d 90 of gestation, d 3 and 18 of lactation, and greater (P < 0.05) than CON on d 18 of lactation. The reproductive performance of sows from all of the social ranks was related to their oxidative stress status during gestation and lactation. Collectively, the reproductive performance, oxidative stress status, and immune status did not differ between sows housed in gestational crates (CON) and pens (HR + MR + LR). Sows in CON and MR did not show inferior reproductive performance during gestation and lactation. Sows in HR and LR had increased oxidative damage during late gestation and lactation which could contribute to the reduced litter size and litter weight in HR and lower farrowing rate in LR. PMID- 24146151 TI - An environmental, economic, and social assessment of improving cattle finishing weight or average daily gain within U.S. beef production. AB - The objective of this study was to assess environmental impact, economic viability, and social acceptability of 3 beef production systems with differing levels of efficiency. A deterministic model of U.S. beef production was used to predict the number of animals required to produce 1 * 10(9) kg HCW beef. Three production treatments were compared, 1 representing average U.S. production (control), 1 with a 15% increase in ADG, and 1 with a 15% increase in finishing weight (FW). For each treatment, various socioeconomic scenarios were compared to account for uncertainty in producer and consumer behavior. Environmental impact metrics included feed consumption, land use, water use, greenhouse gas emissions (GHGe), and N and P excretion. Feed cost, animal purchase cost, animal sales revenue, and income over costs (IOVC) were used as metrics of economic viability. Willingness to pay (WTP) was used to identify improvements or reductions in social acceptability. When ADG improved, feedstuff consumption, land use, and water use decreased by 6.4%, 3.2%, and 12.3%, respectively, compared with the control. Carbon footprint decreased 11.7% and N and P excretion were reduced by 4% and 13.8%, respectively. When FW improved, decreases were seen in feedstuff consumption (12.1%), water use (9.2%). and land use (15.5%); total GHGe decreased 14.7%; and N and P excretion decreased by 10.1% and 17.2%, compared with the control. Changes in IOVC were dependent on socioeconomic scenario. When the ADG scenario was compared with the control, changes in sector profitability ranged from 51 to 117% (cow-calf), -38 to 157% (stocker), and 37 to 134% (feedlot). When improved FW was compared, changes in cow-calf profit ranged from 67% to 143%, stocker profit ranged from -41% to 155% and feedlot profit ranged from 37% to 136%. When WTP was based on marketing beef being more efficiently produced, WTP improved by 10%; thus, social acceptability increased. When marketing was based on production efficiency and consumer knowledge of growth-enhancing technology use, WTP decreased by 12%-leading to a decrease in social acceptability. Results demonstrated that improved efficiency also improved environmental impact, but impacts on economic viability and social acceptability are highly dependent on consumer and producer behavioral responses to efficiency improvements. PMID- 24146152 TI - Influence of pregnancy in mid-to-late gestation on circulating metabolites, visceral organ mass, and abundance of proteins relating to energy metabolism in mature beef cows. AB - In mid-to-late gestation, nutrient demand increases to meet the growth requirements of the conceptus and cows may alter metabolism in response to energy demands of pregnancy. By better understanding the metabolic role of pregnancy, there may be opportunities to better understand maintenance energy costs and improve overall feed efficiency. Eighteen mature Simmental/Angus crossbred cows, pregnant (PREG; n = 9) and nonpregnant (OPEN; n = 9), were used to investigate the effect of pregnancy on BW change, carcass traits, visceral organ mass, and circulating serum metabolites. Cows were blocked by day of expected parturition such that each block was slaughtered 4 to 5 wk before parturition. Cows were individually fed for ad libitum intake using Calan gates for 89 to 105 d. Cows were weighed, ultrasounded for rib (over the 12th and 13th rib) and rump fat, and a serum sample obtained at d 1, 56, and 3 to 5 d before slaughter. At slaughter, organs were removed, trimmed of fat, and weighed. Serum was analyzed for beta hydroxybutyrate (BHBA), NEFA, glucose, urea, total cholesterol, and triiodothyronine (T3). Tissue samples from liver, kidney, sternomandibularis muscle, ruminal papillae, pancreas, and small intestinal mucosa were collected at slaughter and snap frozen in liquid N. Western blots were conducted to quantify abundance of: proliferating cell nuclear antigen (PCNA), ATP synthase, ubiquitin, and Na(+)/K+ ATPase for all tissues; PPARgamma, PPARgamma coactivator 1alpha (PGC1-alpha), 5'-adenosine monophosphate-activated protein kinase (AMPK) and phosphorylated-AMPK (pAMPK) for liver, muscle, and rumen; phosphoenolpyruvate carboxykinase (PEPCK) for liver and kidney; and uncoupling protein 2 (UCP2) for liver. Data were analyzed using PROC MIXED in SAS as a replicated randomized complete block. Liver weights (actual, relative to BW, relative to HCW) were heavier (P <= 0.02) in OPEN. Rumen mass and kidney fat weight, both relative to BW, were also greater (P <= 0.04) in OPEN. On d 56 and at preslaughter, PREG cows had greater (P <= 0.04) BHBA, NEFA and urea concentrations and lower (P = 0.04) cholesterol concentration. Hepatic Na(+)/K+ ATPase abundance was greater (P = 0.04) in PREG cows. In rumen papillae, abundance of pAMPKalpha was increased (P = 0.006) in PREG cows. These data indicate that PREG cows may metabolize energy reserves and alter their metabolism to meet the energetic demands of the growing fetus. PMID- 24146153 TI - Subsequent influences of feeding intact green seaweed Ulva lactuca to growing lambs on the seminal and testicular characteristics in rams. AB - The present experiment was designed to investigate the subsequent influences of supplementing different levels of intact green seaweed Ulva lactuca (0%, 3%, and 5% DM) to growing sexually immature lambs during the growth period (74 d) on the seminal and testicular characteristics of sexually mature rams. Ulva lactuca was manually collected, adequately prepared, and then incorporated into lambs' diets. Eighteen male 3-mo-old lambs of the Awassi breed with a mean BW of 22.57 kg (SD = 1.08) were randomly assigned into treatments. The obtained results indicate that offering Ulva lactuca at the level of 3% or 5% DM to lambs during the growth period had no subsequent impacts (P > 0.05) on liver and kidney functions as well as blood water balance in rams, thereby suggesting that Ulva lactuca can be safely supplemented to lambs during growing. However, our findings point out that feeding a lamb diet supplemented with intact Ulva lactuca failed to demonstrate any subsequent benefit (P > 0.05) on the growth performance, thermoregulatory responses, and plasma oxidative status in rams. Above all, it was clearly evident that supplementing intact Ulva lactuca to lambs had demonstrated subsequent negative influences (P < 0.05) on seminal and testicular characteristics of rams, more noticeably observed at the 5% DM inclusion rate than at 3%. These results were manifested by the inferior (P < 0.05) seminal quality, reduced (P < 0.05) testicular morphometry, changes (P < 0.05) in testicular histopathology, defective (P < 0.05) endocrine signaling, and increased (P < 0.05) seminal oxidative stress in rams fed diets supplemented with Ulva lactuca during the growth period compared to control rams. The deleterious impacts of feeding intact Ulva lactuca on spermatogenesis and germ cell loss were proven to be attributed to the dysfunction of Sertoli cells. Collectively, these results provide novel insights on the subsequent influences of dietary supplementation of intact Ulva lactuca to lambs. The consistent evidence of profound negative impacts on seminal and testicular characteristics as well as the resulting data of no improvement of subsequent growth, thermoregulation, and plasma oxidative status in rams prompts us to tentatively recommend the avoidance of feeding intact Ulva lactuca to lambs. PMID- 24146154 TI - Technical note: Comparison of biomarker and molecular biological methods for estimating methanogen abundance. AB - Quantitative real-time PCR (qPCR) has become a popular method for estimation of methanogen abundance in the ruminant digestive tract. However, there is no established method in terms of primer choice and quantification, which means that results are variable and not directly comparable between studies. Archaeol has been proposed as an alternative marker for methanogen abundance, as it is ubiquitous in methanogenic Archaea, and can be quantified by gas chromatography mass spectrometry (GC-MS). The aim of this experiment was to compare total methanogen populations estimated using the new archaeol approach with estimates based on qPCR. Specific primer sets and probes were used to detect dominant ruminal methanogen species Methanobrevibacter ruminantium, Methanobrevibacter smithii, Methanosphaera stadtmanae, and total methanogen populations. There was variation in the relationships among total methanogen abundance estimates based on archaeol and qPCR. In addition, the universal methanogen primers appeared to preferentially amplify genes from M. smithii. Archaeol had the strongest relationship with the dominant rumen methanogen M. ruminantium, whereas the total methanogen primers had a comparatively weak relationship with archaeol. Archaeol analysis was a useful adjunct to molecular biology methods, but it seems that a valid specific primer for M. ruminantium would be more useful than a biased primer for total methanogens. PMID- 24146155 TI - Effect of hay steaming on forage nutritive values and dry matter intake by horses. AB - Management strategies for horses with respiratory disease include soaking hay before feeding. Hay steaming is an alternative to this practice; however, little is known about its impact on forage nutritive values or intake. The objective was to determine the effect of steaming on forage nutritive value and intake by horses. Two alfalfa (Medicago sativa L.)-orchardgrass (Dactylis glomerata L.) mixed hays were evaluated: a low moldy (NM) and moderately moldy (MM) hay. Six mature horses were used in a 10 d crossover design. Three horses were assigned to each hay type and treatments were switched on d 6. Each day, one bale of each hay was sampled (pre- and poststeaming) and steamed for 90 min using a commercial hay steamer. Two flakes of steamed or unsteamed NM or MM hay were weighed and offered simultaneously to each horse in individual hay nets. Horses were allowed access to hay for 2 h, orts were collected, and 2 h DMI was calculated. Six additional bales of NM and MM were used to evaluate the effect of steaming on total suspended particulate (TSP). Flakes of unsteamed or steamed hay were agitated in an electric cement mixer, and TSP were recorded every min for 30 min using a tapered element oscillating microbalance sampler. Paired t tests and PROC MIXED of SAS (SAS Inst. Inc., Cary, NC) were used to compare steamed and unsteamed hay nutritive values, mold concentration, TSP, and 2 h DMI. Steaming increased hay moisture and therefore reduced DM to 77 and 81% for NM and MM, respectively (P < 0.001). In NM and MM hay, steaming reduced P content by 16 and 17%, respectively (P <= 0.007). Steaming reduced water-soluble carbohydrates (WSC) and ethanol soluble carbohydrates (ESC) by 13% (P = 0.001) and 27% (P = 0.003), respectively, for MM but had no effect on NM (P > 0.05). Steaming reduced mold concentrations in both hays by >= 91% (P < 0.001). Total suspended particulate of MM hay was reduced by 55% (P = 0.043), but TSP in NM hay was not affected by steaming (P = 0.445). Dry matter intake of NM was increased by steaming; horses ingested 0.64 kg of unsteamed and 2.02 kg of steamed hay (P < 0.001). Dry matter intake of MM was not affected by steaming (P > 0.05). For NM hay, steaming decreased P and mold concentrations and increased DMI of the hay but had no effect on TSP. In MM hay, steaming reduced P, WSC, ESC, mold concentrations, and TSP but did not affect DMI. Steaming represents a strategy for reducing TSP and mold concentrations and increasing DMI in some hays but can result in leaching of essential nutrients. PMID- 24146156 TI - Influence of level of dried distillers grains with solubles on feedlot performance, carcass characteristics, serum testosterone concentrations, and spermatozoa motility and concentration of growing rams. AB - The objective of this study was to evaluate the effects of dried distillers grains with solubles (DDGS) on ram lamb feedlot performance, carcass characteristics, serum testosterone concentration, and semen quality. One hundred twenty ram lambs (40.4 +/- 9.1 kg; Suffolk * western white face) were used in a completely randomized design to determine the effects of DDGS on feedlot performance and carcass characteristics. Rams were allotted into one of three dietary treatments (n = 4 pens/treatment; 10 rams/pen): 1) 0DDGS: 85% corn and 15% commercial market lamb pellet, 2) 15DDGS: 15% DDGS substituted for corn (DM basis), and 3) 30DDGS: 30% DDGS substituted for corn (DM basis). Rams were weighed on consecutive days at the beginning (d 0 and 1) and end (d 96 and 97 and d 116 and 117) of the trial. Scrotal circumference was measured on all rams on d 84, 96, and 116. Semen and blood samples were collected on a subset of 48 rams (4 rams/pen; 16 rams/treatment; n = 4) to evaluate semen quality. Blood samples were collected every 14 d throughout the study. Semen samples were collected on d 84, 98, and 112. Rams were fed to market weight, shipped to a commercial abattoir, and harvested for carcass data collection. Initial BW, final BW, change in scrotal circumference, days on feed, carcass characteristics, serum testosterone concentrations, and spermatozoa motility score were not different (P >= 0.23) due to dietary treatment. However, DMI increased linearly (P < 0.001) as DDGS increased in the ration, resulting in a linear increase (P = 0.02) in ADG. Additionally, spermatozoa concentration decreased linearly (P = 0.05) as DDGS concentration increased in the ration. Increasing DDGS in the diet did not have a negative impact on ram feedlot performance or carcass characteristics; however, spermatozoa production may have been negatively affected, necessitating the need for additional research on the impact of DDGS on ram development. PMID- 24146157 TI - Estimation of genetic parameters for birth weight, preweaning mortality, and hot carcass weight of crossbred pigs. AB - Genetic parameters for birth weight (BWT), preweaning mortality (PWM), and HCW were estimated for a crossbred pig population to determine if BWT could be used as an early predictor for later performances. Sire genetic effects for those traits were estimated to determine if early selection of purebred sires used in crossbreeding could be improved. Data were recorded from 1 commercial farm between 2008 and 2010. Data were from 24,376 crossbred pigs from Duroc sires and crossbred Large White * Landrace dams and included 24,376 BWT and PWM records and 13,029 HCW records. For the analysis, PWM was considered as a binary trait (0 for live or 1 for dead piglet at weaning). A multitrait threshold-linear animal model was used, with animal effect divided into sire genetic and dam effects; the dam effects included both genetic and environmental variation due to the absence of pedigree information for crossbred dams. Fixed effects were sex and parity for all traits, contemporary groups for BWT and HCW, and age at slaughter as a linear covariable for HCW. Random effects were sire additive genetic, dam, litter, and residual effects for all traits and contemporary group for PWM. Heritability estimates were 0.04 for BWT, 0.02 for PWM, and 0.12 for HCW. The ratio between sire genetic and total estimated variances was 0.01 for BWT and PWM and 0.03 for HCW. Dam and litter variances explained, respectively, 14% and 15% of total variance for BWT, 2% and 10% for PWM, and 3% and 8% for HCW. Genetic correlations were -0.52 between BWT and PWM, 0.55 between BWT and HCW, and -0.13 between PWM and HCW. Selection of purebred sires for higher BWT of crossbreds may slightly improve survival until weaning and final market weight at the commercial level. PMID- 24146158 TI - Effect of varying concentrations of vitamin C on performance, blood metabolites, and carcass characteristics of steers consuming a common high-sulfur (0.55% S) diet. AB - The objective of this study was to examine the effects of vitamin C (VC) supplementation for an average of 102 d before harvest on finishing performance and blood metabolites of steers receiving a 40% dry distillers grains plus solubles diet (0.55% S). Yearling, Angus-cross steers (n = 140) were blocked by initial BW (432 +/- 25.5 kg), stratified within blocks by intramuscular fat (3.6% +/- 0.30%) determined by ultrasonography, and assigned to treatments (5 steers/pen, 7 pens/treatment). Treatments included 1) no VC control (CON), 2) 5 g VC * steer(-1) * d(-1) (5VC), 3) 10 g VC * steer(-1) * d(-1) (10VC), and 4) 20 g VC * steer(-1) * d(-1) (20VC). Jugular blood was collected from 2 steers/pen before feeding at the beginning and end of the 102-d study, and steers were harvested by block on 3 separate dates (d 91, 105, and 112). Sulfur intake linearly decreased (P = 0.01) as VC inclusion increased (59.2, 57.7, 57.0, and 54.8 +/- 0.79 g S * steer(-1) * d(-1) for CON, 5 VC, 10 VC, and 20 VC, respectively). The CON cattle had greater (P < 0.01) DMI than the VC-supplemented cattle. Inclusion of VC did not influence ADG or final BW, resulting in a tendency for a linear increase (P = 0.08) in G:F as VC inclusion increased (0.150, 0.152, 0.158, and 0.160 +/- 0.004 for CON, 5 VC, 10 VC, and 20 VC, respectively). Ending (2 d before harvest) plasma ascorbate showed a quadratic effect (P < 0.05) because of lesser concentrations exhibited by 5 VC cattle (1,186 ug/L) compared with the CON (1,454 ug/L), 10 VC (1,304 ug/L), and 20 VC (1,436 ug/L; SEM +/- 64.8) cattle. Ending plasma insulin concentrations of CON cattle tended (P = 0.07) to be less than the VC-supplemented cattle. Plasma glucose and NEFA concentrations were not affected (P >= 0.23) by VC inclusion. Hot carcass weight, 12th-rib back fat, marbling, and quality grade were not affected (P >= 0.27) by VC inclusion. Increasing VC inclusion linearly increased (P = 0.02) rib eye area (84.9, 86.5, 88.7, and 89.1 cm(2) +/- 1.17 for CON, 5 VC, 10 VC, and 20 VC, respectively), corresponding to a linear decrease (P = 0.02) in yield grade with increasing inclusions of VC. A tendency (P = 0.06) for a quadratic effect on KPH was observed, in which values generally increased from CON (2.27%) to 5 VC (2.37%) to and 10 VC (2.39%), then decreased in 20 VC (2.20%). In conclusion, VC supplementation to a high-S diet for an average of 102 d before harvest has limited effects on blood metabolites but increased rib eye area and tended to increase feed efficiency of yearling steers. PMID- 24146159 TI - Performance and well-being of sows housed in pens retrofitted from gestation stalls. AB - Pressures from consumers concerned with sow well-being in gestation stalls have encouraged producers to consider how to transition from individual gestation stalls to pens in existing buildings. The aim of this study was to evaluate the performance and well-being of sows in pens that were retrofitted from stalls (2.1 by 0.55 m). Large pens (5.5 by 7.3 m) housed 26 sows and small pens (5.5 by 1.7 m) housed 6 sows, with equal floor space allowance (1.5 m(2)/sow) in both pens. Floor space allowance in pens was set to ensure that pens and stalls occupied the same building space per sow. Data were collected from 815 sows (parity 1 to 8) in 13 large pens, 26 small pens, and 326 stalls that served as control. All sows were mated in stalls and moved to pens or stalls after pregnancy confirmation at 5 wk after mating. Daily feed allowance for sows was dropped on a solid floor in pens and was equal in all 3 housing systems. Sows stayed in their assigned gestation housing treatment for 1 pregnancy. Data were analyzed using the Proc FREQ and the Proc Mixed procedures of SAS. Sows in large pens gained less weight during gestation than sows in small pens and stalls (33.4 vs. 39.5 and 41.5 kg, SE = 1.64; P = 0.01). In addition, the proportion of sows assigned to the study that farrowed was the lowest in large pens (92%, chi(2) = 9.52; P < 0.01) and the highest in stalls (98%), with sows in small pens being intermediate (95%). Consequently, the highest percent of sows were removed from large pens (15.8%, chi(2) = 6.75; P < 0.05) and lowest percent of sows were removed from stalls (9.2%), with sows in small pens being intermediate (11.7%) during the study period. Causes for sow removal were different among the housing treatments. Poor reproductive performance was the top reason for culling sows in large pens and in stalls. In small pens, mortality was the top reason for sow removal. Housing treatment did not affect live litter size at birth (12.5, 12.2 and 12.3 piglets, SE = 0.21) or weaning (10.2, 10.1 and 10.3 piglets, SE = 0.20) for large pens, small pens, or stalls, respectively. Results suggest that the performance and well-being of sows were compromised in pens, as indicated by decreased farrowing rates and increased sow removal rates. The limited floor space allowance and the competitive floor feeding system could be major contributors to the compromised performance and well-being of group-housed sows in this study. PMID- 24146160 TI - Effect of decreasing dietary cation anion difference on feedlot performance, carcass characteristics, and beef tenderness. AB - The manipulation of acid-base balance has been extensively investigated as a means of manipulating Ca homeostasis and managing milk fever in dairy cows. A low dietary cation anion difference (DCAD) increases urinary Ca, blood-ionized Ca, and responsiveness to Ca-homeostatic hormones. Very little attention has been focused on the possibility of using a low dietary DCAD to increase muscle Ca availability, calpain activity, and meat tenderness of beef cattle. Thus, 90 Angus * Simmental crossbred steers were allotted by weight (590.1 +/- 2.4 kg) and breed composition (% Simmental) to 3 treatments (6 pens/treatment, 5 steers/pen) to evaluate the effects of DCAD on beef tenderness. Treatments were initiated 2 wk before slaughter and consisted of 3 DCAD (mEq/100 g) treatments: -16, 0, and +16. Basal diets (DM basis) were 62 to 64% corn, 6 to 9% soybean meal, and 20% corn silage, and were formulated to contain similar concentrations of protein, energy (NEm; NEg), and minerals, with the exception of sodium and chlorine. A commercial chloride ion supplement (PASTURChlor, West Central, Ralston, IA) was added to diets to decrease DCAD and sodium bicarbonate was added to diets to increase DCAD. Performance before initiation of the study did not differ among treatments (P > 0.22). Urine pH did not differ at the initiation of the study (P > 0.57), but did increase at a decreasing rate on d 7 (6.37, 7.69, 8.13) and d 14 (5.68, 7.66, 8.03) of the study as DCAD increased from -16 to 0 to +16, respectively (quadratic, P < 0.02). Gain and gain:feed responded quadratically to DCAD (P < 0.01), increasing from -16 to 0 DCAD and decreasing from 0 to +16 DCAD. Hot carcass weight, dressing percent, fat thickness, LM area, yield grade, marbling score, quality grade distribution, 48 h muscle pH, and Ca content of muscle did not differ among treatments (P > 0.16). In addition, DCAD did not affect Warner-Bratzler shear force among treatments after 7 and 21 d of aging (P > 0.23). Although urine pH was decreased by feeding a -16 DCAD diet, Ca influx into the LM and beef tenderness were not affected by altering the DCAD in finishing beef cattle diets. PMID- 24146161 TI - Comparison of methods of acquiring attenuation maps for cardiac SPECT in the presence of respiratory motion. AB - BACKGROUND: We investigated the effect of the respiratory motion on attenuation corrected (AC) SPECT images for three different SPECT systems, each using a different approach in obtaining attenuation maps: scanning-line sources (SLS) acquired simultaneous with emission; slow cone-beam CT (CBCT) acquired sequentially to emission; and fast helical CT (HCT) acquired sequentially to emission. METHODS: A torso phantom filled with (99m)Tc was used to model a cardiac perfusion study. Stationary baseline acquisitions were followed by the acquisitions with the phantom moving axially using a computer-controlled motion platform to simulate breathing. In addition, HCT acquisitions were made simulating breath-hold at different extents of misalignment between CT and emission. HCT images were also used to simulate the Average-CT method. Acquisitions were repeated with added breast attachments, and the heart insert in two different orientations. Visual comparison was made of AC maps, AC emission slices and polar maps. Quantitative comparisons were made of global uniformity based on the percent fractional standard deviation (%FSD) of the polar map segment values, and the ratio of the segment values in the Anterior and Inferior walls divided by that of the Lateral and Septal walls (AI/LS ratio). RESULTS: The AC maps for the SLS were inferior to the CT's, and most impacted by added large breast attachment. Motion artifacts seen on CBCT slices were minimized in the derived attenuation maps. AC maps obtained from HCT showed inconsistent organ sizes depending on the direction of respiration at the time of acquisition. Both visually and quantitatively CBCT resulted in the best uniformity (up to 3.4 % lower in %FSD) for all the stationary acquisitions, and for the motion acquisition of the female phantom with large breast attachment (up to 4.0 % lower). For the motion acquisition of the male phantoms, HCT resulted in slightly better uniformity (<0.5 % lower) than CBCT. Breath-hold at end-expiration slightly improved (up to 1.1 %) the uniformity over the HCT acquired during regular breathing. Further improvement was achieved with the Average-CT method. For all the systems, phantom respiratory motion reduced the AI/LS ratio compared to when the phantoms were stationary. CONCLUSIONS: The CBCT approach resulted in the best uniformity of the AC emission images. For the female phantom with larger breast attachment, HCT and SLS were truncated at some projection angles introducing artifacts into the AC emission images. The emission image artifacts observed with HCT could be mitigated by performing breath-hold acquisition at end expiration or Average-CT type acquisitions. PMID- 24146163 TI - Temperature variations within and between incubators-a prospective, observational study. AB - PURPOSE: To determine if there is a temperature variation within and between incubators. METHODS: This prospective, experimental trial with external controls was performed at an Assisted Reproductive Technology laboratory in a tertiary care, university hospital. Temperature values were taken at various locations within and between incubators. RESULTS: Even though they were both set to 37.0 degrees C, the same make and model incubators had significantly different internal temperatures. Temperatures differed significantly among top, middle and bottom shelves and between fronts and backs of shelves. CONCLUSION(S): We found temperatures differed within and between our front-loading incubators. Thus, laboratory personnel should evaluate their incubators for temperature variations within and between incubators and, if temperatures differ significantly, develop a plan to deal with discrepancies. PMID- 24146164 TI - Yield and clinical efficacy of funduscopic examinations performed in the pediatric emergency room. AB - Consultations by ophthalmologists to rule out papilledema are frequently requested by emergency room (ER) physicians. The clinical setting and optimal timing for examination are not well established, and the impact on patient management is unclear. We evaluated the yield of emergency funduscopic examinations, aiming at establishing the optimal timing and efficacy of the consultation. The medical records of all children aged 0-18 years referred for funduscopic examinations from the ER between June 2010 and May 2011 were reviewed. Of 19,772 ER visits, 1,920 (9.7 %) were seen by an ophthalmologist and 479 (2.4 %) to rule out papilledema. Headache (44.5 %) and head trauma (18.4 %) were the most common indications. Sixty percent of the 479 patients had been symptomatic for <24 h, all having normal eye exams. Only 6/479, with diverse etiologies, depicted papilledema. Among these six children, visual complaints associating with headache were statistically significant to suggest the presence of papilledema (p = 0.014). Seventy-one of the 479 children underwent neuroimaging studies despite normal funduscopic examinations. A single tumor case (medulloblastoma), symptomatic for weeks, had normal funduscopy. CONCLUSION: The vast majority of ER consultations to rule out papilledema show normal findings, particularly among children with signs and symptoms lasting for <24 h. The yield of funduscopy may be higher if visual disturbances are reported. If neuroimaging studies are considered, emergency room ophthalmological consultation is probably not warranted, except for young infants with neurological signs and symptoms in whom retinal hemorrhages suggestive of physical abuse must be ruled out. PMID- 24146166 TI - Comparison of patients with Kawasaki disease with retropharyngeal edema and patients with retropharyngeal abscess. AB - Kawasaki disease with retropharyngeal edema (KD with RPE) is a rare complication, and it is diagnosed by neck CT. Most reported cases had a delayed diagnosis because those patients' conditions were misdiagnosed as retropharyngeal abscess (RPA). The purpose of this study was to differentiate KD with RPE from RPA. We performed a retrospective case-control study comparing children with KD with RPE to those with RPA hospitalized at the tertiary pediatric hospital in Tokyo between 2005 and 2011. The 39 patients revealing RPE on neck CT were divided into two groups: group A was classified as KD (n = 21) and group B was classified as non-KD (n = 18). Patients in group B were finally evaluated as having RPA clinically and were treated with antibiotic therapy. A significantly higher proportion of patients in group B complained of dysphagia (11 patients vs. 5 patients; p = 0.0170) and neck pain (17 patients vs. 12 patients; p = 0.0106). Neck CT revealed a ring enhancement (16 patients vs. no patients; p < 0.0001) and mass effect in a greater proportion of patients in group B (11 patients vs. 1 patient; p < 0.0003). CONCLUSION: Careful attention to manifestations and close analyses of CT imaging may allow clinicians to differentiate KD with RPE from RPA. PMID- 24146165 TI - Obesity and infection: two sides of one coin. AB - The prevalence of obesity has exponentially risen worldwide. The etiology of obesity is multifactorial, and genetic inheritance and behavioral/environmental causes are considered the main etiological factors. Moreover, evidence that specific infections might promote the development of obesity has steadily accumulated. Only a few works investigate the impact of obesity on the immune response to infections and the risk of infections in the obese population. The aim of this paper was to review the available data regarding the various aspects of the association between obesity and infections and to highlight the possibility that infectious agents may have an etiological role in obesity, an idea known as "infectobesity". Several microbes have been considered as possible promoter of obesity, but most of the data concern adenovirus-36 that exerts an adipogenic action mainly via a direct effect on adipose tissue leading to weight gain, at least in animal models.Obesity affects the immune response leading to an increased susceptibility to infections. Obese adults and children show an increased incidence of both nosocomial and community-acquired infections. Furthermore, obesity may alter the pharmacokinetics of antimicrobial drugs and impact on vaccine response. However, the various aspects of the association of obesity infections remain poorly studied, and a call to research is necessary to better investigate the problem.In conclusion, obesity impacts millions globally, and greater understanding of its etiology and its effects on immunity, infections, and prevention and management strategies is a key public health concern. PMID- 24146167 TI - Loeys-Dietz syndrome in a Southeast Asian Hospital: a case series. AB - Loeys-Dietz syndrome (LDS) is a heritable connective tissue disease in which the activity of the transforming growth factor (TGF) beta signalling pathway is disrupted. The clinical features of LDS represent a clinical continuum that includes LDS type 1, with cutaneous, vascular, skeletal and craniofacial findings, and LDS type 2, with cutaneous, vascular and skeletal findings. We describe five Asian patients with genetically confirmed LDS with mutations in either the TGFBR1 or TGFBR2 gene. Their clinical features were similar to those reported in Caucasian patients. Two patients have novel mutations in TGFBR2. Transcatheter occlusion of patent ductus arteriosus (PDA) was safe and successful in three patients. Treatment with Losartan for aortic root dilatation was well tolerated in our patients, but the outcome is mixed. Among the three patients with follow-up data, aortic root dilatation has improved in two patients but continues to progress in the third patient despite treatment. CONCLUSION: We describe two novel mutations in TGFBR2 leading to LDS; PDA is common in our patients and can be safely occluded via transcatheter procedure. PMID- 24146168 TI - Efficacy of lidocaine lontophoresis using either alternating or direct current in hairless rats. AB - The aim of this study was to determine transport of lidocaine ions through a hairless rat skin in vivo and to compare the efficacy of alternating current (AC) with that of direct current (DC) iontophoresis (IOP). We measured the concentration of lidocaine transported through a cellophane membrane or a hairless rat dorsal skin applying either AC-IOP or DC-IOP. The results revealed that lidocaine concentration increased in a time-dependent manner in vitro in both DC-IOP and AC-IOP. However, the in vivo study showed different tendencies in lidocaine concentration. In the DCIOP group, lidocaine concentration reached its maximum 20 min after current application and then decreased rapidly; the AC-IOP group showed an increase in lidocaine concentration in a time-dependent manner. There were no side effects such as electrical burns in the rats. In conclusion, AC can be applied for long periods and DC for short periods, or their application time can be appropriately scheduled. Our study also suggests the mechanism by which voltage waveforms affect the skin when applied by IOP. In the future, these findings will be a solid foundation for developing various kinds of medical equipment such as scheduled drug delivery system that can easily deliver various types of drug. PMID- 24146169 TI - Evaluation of the occlusal contact of crowns fabricated with the bite impression method. AB - In prosthodontic treatment, reconstruction of a proper occlusal contact relationship is very important as well as reconstruction of a proper interproximal relationship and marginal fitness. Unfortunately, occlusal relationships are sometimes lost in the process of occlusal adjustment of crowns. The purpose of this study was to compare the occlusal contacts of single crown fabricated by two different types of impression techniques. Nine subjects, whose molars required treatment with crown restoration, were enrolled in this study. Full cast crowns were fabricated using two types of impression techniques: the conventional impression method (CIM) and the bite impression method (BIM). The occlusal contacts of crowns were precisely evaluated at the following stages: after occlusal adjustment on the articulator (Step 0), before occlusal adjustment in the mouth (Step 1), after occlusal adjustment at the intercuspal position (Step 2), and after occlusal adjustment during lateral and protrusive excursions (Step 3). The number of occlusal contacts of the crowns on the functional cusps fabricated with BIM was significantly greater than that with CIM after occlusal adjustment. For this reason, the crowns fabricated with BIM might have a more functionally desirable occlusal surface compared to the crowns fabricated with CIM. PMID- 24146170 TI - Treatment of bone loss in osteopenic patients with Crohn's disease: a double blind, randomised trial of oral risedronate 35 mg once weekly or placebo, concomitant with calcium and vitamin D supplementation. AB - OBJECTIVE: Osteoporosis and fractures are frequently encountered in patients with Crohn's disease. In order to prevent fractures, treatment with bone protecting drugs appears warranted early in the course of bone disease when bone loss is not yet prominent. We therefore aimed to demonstrate a beneficial effect on bone density of the bisphosphonate risedronate in osteopenic Crohn's disease patients. METHODS: This double-blind, placebo-controlled randomised trial of risedronate with calcium and vitamin D supplementation was performed in osteopenic Crohn's disease patients. Patients were treated for 2 years with follow-up after 3 and after every 6 months. Disease characteristics and activity and bone turnover markers were assessed at all visits; dual x-ray absorptiometry was performed at baseline, 12 and 24 months; radiographs of the spine at baseline and 24 months. RESULTS: Of 132 consenting patients, 131 were randomised (67 placebo and 64 risedronate). Patient characteristics were similar in both groups, although the risedronate group was slightly heavier (body mass index 24.3 vs 23.0 kg/m(2)). Bone mineral density at lumbar spine increased 0.04 g/cm(2) on average in the risedronate group versus 0.01 g/cm(2) in the placebo group (p=0.007). The mean increase in total hip bone mineral density was 0.03 versus 0.01 g/cm(2), respectively (p=0.071). Fracture prevalence and incidence were similar. Change of T-scores and concentrations of bone turnover markers were consistent with a beneficial effect of risedronate when compared with placebo. The effect of risedronate was primarily demonstrated in the first 12 months of treatment. No serious unexpected suspected adverse events were observed. CONCLUSIONS: A 24 month treatment course with risedronate 35 mg once weekly, concomitant with calcium and vitamin D supplementation, in osteopenic Crohn's disease patients improved bone density at lumbar spine. NTR 163 Dutch Trial Register. PMID- 24146171 TI - Characterization of metal-tagged antibodies used in ICP-MS-based immunoassays. AB - A detailed characterization of metal-tagged antibodies is the prerequisite for the implementation of quantitative concepts in inductively coupled plasma-mass spectrometry (ICP-MS)-based bioanalysis or future medical diagnosis. In this paper, the common modification with bifunctional ligands containing maleimide residues as a reactive group was investigated in detail via size exclusion chromatography (SEC)-ICP-MS and liquid chromatography-time-of-flight (LC-TOF)-MS to determine the preservation of the antibody structure after tagging. Mouse monoclonal IgG modified with metal-coded tags (MeCATs) was used as a model system. Several antibody fragments were identified carrying different numbers of metal tags. In a second step, a functionality test was performed with isolated fragments where the antigen specificity was tested in a dot blot immunoassay. PMID- 24146173 TI - Polymorphisms in the superoxidase dismutase genes reveal no association with human longevity in Germans: a case-control association study. AB - The role of superoxide dismutases (SODs) in aging and oxidative stress regulation has been widely studied and there is growing evidence that imbalances in these processes influence lifespan in several species. In humans, genetic polymorphisms in SOD genes may play an important role in the development of age-related diseases and genetic variation in SOD2 is thought to be associated with longevity. These observations prompted us to perform a case-control association study using a comprehensive haplotype tagging approach for the three SOD genes (SOD1, SOD2, SOD3) by testing a total of 19 SNPs in our extensive collection of 1,612 long-lived individuals (centenarians and nonagenarians) and 1,104 younger controls. Furthermore, we intended to replicate the previous association of the SOD2 SNP rs4880 with longevity observed in a Danish cohort. In our study, no association was detected between the tested SNPs and the longevity phenotype, neither in the entire long-lived sample set nor in the centenarian subgroup analysis. Our results suggest that there is no considerable influence of sequence variation in the SOD genes on human longevity in Germans. PMID- 24146172 TI - Preclinical imaging: an essential ally in modern biosciences. AB - Translational research is changing the practice of modern medicine and the way in which health problems are approached and solved. The use of small-animal models in basic and preclinical sciences is a major keystone for these kinds of research and development strategies, representing a bridge between discoveries at the molecular level and clinical implementation in diagnostics and/or therapeutics. The development of high-resolution in vivo imaging technologies provides a unique opportunity for studying disease in real time, in a quantitative way, at the molecular level, along with the ability to repeatedly and non-invasively monitor disease progression or response to treatment. The greatest advantages of preclinical imaging techniques include the reduction of biological variability and the opportunity to acquire, in continuity, an impressive amount of unique information (without interfering with the biological process under study) in distinct forms, repeated or modulated as needed, along with the substantial reduction in the number of animals required for a particular study, fully complying with 3R (Replacement, Reduction and Refinement) policies. The most suitable modalities for small-animal in vivo imaging applications are based on nuclear medicine techniques (essentially, positron emission tomography [PET] and single photon emission computed tomography [SPECT]), optical imaging (OI), computed tomography (CT), magnetic resonance imaging (MRI), magnetic resonance spectroscopy imaging (MRSI), and ultrasound. Each modality has intrinsic advantages and limitations. More recently, aiming to overcome the inherent limitations of each imaging modality, multimodality devices designed to provide complementary information upon the pathophysiological process under study have gained popularity. The combination of high-resolution modalities, like micro-CT or micro-MRI, with highly sensitive techniques providing functional information, such as micro-PET or micro-SPECT, will continue to broaden the horizons of research in such key areas as infection, oncology, cardiology, and neurology, contributing not only to the understanding of the underlying mechanisms of disease, but also providing efficient and unique tools for evaluating new chemical entities and candidate drugs. The added value of small-animal imaging techniques has driven their increasing use by pharmaceutical companies, contract research organizations, and research institutions. PMID- 24146174 TI - Soft-tissue balancing in total knee arthroplasty: cruciate-retaining versus posterior-stabilised, and measured-resection versus gap technique. AB - PURPOSE: The purpose of this study was to prove the hypothesis that soft tissues are well balanced using the gap technique with a navigation system in cruciate retaining (CR) and posterior-stabilised (PS) total knee arthroplasty (TKA), leading to better clinical outcomes compared with the measured-resection technique. METHODS: One hundred and thirty-five TKAs (90 CR and 45 PS) were performed in patients with varus-type osteoarthritis using the gap technique guided by the offset-type tensor and a navigation system. Soft-tissue balance (joint-component gap and ligament balance) were intraoperatively assessed with the tensor under 40 lb of joint-distraction force. The achievement in the equalised rectangular gap at extension and flexion was assessed and retrospectively compared with the previous series in which the measured-resection technique was used (20 CR and 100 PS TKAs). In addition, clinical outcomes, including range of motion and Knee Society Score were assessed at a minimum two year follow-up. RESULTS: In achieving equalised rectangular gaps at extension and flexion, CR TKAs met criteria in more cases [66.7% (64/90) vs. 44.4% (20/45) of PS TKA] with the gap technique, which was superior to that with the measured resection technique [50.0% (10/20) of CR TKA and 28.0% (28/100) of PS TKA]. However, clinical outcomes showed no significant differences among groups at minimum two year follow-up. CONCLUSIONS: The superiority of CR TKA with the gap technique in achieving equalised rectangular gaps at extension and flexion does not directly reflect two year postoperative clinical outcomes. PMID- 24146175 TI - Primary stability of the Fitmore stem: biomechanical comparison. AB - PURPOSE: After clinical introduction of the Fitmore stem (Zimmer), we noticed the formation of cortical hypertrophies in a few cases. We questioned whether (1) the primary stability or (2) load transfer of the Fitmore stem differs from other stems unassociated with the formation of hypertrophies. We compared the Fitmore stem to the well-established CLS stem. METHODS: Four Fitmore and four CLS stems were implanted in eight synthetic femurs. A cyclic torque around the stem axis and a mediolateral cyclic torque were applied. Micromotions between stems and femurs were measured to classify the specific rotational implant stability and to analyse the bending behaviour of the stem. RESULTS: No statistical differences were found between the two stem designs with respect to their rotational stability (p = 0.82). For both stems, a proximal fixation was found. However, for the mediolateral bending behavior, we observed a significantly (p < 0.01) higher flexibility of the CLS stem compared to the Fitmore stem. CONCLUSION: Hip stem implantation may induce remodelling of the periprosthetic bone structure. Considering the proximal fixation of both stems, rotational stability of the Fitmore(r) stem might not be a plausible explanation for clinically observed formation of hypertrophies. However, bending results support our hypothesis that the CLS stem presumably closely follows the bending of the bone, whereas the shorter Fitmore stem acts more rigidly. Stem rigidity and flexibility needs to be considered, as they may influence the load transfer at the implant-bone interface and thus possibly affect bone remodelling processes. PMID- 24146176 TI - Radiographic quantification of dynamic hip screw migration. AB - PURPOSE: This study aimed to propose a technique to quantify dynamic hip screw (DHS(r)) migration on serial anteroposterior (AP) radiographs by accounting for femoral rotation and flexion. METHODS: Femoral rotation and flexion were estimated using radiographic projections of the DHS(r) plate thickness and length, respectively. The method accuracy was evaluated using a synthetic femur fixed with a DHS(r) and positioned at pre-defined rotation and flexion settings. Standardised measurements of DHS(r) migration were trigonometrically adjusted for femoral rotation and flexion, and compared with unadjusted estimates in 34 patients. RESULTS: The mean difference between the estimated and true femoral rotation and flexion values was 1.3 degrees (95% CI 0.9-1.7 degrees ) and -3.0 degrees (95% CI - 4.2 degrees to -1.9 degrees ), respectively. Adjusted measurements of DHS(r) migration were significantly larger than unadjusted measurements (p = 0.045). CONCLUSION: The presented method allows quantification of DHS(r) migration with adequate bias correction due to femoral rotation and flexion. PMID- 24146177 TI - Relations of maternal psychopathologies, social-obstetrical factors and mother infant bonding at 2-month postpartum: a sample of Turkish mothers. AB - BACKGROUND: The mental health of the mother influences early mother-infant relationship. This study aimed to explore the relations between maternal psychopathologies, particularly postpartum depression, social-obstetrical factors and mother-infant bonding. METHODS: One hundred and eighty-nine mother-infant pairs who participated in the longitudinal study entitled "Mother-Infant Care Study" were evaluated at the second month postpartum. The Brief Symptom Inventory (BSI) had been applied to all mothers in the first 3 days postpartum. At the second month postpartum, mothers were assessed with the Edinburgh Postpartum Depression Scale (EPDS), Postpartum Bonding Questionnaire (PBQ), and Mother Infant Bonding Scale (MIBS). RESULTS: The mean maternal age was 25.1 (+/- 5.2) years. The EPDS scores were higher in the mothers who had been supported lifelong by a psychologist due to psychological problems, had a birth interval of <= 2 years, and had smoking habits at the second month postpartum. Mothers with a female infant had higher PBQ score than those with a male infant. The EPDS score was correlated positively with the PBQ and MIBS scores. There were positive correlations between the EDS scores and all subscales of PBQ and MIBS scores. Some subscales and indexes of the BSI were correlated with the PBQ, MIBS and EPDS scores. CONCLUSION: Identifying postpartum depression and other psychopathologies in mothers is critical for prevention of mother-infant bonding impairment in the early postpartum period. PMID- 24146178 TI - Urinary tract infections in neonates with jaundice in their first two weeks of life. AB - BACKGROUND: Hyperbilirubinemia is a frequently seen condition in neonates. This study was undertaken to determine the role of urinary tract infections (UTIs) in the etiology of indirect hyperbilirubinemia in neonates with jaundice in their first two weeks of life. METHODS: The study was conducted prospectively. The subjects were neonates aged 4-14 days with hyperbilirubinemia which could not be detected by routine tests and was sufficiently severe to necessitate phototherapy. RESULTS: The study was performed in 104 neonates, of whom 18% (n=19) had UTI. The most frequently identified micro-organism was Escherichia coli (43%). Phototherapy duration and rebound bilirubin level were higher in neonates with UTI (P<0.05). CONCLUSION: UTI should be investigated in neonates with hyperbilirubinemia of unknown etiology in the first two weeks of life. PMID- 24146179 TI - Expression of Cx43-related microRNAs in patients with tetralogy of Fallot. AB - BACKGROUND: Abnormal expression of connexin 43 (Cx43) has been reported to play an important role in the development of conotrunccal anomalies. However, less is known about the underlying reason for its abnormal expression. MicroRNAs (miRNAs), as an important part of gene expression regulation, have been implicated in some cardiac diseases. This study aimed to investigate the expression of Cx43 and its related miRNAs in patients with tetralogy of Fallot (TOF), and illustrate the potential role of abnormal miRNAs regulation to Cx43 expression in the pathology of TOF. METHODS: Real-time polymerase chain reaction (PCR) was used to detect the expression of Cx43 and 10 Cx43-related miRNAs in the myocardium from 30 TOF patients and 10 normal controls. Immunohistochemistry was used to detect Cx43 protein expression. Putative miRNA binding sites in the 3'UTR of Cx43 were examined in 200 TOF patients and 200 healthy individuals, using Sanger sequencing, to exclude sequence variations resulting in binding difficulties of miRNAs. RESULTS: Cx43 mRNA and protein expression in the myocardium tissue was significantly increased in TOF patients. The expression of MiR-1 and 206 was significantly decreased in the TOF patients as compared with the controls (P<0.05). No obvious difference was observed in the expression of the other 7 miRNAs between the TOF patients and controls (P>0.05). No meaningful sequence variation was detected in the putative miR1/206 binding sites in the 3'UTR of Cx43. CONCLUSIONS: This study indicated that miR-1 and 206 is down regulated in TOF patients, which may cause an up-regulation of Cx43 protein's synthesis. It provided a clue that miR-1 and 206 might be involved in the pathogenesis of TOF, additional experiments are needed to determine if in fact, miR-1 and 206 contribute substantially to TOF. PMID- 24146180 TI - Influence of nose and mouth leaks on peripheral oxygen saturation during continuous positive airway pressure in neonates. AB - BACKGROUND: Nose and mouth leaks impair effective pressure transmission during neonatal continuous positive airway pressure (CPAP), but little is known about how these leaks affect physiological parameters. This study investigated the influence of nose leaks and spontaneous mouth opening on peripheral oxygen saturation (SpO2) and respiratory rate (RR) using nasopharyngeal CPAP. METHODS: In 32 neonates with a gestational age of 30 (24-38) weeks and a birth weight of 1435 (710-2730) g, SpO2 and RR measurements were taken with and without occlusion of the contralateral nostril in a randomized cross-over trial in 1-minute intervals over a 10-minute period during each condition. Mouth opening and newborn activity were documented. RESULTS: SpO2 with open nostril was comparable to that with occluded nostril [93 (78.5-99.5)% vs. 94 (80-100)%, P=0.20]. RR decreased from 51 (26-82)/min to 48 (32-85)/min (P=0.027). In infants with an SpO2 <= 93% during open nostril (n=17), SpO2 increased after nostril occlusion [91 (80-96)% vs. 89.5 (78.5-93)%, P=0.036]. The mouth was open in 78.5% of measurements with open nostril, and in 87.4% of measurements after nostril occlusion (P=0.005). No significant influence of mouth opening or closure on SpO2 or RR was detected. CONCLUSIONS: In neonates on unilateral nasopharyngeal CPAP with an SpO2 <= 93%, occlusion of the contralateral nostril significantly increased SpO2 and reduced RR. The beneficial physiological effects further support using binasal prongs to minimize nose leaks in this population. Future studies should investigate the beneficial effects of reducing mouth leaks when applying CPAP to these infants. PMID- 24146181 TI - Isolated persistent elevation of alanine transaminase for early diagnosis of pre symptomatic Wilson's disease in Chinese children. AB - BACKGROUND: Recent studies presented a contradictory approach for the investigation of pediatric patients with an isolated increase in alanine transaminase. While classical teaching advised for a thorough investigation, recent studies suggested the yield on further investigation was low and thus not necessary. Yet the approach to the same clinical problem may need to be different due to variable disease prevalence rates among different ethnic populations. For the population with a higher prevalence rate of genetic liver diseases like Wilson's disease, an abnormal liver function may be the first presenting feature for some patients. METHODS: We reviewed 10 Chinese children with Wilson's disease who were diagnosed at a presymptomatic stage because of an isolated persistent elevation of alanine transaminase. RESULTS: All 10 patients did not have overt symptoms of liver impairment or neurological deficit. They were picked up incidentally with an abnormal liver function test. All patients were started on treatment shortly after diagnosis, and they remained well and symptom-free on the latest follow-up. CONCLUSIONS: This case series illustrated that an isolated persistent elevation of alanine transaminase is an important clue to the early diagnosis of pre-symptomatic Wilson's disease. It is particularly relevant in the Asian population where the disease is more prevalent. PMID- 24146183 TI - "No growth" on serial MRI scans of a low grade glioma? PMID- 24146182 TI - Spinal to accessory nerve transfer in traumatic brachial plexus palsy: is body mass index a predictor of outcome? AB - INTRODUCTION: Several factors that affect functional recovery after surgery in severe brachial plexus lesions have been identified, i.e., time to surgery and presence of root avulsions. The body mass index (BMI) of the patient could be one of these possible factors. The objective of the present paper is to systematically study the relationship between BMI and the outcome of abduction following spinal accessory to suprascapular nerve transfer. METHODS: We retrospectively studied 18 cases that followed these inclusion criteria: (1) Male patients with a spinal accessory to suprascapular nerve transfer as the only procedure for shoulder function reanimation; (2) at least C5-C6 root avulsion; (3) interval between trauma and surgery less than 12 months; (4) follow-up was at least 2 years; (5) no concomitant injury of the shoulder girdle. Pearson correlation analysis and linear regression was performed for BMI versus shoulder abduction. RESULTS: The mean range of post-operative abduction obtained across the entire series was 49.7 degrees (SD +/- 30.2). Statistical evaluation revealed a significant, negative moderately strong correlation between BMI and post-operative range of shoulder abduction (r = -0.48, p = 0.04). Upon simple linear regression, time to surgery (p = 0.04) was the only statistically significant predictor of abduction range negatively correlated. CONCLUSIONS: Analysis of this series suggests that a high BMI of patients undergoing brachial plexus surgery is a negative predictor of outcome, albeit less important than others like time from trauma to surgery. Nevertheless, the BMI of patients should be taken into consideration when planning surgical strategies for reconstruction. PMID- 24146184 TI - Oxidative stress in diabetes - circulating advanced glycation end products, lipid oxidation and vascular disease. PMID- 24146185 TI - Quantification of clusterin in paired cerebrospinal fluid and plasma samples. AB - BACKGROUND: Clusterin (ApoJ) is an amyloid-associated protein and plays an important role in Alzheimer's disease (AD) pathology. Recent genome-wide association studies have indicated that certain genetic variants increase the risk of developing AD. To determine if the expression of clusterin is different in AD patients, both systemically and locally in the brain, differs between (subgroups of) AD patients and non-AD cases, an assay available that detects clusterin in both plasma and cerebrospinal fluid (CSF) with equal sensitivity would be helpful. METHODS: We compared four different commercially available antibodies in their ability to detect recombinant clusterin and immune-purified human clusterin. Specificity was tested on western blot and in ELISA systems, and selection was based on the ability to detect clusterin in CSF and plasma. A sandwich ELISA was developed and validated with monoclonal antibody G7 as capture, and rabbit polyclonal (Alexis) antibodies for detection. RESULTS: Our ELISA measured clusterin concentrations in plasma and CSF with dynamic ranges of 2-70 mg/L and 0.5-40 mg/L, respectively. The assays showed 99.8% recovery in CSF and 97% recovery in plasma. Intra-assay coefficient of variation was 1.4% and inter-assay 8.8%. The assay shows no cross-reactivity with related apolipoproteins. Clusterin quantification is dependent on the type of storage for plasma samples. A single freeze/thaw cycle caused fluctuations of clusterin concentrations in plasma, while clusterin in CSF is stable for up to five cycles. CONCLUSIONS: We have successfully developed a clusterin ELISA that reliably measures CSF and plasma clusterin concentrations. In a pilot study, all samples gave results that were well within the dynamic range of the assay, with low variations. Freshly stored plasma samples are crucial for accurate clusterin quantification. PMID- 24146186 TI - Syntaxin-4 is implicated in the secretion of antibodies by human plasma cells. AB - PCs are responsible for the production and secretion of antibodies, the effector molecules of the humoral immune response. The molecular mechanisms responsible for vesicle docking and secretion implicated in the antibody-secretion process are not well-known, as they have not been studied, but it is known that SNARE proteins are responsible for many membrane-fusion processes in the cell. We show here that freshly isolated human colon LP-PCs and T-PCs from MM-PC patients and the U266 cell line, as a model for PC secretion, contain a set of these proteins. SNAP23, STX3, and STX4 were localized mainly in the plasma membrane of PCs, and interactions of SNAP23 with STX3 and with STX4 were proven by IP. Interaction between SNAP23 and STX4 was also confirmed in situ. With the use of siRNA, as well as shRNA, the functional role of SNAP23, STX3, and STX4 in antibody secretion was also examined. The findings demonstrate that in addition to SNAP23, STX4 is implicated in the antibody secretion by a myeloma cell line and by normal human colon LP-PCs. PMID- 24146187 TI - Medical management of Cushing's disease. AB - Cushing's disease (CD), caused by excess adrenocorticotropin secretion from tumorous pituitary corticotrophs, is associated with substantial morbidity and mortality. The primary, definitive therapy for patients with CD is selective pituitary adenomectomy, generally performed via a transsphenoidal approach. Medical therapy has an important adjunctive role in the management of patients with CD, including preoperative patient preparation in patients with severe disease, and temporizing management of hypercortisolism while awaiting the effects of radiation therapy to occur in patients who are not in remission postoperatively. Medical therapy can also be used in patients with hypercortisolism of unclear origin or in the few patients who decline or are unfit for surgery. Available medical options for patients with CD include centrally acting agents (cabergoline and pasireotide), steroidogenesis inhibitors (ketoconazole, metyrapone, mitotane and etomidate) and a glucocorticoid receptor antagonist (mifepristone). Pasireotide and mifepristone have been recently granted regulatory approval in some countries for use in patients with CD, whereas other medications are used "off label" in this patient population. As clinical trials using comparator agents have not been reported, the choice between different medications is based on patient characteristics and preference. Despite impressive advances in pharmacotherapy for patients with CD, much remains to be done. The long term efficacy and safety of medical therapies for hypercortisolism need to be evaluated and the role of combination therapy must be further characterized. As the pathogenesis of CD becomes better understood at the molecular level, it is likely that novel, targeted medical therapies will be developed to treat CD. PMID- 24146188 TI - Management of medically refractory prolactinoma. AB - Resistance to dopamine agonists is defined here as failure to normalize prolactin levels and failure to decrease macroprolactinoma size by >=50 %. Failure to normalize prolactin levels is found in about 25 % of patients treated with bromocriptine and 10-15 % of those treated with cabergoline. Failure to achieve at least a 50 % reduction in tumor size occurs in about one-third of those treated with bromocriptine and 10-15 % of those treated with cabergoline. Treatment approaches for patients resistant to dopamine agonists include changing to another dopamine agonist and increasing the dose of the drug as long as there is continued response to the dose increases and no adverse effects with higher doses. Transsphenoidal surgery is also an option. Clomiphene, gonadotropins, and GnRH can be used if fertility is desired. For those not desiring fertility, estrogen replacement may be used unless there is a macroadenoma, in which case control of tumor growth is also an issue and dopamine agonists are generally necessary. In many patients modest or even no reduction in tumor size may be acceptable as long as there is not tumor growth. Hormone replacement [estrogen or testosterone] may cause a decrease in efficacy of the dopamine agonist. Reduction of endogenous estrogen, use of selective estrogen receptor modulators, and aromatase inhibitors are potential experimental approaches. Temozolomide may be useful as a last resort for aggressive, invasive tumors refractory to other medical and ablative therapies. PMID- 24146189 TI - Rathke's cleft cysts: review of natural history and surgical outcomes. AB - Rathke's cleft cysts (RCCs), also known as pars intermedia cysts, represent benign lesions formed from remnants of the embryologic Rathke's pouch. Commonly asymptomatic, they are identified in nearly 1 in 6 healthy volunteers undergoing brain imaging. When symptomatic, they can cause headaches, endocrine dysfunction, and, rarely, visual disturbances. A systematic review of the published English literature was performed focusing on large modern case series of RCCs to describe their natural history, clinicopathologic features, radiographic features, and surgical outcomes, including rates of recurrence. The natural history of asymptomatic RCCs is one of slow growth, suggesting that observation through serial magnetic resonance imaging is appropriate for smaller asymptomatic RCCs. Symptomatic RCCs can be treated by surgical resection with low morbidity, usually through an endonasal transsphenoidal corridor using either a microscope or an endoscope. Surgical treatment frequently provides symptomatic relief of headaches and visual disturbances, and sometimes even improves endocrine dysfunction. Rates of recurrence after surgical treatment range from 16 to 18 % in large series, and higher rates of recurrence are associated with suprasellar location, inflammation and reactive squamous metaplasia in the cyst wall, superinfection of the cyst, and use of a fat graft into the cyst cavity. PMID- 24146190 TI - The relationship between defibrillation threshold and total mortality. AB - BACKGROUND: The relationship between the defibrillation threshold (DFT) and total mortality is unclear. METHODS: A university hospital prospectively maintained implantable defibrillator (ICD) database identified 508 patients who underwent ICD implantation and had DFT testing performed at implant. Patients were placed in one of three groups based on the implant DFT (high (>=20 J), moderate (19-11 J), or low DFT (<=10 J)). RESULTS: Sixty-seven patients had a high DFT, 216 had a moderate DFT, and 225 had a low DFT. The mean left ventricular ejection fraction (LVEF) was 0.25, 0.28, and 0.30 in the high, moderate, and low DFT groups, respectively, (p = 0.04). There were significantly more patients with a subcutaneous electrode in the high DFT group (p < 0.001), more patients taking amiodarone (p < 0.001), and more patients on oral anticoagulation (p = 0.04). There were a total of 140 deaths during the follow-up period (mean 3.2 +/- 1.7 years). There were 24 deaths in the high DFT group (35.8%), 62 in the moderate DFT group (28.7%), and 54 in the low DFT group (24.0%) (p = 0.05). Implant DFT was a significant predictor of mortality (p = 0.01), as was age, LVEF (p < 0.001), CAD (p = 0.01), amiodarone use (p = 0.02), and hematoma at implant (p = 0.01). An elevated DFT was an independent predictor of mortality after controlling for all significant univariate variables (p = 0.004). CONCLUSIONS: A high-implant DFT predicts an adverse prognosis, even when an adequate ICD safety margin is present. PMID- 24146191 TI - The uniqueness of social attention revisited: working memory load interferes with endogenous but not social orienting. AB - It is well known that perceived eye gaze direction influences attentional orienting. However, it still remains unclear whether social orienting involves exogenous or endogenous attentional control. To address this issue, we examined if social orienting and endogenous orienting were differentially modulated by working memory load, which is known to interfere with endogenous but not exogenous attention. To do so, we manipulated eye direction as either spatially counterpredictive in Experiment 1 or spatially predictive in Experiment 2 while participants performed a cueing task either in isolation or under working memory load. We found that when social attention and endogenous attention diverged spatially in Experiment 1, social orienting elicited by gaze direction remained intact while endogenous orienting elicited by the cue's predictive meaning was suppressed under working memory load, suggesting independence between social orienting and endogenous orienting. Indeed, a comparison between the sum of isolated social orienting and endogenous orienting magnitudes from Experiment 1 relative to their combined measure from Experiment 2 confirmed that social attention and endogenous attention operated in parallel. Together, our data show that social orienting is independent from endogenous orienting and further suggest that paying attention to social information might involve either exogenous or unique attentional mechanisms. PMID- 24146192 TI - Line and word bisection in right-brain-damaged patients with left spatial neglect. AB - Right-brain-damaged patients with left unilateral spatial neglect typically set the mid-point of horizontal lines to the right of the objective center. By contrast, healthy participants exhibit a reversed bias (pseudoneglect). The same effect has been described also when bisecting orthographic strings. In particular, for this latter kind of stimulus, some recent studies have shown that visuo-perceptual characteristics, like stimulus length, may contribute to both the magnitude and the direction bias of the bisection performance (Arduino et al. in Neuropsychologia 48:2140-2146, 2010). Furthermore, word stress was shown to modulate reading performances in both healthy participants, and patients with left spatial neglect and neglect dyslexia (Cubelli and Beschin in Brain Lang 95:319-326, 2005; Rusconi et al. in Neuropsychology 18:135-140, 2004). In Experiment I, 22 right-brain-damaged patients (11 with left visuo-spatial neglect) and 11 matched neurologically unimpaired control participants were asked to set the subjective mid-point of word letter strings, and of lines of comparable length. Most patients exhibited an overall disproportionate rightward bias, sensitive to stimulus length, and similar for words and lines. Importantly, in individual patients, biases differed according to stimulus type (words vs. lines), indicating that at least partly different mechanisms may be involved. In Experiment II, the putative effects on the bisection bias of ortho-phonological information (i.e., word stress endings), arising from the non-neglected right hand side of the stimulus were investigated. The orthographic cue induced a rightward shift of the perceived mid-point in both patients and controls, with short words stressed on the antepenultimate final sequence inducing a smaller rightward deviation with respect to short words stressed on the penultimate final sequence. In conclusion, partly different mechanisms, including both visuo spatial and lexical factors, may support line and word bisection performance of right-brain-damaged patients with left spatial neglect, and healthy participants. PMID- 24146193 TI - Specific expression of k63-linked ubiquitination of calmodulin-like protein 5 in breast cancer of premenopausal patients. AB - PURPOSE: Posttranslational modifications such as ubiquitination regulate many functions of proteins by affecting their interaction with other molecules, their activity, and their subcellular localization. In cancer biology, the ubiquitin network has gained major interest. K63-linked ubiquitination has emerged as a posttranslational modification with functional consequences, as it acts in several processes such as protein trafficking, DNA repair, and inflammation. Moreover, k63-linked ubiquitination is involved in the regulation of carcinogenesis. Based on previous findings, the aim of this study was to evaluate the ubiquitination of CALML5 in breast cancer patients. PATIENTS AND METHODS: The breast cancer cell lines SkBr3, MCF7, HCC1937, and BT474 as well as 23 tumor samples of patients with primary breast cancer and the normal adjacent breast tissue were analyzed by one-dimensional immunoblot. RESULTS: Using specific antibodies against CALML5 and k63-linked ubiquitin, we demonstrate a k63-linked ubiquitination in the nuclear fraction of premenopausal breast cancer patients. K63-linked ubiquitination of CALML5 was found in breast cancer tissue, but not found in surrounding healthy tissue. CONCLUSION: Our findings support the concept that ubiquitination of CALML5 in the nucleus is involved in the carcinogenesis of breast cancer in premenopausal women. PMID- 24146194 TI - The determination of bile leakage in complex hepatectomy based on the guidelines of the International Study Group of Liver Surgery. AB - BACKGROUND: The International Study Group of Liver Surgery (ISGLS) has defined bile leakage as a drain fluid-to-serum total bilirubin concentration (TBC) ratio (the bilirubin ratio) >= 3.0. The aim of the present study was to determine the clinical significance of this definition, and to outline characteristics of bile leakage in complex hepatectomy. METHODS: The TBCs of the serum and drain fluid were measured on postoperative days (POD) 1, 3, and 7 in 241 patients who had undergone hepatobiliary resection. The validation of the bilirubin ratio and predictors of bile leakage were retrospectively assessed. RESULTS: Grade A, B, or C bile leakage was found in 23 (9.5 %), 66 (27.4 %), and 0 patients, respectively. The median duration of drainage was 27 days in grade B bile leakage. The sensitivity and specificity of the bilirubin ratio for detecting grade B bile leakage were 59 and 87 %, respectively. The area under the receiver operating characteristics curve of the drain fluid TBC on POD 3 had the highest predictive value: 68 % sensitivity and 76 % specificity for a drain fluid TBC of 3.7 mg/dL. The multivariate analysis demonstrated that operative time, left trisectionectomy, bilirubin ratio, and TBC of the drain fluid on POD 3 were independent predictors of grade B bile leakage. CONCLUSIONS: In complex hepatectomy, bile leakage develops most frequently after left trisectionectomy and often results in a refractory clinical course. The ISGLS biochemical definition is valid, and a combination of bilirubin ratio and drain fluid TBC may enhance risk prediction for grade B bile leakage. PMID- 24146195 TI - Prospective randomized controlled trial on the use of flexible reinforced laryngeal mask airway (LMA) during total thyroidectomy: effects on postoperative laryngopharyngeal symptoms. AB - BACKGROUND: Sore throat, hoarseness, dysphagia, and cough are common laryngopharyngeal discomforts after thyroidectomy. The incidence and severity of laryngopharyngeal symptoms after the use of a flexible reinforced laryngeal mask airway (LMA) were compared with those that occur after the use of a plain endotracheal tube in patients after thyroidectomy. METHODS: Seventy-six patients scheduled for total thyroidectomy were randomized into a plain endotracheal tube group (group E) or a flexible reinforced LMA group (group L). Total intravenous anesthesia (propofol and remifentanil) was used for maintenance of anesthesia. Hemodynamic variables were recorded during induction of anesthesia. The incidence and severity (100-point numerical rating scales) of laryngopharyngeal symptoms, including sore throat, hoarseness, dysphagia, and cough, were assessed at 1, 24, and 48 h after surgery. RESULTS: All patients were placed successfully with an endotracheal tube or a flexible reinforced LMA. The postoperative incidence and severity of sore throat (25 vs. 33 at 24 h, p = 0.035, 17 vs. 28 at 48 h, p = 0.017; 50 [0-100] vs. 80 [20-100] at 1 h, p = 0.002; 30 [0-80] vs. 50 [0-100] at 24 h, p < 0.001; 0 [0-40] vs. 30 [0-90] at 48 h, p < 0.001) and hoarseness were lower in group L than in group E. At 48 h postoperatively, dysphagia (p = 0.005) and cough (p = 0.028) occurred less frequently in group L than in group E patients. CONCLUSION: A flexible reinforced LMA placed during surgery decreases the incidence and severity of laryngopharyngeal symptoms and is a feasible anesthetic tool compared with a conventional endotracheal tube for thyroidectomy. PMID- 24146196 TI - Metastatic adenocarcinomas of the stomach or esophagogastric junction (UICC stage IV) are not always a palliative situation: a retrospective analysis. AB - BACKGROUND: Gastric cancer is one of the most common cancers. Unfortunately, it is often diagnosed at the advanced stage International Union Against Cancer stage IV. This induced us to carry out an interdisciplinary analysis of this patient group with the Department of Internal Medicine 1. Our aim was to discuss cancers classified initially as unresectable in a meeting of the interdisciplinary tumor board after palliative chemotherapy, and to refer selected patients for surgery after establishing resectability. The outcome of the chemotherapy, operation method, complication rate, and long-term survival were analyzed. METHODS: From 1999 to 2008, 76 patients with metastatic gastric cancer or carcinoma of the esophagogastric junction were discussed by the interdisciplinary tumor board of the University of Erlangen and classified initially as unresectable. The patients then received palliative chemotherapy according to the AIO regimen (weekly high dose 5-fluorouracil/folinic acid [FU/FA] in a 24 h infusion), plus irinotecan. If the tumor was subsequently classified as resectable, the patient underwent either gastric resection or gastrectomy with DII-III dissection. Metastases were resected depending on their location (liver). Peritoneal carcinomatosis was treated additionally by HIPEC. Statistical analysis was with SPSSS version 20. RESULTS: Surgical and general complications and hospital mortality were acceptable. There were no cases of anastomotic leak, but one patient died of fulminant pneumonia. The R0 resection rate was 69 %, and four patients had long term survival of more than 60 months. There were significant survival advantages. CONCLUSIONS: Metastatic gastric cancer or carcinoma of the esophagogastric junction can become resectable after downsizing the tumor with palliative chemotherapy. Long-term survival is achieved in some cases. Therefore, every patient with this type of cancer should be discussed by the interdisciplinary tumour board after palliative chemotherapy to provide him with a chance of cure after re-evaluation. PMID- 24146197 TI - The ALPPS procedure: a surgical option for hepatocellular carcinoma with major vascular invasion. AB - BACKGROUND: Hepatocellular carcinoma (HCC) tends to have a particular invasiveness toward the portal vein (PV) branches and hepatic veins. This situation can hamper major surgical resection with a risk of postoperative liver failure due to the small future liver remnant (FLR) in cirrhotic livers. These patients are then usually directed to palliative treatments with poor results. The associating liver partition and PV ligation (PVL) in staged hepatectomy (ALPPS) strategy is one of the main surgical innovations in recent years in the field of liver surgical oncology. The ALPPS approach could allow surgical resection in patients with HCC and associated major vascular invasion. METHODS: Among 1,143 liver resection performed in our center, the ALPPS approach was employed in order to induce rapid hypertrophy of the left FLR in patients with HCC and associated major vascular invasion. This strategy consists of combining the in situ splitting of the liver along the main portal scissura or on the right side of the falciform ligament and PVL in a strategy of staged hepatectomy. RESULTS: In our experience the ALPPS approach allowed us to achieve a sufficient FLR in two cases of HCC with major vascular invasion, in which the classic two stage strategy could not be applied. In both cases the patients could undergo major hepatectomies without mortality. CONCLUSIONS: This novel strategy could expand the number of patients undergoing major liver resections that were previously considered non-resectable because of the risk of liver decompensation for an insufficient FLR. PMID- 24146198 TI - An objective evaluation of a multi-component, competitive, selection process for admitting surgeons into higher surgical training in a national setting. AB - BACKGROUND: Changing work practices make it imperative that surgery selects candidates for training who demonstrate the spectrum of abilities that best facilitate learning and development of attributes that, by the end of their training, approximate the characteristics of a consultant surgeon. AIMS: The aim of our study was to determine the relative merits of components of a program used for competitive selection of trainees into higher surgical training (HST) in general surgery. METHODS: Applicants (N = 98, males 69, mean age 31 years [range 29-40]) to the Royal College of Surgeons in Ireland program for HST in general surgery between 2006 and 2008 were assessed. Clinical, basic surgical training, logbook, research performance, and reference scores were evaluated. A total of 51 candidates were shortlisted and completed a further objective assessment of their technical skills and interview performances. RESULTS: Shortlisted candidates performed better (p < 0.003) on all assessed parameters. Compared with candidates who were not selected for HST, those who were selected (N = 31) significantly outperformed on individual assessments and overall (p < 0.0001). Logistic regression analysis showed that clinical, technical skills, and research assessments, but not interview, predicted (92.2 %) HST selection outcomes. CONCLUSIONS: Candidates selected for the national HST program in Ireland consistently outperformed those who were not. The assessments reliably and consistently distinguished between candidates, and all of the assessed parameters (except interview) contributed to a highly predictive selection model. This is the largest reported dataset from an objective, transparent, and fair assessment program for selection of the next generation of surgeons. PMID- 24146199 TI - Engineered Salmonella typhimurium expressing E7 fusion protein, derived from human papillomavirus, inhibits tumor growth in cervical tumor-bearing mice. AB - The tumor-suppressing effects of SipB160/HPV16 E7 fusion protein, derived from human papillomavirus, and expressed in Salmonella enterica serovar typhimurium, were evaluated in a cervical cancer model. The expressed E7 protein resulted in efficacious cytotoxicity and tumor growth retardation in TC-1 cervical cancer cells. In addition, in mice bearing TC-1 tumors, live cells of Salmonella expressing HPV16 E7 were administered orally and induced immune responses through interferon-gamma and tumor necrosis factor-alpha cytokine secretion and also suppressed tumor growth (45 %) and prolonged survival (70 %) compared with the control group. These results suggested that the SipB160/HPV16 E7 fusion protein may be a candidate cancer therapeutic agent. PMID- 24146200 TI - Permanent first molar extraction in adolescents and young adults and its effect on the development of third molar. AB - OBJECTIVES: The aim of the present study was to determine the prevalence of permanent first molar (P1M) extraction among Turkish adolescents and young adult subpopulation, and to investigate the effects of P1M extraction on development of the third molars (3Ms) in the same quadrant. MATERIALS AND METHODS: A retrospective study including 2,925 panoramic radiographs (PRs) taken from patients (aged 13-20 years) who were examined to identify cases of had at least one maxillary or mandibular P1Ms extracted was performed. Additionally, 294 PRs with the maxillary or mandibular unilateral loss of a P1M were used to assess the developmental grades of the 3Ms. Statistical analyses were performed by means of parametric tests after performing a Shapiro-Wilks normality test to the data. RESULT: A total of 945 patients (32.3 %) presented with at least one P1M extraction with no gender difference (P = 0.297). There were more cases of mandibular P1Ms extracted (784 patients, 1,066 teeth) than maxillary P1Ms extracted (441 patients, 549 teeth) (P < 0.001). The development of the 3Ms on the extraction side, in the both maxilla and mandible, was significantly accelerated when compared with the contralateral teeth (P = 0.000, P = 0.000, respectively). No statistically significant differences were found in the differences in the developmental of the 3Ms between the maxilla and mandible (P = 0.718). CONCLUSIONS: High prevalence of P1Ms extraction among Turkish adolescents and young adults shows a need for targeted dental actions, including prevention and treatment. The development of the 3Ms on the extraction side, in the both maxilla and mandible, was significantly accelerated. CLINICAL RELEVANCE: To date, no information about prevalence of P1Ms extraction among Turkish adolescents and young adults is documented. In addition, the present study has a larger population and complementary information about 3Ms development than previous studies. PMID- 24146201 TI - Time-course changes in immunoreactivities of glucokinase and glucokinase regulatory protein in the gerbil hippocampus following transient cerebral ischemia. AB - Glucose is a main energy source for normal brain functions. Glucokinase (GK) plays an important role in glucose metabolism as a glucose sensor, and GK activity is modulated by glucokinase regulatory protein (GKRP). In this study, we examined the changes of GK and GKRP immunoreactivities in the gerbil hippocampus after 5 min of transient global cerebral ischemia. In the sham-operated-group, GK and GKRP immunoreactivities were easily detected in the pyramidal neurons of the stratum pyramidale of the hippocampus. GK and GKRP immunoreactivities in the pyramidal neurons were distinctively decreased in the hippocampal CA1 region (CA), not CA2/3, 3 days after ischemia-reperfusion (I-R). Five days after I-R, GK and GKRP immunoreactivities were hardly detected in the CA1, not CA2/3, pyramidal neurons; however, at this point in time, GK and GKRP immunoreactivities were newly expressed in astrocytes, not microglia, in the ischemic CA1. In brief, GK and GKRP immunoreactivities are changed in pyramidal neurons and newly expressed in astrocytes in the ischemic CA1 after transient cerebral ischemia. These indicate that changes of GK and GKRP expression may be related to the ischemia induced neuronal damage/death. PMID- 24146202 TI - Preclinical models for drug selection in myeloproliferative neoplasms. AB - The discovery that an abnormally activated JAK-STAT signaling pathway is central to the pathogenesis of myeloproliferative neoplasms has promoted the clinical development of small-molecule JAK2 inhibitors. These agents have shown remarkable efficacy in disease control, but do not induce molecular remission; on the other hand, interferon holds the promise to target the putative hematopoietic progenitor cell initiating the disease. The presence of additional molecular abnormalities indicates a high molecular complexity of myeloproliferative neoplasms, and the need for simultaneously targeting different targets. Several drugs are currently under study as single agents and in combination. This review briefly describes the several in vitro and in vivo models of myeloproliferative neoplasms that are being used as preclinical models for drug development. PMID- 24146203 TI - Allogeneic hematopoietic stem cell transplantation for multiple myeloma: what place, if any? AB - Despite the curative potential of allogeneic hematopoietic stem cell transplantation (allo HSCT) for patients with multiple myeloma (MM) and reduction of transplant-related mortality with non-myeloablative transplant approaches, the role of this treatment modality in the care of MM patients remains controversial. This controversy is due to the conflicting data emerging from the large cooperative group trials as well as the improvement in outcomes that has been seen with proteosome inhibitors, new immune modulatory drugs as well as the use of post-transplant maintenance therapy. For an individual patient, the risk benefit ratio of allografting remains uncertain. We review the current data and provide recommendations on where and how allo HSCT for myeloma should be further explored. PMID- 24146205 TI - Use of preoperative antidepressants is not associated with postoperative hospital length of stay. AB - PURPOSE: Antidepressant medications are commonly prescribed for the treatment of depression, anxiety, and chronic pain. Their use may lead to a number of side effects with important implications in the perioperative period. Our aim was to examine the effect of preoperative antidepressant administration on post-surgical hospital length of stay (LOS) in elective non-cardiac surgery patients. DESIGN: Historical cohort study. METHODS: Demographic and preoperative data were collected by chart review for all non-cardiac surgery patients who were assessed in the preoperative consult clinic from April 2008 through February 2009. Patients were grouped according to whether or not they were taking antidepressant medications. Median length of stay was compared between patients who took antidepressants preoperatively and those who did not. RESULTS: Data were collected for 3,692 patients. Two hundred eighty-nine (7.8%) patients were taking antidepressants preoperatively. Use of antidepressants was not associated with an increased hospital LOS. The median LOS was four days both for patients who took antidepressants preoperatively (95% confidence interval [CI] 4 to 4) and for those who did not (95% CI 3 to 5) (P = 0.13). CONCLUSIONS: The preoperative use of antidepressant medications was not associated with increased postoperative hospital LOS following elective non-cardiac surgery. PMID- 24146204 TI - WHO classification of myeloproliferative neoplasms (MPN): A critical update. AB - Although the revised World Health Organization (WHO) criteria for the diagnosis and classification of myeloproliferative neoplasms (MPN) were defined by a panel of expert hematopathologists and clinicians, controversy has been repeatedly expressed questioning the clinical usefulness and reproducibility of these diagnostic guidelines. In particular, the distinction between essential thrombocythemia (ET), early/prefibrotic primary myelofibrosis (PMF) and initial stages of polycythemia vera (PV) is still a matter of debate. In this context, it has been argued that clinical correlations with histological features were not firmly substantiated. On the other hand, recently published data from independently performed studies have repeatedly validated the reproducibility of the WHO criteria and provided persuasive evidence that discrimination of early/prefibrotic PMF has a significant impact on the risk of myelofibrotic and leukemic transformation. However, as has been explicitly required, the WHO concept is based on the recognition of characteristic bone marrow patterns and a consensus of clinical and molecular data. PMID- 24146206 TI - Perdeuteration and methyl-selective (1)H, (13)C-labeling by using a Kluyveromyces lactis expression system. AB - The production of stable isotope-labeled proteins is critical in structural analyses of large molecular weight proteins using NMR. Although prokaryotic expression systems using Escherichia coli have been widely used for this purpose, yeast strains have also been useful for the expression of functional eukaryotic proteins. Recently, we reported a cost-effective stable isotope-labeled protein expression using the hemiascomycete yeast Kluyveromyces lactis (K. lactis), which allow us to express exogenous proteins at costs comparable to prokaryotic expression systems. Here, we report the successful production of highly deuterated (>90 %) protein in the K. lactis system. We also examined the methyl selective (1)H, (13)C-labeling of Ile, Leu, and Val residues using commonly used amino acid precursors. The efficiency of (1)H-(13)C-incorporation varied significantly based on the amino acid. Although a high level of (1)H-(13)C incorporation was observed for the Ile delta1 position, (1)H, (13)C-labeling rates of Val and Leu methyl groups were limited due to the mitochondrial localization of enzymes involved in amino acid biosynthesis and the lack of transporters for alpha-ketoisovalerate in the mitochondrial membrane. In line with this notion, the co-expression with branched-chain-amino-acid aminotransferase in the cytosol significantly improved the incorporation rates of amino acid precursors. Although it would be less cost-effective, addition of (13)C-labeled valine can circumvent problems associated with precursors and achieve high level (1)H, (13)C-labeling of Val and Leu. Taken together, the K. lactis system would be a good alternative for expressing large eukaryotic proteins that need deuteration and/or the methyl-selective (1)H, (13)C-labeling for the sensitive detection of NMR resonances. PMID- 24146207 TI - Assessment of in vivo antimalarial activities of some selected medicinal plants from Turkey. AB - Resistant infections lead to increased necessity of searching novel drugs and drug combinations. The purpose of this paper was to investigate antimalarial properties of some selected medicinal plants that have been traditionally used in Turkey for antipyretic and analgesic purposes. Lavandula stoecheas subsp. cariensis, Phlomis nissolii, Phlomis bourgaei, Phlomis leucophracta, Centaurea hierapolitana, Centaurea polyclada, Centaurea lydia, Scrophularia cryptophila, Scrophularia depauperata, Scrophularia floribunda, Rubia davisiana, and Alkanna tinctoria subsp. subleiocarpa were investigated for their in vivo antimalarial activities in mice infected with Plasmodium yoelii. Two hundred fifty to 500 mg/kg doses of plant extracts were given to mice as a single daily dose for 4 days. P. nissolii water extract, C. lydia chloroform extract, S. cryptophila ethanol extract, and C. polyclada methanol extract showed antimalarial activity with reducing parasitaemia. The chemotherapeutic effects of plant extracts ranged between 13.5% and 66.91%. The chemosuppressions exerted by combined plant extracts of P. nissolii, S. cryptophila, and C. lydia with C. polyclada methanol extract were detected as 51.25%, 57.33%, and 58.33%, respectively. Investigation of cytotoxic activities against brine shrimps revealed that methanol extract of C. polycada, chloroform extract of C. lydia, and ethanol extract of S. cryptophila showed cytotoxic activities, while water extract of P. nissolii was not active against brine shrimps. PMID- 24146208 TI - Is there a reduced sensitivity of dihydroartemisinin against praziquantel resistant Schistosoma japonicum? AB - Praziquantel is currently the only drug of choice for the treatment of human schistosomiases. However, it has been proved that Schistosoma japonicum subjected to drug pressure may develop resistance to praziquantel. To evaluate the efficacy of dihydroartemisinin against praziquantel-resistant S. japonicum, mice infected with a praziquantel-resistant isolate and a praziquantel-susceptible isolate of S. japonicum were treated with dihydroartemisinin at a single oral dose of 300 mg/kg given once on each of 35-36 post-infection days, while infected but untreated mice served as controls. All mice were sacrificed 50 days post infection, and the worm burden reductions were estimated. Administration of dihydroartemisinin at a single oral dose of 300 mg/kg on each of 35-36 post infection days reduced total worm burdens of 69.8% and female worm burdens of 86% in mice infected with the praziquantel-susceptible isolate, and total worm burdens of 66.1% and female worm burdens of 85.1% in mice infected with the praziquantel-resistant isolate (both P values > 0.05). It is concluded that the sensitivity of artemisinin derivative dihydroartemisinin does not reduce in praziquantel-resistant S. japonicum. PMID- 24146209 TI - Dihydroartemisinin: a new story of an old drug against Schistosoma mansoni infection. AB - Currently, praziquantel is the drug of choice for the treatment of human Schistosoma mansoni infections. It has not been proved until now that there is real praziquantel resistance, but there is decreased praziquantel sensitivity. A search for novel antischistosomal agents against the parasite has been given a high priority. Dihydroartemisinin, formerly identified as an antimalarial drug, has been shown to be active against both Schistosoma japonicum and S. mansoni in mice. Interestingly, dihydroartemisinin is found to be highly effective against the 14-28-day schistosomula of S. mansoni, and treatment with multiple low doses of the drug achieves a high efficacy with reduced toxicity to the host. The long time development from juveniles to adults allows adequate timing for treatment of this neglected tropical disease. It is supposed that dihydroartemisinin, a safe orally administered agent, may be used for the prevention and control of human S. mansoni infections, notably in areas with reduced praziquantel sensitivity or praziquantel resistance detected. PMID- 24146210 TI - Mosquitocidal essential oils: are they safe against non-target aquatic organisms? AB - In latest years, the importance of the Melaleuca alternifolia essential oil (EO) has been greatly empathised due to its anti-microbial and anti-inflammatory effects, as well as to its toxic properties towards many arthropods of great medical and veterinary importance. In this research, the EO extracted from aerial parts of M. alternifolia was evaluated for its toxicity against larvae of the most invasive mosquito worldwide, Aedes albopictus (Diptera: Culicidae), and towards adults of the water flea, Daphnia magna (Cladocera: Crustacea), a non target aquatic organism that share the same ecological niche of A. albopictus. The chemical composition of M. alternifolia EO was investigated by GC-MS analysis. Tea tree EO was mainly composed by oxygenated monoterpenes, with 1,8 cineole as the major constituent. M. alternifolia EO exerted toxic activity against A. albopictus larvae, with a LC50 = 267.130 ppm. However, this EO had a remarkable acute toxicity also towards adults of the non-target arthropod D. magna, with a LC50 = 80.636 ppm. This research provide useful information for the development of newer and safer mosquito control tools, highlighting that the non target effects against aquatic organisms that share the same ecological niche of A. albopictus larvae are crucial in the development of ecofriendly mosquito control strategies. Further research is needed to investigate the chronic and/or reproductive toxicity of M. alternifolia EO both towards target and non-target aquatic arthropods. PMID- 24146211 TI - Tomatoes, lysophosphatidic acid, and the small intestine: new pieces in the puzzle of apolipoprotein mimetic peptides? PMID- 24146212 TI - Reevaluation of the proposed autocrine proliferative function of prolactin in breast cancer. AB - The pituitary hormone prolactin (PRL) has been implicated in tumourigenesis. Expression of PRL and its receptor (PRLR) was reported in human breast epithelium and breast cancer cells. It was suggested that PRL may act as an autocrine/paracrine growth factor. Here, we addressed the role of locally synthesised PRL in breast cancer. We analysed the expression of PRL in human breast cancer tumours using qPCR analysis and in situ hybridization (ISH). PRL mRNA expression was very low or undetectable in the majority of samples in three cDNA arrays representing samples from 144 breast cancer patients and in 13 of 14 breast cancer cell lines when analysed by qPCR. In accordance, PRL expression did not reach detectable levels in any of the 19 human breast carcinomas or 5 cell lines, which were analysed using a validated ISH protocol. Two T47D-derived breast cancer cell lines were stably transfected with PRL-expressing constructs. Conditioned medium from the T47D/PRL clones promoted proliferation of lactogen dependent Nb2 cells and control T47D cells. Surprisingly, the PRL-producing clones themselves displayed a lower proliferation rate as compared to the control cells. Their PRLR protein level was reduced and the cells were no longer responsive to exogenous recombinant PRL. Taken together, these data strongly indicate that autocrine PRL signalling is unlikely to be a general mechanism promoting tumour growth in breast cancer patients. PMID- 24146213 TI - A sugar-based phase-transitioning delivery system for bone tissue engineering. AB - Bone tissue engineering approaches commonly involve the delivery of recombinant human bone morphogenetic proteins (rhBMPs). However, there are limitations associated with the currently used carriers, including the need for surgical implantation and the associated increase in infection risk. As an alternative to traditional porous collagen sponge, we have adopted a solution of the injectable sucrose acetate isobutyrate (SAIB) as a carrier for rhBMP-2. The ability to deliver rhBMP-2 and other agents by injection reduces the infection risk and lesion size whilst in surgery, with the potential to avoid open surgery altogether in some indications. The primary methodology used for this in vivo study was a C57BL6/J mouse ectopic bone formation model. Specimens were examined by x-ray, microCT, and histology at 3 weeks. SAIB was delivered non-invasively and produced up to 3-fold greater bone volume compared to collagen. To further refine and improve upon the formulation, SAIB containing rhBMP-2 was admixed with candidate compounds including ceramic microparticles, anti-resorptives, and cell signalling inhibitors and further tested in vivo. The formulation combining SAIB/rhBMP-2, the bisphosphonate zoledronic acid (ZA), and hydroxyapatite (HA) microparticles yielded a 10-fold greater bone volume than SAIB/rhBMP-2 alone. To investigate the mechanism underlying the synergy between ZA and HA, we used in vitro binding assays and in vivo fluorescent biodistribution studies to demonstrate that ceramic particles could bind and sequester the bisphosphonate. These data show the utility of SAIB as a non-invasive rhBMP delivery system as well as describing an optimised formulation for bone tissue engineering. PMID- 24146214 TI - Lung cysts as indicator for Birt-Hogg-Dube syndrome. AB - In this case, we describe a patient with a history of recurrent pneumothorax. Based on CT-thorax and histopathology of the lung tissue, the Birt-Hogg-Dube syndrome was suspected and confirmed after genetic testing. Recognizing this syndrome by pulmonologists and radiologists is very important, because the risk on developing of renal cell cancer is high. PMID- 24146215 TI - Anatomical variations of the sphenoid sinus and its adjacent structures: a review of existing literature. AB - The sphenoid sinus, one of the posterior groups of sinuses, has long been regarded as a 'neglected sinus' due to the anatomical location, poor understanding and poor accessibility, till the advent of endoscopes and modern imaging techniques. Increasing knowledge and greater understanding of this sinus has permitted an evolution in surgical practices and boundaries. Various literatures of the past report a great variety of rates of pneumatization, rates of optic nerve protrusion and dehiscence, as well as internal carotid artery (ICA) protrusion and dehiscence. One similarity noted among these studies is that the rates vary according to the ethnicity of the patients. Recommendations have also been made along the way with regard to modified surgical techniques. This review aims to describe the pneumatization of sphenoid sinus and the topographical relation of the optic nerve and ICA in different populations. PMID- 24146217 TI - Capuchins' (Cebus apella) sensitivity to others' goal-directed actions in a helping context. AB - As humans, our ability to help others effectively is at least in part dependent upon our capacity to infer others' goals in a variety of different contexts. Several species of nonhuman primate have demonstrated that they will also help others in some relatively simple situations, but it is not always clear whether this helping is based on an understanding of another agent's goals. Although the results of a number of different studies support the hypothesis that chimpanzees represent others' goals in various helping contexts and are sensitive to these goals when actually helping others, less work has addressed whether more distantly related species actively represent goals when helping. To explore the cognitive mechanisms underlying helping behaviors in species less closely related to humans, we tested whether a species of New World monkey-the brown capuchin (Cebus apella)-would provide an experimenter with a desired out-of-reach object more often than an alternative object when the experimenter attempted to obtain the former object only. We found that capuchins reliably helped by providing the experimenter's goal object (Experiment 1) and that explanations based on the use of several less sophisticated strategies did not account for the overall pattern of data (Experiments 2-4). Results are thus consistent with the hypothesis that capuchins help others based on an understanding of their goals although more work is needed to address the possibility that capuchins may be responding to gestural and postural factors alone. PMID- 24146216 TI - External nasal parameters in Egyptians: an in-depth nasal photogrammatic analysis. AB - PURPOSE: As ethnic influences can result in different appearances of the nose, the purpose of this study was to provide a set of standard values of the external form of the nose with special emphasis on the influence of age and sex on these values to establish norms for the Egyptians. METHODS: Several soft-tissue landmarks on the external nose were obtained by a non-invasive, photogrammetric analysis in 1,000 healthy Egyptians aged 20-70 years. From these landmarks, ten linear distances and six nasal angles were measured and six nasal indices were calculated. RESULTS: A significant sexual dimorphism was found for nasal external volume and area and most linear distances where males presented with higher values than those in females of the corresponding age except for alar length where females showed higher values. Moreover, age significantly influenced nasal volume, area and distances as they showed statistically significant increase till old age. Concerning angles, nasofrontal, nasofacial, nasomental and nasolabial angles were wider in females while mentocervical angle was wider in males. Moreover, nasofrontal, mentocervical and alar slope angles showed significant increase with advancing age while nasofacial, nasomental and nasolabial showed significant decrease. Regarding nasal indices, sexual dimorphism was recognized for anatomic nasal index, nasal tip protrusion, nasal height ratio and nasal tip protrusion-nasal width indices. Moreover, results also showed that the Egyptians have a Mesorrhine type of nose. CONCLUSION: Data collected in the present investigation could serve as a database for the quantitative description of the Egyptian nasal morphology. PMID- 24146218 TI - HER2 in high-risk rectal cancer patients treated in EXPERT-C, a randomized phase II trial of neoadjuvant capecitabine and oxaliplatin (CAPOX) and chemoradiotherapy (CRT) with or without cetuximab. AB - BACKGROUND: HER2 is an established therapeutic target in breast and gastric cancers. The role of HER2 in rectal cancer is unclear, as conflicting data on the prevalence of HER2 expression in this disease have been reported. We evaluated the prevalence of HER2 and its impact on the outcome of high-risk rectal cancer patients treated with neoadjuvant CAPOX and CRT+/-cetuximab in the EXPERT-C trial. PATIENTS AND METHODS: Eligible patients with available tumour tissue for HER2 analysis were included. HER2 expression was determined by immunohistochemistry (IHC) in pre-treatment biopsies and/or surgical specimens (score 0-3+). Immunostaining was scored according to the consensus panel recommendations on HER2 scoring for gastric cancer. Tumours with equivocal IHC result (2+) were tested for HER2 amplification by D-ISH. Tumours with IHC 3+ or D ISH ratio >=2.0 were classified as HER2+. The impact of HER2 on primary and secondary end points of the study was analysed. RESULTS: Of 164 eligible study patients, 104 (63%) biopsy and 114 (69%) surgical specimens were available for analysis. Only 3 of 104 (2.9%) and 3 of 114 (2.6%) were HER2+, respectively. In 77 patients with paired specimens, concordance for HER2 status was found in 74 (96%). Overall, 141 patients were assessable for HER2 and 6 out of 141 (4.3%) had HER2 overexpression and/or amplification. The median follow-up was 58.6 months. HER2 was not associated with a difference in the outcome for any of the study end points, including in the subset of 90 KRAS/BRAF wild-type patients treated+/ cetuximab. CONCLUSIONS: Based on the low prevalence of expression as recorded in the EXPERT-C trial, HER2 does not appear to represent a useful therapeutic target in high-risk rectal cancer. However, the role of HER2 as a potential predictive biomarker of resistance to anti-EGFR-based treatments and a therapeutic target in anti-EGFR refractory metastatic colorectal cancer (CRC) warrants further investigation. TRIAL REGISTRATION: ISRCTN Register: 99828560. PMID- 24146220 TI - A phase II trial of gemcitabine, irinotecan and panitumumab in advanced cholangiocarcinoma. AB - BACKGROUND: Current data suggest that chemotherapy combinations may be superior to single agents in biliary tract cancer. The epidermal growth factor receptor (EGFR) pathway appears to be associated with tumor stage, prognosis and response to therapy. This trial was designed to evaluate the tolerability and efficacy of the combination of panitumumab, a monoclonal anti-EGFR antibody, with gemcitabine and irinotecan. PATIENTS AND METHODS: Patients with advanced (unresectable or metastatic) cholangiocarcinoma, ECOG PS 0-2, and adequate organ function were treated with panitumumab (9 mg/kg) on day 1, and gemcitabine (1000 mg/m(2)) and irinotecan (100 mg/m(2)) on days 1 and 8 of a 21-day cycle. The primary objective was to evaluate the 5-month progression-free survival (PFS). Secondary objectives included overall response rate (ORR) and overall survival (OS). Mutational analyses of EGFR, KRAS and BRAF were carried out when feasible. RESULTS: Thirty five patients received a median of 7 (0-30) cycles. The most common grade 3/4 toxic effects were neutropenia (10 patients, 29%), thrombocytopenia (10 patients, 29%), skin rash (13 patients, 37%) and dehydration (9 patients, 26%). Two patients had CR, 9 had partial response (PR), and 15 had SD for a disease-control rate of 74% (by RECIST) in 28 assessable patients. Two patients went on to have surgical resection. The 5-month PFS was 69%. The median PFS was 9.7 months and the median OS was 12.9 months. In 17 testable samples, no EGFR or BRAF mutations were identified; there were 7 KRAS mutations, with no difference in OS by KRAS status. CONCLUSIONS: This study showed encouraging efficacy of this regimen with good tolerability. Further study in this area is warranted. Clinical Trials Number: The trial was registered with the National Cancer Institute (www.clinicaltrials.gov identifier NCT00948935). PMID- 24146219 TI - A multicenter phase II study incorporating high-dose rituximab and liposomal doxorubicin into the CODOX-M/IVAC regimen for untreated Burkitt's lymphoma. AB - BACKGROUND: Despite improvement with intensive multi-agent chemotherapy, 2-year progression-free survival (PFS) rates for adults with high-risk Burkitt's lymphoma (BL) remains <55%. PATIENTS AND METHODS: We conducted a phase II trial for newly diagnosed classic BL utilizing liposomal doxorubicin (Adriamycin) in lieu of doxorubicin and incorporating intravenous rituximab (at 500 mg/m(2) twice/cycle) into the CODOX-M/IVAC regimen. Correlative analyses included paired serum and cerebrospinal fluid (CSF) rituximab levels and close examination of cardiac function. RESULTS: Among 25 BL patients, the median age was 44 years (23 70) and 4 patients were HIV positive. There were 20 high-risk and 5 low-risk patients. At baseline, 40% of high-risk patients had bone marrow involvement, 35% had bulky disease and 15% had central nervous system involvement. The overall response rate was 100% (complete remission 92%). At 34-month median follow-up, the 2-year PFS and overall survival (OS) rates for all patients were 80% and 84%, respectively (low-risk: both 100%; high-risk: 76% and 81%, respectively). Furthermore, the 2-year PFS, OS, and disease-specific survival (DSS) rates for high-risk, HIV-negative patients were 84%, 89% and 100%, respectively. Adverse events (AEs) appeared to be consistent with prior CODOX-M/IVAC data, although there were several grade 3 cardiac events noted (all declined ejection fraction without clinical symptoms). The mean serum rituximab levels at 24 h after cycles 1 and 3 for patients without relapse were 258 and 306 MUg/ml, respectively, versus 131 and 193 MUg/ml, respectively, for patients with early progression (P = 0.002 and 0.002, respectively). The mean CSF rituximab levels for all patients were 0.11 and 0.24 MUg/ml, respectively, at cycle 1 (24/72 h), which equated to serum:CSF ratios of 0.05% and 0.20%, respectively. CONCLUSIONS: The integration of rituximab into CODOX-M/IVAC for adult BL was feasible and tolerable, while changes in cardiac function warrant continued examination. This regimen was associated with excellent survival rates for HIV-negative BL. Further investigation of the predictive value of serum rituximab is needed. Clinicaltrials.gov NCT00392990. PMID- 24146221 TI - Reprogramming of fatty acid and oxylipin synthesis in rhizobacteria-induced systemic resistance in tomato. AB - The rhizobacterium Pseudomonas putida BTP1 stimulates induced systemic resistance (ISR) in tomato. A previous work showed that the resistance is associated in leaves with the induction of the first enzyme of the oxylipin pathway, the lipoxygenase (LOX), leading to a faster accumulation of its product, the free 13 hydroperoxy octadecatrienoic acid (13-HPOT), 2 days after Botrytis cinerea inoculation. In the present study, we further investigated the stimulation of the oxylipin pathway: metabolites and enzymes of the pathway were analyzed to understand the fate of the 13-HPOT in ISR. Actually the stimulation began upstream the LOX: free linolenic acid accumulated faster in P. putida BTP1 treated plants than in control. Downstream, the LOX products 13-fatty acid hydroperoxides esterified to galactolipids and phospholipids were more abundant in bacterized plants than in control before infection. These metabolites could constitute a pool that will be used after pathogen attack to produce free fungitoxic metabolites through the action of phospholipase A2, which is enhanced in bacterized plants upon infection. Enzymatic branches which can use as substrate the fatty acid hydroperoxides were differentially regulated in bacterized plants in comparison to control plants, so as to lead to the accumulation of the most fungitoxic compounds against B. cinerea. Our study, which is the first to demonstrate the accumulation of an esterified defense metabolite during rhizobacteria-mediated induced systemic resistance, showed that the oxylipin pathway is differentially regulated. It suggests that this allows the plant to prepare to a future infection, and to respond faster and in a more effective way to B. cinerea invasion. PMID- 24146222 TI - Characterization and expression analysis of SOMATIC EMBRYOGENESIS RECEPTOR KINASE (SERK) genes in sexual and apomictic Paspalum notatum. AB - The SOMATIC EMBRYOGENESIS RECEPTOR-LIKE KINASE (SERK) gene plays a fundamental role in somatic embryogenesis of angiosperms, and is associated with apomixis in Poa pratensis. The objective of this work was to isolate, characterize and analyze the expression patterns of SERK genes in apomictic and sexual genotypes of Paspalum notatum. A conserved 200-bp gene fragment was amplified from genomic DNA with heterologous primers, and used to initiate a chromosomal walking strategy for cloning the complete sequence. This procedure allowed the isolation of two members of the P. notatum SERK family; PnSERK1, which is similar to PpSERK1, and PnSERK2, which is similar to ZmSERK2 and AtSERK1. Phylogenetic analyses indicated that PnSERK1 and PnSERK2 represent paralogous sequences. Southern-blot hybridization indicated the presence of at least three copies of SERK genes in the species. qRT-PCR analyses revealed that PnSERK2 was expressed at significantly higher levels than PnSERK1 in roots, leaves, reproductive tissues and embryogenic calli. Moreover, in situ hybridization experiments revealed that PnSERK2 displayed a spatially and chronologically altered expression pattern in reproductive organs of the apomictic genotype with respect to the sexual one. PnSERK2 is expressed in nucellar cells of the apomictic genotype at meiosis, but only in the megaspore mother cell in the sexual genotype. Therefore, apomixis onset in P. notatum seems to be correlated with the expression of PnSERK2 in nucellar tissue. PMID- 24146224 TI - Identification and characterization of a repertoire of genes differentially expressed in developing top ear shoots between a superior hybrid and its parental inbreds in Zea mays L. AB - Heterosis has been widely used in crop breeding and production; however, little is known about the genes controlling trait heterosis. The shortage of genes known to function in heterosis significantly limits our understanding of the molecular basis underlying heterosis. Here, we report 748 genes differentially expressed (DG) in the developing top ear shoots between a maize heterotic F1 hybrid (Mo17 * B73) and its parental inbreds identified using maize microarrays containing 28,608 unigene features. Of the 748 DG, over 600 were new for the inbred and hybrid combination. The DG were enriched for 35 of the total 213 maize gene ontology (GO) terms, including those describing photosynthesis, respiration, DNA replication, metabolism, and hormone biosynthesis. From the DG, we identified six genes involved in glycolysis, three genes in the citrate cycle, and four genes in the C4-dicarboxylic acid cycle. We mapped 533 of the 748 DG to the maize B73 genome, 298 (55.9 %) of which mapped to the QTL intervals of 11 maize ear traits. Moreover, we compared the repertoire of the DG with that of 14-day seedlings of the same inbred and hybrid combination. Only approximately 5 % of the DG was shared between the two organs and developmental stages. Furthermore, we mapped 417 (55.7 %) of the 748 maize DG to the QTL intervals of 26 rice yield-related traits. Therefore, this study provides a repertoire of genes useful for identification of genes involved in maize ear trait heterosis and information for a better understanding of the molecular basis underlying heterosis in maize. PMID- 24146226 TI - Bone microarchitecture and estimated strength in 499 adult Danish women and men: a cross-sectional, population-based high-resolution peripheral quantitative computed tomographic study on peak bone structure. AB - High-resolution peripheral quantitative computed tomography (HR-pQCT) allows in vivo assessment of cortical and trabecular bone mineral density (BMD), geometry, and microarchitecture at the distal radius and tibia in unprecedented detail. In this cross-sectional study, we provide normative and descriptive HR-pQCT data from a large population-based sample of Danish Caucasian women and men (n = 499) aged 20-80 years. In young adults (<35 years), women (n = 100) compared to men (n = 64) had smaller total and cortical areas, inferior metric trabecular indices, higher network inhomogeneity, lower cortical porosity, and lower finite element estimated bone strength. The changes in parameters with age were estimated from multiple regression analyses. In men, with age the greatest changes (from parameter minimum or maximum) until 80 years were found for cortical porosity (1.91 IQR), BV/TV (-1.09 IQR), and trabecular thickness (-0.87 IQR) in the radius and BV/TV (-1.55 IQR), cortical BMD (-1.25 IQR), and cortical porosity (1.25 IQR) in the tibia. In women changes were most pronounced for cortical porosity (4.76 IQR), trabecular inhomogeneity (3.84 IQR), and cortical BMD (-2.86 IQR) in the radius and cortical BMD (-5.06 IQR), cortical porosity (3.86 IQR), and cortical area (-1.64 IQR) in the tibia. These findings emphasize the age- and sex-related differences in bone morphology, with men having a structural advantage over women from early adult life translating into superior indices of bone strength. With age women are further disadvantaged compared to men by greater decrements in cortical and trabecular architecture in the radius and cortical architecture in the tibia. PMID- 24146223 TI - Hypertension, brain damage and cognitive decline. AB - Loss of cognitive function is one the most devastating manifestations of ageing and vascular disease. Cognitive decline is rapidly becoming an important cause of disability worldwide and contributes significantly to increased mortality. There is growing evidence that hypertension is the most important modifiable vascular risk factor for development and progression of both cognitive decline and dementia. High blood pressure contributes to cerebral small and large vessel disease resulting in brain damage and dementia. A decline in cerebrovascular reserve capacity and emerging degenerative vascular wall changes underlie complete and incomplete brain infarcts, haemorrhages and white matter hyperintensities. This review discusses the complexity of factors linking hypertension to brain functional and structural changes, and to cognitive decline and dementia. The evidence for possible clinical markers useful for prevention of decreased cognitive ability, as well as recent data on vascular mechanism in the pathogenesis of cognitive decline, and the role of antihypertensive therapies in long-term prevention of late-life cognitive decline will be reviewed. PMID- 24146228 TI - Screening for colorectal cancer: using data to set prevention priorities. AB - INTRODUCTION: Adherence to colorectal cancer screening recommendations is known to vary by state, but less information is available about within-state variability. In the current study, we assess county-level screening rates for Missouri, with the goal of better targeting public health efforts to increase screening. METHODS: Prevalence of colorectal cancer screening among Missouri adults between the ages of 50 and 74 was obtained from 2008 and 2010 Behavioral Risk Factor Surveillance System data. We used multilevel logistic regression to generate county-specific estimates. After excluding 77 counties with fewer than 30 respondents, information was available about 3,739 individuals in 37 counties, representing 78.5 % of the state population. RESULTS: Across counties, the prevalence of being up-to-date with recommended colorectal cancer screening ranged from 25 to 70 %. CONCLUSION: State-level information about colorectal cancer screening masks substantial within-state variability. Assessing and monitoring county-level disparities in screening can guide public health efforts to increase screening and reduce colorectal cancer mortality. More complete population survey data will make such analysis possible. PMID- 24146229 TI - Health promotion in pediatric primary care: importance of health literacy and communication practices. AB - Health literacy has been shown to predict health behaviors and outcomes above the effects of education or socioeconomic status. Much remains unknown about the health literacy of parents and the role it plays in children's health outcomes or in health disparities. The current study explored the health communication needs and health literacy indicators in a diverse sample of parents (n = 75) to identify potential areas for future interventions. The sample consisted of parents of children 18 to 36 months old who were visiting 3 different pediatric medical offices, 2 of which served low-income families and 1 located in an affluent suburb. When comparisons were made between 2 educational attainment groups, there were variations in indicators of health literacy and health communication needs. These data can be used to guide the development of interventions by primary care providers to improve parent education. PMID- 24146230 TI - Severe cardiomyopathy in an infant after iatrogenic fosphenytoin overdose. PMID- 24146231 TI - Functional endoscopic sinus surgery improves sinus-related symptoms and quality of life in children with chronic rhinosinusitis: a systematic analysis and meta analysis of published interventional studies. AB - AIM: To assess the current knowledge and evaluate the quality of evidence in the use of FESS for the treatment of chronic rhinosinusitis in children, regarding the respective changes in the quality-of-their-life (QoL) and the outcome that follows the operation. MATERIALS/METHODS: Systematic literature review in Medline and other database sources and meta-analysis of pooled data. RESULTS: 15 studies were systematically analyzed. Four represented Level II, five Level III, and six Level IV evidence. The total number of treated patients was 1301. Thirteen research groups reported that pediatric FESS is an effective treatment for chronic rhinosinusitis; the respective positive outcome ranged between 71 and 100% of operated children. Five studies concluded that this treatment modality is associated with significant improvement in the children's postoperative QoL. Systemic diseases and environmental factors may have unfavourable prognostic effects; cystic fibrosis is associated with at least 50% recurrence rate. The rate of major complications following pediatric FESS is 0.6%, and the respective rate of minor complications 2%. CONCLUSION: The surgical management in children with chronic rhinosinusitis, despite the reservations expressed by many clinicians, is effective when optimal medical treatment proves unsuccessful (grade B strength of recommendation), and is associated with improvement in the children's QoL (grade B strength of recommendation). FESS also improves the sinusitis-associated symptoms and QoL in children with cystic fibrosis (grade C strength of recommendation. Most complications of pediatric FESS reported in the literature are minor, and associated with difficulties in the postoperative assessment and care of pediatric patients. PMID- 24146232 TI - Diagnosing and treating mixed phenotype acute leukemia: a multicenter 10-year experience in Mexico. AB - Mixed phenotype acute leukemia (MPAL) in adults represents nearly 2 to 5 % of all acute leukemia cases. There are two large studies throughout the world and only case reports and small series have been reported in Latin America. This study retrospectively analyses the clinical characteristics and survival of 27 patients with MPAL evaluated in three medical institutions of Mexico. All cases meet World Health Organization 2008 criteria; 70.3 % of patients had B lymphoid/myeloid lineage MPAL. Induction chemotherapy protocols included 7 + 3 hyper-CVAD, high density schedules, and pediatric-like regimens such as New York II and total XI. Complete remission was achieved in 23/27 patients (85.2 %). Only one patient died due to chemotherapy-induced aplasia during remission induction (5.2 %). In 68 % of cases, we were able to administer maintenance therapy as a regimen in lymphoblastic leukemia. At the time of analysis, 70.4 % of the patients in the entire cohort had died mainly as result of disease progression (73.6 %). Disease free survival was 13 months (95 % CI, 9.6-16.3 months) and overall survival was 14.8 months (95 % CI 13.4-16.27). Survival rates are low and standardized therapy for the management of this type of leukemia is still lacking. This is the largest series reported in Mexico and to the best of our knowledge in Latin America. PMID- 24146233 TI - Safety and efficacy of low-dose methotrexate for pediatric patients with steroid refractory acute graft-versus-host disease after hematopoietic stem cell transplantation. AB - Low-dose methotrexate (LD-MTX) has long been included in prophylaxis regimens for acute graft-versus-host disease (aGVHD). In addition, LD-MTX is expected as a treatment option to control aGVHD by regulating the cytokine network. In this study, we retrospectively evaluated 35 patients with steroid-refractory acute GVHD to evaluate the safety and efficacy of LD-MTX as a salvage treatment. LD-MTX was administered weekly at a dose of 10 mg/m(2). Overall, 13 patients (37 %) achieved complete response and three (9 %) achieved partial response within 4 weeks after LD-MTX was initiated without any additional agents. Resolution of manifestations of aGVHD in each evaluable organ was observed in 12 of the 23 cases (52 %) with skin aGVHD and in eight of the 23 cases (35 %) with GI aGVHD. Neutropenia and thrombocytopenia (grades III and IV) were observed in nine (26 %) and 17 patients (49 %), respectively. Fatal infectious complications occurred in only three patients (9 %) after LD-MTX treatment. Of the 35 patients studied, 22 were alive with a median follow-up of 60 months and an overall survival rate (Kaplan-Meier estimate) was 62 %. LD-MTX seems suitable for salvage therapy and will not increase risk of infection. Further evaluation of the use of LD-MTX as salvage therapy for steroid-refractory acute GVHD is warranted. PMID- 24146234 TI - Bone marrow aspiration and biopsy-related pain management. PMID- 24146236 TI - Heat dissipation after nonanatomical lung resection using a laser is mainly due to emission to the environment: an experimental ex vivo study. AB - Laser-directed resection of lung metastases is performed more frequently in recent years. The energy-loaded laser rays heat up the lung tissue, considerably. It is still unclear which mechanism is more important for tissue heat dissipation: the lung perfusion or the tissue emission. Therefore, we created a special experimental model to investigate the spontaneous heat dissipation after nonanatomical lung resection using a diode-pumped laser with a high output power. Experiments were conducted on paracardiac pig lung lobes (n = 12) freshly dissected at the slaughterhouse. Nonanatomical resection of lung parenchyma was performed without lobe perfusion in group 1 (n = 6), while group 2 (n = 6) was perfused at a physiological pressure of 25 cm H2O at 37 degrees C with saline via the pulmonary artery. For this, we used a diode-pumped neodymium-doped yttrium aluminum garnet (Nd:YAG) LIMAX(r) 120 laser (Gebruder Martin GmbH & Co. KG, Tuttlingen, Germany) with a wavelength of 1,318 nm and a power output of 100 W. Immediately after completing laser resection, the lungs were monitored with an infrared camera (Type IC 120LV; Trotec, Heinsberg, Germany) while allowed to cool down. The resection surface temperature was taken at 10-s intervals and documented in a freeze-frame until a temperature of 37 degrees C had been reached. The temperature drop per time unit was analyzed in both groups. Immediately after laser resection, the temperature at the lung surface was 84.33 +/- 8.08 degrees C in group 1 and 76.75 +/- 5.33 degrees C in group 2 (p = 0.29). Group 1 attained the final temperature of 37 degrees C after 182.95 +/- 53.76 s, and group 2 after 121.70 +/- 16.02 s (p = 0.01). The temperature drop occurred exponentially in both groups. We calculated both groups' decays using nonlinear regression, which revealed nearly identical courses. The mean time of tissue temperature of >42 degrees C, as a surrogate marker for tissue damage, was 97.14 +/- 26.90 s in group 1 and 65.00 +/- 13.78 s in group 2 (p = 0.02). Heat emission to the environment surpasses heat reduction via perfusion in nonanatomically laser-resected lung lobes. In developing a cooling strategy, a topical cooling method would be promising. PMID- 24146235 TI - Optoacoustic monitoring of cutting efficiency and thermal damage during laser ablation. AB - Successful laser surgery is characterized by a precise cut and effective hemostasis with minimal collateral thermal damage to the adjacent tissues. Consequently, the surgeon needs to control several parameters, such as power, pulse repetition rate, and velocity of movements. In this study we propose utilizing optoacoustics for providing the necessary real-time feedback of cutting efficiency and collateral thermal damage. Laser ablation was performed on a bovine meat slab using a Q-switched Nd-YAG laser (532 nm, 4 kHz, 18 W). Due to the short pulse duration of 7.6 ns, the same laser has also been used for generation of optoacoustic signals. Both the shockwaves, generated due to tissue removal, as well as the normal optoacoustic responses from the surrounding tissue were detected using a single broadband piezoelectric transducer. It has been observed that the rapid reduction in the shockwave amplitude occurs as more material is being removed, indicating decrease in cutting efficiency, whereas gradual decrease in the optoacoustic signal likely corresponds to coagulation around the ablation crater. Further heating of the surrounding tissue leads to carbonization accompanied by a significant shift in the optoacoustic spectra. Our results hold promise for real-time monitoring of cutting efficiency and collateral thermal damage during laser surgery. In practice, this could eventually facilitate development of automatic cut-off mechanisms that will guarantee an optimal tradeoff between cutting and heating while avoiding severe thermal damage to the surrounding tissues. PMID- 24146237 TI - Labial frenectomy with Nd:YAG laser and conventional surgery: a comparative study. AB - Labial frenulums are sagittal fibrous folds of oral mucosa with a periosteal insertion that extend from the lips to the alveolar or gingival mucosa. Occasionally, they assume inadequate size or location and may lead to functional and esthetic limitations. The aim of the present study was to compare pre-, trans , and postsurgical clinical parameters of labial frenectomies performed with conventional surgery and neodymium-doped yttrium aluminum garnet (Nd:YAG) laser. Forty individuals were assessed as a convenience sample and were divided into two groups according to the treatment: group 1 (G1), conventional surgery (n = 22), and G2, Nd:YAG laser surgery (n = 18). Clinical parameters such as frenulum insertion, location, bleeding, surgical time, suturing, preoperative fear, and postoperative discomfort/functional limitations were evaluated. All surgeries were performed by the same operator, and the level of fear, pain, and discomfort related to oral functions were assessed with a visual numeric scale. Most of the frenulums (90%) were classified as papillary or transpapillary insertion. Preoperative fear was similar between groups (p = 0.593). All G2 patients did not require suture (p < 0.001), did not bleed during the procedure (p < 0.001), and had surgical time diminished (p < 0.001). No significant statistical difference regarding pain or oral function could be observed. Three individuals (7.5%) experienced postsurgical complications. Nd:YAG laser frenectomies reduces transoperative bleeding, avoiding the need of suturing, and promotes a significant reduction of surgical time in comparison with conventional surgery. Therefore, further studies are necessary to provide a complete understanding and standardization of the technique as well as the expected clinical results. PMID- 24146238 TI - A system for health: essential element of national security. PMID- 24146239 TI - Strategies for optimizing military physical readiness and preventing musculoskeletal injuries in the 21st century. AB - With downsizing of the military services and significant budget cuts, it will be more important than ever to optimize the health and performance of individual service members. Musculoskeletal injuries (MSIs) represent a major threat to the health and fitness of Soldiers and other service members that degrade our nation's ability to project military power. This affects both financial (such as the economic burden from medical, healthcare, and disability costs) and human manpower resources (Soldiers medically unable to optimally perform their duties and to deploy). For example, in 2012, MSIs represented the leading cause of medical care visits across the military services resulting in almost 2,200,000 medical encounters. They also result in more disability discharges than any other health condition. Nonbattle injuries (NBIs) have caused more medical evacuations (34%) from recent theaters of operation than any other cause including combat injuries. Physical training and sports are the main cause of these NBIs. The majority (56%) of these injuries are the direct result of physical training. Higher levels of physical fitness protect against such injuries; however, more physical training to improve fitness also causes higher injury rates. Thus, military physical training programs must balance the need for fitness with the risks of injuries. The Army has launched several initiatives that may potentially improve military physical readiness and reduce injuries. These include the US Army Training and Doctrine Command's Baseline Soldier Physical Readiness Requirements and Gender Neutral Physical Performance Standards studies, as well as the reimplementation of the Master Fitness Trainer program and the Army Medical Command's Soldier Medical Readiness and Performance Triad Campaigns. It is imperative for military leaders to understand that military physical readiness can be enhanced at the same time that MSIs are prevented. A strategic paradigm shift in the military's approach to physical readiness policies is needed to avoid further degradation of warfighting capability in an era of austerity. We believe this can be best accomplished through leveraging scientific, evidence based best practices by Army senior leadership which supports, prioritizes, and implements innovative, synchronized, and integrated human performance optimization/injury prevention policy changes. PMID- 24146240 TI - Physical fitness: a pathway to health and resilience. AB - Various groups representing a number of different perspectives (for example, operational, architectural, community, institutional, and individual resilience) use the term resilience. We define resilience as the ability to withstand, recover, and grow in the face of stressors and changing demands. Physical fitness is one pathway toward resilience because it is associated with many traits and attributes required for resilience. In addition, physical fitness confers resilience because regular exercise and/or physical activity induces positive physiologic and psychological benefits, protects against the potential consequences of stressful events, and prevents many chronic diseases. This article presents a brief historical overview of the health-promoting effects of exercise and physical activity, followed by a discussion on the concept of hardiness and mental toughness and how they relate to resilience and physical fitness; how physical fitness promotes resilience; the clinical implications of a sedentary lifestyle; and the relevance of physical fitness and resilience to Army Medicine's Performance Triad. PMID- 24146241 TI - Extreme conditioning programs and injury risk in a US Army Brigade Combat Team. AB - CONTEXT: Brigades and battalions throughout the US Army are currently implementing a variety of exercise and conditioning programs with greater focus on preparation for mission-specific tasks. An Army physical therapy clinic working with a light infantry brigade developed the Advanced Tactical Athlete Conditioning (ATAC) program. The ATAC program is a unique physical training program consisting of high-intensity aquatic exercises, tactical agility circuits, combat core conditioning, and interval speed training. Along with ATAC, battalions have also incorporated components of fitness programs such as the Ranger Athlete Warrior program and CrossFit (Crossfit, Inc, Santa Monica, CA) an extreme conditioning program (ECP). OBJECTIVE: To determine if these new programs (ATAC, ECP) had an effect on injury rates and physical fitness. DESIGN: Surveys were administered to collect personal characteristics, tobacco use, personal physical fitness training, Army physical fitness test results, and self-reported injuries. Medical record injury data were obtained 6 months before and 6 months after the implementation of the new program. Predictors of injury risk were assessed using multivariate logistic regression. Odds ratios (OR) and 95% confidence intervals (CI) were reported. RESULTS: Injury incidence among Soldiers increased 12% for overall injuries and 16% for overuse injuries after the implementation of the ATAC/ECPs. However, injury incidence among Soldiers not participating in ATAC/ECPs also increased 14% for overall injuries and 10% for overuse injuries. Risk factors associated with higher injury risk for Soldiers participating in ATAC/ECPs included: greater mileage run per week during unit physical training (OR (>16 miles per week/<=7 miles per week)=2.24, 95% CI, 1.33 3.80); higher body mass index (BMI) (OR (BMI 25-29.9/BMI<25)=1.77, 95% CI, 1.29 2.44), (OR (BMI =30/BMI<25)=2.72, 95% CI, 1.67-4.43); cigarette use (OR (smoker/nonsmoker)=1.80, 95% CI, 1.34-2.42); poor performance on the 2-mile run during the Army Physical Fitness Test (APFT) (OR (=15.51 minutes/<=13.52 minutes)=1.76, 95% CI, 1.13-2.74); Injury risk was lower for those reporting resistance training, (OR (<1 time per week/none)=0.53, 95% CI, 0.31-0.92), (OR (1 2 times per week/none)=0.50, 95% CI, 0.29-0.84), (OR (>=3 times per week/none)=0.45, 95% CI, 0.24-0.85). CONCLUSIONS: Given that Soldiers participating in ATAC/ECPs showed similar changes in injury rates compared to Soldiers not participating in ATAC/ECPs, no recommendation can be made for or against implementation of ATAC/ECPs. PMID- 24146242 TI - Measuring physical activity during US Army Basic Combat Training: a comparison of 3 methods. AB - BACKGROUND: An understanding of the demands of physical activity (PA) during US Army Basic Combat Training (BCT) is necessary to support Soldier readiness and resilience. The purpose of this study was to determine the agreement among 3 different PA measurement instruments in the BCT environment. METHODS: Twenty-four recruits from each of 11 companies wore an ActiGraph accelerometer (Actigraph, LLC, Pensacola, FL) and completed a daily PA log during 8 weeks of BCT at 2 different training sites. The PA of one recruit from each company was recorded using PAtracker, an Army-developed direct observation tool. Information obtained from the accelerometer, PA log, and PAtracker included time spent in various types of PA, body positions, PA intensities, and external loads carried. Pearson product moment correlations were run to determine the strength of association between the ActiGraph and PAtracker for measures of PA intensity and between the PAtracker and daily PA log for measures of body position and PA type. The Bland Altman method was used to assess the limits of agreement (LoA) between the measurement instruments. RESULTS: Weak correlations (r=-0.052 to r=0.302) were found between the ActiGraph and PAtracker for PA intensity. Weak but positive correlations (r=0.033 to r=0.268) were found between the PAtracker and daily PA log for body position and type of PA. The 95% LoA for the ActiGraph and PAtracker for PA intensity were in disagreement. The 95% LoA for the PAtracker and daily PA log for standing and running and all PA types were in disagreement; sitting and walking were in agreement. CONCLUSIONS: The ActiGraph accelerometer provided the best measure of the recruits' PA intensity while the PAtracker and daily PA log were best for capturing body position and type of PA in the BCT environment. The use of multiple PA measurement instruments in this study was necessary to best characterize the physical demands of BCT. PMID- 24146243 TI - Quantification of physical activity performed during US Army Basic Combat Training. AB - PURPOSE: During US Army Basic Combat Training (BCT), graduation requirements, including physical readiness training (PRT), are standardized across training sites. However, there are concerns that the standardization may not be closely followed. Therefore, the purpose of this study was to measure and compare physical activity (PA) performed by recruits at 2 Army BCT sites. METHODS: Twenty four recruits per company from 11 companies (n=144 at Fort Jackson, SC; n=120 at Fort Sill, OK) wore an accelerometer and completed a daily PA log. The PA of one recruit from each company was recorded using an Army-developed direct observation tool (PAtracker). Amounts of time spent in various activity types, intensities, body positions, and in carrying external loads were obtained from the accelerometer, PA log, and PAtracker. Independent samples t tests were used to compare PA percentage time (%T) across training sites. Repeated measures analysis of variance was used to examine weekly differences in time spent in moderate to vigorous intensity PA during morning PRT. RESULTS: Physical activity was measured for 47 days at Fort Jackson and 44 days at Fort Sill. Differences in the percentage of time spent in various physical activities between the 2 sites ranged from 0.4% to 15.3% (2.0-93.7 minutes). At Fort Jackson, time spent in moderate to vigorous PA during PRT significantly increased each week for the first 4 to 6 weeks of BCT. No difference was observed in PAtracker data between the 2 training sites in the percentage of time recruits spent in calisthenics (3.9%+/-3.6% vs 3.8%+/-3.0%, P=.700), and only a small difference was observed in percentage of time recruits spent running (1.2%+/-1.7% vs 1.6%+/-2.0%, P=.037). CONCLUSION: Army recruits at the 2 BCT sites spent similar amounts of time in each PA variable, regardless of the training site and measurement method. PMID- 24146244 TI - Nutrition as a component of the performance triad: how healthy eating behaviors contribute to soldier performance and military readiness. AB - OBJECTIVE: Nutrition is a critical element of Soldier health and performance. Food choices, meal timing, and dietary intake behaviors contribute to nutritional fitness. The objectives of this study were to describe Soldier dietary behaviors and quantify the association between healthy eating behaviors and demographic, lifestyle, and psychosocial factors. METHODS: The Comprehensive Soldier and Family Fitness Global Assessment Tool (GAT) assesses emotional, social, family, and spiritual fitness. In 2012, 57 pilot questions were added to the GAT to create a physical dimension that included nutrition assessments. Participants included 13,858 Active Duty, Reserve, and National Guard Soldiers: 83% male; 85% enlisted; a mean age of 28+/-9 years. A Healthy Eating Score (HES-5) was calculated from 5 questions assessing frequency of fruit, vegetable, whole grain, dairy, and fish intake (Cronbach alpha=0.81). Associations between HES-5 and other dietary habits, physical activity patterns, and GAT psychosocial dimension scores were examined. RESULTS: Soldiers who ate breakfast regularly (6 times/week or more), drank 7 servings or more of water/day, and met weekly exercise recommendations were more likely to be in the highest HES-5 quartile than those who did not. Those who passed their Army Physical Fitness Test (APFT) in the top quartile were also more likely to report high HES-5 scores than those who failed (P<.001). Soldiers with healthy anthropometric measures and the highest emotional, social, family, and spiritual fitness scores were also more likely to be in the top HES-5 quartile than those with unhealthy measures and with the lowest fitness scores (P<.001). CONCLUSION: The HES-5 may be a useful index for characterizing dietary intake behaviors. Healthy dietary intake behaviors are associated with all dimensions of health, physical fitness, and psychosocial status. PMID- 24146245 TI - The importance of leadership in Soldiers' nutritional behaviors: results from the Soldier Fueling Initiative program evaluation. AB - INTRODUCTION: Improving Soldiers' nutritional habits continues to be a concern of the US Army, especially amidst increasing obesity and high injury rates. This study examines leadership influence on nutritional behaviors within the context of the Soldier Fueling Initiative, a program providing nutrition education and improved dining facility menus to Soldiers in Basic Combat Training (BCT) and Advanced Individual Training (AIT). METHODS: A mixed methods design using surveys (N=486) and focus groups (N=112) was used to collect data at Fort Jackson, SC, and Fort Eustis, VA, in 2011. RESULTS: Survey results showed 75% of Soldiers in BCT believed their drill sergeant was helpful in making performance-enhancing food choices, and 86% agreed their drill sergeant believed it is important to eat for performance. Soldiers in AIT perceived their cadre as less helpful than their BCT drill sergeants and agreed less frequently that the AIT cadre believed it was important to eat for performance (P<.05). These measures of leader influence were significantly associated with nutritional attitudes and behaviors in both BCT and AIT. Focus groups revealed 5 key themes related to cadre influence and nutrition behavior (listed in order of most to least frequent): (1) cadre influence food choices through consequences related to selection, (2) cadre teach Soldiers how to eat, (3) cadre rush Soldiers to eat quickly to return to training, (4) cadre influence choice through example but often do not make healthy choices, and (5) cadre have no influence on food choices. COMMENT: Leaders influence most Soldiers' nutrition practices within the training environment, particularly within BCT. Given that leader influence can impact Soldiers' attitudes and behaviors, it is critical that military leaders become knowledgeable about optimal nutrition practices to disseminate appropriate information to their Soldiers, avoid reprimand associated with trainees' food choices, reinforce key messages associated with nutrition programming, and lead by example in their own food choices. PMID- 24146246 TI - Assessment of dietary intake using the healthy eating index during military training. AB - OBJECTIVE: The objectives of this study were to use the healthy eating index (HEI) as a tool to characterize diet quality in Soldiers (n=135) during basic combat training (BCT), and to assess the effects of BCT on diet quality by comparing HEI scores before and after the training period. METHODS: HEI scores were calculated from a 110-item semiquantitative food frequency questionnaire. Soldiers were then divided into tertiles (high, medium, and low) of diet quality based upon HEI scores at the start of BCT. RESULTS: No relationships between pre BCT total HEI score and age, sex, racial background, or physical activity were observed. The odds of being a smoker were 4.75 times higher for those in the low HEI tertile and 3.03 times higher for those in the medium HEI tertile when compared to those in the high HEI tertile (95% CI, 1.67, 13.48 and 1.04, 8.82 respectively). Diet quality improved in the medium and low HEI tertiles over the course of BCT, as total HEI scores increased by 22% and 46% respectively (P<.05) with time in these groups. Although different at the start of BCT, HEI scores were similar between the medium and high HEI tertiles at the end of BCT. CONCLUSION: Study findings suggest that the BCT dining environment elicits positive changes in diet quality for Soldiers who enter military training with lower diet quality, and the HEI appears to be a useful tool to identify military personnel with lower diet quality at the start of training. This may provide the opportunity to target interventions such as diet counseling and education in an effort to improve Soldier health and performance. PMID- 24146247 TI - Sleep as a component of the performance triad: the importance of sleep in a military population. AB - OBJECTIVE: Sleep habits among military populations are problematic. Poor sleep hygiene occurs in parallel with the global increase in obesity and metabolic syndrome and contributes to a decrease in performance. The extent of sleep issues needs to be quantified to provide feedback for optimizing warfighter performance and readiness. This study assessed various health behaviors and habits of US Army Soldiers and their relationship with poor sleep quality by introducing a set of new questions into the Comprehensive Soldier and Family Fitness (CSF2) Global Assessment Tool (GAT). METHODS: Subjects included 14,148 US Army Active, Reserve, and National Guard members (83.4% male) who completed the GAT, a self-report questionnaire that measures 4 fitness dimensions: social, family, emotional, and spiritual. Approximately 60 new questions, including ones on sleep quality, within the fifth CSF2 dimension (physical) were also answered. A sleep score was calculated from 2 questions validated in the Pittsburgh Insomnia Rating Scale (0 to 6). RESULTS: Poor sleepers (5-6) were significantly (P<.001) more likely than good sleepers (0-1) to consider themselves in fair or poor health, be overweight or obese, and score in the lowest quartile of the emotional, social, family, and spiritual fitness dimensions. Additionally, poor sleepers were significantly (P<.001) less likely to have a healthy body mass index and waist circumference, eat breakfast 6 or more times a week, meet aerobic exercise and resistance training recommendations, and pass their Army Physical Fitness Test in the top quartile. CONCLUSION: This study examined sleep quality in a group of military personnel and indicated significant associations between quality of sleep and physical performance, nutritional habits, measures of obesity, lifestyle behaviors and measures of psychosocial status. Targeted educational interventions and resources are needed to improve sleep patterns based on behaviors that can be most easily modified. PMID- 24146248 TI - The challenge of sleep management in military operations. AB - It has long been known that short-term (days) insufficient sleep causes decrements in mental effectiveness that put individuals at increased risk of committing errors and causing accidents. More recently, it has been discovered that chronic poor sleep (over years) is associated with a variety of negative health outcomes (metabolic syndrome, obesity, degraded behavioral health). Implementing an effective sleep health program is, therefore, in the best interests of active duty personnel and their families both in the short- and long term. Like managing physical activity or nutrition, effectively managing sleep health comes with its unique set of challenges arising from the fact that individuals who routinely do not obtain sufficient sleep are generally desensitized to feeling sleepy and are poor at judging their own performance capabilities--and individuals cannot be compelled to sleep. For these reasons, an optimally effective sleep health program requires 3 components: (1) a rigorous, evidence-based sleep education component to impart actionable knowledge about optimal sleep amounts, healthy sleep behaviors, the known benefits of sleep, the short- and long-term consequences of insufficient sleep, and to dispel myths about sleep; (2) a nonintrusive device that objectively and accurately measures sleep to empower the individual to track his/her own sleep/wake habits; and (3) a meaningful, actionable metric reflecting sleep/wake impact on daily effectiveness so that the individual sees the consequences of his/her sleep behavior and, therefore, can make informed sleep health choices. PMID- 24146249 TI - Mild antithrombin deficiency and risk of recurrent venous thromboembolism: a prospective cohort study. AB - BACKGROUND: Antithrombin deficiency, defined by antithrombin levels of <70%, is a major thrombophilic condition associated with an increased risk of venous thromboembolism (VTE). No prospective data are available about the risk of recurrent VTE associated with mildly decreased antithrombin levels (70-80%). METHODS AND RESULTS: Consecutive patients with a first VTE were stratified according to functional antithrombin levels (<70%, 70-80%, >80%) and were followed up for a mean of 8.70 years to assess the incidence of VTE recurrence. A total of 823 patients (mean age, 48.3 years; 41.9% male) were enrolled. Recurrent VTE occurred in 253 patients (3.53% per patient-year). With stratification for antithrombin levels, VTE recurrence occurred in 19 patients with antithrombin levels <70% (5.90% per patient-year), in 20 patients with antithrombin levels 70% to 80% (5.35% per patient-year), and in 214 patients with antithrombin levels >80% (3.31% per patient-year). After adjustment for major VTE risk factors and for anticoagulation duration, the risk of VTE recurrence was significantly higher in patients with antithrombin levels <70% (hazard ratio, 3.48; 95% confidence interval, 2.16-5.61) and antithrombin levels 70% to 80% (hazard ratio, 2.40; 95% confidence interval, 1.51-3.80) compared with patients with antithrombin levels >80%. When the population was stratified according to the presence or absence of major risk factors for the index event, the association remained significant only in patients with unprovoked VTE. CONCLUSIONS: The presence of mild antithrombin deficiency (70-80% antithrombin) in patients with unprovoked VTE is associated with a significantly increased risk of recurrence and should be taken into account when the duration of secondary prevention is determined. CLINICAL TRIAL REGISTRATION URL: http://www.clinicaltrials.gov. Unique identifier: NCT01382550. PMID- 24146250 TI - Sex difference in risk of second but not of first venous thrombosis: paradox explained. AB - BACKGROUND: The risk of recurrent venous thrombosis is 2-fold higher in men than in women. In contrast, no such sex difference in the risk of first venous thrombosis has been reported. We hypothesized that, for a first event, a risk difference between the sexes is masked by female exposure to reproductive factors (oral contraception, pregnancy/puerperium, and postmenopausal hormone therapy). METHODS AND RESULTS: From the Multiple Environmental and Genetic Assessment of Risk Factors for Venous Thrombosis (MEGA) study, a population-based case-control study on risk factors for venous thrombosis, 2915 patients with a first venous thrombosis and their partners as control subjects were included. Odds ratios and 95% confidence intervals for first venous thrombosis were assessed in men compared with women without reproductive risk factors by use of conditional logistic regression. Analyses were stratified in 10-year age categories to account for the variation in exposure to reproductive risk factors over different age groups and adjusted for body mass index and smoking. Overall, men had a 2.1 fold (95% confidence interval, 1.9-2.4) increased risk of first venous thrombosis compared with women without reproductive risk factors. Similar results were found when 10-year age categories were viewed separately. Adjustment for body mass index and smoking and exclusion of cancer patients did not materially affect the results. CONCLUSIONS: When female reproductive risk factors are taken into account, the risk of a first venous thrombosis is twice as high in men as in women. These findings are in line with previous studies on recurrent venous thrombosis and may have implications for future treatment and prevention strategies. PMID- 24146251 TI - Activation of histone deacetylase-6 induces contractile dysfunction through derailment of alpha-tubulin proteostasis in experimental and human atrial fibrillation. AB - BACKGROUND: Atrial fibrillation (AF) is characterized by structural remodeling, contractile dysfunction, and AF progression. Histone deacetylases (HDACs) influence acetylation of both histones and cytosolic proteins, thereby mediating epigenetic regulation and influencing cell proteostasis. Because the exact function of HDACs in AF is unknown, we investigated their role in experimental and clinical AF models. METHODS AND RESULTS: Tachypacing of HL-1 atrial cardiomyocytes and Drosophila pupae hearts significantly impaired contractile function (amplitude of Ca(2+) transients and heart wall contractions). This dysfunction was prevented by inhibition of HDAC6 (tubacin) and sirtuins (nicotinamide). Tachypacing induced specific activation of HDAC6, resulting in alpha-tubulin deacetylation, depolymerization, and degradation by calpain. Tachypacing-induced contractile dysfunction was completely rescued by dominant negative HDAC6 mutants with loss of deacetylase activity in the second catalytic domain, which bears alpha-tubulin deacetylase activity. Furthermore, in vivo treatment with the HDAC6 inhibitor tubastatin A protected atrial tachypaced dogs from electric remodeling (action potential duration shortening, L-type Ca(2+) current reduction, AF promotion) and cellular Ca(2+)-handling/contractile dysfunction (loss of Ca(2+) transient amplitude, sarcomere contractility). Finally, atrial tissue from patients with AF also showed a significant increase in HDAC6 activity and reduction in the expression of both acetylated and total alpha-tubulin. CONCLUSIONS: AF induces remodeling and loss of contractile function, at least in part through HDAC6 activation and subsequent derailment of alpha-tubulin proteostasis and disruption of the cardiomyocyte microtubule structure. In vivo inhibition of HDAC6 protects against AF-related atrial remodeling, disclosing the potential of HDAC6 as a therapeutic target in clinical AF. PMID- 24146252 TI - Prepregnancy obesity and associations with stroke and myocardial infarction in women in the years after childbirth: a nationwide cohort study. AB - BACKGROUND: Cardiovascular events (stroke or myocardial infarction) are often associated with poorer prognosis in younger, compared with older individuals. We examined the associations between prepregnancy obesity and the risks of myocardial infarction and stroke in young, healthy women. METHODS AND RESULTS: All Danish women giving birth during 2004-2009 without a history of renal disease or cardiovascular disease were identified from national registers and followed for a median time of 4.5 years (interquartile range, 2.8-5.8). They were grouped according to prepregnancy body mass index (BMI) in underweight (BMI<18.5 kg/m(2)), normal weight (BMI=18.5-<25 kg/m(2)), overweight (BMI=25-<30 kg/m(2)), and obese (BMI>=30 kg/m(2)). The hazard ratios of myocardial infarction, ischemic stroke, and a composite outcome (myocardial infarction, stroke, cardiovascular death) were assessed using multivariable Cox regression models. We included 273 101 women with a median age of 30.4 years (interquartile range, 27.2-33.8). A total of 68 women experienced a myocardial infarction, and 175 women experienced an ischemic stroke. The adjusted hazard ratios of myocardial infarction compared with normal weight were 2.50 (95% confidence interval [95% CI], 0.97-6.50) in underweight, 1.68 (95% CI, 0.92-3.06) in overweight, and 2.63 (95% CI, 1.41-4.91) in obese women. For ischemic stroke the adjusted hazard ratios were 1.06 (95% CI, 0.44-2.28) in underweight, 1.27 (95% CI, 0.87-1.85) in overweight, and 1.89 (95% CI, 1.25-2.84) in obese women, respectively. For the composite outcome, hazard ratios were 1.34 (95% CI, 0.81-2.20), 1.43 (95% CI, 1.11-1.84), and 1.76 (95% CI, 1.31-2.34) for underweight, overweight, and obese women. CONCLUSIONS: In apparently healthy women of fertile age, prepregnancy obesity was associated with increased risks of ischemic stroke and myocardial infarction in the years after childbirth. PMID- 24146253 TI - Prostaglandin E2 inhibits elastogenesis in the ductus arteriosus via EP4 signaling. AB - BACKGROUND: Elastic fiber formation begins in mid-gestation and increases dramatically during the last trimester in the great arteries, providing elasticity and thus preventing vascular wall structure collapse. However, the ductus arteriosus (DA), a fetal bypass artery between the aorta and pulmonary artery, exhibits lower levels of elastic fiber formation, which promotes vascular collapse and subsequent closure of the DA after birth. The molecular mechanisms for this inhibited elastogenesis in the DA, which is necessary for the establishment of adult circulation, remain largely unknown. METHODS AND RESULTS: Stimulation of the prostaglandin E2 (PGE2) receptor EP4 significantly inhibited elastogenesis and decreased lysyl oxidase (LOX) protein, which catalyzes elastin cross-links in DA smooth muscle cells (SMCs), but not in aortic SMCs. Aortic SMCs expressed much less EP4 than DASMCs. Adenovirus-mediated overexpression of LOX restored the EP4-mediated inhibition of elastogenesis in DASMCs. In EP4-knockout mice, electron microscopic examination showed that the DA acquired an elastic phenotype that was similar to the neighboring aorta. More importantly, human DA and aorta tissues from 7 patients showed a negative correlation between elastic fiber formation and EP4 expression, as well as between EP4 and LOX expression. The PGE2-EP4-c-Src-phospholipase C (PLC)gamma-signaling pathway most likely promoted the lysosomal degradation of LOX. CONCLUSIONS: Our data suggest that PGE2 signaling inhibits elastogenesis in the DA, but not in the aorta, through degrading LOX protein. Elastogenesis is spatially regulated by PGE2-EP4 signaling in the DA. PMID- 24146254 TI - Clinical outcomes of surgical pulmonary valve replacement after repair of tetralogy of Fallot and potential prognostic value of preoperative cardiopulmonary exercise testing. AB - BACKGROUND: Indications for surgical pulmonary valve replacement (PVR) after repair of tetralogy of Fallot have recently been broadened to include asymptomatic patients. METHODS AND RESULTS: The outcomes of PVR in adults after repair of tetralogy of Fallot at a single tertiary center were retrospectively studied. Preoperative cardiopulmonary exercise testing was included. Mortality was the primary outcome measure. In total, 221 PVRs were performed in 220 patients (130 male patients; median age, 32 years; range, 16-64 years). Homografts were used in 117 patients, xenografts in 103 patients, and a mechanical valve in 1 patient. Early (30-day) mortality was 2%. Overall survival was 97% at 1 year, 96% at 3 years, and 92% at 10 years. Survival after PVR in the later era (2005-2010; n=156) was significantly better compared with survival in the earlier era (1993-2004; n=65; 99% versus 94% at 1 year and 98% versus 92% at 3 years, respectively; P=0.019). Earlier era patients were more symptomatic preoperatively (P=0.036) with a lower preoperative peak oxygen consumption (peak Vo2; P<0.001). Freedom from redo surgical or transcatheter PVR was 98% at 5 years and 96% at 10 years for the whole cohort. Peak Vo2, E/CO2 slope (ratio of minute ventilation to carbon dioxide production), and heart rate reserve during cardiopulmonary exercise testing predicted risk of early mortality when analyzed with logistic regression analysis; peak Vo2 emerged as the strongest predictor on multivariable analysis (odds ratio, 0.65 per 1 mL.kg-1.min-1; P=0.041). CONCLUSIONS: PVR after repair of tetralogy of Fallot has a low and improving mortality, with a low need for reintervention. Preoperative cardiopulmonary exercise testing predicts surgical outcome and should therefore be included in the routine assessment of these patients. PMID- 24146255 TI - The effect of an APOE polymorphism on cognitive function depends on age. AB - It remains controversial whether APOE E4 polymorphism is related to cognitive function in general population. We aimed to evaluate an association between the APOE E4 genotype and cognitive function, and whether this association may differ by age. Cognitive function was assessed using the Korean version of modified Mini Mental State Examination (K-mMMSE) in 10,371 Koreans aged 45-74 years in Namwon City. According to the APOE E4 status, all participants were classified as non carriers, heterozygotes, or homozygotes. Multiple linear and logistic regression models were used to evaluate the association between APOE genotypes and cognition. The frequency of APOE genotypes in the study population was 0.4, 10.1, 1.1, 72.9, 14.7 and 0.8 % for E2E2, E2E3, E2E4, E3E3, E3E4, and E4E4, respectively. Compared to the APOE E4 non-carriers, the heterozygotes and homozygotes showed 1.3 and 7.3 % lower K-mMMSE scores at 65-74 years and 0.8 and 4.6 % higher scores at 45-55 years, respectively. Educational attainment modified the effect of APOE E4 on cognitive function in the 45-54 age group (p for interaction =0.003), showing that the E4 carriers with no-formal education showed significantly higher cognitive function than those with formal education. The present study demonstrates that the effect of APOE E4 on cognitive function depends on age and education. PMID- 24146256 TI - Analysis of the role of PrrA, PpsR, and FnrL in intracytoplasmic membrane differentiation of Rhodobacter sphaeroides 2.4.1 using transmission electron microscopy. AB - Oxygen dictates the catabolic "lifestyle" of Rhodobacter sphaeroides. When it is present, the bacteria are fully equipped for aerobic respiration. When it is absent, the cells outfit themselves to make use of energy-gathering options that do not require oxygen. Thus, while respiring on alternate electron acceptors in the absence of oxygen even in the dark, the cells are fully enabled for phototrophy. PrrA, PpsR, and FnrL are global regulatory proteins mediating oxygen control of gene expression in this organism. For each of these, regulon members include a subset of a cluster of genes known as the photosynthesis genes, which encode the structural proteins and enzymes catalyzing biosynthesis of the pigments of the light-harvesting and reaction center complexes. The complexes are housed in a specialized structure called the intracytoplasmic membrane (ICM). Although details are emerging as to the differentiation process leading to fully formed ICM, little is known of necessary regulatory events beyond changes in photosynthesis gene transcription. This study used transmission electron microscopy toward gaining additional insights into potential roles of PrrA, PpsR, and FnrL in the formation of ICM. The major findings were (1) the absence of either PrrA or FnrL negatively affects ICM formation, (2) the lack of ICM in the absence of PrrA is partially, but not fully reversed by removing PpsR from the cell, (3) unlike R. sphaeroides, ICM formation in Rhodobacter capsulatus does not require FnrL. New avenues these findings provide toward identifying additional genes involved in ICM formation are discussed. PMID- 24146257 TI - Novel antiviral agents for respiratory viral infection in immunocompromised adults. AB - Respiratory viruses cause significant morbidity and mortality in immunocompromised populations such as stem cell transplant and solid organ transplant patients. Few viruses causing respiratory tract infection have an approved therapy, and many of the viruses have no therapeutic options at all. In this article, we describe novel agents under development for treatment options against several respiratory viruses. PMID- 24146258 TI - HPV vaccine education: enhancing knowledge and attitudes of community counselors and educators. AB - Educational efforts targeting parents of preadolescents may help them make informed decisions about having their children vaccinated against the human papillomavirus (HPV). We conducted a pilot study examining knowledge, attitudes, and beliefs of community-based health educators and counselors who routinely disseminate sexual health and prevention information through counseling and supporting these parents. We evaluated the impact of a single, brief workshop by administering questionnaires before and after the session. The workshop consisted of an educational intervention that was presented orally by an expert in gynecological oncology and was followed by an open discussion period. Following the information and discussion session, improvements were seen in knowledge accuracy, confidence in being able to discuss HPV vaccine issues with parents, greater willingness to recommend the vaccine, and a better understanding of potential barriers to vaccine uptake. These results suggest that health educators and counselors may be better prepared to encourage their clients to make well informed decisions regarding HPV vaccination. PMID- 24146259 TI - Expression and localization of TRPC proteins in rat ventricular myocytes at various developmental stages. AB - Growing evidence indicates that transient receptor potential canonical (TRPC) channels play important roles in various Ca(2+)-mediated physiological and pathophysiological processes, including development. Many types of TRPC proteins are expressed in the heart. However, limited data are available comparing the expression and localization among TRPC proteins in the ventricular myocyte at various developmental stages. Our purpose is to investigate the expression and localization profile of TRPC proteins in ventricular myocytes of fetal (18.5 days), neonatal (< 24 h after birth) and adult (8 week old) rats. Western blotting, immunofluorescence and confocal laser scanning microscopy were employed. TRPC1/3-6 proteins were expressed in the rat ventricle throughout the three developmental stages. The expression profile of TRPC1/3/4 in the ventricle followed an upward trend from the fetus to the adult. By contrast, TRPC6 in the ventricle was expressed at the highest level in the fetal group and was sharply down-regulated immediately after birth. TRPC5 expression in the ventricle did not change significantly during the three stages. TRPC1/3/5/6 proteins were localized to the T-tubule and TRPC1/3/4/6 to intercalated disks in adult myocytes. The wide spatiotemporal overlap and dynamic regulation of TRPC expression in ventricular myocytes indicates potential complex combinations and redundancy of native TRPC proteins in the heart and gives important clues for further investigations into the exact subunit compositions and functional properties of native TRPC channels in the heart. PMID- 24146260 TI - Phase II clinical study of alternate-day oral therapy with S-1 as first-line chemotherapy for locally advanced and metastatic pancreatic cancer. AB - PURPOSE: Based on the results of first-line chemotherapy for advanced pancreatic cancer, S-1 was confirmed to be non-inferior to gemcitabine. However, the recommended regimen of 4 weeks of administration followed by 2 weeks of drug withdrawal frequently causes adverse effects. On the other hand, we experienced in clinical practice that alternate-day administration of S-1 reduced adverse effects and were tolerable for advanced pancreatic cancer patients unwilling to continue the standard daily administration. We therefore conducted a multicenter cooperative prospective study to compare daily with alternate-day administration of S-1 for advanced pancreatic cancer. METHODS: Patients with advanced pancreatic cancer were eligible for enrollment in this trial. S-1 was administered at a dose of 40-60 mg twice daily, calculated according to body surface area, on Monday, Wednesday, Friday, and Sunday. Each treatment cycle was 42 days. The primary end point was overall survival (OS). Secondary end points were safety, response rate (RR), progression-free survival (PFS), and time to treatment failure (TTF). RESULTS: Forty-eight patients were evaluable for response. OS as the primary end point was 8.4 months (95 % CI 5.4-10.8), and the 1-year survival rate was 29.2 %. PFS was 5.5 months, and TTF was 3.9 months. RR was 10.4 %, and the disease control rate was 79.2 %. Grade 3/4 hematological and non-hematological toxicities were minor. All of these adverse reactions were tolerable and reversible. CONCLUSIONS: The current data demonstrate the mitigation of adverse effects with alternate-day administration of S-1, and this appears to be a more sustainable option for advanced pancreatic cancer. PMID- 24146261 TI - Diffusion of pharmaceuticals: cross-country evidence of anti-TNF drugs. AB - This article studies the diffusion of biopharmaceuticals across European countries, focusing on anti-TNF drugs, which are used to treat autoimmune diseases (e.g., rheumatism, psoriasis). We use detailed sales information on the three brands Remicade, Enbrel and Humira for nine European countries covering the period from the first launch in 2000 until becoming blockbusters in 2009. Descriptive statistics reveal large variations across countries in per-capita consumption and price levels both overall and at the brand level. We explore potential sources for the cross-country consumption differences by estimating several multivariate regression models. Our results show that large parts of the cross-country variation are explained by time-invariant country-specific factors (e.g., disease prevalence, demographics, health care system). We also find that differences in income [gross domestic product (GDP) per capita] and health spending (share of GDP) explain the cross-country variation in consumption, while relative price differences seem to have limited impact. PMID- 24146262 TI - Noncoding RNAs in prostate cancer: the long and the short of it. AB - As the leading culprit in cancer incidence for American men, prostate cancer continues to pose significant diagnostic, prognostic, and therapeutic tribulations for clinicians. The vast spectrum of disease behavior warrants better molecular classification to facilitate the development of more robust biomarkers that can identify the more aggressive and clinically significant tumor subtypes that require treatment. The untranslated portion of the human transcriptome, namely noncoding RNAs (ncRNA), is emerging as a key player in cancer initiation and progression and boasts many attractive features for both biomarker and therapeutic research. Genetic linkage studies show that many ncRNAs are located in cancer-associated genomic regions that are frequently deleted or amplified in prostate cancer, whereas aberrant ncRNA expression patterns have well-established links with prostate tumor cell proliferation and survival. The dysregulation of pathways controlled by ncRNAs results in a cascade of multicellular events leading to carcinogenesis and tumor progression. The characterization of RNA species, their functions, and their clinical applicability is a major area of biologic and clinical importance. This review summarizes the growing body of evidence, supporting a pivotal role for ncRNAs in the pathogenesis of prostate cancer. We highlight the most promising ncRNA biomarkers for detection and risk stratification and present the state-of-play for RNA-based personalized medicine in treating the "untreatable" prostate tumors. PMID- 24146263 TI - Serological markers in psoriatic arthritis: promising tools. AB - The aim of this study was to identify specific biomarkers that could be used to screen for psoriatic arthritis (PsA), as well as to assess disease activity and treatment outcome in affected patients. Forty-three outpatients considered eligible for anti-TNF-alpha treatment (etanercept 50 mg/week) were enrolled. Serum samples of vascular endothelial growth factor (VEGF), metalloproteinase-3 (MMP3), pentraxin 3 (PTX3), and high-sensitive C-reactive protein (hs-CRP) were collected at baseline (t0) and after 6 (t6), 12 (t12), and 24 months (t24) of treatment. Baseline values were compared with those of a group of healthy controls matched for age and sex. Disease activity scores and functional tests (DAS28, BASDAI, PASI, BASFI, HAQ, VAS pain, and VAS patient global disease activity) after treatment were found to be significantly different from baseline values. At baseline, MMP3, hs-CRP and VEGF values in the PsA-patients were found to be significantly higher with respect to levels in the controls. There were no differences in the PTX3 values. MMP3 was significantly lower at t6 (P < 0.0001), t12 (P < 0.0001) and t24 (P < 0.0001). hs-CRP and VEGF were significantly lower, respectively, at t12 (P < 0.01; P < 0.05) and t24 (P < 0.05; P < 0.01). PTX3 was significantly higher at t24 (P < 0.05). A correlation was found between MMP3 and hs-CRP (r = 0.45, P = 0.0005). MMP3, hs-CRP, and VEGF appear to be useful for the early detection of PsA and to monitor disease progression. The rise in PTX3 did not appear to be linked to the inflammatory state of the disease but might be an expression of the atherosclerotic process frequently observed in PsA. PMID- 24146264 TI - Improved clearance of radioiodinated hypericin as a targeted anticancer agent by using a duodenal drainage catheter in rats. AB - We sought to reduce the radioactive intestinal waste after intravenous injection of necrosis avid iodine-131-labeled hypericin in dual-targeting anticancer radiotherapy and to study its pharmacokinetics in rats using a newly designed catheter. Iodine-123-labeled hypericin was prepared with iodogen as oxidant and characterized by high-performance liquid chromatography and mass spectrometry. After iodine-123-labeled hypericin administration, duodenal juice was collected via a catheter from groups of rats (n = 5) at intervals of 0-4, 4-8 or 20-24 h. The content was assessed by gamma-counting. The biodistribution and pharmacokinetics of iodine-123-labeled hypericin were investigated in rats without (n = 5) and with continuous catheterization (n = 5) for 9 h. After labeling, a high radiochemical yield was obtained with iodine-123-labeled hypericin (>95%), as confirmed by high-performance liquid chromatography and mass spectrometry. In the duodenal aspirate from animals with intermittent catheterization during 24 h, radioactivity accounted for 46% of the total with two peaks at 3 h and 8 h, suggesting enterohepatic circulation. Rats with 9 h of catheterization exhibited one peak representing 20% of the radioactivity. Major metabolites appeared to be conjugated iodine-123-labeled hypericin forms. In rats without and with catheter, iodine-123-labeled hypericin showed exponential elimination from plasma with no significant dehalogenation. Delayed iodine-123 labeled hypericin excretion, a higher maximum concentration (Cmax), larger area under concentration-time curve [AUC(0-infinity)] and a longer mean residence time were observed in non-catheterized animals (P < 0.05). The catheterized group exhibited lower urinary excretion than non-catheterized group (P < 0.05). Rats with a catheter showed lower radioactivity (P = 0.01) in the small intestines than those without a catheter (1.82 +/- 0.41 versus 18.95 +/- 4.32 percentage of the injected dose). After iodine-123-labeled hypericin administration, the radioactivity excreted into bile was efficiently removed from the body via a duodenal catheter. Radiation overexposure due to the prolonged elimination of iodine-131-labeled hypericin can be prevented using this approach. PMID- 24146265 TI - Expression characterization and promoter activity analysis of the tilapia (Oreochromis niloticus) myosin light chain 3 promoter in skeletal muscle of fish. AB - A tilapia (Oreochromis niloticus) myosin light chain 3 (Mlc3) promoter region (~4.3 kb) was isolated and characterized. Sequence analysis of the clone revealed high similarity with a tilapia gene encoding the Mlc3 promoter region, exon 1, and intron 1. The clone contained several putative binding sequences for transcription factors, including MEF-2, MYOG, MyoD, PKNOX1, and AREB6. Deletion of a region of the tilapia Mlc3 promoter (801 to -3,881 bp) enhanced promoter activity, as determined by direct injection of a luciferase reporter construct into skeletal muscle of Archocentrus nigrofasciatus. These findings suggest that the region between -801 and -3,881 bp may contain negative regulatory elements. Stable germline transgenic strains of the ornamental fish species A. nigrofasciatus var. carrying the Taiwan coral red fluorescent protein (TcRFP) driven by the Mlc3 promoter were established. F1 adult transgenic A. nigrofasciatus var. exhibited brilliant pink fluorescence in skeletal muscles in the daylight. Therefore, our current study demonstrates the feasibility of using the tilapia Mlc3 promoter to drive fluorescence in new fish species, such as Perciformes. PMID- 24146266 TI - The effectiveness of simultaneous medial spindle and/or lateral tarsal strip procedure in East Asian patients who need endonasal dacryocystorhinostomy. AB - BACKGROUNDS: To evaluate the effectiveness of simultaneous medial spindle procedure (MS) and/or lateral tarsal strip procedure (TS) with an endonasal dacryocystorhinostomy (DCR) for treatment of involutional medial punctal ectropion, horizontal eyelid laxity, and nasolacrimal duct obstruction. METHODS: We conducted a retrospective, interventional study of DCR performed from March 2009 to July 2011 by a single surgeon (Baek SH). Patient age, sex, results of medial and lateral distraction test, surgical procedure, time of tube removal, duration of follow-up, functional and anatomical success rate, and causes of failed surgeries were recorded. Lateral lower eyelid laxity was evaluated by a medial distraction test, and medial lid laxity was evaluated by a lateral distraction test. RESULTS: A total of 241 eyes in 175 patients were included in this study. The proportion of combined surgeries to total DCR was 24.5% (59 of 241 eyes). DCR and MS (D + M) were performed on 23 eyes in 17 patients (9.5%) and DCR and TS (D + T) on 29 eyes in 17 patients (12.0%). Concurrent DCR, MS and TS (D + M + T) were performed on seven eyes in four patients (2.9%). Mean age was significantly higher in the combined surgery groups (63.8 +/- 10.0 years) than in the DCR group (56.2 +/- 10.6 years; p = 0.01, by Mann-Whitney U test). The anatomical success rates were 84.2% in D, 86.9% in D + M, 89.5% in D + T, and 85.7% in D + M + T (p = 0.61 by Kruskal-Wallis test). Functional success rates were 82.4% in D, 86.9% in D + M, 86.2% in D + T, and 85.7% in D + M + T (p = 0.91 by Kruskal-Wallis test). CONCLUSIONS: MS and TS performed concurrently with a DCR may be an effective tool to deal with epiphora due to complex clinical situations such as nasolacrimal duct obstruction, lid laxity, and involutional medial ectropion. It is recommended to examine punctum and lid laxity carefully using slit-lamp biomicroscopy and lid distraction test in patients with epiphora, especially in elderly patients. PMID- 24146267 TI - Idiopathic macular hole: analysis of visual outcomes and the use of indocyanine green or brilliant blue for internal limiting membrane peel. AB - BACKGROUND: Our aim was to analyze outcomes of idiopathic macular hole surgeries in relation to staging and the use of indocyanine green (ICG) or brilliant blue (BB) for internal limiting membrane (ILM) peel. METHODS: Baseline, surgical, and outcome data for 351 consecutive primary macular hole surgeries was prospectively collected using electronic medical record software between 2001 and 2011. The outcomes for these cases were analysed in relation to staging and the use of ICG (0.5 mg/ml) or BB for ILM peel. RESULTS: Mean age was 68.9 years (range 39-87) with 66.4 % females and 54.1 % right eyes. Follow-up duration was median 0.55 years. Vision was significantly improved from logMAR 0.97 (SD 0.45) (Snellen equivalent 20/185) preoperatively to 0.65 (SD 0.51) (20/90) at final follow-up. One hundred and eighteen patients had stage 2 macular holes, 185 stage 3, and 48 stage 4. Mean duration of symptoms varied with stage of hole: stage 2 0.53 years (SD 0.43), stage 3 0.79 years (SD 0.68), and stage 4 1.20 years (SD 1.26), p = 0.0002. Closure rates of the holes were significantly different, with stage 2 closing in 95.8 %, stage 3 in 73.0 %, and stage 4 in 56.3 %, p < 0.0001. At final follow-up, mean visual acuity (VA) was 0.42 (SD 0.33) (20/50) for stage 2, 0.75 (SD 0.53) (20/110) for stage 3, and 0.87 (SD 0.60) (20/145) for stage 4 holes, p < 0.0001. Postoperative VA was 0.71 (SD 0.53) (20/100) for patients in whom ICG was used, and 0.52 (SD 0.43) (20/70) for BB, p = 0.003. The proportion of patients who achieved a closed hole was less for ICG (73.2 %) than BB (89.9 %), p = 0.0005. For those patients with stage 2 hole who achieved hole closure, mean improvement in VA was significantly better for BB (0.47, SD 0.36) than for ICG (0.30, SD 0.31), p = 0.01. CONCLUSIONS: Macular hole stage is a useful measure to help predict the chance of postoperative hole closure and visual outcome. The relationship between duration of symptoms and increasing stage suggests macula hole patients require prompt referral for consideration of early surgery. Better visual outcomes were achieved with BB for ILM peel than with ICG. PMID- 24146268 TI - Quality assessment of corneal storage media and their components. AB - BACKGROUND: To keep the loss of endothelial cell density in donor corneas to a minimum, a storage medium which is adjusted to their nutritional needs is necessary. Different media, used either serum-supplemented or serum-free, are available. The quality of medium- and serum-batches as well as support of endothelial cell viability by the medium are to be tested with a quality assured screening system that allows routine examination. METHODS: A screening system was developed which is based on cell-culture tests with the well-established human corneal endothelial cell line HCEC-12, and therefore can be performed without the need for donor corneas. The cells are plated at a defined density in cell-culture dishes, and are cultured for a defined period of time in the test media. Evaluation is carried out by assaying cell count, activity of cell metabolism (resazurin conversion), and determining the number of apoptotic and necrotic cells (combined vital staining with YO-PRO(r)-1/propidium iodide and subsequent flow cytometry). RESULTS: Human corneal endothelial cells that are cultured in a medium which is adjusted to their nutritional needs achieve higher cell numbers and show a higher metabolic rate. Simultaneously, the percentage of apoptotic and necrotic cells is lower. The screening system developed in this study allows for easy and reliable detection of slightest differences between different media, different processing steps for same media, and different supplements, as well as different serum batches. CONCLUSIONS: The differentiated results show that the screening system is sensitive enough to show even minor quality differences. Therefore, it is more suitable than the hitherto commonly used growth assay with primary, mostly porcine, corneal endothelial cells. PMID- 24146269 TI - Associated morbidity of nasolacrimal duct obstruction--a large community based case-control study. AB - BACKGROUND: To evaluate the prevalence and risk factors of various conditions among patients with nasolacrimal duct obstruction (NLDO). METHODS: A retrospective, observational case control study of 2,615 patients diagnosed with NLDO in the Central District of Clalit Health Services HMO in Israel, from 2003 to 2012; 15,650 control patients were randomly selected from the district HMO members. Medical and socio-demographic information were extracted from patients' electronic medical records. The prevalence of various ocular and systemic conditions as risk factors for NLDO was calculated. RESULTS: The average age of NLDO patients was 68.3 +/- 14.9 years, 34.4 % were male. Age (p < 0.001), ischemic heart disease (OR = 1.29; CI: 1.15-1.44), glaucoma (OR = 1.17; CI: 1.01 1.36), allergic conjunctivitis (OR = 3.59; CI: 3.28-3.94), dry eye (OR = 1.43; CI: 1.31-1.58), epiphora (OR = 6.34; CI: 5.09-7.91), and allergic rhinitis (OR = 1.51; CI: 1.33-1.71) were significantly associated with NLDO. Smoking (OR = 0.86; CI: 0.77-0.96) was significantly less prevalent among NLDO patients. CONCLUSIONS: The etiology of NLDO is multifactorial. The prevalence of associated demographic, systemic, and periocular conditions varies. A better understanding of the patho physiological association between these factors and NLDO may help its prevention and treatment. PMID- 24146270 TI - Mean platelet volume is influenced by many inflammatory and cardiovascular disorders and cardiovascular risk factors. PMID- 24146271 TI - Spectral-domain optical coherence tomography analysis in deprivational amblyopia: a pilot study with unilateral pediatric cataract patients. AB - BACKGROUND: To investigate whether macular and peripapillary retinal nerve fiber layer (RNFL) structure differs among deprivational amblyopic eyes, fellow non amblyopic eyes, and age-matched normal eyes, using spectral-domain optical coherence tomography (SD-OCT). METHODS: Macula and optic disc of 14 unilateral pseudophakic children with deprivational amblyopia, and 14 age-matched normal children (mean age, 7.45 +/- 2.57 years) were scanned with Cirrus(TM) HD-OCT. Macular, RNFL, and macular ganglion cell-inner plexiform layer (GCIPL) thicknesses were measured, and compared between the eyes after correction for axial length-related magnification errors. RESULTS: The average RNFL thickness tended to be greater in amblyopic eyes (99.64 +/- 10.11 MUm) than in fellow non amblyopic eyes (97.28 +/- 12.34 MUm) and normal eyes (95.38 +/- 9.74 MUm), but did not show statistical significance (p = 0.429, p = 0.286 respectively). The nasal RNFL thickness was significantly greater in amblyopic eyes (75.84 +/- 19.22 MUm) than in fellow non-amblyopic eyes (63.42 +/- 14.05 MUm, p = 0.037) and normal eyes (62.38 +/- 9.65 MUm, p = 0.043). The central macular thickness in amblyopic eyes (237.05 +/- 37.74 MUm) showed no significant differences compared to those of fellow non-amblyopic eyes (226.67 +/- 34.71 MUm) and normal eyes (233.74 +/- 27.11 MUm) (p = 0.137, p = 0.792 respectively). The macular GCIPL thickness showed no significant difference among the amblyopic, fellow non amblyopic, and normal eyes (average; 78.94 +/- 6.35 MUm vs 78.77 +/- 6.43 MUm vs 82.22 +/- 5.00 MUm respectively, p > 0.05). CONCLUSIONS: SD-OCT analysis of deprivational amblyopic eyes with unilateral pediatric cataract demonstrated significant increase in nasal RNFL thickness compared to fellow non-amblyopic eyes and age-matched normal eyes. The macular and macular GCIPL thickness did not show any significant difference. Taken together, monocular pattern deprivation in early childhood may have changed the nasal peripapillary RNFL structure. PMID- 24146272 TI - Inner retinal layer comparisons of eyes with exudative age-related macular degeneration and eyes with age-related macular degeneration and glaucoma. AB - BACKGROUND: The incidence of glaucoma increases with age, as does age-related macular degeneration (AMD), with the reported incidence of glaucoma among AMD subjects being 5.4 %. Optical coherence tomography (OCT) can detect glaucomatous changes in the inner retina with high sensitivity. The purpose of this study was to compare ganglion cell complex (GCC) parameters and the thickness of the peripapillary retinal nerve fiber layer (RNFL) in normal eyes to that observed in eyes with age-related macular degeneration (AMD) and eyes with both AMD and glaucoma. METHODS: The GCC components [GCC thickness, focal loss volume (FLV), and global loss volume (GLV)] and peripapillary RNFL thickness were measured using RTVue spectral-domain OCT (SD-OCT). The GCC and RNFL parameters of normal eyes, AMD eyes treated with different types of therapy, and AMD eyes with and without glaucoma were evaluated using nonparametric tests. Univariate and multivariate analyses were used to determine whether the GCC and RNFL parameters could be used to differentiate AMD eyes with glaucoma from those without glaucoma. RESULTS: Seventy-one normal eyes, 120 eyes with AMD, and 23 eyes with AMD and glaucoma were studied. The values of all GCC components were significantly different in the normal eyes from those observed in the eyes with AMD, except for the RNFL thicknesses. The GCC and RNFL parameters were not significantly different between the eyes receiving different types of therapy among the AMD groups. The RNFL thickness was significantly correlated with glaucoma diagnosis in AMD eyes. CONCLUSIONS: These findings indicate that there is damage to the inner retinal layers in eyes with AMD. The RNFL thickness can be a useful parameter for differentiating eyes with AMD from eyes with both AMD and glaucoma. PMID- 24146274 TI - Letter to the Editor: Recent advances in research on cognition and emotion in OCD: a review. AB - Cognitive theories of obsessive-compulsive disorder (OCD) ascertain that catastrophic (mis)interpretations of normally occurring intrusive thoughts are causal to the onset and maintenance of OCD. Recently, Calkins, Berman and Wilhelm have highlighted research validating the cognitive model. However, the current comment article stresses various findings that challenge basic premises of the cognitive theory. Moreover, a review of clinical studies investigating cognitive and behavioral therapies for OCD questions the added value of cognitive interventions over and above behavior therapy consisting of exposure and response prevention for this disorder. We suggest an alternative, potentially more useful route of investigation, stressing executive (dis)functions as the cause of OCD patients to (automatically) act on internal and external stimuli. We further suggest that dysfunctional beliefs proposed as paramount in the pathogenesis of OCD according to the cognitive model may be less important and specific than formerly believed. PMID- 24146273 TI - Analysis of resting heart rate and clinical characteristics in outpatients with stable coronary artery disease in Turkey: PULSE study. AB - BACKGROUND: An association between resting heart rate (RHR) and cardiovascular morbidity and mortality has been shown in patients with coronary artery disease (CAD). We aimed to evaluate the RHR and its relationship with clinical variables in outpatients with stable CAD at secondary and tertiary care centers in Turkey. METHODS: Adults with stable CAD in sinus rhythm were included in this non interventional, national, cross-sectional, multicenter study. Data were collected at a single study visit from 83 centers. RESULTS: The mean +/- standard deviation age of all patients (n = 2,919) was 61 +/- 10 years and 73% were males. The mean (SD) RHR was 73 +/- 12 bpm, and 62% of patients had RHR of >= 70 bpm. Females more frequently had RHR >= 70 bpm compared with males (67% vs. 60%; p = 0.002). RHR was significantly higher in patients with angina than in those without (76 +/ 13 vs. 73 +/- 11 bpm, p < 0.001). Left ventricular ejection fraction and heart rate lower-ing drug use were significantly lower in patients with a RHR >= 70 bpm (p < 0.05). CONCLUSIONS: The RHR of outpatients with stable CAD was not within the level recommended by the guidelines. PMID- 24146275 TI - Vascular endothelial growth factor -634G/C and vascular endothelial growth factor -2578C/A polymorphisms and lung cancer risk: a case-control study and meta analysis. AB - Vascular endothelial growth factor (VEGF) is a major regulator of angiogenesis in the process of tumor growth and metastasis. In present study, we conducted a case control study and meta-analysis to evaluate the genetic effects of VEGF -634G/C and VEGF -2578C/A polymorphisms and risk of lung cancer. A total of 175 subjects were recruited for case-control study and seven studies were included in the meta analysis. Our case-control study showed that VEGF -634G/C polymorphism had no association with lung cancer risk (CC vs. GG: OR = 0.88, 95% CI = 0.37-2.11), whereas there was an association between VEGF -2578CC genotype and decrease in lung cancer risk (CC vs. CA/AA: OR = 0.52, 95% CI = 0.28-0.96). A meta-analysis was further performed and statistically similar results were obtained (CC vs. GG: OR = 0.91, 95% CI = 0.60-1.39 for VEGF -634; CC vs. AA: OR = 0.53, 95% CI = 0.32 0.89 for VEGF -2578). Our study showed that the variant genotypes of the VEGF 2578C/A polymorphism, but not the VEGF -634G/C polymorphism, was associated with lung cancer risk. More studies are needed to detect VEGF -634G/C and VEGF -2578 polymorphisms and their association with lung cancer in different ethnic populations incorporated with environmental exposures. PMID- 24146276 TI - Genetic association of PLCE1, C11orf92-C11orf93, and NOC3L with colorectal cancer risk in the Han population. AB - Colorectal cancer (CRC) is a common malignant tumor that is influenced by an interaction between genetic and environmental factors. Currently, the inherited factors of CRC are unclear. Our study selected 19 tag single nucleotide polymorphisms (tSNPs) to investigate whether they were associated with CRC in the Han population. In this Han Chinese case-control study, we genotyped 203 CRC cases and 296 controls using Sequenom MassARRAY technology and analyzed their associations with CRC using chi(2) tests, SNPStats software, and SHEsis software. Based on chi(2) tests, PLCE1 -rs2077218, rs11187877 (p = 0.049) and C11orf92 C11orf93-rs3802842 (p = 0.023) correlate with CRC risk. In the genetic model analyses, we found the genotype "CC" of rs3802842 in C11orf92-C11orf93 may significantly increase CRC risk in the recessive model (p = 0.0071), whereas "GT" of rs17109928 in NOC3L may decrease the risk in the over-dominant model (p = 0.0091). Using SHEsis software, we found PLCE1 and NOC3L are strongly linked, and the "GCCATTCTGTC" haplotype may increase the risk of CRC (p = 0.049). We found three genes (PLCE1, C11orf92-C11orf93, and NOC3L) are associated with CRC susceptibility. In combination with previous reports, our results suggest that these genes may be associated with CRC in the Han population. PMID- 24146277 TI - Genetic polymorphisms of methylenetetrahydrofolate reductase (MTHFR) gene Ala222Val and susceptibility to ovary cancer: a systematic review and meta analysis. AB - Many studies have reported the role of methylenetetrahydrofolate reductase (MTHFR) gene Ala222Val polymorphism with ovary cancer risk, but the results remained controversial. To derive a more precise estimation of the relationship, a meta-analysis was performed. Odds ratios (ORs) with 95% confidence intervals (CIs) were estimated to assess the association between MTHFR Ala222Val polymorphism and ovary cancer risk. A total of 8 studies including 3,723 cases and 4,001 controls were also involved in this meta-analysis. When all the eligible studies were pooled into this meta-analysis, no significant association between ovary cancer risk and MTHFR Ala222Val polymorphism was found in all genetic models [codominant model: OR = 0.980, 95% CI = 0.756-1.270, P h = 0.088, P = 0.877; dominant model: OR = 1.022, 95% CI = 0.864-1.208, P h = 0.033, P = 0.803; recessive model: OR = 1.050, 95% CI = 0.803-1.373, P h = 0.032, P = 0.723; allele comparison model: OR = 1.028, 95% CI = 0.898-1.178, P h = 0.012, P = 0.685]. In the stratified analysis by ethnicity, no evidence of any associations of this polymorphism with ovary cancer was found in the Caucasian populations. Our meta-analysis supports that the MTHFR Ala222Val polymorphism is not contributed to the risk of ovary cancer from currently available evidence. PMID- 24146278 TI - Quantitative assessment of the influence of prostate stem cell antigen polymorphisms on gastric cancer risk. AB - Prostate stem cell antigen (PSCA) is a glycosylphosphatidylinositol-anchored 123 amino acid protein related to the cell proliferation inhibition and/or cell death induction activity which has attracted considerable attention as a candidate gene for gastric cancer (GC) since it was first identified through genome-wide association approach. Since then, the relationship between PSCA polymorphisms (rs2294008, rs2976392) and GC has been reported in various ethnic groups; however, these studies have yielded inconsistent results. To investigate this inconsistency, we performed a meta-analysis of 16 studies involving a total of 18,820 cases and 35,756 controls for the two widely studied polymorphisms of PSCA on genetic susceptibility for GC. Overall, the summary odds ratio for GC was 1.46 (95% CI 1.30-1.69, P < 10(-5)) and 1.49 (95% CI 1.22-1.82, P < 10(-4)) for PSCA rs2294008 and rs2976392 polymorphisms, respectively. Meanwhile, haplotype analyses of the two polymorphisms revealed a significant association between the combination of these alleles and GC risk. When stratifying for ethnicity, significantly increased risks were found for rs2294008 and rs2976392 polymorphism among East Asians in all genetic models, while no significant associations were observed for the rs2294008 polymorphism in Caucasians. In the stratified analyses according to histological type, and source of controls, evidence of gene-disease association was still obtained. In addition, our data indicate that rs2294008 of PSCA is involved in GC susceptibility and confer its effect primarily in noncardia tumors (OR = 1.30, 95% CI 1.12-1.53, P < 10(-4)). Our findings demonstrated that rs2294008 and rs2976392 polymorphism of PSCA is a risk conferring factor associated with increased GC susceptibility, especially in East Asians. PMID- 24146279 TI - HMGB1 combining with tumor-associated macrophages enhanced lymphangiogenesis in human epithelial ovarian cancer. AB - Within tumor microenvironment, high-mobility group box protein 1 (HMGB1) and tumor-associated macrophages (TAMs) are able to influence ovarian cancer development and progression via facilitating tumor lymphatic metastasis. However, little is known about the association between HMGB1 and TAMs on lymphangiogenesis in epithelial ovarian cancer (EOC). To investigate the effect of HMGB1 and TAMs on lymphangiogenesis in EOC, immunohistochemistry was performed to determine the expressions of HMGB1, TAMs, and lymphatic vessel density (LVD) in a total of 108 ovarian tissue specimens. Then, the relationships between HMGB1 or TAMs and LVD were assessed by correlation test. In our in vitro study, TAMs were isolated from ascites of EOC patients. Effects of HMGB1, TAMs, and HMGB1 combining with TAMs on lymphatic endothelial cell (LEC) proliferation, migration, and the capillary-like tube formation were measured. Results showed that the expression of HMGB1 and the number of TAMs infiltration were overexpressed in malignant ovarian tumors compared with that in normal ovarian and were closely associated with lymph node metastasis. Positive correlations existed between HMGB1 expression or TAMs count and LVD determination. In an in vitro study, data demonstrated that either HMGB1 or TAMs could facilitate lymphangiogenesis by inducing LEC proliferation, migration, and capillary-like tube formation. Meanwhile, HMGB1 combining with TAMs may augment the pro-lymphangiogenic property. Our data suggest that either HMGB1 or TAMs could facilitate lymphangiogenesis, while HMGB1 coculture with TAMs may strengthen the pro-lymphangiogenic potential, which may serve as a therapeutic target for ovarian cancer. PMID- 24146280 TI - Cyclooxygenase 2 promoted the tumorigenecity of pancreatic cancer cells. AB - Pancreatic cancer is one of the leading causes of cancer-related death in the world. It is very urgent to find new therapeutic targets and improve the treatment. Cyclooxygenase 2 (Cox2), a regulator of inflammation signaling, has been found to be involved in tumorigenesis of various tumor types. However, its biological functions in pancreatic cancer cells are not fully understood. Here, we found that the expression of Cox2 was elevated in pancreatic cancer tissues compared with that in the paired normal tissues. The over-expression of Cox2 in pancreatic cancer cells promoted cell proliferation and migration, while the knockdown of the expression of Cox2 inhibited the tumorigenesis of pancreatic cancer cells in vitro and in vivo. Mechanistically, Cox2 regulated the expression of multiple genes involved in cell growth, migration, and cell apoptosis. Taken together, our study revealed the pivotal function of Cox2 in pancreatic cancer, and Cox2 might be an important therapeutic target for the treatment. PMID- 24146281 TI - Catechol-O-methyltransferase Val158Met polymorphism and breast cancer risk in Asian population. AB - The association between the polymorphism of catechol-O-methyltransferase (COMT) Val158Met and breast cancer risk is still inconclusive. We performed a meta analysis to derive a more precise estimation of the relationship. A total of 18 studies including 5,175 cases and 6,463 controls were involved in this meta analysis. When all studies were pooled into the meta-analysis, no significantly elevated breast cancer risk was associated with all genetic models (for additive model: OR = 1.273, 95% CI = 0.947-1.711, P heterogeneity = 0.000; P = 0.110; for dominant model: OR = 1.080, 95% CI = 0.945-1.234, P heterogeneity = 0.001; P = 0.259; for recessive model: OR = 1.242, 95% CI = 0.941-1.641, P heterogeneity = 0.000; P = 0.126; for allele comparison model: OR = 1.096, 95% CI = 0.976-1.230, P heterogeneity = 0.000; P = 0.121). In the subgroup analysis by controls source, the same results were found in all genetic models. In summary, this meta-analysis suggests that the COMT Val158Met polymorphism is not a risk factor for breast cancer development. However, large sample and representative population-based studies with homogeneous breast cancer patients and well-matched controls are warranted to confirm this finding. PMID- 24146282 TI - Neural network modeling of the light profile in a novel photobioreactor. AB - An artificial neural network (ANN) was implemented to model the light profile pattern inside a photobioreactor (PBR) that uses a toroidal light arrangement. The PBR uses Tequila vinasses as culture medium and purple non-sulfur bacteria Rhodopseudomonas palustris as biocatalyzer. The performance of the ANN was tested for a number of conditions and compared to those obtained by using deterministic models. Both ANN and deterministic models were validated experimentally. In all cases, at low biomass concentration, model predictions yielded determination coefficients greater than 0.9. Nevertheless, ANN yielded the more accurate predictions of the light pattern, at both low and high biomass concentration, when the bioreactor radius, the depth, the rotational speed of the stirrer and the biomass concentration were incorporated in the ANN structure. In comparison, most of the deterministic models failed to correlate the empirical data at high biomass concentration. These results show the usefulness of ANNs in the modeling of the light profile pattern in photobioreactors. PMID- 24146283 TI - Effects of signal sequences and folding accessory proteins on extracellular expression of carboxypeptidase Y in recombinant Saccharomyces cerevisiae. AB - Carboxypeptidase Y (CPY) is a yeast vacuolar protease with useful applications including C-terminal sequencing of peptides and terminal modification of target proteins. To overexpress CPY with the pro-sequence (proCPY) encoded by the Saccharomyces cerevisiae PRC1 gene in recombinant S. cerevisiae, the proCPY gene was combined with the gene coding for a signal sequence of S. cerevisiae mating factor alpha (MFalpha), invertase (SUC2), or Kluyveromyces marxianus inulinase (INU1). Among the three constructs, the MFalpha signal sequence gave the best specific activity of extracellular CPY. To enhance the CPY expression level, folding accessory proteins of Kar2p, Pdi1p and Ero1p located in the S. cerevisiae endoplasmic reticulum were expressed individually and combinatorially. A single expression of Kar2p led to a 28 % enhancement in extracellular CPY activity, relative to the control strain of S. cerevisiae CEN.PK2-1D/p426Gal1-MFalphaCPY. Coexpression of Kar2p, Pdi1p and Ero1p gave a synergistic effect on CPY expression, of which activity was 1.7 times higher than that of the control strain. This work showed that engineering of signal sequences and protein-folding proteins would be helpful to overexpress yeast proteins of interest. PMID- 24146284 TI - Relationship between adiposity and cognitive performance in 9-10-year-old children in South India. AB - BACKGROUND: Studies in high-income countries have shown inverse associations between adiposity and cognitive performance in children. We aimed to examine the relationship between adiposity and cognitive function in Indian children. METHODS: At a mean age of 9.7 years, height, weight, triceps and subscapular skinfold thicknesses and waist circumference were recorded for 540 children born in Mysore, India. Body fat percentage was estimated using bioimpedance. Cognitive function was assessed using three core tests from the Kaufman Assessment Battery for children-II edition and additional tests measuring learning, short-term memory, reasoning, verbal and visuo-spatial abilities, attention and concentration. Data on the parents' socioeconomic status, education, occupation and income were collected. RESULTS: According to WHO definitions, 3.5% of the children were overweight/obese (Body Mass Index (BMI)>+1SD) and 27% underweight (BMI<-2SD). Compared to normal children, overweight/obese children scored higher in tests of learning/long-term retrieval, reasoning and verbal ability (unadjusted p<0.05 for all). All the Cognitive Test scores increased with increase in BMI and skinfold thickness, (unadjusted beta=0.10-0.20 SD; p<0.05 for all). The effects, though attenuated, remained mainly significant after adjustment for age, sex and socioeconomic factors. Similar associations were found for waist circumference and percentage body fat. CONCLUSIONS: In this Indian population, in which obesity was uncommon, greater adiposity predicted higher cognitive ability. These associations were only partly explained by socioeconomic factors. Our findings suggest that better nutrition is associated with better cognitive function, and that inverse associations between adiposity and cognitive function in high-income countries reflect confounding by socioeconomic factors. PMID- 24146285 TI - The epidemiology of chronic fatigue syndrome/myalgic encephalitis in children. AB - Most paediatricians regularly see children with chronic fatigue syndrome or myalgic encephalitis (CFS/ME) in their clinics and yet we know little about how common it is, who is affected, whether there are risk factors and how likely a child is to recover (or what might predict recovery). Recent research suggests that this illness is more complicated than previously thought and that rather than being an illness found in middle class families, it is more common in those who are socially deprived. This article reviews what is currently known about this important but little understood condition. PMID- 24146286 TI - Velopharyngeal insufficiency: high detection rate of genetic abnormalities if associated with additional features. AB - OBJECTIVE: To review the clinical and molecular-genetic characteristics of 34 children who were referred to the clinical genetics department with a presenting diagnosis of definite or suspected velopharyngeal insufficiency (VPI, defined as the inability to close off the nasal from the oral cavity during speech) or hyponasal/hypernasal speech. All the patients referred also had additional anomalies and did not therefore comprise the whole VPI population. METHODS: Patients were clinically investigated by a clinical geneticist. Fluorescent in situ hybridisation for chromosome 22q11 deletion and/or array comparative genomic hybridisation (array CGH) analysis was performed in all cases. A literature review was performed using the Pubmed online database. RESULTS: Microdeletions or microduplications were identified in half of the patients. Six patients (~18% of total) carried a chromosome 22q11 microdeletion, one patient had a chromosome 22q11 microduplication, and four patients had microdeletions in other chromosomes that were considered likely to be associated with the phenotype. One patient had KBG syndrome. Thus, an underlying genetic abnormality was found in approximately one-third (35%) of our patients. An additional seven patients harboured copy number variations that were considered benign or of unknown significance. CONCLUSIONS: We present an overview of patients with VPI or hyponasal/hypernasal speech with additional anomalies and their clinical and genetic findings. In one third of these patients, an underlying genetic abnormality was identified. This has important implications for family counselling and medical follow-up. Furthermore, we recommend array CGH testing in all patients with VPI and associated anomalies because of the high percentage of copy number variants identified in these patients. PMID- 24146287 TI - Research activity, barriers and competencies among senior paediatricians in Scotland. PMID- 24146288 TI - A PET/CT-follow-up imaging study to differentiate takotsubo cardiomyopathy from acute myocardial infarction. AB - Takotsubo cardiomyopathy (TTC) is still an under-recognized disease and little data exists on the coexistence of TTC and obstructive coronary artery disease. Our patient case of an 80-year-old female lady highlights the impact of a positron emission tomography/computed tomography (PET/CT) follow-up imaging study to delineate this unique entity from acute coronary syndrome (ACS). Furthermore, we show for the first time that coronary flow reserve and myocardial blood flow is globally impaired in TTC and not only restricted to the non-contracting parts. This indicates a global microcirculatory impairment effect of the heart in the acute stage of TTC. Our case also demonstrates that a transient metabolic defect is also involved in this disease. Follow-up imaging by PET/CT in our patient case unmasked TTC and facilitated to exclude the differential diagnosis of ACS. PMID- 24146289 TI - On evolutionary stability of carrying capacity driven dispersal in competition with regularly diffusing populations. AB - Two competing populations in spatially heterogeneous but temporarily constant environment are investigated: one is subject to regular movements to lower density areas (random diffusion) while the dispersal of the other is in the direction of the highest per capita available resources (carrying capacity driven diffusion). The growth of both species is subject to the same general growth law which involves Gilpin-Ayala, Gompertz and some other equations as particular cases. The growth rate, carrying capacity and dispersal rate are the same for both population types, the only difference is the dispersal strategy. The main result of the paper is that the two species cannot coexist (unless the environment is spatially homogeneous), and the carrying capacity driven diffusion strategy is evolutionarily stable in the sense that the species adopting this strategy cannot be invaded by randomly diffusing population. Moreover, once the invasive species inhabits some open nonempty domain, it would spread over any available area bringing the native species diffusing randomly to extinction. One of the important technical results used in the proofs can be interpreted in the form that the limit solution of the equation with a regular diffusion leads to lower total population fitness than the ideal free distribution. PMID- 24146290 TI - Alzheimer's disease: analysis of a mathematical model incorporating the role of prions. AB - We introduce a mathematical model of the in vivo progression of Alzheimer's disease with focus on the role of prions in memory impairment. Our model consists of differential equations that describe the dynamic formation of beta-amyloid plaques based on the concentrations of Abeta oligomers, PrP(C) proteins, and the Abeta-x-Abeta-PrP(C)complex, which are hypothesized to be responsible for synaptic toxicity. We prove the well-posedness of the model and provided stability results for its unique equilibrium, when the polymerization rate of Abeta-amyloid is constant and also when it is described by a power law. PMID- 24146292 TI - Isolation and molecular characterization of Mycobacterium bovis from Kafue lechwe (Kobus leche kafuensis) from Zambia. AB - Bovine tuberculosis (BTB) is a chronic bacterial disease caused by Mycobacterium bovis. Infections due to M. bovis, which serves as a stable reservoir, can pose serious challenge to control and eradicate in both wildlife and livestock at the interface. This study aimed at isolating and characterizing M. bovis from Kafue lechwe (Kobus leche kafuensis) and black lechwe (Kobus leche smithemani) at the animal/human interface in Zambia. The samples with lesions compatible with BTB collected during the hunting seasons of 2009 and 2010 were cultured for isolation of mycobacteria using Stonebrink with pyruvate (BD Diagnostics, MD, USA) and Middlebrook 7H10 (BD Diagnostics) slants. Isolated mycobacteria were identified using IS6110 polymerase chain reaction and deletion analysis. Molecular characterization of the isolates was performed using spoligotyping and mycobacteria interspersed repetitive unit-variable number tandem repeat (MIRU VNTR) with nine loci. Data was analyzed using BioNumerics software 6.1. Out of the 39 samples, acid fast bacilli were detected in 27 (69.2 %) based on smear microscopy. Seven isolates were found to belong to Mycobacterium tuberculosis complex, and all were identified as M. bovis based on deletion analysis. All seven isolates were identical on spoligotyping as belonging to the SB0120 (SIT 482). MIRU-VNTR differentiated the isolates into five different patterns. This study has confirmed that M. bovis circulates in the Kafue lechwe, and non tuberculous mycobacteria were detected in the black lechwe in Zambia which represents a wildlife reservoir, with a potential to spillover to cattle and humans. Isolates of M. bovis from lechwe antelopes are much conserved as only one spoligotype was detected. The study has shown that three loci differentiated fairly well. This option is cheap and less laborious, and hence a better option in resource-strained country like Zambia. The study further showed that some of the loci recommended by the European Reference Laboratory are not suitable for typing M. bovis in Zambia. PMID- 24146291 TI - Dynamic permeability of the lacunar-canalicular system in human cortical bone. AB - A new method for the experimental determination of the permeability of a small sample of a fluid-saturated hierarchically structured porous material is described and applied to the determination of the lacunar-canalicular permeability [Formula: see text] in bone. The interest in the permeability of the lacunar-canalicular pore system (LCS) is due to the fact that the LCS is considered to be the site of bone mechanotransduction due to the loading-driven fluid flow over cellular structures. The permeability of this space has been estimated to be anywhere from [Formula: see text] to [Formula: see text]. However, the vascular pore system and LCS are intertwined, rendering the permeability of the much smaller-dimensioned LCS challenging to measure. In this study, we report a combined experimental and analytical approach that allowed the accurate determination of the [Formula: see text] to be on the order of [Formula: see text] for human osteonal bone. It was found that the [Formula: see text] has a linear dependence on loading frequency, decreasing at a rate of [Formula: see text]/Hz from 1 to 100 Hz, and using the proposed model, the porosity alone was able to explain 86 % of the [Formula: see text] variability. PMID- 24146293 TI - Molecular characterization of Newcastle disease viruses isolated from rural chicken in northwest Ethiopia reveals the circulation of three distinct genotypes in the country. AB - Newcastle disease (ND) is a highly contagious disease that affects many species of birds and causes significant economic losses to the poultry industry worldwide. Fifteen Newcastle disease virus (NDV) isolates obtained from rural chickens in northwest Ethiopia in 2011 and 2012 were characterized genotypically. The main functional region of the F gene was amplified and sequenced (260 nucleotides). Among the Ethiopian NDV isolates, 2 isolates had the virulent motif (112)R-R-Q-K-R-F(117) at the cleavage site of the fusion protein while 13 isolates contained the lentogenic motif (112)G-G/R-Q-G-R-L(117). Phylogenetic analysis based on the variable region of the F gene indicated that the two isolates exhibiting the virulent motif belonged to lineage 5 (genotype VII) subgenotype d and the remaining 13 isolates were grouped into lineage 2 (genotype II). The nucleotide sequences of lineage 5 isolates were genetically related to the Sudanese NDV isolates, suggesting potential epidemiological link of ND outbreaks between neighbouring countries. The lentogenic strains shared similarities with La Sota vaccine strain and probably originated from the vaccine strain either through direct exposure of birds to the live vaccine or to infectious La Sota-like strains circulating in rural poultry. This study provides genetic evidence on the existence of different NDV genotypes circulating in the rural poultry in Ethiopia. The virulent NDV continues to be a problem in poultry sector in Ethiopia, and their continuous circulation in rural and commercial poultry calls for improved surveillance and intensified vaccination and other control measures. PMID- 24146295 TI - Association study of anti-Mullerian hormone and anti-Mullerian hormone type II receptor polymorphisms with idiopathic primary ovarian insufficiency. AB - STUDY QUESTION: Are the genetic polymorphisms of the anti-Mullerian hormone (AMH) and anti-Mullerian hormone type II receptor (AMHR2) genes associated with idiopathic primary ovarian insufficiency (POI) in a Korean population? SUMMARY ANSWER: The distribution of the AMH and the AMHR2 polymorphisms in a Korean POI population was not significantly different from controls. WHAT IS KNOWN ALREADY: AMH plays an important role in regulating both the primordial follicle recruitment and the cyclic selection of the antral follicles. The AMHR2 -482A>G polymorphism was associated with an earlier menopause and nulliparous women with the GG genotype had a 2.6 years earlier onset of menopause compared with the AA genotype women. Therefore, genetic variants in the AMH signal transduction pathway might affect the ovarian function of women. STUDY DESIGN, SIZE, DURATION: Case-control study. The subjects consisted of 211 idiopathic POI patients and 233 post-menopausal controls. PARTICIPANTS/MATERIALS, SETTING, METHODS: The frequency of the AMH Ile(49)Ser and AMHR2 -482A>G polymorphisms was analyzed in 211 patients with idiopathic POI and in 233 post-menopausal controls, and we also analyzed clinical characteristics, such as age at the time of POI and LH, FSH as well as estradiol levels according to the specific genotype. Genotyping for the AMH Ile(49)Ser and the AMHR2 -482A>G polymorphisms was performed by a minor groove binder primer/probe Taqman assay. MAIN RESULTS AND THE ROLE OF CHANCE: The genotype distributions and allele frequencies for the AMH Ile(49)Ser and the AMHR2 -482A>G polymorphisms were similar between the POI patients and the controls. Within POI population, the AMH Ile(49)Ser and the AMHR2 -482A>G polymorphisms were not associated with age at the time of POI and LH, FSH as well as estradiol levels. Haplotype analysis also showed no significant difference between groups. LIMITATIONS, REASONS FOR CAUTION: Study is limited to a Korean population. WIDER IMPLICATIONS OF THE FINDINGS: Our findings suggest that genetic variants in the AMH signal transduction pathway may not influence the susceptibility of idiopathic POI. This is the first report on the association between the AMH and AMHR2 polymorphisms and idiopathic POI. STUDY FUNDING/COMPETING INTEREST(S): No conflict of interest exists. This study was supported by a grant of Seoul National University Hospital Research Fund (04-2011 0870). TRIAL REGISTRATION NUMBER: N/A. PMID- 24146294 TI - Mechanism of suppression of sustained neuronal spiking under high-frequency stimulation. AB - Using Hodgkin-Huxley and isolated subthalamic nucleus (STN) model neurons as examples, we show that electrical high-frequency stimulation (HFS) suppresses sustained neuronal spiking. The mechanism of suppression is explained on the basis of averaged equations derived from the original neuron equations in the limit of high frequencies. We show that for frequencies considerably greater than the reciprocal of the neuron's characteristic time scale, the result of action of HFS is defined by the ratio between the amplitude and the frequency of the stimulating signal. The effect of suppression emerges due to a stabilization of the neuron's resting state or due to a stabilization of a low-amplitude subthreshold oscillation of its membrane potential. Intriguingly, although we neglect synaptic dynamics, neural circuity as well as contribution of glial cells, the results obtained with the isolated high-frequency stimulated STN model neuron resemble the clinically observed relations between stimulation amplitude and stimulation frequency required to suppress Parkinsonian tremor. PMID- 24146296 TI - Climate change as a three-part ethical problem: a response to Jamieson and Gardiner. AB - Dale Jamieson has claimed that conventional human-directed ethical concepts are an inadequate means for accurately understanding our duty to respond to climate change. Furthermore, he suggests that a responsibility to respect nature can instead provide the appropriate framework with which to understand such a duty. Stephen Gardiner has responded by claiming that climate change is a clear case of ethical responsibility, but the failure of institutions to respond to it creates a (not unprecedented) political problem. In assessing the debate between Gardiner and Jamieson, I develop an analysis which shows a three-part structure to the problem of climate change, in which the problem Gardiner identifies is only one of three sub-problems of climate change. This analysis highlights difficulties with Jamieson's argument that the duty of respect for nature is necessary for a full understanding of climate ethics, and suggests how a human-directed approach based on the three-part analysis can avoid Jamieson's charge of inadequacy. PMID- 24146297 TI - Systematic review and meta-analysis of published randomized controlled trials comparing the role of self-gripping mesh against suture mesh fixation in patients undergoing open inguinal hernia repair. AB - The objective of this article is to analyze systematically the randomized, controlled trials comparing the use of self-gripping mesh (SGM) versus suture mesh fixation (SMF) in patients undergoing open inguinal hernia repair. Randomized, controlled trials comparing the use of SGM versus SMF in patients undergoing open inguinal hernia repair were analyzed using RevMan((r)), and combined outcomes were expressed as odds ratio (OR) and standardized mean difference (SMD). Four randomized, controlled trials recruiting 1,115 patients undergoing open inguinal hernia repair using SGM versus SMF were retrieved from the search of medical electronic databases. There were 553 patients in the SGM group and 562 patients in the SMF group. The incidence of chronic groin pain (OR 1.04; 95% CI 0.72, 1.49; z = 0.21; p = 0.83), recurrence (OR 0.76; 95% CI 0.14, 4.08; z = 0.32; p = 0.75), postoperative complications and length of hospital stay were similar in SGM and SMF groups. The duration of operation (SMD -0.36; 95% CI -0.47, -0.24; z = 5.88; p < 0.00001) was shorter following the use of SGM in open inguinal hernia repair. SGM failed to demonstrate the reduced incidence of postoperative groin pain following open inguinal hernia repair. In addition, hernia recurrence, postoperative complications and length of stay was also unchanged. However, SGM was associated with overall shorter operative time. PMID- 24146298 TI - Treatment of vaginal bleeding irregularities induced by progestin only contraceptives. AB - BACKGROUND: Despite their high effectiveness, progestin-only contraceptives are considered less than ideal by the many women who experience irregular vaginal bleeding when using them. Current treatments to control these bleeding problems are not sufficiently effective. OBJECTIVES: We evaluated preventive and therapeutic approaches to normalise bleeding irregularities associated with the use of progestin-only contraceptives. SEARCH METHODS: Literature was identified through database searches, reference lists, organisations and individuals, covering the period until May-June 2012. SELECTION CRITERIA: Trials with random or systematic allocation, testing interventions for the prevention or treatment of bleeding irregularities associated with the use of progestin-only contraceptives were eligible. DATA COLLECTION AND ANALYSIS: Results are expressed as relative risks (RR) with 95% confidence interval (CI) for categorical data and as weighted mean difference (WMD) with 95% CI for continuous data. When we encountered heterogeneity (visual or statistical) we used the random-effects model (quantitative) or did not produce a summary estimate (qualitative). MAIN RESULTS: Thirty-three randomised controlled trials enrolling 3677 participants were included. Two thirds of the trials were determined to reflect low to moderate risk of bias.Estrogen treatments reduced the number of days of an ongoing bleeding episode in DMPA and Norplant users. However, treatment frequently led to more discontinuation due to gastrointestinal upset.Combinations of oral ethinyl estradiol and levonorgestrel improved bleeding patterns in Norplant users, but method discontinuation rates were unchanged. One trial reported successful use of combined oral contraceptives in treating amenorrhea among DMPA users.Norplant users, but not Implanon users, administered the anti progestin mifepristone reported fewer days of bleeding during treatment than those given placebo. Mifepristone used monthly by new Norplant acceptors reduced bleeding, when compared to placebo.A variety of NSAIDS have been evaluated for their ability to treat abnormal bleeding, with mixed results.Norplant users receiving SERM (tamoxifen) had less unacceptable bleeding after treatment and were more likely to continue using Norplant than those receiving placebo.Tranexamic acid, mifepristone combined with an estrogen and doxycycline were more effective than placebo in terminating an episode of bleeding in women using progestin-only contraceptives, according to three small studies. AUTHORS' CONCLUSIONS: Some women may benefit from the interventions described, particularly with cessation of current bleeding. Several regimens offer promise in regulating bleeding, but findings need to be reproduced in larger trials. The results of this review do not support routine clinical use of any of the regimens included in the trials, particularly for long-term effect. PMID- 24146301 TI - Detection of cytokines in supernatant from hematopoietic stem/progenitor cells co cultured with mesenchymal stem cells and endothelial progenitor cells. AB - This study aimed to investigate the significance of cytokine expression in supernatant from hematopoietic stem/progenitor cells (HSCs/HPCs) co-cultured with mesenchymal stem cells (MSCs) or endothelial progenitor cells (EPCs). Mononuclear cells (MNCs) were isolated from normal human umbilical cord blood and then cultured solely or co-cultured with MSCs or EPCs. Changes in the number of MNCs and HSCs/HPCs were observed, and MNC proliferation was tested by carboxyfluorescein diacetate succinimidyl ester. The cultured supernatants of the treated MSCs and EPCs were collected at 24 h after co-culture and used to determine the concentrations of IL-3, IL-6, stem cell factor (SCF), TPO, Flt3l, and VEGF. The total number and proliferation of MNCs increased significantly when co-cultured with MSCs or EPCs than when cultured alone, particularly when MNCs were co-cultured with EPCs. The differences in IL-3 and Flt3l concentrations between groups were not significant. However, IL-6 in the MSC group was significantly higher than that in the two other groups. The SCF and TPO concentrations were highly expressed in the EPC group. The VEGF concentrations in the MSC group and the EPC group were higher than those in the control group. These results indicated that MSCs and EPCs possibly favor the proliferation of MNCs and HSCs/HPCs. IL-6 and VEGF may be related to hematopoietic reconstitution and homing ability of HSCs/HPCs. TPO may have a specific relationship with the promotion of HSCs/HPCs differentiation. PMID- 24146299 TI - Gadolinium and nephrogenic systemic fibrosis: an update. AB - Nephrogenic systemic fibrosis (NSF) is a multisystem disease seen exclusively in patients with renal impairment. It can be severely debilitating and sometimes fatal. There is a strong association with gadolinium-based contrast agents used in magnetic resonance imaging (MRI). Risk factors include renal impairment and proinflammatory conditions, e.g. major surgery and vascular events. Although there is no single effective treatment for NSF, the most successful outcomes are seen following restoration of renal function, either following recovery from acute kidney injury or following renal transplantation. There have been ten biopsy-proved pediatric cases of NSF, with no convincing evidence that children have a significantly altered risk compared with the adult population. After implementation of guidelines restricting the use of gadolinium-based contrast agents in at-risk patients, there has been a sharp reduction in new cases and no new reports in children. Continued vigilance is recommended: screening for renal impairment, use of more stable gadolinium chelates, consideration of non-contrast enhanced MRI or alternative imaging modalities where appropriate. PMID- 24146302 TI - Obesity paradox. PMID- 24146303 TI - The energy-water nexus: are there tradeoffs between residential energy and water consumption in arid cities? AB - Water scarcity, energy consumption, and air temperature regulation are three critical resource and environmental challenges linked to urban population growth. While appliance efficiency continues to increase, today's homes are larger and residents are using more energy-consuming devices. Recent research has often described the energy-water nexus as a "tradeoff" between energy and water due to reduced temperatures resulting from irrigated vegetation. Accordingly, some arid cities have implemented landscape-conversion programs that encourage homeowners to convert their yards from grass (mesic) to drought-tolerant (xeric) landscapes to help conserve water resources. We investigated these relationships in Phoenix, Arizona by examining energy and water data for the summer months of June September 2005 while temperature variability was analyzed from a local heat wave. Results show parallel consumption patterns with energy and water use strongly correlated and newer homes using more of both. The counterintuitive findings show that "drought-resistant" models may not be beneficial for community health, environment, or economics and that this issue is further complicated by socio economic variables. PMID- 24146304 TI - Relationship between seasonal weather changes, risk of dehydration, and incidence of severe bradyarrhythmias requiring urgent temporary transvenous cardiac pacing in an elderly population. AB - There is little information on any seasonal variations or meteorological factors associated with symptomatic bradyarrhythmias requiring cardiac pacing. The aim of this single-center study was to investigate the seasonal distribution of the incidence of severe, life-threatening bradyarrhythmias requiring urgent temporary transvenous cardiac pacing in an elderly population. Consecutive patients who underwent urgent temporary transvenous cardiac pacing between 2007 and 2012 were enrolled. The baseline characteristics of the patients and some meteorological parameters, including the calculation the daily heat index (HI), were recorded. During the study period, 79 consecutive patients (mean age 82 +/- 8 years, 41% male) underwent urgent temporary transvenous cardiac pacing, mainly for third degree atrioventricular block (79%). The incidence of bradyarrhythmias was significantly higher in summer than in the other seasons (P < 0.001). Moreover, the highest incidence was observed in months with HI > 90 degrees F for >3 h per day for at least 10 days (P < 0.001). A direct correlation was found between the average monthly temperature and the monthly number of patients undergoing temporary cardiac pacing (r = 0.54, P < 0.001). Compared with other patients, those observed during the hottest months were significantly older and more frequently affected by chronic disabling neurological diseases (all P < 0.05). In addition, they more frequently showed biochemical indices of dehydration, renal function impairment and hyperkalemia (all P < 0.05). This study showed an increased incidence of severe bradyarrhythmias in an elderly population during the hottest months of the year. In these months, in subjects characterized by increased susceptibility to dehydration, the risk of developing bradyarrhythmias was increased significantly. PMID- 24146305 TI - Adaptation study of the Turkish version of the Gambling-Related Cognitions Scale (GRCS-T). AB - This study aimed to adapt and to test the validity and the reliability of the Turkish version of the Gambling-Related Cognitions Scale (GRCS-T) that was developed by Raylu and Oei (Addiction 99(6):757-769, 2004a). The significance of erroneous cognitions in the development and the maintenance of gambling problems, the importance of promoting gambling research in different cultures, and the limited information about the gambling individuals in Turkey due to limited gambling research interest inspired the present study. The sample consisted of 354 voluntary male participants who were above age 17 and betting on sports and horse races selected through convenience sampling in betting terminals. The results of the confirmatory factor analysis following the original scale's five factor structure indicated a good fit for the data. The analyses were carried out with 21 items due to relatively inadequate psychometric properties of two GRCS-T items. Correlational analyses and group comparison tests supported the concurrent and the criterion validity of the GRCS-T. Cronbach's alpha coefficient for the whole scale was 0.84 whereas the coefficients ranged between 0.52 and 0.78 for the subscales of GRCS-T. The findings suggesting that GRCS-T is a valid and reliable instrument to identify gambling cognitions in Turkish samples are discussed considering the possible influence of the sample make-up and cultural texture within the limitations of the present study and in the light of the relevant literature. PMID- 24146306 TI - Direct detection of solid inorganic mercury salts at ambient pressure by electron capture and reaction-assisted HePI mass spectrometry. AB - Solid HgCl2 is readily detected at ambient conditions by electron capture in a HePI-MS source. The captured electron occupies the empty 6 s orbital of the Hg atom. The resulting radical-anion HgCl2 (-*) can exist as three "flexomers" of different Cl-Hg-Cl angle. The facile in-source formation of HgCl2 (-*) and the adduct [HgCl3](--) is exploited to detect other solid Hg compounds by exposing them to an external chloride source, such as HCl, NaCl, or vapors emanating from solid TiCl3. In situ oxidation of Hg2Cl2 with H2O2 generated signals for HgCl2 ( *) and [HgCl3] (-), suggesting that oxidation makes Hg 6 s orbital available for electron capture. PMID- 24146307 TI - Isolation of copper oxide (CuO) nanoparticles resistant Pseudomonas strains from soil and investigation on possible mechanism for resistance. AB - The present study deals with isolation and characterization of copper oxide nanoparticles resistant Pseudomonas strains that were isolated from the soil collected from mining and refining sites of Sarcheshmeh copper mine in the Kerman Province of Iran. The three isolates were selected based on high level of copper oxide nanoparticles (CuO NPs) resistance. The isolates were authentically identified as Pseudomonas fluorescens CuO-1, Pseudomonas fluorescens CuO-2 and Pseudomonas sp. CuO-3 by morphological, biochemical and 16S rDNA gene sequencing analysis. The growth pattern of these isolates with all the studied CuO NPs concentrations was similar to that of control (without CuO NPs) indicating that CuO NPs would not affect the growth of isolated strains. A reduction in the amount of exopolysaccharides was observed after CuO NPs-P. fluorescens CuO-1 culture supernatant interaction. The Fourier transform infrared spectroscopy (FT IR) peaks for the exopolysaccharides extracted from the bacterial culture supernatant and the interacted CuO NPs were almost similar. The exopolysaccharide capping of the CuO NPs was confirmed by FT-IR and X-ray diffraction analysis. The study of bacterial exopolysaccharides capped CuO NPs with E. coli PTCC 1338 and S. aureus PTCC 1113 showed less toxicity compared to uncoated CuO NPs. Our study suggests that the capping of nanoparticles by bacterially produced exopolysaccharides serve as the probable mechanism of tolerance. PMID- 24146308 TI - Biodegradation of benzyl benzoate by Pseudomonas desmolyticum NCIM 2112. AB - Commercial grade insecticides are supplemented with the chemical additives to enhance the insecticidal activity before the action of main insecticide commence. Benzyl benzoate is one of such additive used in the formulation of many insecticides. Due to deposition of such additive the soil and plant health get deteriorated. The present research work describes the biodegradation of benzyl benzoate by Pseudomonas desmolyticum NCIM 2112. The biodegradation was influenced by factors such as pH, temperature and other carbon and nitrogen sources. The optimum pH and temperature for biodegradation was found to be 7.0 and 30 degrees C respectively. It was more effective at 0.5 % glucose and lactose concentration and at 0.05 % NaNO3 and peptone concentration. Pseudomonas desmolyticum NCIM 2112 degrades benzyl benzoate into compounds like benzaldehyde and benzoic acid which are nontoxic in nature. Phytotoxicity study shows no germination inhibition in presence of degraded metabolites. PMID- 24146309 TI - Strain-dependent effects of sub-chronically infused losartan against kainic acid induced seizures, oxidative stress, and heat shock protein 72 expression. AB - We studied the involvement of angiotensin (Ang) II AT1 receptors in the pathophysiology of kainate (KA)-induced neurotoxicity, focusing on the regulation of the oxidative stress state and expression of HSP 72 in the frontal cortex and hippocampus in two strains, spontaneously hypertensive rats (SHRs) and normotensive Wistar rats. The KA injection was executed after the rats were infused subcutaneously via osmotic mini-pumps with losartan (10 mg/kg day) for 14 days. Losartan delayed the onset of KA-induced seizures in SHRs but not in Wistar rats without affecting the seizure intensity score. This selective AT1 receptor antagonist decreased the lipid peroxidation only in naive SHRs. However, it attenuated the KA-induced increase in lipid peroxidation in both SHRs and Wistar rats. The adaptive enhancement of cytosolic superoxide dismutase (SOD) activity in KA-treated SHRs was recovered to control level after sub-chronic losartan infusion while no change in mitochondrial SOD activity was detected in the two strains. Both losartan and KA produced a higher expression of HSP 72 in the hippocampus of the two strains compared to naive rats infused with vehicle. Taken together, our findings demonstrate that the efficacy of a sub-chronic systemic losartan infusion in preventing the KA-induced seizure activity and neurotoxicity is more pronounced in SHRs, considered as a model of essential hypertension, than in normotenisve Wistar rats. The results suggest that the blockade of AT1 receptors, commonly used as a strategy for prevention of high blood pressure, may be useful as an adjunctive treatment in status epilepticus to reduce oxidative stress and neurotoxicity. PMID- 24146310 TI - Genetic variants in the fibroblast growth factor pathway as potential markers of ovarian cancer risk, therapeutic response, and clinical outcome. AB - BACKGROUND: The fibroblast growth factor (FGF) and FGF receptor (FGFR) axis plays a critical role in tumorigenesis, but little is known of its influence in ovarian cancer. We sought to determine the association of genetic variants in the FGF pathway with risk, therapeutic response, and survival of patients with ovarian cancer. METHODS: We matched 339 non-Hispanic white ovarian cancer cases with 349 healthy controls and genotyped them for 183 single-nucleotide polymorphisms (SNPs) from 24 FGF (fibroblast growth factor) and FGFR (fibroblast growth factor receptor) genes. Genetic associations for the main effect, gene-gene interactions, and the cumulative effect were determined. RESULTS: Multiple SNPs in the FGF-FGFR axis were associated with an increased risk of ovarian cancer. In particular, FGF1 [fibroblast growth factor 1 (acidic)] SNP rs7727832 showed the most significant association with ovarian cancer (odds ratio, 2.27; 95% CI, 1.31 3.95). Ten SNPs were associated with a reduced risk of ovarian cancer. FGF18 (fibroblast growth factor 18) SNP rs3806929, FGF7 (fibroblast growth factor 7) SNP rs9920722, FGF23 (fibroblast growth factor 23) SNP rs12812339, and FGF5 (fibroblast growth factor 5) SNP rs3733336 were significantly associated with a favorable treatment response, with a reduction of risk of nonresponse of 40% to 60%. Eleven SNPs were significantly associated with overall survival. Of these SNPs, FGF23 rs7961824 was the most significantly associated with improved prognosis (hazard ratio, 0.55; 95% CI, 0.39-0.78) and was associated with significantly longer survival durations, compared with individuals with the common genotype at this locus (58.1 months vs. 38.0 months, P = 0.005). Survival tree analysis revealed FGF2 rs167428 as the primary factor contributing to overall survival. CONCLUSIONS: Significant associations of genetic variants in the FGF pathway were associated with ovarian cancer risk, therapeutic response, and survival. The discovery of multiple SNPs in the FGF-FGFR pathway provides a molecular approach for risk assessment, monitoring therapeutic response, and prognosis. PMID- 24146311 TI - Circulating proteolytic products of carboxypeptidase N for early detection of breast cancer. AB - BACKGROUND: Carboxypeptidase N (CPN) is important in regulating vasoactive peptide hormones, growth factors, and cytokines by specifically cleaving their C terminal basic residues. We investigated whether circulating peptides specifically cleaved by CPN in the tumor microenvironment can be stage-specific indicators of breast cancer. METHODS: CPN activity was measured using an ex vivo peptide cleavage assay by incubating synthesized C3f peptide (His6-C3f_S1304 R1320-His6) in interstitial fluids of breast tumors and adjacent normal breast tissues in mice with orthotopic implantation of the human cell line MDA-MB-231. The nature and extent of peptide cleavage by CPN was investigated by fragment profiling using nanopore fractionation and mass spectrometry. The fragment profiles in interstitial fluid correlated with concentrations of CPN-catalyzed peptides in blood samples taken from the tumor-bearing mice, healthy women, and breast cancer patients. CPN expression in the same set of samples was further examined by immunohistochemistry and immunoblotting. RESULTS: We showed that generation of C3f_R1310-L1319 specifically correlated with the CPN expression level. In both the mouse and clinical patient samples, CPN was clearly increased in tumor tissues compared with normal breast tissue, whereas corresponding CPN abundance in blood remained constant. Concentrations of 6 CPN-catalyzed peptides predominantly increased in sera taken from the mice (n = 8) at 2 weeks after orthotopic implantation. Six homologous peptides displayed significantly higher expression in the patients' plasma as early as the first pathologic stage of breast cancer. CONCLUSIONS: Circulating CPN-catalyzed peptide concentrations reflect the CPN activity in tumors. These biomarkers show strong potential for the noninvasive and early diagnosis of breast cancer. PMID- 24146312 TI - Arabidopsis Fused kinase TWO-IN-ONE dominantly inhibits male meiotic cytokinesis. AB - Arabidopsis Fused kinase TWO-IN-ONE (TIO) controls phragmoplast expansion through its interaction with the Kinesin-12 subfamily proteins that anchor the plus ends of interdigitating microtubules in the phragmoplast midzone. Previous analyses of loss-of-function mutants and RNA interference lines revealed that TIO positively controls both somatic and gametophytic cell cytokinesis; however, knowledge of the full spectrum of TIO functions during plant development remains incomplete. To characterize TIO functions further, we expressed TIO and a range of TIO variants under control of the TIO promoter in wild-type Arabidopsis plants. We discovered that TIO-overexpressing transgenic lines produce enlarged pollen grains, arising from incomplete cytokinesis during male meiosis, and show sporophytic abnormalities indicative of polyploidy. These phenotypes arose independently in TIO variants in which either gametophytic function or the ability of TIO to interact with Kinesin-12 subfamily proteins was abolished. Interaction assays in yeast showed TIO to bind to the AtNACK2/TETRASPORE, and plants doubly homozygous for kinesin-12a and kinesin-12b knockout mutations to produce enlarged pollen grains. Our results show TIO to dominantly inhibit male meiotic cytokinesis in a dosage-dependent manner that may involve direct binding to a component of the canonical NACK-PQR cytokinesis signaling pathway. PMID- 24146313 TI - Breast cancer clinical characteristics and outcomes in Trinidad and Tobago. AB - Trinidad and Tobago (TT) is the country with the highest breast cancer mortality in the Caribbean. It is unknown whether biological, behavioral, environmental, or clinical factors play a significant role in such outcome. A total of 2,614 incident cases, histologically confirmed and recorded in the TT cancer registries between 1995 and 2005, with follow-up through 2009 were analyzed. Half of the cases were diagnosed between the ages of 40-59 years, 12.5% before the age of 40 years; 45% of women were diagnosed at localized stage and 43.7% were hormone receptor positive. Women diagnosed with distant staging were more likely to undergo chemotherapy compared to those with localized staging (OR 1.39; 95% CI 1.01-1.89). Hormone receptor negative cases were significantly less likely to undergo radiation or surgery therapy (OR 0.66; 95% CI 0.56-0.79 and OR 0.67; 95% CI 0.51-0.88 respectively) compared to those who were hormone receptor positive, but more than 1.5 times as likely to undergo chemotherapy. In multivariate analyses, advanced stage disease and negative hormone receptor status were independently significantly associated with poorer survival outcome. No racial/ethnic differences were observed with respect to treatment or survival. Although access to breast cancer screening and treatment is free in Trinidad and Tobago, breast cancer diagnosis occurs at advanced stages; use of multimodality therapy as a first course of treatment is low. PMID- 24146314 TI - Feedback-related negativity codes outcome valence, but not outcome expectancy, during reversal learning. AB - Optimal behavior depends on the ability to assess the predictive value of events and to adjust behavior accordingly. Outcome processing can be studied by using its electrophysiological signatures--that is, the feedback-related negativity (FRN) and the P300. A prominent reinforcement-learning model predicts an FRN on negative prediction errors, as well as implying a role for the FRN in learning and the adaptation of behavior. However, these predictions have recently been challenged. Notably, studies so far have used tasks in which the outcomes have been contingent on the response. In these paradigms, the need to adapt behavioral responses is present only for negative, not for positive feedback. The goal of the present study was to investigate the effects of positive as well as negative violations of expectancy on FRN amplitudes, without the usual confound of behavioral adjustments. A reversal-learning task was employed in which outcome value and outcome expectancy were orthogonalized; that is, both positive and negative outcomes were equally unexpected. The results revealed a double dissociation, with effects of valence but not expectancy on the FRN and, conversely, effects of expectancy but not valence on the P300. While FRN amplitudes were largest for negative-outcome trials, irrespective of outcome expectancy, P300 amplitudes were largest for unexpected-outcome trials, irrespective of outcome valence. These FRN effects were interpreted to reflect an evaluation along a good-bad dimension, rather than reflecting a negative prediction error or a role in behavioral adaptation. By contrast, the P300 reflects the updating of information relevant for behavior in a changing context. PMID- 24146315 TI - Recalling happy memories in remitted depression: a neuroimaging investigation of the repair of sad mood. AB - Major depressive disorder (MDD) is a recurrent mood disorder. The high rate of recurrence of MDD suggests the presence of stable vulnerability factors that place individuals with a history of major depression at an increased risk for the onset of another episode. Previous research has linked the remitted state, and therefore increased vulnerability for depressive relapse, with difficulties in the use of pleasant autobiographical memories to repair sad mood. In the present study, we examined the neural correlates of these difficulties. Groups of 16 currently euthymic, remitted depressed individuals and 16 healthy (control) women underwent functional magnetic resonance imaging (fMRI) during sad mood induction and during recovery from a sad mood state through recall of mood-incongruent positive autobiographical memories. Sad mood was induced in participants by using film clips; participants then recalled positive autobiographical memories, a procedure previously shown to repair negative affect. During both the sad mood induction and automatic mood regulation, control participants exhibited activation in the left ventrolateral prefrontal cortex (vlPFC) and cuneus; in contrast, remitted participants exhibited a decrease in activation in these regions. Furthermore, exploratory analyses revealed that reduced activation levels during mood regulation predicted a worsening of depressive symptoms at a 20-month follow-up assessment. These findings highlight a dynamic role of the vlPFC and cuneus in the experience and modulation of emotional states and suggest that functional anomalies of these brain regions are associated with a history of, and vulnerability to, depression. PMID- 24146316 TI - Maternal supplementation of nucleotides improves the behavioral development of prenatal ethanol-exposed mice. AB - Maternal ethanol consumption during pregnancy can induce learning deficits in the offspring. The objective of this study was to assess whether supplementation of exogenous nucleotides during pregnancy and lactation would ameliorate prenatal ethanol-induced learning and memory deficits in the offspring of mice, and to explore the possible mechanisms. In the present study, pregnant C57BL/6J mice were exposed to ethanol (5 g/kg body weight) intragastrically from gestational day (GD) 6 to GD15. The dams in exogenous nucleotide intervention groups were fed with feed containing 0.01%, 0.04%, or 0.16% nucleotide powder, with control and ethanol groups receiving normal feed. The dams were allowed to deliver naturally and to breast feed their offspring. After weaning, behavioral tests were carried out in the offspring of each group. Serum oxidation indexes were analyzed, and the hippocampus of each offspring was collected and detected for acetyl cholinesterase (AChE) activity and the expression of p-CREB, CREB, and BDNF. The results showed that maternal supplementation with exogenous nucleotides during pregnancy could ameliorate prenatal ethanol-induced learning and memory deficits in the offspring of mice, through improving their antioxidant capacity, reversing hippocampus AChE levels, and allowing the expression of some proteins related to learning and memory. However, different sensitivities were found between the two sexes. PMID- 24146317 TI - Targeting an early and substantial increase in mean arterial pressure is critical in the management of type 1 hepatorenal syndrome: a combined retrospective and pilot study. AB - BACKGROUND: Appreciation of the central role for arterial vasodilatation in the pathogenesis of hepatorenal syndrome (HRS) has led to routine use of vasoconstrictors in combination with albumin as a medical therapy for HRS. Various vasoconstrictors have been explored but the optimal approach for such therapies has not yet been established. AIMS: The purpose of this study was to examine the role of targeting an early and substantial increase in mean arterial pressure (MAP) in the management of type 1 HRS, a condition associated with very poor prognosis. METHODS: A total of 59 patients with type 1 HRS who received a combination therapy of vasoconstrictors and albumin were enrolled into a retrospective cohort study. Subjects having a substantial increase of more than 10 mmHg in MAP by day 3 after initiation of therapy were categorized as MAP responders and the rest as MAP non-responders. In addition, five patients were enrolled into a prospective pilot study in which a titration protocol of vasoconstrictors was followed to achieve early goal-directed therapy (EGDT). RESULTS: MAP responders achieved significantly higher incidence of treatment success or total response, less requirement of dialysis and more incidence of liver transplantation. More importantly, this response is associated with better short-term and long-term overall survival as well as transplant-free survival. The effectiveness of such an approach was further confirmed in the pilot study which followed an EGDT protocol. CONCLUSIONS: Using an early and substantial increase in MAP as a therapeutic target is associated with favorable clinical outcomes in the management of type 1 HRS. PMID- 24146318 TI - The importance of the retinoid X receptor alpha in modulating inflammatory signaling in acute murine colitis. AB - BACKGROUND: In order for vitamin D to signal and regulate inflammatory pathways, it must bind to its receptor (VDR) which must heterodimerize with the retinoid X receptor alpha (RXRalpha). Although the role that vitamin D signaling plays in the development and progression of colitis, a disease characterized by excessive inflammation, has been suggested, little research has been done on determining the role that RXRalpha plays in acute colitis development. AIMS: This study sought to determine the effects that reduced availability of RXRalpha would have on the development of acute murine colitis. Expression of inflammatory markers, VDR and RXRalpha were investigated to determine if the reduction in expression of RXRalpha in RXRalpha(+/-) mice would result in increased inflammatory signaling and receptor downregulation as compared to their wild-type littermates. METHODS: An acute murine model of colitis, the axozymethane (AOM) and dextran sulfate sodium (DSS) model was utilized in wild-type and RXRalpha(+/-) mice. Gross manifestations of colitis measured included weight loss and colitis score. Immunblots and real-time PCR were performed for inflammatory markers and receptor expression. RESULTS: RXRalpha(+/-) mice induced with AOM/DSS colitis demonstrated increased gene expression of Snail and Snail2, transcription factors downstream of inflammatory mediators, as compared to their wild-type littermates. CONCLUSIONS: This demonstrates the importance of RXRalpha in regulating inflammation in acute colitis and also identifies RXRalpha expression as a new consideration when developing successful interventions for acute colitis due to the requirement of numerous receptors for RXRalpha. PMID- 24146319 TI - Continental bottled water assessment by stir bar sorptive extraction followed by gas chromatography-tandem mass spectrometry (SBSE-GC-MS/MS). AB - This study was aimed to determine the presence of 69 organic contaminants in 77 representative bottled waters collected from 27 countries all over the world. All water samples were contained in polyethylene terephthalate bottles. Target compounds were (1) environmental contaminants (including 13 polycyclic aromatic hydrocarbons (PAHs), 31 pesticides including organochlorine (OCPs), organophosphorus, and pyrethroids; 7 polychlorinated biphenyls (PCBs); and 7 triazines) and (2) plasticizers (including 6 phthalates and 5 other compounds). Samples were analyzed by stir bar sorptive extraction followed by gas chromatography-tandem mass spectrometry. PAHs, OCPs, PCBs, and triazines, which are indicators of groundwater pollution, were not detected in most of the samples, except for naphthalene (0.005-0.202 MUg/L, n = 16). On the other hand, plastic components were detected in 77 % of the samples. Most frequently detected compounds were dimethyl phthalate and benzophenone at concentrations of 0.005 0.125 (n = 41) and 0.014-0.921 (n = 32), respectively. Levels detected are discussed in terms of contamination origin and geographical distribution. Target compounds were detected at low concentrations. Results obtained showed the high quality of bottled water in the different countries around the world. PMID- 24146320 TI - Objective classification of ecological status in marine water bodies using ecotoxicological information and multivariate analysis. AB - Some relevant shortcomings have been identified in the current approach for the classification of ecological status in marine water bodies, leading to delays in the fulfillment of the Water Framework Directive objectives. Natural variability makes difficult to settle fixed reference values and boundary values for the Ecological Quality Ratios (EQR) for the biological quality elements. Biological responses to environmental degradation are frequently of nonmonotonic nature, hampering the EQR approach. Community structure traits respond only once ecological damage has already been done and do not provide early warning signals. An alternative methodology for the classification of ecological status integrating chemical measurements, ecotoxicological bioassays and community structure traits (species richness and diversity), and using multivariate analyses (multidimensional scaling and cluster analysis), is proposed. This approach does not depend on the arbitrary definition of fixed reference values and EQR boundary values, and it is suitable to integrate nonlinear, sensitive signals of ecological degradation. As a disadvantage, this approach demands the inclusion of sampling sites representing the full range of ecological status in each monitoring campaign. National or international agencies in charge of coastal pollution monitoring have comprehensive data sets available to overcome this limitation. PMID- 24146321 TI - Reduction of DNA mismatch repair protein expression in airway epithelial cells of premenopausal women chronically exposed to biomass smoke. AB - Biomass burning is a major source of indoor air pollution in rural India. This study examined whether chronic inhalation of biomass smoke causes change in the DNA mismatch repair (MMR) pathway in the airway cells. For this, airway cells exfoliated in sputum were collected from 72 premenopausal nonsmoking rural women (median age 34 years) who cooked with biomass (wood, dung, crop residues) and 68 control women who cooked with cleaner fuel liquefied petroleum gas (LPG) for the past 5 years or more. The levels of particulate matters with diameters less than 10 and 2.5 MUm (PM10 and PM2.5) in indoor air were measured by real-time aerosol monitor. Benzene exposure was monitored by measuring trans,trans-muconic acid (t,t-MA) in urine by high-performance liquid chromatography with ultraviolet detector. Generation of reactive oxygen species (ROS) and level of superoxide dismutase (SOD) in airway cells were measured by flow cytometry and spectrophotometry, respectively. Immunocytochemical assay revealed lower percentage of airway epithelial cells expressing MMR proteins mutL homolog 1 (MLH1) and mutS homolog 2 (MSH2) in biomass-using women compared to LPG-using controls. Women who cooked with biomass had 6.7 times higher level of urinary t,t MA, twofold increase in ROS generation, and 31 % depletion of SOD. Indoor air of biomass-using households had three times more particulate matters than that of controls. ROS, urinary t,t-MA, and particulate pollution in biomass-using kitchen had negative correlation, while SOD showed positive correlation with MSH2 and MLH1 expression. It appears that chronic exposure to biomass smoke reduces MMR response in airway epithelial cells, and oxidative stress plays an important role in the process. PMID- 24146322 TI - Controlled synthesis of uniform BiVO4 microcolumns and advanced visible-light driven photocatalytic activity for the degradation of metronidazole-contained wastewater. AB - Well-defined, uniform bismuth vanadate (BiVO4) microcolumns were synthesized through a refined hydrothermal route. During the fabrication process, a detailed orthogonal design on the synthetic conditions was performed, aiming to optimize the experimental parameters to produce BiVO4 materials (BiVO4 (Opt.)) with the most prominent visible-light-driven photocatalytic efficiency, where the catalytic activities of the synthesized materials were evaluated via the decolorization of methylene blue under visible light irradiation. The BiVO4 (Opt.) were then targetedly produced according to the determined optimal conditions and well characterized by X-ray diffraction, scanning electron microscopy, transmission electron microscopy, ultraviolet and visible diffuse reflectance spectroscopy and photoluminescence spectroscopy. Compared with the commercial P25-TiO2 photocatalysts, the as-synthesized BiVO4 (Opt.) displayed superior visible-light-driven photocatalytic activities for the degradation of metronidazole-contained wastewater with the presence of H2O2. The degradation efficiency of metronidazole reached up to 70 % within 180 min, leading to a brief speculation on the possibly major steps of the visible-light-driven photocatalytic process. The current study provides a distinctive route to design novel shaped BiVO4 architectures with advanced photocatalytic capacities for the treatment of organic pollutants in the aqueous environment. PMID- 24146323 TI - Utilization of two invasive free-floating aquatic plants (Pistia stratiotes and Eichhornia crassipes) as sorbents for oil removal. AB - Free-floating aquatic plants Pistia stratiotes and Eichhornia crassipes are well known invasive species in the tropics and subtropics. The aim of this study was to utilize the plants as cost-effective and environmentally friendly oil sorbents. Multilevel wrinkle structure of P. stratiotes leaf (PL), rough surface of E. crassipes leaf (EL), and box structure of E. crassipes stalk (ES) were observed using the scanning electron microscope. The natural hydrophobic structures and capillary rise tests supported the idea to use P. stratiotes and E. crassipes as oil sorbents. Experiments indicated that the oil sorption by the plants was a fast process. The maximum sorption capacities for different oils reached 5.1-7.6, 3.1-4.8, and 10.6-11.7 g of oil per gram of sorbent for PL, EL, and ES, respectively. In the range of 5-35 degrees C, the sorption capacities of the plants were not significantly different. These results suggest that the plants can be used as efficient oil sorbents. PMID- 24146324 TI - Aerobic inhibition assessment for anaerobic treatment effluent of antibiotic production wastewater. AB - Biological treatment of antibiotic production effluents is an economical approach; however, there are still difficulties to overcome because of the recalcitrant characteristics of these compounds to biodegradation. This study aims to reveal that anaerobic treatment technology can be an option as pretreatment before the activated sludge system treatment to treat antibiotic production effluents. The ISO 8192 method was chosen to test the inhibitory effect of raw and treated antibiotic production effluents in this work. Inhibition tests, which were applied according to ISO 8192, highlighted that the anaerobic treatment effluent is less inhibitory than antibiotic production effluent for activated sludge system. Early EC50 concentrations (30-min values) of raw and treated wastewaters were lower than 180-min values. Also, triple effects (sulfamethoxazole-erythromycin-tetracycline) of antibiotics are more toxic than dual effects (sulfamethoxazole-tetracycline). In light of the experimental results obtained and their evaluation, it can be concluded that anaerobic digestion can be applied as a biological pretreatment method for pharmaceutical industry wastewater including antibiotic mixtures prior to aerobic treatment. PMID- 24146325 TI - Life-threatening complications of deep neck space infections. AB - Odontogenic infections represented a challenge for every craniomaxillofacial surgeon in the pre-antibiotic era, not least due to the frequent association with septic complications and lethal consequences. Nowadays, the incidences of serious infection-related complications are less frequent thanks to the medical progress. Nevertheless, the development of severe infections is still hard to foresee. The following analysis provides an overview of four patients with severe, life threatening odontogenic deep neck space infections treated at the University Clinic for Oral and Maxillofacial Surgery in Innsbruck and describes the etiology, therapy, and outcome for each patient while analyzing differences between the single cases. Crucial aspects in origin, progression, and treatment of DNIs are highlighted, comparing the results with the international literature. PMID- 24146326 TI - Clinical outcome after 1 year of cardiac resynchronisation therapy: national results from the European CRT survey. AB - Cardiac resynchronisation therapy (CRT) is an established treatment option for heart failure patients with electromechanical dyssynchrony. Between 2008 and 2010, the Heart Failure Association (HFA) and the European Heart Rhythm Association (EHRA) of the European Society of Cardiology (ESC) initiated the European CRT survey to describe the current practice and short-term clinical outcome associated with CRT implantations in 13 countries. One year follow-up data from 150 patients collected in 10 Austrian centres are presented in comparison to the total 1,969 patients enrolled throughout Europe. In most cases (n = 120), CRT-D devices were implanted, while CRT-P devices were used in only 23 %. After 12 +/- 3 months, mortality and hospitalisation rates reached 10 and 37 %, respectively. New York Heart Association (NYHA) functional classes improved significantly: NYHA I/II/III/IV were found before implantation in 2/20/71/7 % and after 1 year follow-up in 35/51/9/5 % of the patients, respectively. Left ventricular ejection fraction improved from 27 +/- 8 % to 35 +/- 10 %, left ventricular end-diastolic diameters were reduced from 65 +/- 10 mm to 59 +/- 5 mm. Median NT-proBNP was reduced from 1,886 to 997 pg/ml, QRS duration diminished from 158 +/- 34 to 147 +/- 27 ms. In conclusion, the Austrian data from the CRT survey confirms the efficacy of CRT in heart failure patients, but outlines that these patients still suffer from a high mortality and cardiovascular (CV) hospitalisation rate. PMID- 24146327 TI - Differences in the metabolic status of healthy adults with and without active brown adipose tissue. AB - BACKGROUND: Previous studies have proven the existence of active brown adipose tissue (BAT) in adults; however, its effect on systematic metabolism remains unclear. AIM: The current study was designed to investigate the differences in the metabolic profiles of healthy adults with and without active BAT using positron emission tomography-computed tomography (PET-CT) scans in the un stimulated state. METHODS: A cross-sectional analysis was performed to assess the health of adults using PET-CT whole-body scans at Huashan Hospital Medical Centre between November 2009 and May 2010. A total of 62 healthy adults with active BAT were enrolled in the BAT-positive group. For each positive subject, a same-gender individual who underwent PET-CT the same day and who had no detectable BAT was chosen as the negative control. Body composition was measured, and blood samples were collected for assays of metabolic profiles and other biomarkers. RESULTS: In both the male and female groups, BAT-positive individuals were younger and had lower body mass indexes, fasting insulin, insulin resistance, and leptin, but a greater level of high-density lipoprotein cholesterol compared with the negative controls. In the male group, body fat content and levels of tumor necrosis factor alpha were significantly lower in the BAT-positive than in the negative control group. CONCLUSIONS: The healthy adults with active BAT in an un-stimulated state had favorable metabolic profiles suggesting that active BAT may be a potential target for preventing and treating obesity and other metabolic disorders. PMID- 24146328 TI - Impaired joint motion and contractures in callus distraction and segment transport: a retrospective data analysis. AB - PURPOSE: The temporary loss of motion of adjacent joints is a common complication after distraction osteogenesis of the lower limb. The aim of this study was to investigate the incidence of tendon contracture and impaired joint motion of the knee and/or ankle joint during and after callus distraction with a ring fixator. MATERIAL AND METHODS: Twenty patients (2 female, 18 male, average age: 36 years) were surgically treated for callus distraction and segment transport with an external ring fixator after traumatic bone loss in 21 lower limbs. The impaired joint motion of the adjacent joints during and after treatment was evaluated. RESULTS: During treatment, we observed the free range of motion (ROM) of the ankle joint in 4 cases (19 %), restricted motion in 11 cases (52 %), and complete loss of motion in 6 cases (33 %). After treatment,free ROM was observed in 12 cases (57 %), impaired motion in 3 cases (14 %), and fixed joint position in 6 cases (29 %, 2 arthrodesis). This represents an improvement of motion in eight cases (38 %) and an impairment in two cases (10 %). In 11 cases, the ROM remained unchanged. During treatment, six restrictions in extension (24 %) and five (33 %) restrictions in flexion occurred in the knee joint, ultimately resulting in one loss of extension and three losses of flexion after frame removal. CONCLUSIONS: The impairment of joint motion during bone lengthening with an external ring fixator in the lower extremity occurs in most cases at the ankle joint. Various treatment options are available to address tendon shortening, but accompanying physiotherapy may prevent or moderate its onset. PMID- 24146329 TI - Do gender and age influence the frequency of Helicobacter pylori infection? AB - BACKGROUND: (13)C urea breath test (UBT) is a noninvasive method for detection of Helicobacter pylori (H. pylori) infection. The aim of this study was to determine age and gender differences in patients with positive UBT. PATIENTS AND METHODS: During the period 2008-2011, a total of 3,000 patients, who did not receive Hp eradication therapy before our study, underwent UBT in Laboratory of Clinical Hospital Sveti Duh. Data were analyzed according to age and gender. RESULTS: A total of 1,400 patients were positive (47 %), 670 males and 730 females (the male/female ratio for positive UBT was 0.92). The male predominance was found in people born between 1930 and 1939, 1940 and 1949, and 1960 and 1969, respectively. The majority infected are born between from 1940 and 1979, with the highest point from 1950-1969. CONCLUSIONS: Our study results confirm the importance of epidemiologic characteristics of Hp infection in our region. PMID- 24146330 TI - Sonographic diagnosis of recurrent peroneal tendon subluxation. AB - A case of recurrent peroneal tendon subluxation is reported. Dynamic ultrasonography is the best imaging modality in the diagnosis of peroneal tendon subluxation. PMID- 24146331 TI - Imaging of a case of benign carotidynia with ultrasound, MRI and PET-CT. AB - We present a case of carotidynia that we believe supports its classification as a distinct inflammatory disease entity. Doppler sonography and cervical magnetic resonance imaging are appropriate imaging modalities for diagnosing presumed carotidynia. PMID- 24146332 TI - Primary closure versus delayed closure for non bite traumatic wounds within 24 hours post injury. AB - BACKGROUND: Acute traumatic wounds are one of the common reasons why people present to the emergency department. Primary closure has traditionally been reserved for traumatic wounds presenting within six hours of injury and considered 'clean' by the attending surgeon, with the rest undergoing delayed primary closure as a means of controlling wound infection. Primary closure has the potential benefit of rapid wound healing but poses the potential threat of increased wound infection. There is currently no evidence to guide clinical decision-making on the best timing for closure of traumatic wounds. OBJECTIVES: To determine the effect on time to healing of primary closure versus delayed closure for non bite traumatic wounds presenting within 24 hours post injury. To explore the adverse effects of primary closure compared with delayed closure for non bite traumatic wounds presenting within 24 hours post injury. SEARCH METHODS: In May 2013, for this first update we searched the Cochrane Wounds Group Specialised Register; the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library); Ovid MEDLINE; Ovid MEDLINE (In-Process & Other Non-Indexed Citations); Ovid EMBASE; and EBSCO CINAHL. There were no restrictions with respect to language, date of publication or study setting. SELECTION CRITERIA: Randomised controlled trials comparing primary closure with delayed closure of non bite traumatic wounds. DATA COLLECTION AND ANALYSIS: Two review authors independently evaluated the results of the searches against the inclusion criteria. No studies met the inclusion criteria for this review. MAIN RESULTS: Since no studies met the inclusion criteria, neither a meta-analysis nor a narrative description of studies was possible. AUTHORS' CONCLUSIONS: There is currently no systematic evidence to guide clinical decision-making regarding the timing for closure of traumatic wounds. There is a need for robust research to investigate the effect of primary closure compared with delayed closure for non bite traumatic wounds presenting within 24 hours of injury. PMID- 24146333 TI - Search through complex motion displays does not break down under spatial memory load. AB - Recent work has shown that observers are remarkably effective in searching displays of randomly moving items. In two experiments, we combined working memory tasks with visual search, to test whether search through such complex motion displays, as compared with search through static items, places an extra burden on spatial working memory. In our first experiment, we show that the dual-task interference observed for motion search is specific to spatial working memory, in line with earlier work for static search. In our second experiment, we found dual task interference for both static and motion search, but no difference between them. The results support the suggestion that the same search process is active during search among static and search among moving items. PMID- 24146334 TI - A robust uniqueness-and-anonymity-preserving remote user authentication scheme for connected health care. AB - User authentication plays an important role to protect resources or services from being accessed by unauthorized users. In a recent paper, Das et al. proposed a secure and efficient uniqueness-and-anonymity-preserving remote user authentication scheme for connected health care. This scheme uses three factors, e.g. biometrics, password, and smart card, to protect the security. It protects user privacy and is believed to have many abilities to resist a range of network attacks, even if the secret information stored in the smart card is compromised. In this paper, we analyze the security of Das et al.'s scheme, and show that the scheme is in fact insecure against the replay attack, user impersonation attacks and off-line guessing attacks. Then, we also propose a robust uniqueness-and anonymity-preserving remote user authentication scheme for connected health care. Compared with the existing schemes, our protocol uses a different user authentication mechanism to resist replay attack. We show that our proposed scheme can provide stronger security than previous protocols. Furthermore, we demonstrate the validity of the proposed scheme through the BAN (Burrows, Abadi, and Needham) logic. PMID- 24146335 TI - Waveform variance and latency jitter of the visual evoked potential in childhood. AB - PURPOSE: Recording the visual evoked potential (VEP) in young children is challenging due to movement artifacts with variable fixation or attention. This study examined the effects of latency jitter, noise, and waveform consistency on the averaging of the VEP across childhood age. METHODS: Stimuli were contrast reversing (1.4 Hz) checkerboards of 163 arc minutes and pattern-onset-offset of 0.5 cycle/degree horizontal sine-wave gratings. Subjects were 79 normal children (0.3-16 years age; mean 6.9). Results were compared to recordings of EEG noise only (noise controls). Epochs underwent four averaging methods: (1) latency jitter correction using cross-correlation, (2) correction of phase shifts across a limited bandwidth in the Fourier domain, (3) selection of epochs based on consistency in the time domain, and (4) selection of epochs based on phase consistency in the Fourier domain. Signal-to-noise ratios (SNR) were estimated in both the time and Fourier domains. RESULTS: Compared to standard averaging, all methods improved the amplitude of the primary peak (P100) while generating mild changes in latency. All methods also increased amplitudes of residual peaks in noise controls. In VEPs with an adequate SNR, selective averaging in the Fourier domain provided the greatest improvement in amplitude (61 % increase; p < 0.0001) without prolongation in latency. Correction of latency jitter did not consistently improve amplitude but caused latency prolongation in 24 % of subjects. There was no age-related effect of any averaging method for either stimulus. CONCLUSIONS: Since latency jitter correction does not improve VEP amplitude more than selective averaging, recording artifacts in children are dominated by random phase components rather than inducing latency jitter. PMID- 24146336 TI - Perineal wound healing following ileoanal pouch excision. AB - INTRODUCTION: There is paucity of information relating to perineal wound healing when pouch failure after ileal pouch anal anastomosis necessitates pouch excision (PE). The aim of this study is to evaluate perineal healing and factors associated with the development of persistent perineal sinus (PPS) after PE. METHODS: Perineal wound-related outcomes for patients who underwent PE from 1985 2009 were evaluated by type of closure (extrasphincteric, intersphincteric, and sphincter-preserving (SP)) and other factors (presence of Crohn's disease (CD) and/or perineal fistulae). Primary outcomes were PPS and delayed healing (healing after PPS development). RESULTS: One hundred ten patients (CD 48 %) underwent PE. PPS occurred in 39.8 % patients, 51 % had delayed perineal healing with further procedures, with an overall healing rate of 80.7 %. Closure technique was not associated with PPS (p = 0.37) or eventual healing (p = 0.94). For CD patients, risk of PPS (41 vs. 39 %, p = 0.83) and delayed healing (44 vs. 59 %, p = 0.61) was similar to non-CD patients, but uncomplicated healing took longer (p = 0.04). Four of 15 (26.7 %) patients who underwent SP closure developed PPS; all eventually healed with secondary sphincter excision. CONCLUSIONS: Perineal healing may be prolonged after pouch excision. Since eventual healing can be achieved in most patients, perineal dissection and closure can be tailored to the individual circumstance. Sphincter preservation may be used in non-CD patients if future reconstruction is possible. Extrasphincteric closure is preferable with cancer or perineal sepsis. Sphincter resection allows for complete healing in patients who undergo SP dissection and develop PPS. PMID- 24146337 TI - Surgery for giant primary neuroendocrine carcinoma of the liver. AB - Liver resection for primary hepatic neuroendocrine carcinoma (phNEC) has only scarcely been reported in the literature. We herein report on a 19-year-old female with a solitary 27 * 13-cm-big phNEC, which was initially considered as hemangioma. An extended right hepatectomy (segments V-VIII, partially IVa) was performed. Resection margins were free of tumor (R0 resection). Ki67 expression was 35%. Postoperative course was uneventful, and the patient was discharged on the seventh postoperative day. Two years after surgery, the patient remains disease-free and in good general condition. Large series and longer follow-up studies are required for the better understanding on this rare tumor entity. PMID- 24146338 TI - Lesions originating within the retrorectal space: a diverse group requiring individualized evaluation and surgery. AB - BACKGROUND: Tumors occurring within the retrorectal space are rare and their low incidence has led to a paucity of literature regarding them. METHODS: Adult patients with retrorectal tumors managed at this institution from 1981-2011 were identified. A retrospective chart review was conducted to obtain relevant data. RESULTS: Retrorectal tumors were identified in 87 patients (67 female) with median age at diagnosis of 44 years (19-88), and median follow-up 8 months (0.1 225). Of the 25 different histologic tumors diagnosed, hamartomas were most common (32 %; n = 28) followed by epidermal cysts (11 %; n = 10), and teratomas (10 %; n = 9). Twenty-six percent (23/87) of all tumors were malignant. CT scans were obtained in 84 % (73/87) of patients, MRI in 59 % (51/87), and TRUS in 16 % (14/87). While 74 % (64/87) of tumors were at or below the S4 level, operative approach was strictly posterior in 73 % (46/63) of these tumors. Twenty-eight percent (24/87) of patients underwent diagnostic biopsy with no reported biopsy site recurrence. Thirty percent (7/23) of resected malignant (all recurrences: distant) and eleven percent (7/64) of benign tumors (all recurrences: local) recurred. Survival was 70 % (16/23) for malignant tumors and 98 % (63/64) for benign tumors. CONCLUSIONS: Retrorectal tumors remain heterogeneous and a diagnostic challenge. Pre-operative imaging may help guide surgeons; however, malignancy portends worse outcomes. Despite preoperative biopsy site recurrence concerns, no patient in this study had biopsy site recurrence. As their natural history remains unclear, more studies are necessary to further characterize their behavior. PMID- 24146339 TI - Does intramesorectal proctectomy with rectal eversion affect postoperative complications compared to standard total mesorectal excision in patients with ulcerative colitis? AB - INTRODUCTION: Proctectomy for ulcerative colitis (UC) can be performed via intramesorectal proctectomy with concomitant rectal eversion (IMP/RE) or total mesorectal excision (TME). No data exists comparing the outcomes of the two techniques. METHODS: All UC patients undergoing J-pouch surgery at a single institution over 10.5 years were included. Postoperative complications with IMP/RE vs. TME were analyzed using univariable and multivariable statistics. RESULTS: One hundred nineteen of 201 (59 %) patients underwent IMP/RE. Demographic and disease characteristics were similar between groups. On univariable analysis, IMP/RE had fewer total perioperative complications than TME (p = 0.02), but no differences in postoperative length of stay or readmissions. Multivariable regression accounting for patient age, comorbidities, disease severity, preoperative medications, operative technique, and follow-up time (mean 5.5 +/- 0.2 years) suggested that both anastomotic leak rate (OR 0.32; p = 0.04) and overall postoperative complications (2.10 +/- 0.17 vs. 2.60 +/- 0.20; p = 0.05) were lower in the IMP/RE group. CONCLUSIONS: IMP/RE may be associated with fewer overall postoperative complications compared to TME. However, further studies on functional and long-term outcomes are needed. PMID- 24146340 TI - Surgical management of retroperitoneal leiomyosarcoma arising from the inferior vena cava. AB - Retroperitoneal leiomyosarcomas are uncommon tumors, with approximately 300 documented cases in the literature. Management necessitates complete surgical resection in order to offer patients a chance at long-term cure. Resection often presents a challenge as these tumors are often large, involving adjacent structures, and may require reconstruction of the inferior vena cava (IVC). In this article, we will present background information on retroperitoneal leiomyosarcomas and the technical aspects of surgical resection and vascular reconstructive options of the IVC. PMID- 24146341 TI - Gastric schwannoma: a rare find. PMID- 24146342 TI - CA125 is superior to CA19-9 in predicting the resectability of pancreatic cancer. AB - BACKGROUND: Although carbohydrate antigen 19-9 (CA19-9) has been reported as a biomarker to predict the resectability of pancreatic cancer, several limitations have restricted its clinical use. METHODS: The potential of several serum tumor markers (CA19-9, CA125, CA50, CA242, CA724, carcinoembryonic antigen (CEA), and alpha-fetoprotein (AFP)) to predict the resectability of pancreatic cancer was evaluated by receiver operating characteristic (ROC) analysis in a series of 212 patients with proven pancreatic cancer. RESULTS: Compared with other tumor markers including CA19-9, CA125 has a superior predictive value (CA19-9, ROC area 0.66, cutoff value 289.40 U/mL; CA125, ROC area 0.81, cutoff value 19.70 U/mL). In addition, for patients with unresectable diseases misjudged by CT as resectable, the percentage of CA125 over selected cutoff value was higher than that of CA19-9 (CA19-9, 70.27 %; CA125, 81.08 %). CONCLUSION: CA125 is superior to CA19-9 in predicting the resectability of pancreatic cancer. Aberrant high levels of CA125 may indicate unresectable pancreatic cancer. PMID- 24146343 TI - Low rates of bone mineral density measurement in Medicare beneficiaries with prostate cancer initiating androgen deprivation therapy. AB - BACKGROUND: Men with prostate cancer who undergo androgen deprivation therapy (ADT) are at risk for bone loss and fractures. Our objective was to determine if Medicare beneficiaries with prostate cancer in the state of Texas underwent DXA scans when initiating ADT. METHODS: We identified men diagnosed with prostate cancer between 2005 and 2007 in the Texas Cancer Registry/Medicare linked database, and who received parenteral ADT or orchiectomy. We identified DXA claims within 1 year before or 6 months after starting ADT. We examined use of bone conservation agents in the subgroup of patients enrolled in Medicare Part D. Multivariate logistic regression models were used to examine determinants of DXA use. RESULTS: The analysis included 2,290 men (2,262 parenteral ADT, 28 orchiectomy); 197 (8.6 %) underwent DXA within 1 year before and 6 months after starting ADT. Men aged 75 years or older were more likely to undergo DXA than men aged 66-74 years (OR 1.5; 95 % CI 1.1-2.1). Those living in small urban areas were less likely to undergo DXA than those in big areas (OR 0.40; 95 % CI 0.19 0.82). Of the 1,060 men enrolled in Medicare part D, 59 (5.6 %) received bone conservation agents when starting ADT; 134 (12.6 %) either received bone conservation agents or underwent DXA. CONCLUSIONS: Fewer than one in ten Medicare beneficiaries with prostate cancer initiating ADT underwent a DXA exam. Variation in utilization was also related to residence area size. Further research is needed to identify whether the use of DXA in patients with prostate cancer receiving ADT will result in fracture prevention. PMID- 24146345 TI - Pelargonium sidoides extract for treating acute respiratory tract infections. AB - BACKGROUND: Pelargonium sidoides (P. sidoides), also known as Umckaloabo, is a herbal remedy thought to be effective in the treatment of acute respiratory infections (ARIs). OBJECTIVES: To assess the efficacy and safety of P. sidoides for the treatment of ARIs in children and adults. SEARCH METHODS: In April 2013 we searched MEDLINE, Journals@Ovid, The Cochrane Library, Biosis Previews, Web of Science, CINAHL, CCMed, XToxline, Global Health, AMED, Derwent Drug File and Backfile, IPA, ISTPB + ISTP/ISSHP, EMBASE, Cambase, LILACS, PubMed component "Supplied by Publisher", TRIPdatabase, the publisher databases: Deutsches Arzteblatt, Thieme, Springer, ScienceDirect from Elsevier. We conducted a cited reference search (forward) in Web of Science of relevant papers for inclusion. In addition we searched the study registries ClinicalTrials.gov, Deutsches Register klinischer Studien DRKS (German Clinical Trials Register), International Clinical Trials Registry Platform (ICTRP) - WHO ICTRP, Current Controlled Trials and EU Clinical Trials Register. SELECTION CRITERIA: Double-blind, randomized controlled trials (RCTs) examining the efficacy of P. sidoides preparations in ARIs compared to placebo or any other treatment. Complete resolution of all symptoms was defined as the primary outcome; in addition, we examined resolution of predefined key symptoms. DATA COLLECTION AND ANALYSIS: At least two review authors (AT, JG, WK) independently extracted and quality scored the data. We performed separate analyses by age group and disease entity. Subanalysis considered type of preparation (liquid, tablets). We examined heterogeneity using the I(2) statistic. We calculated pooled risk ratios (RR) using a fixed-effect model if heterogeneity was absent (I(2) < 5%; P > 0.1), or a random-effects model in the presence of heterogeneity. If heterogeneity was substantial (I(2) > 50%; P < 0.10), a pooled effect was not calculated. MAIN RESULTS: Of 10 eligible studies eight were included in the analyses; two were of insufficient quality. Three trials (746 patients, low quality of evidence) of efficacy in acute bronchitis in adults showed effectiveness for most outcomes in the liquid preparation but not for tablets. Three other trials (819 children, low quality of evidence) showed similar results for acute bronchitis in children. For both meta-analyses, we did not pool sub totals due to relevant heterogeneity induced by type of preparation.One study in patients with sinusitis (n = 103 adults, very low quality of evidence) showed significant treatment effects (complete resolution at day 21; RR 0.43, 95% confidence interval (CI) 0.30 to 0.62). One study in the common cold demonstrated efficacy after 10 days, but not five days (very low quality of evidence). We rated the study quality as moderate for all studies (unvalidated outcome assessment, minor attrition problems, investigator-initiated trials only). Based on the funnel plot there was suspicion of publication bias.There were no valid data for the treatment of other acute respiratory tract infections. Adverse events were more common with P. sidoides, but none were serious. AUTHORS' CONCLUSIONS: P. sidoides may be effective in alleviating symptoms of acute rhinosinusitis and the common cold in adults, but doubt exists. It may be effective in relieving symptoms in acute bronchitis in adults and children, and sinusitis in adults. The overall quality of the evidence was considered low for main outcomes in acute bronchitis in children and adults, and very low for acute sinusitis and the common cold. Reliable data on treatment for other ARIs were not identified. PMID- 24146344 TI - Reasons for hospitalisation at the end of life: differences between cancer and non-cancer patients. AB - PURPOSE: Many patients are hospitalised during the final phase of life, even though most prefer to receive care at home until the end. This study aimed to explore the reasons and characteristics of hospitalisation in the final 3 months of life for patients who died non-suddenly, with a comparison between cancer patients and non-cancer patients. METHODS: This study used a nationwide retrospective cross-sectional survey among Dutch general practitioners. RESULTS: Of the 317 hospitalised patients, 65 % had cancer. Most common reasons for hospitalisation in the final 3 months of life were respiratory symptoms (31 %), digestive symptoms (17 %), and cardiovascular symptoms (17 %). Seventy-three percent of patients experienced an acute episode before hospitalisation, and for 46 % of patients, their own GP initiated the hospitalisation. Compared to non cancer patients, cancer patients were significantly more likely to be aged less than 80 (81 versus 46 %), were more likely to be hospitalised because of digestive symptoms (22 versus 7 %), were less likely to have a curative treatment goal before the last hospitalisation (6 versus 22 %) and were less likely to die in hospital (22 versus 49 %). CONCLUSIONS: Respiratory problems were the most common reasons for hospitalisation in the group of patients as a whole. Digestive problems were a frequent reason for hospitalisation in cancer patients and cardiovascular symptoms in non-cancer patients. Hospitalisation can therefore be anticipated by monitoring these relatively common symptoms. Also, timely communication with the patient is recommended about their preferences for hospital or home treatment in the case of an acute episode. PMID- 24146346 TI - Cloning, expression, purification and characterization of his-tagged human glucose-6-phosphate dehydrogenase: a simplified method for protein yield. AB - Glucose-6-phosphate dehydrogenase (G6PD) catalyzes the first step of the pentose phosphate pathway. In erythrocytes, the functionality of the pathway is crucial to protect these cells against oxidative damage. G6PD deficiency is the most frequent enzymopathy in humans with a global prevalence of 4.9 %. The clinical picture is characterized by chronic or acute hemolysis in response to oxidative stress, which is related to the low cellular activity of G6PD in red blood cells. The disease is heterogeneous at genetic level with around 160 mutations described, mostly point mutations causing single amino acid substitutions. The biochemical studies aimed to describe the detrimental effects of mutations on the functional and structural properties of human G6PD are indispensable to understand the molecular physiopathology of this disease. Therefore, reliable systems for efficient expression and purification of the protein are highly desirable. In this work, human G6PD was heterologously expressed in Escherichia coli and purified by immobilized metal affinity chromatography in a single chromatographic step. The structural and functional characterization indicates that His-tagged G6PD resembles previous preparations of recombinant G6PD. In contrast with previous protein yield systems, our method is based on commonly available resources and fully accessible laboratory equipment; therefore, it can be readily implemented. PMID- 24146347 TI - Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) associated to hereditary neuropathy with liability to pressure palsies (HNPP) and revealed after influenza AH1N1 vaccination. AB - Neurological complications of AH1N1 vaccination such as Guillain-Barre syndrome were described in the previous years. Several reports suggest that hereditary neuropathies may be a predisposing factor for immune-mediated neuropathies. We report the case of a 54-year-old female who developed chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) 5 weeks after AH1N1 vaccination. She had no previous neurological history, but neurophysiological features led us to suspect an underlying hereditary neuropathy. PMP22 gene analysis showed a typical deletion, confirming the diagnosis of hereditary neuropathy with liability to pressure palsies (HNPP). We observed a significant clinical and neurophysiological improvement of the neuropathy after intravenous immunoglobulin treatment. This is, to our knowledge, the first reported case of CIDP potentially triggered by AH1N1 vaccination. This and previous observations suggest that genetic-determined neuropathies could predispose to the occurrence of immune mediated neuropathies. One must recall the possibility of a superimposed hereditary neuropathy like HNPP in patients with a clinical presentation of CIDP, especially when positive family history or unexpected neurophysiological features are present. PMID- 24146348 TI - Capsule commentary on Wilson et al., the prevalence of harmful and hazardous alcohol consumption in U.S. older adults. PMID- 24146349 TI - Does patient-centered care mean that informed consent is necessary for clinical performance measures? PMID- 24146350 TI - Moral distress in medical education and training. AB - Moral distress is the experience of cognitive-emotional dissonance that arises when one feels compelled to act contrary to one's moral requirements. Moral distress is common, but under-recognized in medical education and training, and this relative inattention may undermine educators' efforts to promote empathy, ethical practice, and professionalism. Moral distress should be recognized as a feature of the clinical landscape, and addressed in conjunction with the related concerns of negative role modeling and the goals and efficacy of medical ethics curricula. PMID- 24146351 TI - A post-2011 time motion study--the authors' reply. PMID- 24146354 TI - Hand grip strength and its correlation with vitamin D in Indian patients with hip fracture. AB - This case-control study was performed to evaluate 25-hydroxyvitamin D [25(OH)D] deficiency and its correlation with hand grip strength in 95 Indian hip fracture subjects and 95 controls. 25(OH)D deficiency was found in 88.4 % of hip fracture subjects that was significantly higher as compared to controls. Hand grip strength as measured by hand held dynamometer was significantly lower in patients, and there was a significant positive correlation between 25(OH)D and hand grip strength. PURPOSE: The present study was conducted to assess correlation between 25(OH) D and hand grip strength in hip fracture subjects residing in North India. METHODS: Ninety-five patients with hip fracture and similar number of controls were enrolled in the study. Fasting venous samples were analyzed for 25(OH)D, intact parathyroid hormone (PTH), alkaline phosphatase, calcium, and phosphate. Hand grip strength of study subjects was measured using Jamar dynamometer. Correlation between vitamin D levels and hand grip strength was analyzed in study population. RESULTS: The mean age of hip fracture subjects was 61.4 +/- 12.6 years which was comparable in men and women. Out of 95 subjects, 57 were men and 38 were women. Mean 25(OH)D levels were significantly lower whereas intact PTH levels were significantly higher in patient group compared controls (10.29 +/- 6.53 vs 13.6 +/- 4.01 ng/ml; 62.6 +/- 59.3 vs 37.7 +/- 28.8 pg/ml, respectively). The number of subjects with 25(OH)D deficiency and secondary hyperparathyroidism was significantly higher in hip fracture group. The mean hand grip strength among hip fracture subjects was significantly lower compared to that of controls (16.57 +/- 5.74 vs 26.74 +/- 5.23 kg). There was a significant positive correlation between 25(OH)D and hand grip strength ( r = 0.482, p value <0.01) in hip fracture population. CONCLUSION: Majority of hip fracture patients in India have vitamin D deficiency, secondary hyperparathyroidism, and lower hand grip strength compared to controls. Further, there is significant positive correlation between 25(OH)D and hand grip strength. PMID- 24146352 TI - Genotypic testing on HIV-1 DNA as a tool to assess HIV-1 co-receptor usage in clinical practice: results from the DIVA study group. AB - PURPOSE: We have developed a sequencing assay for determining the usage of the genotypic HIV-1 co-receptor using peripheral blood mononuclear cell (PBMC) DNA in virologically suppressed HIV-1 infected patients. Our specific aims were to (1) evaluate the efficiency of V3 sequences in B versus non-B subtypes, (2) compare the efficiency of V3 sequences and tropism prediction using whole blood and PBMCs for DNA extraction, (3) compare the efficiency of V3 sequences and tropism prediction using a single versus a triplicate round of amplification. RESULTS: The overall rate of successful V3 sequences ranged from 100 % in samples with >3,000 copies HIV-1 DNA/10(6) PBMCs to 60 % in samples with <100 copies total HIV 1 DNA /10(6) PBMCs. Analysis of 143 paired PBMCs and whole-blood samples showed successful V3 sequences rates of 77.6 % for PBMCs and 83.9 % for whole blood. These rates are in agreement with the tropism prediction obtained using the geno2pheno co-receptor algorithm, namely, 92.1 % with a false-positive rate (FPR) of 10 or 20 % and of 96.5 % with an FPR of 5.75 %. The agreement between tropism prediction values using single versus triplicate amplification was 98.2 % (56/57) of patients using an FPR of 20 % and 92.9 % (53/57) using an FPR of 10 or 5.75 %. For 63.0 % (36/57) of patients, the FPR obtained via the single amplification procedure was superimposable to all three FPRs obtained by triplicate amplification. CONCLUSIONS: Our results show the feasibility and consistency of genotypic testing on HIV-1 DNA tropism, supporting its possible use for selecting patients with suppressed plasma HIV-1 RNA as candidates for CCR5-antagonist treatment. The high agreement between tropism prediction by single and triple amplification does not support the use of triplicate amplification in clinical practice. PMID- 24146355 TI - Measuring the prevalence of current, severe symptoms of mental health problems in a canadian correctional population: implications for delivery of mental health services for inmates. AB - This study measured the prevalence of current, severe symptoms of a mental health problem in an adult population of inmates in Ontario, Canada. The Resident Assessment Instrument-Mental Health was used to measure the prevalence of symptoms among a sample of 522 inmates. Propensity score weighting was used to adjust for nonrandom selection into the sample. Prevalence estimates were derived for the total inmate population, remand and sentenced, males and females, and Aboriginal and non-Aboriginal inmates. It is estimated that 41.1% of Ontario inmates will have at least one current, severe symptom of a mental health problem; of this group, 13.0%, will evidence two or more symptoms. The number of symptoms is strongly associated with presence of a psychiatric diagnosis and level of mental health care needs. Female (35.1%) and Aboriginal (18.7%) inmates are more likely to demonstrate two or more current, severe symptoms. Greater efforts must be made to bridge the gap between correctional and mental health care systems to ensure inmates in correctional facilities can access and receive appropriate mental health care services. PMID- 24146356 TI - Appraising the risk matrix 2000 static sex offender risk assessment tool. AB - This critical appraisal explores the reliability and validity of the Risk Matrix 2000 static sex offender risk assessment tool that is widely used in the United Kingdom. The Risk Matrix 2000 has to some extent been empirically validated for use with adult male sex offenders; however, this review highlights that further research into the validity of this static tool with sex offender subgroups or types is necessary in order to improve practical utility. The Risk Matrix 2000 relies on static risk predictors, thus it is limited in scope. This article argues that the addition of dynamic items that have been shown to be predictive of sexual recidivism would further enhance the tool. The paper argues that adding dynamic risk items would fit better with a rehabilitative approach to sex offender risk management and assessment. This would also provide a means by which to effectively plan sex offender treatment and evaluate individual offenders' progress in treatment; however, difficulties remain in identifying and assessing dynamic risk factors of sexual offending and so further research is required. PMID- 24146357 TI - Developing an automated database for monitoring ultrasound- and computed tomography-guided procedure complications and diagnostic yield. AB - Monitoring complications and diagnostic yield for image-guided procedures is an important component of maintaining high quality patient care promoted by professional societies in radiology and accreditation organizations such as the American College of Radiology (ACR) and Joint Commission. These outcome metrics can be used as part of a comprehensive quality assurance/quality improvement program to reduce variation in clinical practice, provide opportunities to engage in practice quality improvement, and contribute to developing national benchmarks and standards. The purpose of this article is to describe the development and successful implementation of an automated web-based software application to monitor procedural outcomes for US- and CT-guided procedures in an academic radiology department. The open source tools PHP: Hypertext Preprocessor (PHP) and MySQL were used to extract relevant procedural information from the Radiology Information System (RIS), auto-populate the procedure log database, and develop a user interface that generates real-time reports of complication rates and diagnostic yield by site and by operator. Utilizing structured radiology report templates resulted in significantly improved accuracy of information auto populated from radiology reports, as well as greater compliance with manual data entry. An automated web-based procedure log database is an effective tool to reliably track complication rates and diagnostic yield for US- and CT-guided procedures performed in a radiology department. PMID- 24146358 TI - A centralized platform for geo-distributed PACS management. AB - Picture Archive and Communication System (PACS) is a globally adopted concept and plays a fundamental role in patient care flow within healthcare institutions. However, the deployment of medical imaging repositories over multiple sites still brings several practical challenges namely related to operation and management (O&M). This paper describes a Web-based centralized console that provides remote monitoring, testing, and management over multiple geo-distributed PACS. The system allows the PACS administrator to define any kind of service or operation, reducing the need for local technicians and providing a 24/7 monitoring solution. PMID- 24146359 TI - Reply to the Letter to the Editor: Another look: is there a flaw to current hip septic arthritis diagnostic algorithms? PMID- 24146360 TI - Subungual exostosis of the toes: a systematic review. AB - BACKGROUND: Subungual exostosis is a relatively common benign bone tumor that occurs in the distal phalanges of the toes and can be a source of pain and nail deformity. There is controversy about the treatment of these lesions and there are few studies that have synthesized what is known and provided meaningful information on treatment. QUESTIONS/PURPOSES: We performed a systematic review to address the following questions: (1) What is the best surgical approach for excising these lesions? (2) What is the age range, sex distribution, and presenting symptoms of subungual exostoses and which toe is most frequently affected? (3) What complications arise from treatment? METHODS: Two authors independently searched multiple databases (Medline, 1950-May 2013; Cochrane EBM database, and EMBASE, 1980-May 2013 provided by OVID; ACP Journal Club, 2003-May 2013; CINAHL by EBSCO, 1937-May 2013; and PubMed by NLM, 1940-May 2013), and key words were chosen to achieve a broad search strategy. We included studies on the management of toe exostoses with > 10 cases and we excluded studies that reported on upper extremity exostoses or osteochondromas. Demographic and treatment data were collected from each article by two independent authors and collated. A total of 124 abstracts were screened, and 116 articles were reviewed in full, of which 13 met the inclusion criteria. RESULTS: Complete marginal excision through a fish mouth incision protecting the nail led to a recurrence rate of 4% and satisfactory clinical results, defined as no requirement for postoperative intervention and a satisfactory clinical appearance in 73%. Most studies provided incomplete descriptions of specific surgical techniques used. Fifty-five percent of the patients were younger than 18 years of age. A history of toe trauma before diagnosis was present in approximately 30% of the cases. Delayed diagnosis occurred in approximately 10% of the cases and onychodystrophy occurred in more than 10%. CONCLUSIONS: There is weak evidence to guide management of subungual exostosis. Adequate wound management postexcision aiming to minimize disruption to the nail bed and matrix may prevent onychodystrophy, which is a common complication of treatment. PMID- 24146361 TI - Does obesity affect the surgical outcome and complication rates of spinal surgery? A meta-analysis. AB - BACKGROUND: As obesity becomes more prevalent, it becomes more common among patients considering orthopaedic surgery, including spinal surgery. However, there is some controversy regarding whether obesity is associated with complications, failed reconstructions, or reoperations after spinal surgery. QUESTIONS/PURPOSES: We wished to determine, in patients undergoing spine surgery, whether obesity is associated with (1) surgical site infection, (2) mortality and the need for revision surgery after spinal surgery, and (3) increased surgical time and blood loss. METHODS: A systematic literature search was performed to collect comparative or controlled studies that evaluated the influence of obesity on the surgical and postoperative outcomes of spinal surgery. Two reviewers independently selected trials, extracted data, and assessed the methodologic quality and quality of evidence. Pooled odds ratios (OR) and mean differences (MD) with 95% CIs were calculated using the fixed-effects model or random-effects model. Data were analyzed using RevMan 5.1. MOOSE criteria were used to ensure this project's validity. Thirty-two studies involving 97,326 patients eventually were included. RESULTS: Surgical site infection (OR, 2.33; 95% CI, 1.94-2.79), venous thromboembolism (OR, 3.15; 95% CI, 1.92-5.17), mortality (OR, 2.6; 95% CI, 1.50-4.49), revision rate (OR, 1.43; 95% CI, 1.05-1.93) operating time (OR, 14.55; 95% CI, 10.03-19.07), and blood loss (MD, 28.89; 95% CI, 14.20-43.58), were all significantly increased in the obese group. CONCLUSION: Obesity seemed to be associated with higher risk of surgical site infection and venous thromboembolism, more blood loss, and longer surgical time. Future prospective studies are needed to confirm the relationship between obesity and the outcome of spinal surgery. PMID- 24146362 TI - Limited utility of adipokine levels in the diagnosis of malnutrition in the elderly. AB - BACKGROUND AND AIMS: Adipokine levels may have a role in the diagnostic and prognostic evaluation of malnutrition. The aim of the present study was to evaluate the correlation between malnutrition score and leptin, other biological markers, and body mass index (BMI) in the diagnosis of malnutrition in the elderly. METHODS: In this cross-sectional observational study, we enrolled subjects over 70 years. Exclusion criteria were diabetes mellitus, obvious thyroid disorders, significant edema, renal dysfunction, chronic liver disease, symptomatic cardiovascular diseases, and malignity. Patients' demographic and medical data were recorded and anthropometric measurements were performed. Laboratory parameters including leptin, IGF-1, IGFBP-3, IL-6, TNF-alpha were measured. We defined malnutrition according to mini nutritional assessment (MNA) scale. Patients were divided into four groups according to BMI quartiles. RESULTS: Average age of the patients was 81.9 +/- 4.8 years, 68.2 % female and 31.8 % male. According to their MNA scores, 103 (66.9 %) were well nourished, 33 (21.4 %) were under malnutrition risk and 18 (11.7 %) were malnourished. MNA total and screening scores were positively correlated with albumin, BMI, high density lipoprotein cholesterol and estimated glomerular filtration rate. Serum leptin levels (ng/ml) were 18.9 +/- 22.6, 22.3 +/- 21.9, 51.9 +/- 85.5, and 61.7 +/- 56.1 in BMI groups 1-4, respectively. BMI was positively correlated with leptin and triglyceride levels. Leptin levels were similar among nutritional state groups. Neither BMI nor MNA scores had any significant correlation with adiponectin, ghrelin, IGF-1, or IGFBP-3. CONCLUSIONS: Adipokine levels do not seem to give relevant information in nutritional state assessment. PMID- 24146363 TI - Aerobic training in older adults with type 2 diabetes and vasodepressive carotid sinus hypersensitivity. AB - BACKGROUND AND AIMS: Vasodepressive carotid sinus hypersensitivity (V-CSH) is a common but incurable etiology for fainting in older adults with diabetes (OADM), and is diagnosed by carotid sinus massage (CSM). Aerobic exercise has been shown to be an effective therapy for other neuroautonomic etiologies of syncope (such as orthostatic hypotension), but the effectiveness of aerobic training in V-CSH remains unknown. We examined whether aerobic training could attenuate the vasodepressive response to CSM in OADM (older adults with type 2 diabetes) subjects complicated by V-CSH. METHODS: Forty OADM subjects (mean age 72.2 +/- 0.7) complicated by V-CSH were recruited. Subjects were randomized to each of two groups: an aerobic group (AT, n = 20, 3 months vigorous aerobic exercise), and a nonaerobic (NA, n = 20, no aerobic exercise) group. Exercise sessions were supervised by a certified exercise trainer three times per week. The vasodepressive response [defined as the decrease in systolic blood pressure (SBP) during CSM] was measured before and after the training intervention using a Finometer. RESULTS: The intervention had no impact on the number of subjects that met the criteria for V-CSM in either the AT or NA groups, regardless of the criteria used (-10, -20, -30, -40 and -50 mmHg). There was no training effect on the vasodepressive response in either the AT or NA group (P = 0.214, 2-way analysis of variance, -30 mmHg definition for V-CSH). CONCLUSIONS: Aerobic training has no effect on the SBP response to CSM in OADM subjects with V-CSH. Unlike in other neuroautonomic etiologies for fainting, aerobic exercise is not effective as a treatment for V-CSH, at least in the OADM population. PMID- 24146364 TI - Stimulus in the form of rotation and shaking of a platform and its effect on the formation of trabecular bone in the lumbar vertebrae of mice. AB - BACKGROUND AND AIMS: Elderly individuals who suffer a fracture develop a gait disturbance and require prolonged bedrest. A fracture has a massive impact both physically and mentally and markedly diminishes quality of life. A new form of therapeutic exercise that mitigates the abrupt decrease in bone density in postmenopausal women must soon be developed so that those problems can be avoided. METHODS: The current study used a model of the decrease in bone density in ovariectomized mice to simulate postmenopausal women. The stimulus was provided by a shaking horizontal platform rotating in a circular motion. RESULTS: Comparison of the +/+ (ovariectomized/stimulated) group and +/- group indicated a significant decrease in BV/TV (p < 0.01), Tb.Th (p < 0.01), and Tb.N (p < 0.05) in the +/+ group and a significant increase in OV/BV (p < 0.01), OV/OS (p < 0.01), BFR/BV (p < 0.01), dLS/BS (p < 0.05), MS/BS (p < 0.05), BRs.R (p < 0.01), and Tb.Sp (p < 0.01) in the +/+ group. Physical therapy to prevent a decrease in bone density was studied via stimulus in the form of rotation of a platform. Analysis of bone histomorphometry revealed lessening of the decrease in bone density of the lumbar vertebrae, a feat that the stimulus from conventional physical therapy had failed to achieve. CONCLUSION: The current study delivered a shaking stimulus to mice in a model of postmenopause. Analysis of bone histomorphometry of the lumbar vertebrae suggested lessening of the abrupt decrease in bone density of trabecular bone. If this finding is used clinically, it could lead to physical therapy exercise that would be able to prevent compression fractures of the lumbar vertebrae. PMID- 24146365 TI - Patterns of stigma toward schizophrenia among the general population: a latent profile analysis. AB - OBJECTIVE: Our purpose was to assess stigma toward schizophrenia in a representative sample of the Brazilian general population. METHODS: The sample consisted of 1015 individuals interviewed by telephone. A vignette describing someone with schizophrenia was read, and four stigma aspects regarding this hypothetical individual were assessed: stereotypes, restrictions, perceived prejudice and social distance. Latent profile analysis searched for stigma profiles among the sample. Multinomial logistic regression was used to find correlates of each class. RESULTS: Four stigma profiles were found; 'no stigma' individuals (n = 251) mostly displayed positive opinions. 'Labelers' (n = 222) scored high on social distance; they more often had familial contact with mental illness and more often labeled the vignette's disorder as schizophrenia. 'Discriminators', the group with the majority of individuals (n = 302), showed high levels of stigmatizing beliefs in all dimensions; discriminators were significantly older. 'Unobtrusive stigma' individuals (n = 240) seemed to demonstrate uncertainty or low commitment since they mostly answered items with the middle/impartial option. CONCLUSION: Some findings from the international literature were replicated; however, familial contact increased stigma, possibly denoting a locally modulated determinant. Hereby, our study also adds important cross-cultural data by showing that stigma toward schizophrenia is high in a Latin-American setting. We highlight the importance of analyzing the general population as a heterogeneous group, aiming to better elaborate anti-stigma campaigns. PMID- 24146367 TI - Purification and characterization of RNA allied extracellular tyrosinase from Aspergillus species. AB - Production of L-DOPA, an anti-Parkinson's drug, using biological sources is widely studied in which tyrosinase is known to play a vital role. Tyrosinase is an omnipresent type 3 copper enzyme participating in many essential biological functions. Understanding properties of tyrosinase is essential for developing useful tyrosinase-based applications. Hence, extracellular tyrosinase from Aspergillus flavus UWFP 570 was purified using ammonium sulphate precipitation and DEAE ion exchange chromatography up to 8.3-fold. Purified protein was a riboprotein in nature containing significant amount of RNA which was confirmed colorimetrically and by electrophoresis. Removal of RNA reduced the activity and altered the conformation of tyrosinase as suggested by spectroflurometric results. Optimum pH and temperature of this 140 kDa protein were 7 and 40 degrees C, respectively. Copper sulphate and magnesium chloride enhanced the activity whereas in contrast FeCl3 inhibited the activity completely. Purified tyrosinase transformed L-tyrosine (5 mM) to L-DOPA within 5 h. PMID- 24146368 TI - Carbohydrate hydrogels with stabilized phage particles for bacterial biosensing: bacterium diffusion studies. AB - Bacteriophage particles have been reported as potentially useful in the development of diagnosis tools for pathogenic bacteria as they specifically recognize and lyse bacterial isolates thus confirming the presence of viable cells. One of the most representative microorganisms associated with health care services is the bacterium Pseudomonas aeruginosa, which alone is responsible for nearly 15% of all nosocomial infections. In this context, structural and functional stabilization of phage particles within biopolymeric hydrogels, aiming at producing cheap (chromogenic) bacterial biosensing devices, has been the goal of a previous research effort. For this, a detailed knowledge of the bacterial diffusion profile into the hydrogel core, where the phage particles lie, is of utmost importance. In the present research effort, the bacterial diffusion process into the biopolymeric hydrogel core was mathematically described and the theoretical simulations duly compared with experimental results, allowing determination of the effective diffusion coefficients of P. aeruginosa in the agar and calcium alginate hydrogels tested. PMID- 24146369 TI - Cryopreservation of Brassidium Shooting Star orchid using the PVS3 method supported with preliminary histological analysis. AB - Cryopreservation is an alternative, safe, and cost-effective method for long-term plant genetic resource conservation. This study was conducted to optimize the conditions for cryopreserving the protocorm-like bodies (PLBs) of Brassidium Shooting Star orchid with the PVS3 vitrification method. Five parameters were assessed in this study: PLB size, sucrose concentration, preculture duration, PVS3 duration, and unloading duration. The viability of the cryopreserved PLBs was determined using the triphenytetrazolium chloride assay and growth recovery assessments. The optimum condition for the cryopreservation of the PLBs of Brassidium Shooting Star orchid is based on the size range between 3 and 4 mm precultured with half-strength semi-solid MS media supplemented with 0.25 M sucrose for 24 h, followed by treatment with loading solution mixture of 2 M glycerol and 0.4 M sucrose supplemented with half-strength liquid MS media at 25 degrees C for 20 min. The PLBs were then dehydrated with PVS3 at 0 degrees C for 20 min prior to immersion in liquid nitrogen; finally, the PLBs were immersed with half-strength liquid MS media supplemented with 1.2 M sucrose for 30 min. Histological analyses displayed denser cytoplasm and voluminous nucleus in the cryopreserved PLBs of Brassidium Shooting Star orchid. PMID- 24146366 TI - Strategies for mining fungal natural products. AB - Fungi are well known for their ability to produce a multitude of natural products. On the one hand their potential to provide beneficial antibiotics and immunosuppressants has been maximized by the pharmaceutical industry to service the market with cost-efficient drugs. On the other hand identification of trace amounts of known mycotoxins in food and feed samples is of major importance to ensure consumer health and safety. Although several fungal natural products, their biosynthesis and regulation are known today, recent genome sequences of hundreds of fungal species illustrate that the secondary metabolite potential of fungi has been substantially underestimated. Since expression of genes and subsequent production of the encoded metabolites are frequently cryptic or silent under standard laboratory conditions, strategies for activating these hidden new compounds are essential. This review will cover the latest advances in fungal genome mining undertaken to unlock novel products. PMID- 24146370 TI - Shoot organogenesis from root-derived callus of Rhinacanthus nasutus (L.) Kurz. and assessment of clonal fidelity of micropropagted plants using RAPD analysis. AB - An efficient regeneration system was established for an ethnomedicinal shrub Rhinacanthus nasutus from root-derived callus organogenesis. The root segments were cultured on MS medium supplemented with various concentrations of Kn (1.0 4.0 MUM) alone or in combination with IBA (0.2-0.6 MUM) or 2, 4-D (0.5-1.5 MUM). The optimum frequency (94%) of callus induction was recorded on MS medium supplemented with 3.0 MUM Kn and 0.4 MUM IBA. For shoot regeneration from callus, MS medium supplemented with different concentrations (1.0-7.0 MUM) of BA or TDZ alone or in combination with NAA (0.2-1.0 MUm) was employed. The highest frequency of shoot regeneration (91%) and mean number of shoots (28.3) were observed on MS medium supplemented with 5.0 MUM BA and 0.7 MUM NAA. The shoots were excised and cultured on MS medium with 4.0 MUM IBA produced 3.4 roots per shoot in 88% cultures. Of the 65 plants transferred to soil 54 survived (83%). The plants were transferred to field after successful hardening. RAPD analysis of the regenerated plants showed high similarity with the mother plant. PMID- 24146371 TI - Overview of the carbonic anhydrase family. AB - The purpose of this collection of chapters is to provide a glimpse of where the carbonic anhydrase (CA) field is. This book is by no means fully inclusive, as only a few of the lead researchers around the world contributed; it serves only to show that the CA field is still pushing the boundaries of research as it has done since its discovery, and will do for a long time to come. PMID- 24146372 TI - Physiological functions of the alpha class of carbonic anhydrases. AB - Carbonic anhydrases are ubiquitous enzymes that catalyze the reversible hydration of carbon dioxide. These enzymes are of ancient origin as they are found in the deepest of branches of the evolutionary tree. Of the five different classes of carbonic anhydrases, the alpha class has perhaps received the most attention because of its role in human pathology. This review focuses on the physiological function of this class of carbonic anhydrases organized by their cellular location. PMID- 24146373 TI - Catalytic mechanism of alpha-class carbonic anhydrases: CO2 hydration and proton transfer. AB - The carbonic anhydrases (CAs; EC 4.2.1.1) are a family of metalloenzymes that catalyze the reversible hydration of carbon dioxide (CO2) and dehydration of bicarbonate (HCO3 (-)) in a two-step ping-pong mechanism: [Formula: see text] CAs are ubiquitous enzymes and are categorized into five distinct classes (alpha, beta, gamma, delta and zeta). The alpha-class is found primarily in vertebrates (and the only class of CA in mammals), beta is observed in higher plants and some prokaryotes, gamma is present only in archaebacteria whereas the delta and zeta classes have only been observed in diatoms.The focus of this chapter is on alpha CAs as the structure-function relationship is best understood for this class, in particular for humans. The reader is referred to other reviews for an overview of the structure and catalytic mechanism of the other CA classes. The overall catalytic site structure and geometry of alpha-CAs are described in the first section of this chapter followed by the kinetic studies, binding of CO2, and the proton shuttle network. PMID- 24146374 TI - Structure and catalytic mechanism of beta-carbonic anhydrases. AB - The beta-carbonic anhydrases (beta-CAs) are a structurally distinct family of carbonic anhydrase that is widely distributed in microorganisms, algae, plants, and invertebrates. Like all carbonic anhydrases, beta-CAs catalyze the reaction CO2 + H2O ? HCO3 (-) + H(+), and is typically associated with other enzymes that produce or utilize CO2 or HCO3 (-). beta-CA is required for normal growth for many organisms. Unique among the five different families of carbonic anhydrases, beta-CA is the only family of carbonic anhydrase to exhibit allostery. This chapter summarizes the structure, catalytic mechanism, and allosteric regulation of beta-CA. PMID- 24146375 TI - Prokaryotic carbonic anhydrases of Earth's environment. AB - Carbonic anhydrase is a metalloenzyme catalyzing the reversible hydration of carbon dioxide to bicarbonate. Five independently evolved classes have been described for which one or more are found in nearly every cell type underscoring the general importance of this ubiquitous enzyme in Nature. The bulk of research to date has centered on the enzymes from mammals and plants with less emphasis on prokaryotes. Prokaryotic carbonic anhydrases play important roles in the ecology of Earth's biosphere including acquisition of CO2 for photosynthesis and the physiology of aerobic and anaerobic prokaryotes decomposing the photosynthate back to CO2 thereby closing the global carbon cycle. This review focuses on the physiology and biochemistry of carbonic anhydrases from prokaryotes belonging to the domains Bacteria and Archaea that play key roles in the ecology of Earth's biosphere. PMID- 24146376 TI - Carboxysomal carbonic anhydrases. AB - Cyanobacteria and some chemoautotrophic bacteria enhance their carbon fixation efficiency by actively concentrating bicarbonate within their cytosol. However, converting bicarbonate into carbon dioxide - the form required by RubisCO - would result in its rapid escape through cellular membranes. These organisms resolve this dilemma by sequestering RubisCO behind a semi-permeable protein shell; the resulting large insoluble bodies are known as carboxysomes. For the carbon concentrating mechanism to function, there is an absolute requirement for carbonic anhydrase activity within the carboxysome to convert the bicarbonate to cabon dioxide, and a simultaneous requirement that minimal carbonic anhydrase activity be found within the cystol. Carboxysomal carbomic anhydrases therefore contain additional motifs and domains that generally mediate protein-protein interactions, or encapsulation dependent activation mechanisms. Carboxysomes are found in two deeply divergent varieties. Alpha-Carboxysomes contain a beta carbonic anhydrase, CsoSCA, which is so divergent from canonical beta-carbonic anhydrases that it was originally thought to be the founding member of a new class. Beta carboxysomes have CcmM whose N-terminal domain is an active gamma carbonic ahydrase in some strains, but in others has lost all activity and functions primarily as a protein complex assembly scaffold; in addition, a subset of beta-carboxysomes also contain the beta-carbonic anhydrase CcaA - either in addition to, or instead of, an active CcmM. Here we explore the structures, activities and interactions mediated by the three known carboxysomal carbonic anhydrases, and discuss the mechanisms by which they are recruited to the carboxysome. PMID- 24146377 TI - Carbonic anhydrases and their interplay with acid/base-coupled membrane transporters. AB - Carbonic anhydrases (CAs) have not only been identified as ubiquitous enzymes catalyzing the fast reversible hydration of carbon dioxide to generate or consume protons and bicarbonate, but also as intra- and extracellular proteins, which facilitate transport function of many acid/base transporting membrane proteins, coined 'transport metabolon'. Functional interaction between CAs and acid/base transporters, such as chloride/bicarbonate exchanger (AE), sodium-bicarbonate cotransporter (NBC) and sodium/hydrogen exchanger (NHE) has been shown to require both catalytic CA activity as well as direct binding of the enzyme to specific sites on the transporter. In contrast, functional interaction between different CA isoforms and lactate-proton-cotransporting monocarboxylate transporters (MCT) has been found to be isoform-specific and independent of CA catalytic activity, but seems to require an intramolecular proton shuttle within the enzyme. In this chapter, we review the various types of interactions between acid/base-coupled membrane carriers and different CA isoforms, as studied in vitro, in intact Xenopus oocytes, and in various mammalian cell types. Furthermore, we discuss recent findings that indicate the significance of these 'transport metabolons' for normal cell functions. PMID- 24146378 TI - Carbonic anhydrase related proteins: molecular biology and evolution. AB - The catalytically inactive isoforms of alpha-carbonic anhydrases are known as carbonic anhydrase related proteins (CARPs). The CARPs occur independently or as domains of other proteins in animals (both vertebrates and invertebrates) and viruses. The catalytic inactivity of CARPs is due to the lack of histidine residues required for the coordination of the zinc atom. The phylogenetic analysis shows that these proteins are highly conserved across the species. The three CARPs in vertebrates are known as CARP VIII, X and XI. CARPs orthologous to CARP VIII are found in deuterostome invertebrates, whereas protostomes only possess orthologs of CARP X. The CA-like domains of receptor-type protein tyrosine phosphatases (PTPR) are found only in PTPRG and PTPRZ. Most of these CARPs are predominantly expressed in central nervous system. Among the three vertebrate CA isoforms, CARP VIII is functionally associated with motor coordination in human, mouse and zebrafish and certain types of cancers in humans. Vertebrate expression studies show that CARP X is exclusively expressed in the brain. CARP XI is only found in tetrapods and is highly expressed in the central nervous system (CNS) of humans and mice and is also associated with several cancers. CARP VIII, PTPRZ and PTPRG have been shown to coordinate the function of other proteins by protein-protein interaction, and viral CARPs participate in attachment to host cells, but the precise biological function of CARPs X and XI is still unknown. The findings so far suggest many novel functions for the CARP subfamily, most likely related to binding to other proteins. PMID- 24146379 TI - Membrane associated carbonic anhydrase IV (CA IV): a personal and historical perspective. AB - Carbonic anhydrase IV is one of 12 active human isozymes and one of four expressed on the extracellular surfaces of certain endothelial and epithelial cells. It is unique in being attached to the plasma membrane by a glycosyl phosphatiydyl-inositol (GPI) anchor rather than by a membrane-spanning domain. It is also uniquely resistant to high concentrations of sodium dodecyl sulfate (SDS), which allows purification from tissues by inhibitor affinity chromatography without contamination by other isozymes. This unique resistance to SDS and recovery following denaturation is explained by the two disulfide bonds. The 35-kDa human CA IV is a "high activity" isozyme in CO2 hydration activity, like CA II, and has higher activity than other isozymes in catalyzing the dehydration of HCO3 (-). Human CA IV is also unique in that it contains no oligosaccharide chains, where all other mammalian CA IVs are glycoproteins with one to several oligosaccharide side chains.Although CA IV has been shown to be active in mediating CO2 and HCO3 (-) transport in many important tissues like kidney and lung, and in isolated cells from brain and muscle, the gene for CA IV appears not to be essential. The CA IV knockout mouse produced by targeted mutagenesis, though slightly smaller and produced in lower than expected numbers, is viable and has no obvious mutant phenotype. Conversely, several dominant negative mutations in humans are associated with one form of reitinitis pigmentosa (RP-17), which we attribute to unfolded protein accumulation in the choreocapillaris, leading to apoptosis of cells in the overlying retina. PMID- 24146380 TI - Carbonic anhydrase expression in kidney and renal cancer: implications for diagnosis and treatment. AB - Four different carbonic anhydrases are expressed in the human nephron, the functional unit of the kidney. These are specifically expressed in different nephron segments, emphasizing the critical role carbonic anhydrases play in maintaining the homeostasis of this crucial organ.Whereas the localization of carbonic anhydrases in the kidney has been long established, interest in carbonic anhydrases has increased dramatically for renal cancer, in particular for the clear cell variant of renal cell carcinoma (ccRCC) because carbonic anhydrase IX is specifically expressed in ccRCC. Therefore carbonic anhydrase IX is being studied as potential diagnostic and therapeutic target, despite carbonic anhydrase IX expression in non-renal tissues. PMID- 24146381 TI - Carbonic anhydrase IX: regulation and role in cancer. AB - Tumor microenvironment substantially influences the process of tumorigenesis. In many solid tumors, imbalance between the demand of rapidly proliferating cancer cells and the capabilities of the vascular system generates areas with insufficient oxygen supply. In response to tumor hypoxia, cancer cells modulate their gene expression pattern to match the requirements of the altered microenvironment. One of the most significant adaptations to this milieu is the shift towards anaerobic glycolysis to keep up the energy demands. This oncogenic metabolism is often maintained also in aerobic cells. Lactic acid, its metabolic end-product, accumulates hand-in-hand with carbon dioxide, leading to acidification of the extracellular environment. Carbonic anhydrase IX (CA IX) is the most widely expressed gene in response to hypoxia. Its crucial role in intracellular pH maintenance represents the means by which cancer cells adapt to the toxic conditions of the extracellular milieu. Furthermore, the activity of CA IX stimulates the migratory pathways of cancer cells and is connected with the increase of the aggressive/invasive phenotype of tumors. CA IX expression in many types of tumors indicates its relevance as a general marker of tumor hypoxia. Moreover, its expression is closely related to prognosis of the clinical outcome in several tumor types. All above mentioned facts support the strong position of CA IX as a potential drug therapy target. Here, we summarize the state-of-the-art knowledge on its regulation and role in cancer development. PMID- 24146383 TI - Carbonic anhydrase IX (CAIX) as a mediator of hypoxia-induced stress response in cancer cells. AB - The development of hypoxic microenvironments within many types of solid tumors imposes a significant stress on cancer cells to which they must respond appropriately in order to survive and grow. Tumor-specific, hypoxia-induced upregulation of Carbonic Anhydrase IX (CAIX) is a component of the complex response of cancer cells to the evolving low oxygen environment. Here, we discuss evidence from in vivo tumor models employing inhibition or enhancement of CAIX expression, using gene depletion or overexpression strategies, respectively, or inhibition of its catalytic activity, using CAIX-specific small molecules or antibodies, to demonstrate that CAIX is a functional mediator of tumor growth and metastasis. We also discuss the functional contribution of CAIX to several specific biological processes critical for cancer progression, including pH regulation and cell survival, adhesion, migration and invasion, the maintenance of cancer stem cell function, and the acquisition of chemo and radioresistant properties. The demonstration of CAIX as a functional mediator of cancer progression provides a biological rationale for its use as a cancer-specific, clinically relevant therapeutic target. PMID- 24146384 TI - Carbonic anhydrases and brain pH in the control of neuronal excitability. AB - H(+) ions are remarkably efficient modulators of neuronal excitability. This renders brain functions highly sensitive to small changes in pH which are generated "extrinsically" via mechanisms that regulate the acid-base status of the whole organism; and "intrinsically", by activity-induced transmembrane fluxes and de novo generation of acid-base equivalents. The effects of pH changes on neuronal excitability are mediated by diverse, largely synergistically-acting mechanisms operating at the level of voltage- and ligand-gated ion channels and gap junctions. In general, alkaline shifts induce an increase in excitability which is often intense enough to trigger epileptiform activity, while acidosis has the opposite effect. Brain pH changes show a wide variability in their spatiotemporal properties, ranging from long-lasting global shifts to fast and highly localized transients that take place in subcellular microdomains. Thirteen catalytically-active mammalian carbonic anhydrase isoforms have been identified, whereof 11 are expressed in the brain. Distinct CA isoforms which have their catalytic sites within brain cells and the interstitial fluid exert a remarkably strong influence on the dynamics of pH shifts and, consequently, on neuronal functions. In this review, we will discuss the various roles of H(+) as an intra- and extracellular signaling factor in the brain, focusing on the effects mediated by CAs. Special attention is paid on the developmental expression patterns and actions of the neuronal isoform, CA VII. Studies on the various functions of CAs will shed light on fundamental mechanisms underlying neuronal development, signaling and plasticity; on pathophysiological mechanisms associated with epilepsy and related diseases; and on the modes of action of CA inhibitors used as CNS-targeting drugs. PMID- 24146385 TI - Carbonic anhydrase inhibitors drug design. AB - Inhibition of the metalloenzyme carbonic anhydrase (CA, EC 4.2.1.1) has pharmacologic applications in the field of antiglaucoma, anticonvulsant, antiobesity, and anticancer agents but is also emerging for designing anti infectives (antifungal and antibacterial agents) with a novel mechanism of action. As a consequence, the drug design of CA inhibitors (CAIs) is a very dynamic field. Sulfonamides and their isosteres (sulfamates/sulfamides) constitute the main class of CAIs which bind to the metal ion in the enzyme active site. Recently the dithiocarbamates, possessing a similar mechanism of action, were reported as a new class of inhibitors. Other families of CAIs possess a distinct mechanism of action: phenols, polyamines, some carboxylates, and sulfocoumarins anchor to the zinc-coordinated water molecule. Coumarins and five/six-membered lactones are prodrug inhibitors, binding in hydrolyzed form at the entrance of the active site cavity. Novel drug design strategies have been reported principally based on the tail approach for obtaining all these types of CAIs, which exploit more external binding regions within the enzyme active site (in addition to coordination to the metal ion), leading thus to isoform-selective compounds. Sugar-based tails as well as click chemistry were the most fruitful developments of the tail approach. Promising compounds that inhibit CAs from bacterial and fungal pathogens, of the dithiocarbamate, phenol and carboxylate types have also been reported. PMID- 24146386 TI - Natural products that inhibit carbonic anhydrase. AB - The chemical diversity, binding specificity and propensity to interact with biological targets has inspired many researchers to utilize natural products as molecular probes. Almost all reported carbonic anhydrase inhibitors comprise a zinc binding group in their structure of which the primary sulfonamide moiety ( SO2NH2) is the foremost example and to a lesser extent the primary sulfamate (-O SO2NH2) and sulfamide (-NH-SO2NH2) groups. Natural products that comprise these zinc binding groups in their structure are however rare and relatively few natural products have been explored as a source for novel carbonic anhydrase inhibitors. This chapter will highlight the recent and growing interest in carbonic anhydrase inhibitors sourced from nature, demonstrating that natural product chemical space presents a rich source of potential alternate chemotypes for the discovery of novel drug-like carbonic anhydrase inhibitors. PMID- 24146382 TI - Carbonic anhydrase IX as an imaging and therapeutic target for tumors and metastases. AB - Carbonic anhydrase IX (CAIX) which is a zinc containing metalloprotein, efficiently catalyzes the reversible hydration of carbon dioxide. It is constitutively up-regulated in several cancer types and has an important role in tumor progression, acidification and metastasis. High expression of CAIX generally correlates with poor prognosis and is related to a decrease in the disease-free interval following successful therapy. Therefore, it is considered as a prognostic indicator in oncology.In this review, we describe CAIX regulation and its role in tumor hypoxia, acidification and metastasis. In addition, the molecular imaging of CAIX and its potential for use in cancer detection, diagnosis, staging, and for use in following therapy response is discussed. Both antibodies and small molecular weight compounds have been used for targeted imaging of CAIX expression. The use of CAIX expression as an attractive and promising candidate marker for systemic anticancer therapy is also discussed. PMID- 24146387 TI - Glaucoma and the applications of carbonic anhydrase inhibitors. AB - Inhibition of carbonic anhydrase (CA, EC 4.2.1.1) has pharmacologic applications in the treatment of glaucoma, a disease affecting a large number of people and characterized by an elevated intraocular pressure (IOP). At least three isoforms, CA II, IV and XII are targeted by the sulfonamide inhibitors, some of which are clinically used drugs. Acetazolamide, methazolamide and dichlorophenamide are first generation CA inhibitors (CAIs) still used as systemic drugs for the management of this disease. Dorzolamide and brinzolamide represent the second generation inhibitors, being used topically, as eye drops, with less side effects compared to the first generation drugs. Third generation inhibitors have been developed by using the tail approach, but they did not reach the clinics yet. The most promising such derivatives are the sulfonamides incorporating either tails with nitric oxide releasing moieties or hybrid drugs possessing prostaglandin (PG) F agonist moieties in their molecules. Recently, the dithiocarbamates have also been described as CAIs possessing IOP lowering effects in animal models of glaucoma. CAIs are used alone or in combination with other drugs such as adrenergic agonist/antagonists, or PG analogs, being an important component of the antiglaucoma drugs armamentarium. PMID- 24146388 TI - Carbonic anhydrase inhibitors and high altitude illnesses. AB - Carbonic anhydrase (CA) inhibitors, particularly acetazolamide, have been used at high altitude for decades to prevent or reduce acute mountain sickness (AMS), a syndrome of symptomatic intolerance to altitude characterized by headache, nausea, fatigue, anorexia and poor sleep. Principally CA inhibitors act to further augment ventilation over and above that stimulated by the hypoxia of high altitude by virtue of renal and endothelial cell CA inhibition which oppose the hypocapnic alkalosis resulting from the hypoxic ventilatory response (HVR), which acts to limit the full expression of the HVR. The result is even greater arterial oxygenation than that driven by hypoxia alone and greater altitude tolerance. The severity of several additional diseases of high attitude may also be reduced by acetazolamide, including high altitude cerebral edema (HACE), high altitude pulmonary edema (HAPE) and chronic mountain sickness (CMS), both by its CA inhibiting action as described above, but also by more recently discovered non-CA inhibiting actions, that seem almost unique to this prototypical CA inhibitor and are of most relevance to HAPE. This chapter will relate the history of CA inhibitor use at high altitude, discuss what tissues and organs containing carbonic anhydrase play a role in adaptation and maladaptation to high altitude, explore the role of the enzyme and its inhibition at those sites for the prevention and/or treatment of the four major forms of illness at high altitude. PMID- 24146389 TI - Thermal-stable carbonic anhydrases: a structural overview. AB - The potential of carbonic anhydrase (CA) family as target for the drug design of inhibitors with various medicinal chemistry applications has been recognized from long time, whereas the industrial interest in using these enzymes as biocatalysts for carbon dioxide sequestration and biofuel production is only recently emerging. However, an efficient utilization in these processes often requires stable enzymes, able to work in the harsh conditions typical of the CO2 capture process. In this context CAs active at very high temperatures are of extreme interest. In this chapter we have summarized in a comparative manner all existing data on thermostable CAs both isolated by extremophiles and obtained by protein engineering studies. Among the five CA-classes, the biochemical and structural features of thermostable alpha-, beta- and gamma-CAs have been discussed. Data show that so far alpha-CAs isolated from thermophilic organisms are the best candidates to be used in biotechnological processes, even if plenty of work can be still done in this field also with help of protein engineering. PMID- 24146390 TI - Carbonic anhydrases in industrial applications. AB - Carbonic anhydrases (CAs) catalyze a fundamental reaction: the reversible hydration and dehydration of carbon dioxide (CO2) and bicarbonate ([Formula: see text]), respectively. Current methods for CO2 capture and sequestration are harsh, expensive, and require prohibitively large energy inputs, effectively negating the purpose of removing CO2 from the atmosphere. Due to CA's activity on CO2 there is increasing interest in using CAs for industrial applications such as carbon sequestration and biofuel production. A lot of work in the last decade has focused on immobilizing CA onto various supports for incorporation into CO2 scrubbing applications or devices. Although the proof of principle has been validated, current CAs being tested do not withstand the harsh industrial conditions. The advent of large-scale genome sequencing projects has resulted in several emerging efforts seeking out novel CAs from a variety of microorganisms, including bacteria, micro-, and macro-algae. CAs are also being investigated for their use in medical applications, such drug delivery systems and artificial lungs. This review also looks at possible downstream uses of captured and sequestered CO2, from using it to enhance oil recovery to incorporating it into useful and financially viable products. PMID- 24146391 TI - Representing part-whole relations in conceptual spaces. AB - In this paper, we propose a cognitive semantic approach to represent part-whole relations. We base our proposal on the theory of conceptual spaces, focusing on prototypical structures in part-whole relations. Prototypical structures are not accounted for in traditional mereological formalisms. In our account, parts and wholes are represented in distinct conceptual spaces; parts are joined to form wholes in a structure space. The structure space allows systematic similarity judgments between wholes, taking into consideration shared parts and their configurations. A point in the structure space denotes a particular part structure; regions in the space represent different general types of part structures. We argue that the structural space can represent prototype effects: structural types are formed around typical arrangements of parts. We also show how structure space captures the variations in part structure of a given concept across different domains. In addition, we discuss how some taxonomies of part whole relations can be understood within our framework. PMID- 24146392 TI - The optimal velocity criterion in the diagnosis of unilateral middle cerebral artery stenosis by transcranial Doppler. AB - We evaluated the optimal flow velocity of transcranial doppler (TCD) in detecting unilateral middle cerebral artery (MCA) stenosis and stenosis grading by magnetic resonance angiography (MRA) as the reference standard. 302 nonconsecutive patients with unilateral MCA stenosis detected by TCD underwent MRA of the intracranial arteries. The peak systolic velocity (PSV), mean flow velocity (MFV), and end-diastolic velocity (EDV) of each MCA were recorded. 604 MCA were categorized into four groups depending on the stenosis severity: normal MCA (n = 319, 52.8%), mild stenosis (n = 94, 15.6%), moderate stenosis (n = 66, 10.9%), and severe stenosis (n = 125, 20.7%). Significant differences in PSV, MFV, and EDV between these four groups were observed (P < 0.001, respectively). The optimal cutoff velocities for detecting MCA stenosis were: PSV = 160 cm/s, MFV = 100 cm/s, EDV = 60 cm/s; the optimal cutoff points to distinguish mild from moderate stenosis were: PSV = 200 cm/s, MFV = 120 cm/s, EDV = 80 cm/s; the cutoffs to distinguish moderate from severe stenosis were: PSV = 280 cm/s, MFV = 180 cm/s, EDV = 110 cm/s. Using PSV as the diagnostic criteria, the correlation for diagnosing MCA stenosis using TCD and MCA was good (Kappa number kappa = 0.668); using as MFV criteria, kappa = 0.641. The optimal cutoff PSV values in stenosis grading on TCD were 160, 200, and 280 cm/s. The optimal cutoff MFV values were 100, 120, and 180 cm/s. PSV is more accurate than MFV in detecting and grading MCA stenosis. PMID- 24146393 TI - Design of phage-displayed cystine-stabilized mini-protein libraries for proteinaceous binder engineering. AB - Cystine-stabilized mini-proteins are important scaffolds in the combinatorial search of binders for molecular recognition. The structural determinants of a cystine-stabilized scaffold are the critical residues determining the formation of the native disulfide-bonding configuration, and thus should remain unchanged in the combinatorial libraries so as to allow a large portion of the library sequences to be compatible with the scaffold structure. A high-throughput molecular evolution procedure has been developed to select and screen for the polypeptide sequences folding into a specific cystine-stabilized structure. Patterns of sequence preference that emerge from the resultant sequence profiles provide structural determinant information, which facilitates the designs of combinatorial libraries for combinatorial approaches as in phage display. This methodology enables artificial cystine-stabilized proteins to be engineered with enhanced folding and binding properties. PMID- 24146394 TI - Construction of a filamentous phage display peptide library. AB - The concept of phage display is based on insertion of random oligonucleotides at an appropriate location within a structural gene of a bacteriophage. The resulting phage will constitute a library of random peptides displayed on the surface of the bacteriophages, with the encoding genotype packaged within each phage particle. Using a phagemid/helper phage system, the random peptides are interspersed between wild-type coat proteins. Libraries of phage-expressed peptides may be used to search for novel peptide ligands to target proteins. The success of finding a peptide with a desired property in a given library is highly dependent on the diversity and quality of the library. The protocols in this chapter describe the construction of a high-diversity library of phagemid vector encoding fusions of the phage coat protein pVIII with random peptides, from which a phage library displaying random peptides can be prepared. PMID- 24146395 TI - Engineering bioactive peptide-based therapeutic molecules. AB - Peptides are increasingly emerging as human therapeutic drugs. By screening very large phage display libraries, novel bioactive peptides that bind to the target of interest with desired biological properties can be identified. Peptides that are obtained in this fashion become the basis for therapeutic molecule development. However, naked peptides are usually not sufficient to be therapeutic molecules by themselves. They need to be chemically modified or conjugated to other molecules to obtain desired physicochemical and in vivo properties. In this chapter, we describe a general methodology of identifying bioactive peptides by biopanning of peptide phage libraries. As an example of therapeutic peptide modifications, we also describe a method for fusing the peptides to the Fc portion of antibody molecule to increase in vivo stability and activity. PMID- 24146396 TI - T7 lytic phage-displayed peptide libraries: construction and diversity characterization. AB - In this chapter, we describe the construction of T7 bacteriophage (phage) displayed peptide libraries and the diversity analyses of random amino acid sequences obtained from the libraries. We used commercially available reagents, Novagen's T7Select system, to construct the libraries. Using a combination of biotinylated extension primer and streptavidin-coupled magnetic beads, we were able to prepare library DNA without applying gel purification, resulting in extremely high ligation efficiencies. Further, we describe the use of bioinformatics tools to characterize library diversity. Amino acid frequency and positional amino acid diversity and hydropathy are estimated using the REceptor LIgand Contacts website http://relic.bio.anl.gov. Peptide net charge analysis and peptide hydropathy analysis are conducted using the Genetics Computer Group Wisconsin Package computational tools. A comprehensive collection of the estimated number of recombinants and titers of T7 phage-displayed peptide libraries constructed in our lab is included. PMID- 24146397 TI - Affinity selection using filamentous phage display. AB - Display of peptides on filamentous phage, phage display, is an in vitro selection technique well suited for identification of therapeutic peptide binders for a huge variety of protein targets. The peptides are identified in a process where phage libraries are subjected to affinity selection towards a particular protein target. A successful outcome of an affinity selection is dependent on proper surveillance of the phage life cycle, to make sure that the selection is based on affinity for the target, not on bias in phage propagation rate. In this chapter we present two approaches for protein target presentation and a protocol for phage rescue and propagation, which includes several controls to ensure that all phages initially eluted from the protein target are given equal conditions during the following amplification and selection steps. PMID- 24146398 TI - Bioprospecting open reading frames for peptide effectors. AB - Recent successes in the development of small-molecule antagonists of protein protein interactions designed based on co-crystal structures of peptides bound to their biological targets confirm that short peptides derived from interacting proteins can be high-value ligands for pharmacologic validation of targets and for identification of druggable sites. Evolved sequence space is likely to be enriched for interacting peptides, but identifying minimal peptide effectors within genomic sequence can be labor intensive. Here we describe the use of incremental truncation to diversify genetic material on the scale of open reading frames into comprehensive libraries of constituent peptides. The approach is capable of generating peptides derived from both continuous and discontinuous sequence elements, and is compatible with the expression of free linear or backbone cyclic peptides, with peptides tethered to amino- or carboxyl-terminal fusion partners or with the expression of peptides displayed within protein scaffolds (peptide aptamers). Incremental truncation affords a valuable source of molecular diversity to interrogate the druggable genome or evaluate the therapeutic potential of candidate genes. PMID- 24146399 TI - Identification of ideal peptides for heterovalent ligands. AB - Recent use of hetero-dimerization to improve the affinity of peptide ligands has made peptides an attractive alternative to small molecules and proteins. Using this strategy, we have developed peptides with affinities comparable to antibodies and specificities often better than small molecules or antibodies. These peptides can be used as a delivery vehicle for drugs or diagnostics, especially in the case of tumor targeting cytotoxic drugs or targeted diagnostics. We describe here an assay to identify an ideal pair of peptides suitable for heterovalent ligands. PMID- 24146400 TI - Substrate phage display for protease substrate sequence characterization: bovine factor Xa as a model system. AB - Regulatory proteases modulate proteomic dynamics with a spectrum of specificities against substrate proteins. Substrate phage display is one of the key methodologies in producing substrate sequence information in vitro. Factor Xa, a key regulatory protease in the blood coagulation system, is used as a model system to demonstrate a high-throughput procedure to quantitatively characterize substrate sequences and their susceptibilities for enzymatic cleavage. This methodology can be generalized to proteases for which the active forms (not necessarily purified forms) are available for the in vitro experiments. PMID- 24146401 TI - Engineering peptide therapeutics using MIMETIBODYTM technology. AB - The MIMETIBODYTM platform was developed to expand the opportunities for application of biotherapeutics. While the utility of antibodies as antagonists has been well demonstrated, their application as agonists has been more challenging. For steric reasons, antibodies may be less well suited to perform as agonists or as inhibitors of GPCRs. In contrast, many bioactive peptides function as agonists or by interaction with GPCRs but their development as therapeutics has been challenging due to their small size and metabolic lability. The MIMETIBODYTM platform has been used to develop a variety of stable, long-lived molecules with intrinsic activities similar to that of their parent peptides. This chapter describes methods for construction of expression plasmids, expression and purification strategies, and methods for characterizing the activity of these novel proteins. PMID- 24146402 TI - Evaluation of peptides as protease inhibitors and stimulators. AB - Changes in proteolytic activity are associated with several diseases, including cancer. Proteases are potential drug targets and targeting of proteases is used for treatment of various conditions/diseases, like high blood pressure and HIV. We present here detailed protocols for basic evaluation of the effects of peptides on the activity of proteases, using kallikrein-related peptidases KLK2 and KLK3 (also known as hK2 and PSA), and trypsin as examples. KLK2 and KLK3 are major prostatic proteases, and they are potential targets for prostate cancer treatment. KLK2 has trypsin-like activity and KLK3 chymotrypsin-like activity. By phage display technology, we have developed peptides that specifically stimulate KLK3-activity and other peptides that inhibit KLK2 or trypsin. The effect of the peptides on the proteolytic activity of proteases can be studied using substrates, the cleavage of which generates detectable signal, allowing rapid evaluation of protease activity. The cleavage of protein substrates can be detected by SDS-PAGE, followed by staining of the proteins. We also describe graphical analysis of the IC50-value, the effect of a peptide on Michaelis-Menten constant (K(m)) and the maximal reaction rate (V(max)). PMID- 24146403 TI - Assessment of antimicrobial (host defense) peptides as anti-cancer agents. AB - Cationic antimicrobial (host defense) peptides (CAPs) are able to kill microorganisms and cancer cells, leading to their consideration as novel candidate therapeutic agents in human medicine. CAPs can physically associate with anionic membrane structures, such as those found on cancer cells, causing pore formation, intracellular disturbances, and leakage of cell contents. In contrast, normal cells are less negatively-charged and are typically not susceptible to CAP-mediated cell death. Because the interaction of CAPs with cells is based on charge properties rather than cell proliferation, both rapidly dividing and quiescent cancer cells, as well as multidrug-resistant cancer cells, are targeted by CAPs, making CAPS potentially valuable as anti-cancer agents. CAPs often exist as families of peptides with slightly different amino acid sequences. In addition, libraries of synthetic peptide variants based on naturally occurring CAP templates can be generated in order to improve upon their action. High-throughput screens are needed to quickly and efficiently assess the suitability of each CAP variant. Here we present the methods for assessing CAP mediated cytotoxicity against cancer cells (suspension and adherent) and untransformed cells (measured using the tritiated thymidine-release or MTT assay), and for discriminating between cell death caused by necrosis (measured using lactate dehydrogenase- or (51)Cr-release assays), or apoptosis and necrosis (single-stranded DNA content measured by flow cytometry). In addition the clonogenic assay, which assesses the ability of single transformed cells to multiply and produce colonies, is described. PMID- 24146404 TI - Peptide labelling strategies for imaging agents. AB - The main goal in modern biomedicine is to develop specific diagnostic and therapeutic agents for different diseases. Especially in cancer research tumor targeted molecules are the key factor in the development of new anti-tumor drugs. In addition, the early diagnosis of the disease is an important factor for a successful therapy. Synthetic peptides have been shown to be specific targeting agents for next generation diagnostic and therapeutic agents. Noninvasive in vivo imaging using targeting molecules provides modern method for the diagnosis of the pathological alterations like cancer. To evaluate the usefulness of a synthetic peptide for in vivo diagnostic purposes the preclinical biodistribution and targeting studies are essential. Today the widely used preclinical imaging modalities for the biodistribution and tissue alteration studies in experimental animals are single photon emission computed tomography (SPECT) and magnetic resonance imaging (MRI). Together with conventional histochemistry, the biodistribution and tissue/cell location can be determined. In this chapter we describe the conjugation and labelling methods of the peptides for histochemistry and for the molecular imaging with SPECT and MRI modalities. PMID- 24146405 TI - Peptide optimization and conjugation strategies in the development of molecularly targeted magnetic resonance imaging contrast agents. AB - Peptides are highly selective, high-affinity ligands for a diverse array of disease targets, but suitably derivatizing them for application as diagnostic or therapeutic agents often presents a significant challenge. Covalent modification with metal chelates frequently results in decreased binding affinity, so a variety of strategies must be explored to find suitable locations for modification and facile peptide conjugation chemistries that maintain or enhance binding affinity. In this chapter, we present a paradigm for systematically optimizing peptide binding and determining the favorable sites and methods for peptide conjugation. This strategy is illustrated by two case studies of peptide based targeted gadolinium contrast agents: EP-2104R for diagnosis of thrombosis and EP-3533 for diagnosis of cardiac perfusion and fibrosis. Two different architectures for the peptide-metal complex conjugation were designed: EP-2104R contains a total of four gadolinium (Gd) chelates linked at the N- and C-termini, whereas EP-3533 is derivatized with three Gd chelates, two on the N-terminus and one on a lysine side chain. Detailed protocols are provided for two Gd chelate conjugation methods. PMID- 24146406 TI - Evaluation of prenylated peptides for use in cellular imaging and biochemical analysis. AB - Protein prenylation involves the addition of a farnesyl (C15) or geranylgeranyl (C20) isoprenoid moiety onto the C-terminus of approximately 2 % of all mammalian proteins. This hydrophobic modification serves to direct membrane association of the protein. Due to the finding that the oncogenic protein Ras is naturally prenylated, several researchers have developed inhibitors of the prenyltransferase enzymes as cancer therapeutics. Despite numerous studies on the enzymology of prenylation in vitro, many questions remain about the process of prenylation in living cells. Using a combination of flow cytometry and confocal microscopy, we have shown that synthetic fluorescently labeled prenylated peptides enter a variety of different cell types. Additionally, using capillary electrophoresis we have shown that these peptides can be detected in minute quantities from lysates of cells treated with these peptides. This method will allow for further study of the enzymology of protein prenylation in living cells. PMID- 24146407 TI - Ultraviolet absorption spectroscopy of peptides. AB - UV absorption spectroscopy is commonly used with peptides for determining concentration and enzyme activity, but high-resolution UV spectra can also provide information on peptide secondary and tertiary structure and association behavior. New developments using temperature- and cation-dependent high resolution second derivative absorption methods can also provide information concerning peptide dynamics. Data from several low-resolution spectroscopic techniques, including UV absorption, can be combined to generate an overall picture of peptide structure as a function of environmental conditions. PMID- 24146408 TI - Fluorescence spectroscopy of peptides. AB - In peptides, steady-state fluorescence can be used to measure the intrinsic fluorescence of Trp, Tyr, and Phe residues, as well as associated dyes, which can change upon exposure to different environmental conditions. This technique can be thus used to detect changes in the conformational states of peptides. Time resolved fluorescence can also be used to study fast motions of peptides and their interactions with fluorescence dyes. Data from several low-resolution spectroscopic techniques, including fluorescence, can be combined to generate an overall picture of peptide structure as a function of environmental conditions. PMID- 24146409 TI - Circular dichroism of peptides. AB - Circular dichroism measures the difference between the absorbance of left- and right-handed circularly polarized light, and can be used to monitor the secondary structure of peptides (far UV) and the tertiary structure of larger polypeptides (near UV). This technique is especially useful for helix-coil transitions and other aspects of structural alterations. Data from several low-resolution spectroscopic techniques, including CD, can be combined to generate an overall picture of peptide structure as a function of environmental conditions. PMID- 24146410 TI - Fourier transform infrared spectroscopy of peptides. AB - Fourier transform infrared (FTIR) spectroscopy provides data that are widely used for secondary structure characterization of peptides. A wide array of available sampling methods permits structural analysis of peptides in diverse environments such as aqueous solution (including optically turbid media), powders, detergent micelles, and lipid bilayers. In some cases, side chain vibrations can also be resolved and used for tertiary structure and chemical analysis. Data from several low-resolution spectroscopic techniques, including FTIR, can be combined to generate an empirical phase diagram, an overall picture of peptide structure as a function of environmental conditions that can aid in the global interpretation of large amounts of spectroscopic data. PMID- 24146411 TI - The calcium-phosphate balance, modulation of thyroid autoimmune processes and other adverse effects connected with thyroid arterial embolization. AB - In search of new treatment options for thyroid diseases, when conventional procedures are ineffective, contraindicated or associated with serious side effects, safety of thyroid arteries embolization in the treatment of particular thyroid diseases was evaluated. The study included eight subjects with retrosternal toxic goiter, six patients affected by Graves' disease, five cases of retrosternal non-toxic goiter, two subjects with post-amiodarone hyperthyroidism, and one patient with severe thyroid-related orbitopathy, who underwent selective embolization of thyroid arteries. The study assessed and compared calcium-phosphate balance, modulation of thyroid autoimmunity and the presence of different side effects in patients who underwent the procedure. In addition, the serum concentrations of thyroid hormones, anti-thyroid autoantibodies and thyroid volume have been measured. Five of all enrolled subjects (22.7 %) experienced transient, not clinically relevant hypocalcaemia with no need for calcium supplementation. There were no significant changes in serum calcium levels in patients after embolization of both inferior thyroid arteries. The transient side effects associated with the treatment were neck pain and a slight increase in body temperature. Noted high concentration of free thyroid hormones immediately after the procedure was not accompanied by worsening of symptoms or signs of thyrotoxicosis. In patients with Graves' disease, a significant decrease in thyrotropin receptor antibodies level was observed. Thyroid arterial embolization does not disturb permanently calcium-phosphate balance, modulates positively thyroid autoimmune processes and is associated with no serious post-procedure side effects. Hence, it may be considered as a safe and effective treatment modality for selected thyroid disorders. PMID- 24146412 TI - How to decide intervention thresholds based on FRAX in central south Chinese postmenopausal women. AB - The FRAX tool has been used to determine possible thresholds for therapeutic intervention; however, there are no FRAX-based intervention thresholds available for China, we proposed that the 10-year probability of major osteoporotic fracture and hip fracture of about 4.0 and 1.3%, respectively, may be acceptable intervention thresholds for central south Chinese postmenopausal women. PMID- 24146413 TI - A very rare bilateral adrenal tumor. AB - We report a case of very rare adrenal tumor. A 54-year-old patient was classified as affected by bilateral adrenal incidentaloma that surprisingly, on histology resulted solitary fibrous tumors. Solitary fibrous tumor (SFT) is an uncommon mesenchymal neoplasm. Only five cases of localization of SFT in adrenal gland are reported in the literature, while the frequency of retroperitoneum localization is more frequent, about 30 cases. Immunohistochemically, SFT can be positive for CD34 antigen, vimentin, CD99, and bcl-2 and usually negative for cytokeratins, chromogranin A, NSE, neurofilaments, synoptophysin, and S-100. Surgical excision remains the main treatment in fact the recurrence is locoregional and correlated with positive margins due to incomplete excision, while distant metastases are correlated with atypical or malignant features. PMID- 24146414 TI - Small cell carcinoma of the thyroid gland with a solid brain metastasis detected by F-18-FDG PET/CT. PMID- 24146415 TI - [Training in aesthetic surgery at a university clinic - the "Munich model"]. AB - BACKGROUND: Aesthetic surgery is regarded as one of the 4 pillars of plastic surgery. To assure safety in this field of surgery, a structured and well guided surgical training is indispensable. However, during the specialist training for plastic and aesthetic surgery, plastic aesthetic interventions are often carried out in low numbers only. Objective of the present study was the development, implementation and evaluation of a new training concept in aesthetic surgery. PATIENTS: Over a period of 2 years, 304 aesthetic operations were performed in the fields of body contouring, breast surgery and facial surgery as an "educational surgery". Educational surgeries were performed by resident surgeons under the guidance of experienced specialists and under favourable financial conditions. As indicator for safety of the interventions, the incidence of complications was recorded and assessed. RESULTS: Out of a total of 304 operations included in the study 47.7% were performed as an educational surgery. In the fields of body contouring and breast surgery, the majority of interventions (51.3% and, respectively, 53%) were carried out as educational surgeries. In aesthetic surgeries of the face only 28.4% were educational surgeries. In 4.9% of all cases complications occurred. The incidences of complications were approximately the same in the educational surgeries (5.5%) and in the surgeries carried out by experienced specialists (4.4%), showing no significant difference. CONCLUSION: The presented training concept aims at ensuring high quality in patient care by structure and quality of surgical training. Our data give evidence that a structured training of residents in the field of aesthetic surgery is possible without loss in quality. We expect that sufficient surgical education and the associated quality will consequently contribute to keep aesthetic surgeries a domain of plastic surgery and to prevent these procedures from being taken over by other surgical disciplines. PMID- 24146417 TI - [Highlights of yesterday's Clinical Monatsblatter of Ophthalmology]. PMID- 24146418 TI - [Highlights from today's Klinische Monatsblatter fur Augenheilkunde]. PMID- 24146416 TI - Secondary peaks of S100B in serum relate to subsequent radiological pathology in traumatic brain injury. AB - INTRODUCTION: Patients suffering from severe traumatic brain injury (TBI) often develop secondary brain lesions that may worsen outcome. S100B, a biomarker of brain damage, has been shown to increase in response to secondary cerebral deterioration. The aim of this study was to analyze the occurrence of secondary increases in serum levels of S100B and their relation to potential subsequent radiological pathology present on CT/MRI-scans. METHODS: Retrospective study from a trauma level 1 hospital, neuro-intensive care unit. 250 patients suffering from TBI were included. Inclusion required a minimum of two radiological examinations and at least three serum samples of S100B, with at least one >48 h after trauma. RESULTS: Secondary pathological findings on CT/MRI, present in 39 % (n = 98) of the patients, were highly correlated to secondary increases of >=0.05 MUg/L S100B (P < 0.0001, pseudo-R (2) 0.532). Significance remained also after adjusting for known important TBI predictors. In addition, secondary radiological findings were significantly correlated to outcome (Glasgow Outcome Score, GOS) in uni-(P < 0.0001, pseudo-R (2) 0.111) and multivariate analysis. The sensitivity and specificity of detecting later secondary radiological findings was investigated at three S100B cut-off levels: 0.05, 0.1, and 0.5 MUg/L. A secondary increase of >=0.05 MUg/L had higher sensitivity (80 %) but lower specificity (89 %), compared with a secondary increase of >=0.5 MUg/L (16 % sensitivity, 98 % specificity), to detect secondary radiological findings. CONCLUSIONS: Secondary increases in serum levels of S100B, even as low as >=0.05 MUg/L, beyond 48 h after TBI are strongly correlated to the development of clinically significant secondary radiological findings. PMID- 24146419 TI - [New strategies of strabismus diagnosis and surgery]. PMID- 24146420 TI - [Long-term follow-up and patient satisfaction of squint surgery with adjustable sutures]. AB - OBJECTIVE: Up to now, no long-term results about squint surgery with adjustable sutures have been published although it has been practiced using the current techniques since the 1970s. The aim of the study was to analyse patient satisfaction and objective findings and to compare the results to studies about squint surgery with adjustable as well as non-adjustable sutures. METHODS: Patients who had had squint surgery with adjustable sutures more than 10 years ago were identified according to their surgical records. They were contacted and asked to fill in a questionnaire. The collective consisted in cases which appeared to be difficult in treatment, e.g., 52 % had undergone previous squint surgery. RESULTS: We could analyse answered questionnaires of 113 patients (return rate 41.9 % of all contactable patients). In 34 patients (30 %) postoperative adjustment was actually performed, in the others the suture was only knotted. 89.4 % of patients either had no problems or did not remember the procedure of adjustment or knotting, respectively, the others had slight discomfort. There were no technical problems in surgery or adjustment. After an average period of 11 years, the satisfaction was very high. The reoperation rate was 7 %. CONCLUSIONS: Squint surgery with adjustable sutures is a valuable tool in difficult strabismus cases with good long-term patient satisfaction without specific problems of surgery. PMID- 24146421 TI - [Cycloplegia using a conjunctival insert - comparison to standard procedures]. AB - The widespread combination of tropicamide and phenylephrine eye drops for preoperative mydriasis und cycloplegia is completed by a conjunctival insert called Mydriasert (Thea Pharma GmbH, Berlin) as medicament tracer. This offers potential cycloplegia in a new application form. We tested 10 patients aged 5-41 years (medium 18) with good residual accommodation power. The study design was prospective. We compared the cycloplegic power of either eye drops or conjunctival insert given each at one eye at the same starting point. Then we measured every 15 minutes the pupil width and the accommodation by nearpoint testing. Refraction was measured at the point of smallest accommodation power. As result we found less cycloplegic power of the conjunctival insert (accommodation lag with Mydriasert 3.16 versus tropicamide/phanylephrine eye drops 2.61 D; atropine 1.5 D). The effect of maximal cycloplegia was delayed using the insert (Mydriasert 60 min vs. eye drops 45 min). The subjectively noted comfort for the patients of both application forms is the same using a short interview directly after the testing procedure. In conclusion, the conjuctival medicament insert offers a new application form to induce cycloplegia. The effect is less effective compared to the clinically used standard procedures using eye drops, but should be considered for special patients when eye drop instillation is problematic. PMID- 24146422 TI - [Downshoot in adduction in a case of contralateral superior oblique hypoplasia]. PMID- 24146423 TI - [Impact of age on success rate of lacrimal duct irrigation with silicone tube intubation in connatal lacrimal duct stenosis]. AB - BACKGROUND: Irrigation of the lacrimal duct with silicone tube intubation (TWS/S) remains the preferred treatment in persisting connatal lacrimal duct stenosis (kTWS). The timepoint of operation is however discussed controversely. On the one hand, it is recommended to wait for spontaneous opening of the lacrimal duct within the first year of life, on the other hand a later operation may trigger inflammatory changes within the lacrimal duct system influencing the success rate of the operation negatively. The aim of this study was to analyze the best time point of operation regarding the long-term success rate of the operation. PATIENTS/MATERIALS AND METHODS: 411 lacrimal ducts of 316 children with kTWS between 0 and 48 months of age (164 male, 156 female), who had undergone TWS with S because of kTWS at a tertiary eye care centre between 2007-2011 were included in this study. The children were divided into 6 groups of age (0-6, 7-12, 13-18, 19-24, 24-36, > 36 months) at the time of operation. The operative success was retrospectively evaluated after 36 months. The groups were compared and differences in late success rate analyzed statistically. RESULTS: The average success of operation of TWS/S in kTWS was 89 % (366 of 411 lacrimal ducts). The success rate of operation differed between the groups. If operated at the age of 0-6 months the operation was successful in 94 %, at the age 7-12 months in 91 %, between 13-18 months in 90.5 %, from 19-24 months in 88 %, and from 25-36 months in only 84.5 %. The success rate was therewith at the age of 25-36 months significantly lower than at the age of 0-6 months (p < 0.05). CONCLUSION: TWS/S in kTWS has overall a very high rate of success. The success of the operation decreases however in correlation with age at time of operation and shows with > 25 months significantly poorer results than at 0-6 months. The choice of the best time point for operation merits further investigation. PMID- 24146424 TI - [Letter]. PMID- 24146425 TI - [Commentary]. PMID- 24146426 TI - [Orbital disorders in childhood]. PMID- 24146428 TI - Perspective on the technical challenges involved in the implementation of array CGH in prenatal diagnostic testing. AB - Our aim was to construct a streamlined technical workflow to facilitate a prospective, multi-centre evaluation of array comparative genomic hybridisation (array-CGH) in the prenatal diagnostic context. A collection of commercially available DNA extraction and quantification techniques were evaluated and compared using minimal quantities of amniotic fluid, chorionic villi and cultured cells. When prenatal DNA of suitable quality and quantity was obtained, array-CGH was performed using Oxford Gene Technology's (OGT, Oxford, UK) CytoSureTM ISCA 8 * 60 K oligo array platform. With starting quantities of 2-4 ml amniotic fluid, 2 5 mg chorionic villi or under 150,000 cultured cells the following optimised technical workflow was identified: DNA extraction using the iGENatalTM kit (igenbiotech, Madrid, Spain) and quantification by the Qubit(r) 2.0 Fluorometer with the Qubit(r) dsDNA BR assay kit (InvitrogenTM, Eugene, OR, USA). In addition, it was elucidated that array-CGH can be successfully performed with as little as 125 ng DNA in the experiment using the OGT CytoSureTM ISCA 8 * 60 K oligo array platform. Amidst an on-going debate on whether array-CGH should be applied in the prenatal diagnostic setting, by following the technical recommendations described here genetics laboratories can now gain exposure to prenatal array-CGH testing without compromising the conventional karyotype result. PMID- 24146429 TI - Assessment of reference genes for real-time quantitative PCR gene expression normalization during C2C12 and H9c2 skeletal muscle differentiation. AB - Skeletal muscle differentiation occurs during muscle development and regeneration. To initiate and maintain the differentiated state, a multitude of gene expression changes occur. Accurate assessment of these differentiation related gene expression changes requires good quality template, but more specifically, appropriate internal controls for normalization. Two cell line based models used for in vitro analyses of muscle differentiation incorporate mouse C2C12 and rat H9c2 cells. In this study, we set out to identify the most appropriate controls for mRNA expression normalization during C2C12 and H9c2 differentiation. We assessed the expression profiles of Actb, Gapdh, Hprt, Rps12 and Tbp during C2C12 differentiation and of Gapdh and Rps12 during H9c2 differentiation. Using NormFinder, we validated the stability of the genes individually and of the geometric mean generated from different gene combinations. We verified our results using Myogenin. Our study demonstrates that using the geometric mean of a combination of specific reference genes for normalization provides a platform for more precise test gene expression assessment during myoblast differentiation than using the absolute expression value of an individual gene and reinforces the necessity of reference gene validation. PMID- 24146430 TI - Biochemical characterization, molecular cloning, and structural modeling of an interesting beta-1,4-glucanase from Sclerotinia sclerotiorum. AB - The filamentous fungus Sclerotinia sclerotiorum produces a complete set of cellulolytic enzymes needed for efficient solubilization of native cellulose, the major component of plants. In this work, we reported the molecular characterization of an important glycosyl-hydrolase enzyme classified as endo beta-1,4-glucanase. The importance of this enzyme was revealed with the in-gel activity staining, showing a high degradation capacity of cellulose. When purified from native gel and ran in denaturing polyacrylamide gel, the polypeptide has an apparent molecular mass of about 34 kDa called Endo2. For further characterization of this protein, a mass spectrometry approach was carried out. The LC-MS/MS analysis revealed two peptides belonging to this enzyme. The genomic DNA and cDNA sequences were resolved by PCR amplification and sequencing, revealing a gene with two intron sequences. The open reading frame of 987 bp encoded a putative polypeptide of 328 amino acids having a calculated molecular mass of 33,297 Da. Yet, the molecular modeling and comparative investigation of different 3D cellulase structures showed that this endoglucanase isoform has probably two domains. A core domain having a high similarity with endoglucanases family 5 and a cellulose-binding domain having similarities with those of exo-type cellulases of family 1, linked together by a serine-threonine rich region. These results are with great interests and show new characteristics of S. sclerotiorum glucanase. PMID- 24146427 TI - An experimental approach to the generation of human embryonic stem cells equivalents. AB - Recently, particular attention has been paid to the human embryonic stem cells (hESC) in the context of their potential application in regenerative medicine; however, ethical concerns prevent their clinical application. Induction of pluripotency in somatic cells seems to be a good alternative for hESC recruitment regarding its potential use in tissue regeneration, disease modeling, and drug screening. Since Yamanaka's team in 2006 restored pluripotent state of somatic cells for the first time, a significant progress has been made in the area of induced pluripotent stem cells (iPSC) generation. Here, we review the current state of knowledge in the issue of techniques applied to establish iPSC. Somatic cell nuclear transfer, cell fusion, cell extracts reprogramming, and techniques of direct reprogramming are described. Retroviral and lentiviral transduction are depicted as ways of cell reprogramming with the use of integrating vectors. Contrary to them, adenoviruses, plasmids, single multiprotein expression vectors, and PiggyBac transposition systems are examples of non-integrative vectors used in iPSC generation protocols. Furthermore, reprogramming with the delivery of specific proteins, miRNA or small chemical compounds are presented. Finally, the changes occurring during the reprogramming process are described. It is concluded that subject to some limitations iPSC could become equivalents for hESC in regenerative medicine. PMID- 24146431 TI - Improved transient protein expression by pFluNS1 plasmid. AB - Influenza virus nonstructural protein-1 (NS1) is abundantly expressed in influenza virus infected cells. NS1 is well recognized for counteracting host antiviral activities and regulating host and viral protein expression. When used as a plasmid component in DNA transfection, NS1 was shown to significantly increase expression levels of a cotransfected gene of different plasmid. Our previous studies demonstrated that addition of an NS1 plasmid increased the expression levels of influenza virus secreted neuraminidase (sNA) gene in 293T cells. In this study, we improved the utilization of NS1 as an enhancer for transient protein expression by generating pFluNS1 plasmid to contain two expression cassettes; one encoding an NS1 gene and another encoding a gene of interest. pFluNS1 is expected to codeliver the NS1 gene into the same cells receiving the gene of interest. The plasmid is therefore designed to induce higher protein expression levels than a cotransfection of an NS1 plasmid and a plasmid containing a gene of interest. To test the efficiency of pFluNS1, influenza virus sNA and non-viral DsRed genes were cloned into pFluNS1. The expression of these genes from pFluNS1 was then compared to the expression from a cotransfection of an NS1 plasmid and an expression plasmid coding for sNA or DsRed. We found that gene expression from pFluNS1 reached equal or higher levels to those derived from the cotransfection. Because the expression from pFluNS1 needs only one plasmid, a lesser amount of transfection reagent was required. Thus, the use of pFluNS1 provides a transfection approach that reduces the cost of protein expression without compromising high levels of protein expression. Together, these data suggest that pFluNS1 can serve as a novel alternative for an efficient transient protein expression in mammalian cells. PMID- 24146432 TI - Hydrophobic substitution of surface residues affects lipase stability in organic solvents. AB - A novel lipase has been recently isolated from a local Pseudomonas sp. (GQ243724). In the present study, we have tried to increase the organic solvent stability of this lipase using site-directed mutagenesis. Eight variants N219L, N219I, N219P, N219A, N219R, N219D, S251L, and S251K were designed to change the surface hydrophobicity of this enzyme with respect to the wild-type. Among these variants, the stability of N219L and N219I significantly increased in the presence of all tested organic solvents, whereas two mutants (N219R and N219D) significantly exhibited decreased stabilities in all the organic solvent studied, suggesting that improvement of hydrophobic patches on the enzyme surface enhances the stability in organic media. Furthermore, replacing Ser251 with hydrophobic residues on the enzyme surface dramatically diminished its stability in the tested condition. In spite of the distance of the mutated sites from the active site, the values of k(cat) and K(m) were affected. Finally, structural analysis of the wild-type and mutated variants was carried out in the presence and absence of some organic solvents using circular dichroism and fluorescence spectroscopy. PMID- 24146433 TI - Production of functional native human interleukin-2 in tobacco chloroplasts. AB - Interleukin-2 (IL-2) is an important T lymphocyte-derived cytokine in the mammalian immune system. Non-native, recombinant IL-2 derived from Escherichia coli is used widely in both medical research and treatment of diseases. Recombinant human IL-2 gene has been expressed in plant nuclear genomes, therefore it can be spread to the environment through pollen. Furthermore, all the plant-produced IL-2 reported thus far had been attached with artificial tags or fusion proteins, which may trigger unintended immunological responses and therefore compromise its full utility as a medicine. To expand the potential of using plant chloroplasts to produce functional native human therapeutic proteins, we inserted an engineered human interleukin-2 (hIL-2)-coding gene, without any tags, into the chloroplast genome of tobacco (Nicotiana tabacum L.). Partially purified hIL-2 protein from the leaves of the transplastomic plants induced in vitro proliferation of IL-2-dependent murine T lymphocytes. Our study demonstrates that plant chloroplasts can serve as a bio-factory for production of an active native human interleukin in a self-contained and therefore environmentally safe manner. PMID- 24146434 TI - Social contacts and depression in middle and advanced adulthood: findings from a US national survey, 2005-2008. AB - AIM: Empirical evidence has linked social contacts with mental stability. The aim is to assess how social contacts are associated with depression among the general population. METHODS: We analysed the data of 5,681 adults aged 40 or older, who completed a depression screening as a part of the National Health and Nutrition Examination Survey, 2005-2008. Depression was ascertained using the Patient Health Questionnaire (PHQ), a nine-item screening instrument asking about the frequency of depression symptoms over the past two weeks. A PHQ score of 10 or higher was defined as depression. RESULTS: The prevalence of depression was 5.54% (SE = 0.64) and 8.49% (SE = 0.71), respectively, among men and women. The association between social contacts and depression were more salient among men than women. The odds ratios (ORs) of depression were 2.43 (95% CI = 1.44-4.10), 2.42 (95% CI = 1.37-4.28), 1.00 (reference) and 1.94 (95% CI = 0.80-4.71), respectively, among men who never attended church, attended occasionally, weekly and more than weekly. The corresponding ORs were 1.79 (95% CI = 1.10-2.91), 1.72 (95% CI = 1.06-2.80), 1.00(reference) and 0.98 (95% CI = 0.52-1.84) for women. Compared with the respondents who had 10 or more friends, the ORs of depression were 4.01 (95% CI = 1.89-8.50) and 1.86 (95% CI = 0.92-3.79), respectively, for men and women who had no close friends. CONCLUSIONS: The current study concluded that traditional social contacts remain strongly associated with depression in the digital era. Digital social networking is one of the biggest growing industries, creating a new platform to make social contacts. There is an urgent need to explore how to maximize the potential of digital social networking to strengthen social bonds while minimizing its negative effects. PMID- 24146435 TI - Nanoscale architecture and cellular adhesion of biomimetic collagen substrates. AB - The ability to engineer bioactive sites within the biopolymer collagen has significant potential to dictate cellular microenvironments and processes. We have developed a novel recombinant DNA platform that enables such molecular-level control over this important material. In this investigation, we demonstrated the production of synthetic human collagen using yeast strains that were engineered with human prolyl hydroxylase alpha and beta genes integrated into the genome and a codon-optimized collagen gene carried on a plasmid. To understand the extent to which this synthetic collagen can mimic native human collagen, we examined the relationships between the structural topology and physical stability with the ability to support adhesion of HT-1080 cells. Characterization of these biopolymers included evaluation using circular dichroism spectroscopy, atomic force microscopy, and MTT metabolic activity assays. Although the apparent melting temperatures of the recombinant collagens were ~3-5 less than native sources, the recombinant and native collagens exhibited comparable triple helical structure, polymeric dimensions, adsorption on polystyrene, and cellular adhesion properties below their respective melting temperature values. These results support the feasibility of producing molecularly-engineered collagens that can mimic native substrates for therapeutic and tissue engineering applications. PMID- 24146436 TI - Development of a Cost-Effective Modular Pixelated NaI(Tl) Detector for Clinical SPECT Applications. AB - A new pixelated detector for high-resolution clinical SPECT applications was designed and tested. The modular detector is based on a scintillator block comprised of 2.75*2.75*10 mm3 NaI(Tl) pixels and decoded by an array of 51 mm diameter single-anode PMTs. Several configurations, utilizing two types of PMTs, were evaluated using a collimated beam source to measure positioning accuracy directly. Good pixel separation was observed, with correct pixel identification ranging from 60 to 72% averaged over the entire area of the modules, depending on the PMT type and configuration. This translates to a significant improvement in positioning accuracy compared to continuous slab detectors of the same thickness, along with effective reduction of "dead" space at the edges. The observed 10% average energy resolution compares well to continuous slab detectors. The combined performance demonstrates the suitability of pixelated detectors decoded with a relatively small number of medium-sized PMTs as a cost-effective approach for high resolution clinical SPECT applications, in particular those involving curved detector geometries. PMID- 24146437 TI - Effects of Behavioral Weight Control Intervention on Binge Eating Symptoms Among Overweight Adolescents. AB - This study examined change in binge eating symptoms reported by moderately overweight adolescents following participation in a behavioral weight control intervention. A total of 194 adolescents across two randomized controlled trials participated. Adolescents in both study samples endorsed a mild level of binge eating symptoms at baseline. Results from both Study 1 and Study 2 indicate a significant reduction in binge eating symptoms following participation in a 16 week weight control intervention, F(1,60) = 9.43, p<.01 and F(1,98) = 20.98, p<.01, respectively. Several significant relationships between measures of self concept and binge eating symptoms were noted, with lower self-concept scores related to higher binge eating symptoms scores at baseline. Changes in binge eating symptoms were also related to changes in physical appearance self-concept, global self-concept and physical self-worth at the end of the intervention. In conclusion, findings from this study support an emerging body of evidence suggesting that dietary restriction, as practiced through participation in a weight control intervention, leads to a reduction in binge eating symptoms among overweight adolescents. PMID- 24146438 TI - Disease and Development: Evidence from Hookworm Eradication in the American South. AB - This study evaluates the economic consequences of the successful eradication of hookworm disease from the American South. The hookworm-eradication campaign (c. 1910) began soon after (i) the discovery that a variety of health problems among Southerners could be attributed to the disease and (ii) the donation by John D. Rockefeller of a substantial sum to the effort. The Rockefeller Sanitary Commission (RSC) surveyed infection rates in the affected areas (eleven southern states) and found that an average of forty percent of school-aged children were infected with hookworm. The RSC then sponsored treatment and education campaigns across the region. Follow-up studies indicate that this campaign substantially reduced hookworm disease almost immediately. The sudden introduction of this treatment combines with the cross-area differences in pre-treatment infection rates to form the basis of the identification strategy. Areas with higher levels of hookworm infection prior to the RSC experienced greater increases in school enrollment, attendance, and literacy after the intervention. This result is robust to controlling for a variety of alternative factors, including differential trends across areas, changing crop prices, shifts in certain educational and health policies, and the effect of malaria eradication. No significant contemporaneous results are found for adults, who should have benefited less from the intervention owing to their substantially lower (prior) infection rates. A long-term follow-up of affected cohorts indicates a substantial gain in income that coincided with exposure to hookworm eradication. I also find evidence that eradication increased the return to schooling. PMID- 24146439 TI - Development and application of ab initio QM/MM methods for mechanistic simulation of reactions in solution and in enzymes. AB - Determining the free energies and mechanisms of chemical reactions in solution and enzymes is a major challenge. For such complex reaction processes, combined quantum mechanics/molecular mechanics (QM/MM) method is the most effective simulation method to provide an accurate and efficient theoretical description of the molecular system. The computational costs of ab initio QM methods, however, have limited the application of ab initio QM/MM methods. Recent advances in ab initio QM/MM methods allowed the accurate simulation of the free energies for reactions in solution and in enzymes and thus paved the way for broader application of the ab initio QM/MM methods. We review here the theoretical developments and applications of the ab initio QM/MM methods, focusing on the determination of reaction path and the free energies of the reaction processes in solution and enzymes. PMID- 24146440 TI - Endothelium-independent and endothelium-dependent vasorelaxation by a dichloromethane fraction from Anogeissus Leiocarpus (DC) Guill. Et Perr. (Combretaceae): possible involvement of cyclic nucleotide phosphodiesterase inhibition. AB - Many traditional medicinal herbs from Burkina Faso are used to treat arterial hypertension (HTA). Among them, Anogeissus leiocarpus (A. Leiocarpus) which is well known and widely used in Burkina traditional medicine. Herein we assess the effects of dichloromethane fraction from A. leiocarpus stem bark (ALF), selected as the most active on cyclic nucleotide phosphodiesterases (PDEs) and characterized its specificity towards purified vascular PDE1 to PDE5 isoenzymes and study its effects on a vascular model. ALF potently and preferentially inhibits (IC50=1.6 +/- 0.6 ug/mL) the calmodulin-dependent phosphodiesterase PDE1, being mainly present in vascular smooth muscle and preferentially hydrolyses cGMP. In the same range (IC50 =2.8 +/- 0.2 ug/ml) ALF inhibits PDE2, a cGMP-activated enzyme that is only present in endothelial cells and hydrolyses both cAMP and cGMP. PDE5, which specifically hydrolyses cGMP and which mainly contributes to cGMP hydrolysis is also potently inhibited by ALF (IC50=7.6 +/- 3.5 ug/ml). The potencies of ALF on cAMP hydrolyzing isoenzymes was lesser, being more effective on PDE4 (IC50= 17.6 +/- 3.5 ug/ml) than on PDE3 (60.9 +/- 1.8 ug/ml). Since the major effect of ALF were against cGMP hydrolysis and since cGMP is implicated in endothelium-dependent relaxation, the endothelium-dependent vasorelaxation was studied on isolated porcine coronary arteries rings pre contracted with U46619. The endothelium-dependent vasorelaxation is significantly inhibited by N(omega)-nitro-L-arginine (LNA 300 umol/L, an inhibitor of endothelial NO synthase), but not affected by charybdotoxin (CTX, 100 nM) plus apamin (APA, 100 nM) (two inhibitors of EDHF-mediated responses). The combination of 4-aminopyridine (4-AP, 1 mmol/L, inhibitor of voltage-dependent potassium channels, Kv) plus baryum (Ba(2+), 30 umol/L, inhibitor of the potassium channels with entering correction, Kir) plus ouabain (3 umol/L, inhibitor of ATPase Na(+)/K(+) channels) partially inhibits endothelium-independent vasorelaxant effect. This endothelium-independent relaxant effect was also sensitive to combination of 1H-[1,2,4]-oxadiazole-[4,3-alpha]-quinoxalin1-one (ODQ, 10 uM, soluble guanylyl cyclase inhibitor) and N-[2-(p-Bromocinnamylamino)ethyl]-5 isoquinoline sulfonamide dihydrochloride (H89, 100 nM, Protein Kinase A inhibitor). Taken together, these results indicate that ALF is a powerful vasodilator modulated by the formation of NO from endothelium, but also act by directly relaxing the vascular smooth muscle cells, by inhibiting cGMP hydrolyzing PDEs (PDE1, PDE2 and PDE5) and to a lesser extend on cAMP degradation (PDE3 and PDE4), cAMP and cGMP being second messengers involved in vascular relaxation. PMID- 24146441 TI - Analysis of volatile compounds of Malaysian Tualang (Koompassia excelsa) honey using gas chromatography mass spectrometry. AB - The constituents of honey's volatile compounds depend on the nectar source and differ depending on the place of origin. To date, the volatile constituents of Tualang honey have never been investigated. The objective of this study was to analyze the volatile compounds in local Malaysian Tualang honey. A continuous extraction of Tualang honey using five organic solvents was carried out starting from non-polar to polar solvents and the extracted samples were analysed using gas chromatography-mass spectrometry (GC-MS). Overall, 35 volatile compounds were detected. Hydrocarbons constitute 58.5% of the composition of Tualang honey. Other classes of chemical compounds detected included acids, aldehydes, alcohols, ketones, terpenes, furans and a miscellaneous group. Methanol yielded the highest number of extracted compounds such as acids and 5-(Hydroxymethyl) furfural (HMF). This is the first study to describe the volatile compounds in Tualang honey. The use of a simple one tube, stepwise, non-thermal liquid-liquid extraction of honey is a advantageous as it prevents sample loss. Further research to test the clinical benefits of these volatile compounds is recommended. PMID- 24146442 TI - Antihyperglycemic profile of erinidine isolated from Hunteria umbellata seed. AB - Water decoction made from the seed of Hunteria umbellata is widely used in the traditional management of diabetes mellitus by Nigerian herbalists, particularly, in the southwest region of the country. Recently, a new bisindole alkaloid, erinidine, was isolated but its antihyperglycemic profile remains largely un investigated scientifically. This forms the basis for the current study which is primarily designed at investigating the antihyperglycemic profile of erinidine and other fractions in both in vitro and in vivo models of diabetes mellitus. In the present study, erinidine was isolated and purified using the earlier described methods and its antihyperglycemic potentials tested in in vitro models such as dipeptidylpeptidase (IV), glycogen phosphorylase, HIT-T15 cell insulin secretion, glucose uptake activity, aldose reductase assays and alpha-glucosidase inhibition assay testings. In addition, 50 mg/kg of erinidine and that of other fractions were evaluated in in vivo models of normal and chemically-induced hyperglycemic rats. Results showed that erinidine was a light yellow, amorphous solid with UV (CHCl3) lambda max 256 nm, HRESIMS m/z 382.1881 [(M+H)(+)] (calculated for C22H26N4O2, 382.1876) and melting point of 230 degrees C. The in vitro study showed the antihyperglycemic action of erinidine to be weakly mediated via alpha-glucosidase inhibition mechanism as the results for other in vitro tests such as dipeptidylpeptidase (IV), glycogen phosphorylase, HIT-T15 cell insulin secretion, glucose uptake activity and aldose reductase assays were all negative. However, the in vivo results showed 50 mg/kg erinidine given per os to normal and alloxan-induced hyperglycemic rats to significantly (p<0.05, p<0.001) attenuate an increase in their post-absorptive blood glucose concentrations after 3 g/kg glucose loading in the rats, suggesting its antihyperglycemic mechanism to be via alpha-glucosidase inhibition. This result, although, further corroborated the in vitro findings but also suggests that erinidine needs to be biotransformed in vivo for its inhibitory activity on intestinal glucose absorption to become evident. Thus, the present study suggests erinidine to be the possible antihyperglycemic agent in Hunteria umbellata seed extract mediating its antihyperglycemic action via intestinal glucose uptake inhibition. PMID- 24146443 TI - Phytochemistry, pharmacology and ethnomedicinal uses of Ficus thonningii (Blume Moraceae): a review. AB - The common wild fig, Ficus thonningii, is extensively used in African ethnomedicine for treating a number of disease conditions which include diarrhoea, urinary tract infections, diabetes mellitus, gonorrhoea, respiratory infections, and mental illnesses. This review aims to present a logical analysis of the nutritional, phytochemical and pharmacological properties of F. thonningii in relation to its therapeutic applications. A bibliographic analysis of the uses, phytochemical constituents and phytophamacological properties of Ficus thonningii was carried out using published papers, medicinal plant databases and various ethnobotanical and ethnopharmacological books. Ficus thonningii contains various bioactive compounds which include alkaloids, terpenoids, flavonoids, tannins and active proteins, all of which contribute to its curative properties. In vitro and in vivo pharmacological studies revealed that F. thonningii possesses antimicrobial, antidiarrhoeal, antihelmintic, antioxidant, anti inflammatory and analgesic properties. Acute and sub-chronic toxicity studies have shown that Ficus thonningii is non-toxic if administered orally in low doses. Scientific research has validated the ethnomedicinal claims that Ficus thonningii is useful in disease management. However, there is need to continue identifying, isolating and quantifying the active principles and possibly determine the mechanisms underlying its curative properties. PMID- 24146444 TI - Medicinal formulations of a Kanda tribal healer--a tribe on the verge of disappearance in Bangladesh. AB - The Kanda tribe is one of the lesser known small tribes of Bangladesh with an estimated population of about 1700 people (according to them), and on the verge of extinction as a separate entity. To some extent, they have assimilated with the surrounding mainstream Bengali-speaking population, but they still maintain their cultural practices including traditional medicinal practices, for which they have their own tribal healers. Nothing at all has been documented thus far about their traditional medicinal practices and formulations, which are on the verge of disappearance. The Kanda tribe can be found only in scattered tea gardens of Sreemangal in Sylhet district of Bangladesh; dispersion of the tribe into small separated communities is also contributing to the fast losing of traditional medicinal practices. The objective of the present study was to conduct an ethnomedicinal survey among the traditional healers of the Kanda tribe (in fact, only one such healer was found after extensive searches). Information was collected from the healer with the help of a semi-structured questionnaire and the guided field-walk method. A total of 24 formulations were obtained from the healer containing 34 plants including two plants, which could not be identified. Besides medicinal plants, the Kanda healer also used the body hairs of the Asiatic black bear (Ursus thibetanus) and bats (Pteropus giganteus giganteus) in one of his formulation for treatment of fever with shivering. The ailments treated by the Kanda healer were fairly common ailments like cuts and wounds, skin diseases, helminthiasis, fever, respiratory problems (coughs, asthma), gastrointestinal disorders (stomach pain, constipation, diarrhea), burning sensations during urination, various types of pain (headache, body ache, toothache, ear ache), conjunctivitis, poisonous snake, insect or reptile bites, jaundice, and bone fractures. A number of important drugs in allopathic medicine like quinine, artemisinin, and morphine (to name only a few) have been discovered from observing indigenous medicinal practices. From that view point, the formulations used by the Kanda healer merit scientific studies for their potential in the discovery of cheap and effective new drugs. Scientific validation of the medicinal formulations of the Kanda healer can also be effective for treatment of ailments among this tribe, which does not have or does not want to have any contact with modern medicine. PMID- 24146445 TI - Acute and chronic toxicity studies of the water extract from dried fruits of Terminalia bellerica (Gaertn.) Roxb. In Spargue-Dawley rats. AB - Acute and chronic toxicities of the water extract from the dried fruits of Terminalia bellerica (Gaertn.) Roxb. were assessed in both female and male rats. For the study of acute toxicity, a single oral administration of the water extract at a dose of 5,000 mg/kg body weight (10 female, 10 male) was performed and the results showed no signs of toxicity such as general behavior changes, morbidity, mortality, changes on gross appearance or histopathological changes of the internal organs of rats. The study of chronic toxicity was determined by oral feeding both female and male rats (10 female, 10 male) daily with the test substance at the dose of 300, 600 and 1,200 mg/kg body weight continuously for 270 days. The examinations of signs of toxicity showed no abnormalities in the test groups compared to the controls. In addition, these rats were analyzed for final body and organ weights, necropsy, as well as hematological, blood chemical and histopathological parameters. Taken together, the water extract from the dried fruits of T. bellerica did not cause acute or chronic toxicities in either female or male rats. PMID- 24146446 TI - RAPD-PCR and real-time PCR HRM based genetic variation evaluations of Urtica dioica parts, ecotypes and evaluations of morphotypes in Turkey. AB - Urtica dioica is an ethnobotanically and medicinally important Complementary and Alternative Medicine (CAM) plant worldwide and in Turkey; 90 % of herbal CAM applications depend on it in Turkey. It has a wide range of habitats in nearly all continents. It is found in all three phytogeographical regions in Turkey (Euro-Siberian, Irano-Turanian, Mediterranean) with high adaptivity to heterogeneous geographies such as climate, soil types and altitudes. This fact in relation to the assessment of chemical constituents of the plant and combining with further genetic and morphological variation data can assist and enhance the works for the utility and reliability of CAM applications in effect and activity of this plant species. In this work we have made some preliminary experiments with novel approaches to reveal the ecotypes and genetic variation of mighty ecotypes of Urtica dioica from different phytogeographical regions of Turkey (Euro-Siberian and Mediterranean). The ecotypes have heterogeneity in both its parts (leaf, stem, root) as revealed by Random Amplified Polymorphic DNA Polymerase Chain Reaction (RAPD-PCR) using random primers and High-resolution Melt (HRM) analysis using Urtica dioica specific primers and universal chloroplast DNA (cpDNA) primers and morphological traits such as phenolic contents and antioxidant capacities of plants' leaf infusions as used in medicinal applications in Turkey. This work will contribute a lot for the development of molecular markers to detect the genetic variation and heterogeneity of Urtica dioica to further relate with expected phenotypes that are most useful and relevant in CAM applications. PMID- 24146447 TI - Evaluation of anti-inflammatory and antinociceptive activity of Triphala recipe. AB - The anti-inflammatory and antinociceptive activities of Triphala recipe were studied in animal models. Triphala recipe (4 mg/ear) significantly exhibited an inhibitory effect on the ear edema formation induced by ethyl phenylpropiolate induced, but not on the arachidonic acid-induced ear edema in rats. Furthermore, Triphala recipe at the doses of 300, 600 and 1,200 mg/kg significantly reduced carrageenan-induced hind paw edema. Next, the anti-inflammatory action in chronic inflammation was measured using the cotton pellet-induced granuloma formation assay in rats. Triphala recipe (1,200 mg/kg) reduced neither transudative weight nor granuloma formation. It also did not affect on body weight gain and thymus weight indicating that Triphala recipe does not have a steroid-like effect. In antinociceptive study, Triphala recipe (300, 600, 1,200 mg/kg), elicited significant inhibitory effect on both phases, especially in late phase, of the formalin test in mice suggesting that the antinociceptive action of Triphala recipe may be via both peripheral and at least partly centrally acting. PMID- 24146448 TI - Extract of Perilla frutescens inhibits tumor proliferation of HCC via PI3K/AKT signal pathway. AB - In this study, isoegomaketone(IK) was isolated from Perilla frutescens(L.), a Chinese herbal. The effects of IK were examined by cell viability assay, colony formation assay, xenograft tumor assay and western blotting in HCC cells. We found that IK inhibited cell viability, and its administration decreased tumor volume and weight profoundly. The presence of IK(10 nmol/l) produced a dramatic decrease of pAkt, while total Akt level was not affected. The data suggested that IK from perilla suppressed HCC tumor growth via blocking PI3K/Akt signaling pathway. PMID- 24146449 TI - The anti-tumor effect and biological activities of the extract JMM6 from the stem barks of the Chinese Juglans mandshurica Maxim on human hepatoma cell line BEL 7402. AB - Juglans mandshurica Maxim is a traditional herbal medicines in China, and its anti-tumor bioactivities are of research interest. Bioassay-guided fractionation method was employed to isolate anti-tumor compounds from the stem barks of the Juglans mandshurica Maxim. The anti-tumor effect and biological activities of the extracted compound JMM6 were studied in BEL-7402 cells by MTT, Cell cycle analysis, Hoechst 33342 staining, Annexin V-FITC/PI assay and Detection of mitochondrial membrane potential (DeltaPsim). After treatment with the JMM6, the growth of BEL-7402 cells was inhibited and cells displayed typical morphological apoptotic characteristics. Further investigations revealed that treatment with JMM6 mainly caused G2/M cell cycle arrest and induced apoptosis in BEL-7402 cells. To evaluate the alteration of mitochondria in JMM6 induced apoptosis. The data showed that JMM6 decreased significantly the DeltaPsim, causing the depolarization of the mitochondrial membrane. Our results show that the JMM6 will have a potential advantage of anti-tumor, less harmful to normal cells. This paper not only summarized the JMM6 pick-up technology from Juglans mandshurica Maxim and biological characteristic, but also may provide further evidence to exploit the potential medicine compounds from the stem-barks of the Chinese Juglans mandshurica Maxim. PMID- 24146450 TI - In vitro evaluation of antiplasmodial activity of extracts of Acanthospermum hispidum DC (Asteraceae) and Ficus thonningii Blume (Moraceae), two plants used in traditional medicine in the Republic of Congo. AB - The aim of this study was to evaluate extracts from two medicinal plants, Acanthospermum hispidum and Ficus thonningii, used in traditional medicine in Congo Brazzaville, for in vitro antiplasmodial activities against two laboratory strains of Plasmodium falciparum: the chloroquine sensitive 3D7 and the chloroquine resistant Dd2. ELISA HRP2 assay was used to evaluate the in vitro inhibitory activity of the extracts alone or in combination with chloroquine. Cytotoxicity was assessed on human HeLa cell line and reflected by the selectivity index. Methanolic extract of Acanthospermum hispidum exhibited a strong and a moderate inhibitory activity on the growth of Dd2 and 3D7 at 2.8 ug/ml and 9.2 ug/ml concentrations respectively with a selectivity index >10. The combination of the most active extract (methanolic extract of Acanthospermum hispidum) with chloroquine showed a synergistic interaction on both strains. The good selectivity index of Acanthospermum hispidum on HeLa cells reflects the safety of this plant. Extracts from Ficus thonningii did not show any promising antiplasmodial activity on both 3D7 and Dd2. Except the methanolic extract which exhibited a slight antiplasmodial activity with inhibitory concentration and selectivity index corresponding to 9.61 ug/ml and 11.16 respectively. Methanolic extract of Acanthospermum hispidum exhibited moderate to high inhibitory activity on 3D7 and Dd2 laboratory strains and a synergistic antimalarial effect when combined with chloroquine. Ficus thonningii seems to have no antimalarial activity. Phytochemical analysis, in vivo investigations using animal models and later clinical trials in collaboration with traditional practitioners are necessary to clarify the potential antimalarial activity of both plants. PMID- 24146451 TI - The effect of quince leaf (Cydonia oblonga miller) decoction on testes in hypercholesterolemic rabbits: a pilot study. AB - Current medical literature lacks any evidence of the protective effects of quince leaf on testes. Therefore, the aim of the present study was to assess the effect of quince (Cydonia oblonga Miller) leaf decoction on testicular injury and impaired spermatogenesis induced by hypercholesterolemia in rabbits. Eleven mature New Zealand white male rabbits were randomly divided into three groups: group 1 (hypercholesterolemia, n=3), group 2 (hypercholesterolemia plus quince treatment, n=6), and group 3 (control, n=2). Groups 1 and 2 received a cholesterol-enriched diet for six weeks. Group 2 received C. oblonga leaf decoction as drinking supplement as well. After six weeks, a normal diet was substituted in groups 1 and 2 for another six weeks. Group 3 (control group) was maintained throughout the study on a regular diet. At the end of the 12(th) week, the left testes of the animals were resected for light microscopic study with particular attention to the maturity of germ cells in seminiferous tubules using Johnsen's score. Increase in intertubular connective tissue and diameter of vessels, abundant spermatogonia and primary spermatocytes along the reduced germinal epithelium were noted in all rabbits of the group 1. The remaining animals in groups 2 and 3 had no significant changes in their testicular sections. The mean Johnsen's score of group 1 (4.20 +/- 1.92) was significantly lower than that of group 2 (7.33 +/- 0.52) and group 3 (7.05 +/- 0.07). (P=0.01). In conclusion, quince leaf decoction (C. oblonga Miller) protected rabbit testes and spermatogenesis from damage induced by hypercholesterolemia. PMID- 24146452 TI - Experimental evaluation of the impact of maternal consumption of aqueous leaf extract of Hybanthus enneaspermus on pregnancy in Sprague Dawley rats. AB - The impact of aqueous leaf extract of Hybanthus enneaspermus (HEaq) on pregnancy factors and litter survival was investigated in Sprague Dawley (SD) rat. Control group received distilled water while the test group received 2g/kg body weight of HEaq orally. Blood samples were collected on days one and twenty of pregnancy for total blood count, serum thyroid hormone, thyroid stimulating hormone (TSH) and thyrotropin releasing hormone (TRH) assay. Half the number of rats in each group was sacrificed on day nineteen of pregnancy and the placenta and foetus were removed and weighed. The second half carried their pregnancy to term. Number and weights of litter were recorded at birth and the litter were also subjected to righting reflex test. Post-natal survival rate was determined for each group while effect of HEaq was also examined in-vivo on the activities of pregnant myometrial muscle. HEaq significantly decreased (p<0.05) foetal weight, placenta weight, foetal growth and survival, number and weights of litter at birth, maternal serum triiodotyroxine T3 and TSH level. Mean corpuscular haemoglobin, white blood cell count, platelet count and lipid profile were significantly increased (P<0.05). HEaq increased the frequency and percentage contraction of gravid myometrial muscle in a dose dependent manner. Maternal consumption of aqueous leaf extract of Hybanthus enneaspermus adversely affected pregnancy and development of the foetus, as it precipitated resorption of developing foetus and reduced size and weight of litter at term. PMID- 24146453 TI - Herbal therapies used by hypertensive patients in Turkey. AB - The purpose of this study was to determine herbal therapies used by the patients for regulation of blood pressure. This descriptive study was conducted in three districts of Izmir, Turkey. The study group included 193 patients with hypertension diagnosis who admitted to a primary care center and accepted to participate in the study. Data were collected through an investigator-made questionnaire including questions about socio-demographic features and herbal therapies used for regulation of blood pressure. Percentiles and chi-square statistics tests were used to evaluate the data through SPSS 11.0 program. The subjects included in the study had suffered from hypertension for 8.28 +/- 7.92 years, and 95.9% of them received medication to treat their hypertension. Of all hypertensive patients, 51.3% used herbal therapies for the treatment of hypertension. The patients used herbal therapies most commonly when they felt ill. There were no statistically significant difference between the use of herbal therapies and gender, education, marital status, having health insurance and income level. Health professionals who provide primary health services, especially nurses, need to follow patients regularly and provide patient education on antihypertensive therapy. Nurses must plan the necessary training programs by evaluating the data about, whether the hypertension patients use herbal therapies that can affect their health negatively or not. PMID- 24146454 TI - Traditional knowledge of medicinal plants in the Serra de Mariola Natural Park, South-Eastern Spain. AB - The present study aims to inventory and analyse the ethnobotanical knowledge about medicinal plants in the Serra de Mariola Natural Park. In respect to traditional uses, 93 species reported by local informants were therapeutic, 27 food, 4 natural dyes and 13 handcrafts. We developed a methodology that allowed the location of individuals or vegetation communities with a specific popular use. We prepared a geographic information system (GIS) that included gender, family, scientific nomenclature and common names in Spanish and Catalan for each species. We also made a classification of 39 medicinal uses from ATC (Anatomical, Therapeutic, Chemical classification system). Labiatae (n=19), Compositae (n=9) and Leguminosae (n=6) were the families most represented among the plants used to different purposes in humans. Species with the most elevated cultural importance index (CI) values were Thymus vulgaris (CI=1.431), Rosmarinus officinalis (CI=1.415), Eryngium campestre (CI=1.325), Verbascum sinuatum (CI=1.106) and Sideritis angustifolia (CI=1.041). Thus, the collected plants with more therapeutic uses were: Lippia triphylla (12), Thymus vulgaris and Allium roseum (9) and Erygium campestre (8). The most repeated ATC uses were: G04 (urological use), D03 (treatment of wounds and ulcers) and R02 (throat diseases). These results were in a geographic map where each point represented an individual of any species. A database was created with the corresponding therapeutic uses. This application is useful for the identification of individuals and the selection of species for specific medicinal properties. In the end, knowledge of these useful plants may be interesting to revive the local economy and in some cases promote their cultivation. PMID- 24146455 TI - A randomized, double-blind, placebo-controlled crossover study of Cappra(r) for the treatment of mild or mild to moderate erectile dysfunction in Thai male. AB - Erectile dysfunction (ED) is one of the major health concerns affects the quality of life among Thai male. The treatment of ED by the first-line drugs is limited to a certain group of patients due to their side effects and costs. Alternative medicine can be beneficial for the treatment of ED. This is a randomized, double blind, placebo-controlled, crossover study aimed to assess the efficacy and safety of Cappra((r)), a traditional herbal medicine which was used in Thailand for decades, for the treatment of mild and mild to moderate ED in Thai patients. A total of 63 patients with mild or mild to moderate ED were randomized to receive Cappra((r)) or placebo for two weeks in the first period, followed by one week washout period. The patients were switched to the alternative treatment in the second period. The efficacy was assessed by the International Index of Erectile Function (IIEF) questionnaire and adverse events. Sixty one patients completed the study. There was an improvement of IIEF score for all domains in Cappra((r)) group compared with placebo group. The mean change of IIEF score from baseline for erectile function domain of Cappra((r)) was significantly higher than placebo (4.87 vs 3.44, p = 0.032). The most common adverse events were dizziness (13.3% Cappra((r)), 9.6% placebo), face numbness (1.6% Cappra((r)), 0% placebo), and tachycardia (1.6% Cappra((r)), 0% placebo). The results from this study demonstrated that Cappra((r)) is effective and well-tolerated and can be used as alternative therapy for mild and mild to moderate ED. PMID- 24146456 TI - Medicinal plants used for the treatment of tuberculosis by Bapedi traditional healers in three districts of the Limpopo Province, South Africa. AB - The present study was aimed at documenting medicinal plants used for the treatment of tuberculosis (TB) by the Bapedi traditional healers in three districts of the Limpopo Province, South Africa. Fifty two traditional healers from 17 municipalities covering Capricorn, Sekhukhune and Waterberg districts were interviewed between January and July 2011. Twenty one medicinal plant species belonging to 20 genera and 18 families were documented. The majority (61.9%) are indigenous and the rest are exotics, found near homes as weeds or cultivated in home gardens as ornamentals or food plants. Hyacinthaceae, Moraceae and Rutaceae families were the most represented families in terms of species numbers (9.5% each). Herbs and trees (38% each) constituted the largest proportion of the growth forms of the medicinal plants used. Tuberculosis remedies were mostly prepared from leaves (34%) followed by roots (21%). The therapeutic claims made on medicinal plants used to treat TB by the Bapedi traditional healers are well supported by literature, with 71.4% of the species having antimicrobial properties or have similar ethno medicinal uses in other countries. This study therefore, illustrates the importance of medicinal plants in the treatment and management of TB in the Limpopo Province, South Africa. PMID- 24146457 TI - Gastroprotective effects of Leejung-tang, an oriental traditional herbal formula, on ethanol-induced acute gastric injury in rats. AB - Leejung-tang (LJT, Rechu-to in Japanese and Lizhong-tang in Chinese) is an oriental traditional traditional herbal formula. LJT has been used for treatment of gastrointestinal disorders in Korea, Japan, and China for a long time. In present study, we investigated the protective effects of LJT against absolute ethanol induced gastric injuries. Rats in the control group were given PBS orally (5 mL/kg body weight) as the vehicle, and the absolute-ethanol group (EtOH group) received absolute ethanol (5 mL/kg body weight) by oral gavage. Rats in the positive control group were given omeprazole orally (50 mg/kg body weight) 2 h prior to the administration of absolute ethanol. The treatment groups received LJT (400 mg/kg body weight) 2 h prior to absolute ethanol administration. All rats were sacrificed 1 h after receiving the ethanol treatment. The stomach was excised for macroscopic examination and biochemical analysis. The administration of LJT protected gastric mucosa against ethanol-induced acute gastric injury, including hemorrhage and hyperemia. LJT reduced the increase in lipid peroxidation in ethanol-induced acute gastric lesions. LJT increased GSH content and activities of the antioxidant enzymes, catalase, glutathione-S-transferase, glutathione reductase, glutathione peroxidase, and superoxide dismutase. These results indicate that LJT protects gastric mucosa against ethanol-induced acute gastric injury by increasing their antioxidant content. We suggest that LJT can be developed as an effective drug for the treatment of acute gastric injury. PMID- 24146458 TI - Herbal medicines used by Bapedi traditional healers to treat reproductive ailments in the Limpopo Province, South Africa. AB - The current study focussed on documenting the ethnobotanical knowledge of herbal medicines used by the Bapedi traditional healers to treat reproductive ailments in the Limpopo Province, South Africa. Fifty one healers from 17 municipalities covering Capricorn, Sekhukhune and Waterberg districts of the Limpopo Province were interviewed between January and July 2011. Semi-structured interviews, observations and guided field surveys with the healers were employed. Thirty-six medicinal plant species belonging to 35 genera and 20 families were documented. The most used species were Zanthoxylum humile (25.5%), Catha edulis (21.6%), Ozoroa sphaerocarpa (15.7%), Hypoxis hemerocallidea (13.7%), Hypoxis obtusa (11.7%), Gomphocarpus fruticosus subsp. fruticosus and Gymnosporia senegalensis (9.8% each). The dominant growth forms among the reported medicinal plants were herbs (39%), followed by shrubs and trees with 33% and 28%, respectively. The preferred plant parts were roots (63.9%), followed by bark (13.9%), whole plant (11.1%), tubers (8.3%), bulbs (5.6%), fruits, leaves, stems and twigs (2.8% each). The majority of the species were used to treat gender specific reproductive ailments; while a minority were used for treating reproductive ailments of both genders. Twenty-two species (61.1%) are supported by reports of similar uses in other countries or have proven biological activity. This study illustrates that Bapedi traditional healers possess remarkable knowledge on medicinal plants used for treating and managing reproductive ailments. PMID- 24146459 TI - Temperament determination for melatonin: a bridge from Iranian traditional to modern sleep medicine. AB - History acknowledged Ibn Sina, or Avicenna, the author of the highly skilled textbook of medicine "Al-Qanun Fi Al-Tibb" or "The Canon of Medicine", as one of the greatest physicians in medicine. According to this medical textbook, the explanation of the existence of a cold temperament for sleep was that during sleep hours, people tended to have a movement of the nature of the body toward the inside, which caused the body to become cold during sleep. Temperament determination for molecules, including drugs, has proved several applications. The present study tried to demonstrate that the multitasking melatonin molecule, as a sleep related hormone, had a cold temperament. The consideration of this temperament for melatonin had the potential to connect and integrate Iranian traditional medicine to current medicine, and also opened new frontiers for the physiopathology of modern sleep medicine, based on traditional medicine. PMID- 24146460 TI - A randomized, double-blind, placebo-controlled trial of a Chinese herbal Sophora flower formula in patients with symptomatic haemorrhoids: a preliminary study. AB - Dried flowers and buds of Sophora japonica (Huaihua) are used in China, Japan and Korea for treating haematemesis and bleeding haemorrhoids. This study compared the clinical safety and efficacy of a Sophora flower formula with a placebo for the conservative treatment of symptomatic haemorrhoids. The study was a prospective, double-blind, randomized placebo-controlled trial. The clinical effective rate, symptom score and the incidence of important clinical events were used as observation indices to evaluate the effect of the Sophora flower formula. The results showed that after 7 days of treatment, improvement was observed in 87.0% of the patients' major symptoms in the Sophora flower formula group compared with 81.8% of those in the placebo group. After 14 days, 78.2% patients in the Sophora flower formula group were asymptomatic, whereas 40.9% of those in the placebo group exhibited residual symptoms. However, the difference between both groups was not statistically significant. As the bowel habits of the patients improved and as the patients took sitz baths, their symptoms improved drastically, regardless of the use of the Sophora flower formula. These findings indicate that the traditional Chinese Sophora flower formula is clinically safe; however, its effects on haemorrhoids need to be studied in a larger sample size and with different dosages. The present study results may be a potential clinical reference for physicians prescribing medications for patients with symptomatic haemorrhoids. PMID- 24146461 TI - Determination of volatile aroma compounds of Ganoderma lucidum by gas chromatography mass spectrometry (HS-GC/MS). AB - This study was conducted at Horticulture Department of Cukurova University, Adana, Turkey during 2010-2011. Fresh sample of Ganoderma lucidum collected from Mersin province of Turkey was used as material. Volatile aroma compounds were performed by Headspace Gas Chromatography (HS-GC/MS). Alcohols, aldehydes, acids, phenol, L-Alanine, d-Alanine, 3Methyl, 2-Butanamine, 2-Propanamine were determined. 1-Octen-3-ol (Alcohol) and 3-methyl butanal (Aldehyde) were identified as major aroma compounds. PMID- 24146462 TI - The effective method for investigation meridian tropism theory in rats. AB - This present work describes an effective new method for study traditional Chinese medicine (TCM) on meridian tropism (MT) theory, which plays an essential role in clinical selection of TCM according to syndromes and strengthens the therapeutic effects. The new thread included material basis foundation and its tissue distribution study. Xiheliu, the most popular TCM on heart tropism, was investigated by simple and accurate high performance liquid chromatography (HPLC) method. The analysis of plasma after oral administration the total flavonoid of Xiheliu (TFX) exhibited that tamarixetin and kaempferide had the highest concentration and approximately the highest level within 25 min. The mixture of them could last accelerating the urine excretion more than 7 h after a single dose and could not cause the disorder of ion in rats, which was observed in diuretic activity experiment. In view of the reported biological activities was consistent with the effects of Xiheliu, tamarixetin and kaempferide were likely to be the material basis of it. Tissue distribution study showed that the highest level of analytes was in heart, lung, kidney and liver, and most tissues reached maximum level at 30 min post-dose. Since liver was the most important blood supply tissue, the result of this experiment was in accordance with the MT record of Xiheliu and confirmed that tamarixetin and kaempferide was the material bases of it on MT. This is the first report for the illumination of material basis and the mechanism of Xiheliu on MT by analysis the record of Xiheliu in Compendium of Materia Medica and experimental study. PMID- 24146463 TI - Ethnobotanical study of medicinal plants used by Kurd tribe in Dehloran and Abdanan Districts, Ilam Province, Iran. AB - This paper provides significant ethnobotanical information on pharmaceutical plant uses, where some degree of acculturation exists, so that there is urgency in recording such data. The aim of this work is to catalogue, document, and make known the uses of plants for folk medicine in Dehloran and Abdanan districts, Ilam Province, Iran. An analysis was made of the species used, parts of the plant employed, preparation methods, administration means, and the ailments treated in relation to pathological groups. A folk botanical survey was carried out from February 2007 to October 2009. The information was collected from 81 persons (60% men and 40% women) in 20 villages. The informants reported data on 122 species, belonging to 49 botanical families, were claimed as medicinal. This work is focused on human medicinal plant uses, which represent 95% of the pharmaceutical uses. The most commonly represented families were Asteraceae (37.5%), Lamiaceae (20.8%), Rosaceae (18.7%), Fabaceae (16.7%) and Apiaceae (14.6%). Some of the uses were found to be new when compared with published literature on ethnomedicine of Iran. The folk knowledge about medicinal plant use is still alive in the studied region, and a number of scarcely reported plant uses has been detected, some of them with promising phytotherapeutical applications. The results of the study reveal that some of species play an important role in primary healthcare system of these tribal communities. PMID- 24146464 TI - Standardization of a traditional polyherbo-mineral formulation - Brahmi vati. AB - The present study deals with standardization of an in-house standard preparation and three marketed samples of Brahmi vati, which is a traditional medicine known to be effective in mental disorders, convulsions, weak memory, high fever and hysteria. Preparation and standardization have been done by following modern scientific quality control procedures for raw material and the finished products. The scanning electron microscopic (SEM) analysis showed the reduction of metals and minerals (particle size range 2-5 um) which indicates the proper preparation of bhasmas, the important ingredient of Brahmi vati. Findings of EDX analysis of all samples of Brahmi vati suggested the absence of Gold, an important constituent of Brahmi vati in two marketed samples. All the samples of Brahmi vati were subjected to quantitative estimation of Bacoside A (marker compound) by HPTLC technique. Extraction of the samples was done in methanol and the chromatograms were developed in Butanol: Glacial acetic acid: water (4.5:0.5:5 v/v) and detected at 225nm. The regression analysis of calibration plots of Bacoside A exhibited linear relationship in the concentration range of 50-300 ng, while the % recovery was found to be 96.06% w/w, thus proving the accuracy and precision of the analysis. The Bacoside A content in the in-house preparation was found to be higher than that of the commercial samples. The proposed HPTLC method was found to be rapid, simple and accurate for quantitative estimation of Bacoside A in different formulations. The results of this study could be used as a model data in the standardization of Brahmi vati. PMID- 24146465 TI - Cytotoxic effect of the ethanolic extract of Lophocereus schottii: a Mexican medicinal plant. AB - Lophocereus schottii is a Mexican cactus known as garambullo whose bark is used for the treatment of cancer, diabetes, ulcers, sores, stomach disorders and tuberculosis. The aim of this study was to evaluate the cytotoxic effect of the ethanolic extract of bark of L. Schottii. To assess these effects we established a flow of experiments in a model of BALB/c mice murine lymphoma. We value first survival of mice inoculated with 2 * 10(4) L5178Y murine lymphoma cells, orally treated with 10 mg/Kg of the extract for 10 consecutive days; the second assessment was to determine the influence of the immune system, we carry out studies of lymphoproliferation in mice with the same conditions of the previous study, only that the treatment was for 22 days before the completion cell cultures; the third study was to establish the cytotoxic effect of extract of L. schottii using different concentrations, by murine lymphoma cell cultures and splenocytes from healthy mice and finally we assessed the effect in vivo of extract of L. Schottii in a model of solid murine lymphoma inoculating 1 * 10(7) lymphoma cells in the gastrocnemius muscle observing the development of the tumor. We observed that oral treatment of 10 mg/kg of extract of L. schottii increased survival rate in treated mice; additionally, an intratumoral injection of 50 and 100 mg/kg in a solid murine lymphoma located in the gastrocnemius muscle, allowed a significantly slower tumor evolution. In vitro studies determined that extract inhibited 63% of lymphoma cell growth. With these evidences it is feasible to scientifically validate that ethanolic extract of L. schottii had an effect on L5178Y murine cells lymphoma and could have the same effect in human tumors. PMID- 24146466 TI - Triterpenoids from Gutenbergia nigritana(Benth). Oliv and Hiern. AB - Gutenbergia nigritana (Benth). Oliv and Hein (Asteraceae) is a Nigerian ethnomedicinal plant which has long being used medicinally in traditional systems of medicine. The plant has diverse ethnomedicinal uses which include: The Plant is used in the Ijaw area of Niger Delta region of Nigeria to treat Malaria, convulsion, diarrhea and as a remedy for skin infection. The antibacterial study on dichloromethane extract and chromatographic fractions:dichloromethane soluble part(DC1), ethyl acetate soluble part(E1) and N-butanol soluble portions of methanolic extract were investigated using agar diffusion assay method by measuring the zone of inhibition against clinical isolates: Bacillus subtillis, Escherichia coli, Staphylococcus aureus and Pseudomonas aeruginosa. Extensive Chromatographic separation and preparative TLC were employed in the isolation steps. Column chromatograpy of the dichloromethane extract, gel filteration on sephadex and preparative TLC led to the isolation of two triterpenoids: Lupenol(1) and Lupenol acetate(2). The structures were elucidated by NMR spectroscopy and compared with literature. The dichloromethane extract exhibited antibacterial activity against all the test microorganisms with zones of inhibition ranging between 12-26mm. The chromatographic fraction (Fr-6) exhibited activity against E. coli, Ps. aeruginosa and S. aureus but in-active against B. subtilis, while the methanol soluble portions: dichloromethane and ethyl acetate showed weak activity while the n-butanol portion was in active. Dichloromethane extract of Gutenbergia nigritana leaves exhibited anti-bacterial activity, though the compounds isolated did not show activity, it is likely that the activity might reside in other components present in the dichloromethane extract. PMID- 24146467 TI - Use of antifungal saponin SC-2 of Solanum chrysotrichum for the treatment of vulvovaginal candidiasis: in vitro studies and clinical experiences. AB - Saponin SC-2 from Solanum chrysotrichum showed antifungal activity, demonstrated in vitro, which inhibited the growth of dermatophytes, and in vivo, to be effective in the treatment against tinea pedis and pityriasis capitis. Fungistatic and fungicidal activity of saponin SC-2 on Candida albicans and other Candida species, fluconazole and ketoconazole resistaent strains was demostrated. SC-2-associated ultrastructural alterations in several Candida species were observed. An exploratory clinical, randomized, double-blind, and controlled ketoconazole study of ketoconazole was conducted with the aim of assessing the effectiveness and tolerability of an herbal medicinal product containing SC-2, on women with Vulvovaginal candidiasis (VVC). The results exhibited a percentage of therapeutic clinical effectiveness similar to that of ketoconazole (X(2), p >=0.30), but obtained a smaller percentage of mycological effectiveness, and 100% tolerability. In conclusion, saponin SC-2 possesses fungicidale and fungistatic activity on Candida albicans and other multi resistant Candida species, causes morphological changes and fungal death, and it is an alternative therapy for the treatment of VVC. PMID- 24146468 TI - Quercetin: a potential natural drug for adjuvant treatment of rheumatoid arthritis. AB - Rheumatoid arthritis (RA) is the rheumatism mainly manifested as disabling joint disease and mainly involves hands, wrists, feet and other small joints. Recurrent arthritis attacks, synovial cell hypertrophy and hyperplasia and bone and cartilage damages eventually lead to joint dysfunction and other complications, and there is no cure. Quercetin (QU) is a kind of natural flavonoids, with lipid lowering, anti-inflammatory and other pharmacological activities, and minor toxic side effects. Thus, we assume that QU may be an adjuvant natural drug for treatment of RA. The possible mechanism is through regulation of NF-kappaB, to inhibit the transcription of joint synovitis factors, hinder the generation of inflammatory factors, and inhibit the inflammatory reaction; through inhibiting the activities of VEGF, bFGF, MMP-2 and other cytokines, to inhibit angiogenesis in multiple links and inhibit synovial pannus formation. QU may be an adjuvant natural drug for treatment of RA. PMID- 24146469 TI - Anti-inflammatory and analgesic activity of R.A.P. (Radix Angelicae Pubescentis) ethanol extracts. AB - The objective of this paper was to study the anti-inflammatory and analgesic effects of Radix Angelicae Pubescentis (R.A.P) ethanol extracts. Three classic anti-inflammatory models and two analgesic models were used in this research. In anti-inflammatory tests, all the extracts have a certain inhibition on the acute inflammation induced by xylene, however, 60% ethanol extract significantly inhibited the inflammation in the three models. In analgesic experiment, compared with the blank control group, the comparisons between R.A.P. groups and control group had significant difference (p < 0.01). The incubation period in mouse writhing test or the tail-curl immersion tests could be extended greatly. PMID- 24146470 TI - Antileishmanial activity of some plants growing in Algeria: Juglans regia, Lawsonia inermis and Salvia officinalis. AB - The current study was undertaken to evaluate in vitro the antileishmanial activity of three plants growing wild in Algeria : Juglans regia, Lawsonia inermis and Salvia officinalis. The hydroalcoholic extracts of these plants were tested on the growth of the promastigotes of Leishmania major. The plant extract effects were compared with three controls : CRL1 composed of 1 ml RPMI inoculated with 10(6) of promastigotes, CRL2 composed of 1 ml RPMI inoculated with 10(6) of promastigotes and 100 ul of hydroalcoholic solvent, CRL3 composed of 1 ml RPMI inoculated with 10(6) of promastigotes and 100 ul of Glucantim as a reference drug in the management of leishmaniasis. The results showed that both J. regia and L. inermis extracts reduced the promastigotes number significantly (P<0.01). however, S. officinalis showed a total inhibition of the Leishmania major growth. PMID- 24146471 TI - Comparison of efficacy of neural therapy and physical therapy in chronic low back pain. AB - The aim of this prospective study was to evaluate the effects of neural therapy, and physical therapy on level of pain, disability, quality of life, and psychological status in patients with chronic low back pain. Patients admitted to the physical therapy and rehabilitation outpatient clinic with the complaint of low back pain of at least 3 months duration. Group 1 (n=27), physical therapy (PT, hotpack, ultrasound, TENS 15 sessions), group 2 (n=33), neural therapy (NT, 1:1 mixture of 20 mg/mL Lidocaine HCl (Jetokain simplex(r)) and saline for 5 sessions. For pain, Visual Analogue Scale (VAS), for disability Roland Morris Disability Questionnaire (RMDQ), for quality-of-life Nottingham-Health-Profile (NHP), for depression, and anxiety, Hospital Anxiety-Depression Scale (HADS) were used before and after the treatment. Mean age was 47.3+/-11.32 years, symptom time was 13.78+/-11.98 months. There were no differences for demographic variables between groups. Significant improvements were detected for VAS, RMDQ, NHP-Pain, NHP-Physical activity, HADS for both of two groups after treatment. In addition to these findings, significant improvements were found for NHP-Energy, NHP-Social isolation in NT group. The differences of pre- and post-treatment values of parameters were evaluated for each group. Although there were no differences for VAS, NHP-sleep, NHP-Emotional reaction, HADS between groups, RMDQ, NHP-Pain, NHP-Physical activity, NHP-Social isolation were higher in NT than PT before treatment, the improvements for these parameters were better in NT than PT. In conclusion both of NT and PT are effective on pain, function, quality of life, anxiety, and depression in patients with chronic low back pain. PMID- 24146472 TI - Antioxidative potential of Duranta repens (Linn.) fruits against H2O2 induced cell death in vitro. AB - The effects of Duranta repens fruits were investigated on H2O2 induced oxidative cell death to evaluate its antioxidative potential in vitro. HEK293T cells were treated with different concentrations [0-1000 ug/ ml] of ethanol extract (E-Ex) and methanol extract (M-Ex) of D. repens for 24h, and then treated with 100 uM H2O2 for 24h. Cell viability, antioxidant parameters of cells, and antioxidant constituents of the extracts were determined. Treatment with limited dose of E-Ex or M-Ex increased the survival rate of H2O2-treated HEK293T cells, however the extra-high dose showed growth inhibitory effect. Treatment with E-Ex or M-Ex protected cellular lipid per-oxidation. In vitro analyses showed the 2,2-diphenyl 1-picrylhydrazyl and H2O2 scavenging activities as well as reducing potential of the extracts. We report here that the limited dose of E-Ex and M-Ex possess antioxidative potential, which can protect H2O2-induced oxidative cell damage. PMID- 24146473 TI - Effects of matrine on JAK-STAT signaling transduction pathways in bleomycin induced pulmonary fibrosis. AB - The current study aims to investigate the effects of matrine on the JAK-STAT signaling transduction pathways in bleomycin (BLM)-induced pulmonary fibrosis (PF) and to explore its action mechanism. A total of 72 male C57BL/6 mice were randomized into the control, model, and treatment groups. PF models were established by instilling BLM intratracheally. The treatment group was given daily matrine through gastric lavage. Six mice were sacrificed in each group at 3, 7, 14, and 28 days. The lung tissues were observed using hematoxylin-eosin staining. The expression of JAK, STAT1, and STAT3 was observed using immunohistochemistry and then determined using real-time polymerase chain reaction. Alveolitis and PF significantly improved in the treatment group compared with the model group (P < 0.05). The expression of JAK, STAT1, and STAT3 in the model group increased at day 7, peaked at day 14 and then decreased, but the expression was still higher than that in the control group at day 28 (P < 0.05). The three indices in the treatment group were significantly lower than those in the model group at any detection time point (P < 0.05). PF causes high expression of JAK, STAT1, and STAT3. Matrine exerts an anti-PF effect by inhibiting the JAK-STAT signaling transduction pathways. PMID- 24146474 TI - Antimicrobial and antioxidant activities of two endemic plants from Aksaray in Turkey. AB - This study was designed to examine the in vitro antimicrobial and antioxidant activities of the methanol, ethanol, water, n-hexane and dicholoromethane extracts of two Allium species (Allium scabriflorum and Allium tchihatschewii) which are endemic for the flora of Turkey. The antimicrobial efficiency of the plant was evaluated according to disc diffusion and microdilution broth methods. The antimicrobial test results showed that the extracts of A. scabriflorum and A. tchihatschewii showed varying degrees of antimicrobial activity on the tested microorganisms. The extracts were screened for their possible antioxidant activities by three complementary tests; DPPH free radical-scavenging, scavenging of hydrogen peroxide and metal chelating activity assays. All the extracts of A. scabriflorum and A. tchihatschewii exhibited lower DPPH free radical scavenging activity but higher metal chelating activity when compared to standards. The values of scavenging of hydrogen peroxide of the extracts were higher than the standards that of alpha-tocopherol, BHA, BHT and trolox, but close to that of ascorbic acid. In addition to the antioxidant activity of these plants, the total phenolic compounds and flavonoids were also measured in the extracts. The results presented here may suggest that the extracts of A. scabriflorum and A. tchihatschewii possess antimicrobial and antioxidant properties, and therefore, they can be used as a natural preservative ingredient in food and/or pharmaceutical industry. PMID- 24146475 TI - Evaluation of anti-bacterial and wound healing activity of the fruits of Amorpha fruticosa L. AB - As the traditional Chinese medicine, the fresh fruits of Amorpha fruticosa L. were applied for the treatment of carbuncle, eczema and burn (Das et al., 2007). However, little is known about the functional roles of the fruits of Amorpha fruticosa L. during wound healing progress. In the present study, we evaluated both antimicrobial potential against a wide range of microorganisms and wound healing activity of the seven compounds isolated from the fruits of Amorpha fruticosa L in vitro and in vivo. Our results showed that compounds I (6a,12a dehydroamorphin), V (dehydrosermundone) and VI (tephrosin) isolated from the fruits of Amorpha fruticosa L. performed dominant antimicrobial potential against microorganisms. Moreover, these compounds significantly enhanced fibroblasts proliferation and migration, leading to promotion of wound healing. Thus, it could be possible for the therapeutic utilization of Amorpha fruticosa L. for wound healing in the future. PMID- 24146476 TI - Study on extraction process of tannins from Semen Cuscutae and their anti papilloma activity. AB - The objective of this paper was to study the extraction methods of tannin constituents from Semen Cuscutae and their anti-papilloma effects. Single factor test and orthogonal design methods were used to determine the optimal extraction method; the mouse skin papilloma model induced by DMBA/croton oil was established, which was a classic two-stage carcinogenesis model being used to observe and evaluate the anti-carcinogenic effects of tannins extracted from Semen Cuscutae in different stages. The optimal extraction method of Semen Cuscutae was a 20-fold volume of solvent, a temperature of 50 degrees C, three times of extraction, with 20 min each, skin papilloma experiment revealed that the number of bearing tumors gradually reduced, and the inhibition rate gradually increased with the increase of dose, in the high-dose group, its inhibition rate reached 70.2%. Tannin extract from Semen Cuscutae has an obvious inhibitory effect on skin papilloma development. PMID- 24146477 TI - Experimental study on inhibition of S180 tumor cells by Agrimonia pilosa extract. AB - We evaluated the in vitro and in vivo inhibition of S180 tumor cell growth of the water extract of Agrimonia pilosa. Inhibitory effect of Agrimonia pilosa on in vitro-cultured S180 cell proliferation was measured by MTT assay; mice model of transplanted tumor was established, after 8 days of continuous administration, the tumors were removed, weighed, and compared with the control group, and the in vivo anti-tumor effect of Agrimonia pilosa on mouse sarcoma S180 was compared using inhibition rate. The in vitro anti-tumor experiment indicated that the inhibition rate gradually increases with the increase of extract concentration and the extension of time, with IC50 175.64, 90.59, and 71.74 ug/ml at 24 h, 4 h, and 72 h respectively. In this study, the in vitro MTT assay was used to determine the inhibitory effect of Agrimony pilosa water extract on S180 tumor cells, the method is simple, reliable, and practical; mice model of in vivo transplanted S180 tumor was established, which allowed direct observation of tumor inhibitory effect, and thus found out that the water extract of Agrimonia pilosa has inhibitory effect on S180 tumor cells. PMID- 24146478 TI - Irritantcy potential and sub acute dermal toxicity study of Pistacia lentiscus fatty oil as a topical traditional remedy. AB - The current study was undertaken to assess safety of Pistacia lentiscus fruits fatty oil (PLFO) as a topical traditional remedy. A primary skin and eye irritation tests were conducted with New Zealand white rabbits to determine the potential for PLFO to produce irritation from a single application. In addition, a sub acute dermal toxicity study was performed on 18 NZW rabbits to evaluate possible adverse effect following application of PLFO for 28 days. Based on the results of the current study, PLFO is classified as slightly irritating to the skin and the eye of rabbits (Primary Irritation Index (P.I.I.) = 1.037; Ocular Irritation Index (O.I.I.) = 5.33 at 1 h). In the sub-acute toxicity test, PLFO produced neither mortality nor significant differences in the body and organ weights between control group and treated rabbits. However, a reversible irritant contact dermatitis was observed in the treated areas from the end of the second week of application until the end of experiment. This local phenomenon was accompanied by a significant skin thickening (P<=0.01) since the 12(th) day (ANOVA, F = 11, 07143, P = 0, 00765) which is confirmed with an inflammatory granuloma in histological study. Haematological analysis and blood chemistry values of the 2 groups showed no significant differences in any of the parameters examined. In summary, PLFO is minimally irritating to the eye and skin after a single exposure, but it may cause irritant contact dermatitis and a reversible thickening of skin after prolonged use. PMID- 24146479 TI - Ethno-veterinary practices amongst livestock farmers in Ngamiland District, Botswana. AB - We carried out a study to determine ethno-veterinary knowledge used to treat and prevent livestock diseases in Toteng Village in Ngamiland District, northwestern Botswana. Primary data were collected through simple random sampling of 45 households in Toteng. Respondents were either livestock owners or cattle herders. Respondents were interviewed using a structured questionnaire which had both open and closed-ended questions. Cattle ownership or herdership in Toteng is an inter generational occupation with people ranging from 15 to 94 years old. Cattle were acquired either through inheritance, buying, mafisa (reciprocal exchange) system or government scheme. Women in the study area were more involved in livestock farming activities. Eleven livestock diseases were reported to be prevalent in the study area. The top six diseases were tlhako le molomo -foot and mouth disease (FMD), matlho -eye infections, letshololo-diarrhea, madi -pasteurollosis, mokokomalo -aphosphorisis and pholoso-contagious abortion. At least nine medicinal plant species having ethno-veterinary applications were recorded in the study area. Single plants are mostly used rather than a combination of plants. A number of social strategies were mentioned such as 'go fetola mafudiso' - to change grazing areas, and 'go thaa lesaka' - to ritualistically 'protect a kraal' or livestock against evil spells and predators (lions). Although the intervention of conventional veterinary medicine is pervasive in Toteng, and many livestock owners are resorting to it, there is evidence, however, of generalized ethno veterinary knowledge used to treat and prevent livestock diseases. Local farmers and their herders in Ngamiland are not only knowledgeable and experienced in treating a range of livestock diseases, but also in performing other veterinary tasks such as assisting in births, treating fractures and range management strategies to mitigate particular threats from their local environment. The efficacy of ethno-veterinary knowledge for preventing and treating livestock diseases and range management strategies identified in this study need to be fully investigated and integrated in veterinary extension services. PMID- 24146480 TI - Effect of Paris saponin on antitumor and immune function in U14 tumor-bearing mice. AB - We evaluated the effect of Paris saponin on inhibition of cervical cancer in mice and on immune regulation in tumor-bearing mice. MTT assay was used to examine the effect of Paris saponin on U14 cell proliferatiosn in vitro; the ascites tumor model of U14 cervical cancer was established to observe the effect of Paris saponin on inhibition of the tumor and on survival time of mice; and serum IL-4 and IFN-gamma levels in tumor-bearing mice were detected. The Paris saponin showed significant inhibitory effect on growth of cervical cancer U14 cells both in vitro and in vivo, prolonged the survival time of mice, increased the serum IFN-gamma level of tumor-bearing mice, and reduced the serum IL-4 level. The Paris saponin can inhibit U14 cell growth and prolong survival time of mice; it is speculated that the Paris saponin may express its anti-tumor activity by improving the body's immune system. PMID- 24146481 TI - Analysis on 85 case reports of adverse drug reactions. AB - This study investigated the occurrence and characteristics of adverse drug reactions (ADR) in our hospital and provide references for clinical rational drug use. We collected the 85 case reports of adverse drug reactions in our hospital in 2010 and made retrospective statistical analysis on them. The varieties of anti-infective drugs used are the most used. It also had the highest proportion of adverse drug reactions; the common symptom of adverse drug reactions is skin and accessory damage. Adverse drug reactions are affected by many factors, and relevant departments should strengthen ADR monitoring, to reduce or avoid the occurrence of adverse drug reactions. PMID- 24146482 TI - Study on in-vivo anti-tumor activity of Verbena officinalis extract. AB - We investigated the anti-tumor effects of Verbena officinalis extract on H22 tumor-bearing mice and its effect on immune function. Mice model of H22 solid tumor was established, the mice were divided into five groups and administered the extract, later, tumors were removed and inhibition rates were calculated; spleens were removed and spleen indices were calculated, and the sheep red blood cell-delayed-type hypersensitivity (SRBC-DTH) and the serum hemolysin level were determined. The Verbena officinalis extract had anti-tumor effect, with the inhibition rate reaching 38.78%, it also increased the spleen index to a certain extent, in addition, the changes in DTA and HA were not obvious compared with the model group. The Verbena officinalis extract had in vivo anti-tumor effect, while causing no damage on the immune function. PMID- 24146483 TI - Antimicrobial efficacy and phytochemical analysis of Indigofera trita Linn. AB - An in vitro antimicrobial activity and phytochemical analysis of various extracts of Indigofera trita L. viz. petroleum ether, chloroform, acetone, ethanol and aqueous extracts were carried out. A total of 21 microorganisms (19 bacteria and 2 fungal strains) were used for antimicrobial activity by disc diffusion method and a standard procedure was used to identify the phytochemical constituents. Petroleum ether extract showed moderate inhibitory activity against Staphylococcus aureus (14.40 mm), S. epidermidis (14.20 mm), Salmonella paratyphi A (12.80 mm), Streptococcus mutans (12.20 mm), Escherichia coli, Proteus vulgaris, S. typhi and Burkholderia cepacia (12.00 mm). The chloroform extract also showed antimicrobial activity against S. epidermidis (14.20 mm), S. typhimurium (12.60 mm), S. paratyphi A, S. brunei and Yersinia enterocolitica (12.00 mm). The acetone extract of I. trita showed considerable inhibitory activity against S. epidermidis (18.20 mm), S. typhimurium (14.60 mm), S. infantis (13.80 mm), S. aureus (13.40 mm), Y. enterocolitica (13.00 mm) and Enterobacter aerogenes (12.00 mm) were documented. Ethanol extract showed significant antimicrobial activity against S. epidermidis (18.60 mm), S. paratyphi A (14.60 mm), Y. enterocolitica (13.40 mm), S. typhi (12.40 mm), S. aureus, E. aerogenes, S. typhimurium and S. infantis (12.00 mm). Aqueous extract of I. trita considerably inhibited S. epidermidis (13.80 mm), S. paratyphi A and Y. enterocolitica (12.20 mm), E. aerogenes and Haemophilus parahaemolyticus (12.00 mm). All the five extracts showed a minimal antifungal activity when compared to antibacterial activity. The result revealed that the antimicrobial properties of I. trita might be associated with the presence of phenolic compounds, flavonoids, tannins, glycosides, saponins, phytosterols and alkaloids. PMID- 24146484 TI - Antifertility effects of Pouzolzia mixta in female Wistar rats. AB - The continued use of plants by women to prevent pregnancy suggests there are plants out there with potential use as contraceptives. In Zimbabwe, Pouzolzia mixta is used as a "morning after" contraceptive, thus it may possess postcoital antifertility activity. To test contraceptive activity, animals (n=8/group) were orally pretreated with aqueous (AqPM) or ethanolic (EtPM) extract of P. mixta at 300mg/kg b.wt for 7 days followed by mating with continued treatment for 10 days post-conception. To test for postcoital activity, treatment was initiated on day 1 of pregnancy and continued for 10 days. Laparotomy was performed and implantations counted. For estrogenic activity, immature ovariectomised rats were treated for 7 days after which vaginal opening and uterine weights were determined. In vitro oxytocic effects were performed using uterine tissue in an organ bath with De Jalon's solution. Acetylcholine (Ach) was the positive control. Results showed modest contraceptive activity with EtPM more effective in inhibiting fertility compared to AqPM (37.5% vs 25%) with a similar trend for antiimplantation effects (31% vs 19%). There was potent postcoital antifertility effects with AqPM more effective in inhibiting implantation (94.6% vs 86%) and fertility (87.5% vs 75%) compared to EtPM. Immature rat bioassay for estrogenic activity demonstrated pronounced estrogenic activity by both extracts. Oxytocic effects at 400ng/ml were more pronounced for the AqPM (92% of 100ng/ml Ach) than EtPM (25% of 100ng/ml Ach). Findings demonstrate the antifertility effects of aqueous and ethanolic extracts of P. mixta. The antifertility effects may be attributed to antiimplantation, estrogenic and oxytocic effects of the plant extracts. PMID- 24146485 TI - In vitro inhibitory activities of the extract of Hibiscus sabdariffa L. (family Malvaceae) on selected cytochrome P450 isoforms. AB - Literature is scanty on the interaction potential of Hibiscus sabdariffa L., plant extract with other drugs and the affected targets. This study was conducted to investigate the cytochrome P450 (CYP) isoforms that are inhibited by the extract of Hibiscus sabdariffa L. in vitro. The inhibition towards the major drug metabolizing CYP isoforms by the plant extract were estimated in human liver microsomal incubations, by monitoring the CYP-specific model reactions through previously validated N-in-one assay method. The ethanolic extract of Hibiscus sabdariffa showed inhibitory activities against nine selected CYP isoforms: CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1 and CYP3A4. The concentrations of the extract which produced 50% inhibition of the CYP isoforms ranged from 306 ug/ml to 1660 ug/ml, and the degree of inhibition based on the IC50 values for each CYP isoform was in the following order: CYP1A2 > CYP2C8 > CYP2D6 > CYP2B6 > CYP2E1 > CYP2C19 > CYP3A4 >> CYP2C9 >> CYP2A6. Ethanolic extract of Hibiscus sabdariffa caused inhibition of CYP isoforms in vitro. These observed inhibitions may not cause clinically significant herb-drug interactions; however, caution may need to be taken in co-administering the water extract of Hibiscus sabdariffa with other drugs until clinical studies are available to further clarify these findings. PMID- 24146486 TI - Arteriovenous fistula failure due to two straight shunts formation at draining vein. AB - A 48-year-old asian man was admitted to hospital for the consideration of hemodialysis (HD). An adequate site was decided on for the AVF after Doppler ultrasonography examination of radial artery and cephalic vein. The AVF was formed under local anaesthetic at his right wrist. When seen at the clinic appointment one month later, the AVF was not working. The subsequent Doppler ultrasonography examination revealed two straight shunts at draining vein. The failure of AVF is due to impaired outflow following reduction of the resistance between draining vein and peripheral venous system. PMID- 24146487 TI - Study on in vitro anti-tumor activity of Bidens bipinnata L. extract. AB - We studied the in vitro anti-tumor activity of Bidens Bipinnata L. extract. MTT assay was used to investigate the inhibitory effect of different concentrations of the extracts on human hepatocellular carcinoma (HepG2) cell lines and human cervical carcinoma (Hela) cell lines, and the IC50 values were calculated. The Bidens Bipinnata L. extract had different degrees of inhibitory effects on these two cells, and when exposure time was 48 h, the inhibition rate reached its peak, with IC50 values of 14.80 ug/mL and 13.50 ug/mL respectively. The Bidens Bipinnata L. extract had a good inhibitory effect on human HepG2 cell lines and Hela cell lines, and thus has certain development prospects. PMID- 24146488 TI - Three-dimensional motion of the radial artery and the spatiality, rhythmicity, formability and intensity of TCM pulse diagnosis. AB - Traditional Chinese medicine (TCM) pulse diagnosis can reflect the condition of human bodies. 44 young healthy human beings were involved in the investigation of the relationship between the three dimensional motion of the radial artery and the spatiality, rhythmicity, formability and intensity of TCM pulse diagnosis in TCM pulse diagnostics. The color Doppler vascular imaging, the self-designed cardioelectric phasic marking and non-pressure arm bath-tube were used in the study. Both the radial artery and other arm superficial arteries had three forms of motion, namely diametrical motion, axial motion and the displacement of the axial center. The three forms of motion changed periodically, which was identical with that found in pulsation. The displacement of the vascular axial center was a three-dimensional message of the overall vascular revolving motion observed on a two-e level. Systematically studying the rules of vascular motion and the relationship between the rules of vascular motion and the spatiality, rhythmicity, formability and intensity of TCM pulse patterns has great significance in revealing the specificity of the vascular motion and explaining the mechanisms in the formation of TCM pulse diagnosis. This research could make TCM pulse diagnosis more understandable. PMID- 24146489 TI - Inhibitory effect of saponins and polysaccharides from Radix ranunculi ternati on human gastric cancer BGC823 cells. AB - The effects of different Radix ranunculi ternati extracts on human gastric cancer BGC823 cells were investigated, different methods were used to extract the saponins and polysaccharides from Radix ranunculi ternati, and MTT assay and colony formation assay were used to observe the effects of saponins and polysaccharides from Radix ranunculi ternati on in-vitro cultured human gastric cancer BGC823 cells. The results found that the saponins and polysaccharides from Radix Ranunculi Ternati had certain effects on both the growth and colony formation of human gastric cancer BGC823 cells, while improving the immune function of normal mice, of which saponins had more significant effects than polysaccharides. PMID- 24146490 TI - Study on antibacterial effect of medlar and hawthorn compound extract in vitro. AB - This paper evaluated the antibacterial effect of medlar and hawthorn compound extract in vitro. Water extract method and ethanol extraction method was adopted to prepare the compound extracts, and disc diffusion method and improved test tube doubling dilution method were used to conduct the antibacterial test on the two common pathogenic bacteria, Staphylococcus aureus and Klebsiella pneumonia, in vitro. The results showed that medlar and hawthorn compound extract was moderately sensitive to Staphylococcus aureus, while its inhibiting effect on Klebsiella pneumoniae was particularly significant, moreover, the antibacterial effect of ethanol extract was better than water extract. Medlar and hawthorn compounds had good antibacterial effect on the two pathogenic bacteria. PMID- 24146491 TI - Wound-healing and potential anti-keloidal properties of the latex of Calotropis procera (Aiton) Asclepiadaceae in rabbits. AB - Calotropis Procera (CP) has been used in the management of toothache, fresh skin burns, gum bleeding as well as others to make it qualify as a medicinal plant. This study was designed to assess its wound-healing property in rabbits and its potentials for anti keloidal activity.Fresh latex of Calotropis were obtained and evaluated phytochemically. Fifteen male rabbits were used and four excisional wounds were created on each rabbit. The rabbits were divided into five groups of three each. Group 1 was the negative control and received no treatment. The wounds of group 2 animals were treated with 2mL of Calotropis latex; group 3 with 2mL honey; and group 4 with a mixture of 1ml honey and 1 mL of the latex. The animals in group 5 were given 2mg triamcinolone intramuscularly. All the groups had their wounds treated daily for 21 days. The wounds' diameters were measured on the day of wound creation, thereafter on days 7, 14 and 21 post wound creation. Biopsies of the wounds were taken on days 3 and 21 and viewed histologically. Phytochemical study of the latex revealed the presence of glycosides, tannins and alkaloids. The wounds were found to be significantly (p<0.05) reduced in groups treated with 50% latex in honey and triamcinolone, respectively, on day 7 post wound creation while there was a significant (p<0.05) reduction in wound surface area in all treated groups on days 14 and 21 post wound creation. Histological findings in untreated group showed thick bundle of collagen fibres some of which had broad based configurations, reminiscent of keloid. The group treated with 2mL of Calotropis latex revealed the presence of florid granulation tissues on day 3 while there was a marked reduction in quantity and size of collagen fibres on day 21 post wound creation which was comparable with what was seen for the triamcinolone-treated group.The general effect of Calotropis latex on wound-healing was noted. Likewise it's similarity to that of triamcinolone, an anti-keloidal agent; this makes it a probable candidate for future anti-keloidal study using a suitable model. PMID- 24146492 TI - Study on anti-tumor effect of total glycosides from Radix paeoniae rubra in S180 tumor-bearing mice. AB - The objective of the paper was to study the anti-tumor effect of total glycosides from Radix paeoniae rubra in S180 tumor-bearing mice, and to preliminarily explore its mechanism of action. Mice were made into S180 solid tumor model, grouped and administered with the extracts; tumor inhibition rate was measured by harvesting the tumors, and serum IL-2 and IL-4 levels were measured by taking blood samples. Total glycosides of Radix paeoniae rubra significantly inhibited the growth of tumor cells in tumor-bearing organisms, enhanced the cytotoxic activity of NK cells, and increased the serum IL-2 and IL-4 levels. Total glycosides of Radix paeoniae rubra have some anti-tumor effect in vivo, which might have been accomplished through the regulation of the immune system. PMID- 24146493 TI - Antihyperglycemic and antinociceptive activity evaluation of 'khoyer' prepared from boiling the wood of Acacia catechu in water. AB - 'Khoyer' is prepared by boiling the wood of Acacia catechu in water and then evaporating the resultant brew. The resultant hard material is powdered and chewed with betel leaves and lime with or without tobacco by a large number of the people of Bangladesh as an addictive psycho-stimulating and euphoria-inducing formulation. There are folk medicinal claims that khoyer helps in the relief of pain and is also useful to diabetic patients to maintain normal sugar levels. Thus far no scientific studies have evaluated the antihyperglycemic and antinociceptive effects of khoyer. The present study was carried out to evaluate the possible glucose tolerance efficacy of methanolic extracts of khoyer using glucose-induced hyperglycemic mice, and antinociceptive effects with acetic acid induced gastric pain models in mice. In antihyperglycemic activity tests, the extract at different doses was administered one hour prior to glucose administration and blood glucose level was measured after two hours of glucose administration (p.o.) using glucose oxidase method. The statistical data indicated the significant oral hypoglycemic activity on glucose-loaded mice at all doses of the extracts tested. Maximum anti-hyperglycemic activity was shown at 400 mg extract per kg body weight, which was less than that of a standard drug, glibenclamide (10 mg/kg body weight). In antinociceptive activity tests, the extract also demonstrated a dose-dependent significant reduction in the number of writhing induced in mice through intraperitoneal administration of acetic acid. Maximum antinociceptive activity was observed at a dose of 400 mg extract per kg body weight, which was greater than that of a standard antinociceptive drug, aspirin, when administered at a dose of 400 mg per kg body weight. The results validate the folk medicinal use of the plant for reduction of blood sugar in diabetic patients, as well as the folk medicinal use for alleviation of pain. PMID- 24146494 TI - Effect of four medicinal plants on amyloid-beta induced neurotoxicity in SH-SY5Y cells. AB - Amyloid-beta peptide (Abeta) is implicated in the pathogenesis of Alzheimer's disease (AD), a neurodegenerative disorder. This study was designed to determine the effect of four medicinal plants used to treat neurodegenerative diseases on Abeta-induced cell death. Cytotoxicity of the ethanol extracts of the plants was determined against SH-SY5Y (human neuroblastoma) cells which were untreated, as well as toxically induced with Abeta, using the MTT and neutral red uptake assays. Cell viability was reduced to 16% when exposed to 20 uM Abeta25-35 for 72 h. The methanol extract of the roots of Ziziphus mucronata Willd., Lannea schweinfurthii (Engl.) Engl. and Terminalia sericea Burch. ex DC., were the least toxic to the SH-SY5Ycells at the highest concentration tested (100 ug/ml). All four plants tested were observed to reduce the effects of Abeta-induced neuronal cell death, indicating that they may contain compounds which may be relevant in the prevention of AD progression. PMID- 24146495 TI - Treatment of d-galactose induced mouse aging with Lycium barbarum polysaccharides and its mechanism study. AB - We evaluated the effects of Lycium barbarum polysaccharides LBP) on D-galactose aging model mouse, and explored its possible mechanism. Kunming mice were randomly divided into the control group, the model group, the high-dose LBP group, and the low-dose LBP group. Except the control group, D-galactose was used for modelling. The drug was administrated when modelling. Mouse behavioural, learning and memory changes were observed, and the contents of lipid peroxidation (LPO), lipofuscin (LF) and monoamine oxidase B (MAO-B) in mouse brain tissue and the weight of immune organs were measured after 6 weeks. Compared with the control group, mouse weight gain in the model group reduced significantly. Compared with model group, after mice drank LBP, the times of electric shock was less than aging mice (in which, the high-dose LBP group, P<0.05), and electric shock incubation period was longer (P<0.01). On Day 45 after modelling and drug administration, the contents of LPO, LF and MAO-B in mouse brain tissue in the model group increased significantly, while those in the drug administration groups decreased significantly. The thymus index in the aging model group decreased significantly; the thymus index and the spleen index in the high-dose LBP group and the low-dose LBP group rebounded significantly (P<0.01). We concluded that LBP has an anti-aging effect on D-galactose induced aging model mouse, and its mechanism may be related with the alleviation of glucose metabolism disorder and the resistance of the generation of lipid peroxide and other substances, which damage cell membrane lipid. PMID- 24146496 TI - The effects of beta-elemene on the expression of mTOR, HIF-1A, survivin in lung adenocarcinoma A549 cell. AB - The purpose of this manuscript was to study the regulation effects of beta elemene combined with radiotherapy on three different gene expressions in lung adenocarcinoma A549 cell. mTOR gene, HIF-1alpha gene, Survivin gene were included in the gene group. Cell culture and RT-PCR were applied to finish this research. Hypoxia Control group, Hypoxia beta-elemene group, Hypoxia beta-elemene combined with irradiation group were set to compare the differences of three different gene expressions. The most active effects were found in the group of Hypoxia irradiation combined with beta-elemene. In this group, the mTOR gene, HIF-1alpha gene, Survivin gene expressions were all down-regulated when compared with the single treatment groups, and there were significantly statistical differences. PMID- 24146497 TI - Effect of Chinese medical herbs-Huiru Yizeng Yihao on hyperprolactinemia and hyperplasia of mammary gland in mice. AB - The study investigated the pharmacodynamism and mechanism of Chinese medicinal formula-Huiru Yizeng Yihao (NO.1 HRYZ) on the model rats of hyperpro-lactinemia and the model rats of hyperplasia of mammary gland (HMG), and studied the internal connection between hyperprolactinemia and HMG.. The hyperprolactinemia rat models were established by injecting metoclopramide dihydrochloride in the back of rats. The model rat of HMG was prepared by injecting estradiol in the thigh muscle of the rats and progesterone consecutively, while the tails of rats were clipped with tongs. Rats were treated with either NO.1 HRYZ or positive control drugs for four weeks. The concentrations of sex hormone in rat serum were examined using ELISA kits, and the morphology of mammary gland tissue in all group rats was observed with microscope. NO.1 HRYZ significantly decreased prolactin (PRL) and increased estradiol (E2), progesterone (P), follicle stimulating hormone (FSH), luteinizing hormone (LH) concentrations of hyperprolactinemia rats. It decreased E2, PRL, FSH, gonadotropin-releasing hormone (GnRH), 5-hydroxytryptamine (5-HT) and increased P concentrations of HMG rat. It also eliminated hyperplasia of lobules and gland alveolus compared with the model group. Treatment with NO.1 HRYZ could significantly regulate the sex hormone disorder of hyperprolactinemia and HMG rat models, and could eliminate the formation of HMG. Hyperprolactinemia was closely correlated with HMG, and hyperprolactinemia promoted the formation of HMG. PMID- 24146498 TI - Chemotherapeutic activities of Carthami Flos and its reversal effect on multidrug resistance in cancer cells. AB - Multidrug-resistance (MDR) represents a major cause of failure in cancer chemotherapy. The need for a reduction in MDR by natural-product-based drugs of low toxicity led to the current investigation of applying medicinal herbs in future cancer adjuvant therapy. Carthami Flos (CF), the dried flower of safflower (Carthamus tinctorius L.), is one of the most popular traditional Chinese medicinal herbs used to alleviate pain, increase circulation, and reduce blood stasis syndrome. The drug resistance index of the total extract of CF in MDR KB V1 cells and its synergistic effects with other chemotherapeutic agents were studied. SRB cell viability assays were used to quantify growth inhibition after exposure to single drug and in combinations with other chemotherapeutic agents using the median effect principle. The combination indexes were then calculated according to the classic isobologram equation. The results revealed that CF showed a drug resistance index of 0.096. In combination with other chemotherapeutic agents, it enhanced their chemo-sensitivities by 2.8 to 4.0 folds and gave a general synergism in cytotoxic effect. These results indicate that CF could be a potential alternative adjuvant antitumour herbal medicine representing a promising approach to the treatment of some malignant and MDR cancers in the future. PMID- 24146499 TI - Study on the effect of polysaccharides from Solanum nigrum Linne on cellular immune function in tumour-bearing mice. AB - We investigated the anti-tumour effect of polysaccharides from Solanum nigrum Linne, and its relationship with the immune function of tumour-bearing organisms. MTT assay was used to observe the effect of different doses of polysaccharides from Solanum nigrum Linne on proliferation of lymphocytes in tumour-bearing mice. ELISA assay was also used to detect the levels of IL-2 in mice, and a laser scanning confocal microscope was used to detect the effect of polysaccharides from Solanum nigrum Linne on intralymphocytic free calcium ion concentration in tumour-bearing mice. Different doses of polysaccharides from Solanum nigrum Linne significantly inhibited the growth of mouse H22 solid tumours, improved the survival time of tumour-bearing mice, increased the proliferation of lymphocytes, elevated the levels of IL-2, and increased the concentration of calcium ions in the lymphocytes. Polysaccharides from Solanum nigrum Linne have certain anti tumour effect, which is related with the cellular immune function that regulates the body. PMID- 24146500 TI - Dimethoxyflavone isolated from the stem bark of Stereospermum kunthianum possesses antidiarrhoeal activity in rodents. AB - This study was undertaken to evaluate the antidiarrhoeal activity of 3, 7, 4' trihydroxy-3'-(8"-acetoxy-7"-methyloctyl)-5, 6-dimethoxyflavone, a flavonoid isolated from the stem bark of Stereospermum kunthianum. The antidiarrhoeal activity was evaluated using rodent models with diarrhoea. The normal intestinal transit, castor oil-induced intestinal transit and castor oil-induced diarrhoea tests in mice as well as castor oil-induced intestinal fluid accumulation in rats were employed in the study. The animals were pretreated with distilled water (10 ml/kg for mice, 5 ml/kg for rats), dimethoxyflavone (25 mg/kg or 50 mg/kg), morphine (10 mg/kg), or indomethacin (10 mg/kg) before induction of diarrhoea with castor oil (0.2ml for mice and 2ml for rats). Dimethoxyflavone dose dependently and significantly reduced (P<0.05) castor oil-induced intestinal motility. Its antimotility effect at the dose of 50 mg/kg was higher compared to that of morphine (10 mg/kg). Dimethoxyflavone (25 mg/kg and 50 mg/kg) caused a delay in the onset of diarrhoea reduction in the number and weight of wet stools and total stools in mice with castor oil-induced diarrhoea compared to the distilled water treated mice. Treatment with dimethoxyflavone (25 mg/kg or 50 mg/kg) did not produce any remarkable effect on castor oil-induced intestinal fluid accumulation in rats and normal intestinal transit in mice. The results indicate that dimethoxyflavone possesses antidiarrhoeal activity due to its intestinal antimotility effect and inhibition of other diarrhoeal pathophysiological processes. In conclusion, dimethoxyflavone reduced the frequency and severity of diarrhoea in the diarrhoeal models studied. PMID- 24146501 TI - Determination of antimicrobial effect, antioxidant activity and phenolic contents of desert truffle in Turkey. AB - Terfezia boudieri Chatin (Scop.) Pers., is a famous macrofungus in the world as well as in Turkey for its pleasant aroma and flavour. People believe that this mushroom has some medicinal properties. Therefore, it is consumed as food and for medicinal purposes. Chloroform, acetone and methanol extracts of T. boudieri were tested to reveal its antimicrobial activity against four Gram-positive and five Gram-negative bacteria, and one yeast using a micro dilution method. In this study, the highest minimum inhibitory concentration (MIC) value was observed with the acetone extract (MIC, 4.8 ug/mL) against Candida albicans. Maximum antimicrobial effect was also determined with the acetone extract (MIC, 39-78 ug/mL). The scavenging effect of T. boudieri on 2, 2-diphenyl-1-picrylhydrazyl (DPPH) radicals was measured as 0.031 mg/mL at 5 mg/mL concentration, and its reducing power was 0.214 mg/mL at 0.4 mg/mL. In addition, the phenolic contents were determined as follows: the catechin was 20 mg/g, the ferulic acid was 15 mg/g, the p-coumaric acid was 10 mg/g, and the cinnamic acid was 6 mg/g. The results showed that T. boudieri has antimicrobial activity on the gram negative and positive bacteria as well as yeast, and it also has a high antioxidant capacity. Therefore, T. boudieri can be recommended as an important natural food source. PMID- 24146502 TI - Ethno-botanical study of medicinal plants of Paddar Valley of Jammu and Kashmir, India. AB - The Paddar Valley, historically known as Sapphire Valley situated in Kishtwar district, is a prime landmark in the Jammu region of J&K state and is known for its rich cultural and plant diversity because of diverse habitats such as rivers, streams, meadows and steep mountain slopes. The area is located in the dry temperate region comprising typical vegetation which disappears completely on the eastern slopes, dominated by a variety of economical species which play an important role in the rural life. The inhabitants are dependent on plant resources for food, fuel, timber, shelter, fodder/forage, household articles and traditional medicines in treating diseases like malaria, cancer, gastro intestinal ailments, etc. This paper deals with the observations on traditional therapeutic application by the inhabitants of Paddar Valley. The ethno-botanical information on medicinal plants would not only be useful in conservation of traditional cultures and biodiversity but also community health care and drug development. Exploration survey in Paddar Valley has revealed that people collect and sell these medicinal species through local intermediaries / contractors to earn their livelihood. But the scientific cultivation and appropriate post harvest management would improve employment opportunity and income of local farmers in the region. PMID- 24146503 TI - The inhibitory effect of Binens bipinnata L. extract on U14 tumour in mice. AB - The objective of this paper was to study the in vitro and in vivo inhibitory effect of Bidens bipinnata L. extract on growth of cervical carcinoma U14 cells. MTT method was used to determine the inhibitory effect of Bidens bipinnata L. extract on U14 tumour cells, and the effects of Bidens bipinnata L. extract on inhibition rate of solid tumour and life prolongation rate of ascites tumour were observed through the establishment of two animal models of mouse cervical carcinoma U14 solid tumour and ascites tumour. In the in vitro MTT assay, the inhibition rate gradually increased with the increase of dose of Bidens bipinnata L. and the extension of time. Its inhibition rate was 70.44% at a concentration of 80ug/L. Solid tumour inhibition rates in the high- and low-dose groups and cisplatin group were 49.13%, 2.26% and 75.72% respectively; life prolongation rates in each ascites tumour group were 63.63%, 34.86% and 87.34% respectively. The Bidens bipinnata L. extract has a certain inhibitory effect on growth of mouse cervical carcinoma U14. PMID- 24146504 TI - Effects of Gan lian Yu ping feng powder on the antibody titers to infectious laryngotracheitis vaccine and some nonspecific immune indexes in chickens. AB - The study was conducted in order to investigate the immuno-enhancing property of the Chinese herbal formula, Gan lian Yu ping feng powder. Three hundred and thirty six 45-day-old chicks were randomly divided into eight groups. The chicks in groups A, B, C were orally given 0.25 g/mL (low-), 0.5 g/mL (middle-) and 1.0 g/mL (high) dose of Gan lian Yu ping feng powder in the drinking water respectively for 3 days consecutively. They were then immunised with infectious laryngotracheitis vaccine (ILTV) on the 4th day. Groups D, E, F were given 0.25 g/mL, 0.5 g/mL and 1.0 g/mL dose of Gan lian Yu ping feng powder respectively after the immunisation for three days consecutively. Group G was Wen du qing (a government approved herbal product for ILT) control group, and group H was blank control group. At 52, 59, 73, 87 days of age, 8 chicks of each group were selected randomly for blood sampling to determine the levels of IFN-gamma, IL-4 and the antibody of ILT. Then the chickens were sacrificed, with the thymus, spleen and Bursa of Fabricius being weighed for the calculation of immune organ indexes. The results showed that high and middle dosages of Gan lian Yu ping feng powder given at the day before immunisation and 3 days after immunisation elevated not only the contents of IFN-gamma, the antibody titers of ILT (P<0.01) and the immune organ indexes (P<0.05) significantly, but also reduced the contents of IL-4. There was a significantly different degree of enhancement in the content of IFN-gamma, the antibody of ILT (P<0.01) and the immune organ index (P<0.05). The results indicate that Gan lian Yu ping feng powder effectively improves the immunity in chickens. PMID- 24146505 TI - A comparative study of anti-gastric cancer activity between aqueous extract and ethanol extract of Folium Cordylines Fruticosae. AB - The active components in Folium Cordylines Fruticosae were extracted by heat reflux method. The solvents used were distilled water and ethanol. The effects of two types of extracts on gastric cancer cells were compared; dry extract yields were calculated, as well as the inhibition rates of gastric cancer MGC-803 cell proliferation and the colony cell counts. The micro-Kjeldahl method was used to measure the cell protein contents and to make a comprehensive comparison. The results showed that the MGC-803 cell inhibition rates of three different concentrations (32.5, 75 and 150 mg/ml) of ethanol extracts increased with the increase of concentration, which was 48.9% at a concentration of 150 mg/ml; aqueous extract of Folium Cordylines Fruticosae had very low inhibitory activity at a low concentration (32.5 mg/ml), which was remained at about 20%. After being affected by two types of extracts, cells had uneven sizes, with very low brightness, while the normal cells presented a uniform full form, with high definition. PMID- 24146506 TI - Analysis on 113 cases of adverse reactions caused by beta-lactam antibiotics. AB - The objectives of this study were to learn about the characteristics and rules of the occurrence of adverse reactions caused by lactam antibiotics and provide a reference for clinical drug use. METHODS: A retrospective study was made to analyse the 113 case reports of adverse reactions caused by beta-lactam antibiotics collected in our hospital between 2007 and 2009. RESULTS: 113 cases of ADR involved 17 kinds of beta-lactam antibiotics, headed by ceftriaxone sodium. The most common manifestation was skin and accessory damage; nervous system and gastrointestinal system damage were also easier to find, and the administration route was mainly intravenous infusion. CONCLUSION: The clinical application of beta-lactam antibiotics should pay attention to adverse reaction monitoring and rational drug use to reduce the incidence of adverse reactions. PMID- 24146507 TI - A review of oxidative stress in acute kidney injury: protective role of medicinal plants-derived antioxidants. AB - Acute kidney injury (AKI) is the common clinical syndrome which is associated with increased morbidity and mortality. The severity extends from less to more advanced spectrums which link to biological, physical and chemical agents. Oxidative stress (OS)-related AKI has demonstrated the increasing of reactive oxygen species (ROS) and reactive nitrogen species (RNS) and the decreasing of endogenous antioxidants. Medicinal plants-derived antioxidants can be ameliorated oxidative stress-related AKI through reduction of lipid peroxidation (LPO) and enhancement of activities and levels of endogenous antioxidants. Therefore, medicinal plants are good sources of exogenous antioxidants which might be considered the important remedies to ameliorate pathological alterations in oxidative stress-related AKI. PMID- 24146508 TI - Evaluation of anti-inflammatory, analgesic, and antipyretic effects of ethanolic extract of Pedalium murex Linn. fruits. AB - This study investigated the possible anti-inflammatory, analgesic, and antipyretic effects of ethanolic extract of Pedalium murex Linn. fruits in selected experimental animal models. Anti-inflammatory activity of Pedalium murex Linn., with doses of 200 mg/kg and 400 mg/kg, p.o., was evaluated by Lambda carrageenan induced paw oedema in Wistar albino rats; analgesic activity with doses of 280 mg/kg and 560 mg/kg, p.o., was evaluated by hot plate method and acetic acid induced writhing method in Swiss albino mice; and antipyretic activity with doses of 110 mg/kg and 220 mg/kg, p.o., was evaluated in New Zealand white rabbits by injecting gram -ve lipopolysaccharide obtained from E. coli. Results were analysed by one way ANOVA followed by Dunnet's multiple comparison test. Pedalium murex Linn. showed significant anti-inflammatory activity from 15 min to 180 min as compared to vehicle treated animals. It was comparable to diclofenac sodium at 180 min. The extract did not prolong the reaction time on hot plate method but significantly reduced the number of writhing after acetic acid administration. Also the extract did not show any antipyretic activity on lipopolysaccharide induced pyrexia. It is therefore concluded that the ethanolic extract of Pedalium murex Linn. fruits has an anti inflammatory and peripheral analgesic effects. PMID- 24146509 TI - Antimicrobial and free radical scavenging activities of five Palestinian medicinal plants. AB - Extracts from five indigenous Palestinian medicinal plants including Rosmarinus officinalis, Pisidium guajava, Punica granatum peel, grape seeds and Teucrium polium were investigated for antimicrobial and free radical scavenging activities against eight microorganisms, using well diffusion method. The microorganisms included six bacterial isolates (i.e. Staphylococcus aureus, Escherichia coli, Pseudomonas aeruginos, Klebsiella pneumonia, Bacillus subtilis and Micrococcus luteus) and two fungal isolates (i.e. Candida albicans and Aspergillus niger). A standard antioxidant assay was performed on the plant extracts to assess their capability in scavenging 2,2-diphenyl-1-picrylhydrazyl (DPPH). Of the five tested plant extract, only Rosmarinus offcinalis extract contained significant antimicrobial activity against all eight microbial isolates including Pseudomonas aeruginosa. Extracts from other four plants exhibited a variable antimicrobial activity against all microorganisms, except Pseudomonas aeruginosa. Significant antioxidant activity was detected in all plant extracts. However, extracts from Pisidium guajava leaves contained significantly higher antioxidant activity compared to the other extracts tested. The antimicrobial and scavenging activities detected in this in vitro study in extracts from the five Palestinian medicinal plants suggest that further study is needed to identify active compounds to target diseases caused by a wide-spectrum pathogens. PMID- 24146510 TI - General acteoside of Rehmanniae leaves in the treatment of primary chronic glomerulonephritis: a randomized controlled trial. AB - The objective of the study was to investigate the effectiveness and efficacy of the randomized, parallel, and controlled trial of Traditional Chinese Medicine, general acteoside of Rehmanniae leaves, compared with piperazine ferulate in the treatment of primary chronic glomerulonephritis. Rehmanniae leaves and piperazine ferulate can reduce proteinuria and erythrocyturia effectively in the treatment of primary chronic glomerulonephritis. A total of 400 patients diagnosed with primary chronic glomerulonephritis were recruited from outpatient clinics and were randomly assigned to the treatment group (general acteoside of Rehmanniae leaves, two 200mg tablets, bid) or the control group (piperazine ferulate, four 50-mg tablets, bid ). The primary outcome was 24-h urinary protein. Secondary outcome measures included estimated glomerular filtration rate (eGFR), erythrocyturia, and electrolytes. After 8 weeks of treatment, the treatment group and the control group showed a mean reduction in 24-h proteinuria of 34.81% and 37.66%. The 95% CI of difference of the mean reduction in 24-h proteinuria between the two groups was [-11.50%, 5.80%]. No significant differences were found between the two groups in the erythrocyturia reduction. Neither group showed obvious changes between baseline and 8 weeks in eGFR or electrolytes. Adverse events occurred at a similarly low rate in the treatment group (1.5%) and control group (2.5%, P = 0.7238). Both general acteoside of Rehmanniae leaves and piperazine ferulate can reduce proteinuria and erythrocyturia effectively in the treatment of primary chronic glomerulonephritis. PMID- 24146511 TI - The view of patients with Choronic Obstructive Pulmonary Disease (COPD) on Complementary and Alternative Medicine (CAM) in Eastern Turkey. AB - The purpose of this study was to examine the frequency of complementary and alternative medicine usage in Chronic Obstructive Pulmonary Disease (COPD) patients living in the eastern part of Turkey. In this study a descriptive design was used. The study was conducted with 216 patients who were present at the clinic. Data were gathered by the researchers in a comfortable setting through questionnaire method using the data collection form developed by the researcher. Individualised questionnaire-based interviews were also conducted among the 216 adult patients. The questionnaire included demographic information, clinical information, use of conventional therapies, and complementary and alternative therapy. According to the findings obtained in this research, the frequency of CAM use among Turkish COPD patients (72.1%) was close to the highest levels reported in the literature. PMID- 24146512 TI - Toxicity studies of the water extract from the calyces of Hibiscus sabdariffa L. in rats. AB - Acute and chronic toxicities of the water extract from calyces of Hibiscus sabdariffa were studied in male and female rats. After 14 days of a single oral administration of test substance 5,000 mg/kg body weight, measurement of the body and organ weights, necropsy and health monitoring were performed. No signs and differences of the weights or behaviour compared to the control rats were observed. The results indicated that the single oral administration of H. sabdariffa extract in the amount of 5,000 mg/kg body weight does not produce acute toxicity. The chronic toxicity was determined by oral feeding both male and female rats daily with the extract at the doses of 50, 100, and 200 mg/kg body weight for 270 days. The examinations of signs, animal behaviour and health monitoring showed no defects in the test groups compared to the control groups. Both test and control groups (day 270th) and satellite group (day 298th) were analysed by measuring their final body and organ weights, taking necropsy, and examining haematology, blood clinical chemistry, and microanatomy. Results showed no differences from the control groups. Overall, our study demonstrated that an oral administration of H. sabdariffa extract at the doses of 50, 100 and 200 mg/kg body weight for 270 days does not cause chronic toxicity in rat. PMID- 24146513 TI - Moduratory effect of Thai traditional medicine (Yahom Tultavai) on hepatic cytochrome P450 enzymes and pentobarbital-induced sleeping in mice. AB - Yahom Tultavai is a Thai traditional medicine that has been widely used for the treatment of nausea, vomiting, dizziness and weakness in aged-people, especially. Its formula contains several medicinal plants, and one of them is Kaempferia galanga L., which has ethyl-p-methoxycinnamate (EPMC) as its major compound. Recently, several herbs and traditional medicines have been reported to demonstrate herbal-drug interaction with conventional medicines. This study aims to investigate the effect of Yahom Tultavai extracts on hepatic cytochrome P450 enzymes and pentobarbital-induced sleeping in mice. Three extracts of Yahom Tultavai, using dichloromethane, methanol and distilled water as solvents were orally administered for 28 days prior to determine CYP1A1, CYP1A2, CYP2B, CYP2E1 and CYP3A4 activities. All three extracts significantly inhibited CYP1A1, CYP1A2 and CYP 2E1 activities, but only dichloromethane extract enhanced CYP2B activity. In addition, all three extracts had no effect on CYP3A4 activity. As an indicator for metabolic drug interaction, pentobarbital-induced sleeping time was decreased in connection with the induction of CYP2B activity between 7 and 28 days of dichloromethane extract and EPMC-treated animals when compared to control. In conclusion, Yahom Tultavai extracts affected hepatic microsomal CYP enzyme activities and reduced pentobarbital-induced sleeping time in mice. The results suggest that Yahom Tultavai may potentially cause herbal and conventional drug interaction, which can affect the clinical implication of drug action. Therefore, the co-administration of Yahom Tultavai with certain drugs should be carefully considered. PMID- 24146514 TI - Cytotoxic and antibacterial activity of the mixture of olive oil and lime cream in vitro conditions. AB - The mixture of olive oil and lime cream has been traditionally used to treat external burns in the region of Hatay/Antakya and middle Anatolia. Olive oil and lime cream have been employed by many physicians to treat many ailments in the past. A limited number of studies have shown the antibacterial effect of olive oil and that it does not have any toxic effect on the skin. But we did not find any reported studies on the mixture of olive oil and lime cream. The aim of this paper is to investigate the cytotoxic and antibacterial activity of olive oil and lime cream individually or/and in combination in vitro conditions, by using disk diffusion method and in cell culture. The main purpose in using this mixture is usually to clear burns without a trace. Agar overlay, MTT (Cytotoxicity assay) and antibacterial susceptibility tests were used to investigate the cytotoxic and antibacterial activity of olive oil and lime cream. We found that lime cream has an antibacterial activity but also cytotoxic on the fibroblasts. On the other hand olive oil has limited or no antibacterial effect and it has little or no cytotoxic on the fibroblasts. When we combined lime cream and olive oil, olive oil reduced its cytotoxic impact. These results suggest that mixture of olive oil and lime cream is not cytotoxic and has antimicrobial activity. PMID- 24146515 TI - Morphological and anatomical investigations into the mechanism of leaf pair unrolling in Uraria picta (Jacq.) Desv. Ex DC. (Papilionaceae), a medicinal plant in Nigeria. AB - Uraria picta leaf-pair unrolling inside out is a remarkable feat. A leaf-pair was investigated to understand the mechanism of spontaneous reverse inside out act of the plant. The upper (adaxial) and lower (abaxial) surfaces of the leaf-pair were examined using scanning and light microscopy. The scan showed diversity of hairs varying in shape from straight, pointed, curve, and club to hook. There were deposits of wax on both sides of the leaf-pair. The light microscope showed hairs are restricted to the midrib on the adaxial surface of the leaflets. Hooked hairs dominated the entire abaxial surface of the leaflets. The transverse section of the midrib section showed abundance of structural and mechanical tissues, collenchyma and sclerenchyma tissues. Both morphological and anatomical attributes were used to explain the mechanism and how the plant got its Yoruba vernacular name 'Alupayida' as well as its purported use in changing the sex of the unborn child and in breaking up love affairs. PMID- 24146516 TI - The effects of maggot secretions on the inflammatory cytokines in serum of traumatic rats. AB - The objective of this study was to analyse the changes of inflammatory cytokines level in traumatic rat serum after maggot secretions intervention. Acute traumatic rats were randomly divided into three groups that included maggot secretions group, negative group, and the control group. TNF-alpha, IL-6, SOD, LPO levels were measured by radioimmunoassay. The experimental results showed that TNF-alpha, IL-6, and SOD levels in the model group were significantly increased; LPO level was decreased and showed significant differences. Thus, the content of inflammatory cytokines in acute skin wounds could be reduced by maggot secretions, which play a role in enhancing wound healing. PMID- 24146517 TI - Histological and biochemical effects of arteetherTM on the liver of Wistar rats. AB - ArteetherTM is among the recent drugs that are used to combat chloroquine resistant malarial parasites. This study examined the effects of arteetherTM on enzyme biomarkers of the liver, serum protein concentrations, and liver morphology. Twenty (20) adult albino Wistar rats weighing 200 - 250 g were randomly divided into four groups (A, B, C and D) of five animals each, and used in this study. Group A rats were given intramuscular (i. m.) arteetherTM (3 mg/kg b. w.) daily for 3 days. Group B rats received i. m. arteetherTM (6 mg/kg b. w.) daily for 3 days. Group C rats were given i. m. arteetherTM (3 mg/kg b. w.) daily for 3 days. The same dose was repeated at two-weekly intervals for 4 further weeks, while group D rats which received normal saline (0.9 % w/ v, 3 ml/kg b.w.), served as controls. At the end of the experiment, the body weights of the animals were determined and recorded. Serum levels of alanine transaminase (ALT), aspartate transaminase (ASP), alkaline phosphatase (ALP), total protein (TP) and albumin were assayed, and histological studies were performed. Results obtained show no significant difference (P<0.05) in liver enzymes (ALT, ASP, ALP). TP and albumin were significantly reduced in group C rats. Histological studies revealed no cyto-architectural changes. It is concluded that at therapeutic doses, arteetherTM is well tolerated in Wistar rats. PMID- 24146518 TI - African mistletoes (Loranthaceae); ethnopharmacology, chemistry and medicinal values: an update. AB - Mistletoes of the Loranthaceae and Viscaceae are hemiparasitic plants and their preparations in the form of injectable extracts, infusions, tinctures, fluid extracts or tea bags are widely used in various cultures in almost every continent to treat or manage various health problems including hypertension, diabetes mellitus, inflammatory conditions, irregular menstruations, menopause, epilepsy, arthritis, cancer, etc. The medicinal values of some species of Mistletoes (Loranthaceae) growing in the West African sub-region have been reviewed along with some considerations of their chemistries and local uses. These have been compared with Mistletoes (Loranthaceae and Viscaceae) growing elsewhere in Europe and Asia. This review has attempted to update our knowledge on the values of these hemi-parasites which belong to the genera - Globimetula, Phragmanthera, Agelanthus and Tapinanthus, and which have, for years, been seen as only devastating and notorious plants. They are also seen as epiphyting economic, ornamental and medicinal plants. The hemi-parasitic plants (Mistletoes) are not well understood as very little is known about their biology (taxonomy, host/plant relationship, ecology, toxicology, physiological characteristics, etc.) and chemistry (chemical constituents' profile). Some pharmacological studies carried out on the various crude alcoholic extracts and purified fractions have, however, revealed that mistletoes showed hypotensive, hypoglycaemic, antilipidaemic, anti-oxidative, anti-inflammatory, antimicrobial, etc. effects and were non-toxic in experimental animals at the doses used. The findings showed that mistletoes can be very useful as medicinal agents in ameliorating health problems such as diabetes mellitus, hypertension, arthritis, pain, cancer and a host of other ailments if properly studied and developed. PMID- 24146519 TI - A study of Lycium barbarum polysaccharides (LBP) extraction technology and its anti-aging effect. AB - The objective of the study was to optimise the LBP extraction technology and to study the anti-aging effect of LBP by establishing D-gal aging mouse model. Orthogonal design was used to study the extraction technology. The experimental aging mouse model was formed by continuous injection of D-gal, and the anti-aging capacity of LBP was tested using measuring MDA, CAT and GSH-px contents and SOD activity in blood and SOD, MDA and Hyp levels in skin. The results showed that the optimum LBP extraction option determined by the orthogonal design is as follows: solid-liquid ratio of 1:30, extraction for 2 times, 90 min each time, and power is 100 kHz. Thus, LBP can increase SOD, CAT and GSH-px levels in blood and reduce MDA level. It can also improve skin SOD activity, reduce skin MDA content, and increase Hyp content. We concluded that the extraction method established in this experiment is easy and feasible, and the yield of LBP is high, apparently showing that LBP has the potential of delaying senility in D-gal induced mice. PMID- 24146520 TI - A study of extraction process and in vitro antioxidant activity of total phenols from Rhizoma Imperatae. AB - The study investigated the extraction method of Rhizoma Imperatae and its antioxidant activity, and provided a basis for its rational development. The extraction method of Rhizoma Imperatae was determined using orthogonal design test and by total phenol content, its hydroxyl radical scavenging ability was measured by Fenton reaction, and potassium ferricyanide reduction method was used to determine its reducing power. The results showed that the optimum extraction process of Rhizoma Imperatae was a 50-fold volume of water, 30 degrees C, three times of extraction with 2 h each. Its IC50 for scavenging of hydroxyl radicals was 0.0948 mg/mL, while IC50 of ascorbic acid was 0.1096 mg/mL; in the ferricyanide considerable reduction method, the extract exhibited reducing power comparable to that of the ascorbic acid. The study concluded that Rhizoma Imperatae extract contains relatively large amount of polyphenols, and has a good anti-oxidation ability. PMID- 24146521 TI - Applied orthogonal experiment design for the optimum microwave-assisted extraction conditions of polysaccharides from Rhodiolae Radix. AB - An experiment on polysaccharides from Rhodiolae Radix (PRR) extraction was carried out using microwave-assisted extraction (MAE) method with an objective to establishing the optimum MAE conditions of PRR. Single factor experiments were performed to determine the appropriate range of extraction conditions, and the optimum conditions were obtained using orthogonal experiment design. The results showed that the optimum MAE conditions of PRR were as follows: solid-liquid ratio of 1:45 g/mL, irradiation power of 480 W, and irradiation time of 8 min, while extraction yield of PRR was 3.24 %. PMID- 24146522 TI - Specific neuroprotective effects of manual stimulation of real acupoints versus non-acupoints in rats after middle cerebral artery occlusion. AB - The objective of this study was to investigate the effectiveness and specific effects of acupuncture on ischemic-induced damage in rats after permanent middle cerebral artery occlusion. Cerebral ischemia was induced by middle cerebral artery occlusion in male Wistar rats. The rats were divided into the following 4 groups: normal controls, ischemic, real acupuncture-treated (Shuigou, DU26), and non-acupoint-treated groups. On the third postoperative day, neurological deficit scores, cerebral blood flow, infarction volume, and neuronal cell death counts were measured. In the real acupuncture-treated group, the neurological deficit scores and cerebral blood flow were improved (p < 0.05) and the infarction volume and neuronal cell death counts were reduced (p < 0.01) compared to the ischemic and non-acupoint-treated groups. The present study demonstrated that real acupuncture was effective against focal ischemia-induced damage in rats after middle cerebral artery occlusion, and the effects were specifically related to the right needling location. PMID- 24146523 TI - "Friendships" between new mothers and adult males: adaptive benefits and determinants in wild baboons (Papio cynocephalus). AB - Close associations between adult males and lactating females and their dependent infants are not commonly described in non-monogamous mammals. However, such associations [sometimes called "friendships" (Smuts 1985)] are regularly observed in several primate species in which females mate with multiple males during the fertile period. The absence of mating exclusivity among "friends" suggests that males should invest little in infant care, raising questions about the adaptive significance of friendship bonds. Using data from genetic paternity analyses, patterns of behavior, and long-term demographic and reproductive records, we evaluated the extent to which friendships in four multi-male, multi-female yellow baboon (Papio cynocephalus) groups in Amboseli, Kenya represent joint parental care of offspring or male mating effort. We found evidence that mothers and infants benefited directly from friendships; friendships provided mother-infant dyads protection from harassment from other adult and immature females. In addition, nearly half of all male friends were the genetic fathers of offspring and had been observed mating with mothers during the days of most likely conception for those offspring. In contrast, nearly all friends who were not fathers were also not observed to consort with the mother during the days of most likely conception, suggesting that friendships between mothers and non-fathers did not result from paternity confusion. Finally, we found no evidence that prior friendship increased a male's chances of mating with a female in future reproductive cycles. Our results suggest that, for many male-female pairs at Amboseli, friendships represented a form of biparental care of offspring. Males in the remaining friendship dyads may be trading protection of infants in exchange for some resources or services not yet identified. Our study is the first to find evidence that female primates gain social benefits from their early associations with adult males. PMID- 24146525 TI - Message from the president of the saudi heart association. PMID- 24146527 TI - Gender differences in clinical presentation and management of patients with acute coronary syndrome in Southwest of Saudi Arabia. AB - OBJECTIVE: Gender differences in the clinical presentation and management of patients with acute coronary syndrome (ACS) have been reported in different parts of the world with contradicting results. We aimed at investigating the presence of gender bias in patients admitted with ACS to Aseer Central Hospital (ACH). METHODS: A retrospective cohort of all consecutive patients admitted to ACH with the diagnosis of ACS, during the period between the 1st of June 2007 and the 31st of May 2009 was studied. Data on demographic and clinical profiles, management and outcomes of ACS patients were collected and compared for both genders. RESULTS: The present study included 148 females and 397 males. Females were significantly older than males (62.9 +/- 14.2 vs. 60 +/- 13.4, respectively, P < 0.03), were less likely ever to have smoked (0.7% vs. 26.2%, respectively, P < 0.001), less likely to have had a history of hyperlipidemia (10.8% vs. 22.2%, respectively, P < 0.003) or family history of ischemic heart disease (10.1% vs. 18.9%, respectively, P < 0.014). Female patients presented more with atypical presentation (42.6% vs. 28.9%, respectively, P < 0.003), more with unstable angina (72.3% vs. 50.4%, respectively, P < 0.001), and less with ST-elevation myocardial infarction (18.9% vs. 40.8%, respectively, P < 0.001). Furthermore, they had significantly lower levels of hemoglobin compared to males (12.9 +/- 2.3 vs. 14.5 +/- 2.2 g/L, respectively, P < 0.001), and higher levels of high density lipoprotein (1.1 +/- 0.4 vs. 0.98 +/- 0.4 mmol/L, respectively, P < 0.008). Left ventricular ejection fraction was significantly higher in female patients compared to males (50.9 +/- 14 vs. 45.8 +/- 14, respectively, P < 0.003). Coronary angiography showed a higher rate of normal findings (29.3% vs. 8.9%, respectively, P < 0.001) and less severe disease (46.7% vs. 60.3%, respectively, P < 0.027) in women, however, they were less likely to undergo invasive revascularization procedures (31% vs. 42.8%, respectively, P < 0.013). No significant differences were found between both sexes regarding in-hospital mortality or re-infarction rates. CONCLUSION: We documented gender differences in both clinical presentation as well as management of patients admitted with ACS to ACH. However, there were no significant differences between both genders regarding the clinical in-hospital outcomes. Emphasis should be made to avoid such bias in the future. PMID- 24146526 TI - Surgical treatment of functional mitral regurgitation in dilated cardiomyopathy. AB - Functional mitral regurgitation is a significant complication of end-stage cardiomyopathy. Dysfunction of one or more components of the mitral valve apparatus occurs in 39-74% and affects almost all heart failure patients. Survival is decreased in subjects with more than mild mitral regurgitation irrespective of the aetiology of heart failure. The goal of treating functional mitral regurgitation is to slow or reverse ventricular remodelling, improve symptoms and functional class, decrease the frequency of hospitalization for congestive heart failure, slow progression to advanced heart failure (time to transplant) and improve survival. This article reviews the role of mitral valve surgery in patients with heart failure and dilated cardiomyopathy. PMID- 24146528 TI - Bone mineral density and coronary atherosclerosis. AB - BACKGROUND: The association between low bone mineral density (BMD) and atherosclerosis is still unknown. In this study BMD assessed in patients with and without coronary artery atherosclerosis is determined by angiography. METHODS: A total number of 123 consecutive patients referred for coronary angiography were evaluated by dual X-ray absorptiometry. Obstructive CAD was diagnosed when ?50% of lumen was narrowed. Conventional atherosclerosis risk factors were also assessed. RESULTS: The mean age of the patients was 59 +/- 8 years. There was frequency of 48.7% male. The prevalence of diabetes was 31.2%, hypertension 57%, dyslipoproteinaemia 51%, vitamin D deficiency 50% and history of smoking 80.8%. Coronary angiography was normal in 15 patients (12.6%) while 67 patients (55.5%) had obstructive CAD. DXA scan showed 25 patients (21%) with normal BMD, 39 patients (32.7%) with osteopenia, and 55 others (46.2%) with osteoporosis. Lower BMD results were significantly associated with older age and lower BMI but it was not associated significantly with diabetes, hypertension, lipids levels or smoking. Moreover the prevalence of obstructive CAD and minimal CAD differed between groups with normal and low bone density but this was not significant (p = 0.67 and 0.52, respectively). The mean T score comparison between patients with and without CAD was also not different. CONCLUSIONS: In patients with and without obstructive CAD the prevalence of low BMD results are not different. PMID- 24146529 TI - Usefulness of Tei index in patients with rheumatic mitral regurgitation and apparently normal left ventricular ejection fraction. AB - BACKGROUND AND AIM: Rheumatic mitral regurgitation is rather common in developing countries. It usually progresses insidiously, because the heart compensates for increasing regurgitant volume by left-atrial enlargement, causes left-ventricular overload and dysfunction, and yields poor outcome when it becomes severe. Doppler echocardiographic methods can be used to quantify the severity of mitral regurgitation. It is known that ejection fraction underestimates the presence of left ventricular dysfunction in these patients. This study aimed to study global cardiac function of these patients by using LV Tei index. METHODS: One hundred patients with rheumatic mitral regurge predominantly were included (40 males and 60 females; aged 10-24 years, median 20.6 years). All participants were subjected to full echocardiographic study including total isovolumic index (Tei index = isovolumic relaxation time IRT + isovolumic contraction time ICT/ejection time ET) for the left ventricle. Special attention was paid to grading of severity of the mitral regurgitation. RESULTS: LV ejection fraction was preserved in all cases but, however, the total left isovolumic index was prolonged 0.56 +/- 3 in 64 of them (34 females and 30 males) denoting masked LV dysfunction P < .00001. There was a correlation of increasing severity of dysfunction with the degree of mitral regurgitation. CONCLUSION: Ejection fraction underestimates the presence of left ventricular dysfunction in these patients. However, this was unmasked by the Tei index which could be an additive data for detecting early left ventricular dysfunction. PMID- 24146530 TI - Pulmonary atresia with hypoplastic right ventricle and large subaortic ventricular septal defect. AB - A neonate is presented with a very rare association consisting of pulmonary atresia with large ventricular septal defect but additionally, combined with a hypoplastic right ventricle and well developed pulmonary arteries. The management strategy is described. PMID- 24146531 TI - Pacemaker lead thrombo-endocarditis in an intravenous drug abuser. AB - We report a 30-year-old male intravenous drug abuser presenting with persistent pacemaker lead thrombosis with superimposed pacemaker lead endocarditis. He underwent urgent surgery, but expired due to refractory sepsis. This case confirms that patients with pacemakers are at risk of developing pacemaker lead thrombosis. In addition, they are at high risk of developing pacemaker lead endocarditis if additional risk factors for endocarditis are present. We believe this case report is unusual on account of pacemaker lead thrombosis as well as endocarditis occurring in a patient with history of intravenous drug abuse. Whether pacemaker patients with multiple leads need to be on long-term antiplatelet or anticoagulation therapy necessitates further studies. PMID- 24146532 TI - Right pulmonary artery compression by ascending aortic aneurysm. PMID- 24146533 TI - Left circumflex coronary artery is continuing to form the right coronary artery - Angiographic imaging. PMID- 24146534 TI - Echocardiographic atlas of the mitral regurgitation. AB - Mitral regurgitation (MR) is defined as the loss of the smooth and adequate trimming closure of the mitral valve, which results in the reflux of blood from the left ventricle into the left atrium during systole. The functional competence of the mitral valve relies on the proper and coordinated interaction of the following structures: the mitral annulus, and leaflets, chordate tendineae, papillary muscles, left atrium and the left ventricles. This article will describe the echocardiography assessment of the mitral valve regurgitation with special emphasis on the trans-esophageal and 3D echocardiography. The echocardiography images were all original with special attention to the unique surgical view of the images. PMID- 24146535 TI - Protective effects of total flavonoids from Flos Puerariae on retinal neuronal damage in diabetic mice. AB - PURPOSE: To investigate the potential protective effects of total flavonoids from Flos Puerariae (TFF) on retinal neural cells in diabetic mice. METHODS: C57BL/6J mice were intraperitoneally injected with streptozotocin to generate type I diabetes in a murine model, as indicated by blood glucose levels >=11.1 mmol/l. TFF was administered intragastrically at a dose of 50, 100, or 200 mg/kg/day. After 10 weeks of administration, the mice were euthanized, and the eyes were dissected. Retinal histology was examined, and the thickness of the retina was measured. Ultrastructural changes in the retinal ganglion cells and capillary basement membrane were observed with electron microscopy. Apoptosis of retinal neural cells was determined with the terminal deoxynucleotidyl transferase mediated dUTP-biotin nick end-labeling assay. Bax and Bcl-2 expression in the retinal tissues was determined with immunohistochemical staining and western blotting. RESULTS: Compared with the diabetic mice, the blood glucose level decreased (p<0.01) and the bodyweight increased (p<0.05) in the 100 and 200 mg/kg TFF-treated groups. The thickness of the retina significantly increased (p<0.01), and the retinal capillary basement membrane (BM) thickness was reduced in the 100 and 200 mg/kg TFF-treated diabetic mice (DM). The 100 and 200 mg/kg TFF treatments also attenuated the diabetes-induced apoptosis of retinal neural cells. Consistent with these effects, TFF treatment decreased the Bax expression level and, concurrently, increased the ratio of Bcl-2 to Bax. CONCLUSIONS: TFF attenuated diabetes-induced apoptosis in retinal neurons by inhibiting Bax expression and increasing the ratio of Bcl-2 to Bax, which suggests that TFF might prevent retinal neuronal damage in diabetes mellitus. PMID- 24146536 TI - Increase in retinal ganglion cells' susceptibility to elevated intraocular pressure and impairment of their endogenous neuroprotective mechanism by age. AB - PURPOSE: To investigate age-associated changes in retinal ganglion cell (RGC) response to elevated intraocular pressure (IOP), and to explore the mechanism underlying these changes. Specifically, the effect of aging on inhibitor of apoptosis (IAP) gene family expression was investigated in glaucomatous eyes. METHODS: IOP was induced unilaterally in 82 Wistar rats using the translimbal photocoagulation laser model. IOP was measured using a TonoLab tonometer. RGC survival was evaluated in 3-, 6-, 13-, and 18-month-old animals. Changes in the RNA profiles of young (3-month-old) and old glaucomatous retinas were examined by PCR array for apoptosis; changes in selected genes were validated by real-time PCR; and changes in selected proteins were localized by immunohistochemistry. RESULTS: There were no significant IOP differences between the age groups. However, there was a natural significant loss of RGCs with aging and this was more prevalent in glaucomatous eyes. The number of RGCs in glaucomatous eyes decreased from 669+/-123 RGC/mm2 at 3 months to 486+/-114 RGC/mm2 at 6 months and 189+/-46.5 RGC/mm2 at 18 months (n=4-8, p=0.048, analysis of variance). The PCR array revealed different changes in proapoptotic and prosurvival genes between young and old eyes. The two important prosurvival genes, IAP-1 and X-linked IAP (XIAP), acted in opposite directions in 3-month-old and 15-month-old rats, and were significantly decreased in aged glaucomatous retinas, while their expression increased significantly in young glaucomatous eyes. P53 levels did not vary between young glaucomatous and normal fellow eyes, but were reduced with age. B cell leukemia/lymphoma 2 (Bcl-2) family members and tumor necrosis factor (TNF) alpha expression were unaffected by age. Immunohistochemistry results suggested that the sources of changes in IAP-1 protein expression are RGCs and glial cells, and that most XIAP secretion comes from RGCs. CONCLUSIONS: Decreased IAP-1 and XIAP gene expression in aged eyes may predispose RGCs to increased vulnerability to glaucomatous damage. These findings suggest that aging impairs the endogenous neuroprotective mechanism of RGCs evoked by elevated IOP. PMID- 24146537 TI - Scleral structural alterations associated with chronic experimental intraocular pressure elevation in mice. AB - PURPOSE: To study changes in scleral structure induced by chronic experimental intraocular pressure elevation in mice. METHODS: We studied the effect of chronic bead-induced glaucoma on scleral thickness, collagen lamellar structure, and collagen fibril diameter distribution in C57BL/6 (B6) and CD1 mice, and in collagen 8alpha2 mutant mice (Aca23) and their wild-type littermates (Aca23-WT) using electron and confocal microscopy. RESULTS: In unfixed tissue, the control B6 peripapillary sclera was thicker than in CD1 mice (p<0.001). After 6 weeks of glaucoma, the unfixed CD1 and B6 sclera thinned by 9% and 12%, respectively (p<0.001). The fixed sclera, measured by electron microscopy, was significantly thicker in control Aca23 than in B6 or CD1 mice (p<0.05). The difference between fresh and fixed scleral thickness was nearly 68% in untreated control B6 and CD1 mice, but differed by only 10% or less in fresh/fixed glaucoma scleral comparisons. There were 39.3+/-9.6 lamellae (mean, standard deviation) in control sclera, categorized as 41% cross-section, 24% cellular, 20% oblique, and 15% longitudinal. After glaucoma, mean peripapillary thickness significantly increased in fixed specimens of all mouse strains by 10.3 +/-4.8 um (p=0.001) and the total number of lamellae increased by 18% (p=0.01). The number of cellular and cross-section lamellae increased in glaucoma eyes. After glaucoma, there were more small and fewer large collagen fibrils (p<0.0001). Second harmonic generation imaging showed that the normal circumferential pattern of collagen fibrils in the peripapillary sclera was altered in significantly damaged glaucomatous eyes. CONCLUSIONS: Dynamic responses of the sclera to experimental mouse glaucoma may be more important than baseline anatomic features in explaining susceptibility to damage. These include decreases in nonfibrillar elements, alterations in lamellar orientation, an increased number of smaller collagen fibrils and fewer larger fibrils, and relative increase in the number of scleral fibroblast layers. PMID- 24146538 TI - TOMM40 rs2075650 polymorphism shows no association with neovascular age-related macular degeneration or polypoidal choroidal vasculopathy in a Chinese population. AB - PURPOSE: Age-related macular degeneration (AMD) and Alzheimer disease (AD) are age-related neurodegenerative diseases that share similar environmental risk factors, cellular pathologies, and genetic backgrounds. Recently, the rs2075650 single nucleotide polymorphism in the translocase of outer mitochondrial membrane 40 homolog (TOMM40) gene was identified as a risk factor for AMD and Alzheimer disease. We aimed to examine the associations between the TOMM40 rs2075650 polymorphism and neovascular age-related macular degeneration (nAMD) and polypoidal choroidal vasculopathy (PCV) in a Chinese population. METHODS: The study consisted of 900 subjects, including 300 controls, 300 cases with nAMD, and 300 cases with PCV. Genomic DNA was extracted from venous blood leukocytes. The allelic variant of rs2075650 was determined with matrix-assisted laser desorption/ionization time-of-flight mass spectrometry. Differences in the observed genotypic distributions between the case and control groups were tested using chi-square tests, with age and gender adjusted using logistic regression analysis. RESULTS: The TOMM40 rs2075650 polymorphism was not statistically significantly associated with the nAMD or PCV phenotype (p>0.05). The difference remained insignificant after correction for age and gender differences based on the logistic regression models (p>0.05). CONCLUSIONS: Our data provide no evidence to support an association of rs2075650 in TOMM40 with nAMD or PCV, suggesting that this gene is unlikely to be a major AMD and PCV susceptibility gene locus in the Chinese population. PMID- 24146539 TI - Analysis of cell surface markers specific for transplantable rod photoreceptors. AB - PURPOSE: Transplantation of cells into retinas affected by degenerative diseases to replace dying photoreceptors represents a promising therapeutic approach. Young photoreceptors of 4-day-old mice show the highest capacity to integrate into the retinas of adult mice following grafting. Additional enrichment of these donor cells before transplantation with cell surface marker-dependent sorting methods further increases success rates. Currently, defined cell surface markers specific for transplantable photoreceptors that can be used for enrichment are limited. Therefore, identifying alternative targets would be advantageous. METHODS: Microarray data of young rod photoreceptors were analyzed using the Database for Annotation, Visualization and Integrated Discovery combined with a literature search to identify genes encoding for proteins containing extracellular domains. Candidate genes were further analyzed with reverse transcriptase polymerase chain reaction (RT-PCR) for their retinal specificity. In situ hybridization and immunohistochemistry were used to identify their localization within the retina. RESULTS: Enrichment of candidates by Database for Annotation, Visualization and Integrated Discovery revealed 65 proteins containing extracellular domains. Reverse transcriptase polymerase chain reaction identified Atp8a2, Cacna2d4, Cadm2, Cnga1, Kcnv2, and Pcdh21 as expressed in the retina and only a few additional tissues. In situ hybridization and immunohistochemistry showed specificity of Cacna2d4, Kcnv2, and Pcdh21 for photoreceptors in the retinas of young mice. CONCLUSIONS: Cacna2d4, Kcnv2, and Cnga1 were identified as specific for target cells in the retinas of young mice and could serve as candidates for rod photoreceptor enrichment to replace cells in retinal degenerative diseases. PMID- 24146540 TI - Retinal degeneration increases susceptibility to myopia in mice. AB - PURPOSE: Retinal diseases are often associated with refractive errors, suggesting the importance of normal retinal signaling during emmetropization. For instance, retinitis pigmentosa, a disease characterized by severe photoreceptor degeneration, is associated with myopia; however, the underlying link between these conditions is not known. This study examines the influence of photoreceptor degeneration on refractive development by testing two mouse models of retinitis pigmentosa under normal and form deprivation visual conditions. Dopamine, a potential stop signal for refractive eye growth, was assessed as a potential underlying mechanism. METHODS: Refractive eye growth in mice that were homozygous for a mutation in Pde6b, Pde6b(rd1/rd1) (rd1), or Pde6b(rd10/rd10) (rd10) was measured weekly from 4 to 12 weeks of age and compared to age-matched wild-type (WT) mice. Refractive error was measured using an eccentric infrared photorefractor, and axial length was measured with partial coherence interferometry or spectral domain ocular coherence tomography. A cohort of mice received head-mounted diffuser goggles to induce form deprivation from 4 to 6 weeks of age. Dopamine and 3,4-dihydroxyphenylacetic acid (DOPAC) levels were measured with high-performance liquid chromatography in each strain after exposure to normal or form deprivation conditions. RESULTS: The rd1 and rd10 mice had significantly greater hyperopia relative to the WT controls throughout normal development; however, axial length became significantly longer only in WT mice starting at 7 weeks of age. After 2 weeks of form deprivation, the rd1 and rd10 mice demonstrated a faster and larger myopic shift (-6.14+/-0.62 and -7.38+/-1.46 diopter, respectively) compared to the WT mice (-2.41+/-0.47 diopter). Under normal visual conditions, the DOPAC levels and DOPAC/dopamine ratios, a measure of dopamine turnover, were significantly lower in the rd1 and rd10 mice compared to the WT mice, while the dopamine levels were similar or higher than WT in the rd10 mice. Lower basal levels of DOPAC were highly correlated with increasing myopic shifts. CONCLUSIONS: Refractive development under normal visual conditions was disrupted toward greater hyperopia from 4 to 12 weeks of age in these photoreceptor degeneration models, despite significantly lower DOPAC levels. However, the retinal degeneration models with low basal levels of DOPAC had increased susceptibility to form deprivation myopia. These results indicate that photoreceptor degeneration may alter dopamine metabolism, leading to increased susceptibility to myopia with an environmental visual challenge. PMID- 24146541 TI - P2X7 receptor activation may be involved in neuronal loss in the retinal ganglion cell layer after acute elevation of intraocular pressure in rats. AB - PURPOSE: To investigate whether the P2X7 receptor is involved in retinal ganglion cell (RGC) death after the intraocular pressure (IOP) is elevated in rats. METHODS: After the IOP was elevated to 90 mmHg for 1 h, the rats were subsequently administered oxidized adenosine triphosphate (OxATP) and brilliant blue G (BBG) as P2X7 antagonists. The rats were euthanized 7 days after IOP elevation for histologic evaluation and at 1, 3, and 7 days after IOP elevation to immunostain for the P2X7 receptor and neuron-specific class III beta-tubulin in the retina. Changes in P2X7 receptor expression were measured in total retina extracts using western blot analysis. Quantitative real-time PCR was also performed using the entire retina to determine whether the P2X7 receptor is involved in upregulating tumor necrosis factor (TNF)-alpha, interleukin (IL) 1beta, and IL-6 at 1, 2, and 3 days after the IOP was elevated. RESULTS: RGC density and the inner plexiform layer thickness significantly decreased 7 days after IOP elevation, but were dose-dependently preserved when treated with OxATP or BBG. P2X7 immunoreactivity in the RGCs increased after IOP elevation, with the peak occurring from day 1 through day 3. Protein levels of P2X7 receptor were significantly increased 1, 2, and 3 days after IOP elevation. The messenger ribonucleic acid expression of the P2X7 receptor, TNF-alpha, IL-1beta, and IL-6 was significantly upregulated in the retina after IOP elevation, and was suppressed by treatment with OxATP. CONCLUSIONS: These results suggest the expression of the P2X7 receptor is upregulated in the retina after IOP elevation, leading to RGC death. Upregulation of TNF-alpha, IL-1beta, and IL-6 might be involved in this mechanism of RGC death. Furthermore, P2X7 antagonists may prevent RGC death after IOP elevation. PMID- 24146542 TI - Leukocytes from diabetic patients kill retinal endothelial cells: effects of berberine. AB - PURPOSE: Accumulating evidence in animals suggests that leukocytes are involved in the pathogenesis of diabetic retinopathy. The present study was designed to investigate whether leukocytes from diabetic patients could kill retinal endothelial cells and whether that cytotoxicity could be inhibited in vivo by administration of berberine. METHODS: Human retinal endothelial cells (HRECs) were cocultured (24 h) with leukocytes freshly isolated from nondiabetic and diabetic patients, and leukocyte-mediated death of HRECs was analyzed with flow cytometry. HRECs or leukocytes were incubated with antibodies against intercellular adhesion molecule-1(ICAM-1) or integrin beta-2, or with various concentrations of berberine. The protein expression levels of inflammatory factors were investigated using western blots, and activities of antioxidant enzymes and malondialdehyde content were examined as markers of oxidative stress. In addition, leukocytes were isolated from 28 diabetic patients with retinopathy and nondiabetic patients before and after 1 month in vivo therapy with berberine. The effects of the berberine on leukocyte-mediated killing of endothelial cells was again assessed. RESULTS: Leukocytes from diabetic patients induced more apoptosis of HRECs in a coculture system than did cells from nondiabetic patients, and this killing occurred primarily via direct cell-cell contact. Berberine inhibited the leukocyte-mediated killing of HRECs in vitro, the decrease in antioxidant enzyme activities, the nuclear translocation of nuclear factor kappa B, and the increase in intercellular adhesion molecule-1 and inducible nitric oxide synthase expression and malondialdehyde content in HRECs cultured in high glucose. Berberine also decreased integrin beta-2 expression of leukocytes in vitro and in vivo. Oral consumption of berberine for 1 month likewise inhibited the diabetes-induced increase in leukocyte-mediated killing of HRECs. CONCLUSIONS: Our findings suggest that leukocytes from diabetic patients kill retinal endothelial cells, and that berberine can inhibit this leukocyte mediated killing of vascular endothelium. Coculture of leukocytes with HRECs might serve as a biomarker to study the role of leukocytes in the development of diabetic retinopathy, and the data are consistent with berberine being a therapy against diabetic retinopathy. PMID- 24146543 TI - Hydrogen peroxide and extracellular signal-related kinase 1/2 pathway regulate ferritin levels in retinal pigmented and lens epithelial cells. AB - PURPOSE: Iron plays a central role in the oxidative stress caused by hydrogen peroxide. The ubiquitous iron storage protein, ferritin, safely sequesters iron, reducing its ability to cause oxidative damage. Oxidative stress can activate mitogen-activated protein (MAP) kinase pathways with many downstream effects. The purpose of this study was to determine the effects of hydrogen peroxide on MAP kinase pathways (extracellular signal-related kinase [ERK]1/2, c-Jun N-terminal kinase [JNK], and p38) and ferritin levels in canine lens and retinal epithelial cells (lens epithelial cells [LECs] and retinal pigmented epithelial [RPE] cells). METHODS: Primary cultures of canine LECs and RPE cells were used in these studies. Hydrogen peroxide was delivered either by a single 250 MUM bolus or 0.25 mU/ml glucose oxidase (GO). Immunoblotting was used to determine the activation of the MAP kinase pathways. Ferritin was detected with enzyme immunosorbent assay. RESULTS: Baseline activation of ERK1/2 in the untreated RPE cells and LECs was decreased by treatment with U-0126. Bolus hydrogen peroxide greatly increased ERK1/2 activation that had been blocked by U-0126, whereas GO had no significant effect on ERK1/2 phosphorylation. Hydrogen peroxide, either bolus or constant low levels, increased ferritin levels in the LECs and RPE cells. Surprisingly, U-0126 not only did not inhibit the effect of hydrogen peroxide on the ferritin levels but also increased the ferritin levels in both cell types. Neither bolus nor chronic hydrogen peroxide exposure activated the JNK or p38 pathway. Additionally, neither JNK nor p38 inhibitors had any effect on the ferritin concentrations in the LECs or RPE cells. CONCLUSIONS: Although U-0126 inhibited the hydrogen peroxide-induced increase in ERK1/2 phosphorylation, U-0126's lack of inhibition of the peroxide-induced increase in intracellular ferritin levels indicates that this pathway is not involved in ferritin induction by hydrogen peroxide. This is the first study to demonstrate that hydrogen peroxide and an inhibitor of ERK1/2 activation can increase the levels of the iron storage protein, ferritin. Since ferritin can shield cells from iron-catalyzed damage, this downstream effect likely plays a protective role, which, in the case of the ERK1/2 inhibitor, U-0126, demonstrates a potential therapeutic target. PMID- 24146544 TI - Ultraviolet-visible light spectral transmittance of rabbit corneas after riboflavin/ultraviolet-A (365 nm) corneal collagen cross-linking. AB - PURPOSE: To determine the effect of riboflavin/ultraviolet-A (365 nm) corneal collagen cross-linking on the transmission of the ultraviolet-visible (UV-VIS) light spectrum through the cornea. METHODS: Twelve New Zealand white male rabbits were used in this research. Cross-linking was performed unilaterally on the right eyes of the animals while only the epithelium was removed on the left eyes as the control. Seven weeks after cross-linking, the animals were euthanized, and the enucleated eyes were processed for transmission spectroscopy. To confirm that the cross-linking procedures was done successfully on the right corneas, the tensile force-extension relationship was measured using six corneas from three of the rabbits after the transmission spectrum was determined. RESULTS: Seven weeks after cross-linking, ten of the 12 rabbits had clear corneas in the cross-linked and control eyes. The two rabbits with neovascularization and granular opacities in the right corneas were not included in subsequent measurements. In the cross linked corneas, transmittance was 87.57% at 650 nm, and decreased continuously as the wavelength shortened. From 315 nm, the transmittance rapidly decreased and was 35.52% at 300 nm. In the control corneas, transmittance was 95.95% at 650 nm and decreased continuously as the wavelength shortened. Below 315 nm, the transmittance rapidly decreased, to 40.29% at 300 nm. The transmittance of the cross-linking corneas was 10%-20% lower than that of the control corneas. The difference was 8.38% at 650 nm and increased as the wavelength shortened, reaching a maximum of 20.59% at 320 nm, and decreased rapidly to 4.77% at 300 nm. The tensile force-extension relationship showed that a greater force was necessary to extend the cross-linking corneas over 500 um than that of the control corneas. CONCLUSIONS: The transmittance of the cross-linked corneas was 10%-20% lower than that of the control corneas. The difference increased as the wavelength decrease, reaching a maximum at 320 nm and then decreasing rapidly. Ultraviolet collagen cross-linking exhibited a protective effect against ultraviolet penetration. PMID- 24146545 TI - Revolving images and multi-image keys open new horizons in descriptive taxonomy: ZooKeys working examples. PMID- 24146546 TI - Revolving SEM images visualising 3D taxonomic characters: application to six species of the millipede genus Ommatoiulus Latzel, 1884, with description of seven new species and an interactive key to the Tunisian members of the genus (Diplopoda, Julida, Julidae). AB - A novel illustration technique based on scanning electron microscopy is used for the first time to enhance taxonomic descriptions. The male genitalia (gonopods) of six species of millipedes are used for construction of interactive imaging models. Each model is a compilation of a number of SEM images taken consecutively while rotating the SEM stage 360 degrees , which allows the structure in question to be seen from all angles of view in one plane. Seven new species of the genus Ommatoiulus collected in Tunisia are described: Ommatoiulus chambiensis, Ommatoiulus crassinigripes, Ommatoiulus kefi, Ommatoiulus khroumiriensis, Ommatoiulus xerophilus, Ommatoiulus xenos, and Ommatoiulus zaghouani spp. n. Size differences between syntopic adult males of Ommatoiulus chambiensis and Ommatoiulus xerophilus spp. n. from Chaambi Mountain are illustrated using scatter diagrams. A similar diagram is used to illustrate size differences in Ommatoiulus crassinigripes, Ommatoiulus khroumiriensis spp. n. and Ommatoiulus punicus (Brolemann, 1894). In addition to morphological differences, the latter three species display allopatric distribution and different habitat preferences. A dichotomous interactive key with a high visual impact and an intuitive user interface is presented to serve identification of the 12 Ommatoiulus species so far known from Tunisia. Updates on the North African Ommatoiulus fauna in general are presented. PMID- 24146547 TI - Rotational Scanning Electron Micrographs (rSEM): A novel and accessible tool to visualize and communicate complex morphology. AB - An accessible workflow is presented to create interactive, rotational scanning electron micrographs (rSEM). These information-rich animations facilitate the study and communication of complex morphological structures exemplified here by male arthropod genitalia. Methods are outlined for the publication of rSEMs on the web or in journal articles as SWF files. Image components of rSEMs were archived in MorphBank to ensure future data access. rSEM represents a promising new addition to the toolkit of a new generation of digital taxonomy. PMID- 24146548 TI - Further revision of the genus Megalopsalis (Opiliones, Neopilionidae), with the description of seven new species. AB - The Australian harvestmen genus Megalopsalis (Neopilionidae: Enantiobuninae) is recognised as a senior synonym of the genera Spinicrus and Hypomegalopsalis, and seven new species are described in Megalopsalis: Megalopsalis suffugiens, Megalopsalis walpolensis, Megalopsalis caeruleomontium, Megalopsalis atrocidiana, Megalopsalis coronata, Megalopsalis puerilis and Megalopsalis sublucens. A morphological phylogenetic analysis of the Enantiobuninae is also conducted including the new species. Monophyly of Neopilionidae and Enantiobuninae including 'Monoscutidae' is corroborated, with the Australasian taxa as a possible sister clade to the South American Thrasychirus. PMID- 24146549 TI - Hoplatessara luxuriosa (Silvestri, 1895) (Diplopoda, Polydesmida, Paradoxosomatidae) is native to Australia, not New Guinea. AB - Hoplatessara luxuriosa (Silvestri, 1895) is partly redescribed and illustrated. Its native range is shown to be in the cool-climate uplands of New South Wales, Australia. H. luxuriosa was originally labelled as collected by L.M. D'Albertis at Sorong in New Guinea. D'Albertis collected on Sorong Island in 1872 and spent the following year in Sydney, New South Wales, before returning to Europe with his New Guinea specimens. It is possible that D'Albertis himself collected H. luxuriosa in 1873, and that the mislabelling occurred later. PMID- 24146550 TI - Hydraena (Hydraenopsis) ateneo, new species (Coleoptera, Hydraenidae) and other aquatic Polyphaga from a small habitat patch in a highly urbanized landscape of Metro Manila, Philippines. AB - Seven species of Hydraenidae, Hydrophilidae and Elmidae are recorded from temporary freshwater habitats at the Ateneo de Manila University Campus in the metropolitan area of Manila, Philippines. They were identified as Enochrus (Lumetus) fragiloides d'Orchymont, Helochares (Hydrobaticus) lepidus d'Orchymont, Helochares (Helochares) pallens (MacLeay), Hydraena (Hydraenopsis) scabra d'Orchymont, Hydraena (Hydraenopsis) palawanensis Freitag & Jach (new record for Luzon Island), Stenelmis sp. A further hydraenid species was unknown to science and is newly described: Hydraena (Hydraenopsis) ateneo Freitag, sp. n. Aedeagus, gonocoxite, spermatheca, and female tergite X are illustrated by computer-based line drawings. Habitus images of all three Hydraena Kugelann species recorded and a checklist of the Philippine Hydraena are provided. The presence of these seven species in the Ateneo campus is briefly discussed in regard to the area's history. Measures to maintain and extend semi-natural islands of biodiversity in urban areas are suggested. PMID- 24146551 TI - A redescripton of Lyrosoma pallidum (Eschscholtz) and distributional range extension of Lyrosoma Mannerheim (Coleoptera, Agyrtidae). AB - A redescription with illustrations of the species Lyrosoma pallidum and a key to the Korean species of the family Agyrtidae are provided. New distributional data, including a range extension, of the two Lyrosoma Mannerheim species are presented. Lyrosoma pallidum (Eschscholtz) is recorded for the first time in Korea. PMID- 24146552 TI - A revision of the Larainae (Coleoptera, Elmidae) of Venezuela, with description of nine new species. AB - The species of the riffle beetle subfamily Larainae occurring in Venezuela are revised. Examination of 756 specimens yielded 22 species in nine genera occurring throughout the country. Seven species are newly recorded from the country: Phanoceroides sp. 1, Phanocerus clavicornis Sharp, 1882, Phanocerus congener Grouvelle, 1898, Pharceonus volcanus Spangler & Santiago-Fragoso, 1992, Disersus dasycolus Spangler & Santiago-Fragoso, 1992, Disersus chibcha Spangler & Santiago Fragoso, 1987, and Disersus inca Spangler & Santiago-Fragoso, 1992. Nine species are found to be new to science, which are here described: Hexanchorus dentitibialis sp. n., H. falconensis sp. n., H. flintorum sp. n., H. homaeotarsoides sp. n., H. inflatus sp. n., Phanocerus rufus sp. n., Pharceonus grandis sp. n., Pharceonus ariasi sp. n., Potamophilops bostrychophallus sp. n. Additionally, a key to species, distribution maps, and photographs and genitalia illustrations are provided for all species. PMID- 24146553 TI - Description of Longidorus cholevae sp. n. (Nematoda, Dorylaimida) from a riparian habitat in the Rila Mountains, Bulgaria. AB - A description is provided of Longidorus cholevae sp. n., a bisexual species associated with wild cherry (Prunus avium L.) from the Rila Mountains, Bulgaria. The position of L. cholevae sp. n. among other species of the genus was elucidated by using morphological and molecular data. Phylogenetic analyses were performed of D2-D3 expansion domains of the 28S rRNA and the partial ITS1 containing regions by Neighbor-Joining, Maximum Likelihood and Bayesian Inference methods. The species is characterised by a female body length of 6.1-8.1 mm; long odontostyle (106-129 MUm); lip region wide (21.5-24 MUm) rounded and continuous with the body profile; amphidial pouches short and wide, funnel-shaped; a posteriorly situated guide ring (30-37 MUm); normal arrangement of pharyngeal glands, and short bluntly rounded to hemispherical tail. Four juvenile stages indentified, first stage with elongate conoid tail. Males with 2-4 adanal pairs and a row of 11-13 single ventromedian supplements, spicules 96-120 MUm long. Based both on morphological and molecular data the new species appearred to be the most similar witha group of species distributed in Europe sharing common charcters such as amphidial fovea, lip region and tail shapes, and having similar odontostyle and body length: L. poessneckensis, L. caespiticola, L. macrososma, L. helveticus, L. carniolensis and L. pius. An updated list of Longidorus species and a partial polytomous keys to the Longidorus species with long odontostyle (code A45) and short tail (code H1) are provided. PMID- 24146554 TI - Systematics of a widely distributed western North American springsnail, Pyrgulopsis micrococcus (Caenogastropoda, Hydrobiidae), with descriptions of three new congeners. AB - We describe three new species of springsnails (genus Pyrgulopsis) from the Amargosa River basin, California and Nevada (P. licina sp. n., P. perforata sp. n., P. sanchezi sp. n.), each of which was previously considered to be part of P. micrococcus. We also restrict P. micrococcus to its type locality area (Oasis Valley) and redefine a regional congener, P. turbatrix, to include populations from the central Death Valley region and San Bernardino Mountains that had been previously identified as P. micrococcus. The five species treated herein form genetically distinct lineages that differ from each other by 4.2-12.6% for mtCOI and 5.2-13.6% for mtNDI (based on previously published and newly obtained data), and are diagnosable by shell and/or penial characters. The new molecular data presented herein confirm sympatry of P. licina and P. sanchezi in Ash Meadows (consistent with morphological evidence) and delineate an additional lineage of P. micrococcus (in the broad sense) that we do not treat taxonomically owing to the paucity of morphological material. Conservation measures are needed to ensure the long term persistence of populations of P. micrococcus and a genetically differentiated lineage of P. sanchezi which live in disturbed habitats on private lands. PMID- 24146555 TI - Thrips (Insecta, Thysanoptera) of Iran: a revised and updated checklist. AB - In Iran, as a result of recent changes in nomenclature 201 species and one species group of the insect Order Thysanoptera, are here listed in 70 genera and five families. In considering species listed previously from this country, the presence of 7 species is considered not confirmed, and 12 species are excluded from the Iranian list. Problems in the study of Iranian Thysanoptera are discussed briefly. PMID- 24146556 TI - Systematics of the parasitic wasp genus Oxyscelio Kieffer (Hymenoptera, Platygastridae s.l.), part II: the Australian and southwest Pacific fauna. AB - The Australasian and southwest Pacific species of Oxyscelio (Hymenoptera: Platygastridae s.l.) are revised. A total of 80 species are recognized as valid, 13 of which are redescribed: O. atricoxa (Dodd), O. concoloripes (Dodd), O. flavipes (Kieffer), O. grandis (Dodd), O. hyalinipennis (Dodd), O. magniclava (Dodd), O. mirellus (Dodd), O. montanus (Dodd), O. nigriclava (Dodd), O. nigricoxa (Dodd), O. rugulosus (Dodd), O. shakespearei (Girault), and O. solitarius (Dodd). Oxyscelio glabriscutellum (Dodd) syn. n. is placed as a subjective junior synonym of O. rugulosus. Sixty-seven new species are described, many representing new distributional records for the genus - O. aciculae Burks, sp. n., O. anfractus Burks, sp. n., O. bellariorum Burks, sp. n., O. bicoloripedis Burks, sp. n., O. brevitas Burks, sp. n., O. catenae Burks, sp. n., O. caudarum Burks, sp. n., O. circulorum Burks, sp. n., O. clivi Burks, sp. n., O. clupei Burks, sp. n., O. conjuncti Burks, sp. n., O. contusionis Burks, sp. n., O. corrugationis Burks, sp. n., O. croci Burks, sp. n., O. cuspidis Burks, sp. n., O. densitatis Burks, sp. n., O. dissimulationis Burks, sp. n., O. divisionis Burks, sp. n., O. exiguitatis Burks, sp. n., O. fluctuum Burks, sp. n., O. foliorum Burks, sp. n., O. funis Burks, sp. n., O. gressus Burks, sp. n., O. hamorum Burks, sp. n., O. incisurae Burks, sp. n., O. lenitatis Burks, sp. n., O. leviventris Burks, sp. n., O. limbi Burks, sp. n., O. liminis Burks, sp. n., O. linguae Burks, sp. n., O. lintris Burks, sp. n., O. livens Burks, sp. n., O. mystacis Burks, sp. n., O. nasi Burks, sp. n., O. nitoris Burks, sp. n., O. obliquiatis Burks, sp. n., O. oblongiclypei Burks, sp. n., O. obturationis Burks, sp. n., O. oculi Burks, sp. n., O. palati Burks, sp. n., O. pectinis Burks, sp. n., O. pollicis Burks, sp. n., O. proceritatis Burks, sp. n., O. productionis Burks, sp. n., O. radii Burks, sp. n., O. rami Burks, sp. n., O. rupturae Burks, sp. n., O. sarcinae Burks, sp. n., O. scismatis Burks, sp. n., O. sciuri Burks, sp. n., O. scutorum Burks, sp. n., O. sepisessor Burks, sp. n., O. sinuationis Burks, sp. n., O. sordes Burks, sp. n., O. spatula Burks, sp. n., O. stipulae Burks, sp. n., O. stringerae Burks, sp. n., O. tenuitatis Burks, sp. n., O. truncationis Burks, sp. n., O. tubi Burks, sp. n., O. umbonis Burks, sp. n., O. uncinorum Burks, sp. n., O. valdecatenae Burks, sp. n., O. velamenti Burks, sp. n., O. verrucae Burks, sp. n., O. viator Burks, sp. n., and O. wa Burks, sp. n. The fauna is divided into nine diagnostic species groups, with five species unplaced to group. PMID- 24146557 TI - The Nabidae (Insecta, Hemiptera, Heteroptera) of Argentina. AB - In Argentina, five genera and 14 species are recorded in the subfamilies Prostemmatinae and Nabinae: Hoplistoscelis sordidus Reuter, Lasiomerus constrictus Champion, Metatropiphorus alvarengai Reuter, Nabis argentinus Meyer Dur, Nabis (Tropiconabis) capsiformis Germar, Nabis faminei Stal, Nabis paranensis Harris, Nabis punctipennis Blanchard, Nabis roripes Stal, Nabis setricus Harris, Nabis tandilensis Berg, Pagasa (Pagasa) costalis Reuter, Pagasa (Lampropagasa) fuscipennis Reuter and Pagasa (Pagasa) signatipennis Reuter. PMID- 24146558 TI - Review of the grassland leafhopper genus Exitianus Ball (Hemiptera, Cicadellidae, Deltocephalinae, Chiasmini) from China. AB - The two Chinese species of the leafhopper genus Exitianus Ball (Hemiptera: Cicadellidae: Deltocephalinae: Chiasmini) (Exitianus indicus (Distant) and Exitianus nanus (Distant)) are reviewed. Descriptions of the species and a key for their separation are provided. Exitianus fulvinervis Li & He is considered a junior synonym of Exitianus nanus syn. n. PMID- 24146559 TI - Moreiba gen. n., a new Canarian genus in Laparocerini (Coleoptera, Curculionidae). AB - A new genus Moreiba is described for Strophosoma canariense Franz, 1995 (type species) and placed in Laparocerini. It differs from Laparocerus Schoenherr, 1834 by the small size, the strongly transverse rostrum, the dense longitudinal strigosity on head and rostrum, the body covered by dense, adpressed scales and short, semierect subspatulate to parallel setae, the slender antennae with bisinuate scape and short oval club, the granulate pronotum and all tibiae lacking a mucro in both sexes. Moreiba canariensis (Franz, 1995), comb. n., is the only described species, distributed in El Hierro and Gran Canaria. The tribal placement of the genera Aphyonotus Faust, 1895, Asmaratrox Heller, 1909, Straticus Pascoe, 1886 and Cyrtozemia Pascoe, 1872 is discussed. PMID- 24146560 TI - Malagasyprinus, a new genus of the Saprininae from Madagascar with description of two new species (Coleoptera, Histeridae, Saprininae) (First contribution to the knowledge of the Histeridae of Madagascar). AB - Based on the results of recent phylogenetic analysis of the higher taxa of the Saprininae as well as external morphological characters, especially the presence of deep and large prosternal foveae, and the shape and position of the sensory organs of the antennal club, the species Saprinus (s.str.) caeruleatus Lewis, 1905 is excluded from the genus Saprinus and a new genus Malagasyprinus, exclusive to Madagascar, is established for it. The new genus shows mainly characters that are apomorphic for the subfamily and contains another two, highly similar allopatric species Malagasyprinus perrieri sp. n., and Malagasyprinus diana sp. n., described herein. The three species are best separated from each other by the structure of the prosternum and male terminalia, especially the shape of the aedeagus. We re-describe Malagasyprinus caeruleatus comb. n. and provide Malagasyprinus perrieri and Malagasyprinus diana with brief differential diagnoses. All taxon descriptions are accompanied with color habitat photographs, SEM micrographs and drawings of their male genitalia. A key to the species of Malagasyprinus is given. Sensory structures of the antenna of Malagasyprinus caeruleatus comb. n. are likewise depicted herein. The systematic position of the newly erected genus is discussed. A lectotype of Saprinus caeruleatus Lewis, 1905 is designated. PMID- 24146561 TI - Eremonidiopsis aggregata, gen. n., sp. n. from Cuba, the third West Indian Dioptinae (Lepidoptera, Notodontidae). AB - A new genus and species of Dioptinae (Lepidoptera, Noctuoidea, Notodontidae) is described from Cuba, this being the third taxon of the subfamily known from the West Indies. Eremonidiopsis aggregata, gen. n., sp. n., appears to be closely related to Eremonidia mirifica Rawlins & Miller from Hispaniola among members of the tribe Dioptini. Eremonidiopsis aggregata is known from two localities in the middle and western portions of the northeastern Cuban mountain range, Nipe-Sagua Baracoa. The species inhabits low elevations (300-400 m) covered by lowland rainforest and sclerophyll rainforest. The six known specimens, all males, were part of small swarms flying near the top of an unidentified tree during the day at both collecting sites. These localities are included within protected areas, the "Pico Cristal" National Park in the West and the "Alexander von Humbolt" National Park in the East. PMID- 24146562 TI - Three new species of Oreophryne (Anura, Microhylidae) from Papua New Guinea. AB - I describe three new species of the diverse microhylid frog genus Oreophryne from Papua New Guinea. Two of these occur in two isolated mountain ranges along the northern coast of Papua New Guinea; the third is from Rossel Island in the very southeasternmost part of the country. All three are the first Oreophryne known from these areas to have a cartilaginous connection between the procoracoid and scapula, a feature usually seen in species far to the west or from the central cordillera of New Guinea. Each of the new species also differs from the many other Papuan Oreophryne in a variety of other morphological, color-pattern, and call features. Advertisement-call data for Oreophryne species from the north coast region suggest that they represent only two of the several call types seen in regions further south, consistent with the relatively recent derivation of these northern regions as accreted island-arc systems. The distinctively different, whinnying, call type of the new species from Rossel Island occurs among other Oreophryne from southeastern Papua New Guinea but has been unreported elsewhere, raising the possibility that it may characterize a clade endemic to that region. PMID- 24146563 TI - Shallow water marine gammaridean amphipods of Pulau Tioman, Malaysia, with the description of a new species. AB - Eleven taxa including one new species of gammaridean amphipods are reported from the waters of Pulau Tioman. The presence of Tethygeneia sunda sp. n. represents the first record of the genus from the South China Sea. Additional material of Ampelisca brevicornis (Costa, 1853); Cymadusa vadosa Imbach, 1967; Paradexamine setigera Hirayama, 1984; Ericthonius pugnax (Dana, 1853); Leucothoe furina (Savigny, 1816); Microlysias xenokeras (Stebbing, 1918); Monoculodes muwoni Jo, 1990 are identified from the South China Sea, supporting previous records by Lowry (2000), Huang (1994), Imbach (1967), Margulis (1968) and Nagata (1959). Three additional species, Gitanopsis pusilla K.H. Barnard, 1916, Liljeborgia japonica Nagata, 1965b and Latigammaropsis atlantica (Stebbing, 1888), whilst previously reported from the neighbouring waters, comprise new records for the South China Sea. PMID- 24146564 TI - Stenosternus Karsch, a possible link between Neotropical and Afrotropical Orphninae (Coleoptera, Scarabaeidae). AB - The monotypical orphnine genus Stenosternus Karsch is known from a single specimen of Stenosternus costatus collected on the Sao Tome island (Gulf of Guinea). The holotype of Stenosternus costatus Karsch is re-examined and its characters are discussed and illustrated. Although the genus was implicitly placed by Paulian (1984) in the Old World tribe Orphnini Erichson, re-examination of the holotype of Stenosternus costatus shows that it has characters similar to those of the members of the New World tribe Aegidiini Paulian. Placement of Stenosternus in the Aegidiini is supported by the metepisternum widened posteriorly (forming posterior metepisternal lock for closed elytra) and a keel separating basal and anterolateral parts of propleurae. Relationships of Stenosternus with other orphnine taxa and possible ways of origin of Sao Tomean orphnine fauna are discussed. PMID- 24146565 TI - First record of Clausidium (Copepoda, Clausidiidae) from Brazil: a new species associated with ghost shrimps Neocallichirus grandimana (Gibbes, 1850) (Decapoda, Callianassidae). AB - A new clausidiid copepod was found living in galleries of ghost shrimps Neocallichirus grandimana (Gibbes, 1850) in Natal, Brazil. The new species resembles to Clausidium senegalense Humes, 1957 and Clausidium vancouverense (Haddon, 1912) in the armature of P2-P5 of the female, and shares with Clausidium senegalense similar segmentation and armature of the antenna and maxilla of the female. Nevertheless, it can be easily distinguished from its congeners by the unique characteristics observed in the antenna, maxilliped and first leg of males, as well as by the anal somite, maxillule and maxilliped of the females. This new species extends the group distribution to the Southwest Atlantic and represents the first record of the genus in Brazil. A key for the identification of the species based on females of Clausidium is provided. PMID- 24146566 TI - An introduction to Iranian Collembola (Hexapoda): an update to the species list. AB - The Collembola fauna of Iran is little known and no comprehensive examination of this group of Hexapoda is available for this region. The only notable work on Collembola was carried out by Cox (1982). Recently, studies on the Collembola fauna have started in several regions. In this paper, publications by different researchers are documented and the species that have been found in different regions of Iran until January 2013 are listed. At present, 112 species, belonging to 18 families and 57 genera are known from Iran. PMID- 24146567 TI - Three new species of Omalodes (Omalodes) (Histeridae, Histerinae) from South America. AB - Three new species of Omalodes are described from South America, including descriptions of male and female genitalia. Omalodes (Omalodes) mazuri sp. n. is described from Peru and Bolivia; Omalodes (Omalodes) punctulatus sp. n. from Brazil, and Omalodes (Omalodes) rivus sp. n. from Bolivia and Brazil. This is the first paper with detailed information on the male and female genitalia of the genus, showing a great degree of variation to characterize different species. All three new species can be easily distinguished from other known Omalodes and from each other, on the basis of morphology and male genitalia pattern. PMID- 24146568 TI - The enigmatic Otway odd-clawed spider (Progradungula otwayensis Milledge, 1997, Gradungulidae, Araneae): Natural history, first description of the female and micro-computed tomography of the male palpal organ. AB - The recently described cribellate gradungulid Progradungula otwayensis Milledge, 1997 is endemic to the Great Otway National Park (Victoria, Australia) and known from only one male and a few juvenile specimens. In a recent survey we recorded 47 specimens at several localities across the western part of the Great Otway National park. Our field data suggest that this species is dependant on the microclimate in the hollows of old myrtle beech trees since other hollow trees were very much less inhabited. Furthermore, we describe the female for the first time and study the male palpal organ by using X-ray microtomography. The female genitalia are characterized by eight spermathecae which are grouped in two quartets. The spermophor resembles the general organization of gradungulids, but is similar to Kaiya Gray, 1987 by a convoluted appearance within the embolus. The muscle 30 is located in the cymbium and resembles the organization of other non entelegyne Araneomorphae. PMID- 24146569 TI - First records and description of metallic red females of Euglossa (Alloglossura) gorgonensis Cheesman, with notes on color variation within the species (Hymenoptera, Apidae). AB - Metallic coloration is one of the signatures of orchid bees of the genus Euglossa, with some species showing variation associated with their geographic range. Euglossa (Alloglossura) gorgonensis Cheesman exhibits color variation, ranging from mainly green specimens in the southern extreme of its range (Pacific slope of Colombia), to noticeably reddish specimens in parts of the northern known limits of its range (Pacific slope of southern Costa Rica). Here we present the first description of females from Costa Rica belonging to the reddish extreme of the color variation. PMID- 24146570 TI - Diversity of Porifera in the Mediterranean coralligenous accretions, with description of a new species. AB - Temperate reefs, built by multilayers of encrusting algae accumulated during hundreds to thousands of years, represent one of the most important habitats of the Mediterranean Sea. These bioconstructions are known as "coralligenous" and their spatial complexity allows the formation of heterogeneous microhabitats offering opportunities for a large number of small cryptic species hardly ever considered. Although sponges are the dominant animal taxon in the coralligenous rims with both insinuating and perforating species, this group is until now poorly known. Aim of this work is to develop a reference baseline about the taxonomic knowledge of sponges and, considering their high level of phenotypic plasticity, evaluate the importance of coralligenous accretions as a pocket for biodiversity conservation. Collecting samples in four sites along the coast of the Ligurian Sea, we recorded 133 sponge taxa (115 of them identified at species level and 18 at genus level). One species, Eurypon gracilis is new for science; three species, Paratimea oxeata, Clathria (Microciona) haplotoxa and Eurypon denisae are new records for the Italian sponge fauna, eleven species are new findings for the Ligurian Sea. Moreover, seventeen species have not been recorded before from the coralligenous community. The obtained data, together with an extensive review of the existing literature, increase to 273 the number of sponge species associated with the coralligenous concretions and confirm that this habitat is an extraordinary reservoir of biodiversity still largely unexplored, not only taxonomically, but also as to peculiar adaptations and life histories. PMID- 24146571 TI - A peculiar new species of the genus Tetrasticta Kraatz (Coleoptera, Staphylinidae, Aleocharinae) from Peninsular Malaysia. AB - Tetrasticta gnatha sp. n., collected under the bark of a rotten fallen tree in Peninsular Malaysia, is described. A habitus photograph, line drawings of diagnostic characters, and a diagnosis are provided. The new species is readily distinguished from all known congeners by having long mandibles, and long, curved maxillary palpi. PMID- 24146572 TI - First record of leaf-hole shelters used and modified by leaf beetles (Coleoptera, Chrysomelidae), with descriptions of two new Orthaltica Crotch species from southern India. AB - Behavioural novelties observed in adult leaf beetles of two new Orthaltica Crotch species include: 1) the use of low cost leaf-hole shelters, either in pre-formed holes produced by larger beetles that fed on the same leaf, or artificially created holes as part of an experiment; and 2) the use of faeces to partition the hole. Two new southern Indian species of the genus Orthaltica are described and illustrated: Orthaltica syzygium and Orthaltica terminalia. Host plants are identified for both species. A key to the Indian species of Orthaltica is provided. PMID- 24146573 TI - Updated Italian checklist of Soldier Flies (Diptera, Stratiomyidae). AB - An updated checklist for Stratiomyidae of Italy is presented. Previous knowledge and information are put together in a comprehensive way, integrated also with results obtained by sampling with Malaise traps in some of the test areas of the LIFE+ project ManFor C.BD. At the time of writing, with 91 known species, the Italian fauna of Stratiomyidae is the richest in Europe. Neopachygaster meromelas (Dufour, 1841) and Zabrachia minutissima (Zetterstedt, 1838) are new to the Italian fauna. A comprehensive key to the European species of Chorisops Rondani, 1856 is given. PMID- 24146574 TI - Taxonomic studies on the ant genus Cerapachys Smith (Hymenoptera, Formicidae) from India. AB - The Indianspeciesof the ant genus Cerapachys Smith are keyed. Twelve species are recognized of which 6 are described as new. The species are: Cerapachys aitkenii Forel, Cerapachys alii sp. n., Cerapachys anokha sp. n., Cerapachys besucheti Brown, Cerapachys biroi Forel, Cerapachys indicus Brown, Cerapachys longitarsus (Mayr), Cerapachys nayana sp. n., Cerapachys schoedli sp. n., Cerapachys seema sp. n., Cerapachys sulcinodis Emery and Cerapachys wighti sp. n. Geographic distribution and group affinities of the new species are discussed. A revised key to the Indian species is provided. The rare ergatoid queens of Cerapachys nayana, Cerapachys schoedli and Cerapachys seema are reported. Formed in response to selective pressures these ergatoid queens have a significant role in dispersal strategies and contribute much to our understanding of the biology of these ants. PMID- 24146575 TI - Three new species of cockroach genus Symploce Hebard, 1916 (Blattodea, Ectobiidae, Blattellinae) with redescriptions of two known species based on types from Mainland China. AB - Three new species of Symploce Hebard from China are described: Symploce sphaerica sp. n., Symploce paramarginata sp. n. and Symploce evidens sp. n. Two known species are redescribed and illustrated based on types. A key is given to identify all species of Symploce from mainland China. PMID- 24146576 TI - On the occurrence of the fireworm Eurythoe complanata complex (Annelida, Amphinomidae) in the Mediterranean Sea with an updated revision of the alien Mediterranean amphinomids. AB - The presence of two species within the Eurythoe complanata complex in the Mediterranean Sea is reported, as well as their geographical distributions. One species, Eurythoe laevisetis, occurs in the eastern and central Mediterranean, likely constituting the first historical introduction to the Mediterranean Sea and the other, Eurythoe complanata, in both eastern and Levantine basins. Brief notes on their taxonomy are also provided and their potential pathways for introduction to the Mediterranean are discussed. A simplified key to the Mediterranean amphinomid genera and species of Eurythoe and Linopherus is presented plus an updated revision of the alien amphinomid species reported previously from the Mediterranean Sea. A total of five exotic species have been included; information on their location, habitat, date of introduction and other relevant features is also provided. PMID- 24146577 TI - A new species of Numbakullidae Gutu & Heard, 2002 (Tanaidacea, Peracarida, Crustacea) from the Great Barrier Reef, Australia. AB - A new species of Numbakulla Gutu & Heard, 2002 (Tanaidacea) is described from Heron Island (southern Great Barrier Reef, Queensland) collected during the Census of Coral Reefs Ecosystem (CReefs) program. The new species is the third member of the family and can be recognized by the combination of characters as: length/width ratio of the body, which is 6:7, pereonite 4 longer than the rest, the presence of eyes, a blunt rostrum, antenna article 2 elongated, cheliped carpus with row of inner setae, pereopod 6 carpus with spines, pleopod endopod with denticles. PMID- 24146578 TI - Morphology, bioacoustics, and ecology of Tibicen neomexicensis sp. n., a new species of cicada from the Sacramento Mountains in New Mexico, U.S.A. (Hemiptera, Cicadidae, Tibicen). AB - Tibicen neomexicensis sp. n., a new species of cicada found in the Sacramento Mountains of southcentral New Mexico, is described. Tibicen neomexicensis closely resembles Tibicen chiricahua Davis morphologically, but males of the two species have highly distinct calling songs that differ in phrasal structure, amplitude burst rates, and pulse structure. Unlike Tibicen chiricahua, male Tibicen neomexicensis use conspicuous dorso-ventral abdominal movements to modulate the amplitude and frequency of their calls. Tibicen neomexicensis is also smaller on average than Tibicen chiricahua, and differences in the color patterns of the wing venation identify these two species morphologically. Both species are dependent on pinyon-juniper woodlands and have similar emergence phenologies. These species appear to be allopatric, with Tibicen chiricahua found west of the Rio Grande in New Mexico, Arizona, and Mexico, and Tibicen neomexicensis so far known only from New Mexico, east of the Rio Grande. Tibicen chiricahua and Tibicen neomexicensis males share a common genitalic structure that separates them from all other species of Tibicen, and the possible evolutionary and biogeographic history of these likely sister species is also discussed. PMID- 24146579 TI - Two new species of Chaco Tullgren from the Atlantic coast of Uruguay (Araneae, Mygalomorphae, Nemesiidae). AB - We describe two new species of the nemesiid spider genus Chaco from Rocha Province, Uruguay. These new species are diagnosed based on genital morphology, male tibial apophysis spination, and burrow entrance. We test cospecificity of one species, Chaco costai,via laboratory mating experiments. The new species are diagnosed and illustrated and habitat characteristics, and capture behavior are described. We conduct a cladistic analysis based on a previously published morphological character matrix that now includes the newly described species. PMID- 24146580 TI - Redescription and molecular characterization of Placobdella cryptobranchii (Johnson & Klemm, 1977) (Glossiphoniidae, Hirudinida). AB - Placobdella cryptobranchii (Johnson & Klemm, 1977) was originally described from specimens collected from Ozark Hellbenders (Cryptobranchus alleganiensis bishopi) from the North Fork of the White River in Missouri, U.S.A. Leeches collected during August 2009 to August 2011 from five localities in Missouri (including the type locality) facilitated a redescription and molecular characterization of Placobdella cryptobranchii. Placobdella cryptobranchii has a rusty, reddish-brown dorsum with 2 lateral rows of unpigmented papillae, two unpigmented nuchal bands, unpigmented patches, and pair of four pre-anal papillae. Molecular comparison of CO-I sequence data from Placobdella cryptobranchii revealed a 93-94% similarity to Placobdella ornata and 10-17% difference among other species of Placobdella. PMID- 24146581 TI - Two new species in the family Axinellidae (Porifera, Demospongiae) from British Columbia and adjacent waters. AB - Two new species of Demospongiae are described for British Columbia and adjacent waters in the family Axinellidae, Auletta krautteri sp. n. and Dragmacidon kishinensis sp. n. They represent range extensions for both of these genera. Both are fairly commonly encountered, Auletta krautteri below diving depths (87 to at least 300 m) and Dragmacidon kishinensis in shallow water (intertidal to 30 m). We propose an amended genus diagnosis for Auletta to account for the variability among species in principal spicules that form the ascending tracts to be either oxeas, styles or strongyles rather than just oxeas. PMID- 24146582 TI - Hesperentomon yangi sp. n. from Jiangsu Province, Eastern China, with analyses of DNA barcodes (Protura, Acerentomata, Hesperentomidae). AB - Hesperentomon yangi sp. n. is described from eastern China. Its DNA barcodes are sequenced and compared to the similar species of the genus. Hesperentomon yangi sp. n. is characterized by 12 posterior setae on tergites II-VI, 8 posterior setae on sternites IV-VI (seta Pc absent), absence of seta sd4 on head, absence of seta P2a on tergite VII, 6 and 8 anterior setae on mesosternum and metasternum respectively, and few teeth on comb. It differs from Hesperentomon xiningense Bu & Yin, 2007 and Hesperentomon nanshanensis Bu & Yin, 2007 in the chaetotaxy of mesosternum and metanotum, maxillary gland, length and shape of some sensilla on foretarsus, as well as the body porotaxy. The genetic divergences of DNA barcodes sequences between Hesperentomon yangi sp. n., Hesperentomon xiningense and Hesperentomon nanshanensis are 24.1% on average, which is distinctly higher than the divergences between individuals of the new species (0.5%). Molecular data provide a solid evidence of the new species identified by the morphological characters. PMID- 24146583 TI - A new species of Pseudodiaptomus (Crustacea, Copepoda, Calanoida, Pseudodiaptomidae) from the Prasae River Estuary, Gulf of Thailand. AB - A new species of the calanoid copepod genus Pseudodiaptomus was collected from the Prasae River Estuary, Rayong Province, on the eastern coast of the Gulf of Thailand. This species is definitely assigned to the lobus species group sensu Walter (1986a). The female of the new species differs from other congeners in the elongate genital double-somite with a blunt process ventrally and the second urosomite about 2.54 times as long as wide. The male is also easily distinguished from other congeners by the structure of the right fifth leg. The present new species is a euryhaline species and occurred in brackish waters with salinity ranging from 0.7 to 23.3. Its breeding season may be from June to October, as indicated by the presence of egg-sacs. PMID- 24146584 TI - Two new species of Entomobryidae (Collembola) of Taibai Mountain from China. AB - Taibai Mountain is the highest peak of Qinling Mountain Ridge, a climate and geographical demarcation of the southern and northern China. Collembolan species of family Entomobryidae are reported from this region for the first time in this paper. Two new species, Homidia taibaiensis sp. n. and Sinella triseta sp. n. of Entomobryinae are described. Illustrations and differences with similar species are provided. PMID- 24146585 TI - Taxonomic revision of the genus Carasobarbus Karaman, 1971 (Actinopterygii, Cyprinidae). AB - Representatives of the fish genus Carasobarbus Karaman, 1971 (Actinopterygii: Cyprinidae) from the Middle East and North Africa were previously placed in 14 different genus-group taxa (Barbellion, Barbus, Barynotus, Capoeta, Carasobarbus, Cyclocheilichthys, Kosswigobarbus, Labeobarbus, Luciobarbus, Pseudotor, Puntius, Systomus, Tor and Varicorhinus). The generic assignment of several species changed frequently, necessitating a re-evaluation of their taxonomic status. In this study, the genus Carasobarbus is revised based on comparative morphological examinations of about 1300 preserved specimens from collections of several museums and freshly collected material. The species Carasobarbus apoensis, Carasobarbus canis, Carasobarbus chantrei, Carasobarbus exulatus, Carasobarbus fritschii, Carasobarbus harterti, Carasobarbus kosswigi, Carasobarbus luteus and Carasobarbus sublimus form a monophyletic group that shares the following combination of characters: medium-sized barbels with a smooth last unbranched dorsal-fin ray, nine or 10 branched dorsal-fin rays and six branched anal fin rays; scales large, shield-shaped, with many parallel radii; the lateral line containing 25 to 39 scales; the pharyngeal teeth hooked, 2.3.5-5.3.2 or 2.3.4 4.3.2; one or two pairs of barbels. The species are described in detail, their taxonomic status is re-evaluated and an identification key is provided. A lectotype of Systomus luteus Heckel, 1843 is designated. Carasobarbus Karaman, 1971, Kosswigobarbus Karaman, 1971, and Pseudotor Karaman, 1971 are subjective synonyms, and acting as First Reviser we gave precedence to the name Carasobarbus. PMID- 24146586 TI - New species of oribatid mites of the genera Lepidozetes and Scutozetes (Acari, Oribatida, Tegoribatidae) from Nepal. AB - Two new species of oribatid mites, Lepidozetes acutirostrum sp. n. and Scutozetes clavatosensillus sp. n., are described from Nepal. The genera Lepidozetes and Scutozetes are recorded for the first time for the Oriental region. The identification keys to the known species of these genera are provided. PMID- 24146587 TI - Revision of the Australian ceratocanthinae (coleoptera, scarabaeoidea, hybosoridae). AB - The Australian fauna of Ceratocanthinae (Coleoptera, Scarabaeoidea, Hybosoridae) is revised. Two genera are present, both shared with Asia, with a total of seven species, all localized in eastern Queensland and all except one, endemic to Australia. Cyphopisthes is comprised of three species, two of them new (Cyphopisthes yorkensis sp. n. and Cyphopisthes monteithi sp. n., the latter, together with Cyphopisthes descarpentriesi Paulian, 1977 displaying an unusual ecology, with occurrence in the southern Queensland dry rainforest/scrub habitats), and Pterorthochaetes is comprised of four species, two of them new (Pterorthochaetes danielsi sp. n. and Pterorthochaeres storeyi sp. n.). Descriptions, distribution, ecological remarks and a key to species are provided. PMID- 24146588 TI - Lethrus (Lethrus) schneideri sp. n. (Coleoptera, Geotrupidae) from Greece. AB - Lethrus (Lethrus) schneideri Kral & Hillert, sp. n. from Thrace, Greece, is described. The new species is morphologically most similar and probably closely related to Lethrus (Lethrus) apterus (Laxmann, 1770) and Lethrus (Lethrus) ares Kral, Rejsek & Schneider, 2001. Diagnostic characters (shape of mandibles, ventral mandible processes, pronotum and parameres) are illustrated. Character matrix for separation of males of the Lethrus species closely related to Lethrus schneideri Kral & Hillert, sp. n. and geographic ranges for all species studied are mapped. PMID- 24146589 TI - Taxonomic and nomenclatural notes on the genera Themus Motschulsky and Lycocerus Gorham (Coleoptera, Cantharidae). AB - THE FOLLOWING TAXONOMIC OR NOMENCLATURAL CHANGES ARE PROPOSED: Themus (s.str.) regalis (Gorham, 1889), nom. rest.; Themus (s.str.) scutulatus Wittmer, 1983 = Themus (s.str.) hmong Kazantsev, 2007, syn. n.; Themus (Telephorops) coelestis (Gorham, 1889) = Themus violetipennis Wang & Yang, 1992, syn. n.; Themus (Telephorops) uniformis Wittmer, 1983, stat. n. = Themus (Telephorops) cribripennis Wittmer, 1983, syn. n.; Themus (Haplothemus) licenti Pic, 1938, stat. rev., resurrected from synonymy with Themus coriaceipennis (Fairmaire, 1889); Lycocerus aenescens (Fairmaire, 1889) = Lycocerus tcheonanus (Pic, 1922), syn. n.; Lycocerus asperipennis (Fairmaire, 1891) = Lycocerus wangi (Svihla, 2004), syn. n.; Lycocerus borneoensis nom. n. for Athemellus atricolor (Wittmer, 1972); Lycocerus bilineatus (Wittmer, 1995) = Lycocerus amplus (Wittmer, 1995), syn. n.; Lycocerus fairmairei nom. n. et stat. rev. for Athemus dimidiaticrus (Fairmaire, 1889), originally in Telephorus, resurrected from synonymy with Lycocerus orientalis (Gorham, 1889); Lycocerus confossicollis (Fairmaire, 1891), comb. n. hereby transferred from Cantharis = Lycocerus multiimpressus (Wittmer, 1997), syn. n.; Lycocerus inopaciceps (Pic, 1926) = Athemus (Athemellus) bimaculicollis (Svihla, 2005), syn. n.; Lycocerus nigratus nom. n. for Lycocerus nigricolor (Wittmer, 1972), originally in Podabrinus; Lycocerus plebejus (Kiesenwetter, 1874) = Lycocerus brunneonotaticeps (Pic, 1922), syn. n. = Cantharis rufonotaticeps Pic, 1921 syn. n.; Lycocerus swampingatus (Pic, 1916), comb. n., hereby transferred from Cantharis. The neotypes of Themus violetipennis Wang & Yang, 1992 and Athemus (s.str.) maculithorax Wang & Yang, 1992 are designated respectively. PMID- 24146590 TI - A taxonomic revision of Tyrini of the Oriental region. V. Revision of the genus Lasinus Sharp, 1874 (Coleoptera, Staphylinidae, Pselaphinae). AB - The genus Lasinus Sharp, 1874 of the Pselaphodes complex of genera (Pselaphitae: Tyrini: Tyrina) is revised. The three so far known species, Lasinus mandarinus Raffray, 1890, Lasinus monticola Sawada, 1961 and Lasinus spinosus Sharp, 1874 are redescribed. Eight new species, Lasinus sinicus sp. n. from China, Lasinus mikado sp. n., Lasinus yamamotoi sp. n., Lasinus inexpectatus sp. n., Lasinus yakushimanus sp. n., Lasinus amamianus sp. n., Lasinus saoriae sp. n., and Lasinus okinawanus sp. n. from Japan, are described. And all species are illustrated. Lectotypes are designated for Lasinus mandarinus and Lasinus spinosus. An identification key to species of the genus Lasinus is provided. PMID- 24146591 TI - Pristomyrmex tsujii sp. n. and P. mandibularis Mann (Hymenoptera, Formicidae) from Fiji. AB - Pristomyrmex tsujii sp. n., an endemic species of the Fiji islands, is described from the worker, ergatoid queen, alate queen and male castes. The alate queen and male castes of Pristomyrmex mandibularis Mann are also described for the first time. The ergatoid queens for both species appear to be morphologically intermediate between the worker and alate queen castes. Pristomyrmex tsujii is readily distinguished from Pristomyrmex mandibularis by the lack of well developed propodeal spines. Although both species occur across the Fijian archipelago, they are rarely encountered and workers are most often collected from sifted litter. The descriptions are illustrated with specimen photographs, line drawings and a distribution map. PMID- 24146592 TI - A reclassification of the millipede superfamily Trichopolydesmoidea, with descriptions of two new species from the Aegean region (Diplopoda, Polydesmida). AB - TWO NEW SPECIES ARE DESCRIBED FROM CAVES IN SEVERAL GREEK ISLANDS IN THE AEGEAN SEA: Galliocookia gracilis sp. n., a presumed troglobite from Rhodes, Dodecanese Islands, and Sphaeroparia simplex sp. n., likely a troglophile from Kithnos, Cyclades, and Chios, Eastern Sporades. These genera are assigned to the family Trichopolydesmidae Verhoeff, 1910. Because Sphaeroparia Attems, 1909, an Afrotropical genus, nicely bridges the gap, both morphologically and geographically, between the Euro-Mediterranean Trichopolydesmidae and the much more diverse, pantropical Fuhrmannodesmidae Brolemann, 1916, the latter family is considered as a new junior subjective synonym of the former, syn. n. Thus expanded, the family Trichopolydesmidae is rediagnosed and its position within the superfamily Trichopolydesmoidea refined. Because the families Mastigonodesmidae Attems, 1914, Macrosternodesmidae Brolemann, 1916 and Nearctodesmidae Chamberlin & Hoffman, 1950 are also formally synonymized with Trichopolydesmidae, syn. n., the Trichopolydesmoidea currently contains only two families, Trichopolydesmidae and Opisotretidae Hoffman, 1980. PMID- 24146593 TI - Genus Microsternus Lewis (1887) from China, with description of a new genus Neosternus from Asia (Coleoptera, Erotylidae, Dacnini). AB - This work treats species of the genus Microsternus Lewis, 1887 from Asia and North America. A new genus is described: Neosternus (type species Microsternus higonius Lewis, 1887). A new species is described: Microsternus pengzhongi. A new synonym is provided: Microsternus tricolor taiwanicus Nakane (=Microsternus tricolor Lewis). Three species previously placed in Microsternus Lewis, 1887 are transferred to Neosternus resulting in the following three new combinations: Neosternus higonius (Lewis, 1887), Neosternus taiwanus (Chujo, 1976), and Neosternus hisamatsui (Nakane, 1981). PMID- 24146594 TI - Redescription of the enigmatic genus Genuotermes Emerson (Isoptera, Termitidae, Termitinae). AB - The imago and soldier castes of the Neotropical Termitinae species Genuotermes spinifer Emerson are redescribed. The gut anatomy of the worker is described in detail for the first time, and morphological variations in the soldier are noted and illustrated. The known geographical distribution of Genuotermes spinifer is greatly expanded. PMID- 24146595 TI - The genus Erechthias Meyrick of Ascension Island, including discovery of a new brachypterous species (Lepidoptera, Tineidae). AB - One previously named and two new species of the tineid genus Erechthias Meyrick are described and illustrated from the small, remote, mid-Atlantic Ascension Island. With these additions the Lepidoptera fauna of Ascension now totals 38 known species. Little is known regarding the biology of the two new species of Erechthias, and none of the species has been reared from larvae from Ascension. Erechthias minuscula (Walsingham) is a widespread, largely pantropical species first described from the West Indies. Larvae of Erechthias minuscula are known to be scavengers on a wide variety of dead plant material. Erechthias ascensionae,new species, is one of two species of Erechthias now known to be endemic to the island. The other endemic species, Erechthias grayi, new species, is further remarkable in having wing reduction occurring in both sexes. It is one of the few species of Lepidoptera known where this extreme of brachyptery involving both sexes has evolved. The larvae of Erechthias grayi are believed to be lichenivorous, and larval cases suspected to represent this species are illustrated. PMID- 24146596 TI - Harvestmen of the BOS Arthropod Collection of the University of Oviedo (Spain) (Arachnida, Opiliones). AB - There are significant gaps in accessible knowledge about the distribution and phenology of Iberian harvestmen (Arachnida: Opiliones). Harvestmen accessible datasets in Iberian Peninsula are unknown, an only two other datasets available in GBIF are composed exclusively of harvestmen records. Moreover, only a few harvestmen data from Iberian Peninsula are available in GBIF network (or in any network that allows public retrieval or use these data). This paper describes the data associated with the Opiliones kept in the BOS Arthropod Collection of the University of Oviedo, Spain (hosted in the Department of Biologia de Organismos y Sistemas), filling some of those gaps. The specimens were mainly collected from the northern third of the Iberian Peninsula. The earliest specimen deposited in the collection, dating back to the early 20(th) century, belongs to the P. Franganillo Collection. The dataset documents the collection of 16,455 specimens, preserved in 3,772 vials. Approximately 38% of the specimens belong to the family Sclerosomatidae, and 26% to Phalangidae; six other families with fewer specimens are also included. Data quality control was incorporated at several steps of digitisation process to facilitate reuse and improve accuracy. The complete dataset is also provided in Darwin Core Archive format, allowing public retrieval, use and combination with other biological, biodiversity of geographical variables datasets. PMID- 24146597 TI - Ross Sea Mollusca from the Latitudinal Gradient Program: R/V Italica 2004 Rauschert dredge samples. AB - Information regarding the molluscs in this dataset is based on the Rauschert dredge samples collected during the Latitudinal Gradient Program (LGP) on board the R/V "Italica" in the Ross Sea (Antarctica) in the austral summer 2004. A total of 18 epibenthic dredge deployments/samplings have been performed at four different locations at depths ranging from 84 to 515m by using a Rauschert dredge with a mesh size of 500MUm. In total 8,359 specimens have been collected belonging to a total of 161 species. Considering this dataset in terms of occurrences, it corresponds to 505 discrete distributional records (incidence data). Of these, in order of abundance, 5,965 specimens were Gastropoda (accounting for 113 species), 1,323 were Bivalvia (accounting for 36 species), 949 were Aplacophora (accounting for 7 species), 74 specimens were Scaphopoda (3 species), 38 were Monoplacophora (1 species) and, finally, 10 specimens were Polyplacophora (1 species). This data set represents the first large-scale survey of benthic micro-molluscs for the area and provides important information about the distribution of several species, which have been seldom or never recorded before in the Ross Sea. All vouchers are permanently stored at the Italian National Antarctic Museum (MNA), Section of Genoa, enabling future comparison and crosschecking. This material is also currently under study, from a molecular point of view, by the barcoding project "BAMBi" (PNRA 2010/A1.10). PMID- 24146598 TI - Diversity and distribution of reptiles in Romania. AB - The reptile fauna of Romania comprises 23 species, out of which 12 species reach here the limit of their geographic range. We compiled and updated a national database of the reptile species occurrences from a variety of sources including our own field surveys, personal communication from specialists, museum collections and the scientific literature. The occurrence records were georeferenced and stored in a geodatabase for additional analysis of their spatial patterns. The spatial analysis revealed a biased sampling effort concentrated in various protected areas, and deficient in the vast agricultural areas of the southern part of Romania. The patterns of species richness showed a higher number of species in the warmer and drier regions, and a relatively low number of species in the rest of the country. Our database provides a starting point for further analyses, and represents a reliable tool for drafting conservation plans. PMID- 24146599 TI - Sea anemones (Cnidaria, Anthozoa, Actiniaria) from coral reefs in the southern Gulf of Mexico. AB - Seven sea anemone species from coral reefs in the southern Gulf of Mexico are taxonomically diagnosed and images from living specimens including external and internal features, and cnidae are provided. Furthermore, the known distribution ranges from another 10 species are extended. No species records of sea anemones have been previously published in the primary scientific literature for coral reefs in the southern Gulf of Mexico and thus, this study represents the first inventory for the local actiniarian fauna. PMID- 24146600 TI - Bambusananus cuihuashanensis, a new bamboo-feeding leafhopper species of Athysanini (Hemiptera, Cicadellidae, Deltocephalinae) from Shaanxi, China. AB - Bambusananus cuihuashanensis sp. n. (Hemiptera: Cicadellidae: Deltocephalinae: Athysanini), a new bamboo-feeding leafhopper species, is described and illustrated from Shaanxi Province of China. Checklist, host plants and distribution for each species of Bambusananus is given along with a key to all known species. PMID- 24146601 TI - dPeak: high resolution identification of transcription factor binding sites from PET and SET ChIP-Seq data. AB - Chromatin immunoprecipitation followed by high throughput sequencing (ChIP-Seq) has been successfully used for genome-wide profiling of transcription factor binding sites, histone modifications, and nucleosome occupancy in many model organisms and humans. Because the compact genomes of prokaryotes harbor many binding sites separated by only few base pairs, applications of ChIP-Seq in this domain have not reached their full potential. Applications in prokaryotic genomes are further hampered by the fact that well studied data analysis methods for ChIP Seq do not result in a resolution required for deciphering the locations of nearby binding events. We generated single-end tag (SET) and paired-end tag (PET) ChIP-Seq data for sigma70 factor in Escherichia coli (E. coli). Direct comparison of these datasets revealed that although PET assay enables higher resolution identification of binding events, standard ChIP-Seq analysis methods are not equipped to utilize PET-specific features of the data. To address this problem, we developed dPeak as a high resolution binding site identification (deconvolution) algorithm. dPeak implements a probabilistic model that accurately describes ChIP-Seq data generation process for both the SET and PET assays. For SET data, dPeak outperforms or performs comparably to the state-of-the-art high resolution ChIP-Seq peak deconvolution algorithms such as PICS, GPS, and GEM. When coupled with PET data, dPeak significantly outperforms SET-based analysis with any of the current state-of-the-art methods. Experimental validations of a subset of dPeak predictions from sigma70 PET ChIP-Seq data indicate that dPeak can estimate locations of binding events with as high as 2 to 21 bp resolution. Applications of dPeak to sigma70 ChIP-Seq data in E. coli under aerobic and anaerobic conditions reveal closely located promoters that are differentially occupied and further illustrate the importance of high resolution analysis of ChIP-Seq data. PMID- 24146602 TI - Integrated module and gene-specific regulatory inference implicates upstream signaling networks. AB - Regulatory networks that control gene expression are important in diverse biological contexts including stress response and development. Each gene's regulatory program is determined by module-level regulation (e.g. co-regulation via the same signaling system), as well as gene-specific determinants that can fine-tune expression. We present a novel approach, Modular regulatory network learning with per gene information (MERLIN), that infers regulatory programs for individual genes while probabilistically constraining these programs to reveal module-level organization of regulatory networks. Using edge-, regulator- and module-based comparisons of simulated networks of known ground truth, we find MERLIN reconstructs regulatory programs of individual genes as well or better than existing approaches of network reconstruction, while additionally identifying modular organization of the regulatory networks. We use MERLIN to dissect global transcriptional behavior in two biological contexts: yeast stress response and human embryonic stem cell differentiation. Regulatory modules inferred by MERLIN capture co-regulatory relationships between signaling proteins and downstream transcription factors thereby revealing the upstream signaling systems controlling transcriptional responses. The inferred networks are enriched for regulators with genetic or physical interactions, supporting the inference, and identify modules of functionally related genes bound by the same transcriptional regulators. Our method combines the strengths of per-gene and per module methods to reveal new insights into transcriptional regulation in stress and development. PMID- 24146603 TI - Reassessing Google Flu Trends data for detection of seasonal and pandemic influenza: a comparative epidemiological study at three geographic scales. AB - The goal of influenza-like illness (ILI) surveillance is to determine the timing, location and magnitude of outbreaks by monitoring the frequency and progression of clinical case incidence. Advances in computational and information technology have allowed for automated collection of higher volumes of electronic data and more timely analyses than previously possible. Novel surveillance systems, including those based on internet search query data like Google Flu Trends (GFT), are being used as surrogates for clinically-based reporting of influenza-like illness (ILI). We investigated the reliability of GFT during the last decade (2003 to 2013), and compared weekly public health surveillance with search query data to characterize the timing and intensity of seasonal and pandemic influenza at the national (United States), regional (Mid-Atlantic) and local (New York City) levels. We identified substantial flaws in the original and updated GFT models at all three geographic scales, including completely missing the first wave of the 2009 influenza A/H1N1 pandemic, and greatly overestimating the intensity of the A/H3N2 epidemic during the 2012/2013 season. These results were obtained for both the original (2008) and the updated (2009) GFT algorithms. The performance of both models was problematic, perhaps because of changes in internet search behavior and differences in the seasonality, geographical heterogeneity and age-distribution of the epidemics between the periods of GFT model-fitting and prospective use. We conclude that GFT data may not provide reliable surveillance for seasonal or pandemic influenza and should be interpreted with caution until the algorithm can be improved and evaluated. Current internet search query data are no substitute for timely local clinical and laboratory surveillance, or national surveillance based on local data collection. New generation surveillance systems such as GFT should incorporate the use of near-real time electronic health data and computational methods for continued model-fitting and ongoing evaluation and improvement. PMID- 24146604 TI - Prediction of the P. falciparum target space relevant to malaria drug discovery. AB - Malaria is still one of the most devastating infectious diseases, affecting hundreds of millions of patients worldwide. Even though there are several established drugs in clinical use for malaria treatment, there is an urgent need for new drugs acting through novel mechanisms of action due to the rapid development of resistance. Resistance emerges when the parasite manages to mutate the sequence of the drug targets to the extent that the protein can still perform its function in the parasite but can no longer be inhibited by the drug, which then becomes almost ineffective. The design of a new generation of malaria drugs targeting multiple essential proteins would make it more difficult for the parasite to develop full resistance without lethally disrupting some of its vital functions. The challenge is then to identify which set of Plasmodium falciparum proteins, among the millions of possible combinations, can be targeted at the same time by a given chemotype. To do that, we predicted first the targets of the close to 20,000 antimalarial hits identified recently in three independent phenotypic screening campaigns. All targets predicted were then projected onto the genome of P. falciparum using orthologous relationships. A total of 226 P. falciparum proteins were predicted to be hit by at least one compound, of which 39 were found to be significantly enriched by the presence and degree of affinity of phenotypically active compounds. The analysis of the chemically compatible target combinations containing at least one of those 39 targets led to the identification of a priority set of 64 multi-target profiles that can set the ground for a new generation of more robust malaria drugs. PMID- 24146605 TI - Analysis of initial cell spreading using mechanistic contact formulations for a deformable cell model. AB - Adhesion governs to a large extent the mechanical interaction between a cell and its microenvironment. As initial cell spreading is purely adhesion driven, understanding this phenomenon leads to profound insight in both cell adhesion and cell-substrate interaction. It has been found that across a wide variety of cell types, initial spreading behavior universally follows the same power laws. The simplest cell type providing this scaling of the radius of the spreading area with time are modified red blood cells (RBCs), whose elastic responses are well characterized. Using a mechanistic description of the contact interaction between a cell and its substrate in combination with a deformable RBC model, we are now able to investigate in detail the mechanisms behind this universal power law. The presented model suggests that the initial slope of the spreading curve with time results from a purely geometrical effect facilitated mainly by dissipation upon contact. Later on, the spreading rate decreases due to increasing tension and dissipation in the cell's cortex as the cell spreads more and more. To reproduce this observed initial spreading, no irreversible deformations are required. Since the model created in this effort is extensible to more complex cell types and can cope with arbitrarily shaped, smooth mechanical microenvironments of the cells, it can be useful for a wide range of investigations where forces at the cell boundary play a decisive role. PMID- 24146606 TI - Dynamic change of global and local information processing in propofol-induced loss and recovery of consciousness. AB - Whether unique to humans or not, consciousness is a central aspect of our experience of the world. The neural fingerprint of this experience, however, remains one of the least understood aspects of the human brain. In this paper we employ graph-theoretic measures and support vector machine classification to assess, in 12 healthy volunteers, the dynamic reconfiguration of functional connectivity during wakefulness, propofol-induced sedation and loss of consciousness, and the recovery of wakefulness. Our main findings, based on resting-state fMRI, are three-fold. First, we find that propofol-induced anesthesia does not bear differently on long-range versus short-range connections. Second, our multi-stage design dissociated an initial phase of thalamo-cortical and cortico-cortical hyperconnectivity, present during sedation, from a phase of cortico-cortical hypoconnectivity, apparent during loss of consciousness. Finally, we show that while clustering is increased during loss of consciousness, as recently suggested, it also remains significantly elevated during wakefulness recovery. Conversely, the characteristic path length of brain networks (i.e., the average functional distance between any two regions of the brain) appears significantly increased only during loss of consciousness, marking a decrease of global information-processing efficiency uniquely associated with unconsciousness. These findings suggest that propofol-induced loss of consciousness is mainly tied to cortico-cortical and not thalamo-cortical mechanisms, and that decreased efficiency of information flow is the main feature differentiating the conscious from the unconscious brain. PMID- 24146607 TI - Model of fission yeast cell shape driven by membrane-bound growth factors and the cytoskeleton. AB - Fission yeast serves as a model for how cellular polarization machinery consisting of signaling molecules and the actin and microtubule cytoskeleton regulates cell shape. In this work, we develop mathematical models to investigate how these cells maintain a tubular shape of approximately constant diameter. Many studies identify active Cdc42, found in a cap at the inner membrane of growing cell tips, as an important regulator of local cell wall remodeling, likely through control of exocyst tethering and the targeting of other polarity enhancing structures. First, we show that a computational model with Cdc42 dependent local cell wall remodeling under turgor pressure predicts a relationship between spatial extent of growth signal and cell diameter that is in agreement with prior experiments. Second, we model the consequences of feedback between cell shape and distribution of Cdc42 growth signal at cell tips. We show that stability of cell diameter over successive cell divisions places restrictions on their mutual dependence. We argue that simple models where the spatial extent of the tip growth signal relies solely on geometrical alignment of confined microtubules might lead to unstable width regulation. Third, we study a computational model that combines a growth signal distributed over a characteristic length scale (as, for example, by a reaction-diffusion mechanism) with an axis-sensing microtubules system that places landmarks at positions where microtubule tips touch the cortex. A two-dimensional implementation of this model leads to stable cell diameter for a wide range of parameters. Changes to the parameters of this model reproduce straight, bent, and bulged cell shapes, and we discuss how this model is consistent with other observed cell shapes in mutants. Our work provides an initial quantitative framework for understanding the regulation of cell shape in fission yeast, and a scaffold for understanding this process on a more molecular level in the future. PMID- 24146608 TI - On the role of aggregation prone regions in protein evolution, stability, and enzymatic catalysis: insights from diverse analyses. AB - The various roles that aggregation prone regions (APRs) are capable of playing in proteins are investigated here via comprehensive analyses of multiple non redundant datasets containing randomly generated amino acid sequences, monomeric proteins, intrinsically disordered proteins (IDPs) and catalytic residues. Results from this study indicate that the aggregation propensities of monomeric protein sequences have been minimized compared to random sequences with uniform and natural amino acid compositions, as observed by a lower average aggregation propensity and fewer APRs that are shorter in length and more often punctuated by gate-keeper residues. However, evidence for evolutionary selective pressure to disrupt these sequence regions among homologous proteins is inconsistent. APRs are less conserved than average sequence identity among closely related homologues (>=80% sequence identity with a parent) but APRs are more conserved than average sequence identity among homologues that have at least 50% sequence identity with a parent. Structural analyses of APRs indicate that APRs are three times more likely to contain ordered versus disordered residues and that APRs frequently contribute more towards stabilizing proteins than equal length segments from the same protein. Catalytic residues and APRs were also found to be in structural contact significantly more often than expected by random chance. Our findings suggest that proteins have evolved by optimizing their risk of aggregation for cellular environments by both minimizing aggregation prone regions and by conserving those that are important for folding and function. In many cases, these sequence optimizations are insufficient to develop recombinant proteins into commercial products. Rational design strategies aimed at improving protein solubility for biotechnological purposes should carefully evaluate the contributions made by candidate APRs, targeted for disruption, towards protein structure and activity. PMID- 24146609 TI - Reconstructing the genomic content of microbiome taxa through shotgun metagenomic deconvolution. AB - Metagenomics has transformed our understanding of the microbial world, allowing researchers to bypass the need to isolate and culture individual taxa and to directly characterize both the taxonomic and gene compositions of environmental samples. However, associating the genes found in a metagenomic sample with the specific taxa of origin remains a critical challenge. Existing binning methods, based on nucleotide composition or alignment to reference genomes allow only a coarse-grained classification and rely heavily on the availability of sequenced genomes from closely related taxa. Here, we introduce a novel computational framework, integrating variation in gene abundances across multiple samples with taxonomic abundance data to deconvolve metagenomic samples into taxa-specific gene profiles and to reconstruct the genomic content of community members. This assembly-free method is not bounded by various factors limiting previously described methods of metagenomic binning or metagenomic assembly and represents a fundamentally different approach to metagenomic-based genome reconstruction. An implementation of this framework is available at http://elbo.gs.washington.edu/software.html. We first describe the mathematical foundations of our framework and discuss considerations for implementing its various components. We demonstrate the ability of this framework to accurately deconvolve a set of metagenomic samples and to recover the gene content of individual taxa using synthetic metagenomic samples. We specifically characterize determinants of prediction accuracy and examine the impact of annotation errors on the reconstructed genomes. We finally apply metagenomic deconvolution to samples from the Human Microbiome Project, successfully reconstructing genus level genomic content of various microbial genera, based solely on variation in gene count. These reconstructed genera are shown to correctly capture genus specific properties. With the accumulation of metagenomic data, this deconvolution framework provides an essential tool for characterizing microbial taxa never before seen, laying the foundation for addressing fundamental questions concerning the taxa comprising diverse microbial communities. PMID- 24146610 TI - Dynamic rendering of the heterogeneous cell response to anticancer treatments. AB - The antiproliferative response to anticancer treatment is the result of concurrent responses in all cell cycle phases, extending over several cell generations, whose complexity is not captured by current methods. In the proposed experimental/computational approach, the contemporary use of time-lapse live cell microscopy and flow cytometric data supported the computer rendering of the proliferative process through the cell cycle and subsequent generations during/after treatment. The effects of treatments were modelled with modules describing the functional activity of the main pathways causing arrest, repair and cell death in each phase. A framework modelling environment was created, enabling us to apply different types of modules in each phase and test models at the complexity level justified by the available data. We challenged the method with time-course measures taken in parallel with flow cytometry and time-lapse live cell microscopy in X-ray-treated human ovarian cancer cells, spanning a wide range of doses. The most suitable model of the treatment, including the dose response of each effect, was progressively built, combining modules with a rational strategy and fitting simultaneously all data of different doses and platforms. The final model gave for the first time the complete rendering in silico of the cycling process following X-ray exposure, providing separate and quantitative measures of the dose-dependence of G1, S and G2M checkpoint activities in subsequent generations, reconciling known effects of ionizing radiations and new insights in a unique scenario. PMID- 24146611 TI - Streptococcus mutans, Candida albicans, and the human mouth: a sticky situation. PMID- 24146612 TI - RNA biology in fungal phytopathogens. PMID- 24146613 TI - Alternative roles for CRISPR/Cas systems in bacterial pathogenesis. PMID- 24146614 TI - A structural basis for BRD2/4-mediated host chromatin interaction and oligomer assembly of Kaposi sarcoma-associated herpesvirus and murine gammaherpesvirus LANA proteins. AB - Kaposi sarcoma-associated herpesvirus (KSHV) establishes a lifelong latent infection and causes several malignancies in humans. Murine herpesvirus 68 (MHV 68) is a related gamma2-herpesvirus frequently used as a model to study the biology of gamma-herpesviruses in vivo. The KSHV latency-associated nuclear antigen (kLANA) and the MHV68 mLANA (orf73) protein are required for latent viral replication and persistence. Latent episomal KSHV genomes and kLANA form nuclear microdomains, termed 'LANA speckles', which also contain cellular chromatin proteins, including BRD2 and BRD4, members of the BRD/BET family of chromatin modulators. We solved the X-ray crystal structure of the C-terminal DNA binding domains (CTD) of kLANA and MHV-68 mLANA. While these structures share the overall fold with the EBNA1 protein of Epstein-Barr virus, they differ substantially in their surface characteristics. Opposite to the DNA binding site, both kLANA and mLANA CTD contain a characteristic lysine-rich positively charged surface patch, which appears to be a unique feature of gamma2-herpesviral LANA proteins. Importantly, kLANA and mLANA CTD dimers undergo higher order oligomerization. Using NMR spectroscopy we identified a specific binding site for the ET domains of BRD2/4 on kLANA. Functional studies employing multiple kLANA mutants indicate that the oligomerization of native kLANA CTD dimers, the characteristic basic patch and the ET binding site on the kLANA surface are required for the formation of kLANA 'nuclear speckles' and latent replication. Similarly, the basic patch on mLANA contributes to the establishment of MHV-68 latency in spleen cells in vivo. In summary, our data provide a structural basis for the formation of higher order LANA oligomers, which is required for nuclear speckle formation, latent replication and viral persistence. PMID- 24146615 TI - The DAF-16/FOXO transcription factor functions as a regulator of epidermal innate immunity. AB - The Caenorhabditis elegans DAF-16 transcription factor is critical for diverse biological processes, particularly longevity and stress resistance. Disruption of the DAF-2 signaling cascade promotes DAF-16 activation, and confers resistance to killing by pathogenic bacteria, such as Pseudomonas aeruginosa, Staphylococcus aureus, and Enterococcus faecalis. However, daf-16 mutants exhibit similar sensitivity to these bacteria as wild-type animals, suggesting that DAF-16 is not normally activated by these bacterial pathogens. In this report, we demonstrate that DAF-16 can be directly activated by fungal infection and wounding in wild type animals, which is independent of the DAF-2 pathway. Fungal infection and wounding initiate the Galphaq signaling cascade, leading to Ca(2+) release. Ca(2+) mediates the activation of BLI-3, a dual-oxidase, resulting in the production of reactive oxygen species (ROS). ROS then activate DAF-16 through a Ste20-like kinase-1/CST-1. Our results indicate that DAF-16 in the epidermis is required for survival after fungal infection and wounding. Thus, the EGL-30 Ca(2+)-BLI-3-CST-1-DAF-16 signaling represents a previously unknown pathway to regulate epidermal damage response. PMID- 24146616 TI - Toxoplasma gondii relies on both host and parasite isoprenoids and can be rendered sensitive to atorvastatin. AB - Intracellular pathogens have complex metabolic interactions with their host cells to ensure a steady supply of energy and anabolic building blocks for rapid growth. Here we use the obligate intracellular parasite Toxoplasma gondii to probe this interaction for isoprenoids, abundant lipidic compounds essential to many cellular processes including signaling, trafficking, energy metabolism, and protein translation. Synthesis of precursors for isoprenoids in Apicomplexa occurs in the apicoplast and is essential. To synthesize longer isoprenoids from these precursors, T. gondii expresses a bifunctional farnesyl diphosphate/geranylgeranyl diphosphate synthase (TgFPPS). In this work we construct and characterize T. gondii null mutants for this enzyme. Surprisingly, these mutants have only a mild growth phenotype and an isoprenoid composition similar to wild type parasites. However, when extracellular, the loss of the enzyme becomes phenotypically apparent. This strongly suggests that intracellular parasite salvage FPP and/or geranylgeranyl diphosphate (GGPP) from the host. We test this hypothesis using inhibitors of host cell isoprenoid synthesis. Mammals use the mevalonate pathway, which is susceptible to statins. We document strong synergy between statin treatment and pharmacological or genetic interference with the parasite isoprenoid pathway. Mice can be cured with atorvastatin (Lipitor) from a lethal infection with the TgFPPs mutant. We propose a double-hit strategy combining inhibitors of host and parasite pathways as a novel therapeutic approach against Apicomplexan parasites. PMID- 24146617 TI - Molecular basis for oligomeric-DNA binding and episome maintenance by KSHV LANA. AB - LANA is the KSHV-encoded terminal repeat binding protein essential for viral replication and episome maintenance during latency. We have determined the X-ray crystal structure of LANA C-terminal DNA binding domain (LANADBD) to reveal its capacity to form a decameric ring with an exterior DNA binding surface. The dimeric core is structurally similar to EBV EBNA1 with an N-terminal arm that regulates DNA binding and is required for replication function. The oligomeric interface between LANA dimers is dispensable for single site DNA binding, but is required for cooperative DNA binding, replication function, and episome maintenance. We also identify a basic patch opposite of the DNA binding surface that is responsible for the interaction with BRD proteins and contributes to episome maintenance function. The structural features of LANADBD suggest a novel mechanism of episome maintenance through DNA-binding induced oligomeric assembly. PMID- 24146618 TI - Crystal structure of the gamma-2 herpesvirus LANA DNA binding domain identifies charged surface residues which impact viral latency. AB - Latency-associated nuclear antigen (LANA) mediates gamma2-herpesvirus genome persistence and regulates transcription. We describe the crystal structure of the murine gammaherpesvirus-68 LANA C-terminal domain at 2.2 A resolution. The structure reveals an alpha-beta fold that assembles as a dimer, reminiscent of Epstein-Barr virus EBNA1. A predicted DNA binding surface is present and opposite this interface is a positive electrostatic patch. Targeted DNA recognition substitutions eliminated DNA binding, while certain charged patch mutations reduced bromodomain protein, BRD4, binding. Virus containing LANA abolished for DNA binding was incapable of viable latent infection in mice. Virus with mutations at the charged patch periphery exhibited substantial deficiency in expansion of latent infection, while central region substitutions had little effect. This deficiency was independent of BRD4. These results elucidate the LANA DNA binding domain structure and reveal a unique charged region that exerts a critical role in viral latent infection, likely acting through a host cell protein(s). PMID- 24146619 TI - Fungal iron availability during deep seated candidiasis is defined by a complex interplay involving systemic and local events. AB - Nutritional immunity--the withholding of nutrients by the host--has long been recognised as an important factor that shapes bacterial-host interactions. However, the dynamics of nutrient availability within local host niches during fungal infection are poorly defined. We have combined laser ablation-inductively coupled plasma mass spectrometry (LA-ICP MS), MALDI imaging and immunohistochemistry with microtranscriptomics to examine iron homeostasis in the host and pathogen in the murine model of systemic candidiasis. Dramatic changes in the renal iron landscape occur during disease progression. The infection perturbs global iron homeostasis in the host leading to iron accumulation in the renal medulla. Paradoxically, this is accompanied by nutritional immunity in the renal cortex as iron exclusion zones emerge locally around fungal lesions. These exclusion zones correlate with immune infiltrates and haem oxygenase 1-expressing host cells. This local nutritional immunity decreases iron availability, leading to a switch in iron acquisition mechanisms within mature fungal lesions, as revealed by laser capture microdissection and qRT-PCR analyses. Therefore, a complex interplay of systemic and local events influences iron homeostasis and pathogen-host dynamics during disease progression. PMID- 24146620 TI - Ebola virus RNA editing depends on the primary editing site sequence and an upstream secondary structure. AB - Ebolavirus (EBOV), the causative agent of a severe hemorrhagic fever and a biosafety level 4 pathogen, increases its genome coding capacity by producing multiple transcripts encoding for structural and nonstructural glycoproteins from a single gene. This is achieved through RNA editing, during which non-template adenosine residues are incorporated into the EBOV mRNAs at an editing site encoding for 7 adenosine residues. However, the mechanism of EBOV RNA editing is currently not understood. In this study, we report for the first time that minigenomes containing the glycoprotein gene editing site can undergo RNA editing, thereby eliminating the requirement for a biosafety level 4 laboratory to study EBOV RNA editing. Using a newly developed dual-reporter minigenome, we have characterized the mechanism of EBOV RNA editing, and have identified cis acting sequences that are required for editing, located between 9 nt upstream and 9 nt downstream of the editing site. Moreover, we show that a secondary structure in the upstream cis-acting sequence plays an important role in RNA editing. EBOV RNA editing is glycoprotein gene-specific, as a stretch encoding for 7 adenosine residues located in the viral polymerase gene did not serve as an editing site, most likely due to an absence of the necessary cis-acting sequences. Finally, the EBOV protein VP30 was identified as a trans-acting factor for RNA editing, constituting a novel function for this protein. Overall, our results provide novel insights into the RNA editing mechanism of EBOV, further understanding of which might result in novel intervention strategies against this viral pathogen. PMID- 24146621 TI - The cycle of EBV infection explains persistence, the sizes of the infected cell populations and which come under CTL regulation. AB - Previous analysis of Epstein-Barr virus (EBV) persistent infection has involved biological and immunological studies to identify and quantify infected cell populations and the immune response to them. This led to a biological model whereby EBV infects and activates naive B-cells, which then transit through the germinal center to become resting memory B-cells where the virus resides quiescently. Occasionally the virus reactivates from these memory cells to produce infectious virions. Some of this virus infects new naive B-cells, completing a cycle of infection. What has been lacking is an understanding of the dynamic interactions between these components and how their regulation by the immune response produces the observed pattern of viral persistence. We have recently provided a mathematical analysis of a pathogen which, like EBV, has a cycle of infected stages. In this paper we have developed biologically credible values for all of the parameters governing this model and show that with these values, it successfully recapitulates persistent EBV infection with remarkable accuracy. This includes correctly predicting the observed patterns of cytotoxic T cell regulation (which and by how much each infected population is regulated by the immune response) and the size of the infected germinal center and memory populations. Furthermore, we find that viral quiescence in the memory compartment dictates the pattern of regulation but is not required for persistence; it is the cycle of infection that explains persistence and provides the stability that allows EBV to persist at extremely low levels. This shifts the focus away from a single infected stage, the memory B-cell, to the whole cycle of infection. We conclude that the mathematical description of the biological model of EBV persistence provides a sound basis for quantitative analysis of viral persistence and provides testable predictions about the nature of EBV-associated diseases and how to curb or prevent them. PMID- 24146622 TI - Independent pathways can transduce the life-cycle differentiation signal in Trypanosoma brucei. AB - African trypanosomes cause disease in humans and livestock, generating significant health and welfare problems throughout sub-Saharan Africa. When ingested in a tsetse fly bloodmeal, trypanosomes must detect their new environment and initiate the developmental responses that ensure transmission. The best-established environmental signal is citrate/cis aconitate (CCA), this being transmitted through a protein phosphorylation cascade involving two phosphatases: one that inhibits differentiation (TbPTP1) and one that activates differentiation (TbPIP39). Other cues have been also proposed (mild acid, trypsin exposure, glucose depletion) but their physiological relevance and relationship to TbPTP1/TbPIP39 signalling is unknown. Here we demonstrate that mild acid and CCA operate through TbPIP39 phosphorylation, whereas trypsin attack of the parasite surface uses an alternative pathway that is dispensable in tsetse flies. Surprisingly, glucose depletion is not an important signal. Mechanistic analysis through biophysical methods suggests that citrate promotes differentiation by causing TbPTP1 and TbPIP39 to interact. PMID- 24146623 TI - The structure of classical swine fever virus N(pro): a novel cysteine Autoprotease and zinc-binding protein involved in subversion of type I interferon induction. AB - Pestiviruses express their genome as a single polypeptide that is subsequently cleaved into individual proteins by host- and virus-encoded proteases. The pestivirus N-terminal protease (N(pro)) is a cysteine autoprotease that cleaves between its own C-terminus and the N-terminus of the core protein. Due to its unique sequence and catalytic site, it forms its own cysteine protease family C53. After self-cleavage, N(pro) is no longer active as a protease. The released N(pro) suppresses the induction of the host's type-I interferon-alpha/beta (IFN alpha/beta) response. N(pro) binds interferon regulatory factor-3 (IRF3), the key transcriptional activator of IFN-alpha/beta genes, and promotes degradation of IRF3 by the proteasome, thus preventing induction of the IFN-alpha/beta response to pestivirus infection. Here we report the crystal structures of pestivirus N(pro). N(pro) is structurally distinct from other known cysteine proteases and has a novel "clam shell" fold consisting of a protease domain and a zinc-binding domain. The unique fold of N(pro) allows auto-catalysis at its C-terminus and subsequently conceals the cleavage site in the active site of the protease. Although many viruses interfere with type I IFN induction by targeting the IRF3 pathway, little information is available regarding structure or mechanism of action of viral proteins that interact with IRF3. The distribution of amino acids on the surface of N(pro) involved in targeting IRF3 for proteasomal degradation provides insight into the nature of N(pro)'s interaction with IRF3. The structures thus establish the mechanism of auto-catalysis and subsequent auto inhibition of trans-activity of N(pro), and its role in subversion of host immune response. PMID- 24146624 TI - Specific tandem repeats are sufficient for paramutation-induced trans generational silencing. AB - Paramutation is a well-studied epigenetic phenomenon in which trans communication between two different alleles leads to meiotically heritable transcriptional silencing of one of the alleles. Paramutation at the b1 locus involves RNA mediated transcriptional silencing and requires specific tandem repeats that generate siRNAs. This study addressed three important questions: 1) are the tandem repeats sufficient for paramutation, 2) do they need to be in an allelic position to mediate paramutation, and 3) is there an association between the ability to mediate paramutation and repeat DNA methylation levels? Paramutation was achieved using multiple transgenes containing the b1 tandem repeats, including events with tandem repeats of only one half of the repeat unit (413 bp), demonstrating that these sequences are sufficient for paramutation and an allelic position is not required for the repeats to communicate. Furthermore, the transgenic tandem repeats increased the expression of a reporter gene in maize, demonstrating the repeats contain transcriptional regulatory sequences. Transgene mediated paramutation required the mediator of paramutation1 gene, which is necessary for endogenous paramutation, suggesting endogenous and transgene mediated paramutation both require an RNA-mediated transcriptional silencing pathway. While all tested repeat transgenes produced small interfering RNAs (siRNAs), not all transgenes induced paramutation suggesting that, as with endogenous alleles, siRNA production is not sufficient for paramutation. The repeat transgene-induced silencing was less efficiently transmitted than silencing induced by the repeats of endogenous b1 alleles, which is always 100% efficient. The variability in the strength of the repeat transgene-induced silencing enabled testing whether the extent of DNA methylation within the repeats correlated with differences in efficiency of paramutation. Transgene induced paramutation does not require extensive DNA methylation within the transgene. However, increased DNA methylation within the endogenous b1 repeats after transgene-induced paramutation was associated with stronger silencing of the endogenous allele. PMID- 24146625 TI - The bacterial response regulator ArcA uses a diverse binding site architecture to regulate carbon oxidation globally. AB - Despite the importance of maintaining redox homeostasis for cellular viability, how cells control redox balance globally is poorly understood. Here we provide new mechanistic insight into how the balance between reduced and oxidized electron carriers is regulated at the level of gene expression by mapping the regulon of the response regulator ArcA from Escherichia coli, which responds to the quinone/quinol redox couple via its membrane-bound sensor kinase, ArcB. Our genome-wide analysis reveals that ArcA reprograms metabolism under anaerobic conditions such that carbon oxidation pathways that recycle redox carriers via respiration are transcriptionally repressed by ArcA. We propose that this strategy favors use of catabolic pathways that recycle redox carriers via fermentation akin to lactate production in mammalian cells. Unexpectedly, bioinformatic analysis of the sequences bound by ArcA in ChIP-seq revealed that most ArcA binding sites contain additional direct repeat elements beyond the two required for binding an ArcA dimer. DNase I footprinting assays suggest that non canonical arrangements of cis-regulatory modules dictate both the length and concentration-sensitive occupancy of DNA sites. We propose that this plasticity in ArcA binding site architecture provides both an efficient means of encoding binding sites for ArcA, sigma(70)-RNAP and perhaps other transcription factors within the same narrow sequence space and an effective mechanism for global control of carbon metabolism to maintain redox homeostasis. PMID- 24146626 TI - Genome-wide and cell-specific epigenetic analysis challenges the role of polycomb in Drosophila spermatogenesis. AB - The Drosophila spermatogenesis cell differentiation pathway involves the activation of a large set of genes in primary spermatocytes. Most of these genes are activated by testis-specific TATA-binding protein associated factors (tTAFs). In the current model for the activation mechanism, Polycomb plays a key role silencing these genes in the germline precursors, and tTAF-dependent activation in primary spermatocytes involves the displacement of Polycomb from gene promoters. We investigated the genome-wide binding of Polycomb in wild type and tTAF mutant testes. According to the model we expected to see a clear enhancement in Polycomb binding at tTAF-dependent spermatogenesis genes in tTAF mutant testes. However, we find little evidence for such an enhancement in tTAF mutant testes compared to wild type. To avoid problems arising from cellular heterogeneity in whole testis analysis, we further tested the model by analysing Polycomb binding in purified germline precursors, representing cells before tTAF dependent gene activation. Although we find Polycomb associated with its canonical targets, we find little or no evidence of Polycomb at spermatogenesis genes. The lack of Polycomb at tTAF-dependent spermatogenesis genes in precursor cells argues against a model where Polycomb displacement is the mechanism of spermatogenesis gene activation. PMID- 24146627 TI - A novel intra-U1 snRNP cross-regulation mechanism: alternative splicing switch links U1C and U1-70K expression. AB - The U1 small nuclear ribonucleoprotein (snRNP)-specific U1C protein participates in 5' splice site recognition and regulation of pre-mRNA splicing. Based on an RNA-Seq analysis in HeLa cells after U1C knockdown, we found a conserved, intra U1 snRNP cross-regulation that links U1C and U1-70K expression through alternative splicing and U1 snRNP assembly. To investigate the underlying regulatory mechanism, we combined mutational minigene analysis, in vivo splice site blocking by antisense morpholinos, and in vitro binding experiments. Alternative splicing of U1-70K pre-mRNA creates the normal (exons 7-8) and a non productive mRNA isoform, whose balance is determined by U1C protein levels. The non-productive isoform is generated through a U1C-dependent alternative 3' splice site, which requires an adjacent cluster of regulatory 5' splice sites and binding of intact U1 snRNPs. As a result of nonsense-mediated decay (NMD) of the non-productive isoform, U1-70K mRNA and protein levels are down-regulated, and U1C incorporation into the U1 snRNP is impaired. U1-70K/U1C-deficient particles are assembled, shifting the alternative splicing balance back towards productive U1-70K splicing, and restoring assembly of intact U1 snRNPs. Taken together, we established a novel feedback regulation that controls U1-70K/U1C homeostasis and ensures correct U1 snRNP assembly and function. PMID- 24146628 TI - The transacting factor CBF-A/Hnrnpab binds to the A2RE/RTS element of protamine 2 mRNA and contributes to its translational regulation during mouse spermatogenesis. AB - During spermatogenesis, mRNA localization and translation are believed to be regulated in a stage-specific manner. We report here that the Protamine2 (Prm2) mRNA transits through chromatoid bodies of round spermatids and localizes to cytosol of elongating spermatids for translation. The transacting factor CBF-A, also termed Hnrnpab, contributes to temporal regulation of Prm2 translation. We found that CBF-A co-localizes with the Prm2 mRNA during spermatogenesis, directly binding to the A2RE/RTS element in the 3' UTR. Although both p37 and p42 CBF-A isoforms interacted with RTS, they associated with translationally repressed and de-repressed Prm2 mRNA, respectively. Only p42 was found to interact with the 5'cap complex, and to co-sediment with the Prm2 mRNA in polysomes. In CBF-A knockout mice, expression of protamine 2 (PRM2) was reduced and the Prm2 mRNA was prematurely translated in a subset of elongating spermatids. Moreover, a high percentage of sperm from the CBF-A knockout mouse showed abnormal DNA morphology. We suggest that CBF-A plays an important role in spermatogenesis by regulating stage-specific translation of testicular mRNAs. PMID- 24146629 TI - De novo ORFs in Drosophila are important to organismal fitness and evolved rapidly from previously non-coding sequences. AB - How non-coding DNA gives rise to new protein-coding genes (de novo genes) is not well understood. Recent work has revealed the origins and functions of a few de novo genes, but common principles governing the evolution or biological roles of these genes are unknown. To better define these principles, we performed a parallel analysis of the evolution and function of six putatively protein-coding de novo genes described in Drosophila melanogaster. Reconstruction of the transcriptional history of de novo genes shows that two de novo genes emerged from novel long non-coding RNAs that arose at least 5 MY prior to evolution of an open reading frame. In contrast, four other de novo genes evolved a translated open reading frame and transcription within the same evolutionary interval suggesting that nascent open reading frames (proto-ORFs), while not required, can contribute to the emergence of a new de novo gene. However, none of the genes arose from proto-ORFs that existed long before expression evolved. Sequence and structural evolution of de novo genes was rapid compared to nearby genes and the structural complexity of de novo genes steadily increases over evolutionary time. Despite the fact that these genes are transcribed at a higher level in males than females, and are most strongly expressed in testes, RNAi experiments show that most of these genes are essential in both sexes during metamorphosis. This lethality suggests that protein coding de novo genes in Drosophila quickly become functionally important. PMID- 24146630 TI - A minimal nitrogen fixation gene cluster from Paenibacillus sp. WLY78 enables expression of active nitrogenase in Escherichia coli. AB - Most biological nitrogen fixation is catalyzed by molybdenum-dependent nitrogenase, an enzyme complex comprising two component proteins that contains three different metalloclusters. Diazotrophs contain a common core of nitrogen fixation nif genes that encode the structural subunits of the enzyme and components required to synthesize the metalloclusters. However, the complement of nif genes required to enable diazotrophic growth varies significantly amongst nitrogen fixing bacteria and archaea. In this study, we identified a minimal nif gene cluster consisting of nine nif genes in the genome of Paenibacillus sp. WLY78, a gram-positive, facultative anaerobe isolated from the rhizosphere of bamboo. We demonstrate that the nif genes in this organism are organized as an operon comprising nifB, nifH, nifD, nifK, nifE, nifN, nifX, hesA and nifV and that the nif cluster is under the control of a sigma(70) (sigma(A))-dependent promoter located upstream of nifB. To investigate genetic requirements for diazotrophy, we transferred the Paenibacillus nif cluster to Escherichia coli. The minimal nif gene cluster enables synthesis of catalytically active nitrogenase in this host, when expressed either from the native nifB promoter or from the T7 promoter. Deletion analysis indicates that in addition to the core nif genes, hesA plays an important role in nitrogen fixation and is responsive to the availability of molybdenum. Whereas nif transcription in Paenibacillus is regulated in response to nitrogen availability and by the external oxygen concentration, transcription from the nifB promoter is constitutive in E. coli, indicating that negative regulation of nif transcription is bypassed in the heterologous host. This study demonstrates the potential for engineering nitrogen fixation in a non-nitrogen fixing organism with a minimum set of nine nif genes. PMID- 24146631 TI - Yeast Tdh3 (glyceraldehyde 3-phosphate dehydrogenase) is a Sir2-interacting factor that regulates transcriptional silencing and rDNA recombination. AB - Sir2 is an NAD(+)-dependent histone deacetylase required to mediate transcriptional silencing and suppress rDNA recombination in budding yeast. We previously identified Tdh3, a glyceraldehyde 3-phosphate dehydrogenase (GAPDH), as a high expression suppressor of the lethality caused by Sir2 overexpression in yeast cells. Here we show that Tdh3 interacts with Sir2, localizes to silent chromatin in a Sir2-dependent manner, and promotes normal silencing at the telomere and rDNA. Characterization of specific TDH3 alleles suggests that Tdh3's influence on silencing requires nuclear localization but does not correlate with its catalytic activity. Interestingly, a genetic assay suggests that Tdh3, an NAD(+)-binding protein, influences nuclear NAD(+) levels; we speculate that Tdh3 links nuclear Sir2 with NAD(+) from the cytoplasm. PMID- 24146632 TI - A KH-domain RNA-binding protein interacts with FIERY2/CTD phosphatase-like 1 and splicing factors and is important for pre-mRNA splicing in Arabidopsis. AB - Eukaryotic genomes encode hundreds of RNA-binding proteins, yet the functions of most of these proteins are unknown. In a genetic study of stress signal transduction in Arabidopsis, we identified a K homology (KH)-domain RNA-binding protein, HOS5 (High Osmotic Stress Gene Expression 5), as required for stress gene regulation and stress tolerance. HOS5 was found to interact with FIERY2/RNA polymerase II (RNAP II) carboxyl terminal domain (CTD) phosphatase-like 1 (FRY2/CPL1) both in vitro and in vivo. This interaction is mediated by the first double-stranded RNA-binding domain of FRY2/CPL1 and the KH domains of HOS5. Interestingly, both HOS5 and FRY2/CPL1 also interact with two novel serine arginine (SR)-rich splicing factors, RS40 and RS41, in nuclear speckles. Importantly, FRY2/CPL1 is required for the recruitment of HOS5. In fry2 mutants, HOS5 failed to be localized in nuclear speckles but was found mainly in the nucleoplasm. hos5 mutants were impaired in mRNA export and accumulated a significant amount of mRNA in the nuclei, particularly under salt stress conditions. Arabidopsis mutants of all these genes exhibit similar stress sensitive phenotypes. RNA-seq analyses of these mutants detected significant intron retention in many stress-related genes under salt stress but not under normal conditions. Our study not only identified several novel regulators of pre mRNA processing as important for plant stress response but also suggested that, in addition to RNAP II CTD that is a well-recognized platform for the recruitment of mRNA processing factors, FRY2/CPL1 may also recruit specific factors to regulate the co-transcriptional processing of certain transcripts to deal with environmental challenges. PMID- 24146633 TI - Eleven candidate susceptibility genes for common familial colorectal cancer. AB - Hereditary factors are presumed to play a role in one third of colorectal cancer (CRC) cases. However, in the majority of familial CRC cases the genetic basis of predisposition remains unexplained. This is particularly true for families with few affected individuals. To identify susceptibility genes for this common phenotype, we examined familial cases derived from a consecutive series of 1514 Finnish CRC patients. Ninety-six familial CRC patients with no previous diagnosis of a hereditary CRC syndrome were included in the analysis. Eighty-six patients had one affected first-degree relative, and ten patients had two or more. Exome sequencing was utilized to search for genes harboring putative loss-of-function variants, because such alterations are likely candidates for disease-causing mutations. Eleven genes with rare truncating variants in two or three familial CRC cases were identified: UACA, SFXN4, TWSG1, PSPH, NUDT7, ZNF490, PRSS37, CCDC18, PRADC1, MRPL3, and AKR1C4. Loss of heterozygosity was examined in all respective cancer samples, and was detected in seven occasions involving four of the candidate genes. In all seven occasions the wild-type allele was lost (P = 0.0078) providing additional evidence that these eleven genes are likely to include true culprits. The study provides a set of candidate predisposition genes which may explain a subset of common familial CRC. Additional genetic validation in other populations is required to provide firm evidence for causality, as well as to characterize the natural history of the respective phenotypes. PMID- 24146634 TI - A review of bacteria-animal lateral gene transfer may inform our understanding of diseases like cancer. AB - Lateral gene transfer (LGT) from bacteria to animals occurs more frequently than was appreciated prior to the advent of genome sequencing. In 2007, LGT from bacterial Wolbachia endosymbionts was detected in ~33% of the sequenced arthropod genomes using a bioinformatic approach. Today, Wolbachia/host LGT is thought to be widespread and many other cases of bacteria-animal LGT have been described. In insects, LGT may be more frequently associated with endosymbionts that colonize germ cells and germ stem cells, like Wolbachia endosymbionts. We speculate that LGT may occur from bacteria to a wide variety of eukaryotes, but only becomes vertically inherited when it occurs in germ cells. As such, LGT may happen routinely in somatic cells but never become inherited or fixed in the population. Lack of inheritance of such mutations greatly decreases our ability to detect them. In this review, we propose that such noninherited bacterial DNA integration into chromosomes in human somatic cells could induce mutations leading to cancer or autoimmune diseases in a manner analogous to mobile elements and viral integrations. PMID- 24146636 TI - The human nuclear poly(a)-binding protein promotes RNA hyperadenylation and decay. AB - Control of nuclear RNA stability is essential for proper gene expression, but the mechanisms governing RNA degradation in mammalian nuclei are poorly defined. In this study, we uncover a mammalian RNA decay pathway that depends on the nuclear poly(A)-binding protein (PABPN1), the poly(A) polymerases (PAPs), PAPalpha and PAPgamma, and the exosome subunits RRP6 and DIS3. Using a targeted knockdown approach and nuclear RNA reporters, we show that PABPN1 and PAPalpha, redundantly with PAPgamma, generate hyperadenylated decay substrates that are recognized by the exosome and degraded. Poly(A) tail extension appears to be necessary for decay, as cordycepin treatment or point mutations in the PAP-stimulating domain of PABPN1 leads to the accumulation of stable transcripts with shorter poly(A) tails than controls. Mechanistically, these data suggest that PABPN1-dependent promotion of PAP activity can stimulate nuclear RNA decay. Importantly, efficiently exported RNAs are unaffected by this decay pathway, supporting an mRNA quality control function for this pathway. Finally, analyses of both bulk poly(A) tails and specific endogenous transcripts reveals that a subset of nuclear RNAs are hyperadenylated in a PABPN1-dependent fashion, and this hyperadenylation can be either uncoupled or coupled with decay. Our results highlight a complex relationship between PABPN1, PAPalpha/gamma, and nuclear RNA decay, and we suggest that these activities may play broader roles in the regulation of human gene expression. PMID- 24146635 TI - Hsp70-Hsp40 chaperone complex functions in controlling polarized growth by repressing Hsf1-driven heat stress-associated transcription. AB - How the molecular mechanisms of stress response are integrated at the cellular level remains obscure. Here we show that the cellular polarity machinery in the fission yeast Schizosaccharomyces pombe undergoes dynamic adaptation to thermal stress resulting in a period of decreased Cdc42 activity and altered, monopolar growth. Cells where the heat stress-associated transcription was genetically upregulated exhibit similar growth patterning in the absence of temperature insults. We identify the Ssa2-Mas5/Hsp70-Hsp40 chaperone complex as repressor of the heat shock transcription factor Hsf1. Cells lacking this chaperone activity constitutively activate the heat-stress-associated transcriptional program. Interestingly, they also exhibit intermittent monopolar growth within a physiological temperature range and are unable to adapt to heat stress. We propose that by negatively regulating the heat stress-associated transcription, the Ssa2-Mas5 chaperone system could optimize cellular growth under different temperature regiments. PMID- 24146638 TI - Is the olfactory system of cartilaginous fishes a vomeronasal system? PMID- 24146639 TI - Smooth pursuit adaptation (SPA) exhibits features useful to compensate changes in the properties of the smooth pursuit eye movement system due to usage. AB - Smooth-pursuit adaptation (SPA) refers to the fact that pursuit gain in the early, still open-loop response phase of the pursuit eye movement can be adjusted based on experience. For instance, if the target moves initially at a constant velocity for ~100-200 ms and then steps to a higher velocity, subjects learn to up-regulate the pursuit gain associated with the initial target velocity (gain increase SPA) in order to reduce the retinal error resulting from the velocity step. Correspondingly, a step to a lower target velocity leads to a decrease in gain (gain-decrease SPA). In this study we demonstrate that the increase in peak eye velocity during gain-increase SPA is a consequence of expanding the duration of the eye acceleration profile while the decrease in peak velocity during gain decrease SPA results from reduced peak eye acceleration but unaltered duration. Furthermore, we show that carrying out stereotypical smooth pursuit eye movements elicited by constant velocity target ramps for several hundred trials (=test of pursuit resilience) leads to a clear drop in initial peak acceleration, a reflection of oculomotor and/or cognitive fatigue. However, this drop in acceleration gets compensated by an increase in the duration of the acceleration profile, thereby keeping initial pursuit gain constant. The compensatory expansion of the acceleration profile in the pursuit resilience experiment is reminiscent of the one leading to gain-increase SPA, suggesting that both processes tap one and the same neuronal mechanism warranting a precise acceleration-duration trade-off. Finally, we show that the ability to adjust acceleration duration during pursuit resilience depends on the integrity of the oculomotor vermis (OMV) as indicated by the complete loss of the duration adjustment following a surgical lesion of the OMV in one rhesus monkey we could study. PMID- 24146637 TI - Cytokines and the neurodevelopmental basis of mental illness. AB - Epidemiological studies suggest that prenatal exposure to different types of viral or bacterial infections may be associated with similar outcomes; i.e., an increased risk of mental illness disorders in the offspring. Infections arising from various causes have similar debilitating effects in later life, suggesting that the exact pathogen may not be the critical factor in determining the neurological and cognitive outcome in the offspring. Instead, it is thought that response of the innate immune system, specifically the increased production of inflammatory cytokines, may be the critical mediator in altering fetal brain development pre-disposing the offspring to mental illness disorders later in life. Inflammatory cytokines are essential for normal brain development. Factors such as the site of cytokine production, a change in balance between anti- and pro- inflammatory cytokines, placental transfer of cytokines, the effects of cytokines on glial cells, and the effects of glucocorticoids are important when evaluating the impact of maternal infection on fetal brain development. Although it is clear that cytokines are altered in the fetal brain following maternal infection, further evidence is required to determine if cytokines are the critical factor that alters the trajectory of brain development, subsequently leading to postnatal behavioral and neurological abnormalities. PMID- 24146640 TI - Empathy, motivation, and P300 BCI performance. AB - Motivation moderately influences brain-computer interface (BCI) performance in healthy subjects when monetary reward is used to manipulate extrinsic motivation. However, the motivation of severely paralyzed patients, who are potentially in need for BCI, could mainly be internal and thus, an intrinsic motivator may be more powerful. Also healthy subjects who participate in BCI studies could be internally motivated as they may wish to contribute to research and thus extrinsic motivation by monetary reward would be less important than the content of the study. In this respect, motivation could be defined as "motivation-to help." The aim of this study was to investigate, whether subjects with high motivation for helping and who are highly empathic would perform better with a BCI controlled by event-related potentials (P300-BCI). We included N = 20 healthy young participants naive to BCI and grouped them according to their motivation for participating in a BCI study in a low and highly motivated group. Motivation was further manipulated with interesting or boring presentations about BCI and the possibility to help patients. Motivation for helping did neither influence BCI performance nor the P300 amplitude. Post hoc, subjects were re-grouped according to their ability for perspective taking. We found significantly higher P300 amplitudes on parietal electrodes in participants with a low ability for perspective taking and therefore, lower empathy, as compared to participants with higher empathy. The lack of an effect of motivation on BCI performance contradicts previous findings and thus, requires further investigation. We speculate that subjects with higher empathy who are good perspective takers with regards to patients in potential need of BCI, may be more emotionally involved and therefore, less able to allocate attention on the BCI task at hand. PMID- 24146641 TI - Non-verbal emotion communication training induces specific changes in brain function and structure. AB - The perception of emotional cues from voice and face is essential for social interaction. However, this process is altered in various psychiatric conditions along with impaired social functioning. Emotion communication trainings have been demonstrated to improve social interaction in healthy individuals and to reduce emotional communication deficits in psychiatric patients. Here, we investigated the impact of a non-verbal emotion communication training (NECT) on cerebral activation and brain structure in a controlled and combined functional magnetic resonance imaging (fMRI) and voxel-based morphometry study. NECT-specific reductions in brain activity occurred in a distributed set of brain regions including face and voice processing regions as well as emotion processing- and motor-related regions presumably reflecting training-induced familiarization with the evaluation of face/voice stimuli. Training-induced changes in non-verbal emotion sensitivity at the behavioral level and the respective cerebral activation patterns were correlated in the face-selective cortical areas in the posterior superior temporal sulcus and fusiform gyrus for valence ratings and in the temporal pole, lateral prefrontal cortex and midbrain/thalamus for the response times. A NECT-induced increase in gray matter (GM) volume was observed in the fusiform face area. Thus, NECT induces both functional and structural plasticity in the face processing system as well as functional plasticity in the emotion perception and evaluation system. We propose that functional alterations are presumably related to changes in sensory tuning in the decoding of emotional expressions. Taken together, these findings highlight that the present experimental design may serve as a valuable tool to investigate the altered behavioral and neuronal processing of emotional cues in psychiatric disorders as well as the impact of therapeutic interventions on brain function and structure. PMID- 24146642 TI - Neuropsychology, social cognition and global functioning among bipolar, schizophrenic patients and healthy controls: preliminary data. AB - This study aimed to determine the extent of impairment in social and non-social cognitive domains in an ecological context comparing bipolar (BD), schizophrenic (SKZ) patients and healthy controls (HC). The sample was enrolled at the Department of Psychiatry of Policlinico Hospital, University of Milan; it includes stabilized SKZ patients (n = 30), euthymic bipolar patients (n = 18) and HC (n = 18). Patients and controls completed psychiatric assessment rating scales, the Brief Assessment of Cognition in Schizophrenia (BACS) and the Executive and Social Cognition Battery (ESCB) that contains both ecological tests of executive function and social cognition, in order to better detect cognitive deficits in patients with normal results in standard executive batteries. The three groups differed significantly for gender and substance abuse, however, the differences did not influence the results. BD patients showed less impairment on cognitive performance compared to SKZ patients, even in "ecological" tests that mimic real life scenarios. In particular, BD performed better than SKZ in verbal memory (p < 0.0038) and BACS symbol coding (p < 0.0043). Regarding the ESCB tests, in the Hotel task SKZ patients completed significantly less tasks (p < 0.001), showed a greater number of errors in Multiple Errands Test (MET-HV) (p < 0.0248) and a worse performance in Theory of Mind (ToM) tests (p < 0.001 for the Eyes test and Faux pas test). Both patients' groups performed significantly worse than HC. Finally, significant differences were found between the two groups in GAF scores, being greater among BD subjects (p < 0.001). GAF was correlated with BACS and ESCB scores showing the crucial role of cognitive and ecological performances in patients' global functioning. PMID- 24146643 TI - Avoidant symptoms in PTSD predict fear circuit activation during multimodal fear extinction. AB - Convergent evidence suggests that individuals with posttraumatic stress disorder (PTSD) exhibit exaggerated avoidance behaviors as well as abnormalities in Pavlonian fear conditioning. However, the link between the two features of this disorder is not well understood. In order to probe the brain basis of aberrant extinction learning in PTSD, we administered a multimodal classical fear conditioning/extinction paradigm that incorporated affectively relevant information from two sensory channels (visual and tactile) while participants underwent fMRI scanning. The sample consisted of fifteen OEF/OIF veterans with PTSD. In response to conditioned cues and contextual information, greater avoidance symptomatology was associated with greater activation in amygdala, hippocampus, vmPFC, dmPFC, and insula, during both fear acquisition and fear extinction. Heightened responses to previously conditioned stimuli in individuals with more severe PTSD could indicate a deficiency in safety learning, consistent with PTSD symptomatology. The close link between avoidance symptoms and fear circuit activation suggests that this symptom cluster may be a key component of fear extinction deficits in PTSD and/or may be particularly amenable to change through extinction-based therapies. PMID- 24146644 TI - The focus of attention in working memory-from metaphors to mechanisms. AB - Many verbal theories describe working memory (WM) in terms of physical metaphors such as information flow or information containers. These metaphors are often useful but can also be misleading. This article contrasts the verbal version of the author's three-embedded-component theory with a computational implementation of the theory. The analysis focuses on phenomena that have been attributed to the focus of attention in WM. The verbal theory characterizes the focus of attention by a container metaphor, which gives rise to questions such as: how many items fit into the focus? The computational model explains the same phenomena mechanistically through a combination of strengthened bindings between items and their retrieval cues, and priming of these cues. The author applies the computational model to three findings that have been used to argue about how many items can be held in the focus of attention (Oberauer and Bialkova, 2009; Gilchrist and Cowan, 2011; Oberauer and Bialkova, 2011). The modeling results imply a new interpretation of those findings: The different patterns of results across those studies don't imply different capacity estimates for the focus of attention; they rather reflect to what extent retrieval from WM is parallel or serial. PMID- 24146645 TI - Conditional probability modulates visual search efficiency. AB - We investigated the effects of probability on visual search. Previous work has shown that people can utilize spatial and sequential probability information to improve target detection. We hypothesized that performance improvements from probability information would extend to the efficiency of visual search. Our task was a simple visual search in which the target was always present among a field of distractors, and could take one of two colors. The absolute probability of the target being either color was 0.5; however, the conditional probability-the likelihood of a particular color given a particular combination of two cues varied from 0.1 to 0.9. We found that participants searched more efficiently for high conditional probability targets and less efficiently for low conditional probability targets, but only when they were explicitly informed of the probability relationship between cues and target color. PMID- 24146646 TI - Caffeine promotes global spatial processing in habitual and non-habitual caffeine consumers. AB - Information processing is generally biased toward global cues, often at the expense of local information. Equivocal extant data suggests that arousal states may accentuate either a local or global processing bias, at least partially dependent on the nature of the manipulation, task, and stimuli. To further differentiate the conditions responsible for such equivocal results we varied caffeine doses to alter physiological arousal states and measured their effect on tasks requiring the retrieval of local versus global spatial knowledge. In a double-blind, repeated-measures design, non-habitual (Experiment 1; N = 36, M = 42.5 +/- 28.7 mg/day caffeine) and habitual (Experiment 2; N = 34, M = 579.5 +/- 311.5 mg/day caffeine) caffeine consumers completed four test sessions corresponding to each of four caffeine doses (0, 100, 200, 400 mg). During each test session, participants consumed a capsule containing one of the three doses of caffeine or placebo, waited 60 min, and then completed two spatial tasks, one involving memorizing maps and one spatial descriptions. A spatial statement verification task tested local versus global spatial knowledge by differentially probing memory for proximal versus distal landmark relationships. On the map learning task, results indicated that caffeine enhanced memory for distal (i.e., global) compared to proximal (i.e., local) comparisons at 100 (marginal), 200, and 400 mg caffeine in non-habitual consumers, and marginally beginning at 200 mg caffeine in habitual consumers. On the spatial descriptions task, caffeine enhanced memory for distal compared to proximal comparisons beginning at 100 mg in non-habitual but not habitual consumers. We thus provide evidence that caffeine-induced physiological arousal amplifies global spatial processing biases, and these effects are at least partially driven by habitual caffeine consumption. PMID- 24146647 TI - Learned parametrized dynamic movement primitives with shared synergies for controlling robotic and musculoskeletal systems. AB - A salient feature of human motor skill learning is the ability to exploit similarities across related tasks. In biological motor control, it has been hypothesized that muscle synergies, coherent activations of groups of muscles, allow for exploiting shared knowledge. Recent studies have shown that a rich set of complex motor skills can be generated by a combination of a small number of muscle synergies. In robotics, dynamic movement primitives are commonly used for motor skill learning. This machine learning approach implements a stable attractor system that facilitates learning and it can be used in high-dimensional continuous spaces. However, it does not allow for reusing shared knowledge, i.e., for each task an individual set of parameters has to be learned. We propose a novel movement primitive representation that employs parametrized basis functions, which combines the benefits of muscle synergies and dynamic movement primitives. For each task a superposition of synergies modulates a stable attractor system. This approach leads to a compact representation of multiple motor skills and at the same time enables efficient learning in high-dimensional continuous systems. The movement representation supports discrete and rhythmic movements and in particular includes the dynamic movement primitive approach as a special case. We demonstrate the feasibility of the movement representation in three multi-task learning simulated scenarios. First, the characteristics of the proposed representation are illustrated in a point-mass task. Second, in complex humanoid walking experiments, multiple walking patterns with different step heights are learned robustly and efficiently. Finally, in a multi-directional reaching task simulated with a musculoskeletal model of the human arm, we show how the proposed movement primitives can be used to learn appropriate muscle excitation patterns and to generalize effectively to new reaching skills. PMID- 24146649 TI - Nitric oxide and membrane lipid peroxidation in photosynthetic and non photosynthetic organisms under several stress conditions. PMID- 24146650 TI - Carbon monoxide effects on human ventricle action potential assessed by mathematical simulations. AB - Carbon monoxide (CO) that is produced in a number of different mammalian tissues is now known to have significant effects on the cardiovascular system. These include: (i) vasodilation, (ii) changes in heart rate and strength of contractions, and (iii) modulation of autonomic nervous system input to both the primary pacemaker and the working myocardium. Excessive CO in the environment is toxic and can initiate or mediate life threatening cardiac rhythm disturbances. Recent reports link these ventricular arrhythmias to an increase in the slowly inactivating, or "late" component of the Na(+) current in the mammalian heart. The main goal of this paper is to explore the basis of this pro-arrhythmic capability of CO by incorporating changes in CO-induced ion channel activity with intracellular signaling pathways in the mammalian heart. To do this, a quite well documented mathematical model of the action potential and intracellular calcium transient in the human ventricular myocyte has been employed. In silico iterations based on this model provide a useful first step in illustrating the cellular electrophysiological consequences of CO that have been reported from mammalian heart experiments. Specifically, when the Grandi et al. model of the human ventricular action potential is utilized, and after the Na(+) and Ca(2+) currents in a single myocyte are modified based on the experimental literature, early after-depolarization (EAD) rhythm disturbances appear, and important elements of the underlying causes of these EADs are revealed/illustrated. Our modified mathematical model of the human ventricular action potential also provides a convenient digital platform for designing future experimental work and relating these changes in cellular cardiac electrophysiology to emerging clinical and epidemiological data on CO toxicity. PMID- 24146651 TI - Facing the challenges of global agriculture today: what can we do about drought? PMID- 24146648 TI - Presynaptic long-term plasticity. AB - Long-term synaptic plasticity is a major cellular substrate for learning, memory, and behavioral adaptation. Although early examples of long-term synaptic plasticity described a mechanism by which postsynaptic signal transduction was potentiated, it is now apparent that there is a vast array of mechanisms for long term synaptic plasticity that involve modifications to either or both the presynaptic terminal and postsynaptic site. In this article, we discuss current and evolving approaches to identify presynaptic mechanisms as well as discuss their limitations. We next provide examples of the diverse circuits in which presynaptic forms of long-term synaptic plasticity have been described and discuss the potential contribution this form of plasticity might add to circuit function. Finally, we examine the present evidence for the molecular pathways and cellular events underlying presynaptic long-term synaptic plasticity. PMID- 24146653 TI - SoxB, cell cycle and neurogenesis. PMID- 24146654 TI - Body size, spontaneous activity and thermogenesis effects on energy expenditure: an introduction to a topic on energy metabolism. PMID- 24146652 TI - Alterations of cAMP-dependent signaling in dystrophic skeletal muscle. AB - Autonomic regulation processes in striated muscles are largely mediated by cAMP/PKA-signaling. In order to achieve specificity of signaling its spatial temporal compartmentation plays a critical role. We discuss here how specificity of cAMP/PKA-signaling can be achieved in skeletal muscle by spatio-temporal compartmentation. While a microdomain containing PKA type I in the region of the neuromuscular junction (NMJ) is important for postsynaptic, activity-dependent stabilization of the nicotinic acetylcholine receptor (AChR), PKA type I and II microdomains in the sarcomeric part of skeletal muscle are likely to play different roles, including the regulation of muscle homeostasis. These microdomains are due to specific A-kinase anchoring proteins, like rapsyn and myospryn. Importantly, recent evidence indicates that compartmentation of the cAMP/PKA-dependent signaling pathway and pharmacological activation of cAMP production are aberrant in different skeletal muscles disorders. Thus, we discuss here their potential as targets for palliative treatment of certain forms of dystrophy and myasthenia. Under physiological conditions, the neuropeptide, alpha calcitonin-related peptide, as well as catecholamines are the most-mentioned natural triggers for activating cAMP/PKA signaling in skeletal muscle. While the precise domains and functions of these first messengers are still under investigation, agonists of beta2-adrenoceptors clearly exhibit anabolic activity under normal conditions and reduce protein degradation during atrophic periods. Past and recent studies suggest direct sympathetic innervation of skeletal muscle fibers. In summary, the organization and roles of cAMP-dependent signaling in skeletal muscle are increasingly understood, revealing crucial functions in processes like nerve-muscle interaction and muscle trophicity. PMID- 24146655 TI - Neuroanatomical Differences between First-Episode Psychosis Patients with and without Neurocognitive Deficit: A 3-Year Longitudinal Study. AB - BACKGROUND: The course of cognitive function in first-episode psychosis (FEP) patients suggests that some individuals are normal or near normal whereas some cases present a marked decline. The goal of the present longitudinal study was to identify neuroanatomical differences between deficit and non-deficit patients. METHODS: Fifty nine FEP patients with neuroimage and neurocognitive information were studied at baseline and 3 year after illness onset. A global cognitive function score was used to classify deficit and non-deficit patients at baseline. Analysis of covariances and repeated-measures analysis were performed to evaluate differences in brain volumes. Age, premorbid IQ, and intracranial volume were used as covariates. We examined only volumes of whole brain, whole brain gray and white matter, cortical CSF and lateral ventricles, lobular volumes of gray and white matter, and subcortical (caudate nucleus and thalamus) regions. RESULTS: At illness onset 50.8% of patients presented global cognitive deficit. There were no significant differences between neuropsychological subgroups in any of the brain regions studied at baseline [all F(1, 54) <= 3.42; all p >= 0.07] and follow-up [all F(1, 54) <= 3.43; all p >= 0.07] time points. There was a significant time by group interaction for the parietal tissue volume [F(1, 54) = 4.97, p = 0.030] and the total gray matter volume [F(1, 54) = 4.31, p = 0.042], with the deficit group showing a greater volume decrease. CONCLUSION: Our results did not confirm the presence of significant morphometric differences in the brain regions evaluated between cognitively impaired and cognitively preserved schizophrenia patients at the early stages of the illness. However, there were significant time by group interactions for the parietal tissue volume and the total gray matter volume during the 3-year follow-up period, which might indicate that cognitive deficit in schizophrenia would be associated with progressive brain volume loss. PMID- 24146656 TI - Fine-grained temporal coding of visually-similar categories in the ventral visual pathway and prefrontal cortex. AB - Humans are remarkably proficient at categorizing visually-similar objects. To better understand the cortical basis of this categorization process, we used magnetoencephalography (MEG) to record neural activity while participants learned with feedback-to discriminate two highly-similar, novel visual categories. We hypothesized that although prefrontal regions would mediate early category learning, this role would diminish with increasing category familiarity and that regions within the ventral visual pathway would come to play a more prominent role in encoding category-relevant information as learning progressed. Early in learning we observed some degree of categorical discriminability and predictability in both prefrontal cortex and the ventral visual pathway. Predictability improved significantly above chance in the ventral visual pathway over the course of learning with the left inferior temporal and fusiform gyri showing the greatest improvement in predictability between 150 and 250 ms (M200) during category learning. In contrast, there was no comparable increase in discriminability in prefrontal cortex with the only significant post-learning effect being a decrease in predictability in the inferior frontal gyrus between 250 and 350 ms (M300). Thus, the ventral visual pathway appears to encode learned visual categories over the long term. At the same time these results add to our understanding of the cortical origins of previously reported signature temporal components associated with perceptual learning. PMID- 24146657 TI - The microgenesis of the watercolor effect. AB - The "watercolor effect" is the wash of illusory color that fills in between two enclosing bichromatic contours. We studied the microgenesis of this illusion by varying the duration of the eliciting stimulus (a yellow/purple contour outlining the Mediterranean Sea) and by varying the duration of a blank interval from stimulus offset to an after-coming mask (the ISI). The illusory wash was rated in strength and also matched to a comparison disk of adjustable color but similar luminance. Results indicate that the watercolor effect grows rapidly as stimulus duration is increased to 100 ms and then grows much more slowly. Increasing the ISI beyond 10 ms had no effect, suggesting that the wash arises only during stimulation. Participants who recognized that the bounding contour depicted the Mediterranean reported twice as strong an illusory effect as those who did not, indicating that visual long-term memory modulates the watercolor effect despite the rapidity of its generation. PMID- 24146658 TI - Innovative approaches to the study of social phenotypes in neurodevelopmental disorders: an introduction to the research topic. PMID- 24146659 TI - The induction of synaesthesia with chemical agents: a systematic review. AB - Despite the general consensus that synaesthesia emerges at an early developmental stage and is only rarely acquired during adulthood, the transient induction of synaesthesia with chemical agents has been frequently reported in research on different psychoactive substances. Nevertheless, these effects remain poorly understood and have not been systematically incorporated. Here we review the known published studies in which chemical agents were observed to elicit synaesthesia. Across studies there is consistent evidence that serotonin agonists elicit transient experiences of synaesthesia. Despite convergent results across studies, studies investigating the induction of synaesthesia with chemical agents have numerous methodological limitations and little experimental research has been conducted. Cumulatively, these studies implicate the serotonergic system in synaesthesia and have implications for the neurochemical mechanisms underlying this phenomenon but methodological limitations in this research area preclude making firm conclusions regarding whether chemical agents can induce genuine synaesthesia. PMID- 24146660 TI - Is handwriting constrained by phonology? Evidence from Stroop tasks with written responses and Chinese characters. AB - To what extent is handwritten word production based on phonological codes? A few studies conducted in Western languages have recently provided evidence showing that phonology contributes to the retrieval of graphemic properties in written output tasks. Less is known about how orthographic production works in languages with non-alphabetic scripts such as written Chinese. We report a Stroop study in which Chinese participants wrote the color of characters on a digital graphic tablet; characters were either neutral, or homophonic to the target (congruent), or homophonic to an alternative (incongruent). Facilitation was found from congruent homophonic distractors, but only when the homophone shared the same tone with the target. This finding suggests a contribution of phonology to written word production. A second experiment served as a control experiment to exclude the possibility that the effect in Experiment 1 had an exclusively semantic locus. Overall, the findings offer new insight into the relative contribution of phonology to handwriting, particularly in non-Western languages. PMID- 24146661 TI - Tau in MAPK activation. AB - The nature of "toxic" tau in Alzheimer's disease (AD) has been unclear. During pathogenesis, the importance of tau oligomerization vs. tau phosphorylation is controversial and the investigation of both remains critical toward defining the "toxicity" of tau. The phosphorylation of tau on serines and/or threonines occurs early in the disease course and altering phosphorylation has been shown to disrupt neuropathogenesis. We have recently reported that in PC12-derived cells, tau had a role in signal transduction processes activated by NGF. By depleting tau, NGF-induced MAPK activation was attenuated and by restoring tau, MAPK activation was restored. Furthermore, the phosphorylation of tau on Thr231 was required for tau to potentiate MAPK activation. Here we report the effects of additional disease-related tau phosphorylation sites and tau isoform on the ability of tau to potentiate MAPK activation. Our findings, which tested three other sites of phosphorylation, showed that phosphorylation at these other sites mainly lessened MAPK activation; none potentiated MAPK activation. In comparing 0N3R tau to the other five brain tau isoforms, most showed a trend toward less MAPK activation, with only 2N4R tau showing significantly less activation. Since MAPK activation has been reported in AD brain and is characteristic of cell proliferation mechanisms, tau phosphorylation that promotes MAPK activation could promote cell cycle activation mechanisms. In neurons, the activation of the cell cycle leads to cell death, suggesting that abnormally phosphorylated tau can be a toxic species. The relationship between tau oligomerization and its ability to potentiate MAPK activation needs to be determined. PMID- 24146662 TI - Posttranslational modifications of proopiomelanocortin in vertebrates and their biological significance. AB - Proopiomelanocortin (POMC) is the precursor of several peptide hormones generated in the pituitary gland. After biosynthesis, POMC undergoes several posttranslational modifications, including proteolytic cleavage, acetylation, amidation, phosphorylation, glycosylation, and disulfide linkage formation, which generate mature POMC-derived peptides. Therefore, POMC is a useful model for the investigation of posttranslational modifications. These processes have been extensively investigated in mammals, primarily in rodents. In addition, over the last decade, much information has been obtained about the posttranslational processing of POMC in non-mammalian animals such as fish, amphibians, reptiles, and birds through sequencing and peptide identification by mass spectrometry. One POMC modification, acetylation, is known to modulate the biological activities of POMC-derived alpha-melanocyte-stimulating hormone (alpha-MSH) having an acetyl group at N-terminal through potentiation or inhibition. This bidirectional regulation depends on its intrinsic roles in the tissue or cell; for example, alpha-MSH, as well as desacetyl (Des-Ac)-alpha-MSH, stimulates pigment dispersion in the xanthophores of a flounder. In contrast, alpha-MSH does not stimulate pigment dispersion in the melanophores of the same species, whereas Des-Ac-alpha MSH does. Regulation of pigment-dispersing activities may be associated with the subtle balance in the expression of receptor genes. In this review, we consider the posttranslational modifications of POMC in vertebrates from an evolutionary aspect, with a focus on the relationship between acetylation and the biological activities of alpha-MSH as an important consequence of posttranslational modification. PMID- 24146663 TI - Exocytosis through the Lens. AB - Exocytosis, the process in which material is transported from the cell interior to the extracellular space, proceeds through a complex mechanism. Defects in this process are linked to a number of serious illnesses including diabetes, cancer, and a range of neuropathologies. In neuroendocrine cells, exocytosis involves the fusion of secretory vesicles, carrying signaling molecules, with the plasma membrane through the coordinated interplay of proteins, lipids, and small molecules. This process is highly regulated and occurs in a complex three dimensional environment within the cell precisely coupled to the stimulus. The study of exocytosis poses significant challenges, involving rapidly changing, nano-scale, protein-protein, and protein-lipid interactions, at specialized sites in the cell. Over the last decade our understanding of neuroendocrine exocytosis has been greatly enhanced by developments in fluorescence microscopy. Modern microscopy encompasses a toolbox of advanced techniques, pushing the limits of sensitivity and resolution, to probe different properties of exocytosis. In more recent years, the development of super-resolution microscopy techniques, side stepping the limits of optical resolution imposed by the physical properties of light, have started to provide an unparalleled view of exocytosis. In this review we will discuss how advances in fluorescence microscopy are shedding light on the spatial and temporal organization of the exocytotic machinery. PMID- 24146664 TI - Metabolic adaptation and trophic strategies of soil bacteria-C1- metabolism and sulfur chemolithotrophy in Starkeya novella. AB - The highly diverse and metabolically versatile microbial communities found in soil environments are major contributors to the global carbon, nitrogen, and sulfur cycles. We have used a combination of genome -based pathway analysis with proteomics and gene expression studies to investigate metabolic adaptation in a representative of these bacteria, Starkeya novella, which was originally isolated from agricultural soil. This bacterium was the first facultative sulfur chemolithoautotroph that was isolated and it is also able to grow with methanol and on over 39 substrates as a heterotroph. However, using glucose, fructose, methanol, thiosulfate as well as combinations of the carbon compounds with thiosulfate as growth substrates we have demonstrated here that contrary to the previous classification, S. novella is not a facultative sulfur chemolitho- and methylotroph, as the enzyme systems required for these two growth modes are always expressed at high levels. This is typical for key metabolic pathways. In addition enzymes for various pathways of carbon dioxide fixation were always expressed at high levels, even during heterotrophic growth on glucose or fructose, which suggests a role for these pathways beyond the generation of reduced carbon units for cell growth, possibly in redox balancing of metabolism. Our results then indicate that S. novella, a representative of the Xanthobacteraceae family of methylotrophic soil and freshwater dwelling bacteria, employs a mixotrophic growth strategy under all conditions tested here. As a result the contribution of this bacterium to either carbon sequestration or the release of climate active substances could vary very quickly, which has direct implications for the modeling of such processes if mixotrophy proves to be the main growth strategy for large populations of soil bacteria. PMID- 24146665 TI - Protein-linked glycans in periodontal bacteria: prevalence and role at the immune interface. AB - Protein modification with complex glycans is increasingly being recognized in many pathogenic and non-pathogenic bacteria, and is now thought to be central to the successful life-style of those species in their respective hosts. This review aims to convey current knowledge on the extent of protein glycosylation in periodontal pathogenic bacteria and its role in the modulation of the host immune responses. The available data show that surface glycans of periodontal bacteria orchestrate dendritic cell cytokine responses to drive T cell immunity in ways that facilitate bacterial persistence in the host and induce periodontal inflammation. In addition, surface glycans may help certain periodontal bacteria protect against serum complement attack or help them escape immune detection through glycomimicry. In this review we will focus mainly on the generalized surface-layer protein glycosylation system of the periodontal pathogen Tannerella forsythia in shaping innate and adaptive host immunity in the context of periodontal disease. In addition, we will also review the current state of knowledge of surface protein glycosylation and its potential for immune modulation in other periodontal pathogens. PMID- 24146666 TI - HLA-DM Focuses on Conformational Flexibility Around P1 Pocket to Catalyze Peptide Exchange. AB - Peptides presented by major histocompatibility complex class II (MHCII) molecules to CD4+ T cells play a central role in the initiation of adaptive immunity. This antigen presentation process is characterized by the proteolytic cleavage of foreign and self proteins, and loading of the resultant peptides onto MHCII molecules. Loading and exchange of antigenic peptides is catalyzed by a non classical MHCII molecule, HLA-DM. The impact of HLA-DM on epitope selection has been appreciated for a long time. However, the molecular mechanism by which HLA DM mediates peptide exchange remains elusive. Here, we review recent efforts in elucidating how HLA-DM works, highlighted by two recently solved co-structures of HLA-DM bound to HLA-DO (a natural inhibitor of HLA-DM), or to HLA-DR1 (a common MHCII). In light of these efforts, a model for HLA-DM action in which HLA-DM utilizes conformational flexibility around the P1 pocket of the MHCII-peptide complex to catalyze peptide exchange is proposed. PMID- 24146667 TI - Arabidopsis TNL-WRKY domain receptor RRS1 contributes to temperature-conditioned RPS4 auto-immunity. AB - In plant effector-triggered immunity (ETI), intracellular nucleotide binding leucine rich repeat (NLR) receptors are activated by specific pathogen effectors. The Arabidopsis TIR (Toll-Interleukin-1 receptor domain)-NLR (denoted TNL) gene pair, RPS4 and RRS1, confers resistance to Pseudomonas syringae pv tomato (Pst) strain DC3000 expressing the Type III-secreted effector, AvrRps4. Nuclear accumulation of AvrRps4, RPS4, and the TNL resistance regulator EDS1 is necessary for ETI. RRS1 possesses a C-terminal "WRKY" transcription factor DNA binding domain suggesting that important RPS4/RRS1 recognition and/or resistance signaling events occur at the nuclear chromatin. In Arabidopsis accession Ws-0, the RPS4(Ws) /RRS1(Ws) allelic pair governs resistance to Pst/AvrRps4 accompanied by host programed cell death (pcd). In accession Col-0, RPS4(Col) /RRS1(Col) effectively limits Pst/AvrRps4 growth without pcd. Constitutive expression of HA StrepII tagged RPS4(Col) (in a 35S:RPS4-HS line) confers temperature-conditioned EDS1-dependent auto-immunity. Here we show that a high (28 degrees C, non permissive) to moderate (19 degrees C, permissive) temperature shift of 35S:RPS4 HS plants can be used to follow defense-related transcriptional dynamics without a pathogen effector trigger. By comparing responses of 35S:RPS4-HS with 35S:RPS4 HS rrs1-11 and 35S:RPS4-HS eds1-2 mutants, we establish that RPS4(Col) auto immunity depends entirely on EDS1 and partially on RRS1(Col) . Examination of gene expression microarray data over 24 h after temperature shift reveals a mainly quantitative RRS1(Col) contribution to up- or down-regulation of a small subset of RPS4(Col) -reprogramed, EDS1-dependent genes. We find significant over representation of WRKY transcription factor binding W-box cis-elements within the promoters of these genes. Our data show that RRS1(Col) contributes to temperature conditioned RPS4(Col) auto-immunity and are consistent with activated RPS4(Col) engaging RRS1(Col) for resistance signaling. PMID- 24146668 TI - Contrasting trait syndromes in angiosperms and conifers are associated with different responses of tree growth to temperature on a large scale. AB - Recent large-scale studies of tree growth in the Iberian Peninsula reported contrasting positive and negative effects of temperature in Mediterranean angiosperms and conifers. Here we review the different hypotheses that may explain these trends and propose that the observed contrasting responses of tree growth to temperature in this region could be associated with a continuum of trait differences between angiosperms and conifers. Angiosperm and conifer trees differ in the effects of phenology in their productivity, in their growth allometry, and in their sensitivity to competition. Moreover, angiosperms and conifers significantly differ in hydraulic safety margins, sensitivity of stomatal conductance to vapor-pressure deficit (VPD), xylem recovery capacity or the rate of carbon transfer. These differences could be explained by key features of the xylem such as non-structural carbohydrate content (NSC), wood parenchymal fraction or wood capacitance. We suggest that the reviewed trait differences define two contrasting ecophysiological strategies that may determine qualitatively different growth responses to increased temperature and drought. Improved reciprocal common garden experiments along altitudinal or latitudinal gradients would be key to quantify the relative importance of the different hypotheses reviewed. Finally, we show that warming impacts in this area occur in an ecological context characterized by the advance of forest succession and increased dominance of angiosperm trees over extensive areas. In this context, we examined the empirical relationships between the responses of tree growth to temperature and hydraulic safety margins in angiosperm and coniferous trees. Our findings suggest a future scenario in Mediterranean forests characterized by contrasting demographic responses in conifer and angiosperm trees to both temperature and forest succession, with increased dominance of angiosperm trees, and particularly negative impacts in pines. PMID- 24146670 TI - Comparison of pulpotomy with formocresol and MTA in primary molars: a systematic review and meta- analysis. AB - INTRODUCTION: There are various studies looking at the effects of formocresol (FC) and mineral trioxide aggregate (MTA) on pulpotomy of primary molars. This is a systematic review of literature comparing the success rates of MTA and FC in pulpotomy of primary molars. MATERIALS AND METHODS: The study list was obtained using PubMed, EMBASE, Scopus, Science Citation Index, Iran Medex, Google Scholar, the Cochrane Library, and also some hand searches contains through dental journals approved by the Iranian Ministry of Health. Papers which met the inclusion were accepted. The quality of studies for the meta-analysis was assessed by a series of validity criteria according to Jadad's scale. Eight qualified studies met the criteria. Terms of clinical outcomes and radiographic findings were evaluated in all studies to assess clinical success and root resorption. Fixed model was applied to aggregate the data of homogenous studies. A random effect model was carried out for measuring the effect size of heterogeneous studies. RESULTS: The overall clinical and radiographic success rates based on the data suggested that MTA was superior to FC (P=0.004) with the Odds Ratio=3.535 and 95% confidence interval (1.494-8.369). CONCLUSION: Primary molars pulpotomy with MTA have better clinical and radiographic success rates than FC. (Iranian Endodontic Journal 2008;3:45-9). PMID- 24146669 TI - Sodium transport system in plant cells. AB - Since sodium, Na, is a non-essential element for the plant growth, the molecular mechanism of Na(+) transport system in plants has remained elusive for the last two decades. The accumulation of Na(+) in soil through irrigation for sustainable agricultural crop production, particularly in arid land, and by changes in environmental and climate conditions leads to the buildup of toxic level of salts in the soil. Since the latter half of the twentieth century, extensive molecular research has identified several classes of Na(+) transporters that play major roles in the alleviation of ionic stress by excluding toxic Na(+) from the cytosol or preventing Na(+) transport to the photosynthetic organs, and also in osmotic stress by modulating intra/extracellular osmotic balance. In this review, we summarize the current knowledge of three major Na(+) transporters, namely NHX, SOS1, and HKT transporters, including recently revealed characteristics of these transporters. PMID- 24146671 TI - In vitro comparison of the effectiveness of chlorhexidine and two calcium hydroxide formulations on enterococcus faecalis. AB - INTRODUCTION: The aim of this in vitro study was to compare the effectiveness of three intracanal medicaments in disinfecting the root canal and dentin of experimentally infected human teeth with Enterococcus faecalis (EF). MATERIALS AND METHODS: One hundred extracted human single-rooted teeth were used. After root canal preparation, teeth were mounted in epoxy resin. Following sterilization, the teeth were infected for 28 days with EF. Then root canals were filled with one of three different disinfectants: viscous 2% Chlorhexidine (CHX), calcium hydroxide paste (CH) or a mixture of CH and CHX (n=30 in each group). Antimicrobial assessments were performed at 1, 3 and 7 days (n=10 in each time period). Microbial samples were obtained from root canals before and after the experiment. Also dentin samples were examined. The data was analyzed using Two- Way ANOVA test. RESULTS: The findings showed that there was no difference between experimental groups at different time periods. The mixture of CH/CHX in 7 days was able to eliminate EF completely from root canal system. The most elimination of EF was from dentinal tubules. CONCLUSION: According to the results of this in vitro study, viscous 2% CHX, mixture of CH with distilled water and 2% CHX are all effective disinfectants. PMID- 24146672 TI - The Effect of Three Different Root Canal Irrigant Protocols for Removing Smear Layer on the Apical Microleakage of AH26 Sealer. AB - INTRODUCTION: The purpose of this in vitro study was to assess the apical microleakage of AH26 sealer when three different root canal irrigant regimens were used. MATERIALS AND METHODS: Eighty single-rooted human teeth were randomly divided into three experimental (n=20) and two control groups (n=10). NaOCl was used as irrigant during instrumentation, and apical patency was ensured in all teeth. Final irrigation was implemented as follow: group A- 17% EDTA + 5.25% NaOCl, Group B- 7% citric acid + 5.25% NaOCl, and group C- 20% citric acid + 5.25% NaOCl. The experimental and negative control groups were obturated by laterally condensed gutta-percha with AH26 sealer. The positive control group was obturated without sealer. The teeth were stored in 100% humidity and 37oC for 48 hours. In the experimental groups and positive control group, the root surfaces except for the apical 2 mm were covered with nail polish and sticky wax. In the negative control group, the roots were completely covered. The samples were then immersed in 2% methylene blue dye for 72 hours at 37oC. After that the roots were sectioned longitudinally and the dye penetration was measured. The results were statistically analyzed by One-way Variance and Post Hoc Tukey tests. RESULTS: Statistically significant difference was found between groups (P<0.05). Group C showed the least (1.072 mm) and group A showed the most (2.072 mm) amount of dye penetration. CONCLUSION: When a resin-based sealer is used for the obturation of the root canal system, it is better to use a citric acid irrigant instead of EDTA to remove the smear layer and to improve the apical seal. PMID- 24146673 TI - Assembling of fluid filtration system for quantitative evaluation of microleakage in dental materials. AB - INTRODUCTION: There are several methods for evaluating microleakage in dentistry, for example dye or bacterial leakage, electro-chemical methods, radioisotope labeling and fluid filtration. The purpose of this study was to assemble the fluid filtration system for quantitative evaluation of microleakage in dental materials. MATERIALS AND METHODS: The roots were connected to a tube filled with an underwater pressure supply. A bubble was introduced into the water to measure endodontic leakage. A digital camera and professional software were utilized to record and measure the bubble displacement. RESULTS: Our system was constructed successfully and functioned correctly. CONCLUSION: In this pilot study we found this system efficient for the evaluation of microleakage of dental materials. PMID- 24146674 TI - Technical quality of root canal treatment performed by undergraduate dental students. AB - INTRODUCTION: This study was carried out to evaluate the technical quality of root canal treatment (RCT) performed by undergraduate dental students at the Islamic Azad University in Tehran, Iran. MATERIALS AND METHODS: Four-hundred records of patients who had received RCT at faculty of dentistry, between the years 2004-2006 were evaluated. For each treated tooth at least three periapical x-rays were assessed: preoperative, working length measurement, and postoperative. Evaluation of root canal filling was based on two variables: length and density. The filling length was recorded as adequate, under- or overfilled. Density of filling was recorded as poor or adequate. Fillings with adequate length and density were recorded as acceptable. Detected iatrogenic errors were: ledge formations, root perforations, furcation perforations, strip perforations and presence of fractured instruments. Results were evaluated statistically using one-way ANOVA and Chi-square analysis. RESULTS: Out of the 400 teeth, 50.5% had at least one of the mentioned errors. Acceptable filling was observed in 32.5% of all studied teeth. Ledge was found in 17.5% of the teeth. Canal curvature was the most important factor associated with ledge formation (P<0.05). CONCLUSION: The technical quality of RCT performed by undergraduate dental students using step-back preparation and cold lateral condensation was classified as acceptable in 32.5% of the cases. PMID- 24146675 TI - A comparative study of apical microleakage using the conventional lateral condensation and mechanical lateral condensation techniques. AB - INTRODUCTION: This study compared apical dye penetration using lateral condensation technique (LC) and LC technique with a reciprocal handpiece (mechanical lateral condensation or MLC) as a new method. MATERIALS AND METHODS: Forty-eight human extracted straight canine teeth were used. After crown amputation, the teeth were randomly divided into four experimental groups of 10 teeth each and two negative and positive control groups of 4 teeth each. The groups were as follows: IA, 10 obturations completed by operator A using the LC technique; Group IB, 10 obturations completed by operator B using the LC technique; Group IIA, 10 obturations completed by operator A using the MLC technique; and Group IIB, 10 obturations completed by operator B using the MLC technique. All roots were placed in 2% methylene blue dye and centrifuged at 3000 rpm for 3 minutes. Following centrifugation, the roots were cut along their long axis and evaluated under a stereomicroscope to measure the depth of dye penetration. RESULTS: A t-test showed that the teeth which were filled by the MLC technique had less dye penetration in comparison with LC technique (P<0.05). CONCLUSION: This in vitro study illustrates that canals obturated with the MLC technique had superior apical seal than canals filled with the LC technique. PMID- 24146676 TI - Endodontic re-treatment of maxillary second molar with two separate palatal roots: a case report. AB - Maxillary second molar with two palatal roots is a rare dental anatomy. The diagnosis and treatment of exceeded root may create challenge for clinicians. The authors discuss the retreatment of a maxillary second molar in which exceeded root was undiagnosed in previous treatment. The case report underlines the importance of complete knowledge about root canal morphology which achieved by careful clinical and radiographic examination. In retreatment procedures clinicians should consider missed canals. PMID- 24146677 TI - Delayed tooth replantation after traumatic avulsion: a case report. AB - Avulsion is a serious injury which causes damage to dental and supportive tissues, ranging from 1-16 % among dental injuries and it mostly occurs in maxillary incisors. This report presents a case of replantation of a traumatically avulsed central incisor. The left central incisor of an 8 year-old boy with open apex was avulsed and was left in unclean and dry conditions. Tooth was replaced after 270 min and splinted. After 24 hours, tooth was treated endodontically. The calcium hydroxide paste was applied as intracanal medicament. After one year the calcium hydroxide was not replaced and was maintained in the canal, permanently. The tooth followed for 5 years. During follow up, the tooth kept stable. However, the resulted dent alveolar ankylosis prevented growth of the alveolar process. Spite of the fact that in children, replacement resorption leads to the loss of ankylosed teeth within 1-5 years; this tooth has remained in a stable, infra-position for 5 year and in functional position after coronal restoration. However, in such cases other treatments such as decoronation should be considered. PMID- 24146678 TI - The importance of long time follow-up after vital pulp therapy: a case report. AB - This report describes a case of an eight years old girl who was treated for complicated crown fracture of right maxillary central incisor because of a sport accident. For the tooth total pulpotomy was performed in order to achieve apexogenesis and the tooth was restored with a composite resin. The patient was reviewed over 10 years. At first the tooth showed continued root development and complete apex formation following vital pulp therapy, however, after 10 years the tooth developed pulp necrosis and periapical radiolucency. Following root canal therapy, periapical radiolucency has been healed. PMID- 24146680 TI - Monitoring the production of reactive oxygen species in experimental melanoma. AB - HYPOTHESIS: Melanoma is one of the most aggressive forms of skin cancer characterized by malignant proliferation of melanocytes. The role played by reactive oxygen species and free radicals in the pathology of melanoma in humans is widely accepted today. OBJECTIVE: This paper aims to characterize some types of malignant melanoma obtained experimentally by the inoculation of reference cells for the creation of models and the identification of oxidative stress markers usable for monitoring tumor growth and development. METHODS AND RESULTS: Mice C57Bl/6. Reference cell lines B16, F1, F10. Inoculation of cells was performed in the upper right flank. Tumors were characterized both anatomically and morphologically. For the biochemical characterization of the oxidative stress, tests were performed to determine lipid peroxides, total albumin thiol groups and total antioxidant response. Tumor volume was measured in dynamic. The fastest development has been observed in type B melanoma. For the F and F10 types, the curves profiles are the same. The results indicate an increase of lipid peroxidation reaction in dynamic tumor evolution, suggesting the malignant associated transformations. DISCUSSION: These data demonstrate that an alteration of the antioxidant pattern can be detected in the serum of the experimental animals with melanoma, possibly related to the disease status and progression. Our results can be useful in monitoring the tumor evolution and also to highlight the prolonged damage which actions on the normal cells, suggesting the combination of the classical treatments with an adjuvant antioxidant treatment. PMID- 24146681 TI - Organ failure as an expression of organ remodeling. Involvement of oxidative stress. AB - Organ failure can be defined as a relevant concept of functional-anatomical condition of body structural change. Anatomical, functional disorders of the body are the expression of structural remodeling. The process is complex, including the first functional cell mass reduction (in particular, apoptosis and necrosis), and on the other hand the development of fibrosis process with a starting point at the extracellular matrix. Both mechanisms that take place are caused by etiological factors, enhanced, favoring the developer cytokines mediated by inflammatory processes such as premature death and functional constituent cells of the body; secondly the inflammation leads to fibrosis. The article review is a summary of the knowledge that exist at the level of the anatomical organ remodeling. PMID- 24146682 TI - Agarose gel electrophoresis of joint fluid using Hyrys-Hydrasys SEBIA system as a new prognostic tool for periprosthetic osteolysisin revision arthroplasty. AB - RATIONALE: Prevention of wear-mediated osteolysis, the most common complication in total joint arthroplasty, is a great challenge for orthopedic surgery. Despite the diversity of current biomarkers of periprosthetic osteolysis (products of wear, bone turnover and inflammatory biomarkers), the major interferences and the great amount of sample necessary for analysis limit their use in clinical practice. OBJECTIVE: The aim of this paper is to present three new electrophoretic methods using Hyrys-Hydrasys SEBIA system that have been used for the first time in Electrophoresis Laboratory of our hospital in the analysis of joint fluid for the prevention of periprosthetic osteolysis in revision arthroplasty. METHODS AND RESULTS: Analytical aspects of agarose gel electrophoresis of joint fluid proteins and lipoproteins as well as SDS-agarose gel electrophoresis of joint fluid proteins, their performances and clinical value are presented. The decreased level of albumin and increased level of alpha1 and alpha2 globulins were frequent changes detected on SEBIA electropherograms and good indicator for the presence of an inflammatory reaction generated by particle debris. In addition, a slightly increase of LDL mobility could provide good information about a high oxidative stress. Moreover, the Ig G assessed by using SDS-agarose gel electrophoresis could be a potential biomarker for an immunological reaction towards orthopedic implants. DISCUSSION: Electrophoresis of joint fluid using Hyrys-Hydrasys SEBIA France system is a new analytical technique able to remove the most of current biomarkers disadvantages due to the determination of particular proteins (acute phase proteins, albumin, lipoproteins, and immunoglobulins) by using minimal amounts of joint fluid with minor interferences, minimal cost and rapid results. PMID- 24146683 TI - Credibility elements of eWOM messages in the context of health care services. A Romanian perspective. AB - The purpose of this paper is to investigate the Romanian consumers' determinants of eWOM messages' perceived credibility in the context of health care services. We selected a sample of 127 women and we administered a questionnaire. We used the partial least squares to uncover the established relationships between the variables of the model, namely the argument strength and the source credibility of a eWOM message and the intention to purchase a health care service based on the information embedded in the eWOM messages. The results revealed that all variables had positive direct correlations with each other but the argument strength of a message has the highest impact on the intention. PMID- 24146684 TI - Current strategies in the therapeutic approach for adenocarcinoma of the ampulla of Vater. AB - INTRODUCTION: Ampulla of Vater tumors, neoplastic diseases located at the confluence of the common bile duct with the main pancreatic duct; represent 0.2% of all gastrointestinal cancers. METHOD: Retrospective study of all patients admitted in the Emergency Hospital of Bucharest Romania between January 2008 and January 2013, the only selection criterion used being a pathology report which describes an ampulla of Vater carcinoma. We have also performed a review of the medical literature up to 2013, using the PubMed/Medline, Proquest Hospital Collection, Science Direct, Cochrane Library and Web of Science databases. We have used different combinations of the following keywords: "ampulla of Vater", "carcinoma", "resection", reviewing the reference list of retrieved articles for further relevant studies. RESULTS: Forty eight patients with ampulla of Vater carcinoma were identified, of whom 59.6% men, 71% from urban areas, and a mean age of 66 +/- 13.3 years. Most patients were admitted for obstructive jaundice (49%), right upper quadrant abdominal pain (19%), nausea and loss of appetite in 13%, loss of weight (13%) and upper digestive obstruction in 6% of cases. All patients were evaluated with abdominal transparietal ultrasonography and double contrast, pancreatic protocol, Mutidetector Row Computed Tomography. The abdominal Magnetic Resonance Imaging was performed in 10 cases, upper gastrointestinal endoscopy in 9 cases, and Endoscopic Retrograde Cholangiopancreatography in 39 cases. According to the AJCC Cancer Staging 9% were into stage I, 47% into stage II, 40% into stage III and 4% into stage IV of the disease. The therapeutic approach was surgical for 44 patients and an endoscopic palliation with stent insertion in 4 cases. The surgical procedure was represented by Whipple pancreatoduodenectomy in 27 cases, pylorus preserving pancreatoduodenectomy in 15 cases and exploratory laparotomy in 2 cases. Early morbidity was represented by pancreatic leakage in 4 cases. CONCLUSIONS: There are clinical scenarios in which it is quite challenging to distinguish a primary ampullary adenocarcinoma based on a preoperative workup. Nevertheless, an aggressive approach should be performed, knowing the higher resectability rates and a five-year survival for these patients. Complete surgical resection should be performed in all medically fit patients, candidates for pancreatoduodenectomy, by a high volume, trained surgeon, able to offer a low morbidity and mortality. PMID- 24146685 TI - Bone transport with the lengthening through the physis in patients having congenital pseudarthrosis of tibia - short-term results. PMID- 24146686 TI - "Tips and tricks" in secondary bladder neck sclerosis' bipolar plasma vaporization approach. AB - INTRODUCTION: Secondary bladder neck sclerosis (BNS) represents a common late complication of prostate surgery, however so far insufficiently assessed in the available literature. More over, the previously attempted and analyzed therapeutic modalities failed to achieve acknowledgement as standard treatment for this particular pathology. METHODS: The bipolar plasma vaporization (BPV) was introduced as a viable mean of removing the obstructing scar formation in a gradual fashion. Several "tips and tricks" were described as particularly useful in optimizing the plasma corona vaporization effect. The proper BPV technique is simple and safe while closely relying on certain surgical steps, the simultaneous vaporization and coagulation processes and a superior endoscopic vision. Recent technological advances created the premises for further improvements. RESULTS: The plasma-button vaporization is characterized by a satisfactory surgical speed, remote intraoperative bleeding risks, high-quality endoscopic visibility as well as the achievement of a complete sclerotic tissue removal. Within a short learning curve, a superior final aspect of the prostatic fossa and bladder neck is obtained at the end of surgery. The continuous plasma vaporization mode provides additional technical advantages. The previously described drawbacks of transurethral incision or resection seem to have been overcome by the practical features of the plasma vaporization process. CONCLUSIONS: The BPV technique outlines a promising modality of efficiently ablating the obstructing fibrous tissue in secondary BNS patients. The simplicity and safety of the bipolar vaporization approach, together with the thorough obstructing scar removal in a radical fashion, create the premises for a favorable long term BPV clinical outcome. PMID- 24146687 TI - Considerations on male infertility in genital infections with Chlamydia Trachomatis (CT). AB - AIM: The study tries to highlight the implication of CT infection in male infertility. MATERIAL AND METHODS: There were 857 male patients enrolled in the study. The male cases have been investigated in the Gynecology and Urology Department of Ghencea Medical Center, Bucharest. All the selected cases have been done a spermogram test and for the diagnosis of the Chlamydia Trachomatis infection, the ELISA test was used. The test detects the presence in the serum of the anti-chlamydia specific antibodies of type IgA, IgM, IgG (BAG-Chlamydia-AIA). RESULTS AND DISCUSSIONS: From the total of the investigated subjects, only 233 cases had a modified spermogram. According to the specialty literature, the human factor is involved in 35% of the infertility cases, the male one in 30%, in 20% both factors are involved and in 15% of the cases, there is no incriminating cause after complete investigations. Accordingly, the study supports the literature data. PMID- 24146688 TI - Role of colon capsule Pillcam 2 in obscure gastrointestinal bleeding - case report. AB - INTRODUCTION: The diagnosis and management of gastrointestinal bleeding have always been a challenge to clinicians. In most patients, the source of bleeding is easily identified during conventional upper and/or lower gastrointestinal endoscopies. A significant progress in the evaluation of patients with obscure gastrointestinal bleeding was brought by the advent of capsule endoscopy. Since colonoscopy is not always technically feasible, colon VCE might be useful where the conventional procedure poses substantial risks to patients or it is refused by them. CASE-REPORT: We present the case of a 58-year-old patient, with severe anemia caused by bleeding from a gastrointestinal source. The patient was diabetic, hypertensive and with impaired heart function, aggravated by anemia. We used the Pillcam Colon 2 capsule to investigate the colon and we found 2 tumors in the cecum and transverse colon. CONCLUSION: Pillcam Colon 2 capsule turned out to be an additional patient-friendly method to complement colonoscopy for colon visualization and colorectal cancer screening. PMID- 24146689 TI - Major depression and multiple sclerosis - a case report. AB - Multiple Sclerosis (MS) is a chronic and disabling disease with a considerable social impact and economic consequences. In Europe, it is the most common cause of non-traumatic disability in young adults. Existing therapies that target immune modulation are largely ineffective in halting the progression of the disease and are fraught with severe side effects. Therefore, managing the comorbidities of MS is of utmost importance for long-term patient care and quality of life. PMID- 24146690 TI - Persistent repeated measurements by magnetic resonance spectroscopy demonstrate minimal hepatic encephalopathy: a case report. AB - Minimal Hepatic Encephalopathy (MHE), previously referred to as infraclinical or subclinical is a precursor in the development of clinical hepatic encephalopathy (HE). The demonstration of MHE is done through neuropsychological testing in the absence of clinical evidence of HE, patients showing only a mild cognitive impairment. Neuropsychological tests employed consist of Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) and portosystemic encephalopathy (PSE) test score. Unfortunately, there are numerous occasions when the tests prove irrelevant: in the situation of inexperienced investigators, the patient's poor education, vision problems or concurring central nervous system disease, all of which may delay or deviate from the correct diagnosis. PMID- 24146691 TI - An optimal painless treatment for early hemorrhoids; our experience in Government Medical College and Hospital. AB - OBJECTIVE: To evaluate the efficacy of Infrared Coagulation Therapy (IRC) for hemorrhoids. IRC is a painless, safe and successful procedure. PLACE AND DURATION OF STUDY: Department of Surgery, Government Medical College and Hospital, Sector 32, Chandigarh, India, from August 2006 to October 2008. The choice of procedure depends on the patient's symptoms, the extent of the hemorrhoidal disease, and the experience of the surgeon along with the availability of the techniques/instruments. MATERIALS AND METHODS: This is a prospective study done from August 2006 to October 2008. Total number of 155 patients was included in the study. Infrared Coagulation Therapy (IRC) was performed through a special designed proctoscope. Patients excluded were with coagulopathy disorders, fissure in ano, and anal ulcers. Results - It is an outpatient Department (OPD), non surgical, ambulatory, painless and bloodless procedure, without any hospital stay. Early recovery and minimal recurrence of hemorrhoids were noted without any morbidity or mortality. We have studied 155 patients, treated with IRC on OPD basis. Surgery was required in few patients in whom IRC failed or was contraindicated. Out of the total 155 patients, 127 came for follow up. After the 1st sitting of IRC therapy: out of 127; 43 patients got a total relief, mass shrinkage was of > 75% in 57 cases and < 50% in 14 cases. Twenty-eight cases did not come for follow-up. In the 2nd sitting, out of 84/127; 58 patients got a total relief, >75% relief in 15 cases and >50 % relief in 11 patients. In the 3rd sitting out of 26/84 cases: 13 cases got a total relief and 13 cases refused to take the third sitting; however, in 7 cases the hemorrhoidal mass shrank up to 50% after the two sittings. These 14 were operated as there was no relief from bleeding after giving two sittings of IRC. Our opinion is that, in the above 14 cases, the patient might have not followed the instructions properly for dietary habits. CONCLUSION: IRC is a safe, simple and effective procedure for early hemorrhoids without any complications. IRC is nowadays the world's leading office treatment for hemorrhoids. IRC is a better option than the surgical treatment as it is easy, well tolerated, and remarkably complication-free. In our study, we have not used any course of antibiotics. In the management of early hemorrhoids, IRC should be considered as a simple trouble-free and painless option. PMID- 24146692 TI - Severe acute pancreatitis - a serious complication of leptospirosis. AB - Leptospirosis is a disease caused by pathogenic spirochetes of genus Leptospira. It is considered the most common zoonosis in the world. Acute pancreatitis is a rare complication of leptospirosis (25%). We present the case of a 34-year-old male patient with severe leptospirosis complicated with acute renal failure. After 9 days from the onset of the disease, the patient developed acute necrotizing pancreatitis, infected from the very beginning, associated with multiple organ failure, septic shock and severe anemia. The diagnosis was clinically and biologically stated and confirmed by CT-scan. The patient underwent surgery for infected necrotizing acute pancreatitis of the head and neck of the pancreas, with left retroperitoneal expansion down to the left iliac fossa. We performed a necrosectomy with the evacuation of the tisular debris, multiple drainage of the peritoneal cavity, followed by an open abdomen with synthetic mesh. The postoperative evolution was difficult but constantly progressive. Two reinterventions were necessary. The patient left the hospital in good condition after 75 days postoperatively. PMID- 24146693 TI - Perioperative evaluation of cardiac surgical risk: particularities in the emergency surgery - from the guidelines to the clinical practice. AB - RATIONALE: Cardiac risk in patients undergoing surgery depends on many factors from the patient's cardiovascular history to the surgical procedure itself, with its particularities, the type of anesthesia, fluid exchanges and the supervision of the patient. Therefore, this risk must be carefully considered and it determines the endorsement of perioperative measures with important medical implications. OBJECTIVE: Perioperative cardiac risk evaluation guidelines were published since 2010 and they represent a highly important assessmnet tool. Emergency surgery requires an adaptation of the guidelines to the actual medical situations in extreme conditions. METHODS, RESULTS, DISCUSSION: Analyzing the way the perioperative evaluation itself is conducted is an extremely important tool. Quantifying the clinical application of the guidelines, one can monitor real parameters and find solutions for improving medical care. The current study was conducted on a representative sample of 8326 patients, respecting the recommendation strategies for calculating the surgical risk adapted for the emergency surgery setting. The dominant conclusion is the need to develop a standardized form, summarized for quick and objective assessment of perioperative cardiac risk score. Only a complex medical team could calculate this score while the decisional team leader for the surgical patient remains the surgeon. PMID- 24146694 TI - Giant left atrial thrombus formation in patient with a previous coronary artery bypass grafting. AB - Free-floating left atrial ball thrombus is a rare condition. We report a giant left atrial ball thrombus which was removed under surgery uneventfully, in a 48 year-old male patient with the presence of sinus rhythm and no valvular disease with previous off-pump coronary artery bypass surgery. PMID- 24146695 TI - CML patients in the molecular era - report of five years experience of diagnosis and treatment in a single center. AB - Chronic myeloid leukemia (CML) represents about 15% of all leukemia cases. Although the incidence of the disease is rather low, the therapeutic progress of the last decade has dramatically changed the evolution of this disease, whose survival considerably increased and in whom we now speak even about cure. The success of the therapy is strongly connected to the precocity of the diagnosis and molecular targeted therapy that implies a close monitoring of the patient. The specific molecular assay, that developed a lot in the last years, became an important tool in the management of these patients, providing the possibility of efficient changing in therapy. The purpose of our study was to identify the characteristics of our CML patients in terms of clinical and biological behavior. We analyzed 21 patients diagnosed between October 2007 and December 2010 and compared the data with a historical group of patients, also diagnosed in our department between March 2005 and September 2007. We found a better outcome and overall survival in the study group, due to improved diagnosis and monitoring techniques as well as to better access to therapy. PMID- 24146697 TI - Anterior dislocation of the hip associated with intertrochanteric fracture of the femur - Case presentation. AB - Dislocations of the hip usually occur following high energy trauma, the coxo femoral joint being inherently stable, and can be associated with acetabular fractures or fractures of the head, neck or shaft of femur. However, the combination between the anterior hip dislocation and the ipsilateral intertrochanteric fracture is extremely rare, the literature offering only scarce information. We present the case of a patient, aged 44, victim of a trauma by precipitation from height (12m), diagnosed with left hip anterior dislocation and intertrochanteric fracture of the ipsilateral femur. An emergency surgical treatment was applied in less than 3 hours after trauma. The hip dislocation was reduced under general anesthesia and the intertrochanteric fracture was also reduced and internally fixed with a dynamic hip screw. Radiological and functional evaluation at 6 months after surgery, using the modified Merle D'Aubigne hip score was good. The clinical outcome of such a case depends on the quick evaluation and treatment. Providing a stable reduction of the dislocation and a stable internal fixation of the fracture as soon as possible (within the first 6 hours) will allow an early physical rehabilitation and decrease the risk of complications. PMID- 24146696 TI - Acute non-traumatic pancreatitis in a patient with pancreas divisum: a case report. AB - Pancreas divisum is a frequent congenital anatomical anomaly characterized by the failure of fusion of the ducts of Santorini and Wirsung during fetal development. Although the condition usually remains asymptomatic, it has been reported to be a predisposing factor of chronic and recurrent idiopathic pancreatitis. We report a case of acute non-traumatic pancreatitis in a 54-year-old Caucasian male with pancreas divisum. Diagnosis was established based on the findings from magnetic resonance imaging and magnetic resonance cholangiopancreatography. The patient was managed conservatively and was discharged home having an uneventful clinical course after five days of hospitalization. Although the role of the pancreas in the induction of acute pancreatitis is still a matter of debate, physicians have to be aware about this prevalent pancreatic anatomic abnormality. Timely detection may help in the prevention of potential recurrent pancreatic reaction. PMID- 24146698 TI - Reverse perfusion pattern in myocardial spect with 99mTc-sestaMIBI. AB - RATIONALE: The aim of our study was to investigate the myocardial perfusion deficit in rest images as compared to stress images in myocardial scintigraphy (MS). OBJECTIVES: The aim of this study is to investigate the reverse perfusion (RP) pattern in MS. METHODS AND RESULTS: 263 patients were enrolled in the study (72 females and 191 males; mean age 65.7 +/- 9.5 years old). Mean body mass index (BMI) was of 27.6 +/- 3.8 Kg/m2. 115 patients were positive for a previous history of myocardial infarction (MI). 142 patients reported a revascularization treatment (percutaneous transluminal coronary angioplasty, PTCA, cardiac stent placement, coronary artery bypass grafting, CABG). All the patients underwent MS following standard single day Stress/Rest protocol. In our series, 27 patients presented a RP pattern. We did not find statistically significant differences when considering age (p = 0.7988), sex (p = 0.0657), BMI (p = 0.8611), diabetes (p = 0.8259), dyslipidemia (p = 0.1464) or smoking status (p = 0.6829) in RP patients vs. non-RP patients. A history of MI is related to a RP pattern (p < 0.0001). A history of previous revascularization was not related with RP (p = 0.6868). DISCUSSION: The result of our study suggested that RP is probably related to artifacts of various origins. Further studies are necessary especially in microvascular dysfunction or a long history of disease. PMID- 24146700 TI - The appropriateness of the helical axis technique and six available cardan sequences for the representation of 3-d lead leg kinematics during the fencing lunge. AB - Cardan/Euler angles represent the most common technique for the quantification of segmental rotations. Cardan angles are influenced by their ordered sequence, and sensitive to planar-cross talk from the dominant rotation plane, which may affect the angular parameters. The International Society of Biomechanics (ISB) currently recommends a sagittal, coronal, and then transverse (XYZ) ordered sequence, although it has been proposed that when quantifying non-sagittal rotations this may not be the most appropriate technique. This study examined the influence of the helical and six available Cardan sequences on lower extremity three dimensional (3-D) kinematics of the lead leg during the fencing lunge. Kinematic data were obtained using a 3-D motion capture system as participants completed simulated lunges. Repeated measures ANOVAs were used to compare discrete kinematic parameters, and intraclass correlations were also utilized to determine evidence of planar crosstalk. The results indicate that in all three planes of rotation, peak angle and range of motion angles using the YXZ and ZXY sequences were significantly greater than the other sequences. It was also noted that the utilization of the YXZ and ZXY sequences was associated with the strongest correlations from the sagittal plane, and the XYZ sequence was found habitually to be associated with the lowest correlations. It appears that for accurate representation of 3-D kinematics of the lead leg during the fencing lunge, the XYZ sequence is the most appropriate and as such its continued utilization is encouraged. PMID- 24146699 TI - Hepcidin in neoplastic disease. AB - Abnormalities in iron metabolism are frequent in the neoplastic disease. The relationship between hepcidin and iron homeostasis in cancerous pathology is incompletely known, although it has been studied during the last years. This paper aims to analyze the role of hepcidin in the neoplastic processes, its correlation with carcinogenesis and anemia, and with the disease activity. It must be mentioned that most of the aspects presented need to be verified in practice. Insufficient data are known for showing hepcidin involvement in carcinogenesis, metastasis or in appreciating the response to anemia treatment in neoplasia. PMID- 24146701 TI - Kinematic and kinetic analysis of two gymnastics acrobatic series to performing the backward stretched somersault. AB - Back swing connections during gymnastics acrobatic series considerably influence technical performance and difficulties, particularly in the back somersault. The aim of this study was to compare the take-off's kinetic and kinematic variables between two acrobatic series leading to perform the backward stretched somersault (also called salto): round-off, flic-flac to stretched salto versus round-off, tempo-salto to stretched salto. Five high level male gymnasts (age 23.17 +/- 1.61 yrs; body height 1.65 +/- 0.05 m; body mass 56.80 +/- 7.66 kg) took part in this investigation. A force plate synchronized with a two dimensional movement analysis system was used to collect kinetic and kinematic data. Statistical analysis via the non-parametric Wilcoxon Rank-sum test showed significant differences between the take-offs' variables. The backswing connections were different in the take-off angle, linear momentum, vertical velocity and horizontal and vertical displacements. In conclusion, considering that the higher elevation of the centre of mass in the flight phase would allow best performance and lower the risk of falls, particularly when combined to a great angular momentum, this study demonstrated that the optimal connection series was round off, flic-flac to stretched salto which enabled the best height in the somersault. Analysis of the results suggests that both connections facilitate the performance of single and double (or triple) backward somersaults with or without rotations around the longitudinal axis. Gymnasts could perform these later while gaining height if they chose the round-off, flic-flac technique or gaining some backward displacement if they choose the round-off, salto tempo. PMID- 24146702 TI - Gender, Vertical Height and Horizontal Distance Effects on Single-Leg Landing Kinematics: Implications for Risk of non-contact ACL Injury. AB - There is a lack of studies investigating gender differences in whole-body kinematics during single-leg landings from increasing vertical heights and horizontal distances. This study determined the main effects and interactions of gender, vertical height, and horizontal distance on whole-body joint kinematics during single-leg landings, and established whether these findings could explain the gender disparity in non-contact anterior cruciate ligament (ACL) injury rate. Recreationally active males (n=6) and females (n=6) performed single-leg landings from a takeoff deck of vertical height of 20, 40, and 60 cm placed at a horizontal distance of 30, 50 and 70 cm from the edge of a force platform, while 3D kinematics and kinetics were simultaneously measured. It was determined that peak vertical ground reaction force (VGRF) and the ankle flexion angle exhibited significant gender differences (p=0.028, partial eta(2)=0.40 and p=0.035, partial eta(2)=0.37, respectively). Peak VGRF was significantly correlated to the ankle flexion angle (r= -0.59, p=0.04), hip flexion angle (r= -0.74, p=0.006), and trunk flexion angle (r= -0.59, p=0.045). Peak posterior ground reaction force (PGRF) was significantly correlated to the ankle flexion angle (r= -0.56, p=0.035), while peak knee abduction moment was significantly correlated to the knee flexion angle (r= -0.64, p=0.03). Rearfoot landings may explain the higher ACL injury rate among females. Higher plantar-flexed ankle, hip, and trunk flexion angles were associated with lower peak ground reaction forces, while higher knee flexion angle was associated with lower peak knee abduction moment, and these kinematics implicate reduced risk of non-contact ACL injury. PMID- 24146703 TI - Anticipatory postural adjustments in dart throwing. AB - The aim of this study was to explore the effects of accuracy constraints on the characteristics of anticipatory postural adjustments (APA) in a task that involves a movement consisting of a controlled phase and a ballistic phase. It was hypothesized that APA scaling with task parameters (target size) would be preserved even when the task is performed by muscles that have no direct effects on APA. Sixteen healthy right handed subjects participated in the study. All participants had no prior experience in dart throwing. Subjects' average age was 24.1 +/- 1.9 years. A force platform and a motion capture system were used to register kinetics of the body and kinematics of the throwing arm and throwing accuracy. The experiment consisted of six series of twenty consecutive dart throws to a specified target. Target sizes (T2-T6) were set at 25%, 50%, 75%, 125% and 150% of target 1 (T1) initially set as the spread of the last 20 throws in a 50 throw training session. This allowed to distinguish six indexes of difficulty (ID's) ranging from 2,9 to 5,9. A one-way ANOVA for repeated measures was used for statistical analysis. Results of ANOVA showed a significant effect of target size at Constant Error but no effect at APA time. There were also no significant differences between hit and miss throws. From a control perspective, it can be stated that changes in central commands did not lead to changes in APA time in the analyzed motor task. PMID- 24146704 TI - Reliability of Concentric, Eccentric and Isometric Knee Extension and Flexion when using the REV9000 Isokinetic Dynamometer. AB - The aim of this study was to assess the reliability of isokinetic and ISO knee extensor and flexor muscle strength when using the REV9000 (Technogym) isokinetic dynamometer. Moreover, the reliability of several strength imbalance indices and bilateral ratios were also examined. Twenty-four physically active healthy subjects (age 23+/-3 years) underwent three testing sessions, two on the same day and a third, 7 days later. All sessions proceeded in the same order: five concentric contractions at 60os-1 followed by an isometric contraction (5 seconds) and five eccentric contractions (60os-1). The results of this study showed a high reproducibility in eccentric (0.95-0.97), concentric (0.95-0.96) and isometric (0.93-0.96), isokinetic strength for knee extensor and flexor muscles, thus indicating that the REV9000 isokinetic dynamometer can be used in future sports performance studies. A low-to-moderate reliability was found in the isokinetic strength bilateral ratios while the Hamstring:Quadricep concentric ratio showed moderate reliability. The highest reliability (>0.90) was observed in the dynamic control ratio (Hamstring eccentric:Quadricep concentric) which consequently confirms that it is a more valid indicator for imbalanced reciprocal parameters and can be used in rehabilitation and sports medicine. PMID- 24146705 TI - A time-motion analysis of turns performed by highly ranked viennese waltz dancers. AB - Twenty-four dance couples performing at the 2011 IDSF (International DanceSport Federation) International Slovenia Open were divided into two groups: the first twelve placed couples (top ranked) and the last twelve placed couples (lower ranked). Video recordings were processed automatically using computer vision tracking algorithms under operator supervision to calculate movement parameters. Time and speed of movement were analysed during single natural (right) and reverse (left) turns performed during the Viennese waltz. Both top and lower ranked dancers tended to perform similar proportionate frequencies of reverse (~ 35%) and natural (~ 65%) turns. Analysis of reverse turns showed that the top ranked dancers performed less turns on a curved trajectory (16%) than the lower ranked dancers (33%). The top ranked couples performed all turns at similar speeds (F = 1.31, df = 3, p = 0.27; mean = 2.09m/s) all of which were significantly quicker than the lower ranked couples (mean = 1.94m/s), the greatest differences found for reverse turns (12.43% faster for curved trajectories, 8.42% for straight trajectories). This suggests that the ability to maintain a high speed in the more difficult turns, particularly the reverse turns on a curved trajectory, results in the overall dance appearing more fluent as the speed of movement does not fluctuate as much. This aspect of performance needs to be improved by lower ranked dancers if they wish to improve rating of their performance. Future research should determine which factors relate to the speed of turns. PMID- 24146706 TI - Muscle activation profiles of lower extremities in different throwing techniques and in jumping performance in elite and novice greek judo athletes. AB - The aim of this study was to examine the neuromuscular adaptations of knee muscles during hip throwing techniques and vertical jumps in elite and novice Greek judokas. Ten elite and ten novice judokas performed two hip throws and different vertical jumping tasks. Surface electromyograms were recorded from vastus lateralis and biceps femoris muscles along with generated kinetics. Elite judokas revealed higher EMG activity of agonist muscles during throws and jumps but lower co-activation levels. Better jumping performance, better utilisation of the stretch-shortening cycle mechanism, higher and earlier generated push-off forces and shorter contact time periods characterized elite judokas. Total neuromuscular activation that adopt elite judokas reveals a more mature and skill dependent strategy compared to novice ones. PMID- 24146707 TI - The effect of upper extremity fatigue on grip strength and passing accuracy in junior basketball players. AB - Fatigue is an unavoidable part of a basketball game, which may affect an athlete's performance. The aim of this study was to investigate the effect of upper extremity fatigue on grip strength and passing accuracy in basketball, and ascertain if the effects of different fatigue protocols on grip strength and passing accuracy are the same. Twenty-four juniors under 18 years old (age: 16.75 +/- 0.62 years; body height: 184.5 +/- 3.31 cm; body mass: 77.25 +/- 3.22 kg) volunteered to participate in the study, and were divided into two groups. After a warm-up, both groups performed the basketball passing test and grip strength was recorded for each group under three different testing conditions: rest, 70% and 90% exercise intensity. The protocol used for the first group was the chest press, and for the second group the wrist curls. Results show that after the upper extremity fatigue protocol all parameters of the study (grip strength and passing accuracy) showed a significant decrease, and there was no significant difference between both groups regarding grip strength and passing accuracy. The study suggested that in order to avoid upper extremity fatigue, basketball trainers and coaches need to include upper extremity conditioning exercises into their training sessions. PMID- 24146708 TI - Effects of Different Backpack Loads in Acceleration Transmission during Recreational Distance Walking. AB - It is well established nowadays the benefits that physical activity can have on the health of individuals. Walking is considered a fundamental method of movement and using a backpack is a common and economical manner of carrying load weight. Nevertheless, the shock wave produced by the impact forces when carrying a backpack can have detrimental effects on health status. Therefore, the aim of this study was to investigate differences in the accelerations placed on males and females whilst carrying different loads when walking. Twenty nine sports science students (16 males and 13 females) participated in the study under 3 different conditions: no weight, 10% and 20% body weight (BW) added in a backpack. Accelerometers were attached to the right shank and the centre of the forehead. Results showed that males have lower accelerations than females both in the head (2.62 +/- 0.43G compared to 2.83 + 0.47G) and shank (1.37 +/- 0.14G compared to 1.52 +/- 0.15G; p<0.01). Accelerations for males and females were consistent throughout each backpack condition (p>0.05). The body acts as a natural shock absorber, reducing the amount of force that transmits through the body between the foot (impact point) and head. Anthropometric and body mass distribution differences between males and females may result in women receiving greater impact acceleration compared to men when the same load is carried. PMID- 24146709 TI - Neuromuscular impairment following backpack load carriage. AB - Load Carriage using backpacks is an occupational task and can be a recreational pursuit. The aim of this study was to investigate the mechanisms responsible for changes in neuromuscular function of the m. quadriceps femoris following load carriage. The physiological responses of 10 male participants to voluntary and electrically stimulated isometric contractions were measured before and immediately after two hours of treadmill walking at 6.5 km*h(-1) during level walking with no load [LW], and level walking with load carriage (25 kg backpack) [LC]. Maximal voluntary contraction force decreased by 15 +/- 11 % following LC (p=0.006), with no change following LW (p=0.292). Voluntary activation decreased after LW and LC (p=0.033) with no difference between conditions (p=0.405). Doublet contraction time decreased after both LW and LC (p=0.002), with no difference between conditions (p=0.232). There were no other changes in electrically invoked doublet parameters in either condition. The 20:50 Hz ratio did not change following LW (p=0.864) but decreased from 0.88 +/- 0.04 to 0.84 +/ 0.04 after LC (p=0.011) indicating reduced Ca2+ release from the sarcoplasmic reticulum during excitation contraction coupling. In conclusion, two hours of load carriage carrying a 25 kg back pack caused neuromuscular impairment through a decrease in voluntary activation (i.e. central drive) and fatigue or damage to the peripheral muscle, including impairment of the excitation contraction coupling process. This may reduce physical performance and increase the risk of musculoskeletal injury. PMID- 24146710 TI - A Physiological and Kinematic Comparison of two Different Lean Back Positions During Stationary Rowing on a Concept II Machine. AB - This study compared two different body positions at the finish of a stroke during stationary rowing exercise on physiological and kinematic measurements. Nine male and five female rowers volunteered for the study: mean age (+/- SD), body height and body mass were 27 +/-9 yrs, 180.5 +/-12.3 cm and 81.2 +/-14.2 kg. The two body positions at the finish were controlled at an upright posture or a novel greater lean back position. All subjects completed 3 different experimental trials on a Concept IID rowing machine at 3 different exercise intensities and comparisons were made between the lean back position at the same stroke rate and the same power output as the upright trial. Power output, heart rate, oxygen uptake, energy expenditure and % efficiency were higher (p<0.05) with the greater lean back position at the same stroke rate compared to all other conditions. Range of motion at the hip, ankle, and elbow and the handle velocity and distance moved were greater (p<0.05) with the lean back position. In conclusion, a greater lean back posture at the finish during stationary rowing produces a higher power output and improved efficiency at the same stroke rate but at an elevated physiological cost compared to a more upright position. Despite the higher energy expenditure, the relative gain in power output and efficiency with no negative kinematic changes suggests that a greater lean back position at the finish will enhance performance during stationary rowing exercise. PMID- 24146711 TI - The effect of patellar taping on squat depth and the perception of pain in people with anterior knee pain. AB - Patellar taping is a treatment adjunct commonly used in the management of anterior knee pain. The aim of this cross sectional study was to investigate the effects of medial glide patellar taping on sagittal plane lower-limb joint kinematics and knee pain during a unilateral squat in a symptomatic population complaining of anterior knee pain. Ten participants with a history of unilateral or bilateral anterior knee pain were included in the study. Subjects were required to squat on the symptomatic leg under three conditions: placebo tape, patellar tape and no tape. Kinematic data was recorded using the CODA mpx64 motion analysis system and subjects' pain was assessed using the Numerical Rating Scale. Patellar taping resulted in a significantly greater single-legged squat depth compared to placebo tape (p=0.008) and no tape (p=0.001) and a statistically significant reduction in pain during a squat compared to placebo tape (p=0.001) or no tape (p=0.001). Significant differences were not identified for maximum knee flexion in the patella taping compared to the no tape condition. This study may have significant clinical implications as participants reported less pain and alterations in sagittal plane movement following the application of patellar tape. PMID- 24146712 TI - The influence of body weight on chosen physiological parameters in wrestling. AB - In this study, the authors attempted to determine whether the dynamics of blood lactate and glucose in wrestling depend on the weight class. Blood lactate and glucose curves during and after a wrestling match were determined. We also explained the dynamics of blood lactate and glucose in the context of recent glucose and lactate metabolism research. A sample of 60 youth wrestlers (15-20 years) were divided into three weight groups. Each athlete participated in one wrestling match. During the fight, the athletes' heart rate, glucose, and blood lactate were measured. The differences in body mass between the athletes did not affect the dynamics of lactate and glucose in wrestling competition (Fisher LSD test). We established that lactate and glucose dynamics are the same for all weight groups (Fisher LSD-Lactate 1 < 2 < 3 = 4 > 5, Fisher LSD-Glucose 1 = 2 < 3 < 4 < 5). Understanding lactate and glucose metabolism in wrestling is important for wrestling coaches because they need to evaluate a wrestler's anaerobic energy status. PMID- 24146713 TI - Effect of kinesio tape application on calf pain and ankle range of motion in duathletes. AB - The purpose of this study was to examine the effect of the kinesio tape immediately after its application and after a duathlon competition on calf pain and the ankle range of motion in duathletes. A sample of 28 duathletes (age 29.11 +/- 10.35 years; body height 172.57 +/- 6.17 cm; body mass 66.63 +/- 9.01 kg; body mass index 22.29 +/- 2.00 kg/m(2)) were recruited from the competitors in a duathlon sprint. The Numerical Pain Rating Scale and ankle dorsiflexion range of motion measures were obtained at baseline, immediately after taping and 10 to 15 minutes after ending the duathlon competition. The kinesio tape was applied on the calf of duathletes 20 to 90 minutes before the competition, only on one of their legs (experimental leg) with the other leg acting as a control (control leg) in a randomized order. According to the between-group comparison, no differences were found immediately after the application of the kinesio tape and after the competition in the ankle range of motion and calf pain. However, a significant difference from baseline to immediately after taping was found in the ankle range of motion in the experimental leg. Applying the kinesio tape on the calf seems to immediately increase ankle dorsiflexion range of motion, but not after a duathlon competition. Applying the kinesio tape on the calf does not reduce muscle pain immediately or after a duathlon competition, but it appears to control an increase in pain. PMID- 24146714 TI - Home Advantage in Men's and Women's Spanish First and Second Division Water Polo Leagues. AB - The purpose of this study was to quantify the home advantage in both men's and women's First and Second Division water polo leagues, to compare the results obtained according to sex of participants and the level of competition, and to test for possible differences in home advantage when considering the interaction between these two factors. The sample comprised four seasons from 2007-2008 to 2010-2011 for a total of 1942 games analyzed. The results showed the existence of home advantage in both men's and women's First and Second Divisions. After controlling for the competitive balance of each league in each season, there was a significant difference between men's and women's leagues, with higher home advantage for men's leagues (58.60% compared with 53.70% for women's leagues). There was also a significant difference between the levels of competition, with greater home advantage for the Second Division (57.95% compared with 54.35% for First Division). No significant differences in home advantage were found when considering the interaction between sex of participants and the level of competition. The results in relation to sex of participants and the level of competition are consistent with previous studies in other sports such as football or handball. PMID- 24146715 TI - Game Indicators Determining Sports Performance in the NBA. AB - The main goal of the present study was to identify basketball game performance indicators which best determine sports level in the National Basketball Association (NBA) league. The research material consisted of all NBA game statistics at the turn of eight seasons (2003-11) and included 52 performance variables. Through detailed analysis the variables with high influence on game effectiveness were selected for final procedures. It has been proven that a limited number of factors, mostly offensive, determines sports performance in the NBA. The most critical indicators are: Win%, Offensive EFF, 3rd Quarter PPG, Win% CG, Avg Fauls and Avg Steals. In practical applications these results connected with top teams and elite players may help coaches to design better training programs. PMID- 24146716 TI - Effects of a Circuit Training Program on Muscular and Cardiovascular Endurance and their Maintenance in Schoolchildren. AB - The purpose of this study was to evaluate the effects of a circuit training program along with a maintenance program on muscular and cardiovascular endurance in children in a physical education setting. Seventy two children 10-12 years old from four different classes were randomly grouped into either an experimental group (n = 35) or a control group (n = 37) (two classes for each group). After an eight-week development program carried out twice a week and a four-week detraining period, the experimental group performed a four-week maintenance program once a week. The program included one circuit of eight stations of 15/45 to 35/25 seconds of work/rest performed twice. Abdominal muscular endurance (sit ups in 30 seconds test), upper-limbs muscular endurance (bent arm hang test), and cardiovascular endurance (20-m endurance shuttle run test) were measured at the beginning and at the end of the development program, and at the end of the maintenance program. After the development program, muscular and cardiovascular endurance increased significantly in the experimental group (p < 0.05). The gains obtained remained after the maintenance program. The respective values did not change in the control group (p > 0.05). The results showed that the circuit training program was effective to increase and maintain both muscular and cardiovascular endurance among schoolchildren. This could help physical education teachers design programs that permit students to maintain fit muscular and cardiovascular endurance levels. PMID- 24146717 TI - Changes in selected parameters of swimming technique in the back crawl and the front crawl in young novice swimmers. AB - The study aimed to examine changes in selected angular characteristics and duration of the stroke cycle in the back crawl and the front crawl in children learning to swim. Nine boys and two girls, aged 8-13 years, performed seven consecutive swimming tests. The children's movement technique was recorded with the use of three video cameras. The studied parameters included the angle of incidence between the trunk long axis and the waterline, elbow angle, shoulders roll, stroke cycle duration and stroke length. The results illustrate the development of swimming technique in youth swimmers. The results of the present study indicate the variability and phasing of learning of swimming technique by children. PMID- 24146718 TI - Is the quality of judging in women artistic gymnastics equivalent at major competitions of different levels? AB - In the present study, the reliability and validity of judging at the European championship in Berlin 2011 were analysed and the results were compared to a different level gymnastic competition - Universiade 2009 in Belgrade. For reliability and consistency assessment, mean absolute judge deviation from final execution score, Cronbach's alpha coefficient, intra-class correlations (ICC) and Armor's theta coefficient were calculated. For validity assessment mean deviations of judges' scores, Kendall's coefficient of concordance W and ANOVA eta-squared values were used. For Berlin 2011 in general Cronbach's alpha was above 0.95, minima of item-total correlations were above 0.8, and the ICC of average scores and Armor's theta were above 0.94. Comparison with Universiade 2009 identified vault and floor scores at both competitions to have inferior reliability indices. At both competitions average deviations of judges from the final E score were close to zero (p=0.84) but Berlin 2011 competition showed a higher number of apparatuses with significant Kendall's W (5 vs. 2 for Universiade 2009) and higher eta-squared values indicating higher judge panel bias in all-round and apparatus finals. In conclusion, the quality of judging was comparable at examined gymnastics competitions of different levels. Further work must be done to analyse the inferior results at vault and floor apparatuses. PMID- 24146719 TI - Benefits of bandwidth feedback in learning a complex gymnastic skill. AB - The aim of this study was to examine the effects of two different frequencies of feedback during the process of learning a complex gymnastic skill, the round-off salto backward tucked. Thirty male acrobats participated in the study. They were randomly assigned to two groups: B - bandwidth feedback (n=15) or C - 100% feedback (n=15). Group B was provided with error information regarding the key elements of movement techniques only (bandwidth feedback). Our research demonstrates the advantage of augmented feedback information related to errors in the key elements. Information about errors in the key elements during learning a complex gymnastic skill prevents the gymnast from becoming overwhelmed, which promotes better motor control. These results provide support for the generalisation of bandwidth feedback principles to a complex task. Our research shows that the guidance hypothesis can also be tested in practical settings for a complex movement task. PMID- 24146739 TI - Targeted deletion of FGL2 leads to increased early viral replication and enhanced adaptive immunity in a murine model of acute viral hepatitis caused by LCMV WE. AB - Mounting effective innate and adaptive immune responses are critical for viral clearance and the generation of long lasting immunity. It is known that production of inhibitory factors may result in the inability of the host to clear viruses, resulting in chronic viral persistence. Fibrinogen-like protein 2 (FGL2) has been identified as a novel effector molecule of CD4(+)CD25(+) Foxp3(+) regulatory T (Treg) cells that inhibits immune activity by binding to FCgammaRIIB expressed primarily on antigen presenting cells (APC). In this study, we show that infection of mice with Lymphocytic Choriomeningitis Virus WE (LCMV WE) leads to increased plasma levels of FGL2, which were detected as early as 2 days post infection (pi) and persisted until day 50 pi. Mice deficient in FGL2 (fgl2(-/-)) had increased viral titers of LCMV WE in the liver early p.i but cleared the virus by day 12 similar to wild type mice. Dendritic cells (DC) isolated from the spleens of LCMV WE infected fgl2(-/-) had increased expression of the DC maturation markers CD80 and MHC Class II compared to wild type (fgl2(+/+)). Frequencies of CD8(+) and CD4(+) T cells producing IFNgamma in response to ex vivo peptide re-stimulation isolated from the spleen and lymph nodes were also increased in LCMV WE infected fgl2(-/-) mice. Increased frequencies of CD8(+) T cells specific for LCMV tetramers GP33 and NP396 were detected within the liver of fgl2(-/-) mice. Plasma from fgl2(-/-) mice contained higher titers of total and neutralizing anti-LCMV antibody. Enhanced anti-viral immunity in fgl2(-/-) mice was associated with increased levels of serum alanine transaminase (ALT), hepatic necrosis and inflammation following LCMV WE infection. These data demonstrate that targeting FGL2 leads to early increased viral replication but enhanced anti-viral adaptive T & B cell responses. Targeting FGL2 may enhance the efficacy of current anti-viral therapies for hepatotropic viruses. PMID- 24146740 TI - Evolutionary relationships between Rhynchosporium lolii sp. nov. and other Rhynchosporium species on grasses. AB - The fungal genus Rhynchosporium (causative agent of leaf blotch) contains several host-specialised species, including R. commune (colonising barley and brome grass), R. agropyri (couch-grass), R. secalis (rye and triticale) and the more distantly related R. orthosporum (cocksfoot). This study used molecular fingerprinting, multilocus DNA sequence data, conidial morphology, host range tests and scanning electron microscopy to investigate the relationship between Rhynchosporium species on ryegrasses, both economically important forage grasses and common wild grasses in many cereal growing areas, and other plant species. Two different types of Rhynchosporium were found on ryegrasses in the UK. Firstly, there were isolates of R. commune that were pathogenic to both barley and Italian ryegrass. Secondly, there were isolates of a new species, here named R. lolii, that were pathogenic only to ryegrass species. R. lolii was most closely related to R. orthosporum, but exhibited clear molecular, morphological and host range differences. The species was estimated to have diverged from R. orthosporum ca. 5735 years before the present. The colonisation strategy of all of the different Rhynchosporium species involved extensive hyphal growth in the sub-cuticular regions of the leaves. Finally, new species-specific PCR diagnostic tests were developed that could distinguish between these five closely related Rhynchosporium species. PMID- 24146741 TI - The ability of analysts' recommendations to predict optimistic and pessimistic forecasts. AB - Previous researches show that buy (growth) companies conduct income increasing earnings management in order to meet forecasts and generate positive forecast Errors (FEs). This behavior however, is not inherent in sell (non-growth) companies. Using the aforementioned background, this research hypothesizes that since sell companies are pressured to avoid income increasing earnings management, they are capable, and in fact more inclined, to pursue income decreasing Forecast Management (FM) with the purpose of generating positive FEs. Using a sample of 6553 firm-years of companies that are listed in the NYSE between the years 2005-2010, the study determines that sell companies conduct income decreasing FM to generate positive FEs. However, the frequency of positive FEs of sell companies does not exceed that of buy companies. Using the efficiency perspective, the study suggests that even though buy and sell companies have immense motivation in avoiding negative FEs, they exploit different but efficient strategies, respectively, in order to meet forecasts. Furthermore, the findings illuminated the complexities behind informative and opportunistic forecasts that falls under the efficiency versus opportunistic theories in literature. PMID- 24146742 TI - Glacial history affected phenotypic differentiation in the alpine plant, Campanula thyrsoides. AB - Numerous widespread Alpine plant species show molecular differentiation among populations from distinct regions. This has been explained as the result of genetic drift during glacial survival in isolated refugia along the border of the European Alps. Since genetic drift may affect molecular markers and phenotypic traits alike, we asked whether phenotypic differentiation mirrors molecular patterns among Alpine plant populations from different regions. Phenotypic traits can be under selection, so we additionally investigated whether part of the phenotypic differentiation can be explained by past selection and/or current adaptation. Using the monocarpic Campanula thyrsoides as our study species, a common garden experiment with plants from 21 populations from four phylogeographic groups located in regions across the Alps and the Jura Mountains was performed to test for differentiation in morphological and phenological traits. Past selection was investigated by comparing phenotypic differentiation among and within regions with molecular differentiation among and within regions. The common garden results indicated regional differentiation among populations for all investigated phenotypic traits, particularly in phenology. Delayed flowering in plants from the South-eastern Alps suggested adaptation to long sub mediterranean summers and contrasted with earlier flowering of plants experiencing shorter growing seasons in regions with higher elevation to the West. Comparisons between molecular and phenotypic differentiation revealed diversifying selection among regions in height and biomass, which is consistent with adaptation to environmental conditions in glacial refugia. Within regions, past selection acted against strong diversification for most phenotypic traits, causing restricted postglacial adaptation. Evidence consistent with post-glacial adaptation was also given by negative correlation coefficients between several phenotypic traits and elevation of the population's origin. In conclusion, our study suggests that, irrespective of adaptation of plants to their current environment, glacial history can have a strong and long-lasting influence on the phenotypic evolution of Alpine plants. PMID- 24146743 TI - Association of pro-inflammatory cytokines and iron regulatory protein 2 (IRP2) with Leishmania burden in canine visceral leishmaniasis. AB - Leishmania infantum infection in humans and dogs can evolve with a wide range of clinical presentations, varying from asymptomatic infections to visceral leishmaniasis. We hypothesized that the immune response elicited by L. infantum infection could modulate whether the host will remain asymptomatic or progress to disease. A total of 44 dogs naturally infected with L. infantum were studied. Leishmania burden was estimated in the blood and spleen by qPCR. The expression of IFN-gamma, TNF-alpha, IL-10 and Iron Regulatory Protein 2 (IRP2) were determined in the spleen by quantitative PCR. Sera cytokines were evaluated by ELISA. Dogs were grouped in quartiles according parasite burden. Increased expression of IFN-gamma and TNF-alpha was associated with reduced Leishmania burden, whereas increased IL-10 and IRP2 expressions were associated with higher Leishmania load. Increased plasma albumin and IFN-gamma expression explained 22.8% of the decrease in parasite burden in the spleen. These data confirm that lower IFN-gamma response and higher IL-10 correlated with increased parasite load and severity of the visceral leishmaniasis in dogs. The balance between the branches of immune response and the intracellular iron availability could determine, in part, the course of Leishmania infection. PMID- 24146744 TI - Clinical assessment of anti-viral CD8+ T cell immune monitoring using QuantiFERON CMV(r) assay to identify high risk allogeneic hematopoietic stem cell transplant patients with CMV infection complications. AB - The reconstitution of anti-viral cellular immunity following hematopoietic stem cell transplantation (HSCT) is crucial in preventing cytomegalovirus (CMV) associated complications. Thus immunological monitoring has emerged as an important tool to better target pre-emptive anti-viral therapies. However, traditional laboratory-based assays are too cumbersome and complicated to implement in a clinical setting. Here we conducted a prospective study of a new whole blood assay (referred to as QuantiFERON-CMV(r)) to determine the clinical utility of measuring CMV-specific CD8+ T-cell responses as a prognostic tool. Forty-one evaluable allogeneic HSCT recipients underwent weekly immunological monitoring from day 21 post-transplant and of these 21 (51.2%) showed CMV reactivation and 29 (70.7%) developed acute graft-versus-host disease (GvHD). Patients with acute GvHD (grade >= 2) within 6 weeks of transplant showed delayed reconstitution of CMV-specific T-cell immunity (p = 0.013) and a higher risk of CMV viremia (p = 0.026). The median time to stable CMV-specific immune reconstitution was 59 days and the incidence of CMV reactivation was lower in patients who developed this than those who did not (27% versus 65%; p = 0.031). Furthermore, a failure to reconstitute CMV-specific immunity soon after the onset of CMV viraemia was associated with higher peak viral loads (5685 copies/ml versus 875 copies/ml; p = 0.002). Hence, QuantiFERON-CMV(r) testing in the week following CMV viremia can be useful in identifying HSCT recipients at risk of complicated reactivation. PMID- 24146745 TI - An FMRI study of grammatical morpheme processing associated with nouns and verbs in Chinese. AB - This study examined whether the degree of complexity of a grammatical component in a language would impact on its representation in the brain through identifying the neural correlates of grammatical morpheme processing associated with nouns and verbs in Chinese. In particular, the processing of Chinese nominal classifiers and verbal aspect markers were investigated in a sentence completion task and a grammaticality judgment task to look for converging evidence. The Chinese language constitutes a special case because it has no inflectional morphology per se and a larger classifier than aspect marker inventory, contrary to the pattern of greater verbal than nominal paradigmatic complexity in most European languages. The functional imaging results showed BA47 and left supplementary motor area and superior medial frontal gyrus more strongly activated for classifier processing, and the left posterior middle temporal gyrus more responsive to aspect marker processing. We attributed the activation in the left prefrontal cortex to greater processing complexity during classifier selection, analogous to the accounts put forth for European languages, and the left posterior middle temporal gyrus to more demanding verb semantic processing. The overall findings significantly contribute to cross-linguistic observations of neural substrates underlying processing of grammatical morphemes from an analytic and a classifier language, and thereby deepen our understanding of neurobiology of human language. PMID- 24146746 TI - How safe is safe enough? Radiation risk for a human mission to Mars. AB - Astronauts on a mission to Mars would be exposed for up to 3 years to galactic cosmic rays (GCR)--made up of high-energy protons and high charge (Z) and energy (E) (HZE) nuclei. GCR exposure rate increases about three times as spacecraft venture out of Earth orbit into deep space where protection of the Earth's magnetosphere and solid body are lost. NASA's radiation standard limits astronaut exposures to a 3% risk of exposure induced death (REID) at the upper 95% confidence interval (CI) of the risk estimate. Fatal cancer risk has been considered the dominant risk for GCR, however recent epidemiological analysis of radiation risks for circulatory diseases allow for predictions of REID for circulatory diseases to be included with cancer risk predictions for space missions. Using NASA's models of risks and uncertainties, we predicted that central estimates for radiation induced mortality and morbidity could exceed 5% and 10% with upper 95% CI near 10% and 20%, respectively for a Mars mission. Additional risks to the central nervous system (CNS) and qualitative differences in the biological effects of GCR compared to terrestrial radiation may significantly increase these estimates, and will require new knowledge to evaluate. PMID- 24146747 TI - Coral energy reserves and calcification in a high-CO2 world at two temperatures. AB - Rising atmospheric CO2 concentrations threaten coral reefs globally by causing ocean acidification (OA) and warming. Yet, the combined effects of elevated pCO2 and temperature on coral physiology and resilience remain poorly understood. While coral calcification and energy reserves are important health indicators, no studies to date have measured energy reserve pools (i.e., lipid, protein, and carbohydrate) together with calcification under OA conditions under different temperature scenarios. Four coral species, Acropora millepora, Montipora monasteriata, Pocillopora damicornis, Turbinaria reniformis, were reared under a total of six conditions for 3.5 weeks, representing three pCO2 levels (382, 607, 741 uatm), and two temperature regimes (26.5, 29.0 degrees C) within each pCO2 level. After one month under experimental conditions, only A. millepora decreased calcification (-53%) in response to seawater pCO2 expected by the end of this century, whereas the other three species maintained calcification rates even when both pCO2 and temperature were elevated. Coral energy reserves showed mixed responses to elevated pCO2 and temperature, and were either unaffected or displayed nonlinear responses with both the lowest and highest concentrations often observed at the mid-pCO2 level of 607 uatm. Biweekly feeding may have helped corals maintain calcification rates and energy reserves under these conditions. Temperature often modulated the response of many aspects of coral physiology to OA, and both mitigated and worsened pCO2 effects. This demonstrates for the first time that coral energy reserves are generally not metabolized to sustain calcification under OA, which has important implications for coral health and bleaching resilience in a high-CO2 world. Overall, these findings suggest that some corals could be more resistant to simultaneously warming and acidifying oceans than previously expected. PMID- 24146749 TI - DNA analysis of herbarium Specimens of the grass weed Alopecurus myosuroides reveals herbicide resistance pre-dated herbicides. AB - Acetyl-CoA carboxylase (ACCase) alleles carrying one point mutation that confers resistance to herbicides have been identified in arable grass weed populations where resistance has evolved under the selective pressure of herbicides. In an effort to determine whether herbicide resistance evolves from newly arisen mutations or from standing genetic variation in weed populations, we used herbarium specimens of the grass weed Alopecurus myosuroides to seek mutant ACCase alleles carrying an isoleucine-to-leucine substitution at codon 1781 that endows herbicide resistance. These specimens had been collected between 1788 and 1975, i.e., prior to the commercial release of herbicides inhibiting ACCase. Among the 734 specimens investigated, 685 yielded DNA suitable for PCR. Genotyping the ACCase locus using the derived Cleaved Amplified Polymorphic Sequence (dCAPS) technique identified one heterozygous mutant specimen that had been collected in 1888. Occurrence of a mutant codon encoding a leucine residue at codon 1781 at the heterozygous state was confirmed in this specimen by sequencing, clearly demonstrating that resistance to herbicides can pre-date herbicides in weeds. We conclude that point mutations endowing resistance to herbicides without having associated deleterious pleiotropic effects can be present in weed populations as part of their standing genetic variation, in frequencies higher than the mutation frequency, thereby facilitating their subsequent selection by herbicide applications. PMID- 24146748 TI - Blood flow changes coincide with cellular rearrangements during blood vessel pruning in zebrafish embryos. AB - After the initial formation of a highly branched vascular plexus, blood vessel pruning generates a hierarchically structured network with improved flow characteristics. We report here on the cellular events that occur during the pruning of a defined blood vessel in the eye of developing zebrafish embryos. Time-lapse imaging reveals that the connection of a new blood vessel sprout with a previously perfused multicellular endothelial tube leads to the formation of a branched, Y-shaped structure. Subsequently, endothelial cells in parts of the previously perfused branch rearrange from a multicellular into a unicellular tube, followed by blood vessel detachment. This process is accompanied by endothelial cell death. Finally, we show that differences in blood flow between neighboring vessels are important for the completion of the pruning process. Our data suggest that flow induced changes in tubular architecture ensure proper blood vessel pruning. PMID- 24146750 TI - Association of LEP G2548A and LEPR Q223R polymorphisms with cancer susceptibility: evidence from a meta-analysis. AB - BACKGROUND: Numerous epidemiological studies have examined associations of genetic variations in LEP (G2548A, -2548 nucleotide upstream of the ATG start site) and LEPR (Q223R, nonsynonymous SNP in exon 6) with cancer susceptibility; however, the findings are inconsistent. Therefore, we performed a meta-analysis to comprehensively evaluate such associations. METHODS: We searched published literature from MEDLINE, EMBASE, Web of Science and CBM for eligible publications. We also assessed genotype-based mRNA expression data from HapMap for rs7799039 (G2548A) and rs1137101 (Q223R) in normal cell lines derived from 270 subjects with different ethnicities. RESULTS: The final analysis included 16 published studies of 6569 cases and 8405 controls for the LEP G2548A and 19 studies of 7504 cases and 9581 controls for the LEPR Q223R. Overall, LEP G2548A was statistically significantly associated with an increased risk of overall cancer (AA vs. GG: OR=1.27, 95% CI=1.05-1.54; recessive model: OR=1.19, 95% CI=1.00-1.41). Further stratifications by cancer type showed an increased risk for prostate cancer (recessive model: OR=1.26, 95% CI=1.05-1.51) but not for other cancers. For LEPR Q223R, no statistical evidence for an association with risk of cancer was found for all; however, further stratification by ethnicity showed an increased risk for Africans but not for other ethnicities. No significantly differences in LEP and LEPR mRNA expression were found among genotypes or by ethnicity. CONCLUSIONS: Despite some limitations, this meta analysis found some statistical evidence for an association between the LEP 2548AA genotype and overall risk of cancer, particularly for prostate cancer, but given this variant did not have an effect on mRNA expression, this association warrants additional validation in large and well-designed studies. PMID- 24146751 TI - Screening for protein-DNA interactions by automatable DNA-protein interaction ELISA. AB - DNA-binding proteins (DBPs), such as transcription factors, constitute about 10% of the protein-coding genes in eukaryotic genomes and play pivotal roles in the regulation of chromatin structure and gene expression by binding to short stretches of DNA. Despite their number and importance, only for a minor portion of DBPs the binding sequence had been disclosed. Methods that allow the de novo identification of DNA-binding motifs of known DBPs, such as protein binding microarray technology or SELEX, are not yet suited for high-throughput and automation. To close this gap, we report an automatable DNA-protein-interaction (DPI)-ELISA screen of an optimized double-stranded DNA (dsDNA) probe library that allows the high-throughput identification of hexanucleotide DNA-binding motifs. In contrast to other methods, this DPI-ELISA screen can be performed manually or with standard laboratory automation. Furthermore, output evaluation does not require extensive computational analysis to derive a binding consensus. We could show that the DPI-ELISA screen disclosed the full spectrum of binding preferences for a given DBP. As an example, AtWRKY11 was used to demonstrate that the automated DPI-ELISA screen revealed the entire range of in vitro binding preferences. In addition, protein extracts of AtbZIP63 and the DNA-binding domain of AtWRKY33 were analyzed, which led to a refinement of their known DNA-binding consensi. Finally, we performed a DPI-ELISA screen to disclose the DNA-binding consensus of a yet uncharacterized putative DBP, AtTIFY1. A palindromic TGATCA consensus was uncovered and we could show that the GATC-core is compulsory for AtTIFY1 binding. This specific interaction between AtTIFY1 and its DNA-binding motif was confirmed by in vivo plant one-hybrid assays in protoplasts. Thus, the value and applicability of the DPI-ELISA screen for de novo binding site identification of DBPs, also under automatized conditions, is a promising approach for a deeper understanding of gene regulation in any organism of choice. PMID- 24146752 TI - A 3D fibrous scaffold inducing tumoroids: a platform for anticancer drug development. AB - The development of a suitable three dimensional (3D) culture system for anticancer drug development remains an unmet need. Despite progress, a simple, rapid, scalable and inexpensive 3D-tumor model that recapitulates in vivo tumorigenesis is lacking. Herein, we report on the development and characterization of a 3D nanofibrous scaffold produced by electrospinning a mixture of poly(lactic-co-glycolic acid) (PLGA) and a block copolymer of polylactic acid (PLA) and mono-methoxypolyethylene glycol (mPEG) designated as 3P. Cancer cells cultured on the 3P scaffold formed tight irregular aggregates similar to in vivo tumors, referred to as tumoroids that depended on the topography and net charge of the scaffold. 3P scaffolds induced tumor cells to undergo the epithelial-to-mesenchymal transition (EMT) as demonstrated by up regulation of vimentin and loss of E-cadherin expression. 3P tumoroids showed higher resistance to anticancer drugs than the same tumor cells grown as monolayers. Inhibition of ERK and PI3K signal pathways prevented EMT and reduced tumoroid formation, diameter and number. Fine needle aspirates, collected from tumor cells implanted in mice when cultured on 3P scaffolds formed tumoroids, but showed decreased sensitivity to anticancer drugs, compared to tumoroids formed by direct seeding. These results show that 3P scaffolds provide an excellent platform for producing tumoroids from tumor cell lines and from biopsies and that the platform can be used to culture patient biopsies, test for anticancer compounds and tailor a personalized cancer treatment. PMID- 24146753 TI - Avian influenza infection alters fecal odor in mallards. AB - Changes in body odor are known to be a consequence of many diseases. Much of the published work on disease-related and body odor changes has involved parasites and certain cancers. Much less studied have been viral diseases, possibly due to an absence of good animal model systems. Here we studied possible alteration of fecal odors in animals infected with avian influenza viruses (AIV). In a behavioral study, inbred C57BL/6 mice were trained in a standard Y-maze to discriminate odors emanating from feces collected from mallard ducks (Anas platyrhynchos) infected with low-pathogenic avian influenza virus compared to fecal odors from non-infected controls. Mice could discriminate odors from non infected compared to infected individual ducks on the basis of fecal odors when feces from post-infection periods were paired with feces from pre-infection periods. Prompted by this indication of odor change, fecal samples were subjected to dynamic headspace and solvent extraction analyses employing gas chromatography/mass spectrometry to identify chemical markers indicative of AIV infection. Chemical analyses indicated that AIV infection was associated with a marked increase of acetoin (3-hydroxy-2-butanone) in feces. These experiments demonstrate that information regarding viral infection exists via volatile metabolites present in feces. Further, they suggest that odor changes following virus infection could play a role in regulating behavior of conspecifics exposed to infected individuals. PMID- 24146754 TI - Temporal expression of Pelp1 during proliferation and osteogenic differentiation of rat bone marrow mesenchymal stem cells. AB - BACKGROUND: Osteogenic induction and bone formation are heavily affected by environmental factors, including estrogen, estrogen receptors, and coregulatory proteins, such as the recently reported proline-, glutamic acid-, and leucine rich protein 1(Pelp1). OBJECTIVE: To investigate Pelp1 expression in rat bone mesenchymal stem cells (rBMSCs) during cell proliferation and osteogenic differentiation. METHODS: rBMSCs were cultured in routine and osteogenic differentiation media. Cell proliferation was assessed at days 1, 3, 5, 7, 9, 11, 14, and 21. Pelp1 protein expression in the nucleus and cytoplasm were detected by immunocytochemical analysis. Real-time RT-PCR and western blot were used to detect mRNA and protein expressions of Pelp1, osteocalcin (OCN), and alkaline phosphatase (ALP). RESULTS: Over 21 days, rBMSCs in routine culture exhibited a 1 2 day lag phase and exponential growth from day 3 to 9, plateauing at day 9, and correlated with temporal mRNA expression of Pelp1, which almost reached baseline levels at day 21. In osteogenic induction cultures, Pelp1 mRNA levels rose at day 9 and steadily increased until day 21, reaching 6.8-fold greater value compared with day 1. Interestingly, Pelp1 mRNA expression in osteogenic cultures exhibited a trend similar to that of OCN expression. Pelp1 knockdown by siRNA transfection inhibited undifferentiated rBMSC proliferation, and bone markers OCN and ALP expressions in rBMSCs cultured in routine and osteogenic differentiation media. CONCLUSIONS: Pelp1 may be a key player in BMSCs proliferation and osteogenic differentiation, meriting further consideration as a target for development of therapies for pathological bone loss conditions, such as menopausal bone loss. PMID- 24146757 TI - SIDD: a semantically integrated database towards a global view of human disease. AB - BACKGROUND: A number of databases have been developed to collect disease-related molecular, phenotypic and environmental features (DR-MPEs), such as genes, non coding RNAs, genetic variations, drugs, phenotypes and environmental factors. However, each of current databases focused on only one or two DR-MPEs. There is an urgent demand to develop an integrated database, which can establish semantic associations among disease-related databases and link them to provide a global view of human disease at the biological level. This database, once developed, will facilitate researchers to query various DR-MPEs through disease, and investigate disease mechanisms from different types of data. METHODOLOGY: To establish an integrated disease-associated database, disease vocabularies used in different databases are mapped to Disease Ontology (DO) through semantic match. 4,284 and 4,186 disease terms from Medical Subject Headings (MeSH) and Online Mendelian Inheritance in Man (OMIM) respectively are mapped to DO. Then, the relationships between DR-MPEs and diseases are extracted and merged from different source databases for reducing the data redundancy. CONCLUSIONS: A semantically integrated disease-associated database (SIDD) is developed, which integrates 18 disease-associated databases, for researchers to browse multiple types of DR-MPEs in a view. A web interface allows easy navigation for querying information through browsing a disease ontology tree or searching a disease term. Furthermore, a network visualization tool using Cytoscape Web plugin has been implemented in SIDD. It enhances the SIDD usage when viewing the relationships between diseases and DR-MPEs. The current version of SIDD (Jul 2013) documents 4,465,131 entries relating to 139,365 DR-MPEs, and to 3,824 human diseases. The database can be freely accessed from: http://mlg.hit.edu.cn/SIDD. PMID- 24146756 TI - Disability affects the 6-minute walking distance in obese subjects (BMI>40 kg/m(2)). AB - INTRODUCTION: In obese subjects, the relative reduction of the skeletal muscle strength, the reduced cardio-pulmonary capacity and tolerance to effort, the higher metabolic costs and, therefore, the increased inefficiency of gait together with the increased prevalence of co-morbid conditions might interfere with walking. Performance tests, such as the six-minute walking test (6MWT), can unveil the limitations in cardio-respiratory and motor functions underlying the obesity-related disability. Therefore the aims of the present study were: to explore the determinants of the 6-minute walking distance (6MWD) and to investigate the predictors of interruption of the walk test in obese subjects. METHODS: Obese patients [body mass index (BMI)>40 kg/m(2)] were recruited from January 2009 to December 2011. Anthropometry, body composition, specific questionnaire for Obesity-related Disabilities (TSD-OC test), fitness status and 6MWT data were evaluated. The correlation between the 6MWD and the potential independent variables (anthropometric parameters, body composition, muscle strength, flexibility and disability) were analysed. The variables which were singularly correlated with the response variable were included in a multivariated regression model. Finally, the correlation between nutritional and functional parameters and test interruption was investigated. RESULTS: 354 subjects (87 males, mean age 48.5 +/- 14 years, 267 females, mean age 49.8 +/- 15 years) were enrolled in the study. Age, weight, height, BMI, fat mass and fat free mass indexes, handgrip strength and disability were significantly correlated with the 6MWD and considered in the multivariate analysis. The determination coefficient of the regression analysis ranged from 0.21 to 0.47 for the different models. Body weight, BMI, waist circumference, TSD-OC test score and flexibility were found to be predictors of the 6MWT interruption. DISCUSSION: The present study demonstrated the impact of disability in obese subjects, together with age, anthropometric data, body composition and strength, on the 6-minute walking distance. PMID- 24146758 TI - Adverse events associated with yoga: a systematic review of published case reports and case series. AB - While yoga is gaining increased popularity in North America and Europe, its safety has been questioned in the lay press. The aim of this systematic review was to assess published case reports and case series on adverse events associated with yoga. Medline/Pubmed, Scopus, CAMBase, IndMed and the Cases Database were screened through February 2013; and 35 case reports and 2 case series reporting a total of 76 cases were included. Ten cases had medical preconditions, mainly glaucoma and osteopenia. Pranayama, hatha yoga, and Bikram yoga were the most common yoga practices; headstand, shoulder stand, lotus position, and forceful breathing were the most common yoga postures and breathing techniques cited. Twenty-seven adverse events (35.5%) affected the musculoskeletal system; 14 (18.4%) the nervous system; and 9 (11.8%) the eyes. Fifteen cases (19.7%) reached full recovery; 9 cases (11.3%) partial recovery; 1 case (1.3%) no recovery; and 1 case (1.3%) died. As any other physical or mental practice, yoga should be practiced carefully under the guidance of a qualified instructor. Beginners should avoid extreme practices such as headstand, lotus position and forceful breathing. Individuals with medical preconditions should work with their physician and yoga teacher to appropriately adapt postures; patients with glaucoma should avoid inversions and patients with compromised bone should avoid forceful yoga practices. PMID- 24146755 TI - The tumor suppressor gene, RASSF1A, is essential for protection against inflammation -induced injury. AB - Ras association domain family protein 1A (RASSF1A) is a tumor suppressor gene silenced in cancer. Here we report that RASSF1A is a novel regulator of intestinal inflammation as Rassf1a(+/-) , Rassf1a(-/-) and an intestinal epithelial cell specific knockout mouse (Rassf1a (IEC-KO) ) rapidly became sick following dextran sulphate sodium (DSS) administration, a chemical inducer of colitis. Rassf1a knockout mice displayed clinical symptoms of inflammatory bowel disease including: increased intestinal permeability, enhanced cytokine/chemokine production, elevated nuclear factor of kappa light polypeptide gene enhancer in B cells (NFkappaB) activity, elevated colonic cell death and epithelial cell injury. Furthermore, epithelial restitution/repair was inhibited in DSS-treated Rassf1a(-/-) mice with reduction of several makers of proliferation including Yes associated protein (YAP)-driven proliferation. Surprisingly, tyrosine phosphorylation of YAP was detected which coincided with increased nuclear p73 association, Bax-driven epithelial cell death and p53 accumulation resulting in enhanced apoptosis and poor survival of DSS-treated Rassf1a knockout mice. We can inhibit these events and promote the survival of DSS-treated Rassf1a knockout mice with intraperitoneal injection of the c-Abl and c-Abl related protein tyrosine kinase inhibitor, imatinib/gleevec. However, p53 accumulation was not inhibited by imatinib/gleevec in the Rassf1a(-/-) background which revealed the importance of p53-dependent cell death during intestinal inflammation. These observations suggest that tyrosine phosphorylation of YAP (to drive p73 association and up-regulation of pro-apoptotic genes such as Bax) and accumulation of p53 are consequences of inflammation-induced injury in DSS treated Rassf1a(-/-) mice. Mechanistically, we can detect robust associations of RASSF1A with membrane proximal Toll-like receptor (TLR) components to suggest that RASSF1A may function to interfere and restrict TLR-driven activation of NFkappaB. Failure to restrict NFkappaB resulted in the inflammation-induced DNA damage driven tyrosine phosphorylation of YAP, subsequent p53 accumulation and loss of intestinal epithelial homeostasis. PMID- 24146760 TI - Efficient and interpretable prediction of protein functional classes by correspondence analysis and compact set relations. AB - Predicting protein functional classes such as localization sites and modifications plays a crucial role in function annotation. Given a tremendous amount of sequence data yielded from high-throughput sequencing experiments, the need of efficient and interpretable prediction strategies has been rapidly amplified. Our previous approach for subcellular localization prediction, PSLDoc, archives high overall accuracy for Gram-negative bacteria. However, PSLDoc is computational intensive due to incorporation of homology extension in feature extraction and probabilistic latent semantic analysis in feature reduction. Besides, prediction results generated by support vector machines are accurate but generally difficult to interpret. In this work, we incorporate three new techniques to improve efficiency and interpretability. First, homology extension is performed against a compact non-redundant database using a fast search model to reduce running time. Second, correspondence analysis (CA) is incorporated as an efficient feature reduction to generate a clear visual separation of different protein classes. Finally, functional classes are predicted by a combination of accurate compact set (CS) relation and interpretable one-nearest neighbor (1-NN) algorithm. Besides localization data sets, we also apply a human protein kinase set to validate generality of our proposed method. Experiment results demonstrate that our method make accurate prediction in a more efficient and interpretable manner. First, homology extension using a fast search on a compact database can greatly accelerate traditional running time up to twenty-five times faster without sacrificing prediction performance. This suggests that computational costs of many other predictors that also incorporate homology information can be largely reduced. In addition, CA can not only efficiently identify discriminative features but also provide a clear visualization of different functional classes. Moreover, predictions based on CS achieve 100% precision. When combined with 1-NN on unpredicted targets by CS, our method attains slightly better or comparable performance compared with the state-of-the-art systems. PMID- 24146761 TI - Impact of over-the-counter restrictions on antibiotic consumption in Brazil and Mexico. AB - BACKGROUND: In Latin American countries over-the-counter (OTC) dispensing of antibiotics is common. In 2010, both Mexico and Brazil implemented policies to enforce existing laws of restricting consumption of antibiotics only to patients presenting a prescription. The objective of the present study is therefore to evaluate the impact of OTC restrictions (2010) on antibiotics consumption in Brazil and Mexico. METHODS AND FINDINGS: Retail quarterly sales data in kilograms of oral and injectable antibiotics between January 2007 and June 2012 for Brazil and Mexico were obtained from IMS Health. The unit of analysis for antibiotics consumption was the defined daily dose per 1,000 inhabitants per day (DDD/TID) according to the WHO ATC classification system. Interrupted time series analysis was conducted using antihypertensives as reference group to account for changes occurring independently of the OTC restrictions directed at antibiotics. To reduce the effect of (a) seasonality and (b) autocorrelation, dummy variables and Prais-Winsten regression were used respectively. Between 2007 and 2012 total antibiotic usage increased in Brazil (from 5.7 to 8.5 DDD/TID, +49.3%) and decreased in Mexico (10.5 to 7.5 DDD/TID, -29.2%). Interrupted time series analysis showed a change in level of consumption of -1.35 DDD/TID (p<0.01) for Brazil and -1.17 DDD/TID (p<0.00) for Mexico. In Brazil the penicillins, sulfonamides and macrolides consumption had a decrease in level after the intervention of 0.64 DDD/TID (p = 0.02), 0.41 (p = 0.02) and 0.47 (p = 0.01) respectively. While in Mexico it was found that only penicillins and sulfonamides had significant changes in level of -0.86 DDD/TID (p<0.00) and -0.17 DDD/TID (p = 0.07). CONCLUSIONS: Despite different overall usage patterns of antibiotics in Brazil and Mexico, the effect of the OTC restrictions on antibiotics usage was similar. In Brazil the trend of increased usage of antibiotics was tempered after the OTC restrictions; in Mexico the trend of decreased usage was boosted. PMID- 24146759 TI - Biophysical investigation of the membrane-disrupting mechanism of the antimicrobial and amyloid-like peptide dermaseptin S9. AB - Dermaseptin S9 (Drs S9) is an atypical cationic antimicrobial peptide with a long hydrophobic core and with a propensity to form amyloid-like fibrils. Here we investigated its membrane interaction using a variety of biophysical techniques. Rather surprisingly, we found that Drs S9 induces efficient permeabilisation in zwitterionic phosphatidylcholine (PC) vesicles, but not in anionic phosphatidylglycerol (PG) vesicles. We also found that the peptide inserts more efficiently in PC than in PG monolayers. Therefore, electrostatic interactions between the cationic Drs S9 and anionic membranes cannot explain the selectivity of the peptide towards bacterial membranes. CD spectroscopy, electron microscopy and ThT fluorescence experiments showed that the peptide adopts slightly more beta-sheet and has a higher tendency to form amyloid-like fibrils in the presence of PC membranes as compared to PG membranes. Thus, induction of leakage may be related to peptide aggregation. The use of a pre-incorporation protocol to reduce peptide/peptide interactions characteristic of aggregates in solution resulted in more alpha-helix formation and a more pronounced effect on the cooperativity of the gel-fluid lipid phase transition in all lipid systems tested. Calorimetric data together with (2)H- and (31)P-NMR experiments indicated that the peptide has a significant impact on the dynamic organization of lipid bilayers, albeit slightly less for zwitterionic than for anionic membranes. Taken together, our data suggest that in particular in membranes of zwitterionic lipids the peptide binds in an aggregated state resulting in membrane leakage. We propose that also the antimicrobial activity of Drs S9 may be a result of binding of the peptide in an aggregated state, but that specific binding and aggregation to bacterial membranes is regulated not by anionic lipids but by as yet unknown factors. PMID- 24146762 TI - Deferred pre-emptive switch from calcineurin inhibitor to sirolimus leads to improvement in GFR and expansion of T regulatory cell population: a randomized, controlled trial. AB - BACKGROUND: Measures to prevent chronic calcineurin inhibitor (CNI) toxicity have included limiting exposure by switching to sirolimus (SIR). SIR may favorably influence T regulator cell (T(reg)) population. This randomized controlled trial compares the effect of switching from CNI to SIR on glomerular filtration rate (GFR) and T(reg) frequency. METHODS: In this prospective open label randomized trial, primary living donor kidney transplant recipients on CNI-based immunosuppression were randomized to continue CNI or switched to sirolimus 2 months after surgery; 29 were randomized to receive CNI and 31 to SIR. All patients received mycophenolate mofetil and steroids. The main outcome parameter was estimated GFR (eGFR) at 180 days. T(reg) population was estimated by flowcytometry. RESULTS: Baseline characteristics in the two groups were similar. Forty-eight patients completed the trial. At six months, patients in the SIR group had significantly higher eGFR as compared to those in the CNI group (88.94 +/- 11.78 vs 80.59 +/- 16.51 mL/min, p = 0.038). Patients on SIR had a 12 mL/min gain of eGFR of at the end of six months. Patients in the SIR group showed significant increase in T(reg) population at 30 days, which persisted till day 180. There was no difference in the adverse events in terms of number of acute rejection episodes, death, infections, proteinuria, lipid profile, blood pressure control and hematological parameters between the two groups. Four patients taking SIR developed enthesitis. No patient left the study or switched treatment because of adverse event. CONCLUSIONS: A deferred pre-emptive switch over from CNI to SIR safely improves renal function and T(reg) population at 6 months in living donor kidney transplant recipients. Registered in Clinical Trials Registry of India (CTRI/2011/091/000034). PMID- 24146763 TI - Contribution of priority PAHs and POPs to Ah receptor-mediated activities in sediment samples from the River Elbe Estuary, Germany. AB - The estuary of the River Elbe between Hamburg and the North Sea (Germany) is a sink for contaminated sediment and suspended particulate matter (SPM). One major concern is the effect of human activities on the hydrodynamics, particularly the intensive dredging activities in this area that may result in remobilization of sediment-bound pollutants. The aim of this study was to identify pollutants contributing to the toxicological risk associated with re-suspension of sediments in the Elbe Estuary by use of an effect-directed analysis that combines chemical and biological analyses in with specific fractionation techniques. Sediments were collected from sites along the Elbe Estuary and a site from a small harbor basin of the Elbe Estuary that is known to be polluted. The sixteen priority EPA-PAHs were quantified in organic extracts of sediments. In addition, dioxin equivalents of sediments were investigated by use of the 7-ethoxyresorufin O-deethylase assay with RTL-W1 cells and the Ah receptor-mediated luciferase transactivation assay with H4IIE-luc cells. Quantification of the 16 priority PAHs revealed that sediments were moderately contaminated at all of the sites in the Elbe River Estuary (<0.02-0.906 ug/g dw). Sediments contained relatively small concentrations of dioxin equivalents (Bio-TEQ) with concentrations ranging from 15.5 to 322 pg/g dw, which were significantly correlated with dioxin equivalents calculated based on toxicity reference values and concentrations of PAH. The concentration of Bio-TEQ at the reference site exceeded 200,000 pg/g dw. In a potency balance the 16 PAHs explained between 47 and 118% of the Bio-TEQ in the luciferase assay, which can be explained by the constant input of PAHs bound to SPM from the upper course of the Elbe River into its estuary. Successful identification of a significant portion of dioxin-like activity to priority PAHs in complex environmental samples such as sediments has rarely been reported. PMID- 24146764 TI - Genetic control of spontaneous arthritis in a four-way advanced intercross line. AB - Identifying the genetic basis of complex diseases, such as rheumatoid arthritis, remains a challenge that requires experimental models to reduce the genetic and environmental variability. Numerous loci for arthritis have been identified in induced animal models; however, few spontaneous models have been genetically studied. Therefore, we generated a four-way advanced intercross line (AIL) from four inbred strains, including BXD2/TyJ which spontaneously develops autoimmune arthritis. A genome-wide scan for spontaneous arthritis was performed in a cohort of 366 mice of the fourth generation (G4) of this cross. Five loci contributing to clinical phenotypes were identified in chromosomes 3, 7, 13, 18, and X. Three of the loci found in this study, confirm previously identified loci; whereas two of them are novel loci. Interesting candidate genes for the loci are highlighted. This study provides a genetic overview of spontaneous arthritis in mice and aids to solve the genetic etiology of rheumatoid arthritis and to gain a better understanding of the disease. PMID- 24146765 TI - Fun on the farm: evaluation of a lesson to teach students about the spread of infection on school farm visits. AB - BACKGROUND: School visits to farms are a positive educational experience but pose risks due to the spread of zoonotic infections. A lesson plan to raise awareness about microbes on the farm and preventative behaviours was developed in response to the Griffin Investigation into the E. coli outbreak associated with Godstone Farm in 2009. This study evaluated the effectiveness of the delivery of the lesson plan in increasing knowledge about the spread of infection on the farm, amongst school students. METHODS: Two hundred and twenty-five 9-11 year old students from seven junior schools in England participated. Two hundred and ten students filled in identical questionnaires covering microbes, hand hygiene, and farm hygiene before and after the lesson. Statistical analysis assessed knowledge change using difference in percentage correct answers. RESULTS: Significant knowledge improvement was observed for all sections. In the 'Farm Hygiene' section, girls and boys demonstrated 18% (p<0.001) and 11% (p<0.001) improvement, respectively (girls vs. boys p<0.004). As girls had lower baseline knowledge the greater percentage improvement resulted in similar post intervention knowledge scores between genders (girls 80%, boys 83%). CONCLUSIONS: The lesson plan was successful at increasing awareness of microbes on the farm and infection prevention measures and should be used by teachers in preparation for a farm visit. PMID- 24146766 TI - Calcium dynamics in root cells of Arabidopsis thaliana visualized with selective plane illumination microscopy. AB - Selective Plane Illumination Microscopy (SPIM) is an imaging technique particularly suited for long term in-vivo analysis of transparent specimens, able to visualize small organs or entire organisms, at cellular and eventually even subcellular resolution. Here we report the application of SPIM in Calcium imaging based on Forster Resonance Energy Transfer (FRET). Transgenic Arabidopsis plants expressing the genetically encoded-FRET-based Ca(2+) probe Cameleon, in the cytosol or nucleus, were used to demonstrate that SPIM enables ratiometric fluorescence imaging at high spatial and temporal resolution, both at tissue and single cell level. The SPIM-FRET technique enabled us to follow nuclear and cytosolic Ca(2+) dynamics in Arabidopsis root tip cells, deep inside the organ, in response to different stimuli. A relevant physiological phenomenon, namely Ca(2+) signal percolation, predicted in previous studies, has been directly visualized. PMID- 24146767 TI - Economic evaluation of active implementation versus guideline dissemination for evidence-based care of acute low-back pain in a general practice setting. AB - INTRODUCTION: The development and publication of clinical practice guidelines for acute low-back pain has resulted in evidence-based recommendations that have the potential to improve the quality and safety of care for acute low-back pain. Development and dissemination of guidelines may not, however, be sufficient to produce improvements in clinical practice; further investment in active implementation of guideline recommendations may be required. Further research is required to quantify the trade-off between the additional upfront cost of active implementation of guideline recommendations for low-back pain and any resulting improvements in clinical practice. METHODS: Cost-effectiveness analysis alongside the IMPLEMENT trial from a health sector perspective to compare active implementation of guideline recommendations via the IMPLEMENT intervention (plus standard dissemination) against standard dissemination alone. RESULTS: The base case analysis suggests that delivery of the IMPLEMENT intervention dominates standard dissemination (less costly and more effective), yielding savings of $135 per x-ray referral avoided (-$462.93/3.43). However, confidence intervals around point estimates for the primary outcome suggest that--irrespective of willingness to pay (WTP)--we cannot be at least 95% confident that the IMPLEMENT intervention differs in value from standard dissemination. CONCLUSIONS: Our findings demonstrate that moving beyond development and dissemination to active implementation entails a significant additional upfront investment that may not be offset by health gains and/or reductions in health service utilization of sufficient magnitude to render active implementation cost-effective. PMID- 24146768 TI - Enhanced SCAP glycosylation by inflammation induces macrophage foam cell formation. AB - Inflammatory stress promotes foam cell formation by disrupting LDL receptor feedback regulation in macrophages. Sterol Regulatory Element Binding Proteins (SREBPs) Cleavage-Activating Protein (SCAP) glycosylation plays crucial roles in regulating LDL receptor and 3-hydroxy-3-methyl-glutaryl-CoA reductase (HMGCoAR) feedback regulation. The present study was to investigate if inflammatory stress disrupts LDL receptor and HMGCoAR feedback regulation by affecting SCAP glycosylation in THP-1 macrophages. Intracellular cholesterol content was assessed by Oil Red O staining and quantitative assay. The expression of molecules controlling cholesterol homeostasis was examined using real-time quantitative RT-PCR and Western blotting. The translocation of SCAP from the endoplasmic reticulum (ER) to the Golgi was detected by confocal microscopy. We demonstrated that exposure to inflammatory cytokines increased lipid accumulation in THP-1 macrophages, accompanying with an increased SCAP expression even in the presence of a high concentration of LDL. These inflammatory cytokines also prolonged the half-life of SCAP by enhancing glycosylation of SCAP due to the elevated expression of the Golgi mannosidase II. This may enhance translocation and recycling of SCAP between the ER and the Golgi, escorting more SREBP2 from the ER to the Golgi for activation by proteolytic cleavages as evidenced by an increased N-terminal of SREBP2 (active form). As a consequence, the LDL receptor and HMGCoAR expression were up-regulated. Interestingly, these effects could be blocked by inhibitors of Golgi mannosidases. Our results indicated that inflammation increased native LDL uptake and endogenous cholesterol de novo synthesis, thereby causing foam cell formation via increasing transcription and protein glycosylation of SCAP in macrophages. These data imply that inhibitors of Golgi processing enzymes might have a potential vascular-protective role in prevention of atherosclerotic foam cell formation. PMID- 24146769 TI - Diatom proteomics reveals unique acclimation strategies to mitigate Fe limitation. AB - Phytoplankton growth rates are limited by the supply of iron (Fe) in approximately one third of the open ocean, with major implications for carbon dioxide sequestration and carbon (C) biogeochemistry. To date, understanding how alteration of Fe supply changes phytoplankton physiology has focused on traditional metrics such as growth rate, elemental composition, and biophysical measurements such as photosynthetic competence (Fv/Fm). Researchers have subsequently employed transcriptomics to probe relationships between changes in Fe supply and phytoplankton physiology. Recently, studies have investigated longer-term (i.e. following acclimation) responses of phytoplankton to various Fe conditions. In the present study, the coastal diatom, Thalassiosira pseudonana, was acclimated (10 generations) to either low or high Fe conditions, i.e. Fe limiting and Fe-replete. Quantitative proteomics and a newly developed proteomic profiling technique that identifies low abundance proteins were employed to examine the full complement of expressed proteins and consequently the metabolic pathways utilized by the diatom under the two Fe conditions. A total of 1850 proteins were confidently identified, nearly tripling previous identifications made from differential expression in diatoms. Given sufficient time to acclimate to Fe limitation, T. pseudonana up-regulates proteins involved in pathways associated with intracellular protein recycling, thereby decreasing dependence on extracellular nitrogen (N), C and Fe. The relative increase in the abundance of photorespiration and pentose phosphate pathway proteins reveal novel metabolic shifts, which create substrates that could support other well-established physiological responses, such as heavily silicified frustules observed for Fe limited diatoms. Here, we discovered that proteins and hence pathways observed to be down-regulated in short-term Fe starvation studies are constitutively expressed when T. pseudonana is acclimated (i.e., nitrate and nitrite transporters, Photosystem II and Photosystem I complexes). Acclimation of the diatom to the desired Fe conditions and the comprehensive proteomic approach provides a more robust interpretation of this dynamic proteome than previous studies. PMID- 24146770 TI - Injectable biocomposites for bone healing in rabbit femoral condyle defects. AB - A novel biomimetic bone scaffold was successfully prepared in this study, which was composed of calcium sulfate hemihydrate (CSH), collagen and nano hydroxyapatite (nHAC). CSH/nHAC was prepared and observed with scanning electron microscope and rhBMP-2 was introduced into CSH/nHAC. The released protein content from the scaffold was detected using high performance liquid chromatography at predetermined time interval. In vivo bone formation capacity was investigated by means of implanting the scaffolds with rhBMP-2 or without rhBMP-2 respectively into a critical size defect model in the femoral condyle of rabbit. The releasing character of rhBMP-2 was that an initial burst release (37.5%) was observed in the first day, followed by a sustained release and reached 100% at the end of day 20. The CSH/nHAC showed a gradual decrease in degradation with the content of nHAC increase. The results of X-rays, Micro CT and histological observation indicated that more new bone was formed in rhBMP-2 group. The results implied that this new injectable bone scaffold should be very promising for bone repair and has a great potential in bone tissue engineering. PMID- 24146771 TI - Correlates of social exclusion and negative labeling and devaluation of people living with HIV/AIDS in rural settings: evidence from a General Household Survey in Zambezia Province, Mozambique. AB - BACKGROUND: Increased HIV/AIDS knowledge and access to antiretroviral treatment (ART) have been hypothesized to decrease HIV stigma. However, stigma persists as a barrier to HIV services uptake. We studied the relationship between stigma, knowledge and attitudes towards HIV and its treatment, and confidence in the legal system (legal rights certitude). METHODS: We analyzed data from a household survey of 3749 randomly sampled female heads of households in 259 enumeration areas across 14 districts of Zambezia Province, Mozambique. The questionnaire included questions about beliefs, attitudes and behavior towards PLWHA, HIV transmission knowledge, treatment-related beliefs, and legal rights certitude. Factor analysis distinguished two stigma constructs: Negative labeling and devaluation (NLD) and social exclusion (SoE). Multivariable linear regression was used to determine the association between stigma, knowledge of HIV/AIDS, treatment-related beliefs, and legal rights certitude, while controlling for variance in socio-demographics. RESULTS: A 4-point increase in knowledge about HIV transmission was associated with more than a 3 unit decrease in NLD and SoE stigma scores (p<0.001). Given HIV transmission knowledge, a 25-point increase in legal rights certitude was associated with a 4.62 unit drop in NLD stigma (p<0.001); we did not detect an association between legal rights certitude and SoE stigma. Knowing at least one HIV positive person was associated with lower SoE (-3.17, 95% CI: -5.78, -0.56); no association with NLD (p = 0.1) was detected. ART efficacy belief was associated with higher NLD and lower SoE (2.90 increase and 6.94 decrease, respectively; p <= 0.001). CONCLUSION: Increasing knowledge about HIV transmission and access to ART are likely to reduce stigma, but neither of the two is a panacea. Raising community awareness of the legal rights of PLWHA might improve the efficacy of stigma reduction efforts. Strategies that focus on specific domains of stigma might be more effective than generic stigma reduction strategies. PMID- 24146772 TI - Sparse solution of fiber orientation distribution function by diffusion decomposition. AB - Fiber orientation is the key information in diffusion tractography. Several deconvolution methods have been proposed to obtain fiber orientations by estimating a fiber orientation distribution function (ODF). However, the L 2 regularization used in deconvolution often leads to false fibers that compromise the specificity of the results. To address this problem, we propose a method called diffusion decomposition, which obtains a sparse solution of fiber ODF by decomposing the diffusion ODF obtained from q-ball imaging (QBI), diffusion spectrum imaging (DSI), or generalized q-sampling imaging (GQI). A simulation study, a phantom study, and an in-vivo study were conducted to examine the performance of diffusion decomposition. The simulation study showed that diffusion decomposition was more accurate than both constrained spherical deconvolution and ball-and-sticks model. The phantom study showed that the angular error of diffusion decomposition was significantly lower than those of constrained spherical deconvolution at 30 degrees crossing and ball-and-sticks model at 60 degrees crossing. The in-vivo study showed that diffusion decomposition can be applied to QBI, DSI, or GQI, and the resolved fiber orientations were consistent regardless of the diffusion sampling schemes and diffusion reconstruction methods. The performance of diffusion decomposition was further demonstrated by resolving crossing fibers on a 30-direction QBI dataset and a 40-direction DSI dataset. In conclusion, diffusion decomposition can improve angular resolution and resolve crossing fibers in datasets with low SNR and substantially reduced number of diffusion encoding directions. These advantages may be valuable for human connectome studies and clinical research. PMID- 24146773 TI - The AERO system: a 3D-like approach for recording gene expression patterns in the whole mouse embryo. AB - We have recently constructed a web-based database of gene expression in the mouse whole embryo, EMBRYS (http://embrys.jp/embrys/html/MainMenu.html). To allow examination of gene expression patterns to the fullest extent possible, this database provides both photo images and annotation data. However, since embryos develop via an intricate process of morphogenesis, it would be of great value to track embryonic gene expression from a three dimensional perspective. In fact, several methods have been developed to achieve this goal, but highly laborious procedures and specific operational skills are generally required. We utilized a novel microscopic technique that enables the easy capture of rotational, 3D-like images of the whole embryo. In this method, a rotary head equipped with two mirrors that are designed to obtain an image tilted at 45 degrees to the microscope stage captures serial images at 2-degree intervals. By a simple operation, 180 images are automatically collected. These 2D images obtained at multiple angles are then used to reconstruct 3D-like images, termed AERO images. By means of this system, over 800 AERO images of 191 gene expression patterns were captured. These images can be easily rotated on the computer screen using the EMBRYS database so that researchers can view an entire embryo by a virtual viewing on a computer screen in an unbiased or non-predetermined manner. The advantages afforded by this approach make it especially useful for generating data viewed in public databases. PMID- 24146774 TI - Psychometric assessment of the Chinese version of the Supportive Care Needs Survey short-form (SCNS-SF34-C) among Hong Kong and Taiwanese Chinese colorectal cancer patients. AB - BACKGROUND: Accurate assessment of unmet supportive care needs is essential for optimal cancer patient care. This study used confirmatory factor analysis (CFA) to test the known factor structures of the short form of Supportive Care Need Survey (SCNS-34) in Hong Kong and Taiwan Chinese patients diagnosed with colorectal cancer (CRC). METHODS: 360 Hong Kong and 263 Taiwanese Chinese CRC patients completed the Chinese version of SCNS-SF34. Comparative measures (patient satisfaction, anxiety, depression, and symptom distress) tested convergent validity while known group differences were examined to test discriminant validity. RESULTS: The original 5-factor and recent 4-factor models of the SCNS demonstrated poor data fit using CFA in both Hong Kong and Taiwan samples. Subsequently a modified five-factor model with correlated residuals demonstrated acceptable fit in both samples. Correlations demonstrated convergent and divergent validity and known group differences were observed. CONCLUSIONS: While the five-factor model demonstrated a better fit for data from Chinese colorectal cancer patients, some of the items within its domain overlapped, suggesting item redundancy. The five-factor model showed good psychometric properties in these samples but also suggests conceptualization of unmet supportive care needs are currently inadequate. PMID- 24146775 TI - Ultimate predators: lionfish have evolved to circumvent prey risk assessment abilities. AB - Invasive species cause catastrophic alterations to communities worldwide by changing the trophic balance within ecosystems. Ever since their introduction in the mid 1980's common red lionfish, Pterois volitans, are having dramatic impacts on the Caribbean ecosystem by displacing native species and disrupting food webs. Introduced lionfish capture prey at extraordinary rates, altering the composition of benthic communities. Here we demonstrate that the extraordinary success of the introduced lionfish lies in its capacity to circumvent prey risk assessment abilities as it is virtually undetectable by prey species in its native range. While experienced prey damselfish, Chromis viridis, respond with typical antipredator behaviours when exposed to a common predatory rock cod (Cephalopholis microprion) they fail to visibly react to either the scent or visual presentation of the red lionfish, and responded only to the scent (not the visual cue) of a lionfish of a different genus, Dendrochirus zebra. Experienced prey also had much higher survival when exposed to the two non-invasive predators compared to P. volitans. The cryptic nature of the red lionfish has enabled it to be destructive as a predator and a highly successful invasive species. PMID- 24146776 TI - Poly(dA:dT)-rich DNAs are highly flexible in the context of DNA looping. AB - Large-scale DNA deformation is ubiquitous in transcriptional regulation in prokaryotes and eukaryotes alike. Though much is known about how transcription factors and constellations of binding sites dictate where and how gene regulation will occur, less is known about the role played by the intervening DNA. In this work we explore the effect of sequence flexibility on transcription factor mediated DNA looping, by drawing on sequences identified in nucleosome formation and ligase-mediated cyclization assays as being especially favorable for or resistant to large deformations. We examine a poly(dA:dT)-rich, nucleosome repelling sequence that is often thought to belong to a class of highly inflexible DNAs; two strong nucleosome positioning sequences that share a set of particular sequence features common to nucleosome-preferring DNAs; and a CG-rich sequence representative of high G+C-content genomic regions that correlate with high nucleosome occupancy in vivo. To measure the flexibility of these sequences in the context of DNA looping, we combine the in vitro single-molecule tethered particle motion assay, a canonical looping protein, and a statistical mechanical model that allows us to quantitatively relate the looping probability to the looping free energy. We show that, in contrast to the case of nucleosome occupancy, G+C content does not positively correlate with looping probability, and that despite sharing sequence features that are thought to determine nucleosome affinity, the two strong nucleosome positioning sequences behave markedly dissimilarly in the context of looping. Most surprisingly, the poly(dA:dT)-rich DNA that is often characterized as highly inflexible in fact exhibits one of the highest propensities for looping that we have measured. These results argue for a need to revisit our understanding of the mechanical properties of DNA in a way that will provide a basis for understanding DNA deformation over the entire range of biologically relevant scenarios that are impacted by DNA deformability. PMID- 24146777 TI - Establishment of an in vitro transport assay that reveals mechanistic differences in cytosolic events controlling cholera toxin and T-cell receptor alpha retro translocation. AB - Following retrograde trafficking to the endoplasmic reticulum (ER), cholera toxin A1 (CTA1) subunit hijacks ER-associated degradation (ERAD) machinery and retro translocates into the cytosol to induce toxicity. We previously established a cell-based in vivo assay to identify ER components that regulate this process. However, elucidating cytosolic events that govern CTA1 retro-translocation using this assay is difficult as manipulating cytosolic factors often perturbs toxin retrograde transport to the ER. To circumvent this problem, we developed an in vitro assay in semi-permeabilized cells that directly monitors CTA1 release from the ER into the cytosol. We demonstrate CTA1 is released into the cytosol as a folded molecule in a p97- and proteasome-independent manner. Release nonetheless involves a GTP-dependent reaction. Upon extending this assay to the canonical ERAD substrate T-cell receptor alpha (TCRalpha), we found the receptor is unfolded when released into the cytosol and degraded by membrane-associated proteasome. In this reaction, p97 initially extracts TCRalpha from the ER membrane, followed by TCRalpha discharge into the cytosol that requires additional energy-dependent cytosolic activities. Our results reveal mechanistic insights into cytosolic events controlling CTA1 and TCRalpha retro-translocation, and provide a reliable tool to further probe this process. PMID- 24146778 TI - How to decide whether to move species threatened by climate change. AB - Introducing species to areas outside their historical range to secure their future under climate change is a controversial strategy for preventing extinction. While the debate over the wisdom of this strategy continues, such introductions are already taking place. Previous frameworks for analysing the decision to introduce have lacked a quantifiable management objective and mathematically rigorous problem formulation. Here we develop the first rigorous quantitative framework for deciding whether or not a particular introduction should go ahead, which species to prioritize for introduction, and where and how to introduce them. It can also be used to compare introduction with alternative management actions, and to prioritise questions for future research. We apply the framework to a case study of tuatara (Sphenodon punctatus) in New Zealand. While simple and accessible, this framework can accommodate uncertainty in predictions and values. It provides essential support for the existing IUCN guidelines by presenting a quantitative process for better decision-making about conservation introductions. PMID- 24146779 TI - A tuneable switch for controlling environmental degradation of bioplastics: addition of isothiazolinone to polyhydroxyalkanoates. AB - Controlling the environmental degradation of polyhydroxybutyrate (PHB) and polyhydroxyvalerate (P(HB-co-HV)) bioplastics would expand the range of their potential applications. Combining PHB and P(HB-co-HV) films with the anti-fouling agent 4,5-dichloro-2-n-octyl-4-isothiazolin-3-one (DCOI, <10% w/w) restricted microbial colonisation in soil, but did not significantly affect melting temperature or the tensile strength of films. DCOI films showed reduced biofouling and postponed the onset of weight loss by up to 100 days, a 10-fold increase compared to unmodified films where the microbial coverage was significant. In addition, the rate of PHA-DCOI weight loss, post-onset, reduced by about 150%; in contrast a recorded weight loss of only 0.05% per day for P(HB co-HV) with a 10% DCOI loading was observed. This is in stark contrast to the unmodified PHB film, where a recorded weight loss of only 0.75% per day was made. The 'switch' that initiates film weight loss, and its subsequent reduced rate, depended on the DCOI loading to control biofouling. The control of biofouling and environmental degradation for these DCOI modified bioplastics increases their potential use in biodegradable applications. PMID- 24146780 TI - Human-induced trophic cascades along the fecal detritus pathway. AB - Human presence and activity in tropical forest is thought to exert top-down regulation over the various 'green-world' pathways of plant-based foodwebs. However, these effects have never been explored for the 'brown-world' pathways of fecal-detritus webs. The strong effects of humans on tropical game mammals are likely to indirectly influence fecal detritivores (including Scarabaeine dung beetles), with subsequent indirect impacts on detrivore-mediated and plant facilitating detrital processes. Across a 380-km gradient of human influence in the western Brazilian Amazon, we conducted the first landscape-level assessment of human-induced cascade effects on the fecal detritus pathway, by coupling data on human impact, game mammal and detritivore community structure, and rate measurements of a key detritus process (i.e. dung beetle-mediated secondary seed dispersal). We found evidence that human impact indirectly influences both the diversity and biomass of fecal detritivores, but not detritivore-mediated processes. Cascade strength varied across detritivore groups defined by species' traits. We found smaller-bodied dung beetles were at higher risk of local decline in areas of human presence, and that body size was a better predictor of cascade structure than fecal resource manipulation strategy. Cascade strength was also stronger in upland, unflooded forests, than in seasonally flooded forests. Our results suggest that the impact of human activity in tropical forest on fecal detritus food web structure is mediated by both species' traits and habitat type. Further research will be required to determine the conditions under which these cascade effects influence fecal-detritus web function. PMID- 24146781 TI - Network bursting dynamics in excitatory cortical neuron cultures results from the combination of different adaptive mechanisms. AB - In the brain, synchronization among cells of an assembly is a common phenomenon, and thought to be functionally relevant. Here we used an in vitro experimental model of cell assemblies, cortical cultures, combined with numerical simulations of a spiking neural network (SNN) to investigate how and why spontaneous synchronization occurs. In order to deal with excitation only, we pharmacologically blocked GABAAergic transmission using bicuculline. Synchronous events in cortical cultures tend to involve almost every cell and to display relatively constant durations. We have thus named these "network spikes" (NS). The inter-NS-intervals (INSIs) proved to be a more interesting phenomenon. In most cortical cultures NSs typically come in series or bursts ("bursts of NSs", BNS), with short (~1 s) INSIs and separated by long silent intervals (tens of s), which leads to bimodal INSI distributions. This suggests that a facilitating mechanism is at work, presumably short-term synaptic facilitation, as well as two fatigue mechanisms: one with a short timescale, presumably short-term synaptic depression, and another one with a longer timescale, presumably cellular adaptation. We thus incorporated these three mechanisms into the SNN, which, indeed, produced realistic BNSs. Next, we systematically varied the recurrent excitation for various adaptation timescales. Strong excitability led to frequent, quasi-periodic BNSs (CV~0), and weak excitability led to rare BNSs, approaching a Poisson process (CV~1). Experimental cultures appear to operate within an intermediate weakly-synchronized regime (CV~0.5), with an adaptation timescale in the 2-8 s range, and well described by a Poisson-with-refractory period model. Taken together, our results demonstrate that the INSI statistics are indeed informative: they allowed us to infer the mechanisms at work, and many parameters that we cannot access experimentally. PMID- 24146782 TI - Evaluation of a real-time PCR test for the detection and discrimination of theileria species in the African buffalo (Syncerus caffer). AB - A quantitative real-time PCR (qPCR) assay based on the cox III gene was evaluated for the simultaneous detection and discrimination of Theileria species in buffalo and cattle blood samples from South Africa and Mozambique using melting curve analysis. The results obtained were compared to those of the reverse line blot (RLB) hybridization assay for the simultaneous detection and differentiation of Theileria spp. in mixed infections, and to the 18S rRNA qPCR assay results for the specific detection of Theileria parva. Theileria parva, Theileria sp. (buffalo), Theileria taurotragi, Theileria buffeli and Theileria mutans were detected by the cox III assay. Theileria velifera was not detected from any of the samples analysed. Seventeen percent of the samples had non-species specific melting peaks and 4.5% of the samples were negative or below the detection limit of the assay. The cox III assay identified more T. parva and Theileria sp. (buffalo) positive samples than the RLB assay, and also detected more T. parva infections than the 18S assay. However, only a small number of samples were positive for the benign Theileria spp. To our knowledge T. taurotragi has never been identified from the African buffalo, its identification in some samples by the qPCR assay was unexpected. Because of these discrepancies in the results, cox III qPCR products were cloned and sequenced. Sequence analysis indicated extensive inter- and intra-species variations in the probe target regions of the cox III gene sequences of the benign Theileria spp. and therefore explains their low detection. The cox III assay is specific for the detection of T. parva infections in cattle and buffalo. Sequence data generated from this study can be used for the development of a more inclusive assay for detection and differentiation of all variants of the mildly pathogenic and benign Theileria spp. of buffalo and cattle. PMID- 24146783 TI - Injury profile SIMulator, a Qualitative aggregative modelling framework to predict injury profile as a function of cropping practices, and abiotic and biotic environment. II. Proof of concept: design of IPSIM-wheat-eyespot. AB - IPSIM (Injury Profile SIMulator) is a generic modelling framework presented in a companion paper. It aims at predicting a crop injury profile as a function of cropping practices and abiotic and biotic environment. IPSIM's modelling approach consists of designing a model with an aggregative hierarchical tree of attributes. In order to provide a proof of concept, a model, named IPSIM-Wheat Eyespot, has been developed with the software DEXi according to the conceptual framework of IPSIM to represent final incidence of eyespot on wheat. This paper briefly presents the pathosystem, the method used to develop IPSIM-Wheat-Eyespot using IPSIM's modelling framework, simulation examples, an evaluation of the predictive quality of the model with a large dataset (526 observed site-years) and a discussion on the benefits and limitations of the approach. IPSIM-Wheat Eyespot proved to successfully represent the annual variability of the disease, as well as the effects of cropping practices (Efficiency = 0.51, Root Mean Square Error of Prediction = 24%; bias = 5.0%). IPSIM-Wheat-Eyespot does not aim to precisely predict the incidence of eyespot on wheat. It rather aims to rank cropping systems with regard to the risk of eyespot on wheat in a given production situation through ex ante evaluations. IPSIM-Wheat-Eyespot can also help perform diagnoses of commercial fields. Its structure is simple and permits to combine available knowledge in the scientific literature (data, models) and expertise. IPSIM-Wheat-Eyespot is now available to help design cropping systems with a low risk of eyespot on wheat in a wide range of production situations, and can help perform diagnoses of commercial fields. In addition, it provides a proof of concept with regard to the modelling approach of IPSIM. IPSIM-Wheat-Eyespot will be a sub-model of IPSIM-Wheat, a model that will predict injury profile on wheat as a function of cropping practices and the production situation. PMID- 24146784 TI - Nitrogen distribution and cycling through water flows in a subtropical bamboo forest under high level of atmospheric deposition. AB - BACKGROUND: The hydrological cycle is an important way of transportation and reallocation of reactive nitrogen (N) in forest ecosystems. However, under a high level of atmospheric N deposition, the N distribution and cycling through water flows in forest ecosystems especially in bamboo ecosystems are not well understood. METHODOLOGY/PRINCIPAL FINDINGS: In order to investigate N fluxes through water flows in a Pleioblastus amarus bamboo forest, event rainfall/snowfall (precipitation, PP), throughfall (TF), stemflow (SF), surface runoff (SR), forest floor leachate (FFL), soil water at the depth of 40 cm (SW1) and 100 cm (SW2) were collected and measured through the whole year of 2009. Nitrogen distribution in different pools in this ecosystem was also measured. Mean N pools in vegetation and soil (0-1 m) were 351.7 and 7752.8 kg ha(-1). Open field nitrogen deposition at the study site was 113.8 kg N ha(-1) yr(-1), which was one of the highest in the world. N-NH4(+), N-NO3(-) and dissolved organic N (DON) accounted for 54%, 22% and 24% of total wet N deposition. Net canopy accumulated of N occurred with N-NO3(-) and DON but not N-NH4(+). The flux of total dissolved N (TDN) to the forest floor was greater than that in open field precipitation by 17.7 kg N ha(-1) yr(-1), due to capture of dry and cloudwater deposition net of canopy uptake. There were significant negative exponential relationships between monthly water flow depths and monthly mean TDN concentrations in PP, TF, SR, FFL and SW1. CONCLUSIONS/SIGNIFICANCE: The open field nitrogen deposition through precipitation is very high over the world, which is the main way of reactive N input in this bamboo ecosystem. The water exchange and N consume mainly occurred in the litter floor layer and topsoil layer, where most of fine roots of bamboo distributed. PMID- 24146785 TI - Methods to measure the impact of home, social, and sexual neighborhoods of urban gay, bisexual, and other men who have sex with men. AB - Men who have sex with men (MSM) accounted for 61% of new HIV diagnoses in the United States in 2010. Recent analyses indicate that socio-structural factors are important correlates of HIV infection. NYCM2M was a cross-sectional study designed to identify neighborhood-level characteristics within the urban environment that influence sexual risk behaviors, substance use and depression among MSM living in New York City. The sample was recruited using a modified venue-based time-space sampling methodology and through select websites and mobile applications. This paper describes novel methodological approaches used to improve the quality of data collected for analysis of the impact of neighborhoods on MSM health. Previous research has focused predominately on residential neighborhoods and used pre-determined administrative boundaries (e.g., census tracts) that often do not reflect authentic and meaningful neighborhoods. This study included the definition and assessment of multiple neighborhoods of influence including where men live (home neighborhood), socialize (social neighborhood) and have sex (sexual neighborhood). Furthermore, making use of technological advances in mapping, we collected geo-points of reference for each type of neighborhood and identified and constructed self-identified neighborhood boundary definitions. Finally, this study collected both perceived neighborhood characteristics and objective neighborhood conditions to create a comprehensive, flexible and rich neighborhood-level set of covariates. This research revealed that men perceived their home, social and sexual neighborhoods in different ways. Few men (15%) had the same home, social and sexual neighborhoods; for 31%, none of the neighborhoods was the same. Of the three types of neighborhoods, the number of unique social neighborhoods was the lowest; the size of sexual neighborhoods was the smallest. The resultant dataset offers the opportunity to conduct analyses that will yield context-specific and nuanced understandings of the relations among neighborhood space, and the well-being and health of urban MSM. PMID- 24146786 TI - Can proliferation biomarkers reliably predict recurrence in World Health Organization 2003 defined endometrial stromal sarcoma, low grade? AB - An estimated 1500-3000 invasive Endometrial Stromal Sarcomas (ESS) cases annually occur worldwide. Before 2003, ESS was divided as low and high grade ESS based on mitotic activity. In 2003 the WHO changed the names, excluded mitoses and made nuclear atypia and necrosis the essential diagnostic criteria to distinguish ESS, Low Grade (ESS-LG, recurrence-free survival >90%) and Undifferentiated Endometrial Sarcoma (UES, poor prognosis). We have evaluated in WHO2003 defined ESS-LG whether proliferation biomarkers predict recurrence. Using survival analysis, the prognostic value of classical mitosis counts (Mitotic Activity Index, MAI) in haematoxyllin-eosin (H&E) sections, and immunohistochemical proliferation biomarkers (Ki-67 and PhosphoHistone-3 (PPH3)) were examined in 24 invasive endometrial stromal sarcomas. Three of 24 (12.5%) ESS-LG recurred. The MAI, PPH3 and Ki-67 were all prognostic (P = 0.001, 0.002 and 0.03). MAI values were >3 in the recurrent cases, but never exceeded 10 (the classical threshold for low and high grade). Non-recurrent cases had 0 <= MAI <= 3. PPH3 and Ki67 counts can be easier to perform than MAI and therefore helpful in the diagnosis of ESS, Low Grade. In conclusion, in this small study of WHO2003 defined ESS-LG, high levels of proliferation as measured by MAI, PPH3 and Ki-67 are predictive of recurrence. Larger studies are required to confirm these results. PMID- 24146787 TI - Stiffness dependent separation of cells in a microfluidic device. AB - Abnormal cell mechanical stiffness can point to the development of various diseases including cancers and infections. We report a new microfluidic technique for continuous cell separation utilizing variation in cell stiffness. We use a microfluidic channel decorated by periodic diagonal ridges that compress the flowing cells in rapid succession. The compression in combination with secondary flows in the ridged microfluidic channel translates each cell perpendicular to the channel axis in proportion to its stiffness. We demonstrate the physical principle of the cell sorting mechanism and show that our microfluidic approach can be effectively used to separate a variety of cell types which are similar in size but of different stiffnesses, spanning a range from 210 Pa to 23 kPa. Atomic force microscopy is used to directly measure the stiffness of the separated cells and we found that the trajectories in the microchannel correlated to stiffness. We have demonstrated that the current processing throughput is 250 cells per second. This microfluidic separation technique opens new ways for conducting rapid and low-cost cell analysis and disease diagnostics through biophysical markers. PMID- 24146788 TI - The association between the levels of serum ferritin and sex hormones in a large scale of Chinese male population. AB - BACKGROUND: The ferritin is an important participant of iron-storage but its regulation and related factors were not well defined. The present objective was to explore the potential association between serum ferritin levels and sex hormones. METHODS: 1999 Chinese men in the Fangchenggang Area Male Health and Examination Survey (FAMHES) were recruited in this cross-sectional study. Levels of serum ferritin, total testosterone (free testosterone was calculated from the total one), estradiol and sex hormone-binding protein were detected in venous blood samples. The effects of age, BMI, smoking as well as alcohol consumption were analyzed on ferritin levels, respectively, and then the Pearson's correlation analysis was used to evaluate the association between ferritin levels and sex hormones adjusting for the above factors. RESULTS: The age, BMI and alcohol consumption significantly affected serum ferritin levels, but there was no significant difference between smokers and nonsmokers. Ferritin levels were significantly and negatively associated with total testosterone (R = -0.205, P< 0.001), sex hormone-binding protein (R = -0.161, P<0.001) and free testosterone (R = -0.097, P<0.001). After age and alcohol consumption were adjusted, the above associations were still significant (R = -0.200, -0.181 and -0.083, respectively, all P<0.001). However, there was only borderline negative association between ferritin levels and estradiol (adjusted R = -0.039, P = 0.083). CONCLUSION: The large scale of epidemic results showed the significantly negative associations between serum ferritin levels and sex hormones, which may provide more clues to explore the potential regulation and biological mechanism of ferritin. PMID- 24146789 TI - Impaired decisional impulsivity in pathological videogamers. AB - BACKGROUND: Pathological gaming is an emerging and poorly understood problem. Impulsivity is commonly impaired in disorders of behavioural and substance addiction, hence we sought to systematically investigate the different subtypes of decisional and motor impulsivity in a well-defined pathological gaming cohort. METHODS: Fifty-two pathological gaming subjects and age-, gender- and IQ-matched healthy volunteers were tested on decisional impulsivity (Information Sampling Task testing reflection impulsivity and delay discounting questionnaire testing impulsive choice), and motor impulsivity (Stop Signal Task testing motor response inhibition, and the premature responding task). We used stringent diagnostic criteria highlighting functional impairment. RESULTS: In the Information Sampling Task, pathological gaming participants sampled less evidence prior to making a decision and scored fewer points compared with healthy volunteers. Gaming severity was also negatively correlated with evidence gathered and positively correlated with sampling error and points acquired. In the delay discounting task, pathological gamers made more impulsive choices, preferring smaller immediate over larger delayed rewards. Pathological gamers made more premature responses related to comorbid nicotine use. Greater number of hours played also correlated with a Motivational Index. Greater frequency of role playing games was associated with impaired motor response inhibition and strategy games with faster Go reaction time. CONCLUSIONS: We show that pathological gaming is associated with impaired decisional impulsivity with negative consequences in task performance. Decisional impulsivity may be a potential target in therapeutic management. PMID- 24146790 TI - Genome-wide sequencing of cellular microRNAs identifies a combinatorial expression signature diagnostic of sepsis. AB - RATIONALE: Sepsis is a common cause of death in the intensive care unit with mortality up to 70% when accompanied by multiple organ dysfunction. Rapid diagnosis and the institution of appropriate antibiotic therapy and pressor support are therefore critical for survival. MicroRNAs are small non-coding RNAs that play an important role in the regulation of numerous cellular processes, including inflammation and immunity. OBJECTIVES: We hypothesized changes in expression of microRNAs during sepsis may be of diagnostic value in the intensive care unit (ICU). METHODS: Massively parallel sequencing of microRNAs was utilised for screening microRNA candidates. Putative microRNAs were validated using quantitative real-time PCR (qRT-PCR). This study includes data from both a training cohort (UK) and an independent validation cohort (Sweden). A linear discriminant statistical model was employed to construct a diagnostic microRNA signature. RESULTS: A panel of known and novel microRNAs were detectable in the blood of patients with sepsis. After qRT-PCR validation, microRNA miR-150 and miR 4772-5p-iso were able to discriminate between patients who have systemic inflammatory response syndrome and patients with sepsis. This finding was also validated in independent cohort with an average diagnostic accuracy of 86%. Fractionating the cellular components of blood reveals miR-4772-5p-iso is expressed differentially in monocytes. Functional experiments using primary human monocytes demonstrate that it expressed in response to TLR ligation. CONCLUSIONS: Taken together, these data provide a novel microRNA signature of sepsis that should allow rapid point-of-care diagnostic assessment of patients on ICU and also provide greater insight into the pathobiology of this severe disease. PMID- 24146791 TI - Is consumer response to plain/standardised tobacco packaging consistent with framework convention on tobacco control guidelines? A systematic review of quantitative studies. AB - BACKGROUND AND OBJECTIVES: Standardised or 'plain' tobacco packaging was introduced in Australia in December 2012 and is currently being considered in other countries. The primary objective of this systematic review was to locate, assess and synthesise published and grey literature relating to the potential impacts of standardised tobacco packaging as proposed by the guidelines for the international Framework Convention on Tobacco Control: reduced appeal, increased salience and effectiveness of health warnings, and more accurate perceptions of product strength and harm. METHODS: Electronic databases were searched and researchers in the field were contacted to identify studies. Eligible studies were published or unpublished primary research of any design, issued since 1980 and concerning tobacco packaging. Twenty-five quantitative studies reported relevant outcomes and met the inclusion criteria. A narrative synthesis was conducted. RESULTS: Studies that explored the impact of package design on appeal consistently found that standardised packaging reduced the appeal of cigarettes and smoking, and was associated with perceived lower quality, poorer taste and less desirable smoker identities. Although findings were mixed, standardised packs tended to increase the salience and effectiveness of health warnings in terms of recall, attention, believability and seriousness, with effects being mediated by the warning size, type and position on pack. Pack colour was found to influence perceptions of product harm and strength, with darker coloured standardised packs generally perceived as containing stronger tasting and more harmful cigarettes than fully branded packs; lighter coloured standardised packs suggested weaker and less harmful cigarettes. Findings were largely consistent, irrespective of location and sample. CONCLUSIONS: The evidence strongly suggests that standardised packaging will reduce the appeal of packaging and of smoking in general; that it will go some way to reduce consumer misperceptions regarding product harm based upon package design; and will help make the legally required on-pack health warnings more salient. PMID- 24146792 TI - Using LiDAR data to measure the 3D green biomass of Beijing urban forest in China. AB - The purpose of the paper is to find a new approach to measure 3D green biomass of urban forest and to testify its precision. In this study, the 3D green biomass could be acquired on basis of a remote sensing inversion model in which each standing wood was first scanned by Terrestrial Laser Scanner to catch its point cloud data, then the point cloud picture was opened in a digital mapping data acquisition system to get the elevation in an independent coordinate, and at last the individual volume captured was associated with the remote sensing image in SPOT5(System Probatoired'Observation dela Tarre)by means of such tools as SPSS (Statistical Product and Service Solutions), GIS (Geographic Information System), RS (Remote Sensing) and spatial analysis software (FARO SCENE and Geomagic studio11). The results showed that the 3D green biomass of Beijing urban forest was 399.1295 million m(3), of which coniferous was 28.7871 million m(3) and broad leaf was 370.3424 million m(3). The accuracy of 3D green biomass was over 85%, comparison with the values from 235 field sample data in a typical sampling way. This suggested that the precision done by the 3D forest green biomass based on the image in SPOT5 could meet requirements. This represents an improvement over the conventional method because it not only provides a basis to evalue indices of Beijing urban greenings, but also introduces a new technique to assess 3D green biomass in other cities. PMID- 24146793 TI - Photocatalytic antibacterial effects are maintained on resin-based TiO2 nanocomposites after cessation of UV irradiation. AB - Photocatalysis induced by TiO2 and UV light constitutes a decontamination and antibacterial strategy utilized in many applications including self-cleaning environmental surfaces, water and air treatment. The present work reveals that antibacterial effects induced by photocatalysis can be maintained even after the cessation of UV irradiation. We show that resin-based composites containing 20% TiO2 nanoparticles continue to provide a pronounced antibacterial effect against the pathogens Escherichia coli, Staphylococcus epidermidis, Streptococcus pyogenes, Streptococcus mutans and Enterococcus faecalis for up to two hours post UV. For biomaterials or implant coatings, where direct UV illumination is not feasible, a prolonged antibacterial effect after the cessation of the illumination would offer new unexplored treatment possibilities. PMID- 24146794 TI - Spermatogenesis associated 4 promotes Sertoli cell proliferation modulated negatively by regulatory factor X1. AB - Spermatogenesis associated 4 (Spata4), a testis-specific and CpG island associated gene, is involved in regulating cell proliferation, differentiation and apoptosis. To obtain insight into the role of Spata4 in cell cycling control, we characterized the promoter region of Spata4 and investigated its transcriptional regulation mechanism. The Spata4 promoter is unidirectional transcribed and possesses multiple transcription start sites. Moreover, we present evidence that regulatory factor X1 (RFX1) could bind the typical 14-bp cis-elements of Spata4 promoter, modulate transcriptional activity and endogenous expression of Spata4, and further regulate the proliferation of Sertoli cells. Overexpression of RFX1 was shown to down-regulate both the promoter activity and mRNA expression of Spata4, whereas knockdown of RFX1 demonstrated the opposite effects. Our studies provide insight into Spata4 gene regulation and imply the potential role of RFX1 in growth of Sertoli cells. RFX1 may have negative effect on cell proliferation of Sertoli cells via modulating Spata4 expression levels by binding the conserved 14-bp cis-elements of Spata4 promoter. PMID- 24146795 TI - Using molecular markers to characterize productivity in Chinese hamster ovary cell lines. AB - Selection of high producing cell lines to produce maximum product concentration is a challenging and time consuming task for the biopharmaceutical industry. The identification of early markers to predict high productivity will significantly reduce the time required for new cell line development. This study identifies candidate determinants of high productivity by profiling the molecular and morphological characteristics of a panel of six Chinese Hamster Ovary (CHO) stable cell lines with varying recombinant monoclonal antibody productivity levels ranging between 2 and 50 pg/cell/day. We examined the correlation between molecular parameters and specific productivity (qp ) throughout the growth phase of batch cultures. Results were statistically analyzed using Pearson correlation coefficient. Our study revealed that, overall, heavy chain (HC) mRNA had the strongest association with qp followed by light chain (LC) mRNA, HC intracellular polypeptides, and intracellular antibodies. A significant correlation was also obtained between qp and the following molecular markers: growth rate, biomass, endoplasmic reticulum, and LC polypeptides. However, in these cases, the correlation was not observed at all-time points throughout the growth phase. The repeated sampling throughout culture duration had enabled more accurate predictions of productivity in comparison to performing a single-point measurement. Since the correlation varied from day to day during batch cultivation, single-point measurement was of limited use in making a reliable prediction. PMID- 24146796 TI - Polysaccharide responsiveness is not biased by prior pneumococcal-conjugate vaccination. AB - Polysaccharide responsiveness is tested by measuring antibody responses to polysaccharide vaccines to diagnose for humoral immunodeficiency. A common assumption is that this responsiveness is biased by any previous exposure to the polysaccharides in the form of protein-coupled polysaccharide vaccines, such as those used in many childhood vaccination programmes. To examine this assumption, we investigated the effect of protein-coupled polysaccharide vaccination on subsequent polysaccharide responsiveness. HIV-infected adults (n = 47) were vaccinated twice with protein-coupled polysaccharides and six months later with pure polysaccharides. We measured immunoglobulin G responses against three polysaccharides present in only the polysaccharide vaccine (non-memory polysaccharides) and seven recurring polysaccharides (memory polysaccharides). Responsiveness was evaluated according to the consensus guidelines published by the American immunology societies. Impaired responsiveness to non-memory polysaccharides was more frequent than to memory polysaccharides (51% versus 28%, P = 0.015), but the individual polysaccharides did not differ in triggering sufficient responses (74% versus 77%, P = 0.53). Closer analysis revealed important shortcomings of the current evaluation guidelines. The interpreted responses number and their specificities influenced the likelihood of impaired responsiveness in a complex manor. This influence was propelled by the dichotomous approaches inherent to the American guidelines. We therefore define a novel more robust polysaccharide responsiveness measure, the Z-score, which condenses multiple, uniformly weighted responses into one continuous variable. Using the Z-score, responsiveness to non-memory polysaccharides and memory polysaccharides were found to correlate (R(2) = 0.59, P<0.0001). We found that polysaccharide responsiveness was not biased by prior protein-coupled polysaccharide vaccination in HIV-infected adults. Studies in additional populations are warranted. PMID- 24146797 TI - Podocalyxin-like protein is expressed in glioblastoma multiforme stem-like cells and is associated with poor outcome. AB - Glioblastoma multiforme (GBM) is the most common primary malignant adult brain tumor and is associated with poor survival. Recently, stem-like cell populations have been identified in numerous malignancies including GBM. To identify genes whose expression is changed with differentiation, we compared transcript profiles from a GBM oncosphere line before and after differentiation. Bioinformatic analysis of the gene expression profiles identified podocalyxin-like protein (PODXL), a protein highly expressed in human embryonic stem cells, as a potential marker of undifferentiated GBM stem-like cells. The loss of PODXL expression upon differentiation of GBM stem-like cell lines was confirmed by quantitative real time PCR and flow cytometry. Analytical flow cytometry of numerous GBM oncosphere lines demonstrated PODXL expression in all lines examined. Knockdown studies and flow cytometric cell sorting experiments demonstrated that PODXL is involved in GBM stem-like cell proliferation and oncosphere formation. Compared to PODXL negative cells, PODXL-positive cells had increased expression of the progenitor/stem cell markers Musashi1, SOX2, and BMI1. Finally, PODXL expression directly correlated with increasing glioma grade and was a marker for poor outcome in patients with GBM. In summary, we have demonstrated that PODXL is expressed in GBM stem-like cells and is involved in cell proliferation and oncosphere formation. Moreover, high PODXL expression correlates with increasing glioma grade and decreased overall survival in patients with GBM. PMID- 24146798 TI - The clinical impact of mean vessel size and solidity in breast carcinoma patients. AB - Angiogenesis quantification, through vessel counting or area estimation in the most vascular part of the tumour, has been found to be of prognostic value across a range of carcinomas, breast cancer included. We have applied computer image analysis to quantify vascular properties pertaining to size, shape and spatial distributions in photographed fields of CD34 stained sections. Aided by a pilot (98 cases), seven parameters were selected and validated on a separate set from 293 breast cancer patients. Two new prognostic markers were identified through continuous cox regression with endpoints breast cancer specific survival and distant disease free survival: The average size of the vessels as measured by their perimeter (p = 0.003 and 0.004, respectively), and the average complexity of the vessel shapes measured by their solidity (p = 0.004 and 0.004). The Hazard ratios for the corresponding median-dichotomized markers were 2.28 (p = 0.005) and 1.89 (p = 0.016) for the mean perimeter and 1.80 (p = 0.041) and 1.55 (p = 0.095) for the shape complexity. The markers were associated with poor histologic type, high grade, necrosis, HR negativity, inflammation, and p53 expression (vessel size only). Both markers were found to strongly influence the prognostic properties of vascular invasion (VI) and disseminated tumour cells in the bone marrow. The latter being prognostic only in cases with large vessels (p = 0.004 and 0.043) or low complexity (p = 0.018 and 0.024), but not in the small or complex vessel groups (p>0.47). VI was significant in all groups, but showed greater hazard ratios for small and low complexity vessels (6.54-11.2) versus large and high complexity vessels (2.64-3.06). We find that not only the overall amount of produced vasculature in angiogenic hot-spots is of prognostic significance, but also the morphological appearance of the generated vessels, i.e. the size and shape of vessels in the studied hot spots. PMID- 24146799 TI - The impact of spatial scales and spatial smoothing on the outcome of bayesian spatial model. AB - Discretization of a geographical region is quite common in spatial analysis. There have been few studies into the impact of different geographical scales on the outcome of spatial models for different spatial patterns. This study aims to investigate the impact of spatial scales and spatial smoothing on the outcomes of modelling spatial point-based data. Given a spatial point-based dataset (such as occurrence of a disease), we study the geographical variation of residual disease risk using regular grid cells. The individual disease risk is modelled using a logistic model with the inclusion of spatially unstructured and/or spatially structured random effects. Three spatial smoothness priors for the spatially structured component are employed in modelling, namely an intrinsic Gaussian Markov random field, a second-order random walk on a lattice, and a Gaussian field with Matern correlation function. We investigate how changes in grid cell size affect model outcomes under different spatial structures and different smoothness priors for the spatial component. A realistic example (the Humberside data) is analyzed and a simulation study is described. Bayesian computation is carried out using an integrated nested Laplace approximation. The results suggest that the performance and predictive capacity of the spatial models improve as the grid cell size decreases for certain spatial structures. It also appears that different spatial smoothness priors should be applied for different patterns of point data. PMID- 24146800 TI - Comparative analysis of the Tyr-kinases CapB1 and CapB2 fused to their cognate modulators CapA1 and CapA2 from Staphylococcus aureus. AB - A particular class of tyrosine-kinases sharing no structural similarity with eukaryotic tyrosine-kinases has been evidenced in a large array of bacterial species. These bacterial tyrosine-kinases are able to autophosphorylate on a C terminal tyrosine-rich motif. Their autophosphorylation has been shown to play a crucial role in the biosynthesis or export of capsular polysaccharide. The analysis of the first crystal structure of the staphylococcal tyrosine kinase CapB2 associated with the activating domain of the transmembrane modulator CapA1 had brought conclusive explanation for both the autophosphorylation and activation processes. In order to explain why CapA1 activates CapB2 more efficiently than its cognate transmembrane modulator CapA2, we solved the crystal structure of CapA2B2 and compared it with the previously published structure of CapA1B2. This structural analysis did not provide the expected clues about the activation discrepancy observed between the two modulators. Staphylococcus aureus also encodes for a CapB2 homologue named CapB1 displaying more than 70% sequence similarity and being surprisingly nearly unable to autophosphorylate. We solved the crystal structure of CapA1B1 and carefully compare it with the structure of CapA1B2. The active sites of both proteins are highly conserved and the biochemical characterization of mutant proteins engineered to test the importance of small structural discrepancies identified between the two structures did not explain the inactivity of CapB1. We thus tested if CapB1 could phosphorylate other protein substrates or hydrolyze ATP. However, no activity could be detected in our in vitro assays. Taken together, these data question about the biological role of the homologous protein pairs CapA1/CapB1 and CapA2/CapB2 and we discuss about several possible interpretations. PMID- 24146801 TI - Gastrointestinal viral load and enteroendocrine cell number are associated with altered survival in HIV-1 infected individuals. AB - Human immunodeficiency virus type 1 (HIV-1) infects and destroys cells of the immune system leading to an overt immune deficiency known as HIV acquired immunodeficiency syndrome (HIV/AIDS). The gut associated lymphoid tissue is one of the major lymphoid tissues targeted by HIV-1, and is considered a reservoir for HIV-1 replication and of major importance in CD4+ T-cell depletion. In addition to immunodeficiency, HIV-1 infection also directly causes gastrointestinal (GI) dysfunction, also known as HIV enteropathy. This enteropathy can manifest itself as many pathological changes in the GI tract. The objective of this study was to determine the association of gut HIV-1 infection markers with long-term survival in a cohort of men who have sex with men (MSM) enrolled pre-HAART (Highly Active Antiretroviral Therapy). We examined survival over 15-years in a cohort of 42 HIV-infected cases: In addition to CD4+ T cell counts and HIV-1 plasma viral load, multiple gut compartment (duodenum and colon) biopsies were taken by endoscopy every 6 months during the initial 3-year period. HIV-1 was cultured from tissues and phenotyped and viral loads in the gut tissues were determined. Moreover, the tissues were subjected to an extensive assessment of enteroendocrine cell distribution and pathology. The collected data was used for survival analyses, which showed that patients with higher gut tissue viral load levels had a significantly worse survival prognosis. Moreover, lower numbers of serotonin (duodenum) and somatostatin (duodenum and colon) immunoreactive cell counts in the gut tissues of patients was associated with significant lower survival prognosis. Our study, suggested that HIV-1 pathogenesis and survival prognosis is associated with altered enteroendocrine cell numbers, which could point to a potential role for enteroendocrine function in HIV infection and pathogenesis. PMID- 24146802 TI - A novel branched chain amino acids responsive transcriptional regulator, BCARR, negatively acts on the proteolytic system in Lactobacillus helveticus. AB - Transcriptional negative regulation of the proteolytic system of Lactobacillus helveticus CM4 in response to amino acids seems to be very important for the control of antihypertensive peptide production; however, it remains poorly understood. A 26-kDa protein with N-terminal cystathionine beta-synthase domains (CBS domain protein), which seems to be involved in the regulatory system, was purified by using a DNA-sepharose bound 300-bp DNA fragment corresponding to the upstream regions of the six proteolytic genes that are down-regulated by amino acids. The CBS domain protein bound to a DNA fragment corresponding to the region upstream of the pepV gene in response to branched chain amino acids (BCAAs). The expression of the pepV gene in Escherichia coli grown in BCAA-enriched medium was repressed when the CBS domain protein was co-expressed. These results reveal that the CBS domain protein acts as a novel type of BCAA-responsive transcriptional regulator (BCARR) in L. helveticus. From comparative analysis of the promoter regions of the six proteolysis genes, a palindromic AT-rich motif, 5' AAAAANNCTWTTATT-3', was predicted as the consensus DNA motif for the BCARR protein binding. Footprint analysis using the pepV promotor region and gel shift analyses with the corresponding short DNA fragments strongly suggested that the BCARR protein binds adjacent to the pepV promoter region and affects the transcription level of the pepV gene in the presence of BCAAs. Homology search analysis of the C-terminal region of the BCARR protein suggested the existence of a unique betaalphabetabetaalphabeta fold structure that has been reported in a variety of ACT (aspartate kinase-chorismate mutase-tyrA) domain proteins for sensing amino acids. These results also suggest that the sensing of BCAAs by the ACT domain might promote the binding of the BCARR to DNA sequences upstream of proteolysis genes, which affects the gene expression of the proteolytic system in L. helveticus. PMID- 24146804 TI - Microwhip scorpions (Palpigradi) feed on heterotrophic cyanobacteria in Slovak caves--a curiosity among Arachnida. AB - To date, only morphological and anatomical descriptions of microwhip scorpions (Arachnida: Palpigradi) have been published. This very rare group is enigmatic not only in its relationships to other arachnids, but especially due to the fact that these animals dwell only underground (in caves, soil, and interstitial spaces). We observed the curious feeding habit of the microwhip scorpion Eukoenenia spelaea over the course of one year in Ardovska Cave, located in Slovakia's Karst region. We chose histology as our methodology in studying 17 specimens and based it upon Masson's triple staining, fluorescent light and confocal microscopy. Single-celled cyanobacteria (blue-green algae) were conspicuously predominant in the gut of all studied palpigrades. Digestibility of the consumed cyanobacteria was supported by the presence of guanine crystals, glycogen deposits and haemocytes inside the palpigrade body. Cyanobacteria, the oldest cellular organisms on Earth, are very resistant to severe conditions in caves, including even darkness. Therefore, the cyanobacteria are able to survive in dark caves as nearly heterotrophic organisms and are consumed by cave palpigrades. Such feeding habit is extraordinary within the almost wholly predacious orders of the class Arachnida, and particularly so due to the type of food observed. PMID- 24146803 TI - Strong impact of TGF-beta1 gene polymorphisms on breast cancer risk in Indian women: a case-control and population-based study. AB - INTRODUCTION: TGF-beta1 is a multi-functional cytokine that plays an important role in breast carcinogenesis. Critical role of TGF-beta1 signaling in breast cancer progression is well documented. Some TGF-beta1 polymorphisms influence its expression; however, their impact on breast cancer risk is not clear. METHODS: We analyzed 1222 samples in a candidate gene-based genetic association study on two distantly located and ethnically divergent case-control groups of Indian women, followed by a population-based genetic epidemiology study analyzing these polymorphisms in other Indian populations. The c.29C>T (Pro10Leu, rs1982073 or rs1800470) and c.74G>C (Arg25Pro, rs1800471) polymorphisms in the TGF-beta1 gene were analyzed using direct DNA sequencing, and peripheral level of TGF-beta1 were measured by ELISA. RESULTS: c.29C>T substitution increased breast cancer risk, irrespective of ethnicity and menopausal status. On the other hand, c.74G>C substitution reduced breast cancer risk significantly in the north Indian group (p = 0.0005) and only in the pre-menopausal women. The protective effect of c.74G>C polymorphism may be ethnicity-specific, as no association was seen in south Indian group. The polymorphic status of c.29C>T was comparable among Indo Europeans, Dravidians, and Tibeto-Burmans. Interestingly, we found that Tibeto Burmans lack polymorphism at c.74G>C locus as true for the Chinese populations. However, the Brahmins of Nepal (Indo-Europeans) showed polymorphism in 2.08% of alleles. Mean TGF-beta1 was significantly elevated in patients in comparison to controls (p<0.001). CONCLUSION: c.29C>T and c.74G>C polymorphisms in the TGF beta1 gene significantly affect breast cancer risk, which correlates with elevated TGF-beta1 level in the patients. The c.29C>T locus is polymorphic across ethnically different populations, but c.74G>C locus is monomorphic in Tibeto Burmans and polymorphic in other Indian populations. PMID- 24146805 TI - Measuring the evolution of ontology complexity: the gene ontology case study. AB - Ontologies support automatic sharing, combination and analysis of life sciences data. They undergo regular curation and enrichment. We studied the impact of an ontology evolution on its structural complexity. As a case study we used the sixty monthly releases between January 2008 and December 2012 of the Gene Ontology and its three independent branches, i.e. biological processes (BP), cellular components (CC) and molecular functions (MF). For each case, we measured complexity by computing metrics related to the size, the nodes connectivity and the hierarchical structure. The number of classes and relations increased monotonously for each branch, with different growth rates. BP and CC had similar connectivity, superior to that of MF. Connectivity increased monotonously for BP, decreased for CC and remained stable for MF, with a marked increase for the three branches in November and December 2012. Hierarchy-related measures showed that CC and MF had similar proportions of leaves, average depths and average heights. BP had a lower proportion of leaves, and a higher average depth and average height. For BP and MF, the late 2012 increase of connectivity resulted in an increase of the average depth and average height and a decrease of the proportion of leaves, indicating that a major enrichment effort of the intermediate-level hierarchy occurred. The variation of the number of classes and relations in an ontology does not provide enough information about the evolution of its complexity. However, connectivity and hierarchy-related metrics revealed different patterns of values as well as of evolution for the three branches of the Gene Ontology. CC was similar to BP in terms of connectivity, and similar to MF in terms of hierarchy. Overall, BP complexity increased, CC was refined with the addition of leaves providing a finer level of annotations but decreasing slightly its complexity, and MF complexity remained stable. PMID- 24146806 TI - How psychiatry journals support the unbiased translation of clinical research. A cross-sectional study of editorial policies. AB - INTRODUCTION: Reporting guidelines (e.g. CONSORT) have been developed as tools to improve quality and reduce bias in reporting research findings. Trial registration has been recommended for countering selective publication. The International Committee of Medical Journal Editors (ICMJE) encourages the implementation of reporting guidelines and trial registration as uniform requirements (URM). For the last two decades, however, biased reporting and insufficient registration of clinical trials has been identified in several literature reviews and other investigations. No study has so far investigated the extent to which author instructions in psychiatry journals encourage following reporting guidelines and trial registration. METHOD: Psychiatry Journals were identified from the 2011 Journal Citation Report. Information given in the author instructions and during the submission procedure of all journals was assessed on whether major reporting guidelines, trial registration and the ICMJE's URM in general were mentioned and adherence recommended. RESULTS: We included 123 psychiatry journals (English and German language) in our analysis. A minority recommend or require 1) following the URM (21%), 2) adherence to reporting guidelines such as CONSORT, PRISMA, STROBE (23%, 7%, 4%), or 3) registration of clinical trials (34%). The subsample of the top-10 psychiatry journals (ranked by impact factor) provided much better but still improvable rates. For example, 70% of the top-10 psychiatry journals do not ask for the specific trial registration number. DISCUSSION: Under the assumption that better reported and better registered clinical research that does not lack substantial information will improve the understanding, credibility, and unbiased translation of clinical research findings, several stakeholders including readers (physicians, patients), authors, reviewers, and editors might benefit from improved author instructions in psychiatry journals. A first step of improvement would consist in requiring adherence to the broadly accepted reporting guidelines and to trial registration. PMID- 24146807 TI - Solvothermal preparation of ZnO nanorods as anode material for improved cycle life Zn/AgO batteries. AB - Nano materials with high surface area increase the kinetics and extent of the redox reactions, thus resulting in high power and energy densities. In this study high surface area zinc oxide nanorods have been synthesized by surfactant free ethylene glycol assisted solvothermal method. The nanorods thus prepared have diameters in the submicron range (300 ~ 500 nm) with high aspect ratio. They have uniform geometry and well aligned direction. These nanorods are characterized by XRD, SEM, Specific Surface Area Analysis, solubility in alkaline medium, EDX analysis and galvanostatic charge/discharge studies in Zn/AgO batteries. The prepared zinc oxide nanorods have low solubility in alkaline medium with higher structural stability, which imparts the improved cycle life stability to Zn/AgO cells. PMID- 24146808 TI - Lower HIV provirus levels are associated with more APOBEC3G protein in blood resting memory CD4+ T lymphocytes of controllers in vivo. AB - Immunodeficiency does not progress for prolonged periods in some HLA B57- and/or B27-positive subjects with human immunodeficiency virus type 1 (HIV) infection, even in the absence of antiretroviral therapy (ART). These "controllers" have fewer HIV provirus-containing peripheral blood mononuclear cells than "non controller" subjects, but lymphocytes that harbor latent proviruses were not specifically examined in studies to date. Provirus levels in resting memory cells that can serve as latent reservoirs of HIV in blood were compared here between controllers and ART-suppressed non-controllers. APOBEC3G (A3G), a cellular factor that blocks provirus formation at multiple steps if not antagonized by HIV virion infectivity factor (Vif), was also studied. HLA-linked HIV control was associated with less provirus and more A3G protein in resting CD4+ T central memory (Tcm) and effector memory (Tem) lymphocytes (provirus: p = 0.01 for Tcm and p = 0.02 for Tem; A3G: p = 0.02 for Tcm and p = 0.02 for Tem). Resting memory T cells with the highest A3G protein levels (>0.5 RLU per unit of actin) had the lowest levels of provirus (<1,000 copies of DNA per million cells) in vivo (p = 0.03, Fisher's exact test). Using two different experimental approaches, Vif-positive viruses with more A3G were found to have decreased virion infectivity ex vivo. These results raise the hypothesis that HIV control is associated with increased cellular A3G that may be packaged into Vif-positive virions to add that mode of inhibition of provirus formation to previously described adaptive immune mechanisms for HIV control. PMID- 24146809 TI - Targeted gene deletion of miRNAs in mice by TALEN system. AB - Mice are among the most valuable model animal species with an enormous amount of heritage in genetic modification studies. However, targeting genes in mice is sometimes difficult, especially for small genes, such as microRNAs (miRNAs) and targeting genes in repeat sequences. Here we optimized the application of TALEN system for mice and successfully obtained gene targeting technique in mice for intergenic region and series of microRNAs. Microinjection of synthesized RNA of TALEN targeting each gene in one cell stage of embryo was carried out and injected oocytes were transferred into pseudopregnant ICR female mice, producing a high success rate of the targeted deletion of miRNA genes. In our condition, TALEN RNA without poly(A) tail worked better than that of with poly(A) tail. This mutated allele in miRNA was transmitted to the next generation, suggesting the successful germ line transmission of this targeting method. Consistent with our notion of miRNAs maturation mechanism, in homozygous mutant mice of miR-10a, the non- mutated strand of miRNAs expression was completely diminished. This method will lead us to expand and accelerate our genetic research using mice in a high throughput way. PMID- 24146810 TI - IL-17A and IL-2-expanded regulatory T cells cooperate to inhibit Th1-mediated rejection of MHC II disparate skin grafts. AB - Several evidences suggest that regulatory T cells (Treg) promote Th17 differentiation. Based on this hypothesis, we tested the effect of IL-17A neutralization in a model of skin transplantation in which long-term graft survival depends on a strong in vivo Treg expansion induced by transient exogenous IL-2 administration. As expected, IL-2 supplementation prevented rejection of MHC class II disparate skin allografts but, surprisingly, not in IL 17A-deficient recipients. We attested that IL-17A was not required for IL-2 mediated Treg expansion, intragraft recruitment or suppressive capacities. Instead, IL-17A prevented allograft rejection by inhibiting Th1 alloreactivity independently of Tregs. Indeed, T-bet expression of naive alloreactive CD4+ T cells and the subsequent Th1 immune response was significantly enhanced in IL-17A deficient mice. Our results illustrate for the first time a protective role of IL 17A in CD4+-mediated allograft rejection process. PMID- 24146811 TI - Validation of the memorial Sloan-Kettering Cancer Center nomogram to predict disease-specific survival after R0 resection in a Chinese gastric cancer population. AB - BACKGROUND: Prediction of disease-specific survival (DSS) for individual patient with gastric cancer after R0 resection remains a clinical concern. Since the clinicopathologic characteristics of gastric cancer vary widely between China and western countries, this study is to evaluate a nomogram from Memorial Sloan Kettering Cancer Center (MSKCC) for predicting the probability of DSS in patients with gastric cancer from a Chinese cohort. METHODS: From 1998 to 2007, clinical data of 979 patients with gastric cancer who underwent R0 resection were retrospectively collected from Peking University Cancer Hospital & Institute and used for external validation. The performance of the MSKCC nomogram in our population was assessed using concordance index (C-index) and calibration plot. RESULTS: The C-index for the MSKCC predictive nomogram was 0.74 in the Chinese cohort, compared with 0.69 for American Joint Committee on Cancer (AJCC) staging system (P<0.0001). This suggests that the discriminating value of MSKCC nomogram is superior to AJCC staging system for prognostic prediction in the Chinese population. Calibration plots showed that the actual survival of Chinese patients corresponded closely to the MSKCC nonogram-predicted survival probabilities. Moreover, MSKCC nomogram predictions demonstrated the heterogeneity of survival in stage IIA/IIB/IIIA/IIIB disease of the Chinese patients. CONCLUSION: In this study, we externally validated MSKCC nomogram for predicting the probability of 5 and 9-year DSS after R0 resection for gastric cancer in a Chinese population. The MSKCC nomogram performed well with good discrimination and calibration. The MSKCC nomogram improved individualized predictions of survival, and may assist Chinese clinicians and patients in individual follow-up scheduling, and decision making with regard to various treatment options. PMID- 24146812 TI - The interplay of stress and sleep impacts BDNF level. AB - BACKGROUND: Sleep plays a pivotal role in normal biological functions. Sleep loss results in higher stress vulnerability and is often found in mental disorders. There is evidence that brain-derived neurotrophic factor (BDNF) could be a central player in this relationship. Recently, we could demonstrate that subjects suffering from current symptoms of insomnia exhibited significantly decreased serum BDNF levels compared with sleep-healthy controls. In accordance with the paradigm indicating a link between sleep and BDNF, we aimed to investigate if the stress system influences the association between sleep and BDNF. METHODOLOGY/PRINCIPAL FINDINGS: Participants with current symptoms of insomnia plus a former diagnosis of Restless Legs Syndrome (RLS) and/or Periodic Limb Movement (PLM) and sleep healthy controls were included in the study. They completed questionnaires on sleep (ISI, Insomnia Severity Index) and stress (PSS, Perceived Stress Scale) and provided a blood sample for determination of serum BDNF. We found a significant interaction between stress and insomnia with an impact on serum BDNF levels. Moreover, insomnia severity groups and score on the PSS each revealed a significant main effect on serum BDNF levels. Insomnia severity was associated with increased stress experience affecting serum BDNF levels. Of note, the association between stress and BDNF was only observed in subjects without insomnia. Using a mediation model, sleep was revealed as a mediator of the association between stress experience and serum BDNF levels. CONCLUSIONS: This is the first study to show that the interplay between stress and sleep impacts BDNF levels, suggesting an important role of this relationship in the pathogenesis of stress-associated mental disorders. Hence, we suggest sleep as a key mediator at the connection between stress and BDNF. Whether sleep is maintained or disturbed might explain why some individuals are able to handle a certain stress load while others develop a mental disorder. PMID- 24146813 TI - Alterations in miRNA levels in the dentate gyrus in epileptic rats. AB - The aim of this study was to characterize changes in miRNA expression in the epileptic dentate gyrus. Status epilepticus evoked by amygdala stimulation was used to induce epilepsy in rats. The dentate gyri were isolated at 7 d, 14 d, 30 d and 90 d after stimulation (n=5). Sham-operated time-matched controls were prepared for each time point (n=5). The miRNA expression was evaluated using Exiqon microarrays. Additionally, mRNA from the same animals was profiled using Affymetrix microarrays. We detected miRNA expression signatures that differentiate between control and epileptic animals. Significant changes in miRNA expression between stimulated and sham operated animals were observed at 7 and 30 d following stimulation. Moreover, we found that there are ensembles of miRNAs that change expression levels over time. Analysis of the mRNA expression from the same animals revealed that the expression of several mRNAs that are potential targets for miRNA with altered expression level is regulated in the expected direction. The functional characterization of miRNAs and their potential mRNA targets indicate that miRNA can participate in several molecular events that occur in epileptic tissue, including immune response and neuronal plasticity. This is the first report on changes in the expression of miRNA and the potential functional impact of these changes in the dentate gyrus of epileptic animals. Complex changes in the expression of miRNAs suggest an important role for miRNA in the molecular mechanisms of epilepsy. PMID- 24146814 TI - Detection of Salmonella spp. using a generic and differential FRET-PCR. AB - To facilitate the detection of Salmonella and to be able to rapidly and conveniently determine the species/subspecies present, we developed and tested a generic and differential FRET-PCR targeting their tetrathionate reductase response regulator gene. The differential pan-Salmonella FRET-PCR we developed successfully detected seven plasmids that contained partial sequences of S. bongori and the six S. enterica subspecies. The detection limit varied from ~5 copies of target gene/per PCR reaction for S. enterica enterica to ~200 for S. bongori. Melting curve analysis demonstrated a T m of ~68 degrees C for S. enterica enterica, ~62.5 degrees C for S. enterica houtenae and S. enterica diarizonae, ~57 degrees C for S. enterica indica, and ~54 degrees C for S. bongori, S. enterica salamae and S. enterica arizonae. The differential pan Salmonella FRET-PCR also detected and determined the subspecies of 4 reference strains and 47 Salmonella isolated from clinically ill birds or pigs. Finally, we found it could directly detect and differentiate Salmonella in feline (5/50 positive; 10%; one S. enterica salamae and 4 S. enterica enterica) and canine feces (15/114 positive; 13.2%; all S. enterica enterica). The differential pan Salmonella FRET-PCR failed to react with 96 non-Salmonella bacterial strains. Our experiments show the differential pan-Salmonella FRET-PCR we developed is a rapid, sensitive and specific method to detect and differentiate Salmonella. PMID- 24146815 TI - Direct visualization of the highly polymorphic RNU2 locus in proximity to the BRCA1 gene. AB - Although the breast cancer susceptibility gene BRCA1 is one of the most extensively characterized genetic loci, much less is known about its upstream variable number tandem repeat element, the RNU2 locus. RNU2 encodes the U2 small nuclear RNA, an essential splicing element, but this locus is missing from the human genome assembly due to the inherent difficulty in the assembly of repetitive sequences. To fill the gap between RNU2 and BRCA1, we have reconstructed the physical map of this region by re-examining genomic clone sequences of public databases, which allowed us to precisely localize the RNU2 array 124 kb telomeric to BRCA1. We measured by performing FISH analyses on combed DNA for the first time the exact number of repeats carried by each of the two alleles in 41 individuals and found a range of 6-82 copies and a level of heterozygosity of 98%. The precise localisation of the RNU2 locus in the genome reference assembly and the implementation of a new technical tool to study it will make the detailed exploration of this locus possible. This recently neglected macrosatellite could be valuable for evaluating the potential role of structural variations in disease due to its location next to a major cancer susceptibility gene. PMID- 24146817 TI - Predator recognition in rainbowfish, Melanotaenia duboulayi, embryos. AB - Exposure to olfactory cues during embryonic development can have long term impacts on birds and amphibians behaviour. Despite the vast literature on predator recognition and responses in fishes, few researchers have determined how fish embryos respond to predator cues. Here we exposed four-day-old rainbowfish (Melanotaenia duboulayi) embryos to cues emanating from a novel predator, a native predator and injured conspecifics. Their response was assessed by monitoring heart rate and hatch time. Results showed that embryos have an innate capacity to differentiate between cues as illustrated by faster heart rates relative to controls. The greatest increase in heart rate occurred in response to native predator odour. While we found no significant change in the time taken for eggs to hatch, all treatments experienced slight delays as expected if embryos are attempting to reduce exposure to larval predators. PMID- 24146816 TI - Expression of Tau40 induces activation of cultured rat microglial cells. AB - Accumulation of microtubule-associated protein tau has been observed in the brain of aging and tauopathies. Tau was observed in microglia, but its role is not illustrated. By immunofluorescence staining and the fractal dimension value assay in the present study, we observed that microglia were activated in the brains of rats and mice during aging, simultaneously, the immunoreactivities of total tau and the phosphorylated tau were significantly enhanced in the activated microglia. Furtherly by transient transfection of tau40 (human 2N/4R tau) into the cultured rat microglia, we demonstrated that expression of tau40 increased the level of Iba1, indicating activation of microglia. Moreover, expression of tau40 significantly enhanced the membranous localization of the phosphorylated tau at Ser396 in microglia possibly by a mechanism involving protein phosphatase 2A, extracellular signal-regulated kinase and glycogen synthase kinase-3beta. It was also found that expression of tau40 promoted microglial migration and phagocytosis, but not proliferation. And we observed increased secretion of several cytokines, including interleukin (IL)-1beta, IL-6, IL-10, tumor necrosis factor-alpha and nitric oxide after the expression of tau40. These data suggest a novel role of human 2N/4R tau in microglial activation. PMID- 24146818 TI - Analysis of the effects of polymorphism on pollen profilin structural functionality and the generation of conformational, T- and B-cell epitopes. AB - An extensive polymorphism analysis of pollen profilin, a fundamental regulator of the actin cytoskeleton dynamics, has been performed with a major focus in 3D folding maintenance, changes in the 2-D structural elements, surface residues involved in ligands-profilin interactions and functionality, and the generation of conformational and lineal B- and T-cell epitopes variability. Our results revealed that while the general fold is conserved among profilins, substantial structural differences were found, particularly affecting the special distribution and length of different 2-D structural elements (i.e. cysteine residues), characteristic loops and coils, and numerous micro-heterogeneities present in fundamental residues directly involved in the interacting motifs, and to some extension these residues nearby to the ligand-interacting areas. Differential changes as result of polymorphism might contribute to generate functional variability among the plethora of profilin isoforms present in the olive pollen from different genetic background (olive cultivars), and between plant species, since biochemical interacting properties and binding affinities to natural ligands may be affected, particularly the interactions with different actin isoforms and phosphoinositides lipids species. Furthermore, conspicuous variability in lineal and conformational epitopes was found between profilins belonging to the same olive cultivar, and among different cultivars as direct implication of sequences polymorphism. The variability of the residues taking part of IgE-binding epitopes might be the final responsible of the differences in cross-reactivity among olive pollen cultivars, among pollen and plant-derived food allergens, as well as between distantly related pollen species, leading to a variable range of allergy reactions among atopic patients. Identification and analysis of commonly shared and specific epitopes in profilin isoforms is essential to gain knowledge about the interacting surface of these epitopes, and for a better understanding of immune responses, helping design and development of rational and effective immunotherapy strategies for the treatment of allergy diseases. PMID- 24146819 TI - Development of transgenic minipigs with expression of antimorphic human cryptochrome 1. AB - Minipigs have become important biomedical models for human ailments due to similarities in organ anatomy, physiology, and circadian rhythms relative to humans. The homeostasis of circadian rhythms in both central and peripheral tissues is pivotal for numerous biological processes. Hence, biological rhythm disorders may contribute to the onset of cancers and metabolic disorders including obesity and type II diabetes, amongst others. A tight regulation of circadian clock effectors ensures a rhythmic expression profile of output genes which, depending on cell type, constitute about 3-20% of the transcribed mammalian genome. Central to this system is the negative regulator protein Cryptochrome 1 (CRY1) of which the dysfunction or absence has been linked to the pathogenesis of rhythm disorders. In this study, we generated transgenic Bama minipigs featuring expression of the Cys414-Ala antimorphic human Cryptochrome 1 mutant (hCRY1(AP)). Using transgenic donor fibroblasts as nuclear donors, the method of handmade cloning (HMC) was used to produce reconstructed embryos, subsequently transferred to surrogate sows. A total of 23 viable piglets were delivered. All were transgenic and seemingly healthy. However, two pigs with high transgene expression succumbed during the first two months. Molecular analyzes in epidermal fibroblasts demonstrated disturbances to the expression profile of core circadian clock genes and elevated expression of the proinflammatory cytokines IL 6 and TNF-alpha, known to be risk factors in cancer and metabolic disorders. PMID- 24146821 TI - Wood recognition using image texture features. AB - Inspired by theories of higher local order autocorrelation (HLAC), this paper presents a simple, novel, yet very powerful approach for wood recognition. The method is suitable for wood database applications, which are of great importance in wood related industries and administrations. At the feature extraction stage, a set of features is extracted from Mask Matching Image (MMI). The MMI features preserve the mask matching information gathered from the HLAC methods. The texture information in the image can then be accurately extracted from the statistical and geometrical features. In particular, richer information and enhanced discriminative power is achieved through the length histogram, a new histogram that embodies the width and height histograms. The performance of the proposed approach is compared to the state-of-the-art HLAC approaches using the wood stereogram dataset ZAFU WS 24. By conducting extensive experiments on ZAFU WS 24, we show that our approach significantly improves the classification accuracy. PMID- 24146820 TI - Early elevation of serum MMP-3 and MMP-12 predicts protection from World Trade Center-lung injury in New York City Firefighters: a nested case-control study. AB - OBJECTIVE: After 9/11/2001, some Fire Department of New York (FDNY) workers had excessive lung function decline. We hypothesized that early serum matrix metalloproteinases (MMP) expression predicts World Trade Center-Lung Injury (WTC LI) years later. METHODS: This is a nested case-control analysis of never-smoking male firefighters with normal pre-exposure Forced Expiratory Volume in one second (FEV1) who had serum drawn up to 155 days post 9/11/2001. Serum MMP-1, 2,3,7,8, 9, 12 and 13 were measured. Cases of WTC-LI (N = 70) were defined as having an FEV1 one standard deviation below the mean (FEV1 <= 77%) at subspecialty pulmonary evaluation (SPE) which was performed 32 months (IQR 21-53) post-9/11. Controls (N = 123) were randomly selected. We modeled MMP's ability as a predictor of cases status with logistic regression adjusted for time to blood draw, exposure intensity, weight gain and pre-9/11 FEV1. RESULTS: Each log increase in MMP-3 and MMP-12 showed reduced odds of developing WTC-LI by 73% and 54% respectively. MMP-3 and MMP-12 consistently clustered together in cases, controls, and the cohort. Increasing time to blood draw significantly and independently increased the risk of WTC-LI. CONCLUSIONS: Elevated serum levels of MMP-3 and MMP-12 reduce the risk of developing WTC-LI. At any level of MMP-3 or 12, increased time to blood draw is associated with a diminished protective effect. PMID- 24146822 TI - Chinese herbal medicine for diabetic peripheral neuropathy: an updated meta analysis of 10 high-quality randomized controlled studies. AB - BACKGROUND: Diabetic peripheral neuropathy (DPN) is very common in people with diabetes. Chinese herbal medicine (CHM) therapy has been developed for DPN empirically over the years. The aim of this systematic review and meta-analysis was to assess the efficacy and safety of CHMs for patients suffering from DPN. METHODS: We performed a meta-analysis of randomized-controlled clinical trials (RCTs) evaluating the efficacy and safety of CHM on DPN. Six databases were searched up to November 2012. The primary outcome measures were the absolute values or changing of motor or sensory nerve conduction velocity (NCV), and the secondary outcome measurements were clinical symptoms improvements and adverse events. The methodological quality was assessed by Jadad scale and the twelve criteria recommended by the Cochrane Back Review Group. RESULTS: One hundred and sixty-three studies claimed RCTs. Ten studies with 653 individuals were further identified based on the Jadad score >= 3. These 10 studies were all of high methodological quality with a low risk of bias. Meta-analysis showed the effects of NCV favoring CHMs when compared with western conventional medicines (WCM) (P<0.05 or P<0.01). There is a significant difference in the total efficacy rate between the two groups (P<0.001). Adverse effects were reported in all of the ten included studies, and well tolerated in all patients with DPN. CONCLUSION: Despite of the apparently positive findings and low risk of bias, it is premature to conclude the efficacy of CHMs for the treatment of DPN because of the high clinical heterogeneity and small sample sizes of the included studies. However, CHM therapy was safe for DPN. Further standardized preparation, large sample-size and rigorously designed RCTs are required. PMID- 24146824 TI - Therapeutic efficacy of percutaneous radiofrequency ablation versus microwave ablation for hepatocellular carcinoma. AB - The aim of this study was to investigate the therapeutic efficacy of percutaneous radiofrequency (RF) ablation versus microwave (MW) ablation for hepatocellular carcinoma (HCC) measuring <= 5 cm in greatest diameter. From January 2006 to December 2006, 78 patients had undergone RF ablation whereas 77 had undergone MW ablation. Complete ablation (CA), local tumour progression (LTP) and distant recurrence (DR) were compared. The overall survival curves were calculated with the Kaplan-Meier technique and compared with the log-rank test. The CA rate was 83.4% (78/93) for RF ablation and 86.7%(91/105 for MW ablation. The LTP rate was 11.8% (11/93) for RF ablation and 10.5% (11/105) for MW ablation. DR was found in 51 (65.4%) in the RF ablation and 62 (80.5%) in the MW ablation. There was no significant difference in the 1-, 3-, and 5-year overall survival rates (P = 0.780) and the 1-, 3-, and 5-year disease-free survival rates (P = 0.123) between RF and MW ablation. At subgroup analyses, for patients with tumors <= 3.0 cm, there was no significant difference in the 1-, 3-, and 5-year overall survival rates (P = 0.067) and the corresponding disease-free survival rates(P = 0.849). For patients with tumor diameters of 3.1-5.0 cm, the 1-, 3-, and 5-year overall survival rates were 87.1%, 61.3%, and 40.1% for RF ablation and 85.4%, 36.6%, and 22% for MW ablation, with no significant difference (P = 0.068). The corresponding disease-free survival rates were 74.2%, 54.8%, and 45.2% for the RF ablation group and 53.3%, 26.8%, and 17.1% for the MW ablation group. The disease free survival curve for the RF ablation group was significantly better than that for the MW ablation group (P = 0.018). RF ablation and MW ablation are both effective methods in treating hepatocellular carcinomas, with no significant differences in CA, LTP, DR, and overall survival. PMID- 24146823 TI - Expression of the B-cell receptor component CD79a on immature myeloid cells contributes to their tumor promoting effects. AB - The role of myeloid derived suppressor cells (MDSCs) in promoting tumorigenesis is well-established, and significant effort is being made to further characterize surface markers on MDSCs both for better diagnosis and as potential targets for therapy. Here we show that the B cell receptor adaptor molecule CD79a is unexpectedly expressed on immature bone marrow myeloid cells, and is upregulated on MDSCs generated in multiple different mouse models of metastatic but not non metastatic cancer. CD79a on MDSCs is upregulated and activated in response to soluble factors secreted by tumor cells. Activation of CD79a on mouse MDSCs, by crosslinking with a specific antibody, maintained their immature phenotype (CD11b+Gr1+), enhanced their migration, increased their suppressive effect on T cell proliferation, and increased secretion of pro-tumorigenic cytokines such as IL-6 and CCL22. Furthermore, crosslinking CD79a on myeloid cells activated signaling through Syk, BLNK, ERK and STAT3 phosphorylation. In vivo, CD79+ myeloid cells showed enhanced ability to promote primary tumor growth and metastasis. Finally we demonstrate that CD79a is upregulated on circulating myeloid cells from lung cancer patients, and that CD79a+ myeloid cells infiltrate human breast tumors. We propose that CD79a plays a functional role in the tumor promoting effects of myeloid cells, and may represent a novel target for cancer therapy. PMID- 24146825 TI - Collective response of zebrafish shoals to a free-swimming robotic fish. AB - In this work, we explore the feasibility of regulating the collective behavior of zebrafish with a free-swimming robotic fish. The visual cues elicited by the robot are inspired by salient features of attraction in zebrafish and include enhanced coloration, aspect ratio of a fertile female, and carangiform/subcarangiform locomotion. The robot is autonomously controlled with an online multi-target tracking system and swims in circular trajectories in the presence of groups of zebrafish. We investigate the collective response of zebrafish to changes in robot speed, achieved by varying its tail-beat frequency. Our results show that the speed of the robot is a determinant of group cohesion, quantified through zebrafish nearest-neighbor distance, which increases with the speed of the robot until it reaches [Formula: see text]. We also find that the presence of the robot causes a significant decrease in the group speed, which is not accompanied by an increase in the freezing response of the subjects. Findings of this study are expected to inform the design of experimental protocols that leverage the use of robots to study the zebrafish animal model. PMID- 24146827 TI - Association of a hepatopancreas-specific C-type lectin with the antibacterial response of Eriocheir sinensis. AB - Pattern recognition receptors (PPRs) are part of the initial step of a host defense against pathogens in detecting pathogen-associated molecular patterns. However, determinants of the specificity of this recognition by innate immune molecules of invertebrates remain largely unknown. In this study, we investigated the potential involvement of an invertebrate PRR C-type lectin in the antimicrobial response of the crustacean Eriocheir sinensis. Based on the initial expressed sequence tags (EST) of a hepatopancreatic cDNA library, the full-length EsLecF cDNA was cloned and determined to contain a 477-bp open reading frame encoding a putative 158-amino-acid protein. A comparison with other reported invertebrate and vertebrate C-type lectin superfamily sequences revealed the presence of a common carbohydrate recognition domain (CRD). EsLecF transcripts in E. sinensis were mainly detected in the hepatopancreas and were inducible by a lipopolysaccharide (LPS) injection. The recombinant EsLecF (rEsLecF) protein produced via a prokaryotic expression system and affinity chromatography was found to have a wide spectrum of binding activities towards various microorganisms, and its microbial-binding activity was calcium-independent. Moreover, the binding of rEsLecF induced the aggregation of microbial pathogens. Results of the microorganism growth inhibitory assay and antibacterial assay revealed capabilities of rEsLecF in suppressing microorganism growth and directly killing bacteria, respectively. Furthermore, rEsLecF could enhance cellular encapsulation in vitro. Collectively, the findings presented here demonstrated the successful isolation of a novel C-type lectin in a crustacean and highlighted its critical role in the innate immunity of an invertebrate. PMID- 24146826 TI - Identification and structural-functional analysis of cyclin-dependent kinases of the cattle tick Rhipicephalus (Boophilus) microplus. AB - Cyclin-dependent kinases (CDKs) are a family of serine/threonine kinases essential for cell cycle progression. Herein, we describe the participation of CDKs in the physiology of Rhipicephalus microplus, the southern cattle tick and an important disease vector. Firstly, amino acid sequences homologous with CDKs of other organisms were identified from a R. microplus transcriptome database in silico. The analysis of the deduced amino acid sequences of CDK1 and CDK10 from R. microplus showed that both have caspase-3/7 cleavage motifs despite their differences in motif position and length of encoded proteins. CDK1 has two motifs (DKRGD and SAKDA) located opposite to the ATP binding site while CDK10 has only one motif (SLLDN) for caspase 3-7 near the ATP binding site. Roscovitine (Rosco), a purine derivative that inhibits CDK/cyclin complexes by binding to the catalytic domain of the CDK molecule at the ATP binding site, which prevents the transfer of ATP's gammaphosphoryl group to the substrate. To determine the effect of Rosco on tick CDKs, BME26 cells derived from R. microplus embryo cells were utilized in vitro inhibition assays. Cell viability decreased in the Rosco treated groups after 24 hours of incubation in a concentration-dependent manner and this was observed up to 48 hours following incubation. To our knowledge, this is the first report on characterization of a cell cycle protein in arachnids, and the sensitivity of BME26 tick cell line to Rosco treatment suggests that CDKs are potential targets for novel drug design to control tick infestation. PMID- 24146828 TI - Insulin-like growth factor I (IGF-1) Ec/Mechano Growth factor--a splice variant of IGF-1 within the growth plate. AB - Human insulin-like growth factor 1 Ec (IGF-1Ec), also called mechano growth factor (MGF), is a splice variant of insulin-like growth factor 1 (IGF-1), which has been shown in vitro as well as in vivo to induce growth and hypertrophy in mechanically stimulated or damaged muscle. Growth, hypertrophy and responses to mechanical stimulation are important reactions of cartilaginous tissues, especially those in growth plates. Therefore, we wanted to ascertain if MGF is expressed in growth plate cartilage and if it influences proliferation of chondrocytes, as it does in musculoskeletal tissues. MGF expression was analyzed in growth plate and control tissue samples from piglets aged 3 to 6 weeks. Furthermore, growth plate chondrocyte cell culture was used to evaluate the effects of the MGF peptide on proliferation. We showed that MGF is expressed in considerable amounts in the tissues evaluated. We found the MGF peptide to be primarily located in the cytoplasm, and in some instances, it was also found in the nucleus of the cells. Addition of MGF peptides was not associated with growth plate chondrocyte proliferation. PMID- 24146829 TI - Stabilizing exposure of conserved epitopes by structure guided insertion of disulfide bond in HIV-1 envelope glycoprotein. AB - Entry of HIV-1 into target cells requires binding of the viral envelope glycoprotein (Env) to cellular receptors and subsequent conformational changes that culminates in fusion of viral and target cell membranes. Recent structural information has revealed that these conformational transitions are regulated by three conserved but potentially flexible layers stacked between the receptor binding domain (gp120) and the fusion arm (gp41) of Env. We hypothesized that artificial insertion of a covalent bond will 'snap' Env into a conformation that is less mobile and stably expose conserved sites. Therefore, we analyzed the interface between these gp120 layers (layers 1, 2 and 3) and identified residues that may form disulfide bonds when substituted with cysteines. We subsequently probed the structures of the resultant mutant gp120 proteins by assaying their binding to a variety of ligands using Surface Plasmon Resonance (SPR) assay. We found that a single disulfide bond strategically inserted between the highly conserved layers 1 and 2 (C65-C115) is able to 'lock' gp120 in a CD4 receptor bound conformation (in the absence of CD4), as indicated by the lower dissociation constant (Kd) for the CD4-induced (CD4i) epitope binding 17b antibody. When disulfide-stabilized monomeric (gp120) and trimeric (gp140) Envs were used to immunize rabbits, they were found to elicit a higher proportion of antibodies directed against both CD4i and CD4 binding site epitopes than the wild type proteins. These results demonstrate that structure-guided stabilization of inter-layer interactions within HIV-1 Env can be used to expose conserved epitopes and potentially overcome the sequence diversity of these molecules. PMID- 24146830 TI - Gene expression changes in the injured spinal cord following transplantation of mesenchymal stem cells or olfactory ensheathing cells. AB - Transplantation of bone marrow derived mesenchymal stromal cells (MSC) or olfactory ensheathing cells (OEC) have demonstrated beneficial effects after spinal cord injury (SCI), providing tissue protection and improving the functional recovery. However, the changes induced by these cells after their transplantation into the injured spinal cord remain largely unknown. We analyzed the changes in the spinal cord transcriptome after a contusion injury and MSC or OEC transplantation. The cells were injected immediately or 7 days after the injury. The mRNA of the spinal cord injured segment was extracted and analyzed by microarray at 2 and 7 days after cell grafting. The gene profiles were analyzed by clustering and functional enrichment analysis based on the Gene Ontology database. We found that both MSC and OEC transplanted acutely after injury induce an early up-regulation of genes related to tissue protection and regeneration. In contrast, cells transplanted at 7 days after injury down-regulate genes related to tissue regeneration. The most important change after MSC or OEC transplant was a marked increase in expression of genes associated with foreign body response and adaptive immune response. These data suggest a regulatory effect of MSC and OEC transplantation after SCI regarding tissue repair processes, but a fast rejection response to the grafted cells. Our results provide an initial step to determine the mechanisms of action and to optimize cell therapy for SCI. PMID- 24146831 TI - Turnerbactin, a novel triscatecholate siderophore from the shipworm endosymbiont Teredinibacter turnerae T7901. AB - Shipworms are marine bivalve mollusks (Family Teredinidae) that use wood for shelter and food. They harbor a group of closely related, yet phylogenetically distinct, bacterial endosymbionts in bacteriocytes located in the gills. This endosymbiotic community is believed to support the host's nutrition in multiple ways, through the production of cellulolytic enzymes and the fixation of nitrogen. The genome of the shipworm endosymbiont Teredinibacter turnerae T7901 was recently sequenced and in addition to the potential for cellulolytic enzymes and diazotrophy, the genome also revealed a rich potential for secondary metabolites. With nine distinct biosynthetic gene clusters, nearly 7% of the genome is dedicated to secondary metabolites. Bioinformatic analyses predict that one of the gene clusters is responsible for the production of a catecholate siderophore. Here we describe this gene cluster in detail and present the siderophore product from this cluster. Genes similar to the entCEBA genes of enterobactin biosynthesis involved in the production and activation of dihydroxybenzoic acid (DHB) are present in this cluster, as well as a two-module non-ribosomal peptide synthetase (NRPS). A novel triscatecholate siderophore, turnerbactin, was isolated from the supernatant of iron-limited T. turnerae T7901 cultures. Turnerbactin is a trimer of N-(2,3-DHB)-L-Orn-L-Ser with the three monomeric units linked by Ser ester linkages. A monomer, dimer, dehydrated dimer, and dehydrated trimer of 2,3-DHB-L-Orn-L-Ser were also found in the supernatant. A link between the gene cluster and siderophore product was made by constructing a NRPS mutant, TtAH03. Siderophores could not be detected in cultures of TtAH03 by HPLC analysis and Fe-binding activity of culture supernatant was significantly reduced. Regulation of the pathway by iron is supported by identification of putative Fur box sequences and observation of increased Fe-binding activity under iron restriction. Evidence of a turnerbactin fragment was found in shipworm extracts, suggesting the production of turnerbactin in the symbiosis. PMID- 24146832 TI - Validation of morphometric analyses of small-intestinal biopsy readouts in celiac disease. AB - BACKGROUND: Assessment of the gluten-induced small-intestinal mucosal injury remains the cornerstone of celiac disease diagnosis. Usually the injury is evaluated using grouped classifications (e.g. Marsh groups), but this is often too imprecise and ignores minor but significant changes in the mucosa. Consequently, there is a need for validated continuous variables in everyday practice and in academic and pharmacological research. METHODS: We studied the performance of our standard operating procedure (SOP) on 93 selected biopsy specimens from adult celiac disease patients and non-celiac disease controls. The specimens, which comprised different grades of gluten-induced mucosal injury, were evaluated by morphometric measurements. Specimens with tangential cutting resulting from poorly oriented biopsies were included. Two accredited evaluators performed the measurements in blinded fashion. The intraobserver and interobserver variations for villus height and crypt depth ratio (VH:CrD) and densities of intraepithelial lymphocytes (IELs) were analyzed by the Bland-Altman method and intraclass correlation. RESULTS: Unevaluable biopsies according to our SOP were correctly identified. The intraobserver analysis of VH:CrD showed a mean difference of 0.087 with limits of agreement from -0.398 to 0.224; the standard deviation (SD) was 0.159. The mean difference in interobserver analysis was 0.070, limits of agreement -0.516 to 0.375, and SD 0.227. The intraclass correlation coefficient in intraobserver variation was 0.983 and that in interobserver variation 0.978. CD3(+) IEL density countings in the paraffin embedded and frozen biopsies showed SDs of 17.1% and 16.5%; the intraclass correlation coefficients were 0.961 and 0.956, respectively. CONCLUSIONS: Using our SOP, quantitative, reliable and reproducible morphometric results can be obtained on duodenal biopsy specimens with different grades of gluten-induced injury. Clinically significant changes were defined according to the error margins (2SD) of the analyses in VH:CrD as 0.4 and in CD3(+)-stained IELs as 30%. PMID- 24146833 TI - Adaptation aftereffects in the perception of radiological images. AB - Radiologists must classify and interpret medical images on the basis of visual inspection. We examined how the perception of radiological scans might be affected by common processes of adaptation in the visual system. Adaptation selectively adjusts sensitivity to the properties of the stimulus in current view, inducing an aftereffect in the appearance of stimuli viewed subsequently. These perceptual changes have been found to affect many visual attributes, but whether they are relevant to medical image perception is not well understood. To examine this we tested whether aftereffects could be generated by the characteristic spatial structure of radiological scans, and whether this could bias their appearance along dimensions that are routinely used to classify them. Measurements were focused on the effects of adaptation to images of normal mammograms, and were tested in observers who were not radiologists. Tissue density in mammograms is evaluated visually and ranges from "dense" to "fatty." Arrays of images varying in intermediate levels between these categories were created by blending dense and fatty images with different weights. Observers first adapted by viewing image samples of dense or fatty tissue, and then judged the appearance of the intermediate images by using a texture matching task. This revealed pronounced perceptual aftereffects - prior exposure to dense images caused an intermediate image to appear more fatty and vice versa. Moreover, the appearance of the adapting images themselves changed with prolonged viewing, so that they became less distinctive as textures. These aftereffects could not be accounted for by the contrast differences or power spectra of the images, and instead tended to follow from the phase spectrum. Our results suggest that observers can selectively adapt to the properties of radiological images, and that this selectivity could strongly impact the perceived textural characteristics of the images. PMID- 24146835 TI - The social life of infants in the context of infectious disease transmission; social contacts and mixing patterns of the very young. AB - Insight into how humans interact helps further understanding of the transmission of infectious diseases. For diseases such as pertussis, infants are at particular risk for severe outcomes. To understand the contact pattern of infants, especially those too young to be vaccinated, we sent contact diaries to a representative sample of 1000 mothers in the United Kingdom. We received 115 responses with a total of 758 recorded contacts. The average number of daily contacts for an infant was 6.68 overall and 5.7 for those aged <= 10 weeks. Of the latter, 2.1 (37%) contacts were with non-household members and were >15 minutes duration, suggesting that a cocooning programme may miss a substantial proportion of exposures leading to disease transmission. The least contact was between adolescents and infants. Thus the impact of adolescent (pertussis) vaccination on infants would likely be limited, unless it reduces transmission to other age groups whose contact with infants is greater. PMID- 24146834 TI - Is rising obesity causing a secular (age-independent) decline in testosterone among American men? AB - The testosterone of men in industrial societies peaks in their twenties and tends to decline with increasing age. Apart from this individual-level decline, there have been reports of a secular (age-independent population-level) decline in testosterone among American and Scandinavian men during the past few decades, possibly an indication of declining male reproductive health. It has been suggested that both declines in testosterone (individual-level and population level) are due to increasing male obesity because men in industrial society tend to add body fat as they age, and overall rates of obesity are increasing. Using an unusually large and lengthy longitudinal dataset (991 US Air Force veterans examined in six cycles over 20 years), we investigate the relationship of obesity to individual and population-level declines in testosterone. Over twenty years of study, longitudinal decline in mean testosterone was at least twice what would be expected from cross-sectional estimates of the aging decline. Men who put on weight intensified their testosterone decline, some greatly so, but even among those who held their weight constant or lost weight during the study, mean testosterone declined 117 ng/dl (19%) over 20 years. We have not identified the reason for secular decline in testosterone, but we exclude increasing obesity as a sufficient or primary explanation, and we deny the supposition that men who avoid excessive weight will maintain their youthful levels of testosterone. PMID- 24146836 TI - San Bernardino Cave (Italy) and the appearance of Levallois technology in Europe: results of a radiometric and technological reassessment. AB - The introduction of Levallois technology in Europe marked the transition from the Lower to the early Middle Paleolithic. This new method of flake production was accompanied by significant behavioral changes in hominin populations. The emergence of this technological advance is considered homogeneous in the European archaeological record at the Marine isotopic stage (MIS) 9/MIS 8 boundary. In this paper we report a series of combined electron spin resonance/U-series dates on mammal bones and teeth recovered from the lower units of San Bernardino Cave (Italy) and the technological analyses of the lithic assemblages. The San Bernardino Cave has yielded the earliest evidence of Levallois production on the Italian Peninsula recovered to date. In addition to our results and the review of the archaeological record, we describe the chronological and geographical differences between European territories and diversities in terms of technological developments. The belated emergence of Levallois technology in Italy compared to western Europe corresponds to the late Italian Neanderthal speciation event. The new radiometric dates and the technological analyses of San Bernardino Cave raise the issue of the different roles of glacial refugia in the peopling and the spread of innovative flaking strategies in Europe during the late Middle Pleistocene. PMID- 24146837 TI - Taxonomic precision of different hypervariable regions of 16S rRNA gene and annotation methods for functional bacterial groups in biological wastewater treatment. AB - High throughput sequencing of 16S rRNA gene leads us into a deeper understanding on bacterial diversity for complex environmental samples, but introduces blurring due to the relatively low taxonomic capability of short read. For wastewater treatment plant, only those functional bacterial genera categorized as nutrient remediators, bulk/foaming species, and potential pathogens are significant to biological wastewater treatment and environmental impacts. Precise taxonomic assignment of these bacteria at least at genus level is important for microbial ecological research and routine wastewater treatment monitoring. Therefore, the focus of this study was to evaluate the taxonomic precisions of different ribosomal RNA (rRNA) gene hypervariable regions generated from a mix activated sludge sample. In addition, three commonly used classification methods including RDP Classifier, BLAST-based best-hit annotation, and the lowest common ancestor annotation by MEGAN were evaluated by comparing their consistency. Under an unsupervised way, analysis of consistency among different classification methods suggests there are no hypervariable regions with good taxonomic coverage for all genera. Taxonomic assignment based on certain regions of the 16S rRNA genes, e.g. the V1&V2 regions - provide fairly consistent taxonomic assignment for a relatively wide range of genera. Hence, it is recommended to use these regions for studying functional groups in activated sludge. Moreover, the inconsistency among methods also demonstrated that a specific method might not be suitable for identification of some bacterial genera using certain 16S rRNA gene regions. As a general rule, drawing conclusions based only on one sequencing region and one classification method should be avoided due to the potential false negative results. PMID- 24146838 TI - Defining metabolically healthy obesity: role of dietary and lifestyle factors. AB - BACKGROUND: There is a current lack of consensus on defining metabolically healthy obesity (MHO). Limited data on dietary and lifestyle factors and MHO exist. The aim of this study is to compare the prevalence, dietary factors and lifestyle behaviours of metabolically healthy and unhealthy obese and non-obese subjects according to different metabolic health criteria. METHOD: Cross sectional sample of 1,008 men and 1,039 women aged 45-74 years participated in the study. Participants were classified as obese (BMI >= 30 kg/m(2)) and non obese (BMI < 30 kg/m(2)). Metabolic health status was defined using five existing MH definitions based on a range of cardiometabolic abnormalities. Dietary composition and quality, food pyramid servings, physical activity, alcohol and smoking behaviours were examined. RESULTS: The prevalence of MHO varied considerably between definitions (2.2% to 11.9%), was higher among females and generally increased with age. Agreement between MHO classifications was poor. Among the obese, prevalence of MH was 6.8% to 36.6%. Among the non-obese, prevalence of metabolically unhealthy subjects was 21.8% to 87%. Calorie intake, dietary macronutrient composition, physical activity, alcohol and smoking behaviours were similar between the metabolically healthy and unhealthy regardless of BMI. Greater compliance with food pyramid recommendations and higher dietary quality were positively associated with metabolic health in obese (OR 1.45-1.53 unadjusted model) and non-obese subjects (OR 1.37-1.39 unadjusted model), respectively. Physical activity was associated with MHO defined by insulin resistance (OR 1.87, 95% CI 1.19-2.92, p = 0.006). CONCLUSION: A standard MHO definition is required. Moderate and high levels of physical activity and compliance with food pyramid recommendations increase the likelihood of MHO. Stratification of obese individuals based on their metabolic health phenotype may be important in ascertaining the appropriate therapeutic or intervention strategy. PMID- 24146839 TI - The impact of isoniazid resistance on the treatment outcomes of smear positive re treatment tuberculosis patients in the state of Andhra Pradesh, India. AB - BACKGROUND: Multi drug resistant and rifampicin resistant TB patients in India are treated with the World Health Organization (WHO) recommended standardized treatment regimens but no guidelines are available for the management of isoniazid (INH) resistant TB patients. There have been concerns that the standard eight-month retreatment regimen being used in India (2H3R3Z3E3S3/1H3R3Z3E3/5H3R3E3; H-Isoniazid; R-Rifampicin; Z-Pyrazinamide; E Ethambutol; S-Streptomycin) may be inadequate to treat INH resistant TB cases and leads to poor treatment outcomes. We aimed to assess if INH resistance is associated with unfavorable treatment outcomes (death, default, failure and transferred out) among a cohort of smear positive retreatment TB patients registered in three districts of Andhra Pradesh, India. METHODS: We conducted a retrospective record review of all smear positive retreatment TB patients without rifampicin resistance registered during April-December 2011. RESULTS: Of 1,947 TB patients, 1,127 (58%) were tested with LPA-50 (4%) were rifampicin resistant, 933 (84%) were sensitive to INH and rifampicin and 144 (12%) were INH resistant. Of 144 INH resistant cases, 64 (44%) had poor treatment outcomes (25 (17%) default, 22 (15%) death, 12 (8%) failure and 5 (3%) transfer out) as compared to 287 (31%) among INH sensitive cases [aRR 1.46; 95%CI (1.19-1.78)]. CONCLUSION: Our study confirms that INH resistance is independently associated with unfavorable treatment outcomes among smear positive retreatment TB patients, indicating that the current treatment regimen may be inadequate. These findings call for an urgent need for randomized controlled trials to discover the most effective treatment regimen for managing INH resistant TB. PMID- 24146840 TI - Lack of decorin expression by human bladder cancer cells offers new tools in the therapy of urothelial malignancies. AB - Decorin, a multifunctional small leucine-rich extracellular matrix proteoglycan, has been shown to possess potent antitumour activity. However, there is some uncertainty whether different cancer cells express decorin in addition to non malignant stromal cells. In this study we clarified decorin expression by human bladder cancer cells both in vivo and in vitro. In addition, the effect of adenovirus-mediated decorin expression on human bladder cancer cells in vitro was examined. We first demonstrated using the publicly available GeneSapiens databank that decorin gene expression is present in both normal and malignant human bladder tissues. However, when we applied in situ hybridization with digoxigenin labeled RNA probes for decorin on human bladder carcinoma tissue samples derived from a large radical cystectomy patient cohort (n = 199), we unambiguously demonstrated that invasive and non-invasive bladder carcinoma cells completely lack decorin mRNA. The cancer cells were also negative for decorin immunoreactivity. Instead, decorin expression was localized solely to original non-malignant stromal areas of bladder tissue. In accordance with the aforementioned results, human bladder cancer cells in vitro were also negative for decorin expression as shown by RT-qPCR analyses. The lack of decorin expression by bladder cancer cells was shown not to be due to the methylation of the proximal promoter region of the decorin gene. When bladder cancer cells were transfected with a decorin adenoviral vector, their proliferation was significantly decreased. In conclusion, we have shown that human bladder cancer cells are totally devoid of decorin expression. We have also shown that adenovirus-mediated decorin gene transduction of human bladder cancer cell lines markedly inhibits their proliferation. Thus, decorin gene delivery offers new potential therapeutic tools in urothelial malignancies. PMID- 24146841 TI - Overnight resting of PBMC changes functional signatures of antigen specific T- cell responses: impact for immune monitoring within clinical trials. AB - Polyfunctional CD4 or CD8 T cells are proposed to represent a correlate of immune control for persistent viruses as well as for vaccine mediated protection against infection. A well-suited methodology to study complex functional phenotypes of antiviral T cells is the combined staining of intracellular cytokines and phenotypic marker expression using polychromatic flow cytometry. In this study we analyzed the effect of an overnight resting period at 37 degrees C on the quantity and functionality of HIV-1, EBV, CMV, HBV and HCV specific CD4 and CD8 T cell responses in a cohort of 21 individuals. We quantified total antigen specific T cells by multimer staining and used 10-color intracellular cytokine staining (ICS) to determine IFNgamma, TNFalpha, IL2 and MIP1beta production. After an overnight resting significantly higher numbers of functionally active T cells were detectable by ICS for all tested antigen specificities, whereas the total number of antigen specific T cells determined by multimer staining remained unchanged. Overnight resting shifted the quality of T-cell responses towards polyfunctionality and increased antigen sensitivity of T cells. Our data suggest that the observed effect is mediated by T cells rather than by antigen presenting cells. We conclude that overnight resting of PBMC prior to ex vivo analysis of antiviral T-cell responses represents an efficient method to increase sensitivity of ICS-based methods and has a prominent impact on the functional phenotype of T cells. PMID- 24146842 TI - Mathematical modeling of the role of mitochondrial fusion and fission in mitochondrial DNA maintenance. AB - Accumulation of mitochondrial DNA (mtDNA) mutations has been implicated in a wide range of human pathologies, including neurodegenerative diseases, sarcopenia, and the aging process itself. In cells, mtDNA molecules are constantly turned over (i.e. replicated and degraded) and are also exchanged among mitochondria during the fusion and fission of these organelles. While the expansion of a mutant mtDNA population is believed to occur by random segregation of these molecules during turnover, the role of mitochondrial fusion-fission in this context is currently not well understood. In this study, an in silico modeling approach is taken to investigate the effects of mitochondrial fusion and fission dynamics on mutant mtDNA accumulation. Here we report model simulations suggesting that when mitochondrial fusion-fission rate is low, the slow mtDNA mixing can lead to an uneven distribution of mutant mtDNA among mitochondria in between two mitochondrial autophagic events leading to more stochasticity in the outcomes from a single random autophagic event. Consequently, slower mitochondrial fusion fission results in higher variability in the mtDNA mutation burden among cells in a tissue over time, and mtDNA mutations have a higher propensity to clonally expand due to the increased stochasticity. When these mutations affect cellular energetics, nuclear retrograde signalling can upregulate mtDNA replication, which is expected to slow clonal expansion of these mutant mtDNA. However, our simulations suggest that the protective ability of retrograde signalling depends on the efficiency of fusion-fission process. Our results thus shed light on the interplay between mitochondrial fusion-fission and mtDNA turnover and may explain the mechanism underlying the experimentally observed increase in the accumulation of mtDNA mutations when either mitochondrial fusion or fission is inhibited. PMID- 24146843 TI - Dynamics of collective decision making of honeybees in complex temperature fields. AB - Endothermic heat production is a crucial evolutionary adaptation that is, amongst others, responsible for the great success of honeybees. Endothermy ensures the survival of the colonies in harsh environments and is involved in the maintenance of the brood nest temperature, which is fundamental for the breeding and further development of healthy individuals and thus the foraging and reproduction success of this species. Freshly emerged honeybees are not yet able to produce heat endothermically and thus developed behavioural patterns that result in the location of these young bees within the warm brood nest where they further develop and perform tasks for the colony. Previous studies showed that groups of young ectothermic honeybees exposed to a temperature gradient collectively aggregate at the optimal place with their preferred temperature of 36 degrees C but most single bees do not locate themselves at the optimum. In this work we further investigate the behavioural patterns that lead to this collective thermotaxis. We tested single and groups of young bees concerning their ability to discriminate a local from a global temperature optimum and, for groups of bees, analysed the speed of the decision making process as well as density dependent effects by varying group sizes. We found that the majority of tested single bees do not locate themselves at the optimum whereas sufficiently large groups of bees are able to collectively discriminate a suboptimal temperature spot and aggregate at 36 degrees C. Larger groups decide faster than smaller ones, but in larger groups a higher percentage of bees may switch to the sub optimum due to crowding effects. We show that the collective thermotaxis is a simple but well evolved, scalable and robust social behaviour that enables the collective of bees to perform complex tasks despite the limited abilities of each individual. PMID- 24146844 TI - Discovery of a protective Rickettsia prowazekii antigen recognized by CD8+ T cells, RP884, using an in vivo screening platform. AB - Rickettsia prowazekii has been tested for biological warfare due to the high mortality that it produces after aerosol transmission of very low numbers of rickettsiae. Epidemic typhus, the infection caused by these obligately intracellular bacteria, continues to be a threat because it is difficult to diagnose due to initial non-specific symptoms and the lack of commercial diagnostic tests that are sensitive and specific during the initial clinical presentation. A vaccine to prevent epidemic typhus would constitute an effective deterrent to the weaponization of R. prowazekii; however, an effective and safe vaccine is not currently available. Due to the cytoplasmic niche of Rickettsia, CD8(+) T-cells are critical effectors of immunity; however, the identification of antigens recognized by these cells has not been systematically addressed. To help close this gap, we designed an antigen discovery strategy that uses cell-based vaccination with antigen presenting cells expressing microbe's proteins targeted to the MHC class I presentation pathway. We report the use of this method to discover a protective T-cell rickettsial antigen, RP884, among a test subset of rickettsial proteins. PMID- 24146845 TI - The angular interval between the direction of progression and body orientation in normal, alcohol- and cocaine treated fruit flies. AB - In this study we characterize the coordination between the direction a fruit-fly walks and the direction it faces, as well as offer a methodology for isolating and validating key variables with which we phenotype fly locomotor behavior. Our fundamental finding is that the angular interval between the direction a fly walks and the direction it faces is actively managed in intact animals and modulated in a patterned way with drugs. This interval is small in intact flies, larger with alcohol and much larger with cocaine. The dynamics of this interval generates six coordinative modes that flow smoothly into each other. Under alcohol and much more so under cocaine, straight path modes dwindle and modes involving rotation proliferate. To obtain these results we perform high content analysis of video-tracked open field locomotor behavior. Presently there is a gap between the quality of descriptions of insect behaviors that unfold in circumscribed situations, and descriptions that unfold in extended time and space. While the first describe the coordination between low-level kinematic variables, the second quantify cumulative measures and subjectively defined behavior patterns. Here we reduce this gap by phenotyping extended locomotor behavior in terms of the coordination between low-level kinematic variables, which we quantify, combining into a single field two disparate fields, that of high content phenotyping and that of locomotor coordination. This will allow the study of the genes/brain/locomotor coordination interface in genetically engineered and pharmacologically manipulated animal models of human diseases. PMID- 24146846 TI - Validation of biomarkers for distinguishing Mycobacterium tuberculosis from non tuberculous mycobacteria using gas chromatography-mass spectrometry and chemometrics. AB - Tuberculosis (TB) remains a major international health problem. Rapid differentiation of Mycobacterium tuberculosis complex (MTB) from non-tuberculous mycobacteria (NTM) is critical for decisions regarding patient management and choice of therapeutic regimen. Recently we developed a 20-compound model to distinguish between MTB and NTM. It is based on thermally assisted hydrolysis and methylation gas chromatography-mass spectrometry and partial least square discriminant analysis. Here we report the validation of this model with two independent sample sets, one consisting of 39 MTB and 17 NTM isolates from the Netherlands, the other comprising 103 isolates (91 MTB and 12 NTM) from Stellenbosch, Cape Town, South Africa. All the MTB strains in the 56 Dutch samples were correctly identified and the model had a sensitivity of 100% and a specificity of 94%. For the South African samples the model had a sensitivity of 88% and specificity of 100%. Based on our model, we have developed a new decision tree that allows the differentiation of MTB from NTM with 100% accuracy. Encouraged by these findings we will proceed with the development of a simple, rapid, affordable, high-throughput test to identify MTB directly in sputum. PMID- 24146847 TI - Modeling the neurovascular niche: unbiased transcriptome analysis of the murine subventricular zone in response to hypoxic insult. AB - Premature infants often experience chronic hypoxia, resulting in cognitive & motor neurodevelopmental handicaps. These sometimes devastating handicaps are thought to be caused by compromised neural precursor cell (NPC) repair/recovery resulting in variable central nervous system (CNS) repair/recovery. We have identified differential responses of two mouse strains (C57BL/6 & CD1) to chronic hypoxia that span the range of responsiveness noted in the premature human population. We previously correlated several CNS tissue and cellular behaviors with the different behavioral parameters manifested by these two strains. In this report, we use unbiased array technology to interrogate the transcriptome of the subventricular zone (SVZ) in these strains. Our results illustrate differences in mRNA expression in the SVZ of both C57BL/6 and CD1 mice following hypoxia as well as differences between C57BL/6 and CD1 SVZ under both normoxic and hypoxic conditions. Differences in expression were found in gene sets associated with Sox10-mediated neural functions that explain, in part, the differential cognitive and motor responsiveness to hypoxic insult. This may shed additional light on our understanding of the variable responses noted in the human premature infant population and facilitate early intervention approaches. Further interrogation of the differentially expressed gene sets will provide a more complete understanding of the differential responses to, and recovery from, hypoxic insult allowing for more informed modeling of the ranges of disease severity observed in the very premature human population. PMID- 24146848 TI - Chimpanzees show a developmental increase in susceptibility to contagious yawning: a test of the effect of ontogeny and emotional closeness on yawn contagion. AB - Contagious yawning has been reported for humans, dogs and several non-human primate species, and associated with empathy in humans and other primates. Still, the function, development and underlying mechanisms of contagious yawning remain unclear. Humans and dogs show a developmental increase in susceptibility to yawn contagion, with children showing an increase around the age of four, when also empathy-related behaviours and accurate identification of others' emotions begin to clearly evince. Explicit tests of yawn contagion in non-human apes have only involved adult individuals and examined the existence of conspecific yawn contagion. Here we report the first study of heterospecific contagious yawning in primates, and the ontogeny of susceptibility thereto in chimpanzees, Pan troglodytes verus. We examined whether emotional closeness, defined as attachment history with the yawning model, affected the strength of contagion, and compared the contagiousness of yawning to nose-wiping. Thirty-three orphaned chimpanzees observed an unfamiliar and familiar human (their surrogate human mother) yawn, gape and nose-wipe. Yawning, but not nose-wiping, was contagious for juvenile chimpanzees, while infants were immune to contagion. Like humans and dogs, chimpanzees are subject to a developmental trend in susceptibility to contagious yawning, and respond to heterospecific yawn stimuli. Emotional closeness with the model did not affect contagion. The familiarity-biased social modulatory effect on yawn contagion previously found among some adult primates, seem to only emerge later in development, or be limited to interactions with conspecifics. The influence of the 'chameleon effect', targeted vs. generalised empathy, perspective-taking and visual attention on contagious yawning is discussed. PMID- 24146849 TI - Using HSV-1 genome phylogenetics to track past human migrations. AB - We compared 31 complete and nearly complete globally derived HSV-1 genomic sequences using HSV-2 HG52 as an outgroup to investigate their phylogenetic relationships and look for evidence of recombination. The sequences were retrieved from NCBI and were then aligned using Clustal W. The generation of a maximum likelihood tree resulted in a six clade structure that corresponded with the timing and routes of past human migration. The East African derived viruses contained the greatest amount of genetic diversity and formed four of the six clades. The East Asian and European/North American derived viruses formed separate clades. HSV-1 strains E07, E22 and E03 were highly divergent and may each represent an individual clade. Possible recombination was analyzed by partitioning the alignment into 5 kb segments, performing individual phylogenetic analysis on each partition and generating a.phylogenetic network from the results. However most evidence for recombination spread at the base of the tree suggesting that recombination did not significantly disrupt the clade structure. Examination of previous estimates of HSV-1 mutation rates in conjunction with the phylogenetic data presented here, suggests that the substitution rate for HSV-1 is approximately 1.38 * 10(-7) subs/site/year. In conclusion, this study expands the previously described HSV-1 three clade phylogenetic structures to a minimum of six and shows that the clade structure also mirrors global human migrations. Given that HSV-1 has co-evolved with its host, sequencing HSV-1 isolated from various populations could serve as a surrogate biomarker to study human population structure and migration patterns. PMID- 24146850 TI - Super-resolution imaging of bacteria in a microfluidics device. AB - Bacteria have evolved complex, highly-coordinated, multi-component cellular engines to achieve high degrees of efficiency, accuracy, adaptability, and redundancy. Super-resolution fluorescence microscopy methods are ideally suited to investigate the internal composition, architecture, and dynamics of molecular machines and large cellular complexes. These techniques require the long-term stability of samples, high signal-to-noise-ratios, low chromatic aberrations and surface flatness, conditions difficult to meet with traditional immobilization methods. We present a method in which cells are functionalized to a microfluidics device and fluorophores are injected and imaged sequentially. This method has several advantages, as it permits the long-term immobilization of cells and proper correction of drift, avoids chromatic aberrations caused by the use of different filter sets, and allows for the flat immobilization of cells on the surface. In addition, we show that different surface chemistries can be used to image bacteria at different time-scales, and we introduce an automated cell detection and image analysis procedure that can be used to obtain cell-to-cell, single-molecule localization and dynamic heterogeneity as well as average properties at the super-resolution level. PMID- 24146851 TI - "Wrong, but useful": negotiating uncertainty in infectious disease modelling. AB - For infectious disease dynamical models to inform policy for containment of infectious diseases the models must be able to predict; however, it is well recognised that such prediction will never be perfect. Nevertheless, the consensus is that although models are uncertain, some may yet inform effective action. This assumes that the quality of a model can be ascertained in order to evaluate sufficiently model uncertainties, and to decide whether or not, or in what ways or under what conditions, the model should be 'used'. We examined uncertainty in modelling, utilising a range of data: interviews with scientists, policy-makers and advisors, and analysis of policy documents, scientific publications and reports of major inquiries into key livestock epidemics. We show that the discourse of uncertainty in infectious disease models is multi-layered, flexible, contingent, embedded in context and plays a critical role in negotiating model credibility. We argue that usability and stability of a model is an outcome of the negotiation that occurs within the networks and discourses surrounding it. This negotiation employs a range of discursive devices that renders uncertainty in infectious disease modelling a plastic quality that is amenable to 'interpretive flexibility'. The utility of models in the face of uncertainty is a function of this flexibility, the negotiation this allows, and the contexts in which model outputs are framed and interpreted in the decision making process. We contend that rather than being based predominantly on beliefs about quality, the usefulness and authority of a model may at times be primarily based on its functional status within the broad social and political environment in which it acts. PMID- 24146852 TI - A modular lentiviral and retroviral construction system to rapidly generate vectors for gene expression and gene knockdown in vitro and in vivo. AB - The ability to express exogenous cDNAs while suppressing endogenous genes via RNAi represents an extremely powerful research tool with the most efficient non transient approach being accomplished through stable viral vector integration. Unfortunately, since traditional restriction enzyme based methods for constructing such vectors are sequence dependent, their construction is often difficult and not amenable to mass production. Here we describe a non-sequence dependent Gateway recombination cloning system for the rapid production of novel lentiviral (pLEG) and retroviral (pREG) vectors. Using this system to recombine 3 or 4 modular plasmid components it is possible to generate viral vectors expressing cDNAs with or without inhibitory RNAs (shRNAmirs). In addition, we demonstrate a method to rapidly produce and triage novel shRNAmirs for use with this system. Once strong candidate shRNAmirs have been identified they may be linked together in tandem to knockdown expression of multiple targets simultaneously or to improve the knockdown of a single target. Here we demonstrate that these recombinant vectors are able to express cDNA and effectively knockdown protein expression using both cell culture and animal model systems. PMID- 24146853 TI - Gender differences in perception of romance in Chinese college students. AB - Women often complain that their partners are not romantic enough. This raises the question: how romance is recognized and evaluated in a love relationship? However, there has been essentially no empirical research bearing on this issue. The present set of studies examined possible gender differences in perceptions of romance and the associated neural mechanisms in Chinese college students. In Study 1, 303 participants (198 women, 105 men) were administrated a questionnaire consisting of 60 sentences and required to rate the romance level of each sentence. Results showed higher rating scores in males than females for low romance items, but not for high or medium romance items. In Study 2, 69 participants (37 women, 32 men) were recruited to judge the degree of romance in sentences presented on a computer screen one by one. Compared with females, males again showed higher scores and responded more slowly only to low romance items. In Study 3, 36 participants (18 women, 18 men) currently in love with someone were scanned with functional MRI while they did the romance judgment task from Study 2. Compared with females, greater brain activation was found for males in the frontal lobe, precentral gyrus, precuneus and parahippocampal gyrus for low romance items. The results provide the first piece of evidence for gender differences in romance perception, suggesting enhanced cognitive processing in males when evaluating the degree of romance in romantic scenes. PMID- 24146854 TI - The impact of phenotypic and genetic heterogeneity on results of genome wide association studies of complex diseases. AB - Phenotypic misclassification (between cases) has been shown to reduce the power to detect association in genetic studies. However, it is conceivable that complex traits are heterogeneous with respect to individual genetic susceptibility and disease pathophysiology, and that the effect of heterogeneity has a larger magnitude than the effect of phenotyping errors. Although an intuitively clear concept, the effect of heterogeneity on genetic studies of common diseases has received little attention. Here we investigate the impact of phenotypic and genetic heterogeneity on the statistical power of genome wide association studies (GWAS). We first performed a study of simulated genotypic and phenotypic data. Next, we analyzed the Wellcome Trust Case-Control Consortium (WTCCC) data for diabetes mellitus (DM) type 1 (T1D) and type 2 (T2D), using varying proportions of each type of diabetes in order to examine the impact of heterogeneity on the strength and statistical significance of association previously found in the WTCCC data. In both simulated and real data, heterogeneity (presence of "non cases") reduced the statistical power to detect genetic association and greatly decreased the estimates of risk attributed to genetic variation. This finding was also supported by the analysis of loci validated in subsequent large-scale meta analyses. For example, heterogeneity of 50% increases the required sample size by approximately three times. These results suggest that accurate phenotype delineation may be more important for detecting true genetic associations than increase in sample size. PMID- 24146855 TI - Effectiveness of inactivated influenza vaccines in preventing influenza associated deaths and hospitalizations among Ontario residents aged >= 65 years: estimates with generalized linear models accounting for healthy vaccinee effects. AB - BACKGROUND: Estimates of the effectiveness of influenza vaccines in older adults may be biased because of difficulties identifying and adjusting for confounders of the vaccine-outcome association. We estimated vaccine effectiveness for prevention of serious influenza complications among older persons by using methods to account for underlying differences in risk for these complications. METHODS: We conducted a retrospective cohort study among Ontario residents aged >= 65 years from September 1993 through September 2008. We linked weekly vaccination, hospitalization, and death records for 1.4 million community dwelling persons aged >= 65 years. Vaccine effectiveness was estimated by comparing ratios of outcome rates during weeks of high versus low influenza activity (defined by viral surveillance data) among vaccinated and unvaccinated subjects by using log-linear regression models that accounted for temperature and time trends with natural spline functions. Effectiveness was estimated for three influenza-associated outcomes: all-cause deaths, deaths occurring within 30 days of pneumonia/influenza hospitalizations, and pneumonia/influenza hospitalizations. RESULTS: During weeks when 5% of respiratory specimens tested positive for influenza A, vaccine effectiveness among persons aged >= 65 years was 22% (95% confidence interval [CI], -6%-42%) for all influenza-associated deaths, 25% (95% CI, 13%-37%) for deaths occurring within 30 days after an influenza-associated pneumonia/influenza hospitalization, and 19% (95% CI, 4% 31%) for influenza-associated pneumonia/influenza hospitalizations. Because small proportions of deaths, deaths after pneumonia/influenza hospitalizations, and pneumonia/influenza hospitalizations were associated with influenza virus circulation, we estimated that vaccination prevented 1.6%, 4.8%, and 4.1% of these outcomes, respectively. CONCLUSIONS: By using confounding-reducing techniques with 15 years of provincial-level data including vaccination and health outcomes, we estimated that influenza vaccination prevented ~4% of influenza-associated hospitalizations and deaths occurring after hospitalizations among older adults in Ontario. PMID- 24146856 TI - Regulation of the expression of chaperone gp96 in macrophages and dendritic cells. AB - The chaperone function of the ER-residing heat shock protein gp96 plays an important role in protein physiology and has additionally important immunological functions due to its peptide-binding capacity. Low amounts of gp96 stimulate immunity; high quantities induce tolerance by mechanisms not fully understood. A lack of gp96 protein in intestinal macrophages (IMACs) from Crohn's disease (CD) patients correlates with loss of tolerance against the host gut flora, leading to chronic inflammation. Since gp96 shows dose-dependent direction of immunological reactions, we studied primary IMACs and developed cell models to understand the regulation of gp96 expression. Induction of gp96-expression was higher in in vitro differentiated dendritic cells (i.v.DCs) than in in vitro differentiated macrophages (i.v.MACs), whereas monocytes (MOs) expressed only low gp96 levels. The highest levels of expression were found in IMACs. Lipopolysaccharide (LPS), muramyl dipeptide (MDP), tumour necrosis factor (TNF), and Interleukin (IL)-4 induced gp96-expression, while IL12, IL-17, IL-23 and interferon (IFN)-gamma were not effective indicating that Th1 and Th17 cells are probably not involved in the induction of gp96. Furthermore, gp96 was able to induce its own expression. The ER-stress inducer tunicamycin increased gp96-expression in a concentration- and time-dependent manner. Both ulcerative colitis (UC) and CD patients showed significantly elevated gp96 mRNA levels in intestinal biopsies which correlated positively with the degree of inflammation of the tissue. Since gp96 is highly expressed on the one hand upon stress induction as during inflammation and on the other hand possibly mediating tolerance, these results will help to understand the whether gp96 plays a role in the pathophysiology of inflammatory bowel disease (IBD). PMID- 24146857 TI - Impact of untreated obstructive sleep apnea on left and right ventricular myocardial function and effects of CPAP therapy. AB - BACKGROUND: Obstructive sleep apnea (OSA) has deteriorating effect on LV function, whereas its impact on RV function is controversial. We aimed to determine the effect of OSA and continuous positive airway pressure (CPAP) treatment on left and right ventricular (LV, RV) function using transthoracic echocardiography (TTE) and 2 dimensional speckle tracking (2D ST) analysis of RV deformation capability. METHODS AND RESULTS: 82 patients with OSA and need for CPAP therapy were prospectively enrolled and underwent TTE at study inclusion and after 6 months of follow up (FU). Multivariate regression analysis revealed an independent association between baseline apical right ventricular longitudinal strain (RV-Sl), BMI and the severity of OSA (apical RV-Sl: P = 0.0002, BMI: P = 0.02). After CPAP therapy, LV functional parameters (LVEF: P<0.0001, LV performance index: P = 0.03, stroke volume: P = 0.042), and apical RV-Sl (P = 0.001) improved significantly. The effect of CPAP therapy was related to severity of OSA (LVEF: AHI 5-14, 66.4 +/- 8.8%, 68.5 +/- 10.6% [P = ns]; AHI 15-30:59.8 +/ 7.7%, 68.6 +/- 9.3% [P = 0.002]; AHI>30:54.1 +/- 12.4%, 68.2 +/- 13.6%[P<0.0001]; apical RV-Sl: AHI 5-14: -17.3 +/- 8.7%, -16.0 +/- 10.8% [P = ns], AHI 15-30: -9.8 +/- 6.0%, -15.4 +/- 10.9% [P = 0.028], AHI>30: -6.3 +/- 5.7%, -17.9 +/- 11.2% [P<0.0001]). CONCLUSIONS: OSA seems to have deteriorating effect on LV and RV function. We found a beneficial effect of CPAP on LV and RV functional parameters predominately in patients with severe OSA. 2D speckle tracking might be of value to determine early changes in global and regional right ventricular function. PMID- 24146858 TI - Isolation of Clostridium perfringens type B in an individual at first clinical presentation of multiple sclerosis provides clues for environmental triggers of the disease. AB - We have isolated Clostridium perfringens type B, an epsilon toxin-secreting bacillus, from a young woman at clinical presentation of Multiple Sclerosis (MS) with actively enhancing lesions on brain MRI. This finding represents the first time that C. perfringens type B has been detected in a human. Epsilon toxin's tropism for the blood-brain barrier (BBB) and binding to oligodendrocytes/myelin makes it a provocative candidate for nascent lesion formation in MS. We examined a well-characterized population of MS patients and healthy controls for carriage of C. perfringens toxinotypes in the gastrointestinal tract. The human commensal Clostridium perfringens type A was present in approximately 50% of healthy human controls compared to only 23% in MS patients. We examined sera and CSF obtained from two tissue banks and found that immunoreactivity to ETX is 10 times more prevalent in people with MS than in healthy controls, indicating prior exposure to ETX in the MS population. C. perfringens epsilon toxin fits mechanistically with nascent MS lesion formation since these lesions are characterized by BBB permeability and oligodendrocyte cell death in the absence of an adaptive immune infiltrate. PMID- 24146859 TI - Viral RNA levels and env variants in semen and tissues of mature male rhesus macaques infected with SIV by penile inoculation. AB - HIV is shed in semen but the anatomic site of virus entry into the genital secretions is unknown. We determined viral RNA (vRNA) levels and the envelope gene sequence in the SIVmac 251 viral populations in the genital tract and semen of 5 adult male rhesus monkeys (Macaca mulatta) that were infected after experimental penile SIV infection. Paired blood and semen samples were collected from 1-9 weeks after infection and the monkeys were necropsied eleven weeks after infection. The axillary lymph nodes, testes, epididymis, prostate, and seminal vesicles were collected and vRNA levels and single-genome analysis of the SIVmac251 env variants was performed. At the time of semen collection, blood vRNA levels were between 3.09 and 7.85 log10 vRNA copies/ml plasma. SIV RNA was found in the axillary lymph nodes of all five monkeys and in 3 of 5 monkeys, all tissues examined were vRNA positive. In these 3 monkeys, vRNA levels (log10 SIVgag copies/ug of total tissue RNA) in the axillary lymph node (6.48 +/- 0.50) were significantly higher than in the genital tract tissues: testis (3.67 +/- 2.16; p<0.05), epididymis (3.08 +/- 1.19; p<0.0001), prostate (3.36 +/- 1.30; p<0.01), and seminal vesicle (2.67 +/- 1.50; p<0.0001). Comparison of the SIVmac251 env viral populations in blood plasma, systemic lymph node, and genital tract tissues was performed in two of the macaques. Visual inspection of the Neighbor-Joining phylograms revealed that in both animals, all the sequences were generally distributed evenly among all tissue compartments. Importantly, viral populations in the genital tissues were not distinct from those in the systemic tissues. Our findings demonstrate striking similarity in the viral populations in the blood and male genital tract tissues within 3 months of penile SIV transmission. PMID- 24146860 TI - A polyclonal antibody based immunoassay detects seven subtypes of Shiga toxin 2 produced by Escherichia coli in human and environmental samples. AB - BACKGROUND: Shiga toxin-producing Escherichia coli (STEC) are frequent causes of severe human diseases ranging from diarrhea to hemolytic uremic syndrome. The existing strategy for detection of STEC relies on the unique sorbitol-negative fermentation property of the O157 strains, the most commonly identified serotype has been E. coli O157. It is becoming increasingly evident, however, that numerous non-O157 STEC serotypes also cause outbreaks and severe illnesses. It is necessary to have new methods that are capable of detecting all STEC strains. METHODS AND FINDINGS: Here we describe the development of a sandwich ELISA assay for detecting both O157 and non-O157 STECs by incorporating a novel polyclonal antibody (pAb) against Stx2. The newly established immunoassay was capable of detecting Stx2a spiked in environmental samples with a limit of detection between 10 and 100 pg/mL in soil and between 100 and 500 pg/mL in feces. When applied to 36 bacterial strains isolated from human and environmental samples, this assay detected Stx2 in all strains that were confirmed to be stx2-positive by real-time PCR, demonstrating a 100% sensitivity and specificity. CONCLUSIONS: The sandwich ELISA developed in this study will enable any competent laboratory to identify and characterize Stx2-producing O157 and non-O157 strains in human and environmental samples, resulting in rapid diagnosis and patient care. The results of epitope mapping from this study will be useful for further development of a peptide-based antibody and vaccine. PMID- 24146861 TI - A multifactor analysis of fungal and bacterial community structure in the root microbiome of mature Populus deltoides trees. AB - Bacterial and fungal communities associated with plant roots are central to the host health, survival and growth. However, a robust understanding of the root microbiome and the factors that drive host associated microbial community structure have remained elusive, especially in mature perennial plants from natural settings. Here, we investigated relationships of bacterial and fungal communities in the rhizosphere and root endosphere of the riparian tree species Populus deltoides, and the influence of soil parameters, environmental properties (host phenotype and aboveground environmental settings), host plant genotype (Simple Sequence Repeat (SSR) markers), season (Spring vs. Fall) and geographic setting (at scales from regional watersheds to local riparian zones) on microbial community structure. Each of the trees sampled displayed unique aspects to its associated community structure with high numbers of Operational Taxonomic Units (OTUs) specific to an individual trees (bacteria >90%, fungi >60%). Over the diverse conditions surveyed only a small number of OTUs were common to all samples within rhizosphere (35 bacterial and 4 fungal) and endosphere (1 bacterial and 1 fungal) microbiomes. As expected, Proteobacteria and Ascomycota were dominant in root communities (>50%) while other higher-level phylogenetic groups (Chytridiomycota, Acidobacteria) displayed greatly reduced abundance in endosphere compared to the rhizosphere. Variance partitioning partially explained differences in microbiome composition between all sampled roots on the basis of seasonal and soil properties (4% to 23%). While most variation remains unattributed, we observed significant differences in the microbiota between watersheds (Tennessee vs. North Carolina) and seasons (Spring vs. Fall). SSR markers clearly delineated two host populations associated with the samples taken in TN vs. NC, but overall host genotypic distances did not have a significant effect on corresponding communities that could be separated from other measured effects. PMID- 24146862 TI - Galnon facilitates extinction of morphine-conditioned place preference but also potentiates the consolidation process. AB - Learning and memory systems are intimately involved in drug addiction. Previous studies suggest that galanin, a neuropeptide that binds G-protein coupled receptors, plays essential roles in the encoding of memory. In the present study, we tested the function of galnon, a galanin receptor 1 and 2 agonist, in reward associated memory, using conditioned place preference (CPP), a widely used paradigm in drug-associated memory. Either before or following CPP-inducing morphine administration, galnon was injected at four different time points to test the effects of galanin activation on different reward-associated memory processes: 15 min before CPP training (acquisition), immediately after CPP training (consolidation), 15 min before the post-conditioning test (retrieval), and multiple injection after post-tests (reconsolidation and extinction). Galnon enhanced consolidation and extinction processes of morphine-induced CPP memory, but the compound had no effect on acquisition, retrieval, or reconsolidation processes. Our findings demonstrate that a galanin receptor 1 and 2 agonist, galnon, may be used as a viable compound to treat drug addiction by facilitating memory extinction process. PMID- 24146863 TI - Declines in outpatient antimicrobial use in Canada (1995-2010). AB - BACKGROUND: With rising reports of antimicrobial resistance in outpatient communities, surveillance of antimicrobial use is imperative for supporting stewardship programs. The primary objective of this article is to assess the levels of antimicrobial use in Canada over time. METHODS: Canadian antimicrobial use data from 1995 to 2010 were acquired and assessed by four metrics: population adjusted prescriptions, Defined Daily Doses, spending on antimicrobials (inflation-adjusted), and average Defined Daily Doses per prescription. Linear mixed models were built to assess significant differences among years and antimicrobial groups, and to account for repeated measurements over time. Measures were also compared to published reports from European countries. RESULTS: Temporal trends in antimicrobial use in Canada vary by metric and antimicrobial grouping. Overall reductions were seen for inflation-adjusted spending, population-adjusted prescription rates and Defined Daily Doses, and increases were observed for the average number of Defined Daily Doses per prescription. The population-adjusted prescription and Defined Daily Doses values for 2009 were comparable to those reported by many European countries, while the average Defined Daily Dose per prescription for Canada ranked high. A significant reduction in the use of broad spectrum penicillins occurred between 1995 and 2004, coupled with increases in macrolide and quinolone use, suggesting that replacement of antimicrobial drugs may occur as new products arrive on the market. CONCLUSIONS: There have been modest decreases of antimicrobial use in Canada over the past 15 years. However, continued surveillance of antimicrobial use coupled with data detailing antimicrobial resistance within bacterial pathogens affecting human populations is critical for targeting interventions and maintaining the effectiveness of these products for future generations. PMID- 24146864 TI - P16 and p53 play distinct roles in different subtypes of breast cancer. AB - Breast cancers are heterogeneous and complex diseases, and subtypes of breast cancers may involve unique molecular mechanisms. The p16(INK4a) and p53 pathways are two of the major pathways involved in control of the cell cycle. They also play key roles in tumorigenesis. However, whether the roles of these pathways differ in the subtypes of breast cancer is unclear. Therefore, p16 and p53 expression were investigated in different breast cancer subtypes to ascertain their contributions to these cancers. A total of 400 cases of non-invasive ductal carcinoma in situ (DCIS) and invasive ductal carcinoma (IDC), including the major molecular subtypes luminal-A, luminal-B, Her-2, and triple-negative subtypes, and 50 cases of normal controls were compared. Luminal-A cancers expressed the lowest level of p16 among the subtypes in DCIS, and the level of p16 expression was up regulated in the luminal-A of IDC (P<0.008). Triple-negative breast cancers were characterized by a correlation of p53 overexpression with a high level of p16 expression. Luminal lesion types with high p16 expression in DCIS were found to be more likely to develop into aggressive breast cancers, possibly promoted by p53 dysfunction. Taken together, the present study suggest that p16 expression in luminal-A breast cancers is associated with their progression from DCIS to IDC, and both p53 and p16 expressions are important for the development of triple negative breast cancers in DCIS and IDC. PMID- 24146866 TI - Somatic donor cell type correlates with embryonic, but not extra-embryonic, gene expression in postimplantation cloned embryos. AB - The great majority of embryos generated by somatic cell nuclear transfer (SCNT) display defined abnormal phenotypes after implantation, such as an increased likelihood of death and abnormal placentation. To gain better insight into the underlying mechanisms, we analyzed genome-wide gene expression profiles of day 6.5 postimplantation mouse embryos cloned from three different cell types (cumulus cells, neonatal Sertoli cells and fibroblasts). The embryos retrieved from the uteri were separated into embryonic (epiblast) and extraembryonic (extraembryonic ectoderm and ectoplacental cone) tissues and were subjected to gene microarray analysis. Genotype- and sex-matched embryos produced by in vitro fertilization were used as controls. Principal component analysis revealed that whereas the gene expression patterns in the embryonic tissues varied according to the donor cell type, those in extraembryonic tissues were relatively consistent across all groups. Within each group, the embryonic tissues had more differentially expressed genes (DEGs) (>2-fold vs. controls) than did the extraembryonic tissues (P<1.0 * 10(-26)). In the embryonic tissues, one of the common abnormalities was upregulation of Dlk1, a paternally imprinted gene. This might be a potential cause of the occasional placenta-only conceptuses seen in SCNT-generated mouse embryos (1-5% per embryos transferred in our laboratory), because dysregulation of the same gene is known to cause developmental failure of embryos derived from induced pluripotent stem cells. There were also some DEGs in the extraembryonic tissues, which might explain the poor development of SCNT derived placentas at early stages. These findings suggest that SCNT affects the embryonic and extraembryonic development differentially and might cause further deterioration in the embryonic lineage in a donor cell-specific manner. This could explain donor cell-dependent variations in cloning efficiency using SCNT. PMID- 24146867 TI - The use of a predictive habitat model and a fuzzy logic approach for marine management and planning. AB - Bottom trawl survey data are commonly used as a sampling technique to assess the spatial distribution of commercial species. However, this sampling technique does not always correctly detect a species even when it is present, and this can create significant limitations when fitting species distribution models. In this study, we aim to test the relevance of a mixed methodological approach that combines presence-only and presence-absence distribution models. We illustrate this approach using bottom trawl survey data to model the spatial distributions of 27 commercially targeted marine species. We use an environmentally- and geographically-weighted method to simulate pseudo-absence data. The species distributions are modelled using regression kriging, a technique that explicitly incorporates spatial dependence into predictions. Model outputs are then used to identify areas that met the conservation targets for the deployment of artificial anti-trawling reefs. To achieve this, we propose the use of a fuzzy logic framework that accounts for the uncertainty associated with different model predictions. For each species, the predictive accuracy of the model is classified as 'high'. A better result is observed when a large number of occurrences are used to develop the model. The map resulting from the fuzzy overlay shows that three main areas have a high level of agreement with the conservation criteria. These results align with expert opinion, confirming the relevance of the proposed methodology in this study. PMID- 24146868 TI - Cut-off scores of a brief neuropsychological battery (NBACE) for Spanish individual adults older than 44 years old. AB - The neuropsychological battery used in Fundacio ACE (NBACE) is a relatively brief, and easy to administer, test battery that was designed to detect cognitive impairment in the adulthood. The NBACE includes measures of cognitive information processing speed, orientation, attention, verbal learning and memory, language, visuoperception, praxis and executive functions. The aim of the present study was to establish the cut-off scores for impairment for different levels of age and education that could be useful in the cognitive assessment of Spanish subjects who are at risk for cognitive impairment, especially dementia. Data from 1018 patients with a mild dementia syndrome, and 512 cognitively healthy subjects, older than 44 years, from the Memory Clinic of Fundacio ACE (Barcelona, Spain) were analyzed. In the whole sample, cut-off scores and sensitivity/specificity values were calculated for six conditions after combining 3 age ranges (44 to 64; 65 to 74; and older than 74 years old) by 2 educational levels (until Elementary school; and more than Elementary school). Moreover, general cut-offs are reported for Catalan and Spanish speakers. The results showed that most of NBACE tests reached good sensitivity and specificity values, except for Ideomotor praxis, Repetition and Verbal Comprehension tests, which had a ceiling effect. Word List Learning from the Wechsler Memory Scale-III and Semantic Verbal Fluency were the most useful tests to discriminate between cognitively healthy and demented subjects. The NBACE has been shown to be a useful tool able to detect cognitive impairment, especially dementia, in older than 44 years Spanish persons. PMID- 24146869 TI - M.tuberculosis mutants lacking oxygenated mycolates show increased immunogenicity and protective efficacy as compared to M. bovis BCG vaccine in an experimental mouse model. AB - The existing vaccine against tuberculosis (M. bovis BCG) exerts some protection against the extrapulmonary forms of the disease, particularly in young children, but is not very effective against the pulmonary form of TB, which often results from the reactivation of a latent M. tuberculosis (M.tb)infection. Among the new approaches in TB vaccine development, live attenuated M.tb mutants are a promising new avenue. Here we report on the vaccine potential of two highly attenuated M.tb mutants, MGM1991 and M.tbhma::hyg (HMA), lacking all oxygenated mycolates in their cell wall. In C57BL/6 mice, stronger Th1 (IFN-gamma, IL-2 and TNF-alpha) and IL-17 responses could be induced following subcutaneous vaccination with either of the two mutants, than following vaccination with M. bovis BCG. Significantly more mycobacteria specific IFN-gamma producing CD4(+) and particularly CD8(+) T cells could be detected by intracellular cytokine staining in mice vaccinated with the M.tb mutants. Finally, vaccination with either of the two mutants conferred stronger protection against intratracheal M.tb challenge than vaccination with BCG, as indicated by reduced bacterial replication in lungs at 4 to 12 weeks after challenge. Protection against M. tb dissemination, as indicated by reduced bacterial numbers in spleen, was comparable for both mutants to protection conferred by BCG. PMID- 24146865 TI - Four-year incidence of diabetic retinopathy in a Spanish cohort: the MADIABETES study. AB - OBJECTIVE: To evaluate the incidence of diabetic retinopathy in patients with Type 2 Diabetes Mellitus, to identify the risk factors associated with the incidence of retinopathy and to develop a risk table to predict four-year retinopathy risk stratification for clinical use, from a four-year cohort study. DESIGN: The MADIABETES Study is a prospective cohort study of 3,443 outpatients with Type 2 Diabetes Mellitus, sampled from 56 primary health care centers (131 general practitioners) in Madrid (Spain). RESULTS: The cumulative incidence of retinopathy at four-year follow-up was 8.07% (95% CI = 7.04-9.22) and the incidence density was 2.03 (95% CI = 1.75-2.33) cases per 1000 patient-months or 2.43 (95% CI = 2.10-2.80) cases per 100 patient-years. The highest adjusted hazard ratios of associated risk factors for incidence of diabetic retinopathy were LDL-C >190 mg/dl (HR = 7.91; 95% CI = 3.39-18.47), duration of diabetes longer than 22 years (HR = 2.00; 95% CI = 1.18-3.39), HbA1c>8% (HR = 1.90; 95% CI = 1.30-2.77), and aspirin use (HR = 1.65; 95% CI = 1.22-2.24). Microalbuminuria (HR = 1.17; 95% CI = 0.75-1.82) and being female (HR = 1.12; 95% CI = 0.84-1.49) showed a non-significant increase of diabetic retinopathy. The greatest risk is observed in females who had diabetes for more than 22 years, with microalbuminuria, HbA1c>8%, hypertension, LDL-Cholesterol >190 mg/dl and aspirin use. CONCLUSIONS: After a four-year follow-up, the cumulative incidence of retinopathy was relatively low in comparison with other studies. Higher baseline HbA1c, aspirin use, higher LDL-Cholesterol levels, and longer duration of diabetes were the only statistically significant risk factors found for diabetic retinopathy incidence. This is the first study to demonstrate an association between aspirin use and diabetic retinopathy risk in a well-defined cohort of patients with Type 2 Diabetes Mellitus at low risk of cardiovascular events. However, further studies with patients at high cardiovascular and metabolic risk are needed to clarify this issue. PMID- 24146871 TI - North-South differentiation and a region of high diversity in European wolves (Canis lupus). AB - European wolves (Canis lupus) show population genetic structure in the absence of geographic barriers, and across relatively short distances for this highly mobile species. Additional information on the location of and divergence between population clusters is required, particularly because wolves are currently recolonizing parts of Europe. We evaluated genetic structure in 177 wolves from 11 countries using over 67K single nucleotide polymorphism (SNP) loci. The results supported previous findings of an isolated Italian population with lower genetic diversity than that observed across other areas of Europe. Wolves from the remaining countries were primarily structured in a north-south axis, with Croatia, Bulgaria, and Greece (Dinaric-Balkan) differentiated from northcentral wolves that included individuals from Finland, Latvia, Belarus, Poland and Russia. Carpathian Mountain wolves in central Europe had genotypes intermediate between those identified in northcentral Europe and the Dinaric-Balkan cluster. Overall, individual genotypes from northcentral Europe suggested high levels of admixture. We observed high diversity within Belarus, with wolves from western and northern Belarus representing the two most differentiated groups within northcentral Europe. Our results support the presence of at least three major clusters (Italy, Carpathians, Dinaric-Balkan) in southern and central Europe. Individuals from Croatia also appeared differentiated from wolves in Greece and Bulgaria. Expansion from glacial refugia, adaptation to local environments, and human-related factors such as landscape fragmentation and frequent killing of wolves in some areas may have contributed to the observed patterns. Our findings can help inform conservation management of these apex predators and the ecosystems of which they are part. PMID- 24146870 TI - Generation and analysis of a large-scale expressed sequence Tag database from a full-length enriched cDNA library of developing leaves of Gossypium hirsutum L. AB - BACKGROUND: Cotton (Gossypium hirsutum L.) is one of the world's most economically-important crops. However, its entire genome has not been sequenced, and limited resources are available in GenBank for understanding the molecular mechanisms underlying leaf development and senescence. METHODOLOGY/PRINCIPAL FINDINGS: In this study, 9,874 high-quality ESTs were generated from a normalized, full-length cDNA library derived from pooled RNA isolated from throughout leaf development during the plant blooming stage. After clustering and assembly of these ESTs, 5,191 unique sequences, representative 1,652 contigs and 3,539 singletons, were obtained. The average unique sequence length was 682 bp. Annotation of these unique sequences revealed that 84.4% showed significant homology to sequences in the NCBI non-redundant protein database, and 57.3% had significant hits to known proteins in the Swiss-Prot database. Comparative analysis indicated that our library added 2,400 ESTs and 991 unique sequences to those known for cotton. The unigenes were functionally characterized by gene ontology annotation. We identified 1,339 and 200 unigenes as potential leaf senescence-related genes and transcription factors, respectively. Moreover, nine genes related to leaf senescence and eleven MYB transcription factors were randomly selected for quantitative real-time PCR (qRT-PCR), which revealed that these genes were regulated differentially during senescence. The qRT-PCR for three GhYLSs revealed that these genes express express preferentially in senescent leaves. CONCLUSIONS/SIGNIFICANCE: These EST resources will provide valuable sequence information for gene expression profiling analyses and functional genomics studies to elucidate their roles, as well as for studying the mechanisms of leaf development and senescence in cotton and discovering candidate genes related to important agronomic traits of cotton. These data will also facilitate future whole-genome sequence assembly and annotation in G. hirsutum and comparative genomics among Gossypium species. PMID- 24146872 TI - Improving the identification of high risk precursor B acute lymphoblastic leukemia patients with earlier quantification of minimal residual disease. AB - The stratification of patients with acute lymphoblastic leukemia (ALL) into treatment risk groups based on quantification of minimal residual disease (MRD) after induction therapy is now well accepted but the relapse rate of about 20% in intermediate risk patients remains a challenge. The purpose of this study was to further improve stratification by MRD measurement at an earlier stage. MRD was measured in stored day 15 bone marrow samples for pediatric patients enrolled on ANZCHOG ALL8 using Real-time Quantitative PCR to detect immunoglobulin and T-cell receptor gene rearrangements with the same assays used at day 33 and day 79 in the original MRD stratification. MRD levels in bone marrow at day 15 and 33 were highly predictive of outcome in 223 precursor B-ALL patients (log rank Mantel-Cox tests both P<0.001) and identified patients with poor, intermediate and very good outcomes. The combined use of MRD at day 15 (>= 1 * 10(-2)) and day 33 (>= 5 * 1( 5)) identified a subgroup of medium risk precursor B-ALL patients as poor MRD responders with 5 year relapse-free survival of 55% compared to 84% for other medium risk patients (log rank Mantel-Cox test, P = 0.0005). Risk stratification of precursor B-ALL but not T-ALL could be improved by using MRD measurement at day 15 and day 33 instead of day 33 and day 79 in similar BFM-based protocols for children with this disease. PMID- 24146873 TI - Soil-borne bacterial structure and diversity does not reflect community activity in Pampa biome. AB - The Pampa biome is considered one of the main hotspots of the world's biodiversity and it is estimated that half of its original vegetation was removed and converted to agricultural land and tree plantations. Although an increasing amount of knowledge is being assembled regarding the response of soil bacterial communities to land use change, to the associated plant community and to soil properties, our understanding about how these interactions affect the microbial community from the Brazilian Pampa is still poor and incomplete. In this study, we hypothesized that the same soil type from the same geographic region but under distinct land use present dissimilar soil bacterial communities. To test this hypothesis, we assessed the soil bacterial communities from four land-uses within the same soil type by 454-pyrosequencing of 16S rRNA gene and by soil microbial activity analyzes. We found that the same soil type under different land uses harbor similar (but not equal) bacterial communities and the differences were controlled by many microbial taxa. No differences regarding diversity and richness between natural areas and areas under anthropogenic disturbance were detected. However, the measures of microbial activity did not converge with the 16S rRNA data supporting the idea that the coupling between functioning and composition of bacterial communities is not necessarily correlated. PMID- 24146874 TI - Different involvement of promoter methylation in the expression of organic cation/carnitine transporter 2 (OCTN2) in cancer cell lines. AB - Organic cation/carnitine transporter 2 (OCTN2) is responsible for the cellular uptake of the antineoplastic agent, oxaliplatin. Epigenetic modification is a possible mechanism of altered drug-transporter expression in cancers, leading to altered efficacy of chemotherapeutic drugs. However, the mechanisms governing OCTN2 regulation are not completely understood. In this study, the low levels of OCTN2 in HepG2 and LS174T cells were elevated by the demethylating reagent, decitabine (DCA). To further reveal the epigenetic mechanism of down-regulation of OCTN2, we found that Region-1 within the OCTN2 promoter (spanning -354 to +85) was a determinant of OCTN2 expression in a luciferase reporter assay. Moreover, methylation-specific PCR (MSP) and bisulfite genomic sequencing showed that the degree of individual methylated CpG sites within this region was inversely correlated with the levels of OCTN2 in different cancer cells. Application of DCA to HepG2 and LS174T cells reversed the hypermethylation status of the OCTN2 promoter and increased OCTN2 expression, enhancing cellular uptake of oxaliplatin. Thus, we identified that promoter methylation is responsible for epigenetic down-regulation of OCTN2 in HepG2 and LS174T cells. Given the essential role of OCTN2 in cancer cell uptake of chemotherapeutics, and thus treatment efficacy, pretreatment with a demethylating reagent is a possible strategy for optimizing pharmacotherapies against cancers. PMID- 24146876 TI - Composition, production and procurement of glass at San Vincenzo Al Volturno: an early Medieval monastic complex in Southern Italy. AB - 136 glasses from the ninth-century monastery of San Vincenzo and its workshops have been analysed by electron microprobe in order to situate the assemblage within the first millennium CE glass making tradition. The majority of the glass compositions can be paralleled by Roman glass from the first to third centuries, with very few samples consistent with later compositional groups. Colours for trailed decoration on vessels, for vessel bodies and for sheet glass for windows were largely produced by melting the glass tesserae from old Roman mosaics. Some weakly-coloured transparent glass was obtained by re-melting Roman window glass, while some was produced by melting and mixing of tesserae, excluding the strongly coloured cobalt blues. Our data suggest that to feed the needs of the glass workshop, the bulk of the glass was removed as tesserae and windows from a large Roman building. This is consistent with a historical account according to which the granite columns of the monastic church were spolia from a Roman temple in the region. The purported shortage of natron from Egypt does not appear to explain the dependency of San Vincenzo on old Roman glass. Rather, the absence of contemporary primary glass may reflect the downturn in long-distance trade in the later first millennium C.E., and the role of patronage in the "ritual economy" founded upon donations and gift-giving of the time. PMID- 24146875 TI - Identification of cisplatin-regulated metabolic pathways in pluripotent stem cells. AB - The chemotherapeutic compound, cisplatin causes various kinds of DNA lesions but also triggers other pertubations, such as ER and oxidative stress. We and others have shown that treatment of pluripotent stem cells with cisplatin causes a plethora of transcriptional and post-translational alterations that, to a major extent, point to DNA damage response (DDR) signaling. The orchestrated DDR signaling network is important to arrest the cell cycle and repair the lesions or, in case of damage beyond repair, eliminate affected cells. Failure to properly balance the various aspects of the DDR in stem cells contributes to ageing and cancer. Here, we performed metabolic profiling by mass spectrometry of embryonic stem (ES) cells treated for different time periods with cisplatin. We then integrated metabolomics with transcriptomics analyses and connected cisplatin-regulated metabolites with regulated metabolic enzymes to identify enriched metabolic pathways. These included nucleotide metabolism, urea cycle and arginine and proline metabolism. Silencing of identified proline metabolic and catabolic enzymes indicated that altered proline metabolism serves as an adaptive, rather than a toxic response. A group of enriched metabolic pathways clustered around the metabolite S-adenosylmethionine, which is a hub for methylation and transsulfuration reactions and polyamine metabolism. Enzymes and metabolites with pro- or anti-oxidant functions were also enriched but enhanced levels of reactive oxygen species were not measured in cisplatin-treated ES cells. Lastly, a number of the differentially regulated metabolic enzymes were identified as target genes of the transcription factor p53, pointing to p53 mediated alterations in metabolism in response to genotoxic stress. Altogether, our findings reveal interconnecting metabolic pathways that are responsive to cisplatin and may serve as signaling modules in the DDR in pluripotent stem cells. PMID- 24146877 TI - Effects of high and low fat dairy food on cardio-metabolic risk factors: a meta analysis of randomized studies. AB - IMPORTANCE: Clear guidelines on the health effects of dairy food are important given the high prevalence of obesity, cardiovascular disease and diabetes, and increasing global consumption of dairy food. OBJECTIVE: To evaluate the effects of increased dairy food on cardio metabolic risk factors. DATA SOURCES: Searches were performed until April 2013 using MEDLINE, Science Direct, Google,Embase, the Cochrane Central Register of Controlled Trials, reference lists of articles, and proceedings of major meetings. STUDY SELECTION: Randomized controlled studies with healthy adults randomized to increased dairy food for more than one month without additional interventions. DATA EXTRACTION AND SYNTHESIS: A standard list was used to extract descriptive, methodological and key variables from all eligible studies. If data was not included in the published report corresponding authors were contacted. RESULTS: 20 studies with 1677 participants with a median duration of dietary change of 26 (IQR 10-39) weeks and mean increase in dairy food intake of 3.6 (SD 0.92) serves/day were included. There was an increase in weight with low (+0.82, 0.35 to 1.28 kg, p<0.001) and whole fat dairy food (+0.41, 0.04 to 0.79 kg, p=0.03), but no significant change in waist circumference (-0.07, -1.24 to 1.10 cm) ; HOMA -IR (-0.94, -1.93 to 0.04 units); fasting glucose (+1.32, 0.19 to 2.45 mg/dl) ; LDL-c (1.85,-2.89 to 6.60 mg/dl); HDL-c (-0.19, -2.10 to 1.71 mg/dl); systolic BP (-0.4, -1.6 to 0.8 mmHg); diastolic BP (-0.4, -1.7 to 0.8 mmHg) or CRP (-1.07, -2.54 to 0.39 mg/L). Changes in other cardio-metabolic risk factors were similar for low and whole fat dairy interventions. LIMITATIONS: Most clinical trials were small and of modest quality. . CONCLUSION: Increasing whole fat and low fat dairy food consumption increases weight but has minor effects on other cardio-metabolic risk factors. TRIAL REGISTRATION ACTRN: Australian New Zealand Clinical Trials Registry ACTRN12613000401752, http://www.anzctr.org.au. ETHICS APPROVAL NUMBER: NTX/10/11/115. PMID- 24146878 TI - TOPICOP(c): a new scale evaluating topical corticosteroid phobia among atopic dermatitis outpatients and their parents. AB - BACKGROUND: The fear of using topical corticosteroids, usually called topical corticophobia, is a frequent concern for atopic dermatitis patients and/or their parents. Assessing patients' atopic dermatitis and their parents' topical corticosteroid phobia is an essential step to improving adherence to treatment. Because topical corticophobia appears to be a complex phenomenon, its evaluation by binary responses (yes/no) is too simplistic. Thus, a scale is needed, which is capable of identifying the subtleties of topical corticosteroid phobia. OBJECTIVES: To develop and validate a scale, TOPICOP(c), measuring worries and beliefs about topical corticosteroids among atopic dermatitis outpatients and their parents. METHODS: An initial statistical validation of TOPICOP was carried out, collecting qualitative data about patients' topical corticophobia behaviors and beliefs using focus-group methodology. Then, 208 outpatients or their parents from five French centers completed a self-administered questionnaire built from focus-group results. The scale-development process comprised an explanatory principal component analysis, Cronbach's alpha-coefficients and structural equation modeling. RESULTS: The validated questionnaire comprised 12 items, covering two important dimensions relative to "worries" (6 items) and "beliefs" (6 items). Psychometric properties showed that items had very good communality (>0.60) within their own dimension. The final two-factor solution accounted for 47.3% of the variance. Cronbach's alpha-coefficients were, respectively, 0.79 and 0.78. Structural equation modeling strongly supported the possibility of calculating a global score. CONCLUSIONS: TOPICOP(c) is the first scale aimed at assessing topical corticophobia in adult patients and parents of children with eczema. TOPICOP(r) has excellent psychometric properties and should be easy to use in everyday clinical practice for clinicians and researchers. Further studies are needed to confirm our results and validate TOPICOP(c) in other cultures. PMID- 24146881 TI - Confidence-guided local structure prediction with HHfrag. AB - We present a method to assess the reliability of local structure prediction from sequence. We introduce a greedy algorithm for filtering and enrichment of dynamic fragment libraries, compiled with remote-homology detection methods such as HHfrag. After filtering false hits at each target position, we reduce the fragment library to a minimal set of representative fragments, which are guaranteed to have correct local structure in regions of detectable conservation. We demonstrate that the location of conserved motifs in a protein sequence can be predicted by examining the recurrence and structural homogeneity of detected fragments. The resulting confidence score correlates with the local RMSD of the representative fragments and allows us to predict torsion angles from sequence with better accuracy compared to existing machine learning methods. PMID- 24146879 TI - Induction of autophagy is an early response to gefitinib and a potential therapeutic target in breast cancer. AB - Gefitinib (Iressa((r)), ZD1839) is a small molecule inhibitor of the epidermal growth factor receptor (EGFR) tyrosine kinase. We report on an early cellular response to gefitinib that involves induction of functional autophagic flux in phenotypically diverse breast cancer cells that were sensitive (BT474 and SKBR3) or insensitive (MCF7-GFPLC3 and JIMT-1) to gefitinib. Our data show that elevation of autophagy in gefitinib-treated breast cancer cells correlated with downregulation of AKT and ERK1/2 signaling early in the course of treatment. Inhibition of autophagosome formation by BECLIN-1 or ATG7 siRNA in combination with gefitinib reduced the abundance of autophagic organelles and sensitized SKBR3 but not MCF7-GFPLC3 cells to cell death. However, inhibition of the late stage of gefitinib-induced autophagy with hydroxychloroquine (HCQ) or bafilomycin A1 significantly increased (p<0.05) cell death in gefitinib-sensitive SKBR3 and BT474 cells, as well as in gefitinib-insensitive JIMT-1 and MCF7-GFPLC3 cells, relative to the effects observed with the respective single agents. Treatment with the combination of gefitinib and HCQ was more effective (p<0.05) in delaying tumor growth than either monotherapy (p>0.05), when compared to vehicle-treated controls. Our results also show that elevated autophagosome content following short-term treatment with gefitinib is a reversible response that ceases upon removal of the drug. In aggregate, these data demonstrate that elevated autophagic flux is an early response to gefitinib and that targeting EGFR and autophagy should be considered when developing new therapeutic strategies for EGFR expressing breast cancers. PMID- 24146880 TI - Classification, naming and evolutionary history of glycosyltransferases from sequenced green and red algal genomes. AB - The Archaeplastida consists of three lineages, Rhodophyta, Virideplantae and Glaucophyta. The extracellular matrix of most members of the Rhodophyta and Viridiplantae consists of carbohydrate-based or a highly glycosylated protein based cell wall while the Glaucophyte covering is poorly resolved. In order to elucidate possible evolutionary links between the three advanced lineages in Archaeplastida, a genomic analysis was initiated. Fully sequenced genomes from the Rhodophyta and Virideplantae and the well-defined CAZy database on glycosyltransferases were included in the analysis. The number of glycosyltransferases found in the Rhodophyta and Chlorophyta are generally much lower then in land plants (Embryophyta). Three specific features exhibited by land plants increase the number of glycosyltransferases in their genomes: (1) cell wall biosynthesis, the more complex land plant cell walls require a larger number of glycosyltransferases for biosynthesis, (2) a richer set of protein glycosylation, and (3) glycosylation of secondary metabolites, demonstrated by a large proportion of family GT1 being involved in secondary metabolite biosynthesis. In a comparative analysis of polysaccharide biosynthesis amongst the taxa of this study, clear distinctions or similarities were observed in (1) N linked protein glycosylation, i.e., Chlorophyta has different mannosylation and glucosylation patterns, (2) GPI anchor biosynthesis, which is apparently missing in the Rhodophyta and truncated in the Chlorophyta, (3) cell wall biosynthesis, where the land plants have unique cell wall related polymers not found in green and red algae, and (4) O-linked glycosylation where comprehensive orthology was observed in glycosylation between the Chlorophyta and land plants but not between the target proteins. PMID- 24146882 TI - Dynamics of green Sahara periods and their role in hominin evolution. AB - Astronomically forced insolation changes have driven monsoon dynamics and recurrent humid episodes in North Africa, resulting in green Sahara Periods (GSPs) with savannah expansion throughout most of the desert. Despite their potential for expanding the area of prime hominin habitats and favouring out-of Africa dispersals, GSPs have not been incorporated into the narrative of hominin evolution due to poor knowledge of their timing, dynamics and landscape composition at evolutionary timescales. We present a compilation of continental and marine paleoenvironmental records from within and around North Africa, which enables identification of over 230 GSPs within the last 8 million years. By combining the main climatological determinants of woody cover in tropical Africa with paleoenvironmental and paleoclimatic data for representative (Holocene and Eemian) GSPs, we estimate precipitation regimes and habitat distributions during GSPs. Their chronology is consistent with the ages of Saharan archeological and fossil hominin sites. Each GSP took 2-3 kyr to develop, peaked over 4-8 kyr, biogeographically connected the African tropics to African and Eurasian mid latitudes, and ended within 2-3 kyr, which resulted in rapid habitat fragmentation. We argue that the well-dated succession of GSPs presented here may have played an important role in migration and evolution of hominins. PMID- 24146883 TI - Hemorrhage-adjusted iron requirements, hematinics and hepcidin define hereditary hemorrhagic telangiectasia as a model of hemorrhagic iron deficiency. AB - BACKGROUND: Iron deficiency anemia remains a major global health problem. Higher iron demands provide the potential for a targeted preventative approach before anemia develops. The primary study objective was to develop and validate a metric that stratifies recommended dietary iron intake to compensate for patient specific non-menstrual hemorrhagic losses. The secondary objective was to examine whether iron deficiency can be attributed to under-replacement of epistaxis (nosebleed) hemorrhagic iron losses in hereditary hemorrhagic telangiectasia (HHT). METHODOLOGY/PRINCIPAL FINDINGS: The hemorrhage adjusted iron requirement (HAIR) sums the recommended dietary allowance, and iron required to replace additional quantified hemorrhagic losses, based on the pre-menopausal increment to compensate for menstrual losses (formula provided). In a study population of 50 HHT patients completing concurrent dietary and nosebleed questionnaires, 43/50 (86%) met their recommended dietary allowance, but only 10/50 (20%) met their HAIR. Higher HAIR was a powerful predictor of lower hemoglobin (p = 0.009), lower mean corpuscular hemoglobin content (p<0.001), lower log-transformed serum iron (p = 0.009), and higher log-transformed red cell distribution width (p<0.001). There was no evidence of generalised abnormalities in iron handling Ferritin and ferritin(2) explained 60% of the hepcidin variance (p<0.001), and the mean hepcidinferritin ratio was similar to reported controls. Iron supplement use increased the proportion of individuals meeting their HAIR, and blunted associations between HAIR and hematinic indices. Once adjusted for supplement use however, reciprocal relationships between HAIR and hemoglobin/serum iron persisted. Of 568 individuals using iron tablets, most reported problems completing the course. For patients with hereditary hemorrhagic telangiectasia, persistent anemia was reported three-times more frequently if iron tablets caused diarrhea or needed to be stopped. CONCLUSIONS/SIGNIFICANCE: HAIR values, providing an indication of individuals' iron requirements, may be a useful tool in prevention, assessment and management of iron deficiency. Iron deficiency in HHT can be explained by under-replacement of nosebleed hemorrhagic iron losses. PMID- 24146884 TI - Protein kinase C-dependent signaling controls the midgut epithelial barrier to malaria parasite infection in anopheline mosquitoes. AB - Anopheline mosquitoes are the primary vectors of parasites in the genus Plasmodium, the causative agents of malaria. Malaria parasites undergo a series of complex transformations upon ingestion by the mosquito host. During this process, the physical barrier of the midgut epithelium, along with innate immune defenses, functionally restrict parasite development. Although these defenses have been studied for some time, the regulatory factors that control them are poorly understood. The protein kinase C (PKC) gene family consists of serine/threonine kinases that serve as central signaling molecules and regulators of a broad spectrum of cellular processes including epithelial barrier function and immunity. Indeed, PKCs are highly conserved, ranging from 7 isoforms in Drosophila to 16 isoforms in mammals, yet none have been identified in mosquitoes. Despite conservation of the PKC gene family and their potential as targets for transmission-blocking strategies for malaria, no direct connections between PKCs, the mosquito immune response or epithelial barrier integrity are known. Here, we identify and characterize six PKC gene family members--PKCdelta, PKCepsilon, PKCzeta, PKD, PKN, and an indeterminate conventional PKC--in Anopheles gambiae and Anopheles stephensi. Sequence and phylogenetic analyses of the anopheline PKCs support most subfamily assignments. All six PKCs are expressed in the midgut epithelia of A. gambiae and A. stephensi post-blood feeding, indicating availability for signaling in a tissue that is critical for malaria parasite development. Although inhibition of PKC enzymatic activity decreased NF-kappaB-regulated anti-microbial peptide expression in mosquito cells in vitro, PKC inhibition had no effect on expression of a panel of immune genes in the midgut epithelium in vivo. PKC inhibition did, however, significantly increase midgut barrier integrity and decrease development of P. falciparum oocysts in A. stephensi, suggesting that PKC-dependent signaling is a negative regulator of epithelial barrier function and a potential new target for transmission-blocking strategies. PMID- 24146885 TI - Impulsivity in binge eating disorder: food cues elicit increased reward responses and disinhibition. AB - BACKGROUND: Binge eating disorder (BED) represents a distinct eating disorder diagnosis. Current approaches assume increased impulsivity to be one factor leading to binge eating and weight gain. We used eye tracking to investigate both components of impulsivity, namely reward sensitivity and rash-spontaneous behaviour towards food in BED for the first time. METHODS: Overweight and obese people with BED (BED+; n = 25), without BED (BED-; n = 26) and healthy normal weight controls (NWC; n = 25) performed a free exploration paradigm measuring reward sensitivity (experiment 1) and a modified antisaccade paradigm measuring disinhibited, rash-spontaneous behaviour (experiment 2) using food and nonfood stimuli. Additionally, trait impulsivity was assessed. RESULTS: In experiment 1, all participants located their initial fixations more often on food stimuli and BED+ participants gazed longer on food stimuli in comparison with BED- and NWC participants. In experiment 2, BED+ participants had more difficulties inhibiting saccades towards food and nonfood stimuli compared with both other groups in first saccades, and especially towards food stimuli in second saccades and concerning sequences of first and second saccades. BED- participants did not differ significantly from NWC participants in both experiments. Additionally, eye tracking performance was associated with self-reported reward responsiveness and self-control. CONCLUSIONS: According to these results, food-related reward sensitivity and rash-spontaneous behaviour, as the two components of impulsivity, are increased in BED in comparison with weight-matched and normal-weight controls. This indicates that BED represents a neurobehavioural phenotype of obesity that is characterised by increased impulsivity. Interventions for BED should target these special needs of affected patients. PMID- 24146886 TI - High-throughput sequencing of islet-infiltrating memory CD4+ T cells reveals a similar pattern of TCR Vbeta usage in prediabetic and diabetic NOD mice. AB - Autoreactive memory CD4(+) T cells play a critical role in the development of type 1 diabetes, but it is not yet known how the clonotypic composition and TCRbeta repertoire of the memory CD4(+) T cell compartment changes during the transition from prediabetes to diabetes. In this study, we used high-throughput sequencing to analyze the TCRbeta repertoire of sorted islet-infiltrating memory CD4(+)CD44(high) T cells in 10-week-old prediabetic and recently diabetic NOD mice. We show that most clonotypes of islet-infiltrating CD4(+)CD44(high) T cells were rare, but high-frequency clonotypes were significantly more common in diabetic than in prediabetic mice. Moreover, although the CD4(+)CD44(high) TCRbeta repertoires were highly diverse at both stages of disease development, dominant use of TRBV1 (Vbeta2), TRBV13-3 (Vbeta8.1), and TRBV19 (Vbeta6) was evident in both prediabetic and diabetic mice. Our findings strongly suggest that therapeutic targeting of cells specifically expressing the dominant TCRbeta might reduce pancreatic infiltration in prediabetic mice and attenuate the progression to diabetes. PMID- 24146887 TI - An in vitro mechanism study on the proliferation and pluripotency of human embryonic stems cells in response to magnesium degradation. AB - Magnesium (Mg) is a promising biodegradable metallic material for applications in cellular/tissue engineering and biomedical implants/devices. To advance clinical translation of Mg-based biomaterials, we investigated the effects and mechanisms of Mg degradation on the proliferation and pluripotency of human embryonic stem cells (hESCs). We used hESCs as the in vitro model system to study cellular responses to Mg degradation because they are sensitive to toxicants and capable of differentiating into any cell types of interest for regenerative medicine. In a previous study when hESCs were cultured in vitro with either polished metallic Mg (99.9% purity) or pre-degraded Mg, cell death was observed within the first 30 hours of culture. Excess Mg ions and hydroxide ions induced by Mg degradation may have been the causes for the observed cell death; hence, their respective effects on hESCs were investigated for the first time to reveal the potential mechanisms. For this purpose, the mTeSR(r)1 hESC culture media was either modified to an alkaline pH of 8.1 or supplemented with 0.4-40 mM of Mg ions. We showed that the initial increase of media pH to 8.1 had no adverse effect on hESC proliferation. At all tested Mg ion dosages, the hESCs grew to confluency and retained pluripotency as indicated by the expression of OCT4, SSEA3, and SOX2. When the supplemental Mg ion dosages increased to greater than 10 mM, however, hESC colony morphology changed and cell counts decreased. These results suggest that Mg-based implants or scaffolds are promising in combination with hESCs for regenerative medicine applications, providing their degradation rate is moderate. Additionally, the hESC culture system could serve as a standard model for cytocompatibility studies of Mg in vitro, and an identified 10 mM critical dosage of Mg ions could serve as a design guideline for safe degradation of Mg-based implants/scaffolds. PMID- 24146888 TI - Gender differences in the social pathways linking neighborhood disadvantage to depressive symptoms in adults. AB - Depression debilitates the lives of millions and is projected to be the second leading disease burden worldwide by 2020. At the population level, the causes of depression are found in the everyday social and physical environments in which people live. Research has shown that men and women often experience neighbourhood environments differently and that these variations are often reflected in health outcomes. The current study examines whether social and environmental correlates of depression are similar in men and women. This study examines whether (i) there are gender differences in the association between neighbourhood disadvantage and depressive symptoms, and (ii) dimensions of social capital and cohesion mediate these associations. Data come from the Montreal Neighbourhood Networks and Healthy Aging Study, which consists of a cluster stratified sample of Montreal census tracts (n(ct) = 300) and individuals within those tracts (ni = 2707). Depressive symptoms and social capital were measured with a questionnaire. Neighbourhood disadvantage was measured at the census tract level using data from the 2006 Canada Census. Multilevel logistic regression stratified by gender and a three-step mediation analysis procedure were used. Final sample size for these analyses was 2574 adults. Depressive symptoms had a prevalence of 17.3% in the overall sample. Disadvantage was associated with depressive symptoms in women only (OR = 1.25, 95% CI = 1.01-1.55). Perceived neighbourhood cohesion was shown to mediate the association of disadvantage and depressive symptoms in women (ab = 0.02; 95% CI = 0.003-0.04, p<0.05). Other socio-relational variables, specifically generalized trust and trust in neighbours were associated with depression in women but did not act as mediating variables. Health promotion initiatives meant to combat depression may wish to consider gender differences in the design and implementation of neighbourhood or peer-based programs. PMID- 24146889 TI - Identifying genes relevant to specific biological conditions in time course microarray experiments. AB - Microarrays have been useful in understanding various biological processes by allowing the simultaneous study of the expression of thousands of genes. However, the analysis of microarray data is a challenging task. One of the key problems in microarray analysis is the classification of unknown expression profiles. Specifically, the often large number of non-informative genes on the microarray adversely affects the performance and efficiency of classification algorithms. Furthermore, the skewed ratio of sample to variable poses a risk of overfitting. Thus, in this context, feature selection methods become crucial to select relevant genes and, hence, improve classification accuracy. In this study, we investigated feature selection methods based on gene expression profiles and protein interactions. We found that in our setup, the addition of protein interaction information did not contribute to any significant improvement of the classification results. Furthermore, we developed a novel feature selection method that relies exclusively on observed gene expression changes in microarray experiments, which we call "relative Signal-to-Noise ratio" (rSNR). More precisely, the rSNR ranks genes based on their specificity to an experimental condition, by comparing intrinsic variation, i.e. variation in gene expression within an experimental condition, with extrinsic variation, i.e. variation in gene expression across experimental conditions. Genes with low variation within an experimental condition of interest and high variation across experimental conditions are ranked higher, and help in improving classification accuracy. We compared different feature selection methods on two time-series microarray datasets and one static microarray dataset. We found that the rSNR performed generally better than the other methods. PMID- 24146890 TI - Psychological processes mediate the impact of familial risk, social circumstances and life events on mental health. AB - BACKGROUND: Despite widespread acceptance of the 'biopsychosocial model', the aetiology of mental health problems has provoked debate amongst researchers and practitioners for decades. The role of psychological factors in the development of mental health problems remains particularly contentious, and to date there has not been a large enough dataset to conduct the necessary multivariate analysis of whether psychological factors influence, or are influenced by, mental health. This study reports on the first empirical, multivariate, test of the relationships between the key elements of the biospychosocial model of mental ill health. METHODS AND FINDINGS: Participants were 32,827 (age 18-85 years) self selected respondents from the general population who completed an open-access online battery of questionnaires hosted by the BBC. An initial confirmatory factor analysis was performed to assess the adequacy of the proposed factor structure and the relationships between latent and measured variables. The predictive path model was then tested whereby the latent variables of psychological processes were positioned as mediating between the causal latent variables (biological, social and circumstantial) and the outcome latent variables of mental health problems and well-being. This revealed an excellent fit to the data, S-B chi(2) (3199, N = 23,397) = 126654.8, p<.001; RCFI = .97; RMSEA = .04 (.038-.039). As hypothesised, a family history of mental health difficulties, social deprivation, and traumatic or abusive life-experiences all strongly predicted higher levels of anxiety and depression. However, these relationships were strongly mediated by psychological processes; specifically lack of adaptive coping, rumination and self-blame. CONCLUSION: These results support a significant revision of the biopsychosocial model, as psychological processes determine the causal impact of biological, social, and circumstantial risk factors on mental health. This has clear implications for policy, education and clinical practice as psychological processes such as rumination and self blame are amenable to evidence-based psychological therapies. PMID- 24146891 TI - Atrial myocyte function and Ca2+ handling is associated with inborn aerobic capacity. AB - BACKGROUND: Although high aerobic capacity is associated with effective cardiac function, the effect of aerobic capacity on atrial function, especially in terms of cellular mechanisms, is not known. We aimed to investigate whether rats with low inborn maximal oxygen uptake (VO2 max) had impaired atrial myocyte contractile function when compared to rats with high inborn VO2 max. METHODS AND RESULTS: Atrial myocyte function was depressed in Low Capacity Runners (LCR) relative to High Capacity Runners (HCR) which was associated with impaired Ca(2+) handling. Fractional shortening was 52% lower at 2 Hz and 60% lower at 5 Hz stimulation while time to 50% relengthening was 43% prolonged and 55% prolonged, respectively. Differences in Ca(2+) amplitude and diastolic Ca(2+) level were observed at 5 Hz stimulation where Ca(2+) amplitude was 70% lower and diastolic Ca(2+) level was 11% higher in LCR rats. Prolonged time to 50% Ca(2+) decay was associated with reduced sarcoplasmic reticulum (SR) Ca(2+) ATPase function in LCR (39%). Na(+)/Ca(2+) exchanger activity was comparable between the groups. Diastolic SR Ca(2+) leak was increased by 109%. This could be partly explained by increased ryanodine receptors phosphorylation at the Ca(2+)-calmodulin-dependent protein kinase-II specific Ser-2814 site in LCR rats. T-tubules were present in 68% of HCR cells whereas only 33% LCR cells had these structures. In HCR, the significantly higher numbers of cells with T-tubules were combined with greater numbers of myocytes where Ca(2+) release in the cell occurred simultaneously in central and peripheral regions, giving rise to faster and more spatial homogenous Ca(2+)-signal onset. CONCLUSION: This data demonstrates that contrasting for low or high aerobic capacity leads to diverse functional and structural remodelling of atrial myocytes, with impaired contractile function in LCR compared to HCR rats. PMID- 24146892 TI - Training reveals the sources of Stroop and Flanker interference effects. AB - In the field of cognitive control, dimensional overlap and pathway automaticity are generally believed to be critical for the generation of congruency effects. However, their specific roles in the generation of congruency effects are unclear. In two experiments, with the 4:2 mapping design, we investigated this issue by examining the training-related effects on congruency effects (the Stroop interference effect and the Flanker interference effect in Experiments 1 and 2, respectively) normally expressed as incongruent minus congruent difference and on their subcomponents (the stimulus interference and response interference). Experiment 1 revealed that the stimulus interference in the Stroop task, wherein the task-relevant (printed color of word) and the task-irrelevant (semantics of word) dimensions of the stimuli were processed in different pathways, was present during early training but was virtually eliminated at the late stage of training. This indicates that the two dimensions overlap at the early stage but separate at the late stage. In contrast, Experiment 2 showed that the response interference in a variant of the Flanker task, wherein the task-relevant (central color word printed in black font) and the task-irrelevant (flanking color words printed in black font) dimensions of the stimuli were processed in the same pathway, was enhanced after training. This indicates that the enhanced automaticity of irrelevant-dimension processing induces stronger response competition, which therefore results in the larger response interference. Taken together, the present study demonstrates that (1) dimensional overlap is necessary for the generation of congruency effects, (2) pathway automaticity can affect the size of congruency effects, and (3) training enhances the degree of automatic processing in a given pathway. PMID- 24146893 TI - The pattern of complaints about Australian wind farms does not match the establishment and distribution of turbines: support for the psychogenic, 'communicated disease' hypothesis. AB - BACKGROUND AND OBJECTIVES: With often florid allegations about health problems arising from wind turbine exposure now widespread, nocebo effects potentially confound any future investigation of turbine health impact. Historical audits of health complaints are therefore important. We test 4 hypotheses relevant to psychogenic explanations of the variable timing and distribution of health and noise complaints about wind farms in Australia. SETTING: All Australian wind farms (51 with 1634 turbines) operating 1993-2012. METHODS: Records of complaints about noise or health from residents living near 51 Australian wind farms were obtained from all wind farm companies, and corroborated with complaints in submissions to 3 government public enquiries and news media records and court affidavits. These are expressed as proportions of estimated populations residing within 5 km of wind farms. RESULTS: There are large historical and geographical variations in wind farm complaints. 33/51 (64.7%) of Australian wind farms including 18/34 (52.9%) with turbine size >1 MW have never been subject to noise or health complaints. These 33 farms have an estimated 21,633 residents within 5 km and have operated complaint-free for a cumulative 267 years. Western Australia and Tasmania have seen no complaints. 129 individuals across Australia (1 in 254 residents) appear to have ever complained, with 94 (73%) being residents near 6 wind farms targeted by anti wind farm groups. The large majority 116/129(90%) of complainants made their first complaint after 2009 when anti wind farm groups began to add health concerns to their wider opposition. In the preceding years, health or noise complaints were rare despite large and small-turbine wind farms having operated for many years. CONCLUSIONS: The reported historical and geographical variations in complaints are consistent with psychogenic hypotheses that expressed health problems are "communicated diseases" with nocebo effects likely to play an important role in the aetiology of complaints. PMID- 24146894 TI - Effects of elevated [CO2] and low soil moisture on the physiological responses of Mountain Maple (Acer spicatum L.) seedlings to light. AB - Global climate change is expected to affect how plants respond to their physical and biological environments. In this study, we examined the effects of elevated CO2 ([CO2]) and low soil moisture on the physiological responses of mountain maple (Acer spicatum L.) seedlings to light availability. The seedlings were grown at ambient (392 umol mol(-1)) and elevated (784 umol mol(-1)) [CO2], low and high soil moisture (M) regimes, at high light (100%) and low light (30%) in the greenhouse for one growing season. We measured net photosynthesis (A), stomatal conductance (g s), instantaneous water use efficiency (IWUE), maximum rate of carboxylation (V cmax), rate of photosynthetic electron transport (J), triose phosphate utilization (TPU)), leaf respiration (R d), light compensation point (LCP) and mid-day shoot water potential (Psix). A and g s did not show significant responses to light treatment in seedlings grown at low soil moisture treatment, but the high light significantly decreased the C i/C a in those seedlings. IWUE was significantly higher in the elevated compared with the ambient [CO2], and the effect was greater at high than the low light treatment. LCP did not respond to the soil moisture treatments when seedlings were grown in high light under both [CO2]. The low soil moisture significantly reduced Psix but had no significant effect on the responses of other physiological traits to light or [CO2]. These results suggest that as the atmospheric [CO2] rises, the physiological performance of mountain maple seedlings in high light environments may be enhanced, particularly when soil moisture conditions are favourable. PMID- 24146896 TI - High proportion of intestinal colonization with successful epidemic clones of ESBL-producing Enterobacteriaceae in a neonatal intensive care unit in Ecuador. AB - BACKGROUND AND AIMS: Neonatal infections caused by Extended-spectrum beta lactamase (ESBL)-producing bacteria are associated with increased morbidity and mortality. No data are available on neonatal colonization with ESBL-producing bacteria in Ecuador. The aim of this study was to determine the proportion of intestinal colonization with ESBL-producing Enterobacteriaceae, their resistance pattern and risk factors of colonization in a neonatal intensive care unit in Ecuador. METHODS: During a three month period, stool specimens were collected every two weeks from hospitalized neonates. Species identification and susceptibility testing were performed with Vitek2, epidemiologic typing with automated repetitive PCR. Associations between groups were analyzed using the Pearson X (2) test and Fisher exact test. A forward step logistic regression model identified significant predictors for colonization. RESULTS: Fifty-six percent of the neonates were colonized with ESBL-producing Enterobacteriaceae. Length of stay longer than 20 days and enteral feeding with a combination of breastfeeding and formula feeding were significantly associated with ESBL colonization. The strains found were E. coli (EC, 89%) and K. pneumoniae (KP, 11%) and epidemiological typing divided these isolates in two major clusters. All EC and KP had bla CTX-M group 1 except for a unique EC isolate that had bla CTX-M group 9. Multi-locus sequence typing performed on the K. pneumoniae strains showed that the strains belonged to ST855 and ST897. The two detected STs belong to two different epidemic clonal complexes (CC), CC11 and CC14, which previously have been associated with dissemination of carbapenemases. None of the E. coli strains belonged to the epidemic ST 131 clone. CONCLUSIONS: More than half of the neonates were colonized with ESBL-producing Enterobacteriaceae where the main risk factor for colonization was length of hospital stay. Two of the isolated clones were epidemic and known to disseminate carbapenemases. The results underline the necessity for improved surveillance and infection control in this context. PMID- 24146895 TI - The relationship between visual field index and estimated number of retinal ganglion cells in glaucoma. AB - PURPOSE: To evaluate the relationship between visual field index (VFI) and the estimated number of retinal ganglion cells (RGCs) in glaucoma. METHODS: A multicenter study of 1,245 healthy, glaucomatous and suspected glaucomatous eyes of 1,245 subjects recruited from the Diagnostic Innovations in Glaucoma Study (DIGS) and African Descent and Glaucoma Evaluation Study (ADAGES). All eyes underwent standard automated perimetry (SAP) and time-domain optical coherence tomography (TD-OCT). Estimates of RGC count and percentage of RGCs remaining, compared to age-matched healthy eyes, were calculated from TD-OCT using a previously described formula. Smoothing spline curves were fitted to examine the relationship between VFI and the percent remaining RGCs. The first derivative (i.e., slopes) of these curves was used to explore the relationship between changes in these measures. RESULTS: The relationships between the VFI and both estimated RGC counts and the percent remaining RGCs were nonlinear. A unit number of VFI loss corresponded to substantially greater loss of estimated RGCs and estimated percentage of RGCs remaining in early compared to late disease. CONCLUSIONS: The relationship between VFI and estimated RGC counts is nonlinear and the index substantially underestimates the amount of neural loss early in the disease. Disease severity should be taken into account when interpreting rates of VFI change over time. PMID- 24146897 TI - Effects of ambient particulate matter on human breast cancer: is xenogenesis responsible? AB - BACKGROUND: Recently, evidence from several studies has revealed that air pollution is associated with the increased morbidity and mortality of breast cancer patients. However, to date, the underlying mechanism remains largely unclear. Considering the high prevalence of air pollution and breast cancer in China, it is necessary to understand how air pollution may affect breast cancer. METHODS: We analyzed 1,832 female patients who had resided in the same cities for at least 10 years prior to their diagnosis. Variables including demographic data as well as clinical and tumor characteristics, including the patient's age at menarche, family history of breast cancer, tumor histopathological type, tumor size, lymph node metastasis, distant metastasis, histological grade, estrogen receptor (ER) status, progesterone receptor (PR) status and human epidermal growth factor receptor 2 (HER-2) status at the time of diagnosis were analyzed. RESULTS: Compared to patients residing in low-pollution areas, patients living in high-pollution areas demonstrated a younger age at menarche (p<0.001), a greater family history of breast cancer (p = 0.034) and more invasive cancers (p = 0.028) with higher tumor grades (p = 0.028) and estrogen receptor (ER)-positive status (p = 0.022). Differences in tumor grade were only found in ER-positive cases. CONCLUSIONS: Our findings and clinical data indicate that long-term air pollution exposure may contribute to the development of breast cancer by playing the role of a xenoestrogen, and also provides new insight into the association between air pollution and the morbidity and mortality of breast cancer patients. Furthermore, it is urgently necessary to study the association between air pollution and breast cancer to improve the living quality and health of females, and applicable public health strategies may need to be established or modified as soon as possible. PMID- 24146898 TI - The characteristics of extreme erosion events in a small mountainous watershed. AB - A large amount of soil loss is caused by a small number of extreme events that are mainly responsible for the time compression of geomorphic processes. The aim of this study was to analyze suspended sediment transport during extreme erosion events in a mountainous watershed. Field measurements were conducted in Wangjiaqiao, a small agricultural watershed (16.7 km(2)) in the Three Gorges Area (TGA) of China. Continuous records were used to analyze suspended sediment transport regimes and assess the sediment loads of 205 rainfall-runoff events during a period of 16 hydrological years (1989-2004). Extreme events were defined as the largest events, ranked in order of their absolute magnitude (representing the 95(th) percentile). Ten extreme erosion events from 205 erosion events, representing 83.8% of the total suspended sediment load, were selected for study. The results of canonical discriminant analysis indicated that extreme erosion events are characterized by high maximum flood-suspended sediment concentrations, high runoff coefficients, and high flood peak discharge, which could possibly be explained by the transport of deposited sediment within the stream bed during previous events or bank collapses. PMID- 24146899 TI - Preterm birth, age at school entry and educational performance. AB - OBJECTIVE: To investigate if the lack of gestational age correction may explain some of the school failure seen in ex-preterm infants. DESIGN: A cohort study based on the Avon Longitudinal Study of Parents and Children (ALSPAC). The primary outcome was a low Key Stage 1 score (KS1) score at age 7 or having special educational needs (SEN). Exposure groups were defined as preterm (<37 weeks gestation, n = 722) or term (37-42 weeks, n = 11,268). Conditional regression models were derived, matching preterm to term infants on date of birth (DOB), expected date of delivery (EDD) or expected date of delivery and year of school entry. Multiple imputation was used to account for missing covariate data. RESULTS: When matching for DOB, infants born preterm had an increased odds of a low KS1 score (OR 1.73 (1.45-2.06)) and this association persisted after adjusting for potential confounders (OR 1.57 (1.25-1.97)). The association persisted in the analysis matching for EDD (fully adjusted OR 1.53 (1.21-1.94)) but attenuated substantially after additionally restricting to those infants who entered school at the same time as the control infants (fully adjusted OR 1.25 (0.98-1.60)). A compatible reduction in the population attributable risk fraction was seen from 4.60% to 2.12%, and year of school entry appeared to modify the association between gestational age and the risk of a poor KS1 score (p = 0.029). CONCLUSIONS: This study provides evidence that the school year placement and assessment of ex-preterm infants based on their actual birthday (rather than their EDD) may increase their risk of learning difficulties with corresponding school failure. PMID- 24146900 TI - Mitochondrial sequence variation in African-American primary open-angle glaucoma patients. AB - Primary open-angle glaucoma (POAG) is a major cause of blindness and results from irreversible retinal ganglion cell damage and optic nerve degeneration. In the United States, POAG is most prevalent in African-Americans. Mitochondrial genetics and dysfunction have been implicated in POAG, and potentially pathogenic sequence variations, in particular novel transversional base substitutions, are reportedly common in mitochondrial genomes (mtDNA) from POAG patient blood. The purpose of this study was to ascertain the spectrum of sequence variation in mtDNA from African-American POAG patients and determine whether novel nonsynonymous, transversional or other potentially pathogenic sequence variations are observed more commonly in POAG cases than controls. mtDNA from African American POAG cases (n = 22) and age-matched controls (n = 22) was analyzed by deep sequencing of a single 16,487 base pair PCR amplicon by Ion Torrent, and candidate novel variants were validated by Sanger sequencing. Sequence variants were classified and interpreted using the MITOMAP compendium of polymorphisms. 99.8% of the observed variations had been previously reported. The ratio of novel variants to POAG cases was 7-fold lower than a prior estimate. Novel mtDNA variants were present in 3 of 22 cases, novel nonsynonymous changes in 1 of 22 cases and novel transversions in 0 of 22 cases; these proportions are significantly lower (p<.0005, p<.0004, p<.0001) than estimated previously for POAG, and did not differ significantly from controls. Although it is possible that mitochondrial genetics play a role in African-Americans' high susceptibility to POAG, it is unlikely that any mitochondrial respiratory dysfunction is due to an abnormally high incidence of novel mutations that can be detected in mtDNA from peripheral blood. PMID- 24146901 TI - PCG-cut: graph driven segmentation of the prostate central gland. AB - Prostate cancer is the most abundant cancer in men, with over 200,000 expected new cases and around 28,000 deaths in 2012 in the US alone. In this study, the segmentation results for the prostate central gland (PCG) in MR scans are presented. The aim of this research study is to apply a graph-based algorithm to automated segmentation (i.e. delineation) of organ limits for the prostate central gland. The ultimate goal is to apply automated segmentation approach to facilitate efficient MR-guided biopsy and radiation treatment planning. The automated segmentation algorithm used is graph-driven based on a spherical template. Therefore, rays are sent through the surface points of a polyhedron to sample the graph's nodes. After graph construction--which only requires the center of the polyhedron defined by the user and located inside the prostate center gland--the minimal cost closed set on the graph is computed via a polynomial time s-t-cut, which results in the segmentation of the prostate center gland's boundaries and volume. The algorithm has been realized as a C++ module within the medical research platform MeVisLab and the ground truth of the central gland boundaries were manually extracted by clinical experts (interventional radiologists) with several years of experience in prostate treatment. For evaluation the automated segmentations of the proposed scheme have been compared with the manual segmentations, yielding an average Dice Similarity Coefficient (DSC) of 78.94 +/- 10.85%. PMID- 24146902 TI - Neuroimaging evidence of major morpho-anatomical and functional abnormalities in the BTBR T+TF/J mouse model of autism. AB - BTBR T+tf/J (BTBR) mice display prominent behavioural deficits analogous to the defining symptoms of autism, a feature that has prompted a widespread use of the model in preclinical autism research. Because neuro-behavioural traits are described with respect to reference populations, multiple investigators have examined and described the behaviour of BTBR mice against that exhibited by C57BL/6J (B6), a mouse line characterised by high sociability and low self grooming. In an attempt to probe the translational relevance of this comparison for autism research, we used Magnetic Resonance Imaging (MRI) to map in both strain multiple morpho-anatomical and functional neuroimaging readouts that have been extensively used in patient populations. Diffusion tensor tractography confirmed previous reports of callosal agenesis and lack of hippocampal commissure in BTBR mice, and revealed a concomitant rostro-caudal reorganisation of major cortical white matter bundles. Intact inter-hemispheric tracts were found in the anterior commissure, ventro-medial thalamus, and in a strain specific white matter formation located above the third ventricle. BTBR also exhibited decreased fronto-cortical, occipital and thalamic gray matter volume and widespread reductions in cortical thickness with respect to control B6 mice. Foci of increased gray matter volume and thickness were observed in the medial prefrontal and insular cortex. Mapping of resting-state brain activity using cerebral blood volume weighted fMRI revealed reduced cortico-thalamic function together with foci of increased activity in the hypothalamus and dorsal hippocampus of BTBR mice. Collectively, our results show pronounced functional and structural abnormalities in the brain of BTBR mice with respect to control B6 mice. The large and widespread white and gray matter abnormalities observed do not appear to be representative of the neuroanatomical alterations typically observed in autistic patients. The presence of reduced fronto-cortical metabolism is of potential translational relevance, as this feature recapitulates previously reported clinical observations. PMID- 24146903 TI - 2, 6-Dichlorobenzonitrile causes multiple effects on pollen tube growth beyond altering cellulose synthesis in Pinus bungeana Zucc. AB - Cellulose is an important component of cell wall, yet its location and function in pollen tubes remain speculative. In this paper, we studied the role of cellulose synthesis in pollen tube elongation in Pinus bungeana Zucc. by using the specific inhibitor, 2, 6-dichlorobenzonitrile (DCB). In the presence of DCB, the growth rate and morphology of pollen tubes were distinctly changed. The organization of cytoskeleton and vesicle trafficking were also disturbed. Ultrastructure of pollen tubes treated with DCB was characterized by the loose tube wall and damaged organelles. DCB treatment induced distinct changes in tube wall components. Fluorescence labeling results showed that callose, and acidic pectin accumulated in the tip regions, whereas there was less cellulose when treated with DCB. These results were confirmed by FTIR microspectroscopic analysis. In summary, our findings showed that inhibition of cellulose synthesis by DCB affected the organization of cytoskeleton and vesicle trafficking in pollen tubes, and induced changes in the tube wall chemical composition in a dose dependent manner. These results confirm that cellulose is involved in the establishment of growth direction of pollen tubes, and plays important role in the cell wall construction during pollen tube development despite its lower quantity. PMID- 24146904 TI - Multi-dimensional prioritization of dental caries candidate genes and its enriched dense network modules. AB - A number of genetic studies have suggested numerous susceptibility genes for dental caries over the past decade with few definite conclusions. The rapid accumulation of relevant information, along with the complex architecture of the disease, provides a challenging but also unique opportunity to review and integrate the heterogeneous data for follow-up validation and exploration. In this study, we collected and curated candidate genes from four major categories: association studies, linkage scans, gene expression analyses, and literature mining. Candidate genes were prioritized according to the magnitude of evidence related to dental caries. We then searched for dense modules enriched with the prioritized candidate genes through their protein-protein interactions (PPIs). We identified 23 modules comprising of 53 genes. Functional analyses of these 53 genes revealed three major clusters: cytokine network relevant genes, matrix metalloproteinases (MMPs) family, and transforming growth factor-beta (TGF-beta) family, all of which have been previously implicated to play important roles in tooth development and carious lesions. Through our extensive data collection and an integrative application of gene prioritization and PPI network analyses, we built a dental caries-specific sub-network for the first time. Our study provided insights into the molecular mechanisms underlying dental caries. The framework we proposed in this work can be applied to other complex diseases. PMID- 24146905 TI - Autocrine extra-pancreatic trypsin 3 secretion promotes cell proliferation and survival in esophageal adenocarcinoma. AB - Trypsin or Tumor associated trypsin (TAT) activation of Protease-activated receptor 2 (PAR-2) promotes tumor cell proliferation in gastrointestinal cancers. The role of the trypsin/PAR-2 network in esophageal adenocarcinoma (EA) development has not yet been investigated. The aim of this study is to investigate the role of trypsin/PAR-2 activation in EA tumorogenesis and therapy. We found that esophageal adenocarcinoma cells (EACs) and Barrett's Metaplasia (BART) expressed high levels of type 3 extra-pancreatic trypsinogen (PRSS3), a novel type of TAT. Activity of secreted trypsin was detected in cultured media from EA OE19 and OE33 cultures but not from BART culture. Surface PAR-2 expression in BART and EACs was confirmed by both flow cytometry and immunofluorescence. Trypsin induced cell proliferation (~ 2 fold; P<0.01) in all tested cell lines at a concentration of 10 nM. Inhibition of PAR-2 activity in EACs via the PAR-2 antagonist ENMD (500 uM), anti-PAR2 antibody SAM-11 (2 ug/ml), or siRNA PAR-2 knockdown, reduced cell proliferation and increased apoptosis by up to 4 fold (P<0.01). Trypsin stimulation led to phosphorylation of ERK1/2, suggesting involvement of MAPK pathway in PAR-2 signal transduction. Inhibition of PAR-2 activation or siRNA PAR-2 knockdown in EACs prior to treatment with 5 FU reduced cell viability of EACs by an additional 30% (P<0.01) compared to chemotherapy alone. Our data suggest that extra-pancreatic trypsinogen 3 is produced by EACs and activates PAR-2 in an autocrine manner. PAR-2 activation increases cancer cell proliferation, and promotes cancer cell survival. Targeting the trypsin activated PAR-2 pathway in conjunction with current chemotherapeutic agents may be a viable therapeutic strategy in EA. PMID- 24146906 TI - The mechanism of calcium-induced inhibition of muscle fructose 1,6-bisphosphatase and destabilization of glyconeogenic complex. AB - The mechanism by which calcium inhibits the activity of muscle fructose 1,6 bisphosphatase (FBPase) and destabilizes its interaction with aldolase, regulating glycogen synthesis from non-carbohydrates in skeletal muscle is poorly understood. In the current paper, we demonstrate evidence that Ca(2+) affects conformation of the catalytic loop 52-72 of muscle FBPase and inhibits its activity by competing with activatory divalent cations, e.g. Mg(2+) and Zn(2+). We also propose the molecular mechanism of Ca(2+)-induced destabilization of the aldolase-FBPase interaction, showing that aldolase associates with FBPase in its active form, i.e. with loop 52-72 in the engaged conformation, while Ca(2+) stabilizes the disengaged-like form of the loop. PMID- 24146907 TI - Homo economicus belief inhibits trust. AB - As a foundational concept in economics, the homo economicus assumption regards humans as rational and self-interested actors. In contrast, trust requires individuals to believe partners' benevolence and unselfishness. Thus, the homo economicus belief may inhibit trust. The present three experiments demonstrated that the direct exposure to homo economicus belief can weaken trust. And economic situations like profit calculation can also activate individuals' homo economicus belief and inhibit their trust. It seems that people's increasing homo economicus belief may serve as one cause of the worldwide decline of trust. PMID- 24146908 TI - Chimpanzee alarm call production meets key criteria for intentionality. AB - Determining the intentionality of primate communication is critical to understanding the evolution of human language. Although intentional signalling has been claimed for some great ape gestural signals, comparable evidence is currently lacking for their vocal signals. We presented wild chimpanzees with a python model and found that two of three alarm call types exhibited characteristics previously used to argue for intentionality in gestural communication. These alarm calls were: (i) socially directed and given to the arrival of friends, (ii) associated with visual monitoring of the audience and gaze alternations, and (iii) goal directed, as calling only stopped when recipients were safe from the predator. Our results demonstrate that certain vocalisations of our closest living relatives qualify as intentional signals, in a directly comparable way to many great ape gestures. We conclude that our results undermine a central argument of gestural theories of language evolution and instead support a multimodal origin of human language. PMID- 24146909 TI - The global anaerobic regulator Anr, is involved in cell attachment and aggregation influencing the first stages of biofilm development in Pseudomonas extremaustralis. AB - Pseudomonas extremaustralis is a versatile Antarctic bacterium, able to grow under microaerobic and anaerobic conditions and is related to several non pathogenic Pseudomonads. Here we report on the role of the global anaerobic regulator Anr, in the early steps of P. extremaustralis biofilm development. We found that the anr mutant was reduced in its ability to attach, to form aggregates and to display twitching motility but presented higher swimming motility than the wild type. In addition, microscopy revealed that the wild type biofilm contained more biomass and was thicker, but were less rough than that of the anr mutant. In silico analysis of the P. extremaustralis genome for Anr-like binding sites led to the identification of two biofilm-related genes as potential targets of this regulator. When measured using Quantitative Real Time PCR, we found that the anr mutant expressed lower levels of pilG, which encodes a component of Type IV pili and has been previously implicated in cellular adhesion. Levels of morA, involved in signal transduction and flagella development, were also lower in the mutant. Our data suggest that under low oxygen conditions, such as those encountered in biofilms, Anr differentially regulates aggregation and motility thus affecting the first stages of biofilm formation. PMID- 24146910 TI - Overexpression of N-Myc downstream-regulated gene 2 (NDRG2) regulates the proliferation and invasion of bladder cancer cells in vitro and in vivo. AB - N-Myc downstream-regulated gene 2 (NDRG2) is a candidate tumor suppressor gene, which plays an important role in controlling tumor growth. The aim of this study was to investigate the expression of NDRG2 gene in bladder cancer (BC) tissues and several bladder cancer cell lines, and to seek its clinical and pathological significance. Ninety-seven bladder carcinoma and 15 normal bladder tissue sections were analyzed retrospectively with immunohistochemistry. The human bladder cancer cell line T24 was infected with LEN-NDRG2 or LEN-LacZ. The effects of NDRG2 overexpression on T24 cells and T24 nude mouse xenografts were measured via cell growth curves, tumor growth curves, flow cytometric analysis, western blot and Transwell assay. NDRG2 was highly expressed in normal bladder tissue, but absent or rarely expressed in cacinomatous tissues (chi(2)=8.761, p < 0.01). The NDRG2 level was negatively correlated with tumor grade and pathologic stage(r=-0.248, p < 0.05), as well as increased c-myc level (r=-0.454, p< 0.001). The expression of NDRG2 was low in the three BC cell lines. T24 cells infected with LEN-NDRG2 showed inhibition of proliferation both in vitro and in vivo, and NDRG2 overexpression can inhibit tumor growth and invasion in vitro. PMID- 24146911 TI - Transcriptional analysis of aggressiveness and heterogeneity across grades of astrocytomas. AB - Astrocytoma is the most common glioma, accounting for half of all primary brain and spinal cord tumors. Late detection and the aggressive nature of high-grade astrocytomas contribute to high mortality rates. Though many studies identify candidate biomarkers using high-throughput transcriptomic profiling to stratify grades and subtypes, few have resulted in clinically actionable results. This shortcoming can be attributed, in part, to pronounced lab effects that reduce signature robustness and varied individual gene expression among patients with the same tumor. We addressed these issues by uniformly preprocessing publicly available transcriptomic data, comprising 306 tumor samples from three astrocytoma grades (Grade 2, 3, and 4) and 30 non-tumor samples (normal brain as control tissues). Utilizing Differential Rank Conservation (DIRAC), a network based classification approach, we examined the global and individual patterns of network regulation across tumor grades. Additionally, we applied gene-based approaches to identify genes whose expression changed consistently with increasing tumor grade and evaluated their robustness across multiple studies using statistical sampling. Applying DIRAC, we observed a global trend of greater network dysregulation with increasing tumor aggressiveness. Individual networks displaying greater differences in regulation between adjacent grades play well known roles in calcium/PKC, EGF, and transcription signaling. Interestingly, many of the 90 individual genes found to monotonically increase or decrease with astrocytoma grade are implicated in cancer-affected processes such as calcium signaling, mitochondrial metabolism, and apoptosis. The fact that specific genes monotonically increase or decrease with increasing astrocytoma grade may reflect shared oncogenic mechanisms among phenotypically similar tumors. This work presents statistically significant results that enable better characterization of different human astrocytoma grades and hopefully can contribute towards improvements in diagnosis and therapy choices. Our results also identify a number of testable hypotheses relating to astrocytoma etiology that may prove helpful in developing much-needed biomarkers for earlier disease detection. PMID- 24146912 TI - Organization and biology of the porcine serum amyloid A (SAA) gene cluster: isoform specific responses to bacterial infection. AB - Serum amyloid A (SAA) is a prominent acute phase protein. Although its biological functions are debated, the wide species distribution of highly homologous SAA proteins and their uniform behavior in response to injury or inflammation in itself suggests a significant role for this protein. The pig is increasingly being used as a model for the study of inflammatory reactions, yet only little is known about how specific SAA genes are regulated in the pig during acute phase responses and other responses induced by pro-inflammatory host mediators. We designed SAA gene specific primers and quantified the gene expression of porcine SAA1, SAA2, SAA3, and SAA4 by reverse transcriptase quantitative polymerase chain reaction (RT-qPCR) in liver, spleen, and lung tissue from pigs experimentally infected with the Gram-negative swine specific bacterium Actinobacillus pleuropneumoniae, as well as from pigs experimentally infected with the Gram positive bacterium Staphylococcus aureus. Our results show that: 1) SAA1 may be a pseudogene in pigs; 2) we were able to detect two previously uncharacterized SAA transcripts, namely SAA2 and SAA4, of which the SAA2 transcript is primarily induced in the liver during acute infection and presumably contributes to circulating SAA in pigs; 3) Porcine SAA3 transcription is induced both hepatically and extrahepatically during acute infection, and may be correlated to local organ affection; 4) Hepatic transcription of SAA4 is markedly induced in pigs infected with A. pleuropneumoniae, but only weakly in pigs infected with S. aureus. These results for the first time establish the infection response patterns of the four porcine SAA genes which will be of importance for the use of the pig as a model for human inflammatory responses, e.g. within sepsis, cancer, and obesity research. PMID- 24146913 TI - Is the transport of a gadolinium-based contrast agent decreased in a degenerated or aged disc? A post contrast MRI study. AB - A post contrast magnetic resonance imaging study has been performed in a wide population of low back pain patients to investigate which radiological and phenotypic characteristics influence the penetration of the contrast agent in lumbar discs in vivo. 37 patients affected by different pathologies (disc herniation, spondylolisthesis, foraminal stenosis, central canal stenosis) were enrolled in the study. The selected population included 26 male and 11 female subjects, with a mean age of 42.4 +/- 9.3 years (range 18-60). Magnetic resonance images of the lumbar spine were obtained with a 1.5 T scanner (Avanto, Siemens, Erlangen, Germany) with a phased-array back coil. A paramagnetic non-ionic contrast agent was injected with a dose of 0.4 ml/kg. T1-weighted magnetic resonance images were subsequently acquired at 5 time points, 5 and 10 minutes, 2, 4 and 6 hours after injection. Endplates presented clear enhancement already 5 minutes after injection, and showed an increase in the next 2 hours followed by a decrease. At 5 and 10 minutes, virtually no contrast medium was present inside the intervertebral disc; afterwards, enhancement significantly increased. Highly degenerated discs showed higher enhancement in comparison with low and medium degenerated discs. Discs classified as Pfirrmann 5 showed a statistically significant higher enhancement than Pfirrmann 1, 2 and 3 at all time points but the first one, possibly due to vascularization. Disc height collapse and Modic changes significantly increased enhancement. Presence of endplate defects did not show any significant influence on post contrast enhancement, but the lack of a clear classification of endplate defects as seen on magnetic resonance scans may be shadowing some effects. In conclusion, disc height, high level of degeneration and presence of Modic changes are factors which increase post contrast enhancement in the intervertebral disc. The effect of age could not be demonstrated. PMID- 24146914 TI - Biochemical and molecular characterization of a serine keratinase from Brevibacillus brevis US575 with promising keratin-biodegradation and hide dehairing activities. AB - Dehairing is one of the highly polluting operations in the leather industry. The conventional lime-sulfide process used for dehairing produces large amounts of sulfide, which poses serious toxicity and disposal problems. This operation also involves hair destruction, a process that leads to increased chemical oxygen demand (COD), biological oxygen demand (BOD), and total suspended solid (TSS) loads in the effluent. With these concerns in mind, enzyme-assisted dehairing has often been proposed as an alternative method. The main enzyme preparations so far used involved keratinases. The present paper reports on the purification of an extracellular keratinase (KERUS) newly isolated from Brevibacillus brevis strain US575. Matrix assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOF/MS) analysis revealed that the purified enzyme was a monomer with a molecular mass of 29121.11 Da. The sequence of the 27 N-terminal residues of KERUS showed high homology with those of Bacillus keratinases. Optimal activity was achieved at pH 8 and 40 degrees C. Its thermoactivity and thermostability were upgraded in the presence of 5 mM Ca(2+). The enzyme was completely inhibited by phenylmethanesulfonyl fluoride (PMSF) and diiodopropyl fluorophosphates (DFP), which suggests that it belongs to the serine protease family. KERUS displayed higher levels of hydrolysis, substrate specificity, and catalytic efficiency than NUE 12 MG and KOROPON(r) MK EG keratinases. The enzyme also exhibited powerful keratinolytic activity that made it able to accomplish the entire feather-biodegradation process on its own. The kerUS gene encoding KERUS was cloned, sequenced, and expressed in Escherichia coli. The biochemical properties of the extracellular purified recombinant enzyme (rKERUS) were similar to those of native KERUS. Overall, the findings provide strong support for the potential candidacy of this enzyme as an effective and eco-friendly alternative to the conventional chemicals used for the dehairing of rabbit, goat, sheep and bovine hides in the leather processing industry. PMID- 24146915 TI - T2* "susceptibility vessel sign" demonstrates clot location and length in acute ischemic stroke. AB - OBJECTIVES: The aim of our study was to evaluate, in acute ischemic stroke patients, the diagnostic accuracy of the MRI susceptibility vessel sign (SVS) against catheter angiography (DSA) for the detection of the clot and its value in predicting clot location and length. MATERIALS AND METHODS: We identified consecutive patients (2006-2012) admitted to our center, where 1.5 T MRI is systematically implemented as first-line diagnostic work-up, with: (1) pre treatment 6-mm-thick multislice 2D T2* sequence; (2) delay from MRI-to-DSA <3 hrs; (3) no fibrinolysis between MRI and DSA. The location and length of SVS on T2* was independently assessed by three readers, and compared per patient, per artery and per segment, to DSA findings, obtained by two different readers. Clot length measured on T2* and DSA were compared using intra-class correlation coefficient (ICC), Bland & Altman test and Passing & Bablok regression analysis. RESULTS: On DSA, a clot was present in 85 patients, in 126 of 1190 (10.6%) arteries and 175 of 1870 (9.4%) segments. Sensitivity of the SVS, as sensed by the used protocol at 1.5 T, was 81.1% (69 of 85 patients) and was higher in anterior (55 of 63, 87.3%), than in posterior circulation stroke (14 of 22, 63.6%, p=0.02). Sensitivity/specificity was 69.8/99.6% (per artery) and 76.6/99.7% (per segment). Positive (PPV) and negative predictive value (NPV) and accuracy were all >94%. Inter- and intra-observer ICC was excellent for clot length as measured on T2* (K >= 0.97) and as measured on DSA (K >= 0.94). Correlation between T2* and DSA for clot length was excellent (ICC: 0.88, 95%CI: 0.81-0.92; Bland & Altman: mean bias of 1.6% [95%CI: -4.7 to 7.8%], Passing & Bablok: 0.91). CONCLUSIONS: SVS is a specific marker of clot location in the anterior and posterior circulation. Clot length greater than 6 mm can be reliably measured on T2*. PMID- 24146916 TI - Four amino acids within a tandem QxVx repeat in a predicted extended alpha-helix of the Smad-binding domain of Sip1 are necessary for binding to activated Smad proteins. AB - The zinc finger transcription factor Smad-interacting protein-1 (Sip1; Zeb2, Zfhx1b) plays an important role during vertebrate embryogenesis in various tissues and differentiating cell types, and during tumorigenesis. Previous biochemical analysis suggests that interactions with several partner proteins, including TGFbeta family receptor-activated Smads, regulate the activities of Sip1 in the nucleus both as a DNA-binding transcriptional repressor and activator. Using a peptide aptamer approach we mapped in Sip1 its Smad-binding domain (SBD), initially defined as a segment of 51 amino acids, to a shorter stretch of 14 amino acids within this SBD. Modelling suggests that this short SBD stretch is part of an extended alpha-helix that may fit the binding to a hydrophobic corridor within the MH2 domain of activated Smads. Four amino acids (two polar Q residues and two non-polar V residues) that form the tandem repeat (QxVx)2 in this 14-residue stretch were found to be crucial for binding to both TGFbeta/Nodal/Activin-Smads and BMP-Smads. A full-length Sip1 with collective mutation of these Q and V residues (to A) no longer binds to Smads, while it retains its binding activity to its cognate bipartite target DNA sequence. This missense mutant Sip1(AxAx)2 provides a new molecular tool to identify SBD (in)dependent target genes in Sip1-controlled TGFbeta and/or BMP (de)regulated cellular, developmental and pathological processes. PMID- 24146917 TI - Time course of optical quality and intraocular scattering after refractive lenticule extraction. AB - PURPOSE: To assess the time course of optical quality and intraocular scattering in relation to visual acuity after femtosecond lenticule extraction (FLEx) for the correction of myopia. METHODS: This study evaluated 36 eyes of 36 patients with spherical equivalents of -4.38+/-1.53 D [mean +/- standard deviation] who underwent FLEx. Before surgery, and 1 week and 1, 3 and 6 months after surgery, we assessed the modulation transfer function (MTF) cutoff frequency, Strehl ratio, objective scattering index (OSI), and OQAS values (OVs), using a double pass instrument. We also investigated the relationship of the OSI with corrected distance visual acuity (CDVA) preoperatively and postoperatively. RESULTS: The mean changes in MTF cutoff frequency, Strehl ratio, OSI, OV100%, OV20%, and OV9% preoperatively and 6 months postoperatively were -5.51 +/- 15.01, -0.03 +/- 0.07, 0.35 +/- 0.83, -0.17 +/- 0.48, -0.14 +/- 0.38, and -0.09 +/- 0.22, respectively. We found no significant preoperative correlation between the OSI and logMAR CDVA (Spearman rank correlation coefficient r = 0.068, p = 0.69), and modest, but significant correlations 1 week and 1, 3, and 6 months postoperatively (r = 0.572, r = 0.562, r = 0.542, r = 0.540, p<0.001, respectively). CONCLUSIONS: FLEx induced a transient decrease in optical quality in association with an increase in intraocular scattering in the early postoperative period, possibly due to mild interface haze formation, but gradually recovered with time. It is suggested that this transient degradation in optical quality related to an increase in the intraocular scattering may result in a slight delay of CDVA recovery in the early postoperative period. PMID- 24146919 TI - Microanatomical and histological features in the long bones of Mosasaurine mosasaurs (Reptilia, Squamata)--implications for aquatic adaptation and growth rates. AB - BACKGROUND: During their evolution in the Late Cretaceous, mosasauroids attained a worldwide distribution, accompanied by a marked increase in body size and open ocean adaptations. This transition from land-dwellers to highly marine-adapted forms is readily apparent not only at the gross anatomic level but also in their inner bone architecture, which underwent profound modifications. METHODOLOGY/PRINCIPAL FINDINGS: The present contribution describes, both qualitatively and quantitatively, the internal organization (microanatomy) and tissue types and characteristics (histology) of propodial and epipodial bones in one lineage of mosasauroids; i.e., the subfamily Mosasaurinae. By using microanatomical and histological data from limb bones in combination with recently acquired knowledge on the inner structure of ribs and vertebrae, and through comparisons with extant squamates and semi-aquatic to fully marine amniotes, we infer possible implications on mosasaurine evolution, aquatic adaptation, growth rates, and basal metabolic rates. Notably, we observe the occurrence of an unusual type of parallel-fibered bone, with large and randomly shaped osteocyte lacunae (otherwise typical of fibrous bone) and particular microanatomical features in Dallasaurus, which displays, rather than a spongious inner organization, bone mass increase in its humeri and a tubular organization in its femora and ribs. CONCLUSIONS/SIGNIFICANCE: The dominance of an unusual type of parallel-fibered bone suggests growth rates and, by extension, basal metabolic rates intermediate between that of the extant leatherback turtle, Dermochelys, and those suggested for plesiosaur and ichthyosaur reptiles. Moreover, the microanatomical features of the relatively primitive genus Dallasaurus differ from those of more derived mosasaurines, indicating an intermediate stage of adaptation for a marine existence. The more complete image of the various microanatomical trends observed in mosasaurine skeletal elements supports the evolutionary convergence between this lineage of secondarily aquatically adapted squamates and cetaceans in the ecological transition from a coastal to a pelagic lifestyle. PMID- 24146918 TI - Blocking KCa3.1 channels increases tumor cell killing by a subpopulation of human natural killer lymphocytes. AB - Natural killer (NK) cells are large granular lymphocytes that participate in both innate and adaptive immune responses against tumors and pathogens. They are also involved in other conditions, including organ rejection, graft-versus-host disease, recurrent spontaneous abortions, and autoimmune diseases such as multiple sclerosis. We demonstrate that human NK cells express the potassium channels Kv1.3 and KCa3.1. Expression of these channels does not vary with expression levels of maturation markers but varies between adherent and non adherent NK cell subpopulations. Upon activation by mitogens or tumor cells, adherent NK (A-NK) cells preferentially up-regulate KCa3.1 and non-adherent (NA NK) cells preferentially up-regulate Kv1.3. Consistent with this different phenotype, A-NK and NA-NK do not display the same sensitivity to the selective KCa3.1 blockers TRAM-34 and NS6180 and to the selective Kv1.3 blockers ShK-186 and PAP-1 in functional assays. Kv1.3 block inhibits the proliferation and degranulation of NA-NK cells with minimal effects on A-NK cells. In contrast, blocking KCa3.1 increases the degranulation and cytotoxicity of A-NK cells, but not of NA-NK cells. TRAM-34, however, does not affect their ability to form conjugates with target tumor cells, to migrate, or to express chemokine receptors. TRAM-34 and NS6180 also increase the proliferation of both A-NK and NA NK cells. This results in a TRAM-34-induced increased ability of A-NK cells to reduce in vivo tumor growth. Taken together, our results suggest that targeting KCa3.1 on NK cells with selective blockers may be beneficial in cancer immunotherapy. PMID- 24146920 TI - Conveying movement in music and prosody. AB - We investigated whether acoustic variation of musical properties can analogically convey descriptive information about an object. Specifically, we tested whether information from the temporal structure in music interacts with perception of a visual image to form an analog perceptual representation as a natural part of music perception. In Experiment 1, listeners heard music with an accelerating or decelerating temporal pattern, and then saw a picture of a still or moving object and decided whether it was animate or inanimate--a task unrelated to the patterning of the music. Object classification was faster when musical motion matched visually depicted motion. In Experiment 2, participants heard spoken sentences that were accompanied by accelerating or decelerating music, and then were presented with a picture of a still or moving object. When motion information in the music matched motion information in the picture, participants were similarly faster to respond. Fast and slow temporal patterns without acceleration and deceleration, however, did not make participants faster when they saw a picture depicting congruent motion information (Experiment 3), suggesting that understanding temporal structure information in music may depend on specific metaphors about motion in music. Taken together, these results suggest that visuo-spatial referential information can be analogically conveyed and represented by music and can be integrated with speech or influence the understanding of speech. PMID- 24146921 TI - Aberrant crossed corticospinal facilitation in muscles distant from a spinal cord injury. AB - Crossed facilitatory interactions in the corticospinal pathway are impaired in humans with chronic incomplete spinal cord injury (SCI). The extent to which crossed facilitation is affected in muscles above and below the injury remains unknown. To address this question we tested 51 patients with neurological injuries between C2-T12 and 17 age-matched healthy controls. Using transcranial magnetic stimulation we elicited motor evoked potentials (MEPs) in the resting first dorsal interosseous, biceps brachii, and tibialis anterior muscles when the contralateral side remained at rest or performed 70% of maximal voluntary contraction (MVC) into index finger abduction, elbow flexion, and ankle dorsiflexion, respectively. By testing MEPs in muscles with motoneurons located at different spinal cord segments we were able to relate the neurological level of injury to be above, at, or below the location of the motoneurons of the muscle tested. We demonstrate that in patients the size of MEPs was increased to a similar extent as in controls in muscles above the injury during 70% of MVC compared to rest. MEPs remained unchanged in muscles at and within 5 segments below the injury during 70% of MVC compared to rest. However, in muscles beyond 5 segments below the injury the size of MEPs increased similar to controls and was aberrantly high, 2-fold above controls, in muscles distant (>15 segments) from the injury. These aberrantly large MEPs were accompanied by larger F-wave amplitudes compared to controls. Thus, our findings support the view that corticospinal degeneration does not spread rostral to the lesion, and highlights the potential of caudal regions distant from an injury to facilitate residual corticospinal output after SCI. PMID- 24146922 TI - Early human speciation, brain expansion and dispersal influenced by African climate pulses. AB - Early human evolution is characterised by pulsed speciation and dispersal events that cannot be explained fully by global or continental paleoclimate records. We propose that the collated record of ephemeral East African Rift System (EARS) lakes could be a proxy for the regional paleoclimate conditions experienced by early hominins. Here we show that the presence of these lakes is associated with low levels of dust deposition in both West African and Mediterranean records, but is not associated with long-term global cooling and aridification of East Africa. Hominin expansion and diversification seem to be associated with climate pulses characterized by the precession-forced appearance and disappearance of deep EARS lakes. The most profound period for hominin evolution occurs at about 1.9 Ma; with the highest recorded diversity of hominin species, the appearance of Homo (sensu stricto) and major dispersal events out of East Africa into Eurasia. During this period, ephemeral deep-freshwater lakes appeared along the whole length of the EARS, fundamentally changing the local environment. The relationship between the local environment and hominin brain expansion is less clear. The major step-wise expansion in brain size around 1.9 Ma when Homo appeared was coeval with the occurrence of ephemeral deep lakes. Subsequent incremental increases in brain size are associated with dry periods with few if any lakes. Plio-Pleistocene East African climate pulses as evinced by the paleo lake records seem, therefore, fundamental to hominin speciation, encephalisation and migration. PMID- 24146923 TI - Dielectrophoresis-based discrimination of bacteria at the strain level based on their surface properties. AB - Insulator-based dielectrophoresis can be used to manipulate biological particles, but has thus far found limited practical applications due to low sensitivity. We present linear sweep three-dimensional insulator-based dielectrophoresis as a considerably more sensitive approach for strain-level discrimination bacteria. In this work, linear sweep three-dimensional insulator-based dielectrophoresis was performed on Pseudomonas aeruginosa PA14 along with six isogenic mutants as well as Streptococcus mitis SF100 and PS344. Strain-level discrimination was achieved between these clinically important pathogens with applied electric fields below 10 V/mm. This low voltage, high sensitivity technique has potential applications in clinical diagnostics as well as microbial physiology research. PMID- 24146924 TI - First evaluation after implementation of a quality control system for the second line drug susceptibility testing of Mycobacterium tuberculosis joint efforts in low and high incidence countries. AB - Three networks/projects involving 27 European countries were established to investigate the quality of second-line drug (SLD) susceptibility testing with conventional and molecular methods. 1. The "Baltic-Nordic TB-Laboratory Network" comprised 11 reference laboratories in the Baltic-Nordic States. They performed SLD testing in the first phase with a panel of 20 Mycobacterium tuberculosis strains. After several laboratories made technical changes a second panel of 10 strains with a higher proportion of resistant strains were tested. Although the concordance for Ofloxacin, Kanamycin, and Capreomycin was consistently high, the largest improvements in performance were achieved for the analysis of Ofloxacin resistant (from 88.9 to 95.0%), and Capreomycin resistant (from 71.0 to 88.9%) strains. 2. Within the FP7 TB PAN-NET project (EU Grant agreement 223681) a quality control panel to standardize the EQA (External Quality Assurance) for first-line drugs (FLD) and SLD testing for phenotypic and molecular methods was established. The strains were characterized by their robustness, unambiguous results when tested, and low proportion of secondary drug resistances. 3. The (European Reference Laboratory Network-TB) ERLN-TB network analyzed four different panels for drug resistance testing using phenotypic and molecular methods; in two rounds in 2010 the 31 participating laboratories began with 5 strains, followed by 10 strains and 6 additional crude DNA extracts in 2011 and 2012 were examined by conventional DST and molecular methods. Overall, we demonstrated the importance of developing inter-laboratory networks to establish quality assurance and improvement of SLD testing of M. tuberculosis. PMID- 24146925 TI - Burkholderia mallei and Burkholderia pseudomallei cluster 1 type VI secretion system gene expression is negatively regulated by iron and zinc. AB - Burkholderia mallei is a facultative intracellular pathogen that causes glanders in humans and animals. Previous studies have demonstrated that the cluster 1 type VI secretion system (T6SS-1) expressed by this organism is essential for virulence in hamsters and is positively regulated by the VirAG two-component system. Recently, we have shown that T6SS-1 gene expression is up-regulated following internalization of this pathogen into phagocytic cells and that this system promotes multinucleated giant cell formation in infected tissue culture monolayers. In the present study, we further investigated the complex regulation of this important virulence factor. To assess T6SS-1 expression, B. mallei strains were cultured in various media conditions and Hcp1 production was analyzed by Western immunoblotting. Transcript levels of several VirAG-regulated genes (bimA, tssA, hcp1 and tssM) were also determined using quantitative real time PCR. Consistent with previous observations, T6SS-1 was not expressed during growth of B. mallei in rich media. Curiously, growth of the organism in minimal media (M9G) or minimal media plus casamino acids (M9CG) facilitated robust expression of T6SS-1 genes whereas growth in minimal media plus tryptone (M9TG) did not. Investigation of this phenomenon confirmed a regulatory role for VirAG in this process. Additionally, T6SS-1 gene expression was significantly down regulated by the addition of iron and zinc to M9CG. Other genes under the control of VirAG did not appear to be as tightly regulated by these divalent metals. Similar results were observed for B. pseudomallei, but not for B. thailandensis. Collectively, our findings indicate that in addition to being positively regulated by VirAG, B. mallei and B. pseudomallei T6SS-1 gene expression is negatively regulated by iron and zinc. PMID- 24146926 TI - Drosophila Dyrk2 plays a role in the development of the visual system. AB - The DYRKs (dual-specificity tyrosine phosphorylation-regulated kinases) are a conserved family of protein kinases that are associated with a number of neurological disorders, but whose biological targets are poorly understood. Drosophila encodes three Dyrks: minibrain/Dyrk1A, DmDyrk2, and DmDyrk3. Here we describe the creation and characterization of a DmDyrk2 null allele, DmDyrk2(1w17) . We provide evidence that the smell impaired allele smi35A(1) , is likely to encode DmDyrk2. We also demonstrate that DmDyrk2 is expressed late in the developing third antennal segment, an anatomical structure associated with smell. In addition, we find that DmDyrk2 is expressed in the morphogenetic furrow of the developing eye, that loss of DmDyrk2 in the eye produced a subtle but measurable defect, and that ectopic DmDyrk2 expression in the eye produced a strong rough eye phenotype characterized by increased secondary, tertiary and bristle interommatidial cells. This phenotype was dependent on DmDyrk2 kinase activity and was only manifest when expressed in post-mitotic non-neuronal progenitors. Together, these data indicate that DmDyrk2 is expressed in developing sensory systems, that it is required for the development of the visual system, and that the eye is a good model to identify DmDyrk2 targets. PMID- 24146927 TI - Increased pro-inflammatory cytokines, C-reactive protein and nerve growth factor expressions in serum of patients with interstitial cystitis/bladder pain syndrome. AB - OBJECTIVE: The etiology and pathogenesis of interstitial cystitis/bladder pain syndrome (IC/BPS) are unclear. Chronic inflammation is considered the main pathology of IC/BPS. This study measured the serum c-reactive protein (CRP), nerve growth factor (NGF) and pro-inflammatory cytokine/chemokine interleukin (IL)-1beta, IL-6, tumor necrosis factor (TNF)-alpha, and IL-8 expression in patients with IC/BPS to elucidate the involvement of systemic inflammation in IC/BPS. METHODS: Serum samples were collected from 30 IC/BPS patients and 26 control subjects. The concentrations of serum nerve growth factor (NGF), IL 1beta, IL-6, TNF-alpha, and IL-8 were quantified using a bead-based, human serum adipokine panel kit. Serum C-reactive protein (CRP) was also assessed. Differences of serum CRP, NGF, IL-1beta, IL-6, TNF-alpha, and IL-8 levels between the IC/BPS patients and controls were compared, and correlations between CRP and pro-inflammatory cytokines and chemokine were also evaluated. RESULTS: The results showed that CRP level (p = 0.031), NGF (p = 0.015) and pro-inflammatory cytokines/chemokine IL-1beta, IL-6, TNF-alpha, and IL-8 levels were significantly higher in the patients with IC/BPS than among controls (all p<0.001). Significant associations were observed between IL-1beta and IL-8 (p<0.001), IL-6 and CRP (p = 0.01), IL-6 and IL-8 (p = 0.02), and IL-6 and TNF-alpha (p = 0.03). CONCLUSION: Increased pro-inflammatory cytokines/chemokine (IL-1beta, IL-6, TNF-alpha, and IL 8) expression in the sera of IC/BPS patients implies not only mast cell activation, but also that other inflammatory mediators play important roles in the pathogenesis of IC/BPS. Thus, for some patients, IC/BPS is considered a chronic inflammatory disease. PMID- 24146928 TI - Using bones to shape stones: MIS 9 bone retouchers at both edges of the Mediterranean Sea. AB - A significant challenge in Prehistory is to understand the mechanisms involved in the behavioural evolution of human groups. The degree of technological and cultural development of prehistoric groups is assessed mainly through stone tools. However, other elements can provide valuable information as well. This paper presents two bone retouchers dated to the Middle Pleistocene MIS 9 used for the shaping of lithic artefacts. Originating from Bolomor Cave (Spain) and Qesem Cave (Israel), these two bone retouchers are among the earliest of the Old World. Although the emergence of such tools might be found in the latest phases of the Acheulean, their widespread use seems to coincide with independently emergent post-Acheulean cultural complexes at both ends of the Mediterranean Sea: the post Acheulean/pre-Mousterian of Western Europe and the Acheulo Yabrudian Cultural Complex of the Levant. Both entities seem to reflect convergent processes that may be viewed in a wider cultural context as reflecting new technology-related behavioural patterns as well as new perceptions in stone tool manufacturing. PMID- 24146929 TI - Impact of article language in multi-language medical journals--a bibliometric analysis of self-citations and impact factor. AB - BACKGROUND: In times of globalization there is an increasing use of English in the medical literature. The aim of this study was to analyze the influence of English-language articles in multi-language medical journals on their international recognition--as measured by a lower rate of self-citations and higher impact factor (IF). METHODS AND FINDINGS: We analyzed publications in multi-language journals in 2008 and 2009 using the Web of Science (WoS) of Thomson Reuters (former Institute of Scientific Information) and PubMed as sources of information. The proportion of English-language articles during the period was compared with both the share of self-citations in the year 2010 and the IF with and without self-citations. Multivariable linear regression analysis was performed to analyze these factors as well as the influence of the journals' countries of origin and of the other language(s) used in publications besides English. We identified 168 multi-language journals that were listed in WoS as well as in PubMed and met our criteria. We found a significant positive correlation of the share of English articles in 2008 and 2009 with the IF calculated without self-citations (Pearson r=0.56, p = <0.0001), a correlation with the overall IF (Pearson r = 0.47, p = <0.0001) and with the cites to years of IF calculation (Pearson r = 0.34, p = <0.0001), and a weak negative correlation with the share of self-citations (Pearson r = -0.2, p = 0.009). The IF without self-citations also correlated with the journal's country of origin- North American journals had a higher IF compared to Middle and South American or European journals. CONCLUSION: Our findings suggest that a larger share of English articles in multi-language medical journals is associated with greater international recognition. Fewer self-citations were found in multi-language journals with a greater share of original articles in English. PMID- 24146930 TI - Hemispheric lateralization of motor thresholds in relation to stuttering. AB - Stuttering is a complex speech disorder. Previous studies indicate a tendency towards elevated motor threshold for the left hemisphere, as measured using transcranial magnetic stimulation (TMS). This may reflect a monohemispheric motor system impairment. The purpose of the study was to investigate the relative side to-side difference (asymmetry) and the absolute levels of motor threshold for the hand area, using TMS in adults who stutter (n = 15) and in controls (n = 15). In accordance with the hypothesis, the groups differed significantly regarding the relative side-to-side difference of finger motor threshold (p = 0.0026), with the stuttering group showing higher motor threshold of the left hemisphere in relation to the right. Also the absolute level of the finger motor threshold for the left hemisphere differed between the groups (p = 0.049). The obtained results, together with previous investigations, provide support for the hypothesis that stuttering tends to be related to left hemisphere motor impairment, and possibly to a dysfunctional state of bilateral speech motor control. PMID- 24146932 TI - Investigation of human albumin-induced circular dichroism in dansylglycine. AB - Induced circular dichroism (ICD), or induced chirality, is a phenomenon caused by the fixation of an achiral substance inside a chiral microenvironment, such as the hydrophobic cavities in proteins. Dansylglycine belongs to a class of dansylated amino acids, which are largely used as fluorescent probes for the characterization of the binding sites in albumin. Here, we investigated the ICD in dansylglycine provoked by its binding to human serum albumin (HSA). We found that the complexation of HSA with dansylglycine resulted in the appearance of an ICD band centred at 346 nm. Using this ICD signal and site-specific ligands of HSA, we confirmed that dansylglycine is a site II ligand. The intensity of the ICD signal was dependent on the temperature and revealed that the complexation between the protein and the ligand was reversible. The induced chirality of dansylglycine was susceptive to the alteration caused by the oxidation of the protein. A comparison was made between hypochlorous acid (HOCl) and hypobromous acid (HOBr), and revealed that site II in the protein is more susceptible to alteration provoked by the latter oxidant. These findings suggest the relevance of the aromatic amino acids in the site II, since HOBr is a more efficient oxidant of these residues in proteins than HOCl. The three-dimensional structure of HSA is pH-dependent, and different conformations have been characterised. We found that HSA in its basic form at pH 9.0, which causes the protein to be less rigid, lost the capacity to bind dansylglycine. At pH 3.5, HSA retained almost all of its capacity for binding to dansylglycine. Since the structure of HSA at pH 3.5 is expanded, separating the domain IIIA from the rest of the molecule, we concluded that this separation did not alter its binding capacity to dansylglycine. PMID- 24146931 TI - Overexpression of the transcriptional repressor complex BCL-6/BCoR leads to nuclear aggregates distinct from classical aggresomes. AB - Nuclear inclusions of aggregated proteins have primarily been characterized for molecules with aberrant poly-glutamine repeats and for mutated or structurally altered proteins. They were termed "nuclear aggresomes" and misfolding was shown to promote association with molecular chaperones and proteasomes. Here, we report that two components of a transcriptional repressor complex (BCL-6 and BCoR) of wildtype amino acid sequence can independently or jointly induce the formation of nuclear aggregates when overexpressed. The observation that the majority of cells rapidly downregulate BCL-6/BCoR levels, supports the notion that expression of these proteins is under tight control. The inclusions occur when BCL-6/BCoR expression exceeds 150-fold of endogenous levels. They preferentially develop in the nucleus by a gradual increase in aggregate size to form large, spheroid structures which are not associated with heat shock proteins or marked by ubiquitin. In contrast, we find the close association of BCL-6/BCoR inclusions with PML bodies and a reduction in aggregation upon the concomitant overexpression of histone deacetylases or heat shock protein 70. In summary, our data offer a perspective on nuclear aggregates distinct from classical "nuclear aggresomes": Large complexes of spheroid structure can evolve in the nucleus without being marked by the cellular machinery for protein refolding and degradation. However, nuclear proteostasis can be restored by balancing the levels of chaperones. PMID- 24146933 TI - Zidovudine (AZT) and hepatic lipid accumulation: implication of inflammation, oxidative and endoplasmic reticulum stress mediators. AB - The clinical effectiveness of Zidovudine (AZT) is constrained due to its side effects including hepatic steatosis and toxicity. However, the mechanism(s) of hepatic lipid accumulation in AZT-treated individuals is unknown. We hypothesized that AZT-mediated oxidative and endoplasmic reticulum (ER) stress may play a role in the AZT-induced hepatic lipid accumulation. AZT treatment of C57BL/6J female mice (400 mg/day/kg body weight, i.p.) for 10 consecutive days significantly increased hepatic triglyceride levels and inflammation. Markers of oxidative stress such as protein oxidation, nitration, glycation and lipid peroxidation were significantly higher in the AZT-treated mice compared to vehicle controls. Further, the levels of ER stress marker proteins like GRP78, p-PERK, and p eIF2alpha were significantly elevated in AZT-treated mice. The level of nuclear SREBP-1c, a transcription factor involved in fat synthesis, was increased while significantly decreased protein levels of phospho-acetyl-CoA carboxylase, phospho AMP kinase and PPARalpha as well as inactivation of 3-keto-acyl-CoA thiolase in the mitochondrial fatty acid beta-oxidation pathway were observed in AZT-exposed mice compared to those in control animals. Collectively, these data suggest that elevated oxidative and ER stress plays a key role, at least partially, in lipid accumulation, inflammation and hepatotoxicity in AZT-treated mice. PMID- 24146934 TI - Toothpicking and periodontal disease in a Neanderthal specimen from Cova Forada site (Valencia, Spain). AB - We present a Neanderthal maxilla (CF-1) from Cova Forada site (Oliva, Valencia, Spain) with periodontal disease and evidence of attempts to alleviate pain with the use of a toothpick. Two interproximal grooves have been found on the distal surfaces of the upper left Pm(3) and M(1) of CF-1 maxilla. The location, morphology and size of the grooves coincide with other interproximal grooves found on the teeth of other fossil specimens. Heavy dental wear and periodontal disease would have caused the Cova Forada Neanderthal specimen pain and discomfort, which the individual attempted to mitigate using some kind of dental probe. PMID- 24146935 TI - Effects of visual cues of object density on perception and anticipatory control of dexterous manipulation. AB - Anticipatory force planning during grasping is based on visual cues about the object's physical properties and sensorimotor memories of previous actions with grasped objects. Vision can be used to estimate object mass based on the object size to identify and recall sensorimotor memories of previously manipulated objects. It is not known whether subjects can use density cues to identify the object's center of mass (CM) and create compensatory moments in an anticipatory fashion during initial object lifts to prevent tilt. We asked subjects (n = 8) to estimate CM location of visually symmetric objects of uniform densities (plastic or brass, symmetric CM) and non-uniform densities (mixture of plastic and brass, asymmetric CM). We then asked whether subjects can use density cues to scale fingertip forces when lifting the visually symmetric objects of uniform and non uniform densities. Subjects were able to accurately estimate an object's center of mass based on visual density cues. When the mass distribution was uniform, subjects could scale their fingertip forces in an anticipatory fashion based on the estimation. However, despite their ability to explicitly estimate CM location when object density was non-uniform, subjects were unable to scale their fingertip forces to create a compensatory moment and prevent tilt on initial lifts. Hefting object parts in the hand before the experiment did not affect this ability. This suggests a dichotomy between the ability to accurately identify the object's CM location for objects with non-uniform density cues and the ability to utilize this information to correctly scale their fingertip forces. These results are discussed in the context of possible neural mechanisms underlying sensorimotor integration linking visual cues and anticipatory control of grasping. PMID- 24146936 TI - Necrotizing enterocolitis (NEC) and the risk of intestinal stricture: the value of C-reactive protein. AB - Necrotizing enterocolitis (NEC) is a severe complication frequently seen during the neonatal period associated with high mortality rate and severe and prolonged morbidity including Post-NEC intestinal stricture. The aim of this study is to define the incidence and risk factors of these post-NEC strictures, in order to better orient their medicosurgical care. Sixty cases of NEC were retrospectively reviewed from a single tertiary center with identical treatment protocols throughout the period under study, including systematic X-ray contrast study. This study reports a high rate of post-NEC intestinal stricture (n = 27/48; 57% of survivors), either in cases treated surgically (91%) and after the medical treatment of NEC (47%). A colonic localization of the strictures was more frequent in medically-treated patients than in those with NEC treated surgically (87% vs. 50%). The length of the strictures was significantly shorter in case of NEC treated medically. No deaths were attributable to the presence of post-NEC stricture. The mean hospitalization time in NICU and the median age at discontinuation of parenteral nutrition were longer in the group with stricture, but this difference was not significant. The median age at discharge was significantly higher in the group with stricture (p = 0.02). The occurrence of post-NEC stricture was significantly associated with the presence of parietal signs of inflammation and thrombopenia (<100 000 platelets/mm(3)). The mean maximum CRP concentration during acute phase was significantly higher in infants who developed stricture (p<0.001), as was the mean duration of the elevation of CRP levels (p<0.001). The negative predictive value of CRP levels continually <10 mg/dL for the appearance of stricture was 100% in our study. In conclusion, this retrospective and monocentric study demonstrates the correlation between the intensity of the inflammatory syndrome and the risk of secondary intestinal stricture, when systematic contrast study is performed following NEC. PMID- 24146938 TI - The scaling relationships between leaf mass and leaf area of vascular plant species change with altitude. AB - The scaling relationship between leaf dry mass and leaf surface area has important implications for understanding the ability of plants to harvest sunlight and grow. Whether and how the scaling relationships vary across environmental gradients are poorly understood. We analyzed the scaling relationships between leaf mass and leaf area of 121 vascular plant species along an altitudinal gradient in a subtropical monsoon forest. The slopes increased significantly with altitude, it varied from less than 1 at low altitude to more than 1 at high altitude. This means that plants growing at high altitude allocate proportionately more biomass to support tissues in larger leaves and less in smaller leaves, whereas the reverse is true at low altitude. This pattern can be explained by different leaf strategies in response to environmental pressure and constrains. PMID- 24146937 TI - Long-term potentiation promotes proliferation/survival and neuronal differentiation of neural stem/progenitor cells. AB - Neural stem cell (NSC) replacement therapy is considered a promising cell replacement therapy for various neurodegenerative diseases. However, the low rate of NSC survival and neurogenesis currently limits its clinical potential. Here, we examined if hippocampal long-term potentiation (LTP), one of the most well characterized forms of synaptic plasticity, promotes neurogenesis by facilitating proliferation/survival and neuronal differentiation of NSCs. We found that the induction of hippocampal LTP significantly facilitates proliferation/survival and neuronal differentiation of both endogenous neural progenitor cells (NPCs) and exogenously transplanted NSCs in the hippocampus in rats. These effects were eliminated by preventing LTP induction by pharmacological blockade of the N methyl-D-aspartate glutamate receptor (NMDAR) via systemic application of the receptor antagonist, 3-[(R)-2-carboxypiperazin-4-yl]-propyl-1-phosphonic acid (CPP). Moreover, using a NPC-neuron co-culture system, we were able to demonstrate that the LTP-promoted NPC neurogenesis is at least in part mediated by a LTP-increased neuronal release of brain-derived neurotrophic factor (BDNF) and its consequent activation of tropomysosin receptor kinase B (TrkB) receptors on NSCs. Our results indicate that LTP promotes the neurogenesis of both endogenous and exogenously transplanted NSCs in the brain. The study suggests that pre-conditioning of the host brain receiving area with a LTP-inducing deep brain stimulation protocol prior to NSC transplantation may increase the likelihood of success of using NSC transplantation as an effective cell therapy for various neurodegenerative diseases. PMID- 24146939 TI - Inhibition of influenza A virus infection in vitro by peptides designed in silico. AB - Influenza A viruses are enveloped, segmented negative single-stranded RNA viruses, capable of causing severe human respiratory infections. Currently, only two types of drugs are used to treat influenza A infections, the M2 H(+) ion channel blockers (amantadine and rimantadine) and the neuraminidase inhibitors (NAI) (oseltamivir and zanamivir). Moreover, the emergence of drug-resistant influenza A virus strains has emphasized the need to develop new antiviral agents to complement or replace the existing drugs. Influenza A virus has on the surface a glycoprotein named hemagglutinin (HA) which due to its important role in the initial stage of infection: receptor binding and fusion activities of viral and endosomal membranes, is a potential target for new antiviral drugs. In this work we designed nine peptides using several bioinformatics tools. These peptides were derived from the HA1 and HA2 subunits of influenza A HA with the aim to inhibit influenza A virus infection. The peptides were synthetized and their antiviral activity was tested in vitro against several influenza A viral strains: Puerto Rico/916/34 (H1N1), (H1N1)pdm09, swine (H1N1) and avian (H5N2). We found these peptides were able to inhibit the influenza A viral strains tested, without showing any cytotoxic effect. By docking studies we found evidence that all the peptides were capable to bind to the viral HA, principally to important regions on the viral HA stalk, thus could prevent the HA conformational changes required to carry out its membranes fusion activity. PMID- 24146940 TI - Surface roughness detection of arteries via texture analysis of ultrasound images for early diagnosis of atherosclerosis. AB - There is a strong research interest in identifying the surface roughness of the carotid arterial inner wall via texture analysis for early diagnosis of atherosclerosis. The purpose of this study is to assess the efficacy of texture analysis methods for identifying arterial roughness in the early stage of atherosclerosis. Ultrasound images of common carotid arteries of 15 normal mice fed a normal diet and 28 apoE(-/-) mice fed a high-fat diet were recorded by a high-frequency ultrasound system (Vevo 2100, frequency: 40 MHz). Six different texture feature sets were extracted based on the following methods: first-order statistics, fractal dimension texture analysis, spatial gray level dependence matrix, gray level difference statistics, the neighborhood gray tone difference matrix, and the statistical feature matrix. Statistical analysis indicates that 11 of 19 texture features can be used to distinguish between normal and abnormal groups (p<0.05). When the 11 optimal features were used as inputs to a support vector machine classifier, we achieved over 89% accuracy, 87% sensitivity and 93% specificity. The accuracy, sensitivity and specificity for the k-nearest neighbor classifier were 73%, 75% and 70%, respectively. The results show that it is feasible to identify arterial surface roughness based on texture features extracted from ultrasound images of the carotid arterial wall. This method is shown to be useful for early detection and diagnosis of atherosclerosis. PMID- 24146941 TI - The projection of burden of disease in Islamic Republic of Iran to 2025. AB - OBJECTIVE: Iran as a developing country is in the transition phase, which might have a big impact on the Burden of Disease and Injury (BOD). This study aims to estimate Burden of Disease and Injury (BOD) in Iran up to 2025 due to four broad cause groups using Disability-Adjusted Life Year (DALY). METHODS: The impacts of demographic and epidemiological changes on BOD (DemBOD and EpiBOD) were assessed separately. We estimated DemBOD in nine scenarios, using different projections for life expectancy and total fertility rate. EpiBOD was modeled in two scenarios as a proportion of DemBOD, based on the extracted parameters from an international study. FINDINGS: The BOD is projected to increase from 14.3 million in 2003 to 19.4 million in 2025 (95% uncertainty interval: 16.8, 21.9), which shows an overall increase of 35.3%. Non-communicable diseases (12.7 million DALY, 66.0%), injuries (4.6 million DALY, 24.0%), and communicable diseases, except HIV/AIDS (1.8 million DALY, 9%) will be the leading causes of losing healthy life. Under the most likely scenario, the maximum increase in disease burden due to DemBOD is projected to be observed in HIV/AIDS and Non-communicable diseases (63.9 and 62.4%, respectively) and due to EpiBOD in HIV/AIDS (319.5%). CONCLUSION: It seems that in the following decades, BOD will have a sharp increase in Iran, mainly due to DemBOD. It seems that communicable diseases (except HIV/AIDS) will have less contribution, and especially non-communicable diseases will play a more significant role. PMID- 24146942 TI - Chronic inhibition, self-control and eating behavior: test of a 'resource depletion' model. AB - The current research tested the hypothesis that individuals engaged in long-term efforts to limit food intake (e.g., individuals with high eating restraint) would have reduced capacity to regulate eating when self-control resources are limited. In the current research, body mass index (BMI) was used as a proxy for eating restraint based on the assumption that individuals with high BMI would have elevated levels of chronic eating restraint. A preliminary study (Study 1) aimed to provide evidence for the assumed relationship between eating restraint and BMI. Participants (N = 72) categorized into high or normal-range BMI groups completed the eating restraint scale. Consistent with the hypothesis, results revealed significantly higher scores on the weight fluctuation and concern for dieting subscales of the restraint scale among participants in the high BMI group compared to the normal-range BMI group. The main study (Study 2) aimed to test the hypothesized interactive effect of BMI and diminished self-control resources on eating behavior. Participants (N = 83) classified as having high or normal range BMI were randomly allocated to receive a challenging counting task that depleted self-control resources (ego-depletion condition) or a non-depleting control task (no depletion condition). Participants then engaged in a second task in which required tasting and rating tempting cookies and candies. Amount of food consumed during the taste-and-rate task constituted the behavioral dependent measure. Regression analyses revealed a significant interaction effect of these variables on amount of food eaten in the taste-and-rate task. Individuals with high BMI had reduced capacity to regulate eating under conditions of self-control resource depletion as predicted. The interactive effects of BMI and self-control resource depletion on eating behavior were independent of trait self-control. Results extend knowledge of the role of self-control in regulating eating behavior and provide support for a limited-resource model of self-control. PMID- 24146943 TI - Genome-wide profiling of the activity-dependent hippocampal transcriptome. AB - Activity-dependent gene expression is central for sculpting neuronal connectivity in the brain. Despite the importance for synaptic plasticity, a comprehensive analysis of the temporal changes in the transcriptomic response to neuronal activity is lacking. In a genome wide survey we identified genes that were induced at 1, 4, 8, or 24 hours following neuronal activity in the hippocampus. According to their distinct expression kinetics we assigned these genes to five clusters, each containing approximately 200 genes. Using in situ hybridizations the regulated expression of 24 genes was validated. Apart from known activity dependent genes our study reveals a large number of unknown induced genes with distinct expression kinetics. Among these we identified several genes with complex temporal expression patterns. Furthermore, our study provides examples for activity-induced exon switching in the coding region of genes and activity induced alternative splicing of the 3'-UTR. One example is Zwint. In contrast to the constitutively expressed variant, the induced Zwint transcript harbors multiple regulatory elements in the 3'-UTR. Taken together, our study provides a comprehensive analysis of the transcriptomic response to neuronal activity and sheds new light on expression kinetics and alternative splicing events. PMID- 24146944 TI - Developmental regulation of diacylglycerol acyltransferase family gene expression in tung tree tissues. AB - Diacylglycerol acyltransferases (DGAT) catalyze the final and rate-limiting step of triacylglycerol (TAG) biosynthesis in eukaryotic organisms. DGAT genes have been identified in numerous organisms. Multiple isoforms of DGAT are present in eukaryotes. We previously cloned DGAT1 and DGAT2 genes of tung tree (Vernicia fordii), whose novel seed TAGs are useful in a wide range of industrial applications. The objective of this study was to understand the developmental regulation of DGAT family gene expression in tung tree. To this end, we first cloned a tung tree gene encoding DGAT3, a putatively soluble form of DGAT that possesses 11 completely conserved amino acid residues shared among 27 DGAT3s from 19 plant species. Unlike DGAT1 and DGAT2 subfamilies, DGAT3 is absent from animals. We then used TaqMan and SYBR Green quantitative real-time PCR, along with northern and western blotting, to study the expression patterns of the three DGAT genes in tung tree tissues. Expression results demonstrate that 1) all three isoforms of DGAT genes are expressed in developing seeds, leaves and flowers; 2) DGAT2 is the major DGAT mRNA in tung seeds, whose expression profile is well coordinated with the oil profile in developing tung seeds; and 3) DGAT3 is the major form of DGAT mRNA in tung leaves, flowers and immature seeds prior to active tung oil biosynthesis. These results suggest that DGAT2 is probably the major TAG biosynthetic isoform in tung seeds and that DGAT3 gene likely plays a significant role in TAG metabolism in other tissues. Therefore, DGAT2 should be a primary target for tung oil engineering in transgenic organisms. PMID- 24146945 TI - Combinatorial optimization of cystine-knot peptides towards high-affinity inhibitors of human matriptase-1. AB - Cystine-knot miniproteins define a class of bioactive molecules with several thousand natural members. Their eponymous motif comprises a rigid structured core formed by six disulfide-connected cysteine residues, which accounts for its exceptional stability towards thermic or proteolytic degradation. Since they display a remarkable sequence tolerance within their disulfide-connected loops, these molecules are considered promising frameworks for peptide-based pharmaceuticals. Natural open-chain cystine-knot trypsin inhibitors of the MCoTI (Momordica cochinchinensis trypsin inhibitor) and SOTI (Spinacia oleracea trypsin inhibitor) families served as starting points for the generation of inhibitors of matriptase-1, a type II transmembrane serine protease with possible clinical relevance in cancer and arthritic therapy. Yeast surface-displayed libraries of miniproteins were used to select unique and potent matriptase-1 inhibitors. To this end, a knowledge-based library design was applied that makes use of detailed information on binding and folding behavior of cystine-knot peptides. Five inhibitor variants, four of the MCoTI family and one of the SOTI family, were identified, chemically synthesized and oxidatively folded towards the bioactive conformation. Enzyme assays revealed inhibition constants in the low nanomolar range for all candidates. One subnanomolar binder (Ki = 0.83 nM) with an inverted selectivity towards trypsin and matriptase-1 was identified. PMID- 24146947 TI - 207-nm UV light - a promising tool for safe low-cost reduction of surgical site infections. I: in vitro studies. AB - BACKGROUND: 0.5% to 10% of clean surgeries result in surgical-site infections, and attempts to reduce this rate have had limited success. Germicidal UV lamps, with a broad wavelength spectrum from 200 to 400 nm are an effective bactericidal option against drug-resistant and drug-sensitive bacteria, but represent a health hazard to patient and staff. By contrast, because of its limited penetration, ~200 nm far-UVC light is predicted to be effective in killing bacteria, but without the human health hazards to skin and eyes associated with conventional germicidal UV exposure. AIMS: The aim of this work was to test the biophysically based hypothesis that ~200 nm UV light is significantly cytotoxic to bacteria, but minimally cytotoxic or mutagenic to human cells either isolated or within tissues. METHODS: A Kr-Br excimer lamp was used, which produces 207-nm UV light, with a filter to remove higher-wavelength components. Comparisons were made with results from a conventional broad spectrum 254-nm UV germicidal lamp. First, cell inactivation vs. UV fluence data were generated for methicillin-resistant S. aureus (MRSA) bacteria and also for normal human fibroblasts. Second, yields of the main UV-associated pre-mutagenic DNA lesions (cyclobutane pyrimidine dimers and 6-4 photoproducts) were measured, for both UV radiations incident on 3-D human skin tissue. RESULTS: We found that 207-nm UV light kills MRSA efficiently but, unlike conventional germicidal UV lamps, produces little cell killing in human cells. In a 3-D human skin model, 207-nm UV light produced almost no pre mutagenic UV-associated DNA lesions, in contrast to significant yields induced by a conventional germicidal UV lamp. CONCLUSIONS: As predicted based on biophysical considerations, 207-nm light kills bacteria efficiently but does not appear to be significantly cytotoxic or mutagenic to human cells. Used appropriately, 207-nm light may have the potential for safely and inexpensively reducing surgical-site infection rates, including those of drug-resistant origin. PMID- 24146946 TI - Effects of taurine supplementation on hepatic markers of inflammation and lipid metabolism in mothers and offspring in the setting of maternal obesity. AB - Maternal obesity is associated with obesity and metabolic disorders in offspring. However, intervention strategies to reverse or ameliorate the effects of maternal obesity on offspring health are limited. Following maternal undernutrition, taurine supplementation can improve outcomes in offspring, possibly via effects on glucose homeostasis and insulin secretion. The effects of taurine in mediating inflammatory processes as a protective mechanism has not been investigated. Further, the efficacy of taurine supplementation in the setting of maternal obesity is not known. Using a model of maternal obesity, we examined the effects of maternal taurine supplementation on outcomes related to inflammation and lipid metabolism in mothers and neonates. Time-mated Wistar rats were randomised to either: 1) control : control diet during pregnancy and lactation (CON); 2) CON supplemented with 1.5% taurine in drinking water (CT); 3) maternal obesogenic diet (high fat, high fructose) during pregnancy and lactation (MO); or 4) MO supplemented with taurine (MOT). Maternal and neonatal weights, plasma cytokines and hepatic gene expression were analysed. A MO diet resulted in maternal hyperinsulinemia and hyperleptinemia and increased plasma glucose, glutamate and TNF-alpha concentrations. Taurine normalised maternal plasma TNF-alpha and glutamate concentrations in MOT animals. Both MO and MOT mothers displayed evidence of fatty liver accompanied by alterations in key markers of hepatic lipid metabolism. MO neonates displayed a pro-inflammatory hepatic profile which was partially rescued in MOT offspring. Conversely, a pro-inflammatory phenotype was observed in MOT mothers suggesting a possible maternal trade-off to protect the neonate. Despite protective effects of taurine in MOT offspring, neonatal mortality was increased in CT neonates, indicating possible adverse effects of taurine in the setting of normal pregnancy. These data suggest that maternal taurine supplementation may ameliorate the adverse effects observed in offspring following a maternal obesogenic diet but these effects are dependent upon prior maternal nutritional background. PMID- 24146948 TI - The transcriptional repressor domain of Gli3 is intrinsically disordered. AB - The transcription factor Gli3 is acting mainly as a transcriptional repressor in the Sonic hedgehog signal transduction pathway. Gli3 contains a repressor domain in its N-terminus from residue G106 to E236. In this study we have characterized the intracellular structure of the Gli3 repressor domain using a combined bioinformatics and experimental approach. According to our findings the Gli3 repressor domain while being intrinsically disordered contains predicted anchor sites for partner interactions. The obvious interaction partners to test were Ski and DNA; however, with both of these the structure of Gli3 repressor domain remained disordered. To locate residues important for the repressor function we mutated several residues within the Gli3 repressor domain. Two of these, H141A and H157N, targeting predicted helical regions, significantly decreased transcriptional repression and thus identify important functional parts of the domain. PMID- 24146949 TI - Effect of Nadir CD4+ T cell count on clinical measures of periodontal disease in HIV+ adults before and during immune reconstitution on HAART. AB - BACKGROUND: The contribution of HIV-infection to periodontal disease (PD) is poorly understood. We proposed that immunological markers would be associated with improved clinical measures of PD. METHODS: We performed a longitudinal cohort study of HIV-infected adults who had started highly active antiretroviral therapy (HAART) <2 years. PD was characterized clinically as the percent of teeth with >= 1 site with periodontal probing depth (PPD) >= 5.0mm, recession (REC) >0mm, clinical attachment level (CAL) >= 4.0mm, and bleeding on probing (BOP) at >= 4 sites/tooth and microbiologically as specific periodontopathogen concentration. Linear mixed-effects models were used to assess the associations between immune function and PD. RESULTS: Forty (40) subjects with median 2.7 months on HAART and median nadir CD4+ T-cell count of 212 cells/MUl completed a median 3 visits. Over 24 months, CD4+ T-cell count increased by a mean 173 cells/ul (p<0.001) and HIV RNA decreased by 0.5 log10 copies/ml (p<0.001); concurrently, PPD, CAL and BOP decreased by a mean 11.7%, 12.1%, and 14.7% respectively (all p<0.001). Lower nadir CD4+ T-cell count was associated with worse baseline REC (-6.72%; p=0.04) and CAL (9.06%; p<0.001). Further, lower nadir CD4+ T-cell count was associated with a greater relative longitudinal improvement in PPD in subjects with higher baseline levels of Porphyromonas gingivalis (p=0.027), and BOP in subjects with higher baseline levels of Porphyromonas gingivalis or Treponema denticola (p=0.001 and p=0.006 respectively). Longitudinal changes from baseline in CD4+ T-cell count and level of HIV RNA were not independently associated with longitudinal changes in any clinical markers of PD. CONCLUSION: Degree of immunosuppression was associated with baseline gingival recession. After HAART initiation, measures of active PD improved most in those with lower nadir CD4+ T-cell counts and higher baseline levels of specific periodontopathogens. Nadir CD4+ T-cell count differentially influences periodontal disease both before and after HAART in HIV-infected adults. PMID- 24146950 TI - Anti-inflammatory effect of targeted delivery of SOD to endothelium: mechanism, synergism with NO donors and protective effects in vitro and in vivo. AB - Pro-inflammatory activation of vascular endothelium is implicated in pathogenesis of severe conditions including stroke, infarction and sepsis. We have recently reported that superoxide dismutase (SOD) conjugated with antibodies (Ab/SOD) that provide targeted delivery into endothelial endosomes mitigates inflammatory endothelial activation by cytokines and agonists of Toll-like receptors (TLR). The goal of this study was to appraise potential utility and define the mechanism of this effect. Ab/SOD, but not non-targeted SOD injected in mice alleviated endotoxin-induced leukocyte adhesion in the cerebral vasculature and protected brain from ischemia-reperfusion injury. Transfection of endothelial cells with SOD, but not catalase inhibited NFkappaB signaling and expression of Vascular Cell Adhesion Molecule-1 induced by both cytokines and TLR agonists. These results affirmed that Ab/SOD-quenched superoxide anion produced by endothelial cells in response to proinflammatory agents mediates NFkappaB activation. Furthermore, Ab/SOD potentiates anti-inflammatory effect of NO donors in endothelial cells in vitro, as well as in the endotoxin-challenged mice. These results demonstrate the central role of intracellular superoxide as a mediator of pro-inflammatory activation of endothelium and support the notion of utility of targeted interception of this signaling pathway for management of acute vascular inflammation. PMID- 24146951 TI - Mosquitoes of Western Yunnan Province, China: seasonal abundance, diversity, and arbovirus associations. AB - OBJECTIVE: The western borderland between Yunnan Province, China, and Myanmar is characterized by a climate that facilitates year-round production of mosquitoes. Numerous mosquito-transmitted viruses, including Japanese encephalitis virus circulate in this area. This project was to describe seasonal patterns in mosquito species abundance and arbovirus activity in the mosquito populations. METHODS: Mosquitoes were collected in Mangshi and Ruili cities of Dehong Prefecture near the border of China and Burma in Yunnan Province, the Peoples Republic of China in 2010. We monitored mosquito species abundance for a 12-month period using ultraviolet light, carbon dioxide baited CDC light and gravid traps; and tested the captured mosquitoes for the presence of virus to evaluate mosquito virus associations in rural/agricultural settings in the area. RESULTS: A total of 43 species of mosquitoes from seven genera were collected, including 15 Culex species, 15 Anopheles spp., four Aedes spp., three Armigeres spp., one Mimomyia spp., two Uranotaenia spp. and three Mansonia spp.. Species richness and diversity varied between Mangshi and Ruili. Culex tritaeniorhynchus, Culex quinquefasciatus, Anopheles sinensis and Anopheles peditaeniatus were the most abundant species in both sampling sites. Ultraviolet light traps collected more specimens than CDC light traps baited with dry ice, though both collected the same variety of mosquito species. The CDC gravid trap was the most effective trap for capture of Culex quinquefasciatus, a species underrepresented in light trap collections. A total of 26 virus strains were isolated, which included 13 strains of Japanese encephalitis virus, four strains of Getah virus, one strain of Oya virus, one strain from the orbivirus genus, and seven strains of Culex pipien pallens densovirus. CONCLUSIONS: The present study illustrates the value of monitoring mosquito populations and mosquito-transmitted viruses year-round in areas where the climate supports year-round adult mosquito activity. PMID- 24146952 TI - Iron accumulates in Huntington's disease neurons: protection by deferoxamine. AB - Huntington's disease (HD) is a progressive neurodegenerative disorder caused by a polyglutamine-encoding CAG expansion in the huntingtin gene. Iron accumulates in the brains of HD patients and mouse disease models. However, the cellular and subcellular sites of iron accumulation, as well as significance to disease progression are not well understood. We used independent approaches to investigate the location of brain iron accumulation. In R6/2 HD mouse brain, synchotron x-ray fluorescence analysis revealed iron accumulation as discrete puncta in the perinuclear cytoplasm of striatal neurons. Further, perfusion Turnbull's staining for ferrous iron (II) combined with transmission electron microscope ultra-structural analysis revealed increased staining in membrane bound peri-nuclear vesicles in R6/2 HD striatal neurons. Analysis of iron homeostatic proteins in R6/2 HD mice revealed decreased levels of the iron response proteins (IRPs 1 and 2) and accordingly decreased expression of iron uptake transferrin receptor (TfR) and increased levels of neuronal iron export protein ferroportin (FPN). Finally, we show that intra-ventricular delivery of the iron chelator deferoxamine results in an improvement of the motor phenotype in R6/2 HD mice. Our data supports accumulation of redox-active ferrous iron in the endocytic / lysosomal compartment in mouse HD neurons. Expression changes of IRPs, TfR and FPN are consistent with a compensatory response to an increased intra-neuronal labile iron pool leading to increased susceptibility to iron associated oxidative stress. These findings, together with protection by deferoxamine, support a potentiating role of neuronal iron accumulation in HD. PMID- 24146953 TI - Genetic variation in a microRNA-502 minding site in SET8 gene confers clinical outcome of non-small cell lung cancer in a Chinese population. AB - BACKGROUND: Genetic variants may influence microRNA-target interaction through modulate their binding affinity, creating or destroying miRNA-binding sites. SET8, a member of the SET domain-containing methyltransferase, has been implicated in a variety array of biological processes. METHODS: Using Taqman assay, we genotyped a polymorphism rs16917496 T>C within the miR-502 binding site in the 3'-untranslated region of the SET8 gene in 576 non-small cell lung cancer (NSCLC) patients. Functions of rs16917496 were investigated using luciferase activity assay and validated by immunostaining. RESULTS: Log-rank test and cox regression indicated that the CC genotype was associated with a longer survival and a reduced risk of death for NSCLC [58.0 vs. 41.0 months, P = 0.031; hazard ratio = 0.44, 95% confidential interval: 0.26-0.74]. Further stepwise regression analysis suggested rs16917496 was an independently favorable factor for prognosis and the protective effect more prominent in never smokers, patients without diabetes and patients who received chemotherapy. A significant interaction was observed between rs16917496 and smoking status in relation to NSCLC survival (P<0.001). Luciferase activity assay showed a lower expression level for C allele as compared with T allele, and the miR-502 had an effect on modulation of SET8 gene in vitro. The CC genotype was associated with reduced SET8 protein expression based on immunostaining of 192 NSCLC tissue sample (P = 0.007). Lower levels of SET8 were associated with a non-significantly longer survival (55.0 vs. 43.1 months). CONCLUSION: Our data suggested that the rs16917496 T>C located at miR-502 binding site contributes to NSCLC survival by altering SET8 expression through modulating miRNA-target interaction. PMID- 24146954 TI - Systematic identification of gene families for use as "markers" for phylogenetic and phylogeny-driven ecological studies of bacteria and archaea and their major subgroups. AB - With the astonishing rate that genomic and metagenomic sequence data sets are accumulating, there are many reasons to constrain the data analyses. One approach to such constrained analyses is to focus on select subsets of gene families that are particularly well suited for the tasks at hand. Such gene families have generally been referred to as "marker" genes. We are particularly interested in identifying and using such marker genes for phylogenetic and phylogeny-driven ecological studies of microbes and their communities (e.g., construction of species trees, phylogenetic based assignment of metagenomic sequence reads to taxonomic groups, phylogeny-based assessment of alpha- and beta-diversity of microbial communities from metagenomic data). We therefore refer to these as PhyEco (for phylogenetic and phylogenetic ecology) markers. The dual use of these PhyEco markers means that we needed to develop and apply a set of somewhat novel criteria for identification of the best candidates for such markers. The criteria we focused on included universality across the taxa of interest, ability to be used to produce robust phylogenetic trees that reflect as much as possible the evolution of the species from which the genes come, and low variation in copy number across taxa. We describe here an automated protocol for identifying potential PhyEco markers from a set of complete genome sequences. The protocol combines rapid searching, clustering and phylogenetic tree building algorithms to generate protein families that meet the criteria listed above. We report here the identification of PhyEco markers for different taxonomic levels including 40 for "all bacteria and archaea", 114 for "all bacteria (greatly expanding on the ~30 commonly used), and 100 s to 1000 s for some of the individual phyla of bacteria. This new list of PhyEco markers should allow much more detailed automated phylogenetic and phylogenetic ecology analyses of these groups than possible previously. PMID- 24146956 TI - Urogenital epithelial cells as simple markers of estrogen response in infants: methods and applications. AB - Exposure to estrogen-mimicking chemicals during critical periods of development, such as infancy, may have adverse effects. However, these effects can be difficult to characterize in most epidemiologic studies. For example, growth of reproductive organs may be susceptible to estrogenic chemicals, but measuring it requires skilled ultrasound examination; timing of pubertal onset may be altered, but observing it requires long-term follow up. To address the need for a simple marker of response to estrogenic exposures in infants, we propose a novel application of a classic marker of estrogen response in adult women: cytological evaluation of urogenital epithelial cells. In this cross-sectional study of 34 female and 41 male infants, we demonstrate that epithelial cells can be obtained from swabs of the vaginal introitus (females) and urethral meatus (males), as well as from spun urine, and that these cells respond to differential estrogenic conditions, as indicated by the relative abundance of the superficial epithelial cell type. To model varying estrogen exposure, we sampled from infants who were either newborn (highly exposed to maternal estrogens), or 12 weeks old (12 W) (negligibly exposed to estrogen). Newborns had a higher percentage of superficial cells (%S), as compared to 12 W (mean +/- standard error: 8.3 +/- 1.8 vs. 0.9 +/- 0.2) (p < 0.01), consistent with an estrogen response. This difference in %S from newborn to 12 W was observed similarly for swab (-7.6 +/- 1.7) and urine (-7.3 +/ 2.6) specimens and for males (-9.6 +/- 2.9) and females (-5.2 +/- 2.1). Examination of urogenital epithelial cells can successfully demonstrate estrogen response in both sexes, using cell specimens collected from either swab or urine sampling. In future studies, this simple, non-invasive method may be applied to assess whether estrogen-mimicking chemicals produce an estrogenic response in infants. PMID- 24146955 TI - Cholesterol diet withdrawal leads to an initial plaque instability and subsequent regression of accelerated iliac artery atherosclerosis in rabbits. AB - Effect of long term cholesterol diet withdrawal on accelerated atherosclerosis in iliac artery of New Zealand White (NZW) rabbits has not been explored so far. Atherosclerosis was thus induced in rabbits by a combination of balloon injury and atherogenic diet (AD) (1% cholesterol and 6% peanut oil) feeding for 8 weeks (baseline) followed by chow diet (CD) feeding for 4, 8, 16, 32, 50 and 64 weeks. The plaque characterization was done using histology, real time RT-PCR and vasoreactivity studies. Significant elevation in plasma lipids with AD feeding was normalized following 16 weeks of CD feeding. However, baseline comparison showed advanced plaque features even after 8 weeks of CD period with significant elevation in intima/media thickness ratio and plaque area later showing reduction at 50 and 64 weeks CD periods. Lesion lipid accumulation and CD68 positivity was maintained till 16 weeks of CD feeding which significantly reduced from 32 to 64 weeks CD periods. Baseline comparison showed significant increase in ground substance, MMP-9 and significant decrease in alpha-actin and collagen content at 8 weeks CD period indicating features of unstable plaque. These features regressed up to 64 weeks of CD. Partial restoration of functional vasoconstriction and vasorelaxation was seen after 64 weeks of CD feeding. mRNA expression of MCP-1, VCAM-1, collagen type I and III, MMP-9, TIMP-1, IFN-gamma, TNF-alpha, IL-10 and eNOS supported the above findings. The study thus reveals insights into initial plaque instability and subsequent regression on AD withdrawal in this model. These results are suggestive of an appropriate window for drug intervention for plaque stability/regression and restenosis as well as improves understanding of plaque regression phenomenon in this model. PMID- 24146957 TI - The tumor suppressor gene TUSC2 (FUS1) sensitizes NSCLC to the AKT inhibitor MK2206 in LKB1-dependent manner. AB - TUSC2-defective gene expression is detected in the majority of lung cancers and is associated with worse overall survival. We analyzed the effects of TUSC2 re expression on tumor cell sensitivity to the AKT inhibitor, MK2206, and explored their mutual signaling connections, in vitro and in vivo. TUSC2 transient expression in three LKB1-defective non-small cell lung cancer (NSCLC) cell lines combined with MK2206 treatment resulted in increased repression of cell viability and colony formation, and increased apoptotic activity. In contrast, TUSC2 did not affect the response to MK2206 treatment for two LKB1-wild type NSCLC cell lines. In vivo, TUSC2 systemic delivery, by nanoparticle gene transfer, combined with MK2206 treatment markedly inhibited growth of tumors in a human LKB1 defective H322 lung cancer xenograft mouse model. Biochemical analysis showed that TUSC2 transient expression in LKB1-defective NSCLC cells significantly stimulated AMP-activated protein kinase (AMPK) phosphorylation and enzymatic activity. More importantly, AMPK gene knockdown abrogated TUSC2-MK2206 cooperation, as evidenced by reduced sensitivity to the combined treatment. Together, TUSC2 re-expression and MK2206 treatment was more effective in inhibiting the phosphorylation and kinase activities of AKT and mTOR proteins than either single agent alone. In conclusion, these findings support the hypothesis that TUSC2 expression status is a biological variable that potentiates MK2206 sensitivity in LKB1-defective NSCLC cells, and identifies the AMPK/AKT/mTOR signaling axis as an important regulator of this activity. PMID- 24146958 TI - The state of infectious diseases clinical trials: a systematic review of ClinicalTrials.gov. AB - BACKGROUND: There is a paucity of clinical trials informing specific questions faced by infectious diseases (ID) specialists. The ClinicalTrials.gov registry offers an opportunity to evaluate the ID clinical trials portfolio. METHODS: We examined 40,970 interventional trials registered with ClinicalTrials.gov from 2007-2010, focusing on study conditions and interventions to identify ID-related trials. Relevance to ID was manually confirmed for each programmatically identified trial, yielding 3570 ID trials and 37,400 non-ID trials for analysis. RESULTS: The number of ID trials was similar to the number of trials identified as belonging to cardiovascular medicine (n = 3437) or mental health (n = 3695) specialties. Slightly over half of ID trials were treatment-oriented trials (53%, vs. 77% for non-ID trials) followed by prevention (38%, vs. 8% in non-ID trials). ID trials tended to be larger than those of other specialties, with a median enrollment of 125 subjects (interquartile range [IQR], 45-400) vs. 60 (IQR, 30 160) for non-ID trials. Most ID studies are randomized (73%) but nonblinded (56%). Industry was the funding source in 51% of ID trials vs. 10% that were primarily NIH-funded. HIV-AIDS trials constitute the largest subset of ID trials (n = 815 [23%]), followed by influenza vaccine (n = 375 [11%]), and hepatitis C (n = 339 [9%]) trials. Relative to U.S. and global mortality rates, HIV-AIDS and hepatitis C virus trials are over-represented, whereas lower respiratory tract infection trials are under-represented in this large sample of ID clinical trials. CONCLUSIONS: This work is the first to characterize ID clinical trials registered in ClinicalTrials.gov, providing a framework to discuss prioritization, methodology, and policy. PMID- 24146959 TI - Ischemia-reperfusion lung injury is attenuated in MyD88-deficient mice. AB - Ischemia-reperfusion lung injury is a common cause of acute morbidity and mortality in lung transplant recipients and has been associated with subsequent development of bronchiolitis obliterans syndrome. Recognition of endogenous ligands released during cellular injury (damage-associated molecular patterns; DAMPs) by Toll-like receptors (TLRs), especially TLR4, has increasingly been recognized as a mechanism for inflammation resulting from tissue damage. TLR4 is implicated in the pathogenesis of ischemia-reperfusion injury of multiple organs including heart, liver, kidney and lung. Additionally, activation of TLRs other than TLR4 by DAMPs has been identified in tissues other than the lung. Because all known TLRs, with the exception of TLR3, signal via the MyD88 adapter protein, we hypothesized that lung ischemia-reperfusion injury was mediated by MyD88 dependent signaling. To test this hypothesis, we subjected C57BL/6 wildtype, Myd88(-/-), and Tlr4(-/-) mice to 1 hr of left lung warm ischemia followed by 4 hr of reperfusion. We found that Myd88(-/-) mice had significantly less MCP 1/CCL2 in the left lung following ischemia-reperfusion as compared with wildtype mice. This difference was associated with dramatically reduced lung permeability. Interestingly, Tlr4(-/-) mice had only partial protection from ischemia reperfusion as compared to Myd88(-/-) mice, implicating other MyD88-dependent pathways in lung injury following ischemia-reperfusion. We also found that left lung ischemia-reperfusion caused remote inflammation in the right lung. Finally, using chimeric mice with MyD88 expression restricted to either myeloid or non myeloid cells, we found that MyD88-dependent signaling in myeloid cells was necessary for ischemia-reperfusion induced lung permeability. We conclude that MyD88-dependent signaling through multiple receptors is important in the pathogenesis of acute lung inflammation and injury following ischemia and reperfusion. PMID- 24146960 TI - Generation of breast cancer stem cells by steroid hormones in irradiated human mammary cell lines. AB - Exposure to ionizing radiation was shown to result in an increased risk of breast cancer. There is strong evidence that steroid hormones influence radiosensitivity and breast cancer risk. Tumors may be initiated by a small subpopulation of cancer stem cells (CSCs). In order to assess whether the modulation of radiation induced breast cancer risk by steroid hormones could involve CSCs, we measured by flow cytometry the proportion of CSCs in irradiated breast cancer cell lines after progesterone and estrogen treatment. Progesterone stimulated the expansion of the CSC compartment both in progesterone receptor (PR)-positive breast cancer cells and in PR-negative normal cells. In MCF10A normal epithelial PR-negative cells, progesterone-treatment and irradiation triggered cancer and stemness associated microRNA regulations (such as the downregulation of miR-22 and miR-29c expression), which resulted in increased proportions of radiation-resistant tumor initiating CSCs. PMID- 24146961 TI - Digitoflavone inhibits IkappaBalpha kinase and enhances apoptosis induced by TNFalpha through downregulation of expression of nuclear factor kappaB-regulated gene products in human pancreatic cancer cells. AB - Tumor necrosis factor-alpha (TNFalpha) activates both cell death and cell survival pathways. The activation of survival pathway renders most cancer cells resistant to TNF-induced cytotoxicity. We found that pretreatment with digitoflavone, a plant flavonoid, greatly sensitized TNFalpha-induced apoptotic cell death in several human pancreatic cancer cells. In search of the molecular basis of the sensitization effect of digitoflavone, digitoflavone was found to inhibit TNFalpha-induced activation of nuclear transcription factor-kappa B (NF kappaB) which is the main survival factor in TNFalpha signaling. NF-kappaB suppression occurred through inhibition of IkappaBalpha kinase activation, IkappaBalpha phosphorylation, IkappaBalpha degradation, and NF-kappaB nuclear translocation. This inhibition correlated with suppression of NF-kappaB-dependent genes involved in antiapoptosis (mcl-1, bcl-2, bcl-xl, c-iap1, c-iap2, flip, and survivin), proliferation (c-myc, cyclin d1), and angiogenesis (vegf, cox-2, and mmp-9). In addition, digitoflavone can activate JNK through inhibition of NF kappaB signaling, provide a continuous blockade of the feed-back inhibitory mechanism by JNK-induced NF-kappaB activation. This study found a novel function of digitoflavone and enhanced the value of digitoflavone as an anticancer agent. PMID- 24146962 TI - Methyl jasmonate and 1-methylcyclopropene treatment effects on quinone reductase inducing activity and post-harvest quality of broccoli. AB - Effect of pre-harvest methyl jasmonate (MeJA) and post-harvest 1 methylcyclopropene (1-MCP) treatments on broccoli floret glucosinolate (GS) concentrations and quinone reductase (QR, an in vitro anti-cancer biomarker) inducing activity were evaluated two days prior to harvest, at harvest and at 10, 20, and 30 days of post-harvest storage at 4 degrees C. MeJA treatments four days prior to harvest of broccoli heads was observed to significantly increase floret ethylene biosynthesis resulting in chlorophyll catabolism during post harvest storage and reduced product quality. Post-harvest treatment with 1 methylcyclopropene (1-MCP), which competitively binds to protein ethylene receptors, maintained post-harvest floret chlorophyll concentrations and product visual quality in both control and MeJA-treated broccoli. Transcript abundance of BoPPH, a gene which is responsible for the synthesis of pheophytinase, the primary enzyme associated with chlorophyll catabolism in broccoli, was reduced by 1-MCP treatment and showed a significant, negative correlation with floret chlorophyll concentrations. The GS, glucobrassicin, neoglucobrassicin, and gluconasturtiin were significantly increased by MeJA treatments. The products of some of the GS from endogenous myrosinase hydrolysis [sulforaphane (SF), neoascorbigen (NeoASG), N-methoxyindole-3-carbinol (NI3C), and phenethyl isothiocyanate (PEITC)] were also quantified and found to be significantly correlated with QR. Sulforaphane, the isothiocyanate hydrolysis product of the GS glucoraphanin, was found to be the most potent QR induction agent. Increased sulforaphane formation from the hydrolysis of glucoraphanin was associated with up-regulated gene expression of myrosinase (BoMyo) and the myrosinase enzyme co factor gene, epithiospecifier modifier1 (BoESM1). This study demonstrates the combined treatment of MeJA and 1-MCP increased QR activity without post-harvest quality loss. PMID- 24146963 TI - Weed mapping in early-season maize fields using object-based analysis of unmanned aerial vehicle (UAV) images. AB - The use of remote imagery captured by unmanned aerial vehicles (UAV) has tremendous potential for designing detailed site-specific weed control treatments in early post-emergence, which have not possible previously with conventional airborne or satellite images. A robust and entirely automatic object-based image analysis (OBIA) procedure was developed on a series of UAV images using a six band multispectral camera (visible and near-infrared range) with the ultimate objective of generating a weed map in an experimental maize field in Spain. The OBIA procedure combines several contextual, hierarchical and object-based features and consists of three consecutive phases: 1) classification of crop rows by application of a dynamic and auto-adaptive classification approach, 2) discrimination of crops and weeds on the basis of their relative positions with reference to the crop rows, and 3) generation of a weed infestation map in a grid structure. The estimation of weed coverage from the image analysis yielded satisfactory results. The relationship of estimated versus observed weed densities had a coefficient of determination of r(2)=0.89 and a root mean square error of 0.02. A map of three categories of weed coverage was produced with 86% of overall accuracy. In the experimental field, the area free of weeds was 23%, and the area with low weed coverage (<5% weeds) was 47%, which indicated a high potential for reducing herbicide application or other weed operations. The OBIA procedure computes multiple data and statistics derived from the classification outputs, which permits calculation of herbicide requirements and estimation of the overall cost of weed management operations in advance. PMID- 24146964 TI - Association of GRM7 variants with different phenotype patterns of age-related hearing impairment in an elderly male Han Chinese population. AB - Several single nucleotide polymorphisms (SNPs) of the Glutamate metabotrophic receptor 7 gene (GRM7) have recently been identified by the genome-wide association study (GWAS) as potentially playing a role in susceptibility to age related hearing impairment (ARHI), however this has not been validated in the Han Chinese population. The aim of this study was to determine if these SNPs are also associated with ARHI in an elderly male Han Chinese population. In this case control candidate genes association study, a total of 982 men with ARHI and 324 normal-hearing controls subjects were studied. Using K-means cluster analysis, four audiogram shape subtypes of ARHI were identified in the case group: ''flat shape (FL)'', ''sloping shape (SL)'', ''2-4 kHz abrupt loss (AL) shape'' and ''8 kHz dip (8D) shape''. Results suggested that the SNP rs11928865 (A>T) of GRM7 was significantly associated with ARHI after adjusting for non-genetic factors (p = 0.000472, OR = 1.599, 95%CI = 1.229~2.081). Furthermore, frequency of TT genotype (rs11928865) were significant higher in the SL subgroup and AL subgroup with compared to controls group (p = 9.41E-05, OR = 1.945, 95%CI = 1.393~2.715; p = 0.000109, OR = 1.915, 95%CI = 1.378~2.661 adjusted, respectively) after Bonferroni correction. However, there wasn't significant difference in the frequency of the TT genotype between cases in the FL subgroup or the 8D subgroup with when compared with controls. Results of the current study suggest that, in an elderly male Han Chinese population, GRM7 SNP rs11928865 (TT) occurs more frequently in ARHI patients with SL and AL phenotype patterns. PMID- 24146965 TI - Roles of TLR7 in activation of NF-kappaB signaling of keratinocytes by imiquimod. AB - Imiquimod is known to exert its effects through Toll-like receptor 7 (TLR7) and/or TLR8, resulting in expression of proinflammatory cytokines and chemokines. Keratinocytes have not been reported to constitutively express TLR7 and TLR8, and the action of imiquimod is thought to be mediated by the adenine receptor, not TLR7 or TLR8. In this study, we revealed the expression of TLR7 in keratinocytes after calcium-induced differentiation. After addition of calcium to cultured keratinocytes, the immunological responses induced by imiquimod, such as activation of NF-kappaB and induction of TNF-alpha and IL-8, were more rapid and stronger. In addition, imiquimod induced the expression TLR7, and acted synergistically with calcium to induce proinflammatory cytokines. We confirmed that the responses induced by imiquimod were significantly inhibited by microRNAs suppressing TLR7 expression. These results suggest that TLR7 expressed in keratinocytes play key roles in the activation of NF-kappaB signaling by imiquimod, and that their modulation in keratinocytes could provide therapeutic potential for many inflammatory skin diseases. PMID- 24146966 TI - Obesity and occupational injury: a prospective cohort study of 69,515 public sector employees. AB - BACKGROUND: Obesity and overweight are suggested to increase the risk of occupational injury but longitudinal evidence to confirm this is rare. We sought to evaluate obesity and overweight as risk factors for occupational injuries. METHODOLOGY/PRINCIPAL FINDINGS: A total of 69,515 public sector employees (80% women) responded to a survey in 2000-2002, 2004 or 2008. Body mass index (kg/m(2)) was derived from self-reported height and weight and was linked to records of subsequent occupational injuries obtained from national registers. Different injury types, locations and events or exposures (the manner in which the injury was produced or inflicted) were analyzed by body mass index category adjusting for baseline socio-demographic characteristics, work characteristics, health-risk behaviors, physical and mental health, insomnia symptoms, and sleep duration. During the mean follow-up of 7.8 years (SD = 3.2), 18% of the employees (N = 12,204) recorded at least one occupational injury. Obesity was associated with a higher overall risk of occupational injury; multivariable adjusted hazard ratio (HR) 1.21 (95% CI 1.14-1.27). A relationship was observed for bone fractures (HR = 1.37; 95% CI: 1.10-1.70), dislocations, sprains and strains (HR = 1.36; 95% CI: 1.25-1.49), concussions and internal injuries (HR = 1.26; 95% CI: 1.11-1.44), injuries to lower extremities (HR = 1.62; 95%: 1.46-1.79) and injuries to whole body or multiple sites (HR = 1.37; 95%: 1.10-1.70). Furthermore, obesity was associated with a higher risk of injuries caused by slipping, tripping, stumbling and falling (HR = 1.55; 95% CI: 1.40-1.73), sudden body movement with or without physical stress (HR = 1.24; 95% CI: 1.10-1.41) and shock, fright, violence, aggression, threat or unexpected presence (HR = 1.33; 95% CI: 1.03-1.72). The magnitude of the associations between overweight and injuries was smaller, but the associations were generally in the same direction as those of obesity. CONCLUSIONS/SIGNIFICANCE: Obese employees record more occupational injuries than those with recommended healthy weight. PMID- 24146967 TI - Five-year change in intraocular pressure associated with changes in arterial blood pressure and body mass index. The beijing eye study. AB - PURPOSE: To examine a potential association between longitudinal changes in intraocular pressure (IOP), arterial blood pressure and body mass index (BMI) in a population-based setting. METHODS: The longitudinal population-based Beijing Eye Study included 2355 subjects with an age of 45+ years who were examined in 2006 and in 2011. The participants underwent a detailed ophthalmic examination including tonometry and measurement of arterial blood pressure and BMI. RESULTS: Data on IOP, arterial blood pressure and BMI measured in 2006 and in 2011 were available for 2257 (95.8%) subjects with a mean age of 59.5 +/- 9.7 years. The mean change in IOP was -1.25 +/- 2.26 mm Hg, mean change in mean blood pressure 7.4 +/- 12.1 mmHg, and mean change in BMI was 0.01 +/- 2.04 kg/m(2). In multivariate analysis, the 5-year change in IOP was significantly associated with a higher change in mean blood pressure (P<0.001; standardized regression coefficient Beta:0.11; regression coefficient B:0.02; 95% confidence interval (CI):0.01,0.03) after adjusting for younger age (P<0.001;Beta:-0.18;B:-0.04;95% CI:-0.05,-0.03), shorter body stature (P = 0.002;Beta:-0.06;B:-0.06;95% CI:-0.03, 0.01), thicker central corneal thickness (P<0.001;Beta:0.19;B:0.02;95% CI:0.01,0.02), deeper anterior chamber depth (P = 0.01;Beta:0.05;B:0.33;95% CI:0.07,0.60), and lower intraocular pressure at baseline (P<0.001;Beta:-0.56;B: 0.42;95% CI:-0.45,-0.39). If the analysis included only longitudinal parameters, the change in IOP was significantly associated with a higher change in mean arterial blood pressure (P<0.001;Beta:0.10;B:0.02;95% CI:0.01,0.03) and a higher change in body mass index (P<0.04;Beta:0.04;B:0.04;95% CI:0.01,0.09). CONCLUSIONS: In the 5-year follow-up of our population-based sample, a change in IOP was associated with a corresponding change in arterial blood pressure and with a corresponding change in body mass index. These longitudinal data support the notion of a physiological relationship between arterial blood pressure, intraocular pressure and body mass index. These findings may be of interest for the discussion of the pathogenesis of glaucomatous optic neuropathy. PMID- 24146968 TI - Growth of tropical Dasyatid rays estimated using a multi-analytical approach. AB - We studied the age and growth of four sympatric stingrays: reticulate whipray, Himanutra uarnak (n=19); blue mask, Neotrygon kuhlii (n=34); cowtail, Pastinachus atrus (n=32) and blue-spotted fantail, Taeniura lymma (n=40) rays at Ningaloo Reef, a fringing coral reef on the north-western coast of western Australia. Age estimates derived from band counts within sectioned vertebrae ranged between 1 and 27 years (H. uarnak, 1 - 25 yrs.; N. kuhlii, 1.5 - 13 yrs.; P. atrus, 1 - 27 yrs. and T. lymma, 1 -11 yrs.). Due to limitations of sample sizes, we combined several analytical methods for estimating growth parameters. First, we used nonlinear least squares (NLS) to identify the growth model that best fitted the data. We then used this model, prior information and the data within a Bayesian framework to approximate the posterior distribution of the growth parameters. For all species the two-parameter von Bertalanffy growth model provided the best fit to size-at-age datasets. Based on this model, the Bayesian approach allowed the estimation of median values of W(Dinfinity) (cm) and k (yr(-1)) for the four species (H. uarnak: 149 and 0.12; N. kuhlii: 42 and 0.38; P. atrus 156 and 0.16, and T. lymma 33 and 0.24, respectively). Our approach highlights the value of combining different analytical methods and prior knowledge for estimating growth parameters when data quality and quantity are limited. PMID- 24146969 TI - Glycogen content regulates peroxisome proliferator activated receptor-? (PPAR-?) activity in rat skeletal muscle. AB - Performing exercise in a glycogen depleted state increases skeletal muscle lipid utilization and the transcription of genes regulating mitochondrial beta oxidation. Potential candidates for glycogen-mediated metabolic adaptation are the peroxisome proliferator activated receptor (PPAR) coactivator-1alpha (PGC 1alpha) and the transcription factor/nuclear receptor PPAR-?. It was therefore the aim of the present study to examine whether acute exercise with or without glycogen manipulation affects PGC-1alpha and PPAR-? function in rodent skeletal muscle. Twenty female Wistar rats were randomly assigned to 5 experimental groups (n = 4): control [CON]; normal glycogen control [NG-C]; normal glycogen exercise [NG-E]; low glycogen control [LG-C]; and low glycogen exercise [LG-E]). Gastrocnemius (GTN) muscles were collected immediately following exercise and analyzed for glycogen content, PPAR-? activity via chromatin immunoprecipitation (ChIP) assays, AMPK alpha1/alpha2 kinase activity, and the localization of AMPK and PGC-1alpha. Exercise reduced muscle glycogen by 47 and 75% relative to CON in the NG-E and LG-E groups, respectively. Exercise that started with low glycogen (LG-E) finished with higher AMPK-alpha2 activity (147%, p<0.05), nuclear AMPK alpha2 and PGC-1alpha, but no difference in AMPK-alpha1 activity compared to CON. In addition, PPAR-? binding to the CPT1 promoter was significantly increased only in the LG-E group. Finally, cell reporter studies in contracting C2C12 myotubes indicated that PPAR-? activity following contraction is sensitive to glucose availability, providing mechanistic insight into the association between PPAR-? and glycogen content/substrate availability. The present study is the first to examine PPAR-? activity in skeletal muscle in response to an acute bout of endurance exercise. Our data would suggest that a factor associated with muscle contraction and/or glycogen depletion activates PPAR-? and initiates AMPK translocation in skeletal muscle in response to exercise. PMID- 24146970 TI - Transient receptor potential melastatin 1: a hair cell transduction channel candidate. AB - Sound and head movements are perceived through sensory hair cells in the inner ear. Mounting evidence indicates that this process is initiated by the opening of mechanically sensitive calcium-permeable channels, also referred to as the mechanoelectrical transducer (MET) channels, reported to be around the tips of all but the tallest stereocilia. However, the identity of MET channel remains elusive. Literature suggests that the MET channel is a non-selective cation channel with a high Ca(2+) permeability and ~100 picosiemens conductance. These characteristics make members of the transient receptor potential (TRP) superfamily likely candidates for this role. One of these candidates is the transient receptor potential melastatin 1 protein (TRPM1), which is expressed in various cells types within the cochlea of the mouse including the hair cells. Recent studies demonstrate that mutations in the TRPM1 gene underlie the inherited retinal disease complete congenital stationary night blindness in humans and depolarizing bipolar cell dysfunction in the mouse retina, but auditory function was not assessed. Here we investigate the role of Trpm1 in hearing and as a possible hair cell MET channel using mice homozygous for the null allele of Trpm1 (Trpm1(-/-)) or a missense mutation in the pore domain of TRPM1 (Trpm1(tvrm27/tvrm27)). Hearing thresholds were evaluated in adult (4-5 months old) mice with auditory-evoked brain stem responses. Our data shows no statistically significant difference in hearing thresholds in Trpm1(-/-) or Trpm1(tvrm27/tvrm27) mutants compared to littermate controls. Further, none of the mutant mice showed any sign of balance disorder, such as head bobbing or circling. These data suggest that TRPM1 is not essential for development of hearing or balance and it is unlikely that TRPM1 is a component of the hair cell MET channel. PMID- 24146971 TI - Molecular characterization of monoclonal antibodies that inhibit acetylcholinesterase by targeting the peripheral site and backdoor region. AB - The inhibition properties and target sites of monoclonal antibodies (mAbs) Elec403, Elec408 and Elec410, generated against Electrophorus electricus acetylcholinesterase (AChE), have been defined previously using biochemical and mutagenesis approaches. Elec403 and Elec410, which bind competitively with each other and with the peptidic toxin inhibitor fasciculin, are directed toward distinctive albeit overlapping epitopes located at the AChE peripheral anionic site, which surrounds the entrance of the active site gorge. Elec408, which is not competitive with the other two mAbs nor fasciculin, targets a second epitope located in the backdoor region, distant from the gorge entrance. To characterize the molecular determinants dictating their binding site specificity, we cloned and sequenced the mAbs; generated antigen-binding fragments (Fab) retaining the parental inhibition properties; and explored their structure-function relationships using complementary x-ray crystallography, homology modeling and flexible docking approaches. Hypermutation of one Elec403 complementarity determining region suggests occurrence of antigen-driven selection towards recognition of the AChE peripheral site. Comparative analysis of the 1.9A resolution structure of Fab408 and of theoretical models of its Fab403 and Fab410 congeners evidences distinctive surface topographies and anisotropic repartitions of charges, consistent with their respective target sites and inhibition properties. Finally, a validated, data-driven docking model of the Fab403-AChE complex suggests a mode of binding at the PAS that fully correlates with the functional data. This comprehensive study documents the molecular peculiarities of Fab403 and Fab410, as the largest peptidic inhibitors directed towards the peripheral site, and those of Fab408, as the first inhibitor directed toward the backdoor region of an AChE and a unique template for the design of new, specific modulators of AChE catalysis. PMID- 24146972 TI - Membrane lipid co-aggregation with alpha-synuclein fibrils. AB - Amyloid deposits from several human diseases have been found to contain membrane lipids. Co-aggregation of lipids and amyloid proteins in amyloid aggregates, and the related extraction of lipids from cellular membranes, can influence structure and function in both the membrane and the formed amyloid deposit. Co-aggregation can therefore have important implications for the pathological consequences of amyloid formation. Still, very little is known about the mechanism behind co aggregation and molecular structure in the formed aggregates. To address this, we study in vitro co-aggregation by incubating phospholipid model membranes with the Parkinson's disease-associated protein, alpha-synuclein, in monomeric form. After aggregation, we find spontaneous uptake of phospholipids from anionic model membranes into the amyloid fibrils. Phospholipid quantification, polarization transfer solid-state NMR and cryo-TEM together reveal co-aggregation of phospholipids and alpha-synuclein in a saturable manner with a strong dependence on lipid composition. At low lipid to protein ratios, there is a close association of phospholipids to the fibril structure, which is apparent from reduced phospholipid mobility and morphological changes in fibril bundling. At higher lipid to protein ratios, additional vesicles adsorb along the fibrils. While interactions between lipids and amyloid-protein are generally discussed within the perspective of different protein species adsorbing to and perturbing the lipid membrane, the current work reveals amyloid formation in the presence of lipids as a co-aggregation process. The interaction leads to the formation of lipid-protein co-aggregates with distinct structure, dynamics and morphology compared to assemblies formed by either lipid or protein alone. PMID- 24146973 TI - Exploring a proposed WHO method to determine thresholds for seasonal influenza surveillance. AB - INTRODUCTION: Health authorities find thresholds useful to gauge the start and severity of influenza seasons. We explored a method for deriving thresholds proposed in an influenza surveillance manual published by the World Health Organization (WHO). METHODS: For 2002-2011, we analysed two routine influenza like-illness (ILI) datasets, general practice sentinel surveillance and a locum medical service sentinel surveillance, plus laboratory data and hospital admissions for influenza. For each sentinel dataset, we created two composite variables from the product of weekly ILI data and the relevant laboratory data, indicating the proportion of tested specimens that were positive. For all datasets, including the composite datasets, we aligned data on the median week of peak influenza or ILI activity and assigned three threshold levels: seasonal threshold, determined by inspection; and two intensity thresholds termed average and alert thresholds, determined by calculations of means, medians, confidence intervals (CI) and percentiles. From the thresholds, we compared the seasonal onset, end and intensity across all datasets from 2002-2011. Correlation between datasets was assessed using the mean correlation coefficient. RESULTS: The median week of peak activity was week 34 for all datasets, except hospital data (week 35). Means and medians were comparable and the 90% upper CIs were similar to the 95(th) percentiles. Comparison of thresholds revealed variations in defining the start of a season but good agreement in describing the end and intensity of influenza seasons, except in hospital admissions data after the pandemic year of 2009. The composite variables improved the agreements between the ILI and other datasets. Datasets were well correlated, with mean correlation coefficients of >0.75 for a range of combinations. CONCLUSIONS: Thresholds for influenza surveillance are easily derived from historical surveillance and laboratory data using the approach proposed by WHO. Use of composite variables is helpful for describing influenza season characteristics. PMID- 24146974 TI - Biogas production from protein-rich biomass: fed-batch anaerobic fermentation of casein and of pig blood and associated changes in microbial community composition. AB - It is generally accepted as a fact in the biogas technology that protein-rich biomass substrates should be avoided due to inevitable process inhibition. Substrate compositions with a low C/N ratio are considered difficult to handle and may lead to process failure, though protein-rich industrial waste products have outstanding biogas generation potential. This common belief has been challenged by using protein-rich substrates, i.e. casein and precipitated pig blood protein in laboratory scale continuously stirred mesophilic fed-batch biogas fermenters. Both substrates proved suitable for sustained biogas production (0.447 L CH4/g protein oDM, i.e. organic total solids) in high yield without any additives, following a period of adaptation of the microbial community. The apparent key limiting factors in the anaerobic degradation of these proteinaceous materials were the accumulation of ammonia and hydrogen sulfide. Changes in time in the composition of the microbiological community were determined by next-generation sequencing-based metagenomic analyses. Characteristic rearrangements of the biogas-producing community upon protein feeding and specific differences due to the individual protein substrates were recognized. The results clearly demonstrate that sustained biogas production is readily achievable, provided the system is well-characterized, understood and controlled. Biogas yields (0.45 L CH4/g oDM) significantly exceeding those of the commonly used agricultural substrates (0.25-0.28 L CH4/g oDM) were routinely obtained. The results amply reveal that these high-energy-content waste products can be converted to biogas, a renewable energy carrier with flexible uses that can replace fossil natural gas in its applications. Process control, with appropriate acclimation of the microbial community to the unusual substrate, is necessary. Metagenomic analysis of the microbial community by next-generation sequencing allows a precise determination of the alterations in the community composition in the course of the process. PMID- 24146975 TI - Obstacle avoidance, visual detection performance, and eye-scanning behavior of glaucoma patients in a driving simulator: a preliminary study. AB - The objective of this study was to evaluate differences in driving performance, visual detection performance, and eye-scanning behavior between glaucoma patients and control participants without glaucoma. Glaucoma patients (n = 23) and control participants (n = 12) completed four 5-min driving sessions in a simulator. The participants were instructed to maintain the car in the right lane of a two-lane highway while their speed was automatically maintained at 100 km/h. Additional tasks per session were: Session 1: none, Session 2: verbalization of projected letters, Session 3: avoidance of static obstacles, and Session 4: combined letter verbalization and avoidance of static obstacles. Eye-scanning behavior was recorded with an eye-tracker. Results showed no statistically significant differences between patients and control participants for lane keeping, obstacle avoidance, and eye-scanning behavior. Steering activity, number of missed letters, and letter reaction time were significantly higher for glaucoma patients than for control participants. In conclusion, glaucoma patients were able to avoid objects and maintain a nominal lane keeping performance, but applied more steering input than control participants, and were more likely than control participants to miss peripherally projected stimuli. The eye-tracking results suggest that glaucoma patients did not use extra visual search to compensate for their visual field loss. Limitations of the study, such as small sample size, are discussed. PMID- 24146976 TI - An integrated approach based on multiplexed protein array and iTRAQ labeling for in-depth identification of pathways associated to IVF outcome. AB - The emergence of high-throughput protein quantification methodologies has enabled the comprehensive characterization by longitudinal and cross-sectional studies of biological fluids under physiological and pathological conditions. In particular, the simultaneous investigation of cytokines and growth factors signaling pathways and their associated downstream effectors by integrated multiplexed approaches offers a powerful strategy to gain insights into biological networks and processes in living systems. A growing body of research indicates that bioactive molecules of human reproductive fluids, including human follicular fluid (hFF), may affect oocyte quality, fertilization and embryo development, thus potentially influencing the physiopathology of pregnancy-related conditions. In this work, an iTRAQ labeling strategy has been complemented with a multiplexed protein array approach to analyze hFFs with the aim to investigate biological processes and pathways related to in vitro fertilization (IVF) outcome. The iTRAQ labeling strategy lead to the quantification of 89 proteins, 30 of which were differentially expressed in hFFs with successful compared to unsuccessful IVF outcome. The targeted study, based on multiplexed antibody protein arrays, allowed the simultaneous quantification of 27 low abundance proteins, including growth factors, chemokines and cytokines endowed with pro- and anti-inflammatory activity. A significant number of differentially regulated proteins were involved in biological functions related to blood coagulation, acute phase response signaling and complement system. Overall, the present results provide an integrated overview of protein changes in hFFs associated to IVF outcome, thus improving current knowledge in reproductive medicine and fertility research. PMID- 24146977 TI - Adequately adapted insulin secretion and decreased hepatic insulin extraction cause elevated insulin concentrations in insulin resistant non-diabetic adrenal incidentaloma patients. AB - BACKGROUND: Insulin-resistance is commonly found in adrenal incidentaloma (AI) patients. However, little is known about beta-cell secretion in AI, because comparisons are difficult, since beta-cell-function varies with altered insulin sensitivity. OBJECTIVES: To retrospectively analyze beta-cell function in non diabetic AI, compared to healthy controls (CON). METHODS: AI (n=217, 34%males, 57 +/- 1 years, body-mass-index:27.7 +/- 0.3 kg/m(2)) and CON [n = 25, 32%males, 56 +/- 1 years, 26.7 +/- 0.8 kg/m(2)] with comparable anthropometry (p >= 0.31) underwent oral-glucose-tolerance-tests (OGTTs) with glucose, insulin, and C peptide measurements. 1mg-dexamethasone-suppression-tests were performed in AI. AI were divided according to post-dexamethasone-suppression-test cortisol thresholds of 1.8 and 5 ug/dL into 3 subgroups: pDexa<1.8 ug/dL, pDexa1.8-5 ug/dL and pDexa>5 ug/dL. Using mathematical modeling, whole-body insulin-sensitivity [Clamp-like-Index (CLIX)], insulinogenic Index, Disposition Index, Adaptation Index, and hepatic insulin extraction were calculated. RESULTS: CLIX was lower in AI combined (4.9 +/- 0.2 mg . kg(-1) . min(-1)), pDexa<1.8 ug/dL (4.9 +/- 0.3) and pDexa1.8-5 ug/dL (4.7 +/- 0.3, p<0.04 vs.CON:6.7 +/- 0.4). Insulinogenic and Disposition Indexes were 35%-97% higher in AI and each subgroup (p<0.008 vs.CON), whereas C-peptide-derived Adaptation Index, compensating for insulin-resistance, was comparable between AI, subgroups, and CON. Mathematical estimation of insulin derived (insulinogenic and Disposition) Indexes from associations to insulin sensitivity in CON revealed that AI-subgroups had ~19%-32% higher insulin secretion than expectable. These insulin-secretion-index differences negatively (r=-0.45, p<0.001) correlated with hepatic insulin extraction, which was 13-16% lower in AI and subgroups (p<0.003 vs.CON). CONCLUSIONS: AI-patients show insulin resistance, but adequately adapted insulin secretion with higher insulin concentrations during an OGTT, because of decreased hepatic insulin extraction; this finding affects all AI-patients, regardless of dexamethasone-suppression test outcome. PMID- 24146978 TI - Mast cells modulate acute toxoplasmosis in murine models. AB - The role of mast cells (MCs) in Toxoplasma gondii infection is poorly known. Kunming outbred mice were infected intraperitoneally with RH strain T. gondii, either treated with compound 48/80 (C48/80, MC activator) or disodium cromoglycate (DSCG, MC inhibitor). Compared with infected controls, infected mice treated with C48/80 exhibited significantly increased inflammation in the liver (P < 0.01), spleen (P < 0.05), and mesentery (P < 0.05) tissues, higher parasite burden in the peritoneal lavage fluids (P < 0.01), and increased levels of mRNA transcripts of T. gondii tachyzoite surface antigen 1 (SAG1) gene in the spleen and liver tissues (P < 0.01), accompanied with significantly increased Th1 cytokine (IFN-gamma, IL-12p40, and TNF-alpha) (P < 0.01) and decreased IL-10 (P < 0.01) mRNA expressions in the liver, and increased IFN-gamma (P < 0.01) and IL 12p40 (P < 0.01) but decreased TNF-alpha (P < 0.01) and IL-4 (P < 0.01) in the spleens of infected mice treated with C48/80 at day 9-10 p.i. Whereas mice treated with DSCG had significantly decreased tissue lesions (P < 0.01), lower parasite burden in the peritoneal lavage fluids (P < 0.01) and decreased SAG1 expressions in the spleen and liver tissues (P < 0.01), accompanied with significantly increased IFN-gamma (P < 0.01) and IL-12p40 (P < 0.05) in the liver, and decreased IFN-gamma (P < 0.05) and TNF-alpha (P < 0.01) in the spleens; IL-4 and IL-10 expressions in both the spleen and liver were significantly increased (P < 0.01) in the infected mice treated with DSCG. These findings suggest that mediators associated with the MC activation may play an important role in modulating acute inflammatory pathogenesis and parasite clearance during T. gondii infection in this strain of mice. Thus, MC activation/inhibition mechanisms are potential novel targets for the prevention and control of T. gondii infection. PMID- 24146980 TI - Inferring the relative resilience of alternative states. AB - Ecological systems may occur in alternative states that differ in ecological structures, functions and processes. Resilience is the measure of disturbance an ecological system can absorb before changing states. However, how the intrinsic structures and processes of systems that characterize their states affects their resilience remains unclear. We analyzed time series of phytoplankton communities at three sites in a floodplain in central Spain to assess the dominant frequencies or "temporal scales" in community dynamics and compared the patterns between a wet and a dry alternative state. The identified frequencies and cross scale structures are expected to arise from positive feedbacks that are thought to reinforce processes in alternative states of ecological systems and regulate emergent phenomena such as resilience. Our analyses show a higher species richness and diversity but lower evenness in the dry state. Time series modeling revealed a decrease in the importance of short-term variability in the communities, suggesting that community dynamics slowed down in the dry relative to the wet state. The number of temporal scales at which community dynamics manifested, and the explanatory power of time series models, was lower in the dry state. The higher diversity, reduced number of temporal scales and the lower explanatory power of time series models suggest that species dynamics tended to be more stochastic in the dry state. From a resilience perspective our results highlight a paradox: increasing species richness may not necessarily enhance resilience. The loss of cross-scale structure (i.e. the lower number of temporal scales) in community dynamics across sites suggests that resilience erodes during drought. Phytoplankton communities in the dry state are therefore likely less resilient than in the wet state. Our case study demonstrates the potential of time series modeling to assess attributes that mediate resilience. The approach is useful for assessing resilience of alternative states across ecological and other complex systems. PMID- 24146979 TI - Deletion of the eIF2alpha Kinase GCN2 fails to rescue the memory decline associated with Alzheimer's disease. AB - Emerging evidence suggests that dysregulated translation through phosphorylation of eukaryotic initiation factor-2alpha (eIF2alpha) may contribute to Alzheimer's disease (AD) and related memory impairments. However, the underlying mechanisms remain unclear. Here, we crossed knockout mice for an eIF2alpha kinase (GCN2: general control nonderepressible-2 kinase) with 5XFAD transgenic mice, and investigated whether GCN2 deletion affects AD-like traits in this model. As observed in AD brains, 5XFAD mice recapitulated significant elevations in the beta-secretase enzyme BACE1 and the CREB repressor ATF4 concomitant with a dramatic increase of eIF2alpha phosphorylation. Contrary to expectation, we found that GCN2(-/-) and GCN2(+/-) deficiencies aggravate rather than suppress hippocampal BACE1 and ATF4 elevations in 5XFAD mice, failing to rescue memory deficits as tested by the contextual fear conditioning. The facilitation of these deleterious events resulted in exacerbated beta-amyloid accumulation, plaque pathology and CREB dysfunction in 5XFAD mice with GCN2 mutations. Notably, GCN2 deletion caused overactivation of the PKR-endoplasmic reticulum-related kinase (PERK)-dependent eIF2alpha phosphorylation pathway in 5XFAD mice in the absence of changes in the PKR pathway. Moreover, PERK activation in response to GCN2 deficiency was specific to 5XFAD mice, since phosphorylated PERK levels were equivalent between GCN2(-/-) and wild-type control mice. Our findings suggest that GCN2 may be an important eIF2alpha kinase under the physiological condition, whereas blocking the GCN2 pathway under exposure to significant beta-amyloidosis rather aggravates eIF2alpha phosphorylation leading to BACE1 and ATF4 elevations in AD. PMID- 24146981 TI - Oncogenic features of PHF8 histone demethylase in esophageal squamous cell carcinoma. AB - Esophageal cancer is the sixth leading cause of cancer-related deaths worldwide. It has been reported that histone demethylases are involved in the carcinogenesis of certain types of tumors. Here, we studied the role of one of the histone lysine demethylases, plant homeodomain finger protein 8 (PHF8), in the carcinogenesis of esophageal squamous cell carcinoma (ESCC). Using short hairpin RNA via lentiviral infection, we established stable ESCC cell lines with constitutive downregulation of PHF8 expression. Knockdown of PHF8 in ESCC cells resulted in inhibition of cell proliferation and an increase of apoptosis. Moreover, there were reductions of both anchorage-dependent and -independent colony formation. In vitro migration and invasion assays showed that knockdown of PHF8 led to a reduction in the number of migratory and invasive cells. Furthermore, downregulation of PHF8 attenuated the tumorigenicity of ESCC cells in vivo. Taken together, our study revealed the oncogenic features of PHF8 in ESCC, suggesting that PHF8 may be a potential diagnostic marker and therapeutic target for ESCC. PMID- 24146982 TI - Cell Infectivity in relation to bovine leukemia virus gp51 and p24 in bovine milk exosomes. AB - Exosomes are small membranous microvesicles (40-100 nm in diameter) and are extracellularly released from a wide variety of cells. Exosomes contain microRNA, mRNA, and cellular proteins, which are delivered into recipient cells via these exosomes, and play a role in intercellular communication. In bovine leukemia virus (BLV) infection of cattle, although it is thought to be a minor route of infection, BLV can be transmitted to calves via milk. Here, we investigated the association between exosomes and BLV in bovine milk. BLV structural proteins, gp51 (Env) and p24 (Gag), were detected in bovine milk exosomes from BLV-infected cattle by Western blot analysis. In cells inoculated with these milk exosomes, BLV DNA was not detected during three serial passages by nested PCR. Purification of exosomes from persistently BLV-infected cells was achieved by immuno-magnetic separation using an antibody against exosomes coupled to magnetic beads. Consistently, BLV gp51 and p24 proteins were detected in purified exosomes. Moreover, reverse transcriptase activity was observed in purified exosomes, meaning that exosomes also contain viral enzyme. However, BLV DNA was not detected in serially passaged cells after inoculation of purified exosomes, indicating that exosomes carrying BLV proteins appeared to be not infectious. These results suggest that BLV proteins are released with milk exosomes and could be transferred into recipient cells of calves via milk exosomes as an alternative route not requiring virus infection. Moreover it is also possible that bovine milk exosomes play a role in clearance of BLV proteins from infected cells. PMID- 24146983 TI - Duffy antigen receptor for chemokines regulates post-fracture inflammation. AB - There is now considerable experimental data to suggest that inflammatory cells collaborate in the healing of skeletal fractures. In terms of mechanisms that contribute to the recruitment of inflammatory cells to the fracture site, chemokines and their receptors have received considerable attention. Our previous findings have shown that Duffy antigen receptor for chemokines (Darc), the non classical chemokine receptor that does not signal, but rather acts as a scavenger of chemokines that regulate cell migration, is a negative regulator of peak bone density in mice. Furthermore, because Darc is expressed by inflammatory and endothelial cells, we hypothesized that disruption of Darc action will affect post-fracture inflammation and consequently will affect fracture healing. To test this hypothesis, we evaluated fracture healing in mice with targeted disruption of Darc and corresponding wild type (WT) control mice. We found that fracture callus cartilage formation was significantly greater (33%) at 7 days post-surgery in Darc-KO compared to WT mice. The increased cartilage was associated with greater Collagen (Col) II expression at 3 days post-fracture and Col-X at 7 days post-fracture compared to WT mice, suggesting that Darc deficiency led to early fracture cartilage formation and differentiation. We then compared the expression of cytokine and chemokine genes known to be induced during inflammation. Interleukin (Il)-1beta, Il-6, and monocyte chemotactic protein 1 were all down regulated in the fractures derived from Darc-KO mice at one day post-fracture, consistent with an altered inflammatory response. Furthermore, the number of macrophages was significantly reduced around the fractures in Darc-KO compared to WT mice. Based on these data, we concluded that Darc plays a role in modulating the early inflammatory response to bone fracture and subsequent cartilage formation. However, the early cartilage formation was not translated with an early bone formation at the fracture site in Darc-KO compared to WT mice. PMID- 24146985 TI - Feeding experience of Bemisia tabaci (Hemiptera: Aleyrodidae) affects their performance on different host plants. AB - The sweetpotato whitefly, Bemisia tabaci biotype B is extremely polyphagous with >600 species of host plants. We hypothesized that previous experience of the whitefly on a given host plant affects their host selection and performance on the plants without previous experience. We investigated the host selection for feeding and oviposition of adults and development and survival of immatures of three host-plant-experienced populations of B. tabaci, namely Bemisia-eggplant, Bemisia-tomato and Bemisia-cucumber, on their experienced host plant and each of the three other plant species (eggplant, tomato, cucumber and pepper) without previous experience. We found that the influence of previous experience of the whiteflies varied among the populations. All populations refused pepper for feeding and oviposition, whereas the Bemisia-cucumber and the Bemisia-eggplant strongly preferred cucumber. Bemisia-tomato did not show strong preference to any of the three host plants. Development time from egg to adult eclosion varied among the populations, being shortest on eggplant, longest on pepper, and intermediate on tomato and cucumber except for the Bemisia-cucumber developed similarly on tomato and pepper. The survivorship from egg to adult eclosion of all populations was highest on eggplant (80-98%), lowest on pepper (0-20%), and intermediate on tomato and cucumber. In conclusion, the effects of previous experience of whiteflies on host selection for feeding and oviposition, development, and survivorship varied depending on host plants, and host plants play a stronger role than previous experience. Preference of feeding and oviposition by adults may not accurately reflect host suitability of immatures. These results provided important information for understanding whitefly population dynamics and dispersal among different crop systems. PMID- 24146984 TI - Direct induction of chondrogenic cells from human dermal fibroblast culture by defined factors. AB - The repair of large cartilage defects with hyaline cartilage continues to be a challenging clinical issue. We recently reported that the forced expression of two reprogramming factors (c-Myc and Klf4) and one chondrogenic factor (SOX9) can induce chondrogenic cells from mouse dermal fibroblast culture without going through a pluripotent state. We here generated induced chondrogenic (iChon) cells from human dermal fibroblast (HDF) culture with the same factors. We developed a chondrocyte-specific COL11A2 promoter/enhancer lentiviral reporter vector to select iChon cells. The human iChon cells expressed marker genes for chondrocytes but not fibroblasts, and were derived from non-chondrogenic COL11A2-negative cells. The human iChon cells formed cartilage but not tumors in nude mice. This approach could lead to the preparation of cartilage directly from skin in human, without going through pluripotent stem cells. PMID- 24146986 TI - A pilot study on the feasibility of robot-aided leg motor training to facilitate active participation. AB - Robot-aided gait therapy offers a promising approach towards improving gait function in individuals with neurological disorders such as stroke or spinal cord injury. However, incorporation of appropriate control strategies is essential for actively engaging the patient in the therapeutic process. Although several control algorithms (such as assist-as-needed and error augmentation) have been proposed to improve active patient participation, we hypothesize that the therapeutic benefits of these control algorithms can be greatly enhanced if combined with a motor learning task to facilitate neural reorganization and motor recovery. Here, we describe an active robotic training approach (patient cooperative robotic gait training combined with a motor learning task) using the Lokomat and pilot-tested whether this approach can enhance active patient participation during training. Six neurologically intact adults and three chronic stroke survivors participated in this pilot feasibility study. Participants walked in a Lokomat while simultaneously performing a foot target-tracking task that necessitated greater hip and knee flexion during the swing phase of the gait. We computed the changes in tracking error as a measure of motor performance and changes in muscle activation as a measure of active subject participation. Repeated practice of the motor-learning task resulted in significant reductions in target-tracking error in all subjects. Muscle activation was also significantly higher during active robotic training compared to simply walking in the robot. The data from stroke participants also showed a trend similar to neurologically intact participants. These findings provide a proof-of-concept demonstration that combining robotic gait training with a motor learning task enhances active participation. PMID- 24146987 TI - Incidence and outcome of early acute kidney injury in critically-ill trauma patients. AB - OBJECTIVE: To determine the incidence and effect on mortality of early acute kidney injury in severely injured trauma patients using the Acute Kidney Injury Network creatinine criteria. DESIGN: A retrospective cohort study of severely injured trauma patients admitted to the shock trauma intensive care unit. SETTING: Texas Trauma Institute, a state designated level I trauma unit certified by the American College of Surgeons Committee on Trauma. PATIENTS: 901 severely injured trauma patients admitted over a 15 month period to the shock trauma intensive care unit. INTERVENTIONS: Retrospective analysis of prospectively collected data abstracted from an electronic trauma database. MEASUREMENTS AND MAIN RESULTS: Of 901 eligible patients admitted to the shock trauma intensive care unit after traumatic injury, 54 patients (6%) developed acute kidney injury, of whom 10 (19%) required renal replacement therapy. The 30-day mortality rate for the entire cohort was 83/901 (9.2%). Patients with early acute kidney injury had a mortality rate of 16/54 (29.6%). When corrected for multiple covariates including injury severity scores, the development of early acute kidney injury was associated with a significantly higher risk of death at 30 days with an OR of 3.4 (95% CI 1.6-7.4). CONCLUSIONS: Applying the Acute Kidney Injury Network creatinine criteria in severely injured trauma patients, the incidence of early acute kidney injury was 6%. After correction for injury severity, development of early acute kidney injury was independently associated with significantly higher 30-day mortality. PMID- 24146988 TI - Transcriptional response to deletion of the phosphatidylserine decarboxylase Psd1p in the yeast Saccharomyces cerevisiae. AB - In the yeast, Saccharomyces cerevisiae, the synthesis of the essential phospholipid phosphatidylethanolamine (PE) is accomplished by a network of reactions which comprises four different pathways. The enzyme contributing most to PE formation is the mitochondrial phosphatidylserine decarboxylase 1 (Psd1p) which catalyzes conversion of phosphatidylserine (PS) to PE. To study the genome wide effect of an unbalanced cellular and mitochondrial PE level and in particular the contribution of Psd1p to this depletion we performed a DNA microarray analysis with a ?psd1 deletion mutant. This approach revealed that 54 yeast genes were significantly up-regulated in the absence of PSD1 compared to wild type. Surprisingly, marked down-regulation of genes was not observed. A number of different cellular processes in different subcellular compartments were affected in a ?psd1 mutant. Deletion mutants bearing defects in all 54 candidate genes, respectively, were analyzed for their growth phenotype and their phospholipid profile. Only three mutants, namely ?gpm2, ?gph1 and ?rsb1, were affected in one of these parameters. The possible link of these mutations to PE deficiency and PSD1 deletion is discussed. PMID- 24146989 TI - Toxicity and immunogenicity of Enterotoxigenic Escherichia coli heat-labile and heat-stable toxoid fusion 3xSTa(A14Q)-LT(S63K/R192G/L211A) in a murine model. AB - Diarrhea is the second leading cause of death to young children. Enterotoxigenic Escherichia coli (ETEC) are the most common bacteria causing diarrhea. Adhesins and enterotoxins are the virulence determinants in ETEC diarrhea. Adhesins mediate bacterial attachment and colonization, and enterotoxins including heat labile (LT) and heat-stable type Ib toxin (STa) disrupt fluid homeostasis in host cells that leads to fluid hyper-secretion and diarrhea. Thus, adhesins and enterotoxins have been primarily targeted in ETEC vaccine development. A recent study reported toxoid fusions with STa toxoid (STa(P13F)) fused at the N- or C terminus, or inside the A subunit of LT(R192G) elicited neutralizing antitoxin antibodies, and suggested application of toxoid fusions in ETEC vaccine development (Liu et al., Infect. Immun. 79:4002-4009, 2011). In this study, we generated a different STa toxoid (STa(A14Q)) and a triple-mutant LT toxoid (LT(S63K/R192G/L211A), tmLT), constructed a toxoid fusion (3xSTa(A14Q)-tmLT) that carried 3 copies of STa(A14Q) for further facilitation of anti-STa immunogenicity, and assessed antigen safety and immunogenicity in a murine model to explore its potential for ETEC vaccine development. Mice immunized with this fusion antigen showed no adverse effects, and developed antitoxin antibodies particularly through the IP route. Anti-LT antibodies were detected and were shown neutralizing against CT in vitro. Anti-STa antibodies were also detected in the immunized mice, and serum from the IP immunized mice neutralized STa toxin in vitro. Data from this study indicated that toxoid fusion 3xSTa(A14Q)-tmLT is safe and can induce neutralizing antitoxin antibodies, and provided helpful information for vaccine development against ETEC diarrhea. PMID- 24146990 TI - Large extracellular loop of tetraspanin as a potential vaccine candidate for filariasis. AB - Lymphatic filariasis affects nearly 120 million people worldwide and mass preventive chemotherapy is currently used as a strategy to control this infection. This has substantially reduced the incidence of the infection in several parts of the world. However, a prophylactic vaccine would be more effective in preventing future infections and will supplement the mass chemotherapy efforts. Unfortunately, there is no licensed vaccine available currently to prevent this infection. Molecules expressed on the surface of the parasite are potential candidates for vaccine development as they are exposed to the host immune system. In this study we show that the large extracellular loop of tetraspanin (TSP LEL), a protein expressed on the cuticle of Brugia malayi and Wuchereria bancrofti is a potential vaccine candidate. Our results showed that BmTSP LEL is expressed on the surface of B. malayi infective third stage larvae (L3) and sera from human subjects who are putatively immune to lymphatic filariasis carry high titer of IgG1 and IgG3 antibodies against BmTSP LEL and WbTSP LEL. We also showed that these antibodies in the sera of human subjects can participate in the killing of B. malayi L3 in an antibody dependent cell-mediated cytotoxicity mechanism. Vaccination trials in mice showed that close to 64% protection were achieved against challenge infections with B. malayi L3. Immunized animals showed high titer of anti-WbTSP LEL IgG1, IgG2a and IgG2b antibodies in the sera and IFN-gamma secreting cells in the spleen. Onchocerca volvulus another filarial parasite also expresses TSP LEL. Cross-reactivity studies showed that IgG1 antibody in the sera of endemic normal subjects, recognize OvTSP LEL. Similarly, anti-OvTSP LEL antibodies in the sera of subjects who are immune to O. volvulus were also shown to cross-react with rWbTSP LEL and rBmTSP LEL. These findings thus suggested that rTSP LEL can be developed as a potential vaccine candidate against multiple filarial infections. PMID- 24146992 TI - Form-finding model shows how cytoskeleton network stiffness is realized. AB - In eukaryotic cells the actin-cytoskeletal network provides stiffness and the driving force that contributes to changes in cell shape and cell motility, but the elastic behavior of this network is not well understood. In this paper a two dimensional form-finding model is proposed to investigate the elasticity of the actin filament network. Utilizing an initially random array of actin filaments and actin-cross-linking proteins the form-finding model iterates until the random array is brought into a stable equilibrium configuration. With some care given to actin filament density and length, distance between host sites for cross-linkers, and overall domain size the resulting configurations from the form-finding model are found to be topologically similar to cytoskeletal networks in real cells. The resulting network may then be mechanically exercised to explore how the actin filaments deform and align under load and the sensitivity of the network's stiffness to actin filament density, length, etc. Results of the model are consistent with the experimental literature, e.g. actin filaments tend to re orient in the direction of stretching; and the filament relative density, filament length, and actin-cross-linking protein's relative density, control the actin-network stiffness. The model provides a ready means of extension to more complicated domains and a three-dimensional form-finding model is under development as well as models studying the formation of actin bundles. PMID- 24146991 TI - Drug resistance profiles of Mycobacterium tuberculosis complex and factors associated with drug resistance in the Northwest and Southwest Regions of Cameroon. AB - BACKGROUND: Anti-tuberculosis drug resistance continues to be a major obstacle to tuberculosis (TB) control programmes with HIV being a major risk factor in developing TB. We investigated anti-TB drug resistance profiles and the impact of socioeconomic as well as behavioural factors on the prevalence of TB and drug resistance in two regions of Cameroon with such data paucity. METHODS: This was a hospital-based study in which 1706 participants, comprising 1133 females and 573 males consecutively enrolled from selected TB and HIV treatment centres of the Northwest and Southwest regions. Demographic, clinical and self-reported risk behaviours and socioeconomic data were obtained with the consent of participants using questionnaires. Culture and drug resistance testing were performed according to standard procedures. RESULTS: The prevalence of resistance to at least one anti-TB drug was 27.7% and multi-drug resistance was 5.9%. Smoking, concurrent alcohol consumption and smoking, being on antiretroviral therapy for <= 12 months and previous household contact with TB patient were independently associated with tuberculosis prevalence, while only previous tuberculosis infection was associated with drug resistance in a univariate analysis. CONCLUSION: The study showed a high prevalence of drug resistance TB in the study population with only previous TB infection associated with drug resistance in a univariate analysis. It also provides evidence in our context, of the role of alcohol and smoking in increasing the risk of developing TB, which is more likely in people living with HIV/AIDS. Therefore, it is important for public health authorities to integrate and intensify alcohol/smoking abstention interventions in TB and HIV control programs in Cameroon. PMID- 24146993 TI - Prognostic value of ICH score and ICH-GS score in Chinese intracerebral hemorrhage patients: analysis from the China National Stroke Registry (CNSR). AB - PURPOSE: No strong evidence of efficacy currently exists for different intracerebral hemorrhage (ICH) scoring system in predicting the prognosis of ICH in the Chinese population. This study aimed to test the accuracy of the ICH score and the ICH grading scale (ICH-GS) score in predicting the favorable prognosis in a large cohort of ICH patients in China. METHODS: This study was a multicenter, prospective cohort study. Patients diagnosed with ICH between September 2007 and August 2008 from the nationwide China National Stroke Registry (CNSR) database were screened and enrolled in this study. Demographics of the patients, treatments, mortality as well as the clinic and radiologic findings of ICH were collected. An ICH score and an ICH-GS score were evaluated for all the patients at admission. Follow-ups were conducted by phone at 3, 6 and 12 months after ICH onset. The modified Rankin scale (mRS) score was used to evaluate favorable functional outcome and was obtained at hospital discharge and during the 3-, 6- and 12-month follow-up visits. RESULTS: There were 410 (12.6%) in-hospital mortality out of a total of 3,255 ICH patients. The values of the Area Under Curve (AUC)at discharge, 3-, 6- and 12-month follow-up for ICH score were 0.72, 0.76, 0.76 and 0.75, respectively; while the numbers for the ICH-GS score were 0.71, 0.77, 0.78 and 0.78, respectively. At 6-month and 12-month follow-up, the ICH-GS score presented a significant better value in predicting favorable prognosis than did the ICH score (P=0.0003 and <0.0001, respectively). CONCLUSION: Both the ICH and ICH-GS scores were effective inaccurately predicting the favorable functional outcome of ICH in the Chinese population. For mid-term and long-term prediction, the ICH-GS score was superior over the ICH score. PMID- 24146994 TI - Identification and characterization of a novel trehalose synthase gene derived from saline-alkali soil metagenomes. AB - A novel trehalose synthase (TreS) gene was identified from a metagenomic library of saline-alkali soil by a simple activity-based screening system. Sequence analysis revealed that TreS encodes a protein of 552 amino acids, with a deduced molecular weight of 63.3 kDa. After being overexpressed in Escherichia coli and purified, the enzymatic properties of TreS were investigated. The recombinant TreS displayed its optimal activity at pH 9.0 and 45 degrees C, and the addition of most common metal ions (1 or 30 mM) had no inhibition effect on the enzymatic activity evidently, except for the divalent metal ions Zn(2+) and Hg(2+). Kinetic analysis showed that the recombinant TreS had a 4.1-fold higher catalytic efficiency (Kcat/K m ) for maltose than for trehalose. The maximum conversion rate of maltose into trehalose by the TreS was reached more than 78% at a relatively high maltose concentration (30%), making it a good candidate in the large-scale production of trehalsoe after further study. In addition, five amino acid residues, His172, Asp201, Glu251, His318 and Asp319, were shown to be conserved in the TreS, which were also important for glycosyl hydrolase family 13 enzyme catalysis. PMID- 24146995 TI - Characteristics of acupuncture treatment associated with outcome: an individual patient meta-analysis of 17,922 patients with chronic pain in randomised controlled trials. AB - BACKGROUND: Recent evidence shows that acupuncture is effective for chronic pain. However we do not know whether there are characteristics of acupuncture or acupuncturists that are associated with better or worse outcomes. METHODS: An existing dataset, developed by the Acupuncture Trialists' Collaboration, included 29 trials of acupuncture for chronic pain with individual data involving 17,922 patients. The available data on characteristics of acupuncture included style of acupuncture, point prescription, location of needles, use of electrical stimulation and moxibustion, number, frequency and duration of sessions, number of needles used and acupuncturist experience. We used random-effects meta regression to test the effect of each characteristic on the main effect estimate of pain. Where sufficient patient-level data were available, we conducted patient level analyses. RESULTS: When comparing acupuncture to sham controls, there was little evidence that the effects of acupuncture on pain were modified by any of the acupuncture characteristics evaluated, including style of acupuncture, the number or placement of needles, the number, frequency or duration of sessions, patient-practitioner interactions and the experience of the acupuncturist. When comparing acupuncture to non-acupuncture controls, there was little evidence that these characteristics modified the effect of acupuncture, except better pain outcomes were observed when more needles were used (p=0.010) and, from patient level analysis involving a sub-set of five trials, when a higher number of acupuncture treatment sessions were provided (p<0.001). CONCLUSION: There was little evidence that different characteristics of acupuncture or acupuncturists modified the effect of treatment on pain outcomes. Increased number of needles and more sessions appear to be associated with better outcomes when comparing acupuncture to non-acupuncture controls, suggesting that dose is important. Potential confounders include differences in control group and sample size between trials. Trials to evaluate potentially small differences in outcome associated with different acupuncture characteristics are likely to require large sample sizes. PMID- 24146996 TI - Dolutegravir interactions with HIV-1 integrase-DNA: structural rationale for drug resistance and dissociation kinetics. AB - Signature HIV-1 integrase mutations associated with clinical raltegravir resistance involve 1 of 3 primary genetic pathways, Y143C/R, Q148H/K/R and N155H, the latter 2 of which confer cross-resistance to elvitegravir. In accord with clinical findings, in vitro drug resistance profiling studies with wild-type and site-directed integrase mutant viruses have shown significant fold increases in raltegravir and elvitegravir resistance for the specified viral mutants relative to wild-type HIV-1. Dolutegravir, in contrast, has demonstrated clinical efficacy in subjects failing raltegravir therapy due to integrase mutations at Y143, Q148 or N155, which is consistent with its distinct in vitro resistance profile as dolutegravir's antiviral activity against these viral mutants is equivalent to its activity against wild-type HIV-1. Kinetic studies of inhibitor dissociation from wild-type and mutant integrase-viral DNA complexes have shown that dolutegravir also has a distinct off-rate profile with dissociative half-lives substantially longer than those of raltegravir and elvitegravir, suggesting that dolutegravir's prolonged binding may be an important contributing factor to its distinct resistance profile. To provide a structural rationale for these observations, we constructed several molecular models of wild-type and clinically relevant mutant HIV-1 integrase enzymes in complex with viral DNA and dolutegravir, raltegravir or elvitegravir. Here, we discuss our structural models and the posited effects that the integrase mutations and the structural and electronic properties of the integrase inhibitors may have on the catalytic pocket and inhibitor binding and, consequently, on antiviral potency in vitro and in the clinic. PMID- 24146997 TI - Sequence complexity effects on speech production in healthy speakers and speakers with hypokinetic or ataxic dysarthria. AB - The present study investigated the effects of sequence complexity, defined in terms of phonemic similarity and phonotoactic probability, on the timing and accuracy of serial ordering for speech production in healthy speakers and speakers with either hypokinetic or ataxic dysarthria. Sequences were comprised of strings of consonant-vowel (CV) syllables with each syllable containing the same vowel, /a/, paired with a different consonant. High complexity sequences contained phonemically similar consonants, and sounds and syllables that had low phonotactic probabilities; low complexity sequences contained phonemically dissimilar consonants and high probability sounds and syllables. Sequence complexity effects were evaluated by analyzing speech error rates and within syllable vowel and pause durations. This analysis revealed that speech error rates were significantly higher and speech duration measures were significantly longer during production of high complexity sequences than during production of low complexity sequences. Although speakers with dysarthria produced longer overall speech durations than healthy speakers, the effects of sequence complexity on error rates and speech durations were comparable across all groups. These findings indicate that the duration and accuracy of processes for selecting items in a speech sequence is influenced by their phonemic similarity and/or phonotactic probability. Moreover, this robust complexity effect is present even in speakers with damage to subcortical circuits involved in serial control for speech. PMID- 24146998 TI - Molecular dynamic simulation reveals damaging impact of RAC1 F28L mutation in the switch I region. AB - Ras-related C3 botulinum toxin substrate 1 (RAC1) is a plasma membrane-associated small GTPase which cycles between the active GTP-bound and inactive GDP-bound states. There is wide range of evidences indicating its active participation in inducing cancer-associated phenotypes. RAC1 F28L mutation (RAC(F28L)) is a fast recycling mutation which has been implicated in several cancer associated cases. In this work we have performed molecular docking and molecular dynamics simulation (~0.3 MUs) to investigate the conformational changes occurring in the mutant protein. The RMSD, RMSF and NHbonds results strongly suggested that the loss of native conformation in the Switch I region in RAC1 mutant protein could be the reason behind its oncogenic transformation. The overall results suggested that the mutant protein attained compact conformation as compared to the native. The major impact of mutation was observed in the Switch I region which might be the crucial reason behind the loss of interaction between the guanine ring and F28 residue. PMID- 24146999 TI - Identification of semicarbazones, thiosemicarbazones and triazine nitriles as inhibitors of Leishmania mexicana cysteine protease CPB. AB - Cysteine proteases of the papain superfamily are present in nearly all eukaryotes. They play pivotal roles in the biology of parasites and inhibition of cysteine proteases is emerging as an important strategy to combat parasitic diseases such as sleeping sickness, Chagas' disease and leishmaniasis. Homology modeling of the mature Leishmania mexicana cysteine protease CPB2.8 suggested that it differs significantly from bovine cathepsin B and thus could be a good drug target. High throughput screening of a compound library against this enzyme and bovine cathepsin B in a counter assay identified four novel inhibitors, containing the warhead-types semicarbazone, thiosemicarbazone and triazine nitrile, that can be used as leads for antiparasite drug design. Covalent docking experiments confirmed the SARs of these lead compounds in an effort to understand the structural elements required for specific inhibition of CPB2.8. This study has provided starting points for the design of selective and highly potent inhibitors of L. mexicana cysteine protease CPB that may also have useful efficacy against other important cysteine proteases. PMID- 24147000 TI - Caveolin-1 associated adenovirus entry into human corneal cells. AB - The cellular entry of viruses represents a critical area of study, not only for viral tropism, but also because viral entry dictates the nature of the immune response elicited upon infection. Epidemic keratoconjunctivitis (EKC), caused by viruses within human adenovirus species D (HAdV-D), is a severe, ocular surface infection associated with corneal inflammation. Clathrin-mediated endocytosis has previously been shown to play a critical role in entry of other HAdV species into many host cell types. However, HAdV-D endocytosis into corneal cells has not been extensively studied. Herein, we show an essential role for cholesterol rich, lipid raft microdomains and caveolin-1, in the entry of HAdV-D37 into primary human corneal fibroblasts. Cholesterol depletion using methyl-beta-cyclodextrin (MbetaCD) profoundly reduced viral infection. When replenished with soluble cholesterol, the effect of MbetaCD was reversed, allowing productive viral infection. HAdV-D37 DNA was identified in caveolin-1 rich endosomal fractions after infection. Src kinase activity was also increased in caveolin-1 rich endosomal fractions after infection, and Src phosphorylation and CXCL1 induction were both decreased in caveolin-1-/- mice corneas compared to wild type mice. siRNA knock down of caveolin-1 in corneal cells reduced chemokine induction upon viral infection, and caveolin-1-/- mouse corneas showed reduced cellular entry of HAdV-D37. As a control, HAdV-C2, a non-corneal pathogen, appeared to utilize the caveolar pathway for entry into A549 cells, but failed to infect corneal cells entirely, indicating virus and cell specific tropism. Immuno-electron microscopy confirmed the presence of caveolin-1 in HAdV-D37-containing vesicles during the earliest stages of viral entry. Collectively, these experiments indicate for the first time that HAdV-D37 uses a lipid raft mediated caveolin-1 associated pathway for entry into corneal cells, and connects the processes of viral entry with downstream proinflammatory cell signaling. PMID- 24147001 TI - An exposure to the oxidized DNA enhances both instability of genome and survival in cancer cells. AB - BACKGROUND: Cell free DNA (cfDNA) circulates throughout the bloodstream of both healthy people and patients with various diseases and acts upon the cells. Response to cfDNA depends on concentrations and levels of the damage within cfDNA. Oxidized extracellular DNA acts as a stress signal and elicits an adaptive response. PRINCIPAL FINDINGS: Here we show that oxidized extracellular DNA stimulates the survival of MCF-7 tumor cells. Importantly, in cells exposed to oxidized DNA, the suppression of cell death is accompanied by an increase in the markers of genome instability. Short-term exposure to oxidized DNA results in both single- and double strand DNA breaks. Longer treatments evoke a compensatory response that leads to a decrease in the levels of chromatin fragmentations across cell populations. Exposure to oxidized DNA leads to a decrease in the activity of NRF2 and an increase in the activity of NF-kB and STAT3. A model that describes the role of oxidized DNA released from apoptotic cells in tumor biology is proposed. CONCLUSIONS/SIGNIFICANCE: Survival of cells with an unstable genome may substantially augment progression of malignancy. Further studies of the effects of extracellular DNA on malignant and normal cells are warranted. PMID- 24147002 TI - Stereotactic body radiation therapy for hepatocellular carcinoma: prognostic factors of local control, overall survival, and toxicity. AB - PURPOSE: Stereotactic body radiation therapy (SBRT) for hepatocellular carcinoma (HCC) has been evaluated in several recent studies. The CyberKnife((r)) is an SBRT system that allows for real-time tracking of the tumor. The purpose of this study was to evaluate the prognostic factors for local control and overall survival following this treatment. PATIENTS AND METHODS: 75 patients with 96 liver-confined HCC were treated with SBRT at the Oscar Lambret Comprehensive Cancer Center. Fiducials were implanted in the liver before treatment and were used as markers to track the lesion's movement. Treatment response was scored according to RECIST v1.1. Local control and overall survival were calculated using the Kaplan and Meier method. A stepwise multivariate analysis (Cox regression) of prognostic factors was performed for local control and overall survival. RESULTS: There were 67 patients with Child-Turcotte-Pugh (CTP) Class A and eight patients with CTP Class B. Treatment was administered in three sessions. A total dose of 40-45 Gy to the 80% isodose line was delivered. The median follow-up was 10 months (range, 3-49 months). The local control rate was 89.8% at 1 and 2 years. Overall survival was 78.5% and 50.4% at 1 and 2 years, respectively. Toxicity mainly consisted of grade 1 and grade 2 events. Higher alpha-fetoprotein (aFP) levels were associated with less favorable local control (HR=1.001; 95% CI [1.000, 1.002]; p=0.0063). A higher dose was associated with better local control (HR=0.866; 95% CI [0.753, 0.996]; p=0.0441). A Child-Pugh score higher than 5 was associated with worse overall survival (HR= 3.413; 95% CI [1.235, 9.435]; p=0.018). CONCLUSION: SBRT affords good local tumor control and higher overall survival rates than other historical controls (best supportive care or sorafenib). High aFP levels were associated with lesser local control, but a higher treatment dose improved local control. PMID- 24147003 TI - The suppressive role and aberrent promoter methylation of BTG3 in the progression of hepatocellular carcinoma. AB - BACKGROUND: BTG3 (B-cell translocation gene 3) has been identified as a tumor suppressor and hypermethylation contributes to its down-regulation in some tumors, but its role in hepatocellular carcinoma (HCC) remain unknown. This study aimed to detect the expression and methylation status of BTG3 in HCC cell lines or tissues, and determine its function in HCC progression. METHODOLOGY: The expression of BTG3 was detected in HCC cell lines and HCC tissue by real-time RT PCR, Western blot or immunohistochemistry. The promoter methylation status of BTG3 was measured by using methylation-specific PCR in HCC cell lines. A series of assays were performed to evaluate the effect of BTG3 on proliferation, invasion and cell cycle transition in vitro. RESULTS: BTG3 expression was lower in HCC cell lines than in hepatocyte cell line LO2 (P<0.05). BTG3 was also down regulated in HCC tissues. Its expression was positively correlated with differentiation and distant metastasis (P<0.05). Patients with lower BTG3 expression had shorter overall survival time (P=0.029). DNA methylation directed repression of BTG3 mRNA expression in HCC cell lines. BTG3 suppressed proliferation, invasion and induces G1/S cycle arrest of HCC cells in vitro. CONCLUSION: Down-regulation of BTG3 due to the promoter hypermethylation is closely associated with proliferation, invasion and cell cycle arrest of HCC cells. It may be a novel prognostic biomarker for HCC patients. PMID- 24147006 TI - Integrated analysis of dysregulated lncRNA expression in fetal cardiac tissues with ventricular septal defect. AB - Ventricular septal defects (VSD) are the most common form of congenital heart disease, which is the leading non-infectious cause of death in children; nevertheless, the exact cause of VSD is not yet fully understood. Long non-coding RNAs (lncRNAs) have been shown to play key roles in various biological processes, such as imprinting control, circuitry controlling pluripotency and differentiation, immune responses and chromosome dynamics. Notably, a growing number of lncRNAs have been implicated in disease etiology, although an association with VSD has not been reported. In the present study, we conducted an integrated analysis of dysregulated lncRNAs, focusing specifically on the identification and characterization of lncRNAs potentially involving in initiation of VSD. Comparison of the transcriptome profiles of cardiac tissues from VSD-affected and normal hearts was performed using a second-generation lncRNA microarray, which covers the vast majority of expressed RefSeq transcripts (29,241 lncRNAs and 30,215 coding transcripts). In total, 880 lncRNAs were upregulated and 628 were downregulated in VSD. Furthermore, our established filtering pipeline indicated an association of two lncRNAs, ENST00000513542 and RP11-473L15.2, with VSD. This dysregulation of the lncRNA profile provides a novel insight into the etiology of VSD and furthermore, illustrates the intricate relationship between coding and ncRNA transcripts in cardiac development. These data may offer a background/reference resource for future functional studies of lncRNAs related to VSD. PMID- 24147004 TI - Cell survival following radiation exposure requires miR-525-3p mediated suppression of ARRB1 and TXN1. AB - BACKGROUND: microRNAs (miRNAs) are non-coding RNAs that alter the stability and translation efficiency of messenger RNAs. Ionizing radiation (IR) induces rapid and selective changes in miRNA expression. Depletion of the miRNA processing enzymes Dicer or Ago2 reduces the capacity of cells to survive radiation exposure. Elucidation of critical radiation-regulated miRNAs and their target proteins offers a promising approach to identify new targets to increase the therapeutic effectiveness of the radiation treatment of cancer. PRINCIPAL FINDINGS: Expression of miR-525-3p is rapidly up-regulated in response to radiation. Manipulation of miR-525-3p expression in irradiated cells confirmed that this miRNA mediates the radiosensitivity of a variety of non-transformed (RPE, HUVEC) and tumor-derived cell lines (HeLa, U2-Os, EA.hy926) cell lines. Thus, anti-miR-525-3p mediated inhibition of the increase in miR-525-3p elevated radiosensitivity, while overexpression of precursor miR-525-3p conferred radioresistance. Using a proteomic approach we identified 21 radiation-regulated proteins, of which 14 were found to be candidate targets for miR-525-3p-mediated repression. Luciferase reporter assays confirmed that nine of these were indeed direct targets of miR-525-3p repression. Individual analysis of these direct targets by RNAi-mediated knockdown established that ARRB1, TXN1 and HSPA9 are essential miR-525-3p-dependent regulators of radiation sensitivity. CONCLUSION: The transient up-regulation of miR-525-3p, and the resultant repression of its direct targets ARRB1, TXN1 and HSPA9, is required for cell survival following irradiation. The conserved function of miR-525-3p across several cell types makes this microRNA pathway a promising target for modifying the efficacy of radiotherapy. PMID- 24147005 TI - The coordination of cell growth during fission yeast mating requires Ras1-GTP hydrolysis. AB - The spatial and temporal control of polarity is fundamental to the survival of all organisms. Cells define their polarity using highly conserved mechanisms that frequently rely upon the action of small GTPases, such as Ras and Cdc42. Schizosaccharomyces pombe is an ideal system with which to study the control of cell polarity since it grows from defined tips using Cdc42-mediated actin remodeling. Here we have investigated the importance of Ras1-GTPase activity for the coordination of polarized cell growth during fission yeast mating. Following pheromone stimulation, Ras1 regulates both a MAPK cascade and the activity of Cdc42 to enable uni-directional cell growth towards a potential mating partner. Like all GTPases, when bound to GTP, Ras1 adopts an active conformation returning to an inactive state upon GTP-hydrolysis, a process accelerated through interaction with negative regulators such as GAPs. Here we show that, at low levels of pheromone stimulation, loss of negative regulation of Ras1 increases signal transduction via the MAPK cascade. However, at the higher concentrations observed during mating, hyperactive Ras1 mutations promote cell death. We demonstrate that these cells die due to their failure to coordinate active Cdc42 into a single growth zone resulting in disorganized actin deposition and unsustainable elongation from multiple tips. These results provide a striking demonstration that the deactivation stage of Ras signaling is fundamentally important in modulating cell polarity. PMID- 24147007 TI - Persistent inhibition of ABL tyrosine kinase causes enhanced apoptotic response to TRAIL and disrupts the pro-apoptotic effect of chloroquine. AB - TNF-Related Apoptosis Inducing Ligand (TRAIL) binds to and activates death receptors to stimulate caspase-8 and apoptosis with higher efficiency in cancer than normal cells but the development of apoptosis resistance has limited its clinical efficacy. We found that stable, but not transient knockdown of the ABL tyrosine kinase enhanced the apoptotic response to TRAIL. Re-expression of Abl, but not its nuclear import- or kinase-defective mutant, in the ABL-knockdown cells re-established apoptosis suppression. TRAIL is known to stimulate caspase-8 ubiquitination (Ub-C8), which can facilitate caspase-8 activation or degradation by the lysosomes. In the ABL-knockdown cells, we found a higher basal level of Ub C8 that was not further increased by lysosomal inhibition. Re-expression of Abl in the ABL-knockdown cells reduced the basal Ub-C8, correlating with apoptosis suppression. We found that lysosomal inhibition by chloroquine (CQ) could also enhance TRAIL-induced apoptosis. However, this pro-apoptotic effect of CQ was lost in the ABL-knockdown cells but restored by Abl re-expression. Interestingly, kinase inhibition at the time of TRAIL stimulation was not sufficient to enhance apoptosis. Instead, persistent treatment for several days with imatinib, an ABL kinase inhibitor, was required to cause the enhanced and the CQ-insensitive apoptotic response to TRAIL. Together, these results show that persistent loss of nuclear ABL tyrosine kinase function can sensitize cells to TRAIL and suggest that long-term exposure to the FDA-approved ABL kinase inhibitors may potentiate apoptotic response to TRAIL-based cancer therapy. PMID- 24147008 TI - Biosynthesis of levan, a bacterial extracellular polysaccharide, in the yeast Saccharomyces cerevisiae. AB - Levans are fructose polymers synthesized by a broad range of micro-organisms and a limited number of plant species as non-structural storage carbohydrates. In microbes, these polymers contribute to the formation of the extracellular polysaccharide (EPS) matrix and play a role in microbial biofilm formation. Levans belong to a larger group of commercially important polymers, referred to as fructans, which are used as a source of prebiotic fibre. For levan, specifically, this market remains untapped, since no viable production strategy has been established. Synthesis of levan is catalysed by a group of enzymes, referred to as levansucrases, using sucrose as substrate. Heterologous expression of levansucrases has been notoriously difficult to achieve in Saccharomyces cerevisiae. As a strategy, this study used an invertase (Deltasuc2) null mutant and two separate, engineered, sucrose accumulating yeast strains as hosts for the expression of the levansucrase M1FT, previously cloned from Leuconostoc mesenteroides. Intracellular sucrose accumulation was achieved either by expression of a sucrose synthase (Susy) from potato or the spinach sucrose transporter (SUT). The data indicate that in both Deltasuc2 and the sucrose accumulating strains, the M1FT was able to catalyse fructose polymerisation. In the absence of the predicted M1FT secretion signal, intracellular levan accumulation was significantly enhanced for both sucrose accumulation strains, when grown on minimal media. Interestingly, co-expression of M1FT and SUT resulted in hyper-production and extracellular build-up of levan when grown in rich medium containing sucrose. This study presents the first report of levan production in S. cerevisiae and opens potential avenues for the production of levan using this well established industrial microbe. Furthermore, the work provides interesting perspectives when considering the heterologous expression of sugar polymerizing enzymes in yeast. PMID- 24147009 TI - Generating phenotypic diversity in a fungal biocatalyst to investigate alcohol stress tolerance encountered during microbial cellulosic biofuel production. AB - Consolidated bioprocessing (CBP) of lignocellulosic biomass offers an alternative route to renewable energy. The crop pathogen Fusarium oxysporum is a promising fungal biocatalyst because of its broad host range and innate ability to co saccharify and ferment lignocellulose to bioethanol. A major challenge for cellulolytic CBP-enabling microbes is alcohol inhibition. This research tested the hypothesis that Agrobacterium tumefaciens--mediated transformation (ATMT) could be exploited as a tool to generate phenotypic diversity in F. oxysporum to investigate alcohol stress tolerance encountered during CBP. A random mutagenesis library of gene disruption transformants (n=1,563) was constructed and screened for alcohol tolerance in order to isolate alcohol sensitive or tolerant phenotypes. Following three rounds of screening, exposure of select transformants to 6% ethanol and 0.75% n-butanol resulted respectively in increased (>= 11.74%) and decreased (<= 43.01%) growth compared to the wild -type (WT). Principal component analysis (PCA) quantified the level of phenotypic diversity across the population of genetically transformed individuals and isolated candidate strains for analysis. Characterisation of one strain, Tr. 259, ascertained a reduced growth phenotype under alcohol stress relative to WT and indicated the disruption of a coding region homologous to a putative sugar transporter (FOXG_09625). Quantitative PCR (RT-PCR) showed FOXG_09625 was differentially expressed in Tr. 259 compared to WT during alcohol-induced stress (P<0.05). Phylogenetic analysis of putative sugar transporters suggests diverse functional roles in F. oxysporum and other filamentous fungi compared to yeast for which sugar transporters form part of a relatively conserved family. This study has confirmed the potential of ATMT coupled with a phenotypic screening program to select for genetic variation induced in response to alcohol stress. This research represents a first step in the investigation of alcohol tolerance in F. oxysporum and has resulted in the identification of several novel strains, which will be of benefit to future biofuel research. PMID- 24147011 TI - A hierarchical poisson log-normal model for network inference from RNA sequencing data. AB - Gene network inference from transcriptomic data is an important methodological challenge and a key aspect of systems biology. Although several methods have been proposed to infer networks from microarray data, there is a need for inference methods able to model RNA-seq data, which are count-based and highly variable. In this work we propose a hierarchical Poisson log-normal model with a Lasso penalty to infer gene networks from RNA-seq data; this model has the advantage of directly modelling discrete data and accounting for inter-sample variance larger than the sample mean. Using real microRNA-seq data from breast cancer tumors and simulations, we compare this method to a regularized Gaussian graphical model on log-transformed data, and a Poisson log-linear graphical model with a Lasso penalty on power-transformed data. For data simulated with large inter-sample dispersion, the proposed model performs better than the other methods in terms of sensitivity, specificity and area under the ROC curve. These results show the necessity of methods specifically designed for gene network inference from RNA seq data. PMID- 24147010 TI - An RNA-seq transcriptome analysis of histone modifiers and RNA silencing genes in soybean during floral initiation process. AB - Epigenetics has been recognised to play vital roles in many plant developmental processes, including floral initiation through the epigenetic regulation of gene expression. The histone modifying proteins that mediate these modifications involve the SET domain-containing histone methyltransferases, JmjC domain containing demethylase, acetylases and deacetylases. In addition, RNA interference (RNAi)-associated genes are also involved in epigenetic regulation via RNA-directed DNA methylation and post-transcriptional gene silencing. Soybean, a major crop legume, requires a short day to induce flowering. How histone modifications regulate the plant response to external cues that initiate flowering is still largely unknown. Here, we used RNA-seq to address the dynamics of transcripts that are potentially involved in the epigenetic programming and RNAi mediated gene silencing during the floral initiation of soybean. Soybean is a paleopolyploid that has been subjected to at least two rounds of whole genome duplication events. We report that the expanded genomic repertoire of histone modifiers and RNA silencing genes in soybean includes 14 histone acetyltransferases, 24 histone deacetylases, 47 histone methyltransferases, 15 protein arginine methyltransferases, 24 JmjC domain-containing demethylases and 47 RNAi-associated genes. To investigate the role of these histone modifiers and RNA silencing genes during floral initiation, we compared the transcriptional dynamics of the leaf and shoot apical meristem at different time points after a short-day treatment. Our data reveal that the extensive activation of genes that are usually involved in the epigenetic programming and RNAi gene silencing in the soybean shoot apical meristem are reprogrammed for floral development following an exposure to inductive conditions. PMID- 24147012 TI - Expression of an engineered heterologous antimicrobial peptide in potato alters plant development and mitigates normal abiotic and biotic responses. AB - Antimicrobial cationic peptides (AMPs) are ubiquitous small proteins used by living cells to defend against a wide spectrum of pathogens. Their amphipathic property helps their interaction with negatively charged cellular membrane of the pathogen causing cell lysis and death. AMPs also modulate signaling pathway(s) and cellular processes in animal models; however, little is known of cellular processes other than the pathogen-lysis phenomenon modulated by AMPs in plants. An engineered heterologous AMP, msrA3, expressed in potato was previously shown to cause resistance of the transgenic plants against selected fungal and bacterial pathogens. These lines together with the wild type were studied for growth habits, and for inducible defense responses during challenge with biotic (necrotroph Fusarium solani) and abiotic stressors (dark-induced senescence, wounding and temperature stress). msrA3-expression not only conferred protection against F. solani but also delayed development of floral buds and prolonged vegetative phase. Analysis of select gene transcript profiles showed that the transgenic potato plants were suppressed in the hypersensitive (HR) and reactive oxygen species (ROS) responses to both biotic and abiotic stressors. Also, the transgenic leaves accumulated lesser amounts of the defense hormone jasmonic acid upon wounding with only a slight change in salicylic acid as compared to the wild type. Thus, normal host defense responses to the pathogen and abiotic stressors were mitigated by msrA3 expression suggesting MSRA3 regulates a common step(s) of these response pathways. The stemming of the pathogen growth and mitigating stress response pathways likely contributes to resource reallocation for higher tuber yield. PMID- 24147013 TI - IL7Ralpha expression and upregulation by IFNbeta in dendritic cell subsets is haplotype-dependent. AB - The IL7Ralpha gene is unequivocally associated with susceptibility to multiple sclerosis (MS). Haplotype 2 (Hap 2) confers protection from MS, and T cells and dendritic cells (DCs) of Hap 2 exhibit reduced splicing of exon 6, resulting in production of relatively less soluble receptor, and potentially more response to ligand. We have previously shown in CD4 T cells that IL7Ralpha haplotypes 1 and 2, but not 4, respond to interferon beta (IFNbeta), the most commonly used immunomodulatory drug in MS, and that haplotype 4 (Hap 4) homozygotes have the highest risk of developing MS. We now show that IL7R expression increases in myeloid cells in response to IFNbeta, but that the response is haplotype dependent, with cells from homozygotes for Hap 4 again showing no response. This was shown using freshly derived monocytes, in vitro cultured immature and mature monocyte-derived dendritic cells, and by comparing homozygotes for the common haplotypes, and relative expression of alleles in heterozygotes (Hap 4 vs not Hap 4). As for T cells, in all myeloid cell subsets examined, Hap 2 homozygotes showed a trend for reduced splicing of exon 6 compared to the other haplotypes, significantly so in most conditions. These data are consistent with increased signaling being protective from MS, constitutively and in response to IFNbeta. We also demonstrate significant regulation of immune response, chemokine activity and cytokine biosynthesis pathways by IL7Ralpha signaling in IFNbeta -treated myeloid subsets. IFNbeta-responsive genes are over-represented amongst genes associated with MS susceptibility. IL7Ralpha haplotype may contribute to MS susceptibility through reduced capacity for IL7Ralpha signalling in myeloid cells, especially in the presence of IFNbeta, and is currently under investigation as a predictor of therapeutic response. PMID- 24147014 TI - Comparative analysis of mitochondrial genomes of five aphid species (Hemiptera: Aphididae) and phylogenetic implications. AB - Insect mitochondrial genomes (mitogenomes) are of great interest in exploring molecular evolution, phylogenetics and population genetics. Only two mitogenomes have been previously released in the insect group Aphididae, which consists of about 5,000 known species including some agricultural, forestry and horticultural pests. Here we report the complete 16,317 bp mitogenome of Cavariella salicicola and two nearly complete mitogenomes of Aphis glycines and Pterocomma pilosum. We also present a first comparative analysis of mitochondrial genomes of aphids. Results showed that aphid mitogenomes share conserved genomic organization, nucleotide and amino acid composition, and codon usage features. All 37 genes usually present in animal mitogenomes were sequenced and annotated. The analysis of gene evolutionary rate revealed the lowest and highest rates for COI and ATP8, respectively. A unique repeat region exclusively in aphid mitogenomes, which included variable numbers of tandem repeats in a lineage-specific manner, was highlighted for the first time. This region may have a function as another origin of replication. Phylogenetic reconstructions based on protein-coding genes and the stem-loop structures of control regions confirmed a sister relationship between Cavariella and pterocommatines. Current evidence suggest that pterocommatines could be formally transferred into Macrosiphini. Our paper also offers methodological instructions for obtaining other Aphididae mitochondrial genomes. PMID- 24147015 TI - Population-level impact of active tuberculosis case finding in an Asian megacity. AB - BACKGROUND: The potential population-level impact of private-sector initiatives for tuberculosis (TB) case finding in Southeast Asia remains uncertain. In 2011, the Indus Hospital TB Control Program in Karachi, Pakistan, undertook an aggressive case-finding campaign that doubled notification rates, providing an opportunity to investigate potential population-level effects. METHODS: We constructed an age-structured compartmental model of TB in the intervention area. We fit the model using field and literature data, assuming that TB incidence equaled the estimated nationwide incidence in Pakistan (primary analysis), or 1.5 times greater (high-incidence scenario). We modeled the intervention as an increase in the rate of formal-sector TB diagnosis and evaluated the potential impact of sustaining this rate for five years. RESULTS: In the primary analysis, the five-year intervention averted 24% (95% uncertainty range, UR: 18-30%) of five-year cumulative TB cases and 52% (95% UR: 45-57%) of cumulative TB deaths. Corresponding reductions in the high-incidence scenario were 12% (95% UR: 8-17%) and 27% (95% UR: 21-34%), although the absolute number of lives saved was higher. At the end of five years, TB notification rates in the primary analysis were below their 2010 baseline, incidence had dropped by 45%, and annual mortality had fallen by 72%. About half of the cumulative impact on incidence and mortality could be achieved with a one-year intervention. CONCLUSIONS: Sustained, multifaceted, and innovative approaches to TB case-finding in Asian megacities can have substantial community-wide epidemiological impact. PMID- 24147017 TI - Towards a proper assignment of systemic risk: the combined roles of network topology and shock characteristics. AB - The 2007-2008 financial crisis solidified the consensus among policymakers that a macro-prudential approach to regulation and supervision should be adopted. The currently preferred policy option is the regulation of capital requirements, with the main focus on combating procyclicality and on identifying the banks that have a high systemic importance, those that are "too big to fail". Here we argue that the concept of systemic risk should include the analysis of the system as a whole and we explore systematically the most important properties for policy purposes of networks topology on resistance to shocks. In a thorough study going from analytical models to empirical data, we show two sharp transitions from safe to risky regimes: 1) diversification becomes harmful with just a small fraction (~2%) of the shocks sampled from a fat tailed shock distributions and 2) when large shocks are present a critical link density exists where an effective giant cluster forms and most firms become vulnerable. This threshold depends on the network topology, especially on modularity. Firm size heterogeneity has important but diverse effects that are heavily dependent on shock characteristics. Similarly, degree heterogeneity increases vulnerability only when shocks are directed at the most connected firms. Furthermore, by studying the structure of the core of the transnational corporation network from real data, we show that its stability could be clearly increased by removing some of the links with highest centrality betweenness. Our results provide a novel insight and arguments for policy makers to focus surveillance on the connections between firms, in addition to capital requirements directed at the nodes. PMID- 24147016 TI - Valproic acid treatment inhibits hypoxia-inducible factor 1alpha accumulation and protects against burn-induced gut barrier dysfunction in a rodent model. AB - OBJECTIVE: Burn-induced gut dysfunction plays an important role in the development of sepsis and multiple organ dysfunction. Emerging evidence suggests that hypoxia-inducible factor-1alpha (HIF-1alpha) is critical in paracellular barrier functions via regulating vascular endothelial growth factor (VEGF) and myosin light chain kinase (MLCK) expression. Previous studies have also demonstrated that histone deacetylase inhibitors (HDACIs) can repress HIF-1alpha. This study aims to examine whether valproic acid (VPA), a HDACI, protects against burn-induced gut barrier dysfunction via repressing HIF-1alpha-dependent upregulation of VEGF and MLCK expression. METHODS: Rats were subjected to third degree 55% TBSA burns and treated with/ without VPA (300 mg/kg). Intestinal barrier dysfunction was evaluated by permeability of intestinal mucosa to fluorescein isothiocyanate (FITC)-dextran and histologic evaluation. Histone acetylation, tight junction protein zonula occludens 1 (ZO-1), VEGF, MLCK and HIF 1alpha were measured. In addition, CaCO2 cells were transfected with siRNA directed against HIF-1alpha and were stimulated with CoCl2 (1mM) for 24 hours with/without VPA (2mM) followed by analysis of HIF-1alpha, MLCK, VEGF and ZO-1. RESULTS: Burn insults resulted in a significant increase in intestinal permeability and mucosal damage, accompanied by a significant reduction in histone acetylation, ZO-1, upregulation of VEGF, MLCK expression, and an increase in HIF-1alpha accumulation. VPA significantly attenuated the increase in intestinal permeability, mucosa damage, histone deacetylation and changes in ZO-1 expression. VPA also attenuated the increased VEGF, MLCK and HIF-1alpha protein levels. VPA reduced HIF-1alpha, MLCK and VEGF production and prevented ZO-1 loss in CoCl2-stimulated Caco-2 cells. Moreover, transfection of siRNA directed against HIF-1alpha led to inhibition of MLCK and VEGF production, accompanied by upregulation of ZO-1. CONCLUSIONS: These results indicate that VPA can protect against burn-induced gut barrier dysfunction. These protective effects may be due to its inhibitory action on HIF-1alpha, leading to a reduction in intestinal VEGF and MLCK expression and minimizing ZO-1 degradation. PMID- 24147018 TI - Endemic Asian chytrid strain infection in threatened and endemic anurans of the Northern Western Ghats, India. AB - The Western Ghats of India harbors a rich diversity of amphibians with more than 77% species endemic to this region. At least 42% of the endemic species are threatened due to several anthropogenic stressors. However, information on amphibian diseases and their impacts on amphibian populations in this region are scarce. We report the occurrence of Batrachochytridium dendrobatidis (Bd), an epidermal aquatic fungal pathogen that causes chytridiomycosis in amphibians, from the Western Ghats. In the current study we detected the occurrence of a native Asian Bd strain from three endemic and threatened species of anurans, Bombay Night Frog Nyctibatrachus humayuni, Leith's Leaping Frog Indirana leithii and Bombay Bubble Nest Frog Raorchestes bombayensis, for the first time from the northern Western Ghats of India based on diagnostic nested PCR, quantitative PCR, DNA sequencing and histopathology. While, the Bd infected I. leithii and R. bombayensis did not show any external symptoms, N. humayuni showed lesions on the skin, browning of skin and sloughing. Sequencing of Bd 5.8S ribosomal RNA gene, and the ITS1 and ITS2 regions, revealed that the current Bd strain is related to a haplotype endemic to Asia. Our findings confirm the presence of Bd in northern Western Ghats and the affected amphibians may or may not show detectable clinical symptoms. We suggest that the significance of diseases as potential threat to amphibian populations of the Western Ghats needs to be highlighted from the conservation point of view. PMID- 24147019 TI - Lack of association between Bax promoter (-248G>A) single nucleotide polymorphism and susceptibility towards cancer: evidence from a meta-analysis. AB - BACKGROUND: The Bcl-2-associated X protein (Bax) is a proapoptotic member of the Bcl-2 family known to be activated and upregulated during apoptosis. Single nucleotide polymorphisms (SNPs) in Bax promoter may participate in the process of carcinogenesis by altering its own expression and the cancer related genes. Bax 248G>A polymorphism has been implicated to alter the risk of cancer, but the listed results are inconsistent and inconclusive. In the present study, we performed a meta-analysis to systematically summarize the possible association of this polymorphism with the risk of cancer. METHODOLOGY: We conducted a search of case-control studies on the associations of Bax-248G>A polymorphism with susceptibility to cancer in Pub Med, Science Direct, Wiley Online Library and hand search. Data from all eligible studies based on some key search terms, inclusion and exclusion criteria were extracted for this meta-analysis. Hardy Weinberg equilibrium (HWE) in controls, power calculation, heterogeneity analysis, Begg's funnel plot, Egger's linear regression test, forest plot and sensitivity analysis were performed in the present study. RESULTS: Cancer risk associated with Bax-248G>A polymorphism was estimated by pooled odds ratios (ORs) and 95% confidence intervals (95% CIs). The pooled ORs were calculated in allele contrast, homozygous comparison, heterozygous comparison, dominant and recessive model. Statistical significance was checked through Z and p-value in forest plot. A total of seven independent studies including 1772 cases and 1708 controls were included in our meta-analysis. Our results showed that neither allele frequency nor genotype distributions of this polymorphism were associated with risk for cancer in any of the genetic model. Furthermore, Egger's test did not show any substantial evidence of publication bias. CONCLUSIONS/SIGNIFICANCE: This meta analysis suggests that the Bax-248G>A polymorphism is not an important cancer risk factor. Nevertheless, additional well-designed studies with larger sample size focusing on different ethnicities and cancer types are required to further validate the results. PMID- 24147020 TI - Genetic dissection of quantitative trait Loci for hemostasis and thrombosis on mouse chromosomes 11 and 5 using congenic and subcongenic strains. AB - Susceptibility to thrombosis varies in human populations as well as many inbred mouse strains. Only a small portion of this variation has been identified, suggesting that there are unknown modifier genes. The objective of this study was to narrow the quantitative trait locus (QTL) intervals previously identified for hemostasis and thrombosis on mouse distal chromosome 11 (Hmtb6) and on chromosome 5 (Hmtb4 and Hmtb5). In a tail bleeding/rebleeding assay, a reporter assay for hemostasis and thrombosis, subcongenic strain (6A-2) had longer clot stability time than did C57BL/6J (B6) mice but a similar time to the B6-Chr11(A/J) consomic mice, confirming the Hmtb6 phenotype. Six congenic and subcongenic strains were constructed for chromosome 5, and the congenic strain, 2A-1, containing the shortest A/J interval (16.6 cM, 26.6 Mbp) in the Hmtb4 region, had prolonged clot stability time compared to B6 mice. In the 3A-2 and CSS-5 mice bleeding time was shorter than for B6, mice confirming the Hmtb5 QTL. An increase in bleeding time was identified in another congenic strain (3A-1) with A/J interval (24.8 cM, 32.9 Mbp) in the proximal region of chromosome 5, confirming a QTL for bleeding previously mapped to that region and designated as Hmtb10. The subcongenic strain 4A-2 with the A/J fragment in the proximal region had a long occlusion time of the carotid artery after ferric chloride injury and reduced dilation after injury to the abdominal aorta compared to B6 mice, suggesting an additional locus in the proximal region, which was designated Hmtb11 (5 cM, 21.4 Mbp). CSS-17 mice crossed with congenic strains, 3A-1 and 3A-2, modified tail bleeding. Using congenic and subcongenic analysis, candidate genes previously identified and novel genes were identified as modifiers of hemostasis and thrombosis in each of the loci Hmtb6, Hmtb4, Hmtb10, and Hmtb11. PMID- 24147021 TI - Functional characterisation of the maturation of the blood-brain barrier in larval zebrafish. AB - Zebrafish are becoming increasingly popular as an organism in which to model human disease and to study the effects of small molecules on complex physiological and pathological processes. Since larvae are no more than a few millimetres in length, and can live in volumes as small as 100 microliters, they are particularly amenable to high-throughput and high content compound screening in 96 well plate format. There is a growing literature providing evidence that many compounds show similar pharmacological effects in zebrafish as they do in mammals, and in particular humans. However, a major question regarding their utility for small molecule screening for neurological conditions is whether a molecule will reach its target site within the central nervous system. Studies have shown that Claudin-5 and ZO-1, tight-junction proteins which are essential for blood-brain barrier (BBB) integrity in mammals, can be detected in some cerebral vessels in zebrafish from 3 days post-fertilisation (d.p.f.) onwards and this timing coincides with the retention of dyes, immunoreactive tracers and fluorescent markers within some but not all cerebral vessels. Whilst these findings demonstrate that features of a BBB are first present at 3 d.p.f., it is not clear how quickly the zebrafish BBB matures or how closely the barrier resembles that of mammals. Here, we have combined anatomical analysis by transmission electron microscopy, functional investigation using fluorescent markers and compound uptake using liquid chromatography/tandem mass spectrometry to demonstrate that maturation of the zebrafish BBB occurs between 3 d.p.f. and 10 d.p.f. and that this barrier shares both structural and functional similarities with that of mammals. PMID- 24147022 TI - Breast tumors with elevated expression of 1q candidate genes confer poor clinical outcome and sensitivity to Ras/PI3K inhibition. AB - Genomic aberrations are common in cancers and the long arm of chromosome 1 is known for its frequent amplifications in breast cancer. However, the key candidate genes of 1q, and their contribution in breast cancer pathogenesis remain unexplored. We have analyzed the gene expression profiles of 1635 breast tumor samples using meta-analysis based approach and identified clinically significant candidates from chromosome 1q. Seven candidate genes including exonuclease 1 (EXO1) are consistently over expressed in breast tumors, specifically in high grade and aggressive breast tumors with poor clinical outcome. We derived a EXO1 co-expression module from the mRNA profiles of breast tumors which comprises 1q candidate genes and their co-expressed genes. By integrative functional genomics investigation, we identified the involvement of EGFR, RAS, PI3K / AKT, MYC, E2F signaling in the regulation of these selected 1q genes in breast tumors and breast cancer cell lines. Expression of EXO1 module was found as indicative of elevated cell proliferation, genomic instability, activated RAS/AKT/MYC/E2F1 signaling pathways and loss of p53 activity in breast tumors. mRNA-drug connectivity analysis indicates inhibition of RAS/PI3K as a possible targeted therapeutic approach for the patients with activated EXO1 module in breast tumors. Thus, we identified seven 1q candidate genes strongly associated with the poor survival of breast cancer patients and identified the possibility of targeting them with EGFR/RAS/PI3K inhibitors. PMID- 24147023 TI - Effects of awareness on numerosity adaptation. AB - Numerosity perception is a process involving several stages of visual processing. This study investigated whether distinct mechanisms exist in numerosity adaptation under different awareness conditions to characterize how numerosity perception occurs at each stage. The status of awareness was controlled by masking conditions, in which monoptic and dichoptic masking were proposed to influence different levels of processing. Numerosity adaptation showed significant aftereffects when the participants were aware (monoptic masking) and unaware (dichoptic masking) of adaptors. The interocular transfer for numerosity adaptation was distinct under the different awareness conditions. Adaptation was primarily binocular when participants were aware of stimuli and was purely monocular when participants were unaware of adaptors. Moreover, numerosity adaptation was significantly reduced when the adaptor dots were clustered into chunks with awareness, whereas clustering had no effect on unaware adaptation. These results show that distinct mechanisms exist in numerosity processing under different awareness conditions. It is suggested that awareness is crucial to numerosity cognition. With awareness, grouping (by clustering) influences numerosity coding through altered object representations, which involves higher level cognitive processing. PMID- 24147024 TI - Alteration of innate immunity by donor IL-6 deficiency in a presensitized heart transplant model. AB - Engraftment of IL-6 deficient donor into wild-type recipient could significantly improve allograft survival through T cell lineage particularly regulatory T cells (Tregs) in non-sensitized transplant host. However, its effect on innate immune responses remains uncertain. Our data revealed that donor IL-6 deficiency significantly increased infiltration of two subsets of MDSCs (CD11b+Gr1+myeloid derived suppressor cells), CD11b+Gr1(-low) and CD11b+Gr1(-int) with strong immunosuppression activity in the transplanted graft. It resulted in a dramatic increase of CD11b+Gr1(-low) frequency and a significant decrease of the frequency of CD11b+Gr1(-high) and CD4-CD8-NK1.1+ cells in the recipient's spleen. Unexpectedly, donor IL-6 deficiency could not significantly reduce macrophage frequency irrespective of in the host's spleen or graft. Taken together, suppression of innate immune effector cells and enhanced activity of regulatory MDSCs contributed to tolerance induction by blockade of IL-6 signaling pathway. The unveiled novel mechanism of targeting IL-6 might shed light on clinical therapeutic application in preventing accelerated allograft rejection for those pre-sensitized transplant recipients. PMID- 24147025 TI - Sex-specific effects of NLRP6/AVR and ADM loci on susceptibility to essential hypertension in a Sardinian population. AB - Coronary artery disease, heart failure, fatal arrhythmias, stroke, and renal disease are the most common causes of mortality for humans, and essential hypertension remains a major risk factor. Elucidation of susceptibility loci for essential hypertension has been difficult because of its complex, multifactorial nature involving genetic, environmental, and sex- and age-dependent nature. We investigated whether the 11p15.5 region syntenic to rat chromosome 1 region containing multiple blood pressure quantitative trait loci (QTL) detected in Dahl rat intercrosses harbors polymorphisms that contribute to susceptibility/resistance to essential hypertension in a Sardinian population. Initial testing performed using microsatellite markers spanning 18 Mb of 11p15.5 detected a strong association between D11S1318 (at 2.1 Mb, P = 0.004) and D11S1346 (at 10.6 Mb, P = 0.00000004), suggesting that loci in close proximity to these markers may contribute to susceptibility in our Sardinian cohort. NLR family, pyrin domain containing 6/angiotensin-vasopressin receptor (NLRP6/AVR), and adrenomedullin (ADM) are in close proximity to D11S1318 and D11S1346, respectively; thus we tested single nucleotide polymorphisms (SNPs) within NLRP6/AVR and ADM for their association with hypertension in our Sardinian cohort. Upon sex stratification, we detected one NLRP6/AVR SNP associated with decreased susceptibility to hypertension in males (rs7948797G, P = 0.029; OR = 0.73 [0.57-0.94]). For ADM, sex-specific analysis showed a significant association between rs4444073C, with increased susceptibility to essential hypertension only in the male population (P = 0.006; OR = 1.44 [1.13-1.84]). Our results revealed an association between NLRP6/AVR and ADM loci with male essential hypertension, suggesting the existence of sex-specific NLRP6/AVR and ADM variants affecting male susceptibility to essential hypertension. PMID- 24147026 TI - Variable delta(15)N diet-tissue discrimination factors among sharks: implications for trophic position, diet and food web models. AB - The application of stable isotopes to characterize the complexities of a species foraging behavior and trophic relationships is dependent on assumptions of delta(15)N diet-tissue discrimination factors (?(15)N). As ?(15)N values have been experimentally shown to vary amongst consumers, tissues and diet composition, resolving appropriate species-specific ?(15)N values can be complex. Given the logistical and ethical challenges of controlled feeding experiments for determining ?(15)N values for large and/or endangered species, our objective was to conduct an assessment of a range of reported ?(15)N values that can hypothetically serve as surrogates for describing the predator-prey relationships of four shark species that feed on prey from different trophic levels (i.e., different mean delta(15)N dietary values). Overall, the most suitable species specific ?(15)N values decreased with increasing dietary-delta(15)N values based on stable isotope Bayesian ellipse overlap estimates of shark and the principal prey functional groups contributing to the diet determined from stomach content analyses. Thus, a single ?(15)N value was not supported for this speciose group of marine predatory fishes. For example, the ?(15)N value of 3.70/00 provided the highest percent overlap between prey and predator isotope ellipses for the bonnethead shark (mean diet delta(15)N = 90/00) whereas a ?(15)N value < 2.30/00 provided the highest percent overlap between prey and predator isotope ellipses for the white shark (mean diet delta(15)N = 150/00). These data corroborate the previously reported inverse ?(15)N-dietary delta(15)N relationship when both isotope ellipses of principal prey functional groups and the broader identified diet of each species were considered supporting the adoption of different ?(15)N values that reflect the predators' delta(15)N-dietary value. These findings are critical for refining the application of stable isotope modeling approaches as inferences regarding a species' ecological role in their community will be influenced with consequences for conservation and management actions. PMID- 24147027 TI - F11R is a novel monocyte prognostic biomarker for malignant glioma. AB - OBJECTIVE: Brain tumors (gliomas) contain large populations of infiltrating macrophages and recruited microglia, which in experimental murine glioma models promote tumor formation and progression. Among the barriers to understanding the contributions of these stromal elements to high-grade glioma (glioblastoma; GBM) biology is the relative paucity of tools to characterize infiltrating macrophages and resident microglia. In this study, we leveraged multiple RNA analysis platforms to identify new monocyte markers relevant to GBM patient outcome. METHODS: High-confidence lists of mouse resident microglia- and bone marrow derived macrophage-specific transcripts were generated using converging RNA-seq and microarray technologies and validated using qRT-PCR and flow cytometry. Expression of select cell surface markers was analyzed in brain-infiltrating macrophages and resident microglia in an induced GBM mouse model, while allogeneic bone marrow transplantation was performed to trace the origins of infiltrating and resident macrophages. Glioma tissue microarrays were examined by immunohistochemistry, and the Gene Expression Omnibus (GEO) database was queried to determine the prognostic value of identified microglia biomarkers in human GBM. RESULTS: We generated a unique catalog of differentially-expressed bone marrow-derived monocyte and resident microglia transcripts, and demonstrated that brain-infiltrating macrophages acquire F11R expression in GBM and following bone marrow transplantation. Moreover, mononuclear cell F11R expression positively correlates with human high-grade glioma and additionally serves as a biomarker for GBM patient survival, regardless of GBM molecular subtype. SIGNIFICANCE: These studies establish F11R as a novel monocyte prognostic marker for GBM critical for defining a subpopulation of stromal cells for future potential therapeutic intervention. PMID- 24147029 TI - Tropical secondary forest management influences frugivorous bat composition, abundance and fruit consumption in Chiapas, Mexico. AB - Most studies on frugivorous bat assemblages in secondary forests have concentrated on differences among successional stages, and have disregarded the effect of forest management. Secondary forest management practices alter the vegetation structure and fruit availability, important factors associated with differences in frugivorous bat assemblage structure, and fruit consumption and can therefore modify forest succession. Our objective was to elucidate factors (forest structural variables and fruit availability) determining bat diversity, abundance, composition and species-specific abundance of bats in (i) secondary forests managed by Lacandon farmers dominated by Ochroma pyramidale, in (ii) secondary forests without management, and in (iii) mature rain forests in Chiapas, Southern Mexico. Frugivorous bat species diversity (Shannon H') was similar between forest types. However, bat abundance was highest in rain forest and O. pyramidale forests. Bat species composition was different among forest types with more Carollia sowelli and Sturnira lilium captures in O. pyramidale forests. Overall, bat fruit consumption was dominated by early-successional shrubs, highest late-successional fruit consumption was found in rain forests and more bats consumed early-successional shrub fruits in O. pyramidale forests. Ochroma pyramidale forests presented a higher canopy openness, tree height, lower tree density and diversity of fruit than secondary forests. Tree density and canopy openness were negatively correlated with bat species diversity and bat abundance, but bat abundance increased with fruit abundance and tree height. Hence, secondary forest management alters forests' structural characteristics and resource availability, and shapes the frugivorous bat community structure, and thereby the fruit consumption by bats. PMID- 24147028 TI - CB2 receptor agonists protect human dopaminergic neurons against damage from HIV 1 gp120. AB - Despite the therapeutic impact of anti-retroviral therapy, HIV-1-associated neurocognitive disorder (HAND) remains a serious threat to AIDS patients, and there currently remains no specific therapy for the neurological manifestations of HIV-1. Recent work suggests that the nigrostriatal dopaminergic area is a critical brain region for the neuronal dysfunction and death seen in HAND and that human dopaminergic neurons have a particular sensitivity to gp120-induced damage, manifested as reduced function (decreased dopamine uptake), morphological changes, and reduced viability. Synthetic cannabinoids inhibit HIV-1 expression in human microglia, suppress production of inflammatory mediators in human astrocytes, and there is substantial literature demonstrating the neuroprotective properties of cannabinoids in other neuropathogenic processes. Based on these data, experiments were designed to test the hypothesis that synthetic cannabinoids will protect dopaminergic neurons against the toxic effects of the HIV-1 protein gp120. Using a human mesencephalic neuronal/glial culture model, which contains dopaminergic neurons, microglia, and astrocytes, we were able to show that the CB1/CB2 agonist WIN55,212-2 blunts gp120-induced neuronal damage as measured by dopamine transporter function, apoptosis and lipid peroxidation; these actions were mediated principally by the CB2 receptor. Adding supplementary human microglia to our cultures enhances gp120-induced damage; WIN55,212-2 is able to alleviate this enhanced damage. Additionally, WIN55,212-2 inhibits gp120 induced superoxide production by purified human microglial cells, inhibits migration of human microglia towards supernatants generated from gp120-stimulated human mesencephalic neuronal/glial cultures and reduces chemokine and cytokine production from the human mesencephalic neuronal/glial cultures. These data suggest that synthetic cannabinoids are capable of protecting human dopaminergic neurons from gp120 in a variety of ways, acting principally through the CB2 receptors and microglia. PMID- 24147030 TI - Characterization of Niemann-Pick Type C2 protein expression in multiple cancers using a novel NPC2 monoclonal antibody. AB - Niemann-Pick Type C2 (NPC2) plays an important role in the regulation of intracellular cholesterol homeostasis via direct binding with free cholesterol. However, little is known about the significance of NPC2 in cancer. In this study, we have pinpointed the impact of various different cancers on NPC2 expression. A series of anti-NPC2 monoclonal antibodies (mAbs) with the IgG2a isotype were generated and peptide screening demonstrated that the reactive epitope were amino acid residues 31-40 of the human NPC2 protein. The specificity of these mAbs was confirmed by Western blotting using shRNA mediated knock-down of NPC2 in human SK Hep1 cells. By immunohistochemical staining, NPC2 is expressed in normal kidney, liver, breast, colon, lung, esophageal, uterine cervical, pancreatic and stomach tissue. Strong expression of NPC2 was found in the distal and proximal convoluted tubule of kidney and the hepatocytes of liver. Normal esophageal, uterine cervical, pancreatic, stomach, breast, colon and lung tissue stained moderately to weakly. When compared to their normal tissue equivalents, NPC2 overexpression was observed in cancers of the breast, colon and lung. Regarding to breast cancer, NPC2 up-regulation is associated with estrogen receptor (-), progesterone receptor (-) and human epidermal growth factor receptor (+). On the other hand, NPC2 was found to be down-regulated in renal cell carcinoma, liver cirrhosis and hepatoma tissues. By antigen-capture enzyme immunoassay ELISA, the serum NPC2 is increased in patients with cirrhosis and liver cancer. According to western blot data, the change of glycosylated pattern of NPC2 in serum is associated with cirrhosis and liver cancer. To the best of our knowledge, this is the first comprehensive immunohistochemical and serological study investigating the expression of NPC2 in a variety of different human cancers. These novel monoclonal antibodies should help with elucidating the roles of NPC2 in tumor development, especially in liver and breast cancers. PMID- 24147031 TI - Statin use and markers of immunity in the Doetinchem cohort study. AB - It has been suggested that statins can both stimulate and suppress the immune system, and thereby, may influence autoimmune diseases. Therefore, we studied effects of statins on innate and adaptive immunity, and self-tolerance by measuring serological levels of C-reactive protein (CRP), neopterin, immunoglobulin E (IgE) antibodies and the presence of autoantibodies (antinuclear antibodies (ANA) and IgM rheumatoid factor (RF)) in the general population. We conducted a nested case-control study within the population-based Doetinchem cohort. Data from health questionnaires, serological measurements and information on medication from linkage to pharmacy-dispensing records were available. We selected 332 statin users (cases) and 331 non-users (controls), matched by age, sex, date of serum collection, history of cardiovascular diseases, diabetes mellitus type II and stroke. Multivariate regression analyses were performed to estimate effect of statins on the immune system. The median level of CRP in statin users (1.28 mg/L, interquartile range (IQR): 0.59-2.79) was lower than in non-users (1.62 mg/L, IQR: 0.79-3.35), which after adjustment was estimated to be a 28% lower level. We observed an inverse association between duration of statin use and CRP levels. Elevated levels of IgE (>100 IU/mL) were more prevalent in statin users compared to non-users. A trend towards increased levels of IgE antibodies in statin users was observed, whereas no associations were found between statin use and levels of neopterin or the presence of autoantibodies. In this general population sub-sample, we observed an anti-inflammatory effect of statin use and a trend towards an increase of IgE levels, an surrogate marker for Th (helper) 2 responses without a decrease in neopterin levels, a surrogate marker for Th1 response and/or self-tolerance. We postulate that the observed decreased inflammatory response during statin therapy may be important but is insufficient to induce loss of self-tolerance. PMID- 24147032 TI - Genetic analysis of a rat model of aerobic capacity and metabolic fitness. AB - Aerobic capacity is a strong predictor of all-cause mortality and can influence many complex traits. To explore the biological basis underlying this connection, we developed via artificial selection two rat lines that diverge for intrinsic (i.e. inborn) aerobic capacity and differ in risk for complex disease traits. Here we conduct the first in-depth pedigree and molecular genetic analysis of these lines, the high capacity runners (HCR) and low capacity runners (LCR). Our results show that both HCR and LCR lines maintain considerable narrow-sense heritability (h(2)) for the running capacity phenotype over 28 generations (h(2) = 0.47 +/- 0.02 and 0.43 +/- 0.02, respectively). To minimize inbreeding, the lines were maintained by rotational mating. Pedigree records predict that the inbreeding coefficient increases at a rate of <1% per generation, ~37-38% slower than expected for random mating. Genome-wide 10K SNP genotype data for generations 5, 14, and 26 demonstrate substantial genomic evolution: between-line differentiation increased progressively, while within-line diversity deceased. Genome-wide average heterozygosity decreased at a rate of <1% per generation, consistent with pedigree-based predictions and confirming the effectiveness of rotational breeding. Linkage disequilibrium index r(2) decreases to 0.3 at ~3 Mb, suggesting that the resolution for mapping quantitative trait loci (QTL) can be as high as 2-3 cM. To establish a test population for QTL mapping, we conducted an HCR-LCR intercross. Running capacity of the F1 population (n=176) was intermediate of the HCR and LCR parentals (28 pairs); and the F2 population (n=645) showed a wider range of phenotypic distribution. Importantly, heritability in the F0-F2 pedigree remained high (h(2)~0.6). These results suggest that the HCR-LCR lines can serve as a valuable system for studying genomic evolution, and a powerful resource for mapping QTL for a host of characters relevant to human health. PMID- 24147033 TI - BMP-2 induces versican and hyaluronan that contribute to post-EMT AV cushion cell migration. AB - Distal outgrowth and maturation of mesenchymalized endocardial cushions are critical morphogenetic events during post-EMT atrioventricular (AV) valvuloseptal morphogenesis. We explored the role of BMP-2 in the regulation of valvulogenic extracellular matrix (ECM) components, versican and hyaluronan (HA), and cell migration during post-EMT AV cushion distal outgrowth/expansion. We observed intense staining of versican and HA in AV cushion mesenchyme from the early cushion expansion stage, Hamburger and Hamilton (HH) stage-17 to the cushion maturation stage, HH stage-29 in the chick. Based on this expression pattern we examined the role of BMP-2 in regulating versican and HA using 3D AV cushion mesenchymal cell (CMC) aggregate cultures on hydrated collagen gels. BMP-2 induced versican expression and HA deposition as well as mRNA expression of versican and Has2 by CMCs in a dose dependent manner. Noggin, an antagonist of BMP, abolished BMP-2-induced versican and HA as well as mRNA expression of versican and Has2. We further examined whether BMP-2-promoted cell migration was associated with expression of versican and HA. BMP-2- promoted cell migration was significantly impaired by treatments with versican siRNA and HA oligomer. In conclusion, we provide evidence that BMP-2 induces expression of versican and HA by AV CMCs and that these ECM components contribute to BMP-2-induced CMC migration, indicating critical roles for BMP-2 in distal outgrowth/expansion of mesenchymalized AV cushions. PMID- 24147034 TI - The effect of N-acetylation and N-methylation of lysine residue of Tat peptide on its interaction with HIV-1 TAR RNA. AB - Post-translational modification (PTM) of RNA binding proteins (RBPs) play a very important role in determining their binding to cognate RNAs and therefore regulate the downstream effects. Lysine can undergo various PTMs and thereby contribute to the regulation of different cellular processes. It can be reversibly acetylated and methylated using a pool of respective enzymes, to act as a switch for controlling the binding efficiency of RBPs. Here we have delineated the thermodynamic and kinetic effects of N-acetylation and N monomethylation of lysine on interaction between HIV-1 TAR RNA and its cognate binder Tat peptide ( a model system). Our results indicate that acetylation of lysine 50 (K50), leads to eight- fold reduction in binding affinity, originating exclusively from entropy changes whereas, lysine 51 (K51) acetylation resulted only in three fold decrease with large enthalpy-entropy compensation. The measurement of kinetic parameters indicated major change (4.5 fold) in dissociation rate in case of K50 acetylation however, K51 acetylation showed similar effect on both association and dissociation rates. In contrast, lysine methylation did not affect the binding affinity of Tat peptide to TAR RNA at K50, nonetheless three fold enhancement in binding affinity was observed at K51 position. In spite of large enthalpy-entropy compensation, lysine methylation seems to have more pronounced position specific effect on the kinetic parameters. In case of K50 methylation, simultaneous increase was observed in the rate of association and dissociation leaving binding affinity unaffected. The increased binding affinity for methylated Tat at K51 stems from faster association rate with slightly slower dissociation rate. PMID- 24147035 TI - Innate immune signaling induces interleukin-7 production from salivary gland cells and accelerates the development of primary Sjogren's syndrome in a mouse model. AB - Elevated IL-7 in the target tissues is closely associated with multiple autoimmune disorders, including Sjogren's syndrome (SS). We recently found that IL-7 plays an essential role in the development and onset of primary SS (pSS) in C57BL/6.NOD-Aec1Aec2 mice, a well-defined mouse model of primary SS. However, environmental signals that cause excessive IL-7 production are not well characterized. Innate immune signaling plays a critical role in shaping the adaptive immune responses including autoimmune responses. We and others have previously shown that innate immune signaling can induce IL-7 expression in lungs and intestines of C57BL/6 mice. In this study, we characterized the effects of poly I:C, a double-stranded RNA analog and toll-like receptor 3 agonist, on the induction of IL-7 expression in salivary glands and on pSS development. We showed that poly I:C administration to C57BL/6 mice rapidly induced IL-7 expression in the salivary glands in a type 1 IFN- and IFN-gamma-dependent manner. Moreover, poly I:C-induced IL-7 contributed to the optimal up-regulation of CXCL9 in the salivary glands, which may subsequently promote recruitment of more IFN-gamma producing T cells. Repeated administration of poly I:C to C57BL/6.NOD-Aec1Aec2 mice accelerated the development of SS-like exocrinopathy, and this effect was abolished by the blockade of IL-7 receptor signaling with a neutralizing antibody. Finally, poly I:C or a combination of IFN-alpha and IFN-gamma induced IL-7 gene expression and protein production in a human salivary gland epithelial cell line. Hence, we demonstrate that IL-7 expression in the salivary gland cells can be induced by poly I:C and delineate a crucial mechanism by which innate immune signals facilitate the development of pSS, which is through induction of IL-7 in the target tissues. PMID- 24147036 TI - The role of clathrin in post-Golgi trafficking in Toxoplasma gondii. AB - Apicomplexan parasites are single eukaryotic cells with a highly polarised secretory system that contains unique secretory organelles (micronemes and rhoptries) that are required for host cell invasion. In contrast, the role of the endosomal system is poorly understood in these parasites. With many typical endocytic factors missing, we speculated that endocytosis depends exclusively on a clathrin-mediated mechanism. Intriguingly, in Toxoplasma gondii we were only able to observe the endogenous clathrin heavy chain 1 (CHC1) at the Golgi, but not at the parasite surface. For the functional characterisation of Toxoplasma gondii CHC1 we generated parasite mutants conditionally expressing the dominant negative clathrin Hub fragment and demonstrate that CHC1 is essential for vesicle formation at the trans-Golgi network. Consequently, the functional ablation of CHC1 results in Golgi aberrations, a block in the biogenesis of the unique secretory microneme and rhoptry organelles, and of the pellicle. However, we found no morphological evidence for clathrin mediating endocytosis in these parasites and speculate that they remodelled their vesicular trafficking system to adapt to an intracellular lifestyle. PMID- 24147037 TI - miR-29b, miR-205 and miR-221 enhance chemosensitivity to gemcitabine in HuH28 human cholangiocarcinoma cells. AB - BACKGROUND AND AIMS: Cholangiocarcinoma (CCA) is highly resistant to chemotherapy, including gemcitabine (Gem) treatment. MicroRNAs (miRNAs) are endogenous, non-coding, short RNAs that can regulate multiple genes expression. Some miRNAs play important roles in the chemosensitivity of tumors. Here, we examined the relationship between miRNA expression and the sensitivity of CCA cells to Gem. METHODS: Microarray analysis was used to determine the miRNA expression profiles of two CCA cell lines, HuH28 and HuCCT1. To determine the effect of candidate miRNAs on Gem sensitivity, expression of each candidate miRNA was modified via either transfection of a miRNA mimic or transfection of an anti oligonucleotide. Ontology-based programs were used to identify potential target genes of candidate miRNAs that were confirmed to affect the Gem sensitivity of CCA cells. RESULTS: HuCCT1 cells were more sensitive to Gem than were HuH28 cells, and 18 miRNAs were differentially expressed whose ratios over +/- 2log2 between HuH28 and HuCCT1. Among these 18 miRNAs, ectopic overexpression of each of three downregulated miRNAs in HuH28 (miR-29b, miR-205, miR-221) restored Gem sensitivity to HuH28. Suppression of one upregulated miRNA in HuH28, miR-125a-5p, inhibited HuH28 cell proliferation independently to Gem treatment. Selective siRNA-mediated downregulation of either of two software-predicted targets, PIK3R1 (target of miR-29b and miR-221) or MMP-2 (target of miR-29b), also conferred Gem sensitivity to HuH28. CONCLUSIONS: miRNA expression profiling was used to identify key miRNAs that regulate Gem sensitivity in CCA cells, and software that predicts miRNA targets was used to identify promising target genes for anti-tumor therapies. PMID- 24147038 TI - Ashwagandha (Withania somnifera) reverses beta-amyloid1-42 induced toxicity in human neuronal cells: implications in HIV-associated neurocognitive disorders (HAND). AB - Alzheimer's disease (AD) is characterized by progressive dysfunction of memory and higher cognitive functions with abnormal accumulation of extracellular amyloid plaques and intracellular neurofibrillary tangles throughout cortical and limbic brain regions. At present no curative treatment is available, and research focuses on drugs for slowing disease progression or providing prophylaxis. Withania somnifera (WS) also known as 'ashwagandha' is used widely in Ayurvedic medicine as a nerve tonic and memory enhancer. However, there is a paucity of data on the potential neuroprotective effects of W.somnifera against beta-Amyloid (1-42)-induced neuropathogenesis. In the present study, we have tested the neuroprotective effects of methanol:Chloroform (3:1) extract of ashwagandha against beta-amyloid induced toxicity and HIV-1Ba-L (clade B) infection using a human neuronal SK-N-MC cell line. Our results showed that beta-amyloid induced cytotoxic effects in SK-N-MC cells as shown by decreased cell growth when tested individually. Also, confocal microscopic analysis showed decreased spine density, loss of spines and decreased dendrite diameter, total dendrite and spine area in clade B infected SK-N-MC cells compared to uninfected cells. However, when ashwagandha was added to beta-amyloid treated and HIV-1 infected samples, the toxic effects were neutralized. Further, the MTT cell viability assays and the peroxisome proliferator-activated receptor-gamma (PPARgamma) levels supported these observations indicating the neuroprotective effect of WS root extract against beta-amyloid and HIV-1Ba-L (clade B) induced neuro-pathogenesis. PMID- 24147039 TI - PhysioSpace: relating gene expression experiments from heterogeneous sources using shared physiological processes. AB - Relating expression signatures from different sources such as cell lines, in vitro cultures from primary cells and biopsy material is an important task in drug development and translational medicine as well as for tracking of cell fate and disease progression. Especially the comparison of large scale gene expression changes to tissue or cell type specific signatures is of high interest for the tracking of cell fate in (trans-) differentiation experiments and for cancer research, which increasingly focuses on shared processes and the involvement of the microenvironment. These signature relation approaches require robust statistical methods to account for the high biological heterogeneity in clinical data and must cope with small sample sizes in lab experiments and common patterns of co-expression in ubiquitous cellular processes. We describe a novel method, called PhysioSpace, to position dynamics of time series data derived from cellular differentiation and disease progression in a genome-wide expression space. The PhysioSpace is defined by a compendium of publicly available gene expression signatures representing a large set of biological phenotypes. The mapping of gene expression changes onto the PhysioSpace leads to a robust ranking of physiologically relevant signatures, as rigorously evaluated via sample-label permutations. A spherical transformation of the data improves the performance, leading to stable results even in case of small sample sizes. Using PhysioSpace with clinical cancer datasets reveals that such data exhibits large heterogeneity in the number of significant signature associations. This behavior was closely associated with the classification endpoint and cancer type under consideration, indicating shared biological functionalities in disease associated processes. Even though the time series data of cell line differentiation exhibited responses in larger clusters covering several biologically related patterns, top scoring patterns were highly consistent with a priory known biological information and separated from the rest of response patterns. PMID- 24147040 TI - Prostaglandin E2 induction during mouse adenovirus type 1 respiratory infection regulates inflammatory mediator generation but does not affect viral pathogenesis. AB - Respiratory viruses cause substantial disease and are a significant healthcare burden. Virus-induced inflammation can be detrimental to the host, causing symptoms during acute infection and leading to damage that contributes to long term residual lung disease. Prostaglandin E2 (PGE2) is a lipid mediator that is increased in response to many viral infections, and inhibition of PGE2 production during respiratory viral infection often leads to a decreased inflammatory response. We tested the hypothesis that PGE2 promotes inflammatory responses to mouse adenovirus type 1 (MAV-1) respiratory infection. Acute MAV-1 infection increased COX-2 expression and PGE2 production in wild type mice. Deficiency of the E prostanoid 2 receptor had no apparent effect on MAV-1 pathogenesis. Virus induced induction of PGE2, IFN-gamma, CXCL1, and CCL5 was reduced in mice deficient in microsomal PGE synthase-1 (mPGES-1(-/-) mice). However, there were no differences between mPGES-1(+/+) and mPGES-1(-/-) mice in viral replication, recruitment of leukocytes to airways or lung inflammation. Infection of both mPGES-1(+/+) and mPGES-1(-/-) mice led to protection against reinfection. Thus, while PGE2 promotes the expression of a variety of cytokines in response to acute MAV-1 infection, PGE2 synthesis does not appear to be essential for generating pulmonary immunity. PMID- 24147041 TI - Signal one and two blockade are both critical for non-myeloablative murine HSCT across a major histocompatibility complex barrier. AB - Non-myeloablative allogeneic haematopoietic stem cell transplantation (HSCT) is rarely achievable clinically, except where donor cells have selective advantages. Murine non-myeloablative conditioning regimens have limited clinical success, partly through use of clinically unachievable cell doses or strain combinations permitting allograft acceptance using immunosuppression alone. We found that reducing busulfan conditioning in murine syngeneic HSCT, increases bone marrow (BM):blood SDF-1 ratio and total donor cells homing to BM, but reduces the proportion of donor cells engrafting. Despite this, syngeneic engraftment is achievable with non-myeloablative busulfan (25 mg/kg) and higher cell doses induce increased chimerism. Therefore we investigated regimens promoting initial donor cell engraftment in the major histocompatibility complex barrier mismatched CBA to C57BL/6 allo-transplant model. This requires full myeloablation and immunosuppression with non-depleting anti-CD4/CD8 blocking antibodies to achieve engraftment of low cell doses, and rejects with reduced intensity conditioning (<=75 mg/kg busulfan). We compared increased antibody treatment, G-CSF, niche disruption and high cell dose, using reduced intensity busulfan and CD4/8 blockade in this model. Most treatments increased initial donor engraftment, but only addition of co-stimulatory blockade permitted long-term engraftment with reduced intensity or non-myeloablative conditioning, suggesting that signal 1 and 2 T-cell blockade is more important than early BM niche engraftment for transplant success. PMID- 24147042 TI - Tuberculosis transmission among immigrants and autochthonous populations of the eastern province of Saudi Arabia. AB - BACKGROUND: Eastern province of Saudi Arabia is an industrial zone with large immigrant population and high level of tuberculosis case notification among immigrants. The impact of immigration and current trends of tuberculosis transmission among immigrants and autochthonous population in the region had not been investigated so far using molecular tools. METHODOLOGY: During 2009- 2011, a total of 524 Mycobacterium tuberculosis isolates were collected from the central tuberculosis reference laboratory, representing an estimated 79.2% of the culture positive tuberculosis cases over the study period in the province. These isolates were genotyped by using 24 locus-based MIRU-VNTR typing and spoligotyping followed by first line drug susceptibility testing. The molecular clustering profiles and phylogenetic diversity of isolates were determined and compared to the geographical origins of the patients. PRINCIPLE FINDINGS: Genotyping showed an overall predominance of Delhi/CAS (29.4%), EAI (23.8%) and Ghana (13.3%) lineages, with slightly higher proportions of Delhi/CAS among autochthonous population (33.3 %) and EAI (30.9%) among immigrants. Rate of any drug resistance was 20.2% with 2.5% of multi-drug resistance. Strain cluster analysis indicated 42 clusters comprising 210 isolates, resulting in a calculated recent transmission index of 32.1%. Overall shared cluster ratio was 78.6% while 75.8% were shared between autochthonous population and immigrant population with a predominance of immigrants from South east Asia (40.7%). In contrast, cross national transmission within the immigrant population was limited (24.2%). Younger age (15-30- p value-0.043, 16-45, p value 0.030), Saudi nationality (p value-0.004) and South East Asian origin (p value-0.011) were identified as significant predisposing factors for molecular strain clustering. CONCLUSIONS: The high proportion of molecular clusters shared among the autochthonous and immigrant populations suggests a high permeability of tuberculosis transmission between both populations in the province. These results prompt for the need to strengthen the current tuberculosis control strategies and surveillance programs. PMID- 24147043 TI - High seroprevalence of Mycoplasma pneumoniae IgM in acute Q fever by enzyme linked immunosorbent assay (ELISA). AB - Q fever is serologically cross-reactive with other intracellular microorganisms. However, studies of the serological status of Mycoplasma pneumoniae and Chlamydophila pneumoniae during Q fever are rare. We conducted a retrospective serological study of M. pneumoniae and C. pneumoniae by enzyme-linked immunosorbent assay (ELISA), a method widely used in clinical practice, in 102 cases of acute Q fever, 39 cases of scrub typhus, and 14 cases of murine typhus. The seropositive (57.8%, 7.7%, and 0%, p<0.001) and seroconversion rates (50.6%, 8.8%, and 0%, p<0.001) of M. pneumoniae IgM, but not M. pneumoniae IgG and C. pneumoniae IgG/IgM, in acute Q fever were significantly higher than in scrub typhus and murine typhus. Another ELISA kit also revealed a high seropositivity (49.5%) and seroconversion rate (33.3%) of M. pneumoniae IgM in acute Q fever. The temporal and age distributions of patients with positive M. pneumoniae IgM were not typical of M. pneumoniae pneumonia. Comparing acute Q fever patients who were positive for M. pneumoniae IgM (59 cases) with those who were negative (43 cases), the demographic characteristics and underlying diseases were not different. In addition, the clinical manifestations associated with atypical pneumonia, including headache (71.2% vs. 81.4%, p=0.255), sore throat (8.5% vs. 16.3%, p=0.351), cough (35.6% vs. 23.3%, p=0.199), and chest x-ray suggesting pneumonia (19.3% vs. 9.5%, p=0.258), were unchanged between the two groups. Clinicians should be aware of the high seroprevalence of M. pneumoniae IgM in acute Q fever, particularly with ELISA kits, which can lead to misdiagnosis, overestimations of the prevalence of M. pneumoniae pneumonia, and underestimations of the true prevalence of Q fever pneumonia. PMID- 24147045 TI - Gene expression analysis of the microdissected trophoblast layer of human placenta after the spontaneous onset of labor. AB - BACKGROUND: Despite increasing evidence that human parturition is associated with alteration in gene expression in the uteroplacental unit, the precise mechanisms that elicit spontaneous term labor in humans remain unknown. Our goal in this study was to compare the mRNA expression pattern of the trophoblast layer of normal term placenta between women who had given natural birth (labor group) and those who had undergone an elective cesarean section without labor (non-labor group). METHODS: We collected placental tissue samples from six pregnant women after term vaginal deliveries (labor group) and from six pregnant women after scheduled Cesarean sections (non-labor group). Frozen sections were made immediately after placental delivery. Because the placenta is a heterogeneous tissue composed of several cell types, we used laser capture microdissection to separate the trophoblast layer from the rest of the placental tissues. RESULTS: A number of genes were differentially expressed in the trophoblast layer when the labor and non-labor groups were compared. The expression of SIRT1, KAP1, and CRH was significantly lower in the trophoblast layer of the labor group than of the non-labor group. The expression of IL-1b, NF-kB1 and TLR 8 in the labor group was significantly higher than that in the non-labor group. CONCLUSIONS: Human term labor may be closely associated with inflammatory response. We suggest that downregulation of SIRT1, KAP1, and CRH gene expression in the trophoblast may play a key role in parturition and initiation of labor in pregnant human females. PMID- 24147044 TI - Endogenous human MDM2-C is highly expressed in human cancers and functions as a p53-independent growth activator. AB - Human cancers over-expressing mdm2, through a T to G variation at a single nucleotide polymorphism at position 309 (mdm2 SNP309), have functionally inactivated p53 that is not effectively degraded. They also have high expression of the alternatively spliced transcript, mdm2-C. Alternatively spliced mdm2 transcripts are expressed in many forms of human cancer and when they are exogenously expressed they transform human cells. However no study to date has detected endogenous MDM2 protein isoforms. Studies with exogenous expression of splice variants have been carried out with mdm2-A and mdm2-B, but the mdm2-C isoform has remained virtually unexplored. We addressed the cellular influence of exogenously expressed MDM2-C, and asked if endogenous MDM2-C protein was present in human cancers. To detect endogenous MDM2-C protein, we created a human MDM2-C antibody to the splice junction epitope of exons four and ten (MDM2 C410) and validated the antibody with in vitro translated full length MDM2 compared to MDM2 C. Interestingly, we discovered that MDM2-C co-migrates with MDM2-FL at approximately 98 kDa. Using the validated C410 antibody, we detected high expression of endogenous MDM2-C in human cancer cell lines and human cancer tissues. In the estrogen receptor positive (ER+) mdm2 G/G SNP309 breast cancer cell line, T47D, we observed an increase in endogenous MDM2-C protein with estrogen treatment. MDM2-C localized to the nucleus and the cytoplasm. We examined the biological activity of MDM2-C by exogenously expressing the protein and observed that MDM2-C did not efficiently target p53 for degradation or reduce p53 transcriptional activity. Exogenous expression of MDM2-C in p53-null human cancer cells increased colony formation, indicating p53-independent tumorigenic properties. Our data indicate a role for MDM2-C that does not require the inhibition of p53 for increasing cancer cell proliferation and survival. PMID- 24147046 TI - Molecular characterization of ambiguous mutations in HIV-1 polymerase gene: implications for monitoring HIV infection status and drug resistance. AB - Detection of recent HIV infections is a prerequisite for reliable estimations of transmitted HIV drug resistance (t-HIVDR) and incidence. However, accurately identifying recent HIV infection is challenging due partially to the limitations of current serological tests. Ambiguous nucleotides are newly emerged mutations in quasispecies, and accumulate by time of viral infection. We utilized ambiguous mutations to establish a measurement for detecting recent HIV infection and monitoring early HIVDR development. Ambiguous nucleotides were extracted from HIV 1 pol-gene sequences in the datasets of recent (HIVDR threshold surveys [HIVDR TS] in 7 countries; n=416) and established infections (1 HIVDR monitoring survey at baseline; n=271). An ambiguous mutation index of 2.04*10(-3) nts/site was detected in HIV-1 recent infections which is equivalent to the HIV-1 substitution rate (2*10(-3) nts/site/year) reported before. However, significantly higher index (14.41*10(-3) nts/site) was revealed with established infections. Using this substitution rate, 75.2% subjects in HIVDR-TS with the exception of the Vietnam dataset and 3.3% those in HIVDR-baseline were classified as recent infection within one year. We also calculated mutation scores at amino acid level at HIVDR sites based on ambiguous or fitted mutations. The overall mutation scores caused by ambiguous mutations increased (0.54*10(-2)3.48*10(-2)/DR-site) whereas those caused by fitted mutations remained stable (7.50-7.89*10(-2)/DR site) in both recent and established infections, indicating that t-HIVDR exists in drug-naive populations regardless of infection status in which new HIVDR continues to emerge. Our findings suggest that characterization of ambiguous mutations in HIV may serve as an additional tool to differentiate recent from established infections and to monitor HIVDR emergence. PMID- 24147047 TI - Relationship of CHA2DS2-VASc and CHADS2 score to left atrial remodeling detected by velocity vector imaging in patients with atrial fibrillation. AB - BACKGROUND: The CHADS2/CHA2DS2-VASc scores are used to predict thrombo embolic/stroke in patients with nonvalvular atrial fibrillation (AF). Nevertheless, limited data are available regarding the association between these risk stratification for stroke and left atrial (LA) remodeling status of AF patients. The purpose of this study was to explore the association between these scores and LA remodeling status assessed quantificationally by echocardiography in AF patients. METHODS: One hundred AF patients were divided into 3 groups based on the CHA2DS2-VASc/CHADS2 score: the score of 0 (low stroke risk), the score of 1 (moderate stroke risk) and the score of >=2 (high stroke risk). All patients were performed through conventional and velocity vector imaging echocardiography. Echocardiographic parameters: maximum LA volume index (LAVImax), LA total emptying fraction (LAEFt) and LA mean strain were obtained to assess quantificationally LA remodeling status. RESULTS: On categorizing with CHA2DS2 VASc, the score of 1 group showed augment in LAVImax and attenuation in LA mean strain derived from VVI, compared with the score of 0 group (LAVImax: 40.27+/ 21.91 vs. 26.79+/-7.87, p=0.002; LA mean strain: 15.18+/-6.36 vs. 22+/-8.54, p=0.001). On categorizing with the CHADS2 score, similar trends were seen between the score of >=2 and 1 groups (LAVImax: 43.72+/-13.77 vs. 31.41+/-9.50, p<0.001; LA mean strain: 11.01+/-5.31 vs. 18.63+/-7.00, p<0.001). With multivariate logistic regression, LAVImax (odds ratio: 0.92 , 95% C=I: 0.85 to 0.98, p= 0.01) and LA mean strain reflecting LA remodeling (odds ratio: 1.10, 95% CI: 1.02 to 1.19, p=0.01) were strongly predictive of the CHA2DS2-VASc score of 0. CONCLUSIONS: The superiority of the CHADS2 score may lay in identifying LA remodeling of AF patients with high stroke risk. Whereas, the CHA2DS2-VASc score was better than the CHADS2 score at identifying LA remodeling of AF patients presenting low stroke risk. PMID- 24147048 TI - Temporal variation in population size of European bird species: effects of latitude and marginality of distribution. AB - In the Northern Hemisphere, global warming has been shown to affect animal populations in different ways, with southern populations in general suffering more from increased temperatures than northern populations of the same species. However, southern populations are also often marginal populations relative to the entire breeding range, and marginality may also have negative effects on populations. To disentangle the effects of latitude (possibly due to global warming) and marginality on temporal variation in population size, we investigated European breeding bird species across a latitudinal gradient. Population size estimates were regressed on years, and from these regressions we obtained the slope (a proxy for population trend) and the standard error of the estimate (SEE) (a proxy for population fluctuations). The possible relationships between marginality or latitude on one hand and slopes or SEE on the other were tested among populations within species. Potentially confounding factors such as census method, sampling effort, density-dependence, habitat fragmentation and number of sampling years were controlled statistically. Population latitude was positively related to regression slopes independent of marginality, with more positive slopes (i.e., trends) in northern than in southern populations. The degree of marginality was positively related to SEE independent of latitude, with marginal populations showing larger SEE (i.e., fluctuations) than central ones. Regression slopes were also significantly related to our estimate of density dependence and SEE was significantly affected by the census method. These results are consistent with a scenario in which southern and northern populations of European bird species are negatively affected by marginality, with southern populations benefitting less from global warming than northern populations, thus potentially making southern populations more vulnerable to extinction. PMID- 24147049 TI - TGF-beta1 does not induce senescence of multipotent mesenchymal stromal cells and has similar effects in early and late passages. AB - Transforming growth factor-beta 1 (TGF-beta1) stimulates a broad range of effects which are cell type dependent, and it has been suggested to induce cellular senescence. On the other hand, long-term culture of multipotent mesenchymal stromal cells (MSCs) has a major impact on their cellular physiology and therefore it is well conceivable that the molecular events triggered by TGF-beta1 differ considerably in cells of early and late passages. In this study, we analyzed the effect of TGF-beta1 on and during replicative senescence of MSCs. Stimulation with TGF-beta1 enhanced proliferation, induced a network like growth pattern and impaired adipogenic and osteogenic differentiation. TGF-beta1 did not induce premature senescence. However, due to increased proliferation rates the cells reached replicative senescence earlier than untreated controls. This was also evident, when we analyzed senescence-associated DNA-methylation changes. Gene expression profiles of MSCs differed considerably at relatively early (P 3 5) and later passages (P 10). Nonetheless, relative gene expression differences provoked by TGF-beta1 at individual time points or in a time course dependent manner (stimulation for 0, 1, 4 and 12 h) were very similar in MSCs of early and late passage. These results support the notion that TGF-beta1 has major impact on MSC function, but it does not induce senescence and has similar molecular effects during culture expansion. PMID- 24147050 TI - Homogeneous population of the brown alga Sargassum polycystum in Southeast Asia: possible role of recent expansion and asexual propagation. AB - Southeast Asia has been known as one of the biodiversity hotspots in the world. Repeated glacial cycles during Pleistocene were believed to cause isolation of marine taxa in refugia, resulting in diversification among lineages. Recently, ocean current was also found to be another factor affecting gene flow by restricting larval dispersal in animals. Macroalgae are unique in having mode of reproduction that differs from that of animals. Our study on the phylogeographical pattern of the brown macroalga Sargassum polycystum using nuclear Internal Transcribed Spacer 2 (ITS2), plastidal RuBisCO spacer (Rub spacer) and mitochondrial cytochrome oxidase subunit-III (Cox3) as molecular markers revealed genetic homogeneity across 27 sites in Southeast Asia and western Pacific, in sharp contrast to that revealed from most animal studies. Our data suggested that S. polycystum persisted in single refugium during Pleistocene in a panmixia pattern. Expansion occurred more recently after the Last Glacial Maximum and recolonization of the newly flooded Sunda Shelf could have involved asexual propagation of the species. High dispersal ability through floating fronds carrying developing germlings may also contribute to the low genetic diversity of the species. PMID- 24147051 TI - Prenatal exposure to dietary fat induces changes in the transcriptional factors, TEF and YAP, which may stimulate differentiation of peptide neurons in rat hypothalamus. AB - Gestational exposure to a high-fat diet (HFD) stimulates the differentiation of orexigenic peptide-expressing neurons in the hypothalamus of offspring. To examine possible mechanisms that mediate this phenomenon, this study investigated the transcriptional factor, transcription enhancer factor-1 (TEF), and co activator, Yes-associated protein (YAP), which when inactivated stimulate neuronal differentiation. In rat embryos and postnatal offspring prenatally exposed to a HFD compared to chow, changes in hypothalamic TEF and YAP and their relationship to the orexigenic peptide, enkephalin (ENK), were measured. The HFD offspring at postnatal day 15 (P15) exhibited in the hypothalamic paraventricular nucleus a significant reduction in YAP mRNA and protein, and increased levels of inactive and total TEF protein, with no change in mRNA. Similarly, HFD-exposed embryos at embryonic day 19 (E19) showed in whole hypothalamus significantly decreased levels of YAP mRNA and protein and TEF mRNA, and increased levels of inactive TEF protein, suggesting that HFD inactivates TEF and YAP. This was accompanied by increased density and fluorescence intensity of ENK neurons. A close relationship between TEF and ENK was suggested by the finding that TEF co localizes with this peptide in hypothalamic neurons and HFD reduced the density of TEF/ENK co-labeled neurons, even while the number and fluorescence intensity of single-labeled TEF neurons were increased. Increased YAP inactivity by HFD was further evidenced by a decrease in number and fluorescence intensity of YAP containing neurons, although the density of YAP/ENK co-labeled neurons was unaltered. Genetic knockdown of TEF or YAP stimulated ENK expression in hypothalamic neurons, supporting a close relationship between these transcription factors and neuropeptide. These findings suggest that prenatal HFD exposure inactivates both hypothalamic TEF and YAP, by either decreasing their levels or increasing their inactive form, and that this contributes to the stimulatory effect of HFD on ENK expression and possibly the differentiation of ENK expressing neurons. PMID- 24147052 TI - p53-mediated biliary defects caused by knockdown of cirh1a, the zebrafish homolog of the gene responsible for North American Indian Childhood Cirrhosis. AB - North American Indian Childhood Cirrhosis (NAIC) is a rare, autosomal recessive, progressive cholestatic disease of infancy affecting the Cree-Ojibway first Nations of Quebec. All NAIC patients are homozygous for a missense mutation (R565W) in CIRH1A, the human homolog of the yeast nucleolar protein Utp4. Utp4 is part of the t-Utp subcomplex of the small subunit (SSU) processome, a ribonucleoprotein complex required for ribosomal RNA processing and small subunit assembly. NAIC has thus been proposed to be a primary ribosomal disorder (ribosomopathy); however, investigation of the pathophysiologic mechanism of this disease has been hindered by lack of an animal model. Here, using a morpholino oligonucleotide (MO)-based loss-of-function strategy, we have generated a model of NAIC in the zebrafish, Danio rerio. Zebrafish Cirhin shows substantial homology to the human homolog, and cirh1a mRNA is expressed in developing hepatocytes and biliary epithelial cells. Injection of two independent MOs directed against cirh1a at the one-cell stage causes defects in canalicular and biliary morphology in 5 dpf larvae. In addition, 5 dpf Cirhin-deficient larvae have dose-dependent defects in hepatobiliary function, as assayed by the metabolism of an ingested fluorescent lipid reporter. Previous yeast and in vitro studies have shown that defects in ribosome biogenesis cause stabilization and nuclear accumulation of p53, which in turn causes p53-mediated cell cycle arrest and/or apoptosis. Thus, the nucleolus appears to function as a cellular stress sensor in some cell types. In accordance with this hypothesis, transcriptional targets of p53 are upregulated in Cirhin-deficient zebrafish embryos, and defects in biliary function seen in Cirhin-deficient larvae are completely abrogated by mutation of tp53. Our data provide the first in vivo evidence of a role for Cirhin in biliary development, and support the hypothesis that congenital defects affecting ribosome biogenesis can activate a cellular stress response mediated by p53. PMID- 24147053 TI - Generation of 3D skin equivalents fully reconstituted from human induced pluripotent stem cells (iPSCs). AB - Recent generation of patient-specific induced pluripotent stem cells (PS-iPSCs) provides significant advantages for cell- and gene-based therapy. Establishment of iPSC-based therapy for skin diseases requires efficient methodology for differentiating iPSCs into both keratinocytes and fibroblasts, the major cellular components of the skin, as well as the reconstruction of skin structures using these iPSC-derived skin components. We previously reported generation of keratinocytes from human iPSCs for use in the treatment of recessive dystrophic epidermolysis bullosa (RDEB) caused by mutations in the COL7A1 gene. Here, we developed a protocol for differentiating iPSCs into dermal fibroblasts, which also produce type VII collagen and therefore also have the potential to treat RDEB. Moreover, we generated in vitro 3D skin equivalents composed exclusively human iPSC-derived keratinocytes and fibroblasts for disease models and regenerative therapies for skin diseases, first demonstrating that iPSCs can provide the basis for modeling a human organ derived entirely from two different types of iPSC-derived cells. PMID- 24147054 TI - IL-10 modulates in vitro multinucleate giant cell formation in human tuberculosis. AB - BACKGROUND: Multinucleated giant cells (MGC) are the histologic hallmark of granuloma which is known to limit tuberculosis infection. Both Th1 and Th2 type of cytokines regulate the immune response occurring within the granulomas. The objective of the study was to determine whether tuberculosis patient monocytes differed in their MGC forming ability as compared to healthy controls. METHODS: In vitro MGC formation was carried out by treatment of monocytes with cytokine containing culture supernatant of ConA or PPD stimulated peripheral mononuclear cells. IL-2, TNF-alpha, IL-4, IL-10 and TGF-beta cytokine levels were analysed in culture supernatants using ELISA. IL-4 and IL-10 were added to culture supernatant separately and simultaneously along with their respective neutralizing antibodies and their consequent effect on MGC formation was evaluated. RESULTS: MGC formation was significantly low in patient monocytes incubated with autologous culture supernatant as compared to control culture supernatant. Cytokine analysis of the culture supernatants revealed that while IL 4 levels were similar in patients and controls, increased IL-10 levels were found in patients. Exogenous addition of IL-10 resulted in reduced MGC formation. Contrastingly, when IL-4 was added exogenously, it led to increased MGC formation. The effects of both IL-10 and IL-4 were reversed upon addition of their respective antibodies. CONCLUSION: The findings suggest that one of the factors contributing to the disease could be the effect of cytokines on the functionality of monocytes, which are crucial in the fight against the organism. Significantly reduced MGC formation was observed on addition of IL-10. The findings imply an overriding role of IL-10 in MGC formation. The suppressive effect of IL-10 on MGC formation was further confirmed by addition of IL-10 neutralizing antibody. PMID- 24147055 TI - Prevalence of dementia and subtypes in Valladolid, northwestern Spain: the DEMINVALL study. AB - OBJECTIVE: To describe the prevalence of dementia and subtypes in a general elderly population in northwestern Spain and to analyze the influence of socio demographic factors. METHODS: Cross-sectional, two-phase, door-to-door, population-based study. A total of 870 individuals from a rural region and 2,119 individuals from an urban region of Valladolid, Spain, were involved. The seven minute screen neurocognitive battery was used in the screening phase. A control group was included. RESULTS: A total of 2,170 individuals aged 65 to 104 years (57% women) were assessed. There were 184 subjects diagnosed with dementia. The crude prevalence was 8.5% (95% CI: 7.3-9.7). Age- and sex-adjusted prevalence was 5.5 (95% CI: 4.5-6.5). Main subtypes of dementia were: Alzheimer's disease (AD) 77.7%, Lewy Body disease, 7.6% and vascular dementia (VD) 5.9%. Crude prevalences were 6.6% (AD), 0.6% (Lewy Body disease), and 0.5% (VD). Dementia was associated with age (OR 1.14 for 1-year increase in age), female sex (OR 1.79) and the absence of formal education (OR 2.53 compared to subjects with primary education or more). CONCLUSION: The prevalence of dementia in the study population was lower than the most recent estimates for Western Europe. There was a high proportion of AD among all dementia cases and very low prevalence of VD. Old age, female sex, and low education level were independent risk factors for dementia and AD. PMID- 24147056 TI - Islet-1 may function as an assistant factor for histone acetylation and regulation of cardiac development-related transcription factor Mef2c expression. AB - OBJECTIVE: Islet-1 is an important transcription factor for cardiac development through mediating extensive interactions between DNA and proteins. The present study was to investigate the role of Islet-1 in regulating the expression of cardiac development-related transcription factors and mechanism. METHODS AND RESULTS: The expression of Islet-1 and histone acetylases (HATs) subtype p300 was determined in newborn mouse hearts and mouse embryonic hearts at different development stages using Western blot. The expression of Islet-1 and cardiac development-related transcription factors Mef2c, GATA4 and Tbx5 as well as histone H3 acetylation level were determined in cardiac progenitor cells with and without transfection of Islet-1 interference RNA (RNAi) in lentivirus using PCR and Western blot. Islet-1 peak expression occurred on day E14.5 in mouse embryonic heart, and was present in the promoter regions of Mef2c, GATA4 and Tbx5 that were precipitated with p300 antibody. When Islet-1 was inhibited with specific RNAi in cardiac progenitor cells, the expression of Mef2c and Tbx5, but not GATA4, was significantly suppressed along with selective reduction in histone H3 acetylation in the promoter region of Mef2c, but not GATA4 and Tbx5. The level of Mef2c DNA, not GATA4 and Tbx5, in the complex associated with p300 was significantly decreased in the cells with Islet-1 knockdown. CONCLUSIONS: These data suggested that Islet-1 might function as an assistant factor that was involved in the regulation of histone acetylation and Mef2c expression via assisting p300 on specifically targeting the promoter of Mef2c. PMID- 24147058 TI - Previously unrecognized ornithuromorph bird diversity in the Early Cretaceous Changma Basin, Gansu Province, northwestern China. AB - Here we report on three new species of ornithuromorph birds from the Lower Cretaceous Xiagou Formation in the Changma Basin of Gansu Province, northwestern China: Yumenornis huangi gen. et sp. nov., Changmaornis houi gen. et sp. nov., and Jiuquanornis niui gen. et sp. nov.. The last of these is based on a previously published but unnamed specimen: GSGM-05-CM-021. Although incomplete, the specimens can be clearly distinguished from each other and from Gansus yumenensis Hou and Liu, 1984. Phylogenetic analysis resolves the three new taxa as basal ornithuromorphs. This study reveals previously unrecognized ornithuromorph diversity in the Changma avifauna, which is largely dominated by Gansus but with at least three other ornithuromorphs. Body mass estimates demonstrate that enantiornithines were much smaller than ornithuromorphs in the Changma avifauna. In addition, Changma enantiornithines preserve long and recurved pedal unguals, suggesting an arboreal lifestyle; in contrast, Changma ornithuromorphs tend to show terrestrial or even aquatic adaptions. Similar differences in body mass and ecology are also observed in the Jehol avifauna in northeastern China, suggesting niche partitioning between these two clades developed early in their evolutionary history. PMID- 24147057 TI - Adherence as a predictor of the development of class-specific resistance mutations: the Swiss HIV Cohort Study. AB - BACKGROUND: Non-adherence is one of the strongest predictors of therapeutic failure in HIV-positive patients. Virologic failure with subsequent emergence of resistance reduces future treatment options and long-term clinical success. METHODS: Prospective observational cohort study including patients starting new class of antiretroviral therapy (ART) between 2003 and 2010. Participants were naive to ART class and completed >=1 adherence questionnaire prior to resistance testing. Outcomes were development of any IAS-USA, class-specific, or M184V mutations. Associations between adherence and resistance were estimated using logistic regression models stratified by ART class. RESULTS: Of 314 included individuals, 162 started NNRTI and 152 a PI/r regimen. Adherence was similar between groups with 85% reporting adherence >=95%. Number of new mutations increased with increasing non-adherence. In NNRTI group, multivariable models indicated a significant linear association in odds of developing IAS-USA (odds ratio (OR) 1.66, 95% confidence interval (CI): 1.04-2.67) or class-specific (OR 1.65, 95% CI: 1.00-2.70) mutations. Levels of drug resistance were considerably lower in PI/r group and adherence was only significantly associated with M184V mutations (OR 8.38, 95% CI: 1.26-55.70). Adherence was significantly associated with HIV RNA in PI/r but not NNRTI regimens. CONCLUSION: Therapies containing PI/r appear more forgiving to incomplete adherence compared with NNRTI regimens, which allow higher levels of resistance, even with adherence above 95%. However, in failing PI/r regimens good adherence may prevent accumulation of further resistance mutations and therefore help to preserve future drug options. In contrast, adherence levels have little impact on NNRTI treatments once the first mutations have emerged. PMID- 24147059 TI - Tuberculosis in antiretroviral treatment programs in lower income countries: availability and use of diagnostics and screening. AB - OBJECTIVES: In resource-constrained settings, tuberculosis (TB) is a common opportunistic infection and cause of death in HIV-infected persons. TB may be present at the start of antiretroviral therapy (ART), but it is often under diagnosed. We describe approaches to TB diagnosis and screening of TB in ART programs in low- and middle-income countries. METHODS AND FINDINGS: We surveyed ART programs treating HIV-infected adults in sub-Saharan Africa, Asia and Latin America in 2012 using online questionnaires to collect program-level and patient level data. Forty-seven sites from 26 countries participated. Patient-level data were collected on 987 adult TB patients from 40 sites (median age 34.7 years; 54% female). Sputum smear microscopy and chest radiograph were available in 47 (100%) sites, TB culture in 44 (94%), and Xpert MTB/RIF in 23 (49%). Xpert MTB/RIF was rarely available in Central Africa and South America. In sites with access to these diagnostics, microscopy was used in 745 (76%) patients diagnosed with TB, culture in 220 (24%), and chest X-ray in 688 (70%) patients. When free of charge culture was done in 27% of patients, compared to 21% when there was a fee (p = 0.033). Corresponding percentages for Xpert MTB/RIF were 26% and 15% of patients (p = 0.001). Screening practices for active disease before starting ART included symptom screening (46 sites, 98%), chest X-ray (38, 81%), sputum microscopy (37, 79%), culture (16, 34%), and Xpert MTB/RIF (5, 11%). CONCLUSIONS: Mycobacterial culture was infrequently used despite its availability at most sites, while Xpert MTB/RIF was not generally available. Use of available diagnostics was higher when offered free of charge. PMID- 24147060 TI - F11R expression upon hypoxia is regulated by RNA editing. AB - F11R is a cell adhesion molecule found on the surface of human platelets. It plays a role in platelet aggregation, cell migration and cell proliferation. F11R is subjected to RNA editing, a post-transcriptional modification which affects RNA structure, stability, localization, translation and splicing. RNA editing in the 3'UTR of F11R and RNA levels are increased upon hypoxia. We therefore set to examine if RNA editing plays a role in the increase of F11R RNA seen upon hypoxic conditions. We show that ADAR1, but not ADAR2, takes part in the editing of F11R however editing alone is not sufficient for obtaining an elevation in RNA levels. In addition we show that hyper-edited mature mRNAs are retained in the nucleus and are associated with p54(nrb). We therefore conclude that hypoxia-induced edited RNAs of F11R are preferentially stabilized and accumulate in the nucleus preventing their export to the cytoplasm for translation. This mechanism may be used by additional proteins in the cell as part of the cell's effort to reduce metabolism upon hypoxic stress. PMID- 24147061 TI - Repetitive hops induce postactivation potentiation in triceps surae as well as an increase in the jump height of subsequent maximal drop jumps. AB - Postactivation potentiation (PAP) has been defined as the increase in twitch torque after a conditioning contraction. The present study aimed to investigate the effectiveness of hops as conditioning contractions to induce PAP and increase performance in subsequent maximal drop jumps. In addition, we wanted to test if and how PAP can contribute to increases in drop jump rebound height. Twelve participants performed 10 maximal two-legged hops as conditioning contractions. Twitch peak torques of triceps surae muscles were recorded before and after the conditioning hops. Then, subjects performed drop jumps with and without 10 conditioning hops before each drop jump. Recordings included ground reaction forces, ankle and knee angles and electromyographic activity in five leg muscles. In addition, efferent motoneuronal output during ground contact was estimated with V-wave stimulation. The analyses showed that after the conditioning hops, twitch peak torques of triceps surae muscles were 32% higher compared to baseline values (P < 0.01). Drop jumps performed after conditioning hops were significantly higher (12%, P < 0.05), but V-waves and EMG activity remained unchanged. The amount of PAP and the change in drop jump rebound height were positively correlated (r(2) = 0.26, P < 0.05). These results provide evidence for PAP in triceps surae muscles induced by a bout of hops and indicate that PAP can contribute to the observed performance enhancements in subsequent drop jumps. The lack of change in EMG activity and V-wave amplitude suggests that the underlying mechanisms are more likely intramuscular than neural in origin. PMID- 24147062 TI - The sensory histidine kinases TorS and EvgS tend to form clusters in Escherichia coli cells. AB - Microorganisms use multiple two-component sensory systems to detect changes in their environment and elicit physiological responses. Despite their wide spread and importance, the intracellular organization of two-component sensory proteins in bacteria remains little investigated. A notable exception is the well-studied clustering of the chemoreceptor-kinase complexes that mediate chemotaxis behaviour. However, these chemosensory complexes differ fundamentally from other systems, both structurally and functionally. Therefore, studying the organization of typical sensory kinases in bacteria is essential for understanding the general role of receptor clustering in bacterial sensory signalling. Here, by studying mYFP-tagged sensory kinases in Escherichia coli, we show that the tagged TorS and EvgS sensors have a clear tendency for self-association and clustering. These sensors clustered even when expressed at a level of a few hundred copies per cell. Moreover, the mYFP-tagged response regulator TorR showed clear TorS dependent clustering, indicating that untagged TorS sensors also tend to form clusters. We also provide evidence for the functionality of these tagged sensors. Experiments with truncated TorS or EvgS proteins suggested that clustering of EvgS sensors depends on the cytoplasmic part of the protein, whereas clustering of TorS sensors can be potentially mediated by the periplasmic/transmembrane domain. Overall, these findings support the notion that sensor clustering plays a role in bacterial sensory signalling beyond chemotaxis. PMID- 24147063 TI - Increased histone H3 phosphorylation in neurons in specific brain structures after induction of status epilepticus in mice. AB - Status epilepticus (SE) induces pathological and morphological changes in the brain. Recently, it has become clear that excessive neuronal excitation, stress and drug abuse induce chromatin remodeling in neurons, thereby altering gene expression. Chromatin remodeling is a key mechanism of epigenetic gene regulation. Histone H3 phosphorylation is frequently used as a marker of chromatin remodeling and is closely related to the upregulation of mRNA transcription. In the present study, we analyzed H3 phosphorylation levels in vivo using immunohistochemistry in the brains of mice with pilocarpine-induced SE. A substantial increase in H3 phosphorylation was detected in neurons in specific brain structures. Increased H3 phosphorylation was dependent on neuronal excitation. In particular, a robust upregulation of H3 phosphorylation was detected in the caudate putamen, and there was a gradient of phosphorylated H3(+) (PH3(+)) neurons along the medio-lateral axis. After unilateral ablation of dopaminergic neurons in the substantia nigra by injection of 6-hydroxydopamine, the distribution of PH3(+) neurons changed in the caudate putamen. Moreover, our histological analysis suggested that, in addition to the well-known MSK1 (mitogen and stress-activated kinase)/H3 phosphorylation/c-fos pathway, other signaling pathways were also activated. Together, our findings suggest that a number of genes involved in the pathology of epileptogenesis are upregulated in PH3(+) brain regions, and that H3 phosphorylation is a suitable indicator of strong neuronal excitation. PMID- 24147064 TI - Attenuation of doxorubicin-induced cardiotoxicity by mdivi-1: a mitochondrial division/mitophagy inhibitor. AB - Doxorubicin is one of the most effective anti-cancer agents. However, its use is associated with adverse cardiac effects, including cardiomyopathy and progressive heart failure. Given the multiple beneficial effects of the mitochondrial division inhibitor (mdivi-1) in a variety of pathological conditions including heart failure and ischaemia and reperfusion injury, we investigated the effects of mdivi-1 on doxorubicin-induced cardiac dysfunction in naive and stressed conditions using Langendorff perfused heart models and a model of oxidative stress was used to assess the effects of drug treatments on the mitochondrial depolarisation and hypercontracture of cardiac myocytes. Western blot analysis was used to measure the levels of p-Akt and p-Erk 1/2 and flow cytometry analysis was used to measure the levels p-Drp1 and p-p53 upon drug treatment. The HL60 leukaemia cell line was used to evaluate the effects of pharmacological inhibition of mitochondrial division on the cytotoxicity of doxorubicin in a cancer cell line. Doxorubicin caused a significant impairment of cardiac function and increased the infarct size to risk ratio in both naive conditions and during ischaemia/reperfusion injury. Interestingly, co-treatment of doxorubicin with mdivi-1 attenuated these detrimental effects of doxorubicin. Doxorubicin also caused a reduction in the time taken to depolarisation and hypercontracture of cardiac myocytes, which were reversed with mdivi-1. Finally, doxorubicin caused a significant elevation in the levels of signalling proteins p-Akt, p-Erk 1/2, p Drp1 and p-p53. Co-incubation of mdivi-1 with doxorubicin did not reduce the cytotoxicity of doxorubicin against HL-60 cells. These data suggest that the inhibition of mitochondrial fission protects the heart against doxorubicin induced cardiac injury and identify mitochondrial fission as a new therapeutic target in ameliorating doxorubicin-induced cardiotoxicity without affecting its anti-cancer properties. PMID- 24147065 TI - New agents for targeting of IL-13RA2 expressed in primary human and canine brain tumors. AB - Interleukin 13 receptor alpha 2 (IL-13RA2) is over-expressed in a vast majority of human patients with high-grade astrocytomas like glioblastoma. Spontaneous astrocytomas in dogs resemble human disease and have been proposed as translational model system for investigation of novel therapeutic strategies for brain tumors. We have generated reagents for both detection and therapeutic targeting of IL-13RA2 in human and canine brain tumors. Peptides from three different regions of IL-13RA2 with 100% sequence identity between human and canine receptors were used as immunogens for generation of monoclonal antibodies. Recombinant canine mutant IL-13 (canIL-13.E13K) and canIL-13.E13K based cytotoxin were also produced. The antibodies were examined for their immunoreactivities in western blots, immunohistochemistry, immunofluorescence and cell binding assays using human and canine tumor specimen sections, tissue lysates and established cell lines; the cytotoxin was tested for specific cell killing. Several isolated MAbs were immunoreactive to IL-13RA2 in western blots of cell and tissue lysates from glioblastomas from both human and canine patients. Human and canine astrocytomas and oligodendrogliomas were also positive for IL-13RA2 to various degrees. Interestingly, both human and canine meningiomas also exhibited strong reactivity. Normal human and canine brain samples were virtually negative for IL 13RA2 using the newly generated MAbs. MAb 1E10B9 uniquely worked on tissue specimens and western blots, bound live cells and was internalized in GBM cells over-expressing IL-13RA2. The canIL-13.E13K cytotoxin was very potent and specific in killing canine GBM cell lines. Thus, we have obtained several monoclonal antibodies against IL-13RA2 cross-reacting with human and canine receptors. In addition to GBM, other brain tumors, such as high grade oligodendrogliomas, meningiomas and canine choroid plexus papillomas, appear to express the receptor at high levels and thus may be appropriate candidates for IL 13RA2-targeted imaging/therapies. Canine spontaneous primary brain tumors represent an excellent translational model for human counterparts. PMID- 24147067 TI - Exposure is not enough: suppressing stimuli from awareness can abolish the mere exposure effect. AB - Passive exposure to neutral stimuli increases subsequent liking of those stimuli- the mere exposure effect. Because of the broad implications for understanding and controlling human preferences, the role of conscious awareness in mere exposure has received much attention. Previous studies have claimed that the mere exposure effect can occur without conscious awareness of the stimuli. In two experiments, we applied a technique new to the mere exposure literature, called continuous flash suppression, to expose stimuli for a controlled duration with and without awareness. To ensure the reliability of the awareness manipulation, awareness was monitored on a trial-by-trial basis. Our results show that under these conditions the mere exposure effect does not occur without conscious awareness. In contrast, only when participants were aware of the stimuli did exposure increase liking and recognition. Together these data are consistent with the idea that the mere exposure effect requires conscious awareness and has important implications for theories of memory and affect. PMID- 24147066 TI - Molecular reclassification of Crohn's disease: a cautionary note on population stratification. AB - Complex human diseases commonly differ in their phenotypic characteristics, e.g., Crohn's disease (CD) patients are heterogeneous with regard to disease location and disease extent. The genetic susceptibility to Crohn's disease is widely acknowledged and has been demonstrated by identification of over 100 CD associated genetic loci. However, relating CD subphenotypes to disease susceptible loci has proven to be a difficult task. In this paper we discuss the use of cluster analysis on genetic markers to identify genetic-based subgroups while taking into account possible confounding by population stratification. We show that it is highly relevant to consider the confounding nature of population stratification in order to avoid that detected clusters are strongly related to population groups instead of disease-specific groups. Therefore, we explain the use of principal components to correct for population stratification while clustering affected individuals into genetic-based subgroups. The principal components are obtained using 30 ancestry informative markers (AIM), and the first two PCs are determined to discriminate between continental origins of the affected individuals. Genotypes on 51 CD associated single nucleotide polymorphisms (SNPs) are used to perform latent class analysis, hierarchical and Partitioning Around Medoids (PAM) cluster analysis within a sample of affected individuals with and without the use of principal components to adjust for population stratification. It is seen that without correction for population stratification clusters seem to be influenced by population stratification while with correction clusters are unrelated to continental origin of individuals. PMID- 24147068 TI - Massively parallel sequencing reveals an accumulation of de novo mutations and an activating mutation of LPAR1 in a patient with metastatic neuroblastoma. AB - Neuroblastoma is one of the most genomically heterogeneous childhood malignances studied to date, and the molecular events that occur during the course of the disease are not fully understood. Genomic studies in neuroblastoma have showed only a few recurrent mutations and a low somatic mutation burden. However, none of these studies has examined the mutations arising during the course of disease, nor have they systemically examined the expression of mutant genes. Here we performed genomic analyses on tumors taken during a 3.5 years disease course from a neuroblastoma patient (bone marrow biopsy at diagnosis, adrenal primary tumor taken at surgical resection, and a liver metastasis at autopsy). Whole genome sequencing of the index liver metastasis identified 44 non-synonymous somatic mutations in 42 genes (0.85 mutation/MB) and a large hemizygous deletion in the ATRX gene which has been recently reported in neuroblastoma. Of these 45 somatic alterations, 15 were also detected in the primary tumor and bone marrow biopsy, while the other 30 were unique to the index tumor, indicating accumulation of de novo mutations during therapy. Furthermore, transcriptome sequencing on the 3 tumors demonstrated only 3 out of the 15 commonly mutated genes (LPAR1, GATA2, and NUFIP1) had high level of expression of the mutant alleles, suggesting potential oncogenic driver roles of these mutated genes. Among them, the druggable G-protein coupled receptor LPAR1 was highly expressed in all tumors. Cells expressing the LPAR1 R163W mutant demonstrated a significantly increased motility through elevated Rho signaling, but had no effect on growth. Therefore, this study highlights the need for multiple biopsies and sequencing during progression of a cancer and combinatorial DNA and RNA sequencing approach for systematic identification of expressed driver mutations. PMID- 24147069 TI - Count your eggs before they invade: identifying and quantifying egg clutches of two invasive apple snail species (Pomacea). AB - Winning the war against invasive species requires early detection of invasions. Compared to terrestrial invaders, aquatic species often thrive undetected under water and do not garner notice until too late for early action. However, fortunately for managers, apple snails (Family Ampullariidae, Genus Pomacea) provide their own conspicuous sign of invasion in the form of vibrantly colored egg clutches. Managers can potentially use egg clutches laid in the riparian zone as a means of early detection and species identification. To facilitate such efforts, we quantified differences in characteristics (length, width, depth, mass, egg number) of field-laid clutches for the two most common invasive species of apple snail, P. canaliculata and P. maculata, in native and non-native populations. Pomacea canaliculata native and non-native populations differed noticeably only in width. Native P. maculata clutches possessed significantly greater width, mass and eggs numbers compared with native P. canaliculata. Non native P. maculata clutches significantly exceeded all other populations in all measured characteristics. Consequently, these traits may successfully distinguish between species. Fecundity data also allowed us to develop models that accurately estimated the number of eggs per clutch for each species based on clutch dimensions. We tested one, two and three dimensional models of clutches, including rendering a clutch as either a complete ellipsoid or an ellipsoid intersected by a cylinder to represent the oviposition site. Model comparisons found the product of length and depth, with a different function for each population, best predicted egg number for both species. Comparisons of egg number to clutch volume and mass implied non-native P. canaliculata may be food limited, while non-native P. maculata appeared to produce such enormous clutches by having access to greater nutrients than the native population. With these new tools, researchers and managers can quickly identify, quantify and begin eradication of new non-native apple snail populations. PMID- 24147070 TI - Body mass and white matter integrity: the influence of vascular and inflammatory markers. AB - High adiposity is deleteriously associated with brain health, and may disproportionately affect white matter integrity; however, limited information exists regarding the mechanisms underlying the association between body mass (BMI) and white matter integrity. The present study evaluated whether vascular and inflammatory markers influence the relationship between BMI and white matter in healthy aging. We conducted a cross-sectional evaluation of white matter integrity, BMI, and vascular/inflammatory factors in a cohort of 138 healthy older adults (mean age: 71.3 years). Participants underwent diffusion tensor imaging, provided blood samples, and participated in a health evaluation. Vascular risk factors and vascular/inflammatory blood markers were assessed. The primary outcome measure was fractional anisotropy (FA) of the genu, body, and splenium (corpus callosum); exploratory measures included additional white matter regions, based on significant associations with BMI. Regression analyses indicated that higher BMI was associated with lower FA in the corpus callosum, cingulate, and fornix (p<.001). Vascular and inflammatory factors influenced the association between BMI and FA. Specifically, BMI was independently associated with the genu [beta=-.21; B=-.0024; 95% CI, -.0048 to -.0000; p=.05] and cingulate fibers [beta=-.39; B=-.0035; 95% CI,-.0056 to -.0015; p<.001], even after controlling for vascular/inflammatory risk factors and blood markers. In contrast, BMI was no longer significantly associated with the fornix and middle/posterior regions of the corpus callosum after controlling for these markers. Results partially support a vascular/inflammatory hypothesis, but also suggest a more complex relationship between BMI and white matter characterized by potentially different neuroanatomic vulnerability. PMID- 24147072 TI - Enhanced production, purification, characterization and mechanism of action of salivaricin 9 lantibiotic produced by Streptococcus salivarius NU10. AB - BACKGROUND: Lantibiotics are small lanthionine-containing bacteriocins produced by lactic acid bacteria. Salivaricin 9 is a newly discovered lantibiotic produced by Streptococcus salivarius. In this study we present the mechanism of action of salivaricin 9 and some of its properties. Also we developed new methods to produce and purify the lantibiotic from strain NU10. METHODOLOGY/PRINCIPAL FINDINGS: Salivaricin 9 was found to be auto-regulated when an induction assay was applied and this finding was used to develop a successful salivaricin 9 production system in liquid medium. A combination of XAD-16 and cation exchange chromatography was used to purify the secondary metabolite which was shown to have a molecular weight of approximately 3000 Da by SDS-PAGE. MALDI-TOF MS analysis indicated the presence of salivaricin 9, a 2560 Da lantibiotic. Salivaricin 9 is a bactericidal molecule targeting the cytoplasmic membrane of sensitive cells. The membrane permeabilization assay showed that salivaricin 9 penetrated the cytoplasmic membrane and induced pore formation which resulted in cell death. The morphological changes of test bacterial strains incubated with salivaricin 9 were visualized using Scanning Electron Microscopy which confirmed a pore forming mechanism of inhibition. Salivaricin 9 retained biological stability when exposed to high temperature (90-100 degrees C) and stayed bioactive at pH ranging 2 to 10. When treated with proteinase K or peptidase, salivaricin 9 lost all antimicrobial activity, while it remained active when treated with lyticase, catalase and certain detergents. CONCLUSION: The mechanism of antimicrobial action of a newly discovered lantibiotic salivaricin 9 was elucidated in this study. Salivaricin 9 penetrated the cytoplasmic membrane of its targeted cells and induced pore formation. This project has given new insights on lantibiotic peptides produced by S. salivarius isolated from the oral cavities of Malaysian subjects. PMID- 24147073 TI - Mediators in internet-based cognitive behavior therapy for severe health anxiety. AB - According to the cognitive behavioral model of severe health anxiety (hypochondriasis) four central maintaining mechanisms are how the individual perceives the risk of disease and how negative its consequences would be, attention to bodily sensations, and intolerance of uncertainty. The aim of the present study was to investigate the mediating role of these putative mechanisms in Internet-delivered CBT for severe health anxiety. We analyzed data from an RCT where participants were randomized to Internet-delivered CBT (n=40) or to a control condition (n=41). Mediators and outcome, i.e. health anxiety, were assessed weekly throughout the treatment, enabling fulfillment of the criterion of temporal precedence of changes occurring in the mediator in relation to the outcome to be met. The results showed that reduced perceived risk of disease, less attention to bodily symptoms, and reduced intolerance of uncertainty significantly mediated improvement in health anxiety. The study supports the validity of the cognitive behavioral model of health anxiety. The findings have theoretical and clinical implications as they indicate processes that may be causally related to the improvements observed after CBT for health anxiety. PMID- 24147074 TI - Experimental induction of pulmonary fibrosis in horses with the gammaherpesvirus equine herpesvirus 5. AB - Gammaherpesviruses (gammaHV) are implicated in the pathogenesis of pulmonary fibrosis in humans and murine models of lung fibrosis, however there is little direct experimental evidence that such viruses induce lung fibrosis in the natural host. The equine gammaHV EHV 5 is associated with equine multinodular pulmonary fibrosis (EMPF), a progressive fibrosing lung disease in its natural host, the horse. Experimental reproduction of EMPF has not been attempted to date. We hypothesized that inoculation of EHV 5 isolated from cases of EMPF into the lungs of clinically normal horses would induce lung fibrosis similar to EMPF. Neutralizing antibody titers were measured in the horses before and after inoculation with EHV 5. PCR and virus isolation was used to detect EHV 5 in antemortem blood and BAL samples, and in tissues collected postmortem. Nodular pulmonary fibrosis and induction of myofibroblasts occurred in EHV 5 inoculated horses. Mean lung collagen in EHV 5 inoculated horses (80 ug/mg) was significantly increased compared to control horses (26 ug/mg) (p < 0.5), as was interstitial collagen (32.6% +/- 1.2% vs 23% +/- 1.4%) (mean +/- SEM; p < 0.001). Virus was difficult to detect in infected horses throughout the experiment, although EHV 5 antigen was detected in the lung by immunohistochemistry. We conclude that the gammaHV EHV 5 can induce lung fibrosis in the horse, and hypothesize that induction of fibrosis occurs while the virus is latent within the lung. This is the first example of a gammaHV inducing lung fibrosis in the natural host. PMID- 24147071 TI - Dorsal and ventral hippocampus modulate autonomic responses but not behavioral consequences associated to acute restraint stress in rats. AB - Recent evidence has suggested that the dorsal (DH) and the ventral (VH) poles of the hippocampus are structurally, molecularly and functionally different regions. While the DH is preferentially involved in the modulation of spatial learning and memory, the VH modulates defensive behaviors related to anxiety. Acute restraint is an unavoidable stress situation that evokes marked and sustained autonomic changes, which are characterized by elevated blood pressure (BP), intense heart rate (HR) increases, skeletal muscle vasodilatation and cutaneous vasoconstriction, which are accompanied by a rapid skin temperature drop followed by body temperature increases. In addition to those autonomic responses, animals submitted to restraint also present behavioral changes, such as reduced exploration of the open arms of an elevated plus-maze (EPM), an anxiogenic-like effect. In the present work, we report a comparison between the effects of pharmacological inhibition of DH and VH neurotransmission on autonomic and behavioral responses evoked by acute restraint stress in rats. Bilateral microinjection of the unspecific synaptic blocker cobalt chloride (CoCl2, 1mM) into the DH or VH attenuated BP and HR responses, as well as the decrease in the skin temperature, elicited by restraint stress exposure. Moreover, DH or VH inhibition before restraint did not change the delayed increased anxiety behavior observed 24 h later in the EPM. The present results demonstrate for the first time that both DH and VH mediate stress-induced autonomic responses to restraint but they are not involved in the modulation of the delayed emotional consequences elicited by such stress. PMID- 24147075 TI - Inter-laboratory assessment of a prototype multiplex kit for determination of recent HIV-1 infection. AB - BACKGROUND: Accurate and reliable laboratory-based assays are needed for estimating HIV-1 incidence from cross-sectional samples. We recently described the development of a customized, HIV-1-specific Bio-Plex assay that allows for the measurement of HIV-specific antibody levels and avidity to multiple analytes for improved HIV-1 incidence estimates. METHODS: To assess intra- and inter laboratory assay performance, prototype multiplex kits were developed and evaluated by three distinct laboratories. Longitudinal seroconversion specimens were tested in parallel by each laboratory and kit performance was compared to that of an in-house assay. Additionally, the ability of the kit to distinguish recent from long-term HIV-1 infection, as compared to the in-house assay, was determined by comparing the reactivity of known recent (infected <6 months) and long-term (infected >12 months) drug naive specimens. RESULTS: Although the range of reactivity for each analyte varied between the prototype kit and in-house assay, a measurable distinction in reactivity between recent and long-term specimens was observed with both assays in all three laboratories. Additionally, kit performance was consistent between all three laboratories. The intra-assay coefficient of variation (CV), between sample replicates for all laboratories, ranged from 0.5% to 6.1%. The inter-laboratory CVs ranged from 8.5% to 21.3% for gp160-avidity index (a) and gp120-normalized mean fluorescent intensity (MFI) value (n), respectively. CONCLUSION: We demonstrate the feasibility of producing a multiplex kit for measuring HIV antibody levels and avidity, with the potential for improved incidence estimates based on multi-analyte algorithms. The availability of a commercial kit will facilitate the transfer of technology among diverse laboratories for widespread assay use. PMID- 24147076 TI - Acute disseminated encephalomyelitis onset: evaluation based on vaccine adverse events reporting systems. AB - OBJECTIVE: To evaluate epidemiological features of post vaccine acute disseminated encephalomyelitis (ADEM) by considering data from different pharmacovigilance surveillance systems. METHODS: The Vaccine Adverse Event Reporting System (VAERS) database and the EudraVigilance post-authorisation module (EVPM) were searched to identify post vaccine ADEM cases. Epidemiological features including sex and related vaccines were analysed. RESULTS: We retrieved 205 and 236 ADEM cases from the EVPM and VAERS databases, respectively, of which 404 were considered for epidemiological analysis following verification and causality assessment. Half of the patients had less than 18 years and with a slight male predominance. The time interval from vaccination to ADEM onset was 2 30 days in 61% of the cases. Vaccine against seasonal flu and human papilloma virus vaccine were those most frequently associated with ADEM, accounting for almost 30% of the total cases. Mean number of reports per year between 2005 and 2012 in VAERS database was 40+/-21.7, decreasing after 2010 mainly because of a reduction of reports associated with human papilloma virus and Diphtheria, Pertussis, Tetanus, Polio and Haemophilus Influentiae type B vaccines. CONCLUSIONS: This study has a high epidemiological power as it is based on information on adverse events having occurred in over one billion people. It suffers from lack of rigorous case verification due to the weakness intrinsic to the surveillance databases used. At variance with previous reports on a prevalence of ADEM in childhood we demonstrate that it may occur at any age when post vaccination. This study also shows that the diminishing trend in post vaccine ADEM reporting related to Diphtheria, Pertussis, Tetanus, Polio and Haemophilus Influentiae type B and human papilloma virus vaccine groups is most likely not [corrected] due to a decline in vaccine coverage indicative of a reduced attention to this adverse drug reaction. PMID- 24147077 TI - Effects of acute or chronic ethanol exposure during adolescence on behavioral inhibition and efficiency in a modified water maze task. AB - Ethanol is well known to adversely affect frontal executive functioning, which continues to develop throughout adolescence and into young adulthood. This is also a developmental window in which ethanol is misused by a significant number of adolescents. We examined the effects of acute and chronic ethanol exposure during adolescence on behavioral inhibition and efficiency using a modified water maze task. During acquisition, rats were trained to find a stable visible platform onto which they could escape. During the test phase, the stable platform was converted to a visible floating platform (providing no escape) and a new hidden platform was added in the opposite quadrant. The hidden platform was the only means of escape during the test phase. In experiment 1, adolescent animals received ethanol (1.0 g/kg) 30 min before each session during the test phase. In experiment 2, adolescent animals received chronic intermittent ethanol (5.0 g/kg) for 16 days (PND30 To PND46) prior to any training in the maze. At PND72, training was initiated in the same modified water maze task. Results from experiment 1 indicated that acute ethanol promoted behavioral disinhibition and inefficiency. Experiment 2 showed that chronic intermittent ethanol during adolescence appeared to have no lasting effect on behavioral disinhibition or new spatial learning during adulthood. However, chronic ethanol did promote behavioral inefficiency. In summary, results indicate that ethanol-induced promotion of perseverative behavior may contribute to the many adverse behavioral sequelae of alcohol intoxication in adolescents and young adults. Moreover, the long-term effect of adolescent chronic ethanol exposure on behavioral efficiency is similar to that observed after chronic exposure in humans. PMID- 24147078 TI - Moroccan Leishmania infantum: genetic diversity and population structure as revealed by multi-locus microsatellite typing. AB - Leishmania infantum causes Visceral and cutaneous leishmaniasis in northern Morocco. It predominantly affects children under 5 years with incidence of 150 cases/year. Genetic variability and population structure have been investigated for 33 strains isolated from infected dogs and humans in Morocco. A multilocus microsatellite typing (MLMT) approach was used in which a MLMtype based on size variation in 14 independent microsatellite markers was compiled for each strain. MLMT profiles of 10 Tunisian, 10 Algerian and 21 European strains which belonged to zymodeme MON-1 and non-MON-1 according to multilocus enzyme electrophoresis (MLEE) were included for comparison. A Bayesian model-based approach and phylogenetic analysis inferred two L.infantum sub-populations; Sub-population A consists of 13 Moroccan strains grouped with all European strains of MON-1 type; and sub-population B consists of 15 Moroccan strains grouped with the Tunisian and Algerian MON-1 strains. Theses sub-populations were significantly different from each other and from the Tunisian, Algerian and European non MON-1 strains which constructed one separate population. The presence of these two sub populations co-existing in Moroccan endemics suggests multiple introduction of L. infantum from/to Morocco; (1) Introduction from/to the neighboring North African countries, (2) Introduction from/to the Europe. These scenarios are supported by the presence of sub-population B and sub-population A respectively. Gene flow was noticed between sub-populations A and B. Five strains showed mixed A/B genotypes indicating possible recombination between the two populations. MLMT has proven to be a powerful tool for eco-epidemiological and population genetic investigations of Leishmania. PMID- 24147079 TI - Inhibition of glycogen synthase kinase-3beta prevents remifentanil-induced hyperalgesia via regulating the expression and function of spinal N-methyl-D aspartate receptors in vivo and vitro. AB - A large number of experimental and clinical studies have confirmed that brief remifentanil exposure can enhance pain sensitivity presenting as opioid-induced hyperalgesia (OIH). N-methyl-D-aspartate (NMDA) receptor antagonists have been reported to inhibit morphine analgesic tolerance in many studies. Recently, we found that glycogen synthase kinase-3beta (GSK-3beta) modulated NMDA receptor trafficking in a rat model of remifentanil-induced postoperative hyperalgesia. In the current study, it was demonstrated that GSK-3beta inhibition prevented remifentanil-induced hyperalgesia via regulating the expression and function of spinal NMDA receptors in vivo and in vitro. We firstly investigated the effects of TDZD-8, a selective GSK-3beta inhibitor, on thermal and mechanical hyperalgesia using a rat model of remifentanil-induced hyperalgesia. GSK-3beta activity as well as NMDA receptor subunits (NR1, NR2A and NR2B) expression and trafficking in spinal cord L4-L5 segments were measured by Western blot analysis. Furthermore, the effects of GSK-3beta inhibition on NMDA-induced current amplitude and frequency were studied in spinal cord slices by whole-cell patch clamp recording. We found that remifentanil infusion at 1 MUg.kg(-1).min(-1) and 2 MUg.kg(-1).min(-1) caused mechanical and thermal hyperalgesia, up-regulated NMDA receptor subunits NR1 and NR2B expression in both membrane fraction and total lysate of the spinal cord dorsal horn and increased GSK-3beta activity in spinal cord dorsal horn. GSK-3beta inhibitor TDZD-8 significantly attenuated remifentanil-induced mechanical and thermal hyperalgesia from 2 h to 48 h after infusion, and this was associated with reversal of up-regulated NR1 and NR2B subunits in both membrane fraction and total lysate. Furthermore, remifentanil incubation increased amplitude and frequency of NMDA receptor-induced current in dorsal horn neurons, which was prevented with the application of TDZD-8. These results suggest that inhibition of GSK-3beta can significantly ameliorate remifentanil-induced hyperalgesia via modulating the expression and function of NMDA receptors, which present useful insights into the mechanistic action of GSK 3beta inhibitor as potential anti-hyperalgesic agents for treating OIH. PMID- 24147080 TI - Monkeypox virus infection of rhesus macaques induces massive expansion of natural killer cells but suppresses natural killer cell functions. AB - Natural killer (NK) cells play critical roles in innate immunity and in bridging innate and adaptive immune responses against viral infection. However, the response of NK cells to monkeypox virus (MPXV) infection is not well characterized. In this intravenous challenge study of MPXV infection in rhesus macaques (Macaca mulatta), we analyzed blood and lymph node NK cell changes in absolute cell numbers, cell proliferation, chemokine receptor expression, and cellular functions. Our results showed that the absolute number of total NK cells in the blood increased in response to MPXV infection at a magnitude of 23-fold, manifested by increases in CD56+, CD16+, CD16-CD56- double negative, and CD16+CD56+ double positive NK cell subsets. Similarly, the frequency and NK cell numbers in the lymph nodes also largely increased with the total NK cell number increasing 46.1-fold. NK cells both in the blood and lymph nodes massively proliferated in response to MPXV infection as measured by Ki67 expression. Chemokine receptor analysis revealed reduced expression of CXCR3, CCR7, and CCR6 on NK cells at early time points (days 2 and 4 after virus inoculation), followed by an increased expression of CXCR3 and CCR5 at later time points (days 7-8) of infection. In addition, MPXV infection impaired NK cell degranulation and ablated secretion of interferon-gamma and tumor necrosis factor-alpha. Our data suggest a dynamic model by which NK cells respond to MPXV infection of rhesus macaques. Upon virus infection, NK cells proliferated robustly, resulting in massive increases in NK cell numbers. However, the migrating capacity of NK cells to tissues at early time points might be reduced, and the functions of cytotoxicity and cytokine secretion were largely compromised. Collectively, the data may explain, at least partially, the pathogenesis of MPXV infection in rhesus macaques. PMID- 24147081 TI - Downregulation of CD9 in keratinocyte contributes to cell migration via upregulation of matrix metalloproteinase-9. AB - Tetraspanin CD9 has been implicated in various cellular and physiological processes, including cell migration. In our previous study, we found that wound repair is delayed in CD9-null mice, suggesting that CD9 is critical for cutaneous wound healing. However, many cell types, including immune cells, endothelial cells, keratinocytes and fibroblasts undergo marked changes in gene expression and phenotype, leading to cell proliferation, migration and differentiation during wound repair, whether CD9 regulates kerationcytes migration directly remains unclear. In this study, we showed that the expression of CD9 was downregulated in migrating keratinocytes during wound repair in vivo and in vitro. Recombinant adenovirus vector for CD9 silencing or overexpressing was constructed and used to infect HaCaT cells. Using cell scratch wound assay and cell migration assay, we have also demonstrated that downregulation of CD9 promoted keratinocyte migration in vitro, whereas CD9 overexpression inhibited cell migration. Moreover, CD9 inversely regulated the activity and expression of MMP-9 in keratinocytes, which was involved in CD9-regulated keratinocyte migration. Importantly, CD9 silencing-activated JNK signaling was accompanied by the upregulation of MMP-9 activity and expression. Coincidentally, we found that SP600125, a JNK pathway inhibitor, decreased the activity and expression of MMP-9 of CD9-silenced HaCaT cells. Thus, our results suggest that CD9 is downregulated in migrating keratinocytes in vivo and in vitro, and a low level of CD9 promotes keratinocyte migration in vitro, in which the regulation of MMP-9 through the JNK pathway plays an important role. PMID- 24147082 TI - Assessment of diagnostic skills in specialist examinations should include lessons learnt from misdiagnosis. AB - BACKGROUND: Poor authenticity in high stake clinical exams adversely effects validity. We propose including known misleading diagnostic factors and contextual biases in the assessment of diagnostic skills amongst advanced specialty trainees. We hypothesise that this strategy offers a more realistic and critical assessment of diagnostic skill than strategies in which candidates are presented with directive, bias free information, allowing for assumptions which cannot be made in real life. METHODS: Eleven patient based practice clinical exam stations were presented to nine advanced ophthalmology trainees. Four patients had a history of misdiagnosis or near misdiagnosis of key ophthalmic findings, presumed to result from identifiable biases and misleading information. In those four stations, candidates were presented with authentic, file based information and were asked authentic questions, similar to those with which the patients presented. If the candidates were unsuccessful in identifying key findings, the questions were converted into directive questions about the same key findings (i.e. "examine the patient's eyelids, what is your diagnosis?"), and the candidates re-assessed the patient and re-answered. RESULTS: Ninety-eight doctor patient encounters took place. Of those, 35 encounters were analysed for the purpose of this study. In 63% of those encounters, key findings were missed when the question included authentic biases or misleading background information, but rephrasing the question to a directive exam format led to their correct identification (Fail converted to pass). Key findings were detected despite contextual biases or misleading background information in only 23% of encounters. In 14% the findings were missed with either question phrasing. CONCLUSIONS: Presentation authentic questions provide a more realistic and less forgiving measure of diagnostic skills than directive exam questions. Given the prevalence of diagnostic errors and their importance to patient outcomes, known mechanisms contributing to diagnostic errors should be used as one of the assessment tools of advanced speciality trainees. PMID- 24147083 TI - Complex patterns of chromosome 11 aberrations in myeloid malignancies target CBL, MLL, DDB1 and LMO2. AB - Exome sequencing of primary tumors identifies complex somatic mutation patterns. Assignment of relevance of individual somatic mutations is difficult and poses the next challenge for interpretation of next generation sequencing data. Here we present an approach how exome sequencing in combination with SNP microarray data may identify targets of chromosomal aberrations in myeloid malignancies. The rationale of this approach is that hotspots of chromosomal aberrations might also harbor point mutations in the target genes of deletions, gains or uniparental disomies (UPDs). Chromosome 11 is a frequent target of lesions in myeloid malignancies. Therefore, we studied chromosome 11 in a total of 813 samples from 773 individual patients with different myeloid malignancies by SNP microarrays and complemented the data with exome sequencing in selected cases exhibiting chromosome 11 defects. We found gains, losses and UPDs of chromosome 11 in 52 of the 813 samples (6.4%). Chromosome 11q UPDs frequently associated with mutations of CBL. In one patient the 11qUPD amplified somatic mutations in both CBL and the DNA repair gene DDB1. A duplication within MLL exon 3 was detected in another patient with 11qUPD. We identified several common deleted regions (CDR) on chromosome 11. One of the CDRs associated with de novo acute myeloid leukemia (P=0.013). One patient with a deletion at the LMO2 locus harbored an additional point mutation on the other allele indicating that LMO2 might be a tumor suppressor frequently targeted by 11p deletions. Our chromosome-centered analysis indicates that chromosome 11 contains a number of tumor suppressor genes and that the role of this chromosome in myeloid malignancies is more complex than previously recognized. PMID- 24147084 TI - The identification and characterization of novel N-glycan-based biomarkers in gastric cancer. AB - BACKGROUND AND AIMS: To identify and validate N-glycan biomarkers in gastric cancer (GC) and to elucidate their underlying molecular mechanism of action. METHODS: In total, 347 individuals, including patients with GC (gastric cancer) or atrophic gastritis and healthy controls, were randomly divided into a training group (n=287) and a retrospective validation group (n=60). Serum N-glycan profiling was achieved with DNA sequencer-assisted/fluorophore-assisted carbohydrate electrophoresis (DSA-FACE). Two diagnostic models were constructed based on the N-glycan profiles using logistic stepwise regression. The diagnostic performance of each model was assessed in retrospective, prospective (n=60), and follow-up (n=40) cohorts. Lectin blotting was performed to determine total core fucosylation, and the expression of genes involved in core-fucosylation in GC was analyzed by reverse transcriptase-polymerase chain reaction. RESULTS: We identified at least 9 N-glycan structures (peaks) and the levels of core fucose residues and fucosyltransferase were significantly decreased in GC. Two diagnostic models, designated GCglycoA and GCglycoB, were constructed to differentiate GC from control and atrophic gastritis. The areas under the receiver operating characteristic (ROC) curves (AUC) for both GCglycoA and GCglycoB were higher than those for CEA, CA19-9, CA125 and CA72-4. Compared with CEA, CA19-9, CA125 and CA72-4, the sensitivity of GCglycoA increased 29.66%, 37.28%, 56.78% and 61.86%, respectively, and the accuracy increased 10.62%, 16.82%, 25.67% and 28.76%, respectively. For GCglycoB, the sensitivity increased 27.97%, 35.59%, 55.09% and 60.17% and the accuracy increased 21.26%, 24.64%, 31.40% and 34.30% compared with CEA, CA19-9, CA125 and CA72-4, respectively. After curative surgery, the core fucosylated peak (peak 3) and the total core fucosylated N-glycans (sumfuc) were reversed. CONCLUSIONS: The results indicated that the diagnostic models based on N-glycan markers are valuable and noninvasive alternatives for identifying GC. We concluded that decreased core-fucosylation in both tissue and serum from GC patients may result from the decreased expression of fucosyltransferase. PMID- 24147085 TI - Development and evaluation of a prediction model for underestimated invasive breast cancer in women with ductal carcinoma in situ at stereotactic large core needle biopsy. AB - BACKGROUND: We aimed to develop a multivariable model for prediction of underestimated invasiveness in women with ductal carcinoma in situ at stereotactic large core needle biopsy, that can be used to select patients for sentinel node biopsy at primary surgery. METHODS: From the literature, we selected potential preoperative predictors of underestimated invasive breast cancer. Data of patients with nonpalpable breast lesions who were diagnosed with ductal carcinoma in situ at stereotactic large core needle biopsy, drawn from the prospective COBRA (Core Biopsy after RAdiological localization) and COBRA2000 cohort studies, were used to fit the multivariable model and assess its overall performance, discrimination, and calibration. RESULTS: 348 women with large core needle biopsy-proven ductal carcinoma in situ were available for analysis. In 100 (28.7%) patients invasive carcinoma was found at subsequent surgery. Nine predictors were included in the model. In the multivariable analysis, the predictors with the strongest association were lesion size (OR 1.12 per cm, 95% CI 0.98-1.28), number of cores retrieved at biopsy (OR per core 0.87, 95% CI 0.75 1.01), presence of lobular cancerization (OR 5.29, 95% CI 1.25-26.77), and microinvasion (OR 3.75, 95% CI 1.42-9.87). The overall performance of the multivariable model was poor with an explained variation of 9% (Nagelkerke's R(2)), mediocre discrimination with area under the receiver operating characteristic curve of 0.66 (95% confidence interval 0.58-0.73), and fairly good calibration. CONCLUSION: The evaluation of our multivariable prediction model in a large, clinically representative study population proves that routine clinical and pathological variables are not suitable to select patients with large core needle biopsy-proven ductal carcinoma in situ for sentinel node biopsy during primary surgery. PMID- 24147086 TI - Hematological and hemorheological determinants of the six-minute walk test performance in children with sickle cell anemia. AB - The six-minute walk test is a well-established submaximal exercise reflecting the functional status and the clinical severity of sickle cell patients. The aim of the present cross-sectional study was to investigate the biological determinants of the six-minute walk test performance in children with sickle cell anemia. Hematological and hemorheological parameters, pulmonary function and the six minute walk test performance were determined in 42 children with sickle cell anemia at steady state. The performance during the six-minute walk test was normalized for age, sex and height and expressed as percentage of the predicted six-minute walk distance. We showed that a high level of anemia, a low fetal hemoglobin expression and low red blood cell deformability were independent predictors of a low six-minute walk test performance. This study describes for the first time the impact of blood rheology in the six-minute walk test performance in children with sickle cell anemia. PMID- 24147088 TI - Lifestyle factors, medication use and risk for ischaemic heart disease hospitalisation: a longitudinal population-based study. AB - BACKGROUND: Lifestyle factors have been implicated in ischaemic heart disease (IHD) development however a limited number of longitudinal studies report results stratified by cardio-protective medication use. PURPOSE: This study investigated the influence of self-reported lifestyle factors on hospitalisation for IHD, stratified by blood pressure and/or lipid-lowering therapy. METHODS: A population based cohort of 14,890 participants aged 45+ years and IHD-free was identified from the Western Australian Health and wellbeing Surveillance System (2004 to 2010 inclusive), and linked with hospital administrative data. Adjusted hazard ratios for future IHD-hospitalisation were estimated using Cox regression. RESULTS: Current smokers remained at higher risk for IHD-hospitalisation (adjusted HR=1.57; 95% CI: 1.22-2.03) after adjustment for medication use, as did those considered overweight (BMI=25-29 kg/m(2); adjusted HR=1.28; 95% CI: 1.04 1.57) or obese (BMI of >=30 kg/m(2); adjusted HR=1.31; 95% CI: 1.03-1.66). Weekly leisure-time physical activity (LTPA) of 150 minutes or more and daily intake of 3 or more fruit/vegetable servings reduced risk by 21% (95% CI: 0.64-0.97) and 26% (95% CI: 0.58-0.96) respectively. Benefits of LTPA appeared greatest in those on blood pressure lowering medication (adjusted HR=0.50; 95% CI: 0.31-0.82 [for LTPA<150 mins], adjusted HR=0.64; 95% CI: 0.42-0.96 [for LTPA>=150 mins]). IHD risk in smokers was most pronounced in those taking neither medication (adjusted HR=2.00; 95% CI: 1.41-2.83). CONCLUSION: This study confirms the contribution of previously reported lifestyle factors towards IHD hospitalisation, even after adjustment for antihypertensive and lipid-lowering medication use. Medication stratified results suggest that IHD risks related to LTPA and smoking may differ according to medication use. PMID- 24147087 TI - Identification of a sex-linked SNP marker in the salmon louse (Lepeophtheirus salmonis) using RAD sequencing. AB - The salmon louse (Lepeophtheirus salmonis (Kroyer, 1837)) is a parasitic copepod that can, if untreated, cause considerable damage to Atlantic salmon (Salmo salar Linnaeus, 1758) and incurs significant costs to the Atlantic salmon mariculture industry. Salmon lice are gonochoristic and normally show sex ratios close to 1:1. While this observation suggests that sex determination in salmon lice is genetic, with only minor environmental influences, the mechanism of sex determination in the salmon louse is unknown. This paper describes the identification of a sex-linked Single Nucleotide Polymorphism (SNP) marker, providing the first evidence for a genetic mechanism of sex determination in the salmon louse. Restriction site-associated DNA sequencing (RAD-seq) was used to isolate SNP markers in a laboratory-maintained salmon louse strain. A total of 85 million raw Illumina 100 base paired-end reads produced 281,838 unique RAD-tags across 24 unrelated individuals. RAD marker Lsa101901 showed complete association with phenotypic sex for all individuals analysed, being heterozygous in females and homozygous in males. Using an allele-specific PCR assay for genotyping, this SNP association pattern was further confirmed for three unrelated salmon louse strains, displaying complete association with phenotypic sex in a total of 96 genotyped individuals. The marker Lsa101901 was located in the coding region of the prohibitin-2 gene, which showed a sex-dependent differential expression, with mRNA levels determined by RT-qPCR about 1.8-fold higher in adult female than adult male salmon lice. This study's observations of a novel sex-linked SNP marker are consistent with sex determination in the salmon louse being genetic and following a female heterozygous system. Marker Lsa101901 provides a tool to determine the genetic sex of salmon lice, and could be useful in the development of control strategies. PMID- 24147089 TI - Manganese (Mn) oxidation increases intracellular Mn in Pseudomonas putida GB-1. AB - Bacterial manganese (Mn) oxidation plays an important role in the global biogeochemical cycling of Mn and other compounds, and the diversity and prevalence of Mn oxidizers have been well established. Despite many hypotheses of why these bacteria may oxidize Mn, the physiological reasons remain elusive. Intracellular Mn levels were determined for Pseudomonas putida GB-1 grown in the presence or absence of Mn by inductively coupled plasma mass spectrometry (ICP MS). Mn oxidizing wild type P. putida GB-1 had higher intracellular Mn than non Mn oxidizing mutants grown under the same conditions. P. putida GB-1 had a 5 fold increase in intracellular Mn compared to the non Mn oxidizing mutant P. putida GB 1-007 and a 59 fold increase in intracellular Mn compared to P. putida GB-1 ?2665 ?2447. The intracellular Mn is primarily associated with the less than 3 kDa fraction, suggesting it is not bound to protein. Protein oxidation levels in Mn oxidizing and non oxidizing cultures were relatively similar, yet Mn oxidation did increase survival of P. putida GB-1 when oxidatively stressed. This study is the first to link Mn oxidation to Mn homeostasis and oxidative stress protection. PMID- 24147090 TI - Effect of erosion on productivity in subtropical red soil hilly region: a multi scale spatio-temporal study by simulated rainfall. AB - The effects of water erosion (including long-term historical erosion and single erosion event) on soil properties and productivity in different farming systems were investigated. A typical sloping cropland with homogeneous soil properties was designed in 2009 and then protected from other external disturbances except natural water erosion. In 2012, this cropland was divided in three equally sized blocks. Three treatments were performed on these blocks with different simulated rainfall intensities and farming methods: (1) high rainfall intensity (1.5-1.7 mm min(-1)), no-tillage operation; (2) low rainfall intensity (0.5-0.7 mm min(-1)), no-tillage operation; and (3) low rainfall intensity, tillage operation. All of the blocks were divided in five equally sized subplots along the slope to characterize the three-year effects of historical erosion quantitatively. Redundancy analysis showed that the effects of long-term historical erosion significantly caused most of the variations in soil productivity in no-tillage and low rainfall erosion intensity systems. The intensities of the simulated rainfall did not exhibit significant effects on soil productivity in no-tillage systems. By contrast, different farming operations induced a statistical difference in soil productivity at the same single erosion intensity. Soil organic carbon (SOC) was the major limiting variable that influenced soil productivity. Most explanations of long-term historical erosion for the variation in soil productivity arose from its sharing with SOC. SOC, total nitrogen, and total phosphorus were found as the regressors of soil productivity because of tillage operation. In general, this study provided strong evidence that single erosion event could also impose significant constraints on soil productivity by integrating with tillage operation, although single erosion is not the dominant effect relative to the long-term historical erosion. Our study demonstrated that an effective management of organic carbon pool should be the preferred option to maintain soil productivity in subtropical red soil hilly region. PMID- 24147091 TI - Combining position weight matrices and document-term matrix for efficient extraction of associations of methylated genes and diseases from free text. AB - BACKGROUND: In a number of diseases, certain genes are reported to be strongly methylated and thus can serve as diagnostic markers in many cases. Scientific literature in digital form is an important source of information about methylated genes implicated in particular diseases. The large volume of the electronic text makes it difficult and impractical to search for this information manually. METHODOLOGY: We developed a novel text mining methodology based on a new concept of position weight matrices (PWMs) for text representation and feature generation. We applied PWMs in conjunction with the document-term matrix to extract with high accuracy associations between methylated genes and diseases from free text. The performance results are based on large manually-classified data. Additionally, we developed a web-tool, DEMGD, which automates extraction of these associations from free text. DEMGD presents the extracted associations in summary tables and full reports in addition to evidence tagging of text with respect to genes, diseases and methylation words. The methodology we developed in this study can be applied to similar association extraction problems from free text. CONCLUSION: The new methodology developed in this study allows for efficient identification of associations between concepts. Our method applied to methylated genes in different diseases is implemented as a Web-tool, DEMGD, which is freely available at http://www.cbrc.kaust.edu.sa/demgd/. The data is available for online browsing and download. PMID- 24147092 TI - Use of a recombinant vaccinia virus expressing interferon gamma for post-exposure protection against vaccinia and ectromelia viruses. AB - Post-exposure vaccination with vaccinia virus (VACV) has been suggested to be effective in minimizing death if administered within four days of smallpox exposure. While there is anecdotal evidence for efficacy of post-exposure vaccination this has not been definitively studied in humans. In this study, we analyzed post-exposure prophylaxis using several attenuated recombinant VACV in a mouse model. A recombinant VACV expressing murine interferon gamma (IFN-gamma) was most effective for post-exposure protection of mice infected with VACV and ectromelia virus (ECTV). Untreated animals infected with VACV exhibited severe weight loss and morbidity leading to 100% mortality by 8 to 10 days post infection. Animals treated one day post-infection had milder symptoms, decreased weight loss and morbidity, and 100% survival. Treatment on days 2 or 3 post infection resulted in 40% and 20% survival, respectively. Similar results were seen in ECTV-infected mice. Despite the differences in survival rates in the VACV model, the viral load was similar in both treated and untreated mice while treated mice displayed a high level of IFN-gamma in the serum. These results suggest that protection provided by IFN-gamma expressed by VACV may be mediated by its immunoregulatory activities rather than its antiviral effects. These results highlight the importance of IFN-gamma as a modulator of the immune response for post-exposure prophylaxis and could be used potentially as another post-exposure prophylaxis tool to prevent morbidity following infection with smallpox and other orthopoxviruses. PMID- 24147093 TI - Emerging antigenic variants at the antigenic site Sb in pandemic A(H1N1)2009 influenza virus in Japan detected by a human monoclonal antibody. AB - The swine-origin pandemic A(H1N1)2009 virus, A(H1N1)pdm09, is still circulating in parts of the human population. To monitor variants that may escape from vaccination specificity, antigenic characterization of circulating viruses is important. In this study, a hybridoma clone producing human monoclonal antibody against A(H1N1)pdm09, designated 5E4, was prepared using peripheral lymphocytes from a vaccinated volunteer. The 5E4 showed viral neutralization activity and inhibited hemagglutination. 5E4 escape mutants harbored amino acid substitutions (A189T and D190E) in the hemagglutinin (HA) protein, suggesting that 5E4 recognized the antigenic site Sb in the HA protein. To study the diversity of Sb in A(H1N1)pdm09, 58 viral isolates were obtained during the 2009/10 and 2010/11 winter seasons in Osaka, Japan. Hemagglutination-inhibition titers were significantly reduced against 5E4 in the 2010/11 compared with the 2009/10 samples. Viral neutralizing titers were also significantly decreased in the 2010/11 samples. By contrast, isolated samples reacted well to ferret anti A(H1N1)pdm09 serum from both seasons. Nonsynonymous substitution rates revealed that the variant Sb and Ca2 sequences were being positively selected between 2009/10 and 2010/11. In 7,415 HA protein sequences derived from GenBank, variants in the antigenic sites Sa and Sb increased significantly worldwide from 2009 to 2013. These results indicate that the antigenic variants in Sb are likely to be in global circulation currently. PMID- 24147094 TI - Simulated birdwatchers' playback affects the behavior of two tropical birds. AB - Although recreational birdwatchers may benefit conservation by generating interest in birds, they may also have negative effects. One such potentially negative impact is the widespread use of recorded vocalizations, or "playback," to attract birds of interest, including range-restricted and threatened species. Although playback has been widely used to test hypotheses about the evolution of behavior, no peer-reviewed study has examined the impacts of playback in a birdwatching context on avian behavior. We studied the effects of simulated birdwatchers' playback on the vocal behavior of Plain-tailed Wrens Thryothorus euophrys and Rufous Antpittas Grallaria rufula in Ecuador. Study species' vocal behavior was monitored for an hour after playing either a single bout of five minutes of song or a control treatment of background noise. We also studied the effects of daily five minute playback on five groups of wrens over 20 days. In single bout experiments, antpittas made more vocalizations of all types, except for trills, after playback compared to controls. Wrens sang more duets after playback, but did not produce more contact calls. In repeated playback experiments, wren responses were strong at first, but hardly detectable by day 12. During the study, one study group built a nest, apparently unperturbed, near a playback site. The playback-induced habituation and changes in vocal behavior we observed suggest that scientists should consider birdwatching activity when selecting research sites so that results are not biased by birdwatchers' playback. Increased vocalizations after playback could be interpreted as a negative effect of playback if birds expend energy, become stressed, or divert time from other activities. In contrast, the habituation we documented suggests that frequent, regular birdwatchers' playback may have minor effects on wren behavior. PMID- 24147095 TI - The course of serum inflammatory biomarkers following whiplash injury and their relationship to sensory and muscle measures: a longitudinal cohort study. AB - Tissue damage or pathological alterations are not detectable in the majority of people with whiplash associated disorders (WAD). Widespread hyperalgisa, morphological muscle changes and psychological distress are common features of WAD. However little is known about the presence of inflammation and its association with symptom persistence or the clinical presentation of WAD. This study aimed to prospectively investigate changes in serum inflammatory biomarker levels from the acute (<3 weeks) to chronic (>3 months) stages of whiplash injury. It also aimed to determine relationships between biomarker levels and hyperalgesia, fatty muscle infiltrates of the cervical extensors identified on MRI and psychological factors. 40 volunteers with acute WAD and 18 healthy controls participated. Participants with WAD were classified at 3 months as recovered/mild disability or having moderate/severe disability using the Neck Disability Index. At baseline both WAD groups showed elevated serum levels of CRP but by 3 months levels remained elevated only in the moderate/severe group. The recovered/mild disability WAD group had higher levels of TNF-alpha at both time points than both the moderate/severe WAD group and healthy controls. There were no differences found in serum IL-1beta. Moderate relationships were found between hyperalgesia and CRP at both time points and between hyperalgesia and IL-1beta 3 months post injury. There was a moderate negative correlation between TNF-alpha and amount of fatty muscle infiltrate and pain intensity at 3 months. Only a weak relationship was found between CRP and pain catastrophising and no relationship between biomarker levels and posttraumatic stress symptoms. The results of the study indicate that inflammatory biomarkers may play a role in outcomes following whiplash injury as well as being associated with hyperalgesia and fatty muscle infiltrate in the cervical extensors. PMID- 24147096 TI - Defining the contribution of CNTNAP2 to autism susceptibility. AB - Multiple lines of genetic evidence suggest a role for CNTNAP2 in autism. To assess its population impact we studied 2148 common single nucleotide polymorphisms (SNPs) using transmission disequilibrium test (TDT) across the entire ~3.3 Mb CNTNAP2 locus in 186 (408 trios) multiplex and 323 simplex families with autistic spectrum disorder (ASD). This analysis yielded two SNPs with nominal statistical significance (rs17170073, p = 2.0 x 10(-4); rs2215798, p = 1.6 x 10(-4)) that did not survive multiple testing. In a combined analysis of all families, two highly correlated (r (2) = 0.99) SNPs in intron 14 showed significant association with autism (rs2710093, p = 9.0 x 10(-6); rs2253031, p = 2.5 x 10(-5)). To validate these findings and associations at SNPs from previous autism studies (rs7794745, rs2710102 and rs17236239) we genotyped 2051 additional families (572 multiplex and 1479 simplex). None of these variants were significantly associated with ASD after corrections for multiple testing. The analysis of Mendelian errors within each family did not indicate any segregating deletions. Nevertheless, a study of CNTNAP2 gene expression in brains of autistic patients and of normal controls, demonstrated altered expression in a subset of patients (p = 1.9 x10(-5)). Consequently, this study suggests that although CNTNAP2 dysregulation plays a role in some cases, its population contribution to autism susceptibility is limited. PMID- 24147097 TI - Genetic variation in interleukin 28B and response to antiviral therapy in patients with dual chronic infection with hepatitis B and C viruses. AB - Concurrent infection with hepatitis C virus (HCV) and hepatitis B virus (HBV) was not uncommon in China. To date, information on predictors of response to treatment of dually-infected HCV/HBV is limited. The aim of this study was to evaluated whether determination of the interleukin 28B (IL-28B) polymorphism statuses sufficient to predict treatment response of interferon (IFN)-based therapy in patients chronically infected with both hepatitis B and C viruses. We investigated the role of IL28B variations (rs8099917 and rs12979860) in response to IFN-based treatment and evaluated its association with the risk of the null virological response (NVR) in HCV /HBV dually-infected patients. We found that the overall distributions of the genotypes among the sustained virological response (SVR), NVR groups were significantly different (P<0.001): patients with the rs8099917 TG genotype had an increased risk of NVR (odds ratio [OR] =2.37 95% confidence interval [CI] =1.16-4.83, P =0.017), and those with the GG genotype had a further increased risk of NVR (OR=4.23, 95% CI =1.17-15.3, P=0.027). The rs12979860 allele was also highly associated with treatment failure (CT/TT vs. CC; OR =2.04, 95%CI =1.05-3.97, P =0.037). Moreover, we found that IL28B rs8099917 G variants (TG+GG) interact with HCV genotype 1(G1) to result in higher risk of NVR (P=0.009), and that they are also associated with HBV DNA reactivation (TG+GG vs. TT, P=0.005). Furthermore, multivariate regression analysis show that the rs8099917 G allele was the most important factor significantly associated with a NVR in HCV G1 patients. This study suggest that IL28B genotyping may be a valid pretreatment predictor of which patients are likely to respond to treatment in this group of difficult-to-treat HCV/HBV dually infected patients. PMID- 24147098 TI - Extracts of pomelo peels prevent high-fat diet-induced metabolic disorders in c57bl/6 mice through activating the PPARalpha and GLUT4 pathway. AB - OBJECTIVE: Metabolic syndrome is a serious health problem in both developed and developing countries. The present study investigated the anti-metabolic disorder effects of different pomelo varieties on obese C57BL/6 mice induced by high-fat (HF) diet. DESIGN: The peels of four pomelo varieties were extracted with ethanol and the total phenols and flavonoids content of these extracts were measured. For the animal experiment, the female C57BL/6 mice were fed with a Chow diet or a HF diet alone or supplemented with 1% (w/w) different pomelo peel extracts for 8 weeks. Body weight and food intake were measured every other day. At the end of the treatment, the fasting blood glucose, glucose tolerance and insulin (INS) tolerance test, serum lipid profile and insulin levels, and liver lipid contents were analyzed. The gene expression analysis was performed with a quantitative real-time PCR assay. RESULT: The present study showed that the Citrus grandis liangpinyou (LP) and beibeiyou (BB) extracts were more potent in anti-metabolic disorder effects than the duanshiyou (DS) and wubuyou (WB) extracts. Both LP and BB extracts blocked the body weight gain, lowered fasting blood glucose, serum TC, liver lipid levels, and improved glucose tolerance and insulin resistance, and lowered serum insulin levels in HF diet-fed mice. Compared with the HF group, LP and BB peel extracts increased the mRNA expression of PPARalpha and its target genes, such as FAS, PGC-1alpha and PGC-1beta, and GLUT4 in the liver and white adipocyte tissue (WAT). CONCLUSION: We found that that pomelo peel extracts could prevent high-fat diet-induced metabolic disorders in C57BL/6 mice through the activation of the PPARalpha and GLUT4 signaling. Our results indicate that pomelo peels could be used as a dietary therapy and the potential source of drug for metabolic disorders. PMID- 24147099 TI - Type D personality is associated with psychological distress and poor self-rated health among the elderly: a population-based study in Japan. AB - We investigated the association between Type D personality, psychological distress, and self-ratings of poor health in elderly Japanese people. In August 2010, questionnaires were sent to all residents aged >=65 in three municipalities (n = 21232) in Okayama Prefecture, Japan, and. 13929 questionnaires were returned (response rate: 65.6%). To assess mental and physical health outcomes, we used the Kessler Psychological Distress Scale and a single item question regarding perceived general health. We analyzed 9759 questionnaires to determine odds ratios (ORs) and 95% confidence intervals (CIs) for several health outcomes, adjusting for sex, age, smoking status, frequency of alcohol consumption, overweight status, educational attainment, socioeconomic status, and number of cohabiters. The multiple imputation method was employed for missing data regarding Type D personality. The prevalence of Type D personality in our sample was 46.2%. After adjusting for covariates, we found that participants with Type D personality were at 4-5 times the risk of psychological distress, and twice the risk of poor self-rated health. This association was stronger in participants aged 65-74 years (psychological distress; OR: 5.80, 95% CI: 4.96-6.78, poor self rated health; OR: 2.84, 95% CI: 2.38-3.38) than in those aged over 75 years (psychological distress; OR: 4.54, 95% CI: 3.96-5.19, poor self-rated health; OR: 2.05, 95% CI: 1.79-2.34). Type D personality is associated with adverse health status among Japanese elderly people in terms of mental and physical risk; therefore, further research into the implications of this personality type is warranted. PMID- 24147100 TI - Regional homogeneity abnormalities affected by depressive symptoms in migraine patients without aura: a resting state study. AB - BACKGROUND: Bidirectional relationship between migraine and depression suggests that there might be some etiological risk factors shared. However, few studies investigated resting state abnormalities affected by depressive symptoms in migraine patients without aura (MWoA). MATERIALS AND METHODS: According to their self-rating depression scale (SDS) score, MWoA were divided into twenty in the SDS (+) (SDS > 49) group and 20 in the SDS (-) (SDS <= 49) group. Regional homogeneity (ReHo) method were employed to assess local features of spontaneous brain activity between 1) all MWoA and healthy controls, 2) each subgroup and healthy controls, and 3) SDS (-) group and SDS (+) group. RESULTS: Compared with healthy controls, decreased ReHo in similar regions were shown in the MWoA group and subgroups. It is noteworthy that the caudate showed increased ReHo in the SDS (-) group compared with healthy controls and the SDS (+) group. Moreover, the average ReHo values of the caudate in SDS (-) group were significantly positively correlated with duration of migraine. CONCLUSIONS: Our results suggested that ReHo patterns in migraine patients may be affected by depressive symptoms and serve as a biomarker to reflect depression severity in MWoA. PMID- 24147101 TI - Collective cognition in humans: groups outperform their best members in a sentence reconstruction task. AB - Group-living is widespread among animals and one of the major advantages of group living is the ability of groups to solve cognitive problems that exceed individual ability. Humans also make use of collective cognition and have simultaneously developed a highly complex language to exchange information. Here we investigated collective cognition of human groups regarding language use in a realistic situation. Individuals listened to a public announcement and had to reconstruct the sentence alone or in groups. This situation is often encountered by humans, for instance at train stations or airports. Using recent developments in machine speech recognition, we analysed how well individuals and groups reconstructed the sentences from a syntactic (i.e., the number of errors) and semantic (i.e., the quality of the retrieved information) perspective. We show that groups perform better both on a syntactic and semantic level than even their best members. Groups made fewer errors and were able to retrieve more information when reconstructing the sentences, outcompeting even their best group members. Our study takes collective cognition studies to the more complex level of language use in humans. PMID- 24147102 TI - Evaluation of the psychometric properties of the Functional Assessment of Cancer Therapy-Cervix questionnaire in Brazil. AB - BACKGROUND: Although cervical cancer is the second most common tumor among Brazilian women, studies that evaluate the quality of life of these women are still scarce. This situation is explained by the lack of specific and validated tools for this purpose in Portuguese (Brazil). The aim of this study was to evaluate the psychometric properties of the Portuguese version of the FACT-CX (Functional Assessment of Cancer Therapy-Cervix) questionnaire in a population of Brazilian women with cervical cancer. METHODS: The psychometric properties of the FACT-CX questionnaire were tested in a sample of 100 women diagnosed with cervical cancer who were previously treated in the Barretos Cancer Hospital. We analyzed the internal consistency (Cronbach's alpha), reproducibility (intraclass correlation coefficient--ICC), confirmatory factor analysis, convergent validity (correlation with the SF-36 questionnaire), and discriminant validity by disease stage and two questions related to self-perception of health was also performed. RESULTS: The scales had Cronbach's alpha coefficients ranging from 0.61 to 0.80. However, three scales did not have a statistically significant coefficient greater than 0.70. The ICC ranged from 0.68 to 0.82 and all considered satisfactory. Factor analysis did not generate consistent components. The FACT-G and FACT-CX total scores had good internal consistency and reproducibility, and also correlated well with the General Health and Vitality scales of the SF-36. However, only two FACT-CX scales had a significant correlation with SF-36. Discriminant analysis showed that FACT-CX failed to discriminate groups according to clinical stage but was able to divide the women according to the self perception of health. CONCLUSION: FATC-CX total score had good internal consistency, reproducibility and discriminant validity. In addition, it correlated well with General Health and Vitality scales of SF-36. However, three scales had questionable internal consistency and only two had significant correlation with SF-36. PMID- 24147104 TI - Characterization of plasmid-mediated quinolone resistance (PMQR) genes in extended-spectrum beta-lactamase-producing Enterobacteriaceae pediatric clinical isolates in Mexico. AB - This work describes the characterization of plasmid-mediated quinolone-resistance (PMQR) genes from a multicenter study of ESBL-producing Enterobacteriaceae pediatric clinical isolates in Mexico. The PMQR gene-positive isolates were characterized with respect to ESBLs, and mutations in the GyrA and ParC proteins were determined. The phylogenetic relationship was established by PFGE and the transfer of PMQR genes was determined by mating assays. The prevalence of the PMQR genes was 32.1%, and the rate of qnr-positive isolates was 15.1%; 93.3% of the latter were qnrB and 6.4% were qnrA1. The distribution of isolates in terms of bacterial species was as follows: 23.5% (4/17) corresponded to E. cloacae, 13.7% (7/51) to K. pneumoniae, and 13.6% (6/44) to E. coli. In addition, the prevalence of aac(6')-Ib-cr and qepA was 15.1% and 1.7%, respectively. The molecular characteristics of qnr- and qepA-positive isolates pointed to extended spectrum beta-lactamase (ESBL) CTX-M-15 as the most prevalent one (70.5%), and to SHV-12 in the case of aac(6')-Ib-cr-positive isolates. GyrA mutations at codons Ser-83 and Asp-87, and ParC mutations at codons Ser-80 were observed in 41.1% and 35.2% of the qnr-positive isolates, respectively. The analysis of the transconjugants revealed a co-transmission of bla(CTX-M-15) with the qnrB alleles. In general, the prevalence of PMQR genes (qnr and aac(6')-Ib-cr) presented in this work was much lower in the pediatric isolates, in comparison to the adult isolates in Mexico. Also, ESBL CTX-M-15 was the main ESBL identified in the pediatric isolates, whereas in the adult ones, ESBLs corresponded to the CTX M and the SHV families. In comparison with other studies, among the PMQR-genes identified in this study, the qnrB-alleles and the aac(6')-Ib-cr gene were the most prevalent, whereas the qnrS1, qnrA1 and qnrB-like alleles were the most prevalent in China and Uruguay. PMID- 24147103 TI - Effects of Helicobacter suis gamma-glutamyl transpeptidase on lymphocytes: modulation by glutamine and glutathione supplementation and outer membrane vesicles as a putative delivery route of the enzyme. AB - Helicobacter (H.) suis colonizes the stomach of the majority of pigs as well as a minority of humans worldwide. Infection causes chronic inflammation in the stomach of the host, however without an effective clearance of the bacteria. Currently, no information is available about possible mechanisms H. suis utilizes to interfere with the host immune response. This study describes the effect on various lymphocytes of the gamma-glutamyl transpeptidase (GGT) from H. suis. Compared to whole cell lysate from wild-type H. suis, lysate from a H. suis ggt mutant strain showed a decrease of the capacity to inhibit Jurkat T cell proliferation. Incubation of Jurkat T cells with recombinantly expressed H. suis GGT resulted in an impaired proliferation, and cell death was shown to be involved. A similar but more pronounced inhibitory effect was also seen on primary murine CD4(+) T cells, CD8(+) T cells, and CD19(+) B cells. Supplementation with known GGT substrates was able to modulate the observed effects. Glutamine restored normal proliferation of the cells, whereas supplementation with reduced glutathione strengthened the H. suis GGT-mediated inhibition of proliferation. H. suis GGT treatment abolished secretion of IL-4 and IL-17 by CD4(+) T cells, without affecting secretion of IFN-gamma. Finally, H. suis outer membrane vesicles (OMV) were identified as a possible delivery route of H. suis GGT to lymphocytes residing in the deeper mucosal layers. Thus far, this study is the first to report that the effects on lymphocytes of this enzyme, not only important for H. suis metabolism but also for that of other Helicobacter species, depend on the degradation of two specific substrates: glutamine and reduced glutatione. This will provide new insights into the pathogenic mechanisms of H. suis infection in particular and infection with gastric helicobacters in general. PMID- 24147105 TI - Genetic and familial environmental effects on suicide--an adoption study of siblings. AB - BACKGROUND: While there is clear evidence of familial influences on suicide, the origin of these is less certain. We have investigated genetic and familial environmental factors by studying the occurrence of suicide in biological and adoptive siblings of adoptees who died by suicide compared to siblings of surviving adoptees. METHOD: We used the Danish Adoption Register and Danish population registers to compare 221 siblings of adoptees who died by suicide with the siblings of 1,903 adoptees who did not die by suicide. All adoptions in the Danish Adoption Register are non-familial, i.e. the adoptive parents are biologically unrelated to the adoptee. Analyses were conducted on incidence rates of suicide in biological and adoptive siblings given occurrence of suicide in the adoptees while also taking into account psychiatric disorders. RESULTS: The risk of suicide in full siblings of adoptees who died by suicide before age 60 years was significantly higher than in full siblings of adoptees who had not died by suicide (incidence rate ratios (IRR) = 5.01; 95% confidence interval [CI] = 1.28 19.6). This increase persisted after adjustment for history of psychiatric admission of siblings (IRR = 4.19; 95% CI = 1.00-17.5). CONCLUSIONS: Genetic factors influence risk of suicide, probably independently of psychiatric disorder. This is relevant in provision of advice to families, including possible prevention of suicide. PMID- 24147107 TI - Bitter melon reduces head and neck squamous cell carcinoma growth by targeting c Met signaling. AB - Head and neck squamous cell carcinoma (HNSCC) remains difficult to treat, and despite of advances in treatment, the overall survival rate has only modestly improved over the past several years. Thus, there is an urgent need for additional therapeutic modalities. We hypothesized that treatment of HNSCC cells with a dietary product such as bitter melon extract (BME) modulates multiple signaling pathways and regresses HNSCC tumor growth in a preclinical model. We observed a reduced cell proliferation in HNSCC cell lines. The mechanistic studies reveal that treatment of BME in HNSCC cells inhibited c-Met signaling pathway. We also observed that BME treatment in HNSCC reduced phosphoStat3, c-myc and Mcl-1 expression, downstream signaling molecules of c-Met. Furthermore, BME treatment in HNSCC cells modulated the expression of key cell cycle progression molecules leading to halted cell growth. Finally, BME feeding in mice bearing HNSCC xenograft tumor resulted in an inhibition of tumor growth and c-Met expression. Together, our results suggested that BME treatment in HNSCC cells modulates multiple signaling pathways and may have therapeutic potential for treating HNSCC. PMID- 24147108 TI - Novel multiscale modeling tool applied to Pseudomonas aeruginosa biofilm formation. AB - Multiscale modeling is used to represent biological systems with increasing frequency and success. Multiscale models are often hybrids of different modeling frameworks and programming languages. We present the MATLAB-NetLogo extension (MatNet) as a novel tool for multiscale modeling. We demonstrate the utility of the tool with a multiscale model of Pseudomonas aeruginosa biofilm formation that incorporates both an agent-based model (ABM) and constraint-based metabolic modeling. The hybrid model correctly recapitulates oxygen-limited biofilm metabolic activity and predicts increased growth rate via anaerobic respiration with the addition of nitrate to the growth media. In addition, a genome-wide survey of metabolic mutants and biofilm formation exemplifies the powerful analyses that are enabled by this computational modeling tool. PMID- 24147106 TI - MicroRNA-34a enhances T cell activation by targeting diacylglycerol kinase zeta. AB - The engagement of the T cell receptor (TCR) induces the generation of diacylglycerol (DAG), an important second messenger activating both the Ras/Erk and PKCtheta/NFkappaB pathways. DAG kinases (DGKs) participate in the metabolism of DAG by converting it to phosphatidic acid. DGKzeta has been demonstrated to be able to inhibit DAG signaling following TCR engagement. Deficiency of DGKzeta increases the sensitivity of T cells to TCR stimulation, resulting in enhanced T cell activation ex vivo and in vivo. However, the mechanisms that control DGKzeta expression are poorly understood. Here we demonstrate that DGKzeta mRNA is a direct target of a cellular microRNA miR-34a. The DGKzeta transcript is decreased, whereas the primary miR-34a is upregulated upon TCR stimulation. Ectopic miR-34a expression suppresses DGKzeta protein expression through the seed match binding to both the 3' untranslated region and coding region of DGKzeta mRNA, leading to increased ERK1/2 phosphorylation and surface expression of the T cell activation marker CD69 following TCR cross-linking. In contrast, overexpression of a miR-34a competitive inhibitor increases DGKzeta expression and suppresses TCR-mediated T cell activation. Together, our data demonstrate that miR-34a is a negative regulator for DGKzeta and may play an important role in regulating T cell activation. PMID- 24147109 TI - Fecal protease activity is associated with compositional alterations in the intestinal microbiota. AB - OBJECTIVE: Intestinal proteases carry out a variety of functions in the gastrointestinal (GI) tract. Studies have reported that elevated enteric proteases in patients with GI disease can alter intestinal physiology, however the origin (human vs. microbial) of elevated proteases in patients with GI disease is unclear. AIM: The aim of this study was to investigate the association between protease activity and the microbiota in human fecal samples. DESIGN: In order to capture a wide range of fecal protease (FP) activity stool samples were collected from 30 IBS patients and 24 healthy controls. The intestinal microbiota was characterized using 454 high throughput pyro-sequencing of the 16S rRNA gene. The composition and diversity of microbial communities were determined and compared using the Quantitative Insights Into Microbial Ecology (QIIME) pipeline. FP activity levels were determined using an ELISA-based method. FP activity was ranked and top and bottom quartiles (n=13 per quartile) were identified as having high and low FP activity, respectively. RESULTS: The overall diversity of the intestinal microbiota displayed significant clustering separation (p = 0.001) between samples with high vs. low FP activity. The Lactobacillales, Lachnospiraceae, and Streptococcaceae groups were positively associated with FP activity across the entire study population, whilst the Ruminococcaceae family and an unclassified Coriobacteriales family were negatively associated with FP activity. CONCLUSIONS: These data demonstrate significant associations between specific intestinal bacterial groups and fecal protease activity and provide a basis for further causative studies investigating the role of enteric microbes and GI diseases. PMID- 24147110 TI - Salicylate prevents virus-induced type 1 diabetes in the BBDR rat. AB - Epidemiologic and clinical evidence suggests that virus infection plays an important role in human type 1 diabetes pathogenesis. We used the virus-inducible BioBreeding Diabetes Resistant (BBDR) rat to investigate the ability of sodium salicylate, a non-steroidal anti-inflammatory drug (NSAID), to modulate development of type 1 diabetes. BBDR rats treated with Kilham rat virus (KRV) and polyinosinic:polycytidylic acid (pIC, a TLR3 agonist) develop diabetes at nearly 100% incidence by ~2 weeks. We found distinct temporal profiles of the proinflammatory serum cytokines, IL-1beta, IL-6, IFN-gamma, IL-12, and haptoglobin (an acute phase protein) in KRV+pIC treated rats. Significant elevations of IL-1beta and IL-12, coupled with sustained elevations of haptoglobin, were specific to KRV+pIC and not found in rats co-treated with pIC and H1, a non-diabetogenic virus. Salicylate administered concurrently with KRV+pIC inhibited the elevations in IL-1beta, IL-6, IFN-gamma and haptoglobin almost completely, and reduced IL-12 levels significantly. Salicylate prevented diabetes in a dose-dependent manner, and diabetes-free animals had no evidence of insulitis. Our data support an important role for innate immunity in virus induced type 1 diabetes pathogenesis. The ability of salicylate to prevent diabetes in this robust animal model demonstrates its potential use to prevent or attenuate human autoimmune diabetes. PMID- 24147111 TI - Influence of obstructive jaundice on pharmacodynamics of rocuronium. AB - BACKGROUND: Anesthetics are variable in patients with obstructive jaundice. The minimum alveolar concentration awake of desflurane is reduced in patients with obstructive jaundice, while it has no effect on pharmacodynamics and pharmacokinetics of propofol. In this study, we investigated the influence of obstructive jaundice on the pharmacodynamics and blood concentration of rocuronium. METHODS: Included in this study were 26 control patients and 27 patients with obstructive jaundice. Neuromuscular block of rocuronium was monitored by acceleromyography. Onset time, spontaneous recovery of the height of twitch first (T1) to 25% of the final T1 value (Duration 25%, Dur 25%), recovery index (RI), and spontaneous recovery of train-of-four (TOF) ratios to 70% were measured. The plasma rocuronium concentrations were determined by high performance liquid chromatography using berberine as an internal standard. RESULTS: There was no significant difference in onset time between the two groups. The Dur 25%, the recovery index and the time of recovery of the TOF ratios to 70% were all prolonged in the obstructive jaundice group compared with the control group. The plasma concentration of rocuronium at 60, 90 and 120 min after bolus administration was significantly higher in the obstructive jaundice group. CONCLUSIONS: The neuromuscular blockade by rocuronium is prolonged in obstructive jaundice patients, and therefore precautions should be taken in case of postoperative residual neuromuscular block. The possible reason is impedance of rocuronium excretion due to biliary obstruction and increased plasma unbound rocuronium because of free bilirubin competing with it for albumin binding. PMID- 24147112 TI - Rectified cell migration on saw-like micro-elastically patterned hydrogels with asymmetric gradient ratchet teeth. AB - To control cell motility is one of the essential technologies for biomedical engineering. To establish a methodology of the surface design of elastic substrate to control the long-range cell movements, here we report a sophisticated cell culture hydrogel with a micro-elastically patterned surface that allows long-range durotaxis. This hydrogel has a saw-like pattern with asymmetric gradient ratchet teeth, and rectifies random cell movements. Durotaxis only occurs at boundaries in which the gradient strength of elasticity is above a threshold level. Consequently, in gels with unit teeth patterns, durotaxis should only occur at the sides of the teeth in which the gradient strength of elasticity is above this threshold level. Therefore, such gels are expected to support the long-range biased movement of cells via a mechanism similar to the Feynman Smoluchowski ratchet, i.e., rectified cell migration. The present study verifies this working hypothesis by using photolithographic microelasticity patterning of photocurable gelatin gels. Gels in which each teeth unit was 100-120 um wide with a ratio of ascending:descending elasticity gradient of 1:2 and a peak elasticity of ca. 100 kPa supported the efficient rectified migration of 3T3 fibroblast cells. In addition, long-range cell migration was most efficient when soft lanes were introduced perpendicular to the saw-like patterns. This study demonstrates that asymmetric elasticity gradient patterning of cell culture gels is a versatile means of manipulating cell motility. PMID- 24147113 TI - Interkingdom complementation reveals structural conservation and functional divergence of 14-3-3 proteins. AB - The 14-3-3s are small acidic cytosolic proteins that interact with multiple clients and participate in essential cellular functions in all eukaryotes. Available structural and functional information about 14-3-3s is largely derived from higher eukaryotes, which contain multiple members of this protein family suggesting functional specialization. The exceptional sequence conservation among 14-3-3 family members from diverse species suggests a common ancestor for 14-3 3s, proposed to have been similar to modern 14-3-3epsilon isoforms. Structural features of the sole family member from the protozoan Giardia duodenalis (g14-3 3), are consistent with this hypothesis, but whether g14-3-3 is functionally homologous to the epsilon isoforms is unknown. We use inter-kingdom reciprocal functional complementation and biochemical methods to determine whether g14-3-3 is structurally and functionally homologous with members of the two 14-3-3 conservation groups of the metazoan Drosophila melanogaster. Our results indicate that although g14-3-3 is structurally homologous to D14-3-3epsilon, functionally it diverges presenting characteristics of other 14-3-3s. Given the basal position of Giardia in eukaryotic evolution, this finding is consistent with the hypothesis that 14-3-3epsilon isoforms are ancestral to other family members. PMID- 24147114 TI - Correlational analysis of neck/shoulder pain and low back pain with the use of digital products, physical activity and psychological status among adolescents in Shanghai. AB - PURPOSE: This study investigates the neck/shoulder pain (NSP) and low back pain (LBP) among current high school students in Shanghai and explores the relationship between these pains and their possible influences, including digital products, physical activity, and psychological status. METHODS: An anonymous self assessment was administered to 3,600 students across 30 high schools in Shanghai. This questionnaire examined the prevalence of NSP and LBP and the level of physical activity as well as the use of mobile phones, personal computers (PC) and tablet computers (Tablet). The CES-D (Center for Epidemiological Studies Depression) scale was also included in the survey. The survey data were analyzed using the chi-square test, univariate logistic analyses and a multivariate logistic regression model. RESULTS: Three thousand sixteen valid questionnaires were received including 1,460 (48.41%) from male respondents and 1,556 (51.59%) from female respondents. The high school students in this study showed NSP and LBP rates of 40.8% and 33.1%, respectively, and the prevalence of both influenced by the student's grade, use of digital products, and mental status; these factors affected the rates of NSP and LBP to varying degrees. The multivariate logistic regression analysis revealed that Gender, grade, soreness after exercise, PC using habits, tablet use, sitting time after school and academic stress entered the final model of NSP, while the final model of LBP consisted of gender, grade, soreness after exercise, PC using habits, mobile phone use, sitting time after school, academic stress and CES-D score. CONCLUSIONS: High school students in Shanghai showed high prevalence of NSP and LBP that were closely related to multiple factors. Appropriate interventions should be implemented to reduce the occurrences of NSP and LBP. PMID- 24147115 TI - Effective population size, genetic variation, and their relevance for conservation: the bighorn sheep in Tiburon Island and comparisons with managed artiodactyls. AB - The amount of genetic diversity in a finite biological population mostly depends on the interactions among evolutionary forces and the effective population size (N(e)) as well as the time since population establishment. Because the N(e) estimation helps to explore population demographic history, and allows one to predict the behavior of genetic diversity through time, N(e) is a key parameter for the genetic management of small and isolated populations. Here, we explored an N(e)-based approach using a bighorn sheep population on Tiburon Island, Mexico (TI) as a model. We estimated the current (N(crnt)) and ancestral stable (N(stbl)) inbreeding effective population sizes as well as summary statistics to assess genetic diversity and the demographic scenarios that could explain such diversity. Then, we evaluated the feasibility of using TI as a source population for reintroduction programs. We also included data from other bighorn sheep and artiodactyl populations in the analysis to compare their inbreeding effective size estimates. The TI population showed high levels of genetic diversity with respect to other managed populations. However, our analysis suggested that TI has been under a genetic bottleneck, indicating that using individuals from this population as the only source for reintroduction could lead to a severe genetic diversity reduction. Analyses of the published data did not show a strict correlation between H(E) and N(crnt) estimates. Moreover, we detected that ancient anthropogenic and climatic pressures affected all studied populations. We conclude that the estimation of N(crnt) and N(stbl) are informative genetic diversity estimators and should be used in addition to summary statistics for conservation and population management planning. PMID- 24147117 TI - Distinct tryptophan catabolism and Th17/Treg balance in HIV progressors and elite controllers. AB - Tryptophan (Trp) catabolism into immunosuppressive kynurenine (Kyn) by indoleamine 2,3-dioxygenase (IDO) was previously linked to Th17/Treg differentiation and immune activation. Here we examined Trp catabolism and its impact on Th17/Treg balance in uninfected healthy subjects (HS) and a large cohort of HIV-infected patients with different clinical outcomes: ART-naive, Successfully Treated (ST), and elite controllers (EC). In ART-naive patients, increased IDO activity/expression, together with elevated levels of TNF-alpha and sCD40L, were associated with Treg expansion and an altered Th17/Treg balance. These alterations were normalized under ART. In contrast, Trp 2,3-dioxegenase (TDO) expression was dramatically lower in EC when compared to all other groups. Interestingly, EC displayed a distinctive Trp metabolism characterized by low Trp plasma levels similar to ART-naive patients without accumulating immunosuppressive Kyn levels which was accompanied by a preserved Th17/Treg balance. These results suggest a distinctive Trp catabolism and Th17/Treg balance in HIV progressors and EC. Thus, IDO-induced immune-metabolism may be considered as a new inflammation-related marker for HIV-1 disease progression. PMID- 24147116 TI - The conserved C-terminus of the PcrA/UvrD helicase interacts directly with RNA polymerase. AB - UvrD-like helicases play diverse roles in DNA replication, repair and recombination pathways. An emerging body of evidence suggests that their different cellular functions are directed by interactions with partner proteins that target unwinding activity to appropriate substrates. Recent studies in E. coli have shown that UvrD can act as an accessory replicative helicase that resolves conflicts between the replisome and transcription complexes, but the mechanism is not understood. Here we show that the UvrD homologue PcrA interacts physically with B. subtilis RNA polymerase, and that an equivalent interaction is conserved in E. coli where UvrD, but not the closely related helicase Rep, also interacts with RNA polymerase. The PcrA-RNAP interaction is direct and independent of nucleic acids or additional mediator proteins. A disordered but highly conserved C-terminal region of PcrA, which distinguishes PcrA/UvrD from otherwise related enzymes such as Rep, is both necessary and sufficient for interaction with RNA polymerase. PMID- 24147118 TI - Positive selection in bone morphogenetic protein 15 targets a natural mutation associated with primary ovarian insufficiency in human. AB - Bone Morphogenetic Protein 15 (BMP15) is a TGFbeta-like oocyte-derived growth factor involved in ovarian folliculogenesis as a critical regulator of many granulosa cell processes. Alterations of the BMP15 gene have been found associated with different ovarian phenotypic effects depending on the species, from sterility to increased prolificacy in sheep, slight subfertility in mouse or associated with primary ovarian insufficiency (POI) in women. To investigate the evolving role of BMP15, a phylogenetic analysis of this particular TGFbeta family member was performed. A maximum likelihood phylogenetic tree of several TGFbeta/BMP family members expressed by the ovary showed that BMP15 has a very strong divergence and a rapid evolution compared to others. Moreover, among 24 mammalian species, we detected signals of positive selection in the hominidae clade corresponding to F146, L189 and Y235 residues in human BMP15. The biological importance of these residues was tested functionally after site directed-mutagenesis in a COV434 cells luciferase assay. By replacing the positively selected amino acid either by alanine or the most represented residue in other studied species, only L189A, Y235A and Y235C mutants showed a significant increase of BMP15 signaling when compared to wild type. Additionally, the Y235C mutant was more potent than wild type in inhibiting progesterone secretion of ovine granulosa cells in primary culture. Interestingly, the Y235C mutation was previously identified in association with POI in women. In conclusion, this study evidences that the BMP15 gene has evolved faster than other members of the TGFbeta family and was submitted to a positive selection pressure in the hominidae clade. Some residues under positive selection are of great importance for the normal function of the protein and thus for female fertility. Y235 represents a critical residue in the determination of BMP15 biological activity, thus indirectly confirming its role in the onset of POI in women. PMID- 24147119 TI - TRPV1 channels are functionally coupled with BK(mSlo1) channels in rat dorsal root ganglion (DRG) neurons. AB - The transient receptor potential vanilloid receptor 1 (TRPV1) channel is a nonselective cation channel activated by a variety of exogenous and endogenous physical and chemical stimuli, such as temperature (>=42 degrees C), capsaicin, a pungent compound in hot chili peppers, and allyl isothiocyanate. Large conductance calcium- and voltage-activated potassium (BK) channels regulate the electric activities and neurotransmitter releases in excitable cells, responding to changes in membrane potentials and elevation of cytosolic calcium ions (Ca(2+)). However, it is unknown whether the TRPV1 channels are coupled with the BK channels. Using patch-clamp recording combined with an infrared laser device, we found that BK channels could be activated at 0 mV by a Ca(2+) influx through TRPV1 channels not the intracellular calcium stores in submilliseconds. The local calcium concentration around BK is estimated over 10 MUM. The crosstalk could be affected by 10 mM BAPTA, whereas 5 mM EGTA was ineffectual. Fluorescence and co immunoprecipitation experiments also showed that BK and TRPV1 were able to form a TRPV1-BK complex. Furthermore, we demonstrated that the TRPV1-BK coupling also occurs in dosal root ganglion (DRG) cells, which plays a critical physiological role in regulating the "pain" signal transduction pathway in the peripheral nervous system. PMID- 24147120 TI - Autoantibodies against the beta3-adrenoceptor protect from cardiac dysfunction in a rat model of pressure overload. AB - beta3-Adrenoceptors (beta3-ARs) mediate a negative inotropic effect in human ventricular cardiomyocytes, which is opposite to that of beta1- and beta2-ARs. It has been previously demonstrated that autoantibodies against the beta1/beta2-AR exist in the sera of some patients with heart failure (HF) and these autoantibodies display agonist-like effects. Our aim in this study was to observe whether autoantibodies against the beta3-AR (beta3-AR Abs) exist in the sera of patients with HF and to assess the effects of beta3-AR Abs on rat model of pressure overload cardiomyopthy. In the present study, the level of beta3-AR Abs in the sera of HF patients was screened by ELISA. beta3-AR Abs from HF patients were administrated to male adult rats with abdominal aortic banding (AAB), and the cardiac function was measured by echocardiographic examination and hemodynamic studies. The biological effects of this autoantibody on cardiomyocytes were evaluated using a motion-edge detection system, intracellular calcium transient assay, and patch clamp techniques. Compared to healthy subjects, the frequency of occurrence and titer of beta3-AR Abs in the sera of HF patients were greatly increased, and beta3-AR Abs could prevent LV dilation and improve the cardiac function of rats with AAB. beta3-AR Abs exhibited negative chronotropic and inotropic effects and were accompanied by a decreased intracellular Ca(2+) transient and membrane L-type Ca(2+) current in cardiomyocytes. Our results demonstrated the existence of beta3-AR Abs in the sera of patients with HF and found that this autoantibody could alleviate the cardiac dysfunction induced by pressure-overload in AAB rats. PMID- 24147121 TI - Conceptualizing community mobilization for HIV prevention: implications for HIV prevention programming in the African context. AB - INTRODUCTION: Community mobilizing strategies are essential to health promotion and uptake of HIV prevention. However, there has been little conceptual work conducted to establish the core components of community mobilization, which are needed to guide HIV prevention programming and evaluation. OBJECTIVES: We aimed to identify the key domains of community mobilization (CM) essential to change health outcomes or behaviors, and to determine whether these hypothesized CM domains were relevant to a rural South African setting. METHOD: We studied social movements and community capacity, empowerment and development literatures, assessing common elements needed to operationalize HIV programs at a community level. After synthesizing these elements into six essential CM domains, we explored the salience of these CM domains qualitatively, through analysis of 10 key informant in-depth-interviews and seven focus groups in three villages in Bushbuckridge. RESULTS: CM DOMAINS INCLUDE: 1) shared concerns, 2) critical consciousness, 3) organizational structures/networks, 4) leadership (individual and/or institutional), 5) collective activities/actions, and 6) social cohesion. Qualitative data indicated that the proposed domains tapped into theoretically consistent constructs comprising aspects of CM processes. Some domains, extracted from largely Western theory, required little adaptation for the South African context; others translated less effortlessly. For example, critical consciousness to collectively question and resolve community challenges functioned as expected. However, organizations/networks, while essential, operated differently than originally hypothesized - not through formal organizations, but through diffuse family networks. CONCLUSIONS: To date, few community mobilizing efforts in HIV prevention have clearly defined the meaning and domains of CM prior to intervention design. We distilled six CM domains from the literature; all were pertinent to mobilization in rural South Africa. While some adaptation of specific domains is required, they provide an extremely valuable organizational tool to guide CM programming and evaluation of critically needed mobilizing initiatives in Southern Africa. PMID- 24147122 TI - The use of quantile regression to forecast higher than expected respiratory deaths in a daily time series: a study of New York City data 1987-2000. AB - Forecasting higher than expected numbers of health events provides potentially valuable insights in its own right, and may contribute to health services management and syndromic surveillance. This study investigates the use of quantile regression to predict higher than expected respiratory deaths. Data taken from 70,830 deaths occurring in New York were used. Temporal, weather and air quality measures were fitted using quantile regression at the 90th-percentile with half the data (in-sample). Four QR models were fitted: an unconditional model predicting the 90th-percentile of deaths (Model 1), a seasonal/temporal (Model 2), a seasonal, temporal plus lags of weather and air quality (Model 3), and a seasonal, temporal model with 7-day moving averages of weather and air quality. Models were cross-validated with the out of sample data. Performance was measured as proportionate reduction in weighted sum of absolute deviations by a conditional, over unconditional models; i.e., the coefficient of determination (R1). The coefficient of determination showed an improvement over the unconditional model between 0.16 and 0.19. The greatest improvement in predictive and forecasting accuracy of daily mortality was associated with the inclusion of seasonal and temporal predictors (Model 2). No gains were made in the predictive models with the addition of weather and air quality predictors (Models 3 and 4). However, forecasting models that included weather and air quality predictors performed slightly better than the seasonal and temporal model alone (i.e., Model 3 > Model 4 > Model 2) This study provided a new approach to predict higher than expected numbers of respiratory related-deaths. The approach, while promising, has limitations and should be treated at this stage as a proof of concept. PMID- 24147123 TI - On the myths of indicator species: issues and further consideration in the use of static concepts for ecological applications. AB - The use of static indicator species, in which species are expected to have a similar sensitivity or tolerance to either natural or human-induced stressors, does not account for possible shifts in tolerance along natural environmental gradients and between biogeographic regions. Their indicative value may therefore be considered at least questionable. In this paper we demonstrate how species responses (i.e. abundance) to changes in sediment grain size and organic matter (OM) alter along a salinity gradient and conclude with a plea for prudency when interpreting static indicator-based quality indices. Six model species (three polychaetes, one amphipod and two bivalves) from the North Sea, Baltic Sea and the Mediterranean Sea region were selected. Our study demonstrated that there were no generic relationships between environment and biota and half of the studied species showed different responses in different seas. Consequently, the following points have to be carefully considered when applying static indicator based quality indices: (1) species tolerances and preferences may change along environmental gradients and between different biogeographic regions, (2) as environment modifies species autecology, there is a need to adjust indicator species lists along major environmental gradients and (3) there is a risk of including sibling or cryptic species in calculating the index value of a species. PMID- 24147124 TI - Intra-genomic variation in the ribosomal repeats of nematodes. AB - Ribosomal loci represent a major tool for investigating environmental diversity and community structure via high-throughput marker gene studies of eukaryotes (e.g. 18S rRNA). Since the estimation of species' abundance is a major goal of environmental studies (by counting numbers of sequences), understanding the patterns of rRNA copy number across species will be critical for informing such high-throughput approaches. Such knowledge is critical, given that ribosomal RNA genes exist within multi-copy repeated arrays in a genome. Here we measured the repeat copy number for six nematode species by mapping the sequences from whole genome shotgun libraries against reference sequences for their rRNA repeat. This revealed a 6-fold variation in repeat copy number amongst taxa investigated, with levels of intragenomic variation ranging from 56 to 323 copies of the rRNA array. By applying the same approach to four C. elegans mutation accumulation lines propagated by repeated bottlenecking for an average of ~400 generations, we find on average a 2-fold increase in repeat copy number (rate of increase in rRNA estimated at 0.0285-0.3414 copies per generation), suggesting that rRNA repeat copy number is subject to selection. Within each Caenorhabditis species, the majority of intragenomic variation found across the rRNA repeat was observed within gene regions (18S, 28S, 5.8S), suggesting that such intragenomic variation is not a product of selection for rRNA coding function. We find that the dramatic variation in repeat copy number among these six nematode genomes would limit the use of rRNA in estimates of organismal abundance. In addition, the unique pattern of variation within a single genome was uncorrelated with patterns of divergence between species, reflecting a strong signature of natural selection for rRNA function. A better understanding of the factors that control or affect copy number in these arrays, as well as their rates and patterns of evolution, will be critical for informing estimates of global biodiversity. PMID- 24147125 TI - Temporal association of herpes simplex virus ICP4 with cellular complexes functioning at multiple steps in PolII transcription. AB - The herpes simplex virus type 1 (HSV-1) immediate early protein, ICP4, participates in the regulation of viral gene expression by both activating and repressing RNA polII transcription. We used affinity purification of ICP4 expressed in infected cells followed by mass spectrometry and western blot analysis to determine the composition of cellular complexes associated with ICP4 throughout infection. ICP4 was associated with TFIID complexes containing a distinct set of TAFs. These complexes were most abundant early, but were detected throughout infection, whereas Mediator was found in ICP4 containing complexes later in infection, indicating a temporal pattern for the utilization of these complexes for the transcription of the viral genome. The form of Mediator copurifying with ICP4 was enriched for the kinase domain and also lacked the activator-specific component, Med26, suggesting that Mediator-ICP4 interactions may be involved in repression of viral transcription. The N-terminal 774 amino acids of ICP4, which retains partial function, were sufficient to form complexes with TFIID and Mediator, although these interactions were not as strong as with full-length ICP4. Additionally, components involved in transcription elongation, chromatin remodeling, and mRNA processing were isolated with ICP4. Together our data indicate that ICP4 plays a more integrated role in mediating HSV transcription, possibly affecting multiple steps in transcription and gene expression. PMID- 24147126 TI - Adherence to antiretroviral therapy in Jinja, Uganda: a six-year follow-up study. AB - INTRODUCTION: We report on the adherence experience of a group of people living with HIV on ART over six years in Uganda. METHODS: Between 2005 and 2009, we followed up 41 participants who were also part of a clinical trial comparing home and facility based delivery of ART in Jinja, eastern Uganda. We conducted qualitative in-depth interviews at enrolment, 3, 6, 18 and 30 months to capture experiences with adherence over time. In 2011 we returned to these participants to find out how they were fairing with long term adherence. We managed to retrace 24 participants and interviewed them about their experience. We thematically analysed the data and compared findings over time. RESULTS: Initially there were few barriers to adherence and many followed the adherence guidance closely. By year six, relaxation of these rules was noticeable although self-reported adherence continued to be high. Alcohol consumption was more common than before. Some relatives of the participants who had died claimed that some deaths were a result of alcohol. While participants reported that ART had allowed them to reclaim independence and return to work the changes in work and social routines created new challenges for adherence. Side effects like lipodystrophy were not only causing some stigma but for some tested their faith in the drugs. Many participants reported resumption of sexual lives but apart from those who selected same status partners, disclosure to new partners was minimal. CONCLUSION: Good adherence practice to ART wanes over the long-term, and people who may have disclosed at initiation find it difficult to do so to new partners once they are healthy. Further adherence interventions and support with disclosure over the course of therapy may need to be considered. PMID- 24147127 TI - Zonation of nitrogen and glucose metabolism gene expression upon acute liver damage in mouse. AB - Zonation of metabolic activities within specific structures and cell types is a phenomenon of liver organization and ensures complementarity of variant liver functions like protein production, glucose homeostasis and detoxification. To analyze damage and regeneration of liver tissue in response to a toxic agent, expression of liver specific enzymes was analyzed by in situ hybridization in mouse over a 6 days time course following carbon tetrachloride (CCl4) injection. CCl4 mixed with mineral oil was administered to BALB/c mice by intraperitoneal injection, and mice were sacrificed at different time points post injection. Changes in the expression of albumin (Alb), arginase (Arg1), glutaminase 2 (Gls2), Glutamine synthetase (Gs), glucose-6-phosphatase (G6pc), glycogen synthase 2 (Gys2), Glycerinaldehyd-3-phosphat-Dehydrogenase (Gapdh), Cytochrom p450 2E1 (Cyp2e1) and glucagon receptor (Gcgr) genes in the liver were studied by in situ hybridization and qPCR. We observed significant changes in gene expression of enzymes involved in nitrogen and glucose metabolism and their local distribution following CCl4 injury. We also found that Cyp2e1, the primary metabolizing enzyme for CCl4, was strongly expressed in the pericentral zone during recovery. Furthermore, cells in the damaged area displayed distinct gene expression profiles during the analyzed time course and showed complete recovery with strong albumin production 6 days after CCl4 injection. Our results indicate that despite severe damage, liver cells in the damaged area do not simply die but instead display locally adjusted gene expression supporting damage response and recovery. PMID- 24147128 TI - Cognitive ability in late adolescence and disability pension in middle age: follow-up of a national cohort of Swedish males. AB - Low cognitive ability in late adolescence has previously been shown to be associated with disability pension (DP) in young adulthood. However, most DP's are granted later in working life, and the mechanisms of the association are not fully understood. We aimed to investigate the association between cognitive ability in late adolescence and DP at ages 40-59, and investigate the role of individual and socioeconomic factors. Information on cognitive ability, health status, personality aspects and health behaviours at age 18-20 was obtained from the 1969-70 conscription cohort, comprising 49,321 Swedish men. Data on DP's 1991 2008 was obtained from the Longitudinal Database of Education, Income and Employment. Information on socioeconomic and work-related factors in childhood and adulthood was obtained from national sociodemographic databases. Hazard ratios for DP during follow-up were estimated by Cox proportional hazards models. We found a graded relationship between cognitive ability in late adolescence and DP in middle age. One step decrease on the nine-point stanine scale of cognitive ability was associated with a crude hazard ratio of 1.26 (95% CI 1.24-1.27). Socioeconomic and work-related circumstances in adulthood explained much of the association, but factors measured already in late adolescence also showed importance. The findings suggest an accumulation of risks over the life course. Although attenuated, the graded relationship remained after adjusting for all factors. PMID- 24147129 TI - Experimental placebo analgesia changes resting-state alpha oscillations. AB - The lack of clear understanding of the pathophysiology of chronic pain could explain why we currently have only a few effective treatments. Understanding how pain relief is realised during placebo analgesia could help develop improved treatments for chronic pain. Here, we tested whether experimental placebo analgesia was associated with altered resting-state cortical activity in the alpha frequency band of the electroencephalogram (EEG). Alpha oscillations have been shown to be influenced by top-down processes, which are thought to underpin the placebo response. Seventy-three healthy volunteers, split into placebo or control groups, took part in a well-established experimental placebo procedure involving treatment with a sham analgesic cream. We recorded ongoing (resting) EEG activity before, during, and after the sham treatment. We show that resting alpha activity is modified by placebo analgesia. Post-treatment, alpha activity increased significantly in the placebo group only (p < 0.001). Source analysis suggested that this alpha activity might have been generated in medial components of the pain network, including dorsal anterior cingulate cortex, medial prefrontal cortex, and left insula. These changes are consistent with a cognitive state of pain expectancy, a key driver of the placebo analgesic response. The manipulation of alpha activity may therefore present an exciting avenue for the development of treatments that directly alter endogenous processes to better control pain. PMID- 24147130 TI - Fungi at a small scale: spatial zonation of fungal assemblages around single trees. AB - Biological communities are often structured by environmental factors even at small spatial scales. Fungi are no exception, though the patterns and mechanisms underlying their community structure are usually unknown. Previous work documented zonation in fungi under tree canopies primarily through their fruiting patterns. Here we investigate the existence of zonation patterns in fungal communities around isolated Pinus muricata trees of different ages in northern coastal California. Using a combination of ingrowth bags and pyrosequencing to target underground mycelium we found highly diverse soil fungal communities associated with single trees. Both ectomycorrhizal and non-ectomycorrhizal fungi were present in all samples, but the latter were more species rich, dominated the samples by sequence read abundance, and showed partitioning by canopy-defined zones and tree age. Soil chemistry was correlated with fungal zonation, but host root density was not. Our results indicate different guilds of fungi partition space differently and are driven by distinct environmental parameters. PMID- 24147131 TI - Depression symptom trajectories and associated risk factors among adolescents in Chile. AB - Adolescence is a key period for studying the development of depression, with studies in Europe and North America showing a pattern of elevated risk that begins in early adolescence and continues to increase as adolescents age. Few studies have examined the course of adolescent depression and associated risk factors in low and middle-income countries. This longitudinal cohort study examined depression symptom trajectories and risk factors in a sample of socio economically disadvantaged adolescents in Chile (n = 2,508). Data were collected over an 18-month period as part of a clinical trial for secondary students aged 12 to 18 (median age 14). Clinical levels of depression were prevalent in this sample at baseline (35% for girls and 28% for boys); yet latent growth models of symptom trajectories revealed a pattern of decreasing symptoms over time. There was evidence of an anxiety-depression developmental pathway for girls, with elevated anxiety levels initially predicting poorer depression outcomes later on. Poor problem-solving skills were associated with initial depression levels but did not predict the course of depressive symptoms. Critically, the declining symptom trajectories raise important methodological issues regarding the effects of repeated assessment in longitudinal studies. PMID- 24147132 TI - Frequent periodic leg movement during sleep is an unrecognized risk factor for progression of atrial fibrillation. AB - Sleep apnea has been recognized as a factor predisposing to atrial fibrillation recurrence and progression. The effect of other sleep-disturbing conditions on atrial fibrillation progression is not known. We sought to determine whether frequent periodic leg movement during sleep is a risk factor for progression of atrial fibrillation. In this retrospective study, patients with atrial fibrillation and a clinical suspicion of restless legs syndrome who were referred for polysomnography were divided into two groups based on severity of periodic leg movement during sleep: frequent (periodic movement index >35/h) and infrequent (<=35/h). Progression of atrial fibrillation to persistent or permanent forms between the two groups was compared using Wilcoxon rank-sum test, chi-square tests and logistic regression analysis. Of 373 patients with atrial fibrillation (77% paroxysmal, 23% persistent), 108 (29%) progressed to persistent or permanent atrial fibrillation during follow-up (median, 33 months; interquartile range, 16-50). Compared to patients with infrequent periodic leg movement during sleep (n=168), patients with frequent periodic leg movement during sleep (n=205) had a higher rate of atrial fibrillation progression (23% vs. 34%; p=0.01). Patients with frequent periodic leg movement during sleep were older and predominantly male; however, there were no significant differences at baseline in clinical factors that promote atrial fibrillation progression between both groups. On multivariate analysis, independent predictors of atrial fibrillation progression were persistent atrial fibrillation at baseline, female gender, hypertension and frequent periodic leg movement during sleep. In patients with frequent periodic leg movement during sleep, dopaminergic therapy for control of leg movements in patients with restless legs syndrome reduced risk of atrial fibrillation progression. Frequent leg movement during sleep in patients with restless legs syndrome is associated with progression of atrial fibrillation to persistent and permanent forms. PMID- 24147134 TI - Prevalence of diabetes in the Republic of Ireland: results from the National Health Survey (SLAN) 2007. AB - BACKGROUND: Current estimates of diabetes prevalence in the Republic of Ireland (RoI) are based on UK epidemiological studies. This study uses Irish data to describe the prevalence of doctor-diagnosed diabetes amongst all adults aged 18+ years and undiagnosed diabetes amongst those aged 45+ years. METHODS: The survey of lifestyle attitudes and nutrition (SLAN) 2007 is based on a nationally representative sample of Irish adults aged 18+ years (n = 10,364). Self-reported doctor-diagnosed diabetes was recorded for respondents in the full sample. Diabetes medication use, measured height and weight, and non-fasting blood samples were variously recorded in sub-samples of younger (n = 967) and older (n = 1,207) respondents. RESULTS: The prevalence of doctor-diagnosed diabetes amongst adults aged 18+ years was 3.5% (95% CI 3.1%-3.9%). After adjustment for other explanatory variables; the risk of self-reported doctor-diagnosed diabetes was significantly related to age (p < 0.0001), employment status (p = 0.0003) and obesity (p = 0.0003).Amongst adults aged 45+ years, the prevalence of doctor diagnosed diabetes was 6.1% (95% CI 5.3% - 6.9% ) [corrected] and undiagnosed diabetes was 2.8% (95% CI 1.4% - 4.1%). This represented 31.2% of diabetes cases in this age group. CONCLUSION: Notwithstanding methodological differences, these prevalence estimates are consistent with those in the UK and France. However, the percentage of undiagnosed cases amongst adults aged 45+ years appears to be higher in the RoI. Increased efforts to improve early detection and population level interventions to address adverse diet and lifestyle factors are urgently needed. PMID- 24147133 TI - A chitin deacetylase-like protein is a predominant constituent of tick peritrophic membrane that influences the persistence of Lyme disease pathogens within the vector. AB - Ixodes scapularis is the specific arthropod vector for a number of globally prevalent infections, including Lyme disease caused by the bacterium Borrelia burgdorferi. A feeding-induced and acellular epithelial barrier, known as the peritrophic membrane (PM) is detectable in I. scapularis. However, whether or how the PM influences the persistence of major tick-borne pathogens, such as B. burgdorferi, remains largely unknown. Mass spectrometry-based proteome analyses of isolated PM from fed ticks revealed that the membrane contains a few detectable proteins, including a predominant and immunogenic 60 kDa protein with homology to arthropod chitin deacetylase (CDA), herein termed I. scapularis CDA like protein or IsCDA. Although IsCDA is primarily expressed in the gut and induced early during tick feeding, its silencing via RNA interference failed to influence either the occurrence of the PM or spirochete persistence, suggesting a redundant role of IsCDA in tick biology and host-pathogen interaction. However, treatment of ticks with antibodies against IsCDA, one of the most predominant protein components of PM, affected B. burgdorferi survival, significantly augmenting pathogen levels within ticks but without influencing the levels of total gut bacteria. These studies suggested a preferential role of tick PM in limiting persistence of B. burgdorferi within the vector. Further understanding of the mechanisms by which vector components contribute to pathogen survival may help the development of new strategies to interfere with the infection. PMID- 24147135 TI - Estimated glomerular filtration rate, all-cause mortality and cardiovascular diseases incidence in a low risk population: the MATISS study. AB - BACKGROUND: Chronic kidney disease (CKD) independently increases the risk of death and cardiovascular disease (CVD) in the general population. However, the relationship between estimated glomerular filtration rate (eGFR) and CVD/death risk in a general population at low risk of CVD has not been explored so far. DESIGN: Baseline and longitudinal data of 1465 men and 1459 women aged 35-74 years participating to the MATISS study, an Italian general population cohort, were used to evaluate the role of eGFR in the prediction of all-cause mortality and incident CVD. METHODS: Bio-bank stored sera were used to evaluate eGFR at baseline. Serum creatinine was measured on thawed samples by means of an IDMS calibrated enzymatic method. eGFR was calculated by the CKD-EPI formula. RESULTS: At baseline, less than 2% of enrolled persons had eGFR < 60 mL/min/1.73 m(2) and more than 70% had a 10-year cardiovascular risk score < 10%. In people 60 or more years old, the first and the last eGFR quintiles (<90 and >=109 mL/min/1.73 m(2), respectively) were associated to an increased risk for both all-cause mortality (hazard ratio 1.6, 95% confidence interval 1.2-2.1 and 4.3, 1.6-11.7, respectively) and incident CVD (1.6, 1.0-2.4 and 7.0, 2.2-22.9, respectively), even if adjusted for classical risk factors. CONCLUSIONS: These findings strongly suggest that in an elderly, general population at low risk of CVD and low prevalence of reduced renal filtration, even a modest eGFR reduction is related to all-cause mortality and CVD incidence, underlying the potential benefit to this population of considering eGFR for their risk prediction. PMID- 24147136 TI - The short isoform of the ubiquitin ligase NEDD4L is a CREB target gene in hepatocytes. AB - During cycles of fasting and feeding, liver function is regulated by both transcriptional and post-translational events. Regulated protein degradation has recently emerged as a key mechanism to control abundance of specific hepatic proteins under different nutritional conditions. As glucagon signaling through cAMP and PKA is central to glucose output during fasting, we hypothesized that this signaling pathway may also regulate ubiquitin ligases in the fasted state. Here we show that fasting stimuli promote expression of the short isoform of the E3 ubiquitin ligase Nedd4l in primary mouse hepatocytes. Nedd4l-short mRNA and NEDD4L (short isoform) protein accumulate in glucagon-treated primary mouse hepatocytes and in liver tissues during fasting. We identified a functional cAMP response element in the alternate Nedd4l-short promoter; mutation of this element blunts cAMP-induced expression of a Nedd4l reporter construct. CREB occupies the endogenous Nedd4l locus near this element. CREB and its co-activator CRTC2, both activated by fasting stimuli, contribute to glucagon-stimulated Nedd4l-short expression in primary hepatocytes. siRNA-mediated Nedd4l depletion in primary hepatocytes did not affect gluconeogenic gene expression, glucose output or glycogen synthesis. Our findings reveal a new mechanism of Nedd4l transcriptional regulation in liver cells. PMID- 24147137 TI - Conservation value and permeability of neotropical oil palm landscapes for orchid bees. AB - The proliferation of oil palm plantations has led to dramatic changes in tropical landscapes across the globe. However, relatively little is known about the effects of oil palm expansion on biodiversity, especially in key ecosystem service providing organisms like pollinators. Rapid land use change is exacerbated by limited knowledge of the mechanisms causing biodiversity decline in the tropics, particularly those involving landscape features. We examined these mechanisms by undertaking a survey of orchid bees, a well-known group of Neotropical pollinators, across forest and oil palm plantations in Costa Rica. We used chemical baits to survey the community in four regions: continuous forest sites, oil palm sites immediately adjacent to forest, oil palm sites 2 km from forest, and oil palm sites greater than 5 km from forest. We found that although orchid bees are present in all environments, orchid bee communities diverged across the gradient, and community richness, abundance, and similarity to forest declined as distance from forest increased. In addition, mean phylogenetic distance of the orchid bee community declined and was more clustered in oil palm. Community traits also differed with individuals in oil palm having shorter average tongue length and larger average geographic range size than those in the forest. Our results indicate two key features about Neotropical landscapes that contain oil palm: 1) oil palm is selectively permeable to orchid bees and 2) orchid bee communities in oil palm have distinct phylogenetic and trait structure compared to communities in forest. These results suggest that conservation and management efforts in oil palm-cultivating regions should focus on landscape features. PMID- 24147138 TI - Inquiry-based training improves teaching effectiveness of biology teaching assistants. AB - Graduate teaching assistants (GTAs) are used extensively as undergraduate science lab instructors at universities, yet they often have having minimal instructional training and little is known about effective training methods. This blind randomized control trial study assessed the impact of two training regimens on GTA teaching effectiveness. GTAs teaching undergraduate biology labs (n = 52) completed five hours of training in either inquiry-based learning pedagogy or general instructional "best practices". GTA teaching effectiveness was evaluated using: (1) a nine-factor student evaluation of educational quality; (2) a six factor questionnaire for student learning; and (3) course grades. Ratings from both GTAs and undergraduates indicated that indicated that the inquiry-based learning pedagogy training has a positive effect on GTA teaching effectiveness. PMID- 24147139 TI - Improving fatty acid availability for bio-hydrocarbon production in Escherichia coli by metabolic engineering. AB - Previous studies have demonstrated the feasibility of producing fatty-acid derived hydrocarbons in Escherichia coli. However, product titers and yields remain low. In this work, we demonstrate new methods for improving fatty acid production by modifying central carbon metabolism and storing fatty acids in triacylglycerol. Based on suggestions from a computational model, we deleted seven genes involved in aerobic respiration, mixed-acid fermentation, and glyoxylate bypass (in the order of cyoA, nuoA, ndh, adhE, dld, pta, and iclR) to modify the central carbon metabolic/regulatory networks. These gene deletions led to increased total fatty acids, which were the highest in the mutants containing five or six gene knockouts. Additionally, when two key enzymes in the fatty acid biosynthesis pathway were over-expressed, we observed further increase in strain ?cyoA?adhE?nuoA?ndh?pta?dld, leading to 202 mg/g dry cell weight of total fatty acids, ~250% of that in the wild-type strain. Meanwhile, we successfully introduced a triacylglycerol biosynthesis pathway into E. coli through heterologous expression of wax ester synthase/acyl-coenzyme:diacylglycerol acyltransferase (WS/DGAT) enzymes. The added pathway improved both the amount and fuel quality of the fatty acids. These new metabolic engineering strategies are providing promising directions for future investigation. PMID- 24147141 TI - Catechol-O-methyltransferase Val158Met polymorphism modulates gray matter volume and functional connectivity of the default mode network. AB - The effect of catechol-O-methyltransferase (COMT) Val158Met polymorphism on brain structure and function has been previously investigated separately and regionally; this prevents us from obtaining a full picture of the effect of this gene variant. Additionally, gender difference must not be overlooked because estrogen exerts an interfering effect on COMT activity. We examined 323 young healthy Chinese Han subjects and analyzed the gray matter volume (GMV) differences between Val/Val individuals and Met carriers in a voxel-wise manner throughout the whole brain. We were interested in genotype effects and genotype * gender interactions. We then extracted these brain regions with GMV differences as seeds to compute resting-state functional connectivity (rsFC) with the rest of the brain; we also tested the genotypic differences and gender interactions in the rsFCs. Val/Val individuals showed decreased GMV in the posterior cingulate cortex (PCC) compared with Met carriers; decreased GMV in the medial superior frontal gyrus (mSFG) was found only in male Val/Val subjects. The rsFC analysis revealed that both the PCC and mSFG were functionally correlated with brain regions of the default mode network (DMN). Both of these regions showed decreased rsFCs with different parts of the frontopolar cortex of the DMN in Val/Val individuals than Met carriers. Our findings suggest that the COMT Val158Met polymorphism modulates both the structure and functional connectivity within the DMN and that gender interactions should be considered in studies of the effect of this genetic variant, especially those involving prefrontal morphology. PMID- 24147140 TI - Similarity of cortical activity patterns predicts generalization behavior. AB - Humans and animals readily generalize previously learned knowledge to new situations. Determining similarity is critical for assigning category membership to a novel stimulus. We tested the hypothesis that category membership is initially encoded by the similarity of the activity pattern evoked by a novel stimulus to the patterns from known categories. We provide behavioral and neurophysiological evidence that activity patterns in primary auditory cortex contain sufficient information to explain behavioral categorization of novel speech sounds by rats. Our results suggest that category membership might be encoded by the similarity of the activity pattern evoked by a novel speech sound to the patterns evoked by known sounds. Categorization based on featureless pattern matching may represent a general neural mechanism for ensuring accurate generalization across sensory and cognitive systems. PMID- 24147143 TI - Prevalence of the prescription of potentially interacting drugs. AB - The use of multiple medications is becoming more common, with a correspondingly increased risk of untoward effects and drug-related morbidity and mortality. We aimed at estimating the prevalence of prescription of relevant potentially interacting drugs and at evaluating possible predictors of potentially interacting drug exposure. We retrospectively analyzed data on prescriptions dispensed from January 2004 to August 2005 to individuals of two Italian regions with a population of almost 2.1 million individuals. We identified 27 pairs of potentially interacting drugs by examining clinical relevance, documentation, and volume of use in Italy. Subjects who received at least one prescription of both drugs were selected. Co-prescribing denotes "two prescriptions in the same day", and concomitant medication "the prescription of two drugs with overlapping coverage". A logistic regression analysis was conducted to examine the predictors of potential Drug-Drug Interaction (pDDIs). 957,553 subjects (45.3% of study population) were exposed to at least one of the drugs/classes of the 27 pairs. Overall, pDDIs occurred 2,465,819 times. The highest rates of concomitant prescription and of co-prescription were for ACE inhibitors+NSAIDs (6,253 and 4,621/100,000 plan participants). Considering concomitance, the male/female ratio was <1 in 17/27 pairs (from 0.31 for NSAIDs-ASA+SSRI to 0.74 for omeprazole+clopidogrel). The mean age was lowest for methotrexate pairs (+omeprazole, 59.9 years; +NSAIDs-ASA, 59.1 years) and highest for digoxin+verapamil (75.4 years). In 13/27 pairs, the mean ages were >=70 years. On average, subjects involved in pDDIs received >=10 drugs. The odds of exposure were more frequently higher for age >=65 years, males, and those taking a large number of drugs. A substantial number of clinically important pDDIs were observed, particularly among warfarin users. Awareness of the most prevalent pDDIs could help practitioners in preventing concomitant use, resulting in a better quality of drug prescription and potentially avoiding unwanted side effects. PMID- 24147142 TI - Head movements evoked in alert rhesus monkey by vestibular prosthesis stimulation: implications for postural and gaze stabilization. AB - The vestibular system detects motion of the head in space and in turn generates reflexes that are vital for our daily activities. The eye movements produced by the vestibulo-ocular reflex (VOR) play an essential role in stabilizing the visual axis (gaze), while vestibulo-spinal reflexes ensure the maintenance of head and body posture. The neuronal pathways from the vestibular periphery to the cervical spinal cord potentially serve a dual role, since they function to stabilize the head relative to inertial space and could thus contribute to gaze (eye-in-head + head-in-space) and posture stabilization. To date, however, the functional significance of vestibular-neck pathways in alert primates remains a matter of debate. Here we used a vestibular prosthesis to 1) quantify vestibularly-driven head movements in primates, and 2) assess whether these evoked head movements make a significant contribution to gaze as well as postural stabilization. We stimulated electrodes implanted in the horizontal semicircular canal of alert rhesus monkeys, and measured the head and eye movements evoked during a 100 ms time period for which the contribution of longer latency voluntary inputs to the neck would be minimal. Our results show that prosthetic stimulation evoked significant head movements with latencies consistent with known vestibulo-spinal pathways. Furthermore, while the evoked head movements were substantially smaller than the coincidently evoked eye movements, they made a significant contribution to gaze stabilization, complementing the VOR to ensure that the appropriate gaze response is achieved. We speculate that analogous compensatory head movements will be evoked when implanted prosthetic devices are transitioned to human patients. PMID- 24147144 TI - Evaluation of hepatitis A vaccine in post-exposure prophylaxis, The Netherlands, 2004-2012. AB - BACKGROUND: The secondary attack rate of hepatitis A virus (HAV) among contacts of cases is up to 50%. Historically, contacts were offered immunoglobulin (IG, a human derived blood product) as post-exposure prophylaxis (PEP). Amid safety concerns about IG, HAV vaccine is increasingly recommended instead. Public health authorities' recommendations differ, particularly for healthy contacts >=40 years old, where vaccine efficacy data is limited. We evaluated routine use of HAV vaccine as an alternative to immunoglobulin in PEP, in those considered at low risk of severe infection in the Netherlands. METHODS: Household contacts of acute HAV cases notified in Amsterdam (2004-2012) were invited <=14 days post-exposure, for baseline anti-HAV testing and PEP according to national guidelines: immunoglobulin if at risk of severe infection, or hepatitis A vaccine if healthy and at low risk (aged <30, or, 30-50 years and vaccinated <8 days post-exposure). Incidence of laboratory confirmed secondary infection in susceptible contacts was assessed 4-8 weeks post-exposure. In a vaccinated subgroup, relative risk (RR) of secondary infection with estimated using Poisson regression. RESULTS: Of 547 contacts identified, 191 were susceptible to HAV. Per-protocol, 167 (87%) were vaccinated (mean:6.7 days post-exposure, standard deviation(sd)=3.3) and 24 (13%) were given immunoglobulin (mean: 9.7 days post-exposure, sd=2.8). At follow-up testing, 8/112 (7%) had a laboratory confirmed infection of whom 7 were symptomatic. All secondary infections occurred in vaccinated contacts, and half were >40 years of age. In healthy contacts vaccinated per-protocol <=8 days post exposure, RR(ref. <=15 years) of secondary infection in those >40 years was 12.0 (95%CI:1.3-106.7). CONCLUSIONS: Timely administration of HAV vaccine in PEP was feasible and the secondary attack rate was low in those <40 years. Internationally, upper age-limits for post-exposure vaccination vary. Pending larger studies, immunoglobulin should be considered PEP of choice in people >40 years of age and those vulnerable to severe disease. PMID- 24147145 TI - Effect of temperature on crossbridge force changes during fatigue and recovery in intact mouse muscle fibers. AB - Repetitive or prolonged muscle contractions induce muscular fatigue, defined as the inability of the muscle to maintain the initial tension or power output. In the present experiments, made on intact fiber bundles from FDB mouse, fatigue and recovery from fatigue were investigated at 24 degrees C and 35 degrees C. Force and stiffness were measured during tetani elicited every 90 s during the pre fatigue control phase and recovery and every 1.5 s during the fatiguing phase made of 105 consecutive tetani. The results showed that force decline could be split in an initial phase followed by a later one. Loss of force during the first phase was smaller and slower at 35 degrees C than at 24 degrees C, whereas force decline during the later phase was greater at 35 degrees C so that total force depression at the end of fatigue was the same at both temperatures. The initial force decline occurred without great reduction of fiber stiffness and was attributed to a decrease of the average force per attached crossbridge. Force decline during the later phase was accompanied by a proportional stiffness decrease and was attributed to a decrease of the number of attached crossbridge. Similarly to fatigue, at both 24 and 35 degrees C, force recovery occurred in two phases: the first associated with the recovery of the average force per attached crossbridge and the second due to the recovery of the pre-fatigue attached crossbridge number. These changes, symmetrical to those occurring during fatigue, are consistent with the idea that, i) initial phase is due to the direct fast inhibitory effect of [Pi]i increase during fatigue on crossbridge force; ii) the second phase is due to the delayed reduction of Ca(2+) release and /or reduction of the Ca(2+) sensitivity of the myofibrils due to high [Pi]i. PMID- 24147146 TI - Fine-tuning the antimicrobial profile of biocompatible gold nanoparticles by sequential surface functionalization using polyoxometalates and lysine. AB - Antimicrobial action of nanomaterials is typically assigned to the nanomaterial composition, size and/or shape, whereas influence of complex corona stabilizing the nanoparticle surface is often neglected. We demonstrate sequential surface functionalization of tyrosine-reduced gold nanoparticles (AuNPs(Tyr)) with polyoxometalates (POMs) and lysine to explore controlled chemical functionality driven antimicrobial activity. Our investigations reveal that highly biocompatible gold nanoparticles can be tuned to be a strong antibacterial agent by fine-tuning their surface properties in a controllable manner. The observation from the antimicrobial studies on a gram negative bacterium Escherichia coli were further validated by investigating the anticancer properties of these step-wise surface-controlled materials against A549 human lung carcinoma cells, which showed a similar toxicity pattern. These studies highlight that the nanomaterial toxicity and biological applicability are strongly governed by their surface corona. PMID- 24147147 TI - Effect of orthostasis on endothelial function: a gender comparative study. AB - As the vascular endothelium has multiple functions, including regulation of vascular tone, it may play a role in the pathophysiology of orthostatic intolerance. We investigated the effect of orthostasis on endothelial function using EndoPAT(r), a non-invasive and user-independent method, and across gender. As sex steroid hormones are known to affect endothelial function, this study examined the potential effect of these hormones on the endothelial response to orthostasis by including females at different phases of the menstrual cycle (follicular and luteal-where the hormone balance differs), and females taking an oral contraceptive. A total of 31 subjects took part in this study (11 males, 11 females having normal menstrual cycles and 9 females taking oral contraceptive). Each subject made two visits for testing; in the case of females having normal menstrual cycles the first session was conducted either 1-7 (follicular) or 14-21 days (luteal) after the start of menstruation, and the second session two weeks later, i.e., during the other phase, respectively. Endothelial function was assessed at baseline and following a 20-min orthostatic challenge (active standing). The EndoPAT(r) index increased from 1.71 +/- 0.09 (mean +/- SEM) at baseline to 2.07 +/- 0.09 following orthostasis in females (p<0.001). In males, the index increased from 1.60 +/- 0.08 to 1.94 +/- 0.13 following orthostasis (p<0.001). There were no significant differences, however, in the endothelial response to orthostasis between females and males, menstrual cycle phases and the usage of oral contraceptive. Our results suggest an increased vasodilatatory endothelial response following orthostasis in both females and males. The effect of gender and sex hormones on the endothelial response to orthostasis appears limited. Further studies are needed to determine the potential role of this post orthostasis endothelial response in the pathophysiology of orthostatic intolerance. PMID- 24147148 TI - The impacts of albuminuria and low eGFR on the risk of cardiovascular death, all cause mortality, and renal events in diabetic patients: meta-analysis. AB - BACKGROUND: Precise effects of albuminuria and low estimated glomerular filtration rate (eGFR) on cardiovascular mortality, all-cause mortality, and renal events in diabetic patients are uncertain. MATERIALS AND METHODS: A systematic review was conducted of the literature through MEDLINE, EMBASE, and CINHAL from 1950 to December 2010. Cohort studies of diabetic patients providing adjusted relative risk (RR) of albuminuria and eGFR for risks of cardiovascular mortality, all-cause mortality, and renal events were selected. Two reviewers screened abstracts and full papers of each study using standardized protocol. RESULTS: We identified 31 studies fulfilling the criteria from 6546 abstracts. With regard to the risk of cardiovascular mortality, microalbuminuria (RR 1.76, 95%CI 1.38-2.25) and macroalbuminuria (RR 2.96 95%CI 2.44-3.60) were significant risk factors compared to normoalbuminuria. The same trends were seen in microalbuminuria (RR 1.60, 95%CI 1.42-1.81), and macroalbuminuria (RR 2.64, 95%CI 2.13-3.27) for the risk of all-cause mortality, and also in microalbuminuria (RR 3.21, 95%CI 2.05-5.02) and macroalbuminuria (RR 11.63, 95%CI 5.68-23.83) for the risk of renal events. The magnitudes of relative risks associated with low eGFR along with albuminuria were almost equal to multiplying each risk rate of low eGFR and albuminuria. No significant factors were found by investigating potential sources of heterogeneity using subgroup analysis. CONCLUSIONS: High albuminuria and low eGFR are relevant risk factors in diabetic patients. Albuminuria and low eGFR may be independent of each other. To evaluate the effects of low eGFR, intervention, or race, appropriately designed studies are needed. PMID- 24147150 TI - What happened if various kinds of postconditioning working on the preconditioned ischemic skin flaps. AB - OBJECTIVE: Ischemic pre-conditioning and post-conditioning are useful manipulations to reduce the undesirable effects of ischemia-reperfusion skin flap each. But the impact of post-conditioning on the pre-conditioning skin flap is not manifested. Here we investigated the influence of ischemic post-conditioning in a preconditioned axial pattern skin flap model. METHOD: We used the skin flap in 40 rabbits and divided them into 5 groups randomly. At first we induced the ischemic pre-conditioning of the flap which was applied by 2 periods of 15 minutes of ischemia/15 minutes of reperfusion cycle. Next post-conditioning was performed by 6 cycles of 10 seconds of repeated ischemia/reperfusion periods at different times of just after the reperfusion,5 minutes after the reperfusion,10 minutes after the reperfusion. The animals were allocated into 5 groups: group 1 (Ischemia Group); group 2: (Pre-conditioning Group); group 3: (Pre-conditioning+ Post-conditioning Group); group 4 (Pre-conditioning+ Post-conditioning 5 minutes later Group); group 5 (Pre-conditioning+ Post-conditioning 10 minutes later). The neutrophil count was assessed with histologic analysis before the dissection of the skin flap. Flap viability was assessed 1 week after the operation, and surviving flap area was recorded as a percentage of the whole flap area. LSD test was used for statistical analysis among different groups to evaluate the effects of ischemic pre-conditioning against ischemia. RESULT: Among the varying groups, the neutrophil count varied: Group 1 was 50.12 +/- 5.91; Group 2, 30.00 +/- 2.00, and Group 3, 18.87 +/- 3; Group 4, 22.50 +/- 1.92; Group 5, 30.12 +/- 1.88.The mean +/- SD surviving areas of the flaps for groups 1, 2, 3, 4 and 5 were 31.76 +/- 4.59, 51.26 +/- 3.24,82.18 +/- 5.28,66.85 +/- 3.87 and 51.13 +/- 2.90 respectively. Spearman correlation analysis shows an increase relation between neutrophil count and flap survival rate in the different groups (P <0.05). CONCLUSION: Ischemic post-conditioning has protective effect on ischemic preconditioned skin flaps, but the post-conditioning should be performed within 5 minutes after the end of ischemia. PMID- 24147149 TI - Preserved cardiac function despite marked impairment of cAMP generation. AB - OBJECTIVES: So many clinical trials of positive inotropes have failed, that it is now axiomatic that agents that increase cAMP are deleterious to the failing heart. An alternative strategy is to alter myocardial Ca(2+) handling or myofilament response to Ca(2+) using agents that do not affect cAMP. Although left ventricular (LV) function is tightly linked to adenylyl cyclase (AC) activity, the beneficial effects of AC may be independent of cAMP and instead stem from effects on Ca(2+) handling. Here we ask whether an AC mutant molecule that reduces LV cAMP production would have favorable effects on LV function through its effects on Ca(2+) handling alone. METHODS AND RESULTS: We generated transgenic mice with cardiac-directed expression of an AC6 mutant (AC6mut). Cardiac myocytes showed impaired cAMP production in response to isoproterenol (74% reduction; p<0.001), but LV size and function were normal. Isolated hearts showed preserved LV function in response to isoproterenol stimulation. AC6mut expression was associated with increased sarcoplasmic reticulum Ca(2+) uptake and the EC50 for SERCA2a activation was reduced. Cardiac myocytes isolated from AC6mut mice showed increased amplitude of Ca(2+) transients in response to isoproterenol (p = 0.0001). AC6mut expression also was associated with increased expression of LV S100A1 (p = 0.03) and reduced expression of phospholamban protein (p = 0.01). CONCLUSION: LV AC mutant expression is associated with normal cardiac function despite impaired cAMP generation. The mechanism appears to be through effects on Ca(2+) handling - effects that occur despite diminished cAMP. PMID- 24147151 TI - HIV infection and testing among Latino men who have sex with men in the United States: the role of location of birth and other social determinants. AB - BACKGROUND: In the United States, Latino men who have sex with men (MSM) are disproportionately affected by HIV. Latino MSM are a diverse group who differ culturally based on their countries or regions of birth and their time in the United States. We assessed differences in HIV prevalence and testing among Latino MSM by location of birth, time since arrival, and other social determinants of health. METHODS: For the 2008 National HIV Behavioral Surveillance System, a cross-sectional survey conducted in large US cities, MSM were interviewed and tested for HIV infection. We used generalized estimating equations to test associations between various factors and 1) prevalent HIV infection and 2) being tested for HIV infection in the past 12 months. RESULTS: Among 1734 Latino MSM, HIV prevalence was 19%. In multivariable analysis, increasing age, low income, and gay identity were associated with HIV infection. Moreover, men who were U.S. born or who arrived >=5 years ago had significantly higher HIV prevalence than recent immigrants. Among men not reporting a previous positive HIV test, 63% had been tested for HIV infection in the past 12 months; recent testing was most strongly associated with having seen a health care provider and disclosing male male attraction/sexual behavior to a health care provider. CONCLUSIONS: We identified several social determinants of health associated with HIV infection and testing among Latino MSM. Lower HIV prevalence among recent immigrants contrasts with higher prevalence among established immigrants and suggests a critical window of opportunity for HIV prevention, which should prioritize those with low income, who are at particular risk for HIV infection. Expanding health care utilization and encouraging communication with health care providers about sexual orientation may increase testing. PMID- 24147152 TI - Aldh1-expressing endocrine progenitor cells regulate secondary islet formation in larval zebrafish pancreas. AB - Aldh1 expression is known to mark candidate progenitor populations in adult and embryonic mouse pancreas, and Aldh1 enzymatic activity has been identified as a potent regulator of pancreatic endocrine differentiation in zebrafish. However, the location and identity of Aldh1-expressing cells in zebrafish pancreas remain unknown. In this study we demonstrate that Aldh1-expressing cells are located immediately adjacent to 2F11-positive pancreatic ductal epithelial cells, and that their abundance dramatically increases during zebrafish secondary islet formation. These cells also express neurod, a marker of endocrine progenitor cells, but do not express markers of more mature endocrine cells such as pax6b or insulin. Using formal cre/lox-based lineage tracing, we further show that Aldh1 expressing pancreatic epithelial cells are the direct progeny of pancreatic notch responsive progenitor cells, identifying them as a critical intermediate between multi-lineage progenitors and mature endocrine cells. Pharmacologic manipulation of Aldh1 enzymatic activity accelerates cell entry into the Aldh1-expressing endocrine progenitor pool, and also leads to the premature maturation of these cells, as evidenced by accelerated pax6b expression. Together, these findings suggest that Aldh1-expressing cells act as both participants and regulators of endocrine differentiation during zebrafish secondary islet formation. PMID- 24147153 TI - MiR-221/222 target the DNA methyltransferase MGMT in glioma cells. AB - Glioblastoma multiforme (GBM) is one of the most deadly types of cancer. To date, the best clinical approach for treatment is based on administration of temozolomide (TMZ) in combination with radiotherapy. Much evidence suggests that the intracellular level of the alkylating enzyme O(6)-methylguanine-DNA methyltransferase (MGMT) impacts response to TMZ in GBM patients. MGMT expression is regulated by the methylation of its promoter. However, evidence indicates that this is not the only regulatory mechanism present. Here, we describe a hitherto unknown microRNA-mediated mechanism of MGMT expression regulation. We show that miR-221 and miR-222 are upregulated in GMB patients and that these paralogues target MGMT mRNA, inducing greater TMZ-mediated cell death. However, miR-221/miR 222 also increase DNA damage and, thus, chromosomal rearrangements. Indeed, miR 221 overexpression in glioma cells led to an increase in markers of DNA damage, an effect rescued by re-expression of MGMT. Thus, chronic miR-221/222-mediated MGMT downregulation may render cells unable to repair genetic damage. This, associated also to miR-221/222 oncogenic potential, may poor GBM prognosis. PMID- 24147154 TI - Effectiveness of educational poster on knowledge of emergency management of dental trauma-part 1. Cluster randomised controlled trial for primary and secondary school teachers. AB - OBJECTIVE: To investigate the effectiveness of educational posters in improving the knowledge level of primary and secondary school teachers regarding emergency management of dental trauma. METHODS: A cluster randomised controlled trial was conducted. 32 schools with a total of 515 teachers were randomised into intervention (poster) and control groups at the school level. Teachers' baseline levels of knowledge about dental trauma were obtained by using a questionnaire. Posters containing information on dental trauma management were displayed in the school medical room, the common room used by staff, and on a notice board for 2 weeks in each school of the intervention group; in the control group, no posters were displayed. Teachers in both groups completed the questionnaire after 2 weeks. RESULTS: The teachers in the intervention schools (where posters were displayed for 2 weeks) showed statistically significant improvement in scores in cases where they had not previously learned about dental emergencies from sources other than first aid training, with an average score increase of 2.6656 (score range of questionnaire, -13 to 9; p-value <0.0001). CONCLUSION: Educational posters on the management of dental trauma can significantly improve the level of knowledge of primary and secondary school teachers in Hong Kong. KClinicalTrials.com HKCTR-1307 ClinicalTrials.gov: NCT01707355. PMID- 24147155 TI - The impact of Down syndrome screening on Taiwanese Down syndrome births: a nationwide retrospective study and a screening result from a single medical centre. AB - A retrospective analysis of the Taiwanese National Birth Defect Registration and Notification System was conducted in order to determine the live birth- and stillbirth rates in infants with Down syndrome, trisomy 18, trisomy 13 and Turner syndrome between 2001 and 2010. The objective was to investigate the impact of Down syndrome screening on the Taiwanese Down syndrome live birth rate. In addition, the results of first-trimester Down syndrome screening between 2006 and 2011, and of second-trimester quadruple testing between 2008 and 2011, were obtained from the National Taiwan University Hospital. All Taiwanese infants born between 2001 and 2010 were included in the first part of the analysis, and women receiving first-trimester Down syndrome screening or second-trimester quadruple testing from the National Taiwan University Hospital were included in the second part. The live birth rate of infants with Down syndrome, per 100 000 live births, decreased from 22.28 in 2001 to 7.79 in 2010. The ratio of liveborn DS to total DS was 48.74% in 2001, and then decreased to 25.88% in 2006, when first-trimester screening was widely introduced in Taiwan. This ratio dropped to 20.64% in 2008, when the second-trimester quadruple test was implemented. The overall positive rate in first-trimester screening in the National Taiwan University Hospital was 3.1%, with a Down syndrome detection rate of 100%; the quadruple test had values of 9.0% and 75%, respectively. The use of first-trimester screening and the second-trimester quadruple test may be responsible for the marked decrease in the Taiwanese Down syndrome live birth rate observed between 2001 and 2010. PMID- 24147157 TI - Bile duct involvement portends poor prognosis in resected gallbladder carcinoma. AB - BACKGROUND: Gallbladder cancer (GBC) carries an unfavorable prognosis with high mortality. This retrospective study was conducted to identify prognostic factors after resection of GBC, to assist in selecting appropriate surgical and adjuvant therapy. METHODS: Sixty-two patients from two institutions were identified with GBC by pathology. In 25, the cancer was unresectable at presentation. The remaining 37 patients comprised the study population. Log-rank analysis was used to assess univariate association with disease-free survival (DFS) and disease specific survival (DSS). Cox regression was used for multivariate analysis. RESULTS: Median DFS and DSS were 22.6 and 28.5 months respectively, with a median follow-up of 44.2 months. On univariate analysis, bile duct (BD) involvement was significantly associated with decreased DFS (P <= .001) and DSS (P = .004). BD involvement was uniformly fatal. LN involvement was not significantly associated with DFS or DSS (P = .85, P = .54). CONCLUSIONS: All patients with BD involvement in our population died of the disease. The subset of patients with resectable GBC and BD involvement is a group that is at high risk for recurrence and should be treated as such. In our small population, preoperative and intraoperative methods evaluating BD involvement were unreliable. PMID- 24147156 TI - Reconstitution of membrane protein complexes involved in pneumococcal septal cell wall assembly. AB - The synthesis of peptidoglycan, the major component of the bacterial cell wall, is essential to cell survival, yet its mechanism remains poorly understood. In the present work, we have isolated several membrane protein complexes consisting of the late division proteins of Streptococcus pneumoniae: DivIB, DivIC, FtsL, PBP2x and FtsW, or subsets thereof. We have co-expressed membrane proteins from S. pneumoniae in Escherichia coli. By combining two successive affinity chromatography steps, we obtained membrane protein complexes with a very good purity. These complexes are functional, as indicated by the retained activity of PBP2x to bind a fluorescent derivative of penicillin and to hydrolyze the substrate analogue S2d. Moreover, we have evidenced the stabilizing role of protein-protein interactions within each complex. This work paves the way for a complete reconstitution of peptidoglycan synthesis in vitro, which will be critical to the elucidation of its intricate regulation mechanisms. PMID- 24147158 TI - A Possible Role for TNF-alpha in Coordinating Inflammation and Angiogenesis in Chronic Liver Disease and Hepatocellular Carcinoma. AB - BACKGROUND: Increasing evidence supports the hypothesis that chronic and persistent inflammation contributes to cancer development. However, the molecular mechanisms that lead to cancer in chronic inflammation and the role of angiogenesis in inflammation-associated cancer remain poorly understood. METHODS: NINETY PATIENTS WERE ENROLLED: 30 cases of CHC without cirrhosis, 28 cases of CHC with liver cirrhosis, and 32 cases of HCC and hepatitis C virus infection. Ten wedge liver biopsies, taken during laparoscopic cholecystectomy, served as normal controls. Serum TNF-alpha levels were measured using the ELISA technique; in situ hybridization and immunohistochemical studies were used to detect hepatic levels of messenger RNA (mRNA) transcripts and mature protein, respectively, for both TNF-alpha and VEGF. RESULTS: The highest hepatic expression of TNF-alpha was noticed in liver cirrhosis specimens compared to noncirrhotic CHC and HCC. Hepatic expression of VEGF and serum level of TNF-alpha revealed significant increases in the progression of the disease. Moreover, cases with higher grades of inflammation or stages of fibrosis showed significant increases in serum TNF alpha and expression of TNF-alpha and VEGF. Expression of mRNA of both TNF-alpha and VEGF shows increasing expression with positive correlation to progression of viral hepatitis to cirrhosis with more positivity in cases developed HCC. CONCLUSIONS: VEGF signaling could be one of the molecular signaling pathways involved in TNF-alpha induced angiogenesis which might pose an important link between inflammation and fibrosis in CHC and HCC development and progression. Moreover, serum inflammatory biomarkers can be used to monitor the disease progression. PMID- 24147159 TI - Modified GTX as Second-Line Chemotherapy in Advanced Pancreatic Cancer. PMID- 24147160 TI - Successful retreatment with chemoradiotherapy for local recurrence of pancreatic adenocarcinoma after neoadjuvant therapy and pancreaticoduodenectomy. PMID- 24147163 TI - Upcoming articles. PMID- 24147161 TI - A Case Report of an Extraintestinal GIST Presenting as a Giant Abdominopelvic Tumor. PMID- 24147164 TI - First outbreak response using an oral cholera vaccine in Africa: vaccine coverage, acceptability and surveillance of adverse events, Guinea, 2012. AB - BACKGROUND: Despite World Health Organization (WHO) prequalification of two safe and effective oral cholera vaccines (OCV), concerns about the acceptability, potential diversion of resources, cost and feasibility of implementing timely campaigns has discouraged their use. In 2012, the Ministry of Health of Guinea, with the support of Medecins Sans Frontieres organized the first mass vaccination campaign using a two-dose OCV (Shanchol) as an additional control measure to respond to the on-going nationwide epidemic. Overall, 316,250 vaccines were delivered. Here, we present the results of vaccination coverage, acceptability and surveillance of adverse events. METHODOLOGY/PRINCIPAL FINDINGS: We performed a cross-sectional cluster survey and implemented adverse event surveillance. The study population included individuals older than 12 months, eligible for vaccination, and residing in the areas targeted for vaccination (Forecariah and Boffa, Guinea). Data sources were household interviews with verification by vaccination card and notifications of adverse events from surveillance at vaccination posts and health centres. In total 5,248 people were included in the survey, 3,993 in Boffa and 1,255 in Forecariah. Overall, 89.4% [95%CI:86.4-91.8%] and 87.7% [95%CI:84.2-90.6%] were vaccinated during the first round and 79.8% [95%CI:75.6-83.4%] and 82.9% [95%CI:76.6-87.7%] during the second round in Boffa and Forecariah respectively. The two dose vaccine coverage (including card and oral reporting) was 75.8% [95%CI: 71.2-75.9%] in Boffa and 75.9% [95%CI: 69.8 80.9%] in Forecariah respectively. Vaccination coverage was higher in children. The main reason for non-vaccination was absence. No severe adverse events were notified. CONCLUSIONS/SIGNIFICANCE: The well-accepted mass vaccination campaign reached high coverage in a remote area with a mobile population. Although OCV should not be foreseen as the long-term solution for global cholera control, they should be integrated as an additional tool into the response. PMID- 24147166 TI - How to improve the early diagnosis of Trypanosoma cruzi infection: relationship between validated conventional diagnosis and quantitative DNA amplification in congenitally infected children. AB - BACKGROUND: According to the Chagas congenital transmission guides, the diagnosis of infants, born to Trypanosoma cruzi infected mothers, relies on the detection of parasites by INP micromethod, and/or the persistence of T. cruzi specific antibody titers at 10-12 months of age. METHODOLOGY AND PRINCIPAL FINDINGS: Parasitemia levels were quantified by PCR in T. cruzi-infected children, grouped according to the results of one-year follow-up diagnosis: A) Neonates that were diagnosed in the first month after delivery by microscopic blood examination (INP micromethod) (n = 19) had a median parasitemia of 1,700 Pe/mL (equivalent amounts of parasite DNA per mL); B) Infants that required a second parasitological diagnosis at six months of age (n = 10) showed a median parasitemia of around 20 Pe/mL and 500 Pe/mL at 1 and 6 months old, respectively, and C) babies with undetectable parasitemia by three blood microscopic observations but diagnosed by specific anti - T. cruzi serology at around 1 year old, (n = 22), exhibited a parasitemia of around 5 Pe/mL, 800 Pe/mL and 20 Pe/mL 1, 6 and 12 month after delivery, respectively. T. cruzi parasites were isolated by hemoculture from 19 congenitally infected children, 18 of which were genotypified as DTU TcV, (former lineage TcIId) and only one as TcI. SIGNIFICANCE: This report is the first to quantify parasitemia levels in more than 50 children congenitally infected with T. cruzi, at three different diagnostic controls during one-year follow-up after delivery. Our results show that the parasite burden in some children (22 out of 51) is below the detection limit of the INP micromethod. As the current trypanocidal treatment proved to be very effective to cure T. cruzi - infected children, more sensitive parasitological methods should be developed to assure an early T. cruzi congenital diagnosis. PMID- 24147165 TI - Elimination of schistosomiasis transmission in Zanzibar: baseline findings before the onset of a randomized intervention trial. AB - BACKGROUND: Gaining and sustaining control of schistosomiasis and, whenever feasible, achieving local elimination are the year 2020 targets set by the World Health Organization. In Zanzibar, various institutions and stakeholders have joined forces to eliminate urogenital schistosomiasis within 5 years. We report baseline findings before the onset of a randomized intervention trial designed to assess the differential impact of community-based praziquantel administration, snail control, and behavior change interventions. METHODOLOGY: In early 2012, a baseline parasitological survey was conducted in ~20,000 people from 90 communities in Unguja and Pemba. Risk factors for schistosomiasis were assessed by administering a questionnaire to adults. In selected communities, local knowledge about schistosomiasis transmission and prevention was determined in focus group discussions and in-depths interviews. Intermediate host snails were collected and examined for shedding of cercariae. PRINCIPAL FINDINGS: The baseline Schistosoma haematobium prevalence in school children and adults was 4.3% (range: 0-19.7%) and 2.7% (range: 0-26.5%) in Unguja, and 8.9% (range: 0 31.8%) and 5.5% (range: 0-23.4%) in Pemba, respectively. Heavy infections were detected in 15.1% and 35.6% of the positive school children in Unguja and Pemba, respectively. Males were at higher risk than females (odds ratio (OR): 1.45; 95% confidence interval (CI): 1.03-2.03). Decreasing adult age (OR: 1.04; CI: 1.02 1.06), being born in Pemba (OR: 1.48; CI: 1.02-2.13) or Tanzania (OR: 2.36; CI: 1.16-4.78), and use of freshwater (OR: 2.15; CI: 1.53-3.03) showed higher odds of infection. Community knowledge about schistosomiasis was low. Only few infected Bulinus snails were found. CONCLUSIONS/SIGNIFICANCE: The relatively low S. haematobium prevalence in Zanzibar is a promising starting point for elimination. However, there is a need to improve community knowledge about disease transmission and prevention. Control measures tailored to the local context, placing particular attention to hot-spot areas, high-risk groups, and individuals, will be necessary if elimination is to be achieved. PMID- 24147169 TI - Barriers to treatment access for Chagas disease in Mexico. AB - BACKGROUND: According to World Health Organization (WHO) prevalence estimates, 1.1 million people in Mexico are infected with Trypanosoma cruzi, the etiologic agent of Chagas disease (CD). However, limited information is available about access to antitrypanosomal treatment. This study assesses the extent of access in Mexico, analyzes the barriers to access, and suggests strategies to overcome them. METHODS AND FINDINGS: Semi-structured in-depth interviews were conducted with 18 key informants and policymakers at the national level in Mexico. Data on CD cases, relevant policy documents and interview data were analyzed using the Flagship Framework for Pharmaceutical Policy Reform policy interventions: regulation, financing, payment, organization, and persuasion. Data showed that 3,013 cases were registered nationally from 2007-2011, representing 0.41% of total expected cases based on Mexico's national prevalence estimate. In four of five years, new registered cases were below national targets by 11-36%. Of 1,329 cases registered nationally in 2010-2011, 834 received treatment, 120 were pending treatment as of January 2012, and the treatment status of 375 was unknown. The analysis revealed that the national program mainly coordinated donation of nifurtimox and that important obstacles to access include the exclusion of antitrypanosomal medicines from the national formulary (regulation), historical exclusion of CD from the social insurance package (organization), absence of national clinical guidelines (organization), and limited provider awareness (persuasion). CONCLUSIONS: Efforts to treat CD in Mexico indicate an increased commitment to addressing this disease. Access to treatment could be advanced by improving the importation process for antitrypanosomal medicines and adding them to the national formulary, increasing education for healthcare providers, and strengthening clinical guidelines. These recommendations have important implications for other countries in the region with similar problems in access to treatment for CD. PMID- 24147168 TI - Ongoing spillover of Hantaan and Gou hantaviruses from rodents is associated with hemorrhagic fever with renal syndrome (HFRS) in China. AB - BACKGROUND: Longquan City, Zhejiang province, China, has been seriously affected by hemorrhagic fever with renal syndrome (HFRS) since the first cases were registered in 1974. To understand the epidemiology and emergence of HFRS in Longquan, which may be indicative of large parts of rural China, we studied long term incidence patterns and performed a molecular epidemiological investigation of the causative hantaviruses in human and rodent populations. METHOD/PRINCIPAL FINDINGS: During 1974-2011, 1866 cases of HFRS were recorded in Longquan, including 20 deaths. In 2011, the incidence of HFRS remained high, with 19.61 cases/100,000 population, despite the onset of vaccination in 1997. During 1974 1998, HFRS cases in Longquan occurred mainly in winter, while in the past decade the peak of HFRS has shifted to the spring. Notably, the concurrent prevalence of rodent-borne hantaviruses in the region was also high. Phylogenetic analyses of viral sequences recovered from rodents in Longquan revealed the presence of novel genetic variants of Gou virus (GOUV) in Rattus sp. rats and Hantaan virus (HTNV) in the stripe field mice, respectively. Strikingly, viral sequences sampled from infected humans were very closely related to those from rodents. CONCLUSIONS/SIGNIFICANCE: HFRS represents an important public health problem in Longquan even after years of preventive measures. Our data suggest that continual spillover of the novel genetic variant of GOUV and the new genetic lineage of HTNV are responsible for the high prevalence of HFRS in humans. In addition, this is the first report of GOUV associated with human HFRS cases, and our data suggest that GOUV is now the major cause of HFRS in this region. PMID- 24147167 TI - Cellular growth and mitochondrial ultrastructure of leishmania (Viannia) braziliensis promastigotes are affected by the iron chelator 2,2-dipyridyl. AB - BACKGROUND: Iron is an essential element for the survival of microorganisms in vitro and in vivo, acting as a cofactor of several enzymes and playing a critical role in host-parasite relationships. Leishmania (Viannia) braziliensis is a parasite that is widespread in the new world and considered the major etiological agent of American tegumentary leishmaniasis. Although iron depletion leads to promastigote and amastigote growth inhibition, little is known about the role of iron in the biology of Leishmania. Furthermore, there are no reports regarding the importance of iron for L. (V.) braziliensis. METHODOLOGY/PRINCIPAL FINDINGS: In this study, the effect of iron on the growth, ultrastructure and protein expression of L. (V.) braziliensis was analyzed by the use of the chelator 2,2 dipyridyl. Treatment with 2,2-dipyridyl affected parasites' growth in a dose- and time-dependent manner. Multiplication of the parasites was recovered after reinoculation in fresh culture medium. Ultrastructural analysis of treated promastigotes revealed marked mitochondrial swelling with loss of cristae and matrix and the presence of concentric membranar structures inside the organelle. Iron depletion also induced Golgi disruption and intense cytoplasmic vacuolization. Fluorescence-activated cell sorting analysis of tetramethylrhodamine ester-stained parasites showed that 2,2-dipyridyl collapsed the mitochondrial membrane potential. The incubation of parasites with propidium iodide demonstrated that disruption of mitochondrial membrane potential was not associated with plasma membrane permeabilization. TUNEL assays indicated no DNA fragmentation in chelator-treated promastigotes. In addition, two-dimensional electrophoresis showed that treatment with the iron chelator induced up- or down regulation of proteins involved in metabolism of nucleic acids and coordination of post-translational modifications, without altering their mRNA levels. CONCLUSIONS: Iron chelation leads to a multifactorial response that results in cellular collapse, starting with the interruption of cell proliferation and culminating in marked mitochondrial impairment in some parasites and their subsequent cell death, whereas others may survive and resume proliferating. PMID- 24147170 TI - Human neutrophil peptide-1 (HNP-1): a new anti-leishmanial drug candidate. AB - The toxicity of available drugs for treatment of leishmaniasis, coupled with emerging drug resistance, make it urgent to find new therapies. Antimicrobial peptides (AMPs) have a strong broad-spectrum antimicrobial activity with distinctive modes of action and are considered as promising therapeutic agents. The defensins, members of the large family of AMPs, are immunomodulatory molecules and important components of innate immune system. Human neutrophil peptide-1 (HNP-1), which is produced by neutrophils, is one of the most potent defensins. In this study, we described anti-parasitic activity of recombinant HNP 1 (rHNP-1) against Leishmania major promastigotes and amastigotes. Furthermore, we evaluated the immunomodulatory effect of rHNP-1 on parasite-infected neutrophils and how neutrophil apoptosis was affected. Our result showed that neutrophils isolated from healthy individuals were significantly delayed in the onset of apoptosis following rHNP-1 treatment. Moreover, there was a noteworthy increase in dying cells in rHNP-1- and/or CpG-treated neutrophils in comparison with untreated cells. There is a considerable increase in TNF-alpha production from rHNP-1-treated neutrophils and decreased level of TGF-beta concentration, a response that should potentiate the immune system against parasite invasion. In addition, by using real-time polymerase chain reaction (real-time PCR), we showed that in vitro infectivity of Leishmania into neutrophils is significantly reduced following rHNP-1 treatment compared to untreated cells. PMID- 24147171 TI - Exploring the Trypanosoma brucei Hsp83 potential as a target for structure guided drug design. AB - Human African trypanosomiasis is a neglected parasitic disease that is fatal if untreated. The current drugs available to eliminate the causative agent Trypanosoma brucei have multiple liabilities, including toxicity, increasing problems due to treatment failure and limited efficacy. There are two approaches to discover novel antimicrobial drugs--whole-cell screening and target-based discovery. In the latter case, there is a need to identify and validate novel drug targets in Trypanosoma parasites. The heat shock proteins (Hsp), while best known as cancer targets with a number of drug candidates in clinical development, are a family of emerging targets for infectious diseases. In this paper, we report the exploration of T. brucei Hsp83--a homolog of human Hsp90--as a drug target using multiple biophysical and biochemical techniques. Our approach included the characterization of the chemical sensitivity of the parasitic chaperone against a library of known Hsp90 inhibitors by means of differential scanning fluorimetry (DSF). Several compounds identified by this screening procedure were further studied using isothermal titration calorimetry (ITC) and X ray crystallography, as well as tested in parasite growth inhibitions assays. These experiments led us to the identification of a benzamide derivative compound capable of interacting with TbHsp83 more strongly than with its human homologs and structural rationalization of this selectivity. The results highlight the opportunities created by subtle structural differences to develop new series of compounds to selectively target the Trypanosoma brucei chaperone and effectively kill the sleeping sickness parasite. PMID- 24147173 TI - Identification of seroreactive proteins of Leptospira interrogans serovar copenhageni using a high-density protein microarray approach. AB - BACKGROUND: Leptospirosis is a widespread zoonotic disease worldwide. The lack of an adequate laboratory test is a major barrier for diagnosis, especially during the early stages of illness, when antibiotic therapy is most effective. Therefore, there is a critical need for an efficient diagnostic test for this life threatening disease. METHODOLOGY: In order to identify new targets that could be used as diagnostic makers for leptopirosis, we constructed a protein microarray chip comprising 61% of Leptospira interrogans proteome and investigated the IgG response from 274 individuals, including 80 acute-phase, 80 convalescent-phase patients and 114 healthy control subjects from regions with endemic, high endemic, and no endemic transmission of leptospirosis. A nitrocellulose line blot assay was performed to validate the accuracy of the protein microarray results. PRINCIPAL FINDINGS: We found 16 antigens that can discriminate between acute cases and healthy individuals from a region with high endemic transmission of leptospirosis, and 18 antigens that distinguish convalescent cases. Some of the antigens identified in this study, such as LipL32, the non-identical domains of the Lig proteins, GroEL, and Loa22 are already known to be recognized by sera from human patients, thus serving as proof of-concept for the serodiagnostic antigen discovery approach. Several novel antigens were identified, including the hypothetical protein LIC10215 which showed good sensitivity and specificity rates for both acute- and convalescent phase patients. CONCLUSIONS: Our study is the first large-scale evaluation of immunodominant antigens associated with naturally acquired leptospiral infection, and novel as well as known serodiagnostic leptospiral antigens that are recognized by antibodies in the sera of leptospirosis cases were identified. The novel antigens identified here may have potential use in both the development of new tests and the improvement of currently available assays for diagnosing this neglected tropical disease. Further research is needed to assess the utility of these antigens in more deployable diagnostic platforms. PMID- 24147174 TI - Glyburide reduces bacterial dissemination in a mouse model of melioidosis. AB - BACKGROUND: Burkholderia pseudomallei infection (melioidosis) is an important cause of community-acquired Gram-negative sepsis in Northeast Thailand, where it is associated with a ~40% mortality rate despite antimicrobial chemotherapy. We showed in a previous cohort study that patients taking glyburide ( = glibenclamide) prior to admission have lower mortality and attenuated inflammatory responses compared to patients not taking glyburide. We sought to define the mechanism underlying this observation in a murine model of melioidosis. METHODS: Mice (C57BL/6) with streptozocin-induced diabetes were inoculated with ~6 * 10(2) cfu B. pseudomallei intranasally, then treated with therapeutic ceftazidime (600 mg/kg intraperitoneally twice daily starting 24 h after inoculation) in order to mimic the clinical scenario. Glyburide (50 mg/kg) or vehicle was started 7 d before inoculation and continued until sacrifice. The minimum inhibitory concentration of glyburide for B. pseudomallei was determined by broth microdilution. We also examined the effect of glyburide on interleukin (IL) 1beta by bone-marrow-derived macrophages (BMDM). RESULTS: Diabetic mice had increased susceptibility to melioidosis, with increased bacterial dissemination but no effect was seen of diabetes on inflammation compared to non-diabetic controls. Glyburide treatment did not affect glucose levels but was associated with reduced pulmonary cellular influx, reduced bacterial dissemination to both liver and spleen and reduced IL1beta production when compared to untreated controls. Other cytokines were not different in glyburide-treated animals. There was no direct effect of glyburide on B. pseudomallei growth in vitro or in vivo. Glyburide directly reduced the secretion of IL1beta by BMDMs in a dose-dependent fashion. CONCLUSIONS: Diabetes increases the susceptibility to melioidosis. We further show, for the first time in any model of sepsis, that glyburide acts as an anti-inflammatory agent by reducing IL1beta secretion accompanied by diminished cellular influx and reduced bacterial dissemination to distant organs. We found no evidence for a direct effect of glyburide on the bacterium. PMID- 24147175 TI - Effect of maternal Schistosoma mansoni infection and praziquantel treatment during pregnancy on Schistosoma mansoni infection and immune responsiveness among offspring at age five years. AB - INTRODUCTION: Offspring of Schistosoma mansoni-infected women in schistosomiasis endemic areas may be sensitised in-utero. This may influence their immune responsiveness to schistosome infection and schistosomiasis-associated morbidity. Effects of praziquantel treatment of S. mansoni during pregnancy on risk of S. mansoni infection among offspring, and on their immune responsiveness when they become exposed to S. mansoni, are unknown. Here we examined effects of praziquantel treatment of S. mansoni during pregnancy on prevalence of S. mansoni and immune responsiveness among offspring at age five years. METHODS: In a trial in Uganda (ISRCTN32849447, http://www.controlled trials.com/ISRCTN32849447/elliott), offspring of women treated with praziquantel or placebo during pregnancy were examined for S. mansoni infection and for cytokine and antibody responses to SWA and SEA, as well as for T cell expression of FoxP3, at age five years. RESULTS: Of the 1343 children examined, 32 (2.4%) had S. mansoni infection at age five years based on a single stool sample. Infection prevalence did not differ between children of treated or untreated mothers. Cytokine (IFNgamma, IL-5, IL-10 and IL-13) and antibody (IgG1, Ig4 and IgE) responses to SWA and SEA, and FoxP3 expression, were higher among infected than uninfected children. Praziquantel treatment of S. mansoni during pregnancy had no effect on immune responses, with the exception of IL-10 responses to SWA, which was higher in offspring of women that received praziquantel during pregnancy than those who did not. CONCLUSION: We found no evidence that maternal S. mansoni infection and its treatment during pregnancy influence prevalence and intensity of S. mansoni infection or effector immune response to S. mansoni infection among offspring at age five years, but the observed effects on IL-10 responses to SWA suggest that maternal S. mansoni and its treatment during pregnancy may affect immunoregulatory responsiveness in childhood schistosomiasis. This might have implications for pathogenesis of the disease. PMID- 24147176 TI - Diagnostic accuracy of loopamp Trypanosoma brucei detection kit for diagnosis of human African trypanosomiasis in clinical samples. AB - BACKGROUND: Molecular methods have great potential for sensitive parasite detection in the diagnosis of human African trypanosomiasis (HAT), but the requirements in terms of laboratory infrastructure limit their use to reference centres. A recently developed assay detects the Trypanozoon repetitive insertion mobile element (RIME) DNA under isothermal amplification conditions and has been transformed into a ready-to-use kit format, the Loopamp Trypanosoma brucei. In this study, we have evaluated the diagnostic performance of the Loopamp Trypanosoma brucei assay (hereafter called LAMP) in confirmed T.b. gambiense HAT patients, HAT suspects and healthy endemic controls from the Democratic Republic of the Congo (DRC). METHODOLOGY/PRINCIPAL FINDINGS: 142 T.b. gambiense HAT patients, 111 healthy endemic controls and 97 HAT suspects with unconfirmed status were included in this retrospective evaluation. Reference standard tests were parasite detection in blood, lymph or cerebrospinal fluid. Archived DNA from blood of all study participants was analysed in duplicate with LAMP. Sensitivity of LAMP in parasitologically confirmed cases was 87.3% (95% CI 80.9-91.8%) in the first run and 93.0% (95% CI 87.5-96.1%) in the second run. Specificity in healthy controls was 92.8% (95% CI 86.4-96.3%) in the first run and 96.4% (95% CI 91.1 98.6%) in the second run. Reproducibility was excellent with a kappa value of 0.81. CONCLUSIONS/SIGNIFICANCE: In this laboratory-based study, the Loopamp Trypanosoma brucei Detection Kit showed good diagnostic accuracy and excellent reproducibility. Further studies are needed to assess the feasibility of its routine use for diagnosis of HAT under field conditions. PMID- 24147177 TI - [Primary cutaneous anaplastic lymphoma with large cells presenting as a solitary nodule]. PMID- 24147178 TI - [Secondary syphilis: the great pretender]. PMID- 24147179 TI - Moniletherix. PMID- 24147180 TI - Lichen planus pigmentosus. PMID- 24147181 TI - Lichen planus pigmentosus. PMID- 24147172 TI - Multilocus analysis of divergence and introgression in sympatric and allopatric sibling species of the Lutzomyia longipalpis complex in Brazil. AB - BACKGROUND: Lutzomyia longipalpis, the main vector of visceral leishmaniasis in Latin America, is a complex of sibling species. In Brazil, a number of very closely related sibling species have been revealed by the analyses of copulation songs, sex pheromones and molecular markers. However, the level of divergence and gene flow between the sibling species remains unclear. Brazilian populations of this vector can be divided in two main groups: one producing Burst-type songs and the Cembrene-1 pheromone and a second more diverse group producing various Pulse song subtypes and different pheromones. METHODOLOGY/PRINCIPAL FINDINGS: We analyzed 21 nuclear loci in two pairs of Brazilian populations: two sympatric populations from the Sobral locality (1S and 2S) in northeastern Brazil and two allopatric populations from the Lapinha and Pancas localities in southeastern Brazil. Pancas and Sobral 2S are populations of the Burst/Cembrene-1 species while Lapinha and Sobral 1S are two putative incipient species producing the same pheromone and similar Pulse song subtypes. The multilocus analysis strongly suggests the occurrence of gene flow during the divergence between the sibling species, with different levels of introgression between loci. Moreover, this differential introgression is asymmetrical, with estimated gene flow being higher in the direction of the Burst/Cembrene-1 species. CONCLUSIONS/SIGNIFICANCE: The results indicate that introgressive hybridization has been a crucial phenomenon in shaping the genome of the L. longipalpis complex. This has possible epidemiological implications and is particularly interesting considering the potential for increased introgression caused by man-made environmental changes and the current trend of leishmaniasis urbanization in Brazil. PMID- 24147182 TI - [Nevoid hypertrichosis]. PMID- 24147184 TI - [Phytophotodermatitis of an unusual location from seaweed]. PMID- 24147183 TI - Upper cervical spine injuries: a management of a series of 70 cases. AB - Traumatic injuries of the upper cervical spine are often encountered, and may be associated to severe neurological outcome. This is a retrospective study of 70 patients, admitted over a 14 years period (1996 to 2010), for management of upper cervical spine injuries. Data concerning epidemiology, radiopathology and treatment was reviewed, and clinical and radiological evaluation was conducted. Men are more affected than women, with traffic accidents being the major traumatic cause. A cervical spine syndrome of varied intensity was found in about 90% of patients; neurological deficit was noted in 10 patients (21%). Radiological analysis discovered varied and many combined lesions: C1-C2 dislocation (7 cases), C2-C3 dislocation (9 cases), C1 fracture (10 cases) and C2 fracture (44 cases) including 28 odontoid fractures. Orthopedic treatment was carried out exclusively for 31 patients, and surgical treatment for 38 patients. One patient died before surgery because of a polytraumatisme. Posterior approach was performed in 29 cases including hooks and rods in 18 patients, wiring in 9 cases, and 2 transarticular screw fixations. In 9 cases anterior approach was performed: 5 odontoid screwing and 4 cases of C2-C3 discectomy with bone graft. Nearly all patients were improved in post-operative. Elsewhere, the operating results were marked by a persistent neurological deficit in 2 cases, and infection in 2 cases controlled by medical treatment. Mean follow-up was 23 months and showed good clinical and radiological improvement. Early management of cervical spine injuries can optimize outcome. Treatment modalities are well codified; however controversy remains especially with type II odontoid fractures. PMID- 24147185 TI - Mucoid degeneration of the anterior cruciate ligament: a case report. AB - We report a case of mucoid degeneration of the anterior cruciate ligament (ACL). Mucoid degeneration of the ACL is a very rare cause of knee pain. There have been only some reported cases of mucoid degeneration of the ACL in the English literature. We reviewed previous reports and summarized clinical features and symptoms, including those found in our case. Magnetic Resonance Imaging is the most useful tool for differentiating mucoid degeneration of the ACL from an intraligamentous ganglion or other lesions in the knee joint. If this disease is considered preoperatively, it can be diagnosed easily based on characteristic findings. PMID- 24147186 TI - Emergency peripartum hysterectomy in a tertiary hospital in southern Nigeria. AB - INTRODUCTION: Emergency peripartum hysterectomy, a maker of severe maternal morbidity and near miss mortality is an inevitable surgical intervention to save a woman's life when uncontrollable obstetric haemorrhage complicates delivery. This study was conducted in order to determine the incidence, types, indications and maternal complications of emergency peripartum hysterectomy at the University of Uyo Teaching Hospital, Uyo, Nigeria. METHODS: The case records of all women who underwent emergency peripartum hysterectomy between 1(st) January 2004 and 31(st) December 2011 were studied. RESULTS: There were 12,298 deliveries during the study period and 28 emergency peripartum hysterectomies were performed resulting in a rate of 0.2% or 1 in 439 deliveries. The modal age group of the patients was 26-30 years (35.7%), majority were of low parity (64.4%), while 17.9% attained tertiary level education. Half of the patients (50.0%) were unbooked while 14.3% were antenatal clinic defaulters. Extensive uterine rupture (67.8%) was the most common indication for emergency hysterectomy distantly followed by uterine atony with uncontrollable haemorrhage (17.9%). Subtotal abdominal hysterectomy was performed in 92.8% of the cases. The case fatality rate was 14.3% while the perinatal mortality rate was 64.3%. CONCLUSION: Emergency peripartum hysterectomy is not uncommonly performed in our centre and extensive uterine rupture from prolonged obstructed labour is the most common indication. In addition, it is associated with significant maternal and perinatal mortality. There is need to enlighten women in our communities on the benefits of ANC and hospital delivery as well as the dangers of delivering without skilled attendance. Government should consider enacting legislation to discourage people or organisations who operate unlicensed maternity homes in our environment. PMID- 24147187 TI - Health, Human Capital, and Development. AB - How much does disease depress development in human capital and income around the world? I discuss a range of micro evidence, which finds that health is both human capital itself and an input to producing other forms of human capital. I use a standard model to integrate these results, and suggest a re-interpretation of much of the micro literature. I then discuss the aggregate implications of micro estimates, but note the complications in extrapolating to general equilibrium, especially because of health's effect on population size. I also review the macro evidence on this topic, which consists of either cross-country comparisons or measuring responses to health shocks. Micro estimates are 1-2 orders of magnitude smaller than the cross-country relationship, but nevertheless imply high benefit to-cost ratios from improving certain forms of health. PMID- 24147188 TI - Spontaneous rupture of falciparum malarial spleen presenting as hemoperitoneum, hemothorax, and hemoarthrosis. AB - PATIENT: Male, 29 FINAL DIAGNOSIS: Spontaneous spleen rupture Symptoms: Abdominal distension * abdominal pain * abdominal tenderness * disorientation * fever * hemothorax * hip pain * reduced urine output MEDICATION: - Clinical Procedure: Splenectomy Specialty: Infectious Diseases. OBJECTIVE: Rare diseases. BACKGROUND: Spontaneous rupture of a malarial spleen is uncommon even in the endemic regions of malaria. This may lead to delayed or missed diagnosis of splenic rupture, which may be life threatening. CASE REPORT: We are reporting a patient with P. falciparum malaria who developed a spontaneous splenic rupture encountered in our department. A 29-year-old male patient with history of high grade intermittent fever with chills for 4 days followed by disorientation and reduced urine output and abdominal pain with distension associated with bilateral hip pain and dyspnea with bilateral chest pain (mainly on the left side) for 1 day. There was no history of any trauma or abnormal bleeding. Investigations revealed P. falciparum malaria, hemoperitoneum, hemothorax, and hemoarthrosis. Laparotomy confirmed hemoperitoneum with about 1.5 L of blood-stained fluid, enlarged friable spleen with rupture of the splenic capsule on the inner surface, and active bleeding. Splenectomy was performed. The patient was diagnosed with malarial spleen and received antimalarial therapy. CONCLUSIONS: Splenic rupture with hemoperitoneum should be managed with laparotomy and splenectomy, along with antimalarial drugs. A high index of suspicion is needed to detect these complications early. PMID- 24147189 TI - Exchange of intraoperative balloon occlusion of the internal iliac artery for the common iliac artery during cesarean hysterectomy in a patient with placenta percreta. AB - PATIENT: Female, 36 FINAL DIAGNOSIS: Pregnancy - placenta increta Symptoms: - MEDICATION: - Clinical Procedure: Cesarean hysterectomy Specialty: Obstetrics and Gynecology. OBJECTIVE: Unusual clinical course. BACKGROUND: The generally accepted treatment for placenta percreta is cesarean hysterectomy without attempts to detach the placenta. Preoperative internal iliac artery balloon occlusion (IIABO) has been widely performed to minimize blood loss during cesarean hysterectomy for an abnormal attachment of the placenta. Our case is the first reported case of common iliac artery balloon occlusion (CIABO) being more effective than IIABO for reducing blood loss during a cesarean hysterectomy in the same patient. CASE REPORT: We performed cesarean hysterectomy with IIABO in a 36-year-old Japanese female who had placenta percreta. However, there was still a large amount of blood loss. We immediately changed the balloon from the internal iliac artery to the common iliac artery, which visibly reduced the amount of blood loss. We finally achieved cesarean hysterectomy. CONCLUSIONS: CIABO was found to be more effective than IIABO for reducing blood loss during cesarean hysterectomy. Failure of IIABO can be explained by the presence of extensive anastomoses in the pelvic vasculature. PMID- 24147190 TI - How we can measure quality in colonoscopy? AB - Measuring quality is a current need of medical services either to assess their cost-effectiveness or to identify discrepancies requiring refinement. With the advent of bowel cancer screening and increasing patient awareness of bowel symptoms, there has been an unprecedented increase in demand for colonoscopy. Consequently, there is an expanding open-discussion on missed rates of cancer or precancerous polyps during diagnostic/screening colonoscopy and on the rate of adverse events related to therapeutic colonoscopy. Delivering a quality colonoscopy service is therefore a healthcare priority. Colonoscopy is a multi step process and therefore assessment of all aspects of the procedure must be addressed. Quality in colonoscopy refers to a combination of many patient centered technical and non-technical skills and knowledge aiming to patient's safety and satisfaction through a continuous effort for improvement. The benefits of this endless process are hiding behind small details which can eventually make the difference in colonoscopy. Identifying specific quality metrics help to define and shape an optimal service and forms a secure basis of improvement. Tauhis paper does not aim to give technical details on how to perform colonoscopy but to summarize what to measure and when, in accordance with the current identified quality indicators and standards for colonoscopy. PMID- 24147191 TI - Enteroscopy in small bowel Crohn's disease: A review. AB - Crohn's disease (CD) is a chronic inflammatory condition of the gastrointestinal tract resulting in inflammation, stricturing and fistulae secondary to transmural inflammation. Diagnosis relies on clinical history, abnormal laboratory parameters, characteristic radiologic and endoscopic changes within the gastrointestinal tract and most importantly a supportive histology. The article is intended mainly for the general gastroenterologist and for other interested physicians. Management of small bowel CD has been suboptimal and limited due to the inaccessibility of the small bowel. Enteroscopy has had a significant renaissance recently, thereby extending the reach of the endoscopist, aiding diagnosis and enabling therapeutic interventions in the small bowel. Radiologic imaging is used as the first line modality to visualise the small bowel. If the clinical suspicion is high, wireless capsule endoscopy (WCE) is used to rule out superficial and early disease, despite the above investigations being normal. This is followed by push enteroscopy or device assisted enteroscopy (DAE) as is appropriate. This approach has been found to be the most cost effective and least invasive. DAE includes balloon-assisted enteroscopy, [double balloon enteroscopy (DBE), single balloon enteroscopy (SBE) and more recently spiral enteroscopy (SE)]. This review is not going to cover the various other indications of enteroscopy, radiological small bowel investigations nor WCE and limited only to enteroscopy in small bowel Crohn's. These excluded topics already have comprehensive reviews. Evidence available from randomized controlled trials comparing the various modalities is limited and at best regarded as Grade C or D (based on expert opinion). The evidence suggests that all three DAE modalities have comparable insertion depths, diagnostic and therapeutic efficacies and complication rates, though most favour DBE due to higher rates of total enteroscopy. SE is quicker than DBE, but lower complete enteroscopy rates. SBE has quicker procedural times and is evolving but the least available DAE today. Larger prospective randomised controlled trial's in the future could help us understand some unanswered areas including the role of BAE in small bowel screening and comparative studies between the main types of enteroscopy in small bowel CD. PMID- 24147192 TI - Which endoscopic treatment is the best for small rectal carcinoid tumors? AB - The incidence of rectal carcinoids is rising because of the widespread use of screening colonoscopy. Rectal carcinoids detected incidentally are usually in earlier stages at diagnosis. Rectal carcinoids estimated endoscopically as < 10 mm in diameter without atypical features and confined to the submucosal layer can be removed endoscopically. Here, we review the efficacy and safety of various endoscopic treatments for small rectal carcinoid tumors, including conventional polypectomy, endoscopic mucosal resection (EMR), cap-assisted EMR (or aspiration lumpectomy), endoscopic submucosal resection with ligating device, endoscopic submucosal dissection, and transanal endoscopic microsurgery. It is necessary to carefully choose an effective and safe primary resection method for complete histological resection. PMID- 24147193 TI - Colorectal stenting as first-line treatment in acute colonic obstruction. AB - Tumoral obstructions in almost the entire gastrointestinal tract can be resolved with interventional digestive endoscopy techniques. Self-expanding metal stent (SEMS) insertion in the obstructed colon is a minimally invasive and relatively simple procedure providing an effective first-line treatment for relief of acute malignant obstruction symptoms and serving either as a preoperative or "bridge to surgery" procedure or as palliative definitive care. This technique was introduced in the early 1990s. Although there is still debate about its real value, a lot of reports have been published since then and the procedure is advocated by many surgical groups as the method of choice for the initial treatment of left-sided tumoral colonic obstruction. Before the procedure, colonic obstruction has to be diagnosed by abdominal radiographs, water contrast enema and/or a computed tomography scan. The greatest information is provided by the latter and it is perhaps the method of choice prior to stenting. Skills and training are mandatory, as in all interventional procedures. The key step for success is to cross the malignant stricture with a guidewire. Care must be taken not to over insufflate an obstructed colon during the procedure. SEMS slide over the guidewire through the endoscope working channel or in parallel, outside the endoscope. An average 7% perforation rate has been reported during the procedure and other minor complications can appear in the follow up. However, as a whole, this technique seems to compare favorably with surgery. PMID- 24147194 TI - Post-Anaesthetic Discharge Scoring System to assess patient recovery and discharge after colonoscopy. AB - AIM: To investigate whether discharge scoring criteria are as safe as clinical criteria for discharge decision and allow for earlier discharge. METHODS: About 220 consecutive outpatients undergoing colonoscopy under sedation with Meperidine plus Midazolam were enrolled and assigned to 2 groups: in Control-group (110 subjects) discharge decision was based on the clinical assessment; in PADSS-group (110 subjects) discharge decision was based on the modified Post-Anaesthetic Discharge Scoring System (PADSS). Measurements of the PADDS score were taken every 20 min after colonoscopy, and patients were discharged after two consecutive PADSS scores >= 9. The investigator called each patient 24-48 h after discharge to administer a standardized questionnaire, to detect any delayed complications. Patients in which cecal intubation was not performed and those who were not found at follow-up phone call were excluded from the study. RESULTS: Thirteen patients (7 in Control-group and 6 in PADSS-group) were excluded from the study. Recovery from sedation was faster in PADSS-group than in Control-group (58.75 +/- 18.67 min vs 95.14 +/- 10.85 min, respectively; P < 0.001). Recovery time resulted shorter than 60 min in 39 patients of PADSS-group (37.5%), and in no patient of Control-group (P < 0.001). At follow-up phone call, no patient declared any hospital re-admission because of problems related to colonoscopy and/or sedation. Mild delayed post-discharge symptoms occurred in 57 patients in Control-group (55.3%) and in 32 in PADSS-group (30.7%). The most common symptoms were drowsiness, weakness, abdominal distension, and headache. Only 3 subjects needed to take some drugs because of post-discharge symptoms. CONCLUSION: The Post-Anaesthetic Discharge Scoring System is as safe as the clinical assessment and allows for an earlier patient discharge after colonoscopy performed under sedation. PMID- 24147195 TI - Usefulness of continuous suction mouthpiece during esophagogastroduodenoscopy: A single-center, prospective, randomized study. AB - AIM: To develop a new continuous suction mouthpiece (CSM) and evaluate its usefulness for screening esophagogastroduodenoscopy (EGD). METHODS: A total of 196 patients who were scheduled to undergo screening EGD were assigned to one of two groups: a group using the CSM and a group using a conventional mouthpiece. Extent of salivary flow, frequency of saliva suction, number of choking episodes during the examination, and incidence of aspiration pneumonia after the examination were evaluated and compared between the two groups. Adverse events during and after EGD were also examined. In addition, the oral cavity was meticulously examined after the EGD. RESULTS: The same number of patients was randomly allocated to each group. There were no significant differences between the two groups in sex, age, biopsy procedure, duration of procedure and depth of sedation. Aspiration pneumonia and other significant adverse events were not observed in either group. The grade of extent of salivary flow was significantly lower in patients with the CSM than in patients with the conventional mouthpiece (P < 0.001). Although there was no significant difference, less frequent suctioning and fewer choking episodes were observed in patients with the CSM than in patients with the conventional mouthpiece (P = 0.082 and P = 0.084, respectively). In addition, there were no patients in the CSM group who required saliva suctioning during the procedure. CONCLUSION: Use of the CSM during screening EGD can reduce the extent of salivary flow. The device is expected to reduce complications and contamination with saliva. PMID- 24147197 TI - Contribution of endosonography in an uncommon case of pancreatic cysts. AB - Here we present the case of a 35-year-old female patient with long standing dyspepsia and imaging studies showing the presence of multiple cysts in the head and tail of the pancreas. The patient underwent endosonography that confirmed the presence of multiple simple cysts throughout the entirety of the pancreas without dilation of the pancreatic duct. The majority of the cysts were less than one centimeter in size, and the largest cyst showed a honeycomb appearance. Cytology of aspirates from the two largest cysts was compatible with benign pancreatic cysts. Endosonography also revealed cysts within the left kidney and spleen. Genetic testing confirmed Von Hippel-Lindau disease. We highlight this case because it is unusual for Von Hippel-Lindau disease, a rare clinical entity, to present solely with cysts in the absence of more common manifestations, such as hemangioblastomas in the central nervous system and malignancy. PMID- 24147196 TI - Duodenal subepithelial hyperechoic lesions of the third layer: Not always a lipoma. AB - Endoscopic ultrasonography is the most accurate procedure for the evaluation of subepithelial lesions. The finding of a homogeneous, hyperechoic, well-delimited lesion, originating from the third layer of the gastrointestinal tract (submucosa) suggests a benign tumor, generally lipoma. As other differential diagnoses have not been reported, echoendoscopists might not pursue a definitive pathological diagnosis or follow-up the patient. This case series aims to broaden the spectrum of differential diagnosis for duodenal hyperechoic third layer subepithelial lesions by providing four different and relevant pathologies with this echoendoscopic pattern. PMID- 24147198 TI - Migration of a biliary stent causing duodenal perforation and biliary peritonitis. AB - Migration of endoscopically placed biliary stents is a well-recognized complication of endoscopic retrograde cholangiopancreatography. Less than 1% of migrated stents however cause intestinal perforation. We present a case of a migrated biliary stent that resulted in duodenal perforation and biliary peritonitis. PMID- 24147199 TI - Are diabetic patients being screened for sleep related breathing disorder? AB - Prevalence of both diabetes mellitus and obstructive sleep apnea (OSA) is high among general population. Both of these conditions are associated with significant morbidity. OSA affects approximately 25% of men and 9% of women, and its prevalence is even higher among obese, Hispanics, African American and diabetic patients. Diabetes on the other hand besides having high prevalence in general population has even higher prevalence among ethnic populations as Hispanics and African American. Despite the availability of several simple screening tools for OSA, as Berlin questionnaire, STOP-BANG questionnaire, NAMES Criteria, the utility for screening of OSA among the diabetic population remains marginal. This in turn can lead to significant morbidity and complications related to OSA as well as worsening of diabetes mellitus and increase in diabetic complications due to untreated sleep related breathing disorder. It is therefore imperative for the primary care giver to screen for OSA among the diabetic population as a part of their routine evaluation to prevent worsening of diabetes, and its cardiovascular, renal, ophthalmologic and neurological complications. PMID- 24147200 TI - Current status in diabetic macular edema treatments. AB - Diabetes is a serious chronic condition, which increase the risk of cardiovascular diseases, kidney failure and nerve damage leading to amputation. Furthermore the ocular complications include diabetic macular edema, is the leading cause of blindness among adults in the industrialized countries. Today, blindness from diabetic macular edema is largely preventable with timely detection and appropriate interventional therapy. The treatment should include an optimized control of glycemia, arterial tension, lipids and renal status. The photocoagulation laser is currently restricted to focal macular edema in some countries, but due the high cost of intravitreal drugs, the use of laser treatment for focal and diffuse diabetic macular edema (DME), can be valid as gold standard in many countries. The intravitreal anti vascular endothelial growth factor drugs (ranibizumab and bevacizumab), are indicated in the treatment of all types of DME, but the correct protocol for administration should be defined for the different Retina Scientific Societies. The corticosteroids for diffuse DME, has a place in pseudophakic patients, but its complications restricted the use of these drugs for some patients. Finally the intravitreal interface plays an important role and its exploration is mandatory in all DME patients. PMID- 24147201 TI - Chemo-profiling of eucalyptus and study of its hypoglycemic potential. AB - Constant escalations in the number of diabetics world-wide and the failure of conventional therapy to restore normoglycemia without adverse effects, in spite of tremendous strides in modern medicine, calls for naturopathy and alternative medicine. Because diabetes is multi-factorial and has secondary complications, prevention of hyperglycemia is the central dogma for its management. To date, no oral hypoglycemic exists which can achieve tight glycemic control without side effects. Dietary adjuncts, lifestyle interventions and a resurgence of interest in phyto-therapy have consequently gained ground. Natural hypoglycemics have attracted attention due to ease of incorporation in everyday diet, affordability, less adverse effects, and long term safety. Ethno botanical literature reports more than 800 anti-diabetic plants species. Eucalyptus is well represented in the Aboriginal Pharmacopoeias for its various pharmacological activities. Its hot aqueous decoction has been used as a hypoglycemic in various regions of world. This editorial attempts to summarize the data on the hypoglycemic potential of the different eucalyptus species, highlight the value of its natural biomolecules for the prophylaxis and treatment of type 2 diabetes, describe their mechanistic actions, shed light on the posology and safety aspects of eucalyptus and assess its applicability as a reinforcement to currently used therapy. PMID- 24147202 TI - Diabetic cardiomyopathy: Pathophysiology, diagnostic evaluation and management. AB - Diabetes affects every organ in the body and cardiovascular disease accounts for two-thirds of the mortality in the diabetic population. Diabetes-related heart disease occurs in the form of coronary artery disease (CAD), cardiac autonomic neuropathy or diabetic cardiomyopathy (DbCM). The prevalence of cardiac failure is high in the diabetic population and DbCM is a common but underestimated cause of heart failure in diabetes. The pathogenesis of diabetic cardiomyopathy is yet to be clearly defined. Hyperglycemia, dyslipidemia and inflammation are thought to play key roles in the generation of reactive oxygen or nitrogen species which are in turn implicated. The myocardial interstitium undergoes alterations resulting in abnormal contractile function noted in DbCM. In the early stages of the disease diastolic dysfunction is the only abnormality, but systolic dysfunction supervenes in the later stages with impaired left ventricular ejection fraction. Transmitral Doppler echocardiography is usually used to assess diastolic dysfunction, but tissue Doppler Imaging and Cardiac Magnetic Resonance Imaging are being increasingly used recently for early detection of DbCM. The management of DbCM involves improvement in lifestyle, control of glucose and lipid abnormalities, and treatment of hypertension and CAD, if present. The role of vasoactive drugs and antioxidants is being explored. This review discusses the pathophysiology, diagnostic evaluation and management options of DbCM. PMID- 24147203 TI - Effects of glucagon-like peptide-1 receptor agonists on renal function. AB - Glucagon-like peptide-1 (GLP-1) receptor agonists result in greater improvements in glycemic control than placebo and promote weight loss with minimal hypoglycemia in patients with type 2 diabetes mellitus. A number of case reports show an association of GLP-1 receptor agonists, mainly exenatide, with the development of acute kidney injury. The present review aims to present the available data regarding the effects of GLP-1 receptor agonists on renal function, their use in subjects with chronic renal failure and their possible association with acute kidney injury. Based on the current evidence, exenatide is eliminated by renal mechanisms and should not be given in patients with severe renal impairment or end stage renal disease. Liraglutide is not eliminated by renal or hepatic mechanisms, but it should be used with caution since there are only limited data in patients with renal or hepatic impairment. There is evidence from animal studies that GLP-1 receptor agonists exert protective role in diabetic nephropathy with mechanisms that seem to be independent of their glucose lowering effect. Additionally, there is evidence that GLP-1 receptor agonists influence water and electrolyte balance. These effects may represent new ways to improve or even prevent diabetic nephropathy. PMID- 24147204 TI - Effect of ethnicity on weight loss among adolescents 1 year after bariatric surgery. AB - AIM: To investigate whether or not bariatric surgery weight outcomes vary by ethnicity in a large, nationally representative sample of adolescents. METHODS: The Bariatric Outcomes Longitudinal Database was used for analysis and contains data on surgeries performed on adolescents from 2004 to 2010 from 423 surgeons at 360 facilities across the United States Adolescents (n = 827) between 11 and 19 years old who underwent either gastric bypass or adjustable gastric banding surgery were included in the analysis. Outcome measures included changes in anthropometric measurements [weight (kg) and body mass index] from baseline to 3 (n = 739), 6 (n = 512), and 12 (n = 247) mo after surgery. RESULTS: A year after patients underwent either gastric bypass (51%) or adjustable gastric banding (49%) surgery, mean estimated weight loss for all ethnic groups differed by a maximum of only 1.5 kg, being 34.3 kg (95%CI: 30.0-38.5 kg) for Hispanics, 33.8 kg (95%CI: 27.3-40.3 kg) for non-Hispanic blacks, and 32.8 kg (95%CI: 30.9-34.7 kg) for non-Hispanic whites. No overall pairwise group comparisons were significant, indicating that no ethnic group had better weight loss outcomes than did another. CONCLUSION: Bariatric surgery substantially reduces the weight of severely obese adolescents at 1 year post-procedure with little variation by ethnicity and/or gender. These results suggest that bariatric surgery is a safe and reasonable treatment for all severely obese adolescents with the appropriate indications. PMID- 24147205 TI - Impaired fasting glucose: Pro-diabetic, "atheroprotective" and modified by metabolic syndrome. AB - AIM: To investigate whether impaired fasting glucose (IFG) confers cardiovascular risk. METHODS: A non-diabetic population-based sample representative of middle aged and elderly Turks was studied at 8.5 years' follow-up for incident diabetes and coronary heart disease (CHD). Metabolic syndrome (MetS) was defined by ATP III criteria modified for male abdominal obesity, and IFG and type 2 diabetes were identified by criteria of the American Diabetes Association. Stratification by presence of MetS was used. Outcomes were predicted providing estimates for hazard ratio (HR) obtained by use of Cox proportional hazards regression analysis in models that controlled for potential confounders. RESULTS: In 3181 adults (aged 52 +/- 11.5 years at baseline), analysis stratified by MetS, gender and IFG status distinguished normoglycemic subjects by a "hypertriglyceridemic waist" phenotype consisting of significantly higher waist circumference, fasting triglyceride and lower high-density lipoprotein-cholesterol, regardless of gender and MetS. Additionally, lipoprotein (Lp) (a) tended to be lower in (especially female) participants with MetS. Multivariable linear regression in a subset of the sample demonstrated decreased Lp (a) levels to be associated with increased fasting glucose and insulin concentrations, again particularly in women. In Cox regression analysis, compared with normoglycemia, baseline IFG adjusted for major confounders significantly predicted incident diabetes at a 3-fold HR in men and only women with MetS. Cox models for developing CHD in 339 individuals, adjusted for conventional risk factors, revealed that IFG status protected against CHD risk [HR = 0.37 (95%CI: 0.14-0.998)] in subjects free of MetS, a protection that attenuated partly in male and fully in female participants with MetS. CONCLUSION: IFG status in non-diabetic people without MetS displays reduced future CHD risk, yet is modulated by MetS, likely due to autoimmune activation linked to serum Lp (a). PMID- 24147206 TI - High adiponectin levels fail to protect against the risk of hypertension and, in women, against coronary disease: involvement in autoimmunity? AB - AIM: To investigate whether serum adiponectin protects against cardiometabolic risk in a population sample with prevailing metabolic syndrome. METHODS: Middle aged adults representative of a general population with baseline circulating adiponectin measurements (n = 1224) were analyzed prospectively at a mean of 3.8 years' follow-up, using continuous values or sex-specific tertiles. Total adiponectin was assayed by an ELISA kit. Type-2 diabetes was identified by criteria of the American Diabetes Association. Hypertension was defined as a blood pressure >= 140 mmHg and/or >= 90 mmHg and/or use of antihypertensive medication. Outcomes were predicted using Cox proportional hazards regression analysis in models that were controlled for potential confounders. RESULTS: In models of multiple linear regression, sex hormone-binding globulin, fasting insulin (inverse) and, in men, age were significant independent covariates of serum adiponectin which further tended in women to be positively associated with serum creatinine. Cox regression analyses for incident coronary heart disease (CHD), adjusted for sex, age, non-HDL cholesterol, waist circumference and C reactive protein, revealed significant inverse association with adiponectin tertiles in men but not women (HR = 0.66; 95%CI: 0.32-1.38 for highest tertile). Cox regression for type-2 diabetes in a similar model (wherein glucose replaced non-HDL cholesterol), adiponectin tertiles appeared to protect in each gender. HR for incident hypertension roughly displayed unity in each of the adiponectin tertiles (P-trend = 0.67). CONCLUSION: High adiponectin levels failed to protect against the development of hypertension and, in women, against CHD, presumably paralleling impairment in renal function as well. Involvement of adiponectin in autoimmune complex with loss of antioxidative-antiatherogenic properties may be underlying. PMID- 24147207 TI - Sequential elevation of autoantibodies to thyroglobulin and glutamic acid decarboxylase in type 1 diabetes. AB - We have previously reported the high levels of glutamic acid decarboxylase 65 autoantibodies (GAD65A) in patients with type 1 diabetes and autoimmune thyroid disease. Here we describe a 32-year-old Japanese female with a thirteen-year history of type 1 diabetes whose levels of GAD65A were elevated just after the emergence of anti-thyroid autoimmunity. At 19 years of age, she developed diabetic ketoacidosis and was diagnosed with type 1 diabetes. She had GAD65A, insulinoma-associated antigen-2 autoantibodies (IA-2A), and zinc transporter-8 autoantibodies (ZnT8A), but was negative for antibodies to thyroid peroxidase (TPOAb) and thyroglobulin (TGAb) at disease onset. ZnT8A and IA-2A turned negative 2-3 years after the onset, whereas GAD65A were persistently positive at lower level (approximately 40 U/mL). However, just after the emergence of TGAb at disease duration of 12.5 years, GAD65A levels were reelevated up to 5717 U/mL in the absence of ZnT8A and IA-2A. Her thyroid function was normal and TPOAb were consistently negative. She has a HLA-DRB1*03:01/*04:01-DQB1*02:01/*03:02 genotype. Persistent positivity for GAD65A might be associated with increased risk to develop anti-thyroid autoimmunity. PMID- 24147209 TI - Young Women's Stroke Etiology Differs from that in Young Men: an Analysis of 511 Patients. AB - Women are known to have particular heterogeneity in stroke etiology related to childbearing and hormonal factors. Although there are continued acute stroke treatment advances focusing on clot dissolution or extraction, effective secondary prevention of stroke, however, is dependent on an accurate etiological determination of the stroke. Otherwise, more strokes are likely to follow. Analysis of young women's stroke etiology in a large stroke registry incorporating contemporary neurovascular and parenchymal imaging and cardiac imaging. Young people (18-49 years old) with stroke were consecutively accrued over a 4 year period and an investigative protocol prospectively applied that incorporated multimodality magnetic resonance imaging, angiography, cardiac echo and stroke relevant blood investigations. All patients were classified according to an expanded Trial of Org 10172 in Acute Stroke Treatment - TOAST - classification and neurological deficit by the National Institute of Health stroke admission scores. In 511 registry derived, young stroke patients (mean age 39.8 years, 95% confidence interval: 39.1; 40.7 years), gender (women n=269, 53%) the etiological categories (women; men) included: i) small vessel disease (30/55;25/55), ii) cardioembolic (16/42;26/42), iii) large vessel cervical and intracranial disease (24/43;19/43), the other category (132/226; 91/226), which included, iv) substance abuse (15/41; 26/41, 4.6), v) prothrombotic states (22/37;15/37), vi) dissection (11/30;19/30), vii) cerebral venous thrombosis (15/19; 4/19, 12.4), viii) vasculitis (8/12; 4/12), ix) migraine related (10/11, 1/11) and x) miscellaneous vasculopathy (38/52;14/52). The latter entities comprised of aortic arch atheroma, vessel redundancy syndrome, vertebrobasilar hypoplasia, arterial fenestrations and dolichoectasia. Some conditions occurred solely in women, such as eclampsia (5), Call Fleming syndrome (4), fibromuscular dysplasia (3) and Moya Moya syndrome (2). Categories aside from bland infarction included: ii) intracerebral hemorrhage (43/106; 63/106) and xiii) stroke of undetermined etiology (6/10; 4/10). Admission mean National Institute of Health Stroke Scale scores differed significantly between women and men (4.7; 6.0 t=1.8, P=0.03). Young women's stroke is significantly different from men in 7/12 stroke etiological categories in addition to 4 unique subtypes that require specific management. PMID- 24147208 TI - Pharmacological enhancement of exposure-based treatment in PTSD: a qualitative review. AB - There is a good amount of evidence that exposure therapy is an effective treatment for posttraumatic stress disorder (PTSD). Notwithstanding its efficacy, there is room for improvement, since a large proportion of patients does not benefit from treatment. Recently, an interesting new direction in the improvement of exposure therapy efficacy for PTSD emerged. Basic research found evidence of the pharmacological enhancement of the underlying learning and memory processes of exposure therapy. The current review aims to give an overview of clinical studies on pharmacological enhancement of exposure-based treatment for PTSD. The working mechanisms, efficacy studies in PTSD patients, and clinical utility of four different pharmacological enhancers will be discussed: d-cycloserine, MDMA, hydrocortisone, and propranolol. PMID- 24147210 TI - Delayed post-hypoxic leukoencephalopathy: case report with a review of disease pathophysiology. AB - Delayed post-hypoxic leukoencephalopathy is a rare clinical phenomenon usually observed in a small number of carbon monoxide poisoning survivors. A similar phenomenon is reported here in a patient who successfully recovered from a large overdose of diazepam and methadone, but then abruptly declined 3 weeks after the initial event. Magnetic resnance revealed confluent white matter hyperintensity on fluid-attenuated inversion recovery and T2 weighted sequences, and spectroscopy revealed elevated peaks in choline, creatinine, and lactate. Analysis and review of the literature suggests this phenomenon occurs on average about 19 days after the initial event. Although the pathophysiology remains obscure, it is noted here that the mean lucid interval coincides approximately with the replacement half-life for myelin related lipids and proteins. PMID- 24147211 TI - Amino Acid Sequences Mediating Vascular Cell Adhesion Molecule 1 Binding to Integrin Alpha 4: Homologous DSP Sequence Found for JC Polyoma VP1 Coat Protein. AB - The JC polyoma viral coat protein VP1 was analyzed for amino acid sequences homologies to the IDSP sequence which mediates binding of VLA-4 (integrin alpha 4) to vascular cell adhesion molecule 1. Although the full sequence was not found, a DSP sequence was located near the critical arginine residue linked to infectivity of the virus and binding to sialic acid containing molecules such as integrins (3). For the JC polyoma virus, a DSP sequence was found at residues 70, 71 and 72 with homology also noted for the mouse polyoma virus and SV40 virus. Three dimensional modeling of the VP1 molecule suggests that the DSP loop has an accessible site for interaction from the external side of the assembled viral capsid pentamer. PMID- 24147212 TI - Stroke Outcomes in Thai Elderly Patients Treated with and without Intravenous Thrombolysis. AB - Higher mortality was found in very old patients with acute ischemic stroke treated with intravenous recombinant tissue-plasminogen activator (rtPA) as compared to younger patients. The benefit of thrombolytic treatment in this particular subgroup is still a subject of debate. The purpose of this study was to compare stroke outcomes in Thai patients aged over 70 years treated with and without intravenous rtPA. This was a retrospective review of sequential cases and was not a randomized controlled study. One-hundred and five patients with acute ischemic stroke aged over 70 years who were treated with intravenous rtPA and 105 patients without rtPA treatment (control group) were included in the study. Patients' base-line characteristics and study outcomes of interest were compared. There were significant differences in the base-line characteristics of the two groups. However, for the subgroup of patients aged over 80 years, these characteristics were similar. Those who were treated with intravenous rtPA had a higher rate of favorable outcomes (40% vs 16%; P=0.137) and a lower rate of mortality (22% vs 44%; P=0.128) than patients who did not receive rtPA treatment. In well-matched subgroups of patients aged over 80 years, our retrospective review revealed there was a trend of a higher rate of favorable outcome and lower mortality in patients receiving rtPA treatment. More study is needed to further confirm the suggested benefit of thrombolysis in Asian octogenarian acute stroke patients. PMID- 24147213 TI - A score based on screening tests to differentiate mild cognitive impairment from subjective memory complaints. AB - It is not easy to differentiate patients with mild cognitive impairment (MCI) from subjective memory complainers (SMC). Assessments with screening cognitive tools are essential, particularly in primary care where most patients are seen. The objective of this study was to evaluate the diagnostic accuracy of screening cognitive tests and to propose a score derived from screening tests. Elderly subjects with memory complaints were evaluated using the Mini Mental State Examination (MMSE) and the Brief Cognitive Battery (BCB). We added two delayed recalls in the MMSE (a delayed recall and a late-delayed recall, LDR), and also a phonemic fluency test of letter P fluency (LPF). A score was created based on these tests. The diagnoses were made on the basis of clinical consensus and neuropsychological testing. Receiver operating characteristic curve analyses were used to determine area under the curve (AUC), the sensitivity and specificity for each test separately and for the final proposed score. MMSE, LDR, LPF and delayed recall of BCB scores reach statistically significant differences between groups (P=0.000, 0.03, 0.001 and 0.01, respectively). Sensitivity, specificity and AUC were MMSE: 64%, 79% and 0.75 (cut off <29); LDR: 56%, 62% and 0.62 (cut off <3); LPF: 71%, 71% and 0.71 (cut off <14); delayed recall of BCB: 56%, 82% and 0.68 (cut off <9). The proposed score reached a sensitivity of 88% and 76% and specificity of 62% and 75% for cut off over 1 and over 2, respectively. AUC were 0.81. In conclusion, a score created from screening tests is capable of discriminating MCI from SMC with moderate to good accurancy. PMID- 24147214 TI - Interleukin-1beta secretion in hippocampal sclerosis patients with mesial temporal lobe epilepsy. AB - Mesial temporal lobe epilepsy with hippocampal sclerosis (MTLE-HS) is a common medically intractable epilepsy syndrome. Although pathogenesis of HS still remains highly controversial, genetics may play a role as a predisposing factor. Previous evidence in a Japanese population revealed that the homozygotes for allele T at position -511 of the interleukin (IL)-1beta gene promoter region (IL 1beta-511 T/T) confers susceptibility to the development of HS. However, whether this polymorphism has an effect on IL-1beta levels in MTLEHS patients was not demonstrated. This study aimed to analyze the distribution of this particular polymorphism in a group of Turkish HS patients and correlate the polymorphism with IL-1beta secretion from the lymphocytes, thus revealing a functional role for IL-1beta in the etiopathogenesis of HS. A single base pair polymorphism at position -511 in the promoter region of the IL-1beta gene was analyzed. The spontaneous and 1 ng/mL lipopolysaccharidestimulated production of IL-1beta by peripheral blood mononuclear cells after 4 and 24 h of incubation were measured by ELISA method. The heterozygous type (-511 C/T) was the most common genotype. There was no difference in frequency of allele -511 T between patients and controls. Analysis of IL-1beta levels, genotype and allele distributions showed no significant difference among the groups (P>0.05). Nevertheless, it was seen that patients who carry a T allele at position -511 of the IL-1beta gene had increased IL-1beta levels. T-allele carriage may be important. Only IL-1beta secretion from the lymphocytes has been assessed in this study. Considering the importance of IL-1beta in the etiopathogenesis of HS, further studies are needed to evaluate locally produced IL-1beta levels. PMID- 24147215 TI - Movement Disorders Among Adult Neurological Outpatients Evaluated over 20 Years in Guayaquil, Ecuador. AB - There is little information available on the evolutive pattern of patients with movement disorders in developing countries. We analyzed 579 consecutive adults with movement disorders and prospectively evaluated them at our institution (Department of Neurological Sciences, Kennedy Clinic, Guayaquil, Ecuador) from 1990 to 2009. Mean age was 62.9+/-17.5 years, and 50.8% were men. Patients presented with tremor/rigidity (55%), involuntary movements (23.5%) and abnormalities of stance and gait (21.5%). Overall, 45% of our patients had degenerative disorders of the nervous system. We found significant increases in the relative prevalence of tremor/rigidity and abnormalities of stance and gait, and this reflected an increase in the number of patients with degenerative diseases over the study years. We found a dynamic pattern of movement disorders over the years. Today, causes and relative prevalence of these conditions in our population is more similar to that reported from the developed world than it was 20 years ago. PMID- 24147236 TI - BRAF V600E-Positive Multisite Langerhans Cell Histiocytosis in a Preterm Neonate. AB - Hemorrhagic pustules with a "blueberry muffin" appearance accompanied by respiratory failure in a neonate present a challenging differential diagnosis that includes infections and neoplasms. We present a case of multiorgan, multisite Langerhans cell histiocytosis (LCH), positive for the oncogenic BRAF V600E mutation, in a preterm neonate. Infants with LCH pose a diagnostic challenge due to their heterogeneous presentations. This case is unusual in that the newborn presented with severe multiorgan involvement. Due to the rare incidence, wide spectrum of clinical manifestations, and high mortality rate, clinicians must maintain a high index of suspicion for LCH. PMID- 24147237 TI - Whole blood polymerase chain reaction in a neonate with disseminated herpes simplex virus infection and liver failure. AB - A late preterm neonate born by cesarean section with intact membranes presented at 9 days of life with shock and liver failure. Surface cultures were negative but whole blood polymerase chain reaction was positive for herpes simplex virus type 2, underscoring the value of this test in early diagnosis of perinatally acquired disseminated herpes simplex virus infection without skin lesions. PMID- 24147217 TI - Stem cell transplantation for neuroprotection in stroke. AB - Stem cell-based therapies for stroke have expanded substantially over the last decade. The diversity of embryonic and adult tissue sources provides researchers with the ability to harvest an ample supply of stem cells. However, the optimal conditions of stem cell use are still being determined. Along this line of the need for optimization studies, we discuss studies that demonstrate effective dose, timing, and route of stem cells. We recognize that stem cell derivations also provide uniquely individual difficulties and limitations in their therapeutic applications. This review will outline the current knowledge, including benefits and challenges, of the many current sources of stem cells for stroke therapy. PMID- 24147238 TI - Intravenous Epoprostenol for Management of Pulmonary Arterial Hypertension during Pregnancy. AB - Background Pulmonary arterial hypertension carries a high risk of mortality in pregnancy. Recent advances in treatment may improve disease course and allow for successful management of the pregnancy. Case Report We present the case of a 20 year-old gravida 1, para 0 with diagnosis of severe primary pulmonary hypertension. The patient was managed with epoprostenol (prostacyclin) infusion via an indwelling catheter, which was initiated at 23 weeks' gestation. The dose was adjusted to the patient's symptoms and a successful vaginal delivery was achieved at 36 weeks' gestation. Although maternal postpartum course was uncomplicated, unexplained neonatal demise occurred at 11 days of life. Conclusion Successful management of pulmonary hypertension in pregnancy can be accomplished with a multidisciplinary approach and intensive therapy. Long-term effects of epoprostenol on fetal or neonatal well-being are unknown. PMID- 24147216 TI - Conserved versatile master regulators in signalling pathways in response to stress in plants. AB - From the first land plants to the complex gymnosperms and angiosperms of today, environmental conditions have forced plants to develop molecular strategies to surpass natural obstacles to growth and proliferation, and these genetic gains have been transmitted to the following generations. In this long natural process, novel and elaborate mechanisms have evolved to enable plants to cope with environmental limitations. Elements in many signalling cascades enable plants to sense different, multiple and simultaneous ambient cues. A group of versatile master regulators of gene expression control plant responses to stressing conditions. For crop breeding purposes, the task is to determine how to activate these key regulators to enable accurate and optimal reactions to common stresses. In this review, we discuss how plants sense biotic and abiotic stresses, how and which master regulators are implied in the responses to these stresses, their evolution in the life kingdoms, and the domains in these proteins that interact with other factors to lead to a proper and efficient plant response. PMID- 24147239 TI - Serial intrauterine transfusions for a hydropic fetus with severe anemia and thrombocytopenia caused by parvovirus: lessons learned. AB - Introduction Fetal exsanguination is a rare complication of cordocentesis. Successful correction of fetal thrombocytopenia is essential for the reduction of risks. Case Report A 25-year-old, gravida 3, P2-0-0-0-2, was referred at 27 weeks of gestation for evaluation of newly diagnosed nonimmune hydrops secondary to parvovirus infection. Despite the use of ancillary platelet transfusions to correct the severe fetal thrombocytopenia, prolonged bleeding from the cord puncture site still occurred, necessitating five intrauterine transfusions to ultimately correct the fetal anemia. Conclusions The use of a smaller-diameter procedure needle, correction of the fetal thrombocytopenia early in the procedure, and external cord compression with the ultrasound transducer were ultimately successful measures in allowing for minimal loss of transfused red cells from the intravascular compartment. PMID- 24147240 TI - Spontaneous Complete Uterine Rupture in a Nonlaboring, Early Third-trimester Uterus: Missed Diagnosis by Ultrasound. AB - Objective Describe potential consequences and remedy for not intermittently auscultating fetal heart tones during travel to the imaging department and misdiagnosing a ruptured uterus on ultrasound as a synechiae. Study Design Retrospective chart review of case. Results Spontaneous uterine rupture in pregnancy is a rare and catastrophic event. Fetal monitoring is an important component for diagnosis, but fetal heart auscultation is usually discontinued while the patient is receiving imaging. We present a ruptured uterus at 28 weeks with delayed diagnosis secondary to interrupted fetal heart tone auscultation and a misdiagnosis of a rupture as a synechiae resulting in a seriously compromised newborn at delivery. Conclusion Intermittent fetal heart tone auscultation is a possible method of monitoring when the patient is off continuous fetal monitoring. PMID- 24147241 TI - Twin-twin transfusion syndrome presenting as polyhydramnios in both fetuses secondary to spontaneous microseptostomy. AB - The presence of polyhydramnios and oligohydramnios is pathognomonic for twin-twin transfusion syndrome (TTTS). However, polyhydramnios of both twins can exist in TTTS in the setting of a septostomy of the dividing membrane. In prior reported cases of dual polyhydramnios TTTS, the septostomy was identified through either ultrasound or fetoscopy thus helping to establish the diagnosis of TTTS with an unusual presentation. The presented case is a set of monochorionic, diamniotic twins who presented initially with dual polyhydramnios. Subsequent ultrasound and clinical and pathologic findings were otherwise consistent with TTTS. Unlike prior reported cases, a septostomy of the dividing membrane was never identified with ultrasound or even on post delivery placental examination. However, microseptostomies were demonstrated due to the transfer of indigo carmine between the amniotic sacs at amniocentesis. Thus in the setting of TTTS concern, the diagnosis should be considered with dual polyhydramnios even if a septostomy cannot be identified. PMID- 24147242 TI - Antiviral-resistant fulminant herpes hepatitis in pregnancy. AB - Fulminant herpes hepatitis with disseminated extrahepatic involvement in pregnancy is rare and carries a high mortality risk. Although acyclovir remains standard first-line therapy, effective management of acyclovir-resistant disseminated herpes simplex virus (HSV) in pregnancy remains elusive. We present a case of disseminated HSV resistant to both acyclovir and foscarnet, the first double-agent resistant case in pregnancy reported in the literature to date. In this case, therapeutic delivery was the ultimate treatment resulting in full recovery. PMID- 24147243 TI - Resolution of neonatal hypertrophic cardiomyopathy presumed secondary to acquired maternal ribonucleoprotein and smith autoantibodies. AB - Severe asymmetrical hypertrophic cardiomyopathy without heart block accompanied by neuromuscular hypotonia and feeding difficulties was evident shortly after birth in the second child of a mother with systemic lupus erythematosus who had no indication of gestational diabetes. High-level anti-ribonucleoprotein (RNP) and Smoth (Sm) antibodies arising from transplacental transfer of maternal antibodies were detected in the child's serum. The cardiac abnormalities improved with a commensurate decline in antibody titers. Previously reported cases of neonatal cardiomyopathy with endocardial fibroelastosis have been ascribed to the transplacental transfer of maternal Sjogrens Syndrome (SS) A (Ro) and Sjogrens Syndrome (SS) B (La) antibodies and have been more severe and persistent compared with our patient. We advocate close monitoring of all babies of mothers with systemic autoimmunity for changes in heart rate during pregnancy and signs of heart failure and neuromuscular weakness after delivery. PMID- 24147244 TI - Fetal heterotaxy with tricuspid atresia, pulmonary atresia, and isomerism of the right atrial appendages at 22 weeks. AB - We report the accurate prenatal diagnosis at 22 weeks gestation of right atrial isomerism in association with tricuspid atresia. Several distinctive sonographic features of isomerism of the right atrial appendages were present in this fetus: complex cardiac abnormality, ventriculoarterial discordance, juxtaposition of the aorta and the inferior vena cava to the right side, pulmonary atresia, and anomalous pulmonary venous return to the morphological right atrium. Tricuspid atresia, which is an extremely rare lesion within heterotaxy spectrum disorders, was present. Postnatal investigations confirmed all prenatally diagnosed abnormalities, with additional findings of pulmonary atresia with discontinuous pulmonary arteries and bilateral arterial ducts, asplenia, and bilateral eparterial bronchi. To our knowledge, tricuspid atresia in the setting of isomerism of the right atrial appendages has not previously been diagnosed or reported prenatally. Because of the complexity of cardiac lesions that may be present in cases of atrial isomerism, these disorders should be considered even if sonographic findings are uncommon or atypical. PMID- 24147245 TI - Accidental Electric Shock during Pregnancy: Reflection on a Case. AB - Objectives Data on fetal effects following accidental electric shock during pregnancy are scarce. We report on a case of accidental maternal electric shock associated with benign fetal arrhythmia in a woman at 28 weeks' gestation. Study Design Case report. Results Although electrocution involving low-voltage, low frequency current has been associated with fatal cardiac arrhythmias and conduction abnormalities, two protective parameters in the present case likely reduced the fetal injury: the dry skin at the site of current entry and the hand to-hand pathway of current flow. Conclusion Because the pathophysiology of electric injury is altered during pregnancy, assessment of fetal well-being should be prompted no matter how trivial an incident may appear. PMID- 24147246 TI - An Unusual Case of Early Onset Persistent Escherichia coli Septicemia Associated with Endocarditis. AB - Escherichia coli infection is very common cause of early onset septicemia especially in very low-birth-weight newborns, but E. coli endocarditis has not been described in newborns. E. coli endocarditis, even in the adult population, is a rare and not well-characterized disease and is associated with high mortality. We report a very unusual presentation of persistent E. coli infection associated with endocarditis. PMID- 24147247 TI - Perinatal survival of a fetus with intestinal volvulus and intussusception: a case report and review of the literature. AB - Fetal intestinal volvulus is a rare life-threatening condition. Late diagnosis of volvulus contributes to high rate of morbidity and mortality. It has variable degrees of presentation and survival. Intrauterine volvulus may be complicated by intestinal atresia due to ischemic necrosis. To our knowledge, there are three reported cases of term fetal demise. We report a case of fetal intestinal volvulus with perinatal survival of the largest term infant described with this complication to date. The volvulus was associated with type 3A jejunal atresia and intestinal pathology was noted on prenatal ultrasound. The infant was born via urgent cesarean delivery at 37(6/7) weeks of gestation and underwent emergent exploratory laparotomy with resection of small bowel and primary end-to-end anastomosis. Intrauterine intestinal volvulus may be suspected on prenatal ultrasound but only definitively diagnosed postnatally. Signs of fetal distress and volvulus are rarely associated with reports of survival in the term fetus. We review reported cases of prenatally suspected volvulus in infants documented to survive past the neonatal period. As fetal volvulus and most intestinal atresias/stenoses manifest during the third trimester, we recommend that the limited fetal anatomical survey during growth ultrasounds at 32 to 36 weeks routinely include an assessment of the fetal bowel. PMID- 24147248 TI - Subsequent Pregnancy after Preterm Prelabor Rupture of Membranes before 27 Weeks' Gestation. AB - Objective Midtrimester preterm prelabor rupture of membranes (PPROM) has a high rate of neonatal mortality and morbidity. The aim of this study was to study outcomes of subsequent pregnancies after a pregnancy with PPROM before 27 weeks' gestation. Study Design Retrospective study of subsequent pregnancies of women who suffered PPROM before 27 weeks' gestation from 1994 to 2009. The main outcome measure was the risk of recurrence of PPROM before 27 weeks' gestation. The authors also studied preterm birth and pregnancy outcome in the subsequent pregnancy. Finally, they assessed associative factors for subsequent premature delivery. Results They identified 307 patients, of whom 118 women had a subsequent pregnancy. Of 99 women with complete outcome data, 9 women (9%) had PPROM before 27 weeks' gestation in a subsequent pregnancy and 35 women (35%) had a preterm delivery. In 58 (59%) of pregnancies no major complications occurred. They found three associative factors for premature delivery in a subsequent pregnancy: negative vaginal culture for Group B streptococcus, increasing maternal age and early gestational age at PPROM in the index pregnancy. Conclusions Women with PPROM before 27 weeks have a 9% recurrence risk of early PPROM and a risk of 35% of having a preterm delivery in a subsequent pregnancy. PMID- 24147249 TI - Pancreatic agenesis with congenital diaphragmatic hernia and congenital heart disease: a case report. AB - Pancreatic agenesis is a rare disease that causes neonatal diabetes mellitus and exocrine pancreatic insufficiency. We report the case of a very low birth weight infant with congenital diaphragmatic hernia, and congenital heart disease (ventricular septal defect and patent ductus arteriosus). Failure to gain weight, despite well-managed respiratory and heart failure, was improved by infusion of subcutaneous insulin, administration of pancreatic enzyme, and nutrition of medium-chain-triglyceride -enriched formula. This is the first case of pancreatic agenesis with both malformations where the patient is discharged from the hospital. Early diagnosis and adequate treatments to compensate pancreatic function may prevent mortality and improve growth. PMID- 24147250 TI - Trunnionosis: A pain in the neck. AB - Metal-on-metal (MoM) hip replacements have proven to be a modern day orthopaedic failure. The early enthusiasm and promise of a hard, durable bearing was quickly quashed following the unanticipated wear rates. The release of metal ions into the blood stream has been shown to lead to surrounding soft tissue complications and early failure. The devastating destruction caused has led to a large number of revision procedures and implant extractions. The resulting research into this field has led to a new area of interest; that of the wear at the trunnion of the prosthesis. It had been previously thought that the metal debris was generated solely from the weight bearing articulation, however with the evolution of modularity to aid surgical options, wear at the trunnion is becoming more apparent. The phenomenon of "trunnionosis" is a rapidly developing area of interest that may contribute to the overall effect of metallosis in MoM replacements but may also lead to the release of metal ions in non MoM hip designs. The aim of this paper is to introduce, explain and summarise the evidence so far in the field of trunnionosis. The evidence for this phenomenon, the type of debris particles generated and a contrast between MoM, non MoM and resurfacing procedures are also presented. PMID- 24147252 TI - Multi-factorial sustainability approach is necessary to preserve knee function following osteoarthritis diagnosis. AB - Knee function preservation following a diagnosis of osteoarthritis may benefit from healthy patient lifestyles, exercise or activity habits, and daily living routines. Underlying societal issues and social roles may contribute further to both ecological and knee function preservation concerns. Based on sustainability theory and social ecology concepts we propose that factors such as health history, genetic predisposition, socio-environmental factors and local-regional global physiological system viability contribute to knee function preservation. Addressing only some of these factors or any one factor in isolation can lead the treating physician, surgeon and rehabilitation clinician to less than optimal treatment effectiveness. An example is presented of a 57-year-old man with medial tibiofemoral osteoarthritis. In the intervention decision-making process several factors are important. Patients who would benefit from early knee arthroplasty tend to place osteoarthritic knee pain elimination at the top of their list of treatment expectations. They also have minimal or no desire to continue impact sport, recreational or vocational activities. In contrast, patients who are good candidates for a knee function preservation treatment approach tend to have greater expectations to be able to continue impact sport, recreational or vocational activities, are willing and better able to implement significant behavioral changes and develop the support systems needed for their maintenance, are willing to tolerate and live with minor-to-moderate intermittent knee pain, and learn to become more pain tolerant. PMID- 24147251 TI - Normal and abnormal spine and thoracic cage development. AB - Development of the spine and thoracic cage consists of a complex series of events involving multiple metabolic processes, genes and signaling pathways. During growth, complex phenomena occur in rapid succession. This succession of events, this establishment of elements, is programmed according to a hierarchy. These events are well synchronized to maintain harmonious limb, spine and thoracic cage relationships, as growth in the various body segments does not occur simultaneously at the same magnitude or rate. In most severe cases of untreated progressive early-onset spinal deformities, respiratory insufficiency and pulmonary and cardiac hypertension (cor pulmonale), which characterize thoracic insufficiency syndrome (TIS), can develop, sometimes leading to death. TIS is the inability of the thorax to ensure normal breathing. This clinical condition can be linked to costo-vertebral malformations (e.g., fused ribs, hemivertebrae, congenital bars), neuromuscular diseases (e.g., expiratory congenital hypotonia), Jeune or Jarcho-Levin syndromes or to 50% to 75% fusion of the thoracic spine before seven years of age. Complex spinal deformities alter normal growth plate development, and vertebral bodies become progressively distorted, perpetuating the disorder. Therefore, many scoliotic deformities can become growth plate disorders over time. This review aims to provide a comprehensive review of how spinal deformities can affect normal spine and thoracic cage growth. Previous conceptualizations are integrated with more recent scientific data to provide a better understanding of both normal and abnormal spine and thoracic cage growth. PMID- 24147253 TI - Role of RANKL/RANK in primary and secondary breast cancer. AB - Bone is one of the most preferential metastatic target sites of breast cancer. Bone possesses unique biological microenvironments in which various growth factors are stored and continuously released through osteoclastic bone resorption, providing fertile soil for circulating breast cancer cells. Bone disseminated breast cancer cells in turn produce osteotropic cytokines which modulate bone environments. Under the influences of breast cancer-produced cytokines, osteoblasts express elevated levels of Ligand for receptor activator of nuclear factor-kappaB (RANKL) and stimulate osteoclastogenesis via binding to the receptor receptor activator of nuclear factor-kappaB (RANK) and activating its downstream signaling pathways in hematopoietic osteoclast precursors, which causes further osteoclastic bone destruction. Establishment of crosstalk with bone microenvironments (so called vicious cycle) is an essential event for metastatic breast cancer cells to develop bone metastasis. RANKL and RANK play a central role in this crosstalk. Moreover, recent studies have demonstrated that RANKL and RANK are involved in tumorigenesis and distant metastasis independent of bone microenvironments. Pharmacological disruption of the RANKL/RANK interplay should be an effective therapeutic intervention for primary breast tumors and bone and non-bone metastasis. In this context, denosumab, which is neutralizing monoclonal antibody against RANKL, is a mechanism-based drug for the treatment of bone metastases and would be beneficial for breast cancer patients with bone metastases and potentially visceral organ metastases. PMID- 24147254 TI - Historically significant events in the discovery of RANK/RANKL/OPG. AB - After it was suggested 30 years ago that the osteoblast lineage controlled the formation of osteoclasts, methods were developed that established this to be the case, but the molecular controls were elusive. Over more than a decade much evidence was obtained for signaling mechanisms that regulated the production of a membrane - bound regulator of osteoclastogenesis, in the course of which intercellular communication in bone was revealed in its complexity. The discovery of regulation by tumor necrosis factor ligand and receptor families was made in the last few years of the twentieth century, leading since then to a new physiology of bone, and to exciting drug development. PMID- 24147255 TI - Role of osteoclasts in regulating hematopoietic stem and progenitor cells. AB - Bone marrow (BM) cavities are utilized for hematopoiesis and to maintain hematopoietic stem cells (HSCs). HSCs have the ability to self-renew as well as to differentiate into multiple different hematopoietic lineage cells. HSCs produce their daughter cells throughout the lifespan of individuals and thus, maintaining HSCs is crucial for individual life. BM cavities provide a specialized microenvironment termed "niche" to support HSCs. Niches are composed of various types of cells such as osteoblasts, endothelial cells and reticular cells. Osteoclasts are unique cells which resorb bones and are required for BM cavity formation. Loss of osteoclast function or differentiation results in inhibition of BM cavity formation, an osteopetrotic phenotype. Osteoclasts are also reportedly required for hematopoietic stem and progenitor cell (HSPC) mobilization to the periphery from BM cavities. Thus, lack of osteoclasts likely results in inhibition of HSC maintenance and HSPC mobilization. However, we found that osteoclasts are dispensable for hematopoietic stem cell maintenance and mobilization by using three independent osteoclast-less animal models. In this review, I will discuss the roles of osteoclasts in hematopoietic stem cell maintenance and mobilization. PMID- 24147256 TI - RANKL, a necessary chance for clinical application to osteoporosis and cancer related bone diseases. AB - Osteoporosis is a common bone disease characterized by reduced bone and increased risk of fracture. In postmenopausal women, osteoporosis results from bone loss attributable to estrogen deficiency. Osteoclast differentiation and activation is mediated by receptor activator of nuclear factor-kappaB ligand (RANKL), its receptor receptor activator of nuclear factor-kappaB (RANK), and a decoy receptor for RANKL, osteoprotegerin (OPG). The OPG/RANKL/RANK system plays a pivotal role in osteoclast biology. Currently, a fully human anti-RANKL monoclonal antibody named denosumab is being clinically used for the treatment of osteoporosis and cancer-related bone disorders. This review describes recent advances in RANKL related research, a story from bench to bedside. First, the discovery of the key factors, OPG/RANKL/RANK, revealed the molecular mechanism of osteoclastogenesis. Second, we established three animal models: (1) a novel and rapid bone loss model by administration of glutathione-S transferase-RANKL fusion protein to mice; (2) a novel mouse model of hypercalcemia with anorexia by overexpression of soluble RANKL using an adenovirus vector; and (3) a novel mouse model of osteopetrosis by administration of a denosumab-like anti-mouse RANKL neutralizing monoclonal antibody. Lastly, anti-human RANKL monoclonal antibody has been successfully applied to the treatment of osteoporosis and cancer-related bone disorders in many countries. This is a real example of applying basic science to clinical practice. PMID- 24147257 TI - Feet injuries in rock climbers. AB - While injuries of the upper extremity are widely discussed in rock climbers, reports about the lower extremity are rare. Nevertheless almost 50 percent of acute injuries involve the leg and feet. Acute injuries are either caused by ground falls or rock hit trauma during a fall. Most frequently strains, contusions and fractures of the calcaneus and talus. More rare injuries, as e.g., osteochondral lesions of the talus demand a highly specialized care and case presentations with combined iliac crest graft and matrix associated autologous chondrocyte transplantation are given in this review. The chronic use of tight climbing shoes leads to overstrain injuries also. As the tight fit of the shoes changes the biomechanics of the foot an increased stress load is applied to the fore-foot. Thus chronic conditions as subungual hematoma, callosity and pain resolve. Also a high incidence of hallux valgus and hallux rigidus is described. PMID- 24147259 TI - Methods of predicting vertebral body fractures of the lumbar spine. AB - Lumbar vertebral body (VB) fractures are increasingly common in an ageing population that is at greater risk of osteoporosis and metastasis. This review aims to identify different models, as alternatives to bone mineral density (BMD), which may be applied in order to predict VB failure load and fracture risk. The most representative models are those that take account of normal spinal kinetics and assess the contribution of the cortical shell to vertebral strength. Overall, predictive models for VB fracture risk should encompass a range of important parameters including BMD, geometric measures and patient-specific factors. As interventions like vertebroplasty increase in popularity for VB fracture treatment and prevention, such models are likely to play a significant role in the clinical decision-making process. More biomechanical research is required, however, to reduce the risks of post-operative adjacent VB fractures. PMID- 24147258 TI - Healing of subcutaneous tendons: Influence of the mechanical environment at the suture line on the healing process. AB - Tendon ruptures remain a significant musculoskeletal injury. Despite advances in surgical techniques and procedures, traditional repair techniques maintain a high incidence of rerupture or tendon elongation. Mechanical loading and biochemical signaling both control tissue healing. This has led some researchers to consider using a technique based on tension regulation at the suture line for obtaining good healing. However, it is unknown how they interact and to what extent mechanics control biochemistry. This review will open the way for understanding the interplay between mechanical loading and the process of tendon healing. PMID- 24147260 TI - Feasibility of progressive strength training shortly after hip fracture surgery. AB - AIM: To investigate the feasibility of a 6-wk progressive strength-training programme commenced shortly after hip fracture surgery in community-dwelling patients. METHODS: This prospective, single-blinded cohort study evaluated 31 community-dwelling patients from four outpatient geriatric health centres aged 60 years or older, who started a 6-wk programme at a mean of 17.5 +/- 5.7 d after hip fracture surgery. The intervention consisted primarily of progressive fractured knee-extension and bilateral leg press strength training (twice weekly), with relative loads commencing at 15 and increasing to 10 repetitions maximum (RM), with three sets in each session. The main measurements included progression in weight loads, hip fracture-related pain during training, maximal isometric knee-extension strength, new mobility score, the timed up and go test, the 6-min walk test and the 10-meter fast speed walk test, assessed before and after the programme. RESULTS: Weight loads in kilograms in the fractured limb knee-extension strength training increased from 3.3 +/- 1.5 to 5.7 +/- 1.7 and from 6.8 +/- 2.4 to 7.7 +/- 2.6, respectively, in the first and last 2 wk (P < 0.001). Correspondingly, the weight loads increased from 50.3 +/- 1.9 to 90.8 +/- 40 kg and from 108.9 +/- 47.7 to 121.9 +/- 54 kg in the bilateral leg press exercise (P < 0.001). Hip fracture-related pain was reduced, and large improvements were observed in the functional outcome measurements, e.g., the 6 min walk test improved from 200.6 +/- 79.5 to 322.8 +/- 68.5 m (P < 0.001). The fractured limb knee-extension strength deficit was reduced from 40% to 17%, compared with the non-fractured limb. Ten patients reported knee pain as a minor restricting factor during the last 10 RM knee-extension strength-training sessions, but with no significant influences on performance. CONCLUSION: Progressive strength training, initiated shortly after hip fracture surgery, seems feasible and does not increase hip fracture-related pain. Progressive strength training resulted in improvement, although a strength deficit of 17% persisted in the fractured limb compared with the non-fractured limb. PMID- 24147261 TI - Collecting a comprehensive evidence base to monitor fracture rehabilitation: A case study. AB - AIM: To determine the feasibility and potential role of combining radiostereometric analysis (RSA), gait analysis and activity monitoring in the follow-up of fracture patients. METHODS: Two patients with similar 41B3 tibial plateau fractures were treated by open reduction internal fixation augmented with impaction bone grafting and were instructed to partial weight bear to 10 kg for the first six postoperative weeks. Fracture reduction and fixation were assessed by postoperative computer tomographic (CT) scanning. Both patients had tantalum markers inserted intra-operatively to monitor their fracture stability during healing using RSA and differentially loaded RSA (DLRSA) at 6 and 12 wk postoperatively. Gait analyses were performed at 1, 2, 6, and 12 wk postoperatively. Activity monitors were worn for 4 wk between the 2 and 6 wk appointments. In addition to gait analysis, knee function was assessed using the patient reported Lysholm scores, and doctor reported knee range of motion and stability, at 6 and 12 wk postoperatively. RESULTS: There were no complications. CT demonstrated that both fractures were reduced anatomically. Gait analysis indicated that Patient 1 bore weight to 60% of body weight at 2 wk postoperative and 100% at 6 wk. Patient 2 bore weight at 10% of body weight to 6 wk and had very low joint contact forces to that time. At 12 wk however, there was no difference between the gait patterns in the two patients. Patient 1 increased activities of moderate-vigorous intensity from 20 to 60 min/d between 2 and 6 postoperative weeks, whereas Patient 2 remained more stable at 20-30 min/d. The Lysholm scores were similar for both patients and did not improve between 6 and 12 wk postoperatively. DLRSA examination at 12 wk showed that both patients were comfortable to weight bear to 80 kg and under this weight the fractures displaced less than 0.4 mm. RSA measurements demonstrated over time fracture migrations of less than 2 mm in both cases. However, Patient 2, who followed the postoperative weight bearing instructions most closely, displaced less (0.3 mm vs 1.6 mm). CONCLUSION: This study demonstrates the potential of using a combination of RSA, gait analysis and activity monitoring to obtain a comprehensive evidence base for postoperative weight bearing schedules during fracture healing. PMID- 24147262 TI - Experimental and finite element analysis of tibial stress fractures using a rabbit model. AB - AIM: To determine if rabbit models can be used to quantify the mechanical behaviour involved in tibial stress fracture (TSF) development. METHODS: Fresh rabbit tibiae were loaded under compression using a specifically-designed test apparatus. Weights were incrementally added up to a load of 30 kg and the mechanical behaviour of the tibia was analysed using tests for buckling, bone strain and hysteresis. Structural mechanics equations were subsequently employed to verify that the results were within the range of values predicted by theory. A finite element (FE) model was developed using cross-sectional computer tomography (CT) images scanned from one of the rabbit bones, and a static load of 6 kg (1.5 times the rabbit's body weight) was applied to represent running. The model was validated using the experimental strain gauge data, then geometric and elemental convergence tests were performed in order to find the minimum number of cross sectional scans and elements respectively required for convergence. The analysis was then performed using both the model and the experimental results to investigate the mechanical behaviour of the rabbit tibia under compressive load and to examine crack initiation. RESULTS: The experimental tests showed that under a compressive load of up to 12 kg, the rabbit tibia demonstrates linear behaviour with little hysteresis. Up to 30 kg, the bone does not fail by elastic buckling; however, there are low levels of tensile stress which predominately occur at and adjacent to the anterior border of the tibial midshaft: this suggests that fatigue failure occurs in these regions, since bone under cyclic loading initially fails in tension. The FE model predictions were consistent with both mechanics theory and the strain gauge results. The model was highly sensitive to small changes in the position of the applied load due to the high slenderness ratio of the rabbit's tibia. The modelling technique used in the current study could have applications in the development of human FE models of bone, where, unlike rabbit tibia, the model would be relatively insensitive to very small changes in load position. However, the rabbit model itself is less beneficial as a tool to understand the mechanical behaviour of TSFs in humans due to the small size of the rabbit bone and the limitations of human-scale CT scanning equipment. CONCLUSION: The current modelling technique could be used to develop human FE models. However, the rabbit model itself has significant limitations in understanding human TSF mechanics. PMID- 24147263 TI - Percutaneous pelvic osteotomy in cerebral palsy patients: Surgical technique and indications. AB - AIM: To describe the surgical technique of and indications for percutaneous pelvic osteotomy in patients with severe cerebral palsy. METHODS: Twenty-one non ambulatory children and adolescents (22 hips) were consecutively treated with percutaneous pelvic osteotomy, which was used in conjunction with varus, derotational, shortening femoral osteotomy and soft tissue release, to correct progressive hip subluxation and acetabular dysplasia. The age, gender, Gross Motor Function Classification System level, side(s) of operated hip, total time of follow-up, immediate post-operative immobilization, complications, and the need for revision surgery were recorded for all patients. RESULTS: Seventeen patients (81%) were classified as GMFCS level IV, and 4 (19%) patients were classified as GMFCS level V. At the time of surgery, the mean age was 10.3 years (range: 4-15 years). The mean Reimers' migration percentage improved from 63% (range: 3%-100%) pre-operatively to 6.5% (range: 0%-70%) at the final follow-up (P < 0.05). The mean acetabular angle (AA) improved from 34.1 degrees (range: 19 degrees -50 degrees ) pre-operatively to 14.1 degrees (range: 5 degrees -27 degrees ) (P < 0.05). Surgical correction of MP and AA was comparable in hips with open (n = 14) or closed (n = 8) triradiate cartilage (P < 0.05). All operated hips were pain-free at the time of the final follow-up visit, although one patient had pain for 6 mo after surgery. We did not observe any cases of bone graft dislodgement or avascular necrosis of the femoral head. CONCLUSION: Pelvic osteotomy through a less invasive surgical approach appears to be a valid alternative with similar outcomes to those of standard techniques. This method allows for less muscle stripping and blood loss and a shorter operating time. PMID- 24147264 TI - Reliability of preoperative measurement with standardized templating in Total Knee Arthroplasty. AB - AIM: To investigate the correlation between preoperative measurement in total knee arthroplasty and the prosthetic size implanted. METHODS: A prospective double-blind study of 50 arthroplasties was performed. Firstly, the reliability and correspondence between the size of said measurement and the actual implant utilized was determined. Secondly, the existing correlation between the intra- and interobserver determinations with the intraclass correlation coefficient was analyzed. RESULTS: An overall correspondence of 54%, improving up to 92% when the measured size admitted a difference of one size, was found. Good intra- and interobserver reliability with an intraclass correlation coefficient greater than 0.90 (P < 0.001) was also discovered. CONCLUSION: Agreement between the preoperative measurement with standardized acetate templates and the prosthetic size implanted can be considered satisfactory. We thus conclude it is a reproducible technique. PMID- 24147265 TI - Acute effects of stochastic resonance whole body vibration. AB - AIM: To investigate the acute effects of stochastic resonance whole body vibration (SR-WBV) training to identify possible explanations for preventive effects against musculoskeletal disorders. METHODS: Twenty-three healthy, female students participated in this quasi-experimental pilot study. Acute physiological and psychological effects of SR-WBV training were examined using electromyography of descending trapezius (TD) muscle, heart rate variability (HRV), different skin parameters (temperature, redness and blood flow) and self-report questionnaires. All subjects conducted a sham SR-WBV training at a low intensity (2 Hz with noise level 0) and a verum SR-WBV training at a higher intensity (6 Hz with noise level 4). They were tested before, during and after the training. Conclusions were drawn on the basis of analysis of variance. RESULTS: Twenty-three healthy, female students participated in this study (age = 22.4 +/- 2.1 years; body mass index = 21.6 +/- 2.2 kg/m(2)). Muscular activity of the TD and energy expenditure rose during verum SR-WBV compared to baseline and sham SR-WBV (all P < 0.05). Muscular relaxation after verum SR-WBV was higher than at baseline and after sham SR-WBV (all P < 0.05). During verum SR-WBV the levels of HRV were similar to those observed during sham SR-WBV. The same applies for most of the skin characteristics, while microcirculation of the skin of the middle back was higher during verum compared to sham SR-WBV (P < 0.001). Skin redness showed significant changes over the three measurement points only in the middle back area (P = 0.022). There was a significant rise from baseline to verum SR-WBV (0.86 +/- 0.25 perfusion units; P = 0.008). The self-reported chronic pain grade indicators of pain, stiffness, well-being, and muscle relaxation showed a mixed pattern across conditions. Muscle and joint stiffness (P = 0.018) and muscular relaxation did significantly change from baseline to different conditions of SR-WBV (P < 0.001). Moreover, muscle relaxation after verum SR-WBV was higher than after sham SR-WBV (P < 0.05). CONCLUSION: Verum SR-WBV stimulated musculoskeletal activity in young healthy individuals while cardiovascular activation was low. Training of musculoskeletal capacity and immediate increase in musculoskeletal relaxation are potential mediators of pain reduction in preventive trials. PMID- 24147266 TI - Should aspirin be stopped before carpal tunnel surgery? A prospective study. AB - AIM: To determine whether patients taking aspirin during carpal tunnel release had an increase of complications. METHODS: Between January 2008 and January 2010, 150 patients underwent standard open carpal tunnel release (CTR) under intravenous regional anaesthesia. They were divided into three groups: groups 1 and 2 were made of 50 patients each, on aspirin 100 mg/d for at least a year. In group 1 the aspirin was never stopped. In group 2 it was stopped at least 5 d before surgery and resumed 3 d after. Group 3 acted as a control, with 50 patients who did not take aspirin. The incidence of clinically significant per- or post-operative complications was recorded and divided into local and cardio cerebro-vascular complications. Local complications were then divided into minor and major according to Page and Stern. Local haematomas were assessed at 2 d (before resuming aspirin in group 2) and 14 d (after resuming aspirin in group 2) postoperatively. Patients were reviewed at 2, 14 and 90 d after surgery. RESULTS: There was no significant difference in the incidence of complications in the three groups. A total of 3 complications (2 major and 1 minor) and 27 visible haematomas were recorded. Two major complications were observed respectively in group 1 (non stop aspirin) and in group 3 (never antiaggregated). The minor complication, observed in one patient of group 2 (stop aspirin), consisted of a wound dehiscence, which only led to delayed healing. All haematomas were observed in the first 48 h, no haematoma lasted for more than 2 wk and all resolved spontaneously. A major haematoma (score > 20 cm(2)) was observed in 8 patients. A minor haematoma (score < 20 cm(2)) was recorded in 19 patients. All patients at 90 d after surgery were satisfied with the result in terms of relief of their preoperative symptoms. Major and minor haematomas did not impair hand function or require any specific therapy. CONCLUSION: Our study demonstrates that continuation of aspirin did not increase the risk of complications. It is unnecessary to stop aspirin before CTR with good surgical techniques. PMID- 24147267 TI - Cemented Muller straight stem total hip replacement: 18 year survival, clinical and radiological outcomes. AB - AIM: To present the 18 year survival and the clinical and radiological outcomes of the Muller straight stem, cemented, total hip arthroplasty (THA). METHODS: Between 1989 and 2007, 176 primary total hip arthroplasties in 164 consecutive patients were performed in our institution by the senior author. All patients received a Muller cemented straight stem and a cemented polyethylene liner. The mean age of the patients was 62 years (45-78). The diagnosis was primary osteoarthritis in 151 hips, dysplasia of the hip in 12 and subcapital fracture of the femur in 13. Following discharge, serial follow-up consisted of clinical evaluation based on the Harris Hip Score and radiological assessment. The survival of the prosthesis using revision for any reason as an end-point was calculated by Kaplan-Meier analysis. RESULTS: Twenty-four (15%) patients died during the follow-up study, 6 (4%) patients were lost, while the remaining 134 patients (141 hips) were followed-up for a mean of 10 years (3-18 years). HSS score at the latest follow-up revealed that 84 hips (59.5%) had excellent results, 30 (22.2%) good, 11 (7.8%) fair and 9 (6.3%) poor. There were 3 acetabular revisions due to aseptic loosening. Six (4.2%) stems were diagnosed as having radiographic definitive loosening; however, only 1 was revised. 30% of the surviving stems showed no radiological changes of radiolucency, while 70% showed some changes. Survival of the prosthesis for any reason was 96% at 10 years and 81% at 18 years. CONCLUSION: The 18 year survival of the Muller straight stem, cemented THA is comparable to those of other successful cemented systems. PMID- 24147268 TI - Current practice variations in the management of anterior cruciate ligament injuries in Croatia. AB - AIM: To investigate current preferences and opinions on the diagnosis, treatment and rehabilitation of patients with anterior cruciate ligament (ACL) injury in Croatia. METHODS: The survey was conducted using a questionnaire which was sent by e-mail to all 189 members of the Croatian Orthopaedic and Traumatology Association. Only respondents who had performed at least one ACL reconstruction during 2011 were asked to fill out the questionnaire. RESULTS: Thirty nine surgeons responded to the survey. Nearly all participants (95%) used semitendinosus/gracilis tendon autograft for reconstruction and only 5% used bone patellar tendon-bone autograft. No other graft type had been used. The accessory anteromedial portal was preferred over the transtibial approach (67% vs 33%). Suspensory fixation was the most common graft fixation method (62%) for the femoral side, followed by the cross-pin (33%) and bioabsorbable interference screw (5%). Almost all respondents (97%) used a bioabsorbable interference screw for tibial side graft fixation. CONCLUSION: The results show that ACL reconstruction surgery in Croatia is in step with the recommendations from latest world literature. PMID- 24147269 TI - Effect of risedronate on speed of sound in postmenopausal women with osteoporosis. AB - AIM: To examine the effects of treatment with risedronate for 1 year on speed of sound (SOS) of the calcaneus and bone turnover markers in postmenopausal women with osteoporosis. METHODS: Thirty-eight postmenopausal women with osteoporosis who had been treated with risedronate for > 1 year were enrolled in the study. The SOS and bone turnover markers were monitored during treatment with risedronate for 1 year. RESULTS: The urinary levels of cross-linked N-terminal telopeptides of type I collagen and serum levels of alkaline phosphatase were significantly decreased at 3 mo (-34.7%) and 12 mo (-21.2%), respectively, compared with the baseline values. The SOS increased modestly, but significantly by 0.65% at 12 mo compared with the baseline value. Treatment with risedronate elicited an increase in the SOS of the calcaneus exceeding the coefficient of variation in vivo (0.27%). CONCLUSION: The present study confirmed that risedronate suppressed bone turnover and elicited a clinically significant increase in the SOS of the calcaneus in postmenopausal women with osteoporosis. PMID- 24147270 TI - Treatment of C2 body fracture with unusual distractive and rotational components resulting in gross instability. AB - Cervical fractures can result in severe neurological compromise and even death. One of the most commonly injured segments is the C2 vertebrae, which most frequently involves the odontoid process. In this report, we present the unusual case of a 28-year-old female who sustained a C2 vertebral body fracture (comminuted transverse fracture through the body and both transverse processes) that had both a significant distractive and rotational component, causing the fracture to be highly unstable. Application of halo bracing was unsuccessful. The patient subsequently required a C1-C4 posterior spinal fusion. Follow-up computer tomography imaging confirmed fusion and the patient did well clinically thereafter. PMID- 24147271 TI - Low-grade central osteosarcoma of distal femur, resembling fibrous dysplasia. AB - We report a case of a 32 year-old male, admitted for a lytic lesion of the distal femur. One month after the first X-ray, clinical and imaging deterioration was evident. Open biopsy revealed fibrous dysplasia. Three months later, the lytic lesion had spread to the whole distal third of the femur reaching the articular cartilage. The malignant clinical and imaging features necessitated excision of the lesion and reconstruction with a custom-made total knee arthroplasty. Intra operatively, no obvious soft tissue infiltration was evident. Nevertheless, an excision of the distal 15.5 cm of the femur including 3.0 cm of the surrounding muscles was finally performed. The histological examination of the excised specimen revealed central low-grade osteosarcoma. Based on the morphological features of the excised tumor, allied to the clinical findings, the diagnosis of low-grade central osteosarcoma was finally made although characters of a fibrous dysplasia were apparent. Central low-grade osteosarcoma is a rare, well differentiated sub-type of osteosarcoma, with clinical, imaging, and histological features similar to benign tumours. Thus, initial misdiagnosis is usual with the condition commonly mistaken for fibrous dysplasia. Central low-grade osteosarcoma is usually treated with surgery alone, with rare cases of distal metastases. However, regional recurrence is quite frequent after close margin excision. PMID- 24147273 TI - Uniaxially-aligned PVDF nanofibers as a sensor and transmitter for biotelemetry. AB - Biotelemetry has become an important part of medical research for patient care by remotely monitoring continuing biological processes and physiological functions. However, current biotelemetry systems are complex requiring multiple electronic components to function: a battery, a sensor, and a transmitter, and a receiver. Another paramount concern of biotelemetry is the coupling of its in vivo portion to external supporting equipment. Here we report a novel biotelemetry device made primarily of a coiled bundle of uniaxially-aligned biocompatible polyvinylidene fluoride (PVDF) nanofibers of ~200 nm in diameter and with piezoelectric properties that can serve concurrently as a power source, sensor, and transmitter. We tested this device on a cantilever beam that was periodically deflected at its free end. Without a power supply the coil of a nanofiber bundle is shown to generate and transmit an electrical signal wirelessly in response to the beam deflection which was received by an external receiver. The coil of a nanofiber bundle was encapsulated in a thin biocompatible polymer shell for device integrity and moisture isolation. Our results suggest that the device can potentially serve as a mechanical sensor and biotelemeter for various in vitro and in vivo biomedical applications. PMID- 24147272 TI - Patient versus parental perceptions about pain and disability in children and adolescents with a variety of chronic pain conditions. AB - BACKGROUND: Cross-informant variance is often observed in patient self-reports versus parent proxy reports of pediatric chronic pain and disability. OBJECTIVE: To assess the relationship and merit of the child versus parent perspective. METHODS: A total of 99 patients (eight to 17 years of age [mean 13.2 years]; 71% female, 81% Caucasian) and parents completed the Pediatric Pain Questionnaire and Functional Disability Inventory at their initial clinic visit. Patients' and parents' pain intensity and disability scores were analyzed using an intraclass correlation coefficient (ICC), Wilcoxon signed-rank test, Bland-Altman plot and Spearman's correlation coefficient. The association between clinical/demographic variables and differences in patient/parent pain intensity and disability scores was assessed using multivariable regression. RESULTS: There was significant agreement between patients' self-reports and parents' proxy reports of their child's pain intensity (ICC=0.52; P<0.001) and disability (ICC=0.57; P=0.004) at the individual level. There were no significant group differences in patient versus parent-proxy pain intensity scores (P=0.40) and disability scores (P=0.54). The difference between patient and parent-proxy pain intensity was associated with patients' self-reported pain intensity (P<0.001). The difference between patient and parent-proxy disability was associated with patient's self reported pain disability (P<0.001). Bland-Altman plots revealed major inter-rater variation in the Pediatric Pain Questionnaire and Functional Disability Inventory across their score ranges. A significant relationship (r=0.38; P<0.001) was observed between patients' self-reported pain intensity and disability. CONCLUSIONS: While equal merit should ideally be given to pediatric chronic pain patients' self-reports and their parents' proxy reports of pain intensity and disability, it would appear that, as needed, pediatric patients or parents can offer a clinically valid, single clinical perspective. PMID- 24147274 TI - [The regional chairman's vertical orders of a useless treatment 2]. PMID- 24147275 TI - [New cancer drugs are no better than old]. PMID- 24147276 TI - [Reply: no need to worry]. PMID- 24147277 TI - [Cleaning in hospitals: from aesthetics to infection control]. PMID- 24147279 TI - Anterior segment optical coherence tomography (AS-OCT) cannot be a substitution of gonioscopy. PMID- 24147278 TI - Isotretinoin: update on controversial issues. AB - Acne vulgaris is a commonly seen dermatologic condition that plagues millions and can be very psychosocially disabling. Severe and recalcitrant acne is typically treated with isotretinoin. Isotretinoin is a synthetic vitamin A derivative that has been available since 1982.This therapeutic option has been the most effective at putting severe and recalcitrant acne vulgaris into remission. Despite its effectiveness,it has been associated with inflammatory bowel disease, depression, suicidality, and teratogenicity. We review the current literature on isotretinoin's role in inflammatory bowel disease, depression, and suicidality. In addition, we review whether or not the iPledge program has been successful at reducing pregnancy rates while on isotretinoin. PMID- 24147280 TI - MIM conference focuses on malaria elimination. PMID- 24147281 TI - The case of the locked house. The unfinished mystery. PMID- 24147283 TI - The Editor's offering. PMID- 24147282 TI - The influence of global heating on discretionary physical activity: an important and overlooked consequence of climate change. PMID- 24147284 TI - The Presidents' page. Living in a Bayesian world: can we "Bayes" our approach to decompression? PMID- 24147286 TI - Guidelines for rescue of an unresponsive diver from depth. PMID- 24147288 TI - Weak evidence that HBOT is of benefit in the treatment of patients with Herpes zoster. PMID- 24147287 TI - Hyperbaric oxygen therapy no better than sham in improving post-concussion symptoms following mild traumatic brain injury. PMID- 24147289 TI - An assessment on the effectiveness mumps vaccine during a large outbreak among kindergarten children. PMID- 24147290 TI - Analysis on the rate of passive smoking in Beijing residents from 2001-2008. PMID- 24147291 TI - Investigation on the source of infection regarding an avian influenza (H7N9) in Changxing, Zhejiang province. PMID- 24147292 TI - Informed consent/medical battery: failure to obtain appropriate consent may lead to a claim for battery. Holt v. Alexander, _____ S.W. 2d _____, No. W2003-02541- COA-R3-CV (Ct. App. Tenn. January 13, 2005). PMID- 24147293 TI - Informed consent: cause of action for failure to obtain mother's informed consent may be available to child. Draper v. Jasionowski, 858 A. 2d 1141 (Super. Ct. N.J. 2004). PMID- 24147294 TI - Long-term care: arbitration agreements may be enforceable in Texas. In re Ledet, _____ S.W. 2d _____, No. 04-04-004211-CV (Ct. App. 4th Dist. Tex. December 22, 2004). PMID- 24147296 TI - Professional/general liability: failing to prevent a patient from falling may be a professional liability claim. Grossman v. Barke, 868 A.2d 561 (Super. Ct. Pa. 2005). PMID- 24147295 TI - Emergency medicine: EMTALA's statute of limitations pre-empts state law. Merce v. Greenwood, _____ F. Supp. 2d _____, No. 2:04-CV- 00610 PGC (D. Utah December 17, 2004). PMID- 24147297 TI - Case law update. Ewing v. Northridge Hospital Medical Center, 120 Cal. App. 4th 1289 (Ct. App. Cal. 2004). PMID- 24147298 TI - Case law update. Braick v. Faxton-St. Luke's Healthcare, N.Y. Misc. 2d ,CA2003 000482 (N.Y. Sup. Ct. Oneida Cty. Sept.r 22, 2004). PMID- 24147299 TI - Case law update. Garland Community Hospital v. Rose, S.W. 3d , No. 02-0902 (Tex. November 5, 2004). PMID- 24147300 TI - Case law update. Preston v. Meriter Hospital, Inc., 678 N.W. 2d 347 (Ct. App. Wis. 2004). PMID- 24147301 TI - Case law update. Long v. Jaszczak, 688 N.W. 2d 173 (N.D. 2004). PMID- 24147302 TI - [Public and health and prevention. Abstracts of the International Congress ADELF SFSP. Bordeaux, France. October 17-19, 2013]. PMID- 24147303 TI - Abstracts of the American Society for Clinical Pathology Annual Meeting. September 18-21, 2013. Chicago, Illinois, USA. PMID- 24147304 TI - Making a difference. PMID- 24147305 TI - Hypertension. PMID- 24147306 TI - Reply: To PMID 23781543. PMID- 24147307 TI - Reframing chaos. PMID- 24147308 TI - Comprehensive BMD assessment. PMID- 24147309 TI - Illicit drug overdose. PMID- 24147310 TI - Reply: To PMID 23826601. PMID- 24147311 TI - Under pressure. PMID- 24147312 TI - Will regulation lead the way to safer health care? PMID- 24147313 TI - A long-term I.T. problem. PMID- 24147314 TI - Meaningful user. Interview by Elizabeth Gardner. PMID- 24147315 TI - Evidence-based practice and research. PMID- 24147316 TI - The power of communication. PMID- 24147318 TI - Reported sleep health and viral respiratory illness in nurses. AB - PURPOSE: In this study, differences and relationships among variables in sleep quality/quantity and self-reported viral illness between day and non-day shift hospital nurses were examined. DESIGN AND METHODS: A descriptive, cross-sectional study used the 10-item Karolinska Sleep Questionnaire to measure quality of sleep in 131 direct-care nurses from a 246-bed community-owned hospital in the northwestern United States. FINDINGS: Non-day shift nurses used more techniques to stay awake while at work or aid in sleep at home. No differences were found between shifts in reported absenteeism for viral illness (m=2.9 days), or hours of reported sleep (m=7.5); significant differences were found in non-day shift quality of sleep compared to day shift nurses and between age groups. CONCLUSION: Sleep disturbances are present among nurses and differ depending on shift worked and nurse's age. No association was found between sleep and reported viral illness. PMID- 24147317 TI - A conceptual model for medical-surgical nursing: moving toward an international clinical specialty. AB - Over the last 20 years, medical-surgical nursing has changed and should now be considered an international nursing speciality. Unlike other specialities, there is no opportunity to become a nurse practitioner in most Western countries. These two issues--lack of professional recognition and career development--should be addressed. PMID- 24147319 TI - Shaping a unit's culture through effective nurse-led quality improvement. AB - Staff on a 28-bed medical telemetry unit learned the steps of effective nurse-led quality improvement through their participation in the Transforming Care at the Bedside initiative. The resulting culture change that occurred within the unit is described. PMID- 24147320 TI - Comparison of two breast carcinomas: ductal carcinoma in situ and lobular carcinoma in situ. AB - The incidence of breast carcinoma in situ is increasing, yet poorly understood. Diagnosis and management of two types of carcinoma in situ are addressed. Nurses are in key positions to educate and support patients for informed decisions about their treatment. PMID- 24147321 TI - Evaluation of a cyanoacrylate protectant to manage skin tears in the acute care population. AB - Skin tears are a common problem that can impact the quality of life due to pain and the potential of becoming complicated wounds if not treated properly. The use of a cyanoacrylate skin protectant to manage skin tears was evaluated in 30 patients in an acute care setting. PMID- 24147322 TI - Thou shalt not fall! Decreasing falls in the postoperative orthopedic patient with a femoral nerve block. AB - A Transforming Care at the Bedside model was used to decrease falls in the femoral nerve block (FNB) patient population on a 32-bed orthopedic/neurologic unit in a community hospital setting. A multifaceted, strategic practice and educational bundle was implemented, resulting in a 75% decrease in falls among patients with FNB. PMID- 24147323 TI - Use of a clinical decision support system to improve hypoglycemia management. AB - The number of persons with diabetes who enter the health care system continues to grow. Stringent glycemic management increases the risk for hypoglycemia. The use of a clinical decision support system to assist nurses in treating hypoglycemia accurately may be useful in improving adherence to specific hypoglycemia management guidelines and compliance tracking. PMID- 24147324 TI - Optimizing adolescent transition to adult care for sickle cell disease. AB - Transitioning health care from a pediatric to an adult environment in a patient with sickle cell disease presents challenges. A program developed to assist with transition is described. PMID- 24147325 TI - Cardiac glycosides, digoxin toxicity, and the antidote. PMID- 24147326 TI - Signal-to-noise ratio: filtering out ineffective communication. PMID- 24147327 TI - The role of the advanced practice nurse in promoting smoking cessation in the adult population. PMID- 24147329 TI - CLIA requirements for proficiency testing: the basics for laboratory professionals. PMID- 24147328 TI - Demographic data in research studies. PMID- 24147330 TI - The role of POCT and rapid testing. Here is an overview of an evolving approach to direct patient care. PMID- 24147331 TI - In today's challenging lab environment. Let your LIS do the heavy lifting! PMID- 24147332 TI - Surface modified slides let IHC laboratories do more with less. PMID- 24147334 TI - Urinalysis: new technologies, new potential. PMID- 24147333 TI - The challenges and opportunities for clinical laboratories. Testing for seasonal influenza viruses and beyond. PMID- 24147335 TI - Applications of multiplexing and array method. PMID- 24147336 TI - Optimizing blood gas testing. PMID- 24147337 TI - After the Myriad decision: do hurdles remain for diagnostics competition? PMID- 24147339 TI - A systematic review of the efficacy and pharmacological profile of Herba Epimedii in osteoporosis therapy. AB - The purpose of this systematic review is to assess the efficacy and pharmacological profiles of Herba Epimedii in osteoporosis therapy. Four databases were extensively retrieved that include two Chinese electronic databases (VIP Information and CNKI) and two English electronic databases (CA and MEDLINE). Herba Epimedii has been an important traditional herbal medicine for centuries in China and other Asian countries. Recently, quite a few pharmacological effects of Herba Epimedii, its extracts and active components have been identified that include improving bone health and cardiovascular function, regulating hormone level, modulating immunological function, and inhibiting tumor growth. The anti-osteoporosis activity of Herba Epimedii and its extracts have attracted world-wide attention. The literature search has revealed that a lot of studies have recently been carried out related to the bone strengthening activity of Herba Epimedii and some of its active compounds, such as total flavonoids and icariin. Pharmacokinetic and toxicity studies have confirmed the efficacy and safety of Herba Epimedii and its most abundant active component icariin, while only a few authors have reviewed the anti-osteoporosis properties of the plants. So we summarize the work of various investigators on the effects of Herba Epimedii, its extracts and active components against osteoporosis. The underlying mechanism of osteoprotective action, derivatives of icariin, animal models and cell lines used in the research were also reviewed in this paper. PMID- 24147340 TI - Development of lycopene-loaded nanostructured lipid carriers: effect of rice oil and cholesterol. AB - Nanostructured lipid carriers (NLC) were developed using a skin-compatible surfactant and natural lipid materials (rice oil, cholesterol) to incorporate lycopene. Characteristics of the NLC were explored in comparison with nanoemulsions and solid-lipid nanoparticles (SLN). Photon correlation spectroscopy, laser diffractometry (LD) and differential scanning calorimetry were used to determine particle size and thermal stability. Particle size expressed as LD (0.99) was 405 nm for the SLN, 350 nm for the NLC without cholesterol and 287 nm for the NLC with cholesterol. Rice oil and cholesterol enabled the formation of smaller particles, but cholesterol also reduced drug stability in the NLC. To preserve chemical stability of lycopene in the NLC, cholesterol should be avoided and storage should be at 4 degrees C or at room temperature. PMID- 24147341 TI - Intestinal absorption of raltitrexed and evaluation of the effects of absorption enhancers. AB - Raltitrexed (RTX) has shown clinical activity in a variety of advanced solid tumours. Its oral bioavailability is low and its intestinal absorption mechanism is not clear. In the present study, the absorption mechanism of RTX in the small intestine was investigated, and the effects of absorption enhancers and efflux transporter inhibitors were evaluated by in vitro transport studies using the Caco-2 cell model and in situ perfusion experiments in rats. Oral bioavailability of RTX in rats in the presence or absence of enhancers were also investigated. The results of in vitro and in situ experiments indicated that the kinetic model of combined mechanism (active and passive transport) fitted the concentration time data of RTX best with the highest R2 and lowest SSE (Sum of Squares for Error). The apparent or effective permeability coefficient (P(app) or P(eff)) of RTX remained statistically constant in a certain concentration range, then decreased when the concentration increased. But the decrease trend did not continue with further increase in concentration. And folic acid could competitively inhibit RTX absorption. These results suggested that a combined absorption mechanism for RTX existed. Furthermore, within certain concentration ranges, Carbomer 934P and sodium caprate (Cap-Na) exhibited significant absorption enhancement effects with low toxicity, whereas the enhancement effects of sodium deoxycholate (Deo-Na) were accompanied with acute toxicities. Moreover, probenecid and pantoprazole obviously enhanced RTX absorption, demonstrating that RTX is a substrate of the multidrug resistance protein (MRP) and breast cancer resistance protein (BCRP). A secretion experiment indicated that RTX could be effluxed into the intestines both with bile and by active efflux action. Oral bioavailability of RTX was significantly improved by the investigated absorption enhancers and transporter inhibitors, which is consistent with the in vitro and in situ experiments. PMID- 24147342 TI - Physicochemical compatibility of nebulizable drug admixtures containing colistimethate and tobramycin. AB - Inhalation therapy with nebulizable antibiotic drugs is a mainstay in treating Pseudomonas aeruginosa infections in cystic fibrosis patients. The combination of tobramycin and colistin was found to be superior to monotherapy in killing P. aeruginosa in biofilms. The simultaneous inhalation of tobramycin and colistin might be an option to increase the compliance of patients. The objective of this in-vitro study was to determine whether admixtures of inhalation solutions containing colistin methanesulfonate (CMS) and tobramycin are physicochemically compatible. Physical compatibility was determined by measuring pH and osmolality. Chemical compatibility was determined by testing the antibiotic activity of the mixtures by the pharmacopoeial microbiological assay and comparing the results to those of standard solutions. Samples were analyzed immediately after mixing and after 24 h. Values of pH and osmolality remained unchanged and in physiologically acceptable ranges. Neither for colistin methanesulfonate (CMS) nor for tobramycin losses of antibiotic potency were registered at any time. Admixtures of nebulizer solutions containing CMS and tobramycin were shown to be physicochemically compatible. Further investigations are needed to determine whether drug delivery is affected by mixing the nebulizer solutions to ensure that simultaneous inhalation is recommendable. PMID- 24147343 TI - Slow, spontaneous degradation of lansoprazole, omeprazole and pantoprazole tablets: isolation and structural characterization of the toxic antioxidants 3H benzimidazole-2-thiones. AB - The spontaneous degradation of lansoprazole, omeprazole and pantoprazole tablets upon long-term and forced storage conditions was determined by high performance liquid chromatography (HPLC). The more abundant products could be isolated by liquid chromatography and their molecular weights determined by Mass Spectrometry (MS). Their structures, established according to their spectroscopic data, were compared to those of either the literature or of authentic samples. Thus lansoprazole led mainly to a mixture of 3H-benzimidazole-2-thione (2a) and 3H benzimidazole-2-one (2c), omeprazole mainly to a mixture of 5-methoxy-3H benzimidazole-2-thione (1a) and 2-hydroxymethyl-3, 5-dimethyl-4-methoxypyridine (1b), and pantoprazole, to 5-difluoromethoxy-3H-benzimidazole-2-thione (3a) and 2 hydroxymethyl-3, 4-dimethoxypyridine (3b). Although some of the degradation products had already been observed under different conditions, the detection of benzimidazole-2-thiones is unprecedented and their involvement as possible physiological, yet toxic antioxidants must be emphasized. Plausible, unified mechanisms for the formation of the different degradation products observed herein and in previous papers from the literature are suggested. PMID- 24147344 TI - Magnolol induces apoptosis in MCF-7 human breast cancer cells through G2/M phase arrest and caspase-independent pathway. AB - Magnolol, a small-molecule hydroxylated biphenol, isolated from the root and stem bark of Magnolia officinalis, has been shown to possess antiproliferative effect on various cancer cell lines. In the current study, we found that magnolol potently inhibited proliferation and induced apoptosis in MCF-7 human breast cancer cells. Further mechanistic studies revealed that induction of apoptosis is associated with cell cycle arrest at G2/M phase, increased generation of reactive oxygen species (ROS), reduced mitochondrial membrane potential (MMP), release of cytochrome c (Cyto c) and apoptosis inducing factor (AIF) from mitochondria to cytosol, upregulation of Bax, p21 and p53, and down-regulation of Bcl-2, cyclin B1 and cyclin-dependent kinase 1 (CDK1). Our findings indicated that magnolol induced apoptosis in MCF-7 cells via the intrinsic pathway with release of AIF from mitochondrial and G2/M phase arrest pathway. Therefore, magnolol might be a potential lead compound in the therapy of breast cancer. PMID- 24147345 TI - Biotransformation of baicalin to baicalein significantly strengthens the inhibition potential towards UDP-glucuronosyltransferases (UGTs) isoforms. AB - The aim of the present study was to investigate the influence of biotransformation of baicalin into baicalein towards the inhibition potential towards one of the most important drug-metabolizing enzymes (DMEs) UDP glucuronosyltransferases (UGTs). in vitro incubation method using recombinant UGTs-catalyzed 4-methylumbelliferone (4-MU) glucuronidation was used to evaluate the inhibition towards important UGT isoforms in the liver, including UGT1A1, 1A3, 1A6, 1A9, and 2B7. At the same concentration (100 microM), baicalein showed stronger inhibition potential than baicalin towards all the tested UGT isoforms. Data fitting using Dixon plot and Lineweaver-Burk plot was carried out to determine the inhibition type, and the second plot with the slopes from Lineweaver-Burk plot towards baicalein's concentrations was used to calculate the inhibition kinetic parameters (K(i)). Competitive inhibition type was observed for UGT1A1, 1A6, 1A9 and 2B7, and noncompetitive inhibition was detected for UGT1A3. The inhibition kinetic parameters (K(i)) were calculated to be 1.2, 5.1, 15.3, 26.3, and 48.9 microM for UGT1A1, 1A3, 1A6, 1A9, and 2B7, respectively. All these information reminds us of the necessary monitoring when oral administration of baicalin or baicalin-containing herbs. PMID- 24147346 TI - Treatment with Cordyceps sinensis enriches Treg population in peripheral lymph nodes and delays type I diabetes development in NOD mice. AB - Cordyceps sinensis is a widely used Chinese traditional herb with a long history. In China C. sinensis is usually applied in the treatment of respiratory diseases, however, the efficacy of C. sinensis still lacks experimental evidence. Type I diabetes is a multi-factor related autoimmune disease caused by cellular-mediated destruction of insulin-producing pancreatic beta cells in the islets in human. We tested C. sinensis for its ability to work as an immune modulator in NOD mice, an animal model which mimicks the progression of type I diabetes in humans and found that treatment with C. sinensis extract could slow down disease development in NOD mice. Further research also suggested that treatment with C. sinensis extract increased the frequency of Treg cells and IFN-gama producing Th1 cells in peripheral lymph nodes. However, C. sinensis has no effect on the natural Treg cell differentiation in thymus. PMID- 24147347 TI - CFTR chloride channel is a molecular target of the natural cancer preventive agent resveratrol. AB - The naturally occurring polyphenol compound resveratrol (RES) has been receiving wide attention because of its variety of health benefits and favourable biological activities. Previous studies have shown that RES could induce intestinal chloride secretion in mouse jejunum and stimulate cAMP-dependent Cl- secretion in T84, primary cultured murine nasal septal and human sinonasal epithelial cells, but the precise molecular target is not clear. We therefore tested the hypothesis that RES may stimulate the activity of cystic fibrosis transmembrane conductance regulator (CFTR) chloride channel. Using cell-based fluorescent assays, transepithelial short-circuit current measurements and excised inside-out patch-clamp analysis; we found that RES dose-dependently potentiate CFTR Cl- channel activities, which was reversed by CFTR inhibitors CFTR(inh)-172 and GlyH101. Transepithelial Cl- secretion by CFTR-expressing FRT cells was stimulated by RES with half maximal concentration -80 microM. Intracellular cAMP content was not elevated by RES in FRT cells. Excised inside out patch-clamp analysis indicated that RES significantly increased the chloride currents of CFTR. In ex vivo studies, RES stimulated the transmucosal chloride current of rat colon by short-circuit current assay. These data suggested that CFTR is a molecular target of RES. Our findings add a new molecular target to RES, and RES may represent a novel class of therapeutic lead compounds in treating CFTR-related diseases including CF and habitual constipation. PMID- 24147348 TI - Reliability of predicted renal function in Japanese patients on cisplatin therapy. AB - Cisplatin, cis-Dichlorodiammine platinum (II) (CDDP) remains a major antineoplastic drug for the treatment of solid tumors. Its chief dose-limiting side effect is nephrotoxicity. To make a safe and effective dosing regimen of a drug excreted mainly by the renal route, evaluation of patients' renal function is essential. Creatinine clearance (CLcr) or glomerular filtration rate (GFR) is considered to be a standard renal-function test. Several equations have been used in clinical settings, to predict CLcr and GFR using serum creatinine concentration. We carried out a retrospective analysis of the correlation between 24-hour CLcr measured by a urine collection method; and the predicted CLcr and GFR estimated by various equations such as Jelliffe, Yasuda, Orita, Mawer, Mawer, MDRD and modified MDRD, and Cockcroft-Gault. This study used data from Japanese head-and-neck cancer patients, before and after chemotherapy with CDDP. Slopes of regression lines of scatter plots between measured CLcr and predicted renal function in post-CDDP patients were less compared to pre-CDDP patients. On the other hand, Y-intercepts were noted in the scatter plots on renal function from all equations. These results suggest that evaluation of renal function using predictive formulae may have been over-/under-estimated after CDDP administration. PMID- 24147349 TI - A new ligustrazine derivative--pharmacokinetic evaluation and antitumor activity by suppression of NF-kappaB/p65 and COX-2 expression in S180 mice. AB - A new anticancer ligustrazine derivative, 3beta-hydroxyolea-12-en-28-oic acid 3,5,6-trimethylpyrazin-2-methyl ester (T-OA, C38H58O3N2), was previously reported. It was synthesized via conjugating the effective antitumor ingredients of a classic traditional Chinese medicine (TCM) formulation. In the present study, anticancer efficacy of T-OA was evaluated in vivo using a murine sarcoma S180 model. Reduction of the tumor weight and tumor HE staining regions demonstrated that T-OA had promising inhibition effects and a 50% inhibitory rate in S180 mice. Combining the immunohistochemistry, we found T-OA exerted its antitumor activity by preventing the expression of nuclear transcription factor NF-kappaB/p65 and COX-2 in S180 mice. The acute toxic test showed that LD50 value of T-OA exceeded 6.0 g/kg via gavage in mice. In addition, a simple and rapid HPLC-UV method was developed and validated to study the pharmacokinetic characteristics of the compound. After single-dose oral administration, time to reach peak concentration of T-OA (3.97 microg/mL) was 8.33 h; the elimination half-life and area under the concentration-time curve from t = 0 to the last time of T-OA was 4.50 h and 48.01 microg x h/mL, respectively. PMID- 24147350 TI - The Mortality Review Committee: a novel and scalable approach to reducing inpatient mortality. AB - BACKGROUND: Despite the importance of reducing inpatient mortality, little has been reported about establishing a hospitalwide, systematic process to review and address inpatient deaths. In 2006 the University of Pennsylvania Health System's Mortality Review Committee was established and charged with reducing inpatient mortality as measured by the mortality index--observed/expected mortality. METHODS: Between 2006 and 2012, through interdisciplinary meetings and analysis of administrative data and chart reviews, the Mortality Review Committee identified a number of opportunities for improvement in the quality of patient care. Several programmatic interventions, such as those aimed at improving sepsis and delirium recognition and management, were initiated through the committee. RESULTS: During the committee's first six years of activity, the University HealthSystem Consortium (UHC) mortality index decreased from 1.08 to 0.53, with observed mortality decreasing from 2.45% to 1.62%. Interventions aimed at improving sepsis management implemented between 2007 and 2008 were associated with increases in severe sepsis survival from 40% to 56% and septic shock survival from 42% to 54%. The mortality index for sepsis decreased from 2.45 to 0.88. Efforts aimed at improving delirium management implemented between 2008 and 2009 were associated with an increase in the proportion of patients receiving a "timely" intervention from 18% to 57% and with a twofold increase in the percentage of patients discharged to home. DISCUSSION: The establishment of a mortality review committee was associated with a significant reduction in the mortality index. Keys to success include interdisciplinary membership, partnerships with local providers, and a multipronged approach to identifying important clinical opportunities and to implementing effective interventions. PMID- 24147352 TI - Pressure ulcers and prevention among acute care hospitals in the United States. AB - BACKGROUND: Most pressure ulcers can be prevented with evidence-based practice. Many studies describe the implementation of a pressure ulcer prevention program but few report the effect on outcomes across acute care facilities. METHODS: Data on hospital-acquired pressure ulcers and prevention from the National Database of Nursing Quality Indicators 2010 Pressure Ulcer Surveys were linked to hospital characteristics and nurse staffing measures within the data set. The sample consisted of 1,419 hospitals from across the United States and 710,626 patients who had been surveyed for pressure ulcers in adult critical care, step-down, medical, surgical, and medical/surgical units. Hierarchical logistic regression analysis was performed to identify study variables associated with hospital acquired pressure ulcers among patients at risk for these ulcers. RESULTS: The rate of hospital-acquired pressure ulcers was 3.6% across all surveyed patients and 7.9% among those at risk. Patients who received a skin and pressure ulcer risk assessment on admission were less likely to develop a pressure ulcer. Additional study variables associated with lower hospital-acquired pressure ulcer rates included a recent reassessment of pressure ulcer risk, higher Braden Scale scores, a recent skin assessment, routine repositioning, and Magnet or Magnet applicant designation. Variables associated with a higher likelihood of hospital acquired pressure ulcers included nutritional support, moisture management, larger hospital size, and academic medical center status. CONCLUSIONS: Results provide empirical support for pressure ulcer prevention guideline recommendations on skin assessment, pressure ulcer risk assessment, and routine repositioning, but the 7.9% rate of hospital-acquired pressure ulcers among at-risk patients suggests room for improvement in pressure ulcer prevention practice. PMID- 24147351 TI - Using four-phased unit-based patient safety walkrounds to uncover correctable system flaws. AB - BACKGROUND: A unit-based Patient Safety Leadership Walkrounds (PSWR) model was deployed in six medical/surgical units at The Children's Hospital of Philadelphia to identify patient safety issues in the clinical microsystem. Specific objectives of PSWR were to (1) provide a forum for frontline staff to freely report and discuss patient safety problems with unit local leaders, (2) improve teamwork and communication within and across units, and (3) develop a supportive environment in which staff and leaders brainstorm on potential solutions. METHODS: Baseline data collection and discussion with leaders and staff from the pilot units were used to create a standard set of safety tools and questions. Through multiple Plan-Do-Study-Act cycles, safety tools and questions were refined, while the process of walkrounds in each of the six pilot units was customized. RESULTS: Leaders in all six pilot units indicated that PSWR helped them to uncover previously unidentified safety concerns. Top-impact areas included nurse-medical team relationship, work-flow flaws, equipment defects, staff education, and medication safety. The project engaged 149 individuals across all disciplines, including 33 physicians, and entailed 34 PSWR in its first year. Information from these pilot units initiated safety changes that spread across multiple units, with identification of hospital-wide quality and patient safety issues. CONCLUSIONS: For participating units, the PSWR process is a situational awareness tool that helps management periodically assess new or unresolved vulnerabilities that may affect safety and care quality on the unit. Unit-based PSWR help identify safety concerns at the microsystem level while improving communication about safety events across units and to hospital leaders in the macrosystem. PMID- 24147353 TI - Health information technology and hospital patient safety: a conceptual model to guide research. AB - BACKGROUND: The literature indicates that health information technology (IT) use may lead to some gains in the quality and safety of care in some situations but provides little insight into this variability in the results that has been found. The inconsistent findings point to the need for a conceptual model that will guide research in sorting out the complex relationships between health IT and the quality and safety of care. METHODS: A conceptual model was developed that describes how specific health IT functions could affect different types of inpatient safety errors and that include contextual factors that influence successful health IT implementation. The model was applied to a readily available patient safety measure and nationwide data (2009 AHA Annual Survey Information Technology Supplement and 2009 Healthcare Cost and Utilization Project State Inpatient Databases). FINDINGS: The model was difficult to operationalize because (1) available health IT adoption data did not characterize health IT features and extent of usage, and (2) patient safety measures did not elucidate the process failures leading to safety-related outcomes. The sample patient safety measure- Postoperative Physiologic and Metabolic Derangement Rate--was not significantly related to self-reported health IT capabilities when adjusted for hospital structural characteristics. CONCLUSION: These findings illustrate the critical need for collecting data that are germane to health IT and the possible mechanisms by which health IT may affect inpatient safety. Well-defined and sufficiently granular measures of provider's correct use of health IT functions, the contextual factors surrounding health IT use, and patient safety errors leading to health care-associated conditions are needed to illuminate the impact of health IT on patient safety. PMID- 24147354 TI - "Excuse me:" teaching interns to speak up. AB - BACKGROUND: A consistent finding in health care is that interns (junior physicians) are unwilling to "speak up" to attendings or consultants (senior physicians), which involves the related behaviors of challenging or questioning the actions of attendings, seeking guidance about one's own performance, and reporting one's errors. Training designed to encourage interns to speak up was designed, conducted, and evaluated at University Hospital Galway, an academic teaching hospital affiliated with the National University of Ireland, Galway, in January 2012-March 2012 and November 2012-January 2013. METHOD: Training, which was based on the Crew Resource Management model, was constructed around filmed stories of attending physicians describing situations in which, when they were interns, their communication and assertiveness skills were challenged, and their reflections on what they could have done better. RESULTS: A total of 110 interns attended the training. The feedback from participants was positive. There was a significant increase in knowledge as a result of the training, and some evidence to support a shift in attitudes in the desirable direction relating to the need to speak up to seniors. No effect of the training was found on behavior. CONCLUSIONS: The willingness to share examples of poor performance is an important part of building a good safety culture. Listening to the stories ofattendings describing and reflecting on a situation in which they struggled is a powerful teaching method for training interns in the communication and assertiveness skills that are critical to their job. However, a sustained change in attitudes and behavior to speaking up will require a reinforcement of learning with deliberate practice to develop the skills introduced through the training program. PMID- 24147355 TI - Comparative analysis of selected beta-blockers. AB - The suitability and effectiveness of a few spectrophotometric and chromatographic methods (UV, FT-IR, MS, TLC) for differentiating analysis of 6 beta-blockers: acebutolol, alprenolol, atenolol, metoprolol, pindolol and propranolol have been tested. PMID- 24147356 TI - Application of differential scanning calorimetry in evaluation of solid state interactions in tablets containing acetaminophen. AB - Differential scanning calorimetry (DSC) is an analytical procedure used to determine the differences in the heat flow generated or absorbed by the sample. This method allows to assess purity and polymorphic form of drug compounds, to detect interactions between ingredients of solid dosage forms and to analyze stability of solid formulations. The aim of this study was the assessment of compatibility between acetaminophen (API) and different types of excipients often used in tablets compression: polyvinylpyrrolidone, crospovidone, pregelatinized starch, microcrystalline cellulose and magnesium stearate by differential scanning calorimetry. The study contains results of thermal analysis of excipients and individually performed mixtures of these substances with acetaminophen before and after compression and after 6 months storage of tablets at different temperature and relative humidity conditions (25 +/- 2 degrees C /40 +/- 5% RH, 25 +/- 2 degrees C /60 +/- 5% RH, 40 +/- 2 degrees C /75 +/- 5% RH) for a period of 6 months. To detect possible changes of API chemical structure, gas chromatography-mass spectrometry (GC-MS) was also applied. GC-MS with electron impact ionization (EI) was employed to determine the fragmentation pattern of API. It was shown that the developed formulations showed excellent compatibility among all excipients used except Kollidon CL. The interaction with Kollidon CL is probably a result of a physical reaction as confirmed by GC-MS analyses. Obtained results revealed that DSC can be successfully applied to evaluate possible incompatibilities between acetaminophen and Kollidon. PMID- 24147357 TI - Safety profile of antimicrobial peptides: camel, citropin, protegrin, temporin a and lipopeptide on HaCaT keratinocytes. AB - Antimicrobial peptides (AMPs) are an essential part of the innate immunity of the skin and mucosal surfaces. They have a broad spectrum of antimicrobial activity: antibacterial, antifungal, antiviral as well as antiprotozoal. Numerous studies using AMPs as potential agents against different microbes has been performed during the last two decades. Here we investigated antistaphylococcal activity and safety of following AMPs: camel, citropin, protegrin, temporin A and lipopeptide Palm-KK-NH2. The susceptibility of the strains of Staphylococcus aureus isolated from the patients with erythrodermia to conventional antibiotics and AMPs was determined by the broth dilution method. The cytotoxicity assay was performed on HaCaT keratinocytes. Tested peptides turned out to be very effective against all clinical isolates, including strains resistant to conventional antibiotics. The majority of the examined peptides as well as conventional antimicrobials do not exert any toxic effect on HaCaT cells in minimal inhibitory concentration. Peptides are very promising agents for the topical treatment of staphylococcal skin infections. The most promising seem to be citropin 1.1 and temporin A, as they were toxic only in two highest concentration (50 and 100 microg/mL), with relatively low MIC values. PMID- 24147358 TI - Netilmicin-induced modulation of melanogenesis in HEMa-LP melanocytes. AB - It is known that aminoglycoside antibiotics bind well to melanin biopolymer, but the relation between their affinity to melanin and ototoxicity is not well established. The aim of this work was to examine the impact of netilmicin on melanogenesis in cultured normal human melanocytes (HEMa-LP). The WST-1 assay was used to detect netilmicin cytotoxic effect. Netilmicin induced concentration dependent loss in melanocytes viability. The value of EC50 was found to be - 75.0 mM. The analyzed antibiotic inhibited melanin biosynthesis in a concentration dependent manner. Increasing the drug concentration resulted also in a decrease of cellular tyrosinase activity. Netilmicin-induced modulation of melanogenesis in melanocytes in vitro may explain a potential role of melanin and melanocytes in the mechanisms of aminoglycosides ototoxic effects in vivo. PMID- 24147359 TI - Synthesis and biological evaluation of N-substituted polycyclic imides derivatives. AB - The preparation of 16 derivatives of 3,5,8-trioxo-4-azatricyclo- [5.2.2.0(2.6)]undec-1-yl acetate and 8 derivatives of 1-isobutoxy-4 azatricyclo[5.2.2.0(2.6)]undecane-3,5,8-trione was described. Substituents to the imide N-atom were alkyl-(aryl)piperazine fragments with an alkyl linker being propyl or butyl group. Selected newly obtained compounds were evaluated in vitro against anti-HIV-1 activity. A broad group o fderivatives were tested for their antibacterial and antifungal activity. The pharmacological properties of butyl derivatives of imide 6 were evaluated in three behavioral tests in mice. The molecular structures of starting polycyclic 6-acetyl-imides, 1 and 5, were determined by X-ray crystallography. Presented tests have not revealed any activity of the compounds, however, selected derivatives exerted no neurotoxicity in behavioral tests. PMID- 24147360 TI - New pyridocarbazole derivatives. Synthesis and their in vitro anticancer activity. AB - In this paper, we describe our results of the synthesis and biological testing of analogues of the natural alkaloids olivacine and ellipticine. We have synthesized fourteen new 1-substituted pyrido[4,3-b]carbazole derivatives. All of them were tested in vitro for their anticancer activity on three human tumor cell lines: CCRF/CEM (T lymphoblast leukemia), A549 (lung adenocarcinoma), and MCF7 (breast cancer). Cytotoxicity to non-cancer cells was estimated in cultures of the mice fibroblast cell line 3T3 BALB. The anticancer activity of 9-methoxy-5,6-dimethyl 1-[(1,1-bis-hydroxymethyI-propylamino)-methyl]-6H-pyrido[4,3-b]carbazole (compound 9) was the strongest amongst compounds tested on the three cancer cell lines; it was about 5 times higher than ellipticine and about 10% higher than doxorubicin. PMID- 24147361 TI - Synthesis, cytotoxic evaluation and molecular docking study of novel quinazoline derivatives as PARP-1 inhibitors. AB - Novel series of spiro[(2H,3H)-quinazoline-2,1'-cyclohexane] derivatives (I-XVI) were synthesized and biologically evaluated as cytotoxic agents against human breast carcinoma cell lines (MCF-7) using doxorubicin as a reference drug. Most of the tested compounds displayed promising cytotoxic activity, especially derivatives V, VIb and XIb. The most active compounds were docked into the PARP-1 enzyme binding site to predict the ligand-protein binding modes. Lipinski rule of five and ADME profile suggested strongly that compounds V and VIb are promising agents as breast cancer inhibitors with drug likeness approach that have PARP-1 inhibitory activity. The structures of all newly synthesized compounds were confirmed by microanalysis and IR, 1H-NMR and mass spectral data. PMID- 24147363 TI - Antibacterial activity of Phyllantus emblica, Coriandrum sativum, Culinaris medic, Lawsonia alba and Cucumis sativus. AB - Present study deals with the demonstration of the antibacterial activity of very common medicinal plants of Pakistani origin i.e., Phyllantus emblica, Coriandrum sativum, Culinaris medic, Lawsonia alba and Cucumis sativus. The extracts were prepared in crude form by the use of hydro-alcoholic solution and were screened for antibacterial activity against various bacterial species by disk diffusion method. Assay was performed using clinical isolates of B. cereus, S. aureus, P. aeruginosa and E. coli. Crude extract of Phyllantus emblica fruit exhibited strong activity against standard cultures of all studied bacteria. Lawsonia alba showed good activity against standard cultures of all the used microorganisms. Coriandrum sativum was effective only against Bacillus cereus, while Cucumis sativus and Culinaris medic showed poor activity against Pseudomonas aeruginosa only. Hence, Phyllantus emblica exhibited strong antibacterial activity against a wide range of bacteria it means that Phyllantus emblica extract contains some compounds which have broad spectrum of bactericidal activity. PMID- 24147362 TI - Cytotoxic effect of Potentilla reptans L. rhizome and aerial part extracts. AB - Potentilla reptans L. belongs to the least studied of the plants from Rosaceae family, Potentilla genus. There are no data on cytotoxicity of P. reptans extracts, though traditionaly it was used as antiinflammatory and antiinfective. The aim of these studies was to investigate potential antitumor activity of aqueous extracts (rhizome and aerial parts) of P. reptans on 4T1 mouse breast cancer cell line. _Aqueous extracts of rhizome and aerial parts of P. reptans were tested for cytotoxicity by the MTT colorimetric assay on 4T1 cancer cell line in concentration range 100-800 microg/mL. Aqueous extracts of P. reptans rhizome and aerial parts show concentration dependent cytotoxic effect in the range of tested concentrations. ICE50 value of P. reptans rhizome extract was 280.51 +/- 1.16 microg/mL. IC50 value of P. reptans aerial parts extract was 310.79 +/- 1.22 microg/mL. The significant difference in cytotoxicity among tested concentrations was observed. Aqueous extracts of P. reptans rhizome and aerial parts demonstrated weak cytotoxic activity on 4T1 mouse breast cancer cell line, which is in correlation with current cytotoxicity data for aqueous herbal extracts. Rhizome extract of P. reptans has slightly higher antitumor activity than aerial parts extract. The results represent the first report on cytotoxicity for this plant and further research on human cell lines is indicated. PMID- 24147364 TI - Rhus coriaria ameliorates insulin resistance in non-insulin-dependent diabetes mellitus (NIDDM) rats. AB - We have investigated the effect of methanolic extract of Rhus coriaria (RC) on hyperinsulinemia, glucose intolerance and insulin sensitivity in non-insulin dependent diabetes mellitus (NIDDM) rats. NIDDM was induced by single intraperitoneal injection of streptozotocin (STZ, 100 mg/kg) to 2 days old rat pups. RC (200 mg/kg and 400 mg/kg) was administered orally once a day for 5 weeks after the animals were confirmed diabetic (i.e, 90 days after STZ injection). A group of citrate control rats were also maintained which has received citrate buffer on the 2nd day of their birth. There was a significant increase in blood glucose, glycosylated hemoglobin (HbA1c) and serum insulin levels were observed in NIDDM control rats. Treatment with RC reduced the elevated levels of blood glucose, HbA1c and insulin in the NIDDM rats. An oral glucose tolerance test (OGTT) was also performed in the same groups, in which we found a significant improvement in glucose tolerance in the rats treated with RC. The insulin sensitivity was assessed for both peripheral insulin resistance and hepatic insulin resistance. RC treatment significantly improved insulin sensitivity index (K(ITT)) which was significantly decreased in NIDDM control rats. There was significant rise in homeostasis model assessment of insulin resistance (HOMA-R) in NIDDM control rats whereas RC treatment significantly prevented the rise in HOMA-R in NIDDM treated rats. Our data suggest that methanolic extract of RC significantly delayed the onset of hyperinsulinemia and glucose intolerance and improved insulin sensitivity in NIDDM rats. PMID- 24147365 TI - Molecular properties impact on bioavailability of second generation triazoles antifungal agents. AB - The bioavailability of active compounds depends on their two main features: solubility and permeability. The experimental determination of these factors is rather cumbersome. The free enthalpies of salvation deltaG in water and chloroform, and the electrostatic potential surface around examined molecules were ab initio calculated by HF method for voriconazole, posaconazole and ravuconazole. These quantities are assumed to be the new determinants correctly describing both solubility and the affinity of biologically active compounds to lipophilic tendency to cross cellular membranes. The values of deltaG were compared to the theoretically and experimentally determined partition coefficients. The calculated values of deltaG and electrostatic potentials appeared to be consistent with these partition coefficients. It leads to conclusion that these theoretically derived parameters deltaG and electrostatic potential could be useful tools for fast and precise classification of chemical substances within the Biopharmaceutics Classification System (BCS). PMID- 24147366 TI - In vitro to in vivo profiling: an easy idea for biowaiver study. AB - The aim of this article was to assess and apply the in vitro to in vivo profiling (IVIVP), a new biowaiver approach, in designing a product with specific release pattern. The IVIVP was established by plotting the observed and predicted plasma drug concentrations. For IVIVP, convolution approach was employed to estimate plasma drug concentrations from in vitro dissolution profiles. The IVIVP for T1S exhibited a good correlation coefficient (R2 = 0.963) followed by the T2 (R2 = 0.682), T3 (R2 = 0.665), T1 (R2 = 0.616), and Mepresso (R2 = 0.345). Establishing an IVIVP, based on the convolution approach, can be more useful and practicable in the biowaiver studies, rather than present not useful practice of IVIVC estimated via deconvolution approach. This paper also elaborates that there is good correlation between the in vitro and in vivo profiles of the developed metoprolol tartrate formulations, particularly for T1S. PMID- 24147368 TI - Evaluation and enhancement of physical stability of semi-solid dispersions containing piroxicam into hard gelatin capsules. AB - The aim of the study was to investigate the physical stability of the semi-solid dispersions into the hard gelatine capsules prepared with Gelucire 44/14, Labrasol and different additives such as microcrystalline cellulose (MCC), mannitol and lactose (alpha-monohydrate) used for enhancing the stability of the formulations. The master dispersion prepared with only Gelucire 44/14 (20% w/w) and Labrasol (80% w/w) was stored in a refrigerator (5 +/- 3 degrees C), while the modified dispersions with the additives (2% w/w) were kept in a climatic chamber (25 +/- 2 degrees C / 60 +/- 5% RH) for 12 months. Dissolution tests of the semi-solid dispersions were performed in media with different pH's immediatly after preparation and after 3, 6 and 12 months of storage. FTIR and DSC studies were also carried out at the same time points. The ideal storage condition for the master dispersion was found to be at 5 degrees C. The addition of MCC, mannitol and lactose (alpha-monohydrate) to the original dispersion afforded a solidification effect on the formulation at room temperature and showed the same dissolution behavior (not less than 85% of piroxicam within 30 min in pH 1.2, 4.5 and 6.8; and water) with the master. The dispersion including lactose was stable at 25 degrees C for 12 months. However, the ideal period of storage for the modified dispersions including MCC and mannitol was 6 months at 25 degrees C. FTIR and DSC results both confirmed the amorphous state of piroxicam in all semi solid dispersions under storage conditions for 12 months. PMID- 24147367 TI - Prediction of bioavailability of selected bisphosphonates using in silico methods towards categorization into a biopharmaceutical classification system. AB - The physicochemical properties relevant to biological activity of selected bisphosphonates such as clodronate disodium salt, etidronate disodium salt, pamidronate disodium salt, alendronate sodium salt, ibandronate sodium salt, risedronate sodium salt and zoledronate disodium salt were determined using in silico methods. The main aim of our research was to investigate and propose molecular determinants thataffect bioavailability of above mentioned compounds. These determinants are: stabilization energy (deltaE), free energy of solvation (deltaG(solv)), electrostatic potential, dipole moment, as well as partition and distribution coefficients estimated by the log P and log D values. Presented values indicate that selected bisphosphonates a recharacterized by high solubility and low permeability. The calculated parameters describing both solubility and permeability through biological membranes seem to be a good bioavailability indicators of bisphosphonates examined and can be a useful tool to include into Biopharmaceutical Classification System (BCS) development. PMID- 24147369 TI - Anti-inflammatory activity of lipoic acid in mice peritonitis model. AB - This work aimed to investigate the effect of lipoic acid (LA) on sulfane sulfur (S*) level, infiltration of neutrophils and vascular permeability in a model of zymosan-induced peritonitis. The study showed that lipoic acid increased the sulfane sulfur level. Also, it decreased count of neutrophils and inhibition of intensity of early vascular permeability compared to the control group. These studies indicated that LA exhibits antiinflammatory activity. LA serves as a sulfane sulfur acceptor and releases sulfane sulfur in the form of hydrogen sulfide (H2S), which is probably responsible for its anti-inflammatory activity. PMID- 24147370 TI - Synthesis, kinetics and pharmacological evaluation of mefenamic acid mutual prodrug. AB - A novel mutual prodrug (MA-P) consisting of mefenamic acid (MA) and paracetamol (P) has been synthesized as a gastrosparing NSAID, devoid of ulcerogenic side effects. The structure of synthesized drug was confirmed by elemental analysis, infrared spectroscopy, 1H NMR spectroscopy and mass spectrometry.The kinetics of ester hydrolysis was studied by HPLC at pH 2, pH 7.4 as well as in human plasma. The pharmacological activities (anti-inflammatory, analgesic and ulcerogenic) were evaluated for the synthesized drug. The ulcerogenic reduction in terms of gastric wall mucosa, hexosamine and total proteins were also measured in glandular stomach of rats. The results indicated that MA-P ester has better ulcer index than the parent drug. PMID- 24147371 TI - Influence of combined therapy with rosuvastatin and amitriptyline on the oxidation-reduction status in rats. AB - The aim of the present study was to assess the impact of combined therapy with rosuvastatin (10 mg/kg) and amitriptyline (10 mg/kg) on oxidation-reduction status in the blood of rats. After 2-week application of drugs alone or their combination, the activity of glutathione peroxidase (GPX), glutathione reductase (GR) and total antioxidant status (TAS) were determined. It was noticed that combined therapy with rosuvastatin and amitriptyline significantly increased the activity of GPX in comparison to the group receiving only rosuvastatin and decreased the activity of GR in comparison to groups receiving only rosuvastatin or amitriptyline. However, the activity of these enzymes as a result of combined therapy was placed in the level of the control groups. Our studies indicated that the combined therapy with both drugs caused an increase of TAS compared to the groups of animals receiving only one of these drugs. The results indicate on the oxidation-reduction balance and increasing the antioxidant status in rats treated with rosuvastatin and amitriptyline. PMID- 24147372 TI - Evaluation of self-medication amongst university students in Abbottabad, Pakistan; prevalence, attitude and causes. AB - Self-medication is a serious issue in most parts of the world. This study aims to evaluate self-medication among university students of Abbottabad, Pakistan. This cross-sectional survey study was carried out in COMSATS Institute of Information Technology, Abbottabad during December 1 - December 31,2011. A sample of 275 students was selected for the study using convenience method of sampling. Data were managed and analyzed via SPSS version 16.0. Inferences were drawn using Z test Out of 268 respondents (male = 61.6%, female = 38.6%), 138 were non-health professional students whereas 130 were health professional students. The prevalence of self-medication was 95.5%. Most common factor (45.7%) responsible for self-medication was "low severity of disease". Most common symptom (50.8%) that caused self-medication and stocking of medicines was "storage of medicines for multi purposes". Some respondents (22.7%) got addicted due to self medication. Most of the students trust in allopathic medicines system. High prevalence of self-medication can be controlled through regulatory authorities, mass education and availability of health facilities. PMID- 24147373 TI - Analysis of pharmacists' opinions, attitudes and experiences with generic drugs and generic substitution in the Czech Republic. AB - Generic substitution (GS) is an integral part of drug policy in many countries. Similarly to other countries its introduction in the Czech Republic gave rise to a vibrant discussion. The aim of the study was to map and analyze pharmacists' opinions of, attitudes towards and experiences with generic drugs and GS after the first year from its legislative embodiment in the Czech Republic. All 7,665 members of the Czech Chamber of Pharmacists were addressed to participate in a questionnaire survey between November 2008 and March 2009. The questionnaire consisted of 28 questions concerning the issue of generic drugs and GS and was divided into five sections. All collected data were analyzed using descriptive statistics and correlations were tested by selected parametric and non-parametric tests. A total of 615 completed questionnaire forms were returned (a questionnaire return rate of 8.0%). The demographic characteristics of the respondents were as follows: 470 (76.4%) females, mean age of 37.5 years (SD = 10.4) and 429 (69.6%) pharmacists with a practice specialization. Altogether 345 (56.1%) respondents became aware of the issue of brand name and generic drugs during their undergraduate studies. 378 (61.5%) respondents considered generic drugs as bioequivalent and 455 (74.0%) respondents as therapeutically equivalent to the respective brand name drugs. 99 (16.1%) pharmacists believed that generic products are of lower quality than branded drugs and 69 (11.2%) respondents expected generics to cause more adverse drug reactions. GS was perceived as a positive tool by 476 (77.4%) respondents. Only 71 (11.5%) respondents showed acquaintance with all the legal rules for GS. Legislation awareness and attitude towards GS was correlated with age (p < 0.001). The use of GS in the routine practice depends on the pharmacists' familiarity with the relevant legislation and attitude towards generic drugs and GS. Approaching patients on an individual basis and pharmacists' awareness can minimize adverse drug events caused by generic drugs and at the same time enhance the professional status of pharmacists. PMID- 24147374 TI - Chemical constituents and antibacterial activity of essential oil of Satureja bachtiarica (Lamiaceae). PMID- 24147375 TI - The moral compass for healthcare leaders: building an ethical culture. PMID- 24147376 TI - The case for values as a basis for organizational culture. AB - At a time when almost every aspect of healthcare is rapidly and dramatically changing, it is important for healthcare leaders to maintain a moral compass--a clear sense of the morals or virtues that guide their decisions. A firmly rooted moral compass inspires, leads, guides, and provides a solid foundation--and some sense of security--for organizations navigating massive or significant transformational changes, such as those required by the Affordable Care Act. In addition, "smaller" changes, such as consolidation, rationalization, and relocation of services, have a strong chance of succeeding in organizations that operate within a moral framework from which the organization can shape its future strategies and make important decisions. Finally, an organization's moral compass guides actions, reactions, and behaviors when unexpected or devastating events occur in the lives of consumers, employees, physicians, business partners, patients, families, and members of the community. The direction toward which its moral compass is pointing determines the types and quality of relationships it has with those key stakeholders, and those individuals and groups come to depend on what they have observed and know to be true about how the organization behaves in certain circumstances. While no organization can predict the future and all of the implications of change, key stakeholder groups need and want to know how they will be treated in the face of such change-whether expected or unexpected. In this sense, every organization must establish ways to evaluate the validity of its moral compass and develop--and adhere to--guidelines that determine how its members will behave, whether in ordinary circumstances; in the face of extraordinary, high-impact situations; or in times of massive transformational change. Above all, executive leaders must always be mindful that their own personal moral compass becomes their organization's moral compass. PMID- 24147377 TI - A moral compass for management decision making: a healthcare CEO's reflections. AB - Ethical behavior is good for business in any organization. In healthcare, it results in better patient care, a more committed and satisfied staff, more efficient care delivery, and increased market share. But it requires leaders who have a broad view of the role that ethics programs--and an effective, sustained ethical culture--play. Ethical organizations have integrated and shared ethical values and practices, an effective ethics infrastructure, ongoing ethics education for staff at every level, ethical and morally courageous leaders, and a culture that is consistent with the organization's values. The mission, vision, and values statements of these organizations have been successfully translated into a set of shared values--a moral compass that guides behavior and decision making. PMID- 24147378 TI - Ethics, values, and decision making. PMID- 24147379 TI - Wanted: morally courageous leaders. PMID- 24147381 TI - The professional layman? PMID- 24147380 TI - The imperative of a moral compass-driven healthcare organization. PMID- 24147382 TI - Dentine hypersensitivity--guidelines for the management of a common oral health problem. AB - Dentine hypersensitivity (DHS) remains a worldwide under-reported and under managed problem, despite making some dental treatments more stressful than necessary and having a negative impact on the patient's quality of life. This article is designed to build dental professionals' confidence and remove any confusion regarding the diagnosis, prevention and treatment of sensitive teeth caused by dentine hypersensitivity in those patients known to be at risk. There is a need for simple guidelines, which can be readily applied in general practice. However, it is also obvious that one strategy cannot suit all patients. This review describes a DHS management scheme for dental professionals that is linked to management strategies targeted at three different groups of patient. These patient groups are: 1) patients with gingival recession; 2) treatment patients with toothwear lesions; and 3) patients with periodontal disease and those receiving periodontal treatment. The authors also acknowledge the role of industry as well as dental professionals in a continuing role in educating the public on the topic of sensitive teeth. It is therefore important that educational activities and materials for both dental professionals and consumers use common terminology in order to reduce the possibility for confusion. CLINICAL RELEVANCE: This review article provides practical, evidence-based guidance on the management of dentine hypersensitivity for dental professionals covering diagnosis, prevention and treatment. Sensitivity associated with gingival recession, toothwear and periodontal disease and periodontal treatment are specifically addressed in the article. PMID- 24147383 TI - Factors to consider when treatment planning for patients seeking comprehensive aesthetic dental treatment. AB - Co-operation between specialties, improvements in dental materials, bonding technology, increase in public awareness of 'cosmetic dentistry' and patients' desires to improve their appearance, mean that, increasingly, dental practitioners are being asked how elective treatment may be used to improve their patients' smiles. Traditionally, a dentist's role has been to treat disease and promote oral health. Elective, invasive dental treatment needs careful consideration and, often, interdisciplinary planning. The issues dentists may need to consider and discuss with their patients are outlined with reference to dental literature. CLINICAL RELEVANCE: Requests to dentists to embark upon complex elective treatments to improve their patients' dental appearance are on the increase. It is important that clinicians appropriately assess cases prior to committing to a treatment plan. Considerations to be taken when assessing these patients are discussed. PMID- 24147385 TI - Can oil lubricated dental handpieces be sterilized?: part 1. The problem. AB - HTM 01-05 guidelines state that decontamination of handpieces remains a challenge, in particular the lumen, due to oil impeding access for steam sterilization. This paper discusses important aspects of cleaning and sterilization of the handpiece lumen and critically appraises the literature found on this topic. The paper is not intended to cover precleaning methods in detail. CLINICAL RELEVANCE: The complex structure of handpiece lumens makes them difficult to sterilize. Current knowledge of this subject is necessary for general dental practitioners to decide on investment in new equipment correctly, which has been validated by the manufacturer, in order to comply with HTM 01-05 guidelines. PMID- 24147384 TI - Trauma to the primary dentition and its sequelae. AB - Trauma to the primary dentition is common. This injury may have an impact on the child and his/her parents. The examining dentist should take appropriate factors into consideration before providing the required treatment. This paper discusses the management of trauma to the primary teeth and describes the sequelae of injury to both the primary and secondary dentitions. CLINICAL RELEVANCE: In cases of trauma to the primary teeth, diagnosis and appropriate management is necessary to alleviate the pain and discomfort for the child and to decrease the risk of damage to the permanent successor. It is important to prevent inducing fear and dental anxiety in children during the management of this injury. PMID- 24147386 TI - Domestic abuse--an underreported problem in general dental practice? AB - 'Child abuse' is a topic about which clinicians will be well informed. There are protocols relating to the management of patients suspected of having sustained non-accidental injuries and clinical staff will be expected, as part of mandatory training, to receive education in this area. Domestic abuse (DA) is an under reported, but relatively common problem and has many implications in the management of traumatic injuries in adults. The objective of this paper is to discuss the aetiology, history and presentation of patients who have been subjected to domestic abuse, and to help provide a strategy for their management. CLINICAL RELEVANCE: Domestic abuse is a relatively common problem and, as such, dentists should be aware of this important area and how to manage patients they suspect of having been abused, or who inform them that they have' been subjected to DA. PMID- 24147387 TI - Invisible orthodontics part 3: aesthetic orthodontic brackets. AB - In this, the third part of the series, aesthetic orthodontic treatment will be considered. The previous two articles have looked at invisible orthodontics with Invisalign and lingual brackets. This article will discuss the properties and use of aesthetic brackets, along with examples of orthodontic treatment cases using the aesthetic brackets. CLINICAL RELEVANCE: Increasing demand for aesthetics during orthodontic treatment has resulted in a significant increase in the use of aesthetic brackets. Clinicians need to be aware of the benefits and drawbacks of aesthetic brackets. PMID- 24147388 TI - Computerized tomography, stereolithography and dental implants in the rehabilitation of oral cancer patients. AB - As survival rates improve it is important to consider the quality of life for oral cancer patients post-treatment. The primary goal is removal of the tumour, however, with a gradual increase in survival rates, post-operative rehabilitation is now becoming increasingly important. Specialists in restorative dentistry, along with oral and maxillofacial surgeons, general dental practitioners and other members of the multidisciplinary team play a vital role in planning treatment for, and rehabilitating, these patients. This paper presents a case series to show how recent advances in computerized tomography (CT) and the use of stereolithographic models can help in the rehabilitation of oral cancer patients. CLINICAL RELEVANCE: The principles discussed can also be applied to other patients undergoing dental implant treatment to help plan and carry out treatment and improve the quality of peri-implant tissues. PMID- 24147389 TI - Evolution of surgical guidance in implant dentistry. AB - The optimal positioning of oral implants ensures good biomechanical, functional, aesthetic and phonetic results.The concept of surgical guidance in implant dentistry has been developed to bridge the gap between pre-operative treatment planning and surgical site preparation.This article discusses its evolution, from the early surgical guide systems which used only diagnostic casts as reference, to the latest in computer-assisted navigation. CLINICAL RELEVANCE: Surgical guidance allows the accurate transfer of information from the pre-operative treatment planning phase to the surgical field. It assists the operator in placing the implant in the most ideal position and angulations, with regards to the final prosthesis. PMID- 24147390 TI - The multidisciplinary conservative management of a vital crown root fracture. AB - This case study reports on the multidisciplinary management of a maxillary canine which sustained an unusual labial crown root fracture, resulting in a large veneer-like fragment.The canine was extruded orthodontically and the fragment was re-attached using adhesive materials.This multidisciplinary solution prevented impingement on the biological width, loss of vitality and loss of tooth structure, leading to an optimal soft and hard tissue aesthetic result. Successful clinical and radiographic results after three years were observed, despite canine protected occlusion. CLINICAL RELEVANCE: Multidisciplinary management can result in an improved prognosis of the tooth and, in time, may be the most cost-effective solution for the patient. When discussing treatment options with the patient, utilization of all dental specialties should be considered and offered to the patient. PMID- 24147391 TI - Newer chelating agents. PMID- 24147392 TI - The changing face of dentistry? PMID- 24147393 TI - Dr Drill. PMID- 24147394 TI - Re: Pacifiers: review of risks vs benefits. PMID- 24147395 TI - Oral medicine: 10. Lumps and swellings: neck. PMID- 24147396 TI - Technique tips--Non-surgical management of deep periodontal pockets--avoid the scalpel! PMID- 24147397 TI - Physical signs for the general dental practitioner. Case 104. Peripheral arterial emboli. PMID- 24147398 TI - Latent resilience in ponderosa pine forest: effects of resumed frequent fire. AB - Ecological systems often exhibit resilient states that are maintained through negative feedbacks. In ponderosa pine forests, fire historically represented the negative feedback mechanism that maintained ecosystem resilience; fire exclusion reduced that resilience, predisposing the transition to an alternative ecosystem state upon reintroduction of fire. We evaluated the effects of reintroduced frequent wildfire in unlogged, fire-excluded, ponderosa pine forest in the Bob Marshall Wilderness, Montana, USA. Initial reintroduction of fire in 2003 reduced tree density and consumed surface fuels, but also stimulated establishment of a dense cohort of lodgepole pine, maintaining a trajectory toward an alternative state. Resumption of a frequent fire regime by a second fire in 2011 restored a low-density forest dominated by large-diameter ponderosa pine by eliminating many regenerating lodgepole pines and by continuing to remove surface fuels and small diameter lodgepole pine and Douglas-fir that established during the fire suppression era. Our data demonstrate that some unlogged, fire-excluded, ponderosa pine forests possess latent resilience to reintroduced fire. A passive model of simply allowing lightning-ignited fires to burn appears to be a viable approach to restoration of such forests. PMID- 24147399 TI - Fire history, related to climate and land use in three southern Appalachian landscapes in the eastern United States. AB - Fire-maintained ecosystems and associated species are becoming increasingly rare in the southern Appalachian Mountains because of fire suppression policies implemented in the early 20th century. Restoration of these communities through prescribed fire has been hindered by a lack of information on historical fire regimes. To characterize past fire regimes, we collected and absolutely dated the tree rings on cross sections from 242 fire-scarred trees at three different sites in the southern Appalachian Mountains of Tennessee and North Carolina. Our objectives were to (1) characterize the historical frequency of fire in southern Appalachian mixed pine-oak forests, (2) assess the impact of interannual climatic variability on the historical occurrence of fire, and (3) determine whether changes in human culture and land use altered the frequency of fire. Results demonstrate that fires burned frequently at all three sites for at least two centuries prior to the implementation of fire suppression and prevention in the early to mid 20th century. Composite mean fire return intervals were 2-4 yr, and point mean fire return intervals were 9-13 yr. Area-wide fires that burned across multiple stands occurred at 6-13-yr intervals. The majority of fires were recorded during the dormant season. Fire occurrence exhibited little relationship with reconstructed annual drought conditions. Also, fire activity did not change markedly during the transition from Native American to Euro-American settlement or during the period of industrial logging at the start of the 20th century. Fire activity declined significantly, however, during the fire suppression period, with a nearly complete absence of fire during recent decades. The characterization of past fire regimes should provide managers with specific targets for restoration of fire-associated communities in the southern Appalachian Mountains. The fire chronologies reported here are among the longest tree-ring reconstructions of fire history compiled for the eastern United States and support the hypothesis that frequent burning has played a long and important role in the development of forests in the southern Appalachian Mountains. PMID- 24147401 TI - Examining change over time in habitat attributes using Bayesian reinterpretation of categorical assessments. AB - Prospects for evaluating effects of vegetation restoration have long been limited by availability of appropriately sensitive baseline data. Data that are typically collected to justify investment in restoration are rarely suitable for estimating subsequent change over time, but given how commonly such data are collected, can they contribute something to learning about ecological change over time? We compared vegetation and habitat data from a quantitative reassessment of 25 habitat restoration sites seven years after they were initially assessed using a semiquantitative, categorical scoring system. Our aim was to estimate the change at sites between the first, semiquantitative survey and a second, quantitative survey. We treated the initial values as effectively unknown and used Bayesian models to infer plausible values using three different informative prior distributions, variously comprising the initial site assessments and modeled values from a statewide data set. We successfully constructed models of change over time between the two surveys, and regardless of which prior model was implemented, our data analysis suggested that cover of exotic species was reduced, but canopy cover, the cover of organic litter, and the length of fallen logs were all increased after the seven-year period. A small increase in the mean number of large-diameter trees was likely due to initial measurement error. Site fertility and canopy cover were important covariates in explaining the magnitude of change in total log length. Sites with higher canopy cover decreased more in weed cover and increased more in litter cover. Our approach could be used to retrospectively analyze any ordinal data set where there is a scoring logic that can be interpreted quantitatively. Data sets where treatment contrasts and untreated controls exist will be particularly valuable for testing the utility of our approach. While this novel approach should prove a useful analytical complement to genuine longitudinal monitoring and space-for-time surveys, it is no substitute for initiation of learning about management effectiveness using data from purposefully designed and measured surveys. PMID- 24147400 TI - The weight of the past: land-use legacies and recolonization of pine plantations by oak trees. AB - Most of the world's plantations were established on previously disturbed sites with an intensive land-use history. Our general hypothesis was that native forest regeneration within forest plantations depends largely on in situ biological legacies as a source of propagules. To test this hypothesis, we analyzed native oak regeneration in 168 pine plantation plots in southern Spain in relation to land use in 1956, oak patch proximity, and pine tree density. Historical land-use patterns were determined from aerial photography from 1956, and these were compared with inventory data from 2004-2005 and additional orthophoto images. Our results indicate that oak forest regeneration in pine plantations depends largely on land-use legacies, although nearby, well-conserved areas can provide propagules for colonization from outside the plantation, and pine tree density also affected oak recruit density. More intense land uses in the past meant fewer biological legacies and, therefore, lower likelihood of regenerating native forest. That is, oak recruit density was lower when land use in 1956 was croplands (0.004 +/- 0.002 recruits/m2 [mean +/- SE]) or pasture (0.081 +/- 0.054 recruits/m2) instead of shrubland (0.098 +/- 0.031 recruits/m2) or oak formations (0.314 +/- 0.080 recruits/m2). Our study shows that land use in the past was more important than propagule source distance or pine tree density in explaining levels of native forest regeneration in plantations. Thus, strategies for restoring native oak forests in pine plantations may benefit from considering land-use legacies as well as distance to propagule sources and pine density. PMID- 24147402 TI - Estimating tree growth from complex forest monitoring data. AB - Understanding tree growth as a function of tree size is important for a multitude of ecological and management applications. Determining what limits growth is of central interest, and forest inventory permanent plots are an abundant source of long-term information but are highly complex. Observation error and multiple sources of shared variation (spatial plot effects, temporal repeated measures, and a mosaic of sampling intervals) make these data challenging to use for growth estimation. We account for these complexities and incorporate potential limiting factors (tree size, competition, and resource supply) into a hierarchical state space model. We estimate the diameter growth of white fir (Abies concolor) in the Sierra Nevada of California from forest inventory data, showing that estimating such a model is feasible in a Bayesian framework using readily available modeling tools. In this forest, white fir growth depends strongly on tree size, total plot basal area, and unexplained variation between individual trees. Plot-level resource supply variables (representing light, water, and nutrient availability) do not have a strong impact on inventory-size trees. This approach can be applied to other networks of permanent forest plots, leading to greater ecological insights on tree growth. PMID- 24147403 TI - Management trade-off between aboveground carbon storage and understory plant species richness in temperate forests. AB - Because forest ecosystems have the capacity to store large quantities of carbon (C), there is interest in managing forests to mitigate elevated CO2 concentrations and associated effects on the global climate. However, some mitigation techniques may contrast with management strategies for other goals, such as maintaining and restoring biodiversity. Forest thinning reduces C storage in the overstory and recruitment of detrital C. These C stores can affect environmental conditions and resource availability in the understory, driving patterns in the distribution of early and late-seral species. We examined the effects of replicated (N = 7) thinning experiments on aboveground C and understory vascular plant species richness, and we contrasted relationships between aboveground C and early- vs. late-seral species richness. Finally, we used structural equation modeling (SEM) to examine relationships among early- and late-seral species richness and live and detrital aboveground C stores. Six years following thinning, aboveground C was greater in the high-density treatment and untreated control than in moderate- (MD) and variable-density (VD) treatments as a result of reductions in live overstory C. In contrast, all thinning treatments increased species richness relative to controls. Between the growing seasons of years 6 and 11 following treatments, the live overstory C increment tended to increase with residual density, while richness decreased in MD and VD treatments. The richness of early-seral species was negatively related to aboveground C in MD and VD, while late-seral species richness was positively (albeit weakly) related to aboveground C. Structural equation modeling analysis revealed strong negative effects of live overstory C on early-seral species richness balanced against weaker positive effects on late-seral species richness, as well as positive effects of detrital C stocks. A trade-off between carbon and plant species richness thus emerges as a net result of these relationships among species traits, thinning treatments, and live and detrital C storage. Integrating C storage with traditional conservation objectives may require managing this trade off within stands and landscapes (e.g., maintain early-seral habitat and species within dense, C-rich forests and, conversely, live and detrital C stores in early seral habitats) or separating these goals across scales and species groupings. PMID- 24147404 TI - Chronic nitrogen deposition alters the structure and function of detrital food webs in a northern hardwood ecosystem. AB - During the next century, atmospheric nitrogen (N) deposition is projected to more than double, potentially slowing litter decomposition by altering microbial community composition and function. If the flow of energy though detrital food webs is diminished by the slowing of decay under higher rates of atmospheric N deposition, this agent of global change could also negatively impact the abundance and composition of soil fauna. To test this hypothesis, we studied soil faunal communities in four sugar-maple-dominated forests that comprise a long term N deposition experiment. To examine whether changes in soil faunal communities could then feed back to influence litter decay, litterbags with 13C enriched aspen litter were placed in the forest floor in one study site. The microbial community within the litterbags was characterized using PLFA analysis. Overall, long-term experimental N deposition reduced the abundance of microarthropods (ambient vs. experimental N deposition: 7844 vs. 4357 individuals/m2, respectively; P = 0.004). We attribute this overall decline partly to the reduced energy flow entering the detrital food web, which has been documented in previous work in our system. Although there was no difference in microarthropod species richness between N deposition treatments, there was a shift in community composition within the most abundant group (Oribatida), indicating species-specific responses to N deposition. Experimental N deposition reduced the number of microarthropods colonizing litterbags by 41% (P = 0.014). This was associated with a reduction in 13C mobilization from leaf litter into microbial biomass. Overall, this study demonstrates that chronic N deposition has a detrimental effect on the soil detritus food web, and that the negative effect may feed back to influence litter decay and ecosystem functioning. PMID- 24147405 TI - Bright lights, big city: influences of ecological light pollution on reciprocal stream-riparian invertebrate fluxes. AB - Cities produce considerable ecological light pollution (ELP), yet the effects of artificial night lighting on biological communities and ecosystem function have not been fully explored. From June 2010 to June 2011, we surveyed aquatic emergent insects, riparian arthropods entering the water, and riparian spiders of the family Tetragnathidae at nine stream reaches representing common ambient ELP levels of Columbus, Ohio, USA, streams (low, 0.1-0.5 lux; moderate, 0.6-2.0 lux; high, 2.1-4.0 lux). In August 2011, we experimentally increased light levels at the low- and moderate-treatment reaches to 10-12 lux to represent urban streams exposed to extremely high levels of ELP. Although season exerted the dominant influence on invertebrate fluxes over the course of the year, when analyzed by season, we found that light strongly influenced multiple invertebrate responses. The experimental light addition resulted in a 44% decrease in tetragnathid spider density (P = 0.035), decreases of 16% in family richness (P = 0.040) and 76% in mean body size (P = 0.022) of aquatic emergent insects, and a 309% increase in mean body size of terrestrial arthropods (P = 0.015). Our results provide evidence that artificial light sources can alter community structure and ecosystem function in streams via changes in reciprocal aquatic-terrestrial fluxes of invertebrates. PMID- 24147406 TI - Modeling disturbance-based native invasive species control and its implications for management. AB - Shifts in disturbance regime have often been linked to invasion in systems by native and nonnative species. This process can have negative effects on biodiversity and ecosystem function. Degradation may be ameliorated by the reinstatement of the disturbance regimes, such as the reintroduction of fire in pyrogenic systems. Modeling is one method through which potential outcomes of different regimes can be investigated. We created a population model to examine the control of a native invasive that is expanding and increasing in abundance due to suppressed fire. Our model, parameterized with field data from a case study of the tree Allocasuarina huegeliana in Australian sandplain heath, simulated different fire return intervals with and without the additional management effort of mechanical removal of the native invader. Population behavior under the different management options was assessed, and general estimates of potential biodiversity impacts were compared. We found that changes in fire return intervals made no significant difference in the increase and spread of the population. However, decreased fire return intervals did lower densities reached in the simulated heath patch as well as the estimated maximum biodiversity impacts. When simulating both mechanical removal and fire, we found that the effects of removal depended on the return intervals and the strategy used. Increase rates were not significantly affected by any removal strategy. However, we found that removal, particularly over the whole patch rather than focusing on satellite populations, could decrease average and maximum densities reached and thus decrease the predicted biodiversity impacts. Our simulation model shows that disturbance-based management has the potential to control native invasion in cases where shifted disturbance is the likely driver of the invasion. The increased knowledge gained through the modeling methods outlined can inform management decisions in fire regime planning that takes into consideration control of an invasive species. Although particularly applicable to native invasives, when properly informed by empirical knowledge these techniques can be expanded to management of invasion by nonnative species, either by restoring historic disturbance regimes or by instating novel regimes in innovative ways. PMID- 24147407 TI - Unprecedented carbon accumulation in mined soils: the synergistic effect of resource input and plant species invasion. AB - Opencast mining causes severe impacts on natural environments, often resulting in permanent damage to soils and vegetation. In the present study we use a 14-year restoration chronosequence to investigate how resource input and spontaneous plant colonization promote the revegetation and reconstruction of mined soils in central Brazil. Using a multi-proxy approach, combining vegetation surveys with the analysis of plant and soil isotopic abundances (delta13C and delta15N) and chemical and physical fractionation of organic matter in soil profiles, we show that: (1) after several decades without vegetation cover, the input of nutrient rich biosolids into exposed regoliths prompted the establishment of a diverse plant community (> 30 species); (2) the synergistic effect of resource input and plant colonization yielded unprecedented increases in soil carbon, accumulating as chemically stable compounds in occluded physical fractions and reaching much higher levels than observed in undisturbed ecosystems; and (3) invasive grasses progressively excluded native species, limiting nutrient availability, but contributing more than 65% of the total accumulated soil organic carbon. These results show that soil-plant feedbacks regulate the amount of available resources, determining successional trajectories and alternative stable equilibria in degraded areas undergoing restoration. External inputs promote plant colonization, soil formation, and carbon sequestration, at the cost of excluding native species. The introduction of native woody species would suppress invasive grasses and increase nutrient availability, bringing the system closer to its original state. However, it is difficult to predict whether soil carbon levels could be maintained without the exotic grass cover. We discuss theoretical and practical implications of these findings, describing how the combination of resource manipulation and management of invasive species could be used to optimize restoration strategies, counteracting soil degradation while maintaining species diversity. PMID- 24147408 TI - Topography- and management-mediated resource gradients maintain rare and common plant diversity around paddy terraces. AB - Examining the causes of interspecific differences in susceptibility to bidirectional land-use changes (land abandonment and use-intensification) is important for understanding the mechanisms of global biodiversity loss in agricultural landscapes. We tested the hypothesis that rare (endangered) plant species prefer wet and oligotrophic areas within topography- and management mediated resource (soil water content, nutrient, and aboveground biomass) gradients, making them more susceptible to both abandonment and use intensification of agricultural lands. We demonstrated that topography and management practices generated resource gradients in seminatural grasslands around traditional paddy terraces. Terraced topography and management practices produced a soil moisture gradient within levees and a nutrient gradient within paddy terraces. Both total and rare species diversity increased with soil water content. Total species diversity increased in more eutrophied areas with low aboveground biomass, whereas rare species diversity was high under oligotrophic conditions. Rare and common species were differentially distributed along the human-induced nutrient gradient, with rare species preferring wet, nutrient-poor environments in the agricultural landscapes studied. We suggest that conservation efforts should concentrate on wet, nutrient-poor areas within such landscapes, which can be located easily using land-use and topography maps. This strategy would reduce the costs of finding and conserving rare grassland species in a given agricultural landscape. PMID- 24147409 TI - Differences in ecological structure, function, and native species abundance between native and invaded Hawaiian streams. AB - Poeciliids, one of the most invasive species worldwide, are found on almost every continent and have been identified as an "invasive species of concern" in the United States, New Zealand, and Australia. Despite their global prevalence, few studies have quantified their impacts on tropical stream ecosystem structure, function, and biodiversity. Utilizing Hawaiian streams as model ecosystems, we documented how ecological structure, function, and native species abundance differed between poeciliid-free and poeciliid-invaded tropical streams. Stream nutrient yields, benthic biofilm biomass, densities of macroinvertebrates and fish, and community structures of benthic algae, macroinvertebrates, and fish were compared between streams with and without established poeciliid populations on the island of Hawai'i, Hawaii, USA. Sum nitrate (sigmaNO3(-) = NO3(-) + NO2( )), total nitrogen, and total organic carbon yields were eight times, six times, and five times higher, respectively, in poeciliid streams than in poeciliid-free streams. Benthic biofilm ash-free dry mass was 1.5x higher in poeciliid streams than in poeciliid-free streams. Percentage contributions of chironomids and hydroptilid caddisflies to macroinvertebrate densities were lower in poeciliid streams compared to poeciliid-free streams, while percentage contributions of Cheumatopsyche analis caddisflies, Dugesia sp. flatworms, and oligochaetes were higher. Additionally, mean densities of native gobies were two times lower in poeciliid streams than in poeciliid-free ones, with poeciliid densities being approximately eight times higher than native fish densities. Our results, coupled with the wide distribution of invasive poeciliids across Hawaii and elsewhere in the tropics, suggest that poeciliids may negatively impact the ecosystem structure, function, and native species abundance of tropical streams they invade. This underscores the need for increased public awareness to prevent future introductions and for developing and implementing effective eradication and restoration strategies. PMID- 24147410 TI - Beyond best management practices: pelagic biogeochemical dynamics in urban stormwater ponds. AB - Urban stormwater ponds are considered to be a best management practice for flood control and the protection of downstream aquatic ecosystems from excess suspended solids and other contaminants. Following this, urban ponds are assumed to operate as unreactive settling basins, whereby their overall effectiveness in water treatment is strictly controlled by physical processes. However, pelagic microbial biogeochemical dynamics could be significant contributors to nutrient and carbon cycling in these small, constructed aquatic systems. In the present study, we examined pelagic biogeochemical dynamics in 26 stormwater ponds located in southern Ontario, Canada, during late summer. Initially, we tested to see if total suspended solids (TSS) concentration, which provides a measure of catchment disturbance, landscape stability, and pond performance, could be used as an indirect predictor of plankton stocks in stormwater ponds. Structural equation modeling (SEM) using TSS as a surrogate for external loading suggested that TSS was an imperfect predictor. TSS masked plankton-nutrient relationships and appeared to reflect autochthonous production moreso than external forces. When TSS was excluded, the SEM model explained a large amount of the variation in dissolved organic matter (DOM) characteristics (55-75%) but a small amount of the variation in plankton stocks (3-38%). Plankton stocks were correlated positively with particulate nutrients and extracellular enzyme activities, suggesting rapid recycling of the fixed nutrient and carbon pool with consequential effects on DOM. DOM characteristics across the ponds were mainly of autochthonous origin. Humic matter from the watershed formed a larger part of the DOM pool only in ponds with low productivity and low dissolved organic carbon concentrations. Our results suggest that in these small, high nutrient systems internal processes might outweigh the impact of the landscape on carbon cycles. Hence, the overall benefit that constructed ponds serve to protect downstream environments must be weighed with the biogeochemical processes that take place within the water body, which could offset pond water quality gains by supporting intense microbial metabolism. Finally, TSS did not provide a useful indication of stormwater pond biogeochemistry and was biased by autochthonous production, which could lead to erroneous TSS-based management conclusions regarding pond performance. PMID- 24147411 TI - Assessing upstream fish passage connectivity with network analysis. AB - Hydrologic connectivity is critical to the structure, function, and dynamic process of river ecosystems. Dams, road crossings, and water diversions impact connectivity by altering flow regimes, behavioral cues, local geomorphology, and nutrient cycling. This longitudinal fragmentation of river ecosystems also increases genetic and reproductive isolation of aquatic biota such as migratory fishes. The cumulative effects on fish passage of many structures along a river are often substantial, even when individual barriers have negligible impact. Habitat connectivity can be improved through dam removal or other means of fish passage improvement (e.g., ladders, bypasses, culvert improvement). Environmental managers require techniques for comparing alternative fish passage restoration actions at alternative or multiple locations. Herein, we examined a graph theoretic algorithm for assessing upstream habitat connectivity to investigate both basic and applied fish passage connectivity problems. First, we used hypothetical watershed configurations to assess general alterations to upstream fish passage connectivity with changes in watershed network topology (e.g., linear vs. highly dendritic) and the quantity, location, and passability of each barrier. Our hypothetical network modeling indicates that locations of dams with limited passage efficiency near the watershed outlet create a strong fragmentation signal but are not individually sufficient to disconnect the system. Furthermore, there exists a threshold in the number of dams beyond which connectivity declines precipitously, regardless of watershed topology and dam configuration. Watersheds with highly branched configurations are shown to be less susceptible to disconnection as measured by this metric. Second, we applied the model to prioritize barrier improvement in the mainstem of the Truckee River, Nevada, USA. The Truckee River application demonstrates the ability of the algorithm to address conditions common in fish passage projects including incomplete data, parameter uncertainty, and rapid application. This study demonstrates the utility of a graph-theoretic approach for assessing fish passage connectivity in dendritic river networks assuming full basin utilization for a given species, guild, or community of concern. PMID- 24147412 TI - Effects of wildlife and cattle on tick abundance in central Kenya. AB - In African savannas, large mammals, both wild and domestic, support an abundant and diverse population of tick ectoparasites. Because of the density of ticks and the many pathogens that they vector, cattle in East Africa are often treated with acaricides. While acaricides are known to be effective at reducing tick burdens on cattle, their effects on the overall abundance and community composition of ticks in savanna ecosystems are less well understood. It is also not known how well tick populations can be maintained in the absence of large mammals. We evaluated the effects of wildlife and of acaricide-treated cattle on host-seeking tick populations in a long-term, exclusion experiment in central Kenya. Over seven years, we sampled larval, nymphal, and adult ticks monthly on replicated treatment plots that controlled for the presence of cattle and for the presence of two guilds of large wild mammals: megaherbivores (giraffes and elephants) and all other large wild herbivores (> 15 kg). Two species of ticks were found in this habitat; across all surveys, 93% were Rhipicephalus pulchellus and 7% were R. praetextatus. The presence of acaricide-treated cattle dramatically reduced the abundance of host-seeking nymphal and adult ticks but did not affect the abundance of host-seeking larval ticks. The abundance of larval ticks was determined by the presence of large wild mammals, which appear to import gravid female ticks into the experimental plots. On plots with no large mammals, either wild or domestic, larval and nymphal ticks were rare. Adult R. pulchellus were most abundant in plots that allowed wildlife but excluded cattle. Adult R. praetextatus were relatively abundant in plots without any large mammals. These differences suggest that these ticks utilize different members of the host community. The reduction in ticks that results from the presence of acaricide treated cattle has potential health benefits for humans and wildlife, but these benefits must be weighed against potential costs, including reduced availability of food for birds such as oxpeckers that feed on ticks. PMID- 24147413 TI - Sampling environmental acoustic recordings to determine bird species richness. AB - Acoustic sensors can be used to estimate species richness for vocal species such as birds. They can continuously and passively record large volumes of data over extended periods. These data must subsequently be analyzed to detect the presence of vocal species. Automated analysis of acoustic data for large numbers of species is complex and can be subject to high levels of false positive and false negative results. Manual analysis by experienced surveyors can produce accurate results; however the time and effort required to process even small volumes of data can make manual analysis prohibitive. This study examined the use of sampling methods to reduce the cost of analyzing large volumes of acoustic sensor data, while retaining high levels of species detection accuracy. Utilizing five days of manually analyzed acoustic sensor data from four sites, we examined a range of sampling frequencies and methods including random, stratified, and biologically informed. We found that randomly selecting 120 one-minute samples from the three hours immediately following dawn over five days of recordings, detected the highest number of species. On average, this method detected 62% of total species from 120 one-minute samples, compared to 34% of total species detected from traditional area search methods. Our results demonstrate that targeted sampling methods can provide an effective means for analyzing large volumes of acoustic sensor data efficiently and accurately. Development of automated and semi-automated techniques is required to assist in analyzing large volumes of acoustic sensor data. PMID- 24147414 TI - Carryover effects in amphibians: are characteristics of the larval habitat needed to predict juvenile survival? AB - Carryover effects occur when experiences early in life affect an individual's performance at a later stage. Many studies have shown carryover effects to be important for future performance. However, it is currently unclear whether variation in later environments could overwhelm factors from an earlier life stage. We were interested in whether similar patterns would emerge under the same experimental design with similar taxa. To examine this, we implemented a four-way factorial experimental design with different forestry practices on three species of anurans (each examined in different years) in the aquatic larval environment and terrestrial juvenile environment in outdoor mesocosms in central Missouri, USA. Using Cormack-Jolly-Seber mark-recapture models implemented in program MARK, we investigated whether one environment or both environments best predicted terrestrial juvenile survival. We found only limited evidence of carryover effects for one of three species in one time period. These were the effects of time to metamorphosis and body condition at metamorphosis predicting leopard frog (Lithobates sphenocephalus) survival. However, both effects were counterintuitive and/or very weak. For wood frogs (L. sylvaticus), all of the variables predicting survival had confidence intervals that included zero, but very low survival may have limited our ability to estimate parameters. The terrestrial environment was important for predicting survival in both American toads (Anaxyrus americanus) and southern leopard frogs. The partial harvest forest tended to increase survival relative to control forest and early-successional forest in American toads. Alternately, early-successional forest with downed wood removed increased survival for leopard frogs, but this treatment was no different from control forest for American toads. Previous studies have shown negative effects of recent clearcuts on terrestrial amphibians. It appears that vegetative regrowth after just a few years can mitigate these initial negative effects. Our study shows that variation in later environments probably can overwhelm variation from earlier environments. However, previous evidence of carryover effects suggests that more research is needed to predict when carryover effects are likely to occur. PMID- 24147415 TI - Larval exposure to predator cues alters immune function and response to a fungal pathogen in post-metamorphic wood frogs. AB - For the past several decades, amphibian populations have been decreasing around the globe at an unprecedented rate. Batrachochytrium dendrobatidis (Bd), the fungal pathogen that causes chytridiomycosis in amphibians, is contributing to amphibian declines. Natural and anthropogenic environmental factors are hypothesized to contribute to these declines by reducing the immunocompetence of amphibian hosts, making them more susceptible to infection. Antimicrobial peptides (AMPs) produced in the granular glands of a frog's skin are thought to be a key defense against Bd infection. These peptides may be a critical immune defense during metamorphosis because many acquired immune functions are suppressed during this time. To test if stressors alter AMP production and survival of frogs exposed to Bd, we exposed wood frog (Lithobates sylvaticus) tadpoles to the presence or absence of dragonfly predator cues crossed with a single exposure to three nominal concentrations of the insecticide malathion (0, 10, or 100 parts per billion [ppb]). We then exposed a subset of post-metamorphic frogs to the presence or absence of Bd zoospores and measured frog survival. Although predator cues and malathion had no effect on survival or size at metamorphosis, predator cues increased the time to metamorphosis by 1.5 days and caused a trend of a 20% decrease in hydrophobic skin peptides. Despite this decrease in peptides determined shortly after metamorphosis, previous exposure to predator cues increased survival in both Bd-exposed and unexposed frogs several weeks after metamorphosis. These results suggest that exposing tadpoles to predator cues confers fitness benefits later in life. PMID- 24147416 TI - Methods for estimating spatial trends in Steller sea lion pup production using the Kalman filter. AB - Many species exhibit spatially varying trends in population size and status, often driven by differences among factors affecting individual subpopulations. Estimation and differentiation of such trends may be important for management, and a driving force for monitoring programs. The ability to estimate spatial differences in population trend may depend on assumptions regarding connectivity among subpopulations (stock structure or spatial overlap in stressors), information that is often poorly known. Linear state-space models using the Kalman filter were developed, tested, and applied for trend estimation of pup production for the western Alaska stock of Steller sea lions (Eumetopias jubatus), given only count data. Models were able to estimate trends and abundance even when data were missing. Models that assumed spatial correlation in trend among rookeries were more robust to stock structure assumptions when the stock structure was potentially mis-specified. High levels of spatial correlation among rookeries estimated from Steller sea lion pup count data are consistent with large-scale covariance of population trend within the Steller sea lion metapopulation. PMID- 24147418 TI - Designing effective reserve networks for nonequilibrium metacommunities. AB - The proliferation of efficient fishing practices has promoted the depletion of commercial stocks around the world and caused significant collateral damage to marine habitats. Recent empirical studies have shown that marine reserves can play an important role in reversing these effects. Equilibrium metapopulation models predict that networks of marine reserves can provide similar benefits so long as individual reserves are sufficiently large to achieve self sustainability, or spaced based on the extent of dispersal of the target species in order to maintain connectivity between neighboring reserves. However, these guidelines have not been tested in nonequilibrium metacommunity models that exhibit the kinds of complex spatiotemporal dynamics typically seen in natural marine communities. Here, we used a spatially explicit predator-prey model whose predictions have been validated in a marine system to show that current guidelines are not optimal for metacommunities. In equilibrium metacommunities, there is a community-level trade-off for designing effective reserves: Networks whose size and spacing are smaller than the extent of dispersal maximize global predator abundance but minimize global prey abundance because of trophic cascades, whereas the converse is true for reserve networks whose size and spacing are larger than the extent of dispersal. In nonequilibrium metacommunities, reserves whose size and spacing match the extent of spatial autocorrelation in adult abundance (i.e., the extent of patchiness) escape this community-level trade-off by maximizing global abundance and persistence of both the prey and the predator. Overall, these results suggest that using the extent of adult patchiness instead of the extent of larval dispersal as the size and spacing of reserve networks is critical for designing community-based management strategies. By emphasizing patchiness over dispersal distance, our results show how the apparent complexity of nonequilibrium communities can actually simplify management guidelines and reduce uncertainty associated with the assessment of dispersal in marine environments. PMID- 24147417 TI - Rising catch variability preceded historical fisheries collapses in Alaska. AB - Statistical indicators such as rising variance and rising skewness in key system parameters may provide early warning of "regime shifts" in communities and populations. However, the utility of these indicators has rarely been tested in the large, complex ecosystems that are of most interest to managers. Crustacean fisheries in the Gulf of Alaska and Bering Sea experienced a series of collapses beginning in the 1970s, and we used spatially resolved catch data from these fisheries to test the predictions that increasing variability and skewness would precede stock collapse. Our data set consisted of catch data from 14 fisheries (12 collapsing and two non-collapsing), spanning 278 cumulative years. Our sampling unit for analysis was the Alaska Department of Fish and Game statistical reporting area (mean n for individual fisheries = 42 areas, range 7-81). We found that spatial variability in catches increased prior to stock collapse: a random effects model estimating trend in variability across all 12 collapsing fisheries showed strong evidence of increasing variability prior to collapse. Individual trends in variability were statistically significant for only four of the 12 collapsing fisheries, suggesting that rising variability might be most effective as an indicator when information from multiple populations is available. Analyzing data across multiple fisheries allowed us to detect increasing variability 1-4 years prior to collapse, and trends in variability were significantly different for collapsing and non-collapsing fisheries. In spite of theoretical expectations, we found no evidence of pre-collapse increases in catch skewness. Further, while models generally predict that rising variability should be a transient phenomenon around collapse points, increased variability was a persistent feature of collapsed fisheries in our study. We conclude that this result is more consistent with fishing effects as the cause of increased catch variability, rather than the critical slowing down that is the driver of increased variability in regime shift models. While our results support the use of rising spatial variability as a leading indicator of regime shifts, the failure of our data to support other model-derived predictions underscores the need for empirical validation before these indicators can be used with confidence by ecosystem managers. PMID- 24147419 TI - Sediment-induced turbidity impairs foraging performance and prey choice of planktivorous coral reef fishes. AB - Sedimentation is a substantial threat to aquatic ecosystems and a primary cause of habitat degradation on near-shore coral reefs. Although numerous studies have demonstrated major impacts of sedimentation and turbidity on corals, virtually nothing is known of the sensitivity of reef fishes. Planktivorous fishes are an important trophic group that funnels pelagic energy sources into reef ecosystems. These fishes are visual predators whose foraging is likely to be impaired by turbidity, but the threshold for such effects and their magnitude are unknown. This study examined the effect of sediment-induced turbidity on foraging in four species of planktivorous damselfishes (Pomacentridae) of the Great Barrier Reef, including inshore and offshore species that potentially differ in tolerance for turbidity. An experimental flow tunnel was used to quantify their ability to catch mobile and immobile planktonic prey under different levels of turbidity and velocity in the range encountered on natural and disturbed reefs. Turbidity of just 4 NTU (nephelometric turbidity units) reduced average attack success by up to 56%, with higher effect sizes for species with offshore distributions. Only the inshore species (Neopomacentrus bankieri), which frequently encounters this turbidity on coastal reefs, could maintain high prey capture success. At elevated turbidity similar to that found on disturbed reefs (8 NTU), attack success was reduced in all species examined by up to 69%. These reductions in attack success led to a 21-24% decrease in foraging rates for all mid to outer-shelf species, in spite of increasing attack rates at high turbidity. Although effects of turbidity varied among species, it always depended heavily on prey mobility and ambient velocity. Attack success was up to 14 times lower on mobile prey, leaving species relatively incapable of foraging on anything but immobile prey at high turbidity. Effects of turbidity were particularly prominent at higher velocities, as attack success was overall 20-fold lower and foraging rates 3.3-fold lower at flow velocities > 30 cm/s relative to < or = 10 cm/s. Given that many planktivorous reef fishes predominantly occupy exposed, high-flow habitats, these results provide a reasonable explanation for the lack of planktivores on inshore coral reefs and warn that the performance of visual predators could be impaired at turbidity levels of only 4 NTU. PMID- 24147420 TI - Saponin profile of green asparagus genotypes. AB - The main goal of this study was to determine the saponin profiles of different "triguero" asparagus genotypes and to compare them to green asparagus commercial hybrids. The samples consisted of 31 commercial hybrids and 58 genotypes from the Huetor-Tajar (HT) population variety ("triguero"). The saponin analysis by high performance liquid chromatography-mass spectrometry allowed for the determination of 12 saponins derived from a furostan-type steroidal genin, 4 of which had never been described in the edible part of asparagus. The saponin profile of "triguero" asparagus was a combination of these new saponins and protodioscin. Although protodioscin was the major saponin found in commercial hybrids, some of these 12 saponins were detected as major components in some of the commercial hybrids. The total contents of saponins described in some of these HT genotypes reach values as high as 10-100 times higher than those found in commercial hybrids. PMID- 24147421 TI - MRI of isolated cuboid stress fractures in adults. AB - OBJECTIVE: Isolated cuboid stress fractures are rare. The purpose of this study was to evaluate the MRI appearance of this condition. MATERIALS AND METHODS: A retrospective search for patients with the diagnosis of a cuboid stress fracture was performed for a 19-year period. All patients underwent an initial three-view radiographic foot series for pain. MRI was performed because symptoms persisted beyond 4 weeks. RESULTS: Ten patients, nine of whom were women, were diagnosed with isolated cuboid stress fractures. These patients were divided into an athletic group (mean age, 36.3 years) and nonathletic group (mean age, 55.0 years). In the athletic group, there were five runners, one ballet dancer, and one gymnast, and in the nonathletic group, there was one with osteoporosis, one with a plantar fascia rupture, and one who recently underwent a fasciotomy. Eight stress fractures were linear and two were stellate and all were surrounded by marrow edema. Six fractures were located inferolaterally, one superolaterally, one laterally, one medially, and one was subchondral in location. All but one involved the peroneal sulcus and cuboid crest region. Nine of 10 feet showed pathology in the plantar fascia, seven in the peroneal tendons, and four in the posterior tibial tendon. CONCLUSION: An isolated stress fracture of the cuboid is most likely to occur in the lateral aspect of the cuboid. The cause is likely multifactorial and may include compressive and tensile forces, but plantar fascia dysfunction and age-related bone loss, which are more prevalent in women, may be additional contributing factors. PMID- 24147422 TI - Complexation-induced control of electron propagation based on bounded diffusion through nanopore-tethered ferrocenes. AB - This paper reports complexation-induced control of electron propagation based on bounded diffusion through ferrocene moieties that are covalently tethered onto nanopores (19 or 24 nm in diameter) derived from cylinder-forming polystyrene poly(methylmethacrylate) diblock copolymers. The nanopores are oriented vertically and attach to a gold surface, and thus allow a faradaic current originating from the bounded diffusion to be measured using cyclic voltammetry. Such faradaic current decreases with increasing concentration of beta cyclodextrin (beta-CD) in an aqueous solution, and recovers upon addition of excess 1-adamantanol as a competitive guest to the solution. These observations indicate that electron propagation can be reversibly inhibited by the formation of an inclusion complex with the surface-tethered redox moieties. Interestingly, the decrease in faradaic current is observed at an unexpectedly low beta-CD concentration (ca. 1 * 10(-7) M) due to the enhanced partition of beta-CD into the nanopores. These results will lead to designing highly sensitive molecular switches and electrochemical sensors based on the control of bounded diffusion by the host-guest chemistry of nanopore-tethered redox moieties. PMID- 24147423 TI - Liposome bupivacaine in peripheral nerve blocks and epidural injections to manage postoperative pain. AB - INTRODUCTION: The duration of postsurgical pain greatly outlasts the duration of analgesia (typically < 12 h) following single administration of traditional formulations of local anesthetics. Bupivacaine , one of the most widely studied and extensively used local anesthetics, is now available in a liposomal formulation that has shown promise of providing postsurgical analgesia for a duration of up to 72 h when administered as part of a peripheral (e.g., femoral) or neuraxial (e.g., epidural) nerve block. However, it is currently approved for administration in the surgical site. AREAS COVERED: This publication provides an overview of liposome bupivacaine and its potential utility in peripheral nerve blocks and epidural administration. EXPERT OPINION: The potential to provide postoperative analgesia lasting 3 days with a single administration at the time of surgery holds considerable promise. This modality could have distinct advantages over currently available techniques, such as continuous perineural local anesthetic infusion, as it would preclude the need for a catheter and pump. However, potential risks and benefits of liposome bupivacaine in peripheral and neuraxial nerve blocks must be further elucidated in surgical populations, and US Food and Drug Administration (FDA) approval must be granted for these indications. Until FDA approval is provided, the use of liposome bupivacaine in peripheral and neuraxial nerve blocks must be considered investigational. PMID- 24147424 TI - A comparison between digital radiography, computed tomography, and magnetic resonance in the detection of gunshot residues in burnt tissues and bone. AB - The radiological search for GSR is crucial in burnt material although it has been rarely tested. In this study, thirty-one bovine ribs were shot at near-contact range and burnt to calcination in an oven simulating a real combustion. Computed tomography (CT) and magnetic resonance (MR) were performed before and after carbonization and compared with former analyses with DR (digital radiography); thus comparing the assistance, the radiological methods can provide in the search for GSR in fresh and burnt bone. DR demonstrated the greatest ability in the detection of metallic residues, CT showed lower abilities, while MR showed a high sensitivity only in soft tissues. Thus, DR can be considered as the most sensitive method in the detection of GSR in charred bones, whereas CT and MR demonstrated much less reliability. Nonetheless, the MR ameliorates the analysis of gunshot wounds in other types of remains with large quantities of soft tissues. PMID- 24147425 TI - Vanadium carcinogenic, immunotoxic and neurotoxic effects: a review of in vitro studies. AB - Deleterious health effects induced by inorganic vanadium compounds are linked with carcinogenic, immunotoxic and neurotoxic insults. The goal of this review is to provide a summary of mammalian cell culture studies (from the 1990s to most recent) looking into the mode of the above-mentioned adverse actions of vanadium. Regarding the carcinogenicity potential, the key cell-based studies have evidenced the ability of vanadium to induce genotoxic lesions, cell morphological transformation and anti-apoptotic effects in a certain type of cells. Two contradictory effects of vanadium on the immune functions of cells have been observed in cell culture studies. The first effect involves reduction of cell immune responses such as vanadium-dependent inhibition of cytokine-inducible functions, which may underlie the mechanism of vanadium-induced immunosuppression. The second one involves stimulation of immune activity, for example, a vanadium-mediated increase in cytokine production, which may contribute to vanadium-related inflammation. So far, an in vitro evaluation of vanadium neurotoxicity has only been reported in few articles. These papers indicate probable cytotoxic mechanisms resulting from exposure of neurons and glial cells to vanadium. In summary, this literature review collects in vitro reports on adverse vanadium effects and thus provides vanadium researchers with a single, concise source of data. PMID- 24147430 TI - Nestin is a wide-spectrum abluminal cell marker of salivary gland tumors. AB - Nestin is an intermediate filament that was first identified in neural progenitor cells. It is expressed in various cell types in the nervous system as well as in other systems. In the present study, we investigated nestin expression in non neoplastic salivary gland tissue and in salivary gland tumors. In non-neoplastic salivary glands, nestin expression was observed in only a few abluminal cells. In contrast, diffuse nestin staining was observed in the abluminal cells of pleomorphic adenoma (11 of 11 cases), basal cell adenoma (7 of 7 cases), and epithelial-myoepithelial carcinoma (2 of 2 cases). The stromal cells in basal cell adenoma also expressed nestin. In adenoid cystic carcinoma (6 of 7 cases) and polymorphous low-grade adenocarcinoma (3 of 3 cases), nestin positive cells were observed focally. Nestin was not detected in Warthin tumor (6 cases), classical acinic cell carcinoma (2 cases), mucoepidermoid carcinoma (5 cases), or salivary duct carcinoma (4 cases). Because the nestin expression pattern in each histological salivary gland tumor type is unique, nestin could be a very useful abluminal cell marker for the diagnosis of salivary gland tumors. PMID- 24147429 TI - Extramedullary hematopoiesis in pyogenic granuloma. AB - Extramedullary hematopoiesis (EMH) suggests the presence of hematopoietic stem cells (HSC) outside bone marrow. EMH has been reported, albeit rarely, in pyogenic granuloma (PG), a polypoid lobular capillary hemangioma. However, statistical data have hitherto been lacking on the actual incidence of EMH in PG. Therefore, we here reviewed 157 consecutive cases using routine diagnostic surgical slides and found unequivocal EMH in 17 (10.8%). This indicates that EMH is a rather common finding in PG, which could thus have strong potential to be an important resource for the study of HSC. PMID- 24147428 TI - A multi-country comparison of reasons for dental non-attendance. AB - The purpose of this study was to describe differences across countries with respect to the reasons for dental non-attendance by Europeans currently 50 yr of age and older. The analyses were based on retrospective life-history data from the Survey of Health, Ageing, and Retirement in Europe and included information on various reasons why respondents from 13 European countries had never had regular dental visits in their lifetime. A series of logistic regression models was estimated to identify reasons for dental non-attendance across different welfare-state regimes. The highest proportion of respondents without any regular dental attendance throughout their lifetime was found for the Southern welfare state regime, followed by the Eastern, the Bismarckian, and the Scandinavian welfare-state regimes. Factors such as patients' perception that regular dental treatment is 'not necessary' or 'not usual' appear to be the predominant reason for non-attendance in all welfare-state regimes. The health system-level factor 'no place to receive this type of care close to home' and the perception of regular dental treatment as 'not necessary' were more often referred to within the Southern, Eastern, and Bismarckian welfare-state regimes than in Scandinavia. This could be relevant information for health-care decision makers in order to prioritize interventions towards increasing rates of regular dental attendance. PMID- 24147431 TI - Late distant metastases of malignant thymoma associated with peripheral T-cell lymphocytosis. PMID- 24147432 TI - Alveolar capillary dysplasia with misalignment of pulmonary veins with a wide spectrum of extrapulmonary manifestations. PMID- 24147433 TI - A national cross-sectional study measuring predictors for improved service user outcomes across clinical nurse or midwife specialist, advanced nurse practitioner and control sites. AB - AIM: The aim was to identify key patient outcomes and to compare these outcomes across services that employed clinical specialists (either nurse or midwife) or advanced nurse practitioners with matched, non post-holding services. BACKGROUND: In nursing and evaluation research, it is recognized that, further patient outcome studies, which measure and evaluate the impact of the new advanced roles, are urgently needed. DESIGN: A cross-sectional study design with a comparison group was implemented across Ireland. METHOD: A total of 279 surveys were completed by service users in 41 services in 2009/10. Key outcomes were identified, then chosen as primary outcomes and assessed for differences across post-holding and the matched comparison sites. To identify the priority of importance of the key outcomes, a logistic regression model was computed with difference in overall care observed (yes or no) as the dependent variable, and gender, age grouping and the key outcomes as the independent predictors. RESULTS: Analysis revealed that the key outcomes were, on anxieties, dignity and respect, time waited, confidence in the clinician and the clinician making a positive difference. Results of the logistic modelling of the key outcome on noticing any difference in the care given by the clinical specialists or advanced nurse practitioners compared with the care from others revealed that the single most important predictor was being treated with respect. CONCLUSION: Further studies evaluating advanced health professions roles measuring these six key outcomes, at a minimum, will ensure that service users' main concerns are being accounted for. PMID- 24147434 TI - Purification and identification of anti-oxidant soybean peptides by consecutive chromatography and electrospray ionization-mass spectrometry. AB - Ultrafiltration, ion-exchange chromatography, and gel filtration chromatography were used to purify anti-oxidant peptides from hydrolysates of soybean protein isolates. The <1-kD peptides were found to exhibit much higher anti-oxidant activity as compared to larger ones. Also, the alkaline peptide fractions were shown to have stronger anti-oxidant capacity than acidic and neutral peptides. Interestingly, an anti-oxidant tripeptide, Ser-Phe-Val (352.4 Da), was identified by reversed-phase high-performance liquid chromatography (RP-HPLC) connected online to electrospray ionization mass spectrometry. The tripeptide was further prepared by fluorenylmethoxycarbonyl (Fmoc) solid-phase synthesis and was found to have a dose-dependent protective effect against hydrogen peroxide (H2O2) induced injuries in rat adrenal pheochromocytoma (PC12) cells. PMID- 24147435 TI - Delineating the effects BRCA1 and BRCA2 loss of heterozygosity in pancreatic cancer progression. PMID- 24147448 TI - The Family Life Project: an epidemiological and developmental study of young children living in poor rural communities. AB - About 20% of children in the United States have been reported to live in rural communities, with child poverty rates higher and geographic isolation from resources greater than in urban communities. There have been surprisingly few studies of children living in rural communities, especially poor rural communities. The Family Life Project helped fill this gap by using an epidemiological design to recruit and study a representative sample of every baby born to a mother who resided in one of six poor rural counties over a 1-year period, oversampling for poverty and African American. 1,292 children were followed from birth to 36 months of age. This monograph described these children and used a cumulative risk model to examine the relation between social risk and children's executive functioning, language development, and behavioral competence at 36 months. Using both the Family Process Model of development and the Family Investment Model of development, observed parenting was examined over time in relation to child functioning at 36 months. Different aspects of observed parenting were examined as mediators/moderators of risk in predicting child outcomes. Results suggested that cumulative risk was important in predicting all three major domains of child outcomes and that positive and negative parenting and maternal language complexity were mediators of these relations. Maternal positive parenting was found to be a buffer for the most risky families in predicting behavioral competence. In a final model using both family process and investment measures, there was evidence of mediation but with little evidence of the specificity of parenting for particular outcomes. Discussion focused on the importance of cumulative risk and parenting in understanding child competence in rural poverty and the implications for possible intervention strategies that might be effective in maximizing the early development of these children. PMID- 24147450 TI - A paradigm change: efficient transfection of human leukemia cells by stimuli responsive multicompartment micelles. AB - The controlled nonviral delivery of genetic material using cationic polymers into cells has been of interest during the past three decades, yet the ideal delivery agent featuring utmost transfection efficiency and low cytotoxicity still has to be developed. Here, we demonstrate that multicompartment micelles from stimuli responsive triblock terpolymers, polybutadiene-block-poly(methacrylic acid)-block poly(2-(dimethylamino)ethyl methacrylate) (BMAAD), are promising candidates. The structures exhibit a patchy shell, consisting of amphiphilic (interpolyelectrolyte complexes, MAA and D) and cationic patches (excess D), generating a surface reminiscent to those of certain viruses and capable of undergoing pH-dependent changes in charge stoichiometry. After polyplex formation with plasmid DNA, superior transfection efficiencies can be reached for both adherent cells and human leukemia cells. Compared to the gold standard PEI, remarkable improvements and a number of advantages were identified for this system, including increased cellular uptake and an improved release of the genetic material, accompanied by fast and efficient endosomal escape. Furthermore, high sedimentation rates might be beneficial regarding in vitro applications. PMID- 24147451 TI - The use of essential oils in veterinary ectoparasite control: a review. AB - There is a growing body of evidence indicating the potential value of essential oils as control agents against a range of arthropod ectoparasites, particularly lice, mites and ticks. Toxicity has been demonstrated following immersion and physical contact with treated surfaces, as well as after exposure to the vapour of these oils; the last of these factors implies that there is a neurotoxic, rather than simply a mechanical, pathway in their mode of action. However, the volatile nature of essential oils suggests that their residual activity is likely to be short-lived. A possible advantage of essential oils over conventional ectoparasite treatments may refer to their reported ovicidal efficacy, although it is unclear whether this results from neurotoxicity or mechanical suffocation. There are many difficulties in comparing the findings of existing studies of essential oil toxicity. One major issue is the wide variation among batches in the relative concentrations of oil constituents. A second issue concerns the fact that many experimental designs make it difficult to confirm that the effect seen is attributable to the oil; in many cases inappropriate controls mean that the effects of the excipient on mortality cannot be distinguished. Hence, it is important that an excipient-only control is always included in these bioassays. Furthermore, in direct contact assays, when attempting to identify the toxicity pathway of the essential oil tested, it is important to include a hydrophobic control. Without this, it is impossible to distinguish simple mechanical effects from neurological or other cellular toxicity. The use of essential oils in the control of veterinary ectoparasites is an area which holds considerable potential for the future and research into their use is still at an early stage. More extensive field trials, the standardization of components, the standardization of extraction, the standardization of good experimental design, mammalian toxicology profiling and excipient development, as well as further investigation into the residual activities and shelf-lives of these oils are all required to allow the full realization of their potential. PMID- 24147449 TI - Human augmenter of liver regeneration: probing the catalytic mechanism of a flavin-dependent sulfhydryl oxidase. AB - Augmenter of liver regeneration is a member of the ERV family of small flavin dependent sulfhydryl oxidases that contain a redox-active CxxC disulfide bond in redox communication with the isoalloxazine ring of bound FAD. These enzymes catalyze the oxidation of thiol substrates with the reduction of molecular oxygen to hydrogen peroxide. This work studies the catalytic mechanism of the short, cytokine form of augmenter of liver regeneration (sfALR) using model thiol substrates of the enzyme. The redox potential of the proximal disulfide in sfALR was found to be approximately 57 mV more reducing than the flavin chromophore, in agreement with titration experiments. Rapid reaction studies show that dithiothreitol (DTT) generates a transient mixed disulfide intermediate with sfALR signaled by a weak charge-transfer interaction between the thiolate of C145 and the oxidized flavin. The subsequent transfer of reducing equivalents to the flavin ring is relatively slow, with a limiting apparent rate constant of 12.4 s( 1). However, reoxidation of the reduced flavin by molecular oxygen is even slower (2.3 s(-1) at air saturation) and thus largely limits turnover at 5 mM DTT. The nature of the charge-transfer complexes observed with DTT was explored using a range of simple monothiols to mimic the initial nucleophilic attack on the proximal disulfide. While beta-mercaptoethanol is a very poor substrate of sfALR (~0.3 min(-1) at 100 mM thiol), it rapidly generates a mixed disulfide intermediate allowing the thiolate of C145 to form a strong charge-transfer complex with the flavin. Unlike the other monothiols tested, glutathione is unable to form charge-transfer complexes and is an undetectable substrate of the oxidase. These data are rationalized on the basis of the stringent steric requirements for thiol-disulfide exchange reactions. The inability of the relatively bulky glutathione to attain the in-line geometry required for efficient disulfide exchange in sfALR may be physiologically important in preventing the oxidase from catalyzing the potentially harmful oxidation of intracellular glutathione. PMID- 24147452 TI - Episodic intertrial learning of younger and older participants: effects of age of acquisition. AB - There is clear evidence of a deficit in episodic memory for older adults compared to younger adults. Using an intertrial technique previous research has investigated whether this deficit can be attributed to a decline in encoding or consolidation. On standard memory tests, these two aspects of memory function can be measured by examining the items forgotten or acquired across multiple learning trials. The present study assessed whether age deficits in episodic memory were affected by stimulus characteristics, specifically age of acquisition (AoA). A standard intertrial design was implemented whereby participants studied word lists over several study-test trials. The stimulus characteristics of AoA were manipulated using a pure-list technique. Our findings showed that older adults demonstrate an overall recall deficit which appeared to be a consequence of both an encoding deficit and consolidation weakness. Earlier-acquired words were recalled significantly better than later-acquired words and this was apparently due to both enhanced encoding and consolidation of earlier- over later-acquired words. The key finding is that older adults show a recall advantage for earlier- compared to later-acquired words over the entire experiment to a greater degree than younger adults. PMID- 24147453 TI - Unconjugated hyperbilirubinemia: a blessing in disguise? PMID- 24147454 TI - Education and imaging. Gastrointestinal: severe inflammatory bowel disease associated pyoderma gangrenosum. PMID- 24147455 TI - Education and imaging. Hepatobiliary and pancreatic: pancreaticopleural fistula. PMID- 24147456 TI - Effects of Tyroserleutide on phosphatidylinositol 3'-kinase/AKT pathway in human hepatocellular carcinoma cell. AB - Tyroserleutide (YSL) is an active, low-molecular-weight polypeptide with in vitro and in vivo anticancer effects on human hepatocellular carcinoma BEL-7402 cells. In this study, we studied the effects of YSL on PI3K/AKT in the BEL-7402 cells to explore its anti-tumor mechanism. Results showed that YSL could up-regulate the mRNA and protein expression of tumor suppressor PTEN and increase their activities, meanwhile inhibited the mRNA and protein expression of oncogene AKT and decreased the kinase activities of AKT and PDK1. The resuming balance effect of YSL between PTEN and AKT could prevent the transmission of tumor cell proliferation signals in the PI3K/AKT pathway. Inhibition of AKT would change the status of downstream effectors in the PI3K/AKT pathway: (1) inhibition of AKT up regulated expression of cell cycle regulatory factors of downstream - P21 and P27 which repressed cell cycle and inhibited proliferation of tumor cells. (2) Inhibition of AKT decreased the phosphorylation level of MDM2, and then increased the protein level of P53 which would accelerate death proceeding of tumor cells. (3) Inactivation of AKT removed its inhibition effect on phosphorylation of Bad, which might decrease protein level of apoptosis inhibitor Bcl-2 and Bcl-XL, damaging mitochondria of tumor cells and inducing apoptosis. PMID- 24147457 TI - A selective stepwise heme oxygenase model system: an iron(IV)-oxo porphyrin pi cation radical leads to a verdoheme-type compound via an isoporphyrin intermediate. AB - The selective oxidation of the alpha-position of two heme-Fe(III) tetraarylporphryinate complexes occurs when water(hydroxide) attacks their oxidized Cmpd I-type equivalents, high-valent Fe(IV)?O pi-cation radical species ((P(+*))Fe(IV)?O). Stepwise intermediate formation occurs, as detected by UV-vis spectroscopic monitoring or mass spectrometric interrogation, being iron(III) isoporphyrins, iron(III) benzoyl-biliverdins, and the final verdoheme-like products. Heme oxygenase (HO) enzymes could proceed through heterolytic cleavage of an iron(III)-hydroperoxo intermediate to form a transient Cmpd I-type species. PMID- 24147458 TI - Outcome from spontaneous subarachnoid haemorrhage--results from 2007-2011 and comparison with our previous series. AB - OBJECTIVES: The management of patients with spontaneous subarachnoid haemorrhage (SAH) has changed, in part due to interventions now being extended to patients who are older and in a worse clinical condition. This study evaluates the effects of these changes on a complete 5-year patient material. METHODS: Demographic data and results from 615 patients with SAH admitted from 2007 to 2011 were put together. Aneurysms were found in 448 patients (72.8%). They were compared with the aneurysm group (n = 676) from a previously published series from our centre (2001-2006). Linear regression was used to determine variables predicting functional outcome in the whole aneurysm group (2001-2011). RESULTS: Patients in the more recent aneurysm group were older, and they were in a worse clinical condition on admission. Regarding younger patients admitted in World Federation of Neurosurgical Societies SAH grading (WFNS) 3, there were fewer with a good outcome. In the whole aneurysm group 2001-2011, outcome was best predicted by age, clinical condition at admission, and the size of the bleeding, and not by treatment mode or localization of aneurysm. CONCLUSION: It seems important for the outcome that aneurysms are treated early. The clinical course after that depends largely on the condition of the patient on admission rather than on aneurysm treatment method. This, together with the fact that older patients and those in worse condition are now being admitted, increases demands on neurointensive care. Further improvement in patient outcome depends on better understanding of acute brain injury mechanisms and improved neurointensive care as well as rehabilitation measures. PMID- 24147459 TI - In vitro study of AFB1 and AFM1 effects on human lymphoblastoid Jurkat T-cell model. AB - Aflatoxin B(1) (AFB(1)) is a mycotoxin produced by Aspergillus spp. that can occur as a natural contaminant in foods and feeds of vegetable origin. Post ingestion, AFB(1) can be metabolized in the liver of mammals into hydroxylated aflatoxin M(1) (AFM(1)) that is excreted with milk. Although several studies have been carried out to evaluate effects of AFB(1) on the immune system, studies regarding AFM(1) are moreover lacking. The aim of the current study was to investigate effects of AFB(1) and AFM(1) on immune function using a lymphoblastoid Jurkat T-cell line as an experimental model. Both AFB(1) and AFM(1) produced significant decreases in Jurkat cell proliferation, whereas only minor effects were noted on interleukin (IL)-2 and interferon (IFN)-gamma cytokines mRNA expression in stimulated cells that had been pre-incubated with AFB(1) and AFM(1). Particularly, AFB(1), but not AFM(1), at the highest concentration (50 uM) induced a marked increase in IL-8 mRNA expression. The results of the current study suggested the existence of a concentration threshold for AFB(1) and AFM(1) needed to exert biological activity on cell viability and innate immunity. PMID- 24147460 TI - Self-plagiarism: another reminder to authors. PMID- 24147461 TI - Section editor's notebook: Sedation simulation. PMID- 24147462 TI - Moderate sedation: what radiologists need to know. AB - OBJECTIVE: The number of procedures conducted within the radiology department using moderate sedation is rising. Anecdotal evidence suggests that there is an inconsistency in the education of radiology trainees regarding moderate sedation. CONCLUSION: The purpose of this article is to give an overview and concise summary of the use of moderate sedation as put forth by the American Society of Anesthesia, American College of Radiology, and Society of Interventional Radiology. In addition, we will review the commonly used medications for moderate sedation and their reversal agents. PMID- 24147463 TI - How radiologists get paid: resource-based relative value scale and the revenue cycle. AB - OBJECTIVE: To learn the impact of health care reform, it is important for radiologists to first understand basic administrative aspects of medicine. This article describes the processes of radiology billing, reimbursement, and the revenue cycle, which includes the importance of proper coding, the resource-based relative value scale, and accounts receivable. CONCLUSION: An understanding of the basics of medical practice management can help radiologists effectively provide optimal patient care. This article provides an overview of one component of this topic--the current radiology reimbursement system. PMID- 24147464 TI - Comparison of multiplanar reformatted CT lung tumor measurements to axial tumor measurement alone: impact on maximal tumor dimension and T stage. AB - OBJECTIVE: The purpose of this study was to compare measurements of lung tumor size between axial and multiplanar reformatted CT images, as well as to establish whether the difference between these measurements leads to a change in T stage. MATERIALS AND METHODS: Patients with lung tumors who underwent chest CT up to 31 days before lung resection between December 2010 and March 2012 were included. Axial, sagittal, and coronal CT images were evaluated by two independent readers (1 and 2) who were blinded to clinical data. In 89 patients, lung tumors categorized as T1a (54%), T1b (19%), T2a (24%), or T2b (3%) were analyzed. The longest tumor diameter using multiplanar reformatted CT was compared and correlated with axial CT alone and pathologic T stage. Statistical analysis included a Wilcoxon rank sum test to evaluate differences between measurements, intraclass correlation coefficient (ICC), and kappa statistic to assess agreement. RESULTS: Prediction of T stage using axial CT alone compared with multiplanar reformatted CT agreed in 82% of patients for reader 1 (kappa = 0.660 [95% CI, 0.531-0.789]) and 80% of patients for reader 2 (kappa = 0.695 [95% CI, 0.572-0.818]). Prediction of T stage using multiplanar reformatted CT resulted in upstaging in 18% and 20% of patients (for readers 1 and 2, respectively). Interobserver agreement (ICC [95% CI]) was 0.900 (0.803-0.954) for axial, 0.874 (0.772-0.946) for sagittal, and 0.754 (0.556-0.921) for coronal planes. CONCLUSION: Radiologic measurement of lung tumor T stage was higher using multiplanar reformatted CT as compared with axial CT alone. When available, multiplanar reformatted CT should be used to measure tumor dimension and thus assign an accurate lung cancer T stage. PMID- 24147465 TI - Percutaneous CT-guided aspiration and core biopsy of pulmonary nodules smaller than 1 cm: analysis of outcomes of 305 procedures from a tertiary referral center. AB - OBJECTIVE: We conducted a retrospective analysis to evaluate the diagnostic outcomes of CT-guided aspiration and core biopsy of 305 pulmonary nodules measuring less than 1 cm. MATERIALS AND METHODS: We determined the diagnostic yield of using CT-guided aspiration and core biopsy to analyze 305 lesions in 290 patients. Diagnostic performance was evaluated according to the biopsy method, including aspiration alone, core biopsy alone, and combination use, and the consistency of the nodule, including solid, partly solid ground-glass opacity (GGO), and pure GGO. Final diagnoses were established in 268 of the 305 lesions (87.9%). Nondiagnostic biopsy results were obtained for 27 of the 268 lesions (10.1%). RESULTS: The overall sensitivity, specificity, positive predictive value, and negative predictive value for the diagnosis of malignancy were 93.1% (148 of 159 lesions), 98.8% (81/82), 99.3% (148/149), and 88.0% (81/92), respectively; diagnostic accuracy was 95.0% (229/241). Using multivariate logistic regression analysis, we found that aspiration alone was a significant independent risk factor associated with diagnostic failure (odds ratio, 3.199; p = 0.001). CONCLUSION: The use of CT-guided aspiration and core biopsy resulted in a high diagnostic yield for pulmonary nodules smaller than 1 cm. The use of the aspiration method alone was an independent risk factor associated with diagnostic failure. PMID- 24147466 TI - High-pitch ECG-synchronized pulmonary CT angiography versus standard CT pulmonary angiography: a prospective randomized study. AB - OBJECTIVE: The purpose of this study was to compare high-pitch ECG-synchronized pulmonary CT angiography (CTA) with standard pulmonary CTA with regard to radiation dose and image quality in patients with suspected pulmonary embolism. SUBJECTS AND METHODS: This prospective study was approved by the institutional review board, and participants provided informed consent. Patients with suspected pulmonary embolism (60% women; mean age, 57 +/- 14 years) were randomized to undergo high-pitch ECG-synchronized pulmonary CTA (n = 26) or standard pulmonary CTA (n = 21). Two independent readers assessed subjective image quality of pulmonary arteries, cardiovascular structures, and pulmonary parenchyma. Signal intensity (SI) was measured in one segmental and three central pulmonary arteries. RESULTS: High-pitch ECG-synchronized pulmonary CTA showed higher SI (p < 0.001) for pulmonary arteries. Image quality scores indicated improvement in assessment of cardio-vascular structures (p < 0.001), minimization of motion of central (p < 0.001) pulmonary arteries, and an increase in pulmonary arterial enhancement (p = 0.01) with high-pitch ECG-synchronized pulmonary CTA. Image quality scores for lung assessment were higher for standard pulmonary CTA (p < 0.001). The amount of contrast agent administered was similar between techniques (p = 0.86). Radiation dose was lower for high-pitch ECG-synchronized pulmonary CTA (p < 0.001). CONCLUSION: High-pitch ECG-synchronized pulmonary CTA provides higher pulmonary arterial SI, decreased motion of central pulmonary arteries, and improved assessment of cardiovascular structures with similar contrast dose and lower radiation compared with standard pulmonary CTA. PMID- 24147467 TI - Esophagography after pneumomediastinum without CT findings of esophageal perforation: is it necessary? AB - OBJECTIVE: The purpose of our study was to determine the necessity of fluoroscopic esophagography in patients with pneumomediastinum on CT but without CT findings of esophageal perforation. MATERIALS AND METHODS: From January 1, 2006, through December 31, 2010, there were 4305 fluoroscopic esophagography examinations including 533 with CT identified from a search of our PACS. Patients with pneumomediastinum on CT who were subsequently referred for emergent fluoroscopic esophagography to exclude esophageal perforation were enrolled. Fluoroscopic esophagography examinations performed within 3 days of CT were included. Patients with a history of esophageal disease were excluded. As a result, 103 patients were enrolled in the study; patients were divided into groups on the basis of whether there was additional clinical history of esophageal damage (trauma group) or not (nontrauma group). Images were reviewed by two board-certified radiologists blinded to the clinical data and radiologic reports for the presence or absence of esophageal perforation. A positive result on CT was defined as esophageal injury or periesophageal infiltration that coexisted with periesophageal air. A positive fluoroscopic esophagography result was defined as oral contrast medium leakage from the esophagus. RESULTS: Esophageal perforation was diagnosed in 15 of the 103 patients. The CT findings were significantly correlated with esophageal perforation (p < 0.001 in the trauma group, and p = 0.001 in the nontrauma group). The respective sensitivity and negative predictive value (NPV) of CT versus fluoroscopic esophagography in the trauma group were 100% versus 66.7% and 100% versus 87.9%; in the nontrauma group, the sensitivity and NPV were 100% for CT and fluoroscopic esophagography. Thus, the sensitivity and NPV of CT were either superior or equal to those of fluoroscopic esophagography. CONCLUSION: The results of our study suggest that performing fluoroscopic esophagography in patients with pneumomediastinum is unnecessary when CT is negative for esophageal perforation. PMID- 24147468 TI - Prediction of lymphovascular invasion in rectal cancer by preoperative CT. AB - OBJECTIVE: The purpose of this study was to investigate whether the diameter of superior hemorrhoidal vein on preoperative CT can predict the presence of lymphovascular invasion (LVI). SUBJECTS AND METHODS: This study recruited 102 patients with treatment-naive rectal cancers. The diameters of superior hemorrhoidal vein and inferior mesenteric vein (IMV) on pretreatment CT and postoperative pathologic reports were reviewed. Univariate analysis and receiver operating characteristic curve analysis were applied to determine the correlation between clinical factors and pathologic features and the diameters of superior hemorrhoidal vein and IMV. RESULTS: The diameter of superior hemorrhoidal vein was significantly higher in patients with LVI than in those without (mean diameter, 44 vs 30 mm, respectively; p < 0.001) and was significantly higher in patients with distant metastases than in those without (p = 0.044). There was no significant difference between IMV diameter in LVI and that in distant metastasis (p = 0.521). CONCLUSION: Patients having rectal cancers with LVI showed a significantly increased mean superior hemorrhoidal vein diameter at presentation, which could be identified with pretreatment CT and help to direct the application of neoadjuvant treatment strategies. PMID- 24147469 TI - Indeterminate observations (liver imaging reporting and data system category 3) on MRI in the cirrhotic liver: fate and clinical implications. AB - OBJECTIVE: The purpose of this article is to retrospectively evaluate the imaging characteristics and outcomes of indeterminate observations (Liver Imaging Reporting and Data System category 3) detected on MRI in patients with cirrhosis. MATERIALS AND METHODS: Sixty-nine indeterminate observations in 52 patients with cirrhosis were imaged with hepatobiliary contrast agent-enhanced MRI. Observations were evaluated retrospectively in terms of the location, size, enhancement pattern, and follow-up results. Each observation was categorized as stable or progressed observations according to serial follow-up MRI. RESULTS: The mean follow-up interval was 11.2 months. Forty-six (67%) of the total observations showed arterial enhancement, and 23 (33%) observations showed isointense signal or low signal intensity on arterial phase. The indeterminate observations were classified as arterial enhancement with fade-out appearance (41 observations [59%]), arterial enhancement with washout appearance (five observations [7%]), and nonhyperenhancing observations (23 observations [33%]). Two of 69 observations (3%) were hyperintense on T2-weighted images, and four of 55 observations (7%) were hyperintense on hepatocellular phase. On the final follow-up MRI examinations, four (6%) observations proved to be probable or definite hepatocellular carcinoma, 55 (80%) remained stable, and 10 (14%) decreased in size or were no longer visible. CONCLUSION: The most common cause of indeterminate observations on MRI is hypervascular pseudolesions that were clinically stable on follow-up imaging. PMID- 24147470 TI - Use of diffusion-weighted MRI to differentiate chronic pancreatitis from pancreatic cancer. AB - OBJECTIVE: The purpose of this study was to compare diffusion-weighted MRI (DWI) and conventional (non-DWI) MRI sequences in differentiating mass-forming chronic pancreatitis from pancreatic cancer. MATERIALS AND METHODS: A retrospective cohort study included 36 patients who underwent pancreatic resection for pancreatic cancer (n = 13) and chronic pancreatitis (n = 23) after preoperative MRI with DWI. Two independent reviewers assessed the DW images for signal intensity and apparent diffusion coefficient (ADC) values. Four weeks later, they reviewed the other MR images for size of mass, double-duct sign, pancreatic duct cutoff, and perivascular soft-tissue cuffing. A score for conventional MRI was given with 1 meaning definitely benign and 5 meaning definitely malignant. Univariate and multivariate analyses and receiver operating characteristic (ROC) curve analysis were performed with surgical pathologic examination as the reference standard. RESULTS: The only finding that differentiated the two groups was the presence of a well-defined mass, favoring the diagnosis of cancer (p = 0.02, p < 0.01). There was no significant difference between the two groups in signal intensity on DW images (p = 0.82, p = 0.85) or ADC (p = 0.51, p = 0.76). Double-duct sign, pancreatic duct cutoff, and perivascular soft-tissue cuffing were not useful in differentiating the two groups. The areas under the ROC curve were 0.873 and 0.878 for the conventional MRI scores, compared with 0.602 and 0.552 for ADC measurements (p = 0.02, p = 0.008). CONCLUSION: The addition of DWI to conventional MRI does not facilitate differentiation of pancreatic cancer from chronic pancreatitis. PMID- 24147471 TI - Adrenal cysts: natural history by long-term imaging follow-up. AB - OBJECTIVE: The purpose of this article is to determine the natural history of adrenal cysts on the basis of long-term imaging follow-up. MATERIALS AND METHODS: This retrospective study included patients with adrenal cysts who had at least 12 months of imaging follow-up (1993-2010). Medical records were reviewed. Two radiologists reviewed imaging examinations in consensus and recorded wall thickness (thin, <= 3 mm; thick, > 3 mm), septations, and calcification. CT attenuation value, MRI signal intensity, the presence or absence of enhancement, and typical sonographic features were used to confirm fluid content of the lesions. Cyst wall enhancement was recorded (thin, <= 3 mm and smooth; thick, > 3 mm). Cyst diameter on the initial and most remote follow-up examinations was compared. The Wilcoxon matched-pairs signed rank test was applied to assess statistically significant differences in size and CT attenuation on follow-up examinations. RESULTS: Twenty patients with unilateral adrenal cysts (seven male and 13 female patients; mean age, 44 years; range, 10-75 years) had a mean imaging follow-up period of 64 months (range, 12-198 months). CT, MRI, and ultrasound examinations were obtained in 19, 11, and 13 patients, respectively. Cysts were diagnosed by lack of enhancement on CT or MRI in 12 patients, typical sonographic features in three patients, and combination of CT and sonographic or MRI features in five patients. Signal intensities typical for fluid were found on all MRI examinations, attenuations of less than 20 HU on 17 of 19 (89%) CT examinations, and features of either simple or mildly complicated cysts on all sonograms. Thin walls, wall calcifications, and thin septations were found in 20 (100%), 12 (60%), and four (20%) lesions, respectively. During the follow-up of 20 lesions, the median cyst diameter increased by 26.0% (interquartile range, 6.8 68.4%) in 12 (60%) patients, decreased by 32.9% (interquartile range, 7.1-42.8%) in six (30%) patients, and was unchanged in two (10%) patients. The median baseline CT attenuation values did not significantly change on follow-up CT examinations (p = 0.72). No patient developed a complication of adrenal cyst. Four patients had histologically confirmed benign adrenal cysts. CONCLUSION: Interval enlargement of an adrenal cyst is frequent and as an isolated finding does not indicate malignancy or presence of a complication. However, some adrenal cysts may decrease or remain stable in size over time. PMID- 24147472 TI - Are there useful CT features to differentiate renal cell carcinoma from lipid poor renal angiomyolipoma? AB - OBJECTIVE: This study was an attempt to identify key CT features that can potentially be used to differentiate between lipid-poor renal angiomyolipoma and renal cell carcinoma (RCC). MATERIALS AND METHODS: We conducted an analysis of patients who received nephrectomy or renal biopsy from 2002 to 2011 with suspected RCC. We included tumors smaller than 7 cm with a completed three-phase CT examination. A radiologist and a urology fellow, blinded to histopathologic diagnosis, recorded the imaging findings by consensus and compared the values for each parameter between lipid-poor angiomyolipoma, RCC subtypes, and RCC as a group. Multivariate logistic regression analysis was performed for each univariate significant feature. RESULTS: The sample in our study consisted of 132 patients with 135 renal tumors, including 51 men (age range, 26-84 years; mean age, 57 years) and 81 women (age range, 29-91 years; mean age, 57 years). These tumors included 33 lipid-poor angiomyolipomas, 54 clear-cell RCC, 31 chromophobe RCC, and 17 papillary RCC. Multivariate analysis revealed four significant parameters for differentiating RCC as a group from lipid-poor angiomyolipoma (angular interface, p = 0.023; hypodense rim, p = 0.045; homogeneity, p = 0.005; unenhanced attenuation > 38.5 HU, p < 0.001), five for clear-cell RCC, two for chromophobe RCC, and one for papillary RCC. Lipid-poor angiomyolipoma and clear cell RCC showed early strong enhancement and a washout pattern, whereas chromophobe RCC and papillary RCC showed gradual enhancement over time. CONCLUSION: Specific CT features can potentially be used to differentiate lipid poor renal angiomyolipoma from renal cell carcinoma. PMID- 24147473 TI - Efficacy of imaging-guided percutaneous radiofrequency ablation for the treatment of biopsy-proven malignant cystic renal masses. AB - OBJECTIVE: The purpose of this study was to determine the efficacy of imaging guided percutaneous radiofrequency ablation (RFA) for the treatment of Bosniak category III and IV cystic renal lesions. MATERIALS AND METHODS: Our database was searched to assemble a cohort of biopsy-proven malignant Bosniak category III and IV cystic renal lesions that were treated with imaging-guided percutaneous RFA from 2004 to 2012. The clinical history, imaging features, procedural complications, pathologic results, imaging follow-up, and clinical outcomes of each case were reviewed. RESULTS: A total of 16 patients and 23 biopsy-proven malignant cystic renal lesions were included; two patients with von Hippel-Lindau syndrome had four and three treated lesions each, and a patient with multiple renal tumors had three treated lesions. The other 13 patients each had a single lesion. Clinical follow-up ranged from 2 to 110 months (average, 24 months). The primary treatment efficacy of RFA was 91% (21/23 lesions), and the secondary treatment efficacy was 96% (22/23 lesions). A minority of patients experienced partial loss of renal function. There were no complications related to bleeding or tumor seeding. CONCLUSION: Imaging-guided percutaneous RFA is safe and effective for the treatment of Bosniak category III and IV cystic renal lesions. PMID- 24147474 TI - Unenhanced MDCT in suspected urolithiasis: improved stone detection and density measurements using coronal maximum-intensity-projection images. AB - OBJECTIVE: The purpose of this study was to determine whether coronal maximum intensity-projection (MIP) reformations improve urinary tract stone detection and density measurements compared with routine axial and coronal images. MATERIALS AND METHODS: Forty-five consecutive patients who underwent MDCT for suspected urolithiasis were included. Two radiologists independently determined the number of stones on 5-, 3-, and 1.25-mm axial, 5- and 3-mm coronal, and 5-mm coronal MIP images. The reference standard was obtained by consensus review using all six datasets. Stone density was determined for all calculi 4 mm or larger on all datasets. RESULTS: There were a total of 115 stones. Reader 1 identified 111 (96.5%), 112 (97.4%), 97 (84.3%), 102 (88.7%), 99 (86.1%), and 85 (73.9%) stones and reader 2 identified 105 (91.3%), 102 (88.7%), 85 (73.9%), 89 (77.4%), 89 (77.4%), and 76 (66.1%) stones on the MIP, 1.25-mm axial, 3-mm axial, 3-mm coronal, 5-mm coronal, and 5-mm axial images, respectively. Both readers identified more stones on the MIP images than on the 3- or 5-mm axial or coronal images (p < 0.0001). The mean difference in stone attenuation compared with the thin axial images was significantly less for the MIP images (44.6 HU) compared with 3-mm axial (235 HU), 3-mm coronal (309 HU), and 5-mm coronal (329.6 HU) or axial images (347.8 HU) (p < 0.0001). CONCLUSION: Coronal MIP reformations allow more accurate identification and density measurements of urinary tract stones compared with routine axial and coronal reformations. PMID- 24147477 TI - Journal Club: Voice recognition dictation: analysis of report volume and use of the send-to-editor function. AB - OBJECTIVE: The purpose of this study was to evaluate use of the send-to-editor function of a radiology voice recognition dictation system and compare study volumes of radiologists who self-edit with those of radiologists who send reports to the editor. Use of voice recognition shortcuts was also evaluated. MATERIALS AND METHODS: Voice recognition dictation systems were installed in a six-hospital system, including an 800-bed tertiary care center and five community hospitals, in 2002. This became the only means of radiologist dictation in July 2005. Report volumes, use of the send-to-editor function, and use of shortcuts were tracked from October 2005 through October 2008. A subspecialty private radiology group, ranging from 37 radiologists in July 2005 to 50 radiologists in October 2008, interpreted the imaging studies. Radiologists had no financial incentives to self edit. RESULTS: The percentage of radiologists using the send-to-editor function remained relatively constant at 46%, resulting in 21% of total reports sent to the editor. Radiologists who used the send-to-editor function dictated approximately 41% more reports than those who self-edited. The volume of reports generated by general radiologists reading large volumes of computed radiography cases and sending to the editor was greater than that of radiologists who self edited (p < 0.05). There was no significant difference between radiologists who self-edited and those who sent to the editor with respect to number of shortcuts used. CONCLUSION: Radiologists reading large volumes of computed radiography cases and using the send-to-editor function generated significantly more reports than radiologists who did not, suggesting that the send-to-editor function may be useful for improving productivity among radiologists reading large volumes of computed radiography cases. PMID- 24147476 TI - Reduction in the number and associated costs of unindicated dual-phase head CT examinations after a quality improvement initiative. AB - OBJECTIVE: During this study, we instituted a phased quality improvement initiative designed to educate referring clinicians and departmental radiologists about the recommendations of the American College of Radiology (ACR) Appropriateness Criteria for dual-phase (without and with contrast material) head CT examinations. The primary aims of the study were to evaluate whether the quality improvement initiative was associated with an improvement in ACR Appropriateness Criteria appropriateness ratings and a reduction in the number of unindicated dual-phase head CT examinations performed. A secondary aim was to assess the impact of the quality improvement initiative on health care costs. MATERIALS AND METHODS: This study included-with the exception of the examinations performed during a 3-month training period-all single- and dual-phase head CT examinations performed of adult patients at a tertiary care medical center from January 2009 through October 2011. Both inpatients and outpatient examinations were included. There were no exclusion criteria. RESULTS: Implementation of the initiative enhanced patient safety and reduced health care costs by achieving a significant reduction (p = 0.006) in the number of unindicated dual-phase head CT examinations performed from a median number of 40 per month to 17 per month. CONCLUSION: Although there are potential benefits for dual-phase head CT examinations, the medical and economic risks should be measured against these potential benefits. Incorporating the ACR Appropriateness Criteria applies evidence-based medicine to this algorithm. In this outcomes-driven study, the number of unindicated dual-phase head CT examinations was reduced and imaging efficacy improved primarily through physician education and monitoring. PMID- 24147475 TI - Prostate volumes derived from MRI and volume-adjusted serum prostate-specific antigen: correlation with Gleason score of prostate cancer. AB - OBJECTIVE: The purpose of this article is to study relationships between MRI based prostate volume and volume-adjusted serum prostate-specific antigen (PSA) concentration estimates and prostate cancer Gleason score. MATERIALS AND METHODS: The study included 61 patients with prostate cancer (average age, 63.3 years; range 52-75 years) who underwent MRI before prostatectomy. A semiautomated and MRI-based technique was used to estimate total and central gland prostate volumes, central gland volume fraction (central gland volume divided by total prostate volume), PSA density (PSAD; PSA divided by total prostate volume), and PSAD for the central gland (PSA divided by central gland volume). These MRI-based volume and volume-adjusted PSA estimates were compared with prostatectomy specimen weight and Gleason score by using Pearson (r) or Spearman (rho) correlation coefficients. RESULTS: The estimated total prostate volume showed a high correlation with reference standard volume (r = 0.94). Of the 61 patients, eight (13.1%) had a Gleason score of 6, 40 (65.6%) had a Gleason score of 7, seven (11.5%) had a Gleason score of 8, and six (9.8%) had a Gleason score of 9 for prostate cancer. The Gleason score was significantly correlated with central gland volume fraction (rho = -0.42; p = 0.0007), PSAD (rho = 0.46; p = 0.0002), and PSAD for the central gland (rho = 0.55; p = 0.00001). CONCLUSION: Central gland volume fraction, PSAD, and PSAD for the central gland estimated from MRI examinations show a modest but significant correlation with Gleason score and have the potential to contribute to personalized risk assessment for significant prostate cancer. PMID- 24147478 TI - MDCT of chest, abdomen, and pelvis using attenuation-based automated tube voltage selection in combination with iterative reconstruction: an intrapatient study of radiation dose and image quality. AB - OBJECTIVE: The purpose of this study was intrapatient comparison of image quality and radiation dose between MDCT scans of the chest, abdomen, and pelvis obtained with attenuation-based automated kilovoltage selection and sinogram-affirmed iterative reconstruction and scans obtained with standard kilovoltage selection and a filtered backprojection image reconstruction algorithm. MATERIALS AND METHODS: One hundred one oncology patients who had undergone two chest, abdominal, and pelvis CT scans within 1 year were imaged with standard tube voltage selection of 120 kVp using a filtered backprojection reconstruction algorithm (protocol 1) and with attenuation-based automated tube voltage selection using an iterative reconstruction algorithm (protocol 2). Radiation dose parameters (volumetric CT dose index [CTDIvol], dose-length product, and effective dose) as well as image noise, signal-to-noise ratio, and contrast-to noise ratio were compared. Two independent radiologists evaluated image quality and sharpness. Student t test, Fisher exact test, and Wilcoxon signed-rank test were used for analysis. A p value less than 0.05 was considered significant. RESULTS: Mean +/- SD CTDIvol values were 19.9 +/- 4.43 mGy and 12.53 +/- 4.79 mGy for protocols 1 and 2, respectively (p < 0.0001). Effective dose was 38.2% lower on average using protocol 2 compared with protocol 1 (12.08 vs 19.55 mSv; p < 0.0001). Objective image quality parameters were significantly better in protocol 2 (p < 0.0001). Both radiologists found the overall image quality and sharpness to be similar for both protocols (p > 0.05). CONCLUSION: In patients undergoing CT examination of the chest, abdomen, and pelvis, the combination of attenuation based automated tube voltage selection with iterative reconstruction significantly reduced radiation dose parameters and maintained objective image quality when compared with standard tube voltage selection associated with filtered backprojection reconstruction. PMID- 24147479 TI - Sonography of greater trochanteric pain syndrome and the rarity of primary bursitis. AB - OBJECTIVE: Greater trochanteric pain syndrome is a common condition with clinical features of pain and tenderness at the lateral aspect of the hip. Diagnosing the origin of greater trochanteric pain is important because the treatment varies depending on the cause. We hypothesized that sonographic evaluation of sources for greater trochanteric pain syndrome would show that bursitis was not the most commonly encountered abnormality. MATERIALS AND METHODS: We performed a retrospective review of musculoskeletal sonographic examinations performed at our institution over a 6-year period for greater trochanteric pain syndrome; completed a tabulation of the sonographic findings; and assessed the prevalence of trochanteric bursitis, gluteal tendon abnormalities, iliotibial band abnormalities, or a combination of findings. Prevalence of abnormal findings, associations of bursitis, gluteal tendinosis, gluteal tendon tears, and iliotibial band abnormalities were calculated. RESULTS: The final study population consisted of 877 unique patients: 602 women, 275 men; average age, 54 years; and age range, 15-87 years). Of the 877 patients with greater trochanteric pain, 700 (79.8%) did not have bursitis on ultrasound. A minority of patients (177, 20.2%) had trochanteric bursitis. Of the 877 patients with greater trochanteric pain, 438 (49.9%) had gluteal tendinosis, four (0.5%) had gluteal tendon tears, and 250 (28.5%) had a thickened iliotibial band. CONCLUSION: The cause of greater trochanteric pain syndrome is usually some combination of pathology involving the gluteus medius and gluteus minimus tendons as well as the iliotibial band. Bursitis is present in only the minority of patients. These findings have implications for treatment of this common condition. PMID- 24147480 TI - Update on talar fracture patterns: a large level I trauma center study. AB - OBJECTIVE: Prior studies of talar fracture patterns are dated and based on radiography only. The purpose of our study was to describe talar fracture patterns and associated injuries in a modern large level 1 trauma center setting using both radiography and CT. MATERIALS AND METHODS: The radiolog and clinical data of patients with acute talar fractures diagnosed over an 18-month period were retrospectively reviewed. Data analysis included descriptive statistics for injury mechanisms and associated injuries. RESULTS: Over the study period, a total of 132 talar fractures were detected in 122 patients. The most common talar fracture location was the body (61%). The most common body fractures were dome compression (26%), lateral process (24%), and posterior tubercle (21%). Of the 132 fractures, 62% were comminuted and 21 (16%) were vertical neck fractures compatible with the Hawkins-Canale classification. Both radiography and CT were used in 91% of cases, with CT providing additional information in 112 (93%) cases. By use of CT as the reference standard, the sensitivity of radiography for detecting talar fractures was 74%. The most common fracture missed by radiography was talar dome compression (31% not seen on radiography) Talar fractures were associated with adjacent joint subluxation or dislocation in more than 66% of the cases and adjacent fracture in more than 72% of the cases. CONCLUSION: In our study, the most common site of talar fracture was the body. Current classification systems do not apply to most talar fractures. Talar fracture patterns cannot be characterized with radiography alone. CT is a critical tool for the detection and characterization of talar fractures. There is a high incidence of adjacent fracture and dislocation with acute traumatic talar fractures. PMID- 24147481 TI - CT-guided bone biopsy with a battery-powered drill system: preliminary results. AB - OBJECTIVE: Standard percutaneous bone biopsy involves manual needle insertion. Recently, a battery-powered needle drilling biopsy system (OnControl) has been introduced. We report our experience using this drill biopsy system for CT-guided percutaneous bone biopsy in 25 patients. CONCLUSION: CT-guided percutaneous biopsy using the OnControl bone access system is a safe, quick, and effective method for sampling bone lesions visible on CT. PMID- 24147482 TI - Neuroradiology second opinion consultation service: assessment of duplicative imaging. AB - OBJECTIVE: The purpose of this study was to characterize the performance of the Neuroradiology Second Opinion Consultation Service (NSOCS) at our institution to establish the rate, causes, and implications of requests for repeat imaging. MATERIALS AND METHODS: We queried 11,753 complete reports of all NSOCS studies for calendar year 2010 for the words "repeat" and "follow-up." We categorized study limitations described in these reports into poor image quality, missing or inadequate MR sequences or CT reformats, lack of IV contrast administration where otherwise deemed appropriate, an "other" category for miscellaneous items, and a "clarification" category for indeterminate findings or recommendations for more advanced protocols. The corresponding available electronic medical records were reviewed. An estimated financial analysis of the NSOCS was additionally performed. RESULTS: Repeat imaging studies were recommended in 1.5% of cases. In 0.3% of all cases, a subsequent repeat examination was documented in the electronic medical records. Study limitations were most commonly due to poor image quality (77.5%), followed by missing or inadequate MR sequences or CT reformats (20.3%). The additional estimated cost of repeat imaging was calculated at $14,019.34, with an overall per-patient cost of $2.12 for the service. CONCLUSION: Reviewing outside studies generates a very low rate of requests for and performance of repeat studies, and is not a major additional health care expense. PMID- 24147483 TI - Intravoxel incoherent motion imaging of masticatory muscles: pilot study for the assessment of perfusion and diffusion during clenching. AB - OBJECTIVE: The purpose of this study was to evaluate intravoxel incoherent motion (IVIM) imaging for assessing perfusion and diffusion of masticatory muscles during clenching. SUBJECTS AND METHODS: A prospective study was performed to assess the perfusion and diffusion of masticatory muscles during clenching. The masseter and medial pterygoid muscles participate in clenching, and the lateral pterygoids do not. IVIM parameters (microvascular volume fraction, f; pure diffusion coefficient, D; and perfusion-related incoherent microcirculation, D*) were determined on both the clenching and the balancing sides in 24 volunteers. The Wilcoxon test was used to compare the IVIM parameters at rest and during clenching. RESULTS: The f and D* values of the masseters significantly increased on the clenching side (f = 0.17 +/- 0.10 vs 0.29 +/- 0.11, p < 0.001; D* = 21.3 +/- 18.5 * 10(-3) mm(2)/s vs 42.1 +/- 33.3 * 10(-3) mm(2)/s, p = 0.0008). However, the D values did not change during clenching (1.26 +/- 0.23 * 10(-3) mm(2) vs 1.21 +/- 0.35 * 10(-3) mm(2)). The f values of the medial pterygoids also increased on the clenching side (0.20 +/- 0.09 vs 0.30 +/- 0.09, p < 0.001). On the balancing side, the f values of the masseters (0.19 +/- 0.12 vs 0.30 +/- 0.12, p < 0.001) and medial pterygoids (0.20 +/- 0.09 vs 0.29 +/- 0.11, p = 0.0007) significantly increased during clenching. In contrast, the IVIM values of the lateral pterygoids did not change. CONCLUSION: IVIM imaging may be useful for assessing perfusion and diffusion of the masticatory muscles. PMID- 24147484 TI - Differences in plaque morphology and correlation of stenosis at the carotid artery bifurcation and the carotid siphon. AB - OBJECTIVE: The purpose of this study was to compare the type of plaque and the degree of stenosis in the carotid artery bifurcation and the carotid siphon to explore potential correlations between these parameters. MATERIALS AND METHODS: A total of 119 patients (87 men, 32 women; mean age, 69 years) were retrospectively studied using MDCT angiography. Component types of the carotid artery bifurcation and the carotid siphon plaque were defined according to attenuation values, and the volumes of each plaque component were calculated. The degree of stenosis was calculated according to the North American Symptomatic Endarterectomy Trial method. Data were compared using the Wilcoxon signed-rank test, Spearman correlation analysis, and receiver operating characteristic (ROC) analysis. RESULTS: The results of the Wilcoxon test showed a statistically significant difference (p = 0.0001) between the degree of stenosis at the carotid artery bifurcation and that at the carotid siphon. We observed a statistically significant difference (p = 0.0001) between the total volumes of the carotid artery bifurcation (mean value, 748 mm(3)) and the carotid siphon (mean value, 54 mm(3)) plaque. Moreover, the respective mean percentages of calcified, mixed, and lipid components of plaque were 17%, 56%, and 27% in the carotid artery bifurcation and 73%, 19%, and 8% in the carotid siphon, showing a statistically significant difference (p = 0.001). ROC analysis did not show association between carotid siphon plaque volume and previous cerebrovascular events (Az = 0.562; p = 0.149), whereas the total volume of the carotid artery bifurcation plaque--and, in particular, the volume of the lipid components--showed a statistically significant association (Az = 0.691, and Az = 0.758; p < 0.001). CONCLUSION: No significant association was found between presence of mixed and fatty components of plaque in the carotid artery bifurcation and presence of similar components in the carotid siphon. The carotid artery bifurcation total plaque volume (and, in particular, carotid artery bifurcation lipid volume) was associated with previous cerebrovascular events, whereas no association with the volume of carotid siphon plaque (and its subcomponents) was found. PMID- 24147485 TI - Correlation between standardized uptake value and apparent diffusion coefficient of neoplastic lesions evaluated with whole-body simultaneous hybrid PET/MRI. AB - OBJECTIVE: The purpose of this study was to assess the correlation between standardized uptake value (SUV) and apparent diffusion coefficient (ADC) of neoplastic lesions in the use of a simultaneous PET/MRI hybrid system. SUBJECTS AND METHODS: Twenty-four patients with known primary malignancies underwent FDG PET/CT. They then underwent whole-body PET/MRI. Diffusion-weighted imaging was performed with free breathing and a single-shot spin-echo echo-planar imaging sequence with b values of 0, 350, and 750 s/mm(2). Regions of interest were manually drawn along the contours of neoplastic lesions larger than 1 cm, which were clearly identified on PET and diffusion-weighted images. Maximum SUV (SUVmax) on PET/MRI and PET/CT images, mean SUV (SUVmean), minimum ADC (ADCmin), and mean ADC (ADCmean) were recorded on PET/MR images for each FDG-avid neoplastic soft-tissue lesion with a maximum of three lesions per patient. Pearson correlation coefficient was used to asses the following relations: SUVmax versus ADCmin on PET/MR and PET/CT images, SUVmean versus ADCmean, and ratio of SUVmax to mean liver SUV (SUV ratio) versus ADCmin. A subanalysis of patients with progressive disease versus partial treatment response was performed with the ratio of SUVmax to ADCmin for the most metabolically active lesion. RESULTS: Sixty-nine neoplastic lesions (52 nonosseous lesions, 17 bone metastatic lesions) were evaluated. The mean SUVmax from PET/MRI was 7.0 +/- 6.0; SUVmean, 5.6 +/- 4.6; mean ADCmin, 1.10 +/- 0.58; and mean ADCmean, 1.48 +/- 0.72. A significant inverse Pearson correlation coefficient was found between PET/MRI SUVmax and ADCmin (r = -0.21, p = 0.04), between SUVmean and ADCmean (r = -0.18, p = 0.07), and between SUV ratio and ADCmin (r = -0.27, p = 0.01). A similar inverse Pearson correlation coefficient was found between the PET/CT SUVmax and ADCmin. Twenty of 24 patients had previously undergone PET/CT; five patients had a partial treatment response, and six had progressive disease according to Response Evaluation Criteria in Solid Tumors 1.1. The ratio between SUVmax and ADCmin was higher among patients with progressive disease than those with a partial treatment response. CONCLUSION: Simultaneous PET/MRI is a promising technology for the detection of neoplastic disease. There are inverse correlations between SUVmax and ADCmin and between SUV ratio and ADCmin. Correlation coefficients between SUVmax and ADCmin from PET/MRI were similar to values obtained with SUVmax from the same-day PET/CT. Given that both SUV and ADC are related to malignancy and that the correlation between the two biomarkers is relatively weak, SUV and ADC values may offer complementary information to aid in determination of prognosis and treatment response. The combined tumoral biomarker, ratio between SUVmax and ADCmin, may be useful for assessing progressive disease versus partial treatment response. PMID- 24147486 TI - Comparison of the accuracy of PET/CT and PET/MRI spatial registration of multiple metastatic lesions. AB - OBJECTIVE: The purpose of this study was to compare the accuracy of the spatial registration of conventional PET/CT with that of hybrid PET/MRI of patients with FDG-avid metastatic lesions. SUBJECTS AND METHODS: Thirteen patients with known metastatic lesions underwent FDG PET/CT followed by PET/MRI with a hybrid whole body system. The inclusion criterion for tumor analysis was spherical or oval FDG avid tumor clearly identified with both CT and MRI. The spatial coordinates (x, y, z) of the visually estimated centers of the lesions were determined for PET/CT (PET and CT independently) and PET/MRI (PET, T1-weighted gradient-echo sequence with radial stack-of-stars trajectory, T2-weighted sequence), and the b0 images of an echo-planar imaging (EPI) diffusion-weighted imaging (DWI) acquisition. All MRI sequences were performed in the axial plane with free breathing. The spatial coordinates of the estimated centers of the lesions were determined for PET and CT and PET and MRI sequences. Distance between the isocenter of the lesion on PET images and on the images obtained with the anatomic modalities was measured, and misregistration (in millimeters) was calculated. The degree of misregistration was compared between PET/CT and PET/MRI with a paired Student t test. RESULTS: Nineteen lesions were evaluated. On PET/CT images, the average of the total misregistration in all planes of CT compared with PET was 4.13 +/- 4.24 mm. On PET/MR images, lesion misregistration between PET and T1-weighted gradient-echo images had a shift of 2.41 +/- 1.38 mm and between PET and b0 DW images was 5.97 +/- 2.83 mm. Similar results were calculated for 11 lesions on T2-weighted images. The shift on T2-weighted images compared with PET images was 2.24 +/- 1.12 mm. Paired Student t test calculations for PET/CT compared with PET/MRI T1 weighted gradient-echo images with a radial stack-of-stars trajectory, b0 DW images, and T2-weighted images showed significant differences (p < 0.05). Similar results were seen in the analysis of six lung lesions. CONCLUSION: PET/MRI T1 weighted gradient-echo images with a radial stack-of-stars trajectory and T2 weighted images had more accurate spatial registration than PET/CT images. This may be because that the whole-body PET/MRI system used can perform simultaneous acquisition, whereas the PET/CT system acquires data sequentially. However, the EPI-based b0 DWI datasets were significantly misregistered compared with the PET/CT datasets, especially in the thorax. Radiologists reading PET/MR images should be aware of the potential for misregistration on images obtained with EPI based DWI sequences because of inherent spatial distortion associated with this type of MRI acquisition. PMID- 24147487 TI - Current classification and terminology of pediatric vascular anomalies. AB - OBJECTIVE: The purpose of this article is to review new terminology to diagnose, classify, and refer patients with vascular anomalies for additional imaging, intervention, and treatment. CONCLUSION: In recent decades, much has been learned regarding the histopathology, cause, and treatment of vascular anomalies. As information has been gleaned, a new classification system has emerged that divides vascular anomalies into neoplasms and malformations. Its utility is based on accurate initial diagnosis that correlates consistently with clinical presentation, disease course, and treatment. PMID- 24147488 TI - Angiographic C-arm CT- versus MDCT-guided stereotactic punctures of liver lesions: nonrigid phantom study. AB - OBJECTIVE: Angiographic C-arm CT may allow performing percutaneous stereotactic tumor ablations in the interventional radiology suite. Our purpose was to evaluate the accuracy of using C-arm CT for single and multimodality image fusions and to compare the targeting accuracy of liver lesions with the reference standard of MDCT. MATERIALS AND METHODS: C-arm CT and MDCT scans were obtained of a nonrigid rapid prototyping liver phantom containing five 1-mm targets that were placed under skin-simulating deformable plastic foam. Target registration errors of image fusion were evaluated for single-modality and multimodality image fusions. A navigation system and stereotactic aiming device were used to evaluate target positioning errors on postinterventional scans with the needles in place fused with the C-arm CT or MDCT planning images. RESULTS: Target registration error of the image fusion showed no significant difference (p > 0.05) between both modalities. In five series with a total of 25 punctures for each modality, the lateral target positioning error (i.e., the lateral distance between the needle tip and the planned trajectory) was similar for C-arm CT (mean [+/- SD], 1.6 +/- 0.6 mm) and MDCT (1.82 +/- .97 mm) (p = 0.33). CONCLUSION: In a nonrigid liver phantom, angiographic C-arm CT may provide similar image fusion accuracy for comparison of intra- and postprocedure control images with the planning images and enables stereotactic targeting accuracy similar to that of MDCT. PMID- 24147490 TI - Does digital mammography increase detection of high-risk breast lesions presenting as calcifications? AB - OBJECTIVE: The objective of our study was to evaluate whether the transition from film-screen mammography (FSM) to digital mammography (DM) was associated with increased detection of high-risk breast lesions. MATERIALS AND METHODS: A retrospective search identified 142 cases of atypia or lobular neoplasia (LN) diagnosed in women with mammographic calcifications between January 2004 and August 2010. We excluded lesions upgraded to cancer at excisional biopsy, lesions in women with ipsilateral cancer within 2 years of mammography, and lesions that presented as a mass only. The cases included in the cohort were 82 (57.7%) cases of atypical ductal hyperplasia; 17 (12%) atypical lobular hyperplasia; 25 (17.6%) lobular carcinoma in situ (LCIS); 12 (8.5%) atypia and LCIS; and six (4.2%) other atypia. The institution transitioned from predominantly performing FSM in 2004 to performing only DM by 2010. Pathology was interpreted by breast pathologists. The annual detection rate was calculated by dividing the number of high-risk lesions by mammography volume. RESULTS: Of the 142 cases of atypia or LN, 52 (36.6%) were detected using FSM and 90 (63.4%) were detected using DM. The detection rate was higher with DM (1.24/1000 mammographic studies) than FSM (0.37/1000 mammographic studies). The detection rate by year ranged between 0.21 and 0.64 per 1000 mammographic studies for FSM and between 0.32 and 1.49 per 1000 mammographic studies for DM. The median size of the calcifications was 8 mm on DM and 7 mm on FSM. The most common appearance was clustered amorphous or indistinct calcifications on both FSM and DM. CONCLUSION: The transition from FSM to DM was associated with a threefold increase in the detection rate of high-risk lesions. Improved detection may allow enhanced screening, risk reduction treatment, and possibly breast cancer prevention. However, increased detection of high-risk lesions may also result in oversurveillance and treatment. PMID- 24147489 TI - Fusion imaging-guided radiofrequency ablation for hepatocellular carcinomas not visible on conventional ultrasound. AB - OBJECTIVE: The objective of our study was to assess whether fusion imaging of conventional ultrasound and liver CT or MR images can improve the conspicuity of lesions and feasibility of percutaneous radiofrequency ablation (RFA) for the treatment of hepatocellular carcinomas (HCCs) not visible on ultrasound. Whether peritumoral anatomic landmarks can be used for the placement of an electrode in HCCs not visible on ultrasound even after image fusion was also evaluated. MATERIALS AND METHODS: Planning ultrasound for percutaneous RFA was performed using conventional ultrasound first and then using fusion imaging later during the same session. The visibility of HCCs and feasibility of RFA on conventional ultrasound and on fusion imaging were assessed. We evaluated how many HCCs initially not visible on conventional ultrasound could be visualized and ablated after applying the fusion imaging technique. One hundred twenty HCCs not visible on conventional ultrasound in 96 patients were included. RESULTS: When fusion imaging was applied, 38 of the 120 (31.7%) HCCs that were initially not visible could be seen and RFA was feasible. Among the remaining 82 HCCs still not visible after image fusion, 26 (31.7%) were ablated under the guidance of fusion imaging the technique based on peritumoral anatomic landmarks. Overall, 64 of 120 (53.3%) HCCs (59.4%, 57 of 96 patients) not visible on conventional ultrasound could be ablated under the guidance of the fusion imaging technique. CONCLUSION: Fusion imaging can improve the conspicuity of HCCs and the feasibility of percutaneous RFA of HCCs not visible on conventional ultrasound. Peritumoral anatomic landmarks can be used for electrode placement in HCCs that are still not visible even after image fusion. PMID- 24147491 TI - Breast cancer detected on an incident (second or subsequent) round of screening MRI: MRI features of false-negative cases. AB - OBJECTIVE: The purpose of this article is to evaluate the nature of breast cancers detected in the incident round of screening MRI to determine MRI features of early breast cancer. MATERIALS AND METHODS: From 2003 to 2012, there were 16 incident breast cancers in 15 patients on screening MRI, including nine cancers that were retrospectively identifiable on the prior MRI (false-negative [FN] cancers at prior screening examination). We evaluated the BI-RADS features of these incident cancers in previous and current MRI scans. RESULTS: Of 16 incident cancers, there were 11 mass lesions (69%), three foci (19%), and two nonmasslike enhancement lesions (13%). Of the nine FN cancers (five foci, two masses, and two nonmasslike enhancement lesions), all showed increases in size on the current examination (median, 80% increase); four lesions showed rapid uptake kinetics on prior examinations, and five lesions showed a change in kinetic pattern from slow to rapid uptake. Among the five foci, one focus was isolated and four foci were in a background of other foci, where two foci could be distinguished for their higher signal intensity. CONCLUSION: On screening MRI, any lesion that increases in size, has rapid uptake kinetics or a change in kinetic pattern, or is an isolated focus or focus showing more enhancement than other foci should be viewed with a high degree of suspicion, and a biopsy should be considered. PMID- 24147492 TI - Medicolegal-malpractice and ethical issues in radiology: meaningful use, direct patient communication, and HIPAA. PMID- 24147494 TI - Architectural distortion of the breast. PMID- 24147495 TI - Common blind spots on chest CT: where are they all hiding? Part 2, Extrapulmonary structures. PMID- 24147496 TI - Richard Schatzki: a familiar ring. AB - OBJECTIVE: The Schatzki ring was named for Richard Schatzki, a renowned radiologist who described the entity with his colleague, John E. Gary. The purpose of this article is to shed more light on a man who made such a significant contribution and to chronicle developments concerning this important radiologic finding. CONCLUSION: The Schatzki ring was described long ago, but its cause is poorly understood even today. PMID- 24147497 TI - Business of radiology: financial fundamentals for radiologists. AB - OBJECTIVE: The purposes of this article are to provide a primer on financial statements and to review several financial concepts that are at the foundation of the business of medicine. CONCLUSION: For radiologists to effectively contribute to the leadership and management of their practices, it is imperative that they understand the business aspects of radiology. Radiologists' understanding and participation in practice management may also facilitate job satisfaction and assist the provision of optimal patient care. PMID- 24147498 TI - How to establish a cost-effective mobile mammography program. AB - OBJECTIVE: The purpose of this article is to describe how to establish a cost effective mobile mammography program on the basis of examples from a 20-year experience with film-screen and digital mammography units. CONCLUSION: Mobile mammography programs can reduce many barriers to breast cancer screening faced by medically underserved women. Finding and maintaining resources, having appropriate equipment and infrastructure, and having a dedicated team with an efficient workflow are the key elements of establishing a cost-effective mobile mammography program. PMID- 24147499 TI - PET with 62Cu-ATSM and 62Cu-PTSM is a useful imaging tool for hypoxia and perfusion in pulmonary lesions. AB - OBJECTIVE: Hypoxia is a characteristic of many tumors and portends a worse prognosis in lung, cervical, prostate, and rectal cancers. Unlike the others, lung cancers present a unique challenge in measuring hypoxia, with invasive biopsies and higher rates of complications. Noninvasive imaging studies detecting hypoxia using isotopes of copper-diacetyl-bis(N4-methylthiosemicarbazone) ((62)Cu ATSM) have predicted prognosis and treatment outcomes in some small feasibility trials. These images, however, may not identify all areas of hypoxia. Hence, we hypothesize that the addition of another PET imaging agent, copper-pyruvaldehyde bis(N4-methylthiosemicarbazone) ((62)Cu-PTSM), which can detect areas of perfusion, can augment the information obtained in (62)Cu-ATSM PET scans. SUBJECTS AND METHODS: To characterize tumors on the basis of both perfusion and hypoxia, 10 patients were studied using both (62)Cu-ATSM and (62)Cu-PTSM PET scans. In addition, proteomic arrays looking at specific proangiogenic, survival, and proinflammatory targets were assessed. RESULTS: Six of 10 patients had evaluable PET scans. Our initial experience of characterizing lung tumor hypoxia using (62)Cu-ATSM and (62)Cu-PTSM PET scans showed that visualization of areas with hypoxia normalized for perfusion is feasible. All studied tumors exhibited some hypoxia. Despite the small sample size, a positive relationship was noted between epidermal growth factor levels and (62)Cu-ATSM-detected hypoxia. CONCLUSION: This initial series of (62)Cu-ATSM and (62)Cu-PTSM PET scans shows that evaluating lung masses by visualizing hypoxia and perfusion is a feasible and novel technique to provide more information. Further investigation is warranted to assess the potential role of (62)Cu-ATSM and (62)Cu-PTSM PET techniques combined with proteomics as alternatives to invasive biopsy techniques in clinical care. PMID- 24147500 TI - Value of MDCT in diagnosis and management of esophageal sharp or pointed foreign bodies according to level of esophagus. AB - OBJECTIVE: The purpose of this study was to validate the usefulness of MDCT for diagnosis of a sharp or pointed esophageal foreign body according to esophageal level. MATERIALS AND METHODS: Forty-two patients with a history of sharp or pointed foreign body ingestion were reviewed retrospectively. Two observers interpreted the CT and the conventional radiography datasets separately. If a foreign body was directly identified, it was regarded as a positive finding. Even if no high-density foreign body was found, detection of a secondary finding was considered to be a positive finding. Diagnostic performance of MDCT and conventional radiography were compared according to esophageal level. Final diagnosis was made by esophagoscopy or surgery in addition to the clinicoradiologic result. RESULTS: MDCT was statistically superior to conventional radiography for diagnosis of a thoracic esophageal foreign body for both observers (p < 0.001 for each). No significant difference in sensitivity between CT and conventional radiography for diagnosis of cervical esophageal foreign body was noted regardless of observer. Both observers could identify all complicated conditions with MDCT regardless of esophageal level. However, in two of three cases of complicated thoracic esophageal foreign bodies, neither observer could detect foreign bodies on conventional radiography; furthermore, the observers could not identify pneumomediastinum. CONCLUSION: In cases of sharp or pointed foreign body ingestion, if the result of an initial inspection of oro- and hypopharynx reveals negative findings, the first imaging modality should be MDCT for better diagnosis and management. PMID- 24147501 TI - Imaging of primary and secondary renal lymphoma. AB - OBJECTIVE: This article reviews the CT and MRI patterns of primary and secondary renal lymphomas and discusses the role of percutaneous biopsy in diagnosis and management. CONCLUSION: Renal lymphoma has a variable imaging spectrum and may mimic renal cell carcinoma. An awareness of the typical and atypical imaging features of both primary and secondary renal lymphomas can help the radiologist to suggest these diagnoses and recommend biopsy when appropriate. PMID- 24147502 TI - Fully automated prostate segmentation on MRI: comparison with manual segmentation methods and specimen volumes. AB - OBJECTIVE: The objective of our study was to compare calculated prostate volumes derived from tridimensional MR measurements (ellipsoid formula), manual segmentation, and a fully automated segmentation system as validated by actual prostatectomy specimens. MATERIALS AND METHODS: Ninety-eight consecutive patients (median age, 60.6 years; median prostate-specific antigen [PSA] value, 6.85 ng/mL) underwent triplane T2-weighted MRI on a 3-T magnet with an endorectal coil while undergoing diagnostic workup for prostate cancer. Prostate volume estimates were determined using the formula for ellipsoid volume based on tridimensional measurements, manual segmentation of triplane MRI, and automated segmentation based on normalized gradient fields cross-correlation and graph-search refinement. Estimates of prostate volume based on ellipsoid volume, manual segmentation, and automated segmentation were compared with prostatectomy specimen volumes. Prostate volume estimates were compared using the Pearson correlation coefficient and linear regression analysis. The Dice similarity coefficient was used to quantify spatial agreement between manual segmentation and automated segmentation. RESULTS: The Pearson correlation coefficient revealed strong positive correlation between prostatectomy specimen volume and prostate volume estimates derived from manual segmentation (R = 0.89-0.91, p < 0.0001) and automated segmentation (R = 0.88-0.91, p < 0.0001). No difference was observed between manual segmentation and automated segmentation. Mean partial and full Dice similarity coefficients of 0.92 and 0.89, respectively, were achieved for axial automated segmentation. CONCLUSION: Prostate volume estimates obtained with a fully automated 3D segmentation tool based on normalized gradient fields cross correlation and graph-search refinement can yield highly accurate prostate volume estimates in a clinically relevant time of 10 seconds. This tool will assist in developing a broad range of applications including routine prostate volume estimations, image registration, biopsy guidance, and decision support systems. PMID- 24147503 TI - A systematic review of semiquantitative and qualitative radiologic criteria for the diagnosis of lumbar spinal stenosis. AB - OBJECTIVE: The objective of our study was to perform a systematic review of the semiquantitative and qualitative radiologic criteria that are used for the diagnosis of lumbar spinal stenosis (LSS). MATERIALS AND METHODS: A four-step systematic literature search including the MEDLINE database was performed by an experienced librarian to reveal all semiquantitative or qualitative radiologic criteria used for the diagnosis of LSS. The precise definitions of all criteria, normal or abnormal values (if applicable), and intra- and interrater reliability were noted by two independent readers. Descriptive statistics were used. RESULTS: A total of 14 semiquantitative or qualitative radiologic parameters were identified and distinguished according to relevant anatomic spaces into criteria for central canal stenosis, lateral (recess) stenosis, and foraminal stenosis. Great variability in terms of the exact definitions of the criteria was found. For 10 of the 14 criteria, the intra- and interrater reliability data were found with kappa values ranging from 0.01 to 1.0. CONCLUSION: Our systematic literature review identified 14 different semiquantitative or qualitative radiologic criteria that are used for the diagnosis of LSS; however, these criteria show remarkable variability in terms of their exact individual definitions and intra- and interrater reliability. PMID- 24147504 TI - Association between the volume of carotid artery plaque and its subcomponents and the volume of white matter lesions in patients selected for endarterectomy. AB - OBJECTIVE: The amount of cerebral white matter lesions (WMLs) and the severity of carotid artery disease are correlated in this study. The association between the severity of WMLs and the volume of the different components of carotid artery plaque is also evaluated. MATERIALS AND METHODS: Fifty consecutive patients (39 men, 11 women; mean [SD] age, 71 +/- 9 years) with carotid artery stenosis who underwent carotid endarterectomy were included in this study. On admission, patients underwent head and neck CT angiography (CTA) and brain MRI. The CTA based plaque volume and the percentages of the three main plaque components (fatty, mixed, and calcified) were calculated according to the attenuation values. Leukoaraiosis lesion volume on FLAIR images was determined using a semiautomated segmentation technique. Pearson correlation was conducted between the leukoaraiosis lesion volume on FLAIR images and the volumes of the different plaque components. RESULTS: Pearson correlation analysis was performed to determine WML volume versus total carotid plaque volume (rho = 0.2531; p = 0.0262), fatty plaque volume (rho = 0.387; p = 0.0005), mixed plaque volume (rho = 0.1709; p = 0.15), and calcified plaque volume (rho = 0.0146; p = 0.899). The WML volume was also compared against fatty plaque percentage (rho = 0.343; p = 0.0018), mixed plaque percentage (rho = 0.181; p = 0.124), and calcified plaque percentage (rho = -0.209; p = 0.068). CONCLUSION: The cerebral WML volume and the total volume of the plaque are correlated. The amount of fat within the plaque is an additional risk factor, whereas the calcified component seems to be protective. PMID- 24147505 TI - CT angiography in potential living kidney donors: 80 kVp versus 120 kVp. AB - OBJECTIVE: The purpose of this article is to retrospectively investigate the diagnostic accuracy, image quality, and radiation dose of renal artery CT angiography (CTA), at 80 kVp compared with 120 kVp, in adult kidney donors. MATERIALS AND METHODS: CTA examinations of 258 consecutive potential kidney donors were retrospectively evaluated; 189 patients were scanned using 64-MDCT scanners (higher maximal tube current), and 69 patients were scanned using 16 MDCT scanners (lower maximal tube current). On the basis of the tube potential and scanners, the study population was divided into four groups. Qualitative and quantitative analysis include vascular attenuation measurements, signal-to-noise ratio (SNR), and contrast-to-noise ratio (CNR). Volume CT dose index (CTDIvol) was recorded, and size-specific dose estimate was also estimated. RESULTS: Using 80 kVp for the 16-MDCT scanner, there was a 64.9% reduction in size-specific dose estimate (66.1% reduction in CTDIvol), increased noise, and tube current saturation in all cases. Axial image quality was significantly lower compared with that obtained at 120 kVp (p = 0.02), but image quality and visibility of renal artery branch order were comparable. Using 80 kVp for the 64-MDCT scanner, there was a 40.5% reduction in size-specific dose estimate (43.6% reduction in CTDIvol) and increased SNR and CNR (p < 0.001). No significant differences in 3D image quality and branch order visibility were observed. Tube current saturation was reached in 31% of cases. One hundred fifty-one patients (86 imaged at 80 kVp and 65 imaged at 120 kVp) underwent donor nephrectomy; CTA diagnostic accuracy was 100%. CONCLUSION: Renal artery CTA using 80 kVp combined with limiting the tube current results in a significant reduction in radiation dose and improved SNR and CNR, without deterioration of image quality. PMID- 24147506 TI - Technique to displace bowel loops in MRI-guided high-intensity focused ultrasound ablation of fibroids in the anteverted or anteflexed uterus. AB - OBJECTIVE: In MRI-guided high-intensity focused ultrasound ablation of uterine fibroids, bowel interposition in the sonication path is often problematic. The purpose of this article is to discuss a bowel-manipulation technique to displace the bowel loop, which consisted of sequential applications of urinary bladder filling, rectal filling, and urinary bladder emptying. CONCLUSION: This technique contributed to a decreased screening failure rate and succeeded in consistently displacing the bowel loop, thus allowing safe treatment of fibroids in the anteverted or anteflexed uterus. PMID- 24147507 TI - Pure lobular carcinoma of the breast presenting as a hyperechoic mass: incidence and imaging characteristics. AB - OBJECTIVE: The purpose of this study was to determine the proportion of invasive lobular carcinomas with increased sonographic echogenicity. MATERIALS AND METHODS: A retrospective review of mammographic and sonographic findings included cases of pure invasive lobular carcinoma with available images from January 1998 to June 2010. We assessed ultrasound images for the presence of a mass, internal echogenicity, margin characteristics, and attenuation effects. In hyperechoic tumors, more than 90% of the mass had increased echogenicity compared with surrounding fat. In heterogeneously echogenic tumors, the echogenic component constituted 20-90% of the tumor. Findings at mammography, MRI, and surgery were correlated with sonographic findings. A breast pathologist reviewed histologic findings and confirmed the diagnosis of pure invasive lobular carcinoma. RESULTS: Of 509 invasive lobular carcinomas, 27 (5%) were hyperechoic, of which 13 (48%) were associated with posterior acoustic shadowing. Heterogeneously echogenic cancer was seen in 57 (11%) cases. The most common sonographic finding was a hypoechoic, irregular mass with or without posterior shadowing (n = 323; 63%). In 66 (13%) lesions, focal shadowing was seen without a discrete mass. Fourteen (3%) lesions were isoechoic with respect to surrounding normal adipose tissue without acoustic shadowing. Twenty-two (4%) of the malignant tumors were not identified sonographically. Of these, 15 (68%) had mammographic abnormalities, one (5%) was seen at MRI, and six (27%) presented as palpable masses that were surgically excised. CONCLUSION: Pure invasive lobular carcinomas can present as a hyperechoic mass or with substantial hyperechoic component. All sonographic lesion characteristics should be evaluated and biopsy recommended when there are suspicious features, even in a lesion that is predominantly hyperechoic. PMID- 24147508 TI - Radiography in the initial diagnosis of biologic activity or growth rate of primary bone tumors. PMID- 24147509 TI - Reply: To PMID 23255735. PMID- 24147510 TI - The ethics of unlimited agency in constrained resources. PMID- 24147511 TI - Reply: To PMID 23436848. PMID- 24147512 TI - Estimation of triquetral bone fragment volume. PMID- 24147513 TI - Reply: To PMID 23436851. PMID- 24147514 TI - How will the growing threat of resistant hypertension impact the future treatment of high blood pressure? AB - Hypertension treatment and control efforts represent a major component of primary care with dedicated clinical guidelines and recommendations. However, high blood pressure (BP) control rates are complicated with the difficult to treat and resistant hypertensive patients. This category of patient, therefore, affects the development and implementation of the clinical guidelines. The recommendations of specific algorithms for resistant hypertension and difficult-to-treat patients with elevated BPs have been developed in consideration of new therapies and combination drug treatment. Hypertension treatment guidelines include and will continue to grade evidence from randomized clinical trials with detailed strategies on the management of these high-risk patients. Although resistant hypertension affects high BP control rates, the inclusion of refined pharmaceutical and device treatment strategies in evidence-based guidelines will be expected to have a significant impact on the clinical management of this high risk patient population. PMID- 24147515 TI - Torsades de pointes following clarithromycin treatment. AB - A 75-year-old woman presenting with pre-syncope, shortness of breath and nausea was admitted to the emergency department following treatment with clarithromycin. Shortly after admission she developed a prolonged QT interval leading to torsades de pointes (TdP) and cardiac arrest. She was successfully cardioverted and clarithromycin was discontinued resulting in restoration of her usual QT interval. This case is an example of acquired long QT syndrome; a disorder that can be precipitated by macrolide antibiotics such as clarithromycin. Additional risk factors present in this case include: female gender, old age, heart disease, hypokalemia and hypomagnesemia. In this manuscript we comprehensively review past cases of clarithromycin-induced long QT syndrome (LQTS) and discuss them within the context of this case. PMID- 24147516 TI - Dabigatran etexilate for thromboembolic prophylaxis in non-valvular atrial fibrillation: the RE-LY study and substudies with commentary. AB - In 2010, dabigatran etexilate, a direct thrombin inhibitor, was the first new oral anticoagulant to be approved for thromboembolic prophylaxis in atrial fibrillation in over 50 years. Dabigatran, unlike warfarin, has a short half-life with a rapid onset of anticoagulant effect, does not require dose adjustment or monitoring, and does not interact with food. The RE-LY trial compared two doses of dabigatran (110 and 150 mg twice daily) with adjusted dose warfarin in patients with non-valvular atrial fibrillation and at least 1 stroke risk factor. Compared with warfarin, dabigatran 150 mg twice daily was superior in reducing the risk of stroke or systemic embolism and was associated with a similar rate of major bleeding, while dabigatran 110 mg twice daily was equally effective in reducing stroke or systemic embolism and was associated with less major bleeding. Despite these favorable results, there remains disagreement regarding the optimal dose and overall safety of dabigatran in certain patient populations including the elderly and those with renal dysfunction. PMID- 24147517 TI - Implementation of cardovascular cell therapy network trials: challenges, innovation and lessons learned from experience in the CCTRN. AB - The cardiovascular cell therapy network was developed by the National Heart, Lung and Blood Institute to design and conduct clinical trials to advance the field of cardiovascular (CV) cell-based therapy. The Cardiovascular Cell Therapy Network successfully completed three clinical trials involving approximately 300 subjects across five centers and six satellites. Although the concept of a network within clinical trials research is not new, the knowledge gained in the implementation of such large-scale trials, particularly in novel therapeutic areas such as cell therapy is not often detailed in the literature. The purpose of this communication is to summarize key factors in achieving network goals and share the knowledge gained to promote success in future cardiovascular disease cell therapy trials and networks. PMID- 24147519 TI - Importance of measurement of platelet reactivity to ADP in patients with coronary artery disease: an historical account. AB - The pivotal roles of platelets in physiological hemostasis and pathological thrombosis at the site of plaque rupture are well established. The latter roles provide the fundamental basis for the most widely implemented pharmacologic management of coronary artery disease--dual antiplatelet therapy with aspirin to inhibit platelet thromboxane A2 generation, and a P2Y12 receptor inhibitor to prevent adenosine diphosphate (ADP)-induced platelet activation. Although suboptimal pharmacodynamic efficacy, also described as high on-treatment platelet reactivity to ADP, has been associated with greater risk for post-stenting ischemic event occurrence, enhanced responsiveness is associated with higher risk for bleeding in selected patients. In this review article, we aim to provide an historical account of the one and a half century long journey starting with the first description of platelets through the first report of ex vivo measurement of ADP-induced platelet aggregation, the first demonstration of an association between ADP-induced platelet aggregation and post-stenting ischemic event occurrence, and finally to the most recent description of a 'therapeutic window' concept for P2Y12 receptor inhibitor therapy. PMID- 24147518 TI - Ticagrelor for acute coronary syndromes. AB - Ticagrelor is a potent P2Y12 adenosine diphosphate receptor antagonist characterized by a rapid onset, consistent and reversible antiplatelet effect, and an acceptable safety profile compared with existing adenosine diphosphate receptor blockers. In the large Phase III trial, PLATO, ticagrelor significantly reduced the composite of cardiovascular death, myocardial infarction, or stroke as well as cardiovascular and all-cause mortality compared with clopidogrel in patients presenting with acute coronary syndromes. With its favorable impact on mortality, ticagrelor changes the landscape of anti-thrombotic therapy for patients with acute coronary syndromes. PMID- 24147520 TI - Dissecting the damaging versus regenerative roles of CNS macrophages: implications for the use of immunomodulatory therapeutics. PMID- 24147521 TI - Respect the anaerobic nature of stem cells to exploit their potential in regenerative medicine. PMID- 24147522 TI - The fountain of youth: role of sirtuins in aging and regenerative medicine. PMID- 24147524 TI - Industry update: Latest developments in stem cell research and regenerative medicine. PMID- 24147525 TI - Ventral root axotomy regeneration after mesenchymal stem cell transplantation. PMID- 24147526 TI - Characterization of the cells in repair tissue following autologous chondrocyte implantation in mankind: a novel report of two cases. AB - AIM: Autologous chondrocyte implantation (ACI) is used worldwide for the treatment of cartilage defects. This study has aimed to assess for the first time the cells that are contained within human ACI repair tissues several years post treatment. We have compared the phenotypic properties of cells from within the ACI repair with adjacent chondrocytes and subchondral bone-derived mesenchymal stromal/stem cells (MSCs). MATERIALS & METHODS: Two patients undergoing arthroplasty of their ACI-treated joint were investigated. Tissue and cells were isolated from the repair site, adjacent macroscopically normal cartilage and MSCs from the subchondral bone were characterized for their growth kinetics, morphology, immunoprofile and differentiation capacity. RESULTS: ACI repair tissue appeared fibrocartilaginous, and ACI repair cells were heterogeneous in morphology and size when freshly isolated, becoming more homogeneous, resembling chondrocytes from adjacent cartilage, after culture expansion. The same weight of ACI repair tissue resulted in less cells than macroscopically normal cartilage. During expansion, ACI repair cells proliferated faster than MSCs but slower than chondrocytes. ACI repair cell immunoprofiles resembled chondrocytes, but their differentiation capacity matched MSCs. CONCLUSION: This novel report demonstrates that human ACI repair cell phenotypes resemble both chondrocytes and MSCs but at different stages of their isolation and expansion in vitro. PMID- 24147527 TI - Regeneration of periodontal tissues using allogeneic periodontal ligament stem cells in an ovine model. AB - AIM: To investigate the capacity of allogeneic periodontal ligament stem cells (PDLSCs) to regenerate periodontal tissues using an ovine periodontal defect model. MATERIALS & METHODS: Surgically created zero-wall dehiscence periodontal defects created in Merino sheep were filled with 1 * 10(7) allogeneic PDLSCs attached to Gelfoam((r)), Gelfoam alone or left untreated. After 4 weeks, histological analysis was performed to assess periodontal regeneration. RESULTS: Allogeneic PDLSCs were well tolerated by recipient animals. The mean area of new alveolar bone was significantly greater in the PDLSC + Gelfoam treatment group compared with the defect-alone group. The PDLSC + Gelfoam and Gelfoam-only treatment groups displayed significantly greater length of new cementum and percentage of cementum regrowth compared with the defect-alone group. New Sharpey's fibers were generally more organized and significantly thicker within the PDLSC + Gelfoam treatment group. The PDLSC + Gelfoam treatment group also showed a trend of increased Sharpey's fiber attachment length compared with the Gelfoam-only and defect-alone groups. CONCLUSION: These studies support the potential use of allogeneic PDLSC preparations as viable therapies for periodontal regeneration in the clinical setting. PMID- 24147528 TI - Two-photon polymerization of polyethylene glycol diacrylate scaffolds with riboflavin and triethanolamine used as a water-soluble photoinitiator. AB - AIM: In this study, the suitability of a mixture containing riboflavin (vitamin B2) and triethanolamine (TEOHA) as a novel biocompatible photoinitiator for two photon polymerization (2PP) processing was investigated. MATERIALS & METHODS: Polyethylene glycol diacrylate was crosslinked using Irgacure((r)) 369, Irgacure 2959 or a riboflavin-TEOHA mixture; biocompatibility of the photopolymer extract solutions was subsequently assessed via endothelial cell proliferation assay, endothelial cell viability assay and single-cell gel electrophoresis (comet) assay. Use of a riboflavin-TEOHA mixture as a photoinitiator for 2PP processing of a tissue engineering scaffold and subsequent seeding of this scaffold with GM 7373 bovine aortic endothelial cells was also demonstrated. RESULTS: The riboflavin-TEOHA mixture was found to produce much more biocompatible scaffolds than those produced with Irgacure 369 or Irgacure 2959. CONCLUSION: The results suggest that riboflavin is a promising component of photoinitiators for 2PP fabrication of tissue engineering scaffolds and other medically relevant structures (e.g., biomicroelectromechanical systems). PMID- 24147530 TI - Early evaluation and value-based pricing of regenerative medicine technologies. AB - Since the first pioneering scientists explored the potential of using human cells for therapeutic purposes the branch of regenerative medicine has evolved to become a mature industry. The focus has switched from 'what can be done' to 'what can be commercialized'. Timely health economic evaluation supports successful marketing by establishing the value of a product from a healthcare system perspective. This article reports results from a research project on early health economic evaluation in collaboration with developers, clinicians and manufacturers. We present an approach to determine an early value-based price for a new treatment of cartilage defects of the knee from the area of regenerative medicine. Examples of using evaluation results for the purpose of business planning, market entry, preparing the coverage decision and managed entry are discussed. PMID- 24147529 TI - A 3D in vitro model reveals differences in the astrocyte response elicited by potential stem cell therapies for CNS injury. AB - AIM: This study aimed to develop a 3D culture model to test the extent to which transplanted stem cells modulate astrocyte reactivity, where exacerbated glial cell activation could be detrimental to CNS repair success. MATERIALS & METHODS: The reactivity of rat astrocytes to bone marrow mesenchymal stem cells, neural crest stem cells (NCSCs) and differentiated adipose-derived stem cells was assessed after 5 days. Schwann cells were used as a positive control. RESULTS: NCSCs and differentiated Schwann cell-like adipose-derived stem cells did not increase astrocyte reactivity. Highly reactive responses to bone marrow mesenchymal stem cells and Schwann cells were equivalent. CONCLUSION: This approach can screen therapeutic cells prior to in vivo testing, allowing cells likely to trigger a substantial astrocyte response to be identified at an early stage. NCSCs and differentiated Schwann cell-like adipose-derived stem cells may be useful in treating CNS damage without increasing astrogliosis. PMID- 24147531 TI - Update on vascularization in tissue engineering. AB - Vascularization of engineered tissues is critical for success. Adequate and physiologically regulated blood supply is important for viability of the implanted tissue but even more important for the proper function of parenchymal cells, which is the desired clinical outcome for most applications in regenerative medicine. Several methods are being developed to stimulate revascularization of engineered tissue. Prevascularized scaffolds with a hierarchical vascular pattern, allowing surgical hook-up of the inflow and outflow tracts, that are already preseeded and cultured with primary vascular cells or precursors will be required for larger tissues or tissues with an immediate high metabolism, such as myocardium. The preimplantation presence of a mature vasculature will improve differentiation and maturation of the parenchyma, thus meeting the functional demands of the host. This may also be true for smaller or metabolically less-active tissues, yet for viability and immediate function they may rely on facilitated postimplantation ingrowth of the host vasculature. PMID- 24147532 TI - The role of hypoxia in stem cell potency and differentiation. AB - Regenerative medicine relies on harnessing the capacity of stem cells to grow, divide and differentiate safely and predictably. This may be in the context of expanding stem cells in vitro or encouraging their expansion, mobilization and capacity to regenerate tissues either locally or remotely in vivo. In either case, understanding the stem cell niche is fundamental to recapitulating or manipulating conditions to enable therapy. It has become obvious that hypoxia plays a fundamental role in the maintenance of the stem cell niche. Low O2 benefits the self-renewal of human embryonic, hematopoietic, mesenchymal and neural stem cells, as well as improving the efficiency of genetic reprogramming to induced pluripotency. There is emerging evidence that harnessing or manipulating the hypoxic response can result in safer, more efficacious methodologies for regenerative medicine. PMID- 24147533 TI - Applications of human hematopoietic stem cells isolated and expanded from different tissues in regenerative medicine. AB - Bone marrow transplantation is a well-established stem cell-based therapy for the management of malignant and nonmalignant hematological disorders. In addition to the bone marrow, therapeutic hematopoietic stem cells (HSCs) can also be obtained from umbilical cord blood and mobilized peripheral blood. Transplantation of HSCs isolated from these tissues can be carried out with or without prior enrichment of specific cell types. New methodologies have been developed for lineage specific HSC expansion and their transplantation as a supplementary treatment to whole bone marrow transplantation. In this review we have described the current methodologies for isolating and processing HSCs from various tissues, and discussed strategies to generate sufficient and functional HSCs for clinical and preclinical applications by expansion ex vivo. The various disease conditions in which these cells could be used, and the methods for delivering the cells into patients, are also discussed. PMID- 24147535 TI - A systematic overview on the use and relevance of capillaroscopy in systemic sclerosis. AB - Capillaroscopy is a non-invasive and safe technique that allows the detection and quantification of the early microvascular abnormalities that characterize secondary Raynaud's phenomenon. The well-established role of capillaroscopy for the early diagnosis of systemic sclerosis, its inclusion in the classification criteria, combined with its predictive value for clinical complications of the disease and its potential for monitoring disease progression and treatment response, makes nailfold capillaroscopy an important assessment in clinical practice and research. Capillaroscopy provides a unique window into the microcirculation and its application in diseases in which a microvascular component is suspected; it also may provide new insights into their pathophysiology and natural history. PMID- 24147536 TI - Braided thin-walled biodegradable ureteral stent: preliminary evaluation in a canine model. AB - OBJECTIVES: To evaluate a novel designed degradable ureteral stent. METHODS: A total of 24 male Beagles, each with bilateral stents implanted (a biodegradable ureteral 4.5-Fr stent and a standard 4-Fr biostable stent) were divided into four groups. Intravenous pyelography, B-mode ultrasonography, and blood and urine tests were carried out before the procedure (0 weeks), and at 1-, 2-, 3- and 4 week intervals. Meanwhile, the mechanical characteristics of stents were tested, and scanning electron microscopy images of the biodegradable braided stents were obtained at different time-points postoperatively. In addition, histopathological changes were compared between the two different stents. RESULTS: All biodegradable braided stents began degrading at 1 week, and had completely degraded by 4 weeks. Hydronephrosis was equivalent during the first 2 weeks, but less with the biodegradable stents than with the control biostable stents at 3 and 4 weeks. Preoperative and postoperative blood and urine results were similar. The mechanical properties of the biodegradable stents were better than conventional biostable stents. Scanning electron microscopy images obtained at different weekly intervals showed that stents degraded in a predictable fashion. Histological testing of the urinary tract showed that the stent-related tissue reactivity of the two different stents were similar. CONCLUSIONS: Our novel braided thin-walled biodegradable stents provide temporary renal drainage as good as commercially available biostable stents. They also have good biocompatibility and physical characteristics. Therefore, they might have clinical application. PMID- 24147537 TI - Discovery of a cyclic phosphodiesterase that catalyzes the sequential hydrolysis of both ester bonds to phosphorus. AB - The bacterial C-P lyase pathway is responsible for the metabolism of unactivated organophosphonates under conditions of phosphate starvation. The cleavage of the C-P bond within ribose-1-methylphosphonate-5-phosphate to form methane and 5 phospho-ribose-1,2-cyclic phosphate (PRcP) is catalyzed by the radical SAM enzyme PhnJ. In Escherichia coli the cyclic phosphate product is hydrolyzed to ribose 1,5-bisphosphate by PhnP. In this study, we describe the discovery and characterization of an enzyme that can hydrolyze a cyclic phosphodiester directly to a vicinal diol and inorganic phosphate. With PRcP, this enzyme hydrolyzes the phosphate ester at carbon-1 of the ribose moiety to form ribose-2,5-bisphosphate, and then this intermediate is hydrolyzed to ribose-5-phosphate and inorganic phosphate. Ribose-1,5-bisphosphate is neither an intermediate nor a substrate for this enzyme. Orthologues of this enzyme are found in the human pathogens Clostridium difficile and Eggerthella lenta. We propose that this enzyme be called cyclic phosphate dihydrolase (cPDH) and be designated as PhnPP. PMID- 24147539 TI - Effect of substrate interferences from high-density polyethylene on association of simulated ignitable liquid residues with the corresponding liquid. AB - The effect of substrate interferences from high-density polyethylene (HDPE) on the ability to associate an ignitable liquid residue with the corresponding liquid standard, using statistical procedures, is demonstrated. Gasoline, kerosene, and lighter fluid, at three different evaporation levels, were spiked onto HDPE and subsequently burned to generate simulated ignitable liquid residues (ILRs). Samples were extracted using a passive headspace procedure and analyzed by gas chromatography-mass spectrometry. The total ion chromatograms were subjected to data pretreatment procedures prior to principal components analysis and Pearson product moment correlation. Using the combination of these statistical procedures, simulated ILRs were successfully associated with the corresponding liquid type, despite the presence of compounds inherent to the HDPE substrate, as well as those resulting from pyrolysis of the substrate. PMID- 24147538 TI - Loss of hepatocyte growth factor activator inhibitor type 1 participates in metastatic spreading of human pancreatic cancer cells in a mouse orthotopic transplantation model. AB - Hepatocyte growth factor activator inhibitor type 1 (HAI-1) is a membrane-bound serine protease inhibitor that is expressed on the surface of epithelial and carcinoma cells. On the cell surface, HAI-1 regulates membrane-anchored serine proteases, with matriptase being the most critical target. Matriptase is involved in pericellular processing of biologically active molecules, including protease activated receptor-2 (PAR-2). Previously we reported that S2-CP8 cells, a metastatic variant of the SUIT-2 human pancreatic adenocarcinoma cell line, showed markedly decreased HAI-1 expression. To assess the significance of HAI-1 loss in invasion and spontaneous metastasis of S2-CP8 cells, we established stable S2-CP8 sublines that expressed HAI-1 under the control of a tetracycline regulated promoter. In vitro migration and invasion assays revealed inhibitory effects of HAI-1 on S2-CP8 cell migration and invasion. Matriptase activity was suppressed by the expression of HAI-1. As the enhanced invasiveness in the absence of HAI-1 was alleviated by knockdown of matriptase by 81% and of PAR-2 completely, and PAR-2 antagonist also suppressed the invasion, matriptase mediated PAR-2 activation is involved in HAI-1 loss-induced invasion of S2-CP8 cells. We then analyzed the effect of HAI-1 expression on metastasis of S2-CP8 cells in vivo using a nude mouse orthotopic xenograft model. Although approximately 50% of the control mice developed distant metastasis, mice treated with doxycycline to induce HAI-1 expression did not develop metastasis. These data indicate that HAI-1 loss contributes to invasion and dissemination of a highly metastatic subline of SUIT-2, suggesting crucial roles for the balance of pericellular serine proteases/inhibitors in pancreatic cancer progression. PMID- 24147541 TI - Primary photodynamics of the green/red-absorbing photoswitching regulator of the chromatic adaptation E domain from Fremyella diplosiphon. AB - Phytochromes are red/far-red photosensory proteins that utilize the photoisomerization of a linear tetrapyrrole (bilin) chromophore to detect the red to far-red light ratio. Cyanobacteriochromes (CBCRs) are distantly related cyanobacterial photosensors with homologous bilin-binding GAF domains, but they exhibit greater spectral diversity. Different CBCR subfamilies have been described, with spectral sensitivity varying across the near-ultraviolet and throughout the visible spectrum, but all known CBCRs utilize photoisomerization of the bilin 15,16-double bond as the primary photochemical event. The first CBCR discovered was RcaE, responsible for tuning light harvesting to the incident color environment (complementary chromatic adaptation) in Fremyella diplosiphon. The green/red RcaE photocycle has recently been described in detail. We now extend this analysis by examining femtosecond photodynamics using ultrafast transient absorption techniques with broadband detection and multicomponent global analysis. Excited-state dynamics in both directions are significantly slower than those recently published for the red/green CBCR NpR6012g4. In the forward reaction, the primary Lumi-G photoproduct arises from the longer-lived excited-state populations, leading to a low photoproduct quantum yield. Using dual-excitation wavelength interleaved pump-probe spectroscopy, we observe multiphasic excited-state dynamics in the forward reaction ((15Z)Pg -> (15E)Pr), which we interpret as arising from ground-state inhomogeneity with different tautomers of the PCB chromophore. The reverse reaction ((15E)Pr -> (15Z)Pg) is characterized via pump-probe spectroscopy and also exhibits slow excited-state decay dynamics and a low photoproduct yield. These results provide the first description of excited-state dynamics for a green/red CBCR. PMID- 24147540 TI - Apathy is more severe in vascular than amnestic mild cognitive impairment in a community: the Kurihara Project. AB - AIM: The aim of this study was to estimate the prevalence of apathy, and to compare vascular mild cognitive impairment (vMCI), amnestic MCI (amMCI), and other type using Clinical Assessment for Spontaneity (CAS). METHODS: Agreement to take part in the study was obtained from 590 community dwellers, aged >=75 years living in Kurihara, Japan. Of the 590 subjects, 221 had a clinical dementia rating (CDR) of 0 (normal); 295 had CDR 0.5 (mild cognitive impairment; MCI); and 74 had CDR 1+ (dementia). The CDR 0.5 subjects were divided into three groups: 55 with vMCI (Erkinjuntti et al. criteria), 91 with amMCI and 149 with other type. To evaluate the various aspects of apathy, we used the three CAS subscales: clinical interview (CAS1), self-evaluation (CAS2), and caregiver assessment (CAS3). Three analyses were then performed to determine: (i) the validity of CAS; (ii) the prevalence rate of apathy in CDR 0 versus CDR 0.5 versus CDR 1+; and (iii) the prevalence rate of apathy in normal versus vMCI versus amMCI versus other type. RESULTS: CAS was validated with the Apathy Evaluation Scale. There were significant differences among the three CDR groups in CAS1, CAS2 and CAS3 (P < 0.001). The prevalence rate of apathy in each CAS in the CDR 1+ group was higher than the CDR 0.5 group, which was higher than the CDR 0 group. There was a significant difference in CAS3 score between the four groups (the normal and the three subgroups; P < 0.001). Apathy in vMCI was more severe than in the other three groups (P < 0.05) on CAS3 score. CONCLUSIONS: vMCI subjects have more severe apathy compared with amMCI subjects on caregiver assessment. PMID- 24147542 TI - The role of alloantibodies against human platelet antigen-15 in multiply platelet transfused patients. AB - BACKGROUND: Several studies have documented the role of antibodies against human platelet (PLT) antigen (HPA)-15 in alloimmune-mediated thrombocytopenia including neonatal alloimmune thrombocytopenia, PLT transfusion refractoriness (PTR), and posttransfusion purpura in Caucasian persons. However, the relevance of anti-HPA 15 in PTR among the Japanese population is still unclear. STUDY DESIGN AND METHODS: The sera of 305 multiply PLT transfused (MPT) patients, previously investigated for the presence of human leukocyte antigen (HLA) and HPA antibodies by mixed passive hemagglutination, were reexamined for the presence of HPA-15 alloantibodies, using the monoclonal antibody-specific immobilization of PLT antigens (MAIPA) technique. RESULTS: Among the 305 MPT samples, antibodies against HPA-15 alloantigen was detected in seven (2.3%), two (0.66%) being anti HPA-15a and five (1.64%) being anti-HPA-15b. Additionally, one case of CD109 panreactive antibody was found (0.33%). Among them, one aplastic anemia patient with blood group O developed multispecific anti-HLA and anti-HPA-15b alloantibody after MPTs. However, transfusion with HLA-matched PLTs of blood group AB did not result in adequate PLT count increment. Analysis of the possible influence of immune anti-A and anti-B by the MAIPA assay resulted negative, indicating that anti-HPA-15b is responsible for the refractory state in this patient. CONCLUSION: In this study, we found alloimmunization against HPA-15a and -15b in Japanese populations and demonstrated the relevance of these antibodies in a patient with PTR. PMID- 24147544 TI - Deficient repair regulatory response to injury in keratoconic stromal cells. AB - BACKGROUND: Keratoconus manifests as a conical protrusion of the cornea and is characterised by stromal thinning. This causes debilitating visual impairment, which may necessitate corneal transplantation. Hypothetically, many of the pathological features in keratoconus may be manifestations of defects in wound healing; however, as the pathobiology remains unclear, therapeutic targets related to disease mechanisms are currently lacking. This study investigated the protein expression of cytokines which may control stromal wound healing and the effect of an induced secondary injury (SI) on stromal cells from ex vivo human keratoconus and control corneas. METHODS: Total protein was extracted from stromal cells from human keratoconic and non-keratoconic central corneas (n = 12) with (+SI) and without (-SI) an ex vivo corneal incision wound. The levels of interleukin 1 alpha (IL-1alpha), fibroblast growth factor 2 (FGF-2), nerve growth factor beta (beta-NGF), insulin-like growth factor 1 (IGF-1), tumour necrosis factor alpha (TNF-alpha), epidermal growth factor (EGF), transforming growth factor beta 1 (TGF-beta1), platelet-derived growth factor (PDGF) and hepatocyte growth factor (HGF) were quantified using chemiluminescence-based immunoarrays. RESULTS: In stromal cells from -SI keratoconic corneas (compared with -SI normal corneas), the levels of IL-1alpha, IGF-1, TNF-alpha and TGF-beta1 were increased and the levels of HGF and beta-NGF were reduced. These alterations were also observed in +SI non-keratoconic corneas (compared with -SI non-keratoconic corneas). In stromal cells from +SI keratoconic corneas (compared with -SI keratoconic corneas), the quantities of IL-1alpha, FGF-2, TNF-a, EGF, TGF-a1 and PDGF were decreased. CONCLUSION: The repair-modulating milieu in keratoconic corneas appears comparable to that in wounded normal corneas. Moreover, wounded keratoconic corneas may be less capable of orchestrating a normal reparative response. These novel findings may improve our understanding of the pathobiology and may facilitate the identification of potential biological targets and therapeutic agents to advance the clinical management of this disorder. PMID- 24147545 TI - Recurrent bone fractures due to tenofovir-induced renal phosphate wasting. AB - A 42-y-old HIV-infected man suffered from several stress fractures due to tenofovir-induced proximal tubular injury. Laboratory examination revealed hypophosphatemia due to renal phosphate wasting. Therefore, more attention has to be paid to the monitoring of serum phosphate and alkaline phosphatase levels, since tenofovir-related nephrotoxicity increases the risk of osteomalacia. PMID- 24147543 TI - Comparative study for the effect of photodynamic therapy, imiquimod immunotherapy and combination of both therapies on 40 lesions of actinic keratosis in Japanese patients. AB - We treated 12, 15 and 13 Japanese actinic keratosis (AK) lesions with 5 aminolevulinic acid photodynamic therapy (PDT), 5% imiquimod cream and combination of both therapies, respectively, and compared the effects. Patients underwent the second course, when AK lesions remained after the first course. Efficacy was evaluated 1 month after each treatment. Combination therapy cleared all AK lesions only after the first course, while PDT and imiquimod therapy cleared 41.7% and 66.7% of AK lesions after the first course, respectively. All residual AK lesions after the first course were cleared by the second courses of PDT or imiquimod therapy. During the course, erosion and crust developed significantly more frequently in combination therapy (P < 0.001). Most Japanese AK lesions can be satisfactorily treated with either PDT or imiquimod monotherapy. However, only severe cases may better be treated with combination therapy, which show higher efficacy even though adverse events occur frequently. PMID- 24147548 TI - With a little support from our friends: children, trials and bioethics. PMID- 24147549 TI - FloTrac/Vigileo system monitoring in acute-care surgery: current and future trends. AB - As acute critical-care surgery evolves, it is imperative to introduce reliable devices that can intraoperatively assess a patient's cardiovascular functions. Owing to the fact that traditional methods are usually invasive, non- or less invasive innovations have attracted the attention of clinicians in recent decades. The FloTrac system monitors cardiovascular performance by analyzing peripheral arterial waveforms and a preset database, and it decreases the invasiveness by using a pulmonary arterial catheter. The reliability of cardiac output measurements was confirmed in many critically ill subjects in cardiac surgeries and intensive care units. Moreover, the FloTrac system is easy to set up, and interpreting the information is simple. The FloTrac system also provides a useful preload predictor, that is, stroke volume variation (SVV), for fluid management, which has been proven to enhance surgical safety in the treatment of critically ill patients. Goal-directed therapy guided by SVV and other hemodynamic variables was advocated for peri-operative fluid optimization. Although the evolution of each updated algorithm of the FloTrac system has demonstrated improved accuracy and limited shortcomings, the latest third generation algorithm is still not equal to the gold standard reference. The accuracy of the latest third-generation algorithm is controversial in septic conditions, and its use is still unacceptable in liver transplantation. Due to vasoactive challenges, especially in the administration of norepinephrine, a conclusion could not be reached. Clinicians should recognize the appropriate uses and limitations when using the algorithm during acute critical surgeries. PMID- 24147550 TI - An investigation into bisphenol-A leaching from orthodontic materials. AB - OBJECTIVE: To quantitatively determine the bisphenol-A (BPA) leached from orthodontic materials during simulated intraoral exposure. MATERIALS AND METHODS: Samples of orthodontic materials were subjected to simulated abrasion, immersion in artificial saliva, thermal shock via temperature cycling, and simulated intraoral exposure. Sample aliquots were collected for up to 2 weeks after artificial saliva immersion, derivatized, then analyzed for BPA by gas chromatography/mass spectroscopy. RESULTS: Quantifiable amounts of leached BPA were observed from a thermoformed orthodontic retainer material (7.63 ug/g of material) and an orthodontic adhesive (2.75 ug/g of material). BPA leaching was only observed within the first 3 days of artificial saliva immersion. CONCLUSIONS: Under the test conditions, BPA was observed to leach from two orthodontic materials. While the quantities of leached BPA were below the reference dose for daily intake, existing data of low-dose effects and medical disorders associated with elevated urinary BPA levels suggest that BPA exposure, and thus the use of the leaching materials identified in this study, should be reduced or eliminated. PMID- 24147551 TI - Simple modification in Hautmann neobladder to carry out left ureteroileal anastmosis without mobilization of the ureter. AB - We describe a simple modification in Hautmann neobladder that involves an elongation of its left chimney to advance it through the pelvic mesocolon in order to reach the left ureter in its original place. This technique was carried out on 27 patients who had Hautmann pouch after radical cystectomy, and we reported the outcome and complications that occurred at the site of urteteroileal anastomosis in the first 3 years after surgery. The modification was applied easily without any perioperative complications that were related to this step in particular. During follow up of these cases, we lost three patients who died before the end of the third postoperative year. At a mean follow up of 41.3 +/- 10.2 months, we have not detected any cases of stricture formation or ureteral recurrence at the sites of the ureteroileal anastmosis. There was only one patient who developed acute pyelonephritis (3.7%) as a result of reflux. PMID- 24147552 TI - Research status of the regulation of miRNA on BACE1. AB - MicroRNAs (miRNAs) are noncoding RNAs that are around 22 nucleotides in length. miRNAs play a key role in neuronal development, differentiation, and synaptic plasticity. An increasing amount of evidence indicates that miRNAs regulate the expression of beta-site APP cleaving enzyme (BACE1), a key enzyme in Alzheimer's disease (AD) pathology. Changes in miRNA expression as a causal factor in AD have not been fully elucidated. We hypothesized that the abnormal expression of miRNAs may contribute to AD pathology, specifically through the regulation of BACE1. PMID- 24147553 TI - Synthesis of 2,8-dioxabicyclo[3.3.1]nonane derivatives via a sequential Knoevenagel condensation and hetero-Diels-Alder reaction in an aqueous medium. AB - Utilizing aldehyde-substituted vinylogous carbonates and 1,3-diketones, a simple protocol is presented for the synthesis of 2,8-dioxabicyclo[3.3.1]nonane derivatives via Knoevenagel condensation followed by a hetero-Diels-Alder reaction under green reaction conditions. The structure of a key product is unequivocally confirmed by X-ray crystallography. PMID- 24147556 TI - Laser ablation sampling of materials directly into the formed liquid microjunction of a continuous flow surface sampling probe/electrospray ionization emitter for mass spectral analysis and imaging. AB - Transmission geometry laser ablation directly into a formed liquid microjunction of a continuous flow liquid microjunction surface sampling probe/electrospray ionization emitter was utilized for molecular and elemental detection and mass spectrometry imaging. The ability to efficiently capture and ionize ablated material was demonstrated by the detection of various small soluble n-mers of polyaniline and silver ion solvent clusters formed from laser ablation of electropolymerized polyaniline and silver thin films, respectively. In addition, analysis of surfaces that contain soluble components was accomplished by coating or laminating the sample with an insoluble film to enable liquid junction formation without directly extracting material from the surface. The ability to perform mass spectrometry imaging at a spatial resolution of about 50 MUm was illustrated by using laminated inked patterns on a microscope slide. In general, these data demonstrate at least an order of magnitude signal enhancement compared to the noncontact, laser ablation droplet capture-based surface sampling/ionization approaches that have been previously presented. PMID- 24147554 TI - Developmental expression pattern of two zebrafish rxfp3 paralogue genes. AB - In mammals, the RXFP3 is the cognate receptor of the relaxin-3 peptide (RLN3). In teleosts, many different orthologue genes for RXFP3 are present. In particular, two paralogue genes, rxfp3-2a and rxfp3-2b, likely encode the receptors for the Rln3a peptide. The transcription of these two rxfp3 genes is differentially regulated early during zebrafish embryogenesis. Indeed, reverse transcription polymerase chain reaction analyses show that the rxfp3-2b transcript is always present during embryo development, while the rxfp3-2a transcript is detectable only at larval stage. By in situ hybridization experiments on embryos and larvae, the rxfp3-2b transcript was revealed in the brain and in the retinal ganglion cell layer and thymus. Particularly in the brain, many territories are involved in the rxfp3-2b expression, among them the optic tectum, thalamus, preoptic area, different nerve nuclei, habenula and pineal gland. The RXFP3 spatiotemporal expression pattern appears to be conserved between Danio rerio and mammals, as also previously showed for the corresponding ligand, the RLN3. Interestingly, the brain areas expressing the rxfp3-2b receptor gene are involved in the visual system, emotional behaviors and circadian rhythm and could be functionally related to the neurotransmitter Rln3a-expressing territories. PMID- 24147557 TI - Assessing the impact of substandard copy medicines in developing countries: the experience with imatinib copies. AB - Access to safe, high-quality medicines is an important international healthcare issue. In developing countries, copy medicines may be attractive due to low acquisition price, but their potential risks due to inadequately demonstrated bioequivalence have garnered only limited attention. As a result, policy-makers, physicians and patients may have incomplete information regarding their real world safety and efficacy. Using chronic myeloid leukemia (CML) treatment as an example, we conducted a literature review of case reports and study publications to assess whether the available literature provides evidence on the real-world safety and efficacy of imatinib copies. While several publications described clinical outcomes with imatinib copy treatment, significant gaps in interpretability and quality exist. We conclude that clear demonstration of bioequivalence is critical for copy drugs, and in the presence of uncertain bioequivalence, greater pharmacovigilance and real-world data benchmarked against originator medications are needed to assess the impact of copy medicines and protect patients in developing countries. PMID- 24147558 TI - Optimizing glycemic control: lixisenatide and basal insulin in combination therapy for the treatment of Type 2 diabetes mellitus. AB - Despite availability of new treatments for patients with Type 2 diabetes mellitus (T2DM), optimal management of glycemic control remains challenging. Treatment with basal insulin can improve HbA1c, but may not be sufficient to control postprandial plasma glucose (PPG) levels. Both fasting plasma glucose (FPG) and PPG levels contribute to overall glycemic control. In patients with moderate hyperglycemia, PPG excursions have a greater contribution to overall hyperglycemia, with this contribution being greatest when HbA1c is approximately 7-8% [1] . Glucagon-like peptide-1 receptor agonists (GLP-1RAs) have been designed to restore and maintain GLP-1 levels and attenuate PPG excursions. GLP 1RAs that predominantly affect PPG may complement the FPG lowering provided by basal insulin, possibly improving overall glycemic control without additional weight gain and with limited incidence of hypoglycemia. Lixisenatide as an add-on to basal insulin lowers PPG levels, improves HbA1c control and has a beneficial effect on weight in T2DM patients. PMID- 24147559 TI - Efficient syntheses of korupensamines A, B and michellamine B by asymmetric Suzuki-Miyaura coupling reactions. AB - Efficient asymmetric Suzuki-Miyaura coupling reactions are employed for the first time in total syntheses of chiral biaryl natural products korupensamine A and B in combination with an effective diastereoselective hydrogenation, allowing ultimately a concise and stereoselective synthesis of michellamine B. Chiral monophosphorus ligands L1-3 are effective for the syntheses of a series of functionalized chiral biaryls by asymmetric Suzuki-Miyaura coupling reactions in excellent yields and enantioselectivities (up to 99% ee). The presence of a polar pi interaction between the highly polarized BOP group and the extended pi system of arylboronic acid coupling partner is believed to be important for the high enantioselectivity. PMID- 24147560 TI - Early impairment in brain metabolism detected by MR spectroscopy antedates structural changes in mouse models of spinocerebellar ataxias. PMID- 24147561 TI - Metalloproteins diversified: the auracyanins are a family of cupredoxins that stretch the spectral and redox limits of blue copper proteins. AB - The metal sites of electron transfer proteins are tuned for function. The type 1 copper site is one of the most utilized metal sites in electron transfer reactions. This site can be tuned by the protein environment from +80 mV to +680 mV in typical type 1 sites. Accompanying this huge variation in midpoint potentials are large changes in electronic structure, resulting in proteins that are blue, green, or even red. Here, we report a family of blue copper proteins, the auracyanins, from the filamentous anoxygenic phototroph Chloroflexus aurantiacus that display the entire known spectral and redox variations known in the type 1 copper site. C. aurantiacus encodes four auracyanins, labeled A-D. The midpoint potentials vary from +83 mV (auracyanin D) to +423 mV (auracyanin C). The electronic structures vary from classical blue copper UV-vis absorption spectra (auracyanin B) to highly perturbed spectra (auracyanins C and D). The spectrum of auracyanin C is temperature-dependent. The expansion and divergent nature of the auracyanins is a previously unseen phenomenon. PMID- 24147562 TI - Emotional processing during speech communication and positive symptoms in schizophrenia. AB - AIMS: The recognition of emotion is often impaired in patients with schizophrenia. The relationship of this deficit with symptoms of psychosis remains unclear. In the current study, we investigated the relationship between emotional processing and positive psychotic symptoms in schizophrenia. METHODS: Twenty-eight patients with schizophrenia and 37 healthy participants were included in the study. They were instructed to listen to a set of sentences and judge whether the emotional valence expressed verbally and that expressed by affective prosody were congruous or incongruous. RESULTS: Overall, the patients with schizophrenia had more inaccurate responses than the healthy participants and the poor performance was prominent when the patients processed affectively negative scenarios. The percentage of accurate responses negatively correlated with the severity of positive symptoms when the scenarios and/or the affective prosody had a negative valence. CONCLUSION: Patients with schizophrenia appear to have impaired function in the processing of negative verbal information. Impaired processing of negative verbal and prosodic information seems to be associated with positive symptoms in schizophrenia. PMID- 24147563 TI - Inhaled corticosteroids for asthma: on-demand or continuous use. AB - Continuous inhaled corticosteroid treatment is highly effective in children and adults with mild persistent asthma, although some therapeutic benefits are not lost if treatment is delayed. Many patients do not adhere to continuous treatment with inhaled corticosteroids, but rather take them intermittently, usually at the time of increased symptoms. Based on these observations it has been proposed that for patients with mild persistent asthma inhaled corticosteroids should be used on-demand when symptoms are troublesome, rather than on a continuous basis. The article reviews the pharmacological properties of inhaled corticosteroids used in clinical trials of on-demand treatment, as well as the evidence for the efficacy and safety of on-demand compared with continuous inhaled corticosteroid treatment of mild persistent asthma in adults and children. The place of on-demand treatment with inhaled corticosteroids in the management of asthma is discussed, as well as future directions for different management strategies for this group. PMID- 24147564 TI - Urinary sepsis associated with Takotsubo cardiomyopathy. PMID- 24147565 TI - Ion permeation in the NanC porin from Escherichia coli: free energy calculations along pathways identified by coarse-grain simulations. AB - Using the X-ray structure of a recently discovered bacterial protein, the N acetylneuraminic acid-inducible channel (NanC), we investigate computationally K(+) and Cl(-) ions' permeation. We identify ion permeation pathways that are likely to be populated using coarse-grain Monte Carlo simulations. Next, we use these pathways as reaction coordinates for umbrella sampling-based free energy simulations. We find distinct tubelike pathways connecting specific binding sites for K(+) and, more pronounced, for Cl(-) ions. Both ions permeate the porin preserving almost all of their first hydration shell. The calculated free energy barriers are G(#) ~ 4 kJ/mol and G(#) ~ 8 kJ/mol for Cl(-) and K(+), respectively. Within the approximations associated with these values, discussed in detail in this work, we suggest that the porin is slightly selective for Cl(-) versus K(+). Our suggestion is consistent with the experimentally observed weak Cl(-) over K(+) selectivity. A rationale for the latter is suggested by a comparison with previous calculations on strongly anion selective porins. PMID- 24147566 TI - Peptide nanofibers with dynamic instability through nonequilibrium biocatalytic assembly. AB - We demonstrate the formation of supramolecular peptide nanofibers that display dynamic instability; i.e., they are formed by competing assembly and disassembly reactions, where assembly is favored away from equilibrium. The systems are based on competitive catalytic transacylation and hydrolysis, producing a self assembling aromatic peptide amphiphile from amino acid precursors that temporarily exceeds the critical gelation concentration, until the competing hydrolytic reaction takes over. Analysis by atomic force microscopy shows consecutive nanofiber formation and shortening. The process results in macroscopically observable temporary hydrogelation, which may be repeated upon refueling the system with further addition of the chemically activated amino acid precursor. Nonequilibrium nanostructures open up opportunities for mimicry of the behavior of dynamic gels found in natural systems and provide components for future adaptive nanotechnologies. PMID- 24147567 TI - Current status and future trends in cervical cancer screening. PMID- 24147568 TI - De novo diffuse large B-cell lymphoma with a CD20 immunohistochemistry-positive and flow cytometry-negative phenotype: molecular mechanisms and correlation with rituximab sensitivity. AB - CD20 is expressed in most B-cell lymphomas and is a critical molecular target of rituximab. Some B-cell lymphomas show aberrant CD20 expression, and rituximab use in these patients is controversial. Here we show both the molecular mechanisms and the clinical significance of de novo diffuse large B-cell lymphomas (DLBCL) that show a CD20 immunohistochemistry (IHC)-positive and flow cytometry (FCM)- negative (IHC[+]/FCM[-]) phenotype. Both IHC and FCM using anti-CD20 antibodies L26 and B1, respectively, were analyzed in 37 of the 106 cases of de novo DLBCL; 8 (22%) of these cases were CD79a(+)/CD20(+) with IHC and CD19(+)/CD20(-) with FCM. CD20 (MS4A1) mRNA expression was significantly lower in IHC(+)/FCM(-) cells than in IHC(+)/FCM(+) cells (P = 0.0005). No genetic mutations were detected in MS4A1 promoter and coding regions. Rituximab-mediated cytotoxicity in the CDC assay using IHC(+)/FCM(-) primary cells was significantly lower than in IHC(+)/FCM(+) cells (P < 0.05); however, partial effectiveness was confirmed. FCM using rituximab detected CD20 more efficiently than B1. No significant difference was observed between IHC(+)/FCM(-) and IHC(+)/FCM(+) patients in overall survival (P = 0.664). Thus, lower expression of CD20 mRNA is critical for the CD20 IHC(+)/FCM(-) phenotype. Lower CD20 expression with FCM does not rule out rituximab use in these patients if expression is confirmed with IHC. FCM using rituximab may be more informative than B1 for predicting rituximab effectiveness in IHC(+)/FCM(-) cases. PMID- 24147569 TI - The association of asthma, nasal allergies, and positive skin prick tests with obesity, leptin, and adiponectin. AB - BACKGROUND: Cross-sectional and longitudinal reports show that obese adults have more asthma than non-obese adults. A proposed mechanism is via effects of adipokines (leptin and adiponectin) on the immune system. OBJECTIVE: We wished to measure the associations of asthma and other atopic diseases with serum adipokine levels and to find whether the associations with asthma were strong enough to rule out the possibility that they are secondary to the association of fatness measures with asthma. METHODS: The Global Asthma and Allergy Network of Excellence (GA(2) LEN) clinical follow-up survey is a clinical survey, embedded in a larger multi-centre cross-sectional postal survey, involving, with a case/control design, enrichment of the sample with subjects with asthma and chronic rhinosinusitis (CRS). We recorded serum leptin or adiponectin in 845 men and 1110 women in 15 centres and also anthropometric measures of fatness including body mass index and waist/hip ratio, current asthma, and specific skin prick and IgE sensitisation. We used inverse sampling-probability-weighted rank and regression statistics to measure population associations of disease outcomes with adipokines in males and females, adjusting for confounders (area, age, smoking history, and number of elder siblings) and also mutually adjusting associations with adipokines and fatness measures. RESULTS: One thousand nine hundred and fifty-five subjects aged 16-77 years had information on leptin or adiponectin levels. Leptin and leptin/adiponectin ratio were positively associated with the level of asthma, especially in females (Somers' D of leptin by asthma score, 0.20; 95% CI, 0.08-0.30; P = 0.00079). These associations were attenuated after adjusting for confounders and became non-significant after additionally adjusting for fatness measures and multiple comparisons. CONCLUSIONS AND CLINICAL RELEVANCE: Asthma levels are positively associated with serum leptin. However, we cannot rule out the possibility that this association is secondary to associations of both with fatness measures. PMID- 24147570 TI - Ulnar neuropathy with prominent proximal Martin-Gruber anastomosis. AB - Martin-Gruber anastomosis (MGA) is the most common nerve anastomosis in the upper extremities and it crosses from the median nerve to the ulnar nerve. Proximal MGA is an under recognized anastomosis between the ulnar and median nerves at or above the elbow and should not be missed during nerve conduction studies. We presented two patients with ulnar neuropathy mimicking findings including numbness and tingling of the 4th and 5th digits and mild weakness of intrinsic hand muscles. However, both cases had an apparently remarkable conduction block between the below- and above-elbow sites that was disproportionate to their clinical findings. To explain this discrepancy, a large MGA was detected with stimulation of the median nerve at the elbow. Thus, proximal MGA should be considered in ulnar neuropathy at the elbow when apparent conduction block or/and discrepancy between clinical and electrodiagnostic findings is found. PMID- 24147571 TI - Key action items for the stem cell field: looking ahead to 2014. AB - The stem cell field is at a critical juncture in late 2013. We find ourselves buoyed by building momentum for both transformative basic science discoveries and clinical translation of stem cells. Cellular reprogramming has given the field exciting new avenues as well. The overall prospect of novel stem cell-based therapies becoming a reality for patients in the coming years has never seemed higher. At the same time, we face serious challenges. Some of these challenges, such as stem cell tourism, are familiar to us, although even those are evolving in ways that require adaptability and action by the stem cell field. Other new challenges are also emerging, including an urgent need for formal physician training in stem cells, regulatory compliance balanced with innovation and U.S. Food and Drug Administration reform, and savvy educational outreach. Looking ahead to 2014, both the challenges and opportunities for the stem cell field require a proactive, thoughtful approach to maximize the potential for a positive impact from stem cell advances. In this study, I discuss the key action items for the field as we look ahead to the coming year and beyond. PMID- 24147572 TI - Birth size and the risk of cerebral palsy in term births. PMID- 24147573 TI - Highly selective Janus kinase 3 inhibitors based on a pyrrolo[2,3-d]pyrimidine scaffold: evaluation of WO2013085802. AB - A series of pyrrolo[2,3-d]pyrimidine derivatives have previously been claimed as Janus kinase (JAK) 1 selective inhibitors. Introduction of a 4-aryl substituent onto this bicyclic scaffold modulates the JAK selectivity profile, thus providing JAK3 selective inhibitors. This patent application claims such compounds as JAK3 inhibitors. Many of the compounds exemplified show > 100,000-fold selectivity for JAK3 over JAK2. The inhibitors are claimed to be useful in the treatment of respiratory diseases, arthritis and cancer. PMID- 24147574 TI - Inherently chiral iminoresorcinarenes through regioselective unidirectional tautomerization. AB - Tetraformylresorcin[4]arene is obtained in 48% yield via a chromatography-free Duff reaction. The formylated resorcinarene reacts easily with primary aliphatic and aromatic amines. The resulting imines exist exclusively in keto-enamine forms. Owing to a system of intramolecular hydrogen bonds, the reaction selectively leads to regioisomers with C4 symmetry. They possess an inherent chirality due to a propeller-like skeleton. For chiral amines, inherently chiral diastereoisomers are observed. PMID- 24147575 TI - Patient satisfaction and oral health-related quality of life after treatment with traditional and simplified protocols for complete denture construction. AB - OBJECTIVES: The objective of this randomised controlled clinical trial study was to compare the effectiveness of a traditional and a simplified protocol for construction of conventional CD. BACKGROUND: The replacement of conventional dentures can result in potential functional and aesthetic benefits to the patient. Previous studies suggest that simplified procedures for complete dentures (CD) construction achieve results similar to the traditional methods. MATERIALS AND METHODS: Fifty patients were randomly divided into two equal groups, traditional protocol (T group) and simplified protocol (S group). Treatment outcomes were assessed before the insertion of the new dentures and 30 days and 6 months after the last adjustment. It included measurements of quality of life related to oral conditions measured by the Brazilian version of OHIP Edentulous scale and patients' satisfaction with the upper and lower dentures using a visual analogue scale (VAS), which combines the patient's perception in relation to overall satisfaction with the comfort, stability, ability to chew, ability to talk and aesthetics. RESULTS: The results showed significant reduction in negative impacts of oral conditions on quality of life and improved satisfaction with the upper and lower dentures (p < 0.001) at the 30-day and 6 month follow-up. Quality of life improvement occurred in all dimensions of the OHIP-Edentulous (p < 0.001). Despite the significant reduction in quality of life impacts and significant increase in patients' satisfaction with the dentures, there were no differences between the traditional and simplified protocols (p > 0.05). CONCLUSIONS: It was concluded that the simplified protocol results in patent's perception of treatment outcomes similar to the traditional protocol. PMID- 24147576 TI - Microfluidic assembly of Janus-like dimer capsules. AB - We describe the microfluidic assembly of soft dimer capsules by the fusion of individual capsules with distinct properties. Microscale aqueous droplets bearing the biopolymer chitosan are generated in situ within a chip and, as they travel downsteam, pairs of droplets are made to undergo controlled cross-linking and coalescence (due to a channel expansion) to form stable dimers. These dimers are very much like Janus particles: the size, shape, and functionality of each individual lobe within the dimer can be precisely controlled. Dimers with one lobe much shorter than the other resemble a bowling pin in their overall morphology, while dimers with nearly equal-sized lobes are akin to a snowman. To illustrate the diverse functionalities possible, we have prepared dimers wherein one lobe encapsulates paramagnetic Fe2O3 nanoparticles. The resulting dimers undergo controlled rotation in an external rotating magnetic field, much like a magnetic stir bar. The overall approach described here is simple and versatile: it can be easily adapted in numerous ways to produce soft structures with designed properties. PMID- 24147578 TI - Glutamate drugs and pharmacogenetics of OCD: a pathway-based exploratory approach. AB - INTRODUCTION: Neuropharmacology research in glutamate-modulating drugs supports their development and use in the management of neuropsychiatric disorders, including major depression, Alzheimer's disorder and schizophrenia. Concomitantly, there is a growing use of these agents used in the treatment of obsessive-compulsive disorder (OCD). AREAS COVERED: This article provides a review of glutamate-modulating drugs used in the treatment of OCD. Specifically, the authors examine riluzole, N-acetylcysteine, d-cycloserine, glycine, ketamine, memantine and acamprosate as treatments. Furthermore, recent genetic epidemiology research findings are presented with a focus on the positional candidate genes SLC1A1 (a glutamate transporter), ADAR3 (an RNA-editing enzyme), RYR3 (a Ca(2+) channel), PBX1 (a homeobox transcription factor) and a GWAS candidate gene, DLGAP1 (a protein interacting with post-synaptic density). These genetic findings are submitted to a curated bioinformatics database to conform a biological network for discerning potential pharmacological targets. EXPERT OPINION: In the genetically informed network, known genes and identified key connecting components, including DLG4 (a developmental gene), PSD-95 (a synaptic scaffolding protein) and PSEN1 (presenilin, a regulator of secretase), conform a group of potential pharmacological targets. These potential targets can be explored, in the future, to deliver new therapeutic approaches to OCD. There is also the need to develop a better understanding of neuroprotective mechanisms as a foundation for future OCD drug discovery. PMID- 24147577 TI - DNA double strand cleavage via interstrand hydrogen atom abstraction. AB - Double strand breaks (DSBs) are the most deleterious form of DNA damage. Natural products that produce them are potent cytotoxic agents. Designing molecules that produce DSBs via a single chemical event is challenging. We determined that formation of a C4'-nucleotide radical in duplex DNA under aerobic conditions gives rise to a DSB. The original radical yields a strand break containing a peroxyl radical, which initiates opposite strand cleavage via C4'-hydrogen atom abstraction. This mechanism provides the impetus to design DNA damaging agents that produce DSBs by abstracting a single hydrogen atom from the biopolymer. PMID- 24147579 TI - Extragonadal omental teratoma: a case report. AB - Mature cystic teratomas or dermoid cysts are among the most common ovarian tumors; however, teratomas of extragonadal origin are extremely rare. The most common extragonadal site of these teratomas is the omentum. It is generally accepted that teratomas arise from germ cells that originate in the mature gonads. Of the three proposed causes of omental teratoma, auto-amputation and subsequent re-implantation of gonadal teratoma is the most likely preceding event. A review of the published reports reveals that only 31 cases of teratoma of the greater omentum have been published to date and three cases reported wherein omental teratoma and dermoid of the ovary were coexisting. We report a rare case of an omental teratoma in a 26-year-old woman who underwent ovarian cystectomy for dermoid cyst. This is the fourth case of an omental mature teratoma with coexisting ovarian dermoid cyst. PMID- 24147580 TI - Chloroacetonitrile and n,2-dichloroacetamide formation from the reaction of chloroacetaldehyde and monochloramine in water. AB - Combined chlorine is increasingly being used as an alternative disinfectant to free chlorine to maintain a residual in drinking water distribution systems mainly because it would reduce the formation of regulated disinfection byproducts (DBPs) trihalomethanes and haloacetic acids. However, the use of combined chlorine could promote the formation of currently unregulated nitrogenous DBPs (N DBPs) such as haloacetonitriles and haloacetamides that are found to be more cyto and genotoxic than regulated DBPs. Monochloramine quickly reacts with chloroacetaldehyde, a DBP formed during primary disinfection with free chlorine, forming and reaching pseudoequilibrium (equilibrium constant K1 = 1.87 * 10(3) M( 1)) with the carbinolamine 2-chloro-1-(chloroamino)ethanol. 2-Chloro-1 (chloroamino)ethanol undergoes slow dehydration to form the imine 1-chloro-2 (chloroimino)ethane that decomposes at a faster rate to chloroacetonitrile. 2 Chloro-1-(chloroamino)ethanol is also oxidized by monochloramine to produce the previously unreported DBP N,2-dichloroacetamide. The carbinolamine dehydration step was found to be acid/base catalyzed (k2(0) = 3.30 * 10(-6) s(-1), k2(H) = 2.43 M(-1) s(-1), k2(OH) = 3.90 M(-1) s(-1)). In contrast, N,2-dichloroacetamide formation was observed to be only base catalyzed (k3(OH) = 3.03 * 10(4) M(-2) s( 1)). N,2-dichloroacetamide cytotoxicity (LC50 = 2.56 * 10(-4) M) was found to be slightly lower compared to that reported for chloroacetamide but higher than those of di- and trichloroacetamide. PMID- 24147581 TI - Committee report: publication guidelines and recommendations for studies using electroencephalography and magnetoencephalography. AB - Electromagnetic data collected using electroencephalography (EEG) and magnetoencephalography (MEG) are of central importance for psychophysiological research. The scope of concepts, methods, and instruments used by EEG/MEG researchers has dramatically increased and is expected to further increase in the future. Building on existing guideline publications, the goal of the present paper is to contribute to the effective documentation and communication of such advances by providing updated guidelines for conducting and reporting EEG/MEG studies. The guidelines also include a checklist of key information recommended for inclusion in research reports on EEG/MEG measures. PMID- 24147583 TI - Asthma, tobacco smoke and the indoor environment: a qualitative study of sheltered homeless families. AB - OBJECTIVE: Asthma is common in homeless children with an incidence of 28-40%. There are few published studies investigating asthma in homeless children. This study examines the perspectives of both caregivers and shelter staff regarding challenges and opportunities of caring for children with asthma. METHODS: A focus group of sheltered parents (n = 10) with children who have asthma was conducted to identify barriers to optimal asthma management. Key informant interviews (n = 6) were conducted with shelter staff to discuss the shelter systems and policies to address childhood asthma. Data were audio-recorded and transcribed. A representative analysis team performed qualitative theme analysis. RESULTS: Key themes across 5 domains were identified: asthma education, access to asthma medication and equipment, asthma action plans, structural barriers to asthma management and environmental triggers. Parents identified multiple asthma triggers present in the shelter environment but cited lack of control as a barrier to remediation. Shelter staff desired elimination of asthma triggers but refer to the lack of resources as the primary barrier. Shelter staff favored a smoking ban on shelter property but named challenges to policy implementation. Both parents and staff identified asthma education and increased access to medications would be helpful. CONCLUSIONS: Policies to reduce environmental exposures, such as a smoking ban, to asthma triggers has the potential to improve the health of sheltered children with asthma. PMID- 24147582 TI - Absence of gargling affects topical adverse symptoms caused by inhaled corticosteroids in females. AB - OBJECTIVE: Topical adverse events caused by inhaled corticosteroids (ICS) are suspected to be more common in females. Although gargling or mouth washing after inhalation is recommended as the gold standard for preventing adverse events due to ICS, the preventive effects of this method have not been confirmed in real world studies. This study aimed to examine the association between gargling or mouth washing and the incidence of topical adverse symptoms in males and females in daily practice. METHODS: We analyzed a subpopulation of participants in the Drug Event Monitoring (DEM) project of the Japan Pharmaceutical Association. An anonymous survey was performed in February 2010, to assess the self-perception of topical adverse symptoms during ICS use by conducting interviews of pharmacists using structured questionnaires. RESULTS: A total of 412 males and 480 females were included. The patients used a dry-powder inhaler (DPI) (71.2%), pressurized meter-dose inhaler (pMDI) with (7.5%) or without (16.6%) a spacer or inhalation solution (4.7%) as the delivery device. Topical adverse symptoms occurring after previous prescriptions were reported by 41 (4.6%) subjects. The common symptoms were hoarseness, stomatitis and dry mouth (1.3%, 1.1% and 1.1%, respectively). In the multiple regression model, the presence of symptoms was found to be significantly associated with the absence of gargling or mouth washing after inhalation [adjusted odds ratio (OR): 3.75, 95% confidence interval (95%CI): 1.33 10.59, p = 0.012]. When stratified by gender, the absence of gargling or mouth washing was identified to be a risk factor in females only (OR: 4.32, 95%CI: 1.11 16.87, p = 0.035) and not in males (OR: 3.26, 95%CI: 0.65-16.33, p = 0.151). Furthermore, the association between the absence of gargling or mouth washing and the incidence of topical adverse symptoms was significant in the patients using DPI (OR: 4.85, 95%CI: 1.66-14.14, p = 0.004), but not in those using the other devices. CONCLUSIONS: In this study, the absence of gargling or mouth washing after ICS use was associated with topical adverse symptoms, especially in females. To achieve good adherence to treatment and improve the quality of life, female patients with asthma should strictly practice the gargling or mouth washing method. PMID- 24147584 TI - Epitaxial graphene growth and shape dynamics on copper: phase-field modeling and experiments. AB - The epitaxial growth of graphene on copper foils is a complex process, influenced by thermodynamic, kinetic, and growth parameters, often leading to diverse island shapes including dendrites, squares, stars, hexagons, butterflies, and lobes. Here, we introduce a phase-field model that provides a unified description of these diverse growth morphologies and compare the model results with new experiments. Our model explicitly accounts for the anisotropies in the energies of growing graphene edges, kinetics of attachment of carbon at the edges, and the crystallinity of the underlying copper substrate (through anisotropy in surface diffusion). We show that anisotropic diffusion has a very important, counterintuitive role in the determination of the shape of islands, and we present a "phase diagram" of growth shapes as a function of growth rate for different copper facets. Our results are shown to be in excellent agreement with growth shapes observed for high symmetry facets such as (111) and (001) as well as for high-index surfaces such as (221) and (310). PMID- 24147586 TI - "Honk against homophobia": rethinking relations between media and sexual minorities. AB - The theory of "symbolic annihilation" or "symbolic violence" has been used in academic literature to describe the way in which sexual minorities have been ignored, trivialized, or condemned by the media. This article aims to de-center research from issues of media representation to consider the capacity for minority groups to proactively use new media and its various avenues for interactivity, social networking, and feedback to fight social exclusion. This work suggests that new media has become a space in which the nominally marginal in society may acquire "social artillery"-a term used to describe how sexual minorities utilize their expanding and more readily accessible social connections in digital space to combat instances of homophobia. The research draws on the results of an inquiry into the relation between media and a regional youth social justice group in Australia tackling homophobia. The research demonstrates that the group is becoming increasingly adept and comfortable with using a cross section of media platforms to fulfill their own objectives, rather than seeing themselves as passive subjects of media representation. This article argues that this sets an example for other socially excluded groups looking to renegotiate their relation with the media in regional areas. PMID- 24147587 TI - A network evaluation of attitudes toward gays and lesbians among U.S. military cadets. AB - The U.S. military's ban on open homosexuality has become an increasingly salient issue since its implementation in 1993 and its repeal in 2011. The military is an organization with a unique professional and social organization. Evaluating military attitudes from a network perspective may offer insight into the role of formal and informal leadership in engendering attitudinal change and cultural tolerance around homosexuality. This study evaluates the role of network centrality and network exposure across formal (command networks) and informal (friendship and perceived leadership networks) structures on attitudes toward homosexuality in the military. This work analyzes survey data from a single cadet company within the U.S. Military Academy (n = 139) prior to the repeal of Don't Ask, Don't Tell. Results indicate that popular students tend to show tolerance toward homosexuality, whereas those who hold command leadership positions are more likely to have personal and professional opposition to homosexuality. In addition, formal superior-subordinate relationships are somewhat more likely to suggest social contagion compared to informal leadership and friendship relationships. Recommendations offer guidance for training strategies particularly with respect to a military leaders and socialization. Future research should monitor these issues relative to the post-DADT environment. PMID- 24147588 TI - Psychological violence experienced by men who have sex with men in Puducherry, India: a qualitative study. AB - Men who have sex with men are a hidden population in India. This study explores the psychological violence such men are exposed to in Puducherry, India. Eleven in-depth interviews probe experiences of blackmail, discrimination, and rejection. Some informants modified their behaviors or appearances to avoid harassment and safeguard their families' reputations. Others told how Indian men accepted their behaviors, but rejected their identities. Social pressure to marry was also a recurring theme. Understanding the factors behind these violent experiences may facilitate their amelioration. PMID- 24147589 TI - "There aren't any gays here": encountering heteroprofessionalism in an international development workplace. AB - Western-oriented workplaces use professionalism as a normative value to sustain and promote a cohesive work environment. Yet, through this qualitative study, the author points out some implications of using professionalism to manage staff relationships and behaviors. Using post-conflict Kosovo as the context, the author examined (a) the work experiences of 8 gay male aid workers and (b) the attitudes toward homosexuality of foreign staff members in 2 international aid agencies. The author introduces and suggests heteroprofessionalism as a root to homophobic and heterosexist behaviors present in the study. Heteroprofessionalism is defined as a professional value that screens out homosexuality. PMID- 24147590 TI - Who takes the lead hand? Correlates of handholding position in lesbian couples. AB - When couples hold hands, one partner must take the lead hand and the other the following hand position. As potential correlates or predictors of handholding positions within lesbian couples, this article explored differences in height, age, income, who initiated the relationship, who usually initiates sexual intimacy, previous history of partnership with a male, and who has the most "say" in decision-making. Data revealed only 2 significant variables: The taller partner was more likely to have the lead hand, and a woman who had previously been partnered with a male was more likely to take the trailing hand position. PMID- 24147585 TI - Stem cell therapies for the treatment of radiation-induced normal tissue side effects. AB - SIGNIFICANCE: Targeted irradiation is an effective cancer therapy but damage inflicted to normal tissues surrounding the tumor may cause severe complications. While certain pharmacologic strategies can temper the adverse effects of irradiation, stem cell therapies provide unique opportunities for restoring functionality to the irradiated tissue bed. RECENT ADVANCES: Preclinical studies presented in this review provide encouraging proof of concept regarding the therapeutic potential of stem cells for treating the adverse side effects associated with radiotherapy in different organs. Early-stage clinical data for radiation-induced lung, bone, and skin complications are promising and highlight the importance of selecting the appropriate stem cell type to stimulate tissue regeneration. CRITICAL ISSUES: While therapeutic efficacy has been demonstrated in a variety of animal models and human trials, a range of additional concerns regarding stem cell transplantation for ameliorating radiation-induced normal tissue sequelae remain. Safety issues regarding teratoma formation, disease progression, and genomic stability along with technical issues impacting disease targeting, immunorejection, and clinical scale-up are factors bearing on the eventual translation of stem cell therapies into routine clinical practice. FUTURE DIRECTIONS: Follow-up studies will need to identify the best possible stem cell types for the treatment of early and late radiation-induced normal tissue injury. Additional work should seek to optimize cellular dosing regimes, identify the best routes of administration, elucidate optimal transplantation windows for introducing cells into more receptive host tissues, and improve immune tolerance for longer-term engrafted cell survival into the irradiated microenvironment. PMID- 24147591 TI - The influence of political jurisdiction, age, and sex on handholding in public by same-sex couples. AB - Three hundred-forty lesbians and 62 gay males, largely from North America and in partnered relationships, completed online surveys that explored what handholding means to same-sex couples. The data suggest that lesbians in the United States are more likely now than 1/4 century ago to hold hands in public spaces. Younger lesbians are more likely to hold hands in public than older lesbians, and Canadian lesbians hold hands more often in public than American lesbians. In response to the question, "What does handholding mean to you?," 26% of the female respondents from North America overtly referred to public handholding as either a political act or a risky behavior. The number of comments of that nature was similar, regardless of whether the lesbians resided in the United States or Canada. Data suggest that full acceptance of same-sex couples in public spaces has not yet occurred, even in jurisdictions where same-sex couples have the same legal rights as heterosexual couples. Although the sample size for males was too small to analyze the influence of age or political jurisdiction on public handholding, males, in general, were significantly less likely than females to view handholding as a means of staying "connected" with their partners. PMID- 24147592 TI - Radiation-induced oral mucositis and periodontitis - proposal for an inter relationship. AB - Virtually all patients who receive head and neck radiotherapy develop some degree of oral mucositis. Severe oral mucositis may necessitate an interruption of the course of radiotherapy and thus can serve as a dose-limiting factor. Periodontitis is a host-driven inflammatory response to a pathogenic bacterial biofilm in the subgingival environment, resulting in the progressive destruction of the tissues that support the teeth, specifically the gingiva, periodontal ligament and alveolar bone. This disease affects more than 50% of the population. Considering that radiation-induced oral mucositis and periodontitis are both linked with continuing presence of systemic inflammation, they may be associated through a primed inflammatory response as proposed by the 'two-hit' model. Alternatively, both conditions may be correlated as they represent a dysregulation of the inflammatory response. To date, no studies have looked into the association between these conditions. This review considers the current evidence that provides a rationale for proposing a link between periodontitis and oral mucositis. PMID- 24147593 TI - From formamide to adenine: a self-catalytic mechanism for an abiotic approach. AB - Mechanisms for abiotic reaction pathways from formamide (H2NCHO) to adenine are presented herein. Formamide is a simple C1 building block hypothesized to be a precursor to many protometabolic compounds. On the basis of a step-by-step mechanism of the reaction pathways, formamide is suggested to be more reactive in addition reactions than HCN. In addition to its simplicity, the formamide self catalyzed mechanism is energetically (kinetically) more viable than either a water-catalyzed mechanism or noncatalyzed processes. Moreover, this self catalyzed mechanism accounts for the yields of purine and adenine previously observed in experiments. This mechanism may elucidate processes that were vital for the emergence of life on the early earth. PMID- 24147594 TI - Calcium channel antibodies in patients with absence epilepsy. AB - Autoimmunity has aroused interest in the last years as a contributory mechanism of epilepsy, especially in epilepsies with unknown cause or therapy resistance. Since the relationship of absence epilepsy (AE) with calcium channels is well established, we aimed to investigate related antibodies in patients diagnosed with AE. Consecutive patients with typical absence seizures having either childhood absence epilepsy (CAE) or juvenile absence epilepsy (JAE) with generalized spike and wave discharges on electroencephalography (EEG) were included after their consent. The patients were diagnosed according to the International League Against Epilepsy (ILAE) 2010 criteria. Antibodies against P Q type voltage gated calcium channels (VGCC) and T-type VGCC subunit Cav3.2 (encoded by the CACNA1H gene) were investigated by RIA and ELISA, respectively. We searched for these antibodies in 32 patients with AE and 53 patients with focal epilepsy of unknown cause (FEOUC) as the disease control group; furthermore, 30 healthy persons served as the healthy controls. Eleven patients (34.3%) with AE had CAE and the remaining patients had JAE. Only a 47-year-old female FEOUC patient, who also had systemic lupus erythematosus with normal MRI scans showed antibodies against P-Q type VGCC, whereas no antibody positivity could be found in other FEOUC and AE patients and healthy controls. Our results might suggest that calcium channel antibodies do not play an important role in the pathophysiology of AE. Further studies with larger groups of other epileptic syndromes are needed to confirm our results. PMID- 24147595 TI - Alginate/PEO-PPO-PEO composite hydrogels with thermally-active plasticity. AB - Stimuli-responsive hydrogels with high strength and toughness have received significant interest in recent years. Here, we report thermally active composite hydrogels comprising alginate and one of two poly(ethylene oxide)-poly(propylene oxide)-poly(ethylene oxide) (PEO-PPO-PEO) triblock copolymers. Temperature sensitive structural and mechanical changes are probed using calorimetry, neutron scattering, shear rheology, unconfined compression, and fracture. Below the lower gelation temperature, LGT, the mechanical properties are dominated by alginate. As the LGT is reached, the contribution of PEO-PPO-PEO to the mechanical properties is activated, resulting in order-of-magnitude increases in elastic modulus. Under compression, we show the evolution of plasticity for the composite hydrogels as the LGT is approached and surpassed, resulting in dramatic increases in fracture stress compared to neat alginate hydrogels. Plasticity was observed above the LGT and may be attributed to restructuring from the sliding of packed micelles and strain-hardening due to stress concentration on alginate cross-links and junction zones, ultimately leading to fracture. PMID- 24147596 TI - beta-Ketoenamine-linked covalent organic frameworks capable of pseudocapacitive energy storage. AB - Two-dimensional covalent organic frameworks (2D COFs) are candidate materials for charge storage devices because of their micro- or mesoporosity, high surface area, and ability to predictably organize redox-active groups. The limited chemical and oxidative stability of established COF linkages, such as boroxines and boronate esters, precludes these applications, and no 2D COF has demonstrated reversible redox behavior. Here we describe a beta-ketoenamine-linked 2D COF that exhibits reversible electrochemical processes of its anthraquinone subunits, excellent chemical stability to a strongly acidic electrolyte, and one of the highest surface areas of the imine- or enamine-linked 2D COFs. Electrodes modified with the redox-active COF show higher capacitance than those modified with a similar non-redox-active COF, even after 5000 charge-discharge cycles. These findings demonstrate the promise of using 2D COFs for capacitive storage. PMID- 24147597 TI - Sputum ADAM8 expression is increased in severe asthma and COPD. AB - BACKGROUND: Severe asthma and chronic obstructive pulmonary disease (COPD) are chronic inflammatory airway diseases in which the mechanisms are not fully understood. A disintegrin and metalloproteinase domain 8 (ADAM8) is an enzyme expressed on most leucocytes and may be important for facilitating leucocyte migration in respiratory disease. OBJECTIVE: To investigate ADAM8 mRNA and protein expression in asthma and COPD and its relationship between asthma severity and inflammatory phenotypes. METHODS: Induced sputum was collected from 113 subjects with asthma (severe n = 31, uncontrolled n = 39 and controlled n = 35), 20 subjects with COPD and 21 healthy controls. Sputum ADAM8 mRNA expression was measured by qPCR, and soluble ADAM8 (sADAM8) protein was measured in the sputum supernatant by validated ELISA. RESULTS: ADAM8 mRNA correlated with ADAM8 protein levels (r = 0.27, P < 0.01). ADAM8 mRNA (P = 0.004) and sADAM8 protein (P = 0.014) levels were significantly higher in both asthma and COPD compared with healthy controls. ADAM8 mRNA (P = 0.035) and sADAM8 protein (P = 0.002) levels were significantly higher in severe asthma compared with controlled asthma. Total inflammatory cell count (P < 0.01) and neutrophils (P < 0.01) were also elevated in severe asthmatic sputum. Although ADAM8 mRNA was significantly higher in eosinophilic and neutrophilic asthma (P < 0.001), sADAM8 did not differ between asthma inflammatory phenotypes. ADAM8 expression positively correlated with sputum total cell count and sputum neutrophils. CONCLUSIONS AND CLINICAL RELEVANCE: ADAM8 expression is increased in both severe asthma and COPD and associated with sputum total cell count and neutrophils. ADAM8 may facilitate neutrophil migration to the airways in severe asthma and COPD. PMID- 24147598 TI - Molecular profiling of EGFR family in chronic obstructive pulmonary disease: correlation with airway obstruction. AB - BACKGROUND: Growth factors mediate various cellular responses to environmental stimuli. Specifically, exposure of lung epithelium to oxidative stress induced by cigarette smoke stimulates aberrant epidermal growth factor receptor (ERBB) family activation. This study's objective was to evaluate the expression of ERBB1 4 receptors in the lung tissue of smokers with or without chronic obstructive pulmonary disease (COPD). MATERIALS AND METHODS: ERBBs expression was measured by microarray analysis in lung tissue samples from five patients with COPD and five non-COPD smokers, and by quantitative real-time PCR in additional 20 patients with COPD (GOLD stage II), 15 non-COPD smokers and 10 nonsmoker controls. RESULTS: Microarray data analysis revealed that ERBB receptors expression was elevated in patients with COPD compared to non-COPD smokers, ranging from 1.62- to 2.45-fold, (P < 0.01). Real-time qPCR verified that patients with COPD had higher ERBB1-3 expression levels compared with non-COPD smokers (PERBB1 < 0.001; PERBB2 = 0.003; PERBB3 = 0.003) and nonsmokers (PERBB1 = 0.019; PERBB2 = 0.005; PERBB3 = 0.011). On the other hand, ERBB4 mRNA levels gradually increased from nonsmokers (0.74 +/- 0.19) to non-COPD smokers (1.11 +/- 0.05) to patients with COPD (1.57 +/- 0.28) and were correlated with the degree of airflow obstruction (PFEV1 < 0.001). DISCUSSION: These data suggest that ERBB1-3 overexpression is not related only to smoking exposure but probably to epithelial remodelling and mucociliary system distortion, characterizing COPD. Additionally, the inverse correlation of ERBB4 with FEV1 exhibits a possible link between ERBB4 and COPD severity. PMID- 24147599 TI - Effects of long-term hypoxia and pro-survival cocktail in bone marrow-derived stromal cell survival. AB - The goal of this study was to determine whether a pro-survival cocktail (PSC, consisting of IGF-1, Bcl-XL, and Caspase-I Inhibitor) and long-term hypoxia (LTH) enhance survival and functional properties of bone marrow-derived stromal stem cells (BMSCs), in response to stress conditions. PSC-treated cells retained BMSC surface markers and protected cells from apoptosis under serum starvation and ischemic (1% O2 and 100 MUM H2O2) conditions. LTH promoted osteogenesis, while suppressing adipogenesis. LTH alone did not result in an improvement in the apoptosis rate; however, PSC conferred significant protection regardless of the oxygenation status. One of the possible mechanisms of PSC protection was due to the elevated phospho-AKT in treated groups. PSC treatment or LTH did not alter migration toward stem cell-derived factor-1 alpha (SDF-1alpha) or fetal bovine serum, nor did they enhance cell motility during wound healing. There was no difference in the secreted cytokine profiles of BMSCs treated with PSC after stress when grown in normoxic or LTH. However, LTH did upregulate the vascular endothelial growth factor, hepatocyte growth factor, and SDF-1alpha, while it downregulated other anti- and proinflammatory cytokines and chemokines. We also observed a high degree of interdonor BMSC variability in response to pretreatment with PSC and LTH, confounding the functional results, underscoring the observation that not all donor-derived BMSCs will respond similarly. PMID- 24147600 TI - Metabolite profiling of a NIST Standard Reference Material for human plasma (SRM 1950): GC-MS, LC-MS, NMR, and clinical laboratory analyses, libraries, and web based resources. AB - Recent progress in metabolomics and the development of increasingly sensitive analytical techniques have renewed interest in global profiling, i.e., semiquantitative monitoring of all chemical constituents of biological fluids. In this work, we have performed global profiling of NIST SRM 1950, "Metabolites in Human Plasma", using GC-MS, LC-MS, and NMR. Metabolome coverage, difficulties, and reproducibility of the experiments on each platform are discussed. A total of 353 metabolites have been identified in this material. GC-MS provides 65 unique identifications, and most of the identifications from NMR overlap with the LC-MS identifications, except for some small sugars that are not directly found by LC MS. Also, repeatability and intermediate precision analyses show that the SRM 1950 profiling is reproducible enough to consider this material as a good choice to distinguish between analytical and biological variability. Clinical laboratory data shows that most results are within the reference ranges for each assay. In house computational tools have been developed or modified for MS data processing and interactive web display. All data and programs are freely available online at http://peptide.nist.gov/ and http://srmd.nist.gov/ . PMID- 24147601 TI - Therapeutic potential of interleukin-17 in inflammation and autoimmune diseases. AB - INTRODUCTION: Interleukin-17 (IL-17) is a proinflammatory cytokine that mainly produced by T helper 17 (Th17) cells. In this article, we discussed the role of IL-17 in inflammation and autoimmune diseases, and the therapeutic strategies targeting IL-17. AREAS COVERED: In this article, we discussed the proinflammatory cytokine IL-17 and IL-17 receptors signals, and their regulation. IL-17 expression was abnormal in the bacterium, virus and fungus infection, and its higher level caused the tissue inflammation. IL-17 was involved in the pathological process of autoimmune diseases, such as systemic sclerosis, rheumatoid arthritis, ankylosing spondylitis and systemic lupus erythematosus, and IL-17 has been put as a therapeutic target in the clinic. EXPERT OPINION: IL 17/IL-17R signals and their application in inflammation process still need to be explored. Therapeutic strategies targeting IL-17 in autoimmune diseases ameliorated the inadequate response to anti-TNF-alpha therapy. PMID- 24147602 TI - Synthesis of QS-21-based immunoadjuvants. AB - Three structurally defined QS-21-based immune adjuvant candidates (2a-2c) have been synthesized. Application of the two-stage activation glycosylation approach utilizing allyl glycoside building blocks improved the synthetic accessibility of the new adjuvants. The efficient synthesis and establishment of the stand-alone adjuvanticity of the examined synthetic adjuvant (2b) open the door to the pursuit of a new series of structurally defined QS-saponin-based synthetic adjuvants. PMID- 24147603 TI - Polymeric colloidal particulate systems: intelligent tools for intracellular targeting of antileishmanial cargos. AB - INTRODUCTION: Targeted cargo delivery systems can overcome drawbacks associated with antileishmanials delivery, by defeating challenges of physiological barriers. Various colloidal particulate systems have been developed in the past; few of them even achieved success in the market, but still are limited in some ways. AREAS COVERED: This review is focused on the pathobiology of leishmaniasis, interactions of particulate systems with biological environment, targeting strategies along with current conventional and vaccine therapies with special emphasis on polymeric nanotechnology for effective antileishmanial cargo delivery. EXPERT OPINION: The problems concerned with limited accessibility of chemotherapeutic cargos in conventional modes to Leishmania-harboring macrophages, their toxicity, and resistant parasitic strain development can be sorted out through target-specific delivery of cargos. Vaccination is another therapeutic approach employing antigen alone or adjuvant combinations delivered by means of a carrier, and can provide preventive measures against human leishmaniasis (HL). Therefore, there is an urgent need of designing site-specific antileishmanial cargo carriers for safe and effective management of HL. Among various colloidal carriers, polymeric particulate systems hold tremendous potential as an effective delivery tool by providing control over spatial and temporal distribution of cargos after systemic or localized administration along with enhancing their stability profile at a comparatively cost-effective price leading to improved chances of commercial applicability. PMID- 24147604 TI - Multiple verruciform xanthomas in the setting of congenital hemidysplasia with ichthyosiform erythroderma and limb defects syndrome. AB - Congenital hemidysplasia with ichthyosiform erythroderma and limb defects (CHILD) syndrome is a rare X-linked dominant disease characterized by peculiar cutaneous presentations and skeletal abnormalities. Verruciform xanthoma (VX)-like histologic changes occasionally occur in CHILD syndrome, but typical VX-like lesions coexisting with CHILD syndrome are rare. In this study we report a rare case of multiple, coexisting VXs on the vulva and left lower limb of an 11-year old Chinese girl who also exhibited the typical clinical presentations and limb defects of CHILD syndrome. Histologic and immunohistochemical analyses showed that the lesions were typical VXs. PMID- 24147605 TI - Surface complexation and oxidation of Sn(II) by nanomagnetite. AB - The long-lived fission product 126Sn is of substantial interest in the context of nuclear waste disposal in deep underground repositories. However, the prevalent redox state, the aqueous speciation as well as the reactions at the mineral-water interface under the expected anoxic and reducing conditions are a matter of debate. We therefore investigated the reaction of Sn(II) with a relevant redox reactive mineral, magnetite (Fe(II)Fe(III)2O4) at <2 ppmv O2, and monitored Sn uptake as a function of pH and time. Tin redox state and local structure were investigated by Sn-K X-ray absorption spectroscopy (XAS). We observed a rapid uptake (<30 min) and oxidation of Sn(II) to Sn(IV) by magnetite. The local structure determined by XAS showed two Sn-Fe distances of about 3.15 and 3.60 A in line with edge and corner sharing arrangements between octahedrally coordinated Sn(IV) and the magnetite surface, indicative of formation of tetradentate inner-sphere complexes between pH 3 and 9. Based on the EXAFS derived surface structure, we could successfully model the sorption data with two different complexes, (Magn_sO)4Sn(IV)(OH)2-2 (logK(2,0)(-2) -14.97 +/- 0.35) prevailing from pH 2 to 9, and (Magn_sO)4Sn(IV)(OH)2Fe (logK(2,1)(0) -17.72 +/- 0.50), which forms at pH > 9 by coadsorption of Fe(II), thereby increasing sorption at this high pH. PMID- 24147606 TI - Triple simultaneous primary invasive gynecological malignancies: a case report. AB - Double gynecologic cancer (primary cancers in two organs) is relatively rare. However, triple gynecologic cancer (primary cancers in three organs) is extremely rare. We experienced a case of triple cancer, with primary cervical, endometrial and ovarian cancers, each showing different histopathological features. A 50-year old woman with a preoperative diagnosis of cervical cancer stage Ib1 with a pathological diagnosis of mucinous adenocarcinoma underwent radical hysterectomy. The pathological diagnoses of the extracted masses were endometrioid adenocarcinoma in the uterine corpus and serous adenocarcinoma in the left ovary. Consequently, triple cancer was diagnosed. After the operation, six cycles of a paclitaxel/carboplatin regimen were administered, and no relapse of the cancers has been observed to date. To our knowledge, this is only the second case report in the international literature of concurrent gynecologic triple cancers of epithelial origin; that is, invasive cervical, endometrial and ovarian cancers, each with different histopathological features. PMID- 24147607 TI - The impact of limited English proficiency on asthma action plan use. AB - OBJECTIVE: The goal of this study was to compare rates of asthma action plan use by limited English proficiency (LEP) caregivers to English proficient (EP) caregivers. METHODS: A cross-sectional bilingual survey was distributed at an urban, academic, pediatric emergency department (PED). Surveys were completed by adult caregivers of children with asthma who sought PED care for asthma related chief complaints. LEP was defined as caregiver ability to speak English less than "very well". Data were analyzed using Fisher's exact test and odds ratios (OR). RESULTS: One hundred seven surveys were completed and analyzed. Fifty-one surveys (48%) were completed by LEP caregivers and 56 (52%) by EP caregivers. A 25% difference (p = .01) in action plan use rates between LEP caregivers (39%) and EP caregivers (64%) was observed. EP alone was associated with action plan use (OR 2.8 [95% CI 1.3-6.1]). Variables not associated with plan use included mother acting as caregiver (OR 2.1 [95% CI 0.7-7.0]), age of child >7 years (OR 1.0 [95% CI 0.5-2.4]), caregiver education >= associate degree (OR 1.4 [95% CI 0.6 3.0]), private insurance (OR 0.7 [95% CI 0.3-1.8]), White race (OR 0.7 [95% CI 0.2-2.2]), Latino ethnicity (OR 0.5 [95% CI 0.2-1.3]) and a federally qualified health center (OR 0.8 [95% CI 0.3-2.0]). The main caregiver reasons for plan use were feeling that a plan works/gets results, helps with symptom management and appreciation towards physician attentiveness when a plan is prescribed. The main caregiver reasons for non plan use were they were not informed/given an action plan or perceived the child's asthma as mild/well controlled. CONCLUSION: Compared with EP caregivers, those with LEP experience disparate rates of asthma action plan use. PMID- 24147609 TI - Unusually high efficiency of beta-cyclodextrin clathrate preparation by water free solid-phase guest exchange. AB - An effective preparation procedure is offered for beta-cyclodextrin (bCD) clathrates with volatile guests of moderate hydrophilicity, which otherwise require a finely tuned optimization of the bCD/water/guest ratio. The proposed procedure includes guest exchange in a water-free bCD matrix. As a result, more stable clathrates with a higher inclusion capacity can be prepared than by direct saturation of dried or hydrated bCD. To find an optimal preparation method, the structure-property relationships were studied for four different ways of bCD clathrate formation with guests of varying molecular structure. The study was much simplified by used procedures excluding direct contact of guest and water liquids with bCD. Besides, in clathrate preparation experiments, the thermodynamic activities of water and guest were varied independently, which makes explicit the role of water in this process. Hydration of bCD reduces its inclusion threshold for hydrophobic guests by their activity (relative vapor pressure), giving favorable hydration effect for their inclusion. Besides, water competes with hydrophilic guests for binding sites in bCD at high water activities. Together with bCD dehydration by excess of hydrophilic guests, these observations give a complete thermodynamic picture, which may be fruitful for elaboration of guest encapsulation techniques by cyclodextrins. PMID- 24147610 TI - [Abstracts of the 58th National Congress of Spanish Society of Hospital Pharmacy. October 22-25, 2013. Malaga, Spain]. PMID- 24147611 TI - Physiological daily inhalation rates for health risk assessment in overweight/obese children, adults, and elderly. AB - Physiological daily inhalation rates reported in our previous study for normal weight subjects 2.6-96 years old were compared to inhalation data determined in free-living overweight/obese individuals (n = 661) aged 5-96 years. Inhalation rates were also calculated in normal-weight (n = 408), overweight (n = 225), and obese classes 1, 2, and 3 adults (n = 134) aged 20-96 years. These inhalation values were based on published indirect calorimetry measurements (n = 1,069) and disappearance rates of oral doses of water isotopes (i.e., (2)H2 O and H2 (18)O) monitored by gas isotope ratio mass spectrometry usually in urine samples for an aggregate period of over 16,000 days. Ventilatory equivalents for overweight/obese subjects at rest and during their aggregate daytime activities (28.99 +/- 6.03 L to 34.82 +/- 8.22 L of air inhaled/L of oxygen consumed; mean +/- SD) were determined and used for calculations of inhalation rates. The interindividual variability factor calculated as the ratio of the highest 99th percentile to the lowest 1st percentile of daily inhalation rates is higher for absolute data expressed in m3 /day (26.7) compared to those of data in m3/kg-day (12.2) and m3/m2-day (5.9). Higher absolute rates generally found in overweight/obese individuals compared to their normal-weight counterparts suggest higher intakes of air pollutants (in MUg/day) for the former compared to the latter during identical exposure concentrations and conditions. Highest absolute mean (24.57 m3/day) and 99th percentile (55.55 m3 /day) values were found in obese class 2 adults. They inhale on average 8.21 m3 more air per day than normal weight adults. PMID- 24147612 TI - Role of plain abdominal radiography in the initial investigation of suspected intussusception. PMID- 24147608 TI - The mononuclear phagocyte system in homeostasis and disease: a role for heme oxygenase-1. AB - SIGNIFICANCE: Heme oxygenase-1 (HO-1) is a potential therapeutic target in many diseases, especially those mediated by oxidative stress and inflammation. HO-1 expression appears to regulate the homeostatic activity and distribution of mononuclear phagocytes (MP) in lymphoid tissue under physiological conditions. It also regulates the ability of MP to modulate the inflammatory response to tissue injury. RECENT ADVANCES: The induction of HO-1 within MP-particularly macrophages and dendritic cells-modulates the effector functions that they acquire after activation. These effector functions include cytokine production, surface receptor expression, maturation state, and polarization toward a pro- or anti inflammatory phenotype. The importance of HO-1 in MP is emphasized by their expression of specific receptors that primarily function to ingest heme containing substrate and deliver it to HO-1. CRITICAL ISSUES: MP are the first immunological responders to tissue damage. They critically affect the outcome of injury to many organ systems, yet few therapies are currently available to specifically target MP during disease pathogenesis. Elucidation of the role of HO 1 expression in MP may help to direct broadly applicable therapies to clinical use that are based on the immunomodulatory capabilities of HO-1. FUTURE DIRECTIONS: Unraveling the complexities of HO-1 expression specifically within MP will more completely define how HO-1 provides cytoprotection in vivo. The use of models in which HO-1 expression is specifically modulated in bone marrow-derived cells will allow for a more complete characterization of its immunoregulatory properties. PMID- 24147613 TI - Distinguishing different fictional worlds during sentence comprehension: ERP evidence. AB - The neural mechanism of distinguishing reality from fiction has been explored recently. While people only represent one real world, they are likely to have representations for multiple fictional worlds. This study used event-related potentials to investigate how different fictional events were distinguished during sentence comprehension. Participants read fictional events involving real people (e.g., President Bush) or unreal characters (e.g., Lord Voldemort). Inconsistency of reality was created by introducing real people into the events involving unreal characters or introducing unreal characters into the events involving real people. The results indicated that inconsistency in reality in both types of fictional events elicited a late positive effect, and an interaction between event type and consistency effect was found in medial sites. These results suggested that reality information is important for the construction and updating of situation models. PMID- 24147614 TI - Non-invasive in vivo dermatopathology: identification of reflectance confocal microscopic correlates to specific histological features seen in melanocytic neoplasms. AB - BACKGROUND: Reflectance confocal microscopy (RCM) allows for non-invasive, in vivo evaluation of skin lesions and it has been extensively applied in skin oncology although systematic studies on nevi characterization are still lacking. OBJECTIVE: The aim of this study was to determine whether reliable RCM correlates to histological features used to diagnose melanocytic neoplasms exist. METHODS: We blindly evaluated the RCM and histological features of 64 melanocytic neoplasms (19 non-dysplastic nevi, 27 dysplastic nevi, 14 melanomas) and analysed the data using Spearman's rho calculation. RESULTS: Many histological features can be identified using RCM. Elongated rete ridges corresponded on RCM to edge papillae, whereas flattened rete ridges to several features which involve dermal epidermal junction disruption. Bridging of junctional nesting (JN) corresponded on RCM to both JN with irregular size/shape and JN with short interconnections. While we could reliably identify dermal melanocytes, the RCM features did not reliably distinguish between benign and concerning dermal melanocytic arrangements, suggesting further refinement of dermal melanocytic RCM features is needed. CONCLUSION: Reliable correlates for epidermal and junctional histological features used to diagnose melanocytic neoplasms are identifiable on RCM, suggesting harnessing histological criteria may be a reasonable method to move beyond the algorithmic approach. PMID- 24147616 TI - Risk factors for non-syndromic oral clefts: a matched case-control study in Hubei Province, China. AB - OBJECTIVE: To explore the risk factors for CL/P in Hubei Province, China. METHODS: A hospital-based, matched case-control study was conducted. One hundred and eight cases with CL/P were matched by age and sex with 108 normal controls. Their parents were retrospectively interviewed using a questionnaire. Univariate and multivariate analyses were used to calculate the relative risk by odds ratio and 95% confidence interval. RESULTS: Univariate analysis identified ten factors as significantly related to CL/P (P < 0.05). Multivariate conditional logistic regression models showed that five of these factors were significantly associated with CL/P. Paternal occupational exposure (OR = 13.08, 95% CI: 2.35-72.86), first trimester maternal illness (OR = 36.67, 95% CI: 5.37-250.36), first-trimester maternal bad mood (OR = 8.69, 95% CI: 1.35-55.84), first-trimester maternal diet of eggs or milk (>=5 meals per week, OR = 6.72, 95% CI: 1.23-36.69), and first trimester maternal sexual activity (OR = 5.98, CI 95%:1.14-31.49) were risk factors for CL/P. CONCLUSIONS: In our study, we identified that paternal occupational exposure, first-trimester maternal illness, first-trimester maternal bad mood, first-trimester maternal diet of eggs or milk (>=5 meals per week), and first-trimester maternal sexual activities were significantly associated with increased CL/P. PMID- 24147617 TI - Highly reversible open framework nanoscale electrodes for divalent ion batteries. AB - The reversible insertion of monovalent ions such as lithium into electrode materials has enabled the development of rechargeable batteries with high energy density. Reversible insertion of divalent ions such as magnesium would allow the creation of new battery chemistries that are potentially safer and cheaper than lithium-based batteries. Here we report that nanomaterials in the Prussian Blue family of open framework materials, such as nickel hexacyanoferrate, allow for the reversible insertion of aqueous alkaline earth divalent ions, including Mg(2+), Ca(2+), Sr(2+), and Ba(2+). We show unprecedented long cycle life and high rate performance for divalent ion insertion. Our results represent a step forward and pave the way for future development in divalent batteries. PMID- 24147615 TI - Predictors of very-long-term sociocognitive function after pediatric traumatic brain injury: evidence for the vulnerability of the immature "social brain". AB - Emotion perception (EP) forms an integral part of social communication and is critical to attain developmentally appropriate goals. This skill, which emerges relatively early in development, is driven by increasing connectivity among regions of a distributed sociocognitive neural network and may be vulnerable to disruption from early-childhood traumatic brain injury (TBI). The present study aimed to evaluate the very-long-term effect of childhood TBI on EP, as well as examine the contribution of injury- and non-injury-related risk and resilience factors to variability in sociocognitive outcomes. Thirty-four young adult survivors of early-childhood TBI (mean [M], 20.62 years; M time since injury, 16.55 years) and 16 typically developing controls matched for age, gender, and socioeconomic status were assessed using tasks that required recognition and interpretation of facial and prosodic emotional cues. Survivors of severe childhood TBI were found to have significantly poorer emotion perception than controls and young adults with mild-to-moderate injuries. Further, poorer emotion perception was associated with reduced volume of the posterior corpus callosum, presence of frontal pathology, lower SES, and a less-intimate family environment. Our findings lend support to the vulnerability of the immature "social brain" network to early disruption and underscore the need for context-sensitive rehabilitation that optimizes early family environments to enhance recovery of EP skills after childhood TBI. PMID- 24147618 TI - Electron transport dynamics in TiO(2) films deposited on ti foils for back illuminated dye-sensitized solar cells. AB - In this study, we examine the electron transport dynamics in TiO2 films of back illuminated dye-sensitized solar cells. The TiO2 films are fabricated using electrophoretic deposition (EPD) and the conventional paste-coating (PC) of TiO2 nanoparticles on Ti-foil substrates. Intensity-modulated photocurrent spectroscopy reveals that red-light irradiation is more efficient than blue-light irradiation for generating photocurrents for back-illuminated cells. A single trapping-detrapping diffusion mode, without trap-free diffusion, reveals the electron transport dynamics involved in the backside illumination. The closely packed EPD films exhibit a shorter electron transit time than does the loosely packed PC films. The porosity dependence of the electron diffusion rate is consistent with the 3D percolation model for metallic solid spheres. The EPD films possess longer electron lifetimes because of their smaller void fraction, which suppresses recombination with electrolytes. The EPD cells, which feature rapid electron transport and suppressed recombination in the TiO2 films, exhibit a maximum power conversion efficiency of 7.1%, which is higher than that of PC cells (6.0%). Because the distance between electron injection and collection is close to the film thickness and the transport lacks trap-free diffusion, the performance of back-illuminated cells is more sensitive to TiO2 film thickness and porosity than the performance of the front-illuminated cells. This study demonstrates the advantages of EPD-film architecture in promoting charge collection for high power conversion. PMID- 24147619 TI - New onset of meconium during labor versus primary meconium-stained amniotic fluid - is there a difference in pregnancy outcome? AB - OBJECTIVE: To compare pregnancy outcome between deliveries complicated by new onset of meconium during labor following prior evidence of clear amniotic fluid and labors in which meconium was present to begin with. METHODS: A retrospective cohort study of all singleton term (>=37 + 0 weeks) deliveries complicated by intrapartum meconium-stained amniotic fluid in a tertiary referral medical center during the year 2012. Outcome was compared between deliveries with new onset of meconium during labor following prior evidence of clear amniotic fluid (secondary meconium group) and those in which meconium was already evident at the time of membranes rupture (primary meconium group). RESULTS: Of the 9167 deliveries during the study period, 694 were eligible for the study group. Of these, 537 were complicated by primary meconium and 157 by secondary meconium. Only secondary meconium, but not primary meconium, was independently associated with an increased risk of operative vaginal delivery (OVD) and adverse neonatal outcome. Pregnancies complicated by secondary meconium were independently associated with a higher rate of OVD (28.0% versus 11.4%, p < 0.001), POP position of the fetal head (6.4% versus 2.6%, p = 0.02), and adverse neonatal outcome (17.2% versus 8.9%, p = 0.003). CONCLUSION: Secondary meconium is associated with a higher rate of adverse obstetrical and neonatal outcome compared with primary meconium. PMID- 24147621 TI - Injectable, high modulus, and fatigue resistant composite scaffold for load bearing soft tissue regeneration. AB - High modulus, two-phase, bicontinuous scaffolds were prepared by photocross linking an aqueous suspension of chondrocytes and N-methacrylate glycol chitosan with a hydrolyzable, hydrophobic, acrylated star-copolymer. Two acrylated star copolymers were examined: poly(epsilon-caprolactone-co-d,l-lactide) (5446DLLACL) and poly(epsilon-caprolactone-co-trimethylene carbonate) (7030TMCCL). The scaffolds were assessed for injectability, two-phase interconnectivity, fatigue resistance, and long-term static culture behavior. The 7030TMCCL scaffolds demonstrated decreased moduli of 17% after 1 * 10(6) cycles at 30% strain and 5% after 56 days in culture, compared to the 5446DLLACL scaffolds, which exhibited decreases of 58 and 68%, respectively. The 7030TMCCL scaffolds accumulated more extracellular matrix after 56 days of culture (GAG: 20.1 +/- 1, collagen: 35.5 +/ 1.8 MUg) compared to 5446DLLACL scaffolds (GAG: 13.2 +/- 0.6, collagen: 6.2 +/- 3.4 MUg). Overall, the 7030TMCCL-based scaffolds were shown to be better suited for use as a load bearing soft tissue scaffold. PMID- 24147620 TI - Raising the pKa limit of "soft" nucleophiles in palladium-catalyzed allylic substitutions: application of diarylmethane pronucleophiles. AB - The Tsuji-Trost allylic substitution reaction provides a useful and efficient approach to construct C-C bonds between sp(3)-hybridized carbons. The widely accepted paradigm for classifying the mode of attack of nucleophiles on palladium pi-allyl intermediates in the Tsuji-Trost reaction is based on the pKa of the pronucleophile: (1) stabilized or "soft" carbon nucleophiles and heteroatom nucleophiles (e.g., pronucleophiles with pKa's < 25), and (2) unstabilized or "hard" nucleophiles (those from pronucleophiles with pKa's > 25). One of the keys to the continuing development of allylic substitution processes remains broadening the scope of "soft" nucleophiles. Herein we report a general method for the room temperature Pd-catalyzed allylic substitution with diarylmethane derivatives (pKa's up to 32). The synthetic significance of the method is that it provides a rapid access to products containing allylated diarylmethyl motifs. The method is general for a wide range of nucleophiles derived from diarylmethanes and heterocyclic derivatives. A procedure for the Pd-catalyzed allylic substitutions to afford diallylation products with quaternary centers is also described. With triarylmethanes and alkylated diarylmethanes the corresponding allylated products are isolated. We anticipate that the described method will be a valuable complement to the existing arsenal of nucleophiles in Pd-catalyzed allylic substitutions. Mechanistic studies show that the nucleophile derived from diphenylmethane undergoes external attack on pi-allyl palladium species under our reaction conditions. This unexpected observation indicates that diarylmethane derivatives behave as "soft" or stabilized nucleophiles. The results of this study indicate that the cutoff between "soft" and "hard" nucleophiles should be raised from a pronucleophile pKa of 25 to at least 32. PMID- 24147622 TI - Efficacy of Deferasirox for the treatment of iron overload in Chinese thalassaemia major patients: results from a prospective, open-label, multicentre clinical trial. AB - OBJECTIVE: To assess the efficacy and safety of deferasirox in Chinese thalassaemia major (TM) patients BACKGROUND: EPIC (Evaluation of Patients' Iron Chelation with Exjade((r))) was a large multi-national study and, notably, the first clinical trial of an iron chelator registered with the Chinese State Food and Drug Administration. METHODS: Efficacy and safety of deferasirox were compared in Chinese (n = 117) and non-Chinese (n = 998) TM patients. Deferasirox was initiated at 20 mg kg(-1) day(-1), with titration increments of 5-10 mg kg( 1) day(-1), based on serum ferritin trends and safety parameters. RESULTS: At baseline, Chinese patients were younger than non-Chinese (mean age 6.8 versus 19.5 years), with higher median serum ferritin (4519 vs 3058 ng mL(-1)). Over 1 year, mean actual deferasirox dose was similar for Chinese and non-Chinese patients (24.6 and 24.0 mg kg(-1) day(-1), respectively); median serum ferritin did not change significantly from baseline in Chinese patients (+340 ng mL(-1), P = 0.102) and significantly decreased in non-Chinese patients (-220 ng mL(-1); P < 0.001). In the 1-year extension in Chinese patients, (mean actual deferasirox dose 33.6 mg kg(-1) day(-1)), median serum ferritin decreased (-756 ng mL(-1); P = 0.0397), with a numerically higher reduction in patients aged >=6 to < 12 than <6 years (-982 vs -457 ng mL(-1), respectively). The safety profile of deferasirox in Chinese patients was similar to the overall population with respect to clinically-relevant findings. CONCLUSION: Age and deferasirox exposure influenced study findings, supporting the need for longer-term treatment and dose escalation to >=30 mg kg(-1) day(-1) to achieve neutral or negative iron balance in heavily iron overloaded and younger Chinese patients. PMID- 24147623 TI - Pneumocephalus: a rare complication of epidural catheter placement during epidural blood patch. PMID- 24147624 TI - Lefty1 and lefty2 control the balance between self-renewal and pluripotent differentiation of mouse embryonic stem cells. AB - Lefty expression has been recognized as a stemness marker because Lefty is enriched both in undifferentiated embryonic stem cells (ESCs) and in blastocysts. Here, we examined the function of Lefty1 and Lefty2 in the maintenance of self renewal and pluripotency of mouse ESCs (mESCs). Suppression of Lefty1 or Lefty2 expression in mESCs did not alter the self-renewal properties of mESCs under nondifferentiating conditions, but suppression of these genes did affect Smad2 phosphorylation and differentiation. Lefty1 knockdown mESCs showed enhanced phosphorylation of Smad2 and increased differentiation potential, whereas Lefty2 knockdown mESCs exhibited reduced phosphorylation of Smad2 and enhanced self renewal in the presence of a differentiation signal. In vivo, teratomas developed from Lefty2 knockdown mESCs contained massive expansions of immature neuroepithelium, a marker of malignant teratomas. Taken together, these results suggest that optimal expression of Lefty1 and Lefty2 is critical for the balanced differentiation of mESCs into three germ layers. PMID- 24147625 TI - Approach for identification and quantification of C-terminal peptides: incorporation of isotopic arginine labeling based on oxazolone chemistry. AB - C-termini of proteins often play an important role in various biological processes. The determination of the protein C-terminus is crucial because it provides not only distinct functional annotation but also a way to monitor the proteolysis-modified proteins. In this study, an isotopic labeling approach based on oxazolone chemistry was developed to achieve the identification and quantification of C-termini. Aminolysis reagents such as arginine selectively react with the alpha-carboxyl group at the peptide C-terminus via an oxazolone like intermediate. Side chain carboxyl groups do not participate in this reaction. When an isotopic mixture consisting of 50% arginine ((0)Arg) and 50% C6 arginine ((6)Arg) was introduced to react with C-terminus of protein and followed by proteolysis, the C-terminal peptide could be directly recognized in the mass spectrum due to its unique isotopic paired peaks, and the sequence could be interpreted in MS2. Besides, the incorporation of an additional basic amino acid in the C-terminal peptide greatly enhanced the signal intensity for C-termini detection. Moreover, the isotopic arginine labeling strategy could be applied for relative C-termini quantitation. Our method showed an excellent correlation of the measured ratios to theoretical ratios and high reproducibility within 2 orders of magnitude of the dynamic range. The correlation coefficients (R(2)) were higher than 0.99, with the coefficients of variation (CVs) ranging from 1.16 to 10.91%. Finally, the approach was used to analyze the C-termini from Thermoanaerobacter tengcongensis , which was cultured under different temperatures. As a result, 68 C-termini have been identified, and 53 of them were quantified in total using our strategy. In addition, 24 neo-C-terminal peptides have also been discovered. PMID- 24147626 TI - Right ventricular outflow tract obstruction after sinus of valsalva aneurysm repair. AB - Sinus of Valsalva aneurysm (SVA) is a rare cardiac lesion especially in the western countries and older population. We report an unusual case of a 60-year old Caucasian male with SVA, acute decompensation, and a pressurized prolapsed aortic leaflet cystic remnant via a small supracristal VSD causing recurrent right ventricular outflow tract obstruction following a Bentall procedure PMID- 24147627 TI - Modeling nanosilver transformations in freshwater sediments. AB - Silver nanoparticles (AgNPs), an effective antibacterial agent, are a significant and fast-growing application of nanotechnology in consumer goods. The toxicity of AgNPs released to surface waters during the use or disposal of AgNP-containing products will depend on the chemical transformations the nanoparticles undergo in the environment. We present a simple one-dimensional diagenetic model for predicting AgNP distribution and silver speciation in freshwater sediments. The model is calibrated to data collected from AgNP-dosed large-scale freshwater wetland mesocosms. The model predicts that AgNP sulfidation will retard nanoparticle oxidation and ion release. The resultant Ag2S-coated AgNPs are expected to persist and accumulate in sediment downstream from sources of AgNPs. Silver speciation and persistence in the sediment depend on the seasonally variable availability of organic carbon and dissolved oxygen. The half-life of typical sulfidized (85% Ag2S) AgNPs may vary from less than 10 years to over a century depending on redox conditions. No significant difference in silver speciation and distribution is observed between >=50% Ag2S and 100% Ag2S AgNPs. Formation and efflux of toxic silver ion is reduced in eutrophic systems and maximized in oligotrophic systems. PMID- 24147628 TI - Protease-activated receptor 2 signalling pathways: a role in pain processing. AB - INTRODUCTION: Pain is a complex biological phenomenon that includes intricate neurophysiological, behavioural, psychosocial and affective components. Despite decades of pain research, many patients continue suffering from chronic pain that may be refractory to current medical regimens. Accumulating evidence has indicated an important role of protease-activated receptor 2 (PAR2) in the pathogenesis of pain, including inflammation, neuropathic and cancer pain. AREAS COVERED: In this review, the role of the PAR2 signalling pathway in pain processes, basic mechanism of PAR2 activation and expression of PAR2 in the nervous system is covered. Furthermore, intracellular signalling pathways that are activated by PAR2 are also described. EXPERT OPINION: The role of PAR2 in pain processing is becoming increasingly clear, and although causal implication remains to be established, PAR2 activation has been observed in several disease model systems. Since PAR2 is activated after nerve injury as well as by trypsin and related serine proteases, and PAR2 plays an important role in pain development and maintenance, exploring PAR2 and its corresponding signalling pathways will provide unfathomable knowledge in understanding the molecular basis of pain. This will also help to identify new targets for pharmacological intervention; however, in the context of potential PAR2-directed therapies, several aspects should be clarified. PMID- 24147629 TI - Cardiac safety concerns for domperidone, an antiemetic and prokinetic, and galactogogue medicine. AB - INTRODUCTION: Domperidone is a dopamine D2-receptor antagonist developed as an antiemetic and prokinetic agent. Oral domperidone is not approved in the United States, but it is used in many countries to treat nausea and vomiting, gastroparesis and as a galactogogue (to promote lactation). The US Food and Drug Administration (FDA) have issued a warning about the cardiac safety of domperidone. AREAS COVERED: The authors undertook a review of the cardiac safety of oral domperidone. EXPERT OPINION: The data from preclinical studies are unambiguous in identifying domperidone as able to produce marked hERG channel inhibition and action potential prolongation at clinically relevant concentrations. The compound's propensity to augment instability of action potential duration and action potential triangulation are also indicative of proarrhythmic potential. Domperidone should not be administered to subjects with pre-existing QT prolongation/LQTS, subjects receiving drugs that inhibit CYP3A4, subjects with electrolyte abnormalities or with other risk factors for QT prolongation. With these provisos, it is possible that domperidone may be used as a galactogogue without direct risk to healthy breast feeding women, but more safety information should be sought in this situation. Also, more safety information is required regarding risk to breast feeding infants before domperidone is routinely used in gastroparesis or gastroesphageal reflux in children. PMID- 24147630 TI - Fabrication of wafer-size monolayer close-packed colloidal crystals via slope self-assembly and thermal treatment. AB - We developed a simple and general approach for constructing a wafer-scale monolayer, close-packed polystyrene (PS), and SiO2 sphere arrays, namely colloidal crystals, which have significant potential in various applications. The method combines slope self-assembly and thermal treatment to achieve large-area and high-quality colloidal crystal with a proper slant angle (theta) and latex concentration (volume fraction, phi). The dependence of the structures of colloidal crystals on a dispersion system was also investigated. Moreover, a theoretical analysis of the slope self-assembly method was proposed. In addition, we applied the method to assemble PS spheres on different kinds of substrates, which indicates that the method is a versatile and reliable way to fabricate monolayer colloidal crystals. PMID- 24147631 TI - Oxidative transformation to naphthodithiophene and thia[7]helicenes by intramolecular Scholl reaction of substituted 1,2-bis(2-thienyl)benzene precursors. AB - We present here a strategy to synthesize a variety of substituted naphthodithiophene building blocks through DDQ/acid-mediated oxidative cyclizations. The versatility of the Scholl reaction using the DDQ/acid system was demonstrated by the preparation of a novel substituted tetrathia[7]helicene where three new C-C bonds were formed in a one-pot procedure. The new DDQ/acid method was compared to the known strategies such as FeCl3 oxidation and oxidative photocyclization. By protecting the 1,2-bis(2-thienyl)benzene precursors, it is possible to direct the intermediates to controlled cyclization and effectively suppressing the polymerization. The highly reactive alpha-position of the terminal thiophenes can allow for further functionalization. The efficient preparation of a variety of naphthodithiophene building blocks, the extension to a nonphotochemical synthesis of [n]helicenes, and the ease of isolation of the products are arguments for the use of DDQ/acid system for this Scholl reaction. PMID- 24147632 TI - Comparison between placental gene expression of 11beta-hydroxysteroid dehydrogenases and infantile growth at 10 months of age. AB - AIM: The local expression of two isoenzymes of 11beta-hydroxysteroid dehydrogenase, type 1 (11betaHSD-1) and type 2 (11betaHSD-2), regulates the access of glucocorticoid hormones to their target cells. Reports on the association between the placental expression of 11betaHSD and infantile growth are limited. The aim of the present study was to investigate if the placental gene expression of 11betaHSD affects infantile growth at 10 months of age. METHODS: Placentas and umbilical venous cord blood were obtained from 42 singleton cases of cesarean deliveries between 31 and 40 weeks of gestation at Hamamatsu University Hospital between March 2009 and June 2010. The gene expression of both 11betaHSD-1 and 11betaHSD-2 was measured by quantitative reverse transcription polymerase chain reaction. Adiponectin and leptin levels in umbilical cord blood were measured using enzyme-linked immunoassay. RESULTS: 11betaHSD-1 and 11betaHSD-2 gene expression in human placentas did not correlate with bodyweight or the ponderal index (PI) at 10 months of age, whereas the gene expression of 11betaHSD-1, but not 11betaHSD-2, correlated with birthweight as well as PI at birth. Adiponectin levels in umbilical cord blood significantly correlated with the placental gene expression of 11betaHSD-1 as well as bodyweight and PI at 10 months of age, although no direct correlation was observed between them. CONCLUSION: No direct correlation was observed between the placental gene expression of 11betaHSD and infantile growth at 10 months of age. However, the placental gene expression of 11betaHSD-1 may be indirectly connected with infantile growth via adiponectin-associated metabolic regulation represented by adiponectin levels in umbilical cord blood. PMID- 24147634 TI - Microvascular dysfunction in systemic diseases: how does it relate to Chagas' disease? PMID- 24147635 TI - Direct observation of periodic swelling and collapse of polymer chain induced by the Belousov-Zhabotinsky reaction. AB - By utilizing a quartz crystal microbalance with dissipation (QCM-D), we directly observed the self-oscillating behavior of a polymer chain induced by the Belousov Zhabotinsky (BZ) reaction. We succeeded in measuring self-oscillations of the resonance frequency (Deltaf) and dissipation (DeltaD), which originate in the self-oscillating behavior of the polymer chain on a gold surface induced by the BZ reaction. We synthesized a self-oscillating polymer chain with Ru as the catalyst of the BZ reaction and a chemical adsorption site, so as to directly observe its periodic swelling and collapse on the gold surface. Distinct self oscillation of DeltaD synchronized with the self-oscillation Deltaf was observed. The period of the Deltaf self-oscillation was about 400 s, and the induction time was about 6.5 h. In QCM-D measurements, we found that the peaks of Deltaf and DeltaD oscillations did not coincide in time because the state of the Gaussian chain did not coincide with the maximum value of Deltaf. Moreover, examination of the relationship between Deltaf and DeltaD revealed that their oscillatory waveforms were identical in frequency but differed in phase and amplitude. PMID- 24147636 TI - Evaluating probabilistic forecasts with Bayesian signal detection models. AB - We propose the use of signal detection theory (SDT) to evaluate the performance of both probabilistic forecasting systems and individual forecasters. The main advantage of SDT is that it provides a principled way to distinguish the response from system diagnosticity, which is defined as the ability to distinguish events that occur from those that do not. There are two challenges in applying SDT to probabilistic forecasts. First, the SDT model must handle judged probabilities rather than the conventional binary decisions. Second, the model must be able to operate in the presence of sparse data generated within the context of human forecasting systems. Our approach is to specify a model of how individual forecasts are generated from underlying representations and use Bayesian inference to estimate the underlying latent parameters. Given our estimate of the underlying representations, features of the classic SDT model, such as the receiver operating characteristic (ROC) curve and the area under the ROC curve (AUC), follow immediately. We show how our approach allows ROC curves and AUCs to be applied to individuals within a group of forecasters, estimated as a function of time, and extended to measure differences in forecastability across different domains. Among the advantages of this method is that it depends only on the ordinal properties of the probabilistic forecasts. We conclude with a brief discussion of how this approach might facilitate decision making. PMID- 24147633 TI - Neural circuit modulation during deep brain stimulation at the subthalamic nucleus for Parkinson's disease: what have we learned from neuroimaging studies? AB - Deep brain stimulation (DBS) targeting the subthalamic nucleus (STN) represents a powerful clinical tool for the alleviation of many motor symptoms that are associated with Parkinson's disease. Despite its extensive use, the underlying therapeutic mechanisms of STN-DBS remain poorly understood. In the present review, we integrate and discuss recent literature examining the network effects of STN-DBS for Parkinson's disease, placing emphasis on neuroimaging findings, including functional magnetic resonance imaging, positron emission tomography, and single-photon emission computed tomography. These techniques enable the noninvasive detection of brain regions that are modulated by DBS on a whole-brain scale, representing a key experimental strength given the diffuse and far reaching effects of electrical field stimulation. By examining these data in the context of multiple hypotheses of DBS action, generally developed through clinical and physiological observations, we define a multitude of consistencies and inconsistencies in the developing literature of this rapidly moving field. PMID- 24147637 TI - The prevalence of vitamin D deficiency in children in the Northern Territory. AB - AIMS: The primary aim of this study was to determine the frequency of vitD deficiency/insufficiency in an opportunistic sample of Northern Territory (NT) children. The secondary aim was to evaluate whether: (i) 25(OH)vitD (25(OH)D) levels differ between Indigenous/non-Indigenous children; and (ii) VitD insufficiency is associated with increased acute/infective hospitalisations. METHODS: Twenty-five (OH)D levels were measured in 98 children <16 years between August 2011 and January 2012 (children hospitalised acutely/non-acutely and well children from other studies based in Darwin). VitD deficiency was defined as 25(OH)D < 50 nmol/L, and insufficiency was postulated to be <75 nmol/L. Demographic data were collected, and computer records were reviewed. RESULTS: Median age was 59 months (range 2-161); 3.1% were vitD deficient, 19.4% insufficient. There was no significant difference in mean 25(OH)D level between Indigenous (93.2, standard deviation (SD) 21.9, n = 42) and non-Indigenous (97.3, SD 27.9, n = 56) children (P = 0.32). Median number of hospitalisations/year were similar (P = 0.319) between vitD sufficient (0.34, range 0-12, n = 76) and insufficient (0.22, 0-6, n = 22) children. There was no significant difference between number of infective admissions per year between vitD sufficient/insufficient groups (P = 0.119). CONCLUSIONS: Compared with US data (19% deficient, 65% insufficient) fewer NT children are vitD deficient/insufficient. In our limited sample, being vitD insufficient was not associated with increased acute/infective hospitalisations, but a larger unbiased sample of NT children is needed. More information is needed about the optimum level of vitD for non-bone-related health in children. PMID- 24147639 TI - Influence of professional drivers' personality traits on road traffic safety: case study. AB - The purpose of this paper is to present basic elements of the research directed at identifying and determining the personality traits of professional drivers that affect safe, secure and enjoyable ride on public roads. A quantitative method has been used here, whereas data were acquired from a questionnaire based on a sample of 59 professional drivers. Determining personality traits of professional drivers that are in correlation with a safe and pleasant ride on the roads has been enabled by applying the five-factor model of personality ('Big Five') and the Personality Inventory NEO-PI. From these results it was concluded that safe operation of the vehicle in traffic involves the successful 'conduct' of oneself, which recognises the importance of certain personality traits of professional drivers for traffic safety and the need for appropriate professional selection in the case of employment of professional drivers. Research results implicate development of educational programmes aimed at achieving harmony of psychological, physical and sensory health, that is, programmes for permanent informing, educating and training professional drivers for defensive driving. The research opens the way for new research tasks that should help in creating a specific structure of curricula that can be used in a variety of transportation companies and enterprises to improve general and public safety. PMID- 24147638 TI - SLC22A13 catalyses unidirectional efflux of aspartate and glutamate at the basolateral membrane of type A intercalated cells in the renal collecting duct. AB - In vertebrates, SLC22A13 is an evolutionarily conserved transport protein of the plasma membrane. In humans and rat, it is principally expressed in the kidney. The precise localization and physiological function are unknown. In the present study, immunohistochemistry revealed that expression of SLC22A13 is confined to the basolateral membrane of type A intercalated cells in rat kidney. Double staining confirmed that SLC22A13 co-localizes with anion exchanger 1. LC-MS difference shading showed that heterologous expression of human and rat SLC22A13 in HEK (human embryonic kidney)-293 cells stimulates efflux of guanidinosuccinate, aspartate, glutamate and taurine. Time courses of uptake of [3H]aspartate and [3H]glutamate revealed that SLC22A13 counteracted endogenous uptake. By contrast, OAT2 (organic anion transporter 2), a bidirectional glutamate transporter, increased accumulation of [3H]glutamate. Thus SLC22A13 catalyses unidirectional efflux. Velocity of efflux of standard amino acids was measured by LC-MS/MS. Expression of SLC22A13 strongly stimulated efflux of aspartate, taurine and glutamate. When the intracellular concentrations of aspartate and taurine were increased by pre-incubation, velocities of efflux increased linearly. We propose that in type A intercalated cells, SLC22A13 compensates luminal exit of protons by mediating the basolateral expulsion of the anions aspartate and glutamate. In this context, unidirectional efflux is essential to avoid anion re-entering. Loss of SLC22A13 function could cause distal tubular acidosis. PMID- 24147640 TI - Event-related potentials reveal the effect of prior knowledge on competition for representation and attentional capture. AB - Objects compete for representation in our limited capacity visual system. We examined how this competition is influenced by top-down knowledge using event related potentials. Competition was manipulated by presenting visual search arrays in which the target or distractor was the only color singleton compared to displays in which both singletons were presented. Experiments 1 and 2 manipulated whether the observer knew the color of the target in advance. Experiment 3 ruled out low-level sensory explanations. Results show that, under conditions of competition, the distractor does not elicit an N2pc when the target color is known. However, the N2pc elicited by the target is reduced in the presence of a distractor. These findings suggest that top-down knowledge can prevent the capture of attention by distracting information, but this prior knowledge does not eliminate the competitive influence of the distractor on the target. PMID- 24147641 TI - Synergistic effect of hierarchical nanostructured MoO2/Co(OH)2 with largely enhanced pseudocapacitor cyclability. AB - Pseudocapacitors have demonstrated an ability to deliver high energy and power densities. The main limitation is their poor cyclability and for this reason the architectural design of electrode materials has attracted considerable attention. Here we report the synthesis of hierarchical nanostructured material by growing Co(OH)2 nanoflakes onto MoO2 thin film. The electrode material exhibits a high capacitance of 800 F g(-1) at 20 A g(-1) with only 3% capacitance loss after 5000 cycles and high rate capability with increasing current density from 2 to 40 A g( 1), which are better than those of individual component. The enhanced pseudocapacitor performances benefit from the synergistic effect of the hierarchical nanostructure: (1) faster ion diffusion and electron transport at electrode/electrolyte interface, and (2) mitigation of the electrode destruction caused by ion insertion/deinsertion during charge-storage process. This facile design and rational synthesis offers an effective strategy to enhance the electrochemical performance of pseudocapacitors and shows promising potential for large-scale application in energy storage. PMID- 24147642 TI - Synthesis of Na(1.25)V(3)O(8) nanobelts with excellent long-term stability for rechargeable lithium-ion batteries. AB - Sodium vanadium oxide (Na1.25V3O8) nanobelts have been successfully prepared by a facile sol-gel route with subsequent calcination. The morphologies and the crystallinity of the as-prepared Na1.25V3O8 nanobelts can be easily controlled by the calcination temperatures. As cathode materials for lithium ion batteries, the Na1.25V3O8 nanobelts synthesized at 400 degrees C exhibit a relatively high specific discharge capacity of 225 mA h g(-1) and excellent stability at 100 mA g(-1). The nanobelt-structured electrode can retain 94% of the initial capacity even after 450 cycles at the current density of 200 mA g(-1). The good electrochemical performance is attributed to their nanosized thickness and good crystallinity. The superior electrochemical performance demonstrates the Na1.25V3O8 nanobelts are promising cathode materials for secondary lithium batteries. PMID- 24147643 TI - Increased neural activity during high working memory load predicts low relapse risk in alcohol dependence. AB - Working memory (WM) impairments are often observed in alcohol-dependent individuals, especially in early abstinence, which may contribute to an increased relapse risk after detoxification. Brain imaging studies on visuospatial WM in alcohol-dependent patients compared to controls indicate that information processing requires compensatory increased neural activation to perform at a normal level. However, to date, no study tested whether such increased neural WM activation patterns or the lack thereof predict relapse behavior in alcohol dependent individuals, and whether such differences persist when adequately correcting for individual grey matter differences. We combined analyses of neural activation during an n-back task and local grey matter volumes using Biological Parametric Mapping in 40 detoxified alcohol-dependent patients and 40 matched healthy controls (HC), and assessed prospective relapse risk during a 7-month follow-up period. Despite equal task performance, we found increased functional activation during high versus low cognitive WM load (2-back-0-back) in bilateral rostral prefrontal cortex (BA10) and bilateral ventrolateral prefrontal cortex (BA45,47) in prospective abstainers versus relapsers, and further in left/right lateral/medial premotor cortex (BA6,8) in abstainers versus HC. In prospective abstainers, but not relapsers, subtle cognitive impairment was associated with increased neural task activity in the premotor cortex. These findings suggest that in prospective abstainers, higher functional engagement of presumably less impaired neural resources in executive behavioral control brain areas (BA10, 45, 47, 6, 8) may constitute a resilience factor associated with good treatment outcome. PMID- 24147644 TI - Signaling roadmap modulating naive and primed pluripotency. AB - Human and mouse embryonic stem cells (ESCs) exhibit fundamental differences depicting two distinct states of pluripotency: naive and primed. Mouse ESCs (mESCs) are dependent on leukemia inhibitory factor for growth in culture and possess two active X chromosomes in their female cell lines and correspond to the naive state of pluripotency. Human ESCs (hESCs), however, closely resemble mouse epiblast stem cells and correspond to the primed state. Primed stem cells are dependent on basic FGF for growth and show differentiation bias into different cell lineages. Recent studies have revealed that these two pluripotent states can be interconverted by modifying the culture conditions, although unequivocal evidence for obtaining truly naive hESCs has not been found. Accurate identification of the functions of major pluripotency-related signaling pathways and their cross-talk networks should aid in the successful induction of stable naive pluripotency in human cells. PMID- 24147645 TI - Antibody-free detection of human chorionic gonadotropin by use of liquid crystals. AB - Human chorionic gonadotropin (hCG) is an important biomarker for the diagnosis of pregnancy and cancers. In this study, we report an antibody-free and label-free mechanism for detecting hCG. To replace enzyme-labeled antibodies, we use a short oligopeptide as an hCG receptor to bind hCG. The short oligopeptide sequence, (N )PPLRINRHILTR(-C), is identified after 5 rounds of screening by use of a phage library. After binding, liquid crystal (LC) is used to transduce the binding event into optical signals. The captured hCG can disrupt a thin layer (~6 MUm) of LC covered on the surface. Depending on the initial concentration of hCG, LC gives distinct optical signals visible to the naked eye. The limit of detection (LOD) for this method is approximately 1 IU/mL (2 nM) in both phosphate-buffered saline and urine samples, and only 0.6 MUL of hCG solution is required. This means that as little as 45.5 pg of hCG can be detected by this method. Compared to other detection methods for hCG, this detection method does not require the use of antibody and is label-free. It has the potential to become a portable diagnostic kit for hCG. PMID- 24147646 TI - Synthesis and characterization of recombinant abductin-based proteins. AB - Recombinant proteins are promising tools for tissue engineering and drug delivery applications. Protein-based biomaterials have several advantages over natural and synthetic polymers, including precise control over amino acid composition and molecular weight, modular swapping of functional domains, and tunable mechanical and physical properties. In this work, we describe recombinant proteins based on abductin, an elastomeric protein that is found in the inner hinge of bivalves and functions as a coil spring to keep shells open. We illustrate, for the first time, the design, cloning, expression, and purification of a recombinant protein based on consensus abductin sequences derived from Argopecten irradians . The molecular weight of the protein was confirmed by mass spectrometry, and the protein was 94% pure. Circular dichroism studies showed that the dominant structures of abductin-based proteins were polyproline II helix structures in aqueous solution and type II beta-turns in trifluoroethanol. Dynamic light scattering studies illustrated that the abductin-based proteins exhibit reversible upper critical solution temperature behavior and irreversible aggregation behavior at high temperatures. A LIVE/DEAD assay revealed that human umbilical vein endothelial cells had a viability of 98 +/- 4% after being cultured for two days on the abductin-based protein. Initial cell spreading on the abductin-based protein was similar to that on bovine serum albumin. These studies thus demonstrate the potential of abductin-based proteins in tissue engineering and drug delivery applications due to the cytocompatibility and its response to temperature. PMID- 24147647 TI - An exploratory study of salivary calcitonin gene-related peptide levels relative to acute interventions and preventative treatment with onabotulinumtoxinA in chronic migraine. AB - OBJECTIVE: To determine if baseline/interictal saliva calcitonin gene-related peptide (CGRP) levels would be lower in subjects with chronic migraine receiving onabotulinumtoxinA compared with those receiving saline. BACKGROUND: CGRP is considered central to the pathogenesis of episodic migraine, but its relationship to chronic migraine is less understood. OnabotulinumtoxinA is an effective treatment for chronic migraine and has been demonstrated to inhibit the vesicular release of CGRP. METHODS: This was an exploratory, randomized, placebo controlled, crossover pilot study of 20 subjects that received onabotulinumtoxinA and saline injection (placebo). The amount of CGRP in saliva samples collected on a nonheadache or low headache day, and prior to and after treatment of a headache exacerbation was measured. Daily headache records, medications, and response to treatment were recorded in a diary. RESULTS: A decrease in baseline/interictal saliva CGRP levels for subjects receiving onabotulinumtoxinA from 39.4 +/- 7.5 pg CGRP/mg total protein after the first month to 25.5 +/- 4.1 pg after the third month was observed. However, this difference did not reach significance nor was it significant when compared to the saline treatment. There was a reduction in the number of headache days for both onabotulinumtoxinA and saline over baseline throughout the active phases of the study. However, there was no statistical difference in headache days between groups. Subjects with a greater than 50% response to onabotulinumtoxinA had better 2-hour pain relief with acute treatment than non-responders to onabotulinumtoxinA or saline. CONCLUSION: While CGRP levels were not elevated during a migraine attack in chronic migraine subjects as has been reported in episodic migraine, there was an overall decrease in the baseline/interictal levels in response to onabotulinumtoxinA. PMID- 24147648 TI - Leptin and paraoxonase activity in cord blood from obese mothers. AB - OBJECTIVE: Obesity and/or psychopathological disorders of parents represent risk factors for childhood obesity. The aim of the study was to investigate the link between obesity in pregnancy and oxidative stress. METHODS: Venous blood was collected from 37 women at the eighth month of gestation (19 obese and 28 normal weight). Cord blood was obtained at birth from newborns of obese mothers and controls. Cord blood and maternal blood was used to separate plasma to be used for the evaluation of leptin, oxidized LDL and paraoxonase (PON1) activity. RESULTS: Higher levels of leptin were observed both in maternal blood and cord blood of children of obese women compared to normal-weight women. The data also showed lower levels of PON1 activity in plasma of obese women and in the cord blood of their children. Furthermore, a positive correlation was established between levels of PON1 activity in maternal blood and cord blood, suggesting a relationship between PON1 in maternal plasma and fetal cord blood. CONCLUSIONS: Essential obesity in pregnancy is associated with hyperleptinemia. PON1 exerts an antioxidant role; therefore, our results demonstrated that obesity exposes to an increased susceptibility to oxidative damage in both mothers and newborns. PMID- 24147649 TI - BGG492 (selurampanel), an AMPA/kainate receptor antagonist drug for epilepsy. AB - INTRODUCTION: AMPA-type glutamate receptor (AMPAR) antagonism is under development as a novel mechanism of action for antiepileptic drugs. Selurampanel (BGG492) is an experimental competitive AMPA antagonist currently in clinical trials. AREAS COVERED: This article provides a review of the roles of glutamate receptors, especially of the AMPA type, in normal and epileptic synaptic transmission. It also provides a discussion of the mechanisms of action of AMPAR antagonist compounds. The article includes a summary of the preclinical and clinical data on the efficacy and safety of BGG492 and provides a discussion of the future role of these compounds in clinical therapy. EXPERT OPINION: Since many persons with epilepsy remain inadequately treated, compounds exploiting new mechanisms for seizure control are welcome. Based on available clinical trial data as adjunctive therapy, the AMPAR antagonists will likely be highly useful in a small subset of persons and moderately helpful in a larger subset, similar to other new drugs for epilepsy developed since 1993. It remains impossible to predict which patients will respond to which class of drugs. PMID- 24147650 TI - Real-time gamma imaging of technetium transport through natural and engineered porous materials for radioactive waste disposal. AB - We present a novel methodology for determining the transport of technetium-99m, a gamma-emitting metastable isomer of (99)Tc, through quartz sand and porous media relevant to the disposal of nuclear waste in a geological disposal facility (GDF). Quartz sand is utilized as a model medium, and the applicability of the methodology to determine radionuclide transport in engineered backfill cement is explored using the UK GDF candidate backfill cement, Nirex Reference Vault Backfill (NRVB), in a model system. Two-dimensional distributions in (99m)Tc activity were collected at millimeter-resolution using decay-corrected gamma camera images. Pulse-inputs of ~20 MBq (99m)Tc were introduced into short (<10 cm) water-saturated columns at a constant flow of 0.33 mL min(-1). Changes in calibrated mass distribution of (99m)Tc at 30 s intervals, over a period of several hours, were quantified by spatial moments analysis. Transport parameters were fitted to the experimental data using a one-dimensional convection dispersion equation, yielding transport properties for this radionuclide in a model GDF environment. These data demonstrate that (99)Tc in the pertechnetate form (Tc(VII)O4(-)) does not sorb to cement backfill during transport under model conditions, resulting in closely conservative transport behavior. This methodology represents a quantitative development of radiotracer imaging and offers the opportunity to conveniently and rapidly characterize transport of gamma-emitting isotopes in opaque media, relevant to the geological disposal of nuclear waste and potentially to a wide variety of other subsurface environments. PMID- 24147651 TI - Outcomes of patients undergoing third-time aortic or mitral valve replacement. AB - BACKGROUND AND AIM: Third-time valve surgery is rare and to date little is known about the surgical outcome. We reviewed our experience with third-time aortic valve replacement (AVR) and third-time mitral valve replacement (MVR) during an eight-year period. METHODS: From 2001 to 2013, 32 patients were referred for third-time AVR or third-time MVR to our institution. In this retrospective analysis, patients were evaluated for postoperative morbidity including: hemodialysis, cerebrovascular event, pacemaker implantation, and 30-day and mid term mortality. RESULTS: Third-time replacement was for failed aortic valves in 20 (62.5%) patients and for failed mitral valves in 12 (37.5%) patients. Patients' mean age at the time of surgery was 56.3 +/- 19 years. The mean interval between the first and the second procedure was 10 +/- 7.8 years and between second and third replacement 7.3 +/- 5.6 years. The failed prostheses included nine (28%) bioprostheses and 23 (72%) mechanical prostheses. The reasons for replacement were: infective valve endocarditis (31.3%), prosthesis dysfunction (37.3%), and paravalvular leakage (26%). The 30-day mortality was 18.8% and during follow-up was 31.3%. Hemodialysis was needed for eight patients (25.8%), pacemaker implantation for eight patients (25.8%), and cerebrovascular event occurred in four patients (13.3%). In patients with prosthetic valve endocarditis (n = 10), 30-day and overall mortality were 11.1% and 30%, respectively. CONCLUSION: Third-time aortic or mitral valve replacement is a rare procedure but accompanied with high morbidity and mortality, especially in patients with prosthetic valve endocarditis. PMID- 24147652 TI - Cucurbit[8]uril supramolecular assembly for positively charged ultrathin films as nanocontainers. AB - The design of positively charged ultrathin films for surface modification is of crucial importance for biomedical applications. Herein, we report the layer-by layer assembly of pure positively charged ultrathin films based on the host-guest interaction of cucurbit[8]uril (CB[8]). Two positively charged poly(ethylenimine)s (PEI) functionalized with guest moieties methyl viologen (MV) and indole (ID) were alternately assembled with the formation of CB[8] ternary complex under basic conditions. The growth of the (PEI-MV@CB[8]/PEI-ID) films was monitored by spectroscopic ellipsometry and quartz crystal microbalance. The morphology and structure of the films were characterized by scanning electron microscopy and UV-vis spectroscopy, respectively. These positively charged (PEI MV@CB[8]/PEI-ID) films were very stable in the pH range from 4 to 9 but disassembled immediately when subjected to a competitive guest adamantylamine. Finally, the films were successfully employed as nanocontainers for DNA loading and subsequent directing the transfection of the adhered cells. PMID- 24147653 TI - CuCl2-mediated reaction of [60]fullerene with amines in the presence or absence of dimethyl acetylenedicarboxylate: preparation of fulleropyrroline or aziridinofullerene derivatives. AB - The CuCl2-mediated three-component reaction of C60 with amines and dimethyl acetylenedicarboxylate afforded the fulleropyrrolines in moderate yields. Furthermore, the CuCl2-mediated oxidative [2 + 1] reaction of C60 with aromatic amines bearing a strong electron-withdrawing group provided the aziridinofullerenes and the selective cis-1-bisaziridinofullerenes. PMID- 24147654 TI - MS-275, a class I histone deacetylase inhibitor, protects the p53-deficient mouse against ischemic injury. AB - The administration of pan histone deacetylase (HDAC) inhibitors reduces ischemic damage to the CNS, both in vitro and in animal models of stroke, via mechanisms which we are beginning to understand. The acetylation of p53 is regulated by Class I HDACs and, because p53 appears to play a role in ischemic pathology, the purpose of this study was to discover, using an in vitro white matter ischemia model and an in vivo cerebral ischemia model, if neuroprotection mediated by HDAC inhibition depended on p53 expression. Optic nerves were excised from wild-type and p53-deficient mice, and then subjected to oxygen-glucose deprivation in the presence and absence of a specific inhibitor of Class I HDACs (MS-275, entinostat) while compound action potentials were recorded. Furthermore, transient focal ischemia was imposed on wild-type and p53-deficient mice, which were subsequently treated with MS-275. Interestingly, and in both scenarios, the beneficial effects of MS-275 were most pronounced when p53 was absent. These results suggest that modulation of p53 activity is not responsible for MS-275 mediated neuroprotection, and further illustrate how HDAC inhibitors variably influence p53 and associated apoptotic pathways. Optic nerves from wild-type and p53-deficient mice, engineered to express cyan fluorescent protein (CFP) in neuronal mitochondria, were subjected to oxygen-glucose deprivation (OGD) in the presence and absence of a specific inhibitor of Class I histone deacetylases. The protective effect of MS-275 was evidenced by mitochondrial preservation, and this was most pronounced in the absence of p53. PMID- 24147655 TI - Vibrio cholerae and Vibrio parahaemolyticus detected in seafood products from Senegal. AB - The detection of pathogenic Vibrio in seafood from Senegal has generated five food alerts in the European Union. To investigate the presence and abundance Vibrio cholerae and Vibrio parahaemolyticus in seafood and coastal and estuarine waters, 123 seafood samples and 52 water samples were collected during 2007-2009 from two large seafood markets in Dakar, and from different oceanic and estuarine areas of the country. V. parahaemolyticus was detected in 30.1% of seafood samples, whereas presence of V. cholerae was only found in 1.6%. In water samples, V. parahaemolyticus and V. cholerae were detected in 28.8% and 5.7% of the samples, respectively. Abundance of V. parahaemolyticus in seafood from the fishing areas ranged from <0.3 to 7.5 most probable number (MPN) per gram. In samples from markets, densities of V. parahaemolyticus showed higher values ranging from 0.61 to >110 MPN/g. Densities of V. cholerae in the two positive seafood samples reached values of 0.36 and 0.61 MPN/g, repectively. V. parahaemolyticus strains were found to possess tlh, but not tdh and trh by polymerase chain reaction, and all the strains of V. cholerae were non-O1 or non O139. These results suggest that the prevalence of high salinities in coastal and estuarine environments of Senegal limits the occurrence of V. parahaemolyticus and V. cholerae, despite warmer temperatures prevailing in seawater environments throughout the year. Furthermore, temperature abuse driven by a deficient cold chain over the distribution and retail sales may represent a major risk due to the postharvest multiplication of these Vibrio pathogens. PMID- 24147656 TI - A scoring system approach for the parasite predictive assessment of fish lots: a proof of concept with anisakids. AB - A total of 982 individuals distributed in 11 lots belonging to 10 fish species from three Atlantic FAO fishing areas were sampled and examined to detect the presence of anisakid larvae in fish muscle. After hazard identification by genetic sequencing and exposure assessment by anatomic extent and demographic characterization of infection, all data were fitted for each fish species to a new proposed scoring schema of parasite prediction. In the absence of a criterion standard method for inspection and precise definition of the quantum satis for parasites in contaminated fish lots, the inspection rating scheme called SADE (Site of infection, Assurance of quality, Demography, Epidemiology) may help fish industries to precisely handle and to evaluate the likely outcome of infected fish lots after being diagnosed. For this purpose, a supporting flow diagram for decision was defined and suggested. This new performance assessment tool has the aim of staging fish lots, thus helping in planning manufacture, commercial, and research decisions during self-management programs. This novel scoring system provides an improved inspection format by implementing the occurrence stratification for parasites to guide Hazard Analysis and Critical Control Points (HACCP) programs for the uniform exchange of information among fish industries, administration and researchers, thus facilitating standardization and communication. In the future, this scoring version could be validated (in terms of classification and wording) for similar overall predictive purposes in other muscular parasites infecting seafood products. PMID- 24147657 TI - Chronotype-related differences in childhood and adolescent aggression and antisocial behavior--a review of the literature. AB - Eveningness has been found to negatively affect adolescents' sleep and daytime functioning. Furthermore, eveningness is associated with greater impulsivity than morningness. Externalizing behavior could be chronotype-related, implying that the alteration of the circadian rhythm itself is connected to aspects of emotion and emotion regulation. The present study investigated chronotype-related differences in emotional and behavioral problems, especially aggression and antisocial behavior in children and adolescents. We conducted a comprehensive search via web of knowledge (MEDLINE, web of science), EBSCO, Ovid, PubMed, Google Scholar and PsycINDEX using the keywords: chronotype, chronobiology, morningness, eveningness, owls and larks as well as diurnal preference to fully capture every aspect of chronotype. For aggression we used the search terms: aggression, anger, hostility, violence, anti-social behavior, conduct disorder, oppositional defiant disorder, delinquency, social adjustment and externalizing behavior. N = 13 studies were included concerning chronotype, childhood, adolescence and antisocial behavior. Results showed that children and adolescents being E-types were more affected by daytime impairments. Additionally, behavioral and emotional problems as aggression or antisocial behavior were more pronounced in E- than in M-types. Our findings support an association of eveningness and the impact of aggression on children and adolescents. Longitudinal investigations should be conducted in order to insure causality of the effects in question. In addition, the elevated vulnerability toward aggression in evening types demonstrates the need for prevention and intervention programs that educate youths in proper sleep hygiene and evoke an awareness of the consequences of a habitually diminished sleep quality. PMID- 24147658 TI - Effect of exposure to evening light on sleep initiation in the elderly: a longitudinal analysis for repeated measurements in home settings. AB - Epidemiologic data have demonstrated associations of sleep-onset insomnia with a variety of diseases, including depression, dementia, diabetes and cardiovascular diseases. Sleep initiation is controlled by the suprachiasmatic nucleus of the hypothalamus and endogenous melatonin, both of which are influenced by environmental light. Exposure to evening light is hypothesized to cause circadian phase delay and melatonin suppression before bedtime, resulting in circadian misalignment and sleep-onset insomnia; however, whether exposure to evening light disturbs sleep initiation in home settings remains unclear. In this longitudinal analysis of 192 elderly individuals (mean age: 69.9 years), we measured evening light exposure and sleep-onset latency for 4 days using a wrist actigraph incorporating a light meter and an accelerometer. Mixed-effect linear regression analysis for repeated measurements was used to evaluate the effect of evening light exposure on subsequent sleep-onset latency. The median intensity of evening light exposure and the median sleep-onset latency were 27.3 lux (interquartile range, 17.9-43.4) and 17 min (interquartile range, 7-33), respectively. Univariate models showed significant associations between sleep-onset latency and age, gender, daytime physical activity, in-bed time, day length and average intensity of evening and nighttime light exposures. In a multivariate model, log transformed average intensity of evening light exposure was significantly associated with log-transformed sleep-onset latency independent of the former potential confounding factors (regression coefficient, 0.133; 95% CI, 0.020 0.247; p = 0.021). Day length and nighttime light exposure were also significantly associated with log-transformed sleep-onset latency (p = 0.001 and p < 0.001, respectively). In conclusion, exposure to evening light in home setting prolongs subsequent sleep-onset latency in the elderly. PMID- 24147659 TI - Effects of chronic jet lag on the central and peripheral circadian clocks in CBA/N mice. AB - The disruption of the circadian clock by frequent shifts in the light-dark cycle, such as shift-work or frequent jet lag, increases the risk of many diseases, including cancer. Experimental disruption of the circadian clock also increases tumor development in mice, although most studies used the strains that are genetically impaired in melatonin synthesis and secretion. Here, we examined the effects of experimental chronic jet lag with 8 h advances of the light-dark cycle every 2 days for 10 days on the central and peripheral clocks of CBA/N mice, the strain with normal profiles of melatonin synthesis and secretion. Mice were exposed to constant darkness after the 10 days of chronic jet lag. In the suprachiasmatic nucleus (SCN), chronic jet lag shifted the temporal expression of most clock genes examined without causing total disturbance of circadian oscillations. In the liver, the temporal patterns of Per1, Bmal1, and Dbp expression were phase-shifted, and Per2 expression was significantly upregulated by chronic jet lag. Further, the expression of cell cycle-related genes, c-Myc and p53 in the liver was significantly activated by the chronic jet lag schedule with a significant positive correlation between Per2 and p53 expression. We determined the plasma concentrations of melatonin and corticosterone as candidate hormonal messengers of chronic jet lag, but their overall levels were not affected by chronic jet lag. Moreover, the expression of the MT1 melatonin and glucocorticoid receptors in the liver was suppressed by chronic jet lag. These data suggest that in CBA/N mice, frequent advances of light-dark cycles modify the phases of central clock in the SCN and disturb the peripheral clock in the liver and apoptotic functions, which may be associated with the suppression of hormone receptors. PMID- 24147660 TI - Double versus single cervical cerclage for patients with recurrent pregnancy loss: a randomized clinical trial. AB - AIM: To compare the effectiveness of the double cervical cerclage method versus the single method in women with recurrent second-trimester delivery. METHOD: In this randomized clinical trial, we included 33 singleton pregnancies suffering from recurrent second-trimester pregnancy loss (>=2 consecutive fetal loss during second-trimester or with a history of unsuccessful procedures utilizing the McDonald method), due to cervical incompetence. Patients were randomly assigned to undergo either the classic McDonald method (n = 14) or the double cerclage method (n = 19). The successful pregnancy rate and gestational age at delivery was also compared between the two groups. RESULTS: The two study groups were comparable regarding their baseline characteristics. The successful pregnancy rate did not differ significantly between those who underwent the double cerclage method or the classic McDonald cerclage method (100% vs 85.7%; P = 0.172). In the same way, the preterm delivery rate (<34 weeks of gestation) was comparable between the two study groups (10.5% vs 35.7%; P = 0.106). Those undergoing the double cerclage method had longer gestational duration (37.2 +/- 2.6 vs 34.3 +/- 3.8 weeks; P = 0.016). CONCLUSION: The double cervical cerclage method seems to provide better cervical support, as compared with the classic McDonald cerclage method, in those suffering from recurrent pregnancy loss, due to cervical incompetence. PMID- 24147661 TI - Evaluation of the cost-utility of insulin degludec vs insulin glargine in Sweden. AB - OBJECTIVE: To evaluate the annual cost-utility of insulin degludec compared with glargine in patients with: type 1 diabetes (T1D), type 2 diabetes receiving basal only therapy (T2D-BOT), and type 2 diabetes receiving basal-bolus therapy (T2B BB) in Sweden. METHODS: A cost-utility model was programmed in Microsoft Excel to evaluate clinical and economic outcomes. The clinical trials were designed as treat-to-target, with insulin doses adjusted in order to achieve similar glycemic control between treatments, thus long-term modeling is not meaningful. Basal and bolus insulin doses, incidence of hypoglycemic events, frequency of self monitoring of blood glucose, and possibility for flexibility in timing of dose administration were specified for each insulin in three diabetes populations, based on data collected in Swedish patients with diabetes and a meta-analysis of clinical trials with degludec. Using these characteristics, the model estimated costs from a societal perspective and quality-adjusted life years (QALYs) in the two scenarios. RESULTS: Use of degludec was associated with a QALY gain compared with glargine in T1D (0.31 vs 0.26 QALYs), T2D-BOT (0.76 vs 0.69 QALYs), and T2D BB (0.56 vs 0.47 QALYs), driven by reduced incidence of hypoglycemia and possibility for flexibility around timing of dose administration. Therapy regimens containing degludec were associated with increased costs compared to glargine-based regimens, driven by the increased pharmacy cost of basal insulin, but partially offset by other cost savings. Based on estimates of cost and clinical outcomes, degludec was associated with incremental cost-effectiveness ratios of SEK 19,766 per QALY gained, SEK 10,082 per QALY gained, and SEK 36,074 per QALY gained in T1D, T2-BOT, and T2-BB, respectively. LIMITATIONS: The hypoglycemic event rates in the base case analysis were derived from a questionnaire-based study that relied on patient interpretation and recall of hypoglycemic symptoms. The relative rates of hypoglycemia with degludec compared to glargine were derived from a meta-analysis of phase III trials, which may not reflect the relative rates observed in real-world clinical practice. Both of these key limitations were explored in one-way sensitivity analyses. CONCLUSIONS: Based on reduced incidence of hypoglycemia and possibility for flexibility around timing of dose administration, use of degludec is likely to be cost-effective compared to glargine from a societal perspective in T1D, T2-BOT, and T2-BB in Sweden over a 1-year time horizon. PMID- 24147662 TI - Determining excitation-energy transfer times and mechanisms from stochastic time dependent density functional theory. AB - We developed an approach for calculating excitation-energy transfer times in supermolecular arrangements based on stochastic time-dependent density functional theory (STDDFT). The combination of real-time propagation and the stochastic Schrodinger equation with a Kohn-Sham Hamiltonian allows for simulating how an excitation spreads through an assembly of molecular systems. The influence that approximations, such as the dipole-dipole coupling approximation of Forster theory, have on energy-transfer times can be checked explicitly. As a first application of our approach we investigate a light-harvesting-inspired model ring system, calculating the time it takes for an excitation to travel from one side of the ring to the opposite side under ideal and perturbed conditions. Among other things we find that completely removing a molecule from the ring may inhibit energy transfer less than having an energetically detuned molecule in the ring. In addition, Forster's dipole coupling approximation may noticeably overestimate excitation-energy transfer efficiency. PMID- 24147663 TI - Severe mitral regurgitation after radiotherapy. AB - We present the case of a 69-year-old patient with a history of gynecological neoplasia and a pulmonary metastasis, who in 1996 underwent chemotherapy and mediastinal radiotherapy followed by cancer remission. Ten years later she presented with heart failure and her Doppler echocardiogram showed severe mitral regurgitation with pulmonary hypertension. In 2011, she underwent a mitral valve replacement with a biological prosthesis and the pathology exam revealed valve damage consistent with radiotherapy-induced changes. This unusual mechanism of mitral regurgitation can be demonstrated clearly by echocardiography and should be disseminated among cardiology physicians and in patients who have survived for long periods after radiotherapy, it is important to remember that cardiac complications may indeed occur, and the treating physician is responsible for detecting them. PMID- 24147664 TI - Effects of track and threat information on judgments of hurricane strike probability. AB - Although evacuation is one of the best strategies for protecting citizens from hurricane threat, the ways that local elected officials use hurricane data in deciding whether to issue hurricane evacuation orders is not well understood. To begin to address this problem, we examined the effects of hurricane track and intensity information in a laboratory setting where participants judged the probability that hypothetical hurricanes with a constant bearing (i.e., straight line forecast track) would make landfall in each of eight 45 degree sectors around the Gulf of Mexico. The results from 162 participants in a student sample showed that the judged strike probability distributions over the eight sectors within each scenario were, unsurprisingly, unimodal and centered on the sector toward which the forecast track pointed. More significantly, although strike probability judgments for the sector in the direction of the forecast track were generally higher than the corresponding judgments for the other sectors, the latter were not zero. Most significantly, there were no appreciable differences in the patterns of strike probability judgments for hurricane tracks represented by a forecast track only, an uncertainty cone only, or forecast track with an uncertainty cone-a result consistent with a recent survey of coastal residents threatened by Hurricane Charley. The study results suggest that people are able to correctly process basic information about hurricane tracks but they do make some errors. More research is needed to understand the sources of these errors and to identify better methods of displaying uncertainty about hurricane parameters. PMID- 24147665 TI - It would be a shame if this career option is lost. PMID- 24147667 TI - Consultants need more support to halt decline in numbers, says RCN. PMID- 24147668 TI - Staff are being 'taken for a ride' over pay, claims RCN president. PMID- 24147676 TI - NICE aims to help staff broach the subject of obesity with patients. PMID- 24147682 TI - New inspection regime to look at compassion of care home staff. PMID- 24147683 TI - Is safety being jeopardised by fewer community staff and rising caseloads? PMID- 24147684 TI - Child's tragedy illustrates need for new family role. PMID- 24147690 TI - Sepsis. PMID- 24147693 TI - An end to isolation. PMID- 24147692 TI - Review rouses staff to strive for better care. PMID- 24147706 TI - Let commissioning find its feet before we have more changes. PMID- 24147707 TI - Saturdays did not work for dentists, so how will GPs fare? PMID- 24147708 TI - I am keen to get back into nursing, but fear for the future of the profession. PMID- 24147710 TI - Caring responsibilities deserve funding and social recognition. PMID- 24147711 TI - It saddens me that race seems to have dropped off the agenda. PMID- 24147712 TI - Spiritual care is something that goes beyond religion. PMID- 24147715 TI - Hospice transfer for patients at the end of life: part 1. AB - This is the first of two articles about improving end of life care for terminally ill patients in a district general hospital. The article describes a hospice transfer service developed by joint working between staff at a medical assessment unit and a hospice to improve end of life care for patients who otherwise might die in the medical assessment unit. It discusses the care received by patients in both settings, and the practicalities of offering patients the option of rapid transfer to the hospice for end of life care, where the emphasis of care is on palliation not acute intervention. The second article explores the ethical, legal and practical considerations involved in developing the service. PMID- 24147714 TI - Introduction to genetics and genomics:a revised framework for nurses. AB - The genetics education framework for nurses first published in 2003 has been revised to reflect advances in genomic research and technology and its implications for practice. The framework now comprises eight competency statements. Each of these competencies will be discussed in a series of articles published in subsequent issues of Nursing Standard to update nurses on this dynamic field of health care. PMID- 24147716 TI - Oral cancer: risk factors, treatment and nursing care. AB - Oral cancer occurs in a range of anatomical sites within the oral cavity and pharynx. Although oral cancer is relatively rare in the UK, it can have a significant effect on individuals, with treatment being associated with eating, drinking, speaking and breathing difficulties. Treatment may also result in alterations to body image and functionality, which can lead to depression. Therefore, nurses need to have knowledge of associated risk factors, treatment and nursing care to improve patient outcomes and enhance quality of life. PMID- 24147717 TI - Depression. PMID- 24147718 TI - Move up by moving over. PMID- 24147720 TI - Job satisfaction guaranteed. PMID- 24147723 TI - Ligand binding and complex formation of galectin-3 is modulated by pH variations. AB - Galectin-3-dependent clusters or lattices are formed at the surface as well as in distinct organelles of eukaryotic cells. Incorporation into membrane proximal networks can fix glycoproteins within subcellular domains or sort them into distinct transport pathways. In the present paper we analysed the effect of acidification on the sugar binding and self-oligomerization of galectin-3. Using a fluorescence anisotropy assay we measured decreasing galectin-3 affinities to the blood group antigen GalNAcalpha1-3(Fucalpha1-2)Galbeta1-4Glc under low pH conditions. Binding to the strong interaction partner N-acetyl-D-lactosamine was also lost at pH 5.0, whereas the less efficient ligand lactose was still able to bind. This indicates that variations in the binding specificity to distinct glycans can be observed by altering the pH. The formation of galectin-3-based complexes by interaction with the multivalent glycoproteins asialofetuin or transferrin was also obliterated at acidic pH and the ligand-binding affinity itself was modulated by oligomerization of the lectin. When galectin-3 was added to giant plasma membrane vesicles from the apical surface of epithelial cells, pH modulation could generate or eliminate the formation of membrane domains enriched with p75(NTR) (neurotrophin receptor p75). In conclusion, the results of the present study suggest that the formation and composition of galectin-3 networks can be fine-tuned by changes in the environmental pH. PMID- 24147724 TI - Are two threats worse than one? The effects of face race and emotional expression on fear conditioning. AB - Facial cues of racial outgroup or anger mediate fear learning that is resistant to extinction. Whether this resistance is potentiated if fear is conditioned to angry, other race faces has not been established. Two groups of Caucasian participants were conditioned with two happy and two angry face conditional stimuli (CSs). During acquisition, one happy and one angry face were paired with an aversive unconditional stimulus whereas the second happy and angry faces were presented alone. CS face race (Caucasian, African American) was varied between groups. During habituation, electrodermal responses were larger to angry faces regardless of race and declined less to other race faces. Extinction was immediate for Caucasian happy faces, delayed for angry faces regardless of race, and slowest for happy racial outgroup faces. Combining the facial cues of other race and anger does not enhance resistance to extinction of fear. PMID- 24147725 TI - Measurement of thermal conductivity of PbTe nanocrystal coated glass fibers by the 3omega method. AB - Fiber-based thermoelectric materials can conform to curved surfaces to form energy harvesting devices for waste heat recovery. Here we investigate the thermal conductivity in the axial direction of glass fibers coated with lead telluride (PbTe) nanocrystals using the self-heated 3omega method particularly at low frequency. While prior 3omega measurements on wire-like structures have only been demonstrated for high thermal conductivity materials, the present work demonstrates the suitability of the 3omega method for PbTe nanocrystal coated glass fibers where the low thermal conductivity and high aspect ratio result in a significant thermal radiation effect. We simulate the experiment using a finite difference method that corrects the thermal radiation effect and extract the thermal conductivity of glass fibers coated by PbTe nanocrystals. The simulation method for radiation correction is shown to be generally much more accurate than analytical methods. We explore the effect of nanocrystal volume fraction on thermal conductivity and obtain results in the range of 0.50-0.93 W/mK near room temperature. PMID- 24147726 TI - Crystallographic dependence of CO activation on cobalt catalysts: HCP versus FCC. AB - Identifying the structure sensitivity of catalysts in reactions, such as Fischer Tropsch synthesis from CO and H2 over cobalt catalysts, is an important yet challenging issue in heterogeneous catalysis. Based on a first-principles kinetic study, we find for the first time that CO activation on hexagonal close-packed (HCP) Co not only has much higher intrinsic activity than that of face centered cubic (FCC) Co but also prefers a different reaction route, i.e., direct dissociation with HCP Co but H-assisted dissociation on the FCC Co. The origin is identified from the formation of various denser yet favorable active sites on HCP Co not available for FCC Co, due to their distinct crystallographic structure and morphology. The great dependence of the activity on the crystallographic structure and morphology of the catalysts revealed here may open a new avenue for better, stable catalysts with maximum mass-specific reactivity. PMID- 24147727 TI - Sensor Arrays Based on Polycyclic Aromatic Hydrocarbons: Chemiresistors versus Quartz-Crystal Microbalance. AB - Arrays of broadly cross-reactive sensors are key elements of smart, self-training sensing systems. Chemically sensitive resistors and quartz-crystal microbalance (QCM) sensors are attractive for sensing applications that involve detection and classification of volatile organic compounds (VOCs) in the gas phase. Polycyclic aromatic hydrocarbon (PAH) derivatives as sensing materials can provide good sensitivity and robust selectivity towards different polar and nonpolar VOCs, while being quite tolerant to large humidity variations. Here, we present a comparative study of chemiresistor and QCM arrays based on a set of custom designed PAH derivatives having either purely nonpolar coronas or alternating nonpolar and strongly polar side chain termination. The arrays were exposed to various concentrations of representative polar and nonpolar VOCs under extremely varying humidity conditions (5-80% RH). The sensor arrays' classification ability of VOC polarity, chemical class and compound separation was explained in terms of the sensing characteristics of the constituent sensors and their interaction with the VOCs. The results presented here contribute to the development of novel versatile and cost-effective real-world VOC sensing platforms. PMID- 24147728 TI - Prospective antifungal therapy (PATH) alliance((r)) : focus on mucormycosis. AB - Mucormycosis is increasingly encountered in immunosuppressed patients, such as those with haematological malignancies or stem cell transplantation. We present a descriptive analysis of 121 cases of mucormycosis from the Prospective Antifungal Therapy Alliance((r)) registry (July 2004 to December 2008). Patients with proven or probable mucormycosis were enrolled and followed prospectively for 12 weeks. The most common underlying disease and site of infection were haematologic malignancy (61.2%) and lungs (46.3%) respectively. Rhizopus (n = 63; 52.1%) was the most commonly isolated species, followed by Mucor (n = 28; 23.1%), other or unknown (n = 17; 14.0%), Rhizomucor (n = 9; 7.4%) and Lichtheimia (n = 4; 3.3%). The 12-week Kaplan-Meier survival probability for all patients was 0.41; however, there was large variation in survival probabilities between species, with highest survival probability observed for Lichtheimia (0.5), followed by Rhizopus (0.47), Mucor (0.40), unknown Mucormycetes species (0.40), other Mucormycetes species (0.17) and Rhizomucor (0.15). Prior use of voriconazole decreased 12-week survival probability. Survival probability was higher in patients receiving amphotericin B by Day 3 (0.72) vs. those who started amphotericin B therapy after Day 3 (0.33). The low survival probability observed underscores the importance of further studies of mucormycosis. Optimal treatment selection and timing may improve prognosis. PMID- 24147729 TI - Brachial plexus injury complicating the labor: mother is the victim at this time. AB - OBJECTIVE: Postpartum nerve injuries are rare complications of labor and the lower extremity peripheral nerves are the frequently affected ones. In this case report, we are presenting a patient who developed brachial plexus injury after a forceful vaginal delivery. CASE REPORT: The patient is a 28-year-old woman with right upper extremity pain, numbness and weakness, whose symptoms started just after labor. According to the clinical evaluation, electrodiagnostic study and magnetic resonance imaging, it was diagnosed as the brachial plexus injury. CONCLUSION: We concluded that similar to the ones seen after some surgeries, brachial plexus may be injured also during delivery and the labor positions should be considered. PMID- 24147730 TI - Health-related quality of life and functional outcome in cardiac surgical patients aged 80 years and older: a prospective single center study. AB - BACKGROUND: An increasing number of octogenarians are referred for cardiac surgical procedures. In this subset of patients, information on the health related quality of life (HrQoL) is critical for decision making. However, there is a paucity of prospective data. Thus, we sought to prospectively evaluate the HrQoL in octogenarians undergoing cardiac surgery. METHODS: A prospective HrQoL analysis was performed in 106 elective patients (median age 83.0 +/- 2.6 years, range 80-91.8 years, 59.4% male) undergoing cardiac surgery. The standardized SF 36 Health Survey questionnaire was answered preoperatively, and three and 12 months postoperatively. Preoperative data, perioperative outcome, and postoperative morbidity were analyzed. RESULTS: SF-36 scores for physical functioning (44.3 +/- 2.3 vs. 52.0 +/- 2.7; p < 0.001), role physical (25.2 +/- 3.3 vs. 41.5 +/- 4.1; p < 0.001), bodily pain (57.8 +/- 3.2 vs. 70.7 +/- 2.8; p < 0.01), general health (54.9 +/- 1.7 vs. 59.6 +/- 1.7; p < 0.001), vitality (41.1 +/- 2.1 vs. 50.6 +/- 2.1; p < 0.001), and mental health (67.5 +/- 2.0 vs. 72.4 +/ 1.9; p < 0.05) significantly improved from baseline to three months. Social functioning (75.4 +/- 2.6 vs. 76.1 +/- 2.5; p = 0.79) and role emotional (56.8 +/ 4.5 vs. 58.0 +/- 4.6; p = 0.29) improved slightly without reaching statistical significance. Correspondingly, at three months, physical component scores increased significantly compared to baseline (34.3 +/- 1.0 vs. 39.4 +/- 1.0; p < 0.001). SF-36 scores remained stable between three months and one year. No significant change was seen in the mental component score from baseline to three months (48.6 +/- 1.2 vs. 49.8 +/- 1.1; p = 0.18). CONCLUSIONS: Physical HrQoL is significantly improved in octogenarians three months after cardiac surgery remaining stable at one year postoperatively when compared to baseline. PMID- 24147731 TI - Effectiveness of massive transfusion protocols on mortality in trauma: a systematic review and meta-analysis. AB - INTRODUCTION: The effectiveness of massive transfusion protocols (MTPs) has been assumed from low quality studies with multiple biases. This review aimed to (i) evaluate the association between the institution of an MTP and mortality and (ii) determine the effect of MTPs on transfusion practice post trauma. METHODS: A systematic review of studies that examined patient outcomes before and after the institution of an MTP in the same centre was conducted. The design and results of each study were described. Heterogeneity was assessed using the Q test and the I(2) statistic. Odds ratios (ORs) for dichotomous outcomes from each study were pooled. RESULTS: There were eight studies that satisfied inclusion criteria with marked heterogeneity in study populations (I(2) = 72.1%, P = 0.001). Two studies showed significantly improved mortality following implementation of an MTP, and six studies showed no significant change. Pooled OR for the effect of an MTP on short-term mortality was 0.73 (95% confidence interval: 0.48-1.11). The effect of MTPs on transfusion practice was varied. CONCLUSION: Despite the popularity of MTPs and directives mandating their use in trauma centres, in before-after studies, MTPs have not always been associated with improved mortality. Evidence based standardization of MTPs, improved compliance and analysis of broader endpoints were identified as areas for further research. PMID- 24147732 TI - The challenges, advantages and future of phenome-wide association studies. AB - Over the last decade, significant technological breakthroughs have revolutionized human genomic research in the form of genome-wide association studies (GWASs). GWASs have identified thousands of statistically significant genetic variants associated with hundreds of human conditions including many with immunological aetiologies (e.g. multiple sclerosis, ankylosing spondylitis and rheumatoid arthritis). Unfortunately, most GWASs fail to identify clinically significant associations. Identifying biologically significant variants by GWAS also presents a challenge. The GWAS is a phenotype-to-genotype approach. As a complementary/alternative approach to the GWAS, investigators have begun to exploit extensive electronic medical record systems to conduct a genotype-to phenotype approach when studying human disease - specifically, the phenome-wide association study (PheWAS). Although the PheWAS approach is in its infancy, this method has already demonstrated its capacity to rediscover important genetic associations related to immunological diseases/conditions. Furthermore, PheWAS has the advantage of identifying genetic variants with pleiotropic properties. This is particularly relevant for HLA variants. For example, PheWAS results have demonstrated that the HLA-DRB1 variant associated with multiple sclerosis may also be associated with erythematous conditions including rosacea. Likewise, PheWAS has demonstrated that the HLA-B genotype is not only associated with spondylopathies, uveitis, and variability in platelet count, but may also play an important role in other conditions, such as mastoiditis. This review will discuss and compare general PheWAS methodologies, describe both the challenges and advantages of the PheWAS, and provide insight into the potential directions in which PheWAS may lead. PMID- 24147733 TI - Defining variation in urinary oxalate in hyperoxaluric stone formers. AB - BACKGROUND AND PURPOSE: The development of effective preventive therapy for renal calculi in patients with secondary hyperoxaluria (2 degrees HO) relies on establishing the pattern of normal variation in urinary oxalate (uOx) and attempting to reduce it. Therefore, we evaluated uOx at baseline and at subsequent time points in stone formers with 2 degrees HO. METHODS: We reviewed the charts of 201 recurrent stone formers with 2 degrees HO (uOx >= 40 mg/day). The 24-hour urine collections at baseline and after initiation of clinician directed therapies were analyzed. Mixed models were constructed to analyze uOx over time for individual patients and as a group. Subgroup analyses were performed for enteric and idiopathic 2 degrees HO. Coefficients of variation were computed using the root mean square error from linear models. RESULTS: The etiology of 2 degrees HO was enteric in 17.9% and idiopathic in 82.1% of patients. Among the 943 urine collections analyzed, 196 oxalate values were derived from the enteric group and 747 from the idiopathic group. The median number of uOx values measured per person was four. The median 24-hour uOx (mg/day) was significantly higher for the enteric group than for the idiopathic group at the time of diagnosis: 64.4 (interquartile range [IQR]=48-90) vs 46.0 (IQR=38-56), P<0.001) and during follow-up (58.2 [IQR=46-86] vs 44.2 [IQR=35-53], P<0.001). Over a median follow-up of 22.5 months, 44.4% of the enteric and 61.8% of the idiopathic patients had at least one normal uOx value (P=0.06). The coefficients of variation for the enteric and idiopathic groups were 40.8% and 27.3%, respectively, with variation randomly displayed in either direction for both groups. CONCLUSIONS: Among patients with 2 degrees HO, uOx demonstrates significant random variation over time even with the incorporation of standard treatments, with enteric HO demonstrating higher values and greater variance than idiopathic HO. PMID- 24147735 TI - Three-dimensional paper-based microfluidic device for assays of protein and glucose in urine. AB - The first step in curing a disease is being able to detect the disease effectively. Paper-based microfluidic devices are biodegradable and can make diagnosing diseases cost-effective and easy in almost all environments. We created a three-dimesnional (3D) paper device using wax printing fabrication technique and basic principles of origami. This design allows for a versatile fabrication technique over previously reported patterning of SU-8 photoresist on chromatography paper by employing a readily available wax printer. The design also utilizes multiple colorimetric assays that can accommodate one or more analytes including urine, blood, and saliva. In this case to demonstrate the functionality of the 3D paper-based microfluidic system, a urinalysis of protein and glucose assays is conducted. The amounts of glucose and protein introduced to the device are found to be proportional to the color change of each assay. This color change was quantified by use of Adobe Photoshop. Urine samples from participants with no pre-existing health conditions and one person with diabetes were collected and compared against synthetic urine samples with predetermined glucose and protein levels. Utilizing this method, we were able to confirm that both protein and glucose levels were in fact within healthy ranges for healthy participants. For the participant with diabetes, glucose was found to be above the healthy range while the protein level was in the healthy range. PMID- 24147736 TI - The design of a peptide sequence to inhibit HIV replication: a search algorithm combining Monte Carlo and self-consistent mean field techniques. AB - We developed a search algorithm combining Monte Carlo (MC) and self-consistent mean field techniques to evolve a peptide sequence that has good binding capability to the anticodon stem and loop (ASL) of human lysine tRNA species, tRNA(Lys3), with the ultimate purpose of breaking the replication cycle of human immunodeficiency virus-1. The starting point is the 15-amino-acid sequence, RVTHHAFLGAHRTVG, found experimentally by Agris and co-workers to bind selectively to hypermodified tRNA(Lys3). The peptide backbone conformation is determined via atomistic simulation of the peptide-ASL(Lys3) complex and then held fixed throughout the search. The proportion of amino acids of various types (hydrophobic, polar, charged, etc.) is varied to mimic different peptide hydration properties. Three different sets of hydration properties were examined in the search algorithm to see how this affects evolution to the best-binding peptide sequences. Certain amino acids are commonly found at fixed sites for all three hydration states, some necessary for binding affinity and some necessary for binding specificity. Analysis of the binding structure and the various contributions to the binding energy shows that: 1) two hydrophilic residues (asparagine at site 11 and the cysteine at site 12) "recognize" the ASL(Lys3) due to the VDW energy, and thereby contribute to its binding specificity and 2) the positively charged arginines at sites 4 and 13 preferentially attract the negatively charged sugar rings and the phosphate linkages, and thereby contribute to the binding affinity. PMID- 24147737 TI - A field and modeling study of fractured rock permeability reduction using microbially induced calcite precipitation. AB - Microbially induced calcite precipitation (MICP) offers an attractive alternative to traditional grouting technologies for creating barriers to groundwater flow and containing subsurface contamination, but has only thus far been successfully demonstrated at the laboratory scale and predominantly in porous media. We present results of the first field experiments applying MICP to reduce fractured rock permeability in the subsurface. Initially, the ureolytic bacterium, Sporosarcina pasteurii, was fixed in the fractured rock. Subsequent injection of cementing fluid comprising calcium chloride and urea resulted in precipitation of large quantities (approximately 750 g) of calcite; significant reduction in the transmissivity of a single fracture over an area of several m(2) was achieved in around 17 h of treatment. A novel numerical model is also presented which simulates the field data well by coupling flow and bacterial and solute reactive transport processes including feedback due to aperture reduction via calcite precipitation. The results show that MICP can be successfully manipulated under field conditions to reduce the permeability of fractured rock and suggest that an MICP-based technique, informed by numerical models, may form the basis of viable solutions to aid pollution mitigation. PMID- 24147738 TI - Synthetic biology in plastids. AB - Plastids (chloroplasts) harbor a small gene-dense genome that is amenable to genetic manipulation by transformation. During 1 billion years of evolution from the cyanobacterial endosymbiont to present-day chloroplasts, the plastid genome has undergone a dramatic size reduction, mainly as a result of gene losses and the large-scale transfer of genes to the nuclear genome. Thus the plastid genome can be regarded as a naturally evolved miniature genome, the gradual size reduction and compaction of which has provided a blueprint for the design of minimum genomes. Furthermore, because of the largely prokaryotic genome structure and gene expression machinery, the high transgene expression levels attainable in transgenic chloroplasts and the very low production costs in plant systems, the chloroplast lends itself to synthetic biology applications that are directed towards the efficient synthesis of green chemicals, biopharmaceuticals and other metabolites of commercial interest. This review describes recent progress with the engineering of plastid genomes with large constructs of foreign or synthetic DNA, and highlights the potential of the chloroplast as a model system in bottom up and top-down synthetic biology approaches. PMID- 24147739 TI - S-allyl cysteine protects against MPTP-induced striatal and nigral oxidative neurotoxicity in mice: participation of Nrf2. AB - The neuroprotective properties of S-allyl cysteine (SAC) have been demonstrated in different neurotoxic paradigms, and it may be partially attributable to its antioxidant and anti-inflammatory profile. Recently, SAC has also been shown to induce neuroprotection in the rat striatum in a toxic model induced by 6 hydroxydopamine in rats through a concerted antioxidant response involving Nrf2 transcription factor nuclear transactivation and Phase 2 enzymes' upregulation. In this work, we investigated whether the SAC-induced in vivo striatal and nigral neuroprotection against 1-methyl-4-phenyl-1,2,3,6-tetrahydropiridinium (MPTP) toxicity recruits Nrf2 transactivation in C57BL/6J mice. SAC (120 mg/kg, i.p. * 5 days) partially ameliorated the MPTP (30 mg/kg, i.p. * 5 days)-induced striatal and nigral dopamine and tyrosine hydroxylase depletion, attenuated the loss of Mn SOD and HO-1 activities, and preserved the protein content of these enzymes. While no significant changes were detected for the striatal Nrf2 nuclear protein levels, the nigral Nrf2 nuclear content was decreased by MPTP and stimulated by SAC. Our findings suggest that SAC can exert neuroprotection since the origin of the dopaminergic lesion-at the substantia nigra (SN)-not only by means of direct antioxidant actions, but also through Nrf2 nuclear transactivation and Phase 2 enzymes upregulation. PMID- 24147740 TI - Thalamic synaptic transmission of sensory information modulated by synergistic interaction of adenosine and serotonin. AB - The thalamic synapses relay peripheral sensory information to the cortex, and constitute an important part of the thalamocortical network that generates oscillatory activities responsible for different vigilance (sleep and wakefulness) states. However, the modulation of thalamic synaptic transmission by potential sleep regulators, especially by combination of regulators in physiological scenarios, is not fully characterized. We found that somnogen adenosine itself acts similar to wake-promoting serotonin, both decreasing synaptic strength as well as short-term depression, at the retinothalamic synapse. We then combined the two modulators considering the coexistence of them in the hypnagogic (sleep-onset) state. Adenosine plus serotonin results in robust synergistic inhibition of synaptic strength and dramatic transformation of short term synaptic depression to facilitation. These synaptic effects are not achievable with a single modulator, and are consistent with a high signal-to noise ratio but a low level of signal transmission through the thalamus appropriate for slow-wave sleep. This study for the first time demonstrates that the sleep-regulatory modulators may work differently when present in combination than present singly in terms of shaping information flow in the thalamocortical network. The major synaptic characters such as the strength and short-term plasticity can be profoundly altered by combination of modulators based on physiological considerations. PMID- 24147741 TI - Racialized and gendered disparities in occupational exposures among Chinese and white workers in Toronto. AB - OBJECTIVE: We examined disparities in hazardous employment characteristics and working conditions among Chinese and white workers in Toronto, Canada. DESIGN: We used self-administered questionnaire data from a 2005-2006 population-based survey (n = 1611). Using modified Poisson regression, we examined the likelihood for Chinese workers of experiencing adverse exposures compared to whites. Models were stratified by sex and adjusted for differences in human capital. Work sector was conceptualized as a mediating variable. RESULTS: Chinese workers were generally more likely to report adverse exposures. In many cases, disparities were only evident or more pronounced among women. The shorter length of time in Canada of Chinese relative to whites accounted for some of the observed disparities. Meanwhile, the higher educational level of Chinese compared to whites provided them with no protection from adverse exposures. The risk of experiencing discrimination on the labor market and at work was more than 50% higher among Chinese men and women as compared to whites, and those disparities, though reduced, persisted after adjustment for confounders. CONCLUSIONS: Discrimination is far more prevalent among Chinese than among whites and may explain their disproportionate exposure to other hazards. PMID- 24147744 TI - Bond strength of adhesive luting agents to caries-affected dentin. AB - INTRODUCTION: The aim of this study was to evaluate the bond strength of adhesive luting agents to caries-affected dentin (CAD). METHODS: Forty human molars were sectioned to create dental slices presenting exposed occlusal dentin. Half of the samples were submitted to eight caries-induction demineralizing/mineralizing cycles. The pH-cycling model consisted of three hours in a demineralizing solution followed by 45 hours of immersion in a mineralizing solution. Dentin hardness was measured before and after the pH cycling. Resin cement cylinders were built up over the dentin surface using RelyX Unicem or RelyX ARC/Scotchbond Multipurpose Plus. The cement cylinders were submitted to shear load, and the data were analyzed using two-way analysis of variance (ANOVA) and Tukey test (p<0.05). Hardness data were also submitted to two-way ANOVA and Tukey test (p<0.05). The relationship of hardness vs bond strength was assessed via nonlinear regression analysis. RESULTS: Sound dentin (tested and used in caries induction) showed similar values of hardness and were superior to CAD. Both resin cements showed higher bond strength to sound dentin than to CAD. Independent of substrate, RelyX ARC showed the highest values of bond strength. A positive linear relationship between dentin hardness and bond strength was observed for both cements evaluated. CONCLUSIONS: The adhesive luting agents evaluated showed lower bond strength to CAD. PMID- 24147743 TI - Schmidingerothrix salinarum nov. spec. is the molecular sister of the large oxytrichid clade (ciliophora, hypotricha). AB - In 2012, Foissner described a curious hypotrich: Schmidingerothrix extraordinaria. This ciliate, which he discovered in hypersaline soils (~1000/00) from Namibia, had a frayed buccal lip, three-rowed adoral membranelles, only one frontal cirrus, and a miniaturized first frontal membranelle, while a paroral membrane, dorsal bristle rows and buccal, transverse and caudal cirri were absent. All opisthe structures developed de novo, while parental structures were involved in the proter. When Foissner's study became available, we discovered a similar species in a Portuguese solar saltern, differing from S. extraordinaria mainly by the number of frontoventral cirral rows (3 vs. 1). Furthermore, parental structures were involved in the ontogenesis of both proter and opisthe. The small subunit (SSU) rDNA shows Schmidingerothrix as sister of a large clade containing most classical oxytrichids (e.g. Sterkiella, Oxytricha, Steinia) and many related taxa (e.g. Pattersoniella, Bistichella, Uroleptus). This clade shows a bifurcation named "Oxytricha subclade" and "Uroleptus subclade". Foissner () interpreted the peculiarities of Schmidingerothrix as a reduction caused by the extreme habitat. However, the molecular data do not exclude that Schmidingerothrix presents an ancient state. A morphology-based scheme is presented, showing how the subclades might have evolved from a Schmidingerothrix like ancestor. PMID- 24147742 TI - Risk for anxiety and implications for treatment: developmental, environmental, and genetic factors governing fear regulation. AB - Anxiety disorders are the most common psychiatric disorders, affecting as many as 10% of youth, with diagnoses peaking during adolescence. A core component of these disorders is an unremitting fear in the absence of present threat. One of the most commonly used therapies to treat these disorders is exposure-based cognitive behavioral therapy that identifies the source of the fear and anxiety and then desensitizes the individual to it. This treatment builds on basic principles of fear-extinction learning. A number of patients improve with this therapy, but 40-50% do not. This paper provides an overview of recent empirical studies employing both human imaging and cross-species behavioral genetics to examine how fear regulation varies across individuals and across development, especially during adolescence. These studies have important implications for understanding who may be at risk for anxiety disorders and for whom and when during development exposure-based therapies may be most effective. PMID- 24147745 TI - Assessment of the effect of casein phosphopeptide-amorphous calcium phosphate on postoperative sensitivity associated with in-office vital tooth whitening. AB - The aim of this study was to evaluate the efficacy of tooth mousse containing 10% casein phosphopeptide-amorphous calcium phosphate (CPP-ACP) in reducing tooth sensitivity associated with in-office vital tooth whitening. In-office tooth whitening was performed for 51 participants using 35% hydrogen peroxide gel in a single visit. After the procedure, each participant was randomly assigned to one of three groups: gel without desensitizing agent (n=17), gel with 2% sodium fluoride (n=17), gel with 10% CPP-ACP (n=17). A small amount of the desensitizing gel assigned for each participant was applied directly on the labial surfaces of teeth and left undisturbed for three minutes. The participants were asked to apply the gel assigned to them for three minutes twice daily after brushing their teeth, and to continue this for 14 days. The participants were asked to return for follow-up visits after 24 hours and on days 3, 7, and 14, at which time teeth shade changes were assessed by one evaluator using a value-oriented Vita classic shade guide. The incidence, duration, and intensity of tooth sensitivity experienced was self-assessed on a daily basis for the 14-day study period using a visual analog scale (VAS). The effect of the three gels on tooth sensitivity was assessed using one-way analysis of variance and a chi (2) test (alpha=0.05). The general linear model was used to compare intensity-level differences in the three studied groups and for shade stability over the follow-up period. The results of this study showed that all three gels decreased the intensity of sensitivity associated with tooth whitening. The intensity of sensitivity was lower in the fluoride group than in the other two groups; however, it was not statistically significant (p=0.112 and p=0.532 on day 1 and day 2, respectively). The average shade change was 6.8. None of the tested materials affected the efficacy of tooth whitening, but the shade change among the fluoride group showed more color stability than that of the other two groups. This study suggested that using a gel after tooth whitening can reduce the intensity of tooth sensitivity associated with in-office whitening procedures without affecting the efficiency of tooth whitening. However, it failed to demonstrate that using a 10% CPP-ACP could provide additional therapeutic benefits. PMID- 24147746 TI - The effect of light-curing access and different resin cements on apical bond strength of fiber posts. AB - PURPOSE: This study evaluated the effect of light-curing access on the bond strength of fiber glass posts to the apical area of bovine roots using self adhesive cement or dual-cured cement with an etch-and-rinse adhesive system. MATERIALS AND METHODS: The root canals of 60 bovine teeth were endodontically treated and filled. A 15-mm-length post space was prepared and roots were randomly divided into three groups, simulating the levels of light-curing access: coronal (C), with 15-mm post space; middle (M), in which the coronal thirds of roots were cut out, leaving a 10-mm post space; and apical (A), in which the coronal and middle thirds of roots were cut out, leaving a 5-mm post space. Fiber glass posts (Reforpost # 3, Angelus) were cemented with RelyX U100 (3M ESPE) or RelyX ARC/Scotchbond Multi Purpose Plus (SBMP) (3M ESPE) (n=10) and light-cured. After 24 hours, the apical thirds of roots were sectioned perpendicularly to the long axis and submitted to a push-out test (0.5 mm/min, 200 N). The Kruskal Wallis test compared the three levels of light-curing access, and the Mann Whitney test compared the cements. RESULTS: The bond strength was significantly higher in the groups C (p=0.028) and M (p=0.016) when U100 was used, whereas it was similar for both cements in group A. The bond strengths of posts cemented with ARC/SBMP were significantly higher in group A compared to group C (p=0.031). CONCLUSIONS: The type of cement used and the light-curing access level influenced the bond strength between glass fiber posts and root canals. The bond strength of the RelyX ARC/SBMP cement proved to be more dependent on photoactivation than was the RelyX U100 cement. The light-curing access level did not influence the apical bond strength of RelyX U100. PMID- 24147747 TI - Polymerization shrinkage of different types of composite resins and microleakage with and without liner in class II cavities. AB - AIM: To determine the volumetric polymerization shrinkage of four different types of composite resin and to evaluate microleakage of these materials in class II (MOD) cavities with and without a resin-modified glass ionomer cement (RMGIC) liner, in vitro. MATERIALS AND METHODS: One hundred twenty-eight extracted human upper premolar teeth were used. After the teeth were divided into eight groups (n=16), standardized MOD cavities were prepared. Then the teeth were restored with different resin composites (Filtek Supreme XT, Filtek P 60, Filtek Silorane, Filtek Z 250) with and without a RMGIC liner (Vitrebond). The restorations were finished and polished after 24 hours. Following thermocycling, the teeth were immersed in 0.5% basic fuchsin for 24 hours, then midsagitally sectioned in a mesiodistal plane and examined for microleakage using a stereomicroscope. The volumetric polymerization shrinkage of materials was measured using a video imaging device (Acuvol, Bisco, Inc). Data were statistically analyzed with Kruskal-Wallis and Mann-Whitney U-tests. RESULTS: All teeth showed microleakage, but placement of RMGIC liner reduced microleakage. No statistically significant differences were found in microleakage between the teeth restored without RMGIC liner (p>0.05). Filtek Silorane showed significantly less volumetric polymerization shrinkage than the methacrylate-based composite resins (p<0.05). CONCLUSION: The use of RMGIC liner with both silorane- and methacrylate-based composite resin restorations resulted in reduced microleakage. The volumetric polymerization shrinkage was least with the silorane-based composite. PMID- 24147748 TI - Evaluation of color changes in the Vitapan Classical Shade Guide after disinfection. AB - The purpose of this study was to evaluate how one, two, and three years of simulated treatments affect the colors of Vitapan Classical Shade Guide tabs after being chemically disinfected. Ten shade tabs (one, control; nine, disinfection) were evaluated visually and by chromameter for color changes after disinfection. Results showed that 0.62 DeltaE was found after three years of disinfection. The color changes in the shade guide tabs were perceptible or noticeable to the human eye in eight out of 45 shade tabs (17.8%) after two years and in 13 out of 45 shade tabs (28.9%) after three years of treatment. It was concluded that one shade guide should be retained as a control and periodically compared with the shade guide in use to determine when the shade tabs in use should be replaced or discarded. PMID- 24147749 TI - Bonding of Y-TZP to dentin: effects of Y-TZP surface conditioning, resin cement type, and aging. AB - PURPOSE: To evaluate the effects of two surface treatments, aging, and two resin cements on shear bond strength between dentin and yttrium-stabilized tetragonal zirconia polycrystal ceramic (Y-TZP). MATERIALS AND METHODS: Eighty human molars were embedded in acrylic resin and sectioned 3 mm below the occlusal plane. These teeth and 80 cylindrical Y-TZP specimens (height, 4 mm; diameter, 3.4 mm) were divided into eight groups (n=10) using the following factors: Y-TZP surface treatment (Vi: low-fusing porcelain [vitrification] + hydrofluoric acid etching + silanization or Si: tribochemical silicatization); cementation strategies (PF: Panavia or CC: Clearfil); and storage (nonaging or aging). Bonding surfaces of 40 Y-TZP specimens received Vi treatment, and the rest received Si treatment. Half of the ceramic-tooth assemblies were cemented with Panavia, the rest with Clearfil. Shear tests were executed using 0.4-mm-thick wire at 0.5 mm/min. Data were analyzed by three-way analysis of variance and Tukey test (alpha=0.05). Fractures were analyzed. RESULTS: Y-TZP surface treatments did not affect bond strength (p=0.762, Vi = Si), while resin cements (p<0.001, Panavia > Clearfil) and aging (p=0.006, nonaging > aging) showed a significant effect. Most failures were in adhesive at dentin-cement interfaces; no failure occurred between zirconia and cement. CONCLUSION: When Y-TZP ceramic is bonded to dentin, the weakest interface is that between dentin and resin cement. The resin cement/Y-TZP interface was less susceptible to failures, owing to Y-TZP surface treatments. PMID- 24147750 TI - Cardiac arrest during exercise; rupture of the sinus of Valsalva with dissection into the interventricular septum. PMID- 24147751 TI - Conformational compression and barrier height heterogeneity in the N acetylglutamate kinase. AB - The role of motions in the catalytic cycle of an enzyme is the subject of much debate. Crystallographic results for the enzyme N-acetyl-l-glutamate kinase (NAGK), which is a suitable target for antibacterial drugs, suggest that a conformational compression of the active site favors catalysis. We have used a QM/MM scheme to compute energy profiles of the phosphoryl transfer reaction for 20 conformations of NAGK, starting from four crystal structures that represent different stages of the catalytic process. All paths show a common associative mechanism but with a wide range of barrier heights. The position of several active site residues and water molecules are found to determine the energetic barrier of each conformation, as revealed by principal component and partial least-squares chemometric analyses. In particular, conformations in which the two substrates have a shorter distance separation and a more linear mutual orientation tend to have lower energetic barriers, thus supporting the putative role of conformational compressive motions in catalysis. Interestingly, these motions are the same that lead to opening of the active site, which molecular dynamics simulations indicate is a fast process when the enzyme is free of substrates. Despite the lack of extended sampling, the energy barrier we calculate for the chemical step lies significantly below the apparent energetic barrier derived from experiment. Although not conclusive, this result supports a previous hypothesis, also derived from experiment, that conformational motions, rather than the chemical step, are rate limiting. PMID- 24147752 TI - Pediatric varicocelectomy: a comparative study of conventional laparoscopic and laparoendoscopic single-site approaches. AB - BACKGROUND AND PURPOSE: Laparoscopy is a common approach to manage varicoceles in both the adult and pediatric population. The purpose of this study is to report our experience and compare outcomes between conventional laparoscopy and laparoendoscopic single-site (LESS) surgery for varicocelectomy in the pediatric population. PATIENTS AND METHODS: A retrospective cohort study was performed of all patients who underwent conventional laparoscopic varicocelectomy (LV) and laparoendoscopic single-site varicocelectomy (LESSV) at a single pediatric institution from December 2007 to March 2012. Patient demographics, intraoperative details, narcotic use, and complications were reviewed. RESULTS: LV was performed in 32 patients and LESSV in 11 patients. None had conversion to open surgery. Median age was 16 years for LV (range 12-23) and 15 years for LESSV (range 12-20), P=0.061. Median operative time was 55 minutes for LV (range 28-90) and 46 minutes for LESSV (range 33-59), P=0.037. Nine (81.8%) patients in the LESSV group and 10 (31.2%) patients in the LV group were administered narcotics in the recovery room, P=0.005. One (3.1%) patient in the LV group was administered ketorolac in the recovery room, P=1. Five patients in each group, LESSV (45.5%) and LV (15.6%), received acetaminophen in the recovery room, P=0.092. All procedures were performed on an outpatient basis except for one because of a concomitant procedure. Median follow-up was 22 months in LV and 15 months in LESSV, P=0.015. One (3.1%) postoperative hydrocele was noted after LV and 1 (9.1%) after LESSV, P=0.451. All varicoceles were clinically resolved in both groups. CONCLUSIONS: LESSV is comparable to LV in the pediatric population. Our initial experience indicates that the LESS approach may be more painful in the immediate postoperative period than conventional laparoscopy. The LESS technique warrants further evaluation to determine if one approach is clearly more advantageous. PMID- 24147753 TI - Chiral structure determination of aligned single-walled carbon nanotubes on graphite surface. AB - Chiral structure determination of single-walled carbon nanotube (SWNT), including its handedness and chiral index (n,m), has been regarded as an intractable issue for both fundamental research and practical application. For a given SWNT, the n and m values can be conveniently deduced if an arbitrary two of its three crucial structural parameters, that is, diameter d, chiral angle theta, and electron transition energy E(ii), are obtained. Here, we have demonstrated a novel approach to derive the (n,m) indices from the theta, d, and E(ii) of SWNTs. Handedness and theta were quickly measured based on the chirality-dependent alignment of SWNTs on graphite surface. By combining their measured d and E(ii), (n,m) indices of SWNTs can be independently and uniquely identified from the (theta,d) or (theta,E(ii)) plots, respectively. This approach offers intense practical merits of high-efficiency, low-cost, and simplicity. PMID- 24147755 TI - Anion and solvent induced chirality inversion in macrocyclic lanthanide complexes. AB - A series of the lanthanide(III) or yttrium(III) complexes of the type [LnL(NO3)(H2O)2](NO3)2, [LnL(NO3)(H2O)](NO3)2, [LnL(H2O)2](NO3)3, and [LnLCl(H2O)2]Cl2 where L is an all-R or all-S enantiomer (L(R) or L(S)) of the chiral hexaaza macrocycle, 2(R),7(R),18(R),23(R)- or 2(S),7(S),18(S),23(S) 1,8,15,17,24,31-hexaazatricyclo[25.3.1.1.0.0]-dotriaconta-10,12,14,26,28,30 hexaene, and Ln(III) = Sm(III), Tb(III), Ho(III), Er(III), Tm(III), Yb(III), Lu(III), or Y(III), have been synthesized and structurally characterized. The crystal structure of the free macrocycle shows a highly twisted molecule, preorganized for the formation of helical complexes. The crystal structures of the lanthanide(III) complexes show two different diastereomeric forms of the macrocycle with different configurations at the stereogenic amine nitrogen atoms: (RRRR) or (RSRS) (denoted as L(RI) and L(RII), respectively). The L(RI) diastereomeric form of the nitrate derivatives [LnL(NO3)(H2O)](NO3)2 (Ln = Ho, Er) and [LnL(H2O)2](NO3)3 (Ln = Tm, Yb, Lu) convert slowly to the L(RII) form in methanol or acetonitrile solutions, while this process is not observed for the L(RI) diastereomers of analogous chloride derivatives [LnL(H2O)2]Cl3 (Ln = Tm, Yb, Lu). On the other hand, the L(RI) -> L(RII) conversion for these Tm(III), Yb(III), and Lu(III) chloride derivatives can be triggered by the addition of external nitrate anions. The circular dichroism (CD) and (1)H NMR data indicate initial fast exchange of axial chloride for axial nitrate ligand, followed by slow chirality inversion of the equatorial macrocyclic ligand. PMID- 24147754 TI - Evaluation of hemostatic abnormalities in canine spirocercosis and its association with systemic inflammation. AB - BACKGROUND: Canine spirocercosis is caused by the nematode Spirocerca lupi and is characterized by esophageal fibro-inflammatory nodules that may undergo neoplastic transformation. No sensitive and specific laboratory assays other than histopathology have been reported to differentiate non-neoplastic from neoplastic disease. HYPOTHESIS/OBJECTIVES: Dogs with spirocercosis will have evidence of hypercoagulability based on thromboelastography (TEG)-derived maximal amplitude (MA); increased MA will be correlated with increased acute phase protein (APP) concentrations (C-reactive protein [CRP] and fibrinogen); increased MA and APPs will be exacerbated with neoplastic spirocercosis. ANIMALS: Thirty-nine client owned dogs with naturally occurring spirocercosis and 15 sex-matched healthy controls. METHODS: A prospective comparative study evaluating TEG, activated partial thromboplastin time, prothrombin time, antithrombin (AT) activity, platelet count and D-dimer concentration, and APPs of dogs with non-neoplastic (n = 24) and neoplastic (n = 15) spirocercosis compared to control dogs. RESULTS: Median MA was significantly increased in the non-neoplastic group (P < .01) and neoplastic group (P < .01) compared to the controls. Both APPs were significantly increased in the neoplastic group compared to the non-neoplastic and control groups. MA was strongly correlated with fibrinogen (r = 0.85, P < .001) and CRP (r = 0.73, P < .001). An MA >76 mm provided 96% specificity and 73% sensitivity for differentiation of disease state. CONCLUSIONS AND CLINICAL IMPORTANCE: Canine spirocercosis is associated with increased TEG variables, MA and alpha, and decreased AT activity, which may indicate a hypercoagulable state seemingly more severe with neoplastic transformation. MA was correlated with APP in dogs with spirocercosis and can be used as an adjunctive test to support the suspicion of neoplastic transformation. PMID- 24147756 TI - Analysis of the Sam50 translocase of excavate organisms supports evolution of divergent organelles from a common endosymbiotic event. AB - As free-living organisms the ancestors of mitochondria and plastids encoded complete genomes, proteomes and metabolomes. As these symbionts became organelles all these aspects were reduced - genomes have degenerated with the host nucleus now encoding the most of the remaining endosymbiont proteome, while the metabolic processes of the symbiont have been streamlined to the functions of the emerging organelle. By contrast, the topology of the endosymbiont membrane has been preserved, necessitating the development of complex pathways for membrane insertion and translocation. In this study, we examine the characteristics of the endosymbiont-derived beta-barrel insertase Sam501 in the excavate super-group. A candidate is further characterized in Trichomonas vaginalis, an unusual eukaryote possessing degenerate hydrogen-producing mitochondria called hydrogenosomes. This information supports a mitochondriate eukaryotic common ancestor with a similarly evolved beta-barrel insertase, which has continued to be conserved in degenerate mitochondria. PMID- 24147757 TI - Comparing two psychological interventions in reducing impulsive processes of eating behaviour: effects on self-selected portion size. AB - OBJECTIVE: Palatable food, such as sweets, contains properties that automatically trigger the impulse to consume it even when people have goals or intentions to refrain from consuming such food. We compared the effectiveness of two interventions in reducing the portion size of palatable food that people select for themselves. Specifically, the use of dieting implementation intentions that reduce behaviour towards palatable food via top-down implementation of a dieting goal was pitted against a stop-signal training that changes the impulse-evoking quality of palatable food from bottom-up. DESIGN: We compared the two interventions using a 2 * 2 factorial design. METHODS: Participants completed a stop-signal training in which they learned to withhold a behavioural response upon presentation of tempting sweets (vs. control condition) and formed implementation intentions to diet (vs. control condition). Selected portion size was measured in a sweet-shop-like environment (Experiment 1) and through a computerized snack dispenser (Experiment 2). RESULTS: Both interventions reduced the amount of sweets selected in the sweet shop environment (Experiment 1) and the snack dispenser (Experiment 2). On average, participants receiving an intervention selected 36% (Experiment 1) and 51% (Experiment 2) fewer sweets than control participants. In both studies, combining the interventions did not lead to additive effects: Employing one of the interventions appears to successfully eliminate instrumental behaviour towards tempting food, making the other intervention redundant. CONCLUSIONS: Both interventions reduce self-selected portion size, which is considered a major contributor to the current obesity epidemic. STATEMENT OF CONTRIBUTION: What is already known on this subject? Exposure to temptations, such as unhealthy palatable food, often frustrates people's attainment of long-term health goals. Current approaches to self-control suggest that this is partly because temptations automatically trigger impulsive or hedonic processes that override the influence of more deliberate processes on behaviour. This perspective has stimulated the development of new interventions - which have so far been studied in isolation - aimed at decreasing the influence of impulsive or hedonic processes to decrease unhealthy eating behaviour. What does this study add? Linking sweets to stop signals and diet-prime implementation intentions both reduce self-selected portion size. Combining the interventions does not lead to additive effects. Each intervention reduces self-selected portion size of sweets, making the other redundant. PMID- 24147758 TI - Potential impact of combined high- and low-risk human papillomavirus infection on the progression of cervical intraepithelial neoplasia 2. AB - AIM: Few studies have examined the effect of combined low-risk human papillomavirus (LR-HPV) and high-risk human papillomavirus (HR-HPV) infection on the progression of cervical intraepithelial neoplasia (CIN)2 to CIN3. This multi institutional prospective cohort study investigated the risk of progression of CIN2 with various combinations of HR-HPV and LR-HPV infection. METHODS: Between January 2007 and May 2008, 122 women with CIN2 (aged 20-50 years) from 24 hospitals throughout Japan were enrolled in the study. Ninety-three women were analyzed after a 2-year follow-up with cytology, colposcopy, HR-HPV testing and HPV genotyping. Colposcopy-directed biopsy was performed at entry and the end of this study, or when disease progression was suspected. RESULTS: Among 93 women with CIN2, 87 (93.5%) had HR-HPV infection. Among these 87 cases, 24 (27.6%) progressed to CIN3 and 49 (56.3%) regressed. None of the six women with CIN2 without HR-HPV infection progressed. The progression rate was significantly lower in women with combined HR-HPV and LR-HPV infection (3/28, 10.7%) than in those with HR-HPV infection only (21/59, 35.6%; P = 0.016). Multivariate analyses showed that CIN2 progression in women with HR-HPV infection was negatively associated with LR-HPV co-infection (hazard ratio = 0.152; 95% confidence interval [CI] = 0.042-0.553). CIN2 regression was positively associated with LR HPV co-infection (odds ratio = 4.553; 95% CI = 1.378-15.039). CONCLUSION: The risk of CIN2 progression is low in women with combined infection of HR-HPV and LR HPV. The finding may be useful for management of women diagnosed with CIN2. PMID- 24147759 TI - Two new phenylpropanoid glycosides from the roots of Aruncus sylvester. AB - Two new phenylpropanoid glycosides, 1,3,4-tri-O-(E)-caffeoyl-beta-d glucopyranoside (1) and 1,4-di-O-(E)-caffeoyl-beta-d-glucopyranoside (2), along with four known phenylpropanoid glycosides (3-6), were isolated from the roots of Aruncus sylvester. The structures of 1 and 2 were elucidated using various spectroscopic methods. Compounds 1 and 2 displayed significant scavenging activity of 2,2-diphenyl-1-picrylhydrazyl free radicals with IC50 values of 110 and 258 MUM (ascorbic acid: IC50 = 574 MUM). PMID- 24147760 TI - Hybrid bulk heterojunction solar cells based on the cooperative interaction of liquid crystals within quantum dots and diblock copolymers. AB - In this article, the conjugated rod-rod polythiophene diblock copolymers comprising a regioregular poly(3-hexylthiophene) (P3HT) segment and a side-chain liquid-crystalline polythiophene segment bearing cyanobiphenyl mesogenic pendants (PTcbp), polythiophene-b-poly{3-[10-(4'-cyanobiphenyloxy)decyl]thiophene} (P3HT-b PTcbp), were rationally designed and synthesized. It was observed that the diblock copolymers could self-assemble into high crystalline and oriented nanofibrils upon 1,2-dichlorobenzene solvent vapor annealing, originating from the crystallization of two segments and the orientation of cyanobiphenyl side chain mesogens. Hybrid bulk heterojunction (BHJ) solar cells were then fabricated using P3HT-b-PTcbp as electron donors and ZnO and CdS quantum dots (QDs) modified by 4'-hydroxy-[1,1'-biphenyl]-4-carbonitrile (cbp) liquid-crystalline ligands (cbp@ZnO and cbp@CdS) as electron acceptors. The interaction between the cbp ligands on the surface of ZnO and CdS QDs and cyanobiphenyl side-chain mesogens of diblock copolymers promoted the cooperative self-assembly and controllable well-dispersion of QDs in the polymer matrix and, as a consequence, yielded an intimately contacted polymer-QD nanocomposites. The power conversion efficiency (PCE) of the device based on P3HT-b-PTcbp/cbp@ZnO hybrids was improved by 2.6 times compared with that of P3HT/ZnO hybrids from 0.58 to 0.97. In addition, an overall PCE of a homologous device based on the P3HT-b-PTcbp/cbp@CdS hybrid active layer reached 2.3%. The research paved the way for the further development of high-efficiency hybrid BHJ solar cells by introducing block copolymer nanofibrils with favored crystalline domain orientations and liquid-crystalline organization properties. PMID- 24147761 TI - Fungal diseases mimicking primary lung cancer: radiologic-pathologic correlation. AB - A variety of fungal pulmonary infections can produce radiologic findings that mimic lung cancers. Distinguishing these infectious lesions from lung cancer remains challenging for radiologists and clinicians. In such cases, radiographic findings and clinical manifestations can be highly suggestive of lung cancer, and misdiagnosis can significantly delay the initiation of appropriate treatment. Likewise, the findings of imaging studies cannot replace the detection of a species as the aetiological agent. A biopsy is usually required to diagnose the infectious nature of the lesions. In this article, we review the clinical, histologic and radiologic features of the most common fungal infections that can mimic primary lung cancers, including paracoccidioidomycosis, histoplasmosis, cryptococcosis, coccidioidomycosis, aspergillosis, mucormycosis and blastomycosis. PMID- 24147762 TI - Heat-treated membranes with bioelectricity promote bone regeneration. AB - The barrier membranes maintain a secluded space to prevent the ingrowth of connective tissue and direct the growth of new bone into a desired site; however, they do not stimulate or induce bone regeneration. To enhance the bone bioactivities of membranes, we developed chitosan electret membranes with bioelectricity by grid-controlled constant voltage corona charging. The electret membranes charged with heat treatment (HT electret membranes) exhibited superior electret charge storage stability than the ones charged without heat treatment (RT electret membranes). Human bone marrow stromal cells (hBMSCs) demonstrated better growth on HT electrets membrane. Moreover, hBMSCs osteoblastic differentiation was enhanced on HT electret membranes, as evidenced by osteocalcin and osteopontin expression as assessed by immunocytochemistry, quantitative RT-PCR and western blot analysis. The rabbit calvarial defect model demonstrated that HT electret membranes induced a significantly enhanced bone regeneration compared with RT electret membranes. New bone formation was found at both the periphery and in the center of the defects four weeks after implantation. These results indicated that the chitosan electret membrane has osteogenic potential and could be applied as a novel barrier membrane. PMID- 24147763 TI - Clinical utility of chromosomal microarray analysis in prenatal diagnosis: report of first 6 months in clinical practice. AB - OBJECTIVE: We studied the clinical utility of chromosomal microarray analysis (CMA) in prenatal diagnosis in a clinical setting in New York City. METHODS: Our center began offering CMA to pregnant women undergoing invasive diagnostic procedures for an abnormal structural finding on ultrasound, maternal age of 35 years or older, or elevated risk on aneuploidy screening, beginning March 2012. Our first six months experience is reported. RESULTS: Benign familial variants were the most common finding (16/22 fetuses). Variants of uncertain significance were frequent, especially when fathers were not available for testing (4/22 fetuses). Most patients undertook CMA as part of evaluation of an ultrasound anomaly (52%). One patient terminated a pregnancy based on an ultrasound finding in the setting of a benign familial variant on CMA, and a second terminated a pregnancy based on a copy number variant identified on CMA. CONCLUSION: For CMA to be maximally useful in prenatal diagnosis, parental DNA samples as well as robust datasets to provide predictive phenotypic information are required. The most common reason for undertaking CMA was to evaluate an ultrasound anomaly, and benign familial variants were a common finding. Genetic services are required to provide pre- and post-test genetic counseling and help families interpret results. PMID- 24147764 TI - Insiders or outsiders? Mental health service users' journeys towards full citizenship. AB - The present study explores the journeys towards full citizenship for those using mental health services as they lobbied to be included as full citizens with the same rights and responsibilities as others in society. Qualitative data were collected through semistructured interviews with 17 service users, five government representatives, and seven registered mental health nurses. A conceptual framework of citizenship containing four domains - the extent, content, depth and acts of citizenship - was used to analyse the data. This paper reports the findings from the service users' data in the first domain, the extent of citizenship, defined as the rules and norms of inclusion and exclusion. The degree to which the service user participants were accepted as full citizens with the same civil, political, and social rights as others was contingent on their ability to adopt their society's rules and norms and appear as 'normal' citizens. Participants often experienced being 'othered' and excluded from the many rights and responsibilities of citizenship due to society's perception that service users lack certain attributes of normal, productive citizens. Participants reported that being labelled with a mental illness led to them being marginalized and ostracized, thus placing conditions and barriers on their citizenship status. Findings show that in response to experiencing conditional citizenship, participants shaped their behaviour to assimilate with other citizens. As well, they engaged in practices of inclusion to challenge and broaden the social rules and norms in order to be accepted without disavowing their differences. PMID- 24147765 TI - Rice DB: an Oryza Information Portal linking annotation, subcellular location, function, expression, regulation, and evolutionary information for rice and Arabidopsis. AB - Omics research in Oryza sativa (rice) relies on the use of multiple databases to obtain different types of information to define gene function. We present Rice DB, an Oryza information portal that is a functional genomics database, linking gene loci to comprehensive annotations, expression data and the subcellular location of encoded proteins. Rice DB has been designed to integrate the direct comparison of rice with Arabidopsis (Arabidopsis thaliana), based on orthology or 'expressology', thus using and combining available information from two pre eminent plant models. To establish Rice DB, gene identifiers (more than 40 types) and annotations from a variety of sources were compiled, functional information based on large-scale and individual studies was manually collated, hundreds of microarrays were analysed to generate expression annotations, and the occurrences of potential functional regulatory motifs in promoter regions were calculated. A range of computational subcellular localization predictions were also run for all putative proteins encoded in the rice genome, and experimentally confirmed protein localizations have been collated, curated and linked to functional studies in rice. A single search box allows anything from gene identifiers (for rice and/or Arabidopsis), motif sequences, subcellular location, to keyword searches to be entered, with the capability of Boolean searches (such as AND/OR). To demonstrate the utility of Rice DB, several examples are presented including a rice mitochondrial proteome, which draws on a variety of sources for subcellular location data within Rice DB. Comparisons of subcellular location, functional annotations, as well as transcript expression in parallel with Arabidopsis reveals examples of conservation between rice and Arabidopsis, using Rice DB (http://ricedb.plantenergy.uwa.edu.au). PMID- 24147766 TI - Acrolein involvement in sensory and behavioral hypersensitivity following spinal cord injury in the rat. AB - Growing evidence suggests that oxidative stress, as associated with spinal cord injury (SCI), may play a critical role in both neuroinflammation and neuropathic pain conditions. The production of the endogenous aldehyde acrolein, following lipid peroxidation during the inflammatory response, may contribute to peripheral sensitization and hyperreflexia following SCI via the TRPA1-dependent mechanism. Here, we report that there are enhanced levels of acrolein and increased neuronal sensitivity to the aldehyde for at least 14 days after SCI. Concurrent with injury-induced increases in acrolein concentration is an increased expression of TRPA1 in the lumbar (L3-L6) sensory ganglia. As proof of the potential pronociceptive role for acrolein, intrathecal injections of acrolein revealed enhanced sensitivity to both tactile and thermal stimuli for up to 10 days, supporting the compound's pro-nociceptive functionality. Treatment of SCI animals with the acrolein scavenger hydralazine produced moderate improvement in tactile responses as well as robust changes in thermal sensitivity for up to 49 days. Taken together, these data suggest that acrolein directly modulates SCI associated pain behavior, making it a novel therapeutic target for preclinical and clinical SCI as an analgesic. Following spinal cord injury (SCI), acrolein involvement in neuropathic pain is likely through direct activation and elevated levels of pro-nociceptive channel TRPA1. While acrolein elevation correlates with neuropathic pain, suppression of this aldehyde by hydralazine leads to an analgesic effect. Acrolein may serve as a novel therapeutic target for preclinical and clinical SCI to relieve both acute and chronic post-SCI neuropathic pain. PMID- 24147768 TI - Abstracts of the 2013 Asia Pacific Congress of Allergy, Asthma and Clinical Immunology. November 14-17, 2013. Taipei, Taiwan. PMID- 24147767 TI - Efficacy of punctal occlusion in management of dry eyes after laser in situ keratomileusis for myopia. AB - PURPOSE: To evaluate the effect of punctal plug use in preventing dry eye after laser in situ keratomileusis (LASIK). MATERIALS AND METHODS: A randomized clinical trial at a tertiary eye care center, Riyadh, Saudi Arabia. Participants underwent LASIK for myopia in both eyes and a lower punctal occlusion in one eye only while the other eye served as control. Both eyes received the same postoperative medications except for lubricant duration (subject eye: four times per day for one week; control eye: four times per day for 6 months). Participants were evaluated at 1 week, 2, and 6 months after surgery for signs and symptoms of dry eye. The main outcome measures were visual acuity; ocular surface parameters; and Ocular Surface Disease Index questionnaire. RESULTS: Seventy-eight eyes of 39 patients were included in this study. The Ocular Surface Disease Index scores of eyes with punctal plugs were better at all follow-up visits, and the differences between both eyes were statistically significant (1 week, p < 0.0001; 2 months, p < 0.0001; 6 months, p = 0.008). At the final follow-up visit, the percentage of normal eyes was higher in eyes with punctal plugs for all ocular surface parameters (Schirmer 1 test, 94.9%; tear breakup time, 77.8%; punctate epithelial keratitis score, 71.8%) compared to eyes without occlusion (Schirmer 1 test, 92.3%; tear breakup time, 58.3%; punctate epithelial keratitis score, 53.8%); however, such differences were not statistically significant. CONCLUSION: Punctal plug insertion after LASIK surgeries may minimize the need for frequent lubricant application and hence improve patient satisfaction. PMID- 24147769 TI - Incremental filling technique and composite material--part I: cuspal deformation, bond strength, and physical properties. AB - OBJECTIVES: To evaluate the effect of composite resins (one conventional and two low-shrink composites) and filling techniques on cuspal strains (CS), microtensile bond strength (MUTBS), composite ultimate tensile strength (UTS), and mechanical properties of the composites at various depths in molars with large Class II restorations. MATERIALS AND METHODS: One hundred seventeen human molars received standardized Class II mesio-oclusal-distal cavity preparations and restorations with three composites (Filtek LS [3M-ESPE]; Aelite LS [BISCO]; and Filtek Supreme [3M-ESPE]) using three filling techniques (bulk, eight increments, and 16 increments). CS was measured using strain gauges, after which the same restored teeth were used to assess MUTBS and UTS. The elastic modulus (E) and Vickers hardness (VH) at different depths were determined from microhardness indentations. The CS, MUTBS, UTS, E, and VH data were statistically analyzed using split-plot analysis of variance and Tukey test (p=0.05). RESULTS: The CS was higher when using 16 increments. The 'low-shrink' composites caused lower CS. The MUTBS and UTS were similar for eight- and 16-increment techniques and higher when compared to the bulk filling in all composites. E and VH were constant through the depth when applied in eight or 16 increments. CONCLUSIONS: Type of composite and filling technique affected the CS, MUTBS, UTS, and mechanical properties of large Class II restorations. The eight-increments filling technique resulted in generally less CS with the same MUTBS and UTS than was obtained with 16 increments, without affecting E and VH through the depth of the composites. PMID- 24147770 TI - Availability of zinc and the ligands citrate and histidine to wheat: does uptake of entire complexes play a role? AB - Organic ligands in soils affect the availability of trace metals such as Zn to plants. This study investigated the effects of two of these ligands, citrate and histidine, on Zn uptake by wheat under hydroponic conditions. Uptake of (65)Zn in the presence of these ligands was compared to uptake in the presence of EDTA at the same free Zn concentration (Zn(2+) ~ 50 nM). In the presence of citrate Zn root uptake was enhanced ~3.5 times and in the presence of histidine, by a factor of ~9, compared to the EDTA treatments. Citrate uptake was slightly reduced in the treatment containing ligands and Zn compared to the treatment containing the same ligand concentration but no Zn. In addition, a higher uptake of Zn than of citrate was observed. This suggests that the enhanced Zn uptake was primarily due to increased supply of Zn(2+) by diffusion and dissociation of Zn-citrate complexes at the root surface. Histidine uptake was much higher than citrate uptake and not influenced by the presence of Zn. As histidine forms stronger complexes with Zn than citrate, the results suggest that the enhancement of Zn uptake in the presence of histidine was in part due to the uptake of undissociated Zn-histidine complexes. PMID- 24147772 TI - Resting ST amplitude: prognosis and normal values in an ambulatory clinical population. AB - BACKGROUND: There is limited data describing ST segment amplitude in apparently healthy, asymptomatic populations. We analyzed ST amplitude in the standard resting electrocardiogram (ECG) in a large, multiethnic, stable, clinical population. METHODS: We evaluated computerized ST amplitude measurements from the resting ECGs of 29,281 ambulatory outpatients collected between 1987 and 1999 at the Palo Alto, VA. With the PR interval as the isoelectric line, both elevation criteria (>=0.1 mV, >=0.15 mV, and >=0.2 mV) and depression criteria (<=-0.05 mV or <=-0.1 mV), were applied. Cox-Hazard survival analysis techniques were used to demonstrate in which leads ST amplitude displacement was associated with cardiovascular (CV) death. To create a cohort without ECG patterns clearly associated with disease, we excluded ECGs with inverted T waves, wide QRS, or diagnostic Q waves and coded the remaining "normal" ECGs for ST elevation and depression to determine a normal range. RESULTS: The only ST amplitudes that were significantly and independently associated with time to CV death when adjusted for age, gender, and ethnicity were ST depression in all of the lateral leads (I, V4 -V6 ). When isolated to the inferior leads, (II and AVF), no ST amplitude criteria were associated with CV death. Among the "normal ECG" subgroup the precordial leads exhibited the greatest median ST amplitudes and the most significant differences between the leads, genders and ethnicities. CONCLUSIONS: Significant differences in ST amplitude were present in the precordial leads according to gender and ethnicity. This was particularly apparent when amplitude threshold were set for comparisons. Our findings provide the normal range for ST amplitude that when exceeded, should raise clinical concern. PMID- 24147773 TI - Thermal response of DNA supramolecular polymers assembled with hydrophobic sticky ends. AB - We report the self-assembly and thermal dissociation of DNA dumbbell conjugates having a perylenediimide (PDI) linker on each end separated by 6-16 A-T base pairs. In the presence of NaCl these dumbbells form one-dimensional supramolecular assemblies as a consequence of the hydrophobic association of their PDI sticky ends. The dependence of assembly formation on dumbbell concentration, salt concentration, and temperature can be conveniently monitored by UV-vis spectroscopy. The melting of these linear assemblies follows two limiting mechanisms, depending on the length of the dumbbells. Upon heating in the presence of salt, the assemblies formed by the longer dumbbells undergo a sequential transition from assembly to base-paired monomer to random coiled monomer, whereas the assemblies formed by the shorter dumbbells undergo disassembly and base-pair melting cooperatively. In all cases, the intramolecular hydrophobic association of the PDI chromophores is observed at elevated temperature. The thermal behavior of these one-dimensional assemblies is compared to that of other sticky-ended assemblies. PMID- 24147771 TI - Anticancer activity of small-molecule and nanoparticulate arsenic(III) complexes. AB - Starting in ancient China and Greece, arsenic-containing compounds have been used in the treatment of disease for over 3000 years. They were used for a variety of diseases in the 20th century, including parasitic and sexually transmitted illnesses. A resurgence of interest in the therapeutic application of arsenicals has been driven by the discovery that low doses of a 1% aqueous solution of arsenic trioxide (i.e., arsenous acid) lead to complete remission of certain types of leukemia. Since Food and Drug Administration (FDA) approval of arsenic trioxide (As2O3) for treatment of acute promyelocytic leukemia in 2000, it has become a front-line therapy in this indication. There are currently over 100 active clinical trials involving inorganic arsenic or organoarsenic compounds registered with the FDA for the treatment of cancers. New generations of inorganic and organometallic arsenic compounds with enhanced activity or targeted cytotoxicity are being developed to overcome some of the shortcomings of arsenic therapeutics, namely, short plasma half-lives and a narrow therapeutic window. PMID- 24147774 TI - A multistep flow process for the synthesis of highly functionalized benzoxazoles. AB - An efficient and scalable transformation of 3-halo-N-acyl anilines to the corresponding benzoxazoles within a continuous flow reactor is reported. This transformation proceeds via base-mediated deprotonation, ortho-lithiation, and intramolecular cyclization to provide unstable lithiated benzoxazole moieties. The subsequent in-line electrophilic quench results in the formation of substituted benzoxazoles in high yield and quality. Continuous flow technology allowed for accurate temperature control and immediate in-line quench while minimizing the hold-up time for the unstable lithiated intermediates thereby minimizing associated byproduct formation. PMID- 24147776 TI - Which ureteral access sheath is compatible with your flexible ureteroscope? AB - PURPOSE: Our aim is to evaluate different ureteral access sheaths (UASs), which are available in the international market and their compatibility with different available flexible ureteroscopes (F-URSs) to help the urologist choose the proper ureteral access sheath for his or her endoscope before commencing the procedure. MATERIALS AND METHODS: A total of 21 UASs and 12 F-URSs were evaluated. Measurements were obtained in French (F) units considering different characteristics for each UAS and each F-URS. Insertion test without friction between F-URS and UAS was considered as a successful test and was referred as (YES). RESULTS: All UASs and F-URSs were successfully submitted to the insertion test. All F-URSs that were inserted into UASs without friction had an internal diameter of at least 12F. Different lengths of UAS did not influence the test outcome. CONCLUSION: This study was able to establish a correlation table between different UASs and different flexible ureteroscopes. As of now, the 12/14F UAS is considered the universal UAS that accepts all F-URSs that are available in the endourology field. Nevertheless, we are expecting a significant change with the new standard size 10/12F UAS as well as huge advances in minimizing the size of different endoscopes. PMID- 24147775 TI - Measurement of IL-12 (p40, p35), IL-23p19, and IFN-gamma mRNA in duodenal biopsies of cats with inflammatory enteropathy. AB - BACKGROUND: Dietary hypersensitivity and inflammatory bowel disease (IBD) are important causes of chronic vomiting and diarrhea in cats. IL-23 has been recently found to be a key factor in the immunopathogenesis of IBD in humans but the involvement in IBD has not been investigated in cats. HYPOTHESIS/OBJECTIVES: Expression of genes encoding Il-12p35 and p40, IL-23p19, and IFN-gamma may be up regulated in duodenal biopsy specimens taken from cats with histologic evidence of inflammation. ANIMALS AND METHODS: Duodenal biopsy specimens were collected from control cats (n = 21) and cats with inflammatory enteropathy (n = 13). Routine histopathology, immunohistochemistry (IHC), and qRT-PCR were used to assess expression of MHC class II and to measure gene transcripts encoding the p35, p40, and p19 subunits of the IL-12 family of cytokines and IFN-gamma. RESULTS: There were significant differences in expression of mRNA encoding IL 12p35 and IL-23p19 between healthy cats and cats with inflammatory enteropathy. IL-12p35 mRNA was lower in the duodenal mucosa of cats with inflammatory enteropathy compared with the mucosa of healthy cats (P = .001). In contrast, IL 23p19 mRNA expression was higher in duodenal biopsy specimens from cats with inflammatory enteropathy than in those from healthy controls (P = .001). There was no difference in expression of IL-12p40 and IFN-gamma mRNA (P > .05). The majority of cats with inflammatory enteropathy had histologic evidence of moderate to severe colitis (score 2). CONCLUSIONS AND CLINICAL IMPORTANCE: The results of this preliminary study suggest that IL-23 plays a role in the pathogenesis of feline inflammatory enteropathy. PMID- 24147777 TI - Epigenetic regulation of angiotensin-converting enzyme 2 (ACE2) by SIRT1 under conditions of cell energy stress. AB - ACE2 (angiotensin-converting enzyme 2) counterbalances the actions of ACE (angiotensin-converting enzyme) by metabolizing its catalytic product, the vasoactive and fibrogenic peptide AngII (angiotensin II), into Ang-(1-7) [angiotensin-(1-7)]. Enhanced ACE2 expression may be protective in diabetes, cardiovascular disease and cancer. However, relatively little is known about the specific physiological factors regulating ACE2 expression. In the present paper, we show, by Western blotting and qPCR (quantitative real-time PCR), that ACE2 expression is increased under conditions of cell stress, including hypoxic conditions, IL (interleukin)-1beta treatment and treatment with the AMP mimic AICAR (5-amino-4-imidazolecarboxamide riboside). The NAD+-dependent deacetylase SIRT1 (silent information regulator T1) was found to be up-regulated after AICAR treatment but, conversely, was down-regulated after IL-1beta treatment. ChIP analysis demonstrated that SIRT1 bound to the ACE2 promoter and that binding was increased after AICAR treatment, but decreased after IL-1beta treatment. Inhibition of SIRT1 activity ablated the AICAR-induced increase in ACE2. In conclusion, we have established that the expression of the ACE2 transcript is controlled by the activity of SIRT1 under conditions of energy stress. PMID- 24147778 TI - Expression and purification of the extracellular domain of the human follicle stimulating hormone receptor using Escherichia coli. AB - AIM: Although much is known about the structure and biological functions of follicle-stimulating hormone (FSH) receptor (FSHR), the interaction of FSHR and FSH has been challenging to characterize due to the limited quantity of active FSHR protein produced by simple methods. The goal of this study was to express and purify the extracellular domain (ECD) of human FSHR (hFSHR). METHODS: Total RNA was isolated from normal human ovary tissue. cDNA for hFSHR ECD were amplified and subsequently ligated into the pET32a(+) vector. The plasmid vector construct was confirmed by polymerase chain reaction and sequencing. Expression in Escherichia coli Rosetta (DE3) pLysS strain was induced by isopropyl-thio-beta D-thiogalactoside, and the recombinant products were purified by immuno-affinity chromatography using an Ni-NTA and High-Q column. The recombinant protein was confirmed by western blotting. RESULTS: Following induction, E. coli expressed a recombinant protein of approximately 65 kDa in size, whereas the non-induced E. coli did not express the recombinant protein. The recombinant fragments purified using a High-Q column demonstrated a single band and an abundant yield. The recombinant protein was soluble and specifically recognized by an antibody for hFSHR. Additionally, four mutation sites were detected that resulted in amino acid shifts at position 112 Asn/Thr, 197 Glu/Ala, 198 Leu/Val and 307 Ala/Thr. CONCLUSION: The recombinant hFSHR ECD protein was expressed and purified. This method could be easily scaled for increased production and may facilitate additional applications utilizing FSHR in assisted reproductive technology, a contraceptive FSH vaccine and FSHR-targeted therapeutic agents used to treat ovarian cancer. PMID- 24147779 TI - In vitro antifungal susceptibility of clinical isolates of Arthrographis kalrae, a poorly known opportunistic fungus. AB - The in vitro antifungal activity of amphotericin B (AMB), itraconazole, voriconazole, posaconazole, terbinafine (TRB), caspofungin, anidulafungin and micafungin were evaluated by a broth microdilution technique against 22 isolates of Arthrographis kalrae of clinical origin. TRB showed the highest activity, followed by the azoles, particularly posaconazole. AMB exerted low activity whereas the echinocandins showed almost no antifungal activity. PMID- 24147781 TI - Cob gene pyrosequencing enables characterization of benthic dinoflagellate diversity and biogeography. AB - Dinoflagellates in marine benthic habitats living epiphytically on macroalgae are an important but highly understudied group of protists. Many produce toxins that can have severe economic impacts on marine-based economies, and improved monitoring tools are required to enhance the management of toxin-related hazards. We analysed the distribution and diversity of epibenthic dinoflagellates inhabiting eight sites in Cocos (Keeling) Islands, Papua New Guinea, and Broome and Exmouth, Western Australia. We used pyrosequencing approaches based on two DNA barcoding marker genes - 18S ribosomal RNA (rRNA) and mitochondrial cytochrome b (cob) - and compared these to an approach based on clone libraries (197 sequences) using the cob gene. Dinoflagellate sequences accounted for 133 [64 unique operational taxonomic units (OTU)] out of 10 529 18S rRNA gene sequences obtained from all samples. However, using the dinoflagellate specific assay targeting the cob gene marker, we obtained 9748 (1217 unique OTU) dinoflagellate sequences from the same environmental samples, providing the largest, to date, set of dinoflagellate cob gene sequences and reliable estimates of total dinoflagellate richness within the samples and biogeographic comparisons between samples. This study also reports the presence of potentially toxic species of the genera Gambierdiscus, Ostreopsis, Coolia, Prorocentrum and Amphidinium from the above-mentioned geographical regions. PMID- 24147780 TI - N-acetylgalactosamino dendrons as clearing agents to enhance liver targeting of model antibody-fusion protein. AB - Dendrimer clearing agents represent a unique class of compounds for use in multistep targeting (MST) in radioimmunotherapy and imaging. These compounds were developed to facilitate the removal of excess tumor-targeting monoclonal antibody (mAb) prior to administration of the radionuclide to minimize exposure of normal tissue to radiation. Clearing agents are designed to capture the circulating mAb, and target it to the liver for metabolism. Glycodendrons are ideally suited for MST applications as these highly branched compounds are chemically well-defined, thus advantageous over heterogeneous macromolecules. Previous studies have described glycodendron 3 as a clearing agent for use in three-step MST protocols, and early in vivo assessment of 3 showed promise. However, synthetic challenges have hampered its availability for further development. In this report we describe a new sequence of chemical steps which enables the straightforward synthesis and analytical characterization of this class of dendrons. With accessibility and analytical identification solved, we sought to evaluate both lower and higher generation dendrons for hepatocyte targeting as well as clearance of a model protein. We prepared a series of clearing agents where a single biotin is connected to glycodendrons displaying four, eight, sixteen or thirty-two alpha-thio-N-acetylgalactosamine (alpha-SGalNAc) units, resulting in compounds with molecular weights ranging from 2 to 17 kDa, respectively. These compounds were fully characterized by LCMS and NMR. We then evaluated the capacity of these agents to clear a model (131)I-labeled single chain variable fragment antibody-streptavidin ((131)I-scFv-SAv) fusion protein from blood and tissue in mice, and compared their clearing efficiencies to that of a 500 kDa dextran-biotin conjugate. Glycodendrons and dextran-biotin exhibited enhanced blood clearance of the scFv-SAv construct. Biodistribution analysis showed liver targeting/uptake of the scFv-SAv construct to be 2-fold higher for compounds 1 to 4, as well as for the 500 kDa dextran, over saline. Additionally, the data suggest the glycodendrons clear through the liver, whereas the dextran through reticuloendothelial system (RES) metabolism. PMID- 24147782 TI - Stabilizing Cu2S for photovoltaics one atomic layer at a time. AB - Stabilizing Cu2S in its ideal stoichiometric form, chalcocite, is a long-standing challenge that must be met prior to its practical use in thin-film photovoltaic (PV) devices. Significant copper deficiency, which results in degenerate p-type doping, might be avoided by limiting Cu diffusion into a readily formed surface oxide and other adjacent layers. Here, we examine the extent to which PV-relevant metal-oxide over- and underlayers may stabilize Cu2S thin films with desirable semiconducting properties. After only 15 nm of TiO2 coating, Hall measurements and UV-vis-NIR spectroscopy reveal a significant suppression of free charge carrier addition that depends strongly on the choice of deposition chemistry. Remarkably, the insertion of a single atomic layer of Al2O3 between Cu2S and TiO2 further stabilizes the active layer for at least 2 weeks, even under ambient conditions. The mechanism of this remarkable enhancement is explored by in situ microbalance and conductivity measurements. Finally, photoluminescence quenching measurements point to the potential utility of these nanolaminate stacks in solar energy harvesting applications. PMID- 24147784 TI - Two new schisdilactone-type compounds from Schisandra chinensis. AB - Two new schisdilactone-type compounds, respectively, named schisdilactone H (1) and schisdilactone I (2), were isolated from the stems of Schisandra chinensis. The structures and absolute configurations of these new compounds were elucidated by extensive spectroscopic analysis as well as time-dependent density functional theory electronic circular dichroism calculations. PMID- 24147785 TI - Response to 'Applying the ICMJE authorship criteria to operational research in low-income countries: the need to engage programme managers and policy makers' by Zachariah et al. (2013) TMIH 18, pp. 1025-1028. PMID- 24147783 TI - The GAFa domain of phosphodiesterase-6 contains a rod outer segment localization signal. AB - Photoreceptor phosphodiesterase-6 (PDE6) is a peripheral membrane protein synthesized in the inner segment of photoreceptor cells. Newly synthesized PDE6 is transported to the outer segment (OS) where it serves as a key effector enzyme in the phototransduction cascade. Proper localization of PDE6 in photoreceptors is critically important to the function and survival of photoreceptor cells. The mechanism of PDE6 transport to the OS remains largely unknown. In this study, we investigated potential OS targeting signals of PDE6 by constructing cGMP-binding, cGMP-specific phosphodiesterase-5/PDE6 chimeric proteins and analyzing their localization in rods of transgenic Xenopus laevis. We found that efficient OS localization of chimeric isoprenylated PDE enzymes required the presence of a targeting motif within the PDE6 GAFa domain. Furthermore, the GAFa-dependent localization signal was sufficient to target GAFa fusion protein to the OS. Our results support the idea that effective trafficking of the peripheral membrane proteins to the OS of photoreceptor cells requires a sorting/targeting motif in addition to a membrane-binding signal. PMID- 24147786 TI - OMICS in ecology: systems level analyses of Halobacterium salinarum reveal large scale temperature-mediated changes and a requirement of CctA for thermotolerance. AB - Halobacterium salinarum is an extremely halophilic archaeon that inhabits high salinity aqueous environments in which the temperature can range widely, both daily and seasonally. An OMICS analysis of the 37 degrees C and 49 degrees C proteomes and transcriptomes for revealing the biomodules affected by temperature is reported here. Analysis of those genes/proteins displaying dramatic changes provided a clue to the coordinated changes in the expression of genes within five arCOG biological clusters. When proteins that exhibited minor changes in their spectral counts and insignificant p values were also examined, the apparent influence of the elevated temperatures on conserved chaperones, metabolism, translation, and other biomodules became more obvious. For instance, increases in all eight conserved chaperones and three arginine deiminase pathway enzymes and reductions in most tricarboxylic acid (TCA) cycle enzymes and ribosomal proteins suggest that complex system responses occurred as the temperature changed. When the requirement for the four proteins that showed the greatest induction at 49 degrees C was analyzed, only CctA (chaperonin subunit alpha), but not Hsp5, DpsA, or VNG1187G, was essential for thermotolerance. Environmental stimuli and other perturbations may induce many minor gene expression changes. Simultaneous analysis of the genes exhibiting dramatic or minor changes in expression may facilitate the detection of systems level responses. PMID- 24147787 TI - Facial soft tissue depth statistics and enhanced point estimators for craniofacial identification: the debut of the shorth and the 75-shormax. AB - Several methods that have customarily been used in craniofacial identification to describe facial soft tissue depths (FSTDs) implore improvement. They include the calculation of arithmetic means for skewed data, omission of concern for measurement uncertainty, oversight of effect size, and misuse of statistical significance tests (e.g., p-values for strength of association). This paper redresses these limitations using FSTDs from 10 prior studies (N = 516). Measurement uncertainty was large (>20% of the FSTD), skewness (>= 0.8) existed at 11 of the 23 FSTD landmarks examined, and sex and age each explained <4% of the total FSTD variance (eta(2) calculated as part of MANOVA). These results call for a new and improved conceptualization of FSTDs, which is attained by the replacement of arithmetic means with shorths and 75-shormaxes. The outcomes of this implementation are dramatic reduction in FSTD complexity; improved data accuracy; and new data-driven standards for casework application of methods. PMID- 24147789 TI - Synthesis and reactivity of new bis(N-heterocyclic carbene) iridium(I) complexes. AB - New complexes of the type trans-[IrCl(eta(2)-COE)(NHC)2] (COE = cis-cyclooctene; NHC = N-heterocyclic carbene) have been prepared in one step from the reaction of ca. 4 equiv of NHC or [AgCl(NHC)] with [IrCl(eta(2)-COE)2]2 in benzene. These new complexes have been characterized by techniques including NMR and IR spectroscopy, X-ray crystallography, and elemental analysis. Exposing trans [IrCl(COE)(I(i)Pr(Me))2] to CO yielded trans-[IrCl(CO)(I(i)Pr(Me))2], which is the only bis(NHC) analogue of Vaska's complex trans-[IrCl(CO)(PPh3)2] known to date. The synthesis of trans-[Ir(CO)(I(i)Pr(Me))2(R)] (R = MeO, PhCC, OSiPh3, O2CPh) complexes has been achieved via deprotonation reactions involving the new hydroxide species trans-[Ir(OH)(CO)(I(i)Pr(Me))2]. PMID- 24147788 TI - A multi-colour/multi-affinity marker set to visualize phosphoinositide dynamics in Arabidopsis. AB - Phosphatidylinositolphosphates (PIPs) are phospholipids that contain a phosphorylated inositol head group. PIPs represent a minor fraction of total phospholipids, but are involved in many regulatory processes, such as cell signalling and intracellular trafficking. Membrane compartments are enriched or depleted in specific PIPs, providing a unique composition for these compartments and contributing to their identity. The precise subcellular localization and dynamics of most PIP species is not fully understood in plants. Here, we designed genetically encoded biosensors with distinct relative affinities and expressed them stably in Arabidopsis thaliana. Analysis of this multi-affinity 'PIPline' marker set revealed previously unrecognized localization of various PIPs in root epidermis. Notably, we found that PI(4,5)P2 is able to localize PIP2 -interacting protein domains to the plasma membrane in non-stressed root epidermal cells. Our analysis further revealed that there is a gradient of PI4P, with the highest concentration at the plasma membrane, intermediate concentration in post Golgi/endosomal compartments, and the lowest concentration in the Golgi. Finally, we also found a similar gradient of PI3P from high in late endosomes to low in the tonoplast. Our library extends the range of available PIP biosensors, and will allow rapid progress in our understanding of PIP dynamics in plants. PMID- 24147790 TI - Fatty acids with in vitro binding affinity for human opioid receptors from the fungus Emericella nidulans. AB - Bioassay-guided fractionation of the EtOAc extracts of the epiphytic fungus Emericella nidulans resulted in the isolation of a mixture of two fatty acids. This mixture showed 98% binding affinity to human delta opioid receptor. These two fatty acids were identified as palmitic (PAM), 1, and linoleic acids (LNA), 2, by 1D NMR as well as by GC/MS analysis, after their methylation. We found that different ratio mixtures of 1 and 2 showed variations in selective binding activities to human delta opioid receptors. Five more fatty acids, arachidonic acid (ARA), 3, cis-4,7,10,13,16,19-docosahexanoic acid (DHA), 4, cis-5,8,11,14,17 eicosapentaenoic acid (EPA), 5, linolenic acid (ALA), 6, and gamma-linolenic acid (GLA), 7, were evaluated for their binding affinity for opioid receptors. ARA, 3, displayed affinity to delta and MU human opioid receptors with 68% and 80%, respectively. GLA, 7, showed selective binding affinity to MU receptor with a value of 55%. These findings provide fascinating insight into the use of foods with high concentrations of fatty acids. PMID- 24147791 TI - In-hospital heart rate turbulence and microvolt T-wave alternans abnormalities for prediction of early life-threatening ventricular arrhythmia after acute myocardial infarction. AB - BACKGROUND: In the setting of primary prevention, most implantable cardiac defibrillators (ICD) are implanted more than 6 months after acute myocardial infarction (AMI). Abnormal heart rate turbulence (HRT) and T-wave alternans (TWA) are predictors of long-term sudden cardiac death (SCD). We intended to assess the predictive value of HRT and TWA for early post-AMI SCD and life-threatening ventricular arrhythmias (VA). METHODS: One hundred ninety-nine consecutive patients with AMI were prospectively included (age 61.7 years, LV ejection fraction 45%). One hundred eighty-three patients (92%) underwent percutaneous coronary intervention. We assessed HRT using turbulence slope (TS), turbulence onset (TO), and TWA on channels 1 and 2 (TWA1 and TWA2) using the modified moving average method. Predictive performance for SCD/VA was assessed by area under the receiver operating curve characteristic (ROC-AUC). RESULTS: Within 6 months after AMI, 2 patients (1%) developed life-threatening VA and 3 (1.5%) experienced SCD. TO and TWA1 had poor ROC-AUC (both 0.64) whereas TS and TWA2 failed to show any predictive performance (ROC-AUC 0.48 and 0.57, respectively). When combining TO and TWA1, ROC-AUC increased to 0.80. Importantly, when considering the subset of patients with a LV ejection fraction <=40%, the combined variable of TO and TWA1 remained strongly predictive of a short-term event (ROC-AUC 0.86). CONCLUSIONS: Combined assessment of HRT and TWA showed a high predictive performance for SCD or life-threatening VA within 6 months after AMI. This combined Holter ECG index could be useful to identify high-risk patients who might benefit from early ICD implantation. PMID- 24147792 TI - Multivariable evaluation of term birth weight: a comparison between ultrasound biometry and symphysis-fundal height. AB - OBJECTIVE: To derive a birth weight predictive equation and to compare its diagnostic value with that of ultrasound. METHODS: A longitudinal observational cohort study, including singleton pregnancies at term, was performed at St. Orsola-Malpighi Hospital, University of Bologna (Italy). A birth weight prediction formula, including symphysis-fundal height (SFH), BMI, maternal abdominal circumference (mAC) and parity was derived from a general linear model (GLM) (retrospective study). Moreover, on a new series of patients, the fetal weight was estimated by using both GLM and ultrasound using Hadlock formula (prospective study). The residual analysis and the intraclass correlation coefficient (ICC) were used to test the accuracy of methods in predicting birth weight. RESULTS: Between January and November 2012, 1034 patients were included in the retrospective study and 44 in the prospective one. The following GLM was derived: estimated birth weight (g) = 1485.61 + (SFH (cm) * 23.37) + (11.62 (cm) * mAC) + [BMI * (-6.81)] + (parity (0 = nulliparous, 1 = multiparous) * 72.25). When prospectively applied, the GLM and ultrasound provided a percentage of prediction within +/-10% of the actual weight of 73% and 84%, respectively. Ultrasound estimation, as opposite of GLM one, was significantly associated with neonatal weight (R(2 )= 0.388, F = 26.607, p value <0.001, ICC = 0.767). CONCLUSIONS: Although ultrasound biometry has provided the best values in fetal weight estimation, the predictive performance of both methods is limited. PMID- 24147793 TI - Retinal blood flow velocity in patients with age-related macular degeneration. AB - PURPOSE/AIM OF THE STUDY: To study changes in retinal blood flow velocity in patients with early and neovascular age-related macular degeneration (AMD). We used the Retinal Function Imager (RFI, Optical Imaging Ltd., Rehovot, Israel), a noninvasive diagnostic approach for measuring blood flow velocity. MATERIALS AND METHODS: Sixty eyes of 43 AMD patients and 53 eyes of 35 healthy individuals over the age of 50 were recruited for this study. All patients were scanned by the RFI with analysis of blood flow velocity of secondary and tertiary branches of arteries and veins. Differences among groups were assessed by mixed linear models. RESULTS: The average velocity in AMD patients was significantly lower compared to controls in arteries (3.6 +/- 1.4 versus 4.3 +/- 1.0 mm/sec, p = 0.009) but not in veins (2.6 +/- 0.9 versus 3.1 +/- 0.6 mm/sec, p = 0.08). When comparing the velocity between low- and high-grade AMD eyes, venous velocity was slower in the high grade AMD eyes only in the "narrow" group of vessels. CONCLUSIONS: Decreased blood flow velocity in retinal arteries in patients with AMD was found. Despite the fact that AMD is essentially a choroidal disease, retinal vessels show a functional abnormality, which may suggest that the vascular abnormality in this disease is more generalized. PMID- 24147795 TI - Radiation stability of cations in ionic liquids. 2. Improved radiation resistance through charge delocalization in 1-benzylpyridinium. AB - Hydrophobic room-temperature ionic liquids (ILs) hold promise as replacements for molecular diluents for processing of used nuclear fuel as well as for the development of alternative separations processes, provided that the solvent can be made resistant to ionizing radiation. We demonstrate that 1-benzylpyridinium cations are uniquely suited as radiation resistant cations due to the occurrence of charge delocalization in both their reduced and oxidized forms in the ILs. It is suggested that the excess electron and hole in the latter ILs are stabilized through the formation of pi-electron sandwich dimers that are analogous to the well-known dimer radical cations of aromatic molecules. This charge delocalization dramatically reduces the yield of fragmentation by deprotonation and the loss of benzyl arms, thereby providing a synthetic path to radiation resistant ILs that are suitable for nuclear fuel processing. PMID- 24147794 TI - Wake-up call for China to re-evaluate its shale-gas ambition. PMID- 24147797 TI - Tourniquet device for hemorrhage control during cesarean section of complete placenta previa pregnancies. AB - AIM: To reduce massive and potentially fatal hemorrhage during cesarean section (CS) delivery because of the transverse incision through the lower uterine segment and placenta in central placenta previa (CPP), especially the type in which the placenta attaches to the anterior wall of the uterus. METHODS: Thirty four patients with CPP were enrolled in the study and 14 of them accepted the tourniquet method. The main outcome evaluations were blood loss, the proportion of red blood cell-transfused patients, the need for other hemostatic procedures and complications in either the mother or infant after the completion of the tourniquet procedure. RESULTS: A statistically significant benefit was noted between the two groups of the frequency of post-partum hemorrhage (PPH), the median estimated blood loss and the proportion of transfused patients. The effectiveness of the tourniquet method could be further proved by the relative risk with confidence intervals for PPH data and additional procedures. CONCLUSION: The clinical data of 34 patients show that this is an effective surgical treatment to reduce blood loss and suggest that there is negligible harm to patients and fetuses. PMID- 24147796 TI - Holmium laser enucleation of the prostate is safe in patients with prostate cancer and lower urinary tract symptoms--a retrospective feasibility study. AB - OBJECTIVE: To evaluate the outcome of holmium laser enucleation of the prostate (HoLEP) in the known presence of prostate cancer (PCa) and concomitant lower urinary tract symptoms (LUTS). PATIENTS AND METHODS: We retrospectively identified 62 patients who underwent HoLEP for LUTS in the known presence of PCa at our center. Perioperative data were assessed including complications, functional outcomes, and quality of life (QoL). Giving respect to different disease characteristics, patients were stratified according to treatment strategy setting into palliative (I), radiation (II), and surveillance (III) groups and compared accordingly. RESULTS: Median follow-up (FU) of the entire study cohort was 27 months (range 2-65 mos). Medians of functional parameters (International Prostate Symptom Score): 18.5 vs 4.5, QoL: 4 vs 1, maximal flow rate: 9.0 vs 18.8 mL/s and residual urine: 100 vs 0 mL, all P<0.05) improved significantly in all groups. Perioperative complications were low and without any statistically significant difference between the groups. Postoperatively, voiding was successful in 90.3% of all patients; at last FU, 17% had some degree of urinary incontinence. Treatment strategy groups showed comparable functional outcomes after HoLEP. CONCLUSION: In the presence of PCa and LUTS, HoLEP represents a feasible, safe, and effective treatment option for patients unfit or without indication for radical prostatectomy. This applies as well in a palliative situation of advanced, obstructive PCa as for patients with LUTS who are scheduled for radiation therapy or surveillance in presumably indolent disease. PMID- 24147798 TI - Synthesis of multifunctional PAMAM-aminoglycoside conjugates with enhanced transfection efficiency. AB - The development of multifunctional vectors for efficient and safe gene delivery is one of the major challenges for scientists working in the gene therapy field. In this context, we have designed a novel type of aminoglycoside-rich dendrimers with a defined structure based on polyamidoamine (PAMAM) in order to develop efficient, nontoxic gene delivery vehicles. Three different conjugates, i.e., PAMAM G4-neamine, -paromomycin, and -neomycin, were synthesized and characterized by nuclear magnetic resonance (NMR) and MALDI analysis. The conjugates were found to self-assemble electrostatically with plasmid DNA, and unlike neamine conjugate, each at its optimum showed increased gene delivery potency compared to PAMAM G4 dendrimer in three different cell lines, along with negligible cytotoxicity. These results all disclosed aminoglycosides as suitable functionalities for tailoring safe and efficient multifunctional gene delivery vectors. PMID- 24147799 TI - Total synthesis of (+)-clavilactone A and (-)-clavilactone B by ring-opening/ring closing metathesis. AB - The enantioselective total synthesis of natural enantiomers of clavilactones A and B has been achieved. A key feature of the synthesis is the use of a ring opening/ring-closing metathesis, which allows the one-pot transformation of a strained cyclobutenecarboxylate into a gamma-butenolide. PMID- 24147801 TI - Thermochemical evidence for strong iodine chemisorption by ZIF-8. AB - For the first time, using aqueous solution calorimetry, we clearly identify the chemisorption of an unusually strong iodine charge-transfer (CT) complex within the cages of a metal-organic framework. Specifically, we studied the sorption of iodine gas in zeolitic imidazolate framework-8 (ZIF-8, Zn(2-methylimidazolate)2). Two iodine-loaded ZIF-8 samples were examined. The first, before thermal treatment, contained 0.17 I2/Zn on the surface and 0.59 I2/Zn inside the cage. The second sample was thermally treated, leaving only cage-confined iodine, 0.59 I2/Zn. The energetics of iodine confinement per I2 (relative to solid I2) in ZIF 8 are DeltaHads = -41.47 +/- 2.03 kJ/(mol I2) within the cage and DeltaHads = 18.06 +/- 0.62 kJ/(mol I2) for surface-bound iodine. The cage-confined iodine exhibits a 3-fold increase in binding energy over CT complexes on various organic adsorbents, which show only moderate exothermic heats of binding, from -5 to -15 kJ/(mol I2). The ZIF-8 cage geometry allows each iodine atom to form two CT complexes between opposing 2-methylimidazolate linkers, creating the ideal binding site to maximize iodine retention. PMID- 24147800 TI - Cytokine mRNA expression in bronchoalveolar lavage cells during Dictyocaulus viviparus infection in calves. AB - The purpose of this study was to monitor local cytokine responses to Dictyocaulus viviparus in calves during primary infection and re-infection. Bronchoalveolar lavage fluid (BALF) was collected weekly from experimentally infected calves and interleukin-2 (IL-2), IL-4, IL-5, IL-10 and IFN-gamma mRNA expression was quantified in BALF cells. The major finding was a prominent transient increase in IL-4 mRNA expression, compared with that of uninfected calves, observed in BALF cells collected 2-3 weeks post-primary D. viviparus infection. At 2 weeks post infection, macroscopic worms were also first observed in BALF. Calves re-infected after 10 weeks were partially immune which was evident at slaughter 5 weeks post infection as a lower worm burden than in previously naive calves infected at the same time. IL-4 mRNA expression in BALF cells 2 weeks post-re-infection was increased compared with that of uninfected animals but not as high as that of primarily infected calves. BALF cell expression of the other cytokines tested for was not as clearly effected by the D. viviparus infection. It seems likely that the strong IL-4 response observed during primary infection reflects an innate response to the worms that may initiate an ensuing Th2 response, which confers protective immunity. PMID- 24147802 TI - The novel allele, HLA-DQB1*02:27, identified in a German cord blood donor and his mother. PMID- 24147803 TI - Quantification of insulin. PMID- 24147804 TI - Discovery of a potent inhibitor of replication protein a protein-protein interactions using a fragment-linking approach. AB - Replication protein A (RPA), the major eukaryotic single-stranded DNA (ssDNA) binding protein, is involved in nearly all cellular DNA transactions. The RPA N terminal domain (RPA70N) is a recruitment site for proteins involved in DNA damage response and repair. Selective inhibition of these protein-protein interactions has the potential to inhibit the DNA-damage response and to sensitize cancer cells to DNA-damaging agents without affecting other functions of RPA. To discover a potent, selective inhibitor of the RPA70N protein-protein interactions to test this hypothesis, we used NMR spectroscopy to identify fragment hits that bind to two adjacent sites in the basic cleft of RPA70N. High resolution X-ray crystal structures of RPA70N-ligand complexes revealed how these fragments bind to RPA and guided the design of linked compounds that simultaneously occupy both sites. We have synthesized linked molecules that bind to RPA70N with submicromolar affinity and minimal disruption of RPA's interaction with ssDNA. PMID- 24147805 TI - Long-term psychosocial impact reported by childhood critical illness survivors: a systematic review. AB - AIM: To undertake a qualitative systematic review that explores psychological and social impact, reported directly from children and adolescents at least 6 months after their critical illness. BACKGROUND: Significant advances in critical care have reduced mortality from childhood critical illness, with the majority of patients being discharged alive. However, it is widely reported that surviving critical illness can be traumatic for both children and their family. Despite a growing body of literature in this field, the psychological and social impact of life threatening critical illness on child and adolescent survivors, more than 6 months post event, remains under-reported. DATA SOURCES: Searches of six online databases were conducted up to February 2012. REVIEW METHODS: Predetermined criteria were used to select studies. Methodological quality was assessed using a standardized checklist. An adapted version of the thematic synthesis approach was applied to extract, code and synthesize data. FINDINGS: Three studies met the inclusion criteria, which were all of moderate methodological quality. Initial coding and synthesis of data resulted in five descriptive themes: confusion and uncertainty, other people's narratives, focus on former self and normality, social isolation and loss of identity, and transition and transformation. Further synthesis culminated in three analytical themes that conceptualize the childhood survivors' psychological and social journey following critical illness. CONCLUSIONS: Critical illness in childhood can expose survivors to a complex trajectory of recovery, with enduring psychosocial adversity manifesting in the long term. Nurses and other health professionals must be aware and support the potential multifaceted psychosocial needs that may arise. Parents and families are identified as fundamental in shaping psychological and social well-being of survivors. Therefore intensive care nurses must take opportunities to raise parents' awareness of the journey of survival and provide appropriate support. Further empirical research is warranted to explore the deficits identified with the existing literature. PMID- 24147807 TI - Sarcolemmal specific collagen VI deficient myopathy in a Labrador Retriever. PMID- 24147808 TI - Neuronal electrophysiological function and control of neurite outgrowth on electrospun polymer nanofibers are cell type dependent. AB - Modeling of cellular environments with nanofabricated biomaterial scaffolds has the potential to improve the growth and functional development of cultured cellular models, as well as assist in tissue engineering efforts. An understanding of how such substrates may alter cellular function is critical. Highly plastic central nervous system hippocampal cells and non-network forming peripheral nervous system dorsal root ganglion (DRG) cells from embryonic rats were cultured upon laminin-coated degradable polycaprolactone (PCL) and nondegradable polystyrene (PS) electrospun nanofibrous scaffolds with fiber diameters similar to those of neuronal processes. The two cell types displayed intrinsically different growth patterns on the nanofibrous scaffolds. Hippocampal neurites grew both parallel and perpendicular to the nanofibers, a property that would increase neurite-to-neurite contacts and maximize potential synapse development, essential for extensive network formation in a highly plastic cell type. In contrast, non-network-forming DRG neurons grew neurites exclusively along fibers, recapitulating the simple direct unbranching pathway between sensory ending and synapse in the spinal cord that occurs in vivo. In addition, the two primary neuronal types showed different functional capacities under patch clamp testing. The substrate composition did not alter the neuronal functional development, supporting electrospun PCL and PS as candidate materials for controlled cellular environments in culture and electrospun PCL for directed neurite outgrowth in tissue engineering applications. PMID- 24147810 TI - Neuronal cytoskeleton in synaptic plasticity and regeneration. AB - During development, dynamic changes in the axonal growth cone and dendrite are necessary for exploratory movements underlying initial axo-dendritic contact and ultimately the formation of a functional synapse. In the adult central nervous system, an impressive degree of plasticity is retained through morphological and molecular rearrangements in the pre- and post-synaptic compartments that underlie the strengthening or weakening of synaptic pathways. Plasticity is regulated by the interplay of permissive and inhibitory extracellular cues, which signal through receptors at the synapse to regulate the closure of critical periods of developmental plasticity as well as by acute changes in plasticity in response to experience and activity in the adult. The molecular underpinnings of synaptic plasticity are actively studied and it is clear that the cytoskeleton is a key substrate for many cues that affect plasticity. Many of the cues that restrict synaptic plasticity exhibit residual activity in the injured adult CNS and restrict regenerative growth by targeting the cytoskeleton. Here, we review some of the latest insights into how cytoskeletal remodeling affects neuronal plasticity and discuss how the cytoskeleton is being targeted in an effort to promote plasticity and repair following traumatic injury in the central nervous system. PMID- 24147809 TI - Cognitive processes as mediators of the relation between mindfulness and change in social anxiety symptoms following cognitive behavioral treatment. AB - The present study examined whether pretreatment mindfulness exerts an indirect effect on outcomes following cognitive-behavioral therapy (CBT). Cognitive processes of probability and cost bias (i.e., overestimations of the likelihood that negative social events will occur, and that these events will have negative consequences when they do occur) were explored as potential mediators of the relation between mindfulness and social anxiety symptom change. People with higher levels of mindfulness may be better able to benefit from treatments that reduce biases because mindfulness may aid in regulation of attention. Sixty-seven individuals with a primary diagnosis of social phobia identifying public speaking as their greatest fear received eight sessions of one of two types of exposure based CBT delivered according to treatment manuals. Participants completed self report measures of mindfulness, probability bias, cost bias, and social anxiety symptoms. Mediation hypotheses were assessed by a bootstrapped regression using treatment outcome data. Pretreatment mindfulness was not related to change in social anxiety symptoms from pre- to posttreatment. However, mindfulness had an indirect effect on treatment outcome via its association with probability bias, but not cost bias, at midtreatment. These findings were consistent across three metrics of social anxiety symptoms. Mindfulness may play a role in response to CBT among individuals with social phobia through its relation with probability bias--even when the treatment does not target mindfulness. PMID- 24147811 TI - Inhibition of platelet activation by lachrymatory factor synthase (LFS)-silenced (tearless) onion juice. AB - Onion and garlic are renowned for their roles as functional foods. The health benefits of garlic are attributed to di-2-propenyl thiosulfinate (allicin), a sulfur compound found in disrupted garlic but not found in disrupted onion. Recently, onions have been grown with repressed lachrymatory factor synthase (LFS) activity, which causes these onions to produce increased amounts of di-1 propenyl thiosulfinate, an isomer of allicin. This investigation into the key health attributes of LFS-silenced (tearless) onions demonstrates that they have some attributes more similar to garlic and that this is likely due to the production of novel thiosulfinate or metabolites. The key finding was that collagen-induced in vitro platelet aggregation was significantly reduced by tearless onion extract over normal onion extract. Thiosulfinate or derived compounds were shown not to be responsible for the observed changes in the inflammatory response of AGS (stomach adenocarcinoma) cells to tumor necrosis factor alpha (TNFalpha) when pretreated with model onion juices. A preliminary rat feeding trial indicated that the tearless onions may also play a key role in reducing weight gain. PMID- 24147812 TI - A de novo novel cardiac ryanodine mutation (Ser4155Tyr) associated with catecholaminergic polymorphic ventricular tachycardia. AB - We describe the case of a 14-year-old girl with a history of syncopal episodes triggered by stress or exercise. Catecholaminergic polymorphic ventricular tachycardia was diagnosed with the aid of an implantable loop recorder. The genetic testing of the patient and her family revealed a de novo novel missense mutation (Ser4155Tyr) in the exon 90 of the ryanodine receptor gene. This mutation affects a highly conserved residue (S4155) and results to replacement of serine (S) with tyrosine (Y) leading to change in physical and chemical properties. The girl was treated with an implantable defibrillator, metoprolol and flecainide. Over 1 year of follow-up she had no recurrence of ventricular tachycardia. PMID- 24147813 TI - Detection of anthrax and other pathogens using a unique liquid array technology. AB - A bead-based liquid hybridization assay, Luminex((r)) 100TM, was used to identify four pathogenic bacteria, Bacillus anthracis, Clostridium botulinum, Francisella tularensis subsp. tularensis, and Yersinia pestis, and several close relatives. Hybridization between PCR-amplified target sequences and probe sequences (located within the 23S ribosomal RNA gene rrl and the genes related to the toxicity of each bacterium) was detected in single-probe or multiple-probe assays, depending on the organism. The lower limits of detection (LLDs) for the probes ranged from 0.1 to 10 ng. Sensitivity was improved using lambda exonuclease to digest the noncomplementary target strand. All contributors in 33 binary, ternary, and quaternary mixtures in which all components were present in a 1:1 ratio were identified with an 80% success rate. Twenty-eight binary mixtures in which the two components were combined in various ratios were further studied. All target sequences were detected, even when the minor component was overshadowed by a tenfold excess of the major component. PMID- 24147814 TI - Parasites of freshwater fishes in North America: why so neglected? AB - Fish parasitology has a long tradition in North America and numerous parasitologists have contributed considerably to the current knowledge of the diversity and biology of protistan and metazoan parasites of freshwater fishes. The Journal of Parasitology has been essential in disseminating this knowledge and remains a significant contributor to our understanding of fish parasites in North America as well as more broadly at the international level. However, with a few exceptions, the importance of fish parasites has decreased during the last decades, which is reflected in the considerable decline of funding and corresponding decrease of attention paid to these parasites in Canada and the United States of America. After the 'golden age' in the second half of the 20th Century, fish parasitology in Canada and the United States went in a new direction, driven by technology and a shift in priorities. In contrast, fish parasitology in Mexico has undergone rapid development since the early 1990s, partly due to extensive international collaboration and governmental funding. A critical review of the current data on the parasites of freshwater fishes in North America has revealed considerable gaps in the knowledge of their species composition, host specificity, life cycles, evolution, phylogeography, and relationships with their fish hosts. As to the key question, "Why so neglected?" this is probably because: (1) fish parasites are not in the forefront due to their lesser economic importance; (2) there is little funding for this kind of research, especially if a practical application is not immediately apparent; and (3) of shifting interests and a shortage of key personalities to train a new generation (they switched to marine habitats or other fields). Some of the opportunities for future research are outlined, such as climate change and cryptic species diversity. A significant problem challenging future research seems to be the loss of trained and experienced fish parasitologists. This has 2 major ramifications: the loss of expertise in identifying organisms that other biologists (e.g., ecologists, molecular biologists, evolutionists) work with, and an incomplete comprehension of ecosystem structure and function in the face of climate change, emerging diseases, and loss of biodiversity. PMID- 24147815 TI - Paramagnetic hexacyanometalates. The diversity of spin distribution studied by 13C and 15N MAS NMR spectroscopy. AB - With the aim of probing the spin density distribution in the open-shell cyanometallates Cs2K[M(CN)6] (M = Cr, Mn, Fe), K3[M(CN)6] (M = Mn, Fe), K4[M(CN)6] (M = Cr, Mn), and K4[V(CN)7] have been studied by solid-state (13)C and (15)N NMR spectroscopy. The signals appear in strongly shifted and broad ranges ((13)C, -2100 to -8900 ppm; (15)N, -1900 to 2400 ppm) except K4[V(CN)7], which is NMR-silent. Analysis of the isotropic signal shifts yields negative spin density in all carbon 2s orbitals (up to 12.2% at the six ligands of [Mn(CN)6](3 )) and positive spin density in all nitrogen 2s orbitals (up to 1.1% at the six ligands of [Mn(CN)6](4-) and [Fe(CN)6](3-)). This is in accord with the induction of alternating spin at the CN ligands by successive polarization of sigma bonds triggered by the spin center M(n+). The signal shift anisotropies are related to spin in the carbon and nitrogen 2ppi and 2psigma orbitals. In the case of Cs2K[Cr(CN)6] and K4[Cr(CN)6] much positive spin is found in the nitrogen 2ppi orbitals, which corresponds to direct M -> N spin transfer. On Cs2K[M(CN)6] (M = Mn, Fe), the 2ppi spin density at nitrogen is negative. The results are in accord with and extend the data of polarized neutron diffraction and EPR spectroscopy. Owing to high signal resolution, small deviations of the [M(CN)6](n-) ions from octahedral symmetry and disorder of crystal layers have been detected. This corresponds to the crystal symmetry and to Jahn-Teller distortion. The disorder entails a scatter of spin densities. In the case of K4[Mn(CN)6] it reaches 19% for the C 2s orbitals and 80% for the N 2s orbitals with regard to the respective smallest spin population. PMID- 24147816 TI - Molecular grafting onto a stable framework yields novel cyclic peptides for the treatment of multiple sclerosis. AB - Multiple sclerosis (MS) is an inflammatory disease of the central nervous system (CNS) and is characterized by the destruction of myelin and axons leading to progressive disability. Peptide epitopes from CNS proteins, such as myelin oligodendrocyte glycoprotein (MOG), possess promising immunoregulatory potential for treating MS; however, their instability and poor bioavailability is a major impediment for their use clinically. To overcome this problem, we used molecular grafting to incorporate peptide sequences from the MOG35-55 epitope onto a cyclotide, which is a macrocyclic peptide scaffold that has been shown to be intrinsically stable. Using this approach, we designed novel cyclic peptides that retained the structure and stability of the parent scaffold. One of the grafted peptides, MOG3, displayed potent ability to prevent disease development in a mouse model of MS. These results demonstrate the potential of bioengineered cyclic peptides for the treatment of MS. PMID- 24147817 TI - Sedentary behaviors in fifth-grade boys and girls: where, with whom, and why? AB - BACKGROUND: An understanding of the context surrounding screen- and non-screen based sedentary behavior would facilitate efforts to reduce children's overall sedentary behavior. This study examined the prevalence of specific types of sedentary behavior in children, the social and physical contexts surrounding these behaviors, and differences by gender. METHODS: Participants included 686 fifth graders participating in the Transitions and Activity Changes in Kids Study (TRACK). The Physical Activity Choices instrument measured child participation in seven sedentary behaviors, the social (i.e., with whom) and physical (i.e., where) contexts, and perceptions (i.e., why) of those behaviors. Analysis included mixed-model regression adjusted for race/ethnicity, BMI, and socioeconomic status. RESULTS: Children participated in both screen- and non screen-based sedentary behaviors at very high frequencies. The most popular activities included watching television or videos, listening to music, playing video games (boys only), and talking on the phone or texting (girls only). Children engaged in sedentary behaviors most often at home, at school, or in their neighborhood. In general, the patterns of social context for the behaviors were similar for boys and girls, with the exception of video game playing. Girls perceived listening to music and talking on the phone or texting to be more fun than boys; children did not differ in their other perceptions (i.e., how much choice or how important) of the behaviors. CONCLUSIONS: Multi-level interventions that target reducing sedentary behavior in the home, neighborhood, and school context may be most effective; however, the approach needed will likely differ by gender. PMID- 24147819 TI - Exploring the Arabidopsis sulfur metabolome. AB - Sulfur plays a crucial role in protein structure and function, redox status and plant biotic stress responses. However, our understanding of sulfur metabolism is limited to identified pathways. In this study, we used a high-resolution Fourier transform mass spectrometric approach in combination with stable isotope labeling to describe the sulfur metabolome of Arabidopsis thaliana. Databases contain roughly 300 sulfur compounds assigned to Arabidopsis. In comparative analyses, we showed that the overlap of the expected sulfur metabolome and the mass spectrometric data was surprisingly low, and we were able to assign only 37 of the 300 predicted compounds. By contrast, we identified approximately 140 sulfur metabolites that have not been assigned to the databases to date. We used our method to characterize the gamma-glutamyl transferase mutant ggt4-1, which is involved in the vacuolar breakdown of glutathione conjugates in detoxification reactions. Although xenobiotic substrates are well known, only a few endogenous substrates have been described. Among the specifically altered sulfur-containing masses in the ggt4-1 mutant, we characterized one endogenous glutathione conjugate and a number of further candidates for endogenous substrates. The small percentage of predicted compounds and the high proportion of unassigned sulfur compounds identified in this study emphasize the need to re-evaluate our understanding of the sulfur metabolome. PMID- 24147818 TI - Parental concerns about weight-based victimization in youth. AB - BACKGROUND: The present study aimed to assess parental perceptions of weight based victimization (WBV) and its consequences for children's health as well as how perceptions of WBV vary by parental and child weight status. METHODS: A national sample of American parents with children ages 2-18 years (N=918) completed an online questionnaire to assess their perceptions of how common WBV is, compared to other forms of victimization among youth, their level of concern with this issue both generally and for their own child, and their perceptions of behavioral and psychological consequences of WBV. Descriptive statistics and censored regression models with standardized coefficients were used to analyze the data. RESULTS: Fifty-three percent of parents perceived "being overweight" to be the most common reason that youth are bullied, regardless of parental or child weight status. Parents, both with and without overweight children, endorsed similar levels of general concern about WBV and its psychological and behavioral consequences for youth. However, parents with overweight children were substantially more concerned about WBV affecting their child(ren) and perceived it to be more common, serious, and posed risks to their child(ren)'s health, compared to parents without overweight children. CONCLUSIONS: The present study, to the best of the authors' knowledge, is the first to indicate that parents have substantial concerns about WBV and its health consequences for youth. These findings highlight the need for educators and pediatric healthcare providers to be aware that WBV is a common concern among families, and suggest that increased efforts are needed to address WBV. PMID- 24147820 TI - The clinical research office of the endourological society ureteroscopy global study: indications, complications, and outcomes in 11,885 patients. AB - PURPOSE: To assess the current indications for ureteroscopy (URS) treatment, outcome in terms of stone-free rate, and intra- and postoperative complications using the modified Clavien grading system. PATIENTS AND METHODS: The Clinical Research Office of the Endourological Society collected prospective data as part of the URS Global Study for consecutive patients treated with URS at centers around the world for 1 year. URS was performed according to study protocol and local clinical practice guidelines. The stone size and location were recorded and postoperative outcome and complications, graded according to the modified Clavien grading system, reported. RESULTS: Between January 2010 and October 2012, 11,885 patients received URS at 114 centers in 32 countries; 1852 had only renal stones, 8676 had only ureteral stones, and 1145 patients had both types of stone. Fragmentation was performed principally using a laser device (49.0%) or a pneumatic device (30.3%); no device was used in 17.9% of the patients. A high stone-free rate (85.6%) was achieved. The large majority of patients did not receive any further treatment for renal or ureter stones (89.4%). The postoperative complication rate was low (3.5%). The most frequent complication was fever (1.8%); a blood transfusion was required in 0.2% of patients. The majority of complications were Clavien grade I or II (2.8% of patients). CONCLUSION: URS is an established minimal invasive treatment for urinary stones with a high success rate and low morbidity. Recent advances have expanded the indication for urinary stones, which now ranges from treatment of smaller sized distal ureter stones by semirigid URS to larger sized renal pelvis stones treated by flexible URS. PMID- 24147821 TI - Complementarities of water-focused life cycle assessment and water footprint assessment. PMID- 24147822 TI - Comparison of patient-controlled analgesia versus continuous infusion of tramadol in post-cesarean section pain management. AB - AIM: To evaluate and compare analgesic efficacy, drug consumption and patient satisfaction with the i.v. patient-controlled and continuous infusion modes of administration of tramadol. METHODS: A total of 40 pregnant women in American Society of Anesthesiologists physical status classification system risk classes I II scheduled for cesarean section were randomized into two groups to receive treatment in single-blind fashion. Patients in both groups received tramadol as an i.v. infusion 15 min before the end of surgery under general anesthesia for cesarean section. In the post-anesthesia care unit, the 20 patients allocated to group I were given i.v. tramadol in patient-controlled anesthesia (PCA), while the 20 other patients assigned to group II received it as a continuous infusion. Pain visual analog scores (VAS), mean arterial pressure (MAP), heart rate, total tramadol consumption, sedation scores, side-effects (nausea/vomiting) and patient satisfaction were evaluated seven times in the course of the first postoperative 24 h. The Mann-Whitney U-test and Friedman's anova were used for the statistical treatment of data. RESULTS: VAS, sedation scores and nausea/vomiting scores were similar in both groups (P > 0.05). The 24-h tramadol consumption was significantly lower in group I (420.15 +/- 66.58 mg) than in group II (494.00 +/- 29.45 mg), while patient satisfaction was significantly higher in group I (P < 0.05). CONCLUSION: While tramadol administration by either of the methods used may ensure efficient early postoperative anesthesia in cesarean section patients, i.v. PCA may be preferred because of the lower drug consumption and higher patient satisfaction associated with it. PMID- 24147823 TI - An efficient one-pot synthesis of benzo[4,5]imidazo[1,2-a]quinoxalines via copper catalyzed process. AB - A copper-catalyzed one-pot process for the construction of benzo[4,5]imidazo[1,2 a]quinoxalines under air is described. Aryl chlorides, aryl bromides, and aryl iodides can be applied to the synthesis of these compounds. PMID- 24147824 TI - Radiation stability of cations in ionic liquids. 1. Alkyl and benzyl derivatives of 5-membered ring heterocycles. AB - In order to use hydrophobic room temperature ionic liquids (ILs) as diluents in nuclear separations for advanced fuel cycles, it is desirable to reduce the breakdown of the constituent ions caused by ionizing radiation. In this series, we survey radiation stability for different classes of organic cations used to formulate ILs. While radiolysis of 1-alkyl-3-methylimidazolium cations has been extensively studied, there have not been complementary studies of 1-benzyl derivatives of these cations nor organic cations that are derived from 5-membered ring heterocycles other than imidazole, such as 1,2,4-triazole and thiazole. In part 1, we establish the fragmentation pathways for such cations and quantify product yields for 2.5 MeV electron beam radiolysis of these aromatic cations. Radiolytic reduction of 1-benzyl cations derived from imidazole and 1,2,4 triazole is shown to cause the elimination of benzyl radicals from their electron adducts, whereas this elimination does not occur in the thiazole derivatives due to stabilization of the excess electron as a dimer radical cation. No such elimination occurs in the corresponding 1-alkyl derivatives, but there is significant C-N and C-C bond fragmentation in the aliphatic arms. As such bond dissociation reactions are irreversible, there is significant loss of 1-alkyl cations during the radiolysis. For 1-benzyl derivatives, this electronic excitation causes fragmentation of the C-N bonds in the benzyl arms with the release of the corresponding base and the benzyl carbocation that can subsequently attack this base or add to another cation. Such systems exhibit more predictable fragmentation patterns and yield well-defined products; some of the systems also exhibit increased radiation resistance. The C-N bond fragmentation in the reduced cations can be further suppressed through the use of appropriate electron scavengers, including acids and aromatic imide anions. The observed trends are rationalized using density functional theory calculations, and the implications of these results for the design of IL diluents are examined. PMID- 24147825 TI - 2'-Deoxyuridine 5'-monophosphate substrate displacement in thymidylate synthase through 6-hydroxy-2H-naphtho[1,8-bc]furan-2-one derivatives. AB - Thymidylate synthase (TS) is a target for antifolate-based chemotherapies of microbial and human diseases. Here, ligand-based, synthetic, and X-ray crystallography studies led to the discovery of 6-(3-cyanobenzoyloxy)-2-oxo-2H naphto[1,8-bc]furan, a novel inhibitor with a Ki of 310 nM against Pneumocystis carinii TS. The X-ray ternary complex with Escherichia coli TS revealed, for the first time, displacement of the substrate toward the dimeric protein interface, thus providing new opportunities for further design of specific inhibitors of microbial pathogens. PMID- 24147826 TI - Identification of a novel HLA-B allele HLA-B*07:185 in a Japanese individual. PMID- 24147827 TI - Diagnostic diversity: the role of social class in diagnostic experiences of infertility. AB - Research in the area of the sociology of diagnosis has recently expanded. Despite this development, the foundations of the social aspects of diagnoses, including race, class and gender, are relatively unexplored. Understanding such diversity is important, however, as researchers have shown that diagnoses have significant repercussions on the illness experience. This article is an effort to overcome this gap in the literature by examining class diversity in interpretations and understandings of diagnoses. Using the medicalised condition of infertility as a case example of class differences around diagnoses, I conducted 58 in-depth interviews with infertile women of various class backgrounds in the USA. By comparing the lived experiences of infertility between higher and lower class women, I explore differences in the understanding, interpretation and outcomes of diagnoses, specifically. Furthermore, among lower class women, I examine how they understand infertility outside the medical diagnostic framework. The findings reveal how interpretations and experiences of diagnoses vary depending on an individual's social location. In other words, the study demonstrates that class matters in terms of diagnoses and their understanding. PMID- 24147828 TI - Preliminary study on diffuse axonal injury by Fourier transform infrared spectroscopy histopathology imaging. AB - The objective of this study was to evaluate the application of Fourier transform infrared (FTIR) spectroscopy for detecting diffuse axonal injury (DAI) in a mouse model. Brain tissues from DAI mouse model were prepared with H&E, silver, and beta-amyloid precursor protein (beta-APP) immunohistochemistry stains and were also studied with FTIR. The infrared spectrum images showed high absorption of amide II in the subcortical white matter of the experimental mouse brain, while there was no obvious expression of amide II in the control mouse brain. The areas with high absorption of amide II were in the same distribution as the DAI region confirmed by the silver and beta-APP studies. The result suggests that high absorption of amide II correlates with axonal injury. The use of FTIR imaging allows the biochemical changes associated with DAI pathologies to be detected in the tissues, thus providing an important adjunct method to the current conventional pathological diagnostic techniques. PMID- 24147829 TI - Macromolecular crowding amplifies adipogenesis of human bone marrow-derived mesenchymal stem cells by enhancing the pro-adipogenic microenvironment. AB - The microenvironment plays a vital role in both the maintenance of stem cells in their undifferentiated state (niche) and their differentiation after homing into new locations outside this niche. Contrary to conventional in-vitro culture practices, the in-vivo stem cell microenvironment is physiologically crowded. We demonstrate here that re-introducing macromolecular crowding (MMC) at biologically relevant fractional volume occupancy during chemically induced adipogenesis substantially enhances the adipogenic differentiation response of human bone marrow-derived mesenchymal stem cells (MSCs). Both early and late adipogenic markers were significantly up-regulated and cells accumulated 25-40% more lipid content under MMC relative to standard induction cocktails. MMC significantly enhanced deposition of extracellular matrix (ECM), notably collagen IV and perlecan, a heparan sulfate proteoglycan. As a novel observation, MMC also increased the presence of matrix metalloproteinase -2 in the deposited ECM, which was concomitant with geometrical ECM remodeling typical of adipogenesis. This suggested a microenvironment that was richer in both matrix components and associated ligands and was conducive to adipocyte maturation. This assumption was confirmed by seeding undifferentiated MSCs on decellularized ECM deposited by adipogenically differentiated MSCs, Adipo-ECM. On Adipo-ECM generated under crowding, MSCs differentiated much faster under a classical differentiation protocol. This was evidenced throughout the induction time course, by a significant up-regulation of both early and late adipogenic markers and a 60% higher lipid content on MMC-generated Adipo-ECM in comparison to standard induction on tissue culture plastic. This suggests that MMC helps build and endow the nascent microenvironment with adipogenic cues. Therefore, MMC initiates a positive feedback loop between cells and their microenvironment as soon as progenitor cells are empowered to build and shape it, and, in turn, are informed by it to respond by attaining a stable differentiated phenotype if so induced. This work sheds new light on the utility of MMC to tune the microenvironment to augment the generation of adipose tissue from differentiating human MSCs. PMID- 24147830 TI - Reversible T-wave inversions and neurogenic myocardial stunning in a patient with recurrent stress-induced cardiomyopathy. AB - A 72-year-old female was diagnosed as a stress-induced cardiomyopathy from apical ballooning pattern of left ventricular dysfunction without coronary artery stenosis after the mental stress. ECG showed the transient T-wave inversions after the ST-segment elevations. By the mental stress after 1 year, she showed a transient dysfunction with similar ECG changes again. T-wave inversions recovered earlier, and cardiac sympathetic dysfunction showed a lighter response corresponding to the less severe dysfunction than those after the first onset. Wellens' ECG pattern was associated with the degree of neurogenic myocardial stunning with sympathetic hyperinnervation caused by mental stress. PMID- 24147831 TI - Impact of occluded culprit arteries on long-term clinical outcome in patients with non-ST-elevation myocardial infarction: 48-month follow-up results in the COREA-AMI Registry. AB - BACKGROUND: The prognostic impact of occluded culprit arteries in non-ST elevation myocardial infarction (NSTEMI) patients beyond 12 months has not been investigated. OBJECTIVES: The impact of occluded culprit arteries on a composite of cardiac death (CD), recurrent nonfatal MI (RMI), and target vessel revascularization (TVR) in patients who presented with NSTEMI was investigated during a 48-month follow-up using propensity-score (PS) matching. METHODS: A total of 2,878 NSTEMI patients in the COREA-AMI (COnvergent REgistry of cAtholic and chonnAm university for Acute MI) Registry were classified according to the angiographic flow of culprit arteries (occlusion [OC], n = 1,070; nonocclusion, n = 1,808). After PS matching, the incidence of the primary end-point, a composite of CD, RMI, and TVR was compared. RESULTS: The median follow-up duration was 47.3 months (IQR 32.7-66.2). In the PS-matched population, the 48-month cumulative rates of the primary end-point (27.5% vs. 17.9%, P < 0.001) and each event were higher in the OC group (CD: 9.0% vs. 5.4%, RMI: 16.3% vs. 9.4%, TVR: 10.5% vs. 5.6%, respectively, P < 0.05). In multivariate Cox regression analysis, occluded culprit arteries showed the significant statistical impact on the primary end point (HR 1.689 [1.385-2.059], P < 0.001) and each event (CD: 1.736 [1.218 2.475], RMI: 1.918 [1.468-2.505], TVR: 2.042 [1.453-2.869], respectively, P < 0.05). Furthermore, in the 12-month landmark analysis, occluded culprit arteries were still associated with higher risk of primary end-point beyond 12 months (P < 0.001). CONCLUSIONS: Occluded culprit arteries were independently associated with the higher risk of CD, RMI, and TVR in NSTEMI patients during the 48-month follow up. PMID- 24147832 TI - Physiological serum bilirubin concentrations are inversely associated with the prevalence of cardiovascular autonomic neuropathy in patients with Type 2 diabetes. AB - AIMS: Although severe hyperbilirubinaemia causes kernicterus in neonates, normal to modestly elevated bilirubin concentrations have been reported to be neuroprotective. However, the relationship between serum bilirubin concentrations and cardiovascular autonomic neuropathy in patients with Type 2 diabetes is currently unknown. This study assessed the relationships between physiological serum total bilirubin concentrations and cardiovascular autonomic neuropathy in patients with Type 2 diabetes. METHODS: A total of 2991 patients with Type 2 diabetes were investigated in this cross-sectional study. Cardiovascular autonomic neuropathy was diagnosed by a cardiovascular reflex test. According to the American Diabetes Association criteria, the degree of cardiovascular autonomic dysfunction was graded into normal, early, definite and severe. Cardiovascular autonomic neuropathy was either definite or severe in the present study. An analysis of covariance after adjustment for other covariates was performed. A logistic regression model was used to assess an association of cardiovascular autonomic neuropathy with serum total bilirubin tertiles. RESULTS: Serum total bilirubin concentrations were significantly lower in subjects with cardiovascular autonomic neuropathy. The mean total bilirubin values differed significantly according to the severity of cardiovascular autonomic dysfunction (normal 13.0 MUmol/l; early 12.3 MUmol/l; definite 11.8 MUmol/l; severe 10.1 MUmol/l; P for trend < 0.001) after adjustment for other covariates. In multivariate analysis, serum total bilirubin levels were significantly associated with cardiovascular autonomic neuropathy (odds ratio 0.36; 95% CI 0.21-0.63 for the highest vs. the lowest bilirubin tertile, P < 0.001). CONCLUSIONS: Serum total bilirubin concentrations within the physiologic range are inversely associated with the prevalence of cardiovascular autonomic neuropathy in patients with Type 2 diabetes. PMID- 24147833 TI - Identifying the cellular targets of drug action in the central nervous system following corticosteroid therapy. AB - Corticosteroid (CS) therapy is used widely in the treatment of a range of pathologies, but can delay production of myelin, the insulating sheath around central nervous system nerve fibers. The cellular targets of CS action are not fully understood, that is, "direct" action on cells involved in myelin genesis [oligodendrocytes and their progenitors the oligodendrocyte precursor cells (OPCs)] versus "indirect" action on other neural cells. We evaluated the effects of the widely used CS dexamethasone (DEX) on purified OPCs and oligodendrocytes, employing complementary histological and transcriptional analyses. Histological assessments showed no DEX effects on OPC proliferation or oligodendrocyte genesis/maturation (key processes underpinning myelin genesis). Immunostaining and RT-PCR analyses show that both cell types express glucocorticoid receptor (GR; the target for DEX action), ruling out receptor expression as a causal factor in the lack of DEX-responsiveness. GRs function as ligand-activated transcription factors, so we simultaneously analyzed DEX-induced transcriptional responses using microarray analyses; these substantiated the histological findings, with limited gene expression changes in DEX-treated OPCs and oligodendrocytes. With identical treatment, microglial cells showed profound and global changes post-DEX addition; an unexpected finding was the identification of the transcription factor Olig1, a master regulator of myelination, as a DEX responsive gene in microglia. Our data indicate that CS-induced myelination delays are unlikely to be due to direct drug action on OPCs or oligodendrocytes, and may occur secondary to alterations in other neural cells, such as the immune component. To the best of our knowledge, this is the first comparative molecular and cellular analysis of CS effects in glial cells, to investigate the targets of this major class of anti-inflammatory drugs as a basis for myelination deficits. PMID- 24147835 TI - Detection of parasite antigens in Leishmania infantum-infected spleen tissue by monoclonal antibody-, piezoelectric-based immunosensors. AB - Diseases such as leishmaniases are important causes of morbidity and mortality in Brazil, and their diagnoses need to be improved. The use of monoclonal antibodies has ensured high specificity to immunodiagnosis. The development of an immunosensor, coupling a monoclonal antibody to a bioelectronic device capable of quickly detecting Leishmania sp. antigens both qualitatively and quantitatively, is a promising alternative for the diagnosis of leishmaniasis due to its high specificity, low cost, and portability, compared with conventional methods. The present work was aimed at developing an immunosensor-based assay for detecting Leishmania infantum antigens in tissues of infected hosts. Four hybridomas producing monoclonal antibodies against L. infantum had their specificity confirmed by enzyme-linked immunosorbent assay. These antibodies were immobilized on a gold surface, covered with a thin film of 2-aminoethanethiol (cysteamine) and glutaraldehyde, blocked with glycine, and placed into contact with extracts of L. infantum -infected and noninfected control hamster spleens. The assay was able to detect 1.8 * 10(4) amastigotes/g of infected tissue. These results demonstrated that this assay may be useful for quantifying L. infantum amastigotes in organs of experimental animals for studies on pathogenesis and immunity and that it is a promising tool for the development of a diagnostic method, based on antigen detection, of human and dog visceral leishmaniasis. PMID- 24147834 TI - Tunable porous organic crystals: structural scope and adsorption properties of nanoporous steroidal ureas. AB - Previous work has shown that certain steroidal bis-(N-phenyl)ureas, derived from cholic acid, form crystals in the P6(1) space group with unusually wide unidimensional pores. A key feature of the nanoporous steroidal urea (NPSU) structure is that groups at either end of the steroid are directed into the channels and may in principle be altered without disturbing the crystal packing. Herein we report an expanded study of this system, which increases the structural variety of NPSUs and also examines their inclusion properties. Nineteen new NPSU crystal structures are described, to add to the six which were previously reported. The materials show wide variations in channel size, shape, and chemical nature. Minimum pore diameters vary from ~0 up to 13.1 A, while some of the interior surfaces are markedly corrugated. Several variants possess functional groups positioned in the channels with potential to interact with guest molecules. Inclusion studies were performed using a relatively accessible tris-(N phenyl)urea. Solvent removal was possible without crystal degradation, and gas adsorption could be demonstrated. Organic molecules ranging from simple aromatics (e.g., aniline and chlorobenzene) to the much larger squalene (M(w) = 411) could be adsorbed from the liquid state, while several dyes were taken up from solutions in ether. Some dyes gave dichroic complexes, implying alignment of the chromophores in the NPSU channels. Notably, these complexes were formed by direct adsorption rather than cocrystallization, emphasizing the unusually robust nature of these organic molecular hosts. PMID- 24147836 TI - Epidermal identity is maintained by cell-cell communication via a universally active feedback loop in Arabidopsis thaliana. AB - The transcription factors ARABIDOPSIS THALIANA MERISTEM L1 (ATML1) and PROTODERMAL FACTOR2 (PDF2) are indispensable for epidermal cell-fate specification in Arabidopsis embryos. However, the mechanisms of regulation of these genes, particularly their relationship with cell-cell signalling pathways, although the subject of considerable speculation, remain unclear. Here we demonstrate that the receptor kinase ARABIDOPSIS CRINKLY4 (ACR4) positively affects the expression of ATML1 and PDF2 in seedlings. In contrast, ATML1- and PDF2-containing complexes directly and negatively affect both their own expression and that of ACR4. By modelling the resulting feedback loop, we demonstrate a network structure that is capable of maintaining robust epidermal cell identity post-germination. We show that a second seed-specific signalling pathway involving the subtilase ABNORMAL LEAFSHAPE1 (ALE1) and the receptor kinases GASSHO1 (GSO1) and GASSHO2 (GSO2) acts in parallel to the epidermal loop to control embryonic surface formation via an ATML1/PDF2-independent pathway. Genetic interactions between components of this linear pathway and the epidermal loop suggest that an intact embryo surface is necessary for initiation and/or stabilization of the epidermal loop, specifically during early embryogenesis. PMID- 24147837 TI - Teaching paediatric ward teams to recognise and manage the deteriorating child. AB - BACKGROUND: Issues around the deterioration of hospitalised children are known: the failure to observe and monitor patients adequately, a failure to recognise the deteriorating patient, a failure to communicative effectively within the healthcare team and a failure to respond appropriately or in a timely manner (Pearson, 2008; NPSA, 2009). In response to this, a new 1-day course called RESPOND (Recognising Signs of Paediatric hOspital iNpatients Deterioration) was developed. OBJECTIVES: To describe the development of the RESPOND course and present a preliminary evaluation of the first four courses. METHODS: A written postcourse survey was completed by participants (junior doctors, medical students, nurses and health care assistants) immediately after the course and an electronic survey completed three months later in a large children's hospital in the North West of England. Data were analysed descriptively and by simple thematic analysis of free text responses. RESULTS: Sixty-five participants undertook the RESPOND course over four separate days. Overwhelmingly participants found the course positive, with the most frequently cited benefit being improved multidisciplinary communication. Despite a poor response to the second survey, 18% (12 of 65) of respondents remained positive about the impact of the course. CONCLUSIONS AND RELEVANCE TO PRACTICE: This preliminary evaluation combined with a reduction in hospital cardiac arrest rates suggest that the multiprofessional RESPOND course (in conjunction with an early warning tool and response system) is successful as part of a targeted strategy to promote patient safety within a children's hospital. PMID- 24147838 TI - Structure meets function: actin filaments and myosin motors in the axon. AB - This review focuses on recent advances in the understanding of the organization and roles of actin filaments, and associated myosin motor proteins, in regulating the structure and function of the axon shaft. 'Patches' of actin filaments have emerged as a major type of actin filament organization in axons. In the distal axon, patches function as precursors to the formation of filopodia and branches. At the axon initial segment, patches locally capture membranous organelles and contribute to polarized trafficking. The trapping function of patches at the initial segment can be ascribed to interactions with myosin motors, and likely also applies to patches in the more distal axon. Finally, submembranous rings of actin filaments were recently described in axons, which form an actin-spectrin cytoskeleton, likely contributing to the maintenance of axon integrity. Continued investigation into the roles of axonal actin filaments and myosins will shed light on fundamental aspects of the development, adult function and the repair of axons in the nervous system. PMID- 24147839 TI - Synthesis of cyclic guanidines via Pd-catalyzed alkene carboamination. AB - A new approach to the synthesis of substituted 5-membered cyclic guanidines is described. Palladium-catalyzed alkene carboamination reactions between acyclic N allyl guanidines and aryl or alkenyl halides provide these products in good yield. This method allows access to a number of different cyclic guanidine derivatives in only two steps from readily available allylic amines. PMID- 24147840 TI - Effect of water content on conversion of D-cellobiose into 5-hydroxymethyl-2 furaldehyde in a dimethyl sulfoxide-water mixture. AB - Noncatalytic conversion of D-cellobiose (at 0.5 M) into 5-hydroxymethyl-2 furaldehyde (5-HMF), a platform chemical for fuels and synthetic materials, was analyzed at 120-200 degrees C over a wide range of water mole fraction, xw = 0.007-1 in a binary dimethyl sulfoxide (DMSO)-water mixture by means of the in situ (13)C NMR spectroscopy. Effects of the water content were revealed as follows: (i) The tautomerization of the anomeric residue of D-cellobiose from D glucose to D-fructose type was not initially observed at a lower water content, in contrast to the significant tautomerization into the D-fructose type in a higher water content and pure water. (ii) The lower the water content, the faster the glycosidic-bond cleavage by hydrolysis, because of the high reactivity of solitary water molecules with the large partial charges more naked as in supercritical water clusters due to the isolation by the organic solvent DMSO. (iii) The amount of D-fructose as the intermediate product was larger at the higher xw; despite the increase of D-fructose, the production of 5-HMF from D fructose was slowed down. (iv) A high 5-HMF yield of 71% was reached at xw = 0.20 0.30 that was 6-10 times the initial D-cellobiose concentration. The best yield of 5-HMF was attained in the low xw region when the polymerization paths into NMR undetectable species via 5-HMF and anhydromonosaccharides were effectively suppressed. This study provides a new framework to design optimal, noncatalytic reaction process to produce 5-HMF from cellulosic biomass by tuning the water content as well as the temperature and the reaction time. PMID- 24147841 TI - Immunophenotyping in saliva as an alternative approach for evaluation of immunopathogenesis in chronic periodontitis. AB - BACKGROUND: To date, flow cytometric immunophenotyping has not been used to investigate immune patterns in saliva samples from individuals with inflammatory processes in the oral cavity, such as chronic periodontitis (CP). Saliva analysis could be a non-invasive method for evaluating oral health. The objective of this study is to determine the phenotype of leukocytes and total immunoglobulin A (IgA), IgG, and IgM titers in the saliva of individuals with CP. METHODS: Saliva samples were obtained from patients with CP (n = 12) and from a control group (n = 27) without oral diseases. Flow cytometry was performed to determine the frequency of T cells (CD4(+) and CD8(+)), B cells, and natural killer (NK) cells as well as the total leukocyte population. Immunoglobulin titers were determined by dot enzyme-linked immunosorbent assay. RESULTS: Cell immunophenotyping revealed that patients with CP had a higher frequency of total leukocytes (47.94% +/- 5.1%; P < 0.001), B cells (43.93% +/- 6.2%; P = 0.006), NK cells (0.16% +/- 0.04%; P = 0.03), and CD4(+) T cells (38.99% +/- 4.4%; P = 0.002) than individuals without oral pathologies (24.75% +/- 2.2%, 20.60% +/- 2.7%, 0.09% +/- 0.03%, and 16.82% +/- 3.5%, respectively). No significant differences in salivary total IgA, IgG, and IgM titers were found between the two cohorts studied. Nevertheless, higher total IgG levels were observed in patients with CP, which could indicate a possible correlation between clinical attachment level and salivary IgG (P = 0.07; r(2) = 0.08). CONCLUSION: These results show that cell phenotyping by flow cytometry could be an effective tool for determining leukocyte profiles in saliva samples from patients with CP and healthy individuals. PMID- 24147842 TI - Salivary interleukin-6 and -8 in patients with oral cancer and patients with chronic oral inflammatory diseases. AB - BACKGROUND: Previous research has indicated that salivary interleukin (IL)-6 and IL-8 are potential biomarkers for oral squamous cell carcinoma (OSCC). However, their levels have been found to be significantly elevated in patients with chronic periodontitis (CP) or oral lichen planus (OLP). The data also showed wide variations in levels among the different studies, and no standardization procedure was ever performed. Therefore, the objective of this study is to determine whether CP or OLP confounds the use of IL-6 or IL-8 for OSCC detection. METHODS: Saliva samples were collected from five groups: OSCC before treatment (n = 18); CP (n = 21); disease-active OLP (n = 21); disease-inactive OLP (n = 20); and healthy controls (n = 21). IL-6 and IL-8 concentrations (determined by enzyme linked immunosorbent assays) were compared, using total salivary protein standardized levels to validate the data. The Kruskal-Wallis test (alpha = 0.05) followed by pairwise Mann-Whitney U (post hoc) tests with Bonferroni adjustments (alpha = 0.00625) were used for statistical analysis. RESULTS: Salivary IL-6 levels were significantly higher in patients with OSCC than in patients with CP (P <0.001), disease-active OLP (P = 0.001), disease-inactive OLP (P <0.001), and healthy controls (P <0.001). Salivary IL-8 levels were significantly higher in patients with OSCC than in patients with CP (P <0.001), but only marginally significantly higher than in healthy controls (P = 0.014). Statistical results of standardized IL-6 and IL-8 levels were consistent with the non-standardized levels in all pairs except one. CONCLUSION: Salivary IL-6 may be a useful biomarker in the detection of OSCC, unconfounded by CP or OLP. PMID- 24147844 TI - Mesenchymal stem cells and endothelial progenitor cells stimulate bone regeneration and mineral density. AB - BACKGROUND: Alveolar bone deficiency is a major clinical problem in maxillofacial reconstructive surgery. The available surgical techniques to enhance extracortical bone augmentation are generally unpredictable and not satisfying. The aim of the present study is to quantify extracortical bone augmentation and tissue mineral density (TMD) after cotransplantation of peripheral blood-derived endothelial progenitor cells (EPCs) and bone marrow-derived mesenchymal stem cells (MSCs) by microcomputed tomography (micro-CT). METHODS: Bone regeneration was tested in the guided bone regeneration rat calvaria model. Gold domes filled with beta tricalcium phosphate (beta-TCP; control [CNT]) or beta-TCP mixed with 5 * 10(5) rat EPCs and 5 * 10(5) rat osteogenic transformed MSCs (EPC/otMSCs) were fixed to the exposed calvaria. Rats were sacrificed after 3 months. Bone volume fraction (BV/TV) and TMD were analyzed using micro-CT. In the middle of the dome, a cylindrical region of interest was defined (it represents the area in which implants are placed) and subdivided into bottom, middle, and top to analyze the effect of the distance from the calvaria on bone formation. RESULTS: In the whole cylinder, BV/TV and TMD were higher in the EPC/otMSC group compared with CNT (BV/TV: 22.9% +/- 4.4% versus 29.1 +/- 2.2%, P = 0.02; TMD: 937.79 +/- 18.68 versus 960.78 +/- 5.8 mgHA/ccm, P = 0.03; CNT versus EPC/otMSC, respectively). In each of the three subregions, BV/TV was higher in the EPC/otMSC group compared with CNT (top: 20.25% +/- 2.4% versus 23.74% +/- 1.5%, P = 0.007; middle: 23.2% +/- 4.8% versus 28% +/- 2.2%, P = 0.05; bottom: 25.3% +/- 7.6% versus 35.7% +/- 4.9%, P = 0.02; CNT versus EPC/otMSC, respectively). CONCLUSION: Three dimensional quantification by micro-CT demonstrated that cotransplantation of EPC/otMSCs significantly improved bone formation and mineral density. PMID- 24147843 TI - Altered antigenic profiling and infectivity of Porphyromonas gingivalis in smokers and non-smokers with periodontitis. AB - BACKGROUND: Cigarette smokers are more susceptible to periodontal diseases and are more likely to be infected with Porphyromonas gingivalis than non-smokers. Furthermore, smoking is known to alter the expression of P. gingivalis surface components and compromise immunoglobulin (Ig)G generation. The aim of this study is to evaluate whether the overall IgG response to P. gingivalis is suppressed in smokers in vivo and whether previously established in vitro tobacco-induced phenotypic P. gingivalis changes would be reflected in vivo. METHODS: The authors examined the humoral response to several P. gingivalis strains as well as specific tobacco-regulated outer membrane proteins (FimA and RagB) by enzyme linked immunosorbent assay in biochemically validated (salivary cotinine) smokers and non-smokers with chronic periodontitis (CP: n = 13) or aggressive periodontitis (AgP: n = 20). The local and systemic presence of P. gingivalis DNA was also monitored by polymerase chain reaction. RESULTS: Smoking was associated with decreased total IgG responses against clinical (10512, 5607, and 10208C; all P <0.05) but not laboratory (ATCC 33277, W83) P. gingivalis strains. Smoking did not influence IgG produced against specific cell-surface proteins, although a non significant pattern toward increased total FimA-specific IgG in patients with CP, but not AgP, was observed. Seropositive smokers were more likely to be infected orally and systemically with P. gingivalis (P <0.001), as determined by 16S RNA analysis. CONCLUSION: Smoking alters the humoral response against P. gingivalis and may increase P. gingivalis infectivity, strengthening the evidence that mechanisms of periodontal disease progression in smokers may differ from those of non-smokers with the same disease classification. PMID- 24147845 TI - Dimensional influence of interproximal areas on existence of interdental papillae. AB - BACKGROUND: Restoring papillae in the gingival embrasures of the esthetic zone is a key consideration in periodontal, restorative, and orthodontic treatment. This study analyzes the existence of interdental papillae with regard to the vertical dimensions between the contact point and the alveolar crest and horizontal dimensions between adjacent roots. METHODS: A total of 259 papillae, in 60 patients, were examined. All patients were indicated for full-thickness periodontal flap surgery. A mucoperiosteal flap was raised and, after thorough debridement, horizontal and vertical dimensions between adjacent roots were recorded. The incidence of papillae was analyzed using chi(2) for linear trend analysis. RESULTS: Interdental papillae were present in 85.7% of the cases when the vertical dimensions were 4 mm (P <0.05). Also, papillae were present in 78.5% of cases when the horizontal dimensions were between 0.5 and 1 mm (P <0.05). CONCLUSION: The vertical and horizontal dimensions of interproximal areas had a substantial, independent, and combined effect on the existence of interproximal papillae. PMID- 24147846 TI - The effect of flapless surgery on implant survival and marginal bone level: a systematic review and meta-analysis. AB - BACKGROUND: The clinical outcomes of implants placed using the flapless approach have not yet been systematically investigated. Hence, the present systematic review and meta-analysis aims to study the effect of the flapless technique on implant survival rates (SRs) and marginal bone levels (MBLs) compared with the conventional flap approach. METHODS: An electronic search of five databases (from 1990 to March 2013), including PubMed, Ovid (MEDLINE), EMBASE, Web of Science, and Cochrane Central, and a hand search of peer-reviewed journals for relevant articles were performed. Human clinical trials with data on comparison of SR and changes in MBL between the flapless and conventional flap procedures, with at least five implants in each study group and a follow-up period of at least 6 months, were included. RESULTS: Twelve studies, including seven randomized controlled trials (RCTs), one cohort study, one pilot study, and three retrospective case-controlled trials (CCTs), were included. The SR of each study was recorded, weighted mean difference (WMD) and confidence interval (CI) were calculated, and meta-analyses were performed for changes in MBL. The average SR is 97.0% (range, 90% to 100%) for the flapless procedure and 98.6% (range, 91.67% to 100%) for the flap procedure. Meta-analysis for the comparison of SR among selected studies presented a similar outcome (risk ratio = 0.99, 95% CI = 0.97 to 1.01, P = 0.30) for both interventions. Mean differences of MBL were retrieved from five RCTs and two retrospective CCTs and subsequently pooled into meta analyses; however, none of the comparisons showed statistical significance. For RCTs, the WMD was 0.07, with a 95% CI of -0.05 to 0.20 (P = 0.26). For retrospective CCTs, the WMD was 0.23, with a 95% CI of -0.58 to 1.05 (P = 0.58). For the combined analysis, the WMD was 0.03, with a 95% CI of -0.11 to 0.18 (P = 0.67). The comparison of SR presented a low to moderate heterogeneity, but MBL presented a considerable heterogeneity among studies. CONCLUSION: This systematic review revealed that the SRs and radiographic marginal bone loss of flapless intervention were comparable with the flap surgery approach. PMID- 24147847 TI - Metal-organic frameworks based on previously unknown Zr8/Hf8 cubic clusters. AB - The ongoing study of zirconium- and hafnium-porphyrinic metal-organic frameworks (MOFs) led to the discovery of isostructural MOFs based on Zr8 and Hf8 clusters, which are unknown in both cluster and MOF chemistry. The Zr8O6 cluster features an idealized Zr8 cube, in which each Zr atom resides on one vertex and each face of the cube is capped by one MU4-oxygen atom. On each edge of the cube, a carboxylate from a porphyrinic ligand bridges two Zr atoms to afford a 3D MOF with a very rare (4,12)-connected ftw topology, in which two types of polyhedral cages with diameters of ~1.1 and ~2.0 nm and a cage opening of ~0.8 nm are found. The isostructural Zr- and Hf-MOFs exhibit high surface areas, gas uptakes, and catalytic selectivity for cyclohexane oxidation. PMID- 24147848 TI - Personality traits, self-care behaviours and glycaemic control in type 2 diabetes: the Fremantle diabetes study phase II. AB - AIMS: To determine whether the personality traits of conscientiousness and agreeableness are associated with self-care behaviours and glycaemia in Type 2 diabetes. METHODS: The Big Five Inventory personality traits Agreeableness, Conscientiousness, Extraversion, Neuroticism and Openness were determined along with a range of other variables in 1313 participants with Type 2 diabetes (mean age 65.8 +/- 11.1 years; 52.9% men) undertaking their baseline assessment as part of the community-based longitudinal observational Fremantle Diabetes Study Phase II. Age- and sex-adjusted generalized linear modelling was used to determine whether personality was associated with BMI, smoking, self-monitoring of blood glucose and medication taking. Multivariable regression was used to investigate which traits were independently associated with these self-care behaviours and HbA1c . RESULTS: Patients with higher conscientiousness were less likely to be obese or smoke, and more likely to perform self-monitoring of blood glucose and take their medications (P <= 0.019), with similar independent associations in multivariate models (P <= 0.024). HbA1c was independently associated with younger age, indigenous ethnicity, higher BMI, longer diabetes duration, diabetes treatment, self-monitoring of blood glucose (negatively) and less medication taking (P <= 0.009), but no personality trait added to the model. CONCLUSIONS: Although there was no independent association between personality traits and HbA1c , the relationship between high conscientiousness and low BMI and beneficial self-care behaviours suggests an indirect positive effect on glycaemia. Conscientiousness could be augmented by the use of impulse control training as part of diabetes management. PMID- 24147849 TI - Initial validation of a virtual-reality learning environment for prostate biopsies: realism matters! AB - BACKGROUND AND PURPOSE: A virtual-reality learning environment dedicated to prostate biopsies was designed to overcome the limitations of current classical teaching methods. The aim of this study was to validate reliability, face, content, and construct of the simulator. MATERIALS AND METHODS: The simulator is composed of (a) a laptop computer, (b) a haptic device with a stylus that mimics the ultrasound probe, (c) a clinical case database including three-dimensional (3D) ultrasound volumes and patient data, and (d) a learning environment with a set of progressive exercises including a randomized 12-core biopsy procedure. Both visual (3D biopsy mapping) and numerical (score) feedback are given to the user. The simulator evaluation was conducted in an academic urology department on 7 experts and 14 novices who each performed a virtual biopsy procedure and completed a face and content validity questionnaire. RESULTS: The overall realism of the biopsy procedure was rated at a median of 9/10 by nonexperts (7.1-9.8). Experts rated the usefulness of the simulator for the initial training of urologists at 8.2/10 (7.9-8.3), but reported the range of motion and force feedback as significantly less realistic than novices (P=0.01 and 0.03, respectively). Pearson r correlation coefficient between correctly placed biopsies on the right and left side of the prostate for each user was 0.79 (P<0.001). The 7 experts had a median score of 64% (59%-73%), and the 14 novices a median score of 52% (43%-67%), without reaching statistical significance (P=0.19). CONCLUSION: The newly designed virtual-reality learning environment proved its versatility and its reliability, face, and content were validated. Demonstrating the construct validity will necessitate improvements to the realism and scoring system used. PMID- 24147850 TI - Biophysical and social barriers restrict water quality improvements in the Mississippi River Basin. PMID- 24147851 TI - Cell transplantation in paraplegic patients: the importance of properly assessing the spinal cord morphology. AB - INTRODUCTION: Cell transplantation in paraplegic patients is beginning, but scarce attention is paid to the morphology of lesions. MATERIAL AND METHODS: We studied using magnetic resonance imaging (MRI) the morphology of the injured spinal cord in 200 patients with chronic and complete paraplegia after spinal cord injury (SCI) at the thoracic level. RESULTS: When it was possible to undertake a correct study of the lesion, approximately 35% of patients had images showing spinal cord transection or showed fine tracts of tissue that connected both edges of a virtually transected spinal cord. Approximately 30% of patients had significant kyphosis with chronic spinal cord compression, and approximately 5% of cases had extensive spinal cord atrophy. In only approximately 30% of the patients, MRI revealed a centromedullary cavity, which was generally limited to the level of the vertebral fracture, and failed to show any apparent spinal cord transection. CONCLUSIONS: Humans suffering from chronically established paraplegia show a great variability of lesions, which differs from the standardized images of SCI obtained in animal models. When we design clinical trials, our goal should be to achieve a correct selection of patients, and the morphology of the spinal cord must be one of the main factors to consider. PMID- 24147853 TI - ICSI outcome is significantly better with testicular spermatozoa in patients with necrozoospermia: a retrospective study. AB - OBJECTIVE: To determine whether intracytoplasmic sperm injection (ICSI) outcome with testicular sperm is superior to that of ejaculated sperm in men with incomplete necrozoospermia, defined as sperm viability >=5 to <=45%. STUDY DESIGN: Retrospective study at a Reproductive Medicine Center of a tertiary referral hospital. A total of 231 couples with male infertility due to incomplete necrozoospermia underwent 342 ICSI cycles with freshly ejaculated sperm (ICSI ejaculated) and 182 cycles with testicular sperm (ICSI-TESE). RESULTS: Overall 1624 MII oocytes were injected in the ICSI-ejaculated group with a fertilisation rate of 60.8%, while in ICSI- TESE cycles the fertilisation rate was 59.6% in 874 MII oocytes. The cleavage rate was higher in ICSI-ejaculated cycles than in ICSI TESE cycles (96.3% versus 92.9%; p = 0.004). However, the pregnancy and implantation rates per cycle were significantly higher in the ICSI-TESE group (67/182, 36.8% versus 68/342, 19.9% (p = 0.0001); and 23.7% versus 12.7% (p = 0.0001), respectively). The miscarriage rate was similar (ICSI-ejaculated 26.5% versus ICSI-TESE 17.9%, p = 0.301). Live birth rate per cycle in the ICSI ejaculated group was significantly lower than in the ICSI-TESE (13.7% versus 28.6%, p = 0.0001). CONCLUSIONS: In cases of persistent necrozoospermia, testicular sperm should be favoured over ejaculated sperm. These data call for more research to understand the pathophysiology of refractory necrozoospermia. PMID- 24147852 TI - (13)C and (63,65)Cu ENDOR studies of CO dehydrogenase from Oligotropha carboxidovorans. Experimental evidence in support of a copper-carbonyl intermediate. AB - We report here an ENDOR study of an S = 1/2 intermediate state trapped during reduction of the binuclear Mo/Cu enzyme CO dehydrogenase by CO. ENDOR spectra of this state confirm that the (63,65)Cu nuclei exhibits strong and almost entirely isotropic coupling to the unpaired electron, show that this coupling atypically has a positive sign, aiso = +148 MHz, and indicate an apparently undetectably small quadrupolar coupling. When the intermediate is generated using (13)CO, coupling to the (13)C is observed, with aiso = +17.3 MHz. A comparison with the couplings seen in related, structurally assigned Mo(V) species from xanthine oxidase, in conjunction with complementary computational studies, leads us to conclude that the intermediate contains a partially reduced Mo(V)/Cu(I) center with CO bound at the copper. Our results provide strong experimental support for a reaction mechanism that proceeds from a comparable complex of CO with fully oxidized Mo(VI)/Cu(I) enzyme. PMID- 24147854 TI - Progesterone antagonist, RU486, represses LHCGR expression and LH/hCG signaling in cultured luteinized human mural granulosa cells. AB - Progesterone, the main steroid synthesized by the corpus luteum (CL), prepares the uterus for implantation, maintains the CL survival, and induces progesterone auto-secretion. However, the molecular mechanisms involving the progesterone auto secretion pathways at the luteal phase are not fully understood, especially in humans. We aim to study the molecular mechanism of the progesterone pathway in human granulosa cells. Our model system consists of luteinized human-mural granulosa-cells (hmGCs) obtained from follicles aspirated during in vitro fertilization (IVF) procedures. hmGCs were seeded in culture and were subjected to different hormonal treatments. mRNA levels were analyzed by quantitative real time PCR (qRT-PCR). Progesterone levels were measured by enzyme immunoassay (EIA). We show that exposure of luteinized hmGCs to the progesterone receptor antagonist, RU486 (mifepristone), resulted in inhibition of LHCGR, LH/hCG target genes and progesterone secretion. Exposure of hmGCs to medium that was incubated with hmGCs for 4 d - conditioned medium (CM), which contain 150 +/- 7.5 nM progesterone, resulted in induction of LHCGR and LH/hCG target genes, which was blocked by RU486. In addition, RU486 inhibited some of the progesterone biosynthesis pathway genes. Our results revealed a novel mechanism of the progesterone antagonist pathway in the luteal granulosa cells and emphasis the fundamental role of progesterone in the early luteal phase. PMID- 24147855 TI - Micro-mold design controls the 3D morphological evolution of self-assembling multicellular microtissues. AB - When seeded into nonadhesive micro-molds, cells self-assemble three-dimensional (3D) multicellular microtissues via the action of cytoskeletal-mediated contraction and cell-cell adhesion. The size and shape of the tissue is a function of the cell type and the size, shape, and obstacles of the micro-mold. In this article, we used human fibroblasts to investigate some of the elements of mold design and how they can be used to guide the morphological changes that occur as a 3D tissue self-organizes. In a loop-ended dogbone mold with two nonadhesive posts, fibroblasts formed a self-constrained tissue whose tension induced morphological changes that ultimately caused the tissue to thin and rupture. Increasing the width of the dogbone's connecting rod increased the stability, whereas increasing its length decreased the stability. Mapping the rupture points showed that the balance of cell volume between the toroid and connecting rod regions of the dogbone tissue controlled the point of rupture. When cells were treated with transforming growth factor-beta1, dogbones ruptured sooner due to increased cell contraction. In mold designs to form tissues with more complex shapes such as three interconnected toroids or a honeycomb, obstacle design controlled tension and tissue morphology. When the vertical posts were changed to cones, they became tension modulators that dictated when and where tension was released in a large self-organizing tissue. By understanding how elements of mold design control morphology, we can produce better models to study organogenesis, examine 3D cell mechanics, and fabricate building parts for tissue engineering. PMID- 24147857 TI - Fidelity, mismatch extension, and proofreading activity of the Plasmodium falciparum apicoplast DNA polymerase. AB - Plasmodium falciparum, a parasitic organism and one of the causative agents of malaria, contains an unusual organelle called the apicoplast. The apicoplast is a nonphotosynthetic plastid responsible for supplying the parasite with isoprenoid units and is therefore indispensable. Like mitochondria and the chloroplast, the apicoplast contains its own genome and harbors the enzymes responsible for its replication. In this report, we determine the relative probabilities of nucleotide misincorporation by the apicoplast polymerase (apPOL), examine the kinetics and sequence dependence of mismatch extension, and determine the rates of mismatch removal by the 3' to 5' proofreading activity of the DNA polymerase. While the intrinsic polymerase fidelity varies by >50-fold for the 12 possible nucleotide misincorporations, the most dominant selection step for overall polymerase fidelity is conducted at the level of mismatch extension, which varies by >350-fold. The efficiency of mismatch extension depends on both the nature of the DNA mismatch and the templating base. The proofreading activity of the 12 possible mismatches varies <3-fold. The data for these three determinants of polymerase-induced mutations indicate that the overall mutation frequency of apPOL is highly dependent on both the intrinsic fidelity of the polymerase and the identity of the template surrounding the potential mismatch. PMID- 24147856 TI - Miniaturization: the clue to clinical application of the artificial placenta. AB - The artificial placenta as a fascinating treatment alternative for neonatal lung failure has been the subject of clinical research for over 50 years. Pumpless systems have been in use since 1986. However, inappropriate dimensioning of commercially available oxygenators has wasted some of the theoretical advantages of this concept. Disproportional shunt fractions can cause congestive heart failure. Blood priming of large oxygenators and circuits dilutes fetal hemoglobin (as the superior oxygen carrier), is potentially infectious, and causes inflammatory reactions. Flow demands of large extracorporeal circuits require cannula sizes that are not appropriate for use in preterm infants. NeonatOx, a tailored low-volume oxygenator for this purpose, has proven the feasibility of this principle before. We now report the advances in biological performance of a refined version of this specialized oxygenator. PMID- 24147858 TI - Impact of CD14 promoter variants on measles vaccine responses and vaccine failure in children from Australia and Mozambique. PMID- 24147859 TI - Expression of neuropeptide Y and pro-opiomelanocortin in hypothalamic arcuate nucleus in 17alpha-ethinyl estradiol-induced intrahepatic cholestasis pregnant rat offspring. AB - AIM: The purpose of this study was to investigate the expression of neuropeptide Y (NPY) and pro-opiomelanocortin (POMC) in the hypothalamic arcuate nucleus of intrahepatic cholestasis pregnant (ICP) offspring. METHODS: The model of ICP rats was established by injecting s.c. 17alpha-ethinyl estradiol. The expression of NPY and POMC in female offspring was determined by quantitative real-time reverse transcription polymerase chain reaction, western blotting and immunohistochemistry at birthday and 6 months. RESULTS: ICP group offspring had lower bodyweight at birthday. ICP offspring were markedly heavier than control offspring after 6 months. mRNA and protein expression of NPY and POMC significantly increased at 6 months as compared with the birthday among control offspring. Among ICP offspring, mRNA and protein expression of NPY and POMC also were higher at 6 months than at birthday. The mRNA and protein expression of NPY were higher in ICP offspring than that of control offspring at birthday. The mRNA and protein expression of POMC were decreased in ICP offspring than that of control offspring. After 6 months, the mRNA expression and protein expression of NPY also were higher in ICP offspring than that of control offspring. The mRNA expression and protein expression of POMC also were decreased in ICP offspring than that of control offspring. The results were confirmed by immunohistochemistry. CONCLUSION: ICP offspring demonstrated evidence of persistent appetite stimulation with significantly upregulated NPY expression and reduced POMC expression at birthday and 6 months. ICP offspring showed a hunger state and then gained weight. PMID- 24147860 TI - Brugada phenocopy clinical reproducibility demonstrated by recurrent hypokalemia. AB - Brugada phenocopies (BrP) are clinical entities that are etiologically distinct from true congenital Brugada syndrome (BrS). BrP are characterized by type 1 or type 2 Brugada electrocardiogram (ECG) patterns in precordial leads V1 -V3 ; however, BrP are elicited by various underlying clinical conditions such as electrolyte disturbances, myocardial ischemia, or poor ECG filters. In this report, we describe the first case of clinically reproducible BrP which is important to the conceptual evolution of BrP. PMID- 24147861 TI - Four-component domino strategy for the combinatorial synthesis of novel 1,4 dihydropyrano[2,3-c]pyrazol-6-amines. AB - An efficient one-pot four-component domino protocol for the combinatorial synthesis of novel 1,4-dihydropyrano[2,3-c]pyrazol-6-amines has been achieved. This transformation presumably occurs via cyclization-Knoevenagel condensation Michael addition-tautomerism-intramolecular O-cyclization-elimination sequence of reactions. The significant features of this reaction include expedient one-pot process, short reaction time, no column chromatographic purification, excellent yield, and readily available starting materials. PMID- 24147862 TI - Radiation stability of cations in ionic liquids. 3. Guanidinium cations. AB - Due to their superb structural versatility, guanidinium cations find increasing use as constituent ions in room temperature ionic liquids (ILs). This versatility allows fine-tuning of hydrophobicity, which is an important concern for the use of ILs as diluents for metal ion separations. However, the presence of six C-N bonds in such cations poses a question, whether the guanidinium based ILs can be considered as diluents for nuclear separations, given that the radiation emitted by the decaying radionuclides can break these relatively weak bonds over the use cycle of the solvent. As nothing is presently known about the radiolytic stability of the guanidinium cations, we addressed this question using 2 dialkylamino-1,3-dimethylimidazolidine based cations (R = Et, Pr, and Bu) as a representative model for the entire class of such cations, and assessed their stability in 2.5 MeV electron beam radiolysis. Electron paramagnetic resonance spectroscopy, nuclear magnetic resonance spectroscopy, and mass spectrometry have been used to establish chemical mechanisms for radiation damage in guanidinium cations. Our conclusion is that radiation stability of these cations is not significantly different from that of more familiar aliphatic and aromatic IL cations. In fact, these cations yield exceptionally stable radicals, and fragmentation occurs only in their radiolytically generated excited states. The predominant chemical pathway for the cation decomposition is the elimination of their aliphatic arms, with radiolytic yields of 0.65 to 1.06 to 1.46 per 100 eV from R = Et to R = Bu, respectively. The total loss of the parent cation was estimated as 2.62, 1.65, and 1.98 species per 100 eV. While this attrition is not negligible, it is comparable to other organic cations that have fewer fissile C-N bonds. Many of the products are either modified guanidinium ions or protonated bases that are not expected to interfere with radionuclide separations. PMID- 24147863 TI - A test of a recently devised method of estimating skeletal age at death using features of the adult acetabulum. AB - Estimation of age at death from adult skeletal remains is highly problematic, due in great part to interpopulation variability in skeletal age changes. Thorough testing of aging methods is therefore of key importance. A method recently devised by Calce (Am J Phys Anthropol 148 (2012): 11-23) for placing adult skeletons into three broad age at death classes (17-39, 40-64, 65+ years) on the basis of acetabular morphology is tested on a collection of 18-19th century AD skeletons (N = 185) of documented age at death from London. Results showed that 45% were correctly assigned to age class using this method. This compares with 81% reported by Calce on 20th century North American material. This indicates significant interpopulation differences in the relationship between the Calce acetabular variables and age, even between populations of European ancestry. Until the sources of this variation are better understood, caution should be used before applying this method to estimate age in unknown skeletons. PMID- 24147865 TI - Monoclonal antibody production and the development of an indirect competitive enzyme-linked immunosorbent assay for screening spiramycin in milk. AB - To monitor spiramycin (SP) residue in milk, a monoclonal antibody (mAb)-based indirect competitive enzyme-linked immunosorbent assay (icELISA) was developed. This study described the preparation of three immunogens and the production of a high-affinity mAb. After optimization, the 50% inhibition concentration (IC50) for the developed icELISA was estimated as 0.97 ng/mL in the assay buffer, and the limit of detection and limit of quantitation were 2.51 and 4.40 MUg/L in the milk matrix. The newly developed assay demonstrated negligible cross-reactivity with 15 other macrolide antibiotics, but not with kitasamycin (23.4%). The mean recoveries ranged from 81 to 103% for the spiked samples (5, 10, and 50 MUg/L), and the coefficient of variation ranged from 5.4 to 9.6%. The icELISA was validated by LC-MS/MS method, and all results demonstrated that it was a suitable screening method for detecting SP residue in milk without requiring a cleanup process. PMID- 24147864 TI - Synthesis and evaluation in monkey of [(18)F]4-fluoro-N-methyl-N-(4-(6 (methylamino)pyrimidin-4-yl)thiazol-2-yl)benzamide ([(18)F]FIMX): a promising radioligand for PET imaging of brain metabotropic glutamate receptor 1 (mGluR1). AB - We sought to develop a PET radioligand that would be useful for imaging human brain metabotropic subtype 1 receptors (mGluR1) in neuropsychiatric disorders and in drug development. 4-Fluoro-N-methyl-N-(4-(6-(methylamino)pyrimidin-4 yl)thiazol-2-yl)benzamide (FIMX, 11) was identified as having favorable properties for development as a PET radioligand. We developed a method for preparing [(18)F]11 in useful radiochemical yield and in high specific activity from [(18)F]fluoride ion and an N-Boc-protected (phenyl)aryliodonium salt precursor (15). In baseline experiments in rhesus monkey, [(18)F]11 gave high brain radioactivity uptake, reflecting the expected distribution of mGluR1 with notably high uptake in cerebellum, which became 47% lower by 120 min after radioligand injection. Pharmacological challenges demonstrated that a very high proportion of the radioactivity in monkey brain was bound specifically and reversibly to mGluR1. [(18)F]11 is concluded to be an effective PET radioligand for imaging mGluR1 in monkey brain and therefore merits further evaluation in human subjects. PMID- 24147866 TI - Leishmanicidal activity of a daucane sesquiterpene isolated from Eryngium foetidum. AB - CONTEXT: Eryngium foetidum L. (Apiaceae) is a traditional herb that has been used for numerous medicinal applications, including as a treatment for parasitic infections, especially in the Neotropics from where it originates. OBJECTIVE: This study evaluates the in vitro leishmanicidal and cytotoxicity activities of isolated compounds based on a bioassay-guided fractionation approach. MATERIALS AND METHODS: Defatted aerial parts of E. foetidum were subjected to extraction with methanol followed by partitioning with n-hexane, ethyl acetate and 50% methanol. Then, the first two fractions were subsequently fractionated by column chromatography and HPLC. Compound identity was confirmed by mass spectrometry and NMR spectroscopy. Leishmania tarentolae (promastigotes) and L. donovani (amastigotes) were used as testing parasites. L6 rat myoblasts were used for cytotoxicity. All extracts and fractions were tested at 20 MUg/mL. RESULTS: The initial methanol extract showed 20% growth inhibition of L. tarentolae. Then, the n-hexane and ethyl acetate fractions were also active showing approximately 40% growth inhibition. From these two fractions, the following compounds were isolated: lasidiol p-methoxybenzoate (1), a daucane sesquiterpene; and 4-hydroxy 1,1,5-trimethyl-2-formyl-cyclohexadien-(2,5)-[alpha-acetoxymethyl-cis-crotonate] (2), a terpene aldehyde ester derivative. Compound 1 inhibited the growth of both L. tarentolae and L. donovani with IC50 values of 14.33 and 7.84 MUM, respectively; and showed no cytotoxicity (IC50 > 50 MUM). Compound 2 was inactive in the L. tarentolae assay (IC50 > 50 MUM). DISCUSSION AND CONCLUSION: This study presented the bioassay-guided fractionation with the leishmanicidal and cytotoxicity activities of two compounds isolated for the first time from an Eryngium species. PMID- 24147868 TI - Full-gestational exposure to nicotine and ethanol augments nicotine self administration by altering ventral tegmental dopaminergic function due to NMDA receptors in adolescent rats. AB - In adult rats, we have shown full-gestational exposure to nicotine and ethanol (Nic + EtOH) augmented nicotine self-administration (SA) (increased nicotine intake) compared to pair-fed (PF) offspring. Therefore, we hypothesized that full gestational exposure to Nic + EtOH disrupts control of dopaminergic (DA) circuitry by ventral tegmental area (VTA) NMDA receptors, augmenting nicotine SA and DA release in nucleus accumbens (NAcc) of adolescents. Both NAcc DA and VTA glutamate release were hyper-responsive to intra-VTA NMDA in Nic + EtOH offspring versus PF (p = 0.03 and 0.02, respectively). Similarly, DA release was more responsive to i.v. nicotine in Nic + EtOH offspring (p = 0.02). Local DL-2-Amino 5-phosphonopentanoic acid sodium salt (AP5) (NMDA receptor antagonist) infusion into the VTA inhibited nicotine-stimulated DA release in Nic + EtOH and PF offspring. Nicotine SA was augmented in adolescent Nic + EtOH versus PF offspring (p = 0.000001). Daily VTA microinjections of AP5 reduced nicotine SA by Nic + EtOH offspring, without affecting PF (p = 0.000032). Indeed, nicotine SA in Nic + EtOH offspring receiving AP5 was not different from PF offspring. Both VTA mRNA transcripts and NMDA receptor subunit proteins were not altered in Nic + EtOH offspring. In summary, adolescent offspring exposed to gestational Nic + EtOH show markedly increased vulnerability to become dependent on nicotine. This reflects the enhanced function of a subpopulation of VTA NMDA receptors that confer greater nicotine-induced DA release in NAcc. We hypothesized that concurrent gestational exposure to nicotine and ethanol would disrupt the control of VTA dopaminergic circuitry by NMDA receptors. Resulting in the augmented nicotine self-administration (SA) in adolescent offspring. PMID- 24147867 TI - Direct isolation of flavonoids from plants using ultra-small anatase TiO2 nanoparticles. AB - Surface functionalization of nanoparticles has become an important tool for in vivo delivery of bioactive agents to their target sites. Here we describe the reverse strategy, nanoharvesting, in which nanoparticles are used as a tool to isolate bioactive compounds from living cells. Anatase TiO2 nanoparticles smaller than 20 nm form strong bonds with molecules bearing enediol and especially catechol groups. We show that these nanoparticles enter plant cells, conjugate enediol and catechol group-rich flavonoids in situ, and exit plant cells as flavonoid-nanoparticle conjugates. The source plant tissues remain viable after treatment. As predicted by the surface chemistry of anatase TiO2 nanoparticles, quercetin-based flavonoids were enriched amongst the nanoharvested flavonoid species. Nanoharvesting eliminates the use of organic solvents, allows spectral identification of the isolated compounds, and opens new avenues for use of nanomaterials for coupled isolation and testing of bioactive properties of plant synthesized compounds. PMID- 24147870 TI - Tris(3,5-di-tert-butylcatecholato)molybdenum(VI): Lewis acidity and nonclassical oxygen atom transfer reactions. AB - In the solid state, tris(3,5-di-tert-butylcatecholato)molybdenum(VI) forms a dimer with seven-coordinate molybdenum and bridging catecholates. NMR spectroscopy indicates that the dimeric structure is retained in solution. The molybdenum center has a high affinity for Lewis bases such as pyridine or pyridine-N-oxide, forming seven-coordinate monomers with a capped octahedral geometry, as illustrated by the solid-state structure of (3,5-(t)Bu2Cat)3Mo(py). Structural data indicate that the complexes are best considered as Mo(VI) with substantial pi donation from the nonbridging catecholates to molybdenum. Both the dimeric and the monomeric tris(catecholates) react rapidly with water to form free catechol and oxomolybdenum bis(catecholate) complexes. Monooxomolybdenum complexes are also obtained, more slowly, on reaction with dioxygen, with organic products consisting mostly of 3,5-di-tert-butyl-1,2-benzoquinone with minor amounts of the extradiol oxidation product 4,6-di-tert-butyl-1-oxacyclohepta-4,6 diene-2,3-dione. The pyridine-N-oxide complex reacts on heating (with excess pyO) to form initially (3,5-(t)Bu2Cat)2MoO(Opy) and ultimately MoO3(Opy), with quinone and free pyridine as the only organic products. The decay of (3,5 (t)Bu2Cat)3Mo(Opy) shows an accelerated, autocatalytic profile because the oxidation of its product, (3,5-(t)Bu2Cat)2MoO(Opy), produces an oxo-rich, catecholate-poor intermediate which rapidly conproportionates with (3,5 (t)Bu2Cat)3Mo(Opy), providing an additional pathway for its conversion to the mono-oxo product. The tris(catecholate) fragment Mo(3,5-(t)Bu2Cat)3 deoxygenates Opy in this nonclassical oxygen atom transfer reaction slightly less rapidly than does its oxidized product, MoO(3,5-(t)Bu2Cat)2. PMID- 24147869 TI - On-demand treatment with alverine citrate/simeticone compared with standard treatments for irritable bowel syndrome: results of a randomised pragmatic study. AB - BACKGROUND: In routine practice, irritable bowel syndrome (IBS) symptoms are often difficult to be relieved and impair significantly patients' quality of life (QoL). A randomised, double-blind, placebo-controlled study has shown the efficacy of alverine citrate/simeticone (ACS) combination for IBS symptom relief. AIM: As IBS symptoms are often intermittent, this pragmatic study was designed to compare the efficacy of an on-demand ACS treatment vs. that of usual treatments. METHODS: Rome III IBS patients were enrolled by 87 general practitioners who were randomly allocated to one of two therapeutic strategies: on-demand ACS or usual treatment chosen by the physician. The primary outcome measure was the improvement of the IBSQoL score between inclusion and month 6. RESULTS: A total of 436 patients (mean age: 54.4 years; women: 73.4%) were included, 222 in the ACS arm and 214 patients in the usual treatment arm, which was mainly antispasmodics. At 6 months, improvement of IBSQoL was greater with ACS than with the usual treatment group (13.8 vs. 8.4; p < 0.0008). The IBS-severity symptom score (IBS-SSS) was lower with ACS than in the usual treatment arm with a mean (SE) decrease of 170.0 (6.6) vs. 110.7 (6.7), respectively (p = 0.0001). An IBS SSS < 75 was more frequent in the ACS group (37.7% vs. 16.0%; p < 0.0001). Improvement of both abdominal pain and bloating severity was also greater with the on-demand ACS treatment, which was associated with both lower direct and indirect costs. CONCLUSIONS: After 6 months, on-demand ACS treatment led to a greater improvement of QoL, reduced the burden of the disease and was more effective for IBS symptom relief than usual treatments. PMID- 24147871 TI - Platinum-catalyzed one-pot alkenylation of aldehydes using alkynes and triethylsilane: dual catalysis by platinum(II) chloride. AB - The PtCl2-catalyzed hydrosilylation of terminal alkynes with triethylsilane and subsequent alkenylation of aldehydes with the resultant (E)-alkenylsilanes in a one-pot manner are described. By adding p-benzoquinone and LiI, the latter alkenylation step proceeds smoothly to give allyl silyl ethers in moderate to high yields. This one-pot alkenylation is tolerant to a reasonable range of functional groups. PtCl2 plays a dual role as hydrosilylation and alkenylation catalysts. PMID- 24147872 TI - Mutational and structural characteristics of four novel heterozygous C-propeptide mutations in the proalpha1(I) collagen gene in Chinese osteogenesis imperfecta patients. AB - OBJECTIVE: Osteogenesis imperfecta (OI) with C-propeptide mutations in proalpha1(I) collagen gene are rarely reported. We report four novel C-propeptide mutations in COL1A1 gene from Chinese OI patients. METHODS: Clinical characteristics and radiographic findings were described for four OI patients with C-propeptide mutations in proalpha1(I) collagen gene. Mutations were identified by traditional DNA sequencing based on PCR. The locations of mutations were mapped, and in silico prediction was conducted to analyse their effects on protein structure. Histology studies of skin, bone and muscle tissues were performed. RESULTS: All four C-propeptide heterozygous mutations identified were in the COL1A1 gene. Heterozygous mutation of c.4021C>T (p.Q1341X) disrupted the chain recognition sequences and was found in patients with type IV OI. Mutations of c.3893C>A (p.T1298N) and c.3897C>A (p.C1299X) impeded the formation of disulphide bonds and were associated with type IV OI phenotype. Missense mutation of c.3835A>C (p.N1279H) disrupted Ca(2+) binding and led to a severe type III OI phenotype. In silico programs predicted damaging effects for the patients with type III OI and the creation of an exonic splicing enhancer hexamer sequence for the type IV patients. Expansion of the bone marrow cavity and disorganization of osteocyte alignment was evident in bone specimens; and muscle atrophy and enlargement of intramuscular connective tissue were found in muscle specimens. CONCLUSIONS: Four novel C-propeptide mutations in proalpha1(I) collagen gene were identified in Chinese OI patients, and their clinical severity ranged from moderate type IV to severe type III. In silico prediction of the mutation effect and histological characteristics of tissue specimens was in accordance with the OI phenotypes. PMID- 24147873 TI - Cyclic constraints on conformational flexibility in gamma-peptides: conformation specific IR and UV spectroscopy. AB - Single-conformation spectroscopy has been used to study two cyclically constrained and capped gamma-peptides: Ac-gammaACHC-NHBn (hereafter gammaACHC, Figure 1a), and Ac-gammaACHC-gammaACHC-NHBn (gammagammaACHC, Figure 1b), under jet-cooled conditions in the gas phase. The gamma-peptide backbone in both molecules contains a cyclohexane ring incorporated across each Cbeta-Cgamma bond and an ethyl group at each Calpha. This substitution pattern was designed to stabilize a (g+, g+) torsion angle sequence across the Calpha-Cbeta-Cgamma segment of each gamma-amino acid residue. Resonant two-photon ionization (R2PI), infrared-ultraviolet hole-burning (IR-UV HB), and resonant ion-dip infrared (RIDIR) spectroscopy have been used to probe the single-conformation spectroscopy of these molecules. In both gammaACHC and gammagammaACHC, all population is funneled into a single conformation. With RIDIR spectra in the NH stretch (3200 3500 cm(-1)) and amide I/II regions (1400-1800 cm(-1)), in conjunction with theoretical predictions, assignments have been made for the conformations observed in the molecular beam. gammaACHC forms a single nearest-neighbor C9 hydrogen-bonded ring whereas gammagammaACHC takes up a next-nearest-neighbor C14 hydrogen-bonded structure. The gas-phase C14 conformation represents the beginning of a 2.614-helix, suggesting that the constraints imposed on the gamma peptide backbone by the ACHC and ethyl groups already impose this preference in the gas-phase di-gamma-peptide, in which only a single C14 H-bond is possible, constituting one full turn of the helix. A similar conformational preference was previously documented in crystal structures and NMR analysis of longer gamma peptide oligomers containing the gammaACHC subunit [Guo, L., et al. Angew. Chem. Int. Ed. 2011, 50, 5843-5846]. In the gas phase, the gammaACHC-H2O complex was also observed and spectroscopically interrogated in the molecular beam. Here, the monosolvated gammaACHC retains the C9 hydrogen bond observed in the bare molecule, with the water acting as a bridge between the C-terminal carbonyl and the pi-cloud of the UV chromophore. This is in contrast to the unconstrained gamma-peptide-H2O complex, which incorporates H2O into both C9 and amide-stacked conformations. PMID- 24147874 TI - Ureteral injuries sustained during robot-assisted radical prostatectomy. AB - BACKGROUND AND PURPOSE: During the last decade, the annual volume of robot assisted prostatectomies performed in the United States has risen steadily. Refinements in surgical technique, understanding of anatomy, and experience have led to more complex patients being offered surgery for management of organ confined prostate cancer. Complication rates of robot-assisted prostatectomy have been reported in several articles; however, a paucity of data exists when evaluating ureteral injuries sustained during robot-assisted prostatectomy. No standardized universal criteria for reporting and grading of complications exists; therefore, the Martin-Donat criteria with Clavien-Dindo classification system were used to evaluate ureteral injuries in our series. PATIENTS AND METHODS: From January 2001 to June 2013, 6442 consecutive patients were treated with robot-assisted prostatectomy at the same institution by one of five surgeons. All complications were documented through a prospectively maintained prostate cancer database with supplementation from electronic medical records, operative and nursing notes, claims data, discharge summaries, outpatient and emergency visits, institutional morbidity and mortality data, as well as National Surgical Quality Improvement Program data. The Martin-Donat criteria were used to facilitate the accurate and comprehensive reporting of surgical complications while complication severity was assigned following the Clavien-Dindo classification system. RESULTS: Three patients sustained ureteral injuries (ureteral transection) in our series. Both surgeons were beyond their learning curve (greater than 1000 cases) when the injuries occurred; one patient needed readmission, and all patients had risk factors predisposing them to ureteral injury. Each patient was managed with robot-assisted ureteroneocystostomy (1), open transureteroureterostomy (1) and robot-assisted ureteroureterostomy (1) respectively. CONCLUSIONS: Ureteral injuries are uncommon; however, thorough preoperative evaluation and surgical planning could identify patients at high risk for sustaining ureteral injury during prostatectomy. Measures can be taken preoperatively or intraoperatively to reduce the probability of ureteral injury, eliminating the necessity for additional procedures postoperatively. PMID- 24147875 TI - New roles for icosahedral clusters in intermetallic phases: micelle-like segregation of Ca-Cd and Cu-Cd interactions in Ca10Cd27Cu2. AB - Despite significant progress in the structural characterization of the quasicrystalline state, the chemical origins of long- and short-range icosahedral order remain mysterious and a subject of debate. In this Article, we present the crystal structure of a new complex intermetallic phase, Ca10Cd27Cu2 (mC234.24), whose geometrical features offer clues to the driving forces underlying the icosahedral clusters that occur in Bergman-type quasicrystals. Ca10Cd27Cu2 adopts a C-centered monoclinic superstructure of the 1/1 Bergman approximant structure, in which [110] layers of Bergman clusters in the 1/1 structure are separated through the insertion of additional atoms (accompanied by substantial positional disorder). An examination of the coordination environments of Ca and Cu (in the ordered regions) reveals that the structure can be viewed as a combination of coordination polyhedra present in the nearest binary phases in the Ca-Cd-Cu compositional space. A notable feature is the separation of Ca-Cd and Cu-Cd interactions, with Bergman clusters emerging as Ca-Cd Friauf polyhedra (derived from the MgZn2-type CaCd2 phase) encapsulate a Cu-Cd icosahedron similar to those appearing in Cu2Cd5. DFT chemical pressure calculations on nearby binary phases point to the importance of this segregation of Ca-Cd and Cu-Cd interactions. The mismatch in atomic size between Cu and Cd leads to an inability to satisfy Ca-Cu and Ca-Cd interactions simultaneously in the Friauf polyhedra of the nearby Laves phase CaCd2. The relegation of the Cu atoms to icosahedra prevents this frustration while nucleating the formation of Bergman clusters. PMID- 24147876 TI - Community pharmacists' attitudes toward palliative care: an Australian nationwide survey. AB - BACKGROUND: Pharmacists are among the most accessible health care professionals in the community, yet are often not involved in community palliative care teams. OBJECTIVE: We investigated community pharmacists' attitudes, beliefs, feelings, and knowledge about palliative care as a first step towards determining how best to facilitate the inclusion of community pharmacists on the palliative care team. METHOD: A cross-sectional descriptive survey design was used. SUBJECTS: Community pharmacists around Australia were invited to participate; 250 completed surveys were returned. MEASUREMENTS: A survey was constructed to measure pharmacists' knowledge and experience, emotions and beliefs about palliative care. RESULTS: Pharmacists were generally positive about providing services and supports for palliative care patients, yet they also reported negative beliefs and emotions about palliative care. In addition, pharmacists had good knowledge of some aspects of palliative care, but misconceptions about other aspects. Pharmacists' beliefs and knowledge about palliative care predicted--and therefore underpinned- a positive attitude towards palliative care and the provision of services and supports for palliative care patients. CONCLUSION: The results provide evidence that pharmacists need training and support to facilitate their involvement in providing services and supports for palliative care patients, and highlight areas that training and support initiatives should focus on. PMID- 24147877 TI - Research priorities in geriatric palliative care: policy initiatives. AB - Coordinated palliative care matched to patient needs improves quality of care for vulnerable patients with serious illness and reduces costly use of hospitals and emergency departments. Unfortunately, there is a disconnect in translating geriatric palliative care models and principles into policy and widespread practice. Gaps in policy-relevant research are addressed, including implementation strategies to scale up existing care models, the role of palliative care and geriatrics in health care payment reform efforts, development of quality measures for complex patients, strategies to address workforce shortages, and an approach to hospice reform. PMID- 24147878 TI - The association between BMI and hospitalization for heart failure in 83,021 persons with Type 2 diabetes: a population-based study from the Swedish National Diabetes Registry. AB - AIM'S: The aim was to To study the relationship between BMI and hospitalization for heart failure in people with Type 2 diabetes. METHODS: We identified 83 021 individuals with Type 2 diabetes from the Swedish National Diabetes Registry during 1998-2003, who were followed until hospitalization for heart failure, death or end of follow-up on 31 December 2009. Cox regression analyses were performed, adjusting for age, sex, HbA(1c), blood pressure, diabetes duration, smoking, microalbuminuria, cardiac co-morbidities, glucose-lowering and anti hypertensive medications. RESULTS: During a median follow-up of 7.2 years, 10 969 patients (13.2%) were hospitalized with heart failure. By categories of BMI, with BMI 20 to < 25 kg/m(2) as the reference, hazard ratios for patients during follow up were 1.07 (95% CI 0.91-1.26) for a mean BMI of < 20 kg/m(2), 1.04 (95% CI 0.98 1.11) for BMI 25 to < 27.5 kg/m(2), 1.22 (95% CI 1.15-1.30) for BMI 27.5 to < 30 kg/m(2), 1.54 (95% CI 1.45-1.63) for BMI 30 to < 35 kg/m(2), 2.16 (95% CI 2.00 2.33) for BMI 35 to < 40 kg/m(2) and 3.22 (95% CI 2.88-3.60) for BMI 40 kg/m(2) or higher. There was a significant interaction between BMI and sex (P = 0.0006), with numerically higher hazard ratios for hospitalization for heart failure within each BMI category for men than for women. CONCLUSIONS: Obesity is strongly related to hospitalization for heart failure in people with Type 2 diabetes, and the relationship is somewhat stronger for men than for women. Preventing weight gain and promoting weight loss may be crucial in reducing the incidence of future hospitalizations for heart failure in this population. PMID- 24147879 TI - Central coherence, organizational strategy, and visuospatial memory in children and adolescents with anorexia nervosa. AB - The vast majority of studies in anorexia nervosa that have investigated the domains of central coherence, organizational strategy, and visuospatial memory have focused on adult samples. In addition, studies investigating visuospatial memory have focused on free recall. No study to date has reported the association between recognition memory and central coherence or organizational strategy in younger people with this disorder, yet the capacity to recognize previously seen visual stimuli may contribute to overall visuospatial ability. Therefore, we investigate these domains in children and adolescents with anorexia nervosa compared to age- and gender-matched healthy controls. There were no significant group differences in immediate, delayed, or recognition memory, central coherence, or organization strategy. When compared with controls, patients with anorexia nervosa scored significantly higher on accuracy and took significantly longer when copying the Rey Complex Figure Task. Caution must be taken when interpreting these findings due to lower-than-expected scores in memory performance in the control group and because of a potential lack of sensitivity in the measures used when assessing this younger population. For neuropsychological functions where no normative data exist, we need a deeper, more thorough knowledge of the developmental trajectory and its assessment in young people in the general population before drawing conclusions in anorexia nervosa. PMID- 24147880 TI - Biocomposite cryogels as tissue-engineered biomaterials for regeneration of critical-sized cranial bone defects. AB - Analysis of the in vivo regeneration capability of any tissue-engineered biomaterial is necessary once it shows potential characteristics during in vitro studies. Thus, we applied polyvinyl alcohol-tetraethylorthosilicate-alginate calcium oxide (PTAC) biocomposite cryogel on critical-sized cranial bone defects in wistar rats for examining the comparative bone regeneration of cryogel-treated and nontreated defects over a period of 4 weeks. An in-depth analysis was performed from macroscopic level till the gene level. Bone regeneration in cryogel-treated defects was clearly evident from the results, whereas the nontreated group did not show any defect healing except at few peripheral areas. At the macroscopic level, micro-computed tomography analysis revealed new bone formation. This was further confirmed at the cellular level, wherein, new bone formation was demonstrated by hematoxylin and eosin staining. Osteoblastic differentiation was further validated by immunohistological staining of runt related transcription factor-2 (Runx-2) protein and via calcium-phosphate crystal formation after 2 weeks through scanning electron microscopy and energy dispersive X-ray spectroscopy. Finally, at the gene level, real-time PCR analysis confirmed the mRNA expression of osteoblastic markers, that is, runx-2, collagen type I (Col I), alkaline phosphatase (ALP), and osteocalcin (OCN). Therefore, the results of in vivo cranial defect model studies suggest that PTAC biocomposite cryogels can show suitable potential for human bone regeneration. PMID- 24147881 TI - Preconditioning with levosimendan before implantation of left ventricular assist devices. AB - In this retrospective study, we investigated the impact of preconditioning of the right ventricle with the calcium sensitizer levosimendan immediately before left ventricular assist device (LVAD) implantation on outcome and survival. Nine consecutive LVAD patients (seven suffering from dilative cardiomyopathy and two from ischemic cardiomyopathy) with echocardiographic and invasive evidence of right heart insufficiency received levosimendan with 0.1 MUg/kg body weight/min for 24 h before implantation of the assist device (seven HeartWare and two Jarvik 2000). Administration of levosimendan was safe and had not to be discontinued in any patient. We observed no relevant side effects. Twelve-month survival after implantation of the LVAD was 89% representing a superior outcome compared with the fifth INTERMACS registry data with 75% survival. Two temporary extracorporeal membrane-oxygenation implantations were necessary due to intraoperative right ventricular dysfunction. Only one patient died 5 weeks after LVAD implantation of multiorgan failure, five patients were successfully transplanted, and three patients underwent LVAD implantation for destination therapy. Levosimendan might improve clinical outcome and survival when used as pretreatment in patients with right heart insufficiency prior to LVAD implantation. However, we recommend a larger controlled trial in the future to confirm our preliminary results. PMID- 24147882 TI - EphB4-targeted imaging with antibody h131, h131-F(ab')2 and h131-Fab. AB - Accumulating evidence suggests that overexpression of the tyrosine kinase receptor EphB4, a mediator of vascular development, is a novel target for tumor diagnosis, prognosis and therapy. Noninvasive imaging of EphB4 expression could therefore be valuable for evaluating disease course and therapeutic efficacy at the earliest stages of anti-EphB4 treatment. In this study, we systematically investigated the use of anti-EphB4 antibody h131 (150 kDa) and its fragments (h131-F(ab')2, 110 kDa; h131-Fab, 50 kDa) for near-infrared fluorescence (NIRF) imaging of EphB4 expression in vivo. h131-F(ab')2 and h131-Fab were produced through pepsin and papain digestion of h131 respectively, whose purity was confirmed by FPLC and SDS-PAGE. After conjugation with Cy5.5, in vivo characteristics of h131, h131-F(ab')2 and h131-Fab were evaluated in EphB4 positive HT29 tumor model. Although h131-Cy5.5 demonstrated highest tumor uptake among these probes, its optimal tumor uptake level was obtained at 2 days post injection (p.i.). For h131-Fab-Cy5.5, maximum tumor uptake was achieved at 4 h p.i. However, no significant difference was observed between h131-Fab-Cy5.5 and hIgG-Fab-Cy5.5, indicating the tumor accumulation was mainly caused by passive targeting. In contrast, h131-F(ab')2-Cy5.5 demonstrated prominent tumor uptake at 6 h p.i. The target specificity was confirmed by hIgG-F(ab')2-Cy5.5 control and immunofluorescent staining. Collectively, h131-F(ab')2 exhibited prominent and specific tumor uptake at early time points, which suggests it is a promising agent for EphB4-targeted imaging. PMID- 24147883 TI - Prevalence and implications of a difference in systolic blood pressure between one arm and the other in vascular surgical patients. AB - Inter-arm differences in blood pressure may confound haemodynamic management in vascular surgery. We evaluated 898 patients in the vascular pre-assessment clinic to determine the prevalence of inter-arm differences in systolic and mean arterial pressure, quantify the consequent risk of clinical error in siting monitoring peri-operatively and evaluate systolic inter-arm difference as a predictor of all-cause mortality (median follow-up 49 months). The prevalence of a systolic inter-arm difference >= 15 mmHg was 26% (95% CI 23-29%). The prevalence of an inter-arm mean arterial pressure difference >= 10 mmHg was 26% (95% CI 23-29%) and 11% (95% CI 9-13%) for a difference >= 15 mmHg. Monitoring could be erroneously sited in an arm reading lower for systolic pressure once in every seven to nine patients. The hazard ratio for a systolic inter-arm difference >= 15 mmHg vs < 15 mmHg was 1.03 (95% CI 0.78-1.36, p = 0.84). Large inter-arm blood pressure differences are common in this population, with a high potential for monitoring errors. Systolic inter-arm difference was not associated with medium-term mortality. [Correction added on 17 October 2013, after first online publication: In the Summary the sentence beginning 'We evaluated 898 patients' was corrected from (median (IQR [range]) follow-up 49 months) to read (median follow up 49 months)]. PMID- 24147884 TI - Emergency cerclage versus expectant management for prolapsed fetal membranes: a retrospective, comparative study. AB - AIM: To compare outcomes after emergency cerclage versus expectant management for prolapsed fetal membranes in women with cervical incompetency. METHODS: The January 2000-December 2012 hospital database was analyzed to identify women managed for prolapsed fetal membranes who did not have premature rupture of membranes, clinically discernible chorioamnionitis, or treatment-resistant uterine contractions from 15 to 26 weeks of gestation retrospectively. Durations of pregnancy prolongation and numbers of deliveries after 32 and 28 weeks were compared between women undergoing emergency cervical cerclage and those receiving expectant management. RESULTS: Fifteen of the 35 women underwent emergency cervical cerclage ('cerclage group'), while the other 20 were managed expectantly ('bedrest group'). In the cerclage group, median gestational ages at procedure and delivery times were 22.6 (15.9-26.1) and 32.4 (19.4-41.6) weeks, respectively. Median gestational ages on admission and at delivery in the bedrest group were 23.4 (21.1-26.4) and 26.0 (23.1-36.4) weeks, respectively. The median duration of pregnancy prolongation was 44 days (4-165) in the cerclage group and 12.5 days (2-93) in the bedrest group (P < 0.01). Numbers of deliveries after 28 and 32 weeks were both significantly higher in the cerclage than in the bedrest group (P < 0.05). CONCLUSION: In women with prolapsed fetal membranes but no signs of infection or painful uterine contractions, emergency cervical cerclage prolonged pregnancy duration as compared with expectant management. PMID- 24147885 TI - Spatio-temporal analysis of cellulose synthesis during cell plate formation in Arabidopsis. AB - During cytokinesis a new crosswall is rapidly laid down. This process involves the formation at the cell equator of a tubulo-vesicular membrane network (TVN). This TVN evolves into a tubular network (TN) and a planar fenestrated sheet, which extends at its periphery before fusing to the mother cell wall. The role of cell wall polymers in cell plate assembly is poorly understood. We used specific stains and GFP-labelled cellulose synthases (CESAs) to show that cellulose, as well as three distinct CESAs, accumulated in the cell plate already at the TVN stage. This early presence suggests that cellulose is extruded into the tubular membrane structures of the TVN. Co-localisation studies using GFP-CESAs suggest the delivery of cellulose synthase complexes (CSCs) to the cell plate via phragmoplast-associated vesicles. In the more mature TN part of the cell plate, we observed delivery of GFP-CESA from doughnut-shaped organelles, presumably Golgi bodies. During the conversion of the TN into a planar fenestrated sheet, the GFP-CESA density diminished, whereas GFP-CESA levels remained high in the TVN zone at the periphery of the expanding cell plate. We observed retrieval of GFP CESA in clathrin-containing structures from the central zone of the cell plate and from the plasma membrane of the mother cell, which may contribute to the recycling of CESAs to the peripheral growth zone of the cell plate. These observations, together with mutant phenotypes of cellulose-deficient mutants and pharmacological experiments, suggest a key role for cellulose synthesis already at early stages of cell plate assembly. PMID- 24147886 TI - Potent production of capsaicinoids and capsinoids by Capsicum peppers. AB - The fundamental structure of capsinoids is a fatty acid ester with vanillyl alcohol, whereas in capsaicinoids, a fatty acid amide is linked to vanillylamine. To clarify the relationship between their biosynthesis in Capsicum plants, we carried out an in vivo tracer experiment using stable isotopically labeled putative precursors. Liquid chromatography-tandem mass spectrometry was used to measure the uptake of isotopes into metabolites after injection of the labeled precursors into intact fruits of a pungent cultivar, Peru, and a non-pungent cultivar, CH-19 Sweet. Labeled vanillylamine was incorporated into capsaicinoids in both cultivars. While labeled vanillyl alcohol was incorporated into capsinoids in both cultivars, the accumulation of intact capsaicinoids in Peru was suppressed by over 60% after administration of vanillyl alcohol. In Peru, labeled vanillin was converted to both vanillylamine and, in 5-fold excess, vanillyl alcohol. Moreover, labeled vanillin was converted exclusively to vanillyl alcohol in CH-19 Sweet. These data are consistent with the incorporation of labeled vanillin into capsaicinoids and capsinoids in both cultivars. We conclude that pungent cultivars are highly potent producers of vanillyl alcohol that is incorporated into capsinoids and that biosynthesis of capsinoids is catalyzed by capsaicin synthase. PMID- 24147887 TI - Novel ultrasound-promoted parallel synthesis of trifluoroatrolactamide library via a one-pot Passerini/hydrolysis reaction sequence and their fungicidal activities. AB - An ultrasound-promoted one-pot Passerini/hydrolysis reaction sequence has been developed for the synthesis of trifluoroatrolactamide derivatives using a diverse range of trifluoroacetophenones and isonitriles in acetic acid. Parallel synthesis in a centrifuge tube using a noncontact ultrasonic cell crusher was used in this study as an efficient method for the rapid generation of combinatorial trifluoroatrolactamide libraries, and subsequent biochemical evaluation of the resulting compounds indicated that they possessed excellent broad-spectrum fungicidal activities. N-(4-chlorophenyl)-2-(4-ethylphenyl)-3,3,3 trifluoro-2-hydroxypropanamide and N-(4-chlorophenyl)-3,3,3-trifluoro-2-hydroxy-2 (4-methoxyphenyl)propanamide, in particular, showed significant fungicidal activities against all of the fungal species tested in the current study. PMID- 24147888 TI - Development of a mucin4-targeting SPIO contrast agent for effective detection of pancreatic tumor cells in vitro and in vivo. AB - In search of a unique and reliable contrast agent targeting pancreatic adenocarcinoma, new multifunctional nanoparticles (MnMEIO-silane-NH2-(MUC4)-mPEG NPs) were successfully developed in this study. Mucin4-expression levels were determined through different imaging studies in a panel of pancreatic tumor cells (HPAC, BxPC-3, and Panc-1) both in vitro and in vivo studies. The in vitro T2 weighted MR imaging study in HPAC and Panc-1 tumor cells treated with NPs showed 89.1 +/- 5.7% and -0.9 +/- 0.2% contrast enhancement, whereas in in vivo study, it is found to be -81.5 +/- 4.5% versus -19.6 +/- 5.2% (24 h postinjection, 7.0 T), respectively. The T2-weighted MR and optical imaging studies revealed that the novel contrast agent can specifically and effectively target to mucin4 expressing tumors in nude mice. Hence, it is suggested that MnMEIO-silane-NH2 (MUC4)-mPEG NPs are able to provide an efficient and targeted delivery of MUC4 antibodies to mucin4-expressing pancreatic tumors. PMID- 24147890 TI - Stress-mediated modulations in dopaminergic system and their subsequent impact on behavioral and oxidative alterations: an update. AB - CONTEXT: Stress-induced changes in the dopaminergic system and subsequent enhancement of oxidative load and behavior are associated with a wide range of central and peripheral nervous disorders. Dopamine acts as a key neurotransmitter in the brain plays an important role in the regulation of motor and limbic functions. OBJECTIVE: This article reviews the effect of stress on central dopaminergic system and its subsequent impact on the alterations in behavior and oxidative stress. METHODS: A literature survey in PubMed (Bethesda, MD), Scopus (Philadelphia, PA), SciFinder (Columbus, OH) and Google Scholar (PMV, CA) was performed to gather information regarding the role of stress on central dopaminergic system and its associated behavioral and oxidative alterations. RESULTS: Our collective data on behavioral studies and oxidative distress in stressful conditions show the functional reduction in dopaminergic neuronal system that could be one of the factors for the development of stress-induced motor suppression. Collectively, stress caused significant behavioral and oxidative alterations via suppression of neuronal functions of the central dopaminergic system. CONCLUSIONS: This study provides an insight into the overall pathophysiological alterations in neuronal functions of the central dopaminergic system caused by acute and chronic unpredictable stress that, in our opinion, represent optimal utility as future therapeutic targets for neurodegenerative disorders. PMID- 24147889 TI - The anatomy of a pipe bomb explosion: measuring the mass and velocity distributions of container fragments. AB - Improvised explosive devices such as pipe bombs are prevalent due to the availability of materials and ease of construction. However, little is known about how these devices actually explode, as few attempts to characterize fragmentation patterns have been attempted. In this study, seven devices composed of various pipe materials (PVC, black steel, and galvanized steel) and two energetic fillers (Pyrodex and Alliant Red Dot) were initiated and the explosions captured using high-speed videography. The video footage was used to calculate fragment velocities, which were represented as particle velocity vector maps. In addition, the fragments were weighed. The results demonstrate a correlation between the type of energetic filler and both the size and velocity of the fragments. Larger fragments were produced by Pyrodex filler indicating a less complete fragmentation, compared with smaller fragments produced by double-base smokeless powder. Additionally, higher fragment velocities were seen with Alliant Red Dot filler. PMID- 24147892 TI - Salvage therapy of refractory severe aplastic anemia by decreasing cyclosporine dose regimen. AB - Optimal modalities for immunosuppressive therapy (IST) for severe aplastic anemia (SAA) have to be determined, and especially cyclosporine (CyA) dosing to promote regulatory T cells (Treg) which are lacking and which account for physiopathological mechanisms. We are reporting on three cases of pediatric patients suffering from SAA, initially without hematological response between 4 and 7 months after IST, and who have responded 2 months after the decrease in CyA target trough blood levels to 100 ng/mL, and one case which has early responded by applying low trough blood levels from the beginning. As it has been demonstrated that Treg increase in IST responders and that Treg are stimulated only by low CyA concentrations, these case series suggest that lower CyA doses than actually recommended could be more efficient to enhance the proportion of responders. This report highlights a new field of perspectives for the treatment for SAA. PMID- 24147893 TI - Providing quality nutrition care in acute care hospitals: perspectives of nutrition care personnel. AB - BACKGROUND: Malnutrition is common in acute care hospitals worldwide and nutritional status can deteriorate during hospitalisation. The aim of the present qualitative study was to identify enablers and challenges and, specifically, the activities, processes and resources, from the perspective of nutrition care personnel, required to provide quality nutrition care. METHODS: Eight hospitals participating in the Nutrition Care in Canadian Hospitals study provided focus group data (n = 8 focus groups; 91 participants; dietitians, dietetic interns, diet technicians and menu clerks), which were analysed thematically. RESULTS: Five themes emerged from the data: (i) developing a nutrition culture, where nutrition practice is considered important to recovery of patients and teams work together to achieve nutrition goals; (ii) using effective tools, such as screening, evidence-based protocols, quality, timely and accurate patient information, and appropriate and quality food; (iii) creating effective systems to support delivery of care, such as communications, food production and delivery; (iv) being responsive to care needs, via flexible food systems, appropriate menus and meal supplements, up to date clinical care and including patient and family in the care processes; and (v) uniting the right person with the right task, by delineating roles, training staff, providing sufficient time to undertake these important tasks and holding staff accountable for their care. CONCLUSIONS: The findings of the present study are consistent with other work and provide guidance towards improving the nutrition culture in hospitals. Further empirical work on how to support successful implementation of nutrition care processes is needed. PMID- 24147894 TI - Stem cells derived from tooth periodontal ligament enhance functional angiogenesis by endothelial cells. AB - In regenerative medicine approaches involving cell therapy, selection of the appropriate cell type is important in that the cells must directly (differentiation) or indirectly (trophic effects) participate in the regenerative response. Regardless of the mode of action of the cells, angiogenesis underlies the success of these approaches. Stem cells derived from tooth tissues, specifically the periodontal ligament of teeth (periodontal ligament stem cells [PDLSCs]), have recently been identified as a good source of multipotent cells for cell therapies. PDLSCs have demonstrated properties similar to mesenchymal stem cells (MSCs), yet, unlike MSCs, their vascular potential has not been previously demonstrated. Thus, the aim of this study was to determine if PDLSCs could modulate angiogenesis. In comparison to MSCs and stem cells derived from tooth pulp tissues (SHEDs), we first determined if PDLSCs released soluble proangiogenic factors with the capacity to induce vessel formation by endothelial cells (ECs). Next, the ability of PDLSCs to modulate angiogenesis was examined through their cotransplantation with ECs in subcutaneous sites of immunocompromised mice. Finally, the stability of the PDLSC-mediated vasculature was determined through evaluation of the maturity and functionality of the vessels formed following PDLSC transplantation. It was determined that PDLSCs produced appreciable levels of vascular endothelial growth factor and basic fibroblast growth factor-2, and additionally, were able to initiate in vitro angiogenesis of ECs comparable to MSC- and SHED-mediated angiogenesis. In vivo cotransplantation of ECs with PDLSCs significantly (>50% increase) enhanced the number of blood vessels formed relative to transplantation of ECs alone. Finally, vessels formed following PDLSC cotransplantation were more mature and less permeable than those formed after transplantation of EC alone. These data demonstrate for the first time that PDLSCs have vascular potential, which could make them a very attractive cell population for utilization in regenerative cell therapies. PMID- 24147895 TI - The micronutrient supplements, zinc sulphate and folic acid, did not ameliorate sperm functional parameters in oligoasthenoteratozoospermic men. AB - We investigated the effects of folic acid and zinc sulphate supplementation on the improvement of sperm function in subfertile oligoasthenoteratozoospermic (OAT) men. Eighty-three OAT men participated in a 16-week intervention randomised, double-blind clinical trial with daily treatment of folic acid (5 mg day(-1) ) and zinc sulphate (220 mg day(-1) ), or placebo. Before and after treatment, semen and blood samples were obtained for determining sperm concentration, motility, and morphology, sperm viability, sperm mitochondrial function, sperm chromatin status using toluidine blue, aniline blue, acridine orange and chromomycin A3 staining; and semen and blood folate, zinc, B12 , total antioxidant capacity (TAC) and malondialdehyde (MDA) concentrations. Sperm concentration (*10(6) ml(-1) ) increased in subfertile men receiving the combined treatment of folic acid and zinc sulphate and also in the group receiving only folic acid treatment; however, it was not statistically significant (P = 0.056 and P = 0.05, respectively). Sperm chromatin integrity (%) increased significantly in subfertile men receiving only zinc sulphate treatment (P = 0.048). However, this improvement in sperm quality was not significant after adjusting placebo effect. This study showed that zinc sulphate and folic acid supplementation did not ameliorate sperm quality in infertile men with severely compromised sperm parameters, OAT. Male infertility is a multifactorial disorder, and also nutritional factors play an important role in results of administration of supplementation on sperm parameters. However, these results should be confirmed by multiple studies in larger populations of OAT men. PMID- 24147896 TI - The weak helps the strong: sigma-holes and the stability of MF(4).base complexes. AB - Bonding interactions between an electron-deficient region (a sigma-hole) on M and electron donors in MF4-Base complexes, where M = C, Si, Ge, Sn, and Pb, are examined and rationalized. These interactions are seen to transition from weak primarily noncovalent interactions for all bases when M = C to stronger primarily covalent bonds in adducts as the valence shell expands for the heavier M atoms. For M = Ge, Sn, and Pb, the complexes are particularly stable. The consistent axial preference in these systems is anticipated by previous studies and is readily explained from the vantage point of sigma-hole interactions. A series of bound complexes of common bases such as pyridine, tetrahydrofuran, and water are identified, some of which are even more stable than the SiF4.NH3 and SiF4.N(CH3)3 complexes that have already been identified experimentally. Sigma-hole bonding to di- and poly-substituted central atoms, perhaps on par with halogen bonding, is expected to become increasingly important as an ordering interaction in materials science and engineering. Group 14 compounds have distinct advantages in this respect. PMID- 24147897 TI - Stromal-epithelial crosstalk provides a suitable microenvironment for the progression of ovarian cancer cells in vitro. AB - The tumor microenvironment plays an important role in the progression of cancer. This study focused on carcinoma-associated fibroblasts (CAFs) and stromal epithelial interaction between CAFs and epithelial ovarian carcinoma (EOC) cells. We isolated and established primary cultures of CAFs and co-cultured CAFs and EOC cells in vitro. The co-culture conditioned medium (CC-CM) was harvested and its influence on EOC cells was examined. Cytokine, chemokine, and growth factor levels were screened using a biotin label-based human antibody array system. We found that the stromal-epithelial crosstalk provided a suitable microenvironment for the progression of ovarian cancer cells in vitro. PMID- 24147898 TI - Optimization of particle size and encapsulation efficiency of vancomycin nanoparticles by response surface methodology. AB - CONTEXT: Treating vancomycin-resistant Staphylococcus aureus strains requires high doses of vancomycin, which might lead to adverse reactions such as nephrotoxicity and "red neck syndrome". Use of nanotechnology for antibiotic delivery is a promising approach to overcome antibiotic-resistance. OBJECTIVE: The objective of this study was optimizing the particle size and encapsulation efficiency (EE) of vancomycin nanoparticles prepared from chitosan. MATERIALS AND METHODS: The nanoparticles were prepared by ionotropic gelation method, at different combinations of chitosan concentration, chitosan/tripolyphosphate mass and vancomycin/chitosan mass, using Box-Behnken experimental design. Dynamic light scattering and ultracentrifugation were used to measure the nanoparticle size and EE, respectively. Vancomycin was quantified in samples by spectrophotometery. The optimum conditions were determined by subsequent regression analysis and multicriteria decision analysis of the output data. RESULTS: The nanoparticle size and EE were greatly influenced by the independent variables, which had interactive effects on both responses. The optimum conditions for production of nanoparticles were chitosan concentration of 0.5-1.2 mg/ml, chitosan/tripolyphosphate mass ratio of 3-3.5 and vancomycin/chitosan mass ratio of 1, which yielded nanoparticles between 130 and 150 nm with encapsulation efficiencies of 60-69%. CONCLUSIONS: The size and EE of vancomycin nanoparticles were optimized by the proposed procedure. PMID- 24147899 TI - A negative MYB regulator of proanthocyanidin accumulation, identified through expression quantitative locus mapping in the grape berry. AB - Flavonoids are secondary metabolites with multiple functions. In grape (Vitis vinifera), the most abundant flavonoids are proanthocyanidins (PAs), major quality determinants for fruit and wine. However, knowledge about the regulation of PA composition is sparse. Thus, we aimed to identify novel genomic regions involved in this mechanism. Expression quantitative trait locus (eQTL) mapping was performed on the transcript abundance of five downstream PA synthesis genes (dihydroflavonol reductase (VvDFR), leucoanthocyanidin dioxygenase (VvLDOX), leucoanthocyanidin reductase (VvLAR1), VvLAR2 and anthocyanidin reductase (VvANR)) measured by real-time quantitative PCR on a pseudo F1 population in two growing seasons. Twenty-one eQTLs were identified; 17 of them did not overlap with known candidate transcription factors or cis-regulatory sequences. These novel loci and the presence of digenic epistasis support the previous hypothesis of a polygenic regulatory mechanism for PA biosynthesis. In a genomic region co locating eQTLs for VvDFR, VvLDOX and VvLAR1, gene annotation and a transcriptomic survey suggested that VvMYBC2-L1, a gene coding for an R2R3-MYB protein, is involved in regulating PA synthesis. Phylogenetic analysis showed its high similarity to characterized negative MYB factors. Its spatiotemporal expression profile in grape coincided with PA synthesis. Its functional characterization via overexpression in grapevine hairy roots demonstrated its ability to reduce the amount of PA and to down-regulate expression of PA genes. PMID- 24147900 TI - A selective mitochondrial-targeted chlorambucil with remarkable cytotoxicity in breast and pancreatic cancers. AB - Nitrogen mustards, widely used as chemotherapeutics, have limited safety and efficacy. Mitochondria lack a functional nucleotide excision repair mechanism to repair DNA adducts and are sensitive to alkylating agents. Importantly, cancer cells have higher intrinsic mitochondrial membrane potential (Deltapsimt) than normal cells. Therefore, selectively targeting nitrogen mustards to cancer cell mitochondria based on Deltapsimt could overcome those limitations. Herein, we describe the design, synthesis, and evaluation of Mito-Chlor, a triphenylphosphonium derivative of the nitrogen mustard chlorambucil. We show that Mito-Chlor localizes to cancer cell mitochondria where it acts on mtDNA to arrest cell cycle and induce cell death, resulting in a 80-fold enhancement of cell kill in a panel of breast and pancreatic cancer cell lines that are insensitive to the parent drug. Significantly, Mito-Chlor delayed tumor progression in a mouse xenograft model of human pancreatic cancer. This is a first example of repurposing chlorambucil, a drug not used in breast and pancreatic cancer treatment, as a novel drug candidate for these diseases. PMID- 24147901 TI - Chirality driven metallic versus semiconducting behavior in a complete series of radical cation salts based on dimethyl-ethylenedithio-tetrathiafulvalene (DM-EDT TTF). AB - Enantiopure (S,S) and (R,R) dimethyl-ethylenedithio-tetrathiafulvalene (DM-EDT TTF) 1 donors are synthesized by cross coupling followed by decarboxylation reactions. In the solid state the methyl groups are arranged in axial positions within sofa-type conformation for the six-membered rings. Crystalline radical cation salts formulated as [(S,S)-1]2PF6, [(R,R)-1]2PF6, and [(rac)-1]2PF6 are obtained by electrocrystallization. When the experiment is conducted with enantioenriched mixtures both enantiopure and racemic phases are obtained. The monoclinic enantiopure salts, containing four independent donors in the unit cell, show semiconducting behavior supported by band structure calculations of extended Huckel type. The racemic salt contains only one independent donor in the mixed valence oxidation state +0.5. Under ambient pressure the racemic material is metallic down to 120 K, while an applied pressure of 11.5 kbar completely suppresses the metal-insulator transition. Band structure calculations yield an open Fermi surface, typical for a pseudo-one-dimensional metal, with unperfected nesting, thus ruling out the possibility of charge or spin density modulations to be at the origin of the transition. Raman spectroscopy measurements, in agreement with structural analysis at 100 K, show no indication of low-temperature charge ordering in the racemic material at ambient pressure, thus suggesting Mott-type charge localization for the observed metal-insulator transition. PMID- 24147902 TI - The international experience of single-incision pediatric endosurgery: current state of the art. AB - PURPOSE: As application and awareness of single-incision pediatric endosurgery (SIPES) are increasing, various techniques and indications have been independently described by select centers around the world. In order to facilitate a cooperative approach toward advancing and investigating the practice of SIPES, we conducted a survey among members of the International Pediatric Endosurgery Group (IPEG), asking them about their experience and attitudes toward single-incision endosurgery. MATERIALS AND METHODS: After institutional review board approval, an invitation to participate in an online survey was sent to all IPEG members. Questions focused on demographic information, practice patterns, indications, and equipment used regarding SIPES. RESULTS: Of the 560 contacted active IPEG members, 115 completed the survey (recall 21%). The respondents represented pediatric surgeons from 32 countries on six continents. Of respondents, 97% had heard of, while 71% had performed, SIPES. Reasons for not having performed SIPES included disbelief in benefit (59%), lack of proficiency (34%), and inadequate resources (28%). The most commonly performed SIPES procedures were appendectomy (85%), cholecystectomy (66%), splenectomy (42%), pyloromyotomy (35%), and intestinal surgery (13%), as well as Nissen fundoplication and gynecologic adnexal pathology (7%). The equipment and techniques utilized showed large variation and included some self-devised, innovative, low-resource approaches. Complications with SIPES reported by the survey participants included technical difficulties, wound infection, and prolonged operating time. CONCLUSIONS: SIPES is being performed worldwide for a large spectrum of common indications in pediatric surgery. The equipment and techniques used vary with geographic location and resources. Some encountered complications are common to those seen with conventional minimally invasive surgery, whereas others may be SIPES-specific. Different respondents reported diverging views on pain, operating time, and cost. PMID- 24147904 TI - In vitro evaluation of an external compression device for fontan mechanical assistance. AB - While Fontan palliation in the form of the total cavopulmonary connection has improved the management of congenital single ventricle physiology, long-term outcomes for patients with this disease are suboptimal due to the lack of two functional ventricles. Researchers have shown that ventricular assist devices (VADs) can normalize Fontan hemodynamics. To minimize blood contacting surfaces of the VAD, we evaluated the use of an external compression device (C-Pulse Heart Assist System, Sunshine Heart Inc.) as a Fontan assist device. A mock circulation was developed to mimic the hemodynamics of a hypertensive Fontan circulation in a pediatric patient. The Sunshine C-Pulse compression cuff was coupled with polymeric valves and a compressible tube to provide nonblood-contacting pulsatile flow through the Fontan circulation. The effect of the number, one or two, and placement of valves, before or after the compression cuff, on inferior vena cava pressure (IVCP) was studied. In addition, the effect of device inflation volume and compression rate on maintaining low IVCP was investigated. With one valve located before the cuff, the device was unable to maintain an IVCP below 15.5 mm Hg. With two valves, the C-Pulse was able to maintain IVCP as low as 8.5 mm Hg. The C-Pulse provided pulsatile flow and pressure through the pulmonary branch of the mock circulation with a pulse pressure of 16 mm Hg and 180 mL/min additional flow above unassisted flow. C-Pulse compression reduced IVCP below 12 mm Hg with 13 cc inflation volume and compression rates above 105 bpm. This application of an external compression device combined with two valves has potential for use as an artificial right ventricle by maintaining low IVCP and providing pulsatile flow through the lungs. PMID- 24147903 TI - Repeated monitoring of corneal nerves by confocal microscopy as an index of peripheral neuropathy in type-1 diabetic rodents and the effects of topical insulin. AB - We developed a reliable imaging and quantitative analysis method for in vivo corneal confocal microscopy (CCM) in rodents and used it to determine whether models of type 1 diabetes replicate the depletion of corneal nerves reported in diabetic patients. Quantification was reproducible between observers and stable across repeated time points in two rat strains. Longitudinal studies were performed in normal and streptozotocin (STZ)-diabetic rats, with innervation of plantar paw skin quantified using standard histological methods after 40 weeks of diabetes. Diabetic rats showed an initial increase, then a gradual reduction in occupancy of nerves in the sub-basal plexus so that values were significantly lower at week 40 (68 +/- 6%) than age-matched controls (80 +/- 2%). No significant loss of stromal or intra-epidermal nerves was detected. In a separate study, insulin was applied daily to the eye of control and STZ-diabetic mice and this treatment prevented depletion of nerves of the sub-basal plexus. Longitudinal studies are viable in rodents using CCM and depletion of distal corneal nerves precedes detectable loss of epidermal nerves in the foot, suggesting that diabetic neuropathy is not length dependent. Loss of insulin derived neurotrophic support may contribute to the pathogenesis of corneal nerve depletion in type 1 diabetes. PMID- 24147905 TI - Enzymatically catalyzed synthesis of anti-blooming agent 1,3-dibehenoyl-2-oleoyl glycerol in a solvent-free system: optimization by response surface methodology. AB - Products rich in 1,3-dibehenoyl-2-oleoyl glycerol (BOB) triglyceride (TAG) were produced by enzymatic interesterification of high oleic acid sunflower oil (HOSO) and behenic acid methyl ester (BME) by 1,3-regiospecific lipase Lipozyme RM IM in a solvent-free system. The impact factors of enzyme load, substrate molar ratio of BME to HOSO (BME/HOSO), reaction time, reaction temperature, and pre equilibration water activity of the enzyme on BOB content and BME conversions were investigated by single-factor experiments and then optimized using the response surface methodology (RSM). The optimum conditions were as follows: reaction temperature, 72 degrees C; reaction time, 7.99 h; substrate molar ratio, 2.5:1; enzyme load, 10%; and pre-equilibration water activities of the enzyme, 0.28. The results from the experiments conducted according to the predicted optimal conditions were as follows: the content of BOB was 32.76%, and the conversion of BME was 65.16%. The experimental values agreed with the predicted values, which verified the sufficiency of the quadratic regression models. After purification under the optimal short-range molecular distillation and two-step solvent fractionation, the content of BOB in the target product can reach 77.14%, indicating the great potential for industrial production of the anti-blooming agent. PMID- 24147906 TI - Short antibacterial peptides with significantly reduced hemolytic activity can be identified by a systematic L-to-D exchange scan of their amino acid residues. AB - High systemic toxicity of antimicrobial peptides (AMPs) limits their clinical application to the treatment of topical infections; in parenteral systemic application of AMPs the problem of hemolysis is one of the first to be tackled. We now show that the selectivity of lipidated short synthetic AMPs can be optimized substantially by reducing their hemolytic activity without affecting their activity against methicillin resistant Staphylococcus aureus (MRSA). In order to identify the optimized peptides, two sets of 32 diastereomeric H-(D)Arg WRWRW-(L)Lys(C(O)CnH2n+1)-NH2 (n = 7 or 9) peptides were prepared using a split split procedure to perform a systematic L-to-D exchange scan on the central WRWRW fragment. Compared to the all-L C8-lipidated lead sequence, diastereomeric peptides had very similar antibacterial properties, but were over 30 times less hemolytic. We show that the observed hemolysis and antibacterial activity is affected by both differences in lipophilicity of the different peptides and specific combinations of L- and D-amino acid residues. This study identified several peptides that can be used as tools to precisely unravel the origin of hemolysis and thus help to design even further optimized nontoxic very active short antibacterial peptides. PMID- 24147907 TI - Co-registered positron emission tomography/computed tomography and gadolinium ethoxybenzyl-diethylenetriamine pentaacetic acid magnetic resonance imaging features of multiple angiosarcoma of the liver. AB - Hepatic angiosarcoma is a very rare disease, accounting for only 2% of primary liver malignancy. An 82-year-old man was admitted to our hospital because of jaundice and weight loss. Computed tomography (CT) and magnetic resonance imaging (MRI) showed diffuse and multiple space-occupying lesions. On gadolinium ethoxybenzyl-diethylenetriamine pentaacetic acid (Gd-EOB-DTPA)-enhanced MRI, the tumor was not enhanced intensely in the arterial phase following contrast injection, and was then gradually enhanced homogeneously. In the delayed phase and hepatobiliary phase, the tumor was completely washed out. Whole-body (18) F fluorodeoxyglucose positron emission tomography (FDG-PET)/CT fusion scanning confirmed metabolic activity with maximum uptake value of 3.64 in the lesions. A liver biopsy showed spindle-shaped tumor cells proliferating along sinusoids, with elongated and hyperchromatic nuclei. Immunohistochemical studies showed tumor cells positive for von Willebrand factor and CD34. These findings were consistent with angiosarcoma of the liver. This case report is the first description of co-registered FDG-PET/CT images and Gd-EOB-DTPA-enhanced MRI of primary hepatic angiosarcoma. PMID- 24147908 TI - Usage of neck circumference as novel indicator of erectile dysfunction: a pilot study in Turkish population. AB - Erectile dysfunction (ED) is the most common male sexual problem worldwide. The association between ED and components of metabolic syndrome (MtS) is well established. This study examined neck circumference (NC) as a possible indicator of MtS and also of ED. Ninety-two patients were included and divided into two groups. Group 1 consisted of 47 patients with ED and Group 2 consisted of 45 healthy volunteers. Questionnaires, differences in anthropometric and laboratory measurements between patients with ED and the control group, and a cut-off value for NC were investigated. The mean NC in ED patients was higher in Group 1 than in Group 2 (P = 0.001), and Group 1 also demonstrated more MtS criteria than Group 2 (P < 0.001). The cut-off point of NC was defined as 34.75 cm for ED and MtS. The cut-off values of waist circumference for ED and MtS were 105.5 and 102.5 cm respectively. In the light of these findings, NC may be a new component of MtS in ED patients. Additionally, NC may be a novel indicator of central obesity and ED. We suggest that NC values of 35 cm and over may predict ED in patients with MtS. PMID- 24147909 TI - Use of craniofacial superimposition in historic investigation. AB - A skeleton discovered in Grand Forks, North Dakota was purported to belong to Clelland "Clell" Miller, a James-Younger gang member, who was killed during the Northfield Bank robbery on September 7, 1876. A 3-D image from a computer tomography (CT) scan of the skull was obtained, and a craniofacial superimposition was conducted to determine if the skull could belong to Miller. The superimposition method used in this case was to overlay the CT image of the skull onto Miller's postmortem photograph. In addition to the craniofacial superimposition, the images were juxtaposed to compare similarities or differences in facial morphology between the skull and photograph. Superimposition methods can be used to exclude identifications; however, they should not be used as a conclusive method for identification. In this case, there were sufficient similarities between the skull and Miller's photograph; therefore, the skull could not be eliminated as possibly being that of Miller. PMID- 24147910 TI - Editorial comment on de la Rosette et al. PMID- 24147913 TI - Impact of implant-abutment connection, positioning of the machined collar/microgap, and platform switching on crestal bone level changes. Camlog Foundation Consensus Report. AB - OBJECTIVES: The aim of this consensus meeting was to assess the impact of implant abutment connection, positioning of the machined collar/microgap, and platform switching on crestal bone level changes. MATERIALS AND METHODS: Two comprehensive systematic reviews were prepared in advance of the meeting. Consensus statements, practical recommendations, and implications for future research were based on within group as well as plenary scrutinization and discussions of these systematic reviews. RESULTS: Placing the smooth part of the implant below the alveolar crest may lead to bone loss. Despite a more pronounced bone remodeling, the subcrestal positioning of the microgap may help to retain the bony coverage of the rough surface. Crestal bone remodeling has been observed for either internal and external, or conical and butt-joint connections. There was a trend favoring the platform switching concept to prevent or minimize peri-implant marginal bone loss. CONCLUSIONS: Future research should consider an uniform and comparable study design, either excluding or exactly documenting possible confounding factors. PMID- 24147912 TI - Chronic melatonin treatment rescues electrophysiological and neuromorphological deficits in a mouse model of Down syndrome. AB - The Ts65Dn mouse (TS), the most commonly used model of Down syndrome (DS), exhibits several key phenotypic characteristics of this condition. In particular, these animals present hypocellularity in different areas of their CNS due to impaired neurogenesis and have alterations in synaptic plasticity that compromise their cognitive performance. In addition, increases in oxidative stress during adulthood contribute to the age-related progression of cognitive and neuronal deterioration. We have previously demonstrated that chronic melatonin treatment improves learning and memory and reduces cholinergic neurodegeneration in TS mice. However, the molecular and physiological mechanisms that mediate these beneficial cognitive effects are not yet fully understood. In this study, we analyzed the effects of chronic melatonin treatment on different mechanisms that have been proposed to underlie the cognitive impairments observed in TS mice: reduced neurogenesis, altered synaptic plasticity, enhanced synaptic inhibition and oxidative damage. Chronic melatonin treatment rescued both impaired adult neurogenesis and the decreased density of hippocampal granule cells in trisomic mice. In addition, melatonin administration reduced synaptic inhibition in TS mice by increasing the density and/or activity of glutamatergic synapses in the hippocampus. These effects were accompanied by a full recovery of hippocampal LTP in trisomic animals. Finally, melatonin treatment decreased the levels of lipid peroxidation in the hippocampus of TS mice. These results indicate that the cognitive-enhancing effects of melatonin in adult TS mice could be mediated by the normalization of their electrophysiological and neuromorphological abnormalities and suggest that melatonin represents an effective treatment in retarding the progression of DS neuropathology. PMID- 24147911 TI - Comparison of the structural and dynamic effects of 5-methylcytosine and 5 chlorocytosine in a CpG dinucleotide sequence. AB - Inflammation-mediated reactive molecules can result in an array of oxidized and halogenated DNA-damage products, including 5-chlorocytosine ((Cl)C). Previous studies have shown that (Cl)C can mimic 5-methylcytosine ((m)C) and act as a fraudulent epigenetic signal, promoting the methylation of previously unmethylated DNA sequences. Although the 5-halouracils are good substrates for base-excision repair, no repair activity has yet been identified for (Cl)C. Because of the apparent biochemical similarities of (m)C and (Cl)C, we have investigated the effects of (m)C and (Cl)C substitution on oligonucleotide structure and dynamics. In this study, we have constructed oligonucleotide duplexes containing C, (Cl)C, and (m)C within a CpG dinucleotide. The thermal and thermodynamic stability of these duplexes were found to be experimentally indistinguishable. Crystallographic structures of duplex oligonucleotides containing (m)C or (Cl)C were determined to 1.2 and 1.9 A resolution, respectively. Both duplexes are B-form and are superimposable on a previously determined structure of a cytosine-containing duplex with a rmsd of approximately 0.25 A. NMR solution studies indicate that all duplexes containing cytosine or the cytosine analogues are normal B-form and that no structural perturbations are observed surrounding the site of each substitution. The magnitude of the base stacking-induced upfield shifts for nonexchangeable base proton resonances are similar for each of the duplexes examined, indicating that neither (m)C nor (Cl)C significantly alter base-stacking interactions. The (Cl)C analogue is paired with G in an apparently normal geometry; however, the G-imino proton of the (Cl)C-G base pair resonates to higher field relative to (m)C-G or C-G, indicating a weaker imino hydrogen bond. Using selective 15N-enrichment and isotope-edited NMR, we observe that the amino group of (Cl)C rotates at roughly half of the rate of the corresponding amino groups of the C-G and (m)C-G base pairs. The altered chemical shifts of hydrogen-bonding proton resonances for the (Cl)C-G base pair as well as the slower rotation of the (Cl)C amino group can be attributed to the electron-withdrawing inductive property of the 5-chloro substituent. The apparent similarity of duplexes containing (m)C and (Cl)C demonstrated here is in accord with results of previous biochemical studies and further suggests that (Cl)C is likely to be an unusually persistent form of DNA damage. PMID- 24147914 TI - Chemoenzymatic synthesis of the human CD52 and CD24 antigen analogues. AB - Analogs of the human CD52 and CD24 antigens carrying the common core structure of glycosylphosphatidylinositol (GPI) anchors and the intact polypeptide sequences of CD52 and CD24 were chemoenzymatically synthesized. CD52 and CD24 proteins were obtained by solid-phase peptide synthesis and then coupled to chemically synthesized GPI anchors under the influence of a bacterial enzyme, sortase A, to afford the target molecules in good yields. PMID- 24147915 TI - What is the success of ultrasonography of benign adnexal masses? AB - AIM: To assess the diagnostic accuracy of the ultrasonographic discrimination of benign adnexal masses. METHODS: This was a prospective study, evaluating 245 consecutive cases using real-time gray-scale ultrasonography in a tertiary education hospital. RESULTS: Diagnostic accuracy was high for simple cysts and solid masses as kappa-values of 0.824 and 0.816 and accuracy was moderate for endometriomas, dermoid cysts and cystadenomas as kappa-values of 0.758, 0.689 and 0.627, respectively, and low for hemorrhagic cysts as a kappa-value of 0.587. A logistic regression model was developed using ultrasonographic characteristics of the adnexal masses. Irregularity at lining of the inner wall, presence of solid component, papillary projections and echogenicity were shown to have a strong impact on the diagnosis of benign masses. CONCLUSION: Although ultrasonography is a useful technique for the diagnosis of benign adnexal masses, it is limited in diagnostic accuracy. Pattern recognition is the most favored method for ultrasonographic diagnosis. Logistic regression analysis can contribute to diagnostic accuracy. PMID- 24147916 TI - Evaluation of native mesenchymal stem cells from bone marrow and local tissue in an atrophic nonunion model. AB - INTRODUCTION: It has been reported that cells or growth factors might improve bone regeneration in nonunion. However, the intrinsic potential of the nonunion tissue to regenerate bone is still unclear; in particular, it is not known whether there are progenitor cells within the nonunion. Thus, in this study, a clinically relevant model has been developed to investigate the nature of the cells in atrophic nonunion tissue and to assess their regenerative potential. MATERIALS AND METHODS: Seventeen Wistar rats underwent the procedure to induce an atrophic nonunion at the tibial midshaft by stripping the periosteum and endosteum as well as creating a small (1.0 mm) noncritical gap. The fracture was stabilized with an external fixator. The proliferation ability of bone marrow derived cells and nonunion tissue-derived cells was determined using colony forming assays. The differentiation potential of nonunion tissue-derived cells was also investigated. RESULTS: Noncritical size defect nonunions were successfully induced in all of the animals. The typical characteristics of atrophic nonunions were demonstrated by radiography, micro-CT, and histology. An atrophic nonunion stimulated a systemic response in the bone marrow with an increase in bone marrow-derived mesenchymal stem cells. In contrast, cells derived from the nonunion gap were not able to form colonies. This indicated that the quiescent or inactive cells in the tissue at the atrophic nonunion gap could be induced to differentiate under osteogenic and chondrogenic conditions, but not under adipogenic conditions. Thus, these cells had the characteristics of osteochondral progenitor cells. DISCUSSION: Although there was an increase in the systemic response in the atrophic nonunion model, the intrinsic potential of local tissue from the atrophic nonunion site was impaired. The cells derived from nonunion tissue could be stimulated to differentiate into bone under appropriate conditions. This suggested that there are progenitor cells in atrophic nonunion tissue, which have an intrinsic ability to regenerate bone, but the microenvironment in the atrophic nonunion site might be retarding their function. Consequently, physical or biological agents (such as growth factors or cells) are needed to reactivate the endogenous progenitor cells to make them regenerate bone in atrophic nonunions. PMID- 24147917 TI - Trifluoromethylation of fullerenes: kinetic and thermodynamic control. AB - We present a survey and theoretical interpretation of the experimental results on trifluoromethylation of fullerenes. A thermodynamic model has been developed to describe the C60/70(CF3)n condensed phase mixtures capable of free exchange of addends and, consequently, of isomerization and changing the degrees of addition. It was found that the purely thermodynamic model affords at least satisfactory prediction of composition of products even for apparently nonequilibrium syntheses. Special cases can be identified by means of detailed kinetic modeling based on the BEP approach, which includes stepwise energetic analysis of the possible trifluoromethylation sequences. This analysis reveals two types of reactions with remarkable difference in rates: direct trifluoromethylation and rearrangements of the CF3 groups. Whenever a particular group of compounds is interrelated through direct addition/abstraction of CF3 groups, it is more or less safe to assume that the said group is in equilibrium describable by the thermodynamic model. In the same time, the slower migration of addends is controlled kinetically, and interference of the sublimation processes frequently prevents its equilibration. Among the most illustrative examples of hindered formation via rearrangements in absence of sufficiently favorable direct trifluoromethylation pathways are certain isomers of the C3v-C60(CF3)18, C70(CF3)18, and C70(CF3)20 compounds. PMID- 24147918 TI - Weight loss in a UK commercial all meal provision study: a randomised controlled trial. AB - BACKGROUND: Effective approaches are needed to address the increasing prevalence of overweight and obesity. The present study investigated whether all meal provision was a more effective and acceptable method for weight loss than a self directed diet. METHODS: This randomised controlled trial recruited 112 men and women with a body mass index in the range 27-35 kg m(-2), who had no comorbidities, from the local area of Hull. Participants were randomised to receive either meal provision or follow a self-directed diet for a 12-week period that resulted in an estimated 2928 kJ day(-1) (700 kcal day(-1)) deficit. A dietitian supervised both dietary interventions. RESULTS: At 12 weeks [mean (SEM)], percentage weight loss in the meal provision group was 6.6% (0.5%) compared to 4.3% (0.6%) for those on the self-directed diet. In terms of clinically relevant weight loss, 61% of participants lost 5% or more of their body weight with meal provision compared to 22% on the self-directed diet (P < 0.001). Weight loss was associated with wellbeing in both groups. Attrition was less apparent with 7% of those participants receiving meal provision withdrawing from the study compared to 41% of those following the self-directed diet (P < 0.001). CONCLUSIONS: Meal provision was a more effective and accepted method for weight loss over a 12-week period compared to a self-directed diet. This may in part represent the difference between being given the meal provision food free of charge. However, longer-term maintenance studies need to be undertaken to ascertain their effects on the maintenance of weight loss. PMID- 24147919 TI - Epidemiology of preeclampsia: impact of obesity. AB - Preeclampsia is a pregnancy-specific disorder that affects 2-8% of all pregnancies and remains a leading cause of maternal and perinatal morbidity and mortality worldwide. Diagnosis is based on new onset of hypertension and proteinuria. Multiple organ systems can be affected, with severe disease resulting. The wide range of risk factors reflects the heterogeneity of preeclampsia. Obesity, which is increasing at an alarming rate, is also a risk factor for preeclampsia as well as for later-life cardiovascular disease. Exploring common features may provide insight into the pathophysiologic mechanisms underlying preeclampsia among obese and overweight women. PMID- 24147920 TI - Gestational weight gain recommendations in the context of the obesity epidemic. AB - The impact of the obesity epidemic on women of childbearing age has been of particular concern in recent years as a result of studies linking maternal weight status to long-term adverse outcomes for obese mothers and their offspring. The US Institute of Medicine developed new gestational weight gain guidelines based on this literature that attempts to strike a balance between the known risks and benefits of weight gain during pregnancy. More studies that include large numbers of obese women, examine outcomes beyond the perinatal period, and identify safe and effective pregnancy weight gain interventions are needed before lower weight gain recommendations can be made for obese women. PMID- 24147921 TI - Weighing the impact of obesity on female reproductive function and fertility. AB - Obesity in women is associated with serious reproductive sequelae. Given its prevalence among women of reproductive age, much recent attention has focused on the mechanisms by which obesity affects female reproductive function and fertility. This review summarizes the literature investigating the epidemiology and pathophysiology of obesity in women of reproductive age and proposes research strategies that may help inform approaches to improve reproductive function and outcomes among obese women. PMID- 24147922 TI - Physical activity and maternal obesity: cardiovascular adaptations, exercise recommendations, and pregnancy outcomes. AB - Although a healthy lifestyle approach is intuitive for obese pregnant women, no guidelines currently exist to manage these women throughout pregnancy. Women who are medically prescreened for contraindications can engage in a walking program three to four times per week, starting at 25 min per session and adding 2 min per week until reaching 40 min, with sessions continuing until delivery. A target heart rate of 102-124 beats per minute should be promoted for women 20-29 years of age and a rate of 101-120 beats per minute for women 30-39 years of age. A pedometer step count of 10,000 steps per day is suggested as a goal, as this level of activity provides important health benefits. Combining healthy eating with a walking plan prevents excessive weight gain during pregnancy and promotes a healthy fetal environment. PMID- 24147923 TI - The importance of gestational diabetes beyond pregnancy. AB - Diabetes mellitus is the main health problem affecting Mexico's population. The mechanisms by which susceptibility to it is acquired and diabetes develops are topics of ongoing research. In order to prevent type 2 diabetes, one of the challenges is to fully understand gestational diabetes and the hormonal changes and altered carbohydrate metabolism that are associated with it during fetal development. A recent study by the Instituto Nacional de Perinatologia found a 12.9% prevalence of gestational diabetes; if the current criteria suggested by the American Diabetes Association were applied, this figure would rise to almost 30%. Identifying mothers and children at high risk of developing diabetes mellitus and its comorbid conditions will help facilitate the timely implementation of preventive measures. This will be a rational use of economic resources in Mexico that will vitally benefit public health. PMID- 24147924 TI - Mechanisms by which maternal obesity programs offspring for obesity: evidence from animal studies. AB - Maternal obesity can profoundly affect offspring phenotype and predisposition to obesity and metabolic disease. Carefully controlled studies in precocial and altricial mammalian species provide insights into the involved mechanisms. These include programming of hypothalamic appetite-regulating centers to increase orexigenic relative to anorexigenic drive; increasing maternal, fetal, and offspring adrenal and peripheral tissue glucocorticoid production; and increasing maternal oxidative stress. Outcomes often show offspring sex differences that may play a role in the differential susceptibility of males and females to later-life obesity and other related metabolic diseases. PMID- 24147926 TI - Role of developmental overnutrition in pediatric obesity and type 2 diabetes. AB - Childhood obesity continues to be a significant public health burden. Empirical evidence has begun to identify intrauterine and postnatal pathways that increase the likelihood of excess adiposity and increased risk of type 2 diabetes among offspring. Reviewed here is the evidence supporting a transgenerational vicious cycle that increases obesity and diabetes in offspring and contributes substantially to the increases in obesity and type 2 diabetes observed over the past several decades. The public health impact of these findings is discussed and future research opportunities are outlined. PMID- 24147925 TI - Intergenerational impact of maternal obesity and postnatal feeding practices on pediatric obesity. AB - The postnatal feeding practices of obese and overweight mothers may place their children at increased risk for the development of obesity through shared biology and family environments. This article reviews the feeding practices of obese mothers, describes the potential mechanisms linking maternal feeding behaviors to child obesity risk, and highlights the potential avenues of intervention. Strategies important for improving the quality of the eating environment and preventing the intergenerational transmission of obesity include supporting breastfeeding, improving the food choices of obese women, and encouraging the development of feeding styles that are responsive to hunger and satiety cues. PMID- 24147927 TI - Prepregnancy obesity and the risk of birth defects: an update. AB - The growing number of obese women worldwide has many implications for the reproductive health outcomes of mothers and their children. Specifically, prepregnancy obesity has been associated with certain major birth defects. Provided here is a summary of the most recent and comprehensive meta-analysis of reports of associations between prepregnancy obesity and birth defects, along with an update that includes a brief overview of reports of similar associations published since that meta-analysis. The possible reasons for the observed association between prepregnancy obesity and birth defects are explored, and knowledge gaps that suggest possible avenues for future research are highlighted. PMID- 24147929 TI - Epigenetic programming of obesity and diabetes by in utero exposure to gestational diabetes mellitus. AB - It is now well accepted that offspring exposed to maternal undernutrition, obesity, or gestational diabetes mellitus have an increased risk for chronic diseases later in life, supporting the theory of the early origins of chronic diseases. However, the molecular mechanisms through which the exposure to an altered in utero environment translates into the development of chronic diseases are not yet well understood. Recently reported promising results help to resolve this issue. They suggest that epigenetic modifications are a potential mechanism for fetal metabolic programming. This review provides an overview of the relationship between the exposure to an altered intrauterine environment and fetal metabolic programming, focusing on gestational diabetes mellitus and epigenetic variations at adipokine candidate genes. PMID- 24147928 TI - Interventions to prevent adverse fetal programming due to maternal obesity during pregnancy. AB - Maternal obesity is a global epidemic affecting both developed and developing countries. Human and animal studies indicate that maternal obesity adversely programs the development of offspring, predisposing them to chronic diseases later in life. Several mechanisms act together to produce these adverse health effects. There is a consequent need for effective interventions that can be used in the management of human pregnancy to prevent these outcomes. The present review analyzes the dietary and exercise intervention studies performed to date in both altricial and precocial animals, rats and sheep, with the aim of preventing adverse offspring outcomes. The results of these interventions present exciting opportunities to prevent, at least in part, adverse metabolic and other outcomes in obese mothers and their offspring. PMID- 24147930 TI - Maternal pregnancy weight gain and the risk of placental abruption. AB - To evaluate the relationship between pregnancy weight gain and placental abruption, Missouri's population-based, maternally linked, longitudinal dataset (1989-2005, n = 1,146,935) was assessed. Regardless of baseline body mass index, women who gained less than the optimal amount recommended by the Institute of Medicine had a 67% increased likelihood of placental abruption (adjusted odds ratio [AOR] for placental abruption = 1.673; 95%CI = 1.588-1.762) compared with those who gained an optimal amount of weight, while those who gained more than the recommended optimal amount of weight had a 30% reduced AOR for placental abruption (AOR = 0.695, 95%CI = 0.660-0.731). These findings underscore the importance of maternal weight management as part of preconception care to improve pregnancy outcomes. PMID- 24147931 TI - Role of maternal adiposity prior to and during pregnancy in cognitive and psychiatric problems in offspring. AB - The purpose of this review is to summarize studies that have examined associations between maternal adiposity prior to and during pregnancy and cognitive and psychiatric problems in offspring. Of the 11 studies published since a 2011 systematic review, four examined cognitive outcomes alone, four assessed psychopathology exclusively, and three reported on both cognitive and psychiatric endpoints. Ten studies provided evidence of a link. These data suggest that the offspring of women who are overweight or obese during pregnancy are at increased risk for cognitive deficits, externalizing problems (particularly attention-deficit/hyperactivity disorder), and internalizing psychopathology in childhood and adolescence; however, the effect sizes were small to medium and a definitive causal association remains to be proven. PMID- 24147932 TI - Short-term memory across eye blinks. AB - The effect of eye blinks on short-term memory was examined in two experiments. On each trial, participants viewed an initial display of coloured, oriented lines, then after a retention interval they viewed a test display that was either identical or different by one feature. Participants kept their eyes open throughout the retention interval on some blocks of trials, whereas on others they made a single eye blink. Accuracy was measured as a function of the number of items in the display to determine the capacity of short-term memory on blink and no-blink trials. In separate blocks of trials participants were instructed to remember colour only, orientation only, or both colour and orientation. Eye blinks reduced short-term memory capacity by approximately 0.6-0.8 items for both feature and conjunction stimuli. A third, control, experiment showed that a button press during the retention interval had no effect on short-term memory capacity, indicating that the effect of an eye blink was not due to general motoric dual-task interference. Eye blinks might instead reduce short-term memory capacity by interfering with attention-based rehearsal processes. PMID- 24147934 TI - [Cp2TiCH2CHMe(SiMe3)]+, an alkyl-titanium complex which (a) exists in equilibrium between a beta-agostic and a lower energy gamma-agostic isomer and (b) undergoes hydrogen atom exchange between alpha-, beta-, and gamma-sites via a combination of conventional beta-hydrogen elimination-reinsertion and a nonconventional CH bond activation process which involves proton tunnelling. AB - The compound [Cp2Ti(Me)(CD2Cl2)][B(C6F5)4] reacts with trimethylvinylsilane (TMVS) to form the 1,2-insertion product [Cp2TiCH2CHMe(SiMe3)](+) (III), which exists in solution as equilibrating beta- and gamma-agostic isomers. In addition, while free rotation of the beta-methyl group results in a single, averaged gamma H atom resonance at higher temperatures, decoalescence occurs below ~200 K, and the resonance of the gamma-agostic hydrogen atom at delta ~ -7.4 is observed. Reaction of [Cp2Ti(CD3)(CD2Cl2)](+) with TMVS results in the formation of [Cp2TiCH2CH(CD3)(SiMe3)](+), which converts, via reversible beta-elimination, to an equilibrium mixture of specifically [Cp2TiCH2CH(CD3)(SiMe3)](+) and [Cp2TiCD2CD(CH3)(SiMe3)](+). Complementing this conventional process, exchange spectroscopy experiments show that the beta-H atom of [Cp2TiCH2CHMe(SiMe3)](+) undergoes exchange with the three hydrogen atoms of the beta-methyl group (beta H/gamma-H exchange) but not with the two alpha-H atoms. This exchange process is completely shut down when [Cp2TiCH2CH(CD3)(SiMe3)](+) is used, suggesting an H/D kinetic isotope effect much larger (apparently >16,000) than the maximum possible for an over-the-barrier process. It is proposed that beta-H/gamma-H exchange is facilitated by quantum mechanical proton tunnelling in which a hydrogen atom of the 2-methyl group of the alkene-hydride deinsertion product [Cp2TiH{CH2?CMe(SiMe3)}](+) undergoes reversible exchange with the hydride ligand via the allyl dihydrogen species [Cp2TiH2{(eta(3)-CH2C(SiMe3)CH2}](+). Complementing these findings, DFT calculations were carried out to obtain energies and NMR parameters for all relevant species and thence to obtain better insight into the agostic preference(s) of complex III and the observed exchange processes. In all cases where comparisons between experimental and calculated data were possible, agreement was excellent. PMID- 24147933 TI - Reduction of unwanted submental fat with ATX-101 (deoxycholic acid), an adipocytolytic injectable treatment: results from a phase III, randomized, placebo-controlled study. AB - BACKGROUND: Unwanted submental fat (SMF) is aesthetically unappealing, but methods of reduction are either invasive or lack evidence for their use. An injectable approach with ATX-101 (deoxycholic acid) is under investigation. OBJECTIVES: To evaluate the efficacy and safety of ATX-101 for the reduction of unwanted SMF. METHODS: In this double-blind, placebo-controlled, phase III study, 363 patients with moderate/severe SMF were randomized to receive ATX-101 (1 or 2 mg cm(-2) ) or placebo injections into their SMF at up to four treatment sessions ~28 days apart, with a 12-week follow-up. The co-primary efficacy endpoints were the proportions of treatment responders [patients with >= 1-point improvement in SMF on the 5-point Clinician-Reported Submental Fat Rating Scale (CR-SMFRS)] and patients satisfied with their face and chin appearance on the Subject Self-Rating Scale (SSRS). Secondary endpoints included skin laxity, calliper measurements and patient-reported outcomes. Adverse events were monitored. RESULTS: Significantly more ATX-101 recipients met the primary endpoint criteria vs. placebo: on the clinician scale, 59.2% and 65.3% of patients treated with ATX-101 1 and 2 mg cm( 2) , respectively, were treatment responders vs. 23.0% for placebo (CR-SMFRS; P < 0.001); on the patient scale, 53.3% and 66.1%, respectively, vs. 28.7%, were satisfied with their face/chin appearance (SSRS; P < 0.001). Calliper measurements showed a significant reduction in SMF (P < 0.001), skin laxity was not worsened and patients reported improvements in the severity and psychological impact of SMF with ATX-101 vs. placebo. Most adverse events were transient and associated with the treatment area. CONCLUSIONS: ATX-101 was effective and well tolerated for nonsurgical SMF reduction. PMID- 24147935 TI - Negative public perceptions of juvenile diabetics: applying attribution theory to understand the public's stigmatizing views. AB - Despite a rise in the incidence of juvenile diabetes globally, little research has focused on public perceptions regarding its patients. The need to evaluate whether the public holds stigmatizing views is pressing when one considers the relatively young age of the patients of the disease. The current study extends the attribution theoretic framework to evaluate public stigma regarding juvenile diabetes. The findings suggest that a large percentage of individuals misattribute the causes of the disease and believe it is relatively rare and that its patients are personally responsible for contracting it. Individuals often utilize pejorative terms describing juvenile diabetes as a disease afflicting children who are lazy, unhealthy, fat, obese, lacking exercise, and having eating disorders. PMID- 24147936 TI - Unlocking the puzzling biology of the black Perigord truffle Tuber melanosporum. AB - The black Perigord truffle (Tuber melanosporum Vittad.) is a highly prized food today, with its unique scent (i.e., perfume) and texture. Despite these attributes, it remains relatively poorly studied, lacking "omics" information to characterize its biology and biochemistry, especially changes associated with freshness and the proteins/metabolites responsible for its organoleptic properties. In this study, we have functionally annotated the truffle proteome from the 2010 T. melanosporum genome comprising 12,771 putative nonredundant proteins. Using sequential BLAST search strategies, we identified homologues for 2587 proteins with 2486 (96.0%) fungal homologues (available from http://biolinfo.org/protannotator/blacktruffle.php). A combined 1D PAGE and high accuracy LC-MS/MS proteomic study was employed to validate the results of the functional annotation and identified 836 (6.5%) proteins, of which 47.5% (i.e., 397) were present in our bioinformatics studies. Our study, functionally annotating 6487 black Perigord truffle proteins and confirming 836 by proteomic experiments, is by far the most comprehensive study to date contributing significantly to the scientific community. This study has resulted in the functional characterization of novel proteins to increase our biological understanding of this organism and to uncover potential biomarkers of authenticity, freshness, and perfume maturation. PMID- 24147937 TI - Modulation of the fibrillogenesis inhibition properties of two transthyretin ligands by halogenation. AB - The amyloidogenic protein transthyretin (TTR) is thought to aggregate into amyloid fibrils by tetramer dissociation which can be inhibited by a number of small molecule compounds. Our analysis of a series of crystallographic protein inhibitor complexes has shown no clear correlation between the observed molecular interactions and the in vitro activity of the inhibitors. From this analysis, it emerged that halogen bonding (XB) could be mediating some key interactions. Analysis of the halogenated derivatives of two well-known TTR inhibitors has shown that while flufenamic acid affinity for TTR was unchanged by halogenation, diflunisal gradually improves binding up to 1 order of magnitude after iodination through interactions that can be interpreted as a suboptimal XB (carbonyl Thr106: I...O distance 3.96-4.05 A; C-I...O angle 152-156 degrees ) or as rather optimized van der Waals contacts or as a mixture of both. These results illustrate the potential of halogenation strategies in designing and optimizing TTR fibrillogenesis inhibitors. PMID- 24147938 TI - Comparison of accelerated and conventional corneal collagen cross-linking for progressive keratoconus. AB - PURPOSE: To compare outcomes of accelerated and conventional corneal cross linking (CXL) for progressive keratoconus (KC). MATERIALS AND METHODS: Patients were divided into two groups as the accelerated CXL group and the conventional CXL group. The uncorrected distant visual acuity (UDVA), corrected distant visual acuity (CDVA), refraction and keratometric values were measured preoperatively and postoperatively. The data of the two groups were compared statistically. RESULTS: The mean UDVA and CDVA were better at the six month postoperative when compared with preoperative values in two groups. While change in UDVA and CDVA was statistically significant in the accelerated CXL group (p = 0.035 and p = 0.047, respectively), it did not reach statistical significance in the conventional CXL group (p = 0.184 and p = 0.113, respectively). The decrease in the mean corneal power (Km) and maximum keratometric value (Kmax) were statistically significant in both groups (p = 0.012 and 0.046, respectively in the accelerated CXL group, p = 0.012 and 0.041, respectively, in the conventional CXL group). There was no statistically significant difference in visual and refractive results between the two groups (p > 0.05). CONCLUSIONS: Refractive and visual results of the accelerated CXL method and the conventional CXL method for the treatment of KC in short time period were similar. The accelerated CXL method faster and provide high throughput of the patients. PMID- 24147939 TI - Neutrophil to lymphocyte ratio as a measure of systemic inflammation in psoriasis. AB - OBJECTIVE: Psoriasis is a chronic systemic inflammatory disorder. The neutrophil to lymphocyte ratio (N/L ratio) has been used as a marker for systemic inflammatory status. In our study, we aimed to evaluate N/L ratio in patients with psoriasis. METHODS: This cross-sectional study population consisted of 138 patients with psoriasis and 120 age- and sex-matched control subjects. RESULTS: The patients had significantly higher neutrophil counts and lower lymphocyte counts than the controls. The N/L ratios and high sensitivity C reactive protein (hs-CRP) levels were also significantly higher in patients. The N/L ratios and hs CRP levels were increasing with increasing in Psoriasis Area and Severity Index score. Furthermore, the N/L ratios and hs-CRP levels of patients were found to be positively correlated. CONCLUSIONS: Our data show that the N/L ratio to be a simple, inexpensive and easily assessable marker of systemic inflammation in patients with psoriasis. PMID- 24147940 TI - Paederus dermatitis in Southeastern Anatolia, Turkey: a report of 57 cases. AB - BACKGROUND: Paederus dermatitis (PD), which is an irritant contact dermatitis, is common throughout the world and caused by rove beetles. OBJECTIVES: To assess the clinical features of PD and the level of knowledge of patients from the city of Batman and surrounding areas who presented with the condition. METHODS: We describe 57 patients who presented to our dermatology clinic in the city of Batman between May 2011 and October 2011. Sociodemographic data were collected for all the patients, and their level of knowledge about the disease was assessed with a detailed questionnaire. RESULTS: Fifty-seven patients, of whom 36 (63%) were men and 21 (37%) were women, were included in the study. The mean age of the patients was 24.2 years. The peak time of presentation was August. The neck and the chest were the most common sites of involvement. Clinically, the most common presentation consisted of papulo-pustules on an erythematous base. The most frequent complaints were burning and stinging sensations (66.7%). Only three patients (5%) thought that contact with insects could lead to the disease. CONCLUSIONS: PD is an important public health problem when it is seen epidemically. The public's awareness about the cause of the disease is very low. Knowledge about the clinical features of PD and the emergence of epidemics will prevent misdiagnosis by physicians. Increasing the level of knowledge of people about the cause of the disease and about the behavioural patterns of the insect are important in terms of disease prevention. PMID- 24147941 TI - Diode laser photocoagulation posterior to the ridge in severe stage 3+ threshold retinopathy of prematurity. AB - PURPOSE: To evaluate the results of diode laser photocoagulation (DLP) of the retina posterior to the ridge in eyes with severe Zone II, Stage 3+ threshold retinopathy of prematurity (ROP). METHOD: DLP was applied posterior to the fibrovascular ridge for advanced Zone II, Stage 3+ threshold ROP patients, either as the primary treatment combined with DLP of the avascular retina (group 1), or as a secondary treatment in eyes that had previously undergone DLP of the avascular retina (group 2). Statistical analysis was performed using SPSS software trail version 16.0. Values are presented as mean +/- SD. RESULTS: A total of 50 eyes of 29 premature infants were treated (14 [48%] male, 15 [52%] female). The mean gestational age was 29.5 +/- 2.2 weeks (range: 26-34 weeks). The mean birth weight was 1259 0.72 +/- 409.15 g (range: 500-2050 g). The mean gestational age for DLP of the avascular region anterior to the ridge and DLP posterior to the ridge was 37 +/- 3 weeks and 38 +/- 3 weeks, respectively. The mean follow-up was 26 +/- 5 weeks (18-38 weeks). In 48 eyes, the tractional fibrovascular ridge had regressed. Transient retinal hemorrhage was the most common complication. Three eyes exhibited optic-disc dragging; two eyes progressed to Stage 4a ROP; two eyes presented with macular traction, without any detachment; and one eye developed a vitreous hemorrhage, which resolved spontaneously. There were no statistically significant differences between complicated and uncomplicated eyes regarding gestational age, birth weight and applied laser spot numbers (p > 0.05 for all, Mann-Whitney U test). CONCLUSION: DLP, posterior to the ridge as an additive treatment in the management of severe Zone II, Stage 3+ threshold ROP patients, is safe and effective; this approach could be used as either the primary treatment, or as the follow-up to failed laser treatment of the avascular retina to halt the progression of the disease. PMID- 24147942 TI - Temperature-mediated absorption of phenylmercuric nitrate on polyethylene and polypropylene containers in chloramphenicol eye drops. AB - The aim of this work was to find the effect of temperature and manufacturing source of phenylmercuric nitrate (PMN) on PMN absorption on low-density polyethylene (LDPE) and polypropylene containers in chloramphenicol eye drops. Two factorial experiments were designed to study the effect of temperature on PMN assay in chloramphenicol eye drops stored in LDPE and prepared from two different PMN sources. PMN source had no effect on PMN assay at 2-8 degrees C, however at stress conditions (30 degrees C/75%RH) for 3 weeks, the effect of PMN source on PMN assay was found significant (p < 0.05) in formulations stored in LDPE bottles. Temperature was the major contributor to decreased PMN assay. In formulations stored in polypropylene containers, PMN source had significant effect on PMN assay at 2-8 degrees C and 30 degrees C/75%RH. Overall, new PMN and polypropylene bottles performed better. The eye drops complied with preservative efficacy test both initially and at the end of shelf life. The concentration exponent of PMN is very low and in spite of its high absorption by container/closure, PMN was still able to protect the eye drops at the end of shelf life. It can be inferred that preservative efficacy test is the better indicator of preservative activity. PMID- 24147943 TI - Effects of chronic smoking on central corneal thickness, endothelial cell, and dry eye parameters. AB - OBJECTIVE: To evaluate the effect of chronic cigarette smoking on dry eye parameters, endothelial cells, and corneal thickness. DESIGN: Prospective cross sectional case series. METHODS: In this cross-sectional study, 49 eyes of 49 chronic smokers (smoker group) and 53 eyes of 53 age-matched, healthy non-smokers (non-smoker group) were enrolled. All participants underwent measurements of tear breakup time (TBUT), central corneal thickness (CCT) measurements with contact pachymeter and the Schirmer test with anesthesia. Corneal endothelial cells were evaluated by non-contact specular microscopy and photographed for analysis of cell density and hexagonality and the coefficient of variation in cell size. RESULTS: The mean Schirmer score and TBUT value were significantly lower in the smoker group compared to the non-smoker group (p = 0.015) and p < 0.001, respectively). No statistically significant difference was found in the mean CCT, mean endothelial cell density, endothelial cell size, SD of size, and CV of size between smokers and non-smokers (p > 0.05). However, a lower percentage of endothelial hexagonal cells were observed in smokers than non-smokers (p < 0.001). DISCUSSION AND CONCLUSION: Our results suggest that cigarette smoking seems to affect the Schirmer score, TBUT value, and hexagonal cells of the corneal endothelium. PMID- 24147944 TI - Oxidative stress status in patients with melasma. AB - BACKGROUND: Melasma is an acquired skin disease characterized clinically by development of gray-brown macules or patches. The lesions have geographic borders and most often seen on face and less frequently on the neck and forearms. Pathogenesis has not been completely understood yet. Although the disease constitutes a very disturbing cosmetic problem, it has not obtained an efficient treatment. There were not any studies in the literature that evaluates the role of oxidative stress in melasma. OBJECTIVES: The evaluation of the role of oxidative stress in melasma. METHODS: Fifty melasma patients and 50 healthy volunteers were included in the study. The diagnosis was made clinically and the patients were evaluated by Melasma Area Severity Index. Superoxide dismutase (SOD), glutathione peroxidase (GSH-Px) enzyme activities and malondialdehyde, nitric oxide, protein carbonyl levels were measured both in the melasma group and the control group. RESULTS: SOD and GSH-Px enzyme activities were significantly higher in the patient group in comparison with the control group (p < 0.001). Protein carbonyl levels were significantly lower in the patient group (p < 0.001). CONCLUSION: The results show that the balance between oxidant and anti oxidants was disrupted and the oxidative stress increased in melasma. These results improve the understanding of etiology-pathogenesis of the disease and its treatment. PMID- 24147945 TI - The effect of oral cyclosporine in the treatment of severe alopecia areata. AB - CONTEXT: Alopecia areata (AA) is a common non-scarring hair loss condition with an unpredictable and relapsing disease course. T-cell mediated autoimmune process is mainstay of the pathogenesis of AA, therefore immunosuppressive therapies are widely used in the treatment of AA. OBJECTIVE: The aim of the study was to evaluate efficacy of oral cyclosporine therapy and reveal effects of prognostic factors in the treatment of severe AA. MATERIALS AND METHODS: We evaluated case histories of patients who were admitted to our department between December 2004 and September 2011 for the treatment of severe AA. A total of 25 patients were included in the study. Patients' data that included sex, age, alopecia type, alopecia duration, family history, atopic history, previous treatments, treatment dosage, treatment duration, adverse events and clinical response were retrieved from patients' records. Twelve patients had multifocal AA, nine patients had alopecia universalis and four patients had alopecia totalis. Patients were treated with 2.5-6 mg/kg/d doses of oral cyclosporine for 2-12 months. RESULTS: The mean age of patients was 21.92 +/- 3.56 (range: 19-34) years. All patients were male. The mean duration of disease was 8.3 +/- 6.48 (range: 0.5-21) years. Four patients had positive family history and three patients had atopy history. Three of 25 (16%) patients discontinued treatment due to adverse events. Of remaining 22 patients, significant hair growth was observed in 10 (45.4%) patients; five patients with multifocal AA, three patients with alopecia universalis and two patients with alopecia totalis. In addition to this, six of nine patients with less than four years disease duration showed significant hair growth. But in patients with more than four years disease duration, only 4 of 13 patients showed significant hair growth. CONCLUSION: This study indicates that oral cyclosporine treatment may be a beneficial treatment option for severe AA. In addition to this, disease duration is an important prognostic factor that influences efficacy of oral cyclosporine treatment. PMID- 24147946 TI - Narrow-band ultraviolet B phototherapy in childhood. AB - BACKGROUND: Narrow-band ultraviolet B (UVB) has been used for skin diseases in children. However, the use of phototherapy in childhood has limited due to the possible risk of skin cancer. The aim of this study is to evaluate the efficacy and safety of the narrow-band UVB phototherapy in children for the treatment of various skin diseases. METHODS: The data of the children aged 16 years or under who were treated with narrow-band UVB in our clinic's phototherapy unit were analyzed, retrospectively. RESULTS: The study included 77 children (42 girls, 35 boys) aged 5-16 years (mean 12.18 +/- 3.53) who were treated with a total of 81 courses of narrow-band UVB phototherapy in the last 4.5 years. The majority of patients had vitiligo (47%) and psoriasis (39%). Thirty-four (44.2%) patients showed complete response, 15 (19.5%) good response, 12 (15.6%) partial response, 5 (6.5%) poor response and 11(14.3%) no response. Acute side effects of phototherapy were observed only in 11 (14.3%) patients. CONCLUSIONS: Narrow-band UVB phototherapy is an effective and well-tolerated treatment in childhood. PMID- 24147947 TI - In vitro effects of vitamin supplements on platelet-activating factor and its metabolism in age-related macular degeneration. AB - OBJECTIVE: The purpose of our study was to investigate for the first time a series of vitamin supplements used for age-related macular degeneration (AMD) as potential inhibitors of platelet-activating factor (PAF). MATERIALS AND METHODS: Various vitamin supplements were tested in washed rabbit platelets (WRPs), in order to investigate the interaction between vitamin supplements (InShape, Nutrof, Ocuvite, Vitalux) and inhibition of PAF-induced platelet aggregation. Additionally, we examined their ability to affect PAF-metabolism, through their in vitro effect on PAF basic metabolic enzymes (PAF-CPT, lyso PAF-AT, and PAF AH). RESULTS: Nutrof exhibited the strongest anti-PAF activity, while Vitalux was the most potent anti-inflammatory factor. CONCLUSION: This is the first study to bring in surface potent anti-inflammatory and anti-angiogenic activities of some vitamin supplements used against AMD, through their in vitro anti-PAF effects in WRPs and the rabbit plasma and leukocyte PAF metabolism, suggesting a promising role of vitamin supplements and especially resveratrol, concerning its potent anti-angiogenic activity in AMD. PMID- 24147948 TI - Acute serous macular detachment and cystoid macular edema after uncomplicated phacoemulsification using standard dose subconjunctival cefuroxime. AB - Acute toxic serous macular detachment after cataract surgery is very rare, and has been described previously with the use of high concentrations of intra cameral cefuroxime. We report a case of serous macular detachment and cystoid macular edema 1 day after uncomplicated phacoemulsification using standard dose subconjunctival cefuroxime at the end of surgery. Our case demonstrates that subconjunctival cefuroxime may cause retinal toxicity in a similar fashion to intra-cameral cefuroxime, possibly due to entry of the drug into the anterior chamber through the section or trans-scleral absorption. To our knowledge, this is the first report of this complication with subconjunctival administration of cefuroxime. PMID- 24147949 TI - Retinal endoilluminator toxicity of xenon and light-emitting diode (LED) light source: rabbit model. AB - OBJECTIVE: This study evaluates retinal toxicity due to endoillumination with the light-emitting diode (LED) light source in comparison to endoillumination with xenon light source. MATERIAL AND METHODS: Twenty-five eyes of 14 New Zealand pigmented rabbits were used in the study. The LED light (Omesis Medical Systems, Turkey) group was composed of 7 right eyes, while the other 7 right eyes constituted the xenon group (420 nm filter, 357mW/cm(2)) (Bright Star; DORC, Zuidland, Netherlands). Eleven untreated left eyes composed the control group. Twenty gauge pars plana incision 1.5 mm behind the limbus was performed in the right eyes. Twenty gauge bullet type fiberoptic endoilluminator was inserted into the eye from the incision without any pars plana vitrectomy. Fiberoptic endoilluminator was placed in such a way that it was directed toward visual streak of the rabbit retina with a 5 mm distance to retinal surface. Endoillumination was then applied for 20 min with a maximum light intensity for LED and xenon light. In left control eyes, no surgical procedure and no endoillumination were performed. One week after the endoillumination procedure, both eyes of the rabbits were enucleated following electroretinography. Sections stained with hematoxylin and eosin to evaluate morphologic changes. Retina tissues were assessed by active caspase-3 staining. RESULTS: There was no difference in the shape of the waveforms recorded in the eyes endoilluminated with LED light and xenon light sources compared to control eyes both before and after endoillumination application (p > 0.05). Microscopic evaluation of the retinas with hematoxylin and eosin staining demonstrated that all study groups have normal histologic properties similar to control group. No apoptosis positive cells were found within all sections in all groups. CONCLUSIONS: When the LED light source is used with maximum power and limited duration for endoillumination in rabbit eyes it does not produce phototoxic effects that may be detectable by electrophysiology and histology similar to xenon light. PMID- 24147950 TI - Ursodeoxycholic acid induced generalized fixed drug eruption. AB - Fixed drug eruption (FDE) is a rare form of drug allergies that recur at the same cutaneous or mucosal site in every usage of drug. Single or multiple round, sharply demarcated and dusky red plaques appear soon after drug exposure. Ursodeoxycholic acid (UDCA: 3alpha,7beta-dihydroxy-5beta-cholanic acid) is used for the treatment of cholestatic liver diseases. Some side effects may be observed, such as diarrhea, dyspepsia, pruritus and headaches. We encountered only three cases of lichenoid reaction regarding the use of UDCA among previous studies. In this article, we reported a generalized FDE case related to UDCA intake in a 59-year-old male patient with cholestasis for the first time in the literature. PMID- 24147951 TI - GlyT1 inhibitor reduces oscillatory potentials of the electroretinogram in rats. AB - CONTEXT: Selective inhibitors of glycine transporter type 1 (GlyT1) increase synaptic glycine concentrations and are being developed to treat cognitive and negative symptoms of schizophrenia. However, increases in systemic glycine levels have been associated with visual disturbances and electroretinogram (ERG) alternations. OBJECTIVE: To determine whether the selective GlyT1 inhibitor PF 03463275 causes changes in ERG responses in albino rats. MATERIALS AND METHODS: Male Sprague-Dawley rats were administered PF-03463275 subcutaneously at 1, 3 and 10 mg/kg 1 h prior to ERG acquisition. Scotopic and photopic luminance responses, photopic adaptometry and flicker responses were measured. Plasma and vitreous samples were obtained at necropsy for determination of PF-03463275 concentrations. RESULTS: A dose-dependent reduction (up to ~70%) in the amplitude of the scotopic ERG oscillatory potentials (OPs) was observed following PF 03463275 administration. The amplitude of the OPs was also negatively correlated to the concentration of PF-03463275 in the vitreous humor (r = -0.64, p < 0.0001). With the exception of a small increase in scotopic ERG a-wave amplitude and latency no effects were observed on other ERG parameters tested. CONCLUSIONS: We conclude that inhibition of the GlyT1 transporter in the retina causes ERG changes which may underlie recent reports of visual disturbance with GlyT1 inhibitors in clinical trials. PMID- 24147952 TI - Autoantibody detection to tumor-associated antigens of P53, IMP1, P16, cyclin B1, P62, C-myc, Survivn, and Koc for the screening of high-risk subjects and early detection of esophageal squamous cell carcinoma. AB - The aim of this study was to evaluate the diagnostic values by detecting sera autoantibodies to eight tumor-associated antigens (TAAs) of P53, IMP1, P16, cyclin B1, P62, C-myc, Survivn and Koc full-length recombinant proteins for the screening of high-risk subjects and early detection of esophageal squamous cell carcinoma (ESCC). Enzyme-linked immunosorbent assay was used to detect autoantibodies against the eight selected TAAs in 567 sera samples from four groups, including 200 individuals with normal esophageal epithelia (NOR), 214 patients with esophageal basal cell hyperplasia (BCH), 65 patients with esophageal dysplasia (DYS), and 88 patients with ESCC. In addition, the expression of the eight antigens in esophageal tissues was analyzed by immunohistochemistry. Statistically significant distribution differences were identified among the four groups for each of the individual autoantibodies to six TAAs (P53, IMP1, P16, cyclin B1, P62, and C-myc); the detection rates of antoantibodies were positively correlated with the progression of ESCC. When autoantibody assay successively accumulated to six TAAs (P53, IMP1, P16, cyclin B1, P62, and C-myc), a stepwise increased detection frequency of autoantibodies was found in the four sera groups (6% in NOR, 18% in BCH, 38% in DYS, and 64% in ESCC, respectively), the risks to BHC, DYS, and ESCC steadily increased about 3-, 9-, and 27-folds. The sensitivity and the specificity for autoantibodies against the six TAAs in diagnosing ESCC reached up to 64% and 94%, respectively. The area under the receiver operating characteristic curve for the six anti-TAA autoantibodies was 0.78 (95% confidence interval 0.74-0.83). No more increasing in sensitivity was found with the addition of new anti-TAA autoantibodies. A combination detection of autoantibodies to TAAs might distinguish ESCC patients from normal individuals and the patients with esophageal precancerous lesions. PMID- 24147953 TI - Porous titanium-6 aluminum-4 vanadium cage has better osseointegration and less micromotion than a poly-ether-ether-ketone cage in sheep vertebral fusion. AB - Interbody fusion cages made of poly-ether-ether-ketone (PEEK) have been widely used in clinics for spinal disorders treatment; however, they do not integrate well with surrounding bone tissue. Ti-6Al-4V (Ti) has demonstrated greater osteoconductivity than PEEK, but the traditional Ti cage is generally limited by its much greater elastic modulus (110 GPa) than natural bone (0.05-30 GPa). In this study, we developed a porous Ti cage using electron beam melting (EBM) technique to reduce its elastic modulus and compared its spinal fusion efficacy with a PEEK cage in a preclinical sheep anterior cervical fusion model. A porous Ti cage possesses a fully interconnected porous structure (porosity: 68 +/- 5.3%; pore size: 710 +/- 42 MUm) and a similar Young's modulus as natural bone (2.5 +/- 0.2 GPa). When implanted in vivo, the porous Ti cage promoted fast bone ingrowth, achieving similar bone volume fraction at 6 months as the PEEK cage without autograft transplantation. Moreover, it promoted better osteointegration with higher degree (2-10x) of bone-material binding, demonstrated by histomorphometrical analysis, and significantly higher mechanical stability (P < 0.01), shown by biomechanical testing. The porous Ti cage fabricated by EBM could achieve fast bone ingrowth. In addition, it had better osseointegration and superior mechanical stability than the conventional PEEK cage, demonstrating great potential for clinical application. PMID- 24147954 TI - Evidence for sodium metasilicate receptors on the human osteoblast cell surface; spatial localization and binding properties. AB - We report details of the interaction of sodium metasilicate with osteoblast cellular membranes using Fluoresceinphosphatidylethanolamine (FPE) as a fluorescent indicator of membrane interactions. Fluorescence imaging studies of the FPE-based indicator system revealed areas of localized binding that would be consistent with the presence of a structure with 'receptor-like' properties. From these results, it seems unlikely that silica binds 'non-specifically' to the osteoblast surface. Moreover, the receptors are localized into membrane domains. Such regions of the cell membrane could well be structures such as 'rafts' or other such localized domains within the membrane. The binding profile of silica with the osteoblast cell surface takes place with all the characteristics of a receptor-mediated process best represented by a cooperativity (sigmoidal) binding model with a Hill coefficient of 3.6. PMID- 24147955 TI - Chemical and in vitro assessment of Alaskan coastal vegetation antioxidant capacity. AB - Alaska Native (AN) communities have utilized tidal plants and marine seaweeds as food and medicine for generations, yet the bioactive potential of these resources has not been widely examined. This study screened six species of Alaskan seaweed ( Fucus distichus , Saccharina latissima , Saccharina groenlandica , Alaria marginata , Pyropia fallax , and Ulva lactuca ) and one tidal plant ( Plantago maritima ) for antioxidant activity. Total polyphenolic content (TPC) was determined, and chemical antioxidant capacity was assessed by 2,2-diphenyl-1 picrylhydrazyl (DPPH) radical scavenging, ferrous ion chelating, and nitric oxide (NO) inhibition assays. In vitro inhibition of radical oxygen species (ROS) generation and NO synthesis was evaluated in a RAW 264.7 macrophage culture. Greatest TPC (557.2 MUg phloroglucinol equivalents (PGE)/mg extract) was discovered in the ethyl acetate fraction of F. distichus, and highest DDPH scavenging activity was exhibited by F. distichus and S. groenlandica fractions (IC50 = 4.29-5.12 MUg/mL). These results support the potential of Alaskan coastal vegetation, especially the brown algae, as natural sources of antioxidants for preventing oxidative degeneration and maintaining human health. PMID- 24147956 TI - Nephrolithiasis and pregnancy: has the incidence been rising? AB - INTRODUCTION: The incidence of nephrolithiasis has consistently been increasing over recent decades. This has been attributed to diet, obesity, environmental temperature changes, and comorbid diseases such as diabetes. Incidence change has not been studied in the pregnant population. Herein, we report our experience with stone diagnosis in this unique patient population over the past 2 decades. METHODS: Hospital data from a tertiary women's hospital were examined for international classification of diseases, ninth revision (ICD-9) codes for pregnancy (640-648, V22.0, V22.1, V22.2), and urolithiasis (592.0, 592.1, 592.9) between 1991 and 2011. The change in incidence in nephrolithiasis, pregnancy, and the combination of both was examined. RESULTS: In the 21-year period studied, 876 pregnant patients were given a diagnosis of nephrolithiasis at our hospital. Over the same time, 204,034 pregnant patients and 3262 patients with stones were treated. Comparing patients seen from 1991-2000 to those seen from 2001-2011 revealed a significant increase in patients with stones (78 vs. 226/year, p=0.004), but no change in pregnant patients (9467 vs. 9942/year, p=0.3) or pregnant patients with stones (36 vs. 47, p=0.1). Evaluating patients at 5-year intervals confirmed the expected increase in patients with stones, but no change in incidence of nephrolithiasis in pregnant patients was noted. CONCLUSION: There was no change in incidence of nephrolithiasis in pregnant patients over a 2 decade period. Further research is warranted to determine why the pregnant population does not have the expected increase in nephrolithiasis. Larger, multi institutional studies are needed to validate our results. PMID- 24147957 TI - Effect of exchange of the cysteine molybdenum ligand with selenocysteine on the structure and function of the active site in human sulfite oxidase. AB - Sulfite oxidase (SO) is an essential molybdoenzyme for humans, catalyzing the final step in the degradation of sulfur-containing amino acids and lipids, which is the oxidation of sulfite to sulfate. The catalytic site of SO consists of a molybdenum ion bound to the dithiolene sulfurs of one molybdopterin (MPT) molecule, carrying two oxygen ligands, and is further coordinated by the thiol sulfur of a conserved cysteine residue. We have exchanged four non-active site cysteines in the molybdenum cofactor (Moco) binding domain of human SO (SOMD) with serine using site-directed mutagenesis. This facilitated the specific replacement of the active site Cys207 with selenocysteine during protein expression in Escherichia coli. The sulfite oxidizing activity (kcat/KM) of SeSOMD4Ser was increased at least 1.5-fold, and the pH optimum was shifted to a more acidic value compared to those of SOMD4Ser and SOMD4Cys(wt). X-ray absorption spectroscopy revealed a Mo(VI)-Se bond length of 2.51 A, likely caused by the specific binding of Sec207 to the molybdenum, and otherwise rather similar square-pyramidal S/Se(Cys)O2Mo(VI)S2(MPT) site structures in the three constructs. The low-pH form of the Mo(V) electron paramagnetic resonance (EPR) signal of SeSOMD4Ser was altered compared to those of SOMD4Ser and SOMD4Cys(wt), with g1 in particular shifted to a lower magnetic field, due to the Se ligation at the molybdenum. In contrast, the Mo(V) EPR signal of the high-pH form was unchanged. The substantially stronger effect of substituting selenocysteine for cysteine at low pH as compared to high pH is most likely due to the decreased covalency of the Mo-Se bond. PMID- 24147958 TI - Correction of errors in tandem mass spectrum extraction enhances phosphopeptide identification. AB - The tandem mass spectrum extraction of phosphopeptides is more difficult and error-prone than that of unmodified peptides due to their lower abundance, lower ionization efficiency, the cofragmentation with other high-abundance peptides, and the use of MS(3) on MS(2) fragments with neutral losses. However, there are still no established methods to evaluate its correctness. Here we propose to identify and correct these errors via the combinatorial use of multiple spectrum extraction tools. We evaluated five free and two commercial extraction tools using Mascot and phosphoproteomics raw data from LTQ FT Ultra, in which RawXtract 1.9.9.2 identified the highest number of unique phosphopeptides (peptide expectation value <0.05). Surprisingly, ProteoWizzard (v. 3.0.3476) extracted wrong precursor mass for most MS(3) spectra. Comparison of the top three free extraction tools showed that only 54% of the identified spectra were identified consistently from all three tools, indicating that some errors might happen during spectrum extraction. Manual check of 258 spectra not identified from all three tools revealed 405 errors of spectrum extraction with 7.4% in selecting wrong precursor charge, 50.6% in selecting wrong precursor mass, and 42.1% in exporting MS/MS fragments. We then corrected the errors by selecting the best extracted MGF file for each spectrum among the three tools for another database search. With the errors corrected, it results in the 22.4 and 12.2% increase in spectrum matches and unique peptide identification, respectively, compared with the best single method. Correction of errors in spectrum extraction improves both the sensitivity and confidence of phosphopeptide identification. Data analysis on nonphosphopeptide spectra indicates that this strategy applies to unmodified peptides as well. The identification of errors in spectrum extraction will promote the improvement of spectrum extraction tools in future. PMID- 24147959 TI - Demystifying analytical approaches for urine drug testing to evaluate medication adherence in chronic pain management. AB - This comprehensive review of analytical methods used for urine drug testing for the support of pain management describes the methods, their strengths and limitations, and types of analyses used in clinical laboratories today. Specific applications to analysis of opioid levels are addressed. Qualitative versus quantitative testing, immunoassays, chromatographic methods, and spectrometry are discussed. The importance of proper urine sample collection and processing is addressed. Analytical explanations for unexpected results are described. This article describes the scientific basis for urine drug testing providing information which will allow clinicians to differentiate between valid and questionable claims for urine drug testing to monitor medication adherence among chronic pain patients. PMID- 24147960 TI - Effects of a pain education program for veterans with chronic, noncancer pain: a pilot study. AB - This pilot study examines the effects of a "Pain Education School" developed and implemented in a American Department of Veterans Affairs (VA) Medical Center using the National Center for Health Promotion and Disease Prevention's step-by step guidelines in veterans with chronic or persistent, noncancer pain. This study used a quasi-experimental, one-group, pre-/posttest design. A sample of 88 veterans aged 39 to 84 years old who elected to participate in the 12-week pain education program was evaluated. Paired-samples t-tests were conducted using an efficacy subset analysis strategy. Veterans who elected to complete the program reported a statistically significant difference in their pre- and posttest measures of pain intensity (p = .028), stages of readiness to adopt a self management approach (p = .002), experience of pain (p = .000), and depressive symptoms (p = .000). However, there was not a statistically significant difference found in pain knowledge (p = .790). The current findings provide preliminary evidence that the program may be efficacious, but a randomized controlled trial is warranted to confirm these effects. This manuscript encourages other VAs to transfer this low-intensity approach as a means of creating awareness, and may be utilized as a benchmark of pain education programming. PMID- 24147961 TI - Enhancing youth health in primary care: lessons learned from general practitioners. AB - Primary care represents a fundamental component of the health system, particularly for young people. However, youth access to primary care is less than ideal. To optimize clinician capacity to promote youth health, an interactive training module was developed and tailored to the needs of general practitioners. As part of an exploratory study, 11 participants were interviewed to determine the perceived capacity of the module to promote youth-friendly primary care. Findings suggest the module can enhance clinician skills, knowledge, and confidence to promote youth health; however, it has a limited ability to inform how organizational capacity might be bolstered-this includes the development of interagency networks. In this epoch of primary care reform, these findings are important for two key reasons. First, they reveal the need to bolster clinicians' perceived ability to use youth healthcare skills; second, they highlight the complementary importance of organizational support to ensure and sustain youth friendly practices. The article concludes with a discussion of key implications for policymakers, practitioners, and researchers. PMID- 24147962 TI - Ovarian cancer evolution through stochastic genome alterations: defining the genomic role in ovarian cancer. AB - Ovarian cancer is the fifth leading cause of death among women worldwide. Characterized by complex etiology and multi-level heterogeneity, its origins are not well understood. Intense research efforts over the last decade have furthered our knowledge by identifying multiple risk factors that are associated with the disease. However, it is still unclear how genetic heterogeneity contributes to tumor formation, and more specifically, how genome-level heterogeneity acts as the key driving force of cancer evolution. Most current genomic approaches are based on 'average molecular profiling.' While effective for data generation, they often fail to effectively address the issue of high level heterogeneity because they mask variation that exists in a cell population. In this synthesis, we hypothesize that genome-mediated cancer evolution can effectively explain diverse factors that contribute to ovarian cancer. In particular, the key contribution of genome replacement can be observed during major transitions of ovarian cancer evolution including cellular immortalization, transformation, and malignancy. First, we briefly review major updates in the literature, and illustrate how current gene-mediated research will offer limited insight into cellular heterogeneity and ovarian cancer evolution. We next explain a holistic framework for genome-based ovarian cancer evolution and apply it to understand the genomic dynamics of a syngeneic ovarian cancer mouse model. Finally, we employ single cell assays to further test our hypothesis, discuss some predictions, and report some recent findings. PMID- 24147963 TI - Carbonylation reactions of intramolecular vicinal frustrated phosphane/borane Lewis pairs. AB - The intramolecular frustrated Lewis pair (FLP) Mes2PCH2CH2B(C6F5)2 4 adds cooperatively to carbon monoxide to form the five-membered heterocyclic carbonyl compound 5. The intramolecular FLP 7 contains an exo-3-B(C6F5)2 Lewis acid and an endo-2-PMes2 Lewis base functionality coordinated at the norbornane framework. This noninteracting FLP adds carbon monoxide in solution at -35 degrees C cooperatively to yield a five-membered heterocyclic FLP-carbonyl compound 8. In contrast, FLP 7 is carbonylated in a CO-doped argon matrix at 25 K to selectively form a borane carbonyl 9 without involvement of the adjacent phosphanyl moiety. The free FLP 7 was generated in the gas phase from its FLPH2 product 10. A DFT study has shown that the phosphonium hydrido borate zwitterion 10 is formed exergonically in solution but tends to lose H2 when brought into the gas phase. PMID- 24147964 TI - Sperm impairments in adult vesper mice (Calomys laucha) caused by in utero exposure to bisphenol A. AB - This study aimed to evaluate the effects of in utero administration of bisphenol A (BPA) on semen parameters of vesper mice. Sixty female Calomys laucha were divided into six groups and received by gavage during gestation the following substances: Water (negative control), Olive Oil (vehicle control), Diethylstilbestrol (DES - positive control - 6.5 MUg kg(-1) bw) and BPA (40, 80 and 200 MUg kg(-1) bw). Male offspring were euthanised at 70 days of age, and sperm parameters were analysed. BPA reduced normal sperm morphology (water = 96.1 +/- 0.65; BPA200 = 96.8 +/- 2.3%), sperm membrane integrity (water = 88.8 +/- 1,65; BPA200 = 70.6 +/- 4,15%), sperm motility (water = 87.5 +/- 1.71; BPA200 = 51.3 +/-9.9%) and in vitro penetration rates (water = 55.0 +/- 7.14; BPA200 = 7.47 +/-2.96%), but it did not affect body weight, anogenital distance, sperm DNA integrity and acrosome integrity. In conclusion, in utero exposure to BPA caused a reduction in sperm parameters of adult C. laucha. Natural mating studies should be conducted to verify the effects of BPA on fertility of the animals. PMID- 24147965 TI - Performance of M06, M06-2X, and M06-HF density functionals for conformationally flexible anionic clusters: M06 functionals perform better than B3LYP for a model system with dispersion and ionic hydrogen-bonding interactions. AB - We present a comparative assessment of the performance of the M06 suite of density functionals (M06, M06-2X, and M06-HF) against an MP2 benchmark for calculating the relative energies and geometric structures of the Cl(-).arginine and Br(-).arginine halide ion-amino acid clusters. Additional results are presented for the popular B3LYP density functional. The Cl(-).arginine and Br( ).arginine complexes are important prototypes for the phenomenon of anion-induced zwitterion formation. Results are presented for the canonical (noncharge separated) and zwitterionic (charge separated) tautomers of the clusters, as well as the numerous conformational isomers of the clusters. We find that all of the M06 functions perform well in terms of predicting the general trends in the conformer relative energies and identifying the global minimum conformer. This is in contrast to the B3LYP functional, which performed significantly less well for the canonical tautomers of the clusters where dispersion interactions contribute more significantly to the conformer energetics. We find that the M06 functional gave the lowest mean unsigned error for the relative energies of the canonical conformers (2.10 and 2.36 kJ/mol for Br(-).arginine and Cl(-).arginine), while M06-2X gave the lowest mean unsigned error for the zwitterionic conformers (0.85 and 1.23 kJ/mol for Br(-).arginine and Cl(-).arginine), thus providing insight into the types of physical systems where each of these functionals should perform best. PMID- 24147966 TI - Factors influencing macrosomia in pregnant women in a tertiary care hospital in Malaysia. AB - AIM: To identify the risk factors influencing the development of macrosomia among pregnant women and to develop a regression model to predict macrosomia. METHODS: A cross-sectional study was conducted in a tertiary hospital in Malaysia involving 2332 pregnant women. The data was retrospectively collected from the obstetrics and gynecology department. The factors that influence fetal weight were collected from the antenatal cards and any additional information was collected by face-to-face interview using a questionnaire. A multiple regression model was developed to predict macrosomia using SPSS ver.18. RESULTS: The significant variables that influence macrosomia in this study were mother's age, mother's body mass index (BMI), weight gain, parity, mother's ethnicity, father's BMI, gestational week, diabetes during pregnancy and neonatal sex. Diabetes during pregnancy is an important risk factor for macrosomia; by using this parameter alone the risk of macrosomia can be predicted with a sensitivity rate of 70% and specificity of 70%. By including other maternal factors such as maternal age, pre-pregnancy BMI, weight gain, parity, ethnicity, as well as father's BMI, gestational weeks and neonate sex, the sensitivity and specificity were improved to 80% and 75%, respectively. CONCLUSION: A regression model was developed and this could be used in health centers to predict macrosomia for purpose of referral to higher centers. PMID- 24147967 TI - The discrimination of colored acrylic, cotton, and wool textile fibers using micro-Raman spectroscopy. Part 1: in situ detection and characterization of dyes. AB - Raman spectroscopy has been applied to characterize fiber dyes and determine the discriminating ability of the method. Black, blue, and red acrylic, cotton, and wool samples were analyzed. Four excitation sources were used to obtain complementary responses in the case of fluorescent samples. Fibers that did not provide informative spectra using a given laser were usually detected using another wavelength. For any colored acrylic, the 633-nm laser did not provide Raman information. The 514-nm laser provided the highest discrimination for blue and black cotton, but half of the blue cottons produced noninformative spectra. The 830-nm laser exhibited the highest discrimination for red cotton. Both visible lasers provided the highest discrimination for black and blue wool, and NIR lasers produced remarkable separation for red and black wool. This study shows that the discriminating ability of Raman spectroscopy depends on the fiber type, color, and the laser wavelength. PMID- 24147969 TI - Ocean acidification and host-pathogen interactions: blue mussels, Mytilus edulis, encountering Vibrio tubiashii. AB - Ocean acidification (OA) can shift the ecological balance between interacting organisms. In this study, we have used a model system to illustrate the interaction between a calcifying host organism, the blue mussel Mytilus edulis and a common bivalve bacterial pathogen, Vibrio tubiashii, with organisms being exposed to a level of acidification projected to occur by the end of the 21st century. OA exposures of the mussels were carried out in relative long-term (4 months) and short-term (4 days) experiments. We found no effect of OA on the culturability of V. tubiashii, in broth or in seawater. OA inhibited mussel shell growth and impaired crystalline shell structures but did not appear to affect mussel immune parameters (i.e haemocyte counts and phagocytotic capacity). Despite no evident impact on host immunity or growth and virulence of the pathogen, V. tubiashii was clearly more successful in infecting mussels exposed to long-term OA compared to those maintained under ambient conditions. Moreover, OA exposed V. tubiashii increased their viability when exposed to haemocytes of OA-treated mussel. Our findings suggest that even though host organisms may have the capacity to cope with periods of OA, these conditions may alter the outcome of host-pathogen interactions, favouring the success of the latter. PMID- 24147970 TI - Sulforaphane: translational research from laboratory bench to clinic. AB - Cruciferous vegetables are widely acknowledged to provide chemopreventive benefits in humans, but they are not generally consumed at levels that effect significant change in biomarkers of health. Because consumers have embraced the notion that dietary supplements may prevent disease, this review considers whether an appropriately validated sulforaphane-yielding broccoli sprout supplement may deliver clinical benefit. The crucifer-derived bioactive phytochemical sulforaphane is a significant inducer of nuclear factor erythroid 2 related factor 2 (Nrf2), the transcription factor that activates the cell's endogenous defenses via a battery of cytoprotective genes. For a broccoli sprout supplement to demonstrate bioactivity in vivo, it must retain both the sulforaphane-yielding precursor compound, glucoraphanin, and the activity of glucoraphanin's intrinsic myrosinase enzyme. Many broccoli sprout supplements are myrosinase inactive, but current labeling does not reflect this. For the benefit of clinicians and consumers, this review summarizes the findings of in vitro studies and clinical trials, interpreting them in the context of clinical relevance. Standardization of sulforaphane nomenclature and assay protocols will be necessary to remove inconsistency and ambiguity in the labeling of currently available broccoli sprout products. PMID- 24147971 TI - Is furcation involvement in maxillary molars a predictor for subsequent bone augmentation prior to implant placement? A pilot study. AB - AIM: The aim of this pilot study was to analyze the interfurcal bone height in relation to the possible need for subsequent sinus floor elevation in patients with advanced periodontitis and furcation involvement of first and/or second maxillary molars. MATERIAL AND METHODS: Seventeen dentate patients, who received cone beam computed tomography (CBCT) for detailed preoperative diagnosis and planning of surgical interventions at periodontally involved maxillary molars (17 first and 15 second molars), were consecutively recruited for the study. The minimal bone height in the interfurcal region was measured from CBCT and related to furcation involvement, residual bone above the root tips, and the clinical probing pocket depth (PPD). RESULTS: The minimal interfurcal bone height measured 4.1 +/- 2.6 mm on average with 75% of maxillary molars having <= 6 mm and almost 60% having only <= 4 mm bone height left below the sinus floor. A higher risk for reduced interfurcal bone height of <= 4 mm was given when residual PPD of >= 6 mm was remaining at two or more tooth sites (OR 0.10; 0.11). CONCLUSIONS: The majority of periodontally involved maxillary molars had a substantially reduced interfurcal bone height, particularly with at least two sites with residual PPD >= 6 mm. This was a predictor for a subsequent need for sinus floor elevation when tooth replacement with a dental implant is desired. PMID- 24147972 TI - An exploratory study to evaluate whether medical nutrition therapy can improve dietary intake in hospital patients who eat poorly. AB - BACKGROUND: The Australasian Nutrition Care Day Survey (ANCDS) reported that two fifths of patients consume <=50% of the offered food in Australian and New Zealand hospitals. After controlling for confounders (nutritional status, age, disease type and severity), the ANCDS also established an independent association between poor food intake and increased in-hospital mortality. The present study aimed to evaluate whether medical nutrition therapy (MNT) could improve dietary intake in hospital patients eating poorly. METHODS: An exploratory pilot study was conducted in the respiratory, neurology and orthopaedic wards of an Australian hospital. At baseline, percentage food intake (0%, 25%, 50%, 75% and 100%) was evaluated for each main meal and snack for a 24-h period in patients hospitalised for >=2 days and not under dietetic review. Patients consuming <=50% of offered meals as a result of nutrition-impact symptoms were referred to ward dietitians for MNT. Food intake was re-evaluated on the seventh day after recruitment (post-MNT). RESULTS: One hundred and eighty-four patients were observed over 4 weeks; 32 patients were referred for MNT. Although baseline and post-MNT data for 20 participants [mean (SD) age 68 (17) years, 65% females] indicated a significant increase in median energy and protein intake post-MNT (3600 kJ day(-1) ; 40 g day(-1) ) versus baseline (2250 kJ day(-1) ; 25 g day(-1) ) (P < 0.05), the increased intake met only 50% of dietary requirements. Persistent nutrition impact symptoms affected intake. CONCLUSIONS: In the present pilot study, although dietary intake improved, it remained inadequate to meet participants' estimated requirements as a result of ongoing nutrition-impact symptoms. Appropriate medical management and early enteral feeding could be a possible solution for such patients. PMID- 24147974 TI - Respiratory function parameters in ventilated newborn infants undergoing whole body hypothermia. AB - AIM: Whole body hypothermia (WBH) exerts proven neuroprotective effects in infants with hypoxic-ischaemic encephalopathy (HIE). Our aim was to describe how WBH could impact on respiratory function in mechanically ventilated newborn infants, by recording primary and composite indices of oxygenation and ventilation before, during and after WBH. METHODS: The medical notes of 31 mechanically ventilated full-term newborn infants who underwent WBH for HIE were retrospectively reviewed. Fraction of inspired oxygen (FiO2), tidal volume (TV), mean airway Pressure (MAP), minute ventilation (MV), static compliance of the respiratory system (C(statRS)), ventilation efficiency index (VEI), alveolar arterial gradient (A-a gradient) and oxygenation index (OI) were documented before and during hypothermic treatment, as well as during and after rewarming. RESULTS: Fraction of inspired oxygen, MAP, OI and A-a gradient decreased during induction of hypothermia and tended to increase during rewarming. C(statRS), VEI and TV increased during induction of hypothermia and tended to decrease during rewarming. None of the changes achieved statistical significance. CONCLUSION: These results suggest that WBH might affect respiratory function in mechanically ventilated infants with HIE. Oxygenation might be enhanced by hypothermia, probably as a result of decreased metabolism, while ventilation might also be facilitated as a result of the effect of hypothermia on lung mechanics. PMID- 24147973 TI - Long-term results of definitive radiochemotherapy in locally advanced cancers of the cervical esophagus. AB - The aim of this study was to retrospectively analyze the long-term effectiveness of combined chemoradiation as the definitive treatment of locally advanced cancers of the cervical esophagus. Patients received high-dose external beam radiotherapy and concurrent cisplatin-based chemotherapy. Some patients received intraluminal brachytherapy as a boost. In addition, a majority of the patients received cisplatin-based induction chemotherapy before definitive chemoradiation. Fifty-five patients (46 men, 9 women, median age 58 years, range 35-72 years) with cancers of the cervical esophagus (stage II: 20; stage III: 35 patients) were treated with definitive chemoradiation (median dose 60 Gy, range 50-70 Gy). Actuarial overall survival rates at 2, 3, 5, and 10 years were 35%, 29%, 25%, and 10%, respectively. Thirteen long-term survivors were observed with a follow-up of more than 5 years. Neither gender nor age, tumor length, tumor grade, or clinically detectable lymph node metastases was significant prognostic factors for survival. Twenty-four patients (44%) developed local or regional recurrences, 15 (27%) distant metastases, and 8 (15%) patients developed a second malignancy. Acute and late toxicity of this treatment schedule was moderate. Concurrent chemoradiation offers a chance of long-term survival for locally advanced unresectable carcinomas of the cervical esophagus, with long-term survival rates above 24% and acceptable toxicity. These results substantiate the use of chemoradiation as a curative treatment option for cervical esophageal cancer. PMID- 24147976 TI - Lipase activity in lipidomics - a hidden problem? PMID- 24147975 TI - Mitochondrial fatty acid oxidation alterations in heart failure, ischaemic heart disease and diabetic cardiomyopathy. AB - Heart disease is a leading cause of death worldwide. In many forms of heart disease, including heart failure, ischaemic heart disease and diabetic cardiomyopathies, changes in cardiac mitochondrial energy metabolism contribute to contractile dysfunction and to a decrease in cardiac efficiency. Specific metabolic changes include a relative increase in cardiac fatty acid oxidation rates and an uncoupling of glycolysis from glucose oxidation. In heart failure, overall mitochondrial oxidative metabolism can be impaired while, in ischaemic heart disease, energy production is impaired due to a limitation of oxygen supply. In both of these conditions, residual mitochondrial fatty acid oxidation dominates over mitochondrial glucose oxidation. In diabetes, the ratio of cardiac fatty acid oxidation to glucose oxidation also increases, although primarily due to an increase in fatty acid oxidation and an inhibition of glucose oxidation. Recent evidence suggests that therapeutically regulating cardiac energy metabolism by reducing fatty acid oxidation and/or increasing glucose oxidation can improve cardiac function of the ischaemic heart, the failing heart and in diabetic cardiomyopathies. In this article, we review the cardiac mitochondrial energy metabolic changes that occur in these forms of heart disease, what role alterations in mitochondrial fatty acid oxidation have in contributing to cardiac dysfunction and the potential for targeting fatty acid oxidation to treat these forms of heart disease. PMID- 24147977 TI - How do transporters couple solute movements? AB - Abstract The availability of high-resolution atomic structures for transport proteins provides unprecedented opportunities for understanding their mechanism of action. The details of conformational change can be deduced from these structures, especially when multiple conformations are available. However, the singular ability of transporters to couple the movement of one solute to that of another requires even more information than what is supplied by a crystal structure. This short commentary discusses how recent biochemical and biophysical studies are beginning to reveal how solute coupling is achieved. PMID- 24147978 TI - Incidence and risk factors for herpes zoster following heart transplantation. AB - BACKGROUND: Data on the incidence, timing, and risk factors for herpes zoster (HZ) in heart transplant (HT) recipients are limited. METHODS: We determined HZ incidence rates and actuarial estimates of time to first HZ episode in 314 HT recipients at our institution from 1995 to 2010. We developed Cox models to assess potential risk factors for HZ in HT. RESULTS: Median age at HT was 54 (range, 17-71) years; 237 (76%) were male. There were 60 episodes of HZ in 51 patients, with an overall incidence rate of 31.6 cases (95% confidence interval [CI], 23.5-41.6)/1000 person-years. Although most cases occurred during the first post-HT year, cumulative HZ incidence was 0.078 at 1, 0.15 at 5, and 0.20 at 10 years. Many patients had substantial HZ morbidity, including 14% with HZ ophthalmicus and 45% with post-herpetic neuralgia. Adjusting for age, gender, and acute cellular rejection episodes, exposure to mycophenolate mofetil (MMF) was an independent risk factor for HZ (adjusted hazard ratio [HR] 2.18; 95% CI, 1.20 3.96; P = 0.01), while ganciclovir-based cytomegalovirus prophylaxis reduced HZ risk (adjusted HR 0.09; 95% CI, 0.01-0.71; P = 0.02). Although age and female gender increased HZ risk, the magnitude of their effect was not statistically significant in Cox models. CONCLUSIONS: HZ is common and morbid after HT, particularly with MMF exposure. Ganciclovir prophylaxis is effective in reducing the short-term risk of HZ, but the steady incidence of cases for years post HT makes long-term HZ prevention challenging. Augmenting varicella zoster virus immunity post HT with vaccines warrants further exploration. PMID- 24147979 TI - Metabolic flux between unsaturated and saturated fatty acids is controlled by the FabA:FabB ratio in the fully reconstituted fatty acid biosynthetic pathway of Escherichia coli. AB - The entire fatty acid biosynthetic pathway of Escherichia coli, starting from the acetyl-CoA carboxylase, has been reconstituted in vitro from 14 purified protein components. Radiotracer analysis verified stoichiometric conversion of acetyl-CoA and NAD(P)H to the free fatty acid product, allowing implementation of a facile spectrophotometric assay for kinetic analysis of this multienzyme system. At steady state, a maximal turnover rate of 0.5 s(-1) was achieved. Under optimal turnover conditions, the predominant products were C16 and C18 saturated as well as monounsaturated fatty acids. The reconstituted system allowed us to quantitatively interrogate the factors that influence metabolic flux toward unsaturated versus saturated fatty acids. In particular, the concentrations of the dehydratase FabA and the beta-ketoacyl synthase FabB were found to be crucial for controlling this property. Via changes in these variables, the percentage of unsaturated fatty acid produced could be adjusted between 10 and 50% without significantly affecting the maximal turnover rate of the pathway. Our reconstituted system provides a powerful tool for understanding and engineering rate-limiting and regulatory steps in this complex and practically significant metabolic pathway. PMID- 24147980 TI - Robot-assisted anatrophic nephrolithotomy: description of technique and early results. AB - PURPOSE: To assess the feasibility and report early outcomes of robot-assisted anatrophic nephrolithotomy (RAN) as a treatment modality for patients with complex staghorn calculi. PATIENTS AND METHODS: In this single-center prospective study, seven consecutive patients underwent RAN for complex staghorn calculi. After dissection to the renal hilum and clamping of the renal vessels, a nephrotomy was made along the Brodel line and dissection carried through the collecting system to the calculus. The stone was extracted, and the collecting system and parenchyma were closed in layers; no cooling of the kidney was performed. RESULTS: The mean patient age was 47+/-16 years, mean body mass index was 31.9+/-10.0 kg/m(2), and five of seven patients had complete staghorn calculi. Mean warm ischemia time was 35+/-7 minutes, mean robotic time was 158+/ 51 minutes, and mean estimated blood loss was 121+/-39 mL. Mean length of stay was 3.0+/-1.7 days, and there was one perioperative complication. Five of seven patients had >90% reduction in stone burden, and two (29%) patients were completely stone free. Mean follow-up time was 5.1+/-4.3 months, and there was no decrease in postoperative estimated glomerular filtration rate compared with preoperative values. CONCLUSIONS: Our preliminary experience with RAN demonstrates a safe procedure with encouraging outcomes as a minimally invasive treatment modality for patients with extensive stone burden. Longer follow-up to determine the effect of RAN on renal function is needed. PMID- 24147981 TI - Compositional safety of herbicide-tolerant DAS-81910-7 cotton. AB - DAS-81910-7 cotton is a transgenic event that was transformed to contain the aad 12 and pat genes. These genes code for the AAD-12 and PAT proteins, which confer tolerance to the herbicides 2,4-D and glufosinate, respectively. Crop composition studies were conducted with DAS-81910-7 cotton (both nonsprayed and sprayed with 2,4-D and glufosinate) to comply with requirements of regulatory authorities responsible for evaluating crop safety. Results indicate compositional equivalence between DAS-81910-7 cottonseed and nontransgenic cottonseed and between sprayed and nonsprayed DAS-81910-7 cottonseed. This study builds on the results from many prior studies which support the conclusion that transgenesis is less likely to unexpectedly alter the composition of crops as compared with traditional breeding. PMID- 24147982 TI - Effects of surgical repair on active shoulder position sense and 3-dimensional reaching accuracy in a patient with anterior shoulder instability. AB - The purpose of this report was to investigate whether a subject with anterior shoulder instability exhibited better active shoulder position sense and 3 dimensional (3-D) reaching accuracy after a surgical repair. The 19-year-old male subject underwent an open Bankart repair procedure for his left shoulder followed by a standardized post-operative rehabilitation program. Shoulder position sense was examined with traditional passive matching and active positioning protocols. Reaching accuracy in space with the unrestricted arm motion was also examined. The subject was tested 5 months prior to the surgery and re-tested 6 months after the surgery. With the traditional passive matching protocol, shoulder position sense improved <2 degrees after surgery. However, shoulder position sense improved greatly after surgery with active shoulder abduction (up to 4.25 degrees ) and active shoulder rotation (up to 5.87 degrees ) testing protocols. In addition, reaching accuracy also greatly improved after surgery (up to 10.97 cm) with the most significant improvement when reaching to targets located in the frontal plane. Data suggest that anterior shoulder repair with rehabilitation can improve both active shoulder position sense and reaching accuracy, especially in shoulder positions involving abduction with external rotation. PMID- 24147983 TI - Mechanical evaluation of elastic tubes used in physical therapy. AB - PURPOSE: To quantify the force of elastic tubes at different elongation patterns used in exercises. METHODS: A tensile test of elastic tubes which had seven levels of resistance identified by colors was performed. All samples (n = 105; 15 samples for each color) were 7 cm of length and had two interfaces for fixation. The samples were tested in a tensile testing hydraulic machine, under elongation control, up to 200% of the original length (21 cm). The force values corresponding to an increase of 50%, 100%, 150% and 200% of the samples initial length were recorded. RESULTS: A strong linear association between force and elongation for all colors was found. There were different forces for each elongation investigated for the same tube and between different tubes in almost all percentage of elongation investigated, except for the red and green tubes (all elongations), and for the blue and black tubes at 50% elongation. CONCLUSION: Mechanical tests revealed different elastic forces for different levels of elongation of each tube. The replication of the results in clinical situations is recommended, so the elastic resistance in clinical routine could be evaluated with more propriety. PMID- 24147984 TI - Halide ion effects on human Ether-a-go-go related gene potassium channel properties. AB - The human Ether-a-go-go related gene (hERG) potassium channel has been widely used to counter screen potential pharmaceuticals as a biomarker to predict clinical QT prolongation. Thus, higher throughput assays of hERG are valuable for early in vitro screening of drug candidates to minimize failure in later-stage drug development due to this potentially adverse cardiac risk. We have developed a novel method utilizing potassium fluoride to improve throughput of hERG counter screening with an automated patch clamp system, PatchXpress 7000A. In that method, ~50% substitution of internal Cl(-) with F(-) greatly increases success rate without substantially altering the biophysical properties of the hERG channel or compromising data quality. However, effect of F(-) or other halide ions on hERG channel properties has not been studied in detail. In this study, we examined effects of complete replacement of Cl(-) in internal solution with halide ions, F(-), or Br(-). We found that (1) F(-) slightly shifts the voltage dependence of hERG channel activation to more positive voltages, while Br(-) shifts it to more negative voltages; (2) Br(-) shifts to more positive voltages both the inactivation-voltage relationship and the peak position of channel full activation of hERG; (3) F(-) slows hERG activation, while both F(-) and Br(-) make the channel close faster; (4) neither F(-) nor Br(-) have any effect on hERG inactivation kinetics. In conclusion, compared to Cl(-), F(-) has subtle effect on hERG activation, while Br(-) has distinct effects on certain, but not all biophysical properties of hERG channel. PMID- 24147985 TI - NMR studies of protonation and hydrogen bond states of internal aldimines of pyridoxal 5'-phosphate acid-base in alanine racemase, aspartate aminotransferase, and poly-L-lysine. AB - Using (15)N solid-state NMR, we have studied protonation and H-bonded states of the cofactor pyridoxal 5'-phosphate (PLP) linked as an internal aldimine in alanine racemase (AlaR), aspartate aminotransferase (AspAT), and poly-L-lysine. Protonation of the pyridine nitrogen of PLP and the coupled proton transfer from the phenolic oxygen (enolimine form) to the aldimine nitrogen (ketoenamine form) is often considered to be a prerequisite to the initial step (transimination) of the enzyme-catalyzed reaction. Indeed, using (15)N NMR and H-bond correlations in AspAT, we observe a strong aspartate-pyridine nitrogen H-bond with H located on nitrogen. After hydration, this hydrogen bond is maintained. By contrast, in the case of solid lyophilized AlaR, we find that the pyridine nitrogen is neither protonated nor hydrogen bonded to the proximal arginine side chain. However, hydration establishes a weak hydrogen bond to pyridine. To clarify how AlaR is activated, we performed (13)C and (15)N solid-state NMR experiments on isotopically labeled PLP aldimines formed by lyophilization with poly-L-lysine. In the dry solid, only the enolimine tautomer is observed. However, a fast reversible proton transfer involving the ketoenamine tautomer is observed after treatment with either gaseous water or gaseous dry HCl. Hydrolysis requires the action of both water and HCl. The formation of an external aldimine with aspartic acid at pH 9 also produces the ketoenamine form stabilized by interaction with a second aspartic acid, probably via a H-bond to the phenolic oxygen. We postulate that O-protonation is an effectual mechanism for the activation of PLP, as is N protonation, and that enzymes that are incapable of N-protonation employ this mechanism. PMID- 24147986 TI - Immunolocalisation of ghrelin and obestatin in human testis, seminal vesicles, prostate and spermatozoa. AB - The role of ghrelin and obestatin in male reproduction has not completely been clarified. We explored ghrelin and obestatin localisation in the male reproductive system. Polyclonal antibodies anti-ghrelin and anti-obestatin were used to detect the expression of these hormones in human testis, prostate and seminal vesicles by immunocytochemistry, while in ejaculated and swim up selected spermatozoa by immunofluorescence. Sertoli cells were positive for both peptides and Leydig cells for ghrelin; germ cells were negative for both hormones. Mild signals for ghrelin and obestatin were observed in rete testis; efferent ductules were the most immune reactive region for both peptides. Epididymis was moderately positive for ghrelin; vas deferens and seminal vesicles showed intense obestatin and moderate ghrelin labelling; prostate tissue expressed obestatin alone. Ejaculated and selected spermatozoa were positive for both peptides in different head and tail regions. This study confirms ghrelin localisation in Leydig and Sertoli cells; the finding that ghrelin is expressed in rete testis, epididymis, vas deferens and seminal vesicles is novel, as well as the localisation of obestatin in almost all tracts of the male reproductive system. This research could offer insights for stimulating other studies, particularly on the role of obestatin in sperm physiology, which is still obscure. PMID- 24147987 TI - The impact of patient-provider communication and language spoken on adequacy of depression treatment for U.S. women. AB - Many women with depression are untreated or undertreated for their condition. The quality of patient-provider communication may impact the receipt of depression treatment. We examine the relationship between patient-provider communication and receipt of adequate treatment for depression among women. The study sample consisted of women with depression who visited a provider in the previous 12 months in the 2002-2008 Medical Expenditure Panel Survey (N = 3,179). Multivariate regression was used to examine the independent contribution of sociodemographic characteristics, health care factors, patient-provider communication, and respondent language on depression treatment status (none, some, adequate). We found that more than one-third of women with depression in the United States did not receive adequate treatment. Women reporting that providers usually or always listened carefully were more likely to receive adequate treatment (OR = 1.59; 95% CI = 1.10-2.30 and OR = 1.55; 95% CI = 1.07 2.23, respectively). Non-English-speaking women were 50% less likely to receive adequate treatment (OR = 0.49; 95% CI = 0.30-0.80). Having a usual source of care was associated with an increased likelihood of receiving some and adequate treatment (OR = 1.84; 95% CI = 1.24-2.73 and OR = 2.22; 95% CI = 1.61-3.05, respectively). Effective provider listening behaviors may help increase the number of U.S. women with depression who receive adequate treatment. Efforts to improve language access for limited English-proficient women are likely critical for improving treatment outcomes in this population. Additionally, ensuring that women with depression have consistent access to health care services is important for obtaining adequate depression care. PMID- 24147988 TI - Face-capping MU3-BO in B6(BO)7-: boron oxide analogue of B6H7- with rhombic 4c-2e bonds. AB - Using the first-principle approaches, we predict a B6(BO)7(-) cluster with a face capping MU(3)-BO, which is the boron oxide analogue of closo-B6H7(-) with a face capping MU(3)-H. Detailed topological analysis of electron density clearly reveals the existence of three rhombic 4c-2e bonds around the B/H apex in both C3v B6(BO)7(-) and C3v B6H7(-), which possesses similar electron densities at their bond and ring critical points. The adaptive natural density partitioning (AdNDP) analysis provides a direct and visual picture of the B-B-B-B/H 4c-2e bonds for the first time. Adiabatic and vertical electron detachment energies of the concerned monoanions are calculated to facilitate their future photoelectron spectroscopy measurements and characterizations. The presence of the B6(BO)7(-) and B6H7(-) clusters extends the BO/H isolobal analogy to the whole MU(n)-BO/H series (n = 1, 2, and 3) and enriches the chemistry of boronyl. PMID- 24147989 TI - Magnetic resonance fetal right lung volumetry and its efficacy in predicting postnatal short-term outcomes of congenital left-sided diaphragmatic hernia. AB - AIM: We aimed to investigate whether the ratio of magnetic resonance imaging (MRI)-measured right lung volume (RLV) to ultrasonography-estimated bodyweight (RLV/BW) and observed-to-expected (o/e) RLV are of diagnostic value in predicting postnatal outcomes of left congenital diaphragmatic hernia (CDH). MATERIAL AND METHODS: We included 32 CDH patients and 34 control subjects. Manually outlined fetal right lung areas on MRI were multiplied by the slice thickness and added to determine the entire volume. The association between RLV and RLV/BW with gestational age in the controls was examined using regression analysis. RLV/BW and o/e RLV were compared between surviving and non-surviving neonates with CDH. RESULTS: The expected fetal RLV was derived using the formula RLV (mm(3)) = 1.717 * (gestational weeks)(2.82). In the controls, RLV/BW was nearly constant during the third trimester. The 27 survivors with CDH had a median RLV/BW of 10.7 and a median o/e RLV of 60.0, whereas the five non-surviving neonates had a median RLV/BW of 4.3 and a median o/e RLV of 22.6; the differences were statistically significant. CONCLUSION: Assessment of fetal lungs by MRI volumetry is reliable for clinical use. RLV/BW and o/e RLV are potential predictors of postnatal outcomes of left CDH. PMID- 24147992 TI - Chromatic variation of soot soiling: a possible marker for gunshot wounds in burnt bone. AB - Soot soiling is a crucial forensic parameter around gunshot lesions. Carbonization, however, can severely alter human tissues and mimic such clues. This study aims at evaluating the survival of soot soiling even after carbonization in bone. A total of 36 bovine ribs (half fleshed and half defleshed) were shot with two types of bullet (both 9-mm; full metal-jacketed and unjacketed) with a near-contact range. With unjacketed bullets, the shot left in every case a clear, black, and roughly round soot stain around the entrance wound, whereas full metal-jacketed bullets left no signs of soot. Every specimen then underwent calcination in an oven at 800 degrees C. The analysis of the charred samples clearly showed the survival of the soot soiling in both fleshed and bony samples, with a clear correspondence with the former position, but with a different color (yellow). Thus, soot soiling may survive, although with a different color, even after charring. PMID- 24147993 TI - Ecological coherence of diversity patterns derived from classical fingerprinting and Next Generation Sequencing techniques. AB - Changes in richness and bacterial community structure obtained via 454 Massively Parallel Tag Sequencing (MPTS) and Automated Ribosomal Intergenic Analysis (ARISA) were systematically compared to determine whether and how the ecological knowledge obtained from both molecular techniques could be combined. We evaluated community changes over time and depth in marine coastal sands at different levels of taxonomic resolutions, sequence corrections and sequence abundances. Although richness over depth layers or sampling dates greatly varied [~ 30% and 70-80% new operational taxonomic units (OTU) between two samples with ARISA and MPTS respectively], overall patterns of community variations were similar with both approaches. Alpha-diversity estimated by ARISA-derived OTU was most similar to that obtained from MPTS-derived OTU defined at the order level. Similar patterns of OTU replacement were also found with MPTS at the family level and with 20-25% rare types removed. Using ARISA or MPTS datasets with lower resolution, such as those containing only resident OTU, yielded a similar set of significant contextual variables explaining bacterial community changes. Hence, ARISA as a rapid and low-cost fingerprinting technique represents a valid starting point for more in-depth exploration of community composition when complemented by the detailed taxonomic description offered by MPTS. PMID- 24147994 TI - Piezoelectric vs. conventional drilling in implant site preparation: pilot controlled randomized clinical trial with crossover design. AB - OBJECTIVE: To compare implant stability throughout osseointegration, peri-implant marginal bone loss, and success rates of implants placed with conventional and mixed drilling/piezoelectric osteotomy. MATERIALS AND METHODS: A pilot randomized controlled trial was performed on 15 patients. Each patient received two implants in the mandibular molar region. All sites were prepared with conventionally up to the 2.8 mm wide drill. Osteotomies were randomly finalized with a 3 mm diameter drill (control group) or with two consecutive ultrasonic tips (2.8 mm and 3 mm wide, respectively) (test group). Resonance frequency analysis measurements were taken at implant placement and after 1, 3, 8, and 12 weeks. Peri-implant marginal bone loss 12 months after loading was calculated using periapical radiographs. Wilcoxon test for related samples was used to study differences in implant stability and in peri-implant marginal bone loss between the two groups. RESULTS: Twenty-nine of 30 implants osseointegrated successfully (one failure in the control group). Stability was significantly higher in the test group at the 8th week assessment; differences were non-significant at all other time-points. Longitudinally, differences were observed between the patterns of implant stability changes: in the test group stability increased more progressively, while in the control group an abrupt change occurred between the 8th and 12th weeks assessments. No difference was found in peri-implant marginal bone loss between the groups. All 29 implants were functionally successful at the 15-month visit. CONCLUSIONS: Within the limit of this pilot study (small sample size, short follow-up), data suggested that implant stability might develop slightly faster when implant site osteotomy is performed with a mixed drilling/ultrasonic technique. PMID- 24147997 TI - Work-based assessment: qualitative perspectives of novice nutrition and dietetics educators. AB - BACKGROUND: The assessment of competence for health professionals including nutrition and dietetics professionals in work-based settings is challenging. The present study aimed to explore the experiences of educators involved in the assessment of nutrition and dietetics students in the practice setting and to identify barriers and enablers to effective assessment. METHODS: A qualitative research approach using in-depth interviews was employed with a convenience sample of inexperienced dietitian assessors. Interviews explored assessment practices and challenges. Data were analysed using a thematic approach within a phenomenological framework. Twelve relatively inexperienced practice educators were purposefully sampled to take part in the present study. RESULTS: Three themes emerged from these data. (i) Student learning and thus assessment is hindered by a number of barriers, including workload demands and case-mix. Some workplaces are challenged to provide appropriate learning opportunities and environment. Adequate support for placement educators from the university, managers and their peers and planning are enablers to effective assessment. (ii) The role of the assessor and their relationship with students impacts on competence assessment. (iii) There is a lack of clarity in the tasks and responsibilities of competency-based assessment. CONCLUSIONS: The present study provides perspectives on barriers and enablers to effective assessment. It highlights the importance of reflective practice and feedback in assessment practices that are synonymous with evidence from other disciplines, which can be used to better support a work-based competency assessment of student performance. PMID- 24147998 TI - Overexpression of melanoma-associated antigen D4 is an independent prognostic factor in squamous cell carcinoma of the esophagus. AB - To pursue an urgently needed treatment target for esophageal cancer (EC), we investigated the function of the recently discovered melanoma-associated antigen (MAGE)-D4 in squamous cell EC. MAGE-D4 messenger RNA (mRNA) expression was analyzed in nine EC cell lines using quantitative reverse transcription polymerase chain reaction. In 65 surgical specimens of squamous cell EC with no prior neoadjuvant therapy, MAGE-D4 mRNA expression in EC tissues and corresponding normal tissues was analyzed and compared, and evaluated in terms of clinicopathological factors. In representative cases, MAGE-D4 protein distribution was analyzed immunohistochemically. The heterogeneity of MAGE-D4 mRNA expression was confirmed in EC cell lines by quantitative reverse transcription polymerase chain reaction. In surgical specimens, MAGE-D4 mRNA expression was significantly higher in EC tissues than in corresponding normal tissues (P < 0.001). Patients with the highest MAGE-D4 mRNA expression in EC tissues (top quartile, n = 17) had significantly shorter overall survival than patients with low expression (2-year survival: 44% and 73%, respectively, P = 0.006). Univariate analysis identified age (>=65 years), lymphatic involvement, and high MAGE-D4 mRNA expression as significant prognostic factors; high MAGE-D4 mRNA expression was also an independent prognostic factor in multivariable analysis (hazard ratio: 2.194; P = 0.039) and was significantly associated with Brinkman index (P = 0.008) and preoperative carcinoembryonic antigen level (P = 0.002). Immunohistochemical MAGE-D4b expression was consistent with MAGE-D4 mRNA profiling. Our results suggest that MAGE-D4 overexpression influences tumor progression, and MADE-D4 can be a prognostic marker and a potential molecular target in squamous cell EC. PMID- 24147999 TI - Reactivation of Chagas disease in a bone marrow transplant patient: case report and review of screening and management. AB - We report a patient with an autologous stem cell transplant and history of residence in a Chagas disease (CD) endemic area who developed Chagas reactivation after induction for transplantation. We recommend that patients at risk for CD be screened before transplantation, and patients found to have chronic infection be monitored for reactivation post transplant. PMID- 24148001 TI - Potential treatment of human nonalcoholic fatty liver disease with long-chain omega-3 polyunsaturated fatty acids. AB - Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disorder in the Western world. Its prevalence has increased with the growing obesity epidemic, yet no definitive treatment has been developed, and optimal management remains a clinical challenge. Long-chain omega-3 polyunsaturated fatty acids (PUFAs) have recently been proposed as a potential treatment for liver inflammation associated with fat accumulation. PubMed literature and the ClinicalTrials.gov database were reviewed for the effects of omega-3 PUFA treatment on NAFLD, from mechanisms to the results of preclinical studies, human studies, and unreported ongoing clinical trials, using terms such as NAFLD, nonalcoholic steatohepatitis, omega-3 fatty acids, and fish oil. Articles published over the last 3-4 years were emphasized, and relevancy was ensured by scanning their abstracts. Preliminary studies have confirmed an ameliorative effect, yet the translation of promising early data into therapeutic interventions will have to await the results of larger, properly conducted, ongoing clinical trials. PMID- 24148000 TI - Mitochondrial dysfunction in amyotrophic lateral sclerosis - a valid pharmacological target? AB - Amyotrophic lateral sclerosis (ALS) is an adult-onset neurodegenerative disease characterized by the selective death of upper and lower motor neurons which ultimately leads to paralysis and ultimately death. Pathological changes in ALS are closely associated with pronounced and progressive changes in mitochondrial morphology, bioenergetics and calcium homeostasis. Converging evidence suggests that impaired mitochondrial function could be pivotal in the rapid neurodegeneration of this condition. In this review, we provide an update of recent advances in understanding mitochondrial biology in the pathogenesis of ALS and highlight the therapeutic value of pharmacologically targeting mitochondrial biology to slow disease progression. PMID- 24148004 TI - A new model with an anatomically accurate human renal collecting system for training in fluoroscopy-guided percutaneous nephrolithotomy access. AB - BACKGROUND AND PURPOSE: Obtaining renal access is one of the most important and complex steps in learning percutaneous nephrolithotomy (PCNL). Ideally, this skill should be practiced outside the operating room. There is a need for anatomically accurate and cheap models for simulated training. The objective was to develop a cost-effective, anatomically accurate, nonbiologic training model for simulated PCNL access under fluoroscopic guidance. METHODS: Collecting systems from routine computed tomography urograms were extracted and reformatted using specialized software. These images were printed in a water-soluble plastic on a three-dimensional (3D) printer to create biomodels. These models were embedded in silicone and then the models were dissolved in water to leave a hollow collecting system within a silicone model. These PCNL models were filled with contrast medium and sealed. A layer of dense foam acted as a spacer to replicate the tissues between skin and kidney. RESULTS: 3D printed models of human collecting systems are a useful adjunct in planning PCNL access. The PCNL access training model is relatively low cost and reproduces the anatomy of the renal collecting system faithfully. A range of models reflecting the variety and complexity of human collecting systems can be reproduced. The fluoroscopic triangulation process needed to target the calix of choice can be practiced successfully in this model. CONCLUSIONS: This silicone PCNL training model accurately replicates the anatomic architecture and orientation of the human renal collecting system. It provides a safe, clean, and effective model for training in accurate fluoroscopy-guided PCNL access. PMID- 24148002 TI - Structure and pH-induced structural rearrangements of the putative multidrug efflux pump EmrD in liposomes probed by site-directed spin labeling. AB - EmrD is the only structurally characterized drug/H(+) antiporter of the major facilitator superfamily (MFS). It has been crystallized in a doubly occluded conformation that is considered representative of an intermediate state in the transport cycle of MFS transporters. However, unexpected features of the crystal structure and the lack of functional information available for EmrD limit the utility of the structural data. To assess whether the crystal structure represents a stable state in a native-like environment, we used electron paramagnetic resonance (EPR) spectroscopy to determine the mobility and accessibility of spin labels at 76 positions in six transmembrane (TM) helices of EmrD reconstituted in liposomes. While the EPR data were mostly consistent with the crystal structure, they also revealed significant deviations from the predicted orientation and topology of TM helices at several locations. Additionally, we were unable to reproduce EmrD-dependent multidrug resistance phenotypes in vitro and in cell-based assays of drug transport. In spite of structural and functional discrepancies, we mapped a pH-dependent conformational change in which the cytoplasmic side of the N-terminal half opened locally in response to protonation. This conformational switch is consistent with the expected pH-dependent behavior of MFS H(+)-coupled antiporters. PMID- 24148003 TI - Assessment of coyote-wolf-dog admixture using ancestry-informative diagnostic SNPs. AB - The evolutionary importance of hybridization as a source of new adaptive genetic variation is rapidly gaining recognition. Hybridization between coyotes and wolves may have introduced adaptive alleles into the coyote gene pool that facilitated an expansion in their geographic range and dietary niche. Furthermore, hybridization between coyotes and domestic dogs may facilitate adaptation to human-dominated environments. We genotyped 63 ancestry-informative single-nucleotide polymorphisms in 427 canids to examine the prevalence, spatial distribution and the ecology of admixture in eastern coyotes. Using multivariate methods and Bayesian clustering analyses, we estimated the relative contributions of western coyotes, western and eastern wolves, and domestic dogs to the admixed ancestry of Ohio and eastern coyotes. We found that eastern coyotes form an extensive hybrid swarm, with all our samples having varying levels of admixture. Ohio coyotes, previously thought to be free of admixture, are also highly admixed with wolves and dogs. Coyotes in areas of high deer density are genetically more wolf-like, suggesting that natural selection for wolf-like traits may result in local adaptation at a fine geographic scale. Our results, in light of other previously published studies of admixture in Canis, revealed a pattern of sex biased hybridization, presumably generated by male wolves and dogs mating with female coyotes. This study is the most comprehensive genetic survey of admixture in eastern coyotes and demonstrates that the frequency and scope of hybridization can be quantified with relatively few ancestry-informative markers. PMID- 24148005 TI - Systematic modulation of quantum (electron) tunneling behavior by atomic layer deposition on nanoparticulate SnO2 and TiO2 photoanodes. AB - Ultrathin films of TiO2, ZrO2, and Al2O3 were conformally created on SnO2 and TiO2 photoelectrodes via atomic layer deposition (ALD) to examine their influence upon electron transfer (ET) from the electrodes to a representative molecular receptor, I3(-). Films thicker than 2 A engender an exponential decrease in ET time with increasing film thickness, consistent with tunneling theory. Increasing the height of the barrier, as measured by the energy difference between the transferring electron and the bottom of the conduction band of the barrier material, results in steeper exponential drops in tunneling rate or probability. The variations are quantitatively consistent with a simple model of quantum tunneling of electrons through square barriers (i.e., barriers of individually uniform energy height) that are characterized by individually uniform physical thickness. The findings demonstrate that ALD is a remarkably uniform and precise method for modifying electrode surfaces and imply that standard tunneling theory can be used as a quantitative guide to intentionally and predictively modulating rates of ET between molecules and electrodes. PMID- 24148006 TI - Berries and human health: research highlights from the Fifth Biennial Berry Health Benefits Symposium. AB - The fifth biennial Berry Health Benefits Symposium showcased recent research supporting the positive effects of berry consumption on human health and disease. Remarkably, the vast majority of oral papers covered data accumulated from in vivo studies, which underscores how berry health research has advanced since the inception of this symposium in 2005. Similar to the past, research presented at this meeting was primarily focused on the major commercially cultivated berries in North America, namely, blackberry, blueberry, black raspberry, cranberry, red raspberry, and strawberry. Despite this, on the basis of similar compositional chemistry, it is possible that similar biological effects may also be extended to other small soft-fleshed "berry-type" fruits popular in other parts of the world including Europe, Asia, and South America. Overall, this symposium continues to add to the growing body of data supporting the positive impact of berry fruit consumption on human health promotion and disease risk reduction. PMID- 24148008 TI - Structural and dynamic properties of a hydrogen bond from the study of the CH3Cl HCl complex and isotopic species. AB - The microwave (4-20 GHz range) and infrared (HCl and DCl stretch ranges) spectra of six isotopic species of the CH3Cl-HCl hydrogen bond complex have been recorded for the first time and analyzed with the support of high level ab initio calculations (MP2 and CCSD(T) levels). Accurate molecular parameters, including rotational, quartic centrifugal distortion, and nuclear-quadrupole coupling constants, vibrational frequencies, and anharmonic coupling constants, are presented in this paper. These parameters have then been used to estimate the hydrogen bond geometry and confirm the strong coupling between intramolecular and low frequency intermolecular modes. Experimental and theoretical evidence, in agreement with each other, tend to point out a free rotation of the CH3Cl unit in the complex, emphasizing the very peculiar dynamical properties of a hydrogen bond and, consequently, the necessity of taking those effects into account to correctly model the intra- and intermolecular interactions. PMID- 24148007 TI - Replacement of the V3 domain in the surface subunit of the feline immunodeficiency virus envelope glycoprotein with the equivalent region of a T cell-tropic human immunodeficiency virus type 1 results in a chimeric surface protein that efficiently binds to CXCR4. AB - Feline immunodeficiency virus (FIV) and the T cell-tropic strains of human immunodeficiency virus type 1 (HIV-1) share the use of the chemokine receptor CXCR4 for cell entry. To study this process further we developed a cell surface binding assay based on the expression of a soluble version of the FIV SU C terminally tagged with the influenza virus hemagglutinin epitope (HA). The specificity of the assay was demonstrated by the following evidence: (1) the SU HA protein bound to HeLa cells that express CXCR4 but not to MDCK cells that lack this chemokine receptor; and (2) binding of the SU-HA to HeLa cells was blocked by incubation with the CXCR4 antagonist AMD3100 as well as with the anti-CXCR4 monoclonal antibody (MAb) 12G5. Deletion of the V3 region from the FIV SU glycoprotein abolished its ability to bind CXCR4-expressing cells. Remarkably, substitution of the V3 domain of the FIV SU by the equivalent region of the HIV-1 NL4-3 isolate resulted in efficient cell surface binding of the chimeric SU protein to CXCR4. Moreover, transfection of MDCK cells with a plasmid encoding human CXCR4 allowed the association of the chimeric SU-HA glycoprotein to the transfected cells. Interestingly, while cell binding of the chimeric FIV-HIV SU was inhibited by an anti-HIV-1 V3 MAb, its association with CXCR4 was found to be resistant to AMD3100. Of note, the chimeric FIV-HIV Env glycoprotein was capable of promoting CXCR4-dependent cell-to-cell fusion. PMID- 24148010 TI - Clinical profiles of 710 premenopausal women with adenomyosis who underwent hysterectomy. AB - AIM: The aim of this study was to determine the frequency of various symptoms and their associated characteristics in women with adenomyosis who underwent hysterectomy, and to determine which symptoms are likely to go with which others in these patients. MATERIAL AND METHODS: In 2007, 1697 consecutive patients underwent hysterectomy in our hospital. Among them, 734 (43.3%) were histologically confirmed to have adenomyosis, and 710 of them were premenopausal. The medical charts of all 734 patients were retrieved, and their demographic, clinical information and postoperative findings were recorded. We used the Verbal Descriptor Scale to measure the preoperative severity of dysmenorrhea. The Apriori Algorithm was used for mining the association of different symptoms. RESULTS: Among the 710 premenopausal patients, only 4.5% of them had no symptoms. Dysmenorrhea was the most common complaint, occurring in 81.7% of patients. Dysmenorrhea co-occurred most frequently with menorrhagia. The presence of adhesion, presence of endometriosis, complaint of menorrhagia, longer duration of disease, gravidity, palpable pain during pelvic examination, and diffuse adenomyosis were positively associated with the severity of dysmenorrhea. Age, severity of dysmenorrhea, and complaint of metrorrhagia were positively associated with the risk of menorrhagia. CONCLUSIONS: Dysmenorrhea is the most common complaint in women with adenomyosis, which often goes with that of menorrhagia. Adenomyosis often co-occurs with endometriosis and leiomyomas. Various factors are associated with the risk of having different symptoms. PMID- 24148011 TI - Radiation exposure and the risk of mortality from noncancer respiratory diseases in the life span study, 1950-2005. AB - An apparent association between radiation exposure and noncancer respiratory diseases (NCRD) in the Life Span Study (LSS) of atomic bomb survivors has been reported, but the biological validity of that observation is uncertain. This study investigated the possibility of radiation causation of noncancer respiratory diseases in detail by examining subtypes of noncancer respiratory diseases, temporal associations, and the potential for misdiagnosis and other confounding factors. A total of 5,515 NCRD diagnoses listed as the underlying cause of death on the death certificate were observed among the 86,611 LSS subjects with estimated weighted absorbed lung doses. Radiation dose-response analyses were conducted using Cox proportional hazard regression for pneumonia/influenza, other acute respiratory infections, chronic obstructive pulmonary disease and asthma. The linear excess relative risks (ERR) per gray (Gy) were 0.17 (95% CI 0.08, 0.27) for all NCRD and 0.20 (CI 0.09, 0.34) for pneumonia/influenza, which accounted for 63% of noncancer respiratory disease deaths. Adjustments for lifestyle and sociodemographic variations had almost no impact on the risk estimates. However, adjustments for indications of cancer and/or cardiovascular disease decreased the risk estimates, with ERR for total noncancer respiratory diseases declined by 35% from 0.17 to 0.11. Although it was impossible to fully adjust for the misdiagnosis of other diseases as noncancer respiratory diseases deaths in this study because of limitations of available data, nevertheless, the associations were reduced or eliminated by the adjustment that could be made. This helps demonstrates that the association between noncancer respiratory diseases and radiation exposure in previous reports could be in part be attributed to coincident cancer and/or cardiovascular diseases. PMID- 24148012 TI - Walking the talk. Implementation of transitional care guidance in a UK paediatric and a neighbouring adult facility. AB - OBJECTIVES: To examine the quality of transitional care in a paediatric and adult hospital by investigating (i) adherence to national transition guidance and (ii) whether implementation is associated with better patient/carer experiences. METHODS: A cross-sectional study was conducted in a UK paediatric hospital (PH) and neighbouring adult hospital. Clinics completed a questionnaire to determine characteristics of their transitional care provision and invited patients aged 11 21 years and parents/carers to complete a questionnaire ('Mind the Gap') to assess their satisfaction. RESULTS: Twenty-three clinics participated. Fourteen (70%) reported delivering a transition programme, but only 5 (25%) indicated this was holistic (addressing medical, psychosocial and vocational issues). Participants included 457 young people and 330 parents, 71% and 88% respectively attending the PH. Ratings of current care were significantly lower than ratings of best care. These 'gap' scores were not excessive, although some participants were very dissatisfied. Better satisfaction was associated with attending clinics that provided transitional care, especially when defined as 'holistic' and youth friendly. CONCLUSIONS: Transition programmes that adhere to current guidance are associated with better satisfaction, but variations in provision suggest barriers to implementation. Attention is required to how youth-friendly transitional care is defined with particular reference to the specific clinic model. PMID- 24148013 TI - A factor mixture model approach to elaborating on offender mental health classification with the MMPI-2-RF. AB - A large proportion of prison inmates suffer from mental illnesses or severe personality disorders; therefore, offender classification is a worthwhile endeavor both for efficiently allocating mental health treatment resources and security risk classification. This study sought to elaborate on offender classification by using an advanced statistical technique, factor mixture modeling, which capitalizes on the strengths of both latent trait analysis and latent class analysis. A sample consisting of 616 male and 194 female prison inmates was used for this purpose. The MMPI-2-RF Restructured Clinical (RC) scales were used to elaborate on a variety of latent trait, latent class, and factor mixture models. A 3-factor, 5-class mixture model was deemed optimal in this sample. Remaining MMPI-2-RF scales as well as scores on external criterion measures relevant to externalizing psychopathology were used to further elaborate on the utility of the resulting latent classes. These analyses indicated that 3 of the 5 classes were predominantly different expressions of externalizing personality proclivities, whereas the remaining 2 indicated inmates with substantial internalizing or thought-disordered characteristics. Implications of these findings are discussed. PMID- 24148014 TI - A review of the toxicological and environmental hazards and risks of tetrahydrofuran. AB - We present in this paper a review of the toxicological and environmental hazards, exposures and risks of tetrahydrofuran (THF; CASRN 109-99-9). THF is a polar solvent and monomer that is easily absorbed by all routes of exposure. The acute toxicity of THF is low to moderate by all routes. Irreversible corrosive damage to the eye can result from direct contact. However, THF is neither a skin irritant, nor sensitizer. Studies in vitro and in vivo have shown that THF is not mutagenic. Chronic studies have found benign tumors in the kidneys of male rats and in the livers of female mice. These findings have been examined, and although a mode of action is not known, the weight of evidence suggests that these tumors are likely not relevant to human health, but instead secondary to rodent-specific modes of action. THF produces transient sedative effects in rats at high concentrations but no significant neurobehavioral changes or neuropathology in sub-chronic studies. There were no specific effects reported on reproduction or developmental toxicity in rats or mice, with non-specific developmental toxicity observed only in the presence of significant maternal toxicity. The log K(ow) value for THF is less than 3, indicating a low potential for bioaccumulation. THF is inherently biodegradable, thus is not expected to be environmentally persistent. THF does not present an ecotoxicity hazard based on test results in fish, aquatic invertebrates and plants. Exposures to THF in the workplace, to consumers and via environmental releases were modeled and all found to fall below the derived toxicity thresholds. PMID- 24148015 TI - Effects of inhaled aminophylline on airway constriction and inflammation in ovalbumin-sensitized guinea pigs. AB - BACKGROUND: The systemic administration of theophylline is useful for asthma treatment. However its narrow therapeutic range makes it difficult to use. Little is known about its potential in inhalation therapy, particularly repeated inhalation. OBJECTIVE: The purpose of this study is to investigate the therapeutic usefulness of inhaled aminophylline in an asthma model. METHODS: The effects of pretreatment with inhaled aminophylline (25 mg/mL for 30 min/dose) on airway response and inflammation after an ovalbumin (OVA) challenge and airway hypersensitivity to acetylcholine (Ach) were evaluated using guinea pigs sensitized with OVA. RESULTS: Aminophylline relaxed the ACh-induced contraction of tracheal smooth muscle in vitro in a concentration-dependent manner. Pretreatment with single-dose aminophylline inhalation suppressed OVA-induced airway constriction to the same extent as the intraperitoneal pretreatment with high-dose aminophylline (10-20 mg/kg). However, pretreatment with single-dose aminophylline inhalation did not suppress eosinophil infiltration into airways (neither bronchoalveolar lavage [BAL] fluid nor lung tissue) and did not suppress airway hyperreactivity to ACh, 24 h after OVA challenge. Repeated inhalation of aminophylline (twice daily for 7 days) suppressed the infiltration of eosinophils and suppressed airway hypersensitivity to ACh. In addition, high concentrations of aminophylline inhibited production of oxygen radicals by BAL cells. CONCLUSION: Single-dose inhalation treatment with aminophylline has transient but relatively strong bronchodilating effects due to delivery of high doses into local airways. Repeated inhalation treatment suppressed airway inflammation and hypersensitivity induced by allergens. Therefore, inhaled aminophylline may be useful for asthma treatment. PMID- 24148016 TI - Interpretation of pharmaceutical drug concentrations in young children's head hair. AB - Three separate cases of child administration of prescription drugs are described. Following liquid-liquid extraction, high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) was used to identify and quantify methadone, 2 ethylidene-1,5-dimethyl-3,3-diphenyl-1-pyrrolidine (EDDP), tramadol, amitriptyline, and nortriptyline in children's hair. The children's age ranged from 14 months to 7 years; in all three cases, the drug in question was detected in more than one section of hair. Methadone was detected in the concentration range of 0.65-0.99 and 0.04-0.4 ng/mg; tramadol was detected in the concentration range of 1.5-2.2 ng/mg; amitriptyline and nortriptyline were detected in the concentration range of 0.18-1.06 and 0.38-2.0 ng/mg, respectively. In each case, the children's parents admitted to or were found guilty of drug administration to the child. These cases demonstrate the added value of hair testing and emphasize the importance of using hair samples to complement conventional analyses. PMID- 24148017 TI - Temperature-independent singlet exciton fission in tetracene. AB - We use transient absorption spectroscopy to demonstrate that the dynamics of singlet exciton fission in tetracene are independent of temperature (10-270 K). Low-intensity, broad-band measurements allow the identification of spectral features while minimizing bimolecular recombination. Hence, by directly observing both species, we find that the time constant for the conversion of singlets to triplet pairs is ~90 ps. However, in contrast to pentacene, where fission is effectively unidirectional, we confirm that the emissive singlet in tetracene is readily regenerated from spin-correlated "geminate" triplets following fission, leading to equilibrium dynamics. Although free triplets are efficiently generated at room temperature, the interplay of superradiance and frustrated triplet diffusion contributes to a nearly 20-fold increase in the steady-state fluorescence as the sample is cooled. Together, these results require that singlets and triplet pairs in tetracene are effectively degenerate in energy, and begin to reconcile the temperature dependence of many macroscopic observables with a fission process which does not require thermal activation. PMID- 24148018 TI - Bond length and charge density variations within extended arm chair defects in graphene. AB - Extended linear arm chair defects are intentionally fabricated in suspended monolayer graphene using controlled focused electron beam irradiation. The atomic structure is accurately determined using aberration-corrected transmission electron microscopy with monochromation of the electron source to achieve ~80 pm spatial resolution at an accelerating voltage of 80 kV. We show that the introduction of atomic vacancies in graphene disrupts the uniformity of C-C bond lengths immediately surrounding linear arm chair defects in graphene. The measured changes in C-C bond lengths are related to density functional theory (DFT) calculations of charge density variation and corresponding DFT calculated structural models. We show good correlation between the DFT predicted localized charge depletion and structural models with HRTEM measured bond elongation within the carbon tetragon structure of graphene. Further evidence of bond elongation within graphene defects is obtained from imaging a pair of 5-8-5 divacancies. PMID- 24148019 TI - The complete mitochondrial genome sequence of the Canada goose (Branta canadensis). AB - The Canada goose (Branta canadensis) entire mitochondrial genome of a bird from Western Pennsylvania has 16,760 bp (GenBank accession number NC 007011) and has been analyzed for gene locations, length, start codon and stop codons. This genome from a bird harvested during the non-migratory season is the REFSEQ and the haplotype is designated GCC-A. There are two rRNAs, 22 tRNAs, 13 protein coding regions, and 1 displacement loop region. The base composition of mtDNA was A (30.2%), G (15.1%), C (32.1%), and T (22.6%), so the percentage of A and T (52.8%) was slightly higher than G and C. All genes except ND6 and eight tRNA genes (Gln, Ala, Asn, Cys, Tyr, Ser, Pro and Glu) are encoded on the heavy strand. The gene arrangement is the same as most birds and differs from mammals by an inversion of the mtDNA at the connection between the D-loop and the ND5 junctions. PMID- 24148021 TI - The metabolic cost of flagellar motion in Pseudomonas putida KT2440. AB - Although the flagellar machinery of environmental bacteria endows cells with a phenomenal survival device, it also consumes much of the metabolic currency necessary for fuelling such a vigorous nano-motor. The physiological cost of flagella-related functions of the soil bacterium Pseudomonas putida KT2440 was examined and quantified through the deletion of a ~ 70 kb DNA segment of the genome (~ 1.1%), which includes relevant structural and regulatory genes in this micro-organism. The resulting strain lacked the protruding polar cords that define flagella in the wild-type P. putida strain and was unable of any swimming motility while showing a significant change in surface hydrophobicity. However, these deficiencies were otherwise concomitant with clear physiological advantages: rapid adaptation of the deleted strain to both glycolytic and gluconeogenic carbon sources, increased energy charge and, most remarkably, improved tolerance to oxidative stress, reflecting an increased NADPH/NADP(+) ratio. These qualities improve the endurance of non-flagellated cells to the metabolic fatigue associated with rapid growth in rich medium. Thus, flagellar motility represents the archetypal tradeoff involved in acquiring environmental advantages at the cost of a considerable metabolic burden. PMID- 24148020 TI - Immediate function on the day of surgery compared with a delayed implant loading process in the mandible: a randomized clinical trial over 5 years. AB - OBJECTIVES: To appraise the feasibility of loading four implants with a pre existing denture converted to a fixed dental prosthesis (FDP) on the day of implant surgery compared with waiting for 3- to 4-month healing. METHODS: Patients with an edentulous, fully healed mandible were recruited in a faculty clinic to partake in a blinded two-arm parallel randomized controlled trial (RCT). The participants received four parallel intraforamina mandibular implants with a moderately rough titanium surface (Branemark System Mk III or Mk IV TiUnite; Nobel Biocare AB, Goteborg, Sweden). The implants were loaded on the same day by converting the participants' pre-existing denture in the experimental group. The implants were placed using a one-stage surgery procedure, and the participants' pre-existing denture were soft-relined in the control group. For both groups, the permanent 10- to 12-unit FDP consisting of a type-3 cast precious alloy veneered with acrylic and artificial teeth was placed 3-4 months after implant surgery. All participants have been recalled annually for 5 years for appraisal of bone loss and registration of adverse events. RESULTS: Thirty five of the original 42 participants (83%) returned for clinical and radiological examinations at the 5-year follow-up recall. No selective dropout or specific reasons for dropout was identified in the two study arms; leaving n = 17 (Intention-to-treat group, ITT) in the experimental group, alternatively n = 13 as per protocol group (PP), and n = 18 participants in the control group (ITT = PP). At study commencement, five of the participants assigned to the experimental group did not receive their planned intervention. In the control group, one implant failed to osseointegrate and another failed due to bone loss after 5 years. The crestal bone level changes over 5 years were identical in the experimental and control groups, that is, 1.2 mm (SD = 0.7). There were no differences between the two study arms with regard to incidence of biological and technical adverse events. CONCLUSIONS: Implants in the anterior mandible loaded immediately with a converted pre-existing denture appear to yield analogous clinical outcomes compared with waiting for 3-4 months over the first 5 years following implant surgery. PMID- 24148022 TI - The novel heparin-binding motif in decorin-binding protein A from strain B31 of Borrelia burgdorferi explains the higher binding affinity. AB - Decorin-binding protein A (DBPA), a glycosaminoglycan (GAG)-binding lipoprotein found in Borrelia burgdorferi, is crucial to the transmission of Lyme disease in its earliest stages. Because of its role in the initial transmission of the disease, DBPA is an ideal target for vaccine development. DBPA sequences from different strains also contain considerable heterogeneity, leading to differing affinities for GAGs and proteoglycans among different DBPA sequences. Through biophysical and structural analysis of DBPA from strain B31, we have discovered a novel and important GAG-binding epitope in B31 DBPA. Removal of the epitope greatly attenuated its affinity for DBPA and may explain the differential GAG affinities seen in DBPAs from other strains of B. burgdorferi. Paramagnetic perturbation of the protein with TEMPO-labeled heparin fragments showed bound GAGs are located close to the linker region containing the BXBB motif that plays a significant role in determining the specific affinity and orientation of binding of GAG to DBPA. Thermodynamic contributions of the new motif to GAG binding were also characterized by both nuclear magnetic resonance and isothermal titration calorimetry and compared with those of other DBPA residues previously known to be involved in GAG interactions. These analyses showed the motif is as important as other known binding epitopes. The discovery of the motif offers a possible structural explanation for the previously observed differences in GAG affinities of DBPA variants from different Borrelia strains and improves our understanding of DBPA-GAG interactions. PMID- 24148023 TI - Postnatal development of temporal integration, spike timing and spike threshold regulation by a dendrotoxin-sensitive K+ current in rat CA1 hippocampal cells. AB - Spike timing and network synchronization are important for plasticity, development and maturation of brain circuits. Spike delays and timing can be strongly modulated by a low-threshold, slowly inactivating, voltage-gated potassium current called D-current (ID ). ID can delay the onset of spiking, cause temporal integration of multiple inputs, and regulate spike threshold and network synchrony. Recent data indicate that ID can also undergo activity dependent, homeostatic regulation. Therefore, we have studied the postnatal development of ID -dependent mechanisms in CA1 pyramidal cells in hippocampal slices from young rats (P7-27), using somatic whole-cell recordings. At P21-27, these neurons showed long spike delays and pronounced temporal integration in response to a series of brief depolarizing current pulses or a single long pulse, whereas younger cells (P7-20) showed shorter discharge delays and weak temporal integration, although the spike threshold became increasingly negative with maturation. Application of alpha-dendrotoxin (alpha-DTX), which blocks ID , reduced the spiking latency and temporal integration most strongly in mature cells, while shifting the spike threshold most strongly in a depolarizing direction in these cells. Voltage-clamp analysis revealed an alpha-DTX-sensitive outward current (ID ) that increased in amplitude during development. In contrast to P21-23, ID in the youngest group (P7-9) showed smaller peri-threshold amplitude. This may explain why long discharge delays and robust temporal integration only appear later, 3 weeks postnatally. We conclude that ID properties and ID -dependent functions develop postnatally in rat CA1 pyramidal cells, and ID may modulate network activity and plasticity through its effects on synaptic integration, spike threshold, timing and synchrony. PMID- 24148025 TI - Fruit and vegetable consumption and risk of esophageal cancer: a case-control study in north-west China. AB - The north-western region of China carries a big burden of esophageal cancer with incidence above the national average. This study ascertained the association between fruit and vegetable consumption and the risk of esophageal cancer in this remote part of China. A case-control study was undertaken in Urumqi and Shihezi, Xinjiang Uyghur Autonomous Region of China, between 2008 and 2009. Participants were 359 incident esophageal cancer patients and 380 hospital-based controls. Information on habitual fruit and vegetable consumption was obtained by face-to face interview using a validated semiquantitative food frequency questionnaire. Unconditional logistic regression analyses were performed to assess the strength of the associations. The esophageal cancer patients consumed significantly less fruits (mean 364.3, standard deviation [SD] 497.4 g) and vegetables (mean 711.4, SD 727.9 g) daily than their counterparts without the disease (mean 496.5, SD 634.4 g and mean 894.5, SD 746.1 g, respectively). The adjusted odds ratios were 0.48 (95% confidence interval 0.33-0.71) and 0.46 (95% confidence interval 0.32 0.68) for consuming at least 515 g of fruits and 940 g of vegetables per day, respectively, relative to at most 170 g and 520 g. With respect to nutrients contained in fruits and vegetables, intakes of vitamin C, vitamin E, beta cryptoxanthin, potassium, and magnesium at high levels also reduced the esophageal cancer risk. In conclusion, inverse associations were evident between consumption of fruits and vegetables and the risk of esophageal cancer for adults residing in north-west China. PMID- 24148024 TI - Autophagy and mitophagy in the myocardium: therapeutic potential and concerns. AB - The autophagic-lysosomal degradation pathway is critical for cardiac homeostasis, and defects in this pathway are associated with development of cardiomyopathy. Autophagy is responsible for the normal turnover of organelles and long-lived proteins. Autophagy is also rapidly up-regulated in response to stress, where it rapidly clears dysfunctional organelles and cytotoxic protein aggregates in the cell. Autophagy is also important in clearing dysfunctional mitochondria before they can cause harm to the cell. This quality control mechanism is particularly important in cardiac myocytes, which contain a very high volume of mitochondria. The degradation of proteins and organelles also generates free fatty acids and amino acids, which help maintain energy levels in myocytes during stress conditions. Increases in autophagy have been observed in various cardiovascular diseases, but a major question that remains to be answered is whether enhanced autophagy is an adaptive or maladaptive response to stress. This review discusses the regulation and role of autophagy in the myocardium under baseline conditions and in various aetiologies of heart disease. It also discusses whether this pathway represents a new therapeutic target to treat or prevent cardiovascular disease and the concerns associated with modulating autophagy. PMID- 24148026 TI - A systematic review of infant feeding experience and hospitalisation in developed countries. AB - The review examines whether mode of feeding is associated with risk of hospitalisation for illness during infancy in developed countries. Databases were searched for published studies that included the terms 'infant feeding' and 'hospitalisation'. Six studies were included. Breastfeeding was associated with a reduced risk of hospitalisation and adjusted analyses showed mixed results. CONCLUSION: There is no clear relationship between mode of feeding and reduction of infant hospitalisation for illness in developed countries. PMID- 24148028 TI - Postoperative complications after percutaneous nephrolithotomy: a contemporary analysis by insurance status in the United States. AB - BACKGROUND AND PURPOSE: No published data to date have assessed the insurance related disparities among patients undergoing percutaneous nephrolithotomy (PCNL). Our objective was to examine whether being uninsured is associated with more perioperative complications after PCNL in the United States and to determine possible risk factors that influence PCNL outcomes. PATIENTS AND METHODS: This retrospective cohort study evaluated 13,982 patients who underwent PCNL and were included in Nationwide Inpatient Sample from 1998 through 2010. The main outcome measure was >=1 perioperative complication stratified by insurance status. Associations between this outcome and insurance status were examined using logistic regression models. RESULTS: The overall percentage of patients with >=1 perioperative complication after PCNL was 14.4% (n=2008). When stratified by insurance status, the unadjusted analysis showed significantly higher complication rates among Medicare (17.1%) and Medicaid (16.9%) beneficiaries than privately insured (12.3%) and uninsured (13.4%) patients (P<0.001). In a fully adjusted analysis of patients without medical comorbidity, however, these differences were no longer statistically significant, even when stratified by hospital teaching status. Multivariable-adjusted analysis of preoperative medical comorbidity showed that pulmonary disorders (odds ratio [OR], 7.77; 95% confidence interval [CI], 4.54-13.31), coagulopathy (OR, 6.16; 95% CI, 4.27 8.89), deficiency anemias (OR, 3.82; 95% CI, 3.29-4.44), and paralysis (OR, 2.16; 95% CI, 1.78-2.61) were the strongest predictors of >=1 perioperative complication. CONCLUSIONS: Perioperative morbidity after PCNL varied significantly with insurance status, but this variation was explained mostly by differences in overall health status. PMID- 24148027 TI - Dissociable patterns of abnormal frontal cortical activation during anticipation of an uncertain reward or loss in bipolar versus major depression. AB - OBJECTIVES: Recent research has found abnormalities in reward-related neural activation in bipolar disorder (BD), during both manic and euthymic phases. However, reward-related neural activation in currently depressed individuals with BD and that in currently depressed individuals with major depressive disorder (MDD) have yet to be directly compared. Here, we studied these groups, examining the neural activation elicited during a guessing task in fronto-striatal regions identified by previous studies. METHODS: We evaluated neural activation during a reward task using fMRI in two groups of depressed individuals, one with bipolar I disorder (BD-I) (n = 23) and one with MDD (n = 40), with similar levels of illness severity, and a group of healthy individuals (n = 37). RESULTS: Reward expectancy-related activation in the anterior cingulate cortex was observed in the healthy individuals, but was significantly reduced in depressed patients (BD I and MDD together). Anticipation-related activation was increased in the left ventrolateral prefrontal cortex in the BD-I depressed group compared with the other two groups. There were no significant differences in prediction error related activation in the ventral striatum across the three groups. CONCLUSIONS: The findings extend previous research which has identified dysfunction within the ventrolateral prefrontal cortex in BD, and show that abnormally elevated activity in this region during anticipation of either reward or loss may distinguish depressed individuals with BD-I from those with MDD. Altered activation of the anterior cingulate cortex during reward expectancy characterizes both types of depression. These findings have important implications for identifying both common and distinct properties of the neural circuitry underlying BD-I and MDD. PMID- 24148029 TI - Diffuse symbioses: roles of plant-plant, plant-microbe and microbe-microbe interactions in structuring the soil microbiome. AB - A conceptual model emphasizing direct host-microbe interactions has dominated work on host-associated microbiomes. To understand plant-microbiome associations, however, broader influences on microbiome composition and functioning must be incorporated, such as those arising from plant-plant and microbe-microbe interactions. We sampled soil microbiomes associated with target plant species (Andropogon gerardii, Schizachyrium scoparium, Lespedeza capitata, Lupinus perennis) grown in communities varying in plant richness (1-, 4-, 8- or 16 species). We assessed Streptomyces antagonistic activity and analysed bacterial and Streptomyces populations via 454 pyrosequencing. Host plant species and plant richness treatments altered networks of coassociation among bacterial taxa, suggesting the potential for host plant effects on the soil microbiome to include changes in microbial interaction dynamics and, consequently, co-evolution. Taxa that were coassociated in the rhizosphere of a given host plant species often showed consistent correlations between operational taxonomic unit (OTU) relative abundance and Streptomyces antagonistic activity, in the rhizosphere of that host. However, in the rhizosphere of a different host plant species, the same OTUs showed no consistency, or a different pattern of responsiveness to such biotic habitat characteristics. The diversity and richness of bacterial and Streptomyces communities exhibited distinct relationships with biotic and abiotic soil characteristics. The rhizosphere soil microbiome is influenced by a complex and nested array of factors at varying spatial scales, including plant community, plant host, soil edaphics and microbial taxon and community characteristics. PMID- 24148030 TI - Theoretical study of excess electron attachment dynamics to the guanine-cytosine base pair: electronic structure calculations and ring-polymer molecular dynamics simulations. AB - Electron attachment dynamics to the guanine (G)-cytosine (C) base pair has been studied from a theoretical viewpoint. The BH&HLYP-level calculations show that the dipole-bound planar (G-C)(-) base pair anion can convert into the nonplanar valence-bound anion with a relatively small barrier. This nonplanar valence-bound anion can further convert into a more stable form via proton-transfer through the N-H...N hydrogen-bond from the guanine to cytosine moiety. This excess electron induced proton-transfer process has been studied using quantized ring-polymer molecular dynamics simulations (RPMD) on an interpolated potential energy surface developed on the basis of the B3LYP-level calculations. We compare the RPMD results to the results of classical MD simulations and found that proton-transfer more effectively occurs in quantum RPMD simulations. Both vibrational quantization and corner-cutting mechanism are playing important roles in this proton-transfer process. We have also analyzed the correlation between the proton transfer motion and other vibrational motions including ring-ring deformation motions using the reactive RPMD trajectories. PMID- 24148031 TI - Permanent supportive housing: addressing homelessness and health disparities? AB - Permanent supportive housing (PSH) is an intervention to address long-term homelessness. Evidence has resulted in a shift in US policy toward using PSH rather than shelters and transitional housing. Despite recognizing that individuals transitioning from homelessness to PSH experience a high burden of disease and health disparities, public health research has not considered whether and how PSH improves physical health outcomes. Based on diverse areas of research, we argue that in addition to improved access to quality health care, social determinants of health (including housing itself, neighborhood characteristics, and built environment) affect health outcomes. We identify implications for practice and research, and conclude that federal and local efforts to end long-term homelessness can interact with concurrent efforts to build healthy communities. PMID- 24148032 TI - Universal screening for homelessness and risk for homelessness in the Veterans Health Administration. AB - We examined data for all veterans who completed the Veterans Health Administration's national homelessness screening instrument between October 1, 2012, and January 10, 2013. Among veterans who were not engaged with the US Department of Veterans Affairs homeless system and presented for primary care services, the prevalence of recent housing instability or homelessness was 0.9% and homelessness risk was 1.2%. Future research will refine outreach strategies, targeting of prevention resources, and development of novel interventions. PMID- 24148033 TI - High utilizers of emergency health services in a population-based cohort of homeless adults. AB - OBJECTIVES: We identified predictors of emergency department (ED) use among a population-based prospective cohort of homeless adults in Toronto, Ontario. METHODS: We assessed ED visit rates using administrative data from the Institute for Clinical Evaluative Sciences (2005-2009). We then used logistic regression to identify predictors of ED use. Frequent users were defined as participants with rates in the top decile (>= 4.7 visits per person-year). RESULTS: Among 1165 homeless adults, 892 (77%) had at least 1 ED visit during the study. The average rate of ED visits was 2.0 visits per person-year, whereas frequent users averaged 12.1 visits per person-year. Frequent users accounted for 10% of the sample but contributed more than 60% of visits. Predictors of frequent use in adjusted analyses included birth in Canada, higher monthly income, lower health status, perceived unmet mental health needs, and perceived external health locus of control from powerful others; being accompanied by a partner or dependent children had a protective effect on frequent use. CONCLUSIONS: Among homeless adults with universal health insurance, a small subgroup accounted for the majority of visits to emergency services. Frequent use was driven by multiple predisposing, enabling, and need factors. PMID- 24148034 TI - Resource-limited, collaborative pilot intervention for chronically homeless, alcohol-dependent frequent emergency department users. AB - We introduced case management and homeless outreach to chronically homeless, alcohol-dependent, frequent emergency department (ED) visitors using existing resources. We assessed the difference in differences of ED visits 6 months pre- and postintervention using a prospective, nonequivalent control group trial. Secondary outcomes included changes in hospitalizations and housing. The differences in differences between intervention and prospective patients and retrospective controls were -12.1 (95% CI = -22.1, -2.0) and -12.8 (95% CI = 26.1, 0.6) for ED visits and -8.5 (95% CI = -22.8, 5.8) and -19.0 (95% CI = 34.3, -3.6) for inpatient days, respectively. Eighteen participants accepted shelter; no controls were housed. Through intervention, ED use decreased and housing was achieved. PMID- 24148035 TI - Housing first improves residential stability in homeless adults with concurrent substance dependence and mental disorders. AB - OBJECTIVES: We examined the relationship between substance dependence and residential stability in homeless adults with current mental disorders 12 months after randomization to Housing First programs or treatment as usual (no housing or support through the study). METHODS: The Vancouver At Home study in Canada included 2 randomized controlled trials of Housing First interventions. Eligible participants met the criteria for homelessness or precarious housing, as well as a current mental disorder. Residential stability was defined as the number of days in stable residences 12 months after randomization. We used negative binomial regression modeling to examine the independent association between residential stability and substance dependence. RESULTS: We recruited 497 participants, and 58% (n = 288) met the criteria for substance dependence. We found no significant association between substance dependence and residential stability (adjusted incidence rate ratio = 0.97; 95% confidence interval = 0.69, 1.35) after adjusting for housing intervention, employment, sociodemographics, chronic health conditions, mental disorder severity, psychiatric symptoms, and lifetime duration of homelessness. CONCLUSIONS: People with mental disorders might achieve similar levels of housing stability from Housing First regardless of whether they experience concurrent substance dependence. PMID- 24148036 TI - Opportunities for engaging low-income, vulnerable populations in health care: a systematic review of homeless persons' access to and use of information technologies. AB - We systematically reviewed the health and social science literature on access to and use of information technologies by homeless persons by searching 5 bibliographic databases. Articles were included if they were in English, represented original research, appeared in peer-reviewed publications, and addressed our research questions. Sixteen articles met our inclusion criteria. We found that mobile phone ownership ranged from 44% to 62%; computer ownership, from 24% to 40%; computer access and use, from 47% to 55%; and Internet use, from 19% to 84%. Homeless persons used technologies for a range of purposes, some of which were health related. Many homeless persons had access to information technologies, suggesting possible health benefits to developing programs that link homeless persons to health care through mobile phones and the Internet. PMID- 24148037 TI - Ending homelessness--then what? PMID- 24148038 TI - Implementing housing first in rural areas: pathways Vermont. AB - The benefits of Pathways Housing First in addressing chronic homelessness for persons with severe mental illness have been well established. However, the implementation and effectiveness of such programs in rural areas has yet to be examined. We described the model's adaptations in Vermont, including the use of hybrid assertive community treatment-intensive case management teams, which consisted of service coordinators with geographically based caseloads (staff/client ratio of 1:20) and regional multidisciplinary specialists. The program's innovative and widespread inclusion of technology into operations facilitated efficiency and responsiveness, and a pilot telehealth initiative supplemented in-person client visits. The program achieved a housing retention rate of 85% over approximately 3 years, and consumers reported decreased time spent homeless, demonstrating that program adaptations and technological enhancements were successful. PMID- 24148039 TI - Achieving public health goals through Medicaid expansion: opportunities in criminal justice, homelessness, and behavioral health with the Patient Protection and Affordable Care Act. AB - States are currently discussing how (or whether) to implement the Medicaid expansion to nondisabled adults earning less than 133% of the federal poverty level, a key aspect of the Patient Protection and Affordable Care Act. Those experiencing homelessness and those involved with the criminal justice system- particularly when they struggle with behavioral health diagnoses--are subpopulations that are currently uninsured at high rates and have significant health care needs but will become Medicaid eligible starting in 2014. We outline the connection between these groups, assert outcomes possible from greater collaboration between multiple systems, provide a summary of Medicaid eligibility and its ramifications for individuals in the criminal justice system, and explore opportunities to improve overall public health through Medicaid outreach, enrollment, and engagement in needed health care. PMID- 24148040 TI - Predictors of medical or surgical and psychiatric hospitalizations among a population-based cohort of homeless adults. AB - OBJECTIVES: We identified factors associated with inpatient hospitalizations among a population-based cohort of homeless adults in Toronto, Ontario. METHODS: We recruited participants from shelters and meal programs. We then linked them to administrative databases to capture hospital admissions during the study (2005 2009). We used logistic regression to identify predictors of medical or surgical and psychiatric hospitalizations. RESULTS: Among 1165 homeless adults, 20% had a medical or surgical hospitalization, and 12% had a psychiatric hospitalization during the study. These individuals had a total of 921 hospitalizations, of which 548 were medical or surgical and 373 were psychiatric. Independent predictors of medical or surgical hospitalization included birth in Canada, having a primary care provider, higher perceived external health locus of control, and lower health status. Independent predictors of psychiatric hospitalization included being a current smoker, having a recent mental health problem, and having a lower perceived internal health locus of control. Being accompanied by a partner or dependent children was protective for hospitalization. CONCLUSIONS: Health care need was a strong predictor of medical or surgical and psychiatric hospitalizations. Some hospitalizations among homeless adults were potentially avoidable, whereas others represented an unavoidable use of health services. PMID- 24148041 TI - Efficient targeting of homelessness prevention services for families. AB - OBJECTIVES: We developed and evaluated a model to target homelessness prevention services to families more efficiently. METHODS: We followed 11,105 families who applied for community-based services to prevent homelessness in New York City from October 1, 2004, to June 30, 2008, through administrative records, using Cox regression to predict shelter entry. RESULTS: Over 3 years, 12.8% of applicants entered shelter. Both the complete Cox regression and a short screening model based on 15 risk factors derived from it were superior to worker judgments, with substantially higher hit rates at the same level of false alarms. We found no evidence that some families were too risky to be helped or that specific risk factors were particularly amenable to amelioration. CONCLUSIONS: Despite some limitations, an empirical risk model can increase the efficiency of homelessness prevention services. Serving the same proportion of applicants but selecting those at highest risk according to the model would have increased correct targeting of families entering shelter by 26% and reduced misses by almost two thirds. Parallel models could be developed elsewhere. PMID- 24148042 TI - New to care: demands on a health system when homeless veterans are enrolled in a medical home model. AB - OBJECTIVES: We compared service use among homeless and nonhomeless veterans newly enrolled in a medical home model and identified patterns of use among homeless veterans associated with reductions in emergency department (ED) use. METHODS: We used case-control matching with a nested cohort analysis to measure 6-month health services use, new diagnoses, and care use patterns in veterans at the Providence, Rhode Island, Veterans Affairs Medical Center from 2008 to 2011. RESULTS: We followed 127 homeless and 106 nonhomeless veterans. Both groups had similar rates of chronic medical and mental health diagnoses; 25.4% of the homeless and 18.1% of the nonhomeless group reported active substance abuse. Homeless veterans used significantly more primary, mental health, substance abuse, and ED care during the first 6 months. Homeless veterans who accessed primary care at higher rates (relative risk ratio [RRR] = 1.46; 95% confidence interval [CI] = 1.11, 1.92) or who used specialty and primary care (RRR = 10.95; 95% CI = 1.58, 75.78) had reduced ED usage. Homeless veterans in transitional housing or doubled-up at baseline (RRR = 3.41; 95% CI = 1.24, 9.42) had similar reductions in ED usage. CONCLUSIONS: Homeless adults had substantial health needs when presenting for care. High-intensity primary care and access to specialty care services could reduce ED use. PMID- 24148043 TI - Substance-use disorders and poverty as prospective predictors of first-time homelessness in the United States. AB - OBJECTIVES: We examined whether substance-use disorders and poverty predicted first-time homelessness over 3 years. METHODS: We analyzed longitudinal data from waves 1 (2001-2002) and 2 (2004-2005) of the National Epidemiologic Survey on Alcohol and Related Conditions to determine the main and interactive effects of wave 1 substance use disorders and poverty on first-time homelessness by wave 2, among those who were never homeless at wave 1 (n = 30,558). First-time homelessness was defined as having no regular place to live or having to live with others for 1 month or more as a result of having no place of one's own since wave 1. RESULTS: Alcohol-use disorders (adjusted odds ratio [AOR] = 1.34), drug use disorders (AOR = 2.51), and poverty (AOR = 1.34) independently increased prospective risk for first-time homelessness, after adjustment for ecological variables. Substance-use disorders and poverty interacted to differentially influence risk for first-time homelessness (P < .05), before, but not after, adjustment for controls. CONCLUSIONS: This study reinforces the importance of both substance-use disorders and poverty in the risk for first-time homelessness, and can serve as a benchmark for future studies. Substance abuse treatment should address financial status and risk of future homelessness. PMID- 24148044 TI - Homelessness research: shaping policy and practice, now and into the future. PMID- 24148045 TI - Application of implementation science for homeless interventions. PMID- 24148046 TI - Health care utilization patterns of homeless individuals in Boston: preparing for Medicaid expansion under the Affordable Care Act. AB - OBJECTIVES: We studied 6494 Boston Health Care for the Homeless Program (BHCHP) patients to understand the disease burden and health care utilization patterns for a group of insured homeless individuals. METHODS: We studied merged BHCHP data and MassHealth eligibility, claims, and encounter data from 2010. MassHealth claims and encounter data provided a comprehensive history of health care utilization and expenditures, as well as associated diagnoses, in both general medical and behavioral health services sectors and across a broad range of health care settings. RESULTS: The burden of disease was high, with the majority of patients experiencing mental illness, substance use disorders, and a number of medical diseases. Hospitalization and emergency room use were frequent and total expenditures were 3.8 times the rate of an average Medicaid recipient. CONCLUSIONS: The Affordable Care Act provides a framework for reforming the health care system to improve the coordination of care and outcomes for vulnerable populations. However, improved health care coverage alone may not be enough. Health care must be integrated with other resources to address the complex challenges presented by inadequate housing, hunger, and unsafe environments. PMID- 24148047 TI - Housing instability and mental distress among US veterans. AB - Evidence has suggested increased risk for homelessness and suicide among US veterans, but little is known about the associations between housing instability and psychological distress (including suicidal ideation). We examined frequent mental distress (FMD) and suicidal ideation among a probability-based sample of 1767 Nebraska veterans who participated in the 2010 Behavioral Risk Factor Surveillance Survey who had and had not experienced housing instability in the past 12 months. Veterans experiencing housing instability had increased odds of FMD and suicidal ideation. PMID- 24148048 TI - Latent homeless risk profiles of a national sample of homeless veterans and their relation to program referral and admission patterns. AB - OBJECTIVES: We identified risk and need profiles of homeless veterans and examined the relation between profiles and referrals and admissions to Department of Veterans Affairs (VA) homeless service programs. METHODS: We examined data from the VA's new Homeless Operations Management and Evaluation System on 120,852 veterans from 142 sites nationally in 2011 and 2012 using latent class analyses based on 9 homeless risk factors. The final 4-class solution compared both referral and admission to VA homeless services. RESULTS: We identified 4 latent classes: relatively few problems, dual diagnosis, poverty-substance abuse incarceration, and disabling medical problems. Homeless veterans in the first group were more likely to be admitted to the VA's permanent supportive housing program, whereas those in the second group were more likely to be admitted to more restrictive VA residential treatment. Homeless veterans in the third group were more likely to be admitted to the VA's prisoner re-entry program, and those in the fourth group were more likely to be directed to VA medical services. CONCLUSIONS: The heterogeneous risk and need profiles of homeless veterans supported the diversity of VA homeless services and encouraged the development of specialized services to meet their diverse needs. PMID- 24148049 TI - Relationship between adverse childhood experiences and homelessness and the impact of axis I and II disorders. AB - OBJECTIVES: We investigated the links between homelessness associated with serious mental and physical healthy disparities and adverse childhood experiences (ACEs) in nationally representative data, with Axis I and II disorders as potential mediators. METHODS: We examined data from the National Epidemiologic Survey of Alcohol and Related Conditions in 2001-2002 and 2004-2005, and included 34,653 participants representative of the noninstitutionalized US population who were 20 years old or older. We studied the variables related to 4 classes of Axis I disorders, all 10 Axis II personality disorders, a wide range of ACEs, and a lifetime history of homelessness. RESULTS: Analyses revealed high prevalences of each ACE in individuals experiencing lifetime homelessness (17%-60%). A mediation model with Axis I and II disorders determined that childhood adversities were significantly related to homelessness through direct effects (adjusted odd ratios = 2.04, 4.24) and indirect effects, indicating partial mediation. Population attributable fractions were also reported. CONCLUSIONS: Although Axis I and II disorders partially mediated the relationship between ACEs and homelessness, a strong direct association remained. This novel finding has implications for interventions and policy. Additional research is needed to understand relevant causal pathways. PMID- 24148050 TI - Admission decisions and outcomes of community-acquired pneumonia in the homeless population: a review of 172 patients in an urban setting. AB - OBJECTIVES: We compared admission rates, outcomes, and performance of the CURB-65 mortality prediction score of homeless patients and nonhomeless patients with community-acquired pneumonia (CAP). METHODS: We compared homeless (n = 172) and nonhomeless (n = 1897) patients presenting to a Salt Lake City, Utah, emergency department with CAP from 1996 to 2006. In the homeless cohort, we measured referral from and follow-up with the local homeless health care clinic and arrangement of medical housing. RESULTS: Homeless patients were younger (44 vs 59 years; P < .001) and had lower CURB-65 scores and higher hospitalization risk (severity-adjusted odds ratio = 1.89; 95% confidence interval = 1.33, 2.69) than did nonhomeless patients, with a similar length of stay, median inpatient cost, and median outpatient cost, even after severity adjustment. Of homeless patients, 22% were referred from the homeless health care clinic to the emergency department; 54% of outpatients and 51% of hospital patients were referred back to the clinic, and medical housing was arranged for 23%. CONCLUSIONS: A large cohort of homeless patients with CAP demonstrated higher hospitalization risk than but similar length of stay and costs as nonhomeless patients. The strong relationship between the hospital and homeless health care clinic may have contributed to this finding. PMID- 24148053 TI - Randomized trial of intensive housing placement and community transition services for episodic and recidivist homeless families. AB - OBJECTIVES: We compared Home to Stay, a pilot of intensive housing placement and community transition services for episodic and recidivist homeless families, with a standard services approach. METHODS: Using intention-to-treat analyses, we conducted a modified randomized trial of 138 Home to Stay client families and a control group of 192 client families receiving standard shelter services. RESULTS: Home to Stay clients exited shelter more quickly than clients in the control group (Cox regression, P < .001), more commonly exited shelter with housing subsidies (75% vs 56%), stayed out of shelter longer (Cox regression, P = .011), and spent fewer total days in shelter (376 days vs 449 days). Home to Stay performed best with clients who entered shelter within 180 days of the pilot's start date and had less impact on clients entering shelter before that time. CONCLUSIONS: Relative to standard services, Home to Stay services can accelerate exit from shelter and reduce return to shelter and total sheltered days for episodic and recidivist homeless families. Standard shelter services may be able to narrow this performance gap by incentivizing work with all episodic and recidivist homeless families. PMID- 24148051 TI - A comprehensive assessment of health care utilization among homeless adults under a system of universal health insurance. AB - OBJECTIVES: We comprehensively assessed health care utilization in a population based sample of homeless adults and matched controls under a universal health insurance system. METHODS: We assessed health care utilization by 1165 homeless single men and women and adults in families and their age- and gender-matched low income controls in Toronto, Ontario, from 2005 to 2009, using repeated-measures general linear models to calculate risk ratios and 95% confidence intervals (CIs). RESULTS: Homeless participants had mean rates of 9.1 ambulatory care encounters (maximum = 141.1), 2.0 emergency department (ED) encounters (maximum = 104.9), 0.2 medical-surgical hospitalizations (maximum = 14.9), and 0.1 psychiatric hospitalizations per person-year (maximum = 4.8). Rate ratios for homeless participants compared with matched controls were 1.76 (95% CI = 1.58, 1.96) for ambulatory care encounters, 8.48 (95% CI = 6.72, 10.70) for ED encounters, 4.22 (95% CI = 2.99, 5.94) for medical-surgical hospitalizations, and 9.27 (95% CI = 4.42, 19.43) for psychiatric hospitalizations. CONCLUSIONS: In a universal health insurance system, homeless people had substantially higher rates of ED and hospital use than general population controls; these rates were largely driven by a subset of homeless persons with extremely high-intensity usage of health services. PMID- 24148052 TI - Comparing homeless persons' care experiences in tailored versus nontailored primary care programs. AB - OBJECTIVES: We compared homeless patients' experiences of care in health care organizations that differed in their degree of primary care design service tailoring. METHODS: We surveyed homeless-experienced patients (either recently or currently homeless) at 3 Veterans Affairs (VA) mainstream primary care settings in Pennsylvania and Alabama, a homeless-tailored VA clinic in California, and a highly tailored non-VA Health Care for the Homeless Program in Massachusetts (January 2011-March 2012). We developed a survey, the "Primary Care Quality Homeless Survey," to reflect the concerns and aspirations of homeless patients. RESULTS: Mean scores at the tailored non-VA site were superior to those from the 3 mainstream VA sites (P < .001). Adjusting for patient characteristics, these differences remained significant for subscales assessing the patient-clinician relationship (P < .001) and perceptions of cooperation among providers (P = .004). There were 1.5- to 3-fold increased odds of an unfavorable experience in the domains of the patient-clinician relationship, cooperation, and access or coordination for the mainstream VA sites compared with the tailored non-VA site; the tailored VA site attained intermediate results. CONCLUSIONS: Tailored primary care service design was associated with a superior service experience for patients who experienced homelessness. PMID- 24148054 TI - Navigating the boundaries of emergency department care: addressing the medical and social needs of patients who are homeless. AB - OBJECTIVES: We sought to understand interpersonal and systems-level factors relevant to delivering health care to emergency department (ED) patients who are homeless. METHODS: We conducted semistructured interviews with emergency medicine residents from 2 residency programs, 1 in New York City and 1 in a medium-sized northeastern city, from February to September 2012. A team of researchers reviewed transcripts independently and coded text segments using a grounded theory approach. They reconciled differences in code interpretations and generated themes inductively. Data collection and analysis occurred iteratively, and interviews continued until theoretical saturation was achieved. RESULTS: From 23 interviews, 3 key themes emerged: (1) use of pattern recognition in identifying and treating patients who are homeless, (2) variations from standard ED care for patients who are homeless, and (3) tensions in navigating the boundaries of ED social care. CONCLUSIONS: Our study revealed practical and philosophical tensions in providing social care to patients in the ED who are homeless. Screening for homelessness in the ED and admission practices for patients who are homeless are important areas for future research and intervention with implications for health care costs and patient outcomes. PMID- 24148055 TI - Twenty-five years of child and family homelessness: where are we now? AB - Family homelessness emerged as a major social and public health problem in the United States during the 1980s. We reviewed the literature, including journal articles, news stories, and government reports, that described conditions associated with family homelessness, the scope of the problem, and the health and mental health of homeless children and families. Much of this literature was published during the 1980s and 1990s. This raises questions about its continued applicability for the public health community. We concluded that descriptions of the economic conditions and public policies associated with family homelessness are still relevant; however, the homeless family population has changed over time. Family homelessness has become more prevalent and pervasive among poor and low-income families. We provide public health recommendations for these homeless families. PMID- 24148056 TI - Health care for the homeless: what we have learned in the past 30 years and what's next. AB - In the 1980s, the combined effects of deinstitutionalization from state mental hospitals and the economic recession increased the number and transformed the demographic profile of people experiencing homelessness in the United States. Specialized health care for the homeless (HCH) services were developed when it became clear that the mainstream health care system could not sufficiently address their health needs. The HCH program has grown consistently during that period; currently, 208 HCH sites are operating, and the program has become embedded in the federal health care system. We reflect on lessons learned from the HCH model and its applicability to the changing landscape of US health care. PMID- 24148057 TI - Community-level characteristics associated with variation in rates of homelessness among families and single adults. AB - OBJECTIVES: We modeled rates of family and single-adult homelessness in the United States in metropolitan and nonmetropolitan regions and as a function of community-level demographic, behavioral, health, economic, and safety net characteristics. METHODS: We entered community-level characteristics and US Department of Housing and Urban Development point-in-time counts for a single night in January 2009 into separate mixed-effects statistical analyses that modeled homelessness rates for 4 subpopulations: families and single adults in metropolitan and nonmetropolitan regions. RESULTS: Community-level factors accounted for 25% to 50% of the variance in homelessness rates across models. In metropolitan regions, alcohol consumption, social support, and several economic indicators were uniquely associated with family homelessness, and drug use and homicide were uniquely associated with single-adult homelessness. In nonmetropolitan regions, life expectancy, religious adherence, unemployment, and rent burden were uniquely associated with family homelessness, and health care access, crime, several economic indicators, and receipt of Supplemental Security Income were uniquely associated with single-adult homelessness. CONCLUSIONS: Considering homeless families and single adults separately enabled more precise modeling of associations between homelessness rates and community-level characteristics, indicating targets for interventions to reduce homelessness among these subpopulations. PMID- 24148058 TI - Identifying US veterans who access services from health care for the homeless clinics. AB - Research on veterans experiencing homelessness is predominantly focused on the US Department of Veterans Affairs setting, despite the fact that substantial numbers receive services from Health Care for the Homeless (HCH) clinics. We explored how HCH clinics identified veteran patients through a survey of administrators (49% response rate). The majority (98%) identified veterans but used varied language and approaches. Implementing a streamlined, culturally competent identification process is vital to collecting accurate data, connecting veterans with benefits, and informing treatment plans. PMID- 24148059 TI - Elderly homeless veterans in Los Angeles: chronicity and precipitants of homelessness. AB - OBJECTIVES: We compared the characteristics of chronically homeless and acutely homeless elderly veterans to better understand precipitants of homelessness. METHODS: We conducted interviews with 33 chronically and 26 acutely homeless veterans aged 65 years and older receiving transitional housing services in Los Angeles, California, between 2003 and 2005. We asked questions regarding their sociodemographic characteristics and other social status measures. Other precipitants of homelessness were acquired via observation and open-ended and structured questions. RESULTS: Both veterans groups were more similar than different, with substantial levels of physical, psychiatric, and social impairment. They differed significantly in homelessness history, with chronically homeless veterans having more homelessness episodes and more total time homeless. They were also less educated and had smaller social networks. In response to open ended questioning, elderly homeless veterans revealed how health and substance use issues interacted with loss of social support and eviction to exacerbate homelessness. CONCLUSIONS: Assessment of a range of factors is needed to address risk factors and events leading to homelessness. Further research with larger samples is needed to confirm the characteristics and needs of the elderly homeless veteran population. PMID- 24148060 TI - Challenges associated with screening for traumatic brain injury among US veterans seeking homeless services. AB - We identified the prevalence of traumatic brain injury (TBI) among homeless veterans and assessed the TBI-4, a screening tool created to identify TBI history. Between May 2010 and October 2011, 800 US veterans from two hospitals, one eastern (n = 122) and one western (n = 678) completed some or all measures. Findings suggested that 47% of veterans seeking homeless services had a probable history of TBI (data for prevalence obtained only at the western hospital). However, psychometric results from the screening measure suggested that this may be an underestimate and supported comprehensive assessment of TBI in this population. PMID- 24148061 TI - When health insurance is not a factor: national comparison of homeless and nonhomeless US veterans who use Veterans Affairs Emergency Departments. AB - OBJECTIVES: We examined the proportion of homeless veterans among users of Veterans Affairs (VA) emergency departments (EDs) and compared sociodemographic and clinical characteristics of homeless and nonhomeless VA emergency department users nationally. METHODS: We used national VA administrative data from fiscal year 2010 for a cross-sectional study comparing homeless (n = 64,091) and nonhomeless (n = 866,621) ED users on sociodemographics, medical and psychiatric diagnoses, and other clinical characteristics. RESULTS: Homeless veterans had 4 times the odds of using EDs than nonhomeless veterans. Multivariate analyses found few differences between homeless and nonhomeless ED users on the medical conditions examined, but homeless ED users were more likely to have been diagnosed with a drug use disorder (odds ratio [OR] = 4.12; 95% confidence interval [CI] = 3.97, 4.27), alcohol use disorder (OR = 3.67; 95% CI = 3.55, 3.79), or schizophrenia (OR = 3.44; 95% CI = 3.25, 3.64) in the past year. CONCLUSIONS: In a national integrated health care system with no specific requirements for health insurance, the major differences found between homeless and nonhomeless ED users were high rates of psychiatric and substance abuse diagnoses. EDs may be an important location for specialized homeless outreach (or "in" reach) services to address mental health and addictive disorders. PMID- 24148062 TI - Cooking, healthy eating, fitness and fun (CHEFFs): qualitative evaluation of a nutrition education program for children living at urban family homeless shelters. AB - OBJECTIVES: We assessed the feasibility of a 15-week nutrition education, physical activity, and media literacy program for children living in urban family homeless shelters. METHODS: We developed a qualitative monitoring tool to evaluate program process and impact at 2 shelter sites in the Bronx, New York, from 2009 to 2012. Facilitators recorded indications of participants' understanding of intended messages and demonstrations of changes in attitudes and behaviors. Comments, insights, and actions were recorded as they occurred. Facilitators also documented barriers to delivery of content and activities as intended. We used content analysis to examine data for patterns and identify themes. RESULTS: A total of 162 children participated at the 2 shelter sites. Analysis of qualitative data yielded 3 themes: (1) children's knowledge and understanding of content, (2) children's shift in attitudes or intentions, and (3) interpretations through children's life experience. Food insecurity as well as shelter food service and policies were important influences on children's choices, hunger, and sense of well-being. CONCLUSIONS: Children's experiences highlighted the need to advocate for shelter policies that adequately provide for children's nutritional and physical activity requirements and foster academic development. PMID- 24148063 TI - Housing retention in single-site housing first for chronically homeless individuals with severe alcohol problems. AB - OBJECTIVES: We studied housing retention and its predictors in the single-site Housing First model. METHODS: Participants (n = 111) were chronically homeless people with severe alcohol problems who lived in a single-site Housing First program and participated in a larger nonrandomized controlled trial (2005-2008) conducted in Seattle, Washington. At baseline, participants responded to self report questionnaires assessing demographic, illness burden, alcohol and other drug use, and psychiatric variables. Housing status was recorded over 2 years. RESULTS: Participants were interested in housing, although a sizable minority did not believe they would be able to maintain abstinence-based housing. Only 23% of participants returned to homelessness during the 2-year follow-up. Commonly cited risk factors--alcohol and other drug use, illness burden, psychiatric symptoms, and homelessness history--did not predict resumed homelessness. Active drinkers were more likely to stay in this housing project than nondrinkers. CONCLUSIONS: We found that single-site Housing First programming fills a gap in housing options for chronically homeless people with severe alcohol problems. PMID- 24148064 TI - Relationship among adverse childhood experiences, history of active military service, and adult outcomes: homelessness, mental health, and physical health. AB - OBJECTIVES: We determined whether a report of adverse childhood experiences predicts adult outcomes related to homelessness, mental health, and physical health and whether participation in active military service influences the relationship between childhood and adult adversity. METHODS: Using data from the 2010 Washington State Behavioral Risk Factor Surveillance System, we tested by means of logistic regression the relationship between adverse childhood experiences and 3 adult outcomes--homelessness, mental health, and physical health--as well as differences among those with a history of active military service. RESULTS: Adverse childhood experiences separately predicted increased odds of experiencing homelessness as an adult and mental health and physical health problems. Childhood adversity increased the likelihood of adult homelessness and poor physical health among individuals with no history of active military service and the likelihood of mental health problems among individuals with a history of active military service. CONCLUSIONS: The relationship between childhood adversity and adult adversity changes in degree when history of active military service is controlled, which has implications for Armed Forces recruitment strategies and postmilitary service risk assessment. PMID- 24148065 TI - Homelessness during the transition from foster care to adulthood. AB - OBJECTIVES: We estimated the incidence of homelessness during the transition to adulthood and identified the risk and protective factors that predict homelessness during this transition. METHODS: Using data from the Midwest Evaluation of the Adult Functioning of Former Foster Youth, a longitudinal study of youths aging out of foster care in 3 Midwestern states, and a bounds approach, we estimated the cumulative percentage of youths who become homeless during the transition to adulthood. We also estimated a discrete time hazard model that predicted first reported episode of homelessness. RESULTS: Youths aging out of foster care are at high risk for becoming homeless during the transition to adulthood. Between 31% and 46% of our study participants had been homeless at least once by age 26 years. Running away while in foster care, greater placement instability, being male, having a history of physical abuse, engaging in more delinquent behaviors, and having symptoms of a mental health disorder were associated with an increase in the relative risk of becoming homeless. CONCLUSIONS: Policy and practice changes are needed to reduce the risk that youths in foster care will become homeless after aging out. PMID- 24148066 TI - Risk factors for becoming homeless among a cohort of veterans who served in the era of the Iraq and Afghanistan conflicts. AB - OBJECTIVES: In this population-based cohort study, we assessed baseline risk factors for homelessness, including the role of service in the Iraq or Afghanistan conflicts, among a large cohort of recent veterans. METHODS: Data for this study came from administrative records for 310,685 veterans who separated from active military duty from July 1, 2005, to September 30, 2006. We used survival analysis methods to determine incidence rates and risk factors for homelessness, based on baseline data for military factors, demographic characteristics, and diagnoses of behavioral health disorders and traumatic brain injury. RESULTS: Service in Iraq or Afghanistan and, more specifically, posttraumatic stress disorder among veterans deployed there, were significant risk factors of modest magnitude for homelessness, and socioeconomic and behavioral health factors provided stronger indicators of risk. Gender was not a significant indicator of differential risk. CONCLUSIONS: Although service in Iraq and Afghanistan was significant, socioeconomic and behavioral health indicators show more promise in efforts to use administrative data to inform prevention efforts by identifying veterans who are at elevated risk for becoming homeless upon their return to civilian life. PMID- 24148067 TI - Homelessness and money mismanagement in Iraq and Afghanistan veterans. AB - OBJECTIVES: We examined the empirical link between money mismanagement and subsequent homelessness among veterans. METHODS: We used a random sample of Iraq and Afghanistan War era veterans from the National Post-Deployment Adjustment Survey in 2009-2011. RESULTS: Veterans were randomly selected from a roster of all US military service members in Operation Iraqi Freedom or Operation Enduring Freedom who were separated from active duty or in the Reserves/National Guard. Veterans (n = 1090) from 50 states and all military branches completed 2 waves of data collection 1 year apart (79% retention rate). Thirty percent reported money mismanagement (e.g., bouncing or forging a check, going over one's credit limit, falling victim to a money scam in the past year). Multivariate analysis revealed money mismanagement (odds ratio [OR] = 4.09, 95% CI = 1.87, 8.94) was associated with homelessness in the next year, as were arrest history (OR = 2.65, 95% CI = 1.33, 5.29), mental health diagnosis (OR = 2.59, 95% CI = 1.26, 5.33), and income (OR = 0.30, 95% CI = 0.13, 0.71). CONCLUSIONS: Money mismanagement, reported by a substantial number of veterans, was related to a higher rate of subsequent homelessness. The findings have implications for policymakers and clinicians, suggesting that financial education programs offered by the US Departments of Defense and Veterans Affairs may be targeted to effectively address veteran homelessness. PMID- 24148068 TI - Programmatic impact of 5 years of mortality surveillance of New York City homeless populations. AB - A homeless mortality surveillance system identifies emerging trends in the health of the homeless population and provides this information to key stakeholders in a timely and ongoing manner to effect evidence-based, programmatic change. We describe the first 5 years of the New York City homeless mortality surveillance system and, for the first time in peer-reviewed literature, illustrate the impact of key elements of sustained surveillance (i.e., timely dissemination of aggregate mortality data and real-time sharing of information on individual homeless decedents) on the programs of New York City's Department of Homeless Services. These key elements had a positive impact on the department's programs that target sleep-related infant deaths and hypothermia, drug overdose, and alcohol-related deaths among homeless persons. PMID- 24148069 TI - Comparing homeless smokers to economically disadvantaged domiciled smokers. AB - We compared characteristics of homeless smokers and economically disadvantaged domiciled smokers (Dallas, TX; August 2011-November 2012). Although findings indicated similar smoking characteristics across samples, homeless smokers (n = 57) were exposed to more smokers and reported lower motivation to quit, lower self-efficacy for quitting, more days with mental health problems, and greater exposure to numerous stressors than domiciled smokers (n = 110). The sample groups reported similar scores on measures of affect, perceived stress, and interpersonal resources. Results may inform novel cessation interventions for homeless smokers. PMID- 24148070 TI - Role of gamma-kafirin in the formation and organization of kafirin microstructures. AB - The possible importance of the cysteine-rich gamma-prolamin in kafirin and zein functionality has been neglected. The role of gamma-kafirin in organized microstructures was investigated in microparticles. Residual kafirin (total kafirin minus gamma-kafirin) "microparticles" were non-discrete (amorphous mass of material), as viewed by electron microscopy and atomic force microscopy. Adding 15% gamma-kafirin to residual kafirin resulted in the formation of a mixture of non-discrete material and nanosize discrete spherical structures. Adding 30% gamma-kafirin to the residual kafirin resulted in discrete spherical nanosize particles. Fourier transform infrared spectroscopy indicated that gamma kafirin had a mixture of random-coil and beta-sheet conformations, in contrast to total kafirin, which is mainly alpha-helical conformation. gamma-Kafirin also had a very high glass transition temperature (Tg) (~270 degrees C). The conformation and high Tg of gamma-kafirin probably confer structural stability to kafirin microstructures. Because of its ability to form disulfide cross-links, gamma kafirin appears to be essential to form and stabilize organized microstructures. PMID- 24148072 TI - "It's a struggle but I can do it. I'm doing it for me and my kids": the psychosocial characteristics and life experiences of at-risk homeless parents in transitional housing. AB - Families experiencing homelessness face a number of risks to their psychosocial health and well-being, yet few studies have examined the topic of parenting among homeless families. The purpose of this multimethod, descriptive study was to acquire a better understanding of the psychosocial status and life experiences of homeless parents residing in transitional housing. Quantitative data were collected from 69 parents and primary caregivers living in a transitional housing community, with a cohort of 24 participants also contributing qualitative data. The quantitative results suggest risk associated with depression, parenting stress, and negative parenting practices. The qualitative findings highlight five themes that convey both the challenges faced by homeless parents as well as the resilience they display in spite of such adversity. These results extend current scholarship on homeless families with children and can better inform how couple and family therapists work with this at-risk population. PMID- 24148071 TI - Facile and efficient preparation of anisotropic DNA-functionalized gold nanoparticles and their regioselective assembly. AB - Anisotropic nanoparticles can provide considerable opportunities for assembly of nanomaterials with unique structures and properties. However, most reported anisotropic nanoparticles are either difficult to prepare or to functionalize. Here we report a facile one-step solution-based method to prepare anisotropic DNA functionalized gold nanoparticles (a-DNA-AuNP) with 96% yield and with high DNA density (120 +/- 20 strands on the gold hemisphere). The method is based on the competition between a thiolated hydrophilic DNA and a thiolated hydrophobic phospholipid and has been applied to prepare a-DNA-AuNPs of different sizes and with a variety of DNA sequences. In addition, DNA strands on the a-DNA-AuNPs can be exchanged with other DNA strands with a different sequence. The anisotropic nature of the a-DNA-AuNPs allows regioselective hetero- and homonuclear assembly with high monodispersity, as well as regioselective functionalization of two different DNA strands for more diverse applications. PMID- 24148073 TI - Paraneoplastic cerebellar degeneration caused by ovarian clear-cell carcinoma. AB - Paraneoplastic cerebellar degeneration is a paraneoplastic neurological syndrome caused by the remote effect of certain systemic cancers and is characterized by subacute cerebellar symptoms. A 62-year-old woman suffering from unidentified cerebellar symptoms was admitted to our hospital. Paraneoplastic cerebellar degeneration was suspected and ovarian cancer was detected after the systemic examination for malignancy. The symptoms of vertigo and dysarthria were improved a little after surgical operation and treatments of gamma-globulin, steroid pulse and tacrolimus hydrate. The cerebellar symptoms of paraneoplastic cerebellar degeneration are often evident prior to detection of malignancy. It is important to perform systemic examination for malignancy in case of unidentified cerebellar symptoms. PMID- 24148074 TI - Readability of websites containing information on dental implants. AB - It is recommended that health-related materials for patients be written at sixth grade level or below. Many websites oriented toward patient education about dental implants are available, but the readability of these sites has not been evaluated. OBJECTIVE: To assess readability of patient-oriented online information on dental implants. MATERIALS AND METHODS: Websites containing patient-oriented information on dental implants were retrieved using the Google search engine. Individual and mean readability/grade levels were calculated using standardized formulas. Readability of each website was classified as easy (<= 6th grade level) or difficult (>= 10th grade level). RESULTS: Thirty nine websites with patient-oriented information on dental implant were found. The average readability grade level of these websites was 11.65 +/- 1.36. No website scored at/below the recommended 6th grade level. Thirty four of 39 websites (87.18%) were difficult to read. The number of characters, words, and sentences on these sites varied widely. CONCLUSION: All patient-oriented websites on dental implants scored above the recommended grade level, and majority of these sites were "difficult" in their readability. There is a dire need to create patient information websites on implants, which the majority can read. PMID- 24148075 TI - Evidence that an HMGA1 gene variant associates with type 2 diabetes, body mass index, and high-density lipoprotein cholesterol in a Hispanic-American population. AB - BACKGROUND: High-mobility group AT-hook 1 (HMGA1) is an important regulator of the insulin receptor gene. We have previously shown in three populations of white European ancestry that the HMGA1 gene variant rs146052672 (also designated IVS5 13insC) is associated with type 2 diabetes mellitus (T2DM). The aim of this study was to measure the frequency of this variant and to determine the degree of the association with T2DM and other features of the metabolic syndrome in a replication cohort of Hispanic Americans. METHODS: This was a retrospective cohort study of well-characterized Hispanic-American participants analyzed in the Genomic Resource in Atherosclerosis (GRA) (Cardiovascular Research Institute, University of California, San Francisco). A total of 1144 individuals were studied, 320 of whom had T2DM. We examined associations of the rs146052672 SNP with T2DM, plasma lipids, lipoproteins, and body mass index (BMI). RESULTS: In this Hispanic-American cohort, the HMGA1 rs146052672 minor allele (C-insertion) frequency (MAF) was 21.4% with a carrier frequency of 37.4%, considerably higher than we previously observed among GRA white Europeans (MAF 3.1%). The prevalence of the IVS5-13insC variant was significantly higher in those with T2DM compared to controls [42.2% vs. 35.5%; odds ratio (OR) 1.44 95% confidence interval (CI) 1.09-1.90, P=0.011). The variant was also associated with BMI (positively, P=0.045) and plasma high-density lipoprotein cholesterol (HDL-C) (negatively, P=0.047). CONCLUSIONS: As we saw previously among white Europeans, a functional HMGA1 variant was associated with T2DM in individuals of Hispanic-American ethnicity and was present at a much higher frequency. PMID- 24148076 TI - Software platforms to facilitate reconstructing genome-scale metabolic networks. AB - System-level analyses of microbial metabolism are facilitated by genome-scale reconstructions of microbial biochemical networks. A reconstruction provides a structured representation of the biochemical transformations occurring within an organism, as well as the genes necessary to carry out these transformations, as determined by the annotated genome sequence and experimental data. Network reconstructions also serve as platforms for constraint-based computational techniques, which facilitate biological studies in a variety of applications, including evaluation of network properties, metabolic engineering and drug discovery. Bottom-up metabolic network reconstructions have been developed for dozens of organisms, but until recently, the pace of reconstruction has failed to keep up with advances in genome sequencing. To address this problem, a number of software platforms have been developed to automate parts of the reconstruction process, thereby alleviating much of the manual effort previously required. Here, we review four such platforms in the context of established guidelines for network reconstruction. While many steps of the reconstruction process have been successfully automated, some manual evaluation of the results is still required to ensure a high-quality reconstruction. Widespread adoption of these platforms by the scientific community is underway and will be further enabled by exchangeable formats across platforms. PMID- 24148077 TI - Gender, age, and psychosocial context of the perception of facial esthetics. AB - OBJECTIVE: To explore the effects of gender, age, and psychosocial context on the perception of facial esthetics. METHODS: The study included 1,444 Caucasian subjects aged 16 to 85 years. Two sets of color photographs illustrating 13 male and 13 female Caucasian facial type alterations, representing different skeletal and dentoalveolar components of sagittal maxillary-mandibular relationships, were used to estimate the facial profile attractiveness. The examinees graded the profiles based on a 0 to 10 numerical rating scale. The examinees graded the profiles of their own sex only from a social perspective, whereas opposite sex profiles were graded both from the social and emotional perspective separately. RESULTS: The perception of facial esthetics was found to be related to the gender, age, and psychosocial context of evaluation (p < 0.05). The most attractive profiles to men are the orthognathic female profile from the social perspective and the moderate bialveolar protrusion from the emotional perspective. The most attractive profile to women is the orthognathic male profile, when graded from the social aspect, and the mild bialveolar retrusion when graded from the emotional aspect. The age increase of the assessor results in a higher attractiveness grade. CONCLUSIONS: When planning treatment that modifies the facial profile, the clinician should bear in mind that the perception of facial profile esthetics is a complex phenomenon influenced by biopsychosocial factors. CLINICAL SIGNIFICANCE: This study allows a better understanding of the concept of perception of facial esthetics that includes gender, age, and psychosocial context. PMID- 24148080 TI - Human papillomavirus promotes esophageal squamous cell carcinoma by regulating DNA methylation and expression of HLA-DQB1. AB - AIMS: Esophageal cancer (EC) is one of the most prevalent and deadly cancers worldwide. Along with nutrition, smoking and alcohol consumption, human papillomavirus (HPV) infection is one of the major risk factors, which is modulated by host immune response. This study is aimed at elucidating how HPV modifies host immune system in the EC pathogenesis. METHODS: The HPV and HLA-DQB1 levels in primary esophageal squamous cell (ESC) cancer cells from Han, Khazak and Uygur patients were analyzed by quantitative real-time PCR and immunoblotting. The ability of HPV16 E6/E7 to transform normal primary ESCs was investigated by infecting ESC with pMSCVpuro-carried E6 or E7. The shRNA against HPV16 E6 or E7 was delivered by adenovirus into esophageal squamous cell carcinoma (ESCC) cells with high HPV content. The DNA methylation level of HLA DQB1 was measured by methylation-specific PCR. RESULTS: The HLA-DQB1 expression level was correlated with the levels of HPV and inversely related to DNA methylation level of HLA-DQB1. Overexpressing HPV16 E6 or E7 alone was enough to transform normal primary ESCs. However, single knockdown of either E6 or E7 in ESC cancer cells did not reduce HLA-DQB1 expression. CONCLUSIONS: Oncogenic HPV E6 and E7 genes promoted ESCC pathogenesis by upregulating susceptible HLA-DQB1 via DNA demethylation. PMID- 24148081 TI - Integration of pore features into the evaluation of fingerprint evidence. AB - Fingerprint practitioners rely on level 3 features to make decisions in relation to the source of an unknown friction ridge skin impression. This research proposes to assess the strength of evidence associated with pores when shown in (dis)agreement between a mark and a reference print. Based upon an algorithm designed to automatically detect pores, a metric is defined in order to compare different impressions. From this metric, the weight of the findings is quantified using a likelihood ratio. The results obtained on four configurations and 54 donors show the significant contribution of the pore features and translate into statistical terms what latent fingerprint examiners have developed holistically through experience. The system provides LRs that are indicative of the true state under both the prosecution and the defense propositions. Not only such a system brings transparency regarding the weight to assign to such features, but also forces a discussion in relation to the risks of such a model to mislead. PMID- 24148079 TI - Borrelia chilensis, a new member of the Borrelia burgdorferi sensu lato complex that extends the range of this genospecies in the Southern Hemisphere. AB - Borrelia burgdorferi sensu lato (s.l.), transmitted by Ixodes spp. ticks, is the causative agent of Lyme disease. Although Ixodes spp. ticks are distributed in both Northern and Southern Hemispheres, evidence for the presence of B. burgdorferi s.l. in South America apart from Uruguay is lacking. We now report the presence of culturable spirochetes with flat-wave morphology and borrelial DNA in endemic Ixodes stilesi ticks collected in Chile from environmental vegetation and long-tailed rice rats (Oligoryzomys longicaudatus). Cultured spirochetes and borrelial DNA in ticks were characterized by multilocus sequence typing and by sequencing five other loci (16S and 23S ribosomal genes, 5S-23S intergenic spacer, flaB, ospC). Phylogenetic analysis placed this spirochete as a new genospecies within the Lyme borreliosis group. Its plasmid profile determined by polymerase chain reaction and pulsed-field gel electrophoresis differed from that of B. burgdorferi B31A3. We propose naming this new South American member of the Lyme borreliosis group B. chilensis VA1 in honor of its country of origin. PMID- 24148082 TI - Energy harvesting capability of lipid-merocyanine macromolecules: a new design and performance model development. AB - Light induced cis/trans isomerization in the family of merocyanine (MC) dyes offers a recyclable proton pumping ability which can potentially be used in hybrid bio-electronic devices. In this article, a hexadecyl MC dye is embedded in lipid molecules to make a macromolecular configuration of a lipid/hexadecyl MC membrane. Lipid molecules play a critical role in stabilizing the dye in a membrane structure for practical use in energy devices. In this study, we first examined the proton pumping characteristic of the lipid/hexadecyl MC membrane in a conventional photoelectrochemical cell. Next, a major modification in the cell was introduced by eliminating I2/I-electrolyte which resulted in a two-fold increase in the open circuit voltage compared with that of the conventional cell. In addition, the charging time in the new cell was reduced approximately four orders of magnitude. This research demonstrated that the newly designed lipid- MC cell can act as a promising bioelectronic device based on the green energy of photoinduced MC dye proton pumping. PMID- 24148083 TI - Thermodynamic analysis of transition-state features in picomolar inhibitors of human 5'-methylthioadenosine phosphorylase. AB - Human 5'-methylthioadenosine phosphorylase (MTAP) is solely responsible for 5' methylthioadenosine (MTA) metabolism to permit S-adenosylmethionine salvage. Transition-state (TS) analogues of MTAP are in development as anticancer candidates. TS analogues of MTAP incorporate a cationic nitrogen and a protonated 9-deazaadenine leaving group, which are mimics of the ribocation transition state. MT-ImmA and MT-DADMe-ImmA are two examples of these TS analogues. Thermodynamic analysis of MTA, inhibitor, and phosphate binding reveals the cationic nitrogen to provide -2.6 and -3.6 kcal/mol binding free energy for MT ImmA and MT-DADMe-ImmA, respectively. The protonated deazaadenine provides an additional -1.3 (MT-ImmA) to -1.7 kcal/mol (MT-DADMe-ImmA). MT-DADMe-ImmA is a better match in TS geometry than MT-ImmA and is thermodynamically favored. Binding of TS analogues to the MTAP/phosphate complex is fully entropic, in contrast to TS analogue binding to the related human purine nucleoside phosphorylase/phosphate complex, which is fully enthalpic (Guan, R., Ho, M. C., Brenowitz, M., Tyler, P. C., Evans, G. B., Almo, S. C., and Schramm, V. L. (2011) Biochemistry 50, 10408-10417). The binding thermodynamics of phosphate or TS analogues alone to MTAP are fully dominated by enthalpy. Phosphate anchored in the catalytic site forms an ion pair with the cationic TS analogue to cause stabilization of the enzyme structure in the ternary complex. The ternary-induced conformational changes convert the individual enthalpic binding energies to entropy, resulting in a presumed shift of the protein architecture toward the transition state. Formation of the ternary TS analogue complex with MTAP induces a remarkable increase in thermal stability (DeltaTm 28 degrees C). The enthalpic, entropic, and protein-stability features of TS analogue binding to human MTAP are resolved in these studies. PMID- 24148084 TI - Growing up with cerebral palsy: perceptions of the influence of family. AB - BACKGROUND: Cerebral palsy (CP) is a non-progressive condition present from birth or infancy that includes various neurological patterns of dysfunction. It is characterized by abnormal motor control and/or posture and can involve communication difficulties. Children and youth with CP face multiple social and developmental challenges during their formative years including mild to severe physical limitations, poor socialization, limited recreational activities, and stigmatization. Families play a key role in supporting adaptation to CP. The purpose of this paper was to explore women's perceptions of the ways their families contributed to their overall quality of life with CP. METHODS: Drawing on data from a qualitative study of eight women with CP, the purpose of this analysis was to examine perceptions of the ways in which their families and individual family members contributed to participants' overall quality of life and adaptation to CP. Respondents ranged in age from 22 years to 55 years and had varied forms of CP. The study was based on a feminist biographical approach, which combines biographical methods with feminist principles. RESULTS: Participants provided considerable, rich contextual data on their family life and the pivotal role family played. The analysis identified four themes related to supportive family roles: (1) being an advocate, and teaching advocacy; (2) promoting inclusion and acceptance; (3) integrating therapy into daily life; and (4) the importance of siblings as friends and mentors. CONCLUSIONS: Health-care providers can contribute to the family's ability to facilitate quality of life by providing guidance on how to be advocates and teach advocacy, including the child with CP in family activities, accessing therapy and incorporating beneficial therapies at home, and promoting healthy sibling relationships. PMID- 24148085 TI - Chitosan-assisted immobilization of serratiopeptidase on magnetic nanoparticles, characterization and its target delivery. AB - BACKGROUND: Magnetic nanoparticles (MNPs) gained attentions as universal carrier for drug delivery and for enzyme immobilization. PURPOSE: Target delivery of serratiopeptidase for treatment using this enzyme and applications in drug delivery. METHOD: Serratiopeptidase was immobilized on chitosan amino functionalized MNPs by covalent bonding through glutaraldehyde. Targeting of MNPs with immobilized enzyme (EMNPs) was carried out in vitro in modified diffusion cell and in vivo in rats. RESULTS AND DISCUSSION: MNPs and EMNPs were 15.43 +/- 5.22 and 18.43 +/- 3.23 nm (transmission electron microscopy), crystallite size 16.89 and 21.05 nm (X-ray diffraction) and saturation magnetization 62 and 35.2 emug(-1), respectively. Maximum protein and enzyme loading on EMNPs were 264 mg g(-1) and 325 U g(-1), respectively. In the molecular level, maximum 52 enzyme molecules could bind to each particle showing residual activity 68%, little effect on KM and Vmax, good storage stability. Magnetic targeting of EMNPs increased the delivery (permeation) of drug through membrane in vitro and the enhanced anti-inflammatory effect on carrageenan-induced paw oedema in rats in vivo at much lower doses of enzyme than the doses required for treatment with free enzyme. CONCLUSIONS: The enzymatic preparation of MNPs showed enhanced effects (permeation enhancement and anti-inflammatory activity) at lower concentration with magnetic targeting. PMID- 24148087 TI - Synthesis and characterization of some metal complexes of a proton transfer salt, and their inhibition studies on carbonic anhydrase isozymes and the evaluation of the results by statistical analysis. AB - A novel proton transfer compound (HMeOABT)(+) (HDPC)(-) (1) and its Fe(III), Co(II), Ni(II) and Cu(II) complexes (2-5) have been prepared and characterized by spectroscopic techniques. Complex 4 has distorted octahedral conformation revealed by single crystal X-ray diffraction method. Structures of the other complexes might be proposed as octahedral according to experimental data. All compounds were also evaluated for their in vitro inhibition effects on hCA I and II for their hydratase and esterase activities. Although there is no inhibition for hydratase activities, all compounds have inhibited the esterase activities of hCA I and II. Data have been analyzed by using a one-way analysis of variance. The comparison of the inhibition studies of 1-5 to parent compounds indicates that 1-5 have superior inhibitory effects. The inhibition effects of 2-5 are also compared to inhibitory properties of the metal complexes of MeOABT and H2DPC, revealing an improved transfection profile. PMID- 24148086 TI - The cannabinoid CB2 receptor agonist AM1241 enhances neurogenesis in GFAP/Gp120 transgenic mice displaying deficits in neurogenesis. AB - BACKGROUND AND PURPOSE: HIV-1 glycoprotein Gp120 induces apoptosis in rodent and human neurons in vitro and in vivo. HIV-1/Gp120 is involved in the pathogenesis of HIV-associated dementia (HAD) and inhibits proliferation of adult neural progenitor cells (NPCs) in glial fibrillary acidic protein (GFAP)/Gp120 transgenic (Tg) mice. As cannabinoids exert neuroprotective effects in several model systems, we examined the protective effects of the CB2 receptor agonist AM1241 on Gp120-mediated insults on neurogenesis. EXPERIMENTAL APPROACH: We assessed the effects of AM1241 on survival and apoptosis in cultures of human and murine NPCs with immunohistochemical and TUNEL techniques. Neurogenesis in the hippocampus of GFAP/Gp120 transgenic mice in vivo was also assessed by immunohistochemistry. KEY RESULTS: AM1241 inhibited in vitro Gp120-mediated neurotoxicity and apoptosis of primary human and murine NPCs and increased their survival. AM1241 also promoted differentiation of NPCs to neuronal cells. While GFAP/Gp120 Tg mice exhibited impaired neurogenesis, as indicated by reduction in BrdU+ cells and doublecortin+ (DCX+) cells, and a decrease in cells with proliferating cell nuclear antigen (PCNA), administration of AM1241 to GFAP/Gp120 Tg mice resulted in enhanced in vivo neurogenesis in the hippocampus as indicated by increase in neuroblasts, neuronal cells, BrdU+ cells and PCNA+ cells. Astrogliosis and gliogenesis were decreased in GFAP/Gp120 Tg mice treated with AM1241, compared with those treated with vehicle. CONCLUSIONS AND IMPLICATIONS: The CB2 receptor agonist rescued impaired neurogenesis caused by HIV-1/Gp120 insult. Thus, CB2 receptor agonists may act as neuroprotective agents, restoring impaired neurogenesis in patients with HAD. PMID- 24148088 TI - Andrographolide induced acute kidney injury: analysis of 26 cases reported in Chinese Literature. AB - AIM: Some Chinese herbs have been known for their kidney toxicity. Andrographolide, the primary component of a traditional medicinal herb, Andrographis paniculata, is widely used in China for the treatment of upper and lower respiratory tract infection, and dysentery etc. The aim of the study was to identify and summarize any case of kidney injury attributed to its use in the Chinese literature. METHODS: A systemic analysis of the Chinese literature from January 1978 to August 2013 was conducted of case reports of andrographolide induced acute kidney injury (AKI). RESULTS: We identified 26 cases of andrographolide induced AKI (22 males and four females), with an average age of 31.3 years (range: 21 months to 47 years). 100-750 mg (58% 500 mg) of andrographolide was administered in 100-500 mL 5% glucose solution or normal saline by intravenous drip once a day. The adverse event appeared after one to six doses (19 [73.1%] patients got only one dose; cumulative dose 690 +/- 670 mg) of andrographolide was given, or 0-96 h (median 1 h) after andrographolide was given. The symptoms included flank pain in 23 cases (88.5%), decreased urine volume in five cases (19.2%), and nausea or vomiting in six cases (23.1%). Laboratory tests showed maximum creatinine 352.8 +/- 184.1 (158-889) MUmol/L and blood urea nitrogen 12.1 +/- 7.6 (4.0-40.6) mmol/L. Urine analysis showed proteinuria in 10 (38.5%) cases and occult blood in eight (30.8%) cases. Kidney biopsy was carried out in two cases and both revealed acute tubular necrosis. Management of this adverse event included withdrawal of the culprit drug, conservative therapy, and renal replacement therapy (six cases, 23.1%). All the patients recovered and were discharged with a normal or close to normal serum creatinine. Their average length of hospital stay was 12.1 +/- 4.8 days. CONCLUSIONS: Acute kidney injury may occur shortly after intravenous infusion of andrographolide, with symptoms including flank pain, decreased urine output, and nausea or vomiting. The pathological change might be acute tubular necrosis. Renal replacement therapy may be needed in some patients and with a good recovery rate. The mechanisms of andrographolide induced AKI need to be further studied. PMID- 24148089 TI - Ultrafast conformational dynamics of electron transfer in ExBox4+?perylene. AB - Multielectron acceptors are essential components for artificial photosynthetic systems that must deliver multiple electrons to catalysts for solar fuels applications. The recently developed boxlike cyclophane incorporating two extended viologen units joined end-to-end by two p-phenylene linkers-namely, ExBox(4+)-has a potential to be integrated into light-driven systems on account of its ability to complex with pi-electron-rich guests such as perylene, which has been utilized to great extent in many light-harvesting applications. Photodriven electron transfer to ExBox(4+) has not previously been investigated, however, and so its properties, following photoreduction, are largely unknown. Here, we investigate the structure and energetics of the various accessible oxidation states of ExBox(4+) using a combination of spectroscopy and computation. In particular, we examine photoinitiated electron transfer from perylene bound within ExBox(4+) (ExBox(4+)?perylene) using visible and near infrared femtosecond transient absorption (fsTA) spectroscopy. The structure and conformational relaxation dynamics of ExBox(3+)?perylene(+) are observed with femtosecond stimulated Raman spectroscopy (FSRS). From the fsTA and FSRS spectra, we observe that the central p-phenylene spacer in one of the extended viologen units on one side of the cyclophane becomes more coplanar with its neighboring pyridinium units over the first ~5 ps after photoreduction. When the steady-state structure of chemically generated ExBox(2+) is investigated using Raman spectroscopy, it is found to have the central p-phenylene rings in both of its extended viologen units rotated to be more coplanar with their neighboring pyridinium units, further underscoring the importance of this subunit in the stabilization of the reduced states of ExBox(4+). PMID- 24148090 TI - Building 3D structures of vanadium pentoxide nanosheets and application as electrodes in supercapacitors. AB - Various two-dimensional (2D) materials have recently attracted great attention owing to their unique properties and wide application potential in electronics, catalysis, energy storage, and conversion. However, large-scale production of ultrathin sheets and functional nanosheets remains a scientific and engineering challenge. Here we demonstrate an efficient approach for large-scale production of V2O5 nanosheets having a thickness of 4 nm and utilization as building blocks for constructing 3D architectures via a freeze-drying process. The resulting highly flexible V2O5 structures possess a surface area of 133 m(2) g(-1), ultrathin walls, and multilevel pores. Such unique features are favorable for providing easy access of the electrolyte to the structure when they are used as a supercapacitor electrode, and they also provide a large electroactive surface that advantageous in energy storage applications. As a consequence, a high specific capacitance of 451 F g(-1) is achieved in a neutral aqueous Na2SO4 electrolyte as the 3D architectures are utilized for energy storage. Remarkably, the capacitance retention after 4000 cycles is more than 90%, and the energy density is up to 107 W.h.kg(-1) at a high power density of 9.4 kW kg(-1). PMID- 24148091 TI - Penicillin resistance and serotype distribution of Streptococcus pneumoniae in Ghanaian children less than six years of age. AB - BACKGROUND: The objective of this study was to determine the prevalence of nasopharyngeal carriage, serotype distribution, and penicillin resistance of Streptococcus pneumoniae in children <= 6 years of age in Ghana. METHODS: A cross sectional study was carried out on a cluster-randomized sample of children <= 6 years of age attending nurseries and kindergartens in Accra and Tamale, Ghana. Basic data on age, sex and exposure to antimicrobials in the previous month were collected on all study subjects. Nasopharyngeal swabs were obtained from participants and all pneumococcal isolates were characterized by serotyping and their penicillin resistance determined. RESULTS: The overall prevalence of pneumococcal carriage among the children was 34% in Accra and 31% in Tamale. The predominant serotypes were 19F, 6B, 23F, and 6A with 23% of the isolates being non-typable in Accra and 12% in Tamale. Only two isolates (serotypes 19F and 6B) from Tamale had a MIC >2 MUg/ml and were classified as fully penicillin resistant with 45% of the isolates having intermediate resistance. CONCLUSIONS: These findings indicate that the 13-valent pneumococcal conjugate vaccine (PCV-13) recently introduced in Ghana will cover 48% and 51% of the serotypes identified in Accra and Tamale, respectively. The 23-valent pneumococcal polysaccharide vaccine (PPV-23) will cover 54% of all serotypes detected. The two penicillin resistant isolates (MIC 32 MUg/ml) were serotypes included in both PCV-13 and PPV 23. A nationwide monitoring system of penicillin susceptibility patterns and pneumococcal serotypes is recommended. PMID- 24148092 TI - International trade standards for commodities and products derived from animals: the need for a system that integrates food safety and animal disease risk management. AB - A case is made for greater emphasis to be placed on value chain management as an alternative to geographically based disease risk mitigation for trade in commodities and products derived from animals. The geographic approach is dependent upon achievement of freedom in countries or zones from infectious agents that cause so-called transboundary animal diseases, while value chain based risk management depends upon mitigation of animal disease hazards potentially associated with specific commodities or products irrespective of the locality of production. This commodity-specific approach is founded on the same principles upon which international food safety standards are based, viz. hazard analysis critical control points (HACCP). Broader acceptance of a value chain approach enables animal disease risk management to be combined with food safety management by the integration of commodity-based trade and HACCP methodologies and thereby facilitates 'farm to fork' quality assurance. The latter is increasingly recognized as indispensable to food safety assurance and is therefore a pre-condition to safe trade. The biological principles upon which HACCP and commodity-based trade are based are essentially identical, potentially simplifying sanitary control in contrast to current separate international sanitary standards for food safety and animal disease risks that are difficult to reconcile. A value chain approach would not only enable more effective integration of food safety and animal disease risk management of foodstuffs derived from animals but would also ameliorate adverse environmental and associated socio-economic consequences of current sanitary standards based on the geographic distribution of animal infections. This is especially the case where vast veterinary cordon fencing systems are relied upon to separate livestock and wildlife as is the case in much of southern Africa. A value chain approach would thus be particularly beneficial to under-developed regions of the world such as southern Africa specifically and sub-Saharan Africa more generally where it would reduce incompatibility between attempts to expand and commercialize livestock production and the need to conserve the subcontinent's unparalleled wildlife and wilderness resources. PMID- 24148093 TI - Executive process training in young and old adults. AB - There is a growing body of research on the modifiability of executive functions in different stages of life. Previous studies demonstrate robust training effects but limited transfer in younger and particularly in older adults. The aim of the present study was to investigate whether a theoretically derived intervention for executive functioning, addressing several basic processes (updating, shifting, and inhibition), can induce transfer effects in early and late adulthood. Fifty nine healthy adults, 29 young and 30 older adults, were randomly assigned to either training or no-contact control groups. The training groups received 15 sessions of executive process training for about 45 min/session during 5 weeks. A test battery including a criterion task and near, intermediate, and far transfer tasks was administered before and after training. Results showed pronounced age equivalent gains on the criterion task. Near transfer was seen to non-trained updating and inhibition tasks for the young and older trained participants. However, only the young adults showed intermediate transfer to two complex working memory tasks. No far transfer effects were seen for either age group. These findings provide additional evidence for age-related constraints in the ability to generalize acquired executive skills, and specifically show that training of multiple executive processes is not sufficient to foster transfer beyond the very near in older adults. PMID- 24148094 TI - A comparative analysis of risk factors and stroke risk for Asian and non-Asian men: the Asia Pacific cohort studies collaboration. AB - BACKGROUND: The risk of stroke is high in men among both Asian and non-Asian populations, despite differences in risk factor profiles; whether risk factors act similarly in these populations is unknown. AIM: To study the associations between five major risk factors and stroke risk, comparing Asian with non-Asian men. METHODS: We obtained data from the Asia Pacific Cohort Studies Collaboration, a pooled analysis of individual participant data from 44 studies involving 386 411 men with 9.4 years follow-up. Using cohorts from Asia and Australia/New Zealand Cox models were fitted to estimate risk factor associations for ischemic and haemorrhagic stroke. RESULTS: We identified significant, positive associations between all five risk factors and risk of ischemic stroke. The associations between body mass index, smoking, and diabetes with ischemic stroke were comparable for men from Asia and Australia/New Zealand. The association between systolic blood pressure and ischemic stroke was stronger for Asian than Australia/New Zealand cohorts, whereas the reverse was true for total cholesterol. For haemorrhagic stroke, only systolic blood pressure and smoking were associated with increased risk, although the relationship with systolic blood pressure was significantly stronger for men from Asia than Australia/New Zealand (P interaction = 0.03), whereas the reverse was true for smoking (P interaction = 0.001). There was an inverse trend of total cholesterol with haemorrhagic stroke, significant only for Asian men. CONCLUSIONS: Men from the Asia-Pacific region share common risk factors for stroke. Strategies aimed at lowering population levels of systolic blood pressure, total cholesterol, body mass index, smoking, and diabetes are likely to be beneficial in reducing stroke risk, particularly for ischemic stroke, across the region. PMID- 24148095 TI - Neonatal IGF-1/IGFBP-1 axis and retinopathy of prematurity are associated with increased blood pressure in preterm children. AB - AIM: Preterm children are at risk of developing increased blood pressure (BP). We evaluated possible associations between BP, early insulin-like growth factor-1 (IGF-1) and IGF-binding protein-1 (IGFBP-1) levels and retinopathy of prematurity (ROP) in preterm children. METHODS: The study included 32 infants: median gestational age 28.1 weeks (range 24.6-31.3) and birthweight standard deviation scores (SDS) (+/-SD) 1.0 +/- 2.7. IGF-1 and IGFBP-1 at postnatal weeks 32.6-34.6 and ROP stages were established after birth. BP was measured at the age of 4 years. The ratio (IGF-1)(2)/IGFBP-1 was created to investigate the influence of both IGF-1 and IGFBP-1 to later BP. RESULTS: Diastolic BP correlated with IGFBP 1, inversely correlated with IGF-1 and IGF-1(2)/IGFBP-1 (r = -0.71, p < 0.0001) and positively correlated with catch-up growth velocity from lowest weight SDS to age 36.5 weeks (r = 0.48, p < 0.01), independent of gestational age. Children with moderate-to-severe ROP as neonates had higher mean arterial BP [78 (+/-95%CI 74-83) vs 71 (+/-95%CI 68-75) mm Hg, p < 0.05] adjusted for gestational age and birthweight SDS compared to children diagnosed with no to mild ROP. CONCLUSION: Low neonatal IGF-1(2)/IGFBP-1 and severe ROP were associated with higher BP in 4 year-old children born very preterm and may thus predict future cardiovascular morbidity. PMID- 24148096 TI - Astrocyte-restricted disruption of connexin-43 impairs neuronal plasticity in mouse barrel cortex. AB - There is intensive gap-junctional coupling between glial processes, but their significance in sensory functions remains unknown. Connexin-43 (Cx43), a major component of astrocytic gap-junction channels, is abundantly expressed in astrocytes. To investigate the role of Cx43-mediated gap junctions between astrocytes in sensory functions, we generated Cx43 knockout (KO) mice with a mouse line carrying loxP sites flanking exon 2 of the Cx43 gene and the transgenic line expressing Cre recombinase under control of the glial fibrillary acidic protein promoter, which exhibited a significant loss of Cx43 in astrocytes in the barrel cortex. Although Cx43 expression between the astrocytes measured by immunohistochemistry was virtually abolished in Cx43 KO mice, they had normal architecture in the barrel cortex but the intensity of cytochrome oxide histochemistry decreased significantly. In vivo electrophysiological analysis revealed that the long-term potentiation of the vibrissal evoked responses in the barrel cortex evoked by high-frequency rhythmic vibrissal stimuli (100 Hz, 1 s) was abolished in Cx43 KO mice. Current source density analysis also revealed that astrocytic Cx43 was important to the flow of excitation within the laminar connections in barrel cortex. Behavioral tests showed that the ability of Cx43 KO mice to sense the environment with their whiskers decreased. Even so, the jump stand experiment showed that they could still discriminate rough from smooth surfaces. Our findings suggest that Cx43-mediated gap-junctional coupling between astrocytes is important in the neuron-glia interactions required for whisker related sensory functions and plasticity. PMID- 24148097 TI - Investigation on flavonoid composition and anti free radical potential of Sida cordata. AB - BACKGROUND: Sida cordata, a member of Family Malvaceae is used in folk medicine for various ailments including liver diseases. In this study we investigated, its flavonoid constituents, in vitro antioxidant potential against different free radicals and hepatoprotection against carbon tetrachloride (CCl4)-induced liver damage in rat. METHODS: Dried powder of S. cordata whole plant was extracted with methanol and the resultant (SCME) obtained was fractionated with escalating polarity to obtain n-hexane fraction (SCHE), ethyl acetate fraction (SCEE), n butanol fraction (SCBE) and the remaining soluble portion as aqueous fraction (SCAE). Diverse in vitro antioxidants assays such as DPPH, H2O2, *OH, ABTS, beta carotene bleaching assay, superoxide radical, lipid peroxidation, reducing power, and total antioxidant capacity were studied to assess scavenging potential of methanol extract and its derived fractions. On account of marked scavenging activity SCEE was selected to investigate the hepatoprotective potential against CCl4 induced toxicity in Sprague-Dawley male rats by assessing the level of serum markers (alkaline phosphatase, alanine transaminase, aspartate transaminase, lactate dehydrogenase, bilirubin, and gamma-glutamyltransferase) and of liver antioxidant enzymes such as catalase (CAT), superoxide dismutase (SOD), peroxidase (POD), glutathione-S-transfers (GST), glutathione reductase (GSR), glutathione peroxidase (GSH-Px), and reduced glutathione (GSH) and lipid peroxidation (TBARS). Histology of the liver was performed to study alteration in histoarchitecture. Existence of active flavonoids was established by thin layer chromatographic studies. RESULTS: Considerable amount of flavonoid and phenolic contents were recorded in the methanol extract and its derived fractions. Although the extract and all its derived fractions exhibited good antioxidant activities however, the most distinguished scavenging potential was observed for SCEE. Treatment of SCEE decreased the elevated level of serum marker enzymes induced with CCl4 administration whereas increased the activity of hepatic antioxidant enzymes (CAT, SOD, POD, GST, GSR and GSH-Px). Hepatic concentration of GSH was increased while lipid peroxidation was decreased with SCEE administration in CCl4 intoxicated rats. Presence of apigenin with some unknown compounds was observed in SCEE by using thin layer chromatography. CONCLUSIONS: These results revealed the presence of some bioactive compound in the ethyl acetate fraction, confirming the utility of S. cordata against liver diseases in folk medicine. PMID- 24148099 TI - Expression of the stem cell marker, SOX2, in ameloblastoma and dental epithelium. AB - Ameloblastomas are locally invasive odontogenic tumors that exhibit a high rate of recurrence and often associate with the third molars. They are suggested to originate from dental epithelium because the tumor cells resemble epithelial cells of developing teeth. Expression of the transcription factor SOX2 has been previously localized in epithelial stem and progenitor cells in developing teeth as well as in various tumors. Here, we show that SOX2 is expressed in the epithelial cells of follicular and plexiform ameloblastomas. SOX2 was localized in the dental lamina of developing human primary molars. It was also expressed in the fragmented dental lamina associated with the third molars and in the epithelium budding from its posterior aspect in mice. However, no SOX2 expression was detected in either Hertwig's epithelial root sheath directing the formation of roots or in the epithelial cell rests of Malassez covering the completed roots. SOX2 was associated with supernumerary tooth formation in odontoma-like tumors induced by Wnt signal activation in mice. We propose that SOX2 functions in maintaining the progenitor state of epithelium in ameloblastomas and that ameloblastomas may originate from SOX2-expressing dental lamina epithelium. PMID- 24148098 TI - Binding to any ESCRT can mediate ubiquitin-independent cargo sorting. AB - The ESCRT (endosomal sorting complex required for transport) machinery is known to sort ubiquitinated transmembrane proteins into vesicles that bud into the lumen of multivesicular bodies (MVBs). Although the ESCRTs themselves are ubiquitinated they are excluded from the intraluminal vesicles and recycle back to the cytoplasm for further rounds of sorting. To obtain insights into the rules that distinguish ESCRT machinery from cargo we analyzed the trafficking of artificial ESCRT-like protein fusions. These studies showed that lowering ESCRT binding affinity converts a protein from behaving like ESCRT machinery into cargo of the MVB pathway, highlighting the close relationship between machinery and the cargoes they sort. Furthermore, our findings give insights into the targeting of soluble proteins into the MVB pathway and show that binding to any of the ESCRTs can mediate ubiquitin-independent MVB sorting. PMID- 24148100 TI - Seasonal patterns in microbial communities inhabiting the hot springs of Tengchong, Yunnan Province, China. AB - Studies focusing on seasonal dynamics of microbial communities in terrestrial and marine environments are common; however, little is known about seasonal dynamics in high-temperature environments. Thus, our objective was to document the seasonal dynamics of both the physicochemical conditions and the microbial communities inhabiting hot springs in Tengchong County, Yunnan Province, China. The PhyloChip microarray detected 4882 operational taxonomic units (OTUs) within 79 bacterial phylum-level groups and 113 OTUs within 20 archaeal phylum-level groups, which are additional 54 bacterial phyla and 11 archaeal phyla to those that were previously described using pyrosequencing. Monsoon samples (June 2011) showed increased concentrations of potassium, total organic carbon, ammonium, calcium, sodium and total nitrogen, and decreased ferrous iron relative to the dry season (January 2011). At the same time, the highly ordered microbial communities present in January gave way to poorly ordered communities in June, characterized by higher richness of Bacteria, including microbes related to mesophiles. These seasonal changes in geochemistry and community structure are likely due to high rainfall influx during the monsoon season and indicate that seasonal dynamics occurs in high-temperature environments experiencing significant changes in seasonal recharge. Thus, geothermal environments are not isolated from the surrounding environment and seasonality affects microbial ecology. PMID- 24148101 TI - Short-term health service utilization after a paediatric injury: a population based study. AB - BACKGROUND: The aim of the study is to identify which types of injuries are responsible for a major component of the health burden in a population-based children cohort in North-Eastern Italy. METHODS: All children (1-13 years) residing in Veneto region, who were hospitalized in 2008 with a International Classification of Diseases, ninth edition, Clinical Modification (ICD-9-CM) code for injury in the first diagnostic field were considered. The outcome was defined as the difference in hospital use in the 12 months following the injury and it was compared to the year preceding the injury occurrence. We computed hospitalization rates by gender, age class and injury type. RESULTS: Hospitalization rates for injury are highest in males, especially among school aged children. Rates for intracranial injury exhibit a more pronounced decline with age in females, whereas a more marked rise in upper limb fracture rates among school-aged males is observed. Overall, 3 days of hospital stay per child are attributable to injury. Burns, skull fracture and a high injury severity are associated with a greater number of additional inpatient days. CONCLUSIONS: The impact of specific injury types on health services utilization varies with gender, age and severity. These observed patterns contribute to build a clearer picture of this leading global public health problem and deserve more attention in planning preventive strategies and resource allocation. PMID- 24148103 TI - A test of the revised auricular surface aging method on a modern European population. AB - The accurate age estimation of adults is an important step in the construction of the biological profile of skeletonized remains. The auricular surface of the ilium as it was developed in 1985 by Lovejoy et al., is one of the methods employed for age estimation. This study presents the results of a blind test of the revised auricular surface aging method developed by Buckberry and Chamberlain. A sample of 120 individuals from the Athens Collection was used to test this revised aging technique. Almost all features and composite score were positively correlated with known age-at-death. The calculation of bias demonstrated no obvious trend for either overestimation or underestimation of age when all individuals were pooled together. Inaccuracy showed that absolute errors of estimated ages against known ages are substantial. The data generated from this study suggest that the revised method can be reliable for age estimation on a modern European population. PMID- 24148102 TI - Clinicopathologic features and responses to radiotherapy of myeloid sarcoma. AB - BACKGROUND: To evaluate clinicopathological features, radiotherapeutic parameters, and their associations with responses to radiotherapy (RT) in patients with myeloid sarcoma (MS). METHODS: We reviewed 20 patients receiving RT for MS lesions (in 43 RT courses) and analyzed the patients' clinicopathologic features and radiotherapeutic parameters, and their associations with complete responses (CR) to RT using Fisher's exact test and univariate logistic regression analysis. Generalized Estimating Equation was used to analyze all 43 irradiated lesions and account for the correlations in RT responses among lesions from the same patient. RESULTS: We found that the underlying hematological diseases of the evaluated patients were acute myeloid leukemia (AML) in 14 patients (70%), chronic myeloid leukemia in 4 patients (20%), myelodysplastic syndrome with AML transformation in one patient (5%), and de novo MS in one patient (5%). Most patients (55%) received RT for MS at the time of relapse following bone marrow transplantation (BMT). The most common cytogenetic abnormality was t(8;21)(q22;q22). The median RT dose of 20 Gy (range 6-35 Gy), administered in 1.5-3.5 Gy fractions, provided a 63% CR rate. RT dose, sex, cytogenetics, and bone marrow status at the time of RT had no significant effect on CR. Younger age (<50 y, P = 0.06), BMT prior to RT (P = 0.05), and underlying AML (P = 0.05) were marginally associated with higher CR to RT. CONCLUSIONS: Our results indicate that a modest RT dose (20-30 Gy) achieves good local control of MS. Age, previous BMT, and underlying hematologic disease can affect RT response. PMID- 24148104 TI - Prescription of antidepressants and the risk of road traffic crash in the elderly: a case-crossover study. AB - AIM: To investigate the impact of antidepressants on the risk of road traffic crash in the elderly. METHODS: Reports from the Universal Quebec Automobile Insurance Agency database were matched with data on antidepressant prescription from the Quebec Health Insurance Agency. The case-crossover analysis consisted in comparing exposure during a period immediately before the crash with exposure during earlier periods, for the same subject. RESULTS: One hundred and nine thousand four hundred and six drivers between 66 and 84 years of age involved in a traffic crash between 1988 and 2000 were included. Two thousand nine hundred and nineteen (2.7%) were exposed to an antidepressant on the day of the crash. Case-crossover analysis found an increased risk of crash in drivers with a prescription of antidepressants before their crash when compared with a prescription of antidepressants 4 to 8 months before the crash (OR = 1.19, 95% CI 1.08, 1.30 to 1.42. 95% CI 1.30, 1.55). With the most recent control periods, results were not significant. CONCLUSION: A patient's mental state is probably more similar between two periods that are close to each other than up to 8 months before. Consequently, the risk of crash is likely to be linked to symptoms of depression. PMID- 24148106 TI - Effect of the serotonin transporter gene and of environment on the continuity of anxiety and depression traits throughout adolescence. AB - Aims. Many studies of various stress reactive phenotypes suggest that 5-HTTLPR short allele carriers (S-carriers) are characterised by the stable trait of negative affectivity that is converted to psychopathology only under conditions of stress. In this study, we examined the moderating role of the 5-HTTLPR on the relationship between two objective chronic risk factors, i.e. socioeconomic status (SES) and family structure, and internalising symptoms across adolescence. Methods. A multigroup path analysis was employed in a general adolescent population sample of a 5-year follow-up study. Results. Internalising problems were significantly more stable in the S-carriers. The focus on the main dimensions of internalising problems, i.e. anxiety and depression, revealed two different developmental patterns. In the S-carriers Anxiety problems seemed to be more stable and to predict a possible evolution towards the development of Depressive problems. In the long allele homozygotes (LL-subjects) the anxiety trait was significantly less stable, and, in late-adolescence, seemed to be significantly predicted by SES, suggesting a possible gene-environment interaction (G * E). Family structure seemed to play a role in a G * E perspective only until early-adolescence, while during late-adolescence SES seemed to play a pivotal role in interaction with 5-HTTLPR, with the S-allele playing a protective role. Conclusions. Future models of the developmental link between environmental adversities and internalising behaviour therefore need to consider that the effect of G * E interaction, may be associated with internalising behaviour via different mechanisms during different time frames and that shifts in the strength of this effect should be expected across development. PMID- 24148107 TI - Life with compass: diversity and biogeography of magnetotactic bacteria. AB - Magnetotactic bacteria (MTB) are unique in their ability to synthesize intracellular nano-sized minerals of magnetite and/or greigite magnetosomes for magnetic orientation. Thus, they provide an excellent model system to investigate mechanisms of biomineralization. MTB play important roles in bulk sedimentary magnetism and have numerous versatile applications in paleoenvironmental reconstructions, and biotechnological and biomedical fields. Significant progress has been made in recent years in describing the composition of MTB communities and distribution through innovative cultivation-dependent and -independent techniques. In this review, the most recent contributions to the field of diversity and biogeography of MTB are summarized and reviewed. Emphasis is on the novel insights into various factors/processes potentially affecting MTB community distribution. An understanding of the present-day biogeography of MTB, and the ruling parameters of their spatial distribution, will eventually help us predict MTB community shifts with environmental changes and assess their roles in global iron cycling. PMID- 24148108 TI - Increased population drinking is not always associated with increased number of drink driving convictions. PMID- 24148109 TI - Attitudes toward working in rural areas of Thai medical, dental and pharmacy new graduates in 2012: a cross-sectional survey. AB - BACKGROUND: Inequity in health workforce distribution has been a national concern of the Thai health service for decades. The government has launched various policies to increase the distribution of health workforces to rural areas. However, little is known regarding the attitudes of health workers and the factors influencing their decision to work in rural areas. This study aimed to explore the current attitudes of new medical, dental and pharmacy graduates as well as determine the linkage between their characteristics and the preference for working in rural areas. METHODS: A cross-sectional survey was conducted, using self-administered questionnaires, with a total of 1,225 medical, dental and pharmacy graduates. They were participants of the meeting arranged by the Ministry of Public Health (MOPH) on 1-2 April 2012. Descriptive statistics using mean and percentage, and inferential statistics using logistic regression with marginal effects, were applied for data analysis. RESULTS: There were 754 doctors (44.4%), 203 dentists (42.6%) and 268 pharmacists (83.8%) enrolled in the survey. Graduates from all professions had positive views towards working in rural areas. Approximately 22% of doctors, 31% of dentists and 52% of pharmacists selected 'close proximity to hometown' as the most important reason for workplace selection. The multivariable analysis showed a variation in attributes associated with the tendency to work in rural areas across professions. In case of doctors, special track graduates had a 10% higher tendency to prefer rural work than those recruited through the national entrance examination. CONCLUSIONS: The majority of graduates chose to work in community hospitals, and attitudes towards rural work were quite positive. In-depth analysis found that factors influencing their choice varied between professions. Special track recruitment positively influenced the selection of rural workplaces among new doctors attending the MOPH annual meeting for workplace selection. This policy innovation should be applied to dentists and pharmacists as well. However, implementing a single policy without supporting strategies, or failing to consider different characteristics between professions, might not be effective. Future study of attitudes and factors contributing to the selection of, and retention in, rural service of both new graduates and in-service professionals was recommended. PMID- 24148110 TI - Design of (99m) Tc-DTPA-CLP and preliminary evaluation in rats. AB - Radiopharmaceuticals are localized in (malignant) tumor tissues by different mechanisms. One of these mechanisms, gelatinase enzyme activity, is associated with poor prognosis in cancer patients and potential targets for tumor imaging. There are some gelatinases to be associated with metastatic potential for tumor imaging to possibly predict metastases. In this study, a cyclic decapeptide conjugate, DTPA-CLP (DTPA-Cys-Leu-Pro-Gly-His-Trp-Gly-Phe-Pro-Ser-Cys), was selected as a peptide conjugate because of its selective inhibitory activity toward gelatinases. Peptide-conjugated DTPA-CLP was labeled with (99m) Tc with a radiolabeling efficiency of 97.0 +/- 2.8%. After determining optimization conditions for radiolabeling, a biodistribution study of radiolabeled peptide in albino Wistar rats was performed. According to biodistribution data, (99m) Tc DTPA-CLP showed high uptake in the lung, liver, uterus, and spleen. These results show that (99m) Tc-DTPA-CLP may be used for the imaging of gelatinase activity in metastatic tumors. PMID- 24148111 TI - Transcranial direct current stimulation (tDCS): does it have merit in stroke rehabilitation? A systematic review. AB - Transcranial direct current stimulation has been gaining increasing interest as a potential therapeutic treatment in stroke recovery. We performed a systematic review with meta-analysis of randomized controlled trials to collate the available evidence in adults with residual motor impairments as a result of stroke. The primary outcome was change in motor function or impairment as a result of transcranial direct current stimulation, using any reported electrode montage, with or without adjunct physical therapy. The search yielded 15 relevant studies comprising 315 subjects. Compared with sham, cortical stimulation did not produce statistically significant improvements in motor performance when measured immediately after the intervention (anodal stimulation: facilitation of the affected cortex: standardized mean difference = 0.05, P = 0.71; cathodal stimulation: inhibition of the nonaffected cortex: standardized mean difference = 0.39, P = 0.08; bihemispheric stimulation: standardized mean difference = 0.24, P = 0.39). When the data were analyzed according to stroke characteristics, statistically significant improvements were evident for those with chronic stroke (standardized mean difference = 0.45, P = 0.01) and subjects with mild-to moderate stroke impairments (standardized mean difference = 0.37, P = 0.02). Transcranial direct current stimulation is likely to be effective in enhancing motor performance in the short term when applied selectively to patients with stroke. Given the range of stimulation variables and heterogeneous nature of stroke, this modality is still experimental and further research is required to determine its clinical merit in stroke rehabilitation. PMID- 24148112 TI - [Preterm birth]. PMID- 24148113 TI - [Bronchopulmonary dysplasia and genetics]. PMID- 24148115 TI - [In utero growth retardation and bronchopulmonary dysplasia]. PMID- 24148114 TI - [Inflammation and bronchopulmonary dysplasia]. PMID- 24148116 TI - [Can we analyze the cerebral development of preterm newborns?]. PMID- 24148117 TI - [Unbalanced elastase/alpha1-antitrypsin ratio: a new player in the development of obesity and metabolic syndrome]. PMID- 24148118 TI - [SSR128129E, an extracellularly acting, small-molecule, allosteric inhibitor of FGF receptor signaling]. PMID- 24148119 TI - [Anti-viral treatment: pro or cons type I IFN?]. PMID- 24148120 TI - [Leucine sensing in the regulation of autophagy: glutamate dehydrogenase is on the way]. PMID- 24148121 TI - [Host epigenetic targeting by Legionella pneumophila]. PMID- 24148122 TI - [Xenobiotics and the active gut microbiome: unknown effects unveiled]. PMID- 24148123 TI - [Structure of the Smoothened receptor]. AB - The Smoothened (Smo) receptor is a major component involved in signal transduction of the Hedgehog (Hh) morphogens both during embryogenesis and in the adult. Smo antagonists represent a promi-sing alternative for the treatment of cancers linked to abnormal Hh signalling. The crystal structure of the human Smo receptor bound to an antitumour agent demonstrates that this receptor belongs to the superfamily of G-protein coupled receptors. The antagonist binds to a pocket localized at the extracellular side formed by the seven transmembrane domains and the complex arrangement of the unusually long extracellular loops. The structure of the Smo receptor will promote the development of small molecules interacting with a key therapeutic target with interests in regenerative medicine and cancer. PMID- 24148124 TI - [microRNA: new diagnostic and therapeutic tools in liver disease?]. AB - microRNA are small non coding RNA, which negatively regulate the expression of their targets. Due to their various targets, miRNAs play a key role in number of physiological processes and in oncogenesis. The identification of specific miRNA signatures in various types of tumours, including hepatocellular carcinoma (HCC), highlights the dual role of miRNA, both oncogenes and tumour suppressors. Here, we review the current knowledge concerning the deregulation of miRNA expression in liver disease. All studies focusing on miRNAs argue for their possible use as diagnostic, prognostic and therapeutic markers. Here, we preferentially discuss the promising therapeutic strategies based on miRNAs that have been tested in HCC. PMID- 24148125 TI - [The world according to YAP: a continuous cross-talk between Wnt and Hippo pathways]. AB - Since many years, Wnt canonical pathway was known to be involved in proliferation and cell fate. More recently, Hippo pathway has been recognized as a major actor in the control of organ size homeostasis. Both pathways are induced in the activation of stem cells, modulated during carcinogenesis and both use a second messenger, a cascade of phosphorylations and the same ubiquitin ligase degradation complex. Enough for their roads to cross! This review highlights the recent advances in the understanding of the complex crosstalks between Wnt/beta catenin and Hippo/YAP pathways, focusing on two tissues, liver and intestine. In the future, we hope that the identification of the molecular mechanisms underlining these entangled relationships will open towards novel therapeutic strategies for digestive carcinogenesis. PMID- 24148126 TI - [Electrophysiological, molecular and genetic identifications of the pre-Botzinger complex]. AB - From birth onwards, rhythmic breathing is required for blood oxygenation and survival in mammals. During their lifespan, human or mouse or elephant will spontaneously produce several hundreds of millions of respiratory movements. The central nervous command responsible for these spontaneous rhythmic movements is elaborated by a complex neural network extending within the brainstem. In the medulla, a special part of this network contains respiratory pacemaker neurons that play a crucial role in respiratory rhythmogenesis: the pre-Botzinger complex. This review summarizes and discusses the main electrophysiological, molecular and genetic mechanisms contributing to the function and the perinatal maturation of the pre-Botzinger complex. PMID- 24148127 TI - [Gene therapy for human hearing loss: challenges and promises]. AB - Thanks to the advances accomplished in human genomics during the last twenty years, major progress has been made towards understanding the pathogenesis of various forms of congenital or acquired deafness. The identification of deafness genes, which are potential therapeutic targets, and generation and functional characterization of murine models for human deafness forms have advanced the knowledge of the molecular physiology of auditory sensory cells. These milestones have opened the way for the development of new therapeutic strategies, alternatives to conventional prostheses, hearing amplification for mild-to-severe hearing loss, or cochlear implantation for severe-to-profound deafness. In this review, we first summarize the progress made over the last decade in using gene therapy and antisense RNA delivery, including the development of new methods for cochlear gene transfer. We then discuss the potential of gene therapy for curing acquired or inherited deafness and the major obstacles that must be overcome before clinical application can be considered. PMID- 24148128 TI - [Clathrin-independent endocytosis: free the way!]. AB - Along the years, the interest paid to the study of endocytosis has never wavered as this process plays such an essential role in many cellular functions. Cell growth, adhesion and differentiation, regulation of signaling induced by membrane receptors or infection by viral particles are all dependent on the entry of molecules into the cell. Once the clathrin-dependent endocytosis well characterized, it has become apparent that other entry pathways also existed in the cell. This review is intended to provide an update on recent advances that establish with certainty the existence of endocytic pathways independent of clathrin and highlight their specific regulators. PMID- 24148129 TI - [Phenotypic screens or one stone to kill two birds: discover the target and its pharmacological regulator]. AB - Phenotypic screens, in which chemical libraries are assayed on cells with the aim to isolate compounds that interfere with a given cell function, are a risky but powerful strategy to discover, in the same approach, new therapeutic targets and the compounds able to regulate them. With a strong experience of nearly 10 years in the field, we present the advantages of such an approach, the possible troubles and technical solutions. We also present in this paper a french network which has been recently built and that gather all the competencies needed for screening approaches. PMID- 24148130 TI - [The international network of Pasteur Institutes: an active witness of the French scientific diplomacy]. PMID- 24148131 TI - [Tuberculosis and HIV co-infection: clinical trial under the coordination of the Institut Pasteur in Cambodia]. AB - Tuberculosis is a major cause of death among adults infected by HIV. The CAMELIA (ANRS 1295/CIPRA KH001) randomized clinical trial aimed to determine the optimal timing of ARV initiation after tuberculosis treatment onset to reduce mortality. Here, we describe the trial implementation in five hospitals in Cambodia under the coordination of the Institut Pasteur in Cambodia, its conduct, the challenges and public health benefits in Cambodia and beyond. PMID- 24148132 TI - [Buruli ulcer: a dynamic transversal research model performed through the international network of Pasteur Institutes]. AB - Buruli ulcer is an endemic severe human skin disease caused by Mycobacterium ulcerans, which prevails in western Africa in swampy areas and primarily hits children. Its gravity comes from the extent of tissue destruction, created by the toxin mycolactone. We describe here how the Centre Pasteur of Cameroon, with the help of the ministry of Health, gathered a network of multidisciplinary partners to fight against Buruli ulcer starting in the years 2000. The Centre Pasteur develops three missions : patient care, training of health care workers and research on the insect vector. Ten years of efforts resulted in significant medical advances such as the design of an early diagnostic test using PCR, or the observation that bed net use significantly decreased the risk of Buruli ulcer, offering useful prevention ; on the research side, entomological studies on aquatic bugs, coupled with epidemiological data, point to the role of these insects in the transmission of the disease. This study examplifies how an efficient network can contribute to the prevention and treatment of debilitating infectious diseases. PMID- 24148133 TI - [Race and medicine]. AB - In this article, I argue that the problematic of "race and medicine", which has been the object of many recent debates, has a long history that it may be useful to understand better. I show more specifically that, from the very first uses of the concept of "race" in natural history during the XVIII(th) century, medical concepts and analogies served as important models. These medical models were especially useful to analyze "races" as alterations from an original identity. Different analogies are studied here. 1. The analogy between races' peculiar temperaments and morbid alterations of human constitution. 2. The analogy between the transmission of the alterations along generations and hereditary diseases. In this second analogy, I differentiate between two models: the degeneration of the human type and the transmission of a molecular alteration of one character. PMID- 24148134 TI - [Eating my hat?]. AB - After clearing many hurdles, gene therapy is now reaching the commercialization stage and can be expected to make a modest but real contribution to treatment in the near future. PMID- 24148135 TI - Progression from new methicillin-resistant Staphylococcus aureus colonisation to infection: an observational study in a hospital cohort. AB - BACKGROUND: Patients newly colonised with methicillin-resistant Staphylococcus aureus (MRSA) are at higher risk of clinical MRSA infection. At present, there are limited data on the duration or magnitude of this risk in a hospital population with a known time of MRSA acquisition. METHODS: A retrospective cohort study of 909 adult patients known to have newly identified MRSA colonisation during admission to National University Hospital, Singapore between 1 July 2007 and 30 June 2011 was undertaken. Patients were excluded if they had history of previous MRSA colonisation or infection, or if they had been a hospital inpatient in the preceding 12 months. Data were collected on the development of MRSA infection requiring hospitalisation up to 30 June 2012. RESULTS: Of 840 patients newly colonised with MRSA as identified on active surveillance and not clinical specimens, 546 were men (65.0%) and the median age was 65 years (range 18-103 years). Median follow up was 24 months (range 0 -64 months, 85.1% followed >6 months). Clinical infection occurred in 121 patients (14.4%) with median time to infection of 22 days (95% CI 14-31). Overall 71.9% (87/121) of infected patients developed infection within 60 days of the date MRSA colonisation was detected. However, 17/121 patients (14.0%) developed clinical infection more than six months after documented MRSA acquisition. The most common sites of clinical infection were skin and soft tissue (49/121, 40.5%, 95% CI 31.7-49.8), respiratory tract (37/121, 30.6%, 95% CI 22.5-39.6) and bone and joint infections (14/121, 11.6%, 95% CI 6.5-18.7). Thirteen patients (13/121, 10.7%, 95% CI 5.8 17.7) had bacteraemias, of which six (5.0% 95% CI 1.8-10.5) were primary and seven (5.7%, 95% CI 2.3-11.6) were secondary to infection at other sites. Crude mortality at 30 days and six months was higher in patients with MRSA infection than colonisation alone (aOR 5.49, 95% CI 2.75-10.95, p<0.001 and aOR 2.94, 95% CI 1.78-4.85, p<0.001 respectively). CONCLUSION: Risk of clinical infection is highest soon after MRSA acquisition. Prevention of MRSA acquisition in hospital will have significant impact on morbidity and mortality for patients. PMID- 24148136 TI - Nocturnal blood pressure non-dipping is prevalent in severely obese, prepubertal and early pubertal children. AB - AIM: To investigate the prevalence of nocturnal blood pressure dipping among obese prepubertal and early pubertal children and to analyse the relationship between dipping and measures of insulin-glucose metabolism or sleep-disordered breathing. METHODS: We studied 76 obese children (41% girls) under clinical care, with an average age of 10.4 +/- 1.7 and a body mass index Z-score (BMI Z-score) of 6.2 +/- 1.6. We performed a 24-h ambulatory blood pressure measurement. Non dipping was defined as a nocturnal blood pressure reduction of <10%. We calculated measures of insulin-glucose metabolism from the performed frequently sampled intravenous glucose-tolerance test and from fasting blood samples. Overnight sleep polygraph recordings were performed to assess sleep-disordered breathing. RESULTS: Forty-two percent of the children were systolic non-dippers, and 17% were diastolic non-dippers. There were no associations between systolic or diastolic dipping and measures of insulin-glucose metabolism after adjustments for BMI Z-score, gender and pubertal status. There were no associations between dipping and measures of sleep-disordered breathing. CONCLUSION: Nocturnal non dipping was two times higher among severely obese, prepubertal and early pubertal children, compared to previous reports among children in general. There were no associations between nocturnal dipping and insulin-glucose metabolism or measures of sleep-disordered breathing in this group. PMID- 24148137 TI - A test of the efficacy of a brief, web-based personalized feedback intervention to reduce drinking among 9th grade students. AB - Alcohol use increases substantially during the transition from middle school to high school. This study tested a brief, web-based personalized feedback program aimed at reducing risk factors for drinking, alcohol use, and alcohol-related consequences among 9th grade students. At a 3-month follow-up, students in the intervention group showed positive results relative to those in the control group on variables associated with reduced risk, including positive alcohol expectancies and positive beliefs about alcohol. Students in the intervention group also reported a reduction in drinking frequency and alcohol-related consequences relative to those in the control group. There were, however, no differences in normative beliefs regarding peer drinking or quantity of weekly drinking between the two groups. Results indicate that a brief, web-based personalized normative feedback program delivered in the school setting is a promising approach to reducing alcohol use and the associated consequences among 9th grade students. PMID- 24148138 TI - Gender, history of alcohol use and number of drinks consumed predict craving among drinkers in a field setting. AB - To the extent that craving serves to compel excessive drinking, it would be important to predict the intensity of an individual's craving over the course of a drinking episode. Previous research indicates that regular alcohol use (measured by the AUDIT) and the number of drinks individuals have already consumed that evening independently predict craving to drink (Schoenmakers & Wiers, 2010). The current study aims to replicate those findings by testing whether these same variables predict craving to drink in a sample of 1320 bar patrons in a naturalistic setting. In addition, we extend those findings by testing whether regular alcohol use and self-reported number of drinks consumed interact to predict craving, and whether gender independently predicts craving or interacts with other variables to predict craving. Results indicate that for men, AUDIT score alone predicted craving, whereas for women, AUDIT score and number of drinks consumed interacted to predict craving, with craving highest among women with either high AUDIT scores or relatively high consumption levels. Our findings have implications for targeted intervention and prevention efforts, as women who have a history of harmful alcohol use and consume several drinks in an evening might be at the greatest risk for continued alcohol consumption. PMID- 24148139 TI - Construct validity of the short inventory of problems among Spanish speaking Hispanics. AB - OBJECTIVE: Research on ethnic health disparities requires the use of psychometrically sound instruments that are appropriate when applied to ethnically diverse populations. The Short Inventory of Problems (SIP) assesses alcohol-related consequences and is often used as a measure to evaluate intervention effectiveness in alcohol research; however, whether the psychometric properties of this instrument are comparable across language and ethnicity remains unclear. METHOD: Multi-group confirmatory factor analysis (MGCFA) was used to test for the invariance of the measurement structure of the SIP across White Non-Hispanic English speaking (N=642), Hispanic English speaking (N=275), and Hispanic Spanish speaking (N=220) groups. RESULTS: The MGCFA model in which factor loadings, measurement intercepts, and item residuals were constrained to be equal between English speakers and Spanish speakers exhibited a reasonable fit to the data, chi(2)(221)=1089.612 p<.001, TLI=.926; CFI=.922, RMSEA=.059 (90% CI=.055-.062). The DeltaCFI supported strict factorial invariance, DeltaCFI=.01, across groups; no significant group differences were found between factor loadings, measurement intercepts, or item residuals between English speakers and Spanish speakers. CONCLUSIONS: This study extends the existing confirmatory factor analysis results of the SIP by providing additional data to inform the utility of the SIP among Hispanics. Strict factorial invariance between Spanish and English speakers is necessary to: conclude that the underlying constructs have the same meaning across groups; test for group differences in the latent variables across groups; and presume that group differences are attributable only to true differences between groups. Thus, the SIP is strongly supported for evaluating the effectiveness of alcohol treatment among Hispanics. PMID- 24148141 TI - The endocrown: an alternative approach for restoring extensively damaged molars. AB - Endocrown-type restorations are single prostheses fabricated from reinforced ceramics that can be acid etched, indicated for endodontically treated molar teeth that have significant loss of coronal structure. Endocrowns are formed from a monoblock containing the coronal portion integrated into the apical projection that fills the pulp chamber space, and possibly the root canal entrances. In this study, the proposal was to discuss the indication and use of the endocrown to replace single crowns with intraradicular retention, and to present a clinical case report on the 3-year follow-up of an endocrown-type restoration, fabricated from injected lithium disilicate ceramic (IPS e.Max Press/Ivoclar Vivadent) in a mandibular first molar with extensive coronal destruction from fracture. It was found that endocrown restorations could be made following the development of reinforced ceramics that can be acid etched, that have aggregate strength and esthetics, that bond to the dental structure, and that have developed from broader knowledge of the biomechanical behavior of depulped teeth restored with and without intraradicular posts. Clinical studies have shown that the endocrown has functional longevity, and has become a promising alternative in the esthetic and functional recovery of endodontically treated molar teeth. CLINICAL SIGNIFICANCE: It should be borne in mind that endocrowns offer advantages for the restoration of depulped molar teeth, insofar as they promote adequate function and offer adequate esthetics, and also maintain the biomechanical integrity of the compromised structure of non-vital posterior teeth. By eliminating the use of a post and filling core, the number of adhesive bond interfaces is reduced, thus making the restoration less susceptible to the adverse effects of degradation of the hybrid layer. In this clinical case, the 3-year survival of the endocrown restoration may be considered successful. PMID- 24148140 TI - Characteristics and treatment interests among individuals with substance use disorders and a history of past six-month violence: findings from an emergency department study. AB - The study examined clinical characteristics and treatment interests of individuals identified to have substance use disorders (SUDs) in an urban emergency department (ED) who reported past six-month history of violence or victimization. Specifically, participants were 1441 ED patients enrolled in a randomized controlled trial of interventions designed to link those with SUDs to treatment. To examine factors related to violence type, four groups based on participants' reports of violence toward others were created: no violence (46.8%), partner violence only (17.3%), non-partner violence only (20.2%), and both partner and non-partner violence (15.7%). Four groups based on participants' reports of victimization were also created: no violence (42.1%), victimization from partner only (18.7%), victimization from non-partner only (20.2%), and both partner and non-partner victimization (17.7%). Separate multinomial logistic regression analyses were conducted to examine which variables distinguished the violence and victimization groups from those reporting no violence or victimization. For violence toward others, demographic variables, alcohol and cocaine disorders, and rating treatment for psychological problems were higher for violence groups, with some differences depending on the type of violence. For victimization, demographic variables, having an alcohol disorder, and rating treatment for family/social problems were higher for violence groups, also with some differences depending on the type of violence. Findings from the present study could be useful for designing effective brief interventions and services for ED settings. PMID- 24148142 TI - Growth stimulation in inflorescences of an Arabidopsis tubulin mutant under microgravity conditions in space. AB - Cortical microtubules are involved in plant resistance to hypergravity, but their roles in resistance to 1 g gravity are still uncertain. To clarify this point, we cultivated an Arabidopsis alpha-tubulin 6 mutant (tua6) in the Cell Biology Experiment Facility on the Kibo Module of the International Space Station, and analyzed growth and cell wall mechanical properties of inflorescences. Growth of inflorescence stems was stimulated under microgravity conditions, as compared with ground and on-orbit 1 g conditions. The stems were 10-45% longer and their growth rate 15-55% higher under microgravity conditions than those under both 1 g conditions. The degree of growth stimulation tended to be higher in the tua6 mutant than the wild-type Columbia. Under microgravity conditions, the cell wall extensibility in elongating regions of inflorescences was significantly higher than the controls, suggesting that growth stimulation was caused by cell wall modifications. No clear differences were detected in any growth or cell wall property between ground and on-orbit 1 g controls. These results support the hypothesis that cortical microtubules generally play an important role in plant resistance to the gravitational force. PMID- 24148143 TI - Balancing livestock production and wildlife conservation in and around southern Africa's transfrontier conservation areas. AB - Biodiversity conservation, of which the transfrontier conservation area movement is an integral part, and more effective livestock production/trade are pivotal to future rural development in southern Africa. For that reason, it is imperative to effectively ameliorate the obstacles that have impeded progress towards the coexistence of these two sectors for more than half a century. Transboundary animal diseases, foot and mouth disease in particular, have been and continue to be the most important of these obstacles. Fortunately, new developments in international sanitary standards applicable to trade in commodities and products derived from animals are beginning to make a solution possible. However, while progress in principle has been achieved, practical implementation remains problematic for technical reasons, exacerbated by inconsistent attitudes towards acceptance of non-traditional international trade standards. This paper describes the background to this situation, progress that has been achieved in the recent past and remaining difficulties that need to be overcome to advance towards achievement of balanced rural development in southern Africa. PMID- 24148144 TI - Linguistic and spatial skills predict early arithmetic development via counting sequence knowledge. AB - Utilizing a longitudinal sample of Finnish children (ages 6-10), two studies examined how early linguistic (spoken vs. written) and spatial skills predict later development of arithmetic, and whether counting sequence knowledge mediates these associations. In Study 1 (N = 1,880), letter knowledge and spatial visualization, measured in kindergarten, predicted the level of arithmetic in first grade, and later growth through third grade. Study 2 (n = 378) further showed that these associations were mediated by counting sequence knowledge measured in first grade. These studies add to the literature by demonstrating the importance of written language for arithmetic development. The findings are consistent with the hypothesis that linguistic and spatial skills can improve arithmetic development by enhancing children's number-related knowledge. PMID- 24148145 TI - The neural and linguistic basis of language development. PMID- 24148146 TI - Is the impaired N170 print tuning specific to developmental dyslexia? A matched reading-level study with poor readers and dyslexics. AB - Left N170 print tuning has been associated with visual expertise for print and has been reported to be impaired in dyslexics, using age matched designs. This is the first time N170 print tuning has been compared in adult dyslexics and adult poor readers, matched in reading level. Participants performed a lexical decision task using both word-like stimuli and symbol strings. In contrast to dyslexics, poor readers displayed similar N170 tuning to control expert readers, suggesting that impaired N170 specialization is a hallmark of developmental dyslexia. Our findings provide electrophysiological support for dyslexia being the result of abnormal specialization of the left occipito-temporal areas involved in the expert processing of print. Furthermore, as shown by correlations data and in accordance with the phonological mapping deficit theory, the impaired visual expertise for print described in dyslexics may have been caused by their core phonological deficits. PMID- 24148147 TI - Automated pulmonary nodule detection based on three-dimensional shape-based feature descriptor. AB - Computer-aided detection (CAD) can help radiologists to detect pulmonary nodules at an early stage. In pulmonary nodule CAD systems, feature extraction is very important for describing the characteristics of nodule candidates. In this paper, we propose a novel three-dimensional shape-based feature descriptor to detect pulmonary nodules in CT scans. After lung volume segmentation, nodule candidates are detected using multi-scale dot enhancement filtering in the segmented lung volume. Next, we extract feature descriptors from the detected nodule candidates, and these are refined using an iterative wall elimination method. Finally, a support vector machine-based classifier is trained to classify nodules and non nodules. The performance of the proposed system is evaluated on Lung Image Database Consortium data. The proposed method significantly reduces the number of false positives in nodule candidates. This method achieves 97.5% sensitivity, with only 6.76 false positives per scan. PMID- 24148149 TI - Electrochemical control of photoluminescence in two-dimensional MoS(2) nanoflakes. AB - Two-dimensional (2D) transition metal dichalcogenide semiconductors offer unique electronic and optical properties, which are significantly different from their bulk counterparts. It is known that the electronic structure of 2D MoS2, which is the most popular member of the family, depends on the number of layers. Its electronic structure alters dramatically at near atomically thin morphologies, producing strong photoluminescence (PL). Developing processes for controlling the 2D MoS2 PL is essential to efficiently harness many of its optical capabilities. So far, it has been shown that this PL can be electrically or mechanically gated. Here, we introduce an electrochemical approach to actively control the PL of liquid-phase-exfoliated 2D MoS2 nanoflakes by manipulating the amount of intercalated ions including Li(+), Na(+), and K(+) into and out of the 2D crystal structure. These ions are selected as they are crucial components in many bioprocesses. We show that this controlled intercalation allows for large PL modulations. The introduced electrochemically controlled PL will find significant applications in future chemical and bio-optical sensors as well as optical modulators/switches. PMID- 24148148 TI - Cyclobutane Pyrimidine Dimer Density as a Predictive Biomarker of the Biological Effects of Ultraviolet Radiation in Normal Human Fibroblast. AB - This study compared biological responses of normal human fibroblasts (NHF1) to three sources of ultraviolet radiation (UVR), emitting UVC wavelengths, UVB wavelengths, or a combination of UVA and UVB (solar simulator; emission spectrum, 94.3% UVA and 5.7% UVB). The endpoints measured were cytotoxicity, intra-S checkpoint activation, inhibition of DNA replication and mutagenicity. Results show that the magnitude of each response to the indicated radiation sources was best predicted by the density of DNA cyclobutane pyrimidine dimers (CPD). The density of 6-4 pyrimidine-pyrimidone photoproducts was highest in DNA from UVC irradiated cells (14% of CPD) as compared to those exposed to UVB (11%) or UVA UVB (7%). The solar simulator source, under the experimental conditions described here, did not induce the formation of 8-oxo-7,8-dihydroguanine in NHF1 above background levels. Taken together, these results suggest that CPD play a dominant role in DNA damage responses and highlight the importance of using endogenous biomarkers to compare and report biological effects induced by different sources of UVR. PMID- 24148150 TI - A description of two new species of Ligophorus Euzet & Suriano, (Monogenea: Ancyrocephalidae) from Malaysian mugilid fish using principal component analysis and numerical taxonomy. AB - Ligophorus belanaki n. sp. and Ligophorus kederai n. sp. are described from Liza subviridis Valenciennes, 1836 and Valamugil buchanani Bleeker, 1854, respectively. Ligophorus kederai n. sp. has fenestrated ventral anchors, while in L. belanaki n. sp. the ventral anchor is not fenestrated. Ligophorus belanaki n. sp. is similar to L. careyensis, one of its coexisting congeners, in the overall shape and size of hard parts, but differs in having a flat median piece in the structure of the AMP (antero-median protuberance of the ventral bar), copulatory organ with non-ornamented initial part and longer vaginal tube, compared to raised median piece in the AMP, ornamented initial part and comparatively shorter vaginal tube in L. careyensis. Ligophorus kederai n. sp. is similar to L. fenestrum, a coexisting congener, in having fenestrated ventral anchors, but differs in having longer points and narrower base. Ligophorus fenestrum, unlike L. kederai n. sp., also possesses fenestrated dorsal anchors. The principal component analysis (PCA) scatterplots indicate that the two new and eight known Ligophorus species from Malaysian mugilids can be differentiated based on the morphometries of their anchors, ventral bars and copulatory organ separately and when combined together. Numerical taxonomy (NT) analyses based on Jaccard's Index of Similarity and neighbour-joining clustering, is used to facilitate comparison of these two new species with the 50 known Ligophorus based on morphological and metric characters. The two new species are different from each other and the other 50 species in the overall shapes and sizes of hard parts, as indicated by the NT analyses. PMID- 24148151 TI - Design, synthesis and bioevaluation of novel N-substituted-3,5-bis(arylidene)-4 piperidone derivatives as cytotoxic and antitumor agents with fluorescent properties. AB - Ten new N-substituted-3,5-bis(arylidene)-4-piperidone derivatives (series 1 and 2) were synthesized and subsequently evaluated against human carcinoma cell lines SW1990, MIA PaCa-2, PG-BE1, NCI-H460, and SK-BR-3 for cytotoxic activity by the CCK-8 method, and their fluorescent properties were investigated as well. The compounds were confirmed to display greater cytotoxic activity to the neoplastic cells, and approximately 50% of the IC50 values were lower than 5 MUm. In particular, compounds 1a, 1c, 1d, and 1e bearing 3-bromophenyl groups were revealed as the most active antitumor drug candidates and had the average IC50 values of 1.94, 1.11, 1.16, and 0.817 MUm, respectively. Furthermore, their fluorescent properties were interesting and might contribute to the visualization of their distribution in tumor cells. Some possible reasons for the disparity between cytotoxic activity and fluorescent properties in the two series of compounds were explored. This study revealed high potential of these molecules for further development as fluorescent cytotoxic and antitumor agents. PMID- 24148152 TI - Successful retrieval using ultrathin transnasal esophagogastroduodenoscopy of a significant amount of residual tricyclic antidepressant following serious toxicity: a case report. AB - BACKGROUND: In Japan, ultrathin transnasal esophagogastroduodenoscopy (EGD) with a 4.9-mm diameter endoscope (Olympus XP260) is routinely used to examine the upper gastrointestinal tract. This procedure does not require sedation and does not affect vital signs. Gastric lavage is not empirically employed in the management of all poisoning patients. It is considered only for potentially life threatening overdoses when the procedure can be performed within 1 h of ingestion of the poison. However, there are no absolute indications for gastric lavage. EGD may increase the indications, efficiency and safety of gastric lavage in poisoning patients. FINDINGS: A 35-year-old female was admitted to our emergency department 2 h after ingesting multiple drugs, including a critical dose of the tricyclic antidepressant (TCA) amitriptyline, at which time she was confused and had a Glasgow Coma Scale score of 8 (E1V2M5). Endotracheal intubation was performed. To confirm the type of TCA and in order to determine whether gastric lavage was required, we decided to perform EGD. Endoscopy demonstrated adherence of residual drugs to the stomach wall, in a soluble form and not as a mass. Hence, gastric lavage was performed via the EGD to avoid passage of these drugs into the small bowel. The patient was extubated on day 2, without the development of complications such as aspiration pneumonia, and was discharged on day 5. CONCLUSION: EGD may be useful in poisoning patients for determining the amount of residual drug in the stomach, also allowing direct observation of the effectiveness of gastric lavage. PMID- 24148153 TI - The TREAT-NMD care and trial site registry: an online registry to facilitate clinical research for neuromuscular diseases. AB - BACKGROUND: Rare diseases pose many research challenges specific to their scarcity. Advances in potential therapies have made it more important than ever to be able to adequately identify not only patients with particular genotypes (via patient registries) but also the medical professionals who provide care for them at particular specialist centres of expertise and who may be competent to participate in trials. Work within the neuromuscular field provides an example of how this may be achieved. METHODS: This paper describes the development of the TREAT-NMD Care and Trial Site Registry (CTSR), an initiative of an EU-funded Network of Excellence, and its utility in providing an infrastructure for clinical trial feasibility, recruitment, and other studies. RESULTS: 285 CTSR registered centres, reporting 35,495 neuromuscular patients, are described alongside an analysis of their provision for DMD. Site characteristics vary by country: the average number of DMD patients seen per site in the United States (96) is more than in Germany (25), and paediatric/adult breakdown is also markedly distinct. Over 70% of sites have previous trial experience, with a majority including a Clinical Trials Unit. Most sites also have MLPA diagnostic capability and access to a range of medical specialists. However, in the three countries reporting most sites (US, the UK and Germany), few had access to all core DMD specialists internally. Over 60% of sites did not report any form of transition arrangement. CONCLUSIONS: Registries of care and trial sites have significant utility for research into rare conditions such as neuromuscular diseases, demonstrated by the significant engagement by industry and other researchers with the CTSR. We suggest that this approach may be applicable to other fields needing to identify centres of expertise with the potential to carry out clinical research and engage in clinical trials. Such registries also lend themselves to the developing context of European Reference Networks (ERNs), which seek to build networks of centres of expertise which fit specific criteria, and which may themselves aid the sustainability of such registries. This is particularly the case given the utility of registries such as the CTSR in enabling networks of best-practice care centres. PMID- 24148154 TI - Principal climatic and edaphic determinants of Culicoides biting midge abundance during the 2007-2008 bluetongue epidemic in the Netherlands, based on OVI light trap data. AB - Palaearctic Culicoides midges (Diptera: Ceratopogonidae) represent a vital link in the northward advance of certain arboviral pathogens of livestock such as that caused by bluetongue virus. The effects of relevant ecological factors on weekly Culicoides vector abundances during the bluetongue virus serotype 8 epidemics in the Netherlands in 2007 and 2008 were quantified within a hurdle modelling framework. The relative role of meteorological parameters showed a broadly consistent association across species, with larger catches linked to temperature related variables and lower wind speed. Moreover, vector abundance was found to be influenced by edaphic factors, likely related to species-specific breeding habitat preferences that differed markedly amongst some species. This is the first study on Culicoides vector species in the Netherlands identified during an entomological surveillance programme, in which an attempt is made to pinpoint the factors that influence midge abundance levels. In addition to providing key inputs into risk-mitigating tools for midge-borne pathogens and disease transmission models, the adoption of methods that explicitly address certain features of abundance datasets (frequent zero-count observations and over dispersion) helped enhance the robustness of the ecological analysis. PMID- 24148155 TI - The experiences of culturally and linguistically diverse family caregivers in utilising dementia services in Australia. AB - BACKGROUND: Older people from culturally and linguistically diverse groups are underrepresented in residential aged care but overrepresented in community aged care in Australia. However, little is known about culturally and linguistically diverse family caregivers in utilising dementia services in Australia because previous studies mainly focused on the majority cultural group. Experiences of caregivers from culturally and linguistically diverse groups who are eligible to utilise dementia services in Australia are needed in order to optimize the utilisation of dementia services for these caregivers. METHODS: The aim of the study was to explore the experiences of family caregivers from Chinese, Greek, Italian and Vietnamese groups in utilising dementia services. Gadamer's philosophical hermeneutics was used to interpret the experiences of the participants. Focus group discussions and in-depth individual interviews were used to collect data. Data collection was conducted over a six month period in 2011. In total, 46 family caregivers who were caring for 39 persons with dementia participated. RESULTS: Four themes were revealed: (1) negotiating services for the person with dementia; (2) the impact of acculturation on service utilisation; (3) the characteristics of satisfactory services; and (4) negative experiences in utilising services. The present study revealed that the participation of caregivers from culturally and linguistically diverse groups in planning and managing dementia services ranged markedly from limited participation to full participation. CONCLUSIONS: The findings of this study suggest that caregivers from culturally and linguistically diverse groups need to be fully prepared so they can participate in the utilisation of dementia services available to them in Australia. PMID- 24148156 TI - Identification of maternal uniparental isodisomy of chromosome 10 in a patient with mitochondrial DNA depletion syndrome. PMID- 24148158 TI - Working in caseload midwifery care: the experience of midwives working in a birth centre in North Queensland. AB - BACKGROUND: Pregnancy, birth and child rearing are significant life events for women and their families. The demand for services that are family friendly, women focused, safe and accessible is increasing. These demands and rights of women have led to increased government and consumer interest in continuity of care and the establishment in Australia of birth centres, and the introduction of caseload midwifery models of care. AIM: The aim of this research project was to uncover how birth centre midwives working within a caseload model care constructed their midwifery role in order to maintain a positive work-life balance. METHODS: A Grounded Theory study using semi-structured individual interviews was undertaken with seven midwives who work at a regional hospital birth centre to ascertain their views as to how they construct their midwifery role while working in a caseload model of care. FINDINGS: The results showed that caseload midwifery care enabled the midwives to practice autonomously within hospital policies and guidelines for birth centre midwifery practice and that they did not feel too restricted in regards to the eligibility of women who could give birth at the centre. Work relationships were found to be a key component in being able to construct their birth centre midwifery role. The midwives valued the flexibility that came with working in supportive partnerships with many feeling this enabled them to achieve a good work-life balance. CONCLUSION: The research contributes to the current body of knowledge surrounding working in a caseload model of care as it shows how the birth centre midwives construct their midwifery role. It provides information for development and improvement of these models of care to ensure that sustainability and quality of care is provided to women and their families. PMID- 24148157 TI - Importance of indole N-H hydrogen bonding in the organization and dynamics of gramicidin channels. AB - The linear ion channel peptide gramicidin represents an excellent model for exploring the principles underlying membrane protein structure and function, especially with respect to tryptophan residues. The tryptophan residues in gramicidin channels are crucial for the structure and function of the channel. In order to test the importance of indole hydrogen bonding for the biophysical properties of gramicidin channels, we monitored the effect of N-methylation of gramicidin tryptophans, using a combination of steady state and time-resolved fluorescence approaches along with circular dichroism spectroscopy. We show here that in the absence of the hydrogen bonding ability of tryptophans, tetramethyltryptophan gramicidin (TM-gramicidin) is unable to maintain the single stranded, head-to-head dimeric channel conformation in membranes. Our results show that TM-gramicidin displays a red-shifted fluorescence emission maximum, lower red edge excitation shift (REES), and higher fluorescence intensity and lifetime, consistent with its nonchannel conformation. This is in agreement with the measured location (average depth) of the 1-methyltryptophans in TM-gramicidin using the parallax method. These results bring out the usefulness of 1 methyltryptophan as a fluorescent tool to examine the hydrogen bonding ability of tryptophans in proteins and peptides. We conclude that changes in the hydrogen bonding ability of tryptophans, along with coupled changes in peptide backbone structure induce the loss of single stranded beta(6.3) helical dimer conformation. These results agree with earlier results from size-exclusion chromatography and single-channel measurements for TM-gramicidin, and confirm the importance of indole hydrogen bonding for the conformation and function of ion channels and membrane proteins. PMID- 24148159 TI - Inside stories: maternal representations of first time mothers from pre-pregnancy to early pregnancy. AB - BACKGROUND: According to the psychoanalytical literature, it is during pregnancy that maternal representations of the mother-infant relationship become activated. Midwives who are engaged with the mother and the baby have not drawn upon this concept in their practice. In order for this to happen, it is important to understand better the nature of maternal representations and when they are activated from empirical studies. QUESTION: The research question is: what are the maternal representations of a group of first time mothers from pre-pregnancy, early pregnancy and to the first ultrasound. METHOD: A narrative approach was used to gain insight into the maternal representations of first time pregnant womens' account of their representations. The analysis method was based on thematic approach. PARTICIPANTS: Fifteen women aged between 23 and 38 years. SETTING: A midwives clinic attached to a tertiary hospital in Melbourne, Australia. FINDINGS: First-time pregnant women's maternal representations were activated when a woman begins to plan her pregnancy ('the time is right'), again at the onset of physical changes to her body as a result of conception ('my body is changing'), and at the first early ultrasound at around twelve weeks ('it' is a real baby). CONCLUSION: Maternal representations are important for the midwife and pregnant women because this concept provides another understanding in relation to the psychological dimension of pregnancy. PMID- 24148160 TI - Geochemical, metagenomic and metaproteomic insights into trace metal utilization by methane-oxidizing microbial consortia in sulphidic marine sediments. AB - Microbes have obligate requirements for trace metals in metalloenzymes that catalyse important biogeochemical reactions. In anoxic methane- and sulphide-rich environments, microbes may have unique adaptations for metal acquisition and utilization because of decreased bioavailability as a result of metal sulphide precipitation. However, micronutrient cycling is largely unexplored in cold (<= 10 degrees C) and sulphidic (> 1 mM SigmaH(2)S) deep-sea methane seep ecosystems. We investigated trace metal geochemistry and microbial metal utilization in methane seeps offshore Oregon and California, USA, and report dissolved concentrations of nickel (0.5-270 nM), cobalt (0.5-6 nM), molybdenum (10-5600 nM) and tungsten (0.3-8 nM) in Hydrate Ridge sediment porewaters. Despite low levels of cobalt and tungsten, metagenomic and metaproteomic data suggest that microbial consortia catalysing anaerobic oxidation of methane (AOM) utilize both scarce micronutrients in addition to nickel and molybdenum. Genetic machinery for cobalt containing vitamin B12 biosynthesis was present in both anaerobic methanotrophic archaea (ANME) and sulphate-reducing bacteria. Proteins affiliated with the tungsten-containing form of formylmethanofuran dehydrogenase were expressed in ANME from two seep ecosystems, the first evidence for expression of a tungstoenzyme in psychrophilic microorganisms. Overall, our data suggest that AOM consortia use specialized biochemical strategies to overcome the challenges of metal availability in sulphidic environments. PMID- 24148161 TI - Effects of seed burial on germination, protein mobilisation and seedling survival in Dodonaea viscosa. AB - Ecological restoration of disturbed areas requires substantial knowledge of the germination of native plants and the creation of novel methods to increase seedling establishment in the field. We studied the effects of soil matrix priming on the germination of Dodonaea viscosa seeds, which exhibit physical dormancy. To this end, we buried both pre-scarified (in H2SO4, 3 min) and non-pre scarified seeds in the Parque Ecologico de la Ciudad de Mexico. After seeds were unearthed, they were post-scarified for 0, 2, 6 and 10 min and their germination percentages compared to the germination of a control batch of laboratory-stored seeds. For both control and unearthed seeds, the protein pattern was determined in the enriched storage protein fraction in SDS-PAGE gels stained with Coomassie blue. Percentage germination increased as the scarification time increased. Pre scarification significantly increased percentage germination of post-scarified seeds in relation to the control and non-pre-scarified seeds. In seeds unearthed from the forest site, the buried pre-scarified seeds had relatively high percentage germination, even in the absence of post-scarification treatment. A 48 kDa protein was not found in unearthed, pre-scarified seeds nor in the control germinated seeds, indicating that mobilisation of this protein occurred during soil priming. Burying seeds for a short period, including the beginning of the rainy season, promoted natural priming, which increased protein mobilisation. Functionally, priming effects were reflected in high percentage seedling survival in both the shade house and the field. Seed burial also reduced the requirement for acidic post-scarification. PMID- 24148162 TI - Food security: the optimal diet for people and the planet. PMID- 24148163 TI - Looking for the next breakthrough in tobacco control and health. PMID- 24148164 TI - The Women's Health Initiative Randomized Controlled Dietary Modification Trial: an inconvenient finding and the diet-heart hypothesis. AB - One goal of the US$700 million Women's Health Initiative Randomized Controlled Dietary Modification Trial was to determine whether post-menopausal women who adopted what was regarded as a 'heart healthy' low-fat diet, high in vegetables, fruits and grains, reduced their risk of developing cardiovascular disease. The trial substantially favoured the outcome in the intervention group, who also received an intensive nutritional and behaviour education programme not offered to the control group. These studies neatly disprove the diet-heart hypothesis since adoption of 'heart healthy' eating not only failed to influence future cardiac events in the healthy but it increased such events in the unhealthy and worsened diabetic control in those with type 2 diabetes mellitus. PMID- 24148165 TI - Low-carbohydrate and high-fat intake can manage obesity and associated conditions: occasional survey. AB - This study analyses 127 communications from individuals self-reporting their weight change following adoption of a low-carbohydrate, high-fat (LCHF) eating plan. Total combined self-reported weight loss was 1 900 kg (range 5 kg gain to 84 kg loss). The mean +/- standard deviation weight loss of 15 (+/-12) kg is among the largest yet described. Sixteen subjects reported the LCHF 'cured' (i.e. medications no longer required) one or more of their medical conditions, most commonly type 2 diabetes mellitus (T2DM) (n=14), hypertension (n=8) and hypercholesterolaemia (n=7). Another 9 subjects with either type 1 diabetes mellitus or T2DM reduced medications as did 7 patients with hypertension; 8 no longer suffered from irritable bowel syndrome. These data show that significant and rapid weight loss is possible on an unsupervised eating plan that severely restricts daily carbohydrate intake to approximately <75 g/day. Better weight loss on a carbohydrate-restricted LCHF eating plan than on an iso-caloric high carbohydrate, low-fat (HCLF) diet is well described in the literature, probably due to a paradoxical reduction of hunger by carbohydrate restriction. A randomised controlled clinical trial is urgently required to disprove the hypothesis that the LCHF eating plan can reverse cases of T2DM, metabolic syndrome and hypertension without pharmacotherapy. PMID- 24148166 TI - Electronic cigarettes: the potential benefits outweigh the risks. PMID- 24148167 TI - A decade of tobacco control: the South African case of politics, health policy, health promotion and behaviour change. AB - BACKGROUND: The South African (SA) government has implemented comprehensive tobacco control measures in line with the requirements of the Framework Convention on Tobacco Control. The effect of these measures on smoking prevalence and smoking-related attitudes, particularly among young people, is largely unknown. OBJECTIVE: To describe the impact of a comprehensive health promotion approach to tobacco control amongst SA school learners. METHODS: Four successive cross-sectional Global Youth Tobacco Surveys (GYTSs) were conducted in 1999, 2002, 2008 and 2011 among nationally representative samples of SA grades 8 - 10 school learners. We assessed the prevalence of current smoking (having smoked a cigarette on >=1 day in the 30 days preceding the survey) and smoking-related attitudes and behaviours. RESULTS: Over the 12-year survey period current smoking among learners declined from 23.0% (1999) to 16.9% (2011) - a 26.5% reduction. Reductions in smoking prevalence were less pronounced amongst girls and amongst black learners. We observed an increase in smoking prevalence amongst learners between 2008 and 2011. Smoking-related attitudes and behaviours showed favourable changes over the survey period. CONCLUSION: These surveys demonstrate that the comprehensive and inter-sectorial tobacco control health promotion strategies implemented in SA have led to a gradual reduction in cigarette use amongst school learners. Of concern, however, are the smaller reductions in smoking prevalence amongst girls and black learners and an increase in smoking prevalence from 2008 to 2011. Additional efforts, especially for girls, are needed to ensure continued reduction in smoking prevalence amongst SA youth. PMID- 24148168 TI - The effects of obesity, smoking, and excessive alcohol intake on healthcare expenditure in a comprehensive medical scheme. AB - BACKGROUND: Health risks such as tobacco use, excessive alcohol consumption and unhealthy body weight contribute to the development of chronic health problems. OBJECTIVE: To estimate the associations of tobacco use, excessive alcohol consumption and obesity with healthcare expenditure and chronic diseases among South Africans on a comprehensive medical scheme. METHODS: We performed a cross sectional analysis of health survey and medical claims data for 70 000 South Africans during 2010. RESULTS: Moderately obese individuals, with a body mass index (BMI) of 30 - 35 kg/m2 averaged R2 300 (11%) higher annual medical expenditure in the year 2010 than never-smokers with a BMI <30 kg/m2. This increase is comparable with being a current or past smoker (expenditure increase by R2 600; 13%). Severely obese individuals (BMI >35 kg/m2), however, had increased healthcare costs of R4 400 (23% increase). This exceeds the difference between a 40- and a 50-year-old (increase of R3 200). Being overweight or excessive consumption of alcohol was not significantly associated with medical expenditures. Absolute and relative excess expenditures associated with these health risks are higher among older individuals. In the 54 - 69-year age group, estimated additional expenses were R6 200 for smoking (20% increase over never smokers with BMI <30 kg/m2), R6 600 for moderate obesity (21%) and R15 800 for severe obesity (51% increase). Overweight or heavy drinking was not statistically significantly associated with healthcare expenditure. CONCLUSION: Obesity and tobacco use are associated with significantly increased healthcare expenditure. Severe obesity doubles these excess costs. PMID- 24148169 TI - The extent of problematic alcohol and other drug use within selected South African workplaces. AB - BACKGROUND: The use of alcohol and other drugs (AODs) in the workplace has a major impact on the health and productivity of the workforce globally. Yet information on this issue is limited in South Africa (SA). OBJECTIVE: To describe the nature and extent of AOD problems in selected workplace settings in SA. METHODS: Secondary data analysis was conducted on a large dataset compiled by an Employee Assistance Programme (EAP) service provider in SA. As part of an EAP risk audit, assessments for AOD-related problems were completed for each employee accessing EAP services (n=10 428) between 2005 and 2011. Data on the socio demographic profiles, AOD use and impact of AOD use on the work performance of employees were analysed. RESULTS: Findings indicate that employed men are more likely to experience alcohol-related problems than women, the latter demonstrating a higher percentage of drug-related problems. The majority of referrals to the EAPs emanate from the public, industrial and financial sectors. AOD-related problems were also found to significantly impact on employee work performance. CONCLUSIONS: The study begins to address the knowledge gap on the extent of AOD use in SA workplaces and points to the need for further investigations into the exact nature of AOD use. In addition, the study highlights the need for intervention programmes and policies suited to the workplace. PMID- 24148170 TI - Hookah pipe smoking among health sciences students. AB - BACKGROUND: Hookah pipe smoking is a social practice and has gained popularity, especially among South African youth. The extent of this practice among health sciences students, and their knowledge regarding the health risks, are unknown. This is important, as these students will become future health professionals possibly influencing the practice of individuals and communities. OBJECTIVE: To explore the knowledge, attitudes and practices of hookah pipe smoking among students at the Faculty of Health Sciences, University of Cape Town. METHODS. A cross-sectional study was conducted among undergraduate and postgraduate students. A self-administered questionnaire was distributed as a hard copy and online survey. RESULTS: Of 228 participants, 66% had smoked a hookah pipe before, with 18% still smoking. Most began smoking in high school, with 25% initiating at university. Of the current smokers, 65% smoked occasionally socially, commonly at friends' houses for 30 - 60 min/session. A further 11% smoked cigarettes concurrently and 30% added other substances, mainly cannabis, to pipes. Most current hookah smokers had no interest in quitting (84%). Only 30% of participants had prior health information about hookah pipe smoking. Most knew that it was harmful (91%), with many not knowing why. A total of 80% of participants perceived that the practice was socially acceptable and 84% would recommend it to others.CONCLUSION; The poor knowledge about the dangers of hookah pipe smoking and the extent of its practice among health sciences students is alarming. These findings highlight the need for school and university health promotion campaigns, and for better regulation of hookah pipe smoking. PMID- 24148171 TI - Road traffic crashes in South Africa: the burden of injury to a regional trauma centre. AB - BACKGROUND: Globally, 90% of road traffic crash (RTC) deaths occur in low- and middle-income countries. OBJECTIVE: To document the mortality and morbidity associated with RTCs managed at a busy regional hospital in South Africa and investigate potentially preventable factors associated with RTCs. METHODS: This was a prospective study of all patients presenting to Edendale Hospital following a RTC over a 10-week period from late 2011 to early 2012. All fatalities recorded at the police mortuary for the same period were included. Medical records were reviewed and all admitted patients were interviewed about the circumstances of the accident. We calculated an injury pyramid to compare our data with European data. RESULTS: A total of 305 patients were seen over the study period, 100 required admission and there were 45 deaths due to RTCs in the area. Of the patients admitted, 41 were pedestrians involved in pedestrian vehicle crashes (PVCs) and 59 motor vehicle occupants involved in motor vehicle crashes (MVCs). The majority (n=58) of crashes involved a private vehicle. Only 17% of MVC patients were wearing a seatbelt and 8 were allegedly under the influence of alcohol. On average, RTC patients spent 19 days in hospital and 62 patients required at least 1 operation. According to our injury pyramid, the number of severe and fatal injuries was higher than in Europe. CONCLUSION: Our results demonstrate a high incidence of RTCs associated with a high injury score and significant morbidity. Most crashes were associated with a number of high-risk behaviours. PMID- 24148172 TI - Prevalence, risk factors and risk perception of tuberculosis infection among medical students and healthcare workers in Johannesburg, South Africa. AB - BACKGROUND: Tuberculin skin test (TST) and interferon gamma release assays (IGRAs) are both recommended for routine screening of healthcare workers (HCWs) in low tuberculosis (TB)-burden countries. More recently, based on scarce data, the World Health Organization strongly recommended that IGRA should not be used for occupational screening in high-burden settings. OBJECTIVE: To assess the prevalence of latent tuberculosis infection (LTBI) determined among highly exposed HCWs and low-exposed medical students in Johannesburg, South Africa. Methods. We performed a cross-sectional study using both TSTs and IGRAs to determine the prevalence rate of LTBI in 79 medical students and 120 HCWs providing HIV and/or TB care. RESULTS: The prevalence of LTBI among HCWs was 2- to 4-fold higher than that among medical students (56.7% v. 26.6% TST-positive; 69.2% v.15.2% IGRA-positive, respectively), with 3-fold higher odds for TST positivity and 12-fold higher odds for IGRA positivity among HCWs compared with students. Despite the perception of being at high risk, few HCWs protected themselves against LTBI. The majority of HCWs reported that they would participate in annual TST or IGRA screening. CONCLUSION: Infection control strategies and occupational screening programmes for professional and lay HCWs, as well as medical students, should be implemented in all high-burden settings. Further research is needed to determine whether IGRA or TST is the optimal assay for periodical screening of HCWs in high-burden settings. PMID- 24148173 TI - The prevalence of smoking and the knowledge of smoking hazards and smoking cessation strategies among HIV- positive patients in Johannesburg, South Africa. AB - BACKGROUND: While the detrimental effects of smoking among HIV-positive patients have been well documented, there is a paucity of data regarding cigarette smoking prevalence among these patients in South Africa (SA). OBJECTIVES: To establish the frequency, demographics, knowledge of harmful effects, and knowledge of smoking cessation strategies among HIV-positive patients in Johannesburg, SA. METHODS: We conducted a prospective cross-sectional survey using a structured questionnaire to interview HIV-positive patients attending the HIV Clinic at the Charlotte Maxeke Johannesburg Academic Hospital between 1 July and 31 October 2011. RESULTS: Of 207 HIV-positive patients attending an antiretroviral therapy (ART) roll-out clinic, 31 (15%) were current smokers (23.2% of males and 7.4% of females) and a further 45 (21.7%) were ex-smokers. Most of the current smokers (30/31 patients) indicated their wish to quit smoking, and among the group as a whole, most patients were aware of the general (82.1%) and HIV-related (77.8%) risks of smoking and of methods for quitting smoking. Despite this, however, most (62.3%) were not aware of who they could approach for assistance and advice. CONCLUSIONS: Given the relatively high prevalence of current and ex-smokers among HIV-positive patients, there is a need for the introduction of smoking-cessation strategies and assistance at ART roll-out clinics in SA. PMID- 24148174 TI - Re-defining the extent of malaria transmission in South Africa: implications for chemoprophylaxis. AB - BACKGROUND: Malaria case numbers reported in South Africa have reduced considerably over the last decade, necessitating a revision of the national risk map to guide malaria prevention, including the use of chemoprophylaxis. OBJECTIVES: To update the national malaria risk map based on recent case data and to consider the implications of the new transmission profile for guiding prophylaxis. METHODS: The geographical distribution of confirmed malaria cases detected both passively and actively over the last six malaria seasons was used to redefine the geographic distribution and intensity of malaria transmission in the country. RESULTS: The national risk map was revised to reflect zones of transmission reduced both in their extent and their intensity. Most notably, the area of risk has been reduced in the north-western parts of Limpopo Province and is limited to the extreme northern reaches of KwaZulu-Natal Province. Areas previously considered to be of high risk are now regarded to be of moderate risk. CONCLUSION: Chemoprophylaxis is now only recommended from September to May in the north-eastern areas of Limpopo and Mpumalanga Provinces. The recommended options for chemoprophylaxis have not changed from mefloquine, doxycycline or atovaquone proguanil. PMID- 24148175 TI - Carboxyhaemoglobin levels, health and lifestyle perceptions in smokers converting from tobacco cigarettes to electronic cigarettes. AB - BACKGROUND: Chronic obstructive pulmonary disease and lung cancer are diseases associated with smoking tobacco cigarettes. Smokers find cessation difficult. OBJECTIVES: To determine whether smoking the Twisp electronic cigarette (e cigarette), containing nicotine in a vegetable-based glycerine substance, would reduce carboxyhaemoglobin (COHb) levels in regular cigarette smokers by (i) comparing arterial and venous COHb levels before and after smoking the Twisp e cigarette for 2 weeks; and (ii) evaluating changes in participants' perception of their health and lifestyle following the use of Twisp e-cigarettes. METHODS: A single group within-subject design was used where tobacco cigarette smokers converted to Twisp e-cigarettes for 2 weeks. Prior to using the Twisp e-cigarette and after using this device for 2 weeks, arterial COHb, venous COHb and venous cotinine levels were determined. Additionally, the participants were asked to complete a questionnaire outlining their perceptions on health and lifestyle. RESULTS: Thirteen participants of median age 38 years (range 23 - 46) with a smoking median of 20 cigarettes/day (range 12 - 30) completed the study. COHb levels (%) were significantly reduced after smoking Twisp e-cigarettes for 2 weeks (mean +/- standard deviation (SD) arterial COHb before 4.66+/-1.99 v. after 2.46+/-1.35; p=0.014 and mean +/-SD venous COHb before 4.37+/-2.1 v. after 2.50+/ 1.23; p=0.018). There was excellent agreement between arterial and venous COHb levels (intraclass correlation coefficient 0.916). A decrease in cotinine levels (p=0.001) and an increase in oxygen saturation (p=0.002) were also observed. The majority of participants perceived improvements in their health and lifestyle parameters. CONCLUSION: Smoking the Twisp e-cigarette may be a healthier and more acceptable alternative to smoking tobacco cigarettes. PMID- 24148176 TI - South African tobacco smoking cessation clinical practice guideline. AB - Tobacco smoking (i.e. cigarettes, rolled tobacco, pipes, etc.) is associated with significant health risks, reduced life expectancy and negative personal and societal economic impact. Smokers have an increased risk of cancer (i.e. lung, throat, bladder), chronic obstructive pulmonary disease (COPD), tuberculosis and cardiovascular disease (i.e. stroke, heart attack). Smoking affects unborn babies, children and others exposed to second hand smoke. Stopping or 'quitting' is not easy. Nicotine is highly addictive and smoking is frequently associated with social activities (e.g. drinking, eating) or psychological factors (e.g. work pressure, concerns about body weight, anxiety or depressed mood). The benefits of quitting, however, are almost immediate, with a rapid lowering of blood pressure and heart rate, improved taste and smell, and a longer-term reduction in risk of cancer, heart attack and COPD. Successful quitting requires attention to both the factors surrounding why an individual smokes (e.g. stress, depression, habit, etc.) and the symptoms associated with nicotine withdrawal. Many smokers are not ready or willing to quit and require frequent motivational input outlining the benefits that would accrue. In addition to an evaluation of nicotine dependence, co-existent medical or psychiatric conditions and barriers to quitting should be identified. A tailored approach encompassing psychological and social support, in addition to appropriate medication to reduce nicotine withdrawal, is likely to provide the best chance of success. Relapse is not uncommon and reasons for failure should be addressed in a positive manner and further attempts initiated when the individual is ready.Key steps in smoking cessation include: (i) identifying all smokers, alerting them to the harms of smoking and benefits of quitting; (ii) assessing readiness to initiate an attempt to quit; (iii) assessing the physical and psychological dependence to nicotine and smoking; (iv) determining the best combination of counselling/support and pharmacological therapy; (v) setting a quit date and provide suitable resources and support; (vi) frequent follow-up as often as possible via text/telephone or in person; (vii) monitoring for side-effects, relapse and on-going cessation; and (viii) if relapse occurs, providing the necessary support and encourage a further attempt when appropriate. PMID- 24148177 TI - A comprehensive, health-promotion approach to tobacco control. PMID- 24148178 TI - Electronic cigarettes: the potential risks outweigh the benefits. PMID- 24148179 TI - Raising the CD4+ initiation threshold with our eyes wide open. PMID- 24148180 TI - MiR-370 sensitizes chronic myeloid leukemia K562 cells to homoharringtonine by targeting Forkhead box M1. AB - BACKGROUND: Homoharringtonine (HHT) is a kind of cephalotaxus alkaloid used in traditional Chinese medicine. Although HHT has been successfully used as a therapeutic agent for leukemia, the drug resistance and toxicity are major concerns. MicroRNAs (miRNAs) have been identified to modulate cellular sensitivity to anticancer drugs. We examined the synergistic action between miR 370 and HHT in vitro and in vivo. METHODS: The synergistic action between miR-370 and HHT was examined by flow cytometry. The effect of HHT on miR-370 expression was determined by quantitative RT-PCR (qRT-PCR). The expression of miR-370 and Forkhead box M1 (FoxM1) in 23 patients with newly diagnosed chronic-phase chronic myeloid leukemia (CML-CP) and 10 patients with blast-crisis CML (CML-BP) as well as miR-370-targeted FoxM1 was determined by qRT-PCR and western blot analysis. RESULTS: Ectopic expression of miR-370 sensitized the CML K562 cell line to HHT by targeting FoxM1, the major regulator in cell proliferation and apoptosis. miR 370 significantly promoted HHT-mediated cell apoptosis and miR-370 and HHT cooperated in affecting FoxM1 expression. As well, miR-370 was moderately upregulated after HHT treatment in K562 cells. In addition, the expression of miR 370 was significantly reduced in CML patients as compared with healthy controls. Furthermore, the expression of miR-370 was lower in CML-BP than CML-CP patients. CONCLUSIONS: MiR-370 sensitized K562 cells to HHT by inducing apoptosis in part by downregulation of FoxM1 expression. These findings may provide further information for CML treatment with HHT. PMID- 24148181 TI - High incidence of septic shock caused by Streptococcus pneumoniae serotype 3--a retrospective epidemiological study. AB - BACKGROUND: More than 90 immunologically distinct serotypes of Streptococcus pneumoniae exist, and it is not fully elucidated whether the serotype is a risk factor for severity of invasive pneumococcal disease (IPD). Our hypothesis is that serotypes differ in their capacity to cause septic shock. METHODS: We performed a retrospective study in Southern Sweden based upon 513 patients with IPD in the pre-vaccine era 2006-2008. The serotype, co-morbidity, and sepsis severity were determined. Serotypes were compared to serotype 14 as a reference and grouped according to their invasive potential, that is, high (serogroups 1, 5 and 7), intermediate (serogroups 4, 9, 14 and 18) and, finally, low invasive potential (serogroups 3, 6, 8, 15, 19, 23 and 33). RESULTS: Patients with S. pneumoniae serotype 3 had significantly more often septic shock (25%, odds ratio (OR) 6.33 [95% confidence interval (CI) 1.59-25.29]), higher mortality (30%, OR 2.86 [CI 1.02-8.00]), and more often co-morbidities (83%, OR 3.82 [CI 1.39 10.54]) when compared to serotype 14. A significant difference in age and co morbidities (p <= 0.001) was found when patient data were pooled according to the invasive potential of the infecting pneumococci. The median age and percentage of patients with underlying co-morbidities were 72 years and 79%, respectively, for serogroups associated with low invasiveness, 68 years and 61%, respectively, for serogroups with intermediate invasiveness, and, finally, 62 years and 48%, respectively, for serogroups with high invasiveness. No difference in sepsis severity was found between the three groups. CONCLUSIONS: S. pneumoniae serotype 3 more often caused septic shock compared to serotype 14. Our results support the hypothesis that serotypes with high invasiveness mainly cause IPD in younger patients with less co-morbidities. In contrast, serogroups with low and intermediate invasive potential mostly cause IPD in the elderly with defined co morbidities, and thus can be considered as opportunistic. PMID- 24148182 TI - Bringing transparency into quality comparison research. PMID- 24148183 TI - Engineering precursor metabolite pools for increasing production of antitumor mithramycins in Streptomyces argillaceus. AB - Mithramycin (MTM) is a polyketide antitumor compound produced by Streptomyces argillaceus constituted by a tricyclic aglycone with two aliphatic side chains, a trisaccharide and a disaccharide chain. The biosynthesis of the polyketide aglycone is initiated by the condensation of ten malonyl-CoA units to render a carbon chain that is modified to a tetracyclic intermediate and sequentially glycosylated by five deoxysugars originated from glucose-1-phosphate. Further oxidation and reduction render the final compound. We aimed to increase the precursor supply of malonyl-CoA and/or glucose-1-phosphate in S. argillaceus to enhance MTM production. We have shown that by overexpressing either the S. coelicolor phosphoglucomutase gene pgm or the acetyl-CoA carboxylase ovmGIH genes from the oviedomycin biosynthesis gene cluster in S. argillaceus, we were able to increase the intracellular pool of glucose-1-phosphate and malonyl-CoA, respectively. Moreover, we have cloned the S. argillaceus ADP-glucose pyrophosphorylase gene glgCa and the acyl-CoA:diacylglycerol acyltransferase gene aftAa, and we showed that by inactivating them, an increase of the intracellular concentration of glucose-1-phosphate/glucose-6-phosphate and malonyl-CoA/acetyl CoA was observed, respectively. Each individual modification resulted in an enhancement of MTM production but the highest production level was obtained by combining all strategies together. In addition, some of these strategies were successfully applied to increase production of four MTM derivatives with improved pharmacological properties: demycarosyl-mithramycin, demycarosyl-3D-beta-D digitoxosyl-mithramycin, mithramycin SK and mithramycin SDK. PMID- 24148184 TI - Monitoring CHO cell cultures: cell stress and early apoptosis assessment by mass spectrometry. AB - Mammalian cells, especially CHO (Chinese Hamster Ovary), are an important host for the production of biopharmaceuticals. Early detection of cellular stress and the onset of apoptosis, ultimately leading to a reduced viability of the culture, are important with respect to process development and monitoring. In this work, intact cell MALDI mass spectrometry (ICM MS) biotyping was used to rapidly and sensitively detect cell stress and the onset of apoptosis at line in CHO cell cultures. We describe the identification of specific and highly reproducible stress and apoptosis related changes in m/z signal intensities that allowed prediction of upcoming cell viability changes approximately 24h earlier than standard culture monitoring. Furthermore, early identification of apoptosis onset was comparable to that using a sensitive, albeit offline, detection method. By comparison with ICM MS analysis of apoptosis induced cultures, many of the m/z values were identified as apoptosis-specific. A classification model for discrimination of unknown samples regarding their cellular viability/apoptosis status was developed based on a condensed set of 51 m/z values. The fast, robust and automated acquisition of cell state specific MS signatures could become a promising tool for CHO culture monitoring. PMID- 24148185 TI - Lumpy Skin Disease in Jordan: Disease Emergence, Clinical Signs, Complications and Preliminary-associated Economic Losses. AB - The objectives of this study are to report the emergence of lumpy skin disease (LSD) in Jordan and associated clinical signs, complications and preliminary economic losses. In mid-April, 2013, two adult dairy cattle developed clinical signs suggestive of LSD and were confirmed as positive by PCR. The two cases were in Bani Kenanah district, Irbid governorate, on the Jordanian border of Israel and Syria. The disease spread rapidly to all the districts of Irbid governorate. During the month following the emergence of the disease, data were collected related to the epidemiology of the disease and the numbers of affected cattle on the premises. Forty-one dairy cattle holdings were surveyed. The morbidity rate ranged from 3% to 100%, (Mean = 35.1%, SD +/-28.5%). The mortality rate ranged from 0% to 20%, (Mean = 1.3%, SD +/-4.4%). The case fatality rate ranged from 0% to 100%, (Mean = 6.2%, SD +/-22%). The overall morbidity rate was 26%, mortality rate 1.9% and case fatality rate 7.5%. Skin nodules, anorexia, decreased milk production and decreased body weight were common clinical signs, while mastitis and myiasis were seen as complications in a few affected animals. Decreased body weight ranged from 0% to 80%, (Mean = 23.1%, SD +/-15.7%). Decreased milk production ranged from 0% to 100%, (Mean = 51.5%, SD +/-22.2%). Affected cattle were treated mainly with broad-spectrum antibiotics and anti-inflammatory drugs. The cost of treatment ranged from 0 to 84.3 British Pound/animal, (Mean = 27.9 GBP, SD +/-22.5 GBP). LSD continues to spread through the Middle East region and poses a serious threat to the rest of Asia and Europe. International collaboration and communication is warranted to prevent the further spread of the disease to the rest of Asia and Europe. PMID- 24148186 TI - Elasticated retractors in tracheostomy. AB - We present a novel way of providing and improving retraction whilst performing tracheostomies, using elasticated retractors. The benefits of this method include an improved surgical field and the facility for use by a single surgeon. This type of retraction could potentially be used in a variety of other head and neck procedures. PMID- 24148187 TI - Contacting a conjugated molecule with a surface dangling bond dimer on a hydrogenated Ge(001) surface allows imaging of the hidden ground electronic state. AB - Fabrication of single-molecule logic devices requires controlled manipulation of molecular states with atomic-scale precision. Tuning molecule-substrate coupling is achieved here by the reversible attachment of a prototypical planar conjugated organic molecule to dangling bonds on the surface of a hydrogenated semiconductor. We show that the ground electronic state resonance of a Y-shaped polyaromatic molecule physisorbed on a defect-free area of a fully hydrogenated surface cannot be observed by scanning tunneling microscopy (STM) measurements because it is decoupled from the Ge bulk states by the hydrogen-passivated surface. The state can be accessed by STM only if the molecule is contacted with the substrate by a dangling bond dimer. The reversibility of the attachment processes will be advantageous in the construction of surface atomic-scale circuits composed of single-molecule devices interconnected by the surface dangling bond wires. PMID- 24148188 TI - Current concepts in Alzheimer's Disease: molecules, models and translational perspectives. AB - The field of neuroscience research in AD has been evolving rapidly over the last few years, and has pinpointed a number of candidate targets for molecules with crucial role in the pathophysiology of AD. Recent developments have furthermore enabled new ways of modeling the disease, while an increasing number of preclinically validated targets is currently being taken one step forward and tested in clinical trials. These recent developments are reviewed in the current Special Issues Series on "Current concepts in Alzheimer's disease research: molecules, models and translational perspectives" in a number of state-of-the-art manuscripts. PMID- 24148189 TI - Can life coaching improve health outcomes?--A systematic review of intervention studies. AB - BACKGROUND: In recent years, coaching has received special attention as a method to improve healthy lifestyle behaviours. The fact that coaching has found its way into healthcare and may provide new ways of engaging the patients and making them accountable for their health, justifies the need for an overview of the evidence regarding coaching interventions used in patient care, the effect of the interventions, and the quality of the studies published. However, in order to provide a clear definition of the coaching interventions selected for this review, we have found it necessary to distinguish between health coaching and life coaching. In this review, we will only focus on the latter method and on that basis assess the health related outcomes of life coaching. METHODS: Intervention studies using quantitative or qualitative methods to evaluate the outcome of the life coach interventions were identified through systematic literature searches in PubMed, Embase, Psycinfo, and CINAHL. The quality of the methodology was independently assessed by three of the authors using a criteria list. RESULTS: A total of 4359 citations were identified in the electronic search and five studies were included; two of them were randomized controlled trials and met all quality criteria. The two studies investigating objective health outcomes (HbA1c) showed mixed but promising results, especially concerning the patient group that usually does not benefit from intensified interventions. CONCLUSION: Because of the very limited number of solid studies, this review can only present tendencies for patient outcomes and a preliminary description of an effective life coaching intervention.The coaching method used in these studies aims to improve self-efficacy and self-empowerment. This may explain why the studies including disadvantaged patients showed the most convincing results. The findings also indicate that some patients benefit from being met with an alternative approach and a different type of communication than they are used to from health care personnel.In order to get a closer look at what is in the 'black box', we suggest that the description and categorisation of the coaching methods are described more comprehensively, and that research into this area is supplemented by a more qualitative approach. PMID- 24148190 TI - World Stroke Day: 'Because I care ...'. PMID- 24148191 TI - World Stroke Day: one world voice for stroke. PMID- 24148192 TI - Treatment of refractory uveitic macular edema with dexamethasone intravitreal implants in a pediatric patient with bilateral granulomatous idiopathic panuveitis: a case report. AB - BACKGROUND: Macular edema is a common complication of uveitis and represents a therapeutic challenge, especially in children. Recently, intravitreal dexamethasone implants have been shown to decrease intraocular inflammation and to control uveitic macular edema in patients with non-infectious intermediate or posterior uveitis. FINDINGS: An 11-year-old boy with bilateral granulomatous idiopathic panuveitis and orbital inflammation experienced macular edema refractory to topical steroids and subcutaneous methotrexate. He was treated with off-label bilateral injections of dexamethasone intravitreal implant. Three months later, his vision had improved from 20/200 in both eyes to 20/30 in the right eye and 20/40 in the left eye. Optical coherence tomography showed complete resolution of the cystoid macular edema and subretinal fluid in both eyes. CONCLUSIONS: This is a rare report of the use of bilateral dexamethasone intravitreal implant in a pediatric patient. The implants achieved complete resolution of the uveitic macular edema with no adverse events 3 months post implantation. PMID- 24148193 TI - Flagella interact with ionic plant lipids to mediate adherence of pathogenic Escherichia coli to fresh produce plants. AB - Bacterial attachment to plant and animal surfaces is generally thought to constitute the initial step in colonization, requiring adherence factors such as flagella and fimbriae. We describe the molecular mechanism underpinning flagella mediated adherence to plant tissue for the foodborne pathogen, enterohaemorrhagic Escherichia coli. Escherichia coli H7 flagella interacted with a sulphated carbohydrate (carrageenan) on a glycan array, which occurred in a dose-dependent manner. Adherence of E. coli O157 : H-expressing flagella of serotype H7, H6 or H48 to plants associated with outbreaks from fresh produce and to Arabidopsis thaliana, was dependent on flagella interactions with phospholipids and sulpholipids in plasma membranes. Adherence of purified H7 and H48 flagella to carrageenan was reduced at higher concentrations of KH2 PO4 or KCl, showing an ionic basis to the interactions. Purified H7 flagella were observed to physically interact with plasma membranes in spinach plants and in A.thaliana. The results show a specific interaction between E. coli H7, H6 and H48 flagella and ionic lipids in plant plasma membranes. The work extends our understanding of the molecular mechanisms underpinning E.coli flagella targeting of plant hosts and suggests a generic mechanism of recognition common in eukaryotic hosts belonging to different biological kingdoms. PMID- 24148194 TI - Growth hormone-induced insulin resistance in human subjects involves reduced pyruvate dehydrogenase activity. AB - AIM: Insulin resistance induced by growth hormone (GH) is linked to promotion of lipolysis by unknown mechanisms. We hypothesized that suppression of the activity of pyruvate dehydrogenase in the active form (PDHa) underlies GH-induced insulin resistance similar to what is observed during fasting. METHODS: Eight healthy male subjects were studied four times in a randomized, single-blinded parallel design: Control, GH, Fasting (36 h) and GH + Fasting. GH (30 ng * kg(-1) * min( 1)) or saline was infused throughout the metabolic study day. Substrate metabolism and insulin sensitivity were assessed by indirect calorimetry and isotopically determined rates of glucose turnover before and after a hyperinsulinemic euglycemic clamp. PDHa activity, PDH-E1alpha phosphorylation, PDK4 expression and activation of insulin signalling proteins were assessed in skeletal muscle. RESULTS: Both fasting and GH promoted lipolysis, which was associated with ~50% reduction in insulin sensitivity compared with the control day. PDHa activity was significantly reduced by GH as well as fasting. This was associated with increased inhibitory PDH-E1alpha phosphorylation on site 1 (Ser(293)) and 2 (Ser(300)) and up-regulation of PDK4 mRNA, while canonical insulin signalling to glucose transport was unaffected. CONCLUSION: Competition between intermediates of glucose and fatty acids seems to play a causal role in insulin resistance induced by GH in human subjects. PMID- 24148195 TI - Elemental composition of strawberry plants inoculated with the plant growth promoting bacterium Azospirillum brasilense REC3, assessed with scanning electron microscopy and energy dispersive X-ray analysis. AB - The elemental composition of strawberry plants (Fragaria ananassa cv. Macarena) inoculated with the plant growth-promoting bacterium Azospirillum brasilense REC3, and non-inoculated controls, was studied using scanning electron microscopy (SEM) and energy dispersive X-ray (EDS) analysis. This allowed simultaneous semi quantification of different elements in a small, solid sample. Plants were inoculated and grown hydroponically in 50% or 100% Hoagland solution, corresponding to limited or optimum nutrient medium, respectively. Bacteria inoculated plants increased the growth index 45% and 80% compared to controls when grown in 100% and 50% Hoagland solution, respectively. Thus, inoculation with A. brasilense REC3 in a nutrient-limited medium had the strongest effect in terms of increasing both shoot and root biomass and growth index, as already described for Azospirillum inoculated into nutrient-poor soils. SEM-EDS spectra and maps showed the elemental composition and relative distribution of nutrients in strawberry tissues. Leaves contained C, O, N, Na, P, K, Ca and Cu, while roots also had Si and Cl. The organic fraction (C, O and N) accounted for over 96.3% of the total chemical composition; of the mineral fraction, Na had higher accumulation in both leaves and roots. Azospirillum-inoculated and control plants had similar elemental quantities; however, in bacteria-inoculated roots, P was significantly increased (34.33%), which constitutes a major benefit for plant nutrition, while Cu content decreased (35.16%). PMID- 24148197 TI - Does carbohydrate supplementation enhance tennis match play performance? AB - BACKGROUND: Carbohydrate (CHO) ingestion may be an interesting approach to avoid significant decrement to the tennis match performance. The aim of the present investigation was to assess the effects of CHO supplementation on tennis match play performance. METHODS: Twelve young tennis players (18.0 +/- 1.0 years; 176 +/- 3.4 cm; 68.0 +/- 2.3 kg; body fat: 13.7 +/- 2.4%) with national rankings among the top 50 in Brazil agreed to participate in this study, which utilized a randomized, crossover, double blind research design. The experiment was conducted over a 5-day period in which each player completed two simulated tennis matches of a 3-hour duration. The players received either a CHO or a placebo (PLA) drinking solution during simulated tennis matches. Athlete's performance parameters were determined by filming each match with two video cameras. Each player was individually tracked for the entire duration of the match to measure the following variables: (1) games won; (2) rally duration; (3) strokes per rally; (4) effective playing time (%); (5) aces; (6) double faults; (7) first service in; (8) second service in; (9) first return in and (10) second return in. RESULTS: There were no differences between trials in any of the variables analyzed. CONCLUSIONS: CHO supplementation did not improve tennis match play performance under the present experimental conditions. PMID- 24148198 TI - Identification of non-tuberculous mycobacteria isolated from clinical specimens at a tertiary care hospital: a cross-sectional study. AB - BACKGROUND: Non-tuberculous mycobacteria (NTM) are opportunistic pathogens in immuno-compromised patients. They are also increasingly recognized as pathogens in immuno-competent individuals. Globally, an increase in NTM isolation is being reported with a varied geographic prevalence of different species around the world. There is lack of data on species distribution of these organisms from Pakistan. Treatment options differ according to the species isolated and its susceptibility profile. Knowledge of local species variation would help targeted therapy. This study was performed to determine frequencies of different NTM species isolated from various clinical specimens submitted at a tertiary care hospital laboratory. METHODS: NTM isolated from 25955 clinical specimens over a period of two years (2010 to 2011) were included. All NTM were identified using conventional tests. Drug susceptibility testing (DST) was performed by broth microdilution and interpreted according to Clinical and Laboratory Standards Institute's document M24-A2. RESULTS: A total of 104 NTM were included in the study. Of these, 76% (54/71) rapidly growing mycobacteria (RGM) and 57.6% (19/33) slow growing mycobacteria (SGM) could be further identified. Mycobacterium fortuitum (21/54) was the commonest NTM identified among RGM followed by M. mucogenicum (12/54) and M. smegmatis (11/54). Among SGM, M. avium complex (MAC) was the most frequent (14/19). Clinical significance could be assessed in a limited number (52/104) of NTM isolates and MAC appeared to be the commonest significant NTM. Three extra-pulmonary cases were found to be healthcare associated infections. DST results for RGM showed susceptibility to amikacin (100%), clarithromycin (100%, except M. fortuitum where it is not reportable), linezolid (90%) and moxifloxacin (75%). Whereas SGM were susceptible to clarithromycin (100%), linezolid (58.8%) and moxifloxacin (64.7%). CONCLUSION: This is the first study reporting NTM species and their clinical significance isolated from clinical specimens from Pakistan. Isolation of NTM from clinical specimens should prompt to evaluate their clinical significance. PMID- 24148199 TI - Power to the people: does Eterna signal the arrival of a new wave of crowd sourced projects? PMID- 24148200 TI - Inter-arm blood pressure difference. PMID- 24148202 TI - Neighborhood perceptions moderate the association between the family environment and children's objectively assessed physical activity. AB - This study aimed to investigate whether parents' perceptions of the neighborhood environment moderate associations between the family environment and children's moderate- to vigorous-intensity physical activity (MVPA) outside of school hours. In total, 929 parents of 10-12 year-old children completed a questionnaire concerning the family environment, MVPA levels, and the neighborhood environment. Children wore an Actigraph (AM7164-2.2C) accelerometer. Compared with neighborhood environment factors, the family environment was more frequently associated with children's MVPA. Parental MVPA was positively associated with children's MVPA, but only among children whose parents reported a high presence of sporting venues. Having more restrictive physical activity rules was negatively associated with children's weekday MVPA in neighborhoods with high perceived stranger danger. PMID- 24148201 TI - Discrete land uses and transportation walking in two U.S. cities: the Multi Ethnic Study of Atherosclerosis. AB - This study examines associations of disaggregate land uses with self-reported walking for transportation among participants of the Multi-Ethnic Study of Atherosclerosis (MESA) in Forsyth County, NC and New York, NY. Network distance to each use (in miles), intensity (number of uses per 1/2-mile network buffer) of each use and diversity (number of different uses per 1/2-mile network buffer) of uses were calculated using Geographic Information Systems (GIS). Associations with odds of meeting recommended physical activity levels (150min/week) were examined after controlling for individual- and census-tract-level covariates. Greater distance to and lower intensity of pedestrian-oriented uses, specifically those for social interactions, were associated with lower odds of meeting recommendations in NY. Results suggest that land uses linked to social interactions may be useful for encouraging increased transportation walking. PMID- 24148203 TI - Vestibular functioning and migraine: pilot study comparing those with and without vertigo. AB - BACKGROUND: The current study compared a migrainous vertigo group with a migraine without vertigo group. It was hypothesised that those with migrainous vertigo would have more abnormal test results during a non-migrainous period than those who suffer from migraine without vertigo. METHODS: Both groups, comprising 10 participants each, were tested using: the gaze stabilisation test, dynamic visual acuity test, sensory organisation test, head shake sensory organisation test and functional gait assessment. RESULTS: Eighteen females and 2 males aged 18-53 years participated. There were no significant differences between the two groups for the dynamic visual acuity test, sensory organisation test or head shake sensory organisation test. However, mean dynamic visual acuity loss was greater in both groups than in a normal population, and the head shake sensory organisation (sway) test was well below the normal mean. The functional gait assessment showed a significant difference (p = 0.0025) between the two groups. CONCLUSION: Both groups showed abnormalities in vestibular functioning compared with norms, suggesting that both had some degree of vestibular dysfunction. However, vestibular dysfunction was greater in the migrainous vertigo group than in the migraine without vertigo group, as evidenced by differences in functional gait assessment. PMID- 24148204 TI - Role of serum levels of angiogenic cytokines in assessment of angiogenesis after stem cell therapy of diabetic patients with critical limb ischemia. AB - The release of proangiogenic cytokines into the circulation after stem cell (SC) therapy and compensatory increase of angiogenesis inhibitors may reflect local vasculogenesis but also can increase the risk of side effects. The aim of our study was to evaluate serum levels of angiogenic cytokines with regard to the assessment of local and systemic vasculogenesis in diabetic patients with no option critical limb ischemia (NO-CLI). Twenty-five diabetic patients with NO-CLI treated with SCs isolated from bone marrow or stimulated peripheral blood were included in the study. Serum levels of proangiogenic cytokines (VEGF, bFGF, Ang 1, PDGF-AA, and PDGF-BB) and an antiangiogenic cytokine (endostatin) were assessed 6 months after cell treatment, compared to baseline values, and correlated with the number of injected CD34(+) cells. The clinical effect of SC therapy (assessed by changes in TcPO2) and potential systemic vasculogenesis (assessed by eye fundus examination) were evaluated after 6 months. Serum levels of angiogenic inhibitor endostatin increased significantly after 1 and 3 months (p = 0.0003), but no significant increase in serum levels of proangiogenic cytokines was observed. A significant correlation between number of injected CD34(+) cells and serum levels of endostatin was observed (r = 0.41, p < 0.05); however, proangiogenic cytokines did not correlate with CD34(+) cells. No correlation between increase in TcPO2 after treatment and serum levels of any of the angiogenic cytokines were seen, and no signs of systemic vasculogenesis in the retina were observed after 6 months. Despite the significant increase in the levels of the angiogenic inhibitor endostatin following SC treatment, there was no risk of systemic vasculogenesis after SC therapy as documented by serum levels of proangiogenic cytokines or changes in the retina. PMID- 24148206 TI - Sociotechnical challenges and progress in using social media for health. AB - Social media tools that connect patients, caregivers, and health providers offer great potential for helping people access health advice, receive and give social support, manage or cope with chronic conditions, and make day-to-day health decisions. These systems have seen widespread adoption, but often fail to support the goals as fully as designers and users would like. Through Ackerman's lens of the "sociotechnical gap" and computer supported cooperative work (CSCW) as a science of the artificial, we review contemporary sociotechnical challenges and progress for using social media to support health. These challenges include a tension between privacy and sharing, policy information credibility, accessibility, and tailoring in social spaces. Those studying, building, deploying, and using social media systems to further health goals will benefit from approaching this work by borrowing from Ackerman's framing of CSCW. In particular, this requires acknowledgment that technical systems will not fully meet our social goals, and then adopting design and educational approaches that are appropriate to fill this gap, building less-nuanced systems as partial solutions and tools for advancing our understanding, and by working with the CSCW research community to develop and pursue key lines of inquiry. PMID- 24148207 TI - "Us and them": a social network analysis of physicians' professional networks and their attitudes towards EBM. AB - BACKGROUND: Extant research suggests that there is a strong social component to Evidence-Based Medicine (EBM) adoption since professional networks amongst physicians are strongly associated with their attitudes towards EBM. Despite this evidence, it is still unknown whether individual attitudes to use scientific evidence in clinical decision-making influence the position that physicians hold in their professional network. This paper explores how physicians' attitudes towards EBM is related to the network position they occupy within healthcare organizations. METHODS: Data pertain to a sample of Italian physicians, whose professional network relationships, demographics and work-profile characteristics were collected. A social network analysis was performed to capture the structural importance of physicians in the collaboration network by the means of a core periphery analysis and the computation of network centrality indicators. Then, regression analysis was used to test the association between the network position of individual clinicians and their attitudes towards EBM. RESULTS: Findings documented that the overall network structure is made up of a dense cohesive core of physicians and of less connected clinicians who occupy the periphery. A negative association between the physicians' attitudes towards EBM and the coreness they exhibited in the professional network was also found. Network centrality indicators confirmed these results documenting a negative association between physicians' propensity to use EBM and their structural importance in the professional network. CONCLUSIONS: Attitudes that physicians show towards EBM are related to the part (core or periphery) of the professional networks to which they belong as well as to their structural importance. By identifying virtuous attitudes and behaviors of professionals within their organizations, policymakers and executives may avoid marginalization and stimulate integration and continuity of care, both within and across the boundaries of healthcare providers. PMID- 24148205 TI - Cross-talk of membrane lipids and Alzheimer-related proteins. AB - Alzheimer's disease (AD) is neuropathologically characterized by the combined occurrence of extracellular beta-amyloid plaques and intracellular neurofibrillary tangles in the brain. While plaques contain aggregated forms of the amyloid beta-peptide (Abeta), tangles are formed by fibrillar forms of the microtubule associated protein tau. All mutations identified so far to cause familial forms of early onset AD (FAD) are localized close to or within the Abeta domain of the amyloid precursor protein (APP) or in the presenilin proteins that are essential components of a protease complex involved in the generation of Abeta. Mutations in the tau gene are not associated with FAD, but can cause other forms of dementia. The genetics of FAD together with biochemical and cell biological data, led to the formulation of the amyloid hypothesis, stating that accumulation and aggregation of Abeta is the primary event in the pathogenesis of AD, while tau might mediate its toxicity and neurodegeneration.The generation of Abeta involves sequential proteolytic cleavages of the amyloid precursor protein (APP) by enzymes called beta-and gamma-secretases. Notably, APP itself as well as the secretases are integral membrane proteins. Thus, it is very likely that membrane lipids are involved in the regulation of subcellular transport, activity, and metabolism of AD related proteins.Indeed, several studies indicate that membrane lipids, including cholesterol and sphingolipids (SLs) affect Abeta generation and aggregation. Interestingly, APP and other AD associated proteins, including beta-and gamma-secretases can, in turn, influence lipid metabolic pathways. Here, we review the close connection of cellular lipid metabolism and AD associated proteins and discuss potential mechanisms that could contribute to initiation and progression of AD. PMID- 24148208 TI - Study protocol of the Restore4Stroke self-management study: a multicenter randomized controlled trial in stroke patients and their partners. AB - RATIONALE: Many stroke patients and their partners report long-term negative consequences of stroke on their health-related quality of life. Adequate self management abilities may help manage the consequences of the stroke, but it is unknown what specific intervention might be effective to enhance self-management abilities of stroke patients and their partners. AIM: The study aims to investigate the effectiveness of a 10-week group self-management intervention addressing proactive coping strategies compared with a group education intervention in stroke patients and their partners. DESIGN: The study is a multicenter randomized controlled trial. A total of 106 stroke patients with, if applicable, their partners are randomly assigned to the self-management intervention or the education intervention within each of the 10 participating hospitals and rehabilitation centers. The main inclusion criteria are a symptomatic stroke at least six-weeks ago, living at home, and reporting at least two participation restrictions on the Utrecht Scale for Evaluation of Rehabilitation-Participation's restriction scale. Measurements are performed at baseline, immediately after intervention, three-months, and nine-months postintervention. STUDY OUTCOMES: Primary outcome measures are stroke patients' and partners' proactive coping competencies (Proactive Competence Inventory) and societal participation (Utrecht Scale for Evaluation of Rehabilitation Participation's restriction scale). DISCUSSION: If effective, the results of this study will enable stroke patients and their partners to deal better with the lasting consequences of stroke. In the context of the growing number of people returning home after stroke, a large number of people may profit from this intervention. PMID- 24148209 TI - Composite endpoints in trials of type-2 diabetes. AB - Composite endpoints (CEPs) are being used more frequently as outcomes for trials of drugs in type-2 diabetes. We reviewed the literature to determine how CEPs have been used to date in trials of drugs for type-2 diabetes. A systematic search was undertaken on Medline, Embase and Cochrane databases and Clinicaltrials.gov for randomized controlled trials of currently marketed agents including SGLT-2 inhibitors (dapagliflozin), GLP-1 agonists (exenatide, liraglutide) and DPP-4 inhibitors (linagliptin, saxagliptin, sitagliptin and vildagliptin). CEPs used were identified as well as numbers and percentages of patients achieving each. Thirty-six studies were identified that reported results on >=1 CEP; 15 different CEPs were reported (7 with 2 components, 8 with 3 components). All CEPs addressed goals recommended by the American Diabetes Association (ADA). All included HbA1c<7%; other endpoints measured weight, blood pressure and hypoglycaemic events. Results were obtained for CEPs from 6 months to 2 years. Rates of achieving CEPs decreased with increasing numbers of components and outcomes assessed. CEPs are becoming used as indicators of clinical outcomes in type-2 diabetes trials, but are still not common. More research is required to identify optimal CEPs. Standardization of outcomes and their reporting is needed. PMID- 24148210 TI - Familial adenomatous polyposis of the colon. AB - Familial adenomatous polyposis (FAP) is a well-defined autosomal dominant predisposition to the development of polyposis in the colon and rectum at unusually early ages. The first symptoms of FAP are diarrhea and blood in the stool. Weight loss and weaknesses occur after the development of advanced tumour. The incidence of the FAP disorder is one per 10000 newborns. There are high levels of heterogeneity with regard to the number and timing of the occurrence of polyps. The classical form of FAP is characterized by the presence of more than 100 polyps, which appear in the second decade of life. The average time of occurrence of polyps is 15 years. The earliest symptoms of polyposis have been observed in a three-year-old child. The polyps are characterized by large potential for the development towards malignant tumour. Malignancy can occur from late childhood onwards. Attenuated adenomatous polyposis coli is characterized by a more benign course of disease in contrast to classical FAP. The occurrence of FAP is associated with mutations in the APC tumour suppressor gene, which was described in 1991. The APC gene is located on chromosome 5q21 and is involved in cell proliferation control. A recessive form of adenomatous polyposis is caused by mutations in the base excision repair gene - MUTYH gene. The MUTYH gene is involved in repairing DNA lesions as a result of oxidative DNA damage. MUTYH associated polyposis (MAP) is a predisposition to the development of polyps of the colon but the number of polyps is lower in comparison to classical FAP. The high risks of cancer observed in these two diseases make them important medical issues. Molecular studies of colonic polyposis have been performed in Poland for over fifteen years. A DNA Bank for Polish FAP patients was established at the Institute of Human Genetics in Poznan in which DNA samples from 600 FAP families have been collected. PMID- 24148211 TI - Effect of adenotonsillectomy on visual attention tests among children with sleep disordered breathing: a controlled prospective cohort study. AB - OBJECTIVE: This study aimed to evaluate the effect of adenotonsillectomy on visual attention and daytime sleepiness in children with sleep-disordered breathing. DESIGN: This was a controlled prospective cohort study. SETTING: Outpatients from the Otorhinolaryngology Division of Edmundo Vasconcelos Hospital Complex, Sao Paulo, Brazil. PARTICIPANTS: Patients aged 6-17 years with upper airway obstruction scheduled to undergo adenotonsillectomy (treatment group) in the Otorhinolaryngology Division of Edmundo Vasconcelos Hospital Complex, in Sao Paulo, Brazil. Participants of control group were consecutively selected from another outpatient clinic of paediatric surgery, but those with symptoms of sleep disordered breathing were excluded. MAIN OUTCOME MEASURES: Children were submitted to visual attention tests (TAVIS-3) that discriminates normal subjects from those with attentional disorders in advance of the surgery and 2 months later, and in the same period for the control group. Parents were interviewed about lifestyle, sleep characteristics and daytime sleepiness. RESULTS: The analysis included 27 patients in the adenotonsillectomy group and 30 controls, who had similar age (10.0 +/- 3.3 versus 10.3 +/- 3.7 years; P = 0.8), gender (41% boys versus 57%, respectively) and body mass index. There was marked decrease in daytime sleepiness after surgery (delta between groups: -4.7 +/- 3.8; P < 0.001), as well as reductions in reaction time, errors of omission and errors of commission in the treatment compared with the control group at both time points, before and after surgery. CONCLUSIONS: This study shows that adenotonsillectomy in children and adolescents with sleep-disordered breathing reduces daytime sleepiness and improves the performance in tests of visual attention. PMID- 24148212 TI - Large-area high-performance SERS substrates with deep controllable sub-10-nm gap structure fabricated by depositing Au film on the cicada wing. AB - Noble metal nanogap structure supports strong surface-enhanced Raman scattering (SERS) which can be used to detect single molecules. However, the lack of reproducible fabrication techniques with nanometer-level control over the gap size has limited practical applications. In this letter, by depositing the Au film onto the cicada wing, we engineer the ordered array of nanopillar structures on the wing to form large-area high-performance SERS substrates. Through the control of the thickness of the Au film deposited onto the cicada wing, the gap sizes between neighboring nanopillars are fine defined. SERS substrates with sub 10-nm gap sizes are obtained, which have the highest average Raman enhancement factor (EF) larger than 2 * 108, about 40 times as large as that of commercial Klarite(r) substrates. The cicada wings used as templates are natural and environment-friendly. The depositing method is low cost and high throughput so that our large-area high-performance SERS substrates have great advantage for chemical/biological sensing applications. PMID- 24148213 TI - Communication in interdisciplinary teams: exploring closed-loop communication during in situ trauma team training. AB - OBJECTIVES: Investigate the use of call-out (CO) and closed-loop communication (CLC) during a simulated emergency situation, and its relation to profession, age, gender, ethnicity, years in profession, educational experience, work experience and leadership style. DESIGN: Exploratory study. SETTING: In situ simulator-based interdisciplinary team training using trauma cases at an emergency department. PARTICIPANTS: The result was based on 16 trauma teams with a total of 96 participants. Each team consisted of two physicians, two registered nurses and two enrolled nurses, identical to a standard trauma team. RESULTS: The results in this study showed that the use of CO and CLC in trauma teams was limited, with an average of 20 CO and 2.8 CLC/team. Previous participation in trauma team training did not increase the frequency of use of CLC while >=2 structured trauma courses correlated with increased use of CLC (risk ratio (RR) 3.17, CI 1.22 to 8.24). All professions in the trauma team were observed to initiate and terminate CLC (except for the enrolled nurse from the operation theatre). The frequency of team members' use of CLC increased significantly with an egalitarian leadership style (RR 1.14, CI 1.04 to 1.26). CONCLUSIONS: This study showed that despite focus on the importance of communication in terms of CO and CLC, the difficulty in achieving safe and reliable verbal communication within the interdisciplinary team remained. This finding indicates the need for validated training models combined with further implementation studies. PMID- 24148214 TI - Prevalence and long-term clinical significance of intracranial atherosclerosis after ischaemic stroke or transient ischaemic attack: a cohort study. AB - OBJECTIVES: We investigated the prevalence and long-term risk associated with intracranial atherosclerosis identified during routine evaluation. DESIGN: This study presents data from a prospective cohort of patients admitted to our stroke unit for thrombolysis evaluation. SETTING AND PARTICIPANTS: We included 652 with a final diagnosis of ischaemic stroke or transient ischaemic attack (TIA) from April 2009 to December 2011. All patients were acutely evaluated with cerebral CT and CT angiography (CTA). Acute radiological examinations were screened for intracranial arterial stenosis (IAS) or intracranial arterial calcifications (IAC). Intracranial stenosis was grouped into 30-50%, 50-70% and >70% lumen reduction. The extent of IAC was graded as number of vessels affected. PRIMARY AND SECONDARY OUTCOME MEASURE: Patients were followed until July 2013. Recurrence of an ischaemic event (stroke, ischaemic heart disease (IHD) and TIA) was documented through the national chart system. Poor outcome was defined as death or recurrence of ischaemic event. RESULTS: 101 (15.5%) patients showed IAS (70: 30-50%, 29: 50-70% and 16: >70%). Two-hundred and fifteen (33%) patients had no IAC, 339 (52%) in 1-2 vessels and 102 (16%) in >2 vessels. During follow-up, 53 strokes, 20 TIA and 14 IHD occurred, and 95 patients died. The risk of poor outcome was significantly different among different extents of IAS as well as IAC (log-rank test p<0.01 for both). In unadjusted analysis IAS and IAC predicted poor outcome and recurrent ischaemic event. When adjusted, IAS and IAC independently increased the risk of a recurrent ischaemic event (IAS: HR 1.67; CI 1.04 to 2.64 and IAC: HR 1.22; CI 1.02 to 1.47). CONCLUSIONS: Intracranial atherosclerosis detected during acute evaluation predicts an increased risk of recurrent stroke. PMID- 24148215 TI - Vestibular functioning and migraine: comparing those with and without vertigo to a normal population. AB - OBJECTIVE: This study compared vestibular functioning in a migrainous vertigo group, a migraine without vertigo group and a control group. It was hypothesised that the migrainous vertigo group would perform worse in tests of vestibular function and gait than the other groups during a non-migrainous period. METHODS: Sixty-six participants (22 per group) were assessed using the head shake sensory organisation test, the gaze stabilisation test, the dynamic visual acuity test and the functional gait assessment. Separate analyses of variance and planned pair-wise comparisons (alpha = 0.05) were performed. RESULTS: There was a difference between the results of the non-migraine group and the two migraine groups for the gaze stabilisation pitch test (p < 0.003), in which the control group showed faster head movement. There were also group differences in functional gait (p < 0.0001); the control group scored highest and the migrainous vertigo group scored lowest. There were no differences in the vestibular spinal reflex and balance tests. CONCLUSION: These findings indicate underlying differences in the vestibular ocular reflexes and function of migraine sufferers compared with those who do not suffer migraines, but the difference is most pronounced for those with migrainous vertigo. This suggests that vestibular rehabilitation for migrainous vertigo should focus on vestibular ocular reflexes and functional retraining. PMID- 24148216 TI - Parametric sensitivity analysis for biochemical reaction networks based on pathwise information theory. AB - BACKGROUND: Stochastic modeling and simulation provide powerful predictive methods for the intrinsic understanding of fundamental mechanisms in complex biochemical networks. Typically, such mathematical models involve networks of coupled jump stochastic processes with a large number of parameters that need to be suitably calibrated against experimental data. In this direction, the parameter sensitivity analysis of reaction networks is an essential mathematical and computational tool, yielding information regarding the robustness and the identifiability of model parameters. However, existing sensitivity analysis approaches such as variants of the finite difference method can have an overwhelming computational cost in models with a high-dimensional parameter space. RESULTS: We develop a sensitivity analysis methodology suitable for complex stochastic reaction networks with a large number of parameters. The proposed approach is based on Information Theory methods and relies on the quantification of information loss due to parameter perturbations between time series distributions. For this reason, we need to work on path-space, i.e., the set consisting of all stochastic trajectories, hence the proposed approach is referred to as "pathwise". The pathwise sensitivity analysis method is realized by employing the rigorously-derived Relative Entropy Rate, which is directly computable from the propensity functions. A key aspect of the method is that an associated pathwise Fisher Information Matrix (FIM) is defined, which in turn constitutes a gradient-free approach to quantifying parameter sensitivities. The structure of the FIM turns out to be block-diagonal, revealing hidden parameter dependencies and sensitivities in reaction networks. CONCLUSIONS: As a gradient free method, the proposed sensitivity analysis provides a significant advantage when dealing with complex stochastic systems with a large number of parameters. In addition, the knowledge of the structure of the FIM can allow to efficiently address questions on parameter identifiability, estimation and robustness. The proposed method is tested and validated on three biochemical systems, namely: (a) a protein production/degradation model where explicit solutions are available, permitting a careful assessment of the method, (b) the p53 reaction network where quasi-steady stochastic oscillations of the concentrations are observed, and for which continuum approximations (e.g. mean field, stochastic Langevin, etc.) break down due to persistent oscillations between high and low populations, and (c) an Epidermal Growth Factor Receptor model which is an example of a high-dimensional stochastic reaction network with more than 200 reactions and a corresponding number of parameters. PMID- 24148217 TI - Effect of platelet count on platelet aggregation measured with impedance aggregometry (MultiplateTM analyzer) and with light transmission aggregometry. PMID- 24148218 TI - Dipeptidyl peptidase-4 inhibitors and GLP-1 reduce myocardial infarct size in a glucose-dependent manner. AB - BACKGROUND: The dipeptidyl peptidase-4 (DPP-4) inhibitors Sitagliptin and Vildagliptin lower blood glucose by augmenting endogenous levels of glucagon-like peptide-1 (GLP-1), an incretin which also confers cardioprotection. As such, we hypothesized that treatment with DPP-4 inhibitors are also cardioprotective. METHODS: In ex vivo experiments: Male Sprague-Dawley rats were randomized to receive by oral gavage either Vildagliptin (20 mg/kg/day), Sitagliptin (100 mg/kg/day), or water for 2 weeks. Excised hearts were Langendorff-perfused with buffer containing either 5 mmol/L or 11 mmol/L glucose and subjected to 35 minutes ischaemia/120 minutes reperfusion. In in vivo experiments: Male young Wistar and Sprague-Dawley rats, middle aged Wistar and Goto-Kakizaki diabetic rats were randomized to receive by oral gavage either Sitagliptin (100 mg/kg/day), or water for 2 weeks. Rats were then subjected to 30 minutes ischaemia/120 minutes reperfusion and infarct size ascertained. RESULTS: Two weeks pre-treatment with either Vildagliptin or Sitagliptin reduced ex vivo myocardial infarction (MI) size in hearts perfused with buffer containing 11 mmol/L glucose but not 5 mmol/L glucose. This effect was abolished by Exendin 9 39 (GLP-1 receptor antagonist) and H-89 (PKA antagonist). Treatment of perfused hearts with native GLP-1 was also glucose-sensitive, reducing MI size, at glucose concentrations 7, 9, and 11 mmol/L but not at 5 mmol/L. Finally, Sitagliptin reduced in vivo MI size in middle aged Wistar (7-8 mmol/L glucose) and Goto Kakizaki (9-10 mmol/L glucose) rats where blood glucose was elevated, but not in young Wistar (5 mmol/L glucose) or Sprague-Dawley (5 mmol/L glucose) rats, where blood glucose was normal. CONCLUSIONS: We find that chronic treatment with DPP-4 inhibitors reduced MI size, via the GLP-1 receptor-PKA pathway, in a glucose dependent manner. Glucose-sensitive cardioprotection of endogenous GLP-1 in diabetic patients may in part explain why intensive control of serum glucose levels has been associated with increased cardiovascular risk. PMID- 24148219 TI - DNA prime and peptide boost immunization protocol encoding the Toxoplasma gondii GRA4 induces strong protective immunity in BALB/c mice. AB - BACKGROUND: Toxoplasma gondii is a widespread intracellular parasite, which infects most vertebrate animal hosts and causes zoonotic infection in humans. Vaccine strategy remains a promising method for the prevention and control of toxoplasmosis. T. gondii GRA4 protein has been identified as a potential candidate for vaccine development. In our study, we evaluated the immune response induced by four different immunization vaccination strategies encoding TgGRA4. METHODS: BALB/c mice were intramuscularly (i.m.) immunized four times according to specific immunization schedules. Generally, mice in experimental groups were immunized with polypeptide, pGRA4, peptide/DNA, or DNA/peptide, and mice in the control groups were injected with PBS or pEGFP. After immunization, the levels of IgG antibodies and cytokine productions were determined by enzyme-linked immunosorbent assays (ELISA). The survival time of mice was also evaluated after challenge infection with the highly virulent T. gondii RH strain. RESULTS: The results showed that mice vaccinated with different immunization regimens (polypeptide, pGRA4, peptide/DNA, or DNA/peptide) elicited specific humoral and cellular responses, with high levels of total IgG, IgG2a isotype and gamma interferon (IFN-gamma), which suggested a specific Th1 immunity was activated. After lethal challenge, an increased survival time was observed in immunized mice (11.8 +/- 4.8 days) compared to the control groups injected with PBS or pEGFP (P < 0.05). Mice injected with PBS or pEGFP died within 8 days, and there was no significant difference in the protection level in two groups (P > 0.05). CONCLUSIONS: These results demonstrated that this DNA prime and peptide boost immunization protocol encoding the TgGRA4 can elicit the highest level of humoral and cellular immune responses compared to other immunized groups, which is a promising approach to increase the efficacy of DNA immunization. PMID- 24148220 TI - Immunotherapy for Alzheimer's disease: hoops and hurdles. AB - Alzheimer's disease (AD) is the most common form of dementia, afflicting more than 30 million people worldwide. Currently, there is no cure or way to prevent this devastating disease. Extracellular plaques, containing various forms of amyloid-beta protein (Abeta), and intracellular neurofibrillary tangles (NFTs), composed of hyper-phosphorylated tau protein, are two major pathological hallmarks of the AD brain. Aggregation, deposition, and N-terminal modification of Abeta protein and tau phosphorylation and aggregation are thought to precede the onset of cognitive decline, which is better correlated with tangle formation and neuron loss. Active and passive vaccines against various forms of Abeta have shown promise in pre-clinical animal models. However, translating these results safely and effectively into humans has been challenging. Recent clinical trials showed little or no cognitive efficacy, possibly due to the fact that the aforementioned neurodegenerative processes most likely pre-existed in the patients well before the start of immunotherapy. Efforts are now underway to treat individuals at risk for AD prior to or in the earliest stages of cognitive decline with the hope of preventing or delaying the onset of the disease. In addition, efforts to immunize against tau and other AD-related targets are underway. PMID- 24148221 TI - The macrophage low-grade inflammation marker sCD163 is modulated by exogenous sex steroids. AB - Soluble CD163 (sCD163) is a novel marker linked to states of low-grade inflammation such as diabetes, obesity, liver disease, and atherosclerosis, all prevalent in subjects with Turner syndrome (TS) and Klinefelter syndrome (KS). We aimed to assess the levels of sCD163 and the regulation of sCD163 in regards to treatment with sex hormone therapy in males with and without KS and females with and without TS. Males with KS (n=70) and age-matched controls (n=71) participating in a cross-sectional study and 12 healthy males from an experimental hypogonadism study. Females with TS (n=8) and healthy age-matched controls (n=8) participating in a randomized crossover trial. The intervention comprised of treatment with sex steroids. Males with KS had higher levels of sCD163 compared with controls (1.75 (0.47-6.90) and 1.36 (0.77-3.11) respectively, P<0.001) and the levels correlated to plasma testosterone (r=-0.31, P<0.01), BMI (r=0.42, P<0.001), and homeostasis model of assessment insulin resistance (r=0.46, P<0.001). Treatment with testosterone did not significantly lower sCD163. Females with TS not receiving hormone replacement therapy (HRT) had higher levels of sCD163 than those of their age-matched healthy controls (1.38+/ 0.44 vs 0.91+/-0.40, P=0.04). HRT and oral contraceptive therapy decreased sCD163 in TS by 22% (1.07+/-0.30) and in controls by 39% (0.55+/-0.36), with significance in both groups (P=0.01 and P=0.04). We conclude that levels of sCD163 correlate with endogenous testosterone in KS and are higher in KS subjects compared with controls, but treatment did not significantly lower levels. Both endogenous and exogenous estradiol in TS was associated with lower levels of sCD163. PMID- 24148222 TI - 3-M syndrome: a growth disorder associated with IGF2 silencing. AB - 3-M syndrome is an autosomal recessive disorder characterised by pre- and post natal growth restriction, facial dysmorphism, normal intelligence and radiological features (slender long bones and tall vertebral bodies). It is known to be caused by mutations in the genes encoding cullin 7, obscurin-like 1 and coiled-coil domain containing 8. The mechanisms through which mutations in these genes impair growth are unclear. The aim of this study was to identify novel pathways involved in the growth impairment in 3-M syndrome. RNA was extracted from fibroblast cell lines derived from four 3-M syndrome patients and three control subjects, hybridised to Affymetrix HU 133 plus 2.0 arrays with quantitative real-time PCR used to confirm changes found on microarray. IGF-II protein levels in conditioned cell culture media were measured by ELISA. Of the top 10 downregulated probesets, three represented IGF2 while H19 was identified as the 23rd most upregulated probeset. QRT-PCR confirmed upregulation of H19 (P<0.001) and downregulation of IGF2 (P<0.001). Levels of IGF-II secreted into conditioned cell culture medium were higher for control fibroblasts than those for 3-M fibroblasts (10.2+/-2.9 vs 0.6+/-0.9 ng/ml, P<0.01). 3-M syndrome is associated with a gene expression profile of reduced IGF2 expression and increased H19 expression similar to that found in Silver-Russell syndrome. Loss of autocrine IGF-II in the growth plate may be associated with the short stature seen in children with 3-M syndrome. PMID- 24148223 TI - Enabling autologous human liver regeneration with differentiated adipocyte stem cells. AB - We developed a novel method for differentiating adipocyte-derived stem cells (ASCs) into hepatocyte-like cells (iHeps). ASCs are cultured as spherical cellular aggregates and are then induced by culture in chemically defined media for a short time period to differentiate into spherical culture iHeps (SCi-Heps). SCi-Heps have many of the in vitro functional properties of mature hepatocytes, and they can stably reconstitute functioning human liver in vivo in a murine model system. Implantation studies demonstrate that SCi-Heps have a very low malignant potential. All human liver regenerative procedures, including ultrasound-guided direct liver implantation, are scalable and appropriate for human clinical use. These methods can be used to achieve the major promise of regenerative medicine. It may now be possible to regenerate human liver using autologous stem cells obtained from a readily accessible tissue. PMID- 24148224 TI - Exploration of time-course combinations of outcome scales for use in a global test of stroke recovery. AB - BACKGROUND: Clinical trials for acute ischemic stroke treatment require large numbers of participants and are expensive to conduct. Methods that enhance statistical power are therefore desirable. AIMS: We explored whether this can be achieved by a measure incorporating both early and late measures of outcome (e.g. seven-day NIH Stroke Scale combined with 90-day modified Rankin scale). METHODS: We analyzed sensitivity to treatment effect, using proportional odds logistic regression for ordinal scales and generalized estimating equation method for global outcomes, with all analyses adjusted for baseline severity and age. We ran simulations to assess relations between sample size and power for ordinal scales and corresponding global outcomes. We used R version 2.12.1 (R Development Core Team. R Foundation for Statistical Computing, Vienna, Austria) for simulations and SAS 9.2 (SAS Institute Inc., Cary, NC, USA) for all other analyses. RESULTS: Each scale considered for combination was sensitive to treatment effect in isolation. The mRS90 and NIHSS90 had adjusted odds ratio of 1.56 and 1.62, respectively. Adjusted odds ratio for global outcomes of the combination of mRS90 with NIHSS7 and NIHSS90 with NIHSS7 were 1.69 and 1.73, respectively. The smallest sample sizes required to generate statistical power >=80% for mRS90, NIHSS7, and global outcomes of mRS90 and NIHSS7 combined and NIHSS90 and NIHSS7 combined were 500, 490, 400, and 380, respectively. DISCUSSION: When data concerning both early and late outcomes are combined into a global measure, there is increased sensitivity to treatment effect compared with solitary ordinal scales. This delivers a 20% reduction in required sample size at 80% power. Combining early with late outcomes merits further consideration. PMID- 24148225 TI - Phase II trial of short-course radiotherapy followed by delayed surgery for locoregionally advanced rectal cancer. AB - AIM: A prospective phase II study to investigate the feasibility and the rate of complete pathological response (ypT0) after short-course radiotherapy (SCRT) followed by surgery at 8 weeks. METHOD: Operable patients with localized rectal cancer staged T3-4N0/+ or T2N+ were eligible and received 25 Gy (in one-third of patients, the gross tumor volume received a simultaneous integrated boost up to a total of 30 Gy) in five consecutive fractions to the posterior pelvis followed by surgery 8 weeks later. Pathological response and surgical toxicity were assessed in all patients. RESULTS: Fifty-two patients (median age 68 years) completed the study. The median distance of the tumour from the anal verge was 6.5 cm. The median interval to surgery was 52 days. Three-quarters of patients underwent a low anterior resection. All underwent complete surgical resection and 100% had pathological negative margins. Ten per cent had stage ypT0 after radiotherapy. The median length of hospital stay was 8 days. Toxicity was comparable with the rates reported in the literature. CONCLUSION: In this study, SCRT followed by delayed surgery was feasible and had acceptable toxicity. All patients underwent complete surgical resection and 100% had negative pathological margins. The rate of ypT0 was 10%. PMID- 24148226 TI - The comparative validity of interactive multimedia questionnaires to paper administered questionnaires for beverage intake and physical activity: pilot study. AB - BACKGROUND: Brief, valid, and reliable dietary and physical activity assessment tools are needed, and interactive computerized assessments (ie, those with visual cues, pictures, sounds, and voiceovers) can reduce administration and scoring burdens commonly encountered with paper-based assessments. OBJECTIVE: The purpose of this pilot investigation was to evaluate the comparative validity and reliability of interactive multimedia (IMM) versions (ie, IMM-1 and IMM-2) compared to validated paper-administered (PP) versions of the beverage intake questionnaire (BEVQ-15) and Stanford Leisure-Time Activity Categorical Item (L Cat); a secondary purpose was to evaluate results across two education attainment levels. METHODS: Adults 21 years or older (n=60) were recruited to complete three laboratory sessions, separated by three to seven days in a randomly assigned sequence, with the following assessments-demographic information, two IMM and one paper-based (PP) version of the BEVQ-15 and L-Cat, health literacy, and an IMM usability survey. RESULTS: Responses across beverage categories from the IMM-1 and PP versions (validity; r=.34-.98) and the IMM-1 and IMM-2 administrations (reliability; r=.61-.94) (all P<.001) were significantly correlated. Paired t tests revealed significant differences in sugar-sweetened beverage (SSB) grams and kcal (P=.02 and P=.01, respectively) and total beverage kcal (P=.03), on IMM 1 and IMM-2; however, comparative validity was demonstrated between IMM-2 and the PP version suggesting familiarization with the IMM tool may influence participant responses (mean differences: SSB 63 grams, SEM 87; P=.52; SSB 21 kcal, SEM 33; P=.48; total beverage 65 kcal, SEM 49; P=.19). Overall mean scores between the PP and both IMM versions of the L-Cat were different (both P<.001); however, responses on all versions were correlated (P<.001). Differences between education categories were noted at each L-Cat administration (IMM-1: P=.008; IMM-2: P=.001; PP: P=.002). Major and minor themes from user feedback suggest that the IMM questionnaires were easy to complete, and relevant to participants' typical beverage choices and physical activity habits. CONCLUSIONS: In general, less educated participants consumed more total beverage and SSB energy, and reported less engagement in physical activity. The IMM BEVQ-15 appears to be a valid and reliable measure to assess habitual beverage intake, although software familiarization may increase response accuracy. The IMM-L-Cat can be considered reliable and may have permitted respondents to more freely disclose actual physical activity levels versus the paper-administered tool. Future larger-scale investigations are warranted to confirm these possibilities. PMID- 24148227 TI - Multicolor Layer-by-Layer films using weak polyelectrolyte assisted synthesis of silver nanoparticles. AB - In the present study, we show that silver nanoparticles (AgNPs) with different shape, aggregation state and color (violet, green, orange) have been successfully incorporated into polyelectrolyte multilayer thin films using the layer-by-layer (LbL) assembly. In order to obtain colored thin films based on AgNPs is necessary to maintain the aggregation state of the nanoparticles, a non-trivial aspect in which this work is focused on. The use of Poly(acrylic acid, sodium salt) (PAA) as a protective agent of the AgNPs is the key element to preserve the aggregation state and makes possible the presence of similar aggregates (shape and size) within the LbLcolored films. This approach based on electrostatic interactions of the polymeric chains and the immobilization of AgNPs with different shape and size into the thin films opens up a new interesting perspective to fabricate multicolornanocomposites based on AgNPs. PMID- 24148228 TI - Latitudinal and seasonal variation in reproductive effort of the eastern fence lizard (Sceloporus undulatus). AB - Geographic variation in life-history traits among populations of wide-ranging species is influenced by both spatial and temporal aspects of the environment. Rarely, however, are the effects of both aspects examined concurrently. We collected gravid female lizards (Sceloporus undulatus) from northern (Indiana), central (Mississippi) and southern (Florida) populations, spanning nearly the full latitudinal range of the species, to examine among population differences in strategies of reproductive energy allocation. Adult females from the southern population were smaller, and produced fewer and smaller eggs in their first clutches than did females from the more northern populations. Southern females were more likely to produce a second clutch, and second clutches were smaller than first clutches for females from the 2 northern populations. Together these trends eliminated population differences in overall reproductive output after accounting for body size. The trend for greater reproductive energy to be allocated to first clutches at higher latitudes, and to later clutches at lower latitudes is corroborated by published data from field studies on multiple populations. Distributing reproductive effort by producing more clutches of smaller eggs may be an adaptive response to the long season available for egg incubation and lizard activity in sub-tropical southern environments. In contrast, allocating greater resources to early reproduction may enhance maternal fitness in the relatively short activity seasons that characterize more northern sites. PMID- 24148229 TI - Metal mobility and toxicity to microalgae associated with acidification of sediments: CO2 and acid comparison. AB - The injection and storage of CO2 into marine geological formations has been suggested as a mitigation measure to prevent global warming. However, storage leaks are possible resulting in several effects in the ecosystem. Laboratory scale experiments were performed to evaluate the effects of CO2 leakage on the fate of metals and on the growth of the microalgae Phaeodactylum tricornutum. Metal contaminated sediments were collected and submitted to acidification by means of CO2 injection or by adding HCl. Sediments elutriate were prepared to perform toxicity tests. The results showed that sediment acidification enhanced the release of metals to elutriates. Iron and zinc were the metals most influenced by this process and their concentration increased greatly with pH decreases. Diatom growth was inhibited by both processes: acidification and the presence of metals. Data obtained is this study is useful to calculate the potential risk of CCS activities to the marine environment. PMID- 24148230 TI - Anterior rhinoscopy and middle meatal culture in acute rhinosinusitis. AB - OBJECTIVE: To assess the use of bacterial culture findings for middle meatal samples obtained via anterior rhinoscopy, in the diagnosis of adults with acute rhinosinusitis. MATERIALS AND METHODS: Microbial cultures were prepared for 30 adult patients with acute rhinosinusitis and suspected bacterial involvement, using samples from the nasopharynx, and from the nasal middle meatus obtained via anterior rhinoscopy. Findings for the ipsilateral maxillary antrum were used as a reference. RESULTS: Seventeen patients had a bacterial infection as verified by a positive culture from the maxillary antrum. Middle meatal samples had a similar sensitivity but a better specificity, positive predictive value and negative predictive value, compared with nasopharyngeal samples, although predictive values were not statistically significant at a 95 per cent confidence level. CONCLUSION: Anterior rhinoscopy with culture of middle meatal samples can be recommended as a diagnostic procedure for acute rhinosinusitis. The results can also guide the decision on antibiotic treatment. PMID- 24148231 TI - HOXB1 restored expression promotes apoptosis and differentiation in the HL60 leukemic cell line. AB - BACKGROUND: Homeobox (HOX) genes deregulation has been largely implicated in the development of human leukemia. Among the HOXB cluster, HOXB1 was silent in a number of analyzed acute myeloid leukemia (AML) primary cells and cell lines, whereas it was expressed in normal terminally differentiated peripheral blood cells. METHODS: We evaluated the biological effects and the transcriptome changes determined by the retroviral transduction of HOXB1 in the human promyelocytic cell line HL60. RESULTS: Our results suggest that the enforced expression of HOXB1 reduces cell growth proliferation, inducing apoptosis and cell differentiation along the monocytic and granulocytic lineages. Accordingly, gene expression analysis showed the HOXB1-dependent down-regulation of some tumor promoting genes, paralleled by the up-regulation of apoptosis- and differentiation-related genes, thus supporting a tumor suppressor role for HOXB1 in AML. Finally, we indicated HOXB1 promoter hypermethylation as a mechanism responsible for HOXB1 silencing. CONCLUSIONS: We propose HOXB1 as an additional member of the HOX family with tumour suppressor properties suggesting a HOXB1/ATRA combination as a possible future therapeutic strategy in AML. PMID- 24148232 TI - New insights in osteogenic differentiation revealed by mass spectrometric assessment of phosphorylated substrates in murine skin mesenchymal cells. AB - BACKGROUND: Bone fractures and loss represent significant costs for the public health system and often affect the patients quality of life, therefore, understanding the molecular basis for bone regeneration is essential. Cytokines, such as IL-6, IL-10 and TNFalpha, secreted by inflammatory cells at the lesion site, at the very beginning of the repair process, act as chemotactic factors for mesenchymal stem cells, which proliferate and differentiate into osteoblasts through the autocrine and paracrine action of bone morphogenetic proteins (BMPs), mainly BMP-2. Although it is known that BMP-2 binds to ActRI/BMPR and activates the SMAD 1/5/8 downstream effectors, little is known about the intracellular mechanisms participating in osteoblastic differentiation. We assessed differences in the phosphorylation status of different cellular proteins upon BMP-2 osteogenic induction of isolated murine skin mesenchymal stem cells using Triplex Stable Isotope Dimethyl Labeling coupled with LC/MS. RESULTS: From 150 MUg of starting material, 2,264 proteins were identified and quantified at five different time points, 235 of which are differentially phosphorylated. Kinase motif analysis showed that several substrates display phosphorylation sites for Casein Kinase, p38, CDK and JNK. Gene ontology analysis showed an increase in biological processes related with signaling and differentiation at early time points after BMP2 induction. Moreover, proteins involved in cytoskeleton rearrangement, Wnt and Ras pathways were found to be differentially phosphorylated during all timepoints studied. CONCLUSIONS: Taken together, these data, allow new insights on the intracellular substrates which are phosphorylated early on during differentiation to BMP2-driven osteoblastic differentiation of skin-derived mesenchymal stem cells. PMID- 24148233 TI - Infection by Brazilian and Dutch swine hepatitis E virus strains induces haematological changes in Macaca fascicularis. AB - BACKGROUND: Hepatitis E virus (HEV) has been described as an emerging pathogen in Brazil and seems to be widely disseminated among swine herds. An autochthonous human case of acute hepatitis E was recently reported. To obtain a better understanding of the phenotypic profiles of both human and swine HEV strains, a experimental study was conducted using the animal model, Macaca fascicularis. METHODS: Six cynomolgus monkeys (Macaca fascicularis) were inoculated intravenously with swine HEV genotype 3 that was isolated from naturally and experimentally infected pigs in Brazil and the Netherlands. Two other monkeys were inoculated with HEV genotype 3 that was recovered from Brazilian and Argentinean patients with locally acquired acute and fulminant hepatitis E. The haematological, biochemical, and virological parameters of all animals were monitored for 67 days. RESULTS: Subclinical hepatitis was observed in all monkeys after inoculation with HEV genotype 3 that was recovered from the infected swine and human patients. HEV RNA was detected in the serum and/or faeces of 6 out of the 8 cynomolgus monkeys between 5 and 53 days after inoculation. The mild inflammation of liver tissues and elevations of discrete liver enzymes were observed. Seroconversions to anti-HEV IgM and/or IgG were detected in 7 animals. Reactivities to anti-HEV IgA were also detected in the salivary samples of 3 animals. Interestingly, all of the infected monkeys showed severe lymphopenia and a trend toward monocytosis, which coincided with elevations in alanine aminotransferase and antibody titres. CONCLUSIONS: The ability of HEV to cross the species barrier was confirmed for both the swine (Brazilian and Dutch) and human (Argentinean) strains, thus reinforcing the zoonotic risk of hepatitis E in South America. Cynomolgus monkeys that were infected with HEV genotype 3 developed subclinical hepatitis that was associated with haematological changes. Haematological approaches should be considered in future studies of HEV infection. PMID- 24148234 TI - Computational deconvolution: extracting cell type-specific information from heterogeneous samples. AB - The quanta unit of the immune system is the cell, yet analyzed samples are often heterogeneous with respect to cell subsets which can mislead result interpretation. Experimentally, researchers face a difficult choice whether to profile heterogeneous samples with the ensuing confounding effects, or a priori focus on a few cell subsets of interest, potentially limiting new discoveries. An attractive alternative solution is to extract cell subset-specific information directly from heterogeneous samples via computational deconvolution techniques, thereby capturing both cell-centered and whole system level context. Such approaches are capable of unraveling novel biology, undetectable otherwise. Here we review the present state of available deconvolution techniques, their advantages and limitations, with a focus on blood expression data and immunological studies in general. PMID- 24148235 TI - Natural killer T (NKT) cells in autoimmune hepatitis. AB - Natural killer T (NKT) cells represent an innate-like lymphocyte population endowed with unique antigen recognition and tissue distribution features. Their abundance in the microvascular compartments of the liver allows NKT cells to immediately respond to lipid antigens and soluble factors circulating through the portal vein system by releasing tremendous amounts of different cytokines and chemokines. Subsequently, dependent on the nature of the lipid antigen encountered as well as the accessory signal(s) provided, NKT cells not only contribute to the maintenance of immune tolerance, but also direct adverse immune reactions locally and systemically. Focusing on their potent immunomodulatory features and their interactions with various innate and adaptive immune cells, the role of NKT cells in perpetuating the loss of liver-specific immune tolerance will be discussed. PMID- 24148236 TI - Lineage relationship of effector and memory T cells. AB - Adaptive immunity is characterized by the ability to form long-lived immunological memory. Upon re-exposure to antigen, memory T cells respond more rapidly and robustly than naive T cells, providing better clearance of pathogens. Recent reviews have reinforced the text-book view that memory T cells arise from effector cells. Although this notion is teleologically appealing, emerging data are more consistent with a model where naive cells directly develop into memory cells without transitioning through an effector stage. A clear understanding of the lineage relationships between memory and effector cells has profound implications for the design of vaccines and for the development of effective T cell-based therapies. PMID- 24148237 TI - A fatigue assessment technique for modular and pre-stressed orthopaedic implants. AB - Orthopaedic implants experience large cyclic loads, and pre-clinical analysis is conducted to ensure they can withstand millions of loading cycles. Acetabular cup developments aim to reduce wall thickness to conserve bone, and this produces high pre-stress in modular implants. As part of an implant development process, we propose a technique for preclinical fatigue strength assessment of modular implants which accounts for this mean stress, stress concentrating features and material processing. A modular cup's stress distributions were predicted computationally, under assembly and in vivo loads, and its cyclic residual stress and stress amplitude were calculated. For verification against damage initiation in low-cycle-fatigue (LCF), the peak stress was compared to the material's yield strength. For verification against failure in high-cycle-fatigue (HCF) each element's reserve factor was calculated using the conservative Soderberg infinite life criterion. Results demonstrated the importance of accounting for mean stress. The cup was predicted to experience high cyclic mean stress with low magnitude stress amplitude: a low cyclic load ratio (Rl=0.1) produced a high cyclic stress ratio (Rs=0.80). Furthermore the locations of highest cyclic mean stress and stress amplitude did not coincide. The minimum predicted reserve factor Nf was 1.96 (HCF) and 2.08 (LCF). If mean stress were neglected or if the stress ratio were assumed to equal the load ratio, the reserve factor would be considerably lower, potentially leading to over-engineering, reducing bone conservation. Fatigue strength evaluation is only one step in a broader development process, which should involve a series of verifications with the full range of normal and traumatic physiological loading scenarios, with representative boundary conditions and a representative environment. This study presents and justifies a fatigue analysis methodology which could be applied in early stage development to a variety of modular and pre-stressed prosthesis concepts, and is particularly relevant as implant development aims to maximise modularity and bone conservation. PMID- 24148238 TI - Pneumatic cell stretching system for cardiac differentiation and culture. AB - This paper introduces a compact mechanical stimulation device suitable for applications to study cellular mechanobiology. The pneumatically controlled device provides equiaxial strain for cells on a coated polydimethylsiloxane (PDMS) membrane and enables real time observation of cells with an inverted microscope. This study presents the implementation and operation principles of the device and characterizes membrane stretching. Different coating materials are also analyzed on an unstretched membrane to optimize the cell attachment on PDMS. As a result, gelatin coating was selected for further experiments to demonstrate the function of the device and evaluate the effect of long-term cyclic equiaxial stretching on human pluripotent stem cells (hPSCs). Cardiac differentiation was induced with mouse visceral endoderm-like (END-2) cells, either on an unstretched membrane or with mechanical stretching. In conclusion, hPSCs grew well on the stretching platform and cardiac differentiation was induced. Thus, the platform provides a new possibility to study the effect of stretching on cellular properties including differentiation and stress induced cardiac diseases. PMID- 24148239 TI - The use of gadolinium-carbon nanostructures to magnetically enhance stem cell retention for cellular cardiomyoplasty. AB - In this work, the effectiveness of using Gadonanotubes (GNTs) with an external magnetic field to improve retention of transplanted adult mesenchymal stem cells (MSCs) during cellular cardiomyoplasty was evaluated. As a high-performance T1 weighted magnetic resonance imaging (MRI) cell tracking label, the GNTs are gadolinium-loaded carbon nanotube capsules that render MSCs magnetic when internalized. MSCs were internally labeled with either superparamagnetic GNTs or colloidal diamagnetic lutetium (Lu). In vitro cell rolling assays and ex vivo cardiac perfusion experiments qualitatively demonstrated increased magnetic assisted retention of GNT-labeled MSCs. Subsequent in vivo epicardial cell injections were performed around a 1.3 T NdFeB ring magnet sutured onto the left ventricle of female juvenile pigs (n = 21). Cell dosage, magnet exposure time, and endpoints were varied to evaluate the safety and efficacy of the proposed therapy. Quantification of retained cells in collected tissues by elemental analysis (Gd or Lu) showed that the external magnet helped retain nearly three times more GNT-labeled MSCs than Lu-labeled cells. The sutured magnet was tolerated for up to 168 h; however, an inflammatory response to the magnet was noted after 48 h. These proof-of-concept studies support the feasibility and value of using GNTs as a magnetic nanoparticle facilitator to improve cell retention during cellular cardiomyoplasty. PMID- 24148240 TI - Mechanistic study of IR-780 dye as a potential tumor targeting and drug delivery agent. AB - IR-780 iodide, a near-infrared fluorescent heptamethine dye, has been recently characterized to exhibit preferential accumulation property in the mitochondria of tumor cells. In this study, we investigated the possible mechanisms for its tumor selective activity and its potential as a drug delivery carrier. Results showed that the energy-dependent uptake of IR-780 iodide into the mitochondria of tumor cells was affected by glycolysis and plasma membrane potential. Moreover, OATP1B3 subtype of organic anion transporter peptides (OATPs) may play a dominant role in the transportation of IR-780 iodide into tumor cells, while cellular endocytosis, mitochondrial membrane potential and the ATP-binding cassette transporters did not show significant influence to its accumulation. We further evaluated the potential of IR-780 iodide as a drug delivery carrier by covalent conjugation of IR-780 with nitrogen mustard (IR-780NM). In vivo imaging showed that IR-780NM remained the tumor targeting property, indicating that IR-780 iodide could be potentially applied as a drug delivery agent for cancer targeted imaging and therapy. PMID- 24148241 TI - Water-soluble drug partitioning and adsorption in HEMA/MAA hydrogels. AB - Two-photon confocal microscopy and back extraction with UV/Vis-absorption spectrophotometry quantify equilibrium partition coefficients, k, for six prototypical drugs in five soft-contact-lens-material hydrogels over a range of water contents from 40 to 92%. Partition coefficients were obtained for acetazolamide, caffeine, hydrocortisone, Oregon Green 488, sodium fluorescein, and theophylline in 2-hydroxyethyl methacrylate/methacrylic acid (HEMA/MAA, pKa~5.2) copolymer hydrogels as functions of composition, aqueous pH (2 and 7.4), and salinity. At pH 2, the hydrogels are nonionic, whereas at pH 7.4, hydrogels are anionic due to MAA ionization. Solute adsorption on and nonspecific electrostatic interaction with the polymer matrix are pronounced. To express deviation from ideal partitioning, we define an enhancement or exclusion factor, E = k/phi1, where phi1 is hydrogel water volume fraction. All solutes exhibit E > 1 in 100 wt % HEMA hydrogels owing to strong specific adsorption to HEMA strands. For all solutes, E significantly decreases upon incorporation of anionic MAA into the hydrogel due to lack of adsorption onto charged MAA moieties. For dianionic sodium fluorescein and Oregon Green 488, and partially ionized monoanionic acetazolamide at pH 7.4, however, the decrease in E is more severe than that for similar-sized nonionic solutes. Conversely, at pH 2, E generally increases with addition of the nonionic MAA copolymer due to strong preferential adsorption to the uncharged carboxylic-acid group of MAA. For all cases, we quantitatively predict enhancement factors for the six drugs using only independently obtained parameters. In dilute solution for solute i, Ei is conveniently expressed as a product of individual enhancement factors for size exclusion (Ei(ex)), electrostatic interaction (Ei(el)), and specific adsorption (Ei(ad)):Ei=Ei(ex)Ei(el)Ei(ad). To obtain the individual enhancement factors, we employ an extended Ogston mesh-size distribution for Ei(ex); Donnan equilibrium for Ei(el); and Henry's law characterizing specific adsorption to the polymer chains for Ei(ad). Predicted enhancement factors are in excellent agreement with experiment. PMID- 24148242 TI - Intracellular trafficking and cellular uptake mechanism of mPEG-PLGA-PLL and mPEG PLGA-PLL-Gal nanoparticles for targeted delivery to hepatomas. AB - The lysosomal escape of nanoparticles is crucial to enhancing their delivery and therapeutic efficiency. Here, we report the cellular uptake mechanism, lysosomal escape, and organelle morphology effect of monomethoxy (polyethylene glycol)-poly (D,L-lactide-co-glycolide)-poly (L-lysine) (mPEG-PLGA-PLL, PEAL) and 4-O-beta-D Galactopyranosyl-D-gluconic acid (Gal)-modified PEAL (PEAL-Gal) for intracellular delivery to HepG2, Huh7, and PLC hepatoma cells. These results indicate that PEAL is taken up by clathrin-mediated endocytosis of HepG2, Huh7 and PLC cells. For PEAL-Gal, sialic acid receptor-mediated endocytosis and clathrin-mediated endocytosis are the primary uptake pathways in HepG2 cells, respectively, whereas PEAL-Gal is internalized by sag vesicle- and clathrin-mediated endocytosis in Huh7 cells. In the case of PLC cells, clathrin-mediated endocytosis and sialic acid receptor play a primary role in the uptake of PEAL-Gal. TEM results verify that PEAL and PEAL-Gal lead to a different influence on organelle morphology of HepG2, Huh7 and PLC cells. In addition, the results of intracellular distribution reveal that PEAL and PEAL-Gal are less entrapped in the lysosomes of HepG2 and Huh7 cells, demonstrating that they effectively escape from lysosomes and contribute to enhance the efficiency of intracellular delivery and tumor therapy. In vivo tumor targeting image results demonstrate that PEAL-Gal specifically delivers Rhodamine B (Rb) to the tumor tissue of mice with HepG2, Huh7, and PLC hepatomas and remains at a high concentration in tumor tissue until 48 h, properties that will greatly contribute to enhanced antitumor efficiency. PMID- 24148243 TI - Rejuvenation of chondrogenic potential in a young stem cell microenvironment. AB - Autologous cells suffer from limited cell number and senescence during ex vivo expansion for cartilage repair. Here we found that expansion on extracellular matrix (ECM) deposited by fetal synovium-derived stem cells (SDSCs) (FE) was superior to ECM deposited by adult SDSCs (AE) in promoting cell proliferation and chondrogenic potential. Unique proteins in FE might be responsible for the rejuvenation effect of FE while advantageous proteins in AE might contribute to differentiation more than to proliferation. Compared to AE, the lower elasticity of FE yielded expanded adult SDSCs with lower elasticity which could be responsible for the enhancement of chondrogenic and adipogenic differentiation. MAPK and noncanonical Wnt signals were actively involved in ECM-mediated adult SDSC rejuvenation. PMID- 24148244 TI - 2,4-Dinitrophenol induces neural differentiation of murine embryonic stem cells. AB - 2,4-Dinitrophenol (DNP) is a neuroprotective compound previously shown to promote neuronal differentiation in a neuroblastoma cell line and neurite outgrowth in primary neurons. Here, we tested the hypothesis that DNP could induce neurogenesis in embryonic stem cells (ESCs). Murine ESCs, grown as embryoid bodies (EBs), were exposed to 20 MUM DNP (or vehicle) for 4 days. Significant increases in the proportion of nestin- and beta-tubulin III-positive cells were detected after EB exposure to DNP, accompanied by enhanced glial fibrillary acidic protein (GFAP), phosphorylated extracellular signal-regulated kinase (p ERK) and ATP-linked oxygen consumption, thought to mediate DNP-induced neural differentiation. DNP further protected ESCs from cell death, as indicated by reduced caspase-3 positive cells, and increased proliferation. Cell migration from EBs was significantly higher in DNP-treated EBs, and migrating cells were positive for nestin, beta-tubulin III and MAP2, similar to that observed with retinoic acid (RA)-treated EBs. Compared to RA, however, DNP exerted a marked neuritogenic effect on differentiating ESCs, increasing the average length and number of neurites per cell. Results establish that DNP induces neural differentiation of ESCs, accompanied by cell proliferation, migration and neuritogenesis, suggesting that DNP may be a novel tool to induce neurogenesis in embryonic stem cells. PMID- 24148246 TI - Transplantation of insulin-secreting cells differentiated from human adipose tissue-derived stem cells into type 2 diabetes mice. AB - Currently, there are limited ways to preserve or recover insulin secretory capacity in human pancreas. We evaluated the efficacy of cell therapy using insulin-secreting cells differentiated from human eyelid adipose tissue-derived stem cells (hEAs) into type 2 diabetes mice. After differentiating hEAs into insulin-secreting cells (hEA-ISCs) in vitro, cells were transplanted into a type 2 diabetes mouse model. Serum levels of glucose, insulin and c-peptide were measured, and changes of metabolism and inflammation were assessed in mice that received undifferentiated hEAs (UDC group), differentiated hEA-ISCs (DC group), or sham operation (sham group). Human gene expression and immunohistochemical analysis were done. DC group mice showed improved glucose level, and survival up to 60 days compared to those of UDC and sham group. Significantly increased levels of human insulin and c-peptide were detected in sera of DC mice. RT-PCR and immunohistochemical analysis showed human gene expression and the presence of human cells in kidneys of DC mice. When compared to sham mice, DC mice exhibited lower levels of IL-6, triglyceride and free fatty acids as the control mice. Transplantation of hEA-ISCs lowered blood glucose level in type 2 diabetes mice by increasing circulating insulin level, and ameliorating metabolic parameters including IL-6. PMID- 24148245 TI - CB1 and CB2 receptors are novel molecular targets for Tamoxifen and 4OH Tamoxifen. AB - Tamoxifen (Tam) is classified as a selective estrogen receptor modulator (SERM) and is used for treatment of patients with ER-positive breast cancer. However, it has been shown that Tam and its cytochrome P450-generated metabolite 4-hydroxy Tam (4OH-Tam) also exhibit cytotoxic effects in ER-negative breast cancer cells. These observations suggest that Tam and 4OH-Tam can produce cytotoxicity via estrogen receptor (ER)-independent mechanism(s) of action. The molecular targets responsible for the ER-independent effects of Tam and its derivatives are poorly understood. Interestingly, similar to Tam and 4OH-Tam, cannabinoids have also been shown to exhibit anti-proliferative and apoptotic effects in ER-negative breast cancer cells, and estrogen can regulate expression levels of cannabinoid receptors (CBRs). Therefore, this study investigated whether CBRs might serve as novel molecular targets for Tam and 4OH-Tam. We report that both compounds bind to CB1 and CB2Rs with moderate affinity (0.9-3 MUM). Furthermore, Tam and 4OH-Tam exhibit inverse activity at CB1 and CB2Rs in membrane preparations, reducing basal G-protein activity. Tam and 4OH-Tam also act as CB1/CB2R-inverse agonists to regulate the downstream intracellular effector adenylyl cyclase in intact cells, producing concentration-dependent increases in intracellular cAMP. These results suggest that CBRs are molecular targets for Tam and 4OH-Tam and may contribute to the ER-independent cytotoxic effects reported for these drugs. Importantly, these findings also indicate that Tam and 4OH-Tam might be used as structural scaffolds for development of novel, efficacious, non-toxic cancer drugs acting via CB1 and/or CB2Rs. PMID- 24148247 TI - miR-181a-Twist1 pathway in the chemoresistance of tongue squamous cell carcinoma. AB - Although many researches have been undertaken to disclose the mechanisms of chemoresistance, the mechanisms remain unclear. The aim of this study is to elucidate the role of miR-181a-Twist1 pathway in the chemoresistance of tongue squamous cell carcinoma (TSCC). We found that cisplatin-induced chemoresistance in TSCC cell lines underwent EMT (epithelial-mesenchymal transition) and was accompanied by enhancing metastatic potential (migration and invasion in vitro), miR-181a downregulation and Twist1 upregulation. Functional analyses indicated that miR-181a reversed chemoresistance, inhibited EMT and metastatic potential in TSCC cells. Twist1 was confirmed as a direct miR-181a target gene by luciferase reporter gene assays. Twist1 knockdown by siRNA led to a reversal of the chemoresistance, inhibited EMT and metastatic potential in TSCC cells. Our study demonstrates that miR-181a-Twist1 pathway may play an important role in the development of cisplatin-chemoresistance, with EMT and an increase the metastatic potential of TSCC cells. PMID- 24148248 TI - Aquaporin 5 knockout mouse lens develops hyperglycemic cataract. AB - The scope of this investigation was to understand the role of aquaporin 5 (AQP5) for maintaining lens transparency and homeostasis. Studies were conducted using lenses of wild-type (WT) and AQP5 knockout (AQP5-KO) mice. Immunofluorescent staining verified AQP5 expression in WT lens sections and lack of expression in the knockout. In vivo and ex vivo, AQP5-KO lenses resembled WT lenses in morphology and transparency. Therefore, we subjected the lenses ex vivo under normal (5.6mM glucose) and hyperglycemic (55.6mM glucose) conditions to test for cataract formation. Twenty-four hours after incubation in hyperglycemic culture medium, AQP5-KO lenses showed mild opacification which was accelerated several fold at 48 h; in contrast, WT lenses remained clear even after 48 h of hyperglycemic treatment. AQP5-KO lenses displayed osmotic swelling due to increase in water content. Cellular contents began to leak into the culture medium after 48 h. We reason that water influx through glucose transporters and glucose cotransporters into the cells could mainly be responsible for creating hyperglycemic osmotic swelling; absence of AQP5 in fiber cells appears to cause lack of required water efflux, challenging cell volume regulation and adding to osmotic swelling. This study reveals that AQP5 could play a critical role in lens microcirculation for maintaining transparency and homeostasis, especially by providing protection under stressful conditions. To the best of our knowledge, this is the first report providing evidence that AQP5 facilitates maintenance of lens transparency and homeostasis by regulating osmotic swelling caused by glucose transporters and cotransporters under hyperglycemic stressful conditions. PMID- 24148249 TI - Creating a TALE protein with unbiased 5'-T binding. AB - Transcription activator-like effectors (TALEs) are convenient tools for genome engineering at specific genomic sites. However, their use is constrained because most TALE binding sites are preceded by a highly conserved 5' terminal T nucleotide (5'-T). To remove the 5'-T constraint, we substituted tryptophan 232 in the repeat-1 loop region of the dHax3 N-terminal domain for other amino acids. Furthermore, we randomized four amino acid residues of the hairpin loop region of repeat-1. Although point mutation was insufficient to remove the 5'-T constraint, directed evolution from the randomized library yielded repeat-1 mutants with unbiased targeting sites for 5'-bases. Our result indicates that the repeat-1 loop region of dHax3 is important for 5'-base accommodation, and that molecular evolution of repeat-1 of TALEs is an efficient strategy to remove the 5'-T constraint and thus allow targeting of any DNA sequences. PMID- 24148250 TI - The role of emotional eating and stress in the influence of short sleep on food consumption. AB - Short sleep duration is associated with elevated body mass index (BMI) and increased energy consumption. The present studies were conducted to determine what role emotional eating and stress might play in these relationships. The first was an exploratory questionnaire study in which sleep quality and duration were measured in conjunction with the Dutch Eating Behavior Questionnaire in 184 women. Emotional and external eating scores were significantly higher in those who reported poor sleep quality (but were not related to sleep duration). In a second study of 64 women who were provided with snacks in the laboratory under stressed and control conditions, elevated food consumption was observed in those who scored high on emotional eating and who reported short sleep (a significant stress * emotional eating * sleep duration interaction) but not in those who reported poor sleep quality. No effects were found in liking or wanting of food and few effects were found on appetite. BMI was not related to sleep duration or sleep quality in either study. The results suggest that the relationship between short sleep and elevated food consumption exists in those who are prone to emotional eating. An external stressor elevated consumption in normal sleepers to the level observed in short sleepers, however, it did not significantly elevate consumption in short sleepers. Future examinations of the effects of sleep duration and quality on food consumption should examine emotional eating status. PMID- 24148251 TI - A comparison of attitudes toward meat and animals among strict and semi vegetarians. AB - A number of studies have documented a phenomenon whereby individuals self identify as vegetarians but then simultaneously acknowledge that they eat red meat, chicken, and/or fish. Despite being a consistent and fairly robust effect, there has been little attempt to explain these semi-vegetarians, why they would define themselves in a category whose membership criteria they violate, and ways they might differ from strict vegetarians. The present research highlights possible reasons for the discrepancy and focuses on several dimensions that may demarcate semi-from strict vegetarians: belief in human-animal similarity and liking of and disgust toward meat. Survey results indicated that semi-vegetarians (n=57) were less likely to dislike meat and to find meat disgusting than were strict vegetarians (n=157), even accounting for diet motives. There were no differences between the groups in their beliefs about human-animal similarity although semi-vegetarians who consumed a wider range of animal products perceived marginally less human-animal similarity than those who consumed only fish. The results suggest that semi-vegetarians are distinct from strict vegetarians primarily in their evaluation of and disgust toward meat, likely as a cause or consequence of their occasional consumption of animal flesh. PMID- 24148252 TI - Small mammal community succession on the beach of Dongting Lake, China after the Three Gorges Project. AB - Although the Three Gorges Project (TGP) may have affected the population structure and distribution of plant and animal communities, few studies have analyzed the effect of this project on small mammal communities. Therefore, the present paper compares the small mammal communities inhabiting the beaches of Dongting Lake using field investigations spanning a 20-year period, both before and after the TGP was implemented. Snap traps were used throughout the census. The results indicate that the TGP caused major changes to the structure of the small mammal community at a lake downstream of the dam. First, species abundance on the beaches increased after the project commenced. The striped field mouse (Apodemus agrarius) and the Norway rat (Rattus norvegicus), which rarely inhabited the beach before the TGP, became abundant (with marked population growth) once water was impounded by the Three Gorges Reservoir. Second, dominant species concentration indices exhibited a stepwise decline, indicating that the community structure changed from a single dominant species to a more diverse species mix after TGP implementation. Third, the regulation of water discharge release by the TGP might have caused an increase in the species diversity of the animal community on the beaches. A significant difference in diversity indices was obtained before and after the TGP operation. Similarity indices also indicate a gradual increase in species numbers. Hence, a long-term project should be established to monitor the population fluctuations of the Yangtze vole (Microtus fortis), the striped field mouse and the Norway rat to safeguard against population outbreaks (similar to the Yangtze vole outbreak in 2007), which could cause crop damage to adjacent farmland, in addition to documenting the succession process of the small mammal community inhabiting the beaches of Dongting Lake. PMID- 24148253 TI - Review of lipid and lipoprotein(a) abnormalities in childhood arterial ischemic stroke. AB - National organizations recommend cholesterol screening in children to prevent vascular disease in adulthood. There are currently no recommendations for cholesterol and lipoprotein (a) testing in children who experience an arterial ischemic stroke. While dyslipidemia and elevated lipoprotein (a) are associated with ischemic stroke in adults, the role of atherosclerotic risk factors in childhood arterial ischemic stroke is not known. A review of the literature was performed from 1966 to April 2012 to evaluate the association between childhood arterial ischemic stroke and dyslipidemia or elevated lipoprotein (a). Of 239 citations, there were 16 original observational studies in children (with or without neonates) with imaging-confirmed arterial ischemic stroke and data on cholesterol or lipoprotein (a) values. Three pairs of studies reported overlapping subjects, and two were eliminated. Among 14 studies, there were data on cholesterol in 7 and lipoprotein (a) in 10. After stroke, testing was performed at >three-months in nine studies, at <=three-months in four studies, and not specified in one study. There were five case-control studies: four compared elevated lipoprotein (a) and one compared abnormal cholesterol in children with arterial ischemic stroke to controls. A consistent positive association between elevated lipoprotein (a) and stroke was found [Mantel Haenszel OR 4.24 (2.94-6.11)]. There was no association in one study on total cholesterol, and a positive association in one study on triglycerides. The literature suggests that elevated lipoprotein (a) may be more likely in children with arterial ischemic stroke than in control children. The absence of confirmatory study on dyslipidemia should be addressed with future research. PMID- 24148254 TI - FGFR signalling in women's cancers. AB - FGFs, in a complex with their receptors (FGFRs) and heparan sulfate (HS), are responsible for a range of cellular functions, from embryogenesis to metabolism. Both germ line and somatic FGFR mutations are known to play a role in a range of diseases, most notably craniosynestosis dysplasias, dwarfism and cancer. Because of the ability of FGFR signalling to induce cell proliferation, migration and survival, FGFRs are readily co-opted by cancer cells. Mutations in, and amplifications of, these receptors are found in a range of cancers with some of the most striking clinical findings relating to their contribution to pathogenesis and progression of female cancers. Here, we outline the molecular mechanisms of FGFR signalling and discuss the role of this pathway in women's cancers, focusing on breast, endometrial, ovarian and cervical carcinomas, and their associated preclinical and clinical data. We also address the rationale for therapeutic intervention and the need for FGFR-targeted therapy to selectively target cancer cells in view of the fundamental roles of FGF signalling in normal physiology. PMID- 24148255 TI - Improvement of optical transmittance and electrical properties for the Si quantum dot-embedded ZnO thin film. AB - A Si quantum dot (QD)-embedded ZnO thin film is successfully fabricated on a p type Si substrate using a ZnO/Si multilayer structure. Its optical transmittance is largely improved when increasing the annealing temperature, owing to the phase transformation from amorphous to nanocrystalline Si QDs embedded in the ZnO matrix. The sample annealed at 700 degrees C exhibits not only high optical transmittance in the long-wavelength range but also better electrical properties including low resistivity, small turn-on voltage, and high rectification ratio. By using ZnO as the QDs' matrix, the carrier transport is dominated by the multistep tunneling mechanism, the same as in a n-ZnO/p-Si heterojunction diode, which clearly differs from that using the traditional matrix materials. Hence, the carriers transport mainly in the ZnO matrix, not through the Si QDs. The unusual transport mechanism using ZnO as matrix promises the great potential for optoelectronic devices integrating Si QDs. PMID- 24148256 TI - Neutrophil:lymphocyte ratio as a simple and novel biomarker for prediction of locoregional recurrence after chemoradiotherapy for squamous cell carcinoma of the anus. AB - AIM: The neutrophil: lymphocyte ratio (NLR) is a prognostic marker in several malignancies. This study assessed whether it can be used as a predictor of loco regional recurrence after chemoradiotherapy for anal squamous cell carcinoma (SCC). METHOD: Patients treated with curative intent between 1 January 2004 and 31 December 2011 were identified. Pretreatment blood tests and radiological staging were available from multidisciplinary meeting records. The NLR was calculated from pretreatment blood tests. The relationship between the NLR and clinicopathological parameters was analysed. Modified receiver-operating characteristics curves were constructed to determine the cut-off NLR to dichotomise the data for survival analyses. The measured cut-off was 4.75. RESULTS: Ninety-two patients were identified. Pretreatment T-stages were T1 (n = 7), T2 (n = 36), T3 (n = 35) and T4 (n = 14) and pretreatment N stages were N0 (n = 62) and N+ disease (n = 30). The NLR was significantly higher in N+ disease (P = 0.014) and in patients who developed recurrence (P = 0.003). On multivariate analysis, the NLR maintained its significance, with a hazard ratio (HR) of 1.38 (95% CI = 1.195-1.594) (P < 0.0001). An elevated NLR was associated with worse overall (P < 0.0001) and cancer-specific (P < 0.0001) survival. Multivariate Cox regression analysis demonstrated that an elevated NLR was prognostic for overall survival (HR = 6.381, 95% CI = 1.742-23.372, P = 0.005) and for cancer-specific survival (HR = 10.613, 95% CI = 1.968-57.241, P = 0.006). CONCLUSION: Pretreatment NLR may be a simple biomarker for predicting disease recurrence and overall and cancer-specific survival after potentially curative chemo radiotherapy for SCC of the anus. PMID- 24148257 TI - Group-wise construction of reduced models for understanding and characterization of pulmonary blood flows from medical images. AB - 3D computational fluid dynamics (CFD) in patient-specific geometries provides complementary insights to clinical imaging, to better understand how heart disease, and the side effects of treating heart disease, affect and are affected by hemodynamics. This information can be useful in treatment planning for designing artificial devices that are subject to stress and pressure from blood flow. Yet, these simulations remain relatively costly within a clinical context. The aim of this work is to reduce the complexity of patient-specific simulations by combining image analysis, computational fluid dynamics and model order reduction techniques. The proposed method makes use of a reference geometry estimated as an average of the population, within an efficient statistical framework based on the currents representation of shapes. Snapshots of blood flow simulations performed in the reference geometry are used to build a POD (Proper Orthogonal Decomposition) basis, which can then be mapped on new patients to perform reduced order blood flow simulations with patient specific boundary conditions. This approach is applied to a data-set of 17 tetralogy of Fallot patients to simulate blood flow through the pulmonary artery under normal (healthy or synthetic valves with almost no backflow) and pathological (leaky or absent valve with backflow) conditions to better understand the impact of regurgitated blood on pressure and velocity at the outflow tracts. The model reduction approach is further tested by performing patient simulations under exercise and varying degrees of pathophysiological conditions based on reduction of reference solutions (rest and medium backflow conditions respectively). PMID- 24148259 TI - Production of high quality syngas from argon/water plasma gasification of biomass and waste. AB - Extremely hot thermal plasma was used for the gasification of biomass (spruce sawdust, wood pellets) and waste (waste plastics, pyrolysis oil). The plasma was produced by a plasma torch with DC electric arc using unique hybrid stabilization. The torch input power of 100-110 kW and the mass flow rate of the gasified materials of tens kg/h was set up during experiments. Produced synthetic gas featured very high content of hydrogen and carbon monoxide (together approximately 90%) that is in a good agreement with theory. High quality of the produced gas is given by extreme parameters of used plasma--composition, very high temperature and low mass flow rate. PMID- 24148258 TI - A randomized, double-blind, placebo-controlled phase 2 study of tigatuzumab (CS 1008) in combination with carboplatin/paclitaxel in patients with chemotherapy naive metastatic/unresectable non-small cell lung cancer. AB - INTRODUCTION: Tigatuzumab, a humanized monoclonal DR5 agonist antibody induces apoptosis in human cancer cell lines. The objective of this study was to investigate the antitumor effects of tigatuzumab combined with carboplatin/paclitaxel in chemotherapy-naive patients with metastatic/unresectable non-small cell lung cancer (NSCLC). METHODS: Patients with histologically or cytologically confirmed NSCLC stage IIIB/IV disease by RECIST (version 1.0) and ECOG-PS 0-1 were enrolled at 15 European sites. Patients received tigatuzumab or placebo intravenously with carboplatin/paclitaxel every 3 weeks (1 cycle) for up to 6 cycles. The primary end point was progression-free survival (PFS). Secondary end points were overall survival (OS), objective response rate and safety. RESULTS: 97 patients were analyzed for efficacy (49 tigatuzumab; 48 placebo). Median PFS (95% CI) was 5.4 months (3.3, 6.6) for tigatuzumab compared with 4.3 months (4.1, 5.8) for placebo. Median OS (95% CI) was 8.4 months (6.9, 16.3) for tigatuzumab versus 9.0 months (7.6, 14.5) for placebo. 12 patients (24.5%) in the tigatuzumab arm and 11 patients (22.9%) in the placebo arm had partial response. No patient had complete response. In a prospectively-defined Fc gamma receptor genotype subset (n=25), there was a non significant trend toward increased PFS with tigatuzumab versus placebo (HR=0.47; 95% CI: 0.16, 1.35) but no difference in OS. Tigatuzumab was well tolerated. However, grade 3/4 neutropenia was reported in 10 patients (20.4%) receiving tigatuzumab compared with 4 patients (8.3%) receiving placebo. CONCLUSIONS: Tigatuzumab was well tolerated but did not improve efficacy of carboplatin/paclitaxel in systemic therapy-naive, unselected advanced NSCLC patients. PMID- 24148260 TI - IFN-gamma: The Dr. Jekyll and Mr. Hyde of immunology? PMID- 24148261 TI - Ocular injuries from pressurised bottled drinks in China. AB - BACKGROUND: The objective of this study is to provide a systematic review on ocular injuries induced by glass bottles containing carbonated drinks in China, which emphasised the injury circumstance and visual function loss. METHODS: We performed a literature-based retrospective analysis using predetermined inclusion and exclusion criteria. Demographic characteristics of pressurised bottled drinks related eye injuries were obtained and vision loss was calculated. RESULTS: A total of 26 relevant articles were found suitable for investigation of causative agent and patient demographics, of which 19 articles could be used for calculating vision loss and injury circumstance. Victims were often pertinent workers (46.0%). Most of the trauma was serious and even devastating. Final visual acuity was >10/20 in 29.2%, with severe final vision loss (<10/200) in 30.8%. Visual acuity can improve significantly with treatment (P<0.05). CONCLUSIONS: One in three ocular injuries from glass bottles containing carbonated drinks show severe vision loss. Relevant workers are most frequently injured, followed by inappropriate handlers or openers. Besides manufacturing standards being strictly implemented, many ocular traumas related to bottled carbonated drinks should be prevented through health education. PMID- 24148262 TI - Different evolutionary pathways underlie the morphology of wrist bones in hominoids. AB - BACKGROUND: The hominoid wrist has been a focus of numerous morphological analyses that aim to better understand long-standing questions about the evolution of human and hominoid hand use. However, these same analyses also suggest various scenarios of complex and mosaic patterns of morphological evolution within the wrist and potentially multiple instances of homoplasy that would benefit from require formal analysis within a phylogenetic context.We identify morphological features that principally characterize primate - and, in particular, hominoid (apes, including humans) - wrist evolution and reveal the rate, process and evolutionary timing of patterns of morphological change on individual branches of the primate tree of life. Linear morphological variables of five wrist bones - the scaphoid, lunate, triquetrum, capitate and hamate - are analyzed in a diverse sample of extant hominoids (12 species, 332 specimens), Old World (8 species, 43 specimens) and New World (4 species, 26 specimens) monkeys, fossil Miocene apes (8 species, 20 specimens) and Plio-Pleistocene hominins (8 species, 18 specimens). RESULT: Results reveal a combination of parallel and synapomorphic morphology within haplorrhines, and especially within hominoids, across individual wrist bones. Similar morphology of some wrist bones reflects locomotor behaviour shared between clades (scaphoid, triquetrum and capitate) while others (lunate and hamate) indicate clade-specific synapomorphic morphology. Overall, hominoids show increased variation in wrist bone morphology compared with other primate clades, supporting previous analyses, and demonstrate several occurrences of parallel evolution, particularly between orangutans and hylobatids, and among hominines (extant African apes, humans and fossil hominins). CONCLUSIONS: Our analyses indicate that different evolutionary processes can underlie the evolution of a single anatomical unit (the wrist) to produce diversity in functional and morphological adaptations across individual wrist bones. These results exemplify a degree of evolutionary and functional independence across different wrist bones, the potential evolvability of skeletal morphology, and help to contextualize the postcranial mosaicism observed in the hominin fossil record. PMID- 24148263 TI - The flavokawains: uprising medicinal chalcones. AB - Plant-based compounds have been in the spotlight in search of new and promising drugs. Flavokawain A, B and C are naturally occurring chalcones that have been isolated from several medicinal plants; namely the piper methysticum or commercially known as the kava-kava. Multiple researches have been done to evaluate the bioactivities of these compounds. It has been shown that all three flavokawains may hold promising anti-cancer effects. It has also been revealed that both flavokawain A and B are involved in the induction of cell cycle arrest in several cancer cell lines. Nevertheless, flavokawain B was shown to be more effective in treating in vitro cancer cell lines as compared to flavokawain A and C. Flavokawain B also exerts antinociceptive effects as well as anti-inflammation properties. This mini-review attempts to discuss the biological properties of all the flavokawains that have been reported. PMID- 24148264 TI - Blood-brain-barriers in aging and in Alzheimer's disease. AB - The aging process correlates with a progressive failure in the normal cellular and organ functioning; these alterations are aggravated in Alzheimer's disease (AD). In both aging and AD there is a general decrease in the capacity of the body to eliminate toxic compounds and, simultaneously, to supply the brain with relevant growth and nutritional factors. The barriers of the brain are targets of this age related dysfunction; both the endothelial cells of the blood-brain barrier and the choroid plexus epithelial cells of the blood-cerebrospinal fluid barrier decrease their secretory capacity towards the brain and their ability to remove toxic compounds from the brain. Additionally, during normal aging and in AD, the permeability of the brain barriers increase. As such, a greater contact of the brain parenchyma with the blood content alters the highly controlled neural environment, which impacts on neural function. Of interest, the brain barriers are more than mere obstacles to the passage of molecules and cells, and therefore active players in brain homeostasis, which is still to be further recognized and investigated in the context of health and disease. Herein, we provide a review on how the brain barriers change during aging and in AD and how these processes impact on brain function. PMID- 24148265 TI - Endonasal, transmaxillary, transpterygoid approach to the foramen ovale: radio anatomical study of surgical feasibility. AB - OBJECTIVE: This study aimed to examine the feasibility of an endonasal, transmaxillary, transpterygoid approach to the foramen ovale by examining key anatomical, radiological and surgical landmarks. METHOD: Measurements were taken from 183 patients' computed tomography scans using BrainLAB iPlan 1.1 Cranial software. Endoscopic dissection was then carried out on a cadaver to assess surgical viability. RESULTS: We found that the distances from the posterior maxillary wall to the foramen ovale and from the anterior nasal spine to the foramen ovale were statistically significantly larger in men than women. The distance from the base of the lateral pterygoid plate to the foramen ovale, and the angle between the foramen ovale, the anterior nasal spine and the sphenoid rostrum, were constant between the sexes. The importance of the lateral pterygoid plate in locating the foramen ovale was demonstrated. CONCLUSION: With the increasing popularity of image guidance and assisted navigation in endoscopic surgery, these findings increase anatomico-radiological understanding of the surgical approach investigated. PMID- 24148267 TI - Now that we have a definition for physical frailty, what shape should frailty medicine take? PMID- 24148266 TI - Association of frailty and physical function in patients with non-dialysis CKD: a systematic review. AB - BACKGROUND: Frailty is a condition characterized by a decline in physical function and functional capacity. Common symptoms of frailty, such as weakness and exhaustion, are prevalent in patients with chronic kidney disease (CKD). The increased vulnerability of frail patients with coexisting CKD may place them at a heightened risk of encountering additional health complications. The purpose of this systematic review was to explore the link between frailty, CKD and clinical outcomes. METHODS: We searched for cross sectional and prospective studies in the general population and in the CKD population indexed in EMBASE, Pubmed, Web of Science, CINAHL, Cochrane and Ageline examining the association between frailty and CKD and those relating frailty in patients with CKD to clinical outcomes. RESULTS: We screened 5,066 abstracts and retrieved 108 studies for full text review. We identified 7 studies associating frailty or physical function to CKD. From the 7 studies, we identified only two studies that related frailty in patients with CKD to a clinical outcome. CKD was consistently associated with increasing frailty or reduced physical function [odds ratios (OR) 1.30 to 3.12]. In patients with CKD, frailty was associated with a greater than two-fold higher risk of dialysis and/or death [OR from 2.0 to 5.88]. CONCLUSIONS: CKD is associated with a higher risk of frailty or diminished physical function. Furthermore, the presence of frailty in patients with CKD may lead to a higher risk of mortality. Further research must be conducted to understand the mechanisms of frailty in CKD and to confirm its association with clinical outcomes. PMID- 24148268 TI - A role for the macular carotenoids in visual motor response. AB - OBJECTIVES: Lutein (L), zeaxanthin (Z), and meso-zeaxanthin are the dominant carotenoids within the central retina (there, termed macular pigment, MP). L is also the dominant carotenoid in the brain. The presence of L and Z in both motor and visual areas of the central nervous system is consistent with a role of these carotenoids in visual-motor behavior. The purpose of this study was to provide a first test of this hypothesis. METHODS: Balance ability (measured via the Standing Leg Test) and simple reaction time (measured via a stimulus appearing in one of four quadrants of a computer monitor) were measured in 49 subjects (mean age = 54.8 years). Fixed and variable reaction time, and coincidence anticipation ability (estimating the arrival of the stimulus at a target location moving at four velocities) were assessed in 106 younger subjects (mean age = 23 years) using a customized device. MP optical density was measured in all subjects via customized heterochromatic flicker photometry. RESULTS: MP optical density was significantly (P < 0.05) related to reaction time and to balance ability for the older subjects. Even for the younger group, MP optical density was significantly (P < 0.05) related to fixed and variable position reaction time, as well as coincidence anticipation errors, at high speed. DISCUSSION: L and Z status has been linked to benefits in cognitive function in past research. The present results, and the selective presence of L and Z in visual and motor areas in the brain, are consistent with these carotenoids having a role in visual and motor integration. PMID- 24148269 TI - Synthetic probes of glycosaminoglycan function. AB - Glycosaminoglycans (GAGs) participate in many critical biological processes by modulating the activities of a wide range of proteins, including growth factors, chemokines, and viral receptors. Recent studies using synthetic oligosaccharides and glycomimetic polymers have established the importance of specific structural determinants in controlling GAG function. These findings illustrate the power of synthetic molecules to elucidate glycan-mediated signaling events, as well as the prospect of further advancements to understand the roles of GAGs in vivo and explore their therapeutic potential. PMID- 24148271 TI - The maximum standardized FDG uptake on PET-CT in patients with non-small cell lung cancer. AB - BACKGROUND: Non-small cell lung cancer (NSCLC) accounts for approximately 80% of new diagnoses of pulmonary carcinoma. This study investigated the correlation between 18 F-fluorodeoxyglucose uptake in computerized tomography integrated positron emission tomography and tumor size, lymph node metastasis, and distant metastasis in patients with NSCLC. METHODS: The records of 151 NSCLC patients (139 male, 12 female; mean age 59.60 years) were evaluated retrospectively. RESULTS: Forty-one cases were adenocarcinomas; 45 squamous cell carcinomas; and 65 unspecified NSCLC. When the cases were categorized according to tumor size (group 1, <= 3 cm; group 2, > 3 and <= 5 cm; group 3, > 5 cm), the maximum standardized uptake value (SUVmax) was significantly lower in groups 1 and 2 compared with group 3 (p = 0.006 for each). Considering all cases, tumor SUVmax was not correlated with age, gender, or histopathological type. Lymph node metastases were pathologically proven in 24 cases: 24% of these were adenocarcinomas, 6% squamous cell carcinomas, and 16% unspecified NSCLC. Neither lymph node involvement nor distant metastases were correlated with tumor SUVmax, although lymph node size was positively correlated with lymph node SUVmax (r = 0.775; p < 0.001). CONCLUSIONS: SUVmax was significantly associated with tumor size, but not with distant metastases or lymph node involvement. Therefore, SUVmax on positron emission tomography is not predictive of the presence of metastases. PMID- 24148272 TI - Human induced pluripotent stem cell-derived cortical neurons integrate in stroke injured cortex and improve functional recovery. AB - Stem cell-based approaches to restore function after stroke through replacement of dead neurons require the generation of specific neuronal subtypes. Loss of neurons in the cerebral cortex is a major cause of stroke-induced neurological deficits in adult humans. Reprogramming of adult human somatic cells to induced pluripotent stem cells is a novel approach to produce patient-specific cells for autologous transplantation. Whether such cells can be converted to functional cortical neurons that survive and give rise to behavioural recovery after transplantation in the stroke-injured cerebral cortex is not known. We have generated progenitors in vitro, expressing specific cortical markers and giving rise to functional neurons, from long-term self-renewing neuroepithelial-like stem cells, produced from adult human fibroblast-derived induced pluripotent stem cells. At 2 months after transplantation into the stroke-damaged rat cortex, the cortically fated cells showed less proliferation and more efficient conversion to mature neurons with morphological and immunohistochemical characteristics of a cortical phenotype and higher axonal projection density as compared with non fated cells. Pyramidal morphology and localization of the cells expressing the cortex-specific marker TBR1 in a certain layered pattern provided further evidence supporting the cortical phenotype of the fated, grafted cells, and electrophysiological recordings demonstrated their functionality. Both fated and non-fated cell-transplanted groups showed bilateral recovery of the impaired function in the stepping test compared with vehicle-injected animals. The behavioural improvement at this early time point was most likely not due to neuronal replacement and reconstruction of circuitry. At 5 months after stroke in immunocompromised rats, there was no tumour formation and the grafted cells exhibited electrophysiological properties of mature neurons with evidence of integration in host circuitry. Our findings show, for the first time, that human skin-derived induced pluripotent stem cells can be differentiated to cortical neuronal progenitors, which survive, differentiate to functional neurons and improve neurological outcome after intracortical implantation in a rat stroke model. PMID- 24148274 TI - Sexual harassment among adolescents of different sexual orientations and gender identities. AB - This article examines (a) variation in rates of sexual harassment across mode (e.g., in-person, online) and type of harassment, (b) the impact of sexual harassment (i.e., distressing vs. non-distressing), and (c) how sexual harassment is similarly and differently experienced across sexual orientation and gender identity groups. Data were collected as part of the Teen Health and Technology online survey of 5,907 13 to 18 year-old Internet users in the United States. Past year sexual harassment was reported by 23-72% of youth, depending upon sexual orientation, with the highest rates reported by lesbian/queer girls (72%), bisexual girls (66%), and gay/queer boys (66%). When examined by gender identity, transgender youth reported the highest rates of sexual harassment - 81%. Overall, the most common modes for sexual harassment were in-person followed by online. Distress in the form of interference with school, family, and/or friends; creating a hostile environment; or being very/extremely upset was reported by about half of the sexually harassed bisexual girls and lesbian/queer girls, 65% of the gender non-conforming/other gender youth, and 63% of the transgender youth. Youth with high social support and self-esteem were less likely to report sexual harassment. Findings point to the great importance of sexual harassment prevention for all adolescents, with particular emphasis on the unique needs and experiences of youth of different sexual orientations and gender identities. Socio-emotional programs that emphasize self-esteem building could be particularly beneficial for reducing the likelihood of victimization and lessen the impact when it occurs. PMID- 24148275 TI - PTSD symptom cluster profiles of youth who have experienced sexual or physical abuse. AB - The research examined whether youth (6-17 years old) who were referred for treatment due to sexual, physical, or both types of abuse presented with distinct profiles of PTSD DSM-IV-TR symptom clusters. When examining data for the 749 youth participants, five PTSD symptom cluster profiles were identified with each profile representing approximately 20% of the youth. The five profiles were also differentiated with respect to being referred for physical or sexual abuse, age, parental ratings of internalizing symptoms, and self-reported depression. The youth referred for treatment in the aftermath of child sexual, physical, or both sexual and physical abuse presented with different profiles of PTSD symptom clusters thereby suggesting a need for individualized tailoring of evidenced based treatments. Two cognitive behavioral approaches, designed for traumatized children and either their nonoffending or offending parents, were described for treating youth with the distinct PTSD profiles. PMID- 24148273 TI - Striatal dopaminergic dysfunction at rest and during task performance in writer's cramp. AB - Writer's cramp is a task-specific focal hand dystonia characterized by involuntary excessive muscle contractions during writing. Although abnormal striatal dopamine receptor binding has been implicated in the pathophysiology of writer's cramp and other primary dystonias, endogenous dopamine release during task performance has not been previously investigated in writer's cramp. Using positron emission tomography imaging with the D2/D3 antagonist 11C-raclopride, we analysed striatal D2/D3 availability at rest and endogenous dopamine release during sequential finger tapping and speech production tasks in 15 patients with writer's cramp and 15 matched healthy control subjects. Compared with control subjects, patients had reduced 11C-raclopride binding to D2/D3 receptors at rest in the bilateral striatum, consistent with findings in previous studies. During the tapping task, patients had decreased dopamine release in the left striatum as assessed by reduced change in 11C-raclopride binding compared with control subjects. One cluster of reduced dopamine release in the left putamen during tapping overlapped with a region of reduced 11C-raclopride binding to D2/D3 receptors at rest. During the sentence production task, patients showed increased dopamine release in the left striatum. No overlap between altered dopamine release during speech production and reduced 11C-raclopride binding to D2/D3 receptors at rest was seen. Striatal regions where D2/D3 availability at rest positively correlated with disease duration were lateral and non-overlapping with striatal regions showing reduced D2/D3 receptor availability, except for a cluster in the left nucleus accumbens, which showed a negative correlation with disease duration and overlapped with striatal regions showing reduced D2/D3 availability. Our findings suggest that patients with writer's cramp may have divergent responses in striatal dopamine release during an asymptomatic motor task involving the dystonic hand and an unrelated asymptomatic task, sentence production. Our voxel-based results also suggest that writer's cramp may be associated with reduced striatal dopamine release occuring in the setting of reduced D2/D3 receptor availability and raise the possibility that basal ganglia circuits associated with premotor cortices and those associated with primary motor cortex are differentially affected in primary focal dystonias. PMID- 24148276 TI - Sarcoid-derived fibroblasts: links between genomic instability, energy metabolism and senescence. AB - Bovine papillomavirus 1 (BPV-1) is a well recognized etiopathogenetic factor in a cancer-like state in horses, namely equine sarcoid disease. Nevertheless, little is known about BPV-1-mediated cell transforming effects. It was shown that BPV-1 triggers genomic instability through DNA hypomethylation and oxidative stress. In the present study, we further characterized BPV-1-positive fibroblasts derived from sarcoid tumors. The focus was on cancer-like features of sarcoid-derived fibroblasts, including cell cycle perturbation, comprehensive DNA damage analysis, end-replication problem, energy metabolism and oncogene-induced premature senescence. The S phase of the cell cycle, polyploidy events, DNA double strand breaks (DSBs) and DNA single strand breaks (SSBs) were increased in BPV-1-positive cells compared to control fibroblasts. BPV-1-mediated oxidative stress may contribute to telomere dysfunction in sarcoid-derived fibroblasts. Loss of mitochondrial membrane potential and concurrent elevation in intracellular ATP production may be a consequence of changes in energy-supplying pathways in BPV-1-positive cells which is also typical for cancer cells. Shifts in energy metabolism may support rapid proliferation in cells infected by BPV-1. Nevertheless, sarcoid-derived fibroblasts representing a heterogeneous cell fraction vary in some aspects of metabolic phenotype due to a dual role of BPV-1 in cell transformation and oncogene-induced premature senescence. This was shown with increased senescence-associated beta-galactosidase (SA-beta-gal) activity. Taken together, metabolic phenotypes in sarcoid-derived fibroblasts are plastic, which are similar to greater plasticity of cancer tissues than normal tissues. PMID- 24148277 TI - Protective effects of inhaled carbon monoxide in endotoxin-induced cholestasis is dependent on its kinetics. AB - Carbon monoxide (CO), a product of heme oxygenase (HMOX), has many beneficial biological functions and is a promising therapeutic agent for many pathological conditions. However, the kinetics of inhaled CO and its protective role in endotoxin-induced cholestasis is not fully known. Thus, our objective was to characterize the kinetics of inhaled CO and then investigate its use in early phase experimental endotoxin-induced cholestasis. Female Wistar rats were randomly divided into 4 groups: CON (control), LPS (lipopolysaccharide, 6 mg/kg), CO (250 ppm COx1h), and CO + LPS. Rats were sacrificed at 0-12 h after LPS administration. Tissues and blood were collected for liver injury markers and tissue CO distribution measurements. Livers were harvested for measurements of Hmox activity, Hmox1 mRNA expression, cytokines (IL10, IL6, TNF), and bile lipid and pigment transporters. Half-lives of CO in spleen, blood, heart, brain, kidney, liver, and lungs were 2.4 +/- 1.5, 2.3 +/- 0.8, 1.8 +/- 1.6, 1.5 +/- 1.2, 1.1 +/- 1.1, 0.6 +/- 0.3, 0.6 +/- 0.2 h, respectively. CO treatment increased liver IL10 mRNA and decreased TNF expression 1 h after LPS treatment and prevented the down-regulation of bile acid and bilirubin hepatic transporters (Slc10a1, Abcb11, and Abcc2, p < 0.05), an effect closely related to the kinetics. The protective effect of CO against cholestatic liver injury persisted even 12 h after CO exposure, as shown by attenuation of serum cholestatic markers in CO-treated animals. CO exposure substantially attenuated endotoxin-induced cholestatic liver injury and was directly related to the kinetics of inhaled CO. This data underscores the importance of the kinetics of inhaled CO for the proper design of experimental and clinical studies of using CO as a treatment strategy. PMID- 24148278 TI - Pharmacokinetics and in vivo antistaphylococcal efficacy of TXY541, a 1 methylpiperidine-4-carboxamide prodrug of PC190723. AB - The benzamide derivative PC190723 was among the first of a promising new class of FtsZ-directed antibacterial agents to be identified that exhibit potent antistaphylococcal activity. However, the compound is associated with poor drug like properties. As part of an ongoing effort to develop FtsZ-targeting antibacterial agents with increased potential for clinical utility, we describe herein the pharmacodynamics, pharmacokinetics, in vivo antistaphylococcal efficacy, and mammalian cytotoxicity of TXY541, a novel 1-methylpiperidine-4 carboxamide prodrug of PC190723. TXY541 was found to be 143-times more soluble than PC190723 in an aqueous acidic vehicle (10mM citrate, pH 2.6) suitable for both oral and intravenous in vivo administration. In staphylococcal growth media, TXY541 converts to PC190723 with a half-life of approximately 8h. In 100% mouse serum, the TXY541-to-PC190723 conversion was much more rapid (with a half-life of approximately 3min), suggesting that the conversion of the prodrug in serum is predominantly enzyme-catalyzed. Pharmacokinetic analysis of both orally and intravenously administered TXY541 in mice yielded a half-life for the PC190723 conversion product of 0.56h and an oral bioavailability of 29.6%. Whether administered orally or intravenously, TXY541 was found to be efficacious in vivo in mouse models of systemic infection with both methicillin-sensitive and methicillin-resistant S. aureus. Toxicological assessment of TXY541 against mammalian cells revealed minimal detectable cytotoxicity. The results presented here highlight TXY541 as a potential therapeutic agent that warrants further pre clinical development. PMID- 24148280 TI - Temporal changes in pregnancy-associated glycoproteins across different stages of gestation in the Barbari goat. AB - The objective of this study was to characterize the temporal profile of pregnancy associated glycoproteins (PAGs; isoforms 1-11) across different stages of gestation in the Barbari goat. Placentae were collected from local abattoir, classified according to crown rump length of the corresponding foetus into five groups (0-30, 31-60, 61-90, 91-120, and 121-150 days of gestation), and used for relative quantification of mRNA expression by Pfaffl method. In addition, adult female goats (pregnant, n = 7; non-pregnant, n = 5) were used to estimate weekly plasma PAG and progesterone (P4) concentrations. The relative mRNA expression of PAGs was greater (p<0.05) during 31-60 days of gestation, which correlated well with the temporal changes in plasma PAG concentrations. Relative expression of PAGs decreased steadily as gestation advanced with minimum expression observed just before parturition, except for PAG-4 and PAG-8 that showed constantly higher expression throughout pregnancy. Plasma PAG and P4 concentrations showed a distinct temporal pattern with a significant increase beginning at 2 weeks and return to basal levels by 20 weeks of gestation. However, PAG concentrations reached a peak earlier in gestation (8 weeks) than P4 (10-14 weeks). Correlation analysis indicated a strong positive association (r = 0.748, p<0.01) between plasma PAG and P4 concentrations. In conclusion, results of this study indicate a distinct temporal pattern of PAG expression and secretion during gestation in the Barbari goat. The temporal changes in PAGs and the positive association with P4 are suggestive of their role in maintenance of pregnancy and progressive foetal development. PMID- 24148281 TI - Establishment of an effective acute stroke telemedicine program for Australia: protocol for the Victorian Stroke Telemedicine project. AB - RATIONALE: Urgent treatment of acute stroke in rural Australia is problematic partly because of limited access to medical specialists. Utilization of telemedicine could improve delivery of acute stroke treatments in rural communities. AIM: The study aims to demonstrate enhanced clinical decision making for use of thrombolysis within 4.5 h of ischemic stroke symptom onset in a rural setting using a telemedicine specialist support model. DESIGN: A formative program evaluation research design was used. The Victorian Stroke Telemedicine program was developed and will be evaluated over five stages to ensure successful implementation. The phases include: (a) preimplementation phase to establish the Victorian Stroke Telemedicine program including the clinical pathway, data collection tools, and technology processes; (b) pilot clinical application phase to test the pathway in up to 10 patients; (c) modification phase to refine the program; (d) full clinical implementation phase where the program is maintained for one-year; and (e) a sustainability phase to assess project outcomes over five years. Qualitative (clinician interviews) and quantitative data (patient, clinician, costs, and technology processes) are collected in each phase. STUDY OUTCOMES: The primary outcome is to achieve a minimum 10% absolute increase in eligible patients treated with thrombolysis. Secondary outcomes are utilization of the telestroke pathway and improvements in processes of stroke care (e.g., time to brain scan). We will report door to telemedicine consultation time, length of telemedicine consultation, clinical utility and acceptability from the perspective of clinicians, and 90-day patient outcomes. SUMMARY: This research will provide evidence for an effective telestroke program for use in regional Australian hospitals. PMID- 24148282 TI - Tobacco use among Australian dental hygiene students is declining, but more still needs to be done. AB - While health care professionals have a responsibility to prevent and control the use of tobacco for improved health outcomes, it appears that some dental hygiene students continue to smoke. A survey of Australian dental hygiene students found that up to 16.3% smoke, although this prevalence rate decreased with each year of study. As future role models, it is essential that smoking cessation counselling is embedded in the dental curriculum to not only discourage their own habits, but so that they may promote the importance of being tobacco free to the wider population. PMID- 24148283 TI - The role of traditional Japanese medicine (Kampo) in the practice of psychosomatic medicine: the usefulness of Kampo in the treatment of the stress related symptoms of women, especially those with peri-menopausal disorder. AB - A serious problem currently plaguing the medical field is the widening gap between academic medicine, which studies the features and causes of illness, and the medical care that patients desire. An example of this gap can be observed in the practice of psychotherapy, which is effective only for certain patients. Kampo medicine that combines the advantages of Western medicine with those of traditional Japanese medicine is currently undergoing a revival in the healthcare sector. The therapeutic policies underlying Kampo medicine are based on the physical constitution and current symptoms of each patient. For this reason, Kampo medicine is referred to as "tailor-made medicine" and has properties similar to "mind and body" or psychosomatic medicine. Some women exhibit multiple undefined stress-related symptoms during the peri-menopausal period. In order to accurately diagnose and provide patient-specific treatment, physicians should not only investigate the various stress factors in patients' lives but should also provide a Sho, or a Kampo diagnosis. The therapeutic approach in Kampo medicine is aimed at harmonizing the mind, body, and spirit; this practice involves the use of narrative and holistic medication that treats the entire being of the patient, resulting in an increased number of specialized treatment plans.There are many Kampo prescriptions tailored to treat women who exhibit various stress related symptoms. Both Kampo and psychosomatic medicine are based on the principles of narrative-based medicine, and by integrating these two medical systems, an ideal system can be devised to better cope with the various needs of patients. This new medical system established by integrating and harmonizing Western and Eastern medicine can be used for the treatment of women with stress related symptoms. PMID- 24148284 TI - Creutzfeldt-Jakob disease and ENT. AB - OBJECTIVE: This review addresses Creutzfeldt-Jakob disease in the context of ENT, and aims to summarise the relevant history, pathophysiology and implications for contemporary practice. OVERVIEW: Creutzfeldt-Jakob disease is a rare, fatal, neurodegenerative disorder. It is a prion disease with four different subtypes that can only be definitively diagnosed post-mortem. The main implications for the ENT surgeon lie in the risk of iatrogenic transmission. The three facets of assessing individual patient risk are: patient history; tissue infectivity; and procedure infectivity. CONCLUSION: This is a controversial area in medicine, and ENT in particular. This review highlights a clinically applicable approach for everyday use. PMID- 24148286 TI - Molecular characterization of Hysterothylacium fabri (Nematoda: Anisakidae) from Zeus faber (Pisces: Zeidae) caught off the Mediterranean coasts of Turkey based on nuclear ribosomal and mitochondrial DNA sequences. AB - In the present study, Hysterothylacium fabri was found in the coasts of the Mediterranean Sea, Turkey and characterized by sequencing of nuclear (internal transcribed spacer, ITS) and mitochondrial (cytochrome c oxidase subunit 2, cox2) markers. Pairwise comparison between the entire ITS fragment including ITS-1, 5.8S, ITS-2 sequences of the H. fabri isolates from the Mediterranean Sea (Turkey, KC852206) and other H. fabri isolates from the South China Sea (JQ520158), the South Korea waters (JX974558) showed differences ranged from 0.1 and 1.1%. With the present study, H. fabri from the Mediterranean Sea was characterized for the first time by sequencing of the cox2 gene. PMID- 24148287 TI - Characterisation of major vault protein during the life cycle of the human parasite Schistosoma mansoni. AB - Vaults are ribonucleoproteins (13 MDa) highly conserved among lower and higher eukaryotes. Their association produces a complex composed of three proteins named Major Vault Protein (MVP), vault (PolyADP-ribose) polymerase (VPARP) and Telomerase-associated protein (TEP1), plus a small untranslated RNA. The exact function of this complex is unknown, although the biological role of vaults has been associated with multidrug resistance phenotypes and signal transduction pathways. Genomic analysis showed that model organisms, such as Caenorhabditis elegans and Drosophila melanogaster, do not possess genes encoding vaults. However, we have found that vault-related genes are present in the Schistosoma mansoni genome. These observations raised questions on the involvement of vaults in mechanisms of adaptation of the parasite in its mammalian host. Therefore, molecular characterisation of the putative Major Vault Protein performed using bioinformatics tools showed that this vault component is highly conserved in S. mansoni. The MVP expression level was quantified by qRT-PCR using total RNA from susceptible (LE) and resistant (LE-PZQ) adult worm lineages, cercariae and mechanically transformed schistosomula (MTS) cultured for 3.5, 24, 48 and 72 h in vitro. Our results suggest a stage-specific expression in all developmental stages analysed. Western blotting has shown up-regulation of SmMVP in the MTS 3.5, 72 h and resistant adult worms, and similar levels in all other stages. Furthermore, SmMVP was found differentially expressed in adult males and females from the susceptible lineage. Further studies should clarify whether SmMVP is somehow linked to drug resistance in S. mansoni. PMID- 24148285 TI - Predictors of high sensitivity cardiac troponin T in chronic kidney disease patients: a cross-sectional study in the chronic renal insufficiency cohort (CRIC). AB - BACKGROUND: Cardiac troponin T is independently associated with cardiovascular events and mortality in patients with chronic kidney disease (CKD). Serum levels of high sensitivity cardiac troponin T (hs-TnT) reflect subclinical myocardial injury in ambulatory patients. We sought to determine the distribution and predictors of hs-TnT in CKD patients without overt cardiovascular disease (CVD). METHODS: We studied 2464 participants within the multi-ethnic Chronic Renal Insufficiency Cohort (CRIC) who did not have self-reported CVD. We considered renal and non-renal factors as potential determinants of hs-TnT, including demographics, comorbidities, left ventricular (LV) mass, serologic factors, estimated glomerular filtration rate (eGFR) and albumin to creatinine ratio. RESULTS: Hs-TnT was detectable in 81% of subjects, and the median (IQR) hs-TnT was 9.4 pg/ml (4.3-18.3). Analysis was performed using Tobit regression, adjusting for renal and non-renal factors. After adjustment, lower eGFR was associated with higher expected hs-TnT; participants with eGFR < 30 ml/min/1.73 m(2) had 3-fold higher expected hs-TnT compared to subjects with eGFR > 60. Older age, male gender, black race, LV mass, diabetes and higher blood pressure all had strong, independent associations with higher expected hs-TnT. CONCLUSIONS: Knowledge of the determinants of hs-TnT in this cohort may guide further research on the pathology of heart disease in patients with CKD and help to stratify sub groups of CKD patients at higher cardiovascular risk. PMID- 24148288 TI - Neotropical echinococcosis: second report of Echinococcus vogeli natural infection in its main definitive host, the bush dog (Speothos venaticus). AB - The bush dog (Speothos venaticus) acts as the natural definitive host in the life cycle of Echinococcus vogeli, the causative agent of polycystic hydatid disease, a zoonotic neglected disease in the South America. We report a case of natural infection by Echinococcus vogeli in a bush dog from the Brazilian Amazon, confirmed by the morphological and morphometric examination of adult parasites and their hooks obtained from the small intestine of the canid. Additionally, mitochondrial DNA sequence analysis corroborated these findings. This is the second report of natural infection by E. vogeli in a bush dog. PMID- 24148289 TI - Detrimental effects of cement mortar and fly ash mortar on asthma progression. AB - Currently, concrete additive materials are used worldwide to improve properties of concrete production and to reduce the total cost of the materials used in the concrete. However, the effects of exposure to various gases emitted from mortar mixed with additive materials are poorly understood. To evaluate the pattern of gas emission from cement mortar and additives, the emission levels of gas including ammonia (NH3) and volatile organic compounds (VOCs) were measured from two different mortar types, Ordinary Portland Cement (OPC), and OPC with fly ash on various time points after manufacture. On days 1, 3, 10 and 30 after manufacture, moderate concentrations of NH3 (4, 9, 12 and 5 ppm) were measured in OPC mortar (24h, 150 mm * 150 mm * 50 mm), whereas higher concentrations of NH3 (73, 55, 20 and 5 ppm) were measured in OPC mortar with fly ash (24h, 150 mm * 150 mm * 50 mm). Furthermore, the concentration of VOCs was more than 10 ppm on 1, 3, and 10 days of age in OPC and OPC with fly ash mortars. To examine the mortars' allergic effects on the respiratory system, mice were sensitized with ovalbumin (OVA) and divided into four groups: normal, asthma control, OPC mortar and OPC mortar with fly ash. The mice were housed in corresponding group cage for 10 days with OVA challenges to induce asthma. Histopathologically, increased infiltration of lymphocytes was observed in the lung perivascular area of mice housed in OPC mortar and OPC mortar with fly ash cages compared to lungs of asthma control mice. Moreover, severe bronchial lumen obstruction and increased hypertrophy of bronchial epithelial cells (p<0.05) were observed in the OPC mortar with fly ash group compared to OPC mortar or asthma control groups. Lungs of the two mortar groups generally expressed higher levels of genes related with asthma, including IL-4, eotaxin and epidermal growth factor (EGF) compared to lungs of asthma control mice. Additionally, the OPC mortar with fly ash group showed higher expression of IL-5, 13 and monocyte chemoattractant protein-1 (MCP 1) compared to the asthma control group. These results indicate that OPC mortar and OPC mortar with fly ash might exacerbate asthma. PMID- 24148290 TI - Antiangiogenic effects of marine sponge derived compounds on cancer. AB - The term "angiogenic switch" refers to a time-restricted event during tumor progression where the balance between pro- and anti-angiogenic factors, resulting in the transition from dormant avascularized hyperplasia to outgrowing vascularized tumor and eventually to malignant tumor progression. Targeting angiogenesis and its mechanistic pathways are critical target for cancer therapy. Recently, marine derived compounds, plays major role in cancer research. Several sponge derived compounds such as alkaloids, terpenes, macrocylic lactone and polyketide are leading drugs in the treatment of different types of diseases including cancer. Those marine sponge compounds inhibit cancer cell proliferation and tumor angiogenesis. Hence, this review sheds light on angiogenic regulators and marine sponge derived antiangiogenic compounds for cancer. PMID- 24148291 TI - Efficacy and safety of methimazole ointment for patients with hyperthyroidism. AB - Oral methimazole has been widely used to treat hyperthyroidism, but its usage is restricted by its adverse systemic effects. The aim of this study was to investigate the efficacy and safety of methimazole ointment for the treatment of hyperthyroidism. One hundred forty-four subjects with hyperthyroidism were initially enrolled. These patients were initially divided into two groups and given the following treatments for 12 weeks: patients in group A received 5% methimazole ointment applied to the skin around the thyroid and an oral placebo; and patients in group B received methimazole tablets and placebo ointment. One hundred thirty-one subjects were included in the final analysis. Therapeutic efficacy was assessed via the levels of free triiodothyronine and thyroxine in the serum and by biweekly monitoring of the symptoms of thyrotoxicosis. Adverse effects were recorded. Fifty-nine (89.40%) patients in group A and 57 (87.69%) patients in group B were euthyroid and experienced alleviation of thyrotoxicosis symptoms (complete control; p>0.05). The median times required to achieve complete control for the patients in the two groups were 6.5 weeks and 6.4 weeks for groups A and B, respectively (p>0.05). Systemic adverse effects (e.g., rash, liver dysfunction, leucopenia, etc.) were significantly less common in group A (1.5%) than in group B (12.3%; p<0.05). This study showed that methimazole ointment has a clinical efficacy similar to that of oral tablets, but methimazole ointment caused fewer systemic adverse effects in patients with hyperthyroidism. PMID- 24148292 TI - Population size and the rate of evolution. AB - Does evolution proceed faster in larger or smaller populations? The relationship between effective population size (Ne) and the rate of evolution has consequences for our ability to understand and interpret genomic variation, and is central to many aspects of evolution and ecology. Many factors affect the relationship between Ne and the rate of evolution, and recent theoretical and empirical studies have shown some surprising and sometimes counterintuitive results. Some mechanisms tend to make the relationship positive, others negative, and they can act simultaneously. The relationship also depends on whether one is interested in the rate of neutral, adaptive, or deleterious evolution. Here, we synthesize theoretical and empirical approaches to understanding the relationship and highlight areas that remain poorly understood. PMID- 24148293 TI - DNA technology and evolution of the Central Dogma. PMID- 24148295 TI - High-frequency left prefrontal transcranial magnetic stimulation modulates resting EEG functional connectivity for gamma band between the left dorsolateral prefrontal cortex and precuneus in depression. PMID- 24148294 TI - Genome-scale cold stress response regulatory networks in ten Arabidopsis thaliana ecotypes. AB - BACKGROUND: Low temperature leads to major crop losses every year. Although several studies have been conducted focusing on diversity of cold tolerance level in multiple phenotypically divergent Arabidopsis thaliana (A. thaliana) ecotypes, genome-scale molecular understanding is still lacking. RESULTS: In this study, we report genome-scale transcript response diversity of 10 A. thaliana ecotypes originating from different geographical locations to non-freezing cold stress (10 degrees C). To analyze the transcriptional response diversity, we initially compared transcriptome changes in all 10 ecotypes using Arabidopsis NimbleGen ATH6 microarrays. In total 6061 transcripts were significantly cold regulated (p < 0.01) in 10 ecotypes, including 498 transcription factors and 315 transposable elements. The majority of the transcripts (75%) showed ecotype specific expression pattern. By using sequence data available from Arabidopsis thaliana 1001 genome project, we further investigated sequence polymorphisms in the core cold stress regulon genes. Significant numbers of non-synonymous amino acid changes were observed in the coding region of the CBF regulon genes. Considering the limited knowledge about regulatory interactions between transcription factors and their target genes in the model plant A. thaliana, we have adopted a powerful systems genetics approach- Network Component Analysis (NCA) to construct an in silico transcriptional regulatory network model during response to cold stress. The resulting regulatory network contained 1,275 nodes and 7,720 connections, with 178 transcription factors and 1,331 target genes. CONCLUSIONS: A. thaliana ecotypes exhibit considerable variation in transcriptome level responses to non freezing cold stress treatment. Ecotype specific transcripts and related gene ontology (GO) categories were identified to delineate natural variation of cold stress regulated differential gene expression in the model plant A. thaliana. The predicted regulatory network model was able to identify new ecotype specific transcription factors and their regulatory interactions, which might be crucial for their local geographic adaptation to cold temperature. Additionally, since the approach presented here is general, it could be adapted to study networks regulating biological process in any biological systems. PMID- 24148296 TI - PD-1 analysis on CD28(-) CD27(-) CD4 T cells allows stimulation-independent assessment of CMV viremic episodes in transplant recipients. AB - Expression of the inhibitory receptor programmed death 1 (PD-1) on cytomegalovirus (CMV)-specific CD4 T cells defines a phenotype associated with CMV viremia in transplant recipients. Moreover, CD28(-) CD27(-) double negativity is known as a typical phenotype of CMV-specific CD4 T cells. Therefore, the co expression of inhibitory receptors on CD28(-) CD27(-) CD4 T cells was assessed as a rapid, stimulation-independent parameter for monitoring CMV complications after transplantation. Ninety-three controls, 67 hemodialysis patients and 81 renal transplant recipients were recruited in a cross-sectional and longitudinal manner. CMV-specific CD4 T cell levels quantified after stimulation were compared to levels of CD28(-) CD27(-) CD4 T cells. PD-1 and cytotoxic T lymphocyte associated antigen 4 (CTLA-4) expression on CD28(-) CD27(-) CD4 T cells were related to viremia. A percentage of >=0.44% CD28(-) CD27(-) CD4 T cells defined CMV seropositivity (93.3% sensitivity, 97.1% specificity), and their frequencies correlated strongly with CMV-specific CD4 T cell levels after stimulation (r = 0.73, p < 0.0001). Highest PD-1 expression levels on CD28(-) CD27(-) CD4 T cells were observed in patients with primary CMV viremia and reactivation (p < 0.0001), whereas CTLA-4 expression was only elevated during primary CMV viremia (p < 0.05). Longitudinal analysis showed a significant increase in PD-1 expression in relation to viremia (p < 0.001), whereas changes in nonviremic patients were nonsignificant. In conclusion, increased PD-1 expression on CD28(-) CD27(-) CD4 T cells correlates with CMV viremia in transplant recipients and may serve as a specific, stimulation-independent parameter to guide duration of antiviral therapy. PMID- 24148297 TI - Conservation priority of global Galliformes species based on phylogenetic diversity. AB - In this study, based on phylogenetic diversity (PD), I develop a conservation strategy for Galliformes species around the world. A cladogram of 197 Galliformes species derived from a previous study was used for calculating PD metrics. Branch length is an important aspect of the phylogenetic information a tree can convey, but 2 traditionally-used metrics, the number of phylogenetic groups to which a taxon belongs (I) and the proportion that each taxon contributes to the total diversity of the group (W), are fully node-based and do not take branch length into account. Therefore, to measure PD more appropriately, I combined a branch related metric, pendant edge (P), in addition to I and W. A final combined rank for Galliformes species was obtained by summing the ranks of the 3 metrics. My results showed that the 5% top priority species for conserving evolutionary potential were Galloperdix lunulata, Haematortyx sanguiniceps, Margaroperdix madagarensis, Syrmaticus soemmerringii, Coturnix pectoralis, Polyplectron napoleonis, Alectoris melanocephala, Xenoperdix udzungwensis, Afropavo congensis and Syrmaticus reevesii. The current species priority ranking based on pylogenetic diversity and the official International Union for Conservation of Nature (IUCN) ranking of Galliformes species was significantly correlated when considering the 5 categories of IUCN (critical endangered, endangered, vulnerable, near threatened and least concern). This indicated the feasibility of introducing the PD index into the network of IUCN regional Red List assessment. The 5% top priority countries selected using the complementarity principle possessing diversified Galliformes genetic resources were China, Indonesia, Mexico, India, Colombia, Australia, Brazil, Angola, Congo and Japan (in descending order). China, Indonesia, Mexico, Brazil, India and Colombia are consistently selected among the 4 top priority sets of richness, rarity, endemicity and PD. This result indicated that the priority result from PD is highly congruent with conventional measures. Along with other conventional ecological attributes, the alternative conservation scenario based on PD is reasonable and can be adopted in systematic conservation planning. PMID- 24148298 TI - Capillary electrophoresis as a novel technique for screening natural flavonoids as kinase inhibitors. AB - Capillary electrophoresis (CE) was used for the first time to evaluate the inhibition activity of aglycone flavonoids (such as quercetin and isorhamnetin) and some of their glycosylated derivatives toward human kinases. The cyclin dependant kinase 5 (CDK5/p25) and the glycogen synthase kinase 3beta (GSK3beta) were chosen since they are very promising biological targets for developing treatments against neurodegenerative diseases and cancer. In a previous work, we developed an in-capillary kinase CE assay where the capillary was used as an enzymatic nanoreactor in which the kinase, its substrate, adenosine 5' triphosphate (ATP) and its potential inhibitor were mixed by using transverse diffusion of laminar flow profiles (TDLFP). The product adenosine 5'-diphosphate (ADP) was then detected at 254nm and quantified. In this work, this assay was improved to reduce, for the first time, the dilution effect commonly observed with the TDLFP approach. Under the new conditions established herein, IC50 values for quercetin, kaempferol and flavopiridol were successfully obtained and were in the same order of magnitude of those reported in the literature using the conventional assay using radioactive (33)P-ATP. It was shown that aglycone flavonoids have an inhibition activity more important than their glycosylated derivatives. CE was also proved to be very efficient for evaluating inhibition activity of complex samples such as crude extracts of sea buckthorn (SBT) berries obtained by solvent-free microwave extraction (SFME). This novel approach to combine SFME technique to a CE-based enzymatic assay is very interesting for evaluating the biological activity of natural material in a fast, simple, economic (no use of neither fluorescent nor radiometric labels) and green (no organic solvents) manner. PMID- 24148299 TI - The incorporation of calix[6]arene and cyclodextrin derivatives into sol-gels for the preparation of stationary phases for gas chromatography. AB - New polyethylene-glycol-based sol-gels containing cyclodextrin or calix[6]arene derivatives have been synthesized. An original method for sol-gel preparation and capillary column coating, which consumes smaller quantities of selectors and allows for control of their amounts in the stationary phase, is reported herein. The new stationary phases exhibited excellent column efficiencies over a large range of temperatures and thermal stability up to 280 degrees C. The cyclodextrin derivative generally showed the best separation factors for aromatic positional isomers. The calix[6]arene derivative exhibited the best selectivity for the polychlorobiphenyl congeners and some polycyclic aromatic hydrocarbon isomers. The relationship between the structure and the chromatographic properties of the selectors is discussed. The tert-butyl groups on the upper rim of the calix[6]arene were found to possibly play an important role in the recognition of solutes. The incorporation of the cyclodextrin derivative into the sol-gel matrix did not affect its enantioselective recognition capabilities. PMID- 24148300 TI - Accuracy assessment on the analysis of unbound drug in plasma by comparing traditional centrifugal ultrafiltration with hollow fiber centrifugal ultrafiltration and application in pharmacokinetic study. AB - In present study, accuracy assessment on the analysis of unbound drug in plasma was made by comparing traditional centrifugal ultrafiltration (CF-UF) with hollow fiber centrifugal ultrafiltration (HFCF-UF). We used metformin (MET) as a model drug and studied the influence of centrifugal time, plasma condition and freeze thaw circle times on the ultrafiltrate volume and related effect on the measurement of MET. Our results demonstrated that ultrafiltrate volume was a crucial factor which influenced measurement accuracy of unbound drug in plasma. For traditional CF-UF, the ultrafiltrate volume cannot be well-controlled due to a series of factors. Compared with traditional CF-UF, the ultrafiltrate volume by HFCF-UF can be easily controlled by the inner capacity of the U-shaped hollow fiber inserted into the sample under enough centrifugal force and centrifugal time, which contributes to a more accurate measurement. Moreover, the developed HFCF-UF method achieved a successful application in real plasma samples and exhibited several advantages including high precision, extremely low detection limit and perfect recovery. The HFCF-UF method offers the advantage of highly satisfactory performance in addition to being simple and fast in pretreatment, with these characteristics being consistent with the practicability requirements in current scientific research. PMID- 24148301 TI - Bringing the gut microbiota into focus through microbial culture: recent progress and future perspective. AB - Ever-more-powerful 'omics'-based technologies are allowing us to pry deeper and more clearly into the workings of the human gut microbiota. Culture of the component microbes has fallen somewhat behind these efforts for a number of reasons, not least of which being the perceived difficulty in growing microbial species that have previously eluded all efforts to tame them. However, recent advances in the field are beginning to bring success in this area, allowing holistic study of microbes and microbial communities in defined systems. Innovative approaches to the culture and study of the human microbiota will ultimately guide medical practice, as the importance of a robust gut microbial ecosystem in the maintenance of health is increasingly realized. PMID- 24148303 TI - Expression profile of the pore-forming subunits alpha1A and alpha1D in the foetal bovine hypothalamus: a mammal with a long gestation. AB - This study describes the expression of the voltage operated calcium channels (VOCCs) subunits alpha1A (typical of the P/Q family) and alpha1D (of the L family) in the bovine hypothalamus. The expression of both P/Q and L families has been characterized in the brain of adult mammals. However, their distribution and expression during foetal neuronal differentiation have not yet been determined. The expression profile of the alpha1A and alpha1D pore-forming subunits was investigated during four embryonic stages in bovine foetuses. Our data suggest that the expressions of alpha1A and alpha1D are correlated during development, with an increase only in males that peaks on the last period of gestation. Bovine male hypothalami showed significantly higher alpha1A and alpha1D expression values in comparison to female ones during the whole developmental period. In the females, the expression profiles of both genes were constant during all the developmental time. Immunohistochemical studies confirmed the presence of the alpha1A and alpha1D protein subunits in foetal hypothalamic neurones starting from the third foetal stage. Our data provide new information on the hypothalamic expression of alpha1A and alpha1D subunits during development in a mammal with a long gestation period and a large and convoluted brain. PMID- 24148302 TI - On the essentiality of lipopolysaccharide to Gram-negative bacteria. AB - Lipopolysaccharide is a highly acylated saccharolipid located on the outer leaflet of the outer membrane of Gram-negative bacteria. Lipopolysaccharide is critical to maintaining the barrier function preventing the passive diffusion of hydrophobic solutes such as antibiotics and detergents into the cell. Lipopolysaccharide has been considered an essential component for outer membrane biogenesis and cell viability based on pioneering studies in the model Gram negative organisms Escherichia coli and Salmonella. With the isolation of lipopolysaccharide-null mutants in Neisseria meningitidis, Moraxella catarrhalis, and most recently in Acinetobacter baumannii, it has become increasingly apparent that lipopolysaccharide is not an essential outer membrane building block in all organisms. We suggest the accumulation of toxic intermediates, misassembly of essential outer membrane porins, and outer membrane stress response pathways that are activated by mislocalized lipopolysaccharide may collectively contribute to the observed strain-dependent essentiality of lipopolysaccharide. PMID- 24148304 TI - Improved preparation of acellular nerve scaffold and application of PKH26 fluorescent labeling combined with in vivo fluorescent imaging system in nerve tissue engineering. AB - Acellular nerve scaffold has been widely used for peripheral nerve defect treatment. However, the structure of traditional acellular nerve scaffold is dense; the interval porosity and void diameter are too small to meet the requirement of cell seeding, which limits the application. This study was designed to prepare a novel acellular nerve scaffold by the technique of hypotonic buffer combined with freeze-drying, and use PKH26 fluorescent labeling combined with in vivo fluorescent imaging system to evaluate the biological behavior of tissue-engineered nerve in vitro and in vivo. According to light and electron microscopy, the scaffold, which microarchitecture was similar to the fibrous framework of rabbit sciatic nerves, was cell-free and rich in laminin, collagen I and collagen III. In vitro experiment showed that the novel acellular nerve scaffold could provide a 3-D environment to support the attachment, proliferation and migration of adipose-derived stem cells (ADSCs). ADSCs labeled with fluorescent dye PKH26 were then seeded on scaffolds and implanted subcutaneously into nude mice. After 4 weeks, nerve-like tissue rounded by vessels formed. Cells in the tissue seemed to confirm that they originated from the labeled ADSCs, as confirmed by in vivo fluorescent imaging. In conclusion, the prepared novel acellular nerve scaffold can be used as a new kind of nerve scaffold material, which is more conducible for seeding cells; And PKH26 fluorescent labeling and in vivo fluorescent imaging can be useful for cell tracking and analyzing cell-scaffold constructs in vivo. PMID- 24148305 TI - The potential role of CAMSAP1L1 in symptomatic epilepsy. AB - In a recent genome-wide association study (GWAS) of symptomatic epilepsy in the Chinese population, the most significant single nucleotide polymorphism (SNP) allele was rs2292096 [G] (P=1.0*10(-8), odds ratio [OR]=0.63), in the CAMSAP1L1 gene (also known as CAMSAP2). Here, we report that rs2292096 genotypes tended to associate with expression of CAMSAP1L1 RNA in the temporal lobe (p=0.054) and hippocampus (p=0.20) of epilepsy surgery patients, with expression tending to increase with the G allele. CAMSAP1L1 and beta-tubulin double immunofluorescence exhibited partial overlap. CAMSAP1L1 siRNA transfection of human SH-SY5Y neuroblastoma cells treated with or without retinoic acid reduced the CAMSAP1L1 protein level nearly 60% and stimulated neurite outgrowth, as measured by total length, number of processes and number of branches. Therefore, the rs2292096 G allele of CAMSAP1L1, which was associated with reduced risk of symptomatic epilepsy, tended to associate with increased expression of CAMSAP1L1, which represses neurite outgrowth. Greater neurite growth in response to brain insults might increase formation of ectopic neural circuits and thus the risk of epileptogenesis. PMID- 24148307 TI - Ghrelin but not nesfatin-1 affects certain forms of learning and memory in both rats and mice. AB - Ghrelin and nesfatin-1 are two recently discovered peptide hormones that play opposite roles in the food intake, body-weight control and energy homeostasis in both human and rodents. Beyond its appetite-control function, increasing evidence has shown that ghrelin affects multiple advanced activities in the central nervous system, including memory and emotion. Nesfatin-1 was also widely expressed in extra-hypothalamic brain regions including hippocampus and amygdala. However, the possible actions of nesfatin-1 in those important brain regions are largely unknown. In this study, we micro-infused ghrelin or nesfatin-1 into the lateral amygdala (LA) or area CA1 of the dorsal hippocampus (CA1) and investigated the immediate effects of those two peptide hormones on cognitive and affective behaviors. We found that the micro infusion of ghrelin into the LA or the CA1 interfered with certain types of learning and memory in both rats and mice, while nesfatin-1 had no effect. Our data thus suggested that although nesfatin-1 works as a functional antagonist of ghrelin in the feeding control, only ghrelin affects learning and memory. PMID- 24148306 TI - High expression of prolactin receptor is associated with cell survival in cervical cancer cells. AB - BACKGROUND: The altered expression of prolactin (PRL) and its receptor (PRLR) has been implicated in breast and other types of cancer. There are few studies that have focused on the analysis of PRL/PRLR in cervical cancer where the development of neoplastic lesions is influenced by the variation of the hormonal status. The aim of this study was to evaluate the expression of PRL/PRLR and the effect of PRL treatment on cell proliferation and apoptosis in cervical cancer cell lines. RESULTS: High expression of multiple PRLR forms and PRLvariants of 60-80 kDa were observed in cervical cancer cell lines compared with non-tumorigenic keratinocytes evaluated by Western blot, immunofluorecence and real time PCR. Treatment with PRL (200 ng/ml) increased cell proliferation in HeLa cells determined by the MTT assay at day 3 and after 1 day a protective effect against etoposide induced apoptosis in HeLa, SiHa and C-33A cervical cancer cell lines analyzed by the TUNEL assay. CONCLUSIONS: Our data suggests that PRL/PRLR signaling could act as an important survival factor for cervical cancer. The use of an effective PRL antagonist may provide a better therapeutic intervention in cervical cancer. PMID- 24148308 TI - Quantitative evaluation of E. coli F4 and Salmonella Typhimurium binding capacity of yeast derivatives. AB - The target of the present study was to quantify the capacity of different commercially available yeast derivatives to bind E. coli F4 and Salmonella Typhimurium. In addition, a correlation analysis was performed for the obtained binding numbers and the mannan-, glucan- and protein contents of the products, respectively. In a subsequent experiment, different yeast strains were fermented and treated by autolysis or French press to obtain a concentrated yeast cell wall. The capacity of yeast cell wall products to bind E. coli F4 and Salmonella Typhimurium was assessed with a quantitative microbiological microplate-based assay by measuring the optical density (OD) as the growth parameter of adhering bacteria. Total mannan and glucan were determined by HPLC using an isocratic method and a Refractive Index (RI) Detector. Total protein was determined by Total Kjeldahl Nitrogen (TKN). Statistical analyses were performed with IBM SPSS V19 using Spearman correlation and Mann Whitney U Test.Different yeast derivatives show different binding numbers, which indicate differences in product quality.Interestingly, the binding numbers for Salmonella Typhimurium are consistently higher (between one and two orders of magnitude) than for E. coli F4.We could demonstrate some statistical significant correlations between the mannan- and glucan content of different yeast derivatives and pathogen binding numbers; however, for the different yeast strains fermented under standardized laboratory conditions, no statistically significant correlations between the mannan- and glucan content and the binding numbers for E. coli and Salmonella Typhimurium were found.Interestingly, we could demonstrate that the yeast autolysis had a statistically significant difference on E. coli binding in contrast to the French press treatment. Salmonella binding was independent of these two treatments.As such, we could not give a clear statement about the binding factors involved. We propose that many more factors apart from mannan- and glucan content, such as cell wall structure, strain diversity, structural diversity, structural surroundings, and non-specific interactions play important roles in pathogen immobilization. PMID- 24148309 TI - ENNET: inferring large gene regulatory networks from expression data using gradient boosting. AB - BACKGROUND: The regulation of gene expression by transcription factors is a key determinant of cellular phenotypes. Deciphering genome-wide networks that capture which transcription factors regulate which genes is one of the major efforts towards understanding and accurate modeling of living systems. However, reverse engineering the network from gene expression profiles remains a challenge, because the data are noisy, high dimensional and sparse, and the regulation is often obscured by indirect connections. RESULTS: We introduce a gene regulatory network inference algorithm ENNET, which reverse-engineers networks of transcriptional regulation from a variety of expression profiles with a superior accuracy compared to the state-of-the-art methods. The proposed method relies on the boosting of regression stumps combined with a relative variable importance measure for the initial scoring of transcription factors with respect to each gene. Then, we propose a technique for using a distribution of the initial scores and information about knockouts to refine the predictions. We evaluated the proposed method on the DREAM3, DREAM4 and DREAM5 data sets and achieved higher accuracy than the winners of those competitions and other established methods. CONCLUSIONS: Superior accuracy achieved on the three different benchmark data sets shows that ENNET is a top contender in the task of network inference. It is a versatile method that uses information about which gene was knocked-out in which experiment if it is available, but remains the top performer even without such information. ENNET is available for download from https://github.com/slawekj/ennet under the GNU GPLv3 license. PMID- 24148310 TI - Impact of a population-based HPV vaccination program on cervical abnormalities: a data linkage study. AB - BACKGROUND: Australia was one of the first countries to introduce a publicly funded national human papillomavirus (HPV) vaccination program that commenced in April 2007, using the quadrivalent HPV vaccine targeting 12- to 13-year-old girls on an ongoing basis. Two-year catch-up programs were offered to 14- to 17- year old girls in schools and 18- to 26-year-old women in community-based settings. We present data from the school-based program on population-level vaccine effectiveness against cervical abnormalities in Victoria, Australia. METHODS: Data for women age-eligible for the HPV vaccination program were linked between the Victorian Cervical Cytology Registry and the National HPV Vaccination Program Register to create a cohort of screening women who were either vaccinated or unvaccinated. Entry into the cohort was 1 April 2007 or at first Pap test for women not already screening. Vaccine effectiveness (VE) and hazard ratios (HR) for cervical abnormalities by vaccination status between 1 April 2007 and 31 December 2011 were calculated using proportional hazards regression. RESULTS: The study included 14,085 unvaccinated and 24,871 vaccinated women attending screening who were eligible for vaccination at school, 85.0% of whom had received three doses. Detection rates of histologically confirmed high-grade (HG) cervical abnormalities and high-grade cytology (HGC) were significantly lower for vaccinated women (any dose) (HG 4.8 per 1,000 person-years, HGC 11.9 per 1,000 person-years) compared with unvaccinated women (HG 6.4 per 1,000 person-years, HGC 15.3 per 1,000 person-years) HR 0.72 (95% CI 0.58 to 0.91) and HR 0.75 (95% CI 0.65 to 0.87), respectively. The HR for low-grade (LG) cytological abnormalities was 0.76 (95% CI 0.72 to 0.80). VE adjusted a priori for age at first screening, socioeconomic status and remoteness index, for women who were completely vaccinated, was greatest for CIN3+/AIS at 47.5% (95% CI 22.7 to 64.4) and 36.4% (95% CI 9.8 to 55.1) for women who received any dose of vaccine, and was negatively associated with age. For women who received only one or two doses of vaccine, HRs for HG histology were not significantly different from 1.0, although the number of outcomes was small. CONCLUSION: A population-based HPV vaccination program in schools significantly reduced cervical abnormalities for vaccinated women within five years of implementation, with the greatest vaccine effectiveness observed for the youngest women. PMID- 24148311 TI - Prevalence of the HOXB13 G84E prostate cancer risk allele in men treated with radical prostatectomy. AB - OBJECTIVE: To determine the prevalence and clinical correlates of the G84E mutation in the homeobox transcription factor, or HOXB13, gene using DNA samples from 9559 men with prostate cancer undergoing radical prostatectomy. PATIENTS AND METHODS: DNA samples from men treated with radical prostatectomy at the University of Michigan and John Hopkins University were genotyped for G84E and this was confirmed by Sanger sequencing. The frequency and distribution of this allele was determined according to specific patient characteristics (family history, age at diagnosis, pathological Gleason grade and stage). RESULTS: Of 9559 patients, 128 (1.3%) were heterozygous carriers of G84E. Patients who possessed the variant were more likely to have a family history of prostate cancer than those who did not (46.0 vs 35.4%; P = 0.006). G84E carriers were also more likely to be diagnosed at a younger age than non-carriers (55.2 years vs 58.1 years; P < 0.001). No difference in the proportion of patients diagnosed with high grade or advanced stage tumours according to carrier status was observed. CONCLUSIONS: In the present study, carriers of the rare G84E variant in HOXB13 were both younger at the time of diagnosis and more likely to have a family history of prostate cancer compared with homozygotes for the wild-type allele. No significant differences in allele frequency were detected according to selected clinical characteristics of prostate cancer. Further investigation is required to evaluate the role of HOXB13 in prostate carcinogenesis. PMID- 24148312 TI - Gender differences in the age-stratified prevalence of risk factors in Korean ischemic stroke patients: a nationwide stroke registry-based cross-sectional study. AB - BACKGROUND: Although ethnic or cultural differences affect prevalence of cardiovascular risk factors, limited information is available about the age- and gender-stratified prevalence of the risk factors in Asian stroke population. AIMS AND HYPOTHESIS: We assessed gender- and age-stratified prevalences of major risk factors in Korean stroke patients, and assumed that the gender differences are attenuated by adjustment with lifestyle factors. METHODS: Using the nationwide hospital-based stroke registry, we identified 9417 ischemic stroke patients admitted between April 2008 and January 2011. Prevalence of hypertension, diabetes, hyperlipidemia, atrial fibrillation, prior stroke, and coronary heart disease was assessed in both genders by age groups. We analyzed gender differences of the prevalence among the age groups by calculating prevalence ratio, and further explored the influence of lifestyle factors on the gender difference in multivariable analyses. RESULTS: Hypertension and hyperlipidemia were more common in men until middle age, but after that more common in women, whereas diabetes was more common in women after 65 years of age. Atrial fibrillation increased steadily with age in both genders but was more common in women through all age groups. Prior stroke and coronary heart disease showed inconsistent gender differences. Gender differences in hypertension and diabetes among the age groups were attenuated by adjustment with accompanying risk factors including lifestyle factors. CONCLUSION: Korean women with stroke had more hypertension and hyperlipidemia after middle age, more diabetes after 65 years, and more atrial fibrillation throughout all ages. Strategies to control risk factors in women at risk for stroke are eagerly needed. PMID- 24148313 TI - Finding the most effective cerumenolytic. AB - AIM: To conduct an in-vitro study to determine the most effective topical cerumenolytic. METHOD: Cerumen was collected from patients who attended the ENT out-patient clinic. The collected cerumen was formed into a homogeneous ball. Discs of wax were punched out and weighed to create samples of uniform shape and size. Each cerumen sample was placed in a tube which contained one of six test solutions. The tubes were observed at specific time points. Digital photographs were taken to record the degree of cerumen disintegration. The cerumen discs were then removed from the solutions, dried and re-weighed. RESULTS: Distilled water caused the greatest reduction in the mass of the cerumen disc. Cerumen placed in distilled water and in sodium bicarbonate solution showed substantial disintegration at 12 hours. Cerumen placed in solutions containing oil-based agents showed no visible sign of disintegration and no reduction in dried weight. CONCLUSION: Distilled water resulted in the greatest degree of cerumenolysis. Oil based cerumenolytics were ineffective. PMID- 24148314 TI - IFABP portal region insertion during membrane interaction depends on phospholipid composition. AB - Intestinal fatty acid-binding protein (IFABP) is highly expressed in the intestinal epithelium and it belongs to the family of soluble lipid binding proteins. These proteins are thought to participate in most aspects of the biology of lipids, regulating its availability for specific metabolic pathways, targeting and vectorial trafficking of lipids to specific subcellular compartments. The present study is based on the ability of IFABP to interact with phospholipid membranes, and we characterized its immersion into the bilayer's hydrophobic central region occupied by the acyl-chains. We constructed a series of Trp-mutants of IFABP to selectively probe the interaction of different regions of the protein, particularly the elements forming the portal domain that is proposed to regulate the exit and entry of ligands to/from the binding cavity. We employed several fluorescent techniques based on selective quenching induced by soluble or membrane confined agents. The results indicate that the portal region of IFABP penetrates deeply into the phospholipid bilayer, especially when CL containing vesicles are employed. The orientation of the protein and the degree of penetration were highly dependent on the lipid composition, the superficial net charge and the ionic strength of the medium. These results may be relevant to understand the mechanism of ligand transfer and the specificity responsible for the unique functions of each member of the FABP family. PMID- 24148315 TI - The importance of specialist cardiac histopathological examination in the investigation of young sudden cardiac deaths. AB - AIMS: Post-mortem examination of the heart in young sudden cardiac death (SCD) is vital as the underlying aetiology is often an inherited cardiac disease with implications for surviving relatives. Our aim is to demonstrate the improvement in diagnostic quality offered by a specialist cardiac pathology service established to investigate SCD with fast-track reporting on hearts sent by pathologists in cases of SCD. METHODS AND RESULTS: A tertiary centre prospective observational study was conducted. Detailed histopathological examination was performed in a tertiary centre specialized in the investigation of cardiac pathology in SCD. Hearts from 720 consecutive cases of SCD referred by coroners and pathologists from 2007 to 2009 were included. A comparison was drawn with diagnoses from referring pathologists. Most SCDs occurred in males (66%), with the median age being 32 years. The majority (57%) of deaths occurred at home. The main diagnoses were a morphologically normal heart (n = 321; 45%), cardiomyopathy (n = 207, 29%), and coronary artery pathology (n = 71; 10%). In 158 out of a sample of 200 consecutive cases, a cardiac examination was also performed by the referring pathologist with a disparity in diagnosis in 41% of the cases (kappa = 0.48). Referring pathologists were more inclined to diagnose cardiomyopathy than normality with only 50 out of 80 (63%) normal hearts being described correctly. CONCLUSION: Expert cardiac pathology improves the accuracy of coronial post mortem diagnoses in young SCD. This is important as the majority of cases may be due to inherited cardiac diseases and the autopsy guides the appropriate cardiological evaluation of blood relatives for their risk of sudden death. PMID- 24148316 TI - How to temporarily pace a pacemaker-dependent patient after lead extraction for device infection? PMID- 24148317 TI - Experiencing maternity care: the care received and perceptions of women from different ethnic groups. AB - BACKGROUND: According to the Office for National Statistics, approximately a quarter of women giving birth in England and Wales are from minority ethnic groups. Previous work has indicated that these women have poorer pregnancy outcomes than White women and poorer experience of maternity care, sometimes encountering stereotyping and racism. The aims of this study were to examine service use and perceptions of care in ethnic minority women from different groups compared to White women. METHODS: Secondary analysis of data from a survey of women in 2010 was undertaken. The questionnaire asked about women's experience of care during pregnancy, labour and birth, and the postnatal period, as well as demographic factors. Ethnicity was grouped into eight categories: White, Mixed, Indian, Pakistani, Bangladeshi, Black Caribbean, Black African, and Other ethnicity. RESULTS: A total of 24,319 women completed the survey. Compared to White women, women from minority ethnic groups were more likely to be younger, multiparous and without a partner. They tended to access antenatal care later in pregnancy, have fewer antenatal checks, fewer ultrasound scans and less screening. They were less likely to receive pain relief in labour and, Black African women in particular, were more likely to deliver by emergency caesarean section. Postnatally, women from minority ethnic groups had longer lengths of hospital stay and were more likely to breastfeed but they had fewer home visits from midwives. Throughout their maternity care, women from minority ethnic groups were less likely to feel spoken to so they could understand, to be treated with kindness, to be sufficiently involved in decisions and to have confidence and trust in the staff. CONCLUSION: Women in all minority ethnic groups had a poorer experience of maternity services than White women. That this was still the case following publication of a number of national policy documents and local initiatives is a cause for concern. PMID- 24148318 TI - Lateral root formation and patterning in Medicago truncatula. AB - The plant root system is crucial for anchorage and nutrition, and has a major role in plant adaptation, as well as in interactions with soil micro-organisms. Despite the agronomical and ecological importance of legume plants, whose roots can interact symbiotically with soil bacteria called rhizobia that fix atmospheric dinitrogen, and the evidence that lateral root (LR) development programmes are intercepted and influenced by symbiotic organisms, very little is known concerning the cellular and molecular events governing LR development in legumes. To better understand the interconnections between LR formation and symbiotic processes triggered by rhizobia or symbiotic molecules such as lipo chitooligosaccharides (LCOs), we first need a detailed description of LR development mechanisms in legumes. Using thin sections, we have described the cellular events leading to the formation of a new LR primordium (LRP) in Medicago truncatula, and divided them into seven stages prior to LR emergence. To monitor auxin accumulation we generated transgenic DR5:GUS and DR5:VENUS-N7 reporter lines of M. truncatula, and used them to analyze early stages of LR development. Interesting differences were observed for LR ontogeny compared to Arabidopsis thaliana. Notably, we observed endodermal and cortical contributions to LRP formation, and the associated DR5:GUS expression profile indicated that endodermal and cortical cell divisions were correlated with auxin accumulation. As described for A. thaliana, we observed a preferential zone for LR initiation at 4.45 mm from the root tip. Finally, we studied LR emergence and showed that a significant proportion of new LRP do not emerge straight away and could thus be an additional source of root plasticity. Our results shed new light on the patterning and early development of LRs in M. truncatula. PMID- 24148320 TI - Ecotoxicological evaluation of caffeine and its derivatives from a simulated chlorination step. AB - Caffeine is ubiquitous in surface and ground waters and it has been proposed as a marker of the anthropogenic pressure on the environment. Sewage treatment plants based on active sludges seem to be not very efficient in its complete removal from effluents while additional disinfection treatments by chlorination are able to do it. In a simulation of the chlorination step herein we report that caffeine is transformed in six by-products: 8-chlorocaffeine, 1,3-dimethyl-5-azabarbituric acid, N,N'-dimethylparabanic acid, N,N'-dimethyloxalamide, N-methylurea and N,N' dimethylurea. The ecotoxicity of caffeine and identified compounds was evaluated on the rotifer Brachionus calyciflorus and the alga Pseudokirchneriella subcapitata to assess acute and chronic toxicity, while SOS Chromotest and Ames Test were used to detect the genotoxic potential of the investigated compounds. Moreover, we assessed the possible antigenotoxic effect of the selected compounds using SOS Chromotest after co-incubation with the standard genotoxin, 4 nitroquinoline 1-oxide. Chronic exposure to these compounds caused inhibition of growth population on the rotifer while the algae seemed to be unaffected. Results indicated that caffeine (1), N,N'-dimethyloxamide (4) and N,N'-dimethylparabanic acid (5) reduced beta-galactosidase activity in comparison with positive control, both at 1 and 5mg/L of 4-NQNO with a good dose-response. PMID- 24148319 TI - Comparative analysis of resistant and susceptible macrophage gene expression response to Leishmania major parasite. AB - BACKGROUND: Leishmania are obligated intracellular pathogens that replicate almost exclusively in macrophages. The outcome of infection depends largely on parasite pathogenicity and virulence but also on the activation status and genetic background of macrophages. Animal models are essential for a better understanding of pathogenesis of different microbes including Leishmania. RESULTS: Here we compared the transcriptional signatures of resistant (C57BL/6) and susceptible (BALB/c) mouse bone marrow-derived macrophages in response to Leishmania major (L. major) promastigotes infection.Microarray results were first analyzed for significant pathways using the Kyoto Encylopedia of Genes and Genomes (KEGG) database. The analysis revealed that a large set of the shared genes is involved in the immune response and that difference in the expression level of some chemokines and chemokine receptors could partially explain differences in resistance. We next focused on up-regulated genes unique to either BALB/c or C57BL/6 derived macrophages and identified, using KEGG database, signal transduction pathways among the most relevant pathways unique to both susceptible and resistant derived macrophages. Indeed, genes unique to C57BL/6 BMdMs were associated with target of rapamycin (mTOR) signaling pathway while a range of genes unique to BALB/c BMdMs, belong to p53 signaling pathway. We next investigated whether, in a given mice strain derived macrophages, the different up-regulated unique genes could be coordinately regulated. Using GeneMapp Cytoscape, we showed that the induced genes unique to BALB/c or C57BL/6 BMdMs are interconnected. Finally, we examined whether the induced pathways unique to BALB/c derived macrophages interfere with the ones unique to C57BL/6 derived macrophages. Protein-protein interaction analysis using String database highlights the existence of a cross-talk between p53 and mTOR signaling pathways respectively specific to susceptible and resistant BMdMs. CONCLUSIONS: Taken together our results suggest that strains specific pathogenesis may be due to a difference in the magnitude of the same pathways and/or to differentially expressed pathways in the two mouse strains derived macrophages. We identify signal transduction pathways among the most relevant pathways modulated by L. major infection, unique to BALB/c and C57BL/6 BMdM and postulate that the interplay between these potentially interconnected pathways could direct the macrophage response toward a given phenotype. PMID- 24148321 TI - New priority substances of the European Water Framework Directive: biocides, pesticides and brominated flame retardants in the aquatic environment of Denmark. AB - The biocides cybutryn (Irgarol) and terbutryn, the herbicides aclonifen and bifenox, the insecticides cypermethrin and heptachlor/heptachlor epoxide and the brominated flame retardant hexabromocyclododecane (HBCD) are new priority substances of the Water Framework Directive of the European Union. In order to gain knowledge about their presence in the aquatic environment in an off-season situation with regard to pesticide and biocide applications, these substances were analysed in freshwater, seawater and fish samples from Denmark. Aclonifen, bifenox, cypermethrin and heptachlor were below the limits of detection (LODs) in all samples. However, the LODs for cypermethrin and heptachlor exceeded the annual average environmental quality standards (AA-EQSs). Cybutryn, terbutryn, heptachlor epoxide and HBCD were detected in the majority of samples, with detection frequencies of 100% for heptachlor epoxide and HBCD in water and 90% in fish. No concentration was above maximum allowable concentration (MAC)-EQS values, but AA-EQS values were exceeded for all four compounds by several samples, including 100% of the water samples with regard to heptachlor epoxide. Methodological issues remain for cypermethrin, and to a certain extent for heptachlor/heptachlor epoxide, for which water LODs were above AA-EQSs although a water volume of 12L was combined with very sensitive high resolution mass spectrometry. PMID- 24148322 TI - Upper limb muscular activity and perceived workload during laryngoscopy: comparison of Glidescope(R) and Macintosh laryngoscopy in manikin: an observational study. AB - BACKGROUND: The interaction between operators and their working environment during laryngoscopy is poorly understood. Numerous studies have focused on the forces applied to the patient's airway during laryngoscopy, but only a few authors have addressed operator muscle activity and workload. We tested whether different devices (Glidescope((r)) and Macintosh) use different muscles and how these differences affect the perceived workload. METHODS: Ten staff anaesthetists performed three intubations with each device on a manikin. Surface electromyography was recorded for eight single muscles of the left upper limb. The NASA Task Load Index (TLX) was administered after each experimental session to evaluate perceived workload. RESULTS: A consistent reduction in muscular activation occurred with Glidescope((r)) compared with Macintosh for all muscles tested (mean effect size d=3.28), and significant differences for the upper trapezius (P=0.002), anterior deltoid (P=0.001), posterior deltoid (P=0.000), and brachioradialis (P=0.001) were observed. The overall NASA-TLX workload score was significantly lower for Glidescope((r)) than for Macintosh (P=0.006), and the factors of physical demand (P=0.008) and effort (P=0.006) decreased significantly. CONCLUSIONS: Greater muscular activity and workload were observed with the Macintosh laryngoscope. Augmented vision and related postural adjustments related to using the Glidescope((r)) may reduce activation of the operator's muscles and task workload. PMID- 24148323 TI - Comparison of the prognostic accuracy of scoring systems, cardiopulmonary exercise testing, and plasma biomarkers: a single-centre observational pilot study. AB - BACKGROUND: Current approaches to risk assessment before major surgery have important limitations. The aim of this pilot study was to compare predictive accuracy of preoperative scoring systems, plasma biomarkers, and cardiopulmonary exercise testing (CPET) for complications after major non-cardiac surgery. METHODS: Single-centre, observational study of patients aged >=40 yr undergoing major elective non-cardiac surgery. Before surgery, risk scores were calculated and blood samples collected for measurement of plasma biomarkers. Patients underwent CPET for measurement of anaerobic threshold (AT) and peak oxygen consumption ( peak). After surgery, patients were followed for 28 days to evaluate complications and major adverse cardiac events (MACE). Data are presented as area under the receiver operating characteristic curve (AUROC) with 95% confidence intervals. RESULTS: A total of 100 patients were recruited between April 2009 and October 2010; 17 of whom did not proceed to surgery. CPET variables suggested good predictive accuracy for MACE [AT: AUROC 0.83 (0.69 0.96); peak AUROC 0.81 (0.69-0.96)] and poor predictive accuracy for all complications [AT: AUROC 0.64 (0.52-0.77); peak AUROC 0.64 (0.52-0.77)]. There was a trend towards predictive accuracy of the plasma biomarkers B-type natriuretic peptide and estimated glomerular filtration rate (calculated from serum creatinine) for MACE but not all complications. C-reactive protein, ASA score, and revised cardiac risk index had little or no predictive value. CONCLUSIONS: These pilot data suggest that CPET and plasma biomarkers may improve risk assessment before surgery. Only large clinical studies can confirm this observation and define the optimal use of these tests in clinical practice. PMID- 24148325 TI - Discovery of novel PTP1B inhibitors via pharmacophore-oriented scaffold hopping from Ertiprotafib. AB - An integrated molecular design strategy combining pharmacophore recognition and scaffold hopping was exploited to discover novel PTP1B inhibitors based on the known PTP1B inhibitor Ertiprotafib. A composite pharmacophore model was proposed from the interaction mode of Ertiprotafib, and 21 diverse molecules from five distinct structural classes were designed and synthesized accordingly. New compounds with considerable inhibition against PTP1B were identified from each series, and the most active compound 3a showed IC50 value of 1.3 MUmol L(-1) against human recombinant PTP1B. Docking study indicated that the new inhibitors assumed binding modes similar to that of Ertiprotafib. PMID- 24148326 TI - Bilateral congenital absence of internal carotid arteries in a woman with dementia. A case report. AB - Dysgenesis of THE internal carotid artery is considered a rare condition, present in about 0.01% of subjects. This anomaly is generally asymptomatic and often represents an incidental finding in radiological examinations of the head performed for other reasons. A 75-year-old woman with symptoms of dementia was admitted to our hospital. Computed tomography and magnetic resonance examinations were performed. They showed the absence of both internal carotid arteries and the congenital nature of this abnormality. The usefulness of CT and MRI examinations in patients with this vascular abnormality is discussed. PMID- 24148324 TI - Effects of ex vivo platelet supplementation on platelet aggregability in blood samples from patients treated with acetylsalicylic acid, clopidogrel, or ticagrelor. AB - BACKGROUND: Transfusion of platelet concentrate is often used to treat bleeding in patients on platelet inhibitors, but little is known about its efficacy between different inhibitors. We assessed the effect of ex vivo platelet supplementation on platelet aggregability in blood samples from patients treated with acetylsalicylic acid (ASA), clopidogrel, or ticagrelor. METHODS: Platelet aggregability was investigated with multiple electrode aggregometry with adenosine diphosphate (ADP), arachidonic acid (to assess ASA-dependent aggregability), and thrombin receptor activating peptide-6 (TRAP) as activators in whole-blood samples from patients treated with ASA (n=10), ASA+clopidogrel (n=15), or ASA+ticagrelor (n=15), and from healthy controls (n=10). Aggregability was measured before and after supplementation of AB0-compatible fresh apheresis platelets (+46, +92, and +138*10(9) litre(-1)). RESULTS: Both ASA-dependent and ADP-dependent aggregability improved in a dose-dependent fashion after platelet supplementation. ASA-dependent aggregability was completely restored in all patient groups, but there was only a small improvement in ADP-dependent aggregability in patients on dual antiplatelet therapy. There was less effect of platelet supplementation on ADP- and ASA-dependent aggregability in ticagrelor treated patients than in clopidogrel-treated patients [3.9 (95% confidence interval 1.6-6.3) vs 9.0 (5.2-12.8) AU*min (P=0.021) and 48 (36-59) vs 69 (60-78) AU*min (P=0.004), respectively, at the highest platelet dose]. CONCLUSIONS: Platelet supplementation improved platelet aggregability independently of antiplatelet therapy. The effect on ADP-dependent platelet inhibition was limited however. Reduced effect of platelet transfusion is more likely within 2 h of drug intake in patients treated with ASA+ticagrelor compared with ASA+clopidogrel. PMID- 24148327 TI - Basilar Dependence on a Persistent Hypoglossal Artery Visualized at CT Angiography. A Case Report. AB - The persistent hypoglossal artery is a rare perseverance of an embryonic vessel connecting the anterior and posterior circulations and is generally considered an incidental finding. This report describes a patient with a basilar dependence on a persistent hypoglossal artery visualized at CT angiography. The pertinent findings and clinical implications of this anomalous vessel are discussed. PMID- 24148328 TI - Brain SPECT and Neuropsychological Examination in Patients with a History of Minor Craniocerebral Trauma Nine Years after Head Injury. AB - Focal perfusion deficits disclosed by single photon emission computerized tomography (SPECT) show more diffuse brain dysfunction than computed tomography (CT) examinations in case of head trauma. The aim of the study was to evaluate SPECT as an enhancing and complementary diagnostic method in patients after minor craniocerebral trauma (mCCT) and establish a possible correlation between clinical symptoms and disturbances of cerebral blood flow (CBF). SPECT examination and neuropsychological assessment was performed in seven patients about nine years after head injury, scoring 13-15 points on the Glasgow COMA SCALE and without evidence of structural brain damage. Neuropsychological assessment addressed global cognitive status, verbal and visual memory, working memory, object and space perception, executive function, self-assessment of memory, mood and health-related complaints. A direct relationship was shown between mCCT and the observed CBF disorders, and between the CBF disorders and cognitive dysfunction. Because of its sensitivity, SPECT, should be regarded as a method complementary to CT in mCCT. PMID- 24148329 TI - Voxel-based morphometry in patients with cryptogenic occipital epilepsies. Preliminary data. AB - We evaluated the differences in grey matter concentration (GMC) by voxel-based morphometry (VBM) in patients with cryptogenic occipital epilepsies. VBM analysis was performed in 11 patients with cryptogenic occipital epilepsies compared to 11 healthy controls. VBM analysis in patients revealed focal areas of reduced GMC in the occipital cortex and, more interestingly, increased GMC in the midbrain tegmentum and basal ganglia (globus pallidus and thalamus). VBM may disclose slight structural abnormalities in the brain of cryptogenic epilepsy patients, not evident with standard MRI. To the best of our knowledge, this is the first literature report describing areas of altered GMC in patients with occipital epilepsy. We hypothesize that these findings might be related to epileptic discharges and/or their diffusion and suggest that midbrain, globus pallidus and thalamus may be part of a functional network originating from the occipital areas. PMID- 24148330 TI - Clinical Recovery despite Cortical Cerebral and Cerebellar Damage in Heat Stroke. AB - The prognosis of heat stroke has considerably improved with a mortality rate drop to 10% when therapeutic measurements including external cooling and aggressive rehydration are adopted. The role of imaging in predicting prognosis is uncertain. Some noted that development of cortical cerebellar atrophy is associated with development of a pancerebellar syndrome, while others suggested that evidence of cerebral cortical damage due to hypoxic-ischemic injury implies a poor prognosis. We observed a 17-year-old female who presented with lost of consciousness and seizure while jogging on a hot summer day followed by multi organ failure. Brain MRI revealed a symmetric area of T2 hyperintensity and decreased diffusion in the cortical gyri of the frontal lobes. The patient made a complete recovery. MRI two years later showed disappearance of signal changes in the frontal cortex, but progressive atrophy of the cerebellum which was clinically silent. Our observation challenges the view of a close correlation between the imaging findings and prognosis in heat stroke. PMID- 24148331 TI - Chronic Pituitary Failure Resembling Sheehan's Syndrome Following a Bite of Russell's Viper. A Case Report. AB - Hypopituitarism can be the sequela of a variety of causes like postpartum pituitary necrosis or Sheehan's syndrome, lymphocytic hypophysitis, trauma and encephalitis. A very rare cause is envenomation by a bite of a Russell's viper. Very few cases with documented imaging findings of chronic pituitary failure resulting from snake bite have been reported. We describe a case of hypopituitarism with clinical, endocrine and magnetic resonance (MR) imaging studies occurring as a delayed complication of snake bite. PMID- 24148332 TI - Transient bilateral Basal Ganglia lesions in rotavirus encephalopathy. A case report. AB - Rotavirus gastroenteritis may be associated with the onset of an acute reversible encephalitis. We describe a case of transient bilateral basal ganglia lesions after a prodromal gastroenteritis which completely resolved four months later. Diffusion weighted images were determinant to depict the basal ganglia abnormalities and were helpful to evaluate the prognosis. A review of the literature indicates that many diseases may be accompanied by signal abnormalities within the basal ganglia and that differential diagnosis is possible only through the simultaneous evaluation of imaging, clinical and laboratory findings. PMID- 24148333 TI - MR Imaging of Bilateral Paramedian Thalamic and Mesencephalic Infarcts. A Case Report. AB - We describe MR imaging of bilateral infarction of the paramedian portion of the mesencephalus and thalamus due to an occlusion of the Percheron artery. This entity is due to one of the anatomic variants of the perforating arteries supplying the thalamus and mesenchephalus. Clinically this kind of infarction presents with neurologic impairment as a disorder of consciousness, memory dysfunctions, various types of vertical gaze palsy and psychic changes, which need to be differentiated from delirium and coma. At MRI evaluation infarction of the paramedian portion of thalami and midbrain, with a "butterfly wings" pattern, was demonstrated as high signal intensity areas on FLAIR and FSE-T2W images and with diffusion restriction on DWI images. PMID- 24148334 TI - 64-Slice CT Angiography in the Detection of Intracranial Aneurysms: Comparison with DSA and Surgical Findings. AB - The overall results of CT angiography on 64-slice MSCT published in the last five years are very close to results of DSA which is still a gold standard in the diagnosis of intracranial aneurysms. The aim of this study is to contribute to the confidence in reliability of this method and to try to answer the question of whether CTA should be used as the first diagnostic modality in patients with suspect intracranial aneurysms. In the period from October 2008 to August 2009 we diagnosed 118 aneurysms in 73 patients. We included in this study only those patients who underwent either DSA, surgical treatment or both after MSCTA, and the remainder of the above patients were not treated and are followed up, or died before treatment. So our group comprised 47 patients who were divided into two groups. The first group of 22 patients underwent DSA after MSCTA. We found 36 aneurysms in this group. One aneurysm was falsely positive compared to DSA, while 35 were in concordance with DSA. DSA revealed five aneurysms smaller than 4 mm not disclosed by MSCTA. The second group comprised 25 patients who were operated according to MSCTA findings only. There were 33 aneurysms in this group: 25 aneurysms were operated and surgical findings agreed with MSCTA. Eight aneurysms smaller than 4 mm were not operated and we do not have confirmation for them. In all false positive and false negative cases the misdiagnosed aneurysms were in fact 1-1.5 mm outpouchings that were not responsible for SAH. According to the available literature and our results, MSCTA has proved a very reliable method, simple and safe, competent to be used as a diagnostic modality of choice in the patients with SAH or suspect unruptured aneurysm. DSA should be used in cases of negative or uncertain findings on MSCTA, excluding cases of perimesencephalic SAH with negative MSCTA. The relative disadvantage of this method is its lower sensitivity in the detection of tiny outpouchings, especially in the infraclionid region where this method has still limited possibilities. PMID- 24148335 TI - Multiple cerebral aneurysms associated with atrial myxoma. A case report. AB - Cardiac myxoma is a tumor of mesenchymal origin accounting for half of all primary cardiac neoplasms. Intracranial involvement by atrial myxoma is a rare cause of neurologic deficit. When the myxoma arises in the left atrium, systemic emboli from a cardiac myxoma can lead to infarction, cerebral hemorrhage and aneurysm formation. In the light of the potentially preventable nature of these lesions, the diagnosis of myxomatous aneurysms should be considered in any patient with neurologic symptoms and a history of cardiac myxoma. Because aneurysms are often stable over several years, conservative management with careful clinical and radiological follow-up with MRI and angiography seems sensible. We describe a case in which MR imaging and angiography were used to diagnose multiple cerebral aneurysms caused by left atrial myxoma. PMID- 24148336 TI - Increasing exophthalmia after carotid-cavernous fistula closure with a detachable balloon: problems of incomplete treatment. A case report. AB - A 30-year-old woman with pulsating exophthalmia due to posttraumatic carotid cavernous fistula underwent embolization with a detachable balloon. Because of balloon dislodgement, the drainage was derived to the superior ophthalmic vein and clinical worsening occurred. Complete ophthalmoplegia developed and visual acuity decreased. After a second embolization we inserted two balloons but the same findings were exaggerated. Finally coiling of the internal carotid artery was done and orbital decompression achieved. Ophthalmoplegia, proptosis, chemosis and nerve paralysis intraocular pressure improved. PMID- 24148337 TI - Combined Percutaneous and Endovascular Treatment of Symptomatic Aneurysmal Bone Cyst of the Spine: Clinical Six Months. Follow-up of Six Cases. AB - We describe the usefulness of endovascular and direct percutaneous treatment as a therapy option for aneurysmal bone cysts (ABCs) of the spine. From January 2007 to December 2008, we treated six consecutive patients with symptomatic ABCs resistant to continuous medical management or with acute clinical onset of paraparesis at cervical, thoracic and lumbar spine level. Two patients were treated after emergency laminectomy. All patients were studied with an MRI protocol and multidetector CT with MPR reconstructions followed by angiographic control before treatment. The procedure was performed under general anaesthesia for all patients. Under CT or fluoroscopy guidance, percutaneous treatment was performed either by direct injection of Glubran((r)) diluted at 30% with Lipiodol((r)) only, or combined with endovascular treatment by Onyx(r) injection. Clinical and X-ray follow-up was performed at three and six months. Combined endovascular and percutaneous treatment for ABCs was successful and led to an excellent outcome in five out of six patients with clinical improvement. There were no periprocedural or subsequent clinical complications and the glue resulted in successful selective permanent occlusion with intralesional penetration. Direct sclerotherapy resulted in immediate thrombosis of the malformation with no progression of symptoms. Complete healing was observed in five out of six aggressive lesions. No major complications were noted. At six month follow-up the symptoms had completely resolved and X-ray control showed a partial or total sclerotic reaction of the lesion with stable clinical results (no partial or clinical abnormalities). One patient had a recurrence of the ABC with spinal cord cervical clinical symptomatology. Combined endovascular and percutaneous treatment or direct percutaneous sclerotherapy with glue alone are important, safe, effective therapy options for symptomatic aneurysmal bone cyst. Results are stable and confirmed by clinical and X-ray follow-up six months after treatment. PMID- 24148338 TI - Spontaneous spinal epidural haematoma. A case report. AB - Spinal epidural haematomas are infrequent events caused mainly by trauma or are iatrogenic following invasive spinal procedures (lumbar puncture, surgery or peridural anaesthesia). Spontaneous spinal epidural haematoma is a rare entity requiring emergency intervention in most cases. The incidence is estimated at about two to six cases per year. Early recognition, accurate diagnosis and rapid treatment may result in decreased morbidity and improved outcome. Here, we describe the case of a 60-year-old man who presented sudden paraplegia. Magnetic resonance imaging of thoracolumbar spine demonstrated an epidural mass extending from T11 to L1, causing spinal cord compression. Emergent decompressive surgery was performed and the patient had a significant improvement of neurologic deficits. PMID- 24148339 TI - Vertebroplasty as a Treatment for Primary Benign or Metastatic Cervical Spine Lesions: Up to One Year of Follow-up. AB - This paper illustrates the validity of vertebroplasty (VP) in patients with primary benign or metastatic lesion in the cervical spine. From January 2006 to December 2007, ten consecutive patients were treated with VP for a total of ten vertebral bodies: two symptomatic vertebral haemangiomas at C5 and C4.3, multiple myeloma at C2 (two cases) and one case at C4, five patients with vertebral metastasis from breast or lung cancer at C2, C4 (three cases) and C5. All the patients complained of pain resistant to continuous medical management. All procedures were performed under general anaesthesia by anterolateral approach under CT or fluoroscopy control with manual dislocation of the carotid axis. A transoral approach under fluoroscopy was performed to treat the C2 lesion. Bone biopsy was never performed. VP was performed to prevent fracture after implantation of a double discal prothesis in two patients. For patients with multiple myeloma, VP was performed to prevent new vertebral fracture. VP was performed before of radiotherapy in three patients with metastasis, and just after radiotherapy in two. Two metastatic patients were lost at one year follow up due to death from systematic diffusion. Results were evaluated on the Visual Analogue Scale (VAS) and the Oswestry Disability Index (ODS). A successful outcome was observed with a complete resolution or partial reduction of pain in 90% of patients 24-72 hours after VP. At 12 months follow-up, we recorded a reduction of four points in the VAS evaluation and a 45% reduction in the ODS score. No extravertebral vascular or discal cement leakage was observed. At 12 months, X-ray follow-up showed a stable result. Percutaneous treatment with VP for benign or malignant cervical spine lesions is a valuable, mini-invasive and quick method that allows a complete and enduring resolution of painful vertebral symptoms without fracture of the adjacent or distal vertebral bodies. PMID- 24148340 TI - Abdominal cerebrospinal fluid pseudocyst due to infection with enterococcus faecalis. A case report. AB - Abdominal cerebrospinal fluid pseudocyst is a rare complication of ventriculo peritoneal shunt occurring as a result of non-absorption of cerebrospinal fluid from the abdominal cavity due to inflammation. Usual presentations include abdominal symptoms; abdominal distention, pain, nausea, vomiting and symptoms of raised intracranial pressure like headache due to shunt dysfunction. The diagnosis may be delayed in severely handicapped patients due to poor communicability, multiple associated complications or co-morbidities. Radiological modalities are used for diagnosis as well as treatment. PMID- 24148341 TI - Orbital cavernous hemangiomas: ultrasound and magnetic resonance imaging evaluation. AB - Cavernous hemangioma is the most common intraorbital lesion in adults. The aim of our study was to evaluate the magnetic resonance imaging (MRI) and ultrasound (US) characteristics of cavernous hemangioma and their role in the differential diagnosis of orbital tumors. Eight patients with orbital cavernous hemangiomas, five women and three men with a mean age of 48 years were examined in a period of six years. All patients underwent MRI examination and four patients were also evaluated by US. In all cases MRI depicted a well-defined intraconal tumor. The lesions were homogeneous, isointense to muscle on T1-weighted sequence and hyperintense to muscle on T2-weighted sequence in six patients. In one patient the mass was isointense on T1WI with heterogeneous signal intensity on T2WI and in one patient the lesion had heterogeneous signal intensity on both T1- and T2 weighted sequences. After intravenous contrast medium administration, the tumors showed initial inhomogeneous enhancement with progressive accumulation of contrast material on delayed images in seven patients and initial homogeneous enhancement in one patient. On ultrasonography, the orbital masses appeared slightly hyperechoic, heterogeneous with small areas of slow blood flow. The analysis of imaging characteristics of a well-defined intraconal lesion in an adult patient with painless progressive proptosis can be highly suggestive of the diagnosis of cavernous hemangioma. PMID- 24148342 TI - Desmoplastic Fibroma of the Mandible: Usefulness of CT and MR Imaging in Diagnosis and Treatment. A Case Report. AB - Desmoplastic fibroma (DF) is a rare non-metastasizing benign neoplasm of the bone characterized by aggressive local infiltration, also known as desmoid tumour. Desmoplastic fibroma of the mandible may recur locally when incompletely excised. In particular it can occur adjacent to and display contiguous extension along the mandibular nerve. This case report describes the imaging findings of a histopathologically proven desmoplastic fibroma involving the right mandibular region in a three-year-old Italian girl. We also discuss the usefulness of different imaging modalities (CT and MRI) in DF diagnosis and treatment. PMID- 24148343 TI - MR and Diffusion Tensor Imaging of Vein of Galen Aneurysmal Malformation in an Infant Presenting with Spastic Diplegia and Seizures. A Case Report. AB - A three-year-old girl developed spastic diplegia to the right and irregular tonc clonic movements. Phenobarbital was started because of suspected seizure activity. The Pediatric unit asked for brain MR imaging to investigate neurological symptoms. MR and diffusion tensor imaging showed a haemorrhagic vein of Galen aneurysmal malformation (choroidal type) that shifted the corticospinal tract fibres to one side and the corpus callosum was moved forward. Vein of Galen aneurysmal malformations (VGAM) are characterized by multiple arteriovenous connections draining into a markedly enlarged median draining vein. This ectatic vein is not the vein of Galen, but its embryonic precursor, the median prosencephalic vein of Markowski. During normal development, the posterior portion of the median prosencephalic vein persists as the vein of Galen, while its anterior portion regresses in parallel with the formation of the internal cerebral veins (ICV). With the advent of endovascular neurointerventional techniques, the prospects for successful treatment of these lesions, once dismal, are now much improved. MR and diffusion tensor imaging can help in diagnosis and to guide endovascular interventional procedures. PMID- 24148344 TI - Giant axonal neuropathy: a pictorial essay and review of literature. AB - Giant axonal neuropathy (GAN) is a neurodegenerative disorder classified within the hereditary motor and sensory neuropathies, affecting both the peripheral and central nervous systems. GAN typically presents in early childhood before the age of five years and progresses to death usually by early adulthood. Various imaging findings in giant axonal neuropathy have been described and documented in literature in the form multiple case reports. We here present a pictorial essay of all the major imaging GAN findings described in the literature. In addition, involvement of the dentate nucleus hitherto not described in the literature was noted in the present case. PMID- 24148345 TI - Diastematomyelia. A case report. AB - Diastematomyelia is a rare form of spinal dysraphism characterized by a sagittal cleft of varying extent in the spinal cord, conus medullaris or filum terminale with splaying of the posterior vertebral elements. This condition results from the presence of an osseous, cartilaginous or fibrous septum producing a complete or incomplete sagittal division of the spinal cord into two hemicords. It may be isolated or associated with other segmental anomalies of the vertebral bodies (1). PMID- 24148346 TI - Intrahypothalamic pituitary adenylate cyclase-activating polypeptide regulates energy balance via site-specific actions on feeding and metabolism. AB - Numerous studies have demonstrated that both the hypothalamic paraventricular nuclei (PVN) and ventromedial nuclei (VMN) regulate energy homeostasis through behavioral and metabolic mechanisms. Receptors for pituitary adenylate cyclase activating polypeptide (PACAP) are abundantly expressed in these nuclei, suggesting PACAP may be critical for the regulation of feeding behavior and body weight. To characterize the unique behavioral and physiological responses attributed to select hypothalamic cell groups, PACAP was site-specifically injected into the PVN or VMN. Overall food intake was significantly reduced by PACAP at both sites; however, meal pattern analysis revealed that only injections into the PVN produced significant reductions in meal size, duration, and total time spent eating. PACAP-mediated hypophagia in both the PVN and VMN was abolished by PAC1R antagonism, whereas pretreatment with a VPACR antagonist had no effect. PACAP injections into the VMN produced unique changes in metabolic parameters, including significant increases in core body temperature and spontaneous locomotor activity that was PAC1R dependent whereas, PVN injections of PACAP had no effect. Finally, PACAP-containing afferents were identified using the neuronal tracer cholera toxin subunit B (CTB) injected unilaterally into the PVN or VMN. CTB signal from PVN injections was colocalized with PACAP mRNA in the medial anterior bed nucleus of the stria terminalis, VMN, and lateral parabrachial nucleus (LPB), whereas CTB signal from VMN injections was highly colocalized with PACAP mRNA in the medial amygdala and LPB. These brain regions are known to influence energy homeostasis perhaps, in part, through PACAP projections to the PVN and VMN. PMID- 24148347 TI - Effect of the glucagon-like peptide-1 receptor agonist lixisenatide on postprandial hepatic glucose metabolism in the conscious dog. AB - The impact of the GLP-1 receptor agonist lixisenatide on postprandial glucose disposition was examined in conscious dogs to identify mechanisms for its improvement of meal tolerance in humans and examine the tissue disposition of meal-derived carbohydrate. Catheterization for measurement of hepatic balance occurred ~16 days before study. After being fasted overnight, dogs received a subcutaneous injection of 1.5 MUg/kg lixisenatide or vehicle (saline, control; n = 6/group). Thirty minutes later, they received an oral meal feeding (93.4 kJ; 19% protein, 71% glucose polymers, and 10% lipid). Acetaminophen was included in the meal in four control and five lixisenatide dogs for assessment of gastric emptying. Observations continued for 510 min; absorption was incomplete in lixisenatide at that point. The plasma acetaminophen area under the curve (AUC) in lixisenatide was 65% of that in control (P < 0.05). Absorption of the meal began within 15 min in control but was delayed until ~30-45 min in lixisenatide. Lixisenatide reduced (P < 0.05) the postprandial arterial glucose AUC ~54% and insulin AUC ~44%. Net hepatic glucose uptake did not differ significantly between groups. Nonhepatic glucose uptake tended to be reduced by lixisenatide (6,151 +/- 4,321 and 10,541 +/- 1,854 MUmol.kg(-1).510 min(-1) in lixisenatide and control, respectively; P = 0.09), but adjusted (for glucose and insulin concentrations) values did not differ (18.9 +/- 3.8 and 19.6 +/- 7.9 l.kg(-1).pmol(-1).l(-1), lixisenatide and control, respectively; P = 0.94). Thus, lixisenatide delays gastric emptying, allowing more efficient disposal of the carbohydrate in the feeding without increasing liver glucose disposal. Lixisenatide could prove to be a valuable adjunct in treatment of postprandial hyperglycemia in impaired glucose tolerance or type 2 diabetes. PMID- 24148348 TI - Thrombospondin-1/CD36 pathway contributes to bone marrow-derived angiogenic cell dysfunction in type 1 diabetes via Sonic hedgehog pathway suppression. AB - Refractory wounds in diabetic patients present a significant clinical problem. Sonic hedgehog (SHH), a morphogenic protein central to wound repair, is deficient in diabetes. Regulation of SHH in wound healing is poorly understood. We hypothesize that thrombospondin-1 (TSP-1), through its receptor CD36, contributes to the SHH signaling defect in bone marrow-derived angiogenic cells (BMACs) in type 1 diabetic mice. Isolated BMACs from TSP-1-knockout mice demonstrated improved tube formation, migration, and adhesion in parallel with active SHH signaling. BMACs from STZ-induced type 1 diabetic mice showed significantly impaired Matrigel tube formation (n = 5; P < 0.05 vs. control), which was rescued by TSP-1 depletion (n = 5; P < 0.05 STZ-TSP-1(-/-) vs. STZ-WT) or exogenous SHH (20 mg/l, 24 h, n = 4; P < 0.05 vs. STZ-control). The expression of CD36 was elevated in BMACs from STZ mice (n = 4; P < 0.05). SHH signaling was significantly higher in BMACs from TSP-1(-/-) mice and TSP-1 receptor CD36 knockout mice (n = 6; P < 0.05 vs. WT) but not CD47-knockout mice (n = 3; P > 0.05 vs. WT). The impairment of recombinant human TSP-1 (2.2 nM, 24 h) on BMAC Matrigel tube formation was delayed significantly by CD36 deletion (n = 5; P < 0.05). CD36(-/-) BMACs demonstrated better tube formation under both normal and diabetic conditions with active SHH signaling (n = 4; P < 0.05 vs. WT BMACs). In conclusion, The TSP-1/CD36 pathway contributes to the SHH signaling defect, resulting in BMAC dysfunction in type 1 diabetic mice. PMID- 24148350 TI - Increasing the number of discrete character states for continuous characters generates well-resolved trees that do not reflect phylogeny. AB - Since the introduction of the cladistic method in systematics, continuous characters have been integrated into analyses but no methods for their treatment have received unanimous support. Some methods require a large number of character states to discretise continuous characters in order to keep the maximum level of information about taxa differences within the coding scheme. Our objective was to assess the impact of increasing the character state number on the outcomes of phylogenetic analyses. Analysis of a variety of simulated datasets shows that these methods for coding continuous characters can lead to the generation of well resolved trees that do not reflect a phylogenetic signal. We call this phenomenon the flattening of the tree-length distribution; it is influenced by both the relative quantity of continuous characters in relation to discrete characters, and the number of characters in relation to the number of taxa. Bootstrap tests provide a method to avoid this potential bias. PMID- 24148349 TI - Effects of the green tea polyphenol epigallocatechin-3-gallate on high-fat diet induced insulin resistance and endothelial dysfunction. AB - Insulin resistance, a hallmark of metabolic disorders, is a risk factor for diabetes and cardiovascular disease. Impairment of insulin responsiveness in vascular endothelium contributes to insulin resistance. The reciprocal relationship between insulin resistance and endothelial dysfunction augments the pathophysiology of metabolism and cardiovascular functions. The most abundant green tea polyphenol, epigallocatechin-3-gallate (EGCG), has been shown to have vasodilator action in vessels by activation of endothelial nitric oxide synthase (eNOS). However, it is not known whether EGCG has a beneficial effect in high-fat diet (HFD)-induced endothelial dysfunction. Male C57BL/6J mice were fed either a normal chow diet (NCD) or HFD with or without EGCG supplement (50 mg.kg(-1).day( 1)) for 10 wk. Mice fed a HFD with EGCG supplement gained less body weight and showed improved insulin sensitivity. In vehicle-treated HFD mice, endothelial function was impaired in response to insulin but not to acetylcholine, whereas the EGCG-treated HFD group showed improved insulin-stimulated vasodilation. Interestingly, EGCG intake reduced macrophage infiltration into aortic tissues in HFD mice. Treatment with EGCG restored the insulin-stimulated phosphorylation of eNOS, insulin receptor substrate-1 (IRS-1), and protein kinase B (Akt), which was inhibited by palmitate (200 MUM, 5 h) in primary bovine aortic endothelial cells. From these results, we conclude that supplementation of EGCG improves glucose tolerance, insulin sensitivity, and endothelial function. The results suggest that EGCG may have beneficial health effects in glucose metabolism and endothelial function through modulating HFD-induced inflammatory response. PMID- 24148351 TI - Exploring evolution of brain genes involved in microcephaly through phylogeny and synteny analysis. AB - BACKGROUND: Human brain development is a complicated process. When normal growth and development of brain or central nervous system is impaired, it leads to neurodevelopemental disorders (NDDs). Autosomal Recessive Primary Microcephaly (MCPH) is one of those, for which seven loci (MCPH1-MCPH7) with the corresponding genes (MCPH1, WDR62, CDK5RAP2, CEP152, ASPM, CENPJ, and STIL) have been reported so far. An important field of study is to find out diversity among organisms due to evolution. How species are related to each other can be inferred through finding evolutionary relationship between organisms in the form of ancestors and descendents. METHODS: MEGA5 was used for phylogenetic tree reconstruction. Pair wise and multiple alignment was built through ClustalW algorithm. Neighbor joining (NJ) and maximum parsimony (MP) methods were used for tree reconstruction. Bootstrap analysis was done to check the reliability of trees. Synteny analysis was performed using Ensemble synteny view in ensemble database and genome synteny viewer (GSV). RESULTS: Evolutionary time for single gene trees showed that CENPJ (0.02) evolving rapidly while CDK5RAP2 (0.1) evolving with least rate as compare to other genes. All trees were reconciling the species divergence time. Chimpanzee was inferred as closest specie of Human. In MCPH combined tree, five duplications were observed. Four duplications were before and one was after vertebrate and invertebrate divergence. Two genes MCPH1 and WDR62 were closely related with each other. Synteny analysis indicated that maximum conservation of Human was with Chimpanzee. Highly conserved synteny was observed for Human and Chimpanzee in case of CENPJ with no deletion. CONCLUSION: It has been hypothesized that due to having closest relationship, mutations can affect Chimpanzee likewise as these affect Human. Conservation shows that apart from sequence similarity, function of MCPH genes in closely related species is also same and this function disrupts as a result of mutation and hence leads to the diseased state. Huge genomic and proteomic data is available today which enables us to perform In Silico analysis. Our cost and time effective analysis has opened many insights into disease understanding and it will definitely provide a way towards accurate diagnosis. PMID- 24148352 TI - Microcalorimetry: a powerful and original tool for tracking the toxicity of a xenobiotic on Tetrahymena pyriformis. AB - Fighting against water pollution requires the ability to evaluate the toxicity of pollutants such as herbicides. Tetrahymena pyriformis are ubiquitous ciliated protozoans commonly used in ecotoxicological research. Microcalorimetry can be used in many biological investigations as a universal, non-destructive and highly sensitive tool that provides a continuous real-time monitoring of the metabolic activity. This technique based on the thermal power output was applied to evaluate the influence of herbicide diuron on cultures of T. pyriformis. The heat flux produced upon addition of 0, 3.5, 7.0, 14.0, 28.0, and 56.0 ug mL-1 of diuron was monitored. The biomass change during the growth was also determined by flow cytometry. The results confirmed that the growth of T. pyriformis is progressively inhibited as the concentration of diuron increases and revealed that the state of the living system is severely altered at a concentration of 56.0 ug mL-1. The IC50 was estimated at 13.8 ug mL-1 by microcalorimetry and at 18.6 ug mL-1 by flow cytometry. It was shown that microcalorimetry is not only a very effective tool for the determination of the growth rate constant but that it is also a valuable probe for a rapid detection of the metabolic perturbations and, in ultimate cases, of the critical alterations of the living system under the action of a toxic agent. PMID- 24148353 TI - Impact of benzodiazepines on functional outcome and occurrence of pneumonia in stroke: evidence from VISTA. AB - BACKGROUND: Benzodiazepines have been proposed both as a neuroprotectant and risk factor for pneumonia in acute stroke. AIMS: We assessed the impact of benzodiazepine exposure on the modified Rankin scale score distribution at 90 days as well as pneumonia rates among patients registered in a trials archive. METHOD: We used an age, baseline National Institutes of Health Stroke Score, and thrombolysis-rate adjusted Cochran-Mantel-Haenszel test to test significance (P) followed by proportional odds logistic regression analysis to estimate the odds ratios for improved modified Rankin scale score, and binary logistic regression to estimate the odds ratio for developing pneumonia. RESULTS: Data were available for 5938 patients, of whom 1800 received benzodiazepines. No association of benzodiazepine use and overall stroke outcome could be found (odds ratio 0.90, 95% confidence interval 0.82-1.00, P=0.121). Pneumonia occurred in 12.8% of patients treated with benzodiazepines and in 13.6% of the controls (odds ratio 0.99, 95% confidence interval 0.83-1.18, P=0.904). CONCLUSION: In this nonrandomized comparison, treatment with benzodiazepines as a concomitant medication had no independent impact on stroke outcome. PMID- 24148354 TI - Varicocele decreases epididymal neutral alpha-glucosidase and is associated with alteration of nuclear DNA and plasma membrane in spermatozoa. AB - OBJECTIVE: To assess the relationship between a marker of epididymal function and both the fragmentation of the sperm nucleus and the integrity and maturity of the sperm membrane in patients with or without varicocele. PATIENTS AND METHODS: Semen samples were obtained from men with varicocele grades II and III (n = 60) and from a control group with zoospermia defined as normal (n = 30). Samples were evaluated by a spermiogram, a hypoosmotic swelling test (HOST), neutral alpha glucosidase (NAG) enzyme activity, sperm hyaluronan-binding assay (HBA) and DNA fragmentation using a sperm chromatin dispersion (SCD) test. RESULTS: Seminal plasma NAG levels, percentage of sperm bound to hyaluronic acid, HOST-positive cells and sperm quality were significantly lower in the varicocele compared with the control group. Higher levels of sperm DNA fragmentation, as measured by SCD, were also observed in the varicocele group compared with the control group. Seminal NAG activity levels showed a strong negative correlation with DNA fragmentation and a significant positive correlation with the HBA test and the HOST. CONCLUSIONS: Varicocele causes a reduction in NAG activity by the epididymis that is associated with damage to both the membrane and sperm nucleus and a reduction in the seminal parameters. NAG levels were correlated with the quality of the sperm membrane and nucleus. Data suggest that a reduction of fertilization capacity in men during varicocele can result from damage to both the testis and the epididymis. PMID- 24148355 TI - Preoperative glucose as a screening tool in patients without diabetes. AB - BACKGROUND: Although hyperglycemia has been associated with poor postoperative outcomes, preoperative hyperglycemia is not used as a screening tool in patients without diabetes. We evaluated preoperative glucose as a marker for postoperative outcomes in patients without diabetes to assess its usefulness as a potential screening tool. MATERIALS AND METHODS: Clinical characteristics for a sample of 6683 patients without diabetes who underwent nonemergent vascular and general surgery were collected from the American College of Surgeons National Surgical Quality Improvement Program, Brigham and Women's Hospital database. Last glucose measured within 30 d before surgery was the main predictor variable with postoperative infection within 30 d as the primary outcome. RESULTS: For patients without known diabetes with preoperative glucose of 100-139 and 140-179 mg/dL, postoperative infection rates were significantly higher (9.33% and 10.16%, respectively) than that of patients with preoperative glucose of 70-99 mg/dL (5.62%, P < 0.001). The risk-adjusted odds of postoperative infection increased by 40% (95% CI, 13%-72%) for each 40 mg/dL increase in preoperative glucose over the range 70-179 mg/dL. Follow-up data demonstrated that 15% of patients with preoperative glucose >=100 mg/dL were diagnosed with diabetes within 1 y after surgery. CONCLUSIONS: In patients without known diabetes, preoperative glucose is a significant marker for postoperative complications even at moderate levels of hyperglycemia. Some of these patients likely had prediabetes or unrecognized diabetes at the time of surgery. Further studies are needed to determine whether such screening and follow-up of preoperative hyperglycemia in all patients would be effective in lowering complication rates. PMID- 24148356 TI - The association between post-traumatic stress-related symptoms, resilience, current stress and past exposure to violence: a cross sectional study of the survival of Quechua women in the aftermath of the Peruvian armed conflict. AB - BACKGROUND: The long lasting resilience of individuals and communities affected by mass violence has not been given equal prominence as their suffering. This has often led to psychosocial interventions in post-conflict zones being unresponsive to local realities and ill-equipped to foster local strengths. Responding to the renewed interest in resilience in the field of violence and health, this study examines the resilience and post-traumatic responses of Indigenous Quechua women in the aftermath of the political violence in Peru (1980-2000). METHODS: A cross sectional study examined the relationship between resilience, post-traumatic responses, exposure to violence during the conflict and current life stress on 151 Quechua women participants. Purposive and convenience sampling strategies were used for recruitment in Ayacucho, the area most exposed to violence. The study instruments were translated to Quechua and Spanish and cross-culturally validated. Data was analyzed using hierarchical regression analysis. A locally informed trauma questionnaire of local idioms of distress was also included in the analysis. FINDINGS: Sixty percent of women (n = 91) were recruited from Ayacucho city and the rest from three rural villages; the mean age was 45 years old. Despite high levels of exposure to violence, only 9.3% of the sample presented a level of symptoms that indicated possible PTSD. Resilience did not contribute to the overall variance of post-traumatic stress related symptoms, which was predicted by past exposure to violence, current life stress, age, and schooling (R2 = .421). Resilience contributed instead to the variance of avoidance symptoms (Stand beta = -.198, t = -2.595, p = 0.010) while not for re experiencing or arousal symptoms. CONCLUSIONS: These findings identified some of the pathways in which resilience and post-traumatic responses interrelate in the aftermath of violence; yet, they also point to the complexity of their relationship, which is not fully explained by linear associations, requiring further examination. Age and gender-sensitive health care is considered critical almost fifteen years after the end of the conflict. The notable resilience of Quechua women-despite exposure to a continuum of violence and social inequalities also calls for enhanced recognition of women not only as victims of violence but also as complex social actors in the reconstruction of post-conflict societies. PMID- 24148357 TI - The relationship between adolescents' well-being and their wireless phone use: a cross-sectional study. AB - BACKGROUND: The exposure of young people to radiofrequency electromagnetic fields (RF-EMFs) has increased rapidly in recent years with their increased use of cellphones and use of cordless phones and WiFi. We sought to ascertain associations between New Zealand early-adolescents' subjective well-being and self-reported use of, or exposure to, wireless telephone and internet technology. METHODS: In this cross-sectional survey, participants completed questionnaires in class about their cellphone and cordless phone use, their self-reported well being, and possible confounding information such as whether they had had influenza recently or had a television in the bedroom. Parental questionnaires provided data on whether they had WiFi at home and cordless phone ownership and model. Data were analysed with Ordinal Logistic Regression adjusting for common confounders. Odds ratios (OR) and 95% confidence intervals were calculated. RESULTS: The number and duration of cellphone and cordless phone calls were associated with increased risk of headaches (>6 cellphone calls over 10 minutes weekly, adjusted OR 2.4, CI 1.2-4.8; >15 minutes cordless use daily adjusted OR 1.74, CI 1.1-2.9)). Texting and extended use of wireless phones was related to having a painful 'texting' thumb). Using a wired cellphone headset was associated with tinnitus (adjusted OR 1.8, CI 1.0-3.3), while wireless headsets were associated with headache (adjusted OR 2.2, CI 1.1-4.5), feeling down/depressed (adjusted OR 2.0, CI 1.1-3.8), and waking in the night (adjusted OR 2.4, CI 1.2 4.8). Several cordless phone frequencies bands were related to tinnitus, feeling down/depressed and sleepiness at school, while the last of these was also related to modulation. Waking nightly was less likely for those with WiFi at home (adjusted OR 0.7, CI 0.4-0.99). Being woken at night by a cellphone was strongly related to tiredness at school (OR 3.49, CI 1.97-6.2). CONCLUSIONS: There were more statistically significant associations (36%) than could be expected by chance (5%). Several were dose-dependent relationships. To safeguard young people's well-being, we suggest limiting their use of cellphones and cordless phones to less than 15 minutes daily, and employing a speaker-phone device for longer daily use. We recommend parental measures are taken to prevent young people being woken by their cellphones. PMID- 24148358 TI - Endocannabinoid system and pain: an introduction. AB - The endocannabinoid (EC) system consists of two main receptors: cannabinoid type 1 receptor cannabinoid receptors are found in both the central nervous system (CNS) and periphery, whereas the cannabinoid type 2 receptor cannabinoid receptor is found principally in the immune system and to a lesser extent in the CNS. The EC family consists of two classes of well characterised ligands; the N-acyl ethanolamines, such as N-arachidonoyl ethanolamide or anandamide (AEA), and the monoacylglycerols, such as 2-arachidonoyl glycerol. The various synthetic and catabolic pathways for these enzymes have been (with the exception of AEA synthesis) elucidated. To date, much work has examined the role of EC in nociceptive processing and the potential of targeting the EC system to produce analgesia. Cannabinoid receptors and ligands are found at almost every level of the pain pathway from peripheral sites, such as peripheral nerves and immune cells, to central integration sites such as the spinal cord, and higher brain regions such as the periaqueductal grey and the rostral ventrolateral medulla associated with descending control of pain. EC have been shown to induce analgesia in preclinical models of acute nociception and chronic pain states. The purpose of this review is to critically evaluate the evidence for the role of EC in the pain pathway and the therapeutic potential of EC to produce analgesia. We also review the present clinical work conducted with EC, and examine whether targeting the EC system might offer a novel target for analgesics, and also potentially disease-modifying interventions for pathophysiological pain states. PMID- 24148359 TI - Introducing the Biennial Review of Pain. PMID- 24148360 TI - Implementation of the HbA1c IFCC unit --from the laboratory to the consumer: The New Zealand experience. AB - In 2007, an international consensus statement recommended that HbA1c results should be reported world-wide in IFCC units (mmol/mol) and also the more familiar derived percentage units using a master equation. In New Zealand, the HbA1c IFCC units have been successfully implemented and used exclusively since 3rd October 2011 (following a 2 year period of reporting both units) for both patient monitoring and the diagnosis of diabetes, with a diagnostic cut-off of >=50 mmol/mol. The consultation process in New Zealand dates back to 2003, well before the international recommendations were made. It reflects the close cooperation between the clinical and laboratory communities in New Zealand, particularly through the agency of the New Zealand Society for the Study of Diabetes (NZSSD), a key organisation in New Zealand open to all those involved in the care of people with diabetes and the national advisory body on scientific and clinical diabetes care and standards. There was a phased process of consultation designed to increase familiarity and comfort with the new units and the final step was coupled with the adoption of HbA1c as a diagnostic test with some evidence-based pragmatism around using the rounded cut-off. Genuine clinical engagement is vital in such a process. PMID- 24148361 TI - What is the value of a food and drug administration investigational new drug application for fecal microbiota transplantation to treat Clostridium difficile Infection? PMID- 24148362 TI - Multicentred surgical site infection surveillance using partitioning analysis. AB - BACKGROUND: Surgical site infection (SSI) is an ongoing major public health problem throughout the world that increases healthcare costs. Utilizing a methodology that can help clinicians to continuously collect data about SSIs, analyse it and implement the feedback into routine hospital practice has been identified as a top national priority in Japan. AIM: To conduct an intervention study through 'operations research' using partitioning at multiple facilities, and to reduce the incidence and consequences of SSI. METHODS: The Setouchi SSI Surveillance Group, which consists of seven institutes, started SSI surveillance in 2006. Until May of 2008, there were four surveillance periods (A-D). In all, 3089 patients underwent gastrointestinal surgery and were followed up for 30 days after their operations. Twenty-six factors that have been reported to be related to SSI were evaluated for all patients. The top three factors from each surveillance period were determined and then actual practice improvements were planned for each subsequent period. FINDINGS: The total SSI occurrence was 6.9% for period A, 6.3% for period B, 6.4% for period C and 3.9% for period D. Comparing periods A and D, there was a statistical significance in the decrease of SSI occurrence (P = 0.012). CONCLUSION: Using the results and partitioning analysis of active SSI surveillance to contribute to action plans for improving clinical practice was effective in significantly reducing SSIs. PMID- 24148363 TI - Outbreak of Stenotrophomonas maltophilia on an intensive care unit. AB - BACKGROUND: Stenotrophomonas maltophilia causes opportunistic infections and remains a problem pathogen on intensive care unit (ICU) due to its multidrug resistance. AIM: An outbreak of S. maltophilia on ICU is described in order to highlight the risk from contaminated devices for supply of drinking water. METHODS: The outbreak was investigated by a combination of epidemiology, environmental sampling and molecular typing. FINDINGS: From 2009 to 2011 isolates of S. maltophilia from 23 patients were found to belong to only two genotypes by contrast with isolates from 52 other patients during this period, which represented distinct strains. The monthly incidence for all S. maltophilia strains ranged from 0 to 11% and for the two outbreak strains from 0 to 9%. Admission and weekly pharyngeal screening on ICU showed that the outbreak strains were acquired on ICU (range: 3-90 days). The majority of isolates (74%) were from the respiratory tract. Only two of 12 (17%) colonized intubated patients developed pneumonia. Environmental sampling found the two outbreak strains in two sinks and in the drinking water of the cooling unit in the ICU kitchen. S. maltophilia had formed a biofilm in the flexible tube from the carbon filter to the chiller and from the latter to the tap at the kitchen sink. This cooled water was used for providing drinking water and mouth care to ICU patients. The outbreak strains disappeared after removal of the water-cooler and the monthly incidence fell to <2% of ICU admissions. CONCLUSION: This outbreak report highlights the risk from biofilms in devices that supply drinking water for ICU patients. PMID- 24148364 TI - Stir bar sorptive extraction coupled to liquid chromatography-tandem mass spectrometry for the determination of pesticides in water samples: method validation and measurement uncertainty. AB - Stir bar sorptive extraction followed by liquid desorption and high performance liquid chromatography with tandem mass spectrometry (SBSE-LD-LC-MSMS) has been developed for the determination of 15 pesticides or selected metabolites from different families (herbicides, insecticides, fungicides) in surface water samples. The optimization of parameters that could influence SBSE-LD efficiency was carried out by means of experimental design. Optimized conditions were established as follows concerning extraction time, stirring speed, aqueous medium characteristics (ionic strength and polarity) and back desorption solvent and time, respectively: 3 h (800 rpm), addition of 10% of sodium chloride, no addition of methanol as organic modifier, and 15 min ultrasonic desorption in equivolume mixtures of acetonitrile-methanol. A specific and thorough cleanup procedure was developed and applied to each stir bar to avoid possible carry-over between consecutive extractions with the same stir bar. Pesticide quantification in water was achieved thanks to matrix matched calibration. Mean recoveries ranged from 93 to 101% (RSD <17%, n=30). Validated limits of quantification in matrix were between 0.02 and 1 ug L(-1), depending on the compound. A specific experimental design was conducted to evaluate the measurement uncertainty, which was comprised between 13 and 51%, whatever the pesticide and the concentration level. The applicability of the SBSE-LD-LCMSMS method was evaluated by analyzing surface water samples and by comparing with conventional solid phase extraction LC-MSMS procedure. PMID- 24148365 TI - Investigating of labelling and detection of transthyretin synthetic peptide derivatized with naphthalene-2,3-dicarboxaldehyde. AB - Labelling and detection of a synthetic peptide (PN) mimicking a tryptic fragment of interest for the diagnosis of familial amyloidal polyneuropathy have been investigated optically and electrochemically. We decided to covalently label naphtalene-2,3-dicarboxyaldehyde (NDA), a fluorogenic and electroactive molecule on PN. First, the optimization of the labelling chemical reaction was performed by capillary electrophoresis coupled with laser induced fluorescence detection (CE-LIF). The analytical parameters such as separation efficiency and peak area were considered to propose this optimized derivatization reaction. The results obtained allowed us to establish the pH and ionic strength of the derivatization buffer, the molar ratio between NDA and PN and the reaction time of the labelling. Optimal conditions are obtained when [NDA]/[PN]=40, buffer pH of 9, buffer ionic strength of 70 mM and reaction time of 15 min. Second, differential pulse voltammetry (DPV) and cyclic voltammetry (CV) were also used to characterize NDA-labelled PN and different electroinactive amino acids (histidine, lysine, serine, threonine) which are in the PN sequence. The electrochemical detection experiments demonstrated that the labelled biomolecules could be also easily detected at low concentration. Moreover, the derivatization reaction could be followed to describe more precisely the labelling process of these biomolecules. Optimal conditions for labelling are obtained when [NDA]total/[CN(-)] ratio =1 and [NDA]total/[amino acid or peptide]=100 with a buffer having a pH=9 on a glassy carbon electrode. In all cases, an obvious oxidation peak for the N-2-substituted-1-cyanobenz-[f]-isoindole derivative (CBI) has been observed at 0.5-0.7 V/SCE. The multi-labelling of PN and lysine were shown with DPV. We presumed this result to occur because of the shouldered shape of the DPV peak shape. These experiments confirm that NDA can be used as a derivative agent for PN, allowing for electrochemical and fluorescence detections with a limit of detection of labelled PN estimated at 0.2 uM and 5 uM, respectively. PMID- 24148366 TI - Surface-enhanced Raman spectroscopy detection of polybrominated diphenylethers using a portable Raman spectrometer. AB - Polybrominated diphenylethers (PBDEs), one of the most common brominated flame retardants, are toxic and persistent, generally detected by the chromatographic method. In this work, qualitative and quantitative detection of PBDEs were explored based on surface-enhanced Raman spectroscopy (SERS) technique using a portable Raman spectrometer. Alkanethiol modified silver nanoparticle aggregates were used as the substrate and PBDEs could be pre-concentrated close to the substrate surface through their hydrophobic interactions with alkanethiol. The effect of alkanethiols with different chain length on the SERS detection of PBDEs was evaluated. It was shown that 1-hexanethiol (HT) modified substrate has higher sensitivity, good stability and reusability. Qualitative and quantitative SERS detection of PBDEs in real sea water was accomplished, with the measured detection limits at 1.2*10(2) MUg L(-1). These results illustrate SERS could be used as an effective method for the detection of PBDEs. PMID- 24148367 TI - Determination of trace level cadmium in SRM 3280 Multivitamin/Multielement Tablets via isotope dilution inductively coupled plasma mass spectrometry. AB - Cadmium was quantified at 80.15+/-0.86 ng/g (mean+/-95% expanded uncertainty) in NIST SRM 3280 Multivitamin/Multielement Tablets, using isotope dilution mass spectrometry. The method described utilized various precipitation and solid-phase extraction separation methodologies to isolate Cd from Sn and Mo, present respectively, at 11.1+/-0.9 mg/kg and 70.7+/-4.5 mg/kg in the tablet matrix. This allowed for measurement of (111)Cd/(113)Cd and (111)Cd/(114)Cd isotope ratios using both quadrupole collision cell technology inductively coupled plasma mass spectrometry (Q-CCT-ICP-MS) and sector field (SF)-ICP-MS equipped with a desolvating nebulizer system to mitigate the MoO(+) and MoOH(+) molecular ion interferences that typically affect the envelope of Cd isotopes. PMID- 24148368 TI - On-chip electrochemical microsystems for measurements of copper and conductivity in artificial seawater. AB - The fabrication and characterisation of microelectrochemical sensors for Cu(2+) and conductivity suitable for operation in the marine environment are presented. The impact of the designs on sensor performance and their adequacy to operate in real conditions are discussed. The sensors, tailored to voltammetric and impedimetric measurements, are fabricated on silicon using photolithographic and thin film deposition techniques. The impedimetric sensor is made of Pt interdigitated electrodes which are used for the measurement of conductivity. The voltammetric sensors are based on a three electrode electrochemical cell with on chip Ag|AgCl reference and Pt counter and working electrodes, used for detection of copper by underpotential deposition-stripping voltammetry at microelectrode array. The sensors operated in the Cu(2+) concentrations ranging from 0.48 to 3.97 uM with a limit of detection of 0.115 MUM. The impact of the temperature, the pH and the salinity of the artificial seawater on the sensitivity for Cu(2+) detection are also considered. Measurements of copper concentration and conductivity are validated using certified reference materials and standard solutions. PMID- 24148369 TI - Detection of chemical residues in tangerine juices by a duplex immunoassay. AB - A rapid duplex ELISA for the simultaneous determination of two of the most widely used organophosphorous insecticides in tangerine juices is described. To accomplish this aim, two individual enzyme-linked immunosorbent assays for chlorpyrifos and fenthion pesticides were integrated into one ELISA test. The strategy uses 96-well plates with specific wells coated with the corresponding haptenized conjugate. The optimized duplex ELISA was accomplished within 40 min achieving a detection limit of 0.20+/-0.04 ug/L and 0.50+/-0.06 ug/L, for chlorpyrifos and fenthion, respectively in tangerine juice samples. The determination of residues of both pesticides was carried out by simple sample dilution, without any extra sample clean-up procedure. Results of testing precision, stability, and selectivity demonstrated that the assay provided reliable analytical performances for the simultaneous determination of residues of chlorpyrifos and fenthion in fruit juice samples below the established European maximum residue limits (MRL). In addition, the accuracy and reliability of this duplex bioanalytical method is demonstrated by analyzing blind spiked juice samples and the results, correlated well with those achieved using a well established GC/MS method (recoveries between 95% and 106%). PMID- 24148370 TI - Semiautomated solid-phase extraction manifold with a solvent-level sensor. AB - A semiautomated solid-phase extraction manifold for multiple extractions is presented. The manifold utilizes commercial solid-phase syringe cartridges and automatically introduces and elutes all the solvents during the extraction, reducing the typical workload and stress of the analyst. The manifold consists of a peristaltic pump with solenoid valves in a flow circuit that contains transmissive photomicrosensors. The photomicrosensors were used to control the solvent dispenser and the solvent level inside the cartridge. As solvent-level sensors, the photomicrosensors determined the exact time the solvent reached the top frit to avoid sorbent drying and accurately perform the solvent exchange. The repeatability of the manifold to introduce a particular volume of solvent into the cartridges was measured, and the precisions were between 0.05 and 2.89% (RSD). To evaluate the manifold, the amount of two fluoroquinolones in a fortified blank milk sample was determined. The results of the intra- and inter day precision of multiple extractions from the fortified milk samples resulted in precisions better than 9.0% (RSD) and confirmed that the arrangement of the semiautomated manifold could adequately be used in solid-phase extraction with commercial cartridges. PMID- 24148371 TI - The connection between inverse and classical calibration. AB - Within the context of the simple classical linear calibration procedure (regression of y on x), here it is shown how a distinction between the distributions of the observed dependent variable (yobs) and the calculated (fitted) one (ycalc) leads to the following counterintuitive approach: in order to get the independent x values with lesser systematic deviations, do not identify as direct inputs in the classical calibration equation the new y observed ones (experimentally acquired), but instead the transformed ones by means of a regression towards the mean effect correction. It is shown how the conjunction of both steps, i.e., first the transformation of observed values and then the ulterior use in the classical calibration equation, corresponds to an operation totally equivalent to the direct implementation of the inverse calibration equation (regression of x on y in a single step). The reasoning given here explains in a simple manner why the inverse calibration numerically performs usually better for predictions of interpolated x values. Results are accompanied with the analysis of both theoretical and experimental data. PMID- 24148372 TI - Prediction of the type of milk and degree of ripening in cheeses by means of artificial neural networks with data concerning fatty acids and near infrared spectroscopy. AB - The present study addresses the prediction of the time of ripening and type of mixtures of milk (cow's, ewe's and goat's) in cheeses of varying composition using artificial neural networks (ANN). To accomplish this aim, neural networks were designed using as input data the content of 19 fatty acids obtained with GC FID of the cheese fat and scores obtained from principal component analysis (PCA) of NIR spectra. The best model of neuronal networks for the identification of the type of mixtures of milk was obtained using the information concerning the fatty acid concentration (80% of correct results in the training phase and 75% in the validation phase). Regarding the information of the near-infrared (NIR) spectra a neural network was designed. The aforesaid neural network predicted the ripening of cheeses with 100% accuracy in both training and in validation. PMID- 24148374 TI - Multivariate calibration by near infrared spectroscopy for the determination of the vitamin E and the antioxidant properties of quinoa. AB - Quinoa is a pseudocereal that is grown mainly in the Andes. It is a functional food supplement and ingredient in the preparation of highly nutritious food. In this paper we evaluate the potential of near infrared spectroscopy (NIR) for the determination of vitamin E and antioxidant capacity in the quinoa as total phenol content (TPC), radical scavenging activity by DPPH (2,2-diphenyl-2-picryl hydrazyl) and cupric reducing antioxidant capacity (CUPRAC) expressed as gallic acid equivalent (GAE). For recording NIR a fiber optic remote reflectance probe applied directly on the quinoa samples without treatment was used. The regression method used was modified partial least squares (MPLS). The multiple correlation coefficients (RSQ) and the standard prediction error corrected (SEP(C)) were for the vitamin E (0.841 and 1.70 mg 100 g(-1)) and for the antioxidants TPC (0.947 and 0.08 mg GAE g(-1)), DPPH radical (0.952 and 0.23 mg GAE g(-1)) and CUPRAC ( 0.623 and 0.21 mg GAE g(-1)), respectively. The prediction capacity of the model developed measured by the ratio performance deviation (RPD) for vitamin E (2.51), antioxidants TPC (4.33), DPPH radical (4.55) and CUPRAC (1.55) indicated that NIRS with a fiber optic probe provides an alternative for the determination of vitamin E and antioxidant properties of the quinoa, with a lower cost, higher speed and results comparable with the chemical methods. PMID- 24148373 TI - Evaluation of a method using high performance liquid chromatography with ultraviolet detection for the determination of statins in macromycetes of the genus Pleurotus cultivated by fermentation processes. AB - The applicability of high-performance liquid chromatography with ultraviolet light (HPLC-UV) for the determination of the presence of statins in macromycetes of the genus Pleurotus was analyzed. The fungi were obtained by liquid-state fermentation (LSF) using unconventional sources of carbon as substrates and solid state fermentation (SSF) employing agro industrial wastes. Five statins were used as standards: lovastatin and simvastatin in the lactone form (LOVL and SIML), their corresponding hydro-acidic forms (LOVH and SIMH) and pravastatin (PRA). The following measures were evaluated: the linearity, accuracy and precision, detection limit (DL) and quantification limit (QL). The results demonstrated HPLC UV to be an effective tool for detecting the presence of statins in extracts of LSF and SSF products. Likewise, it was hypothesized that the strains that were used for the study do not produce statins. This finding highlights the importance of continuing to evaluate other strains of the same genus by using techniques such as HPLC to first separate sufficient quantities of the compounds that were detected using the standard technique but that did not match the retention time (tR) of any of the standards used. PMID- 24148375 TI - Synthesis of fluorescent carbon dots via simple acid hydrolysis of bovine serum albumin and its potential as sensitive sensing probe for lead (II) ions. AB - Carbon dots have great potential to be utilised as an optical sensing probe due to its unique photoluminescence and less toxic properties. This work reports a simple and novel synthesis method of carbon dots via direct acid hydrolysis of bovine serum albumin protein in a one-pot approach. Optimisation of the important synthetic parameters has been performed which consists of temperature effect, acid to protein ratio and kinetics of reaction. Higher temperature has promoted better yield with shorter reaction time. The carbon dots obtained shows a strong emission at the wavelength of 400 nm with an optimum excitation of 305 nm. The potential of the carbon dots as optical sensing probe has been investigated on with different cations that are of environmental and health concern. The fluorescence of the carbon dots was significantly quenched particularly by lead (II) ions in a selective manner. Further analytical study has been performed to leverage the performance of the carbon dots for lead (II) ions sensing using the standard Stern-Volmer relationship. The sensing probe has a dynamic linear range up to 6.0 mM with a Stern-Volmer constant of 605.99 M(-1) and a limit of detection (LOD) of 5.05 MUM. The probe performance was highly repeatable with a standard deviation below 3.0%. The probe suggested in this study demonstrates the potential of a more economical and greener approach that uses protein based carbon dots for sensing of heavy metal ions. PMID- 24148376 TI - Improved detection of drugs of abuse using high-performance ion mobility spectrometry with electrospray ionization (ESI-HPIMS) for urine matrices. AB - High-performance ion mobility spectrometry (HPIMS) with electrospray ionization (ESI) has been used to separate drugs of abuse compounds as a function of drift time (ion mobility), which is based on their size, structural shape, and mass-to charge. HPIMS has also been used to directly detect and identify a variety of the most commonly encountered illegal drugs, as well as a mixture of opiates in a urine matrix without extra sample pretreatment. HPIMS has shown resolving power greater than 65 comparable to that of high-performance liquid chromatography (HPLC) with only 1 mL of solvent and sample required using air as the IMS separation medium. The HPIMS method can achieve two-order of magnitude linear response, precise drift times, and high peak area precision with percent relative standard deviations (%RSD) less than 3% for sample quantitation. The reduced mobilities measured agree very well with other IMS measurements, allowing a simple "dilute-and-shoot" method to be used to detect a mixture of codeine and morphine in urine matrix. PMID- 24148377 TI - Supported protein G on gold electrode: characterization and immunosensor application. AB - In this work, we study the electrochemical properties of protein layer grafted on gold electrode for C-reactive protein detection. Two CRP-antibody immobilization methods were used: the first method is based on direct physisorption of CRP antibody onto the gold surface and the second method is based on oriented CRP antibody with protein G intermediate layer. The two developed immunosensors were tested against CRP antigen in phosphate buffer saline solution and in human plasma. The electrochemical characterization of each immobilized layers was achieved by cyclic voltammetry and impedance spectroscopy. The morphology of the deposited biomolecules was observed by Atomic Force Microscopy and the roughness was measured. Moreover, contact angle measurement was used for wettability studies. The response of the developed immunosensors was reproducible, rapid, and highly stable and a detection limit of 100 fg/mL and 10 pg/mL antigen was observed with and without protein G respectively. The developed immunosensors was used for CRP detection in human plasma. PMID- 24148378 TI - Effects of derivatization reagents consisting of n-alkyl chloroformate/n-alcohol combinations in LC-ESI-MS/MS analysis of zwitterionic antiepileptic drugs. AB - In the current study, three antiepileptic drugs with zwitterionic properties, namely vigabatrin, pregabalin and gabapentin, were chosen as model analytes to undergo derivatization by applying various n-alkyl chloroformate/n-alcohol combinations, followed by LC-ESI-MS/MS analysis. The employment of 16 combinations per drug using methyl, ethyl, propyl or butyl chloroformate coupled with methanol, ethanol, propanol or butanol, greatly affected a series of parameters of the derivatives, such as retention time on C8 column, signal expressed via areas, limit of detection values, as well as the yields of the main and side reactions. Practically, even slight modification of n-alkyl group of either chloroformate or alcohol resulted in significant changes in the chromatographic and mass spectrometric behavior of the novel derivative. It was clearly demonstrated that all the estimated parameters were highly correlated with the length of n-alkyl groups of the involved chloroformate and alcohol. The most significant influence was monitored in peak area values, indicating that the length of the n-alkyl chain plays an important role in electrospray ionization efficiency. For this parameter, increasing the n-alkyl chain from methyl to butyl led to increment up to 2089%, 508.7% and 1075% for area values of derivatized vigabatrin, pregabalin and gabapentin, respectively. These changes affected also the corresponding values of limits of detection, with the estimated improvements up to 1553%, 397.7% and 875.0% for the aforementioned derivatized drugs, respectively. Besides the obvious utilization of these conclusions in the development of bioanalytical methods for these analytes with the current protocol, this study offers valuable data which can be useful in more general approaches, giving insights into the effects of this derivatization reaction and its performances. PMID- 24148379 TI - A new approach to bacterial colony morphotyping by matrix-assisted laser desorption ionization time of flight-based mass spectrometry. AB - Matrix assisted laser desorption ionization time of flight mass spectrometry has been explored as a tool to bacterial colony morphotyping. To this end, four colony morphotypes of Pseudomonas aeruginosa and four of Staphylococcus aureus were analysed using intact bacteria. Results suggest that mass spectrometry of intact bacteria could, in some extent, be used to complement the classical morphological classification of bacteria. PMID- 24148380 TI - Chemometrics for the classification and calibration of seawater using the H+ affinity spectrum. AB - In 1819 Alexander Marcet proposed that seawater contains small amounts of all soluble substances and that the relative abundances of some of them were constant. This hypothesis is nowadays known as Marcet's Principle or the principle of constancy of the composition of seawater. Based on this principle, the present research tried to prove that it is possible to detect polluted seawater samples using the seawater H(+) affinity spectrum by the application of the possibilities provided by chemometric tools. Seawater samples were classified using the principal component analysis (PCA) of the HBound spectra of the samples. It was concluded that the sampling points location does not have any influence in the cluster formation, while the season in which they were collected is significant. On the other hand, the seawater composition was calibrated using estuary water samples of different salinities. Once the major constituents were measured, the data analysis concluded that it is possible to make a calibration of the HBound spectrum vs. any of these constituents by means of partial least square (PLS) regression. Thus, the experimental evidence collected in this work confirms that it is possible to detect polluted sea or estuary water samples using these chemometric tools and the H(+) affinity spectrum because with polluted samples these multivariate methods lead to incoherent results. So, suspect polluted zones may be monitored in a simple way with a low cost method and spending much less time. PMID- 24148381 TI - Determination of plasma cholesterol sulfate by LC-APCI-MS/MS in the context of pediatric autism. AB - Cholesterol sulfate (CS) has various biological functions. Previously, plasma CS was measured primarily as a means to diagnose X-linked ichthyosis; however, a recent hypothesis suggests that CS deficiency might be related to autism. As such, an assay capable of measuring both very high (in the case of X-linked ichthyosis) and very low (in the case of autism) plasma CS levels is required. Here we describe a novel LC-APCI-MS/MS method for the determination of CS in human plasma, and we propose normal CS ranges for children, based on studies of a local population of normal Chinese children between the ages of 2 and 10. In addition, we have used this method to measure plasma CS in autistic children. CS was isolated by solid-phase extraction, and quantified by isotope-dilution LC APCI-MS/MS in negative ion mode monitoring 465.3>97.1 m/z (CS) and 472.3>97.1 m/z (CS-d7). Mean recovery of the assay ranged from 88.1 to 112.7%; within- and between-run imprecisions have CVs less than 7.2 and 8.1%, respectively. The assay was linear up to at least 100 umol L(-1). The reference interval of plasma CS in males (range: 1.16-4.23 umol L(-1)) was found to be higher than in females (range: 0.86-3.20 umol L(-1)). Comparison of normal and autistic children showed no statistically significant difference in the plasma CS level. In conclusion, a robust LC-APCI-MS/MS method for plasma CS was developed, and a pediatric reference interval was derived from applying the method to normal and autistic children. PMID- 24148382 TI - Neural networks to estimate the water content of imidazolium-based ionic liquids using their refractive indices. AB - A non-linear model has been developed to estimate the water content of 1-butyl-3 methylimidazolium tetrafluoroborate, 1-butyl-3-methylimidazolium methylsulfate, and 1,3-dimethylimidazolium methylsulfate ionic liquids using their respective refractive index values. The experimental values measured to design the neural network (NN) model were registered at 298.15K. These were determined at different relative humidity values which ranged from 11.1% to 84.3%. The estimated results were compared with experimental measurements of water content obtained by the Karl Fischer technique, and the differences between the real and estimated values were less than 0.06% in the internal validation process. In addition, an external validation test was developed using bibliographical references. In this case, the mean prediction error was less than 5.4%. In light of these results, the NN model shows an acceptable goodness of fit, sufficient robustness, and a more than adequate predictive capacity to estimate the water content of the ILs through the analysis of their refractive index. PMID- 24148383 TI - Simultaneous determination of imidacloprid and carbendazim in water samples by ion chromatography with fluorescence detector and post-column photochemical reactor. AB - A new analytical method has been developed and validated for the simultaneous determination of pesticides from different classes using ion chromatography online photochemical derivatisation-fluorescence detector (IC-hv-FD). Fluorimetric detection was performed at lambdaex/lambdaem=332 nm/367 nm for imidacloprid and then detector was set at lambdaex/lambdaem=247 nm/470 nm for carbendazim. The two pesticides imidacloprid and carbendazim were successfully separated isocratically on an IonPac((r)) AS11 (250 mm * 4 mm i.d; 13 um particle size, Dionex) anion-exchange column using 40 mM KOH with 10% (v/v) acetonitrile and pumped at a flow rate of 1.0 mL min(-1). Under the optimized conditions, the limit of detection (LOD, S/N=3) of imidacloprid and carbendazim were 7.8 ug L(-1) and 67 ug L(-1), respectively. The experimental results showed that there was good linearity with a correlation coefficient (r)>=0.9966 over the range of 0.05 10 mg L(-1) for imidacloprid and 0.2-15 mg L(-1) for carbendazim. Good reproducibility with a relative standard deviation (RSD, n=7) less than 4.5%. Finally, the proposed method was applied with satisfactory results to the analysis of these pesticides in ground water, lake water and river water without any pre-treatment of samples. The average spiked recoveries were in the range of 90-104%. PMID- 24148384 TI - Polymer-supported ionic liquid solid phase extraction for trace inorganic and organic mercury determination in water samples by flow injection-cold vapor atomic absorption spectrometry. AB - A simple and green technique named polymer-supported ionic liquid solid phase extraction (PSIL-SPE) was developed for mercury (Hg) species determination. Inorganic Hg (InHg) species was complexed with chloride ions followed by its introduction into a flow injection on-line system to quantitatively retain the anionic chlorocomplex (HgCl4(2-)) in a column packed with CYPHOS((r)) IL 101 impregnated resin. The trapped InHg was then reduced with stannous chloride (SnCl2) and eluted with the same flow of reducing agent followed by cold vapor atomic absorption spectrometry (CV-AAS) detection. Organic mercury species (OrgHg) did not interact with the impregnated resin and were not retained into the column. Total concentration of OrgHg was evaluated by difference between total Hg and InHg concentration. A 95% extraction efficiency was achieved for InHg when the procedure was developed under optimal experimental conditions. The limit of detection obtained for preconcentration of 40 mL of sample was 2.4 ng L( 1) InHg. The relative standard deviation (RSD) was 2.7% (at 1 ug L(-1) InHg and n=10) calculated from the peak height of absorbance signals (Gaussian-shape and reproducible peaks). This work reports the first polymer-supported IL solid phase extraction approach implemented in a flow injection on-line system for determination of Hg species in mineral, tap and river water samples. PMID- 24148385 TI - A novel method for speciation of Pt in human serum incubated with cisplatin, oxaliplatin and carboplatin by conjoint liquid chromatography on monolithic disks with UV and ICP-MS detection. AB - Conjoint liquid chromatography (CLC) on monolithic convective interaction media (CIM) disks coupled on-line to UV and inductively coupled plasma mass spectrometry (ICP-MS) detectors was used for the first time in speciation analysis of Pt in human serum spiked with Pt-based chemotherapeutics. CIM Protein G and CIM DEAE disks were assembled together in a single housing forming a CLC monolithic column. Such a set-up allows rapid two-dimensional separation by affinity and ion-exchange (IE) modes to be carried out in a single chromatographic run. By applying isocratic elution with Tris-HCl-NaHCO3 buffer (pH 7.4) in the first minute, followed by gradient elution with 1 mol L(-1) NH4Cl (pH 7.4) in the next 9 min, immunoglobulins (IgG) were retained by the Protein G disk enabling subsequent separation of unbound Pt from Pt bound to transferrin (Tf) and albumin (HSA) on the CIM DEAE disk. Further elution with acetic acid (AcOH) in the next 3 min allowed separation of Pt associated with IgG. Separated Pt species were quantified by post-column isotope dilution-ICP-MS. Pt recovery on the CLC column was close to 100%. In comparison to commonly applied procedures that involve separation of protein peaks by size-exclusion chromatography (SEC) followed by IE separation of metal-based chemotherapeutic fractions bound to serum proteins, the CLC method developed is much faster and simpler. Its sensitivity (LOQs adequate for quantification of all separated Pt species, lower than 2.4 ng Pt mL(-1)), good selectivity and method repeatability (RSD+/-3%) enabled investigation of the kinetics of interaction of Pt-based chemotherapeutics with serum proteins and the distribution of Pt species in spiked human serum. Pt species present in spiked serum were bound preferentially to HSA. The proportion of Pt associated with IgG and Tf was lower than 13%. Cisplatin and especially oxaliplatin react rapidly with serum proteins, while carboplatin much less. The method developed may be reliably applied in preclinical and clinical studies of the kinetics of the interaction and distribution of different metallodrugs with proteins in blood serum. PMID- 24148386 TI - Discrimination of grassland species and their classification in botanical families by laboratory scale NIR hyperspectral imaging: preliminary results. AB - The objective of this study was to discriminate by a NIR line scan hyperspectral imaging, taxonomic plant families comprised of different grassland species. Plants were collected from semi-natural meadows of the National Apuseni Park, Apuseni Mountains, Garda area (Romania) according to botanical families. Chemometric tools such as PLS-DA were used to discriminate distinct grassland species, and assign the different species to botanical families. Species within the Poacea family and other Botanical families could be distinguished (R(2)=0.91 and 0.90, respectively) with greater accuracy than those species in the Fabacea family (R(2)=0.60). A correct classification rate of 99% was obtained in the assignment of the various species to the proper family. Moreover a complete study based on wavelength selection has been performed in order to identify the chemical compound related to each botanical family and therefore to the possible toxicity of the plant. This work could be considered as a first step for the development of a complete procedure for the detection and quantification of possible toxic species in semi-natural meadows used by grazing animals. PMID- 24148387 TI - Development of a novel amide-silica stationary phase for the reversed-phase HPLC separation of different classes of phytohormones. AB - A novel amide-bonded silica stationary phase was prepared starting from N-Boc phenylalanine, cyclohexylamine and spherical silica gel (4 um, 60 A). The amide ligand was synthesised with high yield. The resulting amide bonded stationary phase was characterised by SEM, IR and elemental analysis. The resulting selector bearing a polar amide group is used for the reversed-phase chromatography separation of different classes of thirteen phytohormones (plant hormones). The chromatographic behaviours of these analytes on the amide-silica stationary phase were compared with those of RP-C18 column under same conditions. The effects of different separation conditions, such as mobile phase, pH value, flow rate and temperature, on the separation and retention behaviours of the 13 phytohormones in this system were studied. The optimum separation was achieved using reversed phase HPLC gradient elution with an aqueous mobile phase containing pH=6.85 potassium phosphate buffer (20 mM) and acetonitrile with a 22 degrees C column temperature. Under these experimental conditions, the 12 phytohormones could be separated and detected at 230 or 270 nm within 26 min. PMID- 24148388 TI - A new and fast methodology to assess oxidative damage in cardiovascular diseases risk development through eVol-MEPS-UHPLC analysis of four urinary biomarkers. AB - In this work, a new, fast and reliable methodology using a digitally controlled microextraction by packed sorbent (eVol((r))-MEPS) followed by ultra-high pressure liquid chromatography (UHPLC) analysis with photodiodes (PDA) detection, was developed to establish the urinary profile levels of four putative oxidative stress biomarkers (OSBs) in healthy subjects and patients evidencing cardiovascular diseases (CVDs). This data was used to verify the suitability of the selected OSBs (uric acid-UAc, malondialdehyde-MDA, 5-(hydroxymethyl)uracil-5 HMUra and 8-hydroxy-2'-deoxyguanosine-8-oxodG) as potential biomarkers of CVDs progression. Important parameters affecting the efficiency of the extraction process were optimized, particularly stationary phase selection, pH influence, sample volume, number of extraction cycles and washing and elution volumes. The experimental conditions that allowed the best extraction efficiency, expressed in terms of total area of the target analytes and data reproducibility, includes a 10 times dilution and pH adjustment of the urine samples to 6.0, followed by a gradient elution through the C8 adsorbent with 5 times 50 uL of 0.01% formic acid and 3*50 uL of 20% methanol in 0.01% formic acid. The chromatographic separation of the target analytes was performed with a HSS T3 column (100 mm * 2.1 mm, 1.7 um in particle size) using 0.01% formic acid 20% methanol at 250 uL min(-1). The methodology was validated in terms of selectivity, linearity, instrumental limit of detection (LOD), method limit of quantification (LOQ), matrix effect, accuracy and precision (intra-and inter-day). Good results were obtained in terms of selectivity and linearity (r(2)>0.9906), as well as the LOD and LOQ, whose values were low, ranging from 0.00005 to 0.72 ug mL(-1) and 0.00023 to 2.31 ug mL(-1), respectively. The recovery results (91.1-123.0%), intra-day (1.0-8.3%), inter-day precision (4.6-6.3%) and the matrix effect (60.1-110.3%) of eVol((r))-MEPS/UHPLC PDA method were also very satisfactory. Finally, the application of the methodology to the determination of target biomarkers in normal subjects and CVDs patients' revealed that the DNA adducts 5-HMUra and 8-oxodG levels are much more abundant in CVDs patients while no statistic differences were obtain for MDA and UAc. This result points to the importance of 5-HMUra and 8-oxodG as biomarkers of CVDs risk progression and further epidemiological studies are needed to explore the importance of this correlation. PMID- 24148389 TI - Sensitivity and specificity enhanced enzyme-linked immunosorbent assay by rational hapten modification and heterogeneous antibody/coating antigen combinations for the detection of melamine in milk, milk powder and feed samples. AB - The adulteration of food products with melamine has led to an urgent requirement for sensitive, specific, rapid and reliable quantitative/screening methods. To enhance the sensitivity and specificity of the enzyme-linked immunosorbent assay (ELISA) for the detection of melamine in milk, milk powder and feed samples, rational hapten modification and heterogeneous antibody/coating antigen combinations were adopted. Three melamine derivatives with different length of carboxylic spacer at the end were synthesized and linked to carrier proteins for the production of immunogens and coating antigens. Monoclonal antibody against melamine was produced by hybridoma technology. Under optimal experimental conditions, the standard curves of the ELISAs for melamine were constructed in range of 0.1-100 ng mL(-1). The sensitivity was 10-300 times enhanced compared to those in the published literatures. The cross-reactivity values of the ELISAs also demonstrated the assays exhibited high specificity. Five samples were spiked with melamine at different concentrations and detected by the ELISA. The recovery rates of 72.8-123.0% and intra-assay coefficients of variation of 0.8-18.9% (n=3) were obtained. The ELISA for milk sample was confirmed by high-performance liquid chromatography with a high correlation coefficient of 0.9902 (n=6). The proposed ELISA was proven to be a feasible quantitative/screening method for melamine analysis. PMID- 24148390 TI - Rapid and sensitive determination of tellurium in soil and plant samples by sector-field inductively coupled plasma mass spectrometry. AB - In this work, we report a rapid and highly sensitive analytical method for the determination of tellurium in soil and plant samples using sector field inductively coupled plasma mass spectrometry (SF-ICP-MS). Soil and plant samples were digested using Aqua regia. After appropriate dilution, Te in soil and plant samples was directly analyzed without any separation and preconcentration. This simple sample preparation approach avoided to a maximum extent any contamination and loss of Te prior to the analysis. The developed analytical method was validated by the analysis of soil/sediment and plant reference materials. Satisfactory detection limits of 0.17 ng g(-1) for soil and 0.02 ng g(-1) for plant samples were achieved, which meant that the developed method was applicable to studying the soil-to-plant transfer factor of Te. Our work represents for the first time that data on the soil-to-plant transfer factor of Te were obtained for Japanese samples which can be used for the estimation of internal radiation dose of radioactive tellurium due to the Fukushima Daiichi Nuclear Power Plant accident. PMID- 24148391 TI - Carbon nanotubes reinforced hollow fiber solid phase microextraction for the determination of strychnine and brucine in urine. AB - A mixed matrix membrane (MMM), based on carbon nanotubes (CNTs) and hollow fiber (HF), was prepared and combined with solid phase microextraction (SPME) mode to determine strychnine and brucine in urine. This MMM was prepared by dispersing CNTs in water via surfactant assistance, and then immobilizing CNTs into the pores of HF by capillary forces and sonification. The prepared carbon nanotubes reinforced hollow fiber (CNTs-HF) was subsequently wetted by a few microliters of organic solvent (1-octanol), and then applied to extract the target analytes in direct immersion sampling mode. After extraction, analytes were desorbed via ultrasonic-assisted effect, and then detected via high-performance liquid chromatography (HPLC). To achieve the highest extraction efficiency, main extraction parameters such as the type and amount of surfactant, the diameter and doping level of CNTs, extraction time, desorption condition, pH value, stirring rate and volume of the donor phase were optimized. Under the optimum extraction conditions, the method showed good linearity ranges with correlation coefficients higher than 0.9990, good repeatability and batch-to-batch reproducibility with relative standard deviations (RSDs) less than 6% and 5% for strychnine and brucine, respectively, and low limits of detection (0.7 and 0.9 ug L(-1) for strychnine and brucine, respectively). The recoveries were in the range of 83.81 116.14% at three spiked levels. The developed method was successfully applied to real urine sample with mean relative recoveries of 94.28% and 91.30% for strychnine and brucine, respectively. The developed method shows comparable results against reference methods and is a simple, green, and cost-effective microextraction technique. PMID- 24148392 TI - Determination of ultra trace concentrations of selenium using the GFAAS technique following on-line electrochemical pre-concentration on a gold-coated porous carbon electrode. AB - In this work the possibility of determination of selenium in water samples was studied by on-line coupling of electrochemical pre-concentration flow through unit and GFAAS. The pre-concentration unit was created from a commercial electrochemical flow through analyser EcaFlow (Istran Ltd.) and a special two electrode electrochemical flow through cell. The pre-concentration cell consisted of a working electrode made of gold-coated porous carbon and auxiliary electrode made of a Pt-wire. The pre-concentration unit was connected with electrothermal atomisers through 6-way valve with sampling loop. Using the proposed on-line coupling the limit of detection reached 0.01 MUg L(-1) for a 10 mL sample. The total linear range was between 0.03 and 10 MUg L(-1). From the number of ions tested only PO4(3-) ions reduced the signal by about 10% for 50-fold excess. Using this method it was possible to determine Se (IV) or the total inorganic selenium following reduction of Se (VI) by boiling the sample in HCl. The procedure was validated by analysing reference materials and a variety of water samples. A good agreement with the results of ICP-MS was achieved for all samples. PMID- 24148393 TI - Ultra-sensitive non-aggregation colorimetric sensor for detection of iron based on the signal amplification effect of Fe3+ catalyzing H2O2 oxidize gold nanorods. AB - Fe(3+) can catalyze H2O2 to oxidize along on the longitudinal axis of gold nanorods (AuNRs), which caused the aspect ratio of AuNRs to decrease, longitudinal plasmon absorption band (LPAB) of AuNRs to blueshift (Deltalambda) and the color of the solution to change obviously. Thus, a rapid response and highly sensitive non-aggregation colorimetric sensor for the determination of Fe(3+) has been developed based on the signal amplification effect of catalyzing H2O2 to oxidize AuNRs. This simple and selective sensor with a wide linear range of 0.20-30.00 MUM has been utilized to detect Fe(3+) in blood samples, and the results consisted with those obtained by inductively coupled plasma-mass spectroscopy (ICP-MS). Simultaneously, the mechanism of colorimetric sensor for the detection of Fe(3+) was also discussed. PMID- 24148394 TI - Graphite furnace atomic absorption spectrometric detection of vanadium in water and food samples after solid phase extraction on multiwalled carbon nanotubes. AB - Vanadium(V) ions as 8-hydroxyquinoline chelates were loaded on multiwalled carbon nanotubes (MWNTs) in a mini chromatographic column. Vanadium was determined by graphite furnace atomic absorption spectrometry (GFAAS). Various analytical parameters including pH of the working solutions, amounts of 8-hydroxyquinoline, eluent type, sample volume, and flow rates were investigated. The effects of matrix ions and some transition metals were also studied. The column can be reused 250 times without any loss in its sorption properties. The preconcentration factor was found as 100. Detection limit (3 s) and limit of quantification (10 s) for the vanadium in the optimal conditions were observed to be 0.012 ug L(-1) and 0.040 MUg L(-1), respectively. The capacity of adsorption was 9.6 mg g(-1). Relative standard deviation (RSD) was found to be 5%. The validation of the method was confirmed by using NIST SRM 1515 Apple leaves, NIST SRM 1570a Spinach leaves and GBW 07605 Tea certified reference materials. The procedure was applied to the determination of vanadium in tap water and bottled drinking water samples. The procedure was also successfully applied to microwave digested food samples including black tea, coffee, tomato, cabbage, zucchini, apple and chicken samples. PMID- 24148395 TI - A solid phase extraction-ion chromatography with conductivity detection procedure for determining cationic surfactants in surface water samples. AB - A new analytical procedure for the simultaneous determination of individual cationic surfactants (alkyl benzyl dimethyl ammonium chlorides) in surface water samples has been developed. We describe this methodology for the first time: it involves the application of solid phase extraction (SPE-for sample preparation) coupled with ion chromatography-conductivity detection (IC-CD-for the final determination). Mean recoveries of analytes between 79% and 93%, and overall method quantification limits in the range from 0.0018 to 0.038 MUg/mL for surface water and CRM samples were achieved. The methodology was applied to the determination of individual alkyl benzyl quaternary ammonium compounds in environmental samples (reservoir water) and enables their presence in such types of waters to be confirmed. In addition, it is a simpler, less time-consuming, labour-intensive, avoiding use of toxic chloroform and significantly less expensive methodology than previously described approaches (liquid-liquid extraction coupled with liquid chromatography-mass spectrometry). PMID- 24148396 TI - Calibration of membrane inlet mass spectrometric measurements of dissolved gases: differences in the responses of polymer and nano-composite membranes to variations in ionic strength. AB - This work examines the transmission behavior of aqueous dissolved methane, nitrogen, argon and carbon dioxide through two types of membranes: a polysiloxane nano-composite (PNC) membrane and a conventional polydimethylsiloxane (PDMS) membrane. Transmission properties at 30 degrees C were examined by membrane introduction mass spectrometry (MIMS) at nearly constant gas partial pressures in NaCl solutions over a range of ionic strength (0-1 molal). Gas flow rates were examined as a function of dissolved gas concentrations using the Setschenow equation. Although MIMS measurements with PDMS and PNC membranes produced signal responses that were directly proportional to aqueous dissolved gas concentrations, the proportionalities varied with ionic strength and were distinctly different for the two types of membranes. With the exception of carbon dioxide, the PNC membrane had membrane salting coefficients quite similar to Setschenow coefficients reported for gases in aqueous solution. In contrast, the PDMS membrane had membrane salting coefficients that were generally smaller than the corresponding Setschenow gas coefficient for each gas. Differences between Setschenow coefficients and membrane salting coefficients lead to MIMS calibrations (gas-flow vs. gas-concentration proportionalities) that vary with ionic strength. Accordingly, gas-flow vs. gas-concentration relationships for MIMS measurements with PDMS membranes are significantly dependent on ionic strength. In contrast, for PNC membranes, flow vs. concentration relationships are independent (argon, methane, nitrogen) or weakly dependent (CO2) on ionic strength. Comparisons of gas Setschenow and membrane salting coefficients can be used to quantitatively describe the dependence of membrane gas-flow on gas concentrations and ionic strength for both PDMS and PNC membranes. PMID- 24148397 TI - A novel nonenzymatic sensor based on CuO nanoneedle/graphene/carbon nanofiber modified electrode for probing glucose in saliva. AB - Here, we report on a novel nonenzymatic amperometric glucose sensor based on CuO nanoneedle/graphene/carbon nanofiber modified electrode. The results of the scanning electron microscopy indicate that electronic network was formed through their direct binding with the graphene/carbon nanofiber, which leads to larger active surface areas and faster electron transfer for the glucose sensor. High electrocatalytic activity toward the oxidation of glucose was observed with a rapid response (<2 s), a low detection limit (0.1 uM), a wide and useful linear range (1-5.3 mM) as well as good stability and repeatability. Moreover, the common interfering species, such as ascorbic acid, uric acid, dopamine and so forth did not cause obvious interference. The sensor can also be used for quantification of glucose concentration in real saliva samples. Therefore, this work has demonstrated a simple and effective sensing platform for nonenzymatic detection of glucose. PMID- 24148398 TI - Room temperature phosphorimetric determination of bromate in flour based on energy transfer. AB - Determination of bromate ions in contaminated flour samples by using a room temperature phosphorescence (RTP) optosensor is described. The optosensor is based on the non-radiative energy transfer from alpha-bromonaphthalene (a phosphorescent molecule insensitive to the presence of the analyte) acting as donor, to an energy acceptor bromate-sensitive molecule (trifluoperazine hydrochloride). The RTP emission of the selected donor greatly overlaps with the absorption spectrum of the acceptor, resulting in a decrease of the measured signal as the concentration of bromate ions increases. A simple and general procedure is proposed to carry out the incorporation of both the donor and acceptor molecules in an appropriate solid material (sensing phase) through the co-immobilization of the species in a sol-gel inorganic matrix. The optimum amounts of the sol-gel precursors, including silica precursors, type of catalysis, and concentrations of donor and acceptor molecules, have been evaluated in order to obtain the best analytical features of the proposed optosensor for bromate determination. The highly stable developed sensing phase shows a selective and reversible response towards bromate even in presence of dissolved oxygen (a well-known quencher of the RTP). The calibration graphs were linear up to 200 mg L(-1), with a detection limit for bromate dissolved in aqueous medium of 0.2 mg L(-1). Sample throughput of the proposed optosensor was about 18 measurements h(-1). Application of the developed sensing phase was successfully proved for the detection of bromate ions in commercial flours, obtaining good recoveries. PMID- 24148399 TI - Parallel comparative studies on the toxic effects of unmodified CdTe quantum dots, gold nanoparticles, and carbon nanodots on live cells as well as green gram sprouts. AB - By using confocal fluorescence microscopy and direct visualization, a parallel comparative investigation has been systematically made on the relative toxicity of three common nanomaterials, such as unmodified CdTe quantum dots (QDs), Au nanoparticles (Au NPs) and carbon nanodots (C-dots), to live cells as well as green gram sprouts. Bare CdTe QDs exert the most toxic effect on a variety of cell lines (HeLa, MCF-7, NIH/3T3 cells) as well as live plants (green gram sprouts). For cells, this toxic effect leads to the partial death of cells, the decrease of cell metabolic activity, the shrinkage of cells, the breakage of chromatin, the damage of cell membrane integrity, and the fragmentation of mitochondria; for green gram sprouts, the presence of CdTe QDs markedly inhibits their growth. Moreover, the toxic behaviors of CdTe QDs are dose- and time dependent. Under the same conditions, Au NPs only decrease the metabolic activity of cells to a small extent, and do not affect the appearance of cellular/subcellular structures and the plant growth; interestingly, C-dots exert no obvious toxicity to both live cells and the growth of green gram sprouts, showing good biocompatibility. These parallel comparative studies clearly reveal that the relative toxicity of the three nanomaterials in their native forms is bare CdTe QDs>>Au NPs>C-dots, whose IC50 values for normal NIH/3T3 cells are 0.98 MUg/mL, 62 MUg/mL, and >250 MUg/mL, respectively. This quantitative information is of great importance for right choice of the nanomaterials in their practical applications. PMID- 24148400 TI - Square-wave stripping voltammetric determination of caffeic acid on electrochemically reduced graphene oxide-Nafion composite film. AB - An electrochemical sensor composed of Nafion-graphene nanocomposite film for the voltammetric determination of caffeic acid (CA) was studied. A Nafion graphene oxide-modified glassy carbon electrode was fabricated by a simple drop-casting method and then graphene oxide was electrochemically reduced over the glassy carbon electrode. The electrochemical analysis method was based on the adsorption of caffeic acid on Nafion/ER-GO/GCE and then the oxidation of CA during the stripping step. The resulting electrode showed an excellent electrocatalytical response to the oxidation of caffeic acid (CA). The electrochemistry of caffeic acid on Nafion/ER-GO modified glassy carbon electrodes (GCEs) were studied by cyclic voltammetry and square-wave adsorption stripping voltammetry (SW-AdSV). At optimized test conditions, the calibration curve for CA showed two linear segments: the first linear segment increased from 0.1 to 1.5 and second linear segment increased up to 10 uM. The detection limit was determined as 9.1*10(-8) mol L(-1) using SW-AdSV. Finally, the proposed method was successfully used to determine CA in white wine samples. PMID- 24148401 TI - Full method validation for the determination of hexachlorobenzene and hexachlorobutadiene in fish tissue by GC-IDMS. AB - This paper summarizes the validation strategy and the results obtained for the simultaneous determination of hexachlorobenzene (HCB) and hexachlorobutadiene (HCBD) in fish tissue with a maximum of about 10% m/m fat content using a GC-IDMS technique. The method is applicable for the determination of HCB and HCBD at trace levels in different kinds of fish tissue samples in accordance with the requirements of the EU Directive 2008/105/EC establishing Environmental Quality Standard (EQS) levels for biota in aquatic ecosystems (10 ng/g for HCB and 55 ng/g for HCBD). The method validation aimed to assess performance parameters such as linearity, limit of detection/limit of quantification (LOD/LOQ), trueness, selectivity, intermediate precision, repeatability, stability of the extracts and robustness. The validation experiments have been performed by using uncontaminated fish tissue. Trueness was evaluated by using a certified reference material (NIST SRM 1947) (where applicable) and by the standard addition method. Very good linear signal-concentration curves were obtained for both analytes over the whole range of calibration. The repeatability and the intermediate precision of the method, expressed as relative standard deviation (RSD) and calculated at the EQS level, were estimated to be below 3% both for HCB and HCBD. The limits of quantification were 3.7 ng/g for HCB and 15.7 ng/g for HCBD in the fish. An uncertainty budget for the measurement of both HCB and HCBD in fish at about the EQS levels, applying the described method, has been established in the order of 10%. The analytical method and its performance characteristics take into account the requirements of EU Directive 2009/90/EC regarding the establishment of minimum performance criteria for the methods of analysis to be used in the water monitoring activity of the Water Framework Directive. Finally, the validated method was successfully tested on contaminated Silurus glanis from Ebro River (Spain). The method will be used in the homogeneity, stability and interlaboratory comparison studies for the characterization of a new candidate certified reference material. PMID- 24148402 TI - A stable and high-resolution isoelectric focusing capillary array device for micropreparative separation of proteins. AB - A simple capillary array IEF device was developed for high resolution and micropreparative separation of trace amounts of proteins. Based on quasi-chip scale manufacturing, the specific capillaries (600 MUm i.d., 1200 MUm o.d. and 20 mm length) were integrated with the miniaturized polymethyl-methacrylate electrode trays. Electroosmotic flow was suppressed effectively by modified cross linked polyacrylamide coating, and instability of IEF was addressed using the designed concentration of electrolytes via moving reaction boundary theory. As a prototyping, the resolution, reproducibility, throughput, speed and linearity of pH gradient were systemically evaluated with model proteins. The results revealed the following advantages: (i) the reproducibility of array was assessed as RSD values of 0.95% (intra-day) and 2.88% (inter-day); (ii) IEF could be completed in 20 min with up to 400 V/cm electric field; (iii) high resolution separation of model proteins achieved in 20mm length column; (iv) multi-units with 48 micro columns can be easily integrated to obtain high throughput; and (v) good linearity of pH gradient (R=0.9989). More importantly, utility of the device was tested by using hemoglobins sample from human red blood cell. HbA0 and HbA1c with only DeltapI 0.03 have been successfully separated by the developed method. PMID- 24148403 TI - Application of visible and near infrared hyperspectral imaging for non-invasively measuring distribution of water-holding capacity in salmon flesh. AB - Water-holding capacity (WHC) is a primary quality determinant of salmon flesh. One of the limiting factors for not having a direct measurement of WHC for salmon quality grading is that current WHC measurements are destructive, time-consuming, and inefficient. In this study, two hyperspectral image systems operated in the visible and short-wave near infrared range (400-1000 nm) and the long-wave near infrared range (897-1753 nm) were applied for non-invasive determination of four WHC indices, namely percentage liquid loss (PLL), percentage water loss (PWL), percentage fat loss (PFL), and percentage water remained (PWR) of salmon flesh. Two calibration methods of partial least square regression (PLSR) and least squares support vector machines (LS-SVM) were applied, respectively, to establish calibration models of WHC indices based on the spectral signatures of salmon flesh, and the performances of these two methods were compared to determine the optimal spectral calibration strategy. The performances were also compared between two hyperspectral image systems, when full range spectra were considered. Out of 121 wavelength variables, only thirteen (PLL), twelve (PWL), nine (PFL), and twelve variables (PWR) were selected as important variables by using competitive adaptive reweighted sampling (CARS) algorithm to reduce redundancy and collinearity of hyperspectral images. The CARS-PLSR combination was identified as the optimal method to calibrate the prediction models for WHC determination, resulting in good correlation coefficient of prediction (rP) of 0.941, 0.937, 0.815, and 0.970 for PLL, PWL, PFL, and PWR analysis, respectively. CARS-PLSR equations were obtained according to the regression coefficients of the CARS-PLSR models and were transferred to each pixel in the image for visualizing WHC indices in all portions of the salmon fillet. The overall results show that the laborious, time-consuming, and destructive traditional techniques could be replaced by hyperspectral imaging to provide a rapid and non-invasive measurement of WHC distribution in salmon flesh. PMID- 24148404 TI - A sensitive spectrofluorimetric method for the quantification of melamine residue in milk powder using the Mannich reaction in aqueous solutions. AB - The objective of this study was to develop a spectrofluorimetric method for the quantitative determination of melamine. The method was based on the complexation of melamine with a mixture of formaldehyde and chemicals including a ketone group, as described by the Mannich reaction. The complex was determined by spectrofluorimetric measurement as it is characterized by specific spectroscopic properties that are related to the chromophore of the ketone compounds. 1,3 Diphenylpropane-1,3-dione (DPPD) was tested as a ketone compound. The fluorescence spectrum of the complex presented a maximum of absorption at 325 nm.A quenching of the fluorescence occurred when melamine was added into the solution. The kinetic of fluorescence quenching was followed to determine quantitatively the melamine concentration. An internal standard was added to quantify melamine. The method was tested to determine the level of melamine in contaminated milk powder. The recovery value was 97% and the limit of detection was 0.007 MUg mL(-1.) PMID- 24148405 TI - Molecularly imprinted photonic polymer based on beta-cyclodextrin for amino acid sensing. AB - A novel molecularly imprinted photonic polymer (MIPP) using maleic anhydride modified beta-cyclodextrin (beta-CD) and acrylic acid as functional monomers has been presented for amino acid sensing. Reactive beta-CD monomer carrying vinyl carboxylic acid functional groups was first synthesized. MIPP was fabricated by filling precursor solution into the interstitial spaces of polystyrene photonic crystal templates, followed by a thermal polymerization at 55 degrees C. Characterization showed that the MIPP possessed an opal photonic crystal structure. This beta-CD-based MIPP could undergo a swelling change from 590 nm to 704 nm and still retain the molecular imprinting recognition ability during the sensing of L-phenylalanine (L-Phe). A function relationship was found between the diffraction wavelength shift and the logarithm of L-Phe concentration in the range of 10(-8)M to 10(-4)M at pH 6. A wavelength shift of 114 nm for L-Phe was observed within 30s, whereas there were no obvious shifts for d-Phe, L-tyrosine and L-tryptophan, indicating that the beta-CD-based MIPP had high specificity and rapid response to L-Phe. The developed MIPP sensor has been applied to detect L Phe in compound amino acid injection sample. PMID- 24148406 TI - Multianalyte determination of 24 cytostatics and metabolites by liquid chromatography-electrospray-tandem mass spectrometry and study of their stability and optimum storage conditions in aqueous solution. AB - A multianalyte liquid chromatography-electrospray-tandem mass spectrometry (LC ESI-MS/MS) method for determination of 19 cytostatics and 5 metabolites, from 6 different therapeutic families, has been developed, and the structures of the main characteristic fragment ions have been proposed. Instrumental limits of detection and quantification are in the range 0.1-10.3 and 1.0-34.3 ng mL(-1), respectively. Moreover, the stability of the compounds in aqueous solution was investigated in order to establish the best conditions for preparation and storage of both calibration standards and water samples. Dimethylsulphoxide (DMSO) was selected as solvent for preparation of the stock solutions. At room temperature (25 degrees C), 11 of the 24 target compounds were shown to be unstable in water (percentage of organic solvent 4%), with concentration losses greater than 20% in less than 24 h. At 4 degrees C (typical storage temperature for water samples) all compounds, except MTIC and chlorambucil, were stable for 24h, but the number of stable compounds decreased to 10 after 9 days. Freezing of the aqueous solutions improved considerably the stability of various compounds: after 3 months of storage at -20 degrees C, 10 compounds, namely, 5 fluorouracil, carboplatin, gemcitabine, temozolomide, vincristine, vinorelbine, ifosfamide, cyclophosphamide, etoposide, and capecitabine, remained stable (in contrast to only carboplatin and capecitabine at 4 degrees C). The addition of acid improved the stability of methotrexate and its metabolite hydroxy methotrexate but not that of the rest of compounds. The addition of organic solvent (50% methanol or DMSO) prevented the degradation at 4 degrees C of the otherwise unstable compounds oxaliplatin, methotrexate, erlotinib, doxorubicin, tamoxifen, and paclitaxel. To the authors' knowledge, five of the analytes investigated have never been searched for in the aquatic environment (imatinib, 6alpha-hydroxypaclitaxel, endoxifen, (Z)4-hydroxytamoxifen, and temozolomide), and for many of them the stability data provided, and even the analytical LC MS/MS conditions, are the first ever published. PMID- 24148407 TI - The redox behaviour of diazepam (Valium(r)) using a disposable screen-printed sensor and its determination in drinks using a novel adsorptive stripping voltammetric assay. AB - In this study we investigated the possibility of applying disposable electrochemical screen-printed carbon sensors for the rapid identification and quantitative determination of diazepam in beverages. This was achieved utilising a previously unreported oxidation peak. The origin of this peak was investigated further by cyclic voltammetry and gas chromatography/mass spectroscopy. At pH 6 the voltammetric behaviour of this oxidation process was found to involve adsorption of the drug allowing for the development of an adsorptive stripping voltammetric assay. Experimental conditions were then optimised for the determination of diazepam in a beverage sample using a medium exchange technique. It was shown that no elaborate extraction procedures were required as the calibration plots obtained in the absence and presence of the beverage were very similar. PMID- 24148408 TI - Discovered triethylamine as impurity in synthetic DNAs for and by electrochemiluminescence techniques. AB - The purity of the synthetic oligonucleotides is very important because it is crucial for the accuracy of the established biological assays. Herein, it was discovered that one impurity in synthetic DNAs might affect the experiment results of electrochemiluminescence (ECL) detection techniques, which was never reported before. According to a series of experiments using ECL detection methods combined with capillary electrophoresis (CE) (CE-ECL), the impurity was identified as triethylamine (TEA), which came from incomplete removal after HPLC purification of synthetic DNAs. Moreover, CE-ECL technique was for the first time to be proposed for discovering, identifying and sensitive determining the possible impurity such as TEA in various DNA samples, which was usually neglected by other detection techniques for purification quality control of synthetic oligonucleotides. A detection range from 5.00*10(-10) to 2.00*10(-5) M with a detection limit as low as 50 nM (S/N=3) was reached for TEA. Through further designed ECL methods and data analysis, situations which would be really affected by the impurity of TEA were studied. To avoid or eliminate the impact of the TEA impurity on ECL applications, judgment basis for choosing purification ways was discussed according to individual requirements. PMID- 24148409 TI - Application of Kohonen neural network for evaluation of the contamination of Brazilian breast milk with polychlorinated biphenyls. AB - Due to the tendency of polychlorinated biphenyls (PCB) to accumulate in matrixes with high lipid content, the contamination of the breast milk with these compounds is a serious issue, mainly to the newborn. In this study, milk samples were collected from breastfeeding mothers belonging to 4 Brazilian regions (south, southeast, northeast and north). Twelve PCB were analyzed by HS-SPME-GC ECD and the corresponding peak areas were correlated to the answers to a questionnaire of general habits, breastfeeding and characteristics of the living places. To realize this exploratory analyze, self-organizing maps generated applying Kohonen neural network were applied. It was possible to verify the occurrence of different PCB congeners in the breast milk relating to the region of the Brazil that the breastfeeding lives, the proximity to an industry, the proximity to a contaminated river or sea, the type of milk (colostrum, foremilk and hindmilk) and the number of past pregnancies. PMID- 24148410 TI - Synthesis, characterization and application of a novel ion-imprinted polymer for selective solid phase extraction of copper(II) ions from high salt matrices prior to its determination by FAAS. AB - A new Cu(II)-imprinted sorbent has been prepared by using 5-methyl-2 thiozylmethacrylamide (MTMAAm). The monomer of Cu(II)-MTMAAm complex was synthesized and copolymerized in the presence of ethyleneglycol dimethacrylate cross-linker via bulk polymerization method. The resulting Cu(II)-imprinted polymer was characterized by FT-IR spectroscopy and scanning electron microscopy (SEM). Copper ions were removed from the polymer with 1.0 mol L(-1) HNO3 and determined by flame atomic absorption spectrometry (FAAS). The imprinted polymer showed higher selectivity for Cu(II) in comparison to the non-imprinted polymer. Relative selectivity coefficients (k') for Cu(II)/Zn(II), Cu(II)/Ni(II) and Cu(II)/Co(II) were 9.1, 14.8 and 26.6, respectively. The imprinted polymer was examined as a column packing material for solid phase extraction of Cu(II) from various matrices. The effects of solution pH, acid eluents and interfering ions were investigated. The poylmer possesses selective extraction of Cu(II) within pH range from 5.0 to 6.5. The relative standard deviation and limit of detection (3s) of the method were evaluated as 1.4% and 0.9 ug L(-1), respectively. The accuracy of the method was verified by analysis of two certified reference materials (CWW-TM-D and SRM 3280) and then applied to the determination of Cu in seawater, lake water and tap water samples, and hemodialysis concentrates and multivitamin/multielement supplements. PMID- 24148411 TI - Long-tail probe-mediated cycled strand displacement amplification: label-free, isothermal and sensitive detection of nucleic acids. AB - We design a long-tail shaped DNA probe for the label-free, isothermal and sensitive detection of nucleic acids based on cycled strand displacement amplification (Ltail-CSDA). The long-tail probe, a stem-loop structure with a long poly(T) tail at 5'-termini, integrates target-binding and amplification and signaling within one multifunctional design. The specific binding between the long-tail probe and the target triggers a polymerization reaction, during which a long dsDNA product is synthesized and the hybridized target is displaced by the strand displacement activity of polymerase. The displaced target forms another specific probe-target binding and prompts cycled polymerization reactions. The proposed Ltail-CSDA has the distinct advantages of its isothermal nature, free label, simplicity and attomolar sensitivity compared with other existing technologies. More significantly, the dynamic range of the method is extremely large, covering nine orders of magnitude. Using total RNA samples extracted from hepatitis C virus (HCV) as targets, we further demonstrate the detection capability of the method for complex nucleic acid samples, indicating its potential applicability for clinic molecular diagnostic assays. PMID- 24148412 TI - Highly sensitive determination of nitric oxide in biologic samples by a near infrared BODIPY-based fluorescent probe coupled with high-performance liquid chromatography. AB - Nitric oxide (NO) acts as an important regulator and mediator in numerous processes of biological systems. In this work, the analytical potential of a novel near-infrared (NIR, >600 nm) BODIPY-based fluorescent probe for NO, 8-(3,4 diaminophenyl)-4,4-difluoro-4-bora-3a,4a-diaza-di(1,2-dihydro) naphtho[b, g]s indacene (DANPBO-H) has been evaluated in high performance liquid chromatography (HPLC). In 25 mM pH 6.50 borate buffer, DANPBO-H reacted with NO to give the corresponding triazole, DANPBO-H-T, at 35 degrees C for 20 min. DANPBO-H-T was eluted using a mobile phase of methanol/tetrahydrofuran/50mM pH 7.00 H3Cit-NaOH buffer (81:7:12, v/v/v) in 4 min on a C8 column and detected with fluorescence detection at excitation and emission wavelengths of 621 and 631 nm, respectively. The limit of detection (LOD) (signal-to-noise=3) reached to 5.50*10(-10) M. Excellent selectivity was observed against other reactive oxygen/nitrogen species. Various representative biological matrixes including the whole blood and organs of mice, the pangen and radical of rice, human vascular endothelial (ECV 304) cells and mouse macrophage (RAW 264.7) cells were used to verify the feasibility and resistance to interfering effects from complex biological sample matrixes of the developed DANPBO-H-based HPLC method. Compared to the existing derivatization-based HPLC methods for NO, the proposed method eliminates interfering effects from complex biological sample matrixes efficiently owing to the fluorescence detection in the NIR region, and is more advantageous and robust for the sensitive and selective determination of NO in complex biological samples. PMID- 24148413 TI - Determination of okadaic acid in shellfish by using a novel chemiluminescent enzyme-linked immunosorbent assay method. AB - A direct competitive chemiluminescent enzyme-linked immunosorbent assay (CL ELISA) was developed to determine okadaic acid (OA). Concentrations of the capture monoclonal anti-OA antibodies, conjugate of OA-HRP and a composition of blocking buffers were varied to optimize the assay condition. The values of IC10, IC50 and working range (IC20-IC80) for CL-ELISA were 0.01, 0.07, and 0.03-0.2 ng/mL, respectively. Additionally, the analytical recovery values of CL-ELISA from 3 shellfish spiked samples with OA concentrations of 0.03, 0.1 and 0.2 ng/mL ranged from 86.7% to 111.2%. Closely examining the OA concentrations in 19 various shellfish products performed by CL-ELISA revealed that OA concentrations in 6 of the 19 examined samples was undetected, whereas the 13 samples were contaminated with low levels of OA ranging from 1.2 to 8.0 ng/g. PMID- 24148414 TI - Quantitative determination of butylated hydroxyanisole and n-propyl gallate in cosmetics using three-dimensional fluorescence coupled with second-order calibration. AB - This work presents a novel approach for simultaneous determination of butylated hydroxyanisole (BHA) and propyl gallate (PG) in a very interfering environment by combining the sensitivity of molecular fluorescence and the selectivity of the second-order calibration method. The excitation-emission fluorescence matrix data are processed by applying the second-order calibration method based on the self weighted alternating normalized residue fitting (SWANRF) algorithm. The limits of detection (LOD) were 1.2-1.3 ng/ml for BHA and 2.2-2.9 ng/ml for PG. The recoveries from spiked cosmetics samples are in the ranges 95.7-103.9% for BHA and 95.9-105.7% for PG. The proposed method avoids preconcentration and elution procedures, so it considerably decreases the analytical time and the experimental expenses. Because the instrument involved in the measurement is nonsophisticated, the experiments could be carried out in routine laboratories. Then it is compared with the HPLC method in dosage of cosmetics and organic reagents, runtime, cost per analysis and LOD. PMID- 24148415 TI - Development and application of a ruthenium(II) complex-based photoluminescent and electrochemiluminescent dual-signaling probe for nitric oxide. AB - A ruthenium(II) complex, [Ru(bpy)2(DA-phen)](PF6)2 (bpy: 2,2'-bipyridine; DA phen: 5,6-diamino-1,10-phenanthroline), has been developed as a photoluminescent (PL) and electrochemiluminescent (ECL) dual-signaling probe for the highly sensitive and selective detection of nitric oxide (NO) in aqueous and biological samples. Due to the presence of electron transfer process from diamino group to the excited-state of the Ru(II) complex, the PL and ECL intensities of the probe are very weak. After the probe was reacted with NO in physiological pH aqueous media under aerobic conditions to afford its triazole derivative, [Ru(bpy)2(TA phen)](2+) (TA-phen: 5,6-triazole-1,10-phenanthroline), the electron transfer process was inhibited, so that the PL and ECL efficiency of the Ru(II) complex was remarkably increased. The PL and ECL responses of the probe to NO in physiological pH media are highly sensitive with the detection limits at low micromolar concentration level, and highly specific without the interferences of other reactive oxygen/nitrogen species (ROS/RNS) and metal ions. Moreover, the probe has good cell-membrane permeability, and can be rapidly transferred into living cells for trapping the intracellular NO molecules. These features enabled the probe to be successfully used for the monitoring of the endogenous NO production in living biological cell and tissue samples with PL and ECL dual modes. PMID- 24148416 TI - Magnetic solid-phase extraction combined with graphite furnace atomic absorption spectrometry for speciation of Cr(III) and Cr(VI) in environmental waters. AB - A new approach of magnetic solid phase extraction (MSPE) coupled with graphite furnace atomic absorption spectrometry (GFAAS) has been developed for the speciation of Cr(III) and Cr(VI) using zincon-immobilized silica-coated magnetic Fe3O4 nanoparticles (Zincon-Si-MNPs) as the MSPE absorbent. Cr(III) was quantitatively reserved on the absorbent at pH 9.1 while total Cr was reserved at pH 6.5. The absorbed Cr species were eluted by using 2 mol/L HCl and detected by GFAAS. The concentration of Cr(VI) could be calculated by subtracting Cr(III) from total Cr. All the parameters affecting the separation and extraction efficiency of Cr species such as pH, extraction time, concentration and volume of eluent, sample volume and influence of co-existing ions were systematically examined and the optimized conditions were established accordingly. The detection limit (LOD) of the method was 0.016 and 0.011 ng mL(-1) for Cr(III) and Cr(VI), respectively, with the enrichment factor of 100 and 150. The precisions of this method (Relative standard deviation, RSD, n=7) for Cr(III) and Cr(VI) at 0.1 ng mL(-1) were 6.0% and 6.2%, respectively. In order to validate the proposed method, a certified reference material of environmental water was analyzed, and the result of Cr speciation was in good agreement with the certified value. This MSPE-GFAAS method has been successfully applied for the speciation of Cr(III) and Cr(VI) in lake and tap waters with the recoveries of 88-109% for the spiked samples. Moreover, the MSPE separation mechanism of Cr(III) and Cr(VI) based on their adsorption-desorption on Zincon-Si-MNPs has been explained through various spectroscopic characterization. PMID- 24148417 TI - A structure-differential binding method for elucidating the interactions between flavonoids and cytochrome-c by ESI-MS and molecular docking. AB - The study of noncovalent interactions between pharmaceutical molecules and proteins is essential for understanding molecular mechanisms of protein function, and provides foundations for de novo therapeutic agent design. Electrospray ionization mass spectrometry (ESI-MS) has nowadays become a popular tool for analyzing the noncovalent protein complexes, however it usually has difficulty in determining the interaction sites and binding mechanisms. In this work, a new structure-differential binding (SDB) method, combined with ESI-MS and molecular docking (MD) techniques (SDB-ESIMS-MD), was developed and applied to a study of the binding interactions in noncovalent protein-small drug molecule complexes for the characterization of binding sites and binding modes. Using this developed method, protein complexes of flavonoid and flavonoid glycoside ligands and cytochrome-c (Cyt-c) were studied in detail. ESI-MS was used to determine the relative binding affinities and dissociation constants of flavonoid-Cyt-c complexes, and to measure the changes in the stability of the protein complexes with the structural modifications of the ligands for identifying effective binding functional groups. Molecular docking simulations complemented ESI-MS experiments by providing the protein-ligand interaction profile of each complex and displaying the binding mode for each interaction. This SDB-ESIMS-MD method can be applied to a broad range of protein-drug interactions and used to guide further research in the study of structure-binding relationship between drug molecules and targeted biomacromolecules. PMID- 24148418 TI - Dispersive liquid-liquid microextraction for the determination of three cytokinin compounds in fruits and vegetables by liquid chromatography with time-of-flight mass spectrometry. AB - The paper presents a novel approach for the determination of three cytokinin compounds, thidiazuron (TDZ), 1,3-diphenylurea (1,3-DPU) and forchlorfenuron (CPPU), in fruit and vegetables samples using liquid chromatography with electrospray ionization and time-of-flight mass spectrometry (LC-ESI-TOFMS). Analytes were extracted from the sample matrix with ethanol, and the extract, after dilution with water, was submitted to dispersive liquid-liquid microextraction (DLLME). Once acetonitrile and 1,2-dichloroethane had been selected as extraction and disperser solvents, respectively, the influence of the following experimental parameters was studied using a Plackett-Burman design: volume of extraction and disperser solvents, sample mass and time and speed of centrifugation. The best analytical conditions were 250 uL 1,2-dichloroethane, 1.5 mL acetonitrile, 5 g sample mass, and centrifugation at 3000 rpm for 3 min. The optimized method provided DLs in the range 0.02-0.05 ng g(-1), depending on the compound. Satisfactory recovery values between 89 and 106% were obtained for spiked samples (kiwifruit, watermelon, grape and tomato) in the 0.2-1.0 ng g(-1) concentration range, depending on the compound. None of the target analytes was detected in any of the samples analyzed. PMID- 24148419 TI - A high performance microfluidic analyser for phosphate measurements in marine waters using the vanadomolybdate method. AB - We report a high performance autonomous analytical system based on the vanadomolybdate method for the determination of soluble reactive phosphorus in seawater. The system combines a microfluidic chip manufactured from tinted poly (methyl methacrylate) (PMMA), a custom made syringe pump, embedded control electronics and on-board calibration standards. This "lab-on-a-chip" analytical system was successfully deployed and cross-compared with reference analytical methods in coastal (south west England) and open ocean waters (tropical North Atlantic). The results of the miniaturized system compared well with a reference bench-operated phosphate auto-analyser and showed no significant differences in the analytical results (student's t-test at 95% confidence level). The optical technology used, comprising of tinted PMMA and polished fluidic channels, has allowed an improvement of two orders of magnitude of the limit of detection (52 nM) compared to currently available portable systems based on this method. The system has a wide linear dynamic range 0.1-60 MUM, and a good precision (13.6% at 0.4 MUM, n=4). The analytical results were corrected for silicate interferences at 0.7 MUM, and the measurement frequency was configurable with a sampling throughput of up to 20 samples per hour. This portable micro-analytical system has a low reagent requirement (340 MUL per sample) and power consumption (756 J per sample), and has allowed accurate high resolution measurements of soluble reactive phosphorus in seawater. PMID- 24148420 TI - Determination of benzophenone-3 and its main metabolites in human serum by dispersive liquid-liquid microextraction followed by liquid chromatography tandem mass spectrometry. AB - A new analytical method for the determination of benzophenone-3 (2-hydroxy-4 methoxybenzophenone), and its main metabolites (2,4-dihydroxybenzophenone and 2,2'-dihydroxy-4-methoxybenzophenone) in human serum is presented. The method is based on dispersive liquid-liquid microextraction (DLLME) as preconcentration and clean-up technique, followed by liquid chromatography tandem mass spectrometry (LC-MS/MS). Acidic hydrolysis and protein precipitation with HCl 6 M (1:1) (100 degrees C, 1 h) were carried out before extraction. The variables involved in the DLLME process were studied. Under the optimized conditions, 70 uL of acetone (disperser solvent) and 30 uL of chloroform (extraction solvent) were mixed and rapidly injected into 800 uL of hydrolyzed serum sample. Sample pH or ionic strength adjustment were not necessary. The method was validated by analyzing spiked human serum samples. No satisfactory recoveries were obtained when aqueous standards or standards prepared in synthetic serum were used, but excellent recoveries were achieved by using matrix-matched calibration standards. Moreover, limits of detection in the low ug L(-1) level and good repeatability were obtained. In order to show the applicability of the proposed method in the study of percutaneous absorption processes, it was applied to the analysis of serum samples from two volunteers after topical application of a sunscreen cosmetic product containing 2-hydroxy-4-methoxybenzophenone. PMID- 24148421 TI - Preparation and application of surface molecularly imprinted silica gel for selective extraction of melamine from milk samples. AB - Highly selective molecularly imprinted layer-coated silica gel (MIP@SiO2) for melamine (MEL) was prepared by the surface molecular imprinting technique on the supporter of silica gel. Non-imprinted polymer layer-coated silica gel (NIP@SiO2) and bulk molecularly imprinted polymer (MIP) were also prepared for comparison. Characterization and performance tests of the obtained products revealed that MIP@SiO2 not only had excellent selectivity to the target molecule MEL compared with NIP@SiO2, but also displayed absorption capacity superior to MIP due to the molecular recognition sites on the surface of silica gel. As the MIP@SiO2 were adopted as the adsorbents of solid-phase extraction for detecting MEL in milk samples, the recoveries of spiked samples ranged from 75.6% to 96.8% with the relative standard deviation of spiked samples less than 10%, which reveals that the MIP@SiO2 were efficient SPE adsorbents for melamine. PMID- 24148422 TI - Role of Triton X-100 in chemiluminescent enzyme immunoassays capable of diagnosing genetic disorders. AB - The use of Triton X surfactants in developing 1,1'-oxalylimidazole chemiluminescent enzyme immunoassays (ODI CEIs) with extended linear response range for the quantification of unconjugated estriol (uE3), alpha-fetoprotein (AFP), and human chorionic gonadotropin (hCG) is reported for the first time. The wider linear dynamic range in ODI CLEIA results from Triton X series (e.g., Triton X-100, -114, -405, -705) acting as an inhibitor in the interaction between Amplex Red (hydrophobic substrate) and horseradish peroxidase (hydrophilic enzyme) to produce resorufin (hydrophobic fluorescent dye). Triton X-100 acts as the appropriate inhibitor in ODI CLEIA. The maximum concentrations of AFP and hCG quantified with sandwich ODI CLEIA in the presence of Triton X-100 were 8 times higher than when analyzed with the same system in the absence of Triton X-100. In addition, the lowest concentration of uE3 determined using competitive ODI CLEIA in the presence of Triton X-100 was 20 times lower than that measured with competitive ODI CLEIA in the absence of Triton X-100. These results indicate that rapid quantification of AFP, uE3, and hCG using cost effective and highly sensitive ODI CLEIAs in the presence of Triton X-100 can be applied as an accurate, precise, and reproducible method to diagnose genetic disorders (e.g., trisomy 18 and trisomy 21) in fetuses. PMID- 24148423 TI - Extraction of proteins with ionic liquid aqueous two-phase system based on guanidine ionic liquid. AB - Eight kinds of green ionic liquids were synthesized, and an ionic liquid aqueous two-phase system (ILATPS) based on 1,1,3,3-tetramethylguandine acrylate (TMGA) guanidine ionic liquid was first time studied for the extraction of proteins. Single factor experiments proved that the extraction efficiency of bovine serum albumin (BSA) was influenced by the mass of IL, K2HPO4 and BSA, also related to the separation time and temperature. The optimum conditions were determined through orthogonal experiment by the five factors described above. The results showed that under the optimum conditions, the extraction efficiency could reach up to 99.6243%. The relative standard deviations (RSD) of extraction efficiencies in precision experiment, repeatability experiment and stability experiment were 0.8156% (n=5), 1.6173% (n=5) and 1.6292% (n=5), respectively. UV-vis and FT-IR spectra confirmed that there were no chemical interactions between BSA and ionic liquid in the extraction process, and the conformation of the protein was not changed after extraction. The conductivity, DLS and TEM were combined to investigate the microstructure of the top phase and the possible mechanism for the extraction. The results showed that hydrophobic interaction, hydrogen bonding interaction and the salt out effect played important roles in the transferring process, and the aggregation and embrace phenomenon was the main driving force for the separation. All these results proved that guanidine ionic liquid-based ATPSs have the potential to offer new possibility in the extraction of proteins. PMID- 24148424 TI - An efficient GC-IDMS method for determination of PBDEs and PBB in plastic materials. AB - In this study, a fast, inexpensive, simple and reliable analytical method, involving pressurized solvent extraction (PSE) system and gas chromatography, coupled to an ion trap tandem mass spectrometry (GC-ITMS-MS), has been developed. It was validated for determination of 2,2',4,4'-tetrabromodiphenyl (BDE-47), 2,2',3,4,4',5',6-heptabromodiphenyl (BDE-183), 2,2',3,3',4,4',5,5',6 nonabromodiphenyl (BDE-206) and decabromodiphenyl (BDE-209) ethers and decabromobiphenyl (BB-209) in polypropylene (PP), polyethylene (PE) and acrylonitrile butadiene styrene (ABS) polymeric matrix. Certified reference materials (CRM) were used to assess the trueness of the method. Quantification of the analytes was performed by a primary method, i.e. isotope dilution mass spectrometry (IDMS). An important advantage of the method is speed. While the analysis of a single sample could take one and half hours, analyses of six samples take 5h. This is due to the automated PSE system, which allows extraction of six samples simultaneously. Automated system increases the repeatability and reduces analyst dedication and human error input. Recoveries between 79.6% and 93.7% were obtained. GC/ITMS-MS presented high selectivity by eliminating matrix effect so that the LOD values of 0.079-0.493 mg/kg in polymeric matrix were obtained. The method was applied to various selected electrical and electronic products. Sum of the mass fractions of PBDE and PBB analytes in the materials was determined to be under 1000 mg/kg, which is the limit defined by directives. PMID- 24148425 TI - Development of a new chemically modified carbon paste electrode for selective determination of urinary and serum oxalate concentration. AB - The construction and evaluation of a novel modified carbon paste electrode with high selectivity toward oxalate ion are described. The constructed carbon paste potentiometric sensor for oxalate ion is based on the use of a zirconium salan complex as a good ionophore in the carbon paste matrix. The electrode exhibits a Nernstian slope of 29.1 mV/decade to oxalate ion over a wide concentration range from 1.5*10(-6) to 3.9 *10(-2) mol L(-1) with a low detection limit of 7.0*10(-7) mol L(-1). The electrode possesses fast response time, satisfactory reproducibility, appropriate lifetime, and most importantly, good selectivity toward C2O4(2-) relative to a variety of common anions. The potentiometric response of the electrode is independent of the pH of the test solution in the pH range 2.5-8.0. The modified carbon paste electrode was successfully applied as an indicator electrode in potentiometric titration and potentiometric determination of oxalate ion in mineral water, blood serum and urine samples. PMID- 24148426 TI - Two birds with one stone: multifunctional and highly selective fluorescent probe for distinguishing Zn2+ from Cd2+ and selective recognition of sulfide anion. AB - A coumarin-based multifunctional fluorescent sensor containing a di-2 picolylamine (DPA) moiety (1) was presented. Interestingly, this probe could similarly act as ON-OFF type fluorescent sensor for Co(2+) and Cu(2+), then in situ generated 1-Co(II) and 1-Cu(II) ensembles could further serve as OFF-ON type fluorescent sensors to achieve the discrimination of Zn(2+) from Cd(2+) and selective recognition of sulfide anion in aqueous solution via displacement approach, respectively. Specially, 1-Cu(II) could permeate the cell membrane and could be used in fluorescence imaging of S(2-) in living biological samples. These ON-OFF-ON type fluorescent sensors exhibited high selectivity and sensitivity towards the targets. PMID- 24148427 TI - In situ investigation of the depuration of fluoranthene adsorbed on the leaf surfaces of living mangrove seedlings. AB - A novel approach for the in situ determination of fluoranthene (Fla) that was adsorbed onto the leaf surfaces of Avicennia marina (Am), Kandelia obovata (Ko), Bruguiera gymnorrhiza (Bg), and Aegiceras corniculatum (Ac) was established using laser-induced nanosecond time-resolved fluorescence (LITRF). The detection limits for the in situ determination of the Fla adsorbed onto the Am, Ko, Bg and Ac leaf surfaces were 0.03, 0.14, 0.16 and 0.31 ng spot(-1), respectively. Using the LITRF method, the depuration of the adsorbed Fla from the leaf surfaces of the four selected mangrove species was investigated in situ. The results showed that the method was very simple and rapid to perform and it was applicable for a real time in situ survey of the depuration processes of PAHs that were adsorbed onto the mangrove leaves. The depuration of Fla that was adsorbed onto the Am, Ko, Bg and Ac leaf surfaces followed fast and slow phases, both of which varied significantly between the mangrove species in terms of the elimination rate, the remaining Fla residues, and the effect of temperature on the remaining Fla residues on the leaf surfaces. Variations in leaf wax content and the leaf surface roughness among the four mangrove species were responsible for the differences in the rapid phase, while photolysis and penetration into the inner cuticle were dominant mechanisms for the slow depuration. PMID- 24148428 TI - Enantioselective extraction of (+)-(S)-citalopram and its main metabolites using a tailor-made stir bar chiral imprinted polymer for their LC-ESI-MS/MS quantitation in urine samples. AB - This paper reports the application of a chiral imprinted polymer (CIP)-coated stir bar for the selective extraction of (+)-(S)-citalopram (SCIT) and its main metabolites, (+)-(S)-desmethylcitalopram (SDCIT) and (+)-(S) didesmethylcitalopram (SDDCIT), from urine samples. The developed device has been demonstrated to be capable of selectively extracting the three target analytes from urine samples without saturating the imprinted sites. A CIP-coated stir bar sorptive extraction procedure (CIP-SBSE) is proposed for the isolation of SCIT, SDCIT and SDDCIT followed by their subsequent analysis using liquid chromatography ion trap mass spectrometry (LC-ITMS). Deuterated SCIT-d6 was used as an internal standard. The method was validated using a standard procedure, which revealed that a quantification of 5 ng mL(-1) was obtained in urine samples and that the accuracy and precision were within the established values while no matrix effect was observed. PMID- 24148429 TI - Solvent-assisted dispersive solid phase extraction. AB - In this research, a novel extraction technique termed solvent-assisted dispersive solid phase extraction (SADSPE) was developed for the first time. The new method was based on the dispersion of the sorbent into the sample to maximize the contact surface. In this method, the dispersion of the sorbent at a very low milligram level was achieved by injecting a solution of the sorbent into the aqueous sample. Thereby, a cloudy solution formed. The cloudy state resulted from the dispersion of the fine particles of the sorbent in the bulk aqueous sample. After extraction, phase separation was performed by centrifugation and the enriched analyte in the sedimented phase could be determined by instrumental methods. The performance of SADSPE was illustrated with the determination of the trace amounts of cobalt(II) as a test analyte in food and environmental water samples by using flame atomic absorption spectrometry detection. Some key parameters for SADSPE, such as sorbent selection and amount, type and volume of dispersive solvent, pH, chelating agent concentration, and salt concentration, were investigated. Under the most favorable conditions, good limit of detection (as low as 0.2 ug L(-1)) and repeatability of extraction (RSD below 2.2%, n=10) was obtained. The accuracy of the method was tested with standard reference material (SRM-1643e and SRM-1640a) and spiked addition. The advantages of SADSPE method are simplicity of operation, rapidity, low cost, high recovery, and enrichment factor. PMID- 24148430 TI - Novel metal ion-mediated complex imprinted membrane for selective recognition and direct determination of naproxen in pharmaceuticals by solid surface fluorescence. AB - A novel metal ion-mediated complex imprinted membrane (CIM) was prepared by immobilization of complex imprinted polymer (CIP) onto a polypropylene membrane. CIP was introduced as a novel imprinted material using a "complex template" constructed with Cu (II) ion and naproxen that could improve the selective recognition and enrichment properties of the membrane in water medium based on the coordination interaction rather than hydrogen bonding interactions, which could make CIP a promising material to mimic biological recognition process. A simple, sensitive and selective solid surface fluorescence method was proposed for the determination of naproxen in pharmaceuticals sample, using the CIM as the recognition material. Under the optimum conditions, the CIM exhibited large adsorption capacity and high selectivity to naproxen. A good linearity was obtained in the range of 0.50-20 mg/L with an estimated detection limit of 0.11 mg/L. Finally, the proposed method was applied to the analysis of naproxen in pharmaceuticals without complicated pretreatment. The recoveries were 85.0% and 89.1% and the RSDs were 9.2% and 12.0%. The results were consistent with that obtained by high performance liquid chromatography. CIM integrated extraction, concentration, and detection into one-step, which could make the analytical procedure more efficient. PMID- 24148431 TI - Label-free fluorescent detection of thrombin activity based on a recombinant enhanced green fluorescence protein and nickel ions immobilized nitrilotriacetic acid-coated magnetic nanoparticles. AB - Herein, a novel label-free fluorescent assay has been developed to detect the activity of thrombin and its inhibitor, based on a recombinant enhanced green fluorescence protein (EGFP) and Ni(2+) ions immobilized nitrilotriacetic acid coated magnetic nanoparticles (Ni(2+)-NTA MNPs). The EGFP, containing a thrombin cleavage site and a hexahistidine sequence (His-tag) at its N-terminal, was adsorbed onto Ni(2+)-NTA MNPs through Ni(2+)-hexahistidine interaction, and dragged out of the solution by magnetic separation. Thrombin can selectively digest EGFP accompanied by His-tag peptide sequence leaving, and the resulting EGFP cannot be captured by Ni(2+)-NTA MNPs and kept in supernatant. Hence the fluorescence change of supernatant can clearly represent the activity of thrombin. Under optimized conditions, such assay showed a relatively low detection limit (3.0*10(-4) U mL(-1)), and was also used to detect the thrombin inhibitor, Hirudin, and further applied to detect thrombin activity in serum. Combined with the satisfactory reusability of Ni(2+)-NTA MNPs, our method presents a promising candidate for simple, sensitive, and cost-saving protease activity detecting and inhibitor screening. PMID- 24148432 TI - Trace detection of oxygen--ionic liquids in gas sensor design. AB - This paper presents a novel electrochemical membrane sensor on basis of ionic liquids for trace analysis of oxygen in gaseous atmospheres. The faradaic response currents for the reduction of oxygen which were obtained by multiple potential-step-chronoamperometry could be used for real time detection of oxygen down to concentrations of 30 ppm. The theoretical limit of detection was 5 ppm. The simple, non-expensive sensors varied in electrolyte composition and demonstrated a high sensitivity, a rapid response time and an excellent reproducibility at room temperature. Some of them were continuously used for at least one week and first results promise good long term stability. Voltammetric, impedance and oxygen detection studies at temperatures up to 200 degrees C (in the presence and absence of humidity and CO2) revealed also the limitations of certain ionic liquids for some electrochemical high temperature applications. Application areas of the developed sensors are control and analysis processes of non oxidative and oxygen free atmospheres. PMID- 24148433 TI - Separation and flame atomic absorption spectrometric determination of total chromium and chromium (III) in phosphate rock used for production of fertilizer. AB - Due to the commercial value of phosphate rock (PR) as a fertilizer precursor, it is necessary to investigate its heavy metals content. Chromium (Cr) may present as Cr(III) or Cr(VI) in PR; but quantitative differentiation between them is not an easy task. This is due to possible interconversion of Cr species during the digestion/leaching process. In this work, ultrasound digestion (USD) of PR was optimized (300 mg PR, 4.0 mL of 4.0 mol L(-1) nitric acid, 15 min sonication) for the sake of leaching Cr species prior to their determination by flame atomic absorption spectroscopy. Using multi-walled carbon nanotube (MWCNT) as adsorbent, solid phase extraction (SPE) was used to separate Cr(III) from the digestate at pH 9, while total Cr was estimated after reducing Cr(VI) into Cr(III). The optimum USD/SPE method gave LOQ and LOD of Cr(III) of 0.96 mg kg(-1) and 0.288 mg kg(-1), respectively. The method sensitivity was 1.44*10(-3) AU kg mg(-1) within the studied Cr concentration range (5-400 mg kg(-1)). The USD/SPE method was validated by analyzing lake sediments LKSD-4 certified reference material, and by comparison with classical digestion method (CD). Application of USD/SPE on Jordanian PR samples gave total Cr rang 29.1-122.0 mg kg(-1) (+/-1.4-6.3), while Cr(III) ranged between 23.8 and 101.7 mg kg(-1) (+/-1.3-5.5). AFPC Rock Check Program samples gave total Cr range 238.9-394.7 mg kg(-1) (+/-11.5-24.1), while Cr(III) ranged between 202.4 and 335.8 mg kg(-1) (+/-11.4-18.3). These results were very close to the results obtained by the CD method. PMID- 24148434 TI - Centrifugal microfluidic platform for radiochemistry: potentialities for the chemical analysis of nuclear spent fuels. AB - The use of a centrifugal microfluidic platform is for the first time reported as an alternative to classical chromatographic procedures for radiochemistry. The original design of the microfluidic platform has been thought to fasten and simplify the prototyping process with the use of a circular platform integrating four rectangular microchips made of thermoplastic. The microchips, dedicated to anion-exchange chromatographic separations, integrate a localized monolithic stationary phase as well as injection and collection reservoirs. The results presented here were obtained with a simplified simulated nuclear spent fuel sample composed of non-radioactive isotopes of Europium and Uranium, in proportion usually found for uranium oxide nuclear spent fuel. While keeping the analytical results consistent with the conventional procedure (extraction yield for Europium of ~97%), the use of the centrifugal microfluidic platform allowed to reduce the volume of liquid needed by a factor of ~250. Thanks to their unique "easy-to-use" features, centrifugal microfluidic platforms are potential successful candidates for the downscaling of chromatographic separation of radioactive samples (automation, multiplexing, easy integration in glove-boxes environment and low cost of maintenance). PMID- 24148435 TI - In-situ calibration of POCIS for the sampling of polar pesticides and metabolites in surface water. AB - Over the past years, passive sampling devices have been successfully used for the monitoring of various pollutants in water. The present work studied the uptake kinetics in surface water of ten polar pesticides and metabolites, using pharmaceutical POCIS samplers. The aim was to determine sampling rates from in situ calibration and to compare results with those obtained earlier under laboratory conditions, with the final objective of assessing the impact of environmental conditions on POCIS field performance. Field results showed a low efficiency of POCIS uptake capacity for moderately polar compounds, such as propiconazole (log Kow=3.72) and tebuconazole (log Kow=3.7), that were present in the aqueous phase at very low levels. The in-situ sampling rates obtained in this study ranged from 169 to 479 mL g(-1)day(-1) and differ by a factor of 3-7.5 from Rs determined under laboratory conditions. PMID- 24148436 TI - A sensitive, universal and homogeneous method for determination of biomarkers in biofluids by resonance light scattering correlation spectroscopy (RLSCS). AB - In this paper, we reported a sensitive, universal and homogeneous method for assay of biomarkers by combining resonance light scattering correlation spectroscopy (RLSCS) with silver nanoparticles (SNPs) as labeling probes. In the homogeneous assay, the competitive immunoreaction mode was used, and antibody and antigen (or hapten) were labeled with SNPs with strong plasmonic scattering property, respectively. The antibody-labeled SNPs were firstly mixed with a sample containing antigens, and the part of antibody-labeled SNPs was bound to antigens of interest in the sample. And then, the antigen-labeled SNPs were added into the mixed solution above, and they were bound to free antibody-labeled SNPs (excess) to form dimers (or oligomers), which led to the significant increase in the characteristic diffusion time of SNPs in the tiny detection volume (about 0.5 fL). In the competitive mode, the characteristic diffusion time of SNPs decreased with an increase of antigen concentration. The RLSCS is a novel single particle method and can sensitively detect the changes in the characteristic diffusion time of SNPs before and after the immunoreactions. In order to demonstrate the universality of this new method, small biomolecules, 17-beta estradiol (E2), and biomacromolecules, liver cancer antigen alpha-fetoprotein (AFP), were used as assay models. In the optimal conditions, the linear ranges of this method were from 10 pM to 10 nM for E2 and 100 pM to 10 nM for AFP, respectively, and the detection limits were 10 pM for E2 and 100 pM for AFP, respectively. The presented method was successfully used to the determination of E2 levels in human urine and AFP levels in human sera, and the results obtained were in good agreement with conventional ELISA assays. PMID- 24148437 TI - Fluorescent probes that distinguish proteins with single or two close mercapto groups. AB - Two water soluble fluorescent probes with quaternary ammonium salts as solubilization groups were designed and synthesized to detect proteins with close mercapto groups. The unique structure of V-shape oligo(o-phenylene-ethynylene) backbone connecting two maleimide groups as mercapto group recognition sites enables the probes to distinguish a single mercapto group from two close mercapto groups in proteins. The probe had no fluorescence response to proteins with only one mercapto group, but had strong fluorescence response to proteins with mercapto group combination at the concentration of 10(-6) mol/L. The probe worked under a wide range of pH, from 4 to 8. This work also demonstrates the concept of functional group combination detection. PMID- 24148438 TI - Integrated miniature fluorescent probe to leverage the sensing potential of ZnO quantum dots for the detection of copper (II) ions. AB - Quantum dots are fluorescent semiconductor nanoparticles that can be utilised for sensing applications. This paper evaluates the ability to leverage their analytical potential using an integrated fluorescent sensing probe that is portable, cost effective and simple to handle. ZnO quantum dots were prepared using the simple sol-gel hydrolysis method at ambient conditions and found to be significantly and specifically quenched by copper (II) ions. This ZnO quantum dots system has been incorporated into an in-house developed miniature fluorescent probe for the detection of copper (II) ions in aqueous medium. The probe was developed using a low power handheld black light as excitation source and three photo-detectors as sensor. The sensing chamber placed between the light source and detectors was made of 4-sided clear quartz windows. The chamber was housed within a dark compartment to avoid stray light interference. The probe was operated using a microcontroller (Arduino Uno Revision 3) that has been programmed with the analytical response and the working algorithm of the electronics. The probe was sourced with a 12 V rechargeable battery pack and the analytical readouts were given directly using a LCD display panel. Analytical optimisations of the ZnO quantum dots system and the probe have been performed and further described. The probe was found to have a linear response range up to 0.45 mM (R(2)=0.9930) towards copper (II) ion with a limit of detection of 7.68*10(-7) M. The probe has high repeatable and reliable performance. PMID- 24148439 TI - Rapid high-throughput analysis of ochratoxin A by the self-assembly of DNAzyme aptamer conjugates in wine. AB - We report a new label-free colorimetric aptasensor based on DNAzyme-aptamer conjugate for rapid and high-throughput detection of Ochratoxin A (OTA, a possible human carcinogen, group 2B) in wine. Two oligonucleotides were designed for this detection. One is N1 for biorecognition, which includes two adjacent sequences: the OTA-specific aptamer sequence and the horseradish peroxidase (HRP) mimicking DNAzyme sequence. The other is a blocking DNA (B2), which is partially complementary to a part of the OTA aptamer and partially complementary to a part of the DNAzyme. The existence of OTA reduces the hybridization between N1 and B2. Thus, the activity of the non-hybridized DNAzyme is linearly correlated with the concentration of OTA up to 30 nM with a limit of detection of 4 nM (3sigma). Meanwhile, a double liquid-liquid extraction (LLE) method is accordingly developed to purify OTA from wine. Compared with the existing HPLC-FD or immunoassay methods, the proposed strategy presents the most appropriate balance between accuracy and facility, resulting in a considerable improvement of real time quality control, and thereby, preventing chronic poisoning caused by OTA contained red wine. PMID- 24148440 TI - Flow-based ammonia gas analyzer with an open channel scrubber for indoor environments. AB - A robust and fully automated indoor ammonia gas monitoring system with an open channel scrubber (OCS) was developed. The sample gas channel dimensions, hydrophilic surface treatment to produce a thin absorbing solution layer, and solution flow rate of the OCS were optimized to connect the OCS as in-line gas collector and avoid sample humidity effects. The OCS effluent containing absorbed ammonia in sample gas was injected into a derivatization solution flow. Derivatization was achieved with o-phthalaldehyde and sulfite in pH 11 buffer solution. The product, 1-sulfonateisoindole, is detected with a home-made fluorescence detector. The limit of detection of the analyzer based on three times the standard deviation of baseline noise was 0.9 ppbv. Sample gas could be analyzed 40 times per hour. Furthermore, relative humidity of up to 90% did not interfere considerably with the analyzer. Interference from amines was not observed. The developed gas analysis system was calibrated using a solution-based method. The system was used to analyze ammonia in an indoor environment along with an off-site method, traditional impinger gas collection followed by ion chromatographic analysis, for comparison. The results obtained using both methods agreed well. Therefore, the developed system can perform on-site monitoring of ammonia in indoor environments with improved time resolution compared with that of other methods. PMID- 24148441 TI - Multifunctional inorganic-organic hybrid nanospheres for rapid and selective luminescence detection of TNT in mixed nitroaromatics via magnetic separation. AB - Rapid, sensitive and selective detection of 2,4,6-trinitrotoluene (TNT) in aqueous solution differentiating from other nitroaromatics and independent of complicated instruments is in high demand for public safety and environmental monitoring. Despite of many methods for TNT detection, it is hard to differentiate TNT from 2,4,6-trinitrophenol (TNP) due to their highly similar structures and properties. In this work, via a simple and versatile method, LaF3?Ce(3+)-Tb(3+)and Fe3O4 nanoparticle-codoped multifunctional nanospheres were prepared through self-assembly of the building blocks. The luminescence of these nanocomposites was dramatically quenched via adding nitroaromatics into the aqueous solution. After the magnetic separation, however, the interference of other nitroaromatics including 2,4,6-trinitrophenol (TNP), 2,4-dinitrotoluene (DNT), and nitrobenzene (NB) was effectively overcome due to the removal of these coexisting nitroaromatics from the surface of nanocomposites. Due to the formation of TNT(-)-RCONH3(+), the TNT was attached to the surface of the nanocomposites and was quantitatively detected by the postexposure luminescence quenching. Meanwhile, the luminescence intensity is negatively proportional to the concentration of TNT in the range of 0.01-5.0 MUg/mL with the 3sigma limit of detection (LOD) of 10.2 ng/mL. Therefore, the as-developed method provides a novel strategy for rapid and selective detection of TNT in the mixture solution of nitroaromatics by postexposure luminescence quenching. PMID- 24148442 TI - Calculation of cooperativity and equilibrium constants of ligands binding to G quadruplex DNA in solution. AB - Equilibrium model of a ligand binding with DNA oligomer has been considered as a process of small molecule adsorption onto a lattice of multiple binding sites. An experimental example has been used to verify the assertion that during saturation of the macromolecule by a ligand should expect effect of cooperativity due to changes in DNA conformation or the mutual influence between bound ligands. Such phenomenon cannot be entirely described by the classical stepwise complex formation model. To evaluate a ligand binding affinity and cooperativity of ligand-oligomer complex formation the statistical approach has been proposed. This new computational approach used to re-examine previously studded ligand binding towards DNA quadruplexes targets with multiple binding sites. The intrinsic equilibrium constants K1-3 of the mesotetrakis-(N-methyl-4-pyridyl) porphyrin (TMPyP4) binding with the [d(T4G4)]4 and with the [AG3(T2AG3)3] quadruplexes and the correction for the mutual influence between bound ligands (cooperativity parameters omega) was determined from the Job plots based upon the nonlinear least-squares fitting procedure. The re-examination of experimental curves reveals that the equilibrium is affected by the positive cooperative (omega>1) binding of the TMPyP4 ligand with tetramolecular [d(T4G4)]4. However for an intramolecular antiparallel-parallel hybrid structure [AG3(T2AG3)3] the weak anti-cooperativity of TMPyP4 accommodation (omega<1) onto two from three nonidentical sites was detected. PMID- 24148443 TI - Sensitive and selective detection of Ag+ in aqueous solutions using Fe3O4@Au nanoparticles as smart electrochemical nanosensors. AB - Owing to the selective deposition reaction on the surface of magnetic nanoparticles, we reported a simple and selective magnetic electrochemical method for the detection of Ag(+) ions in aqueous solutions. The analyte deposited on the nanoparticles was brought to the surface of a homemade magnetic electrode and detected electrochemically in 0.1 mol/L KCl solution based on the reaction of Ag0 transferred to AgCl. Under the optimal conditions, the linear response range of Ag(+) ions was 0.117-17.7 MUmol/L (R(2)=0.9909) with a detection limit of 59 nmol/L (S/N=3). A series of repeatability measurements 1.0 MUmol/L Ag(+) gave reproducible results with a relative standard deviation (RSD) of 4.5% (n=11). The interference from other metal cations can be eliminated by adding EDTA as a co additive to mask the metal cations. The recoveries ranging from 98.6% to 103.99% after standard additions demonstrate that this sensor has great potential in practical applications. The advantages of this developed method include remarkable simplicity, low cost, and no requirement for probe preparation, among others. PMID- 24148444 TI - Understanding the degradation of electrochemically-generated reactive drug metabolites by quantitative NMR. AB - Phenacetin is known to be metabolized to N-AcetylParaBenzoQuinoneImine (NAPQI), which is a common metabolite of paracetamol (also called acetaminophen or APAP). The electrochemical conversion of APAP to NAPQI was shown in 1989 by Getek and co workers, thus demonstrating the capacity of electrochemistry to mimic the formation of NAPQI from APAP as well as from phenacetin. This study focuses on a preparative electrochemical electrolysis associated with quantitative (1)H NMR. On one hand, this method is able to synthesize reactive metabolites in sufficient concentrations and amounts for NMR analysis. On the other hand, NMR allows the simultaneous detection and quantification of all chemical species, in contrast to mass spectrometry. The combination of electrochemistry with quantitative NMR is thus presented as a relevant method for elucidating the degradation of reactive metabolites and may be considered a valuable complementary tool to EC-MS. PMID- 24148445 TI - Development of a fast capillary electrophoresis-time-of-flight mass spectrometry method for the speciation of organotin compounds under separation conditions of high electrical field strengths. AB - A novel approach has been developed for the separation of organotin species with capillary electrophoresis hyphenated to time-of-flight mass spectrometry. It has been applied to the development of a method for the determination and speciation of organotin compounds namely, dibutyltin (DBT), tributyltin (TBT), diphenyltin (DPT) and triphenyltin (TPT) in water samples. Experiments were made with a special laboratory constructed CE instrument. A non-aqueous buffer system compatible with TOF-MS has been developed using ammonium acetate-acetic acid (50 mM and 1 M) in acetonitrile: methanol (80:20). The total analysis time is less than 3 min for these compounds under the conditions developed. The method has been applied successfully to the determination of these compounds in river water samples. Detection limits of the CE-TOF-MS method were between 1 and 8*10(-7) M, and between 2 and 11*10(-9) M (0.46 to 3.2 ug L(-1)) when used in conjunction with solid phase extraction. The short analysis time as well as good sensitivity and selectivity make it a useful approach for the fast screening of organotin compounds. PMID- 24148446 TI - Naked-eye sensor for rapid determination of mercury ion. AB - A naked-eye paper sensor for rapid determination of trace mercury ion in water samples was designed and demonstrated. The mercury-sensing rhodamine B thiolactone was immobilized in silica matrices and the silica matrices were impregnated firmly and uniformly in the filter paper. As water samples flow through the filter paper, the membrane color will change from white to purple red, which could be observed obviously with naked eye, when concentration of mercury ions equals to or exceeds 10nM, the maximum residue level in drinking water recommended by U.S. EPA. The color change can also be recorded by a flatbed scanner and then digitized, reducing the detection limit of Hg(2+) down to 1.2 nM. Moreover, this method is extremely specific for Hg(2+) and shows a high tolerance ratio of interferent coexisting ions. The presence of Na(+) (2 mM), K(+) (2 mM), Fe(3+) (0.1 mM), Zn(2+) (0.1 mM), Mg(2+) (0.1 mM), Ni(2+) (50 MUM), Co(2+) (50 MUM), Cd(2+) (50 MUM), Pb(2+) (50 MUM), Cu(2+) (50 MUM) and Ag(+) (3.5 MUM) did not interfere with the detection of Hg(2+) (25 nM). Finally, the present method was applied in the detection of Hg(2+) in mineral water, tap water and pond water. PMID- 24148447 TI - Determination of phenylurea pesticides by direct laser photo-induced fluorescence. AB - A direct Laser Photo-Induced Fluorescence (DL-PIF) method is developed for the determination of two phenylurea pesticides, namely fenuron and diflubenzuron. The DL-PIF method uses a tunable Nd:YAG-OPO Laser to obtain the photoproduct(s) and to simultaneously analyse their fluorescence in a short acquisition time on an intensified CCD camera. Compared to classical PIF methods, the use of a tunable laser improves the selectivity (by choosing the suitable excitation wavelength), increases the sensitivity (due to the high energy of the beam) and also reduces the time of analysis. The analytical performances of this method for the determination of both pesticides are satisfactory in comparison to other classical PIF methods published for the determination of phenylurea pesticides. The calibration curves were linear over one order of magnitude and the limits of detection were in the ng mL(-1) range. Satisfactory recoveries were obtained in the analysis of both pesticides in river and sea water spiked samples. PMID- 24148448 TI - Direct separation of faradaic and double layer charging current in potential step voltammetry. AB - Double layer charging current in electrochemical systems has been a challenging problem in the last several decades because it causes interference to the accurate measurement of faradaic current. A method for extracting faradaic current and double layer charging current directly from the measured total current in potential step voltammetry is developed by using iterative target transformation factor analysis (ITTFA). The method constructs initial target vectors based on the theoretical formulae of faradaic and charging current, and then calculates the weights of faradaic and charging current in the measured signal via the iterative transformation of the initial vectors. Therefore, the two currents in one experiment can be obtained simultaneously without any assumption. The potential step voltammetric signals of potassium ferricyanide, copper sulfate and paracetamol were analyzed with the proposed method. The results show that the shape of the obtained voltammogram is an ideal sigmoid curve with horizontal straight baseline and plateaus, and the intensity of the signal is greatly enhanced. Therefore, the method provides a new way to measure the pure faradic current in the potential step voltammetric experiment, and may provide an alternative for improving the sensitivity of quantitative analysis. PMID- 24148449 TI - TCEP-based rSDS-PAGE AND nLC-ESI-LTQ-MS/MS for oxaliplatin metalloproteomic analysis. AB - In this work, the reactivity of the citostatic drugs such as oxaliplatin, cisplatin and carboplatin towards proteins and the stability of Pt-protein complexes along their storage were evaluated. Neither native-PAGE nor nrSDS-PAGE seems to be suitable for the separation of carboplatin-binding proteins. A reducing electrophoretic separation procedure able to maintain the integrity of oxaliplatin-protein complexes has been developed. The method is based on SDS-PAGE under conditions provided by the thiol-free reducing agent tris (2-carboxyethyl) phosphine (TCEP), which allowed the separation of oxaliplatin-binding proteins in narrow bands with almost quantitative recoveries. Different amounts of platinum bound protein bands covering the range 0.3-2.0 MUg were excised and mineralised for platinum determination, showing good linearity. Limits of detection for a mixture of five standard proteins (transferrin, albumin, carbonic anhydrase, myoglobin and cytochrome c) incubated with oxaliplatin were within the range 11.0 44.0 pg of platinum, which were satisfactory for their application to biological samples. The suitability of the TCEP-based SDS-PAGE for the separation of platinum-enriched protein fractions of a kidney cytosol from a rat treated with oxaliplatin was demonstrated. The identification of high Pt to protein ratio cytosolic fractions was carried out by separating the cytosolic platinum-binding proteins by SEC-ICP-MS. Several cytosolic renal proteins were identified in those gel bands containing platinum-enriched protein fractions using nLC-ESI-LTQ-MS/MS after in-gel digested with trypsin. In addition, fractions containing platinum enriched proteins with lower theorical molecular weight were directly analysed by nLC-ESI-LTQ-MS/MS after in-solution tryptic digestion allowing protein identification. PMID- 24148450 TI - Simultaneous quantification of antimicrobial agents for multidrug-resistant bacterial infections in human plasma by ultra-high-pressure liquid chromatography tandem mass spectrometry. AB - Antibiotic-resistant bacterial infection is one of the most serious clinical problems worldwide. Vancomycin, teicoplanin, daptomycin, and colistin are glycopeptide and lipopeptide antibiotics that are frequently used to treat multidrug-resistant bacterial infections. Therapeutic drug monitoring is recommended to ensure both safety and efficacy and to improve clinical outcomes. This study developed a fast, simple, and sensitive ultra-high-pressure liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS) method for the simultaneous determination of the concentrations of these four drugs in human plasma. The sample preparation process includes a simple protein denaturation step using acetonitrile, followed by an 11-fold dilution with 0.1% formic acid. Eight target peaks for the four drugs can be analyzed within 3 min using a KinetexTM 2.6 MUm C18 column. The mass spectrometry parameters were optimized, and two transitions for each target peak were used for multiple reaction monitoring, which provided high sensitivity and specificity. The UHPLC-MS/MS method was validated over clinical concentration ranges. The intra-day and inter-day precisions for the ratio of the peak area of each analyte to the peak area of the internal standard were all below 12.7 and 14.7% relative standard deviations, respectively. The accuracy at low, medium, and high concentrations of the eight target peaks was between 89.3 and 110.7%. The standard curves for the analytes were linear and had coefficients of determination higher than 0.997. The limits of detection were all below 70 ng mL(-1). The use of this method to analyze patient plasma samples confirmed that it is effective for the therapeutic drug monitoring of these four drugs and can be used to improve the therapeutic efficacy and safety of treatment with antibiotics. PMID- 24148451 TI - Ultratrace determination of arsenic in water samples by electrothermal atomic absorption spectrometry after pre-concentration with Mg-Al-Fe ternary layered double hydroxide nano-sorbent. AB - A selective solid phase extraction method, based on nano-structured Mg-Al-Fe(NO3( )) ternary layered double hydroxide as a sorbent, is developed for the pre concentration of ultra-trace levels of arsenic (As) prior to determination by electrothermal atomic absorption spectrometry. It is found that both As(III) and As(V) could be quantitatively retained on the sorbent within a wide pH range of 4 12. Accordingly, the presented method is applied to determination of total inorganic As in aqueous solutions. Maximum analytical signal of As is achieved when the pyrolysis and atomization temperatures are close to 900 degrees C and 2300 degrees C, respectively. Several variables affecting the extraction efficiency including pH, sample flow rate, amount of nano-sorbent, elution conditions and sample volume are optimized. Under the optimized conditions, the limit of detection (3Sb/m) and the relative standard deviation are 4.6 pg mL(-1) and 3.9%, respectively. The calibration graph is linear in the range of 15.0-650 pg mL(-1) with a correlation coefficient of 0.9979, sorption capacity and pre concentration factor are 8.68 mg g(-1) and 300, respectively. The developed method is validated by the analysis of a standard reference material (SRM 1643e) and is successfully applied to the determination of ultra-trace amounts of As in different water samples. PMID- 24148452 TI - Homogenous detection of fumonisin B(1) with a molecular beacon based on fluorescence resonance energy transfer between NaYF4: Yb, Ho upconversion nanoparticles and gold nanoparticles. AB - In this work, we presented a new aptasensor for fumonisin B1 (FB1) based on fluorescence resonance energy transfer (FRET) between NaYF4: Yb, Ho upconversion fluorescent nanoparticles (UCNPs) and gold nanoparticles (AuNPs). The quenchers (AuNPs) were attached to the 5' end of the molecular beacon (MB), and the donors (UCNPs) were attached to the 3' end of the MB. In the absence of target DNA (DNA complementary to FB1 aptamers), the energy donors and acceptors were placed in close proximity, leading to quenching of the fluorescence of the UCNPs. Due to the combination of FB1 and FB1-specific aptamers, this caused some complementary DNA dissociating from the magnetic nanoparticles (MNPs). In the presence of the complementary DNA, the MBs underwent spontaneous conformational change and caused the UCNPs and AuNPs to detach from each other, resulting in restoration of the upconversion fluorescence. Therefore, the fluorescence of UCNPs was restored in a FB1 concentration-dependent manner, which was the basis of the FB1 quantification. The aptasensors showed a linear relationship from 0.01 to 100 ng mL(-1) for FB1 with a detection limit of 0.01 ng mL(-1) in an aqueous buffer. As a practical application, the aptasensor was used to monitor FB1 levels in naturally contaminated maize samples. The results were consistent with that of a classic ELISA method, indicating that the UCNPs-FRET aptasensor, which benefited from the near infrared excitation of NaYF4: Yb, Ho UCNPs, was effective for directly sensing FB1 in foodstuff samples without optical interference. This work also created the opportunity to develop aptasensors for other targets using this FRET system. PMID- 24148453 TI - Chemiluminescence detection of heroin in illicit drug samples. AB - Heroin (3,6-diacetylmorphine) and several important extraction and synthesis impurities (morphine, 6-monoacetylmorphine, codeine and 6-acetylcodeine) were determined in illicit drug samples, using high performance liquid chromatography with 'parallel segmented flow', which enabled the simultaneous use of three complementary modes of detection (UV-absorbance, tris(2,2' bipyridine)ruthenium(III) chemiluminescence and permanganate chemiluminescence). This rapid and sensitive approach for the analysis of street heroin was used to explore the chemistry of a proposed heroin screening test that is based on the relative response with these two chemiluminescence reagents using flow injection analysis. Although heroin was the major constituent of the six drug samples (between 16% and 67% by mass), the synthetic by-product 6-acetylcodeine (2.5 8.3%) made a greater contribution to the total [Ru(bipy)3](3+) chemiluminescence response of the screening test. The signal with permanganate was primarily due to the presence of 6-monoacetylmorphine (0.9-29%), and was therefore indicative of the degree of sample degradation during clandestine manufacture or poor storage conditions prior to the drug seizure. In the second part of the screening test, the sample is treated with sodium hydroxide, which results in a large increase in the signal with permanganate, due to the rapid hydrolysis of heroin to 6 monoacetylmorphine. As the emission of these two reagents with morphinan alkaloids and their derivatives largely depends on the substituent at the O(3) position, the slower hydrolysis of 6-monoacetylmorphine to morphine, and 6 acetylcodeine to codeine, did not have a major impact on the characteristic pattern of responses in the screening test. PMID- 24148454 TI - Speciation of chromium in soils near Sheba Leather Industry, Wukro Ethiopia. AB - A study on speciation of chromium in soils near Sheba Leather Industry was performed by Flame Atomic Absorption (FAAS) after selective extraction of Cr(VI) using the EPA 3060A method, and oxidizing the Cr(III) residue in the soils with HNO3 and H2O2. The extraction method was evaluated using the spiking method with satisfactory results (recoveries>95% and RSDs<5%). The limit of detection (LOD) for Cr(VI) based on three times the standard deviations of the blank (for n=5) was 0.56 ug g(-1). Statistical evaluation indicated that the comparison of the sum of the concentrations of chromium species to that of the total concentration of chromium do not show any difference at 95% level of confidence. Besides, no statistically significant difference at 95% confidence level was observed between the UV-vis spectrophotometry and FAAS results for Cr(VI). However, it is observed that selective extraction of Cr(VI) using EPA 3060A and subsequent determination by FAAS is simple and faster compared to the other method. Furthermore, for comparison and as control two soil samples collected from a distance of about 2 km from the main Industry and effluent stream. The results indicate that higher total chromium content was observed in soils collected from the target area. Nevertheless, the maximum concentrations of Cr(VI) found in soil samples collected around Sheba Leather Industry was 9.9 ug g(-1) and are within the acceptable level of 10 ug g(-1) in accordance with the WHO. PMID- 24148455 TI - Chemical analysis of post explosion samples obtained as a result of model field experiments. AB - Five different explosives were detonated in a series of field experiments. Each experiment (detonation of the charge of each specific explosive) was repeated three times. The experiments were conducted under controlled conditions, exceeding those of research published so far. Detonated charges were uniform in size and, as far as possible, in shape. The explosives used originated from the same batch. Additionally, the same kind of electric detonators were used. Witness plates (sheets of galvanised steel 100 cm * 90 cm * 0.5 mm) were used to collect post-blast residues in a reproducible way. They were placed relatively close to the charge to minimise the influence of the wind. Samples were collected by systematic swabbing of the surface of the plate by acetone moistened cotton swabs. Samples were packed tight, transferred to the laboratory, and extracted with methanol. Extracts were concentrated by solvent evaporation, cleaned by centrifugation, and analysed using HPLC-DAD. Each extract was analysed three times and the mean value of the amount of the given explosive within the extract was calculated. For each of the explosive materials used the results of the repetition of the experiments proved them to be irreproducible. After each detonation of a specific charge different amounts of given explosives were found in post-blast samples. Also, the intuitively expected relationship between the distance from the charge and amount of post-blast residues were not observed. These results are consistent with previously published results of field experiments. The lack of reproducibility may be explained by differences in efficiency of detonation. The efficiency of a detonation may be influenced even by small differences in the shape of the charge as well as by the position and properties of the detonator. The lack of dependency between the amount of the explosive in the post-blast samples and the distance from the charge may be explained by the fact that during detonation, particles of unreacted explosives are not uniformly dispersed in all directions. PMID- 24148456 TI - Dispersive nano solid material-ultrasound assisted microextraction as a novel method for extraction and determination of bendiocarb and promecarb: response surface methodology. AB - A new extraction method, based on Dispersive Nano-Solid material-Ultrasound Assisted Micro-Extraction (DNSUAME), was used for the preconcentration of the bendiocarb and promecarb pesticides in the water samples prior to high performance liquid chromatography (HPLC). The properties of NiZnS nanomaterial loaded on activated carbon (NiZnS-AC) are characterized by FT-IR, TEM, and BET. This novel nanomaterial showed great adsorptive ability towards the bendiocarb and promecarb pesticides. The effective variables such as the amount of adsorbent (mg: NiZnS-AC), the pH and ionic strength of sample solution, the vortex and ultrasonic time (min), the ultrasonic temperature ( degrees C), and desorption volume (mL) are investigated by screening 2(7-4) experiments of Plackett-Burman (PB) design. The important variables optimized by using a central composite design (CCD) were combined by a desirability function (DF). At optimum conditions, the method has linear response over 0.0033-10 ug mL(-1) with detection limit between 0.0010 and 0.0015 ug mL(-1) with relative standard deviations (RSDs) less than 5.5% (n=3). The method has been successfully applied for the determination of the bendiocarb and promecarb pesticides in the water samples. PMID- 24148457 TI - Acetylcholinesterase immobilized capillary reactors coupled to protein coated magnetic beads: a new tool for plant extract ligand screening. AB - The use of immobilized capillary enzyme reactors (ICERs) and enzymes coated to magnetic beads ((NT or CT)-MB) for ligand screening has been adopted as a new technique of high throughput screening (HTS). In this work the selected target was the enzyme acetylcholinesterase (AChE), which acts on the central nervous system and is a validated target for the treatment of Alzheimer's disease, as well as for new insecticides. A new approach for the screening of plant extracts was developed based on the ligand fishing experiments and zonal chromatography. For that, the magnetic beads were used for the ligand fishing experiments and capillary bioreactors for the activity assays. The latter was employed also under non-linear conditions to determine the affinity constants of known ligands, for the first time, as well as for the active fished ligand. PMID- 24148458 TI - Identification of the specified impurities of silver sulfadiazine using a screening of degradation products in different stress physico-chemical media. AB - Determination of silver sulfadiazine degradation products in several stress media was carried out by high pressure liquid chromatography (HPLC) with diode array detector (DAD) and hybrid mass spectrometer triple quadrupole-linear trap. The optimal chromatographic method used a Hypercarb column with a stationary phase 100% carbon, a mobile phase composed by a mixture 45:55 formic acid 1% solution and acetonitrile and detection at 275 nm. Structure elucidation was carried out on the mass spectrometry system using same chromatographic conditions and based on MS/MS techniques. Under these conditions up to 9 possible impurities were demonstrated to be degradation products respecting silver sulfadiazine evolution under different stress conditions: temperature, acid, basic, oxidation, reduction and catalyzed photodegradation. Sulfacetamide, sulfanilic acid (4 aminobenzenesulfonic acid), aniline, pyrimidin-2-amine, 4 aminobenzenesulfonamide, 4-methylidenesulfanilaniline, 4-aminophenol, 4-amino-n methyl benzenesulfonamide and benzenesulfonic acid were identified by mass spectrometry in order to cover the possible degradation paths of silver sulfadiazine. Kinetics were also evaluated to obtain the prediction of shelf life of the substance. The linearity domain for the method was between 0.0005 mg/ml and 0.25mg/ml for each compound. Recovery factors in accuracy determination were between 95 and 105% relative to target concentrations of silver sulfadiazine and the quantitation limit was 0.00025 mg/ml. PMID- 24148459 TI - Development and validation of the first high performance-lateral flow immunoassay (HP-LFIA) for the rapid screening of domoic acid from shellfish extracts. AB - A lateral flow immunoassay (LFIA) has been developed and fully validated to detect the primary amnesic shellfish poisoning (ASP) toxin, domoic acid (DA). The performance characteristics of two versions of the test were investigated using spiked and naturally contaminated shellfish (mussels, scallops, oysters, clams, and cockles). The tests provide a qualitative result, to indicate the absence or presence of DA in extracts of shellfish tissues, at concentrations that are relevant to regulatory limits. The new rapid assay (LFIA version 2) was designed to overcome the performance limitations identified in the first version of the assay. The improved test uses an electronic reader to remove the subjective nature of the generated results, and the positive cut-off for screening of DA in shellfish was increased from 10 ppm (version 1) to 17.5 ppm (version 2). A simple extraction and test procedure was employed, which required minimal equipment and materials; results were available 15 min after sample preparation. Stability of the aqueous extracts at room temperature (22 degrees C) at four time points (up to 245 min after extraction) and across a range of DA concentrations was 100.3+/ 1.3% and 98.8+/-2.4% for pre- and post-buffered extracts, respectively. The assay can be used both within laboratory settings and in remote locations. The accuracy of the new assay, to indicate negative results at or below 10 ppm DA, and positive results at or above 17.5 ppm, was 99.5% (n=216 tests). Validation data were obtained from a 2-day, randomised, blind study consisting of multiple LFIA lots (n=3), readers (n=3) and operators (n=3), carrying out multiple extractions of mussel tissue (n=3) at each concentration (0, 10, 17.5, and 20 ppm). No matrix effects were observed on the performance of the assay with different species (mussels, scallops, oysters, clams, and cockles). There was no impact on accuracy or interference from other phycotoxins, glutamic acid or glutamine with various strip incubations (8, 10, and 12 min). The accuracy of the assay, using naturally contaminated samples to indicate negative results at or below 12.5 ppm and positive results at or above 17.5 ppm, was 100%. Variability between three LFIA lots across a range of DA concentrations, expressed as coefficient of variation (% CV), was 1.1+/-0.4% (n=2 days) based on quantitative readings from the electronic reader. During an 8 week stability study, accuracy of the method with test strips stored at various temperatures (6, 22, 37 and 50 degrees C) was 100%. Validation for both versions included comparisons with results obtained using reference LC-UV methods. PMID- 24148460 TI - Synthesis, adsorption and selectivity studies of N-propyl quaternized magnetic poly(4-vinylpyridine) for hexavalent chromium. AB - The ability of solid N-propyl quaternized magnetic poly(4-vinylpyridine) for the extraction of chromium(VI) in aqueous solutions was investigated. For the synthesized Cr(VI) magnetic polymers, the optimum pH obtained was 4 for both the magnetic ion imprinted polymer (IIP) and the corresponding non-ion imprinted polymer NIP. The amount of the adsorbent which gave the maximum adsorption was determined to be 20 and 65 mg for the magnetic IIP and NIP, respectively. A Cr(VI) concentration which was adsorbed maximally was 5 mg L(-1) which was therefore taken as the optimum. The maximum adsorption capacities for the magnetic polymers were 6.20 and 1.87 mg g(-1) for the magnetic IIP and NIP, respectively. The optimum time for the adsorption of the Cr(VI) analyte was determined as 40 min. The prepared magnetic ion imprinted polymer showed good selectivity towards Cr(VI). The order of selectivity of the investigated anions followed the sequence: Cr2O7(2-)>SO4(2-)>F(-)>NO3(-). PMID- 24148462 TI - A green sorbent of esterified egg-shell membrane for highly selective uptake of arsenate and speciation of inorganic arsenic. AB - Egg-shell membrane (ESM) is a promising adsorbent for heavy metal uptake. However, carboxylic groups on ESM surface barrier arsenic adsorption. Herein, ESM is modified by esterification and the methyl esterified egg-shell membrane (MESM) possesses positive charge within pH 1-9. As a novel green sorbent material, MESM exhibits 200-fold improvement on sorption capacity of arsenate with respect to bare ESM. It presents an ultra-high selectivity of 256:1 toward arsenate against arsenite. At pH 6, 100% sorption efficiency is achieved for 2 MUg L(-1) As(V) by 10 mg MESM, while virtually no adsorption of As(III) is observed. This provides great potential for selective sorption of arsenate in the presence of arsenite. By loading 4.0 mL sample within 0.05-5.00 MUg L(-1) As(V) followed by elution with 300 MUL HCl (1.5 mol L(-1)), a detection limit of 15 ng L(-1) is obtained along with a RSD of 3.5% at 0.5 MUg L(-1). Total inorganic arsenic is achieved by converting As(III) to As(V) and following the same sorption process. This procedure is applied for arsenate determination and inorganic arsenic speciation in Hijiki and water samples. The results are confirmed by graphite furnace atomic absorption spectrometry and spiking recovery. PMID- 24148461 TI - Simultaneous liquid-liquid extraction and dispersive solid-phase extraction as a sample preparation method to determine acidic contaminants in river water by gas chromatography/mass spectrometry. AB - A sample preparation procedure that combines a liquid-liquid extraction (LLE) with a dispersive solid-phase extraction (DSPE) has been devised to determine residues of four phenoxyacid herbicides, two aminopolycarboxylic acids and five acidic anti-inflammatory drugs in small volumes of river water samples. Two aliquots of acetone (3 and 0.5 mL) were used to extract the analytes from a 10 mL water sample at pH 2 containing 5 mg of octadecylsilane (ODS) sorbent and NaCl at a 5.5 M concentration. Acetone was isolated by the salting-out effect, collected, evaporated and the extract was treated with BF3/methanol to obtain the methyl esters of the analytes and determine them by GC with mass spectrometric detection. Recoveries were comprised between 82% and 114% with relative standard deviations about 5-15% (n=5) within a concentration range about 0.03-44 ug L(-1). The amount of ODS added to sample resulted to be a significant factor in the recovery for most of the analytes as deduced from an experimental design; the sample pH was not a so critical factor. A robustness study of the proposed sample preparation was carried out as defined by Youden and Steiner and an estimation of the uncertainties of the measured concentrations was made following the EURACHEM/CITAC guidelines, too. PMID- 24148463 TI - Comparison between magnetic and non magnetic multi-walled carbon nanotubes dispersive solid-phase extraction combined with ultra-high performance liquid chromatography for the determination of sulfonamide antibiotics in water samples. AB - In this manuscript, a new method based on the use of off-line dispersive solid phase extraction (dSPE) combined with ultra-high performance liquid chromatography with diode-array detection was developed to determine 11 sulfonamide antibiotics (sulfanilamide, sulfacetamide, sulfadiazine, sulfathiazole, sulfamerazine, sulfadimidin, sulfamethoxypyridazine, sulfadoxine, sulfamethoxazole, sulfisoxazole and sulfadimethoxine) in mineral waters with different mineral content. For this purpose, pristine multi-walled carbon nanotubes (MWCNTs) and magnetic-MWCNTs (m-MWCNTs) were used as sorbents. Magnetic nanoparticles were synthesized by means of a solvothermal process, assembled onto CNTs through an "aggregation wrap" mechanism and characterized by scanning electron microscopy. Parameters affecting the extraction such as volume and pH of the sample, amount of sorbent and type and volume of eluent were optimized. Once optimum extraction conditions (250 mL of water at pH 6.0 and elution with 25 mL of MeOH) were obtained, the extraction efficiency of the different carbon nanomaterials was compared. Results demonstrated the higher extraction capacity of pristine MWCNTs with recoveries between 61 and 110% (except for sulfacetamide which ranged between 40 and 53%) and between 22 and 77% for m-MWCNTs. Limits of detection lower than 32 ng/L were achieved for all of the analyzed samples. PMID- 24148464 TI - Design and evaluation of a portable optical-based biosensor for testing whole blood prothrombin time. AB - Point-of-care diagnostics (POCD) for blood coagulation benefit patients on-site, but available POCD devices are too expensive to be affordable in many countries. Optically based methodologies are cheap and reliable, and have been exploited in bench-top coagulometers to monitor coagulation with plasma, but not whole blood, which contains cellular components that cause massive interference. However, the POCD testing of whole blood gives a more accurate picture of physiological conditions than does testing plasma. In this study, a portable device for performing the prothrombin time (PT) test was designed, comprising an optical sensor, an electrical processing and control circuit to monitor the optical changes that occurred during the coagulation process in whole blood. The PT was when the slope of the first-order derivative of the coagulation curve, recorded from real-time light transmittance signals, was maximal. The POCD PT testing of 167 samples revealed that 153 (91.6%) were successfully detected and the results were highly consistent with the results of whole blood international normalized ratio (INR) (r=0.985, p<0.001) by the conventional manual method and those of plasma INR (r=0.948, p<0.001) with the ACL TOP 700 bench-top coagulometer (Beckman Colter). Hematological parameters were further analyzed, revealing that fibrinogen titers (p=0.036), red blood cell numbers (p=0.017) and distribution of red cell width (p=0.015) affected the effectiveness of the current POCD PT determination. Furthermore, a highly positive correlation was revealed between fibrinogen titers and the maximum speed of change in transmittance (v/t) (r=0.805, p<0.001), suggesting that fibrinogen might be evaluated simultaneously in this POCD testing. In conclusion, the proposed portable optical-based device performs the highly sensitive and accurate determination of whole blood PT and has commercial potential because of its small volume and low fabrication cost. PMID- 24148465 TI - Diazotization-coupling reaction-based selective determination of nitrite in complex samples using shell-isolated nanoparticle-enhanced Raman spectroscopy. AB - A simple, rapid and selective method based on diazotization-coupling reaction for determination of nitrite ion in complex samples using shell-isolated nanoparticle enhanced Raman spectroscopy (SHINERS) was developed. Based on diazotization coupling reaction, nitrite was transformed into azo dye, which has strong SHINERS activity. Subsequently the concentration of nitrite ion can be determined indirectly from the SHINERS of azo dye. The SHINERS active substrate was composed of gold nanoparticle as core with an ultrathin silica shell having pinhole on the surface. Various factors that influence reaction and SHINERS intensity were investigated. Under the optimal conditions, the linearity was observed in the range of 0.5-6.0 mg L(-1) with good correlation coefficient (r(2)>0.9793). The relative standard deviations (RSDs) for five replicate measurements were less than 14.5%. The limit of detections of the method (S/N=3) were 0.07, 0.08 and 0.10 mg L(-1) at 1137, 1395 and 1432 cm(-1), respectively, without sample preconcentration. The selectivity of the proposed method was also tested. The performance of SHINERS to determine the concentration of nitrite in food, biological and environmental samples was evaluated. The results indicate that SHINERS shows great potential as a useful analytical tool for trace analysis of nitrite in real samples. This proposed method provides a practical protocol for determination of compounds with weak Raman response, and can be expanded for the indirect detection of iodate ion, phenols and aromatic amines. PMID- 24148466 TI - Determination of inhibitory potency of argatroban toward thrombin by electrophoretically mediated microanalysis. AB - Developing an EMMA method for enzymatic assay remains a challenge, particularly using UV detection. Indeed, it is necessary to optimize the separation conditions while allowing the enzymatic reaction to occur within the capillary respecting kinetic constraints and achieving enough sensitivity. In this work, such EMMA methodology was set up to evaluate the inhibitory potency of drugs toward thrombin, a serine protease implicated in the coagulation cascade. To achieve our goal, the separation buffer, the injection sequence, the internal standard and the chromogenic substrate were investigated. The newly developed system was then assessed determining the kinetic Km constant for the selected substrate and compared with the results obtained with a continuous spectrophotometer cell assay. Secondly, the Ki inhibitory constant of the thrombin inhibitor argatroban was determined and found in agreement with the published value. PMID- 24148467 TI - Sol-gel thin-film based mesoporous silica and carbon nanotubes for the determination of dopamine, uric acid and paracetamol in urine. AB - This work describes the preparation, characterization and application of a hybrid material composed of disordered mesoporous silica (SiO2) modified with multiwalled carbon nanotubes (MWCNTs), obtained by the sol-gel process using HF as the catalyst. This hybrid material was characterized by N2 adsorption desorption isotherms, X-ray powder diffraction (XRD), scanning electron microscopy (SEM), high resolution transmission microscopy (HR-TEM), Raman spectroscopy and X-ray photoelectron spectroscopy (XPS). This new hybrid material was used for the construction of a thin film on a glassy carbon electrode. The modified electrode using this material was designated SiO2/MWCNT/GCE. The electrocatalytic properties of the electrode toward dopamine, uric acid and paracetamol oxidation were studied by differential pulse voltammetry. Well defined and separated oxidation peaks were observed in phosphate buffer solution at pH 7.0, in contrast with the ill-defined peaks observed with unmodified glassy carbon electrodes. The electrode had high sensitivity for the determination of dopamine, uric acid and paracetamol, with the limits of detection obtained using statistical methods, at 0.014, 0.068 and 0.098 umol L(-1), respectively. The electrode presented some important advantages, including enhanced physical rigidity, surface renewability by polishing and high sensitivity, allowing the simultaneous determination of these three analytes in a human urine sample. PMID- 24148468 TI - Role of background observed in aptasensor with chemiluminescence detection. AB - One-step chemiluminescent aptasensor was developed using chemically initiated electron exchange luminescence (CIEEL) between high-energy intermediate formed from 1,1'-oxalyldiimidazole chemiluminescence (ODI-CL) reaction and G-quadruplex (ochratoxin A (OTA)-bound aptamer conjugated with TEX615) generated. The sensitivity of chemiluminescent aptasensor, optimized with various variables (e.g., property of microfibers fabricated with 3,4,9,10-perylenetetracarboxylic dimide, determination of fluorescent dye labeled with aptamer, physical properties of buffer solution), was dependent on the background (concentration of high-energy intermediate) generated in ODI-CL reaction. The limit of detection (LOD=background+3*standard deviation, 0.5 nM) of ODI-CL aptasensor with lower background was lower than that (3.7 nM) with 20 times higher background. Also, the ratio of signal to background (S/B) of ODI-CL aptasensor with low background was about 5-fold higher than that with high background. The sensitivities of ODI CL aptasensors, with low as well as high background, capable of accurately and precisely quantifying OTA within 10 min, were better than those of fluorescent aptasensors and as good as those of highly sensitive but time-consuming competitive enzyme-linked immune-sorbent assays (ELISAs) using expensive antibody produced with the sacrifice of small animals. PMID- 24148469 TI - Evaluation of dispersive liquid-liquid microextraction in the stereoselective determination of cetirizine following the fungal biotransformation of hydroxyzine and analysis by capillary electrophoresis. AB - We developed a capillary electrophoresis (CE) and dispersive liquid-liquid microextraction (DLLME) method to stereoselectively analyze hydroxyzine (HZ) and cetirizine (CTZ) in liquid culture media. The CE analyses were performed on an uncoated fused-silica capillary; 50mmolL(-1) sodium borate buffer (pH 9.0) containing 0.8% (w/v) S-beta-CD was used as the background electrolyte. The applied voltage and temperature were +6 kV and 15 degrees C, respectively, and the UV detector was set to 214 nm. Chloroform (300 uL) and ethanol (400 uL) were used as the extraction and disperser solvents, respectively, for the DLLME. Following the formation of a cloudy solution, the samples were subjected to vortex agitation at 2000 rpm for 30s and to centrifugation at 3000 rpm for 5 min. The recoveries ranged from 87.4 to 91.7%. The method was linear over a concentration range of 250-12,500 ng mL(-1) for each HZ enantiomer (r>0.998) and 125-6250 ng mL(-1) for each CTZ enantiomer (r>0.998). The limits of quantification were 125 and 250 ng mL(-1) for CTZ and HZ, respectively. Among the six fungi studied, three species were able to convert HZ to CTZ enantioselectively, particularly the fungus Cunninghamella elegans ATCC 10028B, which converted 19% of (S)-HZ to (S)-CTZ with 65% enantiomeric excess. PMID- 24148470 TI - Pitfalls of assays devoted to evaluation of oxidative stress induced by inorganic nanoparticles. AB - During the last years, there has been a remarkable increase in the use of inorganic nanoparticles (NP) in different applications, including consumer and medical products. Despite these promising applications, the extremely small size of NP allows them to penetrate cells, in which they can interact with intracellular structures causing serious side effects. A number of studies showed that NP cause adverse effects predominantly via induction of an oxidative stress an imbalance between damaging oxidants and protective antioxidants - resulting in inflammation, immune response, cell damages, genotoxicity, etc ... Most of the in vitro methods used for measurement of oxidative stress biomarkers were designed and standardized for conventional organic, inorganic and biochemical compounds. More recently, these methods have been adapted to studies related to various nanomaterials. Thus, this review is an attempt to highlight some current methods employed in and to provide a critical analysis of the major challenges and issues faced in this emerging field. PMID- 24148471 TI - Biomonitoring of 20 trace elements in blood and urine of occupationally exposed workers by sector field inductively coupled plasma mass spectrometry. AB - A sector field inductively coupled plasma mass spectrometry method for the determination of Ag, Al, As, Ba, Be, Cd, Co, Cr, Cs, Cu, Fe, Mn, Ni, Pb, Se, Sr, Tl, U, V and Zn in whole blood and urine was designed. Microwave-assisted digestion with concentrated nitric acid was used for blood samples. Urine samples were analyzed after 1/50 (v/v) dilution with 5% (v/v) nitric acid. For beryllium the necessity of medium resolution mode (R=4000) was shown. Method validation was performed using blood and urine reference materials and by analyzing of spiked samples. For the designed method relative standard deviation (RSD) for the concentration range 0.01-1.0 MUg/L was 5-10%. RSD did not exceed 3% when trace elements concentrations were above 1.0 MUg/L. Method detection limits (3sigma): Ag 0.7 ng/L, Al 16 ng/L, As 3.4 ng/L, Ba 0.02 ng/L, Be 1.5 ng/L, Cd 7.7 ng/L, Co 1.0 ng/L, Cr 2.8 ng/L, Cs 9.8 ng/L, Cu 27 ng/L, Fe 1.1 ng/L, Mn 1.8 ng/L, Ni 17 ng/L, Pb 13 ng/L, Se 0.07 ng/L, Sr 5.7 ng/L, Tl 0.2 ng/L, U 0.1 ng/L, V 0.7 ng/L and Zn 1.2 ng/L. A developed method was applied for trace element biomonitoring of occupationally exposed workers of a beryllium processing enterprise. For preliminary risk assessment technological surface dust had been analyzed by inductively coupled plasma optical emission spectrometry. Based upon results of 50 blood and 40 urine samples analyses occupational exposure evaluation was performed. Exposure risks were found not to exceed acceptable ranges. Possible health hazards were found for Be and also Al, Cr, Mn. Occupational health and safety recommendations for the biomonitored enterprise medical care unit were issued as a result of the current investigation. PMID- 24148472 TI - Graphene based pipette tip solid phase extraction of marine toxins in shellfish muscle followed by UPLC-MS/MS analysis. AB - Graphene is a novel carbonic material with great potentials for the use as sorbent due to its ultrahigh surface area. Herein, we report the use of graphene as sorbent in solid-phase extraction (SPE) using pipette tip as cartridge namely GPT-SPE, together with ultra-performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS), for the analysis of lipophilic marine toxins (LMTs), including yessotoxins (YTX), okadaic acid (OA), dinophysistoxin-1 (DTX1), gymnodimine (GYM), spirolides-1 (SPX1), pectenotoxin-2 (PTX2) and azaspiracid-1 (AZA1) in shellfish. The GPT-SPE procedure was optimized and the performance of graphene was fully validated. Results with high-sensitivity and good reproducibility was obtained and compared with that of other sorbents like C18 silica, multi-walled carbon nanotubes (MWCNTs), commercial Oasis HLB, and Strata X for the extraction of LMTs, which showed superiority and advantages of graphene, such as good recoveries, stability and compatibility with various solvents. In order to exhibit the potentials of graphene as an excellent sorbent material, 67 mussel samples from six coastal cities of China were analyzed. OA was found to be the dominant contaminant, while YTX was also detected with low level. PMID- 24148473 TI - A cell-based potentiometric biosensor using the fungus Lentinus sajor-caju for permethrin determination in treated wood. AB - The characteristics of a potentiometric biosensor for the determination of permethrin in treated wood based on immobilised cells of the fungus Lentinus sajor-caju on a potentiometric transducer are reported this paper. The potentiometric biosensor was prepared by immobilisation of the fungus in alginate gel deposited on a pH-sensitive transducer employing a photocurable acrylic matrix. The biosensor gave a good response in detecting permethrin over the range of 1.0-100.0 uM. The slope of the calibration curve was 56.10 mV/decade with detection limit of 1.00 uM. The relative standard deviation for the sensor reproducibility was 4.86%. The response time of the sensor was 5 min at optimum pH 8.0 with 1.00 mg/electrode of fungus L. sajor-caju. The permethrin biosensor performance was compared with the conventional method for permethrin analysis using high performance liquid chromatography (HPLC), and the analytical results agreed well with the HPLC method (at 95% confidence limit). There was no interference from commonly used organophosphorus pesticides such as diazinon, parathion, paraoxon, and methyl parathion. PMID- 24148474 TI - Determination of quantum dots in single cells by inductively coupled plasma mass spectrometry. AB - In order to assess cytotoxicity of quantum dots (QDs), new reliable analytical techniques that can provide comparative information at a single-cell level are required. In this study, a single cell ICP-MS (SC-ICP-MS) method was established to determine intracellular QDs in single cells after exposure. Uptake kinetics of QDs into cells was studied using the established method. The results were compared and validated by flow cytometry and cell digestion methods. In contrast to other methods, SC-ICP-MS can directly detect QDs and their degradation products via elements, and thus is a promising complement to available methods for single cell analysis and is expected to be a critical tool in the future. PMID- 24148475 TI - Authentication of geographical origin of palm oil by chromatographic fingerprinting of triacylglycerols and partial least square-discriminant analysis. AB - Main goals of the present work were to develop authentication models based on liquid and gas chromatographic fingerprinting of triacylglycerols (TAGs) from palm oil of different geographical origins in order to compare them. For this purpose, a set of palm oil samples were collected from different continents: South eastern Asia, Africa and South America. For the analysis of the information in these fingerprint profiles, a pattern recognition technique such as partial least square discriminant analysis (PLS-DA) was applied to discriminate the geographical origin of these oils, at continent level. The liquid chromatography, coupled to a charged aerosol detector, (HPLC-CAD) TAGs separation was optimized in terms of mobile phase composition and by means of a solid silica core column. The gas chromatographic method with a mass spectrometer was applied under high temperature (HTGC-MS) in order to analyze the intact TAGs. Satisfactory chromatographic resolution within a short total analysis time was achieved with both chromatographic approaches and without any prior sample treatment. The rates of successful in prediction of the geographical origin of the 85 samples varied between 70% and 100%. PMID- 24148476 TI - Phosphorescence detection of L-ascorbic acid with surface-attached N-acetyl-L cysteine and L-cysteine Mn doped ZnS quantum dots. AB - N-Acetyl-L-cysteine (NAC) and L-cysteine (Cys) capped Mn doped ZnS quantum dots (NAC-Mn/ZnS QDs and Cys-Mn/ZnS QDs) are firstly prepared by hydrothermal methods. These QDs display strong phosphorescence emission peaks at 583 and 580 nm upon excitation at 315 and 306 nm, respectively. Since their room-temperature phosphorescence is efficiently quenched by L-ascorbic acid (AA), they have been employed as phosphorescence probes for detecting AA. The linear working ranges are 2.5-37.5 and 2.5-47.5 uM and the limits of detection are 0.72 and 1.38 uM for NAC-Mn/ZnS QDs and Cys-Mn/ZnS QDs, respectively. The possible quenching mechanisms have been discussed in detail. The QDs probes are highly selective to AA over other common ions, amino acids, glucose and bovine serum album. Finally, they have been applied successfully for detection of AA in human urine samples with satisfactory results. The recoveries are 98-104%. Our work provides a simple and convenient phosphorescence method to determine AA in real samples. PMID- 24148477 TI - A high-performance glucose biosensor using covalently immobilised glucose oxidase on a poly(2,6-diaminopyridine)/carbon nanotube electrode. AB - A highly-sensitive glucose biosensor amenable to ultra-miniaturisation was fabricated by immobilisation of glucose oxidase (GOx), onto a poly(2,6 diaminopyridine)/multi-walled carbon nanotube/glassy carbon electrode (poly(2,6 DP)/MWNT/GCE). Cyclic voltammetry was used for both the electrochemical synthesis of poly-(2,6-DP) on the surface of a MWNT-modified GC electrode, and characterisation of the polymers deposited on the GC electrode. The synergistic effect of the high active surface area of both the conducting polymer, i.e., poly (2,6-DP) and MWNT gave rise to a remarkable improvement in the electrocatalytic properties of the biosensor. The transfer coefficient (alpha), heterogeneous electron transfer rate constant and Michaelis-Menten constant were calculated to be 0.6, 4 s(-1) and 0.20 mM at pH 7.4, respectively. The GOx/poly(2,6-DP)/MWNT/GC bioelectrode exhibited two linear responses to glucose in the concentration ranging from 0.42 MUM to 8.0 mM with a correlation coefficient of 0.95, sensitivity of 52.0 MUA mM(-1) cm(-2), repeatability of 1.6% and long-term stability, which could make it a promising bioelectrode for precise detection of glucose in the biological samples. PMID- 24148478 TI - Electrochemical immunoassay for carcinoembryonic antigen using gold nanoparticle graphene composite modified glassy carbon electrode. AB - Carcinoembryonic antigen (CEA), which is typically associated with certain tumors and developing fetus, is widely used as a clinical tumor marker for some familiar cancers. In this work, a simple and sensitive electrochemical CEA sensor was developed by employing immunoreaction. Gold nanoparticle-decorated graphene composites (Au-GN) were successfully synthesized based on the reduction of HAuCl4 in the presence of graphene. Horseradish peroxidase-labeled anti-CEA antibody (HRP-anti-CEA) and HRP were successively adsorbed on the Au-GN modified glassy carbon electrode. The stepwise assembly process of the immunosensor was characterized by cyclic voltammetry and electrochemical impedance spectroscopy. The introduction of CEA antigens on the electrode surface reduced the electrochemical response of the electron transfer mediator due to the strong steric effect. Under the optimized conditions, the peak current change derived from the differential pulse voltammetry (DPV) measurements (DeltaIDPV) was proportional to the CEA concentration from 0.10 to 80 ng mL(-1) with a detection limit of 0.04 ng mL(-1) (S/N=3). In addition, this new protocol shows good selectivity, stability and reproducibility. The determination of CEA in human serum samples was performed and received in excellent accordance with the results determined by the enzyme-linked immunosorbent assay (ELISA). PMID- 24148479 TI - An ultrasensitive chemiluminescent immunosensor for the detection of human leptin using hemin/G-quadruplex DNAzymes-assembled signal amplifier. AB - In this work, we reported a sensitive chemiluminescent immunosensor for the detection of human leptin by using hemin/G-quadruplex DNAzymes to amplify detection signal. In this sensing system, the primary antibody (anti-human leptin) was firstly bound to the 96-well plates, and human leptin and biotinylated secondary antibody were successively combined to form sandwich-type immune complex through specific interactions. Then streptavidin labeled with hemin/G-quadruplex DNAzymes was assembled to the sandwich-type immunocomplex by streptavidin-biotin interaction. The DNAzymes exhibited an excellent catalytic activity to the chemiluminescent reaction of luminol with hydrogen peroxide in strong alkaline solution, leading to significant enhancement in response signal. Under the optimum conditions, the proposed immunosensor showed high sensitivity and selectivity with a low detection limit of 1.9 pg mL(-1) and a wide linear response range of human leptin from 10 to 1000 pg mL(-1). The immunosensor was used to detect human leptin in serum, and the results were in good agreement with the data obtained by conventional ELISA method. PMID- 24148480 TI - Simultaneous determination of 11 monohydroxylated PAHs in human urine by stir bar sorptive extraction and liquid chromatography/tandem mass spectrometry. AB - A simple and sensitive method for simultaneous determination of 11 monohydroxylated polycyclic aromatic hydrocarbons (OH-PAHs) in human urines has been developed based on stir bar sorptive extraction (SBSE) and liquid chromatography/tandem mass spectrometry (HPLC-MS/MS). Factors that may influence the extraction efficiency, such as pH value of matrix, extraction time, desorption solvents and desorption time were optimized. Validation results showed that the method has high sensitivity (quantification limits of 1-3 pg/mL), good reproducibility (RSD between 3.1 and 13.0%) and spiked recoveries (71.9-133.2%). The proposed method was also applied to analysis urines of smokers and nonsmokers, ten trace OH-PAHs were determined and compared between two groups. For the ease operation and satisfactory validiation results, SBSE coupled to HPLC MS/MS may be an excellent alternative method for trace analysis of OH-PAHs in human urines. PMID- 24148481 TI - Development of a multiresidue method for the determination of endocrine disrupters in fish fillet using gas chromatography-triple quadrupole tandem mass spectrometry. AB - Endocrine Disrupter Compounds (EDCs) are responsible for alterations in the endocrine system functions. Aquatic organisms are able to accumulate EDCs residues, being the major source of contamination for top predators and human consumers. This study aimed to develop and validate a method for the determination of 40 EDCs in fish fillet using modified QuEChERS and Gas Chromatography coupled with Mass Spectrometry in tandem (GC-MS/MS). A factorial design was used to optimize the extraction procedure. Method validation presented recoveries from 70.1% to 120.0% with RSD<20% and method limit of detection ranged from 0.3 to 7.5 ug kg(-1), showing good accuracy and precision. This method was successfully applied to the analysis of fish fillet from different species and residues of bisphenol A, chlorpyrifos and bifenthrin were detected. The proposed method proved to be effective for the determination of EDCs in fish fillet at very low concentration levels. PMID- 24148482 TI - Evaluation of the effect of chance correlations on variable selection using Partial Least Squares-Discriminant Analysis. AB - Variable subset selection is often mandatory in high throughput metabolomics and proteomics. However, depending on the variable to sample ratio there is a significant susceptibility of variable selection towards chance correlations. The evaluation of the predictive capabilities of PLSDA models estimated by cross validation after feature selection provides overly optimistic results if the selection is performed on the entire set and no external validation set is available. In this work, a simulation of the statistical null hypothesis is proposed to test whether the discrimination capability of a PLSDA model after variable selection estimated by cross-validation is statistically higher than that attributed to the presence of chance correlations in the original data set. Statistical significance of PLSDA CV-figures of merit obtained after variable selection is expressed by means of p-values calculated by using a permutation test that included the variable selection step. The reliability of the approach is evaluated using two variable selection methods on experimental and simulated data sets with and without induced class differences. The proposed approach can be considered as a useful tool when no external validation set is available and provides a straightforward way to evaluate differences between variable selection methods. PMID- 24148483 TI - Identification of wine aroma precursors in Moscato Giallo grape juice: a nuclear magnetic resonance and liquid chromatography-mass spectrometry tandem study. AB - In this work, several aroma precursors present in Moscato Giallo grape juice were identified and characterized using LC-MS and NMR techniques. A preliminary separation of various fractions was obtained using adsorption on Amberlite((r)) XAD resin and HPLC chromatography on a reverse phase column. Subsequently, U-HPLC with mass spectrometry allowed the identification of some compounds corresponding to mono- and disaccharides linked to terpenes. The MS-MS fragmentation step indicated which kind of glycosides, the moiety sequence and sometimes which kind of terpene were present. NMR enabled the correct identification of glycosides and terpene when the fraction analyzed was sufficiently concentrated and with few components. Twelve glycosidically bound terpenes were characterized: (E) and (Z) furanosyl-linalooloxide-7-O-[alpha-D-apiofuranosyl-(1->6)-1-beta-D glucopyranoside], (E)-furanosyl-linalooloxide-7-O-[1-beta-D-glucopyranoside], (Z) 8-hydroxylinalool-8-O-[1-beta-D-glucopyranoside], 1,2-dihydroxylinalool-1-O-[1 beta-D-glucopyranoside], linalool-3-O-[alpha-L-arabinofuranosyl-(1->6)-1-beta-D glucopyranoside], linalool-3-O-[alpha-L-apiofuranosyl-(1->6)-1-beta-D glucopyranoside], linalool-3-O-[alpha-L-rhamnopyranosyl-(1->6)-1-beta-D glucopyranoside], nerol-1-O-alpha-D-apiofuranosyl-(1->6)-1-beta-D glucopyranoside, geraniol-1-O-[alpha-L-arabinofuranosyl-(1->6)-1-beta-D glucopyranoside], geraniol-1-O-[alpha-L-rhamnopyranosyl-(1->6)-1-beta-D glucopyranoside], and a geranic acid disaccharide derivative. It is the first time that this kind of compounds are directly detected and identified in a mixture with these two techniques. PMID- 24148484 TI - Gold-nanoparticle-embedded nafion composite modified on glassy carbon electrode for highly selective detection of arsenic(III). AB - A Cu(I)-ion-mediating Au reduction is proposed for preparing an Au-nanoparticle embedded nafion (NF(Aunano)) composite. The NF(Aunano) composite consisted of highly dense, well-dispersed, and protecting-agent-free Au nanocrystals with a narrow particle size (4.8+/-0.1 nm) distribution. The NF(Aunano) composite was characterized as a function of composition and particle size distribution using powder X-ray diffraction, transmission electron microscopy, and electrochemical measurements. It was demonstrated that the NF(Aunano) composite provided high activity in the redox behavior of As(III), and was used as a potential sensing material with low Au loading for As(III) detection. An NF(Aunano)-composite modified electrode is easy to prepare and regenerate. The dynamic range of a calibration curve from 0.1 to 12.0 MUg L(-1) (from 1.3 to 160 nM), y=23.98x (in MUA MUM(-1))+0.42 (R(2)=0.999), showed linear behavior with a slope of 23.98 MUA MUM(-1). The detection limit is as low as 0.047 MUg L(-1) (0.63 nM). The chelating agent ethylenediaminetetraacetate (EDTA) can selectively chelate with interfering metal ions, forming bulky complexes or bulky anions that are excluded from the NF film. The presence of EDTA effectively eliminated interference from several metal ions, particularly Cu(II) and Hg(II), which are generally considered to be major interferents in the electroanalysis of As(III). This method was applicable to As(III) analysis in three real water samples, namely groundwater, lake, and drinking waters. PMID- 24148485 TI - Simultaneous and direct determination of iron and nickel in biological solid samples by high-resolution continuum source graphite furnace atomic absorption spectrometry. AB - The simultaneous and direct determination of nickel and iron in plants and lichens has been investigated using high-resolution continuum source graphite furnace atomic absorption spectrometry. The primary resonance line for nickel at 232.003 nm and the adjacent secondary line for iron at 232.036 nm have been used for this purpose. The optimization of the experimental conditions was performed using a pine needles certified reference material (SRM 1575a). The influence of pyrolysis and atomization temperatures, the amount of solid sample introduced into the graphite furnace and the use of aqueous or solid standard for calibration were studied. The spectral interferences caused by absorption of the concomitants of the solid sample were detected and corrected using a least square algorithm. Aliquots of 0.1-1mg of the solid samples were weighed onto the solid sampling platforms and analyzed directly, without addition of any reagents. The limits of detection were 25 ug kg(-1) for nickel and 0.40 mg kg(-1) for iron and the precision, expressed as the relative standard deviation, ranged from 7% to 12%. The proposed method was used to determine both metals in different bioindicator samples with successful results. PMID- 24148486 TI - Integration of stable isotope and trace contaminant concentration for enhanced forensic acetone discrimination. AB - We analyzed 21 neat acetone samples from 15 different suppliers to demonstrate the utility of a coupled stable isotope and trace contaminant strategy for distinguishing forensically-relevant samples. By combining these two pieces of orthogonal data we could discriminate all of the acetones that were produced by the 15 different suppliers. Using stable isotope ratios alone, we were able to distinguish 8 acetone samples, while the remaining 13 fell into four clusters with highly similar signatures. Adding trace chemical contaminant information enhanced discrimination to 13 individual acetones with three residual clusters. The acetones within each cluster shared a common manufacturer and might, therefore, not be expected to be resolved. The data presented here demonstrates the power of combining orthogonal data sets to enhance sample fingerprinting and highlights the role disparate data could play in future forensic investigations. PMID- 24148487 TI - Bovine serum albumin coated CuInS2 quantum dots as a near-infrared fluorescence probe for 2,4,6-trinitrophenol detection. AB - In this paper, a novel near-infrared fluorescence probe for the determination of 2,4,6-trinitrophenol (TNP) was developed based on bovine serum albumin (BSA) coated CuInS2 quantum dot (QD). Water-soluble CuInS2 QDs were directly synthesized in aqueous solution with mercaptopropionic acid (MPA) as stablizers, and it was coated by BSA via an amide link interacting with carboxyl of the MPA capped CuInS2 QDs. The obtained BSA coated CuInS2 QDs (BSA-CuInS2 QDs) can bind TNP in water via the acid-base pairing interaction between electron-rich amino groups of BSA and electron-deficient nitroaromatic rings, and leading the fluorescence quenching of BSA-CuInS2 QDs. The quenched fluorescence intensity of BSA-CuInS2 QDs was proportional to the concentration of TNP in the concentration ranges from 50 nmol/L to 3.0 MUmol/L. The detection limit (LOD) for TNP was 28 nmol/L. The developed fluorescence probe showed a excellent resistant to interference of metal ions such as K(+), Na(+), Zn(2+), Cu(2+), Hg(2+), and Pb(2+). The developed biosensor was applied to the determination of TNP in spiked water samples with satisfactory results. PMID- 24148488 TI - Determination of the trypanocidal drug melarsoprol and its conversion products in biological fluids with HPLC-ICPMS/ESMS. AB - Although melarsoprol, an organoarsenic compound, is widely used for the treatment of trypanosomiasis (human African sleeping sickness), very little is known about its fate in the human body, its active metabolites passing the blood-brain barrier and the mode of action. Previous pharmacological studies based on the determination of melarsoprol by HPLC-UV or by a bioassay method produced different results. We report a HPLC-ICPMS method suitable for determining melarsoprol and its metabolites in biological fluids. The arsenic selective capability of the method allowed the quantitative measurement of melarsoprol and two arsenic-containing conversion products produced when melarsoprol was incubated with human serum and blood. The major product was identified as melarsen [4-[(4,6-diamino-1,3,5-triazin-2-yl)amino]phenyl]arsonic acid by HPLC/electrospray MS, and by accurate mass measurements. Investigations about the stability of melarsoprol in serum showed that within 30 h about 10% of melarsoprol is converted to melarsen. In blood, however, most of the melarsoprol was bound to proteins and only 1% was converted to melarsen after 30 hours. The limit of detection for melarsoprol and its conversion products were in the range of 1 ug AsL(-1) (13 nmol As L(-1)) based on signal to noise ratio of 3 with a 10 uL injection volume allowing direct determination of the compounds in blood and serum (after protein precipitation) at therapeutically realistic concentrations. PMID- 24148489 TI - Ionic liquid-linked dual magnetic microextraction of lead(II) from environmental samples prior to its micro-sampling flame atomic absorption spectrometric determination. AB - A novel and rapid microextraction approach termed as ionic liquid-linked dual magnetic microextraction (IL-DMME), was developed for the atomic absorption spectrometric determination of lead. The developed method based on a combination of dispersive liquid-liquid microextraction (DLLME) and dispersive micro solid phase extraction (D-MU-SPE). In the first DLLME step, 1-butyl-3-methylimidazolium hexafluorophosphate [C4mim][PF6], was selected to extract the lead-pyrrolidine dithiocarbamate (Pb-PDC) complex from sample solution by the assistance of vortex agitator. After the first step, fifty milligrams of Fe3O4 magnetic nanoparticles (MNPs) were added to extraction of the ionic liquid and Pb-PDC complex in aqueous solution. The effective factors in proposed IL-DMME procedure, including volume of 1-butyl-3-methylimidazolium hexafluorophosphate, amount of Fe3O4 magnetic nanoparticles, vortex time, amount of ammonium pyrrolidinedithiocarbamate, sample volume and matrix effect were optimized in details. Under the optimal conditions, the method present has low detection limit (0.57 MUg L(-1)), high preconcentration factor (160) and good repeatability (<7.5%, n=10). The accuracy of the developed method was evaluated by the analysis of the certified reference materials and addition-recovery tests. The method was successfully applied to the determination of lead in water, plant and hair samples. PMID- 24148491 TI - Infrared machine vision system for the automatic detection of olive fruit quality. AB - External quality is an important factor in the extraction of olive oil and the marketing of olive fruits. The appearance and presence of external damage are factors that influence the quality of the oil extracted and the perception of consumers, determining the level of acceptance prior to purchase in the case of table olives. The aim of this paper is to report on artificial vision techniques developed for the online estimation of olive quality and to assess the effectiveness of these techniques in evaluating quality based on detecting external defects. This method of classifying olives according to the presence of defects is based on an infrared (IR) vision system. Images of defects were acquired using a digital monochrome camera with band-pass filters on near infrared (NIR). The original images were processed using segmentation algorithms, edge detection and pixel value intensity to classify the whole fruit. The detection of the defect involved a pixel classification procedure based on nonparametric models of the healthy and defective areas of olives. Classification tests were performed on olives to assess the effectiveness of the proposed method. This research showed that the IR vision system is a useful technology for the automatic assessment of olives that has the potential for use in offline inspection and for online sorting for defects and the presence of surface damage, easily distinguishing those that do not meet minimum quality requirements. PMID- 24148490 TI - Determination of vinblastine in tumour tissue with liquid chromatography-high resolution mass spectrometry. AB - There are virtually no analytical methods that describe determination of vinblastine and other vinca alkaloids in tumour tissue, albeit quantitative data on tumour drug amount is essential for maximal benefit of a particular anticancer treatment. The analytical method presented herein uses state-of-the-art sample preparation, separation and detection techniques to allow sensitive and selective determination of vinblastine in tumour tissue. After cryogenic grinding and sonication, tumour suspensions were extracted by Oasis MAX solid phase extraction and analysed for vinblastine with ultra-high performance liquid chromatography coupled to positive electrospray ionisation-high resolution mass spectrometric detection. The developed analytical method quantifies vinblastine down to 23 ng/g tumour tissue and shows satisfactory linearity (r(2)>0.99), precision (1.1-8.2%), accuracy (98%) and high selectivity with almost complete absence of matrix effects. The proposed method was found suitable to follow vinblastine levels in mice tumours and could be used to support preclinical pharmacologic studies. PMID- 24148492 TI - Determination of 4-aminophenol in a pharmaceutical formulation using surface enhanced Raman scattering: from development to method validation. AB - A surface enhanced Raman scattering (SERS) method able to quantify 4-aminophenol in a pharmaceutical formulation based on acetaminophen, also called paracetamol, was developed and, for the first time, successfully validated. In this context, silver nanoparticles were synthesized according to the method described by Lee Meisel and used as SERS substrate. The repeatability of the silver colloid synthesis was tested using different methods to characterize the size and the zeta potential of silver nanoparticles freshly synthesized. To optimize the SERS samples preparation, a design of experiments implicating concentrations of citrate-reduced silver nanoparticles and aggregating agent was performed in order to maximize the Raman signal enhancement. Finally, an approach based on tolerance intervals and accuracy profiles was applied in order to thoroughly validate the method in a range of concentrations comprised from 3 to 15 ug mL(-1) using normalized band intensities. The standard addition method was selected as method calibration. Therefore, measurements were carried out on 4-aminophenol spiked solutions of the pharmaceutical formulation. Despite the well-known stability and reproducibility problems of SERS, the validation was performed using two operators and five batches of nanoparticles, one for each validation day. PMID- 24148493 TI - Rapid determination of tetrabromobisphenol A and its main derivatives in aqueous samples by ultrasound-dispersive liquid-liquid microextraction combined with high performance liquid chromatography. AB - A method of ultrasound-dispersive liquid-liquid microextraction (US-DLLME) combined with high-performance liquid chromatography/variable wavelength detection (HPLC-VWD) has been developed for rapid measuring tetrabromobisphenol A and its five derivatives in water. Parameters affecting the extraction efficiency including the extraction solvents and dispersive solvents and their volume, ionic strength of the sample, and ultrasound time were optimized, and further validated by orthogonal array design (OAD). The optimized conditions provided enrichment factors for analytes of 74-490. Most analytes had linear responses between 2 and 500 MUg L(-1), with correlation coefficients (r(2)) of 0.9923-0.9994. Limits of detection were 0.13-0.63 MUg L(-1). Relative standard deviations (RSDs) for five replicates ranged from 2.6% to 4.5% for all analytes. When applied to spiked samples of real water, the method provided recoveries of 88.6-106.3% for tap water, 87.8-108.5% for Mi River water, 82.7-113.5% for chemical wastewater, 45.5 115.3% for urine, and 46.4-126.2% for fruit juice, with RSDs (n=5) less than 4%, 6%, 8%, 10%, and 9% respectively. PMID- 24148494 TI - Nano-LC-MS/MS for the quantitation of ceramides in mice cerebrospinal fluid using minimal sample volume. AB - A new nano-liquid chromatography-ESI-MS/MS method has been developed for the sensitive quantitation of C8:0, C16:0, C18:0, C18:1, C20:0, C24:1 and C24:0 ceramide in cerebrospinal fluid of mice using minimal sample volume. Volumes of 2 uL CSF were undertaken a simple, fast extraction procedure involving protein precipitation with methanol and dilution. Ceramides were separated by nano-liquid chromatography with a reversed phase C8 column and detected with a triple quadrupole mass spectrometer. C17:0 ceramide was used as internal standard. The method has been validated in terms of linearity, lower limit of quantitation, precision, accuracy and autosampler stability. Calibration curves covered a range of 2.25-120 pg/uL for most ceramides (7.5-120 pg/uL for C24:0 ceramide). The lower limits of quantitation determined for C8:0, C16:0, C18:1, C18:0, C20:0 and C24:1 ceramide were 0.225 pg on column (2.25 pg/uL) and that for C24:0 ceramide 0.750 pg on column (7.5 pg/uL). Intra- and interday precision and accuracy values, expressed as relative standard deviation and relative error, respectively, were lower than 15% in all cases. Autosampler stability for calibration standards and CSF samples was proven for at least 24h for all analytes. The suitability of the method has been demonstrated by quantifying the analytes, except the non-endogenous C8:0 ceramide, in cerebrospinal fluid samples of 12 mice. Calculated concentrations ranged from 3 to 120 pg/uL in cerebrospinal fluid for all analytes, except for C24:0 ceramide, which could not be detected in any of the analyzed samples. PMID- 24148495 TI - Ultra-high-performance liquid chromatography profiling method for chemical screening of proanthocyanidins in Czech hops. AB - Hops represent an important natural source of bioactive polyphenols, particularly proanthocyanidins, which can contribute to prevention of several civilization diseases, owing to their antioxidant and radical scavenging activity. We have developed a high-throughput ultra-high-performance liquid chromatography time-of flight mass spectrometry profiling method, which can be used for monitoring of bioactive proanthocyanidins in hops. The method was applied for analysis of hops of four Czech varieties (Saaz, Sladek, Preminat and Agnus) from the 2011 crop (9 localities, 11 samples) and the 2012 crop (24 localities, 40 samples). Hop samples were extracted by acetone and the analytes were separated on the Acquity UPLC BEH Shield RP18 column. Partial validation of the method revealed a satisfactory intra-day repeatability of the method for retention times (relative standard deviation within 1.39%) as well as areas under the peaks (within 9.89%). Experimental data were evaluated using principal component analysis and cluster analysis. Significant amounts of di-, tri- and tetramer proanthocyanidins consisting of (epi)catechin and (epi)gallocatechin were found in the hop samples. The dependence of the proantocyanidin composition on both the variety and the growing locality was observed. Specifically, the traditional Saaz variety contained more frequently oligomers formed by (epi)catechin units only, whereas the varieties Premiant and Agnus produced oligomers consisting of (epi)catechin as well as (epi)gallocatechin units. The relative abundance of proanthocyanidins in studied hop varieties from the two crops, 2011 and 2012, did correspond to each other. In the further perspective, the method may also be used for prediction of qualitative marks or authenticity verification of hops. PMID- 24148496 TI - Application of rational functions for the standard addition method. AB - Some rational functions are considered as the basis for calculation of unknown concentration (x0) of an analyte X determined according to the standard addition method (SAM). The correction for dilution of the sample tested during addition of successive increments of standard(ised) solution of X is involved in the related algorithm applied for calculation of the x0 value. The formulae derived were put in context with experimental data, obtained according to the AAS method from Cu measurements in samples obtained by digestion of an ash obtained from incinerated sludge. It was stated that the use of rational functions for modeling purposes strengthens the robustness of the results thus obtained. PMID- 24148497 TI - Determination of iodinated X-ray contrast media in sewage by solid-phase extraction and liquid chromatography tandem mass spectrometry. AB - A method for the quantitative determination of five iodinated X-ray contrast media (ICMs) in sewage was developed by solid-phase extraction and high performance liquid chromatography-tandem mass spectrometry. A fused-core analytical column was successfully applied for the first time for the separation of ICMs. Oasis HLB was selected from the sorbents tested because of its higher recoveries. The optimized method allowed the determination of the ICMs at low ng/L levels in both influent and effluent sewage, with detection limits of 40 ng/L and 10 ng/L for most compounds in influent and effluent sewage, respectively. The five ICMs studied were determined in all samples analysed, with iopromide being the analyte found at the highest concentration (8.9 ug/L), while iopamidol was the analyte found at lowest concentration (1.3 ug/L) in influent sewage. Effluent sewage did not show a significant decrease in ICM concentrations. PMID- 24148498 TI - Simultaneous determination of 76 micropollutants in water samples by headspace solid phase microextraction and gas chromatography-mass spectrometry. AB - This study focuses on the development of an analytical method based on headspace solid phase microextraction (HS-SPME) and gas chromatography-mass spectrometry (GC-MS) for the simultaneous determination of 76 micropollutants in water samples. The selected micropollutants include volatile organic compounds (VOCs) (e.g. chlorobenzenes, chloroalkanes), endocrine disrupting compounds (EDCs) (e.g. bisphenol A and tributyl phosphate), odour compounds (e.g. limonene, phenol), fragrance allergens (e.g. geraniol, eugenol) and some pesticides (e.g. heptachlor, terbutryn). The experimental conditions affecting their extraction, such as the type of fibre, temperature and time of extraction, sample volume and ionic strength of the samples were optimized using HS-SPME. The method showed good linear range, reproducibility between days, repeatability and low detection limits (at ng L(-1) levels). The validated method has been applied to determine the target organic micropollutants in aqueous samples from different experimental research units of surface water, sea water, waste water and those effluents of advance membrane treatments. The optimized method showed good performance in the different types of samples studied. The analysis revealed the presence of several micropollutants at concentrations between 20 and 5000 MUg L(-1), such as ethylbenzene, o-xylene, p-isopropilbenzene, D-limonene, citral and isoeugenol, due to the fact that these species are commonly used in domestic and industrial applications. PMID- 24148499 TI - Microfluidic chip-based analytical system for rapid screening of photocatalysts. AB - A simple and efficient microfluidic chip-based analytical system for rapid screening of photocatalysts was developed. The catalyst screening system consisted of a microchip with multiple channels for parallel reactions, a UV light source, and a CCD camera-based photometric detection system for monitoring the photocatalytic reaction. A novel microfluidic introduction method for loading particle samples into chip microchannels was established using dry sample powders and wedge-structure channel design. With this method, multiple different photocatalyst samples could be quickly introduced into the microchip with good reproducibility without the need of additional pumps or valves. We applied the present system in the rapid screening of doping TiO2 photocatalysts in terms of their activity for methylene blue (MB) degradation under UV light irradiation. Ten parallel photocatalyst screening reactions were achieved within 15 min in the multi-channel chip. We also examined nine element doped TiO2 materials to investigate the doping effects of different elements on TiO2. Compared with conventional systems, the photocatalyst consumption (0.1mg) in the present system was significantly reduced at least 100 times. High reaction rate in chip microreactors was obtained with an increase of two orders of magnitude over bulk reactors. The miniaturization of the photocatalytic reaction on the microchip significantly improves the reaction rates, reduces the sample and reagent consumptions, and increases the throughput of screening for multiple catalyst samples in parallel. The present work provides a novel application for microfluidic chip-based analytical systems, as well as a rapid, highly-efficient and low-consumption method for screening of photocatalysts. PMID- 24148500 TI - Gold nanoparticle coupled with fluorophore for ultrasensitive detection of protamine and heparin. AB - Here we report a novel label-free fluorescent sensor for ultrasensitive detection of protamine and heparin based on the high quenching ability of gold nanoparticles to the fluorescence of fluorescein. The fluorescence was significantly quenched when fluorescein molecules were attached to the surface of gold nanoparticles by electrostatic interaction. Upon addition of protamine, the fluorescein molecules were detached from the surface of the gold nanoparticles due to the stronger adsorption of protamine on the surface of AuNPs, and resulting in the recovery of the fluorescein molecules fluorescence. Heparin is able to bind with Protamine specifically. In the presence of heparin, the interaction of heparin with protamine makes the AuNPs de-aggregate and the fluorescein molecules re-attach to the AuNPs, which lead to marked fluorescence quench again. By measuring the changes in the fluorescence of the fluorescein molecules, the concentration of protamine and heparin were sequentially determined. The linear response range was obtained over the concentration range from 0 to 0.8 MUg/mL and 4 to 1.6 MUg/mL with the low detection limit 0.0067 MUg/mL and 0.0013 MUg/mL for protamine and heparin, respectively. PMID- 24148501 TI - Detection of DNA damage by thiazole orange fluorescence probe assisted with exonuclease III. AB - This work reports a fluorescent dye insertion approach for detection of DNA damage. The capture DNA with overhanging 3'-terminus was immobilized on silicon surface to hybridize with target DNA. The intercalation of cyanine dye of thiazole orange (TO) to the double helix structure of DNA (dsDNA) allowed intense enhancement of fluorescence signal. The DNA damage with chemicals led to poor intercalation of TO into double helix structure, resulting in the decrease of the fluorescence signal. This signal decrease could be further enhanced by exonuclease III (Exo III). With this approach, the target DNA could be detected down to 47 fM. Seven chemicals were chosen as models to monitor DNA damage. The results suggested that the present strategy could be developed to detect DNA damage, to classify the damaging mechanism with chemicals and to estimate the toxic effect of chemicals. PMID- 24148502 TI - Quantitative determination of tocopherols in edible vegetable oils using electrochemical ultra-microsensors combined with chemometric tools. AB - We have developed an electroanalytical method to quantify different isomers of tocopherols in edible vegetable oils. The method uses the square wave voltammetry on a carbon fiber disk ultramicroelectrode in benzene/ethanol+0.1 mol L(-1)H2SO4. Because the oxidation peaks of these natural antioxidants show an important overlapping, we have used two chemometric tools to obtain the multivariate calibration model. One method was the multivariate curve resolution-alternating least square (MCR-ALS), which assumes a linear behavior, i.e., the total signal is the sum of individual signals of components, and another nonlinear method such as artificial neuronal networks (ANNs). From the accuracy and precision analysis between nominal and estimated concentrations by both methods, we could infer that the ANNs method was a good model to quantify tocopherols in edible oil samples. Recovery percentages were between 94% and 99%. In addition, we found a difference of 1.4-6.8% between the total content of tocopherols in edible oil samples and the vitamin E content declared by the manufacturers. PMID- 24148503 TI - Highly reproducible SERS detection in sequential injection analysis: real time preparation and application of photo-reduced silver substrate in a moving flow cell. AB - This paper reports an improved way for performing highly reproducible surface enhanced Raman scattering of different analytes using an automated flow system. The method uses a confocal Raman microscope to prepare SERS active silver spots on the window of a flow cell by photo-reduction of silver nitrate in the presence of citrate. Placement of the flow cell on an automated x and y stages of the Raman microscope allows to prepare a fresh spot for every new measurement. This procedure thus efficiently avoids any carry over effects which might result from adsorption of the analyte on the SERS active material and enables highly reproducible SERS measurements. For reproducible liquid handling the used sequential injection analysis system as well as the Raman microscope was operated by the flexible LabVIEW based software ATLAS developed in our group. Quantitative aspects were investigated using Cu(PAR)2 as a model analyte. Concentration down to 5*10(-6) M provided clear SERS spectra, a linear concentration dependence of the SERS intensities at 1333 cm(-1) was obtained from 5*10(-5) to 1*10(-3) with a correlation coefficient r=0.999. The coefficient of variation of the method Vxo was found to be 5.6% and the calculated limit of detection 1.7*10(-5) M. The results demonstrate the potential of SERS spectroscopy to be used as a molecular specific detector in aqueous flow systems. PMID- 24148504 TI - Magnetically controllable dual-mode nanoprobes for cell imaging with an onion liked structure. AB - A magnetically controllable dual-mode optical probe is demonstrated for cellular imaging with an onion-liked structure, which can exhibit both surface enhanced Raman scattering (SERS) and fluorescence signals. For obtaining such a nanoprobe, Fe3O4 nanoparticles were first encapsulated into an inner layer of silica, which were then coated with a second layer of gold nanoshell (designated as Fe3O4@SiO2@Au). By adjusting the thickness of the gold shell, the surface plasmon resonance (SPR) of Fe3O4@SiO2@Au nanoparticles can be easily tuned from visible to near-infrared (NIR) region. Afterwards, the prepared Fe3O4@SiO2@Au nanoparticles were tagged with a third layer of Raman reporters to exhibit SERS signals and further coated with an outmost layer of dye-doped silica to generate fluorescence. When being excited at different wavelengths as 515nm and 633nm, the distinct fluorescence and SERS signals can be separately observed. More interestingly, an enhanced cellular uptake of the presented nanoprobes was observed in the presence of a magnetic field, which was proved by both fluorescence and SERS images. This onion-liked multi-modal nanoplatform has great potential in bio-imaging, targeted delivery applications and biological separations. PMID- 24148505 TI - Coupling immobilized alkaline phosphatase-based automated diagonal capillary electrophoresis to tandem mass spectrometry for phosphopeptide analysis. AB - Automated diagonal capillary electrophoresis is a two-dimensional separation method that incorporates an immobilized enzyme reactor at the distal end of the first capillary and employs identical electrophoretic separation modes in both dimensions. Components undergo a preliminary separation in the first capillary. Fractions are parked in the reactor where some components undergo transformation. The fractions are then periodically transferred to the second capillary and replaced by the next components in the sample. Components that are not modified by the reactor will have identical mobility in both dimensions and fall on the diagonal of a reconstructed two-dimensional electropherogram, while analyte that undergoes modification will fall off the diagonal. In this study, alkaline phosphatase was immobilized in a monolithic reactor. An LTQ-Orbitrap Velos mass spectrometer was used to monitor analytes as they migrated from the second capillary. The system was used to characterize the phosphorylation status of a tryptic digest of alpha-casein in a background prepared from a 22-fold excess of the tryptic digest of bovine serum albumin. 120 fractions underwent automated treatment in the alkaline phosphatase reactor and separation in the second dimension capillary for over 40 min; nine phosphorylated alpha-casein peptides that produced 20 different phosphorylation states were detected with high confidence. PMID- 24148506 TI - Amperometric phenol biosensor based on covalent immobilization of tyrosinase on Au nanoparticle modified screen printed carbon electrodes. AB - A highly selective and sensitive amperometric biosensor for the detection of phenol was developed based on a platform where Au nanoparticles (AuNPs) are electrodeposited onto a disposable screen printed carbon electrode and tyrosinase is then covalently immobilized on the AuNP's using alkanethiol and cross-linker molecules. The electrocatalytic responses of the tyrosinase modified biosensor for the detection of phenol were measured using both cyclic voltammetry and square wave voltammetry. Temperature, buffer pH and the amount of tyrosinase immobilized on the electrode surface were also optimized for phenol sensing. A high sensitivity of 15.7 uA ppm(-1), a low detectable phenol concentration of 47 ppb alongside a linear response from 47 ppb to 15 ppm was achieved using square wave voltammetry in addition to good selectivity. As a demonstration, the biosensor was applied to determine phenol concentrations in regional water samples from S. Korea. PMID- 24148507 TI - Portable integrated microfluidic analytical platform for the monitoring and detection of nitrite. AB - A wireless, portable, fully-integrated microfluidic analytical platform has been developed and applied to the monitoring and determination of nitrite anions in water, using the Griess method. The colour intensity of the Griess reagent nitrite complex is detected using a low cost Paired Emitter Detector Diode, while on-chip fluid manipulation is performed using a biomimetic photoresponsive ionogel microvalve, controlled by a white light LED. The microfluidic analytical platform exhibited very low limits of detection (34.0+/-0.1 MUg L(-1) of NO2(-)). Results obtained with split freshwater samples showed good agreement between the microfluidic chip platform and a conventional UV-vis spectrophotometer (R(2)=0.98, RSD=1.93% and R(2)=0.99, RSD=1.57%, respectively). The small size, low weight, and low cost of the proposed microfluidic platform coupled with integrated wireless communications capabilities make it ideal for in situ environmental monitoring. The prototype device allows instrument operational parameters to be controlled and analytical data to be downloaded from remote locations. To our knowledge, this is the first demonstration of a fully functional microfluidic platform with integrated photo-based valving and photo detection. PMID- 24148508 TI - A microscale solid-phase extraction poly(dimethylsiloxane) chip for enrichment and fluorescent detection of metal ions. AB - A rapid and simple enrichment system was developed on microfluidic chip which was integrated with on-line complexing and fluorescence detection. Microparticles of ion-exchange resin were trapped into the microchannel by a fabricated weir structure in the end of the microchannel to construct a micro-solid-phase extraction (MU-SPE) device. Some commonly existing metal ions in environment were served as models to evaluate the performance of the proposed microdevice, in combination with on-line derivatization with 8-hydroxyquinolin-5-sulfonic acid (HQS) and fluorescence detection. The concentration and pH value of HQS solution were optimized for metal-HQS fluorescent derivatization. The parameters, which affected the efficiency of the developed method, including composition and concentration of eluent, pH value and the flow rate of HQS solution and elution, were also investigated. Under the optimal conditions, Ca(2+), Mg(2+), Zn(2+) and Pb(2+) were successfully determined by the MU-SPE device on-chip. The experimental enrichment factors for Ca(2+), Mg(2+), Zn(2+) and Pb(2+) were up to 520, 565, 578 and 487 folds, respectively. PMID- 24148509 TI - Voltammetric determination of mixtures of caffeine and chlorogenic acid in beverage samples using a boron-doped diamond electrode. AB - Herein, a boron-doped diamond (BDD) electrode that is anodically pretreated was used for the simultaneous determination of caffeine (CAF) and chlorogenic acid (CGA) by cyclic and adsorptive stripping voltammetry. The dependence of peak current and potential on pH, scan rate, accumulation parameters and other experimental variables were studied. By using square-wave stripping mode after 60 s accumulation under open-circuit voltage, the BDD electrode was able to separate the oxidation peak potentials of CAF and CGA present in binary mixtures by about 0.4V in Britton-Robinson buffer at pH 1.0. The limits of detection were 0.107 ug mL(-1) (5.51*10(-7) M) for CAF, and 0.448 ug mL(-1) (1.26*10(-6) M) for CGA. The practical applicability of this methodology was tested in commercially available beverage samples. PMID- 24148510 TI - Method development for the determination of arsenic by sequential injection/anodic stripping voltammetry using long-lasting gold-modified screen printed carbon electrode. AB - An automated method has been developed for determining the concentration of inorganic arsenic. The technique uses sequential injection/anodic stripping voltammetry with a long-lasting gold-modified screen-printed carbon electrode. The long-lasting gold electrode was electrochemically deposited onto a screen printed carbon electrode at a potential of -0.5 V vs. Ag/AgCl in a supporting electrolyte solution of 1M hydrochloric acid. Under optimal conditions and the applied potentials, the electrode demonstrated that it can be used for a long time without a renewal process. The linear range for the determination of arsenic(III) was 1-100 MUg L(-1), and the limit of detection (LOD) in standard solutions was as low as 0.03 MUg L(-1) for a deposition time of 120 s and sample volume of 1 mL. This method was used to determine the concentration of arsenic(III) in water samples with satisfactory results. The LOD in real samples was found to be 0.5 MUg L(-1). In addition, speciation between arsenic(III) and arsenic(V) has been achieved with the proposed method using deposition potentials of -0.5 V and -1.5 V for the determination of the arsenic(III) concentration and the total arsenic concentration, respectively; the results were acceptable. The proposed method is an automated system that offers a less expensive alternative for determining trace amounts of inorganic arsenic. PMID- 24148511 TI - Two new electrochemical methods for fast and simultaneous determination of codeine and diclofenac. AB - In this paper, we present two new electrochemical methods for fast and simultaneous determination of codeine (CO) and diclofenac (DCF). The first one is based on batch injection analysis with amperometric detection (BIA-MPA) and the second one is based on capillary electrophoresis with capacitively coupled contactless conductivity detection (CE-C(4)D). The proposed BIA-MPA method is highly-precise (RSD of 1.1% and 0.9% for DCF and CO, respectively; n=10), fast (300 injections h(-1)) and has low detection limits (1.1 and 1.0 umol L(-1) for DCF and CO, respectively). The proposed CE-C(4)D method allows the determination of CO and DFC in less than 1 min with high precision (RSD of 0.3% and 0.7% for DCF and CO, respectively; n=10) and low detection limits (11 and 21 umol L(-1) for DCF and CO, respectively). Both proposed methods were applied to the determination of CO and DCF in pharmaceutical samples with similar results to those achieved by high-performance liquid chromatography (HPLC) at a 95% confidence level. PMID- 24148512 TI - Solid-phase supported profluorescent nitroxide probe for the determination of aerosol-borne reactive oxygen species. AB - Reactive oxygen species (ROS) and free radicals play important roles in the chemical transformation and adverse health effects of environmental aerosols. This work presents a simple and sensitive method for sampling and analysis of ROS using a packed column coated with a profluorescent nitroxide scavenger, proxyl fluorescamine (PF). Quantification was performed by extraction and analysis using HPLC with fluorescence detection. For comparison, the conventional method of collecting aerosols into dichlorofluorescin (DCFH) aqueous solution was used as a reference. The method was successfully applied to the determination of ROS in a model secondary organic aerosol (SOA) system generated by ozonolysis of nicotine, as well as in secondhand tobacco smoke (SHS). ROS concentrations between 50-565 nmol m(-3) were detected in fresh SOA and SHS samples. After SHS aging for 22 h, 13-18% of the initial ROS mass remained, suggesting the presence of persistent ROS. The new method offers better stability and reproducibility along with sensitivity comparable to that of DCFH (method detection limit of 3.2 and 1.4 nmol m(-3) of equivalent H2O2 for PF and DCFH respectively). The PF probe was stable during storage at room temperature and not reactive with ozone or NOx, whereas DCFH in the particle-collecting liquid system was strongly influenced by ozone and NOx interferences. This case study provides a good basis for employing solid-phase supported PF for field measurement of specific ROS in other combustion systems (i.e. biomass burning, candles, and diesel exhaust) and environmental aerosols. PMID- 24148513 TI - Restricted accessed material-copper(II) ion imprinted polymer solid phase extraction combined with inductively coupled plasma-optical emission spectrometry for the determination of free Cu(II) in urine and serum samples. AB - A novel restricted accessed material (RAM)-Cu(II) ion imprinted polymer (IIP) was synthesized by the surface imprinted-emulsion method, and possessed a high selectivity to Cu(II) and good macromolecules exclusion property. And a novel method of RAM-IIP packed microcolumn solid phase extraction (SPE) combined with inductively coupled plasma-optical emission spectrometry (ICP-OES) was developed for the determination of trace free Cu(II) in human body fluids. Under the optimized conditions, the adsorption capacity of RAM-IIP for Cu(II) was 15.9 mg g(-1). With a preconcentration factor of 30, the limit of detection was 0.17 ug L(-1), and the relative standard deviation was 2.2% (n=7, c=1 ug L(-1)). The developed method was validated by the analysis of two Certified Reference Materials, and the determined values were in good agreement with the certified values. This method was also successfully applied for the direct analysis of free Cu(II) in human urine and serum samples. While the total Cu can be determined by the proposed method after microwave digestion. The concentrations of free Cu(II) were much lower than that of total Cu, indicating that Cu is mainly coordinated with macromolecules in these biological samples. From this point of view, the developed method exhibits application potential in speciation of free metal ions and metallic complex molecules in biological samples. PMID- 24148514 TI - Magnetically-assisted impedimetric detection of bacteria using phage-modified carbon microarrays. AB - This study presents an investigation on the possibility of improving the detection limit of bacteria with an inexpensive electrochemical, impedimetric sensor platform, by integrating the sensor with magnetic manipulation. The approach uses T4 bacteriophage coated Dynabeads to selectively capture and concentrate E. coli K12 cells from samples, to increase the sensitivity of detection at the surface of functionalized screen-printed carbon microarrays. Fluorescence and flow cytometry measurements indicate that the surface modification of the magnetic beads, with phages, and binding with the bacteria, were successful. Integration of the screen-printed carbon-based impedimetric sensor, with a magnetic manipulation system, was found to improve the sensitivity of the device, decreasing the limit of detection of E. coli K12 from 10(4) to 10(3) cfu/mL. We have also demonstrated that this approach provides for more specific detection of bacteria, enabling the operator to account for non-specific adsorption, and detection of bacteria in more complex (real) samples (milk). PMID- 24148515 TI - One-step fabrication of bio-functionalized nanoporous gold/poly(3,4 ethylenedioxythiophene) hybrid electrodes for amperometric glucose sensing. AB - We report a simple, one-step synthesis of hybrid film by electropolymerizing 3,4 ethylenedioxythiophene (EDOT) on nanoporous gold (NPG) for applications in amperometric glucose biosensors. The enzyme, glucose oxidase (GOx), is entrapped into poly(3,4-ethylenedioxythiophene) (PEDOT) matrix, simultaneously. Scanning electron microscope (SEM) and transmission electron microscopy (TEM) studies show the NPG preserve its original bicontinuous nanoporous structure and the PEDOT film grows uniformly with a thickness of ~10 nm. The modified electrodes have been investigated by cyclic voltammetry (CV) and single potential step chronoamperometry (SPSC). The influence of PEDOT film's thickness has been explored to optimize sensor behaviors. Mediated by p-benzoquinone (BQ), the calibration curves have been obtained by applying relatively low constant potential of 200 mV (vs. SCE). The NPG/PEDOT/GOx (2CVs) biosensor exhibits high sensitivity of 7.3 MUA mM(-1) cm(-2) and a wide linear range of 0.1-15 mM, making it suitable for reliable analytic applications. PMID- 24148516 TI - Low-temperature synthesis of alpha-Fe2O3 hexagonal nanoparticles for environmental remediation and smart sensor applications. AB - This work demonstrates the successful synthesis and characterizations of alpha Fe2O3 hexagonal nanoparticles and their effective utilization for the degradation of hazardous Rhodamine B (RhB) dye and smart chemical sensor applications. The as synthesized materials were characterized by various analytical techniques which revealed that the prepared nanoparticles are well-crystalline, possessing hexagonal shape, grown in high-density and well matched with the rhombohedral alpha-Fe2O3 structures. The as-synthesized alpha-Fe2O3 nanoparticles were used as efficient photocatalyst for the photocatalytic degradation of RhB-dye under light illumination which showed substantial degradation (~79%) of RhB-dye in 140 min. The considerable photo-degradation of RhB-dye attributed to the unique morphology of the synthesized alpha-Fe2O3 nanoparticles which might import the effective electron/hole separation and generate the large number of oxy-radicals. Moreover, the synthesized alpha-Fe2O3 nanoparticles were utilized as efficient electron mediators for the fabrication of 4-nitrophenol chemical sensor in aqueous media. The fabricated chemical sensor exhibited a high-sensitivity of ~367.6 uA (mol L( 1))(-1) cm(-2) and an experimental detection limit of ~1.56*10(-3) mol L(-1) in a short response time of ~10.0 s with linearity in the range of 1.56*10(-3) 12.5*10(-3) mol L(-1) and correlation coefficient (R) of ~0.99963. These investigations demonstrated that the simply synthesized alpha-Fe2O3 nanoparticles can effectively be used as efficient photocatalyst for the photocatalytic degradation of organic dyes and effective electron mediators for the fabrication of highly sensitive chemical sensors in aqueous medium. PMID- 24148517 TI - Chemiluminescence detection of piperazine designer drugs and related compounds using tris(2,2'-bipyridine)ruthenium(III). AB - We present an exploration of the chemiluminescence from reactions of benzylpiperazines and phenylpiperazines with tris(2,2'-bipyridine)ruthenium(III). The selectivity of the reagent towards these compounds was found to be highly dependent upon the pH of the solution, and the relative emission intensity was strongly influenced by electron donating or withdrawing substituents on the phenyl or benzyl ring. In spite of previous investigations showing poor responses for aromatic-substituted amines (compared to their aliphatic amine counterparts), intense emissions were observed with phenylpiperazines under acidic conditions, particularly those with halogen or trifluoromethyl substituents on the aromatic ring. Buffered alkaline conditions provided much broader selectivity for the detection of both phenylpiperazine and benzylpiperazine compounds, which we have applied to a rapid HPLC procedure for the determination of piperazines of forensic interest in 'party pill' samples. PMID- 24148518 TI - Absorbance measurements with light-emitting diodes as sources: silicon photodiodes or light-emitting diodes as detectors? AB - Light-emitting diodes may also serve as light detectors, and the combination of two of these devices, one serving as light source, the other for detection, has been reported repeatedly for use in analytical photometry. A comparative study of the performance of light-emitting diodes in this role and that of a standard photodiode is reported herein. The spectral sensitivities of the light-emitting diodes were found to be as narrow as their emission bands, but shifted to shorter wavelengths, so that the spectral overlaps between emission and sensitivity of the same devices are very limited. The photocurrents of the light-emitting diodes were found to be about ten times lower than those of the photodiode. In the discharge mode (the time for discharge of the p/n-junction by the photocurrent is measured) as well as the photovoltaic mode, both of which had previously been reported for light-emitting diodes used as detectors in photometric devices, the performance of a light-emitting diode was on a level that is adequate for many analytical purposes, but the photodiode generally gave better precision and the signals showed faster settling times. PMID- 24148519 TI - Comprehensive two-dimensional gas chromatography combined to multivariate data analysis for detection of disease-resistant clones of Eucalyptus. AB - In this paper it is reported the use of the chromatographic profiles from volatile fractions of plant clones - in this case, hybrids of Eucalyptus grandis*Eucalyptus urophylla - to determine specimens susceptible to rust disease. The analytes were isolated by headspace solid phase microextraction (HS SPME) and analyzed by comprehensive two-dimensional gas chromatography combined to fast quadrupole mass spectrometry (GC*GC-qMS). Parallel Factor Analysis (PARAFAC) was employed for estimate the correlation between the chromatographic profiles and resistance against Eucalyptus rust, after preliminary variable selection performed by Fisher ratio analysis. The proposed method allowed the differentiation between susceptible and non-susceptible clones and determination of three resistance biomarkers. This approach can be a valuable alternative for the otherwise time-consuming and labor-intensive methods commonly used. PMID- 24148520 TI - Simultaneous determinations of zirconium, hafnium, yttrium and lanthanides in seawater according to a co-precipitation technique onto iron-hydroxide. AB - Very low concentrations (pg mL(-1) or sub-pg mL(-1) level) along with the high salinity are the main problems in determining trace metal contents in seawater. This problem is mainly considered for investigations of naturally occurring YLOID (Y and Lanthanides) and Zr and Hf in order to provide precise and accurate results. The inductively coupled plasma mass spectrometry (ICP-MS), both in high and low resolution, offers many advantages including simultaneous analyses of all elements and their quantitative determination with detection limits of the order of pg mL(-1). However in the analysis of YLOID in seawater, a better determination needs an efficient combination of ICP-MS measurement with a pre concentration technique. To perform an ultra-trace analysis in seawater, we have validated an analytical procedure involving an improved modified co-precipitation on iron hydroxides to ensure the simultaneous quantitative recovery of YLOID, Zr and Hf contents with measurement by a quadrupole ICP-MS. The validity of the method was assessed through a series of co-precipitation experiments and estimation of several quality control parameters for method validation, namely working range and its linearity, detection limit, quantification limit, precision and spike recoveries, and the methodological blank choice, are introduced, evaluated and discussed. Analysis of NASS-6, is the first report on the latest seawater reference material for YLOID, hafnium and zirconium. PMID- 24148522 TI - Application of the isopycnic kinetic plot method for elucidating the potential of sub-2 um and core-shell particles in SFC. AB - In this work the isopycnic method to construct kinetic plots for SFC was used to investigate the performance limits of an SFC system when using sub-2 um fully porous particles and sub-3 um superficially porous (core-shell) particles. This isopycnic kinetic plot method for SFC was developed and tested earlier for SFC separations on native silica with pure CO2 as mobile phase. In the current work, octadecyl based reversed phase columns were used in combination with a mobile phase that contains 10% methanol as modifier in order to study the applicability of the described methodology to assess the kinetic performance limits of experimental setups in which SFC is used and will, according to all probability, be evolving. SFC and HPLC van Deemter and kinetic plots are constructed for columns packed with fully porous particles with various diameters and for a column packed with core-shell particles. The influence of the experimental kinetic performance limits of the particle diameter and morphology in SFC is shown to be the same as in HPLC. Additionally, kinetic plot predictions were constructed for separations on 1 um and 0.5 um particles using the data measured on the 5 um, 3.5 um and 1.8 um fully porous particles. By doing this the potential applicability of 1 um particles on the contemporary SFC and HPLC systems was demonstrated together with the irrelevance of the use of 0.5 um particles in SFC. PMID- 24148521 TI - Electrochemical determination of mercury: a review. AB - Mercury is a metal that has been extensively studied, in large part due to its high toxicity. Therefore, mercury levels must be monitored in different sample types using analytical methods. This review summarizes the electrochemical methods that have been used for mercury analysis in a variety of samples. A critical evaluation of the methods and electrode materials employed for mercury analysis is presented according to the following classifications: bare electrodes, chemically modified electrodes and nanostructured electrodes. The advantages and disadvantages of each type of electrode material regarding mercury analysis are also presented. PMID- 24148523 TI - A combined liquid three-phase micro-extraction and differential pulse voltammetric method for preconcentration and detection of ultra-trace amounts of buprenorphine using a modified pencil electrode. AB - A combination of polytetrafluorethylene membrane-based liquid three-phase micro extraction and voltammetry was used for the micro-separation and determination of buprenorphine. Type of the organic solvent used, pH levels of the donor and acceptor phases, salt concentration, extraction time, stirring rate, and electrochemical parameters as the essential factors affecting the liquid three phase micro-extraction of buprenorphine were investigated. Differential pulse voltammetry exhibited two linear dynamic ranges of 1.0-109.0 pmol L(-1) and 0.109 nmol L(-1)-0.11 umol L(-1) of buprenorphine and the detection limit was found to be as low as 0.6 pmol L(-1) of buprenorphine. Also, the effects of a number of common substances potentially interfering with selectivity were studied. The results indicate that the proposed method is highly selective and sensitive for buprenorphine detection in real samples such as human urine and plasma of both drug-addict and non-addict human subjects. PMID- 24148524 TI - A chiral ligand exchange CE system for monitoring inhibitory effect of kojic acid on tyrosinase. AB - A facile chiral ligand exchange capillary electrophoresis (CLE-CE) system with Zn(II)-L-alanine as the chiral selector in the presence of beta-cyclodextrin has been developed for enantioseparation of dansyl amino acids. The influence of the key factors, such as buffer pH, the ratio of Zn (II) to ligand, the concentration of beta-cyclodextrin and the concentration of the complex, were investigated in detail when D, L-Tyr and D, L-Thr were selected as the model analytes. The proposed method showed favorable quantitative analysis property of dansyl D, L tyrosine with good linearity (r(2)>=0.999) and reproducibility (RSD<=3.8%), then, it was applied in studying the activity of tyrosinase through the determination of L-tyrosine concentration variation after being incubated with the enzyme. Further, the inhibitory efficiency of kojic acid and soy sauce on the tyrosinase was investigated. The IC50 of kojic acid obtained from the sigmoidal inhibitory curve was 21.35 MUM. The results imply that the proposed CLE-CE system has the potential in exploring the activity of enzyme and screening the inhibitors of enzyme. PMID- 24148526 TI - Presenteeism revisited: a comprehensive review. PMID- 24148525 TI - Assessment of early atherosclerotic findings in patients with nasal polyposis. AB - OBJECTIVE: To investigate early markers of atherosclerosis in patients with nasal polyposis (NP) through measurements of carotid artery intima-media thickness (CIMT), flow-mediated vasodilatation (FMD) of the brachial artery and serum paraoxonase-1 (PON-1) activity. METHODS: Forty-five patients with NP were included in the study group and 45 healthy individuals in the control group. The diagnosis of patients with NP was predicated on anterior rhinoscopy, endoscopic nasal examination and coronal paranasal sinus computed tomography (CT). Measurements of CIMT and FMD of the brachial artery were performed by high resolution ultrasonography. Serum PON-1 activity was evaluated by measuring the rate of paraoxon hydrolysis. RESULTS: Mean CIMT values were found to be increased in the NP group compared to the control group. However, mean FMD % values and serum PON-1 activity were significantly lower in the NP group compared to the control group. Moreover; the endoscopic polyps' scores and paranasal sinus CT scores were positively correlated with CIMT and negatively correlated with FMD % values and PON-1 activity. Disease duration also was positively correlated with CIMT and negatively correlated with FMD % values. CONCLUSION: Impaired FMD, increased CIMT and decreased serum PON-1 activity may be considered to be risk factors for accelerated atherosclerosis in patients with NP who may have subclinical atherosclerosis and be at risk for cardiovascular events in the future. PMID- 24148527 TI - FELD better not thinking of metastases only when liver lesions appear after bleomycin-based treatment for non-seminoma testis from metastases. AB - BACKGROUND: Bleomycin has become an integral part of chemotherapy in patients with germ-cell tumors. One of the most feared side effects is bleomycin-induced pneumonitis. In patients with mild or moderate BIP, radiological signs disappear almost completely within nine months after discontinuation of bleomycin treatment. CASE PRESENTATION: We present a patient with a history of non seminoma of the testis and bleomycin-induced pneumonitis. During follow-up, regression of the hypothesis of eosinophilic migration to the liver after regression of bleomycin-induced pneumonitis is highly suspicious based on transient eosinophilia and focal eosinophilic liver disease. CONCLUSION: As follow up may consist of CT scanning in germ-line tumor patients, transient eosinophilic liver lesions reported during regressive bleomycin-induced pneumonitis should not be presumed automatically as metastatic tumor relapse and require further sequential imaging and pathological examination. PMID- 24148528 TI - Genetic control of renal tumorigenesis by the mouse Rtm1 locus. AB - BACKGROUND: The genetic basis of susceptibility to renal tumorigenesis has not yet been established in mouse strains. Mouse lines derived by bidirectional phenotypic selection on the basis of their maximal (AIRmax) or minimal (AIRmin) acute inflammatory responsiveness differ widely in susceptibility to spontaneous and urethane-induced renal tumorigenesis. To map the functional loci modulating renal tumor susceptibility in these mice, we carried out a genome-wide genetic linkage study, using SNP arrays, in an (AIRmax x AIRmin)F2 intercross population treated with a single urethane dose at 1 week of age and phenotyped for renal tumors at 35 weeks of age. RESULTS: AIRmax mice did not develop renal tumors spontaneously nor in response to urethane, whereas in AIRmin mice renal tumors formed spontaneously (in 52% of animals) and after urethane induction (89%). The tumors had a papillary morphology and were positive for alpha-methylacyl-CoA racemase and negative for CD10. By analysis of 879 informative SNPs in 662 mice, we mapped a single quantitative trait locus modulating the incidence of renal tumors in the (AIRmax x AIRmin)F2 intercross population. This locus, which we named Renal tumor modifier QTL 1 (Rtm1), mapped to chromosome 17 at 23.4 Mb (LOD score = 15.8), with SNPs rs3696835 and rs3719497 flanking the LOD score peak. The A allele of rs3719497 from AIRmin mice was associated with a 2.5-fold increased odds ratio for renal tumor development. The LOD score peak included the Tuberous sclerosis 2 (Tsc2) gene which has already been implicated in kidney disease: loss of function by germline retroviral insertion is associated with spontaneous renal tumorigenesis in the Eker rat, and heterozygous-null Tsc2(+/-) mice develop renal cystadenomas. CONCLUSIONS: We mapped Rtm1 as a single major locus modulating renal tumorigenesis in a murine intercross population. Thus, the AIR mouse lines can be considered a new genetic model for studying the role of germline and somatic molecular alterations in kidney neoplastic disease. PMID- 24148529 TI - Preparation of ZnO/Ag nanocomposite and coating on polymers for anti-infection biomaterial application. AB - ZnO/Ag nanocomposites coated with polyvinyl chloride (PVC) were prepared by chemical reduction method, for anti-infection biomaterial application. There is a growing interest in attempts in using biomolecular as the templates to grow inorganic nanocomposites in controlled morphology and structure. By optimizing the experiment conditions, we successfully fabricated high yield of ZnO/Ag nanocomposite with full coverage of high-density polyvinyl chloride (PVC) coating. More importantly, ZnO/Ag nanocomposites were shown to significantly inhibit the growth of Staphylococcus aureus in solution. It was further shown that ZnO/Ag nanocomposites induced thiol depletion that caused death of S. aureus. The coatings were fully characterized using techniques such as scanning electron microscopy (SEM), transmission electron microscopy (TEM) and X-ray diffraction (XRD). Most importantly, compared to uncoated metals, the coatings on PVC promoted healthy antibacterial activity. Importantly, compared to ZnO-Ag uncoated PVC, the ZnO/Ag nanocomposites coated was approximately triplet more effective in preventing bacteria attachment. The result of Thermal Gravimetric Analysis (TGA) indicates that, the ZnO/Ag nanocomposites are chemically stable in the temperature range from 50 to 900 degrees C. This result, for the first time, demonstrates the potential of using ZnO/Ag nanocomposites as a coating material for numerous anti-bacterial applications. PMID- 24148530 TI - Muscle biopsies off-set normal cellular signaling in surrounding musculature. AB - Studies of muscle physiology and muscular disorders often require muscle biopsies to answer questions about muscle biology. In this context, we have often wondered if muscle biopsies, especially if performed repeatedly, would affect interpretation of muscle morphology and cellular signaling. We hypothesized that muscle morphology and cellular signaling involved in myogenesis/regeneration and protein turnover can be changed by a previous muscle biopsy in close proximity to the area under investigation. Here we report a case where a past biopsy or biopsies affect cellular signaling of the surrounding muscle tissue for at least 3 weeks after the biopsy was performed and magnetic resonance imaging suggests that an effect of a biopsy may persist for at least 5 months. Cellular signaling after a biopsy resembles what is seen in severe limb-girdle muscular dystrophy type 2I with respect to protein synthesis and myogenesis despite normal histologic appearance. PMID- 24148531 TI - Updates in the determination of brain death. AB - The concept of brain death must be accurately determined and defined, especially in the light of the latest legislation on brain blood flow measurements. PMID- 24148532 TI - Non-Alcoholic Wernicke Encephalopathy: MR Imaging and Review of the Literature. AB - We describe a patient with non-alcoholic Wernicke's encephalopathy caused by long term parenteral nutrition. The diagnosis is based on clinical and magnetic resonance findings. We also reviewed the literature review in typical and atypical findings at MR examination. PMID- 24148533 TI - Sudden Sensorineural Hearing Loss: MR Imaging. AB - Hearing loss greater than 30 dB over three contiguous pure-tone frequencies occurring within a three day period is defined as sudden hearing loss. It is usually sensorineural (SSNHL), unilateral and appears as an otologic emergency. SSNHL has many possibile etiologies such as: labyrinthine viral infection, ischemic or hemorrhagic illness, trauma, immuno-mediated inner ear disease, tumor, inner ear malformation, and an imbalance between perilymphatic and endolymphatic fluid pressure. Nevertheless in almost 80% of cases SSNHL belongs to the idiopathic category because the etiology is unknown. The aim of this study was to test the diagnostic impact of two MR devices. Fifteen cases of SSNHL studied with a 1.5 T unit in our hospital between January 2006 and December 2008 within two weeks of the onset were retrospectively evaluated. Since January 2009 three more patients affected by SSNHL have been scanned with a 3T MR unit. We discuss the diagnostic sensitivity, clinical usefulness and the cost-benefit ratio of the MR systems. PMID- 24148534 TI - Diffusion Tensor MR Imaging Tractography of the Pyramidal Tracts and Corpus Callosum in Children with Right-Sided Congenital Hemiparesis. A Case Report. AB - This study used diffusion tensor tractography to evaluate the diffusion parameters of the corpsus callosum and asymmetry in the diffusion parameters of the corticospinal tracts in children with congenital hemiparesis. Precision moving critically correlates with the integrity of the pyramidal tracts as evidenced in congenital hemiparesis by the correlation found between corticospinal lesions and motor deficits. Therefore we hypothesize that diffusion parameters correlate with the severity of hemiparesis measured using the Bayley Scales of Infant Development. PMID- 24148535 TI - Aberrant Mid-Sagittal Fiber Tracts Visualized by Diffusion Tensor MR. A Case Report. AB - In hemimegalencephaly, MR imaging often reveals mid-sagittal band-like structures between the lateral ventricles. We describe the clinical presentation, morphologic abnormalities, conventional MR imaging, diffusion tensor MR and fiber tract (FT) reconstruction in a 14-year-old boy with unilateral hemimegalencephaly. We retrospectively examined MR images to determine whether these structures are aberrant mid-sagittal fibers. PMID- 24148536 TI - Neuroradiology of chemotherapeutic. Neurotoxicity in children. AB - Hemolymphoproliferative diseases and brain tumors are among the most common causes of morbidity and mortality in children. In the past few years, increased effectiveness of treatment modalities has significantly increased overall survival, but has also disclosed new aspects of the natural history of these disorders, among which central nervous system involvement due to iatrogenic side effects. Magnetic resonance imaging plays an important, often crucial, role in the diagnosis of several of these disorders. Close interdisciplinary collaboration between hemato-oncologists and neuroradiologists is of paramount importance to provide affected children with an early diagnosis and proper treatment. PMID- 24148537 TI - Occasional finding of a dural arteriovenous fistula in a newborn with orbital lymphangioma. A case report. AB - Dural arteriovenous fistulas (DAVF) are vascular malformations rarely occurring in the paediatric population (1,2,3). Prompt diagnosis and treatment are mandatory to prevent life-threatening complications including congestive heart failure and severe brain injury (1,2). We describe the case of a female newborn with an orbital lymphangioma treated for a posterior fossa DAVF. We emphasize the role of MR imaging as a useful non-invasive tool in the diagnosis of these malformations and in the evaluation of associated brain parenchymal lesions. PMID- 24148538 TI - Deep Sedation in Paediatric MR: a Review of Our Case Histories. AB - Sedation in paediatric MR is a necessary choice because very often we are dealing with uncooperative patients about to undergo lengthy examinations. The aim of this a retrospective study is to demonstrate that profound sedation with halogenated vapour Sevorane, together with specific systems for monitoring vital signs, is a safe and reliable technique. In accordance with current guidelines, it is considered essential to have an expert anaesthetist present in order to reduce the risk of incidents, which, in the case of difficulty in the airways, as seen in literature, could have fatal outcomes. PMID- 24148539 TI - Mechanical thrombolysis using a solitaire stent. AB - Mechanical offers several advantages over drug thrombolysis: in particular, the haemorrhagic risk may be not significantly increased while working out the indications got intravenous drug thrombolysis. Available tools were in our hands inefficient, stiff and dangerous. We found a retrievable stent efficient and easy to handle for this purpose. This experience is described. PMID- 24148540 TI - Stenting and coil embolization of a ruptured dissecting basilar artery aneurysm associated with coil embolization of a pericallosal artery aneurysm. A case report. AB - We describe the case of a 54-year-old woman who underwent endovascular treatment in the setting of a massive subarachnoid haemorrhage due to rupture of a dissecting basilar trunk aneurysm treated with stent implantation and coiling. A further saccular aneurysm in the left pericallosal artery disclosed by four vessel angiography was treated with coiling during the same procedure. Follow-up DSA performed after six months confirmed complete occlusion of both aneurysms and patency of the stent. PMID- 24148541 TI - Combined treatment with stenting and coiling for complex cerebral aneurysms: preliminary experience of twenty aneurysms treated by new generation intracranial stents. AB - We describe our preliminary experience of a combined treatment with stenting and coiling for ruptured and unruptured complex cerebral aneurysms (AA) using new generation stents (Enterprise((r)), LeoPlus((r)), Solitaire((r))). Eighteen patients, 20 AA, were treated by stenting and coiling. Some had sacciform wide necked partially thrombosed aneurysms, other had fusiform AA. Six ruptured AA were treated early, while the other 14 were treated electively. In four out of 20 AA coiling was performed by Jailing technique and in three cases a remodelling technique was also performed. Patients with ruptured AA were previously administered a heparin protocol during the procedure and given aspirin (500 mg) after stenting. Patients with unruptured AA were administered plavix and aspirin for seven days before the procedure. Post-intervention medical therapy was plavix and aspirin for six months, then aspirin (100 mg). MRA and DSA at were performed after six to 12 months. Treatment was successfully performed in all cases. The stent could be navigated within the cerebral arteries without any exchange procedure, and thanks to its retractability, it was positioned accurately. No procedure-related complication occurred. Complete occlusion of the aneurysm was observed in 14/20 AA, partial occlusion with residual sac in 2/20. At four months a residual neck was observed in 4/20 with an increase in residual sac at one year in one case treated by coiling. At one year, MRA showed a reduction of the neck in one case and a stable residual neck in the other. Stenting and coiling for sacciform wide-necked or fusiform aneurysms is a safe procedure without complications. Medical-therapy pre and post procedure associated with follow-up are necessary to establish the occlusion rate. PMID- 24148542 TI - The use of flow-diverting stents in the treatment of giant cerebral aneurysms: preliminary results. AB - The treatment of giant cerebral aneurysms has always been a challenge for neurosurgeons and neuroradiologists. Flow-diverting stents (Silk; Pipeline Embolization Device) are new endovascular devices introduced for the treatment of intracranial aneurysms without release of intrasaccular coils. They are tubular bimetallic endoluminal devices with low porosity. We have employed these stents in the Neuroradiology Unit of Bellaria Hospital (Bologna, Italy) since the end of 2008, treating nine patients with giant carotid cerebral aneurysms using nine Silk stents as soon as the device obtained the CE mark. All patients were pretreated with dual antiplatelet medications before surgery. The Silk stents were deployed through a 4F Balt introducer, which ensured an uneventful and very quick procedure. Control CT angiography or MR angiography was typically performed at discharge and one, three, six and 12 months after treatment. Post-treatment results were: four complete occlusions, three near complete occlusions (residual neck flow) with reduced volume of the aneurysm and two more than 50% reduction of intra-aneurysmal flow. A fatal hemorrhagic complication occurred in one patient, probably due to the antiplatelet treatment. The Silk stent seems a very interesting curative device to treat giant aneurysms with preservation of the parent artery and small adjacent branches. Technical improvements will certainly reduce the thrombogenic effect with the related risks. PMID- 24148543 TI - A Little Talk on Adamkiewicz's Artery. Some Practical Considerations on the Pre Operative Identification of this Artery Starting from a Single Team Experience in Pre-Surgical Selective Embolization of Vascularized Spinal Lesions. AB - The major radicular artery eponymically named "Adamkiewicz's artery" (AKA) is an important vessel supplying the spinal cord, especially the lumbar enlargement. This report emphasizes the importance of anatomical knowledge of this artery and highlights the concept of the potential risk of neurological complications during different procedures: spine orthopedic/neurosurgery, aortic repair (vascular surgery) and endovascular selective embolizations performed by interventional neuro/radiologists. Anatomical considerations are made on the spinal cord arterial circulation with a special focus on the AKA. Our review of the literature considered this anatomical element essential to compare the potential risk of spinal cord ischemic damage during orthopedic/neurosurgical spine procedures, aortic vascular surgery repair procedures and endovascular selective arterial embolizations. Evaluation of the endovascular selective arterial spine embolization risk was based on our series of 410 embolization procedures. Spinal cord infarction and transient or permanent paraplegia may result from inadvertent interruption of the AKA. The presence of intersegmental collaterals may decrease the risk of spinal cord ischemia: this is an important element to bear in mind that may help in spine surgery or aortic repair procedures performed by vascular surgeons. Nevertheless, during aortic repair (open surgery or stent-graft procedures) interruption of bilateral segmental arteries at multiple consecutive levels including that of the AKA may occur thereby increasing the ischemic spinal cord risk, annulling the benefit of intersegmental collaterals. Accidental embolizations of the AKA during endovascular spine procedures (i.e. selective arterial embolizations) performed by interventional neuro/radiologists will cause an almost certain spinal cord infarction due to the consequent embolizations of the anterior spinal artery (ASA). PMID- 24148544 TI - Role of contrast-enhanced magnetic resonance angiography in spinal dural arteriovenous fistula. AB - Spinal dural arteriovenous fistulae (SDAVF) are the most common vascular malformations of the spine. Although digital subtraction angiography (DSA) remains the standard of reference to diagnose and classify vascular spinal lesions, we investigated the clinical value of contrast-enhanced MR angiography (CE-MRA), equipped with TRICKS sequences, in localizing SDAVF before selective catheter angiography and possible subsequent treatment. We studied 16 consecutive patients suspected of harbouring vascular spinal cord malformations and we tried to determine the level and the side of the arterial feeder to the arteriovenous abnormality. In 12 cases the results were compared with DSA and/or possible post operative findings. In nine cases CE-MRA correctly depicted the origin of the fistula: in particular one patient was treated surgically only on the basis of MRA results. Thanks to its elevated spatial and temporal resolution, spinal contrast-enhanced MRA using TRICKS sequences proved reliable in detecting and localizing the SDAVF arterial feeders and can be used as a guide to subsequent selective DSA examination. PMID- 24148545 TI - Medical therapy and multilevel vertebroplasty in osteoporosis: when and why. AB - Vertebroplasty (VP) is a mini-invasive percutaneous technique for the treatment of symptomatic, vertebral body fracture (VBF) caused by porotic or other diseases and its outcome has now been demonstrated by many trials. Beyond the results of these trials on the efficacy and safety of VP, the real problem for patients with osteoporotic and non-osteoporotic vertebral fractures is the risk of new fractures to adjacent or distant vertebra following VP that is reported to range from 10% to 30%. It is still unclear whether this is related to the natural history of the underlying disease (osteoporotic and non-osteoporotic diseases) or to the treatment, especially when a single vertebral fracture in an osteoporotic patient is highly predictive of future fractures. To prevent new fractures to adjacent or distant vertebra following VP in porotic patients multiple non pharmacologic interventions are recommended (diet with vitamin D or calcium supplements, smoking cessation, exercise) in addition to a specific medical therapy to block the activation of osteoclast cells responsible for bone resorption, and to re-establish correct bone remodeling. These drugs include anti catabolic drugs: bisphosphonate, oestrogen hormone, and anabolic drugs: PTH analogues and strontium ranelate. Bisphosphonate are the most commonly used compounds to treat postmenopausal osteoporosis. However, medical treatment appears to be too slow to prevent the natural history of patients with VBF. One session multilevel VP could be performed to prevent vertebral refracture risk in porotic or non-porotic patients with recurrent VBFs also after the first VP even if there is not a true vertebral collapse. Even if there are no limits to how many body levels can be treated in one session, European and American guidelines suggest doing no more than three body levels in the same session to reduce patient discomfort, and to prevent peri-procedural anesthesiologic problems, like uncontrolled fat-embolism, cement leakage, and pulmonary embolism, that could be increased. How many vertebrae could be treated in same session could be analyzed beforehand based on MDCT vertebral morphology and trabecular structure, or on MRI signal changes. Added to medical therapy, multilevel VP can be performed in selected cases to treat VBF related to osteoporosis, preventing fractures or refracture without any further thrombo-embolic or fat uncontrolled embolism peri or post-procedural complications. PMID- 24148546 TI - Intradiscal and intramuscular injection of discogel((r)) - radiopaque gelified ethanol: pathological evaluation. AB - This study assessed the impact and modification of intradiscal, intraforaminal, epidural and intramuscular swine injection of a new material, Discogel((r))- radiopaque gelified ethanol- recently introduced for the mini-invasive treatment of herniated disc. Discogel((r)) is a sterile viscous solution containing ethyl alcohol, cellulose derivative product, added to a radio-opaque element, tungsten. The pig was sedated and under fluoroscopy guidance a needle was positioned within disc L1-L2 followed by intradiscal, intraforaminal, epidural and intramuscular injection of 1 ml of Discogel. As disc control level L4-L5 was considered where nothing was injected. The pig was sacrifed 48 h after injection of discogel and the spine from D10 to S1 was removed and fixed in 10% buffered formalin. The anatomical specimens were cut with an electric saw and analyzed by routine technique then stained with formalin. The specimens containing bone material were treated by DEKAL solution. The specimens were stained with hematoxylin-eosin method and then analyzed by histochemical (Masson -Van Gieson PAS and trichromic stains ) and immunochemical methods. Morphostructural examination disclosed a granular material coloured black by hematoxylin-eosin method (tungsten) in paravertebral tissue both in the muscular and connective tissue. Some inflammatory elements like lymphomonocyte cells and venous stasis were found. No alteration was found where discogel was injected, and the nucleus pulposus, disc, chondromixoid and root ganglium were normal. After intradiscal, intraforaminal, epidural and intramuscular injection of Discogel((r)) no morpho-structural changes in nuclear tissue and annulus were found. Further studies on pigs with immunohistochemical analysis after treatment will confirm the morphological alterations induced by discogel and its action. PMID- 24148547 TI - Press release. "Stem Cell Implants to Treat Spinal Cord Injury: No Scientific Evidence, Beware of Hope Thieves". AB - A new alarm launched by Prof. Giuseppe Carannante, distinguished Turin surgeon and spokesman for SOMIPAR, the Italian medical association for paraplegia, during the association's XIV national congress underway in Palermo, Sicily since Thursday 18(th) March until Saturday 20(th) March. PMID- 24148549 TI - Triassic actinopterygian fishes: the recovery after the end-Permian crisis. AB - In the last 15 years, the discovery of several new actinopterygian fish faunas from the Early and Middle Triassic of the Tethys, cast new light on the timing, speed and range of their recovery after the end-Permian crisis. In addition to several new taxa having been described, the stratigraphical and geographical record of many others have been greatly extended. In fact, most of the new fossiliferous sites are in southern China, thus at the Eastern end of the Tethys, and furthermore a few are somewhat older (Chaohu, Panxian, Luoping) than the major classical Western Tethys sites (Monte San Giorgio). Following these new finds, it is possible to have a better definition of the Triassic recovery stages. Indeed, after a quite short phase till the end of the Smithian (Olenekian, Early Triassic) in which a rather consistent fauna was present all around the Pangea coasts, a major radiation occurred in the Early-Middle Anisian after the new Middle Triassic fish fauna already appeared in the late Early Triassic, thus occuring well before what was previously supposed from the Alps localities. Furthermore, the new assemblages from southern China point to an early broader differentiation among the basal neopterygians rather than in the 'subholosteans', the group that was then dominant in the Western Tethys since the Late Anisian. It stands that during the Norian a new basal neopterygian radiation gave rise to several new branches that dominated the remaining part of the Mesozoic. PMID- 24148548 TI - Proposed thresholds for pancreatic tissue volume for safe intraportal islet autotransplantation after total pancreatectomy. AB - The simple question of how much tissue volume (TV) is really safe to infuse in total pancreatectomy-islet autotransplantation (TP-IAT) for chronic pancreatitis (CP) precipitated this analysis. We examined a large cohort of CP patients (n = 233) to determine major risk factors for elevated portal pressure (PP) during islet infusion, using bivariate and multivariate regression modeling. Rates of bleeding requiring operative intervention and portal venous thrombosis (PVT) were evaluated. The total TV per kilogram body weight infused intraportally was the best independent predictor of change in PP (DeltaPP) (p < 0.0001; R(2) = 0.566). Rates of bleeding and PVT were 7.73% and 3.43%, respectively. Both TV/kg and DeltaPP are associated with increased complication rates, although DeltaPP appears to be more directly relevant. Receiver operating characteristic analysis identified an increased risk of PVT above a suggested cut-point of 26 cmH2O (area under the curve = 0.759), which was also dependent on age. This DeltaPP threshold was more likely to be exceeded in cases where the total TV was >0.25 cm(3)/kg. Based on this analysis, we have recommended targeting a TV of <0.25 cm(3)/kg during islet manufacturing and to halt intraportal infusion, at least temporarily, if the DeltaPP exceeds 25 cmH2O. These models can be used to guide islet manufacturing and clinical decision making to minimize risks in TP-IAT recipients. PMID- 24148550 TI - The influence of psychological factors on health-related quality of life after stroke: a systematic review. AB - BACKGROUND AND PURPOSE: Many stroke patients experience problems with health related quality of life, but much of the variance of health-related quality of life after stroke remains unexplained. Health-related quality of life may be influenced by psychological factors, as these factors reflect the way people approach situations and react to stressful situations. The aim of this study was to systematically examine the relationship between psychological factors and health-related quality of life after stroke. SUMMARY OF REVIEW: A systematic literature search was conducted in online databases PubMed, Embase, PsycINFO, and CINAHL in November 2011. A total of nine studies were included. Personality (i.e., problems of temperament and personality functions and neuroticism) was moderately negatively associated with health-related quality of life (r = 0.26 0.49). Coping (i.e., situational and personal adaptation), internal locus of control, self-worth (i.e. self-esteem and self-efficacy), and hope and optimism were moderately positively associated with health-related quality of life (r = 0.026-0.81). No evidence was found for an association between extraversion and health-related quality of life. CONCLUSIONS: There is still a paucity of studies on psychological determinants of poststroke health-related quality of life. The reviewed studies supported the importance of psychological factors, but further research is needed to supplement the available evidence and to examine how psychological factors can be modified to improve health-related quality of life, and at what moment after the stroke these interventions should be given. PMID- 24148551 TI - Identification, modification, and implementation of an evidence-based psychotherapy for children in a low-income country: the use of TF-CBT in Zambia. AB - BACKGROUND: The need to address the treatment gap in mental health services in low- and middle-income countries (LMIC) is well recognized and particularly neglected among children and adolescents. Recent literature with adult populations suggests that evidence-based mental health treatments are effective, feasible, and cross-culturally modifiable for use in LMIC. This paper addresses a gap in the literature documenting pre-trial processes. We describe the process of selecting an intervention to meet the needs of a particular population and the process of cross-cultural adaptation. METHODS: Community-based participatory research principles were implemented for intervention selection, including joint meetings with stakeholders, review of qualitative research, and review of the literature. Trauma-focused Cognitive Behavioral Therapy (TF-CBT) was chosen as the evidence-based practice for modification and feasibility testing. The TF-CBT adaptation process, rooted within an apprenticeship model of training and supervision, is presented. Clinical case notes were reviewed to document modifications. RESULTS: Choosing an intervention can work as a collaborative process with community involvement. Results also show that modifications were focused primarily on implementation techniques rather than changes in TF-CBT core elements. CONCLUSIONS: Studies documenting implementation processes are critical to understanding why intervention choices are made and how the adaptations are generated in global mental health. More articles are needed on how to implement evidence-based treatments in LMIC. PMID- 24148552 TI - Pharmacokinetics and tolerability of Tenofovir disoproxil fumarate 300 mg once daily: an open-label, single- and multiple-dose study in healthy Chinese subjects. AB - BACKGROUND: Tenofovir disoproxil fumarate (TDF) has been approved worldwide for the treatment of adults with chronic hepatitis B and, in combination with other antiretroviral agents, HIV-1 infection. Although its use for the treatment of HIV has been approved by the Chinese State Food and Drug Administration, there are no data on the pharmacokinetic profile of TDF in Chinese individuals. OBJECTIVES: This study aimed to investigate the pharmacokinetic properties and tolerability of TDF in healthy Chinese subjects. METHODS: This open-label, single- and multiple-dose study was conducted in healthy Chinese volunteers. Subjects received TDF 300 mg once daily, administered as a single dose (day 1) and multiple doses (days 4-10). Multiple plasma samples were collected over time, and the concentrations of TDF were determined using LC-MS/MS. Pharmacokinetic parameters were estimated using a noncompartmental model. Tolerability was determined using clinical evaluation and monitoring of adverse events (AEs). RESULTS: Fourteen volunteers were enrolled (7 men, 7 women; mean age, 24.6 years). TDF was rapidly absorbed; median Tmax was 0.75 hour, and t1/2 was ~21 hours with single dosing. The mean ratio of AUC0-tau steady state/AUC0-24 single dose was 1.55. The pharmacokinetic properties of TDF were consistent between the single dose and multiple doses, and between men and women. No serious AEs were reported, and there were no discontinuations due to AEs. CONCLUSIONS: There was an accumulation of approximately 55% in tenofovir exposure in healthy Chinese between multiple dose and single dose. TDF exhibited a pharmacokinetic profile similar to that of healthy Western subjects in a historical comparison. TDF was generally well tolerated in these healthy Chinese subjects. ClinicalTrials.gov identifier: NCT01480622. PMID- 24148553 TI - Pain management in older adults. AB - BACKGROUND: Chronic pain is prevalent among older adults but is underrecognized and undertreated. The approach to pain assessment and management in older adults requires an understanding of the physiology of aging, validated assessment tools, and common pain presentations among older adults. OBJECTIVE: To identify the overall principles of pain management in older adults with a specific focus on common painful conditions and approaches to pharmacologic treatment. METHODS: We searched PubMed for common pain presentations in older adults with heart failure, end-stage renal disease, dementia, frailty, and cancer. We also reviewed guidelines for pain management. Our review encompassed 2 guidelines, 10 original studies, and 22 review articles published from 2000 to the present. This review does not discuss nonpharmacologic treatments of pain. RESULTS: Clinical guidelines support the use of opioids in persistent nonmalignant pain. Opioids should be used in patients with moderate or severe pain or pain not otherwise controlled but with careful attention to potential toxic effects and half-life. In addition, clinical practice guidelines recommend use of oral nonsteroidal anti inflammatory drugs with extreme caution and for defined, limited periods. CONCLUSION: An understanding of the basics of pain pathophysiology, assessment, pharmacologic management, and a familiarity with common pain presentations will allow clinicians to effectively manage pain for older adults. PMID- 24148554 TI - Automated extraction of clinical traits of multiple sclerosis in electronic medical records. AB - OBJECTIVES: The clinical course of multiple sclerosis (MS) is highly variable, and research data collection is costly and time consuming. We evaluated natural language processing techniques applied to electronic medical records (EMR) to identify MS patients and the key clinical traits of their disease course. MATERIALS AND METHODS: We used four algorithms based on ICD-9 codes, text keywords, and medications to identify individuals with MS from a de-identified, research version of the EMR at Vanderbilt University. Using a training dataset of the records of 899 individuals, algorithms were constructed to identify and extract detailed information regarding the clinical course of MS from the text of the medical records, including clinical subtype, presence of oligoclonal bands, year of diagnosis, year and origin of first symptom, Expanded Disability Status Scale (EDSS) scores, timed 25-foot walk scores, and MS medications. Algorithms were evaluated on a test set validated by two independent reviewers. RESULTS: We identified 5789 individuals with MS. For all clinical traits extracted, precision was at least 87% and specificity was greater than 80%. Recall values for clinical subtype, EDSS scores, and timed 25-foot walk scores were greater than 80%. DISCUSSION AND CONCLUSION: This collection of clinical data represents one of the largest databases of detailed, clinical traits available for research on MS. This work demonstrates that detailed clinical information is recorded in the EMR and can be extracted for research purposes with high reliability. PMID- 24148556 TI - The relationship of individual and neighbourhood deprivation with morbidity in older adults: an observational study. AB - The objective was to determine the relative association of social class and neighbourhood deprivation with primary care consultation for eight morbidities. In 18,047 survey responders aged >=50 years, living in more deprived neighbourhoods was independently associated with new consultation for chronic obstructive pulmonary disease, ischaemic heart disease, diabetes, asthma and depression. Lower social class was associated with diabetes and chronic obstructive pulmonary disease. No such associations were found with otitis media, osteoarthritis or upper respiratory tract infection. These findings suggest a role of social environment in certain morbidities and indicate the importance of identifying and acting on neighbourhood deprivation to reduce health inequalities. PMID- 24148557 TI - Retirement and a healthy lifestyle: opportunity or pitfall? A narrative review of the literature. AB - BACKGROUND: Retirement is a life-course transition in late adult life that is marked by major changes that may affect healthy lifestyles. Our aim is to give an overview of the current knowledge on changes in smoking, alcohol consumption, physical activity and dietary habits during the transition to retirement. This may provide clues to a better targeting and timing of preventive activities at older age. METHODS: Literature search in Medline, Scopus, Embase, PsycInfo, Social SciSearch and SciSearch limited to English-language papers published between 2001 and May 2013. Results of 20 original papers are summarized in a narrative review. RESULTS: Some studies report an increase in alcohol consumption after retirement, whereas others found a decrease or no change at all. Those who retired involuntarily tended to increase their alcohol consumption, whereas retirees who quit voluntarily did not change their alcohol consumption. Leisure time physical activity seems to increase slightly after retirement, especially moderately intensive physical activity. This increase does not compensate the loss of work-related physical activity such as the work itself or work-related transportation. The studies on changes in smoking and dietary habits were too limited to draw conclusions. CONCLUSIONS: The transition to retirement is accompanied with both favourable and unfavourable lifestyle changes, depending on the type of lifestyle, lifestyle indicator and the personal situation of the retiree. The (pre-)retirement period may well offer a suitable opportunity for preventive action, for example in pre-retirement programmes, planning or other retirement-related support. PMID- 24148555 TI - Koala retroviruses: characterization and impact on the life of koalas. AB - Koala retroviruses (KoRV) have been isolated from wild and captive koalas in Australia as well as from koala populations held in zoos in other countries. They are members of the genus Gammaretrovirus, are most closely related to gibbon ape leukemia virus (GaLV), feline leukemia virus (FeLV) and porcine endogenous retrovirus (PERV) and are likely the result of a relatively recent trans-species transmission from rodents or bats. The first KoRV to be isolated, KoRV-A, is widely distributed in the koala population in both integrated endogenous and infectious exogenous forms with evidence from museum specimens older than 150 years, indicating a relatively long engagement with the koala population. More recently, additional subtypes of KoRV that are not endogenized have been identified based on sequence differences and host cell receptor specificity (KoRV B and KoRV-J). A specific association with fatal lymphoma and leukemia has been recently suggested for KoRV-B. In addition, it has been proposed that the high viral loads found in many animals may lead to immunomodulation resulting in a higher incidence of diseases such as chlamydiosis. Although the molecular basis of this immunomodulation is still unclear, purified KoRV particles and a peptide corresponding to a highly conserved domain in the envelope protein have been shown to modulate cytokine expression in vitro, similar to that induced by other gammaretroviruses. While much is still to be learned, KoRV induced lymphoma/leukemia and opportunistic disease arising as a consequence of immunomodulation are likely to play an important role in the stability of koala populations both in the wild and in captivity. PMID- 24148558 TI - Numerical and functional responses to the presence of a competitor--the case of Aggregata sp. (Apicomplexa: Aggregatidae) and Octopicola superba (Copepoda: Octopicolidae). AB - Evidence of interference competition between the eimeriorin coccidian Aggregata sp. and the octopicolid copepod Octopicola superba at the level of the gills of naturally infected Octopus vulgaris is evaluated. Numerical and functional responses are considered for analysis, and the fundamental and realized spatial niches (FSNs and RSNs) are measured as part of the study. While it was not possible to measure the FSN of Aggregata sp., the analysis of the infection levels of O. superba recorded for non-concomitantly and concomitantly infected hosts suggests that the gills and body skin constitute, respectively, the main and accessory sites of infection of the parasite. According to the evidence found, the gills function mainly as an accessory site of infection of Aggregata sp., in specimens in which the caecum and intestine are massively infected. Evidence for a negative interaction between Aggregata sp. and O. superba has been found while controlling for a potential confounding effect of host size. Furthermore, the presence of O. superba on gill lamellae appears to have been negatively affected by the presence of Aggregata sp., while this latter remained mostly undisturbed. The mean number of oocysts of Aggregata sp. in the gills was higher in spring and summer, which were also the seasons presenting the broadest RSN for O. superba. PMID- 24148559 TI - Molecular genetic and cytogenetic characterization of a partial Xp duplication and Xq deletion in a patient with premature ovarian failure. AB - BACKGROUND: The etiology of premature ovarian failure (POF) still remains undefined. Although the majority of clinical cases are idiopathic, there are possibilities of the underestimation of the most common etiologies, probably genetic causes. By reporting a case of POF with a partial Xp duplication and Xq deletion in spite of a cytogenetically 46,XX normal karyotype, we look forward that the genetic cause of POF will be investigated more methodically. METHODS: We performed a basic and clinical study at a university hospital-affiliated fertility center. The study population was a POF patient and her family. Cytogenetic analysis, FMR1 gene analysis, multiplex ligation-dependent probe amplification (MLPA), fluorescent in situ hybridization (FISH), and oligonucleotide-array based comparative genomic hybridization (array CGH) were performed. RESULTS: In spite of normal cytogenetic analysis in the proband and her mother and younger sister, FMR1 gene was not detected in the proband and her younger sister. In Southern blot analysis, the mother showed a normal female band pattern, but the proband and her younger sister showed no 5.2kb methylated band. The abnormal X chromosome of the proband and her sister was generated from the recombination of an inverted X chromosome of the mother during maternal meiosis, and the karyotype of the proband was 46,XX,rec(X)dup(Xp)inv(X)(p22.1q27.3). CONCLUSION: Array CGH followed by FISH allowed precise characterization of the der(X) chromosome and the initial karyotype of the proband had been changed to 46,XX,rec(X)dup(Xp)inv(X)(p22.3q27.3)mat.arr Xp22.33p22.31(216519 8923527)x3,Xq27.3q28(144986425-154881514)x1. This study suggests that further genetic investigation may be needed in the cases of POF with a cytogenetically 46,XX normal karyotype to find out the cause and solution for these disease entities. PMID- 24148560 TI - The arachidonate 5-lipoxygenase-activating protein (ALOX5AP) gene SG13S114 polymorphism and ischemic stroke in Chinese population: a meta-analysis. AB - Previous studies have indicated that the arachidonate 5-lipoxygenase-activating protein (ALOX5AP) gene SG13S114 polymorphism is associated with risk of ischemic stroke (IS), but the results remain inconclusive even in Chinese population. A meta-analysis of 10 case-control studies was conducted on the relationship between ALOX5AP SG13S114 polymorphism and susceptibility to IS in Chinese population published domestically and abroad from September 2007 to December 2012. Data were extracted by two authors and pooled odds ratios (ORs) and 95% confidence intervals (CIs) were calculated. Meta-analysis results showed that the significant association between SG13S114 variant and IS was found under the allelic (OR=0.87, 95% CI: 0.80-0.96, P=0.004), dominant (OR=0.75, 95% CI: 0.62 0.92, P=0.005), and recessive (OR=0.89, 95% CI: 0.82-0.97, P=0.005) genetic models in Chinese population. In subgroup meta-analysis, SG13S114 variant and atherothrombotic stroke, rather than lacunar stroke, showed the significant association under the allelic (OR=0.86, 95% CI: 0.80-0.92, P<0.0001), dominant (OR=0.72, 95% CI: 0.57-0.91, P=0.006), and recessive (OR=0.86, 95% CI: 0.78-0.95, P=0.002) models. ALOX5AP SG13S114 polymorphism is associated with susceptibility to IS in Chinese population. PMID- 24148561 TI - L-carnitine supplementation as a potential antioxidant therapy for inherited neurometabolic disorders. AB - In recent years increasing evidence has emerged suggesting that oxidative stress is involved in the pathophysiology of a number of inherited metabolic disorders. However the clinical use of classical antioxidants in these diseases has been poorly evaluated and so far no benefit has been demonstrated. l-Carnitine is an endogenous substance that acts as a carrier for fatty acids across the inner mitochondrial membrane necessary for subsequent beta-oxidation and ATP production. Besides its important role in the metabolism of lipids, l-carnitine is also a potent antioxidant (free radical scavenger) and thus may protect tissues from oxidative damage. This review addresses recent findings obtained from patients with some inherited neurometabolic diseases showing that l carnitine may be involved in the reduction of oxidative damage observed in these disorders. For some of these diseases, reduced concentrations of l-carnitine may occur due to the combination of this compound to the accumulating toxic metabolites, especially organic acids, or as a result of protein restricted diets. Thus, l-carnitine supplementation may be useful not only to prevent tissue deficiency of this element, but also to avoid oxidative damage secondary to increased production of reactive species in these diseases. Considering the ability of l-carnitine to easily cross the blood-brain barrier, l-carnitine supplementation may also be beneficial in preventing neurological damage derived from oxidative injury. However further studies are required to better explore this potential. PMID- 24148562 TI - Assessment of structural and functional visual outcomes in relapsing remitting multiple sclerosis with visual evoked potentials and optical coherence tomography. AB - The purpose of this study is to consider the clinical utility of optical coherence tomography (OCT) and find a correlation with VEP. Effects of different disease modifying treatments (DMT) were further evaluated by measuring OCT parameters and whether a correlation exists between the RNFL thickness, disease duration and expanded disability status scale (EDSS) were also assessed. 13 patients were on interferon beta-1a (IFN), 14 patients were receiving glatiramer acetate (GA), 19 patients were not being treated with any DMT and 21 healthy controls were included the study. During OCT examination, retinal nerve fiber layer (RNFL) and ganglion cell complex (GCC) thickness was found to be lower in all MS groups but macular volume (MV) was lower only in GA group than controls. Although, P100 latencies were longer than controls in all MS groups, there was no statistically significant difference between IFN and w/o DMT groups. Patients with ON history, P100 latencies were found significantly longer than those without ON. VEP amplitudes were found lower with ON history patients than those without ON, however this was not statistically significant. EDSS strongly correlated with P100 latency, RNLF, GCC but no correlation was observed with VEP amplitude and MV. Our results show that RNFL, GCC and MV were all decreased in MS patients with or without DMT comparing to controls and it is more prominent in eyes with ON. Further follow-up studies are warranted to understand the pathophysiology of CNS axonal degeneration and involvement of optic nerves. PMID- 24148563 TI - Computer-assisted assessment of ultrasound real-time elastography: initial experience in 145 breast lesions. AB - PURPOSE: To develop and evaluate a computer-assisted method of quantifying five point elasticity scoring system based on ultrasound real-time elastography (RTE), for classifying benign and malignant breast lesions, with pathologic results as the reference standard. MATERIALS AND METHODS: Conventional ultrasonography (US) and RTE images of 145 breast lesions (67 malignant, 78 benign) were performed in this study. Each lesion was automatically contoured on the B-mode image by the level set method and mapped on the RTE image. The relative elasticity value of each pixel was reconstructed and classified into hard or soft by the fuzzy c means clustering method. According to the hardness degree inside lesion and its surrounding tissue, the elasticity score of the RTE image was computed in an automatic way. Visual assessments of the radiologists were used for comparing the diagnostic performance. Histopathologic examination was used as the reference standard. The Student's t test and receiver operating characteristic (ROC) curve analysis were performed for statistical analysis. RESULTS: Considering score 4 or higher as test positive for malignancy, the diagnostic accuracy, sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) were 93.8% (136/145), 92.5% (62/67), 94.9% (74/78), 93.9% (62/66), and 93.7% (74/79) for the computer-assisted scheme, and 89.7% (130/145), 85.1% (57/67), 93.6% (73/78), 92.0% (57/62), and 88.0% (73/83) for manual assessment. Area under ROC curve (Az value) for the proposed method was higher than the Az value for visual assessment (0.96 vs. 0.93). CONCLUSION: Computer-assisted quantification of classical five-point scoring system can significantly eliminate the interobserver variability and thereby improve the diagnostic confidence of classifying the breast lesions to avoid unnecessary biopsy. PMID- 24148564 TI - R-RAS2 overexpression in tumors of the human central nervous system. AB - Malignant tumors of the central nervous system (CNS) are the 10th most frequent cause of cancer mortality. Despite the strong malignancy of some such tumors, oncogenic mutations are rarely found in classic members of the RAS family of small GTPases. This raises the question as to whether other RAS family members may be affected in CNS tumors, excessively activating RAS pathways. The RAS related subfamily of GTPases is that which is most closely related to classical Ras and it currently contains 3 members: RRAS, RRAS2 and RRAS3. While R-RAS and R RAS2 are expressed ubiquitously, R-RAS3 expression is restricted to the CNS. Significantly, both wild type and mutated RRAS2 (also known as TC21) are overexpressed in human carcinomas of the oral cavity, esophagus, stomach, skin and breast, as well as in lymphomas. Hence, we analyzed the expression of R-RAS2 mRNA and protein in a wide variety of human CNS tumors and we found the R-RAS2 protein to be overexpressed in all of the 90 CNS cancer samples studied, including glioblastomas, astrocytomas and oligodendrogliomas. However, R-Ras2 was more strongly expressed in low grade (World Health Organization grades I-II) rather than high grade (grades III-IV) tumors, suggesting that R-RAS2 is overexpressed in the early stages of malignancy. Indeed, R-RAS2 overexpression was evident in pre-malignant hyperplasias, both at the mRNA and protein levels. Nevertheless, such dramatic changes in expression were not evident for the other two subfamily members, which implies that RRAS2 is the main factor triggering neural transformation. PMID- 24148565 TI - New voices in global health. PMID- 24148566 TI - Response to the Letter to the Editor, "sleep duration and hypertension: flawed methods call the conclusions into question". PMID- 24148567 TI - Impact of postpartum anxiety and depression on child's mental development from two peri-urban communities of Karachi, Pakistan: a quasi-experimental study. AB - BACKGROUND: Postpartum anxiety and depression has detrimental effects on the overall mental development of children. This study aims to assess the impact of postpartum anxiety and depression on children's mental development on all sub scales in a Pakistani population. METHODS: A quasi-experimental study was conducted in two peri-urban communities of Karachi, a mega city of Pakistan, to assess the impact of postpartum anxiety and depression on children's growth and mental development. A total of 420 women were enrolled, who had given consent out of 651 pregnant women identified, during February 2004 to December 2005. Data for socio-demographic, home environment and family relationship variables were collected between 36 weeks of pregnancy and within 10 days of childbirth. Mother's levels of anxiety and depression were assessed at 1, 2, 6, 12, 18, 24, and 30 months of childbirth. An indigenous, validated screening instrument- Aga Khan University Anxiety and Depression scale was used and diagnostic confirmation was done through a psychologist's interview, based on DSM IV criteria. Children's growth and development was monitored in the same sequence using an Early Childhood Development tool that consists of five subscales; socio emotional, language, cognitive, gross motor and fine motor development. Physical growth was monitored by measuring height and weight of the child. Data was analyzed using SAS 9.2. Multivariable Generalized Estimating Equations (GEE) logistic regression was conducted to identify association of postpartum anxiety and depression with each early childhood development indicator, adjusting for parental and child factors. RESULTS: A significant association of postpartum anxiety and depression with delayed development on all five subscales of children's mental development was found in our study. Interestingly, our study found that higher maternal age had adverse effects on child's emotional whereas positive impact on child's cognitive development. Children's stunting had an adverse impact on all five subscales of children's development. Male children were at higher risk for delayed language and gross motor development relative to female children. CONCLUSIONS: Our study found that postpartum anxiety and depression is associated with adverse outcomes regarding children's mental development on all sub-scales. The impact was accentuated by low family income or child's increasing age. PMID- 24148568 TI - Single-incision mini-slings versus retropubic tension-free vaginal tapes: a multicenter clinical trial. AB - STUDY OBJECTIVE: To compare single-incision mini-slings (SIMSs) and retropubic tension-free vaginal tape (r-TVT) in terms of the long-term efficacy and safety for the treatment of female stress (SUI) or mixed urinary incontinence (MUI). DESIGN: Prospective multicenter cohort trial (registration number NCT00751088) (Canadian Task Force II). SETTINGS: Department of Obstetrics and Gynecology, Italy. PATIENTS: Two hundred-forty women with SUI/MUI. INTERVENTIONS: SIMS or r TVT. MEASUREMENTS AND MAIN RESULTS: The operative time and the use of analgesic tablets were significantly (p < .001) higher and lower, respectively, in the r TVT group versus the SIMS group. After 24 months of follow-up, no difference between the study arms was observed in terms of the complication rate (30/120 [25%] vs 19/120 [15.8%] for the r-TVT and SIMS arms, respectively; relative risk = 1.58; 95% confidence interval, 0.94-2.65; p = .083), whereas the subjective cure rate was significantly lower in the SIMS arm than in the r-TVT arm (57/103 [55.3%] vs 89/106 [84.0%] for the r-TVT and SIMS arms, respectively; relative risk = 0.66; 95% confidence interval, 0.54-0.80]; p < .001). The proportion of retreated patients for SUI/MUI was significantly higher in the SIMS arm than in the r-TVT arm (37/103 [34.9%] vs 12/106 [11.3%] for SIMS and r-TVT arm, respectively; p < .001). CONCLUSION: SIMS has no advantage in terms of safety over r-TVT and was found to be less effective than r-TVT. Thus, its use in the clinical practice should be questioned. PMID- 24148569 TI - Mobilization of progenitors in the subventricular zone to undergo oligodendrogenesis in the Theiler's virus model of multiple sclerosis: implications for remyelination at lesions sites. AB - Remyelination involves the generation of new myelin sheaths around axons, as occurs spontaneously in many multiple sclerosis (MS) lesions and other demyelinating diseases. When considering repairing a diseased brain, the adult mouse subventricular zone (SVZ) is of particular interest since the stem cells in this area can migrate and differentiate into the three major cell types in the central nervous system (CNS). In Theiler's murine encephalomyelitis virus-induced demyelinating disease (TMEV-IDD), we assessed the relative contribution of the SVZ to the remyelination in the corpus callosum at preclinical stages in this MS model. CNPase, MBP and Luxol Fast Blue staining revealed prominent demyelination 35days post-infection (dpi), concomitant with a strong staining in GFAP(+) type B astrocytes in the SVZ and the increased proliferation in this area. The migration of oligodendrocyte progenitors from the SVZ contributed to the remyelination observed at 60 dpi, evident through the number of APC(+)/BrdU(+) mature oligodendrocytes in the corpus callosum of infected animals. These data suggest that the inflammation induced by the Theiler's virus not only provokes strong preclinical demyelination but also, it is correlated with oligodendrocyte generation in the adult SVZ, cells that along with resident progenitor cells contribute to the prompt remyelination observed in the corpus callosum. PMID- 24148571 TI - HPV vaccination in Hong Kong: uptake and reasons for non-vaccination amongst Chinese adolescent girls. AB - OBJECTIVES: The study aims to determine HPV vaccine uptake (>= 1 dose) amongst adolescent girls in Hong Kong and to explore the reasons for non-acceptance of the vaccine. STUDY DESIGN: A total of 1832 secondary school girls (15.5 +/- 2.0 years) were randomly surveyed. Their HPV vaccine uptake was estimated, and their reasons for non-vaccination summarised. RESULTS: A total of 131 (7.2%, 95% CI: 6.0-8.4%) adolescent girls had received the HPV vaccine (>= 1 dose). Vaccine uptake was positively associated with a higher maternal education level and locally born status. Amongst the non-vaccinated girls, 20.6% had never heard of or knew little about the vaccine, 20.2% 'did not know where to receive', and 17.8% were concerned about the cost. CONCLUSIONS: The HPV vaccine uptake amongst adolescent girls in Hong Kong is very low. A school-based education and service programme is needed to improve uptake and prevent disparities in the Chinese population. PMID- 24148570 TI - Positively correlated miRNA-mRNA regulatory networks in mouse frontal cortex during early stages of alcohol dependence. AB - BACKGROUND: Although the study of gene regulation via the action of specific microRNAs (miRNAs) has experienced a boom in recent years, the analysis of genome wide interaction networks among miRNAs and respective targeted mRNAs has lagged behind. MicroRNAs simultaneously target many transcripts and fine-tune the expression of genes through cooperative/combinatorial targeting. Therefore, they have a large regulatory potential that could widely impact development and progression of diseases, as well as contribute unpredicted collateral effects due to their natural, pathophysiological, or treatment-induced modulation. We support the viewpoint that whole mirnome-transcriptome interaction analysis is required to better understand the mechanisms and potential consequences of miRNA regulation and/or deregulation in relevant biological models. In this study, we tested the hypotheses that ethanol consumption induces changes in miRNA-mRNA interaction networks in the mouse frontal cortex and that some of the changes observed in the mouse are equivalent to changes in similar brain regions from human alcoholics. RESULTS: miRNA-mRNA interaction networks responding to ethanol insult were identified by differential expression analysis and weighted gene coexpression network analysis (WGCNA). Important pathways (coexpressed modular networks detected by WGCNA) and hub genes central to the neuronal response to ethanol are highlighted, as well as key miRNAs that regulate these processes and therefore represent potential therapeutic targets for treating alcohol addiction. Importantly, we discovered a conserved signature of changing miRNAs between ethanol-treated mice and human alcoholics, which provides a valuable tool for future biomarker/diagnostic studies in humans. We report positively correlated miRNA-mRNA expression networks that suggest an adaptive, targeted miRNA response due to binge ethanol drinking. CONCLUSIONS: This study provides new evidence for the role of miRNA regulation in brain homeostasis and sheds new light on current understanding of the development of alcohol dependence. To our knowledge this is the first report that activated expression of miRNAs correlates with activated expression of mRNAs rather than with mRNA downregulation in an in vivo model. We speculate that early activation of miRNAs designed to limit the effects of alcohol-induced genes may be an essential adaptive response during disease progression. PMID- 24148572 TI - Cost-effectiveness of administering 13-valent pneumococcal conjugate vaccine in addition to 23-valent pneumococcal polysaccharide vaccine to adults with immunocompromising conditions. AB - BACKGROUND: In June, 2012 a single dose of 13-valent pneumococcal conjugate vaccine (PCV13) was added to the recommendation for immunocompromised adults who were previously recommended to receive only 23-valent pneumococcal polysaccharide vaccine (PPSV23). PCV13 may be more effective, though it covers fewer disease causing strains. OBJECTIVE: We examined the incremental cost-effectiveness of adding one dose of PCV13 to the pre-2012 recommendation of PPSV23 for adults with 4 immunocompromising conditions who are at increased risk of pneumococcal disease: HIV/AIDS, hematologic cancer, solid organ transplants, and end stage renal disease. METHODS: We used a probabilistic model following a single cohort of 302,397 immunocompromised adults. We used vaccination coverage and disease incidence data specific to each immunocompromising condition. Assumptions about PPSV23 and PCV13 vaccine effectiveness were based on two randomized controlled trials and several observational studies conducted among HIV-infected adults. Because no such studies have been conducted among other immunocompromised populations, we made further assumptions about the relative vaccine effectiveness in those groups. Cost-effectiveness ratios were determined for each condition and for all 4 groups in total. RESULTS: Our model indicated that adding one dose of PCV13 to adults in the United States with 4 immunocompromising conditions would cost $16 million (in 2009$) but provide off-setting savings of $21 million per cohort from the societal perspective. These savings come largely from decreased medical costs among adults with end stage renal disease. This dose of PCV13 would prevent 57 cases of invasive pneumococcal disease, 619 cases of hospitalized all cause pneumonia, avert 93 deaths, and save 1360 quality adjusted life years per cohort. CONCLUSION: The addition of one dose of PCV13 to the previously recommended PPSV23 doses for adults with selected immunocompromised conditions potentially reduces both disease and costs. PMID- 24148573 TI - RSV vaccine in development: assessing the potential cost-effectiveness in the Dutch elderly population. AB - OBJECTIVES: Respiratory syncytial virus (RSV) is increasingly recognized as an important cause of morbidity, mortality and health-care utilization in the elderly population. A theoretical model was built to assess the levels of vaccine effectiveness and vaccine costs for which a hypothetical RSV-vaccine for Dutch elderly could be cost-effective. METHODS: Different vaccination strategies were evaluated by changing the levels of vaccine effectiveness and the willingness to pay per quality-adjusted life year gained (QALY). Outcome measures included direct medical costs, QALYs, life years gained, incremental cost-effectiveness ratios (ICERs) and the maximum total vaccination costs per individual (i.e. (vaccine price+administration costs)*nr of doses) while remaining cost-effective. RESULTS: Using base-case assumptions, it was estimated that vaccination of all persons 60 years and older would prevent 3402GP visits, 2989 antibiotic prescriptions, 535 hospitalizations and 249 deaths and would cost ?73,261 per QALY, for a vaccine effectiveness of 70%. Vaccinating only the high risk population of 60 years and older would reduce the estimates to 2042GP visits, 2009 antibiotic prescriptions, 179 hospitalizations and 209 deaths and this reduced the cost per QALY to ?34,796 per QALY. Using the same assumptions, the maximum total vaccination costs per individual ranged from ?26 when vaccinating all persons 60 and older to ?68 when vaccinating only persons aged 85 and above, using a willingness to pay threshold of ?50,000 per QALY. For the high risk population aged 60 years and older the estimated maximum total vaccination costs ranged from ?52 to ?99. CONCLUSION: Vaccination of Dutch elderly against RSV was found cost-effective for several scenarios. As expected, vaccination is more likely to be cost-effective when only including persons who are at increased risk for contracting RSV or the potential complications of RSV. This theoretical study shows that based on the disease burden in the Dutch population aged 60yrs and older there is potential to develop a vaccine that might be considered cost effective in the Netherlands. PMID- 24148574 TI - A cluster randomised controlled trial of a web based decision aid to support parents' decisions about their child's Measles Mumps and Rubella (MMR) vaccination. AB - OBJECTIVE: To evaluate the effectiveness of a web based decision aid versus a leaflet versus, usual practice in reducing parents' decisional conflict for the first dose MMR vaccination decision. The, impact on MMR vaccine uptake was also explored. DESIGN: Three-arm cluster randomised controlled trial. SETTING: Fifty GP practices in the north of, England. PARTICIPANTS: 220 first time parents making a first dose MMR decision. INTERVENTIONS: Web, based MMR decision aid plus usual practice, MMR leaflet plus usual practice versus usual practice only, (control). MAIN OUTCOME MEASURES: Decisional conflict was the primary outcome and used as the, measure of parents' levels of informed decision-making. MMR uptake was a secondary outcome. RESULTS: Decisional conflict decreased post-intervention for both intervention arms to a level where, parents could make an informed MMR decision (decision aid: effect estimate=1.09, 95% CI -1.36 to -0.82; information leaflet: effect estimate=-0.67, 95% CI -0.88 to -0.46). Trial arm was significantly, associated (p<0.001) with decisional conflict at post intervention. Vaccination uptake was 100%, 91%, and 99% in the decision aid, leaflet and control arms, respectively (chi(2) (1, N=203)=8.69; p=0.017). Post hoc tests revealed a statistically significant difference in uptake between the information leaflet, and the usual practice arms (p=0.04), and a near statistically significant difference between the, decision aid and leaflet arms (p=0.05). CONCLUSIONS: Parents' decisional conflict was reduced in both, the decision aid and leaflet arms. The decision aid also prompted parents to act upon that decision and, vaccinate their child. Achieving both outcomes is fundamental to the integration of immunisation, decision aids within routine practice. TRIAL REGISTRATION: ISRCTN72521372. PMID- 24148575 TI - A next-generation, serum-free, highly purified Vero cell rabies vaccine is safe and as immunogenic as the reference vaccine Verorab(r) when administered according to a post-exposure regimen in healthy children and adults in China. AB - BACKGROUND: As an evolution of its currently licensed rabies vaccine Verorab((r)), Sanofi Pasteur has developed a next-generation, serum-free, highly purified Vero rabies vaccine (PVRV-NG). Through this Phase III clinical trial, we aimed to demonstrate the non-inferiority of PVRV-NG over Verorab when administered according to a post-exposure regimen and to assess its clinical safety. METHODS: A total of 816 healthy subjects aged >=10 years were randomized according to a 2:1 ratio to receive PVRV-NG or Verorab. Half of the subjects were aged 10-17 years, the other half were aged >=18 years. All subjects were to receive 5 injections on days 0, 3, 7, 14 and 28. Three blood samples were taken for rabies virus neutralizing antibodies (RVNA) assessment, at baseline, on day 14 and day 42. Solicited adverse reactions (between injections 1, 2 and 3, and within 7 days post-injections 4 and 5) and adverse events (up to 28 days after the last injection) were collected for clinical safety assessment; serious adverse events were reported up to 6-months after the last injection. RESULTS: The proportion of subjects with an RVNA titer >=0.5 IU/mL after the third injection of PVRV-NG was non-inferior to the proportion of those who received Verorab. PVRV-NG was shown to be as immunogenic as Verorab in each age range in the per-protocol and full analysis sets. PVRV-NG induced a strong immune response in both age ranges, with high RVNA levels and increased geometric mean titers compared to baseline after each measured time point. PVRV-NG had a satisfactory safety profile after each injection, similar to Verorab with regards to the nature, frequency, duration and severity of adverse events. Two serious adverse events were reported, none was related to vaccination. CONCLUSIONS: This trial demonstrated the immunogenic non-inferiority of PVRV-NG over Verorab and showed that both vaccines have similar safety profiles. This trial is registered at ClinicalTrials.gov (NCT01339312). This manuscript is the first full report of the study. An abstract of the study results was previously presented at the Rabies in the Americas (RITA) conference in October 2012 in Sao Paulo, Brazil. FUNDING: Sanofi Pasteur. PMID- 24148576 TI - Identification of seizures among adults and children following influenza vaccination using health insurance claims data. AB - INTRODUCTION: Post-licensure surveillance of adverse events following vaccination or prescription drug use often relies on electronic healthcare data to efficiently detect and evaluate safety signals. The accuracy of seizure-related diagnosis codes in identifying true incident seizure events in vaccine safety studies is influenced by factors such as clinical setting of diagnosis and age. To date, most studies of post-vaccination seizure have focused on pediatric populations. More information is needed on how well seizure can be identified in adults and children using algorithms that rely on electronic healthcare data. METHODS: This validation study was part of a larger safety study of influenza vaccination during the 2009-2010 and 2010-2011 influenza seasons. Children and adults receiving influenza vaccination were drawn from an administrative claims database of a large United States healthcare insurer. Potential seizure events were identified using an algorithm of ICD-9 diagnosis codes associated with an emergency department (ED) visit or hospitalization within pre-specified risk windows following influenza vaccination. Seizure events were confirmed through medical record review. The positive predictive value (PPV) of the algorithm was calculated within each diagnostic setting and stratified by age group, ICD-9 code group, and sex. RESULTS: Review confirmed 113 out of 176 potential seizure events. The PPVs were higher in the ED setting (93.9%) than in the inpatient setting (38.3%). The PPVs by age varied within the ED setting (98.2% in <7 years, 76.9% in 7-24 years, 92.3% in >=25 years) and within the inpatient setting (64.7% in <7 years, 33.3% in 7-24 years, 32.3% in >=25 years). CONCLUSIONS: Our algorithm for identification of seizure events using claims data had a high level of accuracy in the emergency department setting in young children and older adults and a lower, but acceptable, level of accuracy in older children and young adults. PMID- 24148577 TI - Evaluating the safety of influenza vaccine using a claims-based health system. AB - INTRODUCTION: As part of the Centers for Disease Control and Prevention's monitoring and evaluation activities for influenza vaccines, we examined relationships between influenza vaccination and selected outcomes in the 2009 2010 and 2010-2011 influenza seasons in a claims-based data environment. METHODS: We included patients with claims for trivalent influenza vaccine (TIV) and/or 2009 pandemic influenza A H1N1 vaccine (H1N1) during the 2009-2010 and 2010-2011 influenza seasons. Patients were followed for several pre-specified outcomes identified in claims. Seizures and Guillain-Barre Syndrome were selected a priori for medical record confirmation. We estimated incidence rate ratios (IRR) using a self-controlled risk interval (SCRI) or a historical comparison design. Outcomes with elevated IRRs, not selected a priori for medical record review, were further investigated with review of claims histories surrounding the outcome date to determine whether the potential event could be ruled-out or attributed to other causes based on the pattern of medical care. RESULTS: In the 2009-2010 season, no significant increased risks for outcomes following H1N1 vaccination were observed. Following TIV administration, the IRR for peripheral nervous system disorders and neuropathy was slightly elevated (1.07, 95% CI: 1.01-1.13). The IRR for anaphylaxis following TIV was 28.55 (95% CI: 3.57-228.44). After further investigation of claims histories, the majority of potential anaphylaxis cases had additional claims around the time of the event indicating alternate explanatory factors or diagnoses. In the 2010-2011 season following TIV administration, a non-significant elevated IRR for anaphylaxis was observed with no other significant outcome findings. CONCLUSION: After claims history review, we ultimately found no increased outcome risk following administration of 998,881 TIV and 538,257 H1N1 vaccine doses in the 2009-2010 season, and 1,158,932 TIV doses in the 2010-2011 season. PMID- 24148578 TI - Response to letter to the editor: Feasibility and toleration criteria in the withdrawal of sedation and mechanical ventilation in trauma patients. PMID- 24148579 TI - Inherited common variants in mitochondrial DNA and invasive serous epithelial ovarian cancer risk. AB - BACKGROUND: Mitochondria are the site of oxidative phosphorylation, a process which generates reactive oxygen species (ROS). Elevated ROS levels can lead to oxidative stress, a cellular state implicated in carcinogenesis. It is hypothesized that alternations in mitochondrial (MT) DNA, including heritable MT single nucleotide polymorphisms (MT-SNPs), have the potential to change the capacity of MT function, leading to increased oxidative stress and cancer risk. We investigated if common MT-SNPs and/or haplogroups and are associated with invasive serous ovarian cancer (OvCa) risk. METHODS: A panel of 64 MT-SNPs designed to tag all common variation in the European MT genome (minor allele frequency (MAF) >1%, r^2 >0.8) was genotyped in study participants of European descent using the Sequenom MassARRAY iPlex Gold(r) system (Sequenom Inc, CA, USA). Invasive serous OvCa cases (n = 405) and frequency age-matched controls (n = 445) were drawn from a population-based case-control study of OvCa in western Canada. Binary logistic regression was used to estimate the odds ratio (OR) and 95% confidence intervals (C.I.) for carriage of the minor versus major allele by case-control status. MitoTool was used to test the relationship between European haplogroup status and case-control status using Fisher's exact test. RESULTS: The most significant disease-SNP association was for rs2857285, a synonymous MT-SNP in ND4 (OR = 4.84, 95% CI: 1.03-22.68, P = 0.045). After adjustment for multiple testing using a Bonferroni correction of the Type 1 error this MT-SNP was not significant. No other MT-SNP had a P-value < 0.05. European haplogroup status was not associated with case status. Most MT-SNPs (73%) genotyped had a MAF <5%. CONCLUSION: Common European MT-SNPs (MAF > 5%) and haplogroups were not associated with invasive serous OvCa risk in this study; however, most European MT-SNPs have a low MAF (<5%), which we were underpowered to adequately assess. Larger studies are needed to clarify the role of low MAF MT-SNPs (MAF < 5%) in invasive serous OvCa risk. PMID- 24148580 TI - Sequential cervical length screening in pregnancies after loop excision of the transformation zone conisation: a retrospective analysis. AB - OBJECTIVE: To review our experience with a screening programme that included four sequential cervical length (CL) measurements from 16 to 22( ) weeks of gestation. DESIGN: Historical cohort study. SETTING: Tertiary-care centre in a university hospital. POPULATION: There were 312 singleton pregnancies in 321 women with a previous large loop excision of the transformation zone (LLETZ), and 62 pregnancies after a second-trimester miscarriage in a previous pregnancy. METHODS: The CL measurements were performed by transvaginal ultrasound at 16, 18, 20, and 22 completed weeks of gestation. MAIN OUTCOME MEASURES: Early preterm delivery before 34 completed weeks of gestation. RESULTS: Early preterm delivery was found in 7.4%. The CL at 16 completed weeks of gestation was smaller in the LLETZ group (36 mm, interquartile range 30-40 mm) compared with the control group (38 mm, interquartile range 32-42 mm; P = 0.040). For the analysis of risk factors for early preterm delivery after LLETZ, only cases with a complete data set were included (n = 145). In a multivariate analysis, two parameters remained significantly predictive, with CL at 16 completed weeks of gestation being the most significant measure (P < 0.001, OR 0.90, 95% CI 0.83-0.98), followed by conception using IVF treatment (P = 0.031, OR 0.64, 95% CI 1.54-34.80). CONCLUSIONS: Even as early as 16 weeks of gestation, women with early preterm delivery reveal a significantly lower CL than those without. Dynamics in the CL do not add to this information. PMID- 24148582 TI - Laurea honoris causa in honour of prof luc picard. Bologna april 21, 2010. PMID- 24148583 TI - Lipid Resonance on In Vivo Proton MR Spectroscopy: Value of Other Metabolites in Differential Diagnosis. AB - In vivo proton MR spectroscopy ((1)H-MRS) can non-invasively provide biochemical information at the same examination as conventional magnetic resonance imaging (MRI). Lipid resonance (0.9-1.5 ppm) is a marker of cell membrane breakdown and tissue necrosis, but its diagnostic significance has not been well described. We retrospectively analyzed spectra to study the different pathological conditions in patients with abnormal lipid resonance. All patients with neurological diseases showing lipid resonance on (1)H-MRS (1.5T) in a tertiary hospital over two years were retrospectively analyzed. (1)H-MRS was performed using the single voxel PRESS technique (TR/TE=3000/144 ms, eight excitations). Spectra were analysed for the presence of NAA (2.0 ppm), creatine (3.0 ppm), choline (3.2 ppm), acetate (1.92 ppm), succinate (2.4 ppm), cytosolic amino acids (0.9 ppm), lactate (1.3 ppm) and lipid (0.9-1.5 ppm) peaks. Ninety-two spectra from 69 patients (38 males, 31 females; aged 9 to 89 years) were analyzed. The final diagnosis was infective (n= 33), (tuberculoma n=17, pyogenic abscess n= 8, fungal abscess n= 3, sterile abscess n= 3, tubercular abscess n= 2), neoplastic (n= 21) (glial tumors n= 9, metastasis n= 8, lymphoma n= 4), and other (n= 15) abnormalities (subacute and chronic stroke n= 6, postictal edema n= 4, multiple sclerosis n= 2, Erdhiem Chester disease n= 2, Rosai Dorfmann disease n= 1). Succinate and acetate were detected only in pyogenic abscesses (2/4 cases), but amino acids were present in both pyogenic (4/8) and fungal (3/3) abscesses. Choline was seen not only in neoplasms (18) but also in tuberculomas (11/17), but was consistently absent in the abscesses. Lactate was present in glioblastoma (7/9), pyogenic (3/8) tubercular (2/2) and fungal (3/3) abscess. Isolated lipid resonance was found in Erdheim Chester disease (2/2) of the orbit, and lipid and choline was seen in Rosai Dorfmann's disease (1/1). Brain lesions containing lipid on (1)H-MRS could be differentiated by the presence of succinate and acetate in pyogenic abscess, and amino acids in pyogenic/fungal abscesses. Choline was seen in neoplasms and in tuberculomas, but not in the abscesses. Thus, the presence of a lipid peak, when combined with features on other MR pulse sequences and available clinical data can help arrive at a specific diagnosis. (1)H-MRS should not be interpreted in isolation: it should always be correlated with conventional imaging features, and performing (1)H-MRS in isolation remains an important pitfall. PMID- 24148581 TI - Pattern of recurrence of early breast cancer is different according to intrinsic subtype and proliferation index. AB - INTRODUCTION: Recurrence risk in breast cancer varies throughout the follow-up time. We examined if these changes are related to the level of expression of the proliferation pathway and intrinsic subtypes. METHODS: Expression of estrogen and progesterone receptor, Ki-67, human epidermal growth factor receptor 2 (HER2), epidermal growth factor receptor (EGFR) and cytokeratin 5/6 (CK 5/6) was performed on tissue-microarrays constructed from a large and uniformly managed series of early breast cancer patients (N = 1,249). Subtype definitions by four biomarkers were as follows: luminal A (ER + and/or PR+, HER2-, Ki-67 <14), luminal B (ER + and/or PR+, HER2-, Ki-67 >=14), HER2-enriched (any ER, any PR, HER2+, any Ki-67), triple-negative (ER-, PR-, HER2-, any Ki-67). Subtype definitions by six biomarkers were as follows: luminal A (ER + and/or PR+, HER2-, Ki-67 <14, any CK 5/6, any EGFR), luminal B (ER + and/or PR+, HER2-, Ki-67 >=14, any CK 5/6, any EGFR), HER2-enriched (ER-, PR-, HER2+, any Ki-67, any CK 5/6, any EGFR), Luminal-HER2 (ER + and/or PR+, HER2+, any Ki-67, any CK 5/6, any EGFR), Basal-like (ER-, PR-, HER2-, any Ki-67, CK5/6+ and/or EGFR+), triple-negative nonbasal (ER-, PR-, HER2-, any Ki-67, CK 5/6-, EGFR-). Each four- or six-marker defined intrinsic subtype was divided in two groups, with Ki-67 <14% or with Ki 67 >=14%. Recurrence hazard rate function was determined for each intrinsic subtype as a whole and according to Ki-67 value. RESULTS: Luminal A displayed a slow risk increase, reaching its maximum after three years and then remained steady. Luminal B presented most of its relapses during the first five years. HER2-enriched tumors show a peak of recurrence nearly twenty months post-surgery, with a greater risk in Ki-67 >=14%. However a second peak occurred at 72 months but the risk magnitude was greater in Ki-67 <14%. Triple negative tumors with low proliferation rate display a smooth risk curve, but with Ki-67 >=14% show sharp peak at nearly 18 months. CONCLUSIONS: Each intrinsic subtype has a particular pattern of relapses over time which change depending on the level of activation of the proliferation pathway assessed by Ki-67. These findings could have clinical implications both on adjuvant treatment trial design and on the recommendations concerning the surveillance of patients. PMID- 24148584 TI - Differentiating Components of Cerebral Arteriovenous Malformations Using T1 Weighted Gradient Recall Echo MR Imaging. AB - Cerebral arteriovenous malformation (AVM) typically shows signal void on conventional MR images, making differentiation of each component difficult. We analyzed the MR signal intensity of AVM components on T1-weighted gradient recalled echo pulse sequence images. We retrospectively studied 29 patients with AVM between 2006 and 2008. Patients were excluded if they had 1) intracranial hemorrhage, 2) previous intervention for AVM. All patients underwent MR study on a 3T system (Magentom TIM Trio, Siemens). Pulse sequences included T1-weighted gradient recalled echo (T1GRE), T2-weighted (T2), time-of-flight (TOF), and contrast-enhanced T1-weighted (cT1) images. Digital subtracted angiography (DSA) was performed in all patients as a diagnostic standard. Signal intensity of each AVM component was recorded and compared between pulse sequences. Nine patients were studied (five men; mean age 39.1 years) and nine AVM were identified (mean size, 3.9 cm). Three different signal intensities (hypo-, iso-, and hyper intensity) were observed in all nine patients on T1GRE. Only one signal intensity was seen on T2 (flow void) and cT1 images (hyperintensity) in nine patients. Two different signal intensities were observed in all seven patients with TOF images. The T1GRE image showed the largest number of different signal intensities of AVM when compared with other pulse sequences, thus providing clearer structural delineation. Routine use of the T1GRE pulse sequence can help pre-therapeutic planning or follow-up of AVM. PMID- 24148585 TI - Non Vascular Congenital Brain Malformations. An MR Study of 5000 Patients. AB - Central nervous system (CNS) malformations are frequently severe and often fatal. Diagnosis during pregnancy is of fundamental importance for a correct clinical evaluation and pharmacological management or, where possible, surgery. Modern imaging technology, pre and post-natal ultrasound scans, but above all magnetic resonance (MR) imaging have revolutionized the diagnostic study of cerebral malformations. In particular, MR provides images of the various brain sections by means of a multidisciplinary non invasive study that today is particularly rapid. MR allows an accurate assessment of cortical development, normal myelinization and the evolution of malformations. We report here our experience with MR carried out after birth on 5000 patients for the study of non vascular cortical anomalies. In only one case was the examination carried out during pregnancy, following ultrasound investigations that showed a developmental anomaly of the corpus callosum. We confirmed 112 malformations with an incidence of 2.24%, greater in males and affecting principally the anatomy of the supratentorial encephalic structures. These cases were selected and MR was carried out based on the clinical picture present at the time of the examination or a suspected diagnosis formulated following ultrasound. The ultrasound investigations were carried out principally in the obstetrics department; only a few were carried out in our unit, together with most of the postnatal ultrasound scans. The percentage of the various malformations was higher than those reported in the literature. PMID- 24148586 TI - Characteristic MR Imaging Findings of Neurocutaneous Melanosis. A Case Report. AB - Neurocutaneous melanosis is a type of phakomatosis characterised by dermal, leptomeningeal and parenchymal melanocytic naevi. Here we describe a case of a 13 year-old boy with dermal and brain parenchymal melanosis without any leptomeningeal melanosis. PMID- 24148587 TI - Diffuse Axonal Injury: CT Findings and Clinical Profiles in Six Consecutive Cases. AB - Diffuse axonal injury is a relatively rare type of brain trauma when prolonged coma with generally poor clinical outcome is often associated with negative neuroimaging findings. Although magnetic resonance imaging is the method of choice for evaluation of diffuse axonal injury, computed tomography still plays an important role as an emergency visualization modality. We compared computed tomography findings with clinical data, short and medium-term outcomes and, if available, autopsy results of six consecutive patients admitted to our hospital during the year of 2009. We found that corpus callosum lesions were most closely associated with diffuse axonal injury, followed by subdural hematoma or hygroma. PMID- 24148588 TI - Diffuse Axonal Injury: a Brief Review and Examples of the Use of Neurofunctional Imaging (Tc-99m HMPAO SPECT) in Diagnosis and Follow-up. AB - Diffuse axonal injury (DAI) is a growing problem nowadays as its social and economic costs amount to millions of dollars. DAI is now thought to be the predominant mechanism of injury in almost half the cases of traumatic brain injury connected with loss of consciousness. Computed tomography and magnetic resonance imaging are substantial techniques to diagnose DAI but they have their limitations. Neuropsychological tests used in follow-up disclose persistent disabilities in patients with total regression of CT and MRI changes. In those situations SPECT is appropriate as it shows lesions not disclosed by other imaging techniques. This article describes two cases in which usefulness of SPECT has been proved. A brief review of DAI has been included. PMID- 24148589 TI - Three-dimensional image analysis of the temporal bone in patients with unilateral attic cholesteatoma. AB - We determined temporal bone anatomy in patients with unilateral attic cholesteatoma. We compared the affected and normal ears of ten patients with unilateral attic cholesteatoma using three-dimensionally reconstructed high resolution computed tomography images of the temporal bone. We determined the eustachian tube angle, eustachian tube length, sizes of the tympanic orifice of the eustachian tube, the pars flaccida, and the mastoid cavity, and distances of the pars flaccida and the tympanic orifice of the eustachian tube from the epitympanic roof. No significant differences were found between the normal and affected ears with regard to the size of the eustachian tube orifice, eustachian tube length or distances of the pars flaccida and the tympanic orifice of the eustachian tube from the epitympanic roof. By contrast, the mastoid cavity and the eustachian tube angle were significantly larger in the normal ears than in the affected ears [mean, 6.99 cm(3) (S.D.,4.9 cm(3)) vs. 1.28 cm(3) (0.81 cm(3)) and 16.7 degrees (4.12 degrees ) vs. 13.89 degrees (5.30 degrees ), respectively]. The pars flaccida was significantly smaller in the normal ears [1.07 cm (0.31 cm)] than in the affected ears [2.19 cm (0.77 cm)]. The inherent anatomy of the eustachian tube may be particularly important in the formation of attic cholesteatomas. PMID- 24148590 TI - Bilateral Hippocampal DWI Lesions in Transient Global Amnesia. A Case Report. AB - Transient global amnesia (TGA) is characterized by anterograde memory disturbance of sudden onset that lasts for 1 to 24 hours. The etiology and pathogenesis of TGA are still uncertain, although an hypoxic-ischemic origin has been recently suggested on the basis of infarct-like diffusion-weighted imaging (DWI) lesions in the hippocampus of some affected individuals. Recent diffusion-weighted imaging (DWI) studies have indicated the presence of focal hyperintensities involving the hippocampus in TGA patients. These lesions detected by DWI, which peak at 48 to 72 hours, are small and punctate (1-3 mm) and in most studies are reported as unilateral. We describe one TGA patient with high signal-intensity lesions in the bilateral hippocampus on DWI at the acute stage. The mechanisms related to the pathophysiology are discussed with emphasis on the hypoxic ischemic origin underlying the observation of infarct-like diffusion-weighted imaging (DWI) abnormalities. PMID- 24148591 TI - Frontoethmoidal encephalocele with subependymal nodular heterotopia: an unusual association. A case report. AB - Frontonasal encephaloceles involve herniation of meninges and brain tissue through defects in the floor of the anterior cranial fossa affecting the frontal, ethmoid and nasal bones. Subependymal nodular heterotopias are malformations of cortical development resulting from abnormal neuronal migration. This report describes the coexistence and association of these two entities which is extremely rare. We describe an unusual case of a six-year-old girl with a frontonasal encephalocele in whom further imaging disclosed subependymal nodular heterotopias. Clinically she presented with swelling over the glabella since birth but otherwise was asymptomatic. CT and MRI showed herniation of brain tissue with the overlying dura and CSF through a defect in the frontal, ethmoid and nasal bones. In addition, MRI revealed heterotopic nodules in the subependymal regions of the lateral ventricles that were isointense with grey matter on all sequences. The patient underwent one stage surgery for correction of the encephalocele. PMID- 24148592 TI - Vasospasm and cerebral infarction from pituitary apoplexy. A case report. AB - Pituitary apoplexy is a potentially life-threatening acute or subacute clinical syndrome occurring from enlargement of the pituitary gland, and pituitary insufficiency, from hemorrhage or ischemia from an unknown pituitary lesion, most frequently being a non-functioning macroadenoma. A close, and multidisciplinary management is required. The purpose of this case report is to increase awareness to pituitary apoplexy presentation and management by reporting clinical features and neuroradiological findings observed in a 70-year-old patient with an unknown pituitary lesion. He presented with pituitary apoplexy and brain ischemia at magnetic resonance imaging (MRI) including diffusion-weighted imaging (DWI), and apparent diffusion coefficient (ADC) maps. MR angiography (MRA) showed diffuse vasospasm of anterior and posterior circulation. Both MRI and cytochemical examination of the cerebrospinal fluid ruled out subarachnoid hemorrhage. Due to concomitant diseases, and absence of visual deficit, the management was conservative by medical and substitutive therapy, without surgery. Clinical follow-up showed clearcut improvement, and this was consistent with MRI and MRA evidence of vasospasm regression, and clearcut pituitary lesion shrinkage. Pituitary lesions with hemorrhagic infarction presenting with pituitary apoplexy may be associated with vasospasm and brain ischemia at diagnosis, also in the absence of subarachnoid hemorrhage. A correct MR evaluation of patients with PA should include DWI, ADC maps, and MRA. Notably, early diagnosis of PA-associated vasospasm and cerebral ischemia avoids the possibility of their detection only after neurosurgery. PMID- 24148593 TI - Evaluation of a Patient with Klumpke's Palsy. A Case Report. AB - Klumpke's palsy is a rare form of paralysis involving the muscles of the forearm and hand, resulting from a brachial plexus injury in which the eighth cervical (C8) and first thoracic (Th1) nerves are injured either before or after they have joined to form the lower trunk. We report a case of a 45 years-old woman with post-traumatic left cervical-brachial pain afflicted by obstetric brachial plexus palsy on the right side. Magnetic Resonance Imaging (MRI) examination of the cervical spine revealed a meningeal stretch in the left side at C7-Th1 level, responsible for pain, and also multiple intraforaminal pseudomeningoceles at C5 C6, C6-C7 and C7-Th1 intersomatic spaces in the right side, due to the perinatal trauma that had determined the obstetric brachial plexus palsy. Spinal pseudomeningocele is an extradural collection of CSF in the surrounding soft tissues due to a dural breach and can represent a predictive finding of injury of the brachial plexus. We obtained clinical and electrophysiological findings of Klumpke's palsy, but MRI examination showed the lack of visualization of C8 and the integrity of Th1 nerve roots and to our knowledge there is no evidence in literature about the possibility to have a partial Klumpke's palsy without Th1 avulsion. The aim of this article was to underline that for the correct assessment of patients with brachial plexus palsy the only use of MRI is insufficient: it is necessary an integration of the information obtained from clinical, electromyographic and MRI study. PMID- 24148594 TI - Magnetic resonance imaging and ultrasonographic evaluation of retinal detachment in orbital uveal melanomas. AB - We assess the role of ultrasonography (US) in the evaluation of retinal detachment in patients with uveal melanomas, in correlation with magnetic resonance imaging (MRI) findings. Twenty-six patients (13? and 13?) with uveal melanomas underwent MRI and US examination. The signal intensity of the tumors and retinal detachments were depicted using MRI. The position of retinal detachment in correlation with the position of intraocular tumor was also evaluated performing ultrasound examination. MRI and US identified uveal melanoma in all 26 patients. In 11 of the 26 patients (42.3%) uveal melanoma was accompanied by retinal detachment. MRI demonstrated retinal detachment in nine patients. US disclosed retinal detachment in two more cases. US has an important role in the depiction of uveal melanomas and associated retinal detachment. It also appears to be more sensitive than MRI in detecting retinal detachment in patients with orbital uveal melanomas. PMID- 24148595 TI - Hydromyelia secondary to spinal epidural abscess. A case report. AB - Spinal epidural abscess (SEA) is a rare condition that can be fatal if untreated. Risk factors are immunocompromised states as well as spinal procedures including epidural anesthesia and spinal surgery. The signs and symptoms of SEA are nonspecific and can range from low back pain to sepsis. The treatment of choice is surgical decompression followed by four to six weeks of antibiotic therapy. The most common causative organism in SEA is staphylococcus aureus and spread is usually haematogenous or contiguous from psoas, paraspinal or retropharyngeal abscesses. The exact mechanism by which an epidural abscess causes spinal cord damage is unclear. In fact, the damage is often out of proportion to the degree of compression demonstrated radiologically. There is only a report of a patient with syrinx formation secondary to epidural abscess. We describe the case of a 48 year-old woman with a two-week history of thoracic back pain and evidence of dorsal SEA probably from contiguous psoas abscess. Neurological examination revealed flaccid paraplegia and loss of sphincter control. A spinal MRI scan with Gd-enhancement revealed focal high intensity signal in the T2-weighted and FLAIR images at the level of the vertebral bodies in segments D3-D11. The patient was treated with posterior decompression and drainage of the SEA, but with a poor outcome. Six weeks after the onset of symptoms, an MRI scan showed a newly-formed hydromyelia formation from D4 to D8. The case reported is the second to describe hydromyelia formation secondary to epidural abscess and a poor outcome, experiencing partial improvement without recovery. For this reason, we confirmed that the essential problem of SEA lies in the need for early diagnosis, because the early signs and symptoms may be vague and the "classic" triad of back pain, fever and variable neurological deficits occur in only 13% of patients by the time of diagnosis. Only timely treatment will avoid or reduce permanent neurological deficits before massive neurological symptoms occur. The clear message is that a high index of suspicion and modern imaging techniques are essential. PMID- 24148596 TI - Multifocal Intramedullary Hemorrhages without Identifiable Predisposing or Precipitating Causes. A Case Report. AB - Spinal cord disease can present in a variety of ways with acute, subacute or chronic onset, and clinical symptoms may vary from incomplete syndromes to complete quadriparesis. Acute quadriparesis beginning with excruciating pain in the chest and back progressing over a short period to quadriparesis is highly suggestive of spinal hemorrhage which can be epidural, subdural, subarachnoid or intramedullary. Intramedullary hemorrhage is the least common type and is mostly associated with predisposing focal diseases like tumor, AVM, cavernomas, spinal artery aneurysm, or due to generalized hematological coagulation abnormality. Nevertheless, spontaneous hematomyelia is also described which can be patchy with more than one segment involvement separated with a non involved segment of cord. We describe a young hematomyelia patient with such a multifocal long segment involvement of the spinal cord on MRI extending from the lower medulla to the conus. PMID- 24148597 TI - Morphology and TGF-beta1 Concentration Analysis of Ligamentum Flavum in Patients with Lumbar Canal Stenosis and Lumbar Disc Herniation. AB - The most common spinal disorder in elderly patients is lumbar spinal canal stenosis, causing low back and leg pain and paresis. The aetiology of degenerative changes occurring in lumbar stenosis remain unclear: some authors hypothesize hyperplasia and others hypertrophy of the LF. The change in LF is known to be related to degenerative changes secondary to the aging process or mechanical instability. This study aimed to analyse the ligamentum flavum (LF) of patients with lumbar canal stenosis and lumbar disc herniation to evaluate the morphology and concentration of the Transforming Growth Factor-beta 1 (TGF-beta 1). The study was undertaken in three phases: A) Measurement of the thickness of the ligamentum flavum in patients with lumbar stenosis and/or herniated lumbar disc through axial T1 weighted lumbo-sacral MR images; B) Removal of ligamentum flavum in patients undergoing intervention for lumbar stenosis and lumbar disc herniation (control group); C) Optical microscopy study of the morphology of degenerated ligamentum and immunohistochemical analysis to assess the concentration of TGF-beta 1 in the LF. Morphological analysis of the LF (i.e. the increase in the number of fibres or distension and relaxation of the same as a result of degenerative processes) and the presence or absence of a high concentration of TGF-beta1 (then more fibroblasts involved in the degenerative process) can be important to establish whether there is hypertrophy or hyperplasia of the LF in lumbar canal stenosis. The current study showed that decreased elasticity of the LF in the elderly is due to a loss of elastic fibres that are degenerated and a concomitant increase in collagenous fibres (hypertrophy). TGF-beta1 concentrations of the LF were higher in lumbar spinal stenosis than in disc herniations. This suggest that LF of lumbar canal stenosis is hypertrophic: LF hypertrophy could be due to thickening of the normal elastic layer and the abnormal collagenous layer and to higher expression of TGF-beta 1 by fibroblasts. PMID- 24148598 TI - Evaluation of angiographic findings in spontaneous aneurysmal subarachnoid hemorrhage patients. AB - This paper describes the angiographic findings of spontaneous aneurysmal subarachnoid hemorrhage (SAH) patients, including frequency, anatomic location and multiplicity of cerebral aneurysms. We retrospectively reviewed the records of 796 SAH patients at our university affiliated hospital. After confirming SAH by lumbar puncture or CT scan, all patients underwent digital subtraction angiography to find the definite anatomic location. The male to Female ratio in SAH patients was 9:10. The mean (SD) age of all patients with SAH was 47.9+/-14.7 years. The mean (SD) age of men with SAH was 46.6 +/-15.6 years and women with SAH was 49.3+/-13.5 years (P=0.015). 357 (44.8%) patients had aneurysms. The mean (SD) age of aneurysmal patients was 49.8+/-14.3 years. The mean (SD) age of men with aneurysm was 47.8 +/-15.9 years and women with aneurysm was 51.3+/-12.9 years (P= 0.03). The male to female ratio in aneurysms was 0.72:1. The most common aneurysm location was in the anterior communicating artery (N=166, 39%). The second most common anatomic location was the middle cerebral artery bifurcation (66 left, 60 right). The total number of patients with single aneurysms was 303 (84.9%) while 54 (15.1%) patients had multiple aneurysms. Among these patients, 49 had two aneurysms, three had three aneurysms and two had four aneurysms. In all, 418 aneurysms were detected. Of 357 patients with aneurysms 150 (42%) had vasospasm during angiography. In conclusion, the most common aneurysm location was the anterior communicating artery and the rate of multiplicity was also higher in our patients. PMID- 24148599 TI - Endovascular embolization for deep Basal Ganglia arteriovenous malformations. AB - We report our experience with basal ganglia AVM embolization and clinical outcomes after embolization. We retrospectively evaluated consecutive 15 patients with AVMs in the basal ganglia with respect to the endovascular treatment of these lesions. Treatment consisted of embolization and radiosurgery in combination. The angiographic follow-up after the last management was 24-36 months (mean 27 months). Clinical follow-up monitoring (range, 24-120 months, mean 76 months) was measured by the Modified Rankin Scale (mRS). The 15 patients studied had a mean age of 25.1 years at diagnosis, and 33.3% were male. Intracranial hemorrhage (ICH) was the event leading to clinical detection in eight patients (53.3%), and 85.5% of these patients were left with hemiparesis. At presentation, eight (53.3%) patients bled a total of 11 times. Twenty-four embolization procedures (16 pedicles embolized) were performed in 15 patients with embolization as the adjunct to radiosurgery. There were three clinically significant complications. Excellent or good outcomes (mRS<=2) were observed in 13 (86.7%) patients. Unfavorable outcomes (mRS<=2) were 13.3% at follow-up, without mortality. Seven (46.7%) patients had complete AVM obliteration at follow up. The risk of incurring a neurological deficit with basal ganglia AVM is high. Treatment of these patients is endovascular embolization with a combination of radiosurgery to prevent neurological injury from a spontaneous ICH. PMID- 24148600 TI - An unusual case of coil migration. A case report. AB - Migration of endovascular coils from aneurysms has been reported in the past. However, we report a case where the entire coil mass migrated out of the aneurysm into the anterior cerebral artery with associated doubling of aneurysm diameter in the intervening two weeks period post-coiling. PMID- 24148601 TI - Endovascular treatment of a fusiform cerebral aneurysm by stenting alone. Two case reports and literature review. AB - This paper illustrates two cases of stent-in-stenting treatment of unruptured, symptomatic, fusiform intracerebral aneurysms. Two unruptured symptomatic fusiform intracerebral aneurysms were treated by the stent-in-stent only technique. The first patient, a 35-year-old woman, had a partially thrombosed fusiform aneurysm in the left carotid siphon with the chief complaint of headache and left ophthalmoplegia. The second patient, a 60-year-old man, had a symptomatic fusiform aneurysm of the left V4 with recurrent transient ischemic attacks. No cervical trauma or infection was present in either patient. A CT, CTA and DSA were performed on hospital admission. Both patients were previously premedicated with Clopidrogel + ASA for five days before treatment. By DSA, both patients were treated under general anesthesia with a heparin protocol plus ASA (500mg) at stent placement. A double stent-in stent was placed in both patients. Post-intervention medical therapy was clopridogel and ASA for three months, then aspirin (100mg) daily for six months. CTA and DSA were performed at six and 12 months. Both stents were positioned without any difficulty and could be navigated within cerebral arteries without any exchange procedure, and thanks to their retractability, they were accurately positioned. No bleeding at post-treatment CT was noted. At 12 months follow-up, a complete disappearance of the aneurysm and preservation of the parent vessel was observed for both patients. No procedure related complication occurred. No intra-stent stenosis or intimal hyperplasia was observed. Stenting for fusiform aneurysms is a safe procedure without complications. Medical therapy pre-post procedure associated with follow-up is necessary to prevent/establish the incidence of occlusion. PMID- 24148602 TI - Toward HLA epitope matching in clinical transplantation. PMID- 24148603 TI - Apigenin potentiates the growth inhibitory effects by IKK-beta-mediated NF-kappaB activation in pancreatic cancer cells. AB - Apigenin is a potential chemopreventive agent for cancer prevention. Because of the central role of transcription factor nuclear factor-kappaB (NF-kappaB) in pancreatic cancer, we investigated the roles of NF-kappaB in apigenin-induced growth inhibition in pancreatic cancer cells. It showed that apigenin reduced cell growth and induced apoptosis in the cells. Apigenin treatment down-regulated not only basal but also TNF-alpha-induced NF-kappaB DNA binding activity, NF kappaB transcription activity, inhibitor of kappaB (IkappaB)-alpha phosphorylation together with translocation of p65 and p50, and it accompanied with the blockade of IkappaB kinase (IKK)-beta activity. Moreover, IKK blockage potentiated the anticancer efficacy of apigenin and IKK-beta overexpression attenuated the apigenin-induced cell growth inhibition. Additionally, apigenin (30 mg/kg) administration suppressed pancreatic cancer growth and IKK-beta activation in nude mice xenograft. These results indicated that apigenin had a potential to inhibit IKK-beta-mediated NF-kappaB activation, and was a valuable agent for the pancreatic cancer treatment. PMID- 24148604 TI - Rutin activates the MAPK pathway and BDNF gene expression on beta-amyloid induced neurotoxicity in rats. AB - Flavonoids are present in foods such as fruits and vegetables. A relationship between the consumption of flavonoid-rich foods and prevention of human disease including neurodegenerative disorders has been demonstrated. We assessed the effect of rutin (3,3',4',5,7-pentahydroxyflavone-3-rhamnoglucoside) on the mitogen-activated protein kinase (MAPK) pathway, memory retrieval and oxidative stress in rats injected with beta-amyloid (Abeta), which is implicated to have an important role in Alzheimer's disease (AD). Abeta was injected bilaterally in the deep frontal cortex of rat brain. Next, rutin and saline were injected (i.p.) for 3 weeks. In comparison to the control group, rutin significantly increased extracellular signal-regulated protein kinase 1 (ERK1), cAMP response element binding protein (CREB) and brain-derived neurotrophic factor (BDNF) gene expression in the hippocampus of rats. Rutin (100 mg/kg) significantly increased memory retrieval compared to the control group. Malondialdehyde (MDA) level in the hippocampus of the rutin group was significantly lower than those in the control group. The content of sulfhydryl groups in the rutin group was higher than that in the control group. The findings show a possibility that rutin may have beneficial effects against neurotoxicity of Abeta on memory in rats. PMID- 24148605 TI - The European Heart Failure Self-care Behaviour Scale: new insights into factorial structure, reliability, precision and scoring procedure. AB - OBJECTIVE: To evaluate a new factorial structure of the European Heart Failure Self-care Behaviour Scale 9-item version (EHFScBS-9), and to test its reliability, floor and ceiling effect, and precision. To propose a new 0-100 score with a higher score meaning better self-care. METHODS: A sample of 1192 Heart Failure (HF) patients (mean age 72 years, 58% male) was enrolled. Psychometric properties of the EHFScBS-9 were tested with confirmative factor analysis, factor score determinacy, determining the floor and ceiling effect, and evaluating the precision with the standard error of measurement (SEM) and the smallest real difference (SRD). RESULTS: We identified three well-fitting factors: consulting behaviour, autonomy-based adherence, and provider-based adherence (comparative fit index=0.96). Reliability ranged from 0.77 to 0.95. The EHFScBS-9 showed no floor and ceiling effect except for the provider-based adherence which had an expected ceiling effect. The SEM and the SRD indicated good precision of the EHFScBS-9. CONCLUSION: The new factorial structure of the EHFScBS-9 showed supportive psychometric properties. PRACTICE IMPLICATIONS: The EHFScBS-9 can be used to compute a total and specific scores for each identified factor. This may allow more detailed assessment and tailored interventions to improve self-care. The new score makes interpretation of the EHFScBS-9 easier. PMID- 24148606 TI - Clinical outcome and vertical transmission variability among canine Neospora caninum isolates in a pregnant mouse model of infection. AB - We compared the clinical outcome and vertical transmission of six canine Neospora caninum isolates using a pregnant BALB/c model. Four of the isolates were obtained from oocysts of naturally infected dogs (Nc-Ger2, Nc-Ger3, Nc-Ger6 and Nc-6Arg) and two were from diseased dogs with neurological signs (Nc-Bahia and Nc Liv). The dams were inoculated with 2*106 tachyzoites of each isolate at day 7 of pregnancy. Morbidity, mortality and the antibody responses were evaluated in both the dams and the offspring, as was parasite transmission to the progeny. The mortality rates varied from 100% in Nc-Bahia and Nc-Liv-infected pups to 19% or less for those infected with the isolates from oocysts. The vertical transmission rates varied from 9 to 53% for N. caninum from oocysts, compared with 100% for the Nc-Liv and Nc-Bahia isolates. All dams showed specific IgG responses against tachyzoite and rNc-GRA7 antigens, confirming Neospora infection. The highest IgG levels were detected in mice inoculated with the Nc-Liv and Nc-Bahia isolates. These results demonstrate marked differences in virulence between the N. caninum isolates obtained from oocysts and neurologically affected dogs. This variability could help us to explain the differences in the outcome of the infection in definitive and intermediate hosts. PMID- 24148607 TI - Association between zinc intake and risk of digestive tract cancers: a systematic review and meta-analysis. AB - BACKGROUND & AIMS: Association between zinc intake and digestive tract cancers risk has been reported in several epidemiological studies, while the results were controversial. The aim of our study was to get a systemic review of this issue. METHODS: PUBMED and EMBASE were searched up to April 2013, supplemented with manual-screening for relevant articles. Two independent reviewers independently extracted data from eligible studies, risk ratio (RR) or odds ratio (OR) with 95% CIs for the highest versus lowest categories of zinc intake was adopted. Either a fixed- or a random-effects model was adopted to estimate overall odds ratios. Besides, dose-response, subgroup, and publication bias analyses were applied. RESULTS: Nineteen studies with approximately 400,000 participants were included in this meta-analysis. The pooled relative risk (RR) of overall digestive tract cancers for the highest versus lowest categories of zinc intake was 0.82 (95% CI: 0.70-0.96; p = 0.013). Comparing the highest with lowest categories, higher zinc intake was significantly associated with reduced colorectal cancer risk (pooled RR = 0.80, 95% CI: 0.70-0.92; p = 0.002), while zinc intake was not statistically associated with gastric cancer risk (pooled RR = 0.91, 95% CI: 0.64-1.29; p = 0.581) or esophageal cancer risk (pooled RR = 0.72, 95% CI: 0.44-1.17; p = 0.187). However, subgroup analyses showed that zinc intake was significantly associated with esophageal cancer risk and gastric cancer risk in Asia, but not in America and Europe. CONCLUSIONS: Dietary zinc intake was inversely associated with digestive tract cancers, especially colorectal cancer risk in this study. PMID- 24148608 TI - Types of stroke recurrence in patients with ischemic stroke: a substudy from the PRoFESS trial. AB - BACKGROUND: Risk profiles for stroke recurrence are poorly characterized. AIMS: We determined the variation in the risk and type of recurrent stroke among index ischemic stroke subtypes, and whether index stroke subtype and conventional stroke risk factors were predictors of stroke recurrence. METHODS: Patients enrolled in the Prevention Regimen for Effectively Avoiding Second Strokes trial were included in this study. RESULTS: In 1794 patients' recurrent stroke subtypes were the same as the index stroke in: 48.3% of patients with large artery atherothrombosis stroke; 50% of patients with cardioembolic stroke; 48.7% of patients with small artery occlusion stroke; 8.1% of patients with stroke of other etiology, and 45.3% of patients with undetermined etiology stroke. Patients with cardioembolic stroke, who were unwilling or unable to take oral anticoagulants, had the greatest risk of stroke recurrence. Predictors of stroke recurrence in multivariable analysis were: older age and previous stroke among large artery atherothrombosis strokes; older age, male sex, previous stroke, previous transient ischemic attack, hypertension, diabetes, and tobacco use among small artery occlusion strokes; older age among cardioembolic strokes; atrial fibrillation and anti-diabetic medications among other etiology strokes; older age, previous stroke and atrial fibrillation among undetermined etiology strokes. Predictors of brain hemorrhage as recurrent stroke were index small artery occlusion stroke, older age, previous stroke, and antiplatelet treatment with aspirin plus extended-release dipyridamole. CONCLUSIONS: Risk predictors for stroke recurrence and for brain hemorrhage differ by index ischemic stroke subtype, information that is important when initiating secondary prevention therapy. PMID- 24148609 TI - Do outcomes differ between work and non-work-related injury in a universal injury compensation system? Findings from the New Zealand Prospective Outcomes of Injury Study. AB - BACKGROUND: Poorer recovery outcomes for workers injured in a work setting, as opposed to a non-work setting, are commonly attributed to differences in financial gain via entitlement to compensation by injury setting (ie. workers compensation schemes). To date, this attribution hasn't been tested in a situation where both work and non-work-related injuries have an equivalent entitlement to compensation. This study tests the hypothesis that there will be no differences in recovery outcomes for workers by injury setting (work and non work) within a single universal entitlement injury compensation scheme. METHODS: Workforce active participants from the Prospective Outcomes of Injury Study (POIS) cohort were followed up at 3- and 12-months following injury. Participants who were injured in the period June 2007- May 2009 were recruited from New Zealand's universal entitlement injury compensation scheme managed by the Accident Compensation Corporation (ACC). An analysis of ten vocational, disability, functional and psychological recovery outcomes was undertaken by injury setting. Modified Poisson regression analyses were undertaken to examine the relationship between injury setting and recovery outcomes. RESULTS: Of 2092 eligible participants, 741 (35%) had sustained an injury in a work setting. At 3 months, workers with work-related injuries had an elevated risk of work absence however, this difference disappeared after controlling for confounding variables (adjusted RR 1.10, 95% CI 0.94-1.29). By 12 months, workers with work-related injuries had poorer recovery outcomes with a higher risk of absence from work (aRR 1.37, 95% CI 1.10-1.70), mobility-related functional problems (aRR 1.35, 95% CI 1.14-1.60), disability (aRR 1.32, 95% CI 1.04-1.68) and impaired functioning related to anxiety/depression (aRR 1.21, 95% CI 1.00-1.46). CONCLUSION: Our study, comparing recovery outcomes for workers by injury setting within a single universal entitlement injury compensation scheme, found mixed support for the hypothesis tested. After adjustment for possible covariates recovery outcomes did not differ by injury setting at 3 months following injury, however, by 12 months vocational, disability and some functional outcomes, were poorer for workers with work-related injuries. Given our findings, and other potential mechanisms for poorer outcomes for workers with work-related injuries, further research beyond differences in entitlement to compensation should be undertaken to inform future interventions. PMID- 24148610 TI - Association of GGCX gene polymorphism with warfarin dose in atrial fibrillation population in Xinjiang. AB - OBJECTIVE: To study the effects of gamma-glutamyl carboxylase (GGCX) rs2592551 polymorphism on warfarin dose in atrial fibrillation patients in Xinjiang region. METHODS: Polymerase chain reaction - restriction fragment length polymorphism and direct sequencing methods were used to detect the rs2592551 genotype in 269 atrial fibrillation patients with warfarin administration. The effects of different genotypes on warfarin dose were statistically analyzed. RESULTS: The rs2592551 polymorphism detection results were 136 cases of wild-type homozygous CC genotype (50.56%), 115 cases of heterozygous CT genotype (42.75%), 18 cases of homozygous TT genotype (6.69%). The allele frequency C was 71.93%, T was 28.07%. The stable warfarin dose average was 2.86 +/- 0.61 mg/d in patients with CC genotype, 3.59 +/- 0.93 mg/d in patients with CT genotype and 4.06 +/- 0.88 mg/d in patients with TT genotype. The warfarin dose in different genotypes were compared, there was statistically significant difference between CC and TT, CC and CT (P <0. 05), but the TT and CT showed no significant difference (P > 0.05). CONCLUSION: In atrial fibrillation population in Xinjiang, patients with CT and TT genotypes in GGCX gene rs259251 loci required for significantly higher warfarin dose than those with CC genotype. Therefore, rs2592551 polymorphism may one of the factors affecting the warfarin dose in patients with atrial fibrillation. PMID- 24148611 TI - Effects of human disturbance on nest placement of the woodpigeon (Columba palumbus): a case study from the Middle Atlas, Morocco. AB - The woodpigeon (Columba palumbus) is a common and widespread bird in Morocco (North Africa). I examined, over 2 years (2010 and 2011), the breeding density and nest placement of this game species in relation to nest site habitat and degree of human disturbance. The study area was in the Middle Atlas Tighboula mountain forest, Morocco, in a disturbed and an undisturbed site. Using data collected in the 2 study sites, I aimed to identify the factors influencing the placement of nests within holm oak trees (Quercus rotundifolia) and their densities. I found that habitat structures, influenced by grazing disturbance, have affected nesting density and the location of nests of this species. Woodpigeons place their nests in a higher position (3.42 +/- 0.19 m) when disturbance intensity is high and lower (1.68 +/- 0.1 m) when disturbance intensity is low, and show higher nesting density in less disturbed zone (3.1 +/- 0.4 nests/ha) than in highly disturbed zones (1.4 +/- 0.2 nests/ha). Grazing disturbance could pose a threat to population persistence at a broader scale and could potentially reduce the abundance of this species by altering the composition and the structure of the forest nesting habitat. Further multi-scale studies are needed to assess the effects of different levels of grazing disturbance on woodpigeon nest density and placement, and to enhance our knowledge of the breeding behavior of this game species under variable environments. PMID- 24148613 TI - Gene expression is dynamically regulated in retinal progenitor cells prior to and during overt cellular differentiation. AB - The retina is comprised of one glial and six neuronal populations that are generated from a multipotent pool of retinal progenitor cells (RPCs) during development. To give rise to these different cell types, RPCs undergo temporal identity transitions, displaying distinct gene expression profiles at different stages of differentiation. Little, however, is known about temporal differences in RPC identities prior to the onset of overt cellular differentiation, during the period when a retinal identity is gradually acquired. Here we examined the sequential onset of expression of regional markers (i.e., homeodomain transcription factors) and cell fate determinants (i.e., basic-helix-loop-helix transcription factors and neurogenic genes) in RPCs from the earliest appearance of a morphologically-distinct retina. By performing a comparative analysis of the expression of a panel of 27 homeodomain, basic-helix-loop-helix and Notch pathway genes between embryonic day (E) 8.75 and postnatal day (P) 9, we identified six distinct RPC molecular profiles. At E8.75, the earliest stage assayed, murine RPCs expressed five homeodomain genes and a single neurogenic gene (Pax6, Six3, Six6, Rx, Otx2, Hes1). This early gene expression profile was remarkably similar to that of 'early' RPCs in the amphibian ciliary marginal zone (CMZ), where RPCs are compartmentalised according to developmental stage, and homologs of Pax6, Six3 and Rx are expressed in the 'early' stem cell zone. As development proceeds, expression of additional homeodomain, bHLH and neurogenic genes was gradually initiated in murine RPCs, allowing distinct genetic profiles to also be defined at E9.5, E10.5, E12.5, E15.5 and P0. In addition, RPCs in the postnatal ciliary margin, where retinal stem cells are retained throughout life, displayed a unique molecular signature, expressing all of the early-onset genes as well as several late-onset markers, indicative of a 'mixed' temporal identity. Taken together, the identification of temporal differences in gene expression in mammalian RPCs during pre-neurogenic developmental stages leads to new insights into how regional identities are progressively acquired during development, while comparisons at later stages highlight the dynamic nature of gene expression in temporally distinct RPC pools. PMID- 24148614 TI - Habitat fragmentation and recent bottlenecks influence genetic diversity and differentiation of the Central European halophyte Suaeda maritima (Chenopodiaceae). AB - PREMISE OF THE STUDY: Central European salt habitats are mainly restricted to the maritime coast but scattered occurrences can also be found inland. In inland habitats, human activities have caused losses and reductions in the size of natural salt sites but have also created new anthropogenic habitats around potash mining dumps colonized by halophytic species in the last 30 yr. We aimed to investigate the effects of bottlenecks, isolation, and ongoing habitat fragmentation on the genetic variation of a species commonly growing in these special habitats. METHODS: We used 10 microsatellite markers to compare genetic diversity and differentiation of 31 populations of Suaeda maritima (Chenopodiaceae) from Central European coasts and inland habitats. Two approaches were applied to analyze the tetraploid data based on allele frequencies directly derived from microsatellite data and from transformed binary data. KEY RESULTS: In comparison to the coastal populations from the North Sea and the English Channel, significantly reduced genetic variation and increased between-population differentiation was revealed for populations from the German inland and the Baltic Sea coast. Genetic structure analyses clearly separated coastal and inland populations. CONCLUSIONS: Our results indicate that gene flow is restricted among populations from inland salt sites and the Baltic Sea coast, presumably due to their isolation, small sizes, genetic bottlenecks and/or founder events. Patterns of allele distribution indicate some occasional genetic exchange among habitat types in the past. Anthropogenic salt sites may facilitate gene flow among inland salt habitats preventing endangered inland halophyte populations from genetic erosion. PMID- 24148612 TI - DNA repair in Mycoplasma gallisepticum. AB - BACKGROUND: DNA repair is essential for the maintenance of genome stability in all living beings. Genome size as well as the repertoire and abundance of DNA repair components may vary among prokaryotic species. The bacteria of the Mollicutes class feature a small genome size, absence of a cell wall, and a parasitic lifestyle. A small number of genes make Mollicutes a good model for a "minimal cell" concept. RESULTS: In this work we studied the DNA repair system of Mycoplasma gallisepticum on genomic, transcriptional, and proteomic levels. We detected 18 out of 22 members of the DNA repair system on a protein level. We found that abundance of the respective mRNAs is less than one per cell. We studied transcriptional response of DNA repair genes of M. gallisepticum at stress conditions including heat, osmotic, peroxide stresses, tetracycline and ciprofloxacin treatment, stationary phase and heat stress in stationary phase. CONCLUSIONS: Based on comparative genomic study, we determined that the DNA repair system M. gallisepticum includes a sufficient set of proteins to provide a cell with functional nucleotide and base excision repair and mismatch repair. We identified SOS-response in M. gallisepticum on ciprofloxacin, which is a known SOS-inducer, tetracycline and heat stress in the absence of established regulators. Heat stress was found to be the strongest SOS-inducer. We found that upon transition to stationary phase of culture growth transcription of DNA repair genes decreases dramatically. Heat stress does not induce SOS-response in a stationary phase. PMID- 24148615 TI - Inclusion of chloroplast genes that have undergone expansion misleads phylogenetic reconstruction in the Chlorophyta. AB - PREMISE OF THE STUDY: Chlorophytes comprise a substantial proportion of green plant diversity. However, sister-group relationships and circumscription of the classes Chlorophyceae, Trebouxiophyceae, and Ulvophyceae have been problematic to resolve. Some analyses support a sister relationship between the trebouxiophycean Leptosira and chlorophyceans, potentially altering the circumscription of two classes, also supported by a shared fragmentation in the chloroplast gene rpoB. We sought to determine whether the latter is a synapomorphy or whether the supporting analyses are vulnerable to systematic bias. METHODS: We sequenced a portion of rpoB spanning the fragmented region in strains for which it had not previously been sampled: four Chlorophyceae, six counterclockwise (CCW) group (ulvophyceans and trebouxiophyceans) and one streptophyte. We then explored the effect of subsampling proteins and taxa on phylogenetic reconstruction from a data set of 41 chloroplast proteins. KEY RESULTS: None of the CCW or streptophyte strains possessed the split in rpoB, including inferred near relatives of Leptosira, but it was found in all chlorophycean strains. We reconstructed alternative phylogenies (Leptosira + Chlorophyceae and Leptosira + Chlorellales) using two different protein groups (Rpo and Rps), both subject to coding-region expansion. A conserved region of RpoB remained suitable for analysis of more recent divergences. CONCLUSIONS: The Rps sequences can explain earlier findings linking Leptosira with the Chlorophyceae and should be excluded from phylogenetic analyses attempting to resolve deep nodes because their expansion violates the assumptions of substitution models. We reaffirm that Leptosira is a trebouxiophycean and that fragmentation of rpoB has occurred at least twice in chlorophyte evolution. PMID- 24148616 TI - Efficacy of oral versus intravenous hypertonic saline in runners with hyponatremia. AB - OBJECTIVES: To determine more conclusively whether intravenous (IV) administration of 3% saline is more efficacious than oral administration in reversing below normal blood sodium concentrations in runners with biochemical hyponatremia. DESIGN: Randomized controlled trial. METHODS: 26 hyponatremic race finishers participating in the 161-km Western States Endurance Run were randomized to receive either an oral (n=11) or IV (n=15) 100mL bolus of 3% saline. Blood sodium concentration (Na(+)), plasma protein (to assess %plasma volume change), arginine vasopressin (AVP), blood urea nitrogen (BUN) and urine (Na(+)) were measured before and 60 min following the 3% saline intervention. RESULTS: No significant differences were noted with respect to pre- to post intervention blood [Na(+)] change between intervention groups, although blood [Na(+)] increased over time in both intervention groups (+2 mmol/L; p<0.0001). Subjects receiving the IV bolus had a greater mean (+/- SD) plasma volume increase (+8.6 +/- 4.5% versus 1.4% +/- 5.7%; p<0.01) without significant change in [AVP] (-0.2 +/- 2.6 versus 0.0 +/- 0.5 pg/mL; p=0.49). 69% of subjects completing the intervention trial were able to produce urine at race finish with a mean (+/- SD) pre-intervention urine [Na(+)] of 15.2 +/- 8.5 mmol/L (range 0 35; NS between groups). [BUN] of the entire cohort pre-intervention was 30.7 +/- 10.5mg/dL (range 13-50). CONCLUSIONS: No group difference was noted in the primary outcome measure of change in blood [Na(+)] over 60 min of observation following a 100mL bolus of either oral or IV 3% saline. Administration of an oral hypertonic saline solution can be efficacious in reversing low blood sodium levels in runners with mild EAH. PMID- 24148618 TI - Loss of DAXX and ATRX are associated with chromosome instability and reduced survival of patients with pancreatic neuroendocrine tumors. AB - BACKGROUND & AIMS: Sporadic pancreatic neuroendocrine tumors (pNETs) are rare and genetically heterogeneous. Chromosome instability (CIN) has been detected in pNETs from patients with poor outcomes, but no specific genetic factors have been associated with CIN. Mutations in death domain-associated protein gene (DAXX) or ATR-X gene (ATRX) (which both encode proteins involved in chromatin remodeling) have been detected in 40% of pNETs, in association with activation of alternative lengthening of telomeres. We investigated whether loss of DAXX or ATRX, and consequent alternative lengthening of telomeres, are related to CIN in pNETs. We also assessed whether loss of DAXX or ATRX is associated with specific phenotypes of pNETs. METHODS: We collected well-differentiated primary pNET samples from 142 patients at the University Hospital Zurich and from 101 patients at the University Hospital Bern (both located in Switzerland). Clinical follow-up data were obtained for 149 patients from general practitioners and tumor registries. The tumors were reclassified into 3 groups according to the 2010 World Health Organization classification. Samples were analyzed by immunohistochemistry and telomeric fluorescence in situ hybridization. We correlated loss of DAXX, or ATRX, expression, and activation of alternative lengthening of telomeres with data from comparative genomic hybridization array studies, as well as with clinical and pathological features of the tumors and relapse and survival data. RESULTS: Loss of DAXX or ATRX protein and alternative lengthening of telomeres were associated with CIN in pNETs. Furthermore, loss of DAXX or ATRX correlated with tumor stage and metastasis, reduced time of relapse-free survival, and decreased time of tumor-associated survival. CONCLUSIONS: Loss of DAXX or ATRX is associated with CIN in pNETs and shorter survival times of patients. These results support the hypothesis that DAXX- and ATRX-negative tumors are a more aggressive subtype of pNET, and could lead to identification of strategies to target CIN in pancreatic tumors. PMID- 24148617 TI - Liver environment and HCV replication affect human T-cell phenotype and expression of inhibitory receptors. AB - BACKGROUND & AIMS: There is an unclear relationship between inhibitory receptor expression on T cells and their ability to control viral infections. Studies of human immune cells have been mostly limited to T cells from blood, which is often not the site of infection. We investigated the relationship between T-cell location, expression of inhibitory receptors, maturation, and viral control using blood and liver T cells from patients with hepatitis C virus (HCV) and other viral infections. METHODS: We analyzed 36 liver samples from HCV antibody positive patients (30 from patients with chronic HCV infection, 5 from patients with sustained virological responses to treatment, and 1 from a patient with spontaneous clearance) with 19 paired blood samples and 51 liver samples from HCV negative patients with 17 paired blood samples. Intrahepatic and circulating lymphocytes were extracted; T-cell markers and inhibitory receptors were quantified for total and virus-specific T cells by flow cytometry. RESULTS: Levels of the markers PD-1 and 2B4 (but not CD160, TIM-3, or LAG-3) were increased on intrahepatic T cells from healthy and diseased liver tissues compared with T cells from blood. HCV-specific intrahepatic CD8(+) T cells from patients with chronic HCV infection were distinct in that they expressed TIM-3 along with PD-1 and 2B4. In comparison, HCV-specific CD8(+) T cells from patients with sustained virological responses and T cells that recognized cytomegalovirus lacked TIM-3 but expressed higher levels of LAG-3; these cells also had different memory phenotypes and proliferative capacity. CONCLUSIONS: T cells from liver express different inhibitory receptors than T cells from blood, independent of liver disease. HCV-specific and cytomegalovirus-specific CD8(+) T cells can be differentiated based on their expression of inhibitory receptors; these correlate with their memory phenotype and levels of proliferation and viral control. PMID- 24148619 TI - Crohn's disease-associated adherent invasive Escherichia coli modulate levels of microRNAs in intestinal epithelial cells to reduce autophagy. AB - BACKGROUND & AIMS: Levels of microRNAs are altered in intestinal tissues of patients with Crohn's disease (CD). The adherent-invasive Escherichia coli (AIEC), which colonize the ileal mucosa of patients with CD, adhere to and invade intestinal epithelial cells. We investigated the mechanism by which AIEC infection alters the expression of microRNAs and the host immune response. METHODS: Levels of microRNAs in human intestinal epithelial T84 cells and in mouse enterocytes were measured using quantitative reverse-transcription polymerase chain reaction. Luciferase assays were used to measure binding of microRNAs to the 3'-untranslated region of messenger RNA targets. Binding of nuclear factor-kappaB to promoters of genes encoding microRNAs was assessed by chromatin immunoprecipitation assays. Autophagy was measured by immunoblot analyses and immunofluorescent labeling of LC3. Anti-microRNAs were transferred to mice using ileal loops. Biopsy specimens from the terminal ileum of patients with ulcerative colitis (n = 20), CD (n = 20), or individuals without inflammatory bowel disease undergoing surveillance colonoscopies (controls, n = 13) were collected during endoscopic examination. RESULTS: AIEC infection up regulated levels of microRNA (MIR) 30C and MIR130A in T84 cells and in mouse enterocytes by activating nuclear factor-kappaB. Up-regulation of these microRNAs reduced the levels of ATG5 and ATG16L1 and inhibited autophagy, leading to increased numbers of intracellular AIEC and an increased inflammatory response. In ileal biopsy samples of patients with CD, there was an inverse correlation between levels of MIR30C and MIR130A and those of ATG5 and ATG16L1, supporting in vitro findings. Inhibition of MIR30C and MIR130A in cultured intestinal epithelial cells and in mouse enterocytes blocked AIEC-induced inhibition of ATG5 and ATG16L1 expression and restored functional autophagy. This resulted in more effective clearance of intracellular AIEC and reduced AIEC-induced inflammation. CONCLUSIONS: Infection with AIEC up-regulates microRNAs to reduce expression of proteins required for autophagy and autophagy response in intestinal epithelial cells. Ileal samples from patients with CD have increased levels of these same microRNAs and reduced levels of ATG5 and ATG16L1. PMID- 24148621 TI - So you want to be a hepatologist? PMID- 24148620 TI - Extensive conversion of hepatic biliary epithelial cells to hepatocytes after near total loss of hepatocytes in zebrafish. AB - BACKGROUND & AIMS: Biliary epithelial cells (BECs) are considered to be a source of regenerating hepatocytes when hepatocyte proliferation is compromised. However, there is still controversy about the extent to which BECs can contribute to the regenerating hepatocyte population, and thereby to liver recovery. To investigate this issue, we established a zebrafish model of liver regeneration in which the extent of hepatocyte ablation can be controlled. METHODS: Hepatocytes were depleted by administration of metronidazole to Tg(fabp10a:CFP-NTR) animals. We traced the origin of regenerating hepatocytes using short-term lineage-tracing experiments, as well as the inducible Cre/loxP system; specifically, we utilized both a BEC tracer line Tg(Tp1:CreER(T2)) and a hepatocyte tracer line Tg(fabp10a:CreER(T2)). We also examined BEC and hepatocyte proliferation and liver marker gene expression during liver regeneration. RESULTS: BECs gave rise to most of the regenerating hepatocytes in larval and adult zebrafish after severe hepatocyte depletion. After hepatocyte loss, BECs proliferated as they dedifferentiated into hepatoblast-like cells; they subsequently differentiated into highly proliferative hepatocytes that restored the liver mass. This process was impaired in zebrafish wnt2bb mutants; in these animals, hepatocytes regenerated but their proliferation was greatly reduced. CONCLUSIONS: BECs contribute to regenerating hepatocytes after substantial hepatocyte depletion in zebrafish, thereby leading to recovery from severe liver damage. PMID- 24148623 TI - Combined targeting of PDK1 and EGFR triggers regression of glioblastoma by reversing the Warburg effect. AB - Glioblastoma multiforme is the most aggressive primary brain tumor in adults. Overexpression of the EGF receptor (EGFR) is recognized as a widespread oncogenic signature in glioblastoma multiforme, but the complexity of its contributions is not fully understood, nor the most effective ways to leverage anti-EGFR therapy in this setting. Hypoxia is known to drive the aggressive character of glioblastoma multiforme by promoting aerobic glycolysis rather than pyruvate oxidation carried out in mitochondria (OXPHOS), a phenomenon termed the Warburg effect, which is a general feature of oncogenesis. In this study, we report that hypoxia drives expression of the pyruvate dehydrogenase kinase (PDK1) and EGFR along with the hypoxia-inducing factor (HIF)-1alpha in human glioblastoma multiforme cells. PDK1 is a HIF-1-regulated gene and our findings indicated that hypoxia-induced PDK1 expression may promote EGFR activation, initiating a feed forward loop that can sustain malignant progression. RNAi-mediated attenuation of PDK1 and EGFR lowered PDK1-EGFR activation and decreased HIF-1alpha expression, shifting the Warburg phenotype to OXPHOS and inhibiting glioblastoma multiforme growth and proliferation. In clinical specimens of glioblastoma multiforme, we found that immunohistochemical expression of PDK1, EGFR, and HIF-1alpha were elevated in glioblastoma multiforme specimens when compared with normal brain tissues. Collectively, our studies establish PDK1 as a key driver and candidate therapeutic target in glioblastoma multiforme. PMID- 24148622 TI - A MELD-based model to determine risk of mortality among patients with acute variceal bleeding. AB - BACKGROUND & AIMS: Patients with cirrhosis with acute variceal bleeding (AVB) have high mortality rates (15%-20%). Previously described models are seldom used to determine prognoses of these patients, partially because they have not been validated externally and because they include subjective variables, such as bleeding during endoscopy and Child-Pugh score, which are evaluated inconsistently. We aimed to improve determination of risk for patients with AVB. METHODS: We analyzed data collected from 178 patients with cirrhosis (Child-Pugh scores of A, B, and C: 15%, 57%, and 28%, respectively) and esophageal AVB who received standard therapy from 2007 through 2010. We tested the performance (discrimination and calibration) of previously described models, including the model for end-stage liver disease (MELD), and developed a new MELD calibration to predict the mortality of patients within 6 weeks of presentation with AVB. MELD based predictions were validated in cohorts of patients from Canada (n = 240) and Spain (n = 221). RESULTS: Among study subjects, the 6-week mortality rate was 16%. MELD was the best model in terms of discrimination; it was recalibrated to predict the 6-week mortality rate with logistic regression (logit, -5.312 + 0.207 * MELD; bootstrapped R(2), 0.3295). MELD values of 19 or greater predicted 20% or greater mortality, whereas MELD scores less than 11 predicted less than 5% mortality. The model performed well for patients from Canada at all risk levels. In the Spanish validation set, in which all patients were treated with banding ligation, MELD predictions were accurate up to the 20% risk threshold. CONCLUSIONS: We developed a MELD-based model that accurately predicts mortality among patients with AVB, based on objective variables available at admission. This model could be useful to evaluate the efficacy of new therapies and stratify patients in randomized trials. PMID- 24148624 TI - A High CSF Signal on FLAIR: It Is Not Always Blood. AB - We describe a patient with progressive neurologic deficit due to middle cerebral branch occlusion. Temporary partial balloon occlusion of the abdominal aorta led to an increased signal in the subarachnoid space on fluid-attenuated inversion recovery images with no evidence of subarachnoid hemorrhage. After spontaneous recanalization, the increased signal of the subarachnoid space returned to normal. We assume that signal changes in the subarachnoid space were due to a temporary increase in blood volume in the superficial brain vessels. PMID- 24148625 TI - Hippocampal asymmetry with hippocampal sulcus remnants in a patient with mild cognitive impairment. A case report. AB - A 65-year-old woman underwent MRI for a mild cognitive impairment (MCI) at Mini Mental State Examination (MMSE). MRI showed hippocampal sulcus remnants bilaterally, although they were larger on the right, and left hippocampal atrophy with increased left fimbriosubicular distance (right side: 1.2 mm; left side: 2.0 mm). The meaning of these findings in relation to clinical aspects is discussed and reviewed according to data from the literature. PMID- 24148626 TI - MRI in a woman with late onset ornithine transcarbamylase deficiency. AB - We describe the brain MR imaging findings of a woman who developed neurologic symptoms due to an acute hyperammonemic encephalopathy resulting from late onset ornithine transcarbamylase deficiency (OCTD). MR images revealed injury (hyperintense foci on long TR images) to the subcortical white matter of the left precentral and supramarginal gyrus and in the left frontal lobe. These findings presumably reflect the distribution of brain injury from hypoperfusion secondary to severe hyperammonemia. If MR findings suggesting hypoperfusion are detected in a patient with hyperammonemia, the diagnosis of OCTD should be considered. Knowledge of the physiopathological mechanisms of OTCD and of MR imaging of hyperammonemic injury may help expedite diagnosis and treatment and prevent the exitus of patients with this genetic disorder. PMID- 24148627 TI - L-2 Hydroxyglutaric Aciduria: Magnetization Transfer Contrast and Diffusion Weighted Magnetic Resonance Imaging Findings. A case Report. AB - We describe the case of a 13-year-old male with u aciduria. Conventional magnetic resonance imaging and diffusion weighted imaging disclosed some previously unreported findings. In particular, we observed an almost total sparing of early myelinated regions, and a restricted diffusion pattern in the dentate nuclei. Magnetization transfer contrast showed a normal range of values in early myelinated regions, and revealed abnormal values in the subcortical temporal white matter, internal capsule and globi palladi. PMID- 24148628 TI - MRI Eye-of-the-Tiger Sign in Organophosphate Poisoning. A Case Report. AB - We describe the eye-of-the-tiger sign on magnetic resonance imaging (MRI) of the brain in a 40-year-old man presenting with extra pyramidal symptoms like chorea, flexion neck dystonia, tongue tremors, dysarthria and postural instability as the sequelae of organophosphorus poisoning six months previously. This typical radiological sign has been described in extrapyramidal parkinsonian disorders including cortical-basal ganglionic degeneration, early onset levodopa-responsive parkinsonism and Steele-Richardson-Olszewski syndrome (progressive supranuclear palsy) but hitherto has not been reported in insecticide poisoning. T2-weighted scans showed low signal intensity surrounding a central region of high signal intensity in the anteromedial globus pallidus (gliosis), producing an eye-of-the tiger appearance with the central hyperintense signal intensity better appreciated in T2W and fluid attenuated inversion recovery (FLAIR) sequences. PMID- 24148629 TI - Radiation-induced mineralizing microangiopathy in a case of recurrent craniopharyngioma. A case report. AB - Mineralizing microangiopathy is a late complication of radiation-induced brain injury that occurs during the treatment of CNS malignancies in children and adults. Early diagnosis of the radiation-induced brain injury helps to tailor the radiation dose and prevent further complications. Here we describe an operated oatient with craniopharyngioma who underwent external beam radiotherapy. The patient developed gradual loss of vision after two years and a review CT scan revealed the local recurrence of tumour with dystrophic calcification of the basal ganglia, frontal and temporal subcortical regions representing recurrent craniopharyngioma with radiation-induced mineralizing microangiopathy. PMID- 24148630 TI - Non-von Hippel-Lindau Hemangioblastoma in the Hippocampus: Characterization with Time-Resolved MRA Using TRICKS Sequence at 3T. A Case Report. AB - Supratentorial hemangioblastomas (HBs) are exceedingly rare tumors accounting for 5%-10% of all HBs and usually present in the setting of von Hippel-Lindau (VHL) disease. Isolated HBs of the central nervous system also occur as a result of spontaneous mutation in the absence of any clinical manifestations of VHL disease. Of 13 temporal lobe HBs, only one non-VHL case was reported in the hippocampus. We describe the TRICKS findings in a case of isolated hemangioblastoma in the hippocampus without VHL disease. To our knowledge, this is the second case report of a hippocampal non-VHL hemangioblastoma. PMID- 24148631 TI - Spontaneous temporal cerebrospinal fluid leak. A case report and literature review. AB - An abnormal communication between the subarachnoid spaces and the tympanic cavity and mastoid cells can determine a cerebrospinal fluid (CSF) leak in the air spaces of the temporal bone. The etiology of CFS leak in the temporal air cells includes acquired, congenital and spontaneous causes. Spontaneous CSF leak, defined as a leak without a manifest cause, is present in about 4% of cases and often occurs in the middle cranial fossa. We describe a case of spontaneous CSF leak in the right temporal air cells that mimicked a skull fracture in a subject with headache and apparent rhinorrhea after a head trauma. Both CT and MRI play a key role in the differential diagnosis between post-traumatic temporal CSF leak due to a fracture and spontaneous leak: traumatic CSF leak often does not require a surgical approach, whereas spontaneous CSF leak may need surgical treatment because of the risk of meningitis. PMID- 24148632 TI - Upward oriented sellar spine. MRI findings. A case report. AB - The sellar spine is a rare congenital malformation due to the persistence of a notochord rest within the fetal sella turcica. We describe a unique case of a sellar spine vertically oriented displacing the pituitary stalk upwards and forwards. The MRI findings are briefly discussed. PMID- 24148633 TI - Cerebral high grade glioma with crossed cerebellar metastases. A report of three cases. AB - We describe three patients with high grade supratentorial gliomas who were operated and later presented with cerebellar mass lesions on the opposite side. Supratentorial infarct with crossed cerebellar atrophy is a well-known entity called crossed cerebellar diaschisis. We hypothesize that supratentorial high grade tumours might also spread to the opposite cerebellum through crossed cerebrocerebellar fiber tracts similar to crossed cerebellar diaschisis. PMID- 24148634 TI - Primary hypothyroidism presenting as a sellar mass which regressed with thyroid hormone therapy. A case report. AB - We describe a15-year-old girl presenting with compensatory pituitary enlargement due to primary hypothyroidism. The hyperplasia regressed following thyroxine administration. The clinical, laboratory and MRI features of the patients are described and the mechanisms of pituitary gland enlargement are discussed. PMID- 24148635 TI - Spontaneous resolution of eosinophilic granuloma in a patient with a psychotic disorder. AB - A 16-year-old female who manifested psychotic symptoms underwent CT and MRI for the evaluation of an incidentally discovered asymptomatic palpable mass of the right occipital region of the skull. The correlation between clinical and radiological data and biopsy data led to the diagnosis of eosinophilic granuloma. The radiological finding is discussed and reviewed in relation to clinical aspects and literature data. PMID- 24148636 TI - An unusual cause of blepharospasm. AB - We describe a rare case of multiple dilated Virchow-Robin spaces in the brainstem in a patient presenting initially with blepharospasm with subsequent spread to involve the face and neck. On magnetic resonance imaging (MRI), these lesions demonstrated an isointense signal to cerebrospinal fluid on all sequences with no mass effect or enhancement. Although rare, this condition should be considered part of the differential diagnosis when evaluating cystic abnormalities in the brainstem. This is the first reported case of blepharospasm with subsequent orofacial and neck dystonia caused by dilated Virchow-Robin spaces. The imaging findings and differential diagnoses are discussed. PMID- 24148637 TI - An unusual presentation of lipofibromatous hamartoma in an infant. A case report. AB - Lipofibromatous hamartomas are rare benign tumors presenting in the third and fourth decades with a predilection for the upper extremity. We describe an unusual presentation of lipofibromatous hamartoma occurring in a one month old female child, where the lesion showed MR findings resembling that of a vascular malformation. PMID- 24148638 TI - Crossed cerebellar atrophy. A case report. AB - Crossed cerebellar atrophy is an uncommon sequelae of contralateral cerebral hemispheric lesion. This condition has been described in patients with supratentorial infarct, tumor, arteriovenous malformation and hemorrhage. Crossed cerebellar atrophy possibly occurs due to interruption of the corticopontocerebellar pathway at supratentorial level. PMID- 24148639 TI - Disseminated paracoccidioidomycosis with a single brainstem lesion. A case report and literature review. AB - Paracoccidioidomycosis is a systemic disease endemic to subtropical areas in Central and South America caused by a dimorphic fungus known as Paracoccidioides brasiliensis. Central nervous system involvement is a severe complication of the systemic disease, and has been found in approximately 13% of patients. This paper describes the case of a patient whose computed tomography scan and magnetic resonance imaging showed a single tumor-like lesion in the brainstem. Histopathological and mycological examinations of stereotactic biopsy smears showed the characteristic yeast cells that confirmed the diagnosis of neuroparacoccidioidomycosis. PMID- 24148640 TI - Endovascular treatment for complex intracranial aneurysms: lessons learnt in five patients. AB - We describe our experience in five cases of endovascular treatment for complex intracranial aneurysms. The senior author (ZW) has clinical experience with more than 6000 cases of brain aneurysms treated with endovascular techniques. Multiple endovascular therapies, such as treatment with Onyx, parent vessel occlusion, stent-assisted coiling, covered stent, can be used in an attempt to provide a solution to various clinical dilemmas associated with the management of these difficult lesions. Here, we focus on the latest five patients and lessons learnt in endovascular techniques for complex intracranial aneurysms.On the basis of the knowledge obtained over the years, multimodality endovascular techniques should be re-evaluated to improve patient outcomes. PMID- 24148641 TI - Giant vertebrobasilar aneurysm treated with bilateral vertebral artery occlusion. Two case reports. AB - Giant vertebrobasilar aneurysms constitute a relatively uncommon subgroup of aneurysms with a high mortality rate. These aneurysms are often difficult to treat with conventional clipping or coiling because of their location and their morphology. Here we describe two patients with giant vertebrobasilar aneurysms, both of which were successfully treated with bilateral vertebral artery occlusion. This approach is suggested as a definitive treatment for vertebrobasilar aneurysms in appropriate circumstances. PMID- 24148642 TI - Endovascular Treatment of Cerebral Arteriovenous Malformation Bleeding during Pregnancy. A Case Report. AB - Cerebral arteriovenous malformations (AVMs) represent congenital anomalies of blood vessels composed of a nidus of anomalous arterial and venous vessels without a capillary network. We describe a case of bleeding cerebral AVM in a pregnant women at the second quarter of gestation and diagnosed by digital subtraction angiography showing a large principal arterial nidus supply. The AVM was treated by endovascular embolization at the 27th week of gestation. The post operative course was uneventful and a caesarean section was performed at the 37th week of gestation. The endovascular approach may represent a safe method in the treatment of this cerebral condition during pregnancy. PMID- 24148643 TI - Endovascular embolization of intracranial iatrogenic pseudoaneurysms. A report of two cases and review of the literature. AB - Iatrogenic pseudoaneurysm is a rare but severe complication of intracranial surgery. Treatment of the condition is difficult. The purpose of this report is to draw attention to the fact that endovascular embolization of pseudoaneurysms with parent artery preservation is possible. We describe two cases of endovascular embolization and review the literature. The conclusion is that endovascular treatment can be safe and curative. PMID- 24148644 TI - Magnetic resonance imaging for spinal cord tumors. A report of twenty cases. AB - This paper discusses spinal cord tumors including imaging characteristics with emphasis on magnetic resonance imaging and advances in treatment. This is a retrospective study of 20 cases patients with neoplasms arising from the spinal cord. All of our cases were explored by magnetic resonance imaging (1.5T) using T1-weighted imaging (Spin Echo), T2-weighted imaging (Spin Echo) and T1-weighted imaging with Gadolinium administration. Pain is the earliest symptom, characteristically occurring at night when the patient is supine. Ependymoma were observed in 11 cases. Astrocytoma was noted in five cases. Other uncommon tumors were identified in four cases: oligodendroglioma (n=1), epidermoid cyst (n=1), hemangioblastoma and metastasis (n=1). In MRI most tumors are isointense or slightly hypointense compared to the normal cord signal with homogenous or irregular enhancement. We describe the characteristic magnetic resonance findings and differential diagnosis of spinal cord tumors. Spinal cord lesions comprise approximately 2-4% of all central nervous system neoplasms. Magnetic resonance imaging plays a central role in the imaging of spinal cord neoplasms. PMID- 24148645 TI - A Solitary Convexity Dural Chondroma: the Proposed Role of Diffusion-Weighted MR Imaging in the Differential Diagnosis of Intracranial Chondroma and Meningioma. A Case Report. AB - Chondromas arising from the dura mater are rare intracranial tumors. We describe a case of intracranial chondroma originating from the durra mater of the convexity, mimicking a meningioma. The neuroradiological and surgical findings are described. The diagnostic clues for the differential diagnosis between chondromas and meningiomas are discussed and reviewed. PMID- 24148646 TI - Rare bilateral lipoma of the internal auditory canals. A case report and review of the literature. AB - About 10% of all intracranial tumors are localized in the cerebellopontine angle and in the internal auditory canal. Less than 2% of these are lipomas. Furthermore, it can be expected that lipomas in this position with a bilateral localization are exceedingly rare. We describe a 70-year-old-woman with lipomas in both internal auditory canals presented in the literature for the first time and include a detailed literature research. PMID- 24148647 TI - Multi-clone infections and the impact of intraspecific competition on trematode colonies with a division of labour. AB - A division of labour occurs in colonies of the trematode Philophthalmus sp. within their first intermediate hosts. Two castes exist: one which reproduces and one which does not reproduce. It has been hypothesized that the benefit of the non-reproductive caste is in competitive interactions. Evidence for this from past experiments with Philophthalmus sp. colonies has been contradictory: the non reproductive caste appears to benefit the colony in some way but not necessarily by combating interspecific competitors. The aims of this study were to consider intraspecific competition as a possible cause of the division of labour in Philophthalmus sp. colonies. Results show that mixed genotype infections occur in Philophthalmus sp. infected hosts and thus intraspecific competition is likely. Furthermore, the total number of individuals per colony is reduced in mixed genotype infections, indicating that intraspecific competition reduces colony fitness. However, the results do not indicate that the division of labour in Philophthalmus sp. plays a role in competitive interactions as the ratio of small, non-reproductive to large, reproductive individuals is unaffected by the presence of intraspecific competition. This is the first study to identify and quantify intraspecific competition in Philophthalmus sp., and to assess its selective role in this species' division of labour. PMID- 24148648 TI - Distinguishing the causes of falls in humans using an array of wearable tri-axial accelerometers. AB - Falls are the number one cause of injury in older adults. Lack of objective evidence on the cause and circumstances of falls is often a barrier to effective prevention strategies. Previous studies have established the ability of wearable miniature inertial sensors (accelerometers and gyroscopes) to automatically detect falls, for the purpose of delivering medical assistance. In the current study, we extend the applications of this technology, by developing and evaluating the accuracy of wearable sensor systems for determining the cause of falls. Twelve young adults participated in experimental trials involving falls due to seven causes: slips, trips, fainting, and incorrect shifting/transfer of body weight while sitting down, standing up from sitting, reaching and turning. Features (means and variances) of acceleration data acquired from four tri-axial accelerometers during the falling trials were input to a linear discriminant analysis technique. Data from an array of three sensors (left ankle+right ankle+sternum) provided at least 83% sensitivity and 89% specificity in classifying falls due to slips, trips, and incorrect shift of body weight during sitting, reaching and turning. Classification of falls due to fainting and incorrect shift during rising was less successful across all sensor combinations. Furthermore, similar classification accuracy was observed with data from wearable sensors and a video-based motion analysis system. These results establish a basis for the development of sensor-based fall monitoring systems that provide information on the cause and circumstances of falls, to direct fall prevention strategies at a patient or population level. PMID- 24148649 TI - snOPY: a small nucleolar RNA orthological gene database. AB - BACKGROUND: Small nucleolar RNAs (snoRNAs) are a class of non-coding RNAs that guide the modification of specific nucleotides in ribosomal RNAs (rRNAs) and small nuclear RNAs (snRNAs). Although most non-coding RNAs undergo post transcriptional modifications prior to maturation, the functional significance of these modifications remains unknown. Here, we introduce the snoRNA orthological gene database (snOPY) as a tool for studying RNA modifications. FINDINGS: snOPY provides comprehensive information about snoRNAs, snoRNA gene loci, and target RNAs. It also contains data for orthologues from various species, which enables users to analyze the evolution of snoRNA genes. In total, 13,770 snoRNA genes, 10,345 snoRNA gene loci, and 133 target RNAs have been registered. Users can search and access the data efficiently using a simple web interface with a series of internal links. snOPY is freely available on the web at http://snoopy.med.miyazaki-u.ac.jp. CONCLUSIONS: snOPY is the database that provides information about the small nucleolar RNAs and their orthologues. It will help users to study RNA modifications and snoRNA gene evolution. PMID- 24148650 TI - Outcomes following liver resection and clinical pathologic characteristics of hepatocellular carcinoma occurring in patients with chronic hepatitis B and minimally fibrotic liver. AB - AIMS: The intent of this analysis is to assess clinico-pathologic and prognostic characteristics of HCC in patients with minimal liver fibrosis (Ishak stage 1-2) after primary surgical liver resection as compared to patients with moderate to severe fibrosis (Ishak stage 3-6) in order to improve screening and treatment of HCC. METHODS: Data were obtained from 200 patients with HBV-related HCC who underwent primary surgical liver resection at a single North American medical institution between 1988 and 2012. A dedicated liver pathologist performed fibrosis staging for each resection specimen using the modified Ishak method. Univariate and multivariate analyses of clinico-pathologic variables were performed to determine those associated with prognosis. RESULTS: Twenty-two percent of patients had minimal fibrosis defined as Ishak stage 1 or 2. Kaplan Meier analysis of 5-year survival showed a non-significant trend toward better outcome among Ishak 1-2 patients compared to Ishak 3-6 (p = 0.09). Ishak 1-2 was associated with lower hazard of death compared to Ishak 3-6 (adjusted HR = 0.38, 95% CI = 0.15-0.99). Ishak 1-2 retained statistical significance after multivariate analysis for overall survival (p = 0.05), but not recurrence-free survival. CONCLUSIONS: A significant proportion of HBV-HCC cases arise in the minimally fibrotic liver. Patients with Ishak 1-2 fibrosis have better overall survival compared to those with Ishak 3-6, indicating that minimally fibrotic patients should be treated as a separate cohort. There is a need to better understand the mechanisms underlying hepatocarcinogenesis and to formulate unique diagnostic and therapeutic algorithms for minimally fibrotic HCC patients. PMID- 24148651 TI - Pelvic floor biometry during a first singleton pregnancy and the relationship with symptoms of pelvic floor disorders: a prospective observational study. AB - OBJECTIVE: To assess pelvic floor biometry during pregnancy and the correlation with symptoms of pelvic floor disorders in women. DESIGN: A prospective observational study. SETTING: Antenatal clinic between August 2009 and May 2011. POPULATION: Nulliparous women in their first pregnancy. METHODS: Pelvic floor was assessed by translabial ultrasound and symptoms of pelvic floor disorders were explored with a standardised questionnaire at each trimester. MAIN OUTCOME MEASURES: Pelvic floor biometry during pregnancy. RESULTS: A total of 405 (91.6%) women completed the study. As the pregnancy advanced, there was significant descent of the bladder neck (BN), cervix, and anorectal junction. The hiatal area (HA) was significantly enlarged, with a mean increase of 15.1 +/- 24.8% at rest, and 24.7 +/- 28.5% at Valsalva, at third trimester when compared with first trimester. Risk factors for stress urinary incontinence (SUI) were: descent of BN at Valsalva (OR 3.2, 95% CI 1.2-8.5), increase in HA at pelvic floor contraction (PFMC; OR 1.3, 95% CI 1.0-1.6), and increase in maternal age (OR 1.1, 95% CI 1.0 1.2), at first trimester; increase in HA at PFMC (OR 1.3, 95% CI 1.1-1.5) at second trimester; and descent of BN at rest (OR 2.3, 95% CI 1.1-4.9) and increase in maternal age (OR 1.1, 95% CI 1.02-1.2) at third trimester. Descent of anorectal junction (OR 1.5, 95% CI 1.1-1.9) and increase in HA at rest (OR 1.2, 95% CI 1.0-1.3) were factors for prolapse symptoms at second and third trimester, respectively. CONCLUSIONS: Pelvic floor changes begin during pregnancy. There was significant descent of the BN, cervix, and anorectal junction, and enlargement of the hiatal area, as the pregnancy advanced. SUI was associated with descent of the BN, and prolapse symptoms were associated with an increase in the hiatal area. PMID- 24148652 TI - Quantitative real-time PCR detection of Zika virus and evaluation with field caught mosquitoes. AB - BACKGROUND: Zika virus (ZIKV), a mosquito borne flavivirus is a pathogen affecting humans in Asia and Africa. ZIKV infection diagnosis relies on serology which is challenging due to cross-reactions with other flaviviruses and/or absence or low titer of IgM and IgG antibodies at early phase of infection- virus isolation, which is labor intensive, time consuming and requires appropriate containment. Therefore, real-time RT-PCR (rRT-PCR) is an appealing option as a rapid, sensitive and specific method for detection of ZIKV in the early stage of infection. So far, only one rRT-PCR assay has been described in the context of the outbreak in Micronesia in 2007. In this study, we described a one step rRT PCR for ZIKV which can detect a wider genetic diversity of ZIKV isolates from Asia and Africa. RESULTS: The NS5 protein coding regions of African ZIKV isolates were sequenced and aligned with representative flaviviruses sequences from GenBank to design primers and probe from conserved regions. The analytical sensitivity of the assay was evaluated to be 32 genome-equivalents and 0.05 plaque forming unit (pfu). The assay was shown to detect 37 ZIKV isolates covering a wide geographic in Africa and Asia over 36 years but none of the 31 other flaviviruses tested showing high analytical specificity. The rRT-PCR could be performed in less than 3 hours. This method was used successfully to detect ZIKV strains from field-caught mosquitoes. CONCLUSION: We have developed a rapid, sensitive and specific rRT-PCR for detection of ZIKV. This assay is a useful tool for detection of ZIKV infection in regions where a number of other clinically indistinguishable arboviruses like dengue or chikungunya co-circulate. Further studies are needed to validate this assay in clinical positive samples collected during acute ZIKV infection. PMID- 24148653 TI - Distinct serum apolipoprotein A-I levels in neuromyelitis optica and acute transverse myelitis. AB - OBJECTIVE: NMO and ATM are intertwined both clinically and pathologically. Apolipoprotein (apo) A-I, the main apolipoprotein of HDL, plays an important role in lipid metabolism in the cerebrospinal fluid and is known to suppress pro inflammatory cytokines generated by activated T cells in some autoimmune diseases as an immune regulator. However, the differences in the levels of serum apoA-I between NMO and ATM patients are unclear. METHODS: In the present study, serum apo A-I levels were measured in 53 NMO patients, 45 ATM patients and 49 healthy subjects. We tested serum apoA-I levels in all participants and investigated EDSS scores of patients with NMO and ATM. Statistical analyses were performed by using SPSS statistical software. RESULT: We found that serum apoA-I levels in patients with NMO were significantly lower in comparison to those with ATM. We also found that serum levels of apoA-I was lower in male subjects in comparison to the female subjects in all groups although these differences were not statistically significant in patients with NMO or ATM. It is also shown in our study that serum apoA-I levels in patients with NMO were significantly elevated after receiving a high dosage of intravenous corticosteroids over a period of one week. However, we did not find any correlation between the apoA-I levels and disease disability. CONCLUSION: From this study, we concluded that serum levels of apoA-I were lower in NMO patients compared to patients with ATM. Serum apoA-I studies might provide some useful clues to differentiate NMO cases from ATM cases. PMID- 24148655 TI - Sutureless 27-gauge needle-guided intrascleral intraocular lens implantation with lamellar scleral dissection. AB - PURPOSE: To report a new technique for performing sutureless intrascleral fixation of a posterior chamber intraocular lens (IOL). DESIGN: Prospective, noncomparative, interventional case series on the results of sutureless intrascleral fixation of a posterior chamber IOL. PARTICIPANTS: Thirty-five eyes of 34 consecutive patients with aphakia, dislocated IOL, or subluxated crystalline lens who underwent posterior chamber sutureless implantation of an IOL were studied. METHODS: The haptics of the IOL were externalized with a 27 gauge needle passed through the ciliary sulcus using the double needle technique. The haptics were fixed in a scleral tunnel made by lamellar scleral dissection. The postoperative tilt of the IOL was measured by swept source optical coherence tomography. MAIN OUTCOME MEASURES: The best-corrected visual acuity (BCVA), corneal endothelial cell density, IOL tilt, and complications were determined. RESULTS: The IOLs were fixed with exact centration and axial stability. No wound leakage was seen even without any sutures. The mean BCVA was 0.48 logarithm of the minimum angle of resolution (logMAR) units preoperatively and 0.17 logMAR units at 3 months postoperatively (P = 0.003). The mean corneal endothelial cell loss was 6.0+/-7.3% (P = 0.63) at 3 months. The mean IOL tilt was 2.3+/-1.9 degrees . The postoperative complications included iris capture by the IOL in 3 eyes (8.6%), ocular hypertension in 2 (5.7%), and cystoid macular edema in 1 (2.9%). There was no postoperative retinal detachment, endophthalmitis, IOL dislocation, or vitreous hemorrhage. CONCLUSIONS: The 27-gauge needle-guided intrascleral posterior chamber IOL implantation technique provides good IOL fixation with reliable wound closure without the use of any sutures. We recommend this technique for secondary IOL implantation. PMID- 24148654 TI - Retinal structure and function in achromatopsia: implications for gene therapy. AB - PURPOSE: To characterize retinal structure and function in achromatopsia (ACHM) in preparation for clinical trials of gene therapy. DESIGN: Cross-sectional study. PARTICIPANTS: Forty subjects with ACHM. METHODS: All subjects underwent spectral domain optical coherence tomography (SD-OCT), microperimetry, and molecular genetic testing. Foveal structure on SD-OCT was graded into 5 distinct categories: (1) continuous inner segment ellipsoid (ISe), (2) ISe disruption, (3) ISe absence, (4) presence of a hyporeflective zone (HRZ), and (5) outer retinal atrophy including retinal pigment epithelial loss. Foveal and outer nuclear layer (ONL) thickness was measured and presence of hypoplasia determined. MAIN OUTCOME MEASURES: Photoreceptor appearance on SD-OCT imaging, foveal and ONL thickness, presence of foveal hypoplasia, retinal sensitivity and fixation stability, and association of these parameters with age and genotype. RESULTS: Forty subjects with a mean age of 24.9 years (range, 6-52 years) were included. Disease-causing variants were found in CNGA3 (n = 18), CNGB3 (n = 15), GNAT2 (n = 4), and PDE6C (n = 1). No variants were found in 2 individuals. In all, 22.5% of subjects had a continuous ISe layer at the fovea, 27.5% had ISe disruption, 20% had an absent ISe layer, 22.5% had an HRZ, and 7.5% had outer retinal atrophy. No significant differences in age (P = 0.77), mean retinal sensitivity (P = 0.21), or fixation stability (P = 0.34) across the 5 SD-OCT categories were evident. No correlation was found between age and foveal thickness (P = 0.84) or between age and foveal ONL thickness (P = 0.12). CONCLUSIONS: The lack of a clear association of disruption of retinal structure or function in ACHM with age suggests that the window of opportunity for intervention by gene therapy is wider in some individuals than previously indicated. Therefore, the potential benefit for a given subject is likely to be better predicted by specific measurement of photoreceptor structure rather than simply by age. The ability to directly assess cone photoreceptor preservation with SD-OCT and/or adaptive optics imaging is likely to prove invaluable in selecting subjects for future trials and measuring the trials' impact. PMID- 24148656 TI - Using intervention mapping for the development of a targeted secure web-based outreach strategy named SafeFriend, for Chlamydia trachomatis testing in young people at risk. AB - BACKGROUND: Many young people at high risk for Chlamydia trachomatis (Ct) are not reached by current sexual health care systems, such as general practitioners and public sexual health care centres (sexually transmitted infection clinics).Ct is the most frequently diagnosed bacterial sexually transmitted infection (STI) among sexually active people and in particular young heterosexuals. Innovative screening strategies are needed to interrupt the transmission of Ct among young people and connect the hidden cases to care. METHODS: Intervention Mapping (IM), a systematic approach to develop theory- and evidence-based interventions, was used to develop a strategy to target Ct testing towards young people who are currently hidden to care in The Netherlands. Both clinical users (i.e. sexual health care nurses) and public users (i.e., young people at risk for Ct) were closely involved in the IM process. A needs assessment study was carried out using semi-structured interviews among users (N = 21), a literature search and by taking lessons learned from existing screening programmes. Theoretical methods and practical applications to reach high risk young people and influence testing were selected and translated into specific programme components. RESULTS: The IM approach resulted in the development of a secure and web-based outreach Ct screening strategy, named SafeFriend. It is developed to target groups of high risk young people who are currently hidden to care. Key methods include web-based Respondent Driven Sampling, starting from young Ct positive sexual health care centre clients, to reach and motivate peers (i.e., sex partners and friends) to get tested for Ct. Testing and the motivation of peers were proposed as the desired behavioural outcomes and the Precaution Adoption Process Model was chosen as theoretical framework. End users, i.e., young people and sexual health care nurses were interviewed and included in the development process to increase the success of implementation. CONCLUSIONS: IM proved useful to develop an intervention for targeted Ct testing among young people. We believe this to be the first web-based outreach screening strategy which combines chain referral sampling with the delivery of targeted Ct testing to high risk young people within their sexual and social networks. PMID- 24148657 TI - Identification and developmental expression of the enzymes responsible for dopamine, histamine, octopamine and serotonin biosynthesis in the copepod crustacean Calanus finmarchicus. AB - Neurochemicals are likely to play key roles in physiological/behavioral control in the copepod crustacean Calanus finmarchicus, the biomass dominant zooplankton for much of the North Atlantic Ocean. Previously, a de novo assembled transcriptome consisting of 206,041 unique sequences was used to characterize the peptidergic signaling systems of Calanus. Here, this assembly was mined for transcripts encoding enzymes involved in amine biosynthesis. Using known Drosophila melanogaster proteins as templates, transcripts encoding putative Calanus homologs of tryptophan-phenylalanine hydroxylase (dopamine, octopamine and serotonin biosynthesis), tyrosine hydroxylase (dopamine biosynthesis), DOPA decarboxylase (dopamine and serotonin biosynthesis), histidine decarboxylase (histamine biosynthesis), tyrosine decarboxylase (octopamine biosynthesis), tyramine beta-hydroxylase (octopamine biosynthesis) and tryptophan hydroxylase (serotonin biosynthesis) were identified. Reverse BLAST and domain analyses show that the proteins deduced from these transcripts possess sequence homology to and the structural hallmarks of their respective enzyme families. Developmental profiling revealed a remarkably consistent pattern of expression for all transcripts, with the highest levels of expression typically seen in the early nauplius and early copepodite. These expression patterns suggest roles for amines during development, particularly in the metamorphic transitions from embryo to nauplius and from nauplius to copepodite. Taken collectively, the data presented here lay a strong foundation for future gene-based studies of aminergic signaling in this and other copepod species, in particular assessment of the roles they may play in developmental control. PMID- 24148659 TI - Preliminary analyses of the frozen mummies of mammoth (Mammuthus primigenius), bison (Bison priscus) and horse (Equus sp.) from the Yana-Indigirka Lowland, Yakutia, Russia. AB - The frozen bodies of a young woolly mammoth (Mammuthus primigenius), a wild horse (Equus sp.) and a steppe bison (Bison priscus) were recently found in the northern Yakutia (northeastern Siberia). All specimens have preserved bones, skin and soft tissues. Whereas the woolly mammoth and the Pleistocene horse were represented by partial frozen bodies, the steppe bison body was recovered in an absolutely complete state. All specimens were found frozen in the permafrost, with some of the tissues mummified. The wild horse and steppe bison are of Holocene age, and the mammoth is of Late Pleistocene age. PMID- 24148660 TI - Incidence and outcome of cerebrovascular events related to cervical artery dissection: the Dijon Stroke Registry. AB - BACKGROUND: Reliable epidemiological data on the true incidence of cerebrovascular events related to spontaneous cervical artery dissection, including stroke and transient ischemic attack, are scarce. AIMS: To evaluate the incidence, characteristics, and outcome of cerebrovascular events due to cervical artery dissection. METHODS: All cerebrovascular events (stroke and transient ischemic attack) occurring in Dijon, France, from 2006 to 2011, were retrieved from a population-based registry. Patients with a cervical artery dissection were identified. Incidence rates, baseline characteristics, and outcome at three months were described. RESULTS: Among the 1368 patients with cerebrovascular events, 27 had cervical artery dissection (2.0%, 52% men, mean age 49.1+/-17.1), including 10 patients with internal carotid artery dissection, 16 patients with vertebral artery dissection, and one patients with both internal carotid artery dissection and vertebral artery dissection. The crude incidence rate of cerebrovascular events due to cervical artery dissection was 2.97/100,000/year. Corresponding rates were 1.21/100,000/year for internal carotid artery dissection, and 1.87/100,000/year for vertebral artery dissection. Seventy per cent of patients had a stroke and among these, higher severity was observed in those with internal carotid artery dissection. A good outcome (m-Rankin score 0 2) was observed in 89% of patients at three-months, whatever the location of the cervical artery dissection. One patient with vertebral artery dissection died at day 38. CONCLUSION: The incidence of cerebrovascular events related to vertebral artery dissection is greater than previously reported, which may indicate a better identification of patients due to improvements in diagnostic procedures. PMID- 24148661 TI - PAT tools for the control of co-extrusion implants manufacturing process. AB - Hot melt extrusion is a novel pharmaceutical manufacturing process technique. In this study, we identified four Critical Quality Attributes (CQAs) of the implant manufacturing process by hot melt extrusion: the implant diameter, the quantity of the Active Pharmaceutical Ingredient (API), the homogeneity distribution of API and the thickness of the membrane. We controlled the implant diameter and the quantity of API in-line with a laser measurement, NIR and Raman spectroscopy, respectively. These two different spectroscopic techniques provided comparable results. In fact, the RMSEC and RMSECV were very close in each PAT technique but NIR spectroscopy was easier to use and less sensitive to external changes. For the control of the homogeneity of API distribution and the thickness of the membrane, we used successfully Raman spectroscopy imaging. These PAT tools help reducing analysis time. PMID- 24148658 TI - Six-month survival and quality of life of intensive care patients with acute kidney injury. AB - INTRODUCTION: Acute kidney injury (AKI) has high incidence among the critically ill and associates with dismal outcome. Not only the long-term survival, but also the quality of life (QOL) of patients with AKI is relevant due to substantial burden of care regarding these patients. We aimed to study the long-term outcome and QOL of patients with AKI treated in intensive care units. METHODS: We conducted a predefined six-month follow-up of adult intensive care unit (ICU) patients from the prospective, observational, multi-centre FINNAKI study. We evaluated the QOL of survivors with the EuroQol (EQ-5D) questionnaire. We included all participating sites with at least 70% rate of QOL measurements in the analysis. RESULTS: Of the 1,568 study patients, 635 (40.5%, 95% confidence interval (CI) 38.0-43.0%) had AKI according to the Kidney Disease Improving Global Outcomes (KDIGO) criteria. Of the 635 AKI patients, 224 (35.3%), as compared to 154/933 (16.5%) patients without AKI, died within six months. Of the 1,190 survivors, 959 (80.6%) answered the EQ-5D questionnaire at six months. The QOL (median with Interquartile range, IQR) measured with the EQ-5D index and compared to age- and sex-matched general population was: 0.676 (0.520-1.00) versus 0.826 (0.812-0.859) for AKI patients, and 0.690 (0.533-1.00) versus 0.845 (0.812-0.882) for patients without AKI (P <0.001 in both). The EQ-5D at the time of ICU admission was available for 774 (80.7%) of the six-month respondents. We detected a mean increase of 0.017 for non-AKI and of 0.024 for AKI patients in the EQ-5D index (P = 0.728). The EQ-5D visual analogue scores (median with IQR) of patients with AKI (70 (50-83)) and patients without AKI (75 (60-87)) were not different from the age- and sex-matched general population (69 (68-73) and 70 (68 77)). CONCLUSIONS: The health-related quality of life of patients with and without AKI was already lower on ICU admission than that of the age- and sex matched general population, and did not change significantly during critical illness. Patients with and without AKI rate their subjective health to be as good as age and sex-matched general population despite statistically significantly lower QOL indexes measured by EQ-5D. PMID- 24148662 TI - A novel approach to monitor coating amount by short-wavelength near-infrared spectroscopy using a tracer with a long-chain hydrocarbyl group. AB - Investigation into the use of near-infrared (NIR) as a Process Analytical Technology has been conducted for in-process monitoring of coating amounts for oral pharmaceutical products. However, the low specificity of NIR spectra has made it time consuming and costly to establish quantitative calibration models for commercial production. Here we revealed that long-chain hydrocarbyl group compounds containing saturated hydrocarbon chains, such as cetyl and stearyl, exhibit specific and strong absorption in the short wavelength (SW)-NIR region (800-1,100 nm) with limited interference from peaks corresponding to other components. To simplify the quantitative model, we used cetanol as a model tracer of coating amount to enhance detection sensitivity and analytical precision. The coating amount on crystalline cellulose granules was determined only from the intensity of NIR absorption at a single wavelength, which was attributed to the tracer. The results showed close agreement with quantitative analyses from gas chromatography and measurement of weight gain. In conclusion, we determined coating amount with considerable accuracy from NIR absorption at a single wavelength in the SW-NIR region using the long-chain hydrocarbyl containing compound as a tracer, thereby eliminating the need for complicated statistics. PMID- 24148663 TI - Improvement of pharmacokinetic and antitumor activity of PEGylated liposomal doxorubicin by targeting with N-methylated cyclic RGD peptide in mice bearing C 26 colon carcinomas. AB - Cyclic Arg-Gly-Asp (cRGD) pentapeptides engrafted liposomes have attracted considerable attention for targeting integrin receptors on tumor vasculature. In this study PEGylated liposomal doxorubicin (PLD) was decorated with three cRGD peptides including Arg-Gly-Asp-D-Tyr-Cys (RGDyC), Arg-Gly-Asp-D-Phe-Lys (RGDfK) and Arg-Gly-Asp-D-Phe-[N-Methyl]Lys (RGDf[N-Met]K). The in vitro liposome-cell association and cytotoxicity experiments demonstrated the RGD-PLDs capability of internalization into integrin expressing HUVEC cells via receptor mediated endocytosis. The biodistribution studies revealed that decreasing the hydrophilicity of the peptide greatly reduces the RGD-PLDs blood clearance rate and increases their localization in C-26 colon carcinoma tumor model. Meanwhile, the most selective version, RGDf[N-Met]K, which has intermediate hydrophilicity revealed the lowest unwanted interactions with other integrin presenting sites, further localization in tumor, and lower doxorubicin (Dox) side effects. RGDf[N Met]K-PLD demonstrated a superior control of tumor growth and increased the survival of mice. In this study, we introduced RGDf[N-Met]K for the first time, as a promising ligand for active targeting of liposomes to solid tumor which merits further investigations. PMID- 24148664 TI - Pegylated liposomal mitoxantrone is more therapeutically active than mitoxantrone in L1210 ascitic tumor and exhibits dose-dependent activity saturation effect. AB - Our previous studies have proved that encapsulation of mitoxantrone into pegylated SUVs (plm60-s) could enhance its antineoplastic efficacy (Li et al., 2008b). However, why plm60-s is more therapeutically active than free mitoxantrone (MIT), and whether pharmacokinetics and activity of plm60-s exhibits dose-dependency are left unknown. In studies with L1210 ascitic tumor-bearing mice in which the dose of MIT was elevated from 2 to 8mg/kg, a saturation of antineoplastic efficacy was observed after plm60-s, and not after free MIT therapy. Total MIT concentrations in plasma, liver and ascitic fluids after plm60 s increased linearly with escalated doses. The released MIT concentrations in ascitic fluid increased continuously before reaching the peak at a dose of 6mg/kg and then decreased. In vitro release experiments using ascitic fluid as release medium revealed that at high concentrations of plm60-s the release of drug was inhibited. At a dose of 4mg/kg, the areas under the curve (AUC) of released MIT in ascitic fluid after plm60-s were higher than those after free MIT, which might be responsible for the enhanced efficacy of plm60-s. These observations may be used to choose a dose regimen of plm60-s to ensure optimal efficacy and to expound the reasons why plm60-s was more therapeutically active. PMID- 24148665 TI - Buccal delivery of metformin: TR146 cell culture model evaluating the use of bioadhesive chitosan discs for drug permeability enhancement. AB - The oral cavity is considered an attractive site of drug administration. Metformin is currently, used in oral diabetes treatment. The aim of the current study was to study the feasibility of metformin, to permeate the buccal epithelium applying a bioadhesive and permeation enhancing drug delivery system. The in vitro TR146 cell culture model was used to study the effect of drug concentration (5-100mM) and the impact of a bioadhesive chitosan formulation (discs) and chitosan in solution (0-20mg/mL) acting as a permeation enhancer. The permeation of metformin occurred by passive diffusion via the paracellular pathway driven by the concentration gradient, yet with a possibility of increasing the metformin transport by using higher, donor concentrations. When using floating baskets, as a new application of the TR146 cell culture model, it was possible to observe a time-dependent effect of the bioadhesive metformin discs and, metformin permeation may be increased due to a combination of bioadhesion and permeation enhancement induced by chitosan, although the permeation enhancing effect of chitosan was not statistically significant. The limited apparent buccal permeability of metformin observed in vitro, suggest that in vivo absorption of therapeutic doses of metformin needs to take place as a combination of buccal and intestinal absorption as metformin therapy requires the use of high doses. PMID- 24148666 TI - Film coatings for taste masking and moisture protection. AB - Taste masking and moisture protection of oral dosage forms contribute significantly to the therapeutic effect of pharmaceutical and nutraceutical formulations either by ensuring patient compliance or by providing stability through shelf life of the dosage form. Among different types of taste, bitter taste is the most relevant for patient acceptance because of the extremely high sensitivity. As hydrolysis is the most common mode of degradation of an active ingredient, moisture protection plays a vital role in the stability of the active during manufacturing and storage. Optimized oral dosage forms need to reliably hinder the release of bitter drug molecules in the mouth or ensure stability of the active compound, while also ensuring fast drug release in the stomach to enable early therapeutic onset. Besides different formulation concepts, film coating is found to be the most effective and commonly used approach for taste masking and moisture protection. Film coating can be achieved through the use of water-soluble, cationic, anionic or neutral insoluble polymers from different chemical structures. Cationic polymers provide efficient moisture protection as well as taste masking without influencing the release of the drug in the gastric fluids. Polymers may be sprayed onto various types of cores from dispersions or solutions in organic, solvents or water in drum or fluidzed bed coaters. Applied quantities need insuring complete coating thickness ranging from 0.5 to 50 MUm or more finally. Insulating excipients, such as hydrophobic plasticizers, lipids, pigments or other insoluble substances will influence the functionality of films. Organoleptic tests are still common in testing the quality of taste-masked formulations. Recently, multi-channel taste sensors have been developed to quantify different types of taste. Dynamic vapor sorption technique and studies at elevated temperature provide effective concepts study the efficacy of the formulations. Efficient taste masking and reliable moisture protection of solid oral dosage forms can be achieved by film coating implementing the options of pharmaceutical polymers and processes. PMID- 24148667 TI - Systematic investigation of the cavi-precipitation process for the production of ibuprofen nanocrystals. AB - Cavi-precipitation process is a combinative particle size reduction technology based on solvent-anti-solvent precipitation coupled high pressure homogenization (HPH). The cavi-precipitation can be used for the efficient production of drug nanocrystals (NC) with improved dissolution rate leading to better bioavailability. The work presented here demonstrates the advantage of cavi precipitation process over the standard HPH processes and standard combination process (decoupled process) where precipitation is performed outside the homogenizer. The model compound ibuprofen (IBP) was solubilized in isopropanol (IPA) to constitute the solvent phase and mixed with the anti-solvent phase (0.1% (w/v) hydroxypropyl methylcellulose with 0.2% (w/v) sodium dodecyl sulphate) at different ratios to carry out the precipitation step. IBP-IPA-Water composition was selected from ternary diagram for a highly supersaturated zone to obtain smaller size particles. The mean particle size [d(0.5)] obtained by this process (300nm) was much smaller when compared to that obtained from the decoupled process (1.5MUm). Optimization of the solvent-anti-solvent ratio and drug concentration was necessary to achieve a smaller particle size. PXRD and DSC results revealed that the solid state properties of the original IBP and the prepared NC samples by cavi-precipitation samples were similar. PMID- 24148668 TI - Impact of differential surface molecular environment on the interparticulate bonding strength of celecoxib crystal habits. AB - The present work investigates the impact of milling on differential compactibility behavior of celecoxib (CEL) crystal habits. Plate shaped (CEL-P) crystals showed better compactibility over acicular (CEL-A) crystals. Milling improved the compactibility of both the forms. However, despite similar particle shape, size, and surface area, milled fractions of the two habits showed significantly different interparticulate bonding strength. The greater bonding strength of milled CEL-P (MCEL-P) over milled CEL-A (MCEL-A) was attributed to the differential cleavage behavior of the two habits that conferred the different surface molecular environment to the milled powders. The preferred cleavage of CEL-P across {020} plane exposed the -CF3 group and the methyl phenyl ring on the surface of MCEL-P. On the other hand, CEL-A preferentially fractured along their shortest axis that increased the exposure of {100} plane on the surface of MCEL A, which exposed the -CF3 group and the pyrazole ring. Surface free energy quantified by determining advancing contact angle revealed greater dispersive component of MCEL-P over MCEL-A. This is consistent with the differential cleavage behavior of CEL-P and CEL-A. This confirmed the role of dispersive component of surface free energy in governing interparticulate bonding strength of CEL. The study supports the postulate that tablet tensile strength is governed by the dispersive intermolecular interactions formed over the interparticulate bonding area. PMID- 24148669 TI - Normothermic machine preservation as an approach to decrease biliary complications of DCD liver grafts. PMID- 24148671 TI - Fitness to practice and feedback to students: a literature review. AB - In the United Kingdom (UK), the Nursing and Midwifery Council (NMC) stipulate that practice experience makes up 50% of the nursing curricula. We argue that mentors play a pivotal role in this experience, being the main practitioner responsible for supporting learning in practice, and the NMC's framework to support learning and assessment in practice establishes the knowledge and skills that mentors must apply in practice with students. This framework acts as a resource guide to mentors on how to successfully facilitate students clinical learning experiences, ensuring that students are "fit to practice" at the point of registration. It is recognised, therefore, that it is the mentor's responsibility, once in practice, to bridge the gap between that which students are taught in the classroom, and their actual application to practice. This paper aims to undertake an analysis of the available literature on how effective feedback from mentors to students can help to ensure this fitness to practice. PMID- 24148672 TI - Key innovations in ruminant evolution: a paleontological perspective. AB - Key innovations are newly acquired structures that permit the performance of a new function and open new adaptive zones, and are, therefore, of paramount significance for understanding the history of the Ruminantia, particularly its diversification through the Miocene. Here we review and discuss what is known about these evolutionary novelties, with special emphasis on the appearance and evolution of cranial appendages and high-crowned (or hypsodont) teeth. Cranial appendages probably favored the diversification of pecorans by being structures strongly related to sexual selection, whereas the acquisition of hypsodont teeth could have expanded potential dietary breadth and allowed species to extend diets into the grazing range without eliminating browsing as a potential diet. When analyzed in conjunction with patterns of faunal diversity and in the context of climatic changes, it seems that the overall view that ruminant cranial appendages and hypsodonty may have started responding to increased patterns of seasonality and the opening-up of ecosystems is roughly valid. Instead, they occurred through several distinct pulses and varied widely among continents. This review is, to our knowledge, the first to highlight that the evolution of these innovations has been far from constant and uniform through time. Furthermore, we identify that both a first attempt to increase hypsodonty starting in the early Miocene and a first evolution of antlers and pronghorns were interrupted as a consequence of wide climatic fluctuations in the early-middle Miocene transition. PMID- 24148670 TI - Proteins of novel lactic acid bacteria from Apis mellifera mellifera: an insight into the production of known extra-cellular proteins during microbial stress. AB - BACKGROUND: Lactic acid bacteria (LAB) has been considered a beneficial bacterial group, found as part of the microbiota of diverse hosts, including humans and various animals. However, the mechanisms of how hosts and LAB interact are still poorly understood. Previous work demonstrates that 13 species of Lactobacillus and Bifidobacterium from the honey crop in bees function symbiotically with the honeybee. They protect each other, their hosts, and the surrounding environment against severe bee pathogens, bacteria, and yeasts. Therefore, we hypothesized that these LAB under stress, i.e. in their natural niche in the honey crop, are likely to produce bioactive substances with antimicrobial activity. RESULTS: The genomic analysis of the LAB demonstrated varying genome sizes ranging from 1.5 to 2.2 mega-base pairs (Mbps) which points out a clear difference within the protein gene content, as well as specialized functions in the honeybee microbiota and their adaptation to their host. We demonstrate a clear variation between the secreted proteins of the symbiotic LAB when subjected to microbial stressors. We have identified that 10 of the 13 LAB produced extra-cellular proteins of known or unknown function in which some are arranged in interesting putative operons that may be involved in antimicrobial action, host interaction, or biofilm formation. The most common known extra-cellular proteins secreted were enzymes, DNA chaperones, S-layer proteins, bacteriocins, and lysozymes. A new bacteriocin may have been identified in one of the LAB symbionts while many proteins with unknown functions were produced which must be investigated further. CONCLUSIONS: The 13 LAB symbionts likely play different roles in their natural environment defending their niche and their host and participating in the honeybee's food production. These roles are partly played through producing extracellular proteins on exposure to microbial stressors widely found in natural occurring flowers. Many of these secreted proteins may have a putative antimicrobial function. In the future, understanding these processes in this complicated environment may lead to novel applications of honey crop LAB proteins. PMID- 24148673 TI - Presentation. PMID- 24148674 TI - Advanced Contrast-Enhanced MR Imaging of the CNS. AB - One of the most frequent uses of magnetic resonance imaging (MRI) since its introduction has been in the assessment of the CNS for neoplasm. In recent years there has been a substantial improvement in the MR protocol for tumors that includes the use of functional imaging techniques. As shown in multiple experimental and clinical studies an optimized use of high quality contrast media and the introduction of these functional MRI methods has improved the detection and delineation of CNS tumors. This results not only in more confident diagnoses, but also in a substantially improved differential diagnostic process. The article reviews and summarizes the technical advances in functional techniques and their impact on the assessment of cerebral pathologies, namely brain tumors, and gives practical information on how to optimize sequence parameters to achieve the optimal tissue and pathology contrast. PMID- 24148675 TI - Human 7T MRI: First Clinical and Neuroscientific Applications. AB - After many years of development and niche applications in a very limited number of laboratories, human 7T magnetic resonance imaging systems are becoming available to a number of clinical and neuroscientific researchers. The spectrum of available methods and their robustness is increasing and the first studies are underway to evaluate the potential applications and benefits for larger clinical studies or even clinical diagnosis. A number of technical and methodological challenges currently limit the application mainly to examinations of the brain. Some of the current possibilities of ultra-high field systems and examples of first applications in patient and research studies are demonstrated to give the reader an overview. PMID- 24148676 TI - Diagnosis of Alzheimer's Disease: Two MRI-Based Approaches. AB - Imaging has been increasingly recognized as a powerful tool for diagnosing Alzheimer's disease (AD). Magnetic resonance imaging (MRI) is advantageous over other imaging modalities due to its non-invasiveness and multi-parametric capabilities. In addition to the morphological assessment, several new MR imaging approaches have shown potential for improved AD diagnosis. This paper focuses on two of these advanced MRI-based approaches: diffusion-weighted imaging and arterial spin labeling. PMID- 24148677 TI - An Atlas of Infectious and Parasitic Diseases of the Central Nervous System. A Cooperative Study of SILAN (Sociedad Iberolatinoamericana de Neurorradiologia). AB - Infectious diseases of the central nervous system vary in frequency in different locations in America and Europe. What is common in Brazil can be a sporadic presentation in Europe. Cooperative work gathering experiences from neuroradiologists working in various places can be achieved and will help to identify uncommon cases that can present in our daily practice. PMID- 24148678 TI - Prospective quantitative imaging study by magnetisation transfer for appearance of perilesional gliosis in solitary cerebral cysticercal lesion. AB - This study aimed to detect perilesional gliosis around solitary cerebral cysticerci (SCC) by magnetisation transfer imaging (MTI), to compare its incidence between patients administered and not administered albendazole. We prospectively randomised patients with SCC and new-onset seizures to treatment with albendazole plus antiepileptics (treatment), or antiepileptics only (control), and performed MRI scans at zero, three, six, 12 and 24 months. Data were analysed for lesion characteristics, perilesional MT hyperintensity and MT ratios, calculated from the lesion and perilesional area. Eighty-one patients' data were analysed (M-41, F-40; ages 6-52 years). About 13% scolices appeared hyperintense on MTI at baseline. T1-isointense cyst walls and perilesional area showed MT hyperintensity in 30 - 41.4%; this proportion increased over time. Persistently visible SCC and stage of degeneration at enrolment did not predict development of MT hyperintensity. MT ratios (range - 98.75 to 49.79) increased over time and differed significantly from normal parenchyma. No difference in MT ratios was noted between treatment and control groups. Qualitative perilesional MT hyperintensity was more often seen in control group. Perilesional gliosis is present in >20% of SCC at six months, and continues to appear on later scans. Gliosis is independent of lesion persistence and stage of degeneration. Pre- and post-contrast MT imaging is equally useful in detection of gliosis. MT ratios from the lesion and perilesional parenchyma are significantly lower than from normal brain tissue at all stages of degeneration, but increase as degeneration occurs and healing progresses. Albendazole therapy does not affect the formation of perilesional gliosis. PMID- 24148679 TI - Involvement of the Choroid Plexus in Neurotuberculosis: MR Findings in Six Cases. AB - The majority of intracranial infections that cause meningitis are considered to start in the choroid plexus of the ventricles, but lesions involving the choroid plexus are rare. There are isolated case reports of the involvement of choroid plexus in tuberculous meningitis. The main imaging findings are abnormal enhancement of the thickened choroid plexus, asymmetric hydrocephalus with sequestrated temporal horn, periventricular edema and intraventricular septae formation. Six patients having tubercular involvement of choroid plexus were treated at our institution. This is probably the largest series of tubercular involvement of choroid plexus highlighting the imaging features of this rare manifestation of CNS tuberculosis. PMID- 24148680 TI - MR Tractography in Horizontal Gaze Palsy and Progressive Scoliosis. A Case Report. AB - Congenital brainstem malformation without associated cerebellar disorder is uncommon. Horizontal gaze palsy with progressive scoliosis is one such rare syndrome with brainstem hypoplasia without any disorder of the cerebellum. It has an autosomal recessive inheritance and is characterised by absent horizontal gaze and severe progressive scoliosis from birth. We describe a 58-year-old man with horizontal gaze palsy and severe thoracolumbar scoliosis with typical MR imaging findings of brainstem hypoplasia, and MR tractography confirmation of complete absence of decussation of the pyramidal tract fibers. PMID- 24148681 TI - Unusual presentation of recurrent pituitary abscess. A case report and literature review. AB - Pituitary abscess is a rare pituitary pathology which may be potentially life threatening if not treated. Therefore, early accurate diagnosis and therapy are extremely important. However, the clinical diagnosis is difficult because there are no clinical symptoms characteristic of pituitary abscess. It is frequently indistinguishable clinically or with neuroimaging studies from other pituitary lesions. The MR diagnosis of pituitary abscess must be suspected in cases of sellar cystic mass with a peripheral rim enhancement after contrast administration. It must be highlighted that pituitary abscess may show various signal intensity on T1-weighted images, as in our case, making the diagnosis even more difficult. We report an unusual case of a 66-year-old woman who presented with a recurrent pituitary abscess, initially misdiagnosed as a pituitary adenoma because of its high signal intensity on T1-weighted images. The woman was operated on three times, using transsphenoidal access with a good final outcome. PMID- 24148682 TI - Pituitary stalk interruption syndrome: the role of MRI and review of the literature. AB - Magnetic resonance imaging (MRI) in patients with congenital growth hormone deficiency (GHD) has revealed several morphological abnormalities of the hypothalamo-pituitary region which include hypoplasia of the anterior pituitary lobe, the absence or marked thinning of the pituitary stalk and ectopia of the posterior pituitary lobe (EPP). This triad of abnormalities is called pituitary stalk interruption syndrome (PSIS). Our study reports the imaging findings of 23 patients with idiopathic GHD and short stature who were examined by MRI. The majority of the patients had abnormal MR studies with findings indicating the presence of the pituitary stalk syndrome. The high correlation between the clinical profile and the MR findings in cases of pituitary dysfunction (most often GHD), defines the significant role of MRI as additional tool for the diagnosis of pituitary hormone deficiency. PMID- 24148683 TI - Neuroimaging in a Three-Year-Old Girl - MRI without Anesthesia: Easier than One Thinks. A Case Report. AB - Magnetic resonance imaging (MRI) is the imaging modality of choice in the diagnosis of structural brain abnormalities in children. Routine scans are usually not reliable in pediatric neuroimaging without sedation before the age of seven. Before this age sedation or general anesthesia with procedural risks and additional costs might be needed. We report on MRI in a 3.1-year-old patient referred after a first seizure performed with a combination of role model and self-experience. MRI with high imaging quality was performed without the need for anesthesia in our daily routine. The imaging procedure was performed without previous preparation needed and within target date.Our reported technique of a combination of role model and self-experience, avoiding anesthesia in a 3.1-year old girl is suitable for children and it is applicable in the daily routine. PMID- 24148684 TI - A modified technique improved histology similarity to human intracranial aneurysm in rabbit aneurysm model. AB - Persistent undigested elastic membranes and collagen in the tunic media of rabbit elastase-induced aneurysm models lowered their histology similarity to human intracranial aneurysm. Our purpose was to make good the deficiency. Ten New Zealand white rabbits were divided into three groups: six rabbit in two groups for evaluating the difference in various treatments, and four rabbits for long term observation. We inflated and occluded the right common carotid artery (CCA) by an endovascular technique. The first group of three rabbits was only given 200u elastase in the proximal segment of right CCA; the second group was given 100u elastase and 1.5mg collagenase, then the right CCA was ligated. The first and second groups were studied by magnetic resonance angiography (MRA), sacrificed at three weeks after aneurysm creation, their histology results were obtained and compared with human aneurysm. The third group underwent the same procedure as the second group only for three months of observation with enhanced MRA. Saccular aneurysms formed in all rabbits. Degeneration of the extracellular matrix and atrophy of smooth muscular cells in tunic media were more apparent in the second group. The third group remained stable for more three months. Two modifications included inflating the right CCA with a balloon and adding collagenase incubation can promote an aneurysm model more histologically similar to human aneurysm. In addition the improved aneurysm model remains stability for a long time. PMID- 24148685 TI - Follow-up Outcomes of Self-Expanding Stents for Carotid Artery Angioplasty at a Single Hospital. AB - Carotid artery angioplasty and stent placement (CASP) is widely accepted as a valuable alternative to carotid endarterectomy, particularly among high-risk patient populations. We analyzed the follow-up data of patients who underwent CASP with self-expanding stents for carotid lesions. Since 2001, self-expanding stents have been deployed in 59 lesions in 56 patients. Forty-seven patients were male, and nine were female. The median age was 73 years, ranging 50 to 83 years. There were 31 asymptomatic lesions and 28 symptomatic lesions. The median follow up period was 27 months, ranging six to 102 months. All lesions received stents and technical success was achieved in 58 (98.3%) out of 59 lesions. The 30-day transient ischemic attack rate was 8.6%, the stroke rate was 3.4%, and the death rate was 0%. No ischemic attack was observed on the ipsilateral side after 30 days. Recurrent stenosis (>50%) was observed in three patients (5.1%) and in two (3.4%) of these, revascularization was performed. Kaplan-Meier analysis showed that the rates for one year and two year freedom from any stroke or death were 93.1% and 90.9%, respectively. The incidence of recurrent carotid stenosis is acceptably low after CASP. CASP is effective to prevent ipsilateral ischemic stroke in symptomatic and asymptomatic patients. PMID- 24148686 TI - Vertebral aggressive hemangioma. A case report and literature review. AB - Aggressive hemangiomas are rare and can compress the spinal cord, nerve roots or both, producing myelopathy or radiculopathy. This report describes an aggressive and compressive hemangioma of the body of the Th9 vertebra in a woman with symptoms of medullary sufferance, treated with embolization of the afferent vessels of the lesion followed by radiotherapy. PMID- 24148687 TI - Letter to the editor. PMID- 24148688 TI - Interactive effects of mechanical ventilation, inhaled nitric oxide and oxidative stress in acute lung injury. AB - To compare conventional mechanical ventilation (CMV) and high-frequency oscillatory ventilation (HFOV), with/without inhaled nitric oxide (iNO), for oxygenation, inflammation, antioxidant/oxidative stress status, and DNA damage in a model of acute lung injury (ALI). Lung injury was induced by tracheal infusion of warm saline. Rabbits were ventilated at [Formula: see text] 1.0 and randomly assigned to one of five groups. Overall antioxidant defense/oxidative stress was assessed by total antioxidant performance assay, and DNA damage by comet assay. Ventilatory and hemodynamic parameters were recorded every 30min for 4h. ALI groups showed worse oxygenation than controls after lung injury. After 4h of mechanical ventilation, HFOV groups presented significant improvements in oxygenation. HFOV with and without iNO, and CMV with iNO showed significantly increased antioxidant defense and reduced DNA damage than CMV without iNO. Inhaled nitric oxide did not beneficially affect HFOV in relation to antioxidant defense/oxidative stress and pulmonary DNA damage. Overall, lung injury was reduced using HFOV or CMV with iNO. PMID- 24148689 TI - The effect of method and gestational age at termination of pregnancy on future obstetric and perinatal outcomes: a register-based cohort study in Aberdeen, Scotland. AB - OBJECTIVE: To determine whether termination of pregnancy (TOP), including the method used or gestational age at termination, affects future obstetric and perinatal outcomes. DESIGN: Register-based cohort. SETTING: Aberdeen Maternity Hospital, Scotland, UK. POPULATION: From the Aberdeen Maternity and Neonatal Databank (AMND) we identified 3186 women who had terminated their first pregnancy and then had a second pregnancy of beyond 24 weeks of gestation between 1986 and 2010. We identified 42,446 women who had their first delivery in the same time period, for comparison. METHODS: Univariate and multivariate logistic regression was used to compare outcomes between groups. Complete case analysis with adjustment of confounding factors was carried out, and adjusted odds ratios (aORs) with 99% confidence intervals are presented. MAIN OUTCOME MEASURES: The primary outcome was spontaneous preterm delivery (SPTD). RESULTS: No statistically significant association was found between TOP in the first pregnancy and SPTD in the next pregnancy (aOR 1.05; 99% CI 0.83-1.32). Neither medical (aOR 1.03; 99% CI 0.72-1.46) nor surgical (aOR 1.06; 99% CI 0.78-1.44) termination appeared to affect the risk of spontaneous preterm delivery in the subsequent pregnancy. Late termination (>=13 weeks of gestation) did not appear to increase the risk of spontaneous preterm delivery compared with early termination (<13 weeks of gestation) (aOR 1.65; 99% CI 0.94-2.92), nor compared with primigravid women (aOR 1.25; 99% CI 0.97-1.62). There was an associated increased risk of antepartum haemorrhage in the next pregnancy following TOP (P < 0.01; aOR 1.26; 99% CI 1.10-1.45). CONCLUSIONS: Evidence on obstetric and perinatal outcomes following TOP remains conflicting. This study suggests that TOP is not associated with an increased risk of spontaneous preterm delivery. Neither the method nor the gestational age of TOP has any effect on this lack of association. PMID- 24148690 TI - The role of 14,15-dihydroxyeicosatrienoic acid levels in inflammation and its relationship to lipoproteins. AB - BACKGROUND: 14,15-Epoxyeicosatrienoic acids (14,15-EETs) generated from arachidonic acid by cytochrome P450 epoxygenases have beneficial effects in certain cardiovascular diseases, and increased 14,15-EET levels protect the cardiovascular system. 14,15-EETs are rapidly hydrolyzed by soluble epoxide hydrolase (sEH) to the corresponding 14,15-dihydroxyeicosatrienoic acids (14,15 DHETs), which are generally less biologically active but more stable metabolite. A functionally relevant polymorphism of the CYP2J2 gene is independently associated with an increased risk of coronary heart disease (CHD), and the major CYP2J2 product is 14,15-EETs. 14,15-DHETs can be considered a relevant marker of CYP2J2 activity. Therefore, the aim of the present study was to evaluate the plasma 14,15-DHET levels to reflect the 14,15-EET levels in an indirectly way in patients with CHD, and to highlight the growing body of evidence that 14,15-EETs also play a role in anti-inflammatory and lipid-regulating effects in patients with CHD. This was achieved by investigating the relationship between 14,15-DHETs and high-sensitivity C-reactive protein (hs-CRP) and blood lipoproteins. METHODS: Samples of peripheral venous blood were drawn from 60 patients with CHD and 60 healthy controls. A 14,15-DHET enzyme-linked immunosorbent assay kit (14,15-DHET ELISA kit) was used to measure the plasma 14,15-DHET levels. Hs-CRP, total cholesterol, triglyceride, high-density lipoprotein cholesterol, and low-density lipoprotein-cholesterol levels were measured. RESULTS: 14,15-DHET levels (2.53 +/ 1.60 ng/mL) were significantly higher in patients with CHD as compared with those of the healthy controls (1.65 +/- 1.54 ng/mL, P < 0.05). There was a significant positive correlation between 14,15-DHETs and hs-CRP levels (R = 0.286, P = 0.027). However, there was no significant correlation between 14,15 DHETs and blood lipoproteins (all, P > 0.05). CONCLUSIONS: Increased plasma 14,15 DHET levels reflect the decreased of 14,15-EET levels in an indirectly way. Indicated that decreased plasma 14,15-EET levels might be involved in the inflammatory reaction process in atherosclerosis. PMID- 24148691 TI - Exploring the effects of task shifting for HIV through a systems thinking lens: the case of Burkina Faso. AB - BACKGROUND: While the impact of task shifting on quality of care and clinical outcomes has been demonstrated in several studies, evidence on its impact on the health system as a whole is limited. This study has two main objectives. The first is to conceptualize the wider range of effects of task shifting through a systems thinking lens. The second is to explore these effects using task shifting for HIV in Burkina Faso as a case study. METHODS: We used a case study approach, using qualitative research methods. Data sources included document reviews, reviews of available data and records, as well as interviews with key informants and health workers. RESULTS: In addition to the traditional measures of impact of task shifting on health outcomes, our study identified 20 possible effects of the strategy on the system as a whole. Moreover, our analysis highlighted the importance of differentiating between two types of health systems effects. The first are effects inherent to the task shifting strategy itself, such as job satisfaction or better access to health services. The second are effects due to health system barriers, for example the unavailability of medicines and supplies, generating a series of effects on the various components of the health system, e.g., staff frustration.Among the health systems effects that we found are positive, mostly unintended, effects and synergies such as increased health workers' sense of responsibility and worthiness, increased satisfaction due to using the newly acquired skills in other non-HIV tasks, as well as improved patient-provider relationships. Among the negative unintended effects are staff frustration due to lack of medicines and supplies or lack of the necessary infrastructure to be able to perform the new tasks. CONCLUSION: Our analysis highlights the importance of adopting a systems thinking approach in designing, implementing and evaluating health policies to mitigate some of the design issues or system bottle-necks that may impede their successful implementation or risk to present an incomplete or misleading picture of their impact. PMID- 24148692 TI - LINAC radiosurgery for cerebral arteriovenous malformations: a single centre prospective analysis and review of the literature. AB - Stereotactic radiosurgery (SRS) is a well established, minimally invasive treatment option for patients diagnosed with cerebral arteriovenous malformations (AVM). We present the experience in linear accelerator-based SRS for cerebral AVM treated over 14 years. We prospectively followed 67 patients with 69 AVM treated with SRS from 1994 to 2008, inclusive. The mean patient age was 37 years (range 7 69) with 36 women and 31 men. The median AVM size, as defined by maximal diameter, was 2.5 cm (range 0.5-4.6 cm) and the median marginal dose was 18 Gy in one fraction. The crude angiographic obliteration rate was 55% with a 3 and 5 year actuarial rate of 39% and 65%, respectively. Median time to obliteration was 4.2 years. Higher treatment dose (p<0.0001) and smaller maximal AVM diameter (p=0.002) were associated with an increased obliteration rate. There were no deaths from treatment. Post-treatment neurological complications occurred in 10 patients (15%) including hemorrhage in two. Twelve patients (18%) required a second SRS procedure. Larger AVM diameter was associated with increased odds of requiring re-treatment (p=0.02). Radiosurgery for intracerebral AVM is a non invasive therapeutic option with low morbidity and a reasonable likelihood of nidus obliteration. Treatment dose and AVM diameter are the main determinants of obliteration. PMID- 24148693 TI - Stem cell therapy in amyotrophic lateral sclerosis. AB - Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder of upper and lower motor neurons, characterized by progressive muscular atrophy and weakness which culminates in death within 2-5 years. Despite various hypotheses about the responsible mechanisms, the etiology of ALS remains incompletely understood. However, it has been recently postulated that stem cell therapy could potentially target several mechanisms responsible for the etiology of ALS and other nervous system disorders, and could be regarded as one of the most promising therapeutic strategies for ALS treatment. We present a brief review of different methods of stem cell therapy in ALS patients and discuss the results with different cell types and routes of administration. PMID- 24148694 TI - [Hand and endocrine diseases]. AB - The whole of hormones likely influence state of hands, modifying colouring and trophicity of the skin and having influence on its muscular, tendineous, osseous, articular components. Thus state of the hands contributes to the recognition of the endocrine diseases: hot and moist hands of the Graves' disease, dry, cold and infiltrated hands in myxoedema, pale and fine hands of hypopituitarism, broad and thick hand of acromegaly, brachymetacarpia in the pseudohypoparathyroidism... Diabetes exposes particularly to tendineous and articular retractions, to whitlows and ungual mycosis. PMID- 24148695 TI - Exercise-induced changes in cardiovascular function after stroke: a randomized controlled trial. AB - BACKGROUND AND AIMS: Cardiovascular co-morbidities are prevalent after stroke, with heart disease, hypertension and impaired glucose tolerance present in the majority of cases. Exercise has the potential to mediate cardiovascular risk factors commonly present in people with stroke. This single-blinded randomized controlled trial compared the effects of high versus low intensity exercise on fitness, cardiovascular risk factors, and cardiac function after stroke. METHODS: Fifty participants (age 50-80 y, >1 y post-stroke) were randomized to a high intensity Aerobic Exercise (AE) or low-intensity non-aerobic Balance/Flexibility (BF) program (6 months, 3 60-min sessions/week). Outcomes assessed by VO2 peak (primary outcome), arterial stiffness, ambulatory capacity, hemodynamics and cardiac function using echocardiography, and lipid, glucose and homocysteine levels. Assessors were blinded to group allocation. RESULTS: Twenty-three (92%) of 25 AE group participants (withdrawals unrelated to the intervention) and all BF group participants completed the program. One BF group participant experienced 2 non-injurious falls during class. No other adverse events occurred. There were no changes in VO2 peak in either group (AE 16.9+/-7 to 17.4+/-7 ml?kg(-1) ?min( 1) vs. BF 16.9+/-6 to 16.6+/-5 ml?kg(-1) ?min(-1) , P=0.45), but AE group demonstrated greater improvement in right atrial emptying fraction (AE 30+/-22 to 37+/-22% vs. BF 35+/-20 to 31+/-20%, P=0.04). Both groups demonstrated improvements in lipid profiles, glucose and homocysteine levels, and ambulatory capacity (P<0.04). CONCLUSIONS: This was the first study to examine the effects of aerobic exercise after stroke on cardiovascular hemodynamics. High-intensity exercise improved right-sided function and early myocardial relaxation. Low intensity exercise may also benefit plasma lipid, glucose and inflammatory markers, and ambulatory capacity. This study is an important step towards understanding mechanisms by which exercise may reduce cardiovascular risk and function. PMID- 24148696 TI - The assembly pathway of an icosahedral single-stranded RNA virus depends on the strength of inter-subunit attractions. AB - The strength of attraction between capsid proteins (CPs) of cowpea chlorotic mottle virus (CCMV) is controlled by the solution pH. Additionally, the strength of attraction between CP and the single-stranded RNA viral genome is controlled by ionic strength. By exploiting these properties, we are able to control and monitor the in vitro co-assembly of CCMV CP and single-stranded RNA as a function of the strength of CP-CP and CP-RNA attractions. Using the techniques of velocity sedimentation and electron microscopy, we find that the successful assembly of nuclease-resistant virus-like particles (VLPs) depends delicately on the strength of CP-CP attraction relative to CP-RNA attraction. If the attractions are too weak, the capsid cannot form; if they are too strong, the assembly suffers from kinetic traps. Separating the process into two steps-by first turning on CP-RNA attraction and then turning on CP-CP attraction-allows for the assembly of well formed VLPs under a wide range of attraction strengths. These observations establish a protocol for the efficient in vitro assembly of CCMV VLPs and suggest potential strategies that the virus may employ in vivo. PMID- 24148697 TI - Novel interaction between the major bacterial heat shock chaperone (GroESL) and an RNA chaperone (CspC). AB - The heat shock response is one of the main global regulatory networks in all organisms and involves an increased cellular level of chaperones and proteases to enable correct protein folding and balanced growth. One of the major heat shock chaperones in Escherichia coli is GroESL, composed of GroES and GroEL (the bacterial Hsp10 and Hsp60 homologues), which is essential for refolding of misfolded proteins. GroESL was previously shown to play a role in the regulation of the heat shock response by promoting the proteolysis of the regulatory protein -sigma32 (RpoH), the heat shock transcription activator. Here we show the involvement of GroESL in another proteolytic process, this of the major RNA chaperone--CspC--that specifically stabilizes the transcripts of several stress related genes. Evidence is provided for an interaction between GroESL and CspC that results in enhanced, temperature-dependent proteolysis of the latter. This interaction is of regulatory importance, as reduction in the cellular levels of CspC leads to a decrease in stability of the major heat shock gene transcripts. PMID- 24148698 TI - Re: Sidebottom AJ, Patel AA, Amin J. Botulinum injection for the management of myofascial pain in the masticatory muscles. A prospective outcome study. PMID- 24148699 TI - Masseteric nerve for reanimation of the smile in short-term facial paralysis. AB - Our aim was to describe our experience with the masseteric nerve in the reanimation of short term facial paralysis. We present our outcomes using a quantitative measurement system and discuss its advantages and disadvantages. Between 2000 and 2012, 23 patients had their facial paralysis reanimated by masseteric-facial coaptation. All patients are presented with complete unilateral paralysis. Their background, the aetiology of the paralysis, and the surgical details were recorded. A retrospective study of movement analysis was made using an automatic optical system (Facial Clima). Commissural excursion and commissural contraction velocity were also recorded. The mean age at reanimation was 43(8) years. The aetiology of the facial paralysis included acoustic neurinoma, fracture of the skull base, schwannoma of the facial nerve, resection of a cholesteatoma, and varicella zoster infection. The mean time duration of facial paralysis was 16(5) months. Follow-up was more than 2 years in all patients except 1 in whom it was 12 months. The mean duration to recovery of tone (as reported by the patient) was 67(11) days. Postoperative commissural excursion was 8(4)mm for the reanimated side and 8(3)mm for the healthy side (p=0.4). Likewise, commissural contraction velocity was 38(10)mm/s for the reanimated side and 43(12)mm/s for the healthy side (p=0.23). Mean percentage of recovery was 92(5)mm for commissural excursion and 79(15)mm/s for commissural contraction velocity. Masseteric nerve transposition is a reliable and reproducible option for the reanimation of short term facial paralysis with reduced donor site morbidity and good symmetry with the opposite healthy side. PMID- 24148700 TI - Health-related quality of life of patients treated with primary chemoradiotherapy for oral cavity squamous cell carcinoma: a comparison with surgery. AB - Our aim was to document the health-related quality of life (QoL) of patients with squamous cell carcinoma (SCC) of the oral cavity who were treated with chemoradiotherapy, and to compare it with that of patients treated with conventional surgery with or without adjuvant treatment. All patients who presented with SCC of the oral cavity treated with chemoradiotherapy alone at the Royal Brisbane & Women's Hospital between 2000 and 2011 and who were alive without disease were included. Health-related QoL was assessed by the University of Washington QoL questionnaire version 4, and the European Organisation for the Research and Treatment of Cancer (EORTC) QoL questionnaires C30 and HN35. The questionnaires were sent to all survivors. Those who responded to chemoradiotherapy were matched with patients who were treated by conventional surgery with or without adjuvant treatment by age, sex, subsite of tumour, and TNM stage. Sixteen patients completed the questionnaires (8 in each group). There was no significant difference between the 2 groups in any of the domains of any of the questionnaires. The overall outcome scores for both treatments in all 3 groups were reasonably high, which suggests that both treatments provided acceptable health-related QoL. The surgical group recorded higher scores than the chemoradiotherapy alone group in all domains of the UW-QoL except shoulder and anxiety. They recorded lower scores in all scales and items of EORTC HN35. There was no significant difference in health-related QoL between the 2 groups. Conventional surgery with or without adjuvant treatment recorded higher scores in most QoL domains including chewing, swallowing, saliva, and speech, issues most important to patients with SCC of the oral cavity. PMID- 24148701 TI - A case of multiple verruciform xanthoma in gingiva. AB - We present an unusual case of multiple verruciform xanthomas in the gingiva of a patient with no systemic diseases. PMID- 24148702 TI - Suspected ventilator-associated respiratory infection in severely ill patients: a prospective observational study. AB - INTRODUCTION: Ventilator-associated respiratory infection (VARI) is an important cause of morbidity in critically-ill patients. Clinical trials performed in heterogeneous populations have suggested there are limited benefits from invasive diagnostic testing to identify patients at risk or to target antimicrobial therapy. However, multiple patient subgroups (for example, immunocompromised, antibiotic-treated) have traditionally been excluded from randomization. We hypothesized that a prospective surveillance study would better identify patients with suspected VARI (sVARI) at high risk for adverse clinical outcomes, and who might be specifically targeted in future trials. METHODS: We performed a prospective observational study in all patients ventilated for greater than 48 hours. sVARI was identified by surveillance for changes in white blood cell count, temperature, sputum, and/or new chest X-ray infiltrates. Indices of disease co-morbidity, as well as mortality, duration of mechanical ventilation, and length of hospital or ICU stay were correlated with sVARI. RESULTS: Of 1806 patients admitted to the ICU over 14 months, 267 were ventilated for greater than 48 hours, and 77 developed sVARI. Incidence of sVARI was associated with iatrogenic immunosuppression or admission for respiratory illness. Any sVARI, whether suspected ventilator-associated pneumonia (sVAP) or ventilator-associated tracheobronchitis (sVAT), was associated with increased length of stay and duration of mechanical ventilation. CONCLUSIONS: Clinical surveillance for sVARI identifies patients at risk for increased morbidity. Iatrogenically immunosuppressed patients, a subgroup previously excluded from randomized clinical trials, represent a growing proportion of the critically-ill at risk for sVARI who might be targeted for future investigations on diagnostic or therapeutic modalities. PMID- 24148703 TI - Netmums: a phase II randomized controlled trial of a guided Internet behavioural activation treatment for postpartum depression. AB - BACKGROUND: Despite the high prevalence of postnatal depression (PND), few women seek help. Internet interventions may overcome many of the barriers to PND treatment use. We report a phase II evaluation of a 12-session, modular, guided Internet behavioural activation (BA) treatment modified to address postnatal specific concerns [Netmums Helping With Depression (NetmumsHWD)]. METHOD: To assess feasibility, we measured recruitment and attrition to the trial and examined telephone session support and treatment adherence. We investigated sociodemographic and psychological predictors of treatment adherence. Effectiveness outcomes were estimated with the Edinburgh Postnatal Depression Scale (EPDS), Generalized Anxiety Disorder-7, Work and Social Adjustment Scale, Postnatal Bonding Questionnaire, and Social Provisions Scale. RESULTS: A total of 249 women were recruited via a UK parenting site, Netmums.com. A total of 83 women meeting DSM-IV criteria for major depressive disorder were randomized to NetmumsHWD (n = 41) or treatment-as-usual (TAU; n = 42). Of the 83 women, 71 (86%) completed the EPDS at post-treatment, and 71% (59/83) at the 6-month follow up. Women completed an average of eight out of 12 telephone support sessions and five out of 12 modules. Working women and those with less support completed fewer modules. There was a large effect size favouring women who received NetmumsHWD on depression, work and social impairment, and anxiety scores at post-treatment compared with women in the TAU group, and a large effect size on depression at 6 months post-treatment. There were small effect sizes for postnatal bonding and perceived social support. CONCLUSIONS: A supported, modular, Internet BA programme can be feasibly delivered to postpartum women, offering promise to improve depression, anxiety and functioning. PMID- 24148704 TI - Abuse liability measures for use in analgesic clinical trials in patients with pain: IMMPACT recommendations. AB - Assessing and mitigating the abuse liability (AL) of analgesics is an urgent clinical and societal problem. Analgesics have traditionally been assessed in randomized clinical trials (RCTs) designed to demonstrate analgesic efficacy relative to placebo or an active comparator. In these trials, rigorous, prospectively designed assessment for AL is generally not performed. The Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials (IMMPACT) convened a consensus meeting to review the available evidence and discuss methods for improving the assessment of the AL of analgesics in clinical trials in patients with pain. Recommendations for improved assessment include: (1) performing trials that include individuals with diverse risks of abuse; (2) improving the assessment of AL in clinical trials (eg, training study personnel in the principles of abuse and addiction behaviors, designing the trial to assess AL outcomes as primary or secondary outcome measures depending on the trial objectives); (3) performing standardized assessment of outcomes, including targeted observations by study personnel and using structured adverse events query forms that ask all subjects specifically for certain symptoms (such as euphoria and craving); and (4) collecting detailed information about events of potential concern (eg, unexpected urine drug testing results, loss of study medication, and dropping out of the trial). The authors also propose a research agenda for improving the assessment of AL in future trials. PMID- 24148706 TI - Salmonella Typhimurium TTSS-2 deficient mig-14 mutant shows attenuation in immunocompromised mice and offers protection against wild-type Salmonella Typhimurium infection. AB - BACKGROUND: Development of Salmonella enterica serovar Typhimurium (S. Typhimurium) live attenuated vaccine carrier strain to prevent enteric infections has been a subject of intensive study. Several mutants of S. Typhimurium have been proposed as an effective live attenuated vaccine strain. Unfortunately, many such mutant strains failed to successfully complete the clinical trials as they were suboptimal in delivering effective safety and immunogenicity. However, it remained unclear, whether the existing live attenuated S. Typhimurium strains can further be attenuated with improved safety and immune efficacy or not. RESULTS: We deleted a specific non-SPI (Salmonella Pathogenicity Island) encoded virulence factor mig-14 (an antimicrobial peptide resistant protein) in ssaV deficient S. Typhimurium strain. The ssaV is an important SPI-II gene involved in Salmonella replication in macrophages and its mutant strain is considered as a potential live attenuated strain. However, fatal systemic infection was previously reported in immunocompromised mice like Nos2-/- and Il-10-/- when infected with ssaV deficient S. Typhimurium. Here we reported that attenuation of S. Typhimurium ssaV mutant in immunocompromised mice can further be improved by introducing additional deletion of gene mig-14. The ssaV, mig-14 double mutant was as efficient as ssaV mutant, with respect to host colonization and eliciting Salmonella-specific mucosal sIgA and serum IgG response in wild-type C57BL/6 mice. Interestingly, this double mutant did not show any systemic infection in immunocompromised mice. CONCLUSIONS: This study suggests that ssaV, mig-14 double mutant strain can be effectively used as a potential vaccine candidate even in immunocompromised mice. Such attenuated vaccine strain could possibly used for expression of heterologous antigens and thus for development of a polyvalent vaccine strain. PMID- 24148708 TI - Firearm-related hospitalizations and in-hospital mortality in the United States, 2000-2010. AB - Most firearm-related injuries are nonfatal and require hospitalization. Using data on 3,257,720 hospitalizations from the National Hospital Discharge Survey (2000-2010), we determined overall and cause-, gender-, and race-specific trends in firearm-related hospitalization (FRH) and determinants of in-hospital firearm mortality. Types of FRH evaluated, according to International Classification of Diseases, Ninth Revision, Clinical Modification, E-diagnostic codes, were accident (codes E922.0-E922.3, E922.8, and E922.9), assault (codes E965.0 E965.4), attempted suicide (codes E955.0-E955.4), legal intervention (code E970), undetermined intent (codes E985.0-E985.3), and war (code E991). A moderate reduction in FRH rates was observed from 2000 to 2011: from 62 FRHs per 100,000 hospitalizations to 57 per 100,000 (P-trend = 0.0016). The majority of FRHs were due to assault (P-trend = 0.19) or accident (P-trend = 0.32) and showed no significant reduction in rates over time, whereas rates for 14% of all FRHs-those due to attempted suicide (P-trend = 0.002) and undetermined intent (P-trend = 0.0029)-declined moderately. Moderate declines were observed among both blacks (from 213.1 FRHs per 100,000 hospitalizations to 164.4 per 100,000; P-trend = 0.049) and whites (from 38.4 FRHs per 100,000 hospitalizations to 32.2 per 100,000; P-trend = 0.031). The decline was significant only among men (effect size = 0.9, P-trend = 0.004). In conclusion, the reduction in FRH was driven by a reduction in self-inflicted and undetermined injuries. FRH rates were 6-fold greater among blacks than among whites and 14-fold greater in men than in women throughout the period. PMID- 24148707 TI - Definitions and drivers of relapse in patients with schizophrenia: a systematic literature review. AB - Relapse in patients with schizophrenia has devastating repercussions, including worsening symptoms, impaired functioning, cognitive deterioration and reduced quality of life. This progressive decline exacerbates the burden of illness on patients and their families. Relapse prevention is identified as a key therapeutic aim; however, the absence of widely accepted relapse definition criteria considerably hampers achieving this goal. We conducted a literature review in order to investigate the reporting of relapses and the validity of hospitalization as a proxy for relapse in patients with schizophrenia. The primary aim was to assess the range and validity of methods used to define relapse in observational or naturalistic settings. The secondary aim was to capture information on factors that predicted or influenced the risk of relapse. A structured search of the PubMed database identified articles that discussed relapse, and hospitalization as a proxy of relapse, in patients with schizophrenia. National and international guidelines were also reviewed. Of the 150 publications and guidelines identified, 87 defined relapse and 62% of these discussed hospitalization. Where hospitalization was discussed, this was as a proxy for, or a component of, relapse in the majority of cases. However, hospitalization duration and type varied and were not always well defined. Scales were used to define relapse in 53 instances; 10 different scales were used and multiple scales often appeared within the same definition. There were 95 references to factors that may drive relapse, including non-adherence to antipsychotic medication (21/95), stress/depression (11/95) and substance abuse (9/95). Twenty-five publications discussed the potential of antipsychotic therapy to reduce relapse rates-continuous antipsychotic therapy was associated with reduced frequency and duration of hospitalization. Non-pharmacological interventions, such as psychoeducation and cognitive behavioural therapy, were also commonly reported as factors that may reduce relapse. In conclusion, this review identified numerous factors used to define relapse. Hospitalization was the factor most frequently used and represents a useful proxy for relapse when reporting in a naturalistic setting. Several factors were reported to increase the risk of relapse, and observation of these may aid the identification of at risk patients. PMID- 24148709 TI - Red meat and processed meat consumption and all-cause mortality: a meta-analysis. AB - High consumption of red meat and processed meat has been associated with increased risk of several chronic diseases. We conducted a meta-analysis to summarize the evidence from prospective studies on red meat and processed meat consumption in relationship to all-cause mortality. Pertinent studies were identified by searching PubMed through May 2013 and by reviewing the reference lists of retrieved articles. Prospective studies that reported relative risks with 95% confidence intervals for the association of red meat or processed meat consumption with all-cause mortality were eligible. Study-specific results were combined by using a random-effects model. Nine prospective studies were included in the meta-analysis. The summary relative risks of all-cause mortality for the highest versus the lowest category of consumption were 1.10 (95% confidence interval (CI): 0.98, 1.22; n = 6 studies) for unprocessed red meat, 1.23 (95% CI: 1.17, 1.28; n = 6 studies) for processed meat, and 1.29 (95% CI: 1.24, 1.35; n = 5 studies) for total red meat. In a dose-response meta-analysis, consumption of processed meat and total red meat, but not unprocessed red meat, was statistically significantly positively associated with all-cause mortality in a nonlinear fashion. These results indicate that high consumption of red meat, especially processed meat, may increase all-cause mortality. PMID- 24148710 TI - Examination of how neighborhood definition influences measurements of youths' access to tobacco retailers: a methodological note on spatial misclassification. AB - Measurements of neighborhood exposures likely vary depending on the definition of "neighborhood" selected. This study examined the extent to which neighborhood definition influences findings regarding spatial accessibility to tobacco retailers among youth. We defined spatial accessibility to tobacco retailers (i.e., tobacco retail density, closest tobacco retailer, and average distance to the closest 5 tobacco retailers) on the basis of circular and network buffers of 400 m and 800 m, census block groups, and census tracts by using residential addresses from the 2008 Boston Youth Survey Geospatial Dataset (n = 1,292). Friedman tests (to compare overall differences in neighborhood definitions) were applied. There were differences in measurements of youths' access to tobacco retailers according to the selected neighborhood definitions, and these were marked for the 2 spatial proximity measures (both P < 0.01 for all differences). For example, the median average distance to the closest 5 tobacco retailers was 381.50 m when using specific home addresses, 414.00 m when using census block groups, and 482.50 m when using census tracts, illustrating how neighborhood definition influences the measurement of spatial accessibility to tobacco retailers. These analyses suggest that, whenever possible, egocentric neighborhood definitions should be used. The use of larger administrative neighborhood definitions can bias exposure estimates for proximity measures. PMID- 24148712 TI - Effectiveness of oral Tranexamic acid administration on blood loss after knee artroplasty: a randomized clinical trial. AB - INTRODUCTION: Some studies have proved that Tranexamic acid infusion is associated with a decrease in blood loss during and after surgery. Due to the availability of an oral form of the drug, the rapid and complete absorption of it and ease of administration without need for specific instruments, we evaluated the effectiveness of the oral form in decreasing blood loss after total knee arthroplasty. MATERIALS AND METHODS: In this double-blind, randomized, parallel clinical trial study, we evaluated 53 patients undergoing knee arthroplasty admitted to Ghaem hospital, Mashhad in 2012. Patients with any history of severe ischemic heart diseases, renal failure, cirrhosis, history of bleeding disorders or thromboembolic events, were excluded from the study. The patients were randomly allocated into 27 patients with and 26 patients without Tranexamic acid. Blood loss (mL) at 12 and at 24h and hematocrit at 24h were measured postoperatively. The results were analyzed with SPSS software (11.5 version) using independent and paired sample t-tests. A p-value <= 0.05 was considered to be significant. RESULTS: The average blood loss after 12h of surgery in the control and Tranexamic acid groups were 462.9 (+/- 147.4) and 274.6 (+/- 139)mL, respectively (p<0.001) and after 24h of surgery they were 588.8 (+/- 193)and 364 (+/- 165.1)mL, respectively (p<0.001). The mean decrease in the hematocrit after surgery was 4.7% in the Tranexamic acid group and 6.8% in the control group (p=0.016). CONCLUSION: Prescription of oral Tranexamic acid before knee arthroplasty can cause remarkable decrease in blood loss after surgery and also less decrease in hematocrit. The advantages of the oral route of the drug versus the intravenous form is that it can be used routinely as a safe and effective way to decrease bleeding after surgery. PMID- 24148713 TI - Warm autoimmune hemolytic anemia secondary to Plasmodium ovale infection: a case report and review of the literature. AB - A three year old male from the Democratic Republic of the Congo was admitted to Monroe Carell Jr. Children's Hospital at Vanderbilt with a 10-day history of fever, emesis, and diarrhea. Examination demonstrated scleral icterus, splenomegaly, and anemia. By peripheral blood smear, the patient was diagnosed with Plasmodium ovale. Immunohematology demonstrated a positive direct antiglobulin test (DAT) for IgG and C3d with pan-agglutination on eluate. These findings, in combination with hemolytic labs, signified presence of an autoimmune hemolytic anemia (AIHA). We believe this to be the first reported case of P. ovale infection-mediated AIHA. PMID- 24148711 TI - A longitudinal study of the association between visual impairment and mobility performance in older adults: the salisbury eye evaluation study. AB - Few longitudinal studies have examined how visual impairment affects mobility as people age. Data from the Salisbury Eye Evaluation Study, a population-based sample of 2,520 adults aged 65 years and older, were used to investigate the longitudinal association between visual impairment and mobility. Baseline, 2 year, 6-year, and 8-year visits occurred between 1993 and 2001. Mobility was assessed by measuring speeds on the following 3 tasks: walking up 7 steps, walking down 7 steps, and walking 4 m. Random-effects linear regression was used to model factors affecting speed. For each year of observation, speeds declined, and the visually impaired had significantly slower speeds than the non--visually impaired on all 3 tests after accounting for other covariates (betawalking up steps = -0.08 steps/second, 95% confidence interval (CI): -0.10, -0.06; betawalking down steps = -0.11 steps/second, 95% CI: -0.14, -0.08; and betawalking 4 m = -0.08 m/second, 95% CI: -0.10, -0.06). However, the interaction between years since baseline and visual impairment status was not significant, indicating that mobility speeds declined at a similar rate in the visually impaired and the non--visually impaired. These results suggest that the impact of visual impairment on speed is significant but does not change as people age. PMID- 24148714 TI - Apheresis activity in Spain: a survey of the Spanish Apheresis Group. AB - The Spanish Apheresis Group is a scientific association of physicians and nurses representing most of the medical centers in the country that are involved in apheresis. The group developed a survey in order to get information about the types and number of apheresis procedures performed in Spain. We received responses from 66 centers and we were able to collect data from at least one center of each autonomous region. There were 7 centers (11%) that did not perform any kind of apheresis procedures, 26 (39%) centers performed therapeutic apheresis procedures only, 18 (27%) centers performed apheresis donations only, and 15 (23%) centers performed both types of apheresis procedures. Regarding therapeutic apheresis in adult patients, plasma exchange (34%) and stem cell collections (30%) were the two therapeutic procedures most frequently reported, followed by erythrocytapheresis (13%) and extracorporeal photochemotherapy (11%). Regarding apheresis donation, our survey showed that the most frequent was multicomponent donation (45%) followed by plasmapheresis (28%) and single plateletapheresis (21%). When analyzing the current instrumentation for performing apheresis procedures, centers used the Spectra, Optia, and Trima devices (TerumoBCT) as the most frequent ones, followed by the MCS+(Haemonetics), Amicus (Fenwal), and Fresenius devices. In conclusion, we report here the first nationwide survey performed in Spain in order to get information about apheresis activities in our country. The survey is representative of Spain because we were able to collect data from at least one center from each of the different 17 autonomous regions, and we found a wide variety of therapeutic and donation procedures, as well as instrumentation used. PMID- 24148716 TI - Editorial. PMID- 24148715 TI - Response to prasugrel and levels of circulating reticulated platelets in patients with ST-segment elevation myocardial infarction. AB - OBJECTIVES: The aim of this study was to determine whether response to prasugrel is associated with the proportion of circulating reticulated platelets (RPs) in patients with ST-segment elevation myocardial infarction (STEMI). BACKGROUND: Despite better pharmacodynamic properties and clinical efficacy of prasugrel compared with clopidogrel, antiplatelet responses to prasugrel are not uniform. The mechanism of this variability in response is not clear. RPs, young hyperactive forms, are increased during situations of enhanced platelet turnover. METHODS: Patients with STEMI treated with primary percutaneous intervention (PCI) and prasugrel were tested for platelet reactivity using purinergic receptor P2Y, G-protein coupled, 12 (P2Y12) assay and multiple electrode aggregometry (MEA). RP levels were determined using flow cytometry with thiazole orange staining. Tests were performed at 2 to 4 days and 30 days post-PCI. Platelet function was compared by varying levels of RPs, analyzed as continuous (regression analysis) and categorical (tertiles) variables. RESULTS: Sixty-two patients were included (mean age: 57.5 +/- 8 years; 21.2% women; 27.7% diabetes). At the early time point, RP levels were strongly correlated with platelet reactivity when evaluated by the P2Y12 assay (Spearman's correlation coefficient: 0.55 for P2Y12 reaction units, -0.49 for percent inhibition) and MEA (Spearman's: 0.50). The upper tertile of RPs displayed higher platelet reactivity compared with the middle and lower tertiles, according to P2Y12 assay and MEA. Similar results with strong correlations between RP and platelet reactivity were noted at 30 days post-PCI. CONCLUSIONS: The proportion of circulating RPs strongly correlates with response to prasugrel in patients with STEMI treated with PCI. High levels of RPs are associated with increased platelet reactivity despite prasugrel treatment. PMID- 24148717 TI - Perfusion CT: Additional Diagnostic and Clinical Information in MCA Stroke. AB - With multidetector computed tomography equipment it is possible to identify early signs of ischemia on non-enhanced CT (NECT) and have access to cerebral hemodynamics using perfusion CT (PCT). Based on specific patterns of hemodynamic changes of cerebral blood flow, cerebral blood volume and mean transit time it is feasible to create probability maps of brain tissue and calculate de potential recuperation ratio. The difference between irreversible and reversible brain damage or "tissue at risk" is essential for choosing an appropriate therapy. We evaluated the sensitivity of NECT and PCT in the diagnosis of middle cerebral artery (MCA) ischemic stroke, established their correlation with the clinical evaluation and analysed their changes in time. Thirty patients with MCA ischemic stroke underwent NECT and PCT in the acute T1 (M=7,0 h; min=0,50; max=24), subacute T2 (M=5,0 d; min=2,0; max=14,0) and chronic phase T3 (M=39,1 d; min=28,0; max=61,0). Clinical assessment and outcome were rated using the modified National Institute of Health Stroke Scale (mNIHSS). In the diagnosis of MCA stroke, PCT was more sensitive (83%) than NECT (70%). On admission, compared MTT values (r=0,560) and cerebral ischemic volume (CIV) (r=0,486) correlated with the clinical severity. Initial NECT changes correlated with the clinical evolution in T2 (r=-0,403) and T3 (r=-0,363). The PRR decreased over time, but it demonstrated a large variation for the same time period. The association of NECT with PCT can yield an early stroke diagnosis. It may possibly predict clinical severity and outcome. In addition, this association could provide an insight into the extent of penumbra and quantify the PRR, which is of paramount importance in therapeutic decision-making. PMID- 24148718 TI - Clinical and Radiological Differences in Alzheimer's Disease with and without a History of Mild Cognitive Impairment. AB - We assessed the influence of a history of amnesic mild cognitive impairment (MCI) in patients with Alzheimer's disease (AD) at presentation from a clinical and radiological point of view. A consecutive sample of patients fulfilling the criteria of probable Alzheimer's disease according to the NINCDS-ADRDA work group not previously diagnosed nor treated underwent neuropsychological assessment including mini-mental test, Blessed dementia rating scale (BDRS), ADAS-Cog, neuropsychiatric inventory (NPI), and a daily living activities scale (DAD). Radiological evaluation consisted of magnetic resonance imaging, left hippocampal volumetry and magnetic resonance spectroscopy (MRS) of the brain. We divided the patients into two groups according to positive/negative history of MCI for a period longer than one year. The AD patients with a history of MCI were more likely to have a history of depression (OR: 5.5; 95% CI: 1.12-26) and have more depressive symptoms at presentation in the NPI than those without a history of MCI. They also had a history of hypertension more frequently than the remainder. The presence/absence of ApoE4 alleles did not have influence in the clinical course. With regard to radiological findings the patients with previous MCI showed lower values of N-acetyl-aspartate (NAA) in parietal (p=0.0001) temporal (p=0.08) and occipital (p=0.00001) lobes than the other group, as well as a smaller left hippocampus although the difference was not statistically significant. A history of MCI in AD patients represents a form of the disease with slower progression from clinical and radiological viewpoints. These patients present with more depressive symptoms and a history of depression than the remainder. The lower NAA levels on MRS are compatible with a longer disease duration when AD is preceded by amnesic MCI. PMID- 24148719 TI - Event-Related Functional Magnetic Resonance Images during the Perception of Phantom Limb. A Brushing Task. AB - The phantom limb phenomenon has been used in amputee patients as a paradigm to study plasticity, mainly of the sensorimotor cortex. Nevertheless, most functional studies have been done in upper limb amputee patients using magnetoencephalography and functional magnetic resonance image imaging (fMRI). In addition, the actual experience of phantom limb sensation has not been widely used to study the neural mechanism of the human brain as a conscious knowledge of the phantom limb perception like the integration of the body image in amputee patients. fMRI studies of patients with lower limb amputation have recently been published, but none of these used an event-related design to try to observe only the stimulus application, correlating images with the subject's indication of phantom perception and discarding images with no phantom perception. In this work, we used the event-related fMRI design in two right-handed patients with identical right, transfemoral amputations, performing the same sensitive stimulation in a 3.0 T MR scanner. For comparison, we applied the same paradigm to six control subjects to compare the resulting functional maps. We found areas with statistical significance in the sensorimotor cortex contralateral to the site of stimulation, in the parietal lobe in Brodmann areas 3 in both cases (Patients and Control Subjects), but we also found activation in the Brodmann areas 6, 40, and 5 with stimulation of the stump. We observed a specific activation of the frontoparietal circuit during phantom limb perception in both amputee patients. PMID- 24148720 TI - Abnormal functioning of the thalamocortical system underlies the conscious awareness of the phantom limb phenomenon. AB - Phantom limb (PL), a phenomenon experienced by most patients after amputation, has mostly served as a paradigm to study experiences that appear to be associated with neural plasticity within the CNS. However, the subjective nature of PL experiences has had no definitive means of reliable assessment other than using patients' direct reports, nor was there a way to study the neural mechanisms involved in the conscious awareness of this mental phenomenon. Here we obtained patients' indirect responses to PL experiences for an objective evaluation using functional magnetic resonance imaging (fMRI). Six control subjects and six lower limb (LL) amputees participated in a motor imagery task for both the intact and the particular phantom toes. While all subjects shared neural processing of distinctive regional cerebral activations during motor imagery of the intact toes (prefrontal (PF), supplementary motor area (SMA), primary motor cortex (M1), superior temporal gyrus (STG)), it was only during motor imagery of the amputated toes in amputees that we observed an increased blood oxygen level-dependent (BOLD) signal in the contralateral basal ganglia at the medial globus pallidus (MGP), substantia nigra (SN), and thalamus. This increased BOLD signal in the basal ganglia-thalamus-cortex pathway during imaginary movement of the phantom toes may reflect an abnormal open loop functioning of the thalamocortical system underlying the conscious awareness of the phantom phenomenon. We suggest that the reduction in afferent information contributes to and coalesces with the higher level reorganization resulting in the subjective conscious awareness of the phantom limb. PMID- 24148721 TI - Imaging in primary central nervous system lymphoma. AB - Primary central nervous system (CNS) lymphoma (PCNSL) accounts for approximately 3% of all primary CNS tumors. Congenital or acquired immunodeficiency is the only established risk factor for PCNSL. Rates decreased slightly in the mid-1990s, concordantly with the decreasing rates of AIDS. However, the incidence has been increasing in the elderly immunocompetent population, and this trend seems to be independent of improvements in diagnostic techniques, and of overall trends in the incidence of brain tumors and systemic lymphomas. This study presents our experience with the imaging features of PCNSL. Computed tomography (CT) and magnetic resonance imaging (MRI) findings were reviewed in a series of 38 cases of pathologically proven PCNSL. The incidence rate of PCNSL was higher in men than in women (58% versus 42%). Mean age at presentation was 63 years; 120 lesions were demonstrated in the 38 patients, with a 53% frequency of tumor multiplicity. Both CT and MR mainly showed solitary or multiple well-defined round or oval-shaped mass lesions, typically hyperdense on unenhanced CT scans, iso to hypointense on T2 MR weighted images. These lesions also showed an increased signal intensity on diffusion-weighted images. Virtually all lesions enhanced after intravenous administration of contrastmedium. On (1)H-magnetic resonance spectroscopy ((1)H-MRS) most lesions presented increased Cho/Cr, Cho/NAA and lactate/Cr ratios when compared to normal gray matter. No changes in the imaging presentation have occurred over the past two decades, apart from lesions now being smaller at diagnosis. Our imaging findings are in agreement with the existing literature data and with the reported increasing trend of multifocal tumors. Our epidemiologic results add value to the existing evidence of increasing incidence rates among the immunocompetent elderly population. PMID- 24148722 TI - Pilocytic astrocytomas in elderly adults. AB - Pilocytic astrocytomas are classified as WHO grade I gliomas that occur predominantly in children and young adults. Reports of the tumors in elderly adults are extremely rare. We describe two cases of pilocytic astrocytoma in elderly adults, a 68-year-old man and a 71-year-old woman. Brain computed tomography (CT) and magnetic resonance imaging (MRI) revealed well-circumscribed lesions associated with contrast enhancement and minimal surrounding edema. Pathological studies revealed findings consistent with pilocytic astrocytomas. Although these tumors are rarely found in elderly adults, pilocytic astrocytomas should be considered in the differential diagnosis if the radiographic features of the tumors are characteristic of pilocytic astrocytomas. PMID- 24148723 TI - Persistent Trigeminal Artery Variant: MR Angiographic Demonstration. A Report of Two Cases. AB - A variant (PTAV) is the persistence after birth of the fetal carotid-basilar anastomosis between the internal carotid artery and a cerebellar artery. We describe two cases of a PTAV demonstrated on MR angiography. A comparison with a persistant trigeminal artery is made and an explanation of the extended Saltzman classification is given. These variants have only little clinical significance, but their recognition is crucial before surgical or interventional procedures or to understand paradoxical cerebellar lesions. MRA appears inferior to selective angiography in diagnosing these variants. PMID- 24148724 TI - MRI Aspects of Neuro-Vascular Conflict of the VIII Nerve. AB - The vascular cross compression syndrome of the vestibule-cochlear nerve is an abnormal contact between the VIII nerve and a vessel leading to tinnitus and/or vertigo due to the nerve irritation. MRI is an important diagnostic tool as it will display the whole course of the nerve and identify the site and the type of neuro-vascular contact. However, MR findings are not specific and diagnosis can only be made on the basis of clinical and otolaryngologic features, after ruling out other possible diseases causing the same symptomatology. We describe 15 patients with neuro-vascular conflict disclosed by MRI examination which was associated with non specific neuro-othologic symptoms. PMID- 24148725 TI - Role of Magnetic Resonance Imaging in Duane's Retraction Syndrome: Presence of the Abducens Nerve Depending on Type. A Clinical-Anatomical Study. AB - This study correlated anatomical findings and clinical evidence in Duane's Retraction Syndrome using brain MRI. The study included 11 patients with different types of Duane's Retraction Syndrome (DRS). Each patient underwent brain MRI. The VI(th) nerve was absent in all patients with DRS-I, present in all patients with DRS-II, while findings varied in patients with DRS-III. Our study confirms the literature on the usefulness of brain MRI in diagnosis of Duane's Retraction Syndrome in children. PMID- 24148726 TI - Giant intradiploic epidermoid cyst of occipital bone. A case report and literature review. AB - Intradiploic epidermoid cysts are congenital benign lesions. They commonly occur intracranially. Intradiploic epidermoid cyst of the calvarium is very rare and few cases have been reported to date. We describe a giant intradiploic epidermoid cyst of the occipital bone with CT and MRI characteristics including DW imaging and ADC values. PMID- 24148727 TI - Isovoxel-based morphology of hippocampi and amygdalae: a comparison of manual and automated volume measurements. AB - This study evaluated the correlation between manual and automated morphometric measurements of hippocampi and amygdalae. Twenty-three patients with no history of seizures and normal electroencephalograms were examined with a standardized MRI protocol that included isovoxel volumetric acquisitions of the brain. Images were evaluated in axial-oblique plane to trace manually the grey matter contours of hippocampi and amygdalae obtaining their volumes. They were also processed automatically carrying out segmentation and sub segmentation aligning images (AC PC) and standardizing them into Talairach space to obtain then comparable grey matter volumes. Tabled results were age, gender and volumes of each side from both, manual and automated measurements. Forward stepwise multiple regression analyses were carried out considering sex and age as independent and hippocampi amygdalae as dependent variables. Linear regression analyses were then carried out considering for the total of cerebral hemispheres each manual measurement as independent and automatically obtained volumes as dependent variables. In the multiple regression analyses the following values were obtained: age-gender vs. manual measurements showed r=0.83; r(2)=0.69; adjustedr(2)=0.64; F(3,19)=14.36 while age-gender vs. automated values showed r=0.86; r(2)=0.74; adjustedr(2)=0.70; F(3,19)=18.81. Linear regression between manual and automated measurements for all hemispheres showed for hippocampus: r=0.97; r(2)=0.95; F(1,44)=896.59. For amygdala results were: r=0.94; r(2)=0.89; F(1,44)=391.11. The results of these analyses suggest that both manual and automated procedures of measurement are highly consistent. A regression between age and volumes of both hippocampus and amygdala was also noted. PMID- 24148728 TI - The impact of imaging on management of cervical cystic hygromas. A report of two unusual cases. AB - Cystic hygromas occur most commonly in the neck, axilla, groin or retroperitoneal space. Occasionally a portion of a cervical cystic hygroma may reside within the mediastinum. It is also extremely rare for cystic hygroma to present in the back of the neck. Hence, we describe our experience of two cases of cystic hygromas in the neck, an extensive cervicomediastinal, and posterior cervical lesion. The different location and extent of each lesion, and different management decisions are discussed. PMID- 24148729 TI - A p1 aneurysm and diabetes insipidus caused by traumatic brain injury. AB - We describe a patient with a P1 aneurysm of the posterior cerebral artery (PCA) with diabetes insipidus (DI) caused by traumatic brain injury. A 21-year-old woman presented with epidural hematoma, left temporal contusion and subarachnoid hemorrhage caused by head trauma. DI occurred with normal anterior hypophyseal function on the second day after admission and cerebral angiography demonstrated an aneurysm at the right P1 portion after one month. DI was treated with administration of desmopressin and the aneurysm and P1 portion of the right PCA were occluded completely. After three months, her DI recovered and decompressin was discontinued. The six month follow-up angiogram confirmed cure of the P1 aneurysm. P1 aneurysm and DI can be caused by traumatic brain injury. Cranial DI caused by head injury with perturbations in water balance may be transitory and resolve. PMID- 24148730 TI - Endovascular treatment for cerebral aneurysms using stents. AB - Endovascular stent placement combined with coil embolization is an established procedure for the treatment of intracranial aneurysms. We describe lesion outcome using stents for the treatment of intracranial aneurysms. Sixty-nine patients (30 females and 39 males; age range 12-78 years) treated with stent placement at Beijing Tiantan Hospital over a six-year period. Seventy- six cerebral aneurysms were encountered and 74 lesions were treated with 79 stents. Outcome was evaluated using the Glasgow Outcome Scale (GOS) score during a mean follow-up period of 32 months. Of the 74 stented aneurysms, 34 (45.9%) were located in the anterior circulation and 40 (54.1%) in the posterior circulation. Forty-eight (64.9%) aneurysms were small and 26 (35.1%) were large or giant. In 67 (90.5%) aneurysms embolization was completed by packing the aneurysm sac with platinum coils. In five small fusiform and four saccular aneurysms, the stent was used alone. Six procedure-related complications were observed and a cause of death in 7.2% of the patients. Follow-up angiography obtained at three months to one year in 68 (91.9%) aneurysms demonstrated complete occlusion in 43 aneurysms with a progressive thrombosis rate of 19.4% (six out of 31 aneurysms). Aneurysm recurrence occurred in four (5.8%) patients, three were treated with coil embolization and one with placement of another stent. Overall long-term outcome was good (GOS Score 4 or 5) in 92.8%, and fatal (GOS Score 1) in 7.2% of the patients. Intracranial stents can be a useful addition to coil embolization for complex broad-based aneurysms. Favorable overall long-term outcome can be achieved in 92.8% of patients when using endovascular stent placement techniques. PMID- 24148731 TI - Treatment of a fusiform vertebral aneurysm with double stent placement. A technical case report and review of the literature. AB - A 34-year-old man admitted to another hospital presented with sudden onset of headache. The CT scan was unremarkable, but magnetic resonance angiography revealed a fusiform aneurysm in the left vertebral artery. Six days later, the patient was sent to our institution for further diagnosis and treatment. Cerebral angiography confirmed a fusiform aneurysm located in the right vertebral artery. At first, we placed a neuroform-3 stent and could see contrast medium stasis in the aneurysm, so we did not fill coils into the aneurysm. Four months later, the patient was admitted for rechecking. DSA showed the aneurysm remained and we placed a LEO stent in the lumen of the Neuroform stent. A control DSA eight months later showed the aneurysm had almost healed. Overlapping stents may induce spontaneous thrombosis of vertebral artery aneurysms and facilitate parent artery reconstruction through flow remodeling and stent endothelialization. This technique may be an option in treating dissecting or fusiform intracranial aneurysms that are not amenable to open surgical treatment or endovascular coil embolization. PMID- 24148732 TI - Successful Management of Hemorrhagic Complications during Onyx-18 Embolization of Cerebral Arteriovenous Malformations. AB - The most frequent and devastating complication of the endovascular treatment of cerebral AVMs is hemorrhage. This report describes three patients with cerebral AVM who encountered bleeding during Onyx-18 embolization. The bleeding was discovered promptly during the procedure and hemorrhage quickly prevented using Onyx-18. All three patients recovered without any new neurological symptoms. Early detection and prevention of bleeding are very important during interventional procedures to avoid craniotomy and improve the prognosis of patients. PMID- 24148733 TI - DWI Reversibility after Intra-Arterial Thrombolysis. A Case Report and Literature Review. AB - We report our case and review the literature on reversal DWI lesions, ADC thresholds and correlation between DWI lesion and outcome measured with clinical scales. A 30-years old woman was admitted to our hospital 18 hours after stroke onset. Considering the absence of alterations on CT and the worsening of symptomatology, the patient underwent MRI, which showed a slightly hyperintense signal in FLAIR images in the left portion of the pons and midbrain and a more evident bilateral DWI hyperintensity of the pons. The patient was treated with mechanical and pharmacological intra-arterial thrombolysis. The patient showed a rapid improvement of symptoms. Two weeks after the treatment her clinical conditions were characterized by a residual right hemiparesis and complete recovery of right motility, respiratory and swallowing difficulties. MR examination demonstrated a slight signal alteration of the pons left hemiportion and a disappearance of the mesencephalic signal alteration and of the right portion of the pons. DWI lesions represent irreversibly damaged tissue but new evidence suggests that DWI lesions may be reversible, especially with reperfusion, by now well demonstrated in animal models. Therefore acute DWI lesions probably contain not only irreversibly injured tissue but also parts of the penumbra. The debate on the capability of ADC maps to discriminate irreversibly from reversibly damaged tissue is a matter of controversy. ADC values in human stoke are not an independent indicator of tissue viability. The use of thresholds may improve reproducibility but not validity. PMID- 24148734 TI - Letter to the editor. Unilateral thalamic infarction in vein of galen and straight sinus thrombosis. AB - Deep cerebral venous thrombosis is an uncommon event. It usually involves the halami and adjacent areas on both sides. Unilateral thalamic infarction is extremely rare subsequent to deep cerebral venous thrombosis. Imaging findings of a female in the postpartum period with unilateral thalamic infarction and basal ganglia edema are presented. PMID- 24148736 TI - Pleiotropic vascular protective effects of statins and anesthetic management. PMID- 24148737 TI - Feasibility of combined paravertebral block and subcostal transversus abdominis plane block in postoperative pain control after minimally invasive esophagectomy. AB - OBJECTIVES: Subcostal transversus abdominis plane (TAP) block and paravertebral block (PVB) offer postoperative analgesia for laparoscopic and thoracoscopic surgery, respectively. We investigated the early postoperative analgesic effects of PVB in combination with subcostal TAP block in patients undergoing minimally invasive esophagectomy (MIE) for esophageal cancer. METHODS: Seventeen patients undergoing MIE without nerve block for postoperative analgesia and 16 patients undergoing MIE with PVB and subcostal TAP block for postoperative analgesia were enrolled for the study. The surgeon performed PVB with bupivacaine at T4, T6, and T8 levels under video-assisted thoracoscopy at the end of the thoracoscopic stage. The anesthesiologist responsible for the anesthesia performed ultrasound guided bilateral subcostal TAP with bupivacaine at the end of the surgery. Postoperative morphine consumption, pain severity, vital capacity, intensive care unit (ICU) stay, and complication rate were compared between groups. RESULTS: The group receiving nerve blocks consumed less morphine on postoperative Day 0 (p = 0.016), experienced lower levels of pain at postoperative 0 hour (p = 0.005) and 2 hours (p = 0.049), and had a shorter ICU stay (p = 0.02). No between-group differences in postoperative vital capacity and respiratory complications were observed. CONCLUSION: PVB in combination with subcostal TAP block could reduce morphine consumption and pain severity in the early postoperative period but did not offer other clinical benefits in MIE. PMID- 24148738 TI - Factors affecting the duration of mechanical ventilation in patients after intestinal transplantation: preliminary results. AB - OBJECTIVE: Intestinal transplantation (ITx) is a definitive therapy for patients with intestinal failure. However, postoperative respiratory care in such patients remains a clinical challenge. In this study, we investigated the factors affecting the duration of mechanical ventilation in patients who underwent ITx. METHODS: In this observational study, eight patients who underwent ITx between 2007 and 2013 were studied. They were divided into two groups, with Group E including three patients who could be successfully extubated within 72 hours and Group V including the remaining five, who could not be extubated. The differences in demographical and clinical data between the two groups were evaluated. RESULTS: The surgery success rate, patient survival rate, and graft survival rate were 100%, 88%, and 75%, respectively. Compared with Group E, postoperative bleeding was significantly higher in Group V (700 +/- 420.7 mL vs. 50.0 +/- 2.0 mL, p = 0.021). In addition, postoperative respiratory complications including pleural effusion and pneumonia (p = 0.017 and p = 0.0714, respectively) were prone to occur in Group V. Other variables including demographic parameters and clinical data showed no significant differences between the two groups. It was not unexpected that the duration of ventilator use and the length of intensive care unit stay were significantly shorter in Group E. CONCLUSION: Postoperative blood loss and postoperative respiratory complications might be the factors responsible for delayed extubation in ITx patients. Because the study had few examinees, further studies with a larger population are needed to verify these issues. PMID- 24148739 TI - Timing of epidural analgesia intervention for labor pain in nulliparous women in Taiwan: a retrospective study. AB - BACKGROUND: Labor pain is probably the most painful event in a woman's life. By the present consensus, epidural analgesia is the most effective and least depressive treatment for labor pain. Recent systematic reviews concluded that the risk of cesarean delivery or instrumental vaginal delivery for women receiving early epidural analgesia has not increased. However, studies designed for discussing this topic in Taiwan are few. In this study, the association of the intervention timing with labor outcomes in nulliparous women in Taiwan is discussed. METHODS: We performed a retrospective chart review in parturients who underwent epidural analgesia for labor pain. Only nulliparae were included and divided into four groups based on the cervical dilatation width of 1, 2, 3, and 4 cm when they underwent epidural analgesia. We retrieved each patient's demographic characteristics, the course of labor and delivery, and the management of epidural analgesia from the medical chart. RESULTS: A total of 799 nulliparae was included. The numbers of parturients with cervical dilatation width of 1, 2, 3, and 4 cm were 119, 338, 258, and 84 respectively. There was no significant difference in demographic factors, regimen of epidural analgesia, loading volume, and anesthesiologist in charge among the four groups. The percentages of cesarean delivery in the four groups were 27.73%, 20.71%, 15.89%, and 20.24%, respectively, and there was no significant difference among these four groups (p = 0.0651). The incidences of instrumental delivery in four groups were 13.51%, 14.59%, 18.65%, and 21.43% respectively, and there was no significant difference among these four groups either (p = 0.2278). CONCLUSION: Our results revealed that the timing of epidural intervention affects neither the cesarean delivery rate nor the instrumental delivery rate on nulliparae in Taiwan with the cervical dilatation width ranging from 1 cm to 4 cm. The fear of increasing cesarean section rate after early epidural analgesia is unfounded. Women in labor can choose pain relief at any time. PMID- 24148740 TI - Thoracotomy for lung lesion does not affect the accuracy of esophageal temperature. AB - BACKGROUND: There are several sites for measuring body temperature. Correct reading of core temperature is imperative for patients undergoing major operations under anesthesia. In certain situations, the sites of measurement may be close to the surgical area, and thus the measurement is easily prejudiced by the influence environment. We hypothesized that the body temperature, if monitored in the esophagus, would be lower than obtained from the tympanic membrane during thoracotomy for lung pathology under general anesthesia. MATERIALS AND METHODS: The study involved 32 patients, of American Society of Anesthesiologists (ASA) physical status I or II, who were to undergo elective thoracotomy for lung disorders. General anesthesia was induced with fentanyl, propofol, and rocuronium and maintained with sevoflurane in oxygen. The tympanic membrane probe was placed prior to when general anesthesia was administered, and the esophageal probe was inserted after administration of general anesthesia. Both the individualized temperatures were recorded at 5-minute intervals, and were compared at each change of surgical situation. RESULTS: The tympanic membrane temperature was higher than esophageal temperature after initiation of one-lung ventilation (OLV) with statistical significance. The magnitude of decrease in temperature between two individualized temperatures, as compared from start of OLV, was greater in tympanic membrane temperature, especially at 30 minutes after OLV (p < 0.02, difference = -0.09 +/- 0.22) and at the time point of the lowest temperature (p = 0.002, difference = -0.14 +/- 0.24). There was no clinical difference of situation found (difference > 0.5 degrees C) in the measuring sequences. CONCLUSION: The accuracy of esophageal temperature seemed not to be affected during thoracotomy for lung lesion, in comparison with that of tympanic temperature. From clinical viewpoints, the monitoring of esophageal temperature could be more reliable in such surgical situation. PMID- 24148741 TI - Pleiotropic vascular protective effects of statins in perioperative medicine. AB - 3-Hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitor (statins) is one of the most commonly prescribed agents for controlling hyperlipidemia. Apart from their lipid-lowering property, statins are well known for their pleiotropic effects, such as improvement of vascular endothelial dysfunction, attenuation of inflammatory responses, stabilization of atherosclerotic plaques, inhibition of vascular smooth muscle proliferation, and modulation of procoagulant activity and platelet function. The vasculo-protective effect of statins is mainly mediated by inhibition of the mevalonate pathway and oxidized low-density lipoprotein generation, thereby enhancing the biosynthesis of endothelium-derived nitric oxide. Accumulating clinical evidence strongly suggests that administration of statins reduces overall mortality, the development myocardial infarction and atrial fibrillation, and length of hospital stay after a major cardiac/noncardiac surgery. This review updates the clinical pharmacology and therapeutic applications of statins during major operations, and highlights the anesthesia considerations for perioperative statin therapy. PMID- 24148742 TI - The immune aspect in neuropathic pain: role of chemokines. AB - Neuropathic pain is a pathological symptom experienced worldwide by patients suffering with nervous system dysfunction caused by various diseases. Treatment of neuropathic pain is always accompanied by a poor response and undesired adverse effects. Therefore, developing a novel "pain-kill" drug design strategy is critical in this field. Recent evidence demonstrates that neuroinflammation and immune response contributes to the development of neuropathic pain. Nerve damage can initiate inflammatory and immune responses, as evidenced by the upregulation of cytokines and chemokines. In this paper, we demonstrated that different chemokines and chemokine receptors (e.g., CX3CL1/CX3CR1, CCL2/CCR2, CCL3/CCR1, CCL4/CCR5 and CCL5/CCR5) serve as mediators for neuron-glia communication subsequently modulate nociceptive signal transmission. By extensively understanding the role of chemokines in neurons and glial cells in nociceptive signal transmission, a novel strategy for a target-specific drug design could be developed. PMID- 24148743 TI - Agonal gasps of cardiac arrest victim can aid in confirming tracheal intubation using Umesh's intubation detector. AB - Several patients of cardiac arrest may be found in a state of agonal gasps that are of insufficient tidal volume and are not considered as a sign of life. However, this volume is sufficient enough to cause appreciable inflation and deflation of the reservoir bag of Umesh's intubation detector (UID) as evidenced in all 12 victims of cardiac arrest with gasping efforts in this study. Therefore, we conclude that the agonal gasps during cardiac arrest can reliably be used to confirm tracheal intubation using the UID device. PMID- 24148744 TI - Brainstem anesthesia presenting as contralateral third nerve palsy following peribulbar anesthesia for cataract surgery. AB - Brainstem anesthesia is a serious complication that has been reported to occur more commonly with retrobulbar anesthesia compared to peribulbar anesthesia. We herein report a case of contralateral third nerve palsy following administration of peribulbar anesthesia for cataract surgery. Two hours after the surgery, the patient recovered completely without any residual neurological deficit. The importance of immediate recognition of clinical signs and symptoms of central spread of the local anesthetic and the mechanical factors of the block that could have contributed to this complication are discussed in this report. PMID- 24148745 TI - Laryngeal mask airway in interventional bronchoscopy for tracheal lesions. PMID- 24148746 TI - The skin-to-epidural depth is a useful guide to avoid the rare complication of thoracic epidural anesthesia. PMID- 24148747 TI - A Cerebral Recovery Index (CRI) for early prognosis in patients after cardiac arrest. AB - INTRODUCTION: Electroencephalogram (EEG) monitoring in patients treated with therapeutic hypothermia after cardiac arrest may assist in early outcome prediction. Quantitative EEG (qEEG) analysis can reduce the time needed to review long-term EEG and makes the analysis more objective. In this study, we evaluated the predictive value of qEEG analysis for neurologic outcome in postanoxic patients. METHODS: In total, 109 patients admitted to the ICU for therapeutic hypothermia after cardiac arrest were included, divided over a training and a test set. Continuous EEG was recorded during the first 5 days or until ICU discharge. Neurologic outcomes were based on the best achieved Cerebral Performance Category (CPC) score within 6 months. Of the training set, 27 of 56 patients (48%) and 26 of 53 patients (49%) of the test set achieved good outcome (CPC 1 to 2). In all patients, a 5 minute epoch was selected each hour, and five qEEG features were extracted. We introduced the Cerebral Recovery Index (CRI), which combines these features into a single number. RESULTS: At 24 hours after cardiac arrest, a CRI <0.29 was always associated with poor neurologic outcome, with a sensitivity of 0.55 (95% confidence interval (CI): 0.32 to 0.76) at a specificity of 1.00 (CI, 0.86 to 1.00) in the test set. This results in a positive predictive value (PPV) of 1.00 (CI, 0.73 to 1.00) and a negative predictive value (NPV) of 0.71 (CI, 0.53 to 0.85). At the same time, a CRI >0.69 predicted good outcome, with a sensitivity of 0.25 (CI, 0.10 to 0.14) at a specificity of 1.00 (CI, 0.85 to 1.00) in the test set, and a corresponding NPV of 1.00 (CI, 0.54 to 1.00) and a PPV of 0.55 (CI, 0.38 to 0.70). CONCLUSIONS: We introduced a combination of qEEG measures expressed in a single number, the CRI, which can assist in prediction of both poor and good outcomes in postanoxic patients, within 24 hours after cardiac arrest. PMID- 24148748 TI - Dissemination of psychosocial treatments for anxiety: the importance of taking a broad perspective. AB - Dissemination methods are used to increase the likelihood that a given treatment or form of clinical practice is implemented by clinicians in the community. Therapist training in treatment methods is an important component of dissemination. Successful dissemination also requires that roadblocks to treatment implementation are identified and circumvented, such as misconceptions that clinicians might hold about a given treatment. The present article offers a commentary on the papers included in the special issue on treatment dissemination for anxiety disorders. Most papers focus on issues concerning the training and education of clinicians with regard to exposure therapy. Training and education is an important step but should be part of a broad, multifaceted approach. There are several other important methods of treatment dissemination, including methods developed and implemented with success by the pharmaceutical industry, might also be used to disseminate psychosocial therapies. Optimal dissemination likely requires a broad perspective in which multiple dissemination methods are considered for implementation. PMID- 24148749 TI - Adult ciliary epithelial stem cells generate functional neurons and differentiate into both early and late born retinal neurons under non-cell autonomous influences. AB - BACKGROUND: The neural stem cells discovered in the adult ciliary epithelium (CE) in higher vertebrates have emerged as an accessible source of retinal progenitors; these cells can self-renew and possess retinal potential. However, recent studies have cast doubt as to whether these cells could generate functional neurons and differentiate along the retinal lineage. Here, we have systematically examined the pan neural and retinal potential of CE stem cells. RESULTS: Molecular and cellular analysis was carried out to examine the plasticity of CE stem cells, obtained from mice expressing green fluorescent protein (GFP) under the influence of the promoter of the rod photoreceptor specific gene, Nrl, using the neurospheres assay. Differentiation was induced by specific culture conditions and evaluated by both transcripts and protein levels of lineage-specific regulators and markers. Temporal pattern of their levels were examined to determine the expression of genes and proteins underlying the regulatory hierarchy of cells specific differentiation in vitro. Functional attributes of differentiation were examined by the presence of current profiles and pharmacological mobilization of intracellular calcium using whole cell recordings and Fura-based calcium imaging, respectively. We demonstrate that stem cells in adult CE not only have the capacity to generate functional neurons, acquiring the expression of sodium and potassium channels, but also respond to specific cues in culture and preferentially differentiate along the lineages of retinal ganglion cells (RGCs) and rod photoreceptors, the early and late born retinal neurons, respectively. The retinal differentiation of CE stem cells was characterized by the temporal acquisition of the expression of the regulators of RGCs and rod photoreceptors, followed by the display of cell type-specific mature markers and mobilization of intracellular calcium. CONCLUSIONS: Our study demonstrates the bonafide retinal potential of adult CE stem cells and suggests that their plasticity could be harnessed for clinical purposes once barriers associated with any lineage conversion, i.e., low efficiency and fidelity is overcome through the identification of conducive culture conditions. PMID- 24148751 TI - New stent surface materials: the impact of polymer-dependent interactions of human endothelial cells, smooth muscle cells, and platelets. AB - Despite the development of new coronary stent technologies, in-stent restenosis and stent thrombosis are still clinically relevant. Interactions of blood and tissue cells with the implanted material may represent an important cause of these side effects. We hypothesize material-dependent interaction of blood and tissue cells. The aim of this study is accordingly to investigate the impact of vascular endothelial cells, smooth muscle cells and platelets with various biodegradable polymers to identify a stent coating or platform material that demonstrates excellent endothelial-cell-supportive and non-thrombogenic properties. Human umbilical venous endothelial cells, human coronary arterial endothelial cells and human coronary arterial smooth muscle cells were cultivated on the surfaces of two established biostable polymers used for drug-eluting stents, namely poly(ethylene-co-vinylacetate) (PEVA) and poly(butyl methacrylate) (PBMA). We compared these polymers to new biodegradable polyesters poly(l lactide) (PLLA), poly(3-hydroxybutyrate) (P(3HB)), poly(4-hydroxybutyrate) (P(4HB)) and a polymeric blend of PLLA/P(4HB) in a ratio of 78/22% (w/w). Biocompatibility tests were performed under static and dynamic conditions. Measurement of cell proliferation, viability, glycocalix width, eNOS and PECAM-1 mRNA expression revealed strong material dependency among the six polymer samples investigated. Only the polymeric blend of PLLA/P(4HB) achieved excellent endothelial markers of biocompatibility. Data show that PLLA and P(4HB) tend to a more thrombotic response, whereas the polymer blend is characterized by a lower thrombotic potential. These data demonstrate material-dependent endothelialization, smooth muscle cell growth and thrombogenicity. Although polymers such as PEVA and PBMA are already commonly used for vascular implants, they did not sufficiently meet the criteria for biocompatibility. The investigated biodegradable polymeric blend PLLA/P(4HB) evidently represents a promising material for vascular stents and stent coatings. PMID- 24148752 TI - Comparison of baseline quality of life measures between renal cell carcinoma patients undergoing partial versus radical nephrectomy. AB - BACKGROUND: To compare demographics, pathologic features, performance scores, comorbidities, symptoms and responses to quality of life (QoL) surveys between nephron-sparing surgery (NSS) and radical nephrectomy (RN) patients prior to surgical intervention. Previous investigators have compared QoL outcomes for patients undergoing RN and NSS; however, there are limited data comparing QoL related characteristics at baseline between these groups. METHODS: We identified 144 patients with localized RCC who underwent either NSS (n = 71) or RN (n = 73) between May '07-November '12. We abstracted baseline data on demographic and clinic-pathologic variables as well as responses to the SF-36 and FACT-G surveys from our prospective registry. We amended the FACT-G with 8 additional questions designed to address RCC-specific QoL. For comparisons between the two groups, we employed Wilcoxon rank-sum and Fisher's Exact tests where appropriate. RESULTS: We observed RN patients to have more aggressive pathology. We noted no difference in performance scores between the two groups; however, RN patients were more likely to have higher Charlson scores (p = 0.022) and various symptoms at presentation (all p <0.001). For the QoL surveys, we did not observe differences on the FACT-G; however, we noted evidence of differential scores between the two groups on specific domains of the SF-36 (e.g. Mental Health; p 0.022) and the RCC specific QoL questions added to the FACT-G. CONCLUSIONS: We report baseline differences between RN and NSS patients on clinico-pathologic as well as QoL related metrics. As issues of survivorship become increasingly important, our results underscore the need to consider baseline status in evaluations of QoL related outcomes for patients undergoing surgery for RCC. PMID- 24148753 TI - Novel oral anticoagulants: a focused review for stroke physicians. AB - Novel oral anticoagulants provide an effective and convenient alternative to warfarin for stroke prevention in patients with atrial fibrillation. However, novel anticoagulants also present new challenges for stroke physicians, such as measurement of anticoagulant effect in emergency situations, use of thrombolysis in acute ischemic stroke, optimal timing of introduction of novel anticoagulants following acute ischemic stroke, and management of intracerebral hemorrhage. In this review, we propose pragmatic approaches to dealing with challenging management issues that will face stroke physicians who care for patients with acute stroke in the novel oral anticoagulant era. PMID- 24148754 TI - Water-in-oil microemulsion doped with gold nanoparticle decorated single walled carbon nanotube: scaffold for enhancing lipase activity. AB - The present work reports the development of water-in-oil (w/o) microemulsion doped with newly designed nanocomposite comprising of gold nanoparticle (GNP) decorated single walled carbon nanotube (SWNT). This nanocomposite included cationic reverse micelle was used to boost the catalytic activity of a surface active enzyme, Chromobacterium viscosum lipase (CV lipase). SWNT was non covalently dispersed using cetyltrimethylammonium bromide (CTAB), cetylalaninetrimethylammonium chloride (CATAC) while GNP was synthesized by reduction of HAuCl4 with reducing/stabilizing agent trisodium citrate. Counterion exchange between cationic SWNT dispersing agent and anionic capping agent of GNP led to the formation of GNP decorated SWNT (SWNT-GNP) nanocomposite. This newly developed SWNT-GNP included CTAB reverse micelle was characterized by several microscopic and spectroscopic techniques. Interfacially located SWNT-GNP included w/o microemulsion (confirmed from biphasic and fluorescence experiment) was used as a proficient host for enhancing the catalytic activity of lipase. Lipase activity within this self-assembled soft nanocomposite improved up to 3.9-fold (second order rate constant, k2=1694+/-16 cm(3) g(-1) s(-1)) compared to standard CTAB reverse micelle (k2=433+/-7 cm(3) g(-1) s(-1)). In case of cetyltripropyl ammonium bromide (CTPAB) based reverse micelle, the observed lipase activity improved to k2=2036+/-11 cm(3) g(-1) s(-1) in the presence of SWNT-GNP composite. Notably, this catalytic activity of lipase within SWNT-GNP included reverse micelle was till date the highest activity found in any w/o microemulsion. The attainment of flexibility in enzyme conformation at the augmented interface was verified using circular dichroism (CD) spectroscopy. PMID- 24148755 TI - Dewatering of Chlorella pyrenoidosa using diatomite dynamic membrane: filtration performance, membrane fouling and cake behavior. AB - The diatomite dynamic membrane (DDM) was utilized to dewater Chlorella pyrenoidosa of 2 g dry weight/L under continuous-flow mode, whose ultimate algae concentration ranged from 43 g to 22 g dry weight/L of different culture time. The stable flux of DDM could reach 30 L/m(2) h over a 24 h operation time without backwash. Influences of extracellular organic matters (EOM) on filtration behavior and membrane fouling were studied. The DDM was divided into three sub layers, the slime layer, the algae layer and the diatomite layer from the outside to the inside of the cake layer based on components and morphologies. It was found that EOM caused membrane fouling by accumulating in the slime and algae layers. The DDM intercepted polysaccharides, protein-like substances, humic-like substances and some low-MW organics. Proteins were indicated the major membrane foulants with increased protein/polysaccharide ratio from the slime layer to the diatomite layer as culture time increased. This method could be applied to subsequent treatment of microalgae coupling technology of wastewater treatment or microalgae harvesting for producing biofuel. PMID- 24148756 TI - Iron and transfusion medicine. AB - Blood bankers have focused their energy to secure blood transfusion, and only recently have studies been published on the effect of blood donation on iron metabolism. In many facilities, hemoglobin measurement is only performed just before or even during blood donation, but the determination of iron stores is largely ignored. The 2013 paradox of transfusion medicine is due to the fact that blood donation may be harmful and leads to iron deficiency with or without anemia, but for other individuals, it may be a healthy measure preventing type 2 diabetes. The purpose of this review is to discuss iron metabolism in the perspective of blood donation, notably regarding their possible genetic profiles that eventually will discriminate "good" iron absorbers from "bad" iron responders. PMID- 24148757 TI - Pandoraviruses are highly derived phycodnaviruses. AB - The recently discovered Pandoraviruses are by far the largest viruses known, with their 2 megabase genomes exceeding in size the genomes of numerous bacteria and archaea. Pandoraviruses show a distant relationship with other nucleocytoplasmic large DNA viruses (NCLDV) of eukaryotes, lack some of the NCLDV core genes and in particular do not appear to be specifically related to the other, better characterized family of giant viruses, the Mimiviridae. Here we report phylogenetic analysis of 6 core NCLDV genes that confidently places Pandoraviruses within the family Phycodnaviridae, with an apparent specific affinity with Coccolithoviruses. We conclude that, despite their many unusual characteristics, Pandoraviruses are highly derived phycodnaviruses. These findings imply that giant viruses have independently evolved from smaller NCLDV on at least two occasions. PMID- 24148750 TI - SET for life: biochemical activities and biological functions of SET domain containing proteins. PMID- 24148758 TI - Depression treatment and short-term healthcare expenditures among elderly Medicare beneficiaries with chronic physical conditions. AB - BACKGROUND: Research on the impact of depression treatment on expenditures is nascent and shows results that vary from negative associations with healthcare expenditures to increased expenditures. However many of these studies did not include psychotherapy as part of the depression treatment. None of these studies included "no treatment" as a comparison group. In addition, no study has included a broad group of chronic physical conditions in studying depression treatment expenditures. OBJECTIVE: We determined the association between depression treatment and short-term healthcare expenditures using a nationally representative sample of Medicare beneficiaries with chronic physical conditions and depression. METHOD: In this retrospective cohort study, we examined the association between depression treatment in the baseline year and healthcare expenditures in the following year using data from 2000 through 2005 of the Medicare Current Beneficiary Survey (MCBS), a nationally representative survey of Medicare beneficiaries. Using the rotating panel design of MCBS, we derived five two-year cohorts: 2000-2001, 2001-2002, 2002-2003, 2003-2004, and 2004-2005. The study sample included 1,055 elderly Medicare beneficiaries aged 65 or over. We compared healthcare expenditures of no depression treatment group with depression treatment groups using t-tests. Linear regressions of log-transformed dollars were used to assess the relationship between depression treatment and healthcare expenditures after controlling for demographic, socio-economic, health status, lifestyle risk factors, year of observation and baseline expenditures. RESULTS: Compared to no depression treatment ($16,795), the average total expenditures were higher for those who used antidepressants only ($17,425) and those who used psychotherapy with or without antidepressants ($19,733). After controlling for the independent variables, antidepressant use and psychotherapy with or without antidepressants were associated with 20.2% (95% CI: 14.1-26.7%) and 29.4% (95% CI: 18.8-41.0%) increase in total expenditures, respectively. We observed that depression treatment was positively associated with inpatient, medical provider and prescription drug expenditures. CONCLUSION: Among the elderly Medicare beneficiaries with chronic physical conditions, depression treatment was associated with greater short-term healthcare expenditures. Future research needs to replicate these findings and also examine whether depression treatment reduces expenditures over a longer period of time. PMID- 24148759 TI - Transport of platinum bonded nucleotides into proteoliposomes, mediated by Drosophila melanogaster thiamine pyrophosphate carrier protein (DmTpc1). AB - The results of the present study suggest that DmTpc1 is actively implicated in the specific uptake of free cytoplasmic Pt bonded nucleotides, and therefore could be linked to the mechanism of action of some platinum-based antitumor drugs. Although DmTpc1 has a low affinity for model [Pt(dien)(N7-5'-dGTP)] and cis-[Pt(NH3)2(py)(N7-5'-dGTP)] compared to dATP it's well known that DNA platination level of few metal atoms per double-stranded molecule may account for the pharmacological activity of platinum based antitumor drugs. This is the first investigation where it has been demonstrated that a mitochondrial carrier is directly involved in the transport of metalated purines related with the cisplatin mechanism of action. Moreover it is shown as a lower hindrance of nucleotide bonded platinum complexes could strongly enhance mitochondrial uptake. Furthermore, a new application of ICP-AES addressed to measure the transport of metalated nucleobases, by using a recombinant protein reconstituted into liposomes, has been here, for the first time, developed and compared with a standard technique such as the liquid scintillation counting. PMID- 24148760 TI - Steroidal glycosides from the bulbs of Bessera elegans and their cytotoxic activities. AB - Examination of the bulbs of Bessera elegans (Liliaceae) led to isolation of nine new and five known steroidal glycosides. The structures of the nine compounds were determined based on the results of spectroscopic analysis, including two dimensional NMR, and hydrolysis followed by chromatographic and spectroscopic analysis. The isolated compounds and derivatives were evaluated for cytotoxicity against HL-60 human promyelocytic leukemia cells, A549 human lung adenocarcinoma cells, and TIG-3 normal human diploid fibroblasts. One compound, the pseudo furostanol glycoside, induced apoptosis in HL-60 and A549 cells in a time dependent manner and cell-cycle arrest at the G0/G1 phase in A549 cells. PMID- 24148761 TI - Solifenacin in women with de novo overactive bladder after tension-free obturator vaginal tape--is it effective? AB - PURPOSE: To our knowledge no group has evaluated antimuscarinic efficacy in patients with de novo overactive bladder after mid urethral sling placement. We assessed solifenacin efficacy in women with de novo overactive bladder after obturator tension-free vaginal tape placement compared to a control group. MATERIALS AND METHODS: We prospectively considered all women with de novo overactive bladder symptoms at a 3-month followup visit after placement of obturator tension-free vaginal tape. Patients with overactive bladder preoperatively and those with obstructive symptoms or signs were excluded from analysis. Women who satisfied inclusion and exclusion criteria (group 1) were compared with a series of consecutive naive patients with overactive bladder symptoms without a previous surgical procedure for stress urinary incontinence (group 2). We prescribed 12-week antimuscarinic therapy with oral solifenacin 5 mg once daily. Objective outcomes included changes from baseline in 3-day voiding diary data. Subjective efficacy was evaluated using the Overactive Bladder Questionnaire Short Form, Urgency Severity Scale and Patient Global Impression of Improvement questionnaires. RESULTS: A total of 110 patients with de novo overactive bladder after obturator tension-free vaginal tape placement completed solifenacin treatment and were included in group 1. They were compared with 120 consecutive naive women with overactive bladder (group 2). Group 1 presented at the 3-month followup visit with significantly less benefit in the mean decrease in urgency and urgency urinary incontinence episodes daily (-1.1 vs -2.3 and -0.2 vs -1.1, respectively, each p <0.0001). In group 1 we also found a lower subjective solifenacin effect. Previous obturator tension-free vaginal tape placement was an independent predictor of failed solifenacin treatment. CONCLUSIONS: Antimuscarinic treatment with solifenacin had significantly lower efficacy in women with de novo overactive bladder after mid urethral sling placement than in controls. PMID- 24148762 TI - Vulval cancer incidence, mortality and survival in England: age-related trends. AB - OBJECTIVE: To explore the trends and age characteristics of vulval cancer incidence, mortality, survival and stage of disease. DESIGN: Retrospective population-based observational study based on cancer registry and Office for National Statistics data. SETTING: England. POPULATION: All women diagnosed with vulval cancer, defined by the site of the tumour (ICD-10 code C51). METHODS: Including all C51 cases, Poisson regression was used to test for trends in incidence and mortality rates, and generalised linear modelling was used to test for trends in relative survival. Excluding women with melanomas, basal cell carcinomas and Paget disease, stage was investigated as a percentage of staged data by age. MAIN OUTCOME MEASURES: Age-standardised incidence and mortality rates, relative survival rates and stage of disease at diagnosis. RESULTS: From 1990, there was a statistically significant increase in overall incidence (P = 0.018) and decrease in mortality (P < 0.001). In addition, there were statistically significant increases in overall survival (1-year, P < 0.001; 5 year, P < 0.001). However, from 1990, incidence increased in women aged 20-39 years (P = 0.002), 40-49 and 50-59 years (both P < 0.001) and 60-69 years (P = 0.030) and decreased in women aged 80 years and above (P < 0.001). There were statistically significant decreases in mortality in women aged >=60 years (P < 0.001), and statistically significant increases in 1-year survival in women aged >=40 years (P <= 0.047) and in 5-year survival in women aged 40-49 and >=60 years (P <= 0.011). Stage patterns by age highlight diagnosis at an earlier stage in younger women and more advanced stage diagnosis in older women. CONCLUSION: Survival from vulval cancer has improved and mortality has decreased since 1990. The overall incidence of disease has increased as a result of more new diagnoses in the under 70-year age group. PMID- 24148763 TI - Role of Rho/ROCK signaling in the interaction of melanoma cells with the blood brain barrier. AB - We have investigated the role of the Rho/ROCK signaling pathway in the interaction of metastatic melanoma cells with the brain endothelium. ROCK inhibition induced a shift of melanoma cells to the mesenchymal phenotype, increased the number of melanoma cells attached to the brain endothelium, and strengthened the adhesion force between melanoma and endothelial cells. Inhibition of ROCK raised the number of melanoma cells migrating through the brain endothelial monolayer and promoted the formation of parenchymal brain metastases in vivo. We have shown that inhibition of the Rho/ROCK pathway in melanoma, but not in brain endothelial cells, is responsible for this phenomenon. Our results indicate that the mesenchymal type of tumor cell movement is primordial in the transmigration of melanoma cells through the blood-brain barrier. PMID- 24148765 TI - Contribution of breathing frequency and inhalation flow rate on performance of N95 filtering facepiece respirators. AB - The investigation of particle penetration through filtering facepiece respirators under cyclic flows is very necessary because cyclic flows represent actual breathing flow patterns. This article reports the development of a procedure to investigate the individual impact of breathing frequency and flow rate on the performance of N95 filtering facepiece respirators. Experiments were performed for two peak inhalation flows (PIFs; 135 and 360 l min(-1)) and two breathing frequencies [24 and 42 breaths per minute (BPM)] for a total of four cyclic flows (Flow A: 135 l min(-1) and 24 BPM; Flow B: 135 l min(-1) and 42 BPM; Flow C: 360 l min(-1) and 24 BPM; and Flow D: 360 l min(-1) and 42 BPM). Each experiment was performed using two different set-ups: the first set-up included both inhalations and exhalations through the filter media and test chamber, while with the second set-up, only inhalation flows were considered. The results showed that, for the most penetrating particle size range, an increase in both PIF and breathing frequency could potentially enhance the penetration with both set-ups; however, the effect of PIF was observed to be much more pronounced than that of frequency. The results indicated that with both set-ups, when the PIF was increased from 135 to 360 l min(-1) (for the given frequency: 24 or 42 BPM), an increase of up to 139-152% in penetration was observed. On the other hand, only a 10-16% increase in penetration occurred when the frequency was changed from 24 to 42 BPM (for a given PIF: 135 or 360 l min(-1)). This suggests that, from low to high respiratory efforts, a huge portion of penetration enhancement is due to PIF variations and only a small portion is contributed by frequency variations. PMID- 24148764 TI - High-throughput screens identify microRNAs essential for HER2 positive breast cancer cell growth. AB - MicroRNAs (miRNAs) are non-coding RNAs regulating gene expression post transcriptionally. We have characterized the role of miRNAs in regulating the human epidermal growth factor receptor 2 (HER2)-pathway in breast cancer. We performed miRNA gain-of-function assays by screening two HER2 amplified cell lines (KPL-4 and JIMT-1) with a miRNA mimic library consisting of 810 human miRNAs. The levels of HER2, phospho-AKT, phospho-ERK1/2, cell proliferation (Ki67) and apoptosis (cPARP) were analyzed with reverse-phase protein arrays. Rank product analyses identified 38 miRNAs (q < 0.05) as inhibitors of HER2 signaling and cell growth, the most effective being miR-491-5p, miR-634, miR-637 and miR-342-5p. We also characterized miRNAs directly targeting HER2 and identified seven novel miRNAs (miR-552, miR-541, miR-193a-5p, miR-453, miR-134, miR-498, and miR-331-3p) as direct regulators of the HER2 3'UTR. We demonstrated the clinical relevance of the miRNAs and identified miR-342-5p and miR-744* as significantly down-regulated in HER2-positive breast tumors as compared to HER2 negative tumors from two cohorts of breast cancer patients (101 and 1302 cases). miR-342-5p specifically inhibited HER2-positive cell growth, as it had no effect on the growth of HER2-negative control cells in vitro. Furthermore, higher expression of miR-342-5p was associated with better survival in both breast cancer patient cohorts. In conclusion, we have identified miRNAs which are efficient negative regulators of the HER2 pathway that may play a role in vivo during breast cancer progression. These results give mechanistic insights in HER2 regulation which may open potential new strategies towards prevention and therapeutic inhibition of HER2-positive breast cancer. PMID- 24148766 TI - alpha-Synuclein and mitochondrial bioenergetics regulate tetrahydrobiopterin levels in a human dopaminergic model of Parkinson disease. AB - Parkinson disease (PD) is a multifactorial disease resulting in preferential death of the dopaminergic neurons in the substantia nigra. Studies of PD-linked genes and toxin-induced models of PD have implicated mitochondrial dysfunction, oxidative stress, and the misfolding and aggregation of alpha-synuclein (alpha syn) as key factors in disease initiation and progression. Many of these features of PD may be modeled in cells or animal models using the neurotoxin 1-methyl-4 phenylpyridinium (MPP(+)). Reducing oxidative stress and nitric oxide synthase (NOS) activity has been shown to be protective in cell or animal models of MPP(+) toxicity. We have previously demonstrated that siRNA-mediated knockdown of alpha syn lowers the activity of both dopamine transporter and NOS activity and protects dopaminergic neuron-like cells from MPP(+) toxicity. Here, we demonstrate that alpha-syn knockdown and modulators of oxidative stress/NOS activation protect cells from MPP(+)-induced toxicity via postmitochondrial mechanisms rather than by a rescue of the decrease in mitochondrial oxidative phosphorylation caused by MPP(+) exposure. We demonstrate that MPP(+) significantly decreases the synthesis of the antioxidant and obligate cofactor of NOS and TH tetrahydrobiopterin (BH4) through decreased cellular GTP/ATP levels. Furthermore, we demonstrate that RNAi knockdown of alpha-syn results in a nearly twofold increase in GTP cyclohydrolase I activity and a concomitant increase in basal BH4 levels. Together, these results demonstrate that both mitochondrial activity and alpha-syn play roles in modulating cellular BH4 levels. PMID- 24148767 TI - The role of interleukin-17 in bone metabolism and inflammatory skeletal diseases. AB - The balance between osteoblast-dependent bone formation and osteoclast-dependent bone resorption maintains bone homeostasis. In inflammatory conditions, this balance shifts toward bone resorption, causing osteolytic bone lesions observed in rheumatoid arthritis and periodontitis. A recently discovered family of cytokine IL-17 is widely reported to mediate diverse inflammatory processes. During the last decade, novel roles for IL-17 in skeletal homeostasis have been discovered indicating the potential importance of this cytokine in bone metabolism. This review will summarize and discuss the involvement of IL-17 during bone homeostasis in both physiologic and pathologic conditions. A better understanding of the role of IL-17 in skeletal systems warrants an advance in bone biology, as well as development of therapeutic strategies against bone-lytic diseases, such as rheumatoid arthritis and periodontitis. PMID- 24148768 TI - Anticoagulant activities of piperlonguminine in vitro and in vivo. AB - Piperlonguminine (PL), an important component of Piper longum fruits, is known to exhibit anti-hyperlipidemic, anti-platelet and anti-melanogenic activities. Here, the anticoagulant activities of PL were examined by monitoring activated-partial thromboplastin-time (aPTT), prothrombin-time (PT), and the activities of thrombin and activated factor X (FXa). The effects of PL on the expressions of plasminogen activator inhibitor type 1 (PAI-1) and tissue-type plasminogen activator (t-PA) were also tested in tumor necrosis factor-alpha (TNF-alpha) activated HUVECs. The results showed that PL prolonged aPTT and PT significantly and inhibited the activities of thrombin and FXa. PL inhibited the generation of thrombin and FXa in HUVECs. In accordance with these anticoagulant activities, PL prolonged in vivo bleeding time and inhibited TNF-alpha induced PAI-1 production. Furthermore, PAI-1/t-PA ratio was significan- tly decreased by PL. Collectively, our results suggest that PL possesses antithrombotic activities and that the current study could provide bases for the development of new anticoagulant agents. PMID- 24148769 TI - BAG5 regulates PTEN stability in MCF-7 cell line. AB - The phosphatase and tensin homolog deleted on chromosome 10 (PTEN) is a tumor suppressing lipid phosphatase that is frequently absent in breast tumors. Thus, the stability of PTEN is essential for tumor prevention and therapy. The ubiquitin-proteasome pathway has an important role in regulating the functions of PTEN. Specifically, carboxyl terminus Hsp70-interacting protein (CHIP), the E3 ubiquitin ligase of PTEN, can regulate PTEN levels. In this study, we report that BCL-2-associated athanogene 5 (BAG5), a known inhibitor of CHIP activity, reduces the degradation of PTEN and maintains its levels via an ubiquitylation-dependent pathway. BAG5 is identified as an antagonist of cell tumorigenicity. PMID- 24148770 TI - Modification of Turnip yellow mosaic virus coat protein and its effect on virion assembly. AB - Turnip yellow mosaic virus (TYMV) is a positive strand RNA virus. We have modified TYMV coat protein (CP) by inserting a c-Myc epitope peptide at the N- or C-terminus of the CP, and have examined its effect on assembly. We introduced the recombinant CP constructs into Nicotiana benthamiana leaves by agroinfiltration. Examination of the leaf extracts by agarose gel electrophoresis and Western blot analysis showed that the CP modified at the N-terminus produced a band co migrating with wild-type virions. With C-terminal modification, however, the detected bands moved faster than the wild-type virions. To further examine the effect, TYMV constructs producing the modified CPs were prepared. With N-terminal modification, viral RNAs were protected from RNase A. In contrast, the viral RNAs were not protected with C-terminal modification. Overall, the results suggest that virion assembly and RNA packaging occur properly when the N-terminus of CP is modified, but not when the C-terminus is modified. PMID- 24148771 TI - Differential expression of alphaB-crystallin causes maturation-dependent susceptibility of oligodendrocytes to oxidative stress. AB - Oligodendrocyte precursor cells (OPCs) are most susceptible to oxidative stress in the brain. However, the cause of differences in susceptibility to oxidative stress between OPCs and mature oligodendrocytes (mOLs) remains unclear. Recently, we identified in vivo that alphaB-crystallin (aBC) is expressed in mOLs but not in OPCs. Therefore, we examined in the present study whether aBC expression could affect cell survival under oxidative stress induced by hydrogen peroxide using primary cultures of OPCs and mOLs from neonatal rat brains. Expression of aBC was greater in mOLs than in OPCs, and the survival rate of mOLs was significantly higher than that of OPCs under oxidative stress. Suppression of aBC by siRNA transfection resulted in a decrease in the survival rate of mOLs under oxidative stress. These data suggest that higher susceptibility of OPCs than mOLs to oxidative stress is due, at least in part, to low levels of aBC expression. PMID- 24148772 TI - Differential expression of the metastasis suppressor KAI1 in decidual cells and trophoblast giant cells at the feto-maternal interface. AB - Invasion of trophoblasts into maternal uterine tissue is essential for establishing mature feto-maternal circulation. The trophoblast invasion associated with placentation is similar to tumor invasion. In this study, we investigated the role of KAI1, an antimetastasis factor, at the maternal-fetal interface during placentation. Mouse embryos were obtained from gestational days 5.5 (E5.5) to E13.5. Immunohistochemical analysis revealed that KAI1 was expressed on decidual cells around the track made when a fertilized ovum invaded the endometrium, at days E5.5 and E7.5, and on trophoblast giant cells, along the central maternal artery of the placenta at E9.5. KAI1 in trophoblast giant cells was increased at E11.5, and then decreased at E13.5. Furthermore, KAI1 was upregulated during the forskolin-mediated trophoblastic differentiation of BeWo cells. Collectively, these results indicate that KAI1 is differentially expressed in decidual cells and trophoblasts at the maternal-fetal interface, suggesting that KAI1 prevents trophoblast invasion during placentation. PMID- 24148773 TI - Gymnaster koraiensis and its major components, 3,5-di-O-caffeoylquinic acid and gymnasterkoreayne B, reduce oxidative damage induced by tert-butyl hydroperoxide or acetaminophen in HepG2 cells. AB - We investigated the protective effects of Gymnaster koraiensis against oxidative stress-induced hepatic cell damage. We used two different cytotoxicity models, i.e., the administration of tert-butyl hydroperoxide (t-BHP) and acetaminophen, in HepG2 cells to evaluate the protective effects of G. koraiensis. The ethyl acetate (EA) fraction of G. koraiensis and its major compound, 3,5-di-O caffeoylquinic acid (DCQA), exerted protective effects in the t-BHP-induced liver cytotoxicity model. The EA fraction and DCQA ameliorated t-BHP-induced reductions in GSH levels and exhibited free radical scavenging activity. The EA fraction and DCQA also significantly reduced t-BHP-induced DNA damage in HepG2 cells. Furthermore, the hexane fraction of G. koraiensis and its major compound, gymnasterkoreayne B (GKB), exerted strong hepatoprotection in the acetaminophen induced cytotoxicity model. CYP 3A4 enzyme activity was strongly inhibited by the extract, hexane fraction, and GKB. The hexane fraction and GKB ameliorated acetaminophen-induced reductions in GSH levels and protected against cell death. PMID- 24148774 TI - Covariant perfusion patterns provide clues to the origin of cognitive fluctuations and attentional dysfunction in dementia with Lewy bodies. AB - BACKGROUND: Fluctuating cognition (FC), particularly in attention, is a core and defining symptom in dementia with Lewy bodies (DLB) but is seen much less frequently in Alzheimer's dementia (AD). However, its neurobiological origin is poorly understood. The aim of our study was therefore to characterize perfusion patterns in DLB patients that are associated with the severity and frequency of FC as measured both clinically and using objective neuropsychological assessments. METHODS: Spatial covariance analyses were applied to data derived from single photon emission computed tomography (SPECT) HMPAO brain imaging in 19 DLB and 23 AD patients. Patients underwent clinical assessment of their FC and cognitive function as well as objective testing of their attention. RESULTS: Covariant perfusion principal components (PCs) were not associated with either FC or cognitive or attentional measures in AD. However, in DLB patients, the second PC (defined as DLB-cognitive motor pattern, DLB-PCI2) which was characterized by bilateral relative increases in cerebellum, basal ganglia, and supplementary motor areas and widespread bilateral decreases in parietal regions, positively correlated with poorer cognitive function, increased FC and worse attentional function measured both clinically and neurophysiologically (p < 0.05) as well as with the severity of bradykinesia (p = 0.04). CONCLUSIONS: FC in DLB appears distinct from those seen in AD, and likely to be driven by internal neurobiological perturbations in brain circuitry as evidenced using spatial covariance analyses of cerebral perfusion. FC and certain aspects of attentional dysfunction in DLB may, in part, depend upon both distributed motor and non-motor networks. PMID- 24148775 TI - Coronary artery stent imaging with CT using an integrated electronics detector and iterative reconstructions: first in vitro experience. AB - BACKGROUND: Despite continuous improvements in CT technology, accurate stent lumen delineation remains challenging. PURPOSE: The aim was to evaluate the quality of coronary stent lumen delineation with CT using a detector with integrated electronics. METHODS: Twelve coronary stents placed in plastic tubes and filled with contrast agent (CT number 250 HU) were imaged with either a 128 section dual-source CT machine equipped with conventional detector or with integrated electronics. On both scanners, images were reconstructed with filtered back projection (slice thickness 0.6 mm; increment 0.4 mm) and sinogram-affirmed iterative reconstruction (slice thickness 0.6 mm; increment 0.4 mm), and with iterative reconstruction (slice thickness 0.5 mm; increment 0.3 mm) on the integrated scanner. Two blinded, independent readers assessed image quality, noise, in-stent diameter, in-stent attenuation, and image sharpness by using signal intensity profiles across stents. RESULTS: Interreader agreement for image quality assessment was substantial (kappa = 0.798). Both readers rated best image quality in data sets from integrated detector at highest spatial resolution (86 or 72% of stents rated best quality). Image noise was significantly lower in data sets scanned with integrated detector, being lowest at 0.6 mm slice thickness (14.3 vs 21.0 HU; P < .001). Differences between measured and true in-stent diameters and differences in attenuation across stents were smallest, and average/maximum image sharpness was highest in data sets from the integrated detector using iterative reconstructions. CONCLUSION: CT coronary stent imaging is significantly improved by using a detector with integrated electronics combined with iterative reconstructions. PMID- 24148776 TI - Dual-standard reference values of left ventricular volumetric parameters by multidetector CT angiography. AB - BACKGROUND: The papillary and trabecular muscles constitute a significant percentage of left ventricular mass and volume. The influence of the papillary and trabecular muscles on left ventricular parameters has not been described with multidetector CT angiography. OBJECTIVE: The aims of this study are (1) to derive reference values for left ventricular volumetric parameters both including and excluding the papillary and trabecular muscles and (2) to establish the optimal segmentation method for measuring these values. METHODS: A total of 179 subjects (mean age, 55.4 +/- 9 years; 102 women) without heart disease and at low risk of cardiovascular disease who underwent CT angiography were selected. Left ventricular volumes, myocardial volume, and ejection fraction were measured with epicardial and 2 endocardial trace methods, including and excluding trace for the papillary and trabecular muscles. Values of all parameters obtained by both endocardial trace methods were compared. RESULTS: Significant difference between both trace groups for all parameters on both sexes was found (P < .001). Significant differences in precision error of remeasurement were found in the including trace (3.6%) compared with the excluding trace (4.7%; P < .05) and in the epicardial trace (2.2%) compared with both endocardial traces (P < .001). CONCLUSION: The left ventricular parameters measured by CT angiography were influenced significantly by the trace method by including or excluding the papillary and trabecular muscles. The dual-standard reference values of left ventricular parameters were established, and the optimal segmentation methods were definite in considering the heart size and image quality studied with retrospective and prospective CT angiography. PMID- 24148777 TI - Prevalence and severity of coronary artery calcium in young persons with diabetes. AB - BACKGROUND: Currently, American Diabetes Association guidelines suggest statin use among persons with diabetes mellitus aged >40 years. The presence of calcified plaque in coronary arteries is a sensitive surrogate of coronary artery disease and has been shown to be an independent predictor of mortality and cardiac events. OBJECTIVE: We aimed to assess the prevalence and severity of calcified plaque in coronary arteries in patients aged <40 years with and without diabetes. METHODS: We included 3723 asymptomatic patients aged <40 years who had undergone coronary calcium scanning. Clinical and demographic data were collected. Agatston score was categorized into Agatston score 0 as normal, 1 to 99 as low, 100 to 399 as intermediate, and >=400 as severe; and statistical analysis was performed. RESULTS: The study population consisted of 4% persons with diabetes (n = 142) and 56% men with a mean age of 35 +/- 5 years. Young persons with diabetes had greater prevalence of Agatston score > 0 than persons without diabetes (43% vs 24%; P < .0001). In addition, 12% of persons with diabetes vs 2.5% of persons without diabetes had an Agatston score >= 100 (P < .0001). The prevalence of calcified plaque in coronary arteries was >50% in persons with diabetes aged >35 years. After taking into account risk factors, the presence of diabetes was associated with a 4-fold higher odds of an Agatston score >= 100 (odds ratio, 4.19; 95% CI, 2.29-7.65; P < .0001). CONCLUSION: Our study found that 43% of young patients with diabetes have detectable coronary atherosclerosis. Given the known clinical implications of calcified plaque in coronary arteries, future studies are needed to evaluate interventions in persons aged <40 years who exhibit subclinical atherosclerosis to reduce future cardiovascular disease events in this vulnerable population. PMID- 24148778 TI - Multidetector CT predictors of prosthesis-patient mismatch in transcatheter aortic valve replacement. AB - BACKGROUND: Prosthesis-patient mismatch (PPM) is a predictor of mortality after aortic valve replacement (AVR). OBJECTIVE: We examined whether accurate 3 dimensional annular sizing with multidetector CT (MDCT) is predictive of PPM after transcatheter AVR (TAVR). METHODS: One hundred twenty-eight patients underwent MDCT then TAVR. Moderate PPM was defined as an indexed effective orifice area <=0.85 cm2/m2 and severe <=0.65 cm2/m2. MDCT annular measurements (area, short and long axis) were compared with the size of the selected transcatheter heart valve (THV) to obtain (1) the difference between prosthesis size and CT-measured mean annular diameter and (2) the percentage of undersizing or oversizing (calculated as 100 * [MDCT annular area--THV nominal area]/THV nominal area). In addition, the MDCT annular area was indexed to body surface area. These measures were evaluated as potential PPM predictors. RESULTS: We found that 42.2% of patients had moderate PPM and 9.4% had severe PPM. Procedural characteristics and in-hospital outcomes were similar between patients with or without PPM. THV undersizing of the mean aortic annulus diameter was not predictive of PPM (odds ratio [OR], 0.84; 95% CI, 0.65-1.07; P = .16; area under the receiver-operating characteristic curve [AUC], 0.58). THV undersizing of annular area was not predictive of PPM (OR, 0.96; 95% CI, 0.80-1.16; P = .69; AUC, 0.52). Indexed MDCT annular area was, however, predictive of PPM (OR, 0.24; 95% CI, 0.10-0.59; P < .001; AUC, 0.66). CONCLUSIONS: PPM is frequent after TAVR. Appropriate annular oversizing does not reduce the rate or severity of PPM. Patient annulus size mismatch, identified by indexed MDCT annular area, is a significant predictor of PPM. PMID- 24148779 TI - Coronary CT angiography versus intravascular ultrasound for estimation of coronary stenosis and atherosclerotic plaque burden: a meta-analysis. AB - BACKGROUND: Numerous studies have compared coronary CT angiography (CTA) with quantitative coronary angiography. However, the ability of coronary CTA to identify atherosclerosis and to accurately measure plaque and coronary area and volume measurements as compared with intravascular ultrasound (IVUS) has not been fully defined. OBJECTIVE: We sought to assess the ability of coronary CTA to quantify coronary and plaque measurements commonly performed with IVUS. METHODS: We searched multiple databases for diagnostic studies that directly compared coronary CTA and IVUS for coronary plaque detection, vessel luminal area, percentage of area stenosis, plaque area, and plaque volume. We used a bivariate mixed-effects binomial regression model to pool test sensitivity and specificity for detection of any coronary plaque. RESULTS: Forty-two studies that evaluated 1360 patients (75% men; mean age, 59 years) were identified. No significant difference was found between coronary CTA and IVUS measurements of vessel lumen cross-sectional area, plaque area, percentage of area stenosis, or plaque volume within the overall cohort and no difference for the measurement of cross sectional area (n = 5 studies) and plaque volume (n = 8 studies) among a subgroup that used automated or semiautomated measurement techniques. Sensitivity and specificity of coronary CTA to detect any plaque compared with IVUS were 93% and 92%, respectively, with an area under the receiver-operating curve of 0.97. CONCLUSIONS: Compared with IVUS, coronary CTA appears to be highly accurate for estimation of luminal area, percentage of area stenosis, plaque volume, and plaque area and for detection of plaque. The use of automated vessel and stenosis measurements appears promising in limited studies to date. PMID- 24148780 TI - The neuroendocrine regulation of the mammalian reproductive axis. Introduction. PMID- 24148781 TI - Intermittent hypoxia: endothelin-1 and hypoxic carotid body chemosensory potentiation. PMID- 24148784 TI - Level set method with automatic selective local statistics for brain tumor segmentation in MR images. AB - The level set approach is a powerful tool for segmenting images. This paper proposes a method for segmenting brain tumor images from MR images. A new signed pressure function (SPF) that can efficiently stop the contours at weak or blurred edges is introduced. The local statistics of the different objects present in the MR images were calculated. Using local statistics, the tumor objects were identified among different objects. In this level set method, the calculation of the parameters is a challenging task. The calculations of different parameters for different types of images were automatic. The basic thresholding value was updated and adjusted automatically for different MR images. This thresholding value was used to calculate the different parameters in the proposed algorithm. The proposed algorithm was tested on the magnetic resonance images of the brain for tumor segmentation and its performance was evaluated visually and quantitatively. Numerical experiments on some brain tumor images highlighted the efficiency and robustness of this method. PMID- 24148783 TI - The genetic heterogeneity and mutational burden of engineered melanomas in zebrafish models. AB - BACKGROUND: Melanoma is the most deadly form of skin cancer. Expression of oncogenic BRAF or NRAS, which are frequently mutated in human melanomas, promote the formation of nevi but are not sufficient for tumorigenesis. Even with germline mutated p53, these engineered melanomas present with variable onset and pathology, implicating additional somatic mutations in a multi-hit tumorigenic process. RESULTS: To decipher the genetics of these melanomas, we sequence the protein coding exons of 53 primary melanomas generated from several BRAF(V600E) or NRAS(Q61K) driven transgenic zebrafish lines. We find that engineered zebrafish melanomas show an overall low mutation burden, which has a strong, inverse association with the number of initiating germline drivers. Although tumors reveal distinct mutation spectrums, they show mostly C > T transitions without UV light exposure, and enrichment of mutations in melanogenesis, p53 and MAPK signaling. Importantly, a recurrent amplification occurring with pre configured drivers BRAF(V600E) and p53-/- suggests a novel path of BRAF cooperativity through the protein kinase A pathway. CONCLUSION: This is the first analysis of a melanoma mutational landscape in the absence of UV light, where tumors manifest with remarkably low mutation burden and high heterogeneity. Genotype specific amplification of protein kinase A in cooperation with BRAF and p53 mutation suggests the involvement of melanogenesis in these tumors. This work is important for defining the spectrum of events in BRAF or NRAS driven melanoma in the absence of UV light, and for informed exploitation of models such as transgenic zebrafish to better understand mechanisms leading to human melanoma formation. PMID- 24148785 TI - Assessment of inflammation in large arteries with 18F-FDG-PET in elderly. AB - This paper presents repeated measurements of atherosclerosis using bimodality positron emission tomography and computed tomography (PET/CT) with 18F fluorodeoxyglucose (18F-FDG) to assess its uptake in aorta, iliac and femoral arteries in three groups of elderly subjects classified as normals (N), hypercholesterolemics (H) and with stable angina (A) in a 12 months follow-up (T0 to T12). The subjects in group H were taking rosuvastatin (20mg/d) for 12 months before the second scan. The calcifications in the arteries were determined by CT imaging and the artery PET images were analyzed slice by slice. The standard uptake values (SUVs) for 18F-FDG uptake were classified in two main groups: calcified and non-calcified arteries and each main group comprises six sub-groups for the three subject groups N, H and A, and for the two measurements 12 months apart. Although the calcifications were present at some portions of the arteries in all subjects (23%, 36% and 44% of calcified sites to total sites analyzed, respectively, in groups N, H and A), the results show the most noticeable SUV changes after 12 months was in group N of non-calcified arteries. In the three groups, the calcified arteries showed no significant differences between T0 and T12 while significant differences were observed for the non-calcified arteries. However, there were no significant changes at T12 between groups N and H following rosuvastatin intake in group H. In conclusion, the quantitative analysis with 18F-FDG-PET/CT could be efficient in the localization of the inflammation and evaluation of its progression in atherosclerosis instead of global evaluations with systemic inflammation biomarkers. PMID- 24148786 TI - Fine mapping and identification of a candidate gene for a major locus controlling maturity date in peach. AB - BACKGROUND: Maturity date (MD) is a crucial factor for marketing of fresh fruit, especially those with limited shelf-life such as peach (Prunus persica L. Batsch): selection of several cultivars with differing MD would be advantageous to cover and extend the marketing season. Aims of this work were the fine mapping and identification of candidate genes for the major maturity date locus previously identified on peach linkage group 4. To improve genetic resolution of the target locus two F2 populations derived from the crosses Contender x Ambra (CxA, 306 individuals) and PI91459 (NJ Weeping) x Bounty (WxBy, 103 individuals) were genotyped with the Sequenom and 9K Illumina Peach Chip SNP platforms, respectively. RESULTS: Recombinant individuals from the WxBy F2 population allowed the localisation of maturity date locus to a 220 kb region of the peach genome. Among the 25 annotated genes within this interval, functional classification identified ppa007577m and ppa008301m as the most likely candidates, both encoding transcription factors of the NAC (NAM/ATAF1, 2/CUC2) family. Re-sequencing of the four parents and comparison with the reference genome sequence uncovered a deletion of 232 bp in the upstream region of ppa007577m that is homozygous in NJ Weeping and heterozygous in Ambra, Bounty and the WxBy F1 parent. However, this variation did not segregate in the CxA F2 population being the CxA F1 parent homozygous for the reference allele. The second gene was thus examined as a candidate for maturity date. Re-sequencing of ppa008301m, showed an in-frame insertion of 9 bp in the last exon that co segregated with the maturity date locus in both CxA and WxBy F2 populations. CONCLUSIONS: Using two different segregating populations, the map position of the maturity date locus was refined from 3.56 Mb to 220 kb. A sequence variant in the NAC gene ppa008301m was shown to co-segregate with the maturity date locus, suggesting this gene as a candidate controlling ripening time in peach. If confirmed on other genetic materials, this variant may be used for marker assisted breeding of new cultivars with differing maturity date. PMID- 24148787 TI - Elevated C-reactive protein values predict nodal metastasis in patients with penile cancer. AB - BACKGROUND: The nodal status is a strong predictor for cancer specific death in patients with penile carcinoma, and the C-reactive protein (CRP) level at diagnosis has recently been shown to be associated with poor clinical outcome in various solid malignancies. Therefore, this retrospective study was performed to evaluate the association between preoperative CRP levels and the incidence of nodal metastasis in patients with squamous cell carcinoma (SCC) of the penis. METHODS: The analysis included 51 penile cancer patients who underwent either radical or partial penectomy for pT1-4 penile cancer between 1990 and 2010. The nodal status was correlated with patient and tumor specific characteristics. RESULTS: Sixteen (31%) patients had lymph node metastasis at the time of penile cancer surgery. Nodal status was associated with tumor stage but did not correlate significantly with tumor grade. In contrast, high presurgical CRP levels were significantly associated with the diagnosis of nodal involvement (p = 0.04). The optimal CRP cut-off value to predict lymph node metastasis was set at 20 mg/l based on ROC analysis. CONCLUSIONS: Since a high preoperative serum CRP level was closely correlated with nodal disease, it could be used as an additional marker to help identify patients with penile cancer who may benefit from inguinal lymph node dissection. PMID- 24148788 TI - Carotid intima-media thickness--a potential predictor for rupture risk of intracranial aneurysms. AB - BACKGROUND: Individual assessment of rupture risk of cerebral aneurysms is challenging, and increased knowledge of predictors for aneurysm rupture is needed. Smoking and hypertension are shared risk factors for atherosclerotic disease and cerebral aneurysms, and patients with atherosclerosis have an increased prevalence of intracranial aneurysms. Carotid ultrasound with evaluation of intima-media thickness (IMT) is a non-invasive, safe, rapid, well validated and reproducible technique for quantification of subclinical atherosclerosis and assessment of cardio- and cerebrovascular risk. Increased IMT is associated with elevated risk for ischemic stroke and myocardial infarction, but sparse data exist on carotid ultrasound findings in patients with intracranial aneurysms. AIMS: The purpose of this study was to investigate carotid IMT in patients with unruptured intracranial aneurysms (UIA) and aneurysmal subarachnoid hemorrhage (aSAH), and to assess if IMT might be associated with aneurysm rupture risk. METHODS: Patients treated for saccular aneurysms (UIA and aSAH) from February 2011 to August 2012 were included. Standardized high resolution B-mode ultrasound assessment of carotid arteries was done after aneurysm treatment, and traditional vascular risk factors were recorded. Healthy partners of young patients with ischemic stroke were used as controls. RESULTS: 69 patients treated for UIA (n=28) and aSAH (n=41) were compared with 80 controls. Mean IMT was higher in patients with aSAH (0.79 mm) than patients with UIA (0.65 mm) and controls (0.63 mm). Multiple multinomial regression analysis comparing aSAH, UIA and control groups demonstrated that IMT was the only variable predicative of aSAH compared to UIA. According to the multiple regression model, the probability of having aSAH compared to non-rupture increased by 62% for each 0.10 mm increment of mean IMT (RRR=1.62, P=0.017). Taking into account only patients harboring intracranial aneurysms, simple binary logistic regression was then applied to the UIA and aSAH groups. According to this model the risk of belonging to the aSAH group increased with higher mean IMT values (OR=1.40 per 0.10 mm increase of mean IMT, P=0.024). CONCLUSION: There is an association between IMT and intracranial aneurysm rupture status at the time of aneurysm treatment. Carotid IMT can be a potential predictor of aneurysm rupture. IMT may thus be a possible adjunct in the risk assessment of aneurysm rupture, and a helpful tool in patient risk stratification and counseling. PMID- 24148790 TI - Can early follow-up after deliberate self-harm reduce repetition? A prospective study of 325 patients. AB - BACKGROUND: Patients who deliberately harm themselves often repeat their self destructive acts. The objective of this study was to assess whether a follow-up visit within 10 days to a psychiatric consultant could reduce the frequency of repeated deliberate self-harm (DSH). METHODS: A cohort of 325 consecutive DSH patients attending two large emergency departments in Stockholm, Sweden, were included and followed for 6 months. Any visit to a psychiatric consultant within 10 days was registered as an early follow-up. Repeated DSH episode within 6 months among the 325 patients was detected via nationwide registers. MAIN OUTCOME MEASURE: Repeated DSH within 6 months. RESULTS: At 6 months follow-up 22 (24%) of 92 patients with an early follow-up had repeated their DSH acts compared to 58 (25%) of 233 patients without an early follow-up (OR 1.06 (95% CI: 0.60-1.85) p value 0.85). After adjustment for possible confounders, multivariable analysis showed an OR of 1.22 (95% CI: 0.62-2.38, p-value 0.56). LIMITATIONS: Early follow up was registered as any visit to a psychiatric consultant and no information regarding actions taken at the visit were obtained. CONCLUSION: After adjusting for other factors associated with repetition there was an association of patients who were offered and thereafter attended an early follow-up visit and a decreased risk of repeated DSH. PMID- 24148789 TI - Alteration of cyclic-AMP response element binding protein in the postmortem brain of subjects with bipolar disorder and schizophrenia. AB - BACKGROUND: Abnormalities of cyclic-AMP (cAMP) response element binding protein (CREB) function has been suggested in bipolar (BP) illness and schizophrenia (SZ), based on both indirect and direct evidence. To further elucidate the role of CREB in these disorders, we studied CREB expression and function in two brain areas implicated in these disorders, i.e., dorsolateral prefrontal cortex (DLPFC) and cingulate gyrus (CG). METHODS: We determined CREB protein expression using Western blot technique, CRE-DNA binding using gel shift assay, and mRNA expression using real-time RT-polymerase chain reaction (qPCR) in DLPFC and CG of the postmortem brain of BP (n=19), SZ (n=20), and normal control (NC, n=20) subjects. RESULTS: We observed that CREB protein and mRNA expression and CRE-DNA binding activity were significantly decreased in the nuclear fraction of DLPFC and CG obtained from BP subjects compared with NC subjects. However, the protein and mRNA expression and CRE-DNA binding in SZ subjects was significantly decreased in CG, but not in DLPFC, compared with NC. CONCLUSION: These studies thus indicate region-specific abnormalities of CREB expression and function in both BP and SZ. They suggest that abnormalities of CREB in CG may be associated with both BP and SZ, but its abnormality in DLPFC is specific to BP illness. PMID- 24148791 TI - Postnatal depression in Mexican American fathers: demographic, cultural, and familial predictors. AB - BACKGROUND: Although maternal postpartum depression (PPD) is a well-documented phenomenon that has been the focus of a large body of literature, much less is known about the prevalence and predictors of depressive symptoms among fathers following the birth of a child. Particularly scarce is research with Mexican American men, an understudied population at high risk given limited socioeconomic resources and elevated rates of maternal PPD. METHODS: The current study used descriptive and path analyses to examine the prevalence and predictors of PPD in 92 Mexican American fathers (M age=31.3 years). RESULTS: At both 15 and 21 postpartum week assessments, 9% of fathers met criteria for PPD. Path analyses suggested that unemployment status, fewer biological children, poor marital relationship quality, and lower orientation to Anglo culture predicted higher 15 week paternal PPD symptoms, which was associated with greater paternal depressive symptoms at 21 weeks. Predictive paths from symptoms of maternal to paternal PPD were not significant. LIMITATIONS: Lack of generalizability to other ethnic groups, sampling of primarily resident fathers, and the absence of historical assessments of depression are limitations of the current study. CONCLUSIONS: Findings support the importance of PPD screenings among Mexican American fathers and suggest certain demographic, familial, and cultural factors may render men particularly vulnerable for maladjustment during the early infancy period. PMID- 24148792 TI - Relationship between measurement invariance and age-related differences in the prevalence of generalized anxiety disorder. AB - BACKGROUND: Generalized anxiety disorder (GAD) peaks in prevalence in middle age and declines in prevalence into old age. Some commentators have suggested that this is not a meaningful epidemiological trend rather a methodological artifact. This study tested this hypothesis by matching respondents of different ages based on their severity and examining whether age influences the probability of endorsing GAD criteria and the prevalence of GAD. METHODS: Self-reported worriers from a nationally representative survey of non-institutionalized adults were selected for investigation (n=1738). All respondents were interviewed using the World Mental Health version of the Composite International Diagnostic Interview. Age-related differences in the prevalence and invariance of the GAD criteria were examined between 16 and 29 years, 30 and 44 years, 45 and 59 years and 60 years+ age groups. Effect sizes were used to assess the impact of statistically significant criterion level non-invariance on the prevalence of GAD. RESULTS: Respondents aged 60 years or more were less likely than younger adults to endorse most of the GAD criteria. Significant non-invariance was identified in each of the age group analyses. Nonetheless these differences had no impact on the prevalence of GAD in three group comparisons. In the other three group comparisons, the impact was minimal (d <= 0.3). LIMITATIONS: Our results support age-related differences in the prevalence of GAD but we are limited to the extent to which we can say why these differences occur. CONCLUSIONS: Age-related prevalence differences in GAD are meaningful epidemiological trends. PMID- 24148793 TI - Patient satisfaction after primary total and unicompartmental knee arthroplasty: an age-dependent analysis. AB - BACKGROUND: Patient-related outcomes have become the focus of increased attention when assessing knee arthroplasty. METHODS: We retrieved questionnaires from 485 (584 knees) patients at a minimum of 3years after undergoing primary knee arthroplasty. We excluded bilateral knee arthroplasty, leaving 141 UKA and 245 TKA who rated their satisfaction and expectation regarding pain, range of motion (ROM), daily living function (DLF), return to recreational activity (RRA) and ability to kneel (ATK) on a scale of 0 (worst) to 10 (best). We further collected data on pain level and the modified Cincinnati rating scale. Range of motion was documented pre- and postoperatively at a minimum of six months. The cohort was subdivided into three age groups and compared with each other (Group 1: <55, n=113; Group 2: 55-64, n=117; Group 3: 65+, n=155). RESULTS: Average satisfaction with pain, ROM and ATK for patients under 55 was higher for UKA than for TKA. Patients>65 with TKA were on average more satisfied than patients with UKA in these three items. However, patients under 55 with UKA were up to 2.9 times more likely to have their expectations met when compared to patients receiving TKA. Patients with UKA under 55 rated their joint as good/excellent in 96.0% versus patients in the same age group with TKA in 81.0%. CONCLUSIONS: We found that overall, younger patients who were treated with UKA demonstrated higher satisfaction scores in most subsets when compared with the patients of the same age group who received TKA. PMID- 24148794 TI - Heme oxygenase-1 mediates the anti-inflammatory effect of molecular hydrogen in LPS-stimulated RAW 264.7 macrophages. AB - BACKGROUND: Molecular hydrogen (H2) as a new medical gas has an anti-inflammatory effect. In the present study, we investigated whether heme oxygenase-1 (HO-1) contributes to the anti-inflammatory effect of H2 in lipopolysaccharide (LPS) stimulated RAW 264.7 macrophages. METHODS: RAW 264.7 macrophages were stimulated by LPS (1 MUg/mL) with presence or absence of different concentrations of H2. Cell viability and injury were tested by 3-(4,5)-dimethylthiahiazo (-z-y1)-3,5-di phenytetrazoliumromide (MTT) assay and lactate dehydrogenase (LDH) release, respectively. The cell culture supernatants were collected to measure inflammatory cytokines [TNF-alpha, IL-1beta, HMGB1 (high mobility group box-1) and IL-10] at different time points. Moreover, HO-1 protein expression and activity were tested at different time points. In addition, to further identify the role of HO-1 in this process, zinc protoporphyrin (ZnPP)-IX, an HO-1 inhibitor, was used. RESULTS: H2 treatment had no significant influence on cell viability and injury in normally cultured RAW 264.7 macrophages. Moreover, H2 treatment dose-dependently attenuated the increased levels of pro-inflammatory cytokines (TNF-alpha, IL-1beta, HMGB1), but further increased the level of anti inflammatory cytokine IL-10 at 3 h, 6 h, 12 h and 24 h after LPS stimulation. Furthermore, H2 treatment could also dose-dependently increase the HO-1 protein expression and activity at 3 h, 6 h, 12 h and 24 h in LPS-activated macrophages. In addition, blockade of HO-1 activity with ZnPP-IX partly reversed the anti inflammatory effect of H2 in LPS-stimulated macrophages. CONCLUSIONS: Molecular hydrogen exerts a regulating role in the release of pro- and anti-inflammatory cytokines in LPS-stimulated macrophages, and this effect is at least partly mediated by HO-1 expression and activation. PMID- 24148795 TI - The use of CT scan and stereo lithography apparatus technologies in a canine individualized rib prosthesis. AB - OBJECTIVE: To design and fabricate canine rib prosthesis with full geometric shape using computed tomography (CT) scan combined with computer-aided design (CAD) and stereo lithographic (SLA) technologies and to evaluate the accuracy of this method. METHODS: After scanned on 64 rows helical CT, the cortex part of the right 7th rib was selected as the prototype for design and manufacture of the rib prosthesis and image data were stored as DICOM format. Three-dimensional (3D) surface reconstruction was applied to produce 3D image of the 7th rib and results were outputted as STL format which were then modified by UG software for establishment of CAD model. RESULTS: The rib prosthesis with full geometric shape was obtained based on CT scanning and SLA technique. About 30,000 point cloud data were acquired after 3D laser scan of the ribs. When comparing the rib prosthesis with the rib prototype, the maximum positive deviation, maximum negative deviation, average deviation and standard deviation were 1.764 mm, 2.126 mm, 0.183/-0.253 mm and 0.346 mm, respectively. There were about 88.17% of the point cloud data within the range of +/-0.5 mm. CONCLUSION: It is feasible to design and fabricate rib prosthesis with full geometric shape by using CT scanning technology combined with CAD and SLA technologies. This method is fast, convenient and precise for manufacturing prosthesis. Optimization and improvement could be processed based on the deviation suggested by the scanning. PMID- 24148796 TI - LeCDJ1, a chloroplast DnaJ protein, facilitates heat tolerance in transgenic tomatoes. AB - The roles of a tomato (Lycopersicon esculentum) chloroplast-targeted DnaJ protein (LeCDJ1) were investigated using wild-type (WT) and sense transgenic tomatoes. The LeCDJ1 expression was upregulated by 38 degrees C, 42 degrees C, 45 degrees C, NaCl, PEG, methyl viologen (MV) and hydrogen peroxide (H2O2), but not by 30 degrees C and 35 degrees C. Meanwhile, LeCDJ1 was involved in the response of plants to abscisic acid (ABA). Under heat stress, the sense plants showed better growth, higher chlorophyll content, lower malondialdehyde (MDA) accumulation and relative electrical conductivity (REC), and also less PSII photoinhibition than WT. Interestingly, the sense plants treated with streptomycin (SM), an inhibitor of organellar translation, still showed higher maximum photochemistry efficiency of PSII (Fv/Fm) and D1 protein levels than the SM-untreated WT, suggesting that the protective effect of LeCDJ1 on PSII was, at least partially, independent of D1 protein synthesis. Furthermore, the relatively lower superoxide radical (O2(*-)) and H2O2 levels in the sense plants were considered to be due to the higher ascorbate peroxidase (APX) and superoxide dismutase (SOD) activity, which seemed unlikely dependent on their transcription level. These results indicated that LeCDJ1 overexpression facilitated heat tolerance in transgenic tomatoes. PMID- 24148797 TI - Clinical and epidemiological aspects related to the detection of adenovirus or respiratory syncytial virus in infants hospitalized for acute lower respiratory tract infection. AB - OBJECTIVE: To characterize and compare clinical, epidemiological, and laboratory aspects of infants with acute lower respiratory infection (ALRI) associated with the detection of adenovirus (ADV) or respiratory syncytial virus (RSV). METHODS: A preliminary respiratory infection surveillance study collected samples of nasopharyngeal aspirate (NPA) for viral research, linked to the completion of a standard protocol, from children younger than two years admitted to a university hospital with ALRI, between March of 2008 and August of 2011. Polymerase chain reaction (PCR) was used for eight viruses: ADV, RSV, metapneumovirus, Parainfluenza 1, 2, and 3, and Influenza A and B. Cases with NPA collected during the first 24 hours of admission, negative results of blood culture, and exclusive detection of ADV (Gadv group) or RSV (Grsv group) were selected for comparisons. RESULTS: The preliminary study included collection of 1,121 samples of NPA, 813 collected in the first 24 hours of admission, of which 50.3% were positive for at least one virus; RSV was identified in 27.3% of cases surveyed, and ADV was identified in 15.8%. Among the aspects analyzed in the Gadv (n = 58) and Grsv (n = 134) groups, the following are noteworthy: the higher mean age, more frequent prescription of antibiotics, and the highest median of total white blood cell count and C-reactive protein values in Gadv. CONCLUSIONS: PCR can detect persistent/latent forms of ADV, an aspect to be considered when interpreting results. Additional studies with quantitative diagnostic techniques could elucidate the importance of the high frequency observed. PMID- 24148798 TI - Association of late-onset neonatal sepsis with late neurodevelopment in the first two years of life of preterm infants with very low birth weight. AB - OBJECTIVE: To establish the influence of late-onset sepsis on neurodevelopment of preterm infants with very low birth weight (VLBW), according to the etiologic agent. METHOD: This was a cohort of newborns with birth weight<1,500 g and gestational age less than 32 weeks, admitted to the institutional intensive care unit (ICU) with up to 48 hours of life, and followed-up at the outpatient follow up clinic for preterm infants with VLBW until 2 years of corrected age. EXCLUSION CRITERIA: death within the first 72 hours of life, congenital malformations and genetic syndromes, children with congenital infection by the human immunodeficiency virus (HIV), congenital infection (STORCH), presence of early onset sepsis and cases with more than one pathogen growth in blood cultures. Septic and non-septic infants were compared regarding neonatal outcomes and mortality. Neurodevelopment was assessed using the Bayley Scale (BSDI-II) at 18 to 24 months of corrected age. RESULTS: 411 preterm infants with VLBW were eligible; the mean gestational age was 29 +/- 2.2 weeks and mean birth weight was 1,041 +/- 281 grams. Late-onset sepsis occurred in 94 preterm infants with VLBW (22.8%). VLBW infants with Gram-positive infection showed motor deficit when compared to the non-septic group, 68.8% vs. 29.3%, respectively (OR 6; 1.6-21.8, p=0.006); the cognitive development was similar between the groups. The overall mortality rate from infection was 26.7%; considering the pathogens, the rates were 18.7% for coagulase-negative Staphylococcus, 21.8% for Gram-positive bacteria, and 50% for Gram-negative bacteria and fungi. CONCLUSION: Neonatal sepsis has a significant influence on late neurodevelopment at 2 years of corrected age in preterm infants with VLBW, and Gram-positive infections are associated with motor deficit. PMID- 24148799 TI - Randomised controlled trial of a brief alcohol intervention in a general hospital setting. AB - BACKGROUND: The evidence suggests that brief alcohol-focused interventions, directed at hazardous and harmful drinkers in non-specialist settings such as primary care are effective in reducing alcohol consumption. However, there is a need for further research in the hospital setting. This is a randomised controlled trial to investigate the effectiveness of a 10-minute brief intervention amongst 'at risk' drinkers admitted to general hospital wards. Unlike some previous trials, this trial is randomised, used blinded assessors, includes an intention-to-treat analysis, included female subjects and excluded people with alcohol dependence. METHODS: A total of 250 'at risk' drinkers admitted to King's College Hospital were identified using the Alcohol Use Disorders Identification Test (AUDIT). Some 154 subjects entered the study and were randomly allocated to the control and intervention groups. Subjects in the control group received no advice about their drinking whilst subjects in the intervention group received 10 minutes of simple advice on reducing alcohol consumption. Recruitment took place between 1995 and 1997. The primary outcome was the AUDIT questionnaire at 12 months. Secondary outcomes were a previous week's Drinks Diary, questionnaires (General Health Questionnaire, Alcohol Problems Questionnaire and the Severity of Alcohol Dependence Questionnaire) and laboratory blood tests (gamma glutamyl transferase, mean cell volume and haemoglobin). RESULTS: At 3-month and 12-month follow-up, all participants were included in the intention-to-treat analysis. At both time points there was no evidence of an intervention effect that could be attributed to the brief intervention. Both the intervention and control groups had an improved AUDIT score and reduced levels of alcohol consumption as measured by a subjective Drinks Diary at 3 months which was maintained at 12 months. CONCLUSIONS: This study has added further evidence on brief interventions in the hospital setting. In contrast to the recent Cochrane review by McQueen et al., the results of this study do not support the effectiveness of a brief alcohol intervention in general hospital wards. However our study was underpowered and there were flaws in the statistical analyses, and these limitations temper the strength of our conclusions. PMID- 24148801 TI - A family history intervention: enhancing cardiovascular risk assessment. PMID- 24148800 TI - Developing the draft descriptive system for the child amblyopia treatment questionnaire (CAT-Qol): a mixed methods study. AB - BACKGROUND: Amblyopia is a visual condition that occurs in childhood. Screening programmes exist within the United Kingdom (UK) to detect amblyopia, and once detected treatment is given.Existing patient reported outcome (PRO) measures for amblyopia do not meet current recommendations for the methods adopted during their development, or the way in which the instruments are administered. The overall aim of this study was to produce a self-complete PRO instrument for amblyopia for children aged 4-7 years that uses children's responses in the development phase. The study comprised a number of stages. This paper reports on the refinement of the descriptive system for the draft instrument (the Child Amblyopia Treatment Questionnaire, CAT-QoL) using qualitative and quantitative methods. METHODS: The study consisted of three components. Children were asked to read, and complete the draft questionnaire as independently as possible. They were then asked about the questionnaire, and its format, in a cognitive debriefing exercise. Observations were made as to the child's ability to read the questionnaire, particular attention was made as to which individual words participants struggled to read. Children were also asked their opinion on the design layout of the questionnaire. Finally, some children were asked to complete a ranking task to help determine the order of the levels of the items as judged by the children. Mid-rank scoring and statistical level of agreement were calculated for the ranking exercise. RESULTS: Thirty-two (n=32) participants completed a draft questionnaire; each of these underwent a cognitive de-briefing interview. Twenty-two (n=22) children completed the ranking exercise. Ten children did not understand the concept of ranking. The results of the qualitative phase (cognitive de-briefing interview) were used to modify the wording of items and layout of the instrument. Results of the ranking exercise were used to inform the order of the response levels for the items. CONCLUSION: Responses of young children can be used in the development of PRO instruments. They are able to help inform the content, wording, and format of an instrument, ensuring good content and face validity. The results have been used to further refine the CAT-QoL, however further research is required to assess the psychometric properties of the instrument. PMID- 24148802 TI - Hydraulic fracturing: a new public health problem 138 years in the making? PMID- 24148803 TI - LTBP-2 competes with tropoelastin for binding to fibulin-5 and heparin, and is a negative modulator of elastinogenesis. AB - Latent transforming growth factor-beta-1 binding protein-2 (LTBP-2) is a protein of ill-defined function associated with elastic fibers during elastinogenesis. Although LTBP-2 binds fibrillin-1, fibulin-5, and heparin/heparan sulfate, molecules critical for normal elastic fiber assembly, it does not interact directly with elastin or its precursor, tropoelastin. We investigated the modulating effect of LTBP-2 on two key interactions of tropoelastin during elastinogenesis a) with fibulin-5 and b) with heparan sulfate (using heparin). Firstly, using solid phase assays we showed that LTBP-2 bound fibulin-5 (Kd=26.47+/-5.68 nM) with an affinity similar to that of the tropoelastin-fibulin 5 interaction (Kd=24.66+/-5.64 nM). Then using a competitive binding assay we showed that LTBP-2 inhibited the tropoelastin-fibulin-5 interaction in a dose dependent manner with almost complete inhibition obtained with 5-fold molar excess of LTBP-2. Interestingly, a fragment of LTBP-2 containing the fibulin-5 binding sequence only partially inhibited the tropoelasin-fibulin-5 interaction suggesting that LTBP-2 was directly blocking only the C-terminal tropoelastin binding site on fibulin-5 and indirectly blocking tropoelastin binding to the N terminal region. In parallel experiments heparin was shown to have minor inhibitory effects on fibulin-5 interactions with tropoelastin and LTBP-2. However, LTBP-2 was shown to significantly inhibit the binding of heparin to tropoelastin with 50% inhibition achieved with 10 fold molar excess of LTBP-2. Confocal microscopy of fibroblast matrix showed strong co-distribution of LTBP-2 with fibulin-5 and fibrillin-1 and partial co-distribution with heparan sulfate proteoglycans, perlecan and syndecan-4. Also addition of exogenous LTBP-2 to ear cartilage chondrocyte cultures blocked elastinogenesis in a concentration dependent manner. Overall the results indicate that LTBP-2 may have a negative regulatory role during elastic fiber assembly, perhaps in displacing elastin microassemblies from complexes with fibulin-5 and/or cell surface heparan sulfate proteoglycans. PMID- 24148804 TI - Heparin-dependent regulation of fibronectin matrix conformation. AB - Extracellular matrix (ECM) conformation is regulated by a variety of stimuli in vivo, including mechanical forces and allosteric binding partners, and these conformational changes contribute to the regulation of cell behavior. Heparin and heparan sulfate, for example, have been shown to regulate the sequestration and presentation of numerous growth factors, including vascular endothelial growth factor, on the heparin 2 binding domain in fibronectin (Fn). However, mechanical force also alters Fn conformation, indicating that the growth factor binding region may be co-regulated by both heparin and mechanical force. Herein, we describe a simple antibody-based method for evaluating the conformation of the heparin 2 binding domain in Fn, and use it to determine the relative contributions of heparin and mechanical strain to the regulation of Fn conformation. We achieved specificity in quantifying conformational changes in this region of Fn by measuring the ratio of two fluorescent monoclonal antibodies, one that is insensitive to Fn conformational changes and a second whose binding is reduced or enhanced by non-equilibrium conformational changes. Importantly, this technique is shown to work on Fn adsorbed on surfaces, single Fn fibers, and Fn matrix fibers in cell culture. Using our dual antibody approach, we show that heparin and mechanical strain co-regulate Fn conformation in matrix fibrils, which is the first demonstration of heparin-dependent regulation of Fn in its physiologically-relevant fibrillar state. Furthermore, the dual antibody approach utilizes commercially available antibodies and simple immunohistochemistry, thus making it accessible to a wide range of scientists interested in Fn mechanobiology. PMID- 24148805 TI - Communication benefits of bilateral cochlear implantation. Retrospective study in 12-year-old children. AB - INTRODUCTION AND OBJECTIVES: Some studies suggest that simultaneous or sequential cochlear implantation in a short period of time offers additional benefits. There is controversy regarding the existence of an age limit after which a second implantation offers less benefit for the acquisition of communication skills. The objectives of this study were to confirm that sequential cochlear implantation offers benefits compared to unilateral implantation and to study whether, at 12 years of age, there are significant differences regarding the age at the time of the second implantation. METHODS: Descriptive and observational study of a population of 12-year-old children carrying cochlear implants (n=69). A liminal pure tone audiometry and an open-field verbal discrimination test (disyllables, common phrases in an open context, with and without noise) were conducted to evaluate audiological benefits. RESULTS: Verbal discrimination results were better among patients who had been implanted before the age of 2 years, although the differences were not statistically significant (P>.5). Children who had received bilateral cochlear implants before the age of 2 years and with a period less than 4 years between both implants presented better verbal discrimination percentages (P<.05). CONCLUSIONS: In our sample, early cochlear implantation with a short period between both implants provided significant benefits regarding intelligibility. There seem to be a specific age and interimplant period, after which the auditory benefit on the first implant becomes reduced. PMID- 24148806 TI - Active recruitment strategy in disadvantaged immigrant populations improves the identification of human immunodeficiency but not of hepatitis B or C virus infections. AB - BACKGROUND: Barriers to access medical screening and care may underestimate the number of diseased subjects among immigrant populations. AIMS: To evaluate the prevalence of human immunodeficiency virus, hepatitis B virus and hepatitis C virus infections among immigrants recruited in a disadvantaged area. METHODS: The study enrolled all subjects seen between 1999 and 2009 at an on-site health and family counselling centre for immigrants. During the first 6 years of the study a pro-active recruitment was performed using a mobile unit. RESULTS: Overall 2681 subjects were enrolled (median age: 31 years; 52.8% males; 82.3% from Sub-Saharan Africa; 13.9% of the women were sex workers). A total of 206 subjects (7.6%) were hepatitis B surface antigen-positive, 84 (3.6%) were anti-hepatitis C virus positive, 129 (5%) were anti-human immunodeficiency virus-positive, 84 (3.1%) were drug users, and 436 (16.3%) were alcohol abusers. The prevalence of hepatitis B surface antigen and anti-hepatitis C virus remained consistent throughout the study period, while the prevalence of human immunodeficiency virus significantly decreased. At multivariate analysis, hepatitis B virus infection was associated with male gender, hepatitis C virus infection with drug addiction, and human immunodeficiency virus infection was associated with female gender, drug addiction, and active recruitment. CONCLUSIONS: An active recruitment strategy should be considered to reach disadvantaged populations at high risk of human immunodeficiency virus infection. PMID- 24148807 TI - Twelve-year follow-up of conservative management of postnatal urinary and faecal incontinence and prolapse outcomes: randomised controlled trial. AB - OBJECTIVE: To determine the long-term (12-year) effects of a conservative nurse led intervention for postnatal urinary incontinence. DESIGN: Follow-up of a randomised controlled trial. SETTING: Community-based intervention in three centres (in the UK and New Zealand). POPULATION: A cohort of 747 women with urinary incontinence at 3 months after childbirth, of whom 471 (63%) were followed up after 12 years. METHODS: Women were randomly allocated to active conservative treatment after delivery (pelvic floor muscle training and bladder training), or to a control group receiving standard care. MAIN OUTCOME MEASURES: Prevalence of urinary incontinence (primary outcome) and faecal incontinence, symptoms and signs of prolapse, and performance of pelvic floor muscle training at 12 years. RESULTS: The significant improvements relative to controls that had been found in urinary incontinence (60 versus 69%; risk difference, RD, -9.1%; 95% confidence interval, 95% CI, -17.3 to -1.0%) and faecal incontinence (4 versus 11%; RD -6.1%; 95% CI -10.8 to -1.6%) at 1 year did not persist for urinary incontinence (83 versus 80%; RD 2.1%; 95% CI -4.9 to 9.1%) or faecal incontinence (19 versus 15%; RD 4.3%; 95% CI -2.5 to 11.0%) at the 12-year follow up, irrespective of incontinence severity at trial entry. The prevalence of prolapse symptoms or objectively measured pelvic organ prolapse also did not differ between the groups. In the short term the intervention motivated more women to perform pelvic floor muscle training (83 versus 55%), but this fell in both groups by 12 years (52 versus 49%). CONCLUSIONS: The moderate short-term benefits of a brief nurse-led conservative treatment for postnatal urinary incontinence did not persist. About four-fifths of women with urinary incontinence 3 months after childbirth still had this problem 12 years later. PMID- 24148808 TI - Endocannabinoids decrease neuropathic pain-related behavior in mice through the activation of one or both peripheral CB1 and CB2 receptors. AB - The two most studied endocannabinoids are anandamide (AEA), principally catalyzed by fatty-acid amide hydrolase (FAAH), and 2-arachidonoyl glycerol (2-AG), mainly hydrolyzed by monoacylglycerol lipase (MGL). Inhibitors targeting these two enzymes have been described, including URB597 and URB602, respectively. Several recent studies examining the contribution of CB1 and/or CB2 receptors on the peripheral antinociceptive effects of AEA, 2-AG, URB597 and URB602 in neuropathic pain conditions using either pharmacological tools or transgenic mice separately have been reported, but the exact mechanism is still uncertain. Mechanical allodynia and thermal hyperalgesia were evaluated in 436 male C57BL/6, cnr1KO and cnr2KO mice in the presence or absence of cannabinoid CB1 (AM251) or CB2 (AM630) receptor antagonists in a mouse model of neuropathic pain. Peripheral subcutaneous injections of AEA, 2-AG, WIN55,212-2 (WIN; a CB1/CB2 synthetic agonist), URB597 and URB602 significantly decreased mechanical allodynia and thermal hyperalgesia. These effects were inhibited by both cannabinoid antagonists AM251 and AM630 for treatments with 2-AG, WIN and URB602 but only by AM251 for treatments with AEA and URB597 in C57BL/6 mice. Furthermore, the antinociceptive effects for AEA and URB597 were observed in cnr2KO mice but absent in cnr1KO mice, whereas the effects of 2-AG, WIN and URB602 were altered in both of these transgenic mice. Complementary genetic and pharmacological approaches revealed that the anti-hyperalgesic effects of 2-AG and URB602 required both CB1 and CB2 receptors, but only CB2 receptors mediated its anti allodynic actions. The antinociceptive properties of AEA and URB597 were mediated only by CB1 receptors. PMID- 24148809 TI - Oxytocin activation of neurons in ventral tegmental area and interfascicular nucleus of mouse midbrain. AB - Oxytocin (OT) was reported to affect cognitive and emotional behavior by action in ventral tegmental area (VTA) and other brain areas. However, it is still unclear how OT activates VTA and related midline nucleus. Here, using patch-clamp recording, we studied the effects of OT on neuron activity in VTA and interfascicular nucleus (IF). OT dose-dependently and selectively excited small neurons located in medial VTA and the majority of IF neurons but not large neurons in lateral VTA. We found the hyperpolarization-activated current (I(h)) and the membrane capacitance of OT-sensitive neuron were significantly smaller than those of OT-insensitive neurons. The action potential width of OT-sensitive neurons was about half that of OT-insensitive neurons. The OT effect was blocked by the OT receptor antagonist atosiban and WAY-267464 but not by tetrodotoxin, suggesting a direct postsynaptic activation of OT receptors. In addition, the phospholipase C (PLC) inhibitor U73122 antagonized the depolarization by OT. Both the nonselective cation channel (NSCC) antagonist SKF96365 and the Na(+)-Ca(2+) exchanger (NCX) blocker SN-6 attenuated OT effects. These results suggested that the PLC signaling pathway coupling to NSCC and NCX contributes to the OT-mediated activation of neurons in medial VTA and IF. Taken together, our results indicate OT directly acted on medial VTA and especially IF neurons to activate NSCC and NCX via PLC. The direct activation by OT of midbrain neurons may be one mechanism underlying OT effects on social behavior. PMID- 24148810 TI - Selective regulation of recombinantly expressed mGlu7 metabotropic glutamate receptors by G protein-coupled receptor kinases and arrestins. AB - mGlu7 receptors are coupled to Gi/Go-proteins and activate multiple transduction pathways, including inhibition of adenylyl cyclase activity and stimulation of ERK1/2 and JNK pathways. mGlu7 receptors play an important role in cognition and emotion and are involved in stress-related disorders such as anxiety and depression and in susceptibility to convulsive seizures. In spite of these potential clinical implications, little is known on the mechanisms that regulate mGlu7-receptor signaling. Here we show that mGlu7 receptor-dependent signaling pathways were regulated in a complementary manner by different GRK subtypes, with GRK4 affecting the adenylyl cyclase and the JNK pathways, and GRK2 selectively affecting the ERK1/2 pathway. Additionally we found that the two isoforms of non visual arrestins, i.e. beta-arrestin1 and beta-arrestin2, exerted opposite effects on mGlu7-receptor signaling, with beta-arrestin1 positively modulating ERK1/2 and inhibiting JNK, and beta-arrestin2 doing the opposite. This represents a remarkable example of "reciprocal regulation" of receptor signaling by the two isoforms of beta-arrestin. Finally we found that beta-arrestin1 amplified mGlu7 receptor-dependent ERK1/2 activation in response to L-AP4 (an orthosteric agonist), but not in response to AMN082 (an atypical mGlu7-receptor allosteric agonist). The different effect of beta-arrestin1 on L-AP4- and AMN082-stimulated ERK1/2 phosphorylation is in line with the emerging concept of beta-arrestin biased agonists. The present study may open new perspectives in elucidating the physio-pathological roles of the mGlu7 receptor and may provide new insights for the possibility to develop specific (biased) agonists that can selectively activate different signaling pathways. PMID- 24148811 TI - Sex-related long-term behavioral and hippocampal cellular alterations after nociceptive stimulation throughout postnatal development in rats. AB - Early noxious stimuli may alter the neurogenesis rate in the dentate gyrus and the behavioral repertoire of adult rats. This study evaluated the long-term effects of noxious stimulation, imposed in different phases of development, on nociceptive and anxiety-like behaviors, hippocampal activation, cell proliferation, hippocampal BDNF and plasma corticosterone levels in 40 day-old male and female adolescents. Noxious stimulation was induced by intra-plantar injection of Complete Freund's adjuvant (CFA), on postnatal days (P) 1 (group P1), 8 (P8) or 21 (P21). Control animals were not stimulated in any way. On P21 a subset of animals from each group received BrdU and was perfused on P40 for identification of proliferating cells in the granule cell layer of the dentate gyrus. Another subset of rats was subjected to behavioral testing on P40 and one week later, to magnetic resonance imaging (MRI) acquisition. Noxious stimulation evoked hypoalgesia in adolescents, mainly in females (P < 0.02), reflected by greater latency to withdraw the paw and less paw lickings in the hot plate test than controls (P < 0.001). It also resulted in more time spent in the open arms, e.g., less anxiety-like behavior than controls (P < 0.01), especially in females (P < 0.01, compared with males). Proliferative cell rate in the dentate gyrus was the highest in P8 males and females (P < 0.001), with males exhibiting more proliferation than females on P1 and P8, which was directly related to the hippocampal levels of BDNF and inversely related to plasma corticosterone. Sex differences were also detected in manganese-enhanced MRI signal, which was more prominent in P1 females than males (P < 0.01). This study represents the first step of investigation on the cellular basis of the sex-dependent long-term consequences of nociceptive stimuli in newborns. PMID- 24148812 TI - The endocannabinoid system mediates aerobic exercise-induced antinociception in rats. AB - Exercise-induced antinociception is widely described in the literature, but the mechanisms involved in this phenomenon are poorly understood. Systemic (s.c.) and central (i.t., i.c.v.) pretreatment with CB1 and CB2 cannabinoid receptor antagonists (AM251 and AM630) blocked the antinociception induced by an aerobic exercise (AE) protocol in both mechanical and thermal nociceptive tests. Western blot analysis revealed an increase and activation of CB1 receptors in the rat brain, and immunofluorescence analysis demonstrated an increase of activation and expression of CB1 receptors in neurons of the periaqueductal gray matter (PAG) after exercise. Additionally, pretreatment (s.c., i.t. and i.c.v.) with endocannabinoid metabolizing enzyme inhibitors (MAFP and JZL184) and an anandamide reuptake inhibitor (VDM11) prolonged and intensified this antinociceptive effect. These results indicate that exercise could activate the endocannabinoid system, producing antinociception. Supporting this hypothesis, liquid-chromatography/mass-spectrometry measurements demonstrated that plasma levels of endocannabinoids (anandamide and 2-arachidonoylglycerol) and of anandamide-related mediators (palmitoylethanolamide and oleoylethanolamide) were increased after AE. Therefore, these results suggest that the endocannabinoid system mediates aerobic exercise-induced antinociception at peripheral and central levels. PMID- 24148813 TI - Brain and peripheral pharmacokinetics of levodopa in the cynomolgus monkey following administration of opicapone, a third generation nitrocatechol COMT inhibitor. AB - OBJECTIVE: The present study aimed at evaluating the effect of opicapone, a third generation nitrocatechol catechol-O-methyltransferase (COMT) inhibitor, on the systemic and central bioavailability of 3,4-dihydroxy-l-phenylalanine (levodopa) and related metabolites in the cynomolgus monkey. METHODS: Four monkeys, implanted with guiding cannulas for microdialysis probes, in the substantia nigra, dorsal striatum and prefrontal cortex, were randomized in two groups that received, in a crossover design, vehicle or 100 mg/kg opicapone for 14 days. Twenty-three hours after last administration of vehicle or opicapone, animals were challenged with levodopa/benserazide (12/3 mg/kg). Extracellular dialysate and blood samples were collected over 360 min (at 30 min intervals) for the assays of catecholamine and COMT activity. RESULTS: Opicapone increased levodopa systemic exposure by 2-fold not changing Cmax values and reduced both 3-O methyldopa (3-OMD) exposure and Cmax values by 5-fold. These changes were accompanied by ~76-84% reduction in erythrocyte COMT activity. In dorsal striatum and substantia nigra, opicapone increased levodopa exposure by 1.7- and 1.4-fold, respectively, reducing 3-OMD exposure by 5- and 7-fold respectively. DOPAC exposure was increased by 4-fold in the substantia nigra. In the prefrontal cortex, opicapone increased levodopa exposure and reduced 3-OMD levels by 2.3- and 2.4-fold, respectively. CONCLUSIONS: Opicapone behaved as long-acting COMT inhibitor that markedly increased systemic and central levodopa bioavailability. Opicapone is a strong candidate to fill the unmet need for COMT inhibitors that lead to more sustained levodopa levels in Parkinson's disease patients. PMID- 24148814 TI - Open-Phylo: a customizable crowd-computing platform for multiple sequence alignment. AB - Citizen science games such as Galaxy Zoo, Foldit, and Phylo aim to harness the intelligence and processing power generated by crowds of online gamers to solve scientific problems. However, the selection of the data to be analyzed through these games is under the exclusive control of the game designers, and so are the results produced by gamers. Here, we introduce Open-Phylo, a freely accessible crowd-computing platform that enables any scientist to enter our system and use crowds of gamers to assist computer programs in solving one of the most fundamental problems in genomics: the multiple sequence alignment problem. PMID- 24148815 TI - Is burnout associated with referral rates among primary care physicians in community clinics? AB - BACKGROUND: There is little empirical research examining the effects of burnout on objective measures of primary care physicians' behaviour in the medical encounter. OBJECTIVES: We studied possible associations between primary care physicians' burnout and the rates of referrals. We conceptualized referral rate as a negative outcome of burnout because high and unnecessary referral rates incur extra costs to health care systems. METHODS: In this cross-sectional study, 136 primary care physicians in one district of one Israeli health maintenance organization (HMO) completed the Maslach Burnout Inventory in the presence of an interviewer. Data on each physician's objective workload and number of referrals for high- and low-cost imaging tests, specialist clinics and treatments by nurses were collected from the HMO's databases. RESULTS: Due to high correlations between referral rate indicators, a Confirmatory Factor Analysis revealed one factor: 'referrals for diagnostic tests and specialist clinics'. Path Analysis using Structural Equation Modelling explained a total of 18.1% of referral rate variance, with board-certified specialist mostly associated (beta = 0.31, P < 0.01), followed by burnout (beta = 0.20, P < 0.05) and objective workload (beta = 0.18, P < 0.05). CONCLUSIONS: In this preliminary investigation, we found that referral rates for diagnostic tests and specialist clinics increased independently for board-certified specialists (compared with GPs), for those with higher burnout levels and when objective workload increases. These findings support the conceptualization of referrals rates as objectively measured negative outcomes of burnout. Further replications with other objective outcomes, additional HMOs and bigger samples are warranted. PMID- 24148816 TI - Impact of risk factors on outcomes in early-stage Hodgkin's lymphoma: an analysis of international staging definitions. AB - BACKGROUND: In early-stage Hodgkin's lymphoma (HL), treatment according to the early favorable or unfavorable subgroup is guided by staging definitions, which differ between various study groups worldwide. We analyzed risk factors used in different international staging systems and their impact on the outcome of early stage HL patients. PATIENTS AND METHODS: In 1173 early-stage HL patients treated homogenously within the German Hodgkin Study Group (GHSG) trials HD10 and HD11, the impact of three staging systems developed and used by the GHSG, the European Organization for Research and Treatment of Cancer (EORTC), and the National Comprehensive Cancer Network (NCCN) in discriminating risk groups for progression free survival (PFS) and overall survival (OS) was assessed and the relevance of their single risk factors was investigated. RESULTS: All the three staging systems defined an unfavorable risk group out of early-stage patients of comparable size (56%, 55%, and 57%), having a significantly poorer PFS and OS as compared with the corresponding favorable group; 5-year differences between early favorable and early unfavorable in terms of PFS were 9.4% (HR 2.61, 95% CI 1.74 3.91), 6.7% (HR 2.10, 95% CI 1.41-3.13), and 8.6% (HR 2.14, 95% CI 1.45-3.16) with the GHSG, EORTC, and NCCN definition, respectively. Sensitivity was high for all systems (84%, 79%, and 83%); however, there was a low specificity with high rates of false-positive results (1-specificity 54%, 53%, and 55%, respectively). Models of high sensitivity included risk factors associated with large tumor burden and high tumor activity. Most risk factors for tumor-specific end points were also predictive of OS. CONCLUSIONS: Differentiating between a favorable and an unfavorable risk group has significant impact on PFS and OS in early-stage HL patients in the modern treatment era. Risk-adapted treatment strategies using new risk factors with higher specificity are needed. PMID- 24148817 TI - Restoring expression of miR-16: a novel approach to therapy for malignant pleural mesothelioma. AB - BACKGROUND: Malignant pleural mesothelioma (MPM) is recalcitrant to treatment and new approaches to therapy are needed. Reduced expression of miR-15/16 in a range of cancer types has suggested a tumour suppressor function for these microRNAs, and re-expression has been shown to inhibit tumour cell proliferation. The miR 15/16 status in MPM is largely unknown. MATERIALS AND METHODS: MicroRNA expression was analysed by TaqMan-based RT-qPCR in MPM tumour specimens and cell lines. MicroRNA expression was restored in vitro using microRNA mimics, and effects on proliferation, drug sensitivity and target gene expression were assessed. Xenograft-bearing mice were treated with miR-16 mimic packaged in minicells targeted with epidermal growth factor receptor (EGFR)-specific antibodies. RESULTS: Expression of the miR-15 family was consistently downregulated in MPM tumour specimens and cell lines. A decrease of 4- to 22-fold was found when tumour specimens were compared with normal pleura. When MPM cell lines were compared with the normal mesothelial cell line MeT-5A, the downregulation of miR-15/16 was 2- to 10-fold. Using synthetic mimics to restore miR-15/16 expression led to growth inhibition in MPM cell lines but not in MeT-5A cells. Growth inhibition caused by miR-16 correlated with downregulation of target genes including Bcl-2 and CCND1, and miR-16 re-expression sensitised MPM cells to pemetrexed and gemcitabine. In xenograft-bearing nude mice, intravenous administration of miR-16 mimics packaged in minicells led to consistent and dose dependent inhibition of MPM tumour growth. CONCLUSIONS: The miR-15/16 family is downregulated and has tumour suppressor function in MPM. Restoring miR-16 expression represents a novel therapeutic approach for MPM. PMID- 24148818 TI - Synergistic inhibition of lung cancer cell lines by (-)-epigallocatechin-3 gallate in combination with clinically used nitrocatechol inhibitors of catechol O-methyltransferase. AB - (-)-Epigallocatechin-3-gallate (EGCG) has exhibited been studied for lung cancer inhibitory activity in vitro and in animal models, but it is rapidly methylated and inactivated by catechol-O-methyltransferase (COMT). Entacapone and tolcapone, COMT inhibitors, are used to mitigate the symptoms of Parkinson's disease. We investigated the synergistic effects of entacapone/tolcapone and EGCG against lung cancer cell lines in culture. EGCG, entacapone and tolcapone inhibited the growth of H1299 human lung cancer cells (IC50 = 174.9, 76.8 and 29.3 uM, respectively) and CL-13 murine lung cancer cells (IC50 = 181.5, 50.7 and 19.7 uM, respectively) as single agents following treatment for 72h. Treatment with 1:10, 1:5, 1:2.5 and 1:1 combinations of EGCG and tolcapone or entacapone resulted in synergistically enhanced growth inhibition. The growth inhibitory effect of the combinations was mediated by induction of intracellular oxidative stress, cell cycle arrest and decreased nuclear translocation of nuclear factor-kappaBeta. Methylation of EGCG was dose dependently inhibited by entacapone and tolcapone (IC50 = 10 and 20 uM, respectively) in a cell-free system, and both compounds increased the intracellular levels of unmethylated EGCG. Treatment of mice with EGCG in combination with tolcapone increased the bioavailability of EGCG and decreased the methylation of plasma norepinephrine: no apparent liver or behavioral toxicity was observed. In conclusion, the combination of EGCG and entacapone/tolcapone synergistically inhibited the growth of lung cancer cells in culture, and the mechanistic basis for this synergy is likely due in part to inhibition of COMT with resultant increase in the levels of unmetabolized EGCG. PMID- 24148819 TI - Suppression of ERbeta signaling via ERbeta knockout or antagonist protects against bladder cancer development. AB - Epidemiological studies showed that women have a lower bladder cancer (BCa) incidence, yet higher muscle-invasive rates than men, suggesting that estrogen and the estrogen receptors, estrogen receptor alpha (ERalpha) and estrogen receptor beta (ERbeta), may play critical roles in BCa progression. Using in vitro cell lines and an in vivo carcinogen N-butyl-N-(4-hydroxybutyl) nitrosamine (BBN)-induced mouse BCa model, we found that ERbeta plays a positive role in promoting BCa progression. Knockdown of ERbeta with ERbeta-shRNA in ERbeta positive human BCa J82, 647v and T24 cell lines led to suppressed cell growth and invasion. Mice lacking ERbeta have less cancer incidence with reduced expression of the proliferation marker Ki67 in BBN-induced BCa. Consistently, our results show that non-malignant urothelial cells with ERbeta knockdown are more resistant to carcinogen-induced malignant transformation. Mechanism dissection found that targeting ERbeta suppressed the expression of minichromosome maintenance complex component 5 (MCM5), a DNA replication licensing factor that is involved in tumor cell growth. Restoring MCM5 expression can partially reverse ERbeta knockdown mediated growth reduction. Supportively, treating cells with the ERbeta-specific antagonist, 4-[2-Phenyl-5,7-bis(trifluoromethyl) pyrazolo[1,5-a]pyrimidin-3 yl]phenol (PHTPP), reduced BCa cell growth and invasion, as well as MCM5 expression. Furthermore, we provide the first evidence that BCa burden and mortality can be controlled by PHTPP treatment in the carcinogen-induced BCa model. Together, these results demonstrate that ERbeta could play positive roles in promoting BCa progression via MCM5 regulation. Targeting ERbeta through ERbeta shRNA, PHTPP or via downstream targets, such as MCM5, could serve as potential therapeutic approaches to battle BCa. PMID- 24148820 TI - Impairing squamous differentiation by Klf4 deletion is sufficient to initiate tongue carcinoma development upon K-Ras activation in mice. AB - Oral squamous cell carcinoma (SCC) is among the most prevalent cancers in the world and is characterized by high morbidity and few therapeutic options. Like most cancers, oral SCC arises from a multistep process involving alterations of genes responsible for balancing proliferation and differentiation. Among these, Krupsilonppel-like factor 4 (Klf4) suppresses cell proliferation and promotes differentiation and thus helps to maintain epithelial homeostasis. However, the prevailing role of Klf4 in maintenance of normal homeostasis in oral epithelium has not been established in vivo. Here, we used an inducible oral-specific mice model to selectively ablate Klf4 in the oral cavity. We generated K14 CreER(Tam)/Klf4 (f/f) mice that survived to adulthood and did not present overt phenotype. However, histologically these mice showed dysplastic lesions, increased cell proliferation and abnormal differentiation in the tongue 4 months after induction, supporting a homeostatic role of Klf4 in the oral epithelia. Furthermore, by breeding these mutants with a transgenic line expressing at endogenous levels K-ras (G12D), we assessed the role of disrupting differentiation gene programs to the carcinogenesis process. The K14-CreER(TAM)/K ras (G12D)/Klf4 (-) (/-) mice rapidly develop oral SCC in the tongue. Thus, our findings support the emerging notion that activation of differentiating gene programs may represent a barrier preventing carcinogenesis in epithelial cells harboring oncogenic mutations, and thus that molecules acting upstream and downstream of Klf4 may represent components of a novel tumor-suppressive pathway. PMID- 24148821 TI - Requirement of estrogen receptor alpha DNA-binding domain for HPV oncogene induced cervical carcinogenesis in mice. AB - Cervical cancer is caused by human papillomavirus (HPV) in collaboration with other non-viral factors. The uterine cervix is hormone responsive and female hormones have been implicated in the pathogenesis of the disease. HPV transgenic mice expressing HPV16 oncogenes E6 (K14E6) and/or E7 (K14E7) have been employed to study a mechanism of estrogen and estrogen receptor alpha (ERalpha) in cervical carcinogenesis. A chronic exposure to physiological levels of exogenous estrogen leads to cervical cancer in the HPV transgenic mice, which depends on ERalpha. The receptor is composed of multiple functional domains including a DNA binding domain (DBD), which mediates its binding to estrogen-responsive elements (EREs) on target genes. A transcriptional control of genes by ERalpha is mediated by either DBD-dependent (classical) or DBD-independent (non-classical) pathway. Although molecular mechanisms of ERalpha in cancer have been characterized extensively, studies investigating importance of each pathway for carcinogenesis are scarce. In this study, we employ knock-in mice expressing an ERalpha DBD mutant (E207A/G208A) that is defective specifically for ERE binding. We demonstrate that the ERalpha DBD mutant fails to support estrogen-induced epithelial cell proliferation and carcinogenesis in the cervix of K14E7 transgenic mice. We also demonstrate that cervical diseases are absent in K14E7 mice when one ERalpha DBD mutant allele and one wild-type allele are present. We conclude that the ERalpha classical pathway is required for cervical carcinogenesis in a mouse model. PMID- 24148822 TI - A siRNA screen identifies RAD21, EIF3H, CHRAC1 and TANC2 as driver genes within the 8q23, 8q24.3 and 17q23 amplicons in breast cancer with effects on cell growth, survival and transformation. AB - RNA interference has boosted the field of functional genomics, by making it possible to carry out 'loss-of-function' screens in cultured cells. Here, we performed a small interfering RNA screening, in three breast cancer cell lines, for 101 candidate driver genes overexpressed in amplified breast tumors and belonging to eight amplicons on chromosomes 8q and 17q, investigating their role in cell survival/proliferation. This screening identified eight driver genes that were amplified, overexpressed and critical for breast tumor cell proliferation or survival. They included the well-described oncogenic driver genes for the 17q12 amplicon, ERBB2 and GRB7. Four of six other candidate driver genes-RAD21 and EIF3H, both on chromosome 8q23, CHRAC1 on chromosome 8q24.3 and TANC2 on chromosome 17q23-were confirmed to be driver genes regulating the proliferation/survival of clonogenic breast cancer cells presenting an amplification of the corresponding region. Indeed, knockdown of the expression of these genes decreased cell viability, through both cell cycle arrest and apoptosis induction, and inhibited the formation of colonies in anchorage independent conditions, in soft agar. Strategies for inhibiting the expression of these genes or the function of the proteins they encode are therefore of potential value for the treatment of breast cancers presenting amplifications of the corresponding genomic region. PMID- 24148823 TI - Urinary metabolites of a polycyclic aromatic hydrocarbon and volatile organic compounds in relation to lung cancer development in lifelong never smokers in the Shanghai Cohort Study. AB - Exposures to polycyclic aromatic hydrocarbons (PAHs) from various environmental and occupational sources are considered a primary risk factor for lung cancer among lifelong never smokers, based largely on results from epidemiologic studies utilizing self-reported exposure information. Prospective, biomarker-based human studies on the role of PAH and other airborne carcinogens in the development of lung cancer among lifelong non-smokers have been lacking. We prospectively investigated levels of urinary metabolites of a PAH and volatile organic compounds in relation to lung cancer risk in a nested case-control study of 82 cases and 83 controls among lifelong never smokers of the Shanghai Cohort Study, a prospective cohort of 18 244 Chinese men aged 45-64 years at enrollment. We quantified three PAH metabolites: r-1,t-2,3,c-4-tetrahydroxy-1,2,3,4 tetrahydrophenanthrene (PheT), 3-hydroxyphenanthrene (3-OH-Phe) and total hydroxyphenanthrenes (total OH-Phe, the sum of 1-, 2-, 3- and 4-OH-Phe), as well as metabolites of the volatile organic compounds acrolein (3-hydroxypropyl mercapturic acid), benzene (S-phenyl mercapturic acid), crotonaldehyde (3-hydroxy 1-methylpropylmercapturic acid) and ethylene oxide (2-hydroxyethyl mercapturic acid). Urinary cotinine was also quantified to confirm non-smoking status. Compared with the lowest quartile, odds ratios (95% confidence intervals) for lung cancer risk for the highest quartile levels of PheT, 3-OH-Phe and total OH Phe were 2.98 (1.13-7.87), 3.10 (1.12-7.75) and 2.59 (1.01-6.65) (all P trend < 0.05), respectively. None of the metabolites of the volatile organic compounds were associated with overall lung cancer risk. This study demonstrates a potentially important role of exposure to PAH in the development of lung cancer among lifelong never smokers. PMID- 24148825 TI - Long-term follow-up of autogenous canine transplants with application of guided bone regeneration. AB - The aim of this study was to evaluate the aesthetics and outcome of autotransplantation of impacted canines unsuitable for orthodontic realignment using a combination of surgery with guided bone regeneration and orthodontic treatment. Ten severely impacted canines in nine consecutive patients (mean age 14.8 years) were included. The recipient mesiodistal space was created orthodontically and the recipient socket prepared using dental implant drills. Following transplantation, bone defects were grafted using guided bone regeneration, teeth were aligned and occlusions adjusted orthodontically. Patients were followed-up every 6 months for an average of 7.1 years (range 2-11 years). The mean pink aesthetic score was 13.33 +/- 0.87. Pocket depths were less than 3 mm. Radiographic examination showed an uninterrupted periodontal space and lamina dura in seven cases, unclear periodontal space in two, and replacement resorption in one case. The analysis showed that canine transplantation combined with guided bone regeneration and orthodontic treatment gives acceptable and predictable aesthetic results. PMID- 24148826 TI - Inhibitory effect of interferon gamma on frequency of Ehrlichia canis-infected cells in vitro. AB - Ehrlichia canis is an obligate intracellular bacterium that infects the macrophage-monocyte cells of dogs, causing canine monocytic ehrlichiosis. Interferon-gamma (IFN-gamma), along with other cytokines, mediates the immune response to such intracellular bacterial invasions. To determine the role of IFN gamma in the immunity of dogs to E. canis infection, peripheral blood mononuclear cells (PBMC) and white blood cells (WBC) were collected from E. canis-infected dogs and added to a culture of E. canis in DH82 cells. The number of E. canis inclusion-positive cells was significantly reduced in cultures containing PBMC and WBC from E. canis-infected dogs compared to uninfected dogs. However, this resistance was inhibited by the addition of an anti-dog IFN-gamma antibody. Resistance was also observed when PBMC were added to the Cell Culture Inserts, which prohibited contact of PBMC to DH82 cells, while allowed the diffusion of soluble cell products. The results of this study indicate that resistance was not dependent on cell to cell contact, but was associated with soluble cell products, such as IFN-gamma. The addition of recombinant canine IFN-gamma to the E. canis culture also reduced the number of infected cells. A commercial recombinant canine IFN-gamma, which is sold in Japan, was also effective at reducing E. canis infected cell number. These results indicate that IFN-gamma has an inhibitory effect on the frequency of E. canis-infected cells in vitro and that contact between effector and target cells is not necessary for the resistance. PMID- 24148827 TI - Porcine reproductive and respiratory syndrome virus inhibition of interferon-beta transcription by IRF3-independent mechanisms in MARC-145 cells in early infection. AB - Interferon beta is an important antiviral molecule whose expression is triggered through recognition of viral components by pattern recognition receptors via a cascade of signaling molecules, while viruses could target these molecules to evade from innate immunity. IFN regulatory factor 3 (IRF3) plays a crucial role in innate immune responses. Here, we demonstrate that PRRSV infection did not induce IFN-beta gene transcription in MARC-145 cells, but inhibited poly (I:C) stimulated IFN-beta gene transcription instead. Such inhibition is time-dependent with the progression of PRRSV infection. We also show that the inhibition of IFN beta transcription in the early stage of infection could not be due to inhibition of phosphorylation and nuclear translocation of IRF3, though significant decrease of p-IRF3 and its nuclear translocation in PRRSV-infected and poly (I:C) cells was observed later at 48 h post-infection. The different patterns of inhibition for IFN-beta transcription and IRF3 phosphorylation have important implications as to the mechanism(s) by which PRRSV suppresses the type I IFN signaling at early stage of infection. There could be mechanism(s) other than effecting on IRF3 or molecules upstream that require further investigation. PMID- 24148828 TI - Markedly increased expression of interleukin-8 in the colorectal mucosa of inflammatory colorectal polyps in miniature dachshunds. AB - Inflammatory colorectal polyps (ICRPs) in miniature dachshunds were recently recognized as a major cause of large bowel diarrhea in this dog breed in Japan. ICRPs are characterized by the formation of multiple small polyps and/or space occupying large polyps in the colorectal area and are thought to be a novel form of inflammatory bowel disease (IBD). To explore key mediators in the pathogenesis of ICRPs, we analyzed several pro-inflammatory cytokine (IL-1beta, IL-6, TNF alpha, IL-8, IL-12p35, IL-12/23p40, and IL-23p19) mRNA expressions in colorectal polyps in ICRP dogs by quantitative PCR. Among these cytokines, IL-8 mRNA expression was markedly up-regulated in large polyps. To examine IL-8 protein expression, we analyzed IL-8 protein level and its location in colorectal mucosal specimens of ICRP dogs by ELISA and immunofluorescence microscopy. IL-8 protein was significantly increased in large polyps and serum in dogs with ICRPs compared to controls. By immunofluorescence microscopy, IL-8 was only localized in macrophages, but not in mucosal epithelial cells or neutrophils. IL-8-positive macrophages were significantly increased in large polyps compared to controls. These results suggest that IL-8 is produced mainly by macrophages and may induce neutrophil infiltration in the colorectal area of ICRP dogs. PMID- 24148830 TI - Insights of biosurfactant producing Serratia marcescens strain W2.3 isolated from diseased tilapia fish: a draft genome analysis. AB - BACKGROUND: Serratia marcescens is an opportunistic bacterial pathogen with broad range of host ranging from vertebrates, invertebrates and plants. S. marcescens strain W2.3 was isolated from a diseased tilapia fish and it was suspected to be the causal agent for the fish disease as virulence genes were found within its genome. In this study, for the first time, the genome sequences of S. marcescens strain W2.3 were sequenced using the Illumina MiSeq platform. RESULT: Several virulent factors of S. marcescens such as serrawettin, a biosurfactant, has been reported to be regulated by N-acyl homoserine lactone (AHL)-based quorum sensing (QS). In our previous studies, an unusual AHL with long acyl side chain was detected from this isolate suggesting the possibility of novel virulence factors regulation. This evokes our interest in the genome of this bacterial strain and hereby we present the draft genome of S. marcescens W2.3, which carries the serrawettin production gene, swrA and the AHL-based QS transcriptional regulator gene, luxR which is an orphan luxR. CONCLUSION: With the availability of the whole genome sequences of S. marcescens W2.3, this will pave the way for the study of the QS-mediated genes expression in this bacterium. PMID- 24148829 TI - Providing clinicians with a patient's 10-year cardiovascular risk improves their statin prescribing: a true experiment using clinical vignettes. AB - BACKGROUND: Statins are effective for primary prevention of cardiovascular (CV) disease, the leading cause of death in the world. Multinational guidelines emphasize CV risk as an important factor for optimal statin prescribing. However, it's not clear how primary care providers (PCPs) use this information. The objective of this study was to determine how primary care providers use information about global CV risk for primary prevention of CV disease. METHODS: A double-blinded, randomized experiment using clinical vignettes mailed to office based PCPs in the United States who were identified through the American Medical Association Physician Masterfile in June 2012. PCPs in the control group received clinical vignettes with all information on the risk factors needed to calculate CV risk. The experimental group received the same vignettes in addition to the subject's 10-year calculated CV risk (Framingham risk score). The primary study outcome was the decision to prescribe a statin. RESULTS: Providing calculated CV risk to providers increased statin prescribing in the two high-risk cases (CV risk > 20%) by 32 percentage points (41% v. 73%; 95% CI = 23-40, p <0.001; relative risk [RR] = 1.78) and 16 percentage points (12% v. 27%, 95% CI 8.5 22.5%, p <0.001; RR = 2.25), and decreased statin prescribing in the lowest risk case (CV risk = 2% risk) by 9 percentage points [95% CI = 1.00-16.7%, p = 0.003, RR = 0.88]. Fewer than 20% of participants in each group reported routinely calculating 10-year CV risk in their patients. CONCLUSIONS: Providers do not routinely calculate 10-year CV risk for their patients. In this vignette experiment, PCPs undertreated low LDL, high CV risk patients. Giving providers a patient's calculated CV risk improved statin prescribing. Providing PCPs with accurate estimates of patient CV risk at the point of service has the potential to improve the efficiency of statin prescribing. PMID- 24148831 TI - The impact of heat waves on transport volumes in an urban emergency medical services system: a retrospective review. AB - INTRODUCTION: Heat waves pose a serious public health risk to particular patient populations, especially in urban areas. Emergency Medical Services (EMS) in many urban areas constitute the first line of regional preparation and response to major heat wave events; however, little is known on heat wave operational impact to the EMS system, such as call volume or demand. OBJECTIVE: To examine the effect of heat wave periods on overall urban EMS system call volume and transport volume as well as the nature of the call types. METHODS: Retrospective review of all emergency medical calls to an urban, two-tiered EMS system performed over a 5 year period from 2006-2010. Heat wave days (HWD) defined as two or more consecutive days of hot weather >32.2 degrees C (90 degrees F) were compared with similar non-heat wave days (nHWD) of the previous year to also include two calendar days prior to and after the heat wave. National Weather Service (NWS) temperature data, daily EMS call volume data, and call type codes were collected and underwent descriptive analysis. RESULTS: Thirty-one HWD were identified and compared with 93 nHWD. The mean maximum temperature for HWD was 34 degrees C (93.2 degrees F) compared with 25.3 degrees C (77.6 degrees F) for nHWD (P < .001). Average daily medical emergency calls (318.4 vs 296.3, P < .001) and actual patients transported per day (247.5 vs 198.3, P < .001) were significantly higher during HWD. There was no difference in daily medical emergency call volume or EMS transports between weekdays or weekend days. No significant differences on various call types were observed between HWD and nHWD except for "heat" related calls (7.7 vs 0.5, P < .001). CONCLUSION: Emergency Medical Services call volumes were significantly increased during heat waves, however there was minimal change in the types of calls received. PMID- 24148832 TI - Burden of peripheral arterial disease in Europe and the United States: a patient survey. AB - BACKGROUND: The aim of the current study was to quantify the burden of peripheral arterial disease (PAD) with respect to health-related quality of life, work productivity and activity impairment, and healthcare resource utilization. METHODS: Data were obtained from the 2010 EU National Health and Wellness Survey (NHWS), which included participants from France, Germany, Italy, Spain, and the UK (5 EU, N = 57,805) as well as the 2010 US NHWS (N = 75,000). The NHWS is an annual, cross-sectional, self-administered Internet survey which employs a stratified random sampling frame to match the age and gender characteristics of the NHWS sample with known population statistics. Participants who self-reported a diagnosis of PAD were compared with participants who did not self-report a diagnosis of PAD on health-related quality of life (mental and physical component summary scores and health utilities from the Short Form-12v2), work productivity and activity impairment (Work Productivity and Activity Impairment questionnaire), and healthcare resource use in terms of the number of physician visits, emergency room visits, and hospitalizations in the past six months through regression modeling adjusting for demographics and health characteristics. RESULTS: A total of 743 (1.29%) and 777 (1.04%) participants self-reported a diagnosis of PAD in the 5 EU and US, respectively. After adjusting for demographics and health characteristics, patients with PAD reported worse health-related quality of life, as measured by health utilities (5 EU: 0.66 vs. 0.70; US: 0.66 vs. 0.72; all p < .05), greater overall work impairment percentage (5 EU: 38.27% vs. 27.48%; US: 23.89% vs. 14.26%) and greater healthcare resource use compared to participants without PAD (all p < .05). CONCLUSIONS: These results suggest a significant burden for patients with PAD in both the 5 EU countries and the US with respect to both quality of life and economic outcomes. Improved management of these patients may have profound effects from both patient and societal perspectives. PMID- 24148834 TI - Synthesis and evaluation of the antimalarial, anticancer, and caspase 3 activities of tetraoxane dimers. AB - The synthesis of a range of mono spiro and dispiro 1,2,4,5-tetraoxane dimers is described. Selected molecules were examined in in vitro assays to determine their antimalarial and anticancer potential. Our studies reveal that several molecules possess potent nanomolar antimalarial and single digit micromolar antiproliferative IC(50)s versus colon (HT29-AK and leukemia (HL60) cell lines. PMID- 24148833 TI - Type I pyridoxal 5'-phosphate dependent enzymatic domains embedded within multimodular nonribosomal peptide synthetase and polyketide synthase assembly lines. AB - BACKGROUND: Pyridoxal 5'-phosphate (PLP)-dependent enzymes of fold type I, the most studied structural class of the PLP-dependent enzyme superfamily, are known to exist as stand-alone homodimers or homotetramers. These enzymes have been found also embedded in multimodular and multidomain assembly lines involved in the biosynthesis of polyketides (PKS) and nonribosomal peptides (NRPS). The aim of this work is to provide a proteome-wide view of the distribution and characteristics of type I domains covalently integrated in these assemblies in prokaryotes. RESULTS: An ad-hoc Hidden Markov profile was calculated using a sequence alignment derived from a multiple structural superposition of distantly related PLP-enzymes of fold type I. The profile was utilized to scan the sequence databank and to collect the proteins containing at least one type I domain linked to a component of an assembly line in bacterial genomes. The domains adjacent to a carrier protein were further investigated. Phylogenetic analysis suggested the presence of four PLP-dependent families: Aminotran_3, Beta_elim_lyase and Pyridoxal_deC, occurring mainly within mixed NRPS/PKS clusters, and Aminotran_1_2 found mainly in PKS clusters. Sequence similarity to the reference PLP enzymes with solved structures ranged from 24 to 42% identity. Homology models were built for each representative type I domain and molecular docking simulations with putative substrates were carried out. Prediction of the protein-protein interaction sites evidenced that the surface regions of the type I domains embedded within multienzyme assemblies were different from those of the self standing enzymes; these structural features appear to be required for productive interactions with the adjacent domains in a multidomain context. CONCLUSIONS: This work provides a systematic view of the occurrence of type I domain within NRPS and PKS assembly lines and it predicts their structural characteristics using computational methods. Comparison with the corresponding stand-alone enzymes highlighted the common and different traits related to various aspects of their structure-function relationship. Therefore, the results of this work, on one hand contribute to the understanding of the functional and structural diversity of the PLP-dependent type I enzymes and, on the other, pave the way to further studies aimed at their applications in combinatorial biosynthesis. PMID- 24148835 TI - Design, synthesis and evaluation of novel 4-dimethylamine flavonoid derivatives as potential multi-functional anti-Alzheimer agents. AB - A series of 4-dimethylamine flavonoid derivatives 5a-5r were designed, synthesized and evaluated as potential multi-functional anti-Alzheimer agents. The results showed that most of the synthesized compounds exhibited high acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibitory activity at the micromolar range (IC50, 1.83-33.20 MUM for AChE and 0.82-11.45 MUM for BChE). A Lineweaver-Burk plot indicated a mixed-type inhibition for compound 5j with AChE, and molecular modeling study showed that 5j targeted both the catalytic active site (CAS) and the peripheral anionic site (PAS) of AChE. Besides, the derivatives showed potent self-induced Abeta aggregation inhibitory activity at 20 MUM with percentage from 25% to 48%. In addition, some compounds (5j-5q) showed potent oxygen radical absorbance capacity (ORAC) ranging from 1.5- to 2.6-fold of the Trolox value. These compounds should be further investigated as multi-potent agents for the treatment of Alzheimer's disease. PMID- 24148836 TI - The effect of pyridyl substituents on the thermodynamics of porphyrin binding to G-quadruplex DNA. AB - Most of the G-quadruplex interactive molecules reported to date contain extended aromatic flat ring systems and are believed to bind principally by pi-pi stacking on the end G-tetrads of the quadruplex structure. One such molecule, TMPyP4, (5,10,15,20-tetra(N-methyl-4-pyridyl)porphyrin), exhibits high affinity and some selectivity for G-quadruplex DNA over duplex DNA. Although not a realistic drug candidate, TMPyP4 is used in many nucleic acid research laboratories as a model ligand for the study of small molecule G-quadruplex interactions. Here we report on the synthesis and G-quadruplex interactions of four new cationic porphyrin ligands having only 1, 2, or 3 (N-methyl-4-pyridyl) substituents. The four new ligands are: P(5) (5-(N-methyl-4-pyridyl)porphyrin), P(5,10) (5,10-di(N-methyl-4 pyridyl)porphyrin), P(5,15) (5,15-di(N-methyl-4-pyridyl)porphyrin), and P(5,10,15) (5,10,15-tri(N-methyl-4-pyridyl)porphyrin). Even though these compounds have been previously synthesized, we report alternative synthetic routes that are more efficient and that result in higher yields. We have used ITC, CD, and ESI-MS to explore the effects of the number of N-methyl-4-pyridyl substituents and the substituent position on the porphyrin on the G-quadruplex binding energetics. The relative affinities for binding these ligands to the WT Bcl-2 promoter sequence G-quadruplex are: K(TMPyP4)~K(P)(5,15)>KP(5,10,15)>>>KP(5,10), KP(5). The saturation stoichiometry is 2:1 for both P(5,15) and P(5,10,15), while neither P(5) nor P(5,10) exhibit significant complex formation with the WT Bcl-2 promoter sequence G-quadruplex. Additionally, binding of P(5,15) appears to interact by an 'intercalation mode' while P(5,10,15) appears to interact by an 'end-stacking mode'. PMID- 24148837 TI - 17(E)-picolinylidene androstane derivatives as potential inhibitors of prostate cancer cell growth: antiproliferative activity and molecular docking studies. AB - We report a rapid and efficient synthesis of A-ring modified 17alpha-picolyl and 17(E)-picolinylidene androstane derivatives from dehydroepiandrosterone. Compounds were validated spectroscopically and structurally characterized by X ray crystallography. Virtual screening by molecular docking against clinical targets of steroidal anticancer drugs (ERalpha, AR, Aromatase and CYP17A1) suggests that 17(E)-picolinylidene, but not 17alpha-picolyl androstanes could specifically interact with CYP17A1 (17alpha-hydroxylase) with similar geometry and affinity as Abiraterone, a 17-pyridinyl androstane drug clinically used in the treatment of prostate cancer. In addition, several 17(E)-picolinylidene androstanes demonstrated selective antiproliferative activity against PC3 prostate cancer cells, which correlates with Abiraterone antiproliferative activity and predicted CYP17A1 binding affinities. Based on these preliminary results, 17(E)-picolinylidene androstane derivatives could be a promising starting point for the development of new compounds for the treatment of prostate cancer. PMID- 24148838 TI - Prognostic value of plasma chitotriosidase activity in acute stroke patients. AB - BACKGROUND AND AIMS: Chitotriosidase, a component of innate immunity, constitutes a sensitive parameter of macrophage activation and its elevated plasma activity reflects an inflammatory response. Given the deleterious effects of inflammation in brain ischemia, we aimed to assess the prognostic value of chitotriosidase activity in acute stroke patients. METHODS: The study comprised 159 acute stroke patients and 51 age-matched controls. Plasma chitotriosidase activity was serially determined by fluorometric assay. Short-term neurological outcome was determined at 48 h and functional outcome at three-months. Predictors of neurological and functional outcome were determined via multivariate analysis, and the additional predictive value of chitotriosidase was tested with the Integrated Discrimination Index and the Net Reclassification Improvement. RESULTS: Stroke patients showed increased levels of baseline chitotriosidase activity compared to controls [114.2 (74.65-182.95) nmol/ml/h vs. 54.4 (32.7 76.4); P < 0.0001]. Chitotriosidase activity (<118.75) was found to be an independent predictor of neurological improvement at 48 h (odds ratio: 3.25; 95% confidence interval: 1.54-6.85; P=0.002), and the addition of plasma chitotriosidase activity showed a better prediction of improvement at 48 h (Integrated Discrimination Index=5.7%, Net Reclassification Improvement=11.6%, P<0.05) over the predictive model constituted only with clinical information. Although patients disabled at three-months showed higher baseline chitotriosidase levels, it was not an independent predictor of long-term disability. CONCLUSIONS: Baseline chitotriosidase activity in acute stroke patients treated with tissue plasminogen activator (tPA) may constitute a prognostic predictor of short-term outcome, adding a moderate additional predictive value. Our results underline the deleterious role of inflammation in acute stroke patients. PMID- 24148839 TI - [IMSIII, SYNTHESIS, and MR-RESCUE studies: the end of endovascular treatment for stroke?]. AB - Last March, in a single issue New England Journal of Medicine published 3 studies that evaluated the efficacy of endovascular treatment for ischemic stroke, leading to a heated controversy between neurologists and interventional neuroradiologists. The negative results have resulted in numerous reviews pointing out serious methodological defects. In this article, we analyze the outcomes of thrombolytic treatment for stroke and discuss the strengths and weaknesses of the three above-mentioned studies. Despite the negative results, these studies can point the way for new trials that will justify this treatment modality that is backed up by scientific evidence. PMID- 24148840 TI - [Atypical Virchow-Robin spaces with secondary obstructive hydrocephalus]. PMID- 24148841 TI - [Primary echinococcosis of the chest wall]. PMID- 24148842 TI - Isolation, cytotoxicity evaluation and HPLC-quantification of the chemical constituents from Artemisia amygdalina Decne. AB - The hexane extracts of both shoot and root parts of Artemisia amygdalina Decne displayed potent cytotoxic effects. Phytochemical analysis of these active extracts led to the isolation of six cytotoxic constituents, viz., Ergostadien 3beta-ol (1), ludartin (2), 5-hydroxy-6,7,3',4'-tetramethoxyflavone (3) (from shoot) and trans-matricaria ester (4), diacetylenic spiroenol ether (5) and cis matricaria ester (6) (from root) for the first time from this plant. The constituents were identified using spectral techniques in the light of literature. Sulphorhodamine B cytotoxicity screening of the isolated constituents was carried out against four human cancer cell lines including Lung (A-549), Leukaemia (THP-1), Prostate (PC-3) and Colon (HCT-116) cell lines. Ludartin (2) exhibited the highest cytotoxicity with IC50 values of 7.4MUM, 3.1MUM, 7.5MUM and 6.9MUM against Lung (A-549), Leukaemia (THP-1), Prostate (PC-3), Colon (HCT-116) cancer cell lines respectively. To test against in vitro skin cancer models [human dermal fibroblasts (CRL-1635)] all the isolates were further subjected to 3-(4,5-Dimethylthiazol-yl)-diphenyl tetrazolium bromide (MTT) cytotoxicity screening. Ludartin (2) being highly cytotoxic was again evaluated against mouse melanoma (B16F10) and human epidermoid carcinoma (A-431) cells by MTT assay displaying IC50 values of 6.6MUM and 19.0MUM respectively. Finally a simple and reliable HPLC method was developed (RP-HPLC-DAD) and validated for the simultaneous quantification of these cytotoxic constituents in A. amygdalina Decne. Excellent specificity and high linearity for all the standard calibration curves having regression coefficients of the respective linear equations in the range of 0.9962-0.9999 was observed. Relative recovery rates varied between 98.37+/-0.90 and 105.15+/-1.74 with relative standard deviation less than 4%. Based on our results, the developed method features good quantification parameters, accuracy, precision and can serve as effective quality control method for standardisation of A. amygdalina Decne. PMID- 24148843 TI - Electrokinetics of non-Newtonian fluids: a review. AB - This work presents a comprehensive review of electrokinetics pertaining to non Newtonian fluids. The topic covers a broad range of non-Newtonian effects in electrokinetics, including electroosmosis of non-Newtonian fluids, electrophoresis of particles in non-Newtonian fluids, streaming potential effect of non-Newtonian fluids and other related non-Newtonian effects in electrokinetics. Generally, the coupling between non-Newtonian hydrodynamics and electrostatics not only complicates the electrokinetics but also causes the fluid/particle velocity to be nonlinearly dependent on the strength of external electric field and/or the zeta potential. Shear-thinning nature of liquids tends to enhance electrokinetic phenomena, while shear-thickening nature of liquids leads to the reduction of electrokinetic effects. In addition, directions for the future studies are suggested and several theoretical issues in non-Newtonian electrokinetics are highlighted. PMID- 24148844 TI - Personalized psychiatry: many questions, fewer answers. PMID- 24148845 TI - Atypical vertical sound localization and sound-onset sensitivity in people with autism spectrum disorders. AB - BACKGROUND: Autism spectrum disorders (ASDs) are associated with auditory hyper- or hyposensitivity; atypicalities in central auditory processes, such as speech processing and selective auditory attention; and neural connectivity deficits. We sought to investigate whether the low-level integrative processes underlying sound localization and spatial discrimination are affected in ASDs. METHODS: We performed 3 behavioural experiments to probe different connecting neural pathways: 1) horizontal and vertical localization of auditory stimuli in a noisy background, 2) vertical localization of repetitive frequency sweeps and 3) discrimination of horizontally separated sound stimuli with a short onset difference (precedence effect). RESULTS: Ten adult participants with ASDs and 10 healthy control listeners participated in experiments 1 and 3; sample sizes for experiment 2 were 18 adults with ASDs and 19 controls. Horizontal localization was unaffected, but vertical localization performance was significantly worse in participants with ASDs. The temporal window for the precedence effect was shorter in participants with ASDs than in controls. LIMITATIONS: The study was performed with adult participants and hence does not provide insight into the developmental aspects of auditory processing in individuals with ASDs. CONCLUSION: Changes in low-level auditory processing could underlie degraded performance in vertical localization, which would be in agreement with recently reported changes in the neuroanatomy of the auditory brainstem in individuals with ASDs. The results are further discussed in the context of theories about abnormal brain connectivity in individuals with ASDs. PMID- 24148846 TI - Functional connectivity between the amygdala and prefrontal cortex in medication naive individuals with major depressive disorder. AB - BACKGROUND: Convergent evidence suggests dysfunction within the prefrontal cortex (PFC) and amygdala, important components of a neural system that subserves emotional processing, in individuals with major depressive disorder (MDD). Abnormalities in this system in the left hemisphere and during processing of negative emotional stimuli are especially implicated. In this study, we used functional magnetic resonance imaging (fMRI) to investigate amygdala-PFC functional connectivity during emotional face processing in medication-naive individuals with MDD. METHODS: Individuals with MDD and healthy controls underwent fMRI scanning while processing 3 types of emotional face stimuli. We compared the strength of functional connectivity from the amygdala between the MDD and control groups. RESULTS: Our study included 28 individuals with MDD and 30 controls. Decreased amygdala-left rostral PFC (rPFC) functional connectivity was observed in the MDD group compared with controls for the fear condition (p < 0.05, corrected). No significant differences were found in amygdala connectivity to any cerebral regions between the MDD and control groups for the happy or neutral conditions. LIMITATIONS: All participants with MDD were experiencing acute episodes, therefore the findings could not be generalized to the entire MDD population. CONCLUSION: Medication-naive individuals with MDD showed decreased amygdala-left rPFC functional connectivity in response to negative emotional stimuli, suggesting that abnormalities in amygdala-left rPFC neural circuitry responses to negative emotional stimuli might play an important role in the pathophysiology of MDD. PMID- 24148847 TI - Elevated incidence of suicide in people living at altitude, smokers and patients with chronic obstructive pulmonary disease and asthma: possible role of hypoxia causing decreased serotonin synthesis. AB - Recent research indicates that suicide rates are elevated in those living at higher altitudes in both the United States and South Korea. A possible mechanism that was proposed is metabolic stress associated with hypoxia. This commentary discusses these results, and also the association between elevated suicide rates and other conditions associated with hypoxia (smoking, chronic obstructive pulmonary disease and asthma). Tryptophan hydroxylase may not normally be saturated with oxygen, so mild hypoxia would decrease serotonin synthesis. Low brain serotonin is known to be associated with suicide. Thus, the commentary proposes and discusses the hypothesis that decreased brain serotonin synthesis associated with hypoxia is a mechanism that may contribute to suicide in conditions causing hypoxia. Finally the commentary proposes various studies that could test aspects of this hypothesis. PMID- 24148848 TI - Mixed depression in the postpartum period: diagnostic and treatment issues. PMID- 24148849 TI - Translational proteomics special issue. PMID- 24148850 TI - Serological autoantibody profiling of type 1 diabetes by protein arrays. AB - The need for biomarkers that illuminate the pathophysiology of type 1 diabetes (T1D), enhance early diagnosis and provide additional avenues for therapeutic intervention is well recognized in the scientific community. We conducted a proteome-scale, two-stage serological AAb screening followed by an independent validation study. In the first stage, the immunoreactivity was compared between T1D cases and healthy controls against ~6000 human proteins using the nucleic acid programmable protein array (NAPPA). Genes identified with higher signal intensities in patients were challenged with a larger sample set during the second stage. Statistical analysis revealed 26 novel autoantigens and a known T1D associated autoantigen. During validation, we verified the presence of AAbs to dual specificity tyrosine-phosphorylation-regulated kinase 2 (DYRK2) using the Luciferase ImmunoPrecipitation System (LIPS) assay (36% sensitivity, 98% specificity). The AUC for a combination of DYRK2A and the classical T1D AAb IA-2A was 0.90 compared to 0.72 for DYRK2A and 0.64 for IA-2A alone. This is the first systematic screening for seroreactivity against a large number of human proteins in T1D patients. We demonstrated the application of protein microarrays to identify novel autoantigens in T1D, expanded the current T1D "autoantigenome" and help fulfill the goal of searching for novel biomarker candidates for T1D. BIOLOGICAL SIGNIFICANCE: Protein microarrays provide a high-throughput platform that enables the profiling of serum antibodies to a large number of protein antigens. The value of AAb biomarkers in diagnosis, prognosis and treatment is well recognized in autoimmune diseases including T1D. We performed a systematic screening for new T1D-associated autoantigens by adapting the innovative protein array platform NAPPA. We believe that the discovery in this study will add information on candidate autoantigens that could potentially improve the diagnosis and help uncover the pathophysiology of T1D. The successful use of NAPPA for T1D AAb profiling will open the window for larger studies including more human antigen genes and other autoimmune diseases. PMID- 24148851 TI - Development and feasibility testing of decision support for patients who are candidates for a prophylactic implantable defibrillator: a study protocol for a pilot randomized controlled trial. AB - BACKGROUND: Patients, identified to be at risk for but who have never experienced a potentially lethal cardiac arrhythmia, have the option of receiving an implantable cardioverter defibrillator (ICD) as prophylaxis against sudden cardiac death - a primary prevention indication. In Canada, there is no clear framework to support patients' decision-making for these devices. Decision support, using a decision aid, could moderate treatment-related uncertainty and prepare patients to make well-informed decisions. Patient decision aids provide information on treatment options, risks, and benefits, to help patients clarify their values for outcomes of treatment options. The objectives of this research are: 1) develop a decision aid, 2) evaluate the decision aid, and 3) determine the feasibility of conducting a trial. METHODS/DESIGN: A development panel comprised of the core investigative team, health service researchers, decision science experts, cardiovascular healthcare practitioners, and ICD patient representatives will collaborate to provide input on the content and format of the aid. To generate probabilities to include in the aid, we will synthesize primary prevention ICD evidence. To obtain anonymous input about the facts and content, we will employ a modified Delphi process. To evaluate the draft decision aid will invite ICD patients and their families (n = 30) to rate its acceptability. After we evaluate the aid, to determine the feasibility, we will conduct a feasibility pilot randomized controlled trial (RCT) in new ICD candidates (n = 80). Participants will be randomized to receive a decision aid prior to specialist consultation versus usual care. Results from the pilot RCT will determine the feasibility of research processes; inform sample size calculation, measure decision quality (knowledge, values, decision conflict) and the influence of health related quality of life on decision-making. DISCUSSION: Our study seeks to develop a decision aid, for patients offered their first ICD for prophylaxis against sudden cardiac death. This paper outlines the background and methods of a pilot randomized trial which will inform a larger multicenter trial. Ultimately, decision support prior to specialist consultation could enhance the decision-making process between patients, physicians, and families, associated with life-prolonging medical devices like the ICD. TRIAL REGISTRATION: ClinicalTrials.gov: NCT01876173. PMID- 24148853 TI - Anti-anxiety self-medication induced by incentive loss in rats. AB - Ethanol can be used to ameliorate negative emotion in anxiety-inducing situations. Two experiments tested whether rats would increase preference for ethanol immediately after anxiogenic sessions of appetitive extinction. It was predicted that preference for ethanol would be greater in inbred Roman low avoidance rats (RLA-I) than in inbred Roman high-avoidance rats (RHA-I), given previous research demonstrating that the former strain exhibits greater sensitivity to incentive loss. Experiment 1 used a consummatory extinction task (22-to-0% sucrose downshift), whereas Experiment 2 used an instrumental extinction task (12-to-0 pellet downshift). In both experiments, postsession ethanol consumption was higher in RLA-I rats than in RHA-I rats. No strain differences in ethanol preference were found after acquisition sessions or in groups given postsession access to water. Because ethanol is an anti-anxiety drug, the present results suggest that rats are capable of changing their consummatory behavior to correct for an aversive emotional state induced by incentive loss. PMID- 24148854 TI - LRRK2 mutations cause mitochondrial DNA damage in iPSC-derived neural cells from Parkinson's disease patients: reversal by gene correction. AB - Parkinson's disease associated mutations in leucine rich repeat kinase 2 (LRRK2) impair mitochondrial function and increase the vulnerability of induced pluripotent stem cell (iPSC)-derived neural cells from patients to oxidative stress. Since mitochondrial DNA (mtDNA) damage can compromise mitochondrial function, we examined whether LRRK2 mutations can induce damage to the mitochondrial genome. We found greater levels of mtDNA damage in iPSC-derived neural cells from patients carrying homozygous or heterozygous LRRK2 G2019S mutations, or at-risk individuals carrying the heterozygous LRRK2 R1441C mutation, than in cells from unrelated healthy subjects who do not carry LRRK2 mutations. After zinc finger nuclease-mediated repair of the LRRK2 G2019S mutation in iPSCs, mtDNA damage was no longer detected in differentiated neuroprogenitor and neural cells. Our results unambiguously link LRRK2 mutations to mtDNA damage and validate a new cellular phenotype that can be used for examining pathogenic mechanisms and screening therapeutic strategies. PMID- 24148855 TI - Abnormal structure-specific peptide transmission and processing in a primate model of Parkinson's disease and l-DOPA-induced dyskinesia. AB - A role for enhanced peptidergic transmission, either opioidergic or not, has been proposed for the generation of l-3,4-dihydroxyphenylalanine (l-DOPA)-induced dyskinesia (LID) on the basis of in situ hybridization studies showing that striatal peptidergic precursor expression consistently correlates with LID severity. Few studies, however, have focused on the actual peptides derived from these precursors. We used mass-spectrometry to study peptide profiles in the putamen and globus pallidus (internalis and externalis) collected from 1-methyl-4 phenyl-1,2,4,6-tetrahydropyridine treated macaque monkeys, acutely or chronically treated with l-DOPA. We identified that parkinsonian and dyskinetic states are associated with an abnormal production of proenkephalin-, prodynorphin- and protachykinin-1-derived peptides in both segments of the globus pallidus. Moreover, we report that peptidergic processing is dopamine-state dependent and highly structure-specific, possibly explaining the failure of previous clinical trials attempting to rectify abnormal peptidergic transmission. PMID- 24148857 TI - Mesenchymal stem cells improve locomotor recovery in traumatic spinal cord injury: systematic review with meta-analyses of rat models. AB - Traumatic spinal cord injury (SCI) is a devastating event with huge personal and societal costs. A limited number of treatments exist to ameliorate the progressive secondary damage that rapidly follows the primary mechanical impact. Mesenchymal stem or stromal cells (MSCs) have anti-inflammatory and neuroprotective effects and may thus reduce secondary damage after administration. We performed a systematic review with quantitative syntheses to assess the evidence of MSCs versus controls for locomotor recovery in rat models of traumatic SCI, and identified 83 eligible controlled studies comprising a total of 1,568 rats. Between-study heterogeneity was large. Fifty-three studies (64%) were reported as randomised, but only four reported adequate methodologies for randomisation. Forty-eight studies (58%) reported the use of a blinded outcome assessment. A random-effects meta-analysis yielded a difference in behavioural Basso-Beattie-Bresnahan (BBB) locomotor score means of 3.9 (95% confidence interval [CI] 3.2 to 4.7; P<0.001) in favour of MSCs. Trial sequential analysis confirmed the findings of the meta-analyses with the upper monitoring boundary for benefit being crossed by the cumulative Z-curve before reaching the diversity-adjusted required information size. Only time from intervention to last follow-up remained statistically significant after adjustment using multivariate random-effects meta-regression modelling. Lack of other demonstrable explanatory variables could be due to insufficient meta-analytic study power. MSCs would seem to demonstrate a substantial beneficial effect on locomotor recovery in a widely used animal model of traumatic SCI. However, the animal results should be interpreted with caution concerning the internal and external validity of the studies in relation to the design of future clinical trials. PMID- 24148856 TI - Seizure-induced reduction in PIP3 levels contributes to seizure-activity and is rescued by valproic acid. AB - Phosphatidylinositol (3-5) trisphosphate (PIP3) is a central regulator of diverse neuronal functions that are critical for seizure progression, however its role in seizures is unclear. We have recently hypothesised that valproic acid (VPA), one of the most commonly used drugs for the treatment of epilepsy, may target PIP3 signalling as a therapeutic mode of action. Here, we show that seizure induction using kainic acid in a rat in vivo epilepsy model resulted in a decrease in hippocampal PIP3 levels and reduced protein kinase B (PKB/AKT) phosphorylation, measured using ELISA mass assays and Western blot analysis, and both changes were restored following VPA treatment. These finding were reproduced in cultured rat hippocampal primary neurons and entorhinal cortex-hippocampal slices during exposure to the GABA(A) receptor antagonist pentylenetetrazol (PTZ), which is widely used to generate seizures and seizure-like (paroxysmal) activity. Moreover, VPA's effect on paroxysmal activity in the PTZ slice model is blocked by phosphatidylinositol 3-kinase (PI3K) inhibition or PIP2 sequestration by neomycin, indicating that VPA's efficacy is dependent upon PIP3 signalling. PIP3 depletion following PTZ treatment may also provide a positive feedback loop, since enhancing PIP3 depletion increases, and conversely, reducing PIP3 dephosphorylation reduces paroxysmal activity and this effect is dependent upon AMPA receptor activation. Our results therefore indicate that PIP3 depletion occurs with seizure activity, and that VPA functions to reverse these effects, providing a novel mechanism for VPA in epilepsy treatment. PMID- 24148858 TI - Biodiesel synthesis by TiO2-ZnO mixed oxide nanocatalyst catalyzed palm oil transesterification process. AB - Biodiesel is a promising alternating environmentally benign fuel to mineral diesel. For the development of easier transesterification process, stable and active heterogeneous mixed metal oxide of TiO2-ZnO and ZnO nanocatalysts were synthesized and exploited for the palm oil transesterification process. The synthesized catalysts were characterized by XRD, FT-IR, and FE-SEM studies for their structural and morphological characteristics. It was found that TiO2-ZnO nanocatalyst exhibits good catalytic activity and the catalytic performance was greatly depends on (i) catalyst concentration (ii) methanol to oil molar ratio (iii) reaction temperature and (iv) reaction time. A highest 98% of conversion was obtained at the optimum reaction parameters with 200 mg of catalyst loading and the biodiesel was analyzed by TLC and (1)H NMR techniques. The TiO2-ZnO nanocatalyst shows good catalytic performance over the ZnO catalyst, which could be a potential candidate for the large-scale biodiesel production from palm oil at the reduced temperature and time. PMID- 24148859 TI - A systematic review of cluster randomised trials in residential facilities for older people suggests how to improve quality. AB - BACKGROUND: Previous reviews of cluster randomised trials have been critical of the quality of the trials reviewed, but none has explored determinants of the quality of these trials in a specific field over an extended period of time. Recent work suggests that correct conduct and reporting of these trials may require more than published guidelines. In this review, our aim was to assess the quality of cluster randomised trials conducted in residential facilities for older people, and to determine whether (1) statistician involvement in the trial and (2) strength of journal endorsement of the Consolidated Standards of Reporting Trials (CONSORT) statement influence quality. METHODS: We systematically identified trials randomising residential facilities for older people, or parts thereof, without language restrictions, up to the end of 2010, using National Library of Medicine (Medline) via PubMed and hand-searching. We based quality assessment criteria largely on the extended CONSORT statement for cluster randomised trials. We assessed statistician involvement based on statistician co-authorship, and strength of journal endorsement of the CONSORT statement from journal websites. RESULTS: 73 trials met our inclusion criteria. Of these, 20 (27%) reported accounting for clustering in sample size calculations and 54 (74%) in the analyses. In 29 trials (40%), methods used to identify/recruit participants were judged by us to have potentially caused bias or reporting was unclear to reach a conclusion. Some elements of quality improved over time but this appeared not to be related to the publication of the extended CONSORT statement for these trials. Trials with statistician/epidemiologist co authors were more likely to account for clustering in sample size calculations (unadjusted odds ratio 5.4, 95% confidence interval 1.1 to 26.0) and analyses (unadjusted OR 3.2, 1.2 to 8.5). Journal endorsement of the CONSORT statement was not associated with trial quality. CONCLUSIONS: Despite international attempts to improve methods in cluster randomised trials, important quality limitations remain amongst these trials in residential facilities. Statistician involvement on trial teams may be more effective in promoting quality than further journal endorsement of the CONSORT statement. Funding bodies and journals should promote statistician involvement and co-authorship in addition to adherence to CONSORT guidelines. PMID- 24148860 TI - Long-term adherence to nasal continuous positive airway pressure therapy by hypertensive patients with preexisting sleep apnea. AB - BACKGROUND AND OBJECTIVE: Although positive screening for and treatment of obstructive sleep apnea (OSA) have been recommended for patients with cardiovascular problems, patient adherence to nasal continuous positive airway pressure (CPAP) therapy primarily for a cardiovascular concern is unknown. Therefore, this study aimed to determine the adherence to CPAP therapy by hypertensive patients with OSA after a screening test performed regardless of OSA related symptoms. SUBJECTS AND METHODS: CPAP therapy was administered to 194 of the 1365 hypertensive patients who underwent the screening. The monthly dropout from CPAP therapy and the adequate use level (4h every night, 70% days in a month) were assessed using the Kaplan-Meier analysis over a 3-year follow-up period. RESULTS: Of the patients, 106 (55%) refused or abandoned the therapy by the end of the follow-up period (adherence, 45%). An adequate use level was maintained by 76 patients (39%). Most of the patients' background characteristics, including age, sex, Epworth sleepiness scale scores, and parameters obtained on polysomnography, were not related to adherence or adequate use level. The good-compliance level on the first visit after CPAP therapy introduction was most strongly related to adherence (95% CI, 0.05-0.32; p<0.001) and adequate use level (95% CI, 0.06-0.33; p<0.05). Fourth quartile of apnea hypopnea index value (greater than 67/h) was also related to adherence (95% CI, 0.21-0.98; p<0.02) and adequate use level (95% CI, 0.19-0.88; p<0.05). CONCLUSIONS: The adherence and use level in this population may not be satisfactory but are comparable with those in previous sleep center reports treating symptomatic OSA patients. Thus, the present results would encourage hypertensive patients to undergo positive screening for OSA, regardless of OSA related symptoms. However, an outcomes study with the same cohort is needed. PMID- 24148861 TI - Comparison of immediate results and mid-term follow-up of surgical and percutaneous closure of ruptured sinus of Valsalva aneurysm. AB - BACKGROUND: The past decade has witnessed considerable improvement in implantation techniques for percutaneous closure of ruptured sinus of Valsalva aneurysm. This study was undertaken to compare the immediate results and mid-term follow-up of traditional surgery and percutaneous closure of ruptured sinus of Valsalva aneurysm in China. METHODS: Between January 1993 and January 2013, a total of 35 patients with ruptured sinus of Valsalva aneurysm were enrolled for attempted closure in our institution. Twenty patients (57.1%) underwent surgical repair and the other 15 patients (42.9%) underwent percutaneous closure. RESULTS: Nineteen patients (95.0%) in the surgical group had complete closure and 14 patients (93.3%) in the percutaneous closure group were treated successfully (p=0.681). Twelve patients with ruptured sinus of Valsalva aneurysm combined with subarterial ventricular septal defect (VSD) underwent surgical repair concomitantly. Two patients in the percutaneous closure group were treated for ruptured sinus of Valsalva aneurysm and perimembranous VSD using occluders concomitantly. One case of severe hemolysis developed 8h after the procedure in the percutaneous closure group. One death and one case of patch leak occurred in the surgical group during hospitalization. The time of hospital stay in the percutaneous closure group was shorter than that in the surgical group (p=0.004). The total medical cost of isolated ruptured sinus of Valsalva aneurysm in the percutaneous closure group was lower compared with that in the surgical group (p=0.046). During a median follow-up of 15 months (2-240 months), there were no deaths, infective endocarditis, device embolization, or malposition. CONCLUSIONS: Percutaneous closure is an attractive alternative to surgery in selected patients with ruptured sinus of Valsalva aneurysm for the better clinical advantages and economic benefits. PMID- 24148862 TI - Intracranial infection caused by spreading through the fossa naviclaris magna - a case report and review of the literature. AB - Fossa navicularis magna is a congenital anomaly representing persistent dehiscence of the basiocciput. This tract from the nasopharynx to the brain is common and carries a potential risk for infection. Nevertheless reports on such dissemination are very rare. We present a child with brain infection via a fossa navicularis magna, the first description to our knowledge, and review the literature on this anomaly. PMID- 24148863 TI - Quantitative assessment of pulmonary aspiration: A novel porcine model. AB - OBJECTIVES: Pulmonary aspiration is a common cause of ventilator-associated pneumonia in the intensive care setting. Current bench and animal models of aspiration are based on the qualitative assessments. The purpose of the present study was to develop a porcine model for the real-time quantitative assessment of aspiration. METHODS: Five sus scrofa piglets were anaesthetized and underwent placement of a pH probe through the endotracheal tube so that the distal tip of the probe resided at the carina. The pH probe was sutured to the posterior tracheal wall via an open approach and the position of the probe tip was verified by flexible endoscopy. 10 mL of acidic solution (pH = 2.7) was delivered through a catheter attached to the outside of the endotracheal tube so that the solution remained between the endotracheal tube and trachea proximal to the inflated endotracheal tube cuff. The pH probe was connected to a pH metre, a multifunctional data acquisition device with an analogue output signal measuring the voltage generated, and a computer for analysis. Leakage of fluid past the endotracheal tube cuff (aspiration) was therefore continuously assessed quantitatively by detecting voltage changes over a period of time. RESULTS: The mean voltage of the tracheal mucosa at the beginning of the experiment (maximum voltage) was 916.6 mV +/- 24.5 mV (range 891.0-945.7 mV). There was a slight drop in voltage at the end of the 2 h period to 840.8 +/- 22.6 mV (range = 812.3-867.3 mV). After deflation of the endotracheal tube cuff, the mean voltage dropped to 497.3 mV +/- 24.8 mV (range 435.7-567.1 mV) with a mean drop in voltage of 419.3 mV +/- 32.6 mV (range 368.9-455.3 mV). CONCLUSIONS: This porcine model allows for the continuous quantitative assessment of aspiration over time. Such a model may be of value for the evaluation of techniques for reducing aspiration. PMID- 24148864 TI - Production of infant scale evaluation (PRISE) in Italian normal hearing children: a validation study. AB - OBJECTIVES: Parental questionnaires are important tools in the evaluation of auditory and language skills of very young children affected by sensorineural hearing loss. One of these instruments is the Production on Infant Scale Evaluation (PRISE). The purposes of this study were to adapt and validate the PRISE on Italian children with normal hearing; and to obtain normative data. METHODS: A back translation technique was used to adapt the Italian version of PRISE. The PRISE was submitted to parents of 234 normal children aged between 3 and 18 months of life. All of them passed local universal newborn hearing screenings and they presented no audiological risk factors. RESULTS: The PRISE internal reliability (Cronbach's alpha) was 0.87. Split-half reliability indexes were lambda(4) = 0.89 and lambda(6) = 0.89. Corrected item-total correlation coefficients were significant for all items. The correlation of PRISE with a modified Infant Toddler Meaningful Auditory Integration Scale (IT-MAIS), collected for convergent validity measurement purposes, was good (r = 0.743). A positive correlation of PRISE scores with age was found, reflecting on the age dependence of pre-verbal skills. CONCLUSION: These findings demonstrate high reliability and convergent validity of the Italian PRISE version. This questionnaire constitutes a robust tool for assessing early language development in infants and toddlers with normal hearing. It seems particularly sensitive to the normal language development in the first years of life, which can be very useful for early rehabilitation of hearing loss. PMID- 24148865 TI - Management of acquired cholesteatoma in children: a 15 year review in ENT service of CHNU de FANN Dakar. AB - OBJECTIVES: To analyze the epidemiology, diagnosis, management and the prognosis of cholesteatoma of the middle ear in children. METHODS: This was a retrospective study of 15 years (from 01 January 1995 to 31 December 2009) for patients aged 0 15 years admitted in ENT ward of FANN hospital for chronic otitis media complicated with cholesteatoma The parameters studied were epidemiology, clinical presentation, disease progression and management. RESULTS: Sixty-six participants were included. We noted a slight male predominance with a sex ratio of 1.44. The average mean age was 10 years. Most patients presented with signs of complications (69.7%) and mastoiditis was the most common complication (63.6%). The otorrhea was noted in almost all patients: n = 64 (97%) and deafness in 49 patients (74, 2%). There was a slight predominance of cholesteatoma on the right side (51.5%). Schuller's view of the mastoid cells was done in 21.2% of patients (n = 14) and showed sclerotic mastoid air cells for all them. Eighty-two percent (82%) of patients presented with conductive hearing loss. A radical mastoidectomy was performed in 66.7% and modified radical mastoidectomy in 33.3% of cases. Mean follow-up was 6 months. Recurrence of cholesteatoma was noted in 13% of cases. CONCLUSIONS: ENT ward of Hospital Fann is one of the two centers in Senegal where cholesteatoma of the middle ear are treated. This low number of cholesteatoma in children in a developing country is in relation to the fact that patients only present when complications develop: 70% of cases. The reason for this in our setting include insufficient human and manpower resources necessary for prompt management of the disease and also lack of awareness among the populace. In these settings we advocate canal wall down mastoidectomy (radical or modified radical) as the treatment of choice. PMID- 24148866 TI - Gleaning evolutionary insights from the genome sequence of a probiotic yeast Saccharomyces boulardii. AB - BACKGROUND: The yeast Saccharomyces boulardii is used worldwide as a probiotic to alleviate the effects of several gastrointestinal diseases and control antibiotics-associated diarrhea. While many studies report the probiotic effects of S. boulardii, no genome information for this yeast is currently available in the public domain. RESULTS: We report the 11.4 Mbp draft genome of this probiotic yeast. The draft genome was obtained by assembling Roche 454 FLX + shotgun data into 194 contigs with an N50 of 251 Kbp. We compare our draft genome with all other Saccharomyces cerevisiae genomes. CONCLUSIONS: Our analysis confirms the close similarity of S. boulardii to S. cerevisiae strains and provides a framework to understand the probiotic effects of this yeast, which exhibits unique physiological and metabolic properties. PMID- 24148867 TI - Vacuum Seed Sowing Manifold: a novel device for high-throughput sowing of Arabidopsis seeds. AB - The small size of Arabidopsis provides both opportunities and difficulties for laboratory research. Large numbers of plants can be grown in a relatively small area making it easy to observe and investigate interesting phenotypes. Conversely, their small size can also make it difficult to obtain large quantities of tissue for investigation using modern molecular techniques. Sowing large numbers of their seed can overcome this; however, their small seed size makes this difficult. Here we present the Vacuum Seed Sowing Manifold (VSSM), a simple device that can be printed using a 3D printer and provides a new high throughput method to sow large numbers of seeds at a range of densities. PMID- 24148868 TI - Screening alternative therapies to control Nosemosis type C in honey bee (Apis mellifera iberiensis) colonies. AB - Nosemosis type C caused by the microsporidium Nosema ceranae is one of the most widespread of the adult honey bee diseases, and due to its detrimental effects on both strength and productivity of honey bee colonies, an appropriate control of this disease is advisable. Fumagillin is the only veterinary medicament recommended by the World Organization for Animal Health (OIE) to suppress infections by Nosema, but the use of this antibiotic is prohibited in the European Union and few alternatives are available at present to control the disease. In the present study three therapeutic agents (Nosestat(r), Phenyl salicylate and Vitafeed Gold(r)) have been tested to control N. ceranae infection in honey bee colonies, and have been compared to the use of fumagillin. None of the products tested was effective against Nosema under our experimental conditions. Low consumption of the different doses of treatments may have had a strong influence on the results obtained, highlighting the importance of this issue and emphasizing that this should be evaluated in studies to test therapeutic treatments of honey bee colonies. PMID- 24148869 TI - Natural killer cell cytotoxicity, cytokine and neuroendocrine responses to opioid receptor blockade during prolonged restraint in pigs. AB - This study evaluated porcine natural killer cell cytotoxicity (NKCC), plasma cytokines including interleukin (IL) 1beta, IL-6, IL-10, IL-12 and tumor necrosis factor-alpha and plasma stress-related hormones including prolactin (PRL), growth hormone (GH), beta-endorphin (BEND), ACTH and cortisol (COR) during a 4h restraint and recovery phase after saline or naloxone (1mg/kg BW) administration. The restraint preceded with saline altered NKCC and IL-12 concentration (an early from 15 to 60 min increase followed by a decrease) and increased other measured cytokines and hormones concentrations. Naloxone pretreatment blocked the suppressive effects of the restraint on NKCC and IL-12 and altered IL-10, IL-6, TNF-alpha, PRL and ACTH concentrations. Furthermore, in naloxone-injected pigs, a positive correlation was found between NKCC and all measured cytokines (with the exception of IL-6) and BEND, ACTH and COR. Results suggest that naloxone sensitive opioid pathways could influence the mechanisms underlying the immune system (including NKCC) response during stress. PMID- 24148870 TI - Comparison of the influence of two different constant-rate infusions (dexmedetomidine versus morphine) on anaesthetic requirements, cardiopulmonary function and recovery quality in isoflurane anaesthetized horses. AB - Twenty adult healthy horses undergoing elective surgery were involved in this prospective, blinded, clinical study. Horses were randomly allocated to receive a constant rate infusion (CRI) of morphine or dexmedetomidine. After induction, anaesthesia was maintained with isoflurane in oxygen/air and mechanical ventilation applied. The end-tidal isoflurane concentration (FEISO) was initially set at 0.9% and adjusted by the anaesthetist, to maintain a light surgical plane of anaesthesia, according to an objective flow-chart. The cardiopulmonary function was only minimally different between groups and maintained within clinically normal ranges. Less ketamine was required, FEISO was lower after 1h and fewer alterations in the anaesthetic depth were needed in horses receiving dexmedetomidine, with better recoveries. One horse receiving morphine developed post-operative colic and pulmonary oedema and two showed box-walking behaviour. This study showed that a dexmedetomidine CRI produced a more stable anaesthetic depth, reduced isoflurane requirements and better recoveries, without post operative complications compared with a morphine CRI. PMID- 24148871 TI - Classical swine fever virus infection modulates serum levels of INF-alpha, IL-8 and TNF-alpha in 6-month-old pigs. AB - Several studies have highlighted the important role of cytokines in disease development of classical swine fever virus (CSFV) infection. In the present study, we examined the kinetics of 7 porcine cytokines in serum from pigs infected with 3 different CSFV strains. Based on the clinical picture in 6-month old Danish pigs, the strains used for inoculation were classified as being of low (Bergen), low to moderate (Eystrup) and moderate to high (Lithuania) virulence. The cytokines interferon-alpha (INF-alpha), interleukin-8 (IL-8) and tumor necrosis factor-alpha (TNF-alpha) showed increased levels after CSFV infection with more or less comparable course in the 3 groups. However, the cytokine level peaked with a 2-3 days delay in pigs infected with the low virulent strain compared to those infected with a moderately or highly virulent strain. These findings may indicate that INF-alpha, IL-8 and TNF-alpha are involved in the immune response during CSFV infection with strains of different virulence. PMID- 24148872 TI - Do-not-resuscitate (DNR) orders in patients with intracerebral hemorrhage. AB - BACKGROUND AND PURPOSE: Do-not-resuscitate orders may be associated with poor outcome in patients with intracerebral hemorrhage because of less active management. AIMS: We sought to characterize the practice of issuing do-not resuscitate orders in intracerebral hemorrhage. We also aimed to identify possible differences in care according to do-not-resuscitate status. METHODS: We conducted a retrospective study of all consecutive intracerebral hemorrhage patients admitted to the Meilahti Hospital of the Helsinki University Central Hospital between January 2005 and March 2010. Data obtained from medical records allowed comparison of characteristics of patients and care of do-not-resuscitate and non-do-not-resuscitate patients as well as patients with early (within 24 h) and late (>24 h) do-not-resuscitate decisions. Logistic regression was used to identify factors independently associated with do-not-resuscitate decisions. RESULTS: Of our 1013 patients, a do-not-resuscitate order was issued in 368 (35%), of which 262 (73%) occurred within 24 h from admission. Advanced age (odds ratio 1.06 per year; 95% confidence interval 1.04-1.08), more severe stroke (1.09 per National Institutes of Health Stroke Scale point; 1.06-1.13), and deterioration soon after admission (5.12, 3.33-7.87) had the strongest associations with do-not-resuscitate decisions. Patients with do-not-resuscitate orders received recommended care including stroke unit care (43% vs. 64%; P < 0.001) and prophylaxis for deep venous thrombosis (45% vs. 54%; P = 0.027) less often than non-do-not-resuscitate patients. This was especially the case when the do-not-resuscitate order was issued early. CONCLUSIONS: In addition to confirming the role of known intracerebral hemorrhage prognostic factors in do-not resuscitate decision-making, our results demonstrate that do-not-resuscitate orders led to less active care of intracerebral hemorrhage patients. PMID- 24148873 TI - Patterns of disease presentation and management in Egyptian primary care: findings from a survey of 2458 primary care patient consultations. AB - BACKGROUND: The Egyptian government is considering embarking on a new wave of health sector reform. Although primary care is seen as central to the anticipated reforms, little is known about the current morbidity and utilization patterns in Egyptian publicly funded primary care. We conducted this survey study of patient encounters to describe the demographic characteristics of patients attending publicly-funded primary care practices, the relative frequency of conditions encountered in these practices, and the rates of drug prescription, investigation and referral. METHOD: Cross-sectional survey of twelve primary care practices and 2458 patient consultations. Additional secondary data were collected from five of the twelve practices for preventive services provided at these practices i.e. immunizations, family planning and ante-natal care. RESULTS: 54% of the attendances were for people below the age of twenty, of which 54% were females. In patients above the age of twenty, women accounted for 73% of consultations. Upper respiratory tract infection was the most common reason for encounter, accounting for 24% of the presentations, followed by gastroenteritis (10%), intestinal parasites (5%), and lower respiratory tract infections (5%). Over 97% of patients were prescribed at least one drug, whereas investigation and referral rates were low (15% and 5% respectively). When the analysis was repeated for practices where data on both curative and preventive services were available (5 practices and 2146 consultations), substantial proportions of patients were found to seek care for immunizations (25%), family planning (12%), and ante-natal care (11%). CONCLUSION: Most patients utilizing primary care practices in Egypt seek care for minor and preventive services with relatively few consultations for more serious conditions. There is also a pattern of prescribing drugs to most primary care patients which may reflect over-prescribing by primary care doctors. PMID- 24148874 TI - Modulation of antisaccade costs through manipulation of target-location probability: only under decisional uncertainty. AB - Latencies of antisaccades made in the direction opposite to a peripheral target are typically slower longer than of prosaccades towards such a target by 50-100 ms. Antisaccades have proved to be an important tool for diagnostic purposes in neurology, psychology and psychiatry, providing invaluable insights into attentional function, decision making and the functionality of eye movement control. Recent findings have suggested, however, that latency differences between pro- and antisaccades can be eliminated by manipulating target-location probabilities. Pro- and antisaccades were equally fast to locations where a target rarely appeared, a finding that may be of promise for more elaborate diagnoses of neurological and psychiatric illness and further understanding of the eye movement system. Here, we tested probability manipulations for a number of different pro- and antisaccade tasks of varied difficulty. Probability only modulated antisaccade costs in a difficult antisaccade task involving decisional uncertainty with low target saliency. For other tasks including standard ones from the literature, target-location probability asymmetries had minimal effects. Probability modulation of antisaccade costs may therefore reflect effects upon decision making rather than saccade generation. This may limit the usefulness of probability manipulations of antisaccades for diagnostic purposes in neurology, psychology and related disciplines. PMID- 24148875 TI - Integrating ergonomics into engineering design: the role of objects. AB - The objective of this study was to explore the role of objects in integrating ergonomic knowledge in engineering design processes. An engineering design case was analyzed using the theoretical concepts of boundary objects and intermediary objects: Boundary objects facilitate collaboration between different knowledge domains, while the aim of an intermediary object is to circulate knowledge and thus produce a distant effect. Adjustable layout drawings served as boundary objects and had a positive impact on the dialog between an ergonomist and designers. An ergonomic guideline document was identified as an intermediary object. However, when the ergonomic guidelines were circulated in the design process, only some of the guidelines were transferred to the design of the sterile processing plant. Based on these findings, recommendations for working with objects in design processes are included. PMID- 24148876 TI - Effect of storage on tensile material properties of bovine liver. AB - Cadaveric tissue models play an important role in the assessment and optimization of novel restraint systems for reducing abdominal injuries. However, the effect of tissue preservation by means of freezing on the material properties of abdominal tissues remains unknown. The goal of this study was to investigate the influence of frozen storage time on the material responses of the liver parenchyma in tensile loading. Specimens from ten bovine livers were equally divided into three groups: fresh, 30-day frozen storage, and 60-day frozen storage. All preserved specimens were stored at -12 degrees C. Dog-bone specimens from each preservation group were randomly assigned to one of three strain rates (0.01s(-1), 0.1s(-1), and 1.0s(-1)) and tested to failure in tensile loading. The local material response recorded at the tear location and the global material response of the whole specimen of the liver parenchyma specimens were investigated based on the experimental data and optimized analytical material models. The local and global failure strains decreased significantly between fresh specimens and specimens preserved for 30 days (p<0.05), and between fresh specimens and specimens preserved for 60 days (p<0.05) for all three loading rates. Changes on the material model parameters were also observed between fresh and preserved specimens. Preservation by means of frozen storage was found to affect both the material and failure response of bovine liver parenchyma in tensile loading. The stiffness of the tissue increased with increased preservation time and increased strain rate. In summary, significant changes (p<0.05) between the failure strain of previously frozen liver parenchyma samples and fresh samples were demonstrated at both global and local levels in this study. In addition, nonlinear and viscoelastic characteristics of the liver parenchyma were observed in tension for both fresh and preserved samples. PMID- 24148877 TI - A novel algorithm based on visual saliency attention for localization and segmentation in rapidly-stained leukocyte images. AB - In this paper, we propose a fast hierarchical framework of leukocyte localization and segmentation in rapidly-stained leukocyte images (RSLI) with complex backgrounds and varying illumination. The proposed framework contains two main steps. First, a nucleus saliency model based on average absolute difference is built, which locates each leukocyte precisely while effectively removes dyeing impurities and erythrocyte fragments. Secondly, two different schemes are presented for segmenting the nuclei and cytoplasm respectively. As for nuclei segmentation, to solve the overlap problem between leukocytes, we extract the nucleus lobes first and further group them. The lobes extraction is realized by the histogram-based contrast map and watershed segmentation, taking into account the saliency and similarity of nucleus color. Meanwhile, as for cytoplasm segmentation, to extract the blurry contour of the cytoplasm under instable illumination, we propose a cytoplasm enhancement based on tri-modal histogram specification, which specifically improves the contrast of cytoplasm while maintaining others. Then, the contour of cytoplasm is quickly obtained by extraction based on parameter-controlled adaptive attention window. Furthermore, the contour is corrected by concave points matching in order to solve the overlap between leukocytes and impurities. The experiments show the effectiveness of the proposed nucleus saliency model, which achieves average localization accuracy with F1-measure greater than 95%. In addition, the comparison of single leukocyte segmentation accuracy and running time has demonstrated that the proposed segmentation scheme outperforms the former approaches in RSLI. PMID- 24148878 TI - Differences in insulin sensitivity, lipid metabolism and inflammation between young adult Pakistani and Norwegian patients with type 2 diabetes: a cross sectional study. AB - BACKGROUND: Immigrants from South Asia to Western countries have a high prevalence of type 2 diabetes mellitus (T2DM). We explored pathogenic factors that might contribute to the high risk of T2DM in Pakistani immigrants to Norway. METHODS: A cross-sectional study was performed in 18 Pakistani and 21 Norwegian men and women with T2DM (age 29 - 45 years), recruited from two hospital out patient clinics. Anthropometrics and a two-step euglycemic, hyperinsulinemic clamp with measurements of non-esterified fatty acids (NEFA) during clamp, was performed in all patients. Insulin sensitivity, given as the Glucose Infusion Rate (GIR) and Insulin Sensitivity Index (ISI), was calculated from the two euglycemic clamp steps. Fasting adipokines and inflammatory mediators were measured. Continuous variables between groups were compared using Student's t test or Mann-Whitney U test as appropriate. Spearman's correlation coefficient and multiple linear regression analyses were used. RESULTS: Despite having a lower BMI, Pakistani patients were more insulin resistant than Norwegian patients, during both low and high insulin infusion rates, after adjustment for sex and % body fat: median (interquartile range) GIR(low insulin): 339.8(468.0) vs 468.4(587.3) MUmol/m2/min (p = 0.060), ISI(low insulin): 57.1(74.1) vs 79.7(137.9) MUmol/m2/min (p = 0.012), GIR(high insulin): 1661.1(672.3) vs 2055.6(907.0) MUmol/m2/min (p = 0.042), ISI(high insulin): 14.2(7.3) vs 20.7(17.2) MUmol/m2/min (p = 0.014). Pakistani patients had lower percentage NEFA suppression 30 minutes into clamp hyperinsulinemia than Norwegians: 41.9(90.6)% vs 71.2(42.1)%, (p = 0.042). The relationship of ISI to BMI, leptin and interleukin-1 receptor antagonist also differed between Norwegians and Pakistanis. CONCLUSIONS: Compared with Norwegian patients, Pakistani patients with T2DM had lower insulin sensitivity, affecting both glucose and lipid metabolism. The relation of insulin sensitivity to BMI and some adipokines also differed between the groups. PMID- 24148879 TI - Nutritional quality of food items on fast-food 'kids' menus': comparisons across countries and companies. AB - OBJECTIVE: To compare energy (calories), total and saturated fats, and Na levels for 'kids' menu' food items offered by four leading multinational fast-food chains across five countries. DESIGN: A content analysis was used to create a profile of the nutritional content of food items on kids' menus available for lunch and dinner in four leading fast-food chains in Australia, Canada, New Zealand, the UK and the USA. SETTING: Food items from kids' menus were included from four fast-food companies: Burger King, Kentucky Fried Chicken (KFC), McDonald's and Subway. These fast-food chains were selected because they are among the top ten largest multinational fast-food chains for sales in 2010, operate in high-income English-speaking countries, and have a specific section of their restaurant menus labelled 'kids' menus'. RESULTS: The results by country indicate that kids' menu foods contain less energy (fewer calories) in restaurants in the USA and lower Na in restaurants in the UK. The results across companies suggest that kids' menu foods offered at Subway restaurants are lower in total fat than food items offered at Burger King and KFC, and food items offered at KFC are lower in saturated fat than items offered at Burger King. CONCLUSIONS: Although the reasons for the variation in the nutritional quality of foods on kids' menus are not clear, it is likely that fast-food companies could substantially improve the nutritional quality of their kids' menu food products, translating to large gains for population health. PMID- 24148880 TI - Associations between scores of psychosomatic health symptoms and health-related quality of life in children and adolescents. AB - BACKGROUND: The aims of the present study are to investigate whether there are differences in health-related quality of life (HRQoL) between girls and boys in two different age groups, to study how much of children's variance in HRQoL can be explained by common psychosomatic health symptoms, and to examine whether the same set of psychosomatic symptoms can explain differences in HRQoL, both between girls and boys and between older and younger school children. METHODS: A cross sectional study was conducted of 253 children, 99 of ages 11-12 years (n=51 girls, n=48 boys) and 154 of ages 15-16 years (n=82 girls, n=72 boys), in Swedish schools. The KIDSCREEN-52 instrument, which covers 10 dimensions of HRQoL and additional questions about psychosomatic health symptoms, were used. Analyses of variance were conducted to investigate differences between the genders and age groups, and in interaction effects on the KIDSCREEN-52 dimensions. Regression analyses were used to investigate the impacts of psychosomatic symptoms on gender and age group differences in HRQoL. RESULTS: Boys rated themselves higher than girls on the KIDSCREEN dimensions: physical and psychological well-being, moods and emotions, self-perception, and autonomy. Main effects of age group were found for physical well-being, psychological well-being, moods and emotions, self perception, autonomy, and school environment, where younger children rated their HRQoL more highly than those aged 15-16 years. Girls rated their moods and emotions dramatically lower than boys in the older age group, but the ratings of emotional status were more similar between genders at younger ages. Psychosomatic symptoms explained between 27% and 50% of the variance in the children's HRQoL. Sleeping difficulties were a common problem for both girls and boys. Depression and concentration difficulties were particularly associated with HRQoL among girls whereas stomach aches were associated with HRQoL among boys. CONCLUSIONS: Girls and adolescents experience poorer HRQoL than boys and younger children, but having psychosomatic symptoms seem to explain a substantial part of the variation. Strategies to promote health among school children, in particular to alleviate sleep problems among all children, depression and concentration difficulties among girls, and stomach aches among boys, are of great importance. PMID- 24148881 TI - What is the cause of the decline in maternal mortality in India? Evidence from time series and cross-sectional analyses. AB - Summary Studies on the causes of maternal mortality in India have focused on institutional deliveries, and the association of socioeconomic and demographic factors with the decline in maternal mortality has not been sufficiently investigated. By using both time series and cross-sectional data, this paper examines the factors associated with the decline in maternal mortality in India. Relative effects estimated by OLS regression analysis reveal that per capita state net domestic product (-1.49611, p<0.05), poverty ratio (0.02426, p<0.05), female literacy rate (-0.05905, p<0.10), infant mortality rate and total fertility rate (0.11755, p<0.05) show statistically significant association with the decline in the maternal mortality ratio in India. The Barro-regression estimate reveals that improvements in economic and demographic conditions such as growth in state income (beta=0.35020, p<0.05) and reduction in poverty (beta=0.01867, p<0.01) and fertility (beta=0.02598, p<0.05) have a greater association with the decline in the maternal mortality ratio in India than institutional deliveries (beta=0.00305). The negative beta-coefficient (beta= 0.69578, p<0.05), showing the effect of the initial maternal mortality ratio on change in maternal mortality ratio in the Barro-regression model, indicates a greater decline in maternal mortality ratio in laggard states compared with advanced states. Overall, comparing the estimates of relative effects, the socioeconomic and demographic factors have a stronger statistically significant association with the maternal mortality ratio than institutional deliveries. Interestingly, the weak association between 'increase in institutional deliveries' and 'decline in maternal mortality ratio' suggests that merely increasing deliveries alone will not help in ensuring maternal survival in India. Quality of services provided by the health facility, birth preparedness and avoiding delay in reaching health facility are also important. Deliveries in health facilities will not necessarily translate into increased survival chances of mothers unless women receive full antenatal care services and delays in reaching health facility are avoided. PMID- 24148882 TI - Intracranial aneurysms in previously irradiated fields: literature review and case report. AB - OBJECTIVE: Radiotherapy is a common treatment for a variety of disease processes in the central nervous system; it has an ever-increasing number of indications and applications. With the life expectancy of cancer patients increasing, delayed complications of radiation have become more apparent. One such potential complication is the appearance of intracranial aneurysms in the irradiated field. The incidence and natural history of these aneurysms is not well understood. To this end, we performed a review of the literature to analyze the current state of knowledge of these rare aneurysms. Furthermore, we present a case treated at our center. METHODS: We reviewed the literature for all reported cases of intracranial aneurysms appearing in an irradiated field, including any available histopathologic analysis. All papers were included irrespective of the language in which it was published. We calculated the mean age at radiation exposure, the interval between radiation exposure, and aneurysm development and the rate of presentation. Herein we also present a case of an intracranial aneurysm in a 38 year-old patient detected in an irradiation field 33 years after the patient underwent craniospinal irradiation for a medulloblastoma. RESULTS: A total of 46 patients with 69 intracranial aneurysms in irradiation fields were reported between 1978 and 2013. The mean age at radiation exposure was 34 years, and the mean lag time between exposure and diagnosis was 12 years (range, 4 months to 50 years). The median lag time between exposure and diagnosis was shorter in patients older than 40 (6 years). Among the reported aneurysms, 83% were saccular, 9% were fusiform, and 9% were considered pseudo-aneurysms. The Median lag time was 20 years for brachytherapy, 8 years for focused radiation, 9 years for whole brain radiation, and 6 years for SRS. Among reported aneurysms, 55% presented with some form of hemorrhage: intracranial rupture with subarachnoid hemorrhage, epistaxis, or otorrhagia. Only 13% were discovered on routine follow up or were found incidentally for work-up of unrelated neurologic symptoms. CONCLUSION: Although rarely reported, intracranial aneurysms in irradiation fields may warrant special attention when diagnosed. These aneurysms may have an inherently weaker structure and may be more prone to rupture. Their repair may also be complicated by more fragile and irregular morphology. The increasing longevity of cancer patients suggests that screening for aneurysms at irradiation sites may be warranted, but further studies are needed to validate this approach. PMID- 24148884 TI - Fifty years of fibrous protein research: a personal retrospective. AB - As a result of X-ray fiber diffraction studies on fibrous proteins and crystallographic data on fragments derived from them, new experimental techniques across the biophysical and biochemical spectra, sophisticated computer modeling and refinement procedures, widespread use of bioinformatics and improved specimen preparative procedures the structures of many fibrous proteins have now been determined to at least low resolution. In so doing these structures have yielded insight into the relationship that exists between sequence and conformation and this, in turn, has led to improved methodologies for predicting structure from sequence data alone. In this personal retrospective a selection of progress made during the past 50years is discussed in terms of events to which the author has made some contribution. PMID- 24148883 TI - Secondary neoplasms after stereotactic radiosurgery. AB - OBJECTIVE: The use of medical radiation has increased 6-fold in the past 30 years. Within neurosurgery, the advent of stereotactic radiosurgery (SRS) has significantly altered the treatment paradigm for both benign and malignant central nervous system diseases. With this increased reliance on radiation has come a responsibility to identify the long-term risks, including the potential development of radiation-induced neoplasms. Although the data regarding traditional radiation exposure and its subsequent risks are well-defined, the data for SRS is less developed. METHODS: We reviewed the published literature to more accurately define the risk of developing secondary neoplasms after stereotactic radiosurgery. RESULTS: A total of 36 cases of SRS-induced neoplasms were identified. More than half of the cases had an initial diagnosis of vestibular schwannoma. Overall, the risk of developing an SRS-induced neoplasm is approximately 0.04% at 15 years. CONCLUSION: The risk of developing an SRS induced neoplasm is low but not zero. Thus, long-term surveillance imaging is advised for patients treated with SRS. PMID- 24148885 TI - Is there a role for high dose chemotherapy and blood stem cell rescue in childhood hepatoblastoma presenting with lung metastases? A case report and literature review. AB - We report the use of high dose chemotherapy with peripheral blood stem cell rescue as a consolidation treatment for a 3-year-old child affected by metastatic hepatoblastoma, who achieved complete lung response only after conventional treatment. The patient is presently alive 27 months after high dose chemotherapy with blood stem cell rescue with no evidence of disease.The role of high dose chemotherapy with blood stem cell rescue to consolidate the complete clearing of lung disease in metastatic hepatoblastoma remains controversial; the data available in the literature and our experience seems to suggest to keep this treatment option open to further consideration in the clinical setting of high risk patients. PMID- 24148886 TI - N-cadherin promoter polymorphisms and risk of osteoarthritis. AB - Osteoarthritis (OA) is the most common form of arthritis. It is characterized by cartilage destruction and bone remodeling, mediated in part by synovial fibroblasts (SFs). Given the functional significance of cadherins in these cells, we aimed at determining the role of genetic variants of N-cadherin (CDH2) in OA of the knee and hip. Six single-nucleotide polymorphisms in the genomic region of the CDH2 gene were genotyped in 312 patients with OA and 259 healthy control subjects. Gene expression of CDH2 was analyzed by qRT-PCR. Liquid chromatography mass spectrometry was used to identify a transcription factor isolated by DNA pulldown. Its potential for binding to gene variants was examined by electrophoretic mobility shift assay, enzyme-linked immunosorbent assay, and chromatin immunoprecipitation. Genetic analysis identified a polymorphism located in the CDH2 promoter region to be associated with risk of OA. The minor allele of rs11564299 had a protective effect against OA. Compared to carriers of the major allele, carriers of the minor allele of rs11564299 displayed increased N-cadherin levels in SFs. Based on in silico analysis, the minor allele was predicted to generate a novel transcription factor binding site, Direct-binding assays and mass spectrometric analysis identified hnRNP K as binding selectively to the minor allele. In summary, a CDH2 promoter polymorphism influences the risk of OA, and hnRNP K was found to be involved in the regulation of elevated N-cadherin expression in patients with OA carrying the minor allele of rs11564299. PMID- 24148887 TI - The current situation on vascular cognitive impairment after ischemic stroke in Changsha. AB - The objectives of the study were to explore the prevalence and effects of vascular cognitive impairment (VCI) among ischemic stroke patients and to provide a basis for prevention and treatment strategies. A stratified cluster random sampling method was performed, and 689 ischemic stroke patients (over 40 years of age) were enrolled. All of the patients had received a neuropsychological assessment battery to assess cognitive function and self-designed questionnaires to collect relevant information. According to the cognitive status, the patients were divided into two groups, a case group and a control group. The caregivers of the patients were given a questionnaire concerning the awareness of and attitudes toward VCI. In this study, we determined that the prevalence of VCI was 41.8%. Aging, paraventricular white matter lesion (WML), macroangiopathy, high levels of alcohol, a lack of hobbies, and excessive sleep were risk factors for vascular cognitive impairment no dementia (VCIND). A high level of education, manual-work, low level of alcohol use, regular health checks, a vegetable-based diet, and more fruit and milk were protective factors for VCIND. Living alone, hyperlipidemia, transient ischemic attack, a family history of stroke, and brain atrophy were risk factors of vascular dementia (VD). A high educational level, a vegetable based diet, and tea were protective factors for VD. The general public awareness of VCI was found to be insufficient, and there was a prejudice toward and lack of funding for the care of VCI patients. The prevalence of VCI is high in ischemic stroke patients, and there are different impact factors at different stages. Despite the high prevalence of VCI, the general public awareness is limited. Appropriate prevention measures should be developed to reduce the prevalence of VCI. PMID- 24148888 TI - Cerebral white matter integrity in children with active versus remitted epilepsy 5 years after diagnosis. AB - INTRODUCTION: Diffusion tensor imaging (DTI) studies have reported white matter abnormalities in childhood-onset epilepsy, but the mechanisms and timing underlying these abnormalities, and their resolution, are not well understood. This study examined white matter integrity in children with active versus remitted epilepsy. METHODS: Tract-based spatial statistics (TBSS) was used to examine whole-brain DTI indices of fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (AD) and radial diffusivity (RD) in 20 children with epilepsy 5-6 years after diagnosis, compared to 29 healthy controls. To determine the status of white matter following cessation of seizures, participants with epilepsy were classified as active versus remitted and comparisons included: (1) controls versus all children with epilepsy, (2) controls versus children with remitted seizures, (3) controls versus children with active seizures, and (4) children with active versus remitted epilepsy. RESULTS: In the active compared to remitted epilepsy group, significantly higher FA and lower MD, AD and RD values were dispersed in the internal capsule, cingulum, body of the corpus callosum, superior corona radiata and superior fronto-occipital fasciculus. Similar differences were found between the active epilepsy and the control group. There were no significant differences between the remitted epilepsy and control groups. CONCLUSION: Children with active epilepsy differed in white matter integrity compared to children with remitted epilepsy and healthy controls. It remains to be determined whether these findings represent the outcomes of seizure remission versus an initial biomarker for those children who will ultimately have intractable epilepsy. PMID- 24148889 TI - Unequal pupils following removal of hyoscine patch. PMID- 24148890 TI - Accuracy of the concentration of morphine infusions prepared for patients in a neonatal intensive care unit. AB - OBJECTIVE: To investigate the accuracy of morphine infusions prepared for neonates in relation to the label strength and to identify the differences in deviation between infusions made in neonatal intensive care unit (NICU) and those dispensed ready-to-use from pharmacy. METHODS: Unused portions of morphine solution for infusion were collected over a 6-weeks period and used to determine the concentration of the drug by high-performance liquid chromatography (HPLC). RESULTS: A total of 19.2% of infusions prepared by nurses in the ward and 7.8% prepared in the pharmacy were outside the limit required by the British Pharmacopoeia (+/-7.5%). Moreover, a deviation in concentration of more than 20% was found in ward-prepared infusions, although this was caused by volume discrepancies of less than 0.2 mL. The frequency and magnitude of deviations found in infusions prepared in pharmacy was lower than in those prepared by NICU. The latter showed significantly higher number of out-of-specification samples (p=0.015); however, deviations from intended concentration occurred in both settings. Significant differences between pharmacy and NICU for volumes of less than 0.5 mL or for less than 1 mL were not identified probably due to small sample size, but statistical data show a trend for differences. CONCLUSIONS: Current practice of preparation of infusions from strengths intended for older children and adults involves dilution of small volumes in a syringe and leads to inaccuracy in the final concentration of infusions for neonatal use. We propose the implementation of standard concentrations for this patient group to effectively eliminate these errors. PMID- 24148891 TI - Epidemiology, aetiology and management of visual impairment in children. AB - An estimated 19 million of the world's children are visually impaired, while 1.4 million are blind. Using the UK as a model for high income countries, from a population-based incidence study, the annual cumulative incidence of severe visual impairment/blindness (SVL/BL) is estimated to be 6/10 000 by age 15 years, with the incidence being highest in the first year of life. The population of visually impaired children within high, middle and lower income countries differ considerably between and within countries. The numerous and mainly uncommon disorders which can cause impaired vision result in heterogeneous population which includes a substantial proportion (for SVI/BL, the majority) of children with additional systemic disorders or impairments whose needs differ substantially from those with isolated vision impairment. Paediatricians and other paediatric professionals have a key role in early detection and multidisciplinary management to minimise the impact of visual impairment (VI) in childhood. PMID- 24148892 TI - The study of the Oxytropis kansuensis-induced apoptotic pathway in the cerebrum of SD rats. AB - BACKGROUND: Locoweeds cause significant livestock poisoning and economic loss all over the world. Animals can develop locoism, a chronic neurological disease, after grazing on locoweeds. Oxytropis kansuensis is a variety of locoweed that contains swainsonine as its main toxic ingredient. The purpose of this study was to investigate the apoptotic pathway induced in the cerebrum by swainsonine. RESULTS: Twenty-four Sprague-Dawley rats were randomly divided into four groups (experimental groups I, II, III and a control group) and 6 SD rats of each group were feed in 3 cages separately. Rats were penned as groups and fed with feeds containing 15% (SW content 0.030/00), 30% (SW content 0.060/00), or 45% (SW content 0.090/00) O. kansuensis for experimental groups I, II, and III, respectively, or complete feed in the case of the control group. One hundred and nineteen days after poisoning, and all rats showed neurological disorders at different degrees, which were considered to be successful established a chronic poisoning model of O. kansuensis. rats were sacrificed and the expression of Fas, FasL, Bcl-2, Bax as well as cleaved caspase-3, -8 and -9 proteins in brain tissues were detected by Western blot. The results showed that SW treatment up regulated Fas and Fas ligand (FasL) (P < 0.05), and that there was an increase in Bax and a decrease in Bcl-2 protein (P < 0.01). Moreover, SW treatment significantly increases the activation of caspase-3, 8 and -9, the key effectors in apoptosis pathway (P < 0.01). CONCLUSION: Our data suggest that SW induces apoptosis in cells of the brain through death receptor and mitochondria-mediated, caspase-dependent apoptotic pathways in the brain tissue of SD rats. PMID- 24148893 TI - Effect of omega-conotoxin MVIIA and Phalpha1beta on paclitaxel-induced acute and chronic pain. AB - The treatment with the chemotherapeutic agent paclitaxel produces a painful peripheral neuropathy, and is associated with an acute pain syndrome in a clinically significant number of patients. However, no standard therapy has been established to manage the acute pain or the chronic neuropathic pain related to paclitaxel. In the present study, we evaluated the analgesic potential of two N type voltage-gated calcium channel (VGCC) blockers, omega-conotoxin MVIIA and Phalpha1beta, on acute and chronic pain induced by paclitaxel. Adult male rats were treated with four intraperitoneal injections of paclitaxel (1+1+1+1mg/kg, in alternate days) and the development of mechanical hyperalgesia was evaluated 24h (acute painful stage) or 15days (chronic painful stage) after the first paclitaxel injection. Not all animals showed mechanical hyperalgesia 24h after the first paclitaxel injection, but those that showed developed a more intense mechanical hyperalgesia at the chronic painful stage. Intrathecal administration (i.t.) of omega-conotoxin MVIIA (3-300pmol/site) or Phalpha1beta (10 300pmol/site) reduced the mechanical hyperalgesia either at the acute or at the chronic painful stage induced by paclitaxel. When administered at the acute painful stage, omega-conotoxin MVIIA (300pmol/site, i.t.) and Phalpha1beta (300pmol/site, i.t.) prevented the worsening of chronic mechanical hyperalgesia. Furthermore, Phalpha1beta (30-300pmol/site, i.t.) elicited less adverse effects than omega-conotoxin MVIIA (10-300 pmol/site, i.t.). Taken together, our data evidence the involvement of N-type VGCC in pain sensitization induced by paclitaxel and point out the potential of Phalpha1beta as a safer alternative than omega-conotoxin MVIIA to treat the pain related to paclitaxel. PMID- 24148894 TI - Body image concern among Australian adolescent girls: the role of body comparisons with models and peers. AB - This study investigated the potential mediating roles of body comparisons with peers and models in the relationship between the internalization of thinness norms and body image concern. A total of 224 Western Australian girls aged 14-15 completed questionnaires assessing their endorsement of thinness norms, body image concerns, and frequency of body comparisons with peers and with models. Both targets of body comparisons were found to significantly mediate the relationship between the endorsement of thinness norms and body image concern, with body comparison with peers a stronger mediator than comparison with models. These findings show that body comparison with peers, in particular, plays a significant role in the experience of body image concerns among adolescent girls, and should be given a higher profile in programs designed to prevent or reduce body image concern. PMID- 24148895 TI - Influence of racial differences on outcomes after thrombolytic therapy in acute ischemic stroke. AB - BACKGROUND: The National Institutes of Neurological Disorders and Stroke and the European Co-operative Acute Stroke III trials enrolled a largely Caucasian population, but the results are often extrapolated onto non-Caucasians. A limited number of nonrandomized studies have proposed that non-Caucasian patients show differential response to tissue plasminogen activator. AIMS AND/OR HYPOTHESIS: We examined if non-Caucasian patients of mixed national origin within the Virtual International Stroke Trials Archives neuroprotection trials responded differently to tissue plasminogen activator compared with Caucasians. METHODS: We matched patients within each race-subtype for age, baseline National Institutes of Health Stroke Scales, and diabetes status, and excluded outliers. We tested for an interaction of race ethnicity with tissue plasminogen activator on predicting outcomes at alpha = 0.05. We compared 90-day ordinal outcome (modified Rankin Scale; primary analysis) and dichotomized outcomes (modified Rankin Scale 0-1; modified Rankin Scale 0-2; survival) within individual race ethnicity. RESULTS: One thousand nine hundred forty-six thrombolysed patients (125 Blacks, 39 Asians, and 1821 Caucasians) were matched with 1946 non-thrombolysed patients in each race ethnicity group. Postmatching, there were no imbalances in baseline National Institutes of Health Stroke Scales and age between the groups (P > 0.05). The interaction of tissue plasminogen activator with race ethnicity was nonsignificant in ordinal (P = 0.4) and in dichotomized outcome models (P > 0.05). Ordinal odds for improved outcomes were 1.5 for all patients (P < 0.05). Ordinal odds for Caucasians were 1.5 (P < 0.05); for Blacks, 2.1 (P < 0.05); and for Asians, 1.2 (P > 0.05; 1.6 after 1:2 matching with nonthrombolysed, because of small numbers). Dichotomized functional outcomes improved after thrombolysis overall, in Caucasians, in Blacks (modified Rankin Scale 0-2 only), and in Asians (after 1:2 matching; P > 0.05). Odds for survival were consistent across all groups. CONCLUSIONS: These results do not suggest a differential response to tissue plasminogen activator based on race ethnicity. Among Asians, data were particularly sparse, and results should be interpreted with caution. PMID- 24148896 TI - A glimpse of Cre-mediated controversies in epicardial signalling. PMID- 24148897 TI - Extracellular vesicles: small but strong. PMID- 24148898 TI - G-protein-coupled inward rectifier potassium current contributes to ventricular repolarization. AB - AIMS: The purpose of this study was to investigate the functional role of G protein-coupled inward rectifier potassium (GIRK) channels in the cardiac ventricle. METHODS AND RESULTS: Immunofluorescence experiments demonstrated that GIRK4 was localized in outer sarcolemmas and t-tubules in GIRK1 knockout (KO) mice, whereas GIRK4 labelling was not detected in GIRK4 KO mice. GIRK4 was localized in intercalated discs in rat ventricle, whereas it was expressed in intercalated discs and outer sarcolemmas in rat atrium. GIRK4 was localized in t tubules and intercalated discs in human ventricular endocardium and epicardium, but absent in mid-myocardium. Electrophysiological recordings in rat ventricular tissue ex vivo showed that the adenosine A1 receptor agonist N6 cyclopentyladenosine (CPA) and acetylcholine (ACh) shortened action potential duration (APD), and that the APD shortening was reversed by either the GIRK channel blocker tertiapin-Q, the adenosine A1 receptor antagonist DPCPX or by the muscarinic M2 receptor antagonist AF-DX 116. Tertiapin-Q prolonged APD in the absence of the exogenous receptor activation. Furthermore, CPA and ACh decreased the effective refractory period and the effect was reversed by either tertiapin Q, DPCPX or AF-DX 116. Receptor activation also hyperpolarized the resting membrane potential, an effect that was reversed by tertiapin-Q. In contrast, tertiapin-Q depolarized the resting membrane potential in the absence of the exogenous receptor activation. CONCLUSION: Confocal microscopy shows that among species GIRK4 is differentially localized in the cardiac ventricle, and that it is heterogeneously expressed across human ventricular wall. Electrophysiological recordings reveal that GIRK current may contribute significantly to ventricular repolarization and thereby to cardiac electrical stability. PMID- 24148899 TI - Eosinophil apoptosis as a therapeutic target in allergic asthma. AB - Asthma is a chronic inflammatory disease of the airways manifesting in many different phenotypes. Allergic asthma, comprising approximately half of patients with asthma, is characterized by the accumulation of eosinophils into the lungs. Eosinophils release factors that damage the surrounding cells and participate in the maintenance and exacerbation of inflammation. In the absence of any inflammatory survival-prolonging factors, eosinophils die by apoptosis in few days but in inflamed airways, eosinophil survival is thought to be prolonged due to the surrounding pro-inflammatory factors such as IL-5, IL-3 and GM-CSF. Resolution of eosinophilic inflammation is an important goal in the treatment of allergic asthma. Apoptosis is a physiological and non-inflammatory way to eliminate these harmful cells, and development of drugs targeting eosinophil apoptosis is one possible strategy for the therapy of allergic asthma. Importance of this strategy is supported by the fact that promotion of eosinophil apoptosis is a property of many anti-asthmatic agents such as glucocorticoids, the current main anti-inflammatory therapy of asthma, theophylline and leukotriene modifiers. beta2 agonists have been shown to modulate eosinophil longevity by increasing survival. Also, anti-IL-5 antibody mesolizumab has shown efficacy in reducing asthma exacerbations in patients with severe eosinophilic asthma. Many potential future anti-asthmatic agents, such as Siglec-8 activating antibody and novel humanized anti-IL-5 antibody MEDI-563, have the property of inducing eosinophil apoptosis. This MiniReview aims to present eosinophil apoptosis as a therapeutic target in the treatment of allergic asthma. We summarize the effects and mechanisms of current and potential future anti-asthmatic drugs on eosinophil apoptosis and additionally, discuss the potential factors that promote eosinophil longevity in the lungs. PMID- 24148900 TI - Maternal hair selenium levels as a possible long-term nutritional indicator of recurrent pregnancy loss. AB - BACKGROUND: Approximately 1% of all couples trying to conceive will suffer from recurrent pregnancy loss (RPL). Nutritional deficiencies have been postulated as a possible cause of RPL and in particular, selenium deficiency has been associated with reproductive failure in animal studies and more recently, in some human studies. This study was undertaken to assess the maternal hair selenium levels in women with RPL without an identified cause and to compare these results with those of women with successful reproductive histories. METHODS: Twenty four patients with RPL and twenty four control subjects with at least one successful pregnancy and no pregnancy failures, who were matched for age and ethnicity, were recruited. A questionnaire was completed, which included demographic and social information and a dietary history. Hair samples were collected and analyzed for selenium content by inductively coupled plasma mass spectrometry. RESULTS: The control subjects had a higher mean income and had completed more years of education compared with the RPL patients. There was no significant difference in the intake of selenium rich foods between the 2 groups. The patients, however, consumed significantly more fruit, cheese, potatoes and chocolate than the controls. The median (range) selenium content was 0.80 ppm (0.19-4.15) and 0.68 ppm (0.43-3.76) in patients and controls respectively (Mann Whitney U test 209.5 p = 0.74). CONCLUSIONS: While there were significant differences in the 2 groups with regard to resources, education and diet our results show that hair selenium concentrations and dietary selenium intake, were similar in the two groups. Both groups had low levels of this important element. PMID- 24148901 TI - Association of regional body fat with metabolic risks in Chinese women. AB - OBJECTIVE: To investigate the association of regional fat depots with metabolic risk factors in Chinese women. DESIGN: Total and regional fat depots including android fat and gynoid fat were measured by dual-energy X-ray absorptiometry. Central fat distribution was defined as android:gynoid fat ratio. Metabolic risk factors were defined as elevated TAG, reduced HDL-cholesterol, elevated blood pressure and elevated fasting plasma glucose. Logistic regression analyses were performed to examine the associations of regional fat depots with metabolic risk factors. The odds ratios of metabolic risks were further calculated according to tertiles of android fat and gynoid fat. SETTING: Participants were recruited from a community-based cross-sectional study. Face-to-face questionnaires, anthropometric and dual-energy X-ray absorptiometry measures were conducted. SUBJECTS: Chinese women (n 609) aged 18-79 years. RESULTS: Android fat and android:gynoid fat ratio were associated with significantly increased odds (OR = 1.4-3.7; P < 0.01) for almost all risk factors, whereas gynoid fat was independently associated with significantly decreased odds (OR = 0.3-0.6; P < 0.01). The inverse associations of gynoid fat with metabolic risk factors remained after adjusting for android fat. Even if their android fat level was in high, women in the highest tertile of gynoid fat had lower odds of having at least two metabolic risk factors compared with women in the lowest gynoid fat tertile (P for trend < 0.01). CONCLUSIONS: There were opposite associations of android and gynoid fat with metabolic risks in Chinese women. Gynoid fat rather than android fat might be a more important inclusion in metabolic disease risk evaluation in female Asians. PMID- 24148902 TI - Enterovirus genotypes causing hand foot and mouth disease in Shanghai, China: a molecular epidemiological analysis. AB - BACKGROUND: A rapid expansion of hand, foot, and mouth disease (HFMD) outbreaks has occurred and caused deaths in China in recent years, but little is known about the other etiologic agents except enterovirus 71 (EV71) and coxsackievirus A 16 (CA16). The objective of this study is to determine the genotype compositions of enterovirus causing HFMD in Shanghai and identify any associations between enterovirus types and clinical manifestations. METHODS: Stool specimens were collected from patients hospitalized for treatment of HFMD, from May 2010 to April 2011. Enterovirus was detected by reverse transcription PCR and directly genotyped by sequencing the PCR products. Phylogenetic analysis was based on the VP1 partial gene. RESULTS: Of 290 specimens, 277 (95.5%) tested positive for enterovirus. The major genotypes were EV71 (63.8%), CA10 (9.0%), CA6 (8.3%), CA16 (6.9%), CA12 (2.4%), and CA4 (1.4%). The EV71 strains belonged to the C4a subtype and CA16 belonged to the B subtype. CA6 was closely related to strains detected in Japan, Taiwan and China, and CA10, CA12 and CA4 were phylogenetically similar to other strains circulating in China. Mean hospital stays and the prevalence of complications in patients with EV71 infection were higher than those in patients in CA6, CA10 or CA16 infection (P < 0.05 for all comparisons). Children with CA12 infection were the youngest, and most likely have the highest risk of complications when compared to the other non-EV71 infection groups. CONCLUSIONS: This study demonstrated a diversified pathogen compositions attributing to HFMD and clinical symptoms differing in enterovirus genotypes. It deserves our attention as early identification of enterovirus genotypes is important for diagnosis and treatment of HFMD patients. PMID- 24148903 TI - Osteomyelitis of the femur mimicking bone tumors: a review of 10 cases. AB - BACKGROUND: The clinical symptoms and radiographic appearance of osteomyelitis can mimic those of bone tumors. METHODS: We reviewed 10 patients with osteomyelitis of the femur who were initially diagnosed as having bone tumors and were subsequently transferred to our institution. RESULTS: Nocturnal pain of moderate intensity occurred in seven patients, and all 10 patients had elevated C reactive protein levels. The radiographic findings included the following: a permeative, moth-eaten osteolytic lesion in six patients, an osteolytic lesion with sclerotic borders in three patients, and cortical destruction with pathological fracture in one patient. Magnetic resonance imaging was performed for eight patients, and only one had a positive penumbra sign. All patients underwent a surgical biopsy to confirm the final diagnosis for histological analysis and cultures. Klebsiella pneumoniae was detected in six patients and Staphylococcus aureus, the most common organism in osteomyelitis, was detected in three. Recurrence of infection occurred in five patients following debridement surgery; of these three had a Klebsiella pneumoniae infection. All patients received antibiotic treatment for an average of 20.4 weeks (range, 4 to 44) and surgical treatment an average of 1.8 times (range, 1 to 4). At the final follow up, all patients were fully recovered with no signs of infection. CONCLUSIONS: When used in combination, clinical examinations, laboratory data, and radiographic findings can reliably distinguishing osteomyelitis from bone tumors. PMID- 24148904 TI - Single-incision laparoscopic partial gastrectomy for gastric submucosal tumors without compromising transumbilical stapling. AB - INTRODUCTION: Although SILS has become an increasingly popular type of surgery, its application for gastric submucosal tumors (SMT) has been only sporadically reported. We herein describe 12 recent cases with gastric SMT located in the greater curvature or anterior wall. The aim is to validate technical feasibility and safety of single-incision laparoscopic partial gastrectomy. Thus far, this is one of the largest series of patients with gastric SMT who underwent SILS. METHODS: From July 2009 to April 2013, single-incision laparoscopic partial gastrectomy was attempted in 12 consecutive patients with gastric SMT. Three trocars were assembled in the umbilical incision, and the lesion was mobilized and staple-resected with endoscopic stapling devices. RESULTS: SILS surgery was successfully completed without any additional trocars. The median operating time was 96.5 min, and median blood loss was 7.5 mL. The median tumor size was 30 mm, with histopathologic diagnosis of gastrointestinal stromal tumor (10) and schwannoma (2). There was no immediate postoperative morbidity. During a median follow-up of 12 months, all patients were on full regular diet without any gastrointestinal symptoms. CONCLUSION: SILS with transumbilical gastric stapling is a safe and practical alternative to conventional multiport laparoscopy in patients with gastric SMT, except for cases originating in the lesser curvature and close to the cardia/ pylorus. PMID- 24148905 TI - Drug use among drivers who drank on alcohol outlets from Porto Alegre, Brazil. AB - BACKGROUND: Driving under the influence of multiple substances is a public health concern, but there is little epidemiological data about their combined use and putative impact on driving in low and middle-income countries where traffic crashes have been clustering in recent years. The aim of this study is to estimate the prevalence of alcohol and drug use - as well as their associated factors - among drivers in the context of alcohol outlets (AOs). METHODS: A probability three-stage sample survey was conducted in Porto Alegre, Brazil. Individuals who were leaving AO were screened, with the selection of 683 drivers who met the inclusion criteria. Drivers answered a structured interview, were breathalyzed, and had their saliva collected for drug screening. Prevalences were assessed using domain estimation and logistic regression models assessed covariates associated with substance use. FINDINGS: Benzodiazepines 3.9% (SE 2.13) and cocaine 3.8% (SE 1.3) were the most frequently detected drugs in saliva. Among drivers who were going to drive, 11% had at least one drug identified by the saliva drug screening, 0.4% two, and 0.1% three drugs in addition to alcohol. In multivariable analyses, having a blood alcohol concentration (BAC)>0.06% was found to be associated with a 3.64 times (CI 95% 1.79-7.39) higher chance of drug detection, compared with interviewees with lower BACs. CONCLUSIONS: To drive under the influence of multiple substances is likely to be found in this setting, highlighting an association between harmful patterns of consume of alcohol and the misuse of other substances. PMID- 24148906 TI - Ethylene promotes germination of Arabidopsis seed under salinity by decreasing reactive oxygen species: evidence for the involvement of nitric oxide simulated by sodium nitroprusside. AB - Both ethylene and nitric oxide (NO) are involved in modulating seed germination in adverse environments. However, the mechanisms by which they interact and affect germination have not been explained. In this study, the relationship between ethylene and NO during germination of Arabidopsis seed under salinity was analysed. Application of exogenous 1-aminocyclopropane-1-carboxylate (ACC, a precursor of ethylene biosynthesis) or sodium nitroprusside (SNP, an NO donor) largely overcame the inhibition of germination induced by salinity. The effects of ACC and SNP were decreased by 2-phenyl-4,4,5,5-tetramethyl-imidazoline-1-oxyl 3-oxide (cPTIO), a specific NO scavenger, or by aminoisobutyric acid (AIB), an inhibitor of ethylene biosynthesis, indicating that ethylene and NO interact during germination under salinity. Further, we demonstrated that ACC increased NO production and that SNP greatly induced the expression of the ACS2 gene involved in ethylene synthesis in Arabidopsis seeds germinating under salinity stress, suggesting that each substance influences the production of the other. Application of exogenous ACC increased germination under oxidative stress induced by hydrogen peroxide (H2O2) while SNP had a much smaller effect on wild-type Arabidopsis (Col-0) and no effect on the ethylene insensitive mutant (ein3-1) seeds, respectively. This shows that NO increased germination under salinity indirectly through H2O2 acting via the ethylene pathway. The endogenous concentration of H2O2 was increased by salinity in germinating seeds but was decreased by exogenous ACC, which stimulated germination ultimately. To explain all these results and the regulation of germination of Arabidopsis seed under salinity we propose a model involving ethylene, NO and H2O2 interaction. PMID- 24148907 TI - Edaravone improves functional and structural outcomes in animal models of focal cerebral ischemia: a systematic review. AB - Edaravone has been used in patients with acute ischemic stroke in Japan for over 10 years but does not have marketing authorization in Europe or America. Either patients in Europe and America are not receiving an effective treatment, or those in Asia are being given a treatment which is not effective. Finding out which of these is true will require further clinical trials, and a better understanding of its efficacy in animal models may help inform the design of those trials so that it might be tested under conditions where there is the greatest prospect of success. We systematically reviewed the efficacy of edaravone in animal models of focal ischemia and summarized data using weighted mean difference DerSimonian and Laird random-effects modeling. We used stratified meta-analysis and metaregression to assess the influence of study design and methodological quality. We identified 49 experiments describing outcome in 814 animals; 30 experiments (519 animals) reported functional and 35 experiments (503 animals) reported structural outcome. Edaravone improved functional and structural outcome by 30.3% (95% confidence interval 23.4-37.2%) and 25.5% (95% confidence interval, 21.1-29.9%), respectively. For functional outcome, there was an inverse relationship between study quality and effect size (P < 0.0017). Effect sizes were larger in studies where randomization or blinded assessment was not reported. There was no evidence of publication bias. Edaravone is a promising treatment for stroke. However, because of the methodological weakness in current animal studies, no sufficient preclinical evidence is available to optimize the study design of clinical trials. Higher quality animal studies are expected to inform further clinical study. PMID- 24148909 TI - Altered brain response to reward and punishment in adolescents with Anorexia nervosa. AB - Adults recovered from Anorexia nervosa (AN) have altered reward modulation within striatal limbic regions associated with the emotional significance of stimuli, and executive regions concerned with planning and consequences. We hypothesized that adolescents with AN would show similar disturbed reward modulation within the striatum and the anterior cingulate cortex, a region connected to the striatum and involved in reward-guided action selection. Using functional magnetic resonance imaging, twenty-two adolescent females (10 restricting-type AN, 12 healthy volunteers) performed a monetary guessing task. Time series data associated with monetary wins and losses within striatal and cingulate regions of interest were subjected to a linear mixed effects analysis. All participants responded more strongly to wins versus losses in limbic and anterior executive striatal territories. However, AN participants exhibited an exaggerated response to losses compared to wins in posterior executive and sensorimotor striatal regions, suggesting altered function in circuitry responsible for coding the affective context of stimuli and action selection based upon these valuations. As AN individuals are particularly sensitive to criticism, failure, and making mistakes, these findings may reflect the neural processes responsible for a bias in those with AN to exaggerate negative consequences. PMID- 24148908 TI - A positive relationship between harm avoidance and brain nicotinic acetylcholine receptor availability. AB - Prior research indicates that disturbance of cholinergic neurotransmission reduces anxiety, leading to the hypothesis that people with heightened cholinergic function have a greater tendency toward anxiety-like and/or harm avoidant behavior. We sought to determine if people with elevated levels of harm avoidance (HA), a dimension of temperament from the Temperament and Character Inventory (TCI), have high alpha4beta2* nicotinic acetylcholine receptor (nAChR) availability. Healthy adults (n=105; 47 non-smokers and 58 smokers) underwent bolus-plus-continuous infusion positron emission tomography (PET) scanning using the radiotracer 2-[18F]fluoro-3-(2(S)azetidinylmethoxy) pyridine (abbreviated as 2-FA). During the uptake period of 2-FA, participants completed the TCI. The central study analysis revealed a significant association between total HA and mean nAChR availability, with higher total HA scores being linked with greater nAChR availability. In examining HA subscales, both 'Fear of Uncertainty' and 'Fatigability' were significant, based on higher levels of these characteristics being associated with greater nAChR availabilities. This study adds to a growing body of knowledge concerning the biological basis of personality and may prove useful in understanding the pathophysiology of psychiatric disorders (such as anxiety disorders) that have similar characteristics to HA. Study findings may indicate that heightened cholinergic neurotransmission is associated with increased anxiety-like traits. PMID- 24148910 TI - Hemispheric asymmetry of primary auditory cortex and Heschl's gyrus in schizophrenia and nonpsychiatric brains. AB - Heschl's gyrus (HG) is reported to have a normal left>right hemispheric volume asymmetry, and reduced asymmetry in schizophrenia. Primary auditory cortex (A1) occupies the caudal-medial surface of HG, but it is unclear if A1 has normal asymmetry, or whether its asymmetry is altered in schizophrenia. To address these issues, we compared bilateral gray matter volumes of HG and A1, and neuron density and number in A1, in autopsy brains from male subjects with or without schizophrenia. Comparison of diagnostic groups did not reveal altered gray matter volumes, neuron density, neuron number or hemispheric asymmetries in schizophrenia. With respect to hemispheric differences, HG displayed a clear left>right asymmetry of gray matter volume. Area A1 occupied nearly half of HG, but had less consistent volume asymmetry, that was clearly present only in a subgroup of archival brains from elderly subjects. Neuron counts, in layers IIIb c and V-VI, showed that the A1 volume asymmetry reflected differences in neuron number, and was not caused simply by changes in neuron density. Our findings confirm previous reports of striking hemispheric asymmetry of HG, and additionally show evidence that A1 has a corresponding asymmetry, although less consistent than that of HG. PMID- 24148911 TI - Convergence and divergence of neuroanatomic correlates and executive task performance in healthy controls and psychiatric participants. AB - The associations between brain matter volume in the cerebral cortex and set shifting and attentional control as operationalized by the Wisconsin Card Sort Test (WCST) and Condition Three of the Delis-Kaplan version of the Color Word Interference Test (CWIT) were investigated in 15 healthy controls and 16 heterogeneously diagnosed psychiatric patients with self-control problems using voxel based morphometry. Both groups underwent standardized magnetic resonance imaging and neuropsychological assessment. WCST and CWIT variables, and a composite, were regressed across the whole brain. Although CWIT performance levels were the same in both groups, neuroanatomic correlates for the psychiatric participants invoked the left hemisphere language system, but the bilateral dorsal attention system in the healthy controls. On its own, no neuroanatomic correlates were observed for the WCST. But when part of a composite with CWIT, neuroanatomic correlates in the dorsal attention system emerged for the psychiatric participants. Psychometric combinations of manifest executive task variables may best represent higher level latent neuro-cognitive control systems. Factor analytic studies of neuropsychological test performances suggest the constructs being measured are the same across psychiatric and non-diagnosed participants, however, imaging modalities indicate the relevant neural architecture can vary by group. PMID- 24148912 TI - Normal brain activation in schizophrenia patients during associative emotional learning. AB - Emotional deficits are among the core features of schizophrenia and both associative emotional learning and the related ability to verbalize emotions can be reduced. We investigated whether schizophrenia patients demonstrated impaired function of limbic and prefrontal areas during associative emotional learning. Patients and controls filled out an alexithymia questionnaire and performed an associative emotional learning task with positive, negative and neutral picture word pairs during fMRI scanning. After scanning, they indicated for each pair whether they remembered it. We conducted standard GLM analysis and Independent Component Analysis (ICA). Both the GLM results and task-related ICA components were compared between groups. The alexithymia questionnaire indicated more cognitive-emotional processing difficulties in patients than controls, but equal experienced intensity of affective states. Patients remembered less picture-word pairs, irrespective of valence. GLM analysis showed significant visual, temporal, amygdalar/hippocampal, and prefrontal activation in all subjects. ICA identified a network of brain areas similar to GLM, mainly in response to negative stimuli. Neither analysis showed differences between patients and controls during learning. Although in previous studies schizophrenia patients showed abnormalities in both memory and emotion processing, neural circuits involved in cross-modal associative emotional learning may remain intact to a certain degree, which may have potential consequences for treatment. PMID- 24148913 TI - Acute effects of atrial fibrillation on atrial and ventricular function: a simultaneous invasive-echocardiographic hemodynamic study. PMID- 24148914 TI - Detection of right ventricular wall motion asynergy confirmed on four-dimensional 320-slice CT by two-dimensional global longitudinal strain of right ventricle using transthoracic-echocardiography in pulmonary hypertension. PMID- 24148915 TI - Synergistic effect of local endothelial shear stress and systemic hypercholesterolemia on coronary atherosclerotic plaque progression and composition in pigs. AB - BACKGROUND: Systemic risk factors and local hemodynamic factors both contribute to coronary atherosclerosis, but their possibly synergistic inter-relationship remains unknown. The purpose of this natural history study was to investigate the combined in-vivo effect of varying levels of systemic hypercholesterolemia and local endothelial shear stress (ESS) on subsequent plaque progression and histological composition. METHODS: Diabetic, hyperlipidemic swine with higher systemic total cholesterol (TC) (n=4) and relatively lower TC levels (n=5) underwent three-vessel intravascular ultrasound (IVUS) at 3-5 consecutive time points in-vivo. ESS was calculated serially using computational fluid dynamics. 3 D reconstructed coronary arteries were divided into 3mm-long segments (n=595), which were stratified according to higher vs. relatively lower TC and low (<1.2Pa) vs. higher local ESS (>=1.2Pa). Arteries were harvested at 9months, and a subset of segments (n=114) underwent histopathologic analyses. RESULTS: Change of plaque volume (DeltaPV) by IVUS over time was most pronounced in low-ESS segments from higher-TC animals. Notably, higher-ESS segments from higher-TC animals had greater DeltaPV compared to low-ESS segments from lower-TC animals (p<0.001). The time-averaged ESS in segments that resulted in significant plaque increased with increasing TC levels (slope: 0.24Pa/100mg/dl; r=0.80; p<0.01). At follow-up, low-ESS segments from higher-TC animals had the highest mRNA levels of lipoprotein receptors and inflammatory mediators and, consequently, the greatest lipid accumulation and inflammation. CONCLUSIONS: This study redefines the principle concept that "low" ESS promotes coronary plaque growth and vulnerability by demonstrating that: (i.) the pro-atherogenic threshold of low ESS is not uniform, but cholesterol-dependent; and (ii.) the atherogenic effects of local low ESS are amplified, and the athero-protective effects of higher ESS may be outweighed, by increasing cholesterol levels. Intense hypercholesterolemia and very low ESS are synergistic in favoring rapid atheroma progression and high risk composition. PMID- 24148916 TI - Aortic valvular interstitial cells apoptosis and calcification are mediated by TNF-related apoptosis-inducing ligand. AB - BACKGROUND/OBJECTIVES: Calcific aortic valvular disease (CAVD) is an actively regulated process characterized by the activation of specific osteogenic signaling pathways and apoptosis. We evaluated the involvement in CAVD of the TNF related apoptosis-inducing ligand (TRAIL), an apoptotic molecule which induces apoptosis by interacting with the death receptor (DR)-4 and DR5, and whose activity is modulated by the decoy receptor (DcR)-1 and DcR2. METHODS: Sections of calcific and normal aortic valves, obtained at surgery time, were subjected to immunohistochemistry and confocal microscopy for TRAIL immunostaining. Valvular interstitial cells (VICs) isolated from calcific (C-VICs) and normal (N-VICs) aortic valves were investigated for the gene and protein expression of TRAIL receptors. Cell viability was assayed by MTT. Von Kossa staining was performed to verify C-VIC ability to produce mineralized nodules. TRAIL serum levels were detected by ELISA. RESULTS: Higher levels of TRAIL were detected in calcific aortic valves and in sera from the same patients respect to controls. C-VICs express significantly higher mRNA and protein levels of DR4, DR5, DcR1, DcR2 and Runx2 compared to N-VICs. C-VICs and N-VICs, cultured in osteogenic medium, express significantly higher mRNA levels of DR4, Runx2 and Osteocalcin compared to baseline. C-VICs and N-VICs were sensitive to TRAIL-apoptotic effect at baseline and after osteogenic differentiation, as demonstrated by MTT assay and caspase-3 activation. TRAIL enhanced mineralized matrix nodule synthesis by C VICs cultured in osteogenic medium. CONCLUSIONS: TRAIL is characteristically present within calcific aortic valves, and mediates the calcification of aortic valve interstitial cells in culture through mechanism involving apoptosis. PMID- 24148917 TI - Fertility transition and adverse child sex ratio in districts of India. AB - Demographic research in India over the last two decades has focused extensively on fertility change and gender bias at the micro-level, and less has been done at the district level. Using data from the Census of India 1991-2011 and other sources, this paper shows the broad pattern of fertility transition and trends in the child sex ratio in India, and examines the determinants of the child sex ratio at the district level. During 1991-2011, while the Total Fertility Rate (TFR) declined by 1.2 children per woman, the child sex ratio fell by 30 points in the districts of India. However, the reduction in fertility was slower in the high-fertility compared with the low-fertility districts. The gender differential in under-five mortality increased in many districts of India over the study period. The decline in the child sex ratio was higher in the transitional compared with the low-fertility districts. The transitional districts are at higher risk of a low child sex ratio due to an increased gender differential in mortality and increase in the practice of sex-selective abortions. The sex ratio at birth and gender differential in mortality explains one-third of the variation, while region alone explains a quarter of the variation in the child sex ratio in the districts of India. PMID- 24148918 TI - Back to the basics: identifying positive youth development as the theoretical framework for a youth drug prevention program in rural Saskatchewan, Canada amidst a program evaluation. AB - BACKGROUND: Despite endorsement by the Saskatchewan government to apply empirically-based approaches to youth drug prevention services in the province, programs are sometimes delivered prior to the establishment of evidence-informed goals and objectives. This paper shares the 'preptory' outcomes of our team's program evaluation of the Prince Albert Parkland Health Region Mental Health and Addiction Services' Outreach Worker Service (OWS) in eight rural, community schools three years following its implementation. Before our independent evaluation team could assess whether expectations of the OWS were being met, we had to assist with establishing its overarching program goals and objectives and 'at-risk' student population, alongside its alliance with an empirically-informed theoretical framework. METHODS: A mixed-methods approach was applied, beginning with in-depth focus groups with the OWS staff to identify the program's goals and objectives and targeted student population. These were supplemented with OWS and school administrator interviews and focus groups with school staff. Alignment with a theoretical focus was determined though a review of the OWS's work to date and explored in focus groups between our evaluation team and the OWS staff and validated with the school staff and OWS and school administration. RESULTS: With improved understanding of the OWS's goals and objectives, our evaluation team and the OWS staff aligned the program with the Positive Youth Development theoretical evidence-base, emphasizing the program's universality, systems focus, strength base, and promotion of assets. Together we also gained clarity about the OWS's definition of and engagement with its 'at-risk' student population. CONCLUSIONS: It is important to draw on expert knowledge to develop youth drug prevention programming, but attention must also be paid to aligning professional health care services with a theoretically informed evidence-base for evaluation purposes. If time does not permit for the establishment of evidence-informed goals and objectives at the start-up of a program, obtaining insight and expertise from program personnel and school staff and administrators can bring the program to a point where this can still be achieved and theoretical linkages made after a program has been implemented. This is a necessary foundation for measuring an intervention's success. PMID- 24148919 TI - Re: Behfar Ehdaie, Richard Sylvester, Harry W. Herr. Maintenance bacillus Calmette-Guerin treatment of non-muscle-invasive bladder cancer: a critical evaluation of the evidence. Eur Urol 2013;64:579-85. PMID- 24148920 TI - The enabling institutional context for integrated water management: lessons from Melbourne. AB - There is widespread international acceptance that climate change, demographic shifts and resource limitations impact on the performance of water servicing in cities. In response to these challenges, many scholars propose that a fundamental move away from traditional centralised infrastructure towards more integrated water management is required. However, there is limited practical or scholarly understanding of how to enable this change in practice and few modern cities have done so successfully. This paper addresses this gap by analysing empirical evidence of Melbourne's recent experience in shifting towards a hybrid of centralised and decentralised infrastructure to draw lessons about the institutional context that enabled this shift. The research was based on a qualitative single-case study, involving interviews and envisioning workshops with urban water practitioners who have been directly involved in Melbourne's water system changes. It was found that significant changes occurred in the cultural-cognitive, normative and regulative dimensions of Melbourne's water system. These included a shift in cultural beliefs for the water profession, new knowledge through evidence and learning, additional water servicing goals and priorities, political leadership, community pressure, better coordinated governance arrangements and strong market mechanisms. The paper synthesises lessons from the case study that, with further development, could form the basis of prescriptive guidance for enabling the shift to new modes of water servicing to support more liveable, sustainable and resilient outcomes for future cities. PMID- 24148921 TI - Influence of solubilizing agents (cyclodextrin or surfactant) on phenanthrene degradation by electro-Fenton process--study of soil washing recycling possibilities and environmental impact. AB - One of the aims in soil washing treatment is to reuse the extracting agent and to remove the pollutant in the meantime. Thus, electro-Fenton (EF) degradation of synthetic soil washing solutions heavily loaded with phenanthrene was suggested for the first time. Two solubilising agents hydroxypropyl-beta-cyclodextrin (HPCD) and Tween 80((r)) (TW 80) were chosen as cyclodextrin (CD) and surfactant representatives, respectively. In order to reuse HPCD and to degrade the pollutant simultaneously, the following optimal parameters were determined: [Fe(2+)] = 0.05 mM (catalyst), I = 2000 mA, and natural solution pH (around 6), without any adjustment. Only 50% of TW 80 (still higher than the critical micelle concentration (CMC)) can be reused against 90% in the case of HPCD while phenanthrene is completely degraded in the meantime, after only 180 min of treatment. This can be explained by the ternary complex formation (Fe(2+)-HPCD organic pollutant) (equilibrium constant K = 56 mM(-1)) that allows OH to directly degrade the contaminant. This confirms that Fe(2+) plays an important role as a catalyst since it can promote formation of hydroxyl radicals near the pollutant and minimize HPCD degradation. After 2 h of treatment, HPCD/phenanthrene solution got better biodegradability (BOD5/COD = 0.1) and lower toxicity (80% inhibition of luminescence of Vibrio fischeri bacteria) than TW 80/phenanthrene (BOD5/COD = 0.08; 99% inhibition of V. fischeri bacteria). According to these data, HPCD employed in this integrated (soil washing + EF degradation) approach gave promising results in order to be reused whereas the pollutant is degraded in the meanwhile. PMID- 24148922 TI - Analysis of task-evoked systemic interference in fNIRS measurements: insights from fMRI. AB - Functional near infrared spectroscopy (fNIRS) is a promising method for monitoring cerebral hemodynamics with a wide range of clinical applications. fNIRS signals are contaminated with systemic physiological interferences from both the brain and superficial tissues, resulting in a poor estimation of the task related neuronal activation. In this study, we use the anatomical resolution of functional magnetic resonance imaging (fMRI) to extract scalp and brain vascular signals separately and construct an optically weighted spatial average of the fMRI blood oxygen level-dependent (BOLD) signal for characterizing the scalp signal contribution to fNIRS measurements. We introduce an extended superficial signal regression (ESSR) method for canceling physiology-based systemic interference where the effects of cerebral and superficial systemic interference are treated separately. We apply and validate our method on the optically weighted BOLD signals, which are obtained by projecting the fMRI image onto optical measurement space by use of the optical forward problem. The performance of ESSR method in removing physiological artifacts is compared to i) a global signal regression (GSR) method and ii) a superficial signal regression (SSR) method. The retrieved signals from each method are compared with the neural signals that represent the 'ground truth' brain activation cleaned from cerebral systemic fluctuations. We report significant improvements in the recovery of task induced neural activation with the ESSR method when compared to the other two methods as reflected in the Pearson R(2) coefficient and mean square error (MSE) metrics (two tailed paired t-tests, p<0.05). The signal quality is enhanced most when ESSR method is applied with higher spatial localization, lower inter-trial variability, a clear canonical waveform and higher contrast-to-noise (CNR) improvement (60%). Our findings suggest that, during a cognitive task i) superficial scalp signal contribution to fNIRS signals varies significantly among different regions on the forehead and ii) using an average scalp measurement together with a local measure of superficial hemodynamics better accounts for the systemic interference inherent in the brain as well as superficial scalp tissue. We conclude that maximizing the overlap between the optical pathlength of superficial and deeper penetration measurements is of crucial importance for accurate recovery of the evoked hemodynamic response in fNIRS recordings. PMID- 24148937 TI - Cancer care coming of age. Abstracts of the COSA (Clinical Oncological Society of Australia) 40th Annual Scientific Meeting. November 12-14, 2013. Adelaide, Australia. PMID- 24148923 TI - Manganism in the 21st century: the Hanninen lecture. AB - Since the original description of the health effects of inhaled occupational manganese (Mn) by Couper in 1837, an extensive literature details the clinical syndrome and pathophysiology of what was thought to be a rare condition. In the last decade, conventional wisdom regarding the clinicopathological effects of Mn has been challenged. Past exposures to Mn were an order of magnitude higher than modern exposures in developed countries; therefore, the clinical syndrome seen in the time of Couper is no longer typical of modern Mn exposed workers. Parkinsonism (rigidity, bradykinesia, rest tremor, and postural instability) is present in 15% of Mn-exposed workers in welding industries, and these parkinsonian signs are associated with reduced health status and quality of life. These parkinsonian signs also overlap considerably with the clinical findings seen in early stages of Parkinson's disease (PD); although, molecular imaging suggests that Mn-exposed workers have dopaminergic dysfunction in a pattern unique from PD. Furthermore, geographic information system studies demonstrate that regions of the US with high industrial Mn emissions have an increased incidence of PD and increased PD associated mortality. This review will contrast historical, descriptive human studies in Mn-exposed subjects with more recent data and will suggest a research agenda for the 21st century. PMID- 24148924 TI - Components of air pollution and cognitive function in middle-aged and older adults in Los Angeles. AB - While experiments in animals demonstrate neurotoxic effects of particulate matter (PM) and ozone (O3), epidemiologic evidence is sparse regarding the relationship between different constituencies of air pollution mixtures and cognitive function in adults. We examined cross-sectional associations between various ambient air pollutants [O3, PM2.5 and nitrogen dioxide (NO2)] and six measures of cognitive function and global cognition among healthy, cognitively intact individuals (n=1496, mean age 60.5 years) residing in the Los Angeles Basin. Air pollution exposures were assigned to each residential address in 2000-06 using a geographic information system that included monitoring data. A neuropsychological battery was used to assess cognitive function; a principal components analysis defined six domain-specific functions and a measure of global cognitive function was created. Regression models estimated effects of air pollutants on cognitive function, adjusting for age, gender, race, education, income, study and mood. Increasing exposure to PM2.5 was associated with lower verbal learning (beta= 0.32 per 10 MUg/m(3) PM2.5, 95% CI=-0.63, 0.00; p=0.05). Ambient exposure to NO2 >20 ppb tended to be associated with lower logical memory. Compared to the lowest level of exposure to ambient O3, exposure above 49 ppb was associated with lower executive function. Including carotid artery intima-media thickness, a measure of subclinical atherosclerosis, in models as a possible mediator did not attenuate effect estimates. This study provides support for cross-sectional associations between increasing levels of ambient O3, PM2.5 and NO2 and measures of domain specific cognitive abilities. PMID- 24148941 TI - Bilateral psoas abscess during pregnancy presenting as an acute abdomen: atypical presentation. AB - Nearly half of skeletal tuberculosis patients have spinal tuberculosis, but psoas abscess develops in only 5% of spinal tuberculosis cases. However, bilateral psoas abscess is a rarity. Psoas abscess occurring in pregnancy could be a clinical dilemma and is hardly reported. We report an unusual presentation of bilateral psoas abscess in pregnancy presenting as an acute abdomen and adnexal mass. PMID- 24148942 TI - Zebrafish sex: a complicated affair. AB - In this review, we provide a detailed overview of studies on the elusive sex determination (SD) and gonad differentiation mechanisms of zebrafish (Danio rerio). We show that the data obtained from most studies are compatible with polygenic sex determination (PSD), where the decision is made by the allelic combinations of several loci. These loci are typically dispersed throughout the genome, but in some teleost species a few of them might be located on a preferential pair of (sex) chromosomes. The PSD system has a much higher level of variation of SD genotypes both at the level of gametes and the sexual genotype of individuals, than that of the chromosomal sex determination systems. The early sexual development of zebrafish males is a complicated process, as they first develop a 'juvenile ovary', that later undergoes a transformation to give way to a testis. To date, three major developmental pathways were shown to be involved with gonad differentiation through the modulation of programmed cell death. In our opinion, there are more pathways participating in the regulation of zebrafish gonad differentiation/transformation. Introduction of additional powerful large scale genomic approaches into the analysis of zebrafish reproduction will result in further deepening of our knowledge as well as identification of additional pathways and genes associated with these processes in the near future. PMID- 24148945 TI - Phthalate exposures and human health concerns: a review and implications for practice. PMID- 24148943 TI - Uncovering the functional constraints underlying the genomic organization of the odorant-binding protein genes. AB - Animal olfactory systems have a critical role for the survival and reproduction of individuals. In insects, the odorant-binding proteins (OBPs) are encoded by a moderately sized gene family, and mediate the first steps of the olfactory processing. Most OBPs are organized in clusters of a few paralogs, which are conserved over time. Currently, the biological mechanism explaining the close physical proximity among OBPs is not yet established. Here, we conducted a comprehensive study aiming to gain insights into the mechanisms underlying the OBP genomic organization. We found that the OBP clusters are embedded within large conserved arrangements. These organizations also include other non-OBP genes, which often encode proteins integral to plasma membrane. Moreover, the conservation degree of such large clusters is related to the following: 1) the promoter architecture of the confined genes, 2) a characteristic transcriptional environment, and 3) the chromatin conformation of the chromosomal region. Our results suggest that chromatin domains may restrict the location of OBP genes to regions having the appropriate transcriptional environment, leading to the OBP cluster structure. However, the appropriate transcriptional environment for OBP and the other neighbor genes is not dominated by reduced levels of expression noise. Indeed, the stochastic fluctuations in the OBP transcript abundance may have a critical role in the combinatorial nature of the olfactory coding process. PMID- 24148944 TI - Phylotranscriptomics: saturated third codon positions radically influence the estimation of trees based on next-gen data. AB - Recent advancements in molecular sequencing techniques have led to a surge in the number of phylogenetic studies that incorporate large amounts of genetic data. We test the assumption that analyzing large number of genes will lead to improvements in tree resolution and branch support using moths in the superfamily Bombycoidea, a group with some interfamilial relationships that have been difficult to resolve. Specifically, we use a next-gen data set that included 19 taxa and 938 genes (~1.2M bp) to examine how codon position and saturation might influence resolution and node support among three key families. Maximum likelihood, parsimony, and species tree analysis using gene tree parsimony, on different nucleotide and amino acid data sets, resulted in largely congruent topologies with high bootstrap support compared with prior studies that included fewer loci. However, for a few shallow nodes, nucleotide and amino acid data provided high support for conflicting relationships. The third codon position was saturated and phylogenetic analysis of this position alone supported a completely different, potentially misleading sister group relationship. We used the program RADICAL to assess the number of genes needed to fix some of these difficult nodes. One such node originally needed a total of 850 genes but only required 250 when synonymous signal was removed. Our study shows that, in order to effectively use next-gen data to correctly resolve difficult phylogenetic relationships, it is necessary to assess the effects of synonymous substitutions and third codon positions. PMID- 24148946 TI - [Analysis of qualifications of medical and health institutions and certified doctors for providing occupational disease diagnosis in China]. AB - OBJECTIVE: To investigate the qualifications and current situations of the medical and health institutions and certified doctors for providing occupational disease diagnosis in China and to provide a reference for developing relevant policies. METHODS: Work reports and questionnaires survey were used to investigate the qualifications of all medical and health institutions and certified doctors for providing occupational disease diagnosis in China and their acceptance and diagnosis of occupational disease cases from 2006 to 2010. The rate for the work reports was 100%, and the response rate for the questionnaires was 71.0%. RESULTS: By the end of 2010, in the 31 provincial-level regions (excluding Hong Kong, Macao, and Taiwan) in China, there had been 503 medical and health institutions which were qualified for providing occupational disease diagnosis, including 207 centers for disease control and prevention, accounting for 41.2%, 145 general hospitals, accounting for 28.8%, 69 enterprise-owned hospitals, accounting for 13.7%, and 64 institutes or centers for occupational disease prevention and control, accounting for 12.7%; 4986 certified doctors got the qualification for providing occupational disease diagnosis, with 9.4 certified doctors on average in each institution, and there was 0.65 certified doctor per 100 000 employees. In addition, 16.5% of the institutions got all the qualifications for diagnosing 9 occupational diseases, and 17.1% of the institutions got the qualification for diagnosing one occupational disease. Each certified doctor accepted diagnosis of 16.8 cases of occupational diseases on average every year. CONCLUSION: A national occupational disease diagnosis network has been established in China, but the imbalance in regional distribution and specialty programs still exists among the qualified medical and health institutions and certified doctors. It is essential to further strengthen the development of regional qualified medical and health institutions and training of qualified doctors. PMID- 24148947 TI - [Effect of carbon disulfide on mitochondrial respiratory chain in spermatogenic cells in male rats]. AB - OBJECTIVE: To investigate the effect of carbon disulfide (CS(2)) on the mitochondrial respiratory chain in testicular spermatogenic cells in male rats and to explore the possible mechanism of reproductive system damage caused by CS(2) in male rats. METHODS: Twenty-four male Sprague-Dawley rats (clean grade) were randomly divided into four groups: three CS(2) exposure groups (CS(2) concentrations: 50, 250, and 1250 mg/m(3)) and a control group. The rats in CS(2) exposure groups were exposed to CS(2) by static inhalation for 10 weeks (2 h/d, 5 d/w), while the rats in control group were exposed to air. Then, all rats were sacrificed by decapitation; testicular tissues were collected, and mitochondrial protein in spermatogenic cells were extracted; the levels of mitochondrial respiratory chain enzyme complex I~V were measured by enzyme-linked immunosorbent assay. RESULTS: Compared with the control group, all CS(2) exposure groups had significantly increased levels of mitochondrial respiratory chain enzyme complex I~V in spermatogenic cells (P < 0.05). There were no significant differences in the levels of respiratory chain enzyme complex I~IV between the CS(2) exposure groups (P < 0.05), but the level of respiratory chain enzyme complex V rose significantly as the concentration of CS(2) increased (P<0.05). CONCLUSION: Various levels of CS(2) exposure may increase the levels of mitochondrial respiratory chain enzyme complex in testicular spermatogenic cells among male rats, thus affecting the normal oxidative phosphorylation in mitochondria. PMID- 24148948 TI - [Effect of carbon disulfide on mitochondrial apoptosis-related proteins in cytoplasm of testicular tissue among male rats]. AB - OBJECTIVE: To investigate the role of mitochondrial pathway in the apoptosis of spermatogenic cells induced by inhalation of carbon disulfide in male rats. METHODS: Twenty-four male Sprague-Dawley rats (clean grade) were divided into four groups according to their body weights: three CS(2) exposure groups (CS(2) concentrations: 50, 250, and 1250 mg/m(3)) and a control group. The rats in CS(2) exposure groups were exposed to CS(2) by static inhalation for 10 weeks (2 h/d, 5 d/w), while the rats in control group were exposed to air. Then, all rats were sacrificed by decapitation; testicular tissues were collected, and cytoplasmic proteins were extracted; the levels of apoptosis-inducing factor (AIF), cytochrome c (cyto c), Bcl-2, Bax, procaspase-9, and procaspase-3 were measured by Western blot, and the activities of caspase-9 and caspase-3 were measured using a test kit. RESULTS: Compared with the control group, all CS(2) exposure groups had significantly increased levels of cyto c in the cytoplasm of testicular tissue (P<0.05); in the 250 mg/m(3) CS(2) exposure group, the Bax/Bcl 2 ratio and activities of caspase-9 and caspase-3 increased significantly (P<0.05), and the content of procaspase-9 and procaspase-3 decreased significantly (P<0.05); in the 1250 mg/m(3) CS(2) exposure group, the relative expression levels of Bax and AIF in cytoplasm increased significantly (P<0.05), and the expression level of Bcl-2 decreased significantly (P<0.05). CONCLUSION: Mitochondrial pathway plays an important role in the CS(2)-induced apoptosis of spermatogenic cells in testicular tissue among male rats. PMID- 24148949 TI - [Association between single nucleotide polymorphisms of PON2 gene and susceptibility to occupational noise-induced deafness among Chinese Han population exposed to high noise levels]. AB - OBJECTIVE: To investigate the association between the single nucleotide polymorphisms (SNPs) of paraoxonase-2 (PON2) gene and the susceptibility to occupational noise-induced deafness among Chinese Han population exposed to high noise levels [>85 dB (A)]. METHODS: A case-control study was conducted in Chinese Han population exposed to high noise levels. The subjects were divided into case group (n = 127) and control group (n = 136) according to the Diagnostic criteria of occupational noise-induced deafness (GBZ 49-2007). The case group was composed of 127 workers with a mean binaural high-frequency hearing threshold not less than 40 dB, as measured using an electro-audiometer, while the control group was composed of 136 workers with a mean binaural high-frequency hearing threshold less than 40 dB, as measured using the electro-audiometer, who were on shift in the same position as the cases and matched with them for age, sex, and years of noise exposure. Peripheral venous blood (2 ml) was collected from each subject during physical examination to extract genomic DNA, and genotypes were identified using a TaqMan probe. RESULTS: PON2 genotypes rs7493 CG+GG, rs7785846 CT+TT, rs12026 CG+GG, and rs7786401 GT+TT were the risk factors for occupational noise induced deafness, and the adjusted odds ratios (95%confidence intervals) were 5.87 (3.11~11.07), 5.92 (3.10~11.32), 5.53 (2.93~10.45), and 5.93 (3.10~11.34), respectively. In addition, the higher the noise exposure levels, the higher the risk of developing occupational noise-induced deafness among the individuals carrying mutant genotypes. CONCLUSION: PON2 genotypes rs7493 CG+GG, rs7785846 CT+TT, rs12026 CG+GG, and rs7786401 GT +TT may be associated with the susceptibility to occupational noise-induced deafness among Chinese Han population exposed to high noise levels, and the effects of mutant genotypes and noise exposure levels may be mutually enhanced. PMID- 24148950 TI - [Effects of chronic aluminum exposure on learning and memory and brain-derived nerve growth factor in rats]. AB - OBJECTIVE: To investigate the effects of chronic aluminum exposure on the learning and memory abilities and brain-derived nerve growth factor (BDNF) in Sprague-Dawley (SD) rats. METHODS: Thirty-two male SD rats were randomly and equally divided into 4 groups: control group and high-, middle-, and low-dose exposure groups. The rats in high-, middle-, and low-dose exposure groups were fed with the feed mixed with AlCl(3) (120.0, 12.0, and 1.2 mg/kg, respectively), while the rats in control group were fed conventionally. After 6 months of feeding, brain aluminum levels were determined by inductively coupled plasma mass spectrometry; Morris water maze was employed to test the learning and memory abilities; the expression and content of BDNF in brain tissue were measured by Western blot and enzyme-linked immuno sorbent assay (ELISA). RESULTS: The high- and middle-dose exposure groups had significantly higher brain aluminum levels than the control group (P<0.05). The Morris water maze test showed that the high- and middle-dose exposure groups had significantly prolonged escape latency (P<0.05), significantly prolonged time taken to first reach the target quadrant (P<0.01), and significantly decreased number of platform crossings and time spent in the target quadrant (P<0.05), as compared with the control group. The Western blot and ELISA showed that the expression and content of BDNF in brain tissue decreased as the dose of AlCl(3) increased, and they were significantly lower in the high- and middle-dose exposure groups than in the control group (P<0.05). CONCLUSION: Chronic aluminum exposure (12.0 and 120.0 mg/kg) can lead to cognitive dysfunction in rats, and the decreased expression of BDNF may be one of the mechanisms of learning and memory deficits induced by aluminum. PMID- 24148951 TI - [Effects of maternal exposure to nano-alumina during pregnancy on neurodevelopment in offspring mice]. AB - OBJECTIVE: To observe the effects of maternal exposure to nano-alumina during pregnancy on the neurodevelopment in offspring mice. METHODS: Female ICR mice began to be exposed to nano-alumina 10 d before mating, and the nano-alumina exposure lasted till offspring mice were born. All the female mice were randomly divided into 5 groups: solvent control group (saline), nano-carbon group (11.76 mg/ml), micro-alumina group (50 mg/ml), 50 nm alumina group (50 mg/ml), and 13 nm alumina group (50 mg/ml). All the mice were treated by nasal drip (10 ul/time) 3 times daily till offspring mice were born. Physiological indices, reflex and sensory function test, endurance test, Morris water maze test, positioning and navigation test, and open field test were used to evaluate the neurodevelopment of newborn mice. RESULTS: On day 28, the body weight of 13 nm alumina group (16.73+/-4.04 g) was significantly lower than that of solvent control group (20.45+/-2.50 g) (P<0.01); the 13 nm alumina group had significantly delayed time to ear opening compared with the solvent control group (4.91+/-0.78 d vs 4.45+/ 0.50 d, P<0.01); compared with the solvent control group, the nano-carbon group, micro-alumina group, 50 nm alumina group, and 13 nm alumina group had significantly delayed time to eruption of teeth (10.05+/-0.23 d vs 10.32+/-0.48 d, 10.75+/-0.45 d, 10.32+/-0.47 d, and 10.79+/-0.49 d, P<0.05 or P<0.01). On days 4 and 7 after birth, compared with the solvent control group, other groups had significantly decreased proportions of mice which passed the cliff avoidance test (P < 0.05 or P < 0.01). On days 12 and 14 after birth, compared with the solvent control group, the nano-carbon group, 50 nm alumina group, and 13 nm alumina group had significantly reduced pre-suspension time in the endurance test (P < 0.05 or P < 0.01). The Morris water maze and positioning and navigation tests showed that the 13 nm alumina group had a significantly increased 5 d incubation period compared with the solvent control group (P < 0.05); compared with the solvent control group, other groups had significantly reduced numbers of platform crossings (P < 0.05 or P < 0.01). The open field test showed that the nano-carbon group and 13 nm alumina group had reduced numbers of rearings compared with the solvent control group (P < 0.05); compared with the solvent control group, other groups had significantly reduced numbers of modifications (P < 0.01). CONCLUSION: Maternal exposure to nano-alumina (13 nm) during pregnancy has inhibitory effects on the physical development and early behavioral development in newborn mice and can also inhibit the learning and memory abilities and adaptability to new environment in offspring mice. The neurodevelopmental toxicity of nano-alumina to newborn mice increases as the particle sizes of nano-alumina decrease, which has been demonstrated by the endurance test and number of rearings. PMID- 24148952 TI - [Effect of 0.1 Gy X-ray irradiation on gene expression profiles in normal human lymphoblastoid cells]. AB - OBJECTIVE: To investigate the effect of 0.1 Gy X-ray irradiation on the gene expression profiles in normal human lymphoblastoid cells using gene microarray and to explore the possible mechanism of the biological effect of low-dose irradiation. METHODS: The NimbleGen 12*135 K microarray corresponding to 45033 genes was used to analyze the gene expression profiles in AHH-1 cells cultured for 6 h and 20 h after 0.1 Gy X-ray irradiation. A gene was identified as the differentially expressed gene if the ratio between its expression levels in irradiation group and control group was higher than 2 or lower than 0.5. RT-PCR and real-time PCR were used to confirm some differentially expressed genes. RESULTS: There were 760 up-regulated genes and 1222 down-regulated genes in the cells at 6 h after 0.1 Gy X-ray irradiation, while there were 463 up-regulated genes and 753 down-regulated genes at 20 h after 0.1 Gy X-ray irradiation; there were 92 differentially expressed genes in common. The expression of GADD45A, CDKN2A, and Cx43 measured using gene microarray was confirmed by RT-PCR and real time PCR. CONCLUSION: Low-dose irradiation can affect the expression of many functional genes, which provides a basis for the research on the mechanism of radiation damage. PMID- 24148953 TI - [Test-retest reliability of Nordic Musculoskeletal Questionnaire in nurses]. AB - OBJECTIVE: To evaluate the test-retest reliability of Nordic Musculoskeletal Questionnaire in nurses and to provide supplementary data for evaluating the reliability of the questionnaire in different occupational populations. METHODS: Nordic Musculoskeletal Questionnaire was translated into Chinese according to the Guidelines for the process of cross-cultural adaptation of self-report measures. We carried out a study to examine the reliability of Chinese-version Nordic Questionnaire among Chinese nurses. This study was conducted in 120 nurses recruited from our hospital, who underwent questionnaire survey twice within one week. The test-retest reliability of questionnaire was analyzed. RESULTS: The Chinese-version Nordic Questionnaire showed a high test-retest reliability, with a Kappa coefficient of 0.72~1.00. CONCLUSION: The Chinese-version Nordic Questionnaire has a high test-retest reliability in nurses, so it can be used for the screening and epidemiological investigation of musculoskeletal disorders in this population. PMID- 24148954 TI - [Disorder of copper homeostasis induced by lead exposure among mice and intervention effect of quercetin]. AB - OBJECTIVE: To investigate the effect of lead exposure on copper and copper metalloenzyme and the intervention effect of quercetin. METHODS: Twenty-four specific pathogen-free male Sprague-Dawley rats of good health were randomly divided into control group (n = 8), lead acetate group (n = 8), and lead acetate + quercetin group (n = 8). The rats in lead acetate group were poisoned by drinking water with 1 g/L lead acetate for 8 weeks, while the rats in control group were fed by drinking water with sodium acetate of the same volume for 8 weeks; the rats in lead acetate+quercetin group were intraperitoneally injected with quercetin (30 mg * kg-1 * d-1) for 8 weeks while drinking water with lead acetate. The Morris water maze was used to test the learning and memory abilities of rats. The lead and copper levels in the serum, hippocampus, cortex, and bone were measured by graphite furnace atomic absorption spectrometry. The level of advanced glycation end products, activity of Cu/Zn superoxide dismutase (SOD), and content and activity of ceruloplasmin (CP) in the hippocampus and serum were measured using a test kit. HE staining was performed to observe the pathological changes in the hippocampus. RESULTS: The Morris water maze test showed that the latency in lead acetate group (52.50+/-12.04 s) was significantly longer than that in control group (28.08+/-7.31 s) (P<0.05), and the number of platform crossings was significantly lower in the lead acetate group than in the control group. Compared with those in the control group, the lead levels in the cortex and hippocampus in lead acetate group increased 2.72-fold and 3.79-fold, and the copper in the cortex and hippocampus, and serum free copper levels in lead acetate group increased 1.15-fold, 1.48-fold, and 6.44-fold. Compared with the control group, the lead acetate group had a lower content of CP in the hippocampus (1.23+/-0.40 U/mg provs0.78+/-0.08 U/mg pro) and 31.81%and 19.49%decreases in CP content and Cu/Zn SOD activity. Free copper level in serum was positively correlated with the latency and lead levels in the serum, cortex, and hippocampus. The escape latency of rats in lead acetate + quercetin group was decreased by 42.15% (P<0.05). The lead levels in the cortex and hippocampus in lead acetate + quercetin group (0.246 +/- 0.58 ug/g and 0.202+/-0.049 ug/g) were significantly lower than those in lead acetate group (0.391+/-0.49 ug/g and 0.546+/-0.120 ug/g), but the free copper and copper levels in the hippocampus and cortex were not significantly reduced. The lead acetate + quercetin group had higher Cu/Zn SOD activity and CP content in the hippocampus than the lead acetate group (P < 0.05). The light microscope observation showed that the number of cells in the hippocampus was reduced with disordered arrangement in the lead acetate group; with quercetin intervention, the hippocampus damage was reduced. CONCLUSION: Lead exposure results in disorder of copper homeostasis, while quercetin may alleviate the damage induced by lead to some extent. PMID- 24148955 TI - [Analysis of clinical features of mild chronic cadmium poisoning induced by different causes]. AB - OBJECTIVE: To analyze the clinical features of mild chronic cadmium poisoning induced by different causes. METHODS: A total of 90 patients with mild chronic cadmium poisoning, who were hospitalized in our center from 2008 to 2011 and had complete clinical data, were divided into two groups according to the causes of poisoning: environmental pollution group (n = 45) and occupational poisoning group (n = 45). The clinical symptoms, signs, laboratory indices, and treatment outcomes of all patients were analyzed. RESULTS: Compared with the environmental pollution group, the occupational poisoning group had more bone pain, less bone injury (based on imaging findings), and significantly increased abnormal rate of urinary retinol-binding protein (RBP) (P < 0.05); there were no significant differences in urinary beta-2 microglobulin (MG) and urinary microalbumin between the two groups (P > 0.05). Urinary cadmium, urinary RBP, and urinary beta-2 MG had no linear correlation between each other in the two groups. Both groups showed significant changes in urinary cadmium levels after treatment (P < 0.05). CONCLUSION: The clinical features of mild chronic cadmium poisoning induced by various causes are different, and active nutritional support therapy plays a positive role in improving prognosis. PMID- 24148956 TI - [Occupational acute dimethylformamide poisoning: an analysis of 16 cases]. AB - OBJECTIVE: To analyze the clinical features and diagnostic points of occupational acute dimethylformamide (DMF) poisoning and to explore the mechanism of occupational acute DMF poisoning. METHODS: A comprehensive analysis was performed on the clinical data of 16 cases of occupational acute DMF poisoning, including symptoms, signs, and laboratory testing results. RESULTS: The main clinical features of occupational acute DMF poisoning were digestive system impairments, especially abdominalgia. Hemorrhagic gastroenteritis was not found by gastroscopy. There was no significant correlation between the degree of abdominalgia and alanine aminotransferase level (r(s) = 0.109, P>0.05). CONCLUSION: Abdominalgia is recommended to be one of the reference indices for the diagnosis and degrading of occupational acute DMF poisoning, The mechanism of DMF poisoning remains unclear but it is considered to be related to methyl isocyanate, the intermediate product of DMF metabolism. PMID- 24148957 TI - [Application of color Doppler ultrasound in examining hypothyroidism among radiation-exposed workers]. AB - OBJECTIVE: To explore the application of color Doppler ultrasound in examining hypothyroidism among radiation-exposed workers. METHODS: A total of 181 radiation exposed workers who had clinical and laboratorial diagnoses of hypothyroidism were divided into X-ray diagnosis group, interventional radiology group, and radiotherapy group. Another 62 healthy people who underwent physical examinations were used as control group. All cases underwent color Doppler ultrasound; thyroid function, sonograms, and blood flow characteristics were analyzed. RESULTS: In the X-ray diagnosis group, interventional radiology group, and radiotherapy group, significant differences in the levels of free thyroxine and thyroid stimulating hormone were found across workers with different lengths of service (P < 0.05). In the X-ray diagnosis group, interventional radiology group, and radiotherapy group, the percentages of individuals having uneven internal echo intensity among clinical hypothyroidism cases were higher than the percentages among subclinical hypothyroidism cases (P < 0.05). The X-ray diagnosis group, interventional radiology group, and radiotherapy group had significantly higher constituent ratios of grade II and III blood flow signals than the control group (P < 0.05). The peak systolic velocity of the superior thyroid artery (V(max)) was significantly higher in the X-ray diagnosis group, interventional radiology group, and radiotherapy group than in the control group (P < 0.05); in each group, Vmax was significantly higher in clinical hypothyroidism cases than in subclinical hypothyroidism cases (P < 0.05). CONCLUSION: As a simple, non invasive, and economic examination, color Doppler ultrasound has been demonstrated as a valuable method for evaluating occupational hypothyroidism and holds promise for clinical application. PMID- 24148958 TI - [Portable gas chromatography for determining airborne acrylonitrile in workplaces]. AB - OBJECTIVE: To establish a method for rapid determination of airborne acrylonitrile using a portable gas chromatograph. METHODS: A single standard sample of acrylonitrile was prepared in a laboratory and sampled by the built-in constant flow pump of the portable gas chromatograph. The sample was then preconcentrated by the preconcentrator, thermally desorbed, separated by capillary columns, and detected by a micro argon ionization detector to determine the retention time. Retention time was then used to perform qualitative analysis. Under the set condition of gas chromatography, the external standard method was used to create a standard curve for quantitative analysis of acrylonitrile. RESULTS: The linear range of acrylonitrile on the portable gas chromatograph was 0.25 to 3.00 mg/m(3). The regression equation was y = 10(-5) x-0.0275, r = 0.9977. The limit of detection was 0.005 mg/m(3), and the lower limit of quantification was 0.25 mg/m(3). The relative standard deviation was lower than 7.09%, and the degree of accuracy was 91.09-105.54%. CONCLUSION: Portable gas chromatography is a simple, repeatable, and accurate method for rapid determination of airborne acrylonitrile. PMID- 24148959 TI - [Determination of glyphosate in air of workplaces by ion chromatography]. AB - OBJECTIVE: To establish a method for determining glyphosate in the air of workplaces by ion chromatography. METHODS: Ultra-fine glass fiber filter paper was used to collect glyphosate from the workplace air. After being ultrasonically eluted with deionized water, samples were determined by ion chromatography using a conductivity detector. RESULTS: Within the range of 0.05-1.00 mg/L, a linear relationship was found with a limit of detection of 0.003 mg/m(3). The minimum detectable concentration was 0.000 41 mg/m(3) (calculated by sampling 75 L of air). For three different concentrations of glyphosate, the intra-batch relative standard deviations (RSDs) were 1.8%, 1.6%, and 0.8%, respectively, and the inter batch RSDs were 1.9%, 2.1%, and 2.2%, respectively. The recovery rate ranged from 94.8% to 97.4%. The elution efficiency ranged from 94.5% to 96.7%. The sampling efficiency was 100%. Samples could be stored at room temperature for at least 7 days. CONCLUSION: This presented method meets the requirements of Guide for establishing occupational health standards-Part 4: Determination methods of air chemicals in workplace and is feasible for determination of glyphosate in the air of workplaces. PMID- 24148960 TI - [Study on MSO/GO-based determination method for trace amount of aqueous Hg2+]. AB - OBJECTIVE: To establish a highly sensitive fluorometric nanobiosensor for determination of aqueous mercury ions (Hg(2+)) using optimized mercury-specific oligonucleotide (MSO) probes and graphene oxide (GO). METHODS: The nanobiosensor was assembled by attaching the self-designed MSO(1) (5' end labeled with fluorophore carboxyfluorescein (FAM), denoted as FAM-MSO(1)) and MSO(2) to the surface of GO through strong non-covalent bonding forces. Upon the addition of Hg(2+), the formation of the T-Hg(2+)-T configuration desorbed the FAM-MSO(1) and MSO(2) from the surface of GO, resulting in a restoration of the fluorescence of FAM-MSO(1). Using the specific mispairing of T-Hg(2+)-T and the changes in fluorescent signals in solutions, quantitative analysis of Hg(2+) could be performed. RESULTS: The average thickness of the prepared GO sheets was only 1.4 nm. For the Hg(2+) nanobiosensor, the optimum concentrations of FAM-MSO(1) and MSO(2) were both 1 umol/L, the optimum volume of 0.5 g/L GO was 5 uL, and the limit of detection was 10 pmol/L; it had low cross-reactivity with 10 other kinds of non-specific metal ions; the fluorescence recovery efficiency was up to 65% in the re-determination of Hg(2+) after addition of Na(2)S(2)O(3). CONCLUSION: The MSO/GO-based nanobiosensor is convenient to operate, highly sensitive, highly specific, highly accurate, and reusable. It can be applied to determine trace amount of Hg(2+) in aqueous solutions. PMID- 24148961 TI - [Study on occupational exposure limit of dimethoxymethane in workplace air]. AB - OBJECTIVE: To study the occupational exposure limit of dimethoxymethane (DMM) in workplace air. METHODS: Literature research was conducted on DMM; information on its physicochemical properties, toxicology, and occupational epidemiology was collected. Upon analyzing these data, an occupational exposure limit of DMM in workplace air was proposed according to the guidelines and principles of developing occupational exposure limits for harmful factors in workplaces. RESULTS: A total of 165 air samples were collected from DMM manufacturers, 14 of which had a DMM concentration over 3000 mg/m(3), accounting for 8.48% of all samples. Compared with the control group, the exposed employees had a significantly increased incidence of discomfort symptoms when exposed to more than 6000 mg/m(3) DMN (P < 0.01).No significant differences in the constituent ratios of abnormal results in physical examinations were found between the exposure groups and control group (P > 0.05). CONCLUSION: We recommend to set the permissible concentration-time weighed average to 3100 mg/m(3) as the occupational exposure limit of DMM in workplace air in China. This occupational exposure limit standard meets the relevant requirements of toxicology and occupational epidemiology, as well as fits well with our country's current economical and technological levels. This standard has high applicability in China's domestic settings. PMID- 24148962 TI - Sex-related differences in maximal rate of isometric torque development. AB - Sex-differences in the maximum rate of torque development (dtau/dt(max)) may be due to differences in maximum muscle strength, because higher torque values mathematically lead to higher values for the rate of change in torque. The rate of change in the isometric torque-time curve is often normalized to the isometric maximum voluntary contraction (MVC) to evaluate males and females on a relative scale. Normalization eliminates sex-differences in dtau/dt(max) in the lower limbs because males and females are more comparable (i.e., differences between the sexes are relatively small) with respect to both muscle size and strength. However, normalization fails to result in parody in dtau/dt(max) of the upper limb, leading to the idea that other factors may be involved. This study determined if sex-differences in dtau/dt(max) in the upper limb can be attributed to differences in isometric MVC and/or a neural variable related to rate of increase in muscle activation (Q(30)). Forty-six participants (23 males, 23 females) performed maximal isometric elbow flexion contractions, "as hard and as fast as possible". Maximum torque (tau(max)), dtau/dt(max), and the rate of increase in surface electromyographic (sEMG) activity (Q(30)) were assessed. Muscle plus bone cross-sectional area (M+B CSA) of the upper arm was calculated to estimate differences in muscle size, only for comparative purposes. Maximum strength (55.5%) and muscle size (41.9%) of the elbow flexors in males were much greater than that of females (p < 0.05). There was a large difference (61.2%) between males and females with respect to dtau/dt(max) that was reduced by statistical correction using an analysis of covariance (ANCOVA). The percent differences were reduced to 36.7% (p < 0.05) for tau(max) and 54.4% (p < 0.05) for Q30, but was nearly eliminated to 13.8% (p > 0.05) when both variables were used simultaneously as covariates. Since sex-differences in the upper limb dtau/dt(max) persist, additional neural or biomechanical factors may be involved. PMID- 24148963 TI - Trunk muscle contributions of to L4-5 joint rotational stiffness following sudden trunk lateral bend perturbations. AB - The purpose of this research was to investigate the contributions of individual muscles to joint rotational stiffness and total joint rotational stiffness about the lumbar spine's L(4-5) joint prior to, and following, sudden dynamic lateral perturbations to the trunk. Kinematic and surface EMG data were collected while subjects maintained a kneeling posture on a robotic platform, while restrained so that motions caused by the perturbation were transferred to the pelvis, causing motion of the trunk and head. The robotic platform caused sudden inertial trunk lateral perturbations to the right or left, with or without timing and direction knowledge. An EMG-driven model of the lumbar spine was used to calculate the muscle forces and contributions to joint rotational stiffness during the perturbations. Data showed 95% and 106% increases in total joint rotational stiffness, about the lateral bend and axial twist axes, when subjects had knowledge of the timing of the perturbation. Also, the contralateral muscles exhibited a significantly larger total joint rotational stiffness about the lateral bend axis, and earlier surface EMG responses, than the ipsilateral muscles. The results indicate that, when the timing of the perturbation was unknown, subjects relied more on delayed muscle forces following the perturbation to stiffen the L(4-5) joint. PMID- 24148964 TI - Interfacial properties of three different bioactive dentine substitutes. AB - Three different bioactive materials suitable as dentine substitutes in tooth repair have been studied: glass-ionomer cement, particulate bioglass, and calcium silicate cement. On 15 permanent human molars, Class V cavities were prepared and the bottom of each cavity was de-mineralized by an artificial caries gel. After the de-mineralization, the teeth were restored with: (1) Bioglass(r)45S5 and ChemFil(r) Superior; (2) BiodentineTM and ChemFil(r) Superior; and (3) ChemFil(r) Superior for a complete repair. The teeth were stored for 6 weeks in artificial saliva, then cut in half along the longitudinal axis: the first half was imaged in a scanning electron microscope (SEM) and the other half was embedded in resin and analyzed by SEM using energy-dispersive X-ray analysis. The glass-ionomer and the bioglass underwent ion exchange with the surrounding tooth tissue, confirming their bioactivity. However, the particle size of the bioglass meant that cavity adaptation was poor. It is concluded that smaller particle size bioglasses may give more acceptable results. In contrast, both the glass-ionomer and the calcium silicate cements performed well as dentine substitutes. The glass-ionomer showed ion exchange properties, whereas the calcium silicate gave an excellent seal resulting from its micromechanical attachment. PMID- 24148965 TI - Medicinal properties of 'true' cinnamon (Cinnamomum zeylanicum): a systematic review. AB - BACKGROUND: In traditional medicine Cinnamon is considered a remedy for respiratory, digestive and gynaecological ailments. In-vitro and in-vivo studies from different parts of the world have demonstrated numerous beneficial medicinal effects of Cinnamomum zeylanicum (CZ). This paper aims to systematically review the scientific literature and provide a comprehensive summary on the potential medicinal benefits of CZ. METHODS: A comprehensive systematic review was conducted in the following databases; PubMed, Web of Science, SciVerse Scopus for studies published before 31st December 2012. The following keywords were used: "Cinnamomum zeylanicum", "Ceylon cinnamon", "True cinnamon" and "Sri Lankan cinnamon". To obtain additional data a manual search was performed using the reference lists of included articles. RESULTS: The literature search identified the following number of articles in the respective databases; PubMed=54, Web of Science=76 and SciVerse Scopus=591. Thirteen additional articles were identified by searching reference lists. After removing duplicates the total number of articles included in the present review is 70. The beneficial health effects of CZ identified were; a) anti-microbial and anti-parasitic activity, b) lowering of blood glucose, blood pressure and serum cholesterol, c) anti-oxidant and free radical scavenging properties, d) inhibition of tau aggregation and filament formation (hallmarks of Alzheimer's disease), e) inhibitory effects on osteoclastogenesis, f) anti-secretagogue and anti-gastric ulcer effects, g) anti nociceptive and anti-inflammatory activity, h) wound healing properties and i) hepato-protective effects. The studies reported minimal toxic and adverse effects. CONCLUSIONS: The available in-vitro and in-vivo evidence suggests that CZ has many beneficial health effects. However, since data on humans are sparse, randomized controlled trials in humans will be necessary to determine whether these effects have public health implications. PMID- 24148966 TI - Knowledge, attitudes and practices of primary care physicians in the Franche Comte region (France) regarding the risk of rabies. AB - Rabies remains a public health concern and is associated with a mortality rate of nearly 100%. An observational survey was undertaken in 2010 to assess the knowledge, attitudes and practices of primary care physicians (PCPs) in our area regarding the risk of rabies. Standardized questionnaires were sent to a random sample of 400 PCPs practicing in the Franche-Comte region (eastern France), requesting their voluntary and anonymous participation. The questionnaires requested socio-demographic details and self-evaluation. Seven clinical situations were selected to assess the attitudes of physicians. The response rate was 38.5%. Most of the PCPs were based in rural and semi-rural areas, 76% knew where their nearest rabies centre was located and 75% of them claimed their knowledge of the risk of rabies was poor. While most of them (>80%) knew which animals transmitted the disease as well as the severity criteria for bites, only 12% knew that there was no contraindication for the rabies vaccine in the event of exposure to the disease. Responses to the seven clinical situations showed that most of them did not know the precise indication for the rabies vaccine and rabies immunoglobulin. Primary care physicians are usually aware of the risk of rabies, but their knowledge of how to manage rabies exposure and prevention often requires updating. The health authorities should provide more detailed information to PCPs and to the general population about the risk of rabies. PMID- 24148967 TI - Semi-quantitative measurement of specific proteins in human cumulus cells using reverse phase protein array. AB - BACKGROUND: The ability to predict the developmental and implantation ability of embryos remains a major goal in human assisted-reproductive technology (ART) and most ART laboratories use morphological criteria to evaluate the oocyte competence despite the poor predictive value of this analysis. Transcriptomic and proteomic approaches on somatic cells surrounding the oocyte (granulosa cells, cumulus cells [CCs]) have been proposed for the identification of biomarkers of oocyte competence. We propose to use a Reverse Phase Protein Array (RPPA) approach to investigate new potential biomarkers of oocyte competence in human CCs at the protein level, an approach that is already used in cancer research to identify biomarkers in clinical diagnostics. METHODS: Antibodies targeting proteins of interest were validated for their utilisation in RPPA by measuring siRNA-mediated knockdown efficiency in HEK293 cells in parallel with Western blotting (WB) and RPPA from the same lysates. The proteins of interests were measured by RPPA across 13 individual human CCs from four patients undergoing intracytoplasmic sperm injection procedure. RESULTS: The knockdown efficiency of VCL, RGS2 and SRC were measured in HEK293 cells by WB and by RPPA and were acceptable for VCL and SRC proteins. The antibodies targeting these proteins were used for their detection in human CCs by RPPA. The detection of protein VCL, SRC and ERK2 (by using an antibody already validated for RPPA) was then carried out on individual CCs and signals were detected for each individual sample. After normalisation by VCL, we showed that the level of expression of ERK2 was almost the same across the 13 individual CCs while the level of expression of SRC was different between the 13 individual CCs of the four patients and between the CCs from one individual patient. CONCLUSIONS: The exquisite sensitivity of RPPA allowed detection of specific proteins in individual CCs. Although the validation of antibodies for RPPA is labour intensive, RRPA is a sensitive and quantitative technique allowing the detection of specific proteins from very small quantities of biological samples. RPPA may be of great interest in clinical diagnostics to predict the oocyte competence prior to transfer of the embryo using robust protein biomarkers expressed by CCs. PMID- 24148968 TI - Memory for symmetry and perceptual binding in patients with schizophrenia. AB - The present study investigated the use of perceptual binding processes in schizophrenic (SC) patients and matched healthy controls, by examining their performance on the recall of symmetrical (vertical, horizontal and diagonal) and asymmetrical patterns varying in length between 2 and 9 items. The results showed that, although SC patients were less accurate than controls in all conditions, both groups recalled symmetrical patterns better than asymmetrical ones. The impairment of SC patients was magnified with supra-span symmetrical arrays, and they were more likely to reproduce symmetrical patterns as asymmetrical, particularly at medium and high length levels. Hierarchical regression analyses further indicated that the between-group differences in the recall of supra-span vertical and horizontal arrays, which require a greater involvement of visual pattern processes, remained significant after removing the variance associated with performance on asymmetrical patterns, which primarily reflects intrafigural spatial processes. It is proposed that schizophrenia may be associated with a specific deficit in the formation and retrieval of the global visual images of studied patterns and in the use of the on-line information about the type of symmetry being tested to guide retrieval processes. PMID- 24148969 TI - Photo-activated porphyrin in combination with antibiotics: therapies against Staphylococci. AB - Staphylococcal infections have become difficult to treat due to antibiotic insensitivity and resistance. Antimicrobial combination therapies may minimize acquisition of resistance and photodynamic therapy is an attractive candidate for these combinations. In this manuscript, we explore combined use of antibiotics and meso-tetra (4-aminophenyl) porphine (TAPP), a cationic porphyrin, for treatment of Staphylococcus aureus contamination. We characterize the antimicrobial activity of photoactivated TAPP and show that activity is largely lost in the presence of a radical scavenger. Importantly, TAPP can be reactivated with continued, albeit attenuated, antibacterial activity. We then show that the antimicrobial activity of illuminated TAPP is additive with chloramphenicol and tobramycin for S. aureus and Escherichia coli, and synergistic for MRSA and Staphylococcus epidermidis. Chloramphenicol+methylene blue, another photosensitizer, also show additivity against S. aureus. In contrast, ceftriaxone and vancomycin do not strongly augment the low level effects of TAPP against S. aureus. Eukaryotic cells exhibit a dose-dependent toxicity with illuminated TAPP. Our results suggest that even sub-minimum inhibitory concentrations of photo activated TAPP could be used to boost the activity of waning antibiotics. This may play an important role in treatments reliant on antibiotic controlled release systems where augmentation with photo-active agents could extend their efficacy. PMID- 24148970 TI - Tumor cells loaded with alpha-galactosylceramide promote therapeutic NKT dependent anti-tumor immunity in multiple myeloma. AB - Tumor cells have been used as the tumor antigen sources for developing cancer vaccines. Due to their low immunogenicity, tumor antigens are combined with various adjuvants to enhance immunogenicity of cancer vaccines. Among them, a natural killer T cell (NKT)-ligand, alpha-galactosylceramide (alphaGC) has been reported as a powerful adjuvant showing therapeutic effects in solid tumors as well as hematological malignancies including lymphoma. In this study, we applied alphaGC-based tumor cell vaccine in mouse multiple myeloma model. The alphaGC loaded MOPC315BM myeloma cell vaccine efficiently retarded tumor growth, induced regression of established tumors, and protected surviving mice from tumor rechallenge. Therapeutic responses were associated with induction of strong humoral immune responses, including myeloma-specific antibodies, and cellular immune responses, including myeloma-specific CD8(+) cytotoxic T lymphocytes and memory T cells. In addition, regulatory T cells were significantly decreased in mice that received the alphaGC-loaded myeloma cell vaccine. Thus, our results demonstrated that alphaGC-loaded myeloma vaccine efficiently promoted NKT dependent anti-tumor immunity in a mouse model. These findings are informative for improving the efficacy of tumor-cell-based immunotherapy for patients with MM and other CD1d-expressing tumors. PMID- 24148971 TI - Internet use and cancer-preventive behaviors in older adults: findings from a longitudinal cohort study. AB - BACKGROUND: The Internet is a key provider of health information, but little is known about its associations with cancer-preventive behaviors. This study investigated the associations between Internet use and cancer-preventive behaviors among older adults. METHODS: Data were taken from Waves 1 to 5 (2002 2011) of the English Longitudinal Study of Aging, a cohort study of men and women 50 years or older in England, United Kingdom. Internet use was recorded at each wave. Breast and colorectal screening, fruit and vegetable consumption, physical activity, and smoking were recorded at Wave 5. Social, cognitive, and physical function variables recorded at Wave 1 were analyzed as predictors of Internet use and included as covariates in analyses linking Internet use to behavior. RESULTS: Of 5,943 respondents, 41.4% did not report any Internet use, 38.3% reported using it in one to three waves ("intermittent users"), and 20.3% used it in all waves ("consistent users"). Internet use was higher in younger, male, White, wealthier, more educated respondents, and those without physical limitations. Multivariable analysis showed that consistent users were more likely than "never users" to report CRC screening, weekly moderate/vigorous physical activity, and five or more daily servings of fruit and vegetables, and less likely to report smoking. There was no significant association between Internet use and breast screening. CONCLUSIONS: Internet use showed a quantitative association with cancer preventive behaviors even after controlling for various social, cognitive, and physical correlates of Internet use. IMPACT: Promoting Internet use among older adults from all backgrounds could contribute to improving cancer outcomes and reducing inequalities. PMID- 24148972 TI - 125Te NMR chemical-shift trends in PbTe-GeTe and PbTe-SnTe alloys. AB - Complex tellurides, such as doped PbTe, GeTe, and their alloys, are among the best thermoelectric materials. Knowledge of the change in (125)Te NMR chemical shift due to bonding to dopant or "solute" atoms is useful for determination of phase composition, peak assignment, and analysis of local bonding. We have measured the (125)Te NMR chemical shifts in PbTe-based alloys, Pb1-xGexTe and Pb1 xSnxTe, which have a rocksalt-like structure, and analyzed their trends. For low x, several peaks are resolved in the 22-kHz MAS (125)Te NMR spectra. A simple linear trend in chemical shifts with the number of Pb neighbors is observed. No evidence of a proposed ferroelectric displacement of Ge atoms in a cubic PbTe matrix is detected at low Ge concentrations. The observed chemical shift trends are compared with the results of DFT calculations, which confirm the linear dependence on the composition of the first-neighbor shell. The data enable determination of the composition of various phases in multiphase telluride materials. They also provide estimates of the (125)Te chemical shifts of GeTe and SnTe (+970 and +400+/-150 ppm, respectively, from PbTe), which are otherwise difficult to access due to Knight shifts of many hundreds of ppm in neat GeTe and SnTe. PMID- 24148973 TI - Fates and transport of PPCPs in soil receiving reclaimed water irrigation. AB - Fates and transport of 9 commonly found PPCPs of the reclaimed water were simulated based on the HYDRUS-1D software that was validated with data generated from field experiments. Under the default scenario in which the model parameters and input data represented the typical conditions of turf grass irrigation in southern California, the adsorption, degradation, and volatilization of clofibric acid, ibuprofen, 4-tert-octylphenol, 4-n-nonylphenol, naproxen, triclosan, diclofenac sodium, bisphenol A and estrone in the receiving soils were tracked for 10 years. At the end, their accumulations in the 90 cm soil profile varied from less than 1 ng g(-1) to about 140 ng g(-1) and their concentrations in the drainage water in the 90 cm soil depth varied from nil to MUg L(-1) levels. The adsorption and microbial degradation processes interacted to contain the PPCPs entirely within surface 40 cm of the soil profiles. Leaching and volatilization were not significant processes governing the PPCPs in the soils. The extent of accumulations in the soils did not appear to produce undue ecological risks to the soil biota. PPCPs did not represent any potential environmental harm in reclaimed water irrigation. PMID- 24148974 TI - Removal potential of anti-estrogenic activity in secondary effluents by coagulation. AB - Anti-estrogenic activity in wastewater is gaining increased attention because of its endocrine-disrupting function. In this study, the level and removal efficiency by coagulation of anti-estrogenic activity in secondary effluents of domestic wastewater treatment plants were studied. Anti-estrogenic activity was detected in secondary effluent samples at a tamoxifen (TAM) equivalent concentration level of 0.38-0.94 mg-TAML(-1). Dissolved organic matters (DOM) with the molecular weight (MW) less than 3000 Da in hydrophobic acids (HOA) and hydrophobic neutrals (HON) fractions of the secondary effluent were the key fractions related to anti-estrogenic activity. Coagulation with FeCl(3) and polyaluminium chloride (PAC) can remove the anti-estrogenic activity of the secondary effluents, but the removal efficiency was limited. The removal efficiency using FeCl(3) coagulant was higher than that induced by PAC. Dissolved organic carbon was continuously removed with increased coagulant dose (0-120 mg L(-1) FeCl(3) or 0-60 mg L(-1) PAC). However, the removal of anti-estrogenic activity was not enhanced further when the coagulant concentration was beyond a critical value (30 mg L(-1) FeCl(3) or 10 mg L(-1) PAC). The highest removal of anti-estrogenic activity was about 36% by FeCl(3) and 20% by PAC. Size exclusion chromatography results indicated difficulty in removing DOM with MW less than 3000 Da in the secondary effluent during coagulation even at a high coagulant concentration, which led to low removal efficiency of anti-estrogenic activity. PMID- 24148975 TI - A Google fight between seizure and syncope. PMID- 24148976 TI - Focal cortical dysplasia IIb presenting as slowly progressive aphasia mimicking a brain tumor. PMID- 24148977 TI - Disclosure and the sunshine act: the goal of transparency! PMID- 24148978 TI - Esthetic paradigms in the interdisciplinary management of maxillary anterior dentition-a review. AB - This article reviews some commonly used esthetic proportions and paradigms in dentistry. Establishing optimal anterior esthetics frequently entails restorative, orthodontic, and periodontal treatment. Several guidelines have been purported to facilitate an esthetic outcome during the rehabilitation of the maxillary anterior teeth. The golden proportion, recurring esthetic dental proportion, tooth width : height ratios, vertical positioning of the maxillary lateral incisor, and the apparent contact dimension are examples of some such guidelines. Evaluation of these esthetic paradigms including their validity, esthetic significance, perception by laypeople, and the range of tolerance to alterations are very important considerations. CLINICAL SIGNIFICANCE: This review presents a comprehensive analysis of some selected esthetic dental paradigms and recommendations for their application in the interdisciplinary management of anterior dental esthetics. PMID- 24148979 TI - Management of shrinkage stresses in direct restorative light-cured composites: a review. AB - In spite of many advances in the field of dental resin composites, polymerization shrinkage continues to be a major problem. Shrinkage creates stresses within the material and its interface leading to marginal failure, staining, secondary caries, restoration displacement, tooth fracture, and postoperative sensitivity. The aim of this review is to explain the factors affecting shrinkage stresses, their consequences, and clinical strategies for their management. CLINICAL SIGNIFICANCE: Polymerization shrinkage stress in dental composites is recognized as a significant material limitation that substantially complicates the placement of restorations. Shrinkage creates stresses within the material and its interface leading to marginal failure, staining, secondary caries, restoration displacement, tooth fracture, and postoperative sensitivity. This review explains the factors affecting shrinkage stresses, their consequences, and clinical strategies for their management. PMID- 24148980 TI - Commentary: polymerization stress: does it really impact the longevity of composite restorations? PMID- 24148981 TI - Managing the peri-implant mucosa: a clinically reliable method for optimizing soft tissue contours and emergence profile. AB - STATE OF THE PROBLEM: The proper representation of soft tissue contours for a natural aspect of the peri-implant mucosa and its mimesis with the adjacent teeth is a crucial aspect of the esthetic area restoration. PURPOSE: This paper describes a method for the easy transfer of the peri-implant tissue morphology onto impression material with a view to achieving an accurate, custom implant restoration. The procedure described is suitable both for single and multi-unit implant-supported prostheses. CLINICAL PROCEDURES: Once the peri-implant mucosa is sculpted by the provisional restoration, the emergence profile is duplicated. The implant analog is embedded into laboratory stone or plaster in a mixing cup and allowed to set. The provisional restoration is removed from the oral cavity and screwed to the implant analog; then, a polyether material is placed in the mixing cup so that the provisional restoration is put into impression material at the level of the prosthetic emergence profile. After the polyether polymerizing, the provisional prosthesis is unscrewed and replaced with the stock hexed transfer for the final impression. Next, cold self-curing resin is poured into this gap and left to set. A custom transfer for this single implant site is thus obtained. This modified transfer is then removed and screwed onto the implant in the oral cavity for the definitive impression. CONCLUSIONS: The technique described enables a faithful reproduction of the peri-implant soft tissues and emergence profile. CLINICAL SIGNIFICANCE: An emergence profile that mimics the natural tooth should be obtained by successful esthetic implant restoration. Moreover, it allows proper hygiene, which is fundamental for implant maintenance. The best way to achieve the correct emergence profile is to sculpture the peri implant mucosa by means of a provisional prosthesis. Prefabricated provisional crowns cannot mimic the complexity and the variations of human soft tissue. Therefore, only a chair-side modification of the provisional restoration can accomplish the optimal result. Such a requirement can be satisfied by the clinical method described in the present report. PMID- 24148982 TI - Commentary: managing the peri-implant mucosa: a clinically reliable method for optimizing soft tissue contours and emergence profile. PMID- 24148983 TI - Influence of adhesive application methods and rebonding agent application on sealing effectiveness of all-in-one self-etching adhesives. AB - STATEMENT OF PROBLEM: The choice of adhesive application methods could affect the microleakage of self-etch adhesives. PURPOSE: To evaluate the effect of acid etching, doubling adhesive application time, doubling adhesive coating, and rebonding agent application on microleakage of self-etch adhesives in Class V cavities. MATERIALS AND METHODS: Seventy human third molars with Class V cavities assigned to five groups according to different adhesive application protocols for the three dentin adhesives (Clearfil S3 Bond, Kuraray Medical, Okayama, Japan; Optibond All-in-One, Kerr Corporation Orange, CA, USA; G-Aenial Bond, GC Corporation, Tokyo, Japan): group 1, manufacturer's recommendations; group 2, prior acid-etching of cavities; group 3, double application time; group 4, two consecutive coats of the adhesives; group 5, rebonding application on restoration margins. After bonding, the cavities were filled with a resin composite (Filtek Supreme XT, 3M ESPE Dental Products, St. Paul, MN, USA). The teeth were thermocycled, and the specimens were examined for microleakage using methylene blue as a marker. RESULTS: For Clearfil S3 Bond and Optibond All-in-One, microleakage in groups 2 and 5 were significantly lower than other groups' enamel margins. In groups 1, 2, 4, and 5, Clearfil S3 Bond exhibited significantly more leakage than the other dentin bonding agents in dentin margins. Microleakage was significantly higher on dentinal margins compared with the enamel margins for Clearfil S3 Bond in all of the groups. Optibond All-in-One showed significantly lower microleakage in dentin margins in all groups except groups 2 and 5. CONCLUSION: Acid-etching usually promoted the reduction of microleakage in enamel margins. On the other hand, rebonding application usually contributed to the reduction of microleakage more than other methods in enamel and dentin margins. CLINICAL RELEVANCE: Acid-etching or rebonding application may contribute to reduction of microleakage of all-in-one self-etching adhesives. PMID- 24148984 TI - Commentary: influence of adhesive application methods and rebonding agent application on sealing effectiveness of all-in-one self-etching adhesives. PMID- 24148985 TI - Effect of enamel bevel on the clinical performance of resin composite restorations placed in non-carious cervical lesions. AB - STATEMENT OF THE PROBLEM: Laboratory testing of enamel bevel reports many advantages; however clinical studies on this topic are scarce and controversial. PURPOSE OF THE STUDY: To evaluate the effect of enamel bevel on the retention rates of composite restorations placed in non-carious cervical lesions (NCCLs). MATERIALS AND METHODS: Forty-two patients with more than 20 teeth in occlusion and having at least two NCCLs participated in this study. The cavities were divided into non-beveled (control) and beveled (short bevel [45 degrees , 1-2 mm long] prepared with a diamond bur) groups. The NCCLs were restored with the 2 step etch-and-rinse adhesive ExciTE and the resin composite 4 Seasons (Ivoclar Vivadent). Eight-four restorations were placed and evaluated at baseline, after 6 and 12 months according to the modified U.S. Public Health Service criteria. RESULTS: The 12-month retention rates (95% confidence interval) for the beveled (91% [77-97%]) and non-beveled [88% (73-95%)] groups were similar. No significant differences were detected between groups in other criteria (Fisher test, p > 0.05). No significant differences were detected in the same group compared across different recall times (McNemar test, p > 0.05). CONCLUSION: Enamel beveling may not be clinically relevant for the retention of composite restorations in NCCLs after 12 months. CLINICAL SIGNIFICANCE: Beveling enamel margins may not be necessary in NCCL restorations restored with the 2-step etch-and-rinse systems. PMID- 24148986 TI - Commentary: effect of enamel bevel on the clinical performance of resin composite restorations placed in non-carious lesions. PMID- 24148987 TI - Critical appraisal: dental amalgam update-part I: clinical efficacy. AB - Dental amalgam use has been controversial ever since the Crawcour brothers of France introduced amalgam to the United States in 1833. It has been criticized for its alleged clinical shortcomings and biologic effects. As a result, we thought that it would be useful to provide an update on dental amalgam in two parts. Part I, presented here, focuses on the clinical aspects of dental amalgam, whereas Part II will focus on dental amalgam's biologic effects. PMID- 24148988 TI - Economic losses due to cystic echinococcosis in India: Need for urgent action to control the disease. AB - Cystic ehinococcosis (CE) caused by Echinococcus granulosus remains a neglected zoonotic disease despite its considerable human and animal health concerns. This is the first systematic analysis of the livestock and human related economic losses due to cystic echinococcosis in India. Data about human cases were obtained from a tertiary hospital. Human hydatidosis cases with and without surgical interventions were extrapolated to be 5647 and 17075 per year assuming a total human population of 1210193422 in India. Data about prevalence of hydatid cysts in important food producing animals were obtained from previously published abattoir based epidemiological surveys that reported a prevalence of 5.39% in cattle, 4.36% in buffaloes, 3.09% in pigs, 2.23% in sheep and 0.41% in goats. Animal population data were sourced from the latest census conducted by the Department of Animal Husbandry, Dairying and Fisheries, India. Other input parameters were obtained from published scientific literature. Probability distributions were included for many input values to account for variability and uncertainty. Sensitivity analyses were conducted to evaluate the effect of important parameters on the estimated economic losses. The analysis revealed a total annual median loss of Rs. 11.47 billion (approx. US $ 212.35 million). Cattle and buffalo industry accounted for most of the losses: 93.05% and 88.88% of the animal and total losses, respectively. Human hydatidosis related losses were estimated to be Rs. 472.72 million (approx. US $ 8.75 million) but are likely to be an under-estimate due to under-reporting of the disease in the country. The human losses more than quadrupled to Rs. 1953 million i.e. approx. US $ 36.17 million, when the prevalence of human undiagnosed cases was increased to 0.2% in the sensitivity analyses. The social loss and psychological distress were not taken into account for calculating human loss. The results highlight an urgent need for a science based policy to control and manage the disease in the country. PMID- 24148989 TI - Convergent evolution of ecomorphological adaptations in geographically isolated Bay gobies (Teleostei: Gobionellidae) of the temperate North Pacific. AB - North Pacific Bay gobies (Teleostei: Gobioidei: Gobionellidae) inhabit bays, beaches, coastal lagoons, and estuaries of temperate Asia and North America, but are absent from the boreal northernmost Pacific. Previously, morphological characters conventionally subdivided the clade into two groups - an elongate bodied, infaunal-inhabiting "Astrabe" group, and a deeper-bodied, non-infaunal "Chasmichthys" group - each with a disjunct East-West (amphi-) Pacific distribution. Here we use mitochondrial and multi-locus nuclear DNA sequence data to show that several morphological characters previously used to delimit these two groups have in fact arisen independently on both sides of the Pacific, revealing convergence of ecologically adaptive characters within a geographically divided clade. Basal divergence of the resultant tree coincides with a dramatic global cooling event at the Eocene/Oligocene transition, without evidence of subsequent trans-Pacific migration. A novel approach to partitioning sequence data by relative rate, as opposed to traditional gene/codon position partitioning, was used to help distinguish phylogenetic signal from noise on a per-site basis. Resulting improvements in topology and nodal support, along with decreased computational effort, suggest that this partitioning strategy may be useful for future studies in phylogenetics and phylogenomics. PMID- 24148990 TI - Phylogenetic relationships and genome divergence among the AA- genome species of the genus Oryza as revealed by 53 nuclear genes and 16 intergenic regions. AB - Rapid radiations have long been regarded as the most challenging issue for elucidating poorly resolved phylogenies in evolutionary biology. The eight diploid AA- genome species in the genus Oryza represent a typical example of a closely spaced series of recent speciation events in plants. However, questions regarding when and how they diversified have long been an issue of extensive interest but remain a mystery. Here, a data set comprising >60 kb of 53 singleton fragments and 16 intergenic regions is used to perform phylogenomic analyses of all eight AA- genome species plus four diploid Oryza species with BB-, CC-, EE- and GG- genomes. We fully reconstruct phylogenetic relationships of AA- genome species with confidence. Oryza meridionalis, native to Australia, is found to be the earliest divergent lineage around 2.93 mya, whereas O. punctata, a BB- genome species, serves as the best outgroup to distinguish their phylogenetic relationships. They separated from O. punctata approximately 9.11 mya during the Miocene epoch, and subsequently radiated to generate the entire AA- genome lineage diversity. The success in resolving the phylogeny of AA- genome species highlights the potential of phylogenomics to determine their divergence and evolutionary histories. PMID- 24148991 TI - Thiazole-aminopiperidine hybrid analogues: design and synthesis of novel Mycobacterium tuberculosis GyrB inhibitors. AB - A series of ethyl-4-(4-((substituted benzyl)amino)piperidin-1-yl)-2 (phenyl/pyridyl)thiazole-5-carboxylates was designed by molecular hybridization and synthesized from aryl thioamides in five steps. The compounds were evaluated for their in vitro Mycobacterium smegmatis (MS) GyrB ATPase assay, Mycobacterium tuberculosis (MTB) DNA gyrase super coiling assay, antituberculosis activity and cytotoxicity. Among the twenty four compounds studied, ethyl-4-(4-((4 fluorobenzyl)amino)piperidin-1-yl)-2-phenylthiazole-5-carboxylate (14) was found to be the promising compound which showed activity against all test with MS GyrB IC50 of 24.0 +/- 2.1 MUM, 79% inhibition of MTB DNA gyrase at 50 MUM, MTB MIC of 28.44 MUM, and not cytotoxic at 50 MUM. PMID- 24148992 TI - Novel state-dependent voltage-gated sodium channel modulators, based on marine alkaloids from Agelas sponges. AB - Clathrodin, alkaloid isolated from Agelas sponges, was reported in 1995 as a voltage-gated sodium channel modulator. Here we describe the design and synthesis of conformationally restricted clathrodin analogues incorporating the 4,5,6,7 tetrahydrobenzo[d]thiazol-2-amine moiety and evaluation of their modulatory activities on human voltage-gated sodium channel isoforms Na(v)1.3, Na(v)1.4 and Na(v)1.7, as well as their selectivity against cardiac isoform Na(v)1.5. Compounds were shown to act as state-dependent modulators of Na(v)1.3, Na(v)1.4 and Na(v)1.7 with IC50 values in the lower micromolar range for the open inactivated state of the channels. Preliminary structure-activity relationship studies have revealed the importance of hydrophobic interactions for binding to all three tested isoforms. Compound 4e with IC50 value of 8 MUM against Na(v)1.4 represents a novel selective state-dependent Na(v)1.4 channel modulator. PMID- 24148993 TI - Acetylcholinesterase inhibitors as Alzheimer therapy: from nerve toxins to neuroprotection. AB - Acetylcholinesterase is a member of the alpha/beta hydrolase protein super family, with a significant role in acetylcholine-mediated neurotransmission. Research in the modulators of AChEs has moved from a potent poison (Sarin, Soman) in war times to the potent medicine (physostigmine) in peaceful times. Natural anti-AChE includes carbamates, glycoalkaloids, anatoxins derived from green algae; synthetic anti-AChE includes highly poisonous organophosphates used as nerve gases and insecticides. Recently, the role of anti-AChE was reassessed from neurotoxins to neuron-protective in the diseases characterized by impaired acetylcholine-mediated neurotransmission like Alzheimer's disease (AD). So, the AChE has been proven to be the most viable therapeutic target for the symptomatic treatment of AD. This review article gives a spectrum of strategies to design AChE inhibitors used in the Alzheimer therapy. PMID- 24148995 TI - A simple and efficient method to observe internal structures of helminths by scanning electron microscopy. AB - Morphological studies of helminths by scanning electron microscopy are generally limited to the external topography of the organisms. In this work, we present a simple technique using ethanol as a cryoprotectant without postfixation in osmium tetroxide that allows for observation of the inner organization of helminths and preserves cellular structures. We tested the technique in three helminths: Echinostoma paraensei, Cruzia tentaculata, and Hassalstrongylus epsilon. The results show that this technique could potentially be applied to study the morphology, ultrastructure, and taxonomy of helminths. PMID- 24148997 TI - Experimental study of plane electrode thickness scaling for 3D vertical resistive random access memory. AB - The vertical scaling for the multi-layer stacked 3D vertical resistive random access memory (RRAM) cross-point array is investigated. The thickness of the multi-layer stack for a 3D RRAM is a key factor for determining the storage density. A vertical RRAM cell with plane electrode thickness (tm) scaled down to 5 nm, aiming to minimize 3D stack height, is experimentally demonstrated. An improvement factor of 5 in device density can be achieved as compared to a previous demonstration using a 22 nm thick plane electrode. It is projected that 37 layers can be stacked for a lithographic half-pitch (F) = 26 nm and total thickness of one stack (T) = 21 nm, delivering a bit density of 72.8 nm(2)/cell. PMID- 24148996 TI - Photochemically altered air pollution mixtures and contractile parameters in isolated murine hearts before and after ischemia. AB - BACKGROUND: The cardiopulmonary effects of the individual criteria air pollutants have been well investigated, but little is known about the cardiopulmonary effects of inhaled multipollutant mixtures that more realistically represent environmental exposures. OBJECTIVES: We assessed the cardiopulmonary effects of exposure to photochemically altered particle-free multipollutant mixtures. METHODS: We exposed mice to filtered air (FA), multipollutant mixtures, or ozone (O3) for 4 hr in a photochemical reaction chamber. Eight hours after exposure, we assessed cardiac responses using a Langendorff preparation in a protocol consisting of 20 min of global ischemia followed by 2 hr of reperfusion. Cardiac function was assessed by measuring the index of left-ventricular developed pressure (LVDP) and contractility (dP/dt) before ischemia. On reperfusion after ischemia, recovery of postischemic LVDP and size of infarct were examined. We used bronchoalveolar lavage (BAL) cell counts to assess lung inflammation. RESULTS: Exposure to the multipollutant mixtures decreased LVDP, baseline rate of left ventricular contraction (dP/dtmaximum), and baseline rate of left ventricular relaxation (dP/dtminimum) compared with exposure to FA. Exposure to O3 also decreased heart rate and dP/dtminimum. Time to ischemic contracture was prolonged in the multipollutant-mixture group relative to that in the FA group. Mice in the multipollutant-mixture group had better recovery of postischemic LVDP and smaller infarct size. Exposure to multipollutant mixtures and to O3 exposure increased numbers of macrophages in the BAL fluid. CONCLUSIONS: Exposure to photochemically altered urban air pollution appears to affect cardiac mechanics in isolated perfused hearts. Inhalation of acute multipollutant mixtures decreases LVDP and cardiac contractility in isolated non-ischemic murine hearts, prolongs ischemic contracture, increases postischemic recovery of LVDP, and reduces infarct size. PMID- 24148998 TI - Efficacy of sperm motility after processing and incubation to predict pregnancy after intrauterine insemination in normospermic individuals. AB - BACKGROUND: Intrauterine insemination (IUI) is widely used to treat infertility, and its adequate indication is important to obtain good pregnancy rates. To assess which couples could benefit from IUI, this study aimed to evaluate whether sperm motility using a discontinuous gradient of different densities and incubation in CO2 in normospermic individuals is able to predict pregnancy. METHODS: A total of 175 couples underwent 175 IUI cycles. The inclusion criteria for women were as follows: 35 years old or younger (age range: from 27 to 35 years) with normal fallopian tubes; endometriosis grades I-II; unexplained infertility; nonhyperandrogenic ovulatory dysfunction. Men with normal seminal parameters were also included. All patients underwent ovarian stimulation with clomiphene citrate and human hMG or r-FSH. When one or (at most) three follicles measuring 18 to 20 mm were observed, hCG (5000 UI) or r-hCG (250 mcg) was administered and IUI performed 36-40 h after hCG. Sperm processing was performed using a discontinuous concentration gradient. A 20 microliters aliquot was incubated for 24 h at 37 degrees C in 5% CO2 following a total progressive motility analysis. The Mann-Whitney and Chi-square tests, as well as a ROC curve were used to determine the cutoff value for motility. RESULTS: Of the 175 couples, 52 (in 52 IUI cycles) achieved clinical pregnancies (CP rate per cycle: 29.7%). The analysis of age, duration and causes of infertility did not indicate any statistical significance between pregnancy and no pregnancy groups, similar to the results for total sperm count and morphology analyses, excluding progressive motility (p < 0.0001). The comparison of progressive motility after processing and 24 h after incubation between these two groups indicated that progressive motility 24 h after incubation was higher in the pregnancy group. The analysis of the progressive motility of the pregnancy group after processing and 24 h after incubation has not shown any motility difference at 24 h after incubation; additionally, in couples who did not obtain pregnancy, there was a statistically significant decrease in progressive motility 24 h after incubation (p < 0.0001). The ROC curve analysis generated a cutoff value of 56.5% for progressive motility at 24 h after incubation and this cutoff value produced 96.1% sensitivity, 92.7% specificity, 84.7% positive predictive value and 98.3% negative predictive value. CONCLUSIONS: We concluded that the sperm motility of normospermic individuals 24 h after incubation at 37 degrees C in 5% CO2, with a cutoff value of 56.5%, is predictive of IUI success. PMID- 24148999 TI - Defining neonatal hypoglycaemia: a continuing debate. AB - Hypoglycaemia is one of the most frequent metabolic problems in neonatal medicine, and maintaining glucose homeostasis is one of the important physiological events during fetal-to-neonatal transition. Although frequently observed transient low blood glucose concentrations in the majority of healthy newborns are the reflections of normal metabolic adaptation processes during this transition, there has been a genuine concern that prolonged or recurrent low blood glucose levels may result in acute systemic effects and long-term neurological and developmental consequences. Hence, it is not surprising that neonatal hypoglycaemia remains one of the most important issues in our day-to-day practice and that we also become obsessed with the numbers and values that we believe are a 'cut-off' for its definition. The aim of this article is to critically appraise some of the available evidence either to support or refute the most widely accepted definition of 'neonatal hypoglycaemia' (blood glucose concentration: <2.6 mmol/l or 47 mg/dl), to highlight our knowledge gaps in defining neonatal hypoglycaemia, and to address the important concept of using an 'operational threshold', rather than focusing too much on a single blood glucose cut-off value, which is often applied to all newborn infants. PMID- 24149000 TI - MitoTimer probe reveals the impact of autophagy, fusion, and motility on subcellular distribution of young and old mitochondrial protein and on relative mitochondrial protein age. AB - To study mitochondrial protein age dynamics, we targeted a time-sensitive fluorescent protein, MitoTimer, to the mitochondrial matrix. Mitochondrial age was revealed by the integrated portions of young (green) and old (red) MitoTimer protein. Mitochondrial protein age was dependent on turnover rates as pulsed synthesis, decreased import, or autophagic inhibition all increased the proportion of aged MitoTimer protein. Mitochondrial fusion promotes the distribution of young mitochondrial protein across the mitochondrial network as cells lacking essential fusion genes Mfn1 and Mfn2 displayed increased heterogeneity in mitochondrial protein age. Experiments in hippocampal neurons illustrate that the distribution of older and younger mitochondrial protein within the cell is determined by subcellular spatial organization and compartmentalization of mitochondria into neurites and soma. This effect was altered by overexpression of mitochondrial transport protein, RHOT1/MIRO1. Collectively our data show that distribution of young and old protein in the mitochondrial network is dependent on turnover, fusion, and transport. PMID- 24149001 TI - Implant-retained dental rehabilitation in head and neck cancer patients: an assessment of success and failure. AB - BACKGROUND: This study aimed to evaluate the rate of osseointegration (ROI) and overall success rate (OSR) of implants placed in native and grafted jaws with or without radiotherapy at a 5-year follow-up in Indian head and neck cancer patients. MATERIAL AND METHODS: Thirty head and neck cancer patients from various socioeconomic strata were accrued. Eighty-five implants were inserted in 17 native and 13 grafted jaws. Nineteen patients received radiation therapy. A 5 year follow-up ROI and OSR of implants were reported. RESULTS: The 5-year ROI and OSR were 88% and 77%, respectively. ROI was 93% for grafted, 85% for native, 83% for irradiated, and 100% for nonirradiated jaws. OSR was 73% for grafted, 80% for native, 71% for irradiated, and 89% for nonirradiated jaws. Patients from higher socioeconomic strata had higher OSR (92%) as compared with those belonging to lower socioeconomic strata (65%). CONCLUSION: The failure rate observed in this study was 24% for implants placed in head and neck cancer patients at a 5-year follow-up. PMID- 24149002 TI - Assessment of drug candidates for broad-spectrum antiviral therapy targeting cellular pyrimidine biosynthesis. AB - Currently available antiviral drugs frequently induce side-effects or selection of drug-resistant viruses. We describe a novel antiviral principle based on targeting the cellular enzyme dihydroorotate dehydrogenase (DHODH). In silico drug design and biochemical evaluation identified Compound 1 (Cmp1) as a selective inhibitor of human DHODH in vitro (IC50 1.5+/-0.2nM). Crystallization data specified the mode of drug-target interaction. Importantly, Cmp1 displayed a very potent antiviral activity that could be reversed by co-application of uridine or other pyrimidine precursors, underlining the postulated DHODH-directed mode of activity. Human and animal cytomegaloviruses as well as adenoviruses showed strong sensitivity towards Cmp1 in cell culture-based infection systems with IC50 values in the low micromolar to nanomolar range. Particularly, broad inhibitory activity was demonstrated for various types of laboratory and clinically relevant adenoviruses. For replication of human cytomegalovirus in primary fibroblasts, antiviral mode of activity was attributed to the early stage of gene expression. A mouse in vivo model proved reduced replication of murine cytomegalovirus in various organs upon Cmp1 treatment. These findings suggested Cmp1 as drug candidate and validated DHODH as a promising cellular target for antiviral therapy. PMID- 24149003 TI - Quantitative determination and pharmacokinetic study of aurantio-obtusin in rat plasma by liquid chromatography-mass spectrometry. AB - A simple and sensitive liquid chromatography-tandem mass spectrometric method was developed and validated to measure aurantio-obtusin content in rat plasma using rhein as internal standard (IS). The analytes were extracted from plasma by a simple liquid-liquid extraction technique using ethyl acetate as extraction solvent. Chromatographic separation was performed on a Zorbax XDB-C18 column (50 mm * 4.6 mm, 2.1 um particle size) using the mobile phase consisting of methanol water (70 : 30, v/v). The detection was achieved by negative ion electrospray ionization in selected reaction monitoring mode, monitoring the transitions m/z 329.1 -> 299.2 and m/z 283.1 -> 183.0 for aurantio-obtusin and IS, respectively. The assay was linear over a concentration range of 4-4,000 ng/mL with a lower limit of quantification of 4.00 ng/mL for aurantio-obtusin. The intra- and inter day precision was <6.8%, and the accuracy values were between -1.7 and 7.1%. The validated method was successfully applied to the pharmacokinetics of aurantio obtusin following intravenous administrations to rats. PMID- 24149005 TI - Very low quality of life after acute stroke: data from the Efficacy of Nitric Oxide in Stroke trial. AB - BACKGROUND AND PURPOSE: Health-related quality of life, a key outcome after stroke, plays a role in the analysis of treatment cost-effectiveness. Some measures of health-related quality of life allow for a quality of life worse than death; the characteristics of such patients have not been well described. METHODS: Data from the Efficacy of Nitric Oxide in Stroke (ENOS) trial were used to explore health-related quality of life after stroke. The EuroQol questionnaire (EQ-5D) was performed at day 90, and a health utility score (HUS) was calculated. HUS was defined as follows: poor-good HUS>0, death HUS=0, and very poor HUS<0. The characteristics and outcomes of patients with HUS<0 were then explored. RESULTS: Of the 2569 patients, 303 (11.8%) died, and of the 2238 with quality of life data available, of whom 724 (32.3%) were completed by a proxy, 1959 (87.5%) had an HUS>0 and 279 (12.5%) had an HUS<0. Patients with HUS<0 were more likely to be older, women, have severe stroke, have proxy responders, and be institutionalized. Dominant hemisphere strokes were more likely to have proxy responders but not HUS<0. HUS was strongly correlated with dependency (modified Rankin Scale, r=-0.78) and disability (Barthel index, r=0.84) and moderately correlated with mood (Zung depression score, r=-0.59) and baseline severity (r=0.51). All but 1 patient with modified Rankin Scale of 5 had an HUS<0. CONCLUSIONS: Very low health-related quality of life is relatively common after stroke, particularly in patients with mobility problems or who are dependent on help for usual activities, and is related to poor functional outcome measures. CLINICAL TRIAL REGISTRATION URL: http://www.controlled-trials.com/. Unique identifier: ISRCTN99414122. PMID- 24149006 TI - Evaluation of patients for paroxysmal atrial fibrillation after ischemic stroke. PMID- 24149004 TI - Isoflurane post-treatment ameliorates GMH-induced brain injury in neonatal rats. AB - BACKGROUND AND PURPOSE: This study investigated whether isoflurane ameliorates neurological sequelae after germinal matrix hemorrhage (GMH) through activation of the cytoprotective sphingosine kinase/sphingosine-1-phosphate receptor/Akt pathway. METHODS: GMH was induced in P7 rat pups by intraparenchymal infusion of bacterial collagenase (0.3 U) into the right hemispheric germinal matrix. GMH animals received 2% isoflurane either once 1 hour after surgery or every 12 hours for 3 days. Isoflurane treatment was then combined with sphingosine-1-phosphate receptor-1/2 antagonist VPC23019 or sphingosine kinase 1/2 antagonist N,N dimethylsphingosine. RESULTS: Brain protein expression of sphingosine kinase-1 and phosphorylated Akt were significantly increased after isoflurane post treatment, and cleaved caspase-3 was decreased at 24 hours after surgery, which was reversed by the antagonists. Isoflurane significantly reduced posthemorrhagic ventricular dilation and improved motor, but not cognitive, functions in GMH animals 3 weeks after surgery; no improvements were observed after VPC23019 administration. CONCLUSIONS: Isoflurane post-treatment improved the neurological sequelae after GMH possibly by activation of the sphingosine kinase/Akt pathway. PMID- 24149007 TI - Subarachnoid extension of intracerebral hemorrhage and 90-day outcomes in INTERACT2. AB - BACKGROUND AND PURPOSE: The prognostic significance of subarachnoid extension of intracerebral hemorrhage was determined in the INTEnsive blood pressure Reduction in Acute Cerebral hemorrhage Trial (INTERACT2) study. METHODS: INTERACT2 was an open randomized controlled trial of early intensive compared with guideline recommended blood pressure lowering in patients with elevated systolic blood pressure within 6 hours of intracerebral hemorrhage. Independent predictors of death or major disability (scores 3-6 on the modified Rankin Scale) at 90 days were analyzed in logistic regression models. RESULTS: Of 2582 participants, 192 (7%) had subarachnoid extension, which was associated with larger hematoma volumes (P<0.0001) and higher National Institute of Health Stroke Scale score (P<0.0001). Subarachnoid extension predicted death or major disability at 90 days (71% versus 53%; unadjusted odds ratio, 2.25; 95% confidence interval, 1.63-3.10; P<0.0001). The association remained significant after adjusting for age, region, lipid-lowering therapy, systolic blood pressure, glucose, location of hematoma, intraventricular extension, and randomized treatment (odds ratio, 2.17; 95% confidence interval, 1.50-3.14; P<0.0001), but not after further adjustment for baseline hematoma volume (P=0.62). CONCLUSIONS: Subarachnoid extension of intracerebral hemorrhage is associated with poor prognosis, which is determined by a larger volume of the underlying intraparenchymal hematoma. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00716079. PMID- 24149009 TI - Ovalbumin-gum arabic interactions: effect of pH, temperature, salt, biopolymers ratio and total concentration. AB - The formation of soluble and insoluble complexes between ovalbumin (OVA) and gum arabic (GA) polysaccharide was investigated under specific conditions (pH 1.0 7.0; temperature 4-55 degrees C; NaCl concentration 0-60mM; total biopolymer concentration 0.05-3.0 wt%) by turbidimetric analysis. For the 2:1 OVA:GA ratio and in the absence of NaCl, soluble and insoluble complexes were observed at pH 4.61 (pHphi1) and 4.18 (pHphi2), respectively, with optimal biopolymer interactions occurring at pH 3.79 (pHopt). Under the same conditions, OVA alone gave only a weak turbidity intensity (turbidity <0.03), whereas GA had none. As the temperature increased, critical pH values shifted toward lower pH, and the maximum turbidity value occurred at 25 degrees C. The region between pHphi1 and pHphi2 was narrowed and the electrostatic interactions became weaker with increasing NaCl concentration. The maximum turbidity value increased as the total biopolymer concentration increased until reaching a critical value (2.0%), afterwards becoming a constant value. PMID- 24149008 TI - Spontaneous swallowing frequency has potential to identify dysphagia in acute stroke. AB - BACKGROUND AND PURPOSE: Spontaneous swallowing frequency has been described as an index of dysphagia in various health conditions. This study evaluated the potential of spontaneous swallow frequency analysis as a screening protocol for dysphagia in acute stroke. METHODS: In a cohort of 63 acute stroke cases, swallow frequency rates (swallows per minute [SPM]) were compared with stroke and swallow severity indices, age, time from stroke to assessment, and consciousness level. Mean differences in SPM were compared between patients with versus without clinically significant dysphagia. Receiver operating characteristic curve analysis was used to identify the optimal threshold in SPM, which was compared with a validated clinical dysphagia examination for identification of dysphagia cases. Time series analysis was used to identify the minimally adequate time period to complete spontaneous swallow frequency analysis. RESULTS: SPM correlated significantly with stroke and swallow severity indices but not with age, time from stroke onset, or consciousness level. Patients with dysphagia demonstrated significantly lower SPM rates. SPM differed by dysphagia severity. Receiver operating characteristic curve analysis yielded a threshold of SPM<=0.40 that identified dysphagia (per the criterion referent) with 0.96 sensitivity, 0.68 specificity, and 0.96 negative predictive value. Time series analysis indicated that a 5- to 10-minute sampling window was sufficient to calculate spontaneous swallow frequency to identify dysphagia cases in acute stroke. CONCLUSIONS: Spontaneous swallowing frequency presents high potential to screen for dysphagia in acute stroke without the need for trained, available personnel. PMID- 24149010 TI - Science made easy. PMID- 24149011 TI - Managing knee ostheoarthritis: efficacy of hyaluronic acid injections. AB - Osteoarthritis (OA) is the most common form of chronic arthritis worldwide. The etiology of pain in osteoarthritis is multifactoral, and includes mechanical and inflammatory processes. The use of intra-articular viscosupplementation in the nonoperative management of patients with osteoarthritis has become quite popular. Recent clinical data have demonstrated that the anti-inflammatory and chondroprotective actions of hyaluronic acid viscosupplementation reduce pain, from 4 to 14 weeks after injection, while improving patient function. Viscosupplements are comparable in efficacy to systemic forms of active intervention, with more local reactions but fewer systemic adverse events, and hyaluronic acid has more prolonged effects than IA corticosteroids. Although several randomized controlled trials have established the efficacy of this treatment modality, additional high quality randomized control studies with appropriate comparison are still required to clearly define the role of intra articular hyaluronic acid injections in the treatment of osteoarthritis. We review the basic science and development of viscosupplementation and discuss the mounting evidence in support of its efficacy and safety profile. PMID- 24149012 TI - [Systemic lupus erythematosus and allergy: an integrative review of the literature]. AB - OBJECTIVES: To investigate, in the literature, the existence of studies that relate the occurrence of allergic diseases in patients with Systemic Lupus Erythematosus (SLE). METHODS: For the study, we used the model of integrative literature review. This was developed in stages: selection of hypotheses or questions for review, selection of research to write the review sample, defining the characteristics of primary research that comprise the review sample, interpretation and reporting the results of the review. For the electronic search of the literature it was used databases of health sciences in general (LILACS, MEDLINE / PubMed and SciELO). We included original full articles, published between 1982 and 2012 in English, Portuguese or Spanish, to evaluate clinical and laboratory aspects of the association between SLE and allergy. RESULTS: The literature review found twenty-four articles that met the inclusion criteria previously established. Most of the studies demonstrated higher allergic diseases prevalence in SLE patients and/or their family members when compared to a control group without the disease, that suggests a possible genetic similarity between the two diseases. There was also an increase in serum IgE levels in SLE patients, which correlated with the presence of allergic reactions and disease activity in some studies. However, were observed in some studies results contrary to these. In addition, some articles have evaluated the association between sex hormones, SLE and allergies, and suggests the ability of estrogen to be related to hyperresponsiveness to endogenous or exogenous antigens. CONCLUSION: The association between allergic diseases, adverse drug reactions and increasing of serum levels of IgE and the presence of SLE remains controversial. Most of the articles analyzed in this review demonstrated an association between allergic diseases and SLE. In Addition, they showed that the increase of serum levels of IgE in patients with SLE is correlated with disease activity. After this integrative review, we conclude that there is need to expand the studies on the relation between these two diseases, for to clarify all doubts of the subject. PMID- 24149013 TI - Psoriatic arthritis classification criteria: Moll and Wright, ESSG and CASPAR -- a comparative study. AB - OBJECTIVES: to evaluate and compare Moll and Wright, ESSG and CASPAR criteria for psoriatic arthritis (PsA) classification. PATIENTS AND METHODS: Study comprised 356 patients (pts): 120 PsA pts in the investigated group, 123 pts with rheumatoid arthritis (RA) and 113 pts with non-inflammatory musculoskeletal symptoms (NIMS) in two control groups. Clinical diagnosis was the gold standard. Moll and Wright, ESSG and CASPAR criteria were applied to all pts. Sensitivity was calculated for each of the classification criteria sets; specificity was assessed in relation to RA and to NIMS groups, separately. Concordance between the investigated criteria sets was determined. RESULTS: Sensitivity was 91.7% for CASPAR, 85.8% for Moll and Wright and 63.3% for ESSG criteria. Specificity for Moll and Wright criteria was 100%, with relation to both RA and to NIMS group. Specificity of CASPAR criteria was 99.2% and 99.1%; specificity of ESSG criteria was 94.3% and 67%, with regard to RA and to NIMS groups, respectively. Significant fair concordance was found only between CASPAR and Moll and Wright criteria (k=0.379 p<0.001). CONCLUSIONS: The highest sensitivity had the CASPAR criteria, followed by Moll and Wright and ESSG. The highest specificity showed Moll and Wright criteria, followed by CASPAR and ESSG. CASPAR criteria demonstrated high specificity when applied to both NIMS and RA group. The lowest specificity was found for the ESSG criteria in relation to NIMS group. The only significant concordance was shown between CASPAR and Moll and Wright criteria. PMID- 24149014 TI - [Inclusion body myositis: series of 30 cases from a Brazilian tertiary center]. AB - OBJECTIVES: To describe a series of 30 consecutive patients with inclusion body myositis (IBM) from our tertiary center, from 1982 to 2012. MATERIALS AND METHODS: All patients fulfilled the criteria of Griggs et al. (1995) for IBM. RESULTS: The mean age of patients at disease onset was 60.8 ? 11.9 years with disease duration of 8.0 ? 5.2 years. Eighty % of patients were Caucasian, with similar distribution between genders. Weight loss in early disease was present in less than a quarter of cases. The main symptom was proximal weakness of the lower limbs followed by weakness of the upper (proximal and/or distal) limbs. One third of patients had dysphagia, whereas dysphonia was present in 16.7%, arthralgias in 6.7%, moderate dyspnea symptoms in 3.3% of cases. All patients received prednisone (1mg/kg/day). Several immunosuppressives were used as corticosteroid sparing according to tolerance, side effects and/or refractoriness. Half of the patients still in follow-up remained stable according to clinical and laboratory data during the study. There were four cases of cancer, four cases associated with viral infections (HIV and hepatitis C virus) and three deaths (two because of sepsis secondary to community bronchopneumonia, and one because of congestive heart failure). CONCLUSIONS: This is the first Brazilian series of cases involving large sample of IBM. The profile of the patients analyzed in this study was comparable to those profiles described in literature, except that of IBM cases of our population are equally distributed in both genders and the interval between symptoms onset and diagnosis of the disease was relatively short. It is relevant to note the high frequency of neoplastic diseases and chronic viral infections in our population, reinforcing the need for specific epidemiological studies to verify these associations, once it is poorly described in the literature. PMID- 24149015 TI - Applicability of the EULAR recommendations on the role of the nurse in the management of chronic inflammatory arthritis in Portugal. AB - OBJECTIVES: To evaluate the level of agreement and applicability of the EULAR recommendations for the role of the nurse in the management of chronic inflammatory arthritis in Portugal. METHODS: Nurses from all Portuguese rheumatology centers were invited to fill-in a questionnaire addressing the level of agreement (1=strongly disagree to 5=strongly agree) and the level of confidence (1=no confidence to 5=complete confidence) in the applicability of each of the recommendations. Comparisons were established between subgroups of nurses. RESULTS: A total of 75 nurses (85% female; mean (SD) of 3.9 (4.1) years of practice, 32% with some type of training in rheumatology) participated in the study. The mean level of agreement with the recommendations was 4.8 (SD 0.3). The level of confidence in their full applicability was 3.6 (SD 0.8). Significantly more nurses with rheumatology training totally agreed with recommendations 7 (88% vs 73%, p=0.03) and 3 (96% vs 65% p=0.04) and were fully confident in the applicability of recommendations 2, 3, 7, 9 and 10, comparing with those without specific training. CONCLUSIONS: The overall level of agreement with EULAR recommendations among Portuguese nurses is high, although rheumatology does not exist as a nursing specialty. Agreement and confidence in the applicability of these recommendations is higher among nurses with specific training, underlining the importance of continuous education for future commitment. PMID- 24149016 TI - Poncet's disease: a symmetric seronegative polyarthritis with enthesopathy refractory to the therapy. AB - Poncet's disease is a reactive polyarthritis associated to active tuberculosis (TB), with excluded presence of mycobacterium in the joints and bones affected, and no other cause for the clinical arthritis. It is a frequently forgotten entity, especially in countries with low tuberculosis prevalence. It is described a case report of a man of Guinea-Bissau that presented symmetrical generalized polyarthralgias and hands swelling, clinical sacroiliitis and multiple enthesopathies. Serum and urinary biochemical testing were normal. Immunologic studies were negative and serum levels of angiotensin-converting enzyme and calcium were normal. Sexual transmitted diseases were excluded. The initial diagnose was undifferentiated polyarthritis or reactive arthritis. A persistent and refractory monoarthritis of the right wrist demanded a direct and cultural exam of the synovial fluid, synovial biopsy and protein chain reaction for TB that were negative. After he developed right wrist arthritis with purulent synovial fluid positive to TB in the direct exam and the detection of M. tuberculosis in the cultural exam. Granula was found in his chest radiograph. He was diagnosed a Poncet's disease reactive to a pulmonary TB infection. PMID- 24149017 TI - Occult macrophage activation syndrome in systemic-onset juvenile idiopathic arthritic syndrome--a case report. AB - Macrophage activation syndrome (MAS) is a severe and life-threatening complication of rheumatic disorders in children. We described a 9-year-old girl in whom MAS developed as a complication of systemic juvenile idiopathic arthritis (S-JIA) at onset with obvious hemophagocytosis presented in the marrow. She suffered from high fever and generalized rash subsequently joints swelling for two weeks before admission. Physical examination revealed mild cervical lymphadenopathy and hepatosplenomegaly. Laboratory findings were: abnormal liver enzymes, increased triglyceride and ferritin levels, anemia .Hyperplasia of hemophagocytic macrophages was remarkable in her bone marrow. Methylprednisolone and cyclosporin therapy resulted in clinical and laboratory improvement. It is unusual that hemophagocytosis presented in the marrow at onset of So-JIA without obvious abnormal coagulation profile, thrombocytopenia and leucopenia. It seemed that MAS may be occult at onset of SJIA. It may be integral to the pathogenesis of SJIA. The proper cyclosporine serum lever at the onset of MAS is as high as 200-300 ng/ml. PMID- 24149018 TI - Acute venous thrombosis as complication and clue to diagnose a SAPHO syndrome case. A case report. AB - This report concerns a male adult admitted for sternal and left arm pain, who was diagnosed and treated for acute deep venous thrombosis in the left subclavian and axillary veins. X-ray and a hybrid single photon emission tomography and computed tomography (SPECT-CT) scintigraphy scan revealed high intensity uptake in both sternoclavicular joints, which corresponded to hyperostosis, thereby suggesting a SAPHO syndrome. Upon reviewing the patient's medical history, we found dermatological pustulosis disease and an intermittent sternal chest pain untreated since 10 years ago. In the biochemical study we found erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) elevation, hyperglobulinemia, and mild anaemia. Initial treatment included nonsteroidal anti inflammatory drugs (NSAIDs) with low response, which then changed to methotrexate, sulfasalazine, and prednisone. The patient's pain was controlled almost completely in 10 months. A control bone scan revealed a marked decrease in intensity of bone deposits according to clinical response. To our knowledge, there are only a few cases of SAPHO and thrombosis and none are followed up with a bone SPECT-CT scan. PMID- 24149019 TI - Laryngotracheal stenosis requiring emergency tracheostomy as the first manifestation of childhood-relapsing polychondritis. AB - Relapsing polychondritis is a rare childhood disorder of unknown etiology, characterized by inflammatory, recurrent and destructive cartilage lesions. The chondritis could be widespread and involves generally laryngeal and auricular hyaline cartilages. We described a 9 years and 4 months old girl, who presented recurrent acute laryngotracheitis and laryngotracheal stenosis, which were the first manifestations of relapsing polychondritis, and was submitted to emergency tracheostomy. She also had ear condritis and arthritis, being treated with prednisolone and methotrexate. In conclusion, we reported a rare case of relapsing polychondritis that presented a life-threatening laryngo-tracheo bronchial disorder requiring tracheostomy. We suggest that the diagnosis of relapsing polychondritis should be considered for patients who present recurrent acute laryngotracheitis with other types of condritis, as well as musculoskeletal manifestations. PMID- 24149020 TI - [Giant rheumatoid nodule - an unexpected diagnosis]. PMID- 24149021 TI - [Patellar fracture after total knee arthroplasty]. PMID- 24149022 TI - [Onset of rheumatoid arthritis in a patient with ankylosing spondylitis]. PMID- 24149023 TI - Proximal metatarsal articular surface shape and the evolution of a rigid lateral foot in hominins. AB - This study quantifies the proximal articular surface shape of metatarsal (MT) 4 and MT 5 using three-dimensional morphometrics. Humans and apes are compared to test whether they have significantly different shapes that are skeletal correlates to comparative lateral foot function. In addition, shod and unshod humans are compared to test for significant differences in surface shape. The MT 4 fossils OH 8, Stw 628, and AL 333-160, and the MT 5 fossils AL 333-13, AL 333 78, OH 8, and Stw 114/115 are compared with humans and apes to assess whether they bear greater similarities to humans, which would imply a relatively stable lateral foot, or to apes, which would imply a flexible foot with a midfoot break. Apes have a convex curved MT 4 surface, and humans have a flat surface. The MT 4 fossils show greater similarity to unshod humans, suggesting a stable lateral foot. Unshod humans have a relatively flatter MT 4 surface compared with shod humans. There is much overlap in MT 5 shape between humans and apes, with more similarity between humans and Gorilla. The fossil MT 5 surfaces are generally flat, most similar to humans and Gorilla. Because of the high degree of shape overlap between humans and apes, one must use caution in interpreting lateral foot function from the proximal MT 5 surface alone. PMID- 24149024 TI - A bioactive probe for glutathione-dependent antioxidant capacity in breast cancer patients: implications in measuring biological effects of arsenic compounds. AB - INTRODUCTION: Glutathione, a major cellular non-protein thiol (NPSH), serves a central role in repairing damage induced by cancer drugs, pollutants and radiation and in the detoxification of several cancer chemotherapeutic drugs and toxins. Current methods measure glutathione levels only, which require cellular extraction, rather than the glutathione recycling dependent antioxidant activity in intact cells. Here, we present a novel method using a bioactive probe of the oxidative pentose phosphate cycle, termed the OxPhosTM test, to quantify glutathione recycling dependent antioxidant activity in whole blood and intact human and rodent cells without the need for the isolation and cytoplasm extraction of cells. METHODS: OxPhosTM test kit (Rockland Immunochemicals, USA), which uses hydroxyethyldisulfide (HEDS) as a probe for the oxidative pentose phosphate cycle, was used in these studies. The results with OxPhosTM test kit in human blood and intact cells were compared with total thiol and high pressure liquid chromatography/electrochemical detection of HEDS metabolism. RESULTS: The OxPhosTM test measured glutathione-dependent antioxidant activity both in intact human and rodent cells and breast cancer patient's blood with a better correlation coefficient and biological variability than the thiol assay. Additionally, human blood and mammalian cells treated with various arsenicals showed a concentration-dependent decrease in activity. DISCUSSION: The results demonstrate the application of this test for measuring the antioxidant capacity of blood and the effects of environmental pollutants/toxins. It opens up new avenues for an easy and reliable assessment of glutathione-dependent antioxidant capacity in various diseases such as stroke, blood borne diseases, infection, cardiovascular disease and other oxidative stress related diseases and as a prognostic indicator of chemotherapy response and toxicity. The use of this approach in pharmacology/toxicology including screening drugs that improve the glutathione-dependent antioxidant capacity and not just the glutathione level is clinically relevant since mammalian cells require glutathione dependent pathways for antioxidant activity. PMID- 24149025 TI - The epidemiology and patterns of acute and chronic toxicity associated with recreational ketamine use. AB - Ketamine was originally synthesised for use as a dissociative anaesthetic, and it remains widely used legitimately for this indication. However, there is increasing evidence of non-medical recreational use of ketamine, particularly in individuals who frequent the night-time economy. The population-level and sub population (clubbers) prevalence of recreational use of ketamine is not known but is likely to be similar, or slightly lower than, that of other recreational drugs such as cocaine, MDMA, and amphetamine. The predominant features of acute toxicity associated with the recreational use of ketamine are neuro-behavioural abnormalities such as agitation, hallucinations, anxiety, and psychosis. Secondary to these, individuals put themselves at greater risk of physical harm/trauma. Cardiovascular features (hypertension and tachycardia) occur less frequently and the risk of death from recreational use is low and is predominately due to the physical harm/trauma. Long-term recreational use of ketamine can be associated with the development of psychological dependence and tolerance. There are reports of gastro-intestinal toxicity, particularly abdominal pain and abnormal liver function tests, and of neuropsychiatric disorders, typically a schizophrenia-like syndrome, in long-term users. Finally, there are increasing reports of urological disorders, particularly haemorrhagic cystitis, associated with long-term use. The management of these problems associated with the long-term use of ketamine is largely supportive and abstinence from ongoing exposure to ketamine. In this review we will collate the available information on the epidemiology of recreational use of ketamine and describe the patterns of acute and chronic toxicity associated with its recreational use and the management of this toxicity. PMID- 24149026 TI - Automated detection of influenza-like illness using clinical surveillance markers at a Department of Veterans Affairs Medical Center. AB - BACKGROUND: Using demographic and clinical measures from emergency department evaluations, we developed an automated surveillance system for influenza-like illness (ILI). METHODS: We selected a random sample of patients who were seen at the Durham, NC Veterans Affairs Medical Center between May 2002 and October 2009 with fever or a respiratory ICD-9 diagnosis code and divided this into subsets for system development and validation. Comprehensive chart reviews identified patients who met a standard case definition for ILI. Logistic regression models predicting ILI were fit in the development sample. We applied the parameter estimates from these models to the validation sample and evaluated their utility using receiver-operator characteristic analysis. RESULTS: The models discriminated ILI very well in the validation sample; the C-statistics were >0.89. CONCLUSIONS: Risk estimates based on statistical models can be incorporated into electronic medical records systems to assist clinicians and could be used in real-time surveillance for disease outbreaks. PMID- 24149028 TI - Impact of open manganese mines on the health of children dwelling in the surrounding area. AB - INTRODUCTION: Chronic manganese (Mn) exposure is a health hazard associated with the mining and processing of Mn ores. Children living in an area with increased environmental exposure to Mn may have symptoms of chronic toxicity that are different from adults who experience occupational exposure. The aim of the study was to compare health outcomes in a pediatric population living near open Mn mines with a group of children from a reference area and then to develop and implement preventive/rehabilitation measures to protect the children in the mining region. METHODS: After environmental assessment, a group of 683 children living in a Mn-rich region of Ukraine were screened by clinical evaluation, detection of sIgA (37 children), micronucleus analysis (56 children), and hair Mn content (166 children). RESULTS: Impaired growth and rickets-like skeletal deformities were observed in 33% of the children. This was a significantly higher percentage than in children in the reference region (15%). The children from the Mn-mining region also had increased salivary levels of immunoglobulin A (104.4+/ 14.2 mcg/ml vs. 49.7+/-6.1 mcg/ml) among the controls (p<0.05), increased serum alpha 1 proteinase inhibitor levels (4.93+/-0.21 g/l compared with 2.91+/-0.22 g/l for controls; p<0.001) and greater numbers of micronuclei in the mucous cells of the oral cavity (0.070+/-0.008 vs. 0.012+/-0.009, p<0.001). CONCLUSIONS: These findings indicate the deleterious health consequences of living in a Mn-mining area. Medical rehabilitation programs were conducted and produced positive results, but further validation of their effectiveness is required. The study provided background information to formulate evidence-based decisions about public health in a region of high Mn exposure. PMID- 24149027 TI - Can environmental or occupational hazards alter the sex ratio at birth? A systematic review. AB - More than 100 studies have examined whether environmental or occupational exposures of parents affect the sex ratio of their offspring at birth. For this review, we searched Medline and Web of Science using the terms 'sex ratio at birth' and 'sex ratio and exposure' for all dates, and reviewed bibliographies of relevant studies to find additional articles. This review focuses on exposures that have been the subject of at least four studies including polychlorinated biphenyls (PCBs), dioxins, pesticides, lead and other metals, radiation, boron, and g-forces. For paternal exposures, only dioxins and PCBs were consistently associated with sex ratios higher or lower than the expected 1.06. Dioxins were associated with a decreased proportion of male births, whereas PCBs were associated with an increased proportion of male births. There was limited evidence for a decrease in the proportion of male births after paternal exposure to DBCP, lead, methylmercury, non-ionizing radiation, ionizing radiation treatment for childhood cancer, boron, or g-forces. Few studies have found higher or lower sex ratios associated with maternal exposures. Studies in humans and animals have found a reduction in the number of male births associated with lower male fertility, but the mechanism by which environmental hazards might change the sex ratio has not yet been established. PMID- 24149030 TI - Deficient crisis-probing practices and taken-for-granted assumptions in health organisations. AB - The practice of crisis-probing in proactive organisations involves meticulous and sustained investigation into operational processes and management structures for potential weaknesses and flaws before they become difficult to resolve. In health organisations, crisis probing is a necessary part of preparing to manage emerging health threats. This study examined the degree of pre-emptive probing in health organisations and the type of crisis training provided to determine whether or not they are prepared in this area. This evidence-based study draws on cross sectional responses provided by executives from chiropractic, physiotherapy, and podiatry practices; dental and medical clinics; pharmacies; aged care facilities; and hospitals. The data show a marked lack of mandatory probing and a generalised failure to reward crisis reporting. Crisis prevention training is poor in all organisations except hospitals and aged care facilities where it occurs at an adequate frequency. However this training focuses primarily on natural disasters, fails to address most other crisis types, is mostly reactive and not designed to probe for and uncover key taken-for-granted assumptions. Crisis-probing in health organisations is inadequate, and improvements in this area may well translate into measurable improvements in preparedness and response outcomes. PMID- 24149029 TI - Environmental risk factors for autism. AB - Autism is a devastating childhood condition that has emerged as an increasing social concern just as it has increased in prevalence in recent decades. Autism and the broader category of autism spectrum disorders are among the increasingly seen examples in which there is a fetal basis for later disease or disorder. Environmental, genetic, and epigenetic factors all play a role in determining the risk of autism and some of these effects appear to be transgenerational. Identification of the most critical windows of developmental vulnerability is paramount to understanding when and under what circumstances a child is at elevated risk for autism. No single environmental factor explains the increased prevalence of autism. While a handful of environmental risk factors have been suggested based on data from human studies and animal research, it is clear that many more, and perhaps the most significant risk factors, remain to be identified. The most promising risk factors identified to date fall within the categories of drugs, environmental chemicals, infectious agents, dietary factors, and other physical/psychological stressors. However, the rate at which environmental risk factors for autism have been identified via research and safety testing has not kept pace with the emerging health threat posed by this condition. For the way forward, it seems clear that additional focused research is needed. But more importantly, successful risk reduction strategies for autism will require more extensive and relevant developmental safety testing of drugs and chemicals. PMID- 24149031 TI - Use of media and public-domain Internet sources for detection and assessment of plant health threats. AB - Event-based biosurveillance is a recognized approach to early warning and situational awareness of emerging health threats. In this study, we build upon previous human and animal health work to develop a new approach to plant pest and pathogen surveillance. We show that monitoring public domain electronic media for indications and warning of epidemics and associated social disruption can provide information about the emergence and progression of plant pest infestation or disease outbreak. The approach is illustrated using a case study, which describes a plant pest and pathogen epidemic in China and Vietnam from February 2006 to December 2007, and the role of ducks in contributing to zoonotic virus spread in birds and humans. This approach could be used as a complementary method to traditional plant pest and pathogen surveillance to aid global and national plant protection officials and political leaders in early detection and timely response to significant biological threats to plant health, economic vitality, and social stability. This study documents the inter-relatedness of health in human, animal, and plant populations and emphasizes the importance of plant health surveillance. PMID- 24149033 TI - Lessons from the pandemic: the need for new tools for risk and outbreak communication. AB - The influenza pandemic of 2009 revealed shortcomings in the existing guidelines for risk and outbreak communication. Concepts such as building trust proved hard to achieve in practice, whereas other issues such as communicating through the internet and coping with the political fallout of disease outbreaks are not dealt with in existing guidelines. This article surveys the current guidelines and makes recommendations for additional tools and guidelines to be developed in four areas: integrating long-term behavior change models with outbreak communications; research to develop a better understanding of communicating through the internet; research to understand how to use communications to build trust; and developing guidelines and principles to understand the political nature of disease outbreaks. PMID- 24149034 TI - Health care logistics: who has the ball during disaster? AB - In contemporary organizations, a wide gamut of options is available for sustaining and supporting health care operations. When disaster strikes, despite having tenable plans for routine replenishment and operations, many organizations find themselves ill-prepared, ill-equipped, and without effective mechanisms in place to sustain operations during the immediate aftermath of a crisis. Health care operations can be abruptly halted due to the non-availability of supply. The purpose of this work is to add to a necessary, growing body of works related specifically to health care logistics preparedness and disaster mitigation. Logistics management is a specialized genre of expertise within the health care industry and is largely contributive to the success or failure of health care organizations. Logistics management requires extensive collaboration among multiple stakeholders-internal and external to an organization. Effective processes and procedures can be largely contributive to the success or failure of organizational operations. This article contributes to the closure of an obvious gap in professional and academic literature related to disaster health care logistics management and provides timely insight into a potential problem for leaders industry-wide. One critical aspect of disaster planning is regard for competent logistics management and the effective provision of necessary items when they are needed most. In many communities, there seems to be little evidence available regarding health care logistics involvement in disaster planning; at times, evidence of planning efforts perceptibly end at intra-organizational doors within facilities. Strategic planners are being continually reminded that health care organizations serve a principal role in emergency preparedness planning and must be prepared to fulfill the associated possibilities without notification. The concern is that not enough attention is being paid to repeated lessons being observed in disasters and emergency events. PMID- 24149032 TI - Bats, emerging infectious diseases, and the rabies paradigm revisited. AB - The significance of bats as sources of emerging infectious diseases has been increasingly appreciated, and new data have been accumulated rapidly during recent years. For some emerging pathogens the bat origin has been confirmed (such as lyssaviruses, henipaviruses, coronaviruses), for other it has been suggested (filoviruses). Several recently identified viruses remain to be 'orphan' but have a potential for further emergence (such as Tioman, Menangle, and Pulau viruses). In the present review we summarize information on major bat-associated emerging infections and discuss specific characteristics of bats as carriers of pathogens (from evolutionary, ecological, and immunological positions). We also discuss drivers and forces of an infectious disease emergence and describe various existing and potential approaches for control and prevention of such infections at individual, populational, and societal levels. PMID- 24149035 TI - Rickettsia felis, an emerging flea-transmitted human pathogen. AB - Rickettsia felis was first recognised two decades ago and has now been described as endemic to all continents except Antarctica. The rickettsiosis caused by R. felis is known as flea-borne spotted fever or cat-flea typhus. The large number of arthropod species found to harbour R. felis and that may act as potential vectors support the view that it is a pan-global microbe. The main arthropod reservoir and vector is the cat flea, Ctenocephalides felis, yet more than 20 other species of fleas, ticks, and mites species have been reported to harbour R. felis. Few bacterial pathogens of humans have been found associated with such a diverse range of invertebrates. With the projected increase in global temperature over the next century, there is concern that changes to the ecology and distribution of R. felis vectors may adversely impact public health. PMID- 24149037 TI - Editorial: international society for disease surveillance conference 2010: enhancing the synergy between research, informatics, and practice in public health. PMID- 24149036 TI - Swine flu: lessons we need to learn from our global experience. AB - There are important lessons to be learnt from the recent 'Swine Flu' pandemic. Before we call it a pandemic, we need to have appropriate trigger points that involve not only the spread of the virus but also its level of virulence. This was not done for H1N1 (swine flu). We need to ensure that we improve the techniques used in trying to decrease the spread of infection-both in the community and within our hospitals. This means improved infection control and hygiene, and the use of masks, alcohol hand rubs and so on. We also need to have a different approach to vaccines. Effective vaccines were produced only after the epidemic had passed and therefore had relatively little impact in preventing many infections. Mass population strategies involving vaccines and antivirals also misused large amounts of scarce medical resources. PMID- 24149038 TI - Track 1: analytics / research methodologies. PMID- 24149039 TI - Track 2: public health surveillance. PMID- 24149040 TI - Track 3: applications of methodologies to new domains. PMID- 24149041 TI - Track 4: informatics. PMID- 24149042 TI - Seroepidemiological survey of human brucellosis in and around Ludhiana, India. AB - Studies have been done on public health significance of brucellosis using serology with little or no emphasis to risk factors. Therefore, this study was designed to investigate seroprevalence of brucellosis and assess epidemiological variables associated with human brucellosis. After obtaining verbal consent, 241 peripheral blood samples were collected from occupationally exposed groups with and without pyrexia of unknown origin. A structured questionnaire was prepared to gather risk factors, such as occupation, age, sex, history of consuming raw milk and other unpasteurised dairy products, direct contact with domestic animals, general knowledge about the route of transmission and awareness level. Purposive sampling was used to select the key informants. All serum samples were first screened by Rose Bengal Plate Test (RBPT) and further analysed by Standard Tube Agglutination Test (STAT). The results revealed that 24.5% were positive by RBPT and diagnosis was established in 26.6% using STAT with a titre range between 80 and 1,280 IU/ml. Among occupational groups, prevalence was 17.8% in veterinarians and pharmacists but was not statistically significant. The most common clinical symptoms at presentation were fever, headache, back pain, arthralgia and myalgia. No female reactor was found and the mean age and standard deviation of seropositive patients was 34.69+/-10.97 years. Risk factors such as residence in rural area, participation in vaccination of animals and eating during working hours were significantly associated (P<0.05) with brucellosis by univariate and multivariate analysis. In conclusion, to deal with occupation-related disease like brucellosis, awareness on risk factors must be part of extension education campaign. Besides, regular surveillance of the disease needs to be integrated into control and prevention programme at a local and national level. PMID- 24149044 TI - Molecular characterization of Cryptosporidium isolates from calves in Argentina. AB - Cryptosporidiosis is responsible for significant fatalities of neonatal calves, resulting in substantial economic loss in dairy farming in several countries. Additionally, the high shedding of environmentally resistant oocysts by calves promotes contamination of drinking water and facilitates outbreaks of cryptosporidiosis in humans. Here we report on the Cryptosporidium species and GP60 subtypes of 45 calves originating from the Humid Pampa, the main productive dairy farming area of Argentina. Polymerase chain reaction (PCR)-restriction fragment length polymorphism (RFLP) analysis of the 18S rRNA gene was done to determine the infecting Cryptosporidium species and only Cryptosporidium parvum was detected. Subtyping by sequence analysis of the GP60 gene revealed 6 different alleles all pertaining to the zoonotic IIa family. Of these, IIaA23G1R1 represents a novel IIa subtype. Other identified subtypes, IIa18G1R1, IIaA20G1R1, IIaA21G1R1, and IIaA22G1R1 have been recognized in very few studies and/or with low frequencies. Interestingly, different alleles prevailed in the provinces of Buenos Aires (IIaA17G1R1 and IIaA21G1R1), Santa Fe (IIaA23G1R1), and Cordoba (IIaA20G1R1 and IIaA21G1R1), and different allele distribution patterns were observed. Subtypes IIaA18G1R1 and IIaA17G1R1, the latter often found in this study, are strongly implicated in zoonotic transmission, suggesting that calves may represent a potential source for human cryptosporidiosis in this region. This is the first published report of a molecular analysis of Cryptosporidium infection in dairy and beef calves from Argentina. PMID- 24149043 TI - International society for disease surveillance conference 2011: building the future of public health surveillance. PMID- 24149045 TI - DNA-based methodology for the quantification of gastrointestinal nematode eggs in sheep faeces. AB - The presence of gastrointestinal nematode eggs in faecal samples is diagnostic of infection by these parasites. However, this technique cannot be used to distinguish between species of importance. The faecal culture technique and subsequent microscopic analysis of developed larvae is currently used to determine which parasite species are present in the samples, but these techniques take a week to perform and have inherent limitations. To overcome these parasite detection and identification problems, we have developed a DNA extraction method for sheep faeces, and a quantitative multiplex PCR (qPCR) test which can both enumerate and identify Haemonchus, Trichostrongylus and Teladorsagia. We demonstrate that the technique is sensitive to 10 eggs per gram and that dilution of DNA to 0.1 fold can overcome PCR inhibition issues for samples obtained from the field, while maintaining assay sensitivity. Further development of these tests for commercial use is warranted, given their potential to provide consistently faster and more accurate diagnoses of these parasites using simple sample collection and laboratory methods which can be easily adapted for the detection of a variety of pathogens from the same faecal sample. PMID- 24149046 TI - Urinary metabolites of organophosphate and pyrethroid pesticides and behavioral problems in Canadian children. AB - BACKGROUND: Exposure to organophosphate pesticides has been associated with neurobehavioral deficits in children, although data on low levels of exposure experienced by the general population are sparse. Pyrethroids are insecticides rapidly gaining popularity, and epidemiological evidence on their potential effects is lacking. OBJECTIVE: We examined the association between exposure to organophosphate and pyrethroid pesticides, indicated by urinary metabolites, and parentally reported behavioral problems in children. METHODS: We used data on children 6-11 years of age from the Canadian Health Measures Survey (2007-2009). We used logistic regressions to estimate odds ratios (ORs) for high scores on the Strengths and Difficulties Questionnaire (SDQ), which may indicate behavioral problems, in association with concentrations of pyrethroid and organophosphate metabolites in the urine of 779 children, adjusting for covariates (sex, age, race/ethnicity, income, parental education, blood lead levels, maternal smoking during pregnancy, and others). RESULTS: At least one urinary metabolite for organophosphates was detected in 91% of children, and for pyrethroids in 97% of children. Organophosphate metabolites were not significantly associated with high SDQ scores. The pyrethroid metabolite cis-DCCA [3-(2,2-dichlorovinyl)-2,2 dimethylycyclopropane carboxylic acid] was significantly associated with high scores for total difficulties on the SDQ (OR for a 10-fold increase = 2.0; 95% CI: 1.1, 3.6), and there was a nonsignificant association with trans-DCCA (OR = 1.6; 95% CI: 0.9, 3.0). CONCLUSION: In contrast with previous studies, we did not observe an association between exposure to organophosphate pesticides and behavioral scores in children. However, some pyrethroid urinary metabolites were associated with a high level of parent-reported behavioral problems. Longitudinal studies should be conducted on the potential risks of pyrethroids. PMID- 24149048 TI - Simulation and fabrication of a new novel 3D injectable biosensor for high throughput genomics and proteomics in a lab-on-a-chip device. AB - Biosensors are used for the detection of biochemical molecules such as proteins and nucleic acids. Traditional techniques, such as enzyme-linked immuno-sorbent assay (ELISA), are sensitive but require several hours to yield a result and usually require the attachment of a fluorophore molecule to the target molecule. Micromachined biosensors that employ electrical detection are now being developed. Here we describe one such device, which is ultrasensitive, real-time, label free and localized. It is called the nanoneedle biosensor and shows promise to overcome some of the current limitations of biosensors. The key element of this device is a 10 nm wide annular gap at the end of the needle, which is the sensitive part of the sensor. The total diameter of the sensor is about 100 nm. Any change in the population of molecules in this gap results in a change of impedance across the gap. Single molecule detection should be possible because the sensory part of the sensor is in the range of bio-molecules of interest. To increase throughput we can flow the solution containing the target molecules over an array of such structures, each with its own integrated read-out circuitry to allow 'real-time' detection (i.e. several minutes) of label free molecules without sacrificing sensitivity. To fabricate the arrays we used electron beam lithography together with associated pattern transfer techniques. Preliminary measurements on individual needle structures in water are consistent with the design. Since the proposed sensor has a rigid nano-structure, this technology, once fully developed, could ultimately be used to directly monitor protein quantities within a single living cell, an application that would have significant utility for drug screening and studying various intracellular signaling pathways. PMID- 24149047 TI - The VHL gene is epigenetically inactivated in pheochromocytomas and abdominal paragangliomas. AB - Pheochromocytoma (PCC) and abdominal paraganglioma (PGL) are neuroendocrine tumors that present with clinical symptoms related to increased catecholamine levels. About a third of the cases are associated with constitutional mutations in pre-disposing genes, of which some may also be somatically mutated in sporadic cases. However, little is known about inactivating epigenetic events through promoter methylation in these very genes. Using bisulphite pyrosequencing we assessed the methylation density of 11 PCC/PGL disease genes in 96 tumors (83 PCCs and 13 PGLs) and 34 normal adrenal references. Gene expression levels were determined by quantitative RT-PCR. Both tumors and normal adrenal samples exhibited low methylation index (MetI) in the EGLN1 (PDH2), MAX, MEN1, NF1, SDHB, SDHC, SDHD, SDHAF2 (SDH5), and TMEM127 promoters, not exceeding 10% in any of the samples investigated. Aberrant RET promoter methylation was observed in two cases only. For the VHL gene we found increased MetI in tumors as compared with normal adrenals (57% vs. 27%; P<0.001), in malignant vs. benign tumors (63% vs. 55%; P<0.05), and in PGL vs. PCC (66% vs. 55%; P<0.0005). Decreased expression of the VHL gene was observed in all tumors compared with normal adrenals (P<0.001). VHL MetI and gene expressions were inversely correlated (R = -0.359, P<0.0001). Our results show that the VHL gene promoter has increased methylation compared with normal adrenals (MetI>50%) in approximately 75% of PCCs and PGLs investigated, highlighting the role of VHL in the development of these tumors. PMID- 24149049 TI - Cascleave 2.0, a new approach for predicting caspase and granzyme cleavage targets. AB - MOTIVATION: Caspases and granzyme B (GrB) are important proteases involved in fundamental cellular processes and play essential roles in programmed cell death, necrosis and inflammation. Although a number of substrates for both types have been experimentally identified, the complete repertoire of caspases and granzyme B substrates remained to be fully characterized. Accordingly, systematic bioinformatics studies of known cleavage sites may provide important insights into their substrate specificity and facilitate the discovery of novel substrates. RESULTS: We develop a new bioinformatics tool, termed Cascleave 2.0, which builds on previous success of the Cascleave tool for predicting generic caspase cleavage sites. It can be efficiently used to predict potential caspase specific cleavage sites for the human caspase-1, 3, 6, 7, 8 and GrB. In particular, we integrate heterogeneous sequence and protein functional information from various sources to improve the prediction accuracy of Cascleave 2.0. During classification, we use both maximum relevance minimum redundancy and forward feature selection techniques to quantify the relative contribution of each feature to prediction and thus remove redundant as well as irrelevant features. A systematic evaluation of Cascleave 2.0 using the benchmark data and comparison with other state-of-the-art tools using independent test data indicate that Cascleave 2.0 outperforms other tools on protease-specific cleavage site prediction of caspase-1, 3, 6, 7 and GrB. Cascleave 2.0 is anticipated to be used as a powerful tool for identifying novel substrates and cleavage sites of caspases and GrB and help understand the functional roles of these important proteases in human proteolytic cascades. AVAILABILITY AND IMPLEMENTATION: http://www.structbioinfor.org/cascleave2/. PMID- 24149050 TI - ATHENA: the analysis tool for heritable and environmental network associations. AB - MOTIVATION: Advancements in high-throughput technology have allowed researchers to examine the genetic etiology of complex human traits in a robust fashion. Although genome-wide association studies have identified many novel variants associated with hundreds of traits, a large proportion of the estimated trait heritability remains unexplained. One hypothesis is that the commonly used statistical techniques and study designs are not robust to the complex etiology that may underlie these human traits. This etiology could include non-linear gene * gene or gene * environment interactions. Additionally, other levels of biological regulation may play a large role in trait variability. RESULTS: To address the need for computational tools that can explore enormous datasets to detect complex susceptibility models, we have developed a software package called the Analysis Tool for Heritable and Environmental Network Associations (ATHENA). ATHENA combines various variable filtering methods with machine learning techniques to analyze high-throughput categorical (i.e. single nucleotide polymorphisms) and quantitative (i.e. gene expression levels) predictor variables to generate multivariable models that predict either a categorical (i.e. disease status) or quantitative (i.e. cholesterol levels) outcomes. The goal of this article is to demonstrate the utility of ATHENA using simulated and biological datasets that consist of both single nucleotide polymorphisms and gene expression variables to identify complex prediction models. Importantly, this method is flexible and can be expanded to include other types of high-throughput data (i.e. RNA-seq data and biomarker measurements). AVAILABILITY: ATHENA is freely available for download. The software, user manual and tutorial can be downloaded from http://ritchielab.psu.edu/ritchielab/software. PMID- 24149051 TI - Exploring high dimensional data with Butterfly: a novel classification algorithm based on discrete dynamical systems. AB - MOTIVATION: We introduce a novel method for visualizing high dimensional data via a discrete dynamical system. This method provides a 2D representation of the relationship between subjects according to a set of variables without geometric projections, transformed axes or principal components. The algorithm exploits a memory-type mechanism inherent in a certain class of discrete dynamical systems collectively referred to as the chaos game that are closely related to iterative function systems. The goal of the algorithm was to create a human readable representation of high dimensional patient data that was capable of detecting unrevealed subclusters of patients from within anticipated classifications. This provides a mechanism to further pursue a more personalized exploration of pathology when used with medical data. For clustering and classification protocols, the dynamical system portion of the algorithm is designed to come after some feature selection filter and before some model evaluation (e.g. clustering accuracy) protocol. In the version given here, a univariate features selection step is performed (in practice more complex feature selection methods are used), a discrete dynamical system is driven by this reduced set of variables (which results in a set of 2D cluster models), these models are evaluated for their accuracy (according to a user-defined binary classification) and finally a visual representation of the top classification models are returned. Thus, in addition to the visualization component, this methodology can be used for both supervised and unsupervised machine learning as the top performing models are returned in the protocol we describe here. RESULTS: Butterfly, the algorithm we introduce and provide working code for, uses a discrete dynamical system to classify high dimensional data and provide a 2D representation of the relationship between subjects. We report results on three datasets (two in the article; one in the appendix) including a public lung cancer dataset that comes along with the included Butterfly R package. In the included R script, a univariate feature selection method is used for the dimension reduction step, but in the future we wish to use a more powerful multivariate feature reduction method based on neural networks (Kriesel, 2007). AVAILABILITY AND IMPLEMENTATION: A script written in R (designed to run on R studio) accompanies this article that implements this algorithm and is available at http://butterflygeraci.codeplex.com/. For details on the R package or for help installing the software refer to the accompanying document, Supporting Material and Appendix. PMID- 24149052 TI - BEReX: Biomedical Entity-Relationship eXplorer. AB - SUMMARY: Biomedical Entity-Relationship eXplorer (BEReX) is a new biomedical knowledge integration, search and exploration tool. BEReX integrates eight popular databases (STRING, DrugBank, KEGG, PhamGKB, BioGRID, GO, HPRD and MSigDB) and delineates an integrated network by combining the information available from these databases. Users search the integrated network by entering key words, and BEReX returns a sub-network matching the key words. The resulting graph can be explored interactively. BEReX allows users to find the shortest paths between two remote nodes, find the most relevant drugs, diseases, pathways and so on related to the current network, expand the network by particular types of entities and relations and modify the network by removing or adding selected nodes. BEReX is implemented as a standalone Java application. AVAILABILITY AND IMPLEMENTATION: BEReX and a detailed user guide are available for download at our project Web site (http://infos.korea.ac.kr/berex). PMID- 24149053 TI - Inferring the soybean (Glycine max) microRNA functional network based on target gene network. AB - MOTIVATION: The rapid accumulation of microRNAs (miRNAs) and experimental evidence for miRNA interactions has ushered in a new area of miRNA research that focuses on network more than individual miRNA interaction, which provides a systematic view of the whole microRNome. So it is a challenge to infer miRNA functional interactions on a system-wide level and further draw a miRNA functional network (miRFN). A few studies have focused on the well-studied human species; however, these methods can neither be extended to other non-model organisms nor take fully into account the information embedded in miRNA-target and target-target interactions. Thus, it is important to develop appropriate methods for inferring the miRNA network of non-model species, such as soybean (Glycine max), without such extensive miRNA-phenotype associated data as miRNA disease associations in human. RESULTS: Here we propose a new method to measure the functional similarity of miRNAs considering both the site accessibility and the interactive context of target genes in functional gene networks. We further construct the miRFNs of soybean, which is the first study on soybean miRNAs on the network level and the core methods can be easily extended to other species. We found that miRFNs of soybean exhibit a scale-free, small world and modular architecture, with their degrees fit best to power-law and exponential distribution. We also showed that miRNA with high degree tends to interact with those of low degree, which reveals the disassortativity and modularity of miRFNs. Our efforts in this study will be useful to further reveal the soybean miRNA miRNA and miRNA-gene interactive mechanism on a systematic level. AVAILABILITY AND IMPLEMENTATION: A web tool for information retrieval and analysis of soybean miRFNs and the relevant target functional gene networks can be accessed at SoymiRNet: http://nclab.hit.edu.cn/SoymiRNet. PMID- 24149054 TI - SeqPig: simple and scalable scripting for large sequencing data sets in Hadoop. AB - SUMMARY: Hadoop MapReduce-based approaches have become increasingly popular due to their scalability in processing large sequencing datasets. However, as these methods typically require in-depth expertise in Hadoop and Java, they are still out of reach of many bioinformaticians. To solve this problem, we have created SeqPig, a library and a collection of tools to manipulate, analyze and query sequencing datasets in a scalable and simple manner. SeqPigscripts use the Hadoop based distributed scripting engine Apache Pig, which automatically parallelizes and distributes data processing tasks. We demonstrate SeqPig's scalability over many computing nodes and illustrate its use with example scripts. AVAILABILITY AND IMPLEMENTATION: Available under the open source MIT license at http://sourceforge.net/projects/seqpig/ PMID- 24149055 TI - Variability between self-reported diabetes and measured glucose among health screening participants in South Central Kentucky. AB - AIMS: To assess self-reported diabetes and random glucose among health screening participants and examine factors associated with these two diabetes outcomes. METHODS: Study subjects were adults aged >=18 years who participated in diabetes screenings via a mobile health clinic operated by the Institute for Rural Health at Western Kentucky University from 2006 to 2011. Data on self-reported diabetes were based on physicians' past diagnosis. Random plasma glucose was obtained during the screenings. Non-fasting plasma glucose levels of >=180mg/dl and >=140mg/dl were used as cutoffs to determine diabetes and diabetes or pre diabetes, respectively. Logistic regression was used to examine factors associated with self-reported diabetes and elevated non-fasting glucose levels controlling for comorbidities and sociodemographic factors. RESULTS: The proportion of self-reported diabetes was 9.6%. The proportion of participants with >=180mg/dl was 3.2% and that with >=140mg/dl was 7.4%. Odds ratios indicated that self-reported diabetes was higher in older and obese groups and those who had hypertension and hypercholesterolemia and family history of diabetes, while elevated non-fasting glucose levels were higher among participants without health insurance and those who reported they had diabetes. CONCLUSIONS: Variability in risks between self-reported diabetes and measured glucose should be incorporated in diabetes self-care. PMID- 24149056 TI - Oxidative status and chymotrypsin-like activity in right and left ventricle hypertrophy in an experimental model of emphysema. AB - Although cardiac muscle hypertrophy has been studied in association with several diseases, its mechanism in patients with emphysema, in particular in relation to oxidative stress and proteolysis, remains unknown. The role of oxidative stress and proteolysis in right and left ventricle hypertrophy was investigated in hamsters with emphysema induced by 2 different doses of papain (20mg/mL, E20 and 40mg/mL, E40). The thickness of the ventricles, total and cardiac weight, lipid peroxidation, carbonyl proteins, total antioxidant capacity (TAC), and proteasomal proteolytic activity were evaluated in the right ventricle (RV) and the left ventricle (LV) of control and emphysema hamsters. RV thickness was increased by 12% in the E20 group and by 29% in the E40 group. Lipid peroxidation measured by chemiluminescence was increased in the E40 group (from 3350.68+/ 392.44URL/g tissue to 4696.63+/-1076.70URL/g tissue, p<0.05). TAC also increased only in the E40 group. In the LV, chemiluminescence values increased from 4044.77+/-503.39 to 5517.10+/-388.27 in the E20 group and to 8169.14+/ 1748.77URL/g tissue in the E40 group (p<0.05, both). TAC significantly increased in the E20 and E40 groups. No differences were detected in substances reactive to thiobarbituric acid or carbonyl proteins when comparing ventricles or doses. Chymotrypsin-like proteolytic activity significantly decreased in both groups and ventricles. Emphysema can induce right and left ventricle lipid peroxidation and result in antioxidant mobilization. These data together support the idea that cardiac hypertrophy in response to emphysema is mediated in part by proteolytic pathways with involvement of reactive species. PMID- 24149057 TI - Memory expression is independent of memory labilization/reconsolidation. AB - There is growing evidence that certain reactivation conditions restrict the onset of both the destabilization phase and the restabilization process or reconsolidation. However, it is not yet clear how changes in memory expression during the retrieval experience can influence the emergence of the labilization/reconsolidation process. To address this issue, we used the context signal memory model of Chasmagnathus. In this paradigm a short reminder that does not include reinforcement allows us to evaluate memory labilization and reconsolidation, whereas a short but reinforced reminder restricts the onset of such a process. The current study investigated the effects of the glutamate antagonists, APV (0.6 or 1.5 MUg/g) and CNQX (1 MUg/g), prior to the reminder session on both behavioral expression and the reconsolidation process. Under conditions where the reminder does not initiate the labilization/reconsolidation process, APV prevented memory expression without affecting long-term memory retention. In contrast, APV induced amnesic effects in the long-term when administered before a reminder session that triggers reconsolidation. Under the present parametric conditions, the administration of CNQX prior to the reminder that allows memory to enter reconsolidation impairs this process without disrupting memory expression. Overall, the present findings suggest that memory reactivation--but not memory expression--is necessary for labilization and reconsolidation. Retrieval and memory expression therefore appear not to be interchangeable concepts. PMID- 24149058 TI - Deletion variant in the ADRA2B gene increases coupling between emotional responses at encoding and later retrieval of emotional memories. AB - A deletion variant of the ADRA2B gene that codes for the alpha2b adrenoceptor has been linked to greater susceptibility to traumatic memory as well as attentional biases in perceptual encoding of negatively valenced stimuli. The goal of the present study was to examine whether emotional enhancements of memory associated with the ADRA2B deletion variant were predicted by encoding, as indexed by the subjectively perceived emotional salience (i.e., arousal) of events at the time of encoding. Genotyping was performed on 186 healthy young adults who rated positive, negative, and neutral scenes for level of emotional arousal and subsequently performed a surprise recognition memory task 1 week later. Experience of childhood trauma was also measured, as well as additional genetic variations associated with emotional biases and episodic memory. Results showed that subjective arousal was linked to memory accuracy and confidence for ADRA2B deletion carriers but not for non-carriers. Our results suggest that carrying the ADRA2B deletion variant enhances the relationship between arousal at encoding and subsequent memory for moderately arousing events. PMID- 24149060 TI - Gait as solution, but what is the problem? Exploring cost, economy and compromise in locomotion. AB - Many studies have examined how legged mammals move, defining 'what' happens in locomotion. However, few ask 'why' those motions occur as they do. The energetic and functional constraints acting on an animal require that locomotion should be metabolically 'cost effective' and this in large part determines the strategies available to accomplish the task. Understanding the gaits utilised, within the spectrum of gaits possible, and determination of the value of specific relationships among speed, stride length, stride frequency and morphology, depends on identifying the fundamental costs involved and the effects of different movement strategies on those costs. It is argued here that a fundamental loss associated with moving on limbs (centre of mass momentum and energy loss) and two costs involved with controlling and replacing that loss (muscular work of the supporting limb during stance and muscular work of repositioning the limbs during swing) interact to determine the cost trade-offs involved and the optimisation strategies available for each species and speed. These optimisation strategies are what has been observed and characterised as gait. PMID- 24149059 TI - Does stress remove the HDAC brakes for the formation and persistence of long-term memory? AB - It has been known for numerous decades that gene expression is required for long lasting forms of memory. In the past decade, the study of epigenetic mechanisms in memory processes has revealed yet another layer of complexity in the regulation of gene expression. Epigenetic mechanisms do not only provide complexity in the protein regulatory complexes that control coordinate transcription for specific cell function, but the epigenome encodes critical information that integrates experience and cellular history for specific cell functions as well. Thus, epigenetic mechanisms provide a unique mechanism of gene expression regulation for memory processes. This may be why critical negative regulators of gene expression, such as histone deacetylases (HDACs), have powerful effects on the formation and persistence of memory. For example, HDAC inhibition has been shown to transform a subthreshold learning event into robust long-term memory and also generate a form of long-term memory that persists beyond the point at which normal long-term memory fails. A key question that is explored in this review, from a learning and memory perspective, is whether stress-dependent signaling drives the formation and persistence of long-term memory via HDAC-dependent mechanisms. PMID- 24149061 TI - Mitophagy is not induced by mitochondrial damage but plays a role in the regulation of cellular autophagic activity. AB - It was postulated that mitophagy removes damaged mitochondria, which is critical for proper cellular homeostasis; dysfunctional mitochondria can generate excess reactive oxygen species (ROS) that can further damage the organelle as well as other cellular components. Although proper cell physiology requires the maintenance of a healthy pool of mitochondria, little is known about the mechanism underlying the recognition and selection of damaged organelles. We investigated the cellular fate of mitochondria damaged by the action of oxidative phosphorylation inhibitors (antimycin A, myxothiazol, KCN, oligomycin, CCCP). Only antimycin A and KCN effectively induce nonspecific autophagy, but not mitophagy, in a wild-type strain; however, low or no autophagic activity was measured in strains deficient in genes, including ATG32, ATG11 and BCK1, encoding proteins that are involved in mitophagy. These results provide evidence for a major role of specific mitophagy factors in the control of a general autophagic cellular response induced by mitochondrial alteration. Moreover, significant reduction of cytochrome b, one of the components of the respiratory chain, could be the first signal of this induction pathway. PMID- 24149062 TI - Ischemic stroke and incidental finding of a right atrial lipoma. AB - A young man presented with recurrent ischemic stroke under antiplatelet therapy. A patent foramen ovale (PFO) was diagnosed by transesophageal echocardiography (TEE) and the patient was referred to our institution for percutaneous closure. An echogenic mass in the right atrium was detected during the intraprocedural TEE. The interventional team decided to perform transcatheter closure of PFO under fluoroscopy and TEE guide, without complications. Subsequent cardiac magnetic resonance (CMR) imaging confirmed an encapsulated and hyperintense mass located in the roof of the right atrium. The signal intensity pattern and the absence of gadolinium contrast uptake allowed a confident diagnosis of lipoma. Cardiac lipoma accounts for about 10% of primary cardiac tumors and frequently rises from the epicardial fat tissue. Echocardiographic images can remain equivocal about the nature of the mass and CMR offers a substantial contribution to a correct diagnosis. The tumor usually appears encapsulated and asymptomatic, but dyspnea, atrial and ventricular arrhythmias and, rarely, peripheral embolization have been reported. To our knowledge, this is the second case reported on paradoxical embolization associated with right atrial lipoma. Although the relationship of cardiac lipoma with stroke is not well defined, the potential proembolic significance of this lesion cannot be excluded, especially when a PFO coexists. PMID- 24149063 TI - Cardiac Resynchronization Therapy MOdular REgistry: ECG and Rx predictors of response to cardiac resynchronization therapy (NCT01573091). AB - AIMS: A variable proportion, up to 30%, of patients who undergo cardiac resynchronization therapy (CRT) do not benefit from treatment. The aim of the Cardiac Resynchronization Therapy MOdular REgistry (CRT MORE) is to determine whether specific electrocardiographic and radiographic parameters can be used to predict clinical and echocardiographic response to CRT. METHODS: The CRT MORE is a prospective, single-arm, multicenter cohort study designed to evaluate the electrocardiographic and radiographic predictors of response to CRT. All study patients receive a pacemaker or implantable defibrillator for CRT delivery in accordance with current guidelines. Enrollment started in December 2011 and is scheduled to end in November 2013. Approximately 1100 consecutive patients will be enrolled in 30 Italian centers and will be followed up for 60 months after implantation. The primary endpoint is the improvement in clinical (Clinical Composite Score) and echocardiographic (a decrease of >= 15% in left ventricular end-systolic volume) parameters at the 6-month follow-up visit. CONCLUSION: This study might provide important information about which electrocardiographic and radiographic parameters better predict CRT response. PMID- 24149064 TI - Skeletal muscle involvement in cardiomyopathies. AB - The link between heart and skeletal muscle disorders is based on similar molecular, anatomical and clinical features, which are shared by the 'primary' cardiomyopathies and 'primary' neuromuscular disorders. There are, however, some peculiarities that are typical of cardiac and skeletal muscle disorders. Skeletal muscle weakness presenting at any age may indicate a primary neuromuscular disorder (associated with creatine kinase elevation as in dystrophinopathies), a mitochondrial disease (particularly if encephalopathy, ocular myopathy, retinitis, neurosensorineural deafness, lactic acidosis are present), a storage disorder (progressive exercise intolerance, cognitive impairment and retinitis pigmentosa, as in Danon disease), or metabolic disorders (hypoglycaemia, metabolic acidosis, hyperammonaemia or other specific biochemical abnormalities). In such patients, skeletal muscle weakness usually precedes the cardiomyopathy and dominates the clinical picture. Nevertheless, skeletal involvement may be subtle, and the first clinical manifestation of a neuromuscular disorder may be the occurrence of heart failure, conduction disorders or ventricular arrhythmias due to cardiomyopathy. ECG and echocardiogram, and eventually, a more detailed cardiovascular evaluation may be required to identify early cardiac involvement. Paediatric and adult cardiologists should be proactive in screening for neuromuscular and related disorders to enable diagnosis in probands and evaluation of families with a focus on the identification of those at risk of cardiac arrhythmia and emboli who may require specific prophylactic treatments, for example, pacemaker, implantable cardioverter-defibrillator and anticoagulation. PMID- 24149065 TI - Patient outcomes from 10 years of annual diabetes reviews in New Zealand. AB - AIMS: To examine trends in patient health outcomes 2001-2010 for patients receiving free annual diabetes reviews in New Zealand. METHODS: Clinical, demographic and hospital admissions data were analysed for 2175 Type 1 and 25,436 Type 2 diabetes mellitus patients presenting at 170 general practices. Changes in clinical measures and proportions of patients achieving guideline targets and receiving recommended processes of care were assessed by calendar year and for patients returning for successive annual diabetes reviews. We also examined trends in hospital admission rates for diabetes complications over the ten years. RESULTS: The proportion of patients achieving guideline levels for blood pressure and cholesterol increased significantly and there were decreases in smoking rates and mean BMI for patients reviewed five times. The proportion of patients meeting guideline levels for HbA1c increased by year but decreased in patients returning for five reviews. There was also a reduction in the proportion of patients with poor glycaemic control (HbA1c>9.0% (75 mmol/mol)). The proportion of Type 2 patients using oral hypoglycaemic agents or insulin and receiving a retinal exam in the last two years increased significantly, and over 90% of patients received foot checks. Hospital admission rates for ischaemic heart disease, peripheral circulatory disorders, and ketoacidosis all decreased over the period 2001-2010 but inpatient admissions for eye, neurological and renal problems specific to diabetes increased. CONCLUSIONS: There have been many improvements in health outcomes for these diabetes patients participating in the New Zealand government's programme to provide free annual health checks, despite the increasing age and diabetes duration of the patient cohorts. PMID- 24149066 TI - Waking and sleeping in the rat made obese through a high-fat hypercaloric diet. AB - Sleep restriction leads to metabolism dysregulation and to weight gain, which is apparently the consequence of an excessive caloric intake. On the other hand, obesity is associated with excessive daytime sleepiness in humans and promotes sleep in different rodent models of obesity. Since no consistent data on the wake sleep (WS) pattern in diet-induced obesity rats are available, in the present study the effects on the WS cycle of the prolonged delivery of a high-fat hypercaloric (HC) diet leading to obesity were studied in Sprague-Dawley rats. The main findings are that animals kept under a HC diet for either four or eight weeks showed an overall decrease of time spent in wakefulness (Wake) and a clear Wake fragmentation when compared to animals kept under a normocaloric diet. The development of obesity was also accompanied with the occurrence of a larger daily amount of REM sleep (REMS). However, the capacity of HC animals to respond to a "Continuous darkness" exposure condition (obtained by extending the Dark period of the Light-Dark cycle to the following Light period) with an increase of Sequential REMS was dampened. The results of the present study indicate that if, on one hand, sleep curtailment promotes an excess of energy accumulation; on the other hand an over-exceeding energy accumulation depresses Wake. Thus, processes underlying energy homeostasis possibly interact with those underlying WS behavior, in order to optimize energy storage. PMID- 24149067 TI - Pyrroloquinoline quinone prevents MK-801-induced stereotypical behavior and cognitive deficits in mice. AB - Pyrroloquinoline quinone (PQQ), an essential nutrient, antioxidant, redox modulator, and nerve growth factor, prevents cognitive deficits associated with oxidative stress-induced neurodegeneration. Previous molecular imaging studies also demonstrate that PQQ binds to N-methyl D-aspartate (NMDA) receptors. In this study, we investigated the effects of PQQ on stereotypical behaviors and cognitive deficits induced by MK-801, a non-competitive NMDA antagonist used to model schizophrenia. Mice were given repeated injections of MK-801 (0.5mg/kg/d) and PQQ (0.2, 2.0, or 20 MUg/kg/d) for 60 days. Behavior was evaluated using a variety of motor, social, and cognitive tests. We found that PQQ administration significantly attenuated MK-801-induced increases in stereotypical behavior and ataxia, suggesting a protective role of PQQ against MK-801-induced neuronal dysfunction and psychiatric disorders. Future studies are necessary to elucidate the underlying mechanisms of PQQ. PMID- 24149068 TI - High doses of salicylate causes prepulse facilitation of onset-gap induced acoustic startle response. AB - Prepulse inhibition of acoustic startle reflex (PPI), a well-established method for evaluating sensorimotor gating function, has been used to detect tinnitus in animal models. Reduced gap induced PPI (gap-PPI) was considered as a sign of tinnitus. The silent gap used in the test contains both onset and offset signals. Tinnitus may affect these cues differently. In this experiment, we studied the effects of a high dose of salicylate (250 mg/kg, i.p.), an inducer of reversible tinnitus and sensorineural hearing loss, on gap-PPI induced by three different gaps: an onset-gap with 0.1 ms onset and 25 ms offset time, an offset-gap with 25 ms onset and 0.1 ms offset time, and an onset-offset-gap with 0.1 ms onset and offset time. We found that the onset-gaps induced smaller inhibitions than the offset-gaps before salicylate treatment. The offset-gap induced PPI was significantly reduced 1-3h after salicylate treatment. However, the onset-gap caused a facilitation of startle response. These results suggest that salicylate induced reduction of gap-PPI was not only caused by the decrease of offset-gap induced PPI, but also by the facilitation induced by the onset-gap. Since the onset-gap induced PPI is caused by neural offset response, our results suggest that salicylate may cause a facilitation of neural response to an offset acoustical signal. Treatment of vigabatrin (60 mg/kg/day, 14 days), which elevates the GABA level in the brain, blocked the offset-gap induced PPI and onset-gap induced facilitation caused by salicylate. These results suggest that enhancing GABAergic activities can alleviate salicylate induced tinnitus. PMID- 24149069 TI - Pregnenolone sulphate enhances spatial orientation and object discrimination in adult male rats: evidence from a behavioural and electrophysiological study. AB - Neurosteroids can alter neuronal excitability interacting with specific neurotransmitter receptors, thus affecting several functions such as cognition and emotionality. In this study we investigated, in adult male rats, the effects of the acute administration of pregnenolone-sulfate (PREGS) (10mg/kg, s.c.) on cognitive processes using the Can test, a non aversive spatial/visual task which allows the assessment of both spatial orientation-acquisition and object discrimination in a simple and in a complex version of the visual task. Electrophysiological recordings were also performed in vivo, after acute PREGS systemic administration in order to investigate on the neuronal activation in the hippocampus and the perirhinal cortex. Our results indicate that, PREGS induces an improvement in spatial orientation-acquisition and in object discrimination in the simple and in the complex visual task; the behavioural responses were also confirmed by electrophysiological recordings showing a potentiation in the neuronal activity of the hippocampus and the perirhinal cortex. In conclusion, this study demonstrates that PREGS systemic administration in rats exerts cognitive enhancing properties which involve both the acquisition and utilization of spatial information, and object discrimination memory, and also correlates the behavioural potentiation observed to an increase in the neuronal firing of discrete cerebral areas critical for spatial learning and object recognition. This provides further evidence in support of the role of PREGS in exerting a protective and enhancing role on human memory. PMID- 24149070 TI - Switch of glycolysis to gluconeogenesis by dexamethasone for treatment of hepatocarcinoma. AB - Gluconeogenesis is a fundamental feature of hepatocytes. Whether this gluconeogenic activity is also present in malignant hepatocytes remains unexplored. A better understanding of this biological process may lead to novel therapeutic strategies. Here we show that gluconeogenesis is not present in mouse or human malignant hepatocytes. We find that two critical enzymes 11beta-HSD1 and 11beta-HSD2 that regulate glucocorticoid activities are expressed inversely in malignant hepatocytes, resulting in the inactivation of endogenous glucocorticoids and the loss of gluconeogenesis. In patients' hepatocarcinoma, the expression of 11beta-HSD1 and 11beta-HSD2 is closely linked to prognosis and survival. Dexamethasone, an active form of synthesized glucocorticoids, is capable of restoring gluconeogenesis in malignant cells by bypassing the abnormal regulation of 11beta-HSD enzymes, leading to therapeutic efficacy against hepatocarcinoma. These findings clarify the molecular basis of malignant hepatocyte loss of gluconeogenesis and suggest new therapeutic strategies. PMID- 24149071 TI - Technological innovation, human capital and social change for sustainability. Lessons learnt from the industrial technologies theme of the EU's Research Framework Programme. AB - Europe is facing a twofold challenge. It must maintain or even increase its competitiveness, a basic requirement in a globalised economy and under the current demographic threat. It needs also to tackle the so-called "grand challenges", especially environmental issues, through a sustainable model of production and consumption. Such challenges should lead to new business and industrial models, based on more sustainable production and consumption chains, from design to end of life. This implies a need for new industrial materials and processes, new skills and, indeed, new values and life-styles. Sustainability and innovation are key elements of EU's Research and Innovation Framework Programmes, particularly in the field of industrial technologies (nanotechnologies, materials and industrial technologies), which objective is to "improve the competitiveness of the European industry and generate knowledge to ensure its transformation from a resource intensive to a knowledge intensive industry". Sustainability and innovation are interrelated challenges for R&D. Research can develop technical solutions to tackle environmental or societal challenges, but such technologies need to be successfully commercialised to have a real environmental impact. Several socio-economic studies carried-out by the European Commission show not only the emerging technological and industrial trends, but they also emphasise the need for linking sustainable technologies with social change. Human capital and new social behaviours are critical factors to combine economic competitiveness and sustainability: technology alone is no longer able to solve global challenges. But what kind of human capital (skills, behaviours, and values) are we referring to? How to encourage the shift towards a greener society through human capital? Which reforms are needed in education systems to move towards a sustainable economy? Are there examples of social innovation to be extrapolated and/or generalised? PMID- 24149072 TI - The incidence and severity of pulmonary hypertension in obstructive sleep apnea with hypothyroidism. AB - BACKGROUND: Hypothyroidism and obstructive sleep apnea (OSA) are both common health problems and can be seen together. Each of these 2 diseases can cause pulmonary hypertension (PH). We aimed to determine whether hypothyroidism with OSA has a significant effect on the frequency and severity of PH. MATERIAL AND METHODS: A total of 236 patients were included in the study. Patients were divided into 3 groups: Group I, Obstructive Sleep Apnea (n=149); Group II, Hypothyroidism (n=56); and Group III, Obstructive Sleep Apnea-Hypothyroidism (n=31). All patients underwent polysomnography and echocardiography and serum levels of thyroid-stimulating hormone (TSH) and free thyroxine 4 (FT4) were analyzed. RESULTS: There were 167 male and 69 female participants, and the mean age was 47.8 +/- 11.5 (Group I: 81.9% male, 18.1% female; Group II: 44.6% male, 55.4% female; Group III: 64.6% male, 35.4% female). Distribution of mean pulmonary arterial pressure on echocardiography was statistically different among the 3 groups (x(2)=14.99, p=0.006). When adjusted according to the apnea-hypopnea index (AHI), age, and body mass index (BMI), a significant relation with PH was determined (p=0.002). CONCLUSIONS: The combination of hypothyroidism with OSA is associated with an increased frequency and severity of PH. When PH is found out of line with the severity of OSA, thyroid dysfunction should be investigated. PMID- 24149073 TI - Disclosing the crosstalk among DNA methylation, transcription factors, and histone marks in human pluripotent cells through discovery of DNA methylation motifs. AB - Gene expression regulation is gated by promoter methylation states modulating transcription factor binding. The known DNA methylation/unmethylation mechanisms are sequence unspecific, but different cells with the same genome have different methylomes. Thus, additional processes bringing specificity to the methylation/unmethylation mechanisms are required. Searching for such processes, we demonstrated that CpG methylation states are influenced by the sequence context surrounding the CpGs. We used such a property to develop a CpG methylation motif discovery algorithm. The newly discovered motifs reveal "methylation/unmethylation factors" that could recruit the "methylation/unmethylation machinery" to the loci specified by the motifs. Our methylation motif discovery algorithm provides a synergistic approach to the differently methylated region algorithms. Since our algorithm searches for commonly methylated regions inside the same sample, it requires only a single sample to operate. The motifs that were found discriminate between hypomethylated and hypermethylated regions. The hypomethylation-associated motifs have a high CG content, their targets appear in conserved regions near transcription start sites, they tend to co-occur within transcription factor binding sites, they are involved in breaking the H3K4me3/H3K27me3 bivalent balance, and they transit the enhancers from repressive H3K27me3 to active H3K27ac during ES cell differentiation. The new methylation motifs characterize the pluripotent state shared between ES and iPS cells. Additionally, we found a collection of motifs associated with the somatic memory inherited by the iPS from the initial fibroblast cells, thus revealing the existence of epigenetic somatic memory on a fine methylation scale. PMID- 24149074 TI - Lifetime trauma exposure and prospective cardiovascular events and all-cause mortality: findings from the Heart and Soul Study. AB - OBJECTIVE: Little is known about the effect of cumulative psychological trauma on health outcomes in patients with cardiovascular disease. The objective of this study was to prospectively examine the association between lifetime trauma exposure and recurrent cardiovascular events or all-cause mortality in patients with existing cardiovascular disease. METHODS: A total of 1021 men and women with cardiovascular disease were recruited in 2000 to 2002 and followed annually. Trauma history and psychiatric comorbidities were assessed at baseline using the Computerized Diagnostic Interview Schedule for DSM-IV. Health behaviors were assessed using standardized questionnaires. Outcome data were collected annually, and all medical records were reviewed by two independent, blinded physician adjudicators. We used Cox proportional hazards models to evaluate the association between lifetime trauma exposure and the composite outcome of cardiovascular events and all-cause mortality. RESULTS: During an average of 7.5 years of follow up, there were 503 cardiovascular events and deaths. Compared with the 251 participants in the lowest trauma exposure quartile, the 256 participants in the highest exposure quartile had a 38% greater risk of adverse outcomes (hazard ratio = 1.38, 95% confidence interval = 1.06-1.81), adjusted for age, sex, race, income, education, depression, posttraumatic stress disorder, generalized anxiety disorder, smoking, physical inactivity, and illicit drug abuse. CONCLUSIONS: Cumulative exposure to psychological trauma was associated with an increased risk of recurrent cardiovascular events and mortality, independent of psychiatric comorbidities and health behaviors. These data add to a growing literature showing enduring effects of repeated trauma exposure on health that are independent of trauma-related psychiatric disorders such as depression and posttraumatic stress disorder. PMID- 24149075 TI - Suicidality in primary care patients with somatoform disorders. AB - OBJECTIVE: To examine rates of suicidality in primary care patients with somatoform disorders and to identify factors that might help to understand and manage active suicidal ideation in these patients. METHODS: We conducted a cross sectional study screening 1645 primary care patients. In total, 142 patients fulfilled the criteria for a somatoform disorder. Suicidality and illness perceptions were assessed in these patients. RESULTS: Of the 142 patients, 23.9% had active suicidal ideation during the previous 6 months; 17.6% had attempted to commit suicide in the past, the majority after onset of the somatoform symptoms. We tested two models with suicidal ideation as a dependent variable. In the first model, comorbid symptoms of depression (odds ratio [OR] = 1.17, 95% confidence interval [CI] = 1.03-1.33) and previous suicide attempts (OR= 3.02, 95% CI = 1.06 8.62) were significantly associated with suicidal ideation. Comorbid symptoms of anxiety did not yield significance. Illness perceptions and age of onset of the symptoms were then added to this model to test the role of somatoform-specific factors in addition to previous factors. In the complete model, comorbid symptoms of depression (OR = 1.15, 95% CI = 1.00-1.32) and dysfunctional illness perceptions (OR = 1.06, 95% CI = 1.01-1.11) were independently associated with active suicidal ideation, whereas the other factors did not yield significance. CONCLUSIONS: According to our data, suicidality seems to be a substantial problem in primary care patients with somatoform disorders. Dysfunctional illness perceptions may play a vital role in the understanding and management of active suicidal ideation in these patients, in addition to more established factors. PMID- 24149076 TI - Timeframes of speciation, reticulation, and hybridization in the bulldog bat explained through phylogenetic analyses of all genetic transmission elements. AB - Phylogenetic comparisons of the different mammalian genetic transmission elements (mtDNA, X-, Y-, and autosomal DNA) is a powerful approach for understanding the process of speciation in nature. Through such comparisons the unique inheritance pathways of each genetic element and gender-biased processes can link genomic structure to the evolutionary process, especially among lineages which have recently diversified, in which genetic isolation may be incomplete. Bulldog bats of the genus Noctilio are an exemplar lineage, being a young clade, widely distributed, and exhibiting unique feeding ecologies. In addition, currently recognized species are paraphyletic with respect to the mtDNA gene tree and contain morphologically identifiable clades that exhibit mtDNA divergences as great as among many species. To test taxonomic hypotheses and understand the contribution of hybridization to the extant distribution of genetic diversity in Noctilio, we used phylogenetic, coalescent stochastic modeling, and divergence time estimates using sequence data from cytochrome-b, cytochrome c oxidase-I, zinc finger Y, and zinc finger X, as well as evolutionary reconstructions based on amplified fragment length polymorphisms (AFLPs) data. No evidence of ongoing hybridization between the two currently recognized species was identified. However, signatures of an ancient mtDNA capture were recovered in which an mtDNA lineage of one species was captured early in the noctilionid radiation. Among subspecific mtDNA clades, which were generally coincident with morphology and statistically definable as species, signatures of ongoing hybridization were observed in sex chromosome sequences and AFLP. Divergence dating of genetic elements corroborates the diversification of extant Noctilio beginning about 3 Ma, with ongoing hybridization between mitochondrial lineages separated by 2.5 myr. The timeframe of species' divergence within Noctilio supports the hypothesis that shifts in the dietary strategies of gleaning insects (N. albiventris) or fish (N. leporinus) are among the most rapid instances of dietary evolution observed in mammals. This study illustrates the complex evolutionary dynamics shaping gene pools in nature, how comparisons of genetic elements can serve for understanding species boundaries, and the complex considerations for accurate taxonomic assignment. PMID- 24149077 TI - Robust regression and posterior predictive simulation increase power to detect early bursts of trait evolution. AB - A central prediction of much theory on adaptive radiations is that traits should evolve rapidly during the early stages of a clade's history and subsequently slowdown in rate as niches become saturated--a so-called "Early Burst." Although a common pattern in the fossil record, evidence for early bursts of trait evolution in phylogenetic comparative data has been equivocal at best. We show here that this may not necessarily be due to the absence of this pattern in nature. Rather, commonly used methods to infer its presence perform poorly when when the strength of the burst--the rate at which phenotypic evolution declines- is small, and when some morphological convergence is present within the clade. We present two modifications to existing comparative methods that allow greater power to detect early bursts in simulated datasets. First, we develop posterior predictive simulation approaches and show that they outperform maximum likelihood approaches at identifying early bursts at moderate strength. Second, we use a robust regression procedure that allows for the identification and down-weighting of convergent taxa, leading to moderate increases in method performance. We demonstrate the utility and power of these approach by investigating the evolution of body size in cetaceans. Model fitting using maximum likelihood is equivocal with regards the mode of cetacean body size evolution. However, posterior predictive simulation combined with a robust node height test return low support for Brownian motion or rate shift models, but not the early burst model. While the jury is still out on whether early bursts are actually common in nature, our approach will hopefully facilitate more robust testing of this hypothesis. We advocate the adoption of similar posterior predictive approaches to improve the fit and to assess the adequacy of macroevolutionary models in general. PMID- 24149078 TI - Introducing a model of cardiovascular prevention in Nairobi's slums by integrating a public health and private-sector approach: the SCALE-UP study. AB - INTRODUCTION: Cardiovascular disease (CVD) is a leading cause of death in sub Saharan Africa (SSA), with annual deaths expected to increase to 2 million by 2030. Currently, most national health systems in SSA are not adequately prepared for this epidemic. This is especially so in slum settlements where access to formal healthcare and resources is limited. OBJECTIVE: To develop and introduce a model of cardiovascular prevention in the slums of Nairobi by integrating public health and private sector approaches. STUDY DESIGN: Two non-profit organizations that conduct public health research, Amsterdam Institute for Global Health and Development (AIGHD) and African Population and Health Research Center (APHRC), collaborated with private-sector Boston Consulting Group (BCG) to develop a service delivery package for CVD prevention in slum settings. A theoretic model was designed based on the integration of public and private sector approaches with the focus on costs and feasibility. RESULTS: The final model includes components that aim to improve community awareness, a home-based screening service, patient and provider incentives to seek and deliver treatment specifically for hypertension, and adherence support. The expected outcomes projected by this model could prove potentially cost effective and affordable (1 USD/person/year). The model is currently being implemented in a Nairobi slum and is closely followed by key stakeholders in Kenya including the Ministry of Health, the World Health Organization (WHO), and leading non-governmental organizations (NGOs). CONCLUSION: Through the collaboration of public health and private sectors, a theoretically cost-effective model was developed for the prevention of CVD and is currently being implemented in the slums of Nairobi. If results are in line with the theoretical projections and first impressions on the ground, scale-up of the service delivery package could be planned in other poor urban areas in Kenya by relevant policymakers and NGOs. PMID- 24149079 TI - Administration of AS03B-adjuvanted A(H1N1)pdm09 vaccine in children aged <3 years enhances antibody response to H3 and B viruses following a single dose of trivalent vaccine one year later. AB - BACKGROUND: We report on a follow-up clinical and serological investigation of 274 children who received seasonal influenza vaccine (trivalent inactivated vaccine [TIV]) 1 year after receipt of either AS03(B)-adjuvanted subunit or whole virus monovalent A(H1N1)pdm09 vaccine and describe the antibody responses to the H3N2 A/Perth/16/2009 and B/Brisbane/60/2008 components of TIV. METHODS: Vaccine responses were analyzed using hemagglutination inhibition (HAI) assays. In children aged <3 years, previous receipt of adjuvanted vaccine resulted in higher HAI antibody responses to H3N2 and B strains compared with nonadjuvanted vaccine (fold change 16.8 vs 4.3 for H3N2 and 7.0 vs 1.6 for B). In children aged >3 years, responses to the H3 and B components of TIV were similar between vaccine groups. Sera taken before and after the pandemic vaccine were also analyzed by HAI using A/Perth/16/2009 virus. This analysis showed that 11.1% of children receiving the AS03(B)-adjuvanted vaccine but only 1.4% in the nonadjuvanted group had a 4-fold rise to A/Perth/16/2009. CONCLUSION: AS03B-adjuvanted A(H1N1)pdm09 influenza vaccine generates a cross-reactive antibody response to H3N2 in children and enhances responses to heterologous subtypes in children aged <3 years 1 year later. PMID- 24149080 TI - Reply to Soentjens et al. PMID- 24149081 TI - Diagnosing acute schistosomiasis. PMID- 24149082 TI - The case against exchange transfusion has yet to be proved. PMID- 24149083 TI - Fabrication of porous Ag hollow sphere arrays based on coated template-plasma bombardment. AB - A facile and flexible strategy is presented to produce porous Ag hollow sphere arrays, with a micro/nanostructure and contaminant-free surface, based on a combination of the bottom-up and top-down fabrication strategies, or by plasma bombardment of Ag-coated monolayer polystyrene sphere templates. The arrays consist of periodically arranged micro-sized hollow spheres with nanoscaled pores (mostly within 100 nm) in the shell layer. These arrays are structurally tunable in spherical size (in the sub-10 MUm range), spacing (from a few nanometers to several microns), shell thickness (over tens of nanometers) and porous configuration by the template and bombarding conditions. The strategy is universal for the fabrication of other porous metal hollow sphere arrays. Such nanoscaled rough and porous Ag hollow sphere arrays have potential applications in catalysis, antibacterial and photonic devices. The arrays show significant surface-enhanced Raman scattering (SERS) activity (the minimum detectable concentration of the standard molecule rhodamine 6G can be down to 10(-14) M) with good stability and reproduction, and are a good candidate for the substrate of SERS effect based devices. PMID- 24149084 TI - Air pollution and respiratory infections during early childhood: an analysis of 10 European birth cohorts within the ESCAPE Project. AB - BACKGROUND: Few studies have investigated traffic-related air pollution as a risk factor for respiratory infections during early childhood. OBJECTIVES: We aimed to investigate the association between air pollution and pneumonia, croup, and otitis media in 10 European birth cohorts--BAMSE (Sweden), GASPII (Italy), GINIplus and LISAplus (Germany), MAAS (United Kingdom), PIAMA (the Netherlands), and four INMA cohorts (Spain)--and to derive combined effect estimates using meta analysis. METHODS: Parent report of physician-diagnosed pneumonia, otitis media, and croup during early childhood were assessed in relation to annual average pollutant levels [nitrogen dioxide (NO2), nitrogen oxide (NOx), particulate matter<=2.5 MUm (PM2.5), PM2.5 absorbance, PM10, PM2.5-10 (coarse PM)], which were estimated using land use regression models and assigned to children based on their residential address at birth. Identical protocols were used to develop regression models for each study area as part of the ESCAPE project. Logistic regression was used to calculate adjusted effect estimates for each study, and random-effects meta-analysis was used to calculate combined estimates. RESULTS: For pneumonia, combined adjusted odds ratios (ORs) were elevated and statistically significant for all pollutants except PM2.5 (e.g., OR=1.30; 95% CI: 1.02, 1.65 per 10-MUg/m3 increase in NO2 and OR=1.76; 95% CI: 1.00, 3.09 per 10 MUg/m3 PM10). For otitis media and croup, results were generally null across all analyses except for NO2 and otitis media (OR=1.09; 95% CI: 1.02, 1.16 per 10 MUg/m3). CONCLUSION: Our meta-analysis of 10 European birth cohorts within the ESCAPE project found consistent evidence for an association between air pollution and pneumonia in early childhood, and some evidence for an association with otitis media. PMID- 24149085 TI - HIV-1 evolution in patients undergoing immunotherapy with Tat, Rev, and Nef expressing dendritic cells followed by treatment interruption. AB - OBJECTIVES: This study aimed to evaluate HIV sequence evolution in whole genes and in CD8 T-cell epitope regions following immunotherapy and subsequent analytical treatment interruption (ATI). A second objective of this study was to analyze associations between vaccine-specific immune responses and epitope mutation rates. DESIGN: HIV-1-infected patients on combined antiretroviral therapy (cART) were subjected to immunotherapy by the administration of an autologous dendritic cell-based therapeutic vaccine expressing Tat, Rev, and Nef and subsequent ATI. METHODS: HIV-1 genes were amplified and sequenced from plasma RNA obtained before initiation of cART as well as during ATI. Control sequences for virus evolution in untreated HIV-1-infected individuals were obtained from the HIV Sequence Database (Los Alamos). CD8 T-cell epitope regions were defined based on literature data and prediction models. HIV-1-specific immune responses were evaluated to analyze their impact on sequence evolution. RESULTS: Viral sequence evolution in the tat, rev, and nef genes of vaccinated patients was similar to that of controls. The number of mutations observed inside and outside CD8 T-cell epitopes was comparable for vaccine-targeted and nontargeted proteins. We found no evidence for an impact of vaccine-induced or enhanced immune responses on the number of mutations inside or outside epitopes. CONCLUSION: Therapeutic vaccination of HIV-1-infected patients with a dendritic cell-based vaccine targeting Tat, Rev, and Nef did not affect virus evolution at the whole gene level nor at the CD8 T-cell epitope level. PMID- 24149086 TI - A systematic review of definitions of extreme phenotypes of HIV control and progression. AB - The study of individuals at opposite ends of the HIV clinical spectrum can provide invaluable insights into HIV biology. Heterogeneity in criteria used to define these individuals can introduce inconsistencies in results from research and make it difficult to identify biological mechanisms underlying these phenotypes. In this systematic review, we formally quantified the heterogeneity in definitions used for terms referring to extreme phenotypes in the literature, and identified common definitions and components used to describe these phenotypes. We assessed 714 definitions of HIV extreme phenotypes in 501 eligible studies published between 1 January 2000 and 15 March 2012, and identified substantial variation among these. This heterogeneity in definitions may represent important differences in biological endophenotypes and clinical progression profiles of individuals selected by these, suggesting the need for harmonized definitions. In this context, we were able to identify common components in existing definitions that may provide a framework for developing consensus definitions for these phenotypes in HIV infection. PMID- 24149087 TI - CD4+ T-cell activation impairs serogroup C Neisseria meningitis vaccine response in HIV-infected children. AB - OBJECTIVE: To investigate the influence of CD4 T-cell activation and regulatory populations in HIV-infected children antibody response to vaccination with a conjugate C polysaccharide vaccine. DESIGN: CD4 T-cell activation was evaluated by expression of CD38, HLA-DR and CCR5 molecules. Regulatory CD4 T cells (TReg) were characterized as FoxP3CD127CD25 and inducer T cells (TInd) as CD4FoxP3CD25CD39. METHODS: All patients (n = 36) were HIV-vertically infected, aged 2-17 years-old and were vaccinated with one vaccine injection. Blood samples were obtained before and after immunization to determine bactericidal antibody titers (SBA), CD4 T-cell activation and frequency of TReg and TInd subsets (multiparametric flow cytometry). RESULTS: Children not-responding (n = 18) to MenC vaccine expressed higher frequency of activated CD4 T cells (HLA-DRCD38CCR5) than responders (n = 18), both before and after vaccination (P < 0.05). A significant higher frequency of TReg was detected in responders compared with nonresponders (P = 0.0001). We also detected an inverse correlation between CD4DRCD38CCR5 (P = 0.01) or CD4DRCD38 (P = 0.02) T cells and TReg cell frequency after vaccination. CD4 T-cell activation negatively correlated (P = 0.006) with postvaccination SBA titers but a positive correlation (P = 0.0001) was detected between TReg cells and SBA. TReg and TInd subsets were inversely correlated (P = 0.04). CONCLUSION: Our findings suggest that higher CD4 T-cell activation leads to poor vaccine response in children living with HIV, which may be associated with a TReg/TInd disequilibrium. PMID- 24149088 TI - Risk of HIV acquisition among circumcised and uncircumcised young men with penile human papillomavirus infection. AB - OBJECTIVES: There are very few data from men on the risk of HIV acquisition associated with penile human papillomavirus (HPV) infection and no data on the potential modifying effect of male circumcision. Therefore, this study evaluated whether HPV is independently associated with risk of HIV. DESIGN: A cohort study of HPV natural history nested within a randomized control trial of male circumcision to reduce HIV incidence in Kisumu, Kenya. METHODS: Prospective data from 2519 men were analyzed using 6-month discrete-time Cox models to determine if HIV acquisition was higher among circumcised or uncircumcised men with HPV compared to HPV-uninfected men. RESULTS: Risk of HIV acquisition was nonsignificantly increased among men with any HPV [adjusted hazard ratio (aHR) 1.72; 95% confidence interval (CI) 0.94-3.15] and high-risk HPV (aHR 1.92; 95% CI 0.96-3.87) compared to HPV-uninfected men, and estimates did not differ by circumcision status. Risk of HIV increased 27% with each additional HPV genotype infection (aHR 1.27; 95% CI 1.09-1.48). Men with persistent (aHR 3.27; 95% CI 1.59-6.72) or recently cleared (aHR 3.05; 95% CI 1.34-6.97) HPV had a higher risk of HIV acquisition than HPV-uninfected men. CONCLUSIONS: Consistent with the findings in women, HPV infection, clearance, and persistence were associated with an increased risk of HIV acquisition in men. Given the high prevalence of HPV in populations at risk of HIV, consideration of HPV in future HIV-prevention studies and investigation into mechanisms through which HPV might facilitate HIV acquisition are needed. PMID- 24149089 TI - Aerobic exercise interacts with neurotrophic factors to predict cognitive functioning in adolescents. AB - Recent findings have suggested that aerobic exercise may have a positive effect on brain functioning, in addition to its well-recognized beneficial effects on human physiology. This study confirmed the cognitive effects of aerobic exercise on the human brain. It also examined the relationships between exercise and the serum levels of neurotrophic factors (BDNF, IGI-1, and VEGF). A total of 91 healthy teens who exercised regularly participated in this study. A between-group design was adopted to compare cognitive functioning subserved by the frontal and temporal brain regions and the serum levels of neurotrophic factors between 45 regular exercisers and 46 matched controls. The exercisers performed significantly better than the controls on the frontal and temporal functioning parameters measured. This beneficial cognitive effect was region-specific because no such positive cognitive effect on task-tapping occipital functioning was observed. With respect to the serum levels of the neurotrophic factors, a negative correlation between neurotrophic factors (BDNF and VEGF) with frontal and medial-temporal lobe function was revealed. Furthermore, the levels of BDNF and VEGF interacted with exercise status in predicting frontal and temporal lobe function. This is the first report of the interaction effects of exercise and neurotrophic factors on cognitive functioning. Herein, we report preliminary evidence of the beneficial effects of regular aerobic exercise in improving cognitive functions in teens. These beneficial effects are region-specific and are associated with the serum levels of neurotrophic factors. Our findings lay the path for future studies looking at ways to translate these beneficial effects to therapeutic strategies for adolescents. PMID- 24149090 TI - Mechanism of ulinastatin protection against lung injury caused by lower limb ischemia-reperfusion. AB - AIM: The aim of this paper was to investigate the mechanism of ulinastatin's protection of lung from injury caused by lower limb ischemia-reperfusion in a rat model. METHODS: Male, Sprague-Dawley rats were divided into three groups: saline control (CON), lung injury group, caused by lower limb ischemia-reperfusion (LIR) by rubber band ligation of the lower limbs for 3 h, followed by reperfusion for 3 h and lung injury with ulinastatin pretreatment intravenously before ligation (UTI). Carotid arterial blood was drawn 3 h postreperfusion for gas analysis, and alveolar lavage of one lung was performed. Rats were then sacrificed and lungs were taken for pathological examination and to detect phosphorylated and total p38, JNK, ERK levels. Inflammatory cell count and cytokines TNF-alpha, IL-1, IL-6 were measured from the lavage fluid. RESULTS: There was significant inflammatory cell infiltration, hemorrhaging, and edema of the lung in the LIR group, all of which were reduced significantly in the UTI group. Oxygenation index in the LIR was lower than the CON while it was higher in the UTI than the LIR group. Compared to the CON group, white blood cell count in the alveolar lavage fluid from LIR group was increased, while this is lower in the UTI. Lavage fluid TNF alpha, IL-beta, and IL-6 levels were higher in the LIR group than the CON group, and were significantly lower in the UTI than the LIR. LIR group exhibited increased phosphorylated ERK, JNK and p38; UTI group rats also had enhanced p-ERK levels, but had decreased p-p38 and p-JNK. CONCLUSION: Ulinastatin pre-treatment reduces lung injury caused by lower limb ischemia-reperfusion via a mechanism that may involve inhibition of inflammatory cytokine production via p-JNK and p p38 pathways. PMID- 24149091 TI - Mind-wandering and negative mood: does one thing really lead to another? AB - Mind-wandering is closely connected with negative mood. Whether negative mood is a cause or consequence of mind-wandering remains an important, unresolved, issue. We sought to clarify the direction of this relationship by measuring mood before and after mind-wandering. We also measured the affective content, time orientation and relevance of mind-wandering to current concerns to explore whether the link between mind-wandering and negative mood might be explained by these characteristics. A novel experience-sampling technique with smartphone application prompted participants to answer questions about mind-wandering and mood across 7 days. While sadness tended to precede mind-wandering, mind wandering itself was not associated with later mood and only predicted feeling worse if its content was negative. We also found prior sadness predicted retrospective mind-wandering, and prior negative mood predicted mind-wandering to current concerns. Our findings provide new insight into how mood and mind wandering relate but suggest mind-wandering is not inherently detrimental to well being. PMID- 24149092 TI - Doctor at triage - effect on waiting time and patient satisfaction in a Jamaican hospital. AB - INTRODUCTION: Waiting time in the Emergency Departments is a major source of patient dissatisfaction in hospitals. Triage attempts to have the most critically ill patients seen first with an overall reduction in waiting time. Triage teams may include specially trained nurses or alternatively a specialist physician. The aim of this study was to determine if inclusion of a specialist physician on the triage team at the University Hospital of the West Indies (UHWI) in Kingston Jamaica reduced waiting time and improved patient satisfaction. METHODS: A prospective, cross sectional survey of ambulatory care patients was undertaken in 2006. Triage was completed by a team consisting of a doctor and two nurses during the first week and by nurses only during the second week. RESULTS: The study showed that there was no significant difference in the length of time patients spent in the emergency department based on whether or not they were triaged by a physician led team or by a team of nurses only. Type of triage team did not affect the level of patient satisfaction. Waiting time was significantly influenced by factors which came into play after triage such as the wait for X ray and laboratory services. CONCLUSIONS: There appears to be no reduction in waiting times experienced by patients at the UHWI emergency department as a result of inclusion of a specialist emergency physician in the triage process. This suggests that specialist emergency department nurses are adequately trained in triage, and that delays in the triage process at UHWI are due to other factors. PMID- 24149096 TI - 'Treatment of the sportsman's groin': British Hernia Society's 2014 position statement based on the Manchester Consensus Conference. AB - INTRODUCTION: The aim was to produce a multidisciplinary consensus to determine the current position on the nomenclature, definition, diagnosis, imaging modalities and management of Sportsman's groin (SG). METHODS: Experts in the diagnosis and management of SG were invited to participate in a consensus conference held by the British Hernia Society in Manchester, U.K. on 11-12 October 2012. Experts included a physiotherapist, a musculoskeletal radiologist and surgeons with a proven track record of expertise in this field. Presentations detailing scientific as well as outcome data from their own experiences were given. Records were made of the presentations with specific areas debated openly. RESULTS: The term 'inguinal disruption' (ID) was agreed as the preferred nomenclature with the term 'Sportsman's hernia' or 'groin' rejected, as no true hernia exists. There was an overwhelming agreement of opinion that there was abnormal tension in the groin, particularly around the inguinal ligament attachment. Other common findings included the possibility of external oblique disruption with consequent small tears noted as well as some oedema of the tissues. A multidisciplinary approach with tailored physiotherapy as the initial treatment was recommended with any surgery involving releasing the tension in the inguinal canal by various techniques and reinforcing it with a mesh or suture repair. A national registry should be developed for all athletes undergoing surgery. CONCLUSIONS: ID is a common condition where no true hernia exists. It should be managed through a multidisciplinary approach to ensure consistent standards and outcomes are achieved. PMID- 24149097 TI - Associations between objectively measured physical activity and academic attainment in adolescents from a UK cohort. AB - BACKGROUND: To test for cross-sectional (at age 11) and longitudinal associations between objectively measured free-living physical activity (PA) and academic attainment in adolescents.Method Data from 4755 participants (45% male) with valid measurement of PA (total volume and intensity) by accelerometry at age 11 from the Avon Longitudinal Study of Parents and Children (ALSPAC) was examined. Data linkage was performed with nationally administered school assessments in English, Maths and Science at ages 11, 13 and 16. RESULTS: In unadjusted models, total volume of PA predicted decreased academic attainment. After controlling for total volume of PA, percentage of time spent in moderate-vigorous intensity PA (MVPA) predicted increased performance in English assessments in both sexes, taking into account confounding variables. In Maths at 16 years, percentage of time in MVPA predicted increased performance for males (standardised beta=0.11, 95% CI 0.00 to 0.22) and females (beta=0.08, 95% CI 0.00 to 0.16). For females the percentage of time spent in MVPA at 11 years predicted increased Science scores at 11 and 16 years (beta=0.14 (95% CI 0.03 to 0.25) and 0.14 (0.07 to 0.21), respectively). The correction for regression dilution approximately doubled the standardised beta coefficients. CONCLUSIONS: Findings suggest a long term positive impact of MVPA on academic attainment in adolescence. PMID- 24149098 TI - Stratification of de novo adult acute myelogenous leukemia with adverse-risk karyotype: can we overcome the worse prognosis of adverse-risk group acute myelogenous leukemia with hematopoietic stem cell transplantation? AB - Karyotype is a powerful prognostic factor for complete remission (CR) and overall survival (OS) in acute myelogenous leukemia (AML). Adverse-risk karyotype AML is now treated with intensive chemotherapy followed by allogeneic hematopoietic stem cell transplantation (allo-HSCT) to overcome relapse. We attempted to stratify patients with this disease using a combination of known factors. We evaluated clinical correlates in 211 adults with AML and adverse-risk karyotypes. We divided the patients into several subgroups based on the number of chromosomal aberrations (NCAs), normal karyotype (NK) mosaicism, and monosomal karyotype (MK) status. CR rates and survival outcomes were compared among the subgroups, and the relapse rate was calculated in the allo-HSCT subgroup. The cutoff of NCA >= 5 showed the worst OS (P < .001) compared with NCA >= 3 or NCA >= 4 even after allo HSCT. NK mosaicism significantly improved OS in both the NCA <5 (P = .024) and NCA >= 5 (P = .030) subgroups, but after allo-HSCT, it showed a favorable effect only in the NCA <5 subgroup. MK showed worse OS (P = .041), but there was no significantly worse effect after allo-HSCT compared with non-MK. Finally, we stratified patients into 4 subgroups, NCA >= 5 and NCA <5 with and without NK mosaicism. The most favorable OS and lower relapse rate after allo-HSCT were achieved by the NCA <5 with NK mosaicism subgroup, and the NCA >= 5 without NK mosaicism subgroup showed the worst prognosis in both entire group and allo-HSCT subgroup analysis. This study reveals that the combination of NCA and NK mosaicism may predict survival outcomes accurately, and suggests that novel treatment strategies for highly adverse-risk group AML should be tailored in the future. PMID- 24149100 TI - Subthalamic nucleus involvement in children: a neuroimaging pattern-recognition approach. AB - A neuroimaging-based pattern-recognition approach has been shown to be very helpful in the diagnosis of a wide range of pediatric central nervous system diseases. Few disorders may selectively affect the subthalamic nucleus in children including Leigh syndrome, succinic semialdehyde dehydrogenase deficiency, kernicterus, chronic end-stage liver failure and near total hypoxic ischemic injury in the full-term neonates. The consideration of the constellation of clinical history and findings as well as additional neuroimaging findings should allow planning the appropriate diagnostic tests to make the correct diagnosis in children with involvement of the subthalamic nucleus. PMID- 24149099 TI - Novel diffusion tensor imaging findings in Krabbe disease. AB - BACKGROUND: Krabbe disease is a lysosomal disorder that primarily affects myelin. Diffusion tensor imaging (DTI) provides quantitative information about the white matter organization and integrity. Radial diffusivity (RD) reflects myelin injury selectively. PURPOSE: To report on quantitative DTI findings (including axial diffusivity (AD) and RD, not previously reported) in two children with Krabbe disease compared to controls. METHODS: A quantitative region of interest (ROI) based DTI analysis was performed for the patients and age- and gender-matched controls. Fractional anisotropy (FA), mean diffusivity, AD and RD values as well as variation ratios between the patients' and controls' values were calculated for nine brain regions. RESULTS: Two boys with Krabbe disease were included in this study. DTI data were acquired at the ages of 6.25 years and 6.5 months. For all regions, FA ratios were negative, while RD and MD ratios positive. The most elevated variation ratios were found for RD. Variation ratios were greater in the centrum semiovale, corpus callosum, and middle cerebellar peduncles than in other anatomical regions, especially in the older patient in comparison with the younger patient. The AD ratios, however, were much lower and close to zero. CONCLUSIONS: DTI allows a quantitative evaluation of white matter damage in Krabbe disease. RD seems to be the most sensitive DTI parameter in agreement with the histopathological findings in Krabbe disease, a primary myelin disorder. This may be important in the early detection of the onset of demyelination. PMID- 24149101 TI - The formal-informal patient payment mix in European countries. Governance, economics, culture or all of these? AB - Cost-sharing for health care is high on the policy agenda in many European countries that struggle with deficits in their public budget. However, such policy often meets with public opposition, which might delay or even prevent its implementation. Increased reliance on patient payments may also have adverse equity effects, especially in countries where informal patient payments are widespread. The factors which might influence the presence of both, formal and informal payments can be found in economic, governance and cultural differences between countries. The aim of this paper is to review the formal-informal payment mix in Europe and to outline factors associated with this mix. We use quantitative analyses of macro-data for 35 European countries and a qualitative description of selected country experiences. The results suggest that the presence of obligatory cost-sharing for health care services is associated with governance factors, while informal patient payments are a multi-cause phenomenon. A consensus-based policy, supported by evidence and stakeholders' engagement, might contribute to a more sustainable patient payment policy. In some European countries, the implementation of cost-sharing requires policy actions to reduce other patient payment obligations, including measures to eliminate informal payments. PMID- 24149103 TI - Reply: To PMID 24149108. PMID- 24149102 TI - Variation at 3p24.1 and 6q23.3 influences the risk of Hodgkin's lymphoma. AB - In addition to HLA, recent genome-wide association studies (GWASs) of Hodgkin's lymphoma (HL) have identified susceptibility loci for HL at 2p16.1, 8q24.21 and 10p14. In this study, we perform a GWAS meta-analysis with published GWAS (totalling 1,465 cases and 6,417 controls of European background), and follow-up the most significant association signals in 2,024 cases and 1,853 controls. A combined analysis identifies new HL susceptibility loci mapping to 3p24.1 (rs3806624; P=1.14 * 10(-12), odds ratio (OR)=1.26) and 6q23.3 (rs7745098; P=3.42 * 10(-9), OR=1.21). rs3806624 localizes 5' to the EOMES (eomesodermin) gene within a p53 response element affecting p53 binding. rs7745098 maps intergenic to HBS1L and MYB, a region previously associated with haematopoiesis. These findings provide further insight into the genetic and biological basis of inherited susceptibility to HL. PMID- 24149104 TI - Augmented reality partial nephrectomy: examining the current status and future perspectives. AB - A minimal access approach to partial nephrectomy has historically been under utilized, but is now becoming more popular with the growth of robot-assisted laparoscopy. One of the criticisms of minimal access partial nephrectomy is the loss of haptic feedback. Augmented reality operating environments are forecast to play a major enabling role in the future of minimal access partial nephrectomy by integrating enhanced visual information to supplement this loss of haptic sensation. In this article, we systematically examine the current status of augmented reality in partial nephrectomy by identifying existing research challenges and exploring future agendas for this technology to achieve wider clinical translation. PMID- 24149105 TI - Gene expression profile during testicular development in patients with SRY negative 46,XX testicular disorder of sex development. AB - OBJECTIVE: To elucidate alternative pathways in testicular development, we attempted to clarify the genetic characteristics of SRY-negative XX testes. MATERIALS AND METHODS: We previously reported 5 cases of SRY-negative 46,XX testicular disorders of sex development and demonstrated that coordinated expression of genes such as SOX9, SOX3, and DAX1 was associated with testicular development. We performed a case-control study between the aforementioned boy with 46,XX testicular disorders of sex development and an age-matched patient with hydrocele testis (46,XY). During their consecutive surgeries, testicular biopsy specimens were obtained. Genes with differential expression compared with XY testis were identified using polymerase chain reaction (PCR)-based subtractive hybridization and sequencing. For validation of differential gene expression, real-time RT-PCR was performed using gene-specific primers. The distribution of candidate proteins in the testicular tissue was clarified by immunohistochemistry in human and rodent specimens. Moreover, in vitro inhibitory assays were performed. RESULTS: We identified 13 upregulated and 7 downregulated genes in XX testis. Among the candidate genes, we focused on ROCK1 (Rho-associated, coiled coil protein kinase 1) in the upregulated gene group, because high expression in XX testis was validated by real-time RT-PCR. ROCK1 protein was detected in germ cells, Leydig cells, and Sertoli cells by immunohistochemistry. Moreover, the addition of specific ROCK1 inhibitor to Sertoli cells decreased SOX9 gene expression. CONCLUSION: On the basis of in vitro inhibitory assay, it is suggested that ROCK1 phosphorylates and activates SOX9 in Sertoli cells. Testes formation might be initiated by an alternative signaling pathway attributed to ROCK1, not SRY, activation in XX testes. PMID- 24149106 TI - Clinical implications of preoperative serum total cholesterol in patients with clear cell renal cell carcinoma. AB - OBJECTIVE: To investigate the clinical implication of preoperative serum total cholesterol (TC) level in patients with clear cell renal cell carcinoma (RCC). METHODS: The records of 364 patients with clear cell RCC who had undergone nephrectomy were retrospectively reviewed. The association among preoperative TC level, clinicopathologic factors, and oncological outcome in terms of cancer specific survival (CSS) and recurrence-free survival period was analyzed by univariate and multivariate analyses. RESULTS: As a continuous variable, lower serum TC level was found to be significantly associated with male sex, symptomatic tumor, advanced TNM stage, higher nuclear grade, microscopic venous invasion, poor Eastern Cooperative Oncology Group Performance Status, larger tumor size, elevated C-reactive protein level, and lower hemoglobin level. Univariate analysis showed that relatively lower preoperative serum TC level was associated with lower recurrence-free survival (P = .040) and CSS (P <.001) rates. Multivariate analysis indicated that in addition to pT stage, M stage, nuclear grade, and Eastern Cooperative Oncology Group Performance Status, serum TC level (hazard ratio, 0.988 per mg/dL; 95% confidence interval, 0.980-0.998; P = .019) was an independent predictor of CSS. CONCLUSION: Low preoperative serum TC level is associated with worse prognosis in patients with clear cell RCC. Consideration of preoperative serum TC level might thus provide additional prognostic information for patients with clear cell RCC. PMID- 24149107 TI - Nephrolithotomy performed concurrently with laparoendoscopic single-site pyeloplasty. AB - INTRODUCTION: The objective of the present study was to evaluate the results of laparoendoscopic single-site (LESS) pyeloplasty and pyelolithotomy, which were performed concurrently in patients with pelviureteric junction obstruction (PUJO) and renal stones. TECHNICAL CONSIDERATIONS: Four patients with PUJO and renal stones underwent pyelolithotomy performed concurrently with LESS pyeloplasty. In 3 patients, a 2.5-cm incision was made in the umbilical region. In the fourth patient, the 2.5-cm vertical incision was made at a site 7 cm below the umbilical region because of a stone in the right lower calyx. After dissection of the pelviureteric junction, an incision of approximately 1 cm was made along the presumed transection line of the renal pelvis. The pyelolithotomy was performed using a 24F rigid nephroscope through a SILS port. Dismembered pyeloplasty was performed after extraction of the renal stones was completed. The mean operation time was 277 minutes (range, 225-373), and the mean lithotomy time was 31 minutes (range, 20-50). No intraoperative or postoperative complications were observed. For all 4 patients, discharge from the hospital was possible after a mean of 3.4 postoperative days (range, 3-4). All patients became stone free. Postoperative ultrasound revealed that hydronephrosis improved in all patients. In all patients, resolution of the symptoms was confirmed. CONCLUSION: LESS nephrolithotomy with pyeloplasty is a safe and effective procedure with a good cosmetic result for patients with PUJO and renal stones. PMID- 24149108 TI - Editorial comment. PMID- 24149109 TI - The management of vesicoureteral reflux in the setting of posterior urethral valve with emphasis on bladder function and renal outcome: a single center cohort study. AB - OBJECTIVE: To represent our experience in the management of posterior urethral valves and concomitant vesicoureteral reflux (VUR). METHODS: A total of 326 children with posterior urethral valve who had underwent valve ablation/bladder neck incision were studied, and those who had persistent VUR and were categorized under 3 main groups were followed up. Group 1 (n = 71) received prophylactic antibiotic, group 2 (n = 50) underwent Deflux injection (2a) (n = 28): Deflux injection alone, group 2b (n = 22) Deflux with concomitant autologous blood injection (HABIT), and group 3 (n = 19) underwent ureteroneocystostomy before referral and was followed up conservatively. VUR resolution, incidence of urinary tract infections (UTI), and bladder function were assessed. RESULTS: Mean duration of follow-up was 3.8 years; VUR resolution occurred in 66.1%, 86.0%, and 94.0% of groups 1-3, respectively (P = .013). Resolution rate in group 2b was significantly higher than group 2a (90.9% vs 78.5%). Patients in group 2 experienced a longer UTI-free period compared with others (P <.05). Urodynamic studies demonstrated significant decrease in maximum voiding detrusor pressure and detrusor overactivity in all groups (P <.001). Children in group 3 ended up with lower compliance compared with others (P <.001). After toilet training, only 2.8%, 21.4%, 13.6%, and 27% children were diagnosed with lower urinary tract dysfunction in groups 1-3, respectively (P = .027). Myogenic failure developed only in 3 boys in group 3. CONCLUSION: Ablation/bladder neck incision leads to significant improvement in VUR status in part because of improvement in bladder function. After successful valve removal, conservative therapy can be regarded as the mainstay of reflux treatment, whereas HABIT is recommended for high grade VUR associated with febrile UTI or deterioration in renal function. PMID- 24149110 TI - Men (aged 40-49 years) with a single baseline prostate-specific antigen below 1.0 ng/mL have a very low long-term risk of prostate cancer: results from a prospectively screened population cohort. AB - OBJECTIVE: To study the use of a baseline prostate-specific antigen (PSA) and digital rectal examination in men (aged 40-49 years) in predicting long-term prostate cancer risk in a prospectively followed, representative population cohort. PATIENTS AND METHODS: Since 1990, a random sample of men in Olmsted County (aged 40-49 years) has been followed up prospectively (n = 268), with biennial visits, including a urologic questionnaire, PSA screening, and physical examination. The ensuing risk of prostate cancer (CaP) was compared using survival analyses. RESULTS: Median follow-up was 16.3 years (interquartile range 14.0-17.3, max 19.1). For men with a baseline PSA <1.0 ng/mL (n = 195), the risk of subsequent Gleason 6 CaP diagnosis by 55 years was 0.6% (95% confidence interval [CI] 0%-1.7%) and 15.7% (95% CI 6.5%-24.9%) for men with a baseline PSA >= 1.0 ng/mL. No man with a low baseline PSA developed an intermediate or high risk CaP, whereas 2.6% of men with a higher baseline PSA did (95% CI 0.58%-4.6%). CONCLUSION: Men (aged 40-49 years) can be stratified with a baseline PSA. If it is below 1.0 ng/mL, there is very little risk for developing a lethal CaP, and as many as 75% of men might be able to avoid additional PSA screening until 55 years. Conversely, men aged 40-49 years with a baseline PSA level >1.0 ng/mL had a significant risk of CaP diagnosis and should be monitored more closely. PMID- 24149111 TI - Lower urinary tract dysfunction in male Iraq and Afghanistan war veterans: association with mental health disorders: a population-based cohort study. AB - OBJECTIVE: To determine the prevalence and correlates of lower urinary tract symptoms (LUTS) among returned Iraq and Afghanistan veterans; in particular its association with mental health diagnoses and medication use. METHODS: We performed a retrospective cohort study of Iraq and Afghanistan veterans who were new users of U.S. Department of Veterans Affairs health care. Mental health diagnoses were defined by International Classification of Disease, 9th Revision, Clinical Modification (ICD-9-CM) codes from medical records. LUTS was defined by ICD-9-CM code, use of prescription medication for LUTS, or procedure for LUTS. We determined the independent association of mental health diagnoses and LUTS after adjusting for sociodemographic and military service characteristics, comorbidities, and medications. RESULTS: Of 519,189 veterans, 88% were men and the mean age was 31.8 years (standard deviation +/- 9.3). The overall prevalence of LUTS was 2.2% (11,237/519,189). Veterans with post-traumatic stress disorder (PTSD) were significantly more likely to have a LUTS diagnosis, prescription, or related procedure (3.5%) compared with veterans with no mental health diagnoses (1.3%) or a mental health diagnosis other than PTSD (3.1%, P <.001). In adjusted models, LUTS was significantly more common in veterans with PTSD with and without other mental health disorders vs those without mental health disorders (adjusted relative risk [ARR] = 2.04, 95% confidence interval [CI] = 1.94-2.15) and in veterans prescribed opioids (ARR = 2.46, 95% CI = 2.36-2.56). CONCLUSION: In this study of young returned veterans, mental health diagnoses and prescription for opioids were independently associated with increased risk of receiving a diagnosis, treatment, or procedure for LUTS. Provider awareness may improve the detection and treatment of LUTS, and improve patient care and quality of life. PMID- 24149112 TI - Lipocalin-2 elicited by advanced glycation end-products promotes the migration of vascular smooth muscle cells. AB - Advanced glycation end-products (AGEs) play key roles in the development of diabetic vascular complications by activating the proliferation and migration of vascular smooth muscle cells. Here, we identified an increase of the migratory properties of human aortic smooth muscle cells (HASMC) through AGE-induced expression of lipocalin-2 (LCN2). Because the AGE-elicited expression of LCN2 was diminished by an antibody against the AGE receptor (RAGE), diphenylene iodonium (DPI), N-acetyl cysteine, LY294002, and SP600125, we suggest that AGEs enhance the expression of LCN2 via a RAGE-NADPH oxidase-reactive oxygen species pathway, leading to the phosphorylation of PI3K-Akt and JNK in HASMCs. In addition, a chromatin immunoprecipitation assay and promoter assay revealed that CCAAT/enhancer binding protein beta is crucial for AGE-induced expression of LCN2. However, any other AGE-related signaling pathway, including ERK1/2, p38, NF kappaB, and AP-1, did not affect the AGE- induced expression of LCN2. Knockdown of LCN2 expression by shRNA showed that AGE-elicited LCN2 expression enhanced the invasive and migratory properties of HASMCs, but showed no effect on cell proliferation. Considering the importance of HASMC migration in the development of atherosclerosis, our study provides a novel insight into diabetic vascular complications. PMID- 24149113 TI - Biological sulfate removal from gypsum contaminated construction and demolition debris. AB - Construction and demolition debris (CDD) contains high levels of sulfate that can cause detrimental environmental impacts when disposed without adequate treatment. In landfills, sulfate can be converted to hydrogen sulfide under anaerobic conditions. CDD can thus cause health impacts or odor problems to landfill employees and surrounding residents. Reduction of the sulfate content of CDD is an option to overcome these problems. This study aimed at developing a biological sulfate removal system to reduce the sulfate content of gypsum contaminated CDD in order to decrease the amount of solid waste, to improve the quality of CDD waste for recycling purposes and to recover sulfur from CDD. The treatment leached out the gypsum contained in CDD by water in a leaching column. The sulfate loaded leachate was then treated in a biological sulfate reducing Upflow Anaerobic Sludge Blanket (UASB) reactor to convert the sulfate to sulfide. The UASB reactor was operated at 23 +/- 3 degrees C with a hydraulic retention time and upflow velocity of 15.5 h and 0.1 m h(-1), respectively while ethanol was added as electron donor at a final organic loading rate of 3.46 g COD L(-1) reactor d(-1). The CDD leachate had a pH of 8-9 and sulfate dissolution rates of 526.4 and 609.8 mg L(-1) d(-1) were achieved in CDD gypsum and CDD sand, respectively. Besides, it was observed that the gypsum dissolution was the rate limiting step for the biological treatment of CDD. The sulfate removal efficiency of the system stabilized at around 85%, enabling the reuse of the UASB effluent for the leaching step, proving the versatility of the bioreactor for practical applications. PMID- 24149115 TI - Effects of ion concentration on thermally-chargeable double-layer supercapacitors. AB - The concept of thermally-chargeable supercapacitor was discussed and validated experimentally. As two double-layer supercapacitor-type devices were placed at different temperatures and connected, due to the thermal dependence of surface charge structures, the electrode potentials became different, and thermal energy could be harvested and stored as electric energy. The important effect of ion concentration was investigated. The results were quite different from the prediction of conventional surface theory, which should be attributed to the unique behaviors of the ions confined in the nanoporous electrodes. PMID- 24149114 TI - Air pollution-mediated susceptibility to inflammation and insulin resistance: influence of CCR2 pathways in mice. AB - BACKGROUND: Epidemiologic and experimental studies support an association between PM2.5 exposure and insulin resistance (IR). Innate immune cell activation has been suggested to play a role in the pathogenesis of these effects. OBJECTIVES: We sought to evaluate the role of CC-chemokine receptor 2 (CCR2) in PM2.5 mediated inflammation and IR. METHODS: Wild-type C57BL/6 and CCR2-/- male mice were fed a high-fat diet and exposed to either concentrated ambient PM2.5 or filtered air for 17 weeks via a whole-body exposure system. We evaluated glucose tolerance and insulin sensitivity. At euthanasia, blood, spleen, and visceral adipose tissue (VAT) were collected, and inflammatory cells were measured using flow cytometry. We used standard immunoblots, immunohistochemical methods, and quantitative PCR (polymerase chain reaction) to assess pathways of interest involving insulin signaling, inflammation, and lipid and glucose metabolism in various organs. Vascular function was assessed using myography. RESULTS: PM2.5 exposure resulted in whole-body IR and increased hepatic lipid accumulation in the liver, which was attenuated in CCR2-/- mice by inhibiting SREBP1c-mediated transcriptional programming, decreasing fatty acid uptake, and suppressing p38 MAPK activity. Abnormal phosphorylation levels of AKT, AMPK in VAT, and adipose tissue macrophage content in wild-type mice were not present in CCR2-/- mice. However, the impaired whole-body glucose tolerance and reduced GLUT-4 in skeletal muscle in response to PM2.5 was not corrected by CCR2 deficiency. CONCLUSIONS: PM2.5 mediates IR by regulating VAT inflammation, hepatic lipid metabolism, and glucose utilization in skeletal muscle via both CCR2-dependent and -independent pathways. These findings provide new mechanistic links between air pollution and metabolic abnormalities underlying IR. PMID- 24149116 TI - Acute effects of three different stretching protocols on the wingate test performance. AB - The purpose of this study was to examine the acute effects of different stretching exercises on the performance of the traditional Wingate test (WT). Fifteen male participants performed five WT; one for familiarization (FT), and the remaining four after no stretching (NS), static stretching (SS), dynamic stretching (DS), and proprioceptive neuromuscular facilitation (PNF). Stretches were targeted for the hamstrings, quadriceps, and calf muscles. Peak power (PP), mean power (MP), and the time to reach PP (TP) were calculated. The MP was significantly lower when comparing the DS (7.7 +/- 0.9 W/kg) to the PNF (7.3 +/- 0.9 W/kg) condition (p < 0.05). For PP, significant differences were observed between more comparisons, with PNF stretching providing the lowest result. A consistent increase of TP was observed after all stretching exercises when compared to NS. The results suggest the type of stretching, or no stretching, should be considered by those who seek higher performance and practice sports that use maximal anaerobic power. PMID- 24149117 TI - Constraint-led changes in internal variability in running. AB - We investigated the effect of a one-time application of elastic constraints on movement-inherent variability during treadmill running. Eleven males ran two 35 min intervals while surface EMG was measured. In one of two 35-min intervals, after 10 min of running without tubes, elastic tubes (between hip and heels) were attached, followed by another 5 min of running without tubes. To assess variability, stride-to-stride iEMG variability was calculated. Significant increases in variability (36 % to 74 %) were observed during tube running, whereas running without tubes after the tube running block showed no significant differences. Results show that elastic tubes affect variability on a muscular level despite the constant environmental conditions and underline the nervous system's adaptability to cope with somehow unpredictable constraints since stride duration was unaltered. PMID- 24149118 TI - A biomechanical assessment of ergometer task specificity in elite flatwater kayakers. AB - The current study compared EMG, stroke force and 2D kinematics during on ergometer and on-water kayaking. Male elite flatwater kayakers (n = 10) performed matched exercise protocols consisting of 3 min bouts at heart and stroke rates equivalent to 85% of VO2peak (assessed by prior graded incremental test). EMG data were recorded from Anterior Deltoid (AD), Triceps Brachii (TB), Latissimus Dorsi (LD) and Vastus Lateralis (VL) via wireless telemetry. Video data recorded at 50 Hz with audio triggers pre- and post-exercise facilitated synchronisation of EMG and kinematic variables. Force data were recorded via strain gauge arrays on paddle and ergometer shafts. EMG data were root mean squared (20ms window), temporally and amplitude normalised, and averaged over 10 consecutive cycles. In addition, overall muscle activity was quantified via iEMG and discrete stroke force and kinematic variables computed. Significantly greater TB and LD mean iEMG activity were recorded on-water (239 +/- 15 vs. 179 +/- 10 MUV. s, p < 0.01 and 158 +/- 12 vs. 137 +/- 14 MUV.s, p < 0.05, respectively), while significantly greater AD activity was recorded on-ergometer (494 +/- 66 vs. 340 +/- 35 MUV.s, p < 0.01). Time to vertical shaft position occurred significantly earlier on ergometer (p < 0.05). Analysis of stroke force data and EMG revealed that increased AD activity was concurrent with increased external forces applied to the paddle shaft at discrete phases of the on-ergometer stroke cycle. These external forces were associated with the ergometer loading mechanism and were not observed on- water. The current results contradict a previous published hypothesis on shoulder muscle recruitment during on-water kayaking. Key pointsWhen exercising at fixed heart and stroke rates, biomechanical differences exist between onergometer and on-water kayaking.Ergometer kayaking results in significantly greater Anterior Deltoid activity but significantly lower Triceps Brachii and Latissimus Dorsi activity, compared with on-water kayaking.The altered muscle recruitment patterns observed on-ergometer are most likely a result of additional forces associated with the ergometer loading mechanism, acting upon the paddle shaft. PMID- 24149119 TI - High-volume resistance training session acutely diminishes respiratory muscle strength. AB - This study investigated the effect of a high-volume compared to a low-volume resistance training session on maximal inspiratory pressure (MIP) and maximal expiratory pressure (MEP). Twenty male subjects with resistance training experience (6.2 +/- 3.2 y), in a crossover trial, completed two resistance training protocols (high-volume: 5 sets per exercise; low-volume: 2 sets per exercise) and a control session (no exercise) on 3 separate occasions. MIP and MEP decreased by 13.6% (p < 0.01) and 14.7% (p < 0.01) respectively from pre session MIP and MEP, following the high-volume session. MIP and MEP were unaffected following the low-volume or the control sessions. MIP returned to pre session values after 40 minutes, whereas MEP remained significantly reduced after 60 minutes post-session by 9.2% compared to pre-session (p < 0.01). The findings suggest that the high-volume session significantly decreased MIP and MEP post session, implicating a substantially increased demand on the respiratory muscles and that adequate recovery is mandatory following this mode of training. Key pointsRespiratory muscular strength performance is acutely diminished following a high-volume whole-body resistance training session.Greater ventilatory requirements and generation of IAP during the high-volume resistance training session may have contributed to the increased demand placed on the respiratory muscles.Protracted return of respiratory muscular strength performance to baseline levels may have implications for individuals prior to engaging in subsequent exercise bouts. PMID- 24149120 TI - Short-term jump activity on bone metabolism in female college-aged nonathletes. AB - There have been few studies examining the short-term effect of high-impact activities on bone metabolism measured by bone serum marker concentrations. The purpose of this study was to examine the effect of short-term high-impact jump activity on bone turnover in female college-aged non-athletes. Twenty six healthy females were randomly assigned to a control or jump group. The subjects jumped 5 days per week for 2 weeks. The participants completed 10 jumps per session. A general health questionnaire and a bone-specific physical activity assessment instrument (BPAQ) were completed. BPAQ scores were calculated based on the past history of exercise. Blood draws were taken in both groups before and after the two-week experimental period. The vertical ground reaction force (VGRF) of all jumps and jump height were measured for each subject daily and the osteogenic index (OI) was measured. Concentrations of serum osteocalcin (OC), Bone Specific Alkaline Phosphatase (BAP), C-Terminal Telopeptides of Type I Collagen (CTX) and plasma Tartrate-Resistant Acid Phosphatase (TRAP5b) were assessed pre and post jump protocol to measure bone formation and resoprtion respectively. A significant interaction (time x group) was found in TRAP5b, and BAP values (p < 0.05). There was a significant decrease in CTX and BAP values in the jump group (p < 0.05) after the two week jump protocol. No significant interactions or changes were observed in OC values for either the jump or the control group. Two weeks of jump activity consisting of 10 jumps/day for 5 days/week with a weekly osteogenic index of 52.6 significantly decreased markers of bone resorption (TRAP5b and CTX) and bone formation (BAP) in young female non-athletes. PMID- 24149121 TI - Views of adolescent female youth on physical activity during early adolescence. AB - Early adolescence is a time when a transition away from sport and physical activity participation is at its highest level among female youth (Hedstrom & Gould, 2004). This has led to the identification of barriers and facilitators of physical activity participation for adolescent females. Consequently there have been calls to overcome barriers and augment facilitators via the creation of gender-relevant programming. Despite these calls and efforts, a gender disparity remains, and a detailed understanding of how girls experience and interpret physical activity within the context of their lives is still lacking. The current project aimed to gain further insight into the foregoing using tenets of Interpretive Phenomenology to further understand the lived physical activity experiences of females during early adolescence, delineating their barriers to participation and the factors enabling participation. Five themes were identified and made into vignettes to facilitate understanding from adolescent females' perspectives: friends or don't know anyone, good or not good enough, fun or not fun; good feeling or gross; and peer support or peer pressure. The physical activity promotion implications for female youth are discussed within the context of these themes. PMID- 24149122 TI - Validation of the mywellness key in walking and running speeds. AB - This study was performed to assess the validity of the MyWellness Key (MWK) accelerometer during a treadmill-based protocol. The identification of different exercise intensities is imperative to objectively measure time spent at a specified exercise intensity. Thirty subjects, 15 men and 15 women (age = 24.5 +/ 2.6 years; body mass index = 22.5 +/- 2.5 kg.m(-1)), participated in a 4-phase treadmill protocol (5 minutes each one) using three different walking velocities (3, 4.5, and 6 km.h(-1)) and run (8 km.h(-1)) while outfitted with a MWK uniaxial accelerometer. Oxygen consumption was measured by indirect calorimetry (ICVO2). RESULTS: The relationship between VO2 predicted from MWK (MWKVO2) and oxygen consumption (VO2 (ICVO2)), yielded a high and significant correlation (r = 0. 944; p < 0.001) with standard error of estimate (SEE) = 2.42 mL.kg(-1).min(-1). The average differences between the two methods (MWKVO2 - ICVO2) were -0.79 (-8. 8% at 3 km.h(-1)), -0.02 (-0.2% at 4.5 km.h(-1)), 0.51 (3.3% at 6 km.h(-1)) and 0.74 (-2.7% at 8 km.h(-1)) ml.kg(-1).min(-1). Only the 3 km.h(-1) speed showed a difference when compared to the criterion measure (p < 0.001). Bland and Altman analysis revealed less than a 1 MET difference in the mean at each point estimate and relatively tight distribution with the standard errors, especially with the 2 moderate walking speeds. CONCLUSIONS: We found a high correlation between oxygen utilization and the MWK with low standard errors estimates. This indicates that this accelerometer can be used to identify exercise intensities that are related to walking and running. Key pointsFirst laboratory validation of a new uniaxial accelerometer, the MyWellness Key.Results indicate a good exercise intensity prediction during walking at moderate to high speeds.Comparing with other laboratory validations, MyWellness Key exercise intensity detection is aligned with other accelerometers.MyWellness Key can be used to give valid measurements for a range of ambulatory activity in addition to the capabilities to give real time feedback to the participant in health promotion studies. PMID- 24149123 TI - Tactical determinants of setting zone in elite men's volleyball. AB - The interactions between two opposing teams lead to the emergence of unique game patterns. In volleyball, attack efficacy emerges as the strongest predictor of the final result and thus it becomes of foremost importance to understand which game patterns afford the attaining of higher attack efficacies. These rely on the quality of the setting action. In turn, the serve and the serve reception constrain the setter's actions and the attacker's efficacy. Therefore, the purpose of this study was to examine predictors of the setting zone in elite level men's volleyball. Thirty-one matches of the 2007 World Cup were analyzed, in total 5117 rallies. The dependent variable was the setting zone, and the independent variables were the server player, serve type, serve direction, serve depth, reception zone, receiver player and reception type. Multinomial logistic regression was applied, in order to obtain the estimated likelihood of occurrence of the dependent variable, based on the values of the independent variables (p < 0.05). Only the serve direction showed not to be predictive of the setting zone. Concerning the remaining variables, the tennis jump serve, serves from the middle player, deep serves, reception near the endline or sidelines, reception by the zone 4 attackers when in defensive zone, and low reception all proved to impair the quality of reception, demanding the setter to play more often in the not acceptable setting zone. Results suggest that, at this level, practice of serve reception should preferably cover the deep tennis jump serve, and attempt to afford the libero more opportunities to receive. By focusing on the variables with the most predictive power, performers may better allocate their attention towards the most pertinent cues at each moment. Knowledge of these interactive models provides valuable insights into the dynamics of the action sequences, affording coaches important information and guidance. Key pointsA set of key variables interact and allow predicting the setting zone, an important variable in determining attack efficacy in high-level men's volleyball.The tennis jump serve, deep serves, receptions near the endline or sidelines, serves from the middle-players, receptions by the zone 4 attackers when in defensive zone, and low reception enhance the utilization of non-ideal setting zones.By focusing on the variables with the most predictive power, performers may better allocate their attention towards the most pertinent cues at each moment.Knowledge of these interactive models provides valuable insights into the dynamics of the action sequences, affording coaches important information and guidance. PMID- 24149124 TI - Is the critical running speed related to the intermittent maximal lactate steady state? AB - The purpose of the present study was to compare the critical speed (CS) with the speed at the maximal lactate steady state (vMLSS) determined by a continuous and an intermittent model in trained runners. Eight male endurance runners (30.3 +/- 10.6 years; 65.0 +/- 8.5 kg; 1.73 +/- 0.6 m; 11.3 +/- 4.0% body fat) volunteered for this investigation and performed an incremental treadmill test, as well as 2 5 30-min constant speed tests to determine the MLSS continuous and MLSS intermittent (5 min of running, interspaced by 1 min of passive rest). The CS was determined by 2 maximal running efforts of 1500 and 3000 m performed on a 400 m running track. The CS was calculated as the slope of the linear regression of distance versus time. Statistical analysis revealed no significant difference between CS and MLSS determined by intermittent running (15.2 +/- 1.0 km.h(-1) vs. 15.3 +/- 0.7 km.h(-1), respectively), however, both were significantly higher than continuous MLSS (14.4 +/- 0.6 km.h(-1)). There was also a significant correlation between CS and MLSS intermittent (r = 0.84, p = 0.008). On the basis of the present results, we conclude that for practical reasons (low cost, non invasive) the CS is an interesting and alternative method to prescribe endurance interval training at maximal lactate steady state intensity, in preference to a continuous protocol. PMID- 24149125 TI - Parental predictors of physical inactivity in spanish adolescents. AB - The purpose of this study was to determine some parental predictors of physical inactivity in Spanish adolescents. The sample comprised 1,978 children, aged between 12 and 16 years. A quantitative and qualitative technical triangulation was employed. The study analyzed data of the parents' educational level, the importance they grant to physical-sport activities, and their physical-sport practice. Quantitative technique: a questionnaire (MACOFYD) was used to collect the data. Descriptive, bivariate, and multinomial regression analyses were employed. Statistical significance was set at p < 0.05. Qualitative technique: four discussion groups were conducted, consisting of parents, physical education teachers, teachers of other subjects, and children aged between 12 and 16 years. The results indicated that adolescents are four times more likely to be physically inactive if their parents have never exercised (odds ratio [OR] = 4.065, and = 3.487, for the fathers and mothers, respectively, p < 0.05). When parents grant "some" or "much" importance to physical-sport practice, adolescents are less likely to be physically inactive (OR = 0.185 and 0.118 respectively, p < 0.01). No significant correlation was found between adolescents' physical-sport activity and parents' educational level. However, young people reproach their parents because they emphasize academic goals more than physical-sport practice an observation that teachers also confirm. Young people perceive their parents as being the education agents with the greatest influence over their inactive lifestyles. Many parents are unaware of their influence and, therefore, do not take responsibility, declaring that the teachers' influence is greater. PMID- 24149126 TI - A comparison of pairs figure skaters in repeated jumps. AB - Trends in pairs figure skating have shown that increasingly difficult jumps have become an essential aspect of high-level performance, especially in the latter part of a competitive program. We compared a repeated jump power index in a 60 s repeated jump test to determine the relationship of repeated jump test to competitive rank and to measure 2D hip, knee, and ankle angles and angular velocities at 0, 20, 40, and 60 s. Eighteen National Team Pairs Figure Skaters performed a 60 s repeated jump test on a large switch-mat with timing of flight and ground durations and digital video recording. Each 60-s period was divided into 6, 10-s intervals, with power indexes (W/kg) calculated for each 10-s interval. Power index by 10-s interval repeated measures ANOVAs (RMANOVA) showed that males exceeded females at all intervals, and the highest power index interval was during 10 to 20 s for both sexes. RMANOVAs of angles and angular velocities showed main effects for time only. Power index and jumping techniques among figure skaters showed rapid and steady declines over the test duration. Power index can predict approximately 50% of competitive rank variance, and sex differences in jumping technique were rare. Key pointsThe repeated jumps test can account for about 50% of the variance in pairs ranks.Changes in technique are largely due to fatigue, but the athletes were able to maintain a maximum flexion knee angle very close to the desired 90 degrees. Changes in angular velocity and jump heights occurred as expected, again probably due to fatigue.As expected from metabolic information, the athletes' power indexes peak around 20s and decline thereafter. Coaches should be aware of this time as a boundary beyond which fatigue becomes more manifest, and use careful choreographic choices to provide rest periods that are disguised as less demanding skating elements to afford recovery.The repeated jumps test may be a helpful off-ice test of power-endurance for figure skaters. PMID- 24149127 TI - The effects of man-marking on work intensity in small-sided soccer games. AB - THE AIM OF THIS STUDY WAS TO EXAMINE THE EFFECT OF MANIPULATING DEFENSIVE RULES: with and without man-marking (MM and NMM) on exercise intensity in 3 vs. 3 small- sided games (SSGs). Twelve adolescent soccer players (age: 16.2 +/- 0.7 years; body mass: 55.7 +/- 6.4 kg; body height: 1.70 +/- 0.07 m) participated in this repeated measures study. Each participant performed in four different SSGs formats: 3 vs. 3 MM with and without goals and 3 vs. 3 NMM with and without goals. Each SSG lasted 3 x 4 minutes interspersed with 4 minutes passive recovery. The percentage heart rate reserve (%HRreserve) was recorded continuously during SSG and session-rating of perceived exertion (session-RPE) after the SSG. MANOVA showed that defensive rule had significant effects on intensity (F = 5.37, p < 0.01). Specifically, MM during SSG induced significantly higher %HRreserve compared to NMM (Goal: 80.5 vs. 75.7%; No goal: 80.5 vs. 76.1%; p < 0.05, effect size = 0.91-1.06), irrespective of the presence or absence of goals. However, only MM with the presence of goals induced significant higher session-RPE compared to NMM (7.1 vs. 6. 0; p < 0.05, effect size = 1.36), whereas no difference in session-RPE was observed between MM and NMM (7.4 vs. 6.9; p > 0.05, effect size = 0.63) when no goals were used. Higher intra-class reliability and lower coefficient of variation values were also reported in MM as compared to NMM. This study in youth soccer players shows there is ~4.5% increase in heart rate response by using the man-marking in 3 vs. 3 SSG thus the intensity of SSG can be significantly increased when using man-marking tactics. Key pointsIntensity level of exercise during games can be raised if man-marking rule is adopted.No significant differences in perceived exertion were found in no goal SSG with and without man-marking.Adding goals in 3 vs. 3 SSG can lower perceived exertion without leading to large variations in intensity level. PMID- 24149128 TI - Validity of the Brunel Mood Scale for use With Malaysian Athletes. AB - The aim of the present study was to investigate the factorial validity of the Brunel Mood Scale for use with Malaysian athletes. Athletes (N = 1485 athletes) competing at the Malaysian Games completed the Brunel of Mood Scale (BRUMS). Confirmatory Factor Analysis (CFA) results indicated a Confirmatory Fit Index (CFI) of .90 and Root Mean Squared Error of Approximation (RMSEA) was 0.05. The CFI was below the 0.95 criterion for acceptability and the RMSEA value was within the limits for acceptability suggested by Hu and Bentler, 1999. We suggest that results provide some support for validity of the BRUMS for use with Malaysian athletes. Given the large sample size used in the present study, descriptive statistics could be used as normative data for Malaysian athletes. Key pointsFindings from the present study lend support to the validity of the BRUMS for use with Malaysian athletes.Given the size of the sample used in the present study, we suggest descriptive data be used as the normative data for researchers using the scale with Malaysian athletes.It is suggested that future research investigate the effects of cultural differences on emotional states experienced by athletes before, during and post-competition. PMID- 24149129 TI - Comparison of pathway and center of gravity of the calcaneus on non-involved and involved sides according to eccentric and concentric strengthening in patients with achilles tendinopathy. AB - This study compares the changes in pathway and center of gravity (COG) on the calcaneus of non-involved and involved sides according to eccentric and concentric strengthening in patients with unilateral Achilles tendinopathy. The goal was to define the biomechanical changes according to eccentric strengthening for the development of clinical guidelines. Eighteen patients with Achilles tendinopathy were recruited at the K Rehabilitation Hospital in Seoul. The subjects were instructed to perform 5 sessions of concentric strengthening. The calcaneal pathway was measured using a three-dimensional (3D) motion analyzer, and COG was measured by a force plate. Subsequently, eccentric strengthening was implemented, and identical variables were measured. Concentric and eccentric strengthening was carried out on both the involved and non-involved sides. There was no significant difference in the calcaneal pathway in patients with Achilles tendinopathy during concentric and eccentric strengthening. However, during eccentric strengthening, the calcaneal pathway significantly increased on the involved side compared to the non-involved side for all variables excluding the z axis. COG significantly decreased on the involved side when compared to the non involved side in patients with Achilles tendinopathy during eccentric and concentric strengthening. During concentric strengthening, all variables of the COG significantly increased on the involved side compared to the non-involved side. Compared with eccentric strengthening, concentric strengthening decreased the stability of ankle joints and increased the movement distance of the calcaneus in patients with Achilles tendinopathy. Furthermore, eccentric strengthening was verified to be an effective exercise method for prevention of Achilles tendinopathy through the reduction of forward and backward path length of foot pressure. The regular application of eccentric strengthening was found to be effective in the secondary prevention of Achilles tendinopathy in a clinical setting. PMID- 24149130 TI - Confirmation of the Basic Psychological Needs in Exercise Scale (BPNES) With a Sample of People who do Healthy Exercise. AB - This study aimed to cross-validate the psychometric properties of the Basic Psychological Needs in Exercise Scale (BPNES) by Vlachopoulos and Michailidou, 2006 in a Spanish context. Two studies were conducted. Confirmatory factor analysis results confirmed the hypothesized three-factor solution In addition, we documented evidence of reliability, analysed as internal consistency and temporal stability. Future studies should analyse the scale's validity and reliability with different populations and check their experimental effect. Key pointsThe Basic Psychological Needs in Exercise Scale (BPNES) is valid and reliable for measuring basic psychological needs in healthy physical exercise in the Spanish context.The factor structure of three correlated factors has shown minimal invariance across gender. PMID- 24149131 TI - Candidate gene analysis in israeli soldiers with stress fractures. AB - To investigate the association of polymorphisms within candidate genes which we hypothesized may contribute to stress fracture predisposition, a case-control, cross- sectional study design was employed. Genotyping 268 Single Nucleotide Polymorphisms- SNPs within 17 genes in 385 Israeli young male and female recruits (182 with and 203 without stress fractures). Twenty-five polymorphisms within 9 genes (NR3C1, ANKH, VDR, ROR2, CALCR, IL6, COL1A2, CBG, and LRP4) showed statistically significant differences (p < 0.05) in the distribution between stress fracture cases and non stress fracture controls. Seventeen genetic variants were associated with an increased stress fracture risk, and eight variants with a decreased stress fracture risk. None of the SNP associations remained significant after correcting for multiple comparisons (false discovery rate- FDR). Our findings suggest that genes may be involved in stress fracture pathogenesis. Specifically, the CALCR and the VDR genes are intriguing candidates. The putative involvement of these genes in stress fracture predisposition requires analysis of more cases and controls and sequencing the relevant genomic regions, in order to define the specific gene mutations. Key pointsUnderstanding the possible contribution of genetic variants to stress fracture pathogenesis.There is a paucity of data on the involvement of polymorphisms in specific genes in active military personnel/athletes which may contribute to stress fractures development.The results from the current study should facilitate a more comprehensive look at the genetic component of stress fractures. PMID- 24149132 TI - The effect of a silicone swim cap on swimming performance in tropical conditions in pre-adolescents. AB - We tested whether the silicone swim caps (SC) worn by young swimmers in a tropical climate negatively influence aerobic performance. Nine trained pre- adolescents [11.8 (+/- 0.8) years] swam randomized 800-m trials (water: 32.9 degrees C, outdoors: shade, 29.2 +/- 0.2 degrees C, 74 +/- 0.3 % rh) with a SC or a nude head (NH). Performance times and heart rate (HR) were monitored continuously. Rectal temperature (Trec) was measured before and after trials. The rating of perceived exertion (RPE) was assessed. Stroke frequency (SF), stroke length (SL) and stroke index (SI) were measured every 50-m. The SC trial was significantly longer than NH (799 +/- 16 and 781 +/- 16 seconds, respectively). Mean delta Trec was significantly greater in SC (0.2 +/- 0.1 degrees C vs. -0.1 +/- 0.1 degrees C in SC vs. NH), mean SI was significantly different in SC versus NH (1.83 +/- 0.07 vs 1.73 +/- 0.06); but RPE and mean HR, SF and SL showed no change. We conclude that a silicone swim cap worn in tropical environment significantly decreased 800-m crawl performance without affecting HR or RPE. Silicone swim caps worn by young swimmers in a tropical environment may also have negative effects on training capacity. Key pointsSwimming in tropical climate represents a physiological stressSwimming with swim cap in warm water could induce thermal stressThermoregulation processes have to be used in order to make training in tropical climate safer. PMID- 24149133 TI - A gender-based kinematic and kinetic analysis of the snatch lift in elite weightlifters in 69-kg category. AB - The objective of this study was to compare the kinematic and kinetic differences in snatch performances of elite 69-kg men and women weightlifters, the only category common to both genders. The heaviest lifts performed by 9 men and 9 women weightlifters competing in 69-kg weight class in Group A in the 2010 World Weightlifting Championship were analyzed. The snatch lifts were recorded using 2 cameras (PAL). Points on the barbell and body were manually digitized by using Ariel Performance Analysis System. The results showed that maximal extension angle of the ankle and knee during the first pull, the knee angle at the end of the transition phase, and maximal extension angle of the knee in the second pull were significantly greater in men (p < 0.05). The angular velocity of the hip was significantly greater in men during the first pull (p < 0.05). During the second pull, women showed significantly greater maximal angular velocity at the hip and ankle joints (p < 0.05). Moreover, the maximal vertical linear velocity of the barbell was significantly greater in women (p < 0.05). The absolute mechanical work and power output in the first pull and power output in the second pull were significantly greater in men (p < 0.05). However, the relative mechanical work was significantly greater in women during the second pull (p < 0.05). The results revealed that in 69-kg weight class, women were less efficient than men in the first pull, which is strength oriented, whereas they were as efficient as men in the second pull, which is more power oriented. Key pointsWomen weightlifters should do assistant exercises to strengthen their ankle flexor and knee extensor muscles in order to increase their maximal strength in the first pull.Women weightlifters should be able to execute a deeper and faster knee flexion in the transition phase in order to obtain a greater explosive strength during the second pull. PMID- 24149134 TI - Metabolic demands of match performance in young soccer players. AB - The aim of the present study was to determine metabolic responses, movement patterns and distance covered at running speeds corresponding to fixed blood lactate concentrations (FBLs) in young soccer players during a match play. A further aim of the study was to evaluate the relationships between FBLs, maximal oxygen consumption (VO2max) and distance covered during a game. A multistage field test was administered to 32 players to determine FBLs and VO2max. Blood lactate (LA), heart rate (HR) and rate of perceived exertion (RPE) responses were obtained from 36 players during tournament matches filmed using six fixed cameras. Images were transferred to a computer, for calibration and synchronization. In all players, values for LA and HR were higher and RPE lower during the 1(st) half compared to the 2(nd) half of the matches (p < 0.01). Players in forward positions had higher LA levels than defenders, but HR and RPE values were similar between playing positions. Total distance and distance covered in jogging, low-moderate-high intensity running and low intensity sprint were higher during the 1(st) half (p < 0.01). In the 1(st) half, players also ran longer distances at FBLs [p<0.01; average running speed at 2mmol.L(-1) (FBL2): 3.32 +/- 0.31m.s(-1) and average running speed at 4mmol.L(-1) (FBL4): 3.91 +/- 0.25m.s(-1)]. There was a significant difference between playing positions in distance covered at different running speeds (p < 0.05). However, when distance covered was expressed as FBLs, the players ran similar distances. In addition, relationships between FBLs and total distance covered were significant (r = 0.482 to 0.570; p < 0.01). In conclusion, these findings demonstrated that young soccer players experienced higher internal load during the 1(st) half of a game compared to the 2(nd) half. Furthermore, although movement patterns of players differed between playing positions, all players experienced a similar physiological stress throughout the game. Finally, total distance covered was associated to fixed blood lactate concentrations during play. Key pointsBased on LA, HR and RPE responses, young top soccer players experienced a higher physiological stress during the 1(st) half of the matches compared to the 2(nd) half.Movement patterns differed in accordance with the players' positions but that all players experienced a similar physiological stress during match play.Approximately one quarter of total distance was covered at speeds that exceeded the 4 mmol.L(-1) fixed LA threshold.Total distance covered was influenced by running speeds at fixed lactate concentrations in young soccer players during match play. PMID- 24149135 TI - Integration of scientific research training into undergraduate medical education: a reminder call. AB - There is an increasingly growing trend towards integrating scientific research training into undergraduate medical education. The importance and compulsoriness of this trend has been greatly highlighted at the Boyer Commission on Educating Undergraduates in the Research University. Despite the importance and benefits of undergraduate research, attempts of medical schools to encourage undergraduates to take part in formal research training during undergraduate medical education remain unsatisfactory. This article serves as a 'reminder call' highlighting the requisite to integrate scientific research training into undergraduate medical curricula. PMID- 24149136 TI - Language outcomes at 12 years for children exposed prenatally to cocaine. AB - PURPOSE: In this study, the authors aimed to examine the long-term effects of prenatal cocaine exposure (PCE) on the language development of 12-year-old children using a prospective design, controlling for confounding prenatal drug exposure and environmental factors. METHOD: Children who were exposed to cocaine in utero (PCE; n = 183) and children who were not exposed to cocaine (i.e., no cocaine exposure [NCE]; n = 181) were followed prospectively from birth to 12 years of age and were compared on language subtests of the Test of Language Development-Intermediate, Third Edition ( Hammill & Newcomer, 1997b), and phonological processing as measured by the Comprehensive Test of Phonological Processing ( Wagner & Torgesen, 1999). The authors evaluated the relationship of PCE to language development through a multivariate analysis of covariance and regression analyses while controlling for confounders. RESULTS: Results show that PCE has small effects on specific aspects of language, including syntax and phonological processing. The caregiver variables of lower maternal vocabulary, more psychological symptoms, and a poorer home environment also had consistent effects on language and phonological processing scores. CONCLUSIONS: These findings suggest that PCE continues to have small, subtle effects on specific aspects of language at age 12 years. Phonological processing skills were significantly related to the reading outcomes of letter-word identification, reading fluency, and reading comprehension, indicating that PCE also has small but lasting effects on the language skills that are related to later literacy skills. PMID- 24149137 TI - Impact of molecular alterations and targeted therapy in appendiceal adenocarcinomas. AB - Appendiceal adenocarcinomas (AAs) are rare and this has limited their molecular understanding. The purpose of our study was to characterize the molecular profile of AA and explore the role of targeted therapy against cyclooxygenase-2 (COX-2) and epidermal growth factor receptor (EGFR). PATIENTS AND METHODS: We performed a retrospective review of 607 patients with AA at a single institution. A total of 149 patients underwent molecular testing for at least one of the following: activating mutations in KRAS, BRAF, cKIT, EGFR, or PI3K; protein expression of c KIT or COX-2; or microsatellite instability (MSI) status by immunohistochemistry. Kaplan-Meier product limit method and log-rank test were used to estimate overall survival (OS) and to determine associations among OS, COX-2 expression, KRAS mutations, and other characteristics. RESULTS: Age, grade, stage, signet ring cells, mucinous histology, and completeness of cytoreduction score correlated with survival outcomes. COX-2 expression, KRAS, PI3K, and BRAF mutations were seen in 61%, 55%, 17%, and 4% of patients, respectively. High MSI was seen in 6% of patients. KRAS mutation was strongly associated with well differentiated or moderately differentiated AA (p < .01). COX-2 expression (p = .33) and the presence of KRAS mutation (p = .91) had no impact on OS. The use of celecoxib in patients whose tumors expressed COX-2 (p = .84) and the use of cetuximab or panitumumab in patients with KRAS wild-type tumors (p = .83) also had no impact on OS. CONCLUSION: In this cohort, we demonstrated that COX-2 expression and KRAS mutations were frequently seen in AA, although neither exhibited any prognostic significance. MSI was infrequent in AA. Targeted therapy against COX-2 and EGFR appeared to provide no clinical benefit. Well and moderately differentiated AA were molecularly distinct from poorly differentiated AA. PMID- 24149138 TI - Anti-Mullerian hormone and antral follicle count reveal a late impairment of ovarian reserve in patients undergoing low-gonadotoxic regimens for hematological malignancies. AB - The impact of cancer therapy on the reproductive potential of patients is increasingly recognized because survival rates of patients have clearly improved in recent years. Different fertility preservation methods, either generally accepted or still experimental, are currently available, and counseling of patients requires a delicate balance between the efficacy and side effects of the proposed method and the characteristics of both the tumor and the therapy. Deeper knowledge of the effects of cancer therapy on the reproductive potential of patients over time is required to identify the most appropriate fertility preservation method. In this paper, we report a case-control study in which female patients who were diagnosed with hematological malignancies and treated with chemotherapy and/or radiotherapy were compared with age-matched controls in terms of ovarian reserve, as measured by ultrasound examination and hormonal status. By stratifying patients for gonadotoxicity of the therapy received and time elapsed from the end of the therapy, we report that patients treated with low gonadotoxic therapies, while being similar to age-matched controls in their ovarian reserve when evaluated within a few years from the end of the therapy, show a clear impairment over longer times. We also report that anti-Mullerian hormone is the most sensitive hormonal parameter in detecting changes in ovarian reserve when compared with follicle-stimulating hormone or inhibin-B. This study stresses the importance of accurate counseling at the time of diagnosis of cancer and emphasizes the risks of infertility with low gonadotoxic therapies that may reduce the reproductive window of survivors. PMID- 24149139 TI - The physiological demands of table tennis: a review. AB - Although table tennis has a tradition lasting more than 100 years, relatively little is known about players' physiological requirements - especially during competition. In this review we discuss research studies that have led to our current understanding of how the body functions during table tennis training and competition and how this is altered by training. Match and practice analysis of the table tennis game indicates that during intense practice and competition it is predominantly the anaerobic alactic system that is called into play, while the endurance system is relied on to recovery the anaerobic stores used during such effort. It is thus important for coaches to keep in mind that, while the anaerobic alactic system is the most energetic system used during periods of exertion in a table tennis game, a strong capacity for endurance is what helps a player recover quicker for the following match and the next day of competition. This paper provides a review of specific studies that relate to competitive table tennis, and highlights the need for training and research programs tailored to table tennis. Key PointsMatch and practice analysis of the table tennis game indicates that during intense practice and competition it is predominantly the anaerobic alactic system that is called into play.The endurance system is relied on to recovery the anaerobic stores used during hard practice and competition effort.It is important for coaches to keep in mind that, while the anaerobic alactic system is the most energetic system used during periods of exertion in a table tennis game, a strong capacity for endurance is what helps a player recover quicker for the following match and the next day of competition. PMID- 24149140 TI - Psychological preparation of competitive judokas - a review. AB - The purpose of this article was to review a series of studies (n = 18) on psychological preparation of competitive judokas. These studies were grouped according to the type of study performed - observational, experimental, and case studies. In addition, five psychological categories were identified: (a) imagery, (b) motivation, (c) stress, anxiety, and mood states, (d) eating attitudes and weight control, and (e) coach/athlete interactions. The main findings of this review are that (a) there is a lack of data regarding the use of imagery to improve judo performance; (b) goal involvement states of competitive judokas fluctuate and undergo abrupt changes during actual combat, according to the ecological constraints of the situation; (c) cortisol levels and somatic and cognitive anxiety tend to increase prior to and during a judo combat; (d) weight reduction programs that judokas undergo prior to a judo combat can lead to unpleasant moods, and cultural differences can lead to conflicting results; (e) psychological preparation plans should be tailored to each individual judoka, as there can be significant individual differences among the judokas. Based on the findings of our review, a number of research limitations and methodological concerns are discussed. Key PointsThis article reviews a series of studies (n = 18) examining psychological aspects of judokas who compete at the intermediate level, national team level, and international level, and who hold international titles.Weight reduction programs that judokas undergo prior to a judo combat can lead to unpleasant moods.Psychological preparation plans should be tailored to each individual judoka, as there can be significant individual differences among competitive judokas.An effort should be made to conduct experimental-designed studies in order to assess the effectiveness of psychological interventions in judo. PMID- 24149141 TI - Effect of adaptive paced cardiolocomotor synchronization during running: a preliminary study. AB - Cardiolocomotor synchronization (CLS) has been well established for individuals engaged in rhythmic activity, such as walking, running, or cycling. When frequency of the activity is at or near the heart rate, entrainment occurs. CLS has been shown in many cases to improve the efficiency of locomotor activity, improving stroke volume, reducing blood pressure variability, and lowering the oxygen uptake (VO2). Instead of a 1:1 frequency ratio of activity to heart rate, an investigation was performed to determine if different harmonic coupling at other simple integer ratios (e.g. 1:2, 2:3, 3:2) could achieve any performance benefits. CLS was ensured by pacing the stride rate according to the measured heartbeat (i.e., adaptive paced CLS, or forced CLS). An algorithm was designed that determined the simplest ratio (lowest denominator) that, when multiplied by the heart rate will fall within an individualized, predetermined comfortable pacing range for the user. The algorithm was implemented on an iPhone 4, which generated a 'tick-tock' sound through the iPhone's headphones. A sham-controlled crossover study was performed with 15 volunteers of various fitness levels. Subjects ran a 3 mile (4.83 km) simulated training run at their normal pace on two consecutive days (randomized one adaptive pacing, one sham). Adaptive pacing resulted in faster runs run times, with subjects running an average of 26:03 +/- 3:23 for adaptive pacing and 26:38 +/- 3:31 for sham (F = 5.46, p < 0.05). The increase in heart rate from the start of the race as estimated by an exponential time constant was significantly longer during adaptive pacing, tau = 0.99 +/- 0.30, compared to sham, tau = 1.53 +/- 0.34 (t = -6.62, p < 0.01). Eighty-seven percent of runners found it easy to adjust their stride length to match the pacing signal with seventy-nine percent reporting that pacing helped their performance. These results suggest that adaptive paced CLS may have a beneficial effect on running performance and may be useful as a training aid. Key PointsSham controlled crossover study using 15 experienced runners running 3 miles (4.83 km).Adaptive CLS pacing resulted in statistically significant 35 second average decrease in run-time (p < 0.05).Increase in heart rate during the run was significantly slower during adaptive pacing (p < 0.01). PMID- 24149142 TI - Interactive effects of visual and auditory intervention on physical performance and perceived effort. AB - The purpose of this study was to investigate the effects of using different types of media on physical performance and perceived exertion. This study was divided into two parts. In Part 1, we examined the effects of different combination of audio and video interventions on physical performance and rating of perceived effort (RPE). We recruited 20 collegiate students who performed a 12-minute cycling task (where they were asked to bike as hard as possible) under 4 conditions (music, video, music and video, and control) in a randomized order. Results indicated participants in the 2 media groups (music & audio) reported a significantly lower score for RPE. In addition, there was also an effect of media type where participants in music condition perceived less effort on the cycling task compared to the video condition. Part 2 examined how music preference influenced physical performance, but used a running task (where they were asked to run as hard as possible), and by recruiting a much larger sample. Seventy-five students were assigned into 5 groups (high preference and high motivation, high preference and low motivation, low preference and low motivation, low preference and high motivation, and control) based on responses on the Brunel Music Rating Inventory (BMRI. Results showed that music preference, but not its motivational quality, had a significant effect on physical performance. Overall, these results show that listening to music, and in particular preferred music increases physical performance and reduces perceived effort. Key PointsAmong different sensory stimulations, music can enhance physical performance more strongly than video.In addition to the motivational level of the music, music preference can also influence the physical performance of aerobic exercise participants. PMID- 24149143 TI - Comparison of live high: train low altitude and intermittent hypoxic exposure. AB - Live High:Train Low (LHTL) altitude training is a popular ergogenic aid amongst athletes. An alternative hypoxia protocol, acute (60-90 min daily) Intermittent Hypoxic Exposure (IHE), has shown potential for improving athletic performance. The aim of this study was to compare directly the effects of LHTL and IHE on the running and blood characteristics of elite triathletes. Changes in total haemoglobin mass (Hbmass), maximal oxygen consumption (VO2max), velocity at VO2max (vVO2max), time to exhaustion (TTE), running economy, maximal blood lactate concentration ([La]) and 3 mM [La] running speed were compared following 17 days of LHTL (240 h of hypoxia), IHE (10.2 h of hypoxia) or Placebo treatment in 24 Australian National Team triathletes (7 female, 17 male). There was a clear 3.2 +/- 4.8% (mean +/- 90% confidence limits) increase in Hbmass following LHTL compared with Placebo, whereas the corresponding change of -1.4 +/- 4.5% in IHE was unclear. Following LHTL, running economy was 2.8 +/- 4.4% improved compared to IHE and 3mM [La] running speed was 4.4 +/- 4.5% improved compared to Placebo. After IHE, there were no beneficial changes in running economy or 3mM [La] running speed compared to Placebo. There were no clear changes in VO2max, vVO2max and TTE following either method of hypoxia. The clear difference in Hbmass response between LHTL and IHE indicated that the dose of hypoxia in IHE was insufficient to induce accelerated erythropoiesis. Improved running economy and 3mM [La] running speed following LHTL suggested that this method of hypoxic exposure may enhance performance at submaximal running speeds. Overall, there was no evidence to support the use of IHE in elite triathletes. Key PointsDespite a clear 3.2% increase in haemoglobin mass following 17 days of Live High: Train Low altitude training, no change in maximal aerobic capacity was observed.There were positive changes in running economy and the lactate-speed relationship at submaximal running speeds following Live High: Train Low altitude training.There was no evidence to support the use of daily 60-90 minute Intermittent Hypoxic Exposure in elite triathletes. PMID- 24149144 TI - Resistance training for explosive and maximal strength: effects on early and late rate of force development. AB - The aim of the present study was to verify whether strength training designed to improve explosive and maximal strength would influence rate of force development (RFD). Nine men participated in a 6-week knee extensors resistance training program and 9 matched subjects participated as controls. Throughout the training sessions, subjects were instructed to perform isometric knee extension as fast and forcefully as possible, achieving at least 90% maximal voluntary contraction as quickly as possible, hold it for 5 s, and relax. Fifteen seconds separated each repetition (6-10), and 2 min separated each set (3). Pre- and post-training measurements were maximal isometric knee extensor (MVC), RFD, and RFD relative to MVC (i.e., %MVC.s(-1)) in different time-epochs varying from 10 to 250 ms from the contraction onset. The MVC (Nm) increased by 19% (275.8 +/- 64.9 vs. 329.8 +/ 60.4, p < 0.001) after training. In addition, RFD (Nm.s(-1)) increased by 22-28% at time epochs up to 20 ms from the contraction onset (0-10 ms = 1679. 1 +/- 597.1 vs. 2159.2 +/- 475.2, p < 0.001; 0-20 ms = 1958.79 +/- 640.3 vs. 2398.4 +/- 479.6, p < 0. 01), with no changes verified in later time epochs. However, no training effects on RFD were found for the training group when RFD was normalized to MVC. No changes were found in the control group. In conclusion, very early and late RFD responded differently to a short period of resistance training for explosive and maximal strength. This time-specific RFD adaptation highlight that resistance training programs should consider the specific neuromuscular demands of each sport. Key PointsThe time-specific RFD adaptation evoked by resistance training highlight that the method of analyzing RFD is essential for the interpretation of results.Confirming previous data, maximal contractile RFD and maximal force can be differently influenced by resistance training. Thus, the resistance training programs should consider the specific neuromuscular demands of each sport.In active non-strength trained individuals, a short-term resistance training program designed to increase both explosive and maximal strength seems to reduce the adaptive response (i.e. increased RFDMAX) evoked by training with an intended ballistic effort (i.e. high-RFD contraction). PMID- 24149145 TI - The effect of landing surface on the plantar kinetics of chinese paratroopers using half-squat landing. AB - The objective of the study was to determine the effect of landing surface on plantar kinetics during a half-squat landing. Twenty male elite paratroopers with formal parachute landing training and over 2 years of parachute jumping experience were recruited. The subjects wore parachuting boots in which pressure sensing insoles were placed. Each subject was instructed to jump off a platform with a height of 60 cm, and land on either a hard or soft surface in a half-squat posture. Outcome measures were maximal plantar pressure, time to maximal plantar pressure (T-MPP), and pressure-time integral (PTI) upon landing on 10 plantar regions. Compared to a soft surface, hard surface produced higher maximal plantar pressure in the 1(st) to 4(th) metatarsal and mid-foot regions, but lower maximal plantar pressure in the 5(th) metatarsal region. Shorter T- MPP was found during hard surface landing in the 1(st) and 2(nd) metatarsal and medial rear foot. Landing on a hard surface landing resulted in a lower PTI than a soft surface in the 1(st)phalangeal region. For Chinese paratroopers, specific foot prosthesis should be designed to protect the1(st) to 4(th)metatarsal region for hard surface landing, and the 1(st)phalangeal and 5(th)metatarsal region for soft surface landing. Key PointsUnderstanding plantar kinetics during the half-squat landing used by Chinese paratroopers can assist in the design of protective footwear.Compared to landing on a soft surface, a hard surface produced higher maximal plantar pressure in the 1(st) to 4(th) metatarsal and mid-foot regions, but lower maximal plantar pressure in the 5(th) metatarsal region.A shorter time to maximal plantar pressure was found during a hard surface landing in the 1(st) and 2(nd) metatarsals and medial rear foot.Landing on a hard surface resulted in a lower pressure-time integral than landing on a soft surface in the 1(st) phalangeal region.For Chinese paratroopers, specific foot prosthesis should be designed to protect the 1(st) to 4(th) metatarsal region for a hard surface landing, and the 1(st) phalangeal and 5(th) metatarsal region for a soft surface landing. PMID- 24149146 TI - Microcirculation Under an Elastic Bandage During Rest and Exercise - Preliminary Experience With the Laser-Doppler Spectrophotometry System O2C. AB - There is an abundace of studies on the influence of rest and exercise as well as external compression on cutaneous, subcutaneous and muscle tissue blood flow using different measurement techniques. As a novel approach, we simultaneously examined the influence of a custom- made elastic thigh bandage on cutaneous and subcutaneous venous blood oxygenation (SO2), postcapillary venous filling pressures (rHb) and blood flow (flow) using the non-invasive laser- Doppler spectrophotometry system "Oxygen-to-see(O2C)". Parameters were obtained in 20 healthy volunteers in 2 mm and 8 mm tissue depth during rest, 5 and 10 minutes of moderate bicycle exercise following a 10-minute recovery period. Without the bandage, results matched the known physiological changes indicating higher blood backflow from superficial and deep veins. Underneath the elastic bandage, we observed lower post-capillary filling pressures during exercise. However, after the bandage was removed in the post-exercise period, all obtained parameters of microcirculation remained increased, indicating a higher amount of local venous blood volume in this area. Our observations might be the result of external compression, thermoregulatory and exercise-dependent vascular mechanisms. With the O2C device, a promising new non- invasive technique of measuring local microcirculation in soft tissue exists. This study gives new insights in the field of non-invasive diagnostics with special regard to the influence of elastic bandages on local microcirculation. Key PointsIt can be demonstrated that a novel non-invasive laser-Doppler spectrophotometry system allows the determination of capillary-venous microcirculation in an in-vivo study during exercise-rest cycles.The results received with this technique indicate that a) without an elastic thigh bandage, turnover rates of capillary and post-capillary microperfusion in skin and subcutaneous fat tissue increase under physical exertion, b) skin blood flow decreases while subcutaneous blood flow remained constant in the subsequent recovery phase. While wearing the bandage, c) venous back flow during exercise is increased, whereas d) in the recovery phase, microcirculation remained increased in both tissue depths after removing the bandage.In conclusion, the elastic bandage has a negative impact on local microcirculation and capillary-venous back flow, which is possibly due to a displacement of blood volume into the deep venous system and heat accumulation impairing the thermoregulatory response at the same time. PMID- 24149147 TI - Effects of nordic walking compared to conventional walking and band-based resistance exercise on fitness in older adults. AB - The purpose of this study was to compare the effects of Nordic walking with conventional walking and band-based resistance exercise on functional fitness, static balance and dynamic balance in older adults. Volunteers (n = 65) were divided into four groups: Nordic walking (NW), conventional walking (CW), resistance (RES), and control. Each group performed activity 50-70 min.day(-1) (warm-up 10-15 min, main exercise 30-40, and cool down 10-15 min), 3 days.week( 1) (NW and CW) or 2 day.week(-1) (RES) for 12 wks. Upper-body strength improved (p < 0. 05) in the RES (22.3%) and the NW (11.6%) groups compared to the CW and control groups. Cardio- respiratory fitness improved more in the NW (10.9%) and CW (10.6%) groups compared to the RES and control groups. Upper- and lower-body flexibility also improved in all exercise groups compared to the control group. There were no improvements in balance measures in any group. While all modes of exercise improved various components of fitness, Nordic walking provided the best well-rounded benefits by improving upper-body strength, cardiovascular endurance, and flexibility. Therefore, Nordic walking is recommended as an effective and efficient mode of concurrent exercise to improve overall functional fitness in older adults. Key PointsNordic walking, conventional walking, and resistance training are beneficial for older adults.Nordic walking and conventional walking both improve cardio-respiratory fitness while resistance training does not.Nordic walking provides additional benefits in upper-body muscular strength compared to conventional walking.Nordic walking is an effective and efficient mode of exercise to improve overall fitness in older adults. PMID- 24149148 TI - Functional and neuromuscular changes in the hamstrings after drop jumps and leg curls. AB - The purpose of this study was to use a holistic approach to investigate changes in jumping performance, kinaesthesia, static balance, isometric strength and fast stepping on spot during a 5-day recovery period, following an acute bout of damaging exercise consisted of drop jumps and leg curls, where specific emphasis was given on the hamstring muscles. Eleven young healthy subjects completed a series of highly intensive damaging exercises for their hamstring muscles. Prior to the exercise, and during the 5-day recovery period, the subjects were tested for biochemical markers (creatine kinase, aspartate aminotransferase, and lactate dehydrogenase), perceived pain sensation, physical performance (squat jump, counter movement jump, maximal frequency leg stamping, maximal isometric torque production and maximally explosive isometric torque production), kinaesthesia (active torque tracking) and static balance. We observed significant decreases in maximal isometric knee flexion torque production, the rate of torque production, and majority of the parameters for vertical jump performance. No alterations were found in kinaesthesia, static balance and fast stepping on spot. The highest drop in performance and increase in perceived pain sensation generally occurred 24 or 48 hours after the exercise. Damaging exercise substantially alters the neuromuscular functions of the hamstring muscles, which is specifically relevant for sports and rehabilitation experts, as the hamstrings are often stretched to significant lengths, in particular when the knee is extended and hip flexed. These findings are practically important for recovery after high-intensity trainings for hamstring muscles. Key PointsHamstring function is significantly reduced following specifically damaging exercise.It fully recovers 120 hours after the exercise.Prevention of exercise-induced muscle damage is cruicial for maintaining normal training regime. PMID- 24149149 TI - Variations in neuromuscular activity of thigh muscles during whole-body vibration in consideration of different biomechanical variables. AB - The intention of this study was to systematically analyze the impact of biomechanical variables in terms of different vibration frequencies, amplitudes and knee angles on quadriceps femoris and hamstring activity during exposure to whole-body vibration (WBV). 51 healthy men and women (age 55 +/- 8 years) voluntary participated in the study and were randomly allocated to five different vibration-frequency groups. Each subject performed 9 static squat positions (3 amplitudes x 3 knee angles) on a side alternating vibration platform. Surface electromyography (EMG) was used to record the neuromuscular activity of the quadriceps femoris and hamstring muscles. Maximal voluntary contractions (MVCs) were performed prior to the measurements to normalize the EMG signals. A three way mixed ANOVA was performed to analyze the different effects of the biomechanical variables on muscle activity. Depending on the biomechanical variables, EMG muscle activity ranged between 18.2 and 74.1 % MVC in the quadriceps femoris and between 5.2 and 27. 3 % MVC in the hamstrings during WBV. The highest levels of muscle activation were found at high frequencies and large amplitudes. Especially in the quadriceps femoris muscle, a WBV frequency of 30 Hz led to a significant increase in muscle activity compared to the other tested frequencies. However, it seems that knee angle is only relevant for the quadriceps femoris muscle. The results of this study should give more information for developing individual training protocols for WBV treatment in different practical applications. Key PointsWBV leads to a higher muscle activity of the quadriceps femoris than of the hamstrings.The maximum levels of muscle activity were significantly reached at high amplitude and high frequency.The knee angle only significantly affects the quadriceps femoris.Certain combinations of the biomechanical variables have similar effects on the level of muscle activity. PMID- 24149150 TI - Landing techniques in beach volleyball. AB - The aims of the present study were to establish a detailed and representative record of landing techniques (two-, left-, and right-footed landings) in professional beach volleyball and compare the data with those of indoor volleyball. Beach volleyball data was retrieved from videos taken at FIVB World Tour tournaments. Landing techniques were compared in the different beach and indoor volleyball skills serve, set, attack, and block with regard to sex, playing technique, and court position. Significant differences were observed between men and women in landings following block actions (chi(2)(2) = 18.19, p < 0.01) but not following serve, set, and attack actions. Following blocking, men landed more often on one foot than women. Further differences in landings following serve and attack with regard to playing technique and position were mainly observed in men. The comparison with landing techniques in indoor volleyball revealed overall differences both in men (chi(2)(2) = 161.4, p < 0.01) and women (chi(2)(2) = 84.91, p < 0.01). Beach volleyball players land more often on both feet than indoor volleyball players. Besides the softer surface in beach volleyball, and therefore resulting lower loads, these results might be another reason for fewer injuries and overuse conditions compared to indoor volleyball. Key PointsAbout 1/3 of all jumping actions in beach volleyball result in a landing on one foot.Especially following block situations men land on one foot more often than women.Landing techniques are related to different techniques and positions.Landings on one foot are less common in beach volleyball than indoor volleyball. This could be a reason for fewer injuries and overuse conditions. PMID- 24149151 TI - Energy system contributions during incremental exercise test. AB - The main purpose of this study was to determine the relative contributions of the aerobic and glycolytic systems during an incremental exercise test (IET). Ten male recreational long-distance runners performed an IET consisting of three minute incremental stages on a treadmill. The fractions of the contributions of the aerobic and glycolytic systems were calculated for each stage based on the oxygen uptake and the oxygen energy equivalents derived by blood lactate accumulation, respectively. Total metabolic demand (WTOTAL) was considered as the sum of these two energy systems. The aerobic (WAER) and glycolytic (WGLYCOL) system contributions were expressed as a percentage of the WTOTAL. The results indicated that WAER (86-95%) was significantly higher than WGLYCOL (5-14%) throughout the IET (p < 0.05). In addition, there was no evidence of the sudden increase in WGLYCOL that has been previously reported to support to the "anaerobic threshold" concept. These data suggest that the aerobic metabolism is predominant throughout the IET and that energy system contributions undergo a slow transition from low to high intensity. Key PointsThe aerobic metabolism contribution is the predominant throughout the maximal incremental test.The speed corresponding to the aerobic threshold can be considered the point in which aerobic metabolism reaches its maximal contribution.Glycolytic metabolism did not contribute largely to the energy expenditure at intensities above the anaerobic threshold. PMID- 24149152 TI - Differential response of heat shock proteins to uphill and downhill exercise in heart, skeletal muscle, lung and kidney tissues. AB - Running on a horizontal plane is known to increase the concentration of the stress biomarker heat-shock protein (HSP), but no comparison of the expression of HSP70 has yet been established between the uphill (predominantly concentric) and downhill (predominantly eccentric) muscle contractions exercise. The objective of the study was to investigate the relationships between eccentric and concentric contractions on the HSP70 response of the lung, kidney, gastrocnemius, soleus and heart. Twenty-four male Wistar weanling rats were divided into four groups: non exercised and three different grades of treadmill exercise groups: horizontal, uphill (+7%) and downhill (-7% of inclination). At the optimal time-point of six hours after the exercise, serum uric acid, creatine kinase (CK) and lactate dehydrogenase (LDH) were determined by standard methods and HSP70 by the Western blot analysis. HSP70 responds differently to different types of running. For kidney, heart, soleus and gastrocnemius, the HSP70 expression increased, 230, 180, 150 and 120% respectively of the reference (horizontal). When the contraction was concentric (uphill) and compared to downhill the increase in response of HSP70 was greater in 80% for kidney, 75% for gastrocnemius, 60% for soleus and 280% for the heart. Uric acid was about 50% higher (0.64 +/- 0.03 mg.dL(-1)) in the uphill group as compared to the horizontal or downhill groups. Similarly, the activities of serum CK and LDH were both 100% greater for both the uphill and downhill groups as compared to the horizontal group (2383 +/- 253 and 647.00 +/- 73 U/L, respectively). The responsiveness of HSP70 appeared to be quite different depending on the type of tissue, suggesting that the impact of exercise was not restricted to the muscles, but extended to the kidney tissue. The uphill exercise increases HSP70 beyond the eccentric type and the horizontal running was a lower HSP70 responsive stimulus. Key PointsExercise can induce increases in HSP70 in the lung, kidney and heart, and in the soleus and gastrocnemius muscles, probably due to systemic alterations such as hypoxia, increase in temperature and the production of free radicals.Predominantly concentric contractions (running uphill), seem to be the most efficient way of increasing the HSP70 concentrations in the different tissues, followed by eccentric contraction (downhill) and lastly the concentric-eccentric cycle (horizontal).The energy demand, already known to influence HSP70, appears not to be the only factor responsible for the response of these proteins, considering that for the kidney and the soleus muscle, downhill running was more efficient in raising the HSP70 response than horizontal running.Future research should explore the mechanisms by which the eccentric, concentric and eccentric-concentric contractions are capable of influencing the responses of the heat shock proteins, opening possibilities for increasing the levels of these proteins in desirable situations, such as to protect against excess free radicals or injuries. PMID- 24149153 TI - Trunk muscle activities during abdominal bracing: comparison among muscles and exercises. AB - Abdominal bracing is often adopted in fitness and sports conditioning programs. However, there is little information on how muscular activities during the task differ among the muscle groups located in the trunk and from those during other trunk exercises. The present study aimed to quantify muscular activity levels during abdominal bracing with respect to muscle- and exercise-related differences. Ten healthy young adult men performed five static (abdominal bracing, abdominal hollowing, prone, side, and supine plank) and five dynamic (V- sits, curl-ups, sit-ups, and back extensions on the floor and on a bench) exercises. Surface electromyogram (EMG) activities of the rectus abdominis (RA), external oblique (EO), internal oblique (IO), and erector spinae (ES) muscles were recorded in each of the exercises. The EMG data were normalized to those obtained during maximal voluntary contraction of each muscle (% EMGmax). The % EMGmax value during abdominal bracing was significantly higher in IO (60%) than in the other muscles (RA: 18%, EO: 27%, ES: 19%). The % EMGmax values for RA, EO, and ES were significantly lower in the abdominal bracing than in some of the other exercises such as V-sits and sit-ups for RA and EO and back extensions for ES muscle. However, the % EMGmax value for IO during the abdominal bracing was significantly higher than those in most of the other exercises including dynamic ones such as curl-ups and sit-ups. These results suggest that abdominal bracing is one of the most effective techniques for inducing a higher activation in deep abdominal muscles, such as IO muscle, even compared to dynamic exercises involving trunk flexion/extension movements. Key PointsTrunk muscle activities during abdominal bracing was examined with regard to muscle- and exercise-related differences.Abdominal bracing preferentially activates internal oblique muscles even compared to dynamic exercises involving trunk flexion/extension movements.Abdominal bracing should be included in exercise programs when the goal is to improve spine stability. PMID- 24149154 TI - Loading and concurrent synchronous whole-body vibration interaction increases oxygen consumption during resistance exercise. AB - Exercise is commonly used as an intervention to increase caloric output and positively affect body composition. A major challenge is the low compliance often seen when the prescribed exercise is associated with high levels of exertion. Whole-body vibration (WBV) may allow increased caloric output with reduced effort; however, there is limited information concerning the effect of WBV on oxygen consumption (VO2). Therefore, this study assessed the synergistic effects of resistance training and WBV on VO2. We examined VO2 at different loads (0%, 20%, and 40% body weight (BW)) and vibration intensities (No vibration (NV), 35HZ, 2-3mm (35L), 50Hz, 57mm (50H)) in ten men (26.5 +/- 5.1 years). Data were collected during different stages (rest, six 30s sets of squatting, and recovery). Repeated measures ANOVA showed a stage x load x vibration interaction. Post hoc analysis revealed no differences during rest; however, a significant vibration x load interaction occurred during exercise. Both 35L and 50H produced greater VO2 than NV at a moderate load of 20%BW. Although 40%BW produced greater VO2 than 20%BW or 0%BW using NV, no significant difference in VO2 was seen among vibratory conditions at 40%BW. Moreover, no significant differences were seen between 50H and 35L at 20%BW and NV at 40%BW. During recovery there was a main effect for load. Post hoc analyses revealed that VO2 at 40%BW was significantly higher than 20%BW or 0%BW, and 20%BW produced higher VO2 than no load. Minute-by minute analysis revealed a significant impact on VO2 due to load but not to vibratory condition. We conclude that the synergistic effect of WBV and active squatting with a moderate load is as effective at increasing VO2 as doubling the external load during squatting without WBV. Key PointsSynchronous whole body vibration in conjunction with moderate external loading (app 20% BW) can increase oxygen consumption to the same extent as heavier loading (40% BW) during performance of the parallel squat.While the application of synchronous whole body vibration had no effect on recovery oxygen, under bot vibratory and non-vibratory conditions, the heavier the external load the greater the recovery oxygen consumption levels.Regardless of vibratory condition, during the squatting exercise bout 40% BW produced higher heart rates than 20%BW or 0% BW, and 20% BW produced higher heart rates than 0% BW.There were strong trends toward higher heart rates in both vibratory conditions (50 Hz, 5-6mm; 35 Hz, 2-3 mm) than in the non-vibratory condition regardless of external loading. PMID- 24149155 TI - Challenges in Maintaining Emotion Regulation in a Sleep and Energy Deprived State Induced by the 4800Km Ultra-Endurance Bicycle Race; The Race Across AMerica (RAAM). AB - Multiday ultra-endurance races present athletes with a significant number of physiological and psychological challenges. We examined emotions, the perceived functionality (optimal-dysfunctional) of emotions, strategies to regulate emotions, sleep quality, and energy intake-expenditure in a four-man team participating in the Race Across AMerica (RAAM); a 4856km continuous cycle race. Cyclists reported experiencing an optimal emotional state for less than 50% of total competition, with emotional states differing significantly between each cyclist over time. Coupled with this emotional disturbance, each cyclist experienced progressively worsening sleep deprivation and daily negative energy balances throughout the RAAM. Cyclists managed less than one hour of continuous sleep per sleep episode, high sleep latency and high percentage moving time. Of note, actual sleep and sleep efficiency were better maintained during longer rest periods, highlighting the importance of a race strategy that seeks to optimise the balance between average cycling velocity and sleep time. Our data suggests that future RAAM cyclists and crew should: 1) identify beliefs on the perceived functionality of emotions in relation to best (functional-optimal) and worst (dysfunctional) performance as the starting point to intervention work; 2) create a plan for support sufficient sleep and recovery; 3) create nutritional strategies that maintain energy intake and thus reduce energy deficits; and 4) prepare for the deleterious effects of sleep deprivation so that they are able to appropriately respond to unexpected stressors and foster functional working interpersonal relationships. Key PointsCompleting the Race Across AMerica (RAAM); a 4856km continuous cycle race associated with sleep disturbance, an energy deficient state, and experiencing intense unwanted emotions.Cyclists reported experiencing an optimal emotional state for less than 50% of total competition and actual sleep and sleep efficiency was better maintained during longer rest periods.We suggest that future RAAM cyclists and crew should:Identify individual beliefs on the perceived functionality of emotional states in relation to best (optimal) and worst (dysfunctional) performance as the starting point to identifying if emotion regulation strategies should be initiated.Plan for enhanced sleep and recovery not just plan and train for maintaining a high average velocity;Create nutritional strategies that maintain energy intake and thus reduce energy deficits;Psychologically prepare cyclists and crew for the deleterious effects of sleep deprivation so that they both are able to appropriately respond to unexpected stressors and foster functional interpersonal working relationships. PMID- 24149156 TI - Effects of the 11+ and Harmoknee Warm-up Programs on Physical Performance Measures in Professional Soccer Players. AB - The purpose of this study was to examine the effects of the 11+ and HarmoKnee warm-up programs on performance measures in professional soccer players. Thirty six male professional soccer players (age: 18.9 +/- 1.4 years) were divided into 3 groups, the 11+, HarmoKnee and control group (n = 12 per group). The experimental groups performed the programs 3 times per week for 2 months (24 sessions), whereas the control group only performed their regular soccer training. The performance tests carried out were: 10m speed tests with and without a ball, 20m single sprint, vertical jump, Wall-Volley and Illinois agility tests. The 11+ group demonstrated significant increases from pre-to-post time points in the vertical jump (3.7%), Wall- Volley (5.4%) and Illinois agility tests (1.7%), while the HarmoKnee group showed a significant increase in Wall Volley test, with a 5.2% increase. The repeated measures analysis revealed differences between the groups (large effect size) in the 11+ and HarmoKnee groups, compared to the control group, in 10m speed tests with and without a ball, 20m single sprint and Illinois agility tests (p < 0.05). Thus 8-weeks performing the 11+ warm-up program can enhance jump height, agility and soccer skill while the HarmoKnee program generally only improves soccer skill in young professional male soccer players. Key PointsThe 11+ improves performance by means of Illinois agility, vertical jump and Wall-Volley tests whereas HarmoKnee improves Wall-Volley test. Incorporating 11+ as a part of the warm-up program by the young teams would be beneficial in agility, leg power and soccer skill respectively.Further modification of both programs may be required to fully realize the players' speed performance potential.Data from this research can be helpful for soccer trainers in choosing programs to enhance performances in young male professional soccer players. PMID- 24149157 TI - The effect of acute vibration exercise on short-distance sprinting and reactive agility. AB - Vibration exercise (VbX) has been a popular modality to enhancing physical performance, where various training methods and techniques have been employed to improve immediate and long-term sprint performance. However, the use of acute side-alternating VbX on sprint and agility performance remains unclear. Eight female athletes preformed side-alternating vibration exercise (VbX) and control (no VbX) in a cross over randomised design that was conducted one week apart. After performing a warm-up, the athletes undertook maximal 5m sprints and maximal reactive agility sprints (RAT), this was followed by side-alternating VbX (26 Hz, 6mm) or control (no VbX). Immediately following the intervention, post-sprint tests and RAT were performed. There was a significant treatment effect but there was no time effect (pre vs. post) or interaction effect for sprint and RAT; however, side-alternating VbX did not compromise sprint and agility performance. Key PointsAcute VbX could be beneficial for the acceleration phase (1.5m) of a short-distance sprint.Acute VbX does not have positive influence on short distance (3m & 5m) sprint performance.Acute VbX does not enhance reactive agility performance. PMID- 24149158 TI - The effects of aerobic exercise intensity and duration on levels of brain-derived neurotrophic factor in healthy men. AB - This study examined the combined effects of aerobic exercise intensity and duration on serum brain-derived neurotrophic factor (sBDNF) levels in healthy human adult males aged 18-25 years. Forty five participants were randomly assigned to one of six exercise conditions based on varying intensity (80% or 60% of heart rate reserve, or control) and duration (20 or 40 min). Vigorous (80% heart rate reserve, "Vig") and moderate (60% heart rate reserve, "Mod") exercise was carried out on cycle ergometers. Control subjects remained seated and at rest during the exercise period. Pre- and post-exercise blood draws were conducted and sBDNF measured. Physical exercise caused an average ~ 32% increase in sBDNF levels relative to baseline that resulted in concentrations that were 45% higher than control conditions. Comparing the six conditions, sBDNF levels rose consistently among the four exercise conditions (Vig20 = 26.38 +/- 34.89%, Vig40 = 28.48 +/- 19.11%, Mod20 = 41.23 +/- 59.65%, Mod40 = 30.16 +/- 72.11%) and decreased consistently among the controls (Con20 = -14.48 +/- 16.50, Con40 = 10.51 +/- 26.78). Vig conditions had the highest proportion of subjects that experienced a significant (? 10%) increase in sBDNF levels, followed by Mod and control conditions. An analysis of modeled sBDNF integrals (area under the curve) demonstrated substantially greater values for Vig40 and Mod40 conditions compared to Vig20 and Mod20 conditions. Collectively, these results demonstrate that neither duration (20 vs. 40 min) nor intensity (60 vs. 80% HR reserve) significantly affects the benefits of exercise if only the sBDNF increase at a single post-exercise time point is considered. However, when comparing either the probability of achieving a significant BDNF gain or the integral (i.e. the volume of circulating BDNF over time) the Vig40 condition offers maximal benefits. Thus, we conclude that the future study of aerobic exercise effects on BDNF-mediated neuroprotection should take the volume of BDNF release over time into account. Key PointsAerobic exercise caused a ~32% increase in serum BDNF in adult human males while serum BDNF decreased 13% in sedentary control subjects.Vigorous intensity (80% heart rate reserve), long duration (40 min) exercise offered the greatest probability of a significant BDNF elevation.Long duration exercise offered the greatest numerical benefits in terms of BDNF integral.Neither intensity nor duration affected the mean elevation in BDNF amplitude caused by exercise. PMID- 24149159 TI - The effects of surface-induced loads on forearm muscle activity during steering a bicycle. AB - On the bicycle, the human upper extremity has two essential functions in steering the bicycle and in supporting the body. Through the handlebar, surface- induced loads are transmitted to the hand and arm of the bicycle rider under vibration exposure conditions. Thus, the purpose of the study was to investigate the effect of vibration exposure on forearm muscle activity for different road surfaces (i.e. smooth road, concrete stone pavement, rough road) and for different bicycles. Ten subjects participated in experiments and two types of bicycles, i.e. Road Bike (RB) and Mountain Bike (MTB) are compared. The acceleration magnitudes were dominant along x and z-axes. The r.m.s acceleration values in the z direction at the stem of MTB were at most 2.56, 7.04 and 10.76 m.s(-2) when pedaling respectively on asphalt road, concrete pavement and rough road. In the case of RB the corresponding values were respectively 4.43, 11.75 and 27.31 m.s( 2). The cumulative normalized muscular activity levels during MTB trials on different surfaces had the same tendency as with acceleration amplitudes and have ranked in the same order from lowest to highest value. Although road bike measurements have resulted in a similar trend of increment, the values computed for rough road trials were higher than those in MTB trials. During rough road measurements on MTB, rmsEMG of extensor muscles reached a value corresponding to approximately 50% of MVC (Maximum Voluntary Contraction). During RB trials performed on rough road conditions, rmsEMG (%MVC) values for the forearm flexor muscles reached 45.8% of their maximal. The level of muscular activity of forearm muscles in controlling handlebar movements has been observed to be enhanced by the increase in the level of vibration exposed on the bicycle. Since repeated forceful gripping and pushing forces to a handle of a vibratory tool can create a risk of developing circulatory, neurological, or musculoskeletal disorder, a bicycle rider can be considered vulnerable to developing vibration related overuse injuries and/or performance diminishing consequences. Key PointsThe muscular activity level in the forearms increases in response to random vibration transmitted to the bicycle to control handlebar movements.The level of vibration transmission depends on irregularities on road surface and bicycle type.A bicycle rider can be considered vulnerable to developing vibration related overuse injuries and/or performance diminishing consequences. PMID- 24149160 TI - Familiarization Effects of an Elliptical All-out Test and the Wingate Test Based on Mechanical Power Indices. AB - The Wingate all-out test (WAT) is commonly used to estimate anaerobic capabilities of athletes by using an upper or lower body cycle ergometer, however, a new test modality called elliptical all-out test (EAT) which measures activated whole-body locomotor tasks has recently been proposed. The purpose of this study was to evaluate the familiarization effects of a 30-s EAT versus WAT. Twenty male trained athletes performed pre-familiarization (Trial- I), post familiarization (Trial-II) and retest of Trial-II (Trial-III) sessions on both cycle ergometer and elliptical trainer. Peak power (PP), average power (AP), power drop (PD) and fatigue index ratio (FI%) were analyzed using student's t test for paired samples and correlated by intra-class correlation coefficients (ICC). Moreover, an error detection procedure was administered using data attained from illogical interrelations among 5-s segments of 30-s tests. The main results showed that there were significant familiarization effects in all mechanical power outputs obtained from Trial-I and Trial-II in both EAT (ICC = 0.49-0.55) and WAT (ICC = 0.50-0.57) performances (p <= 0.01). Significant segmental disorders were detected in power production during Trial-I of EAT, however, none existed in any of test trails in the WAT (p <= 0.001). After familiarization sessions, reliability coefficients between Trial-II and Trial-III showed moderate to strong-level agreements for both EAT (ICC = 0.74-0.91) and the WAT (ICC=0.76-0.93). Our results suggested that prior to the performance tests, combination of a well designed familiarization session with one full all-out test administration is necessary to estimate the least moderately reliable and accurate test indices for both WAT and EAT. Key PointsA well designed familiarization session, and then, one additional all-out test administration, several days prior to main test, is suggested to estimate more accurate and reliable retest correlations for both cycling and elliptical all-out test modalities.Because of greater muscle recruitment and different movement pattern, familiarization seems more effective for a 30-s all-out test performed on an elliptical trainer compared to a cycle ergometer. PMID- 24149161 TI - The effectiveness of electromyographic biofeedback as part of a meniscal repair rehabilitation programme. AB - The objective of the study was to assess the effectiveness of using electromyographic biofeedback in the early stages of rehabilitation after meniscal repair. In this randomised, controlled, parallel group study, the evolution of patients with meniscal lesions treated by meniscal suture who received (study group, n = 33) or did not receive (control group, n = 31) electromyographic biofeedback as part of their early rehabilitation programme has been compared. A total of 64 patients with previous meniscal repair participated in the study. The patients received a baseline assessment (after 1 postoperative week) and a follow-up (after 8 postoperative weeks) consisting of surface electromyography, dynamometry of thigh muscles and the assessment of the Knee injury and Osteoarthritis Outcome Score (KOOS). The electrical potential in contraction and the speed for contraction and relaxation for all monitored muscles increased significantly in the study group (p < 0.05). The difference between groups in the assessed score was significant for sport and recreational function (p < 0.05). The strength of the thigh muscles was not significantly influenced by the introduction of electromyographic biofeedback (EMG- BFB) in the rehabilitation programme. Electromyographic biofeedback helped patients to control their muscles after meniscal repair to accomplish physical activities that require better neuromuscular coordination and control. For these reasons, one may consider electromyographic biofeedback as an important component of rehabilitation after meniscal repair. Key PointsExercises during the early phases of rehabilitation after meniscal repair are difficult to perform because of pain, oedema, and possibly a disruption in normal joint receptor activity.Electromyographic biofeedback is a painless, non-invasive method that can be used in muscle recovery after meniscal repair and enhances the rehabilitation process, especially related to muscular function.The rehabilitation programme that includes electromyographic biofeedback after meniscal repair increased the speed of muscle response to acoustic stimulation in both the initiation of contraction (onset time) and relaxation (offset time) and, also, the capacity of performing some specific physical acti-vities after 8 weeks of rehabilitation (according to KOOS values).Electromyographic biofeedback is not responsible for the decrease in pain, swelling or other postoperative symptoms but it is important in order to help the patient to conduct the activities which require neuromuscular coordination and muscle control. PMID- 24149162 TI - Effects of stabilization exercise using a ball on mutifidus cross-sectional area in patients with chronic low back pain. AB - The purpose of this study was to compare the effects of lumbar stabilization exercises using balls to the effects of general lumbar stabilization exercises with respect to changes in the cross section of the multifidus (MF), weight bearing, pain, and functional disorders in patients with non-specific chronic low back pain. Twelve patients participated in either a 8 week (3 days per week) stabilization exercise program using balls and control group (n = 12). The computer tomography (CT) was used to analyze MF cross-sectional areas (CSA) and Tetrax balancing scale was used to analyze left and right weight bearing differences. Both groups had significant changes in the CSA of the MF by segment after training (p < 0.05) and the experimental group showed greater increases at the L4 (F = 9.854, p = 0.005) and L5 (F = 39. 266, p = 0.000). Both groups showed significant decreases in weight bearing, from 9.25% to 5.83% in the experimental group and from 9.33% to 4.25% in the control group (p < 0.05), but did not differ significantly between the two groups. These results suggests that stabilization exercises using ball can increases in the CSA of the MF segments, improvement in weight bearing, pain relief, and recovery from functional disorders, and the increases in the CSA of the MF of the L4 and L5 segments for patients with low back pain. Key PointsCompared with the stabilization exercise using a ball and general stabilization exercise increased the CSA of the MF, weight bearing, pain, and functional ability in patients with low back pain.We verified that increases in the CSA of the MF of the L4 and L5 segments and functional ability during the stabilization exercise using a ball.The stabilization exercise using a ball was shown to be an effective exercise method for patients with low back pain in a rehabilitation program by increasing functional ability and the CSA of the MF. PMID- 24149163 TI - Can a Specific Neck Strengthening Program Decrease Cervical Spine Injuries in a Men's Professional Rugby Union Team? A Retrospective Analysis. AB - Cervical spine injuries in Rugby Union are a concerning issue at all levels of the game. The primary aim of this retrospective analysis conducted in a professional Rugby Union squad was to determine whether a 26-week isometric neck strengthening intervention program (13-week strengthening phase and 13-week maintenance phase) was effective in reducing the number and severity of cervical spine injuries. The secondary aim was to determine whether at week five, where the program had been the similar for all players, there was increased isometric neck strength. All 27 players who were common to both the 2007-2008 and 2008-2009 seasons were included in this analysis and data was extracted from a Sports Medicine/Sports Science database which included the squad's injury records. Primary outcome variables included; the number of cervical spine injuries and the severity of these injuries as determined by the total number of days lost from training and competition. Secondary outcome variables included isometric neck strength in flexion, extension and left and right lateral flexion. Using non parametric statistical methods, no significant differences were evident for the total number of cervical spine injuries (n = 8 in 2007-2008, n = 6 in 2008-2009) or time loss due to these injuries (100 days in 2007-2008, 40 days in 2008-2009). However, a significant (p = 0.03) reduction in the number of match injuries was evident from 2007-2008 (n = 11) to 2008-09 (n = 2). Non-significant increases in isometric neck strength were found in all directions examined. A significant reduction in the number of match injuries was evident in this study. However, no other significant changes to primary outcome variables were achieved. Further, no significant increases in isometric neck strength were found in this well-trained group of professional athletes. Key PointsWhile many authors have proposed that neck strengthening could be an effective strategy in preventing cervical spine injuries in Rugby Union, there is currently little information in the literature pertaining to how such a study might be conducted.A significant decrease in the number of injuries recorded in matches can be achieved using a specific neck strengthening program at the elite level.In an elite rugby union team as investigated in this study a significant increase in neck strength is difficult to achieve in a short period of time such as five weeks. PMID- 24149164 TI - Motivational profiles in physical education and their relation to the theory of planned behavior. AB - The aim of this study was to establish motivational profiles for doing physical activity according to the variables from the theory of planned action in a sample of 698 students aged 14 to 16. The instruments used were the Questionnaire of Behavioral Regulation in Sport (BRQ-R) and the Questionnaire of the Theory of Planned Behavior (TCP). Cluster analysis revealed two motivational profiles: a "self-determined "profile with high scores in intrinsic motivation and low scores in extrinsic motivation and amotivation, and a "non self- determined "profile with low scores in intrinsic motivation and high scores in extrinsic motivation and amotivation. Positive significant differences in attitudes, norms, and intent to control were found for the self-determined profile related to "non self determined "profile. Key PointsA "self-determined "profile was found with higher scores for the four types of intrinsic motivations (general, knowledge, stimulation and achievement) and identified regulation than for introjected and external regulation.A "non self-determined "profile was found with higher scores for external, introjected regulation and amotivation than for the four types of intrinsic motivation (general, knowledge, stimulation and achievement).In the context of the "non self-determined profile "we could encourage programs that adapt to these needs in such a way that they contribute to increasing the rates of doing physical activity in the population. PMID- 24149165 TI - Monitoring external and internal loads of brazilian soccer referees during official matches. AB - This study aimed to assess the external and internal loads of Brazilian soccer referees during official matches. A total of 11 field referees (aged 36.2 +/- 7.5 years) were monitored during 35 matches. The external (distance covered, mean and maximal speed) and internal load parameters (session ratings of perceived exertion [RPE] training load [TL], Edwards' TL, and time spent in different heart rate [HR] zones) were assessed in 3-4 matches per referee. External load parameters were measured using a wrist Global Positioning System (GPS) receiver. No differences in distance covered (5.219 +/- 205 vs. 5.230 +/- 237 m) and maximal speed (19.3 +/- 1.0 vs. 19.4 +/- 1.4 km.h(-1)) were observed between the halves of the matches (p > 0.05). However, the mean speed was higher in the first half of the matches (6.6 +/- 0.4 vs. 6.4 +/- 0.3 km.h(-1)) (p < 0.05) than in the second half. The mean HR during the matches was ~89% of HRmax. In ~95% of the matches, the referees demonstrated a HR >= 80% of HRmax. Nonetheless, the time spent at 90-100% of HRmax was higher in the first half (59.9 vs. 52.3%) (p < 0.05). Significant correlations between session RPE TL and distance covered at 90 100% of HRmax (r = 0.62) and session RPE TL and maximal speed (r = 0.54) (p < 0.05) were noted. Furthermore, there was a positive correlation between session RPE TL and Edwards' TL (r = 0.61) (p < 0.05). Brazilian soccer referees demonstrated high external and internal load demands during official matches. The portable GPS/HR monitors and session RPE method can provide relevant information regarding the magnitude of the physiological strain during official matches. Key PointsHigh external and internal loads were imposed on Brazilian soccer referees during official matches.There was a high positive correlation between a subjective marker of internal load (session RPE) and parameters of external load (distance covered between 90-100% of HRmax and maximal speed).There was a high positive correlation between session RPE method and Edwards' method.Session RPE seems to be a reliable marker of internal load.The portable GPS/HR monitors and the session RPE method can provide relevant information regarding the magnitude of external and internal loads of soccer referees during official matches. PMID- 24149166 TI - Effect of pre-cooling on repeat-sprint performance in seasonally acclimatised males during an outdoor simulated team-sport protocol in warm conditions. AB - Whether precooling is beneficial for exercise performance in warm climates when heat acclimatised is unclear. The purpose of this study was to determine the effect of precooling on repeat-sprint performance during a simulated team-sport circuit performed outdoors in warm, dry field conditions in seasonally acclimatised males (n = 10). They performed two trials, one with precooling (PC; ice slushy and cooling jacket) and another without (CONT). Trials began with a 30 min baseline/cooling period followed by an 80 min repeat-sprint protocol, comprising 4 x 20-min quarters, with 2 x 5-min quarter breaks and a 10-min half time recovery/cooling period. A clear and substantial (negative; PC slower) effect was recorded for first quarter circuit time. Clear and trivial effects were recorded for overall circuit time, third and fourth quarter sprint times and fourth quarter best sprint time, otherwise unclear and trivial effects were recorded for remaining performance variables. Core temperature was moderately lower (Cohen's d=0.67; 90% CL=-1.27, 0.23) in PC at the end of the precooling period and quarter 1. No differences were found for mean skin temperature, heart rate, thermal sensation, or rating of perceived exertion, however, moderate Cohen's d effect sizes suggested a greater sweat loss in PC compared with CONT. In conclusion, repeat- sprint performance was neither clearly nor substantially improved in seasonally acclimatised players by using a combination of internal and external cooling methods prior to and during exercise performed in the field in warm, dry conditions. Of practical importance, precooling appears unnecessary for repeat-sprint performance if athletes are seasonally acclimatised or artificially acclimated to heat, as it provides no additional benefit. Key PointsPre-cooling did not improve repeated sprint performance during a prolonged team-sport circuit in field conditions.If individuals are already heat acclimatised/acclimated, pre-cooling is unnecessary for performance enhancement.Acclimation/acclimatisation seems to be the more powerful method for protecting against heat strain. PMID- 24149167 TI - The association between physical activity and sex-specific oxidative stress in older adults. AB - Oxidative stress increases with advancing age and is a mediator of several diseases including cancer, cardiovascular disease, and diabetes. Moreover, postmenopausal women have a lower estrogen concentration, which is associated with elevated oxidative stress. However, there is no definitive evidence regarding the relationship between daily physical activity and oxidative stress status in older adults, including postmenopausal women. Twenty-nine adults (age, 70.1 +/- 1.0 years, mean +/- SE; 12 women and 17 men) were examined in this cross sectional study. Prior to blood collection, the participants were asked to wear a uniaxial accelerometer for 4 consecutive weeks to determine their level of physical activity. After a 48-h period of physical activity avoidance and a 10-h overnight fast, venous blood samples were obtained from each participant. Fasting plasma derivatives of reactive oxygen metabolites (d-ROMs) and malondialdehyde (MDA) concentrations of oxidative stress markers were negatively correlated with the amount of physical activity in women (d-ROMs; r = -0.708, p = 0.002) (MDA; r = -0.549, p = 0. 028), but not in men. Fasting plasma biological antioxidant potential of antioxidant capacity marker was positively correlated with the amount of physical activity in women (BAP; r = 0.657, p = 0.006) (GSH; r = 0.549, p = 0.028), but not in men. Moreover, superoxide dismutase activity of antioxidant capacity marker was positively correlated with the amount of physical activity in men (r = 0.627, p = 0.039), but not in women. There were no associations between physical activity and other oxidative stress markers (reduced and oxidized glutathione, glutathione peroxidise, thioredoxin). These findings suggest that regular physical activity may have a protective effect against oxidative stress by increasing total antioxidant capacity, especially in postmenopausal women. Key PointsIt is important to consider daily physical activity status when evaluating antioxidant capacity.Sex differences affect the alteration of oxidative stress markers induced by daily physical activity.Regular physical activity may have a protective effect against oxidative stress by increasing total antioxidant capacity, especially in postmenopausal women. PMID- 24149168 TI - In vivo motion of femoral condyles during weight-bearing flexion after anterior cruciate ligament rupture using biplane radiography. AB - The purpose of this study was to investigate in vivo three- dimensional tibiofemoral kinematics and femoral condylar motion in knees with anterior cruciate ligament (ACL) deficiency during a knee bend activity. Ten patients with unilateral ACL rupture were enrolled. Both the injured and contralateral normal knees were imaged using biplane radiography at extension and at 15 degrees , 30 degrees , 60 degrees , 90 degrees , and 120 degrees of flexion. Bilateral knees were next scanned by computed tomography, from which bilateral three-dimensional knee models were created. The in vivo tibiofemoral motion at each flexion position was reproduced through image registration using the knee models and biplane radiographs. A joint coordinate system containing the geometric center axis of the femur was used to measure the tibiofemoral motion. In ACL deficiency, the lateral femoral condyle was located significantly more posteriorly at extension and at 15 degrees (p < 0.05), whereas the medial condylar position was changed only slightly. This constituted greater posterior translation and external rotation of the femur relative to the tibia at extension and at 15 degrees (p < 0.05). Furthermore, ACL deficiency led to a significantly reduced extent of posterior movement of the lateral condyle during flexion from 15 degrees to 60 degrees (p < 0.05). Coupled with an insignificant change in the motion of the medial condyle, the femur moved less posteriorly with reduced extent of external rotation during flexion from 15 degrees to 60 degrees in ACL deficiency (p < 0.05). The medial- lateral and proximal-distal translations of the medial and lateral condyles and the femoral adduction-abduction rotation were insignificantly changed after ACL deficiency. The results demonstrated that ACL deficiency primarily changed the anterior-posterior motion of the lateral condyle, producing not only posterior subluxation at low flexion positions but also reduced extent of posterior movement during flexion from 15 degrees to 60 degrees . Key PointsThree-dimensional tibiofemoral kinematics and femoral condylar motion in ACL-deficient knees during upright weight-bearing flexion were measured using biplane radiography with the geometric center axis.ACL deficiency caused posterior subluxation of the lateral condyle with excess external femoral rotation at early flexion positions.On flexion from 15 degrees to 60 degrees , the lateral condyle moved slightly posteriorly in ACL deficiency leading to reduced extent of external femoral rotation. PMID- 24149169 TI - Sagittal spinal morphology in highly trained adolescent tennis players. AB - Sports with a predominance of forward-bending and extension postures have been associated with alterations in the sagittal spinal curvatures and greater risk of spinal injury. Because, the tennis players adopt these postures, the aims of this study were: 1) to describe spinal curvatures and pelvic tilt in male and female highly trained adolescent tennis players during relaxed standing posture and with thoracic spine corrected (in prone lying on the floor); and 2) to determine the frequency of thoracic hyperkyphosis and lumbar hypo/hyper lordosis in these postures. Forty adolescent tennis players (24 male and 16 female) aged 13-18 years, participated voluntarily in this study. The Spinal Mouse system was used to measure sagittal spinal curvatures and pelvic tilt. The mean values in the relaxed standing posture were 43.83 degrees +/- 7.87 degrees (thoracic kyphosis), - 27.58 degrees +/- 7.01 degrees (lumbar lordosis), and 13.38 degrees +/- 5.57 degrees (pelvic tilt) for male tennis players, respectively; and 36.13 degrees +/- 6.69 degrees (thoracic kyphosis), - 32.69 degrees +/- 5.06 degrees (lumbar lordosis), 20.94 degrees +/- 5.36 degrees (pelvic tilt) for female tennis players (p < 0.05 between genders in all spinal parameters). The male and female tennis players showed a frequency of 62.5% and 93.8% (p = 0.032) for neutral thoracic kyphosis, and 83.3% and 93.8% (p = 0.062) in neutral lumbar lordosis, respectively. In conclusion, due to the high percentage of neutral spinal curvatures in both male and female tennis players, to practice tennis in these levels does not alter sagittal spinal morphology in the relaxed standing posture in adolescent highly trained tennis players. Key PointsThis study evaluated thoracic and lumbar spinal curvatures and pelvic tilt during several postures in young highly trained tennis players.Female tennis players showed statistically significant greater anterior pelvic tilt, lumbar lordosis and lower thoracic kyphosis than male tennis players.The high percentage of neutral thoracic kyphosis and lumbar lordosis posture in both groups of young tennis players in relaxed standing might affirm that tennis does not negatively affect sagittal spinal posture at these ages.A specific postural program could be recommended to improve the slumped sitting and maximal trunk flexion in knees extended postures. PMID- 24149170 TI - Cardiorespiratory responses to stationary running in water and on land. AB - The aim of the study was to compare maximal and submaximal cardiorespiratory responses between progressive tests on a treadmill on land (TRE), and stationary running on land (SRL) and in water (SRW), while also comparing two methods of determining the second turn point (ST) (ventilatory curve and heart rate deflection point). The study sample consisted of nine active women (23 +/- 1.94 years) that performed three maximal protocols in separate days. Heart rate (HR) and oxygen uptake (VO2) were measured in all sessions. The data were analyzed using repeated-measures ANOVA and two-way repeated measures ANOVA with post-hoc Bonferroni test. Greater values of maximal HR (HRmax) and HR at ST (HRST) were observed during exercise performed on TRE and during the SRL, compared to the SRW (p < 0.05). The results for maximal VO2 (VO2max) and VO2 at ST (VO2ST) showed greater and significant values on TRE compared to STL and STW (p < 0.05). Furthermore, the HR and VO2 corresponding to the ST showed similar values between the two methods. Thus, the main conclusion of the present study was that the HR deflection point seems to be a simple and practical alternative method for determining the ST in all protocols analyzed. Key PointsThe maximal and submaximal (second turn point) oxygen uptake were influenced by the type of exercise, as these responses were similar in both water-based and land-based stationary running protocols and different from those obtained during the treadmill running, that presented greater values compared with both stationary running protocols.The heart rate deflection point can be used for determining the second turn point during stationary running test in aquatic environment.Caution is necessary in the interpretation of the application of the heart rate deflection point in water aerobics exercises because we analyzed only young women performing one water-based exercise. PMID- 24149171 TI - Effects of different contextual interference training programs on straight sprinting and agility performance of primary school students. AB - The aim of this study was to evaluate the effect of a different degree of contextual interference (CI) training program on the change of direction ability (CODA) itself and on the straight sprinting (SSP) performance (5 m and 15 m) in students in the first year of primary school. It also evaluated which CI training program was more effective. Eighty eight students (6.42 +/- 0.38 yr) volunteered as participants for the present study. Participants were randomized into 5 different CI training programs (LCI: low contextual interference, MCI: moderate contextual interference, HCI: high contextual interference, VCI: variable contextual interference, and CG: control group) during a 3 week period. Significant CODA improvements (p < 0.05) in pre-post-test were found in MCI (4.39%, ES 0.41) and VCI (9.37%, ES 1. 12) groups. Furthermore, LCI, MCI and HCI groups ameliorated their SSP performance, both in 5 m (5. 92%, ES 0.81; 6.67%, ES 0.90; 8.05%, ES 1.33 respectively) and 15 m SSP (5.86%, ES 0.76; 6.47%, ES 0.80; 2.47% ES 0.41 respectively). These results suggest that training through games of tag (VCI) was the most effective in improving the CODA and training with moderate contextual interference (MCI) was the only type which induced improvements in both capacities (SSP and CODA). Key PointsWe investigated the CODA and SSP performance of students in the first year of primary school and the influence of 5 different training programs on their CODA and SSP ability.Training through games of tag (VCI) was the most effective in improving the CODATraining with moderate contextual interference (MCI) was the only one which induced improvements in both capacities (SSP and CODA). PMID- 24149172 TI - (18)F-FDG PET/CT surveillance at 3-6 and 12 months for detection of recurrence and second primary cancer in patients with head and neck squamous cell carcinoma. AB - BACKGROUND: Early detection of recurrence of head and neck squamous cell carcinoma (HNSCC), which is often obscured by surgical or radiotherapy-induced tissue distortion, is essential for proper patient management. METHODS: A total of 143 consecutive patients with previously untreated HNSCC were evaluated by whole-body fluorine 18-fluorodeoxyglucose positron emission tomography/computed tomography ((18)F-FDG PET/CT) and regular clinical follow-up after curative treatment. The (18)F-FDG PET/CT was performed ~3-6 and 12 months after treatment and findings suspicious for recurrence or SPC were confirmed using histopathology. RESULTS: The sensitivities of 3-6- and 12-month PET/CT scans at patient level were 96% and 93%, respectively, and those of regular clinical follow-up were 11% and 19%, respectively (McNemar test, P<0.001). In patients with no clinical suspicion, PET/CT detected 95% and 91% of recurrent patients at 3-6 and 12 months, respectively. The sensitivity of PET/CT for the identification of SPC was 29% and 80% at 3-6 and 12 months, respectively. A positive interpretation of PET/CT was significantly associated with poor overall survival (log-rank test, P<0.001). CONCLUSION: The (18)F-FDG PET/CT surveillance is beneficial for the detection of recurrence that may be missed by regular follow up physical and endoscopic examinations of the head and neck area after curative treatment for HNSCC. PMID- 24149173 TI - Diabetes type II, other medical conditions and pancreatic cancer risk: a prospective study in The Netherlands. AB - BACKGROUND: To date, only a few risk factors for pancreatic cancer have been established. We examined prospectively relations between several medical conditions and pancreatic cancer incidence. METHODS: In 1986, 120 852 participants completed a baseline questionnaire on cancer risk factors, including several self-reported physician diagnosed medical conditions. At baseline, a random subcohort of 5000 participants was selected using a case-cohort approach for analysis. After 16.3 years of follow-up, 448 pancreatic cancer cases (63% microscopically confirmed) were available for analysis. RESULTS: Diabetes mellitus type II and hepatitis were positively associated with pancreatic cancer risk (multivariable-adjusted hazard ratio: 1.79; 95% confidence interval: 1.12 2.87 and hazard ratio: 1.37; 95% confidence interval: 1.04-1.81, respectively). Furthermore, a positive trend in risk with increasing years of diagnosis of diabetes (P=0.004) and of hepatitis (P=0.02) was observed. However, an inverse association was observed between hypertension and pancreatic cancer risk, this was found among microscopically confirmed cases only (hazard ratio: 0.66; 95% confidence interval: 0.49-0.90), while years since diagnosis of hypertension significantly decreased cancer risk (P for trend=0.02). CONCLUSION: In this prospective study, a positive association was observed between self-reported physician diagnosed diabetes mellitus type II and hepatitis and pancreatic cancer risk, whereas an inverse association was observed with hypertension. PMID- 24149174 TI - Ethnicity and outcome of young breast cancer patients in the United Kingdom: the POSH study. AB - BACKGROUND: Black ethnic groups have a higher breast cancer mortality than Whites. American studies have identified variations in tumour biology and unequal health-care access as causative factors. We compared tumour pathology, treatment and outcomes in three ethnic groups in young breast cancer patients treated in the United Kingdom. METHODS: Women aged <= 40 years at breast cancer diagnosis were recruited to the POSH national cohort study (MREC: 00/06/69). Personal characteristics, tumour pathology and treatment data were collected at diagnosis. Follow-up data were collected annually. Overall survival (OS) and distant relapse free survival (DRFS) were assessed using Kaplan-Meier curves, and multivariate analyses were performed using Cox regression. RESULTS: Ethnicity data were available for 2915 patients including 2690 (91.0%) Whites, 118 (4.0%) Blacks and 87 (2.9%) Asians. Median tumour diameter at presentation was greater in Blacks than Whites (26.0 mm vs 22.0 mm, P=0.0103), and multifocal tumours were more frequent in both Blacks (43.4%) and Asians (37.0%) than Whites (28.9%). ER/PR/HER2-negative tumours were significantly more frequent in Blacks (26.1%) than Whites (18.6%, P=0.043). Use of chemotherapy was similarly high in all ethnic groups (89% B vs 88.6% W vs 89.7% A). A 5-year DRFS was significantly lower in Blacks than Asians (62.8% B vs 77.0% A, P=0.0473) or Whites (62.8 B% vs 77.0% W, P=0.0053) and a 5-year OS for Black patients, 71.1% (95% CI: 61.0 79.1%), was significantly lower than that of Whites (82.4%, 95% CI: 80.8-83.9%, W vs B: P=0.0160). In multivariate analysis, Black ethnicity had an effect on DRFS in oestrogen receptor (ER)-positive patients that is independent of body mass index, tumour size, grade or nodal status, HR: 1.60 (95% CI: 1.03-2.47, P=0.035). CONCLUSION: Despite equal access to health care, young Black women in the United Kingdom have a significantly poorer outcome than White patients. Black ethnicity is an independent risk factor for reduced DRFS particularly in ER-positive patients. PMID- 24149175 TI - Comparison of TNM staging systems for nasopharyngeal carcinoma, and proposal of a new staging system. AB - BACKGROUND: There are few systematic evaluations regarding the sixth and seventh editions of the UICC/AJCC TNM Staging System (TNM6th, TNM7th) and Chinese 2008 Staging System (TNMc2008) for nasopharyngeal carcinoma (NPC). METHODS: We classified 2333 patients into intensity-modulated radiotherapy (IMRT) cohort (n=941) and conventional radiotherapy (CRT) cohort (n=1392). Tumour staging defined by TNM6th, TNM7th and TNMc2008 was compared based on Akaike information criterion (AIC) and Harrell's concordance index (c-index). RESULTS: For T classification, TNM6th (AIC=2585.367; c-index=0.6390385) had superior prognostic value to TNM7th (AIC=2593.242; c-index=0.6226889) and TNMc2008 (AIC=2593.998; c index=0.6237146) in the IMRT cohort, whereas TNMc2008 was superior (AIC=5999.054; c-index=0.623547) in the CRT cohort. For N-classification, TNMc2008 had the highest prognostic value in both cohorts (AIC=2577.726, c-index=0.6297874; AIC=5956.339, c-index=0.6533576). Similar results were obtained when patients were stratified by chemotherapy types, age and gender. Using staging models in the IMRT cohort, we failed to identify better stage migrations than TNM6th T classification and TNMc2008 N-classification. We therefore proposed to combine these categories; resultantly, stage groups of the proposed staging system showed superior prognostic value over TNM6th, TNM7th and TNMc2008. CONCLUSION: TNM6th T classification and TNMc2008 N-classification have superior prognostic value in the IMRT era. By combining them with slight modifications, TNM criteria can be unified and its prognostic value be improved. PMID- 24149176 TI - Allogeneic stem cell transplantation for patients with advanced rhabdomyosarcoma: a retrospective assessment. AB - BACKGROUND: Allogeneic haematopoietic stem cell transplantation (allo-SCT) may provide donor cytotoxic T cell-/NK cell-mediated disease control in patients with rhabdomyosarcoma (RMS). However, little is known about the prevalence of graft-vs RMS effects and only a few case experiences have been reported. METHODS: We evaluated allo-SCT outcomes of 30 European Group for Blood and Marrow Transplantation (EBMT)-registered patients with advanced RMS regarding toxicity, progression-free survival (PFS) and overall survival (OS) after allo-SCT. Twenty patients were conditioned with reduced intensity and ten with high-dose chemotherapy. Twenty-three patients were transplanted with HLA-matched and seven with HLA-mismatched grafts. Three patients additionally received donor lymphocyte infusions (DLIs). Median follow-up was 9 months. RESULTS: Three-year OS was 20% (s.e.+/-8%) with a median survival time of 12 months. Cumulative risk of progression was 67% (s.e.+/-10%) and 11% (s.e.+/-6%) for death of complications. Thirteen patients developed acute graft-vs-host disease (GvHD) and five developed chronic GvHD. Eighteen patients died of disease and four of complications. Eight patients survived in complete remission (CR) (median: 44 months). No patients with residual disease before allo-SCT were converted to CR. CONCLUSION: The use of allo-SCT in patients with advanced RMS is currently experimental. In a subset of patients, it may constitute a valuable approach for consolidating CR, but this needs to be validated in prospective trials. PMID- 24149177 TI - High ALK mRNA expression has a negative prognostic significance in rhabdomyosarcoma. AB - BACKGROUND: Anaplastic lymphoma kinase (ALK) is a receptor tyrosine kinase aberrantly expressed in cancer, but its clinical and functional importance remain controversial. Mutation or amplification of ALK, as well as its expression levels assessed by conventional immunohistochemistry methods, has been linked to prognosis in cancer, although with potential bias because of the semi quantitative approaches. Herein, we measured ALK mRNA expression in rhabdomyosarcoma (RMS) and determined its clinical impact on patients' stratification and outcome. METHODS: Specimens were obtained from RMS patients and cell lines, and ALK expression was analysed by quantitative RT-PCR, western blotting, IHC, and copy number analysis. RESULTS: High ALK mRNA expression was detected in the vast majority of PAX3/7-FOXO1-positive tumours, whereas PAX3/7 FOXO1-negative RMS displayed considerably lower amounts of both mRNA and protein. Notably, ALK mRNA distinguished unfavourable PAX3/7-FOXO1-positive tumours from PAX3/7-FOXO1-negative RMS (P<0.0001), and also correlated with larger tumour size (P<0.05) and advanced clinical stage (P<0.01), independently of fusion gene status. High ALK mRNA levels were of prognostic relevance by Cox univariate regression analysis and correlated with increased risk of relapse (P=0.001) and survival (P=0.01), whereas by multivariate analysis elevated ALK mRNA expression resulted a negative prognostic marker when clinical stage was not included. CONCLUSION: Quantitative assessment of ALK mRNA expression helps to improve risk stratification of RMS patients and identifies tumours with adverse biological characteristics and aggressive behaviour. PMID- 24149178 TI - Neoadjuvant chemotherapy adaptation and serial MRI response monitoring in ER positive HER2-negative breast cancer. AB - BACKGROUND: Changing the neoadjuvant chemotherapy regimen in insufficiently responding breast cancer is not a standard policy. We analysed a series of patients with 'luminal'-type breast cancer in whom the second half of neoadjuvant chemotherapy was selected based on the response to the first half. METHODS: Patients with oestrogen receptor-positive (ER+) human epidermal growth factor receptor 2-negative (HER2-) breast cancer received three courses of neoadjuvant dose-dense doxorubicin and cyclophosphamide (ddAC). Three further courses of ddAC were administered in case of a 'favourable response' on the interim magnetic resonance imaging (MRI) and a switch to docetaxel and capecitabine (DC) was made in case of an 'unfavourable response', using previously published response criteria. The efficacy of this approach was evaluated by tumour size reductions on serial contrast-enhanced MRI, pathologic response and relapse-free survival. RESULTS: Two hundred and forty-six patients received three courses of ddAC. One hundred and sixty-four patients (67%) had a favourable response at the interim MRI, with a mean tumour size reduction of 31% after the first three courses and 34% after the second three courses. Patients with unfavourable responsive tumours had a mean tumour size reduction of 12% after three courses and received three courses of DC rather than ddAC. This led to a mean shrinkage of 27%. CONCLUSION: The tumour size reduction of initially less responsive tumours after treatment adaptation adds further evidence that a response-adapted strategy may enhance the efficacy of neoadjuvant chemotherapy. PMID- 24149179 TI - Nut consumption and risk of pancreatic cancer in women. AB - BACKGROUND: Increasing nut intake has been associated with reduced risk of diabetes mellitus, which is a risk factor for pancreatic cancer. METHODS: We prospectively followed 75 680 women in the Nurses' Health Study, and examined the association between nut consumption and pancreatic cancer risk. Participants with a previous history of cancer were excluded. Nut consumption was assessed at baseline and updated every 2 to 4 years. Relative risks (RRs) and 95% confidence intervals (95% CIs) were estimated using Cox proportional hazards models. RESULTS: We documented 466 incident cases of pancreatic cancer. After adjusting for age, height, smoking, physical activity, and total energy intake, women who consumed a 28-g (1 oz) serving size of nuts >=2 times per week experienced a significantly lower risk of pancreatic cancer (RR, 0.65; 95% CI, 0.47-0.92; P for trend=0.007) when compared with those who largely abstained from nuts. The results did not appreciably change after further adjustment for body mass index (BMI) and history of diabetes mellitus (RR, 0.68; 95% CI, 0.48-0.95; P for trend=0.01). The inverse association persisted within strata defined by BMI, physical activity, smoking, and intakes of red meat, fruits, and vegetables. CONCLUSION: Frequent nut consumption is inversely associated with risk of pancreatic cancer in this large prospective cohort of women, independent of other potential risk factors for pancreatic cancer. PMID- 24149180 TI - Prognostic/predictive value of 207 serum factors in colorectal cancer treated with cediranib and/or chemotherapy. AB - BACKGROUND: The prognostic and predictive value of multiple serum biomarkers was evaluated using samples from a randomised phase III study (HORIZON II) investigating chemotherapy with or without cediranib in metastatic colorectal cancer (mCRC). METHODS: Baseline levels of 207 protein markers were measured in serum samples from 582 HORIZON II (FOLFOX/XELOX plus cediranib 20 mg (n=330) or placebo (n=252)) patients. Median baseline values of each biomarker were used to categorise patients as high or low. Markers were then assessed for their association with efficacy, defined by progression-free survival (PFS) and overall survival (OS). A generalised boosted regression model identified markers of particular interest. RESULTS: Correlation of protein levels with PFS and OS suggested that multiple factors had a prognostic value, independent of treatment arm, including IL-6, IL-8, C-reactive protein (CRP), ICAM-1 and carcinoembryonic antigen (CEA). Among the angiogenesis regulators, low levels of vascular endothelial growth factor (VEGF), VEGF-D, VEGFR-1, VEGFR-3, NRP1 and Tie-2 correlated with better outcome. CONCLUSION: This large data set generated using serum samples from mCRC patients treated with chemotherapy and VEGF inhibitors, defines baseline characteristics for 207 serum proteins. Multiple prognostic factors were identified that could be disease related or predict which patients derive most benefit from 5-fluorouracil (5-FU)-based chemotherapy, meriting further exploration in prospective studies. PMID- 24149181 TI - Foods, nutrients and the risk of oral and pharyngeal cancer. AB - BACKGROUND: Besides tobacco and alcohol, dietary habits may have a relevant role in oral cavity and pharyngeal (OCP) cancer. METHODS: We analysed the role of selected food groups and nutrients on OCP cancer in a case-control study carried out between 1997 and 2009 in Italy and Switzerland. This included 768 incident, histologically confirmed squamous cell carcinoma cases and 2078 hospital controls. Odds ratios (ORs) were estimated using logistic regression models including terms for tobacco, alcohol and other relevant covariates. RESULTS: Significant inverse trends in risk were observed for all vegetables (OR=0.19, for the highest vs the lowest consumption) and all fruits (OR=0.39), whereas significant direct associations were found for milk and dairy products (OR=1.50), eggs (OR=1.71), red meat (OR=1.55), potatoes (OR=1.85) and desserts (OR=1.68), although trends in risk were significant only for potatoes and desserts. With reference to nutrients, significant inverse relations were observed for vegetable protein (OR=0.45, for the highest vs the lowest quintile), vegetable fat (OR=0.54), polyunsaturated fatty acids (OR=0.53), alpha-carotene (OR=0.51), beta carotene (OR=0.28), beta-cryptoxanthin (OR=0.37), lutein and zeazanthin (OR=0.34), vitamin E (OR=0.26), vitamin C (OR=0.40) and total folate (OR=0.34), whereas direct ones were observed for animal protein (OR=1.57), animal fat (OR=2.47), saturated fatty acids (OR=2.18), cholesterol (OR=2.29) and retinol (OR=1.88). Combinations of low consumption of fruits and vegetables, and high consumption of meat with high tobacco and alcohol, led to 10- to over 20-fold excess risk of OCP cancer. CONCLUSION: Our study confirms and further quantifies that a diet rich in fruits and vegetables and poor in meat and products of animal origin has a favourable role against OCP cancer. PMID- 24149182 TI - A dose-escalating phase I of imatinib mesylate with fixed dose of metronomic cyclophosphamide in targeted solid tumours. AB - BACKGROUND: Preclinical findings suggest that imatinib mesylate (IM) and metronomic cyclophosphamide (MC) combination provides synergistic antiangiogenic activity on both pericytes and endothelial cells. METHODS: We have designed a 3+3 dose-escalating phase I trial with a fixed dose of MC (50 mg two times daily) plus IM (400 mg per day; 300 and 400 mg two times daily). Enrolled patients had IM- and sutininib-refractory advanced gastrointestinal stromal tumours (GIST) (n=17), chordoma (n=7) and mucosal melanoma (n=2). Dose-limiting toxicities were monitored for the first 6 weeks. Progression-free survival (PFS) and response assessment are based on RECIST 1.0 guidelines. Pharmacokinetics of IM were measured before and after exposure to MC. RESULTS: No dose-limiting toxicity was observed. Fourteen patients of the expanded cohort received 400 mg two times daily of IM with MC. Apart from a case of possibly related acute leukaemia occurring after 4 years of treatment, we did not see unexpected toxicity. No drug drug pharmacokinetic interaction was observed. There was no objective response. We have observed long-lasting stable disease in chordoma patients (median PFS=10.2 months; range, 4.2-18+) and short-term stable disease in heavily GIST pretreated patients (median PFS=2.3 months; range, 2.1-6.6). CONCLUSION: This combination is feasible and may warrant further exploration in refractory GIST or chordoma patients. PMID- 24149183 TI - Reducing falls and fall-related injuries in mental health: a 1-year multihospital falls collaborative. AB - Despite much research on falls occurring on medical-surgical units and in long term care settings, falls on inpatient psychiatry units are understudied. On the basis of fall injury program characteristics across multiple inpatient psychiatry units, we developed and implemented an operational strategic plan to address each falls prevention program element and enhance program infrastructure and capacity. Expert faculty provided lectures, coaching, and mentoring through biweekly conference calls and collaborative e-mail exchange. Findings support continued efforts to integrate measures to reduce serious fall-related injuries. PMID- 24149184 TI - Neural development: Tracing interneuron roots. PMID- 24149185 TI - Controlled substances and innovation of biomedicine: a preclinical perspective. PMID- 24149186 TI - Empirical evidence for low reproducibility indicates low pre-study odds. PMID- 24149187 TI - New victims of current drug laws. PMID- 24149188 TI - Hepatic encephalopathy: effects of liver failure on brain function. AB - Liver failure affects brain function, leading to neurological and psychiatric alterations; such alterations are referred to as hepatic encephalopathy (HE). Early diagnosis of minimal HE reveals an unexpectedly high incidence of mild cognitive impairment and psychomotor slowing in patients with liver cirrhosis - conditions that have serious health, social and economic consequences. The mechanisms responsible for the neurological alterations in HE are beginning to emerge. New therapeutic strategies acting on specific targets in the brain (phosphodiesterase 5, type A GABA receptors, cyclooxygenase and mitogen-activated protein kinase p38) have been shown to restore cognitive and motor function in animal models of chronic HE, and NMDA receptor antagonists have been shown to increase survival in acute liver failure. This article reviews the latest studies aimed at understanding how liver failure affects brain function and potential ways to ameliorate these effects. PMID- 24149189 TI - A test is not a test. PMID- 24149190 TI - Nitric oxide is less effective at inhibiting neointimal hyperplasia in spontaneously hypertensive rats. AB - Exogenous administration of nitric oxide (NO) markedly decreases neointimal hyperplasia following arterial injury in several animal models. However, the effect of NO on neointimal hyperplasia in hypertension remains unknown. Here, we employ the spontaneously hypertensive rat (SHR) strain, inbred from Wistar Kyoto (WKY) rats, and the carotid artery balloon injury model to assess the effects of NO on neointimal hyperplasia development. 2weeks after arterial injury, we showed that both rat strains developed similar levels of neointimal hyperplasia, but local administration of NO was less effective at inhibiting neointimal hyperplasia in the SHR compared to WKY rats (58% vs. 79%, P<0.001). Interestingly, local administration of NO did not affect systemic blood pressure in either rat strain. Compared to WKY, the SHR displayed more proliferation in the media and adventitia following balloon injury, as measured by BrdU incorporation. The SHR also showed more inflammation in the adventitia after injury, as well as more vasa vasorum, than WKY rats. NO treatment reduced the vasa vasorum in the SHR but not WKY rats. Finally, while NO decreased both injury induced proliferation and inflammation in the SHR, it did not return these parameters to levels seen in WKY rats. We conclude that NO is less effective at inhibiting neointimal hyperplasia in the SHR than WKY rats. This may be due to increased scavenging of NO in the SHR, leading to diminished bioavailability of NO. These data will help to develop novel NO-based therapies that will be equally effective in both normotensive and hypertensive patient populations. PMID- 24149191 TI - Whole-body vibration and rehabilitation of chronic diseases: a review of the literature. AB - The objectives of the study were to review the current literature and findings on the effects of whole-body vibration (WBV) as a training method on performance and its ability to aid in the rehabilitation of chronic diseases (neurological, musculoskeletal or metabolic conditions). Six electronic databases were searched. The combination of the search terminology used included WBV and several neurological, musculoskeletal and metabolic conditions. Twenty six papers were found to be relevant for this review and were included for critical evaluation with regards to sample characteristics, research intervention and methodology. Most studies were conducted on patients diagnosed with neurological conditions (n = 15) while less were performed on patients suffering from musculoskeletal (n = 7) or metabolic (n = 4) disorders. Comparisons were difficult to draw on because of the different pathologies and the differences in the methodology of each study. Some of the observed methodological flaws included limitations in relation to insufficient randomisation, lack of sample homogeneity (size, age variability) and poor blinding in most studies. No consensus could be reached as to whether WBV is more effective than other interventions or no intervention at all, while the additional effects that WBV may have in relation to other interventions could not be assumed. Nevertheless, chronic WBV training seems to only improve strength in neurological patients while balance and mobility improves only in patients suffering from musculoskeletal or metabolic but not from neurological conditions. Although WBV did not prove to be more effective compared to other training methods, it can be used, in some cases, as a less fatiguing and less time consuming method to enhance physical capabilities. Future research should focus on the effectiveness of WBV in relation to no treatment at all, and to age. Key pointsChronic WBV training seems to only improve strength in neurological patients while balance and mobility improves only in patients suffering from musculoskeletal or metabolic conditions.WBV did not prove to be more effective than other interventions, while the positive effects of WBV in relation to no intervention at all could not be established.No consensus could be reached as to which vibration type is more effective.WBV training could be used as a safe, less fatiguing and less time-consuming type of exercise for patients with neurologic conditions instead of other more demanding interventions. PMID- 24149193 TI - Reliability of the one-repetition maximum test based on muscle group and gender. AB - The purpose of the present study was to examine the influence of muscle group location and gender on the reliability of assessing the one-repetition maximum (1RM) test. Thirty healthy males (n = 15) and females (n = 15) who experienced at least 3 months of continuous resistance training during the last 2 years aged 18 35 years volunteered to participate in the study. The 1RM for the biceps curl, lat pull down, bench press, leg curl, hip flexion, triceps extension, shoulder press, low row, leg extension, hip extension, leg press and squat were measured twice by a trained professional using a standard published protocol. Biceps curl, lat pull down, bench press, leg curl, hip flexion, and squat 1RM's were measured on the first visit, then 48 hours later, subjects returned for their second visit. During their second visit, 1RM of triceps extension, shoulder press, low row, leg extension, hip extension, and leg press were measured. One week from the second visit, participants completed the 1 RM testing as previously done during the first and second visits. The third and fourth visits were separated by 48 hours as well. All four visits to the laboratory were at the same time of day. A high intraclass correlation coefficient (ICC > 0.91) was found for all exercises, independent of gender and muscle group size or location, however there was a significant interaction for muscle group location (upper body vs. lower body) in females (p < 0.027). In conclusion, a standardized 1RM testing protocol with a short warm-up and familiarization period is a reliable measurement to assess muscle strength changes regardless of muscle group location or gender. Key pointsThe one repetition maximum (1RM) test is considered the gold standard for assessing muscle strength in non-laboratory situations.This study was done to examine the influence of muscle group location and gender on the reliability of assessing the 1RM test.The standardized 1RM testing protocol with a short warm-up and familiarization period is a reliable measurement technique to assess muscle strength changes regardless of muscle group location or gender. PMID- 24149192 TI - How Healthy is the Behavior of Young Athletes? A Systematic Literature Review and Meta-Analyses. AB - Participation in sports during adolescence is considered a healthy behavior. The extent to which adolescent athletes engage in other healthful (or risky) behaviors is less clear, however. We conducted a systematic literature review following the PRISMA Statement to assess the frequency of risky behaviors among athletes in this age group. We searched the PubMed, PsycINFO and SCA Sociological Abstracts databases for observational studies published in English over the last twenty years on the frequency of selected risk behaviors (alcohol consumption, smoking behavior, use of illicit drugs, unhealthy nutrition, and doping) in adolescent athletes. Two independent reviewers selected articles following the PRISMA Statement. Behavior frequency was assessed as was comparability of study design and methods. When possible, meta- analyses were performed using data from subgroups of studies in which operational indicators were comparable. Seventy eight articles met eligibility criteria. Although report of risky behaviors varied across studies, we observed overall, that studies tend to report higher alcohol use, less smoking, less recreational drug use, and more smokeless tobacco use in (high-involved) athletes. Considerable heterogeneity was noted in study design, definition of target groups and use of operational indicators (I(2) ranged from 93.2% to 100%). Especially the higher prevalence of using alcohol and smokeless tobacco needs more attention in interventions targeted to this group. Overall, greater consensus on methods used to assess risky behaviors in adolescent athletes. Key pointsThis is the first systematic review focusing on different health related risk behaviors of adolescent athletes aged <= 18 years from different countries.Health related risk behaviors such as alcohol consumption are common among recreational and elite adolescent athletes.Athletes were more likely to consume alcohol, smokeless tobacco, and steroids and less likely to smoke and to use marihuana than non-athletes.Studies show high heterogeneity in the operational indicators, statistical methods, and target groups. Therefore, greater consensus around key definitions and study methods is needed to advance knowledge. PMID- 24149194 TI - The relationship between school performance and the number of physical education classes attended by korean adolescent students. AB - Increased physical activity (PA) is the relationship with improved cognitive and memory functions of the brain. The physical education (PE) classes held in school comprise a type of PA. However, there is no epidemiological evidence showing a relationship between school performance and the number of PE classes attended per week in adolescent students. Therefore, the purpose of this study is to examine whether the number of PE classes attended per week is related with school performance in Korean adolescent students. In 2009, 75,066 adolescent students from middle school first grade to high school third grade participated in the 5th Korea Youth Risk Behavior Web-based Survey (KYRBWS-V) project. The relationship between school performance and the number of PE classes attended per week was assessed using multivariate logistic regression analysis after adjusting for covariate variables such as gender, age, body mass index, parents' education level, family's economic status, vigorous and moderate PA, and muscle strengthening exercises. The odds ratio (OR) for attending <3 PE classes per week and school performance was 1.125 for good school performance, 1.147 for average school performance, 1.146 for poor school performance, and 1.191 for very poor school performance, when compared to very good school performance. It was concluded that attending >=3 PE classes per week was positively correlated with improved school performance and that attending <3 PE classes per week was negatively correlated with school performance in Korean adolescent students. Key pointsKorean adolescents, attending >=3 PE classes per week was positively correlated with school performance.Korean adolescents, attending <3 PE classes per week was negatively correlated with school performance. PMID- 24149195 TI - Increased distance of shooting on basketball jump shot. AB - The present study analyzed the effect of increased distance on basketball jump shot outcome and performance. Ten male expert basketball players were filmed and a number of kinematic variables analyzed during jump shot that were performed from three conditions to represent close, intermediate and far distances (2.8, 4.6, and 6.4m, respectively). Shot accuracy decreased from 59% (close) to 37% (far), in function of the task constraints (p < 0.05). Ball release height decreased (p < 0.05) from 2.46 m (close) to 2.38m (intermediate) and to 2.33m (long). Release angle also decreased (p < 0.05) when shot was performed from close (78.92 degrees ) in comparison to intermediate distances (65.60 degrees ). While, ball release velocity increased (p < 0.05) from 4.39 m/s (close) to 5.75 m.s(-1) (intermediate) to 6.89 m.s(-1) (far). These changes in ball release height, angle and velocity, related to movement performance adaptations were suggested as the main factors that influence jump shot accuracy when distance is augmented. Key pointsThe increased distance leads to greater spatial con-straint over shot movement that demands an adapta-tion of the movement for the regulation of the accu-racy and the impulse generation to release the ball.The reduction in balls release height and release angle, in addition to the increase in balls release ve-locity, were suggested as the main factors that de-creased shot accuracy with the distance increased.Players should look for release angles of shooting that provide an optimal balls release velocity to im-prove accuracy. PMID- 24149196 TI - The effects of an early return to training on the bone-tendon junction post-acute micro-injury healing. AB - Bone-tendon junction (BTJ) overuse injuries are common athletic and occupational problems. BTJ injuries may sometimes be caused by resuming training too early after injury. To study the effects of post-injury resuming training within 48 hours on the acute injury healing process, as it is often the case for athletes. Twelve mature female rabbits were assigned to one of the following groups: acute injury (AI, n = 6), post-injury early return to training (PIERT, n = 6) and normal control (CON, n = 6). Tissue specimens were harvested at week 4. The radiological and histological characteristics of the AI and PIERT groups were compared among the groups. The trabecular thickness of the PIERT group was significantly different from those of the AI and CON group. A histological evaluation revealed poor collagen fibre alignment, extensive scar tissue and lowered cell density in the AI and PIERT groups compared with the CON group, but no significant differences were observed between the AI group and the PIERT group. The fibrocartilage zone and proteoglycan area in the PIERT group were significantly different from those in AI group. No differences were observed in the Total VOI volume (TV), Object volume (OBV), Percent object volume (BV/TV) and trabecular number (Tb.N) among the AI, PIERT and CON groups. In conclusion, a repeatable animal model of bone-tendon junction acute micro-damage by puncture was established. Resuming training in 48 hours did not significantly deteriorate the BTJ injury healing, but improved bone remodelling and increased fibrocartilage zone thickness. Key pointsAn easy and repeatable bone-tendon junction injury model was established in this study, it will provide a platform to the injury research.Post-injury resuming training in 48 hours did not delay the acute bone-tendon junction injury healing process, it provided a basic theory for the post-injury training.To find the proper post-injury training intensity will help athletes to train scientifically, it is the destination of our next research. PMID- 24149197 TI - Effects of run-up velocity on performance, kinematics, and energy exchanges in the pole vault. AB - This study examined the effect of run-up velocity on the peak height achieved by the athlete in the pole vault and on the corresponding changes in the athlete's kinematics and energy exchanges. Seventeen jumps by an experienced male pole vaulter were video recorded in the sagittal plane and a wide range of run-up velocities (4.5-8.5 m/s) was obtained by setting the length of the athlete's run up (2-16 steps). A selection of performance variables, kinematic variables, energy variables, and pole variables were calculated from the digitized video data. We found that the athlete's peak height increased linearly at a rate of 0.54 m per 1 m/s increase in run-up velocity and this increase was achieved through a combination of a greater grip height and a greater push height. At the athlete's competition run-up velocity (8.4 m/s) about one third of the rate of increase in peak height arose from an increase in grip height and about two thirds arose from an increase in push height. Across the range of run-up velocities examined here the athlete always performed the basic actions of running, planting, jumping, and inverting on the pole. However, he made minor systematic changes to his jumping kinematics, vaulting kinematics, and selection of pole characteristics as the run-up velocity increased. The increase in run-up velocity and changes in the athlete's vaulting kinematics resulted in substantial changes to the magnitudes of the energy exchanges during the vault. A faster run up produced a greater loss of energy during the take-off, but this loss was not sufficient to negate the increase in run-up velocity and the increase in work done by the athlete during the pole support phase. The athlete therefore always had a net energy gain during the vault. However, the magnitude of this gain decreased slightly as run-up velocity increased. Key pointsIn the pole vault the optimum technique is to run-up as fast as possible.The athlete's vault height increases at a rate of about 0.5 m per 1 m/s increase in run-up velocity.The increase in vault height is achieved through a greater grip height and a greater push height. At the athlete's competition run-up velocity about one third of the rate of increase in vault height arises from an increase in grip height and two thirds arises from an increase in push height.The athlete has a net energy gain during the vault. A faster run-up velocity produces a greater loss of energy during the take-off but this loss of energy is not sufficient to negate the increase in run-up velocity and the increase in the work done by the athlete during the pole support phase. PMID- 24149198 TI - Muscle activity response to external moment during single-leg drop landing in young basketball players: the importance of biceps femoris in reducing internal rotation of knee during landing. AB - Internal tibial rotation with the knee close to full extension combined with valgus collapse during drop landing generally results in non-contact anterior cruciate ligament (ACL) injury. The purpose of this study was to investigate the relationship between internal rotation of the knee and muscle activity from internal and external rotator muscles, and between the internal rotation of knee and externally applied loads on the knee during landing in collegiate basketball players. Our hypothesis was that the activity of biceps femoris muscle would be an important factor reducing internal knee rotation during landing. The subjects were 10 collegiate basketball students: 5 females and 5 males. The subjects performed a single-leg drop landing from a 25-cm height. Femoral and tibial kinematics were measured using a 3D optoelectronic tracking system during the drop landings, and then the knee angular motions were determined. Ground reaction forces and muscle activation patterns (lateral hamstring and medial hamstring) were simultaneously measured and computed. Results indicated that lower peak internal tibial rotation angle at the time of landing was associated with greater lateral hamstring activity (r = -0.623, p < 0.001). When gender was considered, the statistically significant correlation remained only in females. There was no association between the peak internal tibial rotation angle and the knee internal rotation moment. Control of muscle activity in the lateral to medial hamstring would be an important factor in generating sufficient force to inhibit excessive internal rotation during landing. Strengthening the biceps femoris might mitigate the higher incidence of non-contact ACL injury in female athletes. Key pointsLower activity of the external rotator muscle of the knee, which inhibits internal rotation of the knee, may be the reason why females tend to show a large internal rotation of the knee during drop landing.Externally applied internal rotation moment of the knee during landing would not be expected to explain why female athletes tend to show excessive internal knee rotation.Biceps femoris strength training might help decrease the incidence of non-contact ACL injury in female athletes. PMID- 24149199 TI - Prediction of enjoyment in school physical education. AB - The specific aim of this study was to examine whether motivational climate, perceived physical competence, and exercise motivation predict enjoyment in school physical education within the same sample of adolescents across three years of secondary school. A sample of 639 students (girls = 296, boys = 343) aged between 13- to 15-years at the commencement of the study completed the Intrinsic Motivation Climate in Physical Education Questionnaire, Physical Self Perception Profile, Physical Education Motivation Scale, and Physical Education Enjoyment Scale. Results derived from path analyses indicated that task-involving motivational climate predicted enjoyment in physical education via perceived physical competence and intrinsic motivation in both girls and boys. In particular, these results supported previous findings of Vallerand et. al (1997) with the self-determination theory and the achievement goal theory. Ego-involving climate was not a significant predictor either in girls or boys. The current results provide continuing support for the investigation of Vallerand's model in the physical education setting, and highlight that motivational climate is an area that requires further evaluation as a contributing factor in the improvement of physical education teaching. A better understanding of the role of motivational climate may assist efforts to promote children's and adolescents' perceived physical competence, intrinsic motivation, and enjoyment in the school physical education setting. Key pointsThe findings of the current study support existing suggestions of Vallerand's (1997) model in which social factors mediated by a psychological mediator, and exercise motivation are related to positive consequences in the PE context.Task-involving motivational climate predicted PE enjoyment via perceived physical competence and intrinsic motivation with both girls and boys. Task-involving motivational climate in PE lessons at Grade 7 had a strong association with PE enjoyment via perceived physical competence and intrinsic motivation at Grade 9 for both girls and boys.Ego-involving climate did not fit either the data for the girls or boys, as PE lessons based on ego involving motivational climate did not significantly influence on the level of PE enjoyment.The results of the current study and previous practical findings support task-involving teaching methods to promote adolescent's PE enjoyment through secondary school years. School PE could be most effective if based on task-involving motivational climate, in which the main objective is increasing students' perceived physical competence, intrinsic motivation, and enjoyment. PMID- 24149200 TI - Retired matches among male professional tennis players. AB - The aim of this study was to explore the effect of characteristics of various games and players on the proportion of retired tennis matches in the Open Era of tennis. The data included over 420,000 matches played among 17,553 tennis players in the period from 1968 to the end of 2010. The influence of the surface type was clearly confirmed, with the proportion of retired matches being higher on hard and clay courts compared to grass and carpet surfaces. Similarly, more retired matches were observed in outdoor venues than in indoor ones. The impact of other variables, tournament types, rounds at which the game was played and both players' ranks, is more ambiguous. Our interpretation of the obtained results is presented in the paper. Network analytic methods were applied to extract players with the most retired matches in their careers. Eventually, we defined a group of top tennis players and gave a more precise insight into retired matches in that group. Correspondence analysis was used to visually display the two-mode network of top players and the proportion of retired matches by surface type. Key pointsThe proportion of retired matches among professional tennis players has been increasing recently.Clay and hard courts are the most risky surfaces in relation to retired matches, particularly if the match is played at an outdoor venue.The difference in rankings of both players is proportional to the number/proportion of retired matches in professional tennis.Network analytic techniques could serve as an effective method to ascertain (a) group(s) of tennis players with the highest number of retired matches played among them. PMID- 24149201 TI - Effects of dynamic and static stretching within general and activity specific warm-up protocols. AB - The purpose of the study was to determine the effects of static and dynamic stretching protocols within general and activity specific warm-ups. Nine male and ten female subjects were tested under four warm-up conditions including a 1) general aerobic warm-up with static stretching, 2) general aerobic warm-up with dynamic stretching, 3) general and specific warm-up with static stretching and 4) general and specific warm-up with dynamic stretching. Following all conditions, subjects were tested for movement time (kicking movement of leg over 0.5 m distance), countermovement jump height, sit and reach flexibility and 6 repetitions of 20 metre sprints. Results indicated that when a sport specific warm-up was included, there was an 0.94% improvement (p = 0.0013) in 20 meter sprint time with both the dynamic and static stretch groups. No such difference in sprint performance between dynamic and static stretch groups existed in the absence of the sport specific warm-up. The static stretch condition increased sit and reach range of motion (ROM) by 2.8% more (p = 0.0083) than the dynamic condition. These results would support the use of static stretching within an activity specific warm-up to ensure maximal ROM along with an enhancement in sprint performance. Key pointsActivity specific warm-up may improve sprint performance.Static stretching was more effective than dynamic stretching for increasing static range of motion.There was no effect of the warm-up protocols on countermovement jump height or movement time. PMID- 24149202 TI - Modulatory effect of subthalamic nucleus on the development of fatigue during exhausting exercise: an in vivo electrophysiological and microdialysis study in rats. AB - The purpose of the study was to investigate the modulatory effect of changes of subthalamic nucleus (STN) activity on the development of central fatigue during exhausting exercise, and reveal the possible mechanism that might affect STN activity from the perspective of neurotransmitters. Rats were randomly divided into electrophysiology and microdialysis study groups. For electrophysiological study, electrical activity in sensorimotor cortex and STN were simultaneously recorded before, during and 90min after the exhausting exercise. For microdialysis study, extracellular fluid of STN was continuously collected with a microdialysis probe and glutamate (Glu), gamma-aminobutyric acid (GABA) levels were subsequently detected with high performance liquid chromatography (HPLC). The behavioral studies showed that rats ran well initiatively with the treadmill exercise in the beginning, 45 +/- 11.5min later, movement capacity reduced obviously (which was termed as 'early fatigue'). Correspondingly, STN activity increased significantly compared with rest condition (p < 0.05), while, cortex activity decreased significantly (p < 0.05). Subsequently, rats continued their exercise with minor external stimulation till exhaustion. Cortex activity reached the minimum value under exhaustion condition, while STN activity changed insignificantly (p > 0.05). For microdialysis study, the dynamic change of Glu/GABA ratio was consistent with the change of STN activity during the development of 'early fatigue' rather than the development of exhaustion. In conclusion, the present study shows that, the development of the cortex fatigue during exhausting exercise consists of two phases, 'early fatigue' and exhaustion. Our results suggest that, dynamic changes of STN activity are closely relevant to the development of 'early fatigue' rather than exhaustion, and the changes of STN activity during the development of 'early fatigue' might be partly related to the variance of Glu and GABA levels in STN extracellular fluid. Key pointsThe development of the cortex fatigue during exhausting exercise consists of two phases, 'early fatigue' and exhaustion.Dynamic changes of STN activity are closely relevant to the development of 'early fatigue' rather than exhaustion.The changes of STN activity during the development of 'early fatigue' might be partly related to the variance of Glu and GABA levels in STN extracellular fluid. PMID- 24149203 TI - Fundamental study of detection of muscle hypertrophy-oriented gene doping by myostatin knock down using RNA interference. AB - To investigate the feasibility of developing a method for detection of gene doping in power-athletes, we devised an experimental model system. Myostatin is a potent negative regulator of skeletal muscle development and growth, and myostatin-knockout mice exhibit a double-muscle phenotype. To achieve knockdown, we constructed plasmids expressing short hairpin interfering RNAs (shRNAs) against myostatin. These shRNAs were transfected into C2C12 cultured cells or injected into the tibialis anterior (TA) muscle of adult mice. By performing in vitro and in vivo experiments, we found that some shRNAs effectively reduced the expression of myostatin, and that the TA muscle showed hypertrophy of up to 27.9%. Then, using real-time PCR, we tried to detect the shRNA plasmid in the serum or muscles of mice into which it had been injected. Although we were unable to detect the plasmid in serum samples, it was detectable in the treated muscle at least four weeks after induction. We were also able to detect the plasmid in muscle in the vicinity of the TA. This gene doping model system will be useful for further studies aimed at doping control. Key pointsUsing a myostatin knockdown plasmid, we have succeeded in creating a model system for gene doping using mice that resulted in muscle hypertrophy greater than that reported previously.We confirmed that there was a limit of gene doping detection using real-time PCR, either from serum or muscle smple.This model experimental system can be utilized for examining indirect methods of gene doping detection such as immune responses to gene transfer or a profiling approach using DNA microarray. PMID- 24149204 TI - Practicing field hockey skills along the contextual interference continuum: a comparison of five practice schedules. AB - To overcome the weakness of the contextual interference (CI) effect within applied settings, Brady, 2008 recommended that the amount of interference be manipulated. This study investigated the effect of five practice schedules on the learning of three field hockey skills. Fifty-five pre-university students performed a total of 90 trials for each skill under blocked, mixed or random practice orders. Results showed a significant time effect with all five practice conditions leading to improvements in acquisition and learning of the skills. No significant differences were found between the groups. The findings of the present study did not support the CI effect and suggest that either blocked, mixed, or random practice schedules can be used effectively when structuring practice for beginners. Key pointsThe contextual interference effect did not surface when using sport skills.There appears to be no difference between blocked and random practice schedules in the learning of field hockey skills.Low (blocked), moderate (mixed) or high (random) interference practice schedules can be used effectively when conducting a multiple skill practice session for beginners. PMID- 24149205 TI - Intervention for spanish overweight teenagers in physical education lessons. AB - Physical education is a favourable educational framework for the development of programmes aimed at increasing physical activity in children and thus reducing sedentarism. The progressive increase of overweight students demands global control and follow-up measurement of these behaviours in both in and out of school. The pedometer can be a useful tool in this field. It is easy to use and allow Physical Education (PE) departments to quantify their students' number of steps/day. The aim of this study was to determine the effect of a pedometer intervention on body fat and BMI levels in overweight teenagers. Besides, the effects of the programme are analysed according to two other variables: pedometer ownership and gender, distinguishing between out-of-school and school hours, weekdays and weekends. The sample comprises 112 overweight students (49 boys and 63 girls) from 5 secondary schools. Participants were asked to follow a physical activity programme consisting on a minimum of 12000 and 10000 steps/day for boys and girls, respectively. It also allowed them to get up to 2 extra points in their PE marks. Results were measured after 6 weeks of programme application as well as after 6 weeks of retention. Results revealed significantly reduced BMI in the teenagers with their own pedometer (p < 0.05). The difference observed in the number of steps/day between boys (12050) and girls (9566) was significant in all measured time periods (p < 0.05). Besides, both overweight boys and girls were observed to take 1000 steps/day less at weekends than in weekdays. Therefore, it is concluded that the proposal of 12000 and 10000 steps for overweight boys and girls, respectively, accompanied by a reinforcement programme in their final PE marks, seems sufficient to obtain significant BMI reductions. Besides, PE is shown a favourable framework for the proposal of pedometer-impelled weight loss programmes in overweight youth. Key pointsA programme of 12000 and 10000 steps for overweight boys and girls, respectively with reinforcement in physical education marks, the body mass index improves.Body mass index more reduced was in Spanish adolescent overweight that used their own pedometer.The steps/day between boys (12050) and girls (9566) with overweight was different (p < 0.05).Overweight boys and girls were observed to take 1000 steps/day less at weekends than in weekdays.In physical education is possible to apply a programme of steps in obese youth of secondary education schools. PMID- 24149206 TI - Effects of an 8-month yoga intervention on arterial compliance and muscle strength in premenopausal women. AB - Previous studies have indicated that Yoga exercise has a positive effect on reducing blood pressure and heart rate. However, no randomized controlled studies to date have investigated its effects on arterial compliance. The purpose of this study was to investigate the effects of an 8-month Yoga intervention on arterial compliance and muscle strength in normal premenopausal women 35-50 years of age. Thirty-four women were randomly assigned either to a Yoga exercise group (YE, n = 16) or a control group (CON, n = 18). Participants in YE group performed 60 minutes of an Ashtanga Yoga series 2 times/week with one day between sessions for 8 months. Each Yoga session consisted of 15 minutes of warm-up exercises, 35 minutes of Ashtanga Yoga postures and 10 minutes of cool-down with relaxation; and the session intensity was progressively increased during the 8 months. Participants in CON were encouraged to maintain their normal daily lifestyles monitored by the bone-specific physical activity questionnaire at 2 month intervals for 8 months. Arterial compliance (pulse contour analysis) and muscle strength (1 Repetition Maximum) were assessed at baseline and after the intervention. Arterial compliance of the large and small arteries was not affected by the 8 month Yoga training (p > 0.05). Also, there were no significant (p > 0.05) group, time, or group * time interaction effects for cardiovascular variables. YE group significantly (p < 0.01) improved leg press muscle strength compared to CON (11.4% vs. -6.5%). Eight months of Ashtanga Yoga training was beneficial for improving leg press strength, but not arterial compliance in premenopausal women. Key pointsThe 8 month Yoga training did not affect arterial compliance of the large and small arteries.None of the cardiovascular variables were changed by the Yoga intervention.Isotonic muscle strength was not altered by the Yoga intervention, with the exception of leg press. PMID- 24149207 TI - Is a cognitive-behavioural biofeedback intervention useful to reduce injury risk in junior football players? AB - Athletes participating in sport are exposed to a relatively high injury risk. Previous research has suggested that it could be possible to reduce sports injuries through psychological skills training. The purpose of this study was to examine the extent to which a cognitive behavioural biofeedback intervention could reduce the number of sports injuries in a sample of players in Swedish elite football high schools. Participants from four elite football high schools (16-19 years old) were divided into one experiment (n = 13) and one control group (n = 14). Participants were asked to complete three questionnaires to assess anxiety level (Sport Anxiety Scale), history of stressors (Life Event Scale for Collegiate Athletes) and coping skills (Athletic Coping Skills Inventory - 28) in a baseline measure. Mann-Whitney U-tests showed no significant differences in pre intervention scores based on the questionnaires. The experimental group participated in a nine-week intervention period consisting of seven sessions, including: somatic relaxation, thought stopping, emotions/problem focused coping, goal setting, biofeedback training as well as keeping a critical incident diary. A Mann-Whitney U test showed no significant difference between the control and experimental group U (n1 = 13, n2 = 14) = 51.00, p = 0.054. However, considering the small sample, the statistical power (0.05 for present study), to detect effects was low. The results of the study are discussed from a psychological perspective and proposals for future research are given. Key pointsCognitive behavioral training together with biofeedback training seems to be an effective strategy to decrease the occurrence of injuries.More intervention studies should be conducted applying existing biofeedback methodology, especially in the injury preventive area.Future research should develop a bio-psychological injury model aimed at predicting injury occurrence which describes the physiological stress responses and how they can be measured in more detail. PMID- 24149208 TI - The perceptual cognitive processes underpinning skilled performance in volleyball: evidence from eye-movements and verbal reports of thinking involving an in situ representative task. AB - An extensive body of work has focused on the processes underpinning perceptual cognitive expertise. The majority of researchers have used film-based simulations to capture superior performance. We combined eye movement recording and verbal reports of thinking to explore the processes underpinning skilled performance in a complex, dynamic, and externally paced representative volleyball task involving in situ data collection. Altogether, 27 female volleyball players performed as centre backcourt defenders in simulated sessions while wearing an eye-tracking device. After each sequence, athletes were questioned concerning their perception of the situation. The visual search strategies employed by the highly-skilled players were more exploratory than those used by skilled players, involving more fixations to a greater number of locations. Highly-skilled participants spent more time fixating on functional spaces between two or more display areas, while the skilled participants fixated on the ball trajectory and specific players. Moreover, highly-skilled players generated more condition concepts with higher levels of sophistication than their skilled counterparts. Findings highlight the value of using representative task designs to capture performance in situ. Key pointsDecision-making in complex sports relies deeply on perceptual-cognitive expertise. In turn, the effect of expertise is highly dependent on the nature and complexity of the task.Nonetheless, most researchers use simple tasks in their research designs, risking not capturing performance in a meaningful way. We proposed to use a live action setting with a complex task design, representative of real world situations.We combined eye movement registration with collection of immediate retrospective verbal reports. Although the two data sets are not directly comparable, they may be used in a complementary manner, providing a deeper and fuller understanding of the processes underpinning superior performance.Highly-skilled players exhibited more exploratory visual search behaviors than their skilled counterparts, performing more fixations into more locations. They also attended more to functional spaces between two or more areas of the display. Furthermore, highly-skilled players produced more condition concepts and with superior level of sophistication, revealing a deeper and more meaningful attunement to the task constraints. PMID- 24149209 TI - Localised muscle tissue oxygenation during dynamic exercise with whole body vibration. AB - Despite increasing use of whole body vibration during exercise an understanding of the exact role of vibration and the supporting physiological mechanisms is still limited. An important aspect of exercise analysis is the utilisation of oxygen, however, there have been limited studies considering tissue oxygenation parameters, particularly during dynamic whole body vibration (WBV) exercise. The aim of this study was to determine the effect of adding WBV during heel raise exercises and assessing changes in tissue oxygenation parameters of the lateral gastrocnemius using Near Infra Red Spectroscopy (NIRS). Twenty healthy subjects completed ten alternating sets of 15 heel raises (vibration vs. no vibration). Synchronous oxygenation and motion data were captured prior to exercise to determine baseline levels, for the duration of the exercise and 20 sec post exercise for the recovery period. Both vibration and no vibration conditions elicited a characteristic increase in deoxyhaemoglobin and decreases in oxyhaemoglobin, total haemoglobin, tissue oxygenation index and normalised tissue haemoglobin index which are indicative of local tissue hypoxia. However, the addition of vibration elicited significantly lower (p < 0. 001) depletions in oxyhaemoglobin, total haemoglobin, normalised tissue haemoglobin index but no significant differences in deoxyhaemoglobin. These findings suggest that addition of vibration to exercise does not increase the cost of the exercise for the lateral gastrocnemius muscle, but does decrease the reduction in local muscle oxygenation parameters, potentially resulting from increased blood flow to the calf or a vasospastic response in the feet. However, further studies are needed to establish the mechanisms underlying these findings. Key pointsWhole body vibration affects tissue oxygenation of the lateral gastrocnemius.The underlying mechanism could be either increased blood flow or a vasospastic response in the feet.The local metabolic cost of heel raise activity on the lateral gastrocnemius does not appear to be increased by whole body vibration. PMID- 24149210 TI - Painful os Acromiale: Conservative Management in a Young Swimmer Athlete. AB - An os acromiale (OA) arises from a fusion failure of the anterior acromial apophysis. This case report presents the successful management of a painful OA associated to rotator cuff impingement in a competitive swimmer, based on ultrasonographic diagnosis and conservative management. Rest from sport activity, oral anti-inflammatory drugs and previous attempt of treatment of shoulder pain were ineffective. After two months of conservative treatment consisting of avoidance of swimming, local anti-inflammatory, physical therapy with ice, strengthening exercises with elastic bands to strengthen the scapular stabilizing muscles, rotator cuff and lowering humeral head muscles, the patient was pain free and all specific clinical tests for impingement syndrome (Neer, Hawkins, Whipple and Yocum tests) were negative. Digital compression of the OA site was not painful, and the Jobe and Palm-up tests were negative. The athlete returned to swim continuing the rehabilitation exercises, and the successful results were maintained at one year follow up. An unstable and symptomatic OA can be easily diagnosed with ultrasound exam. Rehabilitation for rotator cuff tendinopathies or/and bursitis can be a valid alternative to surgery. Key pointsAn os acromiale (OA) arises from a fusion failure of the anterior acromial apophysis.A correct diagnosis of OA associated to rotator cuff impingement can be performed by ultrasonographic exam.A conservative management of rotator cuff impingement syndrome, associated to OA, can be planned in athletic patients as a valid alternative to surgery. PMID- 24149211 TI - How friendly is a little friendly competition? Evidence of self-interest and empathy during outcome evaluation. AB - Although previous studies have shown that brain potentials recorded from passive observers differ when gambling-task outcomes are delivered to a friend or a stranger, it is unclear how these outcome evaluations are reflected in brain potentials during active competition. The present study recorded event-related potentials (ERP) from 16 normal adults playing an interactive gambling task against both a friend and a stranger. In this task, the P300 was modulated by the feedback valence (gain or loss) and the nature of the interpersonal relationship, such that it was larger when competing against strangers. Regression analyses indicated that empathy to another's personal distress was negatively related to P300 amplitudes when competing against friends. The dFRN, defined as the difference between losses and gains, varied with Perspective-Taking when competing against friends, such that smaller dFRN amplitudes were correlated with increased Perspective-Taking. The modulation of ERP components indicates that interpersonal relationships may influence outcome evaluations in competitive situations. Correlations between ERP components and empathy measures also provide preliminary support of a relationship between one's empathy and the processing of outcomes during competition against a friend. PMID- 24149214 TI - The "sugar pack" health marketing campaign in Los Angeles County, 2011-2012. AB - As part of a comprehensive approach to combating the obesity epidemic, the Los Angeles County Department of Public Health launched the "Sugar Pack" health marketing campaign in fall 2011. Carried out in three stages, the campaign sought to educate and motivate the public to reduce excess calorie intake from sugar sweetened beverage consumption. The primary Sugar Pack creative concepts provided consumers with information about the number of sugar packs contained in sugary drinks. Data from formative market research as well as lessons from previous campaigns in other U.S. jurisdictions informed the development of the materials. These materials were disseminated through a multipronged platform that included paid outdoor media on transit and billboards and messaging using social media (i.e., Twitter, Facebook, YouTube, and sendable e-cards). Initial findings from a postcampaign assessment indicate that the Sugar Pack campaign reached broadly into targeted communities, resulting in more than 515 million impressions. Lessons learned from the campaign suggest that employing health marketing to engage the public can lead to increased knowledge, favorable recognition of health messages, and self-reported intention to reduce sugar-sweetened beverage consumption, potentially complementing other obesity prevention strategies in the field. PMID- 24149215 TI - Reducing the risk of HIV/AIDS in African American college students: an exploratory investigation of the efficacy of a peer educator approach. AB - This study explores the impact of a peer-led HIV intervention, based on the health belief model and social cognitive theory of behavior change, on a sample of African American college students. Certified peer educators were trained by the researcher to implement the four-module HIV prevention intervention. Pre /postassessments revealed that after the intervention, students were less embarrassed to put a condom on themselves or on their partner, were more likely to use a condom, and ask their sex partner if they had ever been tested for HIV. It was concluded that peer education, which focuses on susceptibility, severity, benefits, self-efficacy (components of the health belief model), skill building, and peer influence (social cognitive theory) is an effective strategy in reducing HIV risk behaviors among African American college students. PMID- 24149216 TI - Experience preferred: insights from our newest public health professionals on how internships/practicums promote career development. AB - Universities offering undergraduate degrees in health promotion or health education and/or graduate degrees in public health typically require an internship, practicum, or fieldwork experience. This type of mentored experience is an important aspect of career development for the next generation of public health professionals and benefits not only the students but also the profession and the communities in which they work. This article provides perspectives from four public health professionals who have recently graduated from designated minority-serving institutions and highlights the ways in which internship, practicum, or fieldwork experiences have contributed to their career development. From a career development perspective, internships provide unique opportunities to develop professional networks, practice competencies learned in the classroom, gain experience in different environments, and share lessons learned with others in our field. The diversification of the public health research and practice workforce is increasingly recognized as crucial in building health equity. Internship programs that focus specifically on the academic and professional development of students underrepresented in public health provide experiences that meet or supplement academic requirements, and provide students with real world experience and an expanded network of mentors and role models. PMID- 24149212 TI - Recurrent patterns of DNA methylation in the ZNF154, CASP8, and VHL promoters across a wide spectrum of human solid epithelial tumors and cancer cell lines. AB - The study of aberrant DNA methylation in cancer holds the key to the discovery of novel biological markers for diagnostics and can help to delineate important mechanisms of disease. We have identified 12 loci that are differentially methylated in serous ovarian cancers and endometrioid ovarian and endometrial cancers with respect to normal control samples. The strongest signal showed hypermethylation in tumors at a CpG island within the ZNF154 promoter. We show that hypermethylation of this locus is recurrent across solid human epithelial tumor samples for 15 of 16 distinct cancer types from TCGA. Furthermore, ZNF154 hypermethylation is strikingly present across a diverse panel of ENCODE cell lines, but only in those derived from tumor cells. By extending our analysis from the Illumina 27K Infinium platform to the 450K platform, to sequencing of PCR amplicons from bisulfite treated DNA, we demonstrate that hypermethylation extends across the breadth of the ZNF154 CpG island. We have also identified recurrent hypomethylation in two genomic regions associated with CASP8 and VHL. These three genes exhibit significant negative correlation between methylation and gene expression across many cancer types, as well as patterns of DNaseI hypersensitivity and histone marks that reflect different chromatin accessibility in cancer vs. normal cell lines. Our findings emphasize hypermethylation of ZNF154 as a biological marker of relevance for tumor identification. Epigenetic modifications affecting the promoters of ZNF154, CASP8, and VHL are shared across a vast array of tumor types and may therefore be important for understanding the genomic landscape of cancer. PMID- 24149217 TI - Characterizing bicycle collisions by neighborhood in a large Midwestern city. AB - INTRODUCTION: Local environmental factors provide important contributions to bicycle safety. The purpose of this study was to characterize bicycle collisions by neighborhood in Cincinnati, Ohio. BACKGROUND: The majority of prior bicycle safety research has focused on helmet use, especially among youth. Studies that have considered the neighborhood have centered on the built environment and its facilitation of bicycling (e.g., connectivity of roads and road conditions). Other broad conditions may be associated with injury beyond the use of protective equipment and the physical environment. METHOD: This study sought to determine spatial clustering, local patterning, temporal differences (time of day and season of year), and significant neighborhood-level predictors of bicycle collisions. Bicycle collision data were obtained from the Cincinnati, Ohio Police Department. CONCLUSIONS: This study showed that collisions occur at higher rates in the south-central and southwest neighborhoods of Cincinnati, Ohio. There were seasonal and time-of-day differences with respect to collision rates with summer and afternoon being the most common collision times. Neighborhood ethnicity, population density and presence of public transportation were all significant predictors of bicycle collisions. These findings will be disseminated to local city authorities and bicycle advocacy groups. PMID- 24149220 TI - Placebo effects in competitive sport: qualitative data. AB - The paper examines the placebo effect in sports performance. The possibility that the placebo effect is a more common phenomenon than the quantity of published research would suggest is briefly addressed. It is suggested that the placebo control design often used in sports performance research masks any placebo effects and thus presents a false picture of the mechanisms underlying performance-enhancing interventions in the real world. An electronic survey was sent to 48 competitive, international and professional athletes. Questions related to the placebo effect in competitive sport. Thirty responses were received. Data indicate that the majority (97%) of respondents believe that the placebo effect can exert an influence on sports performance, and that a significant number (73%) have experienced what they defined as a placebo effect. Inductive content analysis reveals that these experiences fall into several categories such as explicit placebo effects, inadvertent false beliefs, ritual and reverse placebo effects. Furthermore, 10 respondents (33%) offer explanations as to the nature of the placebo effect. Again, inductive content analysis reveals that these explanations fall into several categories including deliberate changes in competitive strategy, belief/expectancy, faith in a third party, and marketing. Overall, responses support previous experimental research and anecdotal reports that have found a relationship between belief and sports performance. It is suggested that further research be structured to not simply control for the placebo effect, but to elucidate it. Key pointsA survey of 30 athletes revealed that 73% have experienced a placebo effect in sport.Athletes suggest several potential explanations for these effects.Findings support the idea that placebo effects might be common in sport.Researchers and practitioners should be aware of the possible impact of these effects on research findings and competitive performance. PMID- 24149219 TI - Baseball throwing mechanics as they relate to pathology and performance - a review. AB - It is a commonly held perception amongst biomechanists, sports medicine practitioners, baseball coaches and players, that an individual baseball player's style of throwing or pitching influences their performance and susceptibility to injury. With the results of a series of focus groups with baseball managers and pitching coaches in mind, the available scientific literature was reviewed regarding the contribution of individual aspects of pitching and throwing mechanics to potential for injury and performance. After a discussion of the limitations of kinematic and kinetic analyses, the individual aspects of pitching mechanics are discussed under arbitrary headings: Foot position at stride foot contact; Elbow flexion; Arm rotation; Arm horizontal abduction; Arm abduction; Lead knee position; Pelvic orientation; Deceleration-phase related issues; Curveballs; and Teaching throwing mechanics. In general, popular opinion of baseball coaching staff was found to be largely in concordance with the scientific investigations of biomechanists with several notable exceptions. Some difficulties are identified with the practical implementation of analyzing throwing mechanics in the field by pitching coaches, and with some unquantified aspects of scientific analyses. Key pointsBiomechanical analyses including kinematic and kinetic analyses allow for estimation of pitching performance and potential for injury.Some difficulties both theoretic and practical exist for the implementation and interpretation of such analyses.Commonly held opinions of baseball pitching authorities are largely held to concur with biomechanical analyses.Recommendations can be made regarding appropriate pitching and throwing technique in light of these investigations. PMID- 24149218 TI - NMR studies of nucleic acid dynamics. AB - Nucleic acid structures have to satisfy two diametrically opposite requirements; on one hand they have to adopt well-defined 3D structures that can be specifically recognized by proteins; on the other hand, their structures must be sufficiently flexible to undergo very large conformational changes that are required during key biochemical processes, including replication, transcription, and translation. How do nucleic acids introduce flexibility into their 3D structure without losing biological specificity? Here, I describe the development and application of NMR spectroscopic techniques in my laboratory for characterizing the dynamic properties of nucleic acids that tightly integrate a broad set of NMR measurements, including residual dipolar couplings, spin relaxation, and relaxation dispersion with sample engineering and computational approaches. This approach allowed us to obtain fundamental new insights into directional flexibility in nucleic acids that enable their structures to change in a very specific functional manner. PMID- 24149221 TI - Longitudinal changes in the spinal kinematics of oarswomen during step testing. AB - Earlier studies have investigated the biomechanics of rowing during step testing with a focus on lumbo-pelvic kinematics and force output and noted that these parameters change with work intensity. The aim of this study was to investigate how the biomechanics of the rowing stroke changes over time as a result of coaching and training and to see if these change were related to a change in physiological performance. An electromagnetic motion measuring device in conjunction with a load cell was used to determine the ergometer rowing kinematics of 7 elite international oarswomen during routine step tests over a two year period. Force output was observed to improve over the two year time period, with peak force significantly rising by 40-80 N. This was associated with significant increases in stroke length of between 15 and 19 cm. Both of these are indicative of improvement in performance. Kinematic variables were also observed to change, with greater pelvic rotation and associated lumbar spine motion at the later time point. The findings of this study demonstrate that rowing technique changes with time, and suggest that kinematics measures of rowing technique may be important tools to monitor athletes. Key pointsKinematics of rowing technique change with time and reflect improvements in performanceImproved kinematics appear to be associated with improved rowing efficiencyImprovement in stroke length linked in part to improvements in lumbo-pelvic technique. PMID- 24149222 TI - When does a gait transition occur during human locomotion? AB - When a treadmill accelerates continuously, the walk-run transition has generally been assumed to occur at the instant when a flight phase is first observed, while the run-walk transition has been assumed to occur at the instant of the first double support period. There is no theoretical or empirical evidence to suggest that gait transitions occur at the instant of these events, nor even whether transitions are abrupt events. The purpose of this study was to determine whether the gait transitions during human locomotion occur abruptly, and if so, to determine the instant during a stride at which a transition occurs. The time history of the vertical velocity of the hip (vhip) and the angular velocity of the ankle (omegaankle) were compared between constant speed strides (walking or running) and strides at and near the walk-run and run-walk transitions to determine if and when the transition strides resemble the stride of the corresponding constant speed strides. For both the walk-run and run-walk transitions, the stride prior to the transition resembled the original gait pattern, while the stride following the transition resembled the new gait pattern. The transition stride, however, did not resemble either a walking or a running stride during either of the transition directions. It was concluded that gait transitions are initiated at about midstance of the transition stride, but the transition is not completed until after an adjustment period of between one step and one stride. Thus, gait transitions are not abrupt events during human locomotion. Key pointsGait transitions are not abrupt events.Initiation of a gait transitions occur at about midstance of the transition stride.Gait transitions are completed approximately at the next heelstrike of the ipsilateral foot.Time period between initiation and completion of transition does not resemble either a walk or a run. PMID- 24149223 TI - Effects of Whole-body Vibration Training on Sprint Running Kinematics and Explosive Strength Performance. AB - The aim of this study was to investigate the effect of 6 wk of whole body vibration (WBV) training on sprint running kinematics and explosive strength performance. Twenty-four volunteers (12 women and 12 men) participated in the study and were randomised (n = 12) into the experimental and control groups. The WBV group performed a 6-wk program (16-30 min.d(-1), 3 times a week) on a vibration platform. The amplitude of the vibration platform was 2.5 mm and the acceleration was 2.28 g. The control group did not participate in any training. Tests were performed Pre and post the training period. Sprint running performance was measured during a 60 m sprint where running time, running speed, step length and step rate were calculated. Explosive strength performance was measured during a counter movement jump (CMJ) test, where jump height and total number of jumps performed in a period of 30 s (30CVJT). Performance in 10 m, 20 m, 40 m, 50 m and 60 m improved significantly after 6 wk of WBV training with an overall improvement of 2.7%. The step length and running speed improved by 5.1% and 3.6%, and the step rate decreased by 3.4%. The countermovement jump height increased by 3.3%, and the explosive strength endurance improved overall by 7.8%. The WBV training period of 6 wk produced significant changes in sprint running kinematics and explosive strength performance. Key pointsWBV training.Sprint running kinematics.Explosive strength performance. PMID- 24149224 TI - Eating Attitudes, Perfectionism and Body-esteem of Elite Male Judoists and Cyclists. AB - This study tested the hypothesis that male athletes who feel pressured to maintain a specific body weight present an elevated risk of subclinical eating disorders. Twelve judoists (19.5 +/- 0.5 yr), fifteen cyclists (21.2 +/- 2.8 yr) and seventeen non- competitive students matched for BMI and used as controls (21.8 +/- 1.8 yr) were studied using the Eating Attitudes Test (EAT-26). The Multidimensional Perfectionism Scale, the Body Esteem Scale and the Profile of Mood States were also used to evaluate the relationships between eating disorders and psychological characteristics. Athletes completed the tests during their competitive period and controls completed the same scales at the same time. Scores obtained on EAT-26 differed significantly from the control group on EAT (p < 0.01), Dieting (p < 0.01), and Bulimia scores (p < 0.05). Sixty percent of the athletes used weight loss methods. Self-induced vomiting, use of laxatives and diet pills were reported by 4%, 10%, and 8.5% of them, respectively. Increasing exercise was the primary method used by controls to lose body weight. Athletes reported greater negative feelings about their physical appearance and their Body Weight Satisfaction than controls (p < 0.01, p < 0.05, respectively). Our results also showed that depression mood accounted for 73% of the variance in Bulimia scores and for 64% of the variance in Global EAT scores in athletes. Body-esteem Appearance and depression accounted for a significant proportion of the variance in Dieting scores. There was no difference in perfectionism and mood between athletes and controls. This study highlights that these athletes may tread a fine line between optimal competitive attitudes and detrimental health behaviors. Key pointsPrevalence of eating disorders has become a growing concern among athletic populations, but very little information is available concerning male athletes.This study highlights that these athletes may tread a fine line between optimal competitive attitudes and detrimental health behaviors. PMID- 24149225 TI - Underwater Stroke Kinematics During Breathing and Breath-holding Front Crawl Swimming. AB - The aim of the present study was to determine the effects of breathing on the three - dimensional underwater stroke kinematics of front crawl swimming. Ten female competitive freestyle swimmers participated in the study. Each subject swam a number of front crawl trials of 25 m at a constant speed under breathing and breath-holding conditions. The underwater motion of each subject's right arm was filmed using two S-VHS cameras, operating at 60 Hz, which were positioned behind two underwater viewing windows. The spatial coordinates of selected points were calculated using the DLT procedure with 30 control points and after the digital filtering of the raw data with a cut-off frequency of 6 Hz, the hand's linear displacements and velocities were calculated. The results revealed that breathing caused significantly increases in the stroke duration (t9 = 2.764; p < 0.05), the backward hand displacement relative to the water (t9 = 2.471; p<0.05) and the lateral displacement of the hand in the X - axis during the downsweep (t9 = 2.638; p < 0.05). On the contrary, the peak backward hand velocity during the insweep (t9 = 2.368; p < 0.05) and the displacement of the hand during the push phase (t9 = -2.297; p < 0.05) were greatly reduced when breathing was involved. From the above, it was concluded that breathing action in front crawl swimming caused significant modifications in both the basic stroke parameters and the overall motor pattern were, possibly due to body roll during breathing. Key pointsThe breathing action increases the duration of the total underwater pull.The breathing action increases the absolute backward displacement of the hand.The breathing action caused significant modifications in the overall motor pattern, possibly due to body roll during breathing. PMID- 24149226 TI - Physical Demands of Different Positions in FA Premier League Soccer. AB - The purpose of this study was to evaluate the physical demands of English Football Association (FA) Premier League soccer of three different positional classifications (defender, midfielder and striker). Computerised time-motion video-analysis using the Bloomfield Movement Classification was undertaken on the purposeful movement (PM) performed by 55 players. Recognition of PM had a good inter-tester reliability strength of agreement (kappa= 0.7277). Players spent 40.6 +/- 10.0% of the match performing PM. Position had a significant influence on %PM time spent sprinting, running, shuffling, skipping and standing still (p < 0.05). However, position had no significant influence on the %PM time spent performing movement at low, medium, high or very high intensities (p > 0.05). Players spent 48.7 +/- 9.2% of PM time moving in a directly forward direction, 20.6 +/- 6.8% not moving in any direction and the remainder of PM time moving backward, lateral, diagonal and arced directions. The players performed the equivalent of 726 +/- 203 turns during the match; 609 +/- 193 of these being of 0 degrees to 90 degrees to the left or right. Players were involved in the equivalent of 111 +/- 77 on the ball movement activities per match with no significant differences between the positions for total involvement in on the ball activity (p > 0.05). This study has provided an indication of the different physical demands of different playing positions in FA Premier League match-play through assessment of movements performed by players. Key pointsPlayers spent ~40% of the match performing Pur-poseful Movement (PM).Position had a significant influence on %PM time spent performing each motion class except walking and jogging. Players performed >700 turns in PM, most of these being of 0 degrees -90 degrees .Strikers performed most high to very high intensity activity and most contact situations.Defenders also spent a significantly greater %PM time moving backwards than the other two posi-tions.Different positions could benefit from more specific conditioning programs. PMID- 24149227 TI - MRI Findings Do not Correlate with Outcome in Athletes with Chronic Groin Pain. AB - This trial aimed to assess the value of MRI in the differential diagnosis of chronic groin pain in athletes, a condition caused by various pathologies, the most common being posterior abdominal wall deficiency, osteitis pubis and muscular imbalance. Nineteen subjects with clinically ruled-out hernia and recurrent episodes of exercise-triggered groin pain were assessed. Dynamic MRI was performed under Valsalva manoeuver and at rest within a training- free period and after training activity. Follow-up was performed after 4 years using a questionnaire and physical examination. An incipient hernia was seen in one case, Valsalva manoeuver provoked a visible bulging in 7 others (3 bilateral). Eight athletes showed symphysitis (accompanied by bulging in 3 cases). MRI visualized one hydrocele, one osteoma of the left femur, one enchondroma of the pubic bone, and one dilated left ureter without clinical symptoms or therapeutic relevance. MRI findings after training and during the training free period did not vary. Fifteen participants were available for a follow-up control examination 4 years later - one suffered from ongoing pain, eleven were free of symptoms and three had improvement. However, most of them improved only with changing or reducing training. There were four participants with a specific therapy of their MRI findings. MRI revealed a variety of pathological findings in athletes suffering from chronic groin pain, but it was not reliable enough in differentiating between diagnoses requiring conservative or operative treatment. The MRI examination within the training interval did not have an advantage to that within the training-free period. Further randomized prospective trials with a long follow-up should establish whether MRI findings could be of help in the choice between conservative and surgical treatment for chronic groin pain. Key pointsMRI findings after training and during the train free period did not vary.MRI revealed a variety of pathological findings in athletes suffering from chronic groin pain, but it was not reliable enough in differentiating between diagnoses requiring conservative or operative treatment. PMID- 24149228 TI - The effect of gender and fatigue on the biomechanics of bilateral landings from a jump: peak values. AB - Female athletes are substantially more susceptible than males to suffer acute non contact anterior cruciate ligament injury. A limited number of studies have identified possible biomechanical risk factors that differ between genders. The effect of fatigue on the biomechanics of landing has also been inadequately investigated. The objective of the study was to examine the effect of gender and fatigue on peak values of biomechanical variables during landing from a jump. Thirty-two recreational athletes performed bilateral drop jump landings from a 40 cm platform. Kinetic, kinematic and electromyographic data were collected before and after a functional fatigue protocol. Females landed with 9 degrees greater peak knee valgus (p = 0.001) and 140% greater maximum vertical ground reaction forces (p = 0.003) normalized to body weight compared to males. Fatigue increased peak foot abduction by 1.7 degrees (p = 0.042), peak rectus femoris activity by 27% (p = 0.018), and peak vertical ground reaction force (p = 0.038) by 20%. The results of the study suggest that landing with increased peak knee valgus and vertical ground reaction force may contribute to increased risk for knee injury in females. Fatigue caused significant but small changes on some biomechanical variables. Anterior cruciate ligament injury prevention programs should focus on implementing strategies to effectively teach females to control knee valgus and ground reaction force. Key pointsFemale athletes landed with increased knee valgus and VGRF which may predispose them to ACL injury.Fatigue elicited a similar response in male and female athletes.The effectiveness of sports injury prevention programs may improve by focusing on teaching females to land softer and with less knee valgus. PMID- 24149229 TI - Effects of protein supplementation on muscular performance and resting hormonal changes in college football players. AB - The effect of protein supplementation on athletic performance and hormonal changes was examined in 21 experienced collegiate strength/power athletes participating in a 12-week resistance training program. Subjects were randomly assigned to either a protein supplement (PR; n = 11) or a placebo (PL; n = 10) group. During each testing session subjects were assessed for strength (one repetition maximum [1-RM] bench press and squat), power (Wingate anaerobic power test) and body composition. Resting blood samples were analyzed at weeks 0 (PRE), 6 (MID) and 12 (POST) for total testosterone, cortisol, growth hormone, and IGF 1. No difference was seen in energy intake between PR and PL (3034 +/- 209 kcal and 3130 +/- 266 kcal, respectively), but a significant difference in daily protein intake was seen between PR (2.00 g.kg body mass[BM](-1).d(-1)) and PL (1.24 g.kgBM(-1).d(-1)). A greater change (p < 0.05) in the ? 1-RM squat was seen in PR (23.5 +/- 13.6 kg) compared to PL (9.1 +/- 11.9 kg). No other significant strength or power differences were seen between the groups. Cortisol concentrations were significantly lower at MID for PL and this difference was significantly different than PR. No significant changes were noted in resting growth hormone or IGF-1 concentrations in either group. Although protein supplementation appeared to augment lower body strength development, similar upper body strength, anaerobic power and lean tissue changes do not provide clear evidence supporting the efficacy of a 12-week protein supplementation period in experienced resistance trained athletes. Key pointsCollegiate strength/power athletes may not meet daily recommended energy or protein needs.When athletes are provided a protein supplement they appear to meet the recommended daily protein intake for strength/power athletes.Protein supplementation did augment lower body strength development in experienced strength/power athletes.Results of upper body strength, anaerobic power and lean tissue changes did not support the efficacy of a 12-week protein supplementation period in experienced resistance trained athletes. PMID- 24149230 TI - Strength Performance Assessment in a Simulated Men's Gymnastics Still Rings Cross. AB - Athletes in sports such as the gymnastics who perform the still rings cross position are disadvantaged due to a lack of objective and convenient measurement methods. The gymnastics "cross "is a held isometric strength position considered fundamental to all still rings athletes. The purpose of this investigation was to determine if two small force platforms (FPs) placed on supports to simulate a cross position could demonstrate the fidelity necessary to differentiate between athletes who could perform a cross from those who could not. Ten gymnasts (5 USA Gymnastics, Senior National Team, and 5 Age Group Level Gymnasts) agreed to participate. The five Senior National Team athletes were grouped as cross Performers; the Age Group Gymnasts could not successfully perform the cross position and were grouped as cross Non- Performers. The two small FPs were first tested for reliability and validity and were then used to obtain a force-time record of a simulated cross position. The simulated cross test consisted of standing between two small force platforms placed on top of large solid gymnastics spotting blocks. The gymnasts attempted to perform a cross position by placing their hands at the center of the FPs and pressing downward with sufficient force that they could remove the support of their feet from the floor. Force-time curves (100 Hz) were obtained and analyzed for the sum of peak and mean arm ground reaction forces. The summed arm forces, mean and peak, were compared to body weight to determine how close the gymnasts came to achieving forces equal to body weight and thus the ability to perform the cross. The mean and peak summed arm forces were able to statistically differentiate between athletes who could perform the cross from those who could not (p < 0.05). The force-time curves and small FPs showed sufficient fidelity to differentiate between Performer and Non- Performer groups. This experiment showed that small and inexpensive force platforms may serve as useful adjuncts to athlete performance measurement such as the gymnastics still rings cross. Key pointsStrength-related skills are difficult to assess in some sports and thus require special means.Small force platforms have sufficient fidelity to assess the differences between gymnasts who can perform a still rings cross from those who cannot.Strength assessment via small force platforms may serve as a means of assessing skill readiness, strength symmetry, and progress in learning a still rings cross. PMID- 24149231 TI - Absence of gender differences in the fatigability of the forearm muscles during intermittent isometric handgrip exercise. AB - Previous studies have reported women to have a greater resistance to fatigue than men during sustained handgrip exercise, however, observed gender differences in fatigue has been shown to be a function of contraction type. The purpose of the present study was to determine if gender differences exist in forearm muscle fatigue during intermittent handgrip contractions. Women [n = 11, 23.5 +/- 1.5 (SE) yr] and men (n = 11, 24.1 +/- 1.5 yr) performed intermittent isometric handgrip contractions at a target force of 50% of maximal voluntary contraction (MVC) for 5 s followed by 5 s rest until task failure. Rate of fatigue was calculated from MVCs taken every 2 min during exercise, and recovery of muscle strength was measured in 5 min increments until 45 min post-task failure. Forearm muscle strength was less for women than men (W: 341.5 +/- 11.9 N; M: 480.2 +/- 28.0 N; p <= 0.05). No gender difference was present in time to task failure (W: 793.3 +/- 92.5 s; M: 684.8 +/- 76.3 s) or in the decrease in muscle force generating capacity at task failure (W: -47.6 +/- 1.0%; M: -49.9 +/- 1.3%). Rate of muscle fatigue was found to be similar between women and men (W: -3.6 +/- 0.5 %.min(-1); M: -4.3 +/- 0.6 %.min(-1)) and no gender difference was found in the recovery of muscle strength following task failure. In summary, no gender difference was found in the fatigability of the forearm muscles during intermittent submaximal handgrip contractions, independent of muscle strength. Key pointsThe aim of the present study was to determine if gender differences exist in forearm muscle fatigue during intermittent isometric handgrip contractions.Both unmatched and matched for strength gender comparisons found women and men to exhibit a similar exercise tolerance, rate of fatigue, and recov ery of handgrip force following repeated forearm muscle contractions.These results indicate that maximal handgrip strength is not a key determinant of exercise toler-ance during intermittent isometric forearm exercise performed at a moderate relative contraction inten-sity. PMID- 24149232 TI - Assessment of the quadriceps femoris muscle in women after injury induced by maximal eccentric isokinetic exercise with low angular speed. AB - The objectives of this study were to propose a model for exercise- induced muscle injury by way of a maximal eccentric isokinetic exercise at low angular speed, and assess the time course of functional recovery of the injured quadriceps femoris muscle from the maximal voluntary contraction (MVC) torque and electrical activity (root mean square - RMS and median frequency - MDF). The effectiveness of the proposed eccentric exercise in inducing injury was assessed from the activity of creatine kinase (CK). In addition, the presence of edema of the quadriceps femoris muscle was assessed by a visual inspection of the intensity of the magnetic resonance imaging (MRI) signal. These measurements were carried out before and after the exercise. Ten healthy women (21.9 +/- 1.5) took part in this study. The injury was induced by 4 series of 15 maximal eccentric isokinetic contractions at 5 degrees /s. The MVC torque reduced up to the 4(th) day after the exercise (p < 0.05). The RMS of the vastus medialis oblique (VMO) and the rectus femoris (RF) muscles decreased on the 2(nd) (VMO and RF; p < 0.05) and 3(rd) (RF; p < 0.05) days after. The MDF of the VMO increased immediately after (p < 0.05), whilst the MDF of the RF and VL decreased immediately after (RF; p < 0.05), on the 1(st) (RF and VL; p < 0.05) and on the 2(nd) (VL; p < 0.05) days after. The CK activity increased on the 2(nd) day after (p < 0.05). An increase in the intensity of the MRI signal was observed on the 2(nd) and 7(th) days after. IN CONCLUSION: 1- the eccentric exercise with low angular speed was effective in inducing injury, 2- the quadriceps femoris already started its functional recovery, as shown by the MVC torque and electrical activity, in the first week after the exercise, despite the presence of an increase in the intensity of the MRI signal. Key pointsThe low angular speed eccentric exercise was effec-tive in inducing injury of the quadriceps femoris muscle, and could be used as a muscle injury induc-ing model in future studies;The quadriceps femoris muscle injured by eccentric exercise started its functional recovery in the first week after low angular speed eccentric exercise. PMID- 24149233 TI - The use of neural network technology to model swimming performance. AB - THE AIMS OF THE PRESENT STUDY WERE: to identify the factors which are able to explain the performance in the 200 meters individual medley and 400 meters front crawl events in young swimmers, to model the performance in those events using non-linear mathematic methods through artificial neural networks (multi-layer perceptrons) and to assess the neural network models precision to predict the performance. A sample of 138 young swimmers (65 males and 73 females) of national level was submitted to a test battery comprising four different domains: kinanthropometric evaluation, dry land functional evaluation (strength and flexibility), swimming functional evaluation (hydrodynamics, hydrostatic and bioenergetics characteristics) and swimming technique evaluation. To establish a profile of the young swimmer non-linear combinations between preponderant variables for each gender and swim performance in the 200 meters medley and 400 meters font crawl events were developed. For this purpose a feed forward neural network was used (Multilayer Perceptron) with three neurons in a single hidden layer. The prognosis precision of the model (error lower than 0.8% between true and estimated performances) is supported by recent evidence. Therefore, we consider that the neural network tool can be a good approach in the resolution of complex problems such as performance modeling and the talent identification in swimming and, possibly, in a wide variety of sports. Key pointsThe non-linear analysis resulting from the use of feed forward neural network allowed us the development of four performance models.The mean difference between the true and estimated results performed by each one of the four neural network models constructed was low.The neural network tool can be a good approach in the resolution of the performance modeling as an alternative to the standard statistical models that presume well-defined distributions and independence among all inputs.The use of neural networks for sports sciences application allowed us to create very realistic models for swimming performance prediction based on previous selected criterions that were related with the dependent variable (performance). PMID- 24149234 TI - Number of trials necessary to achieve performance stability of selected ground reaction force variables during landing. AB - The objectives were to determine the number of trials necessary to achieve performance stability of selected ground reaction force (GRF) variables during landing and to compare two methods of determining stability. Ten subjects divided into two groups each completed a minimum of 20 drop or step-off landings from 0.60 or 0.61 m onto a force platform (1000 Hz). Five vertical GRF variables (first and second peaks, average loading rates to these peaks, and impulse) were quantified during the initial 100 ms post-contact period. Test-retest reliability (stability) was determined using two methods: (1) intra-class correlation coefficient (ICC) analysis, and (2) sequential averaging analysis. Results of the ICC analysis indicated that an average of four trials (mean 3.8 +/- 2.7 Group 1; 3.6 +/- 1.7 Group 2) were necessary to achieve maximum ICC values. Maximum ICC values ranged from 0.55 to 0.99 and all were significantly (p < 0. 05) different from zero. Results of the sequential averaging analysis revealed that an average of 12 trials (mean 11.7 +/- 3.1 Group 1; 11.5 +/- 4.5 Group 2) were necessary to achieve performance stability using criteria previously reported in the literature. Using 10 reference trials, the sequential averaging technique required standard deviation criterion values of 0.60 and 0.49 for Groups 1 and 2, respectively, in order to approximate the ICC results. The results of the study suggest that the ICC might be a less conservative, but more objective method for determining stability, especially when compared to previous applications of the sequential averaging technique. Moreover, criteria for implementing the sequential averaging technique can be adjusted so that results closely approximate the results from ICC. In conclusion, subjects in landing experiments should perform a minimum of four and possibly as many as eight trials to achieve performance stability of selected GRF variables. Researchers should use this information to plan future studies and to report the stability of GRF data in landing experiments. Key pointsThe number of trials obtained from a subject in an experiment influences the stability (test-retest reli-ability) and thus validity of the data.One trial might not be representative of a subject's more general performance.Multiple-trial protocols have been recommended by several researchers for a variety of activities, but the number of trials necessary to achieve stabil ity of ground reaction force variables during land-ing has not been examined.Researchers have used different criteria and meth-odologies for determining stability, making com-parisons among studies and activities difficult.In the current study, test-retest intra-class correla-tion coefficient revealed that on average four trials were necessary for stability, while the more con-servative sequential averaging analysis suggested that 12 trials were necessary for stability.Researchers should be aware of the stability of landing data and collect enough trials from each subject within a single testing session to maximize reliability of their data. PMID- 24149235 TI - Electromyographic analysis on a windsurfing simulator. AB - Recent technical innovations in windsurfing have been concentrated on the evolution of the sails and the board. It is only recently that manufacturers have become interested in the wishbones which have evolved becoming thinner and lighter than in the past. A group of six experienced windsurfers participated in an experiment on a land based windsurfing simulator. The goal of the study was to analyze the muscular force used for different techniques for holding onto the wishbone. The test consisted in recording the global electromyographic activity of several muscles on the forearm using surface electrodes. There were two different wind force conditions possible with the simulator: medium (15 kg) and strong (25 kg). Three different wishbone diameters were tested (28, 30 and 32 mm). Four different hand positions on the wishbone were analyzed: leading hand and/or following hand in pronation and/or supination. The electrical muscular activity obtained varied significantly (p < 0.05) depending on the type of grip and according to the diameter of the wishbone. The position with the two hands in supination on a wishbone of 28 mm in diameter was the most economical in muscular terms, notably the flexions of the forearm. The confirmation of the results should lead windsurfers to reconsider the positioning of the wishbone and the adapted posture to waste the least amount of energy possible. Key pointsFemale athletes landed with increased knee valgus and VGRF which may predispose them to ACL injury.Fatigue elicited a similar response in male and female athletes.The effectiveness of sports injury prevention programs may improve by focusing on teaching females to land softer and with less knee valgus. PMID- 24149236 TI - Determining cardiovascular disease risk in elementary school children: developing a healthy heart score. AB - At least 50% of children have one or more cardiovascular disease (CVD) risk factor. We aimed to 1) determine the prevalence of CVD risk factors in a sample of Canadian children, and 2) create a Healthy Heart Score that could be used in a school setting, to identify children with a greater number and severity of CVD risk factors. Children (n = 242, 122M, 120F, aged 9-11 years) were assessed for cardiovascular fitness, physical activity, systolic/diastolic blood pressure, and body mass index (BMI). Biological values were converted to age and sex specific percentiles and allocated a score. Healthy Heart Scores could range between 5 and 18, with lower scores suggesting a healthier cardiovascular profile. Seventy seven children volunteered for blood samples in order to assess the relationship between the Healthy Heart Score and (total cholesterol (TC), high and low-density lipoprotein cholesterol (HDL, LDL) and triglycerides (TG). Fifty eight percent of children had elevated scores for at least 1 risk factor. The group mean Healthy Heart Score was 8 (2.2). The mean score was significantly higher in boys (9 (2.2)) compared with girls (8 (2.1), p < 0.01). A high score was significantly associated with a low serum HDL, a high TC:HDL and a high TG concentration. Our results support other studies showing a high prevalence of CVD risk factors in children. Our method of allocation of risk score, according to percentile, allows for creation of an age and sex specific CVD risk profile in children, which takes into account the severity of the elevated risk factor. Key pointsThere was a high incidence of elevated risk factors for cardiovascular disease in Canadian elementary school children.Physical fitness and physical activity levels were particularly low.In this cohort, boys had increased levels of cardiovascular disease risk factors compared with age-matched girls. PMID- 24149237 TI - Organic nanowire hierarchy over fabric platform for flexible cold cathode. AB - Organic charge transfer (CT) complexes initiated a growing interest in modern electronic devices owing to their easy processability and unique characteristics. In this work, three-dimensional field emitters comprising metal-organic charge transfer complex nanostructures of AgTCNQ and CuTCNQ (TCNQ, 7,7,8,8 tetracyanoquinodimethane) over flexible fabric substrate are realized. Deliberate control over the reaction parameter during organic solid phase reaction leads to modification in structural parameters of the nanowires (i.e. length, diameter) as well as their arrangement atop the carbon fibers. The optimized arrays of AgTCNQ and CuTCNQ nanowires exhibit excellent field electron emission performance with very low turn-on (1.72 and 2.56 V MUm(-1)) and threshold fields (4.21 and 6.33 V MUm(-1)) respectively, which are comparable to those of the best organic field emitters reported to date. The underlying conducting carbon cloth with special woven-like geometry not only offers a flexible platform for nanowire growth, but also provides an additional field enhancement to ease the electron emission. PMID- 24149238 TI - On the internal representation of numerical magnitude and physical size. AB - A nascent idea in the numerical cognition literature--the analogical hypothesis (Pinel, Piazza, Bihan, & Dehaene, 2004)--assumes a common noisy code for the representation of symbolic (e.g., numerals) and nonsymbolic (e.g., numerosity, physical size, luminance) magnitudes. The present work subjected this assumption to various tests from the perspective of General Recognition Theory (GRT; Ashby &Townsend, 1986)--a multidimensional extension of Signal Detection Theory (Green & Swets, 1966). The GRT was applied to the dimensions of numerical magnitude and physical size with the following goals: (a) characterizing the internal representation of these dimensions in the psychological space, and (b) assessing various types of (in)dependence and separability governing the perception of these dimensions. The results revealed various violations of independence and separability with Stroop incongruent, but not with Stroop congruent stimuli. The outcome suggests that there are deep differences in architecture between Stroop congruent and incongruent stimuli that reach well beyond the semantic relationship involved. PMID- 24149239 TI - Attentional adjustment to conflict strength: evidence from the effects of manipulating flanker-target SOA on response times and prestimulus pupil size. AB - Current models of cognitive control assume gradual adjustment of processing selectivity to the strength of conflict evoked by distractor stimuli. Using a flanker task, we varied conflict strength by manipulating target and distractor onset. Replicating previous findings, flanker interference effects were larger on trials associated with advance presentation of the flankers compared to simultaneous presentation. Controlling for stimulus and response sequence effects by excluding trials with feature repetitions from stimulus administration (Experiment 1) or from the statistical analyses (Experiment 2), we found a reduction of the flanker interference effect after high-conflict predecessor trials (i.e., trials associated with advance presentation of the flankers) but not after low-conflict predecessor trials (i.e., trials associated with simultaneous presentation of target and flankers). This result supports the assumption of conflict-strength-dependent adjustment of visual attention. The selective adaptation effect after high-conflict trials was associated with an increase in prestimulus pupil diameter, possibly reflecting increased cognitive effort of focusing attention. PMID- 24149240 TI - Things can be told apart: no influence of response categories and labels on the distance effect in Stroop tasks. AB - A recent finding suggests that people use spatial distances of responses to separate nonspatial information in a simple categorization task like the Stroop task. It was suggested that the larger the distance becomes the easier the categorization will get; indeed, with large distances between response keys a smaller Stroop effect was observed by Lakens and colleagues (2011) as compared with small distances. This is a noteworthy finding albeit the published experiments suffer from two confounds which open the door for explanations of the distance effects in terms of spatial mismatch and recoding strategies. We conceptually replicated the results previously observed without these confounds and confirm the main result of Lakens et al. (2011) in that Stroop effects were significantly smaller if the distance between the response keys increased. PMID- 24149241 TI - The embodied nature of motor imagery processes highlighted by short-term limb immobilization. AB - We investigated the embodied nature of motor imagery processes through a recent use-dependent plasticity approach, a short-term limb immobilization paradigm. A splint placed on the participants' left-hand during a brief period of 24 h was used for immobilization. The immobilized participants performed two mental rotation tasks (a hand mental rotation task and a number mental rotation task) before (pre-test) and immediately after (post-test) the splint removal. The control group did not undergo the immobilization procedure. The main results showed an immobilization-induced effect on left-hand stimuli, resulting in a lack of task-repetition benefit. By contrast, accuracy was higher and response times were shorter for right-hand stimuli. No immobilization-induced effects appeared for number stimuli. These results revealed that the cognitive representation of hand movements can be modified by a brief period of sensorimotor deprivation, supporting the hypothesis of the embodied nature of motor simulation processes. PMID- 24149242 TI - In touch with the Simon effect. AB - Cognitive control has been extensively studied using the auditory and visual modalities. In the current study, a tactile version of the Simon task was created in order to test control mechanisms in a modality that was less studied, to provide comparative and new information. A significant Simon effect--reaction time gap between congruent (i.e., stimulus and response in the same relative location) and incongruent (i.e., stimulus and response in opposite locations) stimuli--provided grounds to further examine both general and tactile-specific aspects of cognitive control in three experiments. By implementing a neutral condition and conducting sequential and distributional analysis, the present study: (a) supports two different independent mechanisms of cognitive control- reactive control and proactive control; (b) reveals facilitation and interference within the tactile Simon effect; and (c) proposes modality differences in activation and processing of the spatially driven stimulus-response association. PMID- 24149243 TI - Refining the continuous tracking paradigm to investigate implicit motor learning. AB - In two experiments we investigated factors that undermine conclusions about implicit motor learning in the continuous tracking paradigm. In Experiment 1, we constructed a practice phase in which all three segments of the waveform pattern were random, in order to examine whether tracking performance decreased as a consequence of time spent on task. Tracking error was lower in the first segment than in the middle segment and lower in the middle segment than in the final segment, indicating that tracking performance decreased as a function of increasing time-on-task. In Experiment 2, the waveform pattern presented in the middle segment was identical in each trial of practice. In a retention test, tracking performance on the repeated segment was superior to tracking performance on the random segments of the waveform. Furthermore, substitution of the repeated pattern with a random pattern (in a transfer test) resulted in a significantly increased tracking error. These findings imply that characteristics of the repeated pattern were learned. Crucially, tests of pattern recognition implied that participants were not explicitly aware of the presence of a recurring segment of waveform. Recommendations for refining the continuous tracking paradigm for implicit learning research are proposed. PMID- 24149244 TI - Increasing predictive estimations without further learning: the peak-shift effect. AB - The peak of learned responding normally occurs at the learning stimulus itself, but can shift to a different stimulus after discriminative learning. This provides important information about the nature of the generalization mechanism, and reveals alternative pathways through which learned responses can increase. Over two experiments, we established the peak-shift effect in a human predictive learning paradigm. Participants were asked to predict the occurrence of a neutral outcome (drawing of a lightning bolt) based on preceding geometrical figures (rings of different sizes). During learning, the middle-sized ring was sometimes followed by the outcome, whereas a larger ring was never followed by the outcome. At test, we presented larger and smaller rings (Experiment 1), or only a slightly smaller ring (Experiment 2). We consistently observed highest prediction of the outcome to the slightly smaller ring. Predictive estimations in humans can reach their height to stimuli that have never actually participated in the learning experiences. We argue that the results are most in line with an associative learning account, rather than an adaptation-level or a rule-learning account. PMID- 24149245 TI - Evaluative stimulus (in)congruency impacts performance in an unrelated task: evidence for a resource-based account of evaluative priming. AB - In two experiments, we assessed evaluative priming effects in a task that was unrelated to the congruent or incongruent stimulus pairs. In each trial, participants saw two valent (positive or negative) pictures that formed evaluatively congruent or incongruent stimulus pairs and a letter that was superimposed on the second picture. Different from typical evaluative priming studies, participants were not required to respond to the second of the valent stimuli, but asked to categorize the letter that was superimposed on the second picture. We assessed the impact of the evaluative (in)congruency of the two pictures on the performance in responding to the letter. In addition, we manipulated attention to the evaluative dimension by asking participants in one experimental group to respond to the valence of the pictures on a subset of trials (evaluative task condition). In both experiments, we found evaluative priming effects in letter categorization responses: Participants categorized the letter faster (and sometimes more correctly) in trials with congruent picture pairs. These effects were present only in the evaluative task condition. These findings can be explained with different resource-based accounts of evaluative priming and the additional assumption that attention to valence is necessary for evaluative congruency to affect processing resources. According to resource-based accounts valence-incongruent trials require more cognitive resources than valence congruent trials (e.g., Hermans, Van den Broeck, & Eelen, 1998). PMID- 24149246 TI - Retaining nurses in the workplace. PMID- 24149247 TI - The art and science of medical interpretation: accessibility and lack of bias are both crucial. PMID- 24149248 TI - Listening to RNs. PMID- 24149249 TI - Interdisciplinary care. PMID- 24149250 TI - ED visits for nonmedical CNS stimulants rise dramatically: attempts to improve school performance or sexual arousal may drive use. PMID- 24149253 TI - Evidence supports midwife-led care models: fewer premature births, epidurals, and episiotomies; greater patient satisfaction. PMID- 24149255 TI - Back pain treatment: common, costly, and getting worse: moving away from accepted standards of care toward more questionable practices. PMID- 24149256 TI - U.S. Obesity: some good news, some bad: a more comprehensive approach is called for. PMID- 24149258 TI - The pros and cons of designating obesity a disease: the new AMA designation stirs debate. PMID- 24149264 TI - Hearing the voices of newly licensed RNs: the transition to practice: a qualitative study suggests that new nurses need more guidance and support than they're getting. AB - OBJECTIVE: The future of nursing depends on newly licensed RNs (NLRNs), who often need help in transitioning from an academic to a clinical setting. This study sought to describe the NLRN's orientation experience and to identify ways of enhancing it. METHODS: Using qualitative methods, a convenience sample of NLRNs was recruited and 21 were interviewed; audio recordings of the interviews were transcribed and validated for accuracy. Interpretative analysis of the transcripts sought to identify major patterns and themes. RESULTS: Four patterns and 10 themes emerged from the data analysis: preceptor variability (with themes of satisfactory and unsatisfactory preceptorship), professional growth and confidence changing with time (with themes of learning through experience, learning to manage time, and learning to communicate), a sense of being nurtured (with themes of support through the program, the preceptor, and peers), and enhancing the transition (with themes of orientation enhancements and human resource enhancements). CONCLUSIONS: These qualitative findings provide insight into the NLRN's transition from student to professional and suggest ways institutions might enhance orientation. Further study is warranted. PMID- 24149266 TI - Postoperative tamoxifen in women with ductal carcinoma in situ. PMID- 24149269 TI - Coccidioidomycosis: a differential diagnosis for visitors to the southwest. PMID- 24149270 TI - Nurse develops runaway intervention program. PMID- 24149271 TI - A community garden: helping patients with diabetes to better care for themselves. PMID- 24149276 TI - Caring for class III obese patients. AB - The Pennsylvania Patient Safety Reporting System is a confidential, statewide Internet reporting system to which all Pennsylvania hospitals, outpatient-surgery facilities, and birthing centers, as well as some abortion facilities, must file information on medical errors.Safety Monitor is a column from Pennsylvania's Patient Safety Authority, the authority that informs nurses on issues that can affect patient safety and presents strategies they can easily integrate into practice. For more information on the authority, visit www.patientsafetyauthority.org. For the original article discussed in this column or for other articles on patient safety, click on "Patient Safety Advisories" and then "Advisory Library" in the left-hand navigation menu. PMID- 24149277 TI - Surprise. PMID- 24149278 TI - Natural gold particles in Eucalyptus leaves and their relevance to exploration for buried gold deposits. AB - Eucalyptus trees may translocate Au from mineral deposits and support the use of vegetation (biogeochemical) sampling in mineral exploration, particularly where thick sediments dominate. However, biogeochemistry has not been routinely adopted partly because biotic mechanisms of Au migration are poorly understood. For example, although Au has been previously measured in plant samples, there has been doubt as to whether it was truly absorbed rather than merely adsorbed on the plant surface as aeolian contamination. Here we show the first evidence of particulate Au within natural specimens of living biological tissue (not from laboratory experimentation). This observation conclusively demonstrates active biogeochemical adsorption of Au and provides insight into its behaviour in natural samples. The confirmation of biogeochemical adsorption of Au, and of a link with abiotic processes, promotes confidence in an emerging technique that may lead to future exploration success and maintain continuity of supply. PMID- 24149279 TI - Simultaneous coinfection with Cryptococcus neoformans and Mycobacterium tuberculosis in an adult. PMID- 24149280 TI - Acute urinary retention from coprostatic colon: an unusual presentation of 'adult Hirschsprung's disease'. PMID- 24149281 TI - Jelly-like pleural effusion. PMID- 24149282 TI - Psychological burden in inpatient relatives: the forgotten side of medical management. AB - BACKGROUND: The burden of the hospital experience is a broad issue that has been evaluated in a particular context of intensive care unit (ICU). It is likely, however, that the load is heavy on families even in other hospital wards and not just in the ICU. The present study was designed to assess the prevalence of anxiety and depression in family members of patients admitted in a general medicine department, and to identify associated factors with those symptoms. METHODS: Patients' and relatives' socio-demographic data and information pertaining to the patients' health characteristics were collected. Family members completed the Arabic version of Hospital Anxiety and Depression Scale (HADS). Associations between anxiety or depression and covariates of interest were investigated using generalized estimating equations, for univariate and multivariate logistic regression analysis. RESULTS: The prevalence of anxiety (55.6%) and depression (41.1%) in family members remains high. The multivariate model identified three groups of factors associated with these symptoms: (i) Patient related: a short length of hospital stay is associated with depression (OR 1.04, 95% CI 1.01-1.08; P = 0.02); (ii) Family related: rural residence is associated with depression (OR 2.56, 95% CI 1.01-6.74; P = 0.04), and female gender is associated with anxiety and depression (OR 2.60, 95% CI 1.41-4.81; P = 0.002), (OR 3.04, 95% CI 1.62-5.70; P = 0.01), respectively; and (iii) Caregiver related: short length of visit (OR 1.08, 95% CI 1.03-1.13; P = 0.002) is associated with anxiety, admission to a share room (OR 2.56, 95% CI 1.25-5.23; P = 0.01) is associated with depression and a need for more information is associated with anxiety and depression (OR 1.78, 95% CI 1.02-3.10; P = 0.04),(OR 1.77, 95% CI 1.01-3.11; P = 0.04), respectively. CONCLUSION: The prevalence of symptoms of anxiety and depression in family members remains high at the end of acute health care. It is hoped that improving the provision of information will decrease the risk of psychological distress. PMID- 24149283 TI - Scrub typhus after a trip to India. PMID- 24149284 TI - Sublingual gas gangrene after dental therapy. PMID- 24149285 TI - Downbeat nystagmus secondary to familial hemophagocytic lymphohistiocytosis. AB - Hemophagocytic lymphohistiocytosis is a rare autosomal recessive disorder characterized by severe inflammation induced by defective natural killer cell function, which triggers a state of highly stimulated but ineffective immune response. This disorder can affect multiple organ systems, and neurologic manifestations include irritability, seizures, impaired consciousness, meningismus, and cranial nerve palsies. We describe a unique case of hemophagocytic lymphohistiocytosis in which downbeat nystagmus developed due to cerebellar swelling with compression of the cervicomedullary junction. PMID- 24149286 TI - Diagnosing giant cell arteritis: is ultrasound enough? PMID- 24149288 TI - The periodicity of Plasmodium vivax and Plasmodium falciparum in Venezuela. AB - We investigated the periodicity of Plasmodium vivax and P. falciparum incidence in time-series of malaria data (1990-2010) from three endemic regions in Venezuela. In particular, we determined whether disease epidemics were related to local climate variability and regional climate anomalies such as the El Nino Southern Oscillation (ENSO). Malaria periodicity was found to exhibit unique features in each studied region. Significant multi-annual cycles of 2- to about 6 year periods were identified. The inter-annual variability of malaria cases was coherent with that of SSTs (ENSO), mainly at temporal scales within the 3-6 year periods. Additionally, malaria cases were intensified approximately 1 year after an El Nino event, a pattern that highlights the role of climate inter-annual variability in the epidemic patterns. Rainfall mediated the effect of ENSO on malaria locally. Particularly, rains from the last phase of the season had a critical role in the temporal dynamics of Plasmodium. The malaria-climate relationship was complex and transient, varying in strength with the region and species. By identifying temporal cycles of malaria we have made a first step in predicting high-risk years in Venezuela. Our findings emphasize the importance of analyzing high-resolution spatial-temporal data to better understand malaria transmission dynamics. PMID- 24149287 TI - Deep sequencing of the T-cell receptor repertoire in CD8+ T-large granular lymphocyte leukemia identifies signature landscapes. AB - New massively parallel sequencing technology enables, through deep sequencing of rearranged T-cell receptor (TCR) Vbeta complementarity-determining region 3 (CDR3) regions, a previously inaccessible level of TCR repertoire analysis. The CDR3 repertoire diversity reflects clonal composition, the potential antigenic recognition spectrum, and the quantity of available T-cell responses. In this context, T-large granular lymphocyte (T-LGL) leukemia is a chronic clonal lymphoproliferation of cytotoxic T cells often associated with autoimmune diseases and various cytopenias. Using CD8(+) T-LGL leukemia as a model disease, we set out to evaluate and compare the TCR deep-sequencing spectra of both patients and healthy controls to better understand how TCR deep sequencing could be used in the diagnosis and monitoring of not only T-LGL leukemia but also reactive processes such as autoimmune disease and infection. Our data demonstrate, with high resolution, significantly decreased diversity of the T cell repertoire in CD8(+) T-LGL leukemia and suggest that many T-LGL clonotypes may be private to the disease and may not be present in the general public, even at the basal level. PMID- 24149289 TI - Review of rule modification in sport. AB - The goal of this qualitative review was to analyze the state of the bibliography about rule modification in sport. In the literature reviewed, there are few studies of rule modification and related aspects. Most studies omit mentioning the purpose of the modifications, but they do refer to the goals of their analysis (improving players' performance, attracting spectators and athletes, attending to commercial pressure, adapting the sport to children's needs and interests, preventing injuries). Eighty percent of the studies did not report the outcome of the previous modifications they analyzed. More than half of the studies (60%) achieved the proposed goals. Nearly two-thirds (63.83%) analyzed the effect of rule modification on game actions occurring during the game or through a test. Most of the studies (91.5%) did not consult the participants. Three-fourths of the studies (74.46%) examined the effect of rule modification without any knowledge of a previous analysis or without any previous analysis, and 74.47% studied rule modification related to internal logic. Modifications to be introduced in a sport should be analyzed through a reflective process before their final introduction. The following points should be considered: establishing goals, respecting the basic rules without modifying them, becoming familiar with players' and coaches' opinions, determining the effect of the modification on a wide spectrum of variables, elaborating useful proposals for the organizations that are responsible for competitions, using more than one type of data, modifying the internal logic and, preferably, the functional rules, and following some basic stages to consolidate rule modification. Key pointsRule modification involves processes that seek change in the game conditions with a certain goal in mind.The rules related to internal logic model the game actions that are characteristic of a sport.Functional rules facilitate achieving the goals.There are few valid research studies on which to base the modifications.Modifications in a sport should be validated after a reflective process before they are introduced. PMID- 24149290 TI - Muscle strength and golf performance: a critical review. AB - Golf has become an increasingly popular sport and a growing body of research trying to identify its main physical requirements is being published. The aim of this review was twofold: first, to examine the existing scientific literature regarding strength training and golf in healthy, non-injured, subjects; and second, to reach conclusions that could provide information on how to design more effective strength training programs to improve golf performance as well as directions for future research. Studies which analyzed the relationship between muscle strength, swing performance variables (club head speed, driving distance, ball speed) and skill (handicap, score) were reviewed. Changes in swing performance following different strength training programs were also investigated. Finally, a critical analysis about the methodologies used was carried out. The results of the reviewed studies seem to indicate that: 1) a positive relationship exists between handicap and swing performance (even though few studies have investigated this issue); 2) there is a positive correlation between skill (handicap and/or score) and muscle strength; and 3) there is a relationship between driving distance, swing speed, ball speed and muscle strength. Results suggest that training leg-hip and trunk power as well as grip strength is especially relevant for golf performance improvement. Studies that analyzed variations in swing performance following resistance-only training programs are scarce, thus it is difficult to prove whether the observed improvements are attributable to changes in strength levels. Many of the studies reviewed presented some methodological errors in their design and not all strength assessment protocols seemed appropriate. Further studies should determine muscle strength needs in relation to final swing performance, using well designed experiments and strict isoinertial assessment protocols which adequately relate to specific golf motion, age and skill level. More studies with elite participants, either professional or amateur, would be especially desirable. Key pointsPOSITIVE CORRELATIONS EXIST BETWEEN: 1) handicap and swing performance variables; 2) muscle strength and skill (handicap and/or golf score); and 3) driving dis-tance, swing speed, ball speed and muscle strength.Leg-hip, trunk power and grip strength seem espe-cially relevant for golf performance improvement.Further research should determine muscle strength needs in relation to final swing performance, using well designed experiments and strict assessment pro-tocols which adequately relate to specific golf mo-tion, age and skill level. PMID- 24149292 TI - Inter-joint coordination in producing kicking velocity of taekwondo kicks. AB - The purpose of this study was to investigate joint kinematics of the kicking leg in Taekwondo and to examine the role of inter-joint coordination of the leg in producing the kicking velocity. A new inter-joint coordination index that encompasses three- dimensional hip and knee motions, was defined and applied to the joint kinematic results. Twelve elite Taekwondo athletes participated in this study and performed the back kick, thrashing kick, turning-back kick and roundhouse kick. Our results indicate that the back kick utilized a combination of hip and knee extension to produce the kicking velocity, and was characterized by a pushlike movement. The thrashing kick and turning-back kick utilized a greater degree of hip abduction than the roundhouse kick and back kick, and included complicated knee motions. The new index successfully categorized the thrashing kick and turning-back kick into a push-throw continuum, indicating a change from negative index (opposite direction) to positive index (same direction) of hip and knee motions at the end of the movement. This strategy of push-throw continuum increases the kicking velocity at the moment of impact by applying a throwlike movement pattern. Key pointsA variety of Taekwondo kicks have unique inter-joint coordination of the kicking leg.The back kick used a combination of hip and knee extension to produce the kicking velocity, and was characterized by a pushlike movement.The new index explained well the inter-joint coordination of three DOF joint motions of two joints in producing kicking velocity (positive values for throwlike movements and negative values for pushlike movements).The index successfully categorized the thrashing kick and turning-back kick into a push-throw continuum. PMID- 24149291 TI - The potential neural mechanisms of acute indirect vibration. AB - There is strong evidence to suggest that acute indirect vibration acts on muscle to enhance force, power, flexibility, balance and proprioception suggesting neural enhancement. Nevertheless, the neural mechanism(s) of vibration and its potentiating effect have received little attention. One proposal suggests that spinal reflexes enhance muscle contraction through a reflex activity known as tonic vibration stretch reflex (TVR), which increases muscle activation. However, TVR is based on direct, brief, and high frequency vibration (>100 Hz) which differs to indirect vibration, which is applied to the whole body or body parts at lower vibration frequency (5-45 Hz). Likewise, muscle tuning and neuromuscular aspects are other candidate mechanisms used to explain the vibration phenomenon. But there is much debate in terms of identifying which neural mechanism(s) are responsible for acute vibration; due to a number of studies using various vibration testing protocols. These protocols include: different methods of application, vibration variables, training duration, exercise types and a range of population groups. Therefore, the neural mechanism of acute vibration remain equivocal, but spinal reflexes, muscle tuning and neuromuscular aspects are all viable factors that may contribute in different ways to increasing muscular performance. Additional research is encouraged to determine which neural mechanism(s) and their contributions are responsible for acute vibration. Testing variables and vibration applications need to be standardised before reaching a consensus on which neural mechanism(s) occur during and post-vibration. Key pointsThere is strong evidence to suggest that acute indirect vibration acts on muscle to enhance force, power, flexibility, balance and proprioception, but little attention has been given to the neural mechanism(s) of acute indirect vibration.Current findings suggest that acute vibration exposure may cause a neural response, but there is little consensus on identifying which neural mechanism(s) are specifically responsible. This is due to a number of studies using various vibration testing protocols (i.e.varying frequencies, amplitudes, durations, and methods of application).Spinal reflexes, muscle tuning and neuromuscular aspects and central motor command are all viable neuromechanical factors that may contribute at different stages to transiently increasing muscular performance.Additional research is encouraged to determine when (pre, during and post) the different neural mechanism(s) respond to direct and indirect vibration stimuli. PMID- 24149293 TI - Repetitive Peripheral Magnetic Stimulation (15 Hz RPMS) of the Human Soleus Muscle did not Affect Spinal Excitability. AB - The electric field induced by repetitive peripheral magnetic stimulation (RPMS) is able to activate muscles artificially due to the stimulation of deep intramuscular motor axons. RPMS applied to the muscle induces proprioceptive input to the central nervous system in different ways. Firstly, the indirect activation of mechanoreceptors and secondly, direct activation of afferent nerve fibers. The purpose of the study was to examine the effects of RPMS applied to the soleus. Thirteen male subjects received RPMS once and were investigated before and after the treatment regarding the parameters maximal M wave (Mmax), maximal H-reflex (Hmax), Hmax/Mmax-ratio, Hmax and Mmax onset latencies and plantar flexor peak twitch torque associated with Hmax (PTH). Eleven male subjects served as controls. No significant changes were observed for Hmax and PTH of the treatment group but the Hmax/Mmax-ratio increased significantly (p = 0.015) on account of a significantly decreased Mmax (p = 0.027). Hmax onset latencies were increased for the treatment group (p = 0.003) as well as for the control group (p = 0.011) while Mmax onset latencies did not change. It is concluded that the RPMS protocol did not affect spinal excitability but acted on the muscle fibres which are part of fast twitch units and mainly responsible for the generation of the maximal M wave. RPMS probably modified the integrity of neuromuscular propagation. Key pointsRPMS probably did not affect spinal excitability.Data suggested that RPMS likely acted on the muscle fibres which are part of fast twitch units and mainly responsible for the generation of the maximal M wave.RPMS probably modified the integrity of neuromuscular propagation. PMID- 24149294 TI - Functional status and inflammation after preseason training program in professional and recreational soccer players: a proteomic approach. AB - The purpose of the study was to determine if an intensive pre- season training program modifies the inflammatory status in professional soccer players and if this inflammatory profile may be associated with the physical state. We compared plasma protein biomarkers, using proteomics, and the physiological state and cardiac function in 12 professional soccer players and 9 recreational soccer players. Reduced cardiac low frequency [LF] after the pre- season training program previous competition with respect to recreational soccer players was found. No differences were found in cardiac high frequency, cardiac high frequency/low frequency ratio, tension index and oxygen volume consumption. Alpha 1-antitrypsin isotype-3, fibrinogen-gamma isotypes-1, 2 and 3 and vitamin-D binding protein isotype-1 were reduced in professionals players compared with those in recreational players. However, an increased content of alpha-1 antitrypsin isotype-6 and alpha-1-antichymotrypsin 1 and 4 were found in professional soccer players. Spearman's analysis showed a positive correlation between LF and fibrinogen-gamma chain isotype 3; but LF was negatively correlated with alpha-antichymotrypsin isotype 4. Professional soccer players submitted to an intensive training showed differences in the content of plasma proteins associated with inflammatory/oxidative stress and thrombosis with respect to recreational soccer players. Proteomics analysis in combination with the analysis of cardiac function assessment may be useful to know more in depth molecular processes associated with sport and intensive exercise. Key pointsProteomics allow us to find differences in the plasma protein content in sportsmen.Just after pre-season training program, professional soccer players showed lower content of circulating proteins associated with inflammation compared to recreational soccer players.Proteomic analysis in combination with the analysis of cardiac function may be useful to know more in depth molecular inflammatory and oxidative processes associated with the sport. PMID- 24149295 TI - Effect of Self-Selected and Induced Slow and Fast Paddling on Atroke Kinematics During 1000 m Outrigger Canoeing Ergometry. AB - This study aimed to identify the effect of different stroke rates on various kinematic parameters during 1000 m outrigger canoeing. Sixteen, experienced female outrigger canoeists completed three 1000 m outrigger ergometer time trials, one trial each using a self-selected, a Hawaiian (<= 55 strokes.min(-1)) and a Tahitian (>= 65 strokes.min(-1)) stroke rate. Stroke rate, stroke length, stroke time, proportion of time spent in propulsion and recovery, torso flexion angle and 'twist' were measured and compared with repeated measures ANOVAs. Stroke rate, stroke length and stroke time were significantly different across all interventions (p < 0.05) despite no difference in the percentage of time spent in the propulsive and recovery phases of the stroke. Stroke length and stroke time were negatively correlated to stroke rate for all interventions (r = 0.79 and -0.99, respectively). Female outrigger canoeists maintain consistent stroke kinematics throughout a 1000 m time trial, most likely as a learned skill to maximize crew paddling synchrony when paddling on-water. While the Hawaiian stroke rate resulted in the greatest trunk flexion movement and 'twist' action, this potential increased back injury risk may be offset by the slow stroke rate and long stroke length and hence slow rate of force development. Key pointsAs outrigger canoeing stroke rate increased, stroke length decreased but the proportion of the stroke time spent in the propulsive phase was kept consistent.The outrigger canoeing technique involved a similar amount of torso flexion-extension movement to rowing, with an additional twisting motion of the torso evidenced, that may increase the risk of back injury.A slower stroke rate, to lessen the rate of force production, may minimize potential back injury in outrigger canoeists and dragon boat paddlers. PMID- 24149296 TI - Substrate Utilization is Influenced by Acute Dietary Carbohydrate Intake in Active, Healthy Females. AB - The present study compared the metabolic responses between a single low carbohydrate (LC) and low-fat (LF) meal followed by an aerobic exercise bout in females. Subjects included 8 active, premenopausal females. Subjects completed a LC and LF testing session. Respiratory gas exchange (RER) measurements were taken for 20 min fasted, for 55 min postprandial (PP), and during 30 min of exercise. Blood was collected for assessment of glucose (G), insulin (IN), triglycerides (TG), and free fatty acids (FFA) during the final 10 min of each time period. The LF meal provided 396 kcal (78% carbohydrate, 7% fat, and 15% protein). The LC meal provided 392 kcal (15% carbohydrate, 68% fat, and 18% protein). No significant differences existed between test meals for fasting blood measurements. PP IN (MUU.mL(-1)) levels were significantly lower following LC compared to LF [10.7 (6.1) vs. 26.0 (21.0)]. Postexercise (PE) FFA (mEq.L(-1)) levels were significantly greater following LC [1.1 (0.3) vs. 0.5 (0.3)]. PE TG (mg.dL(-1)) levels were significantly greater following LC [152.0 (53.1) vs. 114.4 (40.9)]. RER was significantly lower at all time points following LC compared to LF. In moderately active adult females, ingestion of a single LC meal resulted in greater lipid oxidation at rest and during exercise as compared to a single LF meal. Although macronutrient distribution appears to have dictated substrate utilization in the present study, more research is needed regarding the long-term effects of macronutrient redistribution with and without exercise on substrate utilization. Key pointsThe relative carbohydrate content of a single meal has a significant impact on postprandial metabolism and substrate utilization in healthy, active females.A single bout of aerobic exercise performed within an hour of meal ingestion has the potential to modify the postprandial response.Interventions aimed at improving body composition and preventing chronic disease should focus on dietary macronutrient redistribution and postprandial metabolism in concert with exercise training. PMID- 24149297 TI - Seasonal Differences in Physical Activity and Sedentary Patterns: The Relevance of the PA Context. AB - The aim of this pilot study was to characterize seasonal variation in the moderate to vigorous physical activity (MVPA) and sedentary behavior of Portuguese school youth, and understand the influence of activity choices and settings. The participants in this study were 24 students, aged 10-13 years. Accelerometers measured daily PA over 7 consecutive days, in different seasons May - June and January - February. In summer, boys accumulated more minutes in MVPA (928 minutes/week) than girls (793 minutes/week). In winter the pattern was reversed with girls accumulating more activity than boys (736 minutes/week vs. 598 minutes/week). The repeated measures ANOVA revealed significant effects for season (F = 5.98, p = 0.023) and in- school vs. out-of-school (F = 6.53, p = 0.018). Youth were more active in the summer and activity levels were higher after school than in school. Summer season provided relevant contexts for youth physical activity accumulation. Winter season may have been a significant barrier to boy's preferred PA context. Differences in choices of outdoor or indoor PA, after school, explained the gender differences in seasonal activity patterns. Key pointsDetailed temporal profiling of the accelerometer data.Information provided about the context of PA.Boys had different activity patterns with considerably less MVPA and more sedentary behavior during the winter time.Girls had more consistent PA patterns across seasons. PMID- 24149298 TI - Performance and kinematics of various throwing techniques in team-handball. AB - In team-handball competition, the players utilize various throwing techniques that differ in the lower body movements (with and without run-up or jump). These different lower body movements influence changes in the upper body movements and thus also affect the performance. A comprehensive analysis of 3D-kinematics of team-handball throws that may explain these differences in performance is lacking. Consequently, the purpose of this study was (1) to compare performance (ball velocity and throwing accuracy) between the jump throw, standing throw with and without run-up, and the pivot throw; (2) to calculate the influence of kinematic parameters to ball velocity; and (3) to determine if these four throwing techniques differ significantly in kinematics. Three-dimensional kinematic data (angles, angular velocities and their timing, ball velocity and velocity of the center of mass) of 14 elite team-handball players were measured using an 8 camera Vicon MX13 motion capture system (Vicon, Oxford, UK), at 250 Hz. Significant difference was found between the four throwing techniques for ball velocity (p < 0. 001), maximal velocity of the center of mass in goal directed movement (p < 0.001), and 15 additional kinematic variables (p < 0.003). Ball velocity was significant impacted by the run-up and the pelvis and trunk movements. Depending on floor contact (standing vs. jump throws), elite players in the study used two different strategies (lead leg braces the body vs. opposed leg movements during flight) to accelerate the pelvis and trunk to yield differences in ball velocity. However, these players were able to utilize the throwing arm similarly in all four throwing techniques. Key pointsElite team handball players achieved the greatest ball velocity in the standing throw with run-up (100%), followed by the standing throw without run-up (93%), jump throw (92%) and pivot throw (85%).Depending on the floor contact (standing vs. jump throws) the elite players of the study used two different strategies (lead leg braces the body vs. opposed leg movements during flight) to accelerate the pelvis and trunk that caused differences in ball velocity.Elite team-handball players were able to utilize the throwing arm similarly in all four throwing techniques. PMID- 24149299 TI - Changes in quadriceps muscle activity during sustained recreational alpine skiing. AB - During a day of skiing thousands of repeated contractions take place. Previous research on prolonged recreational alpine skiing show that physiological changes occur and hence some level of fatigue is inevitable. In the present paper the effect of prolonged skiing on the recruitment and coordination of the muscle activity was investigated. Six subjects performed 24 standardized runs. Muscle activity during the first two (PREskiing) and the last two (POSTskiing) runs was measured from the vastus lateralis (VL) and rectus femoris (RF) using EMG and quantified using wavelet and principal component analysis. The frequency content of the EMG signal shifted in seven out of eight cases significantly towards lower frequencies with highest effects observed for RF on outside leg. A significant pronounced outside leg loading occurred during POSTskiing and the timing of muscle activity peaks occurred more towards turn completion. Specific EMG frequency changes were observed at certain time points throughout the time windows and not over the whole double turn. It is suggested that general muscular fatigue, where additional specific muscle fibers have to be recruited due to the reduced power output of other fibers did not occur. The EMG frequency decrease and intensity changes for RF and VL are caused by altered timing (coordination) within the turn towards a most likely more uncontrolled skiing technique. Hence, these data provide evidence to suggest recreational skiers alter their skiing technique before a potential change in muscle fiber recruitment occurs. Key pointsThe frequency content of the EMG signal shifted in seven out of eight cases significantly towards lower frequencies with highest effects observed for RF.General muscular fatigue, where additional specific fibers have to be recruited due to the reduced power output of other fibers, did not occur.A modified skiing style towards a less functional and hence more uncontrolled skiing technique seems to be a key issue with respect to the influence on muscle recruitment for applied prolonged skiing session. PMID- 24149300 TI - The effect of regular exercise on development of sarcoma tumor and oxidative damage in mice liver. AB - Regular exercise has the capability of decreasing the incidence and progress of certain cancers. Murine sarcoma, (S-180) cells were transplanted to control (TC), exercise trained (10 week, 1 hour day, 5 times/ week) mice, which had the swimming training terminated at the time of transplantation (ETT), and also to a group of mice that continued to exercise during tumor bearing (ETC). Continuous exercise decreased the size of tumor by about 50%. The accumulation of reactive carbonyl groups (RCD), were not significantly different for any group. The oxidative modification of proteins in the liver of the animals decreased in the exercise- trained non-tumor bearing group compared with control or tumor-bearing groups. No significant alteration was detected in the level of mutant p53. The data indicate that regular exercise retards the development of sarcoma solid tumors and it seems unlikely that massive uncompensated oxidative stress takes place in the tumor. Key pointsRegular exercise has a capability to reduce the inci-dence and progress of certain cancers.Free radicals could act as a promoters and suppres-sors of cancers.Exercise can suppress the development of Sarcoma, but the underlying mechanisms are not known. PMID- 24149301 TI - Effects of whole-body vibration training on bone-free lean body mass and muscle strength in young adults. AB - Resistance training with whole-body vibration (WBV) is becoming increasingly popular as an alternative to conventional resistance training or as supplementary training. Despite its growing popularity, the specific effects of WBV training on muscle morphology, strength, and endurance are not well understood, particularly in young adults. The aim of this study was to determine the effects of WBV training on bone-free lean body mass (BFLBM), and maximal muscle strength and endurance in healthy, untrained, young individuals. Eighteen healthy men and women (21-39 years) were randomly assigned to either a body-weight exercise with WBV (VT) group or a control exercise group without WBV (CON). Participants performed eight exercises per 40- min session on a vibration platform (VT group, frequency = 30-40 Hz; amplitude = 2 mm) twice weekly for 12 weeks. Anthropometry, total and regional BFLBM (trunks, legs, and arms) measured by dual- energy X-ray absorptiometry, and muscle strength and endurance measured by maximal isometric lumbar extension strength, maximal isokinetic knee extension and flexion strength, and the number of sit- ups performed were recorded and compared. Two way repeated-measures ANOVA revealed no significant changes between the groups in any of the measured variables. We conclude that 12 weeks of body weight vibration exercise compared to body weight exercise alone does not provide meaningful changes to BFLBM or muscle performance in healthy young adults. Key pointsA randomized controlled trial was conducted to investigate the effects of body weight exercise combined with whole-body vibration on bone-free lean body mass and maximal muscle strength and endurance in healthy young individuals.Body weight exercises for lower extremities and trunk muscles were performed twice weekly for 12 weeks.Participants in the exercise with whole-body vibration group increased the vibration frequency from 30, 35, to 40 Hz at a constant amplitude of 2 mm during the trial.A 12-week body-weight exercise program with whole-body vibration did not significantly increase bone-free lean body mass in healthy young individuals, and no additional increases in maximal muscle strength and endurance were observed. PMID- 24149302 TI - Integrating pilates exercise into an exercise program for 65+ year-old women to reduce falls. AB - The purpose of this study was to determine if Pilates exercise could improve dynamic balance, flexibility, reaction time and muscle strength in order to reduce the number of falls among older women. 60 female volunteers over the age of 65 from a residential home in Ankara participated in this study. Participants joined a 12-week series of 1-hour Pilates sessions three times per week. Dynamic balance, flexibility, reaction time and muscle strength were measured before and after the program. The number of falls before and during the 12-week period was also recorded. Dynamic balance, flexibility, reaction time and muscle strength improved (p < 0. 05) in the exercise group when compared to the non-exercise group. In conclusion, Pilates exercises are effective in improving dynamic balance, flexibility, reaction time, and muscle strength as well as decreasing the propensity to fall in older women. Key pointsPilates-based exercises improve dynamic balance, reaction time and muscle strength in the elderly.Pilates exercise may reduce the number of falls in elderly women by increasing these fitness parameters. PMID- 24149303 TI - The Relationship between Performance and Trunk Movement During Change of Direction. AB - The purpose of this study was to obtain the trunk kinematics data during a change of-direction task and to determine the relationship between trunk kinematics and the change-of-direction performance. The design of this investigation was a descriptive laboratory study. Twelve healthy male collegiate soccer players (age: 21.3 +/- 1.0 yrs, body mass: 67. 7 +/- 6.7 kg, and height: 1.75 +/- 0.05 m) participated in this study. Participants performed a shuttle run cutting task with a 180 degree pivot as quickly as possible. The shuttle run cutting time, ground contact time during a change-of-direction, and trunk inclination angle were measured. The shuttle run cutting time tends to correlate positively with ground contact time. During the change- of-direction task, the trunk forward inclination angle gradually increased during the first 50% of the stance phase and decreased subsequently whereas the trunk flexed, maintaining a left inclination during the first 40% of the stance phase and changing exponentially in the opposite direction. Forward angular displacement of the trunk between foot contact and maximum trunk inclination correlated positively with the shuttle run cutting time (r = 0.61, p < 0.05) and ground contact time (r = 0.65, p < 0.05). These findings suggest that the change-of-direction performance could be related to the small angular displacement of the trunk during a change of direction. Moreover, it was considered that there might be optimal inclination angles related to change-of-direction performance. Therefore, coaches in field sports should check body posture and trunk movements during changes of direction. Key pointsSmall forward angular displacement of the trunk during a direction change is related to the change-of-direction performance.Trunk stability during a change of direction is an important factor in the change-of-direction performance.There might be a range of optimal angles of trunk inclination during a change of direction.Coaches in field sports should check the body posture and trunk movement of players when they require a change of direction or when they participate in sport-specific change-of-direction training. PMID- 24149304 TI - The Relationship between Goal Orientations, Motivational Climate and Selfreported Discipline in Physical Education. AB - The purpose of this study was to test a motivational model on the links between situational and dispositional motivation and self-reported indiscipline/discipline based on the achievement goals theory. The model postulates that a task-involving motivational climate facilitates self-reported discipline, either directly or mediated by task orientation. In contrast, an ego involving motivational climate favors self-reported indiscipline, either directly or by means of ego orientation. An additional purpose was to examine gender differences according to the motivational model proposed. Children (n = 565) from a large Spanish metropolitan school district were participants in this study and completed questionnaires assessing goal orientations, motivational climates and self-reported discipline. The results from the analysis of structural equation model showed the direct effect of motivational climates on self-reported discipline and provided support to the model. Furthermore, the gender differences found in self-reported discipline were associated with the differences found in the students' dispositional and situational motivation pursuant to the model tested. The implications of these results with regard to teaching instructional actions in physical education classes are discussed. Key pointsA task-involving motivational climate predicts self-reported discipline behaviors, either directly or mediated by task orientation.An ego-involving motivational climate favors self reported undisciplined, either directly or mediated by ego orientation.A significant gender difference was found in the motivational disposition perceived climate and self-reported discipline. PMID- 24149305 TI - Assessment of Subjective Perceived Exertion at the Anaerobic Threshold with the Borg CR-10 Scale. AB - The purpose of this study was to evaluate the anaerobic threshold (AT) with a graphic visual method for estimating the intensity of ventilatory and metabolic exertion and to determine the ratings of perceived exertion (RPE) on the Borg CR 10 scale during a continuous ramp type exercise test (CT-R). Forty healthy, physically active and sedentary young women (age 23.1 +/- 3.52 years) were divided into two groups according to their fitness level: active group (AG) and sedentary group (SG) and were submitted to a CT-R on a cycloergometer with 20 to 25 W/min increments. Shortly before the end of each one-minute period, the subjects were asked to rate dyspnea (RPE-D) and leg fatigue (RPE-L) on the Borg CR-10 scale. After the AT was determined with the graphic visual method, the score that the volunteers gave on the Borg CR10 scale was verified. Data were analyzed using the Mann-Whitney and Spearman correlation tests with the significance level set at 5%. The mean ratings of RPE-L and RPE-D at the AT level were not significantly different between groups (p > 0.05). Significant correlations were found between VO2, heart rate (HR), power output and RPE for both groups. The muscular and respiratory RPE, according to the Borg CR-10 scale, were correlated with the AT, suggesting that scores close to 5, which correspond to a "strong" perception, may be used as parameters for quantifying aerobic exercise intensity for active and sedentary individuals. The similar perception of exercise intensity, which corresponded to the AT of different individuals, makes it possible to prescribe exercise at an intensity equivalent to the AT by means of the RPE. Key pointsInterest in quantitative and systematic determination of the AT is growing, however, qualitative studies measure the AT by perceived exertion, are still unsubstantial.Borg CR-10 scale is a category scale with ratio properties consisting of numbers related to verbal expressions, which allows rate comparison between intensities as well as a determination of intensity levels.Scores close to 5 expressed on the Borg CR-10 scale, which correspond to a "strong" perception, may be used as parameters for quantifying the aerobic exercise intensity of both active and sedentary women. PMID- 24149306 TI - Self-generated coping strategies among muslim athletes during ramadan fasting. AB - The study explored the self-generated coping strategies employed by Muslim athletes from South East Asian region during the Ramadan fasting month. Sixty five National elite Muslim athletes responded to an open-ended question on coping strategies employed during Ramadan fasting. Inductive content analysis identified five general dimensions from 54 meaning units which were abstracted into 14 first order themes and 10 second order themes. The general dimension included four problem-focused coping: training modifications, dietary habits, psychological, rest and recovery, and one emotion-focused coping i.e., self- control. The coping strategies employed were diverse and dynamic in nature and no specific pattern was evident. The most frequently employed strategies were associated with training and dietary habits. Emotion focused coping was the least frequently used by the athletes. Key pointsMuslim athletes employ diverse self -generated coping strategies during Ramadan fasting which can be categorized as anticipatory coping, preventative coping and proactive coping.Frequently employed coping strategies are task focused such as training modifications and adjustments in dietary habits. PMID- 24149307 TI - Age-related, site-specific muscle loss in 1507 Japanese men and women aged 20 to 95 years. AB - We investigated the relationship between age and muscle size in both the appendicular and trunk regions of 1507 Japanese men and women aged 20 to 95 years. Seven hundred twenty-two men (young [aged 20-39 years], n = 211; middle aged [aged 40-59 years], n = 347; and old [aged 6095 years], n = 164) and 785 women (young, n = 207; middle-aged, n = 341; and old, n = 237) were recruited for this cross-sectional study. Muscle thickness (MTH) and subcutaneous fat thickness (FTH) were measured by ultrasound at 8 sites on the anterior and posterior aspects of the body. MTH was expressed in terms relative to limb length (MTH/L) or height (MTH/Ht). Percent body fat was estimated from FTH, and fat-free mass (FFM) was calculated. In men, a graded decrease in FFM was found in all age groups. In women, FFM was similar in the young and middle-aged groups, but was lower in the oldest group. Age was significantly and inversely correlated with FFM in men (r = - 0.358, p < 0.01), but not in women (r = -0.08). On the other hand, age was strongly and inversely correlated with quadriceps MTH/L (men, r = 0.529; women, r = -0.489; both p < 0.001) and abdomen MTH/Ht (men, r = -0.464; women, r = -0.446; both p < 0.001) in both men and women, while there were only weak correlations between age and other lower limb and trunk sites. Our results indicated that sarcopenia is observed as a site-specific loss of skeletal muscle mass, especially for the quadriceps and abdominal muscles, in Japanese men and women aged 20 to 95 years. Key pointsIt is not fully understood whether age related changes in muscle size differ between the appendicular and trunk muscles and/or between muscle groups located in the anterior and posterior aspects of the body in a large population.Age-related muscle loss is observed as a site specific, especially of the quadriceps and abdominal muscles, in Japanese men and women aged 20 to 95 years.The age-related muscle losses are not supported by the muscle activation pattern of normal daily activities evaluated by EMG activity. PMID- 24149308 TI - The lower extremity biomechanics of single- and double-leg stop-jump tasks. AB - The anterior cruciate ligament (ACL) injury is a common occurrence in sports requiring stop-jump tasks. Single- and double-leg stop-jump techniques are frequently executed in sports. The higher risk of ACL injury in single-leg drop landing task compared to a double-leg drop landing task has been identified. However the injury bias between single- and double-leg landing techniques has not been investigated for stop-jump tasks. The purpose of this study was to determine the differences between single- and double-leg stop-jump tasks in knee kinetics that were influenced by the lower extremity kinematics during the landing phase. Ground reaction force, lower extremity kinematics, and knee kinetics data during the landing phase were obtained from 10 subjects performing single- and double leg stop-jump tasks, using motion-capture system and force palates. Greater peak posterior and vertical ground reaction forces, and peak proximal tibia anterior and lateral shear forces (p < 0.05) during landing phase were observed of single leg stop-jump. Single-leg stop-jump exhibited smaller hip and knee flexion angle, and knee flexion angular velocity at initial foot contact with the ground (p < 0.05). We found smaller peak hip and knee flexion angles (p < 0.05) during the landing phase of single-leg stop-jump. These results indicate that single-leg landing may have higher ACL injury risk than double-leg landing in stop-jump tasks that may be influenced by the lower extremity kinematics during the landing phase. Key pointsNon-contact ACL injuries are more likely to occur during the single-leg stop-jump task than during the double-leg stop-jump task.Single-leg stop-jump exhibited greater peak proximal tibia anterior and lateral shear forces, and peak posterior and vertical ground reaction forces during the landing phase than the double-leg stop-jump task.Single-leg stop-jump exhibited smaller hip flexion angle, knee flexion angle, and knee flexion angular velocity at initial foot contact with the ground.Single-leg stop-jump exhibited greater peak knee extension and valgus moment during the landing phase than the double-leg stop-jump task.Single-leg stop-jump extended the hip joint at initial foot contact with the ground. PMID- 24149309 TI - POLYGON - A New Fundamental Movement Skills Test for 8 Year Old Children: Construction and Validation. AB - Inadequately adopted fundamental movement skills (FMS) in early childhood may have a negative impact on the motor performance in later life (Gallahue and Ozmun, 2005). The need for an efficient FMS testing in Physical Education was recognized. The aim of this paper was to construct and validate a new FMS test for 8 year old children. Ninety-five 8 year old children were used for the testing. A total of 24 new FMS tasks were constructed and only the best representatives of movement areas entered into the final test product - FMS POLYGON. The ICC showed high values for all 24 tasks (0.83-0.97) and the factorial analysis revealed the best representatives of each movement area that entered the FMS-POLYGON: tossing and catching the volleyball against a wall, running across obstacles, carrying the medicine balls, and straight running. The ICC for the FMS-POLYGON showed a very high result (0.98) and, therefore, confirmed the test's intra-rater reliability. Concurrent validity was tested with the use of the "Test of Gross Motor Development" (TGMD-2). Correlation analysis between the newly constructed FMS-POLYGON and the TGMD-2 revealed the coefficient of -0.82 which indicates a high correlation. In conclusion, the new test for FMS assessment proved to be a reliable and valid instrument for 8 year old children. Application of this test in schools is justified and could play an important factor in physical education and sport practice. Key pointsAll 21 newly constructed tasks demonstrated high intra-rater reliability (0.83-0.97) in FMS assessment. High reliability was also noted in the FMS-POLYGON test (0.98).A high correlation was found between the FMS-POLYGON and TGMD-2 which is a confirmation of the new test's concurrent validity.The research resolved the problem of long and detailed FMS assessment by adding a new dimension using quick and effective norm-referenced approach but also covering all the most important movement areas.New and validated test can be of great use primarily in school practice for physical education teachers and FMS experts. PMID- 24149310 TI - Higher Precision of Heart Rate Compared with VO2 to Predict Exercise Intensity in Endurance-Trained Runners. AB - The aim of the present study was to assess the precision of oxygen uptake with heart rate regression during track running in highly-trained runners. Twelve national and international level male long-distance road runners (age 30.7 +/- 5.5 yrs, height 1.71 +/- 0.04 m and mass 61.2 +/- 5.8 kg) with a personal best on the half marathon of 62 min 37 s +/- 1 min 22 s participated in the study. Each participant performed, in an all-weather synthetic track five, six min bouts at constant velocity with each bout at an increased running velocity. The starting velocity was 3.33 m.s(-1) with a 0.56 m.s(-1) increase on each subsequent bout. VO2 and heart rate were measured during the runs and blood lactate was assessed immediately after each run. Mean peak VO2 and mean peak heart rate were, respectively, 76.2 +/- 9.7 mL.kg(-1).min(-1) and 181 +/- 13 beats.min(-1). The linearity of the regressions between heart rate, running velocity and VO2 were all very high (r > 0.99) with small standard errors of regression (i.e. Sy.x < 5% at the velocity associated with the 2 and 4 mmol.L(-1) lactate thresholds). The strong relationships between heart rate, running velocity and VO2 found in this study show that, in highly trained runners, it is possible to have heart rate as an accurate indicator of energy demand and of the running speed. Therefore, in this subject cohort it may be unnecessary to use VO2 to track changes in the subjects' running economy during training periods. Key pointsHeart rate is used in the control of exercise intensity in endurance sports.However, few studies have quantified the precision of its relationship with oxygen uptake in highly trained runners.We evaluated twelve elite half-marathon runners during track running at various intensities and established three regressions: oxygen uptake / heart rate; heart rate / running velocity and oxygen uptake / running velocity.The three regressions presented, respectively, imprecision of 4,2%, 2,75% and 4,5% at the velocity associated with the 4 mmol.L(-1) threshold.The results of the present study show that, in highly trained runners, it is possible to use heart rate as an accurate index of the external work rate during sub maximal running speeds. PMID- 24149311 TI - The effect of whole-body vibration frequency and amplitude on the myoelectric activity of vastus medialis and vastus lateralis. AB - The aim of this study was to evaluate the efficiency of training protocols for whole body vibration (WBV) training through the modulation of the frequency and amplitude of vibration. Despite the large number of studies regarding effects of such training, there is still lack of knowledge regarding optimum training protocols. The study analyzed the influence of whole-body vibration parameters (i.e., the frequency and amplitude) on the myoelectric activity of vastus lateralis and vastus medialis in 29 females with the use of electromyography (EMG). The first and second of the eight consecutive trials were performed without vibrations; the remaining six trials were performed in a randomized order on a platform vibrating at different amplitude (2mm and 4mm) and frequency (20 Hz, 40 Hz and 60 Hz) combinations. The results revealed significantly higher EMG amplitude of both muscles during the vibration as compared with the non- vibrated trials (trial 1 and 2). Furthermore, the EMG activity significantly increased both with the amplitude and frequency, being the highest when the frequency and amplitude of reached 60 Hz and 4 mm, respectively. The study aims to determine the optimal vibration parameters in the aspect of purposeful stimulation of chosen leg muscles. Based on the results of the presented investigation, sports trainers and physiotherapists may be able to optimize training programs involving vibration platforms. Key pointsThe observed vibration effect significantly increases both with the amplitude and frequency.Certain frequency/amplitude combinations of mechanical vibrations cause the same level of myoelectric muscle activity. PMID- 24149313 TI - Effectiveness of multimedia-supported education in practical sports courses. AB - Multimedia-assisted teaching and learning have become standard forms of education. In sports, multimedia material has been used to teach practical aspects of courses, such as motor skills. The main goal of this study is to examine if multimedia technology impacts learning in the field of sport motor skill acquisition. This question was investigated during a practical sports education course involving 35 students who participated in a university soccer class. The whole course was split into two groups: Group A was taught traditionally with no assistance of multimedia and Group B was prepared with multimedia-assisted instructional units. To quantify selected skills of soccer technique and tactic, the test subjects performed a specific passing test and a tactical assessment. Furthermore, a ques-tionnaire was used to assess the subjective impressions of the test subjects. All testing instruments were applied before and after a six-week-long teaching period. A comparison of the gathered data between the two groups resulted in no significant differences, neither concerning the results of the technique test nor concerning the tactic test. However, the results of the ques-tionnaire showed a positive agreement among the participants in the usability and assistance of multimedia for the sports practical course. Considering the reviewed conditions, it can be concluded that the use of multimedia content doesn't affect the learning effects. Key pointsMultimedia-assisted learning showed no positive learning effects on technical skills in soccer.Multimedia-assisted learning showed no positive learning effects on tactical skills in soccer.Students participating in practical sports courses have very good attitudes towards the use of multi-media learning material. This may be considered for motivational effects. PMID- 24149312 TI - The effects of intermittent hypoxic training on aerobic capacity and endurance performance in cyclists. AB - The aim of the present study was to evaluate the efficacy of intermittent hypoxic training (IHT) with 95 % of lactate threshold workload (WRLT) on aerobic capacity and endurance performance in well-trained cyclists. Twenty male elite cyclists, randomly divided into a hypoxia (H) group (n=10; age 22 +/- 2.7years; VO2max 67.8 +/- 2.5 ml.kg(-1).min(-1); body height (BH) 1.78 +/- 0.05 m; body mass (BM) 66.7 +/- 5.4kg; fat free mass (FFM) 59.3 +/- 5.1kg; fat content (FAT%) 11.3 +/- 2.1%), and a control (C) group (n = 10; age 23.5 +/- 3. 5years; VO2max 67.7 +/- 2.0 ml.kg(-1).min(-1); BH 1.79 +/- 3.2 m; BM 69.2 +/- 5.5 kg; FFM 63.6 +/- 4.8 kg; FAT% 7.9 +/- 1.94 %) took part in the research project. The training program used during the experiment was the same for the both groups. For three weeks, the subjects in H group performed 3 training sessions per week in normobaric hypoxia environment (IHT - O2 = 15. 2%). During the elemental core of the IHT session, the intensity was set at 95% WRLT for 30-min in 1(st) microcycle, 35-min in 2(nd) microcycle and 40-min in 3(rd) microcycle. The same training procedure was provided in C group, yet the intensity of the main sessions were set at 100% WRLT in the normoxia environment. The results indicate a significant (p < 0.05) increase in VO2max,VO2LT, WRmax, WRLT and change in lactate concentration (?LA) during incremental test in H group. Also a significant (p < 0.05) decrease in time of the time trial was seen, associated with a significant increase (p < 0.05) in average generated power (Pavg) and average speed (Vavg) during the time trial. The intermittent hypoxic training (IHT) applied in this research did not significantly affect the hematological variables considered: number of erythrocytes (RBC), hemoglobin concentration (HGB) and haematocrit value (HCT). Significant blood value increases (p < 0.05) were only observed in MCV in H group. This data suggests that intermittent hypoxic training at lactate threshold intensity and medium duration (30-40min) is an effective training means for improving aerobic capacity and endurance performance at sea level. Key pointsThe efficacy of the intermittent hypoxic training is mostly dependent on volume and intensity of exercise in the hypoxic environment.The observed results suggests that intermittent hypoxic training at lactate threshold intensity and medium duration (30-40min) is an effective training means for improving aerobic capacity and endurance performance at sea level. PMID- 24149314 TI - Handball coaches' perceptions about the value of working competences according to their coaching background. AB - The purpose of this study was to analyze the value attributed to given working competences, by Portuguese handball coaches according to their coaching background, certification level, coaching experience, and level of education. A sample of 207 handball coaches responded to a questionnaire which included demographic characteristics and a scale focused on perceptions of the level of importance attributed to working competences. Data analysis included an exploratory factorial analysis applying Maximum Likelihood Factoring (MLF) and Oblimin rotation. These factors were submitted to a One-way ANOVA and Tukey's post hoc multiple comparisons to analyse coaches' perceptions according to their coaching background. A six factor solution was found where three major domains of competences were highlighted; the first one related to training and competition (e.g. planning and conducting the training, team administration in competition, annual and multi-annual planning, and coaching methodology); the second one related to social and cultural issues and management (e.g. implementation of youth sport development projects, team leadership and coach education) and the third one related to the cognitive background (meta-cognitive competences). The importance ascribed to some working competences was influenced by their coaching experience and certification level. Highly experienced and qualified coaches perceived competences of everyday practice, social, cultural and management issues related to training and competition as more important than the other coaches. This study suggests the need to consider some working competences, until now not explicitly present in the Portuguese coaching education curriculum which could enable coaches to choose the best way to practice/work in a manner that will foster and support their professional development. Key pointsThree major domains of competences were highlighted by Portuguese handball coaches. The first one related to training and competition, the second one related to social and cultural issues and management and the third one related to the cognitive background.The importance ascribed by Portuguese handball coaches to some working competences was influenced by their coaching experience and certification level, as high experienced coaches and coaches with higher certification levels perceived competences related to training and competition of the everyday practice and social, cultural issues and management as more important.The value attributed by Portuguese handball coaches to working competences did not vary according to the coaches' academic education level.Portuguese handball coaches valued the meta-cognitive competences, the competences to implement sport development project and related to annual and multi-annual planning independently of their coaching background. PMID- 24149315 TI - Optimum projection angle for attaining maximum distance in a soccer punt kick. AB - To produce the greatest horizontal distance in a punt kick the ball must be projected at an appropriate angle. Here, we investigated the optimum projection angle that maximises the distance attained in a punt kick by a soccer goalkeeper. Two male players performed many maximum-effort kicks using projection angles of between 10 degrees and 90 degrees . The kicks were recorded by a video camera at 100 Hz and a 2 D biomechanical analysis was conducted to obtain measures of the projection velocity, projection angle, projection height, ball spin rate, and foot velocity at impact. The player's optimum projection angle was calculated by substituting mathematical equations for the relationships between the projection variables into the equations for the aerodynamic flight of a soccer ball. The calculated optimum projection angles were in agreement with the player's preferred projection angles (40 degrees and 44 degrees ). In projectile sports even a small dependence of projection velocity on projection angle is sufficient to produce a substantial shift in the optimum projection angle away from 45 degrees . In the punt kicks studied here, the optimum projection angle was close to 45 degrees because the projection velocity of the ball remained almost constant across all projection angles. This result is in contrast to throwing and jumping for maximum distance, where the projection velocity the athlete is able to achieve decreases substantially with increasing projection angle and so the optimum projection angle is well below 45 degrees . Key pointsThe optimum projection angle that maximizes the distance of a punt kick by a soccer goalkeeper is about 45 degrees .The optimum projection angle is close to 45 degrees because the projection velocity of the ball is almost the same at all projection angles.This result is in contrast to throwing and jumping for maximum distance, where the optimum projection angle is well below 45 degrees because the projection velocity the athlete is able to achieve decreases substantially with increasing projection angle. PMID- 24149316 TI - Step counts and body mass index among 9-14 years old greek schoolchildren. AB - The main purpose of this study was the identification of the current pedometer determined physical activity levels of a large sample of 9 -14 years old Greek schoolchildren and the determination of the association between daily step counts and body mass index through the comparison of step counts among overweight, obese and normal-weight children. A total of 532 children (263 boys and 269 girls) were measured for height and weight. Their activity levels were analyzed using pedometers to measure mean steps for 7 consecutive days. Overweight and obese status was determined using the international reference standard (Cole et al., 2000). According to data analysis mean step counts ranged from 15371 to10539 for boys and from 11536 to 7893 for girls. Steps per day were significantly more for boys compared to girls. Children with normal weight performed significantly more steps per day compared to their overweight and obese classmates. Daily step counts reported in this study for 9 -14 year old schoolchildren were relatively low when compared to step counts from other European countries. Only 33.9% of the participants satisfied the body mass index referenced standards for recommended steps per day. Finally, the results of this study provide baseline information on youth pedometer determined physical activity and on youth body mass index levels. High prevalence of low daily step counts and BMI determined obesity was revealed prompting for further exploration of the relationship between objectively measured physical activity and adiposity in particular for children and adolescents that experience both health risk factors. Key pointsThe mean steps/day taken by both boys and girls in Greece 9-14 years old were 13.446 and 10.656 respectively.Daily step counts tended to be leveled for ages 9-12 years and a significant drop in steps/day was apparent for children aged 13 -14 years.According to the IOTF criteria, 23% of the boys that participated in this study were overweight and 7.8% were obese, while in girls the respective rates were 24.8% and 4.7%.Children with normal weight performed significantly more steps/day than the overweight and the obese children. PMID- 24149317 TI - Effects of 12 weeks of combined exercise training on visfatin and metabolic syndrome factors in obese middle-aged women. AB - Visfatin is a highly expressed protein with insulin-like functions located predominantly in visceral adipose tissue and has been linked to obesity and increased health risks. The purpose of this study was to examine the effects of 12 weeks of combined exercise training on visfatin and metabolic syndrome factors in obese middle-aged women. Subjects were randomly assigned to either a training (n = 10) or control (n = 10) group. The training group exercised for 1 hour, 3 days per week during the 12 week supervised training program. The training program included 3 sets of 10 repetition maximum (10RM) resistance exercise as well as aerobic exercise at an intensity of 60-70% of their heart rate reserve (HRR). The control group was asked to maintain their normal daily activities. Two way (group X time) repeated measured analysis of variance revealed no significant main effects, but there was a significant group X time interaction for the following variables: body weight (p < 0.01), percent body fat (% fat) (p < 0.01), waist hip ratio (WHR) (p < 0.01), diastolic blood pressure (DBP) (p < 0.05), fasting glucose level (p < 0.01), triglyceride levels (TG) (p < 0.01), high density lipoprotein cholesterol levels (HDL-C) (p < 0.05), and visfatin (p < 0.01). In conclusion, the 12 week combined resistance and aerobic training program used in this study was very effective for producing significant benefits to body composition and metabolic syndrome factors, as well as lowering visfatin levels in these obese middle-aged women. Key pointsRecent studies have linked visfatin to obesity and increased health risks.The study was done to investigate the effects of 12 weeks of combined exercise training on visfatin and metabolic syndrome factors in obese middle-aged women.The exercise program used in this study was found to be very effective for lowering visfatin levels in obese middle aged women. PMID- 24149318 TI - Bilateral volleyball-related deformity of the little fingers: mallet finger and clinodactyly mimic. AB - A 14-year-old male high school volleyball player was seen to evaluate right- and left-hand little-finger distal interphalangeal joint deformity and pain. His symptoms began during his second season of competitive play. The distal interphalangeal (DIP) joints of the little fingers flexed 20-30 degrees , and a 10-15 degrees valgus deformity was seen at the same joints. Pain was relieved with rest but returned immediately after playing volleyball, so plain radiographs were obtained. The flexion and valgus deformity was obvious on plain radiographs and through a clinical examination. Thus, a bilateral little-finger distal phalanx base epiphysis injury was seen. This injury is characterized by a biplanar Salter Harris physeal injury; type 5 on anteroposterior radiographs and type 2 on lateral plain radiographs. The deformity occurred as a result of competitive volleyball play. To our knowledge, this is the first reported case of a bilateral biplanar physial injury of the base of distal phalanges of the little fingers. Flexion and valgus deformities of DIP joints are a result of repeated micro traumas around the physis. Key pointsAs a result of repeated micro traumas to the physial region, flexion and valgus deformities of the distal interphalangeal (DIP) joints should be occurred.Sports injuries to the hand often require treatment in orthopedic departments to avoid permanent deformities.Short- or long-term functional results can be gained by simple splinting procedures and abstention from play. PMID- 24149319 TI - Theoretical exploration to second-order nonlinear optical properties of new hybrid complexes via coordination interaction between (metallo)porphyrin and [MSiW11O39](3-) (M=Nb(V) or V(V)) polyoxometalates. AB - The second-order nonlinear optical (NLO) properties of hybrid complexes via coordination interaction between porphyrin and Keggin-type polyoxometalates (POMs) alpha-[MSiW11O39](3-) (M=Nb(V) or V(V)) are investigated by time-dependent density functional theory (TDDFT). The calculated results show that this kind of organic-inorganic hybrid complexes possesses remarkably large molecular second order NLO polarizability, especially for the ZnP3P-C=C-4-Py-[VSiW11O39](3-) (complex 4), which has a computed beta0 value of 261,410 a.u. and might be an excellent second-order NLO material. The effects of substituted metal atom (M), metalloporphyrin, and pi-conjugation on NLO response are analyzed, the substituted metal atom (M) with a large electronegativity, the metalloporphyrin, and the lengthening of pi-conjugation are helpful in enhancing the optical nonlinearity of these systems, which reveal the general rules to design the complexes with large optical nonlinearities. Furthermore, the solvent effect largely affects the first-order hyperpolarizability of the complex, it implies that the second-order polarizabilities increased with the increase of the solvent in polarity. PMID- 24149320 TI - Insight into the mechanism of aminomutase reaction: a case study of phenylalanine aminomutase by computational approach. AB - The Taxus canadensis phenylalanine aminomutase (TcPAM) catalyze the isomerization of (S)-alpha-phenylalanine to the (R)-beta-isomer. The active site of TcPAM contains the signature 5-methylene-3,5-dihydroimidazol-4-one (MIO) prosthesis, observed in the ammonia lyase class of enzymes. Up to now, there are two plausible mechanisms for these MIO-dependent enzymes, i.e., the amino-MIO adduct mechanism and the Friedel-Crafts-type reaction mechanism. In response to this mechanistic uncertainty, the phenylalanine aminomutase mechanism was investigated by using density functional methods. The calculation results indicate that: (1) the reaction prefers the amino-MIO adduct mechanism where the 2,3-amine shift process contains six elementary steps; (2) the ammonia elimination step proceeds through an E2 mechanism; (3) a single C1Calpha bond rotation of 180 degrees in the cinnamate skeleton occurs in the active site prior to the rebinding of NH2 group to the cinnamate. This can be used to explain the stereochemistry of the TcPAM reaction product which is contrary to those of the PaPAM and SgTAM enzymes. Based on these calculations, the roles of important residues in the active site were also elucidated. PMID- 24149321 TI - Associations between the Rho kinase-1 catalytic and PH domain regulatory unit. AB - Rho-associated kinase, or ROCK, is an important mediator of ventricular remodeling in cardiac hypertrophy. It has a kinase catalytic domain, a coiled coil domain and a Pleckstrin-Homology domain (PH domain) with a C1 domain insert. The C-terminal region including the PH domain and C1 domain insert is involved in an autoregulatory role for ROCK. We sought to evaluate whether a self association complex could form using computational docking approaches. We found that both the PH domain and the C1 domain could dock with the catalytic domain and we further found that they could dock in poses that are complementary to each other forming a three domain complex. We also confirmed a binding response using a surface plasmon resonance experimental approach. Information about the regulation of ROCK might lead to new strategies to develop lead inhibitor compounds to modulate cardiac remodeling. PMID- 24149322 TI - Reversible oxidation of a water-soluble tellurophene. AB - Oxidation of a novel water-soluble tellurophene [2,5-tellurophene bisphenoxy(octaethylene glycol monomethyl ether)] by peroxide is electrochemically reversible. This tellurophene can also be oxidized by self photosensitized singlet oxygen in an aqueous solution. The oxidized tellurophenes are studied by optical absorption spectroscopy, (1)H NMR, and electrochemistry. PMID- 24149324 TI - Biomechanical characteristics and determinants of instep soccer kick. AB - Good kicking technique is an important aspect of a soccer player. Therefore, understanding the biomechanics of soccer kicking is particularly important for guiding and monitoring the training process. The purpose of this review was to examine latest research findings on biomechanics of soccer kick performance and identify weaknesses of present research which deserve further attention in the future. Being a multiarticular movement, soccer kick is characterised by a proximal-to-distal motion of the lower limb segments of the kicking leg. Angular velocity is maximized first by the thigh, then by the shank and finally by the foot. This is accomplished by segmental and joint movements in multiple planes. During backswing, the thigh decelerates mainly due to a motion-dependent moment from the shank and, to a lesser extent, by activation of hip muscles. In turn, forward acceleration of the shank is accomplished through knee extensor moment as well as a motion-dependent moment from the thigh. The final speed, path and spin of the ball largely depend on the quality of foot-ball contact. Powerful kicks are achieved through a high foot velocity and coefficient of restitution. Preliminary data indicate that accurate kicks are achieved through slower kicking motion and ball speed values. Key pointsSoccer kick is achieved through segmental and joint rotations in multiple planes and via the proximal-to-distal sequence of segmental angular velocities until ball impact. The quality of ball - foot impact and the mechanical behavior of the foot are also important determinants of the final speed, path and spin of the ball.Ball speed values during the maximum instep kick range from 18 to 35 msec(-1) depending on various factors, such as skill level, age, approach angle and limb dominance.The main bulk of biomechanics research examined the biomechanics of powerful kicks, mostly under laboratory conditions. A powerful kick is characterized by the achievement of maximal ball speed. However, maximal ball speed does not guarantee a successful kick: in each case, the ball must reach the target. As already explained, when the player is instructed to hit the ball accurately, joint and segment velocities are lower as opposed to a fast and powerful kick performance. It is therefore apparent that future research should focus on biomechanics of fast but accurate kicking. PMID- 24149323 TI - Epigenetic regulation of DACH1, a novel Wnt signaling component in colorectal cancer. AB - Colorectal cancer (CRC) is one of the common malignant tumors worldwide. Both genetic and epigenetic changes are regarded as important factors of colorectal carcinogenesis. Loss of DACH1 expression was found in breast, prostate, and endometrial cancer. To analyze the regulation and function of DACH1 in CRC, 5 colorectal cancer cell lines, 8 cases of normal mucosa, 15 cases of polyps and 100 cases of primary CRC were employed in this study. In CRC cell lines, loss of DACH1 expression was correlated with promoter region hypermethylation, and re expression of DACH1 was induced by 5-Aza-2'-deoxyazacytidine treatment. We found that DACH1 was frequently methylated in primary CRC and this methylation was associated with reduction in DACH1 expression. These results suggest that DACH1 expression is regulated by promoter region hypermethylation in CRC. DACH1 methylation was associated with late tumor stage, poor differentiation, and lymph node metastasis. Re-expression of DACH1 reduced TCF/LEF luciferase reporter activity and inhibited the expression of Wnt signaling downstream targets (c-Myc and cyclinD1). In xenografts of HCT116 cells in which DACH1 was re-expressed, tumor size was smaller than in controls. In addition, restoration of DACH1 expression induced G2/M phase arrest and sensitized HCT116 cells to docetaxel. DACH1 suppresses CRC growth by inhibiting Wnt signaling both in vitro and in vivo. Silencing of DACH1 expression caused resistance of CRC cells to docetaxel. In conclusion, DACH1 is frequently methylated in human CRC and methylation of DACH1 may serve as detective and prognostic marker in CRC. PMID- 24149325 TI - The role of echocardiography in the differential diagnosis between training induced myocardial hypertrophy versus cardiomyopathy. AB - Increased myocardial mass due to regular high-volume intense exercise training (so-called athlete's heart) is not uncommon. Although directly correlated with the extent of training loads, myocardial hypertrophy is not present exclusively in well-trained or elite athletes. Athlete's heart is considered a physiological phenomenon with no known harmful consequences. However, extreme forms of myocardial hypertrophy due to endurance training resemble a structural heart disease such as hypertrophic cardiomyopathy, a condition associated with substantially increased risk of cardiac event. Endurance sports such as rowing and road cycling, rather than strength/power training, are most commonly associated with left ventricular (LV) wall thickness compatible with hypertrophic cardiomyopathy. The differentiation between physiological and maladaptive cardiac hypertrophy in athletes is undoubtedly important, since untreated cardiac abnormality often possesses a real threat of premature death due to heart failure during intense physical exertion. Luckily, the distinction from pathological hypertrophy is usually straightforward using transthoracic echocardiography, as endurance athletes, in addition to moderately and proportionally thickened LV walls with normal acoustic density, tend to possess increased LV diameter. In more uncertain cases, a detailed evaluation of myocardial function using (tissue) Doppler and contrast echocardiography is effective. When a doubt still remains, knowledge of an athlete's working capacity may be useful in evaluating whether the insidious cardiac pathology is absent. In such cases cardiopulmonary exercise testing typically resolves the dilemma: indices of aerobic capacity are markedly higher in healthy endurance athletes compared to patients. Other characteristics such as a decrease of LV mass due to training cessation are also discussed in the article. Key pointsTransthoracic echocardiography is still the most common relevant differentiation technique applied to distinguish athlete's heart from the cardiomyopathy.Conventional echocardiographic criteria such as left ventricular chamber size and diastolic function parameters are to be regarded first when making differential diagnosis between substantially increased wall thickness in athlete's heart (i.e. physiological adaptation) versus a disease (usually hypertrophic cardiomyopathy).When conventional echocardiographic parameters fail to diagnose the nature of myocardial hypertrophy, other differentiation criteria such as aerobic fitness, cardiac performance in response to physical exertion, and changes in echocardiographic parameters due to detraining, must be taken into consideration.Tissue Doppler, contrast and three dimensional imaging are state-of-the-art echocardiographic techniques which have recently appeared in the differential diagnostics. PMID- 24149326 TI - Young athletes' motivational profiles. AB - The aim of this study was to examine the relationship between motivational characteristics and dispositional flow. In order to accomplish this goal, motivational profiles emerging from key constructs within Achievement Goal Theory and Self-Determination Theory were related to the dispositional flow measures. A sample of 413 young athletes (Age range 12 to 16 years) completed the PMCSQ-2, POSQ, SMS and DFS measures. Cluster analysis results revealed three profiles: a "self-determined profile "characterised by higher scores on the task-involving climate perception and on the task orientation; a "non-self-determined profile", characterised by higher scores on ego-involving climate perception and ego orientation; and a "low self-determined and low non-self-determined profile "which had the lowest dispositional flow. No meaningful differences were found between the "self-determined profile "and the "non-self-determined profile "in dispositional flow. The "self-determined profile "was more commonly associated with females, athletes practising individual sports and those training more than three days a week. The "non-self-determined profile "was more customary of males and athletes practising team sports as well as those training just two or three days a week. Key pointsThe "self-determined profile "was characterized by high task orientation, high task-involving climate perception and was more commonly associated with females, athletes practising individual sports and those training more than three days a week.The "non-self-determined profile "was characterized by high ego orientation, high ego-involving climate perception and was more customary of males and athletes practising team sports as well as those training two or three days a week.Both profiles revealed a moderate tendency toward dispositional flow, with no significant differences between the two profiles.The "low self-determined and low non-self-determined profile "had low scores on all of the variables in the study. PMID- 24149327 TI - The relationship between imagery type and collective efficacy in elite and non elite athletes. AB - This study investigated the relationship between imagery function and individual perceptions of collective efficacy as a function of skill level. Elite (n = 70) and non elite (n = 71) athletes from a number of interactive team sports completed the Sport Imagery Questionnaire (SIQ) and the Collective Efficacy Inventory (CEI). Multiple hierarchical regression analysis was then used to examine which SIQ sub-scales predicted individual perceptions of collective efficacy. For the elite sample, Motivational General-Mastery (MG-M) imagery accounted for approximately 17% of the variance in collective efficacy scores. No significant predictions were observed in the non elite sample. The findings suggest MG-M imagery as a potential technique to improve levels of collective efficacy although competitive level may moderate the effectiveness of such interventions. Key pointsAs imagery is an individual intervention, an examination of individual perceptions of collective efficacy was most appropriate.Elite athletes who use more MG-M imagery also have higher individual perceptions of collective efficacy.For non-elite athletes, none of the imagery functions tested predicted individual perceptions of collective efficacy.Performance accomplishments provided by MG-M imagery may increase individual perceptions of collective efficacy.Future research should investigate further the effects of imagery intervention programmes on collective efficacy beliefs. PMID- 24149328 TI - Is blood lactate removal during water immersed cycling faster than during cycling on land? AB - The aim of the present study was to compare lactate removal during active recovery performed during cycling in water immersion (CW) and during cycling on land (CL), after a similar exercise bout in male adults. Eleven healthy and physically active men, aged between 20 and 26 years old participated in the experiment. Before the experimental tests, the ventilatory threshold of the subjects was determined. Each subject completed the experimental tests twice, with one week separating the two periods of experiment. The subjects exercised on the treadmill during 6 min at a speed 10% above the speed corresponding to their ventilatory threshold. Subsequently, the subjects recovered from the exercise bout either on a stationary bike (CL) or on a aquatic-specific bike (CW). On the subsequent week the subjects performed the same protocol but with a different recovery condition. Recovery condition assignment for the first test was counterbalanced (six subjects started with one condition and five with the other). Capillary blood samples were collected after each test and during the recovery period (at 3, 6, 9 and 15 minutes) and blood lactate was measured. The blood lactate values during CW were lower than during CL and significant differences were observed at the 6(th) minute (p <= 0.05) and at the 15(th) minute of recovery (p <= 0.05). Therefore, we may conclude that active recovery using cycling in water immersion may be more efficient than cycling on land for blood lactate removal. Key pointsPrevious studies have found positive effects of half liquid environment on blood lactate removal.However, few studies have compared lactate removal in half liquid and in dry land conditions with the use of stationary bikes.We have compared the lactate removal during active recovery on half-liquid cycling and active recovery on dry land cycling after a similar exercise bout in male adults.The blood lactate values during the recovery were lower after half-liquid cycling when compared with dry land cycling and significant differences were observed at the 6(th) minute and at the 15(th) minute of recovery.We may conclude that active recovery using half-liquid cycling may be more efficient than dry land cycling for blood lactate removal. PMID- 24149329 TI - Functional model of monofin swimming technique based on the construction of neural networks. AB - In this study we employed an Artificial Neuronal Network to analyze the forces flexing the monofin in reaction to water resistance. In addition we selected and characterized key kinematic parameters of leg and monofin movements that define how to use a monofin efficiently and economically to achieve maximum swimming speed. By collecting the data recorded by strain gauges placed throughout the monofin, we were able to demonstrate the distribution of forces flexing the monofin in a single movement cycle. Kinematic and dynamic data were synchronized and used as entry variable to build up a Multi-Layer Perception Network. The horizontal velocity of the swimmer's center of body mass was used as an output variable. The network response graphs indicated the criteria for achieving maximum swimming speed. Our results pointed out the need to intensify the angular velocity of thigh extension and dorsal flexion of the feet, to strengthen velocity of attack of the tail and to accelerate the attack of the distal part of the fin. The other two parameters which should be taken into account are dynamics of tail flexion change in downbeat and dynamics of the change in angle of attack in upbeat. Key pointsThe one-dimensional structure of the monofin swimming creates favorable conditions to study the swimming technique.Monofin swimming modeling allows unequivocal interpretation of the propulsion structure. This further permits to define the mechanisms, which determine efficient propulsion.This study is the very first one in which the Neuronal Networks was applied to construct a functional/applicable to practice model of monofin swimming.The objective suggestions lead to formulating the criteria of monofin swimming technique, which plays the crucial role in achieving maximal swimming speed.Theoretical and empirical (realistic) verification created by parameters indicate by neural networks, paves the way for creating suitable models, which could be employed for other sports. PMID- 24149330 TI - Prospective epidemiological study of basketball injuries during one competitive season: ankle sprains and overuse knee injuries. AB - This prospective cohort study aims to assess the overall incidence of acute and overuse basketball injuries and identifies risk factors associated with ankle sprains and knee overuse injuries. In total, 164 senior players (23.7 years +/- 7.0) of all levels of play, and including both men and women, participated voluntarily during one season. A total of 139 acute and 87 overuse injuries were reported, resulting in an overall injury incidence of 9.8 (8.5 to 11.1) per 1,000 hours. The incidence of acute injuries was 6.0/1,000 hours. Ankle sprains (n = 34) accounted for most acute injuries, and 52.9% of all players with ankle sprains reported a previous ankle sprain. Relative Risks (RR) and Odds Ratio (OR) with their 95% Confidence Intervals (CI) were calculated to determine significant differences. Landing on an opponent's foot was the major inciting event, significantly more so than non contact mechanisms (RR=2.1 [95% CI: 1.0-4.2]). Acute knee injuries resulted in the highest playing absence (7 weeks 2 days +/- 9 weeks 1 day). Overuse injury incidence was 3.8/1,000 hours. The knee (1.5/1,000 hours) was the most common site. Forward players sustained less knee overuse injuries than players of all other playing positions, and significantly less than center players (OR=0.5 [95% CI: 0.2-0.9]). This study showed that ankle sprains and overuse knee injuries are the most common injuries in basketball, both accounting for 14.8%. Injury prevention programmes however should not concentrate on those injuries only, but might one to consider that acute knee injuries, in spite of the fact that they occur less frequently, also merit further research. Key pointsAnkle sprains are the most common acute injuries in basketball with the inciting event being landing on an opponent's foot or changing direction.Anterior knee pain is the most common overuse injury. Etiologic factors are well described in literature, but prevention strategies are lacking.Acute knee injuries account for the highest inactivity and should therefore also be prevented.Most of the injuries are due to contact mechanisms and therefore the definition of basketball as a non contact sport is questionable.Highest injury risks are found in women and in the lower levels. PMID- 24149331 TI - Efficacy of a sports specific balance training programme on the incidence of ankle sprains in basketball. AB - The purpose of the study was to determine the efficacy of a 22- week prescribed sports specific balance training programme on the incidence of lateral ankle sprains in basketball players. A controlled clinical trial was set up. In total 54 subjects of six teams participated and were assigned to either an intervention (IG) or a control group (CG). The IG performed a prescribed balance training programme on top of their normal training routine, using balance semi-globes. The programme consisted of 4 basketball skills each session and its difficulty was progressively thought-out. The intervention lasted 22 weeks and was performed 3 times a week for 5 to 10 minutes. Efficacy of the intervention on the incidence of lateral ankle sprains was determined by calculating Relative Risks (RR, including their 95% Confidence Intervals or CI) and incidence rates expressed per 1000h. RR (95% CI) showed a significantly lower incidence of lateral ankle sprains in the IG compared to the CG for the total sample (RR= 0.30 [95% CI: 0.11 0.84]) and in men (RR= 0.29 [95% CI: 0.09-0.93]). The difference in RR was not confirmed when examining the incidence rates and their 95%CI's, which overlapped. The risk for new or recurrent ankle sprains was slightly lower in the IG (new: RR= 0.76 [95% CI: 0.17-3.40]; re-injury: RR= 0.21 [95% CI: 0.03-1.44]). Based on these pilot results, the use of balance training is recommended as a routine during basketball activities for the prevention of ankle sprains. Key pointsWe could not establish a true preventive effect of the training, most likely due to the low sample size.Although not significant, large differences in incidence rates were found between the intervention and control group and relative risks showed a significant difference.Our results were in line with previous results and therefore proprioceptive balance training should become a part of the training routine.Concerning this study and the literature, proprioceptive balance training should last 5-15 minutes and should be performed 2 to 3 times a week. PMID- 24149332 TI - Angiotensin I converting enzyme gene polymorphism and exercise trainability in elderly women: an electrocardiological approach. AB - Angiotensin I converting enzyme (ACE) gene Insertion / Deletion (I/D) polymorphism is associated with exercise trainability and exercise induced left ventricular hypertrophy. However, it is unclear whether this polymorphism influences exercise trainability in the elderly, and the electrocardiological alterations by exercise training is unknown among the genotypes. We herein investigated the association between ACE gene insertion/deletion (I/D) polymorphism, exercise trainability and the electrocardiological alternations by exercise in elderly women. Eighty four elderly women participated in this study. In all subjects the leg extension power (LEP) and lactate threshold (LT) were determined in order to evaluate the muscle strength, aerobic capacity and to also select the appropriate training intensity for each individual. They performed bench step exercise training for 12 weeks. A resting electrocardiogram was recorded for the obtained QTc interval in before and after the program. The baseline of aerobic capacity was higher in I/I than that in I/D, and the QTc interval was shorter in I/I than that in I/D. All other characteristics were similar among the genotypes. The QTc interval tended to be shorten only in the D/D. Furthermore, the value of the QTc interval change showed a significant difference between the I/I and D/D genotype after the program. The LT and LEP demonstrated a similar response among the genotypes. The D allele of ACE gene I/D polymorphism may therefore play a role in the electrocardiological aspect during exercise training, however, it was not found to influence the aerobic capacity. Key pointsThe D allele of ACE gene I/D polymorphism may play a role in the electrocardiological aspects during exercise trainingACE gene I/D polymorphism was not determined the aerobic capacity and leg strength in elderly people.The ACE gene I/D polymorphism did not influence aerobic and strength trainability in elderly people. PMID- 24149333 TI - Igf-I and fgf-2 responses to wingate anaerobic test in older men. AB - REDUCED ACTIVITY OF THE POTENT ANABOLIC EFFECTORS: insulin-like growth factor-I (IGF-I) and fibroblast growth factor-2 (FGF-2), play a role in aging associated muscle loss. The effect of fitness level on IGF-I and FGF-2 responses to all-out anaerobic exercise in older men was studied. Twenty four healthy older males: 12 higher fit (58 +/- 1y) and 12 lower fit (59 +/- 1y) underwent the Wingate anaerobic test. Serum levels of IGF-I and FGF-2 were measured before, immediately after exercise, and 50 min into recovery. Immediately post exercise, the average peak power output and serum lactate were higher (p < 0.05) in the higher fit (446.0 +/- 14. 9 kgm.min(-1) for mean (+/- SD) peak power and 12.6 +/- 1.1 mml.l( 1) for lactate) compared with the lower fit individuals (284.0 +/- 6.5 kgm.min( 1) and 8.5 +/- 0.7 mml.l(-1), respectively). Pre-exercise IGF-I was lower and FGF 2 was higher in the higher fit (335.0 +/- 54.0 ng.ml(-1) and 1.6 +/- 0.1 ng.ml( 1), respectively) compared with lower fit individuals (402.0 +/- 50.0 ng.ml(-1) and 1.4 +/- 0.2 ng.ml(-1), respectively). Following the anaerobic exercise, in both groups, FGF-2 decreased dramatically (p < 0.05); in the higher fit individuals FGF-2 level was 0.4 +/- 0.1 pg.ml(-1) compared to 0.1 +/- 0.02 pg.ml( 1) in the lower fit individuals. In contrast to FGF-2, IGF-I increased transiently to levels of 405.0 +/- 62.0 ng.ml(-1) in the higher fit individuals and to levels of 436 +/- 57.0 ng.ml(-1) in the lower fit individuals. However, the IGF-I elevation was significant (p < 0. 05) only in the higher fit individuals. In conclusion, the present study demonstrates that during aging, fitness level can alter circulating levels of IGF-I and FGF-2. Furthermore, fitness level can affect the response of both mediators to all-out anaerobic exercise. Key pointsThe present study suggests that during aging, fitness level can alter circulating levels of IGF-I and FGF-2.Furthermore, fitness level can affect the response of both mediators to all-out anaerobic exercise.Anaerobic muscle activity is represented in many daily life activities of elderly individuals.This may have clinical implications during aging, where the declined activity of growth factors is a major determinant of the loss of muscle strength and function. PMID- 24149334 TI - Analysis of the distances covered by first division brazilian soccer players obtained with an automatic tracking method. AB - Methods based on visual estimation still is the most widely used analysis of the distances that is covered by soccer players during matches, and most description available in the literature were obtained using such an approach. Recently, systems based on computer vision techniques have appeared and the very first results are available for comparisons. The aim of the present study was to analyse the distances covered by Brazilian soccer players and compare the results to the European players', both data measured by automatic tracking system. Four regular Brazilian First Division Championship matches between different teams were filmed. Applying a previously developed automatic tracking system (DVideo, Campinas, Brazil), the results of 55 outline players participated in the whole game (n = 55) are presented. The results of mean distances covered, standard deviations (s) and coefficient of variation (cv) after 90 minutes were 10,012 m, s = 1,024 m and cv = 10.2%, respectively. The results of three-way ANOVA according to playing positions, showed that the distances covered by external defender (10642 +/- 663 m), central midfielders (10476 +/- 702 m) and external midfielders (10598 +/- 890 m) were greater than forwards (9612 +/- 772 m) and forwards covered greater distances than central defenders (9029 +/- 860 m). The greater distances were covered in standing, walking, or jogging, 5537 +/- 263 m, followed by moderate-speed running, 1731 +/- 399 m; low speed running, 1615 +/- 351 m; high-speed running, 691 +/- 190 m and sprinting, 437 +/- 171 m. Mean distance covered in the first half was 5,173 m (s = 394 m, cv = 7.6%) highly significant greater (p < 0.001) than the mean value 4,808 m (s = 375 m, cv = 7.8%) in the second half. A minute-by-minute analysis revealed that after eight minutes of the second half, player performance has already decreased and this reduction is maintained throughout the second half. Key pointsA novel automatic tracking method was presented. No previous work was found in the literature reporting data of simultaneous trajectories of all soccer players obtained by an automatic tracking method.The study reveals 7% reduction in mean distance covered in the second half and moreover after eight minutes of the second half, player performance has already decreased and this reduction is maintained throughout the second half. PMID- 24149335 TI - Effects of age increment and 36-week exercise training on antioxidant enzymes and apoptosis in rat heart tissue. AB - This study investigated the onset of age-related changes in the myocardial antioxidant enzymes and apoptosis and the vulnerability of the myocardium to oxidative stress following exercise training. Few studies have investigated the influence of the most prevalent life-prolonging strategy physical exercise, on the age increment alterations in the myocardial antioxidant enzymes and apoptosis at mid age and to determine whether exercise-induced antioxidant defense system could attenuate lipid peroxidation. Thirty six male Wistar rats were randomly assigned to exercise trained (n = 18) and sedentary (n = 18) groups. The rats in the training group went under 12, 24 and 36 weeks of moderate exercise trainings (25 m.min(-1) for 60-min with a 0% slope). Six sedentary controls were killed together with each exercise group at the end of the training programs. Levels of thiobarbituric acid-reactive substances (TBARS) and catalase (CAT) activity in myocardial homogenates were unchanged by training irrespective of the protocol duration. However, an increased content of the TBARS was detected in hearts from both the 24 and 36-week trained and sedentary control rats when compared with their corresponding 12-week groups (p<0.01). The activity of superoxide dismutase (SOD) remained unchanged after the 12-week training period whereas a significant increase was observed in heart homogenates of 24-week trained animals as compared with their sedentary controls (p<0.05). The activity of glutathione peroxidase (GPX) remained unchanged. The rates of apoptosis which was detected by ELISA assays, were significantly modified after 24 and 36-week of training (p<0.05). These results demonstrate that a long-term endurance training (24 weeks) induced increases in SOD activities in rat myocardium and elicited a marked reduction in apoptosis rate. However, a shorter training program (12 weeks) was not effective in increasing heart antioxidant defenses. Key pointsExercise training induces activity of myocardial SOD.Long-term regular moderate-intensity exercise decreases the rate of myocardial apoptosis.Short-term regular moderate-intensity exercises do not change the rate of myocardial anti oxidant capacity and apoptosis. PMID- 24149336 TI - Large and small arterial elasticity in healthy active and sedentary premenopausal women. AB - The purpose of this study was to compare large and small arterial elasticity in apparently healthy sedentary and recreationally active adult women, and to examine if age affects large and small arterial elasticity. This cross-sectional study consisted of 43 premenopausal women without overt cardiovascular disease (age = 43.4 +/- 4.7 yrs; mean +/- SD). The subjects were grouped into a sedentary group or a leisurely active group (30 min, 3d wk of low intensity) in addition to the following age groups: 35-40 years, n = 13; 41-45 years, n = 14; 46-54 years, n = 16. Subjects rested supine while pulse contour analysis was measured from the radial artery using an HDI/Pulsewave CR-2000 instrument (Hypertension Diagnostic, Inc.) to examine arterial elasticity in the large and small arteries. Activity level and menopausal status was based on self-report. There were no differences in large (14.5 +/- 1.0 ml/mmHg x 10; 14.9 +/- 0.9 ml/mmHg x 10; mean +/- SD) and small (5.5 +/- 0.5 ml/mmHg x 100; 6.4 +/- 0.4 ml/mmHg x 100) arterial elasticity between the sedentary group and the recreationally active group, respectively. Large (12.8 +/- 0.9 ml/mmHg x 10) arterial elasticity was lower in the oldest group (p = 0.008) compared to the youngest group (17.6 +/- 5.9 ml/mmHg x 10). After adjusting for body mass index, large arterial elasticity (p = 0.022) remained lower in the oldest group. There was a trend for small arterial elasticity to be lower in the older group compared to the young group (p = 0.063). There was no difference in large and small arterial elasticity between healthy sedentary and recreationally active premenopausal women. This suggests that more strenuous physical activity may be necessary to gain beneficial effects on the vasculature. Large arterial elasticity is decreasing with advancing age independent of body mass index. Key pointsThere was no difference in large and small artery elasticity between healthy sedentary and recreationally active women.Large artery elasticity decreases with advancing age.Subjects with the highest systolic blood pressure had the largest decrease in large artery elasticity. PMID- 24149337 TI - Player movement patterns in an elite junior Australian rules football team: an exploratory study. AB - This study explored the physical movement patterns associated with an elite Under 18 Australian Football (AF) team. Five field positions were selected with observations recording the number and relative per cent of "working "efforts (jogging, running, and sprinting), "resting "efforts (walking) and the total distances associated with "working "or "resting "efforts. Intra-observer reliability, using test- retest method, showed correlations were r = 0.98 or greater. The Wing position covered 11,877 m, the greatest total distance during an entire game, whilst the HBF and Centre positions both recorded 11,545 m and 11,537 m respectively and the Ruck position covered 9,203 m. The HBF recorded the greatest frequency of 'working' and 'resting' efforts (180 and 182 respectively), whilst the Wing (166 and 158), Centre (162 and 149) and Ruck (161 and 166) showed similarities in their results. The Wing position recorded the longest average distance per 'working' effort (58 m) whilst the Centre position recorded the longest average distance per 'resting' effort (17 m). Results also show the completion of less total efforts and smaller total distances, in Under 18 players, recorded compared to professional senior AF data. The results from this study suggest that further in-depth research is required into movement patterns and game activity demands in this AF playing group. Key pointsLittle information currently exists in the movement patterns and physical activity levels in Australian football at both senior and junior levels.The results from this preliminary study found differences in the number of physical efforts and the total volume of work completed in junior Australian football players when compared to previous research in senior players.Further in-depth research is required in movement analysis, particularly at the junior level, in order to assist junior coaching staff in developing specific programs for this population group. PMID- 24149338 TI - Reliability of kinematics and kinetics associated with horizontal single leg drop jump assessment. A brief report. AB - Determining the reliability of a unilateral horizontal drop jump for displacement provided the focus for this research. Eighteen male subjects were required to step off a 20cm box and land on a force plate with one leg and thereafter jump for maximal horizontal displacement on two different days. Dependent variables from the jump assessment included mean and peak vertical (V) and horizontal (H) ground reaction forces (GRF) and impulses, horizontal displacement and contact time. The between-trial variability of all kinematic and kinetic measures was less than 7%. The most consistent measure over both trials was the horizontal displacement jumped (1.2 to 1.4%) and the most variable were the contact time the first day (6.5%) and peak HGRF the second day (4.3%). In all cases there was less variation associated with the second rather than the first day. In terms of test retest variability the percent changes in the means and coefficient of variations (CVs) were all under 10%. The smallest changes in the mean (0.43 %), least variation (< 2.26 %) and second highest intraclass correlation co-efficient (ICC = 0.95) were found for horizontal displacement jumped. The highest ICC (0.96) was found for horizontal impulse. Given the reliability of the single leg drop jump, it may offer better prognostic and diagnostic information than that obtained with bilateral vertical jumps. Key pointsThere is a need for greater understanding and utilisation of assessment techniques that assess both the horizontal and vertical components of force/power production.The single leg drop jump is an assessment that exhibits high face validity (a unilateral jump involving both vertical and horizontal propulsive forces that also involves pre-load) but reliability needed to be quantified.The reliability of the many kinematic and kinetic variables quantified in this study were similar to those published in research in this area and future research needs to determine the clinical and practical significance of this test. PMID- 24149339 TI - Photoresponsive dendron-like metallocomplexes of the crown-containing styryl derivatives of 2,2'-bipyridine. AB - We studied 15-crown-5 ether mono- and bis(styryl) derivatives of 2,2'-bipyridine ( and ) as a scaffold to construct photoresponsive complexes possessing metallodendrimer structure. The synthesis and optical properties of one dimensional (1D) Ca(2+)-containing and octahedral 3D Zn(2+)-containing complexes with crowned styryl derivatives of 2,2'-bipyridine are described. Bimetallic Ca(2+), Zn(2+)-containing complexes of and possess well-defined structures and particular optical characteristics. The effective size of the complexes was estimated by diffusion-ordered NMR spectroscopy (DOSY) by measuring translation diffusion coefficients. The NMR data on the compositions of the formed complexes are in full agreement with those obtained by an optical method. The properties of the zinc polypyridyl complexes are modified by intermolecular interactions between the crown ether center and the metal ions, so they are potentially useful in the preparation of chemical sensors. PMID- 24149340 TI - Isolation and characterization of a novel wheat cysteine-rich receptor-like kinase gene induced by Rhizoctonia cerealis. AB - Cysteine-rich receptor kinases (CRKs) belong to the receptor-like kinase family. Little is known about CRK genes in wheat. We isolated a wheat CRK gene TaCRK1 from Rhizoctonia cerealis-resistant wheat CI12633 based on a differentially expressed sequence identified by RNA-Sequencing (RNA-Seq) analysis. TaCRK1 was more highly expressed in CI12633 than in susceptible Wenmai 6. Transcription of TaCRK1 in wheat was induced in CI12633 after R. cerealis infection and exogenous abscisic acid (ABA) treatment. The deduced TaCRK1 protein contained a signal peptide, two DUF26 domains, a transmembrane domain, and a serine/threonine protein kinase domain. Transient expression of a green fluorescence protein fused with TaCRK1 in wheat and onion indicated that TaCRK1 may localize to plasma membranes. Characterization of TaCRK1 silencing induced by virus-mediated method in CI12633 showed that the downregulation of TaCRK1 transcript did not obviously impair resistance to R. cerealis. This study paves the way to further CRK research in wheat. PMID- 24149341 TI - Evidence for a Non-Genomic Action of Testosterone in Skeletal Muscle Which may Improve Athletic Performance: Implications for the Female Athlete. AB - This review will focus on the proposed second mode of testosterone action (now termed non-genomic) that appears to occur independently of the traditional transcriptional mechanism in mammalian skeletal muscle cells which may enhance skeletal muscle contractile properties. This mechanism of testosterone action differs from the traditional pathway, originating at the cell membrane, having a rapid onset of action, requiring second messengers to execute its effects and is insensitive to inhibitors of traditional androgen receptor action, transcription and protein synthesis. Importantly, unlike the traditional action of testosterone in skeletal muscle, this non-genomic pathway is shown to have a direct acute effect on calcium-dependent components important for the contractile process. The changes within the contractile apparatus may enhance the ability of the muscle to produce explosive power during athletic performance. Rapid increases in Inositol triphosphate mass and calcium release from the sarcoplasmic reticulum have been reported in rodent skeletal muscle cells, and a rapid androgen (dihydrotestosterone)-induced increase in peak force production has been recorded in intact rodent skeletal muscle fibre bundles while showing increases in the activity of the Ras/MAP/ERK mediated pathway. Because the non-genomic action of testosterone is enhanced during increases in exposure to testosterone and is acute in its action, implications for athletic performance are likely greater in females than males due to natural fluctuations in circulating testosterone levels during the female menstrual cycle, reproductive pathology, and changes induced by hormonal contraceptive methods. Research should be undertaken in humans to confirm a pathway for non-genomic testosterone action in human skeletal muscle. Specifically, relationships between testosterone fluctuations and physiological changes within skeletal muscle cells and whole muscle exercise performance need to be examined. Key pointsNon-genomic calcium mediated events activated by testosterone have been identified in skeletal muscle cells.The non-genomic action originates at the cell membrane, is rapid in onset and is directed by second messengers' calcium and IP3.A possible action of non-genomic testosterone may be the initiation of a more efficient contraction through the mobilisation of calcium from the SR resulting in greater force production or velocity of contraction in fast twitch fibres.Physiologically, females with menstrual disorders that cause hyperandrogenism may have a performance advantage in events that require great force or power production. PMID- 24149342 TI - Longitudinal study of repeated sprint performance in youth soccer players of contrasting skeletal maturity status. AB - The purpose of the study was to evaluate the developmental changes in performance in a repeated-sprint ability (RSA) test in young soccer players of contrasting maturity status. A total of 83 regional level Portuguese youth soccer players, aged 11-13 years at baseline was assessed annually. Stature, body mass, 7x34.2-m sprint protocol (25-s active recovery), 20-m multi-stage continuous shuttle endurance run and counter-movement jump (CMJ) without the use of the arms were measured. Fat-free mass (FFM) was determined by age and gender-specific formulas. Developmental changes in total sprint time across ages were predicted using multilevel modeling. Corresponding measurements were performed on an independent cross-sectional subsample of 52 youth soccer players 11-17 years to evaluate the predictive model. CA, CA(2), maturational status (SA-CA), body size (mass and stature), FFM, aerobic endurance, lower limb explosive strength and annual volume training significantly improved the statistical fit of the RSA multilevel model. In 'late' maturing athletes, the best model for predicting change in RSA was expressed by the following equation: 86.54 - 2.87 x CA + 0.05 x CA(2) - 0.25 x FFM + 0.15 x body mass + 0.05 x stature - 0.05 x aerobic endurance - 0.09 x lower limb explosive strength - 0.01 x annual volume training. The best fitting models for players who were 'on time' and 'early' maturing were identical to the best model for late maturing players, less 0.64 seconds and 1.74 seconds, respectively. Multilevel modeling provided performance curves that permitted the prediction of individual RSA performance across adolescent years in regional level soccer players. Key pointsRepeated-sprint ability tests are a valuable sport-specific field test of sprint performance in youth soccer players. Here, the test had reasonable reliability and can be useful to trainers and coaches in the assessment of young athletes and in monitoring changes over time.The total sprint time of youth soccer players advanced in biological maturation improves more, on average, than that of players who are on time (average) and late in maturation. The performance difference between early and late maturing players is consistent after about 13 years of age.Multilevel modeling is a promising statistical technique for analyzing the development of functional capacity in a sport. It has the potential to provide useful information to assist trainers and coaches in evaluating and facilitating the development of individual players. PMID- 24149343 TI - Time-of-Day Effects on EMG Parameters During the Wingate Test in Boys. AB - In boys, muscle power and strength fluctuate with time-of-day with morning nadirs and afternoon maximum values. However, the exact underlying mechanisms of this daily variation are not studied yet. Thus, the purpose of this study was to examine the time-of-day effects on electromyographic (EMG) parameters changes during a Wingate test in boys. Twenty-two boys performed a 30-s Wingate test (measurement of muscle power and fatigue) at 07:00 and 17:00-h on separate days. Surface EMG activity was recorded in the Vastus lateralis, rectus femoris and vastus medialis muscles throughout the test and analyzed over a 5-s span. The root-mean-square (RMS) and mean-power-frequency (MPF) were calculated. Neuromuscular efficiency (NME) was estimated from the ratio of power to RMS. Muscle power (8.22 +/- 0.92 vs. 8.75 +/- 0.99 W.kg(-1) for peak power and 6.96 +/ 0. 72 vs. 7.31 +/- 0.77 W.kg(-1) for mean power, p < 0.001) and fatigue (30.27 +/- 7.98 vs. 34.5 +/- 10. 15 %, p < 0.05) during the Wingate test increased significantly from morning to evening. Likewise, MPF (102.14 +/- 18.15 vs. 92.38 +/- 12.39 Hz during the first 5-s, p < 0.001) and NME (4.78 +/- 1.7 vs. 3.88 +/- 0.79 W.mV(-1) during the first 5-s, p < 0.001) were higher in the evening than the morning; but no significant time-of-day effect was noticed for RMS. Taken together, these results suggest that peripheral mechanisms are more likely the cause of the child's diurnal variations of muscle power and fatigue during the Wingate test. Key pointsIn boys, performances during the Wingate test fluctuate with the time-of-day.MPF and NME are higher in the evening during the Wingate cycling test.RMS is unaffected by the time-of-day.The evening improvement in muscle power and fatigue is due to an enhancement of the muscle contractile properties. PMID- 24149344 TI - Effects of a combined aerobic and strength training program in youth patients with acute lymphoblastic leukemia. AB - Cure rates of youth with Acute Lymphoblastic Leukemia (ALL) have increased in the past decades, but survivor's quality of life and physical fitness has become a growing concern. Although previous reports showed that resistance training is feasible and effective, we hypothesized that a more intense exercise program would also be feasible, but more beneficial than low- to moderate-intensity training programs. We aimed to examine the effects of an exercise program combining high-intensity resistance exercises and moderate-intensity aerobic exercises in young patients undergoing treatment for ALL. A quasi-experimental study was conducted. The patients (n = 6; 5-16 years of age) underwent a 12-week intra-hospital training program involving high-intensity strength exercises and aerobic exercise at 70% of the peak oxygen consumption. At baseline and after 12 weeks, we assessed sub-maximal strength (10 repetition-maximum), quality of life and possible adverse effects. A significant improvement was observed in the sub maximal strength for bench press (71%), lat pull down (50%), leg press (73%) and leg extension (64%) as a result of the training (p < 0.01). The parents' evaluations of their children's quality of life revealed an improvement in fatigue and general quality of life, but the children's self-reported quality of life was not changed. No adverse effects occurred. A 12-week in-hospital training program including high-intensity resistance exercises promotes marked strength improvements in patients during the maintenance phase of the treatment for Acute Lymphoblastic Leukemia without side-effects. Parents' evaluations of their children revealed an improvement in the quality of life. Key pointsPatients with ALL present low muscle strength and poor quality of life.High-intensity resistance exercises combined with moderate-intensity aerobic exercise improved muscle strength and quality of life during the maintenance phase of ALL treatment.The exercise training program seemed to be tolerable and safe in ALL patients. PMID- 24149345 TI - Order effects of concurrent endurance and resistance training on post-exercise response of non-trained women. AB - Physical exercise is used for the promotion and maintenance of good health and for the improvement of physical fitness. Both endurance and resistance exercises are needed to carry out a complete training program. Because time may be a barrier to physical exercise practice, the aim of this study was to verify whether the order of execution of endurance and resistance exercises, in concurrent training, has different effects on the metabolic responses during recovery. Thirteen healthy women [24.40 (1.67) years, Mean (SD)] were investigated for energy expenditure (EE), oxygen consumption (VO2), ventilation (Ve), respiratory frequency (RF), proportion of oxygen in expired air (FeO2) and ratings of perceived exertion (RPE) both before and after three concurrent endurance and resistance trainings, carried out in different orders: endurance resistance training (ERT), resistance-endurance training (RET) and alternating endurance-resistance training (AERT). AERT elicited a significantly greater increase of EE, VO2, and Ve and a greater decrease of FeO2. ERT elicited a lower increase of RPE. Acute post-exercise physiological responses to concurrent endurance and resistance physical exercise seem to depend on the order of execution of the two parts: among the selected protocols, AERT seems to elicit the best responses. Key pointsThe concurrent execution of both endurance and resistance exercise, in the same training session, could be a practical solution to conform to guidelines for health in the presence of lack of time.The order of concurrent execution of both endurance and resistance exercise, in the same training session, influences the amplitude of some post-exercise physiological responses. PMID- 24149346 TI - Bioharness(TM) multivariable monitoring device: part. I: validity. AB - The Bioharness(TM) monitoring system may provide physiological information on human performance but there is limited information on its validity. The objective of this study was to assess the validity of all 5 Bioharness(TM) variables using a laboratory based treadmill protocol. 22 healthy males participated. Heart rate (HR), Breathing Frequency (BF) and Accelerometry (ACC) precision were assessed during a discontinuous incremental (0-12 km.h(-1)) treadmill protocol. Infra-red skin temperature (ST) was assessed during a 45 min(-1) sub-maximal cycle ergometer test, completed twice, with environmental temperature controlled at 20 +/- 0.1 degrees C and 30 +/- 0.1 degrees C. Posture (P) was assessed using a tilt table moved through 160 degrees . Adopted precision of measurement devices were; HR: Polar T31 (Polar Electro), BF: Spirometer (Cortex Metalyser), ACC: Oxygen expenditure (Cortex Metalyser), ST: Skin thermistors (Grant Instruments), P:Goniometer (Leighton Flexometer). Strong relationships (r = .89 to .99, p < 0.01) were reported for HR, BF, ACC and P. Limits of agreement identified differences in HR (-3.05 +/- 32.20 b.min(-1)), BF (-3.46 +/- 43.70 br.min(-1)) and P (0.20 +/- 2.62 degrees ). ST established a moderate relationships (-0.61 +/ 1.98 degrees C; r = 0.76, p < 0.01). Higher velocities on the treadmill decreased the precision of measurement, especially HR and BF. Global results suggest that the BioharressTM is a valid multivariable monitoring device within the laboratory environment. Key pointsDifferent levels of precision exist for each variable in the Bioharness(TM) (Version 1) multi-variable monitoring deviceAccelerometry and posture variables presented the most precise dataData from the heart rate and breathing frequency variable decrease in precision at velocities >= 10 km.h(-1)Clear understanding of the limitations of new applied monitoring technology is required before it is used by the exercise scientist. PMID- 24149347 TI - Bioharness(TM) Multivariable Monitoring Device: Part. II: Reliability. AB - The Bioharness(TM) monitoring system may provide physiological information on human performance but the reliability of this data is fundamental for confidence in the equipment being used. The objective of this study was to assess the reliability of each of the 5 Bioharness(TM) variables using a treadmill based protocol. 10 healthy males participated. A between and within subject design to assess the reliability of Heart rate (HR), Breathing Frequency (BF), Accelerometry (ACC) and Infra-red skin temperature (ST) was completed via a repeated, discontinuous, incremental treadmill protocol. Posture (P) was assessed by a tilt table, moved through 160 degrees . Between subject data reported low Coefficient of Variation (CV) and strong correlations(r) for ACC and P (CV< 7.6; r = 0.99, p < 0.01). In contrast, HR and BF (CV~19.4; r~0.70, p < 0.01) and ST (CV 3.7; r = 0.61, p < 0.01), present more variable data. Intra and inter device data presented strong relationships (r > 0.89, p < 0.01) and low CV (<10.1) for HR, ACC, P and ST. BF produced weaker relationships (r < 0.72) and higher CV (<17.4). In comparison to the other variables BF variable consistently presents less reliability. Global results suggest that the Bioharness(TM) is a reliable multivariable monitoring device during laboratory testing within the limits presented. Key pointsHeart rate and breathing frequency data increased in variance at higher velocities (i.e. >= 10 km.h(-1))In comparison to the between subject testing, the intra and inter reliability presented good reliability in data suggesting placement or position of device relative to performer could be important for data collectionUnderstanding a devices variability in measurement is important before it can be used within an exercise testing or monitoring setting. PMID- 24149348 TI - Rapid hamstrings/quadriceps strength capacity in professional soccer players with different conventional isokinetic muscle strength ratios. AB - Muscle strength imbalance can be an important factor in hamstrings muscle strain. A hamstrings/quadriceps (H/Q) strength ratio based on concentric peak torque values (Hcon:Qcon) has traditionally been used to describe the potential for knee joint destabilization. Because certain standard actions in soccer are explosive, the analysis of the H/Q strength ratio based on the rate of torque development (Hrtd:Qrtd) might also be useful in the evaluation of joint stability. The objective of this study was to compare the Hrtd:Qrtd between professional soccer players with heterogeneous values of Hcon:Qcon. Thirty-nine professional soccer players took part in the following procedures on different days: 1) Familiarization session with the isokinetic dynamometer, and 2) Two maximal isometric actions and five maximal concentric actions at 60 degrees .s(-1) for hamstrings (H) and quadriceps (Q). Participants were ranked according to their Hcon:Qcon ratio. The median third was excluded to form a high torque group (HTG), and a low torque group (LTG). Peak isometric (H) and concentric (H and Q) torques and rate of torque development (H) were significantly greater in the HTG group. Similarly, Hcon:Qcon (0.68 +/- 0.02 vs. 0.52 +/- 0.03) and Hrtd:Qrtd (0.54 +/- 0.12 vs. 0.43 +/- 0.16) were significantly greater in the HTG group than in the LTG group. There was no significant correlation between Hcon:Qcon and Hrtd:Qrtd. It can be concluded that Hcon:Qcon and Hrtd:Qrtd are determined, but not fully defined, by shared putative physiological mechanisms. Thus, the physiologic and clinical significance of Hcon:Qcon and Hrtd:Qrtd to an athlete's individual evaluation might be different. Key pointsSoccer players with high (0.66-0.70) and low (0.50-0.54) conventional concentric hamstrings:quadriceps ratios (Hcon:Qcon) tend to demonstrate similar profiles (i.e., high and low, respectively) in their rate of the torque development H/Q ratio (Hrtd:Qrtd).The lack of a significant relationship between Hcon:Qcon and Hrtd:Qrtd suggests that these ratios are determined, but not fully defined, by shared putative physiological mechanisms.Preseason screening programs that monitor hamstrings:quadriceps ratios should recognize that the physiologic and clinical significance of Hcon:Qcon and Hrfd:Qrfd to an athlete's individual evaluation might be different. PMID- 24149349 TI - The effects of vibration during maximal graded cycling exercise: a pilot study. AB - Whole Body Vibration training is studied and used in different areas, related to sport performance and rehabilitation. However, few studies have investigated the effects of Vibration (Vib) exposure on aerobic performance through the application of this concept to cycling exercise. A specifically designed vibrating cycloergometer, the powerBIKE(TM), was used to compare the effects of Vib cycling exercise and normal cycling on different physiological parameters during maximal graded exercise test. Twelve recreationally active male adults (25 +/- 4.8 yrs; 181.33 +/- 5.47 cm; 80.66 +/- 11.91 kg) performed two maximal incremental cycling tests with and without Vib in a block-randomized order. The protocol consisted of a 4 min warm up at 70 rev.min(-1) followed by incremental steps of 3 min each. Cycling cadence was increased at each step by 10 rev.min(-1) until participants reached their volitional exhaustion. Respiratory gases (VO2, VCO2), Heart Rate, Blood Lactate and RPE were collected during the test. Paired t tests and Cor-relation Coefficients were used for statistical analysis. A significantly greater (P<0.05) response in the VO2, HR, BLa and RPE was observed during the Vib trial compare to normal cycling. No significant differences were found in the maximal aerobic power (Vib 34.32 +/- 9.70 ml.kg(-1).min(-1); no Vib 40.11 +/- 9.49 ml.kg(-1).min(-1)). Adding Vib to cycling exercise seems eliciting a quicker energetic demand during maximal exercise. However, mechanical limitations of the vibrating prototype could have affected the final outcomes. Future studies with more comparative setting are recommended to deeply appraise this concept. PMID- 24149350 TI - Effect of Kayak Ergometer Elastic Tension on Upper Limb EMG Activity and 3D Kinematics. AB - Despite the prevalence of shoulder injury in kayakers, limited published research examining associated upper limb kinematics and recruitment patterns exists. Altered muscle recruitment patterns on-ergometer vs. on-water kayaking were recently reported, however, mechanisms underlying changes remain to be elucidated. The current study assessed the effect of ergometer recoil tension on upper limb recruitment and kinematics during the kayak stroke. Male kayakers (n = 10) performed 4 by 1 min on-ergometer exercise bouts at 85%VO2max at varying elastic recoil tension; EMG, stroke force and three-dimensional 3D kinematic data were recorded. While stationary recoil forces significantly increased across investigated tensions (125% increase, p < 0.001), no significant differences were detected in assessed force variables during the stroke cycle. In contrast, increasing tension induced significantly higher Anterior Deltoid (AD) activity in the latter stages (70 to 90%) of the cycle (p < 0.05). No significant differences were observed across tension levels for Triceps Brachii or Latissimus Dorsi. Kinematic analysis revealed that overhead arm movements accounted for 39 +/- 16% of the cycle. Elbow angle at stroke cycle onset was 144 +/- 10 degrees ; maximal elbow angle (151 +/- 7 degrees ) occurred at 78 +/- 10% into the cycle. All kinematic markers moved to a more anterior position as tension increased. No significant change in wrist marker elevation was observed, while elbow and shoulder marker elevations significantly increased across tension levels (p < 0.05). In conclusion, data suggested that kayakers maintained normal upper limb kinematics via additional AD recruitment despite ergometer induced recoil forces. Key pointsKayak ergometer elastic tension significantly alters Anterior Deltoid recruitment patterns.Kayakers maintain optimal arm kinematics despite changing external forces via altered shoulder muscle recruitment.Overhead arm movements account for a high proportion of the kayak stroke cycle. PMID- 24149351 TI - Reliability and Validity of the OMNI-Vibration Exercise Scale of Perceived Exertion. AB - This study examined reliability and concurrent validity of the newly developed OMNI-vibration exercise scale (OMNI-VIBRO) to measure Ratings of Perceived Exertion (RPE) during vibration exercise in twenty recreationally active students (12 males and 8 females). The criterion variables were muscle activity of the Vastus Medialis (VM), Vastus Lateralis (VL), Biceps Femoris (BF), and Medial Gastrocnemius (MG) muscles, as well as accelerations (12.5, 20.2, 30.9, 36.3, 60.1, and 88.4 m.s(-2)). RPE was registered during the final of each 30 s condition. Each participant attended two laboratory testing sessions. Positive linear regression coefficients (p < 0.001) were found between RPE (OMNI-VIBRO) and acceleration (r = 0.976) and muscle activity of lower-body muscles (r = 0.942). Between session (test-retest), reliability of RPE (OMNI-VIBRO) was good (ICC: 0.790. 95% CI: 0.699-0.854). CONCLUSIONS: findings provided concurrent validation of the OMNI-VIBRO to measure RPE for the active muscle and overall body in recreationally active students performing lower-body vibration exercise. Key pointsThe pictorial-verbal category scale of perception of exertion (OMNI VIBRO) during lower body vibration exercise on a vibration platform showed good concurrent validity.The OMNI-VIBRO method in conjunction with WBV exercise would allow coaches, fitness professionals, or health-care personnel to assess the intensity that corresponds to the level of the vibratory stimulus.The OMNI-VIBRO could be a useful tool of measuring the different intensities of a vibratory training session and altering the vibratory stimulus in a periodized fashion. PMID- 24149352 TI - Kinematics of the typical beach flags start for young adult sprinters. AB - This study profiled beach flags start kinematics for experienced young adult sprinters. Five males and three females (age = 20.8 +/- 2.1 years; height = 1.70 +/- 0.06 meters [m]; mass = 63.9 +/- 6.0 kilograms) completed four sprints using their competition start technique. A high-speed camera, positioned laterally, filmed the start. Data included: start time; hand clearance time; posterior movement from the start line; feet spacing during the start; elbow, hip, knee, trunk lean, and trajectory angles at take-off; and first step length. Timing gates recorded 0-2, 0-5, and 0-20 m time. Spearman's correlations identified variables relating (p <= 0.05) to faster start and sprint times. The beach flags start involved sprinters moving 0.18 +/- 0.05 m posterior to the start line by flexing both legs underneath the body before turning. Following the turn, the feet were positioned 0.47 +/- 0.07 apart. This distance negatively correlated with start (rho = -0.647), 0-2 (rho = -0.683), and 0-5 m (rho = -0.766) time. Beach flags start kinematics at take-off resembled research analyzing track starts and acceleration. The elbow extension angle (137.62 +/- 13.45 degrees ) of the opposite arm to the drive leg correlated with 0-2 (rho = -0.762), 0-5 (rho = 0.810), and 0-20 m (rho = -0.810) time. Greater arm extension likely assisted with stability during the start, leading to enhanced sprint performance. The drive leg knee extension angle (146.36 +/- 2.26 degrees ) correlated with start time (rho = -0.677), indicating a contribution to a faster start completion. A longer first step following the start related to faster 0-5 m time (rho = 0.690). Sprinters quicker over 0-2 and 0-5 m were also quicker over 20 m (rho = 0.881-0.952). Beach flags sprinters must ensure their start is completed quickly, such that they can attain a high speed throughout the race. Key pointsThere are specific movement patterns adopted by beach flags sprinters during the start. Sprinters will move posterior to the start time prior to turning. Following the turn, sprinters must position their feet such that force output is optimized and low body position at take-off can be attained.The body position at take-off from the beach flags start is similar to that of established technique parameters for track sprinters leaving starting blocks, and field sport athletes during acceleration. A greater range of motion at the arms can aid with stability during the turn and at take-off from the start. Greater knee extension of the drive leg at take-off can assist with reducing the duration of the start.The beach flags start must allow for a quick generation of speed through the initial stages of the sprint, as this can benefit the later stages. A longer first step following the start can help facilitate speed over the initial acceleration period. Beach flags sprinters must also attempt to maintain their speed throughout the entirety of the race. PMID- 24149353 TI - Golfing skill level postural control differences: a brief report. AB - Golfers have better balance than their age-matched counterparts; however, it is uncertain if this persists during the swing as a function of skill level. The purpose of the study was to investigate dynamic postural control (center of mass (COM) motion) measured during different phases of the swing in golfers of varying proficiency. Eighteen healthy golfers were grouped by handicap: novice (no handicap, n = 7), intermediate (handicap 15-19, n = 7), and advanced (handicap 9 14, n = 4). Indoor testing was performed hitting 3 tee shots using a common driver. A five-camera (60 Hz) motion analysis system (9 markers) was used to extract kinematics data. There were no significant group differences in gender, age, or BMI. Advanced players had lower COM displacement with respect to address at the time of maximum arm speed (p = 0. 001) compared to intermediate (57%, p = 0.014) and novice (73%, p = 0.023). These changes persisted after COM distance and time normalization. Advanced golfers had improved COM linearity during the downswing (p < 0.001) compared to intermediate (30%, p = 0.029) and novice (51%, p < 0.001). Advanced players had decreased COM displacement at the time of maximum arm speed and a more linear COM path during the early downswing. Further study should focus on these changes during ball launch conditions. Key pointsStudies suggest that static and dynamic balance is important in golf. However, none have investigated dynamic postural control during the golf swing in golfers of varying proficiency.Our findings suggest advanced players demonstrated improved postural control at the point of maximum arm speed when compared to less skilled players. Furthermore, center of mass acceleration in advanced players is closer to impact than less-skilled players.We observed an increased center of mass linearity of trajectory during the early downswing for advanced players over novice players. We theorized this strategy may help advanced golfers to improve the economy of COM motion during golf swing and improve the performance of the shot. PMID- 24149354 TI - The effect of an acute bout of rubber tube running constraint on kinematics and muscle activity. AB - We examined the effect of an acute bout of treadmill running with rubber tube (RT) and without rubber tube (NT) elastic constraints on electromyographic (EMG), 3D kinematics variability, and blood lactate concentration (LA). In the RT test, the constraints were attached to the hips and ankles. The selected variables were compared between 30 min of NT running and 30 minutes of RT running in 13 healthy recreationally trained male runners who had no prior exposure to RT. Statistical analysis revealed significantly higher EMG variability (p < 0.01) and muscle activity (p < 0.05) during RT compared to NT that decreased over time approaching NT, indicating movement pattern adaptation. 3D-kinematics and their variability remained generally unaltered. Changes occurred predominantly in the sagittal plane, specifically to the knee and the swing. A significant increase in LA was measured at the end of RT (p < 0.05). These findings suggest that RT running influences muscle recruitment and variability, but has only a minor influence on kinematics. Changes in LA were significant, although relatively small. The observed adaptations in EMG and kinematics suggest that the RTs provide a possibility to create within movement variability in various sports, and thus, variable training conditions may foster strategies to increase the ability to flexibly adapt to different and new situations. Key pointsAdaptation to training device occurred quite rapidly.Changes in muscle activity were more pronounced than kinematic changes due to the training device.Training device may be used to increase within-movement variability.Participants may learn to flexibly adapt to variable constraints. PMID- 24149355 TI - The effect of instability training on knee joint proprioception and core strength. AB - Although there are many studies demonstrating increased trunk activation under unstable conditions, it is not known whether this increased activation would translate into meaningful trunk strength with a prolonged training program. Additionally, while balance-training programs have been shown to improve stability, their effect on specific joint proprioception is not clear. Thus the objective of this study was to examine training adaptations associated with a 10 week instability-training program. Participants were tested pre- and post training for trunk extension and flexion strength and knee proprioception. Forty three participants participated in either a 10-week (3 days per week) instability training program using Swiss balls and body weight as resistance or a control group (n = 17). The trained group increased (p < 0. 05) trunk extension peak torque/body weight (23.6%) and total work output (20.1%) from pre- to post training while the control group decreased by 6.8% and 6.7% respectively. The exercise group increased their trunk flexion peak torque/body weight ratios by 18.1% while the control group decreased by 0.4%. Knee proprioception (combined right and left joint repositioning) improved 44.7% from pre- to post-training (p = 0.0006) and persisted (21.5%) for 9 months post-training. In addition there was a side interaction with the position sense of the right knee at 9 months showing 32.1% (p = 0.03) less deviation from the reference angle than the right knee during pre-testing. An instability-training program using Swiss balls with body weight as resistance can provide prolonged improvements in joint proprioception and core strength in previously untrained individuals performing this novel training stress which would contribute to general health. Key pointsAlthough traditional free weight resistance exercises have been recommended as most beneficial for improving strength and power in athletes (Behm et al., 2010b), an IT program using Swiss balls and body weight as a resistance may provide an alternative starting point for the sedentary untrained population.As it is well documented that force or strength is decreased when unbalanced (Behm et al., 2010b) and balance-training programs improve balance (Behm and Kean 2006), this type of instability RT program can provide significant adaptations to improve trunk strength especially with the untrained.This type of training should also be incorporated into a new program as the improvements in joint proprioception may help protect from joint injuries over a protracted period.The finding that improved joint proprioception persists for months after training should be emphasized to those individuals whose training is regularly or inconsistently interrupted. PMID- 24149356 TI - Water Polo Game-Related Statistics in Women's International Championships: Differences and Discriminatory Power. AB - The aims of this study were (i) to compare women's water polo game-related statistics by match outcome (winning and losing teams) and phase (preliminary, classificatory, and semi-final/bronze medal/gold medal), and (ii) identify characteristics that discriminate performances for each phase. The game-related statistics of the 124 women's matches played in five International Championships (World and European Championships) were analyzed. Differences between winning and losing teams in each phase were determined using the chi-squared. A discriminant analysis was then performed according to context in each of the three phases. It was found that the game-related statistics differentiate the winning from the losing teams in each phase of an international championship. The differentiating variables were both offensive (centre goals, power-play goals, counterattack goal, assists, offensive fouls, steals, blocked shots, and won sprints) and defensive (goalkeeper-blocked shots, goalkeeper-blocked inferiority shots, and goalkeeper-blocked 5-m shots). The discriminant analysis showed the game-related statistics to discriminate performance in all phases: preliminary, classificatory, and final phases (92%, 90%, and 83%, respectively). Two variables were discriminatory by match outcome (winning or losing teams) in all three phases: goals and goalkeeper-blocked shots. Key pointsThe preliminary phase that more than one variable was involved in this differentiation, including both offensive and defensive aspects of the game.The game-related statistics were found to have a high discriminatory power in predicting the result of matches with shots and goalkeeper-blocked shots being discriminatory variables in all three phases.Knowledge of the characteristics of women's water polo game-related statistics of the winning teams and their power to predict match outcomes will allow coaches to take these characteristics into account when planning training and match preparation. PMID- 24149357 TI - Effects of high intensity training and continuous endurance training on aerobic capacity and body composition in recreationally active runners. AB - The aim of the study was to examine the effects of two different training programs (high-intensity-training vs. continuous endurance training) on aerobic power and body composition in recreationally active men and women and to test whether or not participants were able to complete a half marathon after the intervention period. Thirty-four recreational endurance runners were randomly assigned either to a Weekend-Group (WE, n = 17) or an After-Work- Group (AW, n = 17) for a 12 week-intervention period. WE weekly completed 2 h 30 min of continuous endurance running composed of 2 sessions on the weekend. In contrast, AW performed 4 30 min sessions of high intensity training and an additional 30 min endurance run weekly, always after work. During an exhaustive treadmill test aerobic power was measured and heart rate was continuously recorded. Body composition was assessed using bio-impedance. Following the intervention period all subjects took part in a half-marathon. AW significantly improved peak oxygen uptake (VO2 peak) from 36.8 +/- 4.5 to 43.6 +/- 6.5 [mL.min(-1).kg(-1)], velocity at lactate threshold (VLT) from 9.7 +/- 2.2 to 11.7 +/- 1.8 [km.h(-1)] and visceral fat from 5.6 +/- 2.2 to 4.7 +/- 1.9 In WE VO2 peak signifi-cantly increased from 38.8 +/- 5.0 to 41.5 +/- 6.0 [mL.min(-1).kg(-1)], VLT from 9.9 +/- 1.3 to 11.2 +/- 1.7 [km.h(-1)] and visceral fat was reduced from 5.7 +/- 2.1 to 5.4 +/- 1.9 (p < 0.01). Only the improvements of VO2 peak were significantly greater in AW compared with WE (pre/post group interaction: F=15.4, p = 0.01, eta(2) = 0.36). Both groups completed a half marathon with no significant differences in performance (p = 0.63). Short, intensive endurance training sessions of about 30 min are effective in improving aerobic fitness in recreationally active runners. Key pointsContinuous endurance training and high intensity training lead to significant improvements of aerobic capacity and body compositionBoth training methods enable recreationally active runners to finish a half-marathonHigh intensity training is favorable to improve VO2 peak. PMID- 24149358 TI - The effect of regular exercise training during pregnancy on postpartum brachial ankle pulse wave velocity, a measure of arterial stiffness. AB - The aim of our study was to use brachial-ankle pulse wave velocity (baPWV) measurements to noninvasively assess the effect of exercise training on arterial stiffness in normal pregnant women. Arterial stiffness was assessed at the beginning of the early second trimester of pregnancy and 1 month after delivery in 17 women with normal singleton pregnancies who exercised regularly throughout pregnancy: 81 matched controls were used for comparison. No significant differences were observed in baPWV between the exercise and control groups at the beginning of the second trimester. BaPWV 1 month after delivery (1160.2 +/- 109.1 cm.second(-1)) was signifi-cantly higher than that in the early second trimester (1116.7 +/- 87.9 cm.second(-1)) in the control group (indicating increased arterial stiffness), but not in the exercise group (1145.9 +/- 88.1 cm/second vs 1122.7 +/- 100.2 cm.second(-1), respectively: not significant). The results indicated that regular maternal exercise training decreased arterial stiffness in normal pregnant women, which suggests that regular exercise may help prevent hypertensive disorders during pregnancy. Key pointsRegular maternal exercise training decreased arterial stiffness in normal pregnant women, which suggests that regular exercise may help prevent hypertensive disorders during pregnancy.Maternal exercise suggests that disturbances in arterial function during pregnancy may be prevented by regular exercise. PMID- 24149359 TI - Effects of six months of combined aerobic and resistance training for elderly patients with a long history of type 2 diabetes. AB - This study evaluated the effects of a 6-month combined aerobic and resistance training program on the body composition, glycemic control, lipid profile, and functional capacity of older patients with a long history of type 2 diabetes. 25 subjects (65.9 +/- 4. 2 yrs; M/F: 13/12) with a long history of type 2 diabetes (16.7 +/- 6.7 yrs) were randomly allocated into either the exercise or control groups. The exercise group trained three sessions a week. Each session consisted of a warm-up period, 30 minutes of moderate aerobic exercise, 10 minutes of resistance training with five leg muscle exercises (two sets of 10-12 repetitions at 50-70% of 1RM for each activity), and a cool-down period. The variables of body composition, glycemic control, lipid profile, and functional capacity were measured before and after the study period. Exercise training decreased waist-hip ratio and body fat of the trained subjects. Concentrations of fasting and 2-hour post-glucose challenge plasma glucose and serum insulin, and glycosylated hemoglobin decreased significantly in the exercise group. Exercise training improved the lipid profile and also increased the leg muscle strength and 6 minute walking distance of the trained subjects. The control group, however, increased their body fat and fasting plasma glucose, while other variables were not changed during the study period. The current results demonstrate that elderly patients with a long history of type 2 diabetes can benefit from the 6-month combined aerobic and resistance training program. Key pointsExercise training is effective for elderly patients with long-term type 2 diabetesExercise prescription for elderly patients with type 2 diabetes should contain both aerobic and resistance activities. PMID- 24149360 TI - Notational Analysis of European, World, and Olympic BMX Cycling Races. AB - The objectives of this study were 1) to describe the technical requirements of different tracks where classifying points are disputed for the Olympics as the European continent tracks (E), world championship competitions tracks (W), and Olympic Games track - Beijing, 2008- (O); and 2) to compare and establish differences or similarities between the three previous contexts. The sample used for this study was made of the 8 best qualifying male athletes from each competition (n = 48) during the 2007 and 2008 seasons (pre-Olympic and Olympic years). A descriptive design was used, based on systematic structured observation of the competitions filmed on video, paying attention to the different techniques used (overtaking skills, complete pedalling cycles and registered effort times). The results show that aerial techniques predominate over non aerial techniques on O and W type tracks more than on E tracks by ~20% (p < 0.001), pedaling cycles predominate in E vs. W and O by 11.85 and 24.23% respectively (p <= 0.05), and effort times predominate in O vs. W and E by 6.50 and 12.94% respectively (p <= 0.01). In conclusion, O and W tracks stand out because of the aerial component and greater technical complexity in comparison to E tracks, which has a decisive effect on the way the riders train in relation to the type of championship they aim to compete in. Key pointsEuropean tracks involve more non aerial techniques than world and Olympic tracks, respectively; more non aerial techniques are associated with more pedaling effort time.Bicycle motocross cyclists develop greater values of aerial Techniques in World and Olympic tracks compared with the European tracks and, consequently, reduced non aerial techniques.European tracks involve less technical jumps but more simple jumps. World tracks involve more technical jumps than European and Olympic tracks, but Olympic track jumps, despite being less in number, are more difficult and decisive than the rest.Olympic and World class tracks involve less physical demand than European tracks because of the greater technical requirements and less pedaling cycles.Training should be developed according to the objectives established for each athlete taking into account the type of track in which the competition is going to take place. PMID- 24149361 TI - Comparison of trunk muscle activity during bridging exercises using a sling in patients with low back pain. AB - The aims of this study were to compare the activation of global and local muscles of the trunk during bridging with sling exercise (BSE), bridging with ball exercise (BBE), and normal bridging exercise (NBE) and to conduct and analyze these exercises in supine and prone positions to prove the effectiveness of sling exercises. Thirty patients with current low back pain (LBP) were recruited. In the supine and prone bridging exercise, each subject lifted their pelvis with their legs and feet in contact with the sling, ball, or normal surface. The electrical activities of the inferior oblique (IO), rectus abdominis (RA), multifidus (MF), and erector spinae (ES) muscles during the bridging exercises on the 3 surfaces were measured using surface electromyography (sEMG). For normalization, maximum sEMG signals were evaluated during each maximum voluntary isometric contraction (MVIC) maneuver. The root mean square during the exercise was normalized as a percentage of the MVIC (%MVIC). In the supine and prone positions, %MVIC of the IO, RA, MF, and ES during BSE was significantly higher than those during BBE and NBE (p < 0.05). In the supine position, %MVIC of the RA and ES during BBE was significantly higher than that during NBE (p < 0.05). In the prone position, all %MVIC during BBE were significantly higher than NBE (p < 0.05). These results verify the theory that the use of an unstable surface increases the activation of global and local trunk muscles during bridging exercises in the supine and prone positions. In conclusion, the use of BSE in a rehabilitation program may have therapeutic effects for patients with LBP by increasing trunk muscle activation. Key pointsCompared with the BBE and NBE, the BSE increased the %MVIC values of the IO, RA, MF, and ES muscles in the supine and prone positions in the patients with LBP.We verified that activation of the global and local trunk muscles was increased by the use of unstable surfaces during the bridging exercises in the supine and prone positions.The BSE was shown to be an effective exercise method for patients with LBP in a rehabilitation program by increasing trunk muscle activation. PMID- 24149362 TI - Notational Analysis of Elite Men's Water Polo Related to Specific Margins of Victory. AB - The present study aimed to analyze the water polo matches of the men's World Championships, comparing technical and tactical aspects of winning and losing teams, during closed (<= 3 goals of margin of victory at the end of the 4(th) quarter; winning, W; losing, L) and unbalanced (>3 goals; winning, MW; losing, ML) games. Therefore, 42 of the 48 (6 were draw at end of the 4(th) quarter) matches were considered. According to each game situation (i.e., even, counterattack, power-play, transition), a notational analysis was performed in relation to the following aspects: occurrence of actions, action outcome, execution and origin of shots, and mean duration. In addition, the occurrence of the offensive (and role) and defensive arrangements of even and power-play were analyzed. To show differences (p < 0.05) in terms of margin of victory, an analysis of variance was applied. Although ML (74 +/- 11%) performed more even actions than W (68 +/- 7%) and MW (69 +/- 6%), the latter teams (W = 9 +/- 6%; MW = 13 +/- 6%) performed more counterattacks than L (3 +/- 2%) and ML (5 +/- 5%). Power-play is more played during closed (W = 20 +/- 3%; L = 22 +/- 3%) than unbalanced games (MW = 17 +/- 4%; ML = 16 +/- 7%). Moreover, differences in terms of margin of victory emerged for mean duration (even, power-play, transition), action outcome (even, power-play), zone origin (even, counterattack, power-play) and technical execution (even, power-play) of shots, and even and power-play offensive (and role) and defensive arrangements. Divergences mainly emerged between closed and unbalanced games, highlighting that the water polo matches of the men's World Championships need to be analyzed either considering the winning and losing outcome of match and specific margins of victory. Thus, coaches can advance their knowledge, considering that closed and unbalanced games are largely characterized by the opponent's exclusion fouls to perform power-play actions, and by a divergent grade of defensive skills regardless of game situation, respectively. Key pointsThe water polo matches of the men's World Championships need to be analyzed considering successful/unsuccessful teams as well as specific margins of victory.Closed matches are mainly characterized by a high occurrence of the opponent's exclusion fouls to perform the power-play actions.For the unbalanced matches, a divergent grade of defensive skills between teams has been highlighted.Coaches can improve their training, considering the opponent's exclusion fouls to perform the power-play actions towards a closed match, and caring the defensive skills of each game situation towards an unbalanced match. PMID- 24149363 TI - Effects of distance specialization on the backstroke swimming kinematics. AB - The purpose of the present study was to investigate different biomechanical variables of backstroke technique in swimmers specialized in different distance events, in order to investigate the capacity to modify the timing of the arm stroke when changing the swimming velocity from sub-maximal to maximal. Two 25-m backstroke trials respectively at 70% of maximum velocity (V70) and at 100% of maximum velocity (Vmax) were performed by 9 200-m distance swimmers and 9 50-m distance swimmers. Swimming velocity, stroke length, stroke rate, duration of different phases of the arm stroke and selected kinematic variables were assessed in both cases. In the 50-m distance swimmers, the duration of the propulsive phase at Vmax, expressed as a percentage of the duration of the total underwater arm stroke, increased significantly (p = 0.001) with increasing swimming velocity. Specifically, both the pull and push phases were fundamental in the increase of duration of the propulsive phase. When compared to 200-m specialists, 50-m distance swimmers seem to be more able to modify their arm stroke phases duration when increasing the swimming velocity in backstroke. Key pointsThe 50-m DS are able to find an optimal timing among the stroke phases increasing the duration of the propulsive phase.The 50-m DS, when increasing the swimming velocity, show a more efficient relationship between propulsive and non propulsive phases with respect to the 200-m DS.Both pull and push phases are key factors for increasing the duration of the propulsive phase for the 50-m DS. PMID- 24149364 TI - Modelling the Progression of Competitive Performance of an Academy's Soccer Teams. AB - Progression of a team's performance is a key issue in competitive sport, but there appears to have been no published research on team progression for periods longer than a season. In this study we report the game-score progression of three teams of a youth talent-development academy over five seasons using a novel analytic approach based on generalised mixed modelling. The teams consisted of players born in 1991, 1992 and 1993; they played totals of 115, 107 and 122 games in Asia and Europe between 2005 and 2010 against teams differing in age by up to 3 years. Game scores predicted by the mixed model were assumed to have an over dispersed Poisson distribution. The fixed effects in the model estimated an annual linear pro-gression for Aspire and for the other teams (grouped as a single opponent) with adjustment for home-ground advantage and for a linear effect of age difference between competing teams. A random effect allowed for different mean scores for Aspire and opposition teams. All effects were estimated as factors via log-transformation and presented as percent differences in scores. Inferences were based on the span of 90% confidence intervals in relation to thresholds for small factor effects of x//1.10 (+10%/-9%). Most effects were clear only when data for the three teams were combined. Older teams showed a small 27% increase in goals scored per year of age difference (90% confidence interval 13 to 42%). Aspire experienced a small home-ground advantage of 16% (-5 to 41%), whereas opposition teams experienced 31% (7 to 60%) on their own ground. After adjustment for these effects, the Aspire teams scored on average 1.5 goals per match, with little change in the five years of their existence, whereas their opponents' scores fell from 1.4 in their first year to 1.0 in their last. The difference in progression was trivial over one year (7%, -4 to 20%), small over two years (15%, -8 to 44%), but unclear over >2 years. In conclusion, the generalized mixed model has marginal utility for estimating progression of soccer scores, owing to the uncertainty arising from low game scores. The estimates are likely to be more precise and useful in sports with higher game scores. Key pointsA generalized linear mixed model is the approach for tracking game scores, key performance indicators or other measures of performance based on counts in sports where changes within and/or between games/seasons have to be considered.Game scores in soccer could be useful to track performance progression of teams, but hundreds of games are needed.Fewer games will be needed for tracking performance represented by counts with high scores, such as game scores in rugby or key performance indicators based on frequent events or player actions in any team sport. PMID- 24149365 TI - The effects of a carbohydrate-protein gel supplement on alpine slalom ski performance. AB - Alpine slalom ski racing is a high intensity, complex sport in which racers execute turns every second. Acute fatigue can make the difference in not finishing a run (DNF) or finishing out of contention. The quantity and quality of training often dictates racing success. It is not known if nutritional supplementation can improve performance in this high intensity, short duration activity. The objective of this study was to determine if ingesting a carbohydrate-protein energy gel (GEL) improves finishing success and number of gates completed during 2 hr slalom sessions on two consecutive days of training. Twenty-four racers were matched; one group ingested the GEL, the second group received a liquid placebo (PLA). Total carbohy-drate, protein, and water ingested by the GEL group were 60g, 15g, and 450 mL, while the PLA group ingested 450 mL of PLA. The GEL group had significantly fewer DNF's (7/48 vs. 18/48; p = 0.02) on both days, completed a greater number of training gates on Day 2 (260.3 +/- 20.1 vs. 246.3 +/- 17.5 gates; p = 0.03), and had a lower RPE (3.9 +/- 1.2 vs. 5.3 +/- 1.2 on Day 2 (p = 0.004) vs. PLA. The statistical analysis of combined finishing times was not possible due to the high number of DNF's in the PLA group. High intensity slalom performance can be im-proved by the ingestion of an energy gel. The GEL allowed the athletes to improve training quantity and quality and their per-ception of effort was less than skiers who ingested a placebo. Key pointsNutritional supplementation with a carbohydrate/protein sports gel during high intensity ski training improved training volume as measured by the number gates completed.Supplementation also reduced the number of DNF's during training.Racers' perception of effort was significantly lower with the supplement ingestion compared to a non-caloric placebo.This applied study was conducted under real life field conditions and training environments. PMID- 24149366 TI - Field of vision influences sensory-motor control of skilled and less-skilled dart players. AB - One characteristic of perceptual expertise in sport and other domains is known as 'the quiet eye', which assumes that fixated information is processed during gaze stability and insufficient spatial information leads to a decrease in performance. The aims of this study were a) replicating inter- and intra-group variability and b) investigating the extent to which quiet eye supports information pick-up of varying fields of vision (i.e., central versus peripheral) using a specific eye-tracking paradigm to compare different skill levels in a dart throwing task. Differences between skill levels were replicated at baseline, but no significant differences in throwing performance were revealed among the visual occlusion conditions. Findings are generally in line with the association between quiet eye duration and aiming performance, but raise questions regarding the relevance of central vision information pick-up for the quiet eye. Key pointsInvestigation of throwing performance and quiet eye duration in dart throwing under several vision conditionsFirst investigation using a dynamic occlusion paradigm, manipulating field of vision in situReplication of previous findings concerning throwing performance and quiet eye durationNew insights about the role of central (and peripheral) vision concerning the quiet eye phenomena. PMID- 24149367 TI - Does single intramuscular application of autologous conditioned plasma influence systemic circulating growth factors? AB - Platelet-rich plasma (PRP) has been employed to treat sports injuries to possibly accelerate healing and regeneration. This method offers some potential, especially for athletes. Growth factors are generally prohibited by the World Anti Doping Agency with exception to PRP which may induce adverse effects. The aim of this study was to evaluate any systemic increase of growth factors such as Insulin Like Growth Factor-1, Endothelial Growth Factors, Platelet-Derived Growth Factors, Fibroblast Growth Factors, Vascular-Endothelial Growth Factor and Transforming Growth Factors after local intramuscular administration of PRP in young, healthy male subjects keeping in mind adverse treatment effects. Enriched plasma from centrifuged blood samples was injected into the gluteus muscle. Venous blood was collected and serum prepared before as well as 0.5, 3 and 24 hours after PRP administration. Growth factors were analyzed using ELISA test kits. No significant systemic increase of growth factor levels was found after PRP injection except TGF-beta2. For that reason the PRP method may be applied for muscle injury treatment in elite athletes although further studies are necessary to clarify the response to the unspecific increased TGF-beta2 blood levels, which could increase the risk for local fibrosis. Key pointsMuscle injuryAutologous conditioned plasmaSystemic circulating growth factorsDoping. PMID- 24149368 TI - Detraining-related changes in left ventricular wall thickness and longitudinal strain in a young athlete likely to have hypertrophic cardiomyopathy. AB - One of the diagnostic criteria in order to differentiate between physiological and pathological left ventricular hypertrophy is the wall thickness reduction after at least 3-month detraining period, which is considered a marker of the athlete's heart. This report describes detraining-related regression of LV hypertrophy and improvement in myocardial deformation in a junior athlete likely to have hypertrophic cardiomyopathy. Key pointsHypertrophic cardiomyopathy in adolescent athletes can be discovered by 12-lead ECGPhysical training is an important trigger for the clinical presentation of hypertrophic cardiomyopathyReverse LV remodeling (wall thickness reduction) with detraining is a common echocardiographic finding in athletes with physiological hypertrophyThis report demonstrates that reverse remodeling can also be found in adolescent athletes likely to have hypertrophic cardiomyopathy. PMID- 24149369 TI - Ultra-high aspect ratio replaceable AFM tips using deformation-suppressed focused ion beam milling. AB - Fabrication of ultra-high aspect ratio exchangeable and customizable tips for atomic force microscopy (AFM) using lateral focused ion beam (FIB) milling is presented. While on-axis FIB milling does allow high aspect ratio (HAR) AFM tips to be defined, lateral milling gives far better flexibility in terms of defining the shape and size of the tip. Due to beam-induced deformation, it has so far not been possible to define HAR structures using lateral FIB milling. In this work we obtain aspect ratios of up to 45, with tip diameters down to 9 nm, by a deformation-suppressing writing strategy. Several FIB milling strategies for obtaining sharper tips are discussed. Finally, assembly of the HAR tips on a custom-designed probe as well as the first AFM scanning is shown. PMID- 24149370 TI - Epigenetic regulation of miR-21 in colorectal cancer: ITGB4 as a novel miR-21 target and a three-gene network (miR-21-ITGBeta4-PDCD4) as predictor of metastatic tumor potential. AB - Previous studies have uncovered several transcription factors that determine biological alterations in tumor cells to execute the invasion-metastasis cascade, including the epithelial-mesenchymal transition (EMT). We sought to investigate the role of miR-21 in colorectal cancer regulation. For this purpose, miR-21 expression was quantified in a panel of colorectal cancer cell lines and clinical specimens. High expression was found in cell lines with EMT properties and in the vast majority of human tumor specimens. We demonstrate in a cell-specific manner the occupancy of MIR-21 gene promoter by AP-1 and ETS1 transcription factors and, for the first time, the pattern of histone posttranslational modifications necessary for miR-21 overexpression. We also show that Integrin-beta4 (ITGbeta4), exclusively expressed in polarized epithelial cells, is a novel miR-21 target gene and plays a role in the regulation of EMT, since it is remarkably de repressed after transient miR-21 silencing and downregulated after miR-21 overexpression. miR-21-dependent change of ITGbeta4 expression significantly affects cell migration properties of colon cancer cells. Finally, in a subgroup of tumor specimens, ROC curve analysis performed on quantitative PCR data sets for miR-21, ITGbeta4, and PDCD4 shows that the combination of high miR-21 with low ITGbeta4 and PDCD4 expression is able to predict presence of metastasis. In conclusion, miR-21 is a key player in oncogenic EMT, its overexpression is controlled by the cooperation of genetic and epigenetic alterations, and its levels, along with ITGbeta4 and PDCD4 expression, could be exploited as a prognostic tool for CRC metastasis. PMID- 24149371 TI - Continuous low-dose irradiation by I-125 seeds induces apoptosis of gastric cancer cells regardless of histological origin. AB - The efficacy of conventional radiation therapy for gastric cancer is controversial. In this study, we evaluated the in vitro and in vivo effects of continuous low-dose-rate irradiation by I-125 seeds on different histological types of gastric cancer cell lines. Three human gastric cancer cell lines (MKN74, MKN45, and NUGC4) were treated with or without continuous low-dose irradiation by I-125 seeds in vitro and in vivo. Cell viability, apoptosis, caspase-3 assay, and cell-cycle distribution were examined in vitro. Body weight and tumor volumes of BALB/c nude mice bearing MKN74, MKN45, and NUGC4 gastric cancer xenografts were measured, and in vivo cell proliferation and apoptosis assays were performed by Ki67 and TUNEL staining, respectively. Continuous low-dose-rate irradiation by I 125 seeds reduced cell viability and induced cell apoptosis through the activation of caspase-3, and led to the accumulation of cells in the G 2/M phase in vitro. It also suppressed the growth of gastric cancer xenografts in nude mice, while inhibiting cell proliferation and inducing apoptosis as demonstrated by Ki67 and TUNEL staining. Therefore, our data suggest that continuous low-dose rate irradiation by I-125 seeds could be a promising new option for gastric cancer treatment, regardless of histological origin. PMID- 24149372 TI - Sirt6 regulates postnatal growth plate differentiation and proliferation via Ihh signaling. AB - Sirtuin 6 (Sirt6) is a mammalian homologue of NAD+-dependent histone deacetylase Sir2. Although Sirt6-/- mice exhibit growth retardation, the role of Sirt6 in cartilage metabolism is unclear. The aim of this study was to investigate the Sirt6 signaling pathway in cartilage metabolism. Immunohistological evaluation of the tibial growth plate in Sirt6-/- mice exhibited impaired proliferation and differentiation of chondrocytes, reduced expression of Indian hedgehog (Ihh), and a senescent phenotype. When Sirt6 was knocked down in chondrocytes in vitro, expression of Ihh and its downstream genes were reduced. Impaired differentiation by Sirt6 silencing was completely rescued by administration of a Hh signal agonist. When sirtuins were activated, chondrocyte differentiation was enhanced together with activation of Ihh signal, and these effects were abrogated by Sirt6 silencing. ChIP assay revealed the affinity of ATF4 to the Ihh promoter was markedly decreased by Sirt6 knockdown. These data indicate Sirt6 directly controls proliferation and differentiation of chondrocytes. PMID- 24149373 TI - Invited commentaries. PMID- 24149374 TI - In response. PMID- 24149375 TI - In response. PMID- 24149376 TI - Vortex magnetic structure in framboidal magnetite reveals existence of water droplets in an ancient asteroid. AB - The majority of water has vanished from modern meteorites, yet there remain signatures of water on ancient asteroids. How and when water disappeared from the asteroids is important, because the final fluid-concentrated chemical species played critical roles in the early evolution of organics and in the final minerals in meteorites. Here we show evidence of vestigial traces of water based on a nanometre-scale palaeomagnetic method, applying electron holography to the framboids in the Tagish Lake meteorite. The framboids are colloidal crystals composed of three-dimensionally ordered magnetite nanoparticles and therefore are only able to form against the repulsive force induced by the surface charge of the magnetite as a water droplet parches in microgravity. We demonstrate that the magnetites have a flux closure vortex structure, a unique magnetic configuration in nature that permits the formation of colloidal crystals just before exhaustion of water from a local system within a hydrous asteroid. PMID- 24149377 TI - Young children's use of honesty as a basis for selective trust. AB - The ability of 3- to 5-year-old children to reason about trust in relation to the honest behavior of others was examined across five studies (total N=496). Results showed that although 4-year-olds differentiated between honest and dishonest sources in their trust judgments, only 5-year-olds demonstrated a clear capacity to differentiate between honesty and a trust-irrelevant dimension (i.e., cleanliness) in these trust judgments. This was seen in their tendency to trust honest characters more than clean ones and to distrust dishonest characters more than unclean ones. This was also seen in their tendency to choose honest unclean characters over dishonest clean ones in their trust judgments. Results suggest that children use honesty as a basis for selective trust even before they appreciate which specific traits are relevant to trust. PMID- 24149378 TI - Perception-action development from infants to adults: perceiving affordances for reaching through openings. AB - Perceiving possibilities for action-affordances-requires sensitivity, accuracy, and consistency. In the current study, we tested children of different ages (16 month-olds to 7-year-olds) and adults to examine the development of affordance perception for reaching through openings of various sizes. Using a psychophysical procedure, we estimated individual affordance functions to characterize participants' actual ability to fit their hand through openings and individual decision functions to characterize attempts to reach. Decisions were less accurate in younger children (16-month-olds to 5-year-olds); they were more likely to attempt impossible openings and to touch openings prior to refusing, suggesting a slow developmental trend in learning to perceive affordances for fitting through openings. However, analyses of multiple outcome measures revealed that the youngest participants were equally consistent in their decision making as the oldest ones and that every age group showed sensitivity to changes in the environment by scaling their attempts to opening size. PMID- 24149379 TI - Influence of exercise order on maximum strength and muscle thickness in untrained men. AB - Traditional exercise order dictates large muscle group or multijoint exercises should be performed before small muscle group or single joint exercises. The purpose of this study was to examine the influence of exercise order on strength and muscle thickness (MT) in untrained men after 12 weeks of linear periodized resistance training. The participants were randomly assigned into three groups. One group began with large and progressed toward small muscle group exercises (LG SM) while another started with small and advanced to large muscle group exercises (SM-LG). The exercise order for LG-SM was bench press (BP), lat pull-down (LPD), triceps extension (TE), and biceps curl (BC). The order for the SM-LG was BC, TE, LPD, and BP. The third group served as a control group (CG). Training frequency was two sessions/week with at least 72 hours between sessions. One repetition maximum (1RM) for all exercises, biceps and triceps MT (assessed by ultrasound techniques) were collected at baseline and after 12 weeks. After 12 weeks, all exercises for both training groups presented significant 1RM strength gains when compared to CG with exception of BC in LG-SM. Between baseline and post training, all exercises for both training groups presented significant strength gains with exception of BC in LG-SM and BP in SM-LG. Triceps MT for both training groups were significantly higher when compared to the CG, but with no significant differences between them (p > 0.05). Significant differences in MT from pre- to post-training were found only for the SM-LG group (p < 0.05), while the biceps MT presented significant differences only between LG-SM and CG (p < 0.05), Effect size data demonstrated differences in 1RM and triceps MT based on exercise order. In conclusion, if an exercise is important for specific training goals, it should be performed at the beginning of the training session, whether or not it is a large or a small muscle group exercise. Key pointsThe two linear periodized resistance training programs utilized promotes strength and muscle volume gains in untrained men.Exercise order may be particularly important to improve strength during 12 weeks of linear periodized resistance training.If an exercise is important for the training goals of a program, then it should be placed at the beginning of the training session, whether or not it is a large or a small muscle group exercise. PMID- 24149380 TI - Prediction of sport adherence through the influence of autonomy-supportive coaching among spanish adolescent athletes. AB - The purpose of this study was to test a motivational model of the coach-athlete relationship, based on self-determination theory and on the hierarchical model of intrinsic and extrinsic motivation. The sample comprised of 608 athletes (ages of 12-17 years) completed the following measures: interest in athlete's input, praise for autonomous behavior, perceived autonomy, intrinsic motivation, and the intention to be physically active. Structural equation modeling results demonstrated that interest in athletes' input and praise for autonomous behavior predicted perceived autonomy, and perceived autonomy positively predicted intrinsic motivation. Finally, intrinsic motivation predicted the intention to be physically active in the future. The results are discussed in relation to the importance of the climate of autonomy support created by the coach on intrinsic motivation and adherence to sport by adolescent athletes. Further, the results provide information related to the possible objectives of future interventions for the education of coaches, with the goal of providing them with tools and strategies to favor the development of intrinsic motivation among their athletes. In conclusion, the climate of autonomy support created by the coach can predict the autonomy perceived by the athletes which predicts the intrinsic motivation experienced by the athletes, and therefore, their adherence to athletic practice. Key pointsImportance of the climate of autonomy support created by the coach on intrinsic motivation and adherence to sport by adolescent athletes.Interest in athletes' input and praise for autonomous behavior predicted perceived autonomy, and perceived autonomy positively predicted intrinsic motivation.Intrinsic motivation predicted the intention to be physically active in the future. PMID- 24149381 TI - Kinematic description of elite vs. Low level players in team-handball jump throw. AB - The jump throw is the most applied throwing technique in team- handball (Wagner et al., 2008); however, a comprehensive analysis of 3D-kinematics of the team handball jump throw is lacking. Therefore, the purpose of our study was: 1) to measure differences in ball release speed in team- handball jump throw and anthropometric parameters between groups of different levels of performance and (2) to analyze upper body 3D-kinematics (flexion/extension and rotation) to determine significant differences between these groups. Three-dimensional kinematic data was analyzed via the Vicon MX 13 motion capturing system (Vicon Peak, Oxford, UK) from 26 male team-handball players of different performance levels (mean age: 21.2 +/- 5.0 years). The participants were instructed to throw the ball (IHF Size 3) onto a target at 8 m distance, and to hit the center of a square of 1 * 1 m at about eye level (1.75 m), with maximum ball release speed. Significant differences between elite vs. low level players were found in the ball release speed (p < 0.001), body height (p < 0.05), body weight (p < 0.05), maximal trunk internal rotation (p < 0.05), trunk flexion (p < 0.01) and forearm pronation (p < 0.05) as well as trunk flexion (p < 0.05) and shoulder internal rotation (p < 0.001) angular velocity at ball release. Results of our study suggest that team-handball players who were taller and of greater body weight have the ability to achieve a higher ball release speed in the jump throw, and that an increase in trunk flexion and rotation angular velocity improve the performance in team-handball jump throw that should result in an increase of ball release speed. Key pointsTeam-handball players who were taller and of greater body weight have the ability to achieve a higher ball release speed.An increase in trunk flexion, trunk rotation and shoulder internal rotation angular velocity should result in an increase of ball release speed.Trunk movements are normally well observable for experienced coaches, easy correctable and therefore practical to improve the performance in team-handball jump throw of low level players during training without using complex measurement devices. PMID- 24149382 TI - The effects of intermittent exercise on physiological outcomes in an obese population: continuous versus interval walking. AB - This study compared the effects of 12 weeks of caloric restriction and interval exercise (INT) and caloric restriction and continuous aerobic exercise (CON) on physiological outcomes in an obese population. Forty-four individuals (BMI >= 30 kg.m(-2)) were randomised into the INT or CON group. Participant withdrawal resulted in 12 and 14 participants in the INT and CON groups, respectively. All participants were on a strict monitored diet. Exercise involved two 15-min bouts of walking performed on five days per week. Interval exercise consisted of a 2:1 min ratio of low-intensity (40-45% VO2peak) and high- intensity (70-75% VO2peak) exercise, while the CON group exercised between 50-55% VO2peak. Exercise duration and average intensity (%VO2peak) were similar between groups. There were no significant differences (p > 0.05) between the two groups for any variable assessed apart from very low density lipoprotein (VLDL-C), which significantly decreased over time in the INT group only (p < 0.05, d = 1.03). Caloric restriction and interval exercise compared to caloric restriction and continuous aerobic exercise resulted in similar outcome measures apart from VLDL-C levels, which significantly improved in the INT group only. Key pointsTwelve weeks of interval exercise and caloric restriction resulted in significant improvement in very low density lipoprotein cholesterol in an obese population, as compared to continuous aerobic exercise and caloric restriction.Twelve weeks of either interval exercise or continuous exercise resulted in similar improvements in aerobic fitness in an obese population. PMID- 24149383 TI - Relationship between training status and maximal fat oxidation rate. AB - This study aimed to compare maximal fat oxidation rate parameters between moderate- and low-performance runners. Eighteen runners performed an incremental treadmill test to estimate individual maximal fat oxidation rate (Fatmax) based on gases measures and a 10,000-m run on a track. The subjects were then divided into a low and moderate performance group using two different criteria: 10,000-m time and VO2max values. When groups were divided using 10,000-m time, there was no significant difference in Fatmax (0.41 +/- 0.16 and 0.27 +/- 0.12 g.min(-1), p = 0.07) or in the exercise intensity that elicited Fatmax (59.9 +/- 16.5 and 68.7 +/- 10.3 % O2max, p = 0.23) between the moderate and low performance groups, respectively (p > 0.05). When groups were divided using VO2max values, Fatmax was significantly lower in the low VO2max group than in the high VO2max group (0. 29 +/- 0.10 and 0.47 +/- 0.17 g.min(-1), respectively, p < 0.05) but the intensity that elicited Fatmax did not differ between groups (64.4 +/- 14.9 and 61.6 +/- 15.4 %VO2max). Fatmax or %VO2max that elicited Fatmax was not associated with 10,000 m time. The only variable associated with 10,000-m running performance was %VO2max used during the run (p < 0.01). In conclusion, the criteria used for the division of groups according to training status might influence the identification of differences in Fatmax or in the intensity that elicits Fatmax. Key pointsThe results of the present study suggest that the criteria used to categorize aerobic training status of subjects can influence the magnitude of differences in Fatmax.The Fatmax is similar between groups with similar 10,000-m running performance.The 10,000-m running performance seems to be associated with an increased ability to oxidize carbohydrate. PMID- 24149384 TI - Stability of patterns of behavior in the butterfly technique of the elite swimmers. AB - The purpose of this study was to find patterns in the butterfly swimming technique, with an adaptation of the Behavioral Observation System Tech. This, as an instrument for ad-hoc qualitative analysis, enables the study of the stability of the technical implementation. When used in the training of swimmers, analysis can reduce the variability of behavioral tuning swimming technique. Through the analysis of temporal patterns (T-pattern) and a sequence of five cycles running at hand maximum speed, the behavior of four technical Portuguese elite swimmers, with a record of 259 alphanumeric codes and a total of 160 configurations, were studied. The structure of the original instrument, based on a mixed system of categories and formats Field, can record technical features, observed during the execution of hand cycles. The validity was ensured through the index of intra observer reliability (95%) and inter-observer accuracy (96%). To detect patterns in each swimmer, the Theme 5.0 software was used, which allowed to identify the stable structures of technical performance within a critical interval of time (p <0.05) - t-patterns. The patterns were different, adjusting to the characteristics of technical implementation of the swimmers. It was found that the swimmer can create settings with different levels of structure complexity, depending on the implementation of changes within the hand cycle. Variations of codes in each configuration obtained using the SOCTM, allowed determining the differences between swimmers. However, the records showed a clear behavioral similarity when comparing the result with a general pattern of the butterfly technique. The potential quality of this instrument seems to be important due to the patterns obtained from a temporal sequence. Key pointsThe patterns were different, adjusting to the characteristics of technical implementation of the swimmers.The swimmer can make settings with different levels of structure complexity, depending on the implementation of changes within the hand cycle.Variations of codes in each configuration obtained using the SOCTM, allowed determining the differences between swimmers.The records showed a clear behavioral similarity when comparing the result with a general pattern of the butterfly technique.The potential quality of this instrument seems to be important due to the patterns obtained from a temporal sequence. PMID- 24149385 TI - Rugby Game-Related Statistics that Discriminate Between Winning and Losing Teams in Irb and Super Twelve Close Games. AB - The aim of the current study was to identify the Rugby game- related statistics that discriminated between winning and losing teams in IRB and S12 close games. Archival data reported to game-related statistics from 120 IRB games and 204 Super Twelve games played between 2003 and 2006. Afterwards, a cluster analysis was conducted to establish, according to game final score differences, three different match groups. Only the close games group was selected for further analysis (IRB n = 64 under 15 points difference and Super Twelve n = 95 under 11 points difference). An analysis to the structure coefficients (SC) obtained through a discriminant analysis allowed to identify the most powerful game related statistics in discriminating between winning and losing teams. The discriminant functions were statistically significant for Super Twelve games (Chi square = 33.8, p < 0.01), but not for IRB games (Chi- square = 9.4, p = n.s.). In the first case, winners and losers were discriminated by possessions kicked (SC = 0.48), tackles made (SC = 0.45), rucks and pass (SC = -0.40), passes completed (SC = 0. 39), mauls won (SC = -0.36), turnovers won (SC = -0.33), kicks to touch (SC = 0.32) and errors made (SC = -0.32). The minus sign denotes higher values in losing teams. Rugby game-related statistics were able to discriminate between winners and losers in Super Twelve close games and suggest that a kicking based game supported by an effective defensive structure is more likely to win matches than a possession based one. Key pointsWinning teams made fewer passes and won fewer turnovers on their opposition's possession.International competitions that include teams from all nations are unlikely to show statistically significant differences between winning and losing teams when the difference between the final score is 15 points or less.Regional competitions do elicit significant differences between winning and losing teams and suggest that a kicking based game plan is a more effective style of play during the S12 competition than an open running possession dominated game. PMID- 24149386 TI - The influence of ball velocity and court illumination on reaction time for tennis volley. AB - The he purpose of this study is to examine the effects of ball velocity, court illumination, and volley type on the reaction time (RT) of a tennis athlete for a volley stroke. Eights cases with two different ball velocities (high and low), two volley types (forehand and backhand ) and two court illumination levels (dark and bright) were studied. The 30 participating subjects consisted of 18 male and 12 female college tennis athletes (age: 24 +/- 3.2 yr), with a United States Tennis Association (USTA) ranking above 2.5. In order to ensure the validity of real-world correlations, the experiments were designed to simulate real competition situations. Reaction times were measured for volley strokes in response to different approaching ball velocities (high: 25.05 +/- 0.37 m/s and low: 17.56 +/- 0.92 m.s(-1)) for several volley types (forehand and backhand) and court illumination levels (55649 +/- 4292 lux and 363.24 +/- 6.53 lux on the court). During the tests, the signals from an electromyogram sensor and a 3-axis accelerometer (+/- 50 g) were recorded using an NI DAQ card (NI PXI-6251) and then analyzed to determine reaction time (RT), premotor reaction time (PRT), and motor reaction time (MRT) through the LabVIEW system. Subsequent 3-way ANOVA analysis indicated no RT, PRT, or MRT interaction between ball velocity, volley type and illumination. The ball velocity and illumination parameters did affect RT and PRT values significantly with p < 0.05, no significant variation in MRT was observed across any implemented experimental conditions. All experimental results indicate that ball velocity and illumination levels strongly affect the value of PRT, but have no significant effect on the value of MRT, the changes in RT were dominated by PRT. Key pointsRT can generally be divided into two components with the help of the electromyogram (EMG) signal - the premotor reaction time (PRT) and the motor reaction time (MRT).The purpose of this study is to examine the effects of ball velocity, court illumination level, and volley type on the reaction time (RT) of the tennis athlete for volley strokes.Results strongly suggest that changes in RT were dominated by PRT; in light of this correspondence, it is clear that the ability to sense visual stimuli may be enhanced by proper training and practice. PMID- 24149387 TI - Coaches' perceptions of competence and acknowledgement of training needs related to professional competences. AB - The purpose of the present study was to examine coaches' perceptions of competence and acknowledgement of training needs related to professional competences according to the professional experience and academic education. The participants were 343 coaches from several sports, who answered to a questionnaire that includes a scale focused on perceptions of competence and another scale on acknowledgment of training needs. An exploratory factor analysis with Maximum Likelihood Factoring was used with Oblimin rotation for the identification of emergent factors. Comparison on coaches' perceptions in function of coaching experience and coaches' academic background were made applying One-way ANOVA and Tukey's post hoc multiple comparisons. Factor analysis on coaches' perceptions of competence and acknowledgement of training needs made apparent three main areas of competences, i.e. competences related to annual and multi-annual planning; competences related to orientation towards practice and competition; and personal and coaching education competences. Coaches' perceptions were influenced by their experience, as low experienced coaches rated themselves at lower levels of competence and with more training needs; also coaches with high education, in Physical Education or others, perceived themselves as more competent than coaches with no higher education. Finally, the majority of the coaches perceived themselves to be competent but, nevertheless, they indicated to have training needs, which brings an important feedback to coach education. This suggests that coaches are interested in increasing their knowledge and competence in a broad range of areas which should be considered in future coach education programs. Key pointsCoaches' perceptions of competence and acknowledgement of training needs resulted in three main areas: competences related to annual and multi-annual planning, competences related to practice and competition orientation and, finally, personal and coaching education competences.The professional tasks that coaches had the most need in performing were related to the training orientation.Coaches with higher education degrees (P.E. or others) perceive themselves as more competent than coaches with no higher education.Low experienced coaches perceived themselves less competent than high experienced coaches. Also, they pointed out more training needs in issues related to practice and competition orientation, and annual and multi-annual planning. PMID- 24149388 TI - Can 8-weeks of Training Affect Active Drag in Young Swimmers? AB - The aim of this study was to assess the effects of 8-weeks of training on active drag in young swimmers of both genders. Eight girls and twelve boys' belonging to the same swimming team and with regular competitive participation in national and regional events for the previous two seasons participated in this study. Active drag measurements were conducted in two different evaluation moments: at the beginning of the season and after 8 weeks of training (6.0 +/- 0.15 training units per week, 21.00 +/- 3.23 km per week and 3.50 +/- 0.23 km per training unit). The maximal swimming velocity at the distance of 13 m, active drag and drag coefficient were measured on both trials by the method of small perturbations with the help of an additional hydrodynamic body. After 8 weeks of training, mean active drag (drag force and drag coefficient) decreased in girls and boys, although no significant differences were found between the two trials. It seems that 8 weeks of swimming training were not sufficient to allow significant improvements on swimming technique. Key pointsThe velocity perturbation method seems to be a good, simple and reliable approach to assess active drag in young swimmers.Eight weeks of swimming training were not sufficient to allow significant improvements on swimming hydrodynamics.There were no differences between boys and girls concerning active drag. A possible explanation may be related to the similar values of body mass and height in boys and girls found in this study.Specific training sets concerning technique correction and improvement in young swimmers might be a main aim during training planning. PMID- 24149389 TI - Motivation and performance in physical education: an experimental test. AB - The purpose of this study was to analyse, experimentally, the relationships between motivation and performance in a lateral movement test in physical education. The study group consisted of 363 students (227 boys and 136 girls), aged between 12 and 16, who were randomly divided into three groups: an experimental group in which an incremental ability belief was induced, another experimental group in which an entity ability belief was induced, and a control group where there was no intervention. Measurements were made of situational intrinsic motivation, perceived competence in executing the task and performance. The results revealed that the incremental group reported higher scores on the situational intrinsic motivation scale. The entity group demonstrated better performance in the first test attempt than the incremental group but, in the second attempt, the performance was similar in the different groups. Perhaps the initial differences in performance disappeared because the incremental group counted on improving in the second attempt. These results are discussed in relation to the intensity with which the teacher conveys information relating to incremental ability belief of the pupil to increase intrinsic motivation and performance. Key pointsThe incremental group showed more situational intrinsic motivation.The entity group showed higher performance in the first test attempt, but significant differences disappeared in the second attempt.It seems that this incremental belief and greater intrinsic motivation made the students trust they would improve their performance in the second attempt at the lateral movement test. PMID- 24149390 TI - Four ball best ball 1. AB - In this paper a four-ball-best-ball (4BBB) model for pairs of golf players is set up. The 4BBB match-play scoring system is seen to satisfy a basic requirement of fairness. It is shown that it is not strictly possible to rate individual players as 4BBB players. However, a (reasonably broad) class of individual players is identified such that it is possible to rate them individually as 4BBB players. The capacity of an individual to play birdies is seen to be a very important determinant in being a successful member of a 4BBB pair, but there are other minor factors as well. Consideration is given to equal and unequal 4BBB pairs. The transitive law is seen to apply for 4BBB pairs. Thus, if pair A is better than pair B, and pair B is better than pair C, then pair A must be better than pair C. Correspondingly, if pair A is equal to pair B, and pair B is equal to pair C, then pair A is equal to pair C. Consideration is given to some strategic issues in 4BBB match-play golf. For example, the conditions under which a player should take a greater risk and have a higher probability of obtaining a bogie in order to achieve a higher probability of scoring a birdie, are determined. Also, the conditions under which a player, noting that his partner is about to have a 'bad' hole and score only a par or a bogie, should 'play safe', are determined. Thirdly, players who can interact in certain ways are seen to have an advantage over those pairs that cannot do this. Finally, one pair's optimal strategy when they see that their opponents are about to score a par or a bogie, but not a birdie, is analyzed. Key pointsA model for four-ball-best-ball match-play golf is established, and used to show that, although there can be other factors, the capacity of an individual to play birdies is a very important determinant in that player being a successful member of a four-ball-best-ball pair.Although it is not possible in general to rate play-ers individually as 4BBB players, a class of indi-vidual players is identified such that rating the players within that class is possible.Equal and unequal 4BBB pairs are considered, and the transitive law is seen to apply for 4BBB pairs. For example, if pair A is better than pair B, and pair B is better than pair C, then pair A must be better than pair C.Several strategic issues for individual players and pairs of players are considered, and optimal strate-gies identified. PMID- 24149391 TI - A comparison of wakeboard-, water skiing-, and tubing-related injuries in the United States, 2000-2007. AB - The purpose of the study was to compare tubing-related injuries to wakeboarding- and water skiing-related injuries. Data was collected from the 2000-2007 National Electronic Injury Surveillance Survey for 1,761 individuals seeking care at an emergency department due to a tubing-, wakeboarding, or water skiing-related injury. Data included patient age and sex, as well as injury characteristics including body region injured (i.e., head and neck, trunk, shoulder and upper extremity, and hip and lower extremity) and diagnosis of injury (e.g., contusion, laceration, or fracture). Case narratives were reviewed to ensure that a tubing-, wakeboarding-, or water skiing-related injury occurred while the individual was being towed behind a boat. Severe injury (defined as an injury resulting in the individual being hospitalized, transferred, held for observation) was compared among the groups using logistic regression. Wakeboard- and tubing-related injuries more commonly involved the head and neck, while water skiing- related injuries were likely to involve the hip and lower extremity. Tubing-related injuries, compared to water skiing-related injuries, were more likely to be severe (OR 2.31, 95% CI 1.23-4. 33). Like wakeboarding and water skiing, tubing has inherent risks that must be understood by the participant. While tubing is generally considered a safer alternative to wakeboarding and water skiing, the results of the current study suggest otherwise. Both the number and severity of tubing- related injuries could be prevented through means such as advocating the use of protective wear such as helmets while riding a tube or having recommended safe towing speeds prominently placed on inner tubes. Key pointsIncrease annual injury rate trend in wakeboard injuries.Wakeboard- and tubing-related injuries more often to head and neck, waterskiing-related injuries more often to hip and lower extremity.Tubing-related injuries over 2-times as likely to be severe compared to waterskiing-related injuries. PMID- 24149392 TI - Heart Rate and Motion Analysis by GPS in Beach Soccer. AB - Although beach soccer has become increasingly popular in recent years very little scientific research has been conducted into the sport. A pilot study was carried out with the aim of examining the physiological (heart rate) and physical (motion analysis) responses of beach soccer players during competitive matches. Ten players (age 25.5 +/- 0.5 years; height 1.80 +/- 0.08 m; weight 78.2 +/- 5.6 kg.) were studied over five beach soccer matches. The physiological demands were analysed by measuring heart rate (HR) using telemetric devices, while the physical profile was evaluated by recording motion and speed by means of GPS devices. During competitive matches, players obtained a HRmean of 165.2 bpm (86.5% HRmax), with 59.3% of the time participating (TP) corresponding to values above 90% of the HRmax. The distance covered per minute of participation was 97.7 m, with 9.5% of this distance corresponding to high-intensity running and 2.5% to sprint; the work:rest ratio was 1.4:1 and the maximum speed 21.7 km.h(-1). These results showed that beach soccer is an intermittent physical activity of greater intensity than other team games. It requires a major contribution from the anaerobic system as emphasis is placed on players making quick bursts of high intensity activity separated by brief rest periods. Key pointsThe distance covered per minute of play is around 100 m.Beach soccer is an intermittent sport with a work:rest ratio of 1.4:1.The playing surface in beach soccer is an important handicap to obtain maximum speeds.Beach soccer has a high physiological intensity, with more than half of the game is spent at intensities above 90 % of the HRmax. PMID- 24149393 TI - Muscle fibre type composition and body composition in hammer throwers. AB - Aim of the present study was to describe the muscle fibre type composition and body composition of well-trained hammer throwers. Six experienced hammer throwers underwent the following measurements: one repetition maximum in squat, snatch, and clean, standing broad jump, backward overhead shot throw and the hammer throw. Dual x-ray absorptiometry was used for body composition analysis. Fibre type composition and cross sectional area was determined in muscle biopsy samples of the right vastus lateralis. Eight physical education students served as a control group. One repetition maximum in squat, snatch and clean for the hammer throwers was 245 +/- 21, 132 +/- 13 and 165 +/- 12kg, respectively. Lean body mass was higher in hammer throwers (85.9 +/- 3. 9kg vs. 62.7 +/- 5.1kg (p < 0.01). The percentage area of type II muscle fibres was 66.1 +/- 4% in hammer throwers and 51 +/- 8% in the control group (p < 0.05). Hammer throwers had significantly larger type IIA fibres (7703 +/- 1171 vs. 5676 +/- 1270MUm(2), p < 0.01). Hammer throwing performance correlated significantly with lean body mass (r = 0.81, p < 0.05). These data indicate that hammer throwers have larger lean body mass and larger muscular areas occupied by type II fibres, compared with relatively untrained subjects. Moreover, it seems that the enlarged muscle mass of the hammer throwers contributes significantly to the hammer throwing performance. Key pointsWell-trained hammer throwers had increased lean body mass, higher type IIA muscle fibres cross sectional areas, as well as higher bone mineral density, compared to controls.Increased lean body mass was closely related with hammer throwing performance.The relative high percentage of type IIX muscle fibres in vastus lateralis in hammer throwers warrants further investigation. PMID- 24149394 TI - A comparison between ventilation and heart rate as indicator of oxygen uptake during different intensities of exercise. AB - The aim of this study is to compare the relation between ventilation (VE) and oxygen uptake (VO2) [VO2=f(VE)] and between heart rate (HR) and VO2 [VO2=f(HR)]. Each one of the subjects performed three types of activities of different intensities (walking without load, walking with load and intermittent work). VO2, VE, and HR were measured continuously by using indirect calorimetry and an electrocardiogram. Linear regressions and coefficients of determination (r(2)) were calculated to compare the relation VO2 =f(VE) and VO2 =f(HR) for two different regroupings: by session duration (r(2) session) and by subject (r(2) subject). Results showed that r(2) session of the relation VO2 =f(VE) were significantly higher than those of the relation VO2 =f(HR) for steady state activities (walking with or without load during 3 or 6 min, p < 0.01) and for activities without oxygen consumption steady state (walking with or without load during 1 min, p < 0.01 and intermittent work, p < 0.05). VE is more strongly correlated with VO2 than with HR. This is a very promising approach to develop a new method to estimate energy expenditure. Key pointsVentilation is more strongly correlated with oxygen uptake than heart rate during physical activities of different intensities.This study shows the interest to looking for ventilation to estimate energy expenditure.This study is a promising approach to develop a new method to estimate energy expenditureAn interesting perspective could be to develop a light and portable device to measure ventilation based on the coupling of four magnetometers. PMID- 24149395 TI - The effect of chinese yuanji-dance on dynamic balance and the associated attentional demands in elderly adults. AB - Walking performance changes with age. This has implications for the problem of falls in older adults. The aim of this study was to investigate the effects of Yuanji-Dance practice on walking balance and the associated attention demand in healthy elderly. Fifteen community-dwelling elderly (comparison group, no regular exercise habit) and fifteen Yuanji- Dance elderly (exercise group, dancing experience: 5.40 +/- 1.95 years), aged 60-70 years, were included in this study. The subjects in exercise group participated in a 90-minute Yuanji-Dance practice at least three times per week and the comparison group continued their normal daily physical activity. Walking balance measures (including walking velocity, step length, step width, and percentage of time spent in double limb support, COM velocity and COM-COP inclination angles) and attentional demand tests (button reaction time and accuracy) were conducted under different conditions. Our results showed that stride lengths, walking velocities, peak A/P velocities (AP V) of the COM, medial COM-COP inclination (M angle) angles, reaction time, and accuracy decrease significantly as the dual-task (walking plus hand button pressing tasks) applied for either the comparison or exercise groups. These results demonstrated that walking performance is attenuated in our elderly participants as the cognitive tasks applied. Analysis also identified a significantly faster RT for our exercise group both in standing and walking conditions. This may indicate that physical exercise (Yuanji-Dance) may have facilitating effects on general cognitive and perceptual- motor functions. This implies that Chinese Yuanji-Dance practice for elderly adults may improve their personal safety when walking especially under the condition of multiple task demand. Key pointsThe purpose of this study was to investigate the training effects of a Chinese traditional exercise, Yuanji-Dance, on walking balance and the associated attention demand in the healthy elderly.Walking performance is attenuated in elderly participants as the cognitive tasks applied.A significantly faster reaction time for our exercise group both in standing and walking conditions.Yuanji-Dance exercise training can improve the information processing speed of elderly people and has no influence of the dynamic walking balance. PMID- 24149396 TI - Trunk Rotation and Weight Transfer Patterns between Skilled and Low Skilled Golfers. AB - The purpose of this study was to examine trunk rotational patterns and weight transfer patterns that may differentiate swing skill level in golfers. Thirteen skilled golfers (mean handicap = 0.8 +/- 2.6) and seventeen low skilled golfers (mean handicap = 30.8 +/- 5.5) participated in this study. Kinematic and kinetic data were obtained through high-speed 3-D videography and force plates while the participant performed a full shot golf swing with a driver. Data at six temporal events during the swing were selected for the analysis. The results indicated that significant differences existed between the groups in the multiple events, as the skilled golfers showed the following motion patterns when compared to the low skilled golfers; 1) An earlier trunk horizontal rotation with a rapid weight transfer to the trail foot during the backswing; 2) An earlier pelvic horizontal rotation accompanied with an earlier weight transfer to the lead foot during the downswing motion; and 3) Less upper trunk horizontal rotation and more posterior pelvic rotation at the follow through. Collectively, these finding may be useful for instruction of golfers to improve their swing mechanics on a full shot golf swing. Key pointsDifferent trunk rotation and weight transfer patterns were found between skilled and low skilled golfers.Earlier trunk rotation accompanied with earlier weight transfer to the trail foot during the back swing was evident in the skilled golfers.Earlier pelvic horizontal rotation with a rapid weight transfer to the lead foot during the downswing was evident in the skilled golfers. PMID- 24149397 TI - Potential for Non-Contact ACL Injury Between Step-Close-Jump and Hop-Jump Tasks. AB - This study aimed to compare the kinematics and kinetics during the landing of hop jump and step-close-jump movements in order to provide further inferring that the potential risk of ACL injuries. Eleven elite male volleyball players were recruited to perform hop-jump and step-close-jump tasks. Lower extremity kinematics and ground reaction forces during landing in stop-jump tasks were recorded. Lower extremity kinetics was calculated by using an inverse dynamic process. Step-close-jump tasks demonstrated smaller peak proximal tibia anterior shear forces during the landing phase. In step-close-jump tasks, increasing hip joint angular velocity during initial foot-ground contact decreased peak posterior ground reaction force during the landing phase, which theoretically could reduce the risk of ACL injury. Key pointsThe different landing techniques required for these two stop-jump tasks do not necessarily affect the jump height.Hop-jump decreased the hip joint angular velocity at initial foot contact with ground, which could lead to an increasing peak posterior GRF during the landing phase.Hop-jump decreased hip and knee joint angular flexion displacement during the landing, which could increase the peak vertical loading rate during the landing phase. PMID- 24149398 TI - The influence of velocity overshoot movement artifact on isokinetic knee extension tests. AB - EXERCISE ON AN ISOKINETIC DEVICE INVOLVES THREE DISTINCT MOVEMENT PHASES: acceleration, constant velocity, and deceleration. Inherent in these phases are unique occurrences that may confound test data and, thereby, test interpretation. Standard methods of data reduction like windowing and other techniques consist of removing the acceleration and deceleration phases in order to assure analysis under constant velocity conditions. However, none of these techniques adequately quantify the velocity overshoot (VO) movement artifact which is a result of the devices resistance imposed to the limb. This study tested the influence of VO on isokinetic data interpretation. A computational algorithm was developed to accurately identify each movement phase and to delineate the VO segment. Therefore, the VO was then treated as a fourth and independent phase. A total of sixteen healthy men (26.8 +/- 4.7 yrs, 1.76 +/- 0.05 m, and 79.2 +/- 9.4 kg) performed two sets of ten maximal concentric extension repetitions of their dominant knee (at 60 degrees .s(-1) and 180 degrees .s(-1)), on separate days and in a counterbalanced order, on a Biodex System 3 Pro dynamometer. All the phases of the isokinetic exercise were measured in terms of their biomechanical descriptors and according to the developed algorithm, the windowing method, and a data reduction technique that eliminates the first and last 10 degrees of the total range of motion. Results showed significant differences (p < 0.05) between the constant velocity phases found by each method: the largest segment was obtained with the windowing method; the second one, with the algorithm; and the smallest, with data reduction technique. The point of peak torque was not affected by none of the techniques, but significant differences (p < 0.05) were found between the data including and not including the VO phase, concerning total work, time interval, and average length of load range: VO represents more than 10% of the amount calculated in constant velocity phase. As a consequence, the correct removal of VO was suggested as a required procedure to adequately interpret isokinetic tests. Therefore, the use of the proposed algorithm is advisable in order to perform analysis according to the isokinetic definition. Key pointsIsokinetic test interpretation must be focused on the constant velocity range; traditional analysis usually removes the acceleration and deceleration phases but does not give particular attention to velocity overshoot range.The study of effects of velocity overshoot artifact requires a specific method for accurately delineate its interval and investigate its impact over biomechanical descriptors; this paper proposed a computational algorithm for identifying the velocity overshoot interval.Velocity overshoot has significant impact over biomechanical descriptors analyzed during isokinetic knee extension tests at 60 degrees .s(-1) and 180 degrees .s(-1); the algorithm proposed is an advisable method for performing isokinetic tests analysis according to the isokinetic definition. PMID- 24149399 TI - Ground reaction force differences between running shoes, racing flats, and distance spikes in runners. AB - Various shoes are worn by distance runners throughout a training season. This study measured the differences in ground reaction forces between running shoes, racing flats, and distance spikes in order to provide information about the potential effects of footwear on injury risk in highly competitive runners. Ten male and ten female intercollegiate distance runners ran across a force plate at 6.7 m.s(-1) (for males) and 5.7 m.s(-1) (for females) in each of the three types of shoes. To control for differences in foot strike, only subjects who exhibited a heel strike were included in the data analysis. Two repeated-measures ANOVAs with Tukey's post-hoc tests (p < 0.05) were used to detect differences in shoe types among males and females. For the males, loading rate, peak vertical impact force and peak braking forces were significantly greater in flats and spikes compared to running shoes. Vertical stiffness in spikes was also significantly greater than in running shoes. Females had significantly shorter stance times and greater maximum propulsion forces in racing flats compared to running shoes. Changing footwear between the shoes used in this study alters the loads placed on the body. Care should be taken as athletes enter different phases of training where different footwear is required. Injury risk may be increased since the body may not be accustomed to the differences in force, stance time, and vertical stiffness. Key pointsTo determine the differences in ground reaction forces between regular running shoes and competitive footwear, force plate data was obtained from 10 males (6.7 m.s(-1)) and 10 females (5.7 m.s(-1)) for each of three shoe types.Data from men and women were analyzed in two separate groups, and significant differences were found for various GRF components between the three types of shoes.The significant increases in GRF components in competitive footwear suggest that the body must deal with greater impact forces in these shoes than in running shoes at the same running speed.The results from this study warrant the recommendation that runners transition gradually from periods when most or all of their training is done in running shoes to more competitive seasons when more of their training is done in racing flats and spikes. PMID- 24149400 TI - Comparison of Plantar Pressure Distribution between Different Speed and Incline During Treadmill Jogging. AB - The aim of this study was to examine the effect of changes in speed and incline slope on plantar pressure distribution of the foot during treadmill jogging. Plantar pressure parameters were measured with the Pedar-X system in twenty healthy girls (mean age of 20.7 years, mean height of 1.60m, and a mean weight of 53.35kg). Because variations in walking speed or slope can significantly change the magnitude of plantar pressure, comparisons of plantar pressure distribution between the two independent protocols during treadmill jogging were considered in this study. First, the subjects ran at the same speed of 2 m.s(-1) with different incline slopes of 0%, 5%, 10%, and 15%. Second, they ran on the same slope of 0% with different speeds of 1.5 m.s(-1), 2.0 m.s(-1), and 2.5 m.s(-1). The peak pressure of the eight plantar surface areas, apart from the medial forefoot and the hallux, significantly increased (p < 0.05) with an increase of 33% of peak pressure from 1.5 m.s(-1) to 2.5 m.s(-1) (speed) at heel region. In contrast, the peak pressures at the heel, medial fore-foot, toe and hallux decreased significantly (p < 0. 05) with increasing incline slope. At the heel, peak pressure reduced by 27% from 0% to 15% incline, however, pressure at the lateral midfoot region increased as following. Different speeds and incline slopes during jogging were associated with changes in plantar pressures. By systematic investigation of foot kinematics and plantar pressure during jogging with varying incline slope and speed, the results of this study provided further insight into foot biomechanics during jogging. Key pointsThe study aimed to compare the plantar pressure distribution of the foot between different incline and speed during treadmill jogging by using plantar insole measurement system.With the increase of speed, apart from the hallux and medical forefoot, the peak pressure of all regions was raised significantly.As the slope increased, there was reduced peak pressure of the heel, medial forefoot, and hallux and toes. PMID- 24149401 TI - The efficacy of tranexamic acid and corticosteroid on edema and ecchymosis in septorhinoplasty. AB - The aim of this study was to investigate the efficacy of tranexamic acid (TA) and methylprednisolone on periorbital edema, ecchymosis, and intraoperative bleeding in patients who underwent open septorhinoplasty (oSRP). Seventy-five patients performing hump extraction and osteotomies were allocated into 3 groups as follows: group 1, 25 patients as control; group 2, 25 patients who were administered oral TA as first dose 1 g starting 2 hours before surgery, 3 g daily in divided doses (1 g, every 8 hours) for 5 days; and group 3, 25 patients who were administered a single dose of 1 mg/kg intravenous methylprednisolone at the beginning of the surgery. Operation time, amount of intraoperative bleeding, and complications were recorded. Scoring of eyelid edema and periorbital ecchymosis was evaluated on postoperative first, third, and seventh days using scale of 0 to 4 by 2 observers. In groups using TA and methylprednisolone, periorbital edema and ecchymosis scores were significantly lower compared with the control group (P < 0.05). No significant difference was seen clinically and statistically in preventing or decreasing both periorbital edema and ecchymosis between group 2 and group 3. Patients given TA showed significantly less intraoperative bleeding compared with controls and patients who were administered methylprednisolone. We observed that the administration of methylprednisolone significantly decreases periorbital edema and ecchymosis. Additionally, our results support that TA use in patients who underwent oSRP with osteotomies was found clinically and statistically effective for prevention of bleeding during oSRP operations and reduction of both periorbital edema and ecchymosis. PMID- 24149402 TI - Morphological features of cell death and tissue remolding of fat grafts. AB - BACKGROUND: Fat tissue graft has been commonly used for soft tissue augmentation. However, the mechanisms underlying the maintenance of graft volume and weight are still unclear. As morphological features provide direct evidences for cell death and survival, we aimed to investigate the fate of grafted adipocytes and the dynamic changes in the remodeling of adipose tissues by transmission electron microscopy technique. METHODS: The unilateral inguinal fat pad of C57BL/6J mice was autografted to the dorsa of the mice. Perilipin expression and morphological changes were investigated by immunohistochemistry staining and transmission electron microscopy, respectively, in grafted tissues collected at posttransplantation days 0, 1, 3, 5, 7, 14, and 30. RESULTS: Transmission electron microscopy analysis revealed that most adipocytes in grafts showed traits of cell death on postgrafting day 3. Multilocular adipocytes with naive nuclei were observed as early as day 5 and a larger number of multilocular adipocytes were found on day 14. Perilipin immunostaining revealed that only some adipocytes located in the margin of grafts survived through the ischemic injury. New adipocytes were visualized at the periphery of the grafts, although the scope of viable adipocyte zonal areas increased from day 5 to day 30. CONCLUSIONS: The results provide ultrastructural evidences associated with the remodeling dynamics of adipose tissue grafts. It is suggested that maximized volume of graft should be obtained through promoting regeneration other than improving survival of grafted adipose tissues. PMID- 24149403 TI - A scanning electron microscope study and statistical analysis of adipocyte morphology in lipofilling: comparing the effects of harvesting and purification procedures with 2 different techniques. AB - BACKGROUND: The aim of this study was to evaluate the effects on adipocyte morphology of 2 techniques of fat harvesting and of fat purification in lipofilling, considering that the number of viable healthy adipocytes is important in fat survival in recipient areas of lipofilling. METHODS: Fat harvesting was performed in 10 female patients from flanks, on one side with a 2 mm Coleman cannula and on the other side with a 3-mm Mercedes cannula. Thirty milliliter of fat tissue from each side was collected and divided into three 10 mL syringes: A, B, and C. The fat inside syringe A was left untreated, the fat in syringe B underwent simple sedimentation, and the fat inside syringe C underwent centrifugation at 3000 rpm for 3 minutes. Each fat graft specimen was processed for examination under low-vacuum scanning electron microscope. Diameter (MU) and number of adipocytes per square millimeter and number of altered adipocytes per square millimeter were evaluated. Untreated specimens harvested with the 2 different techniques were first compared, then sedimented versus centrifuged specimens harvested with the same technique were compared. Statistical analysis was performed using Wilcoxon signed rank test. RESULTS: The number of adipocytes per square millimeter was statistically higher in specimens harvested with the 3 mm Mercedes cannula (P = 0.0310). The number of altered cells was statistically higher in centrifuged specimens than in sedimented ones using both methods of fat harvesting (P = 0.0080) with a 2-mm Coleman cannula and (P = 0.0050) with a 3-mm Mercedes cannula. Alterations in adipocyte morphology consisted in wrinkling of the membrane, opening of pore with leakage of oily material, reduction of cellular diameter, and total collapse of the cellular membrane. CONCLUSIONS: Fat harvesting by a 3-mm cannula results in a higher number of adipocytes and centrifugation of the harvested fat results in a higher number of morphologic altered cells than sedimentation. PMID- 24149404 TI - Feasibility of a deepithelialized superior gluteal artery perforator propeller flap for various lumbosacral defects. AB - Skin and soft tissue defects in the lumbosacral area are commonly encountered in the field of reconstructive surgery, and it is well documented that the superior gluteal artery perforator (SGAP) flap provides excellent coverage of these defects. In this article, we describe our experience using a modified version of the SGAP propeller flap, in which the distal redundant portion of an elevated SGAP flap is deepithelialized, thereby maximizing the effect of the soft tissue augmentation. Thirteen patients with lumbosacral soft tissue defects treated between May 2010 and June 2012 were included in this study. The wound causes were pressure ulcer (n = 9), pseudomeningocele (n = 2), and hardware exposure (n = 2). In all patients, an elevated SGAP flap was rotated 180 degrees over the defect area and the extra distal portion of the flap was deepithelialized and used as a soft tissue filler or tamponade. During the follow-up period (mean, 26 months), 12 of 13 flaps survived completely. One flap was totally necrosed due to progressive venous congestion and was reconstructed with local advancement flaps. No further complications were noted. Because of the redundancy and pliability of the tissue in the gluteal area, a flap relatively wider or longer than the defect can be elevated safely. Hence, the redundant tissue volume can be tucked inside to facilitate soft tissue augmentation of the area. We propose that the deepithelialized version of the SGAP propeller flap is an effective option for the reconstruction of various lumbosacral soft tissue defects because it offers thick and healthy soft tissue from a distant site to the defect areas. PMID- 24149405 TI - Novel reconstructive methods of the conchal central strut using an absorbable plate after total harvesting of the conchal cartilage. AB - PURPOSE: Conchal cartilage is widely used in the field of plastic surgery, but donor-site morbidity is inevitable when all of the conchal cartilage is harvested. To maintain ear shape, the authors introduce a new method using an absorbable plate to reconstruct the conchal central strut after total harvesting of the conchal cartilage. METHODS: In total, 18 subjects underwent surgery, and 14 subjects who were followed up for more than 12 months were included in this article. Before the total harvesting of the conchae, an absorbable plate was adjusted to the proper curvature and length. After harvesting, the central strut was reconstructed by the precrafted absorbable plate. When the harvested cartilage was too large or one implant was not sufficient to reconstruct the central strut, an additional implant was added to the cymba conchae.Outcomes were evaluated by photogrammetry and questionnaires. Seven items were selected to evaluate the shape of the ear and conchal cavity. The authors compared preoperative and postoperative photographs, looking at proportion indices of 7 items using Photoshop. Ten assessors who did not participate in the operation were also shown preoperative and postoperative photographs and answered questionnaires about the shapes of the ear, conchal cavity, and conchal central strut. RESULTS: Except for the effective conchal cavity height index, no statistically significant differences were observed between preoperative and postoperative ear shapes. Additionally, the questionnaire showed excellent assessments for all items. CONCLUSIONS: Reconstruction of the central strut using an absorbable plate after total harvest of the conchal cartilage was a simple and effective method to prevent ear collapse. PMID- 24149406 TI - Medical student perceptions of plastic surgeons as hand surgery specialists. AB - PURPOSE: Plastic surgeons are often not perceived as hand surgery specialists. Better educating medical students about the plastic surgeon's role in hand surgery may improve the understanding of the field for future referring physicians. The purposes of this study were to assess medical students' understanding of hand surgery specialists and to analyze the impact of prior plastic, orthopedic, and general surgery clinical exposure on this understanding. METHODS: An online survey including 8 hand-related clinical scenarios was administered to students at a large academic medical center. After indicating training level and prior clinical exposure to plastic surgery or other surgical subspecialties, students selected one or more appropriate surgical subspecialists for management of surgical hand conditions. RESULTS: A response rate of 56.4% was achieved. Prior clinical exposure to plastic, orthopedic, and general surgery was reported by 29%, 43%, and 90% of fourth year students, respectively. Students generally chose at least 1 acceptable specialty for management of hand conditions with improvement over the course of their training (P = 0.008). Overall, students perceived orthopedic surgeons as hand specialists more so than plastic and general surgeons. Clinical exposure to plastic surgery increased the selection of this specialty for nearly all scenarios (22%-46%, P = 0.025). Exposure to orthopedic and general surgery was associated with a decrease in selection of plastic surgery for treatment of carpal tunnel and hand burns, respectively. CONCLUSIONS: Medical students have a poor understanding of the plastic surgeon's role in hand surgery. If plastic surgeons want to continue to be recognized as hand surgeons, they should better educate medical students about their role in hand surgery. This can be achieved by providing a basic overview of plastic surgery to all medical students with emphasis placed on hand and peripheral nerve surgery. PMID- 24149407 TI - Orbital floor reconstruction with ethyl-2-cyanoacrylate. AB - The orbital floor is one of the most frequently broken bones in maxillofacial fracture, and orbital reconstruction is needed in many cases. Various materials are used for orbital floor reconstruction. We report here orbital reconstruction using autologous orbital bone with cyanoacrylate. Entrapped soft tissues were freed and repositioned intraorbitally and bone fragments were gathered with a microscope simultaneously. The bone fragments were fixed to a board of bone with ethyl-2-cyanoacrylate and returned to the orbital fracture site. Of 96 fresh orbital floor fractures, this method was used for 31 (32.3%) patients. Simple reduction was performed in 48 patients. Bone graft with iliac crest was performed in the other 12 patients. Reconstruction with alloplastic materials was performed in 5 patients. Diplopia was corrected in 26 patients on whom this method was performed. The reconstructed bone collapsed into the maxillary sinus in 1 patient who underwent iliac bone graft on reoperation. Another 4 patients did not show diplopia preoperatively. None of the patients showed enophthalmos, foreign body reaction, or infection postoperatively. We were able to perform orbital bone reconstruction with autologous orbital bone without another donor site in 30 (62.5%) of 48 cases that required grafting. The indications for this method are that a sufficient quantity of bone fragments can be obtained and returned on a board of bone which can be stabilized in the orbit without collapsing into the maxillary sinus. Good results were obtained, and we consider this to be a safe and useful method. PMID- 24149408 TI - Aesthetic and functional mandibular reconstruction with immediate dental implants in a free fibular flap and a low-profile reconstruction plate: five-year follow up. AB - BACKGROUND: Aesthetic and functional mandibular reconstruction can be achieved in 1-stage. It involves simultaneous dental implant placement in a free vascularized fibula transfer with a low-profile reconstruction plate. The aim of this study was to assess the postoperative aesthetic profile and oral functional result. MATERIAL AND METHODS: Ten patients with a mean age of 31.6 years and an average follow-up time of 83.7 months underwent 1-staged mandibular reconstructions after segmental mandibulectomies. Simultaneous dental implantation was placed at the fibular segment according to the maxillary dentition. The fibula-implant construct was stabilized superiorly with miniplates and an additional low-profile reconstruction plate recreated the inferior mandibular contour. Any remaining vascularized soft tissue was used for augmentation. Palatal mucosa grafts were placed around the dental implant healing abutment at the uncovering stage surface. Aesthetic profile and oral function were evaluated postoperatively for 5 years. RESULTS: All microsurgical transplantations were successful. None of the patients required subsequent revisions. All patients completed prosthodontic rehabilitation. All patients had palatal mucosal grafts placed around the dental implants. The mean probing pocket depths were shallower around the implants, 3.09 +/- 0.82 mm at mesial, 3.33 +/- 1.05 mm at distal, 3.02 +/- 1.13 mm at buccal, and 3.23 +/- 1.17 mm at lingual surfaces. Radiographs revealed no statistical differences in mean of the mesial [0.27 +/- 0.26 mm] and distal [0.33 +/- 0.25 mm] of peri-implant bone loss. The prosthetic load mean follow-up time was 71.7 months with a satisfactory implant-supported prosthesis. Two slender female patients palpated the reconstruction plate beneath the soft tissue envelope. CONCLUSIONS: This approach is selectively fashioned for patients with benign disease when the overlying soft tissue drape is adequate. The technique described results in improved appearance and function through definition of the lower third of the face and simultaneous dental implant replacement. PMID- 24149409 TI - Feasibility of autologous fat transfer for replacement of implant volume in complicated implant-assisted latissimus dorsi flap breast reconstruction. AB - Lipomodeling is gaining popularity and has been widely used in various settings of reconstructive breast surgery. Implant-assisted latissimus dorsi (LD) flap reconstruction of breast is a popular method among the reconstructive surgeons. When this type of reconstruction is met with complications such as infection and capsular contracture, it necessitates removal of implants and patients are left with very limited options of reconstructions. We aim to assess the feasibility of lipomodeling in this setting.Retrospective analysis of prospectively maintained database of 10 patients who underwent lipomodeling to correct the volume deficit after implant removal in patients with implant-assisted LD flaps was carried out. A custom-made questionnaire using a 4-point Likert scale and a visual analog scale was used to assess the patient-reported outcomes. Patients were discharged from care after completion of treatment and were followed up by questionnaire. First questionnaire was sent to assess satisfaction at medium term and the second questionnaire was to assess satisfaction in the longer term.Mean number of sessions were 3 (range, 2-4) and mean duration of treatment was 14 months. Mean duration of initial follow-up was 15 months (range, 3-25 months) and that of longer follow-up was 40 months (range, 19-60 months). Variable amount of fat was harvested and transferred during different sessions. Patients were happy to undergo multiple sessions of fat transfer. No major complications were observed in our series and overall satisfaction was high with a mean score of 9.3 (range, 8-10) in the longer term. Persistence of higher satisfaction during a longer period is reassuring as one of the concerns regarding fat transfer is the unpredictable resorption rate.Lipomodeling is a useful feasible option to replace implant volume in patients with complicated implant-assisted LD reconstruction. Multiple sessions of lipomodeling seem to be acceptable to patients. This technique was associated with negligible complications and high patient satisfaction was maintained during longer periods of follow-up. PMID- 24149411 TI - Tissue expander complications in the pediatric burn patient: a 10-year follow-up. AB - BACKGROUND: This study is a 10-year follow-up to our previous publication reviewing the complication rates of tissue expansion in the pediatric burn population. The purpose of this study was to determine if our institutional experience with tissue expanders had remained stable during the subsequent 10 years. METHODS: There were 240 patients who were identified at a major pediatric burn center who underwent reconstruction with a tissue expander (256 tissue expanders) from 1996 to 2006. Data were obtained retrospectively by reviewing patient medical records. Complications were categorized into absolute and relative complications. RESULTS: Absolute complications occurred in 36 (14.1%) of 256 expanders placed and relative complications occurred in 26 (10.2%) of 256 expanders placed. There was no statistical difference between this study and our previous study for overall complication rates and complications for all sites. The highest complication rate occurred when the scalp was a surgical site. Betadine skin preparation was associated with a 10% reduction in infection related complications compared to other skin preparations. The operating surgeon or age of patient was not found to be associated with increased complication rates. CONCLUSIONS: After changing our tissue expander protocol, the complication rates at our institution have remained stable during the 10-year follow-up period. Tissue expansion in the pediatric burn population continues to be a safe and effective reconstructive option with acceptable complication rates. PMID- 24149412 TI - The Measurement and Interpretation of Children's Physical Activity. AB - The accurate and reliable assessment of physical activity is necessary for any research study where physical activity is either an outcome measure or an intervention. The aim of this review is to examine the use of objective measurement techniques for the assessment and interpretation of children's physical activity. Accurate measurement of children's activity is challenging, as the activity is characteristically sporadic and intermittent, consisting of frequent, short bouts. Objective measures of physical activity include heart rate telemetry, pedometry and accelerometry, and each of these methods has strengths and limitations. Heart rate is suited to the measurement of sustained periods of moderate and vigorous activity, pedometry provides a valid measure of total activity, and accelerometry provides a valid measure of total activity as well as the pattern and intensity of activity. As the weaknesses of heart rate and accelerometry for the assessment of activity are not inter-correlated, a combination of the two methods may be more accurate than either method alone. Recent evidence suggests that the Actiheart, an integrated accelerometer and heart rate unit, provides a more accurate prediction of children's energy expenditure than either heart rate or accelerometry alone. However, the cost of the Actiheart is prohibitive for large-scale studies. The pedometer is recommended when only the total amount of physical activity is of interest. When the intensity or the pattern of activity is of interest, accelerometry is the recommended measurement tool. Key pointsThe use of objective measures to assess physical activity in children is recommended.Pedometers provide an inexpensive objective measure of total activity that is highly correlated with more sophisticated techniques, e.g. accelerometry, and has been used to identify relationships between health and activity in children.Accelerometry allows examination of the temporal pattern and intensity of children's activity, including sporadic physical activity and bouts of physical activity. PMID- 24149413 TI - Can We Confidently Study VO2 Kinetics in Young People? AB - The study of VO2 kinetics offers the potential to non-invasively examine the cardiorespiratory and metabolic response to dynamic exercise and limitations to every day physical activity. Its non-invasive nature makes it hugely attractive for use with young people, both healthy and those with disease, and yet the literature, whilst growing with respect to adults, remains confined to a cluster of studies with these special populations. It is most likely that this is partly due to the methodological difficulties involved in studying VO2 kinetics in young people which are not present, or present to a lesser degree, with adults. This article reviews these methodological issues, and explains the main procedures that might be used to overcome them. Key pointsThe VO2 kinetic response to exercise represents the combined efficiency of the cardiovascular, pulmonary and metabolic systems, and an accurate assessment of the response potentially provides a great deal of useful information via non-invasive methodology.An accurate assessment of the VO2 kinetic response is however inherently difficult with children and especially those with reduced exercise tolerance, due primarily to the apparent breath-by-breath noise which masks the true underlying physiological response, and the small amplitudes of the response signal.Despite this, it is possible to assess and quantify the VO2 kinetic response with children if appropriate steps are taken to apply carefully selected methodologies and report response variables with confidence intervals. In this way, both the researcher and the reader can be confident that the data reported is meaningful. PMID- 24149414 TI - Exercise testing and training with the young cystic fibrosis patient. AB - The purpose of the article is to review the literature related to exercise and Cystic fibrosis (CF), with particular focus on the young CF patient. Exercise intolerance is a characteristic of CF, however, recent studies in adults have advanced our understanding of how exercise can be used effectively as a prognostic marker and for rehabilitation purposes. New analyses from exercise testing have shown to have prognostic value, and different methods of exercise training have been reported to improve the functional capacity and quality of life of the young CF patient. There is a growing awareness and belief among clinicians of the benefits of exercise testing and training, however, recent work suggests that exercise is being underused in the healthcare management of the CF patient. More research is needed to identity which exercise tests and training programmes would be most feasible to incorporate into CF centres routine clinical procedures. Key pointsNew methods of health assessment from exercise testing in the young CF patient have shown to have prognostic value.The introduction of new training methods into exercise programmes can improve the functional capacity and quality of life of young patients with CF.Exercise is still being underused in the healthcare management of the CF patient. PMID- 24149415 TI - Advances in paediatric strength assessment: changing our perspective on strength development. AB - Our knowledge of the age and sex associated changes in strength during childhood and adolescence is relatively limited compared to other physiological parameters. However, those studies available on the age and sex associated change in strength are relatively consistent, especially for the lower limbs. Caution must be taken when transferring this knowledge to other muscle joints as the development in strength appears to be both muscle action and joint specific. Strength appears to increase in both boys and girls until about the age of 14 y where it begins to plateau in girls and a spurt is evident in boys. By 18 y there are few overlaps in strength between boys and girls. The exact age in which sex differences become apparent appears to be both muscle group and muscle action specific and there is a suggestion that sex differences in upper body strength occur earlier than lower body strength. What is less clear is the complex factors that contribute to the production of strength during childhood and adolescence. There are few well controlled longitudinal studies that have concurrently examined the influence of known variables using appropriate statistical techniques. Most studies have shown that maturation does not exert an independent effect when other factors, such as stature and body mass are accounted for. Also, the assumption that muscle cross sectional area is the most important parameter in strength production does not hold when examined with other known variables. Consistently, stature appears to play a key role in strength development and this may be attributed to the strength spurt that has been linked to peak height velocity, and the muscle moment arm. Advances in technology have provided us with more accurate techniques to examine these explanatory variables but the complex interaction of neural, mechanical and muscular remains to be clearly identified from well controlled longitudinal studies. Key pointsThe age associated development in strength is attributable to changes in growth and maturation. Sex differences appear at around 14y and very few girls out perform boys in strength tests at 18y.Stature and mass appear to be important explanatory variables in the development of muscle strength. PHV is a particularly important time for maximal gains in strength during childhood.The muscle moment arm is possibly the most important factor in the development of muscle strength with age but further longitudinal studies using MRI are needed. PMID- 24149416 TI - Exercise and bone mineral accrual in children and adolescents. AB - Osteoporosis is a serious skeletal disease causing an increase in morbidity and mortality through its association with age-related fractures. Although most effort in fracture prevention has been directed at retarding the rate of age related bone loss and reducing the frequency and severity of trauma among elderly people, evidence is growing that peak bone mass is an important contributor to bone strength during later life. Indeed, there has been a large emphasis on the prevention of osteoporosis through the optimization of peak bone mass during childhood and adolescence. The prepubertal human skeleton is sensitive to the mechanical stimulation elicited by exercise and there is increasing evidence that regular weight-bearing exercise is an effective strategy for enhancing bone mineral throughout growth. Physical activity or participation in sports needs to start at prepubertal ages and be maintained through pubertal development to obtain the maximal peak bone mass achievable. High strain eliciting sports like gymnastics, or participation in sports or weight bearing physical activity like soccer, are strongly recommended to increase peak bone mass. Many other factors also influence the accumulation of bone mineral during childhood and adolescence, including heredity, gender, diet and endocrine status. However, this review article will focus solely on the effects of physical activity and exercise providing a summary of current knowledge on the interplay between activity, exercise and bone mass development during growth. Due to the selection bias and other confounding factors inherent in cross-sectional studies, longitudinal and intervention studies only will be reviewed for they provide a greater opportunity to examine the influence of mechanical loading on bone mineral accretion over time. Key pointsPre-pubertal children's ability to thermoregulate when exposed to hot and humid environments is deficient compared to adults.Research into the severity of heat-related illness in pre-pubertal children is inconclusive.Discretion should be used in applying findings from indoor studies to outdoor activities due to the influence of the velocity of circulating air on thermoregulation. PMID- 24149417 TI - Effects of exercise training on blood lipids and lipoproteins in children and adolescents. AB - THE FOLLOWING REVIEW AIMS TO DESCRIBE WHAT IS KNOWN ABOUT THE EFFECTS OF EXERCISE TRAINING IN CHILDREN AND ADOLESCENTS ON THE FOLLOWING BLOOD LIPIDS AND LIPOPROTEINS: total cholesterol (TC), high density lipoprotein cholesterol (HDL C), low density lipoprotein cholesterol (LDL-C), and triglycerides (TG). Only studies that described mode, frequency, duration and intensity of the exercise were included in the review. The results of the studies reviewed were equivocal. Clearly the effects of exercise training on the blood lipid and lipoprotein levels of normolipidemic children and adolescents are equivocal. Of the 14 studies reviewed, six observed a positive alteration in the blood lipid and lipoprotein profile, four of the studies observed no alteration in the blood lipid and lipoprotein profile and one study observed a negative effect on HDL-C but an overall improvement in the lipid and lipoprotein profile due to the decrease in the TC/HDL ratio. It appears that methodological problems present in the majority of the exercise training studies limits the ability to make a conclusive, evidence based statement regarding the effect exercise training has on blood lipid levels in normolipidemic children. Most of the research design flaws can be linked to one or more of the following: small numbers of subjects in each study, low or no representation of girls, inclusion of both boys and girls in the subject pool, inclusion of boys and girls at different maturational stages in the subject pool, exercise training regimes that do not adequately control for exercise intensity, exercise training regimes that do not last longer than 8 weeks and exercise training studies that do not have an adequate exercise volume to elicit a change. Ideally, future research should focus on longitudinal studies which examine the effects of exercise training from the primary school years through adulthood. Key pointsExercise training has limited to no effect on blood lipid levels in children and adolescents.Few well controlled studies have been done to examine the effect exercise training has on selected cardiovascular risk factors and those studies that have been completed contain methodological flaws which makes interpretation of the results difficult.More studies, particularly those of a longitudinal design, are required before a conclusion can be drawn regarding the effects exercise training has on selected cardiovascular risk factors in children and adolescents. PMID- 24149418 TI - Effect of obesity on cardiac function in children and adolescents: a review. AB - Increases in cardiac mass, ventricular dimensions, and stroke volume are typically observed in obese adults, accompanied by evidence of diminished ventricular systolic and diastolic function. Given sufficient severity and duration of excessive body fat, signs of overt congestive heart failure may ensue (cardiomyopathy of obesity). This review of cardiac findings in obese children and adolescents indicates similar anatomic features as well as early subclinical findings of ventricular dysfunction. However, cardiac functional reserve (cardiovascular fitness) appears to be preserved even in those with morbid levels of obesity. Key pointsExcessive body fat increases the work output of the heart.Longstanding increases in heart work result in abnormalities of heart function.Early findings of such changes can be observed in adolescents with severe obesity. PMID- 24149419 TI - Energy regulation in young people. AB - Obesity in young people is now realised as a worldwide crisis of epidemic proportion. The aetiology of this disease suggests a disruption in regulation of energy at the population level, leading to a positive energy balance and excess adiposity. The relative contribution of food intake and physical inactivity remains to be elucidated. Treatment interventions have aimed to create a deficit in energy balance through manipulation of physical activity, behavioural components or, to a lesser extent, dietary modification. Whether such intervention is maintained in the long-term is as yet unclear, however it seems a combination of therapies is optimal. Mindful of a mismatch between energy intake and expenditure, recent work has begun to examine the acute relationship between physical activity and food intake in children. Initial findings suggest a short term delay in compensation through energy intake for exercise- induced energy expenditure. The overarching study of energy regulation in children and adolescents is clearly multifaceted in nature and variables to be assessed or manipulated require careful consideration. The collection of paediatric physical activity, energy expenditure and food intake data is a time-consuming process, fraught with potential sources of error. Investigators should consider the validity and reliability of these and other issues, alongside the logistics of any proposed study. Despite these areas of concern, recent advances in the field should provide exciting opportunities for future research in paediatric energy regulation on a variety of levels. Key pointsPhysical activity appears to be an effective intervention in paediatric weight-management, however future studies need to be extended over the longer-term employing consistent protocols to aid comparison.In the short-term, exercise-induced energy expenditure and subsequent energy intake do not appear to be tightly regulated in young people; this acute imbalance is similar to the 'loose coupling' of energy described for adults.The relationship between energy expenditure and food intake in young people requires further examination in longer-term interventions. A rigorous protocol is necessary to study parameters under free-living conditions. PMID- 24149420 TI - Supplement use by Young Athletes. AB - This paper reviews studies of supplement use among child and adolescent athletes, focusing on prevalence and type of supplement use, as well as gender comparisons. Supplement use among adult athletes has been well documented however there are a limited number of studies investigating supplement use by child and adolescent athletes. A trend in the current literature revealed that the most frequently used supplements are in the form of vitamin and minerals. While health and illness prevention are the main reasons for taking supplements, enhanced athletic performance was also reported as a strong motivating factor. Generally, females are found to use supplements more frequently and are associated with reasons of health, recovery, and replacing an inadequate diet. Males are more likely to report taking supplements for enhanced performance. Both genders equally rated increased energy as another reason for engaging in supplement use. Many dietary supplements are highly accessible to young athletes and they are particularly vulnerable to pressures from the media and the prospect of playing sport at increasingly elite levels. Future research should provide more direct evidence regarding any physiological side effects of taking supplements, as well as the exact vitamin and mineral requirements for child and adolescent athletes. Increased education for young athletes regarding supplement use, parents and coaches should to be targeted to help the athletes make the appropriate choices. Key pointsSupplement use among the child and adolescent athlete population is widespread with the most frequently used supplement being a form of vitamin/mineral supplement.The effects of supplement use on the growth and development of children and adolescents remain unclear and thus use of supplements by this population should be discouraged.It is likely that there is a misunderstanding as to the role of vitamins and minerals in the diet, their function in maintaining overall health, their role in athletic performance, and how they are best obtained from the diet therefore further education for adolescent athletes and athletes in general is needed. PMID- 24149421 TI - Carbohydrate intake considerations for young athletes. AB - Good nutritional practices are important for exercise performance and health during all ages. Athletes and especially growing children engaged in heavy training have higher energy and nutrient requirements compared to their non active counterparts. Scientific understanding of sports nutrition for the young athlete is lacking behind the growing number of young athletes engaged in sports. Most of the sports nutrition recommendations given to athletic children and adolescents are based on adult findings due to the deficiency in age specific information in young athletes. Therefore, this review reflects on child specific sports nutrition, particularly on carbohydrate intake and metabolism that distinguishes the child athlete from the adult athlete. Children are characterised to be in an insulin resistance stage during certain periods of maturation, have different glycolytic/metabolic responses during exercise, have a tendency for higher fat oxidation during exercise and show different heat dissipation mechanisms compared to adults. These features point out that young athletes may need different nutritional advice on carbohydrate for exercise to those from adult athletes. Sport drinks for example may need to be adapted to children specific needs. However, more research in this area is warranted to clarify sports nutrition needs of the young athlete to provide better and healthy nutritional guidance to young athletes. Key pointsAthletic girls show lower carbohydrate intakes compared to boys.Substrate oxidation during exercise appears to be maturity related, fat being the preferred fuel for oxidation in younger athletic children.Children appear to have lower endogenous but greater exogenous carbohydrate oxidation rates during exercise.Carbohydrate intake during exercise appears to show no additional performance improvement in young athletes. Perhaps fat intake or a combination of both nutrients may be a better approach for nutrient supplementation during exercise.Gastric emptying physiology of young athletes is not well known. Adult sport drinks showed a tendency to delay gastric emptying in young athletes during exercise at higher intensities.More research is needed in paediatric sports nutrition. PMID- 24149423 TI - Physical activity - a neat solution to an impending crisis. AB - Childhood obesity is arguably the most significant global public health threat, yet effective strategies to contain or prevent the disease are not available. This review examines the physical activity patterns of children and the role physical activity plays in daily energy expenditure. The prevailing focus on moderate to vigorous activity in childhood means there is limited objective information on either sedentary behaviour or non-exercise activity thermogenesis (NEAT), the energy expended during the activities of daily living. Most strategies targeting the prevention of childhood obesity have focused upon adding moderate to vigorous activity and have not been particularly successful. The low efficacy of more purposeful activity is perhaps not surprising because of the small variance in children's physical activity levels explained by moderate to vigorous activity. Subtle changes in NEAT have in contrast been shown to account for differences in fat-mass gain or resistance in adults. Theoretically, manipulating a child's living environment to enhance NEAT would create a positive gain in TDEE, a gain that could lead to the prevention of excess fat-mass. More careful consideration of the specific aspects of physical activity that are most influential in the maintenance of body weight in childhood is a priority. Appreciating the role NEAT may play in the variation of total daily energy expenditure in children is a future challenge for physical activity research. Key pointsExcessive weight gain affects children in both developed and developing countries alike, and results initially from small energy imbalances. Increasing the energy expended in daily living has the potential to re-adjust energy balance and prevent initial excess weight gain.Sedentary behaviour and light intensity movement, as opposed to moderate or vigorous movement, dominate a child's day. We need to understand more about which aspects of activity account for variance in total daily energy expenditure in children.Finding innovative and creative ways to increase the daily energy children expend should be a priority. PMID- 24149422 TI - Trainability of young athletes and overtraining. AB - Exercise adaptations to strength, anaerobic and aerobic training have been extensively studied in adults, however, young people appear to respond differently to such exercise stimulus in comparison to adults. In addition, because overtraining in young athletes has received little attention, this important area is also discussed. Resistance training in children can be safe and effective. It has the potential to improve sport performance, enhance body composition and reduce the rate of sport incurred injury. Furthermore, with the appropriate stimulus, prepubertal and adolescent athletes can show significant increments in muscle strength (13 - 30%). Children can improve anaerobic power (3%-10% Mean Power and 4%-20% in Peak Power), although the mechanisms responsible for the improvements in children remain unclear. Children show a 'reduced' trainability of peak VO2 in comparison to adults. Nevertheless, their aerobic power is trainable, with improvements reported at approximately 5%. Moreover, improvements in other variables like exercise economy or lactate threshold may occur without significant changes in peak VO2 The limited evidence available indicates that overtraining is occurring in young athletes (30% prevalence), highlighting the importance of further research in to all the possible contributing factors - physiological, psychological and emotional - when investigating overtraining. Key pointsChildren's strength, anaerobic and aerobic power is trainable, although the improvements may be smaller than seen in adults.Children can demonstrate significant gains in muscle strength with resistance training (13 - 30%).Improvements in mean power (3 - 10%) and peak power (4 - 20%) are reported in children.Aerobic fitness can improve with training in children by approximately 5%.Limited available evidence indicates an occurrence of overtraining in young athletes of around 30%. PMID- 24149424 TI - PRIDE for PLAY: Personal Responsibility in Daily Effort for Participation in Lifelong Activity for Youths. A Singaporean Context. AB - Singapore, a developed city state of four million people is experiencing the pitfalls that come with rapid modernisation and economic progress- elevated disease risk factors among adults and young people. Weekly compulsory physical education classes of 70 minutes in schools and the associated sports activities after classes are inadequate to meet emergent physical activity guidelines of a daily accumulation of at least 90 minutes of physical activity of at least moderate intensity. Daily play sessions that are exclusive of an active daily recess, physical education classes taught by trained specialists and after-school sport sessions, can provide many developmental and holistic health benefits that may carry over into adulthood. A school environment that is play-encouraging, play-enabling and play-inviting can be a useful, innovative and natural way of inculcating a love for movement and help redress a serious trend of physical activity insufficiency while youngsters engage electronic gaming activities. Pilot initiatives for the PRIDE (personal responsibility in daily effort) for PLAY (participation in lifelong activity for youths) programme is a radicalised approach in a number of primary schools in Singapore to infuse daily physical play of between 20 to 45 minutes during curriculum hours. The hope is that PRIDE for PLAY will reap benefits of improved holistic health of youngsters- better physical, social, emotional and mental attributes. While PRIDE for PLAY is no panacea to all of the ills of modernisation, it will go some way in helping the students of tomorrow to be physically healthy, socially more engaged and tolerant of others, mentally more apt to problem-solve and emotionally more proficient to embrace working life in adulthood. Key pointsPhysical play is natural among young people and a daily dose of play can help young people meet daily requirements for accumulated physical activity of at least 90 minutes and at least of a moderate intensity.Play is critical for child development and provides a healthy balance for many sedentary lifestyle activities.Parents, care-givers and teachers should emphasise and partake in daily play with young people. PMID- 24149425 TI - Lifelong caloric restriction reprograms hepatic fat metabolism in mice. AB - Calorie lowering slows the aging process and extends life span in diverse species by so far unknown mechanisms. The inverse linear relationship between calorie intake and life span suggests that regulators of energy metabolism are of importance in aging. The present study shows that lifelong caloric restriction in mice induces a metabolic adaptation with reduced lipogenesis and enhanced lipolysis and ketogenesis. This process, that is, the reprogramming of hepatic fat metabolism, is associated with a marked rise of fibroblastic growth factor 21 as a putative starvation master regulator. Due to the life span-extending properties of fibroblastic growth factor 21, the rise in fibroblastic growth factor 21 might contribute to the markedly better health status found in mice upon lifelong caloric restriction feeding. In addition, adropin, known as a peptide that controls lipid homeostasis, is significantly upregulated, underlining the diminution of lipogenesis that was further substantiated by decreased expression of liver-X-receptor alpha and its target genes sterol regulatory element-binding protein-1c, fatty acid synthase, and member 1 of human transporter subfamily ABCA upon lifelong caloric restriction feeding. PMID- 24149426 TI - Changes in energy-regulated molecules in the trophocytes and fat cells of young and old worker honeybees (Apis mellifera). AB - Trophocytes and fat cells of honeybees (Apis mellifera) have been used for cellular senescence studies, but the changes in the expression, concentration, and activity of cellular energy-regulated molecules that occur with aging in worker bees is unknown. In this study, energy-regulated molecules were evaluated in the trophocytes and fat cells of young and old workers. The results showed that (i) adenosine monophosphate-activated protein kinase-alpha2 (AMPK-alpha2) expression increased with aging, whereas phosphorylated AMPK-alpha2 expression, the phosphorylated AMPK/AMPK ratio, and AMPK activity decreased with aging; (ii) adenosine diphosphate and adenosine triphosphate concentrations decreased with aging, the AMP concentration was unchanged, the adenosine diphosphate/adenosine triphosphate ratio did not change with aging, and the AMP/adenosine triphosphate ratio increased with aging; (iii) the cyclic AMP concentration decreased with aging, and cyclic AMP-specific phosphodiesterases activity increased with aging; (iv) silent information regulator 2 (Sir2) expression increased with aging, whereas its activity decreased with aging; and (v) peroxisome proliferator activated receptor-alpha expression decreased with aging. These results show that the trophocytes and fat cells of young workers have higher cellular energy status and express higher levels of energy-regulated molecules than those of old workers and that aging results in a decline in the energy status of trophocytes and fat cells in worker honeybees. PMID- 24149427 TI - How long must humans live? AB - Species are defined by biological criteria. This characterization, however, misses the most unique aspect of our species; namely, an ability to invent technologies that reduce mortality risks. Old animals are rare in nature, but survival to old age has become commonplace in humans. Science now asks how long can humans live, but we suggest a more appropriate question is: How long must humans live? Three lines of evidence are used to identify the biological equivalent of a warranty period for humans and why it exists. The effective end of reproduction, the age when the sex ratio is unity, and the acceleration of mortality reveal that approximately 50-55 years is sufficient time for our species to achieve its biological mandate-Darwinian fitness. Identifying this boundary is biomedically important because it represents a transition from expected health and vigor to a period when health and vigor become progressively harder to maintain. PMID- 24149428 TI - Liver aging and pseudocapillarization in a Werner syndrome mouse model. AB - Werner syndrome is a progeric syndrome characterized by premature atherosclerosis, diabetes, cancer, and death in humans. The knockout mouse model created by deletion of the RecQ helicase domain of the mouse Wrn homologue gene (Wrn(?hel/?hel)) is of great interest because it develops atherosclerosis and hypertriglyceridemia, conditions associated with aging liver and sinusoidal changes. Here, we show that Wrn(?hel/?hel) mice exhibit increased extracellular matrix, defenestration, decreased fenestration diameter, and changes in markers of liver sinusoidal endothelial cell inflammation, consistent with age-related pseudocapilliarization. In addition, hepatocytes are larger, have increased lipofuscin deposition, more frequent nuclear morphological anomalies, decreased mitochondria number, and increased mitochondrial diameter compared to wild-type mice. The Wrn(?hel/?hel) mice also have altered mitochondrial function and altered nuclei. Microarray data revealed that the Wrn(?hel/?hel) genotype does not affect the expression of many genes within the isolated hepatocytes or liver sinusoidal endothelial cells. This study reveals that Wrn(?hel/?hel) mice have accelerated typical age-related liver changes including pseudocapillarization. This confirms that pseudocapillarization of the liver sinusoid is a consistent feature of various aging models. Moreover, it implies that DNA repair may be implicated in normal aging changes in the liver. PMID- 24149429 TI - Cranberry interacts with dietary macronutrients to promote healthy aging in Drosophila. AB - Botanicals possess numerous bioactivities, and some promote healthy aging. Dietary macronutrients are major determinants of life span. The interaction between botanicals and macronutrients that modulates life span is not well understood. Here, we investigated the effect of a cranberry-containing botanical on life span and the influence of macronutrients on the longevity-related effect of cranberry in Drosophila. Flies were supplemented with cranberry on three dietary conditions: standard, high sugar-low protein, and low sugar-high protein diets. We found that cranberry slightly extended life span in males fed with the low sugar-high protein diet but not with other diets. Cranberry extended life span in females fed with the standard diet and more prominently the high sugar low protein diet but not with the low sugar-high protein diet. Life-span extension was associated with increased reproduction and higher expression of oxidative stress and heat shock response genes. Moreover, cranberry improved survival of sod1 knockdown and dfoxo mutant flies but did not increase wild-type fly's resistance to acute oxidative stress. Cranberry slightly extended life span in flies fed with a high-fat diet. These findings suggest that cranberry promotes healthy aging by increasing stress responsiveness. Our study reveals an interaction of cranberry with dietary macronutrients and stresses the importance of considering diet composition in designing interventions for promoting healthy aging. PMID- 24149430 TI - Predictors of hearing acuity: cross-sectional and longitudinal analysis. AB - BACKGROUND: This study aimed to identify predictors of hearing thresholds (best ear pure-tone average at 1, 2, and 4 kHz) and hearing deterioration in order to define potential target groups for hearing screening. METHODS: We analyzed data from the Maastricht Aging Study, a Dutch cohort (aged 24-81 years; N = 1,721) that was observed for 12 years. Mixed model analysis was used to calculate each participant's average hearing threshold deterioration rate during the follow-up period. We built ordinary least square linear regression models to predict the baseline threshold and deterioration rate. Potential predictors included in these models were age, gender, type of occupation, educational level, cardiovascular disease, diabetes, systemic inflammatory disease, hypertension, obesity, waist circumference, smoking, and physical activity level. We also examined the relationship between baseline threshold and the deterioration rate. RESULTS: Poorer baseline thresholds were strongly associated with faster hearing deterioration. Higher age, male gender, manual occupation, and large waist circumference were statistically significantly associated with poorer baseline thresholds and faster deterioration, although the effects of occupation type and waist circumference were small. CONCLUSIONS: This study indicates that age and gender must be taken into account when determining the target population for adult hearing screening and that the time interval between repeated screenings should be based either on age or on the hearing thresholds at the first screening. PMID- 24149431 TI - Functional status in the young-old: establishing a working prototype of an extended-instrumental activities of daily living scale. AB - BACKGROUND: Instrumental activities of daily living (IADLs) exhibit strong predictive power for the presence of dementia and mild cognitive impairment. However, IADLs are often less effective in younger cohorts or in healthy community-dwelling samples, presenting with large ceiling effects. This study aimed to construct an IADL scale with an extended range. An effort was made to incorporate leisure activity tasks that were more stimulating, and potentially more challenging, into a set of traditional IADLs. METHODS: Beginning with a set of IADL and leisure activity items, nonparametric item response theory methodology was used to construct a scale with appropriate dimensionality, monotonicity, item discrimination power, and scalability within a large cohort of young-old (aged 65-75). Dimensionality was further scrutinized by principal component analysis of the residuals. The predictive validity of the resulting scale for poor cognitive performance was evaluated using logistic regression. RESULTS: A reliable (rho = .73) unidimensional construct was established, meeting the Mokken item response theory criteria of medium scalability. Excluding demented participants, the adjusted model proved sensitive to relatively subtle cognitive deficits; each additional task endorsed (nine-item scale) significantly decreased the odds of being in the bottom quarter of composite domains relating to processing speed (odds ratio = 0.73 [confidence interval: 0.56-0.97], p < .05) and visuospatial ability (odds ratio = 0.70 [confidence interval: 0.73-0.87], p < .01). CONCLUSIONS: A reliable extended-IADL scale was constructed meeting item response theory assumptions relating to unidimensionality, monotonicity, and invariant item ordering. The range of measurement extends well beyond traditional IADL scales. Finally, the scale appears to be sensitive to cognitive differences within the normal spectrum. PMID- 24149432 TI - Longitudinal changes in leukocyte telomere length and mortality in humans. AB - BACKGROUND: Leukocyte telomere length (LTL) ostensibly shortens with age and has been moderately associated with mortality. In humans, these findings have come almost solely from cross-sectional studies. Only recently has LTL shortening within individuals been analyzed in longitudinal studies. Such studies are relevant to establish LTL dynamics as biomarkers of mortality as well as to disentangle the causality of telomeres on aging. METHODS: We present a large longitudinal study on LTL and human mortality, where the 10-year change of LTL is analyzed in 1,356 individuals aged 30-70 years. RESULTS: We find age, smoking status, and alcohol consumption to be associated with LTL attrition and confirm a strong association with baseline LTL. The latter association might be an epiphenomenon of regression to the mean. We do not find an association of mortality with either absolute LTL or LTL attrition. Further, we show that DNA quality has an impact on TS ratios. CONCLUSIONS: This study establishes that certain lifestyle factors influence LTL dynamics. However, it questions the applicability of LTL dynamics as a predictor of mortality. We suggest cautiousness when assessing actual LTL attrition due to the need for high-quality DNA and the phenomena of regression to the mean. PMID- 24149433 TI - Neuropsychological, physical, and functional mobility measures associated with falls in cognitively impaired older adults. AB - BACKGROUND: Older people with cognitive impairment have an elevated fall risk, with 60% falling annually. There is a lack of evidence for fall prevention in this population, in part due to limited understanding of risk factors. This study examined fall risk in older people with cognitive impairment with an emphasis on identifying explanatory and modifiable risk factors. METHODS: One hundred and seventy-seven community-dwelling older people with mild-moderate cognitive impairment (Mini-Mental State Examination 11-23/Addenbrooke's Cognitive Examination-Revised <83) underwent neuropsychological, physical, and functional assessments. Falls were recorded prospectively for 12 months with the assistance of carers. RESULTS: Of the 174 participants available to follow-up, 111 (64%) fell at least once and 71 (41%) at least twice. Higher fall rates were associated with slower reaction time, impaired balance (sway on floor and foam, semitandem, near-tandem, tandem stance), and reduced functional mobility (co-ordinated stability, timed up-and-go, steps needed to turn 180 degrees , sit-to-stand, gait velocity). Higher fall rates were also associated with increased medication use (central nervous system, total number) and poorer performances in cognitive (Addenbrooke's Cognitive Examination-Revised: visuospatial domain, cube drawing; Trail-Making Test) and psychological (Geriatric Depression Scale, Goldberg Anxiety Scale, Falls Efficacy Scale-International) tests. Multivariate analysis identified increased sway on foam, co-ordinated stability score, and depressive symptoms to be significantly and independently associated with falls while controlling for age, years of education, and Addenbrooke's Cognitive Examination Revised score. CONCLUSIONS: This study identified several risk factors of falls in older people with cognitive impairment, a number of which are potentially modifiable. Future research involving targeted interventions addressing medication use, balance, mood, and functional performance may prove useful for fall prevention in this population. PMID- 24149435 TI - Excited state electron transfer from aminopyrene to graphene: a combined experimental and theoretical study. AB - The quenching of the fluorescence of 1-aminopyrene (1-Ap) by reduced graphene oxide (rGO) has been investigated using spectroscopic techniques. In spite of the upward curvature in the Stern-Volmer plot, the unchanged spectral signature of the absorption of 1-Ap in the presence of rGO and the decrease in fluorescence lifetime with increasing rGO concentration point toward the dynamic nature of the quenching. Detailed analysis of steady state and time-resolved spectroscopic data has shown that the quenching arises due to the photoinduced electron transfer from 1-Ap to rGO. This is again supported by estimating the Gibb's free energy change for the ground as well as excited state electron transfer. Ab initio calculations under the density functional theory (DFT) formalism reveal that the possibility of pi-pi stacking is very slim in the 1-Ap-rGO system and the electron density resides completely on 1-Ap in the highest occupied molecular orbital (HOMO) and on graphene in the lowest unoccupied molecular orbital (LUMO), supporting the experimental findings of the intermolecular electron transfer between 1-Ap and rGO in the excited state. PMID- 24149437 TI - The piezoresistive effect in graphene-based polymeric composites. AB - The strain-dependent electrical resistance of polyvinyl ester-based composites filled with different weight fractions of graphene nanoplatelets (GNPs) has been experimentally investigated. The GNP synthesis and nanocomposite fabrication process have been optimized in order to obtain highly homogeneous filler dispersion and outstanding electrical properties. The produced nanocomposites showed a low percolation threshold of 0.226 wt% and electrical conductivity of nearly 10 S m(-1) at only 4 wt% of GNPs. The piezoresistive response of thin nanocomposite laminae has been assessed by measuring the variation of the electrical resistance as a function of the flexural strain in three-point bending tests under both quasi-static monotonic and dynamic cyclic loading conditions. The obtained results showed higher strain sensitivity than traditional metal foil strain gauges or recently investigated carbon-based nanocomposite films. PMID- 24149439 TI - Remarkable anticancer activity of ferrocenyl-terpyridine platinum(ii) complexes in visible light with low dark toxicity. AB - Ferrocenyl platinum(ii) complexes (), viz. [Pt(Fc-tpy)Cl]Cl (), [Pt(Fc tpy)(NPC)]Cl (, HNPC = N-propargyl carbazole) and [Pt(Fc-bpa)Cl]Cl (), were prepared, characterized and their anti-proliferative properties in visible light in human keratinocyte (HaCaT) cell lines have been studied. [Pt(Ph-tpy)Cl]Cl () was prepared and used as a control. Complexes and , structurally characterized by X-ray crystallography, show distorted square-planar geometry for the platinum(ii) centre. Complexes and having the Fc-tpy ligand showed an intense absorption band at ~590 nm. The ferrocenyl complexes are redox active showing the Fc(+)-Fc couple near 0.6 V vs. SCE in DMF-0.1 M tetrabutylammonium perchlorate (TBAP). Complexes showed external binding to calf thymus DNA. Both and showed remarkable photocytotoxicity in HaCaT cell lines giving respective IC50 values of 9.8 and 12.0 MUM in visible light of 400-700 nm with low dark toxicity (IC50 >60 MUM). Fluorescent imaging studies showed the spread of the complexes throughout the cell localising both in cytoplasm and the nucleus. The ferrocenyl complexes triggered apoptosis on light exposure as evidenced from the Annexin V-FITC/PI and DNA ladder formation assays. Spectral studies revealed the formation of ferrocenium ions upon photo-irradiation generating cytotoxic hydroxyl radicals via a Fenton type mechanism. The results are rationalized from a TDDFT study that shows involvement of ferrocene and the platinum coordinated terpyridine moiety as respective HOMO and LUMO. PMID- 24149438 TI - Role of chemokines and their receptors in chronic lymphocytic leukemia: function in microenvironment and targeted therapy. AB - Chemokines produced in distinct tissue microenvironments sustain migration of mature lymphocytes in lymphoglandula. Chemokine receptors expressed on chronic lymphocytic leukemia (CLL) cells regulate the migration of the leukemia cells within the bone marrow (BM), lymphoid organs in collaboration with chemokines. Chemokines form a pro-survival circuitry by regulating leukocyte trafficking, maintaining extended lymphocyte survival. Therefore, chemokines in tumor cell microenvironment interactions represent a target for treatment of CLL. AMD3100 disrupts the CLL/microenvironment interactions and influences CXCL12/CXCR4 survival signaling. Fostamatinib, ibrutinib, and GS-1101 as B-cell receptor (BCR) related kinase inhibitors inhibit BCR- and chemokine-receptor-signal-regulated kinase and have a good clinical response in CLL. Lenalidomide, sorafenib, and dasatinib are other additional drugs associated with chemokine in microenvironment. Inhibiting signaling through chemokine and microenvironment associated signaling are emerging as innovative therapeutic targets in CLL. In this article, we reviewed the role of chemokines in CLL microenvironment and novel therapeutics targeting CLL microenvironment. PMID- 24149440 TI - The TOMM machinery is a molecular switch in PINK1 and PARK2/PARKIN-dependent mitochondrial clearance. AB - Loss-of-function mutations in PARK2/PARKIN and PINK1 cause early-onset autosomal recessive Parkinson disease (PD). The cytosolic E3 ubiquitin-protein ligase PARK2 cooperates with the mitochondrial kinase PINK1 to maintain mitochondrial quality. A loss of mitochondrial transmembrane potential (DeltaPsi) leads to the PINK1 dependent recruitment of PARK2 to the outer mitochondrial membrane (OMM), followed by the ubiquitination and proteasome-dependent degradation of OMM proteins, and by the autophagy-dependent clearance of mitochondrial remnants. We showed here that blockade of mitochondrial protein import triggers the recruitment of PARK2, by PINK1, to the TOMM machinery. PD-causing PARK2 mutations weakened or disrupted the molecular interaction between PARK2 and specific TOMM subunits: the surface receptor, TOMM70A, and the channel protein, TOMM40. The downregulation of TOMM40 or its associated core subunit, TOMM22, was sufficient to trigger OMM protein clearance in the absence of PINK1 or PARK2. However, PARK2 was required to promote the degradation of whole organelles by autophagy. Furthermore, the overproduction of TOMM22 or TOMM40 reversed mitochondrial clearance promoted by PINK1 and PARK2 after DeltaPsi loss. These results indicated that the TOMM machinery is a key molecular switch in the mitochondrial clearance program controlled by the PINK1-PARK2 pathway. Loss of functional coupling between mitochondrial protein import and the neuroprotective degradation of dysfunctional mitochondria may therefore be a primary pathogenic mechanism in autosomal recessive PD. PMID- 24149441 TI - Bifidogenic effect of whole-grain wheat during a 12-week energy-restricted dietary intervention in postmenopausal women. AB - BACKGROUND/OBJECTIVES: Consumption of whole-grain products is known to have beneficial effects on human health. The effects of whole-grain products on the intestinal microbiota and intestinal integrity have, however, only been studied limitedly. We investigate changes of the human gut microbiota composition after consumption of whole-grain (WW) or refined wheat (RW) and further study effects on gut wall integrity. SUBJECTS/METHODS: Quantitative PCR was used to determine changes in the gut bacterial composition in postmenopausal women following a 12 week energy-restricted dietary intervention with WW (N=38) or RW (N=34). Intestinal integrity was determined by measuring trans-epithelial resistance (TER) across a Caco-2 cell monolayer, following exposure to faecal water. RESULTS: No significant differences in microbiota composition were observed between the two dietary groups; however, the whole-grain intervention increased the relative abundance of Bifidobacterium compared to baseline, supporting a prebiotic effect of whole-grain wheat. Faecal water increased TER independent of dietary intervention, indicating that commensal bacteria produce metabolites that generally provide a positive effect on intestinal integrity. Combining microbiota composition data from the run-in period with its effect on TER revealed a tendency for a negative correlation between the relative abundance of Bifidobacterium and TER (P=0.09). This contradicts previous findings but supports observations of increased Salmonella infection in animal models following treatment with bifidogenic prebiotics. CONCLUSIONS: The present study shows that whole-grain wheat consumption increases the abundance of bifidobacteria compared to baseline and may have indirect effects on the integrity of the intestinal wall. PMID- 24149442 TI - Comparison of various surrogate obesity indicators as predictors of cardiovascular mortality in four European populations. AB - BACKGROUND/OBJECTIVES: Body mass index (BMI) is the most commonly used surrogate marker for evaluating the risk of cardiovascular disease (CVD) mortality in relation to general obesity, while abdominal obesity indicators have been proposed to be more informative in risk prediction. SUBJECT/METHODS: A prospective cohort study consisting of 46 651 Europeans aged 24-99 years was conducted to investigate the relationship between CVD mortality and different obesity indicators including BMI, waist circumference (WC), waist-to-hip ratio (WHR), waist-to-stature ratio (WSR), A Body Shape Index (ABSI) and waist-to-hip to-height ratio (WHHR). Hazard ratio (HR) was estimated by the Cox proportional hazards model using age as timescale, and compared using paired homogeneity test. RESULTS: During a median follow-up of 7.9 years, 3435 participants died, 1409 from CVD. All obesity indicators were positively associated with increased risk of CVD mortality, with HRs (95% confidence intervals) per standard deviation increase of 1.19 (1.12-1.27) for BMI, 1.29 (1.21-1.37) for WC, 1.28 (1.20-1.36) for WHR, 1.35 (1.27-1.44) for WSR, 1.34 (1.26-1.44) for ABSI and 1.34 (1.25-1.42) for WHHR in men and 1.37 (1.24-1.51), 1.49 (1.34-1.65), 1.45 (1.31-1.60), 1.52 (1.37-1.69), 1.32 (1.18-1.48) and 1.45 (1.31-1.61) in women, respectively. The prediction was stronger with abdominal obesity indicators than with BMI or ABSI (P<0.05 for all paired homogeneity tests). WSR appeared to be the strongest predictor among all the indicators, with a linear relationship with CVD mortality in both men and women. CONCLUSIONS: Abdominal obesity indicators such as WC, WHR, WSR and WHHR, are stronger predictors for CVD mortality than general obesity indicator of BMI. PMID- 24149443 TI - Continuous glucose monitoring in children with glycogen storage disease type I. AB - BACKGROUND/OBJECTIVES: Glycogen storage disease type I (GSD I) is an autosomal recessive metabolic disorder caused by defects in the glucose-6-phosphatase complex. Deficient activity in the glucose-6-phosphatase-alpha catalytic unit characterizes GSD Ia and defects in the glucose-6-phosphate transporter protein characterize GSD Ib. Type Ia involves the liver, kidney and intestine (and Ib also leukocytes), and the clinical manifestations are hepatomegaly, failure to thrive, severe fasting hypoglycemia within 3-4 h after a meal, hyperlactatemia, hyperuricemia and hyperlipidemia. The aim of the present study was to examine the safety and efficacy of a continuous subcutaneous glucose monitoring system to determine the magnitude and significance of hypoglycemia in GSD I and to evaluate the efficacy of the revised dietary treatment. SUBJECTS/METHODS: Sixteen children with GSD I were studied over a 72-h period. Continuous glucose monitoring (CGM) was repeated in all patients 3-6 months after the first monitoring to examine the effects of revised dietary instructions on glycemic control. RESULTS: All the patients completed the study without any major adverse events. Significant periods of asymptomatic hypoglycemia (below 4 mmol/l, 70 mg/dl) were noted. There was a close correlation between CGM sensor and capillary blood glucose values measured by a glucometer. CGM indicated a considerable reduction in duration of hypoglycemia, liver size and improvements in secondary metabolic derangements such as hyperlacticacidemia and hyperlipidemia. CONCLUSIONS: CGM could be applied in the clinical setting to help the physician to identify hypoglycemic events, and repeated CGM may serve as a safe and useful tool for the assessment of the long-term management of patients with GSD I. PMID- 24149444 TI - Dietary factors associated with subclinical inflammation among girls. AB - BACKGROUND/OBJECTIVES: Dietary patterns and biomarkers of inflammation have been scarcely associated. The aim was to assess dietary factors associated with subclinical inflammation among girls. SUBJECTS/METHODS: Fasting blood samples were collected from 12- to 17-year old girls (n=219) to measure adiponectin, leptin, tumor necrosis factor-alpha, plasminogen activator inhibitor 1 (PAI-1), interleukin-6 (IL-6) and high-sensitivity C-reactive protein (hs-CRP) levels. Body mass index (BMI) and waist-to-height ratio (WHtR), and food intake were also measured. Western (WDP) and Mediterranean (MDP) dietary patterns were identified. RESULTS: BMI and WHtR were associated with adiponectin, leptin and hs-CRP (the last, only associated with BMI). Intakes of beta-carotene equivalents and vitamin C were associated with adiponectin; saturated fatty acids (SFA), vitamin A, manganese and selenium with leptin; linoleic acid with PAI-1; and oleic acid and vitamin E with IL-6. Selenium was inversely associated with adiponectin, whereas magnesium was positively associated with IL-6. MDP was associated with higher plasma concentrations of adiponectin (beta=0.174, P<0.05); after adjustment for BMI, associations were not significant (beta=0.144, P=0.076). WDP was negatively associated with adiponectin (beta=-0.177, P<0.05) and positively with IL-6 (beta=0.183, P<0.05). CONCLUSIONS: Subclinical inflammation is detectable with increasing BMI and also WHtR. Measures of adiposity (BMI and WHtR) are significant predictors of adiponectin, leptin and hs-CRP. Dietary patterns per se have a small role in affecting inflammatory markers among adolescents. PMID- 24149445 TI - Higher insulin sensitivity in vegans is not associated with higher mitochondrial density. AB - BACKGROUND/OBJECTIVES: Vegans have a lower incidence of insulin resistance (IR) associated diseases and a higher insulin sensitivity (IS) compared with omnivores. The aim of this study was to examine whether the higher IS in vegans relates to markers of mitochondrial biogenesis and to intramyocellular lipid (IMCL) content. SUBJECTS/METHODS: Eleven vegans and 10 matched (race, age, sex, body mass index, physical activity and energy intake) omnivorous controls were enrolled in a case-control study. Anthropometry, bioimpedance (BIA), ultrasound measurement of visceral and subcutaneous fat layer, parameters of glucose and lipid homeostasis, hyperinsulinemic euglycemic clamp and muscle biopsies were performed. Citrate synthase (CS) activity, mitochondrial DNA (mtDNA) and IMCL content were assessed in skeletal muscle samples. RESULTS: Both groups were comparable in anthropometric and BIA parameters, physical activity and protein energy intake. Vegans had significantly higher glucose disposal (M-value, vegans 8.11+/-1.51 vs controls 6.31+/-1.57 mg/kg/min, 95% confidence interval: 0.402 to 3.212, P=0.014), slightly lower IMCL content (vegans 13.91 (7.8 to 44.0) vs controls 17.36 (12.4 to 78.5) mg/g of muscle, 95% confidence interval: -7.594 to 24.550, P=0.193) and slightly higher relative muscle mtDNA amount (vegans 1.36+/ 0.31 vs controls 1.13+/-0.36, 95% confidence interval:-0.078 to 0.537, P=0.135). No significant differences were found in CS activity (vegans 18.43+/-5.05 vs controls 18.16+/-5.41 MUmol/g/min, 95% confidence interval: -4.503 to 5.050, P=0.906). CONCLUSIONS: Vegans have a higher IS, but comparable mitochondrial density and IMCL content with omnivores. This suggests that a decrease in whole body glucose disposal may precede muscle lipid accumulation and mitochondrial dysfunction in IR development. PMID- 24149446 TI - The effects of American Society of Anesthesiologists physical status on length of stay and inpatient cost in the surgical treatment of isolated orthopaedic fractures. AB - OBJECTIVES: To identify the impact of the American Society of Anesthesiologists (ASA) physical status on postoperative length of stay (LOS) and to document the cost due to LOS after surgical management of the 8 most common lower extremity and 2 most common upper extremity isolated orthopaedic fractures. DESIGN: Retrospective chart review. SETTING: All patients who presented and underwent one of the 10 selected isolated orthopaedic surgical procedures at a large tertiary care center between January 1, 2000, and December 31, 2010. PATIENTS/PARTICIPANTS: Charts for patients undergoing the 10 selected isolated orthopaedic surgical fracture procedures more than 10 years were reviewed. Thirteen thousand seven hundred seventy-six distinct operations were identified. One thousand three hundred ninety-eight distinct operations were included in analysis after selection. INTERVENTION: This was an observational study. Patients who received operative management for isolated orthopaedic fractures were identified utilizing a CPT code search for analysis in a retrospective chart review. MAIN OUTCOME MEASUREMENTS: LOS and cost secondary to LOS. RESULTS: ASA physical status proved the strongest predictor of postoperative LOS for the 8 most common lower extremity and 2 most common upper extremity isolated orthopaedic procedures. ASA was also a significant predictor of inpatient cost for all isolated orthopaedic procedures included in the study with the exception of CPT code 27536. CONCLUSIONS: ASA classification is an indicator for variance in LOS and total inpatient cost for hospitalized patients. Given that ASA classification is a universally collected data point, this method can be used in almost any hospital system and for any operative service. In addition, this study provides a foundation for many other studies to be conducted which will include multiple institutions and fracture types, such that ASA can be used as a more generalizable predictor of LOS and inpatient cost in orthopaedic trauma patients. This model may be used to accurately predict a patient's postoperative course and the expected cost to the health care system of a given procedure. LEVEL OF EVIDENCE: Prognostic Level IV. See Instructions for Authors for a complete description of levels of evidence. PMID- 24149447 TI - Systematic review of the treatment of periprosthetic distal femur fractures. AB - OBJECTIVES: To systematically review and compare nonoperative and operative treatments for the management of periprosthetic distal femur fractures adjacent to total knee arthroplasties. Specific operative interventions compared included locked plating, retrograde intramedullary nailing (RIMN), and conventional (nonlocked) plating. Where possible, data were pooled to arrive at summary estimates of treatment effect [odds ratios (ORs) with associated 95% confidence intervals (CIs)]. METHODS: A comprehensive database search (via Pubmed, Medline, Cochrane Database, and the Orthopaedic Trauma Association database) was completed, yielding 44 eligible studies with a total of 719 fractures for analysis. Pertinent outcomes including malunion, nonunion, and the need for secondary surgical procedures were compared statistically. RESULTS: Both locked plating and RIMN demonstrated significant advantages over nonoperative treatment. Some advantages were also observed when locked plating and RIMN were compared with conventional (nonlocked) plates. Comparison of locked plating and RIMN showed no significant differences with regard to nonunion rates (OR = 0.39, 95% CI = 0.13-1.15; P = 0.09) or rate of secondary surgical procedures (OR = 0.65, 95% CI = 0.31-1.35; P = 0.25). However, RIMN demonstrated a significantly higher malunion rate when compared with locked plating (OR = 2.37, 95% CI = 1.17-4.81; P = 0.02). CONCLUSIONS: Locked plating and RIMN offer significant advantages over nonoperative treatment and conventional (nonlocked) plating techniques in the management of periprosthetic femur fractures above total knee arthroplasties. Locked plating demonstrated a trend toward increased nonunion rates when compared with RIMN. Malunion was significantly higher with RIMN compared with locked plating. PMID- 24149448 TI - Reexamination of pelvic inlet and outlet images using 3-dimensional computed tomography reconstructions. AB - OBJECTIVES: Inlet and outlet views are essential in the evaluation of patients with pelvic injuries. The optimal angles that should be used to obtain these views are still debated. METHODS: Computed tomography scans of 70 patients without pelvic ring injuries were analyzed. Using the raw data from the computed tomography images, virtual pelvic x-rays were generated. The images were rotated 1 degree at a time and a total of 360 images were generated. The same procedure was repeated to create solid 3-dimensional (3D) reconstructions. Two trauma trained orthopaedic surgeons then reviewed all 360 images to select inlet and outlet views as described in previous literature. Intraclass correlation coefficients were calculated for each inlet and outlet value. RESULTS: The average inlet angle (caudal tilt) that was required to achieve a view where the promontory overlaps the S1 body was found to be 26.7 degrees (95% confidence interval, 25-29) with virtual x-rays and 24.3 degrees (95% confidence interval, 22-26) with 3D reconstructions. The average outlet angle (cephalad tilt) that was required to achieve a view where the superior border of the pubic symphysis overlaps the S2 body was 43.7 degrees (95% confidence interval, 42-45) with virtual x-rays and 43.8 degrees (95% confidence interval, 42-45) with 3D reconstructions. There was no difference in these angles based on gender, whereas sacral dysmorphism increased the angle needed to obtain the outlet view by an average of 5 degrees. CONCLUSIONS: This study demonstrated that the ideal angle to obtain inlet views should be approximately 25 degrees and to obtain outlet views should be approximately 45 degrees during screening x-rays to evaluate patients who were diagnosed with pelvic injuries. Application of these new values in the clinical practice would provide higher rates of adequate studies and further prospective clinical studies should be performed to validate these parameters. PMID- 24149449 TI - Coordination between ribs motion and thoracoabdominal volumes in swimmers during respiratory maneuvers. AB - This work aimed to verify if swimmers present better chest wall coordination during breathing than healthy non-athletes analyzing the correlation between ribs motion and the variation of thoracoabdominal volumes. The results of two up-to date methods based on videogrammetry were correlated in this study. The first one measured the volumes of 4 separate compartments of the chest wall (superior thorax, inferior thorax, superior abdomen and inferior abdomen) as a function of time. The second calculated the rotation angle of the 2(nd) to the 10(th) ribs around the quasi-transversal axis also in function of time. The chest wall was represented by 53 markers, attached to the ribs, vertebrae, thorax and abdomen of 15 male swimmers and of 15 non- athletes. A kinematical analysis system equipped with 6 digital video cameras (60Hz) was used to obtain the 3D coordinates of the markers. Correlating the curves of ribs rotation angles with the curves of the separate volumes, swimmers presented higher values than non-athletes when the superior and inferior abdomen were considered and the highest correlation values were found in swimmers for the inferior thorax. These results suggest a better coordination between ribs motion and thoracoabdominal volumes in swimmers, indicating the prevalent and coordinated action of the diaphragm and abdominal muscles to inflate and deflate the chest wall. The results further suggest that swimming practice leads to the formation of an optimized breathing pattern and can partially explain the higher lung volumes found in these athletes reported in literature. Key pointsThe study revealed that swimmers present higher correlation between the ribs motion and the variation of abdominal volumes than non-swimmers, suggesting that swimming practice might lead to the formation of an optimized breathing pattern, increasing the coordination between the thoracoabdominal volumes and the ribs motion.No previous work was found in the literature reporting this optimized breathing pattern in swimmers.The higher coordination between the thoracoabdominal volumes and the ribs motion found in swimmers can partially explain the higher lung volumes reported in literature for these athletes. PMID- 24149450 TI - Predicting the intra-cyclic variation of the velocity of the centre of mass from segmental velocities in butterfly stroke: a pilot study. AB - The purpose of this study was to analyze the relationship between the intra-cycle variation of the horizontal velocity of displacement of the center of mass (dV), the hand's and feet's velocity, as well as, to identify the variables that most predict the dV's, in butterfly stroke. The study was divided in two parts. The aim of Part I was to investigate the behavior of variables in study at slow swimming velocities and the purpose of Part II was the same but at high swimming velocities. 3 male Portuguese swimmers and 1 female swimmer, of international level were studied in Part I. The swimmers were submitted to an incremental set of 200 m butterfly swims. In the Part II, 7 Portuguese male swimmers of national and international level were studied. Each swimmer performed two maximal 25 m butterfly swims. Both protocols were recorded from four different plans, allowing a 3D analysis. It was calculated the dV, the 3D components (Vx, Vy, Vz) of the hand's velocity and the 2D components (Vx, Vy) of the feet's velocity. Several variables presented significant correlation coefficients with dV at all selected velocities (high velocity ranged from r = 0.58 for Vx-out to r = 0.82 for Vy 1dwn; slow velocity ranged from r = -0.45 for Vx-1dwn to r=0.73 for Vx-ups; overall velocity ranged from r= 0.34 for Vz-ent to r = 0.82 for Vx-ins). It was also computed a regression model to predict dV. For high velocity (up to 1.75 +/- 0.09 m.s(-1)), the variables that best predict dV were Vy during the first downbeat, Vx and Vy during the arm's insweep (r(2) = 0.93). At slow velocity (up to 1.48 m.s(-1)), the variables included in the forward step-by-step regression model were Vx during upsweep, Vy and Vx during insweep (r(2) = 0.69). For overall velocity, the variables that most fit the regression model were Vx during upsweep, Vy during second downbeat and Vz during entry (r(2)= 0.94). In order to reduce dV, butterfliers should increase hand's velocity in all orthogonal components at the end of the underwater path, should increase the vertical velocity during the downbeats and decrease the velocity during the hand's entry. Key pointsSegmental velocities are a determinant phenomenon for swimming performance and should be carefully analyzed by coaches and butterfliers.Butterfliers must finish the last phase of the underwater path with a high hand's velocity in order to reduce the speed fluctuation and increase the swimming velocity.Butterfliers should also pay more attention to downbeats, since they are important to reduce the speed fluctuation during the hand's entry, as well as, the arm's recovery. PMID- 24149451 TI - Acute effects of self-selected regimen of rapid body mass loss in combat sports athletes. AB - The purpose of the study was to assess the acute effects of the self-selected regimen of rapid body mass loss (RBML) on muscle performance and metabolic response to exercise in combat sports athletes. Seventeen male athletes (20.8 +/- 1.0 years; mean +/- SD) reduced their body mass by 5.1 +/- 1.1% within 3 days. The RBML was achieved by a gradual reduction of energy and fluid intake and mild sauna procedures. A battery of tests was performed before (Test 1) and immediately after (Test 2) RBML. The test battery included the measurement of the peak torque of knee extensors for three different speeds, assessment of total work (Wtot) performed during a 3-min intermittent intensity knee extension exercise and measurements of blood metabolites (ammonia, lactate, glucose and urea). Absolute peak torque was lower in Test 2 compared with Test 1 at angular velocities of 1.57 rad.s(-1) (218.6 +/- 40.9 vs. 234.4 +/- 42.2 N.m; p = 0.013) and 3.14 rad.s(-1) (100.3 +/- 27.8 vs. 111.7 +/- 26.2 N.m; p = 0.008). The peak torque in relation to body mass remained unchanged for any speed. Absolute Wtot was lower in Test 2 compared with Test 1 (6359 +/- 2326 vs. 7452 +/- 3080 J; p = 0.003) as well as Wtot in relation to body mass (89.1 +/- 29.9 vs. 98.6 +/- 36.4 J.kg(-1); p = 0.034), respectively. As a result of RBML, plasma urea concentration increased from 4.9 to 5.9 mmol.l(-1) (p = 0.003). The concentration of ammonia in a post-test sample in Test 2 tended to be higher in comparison with Test 1 (80.9 +/- 29.1 vs. 67.6 +/- 26.5 mmol.l(-1); p = 0.082). The plasma lactate and glucose responses to exercise were similar in Test 1 and Test 2. We conclude that the self-selected regimen of RBML impairs muscle performance in 3 min intermittent intensity exercise and induces an increase in blood urea concentration in experienced male combat sports athletes. Key pointsPrevious studies have revealed a negative effect of rapid body mass loss on performance. However, there are some performance characteristics that may not change or even improve.The methods used for inducing rapid body mass loss have been prescribed by researchers and not chosen by the subjects in many previous studies. The duration of tests, which have revealed a negative impact of rapid body mass loss on performance have also been rather long (5-6 min) in previous studies.We assessed the acute effects of the self-selected regimen of rapid body mass loss on muscle performance and metabolic response to 3-min intermittent intensity exercise in experienced male combat sports athletes.The results suggest that the self-selected regimen of rapid body mass loss impairs muscle performance in 3-min intermittent intensity exercise and induces an increase in blood urea concentration. Hence, the recent changes in the rules of some events (wrestling), including shortening of the duration of a match, have not reduced the likelihood of the occurrence of a negative impact of rapid body mass loss on athletes' performance capacity. PMID- 24149452 TI - Gender Differences and Biomechanics in the 3000M Steeplechase Water Jump. AB - Since 1996, women have been competing in the 3000m steeplechase race internationally. Whenever women and men both compete in similar events with different equipment (the barriers are lower for women) consideration should be given as to how techniques should be coached differently. This study investigated the differences in water-jump technique between men and women after accounting for differences in running speed and which techniques led to maintenance of race pace through the water-jump. Eighteen men and 18 women were filmed at two major track and field meets during the 2004 season. Peak Motus 8.2 was used to digitize all seven jumps from each athlete. Various characteristics of water-jump technique were measured or calculated and compared using two multiple linear regressions (one for men and one for women) to determine which characteristics led to maintaining race pace speeds through the water jump obstacle. Repeated measures ANOVA was used to determine any differences between men and women in the measured characteristics of technique.Velocity through the jump divided by race pace was predicted very well by approach velocity and landing distance for men and women. Other characteristics of the movement were non-significant. Differences between genders were found in: approach velocity, take-off distance, landing distance, push-off angle, velocity through jump, and exit velocity. Men and women steeplechasers must focus on approach velocity and landing distance to complete the water-jump close to their race pace. Coaches need to consider many characteristics of technique that differ between men and women. Key pointsWomen may need to be coached differently than men in the steeplechase water jump due to different techniques required.Men and women must focus on a high approach velocity to complete the steeplechase water jump successfully.Men and women must generate a relatively long landing distance to maintain velocity and keep from having to use extra energy exiting the water pit.Women's race paces were affected more than men's by the water jump in a negative way. PMID- 24149453 TI - The role of shoulder maximum external rotation during throwing for elbow injury prevention in baseball players. AB - The objective of the present study was to examine whether the passive range of shoulder external rotation (ER), the maximum shoulder external rotation angle (MER) during throwing, and the ratio of MER to ER are related to the incidence of the elbow injury. A mixed design with one between-factor (a history of the elbow injury) and two within-factors (ER and MER) was used to analyze the difference between baseball players with and without a history of medial elbow pain. Twenty high school baseball players who had experienced the medial elbow pain within the previous month but who were not experiencing the pain on the day of the experiment were recruited (elbow-injured group). Another twenty baseball players who had never experienced the medial elbow pain were also used for testing (control group). MER during throwing, ER, and the ratio of MER to ER were obtained in both of the group. A Mann-Whitney test was used for the group comparison (p < 0.05). The ratio of MER to ER was significantly greater in the elbow-injured group (1.52 +/- 0.19) than that in the control group (1.33 +/- 0.23) (p = 0.008). On the other hand, there was no statistical significance in MER and ER between two groups. The findings of the study indicate that MER/ER relation could be associated with the incidence of the elbow injury in baseball players. Key pointsIt is accepted that the greatest elbow valgus stress appears at the position of shoulder maximum external rotation (MER) in the acceleration phase of the throwing movement. As a consequence, shoulders with restricted range of motion of external rotation (ER) compensate with a valgus stress on their elbow joints.In this study, we evaluated the relation between MER and ER of shoulder in players with/without elbow injuries.The result of this study demonstrated that the elbow injured group showed significantly greater MER/ER relation than the control group.The current finding suggests that great MER combined with the ROM restriction may be one of the risk factors to cause medial elbow pain in baseball players. PMID- 24149454 TI - Lung Diffusion Capacity can Predict Maximal Exercise in Apparently Healthy Heavy Smokers. AB - Chronic exposure to tobacco smoking may damage lung and heart function. The aim of this study was to assess maximal exercise capacity and its relationship with lung function in apparently healthy smokers. We recruited 15 heavy smokers (age 47 years +/- 7, BMI 25 kg/m(2) +/- 3, pack/years 32 +/- 9) without any cardiovascular or pulmonary signs and symptoms. Fifteen healthy non smoking subjects were enrolled as a control group. All subjects underwent pulmonary function tests, electrocardiograms at rest and graded cycle exercise tests. In smokers and controls, resting lung and cardiac function parameters were in the normal range, apart from diffusing lung capacity (TLCO) values which were significantly lower in smokers (p < 0.05). As compared to controls, smokers presented lower maximal exercise capacity with lower values at peak of exercise of oxygen uptake (peak VO2), workload, oxygen uptake/watt ratio and oxygen pulse (p < 0.05) and higher dyspnoea perception (p < 0.05). Moreover, peak VO2, maximal workload and oxygen pulse at peak exercise were related to and predicted by TLCO (p < 0. 05). Our study confirms that maximal exercise capacity is reduced in apparently healthy heavy smokers, and shows that TLCO explains some of the variance in maximal exercise. Key pointsChronic exposure to tobacco smoking may damage lung and heart function.Smokers present lower diffusion capacity and maximal exercise capacity.In smokers maximal exercise capacity can be predicted by resting diffusion lung capacity. PMID- 24149455 TI - The effects of multiple cold water immersions on indices of muscle damage. AB - The aim of this investigation was to elucidate the efficacy of repeated cold water immersions (CWI) in the recovery of exercise induced muscle damage. A randomised group consisting of eighteen males, mean +/- s age, height and body mass were 24 +/- 5 years, 1.82 +/- 0.06 m and 85.7 +/- 16.6 kg respectively, completed a bout of 100 drop jumps. Following the bout of damaging exercise, participants were randomly but equally assigned to either a 12 min CWI (15 +/- 1 degrees C; n = 9) group who experienced immersions immediately post-exercise and every 24 h thereafter for the following 3 days, or a control group (no treatment; n = 9). Maximal voluntary contraction (MVC) of the knee extensors, creatine kinase activity (CK), muscle soreness (DOMS), range of motion (ROM) and limb girth were measured pre-exercise and then for the following 96 h at 24 h increments. In addition MVC was also recorded immediately post-exercise. Significant time effects were seen for MVC, CK, DOMS and limb girth (p < 0.05) indicating muscle damage was evident, however there was no group effect or interaction observed showing that CWI did not attenuate any of the dependent variables (p > 0.05). These results suggest that repeated CWI do not enhance recovery from a bout of damaging eccentric contractions. Key pointsCryotherapy, particularly cold water immersions are one of the most common interventions used in order to enhance recovery post-exercise.There is little empirical evidence demonstrating benefits from cold water immersions. Research evidence is equivocal, probably due to methodological inconsistencies.Our results show that the cryotherapy administered did not attenuate any markers of EIMD or enhance the recovery of function.We conclude that repeated cold water immersions are ineffective in the recovery from heavy plyometric exercise and suggest athletes and coaches should use caution before using this intervention as a recovery strategy. PMID- 24149456 TI - Myoelectric alterations after voluntary induced high - and low - frequency fatigue. AB - The aim of the study was to find whether voluntary induced high- and low frequency peripheral fatigue exhibit specific alteration in surface EMG signal (SEMG) during evoked and maximum voluntary contractions. Ten male students of physical education performed 60 s long stretch-shortening cycle (SSC) exercise with maximal intensity and 30 s long concentric (CON) exercise with maximal intensity. To verify voluntary induced peripheral fatigue, knee torques during low- (T20) and high-frequency electrical stimulation (T100) of relaxed vastus lateralis muscle (VL) were obtained. Contractile properties of the VL were measured with passive twitch and maximal voluntary knee extension test (MVC). Changes in M-waves and SEMG during MVC test were used to evaluate the differences in myoelectrical signals. T100/T20 ratio decreased by 10.9 +/- 8.4 % (p < 0.01) after the SSC exercise and increased by 35.9 +/- 17.5 % (p < 0.001) after the CON exercise. Significant SEMG changes were observed only after the CON exercise where peak to peak time of the M-waves increased by 9.2 +/- 13.3 % (p < 0.06), SEMG amplitude during MVC increased by 32.9 +/- 21.6 % (p < 0.001) and SEMG power spectrum median frequency decreased by 11.0 +/- 10.5 % (p < 0.05). It is concluded that high frequency fatigue wasn't reflected in SEMG, however the SEMG changes after the CON seemed to reflect metabolic changes due to acidosis. Key pointsThe SSC exercise induced high-frequency fatigue which was not reflected in any SEMG change.The CON exercise induced dominantly low-frequency fatigue where only SEMG during MVC changedMuscle fibre membrane excitability was not changed due to low- and high-frequency fatigue but mainly reflected metabolic changes.Changes in muscle compound action potential did not follow those changes seen after electrically elicited HF and LF fatigue. PMID- 24149457 TI - Pedometer accuracy during stair climbing and bench stepping exercises. AB - The purpose of the present investigation was to examine pedometer accuracy during stair climbing and descending as well as during the performance of a bench stepping exercise. Ten healthy men participated in the present investigation. All subjects ascended and descended an 18 cm high public staircase, and performed a bench stepping exercise by using a 10, 20 and 30 cm high platforms, while wearing three different commercial pedometers (DW-800, YM, HJ- 700IT; OM, Lifecorder; KZ). In both situations, the stepping rate was controlled at 40, 50, 80, 100 and 120 steps.min(-1). The pedometer scores tended to underestimate the actual number of steps during stair climbing with a slower stepping rate and/or the lower height of a platform. During the stair ascending and descending and the bench stepping exercise using 20 to 30 cm high platforms at 80 to 120 steps.min(-1), the magnitude of the measurement error was -3.8 +/- 10. 8 % for KZ, -2.1 +/- 9.8 % for YM and -11.0 +/- 18.9 % for OM. These results indicate that the KZ and the YM can accurately assess the number of steps during stair climbing using 20 to 30 cm high platforms at 80 to 120 steps.min(-1). Key pointsPedometers can assess the number of step accurately within an acceptable range of measurement error during the stair climbing activities at a stepping rate of 80 step.min(-1) or faster with 18 cm or higher stairs. PMID- 24149458 TI - Self-reported dietary intake following endurance, resistance and concurrent endurance and resistance training. AB - With regards to obesity-related disease the impact of exercise training on health depends on the ability of exercise to promote a negative energy balance. Exercise's effect on promoting a negative energy balance is more likely to occur if exercise can induce a favourable dietary intake such as a reduced relative fat content in the diet. As such, the aim of this study was to evaluate and compare the effectiveness of aerobic training, weight training and concurrent aerobic and weight training on self-reported dietary intake. The effects of 16 weeks of aerobic (n = 12), weight (n = 13) and concurrent aerobic and weight training (n = 13) on self-reported dietary intakes were compared in previously sedentary males using the computer-based Dietary Manager((r)) software programme. Only the concurrent aerobic and weight training group showed significant (p <= 0.05) reductions in total kilocalories, carbohydrates, proteins and fats consumed while the aerobic training group showed significant reductions in fat intake at the completion of the experimental period (before: 91.0 +/- 42.1g versus after: 77.1 +/- 62.1g). However, no changes were observed in self-reported dietary intake in the weight training or non-exercising control groups. It is concluded that concurrent aerobic and weight training is the most effective mode of exercise at promoting a favourable improvement in self-reported dietary intake in the short term. This finding provides support for efforts to promote increases in overall physical activity in an attempt to modify the patterns of dietary intake. Key pointsConcurrent aerobic and weight training can significantly reduce the amount of total kilocalories, carbohydrates, proteins and fats consumed.Aerobic training can significantly reduce fat intake.Weight training resulted in no changes in dietary intake.Concurrent aerobic and weight training is the most effective mode of exercise at promoting a favourable improvement in self-reported dietary intake. PMID- 24149459 TI - Relations of self-appraisal and mood changes with voluntary physical activity changes in african american preadolescents in an after-school care intervention. AB - There is an increasing prevalence of overweight in preadolescents that predicts physical problems over the lifespan. Physical inactivity has been implicated as an associated factor, with African American youth being at an increased risk. Based on social cognitive theory, and proposed correlates of physical activity in youth, changes over 12 weeks in measures of self-appraisal (general self, physical appearance, physical self-concept, exercise barriers self-efficacy) and mood (tension, vigor), and their relations with voluntary physical activity changes, were assessed within an after-school care physical activity intervention. Participants were volunteers recruited from children already registered for a 12-week segment of YMCA after-school care. The treatment group consisted of 146 African American preadolescents with the control group comprised of 123 African American preadolescents who were scheduled to receive the program during the next sequence that it was offered. Results indicated the intervention group reported significantly more positive self-appraisals, reduced tension, and enhanced vigor. Bivariate and multiple regression analyses indicated that when each of the 4 self-appraisal and 2 mood factors were simultaneously entered into a regression equation, 36% of the variance in voluntary physical activity was explained. Findings support the treatment's association with theoretically based correlates of physical activity in the present sample, and suggest directions for physical activity interventions for youth. Key pointsSocial cognitive theory offers a framework for understanding correlates of physical activity in youth.This study suggests that it is possible for a convenient physical activity intervention, led by after-school care counselors with minimal training, to improve participants' self-perceptions, mood, and voluntary physical activity.Improvements in self-perceptions and mood appeared to be significantly associated with increased free-time physical activity in African American 8- to 12-year-olds.This study's findings may lead to a better understanding of physical activity promotion in youth, and foster improvements in physical activity curricula. PMID- 24149460 TI - Pre-activity modulation of lower extremity muscles within different types and heights of deep jump. AB - The purpose of this study was to determine modulation of pre- activity related to different types and heights of deep jump. Sixteen male soccer players without experience in deep jumps training (the national competition; 15.0 +/- 0.5yrs; weight 61.9 +/- 6.1kg; height 1.77 +/- 0.07m), who participated in the study, performed three types of deep jump (bounce landing, counter landing, and bounce drop jump) from three different heights (40cm, 60cm, and 80cm). Surface EMG device (1000Hz) was used to estimate muscle activity (maximal amplitude of EMG - AmaxEMG; integral EMG signal - iEMG) of five muscles (mm.gastrocnemii, m.soleus, m.tibialis anterior, m.vastus lateralis) within 150ms before touchdown. All the muscles, except m. gastrocnemius medialis, showed systematic increase in pre activity when platform height was raised. For most of the lower extremity muscles, the most significant differences were between values of pre-activity obtained for 40 cm and 80 cm platforms. While the amount of muscle pre-activity in deep jumps from the heights above and beneath the optimal one did not differ significantly from that generated in deep jumps from the optimal drop height of 60 cm, the patterns of muscle pre-activity obtained for the heights above the optimal one did differ from those obtained for the optimal drop height. That suggests that deep jumps from the heights above the optimal one do not seem to be an adequate exercise for adjusting muscle activity for the impact. Muscle pre activity in bounce drop jumps differed significantly from that in counter landing and bounce landing respectively, which should indicate that a higher amount of pre-activity generated during bounce drop jumps was used for performing take offs. As this study included the subjects who were not familiar with deep jumps training, the prospective studies should reveal the results of athletes with previous experience. Key pointsHeight factor proved to be more relevant for the change in pre-activation level compared to the drop jump type factor.There is evident qualitative difference in pattern of pre-activation from lower and higher drop heights, compared to pattern of pre-activation obtained from optimal drop height.Drop jumps from the heights above the optimal one are not adequate for nicely preparing muscle activity for the impact. PMID- 24149461 TI - Lactate kinetics after intermittent and continuous exercise training. AB - The purpose of this study was to assess, the effects of continuous and intermittent exercise training on lactate kinetic parameters and maximal aerobic speed (MAS) using field tests. Twenty-four male sport students were equally divided into continuous (CT) and intermittent (IT) physically trained groups. Another six participants acted as non-trained controls (CG). The trained participants practiced 6-days per week for 6 weeks. Before and after training, all participants completed an incremental exercise test to assess their MAS, and a 30- second supra-maximal exercise followed by 30 minutes of active recovery to determine the individual blood lactate recovery curve. It was found that exercise training has significantly increased MAS (p < 0.001), the lactate exchange and removal abilities as well as the lactate concentrations at the beginning of the recovery ([La]-(0)); for both CT and IT groups; this was accompanied by a significant reduction of the time to lactate-peak. Nevertheless, the improvement in MAS was significantly higher (p < 0.001) post-intermittent (15.1 % +/- 2.4) than post-continuous (10.3 % +/- 3.2) training. The lactate-exchange and removal abilities were also significantly higher for IT than for CT-group (P<0.05). Moreover, IT-group showed a significantly shorter half-time of the blood lactate (t-1/2-[La]) than CT-group (7.2 +/- 0.5 min vs 7.7 +/- 0.3 min, respectively) (p < 0.05). However, no significant differences were observed in peak blood lactate concentration ([La]peak), time to reach [La]peak (t-[La]peak), and [La]-(0) between the two physically-trained groups. We conclude that both continuous and intermittent training exercises were equally effective in improving t-[La]peak and [La]peak, although intermittent training was more beneficial in elevating MAS and in raising the lactate exchange (gamma1) and removal (gamma2) indexes. Key pointsCoaches and athletes need to be aware of the potentiality positive effects of exercise intensity.Improvements in physical fitness are associated with a concomitant increase in the lactate removal ability.In order to reduce lactate accumulation and increase maximal aerobic speed maximally, interval training method, with work speeds equal to 90% - 100% of MAS, may be the effective way when compared with continuous training method. PMID- 24149462 TI - Intramuscular temperature differences between the mid-point and peripheral effective radiating area with ultrasound. AB - The purpose of the study was to determine whether uniform intramuscular heating is achieved throughout a treatment area 2 times the transducer head at both 1 and 3 MHz. Seven male and three female subjects (Age: 23.6 +/- 1.0 yrs, Weight: 83.8 +/- 23.2 kg, Site Skinfold: 13.9 +/- 7.3 mm) underwent two ultrasound treatments (1 and 3 MHz) in the triceps surae muscle group. Thermocouples were inserted at the midpoint and periphery of the treatment area. Ten minute baseline temperatures were recorded followed by a ten minute ultrasound treatment. Two (site) X 10 (time) repeated measures ANOVAs were separately used to determine significance for 1 and 3 MHz treatments. Post-hoc testing was performed using the Bonferroni adjustment. A significant site-by-time interaction was observed for both the 1 and 3 MHz treatments. From baseline to the end of the treatment, temperature increased approximately 2.62 degrees C and 1.58 degrees C for the midpoint and periphery of the 1 MHz treatment and 5.88 degrees C and 3.64 degrees C for the 3 MHz treatment. The differences in temperature suggest that uniform heating does not occur throughout the treatment area. Key points3 MHz is more effective in raising intramuscular temperature within ERA.Stroke count/rate of transducer may play a factor in heating tissue.Treatment size may alter uniform heating. PMID- 24149463 TI - Soccer related sudden deaths in Turkey. AB - Regular physical exercise is recommended by the medical community, because it offers the potential to reduce the incidence of coronary events. On the other hand, vigorous exertion may act as a trigger of acute myocardial infarction and sudden cardiac death in susceptible individuals. Death during sports activities differs among sports disciplines and countries. In Turkey, soccer attracts more spectators than any other sports activity and the attention of the press and media, and is preferred over other sports by many young and middle-aged individuals. As autopsy-based studies are infrequent in literature and there is a lack of data detailing sudden death during physical activity in Turkey, we present a Turkish series of sudden deaths that occurred during soccer games based on data provided by the Morgue Specialization Department of the Council of Forensic Medicine. We identified 15 male cases of soccer-related sudden death aged from 10 to 48 years. Coronary artery disease was identified as the cause of sudden death in 11 cases. Key pointsThis study is one of the largest series of soccer related SD with reported 15 cases.In our series, CAD is the most common cause of SCD also in very young athletes in contrast with international literature.In autopsy, detailed cardio-vascular system evaluation and toxicological analysis including doping agents are essential to determine precise cause of exercise induced SD.Medical screening is important for all people interested in sport, not only for athletes, as a powerful means of prevention. PMID- 24149464 TI - Force-velocity, impulse-momentum relationships: implications for efficacy of purposefully slow resistance training. AB - The purpose of this brief review is to explain the mechanical relationship between impulse and momentum when resistance exercise is performed in a purposefully slow manner (PS). PS is recognized by ~10s concentric and ~4-10s eccentric actions. While several papers have reviewed the effects of PS, none has yet explained such resistance training in the context of the impulse-momentum relationship. A case study of normal versus PS back squats was also performed. An 85kg man performed both normal speed (3 sec eccentric action and maximal acceleration concentric action) and PS back squats over a several loads. Normal speed back squats produced both greater peak and mean propulsive forces than PS action when measured across all loads. However, TUT was greatly increased in the PS condition, with values fourfold greater than maximal acceleration repetitions. The data and explanation herein point to superior forces produced by the neuromuscular system via traditional speed training indicating a superior modality for inducing neuromuscular adaptation. Key pointsAs velocity approaches zero, propulsive force approaches zero, therefore slow moving objects only require force approximately equal to the weight of the resistance.As mass is constant during resistance training, a greater impulse will result in a greater velocity.The inferior propulsive forces accompanying purposefully slow training suggest other methods of resistance training have a greater potential for adaptation. PMID- 24149466 TI - Glucosamine and caveat emptor. PMID- 24149465 TI - Development of a peptide-based vaccine targeting TMPRSS2:ERG fusion-positive prostate cancer. AB - Identification of novel vaccine targets is critical for the design and advancement of prostate cancer (PCa) immunotherapy. Ideal targets are proteins that are abundant in prostate tumors while absent in extra-prostatic tissues. The fusion of the androgen-regulated TMPRSS2 gene with the ETS transcription factor ERG occurs in approximately 50 % of prostate cancer cases and results in aberrant ERG expression. Because expression of ERG is very low in peripheral tissue, we evaluated the suitability of this protein as an antigen target in PCa vaccines. ERG-derived HLA-A*0201-restricted immunogenic epitopes were identified through a 3-step strategy that included in silico, in vitro, and in vivo validation. Algorithms were used to predict potential HLA-A*0201-binding epitopes. High scoring epitopes were tested for binding to HLA-A*0201 using the T2-based stabilization assay in vitro. Five peptides were found to bind HLA-A*0201 and were subsequently tested for immunogenicity in humanized, HLA-A*0201 transgenic mice. The in vivo screening identified three immunogenic peptides. One of these peptides, ERG295, overcame peripheral tolerance in HLA-A*0201 mice that expressed prostate-restricted ERG. Also, this peptide induced an antigen-specific response against ERG-expressing human prostate tumor cells. Finally, tetramer assay showed detectable and responsive ERG295-specific cytotoxic lymphocytes in peripheral blood of HLA-A*0201(+) prostate cancer patients. Detection of ERG-specific CTLs in both mice and the blood of prostate cancer patients indicates that ERG specific tolerance can be overcome. Additionally, these data suggest that ERG is a suitable target antigen for PCa immunotherapy. PMID- 24149467 TI - Water transport mechanism through open capillaries analyzed by direct surface modifications on biological surfaces. AB - Some small animals only use water transport mechanisms passively driven by surface energies. However, little is known about passive water transport mechanisms because it is difficult to measure the wettability of microstructures in small areas and determine the chemistry of biological surfaces. Herein, we developed to directly analyse the structural effects of wettability of chemically modified biological surfaces by using a nanoliter volume water droplet and a hi speed video system. The wharf roach Ligia exotica transports water only by using open capillaries in its legs containing hair- and paddle-like microstructures. The structural effects of legs chemically modified with a self-assembled monolayer were analysed, so that the wharf roach has a smart water transport system passively driven by differences of wettability between the microstructures. We anticipate that this passive water transport mechanism may inspire novel biomimetic fluid manipulations with or without a gravitational field. PMID- 24149468 TI - Pre-pubertal children and exercise in hot and humid environments: a brief review. AB - The ability of pre-pubertal children to regulate their body temperature under thermoneutral environments is similar to that of an adult albeit via differing routes. However, this ability is challenged when exposed to extreme environments. Thermoregulatory responses of pre-pubertal children differ from adults via adaptations that occur during growth and maturation and disadvantage children when exercising in hot and humid environments. When ambient temperatures exceed that of the skin, an influx of thermal energy from the environment increases thermal stress. When coupled with exercise, the increased thermal stress results in reduced physical performance and an increased risk of developing heat-related illness. Evidence suggesting the severity of heat-related illness is greater in pre-pubertal children than adults is inconclusive because age-related differences in thermoregulatory responses are attributed to either morphologic or functional changes. Additionally, the majority of research on pre-pubertal children exercising in the heat has been maturational or comparative studies with adults conducted in the near absence of convective cooling, complicating extrapolation to field-based environments. However, current consensus is that pre-pubertal children are disadvantaged when exercising in extreme temperatures and that care should be taken in preparing for and conducting sporting activities in hot and humid environments for pre-pubertal children. Key pointsPre-pubertal children's ability to thermoregulate when exposed to hot and humid environments is deficient compared to adults.Research into the severity of heat-related illness in pre pubertal children is inconclusive.Discretion should be used in applying findings from indoor studies to outdoor activities due to the influence of the velocity of circulating air on thermoregulation. PMID- 24149469 TI - The social support experiences of major junior ice hockey players in a physically removed region of Canada. AB - The present report from a larger project overviews the sources and types of social support resourced by 10 major junior athletes while they performed out of one physically removed Canadian region. Retrospective interviews and content analysis were conducted during three stages (3, 3, and 4 respondents). The data were segmented into meaning units, coded into a hierarchy of themes, and verified by each respondent and an expert panel (former athlete, coach, parent of former athlete). The respondents sought out three types of social support from four different sources (providers) that were adapted to their remote location, including teachers and general community support. Implications are considered in terms of applied research and practice with aspiring adolescent athletes located in removed locations. Key pointsThe study extends knowledge about the sources and types of social support resourced by elite major junior ice hockey players located in one physically removed Canadian region.From the respondents' views, three types of social support were sought from four different sources.Implications are considered in terms of sport psychology research and applied practice. PMID- 24149470 TI - Running 338 Kilometres within Five Days has no Effect on Body Mass and Body Fat But Reduces Skeletal Muscle Mass - the Isarrun 2006. AB - We investigated the change of body composition in ultra- endurance runners during a multi-stage ultra-endurance run, the Isarrun 2006 in Bavaria, Germany, where athletes had to run 338 km within 5 days. Body mass, skin fold thicknesses and circumferences of extremities were measured in 21 well-experienced extreme endurance male runners (mean +/- SD, 41.5 +/- 6.9 years, 72.6 +/- 6.4 kg, 178 +/- 5 cm, BMI 23.0 +/- 2.0 kg.m(-2)), who finished mainly within the first half of the ranking, in order to calculate skeletal muscle mass and body fat mass to prove changes after the race. Body mass and calculated fat mass did not change significantly (p>0.05), but, calculated skeletal muscle mass decreased significantly (p<0.05) by 0.63 +/- 0.79 kg by the end of the race. The most apparent decline (p<0.01) of the calculated skeletal muscle mass was during the first stage, and no changes were observed during the last 4 stages. We conclude, that a multi- stage ultra-endurance run over 338 km within 5 days leads to no changes of body mass or body fat mass, but a statistically significant decrease of skeletal muscle mass of 0.63 +/- 0.79 kg by the end of the race in well trained and well-experienced ultra-endurance runners. The change of skeletal muscle mass has to be evaluated in further studies at ultra-endurance races with suitable methods to detect changes in hydration status and water metabolism. Key pointsUltra-runners at the Isarrun 2006 suffered no loss of body mass.Skeletal muscle mass decreased highly significantly during the first stage but no significant changes of skeletal muscle mass were observed during the following 4 stages of the Isarrun 2006.Body fat mass remained stable during the Isarrun 2006. PMID- 24149471 TI - The Time-Course of Voluntary and Electrically Evoked Muscle Performance During and After Stretch-Shortening Exercise is Different. AB - The aim of the study was to establish the dynamics of maximal voluntary contraction force (MVCF), height of drop jump (DJ) and electrically evoked quadriceps muscle force at different stimulation frequencies during and after 100 DJs (stretch-shortening exercise, SSE). Healthy untrained men (n = 11; age = 21.8 +/- 1.7 years) participated in the study. DJs were performed with 30 s intervals between jumps from the height of 0.5 m with counter-movement to 90 degrees angle in the knee and immediate maximal rebound. The force of the quadriceps muscle, evoked by electrical stimulation at 1 Hz (Pt), 20 Hz (P20) and 100 Hz (P100) frequencies (electrically evoked performance, EEP), MVCF and height of DJ (voluntary evoked performance, VEP) were established during SSE (after 10, 50, 100 DJ) as well as at 1, 4, 8, 24, 48 and 72 h after SSE. Time-course of P20 and P100 during and after SSE was time (ANOVA: p < 0.001) and frequency dependent (ANOVA: p < 0.001) The Pt, P20 and P100 decreased significantly (p < 0.01) more than MVCF and H of DJ during SSE. At the beginning of SSE (during 1-10 DJs) P20 and P100 decreased significantly (p < 0.001) more than during 11-50 and 51-100 DJs. There was a significant (p < 0.05) increase in Pt, P20 and P100 from 8 h to 48 h, whereas height of DJ and MVCF significantly decreased at that time. In conclusion, the differences in time course of VEP and EEP are most evident at beginning of SSE, where VEP does not change as EEP decreases, and within 8-48 hours after SSE, where VEP decreases as EEP increases. Key pointsThere was no change in voluntary muscle performance while electrically evoked performance decreased significantly during first 10 drop jumps.There was a significant increase in electrically evoked muscle performance from 8 h to 48 h after 100 drop jumps, whereas voluntary contraction force, decreased significantly.The secondary decrease in the height of drop jump as well as in maximal voluntary contraction force correlated significantly with muscle soreness within 24-48 h after exercise. PMID- 24149472 TI - Effects of different resistance exercise protocols on nitric oxide, lipid peroxidation and creatine kinase activity in sedentary males. AB - The purpose of this study was to determine the changes of oxidative response and exercise-induced muscle damage after two different resistance exercise protocols. Whether training with low or high intensity resistance programs cause alterations in the activities of lipid peroxidation, nitric oxide (NOx), and creatine kinase (CK) activity in human plasma was investigated. Twenty untrained males participated into this study. Ten of the subjects performed high intensity resistance (HR) exercise circuit and the rest of them performed low intensity resistance (LR) exercise circuit of 4 different exercises as a single bout. Venous blood samples were drawn pre-exercise, immediately after the exercise, and at the 6(th), 24(th), 48(th) and the72(nd) hours of post-exercise. Samples were analyzed for markers of muscle damage (CK), lipid peroxidation (MDA) and NOx. NOx production increased in HR group (p < 0.05). The MDA response to the two different resistance exercise protocol in this study caused a significant increase between pre and post-exercise values in both groups (p < 0.05). Also, there was a significant difference in the MDA level between the two groups in post-exercise values (p < 0.05) and higher values were observed in HR group. CK activities showed a significant increase in all post exercise values (p < 0.05) of both groups but there were no difference between HR and LR groups. These findings support that high intensity resistance exercise induces free radical production more than low intensity resistance exercise program. Key pointsHigh intensity resistance exercise caused increases in NOx, MDA and CK levels.Light intensity resistance exercises increased MDA and CK levels but did not affect NOx levels.Damage arose during resistance exercises may be related to the level of resistance applied. PMID- 24149473 TI - Exercise performance and muscle contractile properties after creatine monohydrate supplementation in aerobic-anaerobic training rats. AB - The purpose of this study was to investigate the effects of creatine monohydrate supplementation on exercise performance and contractile variables in aerobic anaerobic training rats. Twenty 90-day-old male Sprague Dawley rats were divided into two groups - creatine (Cr) and controls (K). The creatine group received creatine monohydrate as a nutritional supplement, whereas the control group was given placebo. Both groups were trained 5 days a week on a treadmill for 20 days in a mixed (aerobic-anaerobic) metabolic working regimen (27 m.min(-1), 15% elevation for 40 min). The exercise performance (sprint-test), contractile properties (m. tibialis anterior), oxidative enzyme activity (SDH, LDH, NADH2) in m. soleus and blood hematological and chemical variables were assessed in the groups at the end of the experiment. It was found out that creatine supplementation improved the exercise performance after 20 days of administration in a dose of 60 mg per day on the background of a mixed (aerobic-anaerobic) exercise training. At the end of the trial the Cr-group demonstrated better values for the variables which characterize the contractile properties of m. tibialis anterior containing predominantly types IIA and IIB muscle fibers. On the other hand, a higher oxidative capacity was found out in m. soleus (type I muscle fibers) as a result of 20-day creatine supplementation. No side effects of creatine monohydrate supplementation were assessed by the hematological and blood biochemical indices measured in this study. Key pointsThe creatine monohydrate supplementation of the rats diet improves their exercise performance after 20 days administration in a dose of 60 mg per day on the background of a mixed (aerobic-anaerobic) exercise training.The creatine supplemented rats demonstrate better contractile properties of m. tibialis anterior which muscle contains predominantly types IIA and IIB muscle fibers.The soleus muscle (type I muscle fibers) demonstrates a higher oxidative capacity as a result of 20-days creatine supplementation. PMID- 24149474 TI - Daily running promotes spatial learning and memory in rats. AB - Previous studies have shown that physical activity improves learning and memory. Present study was performed to determine the effects of acute, chronic and continuous exercise with different periods on spatial learning and memory recorded as the latency and length of swim path in the Morris water maze testing in subsequent 8 days. Four rat groups were included as follows: 1- Group C (controls which did not exercise). 2- Group A (30 days treadmill running before and 8 days during the Morris water maze testing period). 3- Group B (30 days exercise before the Morris water maze testing period only) and 4- Group D (8 days exercise only during the Morris water maze testing period). The results showed that chronic (30 days) and continuous (during 8 days of Morris water maze testing days) treadmill training produced a significant enhancement in spatial learning and memory which was indicated by decreases in path length and latency to reach the platform in the Morris water maze test (p < 0.05). The benefits in these tests were lost in three days, if the daily running session was abandoned. In group D with acute treadmill running (8 days exercise only) the difference between the Group A disappeared in one week and benefit seemed to be obtained in comparison with the controls without running program. In conclusion the chronic and daily running exercises promoted learning and memory in Morris water maze, but the benefits were lost in few days without daily running sessions in adult rats. Key pointsDaily running influence on spatial memory.The velocity of learning can be influenced by running activity.Path length is important parameter for measuring the speed of learning. PMID- 24149475 TI - IGF-1 Gene Expression in Rat Colonic Mucosa After Different Exercise Volumes. AB - The evidence is increasing for a close link between the insulin/insulin-like growth factor (IGF) system and colon cancer prevention by physical exercise. To reveal exercise-induced alterations in colon mucosa, gene expression of IGF-1 and related genes and serum IGF-1 were investigated. Twenty male Wistar rats performed a 12 week voluntary exercise program. Nine rats served as the control group. Gene expression of IGF-1, IGF-1 receptor (IGF-1R) and IGF-binding protein 3 (IGF-BP3) were quantified by real-time RT-PCR. Circulating IGF-1 was analyzed exercise volume-dependent. Based on 3 distinguished groups with low (L-EX, <2629 m.night(-1)), medium (M-EX, 3003-7458 m.night(-1)) and high exercise volume (H EX, >8314 m.night(-1)), we observed lower serum IGF-1 levels (P < 0.05) in all exercise groups as compared to the control group and IGF-1 levels declined proportional to the increase in exercise volume. A significant (p < 0.05) positive correlation was found between IGF-1 concentration and body mass (r = 0.50) and a significant negative correlation exists between body mass and exercise volume (r = -0.50). Significant differences in colonic mRNA levels of IGF-1, IGF-1R and IGF-BP3 could not be observed. Based on our data we propose that the exercise as well as the body mass reduction leads to a decrease in circulating IGF-1 and this might represent a prime link to colon cancer prevention. Key pointsThere were significantly lower serum IGF-1 levels in all exercise groups as compared to the control group.GF-1 levels declined proportional to the increase in exercise volume.A significant positive correlation was found between IGF-1 concentration and body mass and a significant negative correlation was found between body mass and exercise volume.Significant differences in colonic mRNA levels of IGF-1, IGF-1R and IGF-BP3 could not be observed. PMID- 24149476 TI - Effects of gender on stroke rates, critical speed and velocity of a 30-min swim in young swimmers. AB - Our objective was to analyze the effect of gender on the relationship between stroke rates corresponding to critical speed (SRCS) and maximal speed of 30 min (SRS30) in young swimmers. Twenty two males (GM1) (Age = 15.4 +/- 2.1 yr., Body mass = 63.7 +/- 12.9 kg, Stature = 1.73 +/- 0.09 m) and fourteen female (GF) swimmers (Age = 15.1 +/- 1.6 yr., Body mass = 58.3 +/- 8.8 kg, Stature = 1.65 +/- 0.06 m) were studied. A subset of males (GM2) was matched to the GF by their velocity for a 30 min swim (S30). The critical speed (CS) was determined through the slope of the linear regression line between the distances (200 and 400 m) and participant's respective times. CS was significantly higher than S30 in males (GM1 - 1.25 and 1.16 and GM2 - 1.21 and 1.12 m.s(-1)) and females (GF - 1.15 and 1.11 m.s(-1)). There was no significant difference between SRCS and SRS30 in males (GM1 - 34.16 and 32.32 and GM2 - 34.67 and 32.46 cycle.s(-1), respectively) and females (GF - 34.18 and 33.67 cycle.s(-1), respectively). There was a significant correlation between CS and S30 (GM1 - r = 0.89, GF - r = 0.94 and GM2 - r = 0.90) and between SRCS and SRS30 (GM1 - r = 0.89, GF - r = 0.80 and GM2 - r = 0.88). Thus, the relationship between SRCS and SRS30 is not influenced by gender, in swimmers with similar and different aerobic capacity levels. Key pointsThe main finding of this study was that the relationship between SRCS and SRS30, which is not dependent on gender, in swimmers with similar and different aerobic capacity levels.In swimmers who had different S30 values, CS was higher than S30 in boys and girls, and CS and S30 were higher in boys than girls, but SRCS and SRS30 were similar between genders.In swimmers who had similar S30 values, CS was higher than S30 in boys and girls. However, boys still presented higher values of CS than girls. SRCS was higher than SRS30 in boys, but these variables were similar in girls. SRCS and SRS30 were similar between genders.Girls presented lower submaximal blood lactate levels than boys. PMID- 24149477 TI - Evaluating the effects of a low volume stairclimbing programme on measures of health-related fitness in sedentary office workers. AB - Despite its obvious advantages, few studies have examined health outcomes of regular stariclimbing. In this study, we investigated the training effects of eight weeks of stairclimbing on recognised measures of health-related fitness in an occupational setting. Forty-five public sector employees (22 male, 23 female) aged 42.3 +/- 9.0 years were randomly assigned to control (n = 16) or stairclimbing (n = 29) groups. Stairclimbing training began with 1 bout 5d.wk(-1) in week 1, increasing by one climb per day every two weeks until week 5, where a maintenance level of 3 climbs per day was reached. Participants climbed on staircases located within an 8 storey office block, consisting of 145 steps. The prescribed exercise intensity involved climbing the 8 flights of stairs at a rate of 75 steps.min(-1). All participants agreed not to change their diet or lifestyle over the experimental period. Relative to controls, the stairclimbing group showed a significant increase of 9.4% in predicted VO2max (p < 0. 05). No significant changes in blood pressure, blood lipid concentrations or body composition were noted. These findings provide evidence that stairclimbing can enhance an important component of health-related fitness, namely cardiovascular fitness. Given that such improvement resulted from less than 30 minutes per week of moderate exercise, stairclimbing in the workplace should be promoted as a health-enhancing physical activity. Key pointsLow volumes of stairclimbing significantly increased a key component of cardiorespiratory fitness, namely VO2max.Stairclimbing can therefore be promoted within the typical urban workplace as a health enhancing activity.Indices of morphological or metabolic fitness may require larger volumes of stairclimbing than as prescribed in the current study. PMID- 24149478 TI - The effect of high resistance weight training on reported pain in older adults. AB - The present study examined the effect of a progressive, whole- body, high resistance training program on reported pain in older adults. Ninety-eight participants (60 - 83 years) completed the McGill Pain Questionnaire prior to and after an eight week training period. Seventy-nine of the participants completed a progressive, high resistance training program of 11 different exercises on three days a week. At the end of eight weeks, the training group achieved significant strength gains ranging from 62% -119% (p <= 0.005). Pain measures for the training and control groups were compared using an analysis of covariance on post test pain measures after an adjustment by pre-test scores. (p <= 0.05). The training group reported less perceived pain than the control group in four pain measures (overall pain intensity, sensory dimension, miscellaneous pain measures, number of pain descriptors selected). There were no differences reported for the affective or evaluative dimensions of perceived pain, the number of painful areas, or the present pain. Results suggest that eight weeks of progressive, whole-body weight training has a positive impact on perception of pain in older adults. Key pointsImproved strength in older adults had a positive effect on the perception of pain.The number of painful areas identified and self-reported pain qualities were diminished following high resistance weight training.The McGill Pain Questionnaire was an effective tool for measuring changes in pain perception as a result of training. PMID- 24149479 TI - Electromyographic activity of the biceps brachii after exercise-induced muscle damage. AB - It is well known that strenuous eccentric exercise may result in muscle damage. We proposed that vigorous eccentric exercise (EE) would impair myoelectric activity of the biceps brachii. This study utilised a 7-day prospective time series design. Ten healthy males performed a session of 70 maximal EE elbow flexion contractions. Analysis of surface electromyography activity (sEMG) was performed on the signals recorded during isometric contractions at 50% (IC50) and 80% (IC80) of maximum voluntary isometric torque (MVT), deriving RMS and MDF as sEMG parameters. Linear regression of the RMS and MDF time-series (20-s sustained IC50 and IC80) was used to extract intercepts and slopes of these signals on each day. Plasma creatine kinase activity (CK), MVT, arm circumference, subjective perception of soreness and elbow joint range of motion were also measured to assess effectiveness of EE to evoke muscle damage. CK increased over resting values until day 5 after EE, and remained significantly (p < 0.05) elevated even on day 7. MVT had decreased to 45% of its initial value by day 2 after EE, and remained significantly depressed for the following 6 days. In addition, muscle soreness and arm circumference increased, and range of motion decreased after EE. A significant shift of MDF intercept towards lower frequencies at both IC50 and IC80 was observed after EE in the exercised arm, and these values gradually recovered within the next 3 days during IC50. Although there were some changes in RMS values, these alterations were persistent in both control and exercised arms, and did not follow a consistent pattern. In conclusion, a prolonged reduction in MDF intercept was observed after EE, but this was not closely time-associated with the biochemical, anthropometric or functional markers of muscle damage. Compared to RMS, MDF was a more consistent measure to reflect changes in sEMG. Key pointsEMG can be a useful tool to detect exercise-induced muscle damage,MDF decreased after eccentric exercise,This decrease could be related to a reduction in the recruitment of fast twitch fibres, andCompared to RMS, MDF was a more consistent parameter to reflect the changes in EMG after eccentric exercise. PMID- 24149480 TI - The impact of short term supervised and home-based walking programmes on heart rate variability in patients with peripheral arterial disease. AB - The aims of the study were to determine whether heart rate variability (HRV) measured at rest and during exercise could be altered by an exercise training programme designed to increase walking performance in patients with peripheral arterial disease. Forty-four volunteers were randomised into 12 weeks of either: supervised walking training twice weekly for 30 min at 75% VO2peak (SU), home based walking training sessions: twice weekly, 30 min per week (HB) or no exercise (CT). HRV measures were calculated from a 5-min resting ECG. Each patient then underwent maximal, graded exercise treadmill testing. All measures were repeated after 12 weeks. The SU group showed significantly (p < 0.001) increased maximal walking time (MWT) but no change in VO2peak. There were no statistically significant changes in any of the measures of HRV in any group. Effect sizes for change in HRV measures were all very small and in some cases negative. Improved walking performance was not accompanied by central cardiorespiratory or neuroregulatory adaptations in the present study. The lack of any change in HRV was possibly due to either the low intensity or discontinuous nature of exercise undertaken. Key pointsIt is known that exercise can positively influence heart rate variability in some cardiac patients.It is known that exercise can increase walking performance in peripheral vascular disease patients.Exercise training improved walking performance in peripheral vascular disease patients but HRV was unaltered.This may be due to low overall physiological demands on the cardiovascular system or the intermittent nature of the exercise. PMID- 24149481 TI - Age-Associated Changes In VO2 and Power Output - A Cross-Sectional Study of Endurance Trained New Zealand Cyclists. AB - Age-associated changes in power and maximal oxygen consumption (VO2max) were studied in a cross section of endurance trained cyclists. Subjects (n = 56) performed incremental cycling exercise, during which capillary blood lactate [La( )] was measured. Power output increased by 30 Watts during each 5 minutes stage, with initial power output based on individual ability. When [La(-)] was >4.5 mmol.L(-1), subjects were given a 10 min recovery at a power output approximately 50% below estimated power at [La(-)]4mmol. Subjects then performed an incremental test (1 minute stages) to VO2max. Decline in VO2max was 0.65 ml.kg(-1).min( 1).year(-1) (r = -0.72, p < 0.01) for males, and 0.39 ml.kg(-1).min(-1).year(-1) (r = -0.54, p < 0.05) for females. Power at VO2max decreased by 0.048 W kg( 1).year(-1) (r = -0.72, p < 0.01) in males. Power at [La(-)]4mmol decreased by 0.044 W kg(-1).year(-1) (r = -0.76, p < 0.01) in males, and by 0.019 W kg( 1).year(-1) (r = -0.53, p < 0.05) in females. Heart rate at VO2max (HRmax) showed a weaker correlation with age in males (r = -0.36, p < 0.05). The age-associated changes in maximum aerobic power and sub-maximal power were gender- specific, thus suggesting different age-related effects on the systems which support exercise in males and females. Key pointsVO2max decreased with age by 0.65 ml.kg( 1).min(-1).year(-1) in male, and by 0.39 ml.kg(-1).min(-1).year(-1) in female endurance trained cyclists.Power at VO2max decreased with age by 0.048 Watts.kg( 1).year(-1) in male endurance trained cyclists.Sub-maximal power at a blood lactate concentration of 4mmol.L(-1) decreased by 0.044 Watts.kg(-1).year(-1) in male, and by 0.019 Watts.kg(-1).year(-1) in female endurance trained cyclists. PMID- 24149482 TI - A comparison of golf shoe designs highlights greater ground reaction forces with shorter irons. AB - In an effort to reduce golf turf damage the traditional metal spike golf shoe has been redesigned, but shoe-ground biomechanical evaluations have utilised artificial grass surfaces. Twenty-four golfers wore three different golf shoe traction designs (traditional metal spikes, alternative spikes, and a flat-soled shoe with no additional traction) when performing shots with a driver, 3 iron and 7 iron. Ground action forces were measured beneath the feet by two natural grass covered force platforms. The maximum vertical force recorded at the back foot with the 3 iron and 7 iron was 0.82 BW (body weight) and at the front foot 1.1 BW approximately in both the metal spike and alternative spike golf shoe designs. When using the driver these maximal vertical values were 0.49 BW at the back foot and 0.84 BW at the front foot. Furthermore, as performance of the backswing and then downswing necessitates a change in movement direction the range of force generated during the complete swing was calculated. In the metal spike shoe the vertical force generated at the back foot with both irons was 0.67 BW and at the front foot 0.96 BW with the 3 iron and 0.92 BW with the 7 iron. The back foot vertical force generated with the driver was 0.33 BW and at the front foot 0.83 BW wearing the metal spike shoe. Results indicated the greater force generation with the irons. When using the driver the more horizontal swing plane associated with the longer club reduced vertical forces at the back and front foot. However, the mediolateral force generated across each foot in the metal and alternative spike shoes when using the driver was greater than when the irons were used. The coefficient of friction was 0. 62 at the back and front foot whichever shoe was worn or club used. Key pointsDuring the golf swing ground reaction forces at the golf shoe to natural grass turf interface were greater with irons than with the longer driver.In the golf swing maximal vertical forces were greater at the front (left) foot in the than at the back foot for a right handed golfer.Similar maximum vertical ground reaction forces were recorded with each club when a 8 mm metal spike golf shoe or an alternative spike golf shoe were worn.Force generation and coefficients of friction were similar for the alternative spike design and traditional metal seven spike golf shoe on natural grass turf.Data collection possible due to application of technical developments to golf from work on other natural turf based sports. PMID- 24149483 TI - Influence of Ramadan Fasting on Anaerobic Performance and Recovery Following Short time High Intensity Exercise. AB - The aim of this study was to investigate the effects of Ramadan fasting on anaerobic power and capacity and the removal rate of lactate after short time high intensity exercise in power athletes. Ten male elite power athletes (2 wrestlers, 7 sprinters and 1 thrower, aged 20-24 yr, mean age 22.30 +/- 1.25 yr) participated in this study. The subjects were tested three times [3 days before the beginning of Ramadan (Pre-RF), the last 3 days of Ramadan (End-RF) and the last 3 days of the 4(th) week after the end of Ramadan (After-RF)]. Anaerobic power and capacity were measured by using the Wingate Anaerobic Test (WAnT) at Pre-RF, End-RF and After- RF. Capillary blood samples for lactate analyses and heart rate recordings were taken at rest, immediately after WAnT and throughout the recovery period. Repeated measures of ANOVA indicated that there were no significant changes in body weight, body mass index, fat free mass, percentage of body fat, daily sleeping time and daily caloric intake associated with Ramadan fasting. No significant changes were found in total body water either, but urinary density measured at End-RF was significantly higher than After-RF. Similarity among peak HR and peak LA values at Pre-RF, End- RF and After-RF demonstrated that cardiovascular and metabolic stress caused by WAnT was not affected by Ramadan fasting. In addition, no influence of Ramadan fasting on anaerobic power and capacity and removal rate of LA from blood following high intensity exercise was observed. The results of this study revealed that if strength-power training is performed regularly and daily food intake, body fluid balance and daily sleeping time are maintained as before Ramadan, Ramadan fasting will not have adverse effects on body composition, anaerobic power and capacity, and LA metabolism during and after high intensity exercise in power athletes. Key pointsNo significant changes were assessed on body composition, daily sleeping time and caloric intake, and body fluid balance in regularly trained power athletes during Ramadan fasting.Ramadan fasting has no adverse effect on power outputs of short time high intensity exercise.No influence of Ramadan fasting on LA metabolism during high intensity exercise and passive recovery in regularly trained power athletes. PMID- 24149484 TI - Acute effects of two massage techniques on ankle joint flexibility and power of the plantar flexors. AB - The purpose of this study was to determine if three minutes of petrissage and tapotement forms of massage would influence plantar flexors' flexibility, and muscle power. Nineteen participants were randomly subjected to three conditions (control and two massages) before performing two power tests. Prior to the intervention, subjects completed ankle joint flexibility assessments. The conditions were; (1) control, where subjects lay prone and had a therapist's hands resting, (2) vigorous petrissage, and (3) tapotement applied at a rate of 4Hz; all on the triceps surae. Following completion of the intervention, subjects immediately completed a post- ankle joint flexibility test, followed by a drop jump and concentric calf raise. The power measures were; concentric peak force, rate of force development, and drop-jump height / contact time. The data showed a significant increase (p < 0.05) in ankle joint angle on the right leg and a corresponding tendency on the left. No significant change was seen with the power measures. Results suggest that massage can increase plantar flexors' flexibility without a change in power and thus may be an alternative to static stretching during an athletic warm-up. Key pointsThree minutes of petrissage and tapotement forms of massage increased ankle flexibility.Massage did not adversely affect jump power measures.Massage may be an effective alternative to static stretching as a component of a pre-event warm-up. PMID- 24149485 TI - A physical activity questionnaire: reproducibility and validity. AB - This study evaluates the Quantification de L'Activite Physique en Altitude chez les Enfants (QAPACE) supervised self-administered questionnaire reproducibility and validity on the estimation of the mean daily energy expenditure (DEE) on Bogota's schoolchildren. The comprehension was assessed on 324 students, whereas the reproducibility was studied on a different random sample of 162 who were exposed twice to it. Reproducibility was assessed using both the Bland-Altman plot and the intra-class correlation coefficient (ICC). The validity was studied in a sample of 18 girls and 18 boys randomly selected, which completed the test - re-test study. The DEE derived from the questionnaire was compared with the laboratory measurement results of the peak oxygen uptake (Peak VO2) from ergo spirometry and Leger Test. The reproducibility ICC was 0.96 (95% C.I. 0.95-0.97); by age categories 8-10, 0.94 (0.89-0. 97); 11-13, 0.98 (0.96- 0.99); 14-16, 0.95 (0.91-0.98). The ICC between mean TEE as estimated by the questionnaire and the direct and indirect Peak VO2 was 0.76 (0.66) (p<0.01); by age categories, 8-10, 11-13, and 14-16 were 0.89 (0.87), 0.76 (0.78) and 0.88 (0.80) respectively. The QAPACE questionnaire is reproducible and valid for estimating PA and showed a high correlation with the Peak VO2 uptake. Key pointsThe presence of a supervisor, the limited size of the group with the possibility of answering to their questions could explain the high reproducibility for this questionnaire.No study in the literature had directly addressed the issue of estimating a yearly average PA including school and vacation period.A two step procedure, in the population of schoolchildren of Bogota, gives confidence in the use of the QAPACE questionnaire in a large epidemiological survey in related populations. PMID- 24149486 TI - Effects of a short-term plyometric and resistance training program on fitness performance in boys age 12 to 15 years. AB - The purpose of this study was to compare the effects of a six week training period of combined plyometric and resistance training (PRT, n = 13) or resistance training alone (RT, n = 14) on fitness performance in boys (12-15 yr). The RT group performed static stretching exercises followed by resistance training whereas the PRT group performed plyometric exercises followed by the same resistance training program. The training duration per session for both groups was 90 min. At baseline and after training all participants were tested on the vertical jump, long jump, medicine ball toss, 9.1 m sprint, pro agility shuttle run and flexibility. The PRT group made significantly (p < 0.05) greater improvements than RT in long jump (10.8 cm vs. 2.2 cm), medicine ball toss (39.1 cm vs. 17.7 cm) and pro agility shuttle run time (-0.23 sec vs. -0.02 sec) following training. These findings suggest that the addition of plyometric training to a resistance training program may be more beneficial than resistance training and static stretching for enhancing selected measures of upper and lower body power in boys. Key pointsYouth conditioning programs which include different types of training and different loading schemes (e.g., high velocity plyometrics and resistance training) may be most effective for enhancing power performance.The effects of resistance training and plyometric training may be synergistic in children, with their combined effects being greater that each program performed alone. PMID- 24149487 TI - No influence of hypoxia on coordination between respiratory and locomotor rhythms during rowing at moderate intensity. AB - Besides neuro-mechanical constraints, chemical or metabolic stimuli have also been proposed to interfere with the coordination between respiratory and locomotor rhythms. In the light of the conflicting data observed in the literature, this study aimed to assess whether acute hypoxia modifies the degree of coordination between respiratory and locomotor rhythms during rowing exercises in order to investigate competitive interactions between neuro-mechanical (movement) and chemical (hypoxia) respiratory drives. Nine male healthy subjects performed one submaximal 6-min rowing exercise on a rowing ergometer in both normoxia (altitude: 304 m) and acute hypoxia (altitude: 2877 m). The exercise intensity was about 40 % and 35 % (for normoxia and hypoxia conditions, respectively) of the individual maximal power output measured during an incremental rowing test to volitional exhaustion carried out in normoxia. Metabolic rate and minute ventilation were continuously collected throughout exercise. Locomotor movement and breathing rhythms were continuously recorded and synchronized cycle-by-cycle. The degree of coordination was expressed as a percentage of breaths starting during the same phase of the locomotor cycle. For a same and a constant metabolic rate, acute hypoxia did not influence significantly the degree of coordination (mean +/- SEM, normoxia: 20.0 +/- 6.2 %, hypoxia: 21.3 +/- 11.1 %, p > 0.05) while ventilation and breathing frequency were significantly greater in hypoxia. Our results may suggest that during rowing exercise at a moderate metabolic load, neuro-mechanical locomotion-linked respiratory stimuli appear "stronger "than peripheral chemoreceptors- linked respiratory stimuli induced by hypoxia, in the context of our study. Key pointsChanges in breathing frequency and ventilation induced by altitude have no effect on the degree of coordination between locomotor and breathing rhythms during moderate rowing exercise.During moderate rowing exercise in hypoxia, the neuro-mechanical drives still dominate over chemoreceptive stimuli.These above statements have to be taken carefully because it might be quite different during activities where the coupling between locomotor and breathing rhythms is less constrained (e.g., running, cycling). PMID- 24149488 TI - Sleep deprivation induced anxiety and anaerobic performance. AB - The aim of this study was to investigate the effects of sleep deprivation induced anxiety on anaerobic performance. Thirteen volunteer male physical education students completed the Turkish version of State Anxiety Inventory and performed Wingate anaerobic test for three times: (1) following a full-night of habitual sleep (baseline measurements), (2) following 30 hours of sleep deprivation, and (3) following partial-night sleep deprivation. Baseline measurements were performed the day before total sleep deprivation. Measurements following partial sleep deprivation were made 2 weeks later than total sleep deprivation measurements. State anxiety was measured prior to each Wingate test. The mean state anxiety following total sleep deprivation was higher than the baseline measurement (44.9 +/- 12.9 vs. 27.6 +/- 4.2, respectively, p = 0.02) whereas anaerobic performance parameters remained unchanged. Neither anaerobic parameters nor state anxiety levels were affected by one night partial sleep deprivation. Our results suggest that 30 hours continuous wakefulness may increase anxiety level without impairing anaerobic performance, whereas one night of partial sleep deprivation was ineffective on both state anxiety and anaerobic performance. Key pointsShort time total sleep deprivation (30 hours) increases state anxiety without any competition stress.Anaerobic performance parameters such as peak power, mean power and minimum power may not show a distinctive difference from anaerobic performance in a normal sleep day despite the high anxiety level induced by short time sleep deprivation.Partial sleep deprivation does not affect anxiety level and anaerobic performance of the next day. PMID- 24149489 TI - Nutritional Intake of Young Italian High-Level Soccer Players: Under-Reporting is the Essential Outcome. AB - It is recognized that much of the dietary data on adolescents and athletes is prone to reporting error, mostly through under-reporting. Nevertheless, in the majority of studies assessing the nutritional intake of young soccer players under-reporting has not been taken into consideration. The purpose of this study was to assess the dietary intake of a sample of young male Italian high-level soccer players on two time points to evaluate the degree of under- reporting. Seventy-five male high level soccer players (age range: 15-17 years) completed 4 day food records on two separate occasions (T0; T1, 3 months after T0). Under reporting was assessed by the ratio of reported estimated energy intake (EEI) to estimated energy expenditure (EEE). Forty- three subjects, whose food records were judged accurate enough both at T0 and T1, were included in the data analysis (inclusion rate 57.3%). No significant weight changes were documented between T0 and T1 and in the two weeks preceding both T0 and T1. Reported mean daily energy intake was significantly lower than mean estimated daily energy expenditure both at T0 and T1 (p < 0.001). The average EEI/EEE ratio was 0.75 + 0.2 both at T0 and T1. It was <= 80% in 27 subjects (62.8%) at T0 and in 23 (53.4%) at T1; it reached 50% in 4 subjects both at T0 and T1. The degree of under- reporting of the young soccer players was in line with the available data on this age group. This study emphasizes that under-reporting is a critical issue in the evaluation of young athletes dietary intake, which should be considered in the interpretation of data, particularly when energy inadequacies are reported. Further studies with uniformed methods are needed, in order to reduce the degree of under-reporting, obtain reliable data on the dietary intake of young soccer players and evaluate the efficacy of targeted nutrition education programs. Key pointsUnder-reporting is a critical issue in the evaluation of young athletes' dietary intake, which should be always considered in the interpretation of data.The young athletes' motivation and parents' co-operation are key points that should be enhanced in this kind of studies.The nutritional intakes of young Italian high-level soccer players are likely to be qualitative inadequate, due to excessive cholesterol and very poor fiber intakes. PMID- 24149490 TI - Effects of acute eccentric contractions on rat ankle joint stiffness. AB - The sensation of joint stiffness is frequently observed after eccentric contractions (ECs) in human, but the joint stiffness of animals after ECs has not been examined previously. This study tested whether a bout of ECs affects rat ankle joint stiffness. We also evaluate muscle passive tension in the rat hindlimb to examine the relationships of ankle joint stiffness with muscle passive tension. Anesthetized male Wistar rats (n = 23) were firmly secured on a platform in the prone position. A bout of ECs was performed on the gastrocnemius muscle with a combination of electrically induced tetanic contractions via a skin electrode and simultaneous forced dorsiflexion of the ankle joint (velocity, 15 degrees /s; from 0 degrees to 45 degrees ). Passive resistive torque (PRT) of the ankle joint was measured to evaluate joint stiffness. Passive tension of the exposed gastrocnemius muscle was also measured when the maximum value of joint stiffness was obtained. The PRT on days 2, 3, and 4 was significantly higher than the pre-treatment value (days 2 and 4; p < 0.001, days 3; p < 0.01). The passive tension on day 4 was significantly higher than that of the sham-operated group. The muscle wet mass was identical in both groups, suggesting the absence of edema. We conclude PRT increases after ECs in rat ankle joint. We also show the possibility that it is associated with muscle passive tension, independent of edema formation. Key pointsWe confirmed that ECs raise joint PRT and are associated with reduction of muscle passive tension.The changes in joint stiffness and muscle passive tension after ECs have been examined independently and the direct relationships have not been examined previously.We experimentally showed that ECs increased both joint PRT and muscle passive tension and these two parameters were significantly correlated. PMID- 24149491 TI - Neuromuscular fatigue during a modified biering-sorensen test in subjects with and without low back pain. AB - Studies employing modified Biering-Sorenson tests have reported that low back endurance is related to the potential for developing low back pain. Understanding the manner in which spinal musculature fatigues in people with and without LBP is necessary to gain insight into the sensitivity of the modified Biering-Sorenson test to differentiate back health. Twenty male volunteers were divided into a LBP group of subjects with current subacute or a history of LBP that limited their activity (n = 10) and a control group (n = 10). The median frequency of the fast Fourier transform was calculated from bilateral surface electromyography (EMG) of the upper lumbar erector spinae (ULES), lower lumbar erector spinae (LLES) and biceps femoris while maintaining a prescribed modified Biering-Sorensen test position and exerting isometric forces equivalent to 100, 120, 140 and 160% of the estimated mass of the head-arms-trunk (HAT) segment. Time to failure was also investigated across the percentages of HAT. Fatigue time decreased with increasing load and differences between groups increased as load increased, however these differences were not significant. Significant differences in the EMG median frequency between groups occurred in the right biceps femoris (p <= 0.05) with significant pairwise differences occurring at 140% for the left biceps femoris and at 160% for the right biceps femoris. There were significant pairwise differences at 120% for average EMG of the right biceps femoris and at 140% for the right ULES, and right and left biceps femoris (p <= 0.05). The modified Biering-Sorensen test as usually performed at 100% HAT is not sufficient to demonstrate significant differences between controls and subjects with varying degrees of mild back disability based on the Oswestry classification. Key pointsThe results do not wholly support the modified Biering-Sorensen test utilizing resistance of 100% HAT to discern differences in fatigue in subjects with mild low back pain.A greater activation of the biceps femoris by low back pain individuals probably contributed to the lack of significant differences in back fatigue times.The possibility exists that subjects with more sophisticated strategies could yield higher fatigue times despite inferior neuromuscular fatigue and the existence of low back pain. PMID- 24149492 TI - High-velocity resistance exercise protocols in older women: effects on cardiovascular response. AB - Acute cardiovascular responses to different high-velocity resistance exercise protocols were compared in untrained older women. Twelve apparently healthy volunteers (62.6 +/- 2.9 y) performed three different protocols in the bench press (BP). All protocols involved three sets of 10 repetitions performed with a 10RM load and 2 minutes of rest between sets. The continuous protocol (CP) involved ten repetitions with no pause between repetitions. The discontinuous protocols were performed with a pause of five (DP5) or 15 (DP15) seconds between the fifth and sixth repetitions. Heart rate (HR), systolic blood pressure (SBP), rate pressure product (RPP), Rating of Perceived Exertion (RPE), and blood lactate (BLa) were assessed at baseline and at the end of all exercise sets. Factorial ANOVA was used to compare the cardiovascular response among different protocols. Compared to baseline, HR and RPP were significantly (p < 0.05) higher after the third set in all protocols. HR and RPP were significantly (p < 0.05) lower in DP5 and DP15 compared with CP for the BP exercise. Compared to baseline, RPE increased significantly (p < 0.05) with each subsequent set in all protocols. Blood lactate concentration during DP5 and DP15 was significantly lower than CP. It appears that discontinuous high-velocity resistance exercise has a lower cardiovascular demand than continuous resistance exercise in older women. Key pointsThe assessment of cardiovascular responses to high-velocity resistance exercise in older individuals is very important for exercise prescription and rehabilitation in elderly population.Discontinuous protocol decrease myocardial oxygen consumption (HR x SBP) during the performance of dynamic high-velocity resistance exercise in older women.The decrease in RPP (~ 8.5%) during the discontinuous protocol has clinical implications when developing high-velocity resistance exercise strategies for elderly individuals. PMID- 24149493 TI - Exertional rhabdomyolysis of the bilateral adductor magnus. AB - We present a case study of a person (63 year-old man), who has been using statins for 18 years, with rhabdomyolysis of the bilateral adductor muscles associated with strenuous and prolonged eccentric exercises (hiking) in a hot environment. Clinical examination showed predominantly on the right side muscle swelling and palpational pain of the bilateral adductor muscle groups and bilateral tibial edema. His serum creatine kinase (CK) level was 12218 IU/L. T2-weighted magnetic resonance (MR) images showed a high signal intensity in the bilateral adductor muscles of the hip. The patient did not develop complications and returned to his previous performance level in 30 days following adequate hydration and resting of the affected muscles. Strenuous eccentric exercise should be avoided during the course of statin use and clinicians should be aware of present observations when considering the significance of acute CK elevations in patients on statin treatment. Key pointsStatin use can be one of the causes of the rhabdomyolysis following a strenuous eccentric exercise.Elevated CK levels and MRI imaging are important for the diagnosis.The treatment consists of complete rest and adequate hydration. PMID- 24149494 TI - Sequestration of Martian CO2 by mineral carbonation. AB - Carbonation is the water-mediated replacement of silicate minerals, such as olivine, by carbonate, and is commonplace in the Earth's crust. This reaction can remove significant quantities of CO2 from the atmosphere and store it over geological timescales. Here we present the first direct evidence for CO2 sequestration and storage on Mars by mineral carbonation. Electron beam imaging and analysis show that olivine and a plagioclase feldspar-rich mesostasis in the Lafayette meteorite have been replaced by carbonate. The susceptibility of olivine to replacement was enhanced by the presence of smectite veins along which CO2-rich fluids gained access to grain interiors. Lafayette was partially carbonated during the Amazonian, when liquid water was available intermittently and atmospheric CO2 concentrations were close to their present-day values. Earlier in Mars' history, when the planet had a much thicker atmosphere and an active hydrosphere, carbonation is likely to have been an effective mechanism for sequestration of CO2. PMID- 24149496 TI - Temperature multiscale entropy analysis: a promising marker for early prediction of mortality in septic patients. AB - A few studies estimating temperature complexity have found decreased Shannon entropy, during severe stress. In this study, we measured both Shannon and Tsallis entropy of temperature signals in a cohort of critically ill patients and compared these measures with the sequential organ failure assessment (SOFA) score, in terms of intensive care unit (ICU) mortality. Skin temperature was recorded in 21 mechanically ventilated patients, who developed sepsis and septic shock during the first 24 h of an ICU-acquired infection. Shannon and Tsallis entropies were calculated in wavelet-based decompositions of the temperature signal. Statistically significant differences of entropy features were tested between survivors and non-survivors and classification models were built, for predicting final outcome. Significantly reduced Tsallis and Shannon entropies were found in non-survivors (seven patients, 33%) as compared to survivors. Wavelet measurements of both entropy metrics were found to predict ICU mortality better than SOFA, according to a combination of area under the curve, sensitivity and specificity values. Both entropies exhibited similar prognostic accuracy. Combination of SOFA and entropy presented improved the outcome of univariate models. We suggest that reduced wavelet Shannon and Tsallis entropies of temperature signals may complement SOFA in mortality prediction, during the first 24 h of an ICU-acquired infection. PMID- 24149495 TI - Synthesis and evaluation of 1,4-dihydropyridine derivatives with calcium channel blocking activity. AB - 1,4-Dihydropyridines (DHPs) are an important class of L-type calcium channel blockers that are used to treat conditions such as hypertension and angina. Their primary target in the cardiovascular system is the Cav1.2 L-type calcium channel isoform, however, a number of DHPs also block low-voltage-activated T-type calcium channels. Here, we describe the synthesis of a series of novel DHP derivatives that have a condensed 1,4-DHP ring system (hexahydroquinoline) and report on their abilities to block both L- and T-type calcium channels. Within this series of compounds, modification of a key ester moiety not only regulates the blocking affinity for both L- and T-type channels, but also allows for the development of DHPs with 30-fold selectivity for T-type channels over the L-type. Our data suggest that a condensed dihydropyridine-based scaffold may serve as a pharmacophore for a new class of T-type selective inhibitors. PMID- 24149497 TI - Perioperative cognitive aids in anesthesia: what, who, how, and why bother? PMID- 24149498 TI - Much ado about checklists: who says I need them and who moved my cheese? PMID- 24149499 TI - Closed-loop systems in anesthesia: reality or fantasy? PMID- 24149500 TI - Expired oxygen as the unappreciated issue in preventing airway fires: getting to "never". PMID- 24149501 TI - We're on the road to depo-local anesthetics, but we aren't there yet. PMID- 24149502 TI - History is. PMID- 24149503 TI - Anesthesia, sleep and death: from mythology to the operating room. PMID- 24149504 TI - Oxygen transport rate and erythrocyte deformability. PMID- 24149505 TI - In response. PMID- 24149506 TI - Tapia's syndrome: a rare complication of airway trauma. PMID- 24149507 TI - In response. PMID- 24149508 TI - Heparin resistance and excessive thrombocytosis. PMID- 24149509 TI - Smartphone assisted laryngoscopy: a new technique to overcome light failure in a laryngoscope. PMID- 24149511 TI - Reconstructing geographical movements and host species transitions of foot-and mouth disease virus serotype SAT 2. AB - Of the three foot-and-mouth-disease virus SAT serotypes mainly confined to sub Saharan Africa, SAT 2 is the strain most often recorded in domestic animals and has caused outbreaks in North Africa and the Middle East six times in the last 25 years, with three apparently separate events occurring in 2012. This study updates the picture of SAT 2 phylogenetics by using all available sequences for the VP1 section of the genome available at the time of writing and uses phylogeographic methods to trace the origin of all outbreaks occurring north of the Sahara since 1990 and identify patterns of spread among countries of endemicity. Transitions between different host species are also enumerated. Outbreaks in North Africa appear to have origins in countries immediately south of the Sahara, whereas those in the Middle East are more often from East Africa. The results of the analysis of spread within sub-Saharan Africa are consistent with it being driven by relatively short-distance movements of animals across national borders, and the analysis of host species transitions supports the role of the African buffalo (Syncerus caffer) as an important natural reservoir. IMPORTANCE: Foot-and-mouth disease virus is a livestock pathogen of major economic importance, with seven distinct serotypes occurring globally. The SAT 2 serotype, endemic in sub-Saharan Africa, has caused a number of outbreaks in North Africa and the Middle East during the last decades, including three separate incidents in 2012. A comprehensive analysis of all available RNA sequences for SAT 2 has not been published for some years. In this work, we performed this analysis using all previously published sequences and 49 newly determined examples. We also used phylogenetic methods to infer the source country for all outbreaks occurring outside sub-Saharan Africa since 1990 and to reconstruct the spread of viral lineages between countries where it is endemic and movements between different host species. PMID- 24149512 TI - Small genomes and sparse metabolisms of sediment-associated bacteria from four candidate phyla. AB - Cultivation-independent surveys of microbial diversity have revealed many bacterial phyla that lack cultured representatives. These lineages, referred to as candidate phyla, have been detected across many environments. Here, we deeply sequenced microbial communities from acetate-stimulated aquifer sediment to recover the complete and essentially complete genomes of single representatives of the candidate phyla SR1, WWE3, TM7, and OD1. All four of these genomes are very small, 0.7 to 1.2 Mbp, and have large inventories of novel proteins. Additionally, all lack identifiable biosynthetic pathways for several key metabolites. The SR1 genome uses the UGA codon to encode glycine, and the same codon is very rare in the OD1 genome, suggesting that the OD1 organism could also transition to alternate coding. Interestingly, the relative abundance of the members of SR1 increased with the appearance of sulfide in groundwater, a pattern mirrored by a member of the phylum Tenericutes. All four genomes encode type IV pili, which may be involved in interorganism interaction. On the basis of these results and other recently published research, metabolic dependence on other organisms may be widely distributed across multiple bacterial candidate phyla. IMPORTANCE: Few or no genomic sequences exist for members of the numerous bacterial phyla lacking cultivated representatives, making it difficult to assess their roles in the environment. This paper presents three complete and one essentially complete genomes of members of four candidate phyla, documents consistently small genome size, and predicts metabolic capabilities on the basis of gene content. These metagenomic analyses expand our view of a lifestyle apparently common across these candidate phyla. PMID- 24149515 TI - Prostasomes: extracellular vesicles from the prostate. AB - The term 'prostasomes' is generally used to classify the extracellular vesicles (EVs) released into prostatic fluid by prostate epithelial cells. However, other epithelia within the male reproductive tract also release EVs that mix with 'true' prostasomes during semen emission or ejaculation. Prostasomes have been proposed to regulate the timing of sperm cell capacitation and induction of the acrosome reaction, as well as to stimulate sperm motility where all three are prerequisite processes for spermatozoa to attain fertilising capacity. Other proposed functions of prostasomes include interfering with the destruction of spermatozoa by immune cells within the female reproductive tract. On the other hand, it is unclear whether the distinct presumed functions are performed collectively by a single type of prostasome or by separate distinct sub populations of EVs. Moreover, the exact molecular mechanisms through which prostasomes exert their functions have not been fully resolved. Besides their physiological functions, prostasomes produced by prostate tumour cells have been suggested to support prostate cancer spread development, and prostasomes in peripheral blood plasma may prove to be valuable biomarkers for prostate cancer. PMID- 24149513 TI - Infectious bronchitis virus generates spherules from zippered endoplasmic reticulum membranes. AB - Replication of positive-sense RNA viruses is associated with the rearrangement of cellular membranes. Previous work on the infection of tissue culture cell lines with the betacoronaviruses mouse hepatitis virus and severe acute respiratory syndrome coronavirus (SARS-CoV) showed that they generate double-membrane vesicles (DMVs) and convoluted membranes as part of a reticular membrane network. Here we describe a detailed study of the membrane rearrangements induced by the avian gammacoronavirus infectious bronchitis virus (IBV) in a mammalian cell line but also in primary avian cells and in epithelial cells of ex vivo tracheal organ cultures. In all cell types, structures novel to IBV infection were identified that we have termed zippered endoplasmic reticulum (ER) and spherules. Zippered ER lacked luminal space, suggesting zippering of ER cisternae, while spherules appeared as uniform invaginations of zippered ER. Electron tomography showed that IBV-induced spherules are tethered to the zippered ER and that there is a channel connecting the interior of the spherule with the cytoplasm, a feature thought to be necessary for sites of RNA synthesis but not seen previously for membrane rearrangements induced by coronaviruses. We also identified DMVs in IBV-infected cells that were observed as single individual DMVs or were connected to the ER via their outer membrane but not to the zippered ER. Interestingly, IBV-induced spherules strongly resemble confirmed sites of RNA synthesis for alphaviruses, nodaviruses, and bromoviruses, which may indicate similar strategies of IBV and these diverse viruses for the assembly of RNA replication complexes. IMPORTANCE: All positive-sense single-stranded RNA viruses induce rearranged cellular membranes, providing a platform for viral replication complex assembly and protecting viral RNA from cellular defenses. We have studied the membrane rearrangements induced by an important poultry pathogen, the gammacoronavirus infectious bronchitis virus (IBV). Previous work studying closely related betacoronaviruses identified double-membrane vesicles (DMVs) and convoluted membranes (CMs) derived from the endoplasmic reticulum (ER) in infected cells. However, the role of DMVs and CMs in viral RNA synthesis remains unclear because these sealed vesicles lack a means of delivering viral RNA to the cytoplasm. Here, we characterized structures novel to IBV infection: zippered ER and small vesicles tethered to the zippered ER termed spherules. Significantly, spherules contain a channel connecting their interior to the cytoplasm and strongly resemble confirmed sites of RNA synthesis for other positive-sense RNA viruses, making them ideal candidates for the site of IBV RNA synthesis. PMID- 24149516 TI - MiR199a is implicated in embryo implantation by regulating Grb10 in rat. AB - MiR199a was found to be differentially expressed in rat uteri between the prereceptive and receptive phase via microRNA (miRNA) microarray analysis in our previous study. However, the role of miR199a in rat embryo implantation remained unknown. In the study, northern blot results showed that the expression levels of miR199a were higher on gestation days 5 and 6 (g.d.5-6) in rat uteri than on g.d.3-4 and g.d.7-8. In situ localization of miR199a in rat uteri showed that miR199a was mainly localized in the stroma or decidua. The expression of miR199a was not significantly different in the uteri of pseudopregnant rats and evidently increased in the uteri of rats subjected to activation of delayed implantation and experimentally induced decidualization. Treatment with 17beta-estradiol or both 17beta-estradiol and progesterone significantly diminished miR199a levels. Gain of function of miR199a in endometrial stromal cells isolated from rat uteri inhibited cell proliferation and promoted cell apoptosis. Loss of function of miR199a displayed opposite roles on cell proliferation and apoptosis. Further investigation uncovered a significant inverse association between the expression of miR199a and growth factor receptor-bound protein 10 (Grb10), an imprinted gene, and miR199a could bind to the 3'UTR of Grb10 to inhibit Grb10 translation. In addition, in vivo analysis found that the immunostaining of GRB10 was attenuated in the stroma or decidua from g.d.4 to 6, contrary to the enhancement of miR199a. Collectively, upregulation of miR199a in rat uterus during the receptive phase is regulated by blastocyst activation and uterine decidualization. Enforced miR199a expression suppresses cell proliferation partially through targeting Grb10. PMID- 24149517 TI - Risk-taking differences across the adult life span: a question of age and domain. AB - BACKGROUND: Older adults face important risky decisions about their health, their financial future, and their social environment. We examine age differences in risk-taking behaviors in multiple risk domains across the adult life span. METHODS: A cross-sectional study was conducted in which 528 participants from 18 to 93 years of age completed the Domain-Specific Risk-Taking (DOSPERT) scale, a survey measuring risk taking in 5 different domains. RESULTS: Our findings reveal that risk-taking tendencies in the financial domain reduce steeply in older age (at least for men). Risk taking in the social domain instead increases slightly from young to middle age, before reducing sharply in later life, whereas recreational risk taking reduces more steeply from young to middle age than in later life. Ethical and health risk taking reduce relatively smoothly with age. Our findings also reveal gender differences in risk taking with age. Financial risk taking reduced steeply in later life for men but not for women, and risk taking in the social domain reduced more sharply for women than for men. DISCUSSION: We discuss possible underlying causes of the domain-specific nature of risk taking and age. PMID- 24149514 TI - Interaction between the hemagglutinin-neuraminidase and fusion glycoproteins of human parainfluenza virus type III regulates viral growth in vivo. AB - Paramyxoviruses, enveloped RNA viruses that include human parainfluenza virus type 3 (HPIV3), cause the majority of childhood viral pneumonia. HPIV3 infection starts when the viral receptor-binding protein engages sialic acid receptors in the lung and the viral envelope fuses with the target cell membrane. Fusion/entry requires interaction between two viral surface glycoproteins: tetrameric hemagglutinin-neuraminidase (HN) and fusion protein (F). In this report, we define structural correlates of the HN features that permit infection in vivo. We have shown that viruses with an HN-F that promotes growth in cultured immortalized cells are impaired in differentiated human airway epithelial cell cultures (HAE) and in vivo and evolve in HAE into viable viruses with less fusogenic HN-F. In this report, we identify specific structural features of the HN dimer interface that modulate HN-F interaction and fusion triggering and directly impact infection. Crystal structures of HN, which promotes viral growth in vivo, show a diminished interface in the HN dimer compared to the reference strain's HN, consistent with biochemical and biological data indicating decreased dimerization and decreased interaction with F protein. The crystallographic data suggest a structural explanation for the HN's altered ability to activate F and reveal properties that are critical for infection in vivo. IMPORTANCE: Human parainfluenza viruses cause the majority of childhood cases of croup, bronchiolitis, and pneumonia worldwide. Enveloped viruses must fuse their membranes with the target cell membranes in order to initiate infection. Parainfluenza fusion proceeds via a multistep reaction orchestrated by the two glycoproteins that make up its fusion machine. In vivo, viruses adapt for survival by evolving to acquire a set of fusion machinery features that provide key clues about requirements for infection in human beings. Infection of the lung by parainfluenzavirus is determined by specific interactions between the receptor binding molecule (hemagglutinin-neuraminidase [HN]) and the fusion protein (F). Here we identify specific structural features of the HN dimer interface that modulate HN-F interaction and fusion and directly impact infection. The crystallographic and biochemical data point to a structural explanation for the HN's altered ability to activate F for fusion and reveal properties that are critical for infection by this important lung virus in vivo. PMID- 24149518 TI - Ecological Relevance Determines Task Priority in Older Adults' Multitasking. AB - OBJECTIVES: Multitasking is a challenging aspect of human behavior, especially if the concurrently performed tasks are different in nature. Several studies demonstrated pronounced performance decrements (dual-task costs) in older adults for combinations of cognitive and motor tasks. However, patterns of costs among component tasks differed across studies and reasons for participants' resource allocation strategies remained elusive. METHOD: We investigated young and older adults' multitasking of a working memory task and two sensorimotor tasks, one with low (finger force control) and one with high ecological relevance (postural control). The tasks were performed in single-, dual-, and triple-task contexts. RESULTS: Working memory accuracy was reduced in dual-task contexts with either sensorimotor task and deteriorated further under triple-task conditions. Postural and force performance deteriorated with age and task difficulty in dual-task contexts. However, in the triple-task context with its maximum resource demands, older adults prioritized postural control over both force control and memory. DISCUSSION: Our results identify ecological relevance as the key factor in older adults' multitasking. PMID- 24149520 TI - Should athletes be allowed to use performance enhancing drugs? PMID- 24149521 TI - Saturated fat is not the major issue. PMID- 24149519 TI - Bariatric surgery versus non-surgical treatment for obesity: a systematic review and meta-analysis of randomised controlled trials. AB - OBJECTIVE: To quantify the overall effects of bariatric surgery compared with non surgical treatment for obesity. DESIGN: Systematic review and meta-analysis based on a random effects model. DATA SOURCES: Searches of Medline, Embase, and the Cochrane Library from their inception to December 2012 regardless of language or publication status. ELIGIBILITY CRITERIA: Eligible studies were randomised controlled trials with >= 6 months of follow-up that included individuals with a body mass index >= 30, compared current bariatric surgery techniques with non surgical treatment, and reported on body weight, cardiovascular risk factors, quality of life, or adverse events. RESULTS: The meta-analysis included 11 studies with 796 individuals (range of mean body mass index at baseline 30-52). Individuals allocated to bariatric surgery lost more body weight (mean difference -26 kg (95% confidence interval -31 to -21)) compared with non-surgical treatment, had a higher remission rate of type 2 diabetes (relative risk 22.1 (3.2 to 154.3) in a complete case analysis; 5.3 (1.8 to 15.8) in a conservative analysis assuming diabetes remission in all non-surgically treated individuals with missing data) and metabolic syndrome (relative risk 2.4 (1.6 to 3.6) in complete case analysis; 1.5 (0.9 to 2.3) in conservative analysis), greater improvements in quality of life and reductions in medicine use (no pooled data). Plasma triglyceride concentrations decreased more (mean difference -0.7 mmol/L ( 1.0 to -0.4) and high density lipoprotein cholesterol concentrations increased more (mean difference 0.21 mmol/L (0.1 to 0.3)). Changes in blood pressure and total or low density lipoprotein cholesterol concentrations were not significantly different. There were no cardiovascular events or deaths reported after bariatric surgery. The most common adverse events after bariatric surgery were iron deficiency anaemia (15% of individuals undergoing malabsorptive bariatric surgery) and reoperations (8%). CONCLUSIONS: Compared with non-surgical treatment of obesity, bariatric surgery leads to greater body weight loss and higher remission rates of type 2 diabetes and metabolic syndrome. However, results are limited to two years of follow-up and based on a small number of studies and individuals. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42012003317 (www.crd.york.ac.uk/PROSPERO). PMID- 24149522 TI - Movement skill assessment of typically developing preschool children: a review of seven movement skill assessment tools. AB - The importance of movement is often overlooked because it is such a natural part of human life. It is, however, crucial for a child's physical, cognitive and social development. In addition, experiences support learning and development of fundamental movement skills. The foundations of those skills are laid in early childhood and essential to encourage a physically active lifestyle. Fundamental movement skill performance can be examined with several assessment tools. The choice of a test will depend on the context in which the assessment is planned. This article compares seven assessment tools which are often referred to in European or international context. It discusses the tools' usefulness for the assessment of movement skill development in general population samples. After a brief description of each assessment tool the article focuses on contents, reliability, validity and normative data. A conclusion outline of strengths and weaknesses of all reviewed assessment tools focusing on their use in educational research settings is provided and stresses the importance of regular data collection of fundamental movement skill development among preschool children. Key pointsThis review discusses seven movement skill assessment tool's test content, reliability, validity and normative samples.The seven assessment tools all showed to be of great value. Strengths and weaknesses indicate that test choice will depend on specific purpose of test use.Further data collection should also include larger data samples of able bodied preschool children.Admitting PE specialists in assessment of fundamental movement skill performance among preschool children is recommended.The assessment tool's normative data samples would benefit from frequent movement skill performance follow-up of today's children. ABBREVIATIONS: MOT 4-6: Motoriktest fur vier- bis sechsjahrige Kinder, M-ABC: Movement Assessment Battery for Children, PDMS: Peabody Development Scales, KTK: Korper-Koordinationtest fur Kinder, TGDM: Test of Gross Motor Development, MMT: Maastrichtse Motoriektest, BOTMP: Bruininks-Oseretsky Test of Motor Proficiency. ICC: intraclass correlation coefficient, NR: not reported, GM: gross motor, LV: long version, SV: short version, LF: long form, SF: short form, STV: subtest version, SEMs: standard errors of measurement, TMQ: Total Motor Quotient, TMC: Total Motor Composite, CSSA: Comprehensive Scales of Student Abilities MSEL: Mullen Scales of Early learning: AGS Edition AUC: Areas under curve BC: Battery composite ROC: Receiver operating characteristic. PMID- 24149523 TI - Reflecting on the delivery of a longitudinal coping intervention amongst junior national netball players. AB - Recent research suggests that appropriately-tailored interventions can assist adolescents enhance their coping skills (Frydenberg and Lewis, 2004). The present paper reflects upon the delivery of a longitudinal coping intervention utilized by junior national netball players. Reflection is focused on issues such as the rationale for the intervention, operational issues surrounding the delivery and management of the work. It is also focused on interpersonal issues relating to intervention implementation. We contend that being explicit about developmental and applied processes may enable theoretically sound and efficacious practices to be identified. In addition, unpacking operational issues related to delivery may assist applied sport and exercise psychologists in the development of related work. Key pointsThis paper exemplifies the potential benefits of reflective practice and offers an insight into the lessons learned during longitudinal applied research.We conclude that intervention-based research must accommodate the idiosyncrasies of an organization and requires the sport organisation to buy into the value of the work.Whilst thoughts and associations are offered, readers are encouraged to consider these and alternative associations. PMID- 24149524 TI - Physiological assessment of head-out aquatic exercises in healthy subjects: a qualitative review. AB - In the last decades head-out aquatic exercises became one of the most important physical activities within the health system. Massive research has been produced throughout these decades in order to better understand the role of head-out aquatic exercises in populations' health. Such studies aimed to obtain comprehensive knowledge about the acute and chronic response of subjects performing head-out aquatic exercises. For that, it is assumed that chronic adaptations represent the accumulation of acute responses during each aquatic session. The purpose of this study was to describe the "state of the art "about physiological assessment of head-out aquatic exercises based on acute and chronic adaptations in healthy subjects based on a qualitative review. The main findings about acute response of head-out aquatic exercise according to water temperature, water depth, type of exercise, additional equipment used, body segments exercising and music cadence will be described. In what concerns chronic adaptations, the main results related to cardiovascular and metabolic adaptations, muscular strength, flexibility and body composition improvements will be reported. Key pointsSeveral papers reported consistent and significant improvement in physical fitness (e.g., aerobic capacity, muscular strength, flexibility and body composition) after a program of head-out aquatic exercise with at least eight weeks.Chronic adaptations to head-out aquatic exercise programs are the cumulative result of appropriate acute responses during the exercise session.Appropriate acute adaptations can be obtained taking into account the water temperature, water depth, type of exercise and its variants, the equipment used and the segmental cadence according to the subjects' profile. PMID- 24149525 TI - Effect of energy expenditure and training status on leptin response to sub maximal cycling. AB - We examined the leptin response and related hormones during and after two sub maximal exercise protocols in trained and untrained subjects. During this study, plasma concentrations of leptin [Lep], insulin [I], cortisol [C], growth hormone [GH], glucose [G] and lactate [La] were measured. 7 elite volleyball trained players (TR) and 7 untrained (UTR) subjects (percent body fat: 13.2 +/- 1.8 versus 15.7 +/- 1.0, p < 0.01, respectively) were examined after short and prolonged sub-maximal cycling exercise protocols (SP and PP). Venous blood samples were collected before each protocol, during, at the end, and after 2 and 24 h of recovery. SP and PP energy expenditures ranged from 470 +/- 60 to 740 +/- 90 kcal for TR and from 450 +/- 60 to 710 +/- 90 kcal for UTR, respectively. [Lep] was related to body fat percentage and body fat mass in TR (r = 0. 84, p < 0.05 and r = 0.93, p < 0.01) and in UTR (r = 0.89, p < 0.01 and r = 0.92, p < 0. 01, respectively). [Lep] did not change significantly during both protocols for both groups but was lower (p < 0.05) in all sampling in TR when compared to UTR. Plasma [I] decreased (p < 0.01) and [GH] increased (p < 0.01) significantly during both SP and PP and these hormones remained lower (I: p < 0.01) and higher (GH: p < 0.01) than pre-exercise levels after a 2-h recovery period, returning to base-line at 24-h recovery. Plasma [La] increased (p < 0.01) during both protocols for TR and UTR. There was no significant change in [C] and [G] during and after both protocols for all subjects. It is concluded that 1) leptin is not sensitive to acute short or prolonged sub-maximal exercises (with energy expenditure under 800 kcal) in volleyball/ anaerobically trained athletes as in untrained subjects, 2) volleyball athletes showed significantly lower resting and exercise leptin response with respect to untrained subjects and 3) it appears that in these anaerobically trained athletes leptin response to exercise is more sensitive to the level of energy expenditure than hormonal or metabolic modifications induced by acute exercise. Key pointsTrials concerning acute exercise and leptin indicated discrepant results.Acute exercise with energy expenditure higher than 800 kcal can decrease leptinemia.Elite volleyball players presented decreased leptin levels than untrained subjects. PMID- 24149526 TI - Influence of two different rest interval lengths in resistance training sessions for upper and lower body. AB - Rest intervals between sets appear to be an important variable that can directly affect training volume and fatigue. The purpose of the present study was to compare the influence of two and five-minute rest intervals on the number of repetitions per set, per exercise and total repetitions in resistance training sessions. Fourteen trained men (23.0 +/- 2. 2 yrs; 74.9 +/- 4.1 kg; 1.75 +/- 0.03 m) completed three sets per exercise, with 10RM load in four training sessions. Two sessions involved lower body exercises (leg press, leg extension and leg curl), with two-minute (SEQA) and with five-minute interval (SEQB). The other two sessions involved upper body exercises (bench press, pec-deck and triceps pulley), with two (SEQC) and five-minute intervals (SEQD). For two-minute, five of six exercises presented reductions in the second set, compared with the first set, and for the third set compared with the first and second sets. For five minute, three of the six exercises presented reductions in the third set, compared with the first sets, and two of the six for the third set, compared with the second sets. The total number of repetitions in SEQA (66.7 +/- 4.9) was significantly smaller than in SEQB (80.9 +/- 6.9). Similarly, the total repetitions was significantly lower in SEQC (71.1 +/- 4.7) compared with SEQD (83.7 +/- 6.1). The results indicate that the training session performance is reduced by shorter intervals, being the initial exercises less affected during the progression of the sets. Key pointsShorter rest interval between the sets and exercise in resistance training sessions for upper and lower body resulted in significant declines on the number of repetitions during the progression of the sets and exercises.Longer rest intervals seem to be necessary to avoid significant declines in the number of repetitions during the progression of sets and exercises during a resistance training sequence, principally for the exercises performed last.An important variable when maximal strength is desired is the volume of repetitions or total work. To achieve specific volumes longer rest interval is necessary. PMID- 24149527 TI - Variability of coordination parameters at 400-m front crawl swimming pace. AB - This study examined the variability of physiological, perceptual, stroke and coordination parameters in both genders during several swim trials at the 400-m pace speed. Twelve national level competitors (6 men, 6 women) swam 400-m at maximal speed. They then swam three additional trials (100, 200 and 300-m) at the pace (speed) of the previous 400-m. Three cameras were used to determine stroke cycle [speed (V), stroke length (SL), stroke rate (SR)] and coordination [index of coordination (IdC), stroke phases] parameters. Physiological [heart rate (HR) and lactate [La-] and perceptual [subjective workload (TWL)] parameters were assessed after each swim trial. Inter-trial data indicated that HR, [La-] and TWL increased significantly with the distance swum (p < 0.05). Inter-trial comparison did not show significant variation of stroke cycle and coordination parameters. Inter-lap data were examined within the 400-m and showed that V and SL decreased significantly at the beginning of the trial (p < 0.05), but IdC and SR remained unchanged (p > 0.05). Thus, despite changes in both physiological and perceptual responses consecutive to increasing fatigue, coordination parameters remained stable during an all-out 400-m freestyle swim. The examination of these parameters based on short-distance trials appears then to be valid, which offers interesting perspectives for swim testing. Key points"During a maximal 400-m, fatigue led to an increase in both physiological (heart rate and blood lactate) and perceptual (subjective workload) parameters.The consequence was a decrease in stroke length and therefore in the swimming speed.However, inter-arm coordination did not change during this aerobic task.This indicates that inter-arm coordination can be examined on the basis of short-distance trials rather than on the full distance. PMID- 24149528 TI - Instrumentation and Motivations for Organised Cycling: The Development of the Cyclist Motivation Instrument (CMI). AB - 'Serious leisure' cycling has developed as a reinterpretation of the traditional form of the sport. This short term, informal, unstructured and unconventional conceptualisation represents a challenge to participant numbers in the mainstream sport. The purpose of this study was twofold: (i) to ascertain the cultural, subcultural and ecological factors of participation in this new conceptualised form enabling clubs, associations and governments to a deeper understanding about participants practices and (ii) as an ongoing validation to previous qualitative work (see O'Connor and Brown, 2005). This study reports on the development and psychometric properties (principal components analysis, confirmatory factor analysis) of the Cyclists' Motivation Instrument. Four hundred and twenty two cyclists (371 males, 51 females) who were registered members of the state competitive cycling body completed a fifty-one item instrument. Five factors were identified: social, embodiment, self-presentation, exploring environments and physical health outcomes and these accounted for 47.2% of the variance. Factor alpha coefficients ranged from .63 to .88, overall scale reliability was .92, suggesting moderate to high reliability for each of the factors and the overall scale. Key pointsSerious leisure' cyclists' are fitness seeking enthusiasts that attach different meanings to the act of cycling and participate in different physical, social and natural environments in comparison to other cyclists.This study develops and validates a new tool, the Cyclists Motivation Instrument (CMI), and presents the initial psychometric properties (principal components analysis, confirmatory factor analysis).FIVE FACTORS WERE IDENTIFIED: social, embodiment, self-presentation, exploring environments and physical health outcomes.The scale demonstrates adequate reliability (total scale, alpha = 0.92) and validity. PMID- 24149529 TI - Effects of Acute Moderate and Strenuous Exercise Bouts on IL-17 Production and Inflammatory Response in Trained Rats. AB - In this study, we aimed to compare the effects of a single bout of acute moderate and strenuous running exercise on the production of interleukin-17 (IL-17), interleukin-6 (IL-6), interleukin-1 receptor antagonist (IL-1ra) and inflammatory response of skeletal muscles in regularly trained rats. Eight week old rats were trained by treadmill running 5 days per week for 13 weeks at the durations of 30 min (moderate) and 60 min (strenuous). Two days after the last training session, the animals were subjected to a single bout of moderate or strenuous exercise and serum samples were analyzed for IL-17, IL-6, IL-1ra levels and myeloperoxidase (MPO) activity of gastrocnemius muscle were determined. IL-17 level significantly increased in strenuous exercise group when compared to that of sedentary controls (p < 0.01), On the other hand, only in the moderate exercise group, there was a negative correlation between IL-6 and IL-17 levels (r = - 0.857 and p = 0.014). In conclusion, acute single bout of strenuous exercise increased IL-17 production in trained rats and, this cytokine may be involved in inflammatory process of skeletal muscles. Key pointsA single bout of acute strenuous running exercise markedly elevated IL-17 production.This preliminary result should be supported by forthcoming studies that investigate the role of IL-17 in acute inflammatory process of skeletal muscle. PMID- 24149530 TI - Validity of a dietary calcium questionnaire modified to include supplement use in athletes. AB - When conducting research in the area of bone health, accurate measurement of calcium intake is crucial. The rapid assessment method (RAM) is one technique that has frequently been used for its measurement of calcium intake. However, the RAM and other currently established questionnaires lack the assessment of dietary supplement use, which is common for athletes. Our objective was to evaluate the validity of a RAM questionnaire designed to assess daily calcium consumption which was further modified to meet the needs of athletes who frequently consume dietary supplements. Usefulness of the modified RAM for athletes and non-athletes was evaluated as well as utility among those who do and do not use supplements. The 47 volunteers (n = 31 women, 16 men) were between the ages of 18 and 25 including, 33 athletes and 14 controls. The population also contained 23 supplement users and 24 non-supplement users. Participants completed the modified RAM and were instructed to complete a three-day diet record (3DR), logging food intake for 2 weekdays and 1 weekend day. The data collected via the modified RAM was compared with the 3DR. Mean calcium intake was 935mg +/- 420mg and 1085mg +/- 573mg, for the modified RAM and 3DR respectively. A strong positive correlation (r) was found between calcium intake measured with the modified RAM and 3DRs (r(45) = 0.854, p < 0.01). Intraclass correlation coefficients (ICC) revealed that agreement between the two instruments was good (ICC = 0.76, df = 45, p < 0.01) and much improved when compared to agreements without consideration of supplements (ICC = 0.05, df = 21, p > 0.05). We have found the modified RAM to be a valid tool which can be used to estimate calcium intake in the athletes and controls we strive to study. The accuracy of this instrument improved by including assessment of dietary supplement sources of calcium. Key pointsWhen conducting research on bone health, accurate measurement of calcium intake is crucial. The rapid assessment method (RAM) is one technique that has frequently been used for its measurement; however, currently established questionnaires lack assessment of dietary supplement use, which is common for athletes.We report that estimated calcium intake from the LMU RAM modified to evaluate supplement use has good agreement with three-day diet records (3DRs). There was a strong correlation between the two methods with about 69% (r = 0.83, r(2) = 0.69) of the variability in calcium intake quantified via the LMU RAM being accounted for by the 3DR.Calculated intraclass correlation coefficients between 0.63 and 0.77 reveal that the LMU RAM appears to be a valid tool of measuring daily calcium intake in athletes and non-athletes and among those who do and do not use supplements.When evaluating calcium intake without considering supplements, agreement (ICC) and correlation (r) values decreased considerably.We found the LMU RAM to be a valid measurement of calcium intake in athletes and controls. Without the addition of a section on supplement use, estimated calcium intake would have decreased an average of 32%. PMID- 24149531 TI - The effects of approach angle on penalty kicking accuracy and kick kinematics with recreational soccer players. AB - Kicking accuracy is an important component of successful penalty kicks, which may be influenced by the approach angle. The purpose of this study was to examine the effects of approach angle on kicking accuracy and three-dimensional kinematics of penalty kicks. Seven male amateur recreational soccer players aged (mean +/- s) 26 +/- 3 years, body mass 74.0 +/- 6.8 kg, stature 1.74 +/- 0.06 m, who were right foot dominant, kicked penalties at a 0.6 x 0.6 m target in a full size goal from their self-selected approach angle, 30 degrees , 45 degrees and 60 degrees (direction of the kick was 0 degrees ). Kicking accuracy and three-dimensional kinematics were recorded. Results revealed that there was no significant difference in kicking accuracy (p = 0.27) or ball velocity (p = 0.59) between the approach angles. Pelvic rotation was significantly greater under the 45 degrees and the 60 degrees approach angles than during the self-selected approach angle (p < 0.05). Thigh abduction of the kicking leg at impact using the 60 degrees approach angle was significantly greater than during the self- selected approach (p = 0.01) and the 30 degrees approach (p = 0.04). It was concluded that altering an individual's self-selected approach angle at recreational level did not improve kicking accuracy or ball velocity, despite altering aspects of underlying technique. Key pointsPenalty kicking accuracy and ball velocity were not improved by altering recreational soccer players' natural approach angle.However, widening the approach angle produced greater pelvic rotation and thigh abduction.Wider approach angles increased the range of motion of the pelvis, opening up the hips before ball contact, creating a greater arc of movement during the backswing and the follow-through.Wider approach angles also led to an increase in thigh abduction at impact, enabling the kicking foot to be placed further under the ball, which may improve ball contact. PMID- 24149532 TI - Kinematic analyses of the golf swing hub path and its role in golfer/club kinetic transfers. AB - This study analyzed the fundamental geometric and kinematic characteristics of the swing hub path of the golf shot for four diverse subjects. In addition, the role of the hub path geometry in transferring the kinetic quantities from the golfer to the club were investigated. The hub path was found to have a complex geometry with significantly changing radii, and a constantly moving center-of curvature during the downswing for all subjects. While the size and shape of the hub path differed considerably among the subjects, a three phase radius-based pattern was revealed that aligned with distinct stages of the downswing. Artificially controlling and optimizing the hub path of the better golfer in the group indicated that a non-circular hub path was superior to a constant radius path in minimizing the kinetic loading while generating the highest possible club head velocity. The shape and purpose of the hub path geometry appears to result from a complex combination of achieving equilibrium between the golfer and the club, and a purposeful configuring of the path to control the outward movement of the club while minimizing the kinetic loading on the golfer yet transferring the maximum kinetic quantities to the club. Describing the downswing relative to the hub path phasing is presented and was found to be informative since the phases align with significant swing, kinetic and kinematic markers. These findings challenge golf swing modeling methodologies which fix the center-of-curvature of the hub path thus constraining it to constant radius motion. Key pointsThe golf swing hub path was found to have a complex geometry with significantly changing radii, and a constantly moving center-of-curvature during the downswing.The hub path differed considerably among subjects, however a three phase radius-based pattern was revealed that aligned with distinct stages of the downswing.The shape and purpose of the hub path geometry appears to result from a complex combination of achieving equilibrium between the golfer and the club, and a purposeful configuring of the path to control the outward movement of the club while minimizing the kinetic loading on the golfer yet transferring the maximum kinetic quantities to the club. PMID- 24149533 TI - Arthrometric evaluation of stabilizing effect of knee functional bracing at different flexion angles. AB - Previous in-vivo investigations on the stabilizing efficacy of knee bracing for ACL reconstructed patients have been often limited to 20-30 degrees of knee flexion. In this study, the effectiveness of a uniaxial hinged functional brace to improve the knee stability was assessed at 30, 60 and 90 degrees of knee flexion. Arthrometry tests were conducted on 15 healthy subjects before and following wearing the brace and the tibial displacements were measured at up to 150 N anterior forces. Results indicated that functional bracing has a significant stabilizing effect throughout the range of knee flexion examined (p < 0.05). The rate of effectiveness, however, was not consistent across the flexion range, e.g., 50% at 30 degrees and only 4% at 90 degrees. It was suggested that accurate sizing and fitting as well as attention to correct hinge placement relative to the femoral condyles can limit brace migration and improve its effectiveness in mid and deep knee flexion. With using adaptive limb fittings, through flexible pads, and a polycentric joint a more significant improvement of the overall brace performance and efficacy might be obtained. Key pointsFunctional bracing improves the knee joint stability mostly in extension posture.Unlike the non-braced condition, the least knee joint stability appears in mid and deep flexion angles when using a hinged brace.Accurate sizing and fitting and attention to correct hinge placement relative to the femoral condyles can limit brace migration and improve its effectiveness in mid and deep knee flexion.The overall brace performance and efficacy might be improved significantly using adaptive limb fittings through flexible pads and/or polycentric joints. PMID- 24149534 TI - Initial metabolic state and exercise-induced endotoxaemia are unrelated to gastrointestinal symptoms during exercise. AB - The aim of the study was to investigate the association between the initial metabolic state and exercise-induced endotoxaemia on the appearance of gastrointestinal symptoms (GIS) during exercise. Eleven males (36.6 +/- 4.9 yrs, 1.7 +/- 0.1 m, 74.5 +/- 7.7 kg, DEXA body fat % 17.2 +/- 6.6, VO2max 57.4 +/- 7.4 ml.kg(-1).min(-1)) underwent two isoenergetic diets designed to change their initial metabolic status by either depleting or maintaining their hepatic and muscular glycogen content. These diets and accompanying exercise sessions were performed by each participant in the days before completing a laboratory-based duathlon (5-km run, 30-km cycling, 10-km run). Blood samples were obtained before, immediately and 1- and 2-h following the duathlon for determination of insulin (IN), glucagon (GL), endotoxin, aspartic aminotransferase (AST), and alanine aminotransferase (ALT) markers. GIS were assessed by survey before and after exercise. Diet content produced a different energy status as determined by macronutrient content and the IN/GL ratio (p < 0.05), and mild exercise-induced endotoxaemia was observed in both experimental duathlons. Regardless of the diet, the AST/ALT ratio following exercise and in the recovery phase indicated hepatocyte and liver parenchyma structural damage. In spite of GIS, no significant correlations between endotoxin levels and GIS were found. In conclusion, increased markers of endotoxaemia observed with the high-intensity exercise were unrelated to hepatic function and/or GIS before and after exercise. Key pointsGastrointestinal symptoms before, during, and after a competition are reported by approximately 20%-50% of the athletes participating in endurance events such as marathon, cycling and triathlon.Energy status, exercise-induced endotoxaemia and liver structural damage might be related to gastrointestinal symptoms.In this study, gastrointestinal symptoms observed before and after endurance exercise were unrelated to endotoxin levels or hepatic structural damage. PMID- 24149535 TI - Differences in ball sports athletes speed discrimination skills before and after exercise induced fatigue. AB - Substantial research exists in relation to the effect of fatigue on the cognitive skills of athletes. Very few studies in the sport domain, however, have investigated decision-making time and accuracy in relation to the discrimination of the speed of a moving object following exercise at maximal intensity. The purpose of this study was to examine differences in the pre- and post-fatigue speed discrimination skills of elite ballgames athletes to determine if they prioritize accuracy or speed of decision-making when physically exhausted. The participants in the study were 163 males (M = 21.17, SD = 4.18) Estonian national level soccer (n = 79), basketball (n = 63) and volleyball (n = 21) players. Peak oxygen uptake (VO2max) was assessed during completion of an incremental exercise test on a treadmill. Speed discrimination stimuli were images of red square shapes on a grey background presented moving along the sagittal axis at four different virtual velocities on a computer (PC) screen. Repeated measures MANOVA revealed a significant main effect for the decision-making time factor. A second MANOVA revealed a significant main effect for the decision-making accuracy factor. The soccer group made a significantly lower number of errors than the basketball group (p = 0.015) in pre- and post-fatigue decision-making accuracy. The results showed that athletes' decision-making time decreased and decision making errors increased after a maximal aerobic capacity exercise task. A comparison of the pre- and post-fatigue speed discrimination skills of experienced basketball, volleyball and soccer players indicated that the only significant difference was for decision-making accuracy between the soccer and basketball groups. The current findings clearly demonstrated that the athletes made decisions faster at the expense of accuracy when fatigued. Key pointsThe purpose of this study was to examine differences in the pre- and post-fatigue speed discrimination skills of elite ballgames athletes to determine if they prioritize accuracy or speed of decision-making when physically exhausted.Speed discrimination stimuli were images of red square-shapes on a grey background presented moving along the sagittal axis at four different virtual velocities on a computer (PC) screen that represented the frontal plane.The participants exercised on a treadmill to level of 100% of peak oxygen uptake (VO2max).Repeated measures MANOVA revealed significant main effects for both the decision-making time and accuracy factors. The current findings clearly demonstrated that the athletes made decisions faster but with greater errors when fatigued.Post hoc analyses of the differences between the ball game sport groups indicated that soccer group participants reported a significantly lower number of errors than the basketball group (p = .015) in pre- and post-fatigue decision-making accuracy.Further investigations are required to clarify the equivocal set of previous findings regarding the relationship between the cognitive function of athletes at varying physical workload intensities. PMID- 24149536 TI - Gender specific strategies in demanding hopping conditions. AB - Difference in leg stiffness between females and males is considered to be a cause of higher rates of Anterior Cruciate Ligament injury in female athletes. Females are believed to have lower stiffness and as a consequence different recruitment strategies to adapt functional tasks. The aim of the current study was to evaluate how leg stiffness is tuned to demanding conditions. 22 healthy subjects (11 Male-11 Female; age: 20-43 years) participated in this study. Subjects performed two-legged hopping tasks (at their preferred rate, as fast as possible and with added mass of 10% bodyweight) on a force platform. Leg stiffness was calculated for each condition as the ratio between peak ground reaction force and vertical displacement of center of mass. In the preferred and added mass conditions males showed substantially higher leg stiffness than females (p= 0.006 and p = 0.002, respectively). When hopping as fast as possible the gender bias in leg stiffness disappeared (p = 0.880). Added mass had no significant effect on change in leg stiffness. Results have shown that females increased their leg stiffness more than males indicating they have no gender limiting capacity to reach objectives of higher demanding tasks (i.e.fastest hopping).The relationship between observed gender differences in leg stiffness and increased Anterior Cruciate Ligament injury rate in females requires further study. Key pointsLeg stiffness is an adaptable property of neuro musculoskeletal system to different functional loading conditions.Females can increase their leg stiffness more than males indicating they have no gender limiting capacity to reach objectives of higher demanding tasks as fastest hopping. PMID- 24149537 TI - A common variation in the promoter region of interleukin-6 gene shows association with exercise performance. AB - Skeletal muscle-derived interleukin-6 (IL-6) is a pleiotropic cytokine which regulates body metabolism during strenuous physical exercise. OBJECTIVE: The effect of a potentially functional single nucleotide polymorphism (SNP) -174G/C of the IL6 gene (rs1800795) promoter was examined on maximal oxygen uptake (VO2max), body mass index (BMI) and plasma IL-6 levels in response to physical training. Fifty four male military conscripts were studied for 8 weeks during their basic training. At weeks 1, 5 and 8, VO2max and anthropometrics were measured, and blood samples collected before and after acute aerobic exercise. Acute exercise increased plasma IL-6 in subjects with genotype CG. Moreover, during the 8-week training period, a tendency for increased plasma IL-6 was observed in subjects with this genotype. VO2max values increased in all genotype groups, but subjects with genotype CG made the greatest gains in VO2max. Training significantly decreased BMI only in subjects with genotype CG. Our findings suggest that the allele C may have an effect on plasma IL-6 response to acute exercise in healthy male subjects. Exercise training has a favourable effect on VO2max and BMI, with the most prominent effects in subjects with genotype CG. Thus we conclude that this SNP may account for individual response to exercise training. Key pointsAllele C of the IL6 promoter SNP -174G/C may have an effect on plasma IL-6 response to acute exercise.All subjects responded to physical exercise, but the improvement in VO2max and decrease in BMI after training are more pronounced in the individuals with genotype CG, hence the IL6 promoter SNP 174G/C may have an influence on training responses.The small number of subjects investigated in the present study warrants further research to confirm these findings in large cohorts. PMID- 24149538 TI - Game Related Statistics Discriminating Between Starters and Nonstarters Players in Women'S National Basketball Association League (WNBA). AB - The aim of the present study was to identify the game-related statistics that allow discriminating between starters and nonstarter players in women's basketball when related to winning or losing games and best or worst teams. The sample comprised all 216 regular season games from the 2005 Women's National Basketball Association League (WNBA). The game-related statistics included were 2 and 3- point field-goals (both successful and unsuccessful), free-throws (both successful and unsuccessful), defensive and offensive rebounds, assists, blocks, fouls, steals, turnovers and minutes played. Results from multivariate analysis showed that when best teams won, the discriminant game-related statistics were successful 2-point field-goals (SC = 0.47), successful free-throws (SC = 0.44), fouls (SC = -0.41), assists (SC = 0.37), and defensive rebounds (SC = 0.37). When the worst teams won, the discriminant game-related statistics were successful 2 point field- goals (SC = 0.37), successful free-throws (SC = 0.45), assists (SC = 0.58), and steals (SC = 0.35). The results showed that the successful 2-point field-goals, successful free-throws and the assists were the most powerful variables discriminating between starters and nonstarters. These specific characteristics helped to point out the importance of starters' players shooting and passing ability during competitions. Key pointsThe players' game-related statistical profile varied according to team status, game outcome and team quality in women's basketball.The results of this work help to point out the different player's performance described in women's basketball compared with men's basketball.The results obtained enhance the importance of starters and nonstarters contribution to team's performance in different game contexts.Results showed the power of successful 2-point field-goals, successful free-throws and assists discriminating between starters and nonstarters in all the analyses. PMID- 24149539 TI - Isometric gluteus medius muscle torque and frontal plane pelvic motion during running. AB - The objective of this study was to investigate the relationship between isometric GM torque and the degree of frontal plane pelvic drop during running. Twenty-one healthy, recreational runners (9 males, 12 females) who ran 8.05 km or more per week were obtained from a sample of convenience. GM maximal isometric torque was collected prior to the run. Subjects then ran on a treadmill for 30 minutes while bilateral three-dimensional pelvic kinematic data were collected for 10 seconds at each 2 minute increment. Left side pelvic drop showed a slight increase (effect size = 0.61); while, the right side pelvic drop remained stable (effect size = 0.18). Pearson's Correlations showed no relationship between GM isometric torque and frontal plane pelvic drop for any of the data collection periods during the 30-minute run. These results suggest that isometric GM torque was a poor predictor of frontal plane pelvic drop. One should question whether a dynamic rather than static measure of GM strength would be more appropriate. Future research is needed to identify dynamic strength measures that would better predict biomechanical components of running gait. Key pointsThere is a lack of research linking static, clinical measures to dynamic running gait observations.Isometric gluteus medius muscle torque is a poor predictor of frontal plane pelvic drop in running.Future studies should identify dynamic strength measures that correlate with elements of running biomechanics. PMID- 24149540 TI - Validity of the emotional intelligence scale for use in sport. AB - This study investigated the factorial validity of the 33-item self-rated Emotional Intelligence Scale (EIS: Schutte et al., 1998) for use with athletes. In stage 1, content validity of the EIS was assessed by a panel of experts (n = 9). Items were evaluated in terms of whether they assessed EI related to oneself and EI focused on others. Content validity further examined items in terms of awareness, regulation, and utilization of emotions. Content validity results indicated items describe 6-factors: appraisal of own emotions, regulation of own emotions, utilization of own emotions, optimism, social skills, and appraisal of others emotions. Results highlighted 13-items which make no direct reference to emotional experiences, and therefore, it is questionable whether such items should be retained. Stage 2 tested two competing models: a single factor model, which is the typical way researchers use the EIS and the 5-factor model (optimism was discarded as it become a single-item scale fiolliwng stage 1) identified in stage 1. Confirmatory factor analysis (CFA) results on EIS data from 1,681 athletes demonstrated unacceptable fit indices for the 33-item single factor model and acceptable fit indices for the 6-factor model. Data were re-analyzed after removing the 13-items lacking emotional content, and CFA results indicate partial support for single factor model, and further support for a five-factor model (optimism was discarded as a factor during item removal). Despite encouraging results for a reduced item version of the EIS, we suggest further validation work is needed. Key pointsGiven the inherent link between construct measurement and theory testing, it is imperative for researchers to pay close attention to measurement issues showed poor fit indices. The present study investigated a self-report emotional intelligence for use in sportResults indicate that a single-item model shows poor fit with acceptable fit indices for a 6-factor model.A revised 5-factor and 19-item model showed improved model fit.Despite encouraging results, we suggest further validation work is needed. PMID- 24149541 TI - Hip rotational velocities during the full golf swing. AB - Since labral pathology in professional golfers has been reported, and such pathology has been associated with internal/external hip rotation, quantifying the rotational velocity of the hips during the golf swing may be helpful in understanding the mechanism involved in labral injury. Thus, the purpose of this study was to determine the peak internal/external rotational velocities of the thigh relative to the pelvis during the golf swing. Fifteen female, collegiate golfers participated in the study. Data were acquired through high-speed three dimensional (3-D) videography using a multi-segment bilateral marker set to define the segments, while the subjects completed multiple repetitions of a drive. The results indicated that the lead hip peak internal rotational velocity was significantly greater than that of the trail hip external rotational velocity (p = 0.003). It appears that the lead hip of a golfer experiences much higher rotational velocities during the downswing than that of the trail hip. In other structures, such as the shoulder, an increased risk of soft tissue injury has been associated with high levels of rotational velocity. This may indicate that, in golfers, the lead hip may be more susceptible to injury such as labral tears than that of the trailing hip. Key pointsLead hip of golfer experiences significantly higher rotational velocities than the trail hip.Golfers may be more susceptible to injuries on the lead hip.Clubhead velocities were consistent with elite female golfers. PMID- 24149542 TI - A physiological case study of a paralympic wheelchair tennis player: reflective practise. AB - This study was designed to examine the physiological changes caused by long-term training in a world class female tennis player in preparation for a major championship. Additionally, we aim to describe the training interventions and determine a suitable cooling strategy that was to be used at the 2004 Paralympic Games. The athlete underwent regular physiological assessment during 2003-2004. Physiological measures involved body composition, submaximal and peak oxygen uptake and key variables associated with maximal sprinting. In addition, a suitable match-play cooling intervention and hydration strategy was also explored. Body composition improved over the course of the study. Aerobic capacity fell by 21%, yet the submaximal physiological variables such as lactate profile and pushing economy improved. The trade off of aerobic capacity was perhaps noticeably counter-balanced with the maintenance of the peak sprinting speed and improvement found in the fatigue profile across ten repeated sprints. The extensive training programme was responsible for these changes and these adaptations resulted in a more confident athlete, in peak physical condition leading into the Paralympic Games. It is difficult to appreciate the extent to which this work had an impact on tennis performance given the skill requirements of wheelchair tennis and this warrants future attention. Key pointsPhysiological adaptations were apparent over the two-year training period.The training emphasis resulted in a reduction in aerobic capacity, yet an improvement in repetitive sprint performance was seen leading into the Major competition.An effective cooling technique was identified that could be used during wheelchair tennis performance.The athlete and coaches were complimentary to the physiological support provided, which resulted in a more confident athlete at the Paralympic Games. PMID- 24149543 TI - Stress fracture of the first rib in a high school weight lifter. AB - A 17-year-old boy, who played a weight lifting in high school, sustained stress fracture of the first rib without any causes. We successfully treated first rib stress fracture with limitation of using the upper extremity and with using low intensity pulsed ultrasound. Key pointsStress fracture of the first rib in a weight lifter was successfully treated with limitation of sports activity and with LIPUS treatment. PMID- 24149545 TI - Underestimation of heritability using a mixed model with a polygenic covariance structure in a genome-wide association study for complex traits. AB - Recently, the use of a mixed model methodology in genome-wide association studies (GWAS) has been considered effective for controlling population stratification and explaining the polygenic effects of complex traits. However, estimating polygenic variance components and heritability was biased when the mixed model was used. This bias results from a diluted genetic relationship covariance structure, particularly with a limited number of underlying causal variants. We simulated disease and quantitative phenotypes with a variety of heritabilities (0.1, 0.2, 0.3, 0.4, and 0.5), prevalence rates (0.1, 0.2, 0.3, and 0.5), and causal variant numbers (10, 30, 50, and 100). Heritabilities from the simulated data using restricted maximum likelihood were underestimated in many populations (P<0.05). The underestimation increased with a large heritability, a small prevalence, and a small number of causal variants. The underestimation was larger in analyzing disease traits compared with quantitative traits. This study suggests an underestimated heritability in GWAS upon using the mixed model methodology with an excessively larger number of variants versus causal variants. PMID- 24149546 TI - A non-genetic, epigenetic-like mechanism of telomere length inheritance? PMID- 24149548 TI - The influence of musical cadence into aquatic jumping jacks kinematics. AB - The aim of this study was to analyze the relationships between the head-out aquatic exercise "Jumping jacks" kinematics and the musical cadence in healthy and fit subjects. Five young women, with at least one year of experience conducting head- out aquatic programs were videotaped in the frontal plane, with a pair of cameras providing a double projection (above and below the water surface). Subjects performed an incremental protocol of five bouts (120 b.min( 1), 135 b.min(-1), 150 b.min(-1), 165 b.min(-1) and 180 b.min(-1)) with 16 full cycles of the "Jumping jacks" exercise. Data processing and calculation of upper limbs' (i.e. hands), lower limbs' (i.e. feet) and center of mass' 2D linear velocity and displacement were computed with the software Ariel Performance Analysis System and applying the 2D-DLT algorithm. Subjects decreased the cycle period during the incremental protocol. Significant and negative relationships with the musical cadence were verified for the center of mass and upper limbs vertical displacement. On the other hand, for the lower limbs lateral velocity, a significant and positive relationship was observed. It is concluded that expert and fit subjects increase the lower limb's velocity to maintain the range of motion, while the upper limb's displacement is reduced to coupe the music cadence. Key pointsWhile performing the Jumping Jacks, expert and fit subjects increase their lower limbs segmental velocity to maintain the range of motion.The upper limbs displacement is reduced to maintain the music cadence.Expert and fit subjects present similar response for alternating or simultaneously head-out aquatic exercises when increasing the music cadence. PMID- 24149547 TI - Circadian rhythms in exercise performance: implications for hormonal and muscular adaptation. AB - Almost all physiological and biochemical processes within the human body follow a circadian rhythm (CR). In humans, the suprachiasmatic nucleus regulates sleep- wake cycle and other daily biorhythms in line with solar time. Due to such daily physiological fluctuations, several investigations on neuromuscular performance have reported a distinct CR during exercise. Generally, peak performances have been found to occur in the early evening, at approximately the peak of core body temperature. The increase in core body temperature has been found to increase energy metabolism, improve muscle compliance and facilitate actin-myosin crossbridging. In addition, steroidal hormones such as testosterone (T) and cortisol (C) also display a clear CR. The role of T within the body is to maintain anabolism through the process of protein synthesis. By contrast, C plays a catabolic function and is involved in the response of stress. Due to the anabolic and catabolic nature of both T and C, it has been postulated that a causal relationship may exist between the CR of T and C and muscular performance. This review will therefore discuss the effects of CR on physical performance and its implications for training. Furthermore, this review will examine the impact of muscular performance on CR in hormonal responses and whether could variations in T and C be potentially beneficial for muscular adaptation. Key pointsA distinct CR can be observed in physical performance.CR of exercise performance is highly associated with CR in core body temperatureBoth T and C display a clear CR, however, the current evidence does not show a clear relationship with neuromuscular adaptations.TST is able to induce changes in physical performance variables at the particular time point, but not for the circadian profile of T and C. PMID- 24149549 TI - Validity of the modified conconi test for determining ventilatory threshold during on-water rowing. AB - The objectives of this study were to design a field test based on the Conconi protocol to determine the ventilatory threshold of rowers and to test its reliability and validity. A group of sixteen oarsmen completed a modified Conconi test for on-water rowing. The reliability of the detection of the heart rate threshold was evaluated using heart rate breaking point in the Conconi test and retest. Heart rate threshold was detected in 88.8% of cases in the test-retest. The validity of the modified Conconi test was evaluated by comparing the heart rate threshold data acquired with that obtained in a ventilatory threshold test (VT2). No significant differences were found for the values of different intensity parameters i.e. heart rate (HR), oxygen consumption (VO2), stroke rate (SR) and speed (S) between the heart rate threshold and the ventilatory threshold, (170.9 +/- 6.8 vs. 169.3 +/- 6.4 beats.min(-1); 42.0 +/- 8.6 vs. 43.5 +/- 8.3 ml.kg(-1).min(-1); 25.8 +/- 3.3 vs. 27.0 +/- 3.2 strokes.min(-1) and 14.4 +/- 0.8 vs. 14.6 +/- 0.8 km.h(-1)). The differences in averages obtained in the Conconi test-retest were small with a low standard error of the mean. The reliability data between the Conconi test-retest showed low coefficients of variations (CV) and high intraclass correlation coefficients (ICC). The total errors for the Conconi test-retest are low for the measured variables (1.31 HR, 0.87 VO2, 0.65 SR, and 0.1 S). The Bland- Altman's method for analysis validity showed a strong concordance according to the analyzed variables. We conclude that the modified Conconi test for on-water rowing is a valid and reliable method for the determination of the second ventilatory threshold (VT2). Key pointsThe Modified Conconi test for on-water rowing is a simple and non-invasive method for the determination of anaerobic threshold for on-water rowing.The modified Conconi protocol for rowing was also shown to be a valid protocol for the calculation of the second ventilatory threshold using the ventilatory method.The Bland-Altman analysis suggests an adequate concordance for the modified Conconi test with the ventilatory method for the measurement of the ventilatory threshold. PMID- 24149550 TI - Effects of between-set interventions on neuromuscular function during isokinetic maximal concentric contractions of the knee extensors. AB - The presents study investigated the effects of between-set interventions on neuromuscular function of the knee extensors during six sets of 10 isokinetic (120 degrees .s(-1)) maximal concentric contractions separated by three minutes. Twelve healthy men (age: 23.9 +/- 2.4 yrs) were tested for four different between set recovery conditions applied during two minutes: passive recovery, active recovery (cycling), electromyostimulation and stretching, in a randomized, crossover design. Before, during and at the end of the isokinetic session, torque and thigh muscles electromyographic activity were measured during maximal voluntary contractions and electrically-evoked doublets. Activation level was calculated using the twitch interpolation technique. While quadriceps electromyographic activity and activation level were significantly decreased at the end of the isokinetic session (-5.5 +/- 14.2 % and -2.7 +/- 4.8 %; p < 0.05), significant decreases in maximal voluntary contractions and doublets were observed after the third set (respectively -0.8 +/- 12.1% and -5.9 +/- 9.9%; p < 0.05). Whatever the recovery modality applied, torque was back to initial values after each recovery period. The present results showed that fatigue appeared progressively during the isokinetic session with peripheral alterations occurring first followed by central ones. Recovery interventions between sets did not modify fatigue time course as compared with passive recovery. It appears that the interval between sets (3 min) was long enough to provide recovery regardless of the interventions. Key pointsAllowing three minutes of recovery between sets of 10 maximal concentric contractions would help the subjects to recover from the peripheral fatigue induced by each set and therefore to start each new set with a high intensity.During this type of session, with three minutes between sets, passive recovery is sufficient; there is no need to apply complicated recovery interventions. PMID- 24149551 TI - The single match approach to strike rate adjustments in batting performance measures in cricket. AB - Batting performance measures containing strike rate adjustments take into account the important fact that if two batsmen had scored the same number of runs in a match, the one with the better strike rate had performed best. But match conditions can influence the batting and bowling performances of cricket players. On a good pitch a batsman can get a good score at a high strike rate, but if the pitch was bad, a similar good score is normally accompanied by a much lower strike rate. The main objective of this study is to propose a method that can be used to make batsmen's scores comparable despite the fact that playing conditions might have been very different. The number of runs scored by a batsman is adjusted by comparing his strike rate with the overall strike rate of all the players in the specific match. These adjusted runs are then used in the most appropriate formula to calculate the average of the batsman. The method is illustrated by using the results of the Indian Premier League 2009 Twenty20 Series played during May and June 2009. The main conclusion is that the traditional average is not the most appropriate measure to compare batsmen's performances after conclusion of a short series. Key pointsIt is unfair to compare the score of a batsman obtained on a good pitch under ideal batting conditions with that of a batsman who had to battle under severe conditions.By comparing a batsman's strike rate with the overall strike rate of the players in the specific match, his score can be adjusted to get a better figure for his true performance.The results demonstrate clearly that the use of adjusted scores lead to rankings that differ from those based on the traditional measures. PMID- 24149552 TI - Muscle strength and damage following two modes of variable resistance training. AB - Nautilus Machine (NM) and Elastic Resistance (ER) have gained considerable popularity among athletes and recreational lifters seeking to increase muscle strength. However, there is controversy concerning the use of ER for increasing muscle hypertrophy and strength among healthy-trained individuals. The aim of the study was to compare the effect of repeated near maximal contractions by ER/NM on indicators of muscle damage including: maximal strength decrement (MVIC), rate of muscle soreness (DOMS), concentration of plasma creatine kinase (CK) and increased high muscle signal on T2 weighted images using magnetic resonance imaging (MRI). Nine healthy male subjects completed two modalities of exercise (5 sets * 10RM ER/NM) in a counterbalance cross-over study design with three weeks "wash-out" period between experiments. The MVIC was measured and DOMS rated and recorded for 4 consecutive days while blood samples were collected on day 1, 3, 5 and 7. Prior to and forty eight hours after completion of each mode of exercise, subjects underwent MRI scanning. The average of applied forces demonstrated significantly higher value for NM compared with ER (362 +/- 34.2 N vs 266.73 +/- 44.6 N respectively) throughout the 5 sets of dynamic exercise (all p < 0.05). However, the indicators of muscle damage (T2 relaxation time, DOMS, MVIC and serum CK) exhibited a very similar response across both modes of training. Plasma CK increased significantly following both modes of training with the peak value on Day 3 (p < 0.05). The time course of muscle soreness reached a significant level after both modes of exercise and showed a peak value on the 2(nd) day (p < 0.05). The T2 relaxation time demonstrated a statistically significant increase following ER and NM compared with the pre-test value (p < 0.05). The similarity of these responses following both the ER and NM exercise training session suggests that both modes of training provide a similar training stress; despite a considerably lower external force generation during ER. The importance of these findings is underlined by the fact that exercise-induced muscle damage has been shown to be the underlying mechanism of further muscle hypertrophy. Key pointsExercise induced muscle soreness increased levels of plasma CK, increased MRI T2 signal and prolonged strength loss indicate the moderate to intense nature of the training protocol.The similarity of these responses following both the Elastic Resistance and Nautilus Machine exercise training session suggests that both modes of training provide a similar training stress; despite a considerably lower external force generation during ER.The data in the present study suggest elastic training is a viable mode of resistance exercise that can provide a training stimulus greater than that employed in rehabilitation settings. PMID- 24149553 TI - Relationship of initial self-regulatory ability with changes in self-regulation and associated fruit and vegetable consumption in severely obese women initiating an exercise and nutrition treatment: moderation of mood and self-efficacy. AB - An emphasis on increasing self-regulation is an alternate to nutrition education, which has had poor results in the behavioral treatment of obesity. Although appropriately designed weight-loss treatments may enhance one's self-regulatory ability to control eating, whether improvements are moderated by psychosocial factors such as initial self-regulatory skills use, self-efficacy to control eating, and mood is unknown. Severely obese women (BMI 35-50 kg.m(-2)) were randomized into 26-week treatments of exercise supported by cognitive-behavioral methods paired with either nutrition education (n = 114) or cognitive-behavioral methods applied to controlled eating (n = 121). Improvement in self-regulation for controlled eating was 36.9% greater (p < 0.01) for the group incorporating cognitive-behavioral methods for controlled eating. Change in self-regulation was significantly associated with self-regulation at baseline (beta = -0.33). Both mood and self-efficacy for controlled eating significantly moderated this relationship. Increased self-regulation was associated with both increases in fruit and vegetable consumption and fruit and vegetable intake at treatment end. The present findings increase our understanding of psychosocial variables associated with increased self-regulatory skills usage and improvements in eating that, after replication, may be used to improve the effects of behavioral weight loss treatments. Key pointsInitial self-regulatory abilities do not appear to affect improvements in self-regulation for eating, however direct training in behavioral skills are predictors of change.The relationship of self-regulation improvements and improved eating is significant, and affected by mood and self efficacy in women with obesity.Instruction in behavioral skills such as cognitive restructuring and relapse prevention is associated with better improvements in eating than typical methods of nutrition education.Cognitive-behavioral methods for exercise may be paired with cognitive-behavioral methods for eating to maximize longer-term effects on eating behaviors. PMID- 24149554 TI - Effects of exercise and caffeic acid phenethyl ester after chronic exercise rat model. AB - In order to understand whether exercise and caffeic acid phenethyl ester (CAPE) has an effect on obesity and weight control, we investigated the effects of CAPE, and exercise on lipid parameters (triglyceride, total cholesterol, HDL-C, LDL-C), and adipokine substances such as leptin and resistin in rats. 40 male rat were randomly assigned into 4 groups. It was determined that CAPE does not have any significant effect on these parameters but that lipid parameters and leptin values in exercise groups decreased considerably, while no significant change occurred in resistin levels. In order to understand whether diet has an effect on exercise, body weights of all animal groups in pre and post-exercise were compared. A significant weight gain was observed (p = 0.005) in all groups. This study concluded that exercise has a considerable effect on leptin and lipid parameters; however, exercise alone was not sufficient for weight control and could be effective in weight control only when accompanied by a restricted diet. Key pointsCaffeic acid phenethyl ester is not effective on weight control, lipid parameters, and adipokine substances such as leptin and resistin.Exercise can be effective in weight control only when accompanied by a restricted diet. PMID- 24149555 TI - Improving Functional Performance and Muscle Power 4-to-6 Months After Anterior Cruciate Ligament Reconstruction. AB - The purpose of this study was to examine the effects of 8-week retraining programs, with either two or three training sessions per week, on measures of functional performance and muscular power in athletes with anterior cruciate ligament reconstruction (ACLR). Sixteen male athletes were randomly assigned to two groups after ACLR: a functional training group (FTG, n = 8) training 2 intense sessions per week (4hrs/week), and a control group (CG, n = 8) training 3 sessions per week with moderate intensity (6hrs/week). The two groups were assessed at four and six months post-ACLR and the effects of retraining were measured using the following assessments: the functional and the muscular power tests, and the agility T-test. After retraining, the FTG had improved more than the CG in the operated leg in the single leg hop test (+34.64% vs. +10.92%; large effect), the five jump test (+8.87% vs. +5.03%; medium effect), and single leg triple jump (+32.15% vs. +16.05%; medium effect). For the agility T-test, the FTG had larger improvements (+17.26% vs. +13.03%, medium effect) as compared to the CG. For the bilateral power tests, no significant training effects were shown for the two groups in the squat jump (SJ), the counter movement jump (CMJ) and the free arms CMJ (Arm CMJ). On the other hand, the unilateral CMJ test with the injured and the uninjured legs showed a significant increase for the FTG with respect to CG (p < 0.05). The present study introduces a new training modality in rehabilitation after ACLR that results in good recovery of the operated limb along with the contra-lateral leg. This may allow the athletes to reach good functional and strength performance with only two physical training sessions per week, better preparing them for a return to sport activity at 6 months post- ACLR and eventually sparing time for a possible progressive introduction of the sport specific technical training. Key pointsFunctional training (plyometrics, neuromuscular, proprioceptive and agility exercises) in athletes during 4th to 6th months post-ACLR further improved functional outcomes, compared to a conventional rehabilitation program.The former program was more time-efficient compared to the latter one as indicated by the weekly training duration (4hrs/week vs. 6hrs/week).This study provides evidence of the functional training in knee rehabilitation and provides important information that is highly relevant to clinicians, physiotherapists, coaches and trainers who are in charge of the injured athletes during the later phase of the rehabilitation after ACLR. PMID- 24149556 TI - Effect of immediate and delayed cold water immersion after a high intensity exercise session on subsequent run performance. AB - The purpose of the study was to determine the effects of cold water immersion (CWI) performed immediately or 3 h after a high intensity interval exercise session (HIIS) on next-day exercise performance. Eight male athletes performed three HIIS at 90%VO2max velocity followed by either a passive recovery (CON), CWI performed immediately post-exercise (CWI(0)) or CWI performed 3 h post-exercise (CWI(3)). Recovery trials were performed in a counter balanced manner. Participants then returned 24 h later and completed a muscle soreness and a totally quality recovery perception (TQRP) questionnaire, which was then followed by the Yoyo Intermittent Recovery Test [level 1] (YRT). Venous blood samples were collected pre-HIIS and pre-YRT to determine C-Reactive Protein (CRP) levels. Significantly more shuttles were performed during the YRT following CWI(0) compared to the CON trial (p=0.017, ES = 0. 8), while differences between the CWI(3) and the CON trials approached significance (p = 0.058, ES = 0.5). Performance on the YRT between the CWI(0) and CWI(3) trials were similar (p = 0.147, ES = 0. 3). Qualitative analyses demonstrated a 98% and 92% likely beneficial effect of CWI(0) and CWI(3) on next day performance, compared to CON, respectively, while CWI(0) resulted in a 79% likely benefit when compared to CWI(3). CRP values were significantly lower pre-YRT, compared to baseline, following CWI(0) (p = 0.0.36) and CWI(3) (p = 0.045), but were similar for CON (p = 0.157). Muscle soreness scores were similar between trials (p = 1.10), while TQRP scores were significantly lower for CON compared to CWI(0) (p = 0.002 ) and CWI(3) (p = 0.024). Immediate CWI resulted in superior next-day YRT performance compared to CON, while delayed (3 h) CWI was also likely to be beneficial. Qualitative analyses suggested that CWI(0) resulted in better performance than CWI(3). These results are important for athletes who do not have immediate access to CWI following exercise. Key pointsPerformance of cold water immersion as a recovery procedure following exercise is better than performing no recovery procedureAthletes, coaches and sport trainers should implement cold water immersion post-exercise irrespective of the time of administration.Where possible, cold water immersion should be performed immediately post-exercise to gain maximal recovery benefits. PMID- 24149557 TI - Effect of dance exercise on cognitive function in elderly patients with metabolic syndrome: a pilot study. AB - Metabolic syndrome is associated with an increased risk of cognitive impairment. The purpose of this prospective pilot study was to examine the effects of dance exercise on cognitive function in elderly patients with metabolic syndrome. The participants included 38 elderly metabolic syndrome patients with normal cognitive function (26 exercise group and 12 control group). The exercise group performed dance exercise twice a week for 6 months. Cognitive function was assessed in all participants using the Korean version of the Consortium to Establish a Registry for Alzheimer's disease (CERAD-K). Repeated-measures ANCOVA was used to assess the effect of dance exercise on cognitive function and cardiometabolic risk factors. Compared with the control group, the exercise group significantly improved in verbal fluency (p = 0.048), word list delayed recall (p = 0.038), word list recognition (p = 0.007), and total CERAD-K score (p = 0.037). However, no significance difference was found in body mass index, blood pressure, waist circumference, fasting plasma glucose, triglyceride, and HDL cholesterol between groups over the 6-month period. In the present study, six months of dance exercise improved cognitive function in older adults with metabolic syndrome. Thus, dance exercise may reduce the risk for cognitive disorders in elderly people with metabolic syndrome. Key pointsMetabolic syndrome (MS) is associated with an increased risk of cognitive impairment.Aerobic exercise improves cognitive function in elderly people and contributes to the prevention of degenerative neurological disease and brain damage. Dance sport is a form of aerobic exercise that has the additional benefits of stimulating the emotions, promoting social interaction, and exposing subjects to acoustic stimulation and music.In the present study, dance exercise for a 6-month period improved cognitive function in older adults with MS. In particular, positive effects were observed in verbal fluency, word list delayed recall, word list recognition, and the total CERAD-K score.Our data suggest that the implementation of dance exercise programs may be an effective means of prevention and treatment of cognitive disorders. PMID- 24149558 TI - Prevalence of obesity in korean adolescents and its relationship with the weekly frequency of the physical education classes. AB - The purpose of this study was to investigate differences in the prevalence of obesity among Korean adolescents and to determine the relationship of obesity prevalence with weekly frequency of physical education (PE) classes. In 2009, 72,399 students from grades 7 to 12 participated in the fifth Korea Youth Risk Behavior Web-based Survey (KYRBWS-V) project. Body mass index (BMI) and the frequency of PE classes attended were assessed by the KYRBWS- V. BMI was computed to classify the participants as underweight, normal weight, overweight, and obese. The association between the frequency of PE classes and BMI were examined using one-way ANOVA and logistic regression analysis. The differences in the weekly frequency of PE classes and the BMI values among both the boys and girls were significant (p < 0.001). A post-hoc test showed that underweight boys and girls attended the PE classes more frequently (p < 0.001), and overweight girls attended these classes less frequently (p < 0.01) than the other groups did; moreover, obese boys and girls, compared to boys and girls in the other groups, attended less number of PE classes per week while at school (p < 0.05). Besides, the odds ratio (95% confidence interval, CI) for normal-weight vs. underweight boys attending 1 PE class, 2 PE classes, and >= 3 PE classes per week were 1.168 (1.011-1.349, p = 0.035), 1.621 (1.450-1.812, p < 0.001), and 3.023 (2.704-3.381, p < 0.001), respectively, compared with those for boys who did not attend PE classes. The OR (95% CI) of normal-weight vs. obese boys attending >= 3 PE classes attended across normal vs. obese boys was 0.862 (0.762-0.974, p = 0.017), compared with those of boys who did not attend PE classes. The OR (95% CI) for normal-weight vs. underweight girls who attended 2 PE classes and >= 3 PE classes per week were 1.235 (1.131-1.349, p < 0.001) and 2.238 (2.048-2.446, p < 0.001), respectively, compared with those of girls who did not attend PE classes. The OR (95% CI) of for normal-weight vs. overweight girls who attended >= 3 PE classes per week were 0.886 (0.787- 0.997, p = 0.045) and 0.772 (0.679-0.878, p < 0.001), respectively, compared with those of girls who did not attend PE classes. The OR (95% CI) for normal-weight vs. obese girls who attended 2 PE classes and >= 3 PE classes per week were 0.788 (0.675-0.919, p = 0.002) and 0.709 (0.599-0.838, p < 0.001), respectively, compared with those of girls who did not attend the PE class. Increase in the frequency of PE classes should be considered in any attempt for curbing weight-related problems in Korean adolescents. Key pointsIncrease in the frequency of PE classes is a factor that should be considered to improve weight status. PMID- 24149559 TI - Obesity-related cardiovascular risk factors after long- term resistance training and ginger supplementation. AB - Obesity and its metabolic consequences are major risk factors for cardiovascular morbidity and mortality. However, lifestyle interventions, including exercise training and dietary components may decrease cardiovascular risk. Hence, this study was conducted to assess the effects of ginger supplementation and progressive resistance training on some cardiovascular risk factors in obese men. In a randomized double-blind design, 32 obese Iranian men (BMI >= 30) were assigned in to one of four groups: Placebo (PL, n = 8); ginger group (GI, n = 8) that consumed 1 gr ginger/d for 10 wk; resistance training plus placebo (RTPL, n = 8); and 1gr ginger plus resistance exercise (RTGI, n = 8). Progressive resistance training was performed three days per week for 10 weeks and included eight exercises. At baseline and after 10 weeks, body composition and anthropometric indices were measured. To identify other risk factors, venous blood samples were obtained before and 48-72 hours after the last training session for measurement of blood lipids (LDL-C, HDL-C, TG), systemic inflammation (CRP), and insulin resistance (HOMA-IR). After 10 weeks both RTGI and RTPL groups showed significant decreases in waist circumference (WC), waist-to-hip ratio (WHR), body fat percent, body fat mass, total cholesterol, and insulin resistance (p < 0.05) and a significant increase in fat free mass (FFM) (p < 0.05), while it remained unchanged in PL and GI. Further, significant decreases in the mean values of CRP were observed in all groups except PL (p < 0.05). Our results reveal that resistance training is an effective therapeutic strategy to reduce cardiovascular risk in obese Iranian men. Further, ginger supplementation alone or in combination with resistance training, also reduces chronic inflammation. However more research on the efficacy of this supplement to reduce cardiovascular risk in humans is required. Key pointsLong- term resistance training reduced cardiovascular risk factors in obese men.Ginger supplementation can also decrease chronic low grade inflammation in obese men.More researches are warranted to elicit the effects of these interventions on cardiovascular risk factors in humans. PMID- 24149560 TI - Effects of a 4-week eccentric training program on the repeated bout effect in young active women. AB - The aim of this study was to analyze the responses of women to the repeated bout effect (RBE) and to a short eccentric training program. Twenty-four young females were randomly assigned to a training group (TG, n = 14) or a control group (CG, n = 10). They performed two identical acute eccentric bouts (120 repetitions at 70% of 1RM) in a leg-press device in an 8 weeks interval. TG followed a 4-week eccentric-training program between the bouts. Maximal isometric contraction, range of motion, peak power and quadriceps muscle soreness were compared between and within groups before and after the two acute eccentric bouts. TG and CG presented significant losses of isometric strength and peak power, and an increment in soreness after the first bout. Isometric strength and peak power were recovered faster in CG after the second bout (p < 0.05) compared with TG, which showed a similar recovery of these parameters after the second bout compared with the first one. A decrease in soreness and a faster recovery of range of motion were found in TG (p < 0.05) following the second bout compared with the first one, but not in CG. Data indicate that a 4-week eccentric training program may prevent the RBE over those adaptations related with muscle damage (e.g. strength loss), but it may increase RBE impact on inflammatory processes (e.g. soreness). Key pointsAn acute bout of eccentric exercise induces losses of strength, peak power and range of motion, and increases muscle soreness in young active women.When the acute eccentric bout is repeated by young women, the losses of strength and power are smaller, indicating less muscle damage. However, muscle pain and range of motion do not present any difference with the results obtained after the first bout, which would indicate that the repeated bout effect does not affect inflammatory response after acute eccentric exercise.Four weeks of eccentric training is enough to increase maximal isometric strength, but not dynamic strength (1RM) or peak power. Furthermore, this training seems to prevent those adaptations provided by the repeated bout effect related with muscle damage. On the other hand, the eccentric training seems to be a positive tool to decrease muscle soreness, and thus the inflammatory response, associated to a repeated acute eccentric bout. PMID- 24149561 TI - The effect of mild symptomatic patellar tendinopathy on the quadriceps contractions and the Fente motion in elite fencers. AB - To investigate how mild symptomatic patellar tendinopathy (PT) affects quadriceps contractions and the Fente motion, this case-control study examined elite fencers who continue to train and play fully with mild tendon pains. Twenty-four elite fencers (10 women) with mild symptomatic PT and 24 controls (10 women) participated in the study. Concentric/eccentric isokinetic strength of the quadriceps was tested, and peak torque and total work were recorded. Kinematic data from the knee during the Fente motion were collected. The first analysis period (P1) was after heel contact to the maximal flexion of the knee, and the second (P2) was right after P1 to heel-off. Normalized peak torque and work of concentric/eccentric contractions were not significantly different. Affected fencers demonstrated significantly reduced angular velocities at P2 (p = 0.042). The male fencers did not demonstrate any differences. The affected female fencers demonstrated significantly weaker concentric peak torque at 60 degrees .s(-1) (p = 0. 009) and 180 degrees .s(-1) (p = 0.047) and less concentric work at 60 degrees .s(-1) (p = 0.020). They also demonstrated significantly reduced average angular velocities at P2 (p = 0.001). Therefore, mild symptomatic PT seems to have an effect on the isokinetic concentric contraction of the quadriceps and the angular velocity of the knee during the backward Fente motion in elite female fencers who are participating fully in training and competition. Key pointsIt is likely that even mild symptomatic patellar tendinopathy could affect the athletic performances in elite fencers.Elite female fencers are more likely to be affected substantially by symptomatic patellar tendinopathy in their sporting ability than male fencers.Because weak concentric knee extensors may affect the performance in fencing, not only eccentric training for symptomatic patellar tendinopathy but also proper concentric training of the quadriceps may be helpful in a rehabilitation program of elite female fencers who are participating fully in their training and competition. PMID- 24149562 TI - The effect of patellar taping on some landing characteristics during counter movement jumps in healthy subjects. AB - The aim of the present study was to determine the effect of patellar taping (PT) on landing characteristics of the vertical ground reaction force (VGRF) and on flight time during a counter movement jump (CMJ). Eleven healthy male subjects (age: 31.1 +/- 4.2 years) volunteered for the study. Each subject performed six CMJs under two different jumping conditions: with PT and without PT (WPT). The order of the two conditions was randomized. All of the measured variables had fair-to-good reliability (intra-class correlation coefficient > 0.75). When we compared the PT and WPT groups, we did not find a significant difference in the magnitude of the first (F1) and second (F2) peaks of the VGRF. We also did not find a significant difference in the time to production of these peaks (T1 and T2), and the time to stabilization (TTS) (p < 0. 05). Furthermore, the flight time was similar in the two groups (0.475 +/- 0.046 and 0.474 +/- 0.056 s, respectively, for PT and WPT). These results suggest that PT does not jeopardize performance during CMJ. Furthermore, it also does not soften the VGRF generated during the landing, indicating that PT may be of limited utility in preventing injuries associated with this type of movement. Key pointsWe investigated whether patellar taping interferes with athletic performance, as has been suggested by previous studies.We also explored the effect of patellar taping on the forces generated during the landing phase of counter movement jumps.Patellar taping had no effect on the flight time during counter movement jumps.Patellar taping also had no effect on the vertical ground reaction force variables measured during the landing phase of counter movement jumps.This information may be relevant to athletes and trainers who are concerned about the effects of patellar taping on performance. PMID- 24149563 TI - Development of a field test for evaluating aerobic fitness in middle-aged adults: validity of a 15-m incremental shuttle walk and run test. AB - The purpose of this study was to develop a standardized and externally paced field test (15-m Incremental Shuttle Walk and Run Test [15mISWRT]), incorporating an incremental and progressive structure, to assess aerobic fitness in middle aged adults. 68 middle-aged men performed three tests in random order between one to two week intervals: 15-m ISWRT, cardiopulmonary exercise test (CPX), and 1500 m fast walk. Variables evaluated were 15-m ISWRT performance (distance completed), VO2max measured by CPX, 1500-m fast walk performance (walking time), and HR response in 15-m ISWRT and 1500-m fast walk. Validity of the 15-m ISWRT was tested by comparing the associations among the 15-m ISWRT performance, VO2max and the 1500-m fast walk performance. Changes in HR response during the 15-m ISWRT and the 1500-m fast walk were also compared. Correlations between each variable were as follows: the correlation between 15- m ISWRT performance and VO2max was very high, r = 0.86 (p < 0.01), the correlation between the 1500-m fast walk and VO2max was r = -0.51 (p < 0.01). HR response during the 15-m ISWRT gently increased initially, whereas HR response during the 1500-m fast walk rapidly increased from the start. In conclusion, our findings indicate that the 15-m ISWRT is valid and safe for evaluating VO2max in middle-aged adults. Key pointsThe 15-m ISWRT is valid and safe for evaluating VO2max in middle-aged adults.In comparison with the 1500-m fast walk, the 15-m ISWRT may be a more favourable field-based assessment of aerobic fitness in the middle-aged adults.The 15-m ISWRT could become a valid means for evaluating aerobic fitness as an alternative to CPX in institutions and situations where CPX is difficult to implement. PMID- 24149564 TI - Water temperature, voluntary drinking and fluid balance in dehydrated taekwondo athletes. AB - Voluntary drinking is one of the major determiners of rehydration, especially as regards exercise or workout in the heat. The present study undertakes to search for the effect of voluntary intake of water with different temperatures on fluid balance in Taekwondo athletes. Six young healthy male Taekwondo athletes were dehydrated by moderate exercise in a chamber with ambient temperature at 38-40 degrees C and relative humidity between 20-30%. On four separate days they were allowed to drink ad libitum plane water with the four temperatures of 5, 16, 26, and 58 degrees C, after dehydration. The volume of voluntary drinking and weight change was measured; then the primary percentage of dehydration, sweat loss, fluid deficit and involuntary dehydration were calculated. Voluntary drinking of water proved to be statistically different in the presented temperatures. Water at 16 degrees C involved the greatest intake, while fluid deficit and involuntary dehydration were the lowest. Intake of water in the 5 degrees C trial significantly correlated with the subject's plasma osmolality change after dehydration, yet it showed no significant correlation with weight loss. In conclusion, by way of achieving more voluntary intake of water and better fluid state, recommending cool water (~16 degrees C) for athletes is in order. Unlike the publicly held view, drinking cold water (~5 degrees C) does not improve voluntary drinking and hydration status. Key pointsFor athletes dehydrated in hot environments, maximum voluntary drinking and best hydration state occurs with 16 degrees C water.Provision of fluid needs and thermal needs could be balanced using 16 degrees C water.Drinking 16 degrees C water (nearly the temperature of cool tap water) could be recommended for exercise in the heat. PMID- 24149565 TI - Effect of different levels of localized muscle fatigue on knee position sense. AB - There is little information available regarding how proprioceptive abilities decline as the amount of exertion increases during exercise. The purpose of this study was to determine the role of different levels of fatigue on knee joint position sense. A repeated measures design was used to examine changes in active joint reposition sense (AJRS) prior to and following three levels of fatigue. Eighteen participants performed knee extension and flexion isokinetic exercise until torque output was 90%, 70%, or 50% of the peak hamstring torque for three consecutive repetitions. Active joint reposition sense at 15, 30, or 45 degrees was tested following the isokinetic exercise session. Following testing of the first independent measure, participants were given a 20 minute rest period. Testing procedures were repeated for two more exercise sessions following the other levels of fatigue. Testing of each AJRS test angle was conducted on three separate days with 48 hours between test days. Significant main effect for fatigue was indicated (p = 0.001). Pairwise comparisons indicated a significant difference between the pre-test and following 90% of peak hamstring torque (p = 0.02) and between the pre-test and following 50% of peak hamstring torque (p = 0.02). Fatigue has long been theorized to be a contributing factor in decreased proprioceptive acuity, and therefore a contributing factor to joint injury. The findings of the present study indicate that fatigue may have an effect on proprioception following mild and maximum fatigue. Key pointsA repeated measures design was used to examine the effect of different levels of fatigue on active joint reposition sense (AJRS) of the knee at joint angles of 15 degrees , 30 degrees and 45 degrees of flexion.A statistically significant main effect for fatigue was found, specifically between no fatigue and mild fatigue and no fatigue and maximum fatigue.A statistically significant interaction effect between AJRS and fatigue was not found.Secondary analysis of the results indicated a potential plateau effect of AJRS as fatigue continues to increase.Further investigation of the effect of increasing levels of fatigue on proprioception is warranted. PMID- 24149566 TI - Injury incidence in a spanish sub-elite professional football team: a prospective study during four consecutive seasons. AB - The aim of this study was to investigate the injury incidence and injury characteristics of a Spanish sub-elite professional football team during four consecutive seasons. A team was followed prospectively from the season 2003-2004 to 2006-2007 and individual player exposure and time loss injuries were recorded during all club training sessions and matches. A total of 313 time-loss injuries were recorded. The mean injury incidence was 10.9 injuries/1000 hours (5.2 injuries/1000 training hours and 44.1 injuries/1000 match hours). The injury incidence during competitive matches was higher (p < 0.001) than in friendly matches (55.8 vs. 22.6 injuries/1000 hours). The incidence of major injuries (>28 days absence) was 0.4 injuries/1000 hours. The thigh was the most commonly (35%) injured region and caused 29% of all competitive match absence. Muscle injuries in the four main groups of the lower limbs (hamstrings, adductors, quadriceps and calf muscles) caused 43% of competitive match unavailability. The results of this study show that the risk to sustain a major injury in the course of the season was low for sub- elite footballers in comparison to elite players. Thigh strains were the first cause of absence in competition due to injury. Key pointsThe incidence of major injuries (absence greater than 4 weeks) was lower in a Spanish sub-elite football team than in elite European teams.The risk of sustaining an injury was 2.5 fold higher (p < 0.001) in official than in friendly matches.Lower limb muscular (hamstrings, quadriceps, hip adductors and calf muscles) and joint (knee and ankle) injuries were the main causes of match unavailability. PMID- 24149567 TI - Inversion/Eversion strength dysbalance in patients with medial tibial stress syndrome. AB - The main purpose of the study is to investigate the inversion/eversion muscle strength balance of the ankle in patients with medial tibial stress syndrome (MTSS). A dysbalance of these muscles may play a role in the pathophysiology of MTSS. Another aim is to measure the medial longitudinal arch and navicular drop in patients with MTSS. A total of 11 patients diagnosed with MTSS in the outpatient clinic of Ege University School of Medicine Sports Medicine Department were enrolled in this study. The control group consisted of 11 regularly exercising individuals. The mean age of the patient group and the control group was 21. 0 +/- 1.9 years (18-23 years) and 23.2 +/- 2.9 years (18-27 years), respectively. A detailed exercise questionnaire was administered to all subjects. Isokinetic muscle strength testing was performed at 30 degrees /sec and 120 degrees /sec to assess invertor and evertor muscle strength of the ankle. Photographs of the weight bearing and non-weight bearing foot were taken to measure the medial longitudinal arch deformation and the navicular drop. At 30 degrees /sec, the average eversion concentric strength was significantly higher in the patient group, and the inversion/eversion strength ratio was significantly higher in the control group (p < 0.05). At 120 degrees /sec velocity, average concentric eversion strength was significantly higher in the patient group (p < 0.05). The measurements of pronation indicators did not reveal any statistically significant differences between the two groups (p > 0.05). MTSS may occur without an increase of pronation indicators like medial longitudinal arch deformation or navicular drop. In such cases, one of the predisposing factors may be the strength dysbalance of the invertor/evertor muscles in favour of the evertor muscles. This observation may be of additional value in the prevention and therapy of MTSS. Key pointsAt 30 degrees /sec, the average eversion concentric strength was significantly higher in the MTSS group, and the inversion/eversion strength ratio was significantly higher in the control group.At 120 degrees /sec velocity, average concentric eversion strength was significantly higher in the MTSS group.MTSS may occur without an increase of pronation indicators like medial longitudinal arch deformation or navicular drop. In such cases, one of the predisposing factors may be the strength dysbalance of the invertor/evertor muscles in favour of the evertor muscles. PMID- 24149568 TI - Tibial bone density in athletes with medial tibial stress syndrome: a controlled study. AB - Medial tibial stress syndrome (MTSS) is a common overuse injury of the lower extremity predominantly observed in weight bearing activities. Knowledge about the pathological lesions and their pathophysiology is still limited. Only a single study was found to have investigated tibial bone density in the pain region, revealing lower density in athletes with long standing (range, 5-120 month) MTSS. In a follow-up study, bone density was determined to return to normal levels after recovery. The purpose of the present study was to investigate tibial bone density in athletes with shorter MTSS history (range, 3-10 weeks). A total of 11 athletes (7 males, 4 females) diagnosed with medial tibial stress syndrome were included in the study. The control group consisted of 11 regularly exercising individuals (7 males, 4 females). Tibial, femoral and vertebral bone densities were measured by dual energy x-ray absorptiometry. Total calcium intake was calculated by evaluating detailed nutrition history. No statistically significant differences were found in the tibial, femoral and vertebral bone densities between the groups. No statistically significant difference was found among groups, considering for calcium intake. Tibial bone densities were not lower in athletes with MTSS of 5.0 weeks mean duration (range, 3-10 weeks) compared to the healthy control group. Longitudinal studies with regular tibial bone density measurements in heavily trained athletes are necessary to investigate tibial density alterations in MTSS developing athletes during the course of the symptoms. Key pointsTibial, femoral and vertebral bone densities were measured by dual energy x-ray absorptiometry.No differences were found between the MTSS group (MTSS history 3-10 weeks) and the healthy athletes group. PMID- 24149569 TI - Physiological responses of elderly recreational alpine skiers of different fitness and skiing abilities. AB - We measured physiological responses of elderly recreational skiers of different fitness and skiing abilities. Six subjects (mean age: 61.2 +/- 4.6 yrs; Wt: 76.8 +/- 15.6 kg; Ht: 1.69 +/- 0.10 m; BMI: 26.9 +/- 5.0) were tested in a laboratory and during 30 and 75 min of recreational downhill skiing. Oxygen uptake (VO2), heart rate (HR), blood lactate (LA) concentration, and diastolic (DBP) and systolic (SBP) blood pressure were used to estimate energy demands while skiing. During maximal testing in a laboratory, subjects achieved a mean maximal VO2max of 28.2 +/- 7.5 ml.kg(-1).min(-1) and a mean HRpeak of 165 +/- 4 bpm (98 +/- 1% of HRmax). Mean maximal workload measured on a cycle ergometer was 2.2 +/- 0.7 W.kg(-1) with a mean LApeak of 7.4 +/- 1 mmol.l(-1). During field testing, mean VO2 during skiing was 12 +/- 2 ml.kg(-1).min(-1) (45 +/- 16% of VO2max). Skiing VO2peak was 19 +/- 5 ml. kg(-1).min(-1) (72 +/- 23% of VO2max) was lower than VO2max in the lab (p = 0.04). Mean HR during skiing was 126 +/- 2 bpm (77 +/- 1% of HRmax from lab tests). Skiing HRpeak was 162 +/- 2 bpm. This was not different from HRmax in the lab (p = 0.68). Mean LA after 30 and 75 min of skiing was not different (2.2 +/- 0.8 mmol.l(-1) and 2.0 +/- 0.8, respectively, p = 0.71). Both LA samples during skiing were lower than lab tests (p < 0.0001). There was no difference for DBP between field and laboratory tests; however, SBP increased after 30 min of skiing to 171 +/- 20 (p < 0.009) and 165 +/- 17 (p < 0.003) after 75 min. These remained below the mean peak SBP determined in lab tests (218+31). Mean oxygen demand during 30 and 75 min of recreational skiing is only 45% of VO2max while mean HR is 77% of HRmax. This departure from linearity not often seen in typical aerobic activities suggests that alpine skiing requires a combination of aerobic and anaerobic activity. Blood LA remained low during skiing suggesting that elderly skiers may govern their intensity via signals closer to VO2 and LA compared to HR or BP. Key pointsRecreational Alpine skiing for elderly population does not pose health risksBlood pressure and heart rate during recreational Alpine skiing is retain within normal limitsBlood lactate levels remain relatively low and do not contribute to fatigueOxygen uptake and blood lactate are better markers of intensity in elderly Alpine skier compared to heart rate and blood pressure. PMID- 24149570 TI - A comparison of ground reaction forces determined by portable force-plate and pressure-insole systems in alpine skiing. AB - For the determination of ground reaction forces in alpine skiing, pressure insole (PI) systems and portable force plate (FP) systems are well known and widely used in previous studies. The purposes of this study were 1) to provide reference data for the vertical component of the ground reaction forces (vGRF) during alpine skiing measured by the PI and FP systems, and 2) to analyze whether the differences in the vGRF measured by the PI and the FP depend on a skier's level, skiing mode and pitch. Ten expert and ten intermediate level skiers performed 10 double turns with the skiing technique "Carving in Short Radii" as High Dynamic Skiing mode and "Parallel Ski Steering in Long Radii" as Low Dynamic Skiing mode on both the steep (23 degrees ) and the flat (15 degrees ) slope twice. All subjects skied with both the PI and the FP system simultaneously. During the outside phase, the mean vGRF and the maximum vGRF determined by the FP are greater than the PI (p < 0.01). Additionally during the inside phase, the mean vGRF determined by the FP were greater than the PI (p < 0.01). During the edge changing phases, the mean vGRF determined by the FP were greater than the PI (p < 0.01). However, the minimum vGRF during the edge changing phases determined by the FP were smaller than the PI (p < 0.01) in the High-Steep skiing modes of Experts and Intermediates (p < 0.001). We have found that generally, the PI system underestimates the total vGRF compared to the FP system. However, this difference depends not only the phase in the turn (inside, outside, edge changing), but also is affected by the skier's level, the skiing mode performed and pitch. Key pointsTypically, during the steering phases of the ski turns the total vGRFs measured by the pressure-insole system were lower compared to the portable force-plate system.However, in some skiing modes during the edge changing phase, the pressure-insole system overestimates the total vGRF compared to the portable force-plate system.Differences between the forces determined by the both systems depend on the phase in the turn (inside, outside, edge changing) and are affected additionally by the skier's level, the performed skiing mode and pitch. PMID- 24149571 TI - Posterior tibial slope as a risk factor for anterior cruciate ligament rupture in soccer players. AB - Anterior cruciate ligament (ACL) is the primary stabilizer of the knee. An impairment of any of the dynamic or static stability providing factors can lead to overload on the other factors and ultimately to deterioration of knee stability. This can result in anterior tibial translation and rupture of the ACL. The purpose of this study was to examine the influence of tibial slope on ACL injury risk on soccer players. A total of 64 elite soccer players and 45 sedentary controls were included in this longitudinal and controlled study. The angle between the tibial mid-diaphysis line and the line between the anterior and posterior edges of the medial tibial plateau was measured as the tibial slope via lateral radiographs. Individual player exposure, and injuries sustained by the participants were prospectively recorded. Eleven ACL injuries were documented during the study period. Tibial slope was not different between soccer players and sedentary controls. Tibial slope in the dominant and non-dominant legs was greater for the injured players compared to the uninjured players. The difference reached a significant level only for the dominant legs (p < 0.001). While the tibial slopes of the dominant and non-dominant legs were not different on uninjured players (p > 0.05), a higher tibial slope was observed in dominant legs of injured players (p < 0.05). Higher tibial slope on injured soccer players compared to the uninjured ones supports the idea that the tibial slope degree might be an important risk factor for ACL injury. Key pointsDominant legs' tibial slopes of the injured players were significantly higher compared to the uninjured players (p < 0.001).Higher tibial slope was determined in dominant legs compared to the non-dominant side, for the injured players (p = 0.042). Different tibial slope measures in dominant and non-dominant legs might be the result of different loading and/or adaptation patterns in soccer. PMID- 24149572 TI - Exercise-related bilateral leg atypical claudication in female olympic taekwondo player: a case report. AB - We report the case of an Olympic taekwondo athlete with an atypical bilateral intermittent claudication that represented a handicap in her performance during competition fight. Diagnosis of chronic compartment syndrome was established by confirmation of compartment hypertension and the patient was submitted to fasciectomy. Recurrence of symptoms like numbness or tingling after 6 months raised the suspicion of deep compartmental hypertension that, once confirmed, was treated by a repeat deep fasciectomy. New symptoms appeared 4 months after surgery but no hypertension in the compartment was detected. Functional popliteal artery entrapment syndrome (FPAES) was suspected, an unusual form of this syndrome, in which a hypertrophic plantaris tendon as the cause of the entrapment was observed. Resection of the band was performed in a third operation. The patient evolved favourably, maintaining high competition level. Key pointsWe need a thorough clinical examination to reach a satisfactory clinical diagnosis.FPAES is an uncommon disease that is frequently misdiagnosed and overlooked.Dynamic tests are essential for diagnosis de FPAES. PMID- 24149574 TI - A Bayesian-optimized spline representation of the electrocardiogram. AB - We introduce an implementation of a novel spline framework for parametrically representing electrocardiogram (ECG) waveforms. This implementation enables a flexible means to study ECG structure in large databases. Our algorithm allows researchers to identify key points in the waveform and optimally locate them in long-term recordings with minimal manual effort, thereby permitting analysis of trends in the points themselves or in metrics derived from their locations. In the work described here we estimate the location of a number of commonly-used characteristic points of the ECG signal, defined as the onsets, peaks, and offsets of the P, QRS, T, and R' waves. The algorithm applies Bayesian optimization to a linear spline representation of the ECG waveform. The location of the knots-which are the endpoints of the piecewise linear segments used in the spline representation of the signal-serve as the estimate of the waveform's characteristic points. We obtained prior information of knot times, amplitudes, and curvature from a large manually-annotated training dataset and used the priors to optimize a Bayesian figure of merit based on estimated knot locations. In cases where morphologies vary or are subject to noise, the algorithm relies more heavily on the estimated priors for its estimate of knot locations. We compared optimized knot locations from our algorithm to two sets of manual annotations on a prospective test data set comprising 200 beats from 20 subjects not in the training set. Mean errors of characteristic point locations were less than four milliseconds, and standard deviations of errors compared favorably against reference values. This framework can easily be adapted to include additional points of interest in the ECG signal or for other biomedical detection problems on quasi-periodic signals. PMID- 24149573 TI - Homeland security in the C. elegans germ line: insights into the biogenesis and function of piRNAs. AB - While most eukaryotic genomes contain transposable elements that can provide select evolutionary advantages to a given organism, failure to tightly control the mobility of such transposable elements can result in compromised genomic integrity of both parental and subsequent generations. Together with the Piwi subfamily of Argonaute proteins, small, non-coding Piwi-interacting RNAs (piRNAs) primarily function in the germ line to defend the genome against the potentially deleterious effects that can be caused by transposition. Here, we describe recent discoveries concerning the biogenesis and function of piRNAs in the nematode Caenorhabditis elegans, illuminating how the faithful production of these mature species can impart a robust defense mechanism for the germ line to counteract problems caused by foreign genetic elements across successive generations by contributing to the epigenetic memory of non-self vs. self. PMID- 24149575 TI - Allosteric coupling of the inner activation gate to the outer pore of a potassium channel. AB - In potassium channels, functional coupling of the inner and outer pore gates may result from energetic interactions between residues and conformational rearrangements that occur along a structural path between them. Here, we show that conservative mutations of a residue near the inner activation gate of the Shaker potassium channel (I470) modify the rate of C-type inactivation at the outer pore, pointing to this residue as part of a pathway that couples inner gate opening to changes in outer pore structure and reduction of ion flow. Because they remain equally sensitive to rises in extracellular potassium, altered inactivation rates of the mutant channels are not secondary to modified binding of potassium to the outer pore. Conservative mutations of I470 also influence the interaction of the Shaker N-terminus with the inner gate, which separately affects the outer pore. PMID- 24149577 TI - Clinical aspects and indications for endovenous treatments for varicose veins. AB - Endovenous laser treatment has been around for more than a decade. A brief history of circumstances that have made this treatment modality possible is provided. PMID- 24149576 TI - Akt-p53-miR-365-cyclin D1/cdc25A axis contributes to gastric tumorigenesis induced by PTEN deficiency. AB - Although PTEN/Akt signaling is frequently deregulated in human gastric cancers, the in vivo causal link between its dysregulation and gastric tumorigenesis has not been established. Here we show that inactivation of PTEN in mouse gastric epithelium initiates spontaneous carcinogenesis with complete penetrance by 2 months of age. Mechanistically, activation of Akt suppresses the abundance of p53, leading to decreased transcription of miR-365, thus causing upregulation of cyclin D1 and cdc25A, which promotes gastric cell proliferation. Importantly, genetic ablation of Akt1 restores miR-365 expression and effectively rescues gastric tumorigenesis in PTEN-mutant mice. Moreover, orthotopic restoration of miR-365 represses PTEN-deficient-induced hyperplasia. In human gastric cancer tissues, miR-365 reduction correlates with poorly differentiated histology, deep invasion and advanced stage, as well as the deregulation of PTEN, phosphorylated Akt, p53, cyclin D1 and cdc25A. These data demonstrate that the PTEN-Akt-p53-miR 365-cyclin D1/cdc25A axis serves as a new mechanism underlying gastric tumorigenesis, providing potential new therapeutic targets. PMID- 24149578 TI - Efficacy of different treatments of root canal walls on the pull-out bond strength of the fiber posts. AB - The aim of this study was to evaluate the efficacy of different irrigation protocols, including laser, on the retention of the fiber-reinforced composite posts to root canal dentinal walls using pull-out tests. Root canals of 60 single rooted human teeth were filled and post spaces were prepared. Finally, specimens were divided randomly into five groups, each consisting of 12 specimens as follows: 5% NaOCl (control group), 17% EDTA, ultrasonic with 17% EDTA, single 1.5 W Er:YAG laser application, and the combined use of Er:YAG laser and 17% EDTA. After the root canal procedures, fiber posts were cemented to the root canal. Pull-out tests were performed using a universal testing machine at a crosshead speed of 2 mm/min. The data were analyzed using a one-way ANOVA and Bonferroni post hoc test (p = 0.05). Irradiation by the Er:YAG laser with/without EDTA positively affected the pull-out bond strength (p < 0.001). The pull-out strength was significantly higher in the ultrasonic group than that of the single irrigation with NaOCl or EDTA (p < 0.001). Er:YAG laser irradiation with/without EDTA enhanced the bond strength of fiber posts to root canal dentin walls. Additionally, ultrasonic-EDTA combination increased the bond strength. PMID- 24149579 TI - Effect of pretreatment with an Er:YAG laser and fluoride on the prevention of dental enamel erosion. AB - The aim of this study was to evaluate the effect of the Er:YAG laser and its association with fluoride (1.23% acidulate phosphate fluoride gel) on the prevention of enamel erosion. Sixty specimens were obtained from bovine enamel (4 * 4 mm), which were ground flat, polished, and randomly divided into five groups according to the preventive treatments: control-fluoride application; L--Er:YAG laser; L+F--laser + fluoride; F+L--fluoride + laser; L/F--laser/fluoride simultaneously. Half of the enamel surface was covered with nail varnish (control area), and the other half was pretreated with one of the preventive strategies to subsequently be submitted to erosive challenge. When the laser was applied, it was irradiated for 10 s with a focal length of 4 mm and 60 mJ/2 Hz. Fluoride gel was applied for 4 min. Each specimen was individually exposed to regular Coca Cola(r) for 1 min, four times/day, for 5 days. Wear analysis was performed with a profilometer, and demineralization was assessed with an optical microscope. Data were analyzed using the Kruskal-Wallis test (wear)/Dunn test and ANOVA/Fisher's exact tests. The group L/F was similar to control group. The other groups showed higher wear, which did not present differences among them. In the demineralization assessment, the groups F+L and L/F showed lower demineralization in relation to the other groups. It can be concluded that none preventive method was able to inhibit dental wear. The treatments L/F and F+L showed lower enamel demineralization. PMID- 24149580 TI - A randomized controlled trial of the efficacy and respiratory effects of patient controlled intravenous remifentanil analgesia and patient-controlled epidural analgesia in laboring women. AB - BACKGROUND: Safe and effective alternatives are required in labor when epidural analgesia is not appropriate. We hypothesized that patient-controlled IV remifentanil labor analgesia would not be inferior to patient-controlled epidural labor analgesia. METHODS: This randomized nonblinded controlled noninferiority study in healthy women with a singleton fetus and vertex presentation was performed at 1 site. Women were randomized to receive patient-controlled IV analgesia titrated from 20 mcg up to a maximum bolus dose of 60 mcg with a lockout interval of 1 to 2 minutes, or patient-controlled epidural analgesia 0.1% bupivacaine with 2 mcg/mL fentanyl (initiation bolus 15 mL; maintenance bolus 10 mL, lockout interval 20 minutes, basal infusion 5 mL/h). Crossover was permitted after 30 minutes. The primary study outcome was efficacy (assessed as hourly numerical rating scale [NRS] pain score [11-point NRS] and maternal satisfaction [11-point NRS]); the secondary outcome was safety (maternal apnea). Supplementary oxygen was administered continuously during the respiratory monitoring period. During the first hour of analgesia, the heart rate, respiratory rate, pulse oximetry (SpO2), and end-tidal CO2, as an indication of apnea, were compared. Apnea lasting >40 seconds was managed by light stimulation by the attending anesthesiologist. RESULTS: Forty women were recruited to the following groups: remifentanil n = 19 (1 exclusion), epidural n = 20. Four crossed over: 3 from the remifentanil to epidural group and 1 from the epidural to remifentanil group. Mean (+/- SD) baseline NRS pain scores were similar, 8.4 +/- 1.5 for remifentanil and 8.7 +/- 1.2 for epidural analgesia, P = 0.52. Baseline adjusted mean NRS reduction at 30 minutes for remifentanil was -4.5 (+/- 0.6) vs -7.1(+/- 0.6) for epidural analgesia, P < 0.0001 for both. Pain score at 30 minutes was 3.7 +/- 2.8 for remifentanil and 1.5 +/- 2.2 for epidural analgesia, P = 0.009. Remifentanil was inferior to epidural analgesia with respect to the NRS at all time points, because the observed difference in NRS was greater than the expected -1.5 units. Maternal satisfaction was 8.6 +/- 1.4 for the remifentanil group and 9.1 +/- 1.5 for epidural group, P = 0.26. Mean respiratory rate was lower in the remifentanil group, 18 +/- 4 vs 21 +/- 4 breaths/min in the epidural group, P = 0.03. Mean SpO2 was lower in the remifentanil group 96.8% +/- 1.4 vs 98.4 +/- 1.2 for epidural group, P < 0.0001. There were 9 apnea events; all occurred in 5 women receiving remifentanil (5/19 [26.3%], P = 0.046). Apgar scores and neonatal respiratory outcomes were similar. CONCLUSION: IV remifentanil is inferior to epidural analgesia for provision of labor analgesia; however, remifentanil does provide a satisfactory level of labor analgesia. Laboring women receiving remifentanil require suitable monitoring to detect and alert for apnea. PMID- 24149582 TI - Examination of publications from academic anesthesiology faculty in the United States. AB - BACKGROUND: Leaders in academic anesthesiology in the United States have called for an examination of the state of scholarship within anesthesiology departments. National Institutes of Health funding and publication quality of subsets of U.S anesthesiologists have been examined; however, the publication output of and the demographic characteristics that are associated with academic anesthesiologists, defined as faculty associated with a medical college, are unknown. A database from the American Association of Medical Colleges containing demographic information of all academic anesthesiologists in the United States was used to examine the publication output and demographic characteristics of anesthesiology faculty during a 2-year period from 2006 to 2008. METHOD: All the publications found in the PubMed database for each faculty member were retrieved and included in a database containing their demographics including institution, gender, academic degree, academic rank, nature of appointment (part versus full-time), status of appointment (joint versus primary), departmental division, subspecialty certification status, and additional graduate medical education training. RESULTS: Six thousand one hundred forty-three faculty who held positions at the 108 U.S. academic anesthesiology programs published 8521 manuscripts between 2006 and 2008. Thirty-seven percent of faculty published a manuscript, and the overall median publication rate was 0. The proportion of faculty with at least 1 publication was larger among faculty with higher rank (Odds Ratio [OR] for professors versus instructors = 6.4; confidence interval [CI], 4.57-8.49; P < 0.0001), male gender (OR 1.3; CI, 0.14-1.47; P < 0.0001), possessing a courtesy appointment status (OR 2.1; CI, 1.25-3.52; P = 0.0048) and lacking postgraduate training and subspecialty certification (OR for MD versus MD w/training + certification 1.3; CI, 1.11-1.60; P = 0.0020). Those faculty with an MD had lower probablility of publishing when compared with MD/PhD or PhD faculty (OR 0.45; CI, 0.32-0.65; P < 0.0001; OR 0.27; CI, 0.20-0.37; P < 0.0001, respectively). Within the group of faculty who published at least 1 paper, full professor faculty had 3.8 times more publications than instructors (CI, 2.99-4.88; P < 0.0001), and those who lacked postgraduate training had 1.4 times more publications than those who were trained and certified (CI, 1.16-1.78; P = 0.0009). PhD degree (P = 0.006), male gender (P = 0.013), and courtesy anesthesia appointment (P = 0.037) also were associated with higher publication rates. CONCLUSIONS: The overall publication rate of anesthesiologists associated with medical schools was low in this time period. These data establish the pre-"call to action" baseline of scholarly activity by U.S. academic anesthesiologists for future comparisons. Increased use of structured resident and fellow research education programs as well as recruiting more MD/PhD and PhD scientists to the field may help to improve the publication productivity of academic anesthesiology departments. PMID- 24149581 TI - The bundle "plus": the effect of a multidisciplinary team approach to eradicate central line-associated bloodstream infections. AB - BACKGROUND: Central line-associated bloodstream infections (CLABSIs) have decreased significantly over the last decade. Further reductions in CLABSI rates should be possible. We describe a multidisciplinary approach to the reduction of CLABSIs. METHODS: This was an observational study of critically ill patients requiring central venous catheters in 8 intensive care units in a tertiary medical center. We implemented a catheter bundle that included hand hygiene, education of providers, chlorhexidine skin preparation, use of maximum barrier precautions, a dedicated line cart, checklist, avoidance of the femoral vein for catheter insertion, chlorhexidine-impregnated dressings, use of anti-infective catheters, and daily consideration of the need for the catheter. Additional measures included root cause analyses of all CLABSIs, creation of a best practice atlas for internal jugular catheters, and enhanced education on blood culture collection. Data were analyzed using the Poisson test and regression. RESULTS: CLABSI, catheter use, and microbiology were tracked from 2004 to 2012. There was a 92% reduction in CLABSIs (95% lower confidence limit: 67.4% reduction, P < 0.0001). Central venous catheter use decreased significantly from 2008 to 2012 (P = 0.032, -151 catheters per year, 95% confidence limits: -277 to -25), whereas peripherally inserted central catheter use increased (P = 0.005, 89 catheters per year, 95% confidence limits: 50 to 127). There was no apparent association between unit-specific Acute Physiology And Chronic Health Evaluation III/IV scores and CLABSI. Three units have not had a CLABSI in more than a year. The most common organism isolated was coagulase-negative staphylococcus. Since the implementation of minocycline/rifampin catheters, no cases of methicillin resistant Staphylococcus aureus CLABSI have occurred. CONCLUSIONS: The implementation of a standard catheter bundle combined with chlorhexidine dressings, minocycline/rifampin catheters, and other behavioral changes was associated with a sustained reduction in CLABSIs. PMID- 24149583 TI - Peripheral quantitative computed tomography (pQCT) to assess bone health in children, adolescents, and young adults: a review of normative data. AB - The bone health of adults is dependent on the appropriate acquisition of peak bone mineral mass during late childhood and adolescence. Measurement of bone mineral density (BMD) in clinical practice is accomplished usually by dual energy x-ray absorptiometry that provides 2-dimensional (areal) values for BMD, does not distinguish cortical from trabecular bone, and should be adjusted for height and weight when used for children and adolescents. Peripheral quantitative computed tomography (pQCT) provides volumetric measures of BMD and geometry in both cortical and trabecular bone and, unlike dual energy x-ray absorptiometry, does not need adjustment for body size. Studies of bone health in young people require reference data for normative comparison. A literature review from 1946 to 2012 identified 1886 titles suggesting use of pQCT, with only 32 reporting some form of normative data. A detailed review of these 32 reports revealed a lack of consensus among users for standard scan locations in upper and lower limbs, acquisition protocols and analytical steps, and variables reported. Meaningful and effective use of pQCT for assessing bone strength and overall bone health in all age groups will require better defined normative data derived with common measuring techniques, equipment, and analytical approaches. PMID- 24149586 TI - Orotate containing anionic luminescent iridium(III) complexes and their use in soft salts. AB - Two anionic iridium complexes [(R-ppy)2Ir(O^N)]TBA with R-ppy = 2-phenylpyridine or 4,5'-dimethyl-2-phenylpyridine, O^N = dianionic form of orotic acid and TBA = tetrabutylammonium have been synthesised and fully characterised by UV-Vis, emission, IR, NMR and cyclic voltammetric studies. These cyclometallated luminescent complexes containing a dianionic bidentate ancillary ligand show bright emission (60-70% PLQY) with maxima in the green region of the visible spectrum. Coupled with the ionic iridium complexes [(ppy)2Ir(N^N)]X, where N^N = 2-picolylamine or 2,2'-bipyridyl, and X = Cl(-) or CH3CO2(-), a series of new soft salts of general formula [(ppy)2Ir(N^N)][(R-ppy)2Ir (O^N)] have been obtained and fully characterized, with enhanced luminescent properties up to ca. 80% of phosphorescence quantum yields. PMID- 24149584 TI - REST/NRSF-mediated intrinsic homeostasis protects neuronal networks from hyperexcitability. AB - Intrinsic homeostasis enables neuronal circuits to maintain activity levels within an appropriate range by modulating neuronal voltage-gated conductances, but the signalling pathways involved in this process are largely unknown. We characterized the process of intrinsic homeostasis induced by sustained electrical activity in cultured hippocampal neurons based on the activation of the Repressor Element-1 Silencing Transcription Factor/Neuron-Restrictive Silencer Factor (REST/NRSF). We showed that 4-aminopyridine-induced hyperactivity enhances the expression of REST/NRSF, which in turn, reduces the expression of voltage-gated Na(+) channels, thereby decreasing the neuronal Na(+) current density. This mechanism plays an important role in the downregulation of the firing activity at the single-cell level, re-establishing a physiological spiking activity in the entire neuronal network. Conversely, interfering with REST/NRSF expression impaired this homeostatic response. Our results identify REST/NRSF as a critical factor linking neuronal activity to the activation of intrinsic homeostasis and restoring a physiological level of activity in the entire neuronal network. PMID- 24149587 TI - Detector-induced backaction on the counting statistics of a double quantum dot. AB - Full counting statistics of electron transport is of fundamental importance for a deeper understanding of the underlying physical processes in quantum transport in nanoscale devices. The backaction effect from a detector on the nanoscale devices is also essential due to its inevitable presence in experiments. Here we investigate the backaction of a charge detector in the form of a quantum point contact (QPC) on the counting statistics of a biased double quantum dot (DQD). We show that this inevitable QPC-induced backaction can have profound effects on the counting statistics under certain conditions, e.g., changing the shot noise from being sub-Poissonian to super-Poissonian, and changing the skewness from being positive to negative. Also, we show that both Fano factor and skewness can be either enhanced or suppressed by increasing the energy difference between two single-dot levels of the DQD under the detector-induced backaction. PMID- 24149588 TI - The sports science of curling: a practical review. AB - Curling is a sport played on ice in which two teams each deliver 8 granite stones towards a target, or 'house'. It is the only sport in which the trajectory of the projectile can be influenced after it has been released by the athlete. This is achieved by sweeping the ice in front of the stone to change the stone-ice friction and thereby enable to stone to travel further, curl more or stay straight. Hard sweeping is physically demanding. Different techniques of sweeping can also have different effects on the stone. This paper will review the current research behind sweeping a curling stone, outline the physiological demands of sweeping, the associated performance effects and suggest potential strategies of sweeping that can be used by both coaches and curling teams. Key pointsSweeping a curling stone can be highly physically demanding.Effective sweeping requires a combination of downward force and brush head speed, determined by the stone velocity.Sweeping on the left or right of a stone can help the stone to remain straight or curl more depending on the rotation of the stone.This can lead to the development of sweeping and playing tactics and contribute to team selection. PMID- 24149589 TI - Does the Level of Graphical Detail of a Virtual Handball Thrower Influence a Goalkeeper's Motor Response? AB - The authors investigated how different levels of detail (LODs) of a virtual throwing action can influence a handball goalkeeper's motor response. Goalkeepers attempted to stop a virtual ball emanating from five different graphical LODs of the same virtual throwing action. The five levels of detail were: a textured reference level (L0), a non-textured level (L1), a wire-frame level (L2), a point light-display (PLD) representation (L3) and a PLD level with reduced ball size (L4). For each motor response made by the goalkeeper we measured and analyzed the time to respond (TTR), the percentage of successful motor responses, the distance between the ball and the closest limb (when the stopping motion was incorrect) and the kinematics of the motion. Results showed that TTR, percentage of successful motor responses and distance with the closest limb were not significantly different for any of the five different graphical LODs. However the kinematics of the motion revealed that the trajectory of the stopping limb was significantly different when comparing the L1 and L3 levels, and when comparing the L1 and L4 levels. These differences in the control of the goalkeeper's actions suggests that the different level of information available in the PLD representations (L3 and L4) are causing the goalkeeper to adopt different motor strategies to control the approach of their limb to stop the ball. Key pointsVirtual reality technology can be used to analyze sport performance because it enables standardization and reproduction of sport situations.Defining a minimal graphical level of detail of a virtual action could decrease the real time calculation of a virtual reality system.A Point Light Display graphical representation of a virtual throwing motion seems to influence the regulation of action of real handball goalkeepers. PMID- 24149590 TI - Effect of BETA 1, 3/1, 6 GLUCAN on Upper Respiratory Tract Infection Symptoms and Mood State in Marathon Athletes. AB - This was a placebo-controlled, double-blind study designed to evaluate the effect of a commercially available dietary supplement on upper-respiratory tract symptoms (URTI) and mood state. Seventy-five marathon runners (35 men, 40 women) ranging in age from 18-53 years, mean age: 36 +/- 9, self-administered placebo, 250 mg or 500 mg of BETA 1,3/1,6 GLUCAN (commercial name Wellmune WGP((r))) daily during the 4 week post-marathon trial period following the 2007 Carlsbad Marathon. Subjects filled out the profile of mood state (POMS) assessment and a questionnaire style health log measuring health status and URTI symptoms after 2- and 4-week treatment administrations. During the course of the 4-week study, subjects in the treatment groups (250 mg and 500 mg BETA-GLUCAN per day) reported significantly fewer URTI symptoms, better overall health and decreased confusion, fatigue, tension, and anger, and increased vigor based on the POMS survey compared to placebo. BETA-GLUCAN may prevent URTI symptoms, and improve overall health and mood following a competitive marathon. Key pointsBeta-Glucan supplementation maintains immune function in endurance athletes.Beta-Glucan supplementation reduces post-exercise URTIs in marathon runners.Maintenance of post-exercise immune function is associated with improved mood state, including reduced fatigue and increased vigor in athletes. PMID- 24149591 TI - The effects of Creatine Long-Term Supplementation on Muscle Morphology and Swimming Performance in Rats. AB - Creatine (Cr) has been shown to increase the total muscle mass. The purpose of this study was to investigate the effect of Cr supplementation on muscle morphology and swimming performance, using an animal model. Each rat was subjected to exercise 15-minute period daily for the 12 weeks. The rats were randomly divided into four groups: no Cr supplementation (CON), no Cr supplementation and incomplete food intake (lacking lysine and methionine in diet for rats) (INCO), Cr supplementation 1 g.kg(-1).day(-1) (CREAT-I) and Cr supplementation 2 g.kg(-1).day(-1) (CREAT-II). Three months later, all groups adult rats exercised in swimming pool chambers. Swimming time was recorded as minute for each rat. Following swimming performance period, the animals were killed by cervical dislocation and the gastrocnemius and diaphragm muscles were dissected. Serial slices of 5-7 MUm were allocated paraffin wax and histochemical staining procedure of cross-sections was carried out with heamatoxylin-eosin technics. All groups gained body weight at the end of 12 weeks but there was no statistical difference among them. Swimming time values were statistical difference between CREAT-II and CON group as well as between CREAT-I and CON group (p < 0.05). In the INCO group was determined increased connective tissue cell of the muscle sample. In contrast, in the CREAT-I and CREAT-II group, the basic histological changes were large-scale muscle fibers and hypertrophic muscle cells. These results suggest that long-term creatine supplementation increased the number of muscle fibers and enhanced endurance swimming performance in rats. Key pointsThere is no study about the effects of creatine long-term supplementation on muscle morphology and swimming performance in rats.Long-term creatine supplementation increase muscle hypertrophy (but not body weight) and enhance endurance swimming performance in rats.The quantitative analysis indicated that the number of muscle fibers per defined area increased in creatine supplementation groups. PMID- 24149592 TI - Differences in game statistics between winning and losing rugby teams in the six nations tournament. AB - The objective of the present study was to analyze the differences in rugby game statistics between winning and losing teams. The data from 58 games of round robin play from the Six Nations tournament from the 2003-2006 seasons were analyzed. The groups of variables studied were: number of points scored, way in which the points were scored; way teams obtained the ball and how the team used it; and technical and tactical aspects of the game. A univariate (t-test) and multivariate (discriminant) analysis of data was done. Winning teams had average values that were significantly higher in points scored, conversions, successful drops, mauls won, line breaks, possessions kicked, tackles completed, and turnovers won. Losing teams had significantly higher averages for the variables scrums lost and line-outs lost. The results showed that: a) in the phases of obtaining the ball and more specifically in scrummage and line-out, winning teams lose fewer balls than losing teams (winning teams have an efficacy of 90% in both actions); b) the winning team tends to play more with their feet when they obtain the ball, to utilize the maul as a way of attacking, and to break the defensive line more often than the losing team does; and c) On defence, winning teams recovered more balls and completed more tackles than losing teams, and the percentage of tackles completed by winning teams was 94%. The value presented could be used as a reference for practice and competition in peak performance teams. Key pointsThis paper increases the knowledge about rugby match analysis.Give normative values to establish practice and match goals.Give applications ideas to connect research with coaches practice. PMID- 24149593 TI - Familiarisation and reliability of sprint test indices during laboratory and field assessment. AB - The aim of the study was to assess the reliability of sprint performance in both field and laboratory conditions. Twenty-one male (mean +/- s: 19 +/- 1 years, 1.79 +/- 0.07 m, 77.6 +/- 7.1 kg) and seventeen female team sport players (mean +/- s: 21 +/- 4 years, 1.68 +/- 0. 07 m, 62.7 +/- 4.7 kg) performed a maximal 20 metre sprint running test on eight separate occasions. Four trials were conducted on a non-motorised treadmill in the laboratory; the other four were conducted outdoors on a hard-court training surface with time recorded by single-beam photocells. Trials were conducted in random order with no familiarisation prior to testing. There was a significant difference between times recorded during outdoor field trials (OFT) and indoor laboratory trials (ILT) using a non motorised treadmill (3.47 +/- 0.53 vs. 6.06 +/-1.17s; p < 0.001). The coefficient of variation (CV) for time was 2.55-4.22% for OFT and 5.1-7.2% for ILT. During ILT peak force (420.9 +/- 87.7N), mean force (147.2 +/- 24.7N), peak power (1376.8 +/- 451.9W) and mean power (514.8 +/- 164.4W), and were measured. The CV for all ILT variables was highest during trial 1-2 comparison. The CV (95% confidence interval) for the trial 3-4 comparison yielded: 9.4% (7.7-12. 1%), 7.9% (6.4-10.2%), 10.1% (8.2-13.1%) and 6.2% (5.1-8.0%) for PF, MF, PP and MP and respectively. The results indicate that reliable data can be derived for single maximal sprint measures, using fixed distance protocols. However, significant differences in time/speed over 20-m exist between field and laboratory conditions. This is primarily due to the frictional resistance in the non- motorised treadmill. Measures of force and power during ILT require at least 3 familiarisations to reduce variability in test scores. Key pointsReliable data can be derived from single maximal sprint measures in both indoor and outdoor environments using fixed distance protocols.There may be significant time differences to complete fixed distance trials between the two environments.Measures of mean force, peak force and peak power during indoor trials may require multiple trials to reduce variability in test scores. PMID- 24149594 TI - Effects of long-term physical activity on cardiac structure and function: a twin study. AB - Previous studies have shown that athletic training or other physical activity causes structural and functional adaptations in the heart, but less is known how long-term physical activity affects heart when genetic liability and childhood environment are taken into account. The aim of this study was to investigate the effects of long-term physical activity vs. inactivity on cardiac structure and function in twin pairs discordant for physical activity for 32 years. Twelve same sex twin pairs (five monozygotic and seven dizygotic, 50-67 years) were studied as a part of the TWINACTIVE study. Discordance in physical activity was initially determined in 1975 and it remained significant throughout the follow-up. At the end of the follow-up in 2007, resting echocardiographic and electrocardiographic measurements were performed. During the follow-up period, the active co-twins were on average 8.2 (SD 4.0) MET hours/day more active than their inactive co twins (p < 0.001). At the end of the follow-up, resting heart rate was lower in the active than inactive co-twins [59 (SD 5) vs. 68 (SD 10) bpm, p=0.03]. The heart rate-corrected QT interval was similar between the co-twins. Also, there was a tendency for left ventricular mass per body weight to be greater and T wave amplitude in lead II to be higher in the active co-twins (18% and 15%, respectively, p=0.08 for both). Similar trends were found for both monozygotic and dizygotic twin pairs. In conclusion, the main adaptation to long- term physical activity is lowered resting heart rate, even after partially or fully controlling for genetic liability and childhood environment. Key pointsThe main adaptation to long-term physical activity is lowering of resting heart rate, even after controlling for genetic liability.VO2peak is increased in the active co twins compared with their inactive co-twins and accordingly, also submaximal heart rates during the clinical exercise test are lower in physically active co twins.There is a tendency for increased LVM per body weight and heightened T wave amplitude in the active co-twins. PMID- 24149595 TI - Repeated abdominal exercise induces respiratory muscle fatigue. AB - Prolonged bouts of hyperpnea or resisted breathing are known to result in respiratory muscle fatigue, as are primarily non respiratory exercises such as maximal running and cycling. These exercises have a large ventilatory component, though, and can still be argued to be respiratory activities. Sit-up training has been used to increase respiratory muscle strength, but no studies have been done to determine whether this type of non-respiratory activity can lead to respiratory fatigue. The purpose of the study was to test the effect of sit-ups on various respiratory muscle strength and endurance parameters. Eight subjects performed pulmonary function, maximum inspiratory pressure (MIP) and maximum expiratory pressure (MEP) measurements, and an incremental breathing test before and after completing a one-time fatiguing exercise bout of sit-ups. Each subject acted as their own control performing the same measurements 3-5 days following the exercise bout, substituting rest for exercise. Following sit-up induced fatigue, significant decreases were measured in MIP [121.6 +/- 26 to 113.8 +/- 23 cmH2O (P <0.025)], and incremental breathing test duration [9.6 +/- 1.5 to 8.5 +/ 0.7 minutes (P <0.05)]. No significant decreases were observed from control pre test to control post-test measurements. We conclude that after a one-time fatiguing sit-up exercise bout there is a reduction in respiratory muscle strength (MIP, MEP) and endurance (incremental breathing test duration) but not spirometric pulmonary function. Key pointsExercise that is primarily abdominal in nature can lead to inspiratory muscle fatigue.This exercise also can cause expiratory muscle fatigue, which would be expected.This study shows a link between a predominantly non-respiratory exercise and decreases in both respiratory muscle strength and endurance. PMID- 24149596 TI - Effects of prolonged tendon vibration stimulation on eccentric and concentric maximal torque and emgs of the knee extensors. AB - The purpose of present study was to compare the effect of Ia afferent attenuation on the activity of alpha motor neuron (MN) during concentric and eccentric action. Eight male subjects were enrolled in the present study. The experiments consisted of two sessions of MVC measurements, since all subjects performed both maximal concentric and eccentric action. EMG signals were simultaneously measured. To establish the baseline of strength, subjects were asked to perform MVC of knee extension in each session. After finishing the measurements, 20 min of vibration stimulation was applied. Immediately after finishing vibration stimulation, the MVC and AEMG were again measured. The means of MVC for concentric knee extension at pre and post- vibration stimulation were 192.2 +/- 49.3 Nm and 162.3 +/- 47.9 Nm, respectively. The means of MVC for eccentric knee extension at pre and post-vibration stimulation were 299.7 +/- 77.0 Nm and 247.3 +/- 88. 6 Nm, respectively. Two-factor repeated ANOVA detected significant differences in the MVC. Both main effects for pre-post condition (F(1,7)=, p = 0.0033) and action (F(1,7)=26.35, p = 0.0013) were noted. No interaction effect (action x condition) was noted. The means of AEMG (vastus lateralis (VL), vastus medialis (VM), rectus femoris (RF)) at pre and post -vibration stimulation were decreased. Two-factor repeated ANOVA detected significant differences in AEMG (VM and VL). Both main effects for pre-post condition (VL;F(1,7)=7.27, p = 0.0308, VM; F(1,7)=9.55, p = 0.0175) and action (F(1,7)=12.40, p = 0.0097) were noted in the VL and the VM but not in the RF. Furthermore, significant interaction (action x condition) effect was noted in the VM (F(1,7)=7.03, p = 0.0328) but not in the VL. The MVC and the EMG activity of the VL in response to the prolonged vibration stimulation were significantly reduced in eccentric contraction over concentric contraction. These results represented that a deactivation effect on the alpha MN of the VL during eccentric action was greater than that of concentric action. Key pointsA deactivation effect on the alpha motor neuron of the vastus lateralis during eccentric action was greater than that of maximal concentric action. PMID- 24149597 TI - Short-term bone biochemical response to a single bout of high-impact exercise. AB - Bone response to a single bout of exercise can be observed with biochemical markers of bone formation and resorption. The purpose of this study was to examine the response of bone biochemical markers to a single bout of exhaustive high-impact exercise. 15 physically active young subjects volunteered to participate. The subjects performed continuous bilateral jumping with the ankle plantarflexors at 65 % of maximal ground reaction force (GRF) until exhaustion. Loading was characterized by analyzing the GRF recorded for the duration of the exercise. Venous blood samples were taken at baseline, immediately after, 2h and on day 1 and day 2 after the exercise. Procollagen type I amino terminal propeptide (P1NP, marker of bone formation) and carboxyterminal crosslinked telopeptide (CTx, marker of bone resorption) were analyzed from the blood samples. CTx increased significantly (32 %, p = 0.015) two days after the exercise and there was a tendensy towards increase seen in P1NP (p = 0.053) one day after the exercise. A significant positive correlation (r = 0.49 to 0.69, p <= 0.038) was observed between change in P1NP from baseline to day 1 and exercise variables (maximal slope of acceleration, body weight (BW) adjusted maximal GRF, BW adjusted GRF exercise intensity and osteogenic index). Based on the two biochemical bone turnover markers, it can be concluded that bone turnover is increased in response to a very strenuous single bout of exhaustive high-impact exercise. Key pointsStudies on bone acute biochemical response to loading have yielded unequivocal results.There is a paucity of research on the biochemical bone response to high impact exercise.An increase in bone turnover was observed one to two days post exercise. PMID- 24149598 TI - Paths to expertise in portuguese national team athletes. AB - The purpose of this study was to identify the quantity and type of sporting activities undertaken by expert team sport athletes in the earlier stages of the long- term athlete development. Experts in roller-hockey (n = 19), volleyball (n = 14), soccer (n = 42) and basketball (n = 37) provided detailed information about the sporting activities they undertook throughout their careers. Results showed considerable variation between and within sports; however, generally, athletes began participating in sports between 6 and 10 years of age. The pattern of participation in specific and non-specific (team, individual and combat) sports for each stage of involvement demonstrated an increase in the number of activities participated in until early adolescence. Our results suggest that involvement in multiple sports during early stages of development is an alternative to early specialization and add further evidence of the complexity of skill acquisition in sport. Key pointsAlthough most athletes began sport participation between 6 and 10 years of age, there was significant variation across groups suggesting considerable flexibility in the pathways to expertise.The path to expertise in volleyball was clearly distinct from the paths of basketball, soccer and roller-hockey.There is a considerable involvement in sports other than the athlete's primary sport, suggesting early specialization is not required for these sports.The pattern of participation in specific and non specific sports for each stage of involvement demonstrated an increase in the number of activities participated in until early adolescence. PMID- 24149599 TI - The validity of submaximal ratings of perceived exertion to predict one repetition maximum. AB - The One Repetition Maximum (1-RM) test is commonly used to assess strength. However, direct assessments of 1-RM are time consuming and unsafe for novice lifters. Whilst various equations exist to predict 1-RM, there is limited research on the validity of these equations. The purpose of this study was to assess the validity of using sub-maximal ratings of perceived exertion (RPE) to predict 1-RM in young adults, using the Borg 6-20 RPE Scale. Twenty healthy participants (ten male (Mean +/- SD, 20.8 +/- 0.6 y, 75.7 +/- 9.3 kg, 1.8 +/- 0.07 m) and ten female (20.3 +/- 0.7 y, 68.4 +/- 10.0 kg, 1.68 +/- 0.03 m)) completed two trials involving resistance exercises for both the upper and lower body. In the first trial the 1-RM for the bilateral biceps curl (BC) and the bilateral knee extension (KE) were determined for each participant. In the second trial, participants performed blinded repetitions which were equivalent to 20, 40 and 60 % of 1-RM for both exercises. The RPE was recorded immediately after two repetitions had been completed at each intensity. The order of intensity of the repetitions was randomly assigned with participants wearing blindfolds to exclude the possibility of pre-determined judgments about load and RPE. Individual RPE recorded at each intensity was subjected to linear regression analysis and the line of best fit was extrapolated to RPE 20 to predict 1-RM in both exercises. There was no significant difference (p > 0.05) between the 1-RM predicted from RPE 20 and measured 1-RM for both exercises for the men and women. Measured and predicted values for men were 46.0 +/- 4.6 and 45.2 +/- 6. 1 kg for biceps curl, and 46.3 +/- 3.8 and 43.0 +/- 7.1 kg for knee extension, respectively. Measured and predicted values for women were 18.6 +/- 5.7 and 19.3 +/- 5.6 kg for biceps curl, and 25.5 +/- 9.6 and 27.2 +/- 12.6 kg for knee extension, respectively. Pearson product-moment correlation coefficients between actual and predicted 1-RM for the BC and KE were 0.97 and 0.92, respectively. These results provide evidence that submaximal ratings of perceived exertion can be used to provide reasonably accurate estimates of 1-RM in young and active men and women. Key pointsThe direct measurement of 1-RM is time consuming and impractical for large groups. This has led to the development of prediction models which employ sub maximal loads in order to minimise the limitations and risks of maximal strength assessment.The principle of using the ratings of perceived exertion from sub maximal work rates to predict maximal work rate has been established.With the exception of the present study, there are no published studies on the efficacy of using the Borg 6-20 RPE scale for predicting maximal strength.Perceived exertion ratings from the Borg 6-20 Scale may be used to provide reasonably accurate estimates of 1-RM.Sub-maximal exercise intensities in the range of 20 - 60% of the 1-RM can be used estimate the 1-Repetition Maximum for upper and lower body exercise. PMID- 24149600 TI - Noninvasive determination of knee cartilage deformation during jumping. AB - The purpose of this investigation was to use a combination of image processing, force measurements and finite element modeling to calculate deformation of the knee cartilage during jumping. Professional athletes performed jumps analyzed using a force plate and high-speed video camera system. Image processing was performed on each frame of video using a color recognition algorithm. A simplified mass-spring-damper model was utilized for determination of global force and moment on the knee. Custom software for fitting the coupling characteristics was created. Simulated results were used as input data for the finite element calculation of cartilage deformation in the athlete's knee. Computer simulation data was compared with the average experimental ground reaction forces. The results show the three-dimensional mechanical deformation distribution inside the cartilage volume. A combination of the image recognition technology, force plate measurements and the finite element cartilage deformation in the knee may be used in the future as an effective noninvasive tool for prediction of injury during jumping. Key pointsEven there are many existing mathematical models of force distribution during running or jumping (Liu et al, 1998), to our knowledge there is no interdisciplinary approach where imaging processing, finite element modeling and experimental force plate system are employed.The aim is to explore noninvasive deformation in the knee cartilage during athlete's jumping on the force plate.An original image algorithms and software were developed as well as complex mathematical models using high performance computational power of finite element modeling together with one dimensional dynamics model.The initial results showed cartilage deformation in the knee and future research will be focused on the methodology and more precisely determination of the stress and strain distribution in the knee cartilage during training phase of sportsman. PMID- 24149601 TI - Effects of Sodium Phosphate Loading on Aerobic Power and Capacity in off Road Cyclists. AB - The main aim of this paper was to evaluate the effects of short- term (6 days) phosphate loading, as well as prolonged (21 days) intake of sodium phosphate on aerobic capacity in off-road cyclists. Nineteen well-trained cyclists were randomly divided into a supplemental (S) and control group (C). Group S was supplemented for 6 days with tri-sodium phosphate, in a dose of 50 mg.kg(-1) of FFM/d, while a placebo was provided for the C group. Additionally, group S was further subjected to a 3-week supplementation of 25 mg.kg(-1) FFM/d, while group C received 2g of glucose. The results indicate a significant (p < 0.05) increase in VO2max, VEmax, and O2/HR, due to sodium phosphate intake over 6 days. Also a significant (p < 0.05) decrease in HRrest and HRmax occurred. The supplementation procedure caused a significant increase (p < 0.05) in Pmax and a shift of VAT towards higher loads. There were no significant changes in the concentration of 2,3-DPG, acid-base balance and lactate concentration, due to phosphate salt intake. Key pointsStudies on bone acute biochemical response to loading have yielded unequivocal results.There is a paucity of research on the biochemical bone response to high impact exercise.An increase in bone turnover was observed one to two days post exercise. PMID- 24149602 TI - The effect of tapering period on plasma pro-inflammatory cytokine levels and performance in elite male cyclists. AB - The aim of this study was to investigate the effect of two different tapering period lengths on the concentration of plasma interleukin- 6 (IL-6), interleukin (IL-1beta) and tumor necrosis factor-alpha (TNF-alpha) and performance in elite male cyclists. To this end, after completing 8 weeks progressive endurance exercise, twenty four high-level endurance cyclists were randomly assigned to one of two groups: a control group of cyclists (n = 12) continued performing progressive weekly training volume for 3 weeks while a taper group of cyclists (n = 12) proceeded with a 50% reduction in weekly training volume relative to the control group. A simulated 40 min time trial (40TT) performance ride was used as the criterion index of performance before and after the tapering period to evaluate the physiological and performance effects of each protocol. Blood samples were collected immediately post-40TT from all participants at the beginning of week 1, and the end of weeks 4, 8, 9 and 11. IL-1beta, IL-6 and TNFalpha were assayed using a standard commercial ELISA kits (Quantikine; R & D Systems, Minneapolis, MN). The mean time to complete the 40TT in the taper group decreased significantly (p < 0.01) after both 1 and 3 weeks with reduced training volume relative to the control group. There were significant reductions in (p < 0.001) IL-1beta, IL-6 and TNFalpha concentrations in the taper group relative to the control group at the end of the 3 week tapering period, but not at the end of the 1 week tapering period. These results demonstrate that both a 1 and a 3 week taper period will result in improved physical performance in trained cyclists but only a 3 week taper period will result in attenuation of post-exercise pro- inflammatory cytokines when compared to those continuing a more intense training regimen. Key pointsThe excessive endurance exercise-induced elevations in pro inflammatory cytokines would, in turn, stimulate the release of anti-inflammatory cytokines.Elevations in pro-inflammatory cytokines indicate athletes are highly susceptible to infections.1and 3-week taper periods will reduce circulating pro inflammatory cytokine levels thereby possibly limiting the chances of infection and potentially reducing the effects of these cytokines in inducing fatigue-like symptoms in athletes. PMID- 24149603 TI - Kinetic assessment of golf shoe outer sole design features. AB - This study assessed human kinetics in relation to golf shoe outer sole design features during the golf swing using a driver club by measuring both within the shoe, and beneath the shoe at the natural grass interface. Three different shoes were assessed: metal 7- spike shoe, alternative 7-spike shoe, and a flat soled shoe. In-shoe plantar pressure data were recorded using Footscan RS International pressure insoles and sampling at 500 Hz. Simultaneously ground reaction force at the shoe outer sole was measured using 2 natural grass covered Kistler force platforms and 1000 Hz data acquisition. Video recording of the 18 right-handed golfers at 200 Hz was undertaken while the golfer performed 5 golf shots with his own driver in each type of shoe. Front foot (nearest to shot direction) maximum vertical force and torque were greater than at the back foot, and there was no significant difference related to the shoe type. Wearing the metal spike shoe when using a driver was associated with more torque generation at the back foot (p < 0. 05) than when the flat soled shoe was worn. Within shoe regional pressures differed significantly with golf shoe outer sole design features (p < 0.05). Comparison of the metal spike and alternative spike shoe results provided indications of the quality of regional traction on the outer sole. Potential golf shoe outer sole design features and traction were presented in relation to phases of the golf swing movement. Application of two kinetic measurement methods identified that moderated (adapted) muscular control of foot and body movement may be induced by golf shoe outer sole design features. Ground reaction force measures inform comparisons of overall shoe functional performance, and insole pressure measurements inform comparisons of the underfoot conditions induced by specific regions of the golf shoe outer sole. Key pointsAssessments of within golf shoe pressures and beneath shoe forces at the natural grass interface were conducted during golf shots with a driver.Application of two kinetic measurement methods simultaneously identified that moderated (adapted) muscular control of the foot and body movement may be induced by golf shoe outer sole localised design features.Ground force measures inform overall shoe kinetic functional performance.Insole pressure measurement informs of underfoot conditions induced by localised specific regions of the golf outer sole.Significant differences in ground-shoe torque generation and insole regional pressures were identified when different golf shoes were worn. PMID- 24149604 TI - Net heart rate to prescribe physical activity in middle-aged to older active adults. AB - THIS STUDY HAD A TWOFOLD PURPOSE: i) to develop a regression equation to estimate metabolic equivalent (MET) in walk/run by heart rate increment above rest (NetHR), and; ii) to determine NetHR thresholds for light, moderate, and vigorous physical activity (PA), from middle aged to elderly. Sample 1 (prediction sample) comprised 39 subjects (19 male and 20 female), with 58.2 +/- 11.0 years old. Sample 2 (validation sample) comprised 40 subjects (18 male and 22 female) with 63.3 +/- 7.0 years old. Each participant did the following activities in sequence, a 15min rest period in supine position, walk at 3km/h, walk at 4.5km/h, and walk at 6km/h, for 6 min at each walk velocity interval. The oxygen up-take (VO2) and heart rate (HR) were continuously and simultaneously assessed. A hierarchical linear model was used to analyze the relationship between metabolic equivalent (MET) and NetHR. The regression equation for MET prediction was: MET = 1.265780 + 0.109479 NetHR. The NetHR thresholds (upper limit) for light, moderate and vigorous PA were 16 and 35 and 70 bpm, respectively. NetHR is a practical, valid and non-invasive method to prescribe physical activity, taking in account individual characteristics (HR at rest combined with NetHR) in middle-aged to older adults. Key pointsPhysical activity intensity can be prescribed by NetHR, in middle aged to older active adults.NetHR thresholds (upper limit) for light (<3 MET), moderate (3 to 6 MET) and vigorous (6 to 9 MET) PA were respectively 17, 43 and 67 bpm.WE CAN ESTIMATE MET INTENSITY LEVEL BY EQUATION: MET = 1.265780 + 0.109479 .NetHR. PMID- 24149605 TI - Post-season detraining effects on physiological and performance parameters in top level kayakers: comparison of two recovery strategies. AB - This study analyzed changes in physiological parameters, hormonal markers and kayaking performance following 5-wk of reduced training (RT) or complete training cessation (TC). Fourteen top-level male kayakers were randomly assigned to either a TC (n = 7) or RT group (n = 7) at the end of their competitive season (T1). Subjects undertook blood sampling and an incremental test to exhaustion on a kayak ergometer at T1 and again following 5 weeks of RT or TC (T2). Maximal oxygen uptake (VO2max) and oxygen uptake at second ventilatory threshold (VT2) significantly decreased following TC (-10.1% and -8.8%, respectively). Significant decreases were also observed in RT group but to a lesser extent ( 4.8% and -5.7% respectively). Heart rate at VT2 showed significant increases following TC (3.5%). However, no changes, were detected in heart rate at VO2max in any group. Peak blood lactate remained unchanged in both groups at T2. Paddling speed at VO2max declined significantly at T2 in the TC group (-3.3%), while paddling speed at VT2 declined significantly in both groups (-5.0% and 4.2% for TC and RT, respectively). Stroke rate at VO2max and at VT2 increased significantly only following TC by 5.2% and 4.9%, respectively. Paddling power at VO2max and at VT2 decreased significantly in both groups although the values observed following RT were higher than those observed following TC. A significant decline in cortisol levels (-30%) was observed in both groups, while a higher increase in testosterone to cortisol ratio was detected in the RT group. These results indicate that a RT strategy may be more effective than complete TC in order to avoid excessive declines in cardiovascular function and kayaking performance in top-level paddlers. Key pointsShort-term (5-wk) training cessation in top-level athletes results in larger declines in physiological and performance parameters when compared to a reduced training approach.Following a competitive season in top-level athletes, both TC and RT strategies reflect an increased androgenic-anabolic activity. A higher T:C ratio was observed for the RT compared to the TC group.These results suggest the convenience of maintaining some reduced training program during transition periods in an attempt to minimize decreases in endurance performance between seasons. PMID- 24149606 TI - Scale development for measuring and predicting adolescents' leisure time physical activity behavior. AB - The aim of this study was to develop a scale for assessing and predicting adolescents' physical activity behavior in Spain and Luxembourg using the Theory of Planned Behavior as a framework. The sample was comprised of 613 Spanish (boys = 309, girls = 304; M age =15.28, SD =1.127) and 752 Luxembourgish adolescents (boys = 343, girls = 409; M age = 14.92, SD = 1.198), selected from students of two secondary schools in both countries, with a similar socio-economic status. The initial 43-items were all scored on a 4-point response format using the structured alternative format and translated into Spanish, French and German. In order to ensure the accuracy of the translation, standardized parallel back translation techniques were employed. Following two pilot tests and subsequent revisions, a second order exploratory factor analysis with oblimin direct rotation was used for factor extraction. Internal consistency and test-retest reliabilities were also tested. The 4-week test-retest correlations confirmed the items' time stability. The same five factors were obtained, explaining 63.76% and 63.64% of the total variance in both samples. Internal consistency for the five factors ranged from alpha = 0.759 to alpha = 0. 949 in the Spanish sample and from alpha = 0.735 to alpha = 0.952 in the Luxembourgish sample. For both samples, inter-factor correlations were all reported significant and positive, except for Factor 5 where they were significant but negative. The high internal consistency of the subscales, the reported item test-retest reliabilities and the identical factor structure confirm the adequacy of the elaborated questionnaire for assessing the TPB-based constructs when used with a population of adolescents in Spain and Luxembourg. The results give some indication that they may have value in measuring the hypothesized TPB constructs for PA behavior in a cross cultural context. Key pointsWhen using the structured alternative format, weak internal consistency was obtained. Rephrasing the items and scoring items on a Likert-type scale enhanced greatly the subscales reliability.Identical factorial structure was extracted for both culturally different samples.The obtained factors, namely perceived physical competence, parents' physical activity, perceived resources support, attitude toward physical activity and perceived parental support were hypothesized as for the original TPB constructs. PMID- 24149607 TI - Number of successive cycles necessary to achieve stability of selected ground reaction force variables during continuous jumping. AB - Because of inherent variability in all human cyclical movements, such as walking, running and jumping, data collected across a single cycle might be atypical and potentially unable to represent an individual's generalized performance. The study described here was designed to determine the number of successive cycles due to continuous, repetitive countermovement jumping which a test subject should perform in a single experimental session to achieve stability of the mean of the corresponding continuously measured ground reaction force (GRF) variables. Seven vertical GRF variables (period of jumping cycle, duration of contact phase, peak force amplitude and its timing, average rate of force development, average rate of force relaxation and impulse) were extracted on the cycle-by-cycle basis from vertical jumping force time histories generated by twelve participants who were jumping in response to regular electronic metronome beats in the range 2-2.8 Hz. Stability of the selected GRF variables across successive jumping cycles was examined for three jumping rates (2, 2.4 and 2.8 Hz) using two statistical methods: intra-class correlation (ICC) analysis and segmental averaging technique (SAT). Results of the ICC analysis indicated that an average of four successive cycles (mean 4.5 +/- 2.7 for 2 Hz; 3.9 +/- 2.6 for 2.4 Hz; 3.3 +/- 2.7 for 2.8 Hz) were necessary to achieve maximum ICC values. Except for jumping period, maximum ICC values took values from 0.592 to 0.991 and all were significantly (p <= 0.05) different from zero. Results of the SAT revealed that an average of ten successive cycles (mean 10.5 +/- 3.5 for 2 Hz; 9.2 +/- 3.8 for 2.4 Hz; 9.0 +/- 3.9 for 2.8 Hz) were necessary to achieve stability of the selected parameters using criteria previously reported in the literature. Using 10 reference trials, the SAT required standard deviation criterion values of 0.49, 0.41 and 0.55 for 2 Hz, 2.4 Hz and 2.8 Hz jumping rates, respectively, in order to approximate the ICC results. The results of the study suggest that the ICC might be a less conservative but more objective method to evaluate stability of the data. Based on these considerations, it can be recommended that a force time history due to continuous, repetitive countermovement jumping should include minimum of four (the average from the ICC analysis) and possibly as many as nine successive jumping cycles (the upper limit of the ICC analysis) to establish stable mean values of the selected GRF data. This information is important for both experimental measurements and analytical studies of GRF signals due to continuous, repetitive countermovement jumping. Key pointsThe number of successive jumping cycles due to continuous, repetitive countermovement jumping obtained from a test subject during in a single testing session influences the stability of the corresponding ground reaction force variables on a cycle-by cycle basis.Researchers have used different criteria and methods for determining stability of ground reaction force data for a variety of activities, making comparisons among studies and activities difficult.In the present study, segmental averaging technique indicated that an average of ten successive jumping cycles were necessary to achieve stability of the selected force parameters using criteria previously reported in the literature, while less conservative test retest intra-class correlation (ICC) analysis showed that an average of four successive jumping cycles were necessary for stability.Based on these considerations, it can be recommended that a force time history due to continuous, repetitive countermovement jumping should include minimum of four (the average from the ICC analysis) and possibly as many as nine successive jumping cycles (the upper limit of the ICC analysis) to achieve stability of jumping force data on a cycle-by-cycle basis.Knowledge about the stability of jumping force data is an important to maximize reliability of their experimental and analytical characterizations. PMID- 24149608 TI - Improved motor-timing: effects of synchronized metro-nome training on golf shot accuracy. AB - This study investigates the effect of synchronized metronome training (SMT) on motor timing and how this training might affect golf shot accuracy. Twenty-six experienced male golfers participated (mean age 27 years; mean golf handicap 12.6) in this study. Pre- and post-test investigations of golf shots made by three different clubs were conducted by use of a golf simulator. The golfers were randomized into two groups: a SMT group and a Control group. After the pre-test, the golfers in the SMT group completed a 4-week SMT program designed to improve their motor timing, the golfers in the Control group were merely training their golf-swings during the same time period. No differences between the two groups were found from the pre-test outcomes, either for motor timing scores or for golf shot accuracy. However, the post-test results after the 4-weeks SMT showed evident motor timing improvements. Additionally, significant improvements for golf shot accuracy were found for the SMT group and with less variability in their performance. No such improvements were found for the golfers in the Control group. As with previous studies that used a SMT program, this study's results provide further evidence that motor timing can be improved by SMT and that such timing improvement also improves golf accuracy. Key pointsThis study investigates the effect of synchronized metronome training (SMT) on motor timing and how this training might affect golf shot accuracy.A randomized control group design was used.The 4 week SMT intervention showed significant improvements in motor timing, golf shot accuracy, and lead to less variability.We conclude that this study's results provide further evidence that motor timing can be improved by SMT training and that such timing improvement also improves golf accuracy. PMID- 24149609 TI - A Study of Shuttlecock's Trajectory in Badminton. AB - The main purpose of this study was to construct and validate a motion equation for the flight of the badminton and to find the relationship between the air resistance force and a shuttlecock's speed. This research method was based on motion laws of aerodynamics. It applied aerodynamic theories to construct motion equation of a shuttlecock's flying trajectory under the effects of gravitational force and air resistance force. The result showed that the motion equation of a shuttlecock's flight trajectory could be constructed by determining the terminal velocity. The predicted shuttlecock trajectory fitted the measured data fairly well. The results also revealed that the drag force was proportional to the square of a shuttlecock velocity. Furthermore, the angle and strength of a stroke could influence trajectory. Finally, this study suggested that we could use a scientific approach to measure a shuttlecock's velocity objectively when testing the quality of shuttlecocks. And could be used to replace the traditional subjective method of the Badminton World Federation based on players' striking shuttlecocks, as well as applying research findings to improve professional knowledge of badminton player training. Key pointsThe motion equation of a shuttlecock's flying trajectory could be constructed by determining the terminal velocity in aerodynamics.Air drag force is proportional to the square of a shuttlecock velocity. Furthermore, the angle and strength of a stroke could influence trajectory. PMID- 24149610 TI - Effects of high-dose creatine supplementation on kidney and liver responses in sedentary and exercised rats. AB - This study evaluated the effects of high-dose of short-term creatine supplementation (5g.kg(-1).day(-1) to 1 week) and long-term creatine supplementation (1g.kg(-1). day(-1) to 4-8 weeks) on kidney and liver structure and function of sedentary and exercised Wistar rats (Exercise sessions consisted of swimming at 80% of maximal work load supported during 5 days per week with daily sessions of 60 minutes throughout the duration of the supplementation). Seventy- two animals (245 +/- 5g) were divided into four groups (n = 18): control diet Sedentary (SED), Creatine diet Sedentary (CRE), control diet Exercised (EXE), and Creatine diet Exercised (EXECRE). Histological and blood biochemical studies were performed after one, four, and eight weeks of creatine supplementation and exercise (n = 6). No differences were found when comparing SED, EXE and EXECRE groups for kidney and liver structure and function at one, four and eight weeks. However, the CRE group showed higher levels of creatinine (1.1 +/- 0.2 vs. 0.4 +/- 0.1 mg.dl(-1); p < 0.05), and urea (37 +/- 3 vs. 19 +/- 1 mg.dl(-1); p < 0.05) when compared with all others groups at four and eight weeks. At eight weeks, the CRE group presented increased levels of ALT (41 +/- 7 vs. 23 +/- 7 U.L(-1); p < 0.05), AST (89 +/- 6 vs. 62 +/- 5 U.L(-1); p < 0.05), GGT (8.0 +/- 0.9 vs. 3.9 +/- 1.0 U.L(-1); p < 0.05), and AP (125 +/- 10 vs. 69 +/ 9 U.L(-1); p < 0.05) also when compared with all others groups. Moreover, the CRE group demonstrated some structural alterations indicating renal and hepatic damage at four and eight weeks, respectively. These results suggest that long term creatine supplementation (up to 4-8 weeks) may adversely affect kidney and liver structure and function of sedentary but not of exercised rats. Key pointsCreatine supplementation is an established ergogenic aid in sports and is now claimed to have therapeutical applications in a variety of diseases.Although acknowledged, this nutritional supplement is rarely monitored precisely about their possible side effects.Previous studies indicated that short-term creatine supplementation associate with the physical exercise may be safe, but the effect of long-term creatine supplementation is still unknown.There is a need for further research to elucidate the controversial points refers to renal and hepatic function after creatine supplementation.The results of the current study indicate that supraphysiological long-term creatine supplementation (up to 4-8 weeks) may adversely affect kidney and liver structure and function of sedentary but not of exercised rats. PMID- 24149611 TI - Circuit resistance exercise improves glycemic control and adipokines in females with type 2 diabetes mellitus. AB - The aim of study was to evaluate whether circuit resistance exercise (CE) improves glycemic control and adipokine levels in comparison with walking exercise (WE) in 15 adult postmenopausal Korean females with type 2 diabetes mellitus (T2DM). The participants were randomly assigned to either the CE or WE group. Subjects exercised for 1 h, three times per week for 12 weeks. The parameters measured were body composition, respiratory rate, blood glucose, insulin and adipokines. The body composition of the CE group showed a significant reduction (all p < 0.05) in body weight, body mass index (BMI), and percentage of body fat and a significant increase in muscle mass. Respiratory function was also significantly increased in the CE group. Additionally, hemoglobin A1c (HbA1c) changed favorably in the CE group, as were the concentrations of adipokines such as retinol binding protein 4 (RBP-4) (p < 0.05), adiponectin (p < 0.01), and monocyte chemoattractant protein-1 (MCP-1) (p < 0.01). In addition, significant correlations with CE were evident for homeostatic model assessment insulin resistance (HOMA-IR) and glucose (r = 0.69, p < 0.001), muscle mass and glucose (r = 0.45, p < 0.05), and muscle mass and HbA1c (r = 0.39, p < 0.05). The beneficial effects of CE include the development of muscle mass, which effectively increases glucose use and reduces the amount of insulin required. Thus, our results suggest that CE improves glycemic control and adipokines resulting from incrementally increased muscle mass and reductions of body weight, BMI and percentage of body fat for T2DM postmenopausal Korean women. Key pointsCE induced weight loss and muscle mass increment increases the level of adiponectin secreted by adipocytes due to heightened glucose utilization and fat oxidation.Aerobic exercise decreases body weight, fat and adipokines in high intensity and frequency, while resistance exercise decreases these parameters in low intensity, time and frequency.CE can improves glycemic control and adipokines resulting from reduction of body fat postmenopausal Korean women with T2DM. PMID- 24149612 TI - The reliability of adolescent thermoregulatory responses during a heat acclimation protocol. AB - This study investigated the between trial variation of thermoregulatory measures during a heat acclimation protocol. Eight 14-16 y old boys completed three bouts of 20-min cycling at 45 % peak VO2 in a hot environment (35.1 +/- 1.2 degrees C and 46. 4 +/- 1.0 % relative humidity) on two occasions separated by a minimum of 24 h. Reliability was assessed through analysis of within-subject variation, the change in the mean, and retest correlation for measurements of aural temperature (Tau), mean skin temperature (Tsk), heart rate (HR) and oxygen uptake (VO2). Between trial differences were low for Tau, Tskbout1, Tskbout2and3 and HR with coefficients of variation 0.6 %, 1.5 %, 0.5 % and 4.0 %, respectively. The results demonstrate good reliability that will allow future investigators to precisely determine the extent of heat acclimation protocols in relation to the measurement error. Key pointsTo allow paediatric heat acclimation guidelines to be produced, the extent of heat acclimation needs to be established once biological and mechanical variation has been accounted for.The results of the present study indicate that between trial differences were low for aural temperature, mean skin temperature and heart rate with coefficient of variation values ranging from 0.6 - 4.0 %.Future investigators will be able to utilise the coefficient of variation values to establish the effectiveness of heat acclimation with precision alongside the selection of appropriate sample size. PMID- 24149614 TI - Surgical treatment of stress fracture of the scaphoid of an adolescent gymnast. AB - Stress fracture of the carpal scaphoid is very rare. We present stress fracture of the scaphoid in an adolescent gymnast who was treated with internal fixation. Key pointsThere is a risk of stress fracture of the scaphoid in gymnast.Internal fixation with a screw is one of the good options for stress fracture of the scaphoid. PMID- 24149613 TI - Exercise limitations in a competitive cyclist twelve months post heart transplantation. AB - It has been well documented that for heart transplant recipients (HTrecipient) post transplantation exercise capacity does not exceed 60% of healthy age-matched controls. Few studies have been undertaken to determine the cause of exercise limitations following heart transplantation (HT) for an elite athlete. Participant was a 39 year old elite male cyclist who suffered an acute myocardial infarction after a cycling race and received a heart transplant (HT) four months later. Six weeks prior to his AMI fitness testing was completed and a predicted VO2max of 58 mL.kg(-1).min(-1) and HRmax of 171 bpm was achieved. The participant underwent maximal exercise testing 6 and 12 months post transplant to determine exercise limitations. His results 6 and 12 months post transplant were a VO2max of 33.8 and 44.2 mL.kg(-1).min(-1) respectively, and a HR max that was 97% and 96% of HRmax measured. The participant showed an increase in both HRmax and VO2max 12 months post HT compared to previous testing. Results suggest that the limiting factors to exercise following HT are likely due to peripheral function, which became diminished as a result accumulated from 4 months of congestive heart failure, the strain of HT, and immunosuppressive therapy leading up to the exercise testing. Lifestyle before HT and a more aggressive approach to HT recovery should be considered necessary in the improvement of peripheral functioning following HT. Key pointsPhysical work capacity following heart transplantation is not limited by cardiac denervation.Heart transplant rehabilitation should focus efforts on endothelial and muscular limitations. PMID- 24149615 TI - Subcutaneous Peroneus Longus Tendon Rupture Associated with OS Peroneum Fracture. AB - We report a rare case of subcutaneous peroneus longus tendon rupture associated with os peroneum fracture. Three dimensional computed tomographic scan was useful to understand this disorder. We treated the patient with excision of fractured os peroneum and tenodesis of the proximal stump of the ruptured peroneus longus tendon to the lateral aspect of the calcaneus. Key pointsIn order to understand a rare case of subcutaneous peroneus longus tendon rupture associated with os peroneum fracture, three dimensional computed tomographic scan was useful.The patient was treated with excision of fractured os peroneum and tenodesis of the proximal stump of the ruptured peroneus longus tendon to the lateral aspect of the calcaneus. PMID- 24149616 TI - Gastrointestinal follicular lymphoma with lymphoepithelial lesions. PMID- 24149617 TI - Lobbying bill could curtail public health campaigns, warns BMA. PMID- 24149619 TI - Degradation of human hemoglobin by organic C-nitroso compounds. AB - The crystal structure of the nitrosomethane adduct of human Hb shows N-binding of the MeNO ligands to heme Fe. The structure of the EtNO adduct reveals a surprising 4.9 A heme slippage in the beta subunit, and explains the ability of C nitroso compounds to degrade Hb removing it from circulation. PMID- 24149620 TI - Perpetual expression of PAMPs necessary for optimal immune control and clearance of a persistent pathogen. AB - Pathogen-associated molecular patterns (PAMPs) are known to be fundamental in instigating immune responses, but their role in influencing these responses beyond their initiation is less well understood. Here, using the protozoan parasite Trypanosoma cruzi, which is deficient in strong PAMPs, we demonstrate a requirement for the continuous expression of PAMPs for optimal anti-pathogen immunity. Although co-inoculating with, temporary anchoring of and transgenic expression of exogenous PAMPs all result in enhanced early adaptive immune responses, only the continuous expression of bacterial PAMPs on transgenic T. cruzi sustains these responses, resulting in enhanced pathogen clearance. These findings demonstrate that PAMPs function to potentiate adaptive immune responses well beyond their initiation and may determine the efficiency of control of pathogens capable of long-term persistence. PMID- 24149623 TI - Serotype profile and molecular characterization of antimicrobial resistance in non-typhoidal Salmonella isolated from gastroenteritis cases over nine years. AB - Resistance to third-generation cephalosporins in non-typhoidal Salmonella (NTS) is emerging worldwide. We report the occurrence of extended-spectrum beta lactamase (ESBL) phenotypes in 53.4 % of NTS isolated over a period of nine years from gastroenteritis cases. ESBL and AmpC co-production was observed in 21 % of the isolates. Occurrence of blaCTX-M-15 and blaCMY-2 resistance genes was observed in 11.6 % and 37 % of the isolates respectively. Overall, Salmonella enterica serovar Senftenberg was the predominant serovar carrying blaCTX-M-15 and blaCMY-2 resistance genes. We report for the first time from India, one isolate each of S. enterica serovar Thompson, S. enterica serovar Infantis and S. enterica serovar Newport, carrying the blaCTX-M-15 gene. We also report for the first time from India, a case of gastroenteritis due to S. enterica serovar Thompson. PMID- 24149622 TI - Pyomelanin production: a rare phenotype in Acinetobacter baumannii. PMID- 24149621 TI - Perspectives on the mechanism of transcriptional regulation by long non-coding RNAs. AB - Long non-coding RNAs (lncRNAs) are increasingly being recognized as epigenetic regulators of gene transcription. The diversity and complexity of lncRNA genes means that they exert their regulatory effects by a variety of mechanisms. Although there is still much to be learned about the mechanism of lncRNA function, general principles are starting to emerge. In particular, the application of high throughput (deep) sequencing methodologies has greatly advanced our understanding of lncRNA gene function. lncRNAs function as adaptors that link specific chromatin loci with chromatin-remodeling complexes and transcription factors. lncRNAs can act in cis or trans to guide epigenetic modifier complexes to distinct genomic sites, or act as scaffolds which recruit multiple proteins simultaneously, thereby coordinating their activities. In this review we discuss the genomic organization of lncRNAs, the importance of RNA secondary structure to lncRNA functionality, the multitude of ways in which they interact with the genome, and what evolutionary conservation tells us about their function. PMID- 24149624 TI - Role of carbonic anhydrases in pathogenic micro-organisms: a focus on Aspergillus fumigatus. AB - Aspergillus fumigatus is a ubiquitous saprophytic fungus responsible for organic material decomposition, and plays an important role in recycling environmental carbon and nitrogen. Besides its important role in the environment, this fungus has been reported as one of the most important fungal pathogens in immunocompromised patients. Due to changes in CO2 concentration that some pathogens face during the infection process, studies have been undertaken to understand the pathogenic roles of carbonic anhydrases (CAs), well-known CO2 hydration catalytic enzymes. As a basis for a discussion of the possible roles of CAs in A. fumigatus pathogenicity, this review describes the main characteristics of the A. fumigatus infection and the challenges for its treatment. In addition, it gathers findings from studies with CA inhibitor drugs as anti-infective agents in different pathogens. PMID- 24149625 TI - Genetic diversity and virulence properties of Streptococcus dysgalactiae subsp. equisimilis from different sources. AB - A recent increase in virulence of pathogenic Streptococcus dysgalactiae subsp. equisimilis (SDSE) has been widely proposed. Such an increase may be partly explained by the acquisition of new virulence traits by horizontal gene transfer from related streptococci such as Streptococcus pyogenes (GAS) and Streptococcus agalactiae (GBS). A collection of 54 SDSE strains isolated in Italy in the years 2000-2010 from different sources (paediatric throat carriage, invasive and non invasive diseases) was characterized by emm typing and pulsed-field gel electrophoresis (PFGE) analysis. The virulence repertoire was evaluated by PCR for the presence of GAS superantigen (spe) genes, the streptolysin S (sagA) gene, the group G fibronectin-binding protein (gfbA) gene and GAS-GBS alpha-like protein family (alp) genes; moreover, the ability to invade human epithelial cells was investigated. Resistance to tetracycline, erythromycin and clindamycin was assessed. The combined use of emm typing and PFGE proved to be a reliable strategy for the epidemiological analysis of SDSE isolates. The most frequent emm types were the same as those more frequently reported in other studies, thus indicating the diffusion of a limited number of a few successful emm types fit to disseminate in humans. The speG gene was detected in SDSE strains of different genetic backgrounds. Erythromycin resistance determined by the erm(T) gene, and the unusual, foggy MLSB phenotype, observed in one and seven strains, respectively, have never previously, to our knowledge, been reported in SDSE. Moreover, a new member of the alp family was identified. The identification of new antibiotic and virulence determinants, despite the small size of the sample analysed, shows the importance of constant attention to monitoring the extent of lateral gene transfer in this emerging pathogen. PMID- 24149626 TI - Commentary on "Venous thromboembolism after face-lift surgery using local anesthesia: results of a multicenter survey". PMID- 24149628 TI - Lower limb strength in professional soccer players: profile, asymmetry, and training age. AB - Kicking and cutting skills in soccer are clearly unilateral, require asymmetrical motor patterns and lead to the development of asymmetrical adaptations in the musculoskeletal function of the lower limbs. Assuming that these adaptations constitute a chronicity-dependent process, this study examined the effects of professional training age (PTA) on the composite strength profile of the knee and ankle joint in soccer players. One hundred soccer players (n=100) with short (5-7 years), intermediate (8-10 years) and long (>11 years) PTA were tested bilaterally for isokinetic concentric and eccentric strength of the knee and ankle muscles. Knee flexion-extension was tested concentrically at 60 degrees , 180 degrees and 300 degrees /sec and eccentrically at 60 degrees and 180 degrees /sec. Ankle dorsal and plantar flexions were tested at 60 degrees /sec for both the concentric and eccentric mode of action. Bilaterally averaged muscle strength [(R+L)/2] increased significantly from short training age to intermediate and stabilized afterwards. These strength adaptations were mainly observed at the concentric function of knee extensors at 60 degrees /sec (p = 0. 023), knee flexors at 60 degrees /sec (p = 0.042) and 180 degrees /sec (p = 0.036), and ankle plantar flexors at 60o/sec (p = 0.044). A linear trend of increase in isokinetic strength with PTA level was observed for the eccentric strength of knee flexors at 60 degrees /sec (p = 0.02) and 180 degrees /sec (p = 0.03). Directional (R/L) asymmetries decreased with PTA, with this being mainly expressed in the concentric function of knee flexors at 180 degrees /sec (p = 0.04) and at 300 degrees /sec (p = 0.03). These findings confirm the hypothesis of asymmetry in the strength adaptations that take place at the knee and ankle joint of soccer players mainly along with short and intermediate PTA. Players with a longer PTA seem to adopt a more balanced use of their lower extremities to cope with previously developed musculoskeletal asymmetries and possibly reduce injury risk. This has certain implications regarding proper training and injury prevention in relation to professional experience in soccer. Key pointsMuscle strength increased from the low (5-7 years) to the intermediate professional training age (8-10 years) and stabilized thereafter.Soccer practicing and competition at the professional level induces critical strength adaptations (asymmetries) regarding the function of the knee and ankle musculature.Soccer players with long professional training age showed a tendency for lower isokinetic strength asymmetries than players with intermediate and short professional training age. PMID- 24149627 TI - The role of post-exercise nutrient administration on muscle protein synthesis and glycogen synthesis. AB - Nutrient administration following an exercise bout vastly affects anabolic processes within the human body, irrespective of exercise mode. Of particular importance are protein and carbohydrates whereby these two macronutrients portray distinct functions as anabolic agents. It has been confirmed that protein and/or amino acid ingestion following resistance training is required to reach a positive protein/nitrogen balance, and carbohydrate intake during recovery is the most important consideration to replenish glycogen stores from an exhaustive exercise bout. Several factors play significant roles in determining the effectiveness of protein and carbohydrate supplementation on post-exercise protein and glycogen synthesis. Improper application of these factors can limit the body's ability to reach an anabolic status. The provided evidence clearly denotes the importance these two macronutrients have in regards to post-exercise nutrition and anabolism. Therefore, the purpose of this review is to discuss the impact of dietary protein and carbohydrate intake during the recovery state on muscle protein synthesis and glycogen synthesis. Key pointsPost-exercise nutrient intake is essential for promoting protein synthesis and glycogen synthesis.The timing and amount of protein and/or carbohydrate ingested affects the rate and amount of synthesis.The type/form of protein and/or carbohydrate ingested after exercise alters anabolic processes during the recovery period. PMID- 24149629 TI - Perceived barriers by university students in the practice of physical activities. AB - The main goal of this research is to study in detail the main characteristics of university students in order to find out the reasons why they have adopted an inactive lifestyle. In order to do so, a questionnaire on the analysis of sports habits and lifestyle was given to 323 students. They were taken from a representative sample of 1834 students. These 323 students had pointed out at the moment of the fieldwork, not having practiced any sport in their spare time. Our findings point out that there are diverse reasons for this. On one hand, reasons referred to as external barriers such as lack of time, on the other hand, internal barriers such as not liking the physical activity, not seeing its practicality or usefulness, feeling lazy or with apathy, or thinking that they are not competent in this type of activities. Other reasons such as the lack of social support are grouped within the external barriers. Finally, it is important to stress that there are also differences based on gender with respect to motivation. Key pointsExternal barriers prevail in university students. The lack of time is among the most highlighted ones.Statistically significant results have been found regarding the gender variable.The results are very important since they are considered to be valuable information for university institutions when guiding and diversifying their offer of physical and sport activities. Also as a guide in the design of support policies and national sport management guidelines. PMID- 24149630 TI - Consistency in acceleration patterns of football players with different skill levels. AB - The aims of the present study were to compare the consistency in the lower limb acceleration patterns during inside and instep kicks performed by players with different skill levels, and to investigate the correlation between subjective rating scores for skill level relative to their kicking performance and knee acceleration repeatability. Thirteen club-level male soccer players of ages between 15-16 years participated in this study. Skill levels of individual players were quantified previously by evaluating shooting performance as a numerical value ranging from 1 to 10. Further evaluations were held through tri axial acceleration data recorded at proximal tibial tuberosity beneath each patella on the players' knees, in a procedure in which players were asked to complete four randomly ordered shooting trials of inside and instep kicks with 2 minute resting intervals. Hence, the mainstream data used in consistency calculations are in the form 4 by 1200 matrices (acceleration vs. time) per subject. In order to evaluate the consistency of acceleration data, the mean of the standard deviations (mSD) were calculated, and the associated Pearson-r correlation coefficients were incorporated to obtain mSD vs. skill correlations. As a result, repeatability was found to increase with skill level at z-axis acceleration for instep kicks only. However, it is possible to find the most appropriate orientation (for the two kicks) for meaningful correlations using vector rotations on the 3 orthogonal acceleration data, and this study shows that, after such suitable vector rotations, positive repeatability results could also be acquired for the inside kicks. Key pointsThe repeatability of the acceleration waveforms are well correlated with the skill level of the subjects.Accelerometry might be used as an objective and cost effective assessment that allows interpreting consistency of the action. PMID- 24149631 TI - Emotional intelligence and emotions associated with optimal and dysfunctional athletic performance. AB - This study investigated relationships between self-report measures of emotional intelligence and memories of pre-competitive emotions before optimal and dysfunctional athletic performance. Participant-athletes (n = 284) completed a self-report measure of emotional intelligence and two measures of pre-competitive emotions; a) emotions experienced before an optimal performance, and b) emotions experienced before a dysfunctional performance. Consistent with theoretical predictions, repeated MANOVA results demonstrated pleasant emotions associated with optimal performance and unpleasant emotions associated with dysfunctional performance. Emotional intelligence correlated with pleasant emotions in both performances with individuals reporting low scores on the self-report emotional intelligence scale appearing to experience intense unpleasant emotions before dysfunctional performance. We suggest that future research should investigate relationships between emotional intelligence and emotion-regulation strategies used by athletes. Key pointsAthletes reporting high scores of self-report emotional intelligence tend to experience pleasant emotions.Optimal performance is associated with pleasant emotions and dysfunctional performance is associated with unpleasant emotions.Emotional intelligence might help athletes recognize which emotional states help performance. PMID- 24149632 TI - The efficiency of tennis doubles scoring systems. AB - In this paper a family of scoring systems for tennis doubles for testing the hypothesis that pair A is better than pair B versus the alternative hypothesis that pair B is better than A, is established. This family or benchmark of scoring systems can be used as a benchmark against which the efficiency of any doubles scoring system can be assessed. Thus, the formula for the efficiency of any doubles scoring system is derived. As in tennis singles, one scoring system based on the play-the-loser structure is shown to be more efficient than the benchmark systems. An expression for the relative efficiency of two doubles scoring systems is derived. Thus, the relative efficiency of the various scoring systems presently used in doubles can be assessed. The methods of this paper can be extended to a match between two teams of 2, 4, 8, ...doubles pairs, so that it is possible to establish a measure for the relative efficiency of the various systems used for tennis contests between teams of players. Key pointsA relatively straightforward expression or formula for the efficiency of a tennis doubles scoring system has been established.The expression for the relative efficiency of two tennis doubles scoring systems is a simple one, and is the same as that for two singles scoring systems.The methodology of this paper can be used and extended so that the efficiency of a scoring system for a match between two teams of doubles pairs can be measured. PMID- 24149634 TI - Association of cardiorespiratory fitness with elevated hepatic enzyme and liver fat in Japanese patients with impaired glucose tolerance and type 2 diabetes mellitus. AB - No study has so far determined whether a favorable level of cardiorespiratory fitness (CF) contributes to a reduced risk of elevated hepatic enzymes and a high degree of liver fat in patients having various metabolic risks. This study investigated the association between the maximal oxygen uptake (VO2 max) and the prevalence of elevated liver enzymes and high liver fat, while considering such factors as abdominal obesity, hyperinsulinemia and the other metabolic risks. The study enrolled newly diagnosed Japanese patients (n = 84; 52 males and 32 females; aged 25-69 years) with impaired glucose tolerance (IGT) and type 2 diabetes mellitus (Type2DM) who did not receive any intervention or pharmacological therapy. The subjects were divided into 3 groups according to the distribution of the VO2max for each sex. The odds ratios (ORs) for the prevalence of elevated aspartate and alanine aminotransferase (AST and ALT) and high degree of liver fat adjusted for age, sex, disease type, daily ethanol intake, and current smoking were significantly lower in the moderate- and high CF groups in comparison to the low CF group. In addition, a significant OR for AST was maintained in the moderate and high CF group after adjusting for abdominal obesity and/or hyperinsulinemia. The significant ORs for the prevalence of elevated ALT and a high degree of liver fat were attenuated after adjusting for abdominal obesity and/or hyperinsulinemia. No significant OR for the prevalence of elevated gamma-glutamyl transferase (GGT) was recognized in all logistic models. These results indicated that CF was negatively and independently associated with the prevalence of elevated AST even in Japanese diabetic patients having various metabolic risks. It was concluded that the AST level might be useful as a simple marker reflecting physical inactivity in such subjects. Key pointsThe prevalence of elevated AST was negatively, and strongly associated with the CF level independent of abdominal obesity, hyperinsulinemia, and the other confounders in the subjects with glucose intolerance.The association between the CF level and both an elevated ALT level and a high degree of liver fat, as defined by the L/S ratio of CT images depended on abdominal fat and/or hyperinsulinemia in the subjects with glucose intolerance.No association was recognized between CF and elevated GGT in the subjects with glucose intolerance in the subjects with glucose intolerance.Having a favorable level of CF could lead to a reduced risk of hepatic-related abnormalities even in diabetic patients having the other metabolic risks. PMID- 24149633 TI - Physiological, biomechanical and anthropometrical predictors of sprint swimming performance in adolescent swimmers. AB - The purpose of this study was to analyze the relationships between 100-m front crawl swimming performance and relevant biomechanical, anthropometrical and physiological parameters in male adolescent swimmers. Twenty five male swimmers (mean +/- SD: age 15. 2 +/- 1.9 years; height 1.76 +/- 0.09 m; body mass 63.3 +/- 10.9 kg) performed an all-out 100-m front crawl swimming test in a 25-m pool. A respiratory snorkel and valve system with low hydrodynamic resistance was used to collect expired air. Oxygen uptake was measured breath-by-breath by a portable metabolic cart. Swimming velocity, stroke rate (SR), stroke length and stroke index (SI) were assessed during the test by time video analysis. Blood samples for lactate measurement were taken from the fingertip pre exercise and at the third and fifth minute of recovery to estimate net blood lactate accumulation (DeltaLa). The energy cost of swimming was estimated from oxygen uptake and blood lactate energy equivalent values. Basic anthropometry included body height, body mass and arm span. Body composition parameters were measured using dual-energy X ray absorptiometry (DXA). Results indicate that biomechanical factors (90.3%) explained most of 100-m front crawl swimming performance variability in these adolescent male swimmers, followed by anthropometrical (45.8%) and physiological (45.2%) parameters. SI was the best single predictor of performance, while arm span and ?La were the best anthropometrical and physiological indicators, respectively. SI and SR alone explained 92.6% of the variance in competitive performance. These results confirm the importance of considering specific stroke technical parameters when predicting success in young swimmers. Key pointsThis study investigated the influence of different anthropometrical, physiological and biomechanical parameters on 100-m swimming performance in adolescent boys.Biomechanical factors contributed most to sprint swimming performance in these young male swimmers (90.3% of variability in performance), followed by anthropometrical (45.8%) and physiological (45.2%) parameters.Two selected variables (stroke index and stroke rate) explained 92.6% of the variance in competitive performance in these adolescent swimmers. PMID- 24149635 TI - Tracking the performance of world-ranked swimmers. AB - Tracking the swimming performance is important to analyze its progression and stability between competitions and help coaches to define realistic goals and to select appropriate training methods. The aim of this study was to track world ranked male swimmer's performance during five consecutive seasons (from 2003/2004 to 2007/2008) in Olympic freestyle events. An overall of 477 swimmers and 2385 season best performances were analyzed. FINA's male top-150 rankings for long course in the 2007-2008 season were consulted in each event to identify the swimmers included. Best performances were collected from ranking tables provided by the National Swimming Federations or, when appropriate, through an internet database (www. swimranking.net). Longitudinal assessment was performed based on two approaches: (i) mean stability (descriptive statistics and ANOVA repeated measures, followed by a Bonferroni post-hoc test) and; (ii) normative stability (Pearson Correlation Coefficient and the Cohen's Kappa tracking index). Significant variations in the mean swimming performance were observed in all events between all seasons. Performance enhancement was approximately 0.6 to 1 % between seasons leading up to the Olympics and approximately 3 to 4 % for the overall time-frame analyzed. The performance stability based on overall time frame was moderate for all freestyle events, except in the 50-m (K = 0.39 +/- 0.05) where it was low. Self-correlations ranged between a moderate (0.30 <= r < 0.60) and a high (r >= 0.60) stability. There was also a performance enhancement during all five seasons analyzed. When more strict time frames were used, the analysis of swimming performance stability revealed an increase in the third season. So, coaches should have a long term view in what concerns training design and periodization of world-ranked swimmers, setting the third season of the Olympic Cycle as a determinant time frame, due to performance stability until Olympic Games season. Key pointsWorld-ranked swimmers' performance increased each season by approximately 0.6 to 1% during the five consecutive seasons analyzed.The stability of swimmers' performance based on the overall Olympic cycle period was moderate.Coaches should set the third season of the Olympic Cycle as a determinant milestone. In that specific season, performance turns out to be high when having the Olympic Games season as a main goal. PMID- 24149636 TI - Concussion occurrence and knowledge in italian football (soccer). AB - The purpose of the study was to investigate concussion history, knowledge, injury identification, and management strategies among athletes, coaches, and medical staff in Italian club level football (soccer) clubs. Surveys (N=727) were distributed among Italian football clubs. Athletes' surveys were designed to evaluate athlete knowledge of concussive signs and symptoms and injury reporting. Coaches' surveys explored the understanding of concussive signs and symptoms and management practices. Medical staff surveys explored the standard of care regarding concussions. A total of 342 surveys were returned, for a 47% response rate. Descriptive analyses indicated 10% of athletes sustaining a concussion in the past year and 62% of these injuries were not reported, primarily due to the athletes not thinking the injury was serious enough. Coaches consistently identified non-concussion related symptoms (98.7%), but were unable to identify symptoms associated with concussion (38.9%). Most understood that loss of consciousness is not the sole indicator of injury (82.6%). Medical staff reported a heavy reliance on the clinical exam (92%) and athlete symptom reports (92%) to make the concussion diagnosis and return to play decision, with little use of neurocognitive (16.7%) or balance (0.0%) testing. Italian football athletes appear to report concussions at a rate similar to American football players, with a slightly higher rate of unreported injuries. Most of these athletes were aware they were concussed, but did not feel the injury was serious enough to report. Although coaches served as the primary person to whom concussions were reported, the majority of coaches were unable to accurately identify concussion related symptoms. With little use for neurocognitive and postural control assessments, the medical personnel may be missing injuries or returning athletes to play too soon. Collectively, these findings suggest that athletes, coaches, and medical personnel would benefit from concussion based educational materials on the signs, symptoms, and evaluative techniques of concussion. Key pointsItalian football (soccer) athletes report less than 40% of concussions.Injuries are most commonly reported to coaches, who may not be fully aware of concussive signs and symptoms.International educational measures on concussion awareness and management may be of use. PMID- 24149637 TI - Sensitivity of body sway parameters during quiet standing to manipulation of support surface size. AB - The centre of pressure (COP) movement during stance maintenance on a stable surface is commonly used to describe and evaluate static balance. The aim of our study was to test sensitivity of individual COP parameters to different stance positions which were used to address size specific changes in the support surface. Twenty-nine subjects participated in the study. They carried out three 60-second repetitions of each of the five balance tasks (parallel stance, semi tandem stance, tandem stance, contra-tandem stance, single leg stance). Using the force plate, the monitored parameters included the total COP distance, the distance covered in antero-posterior and medio-lateral directions, the maximum oscillation amplitude in antero-posterior and medio-lateral directions, the total frequency of oscillation, as well as the frequency of oscillation in antero posterior and medio-lateral directions. The parameters which describe the total COP distance were the most sensitive to changes in the balance task, whereas the frequency of oscillation proved to be sensitive to a slightly lesser extent. Reductions in the support surface size in each of the directions resulted in proportional changes of antero-posterior and medio- lateral directions. The frequency of oscillation did not increase evenly with the increase in the level of difficulty of the balance task, but reached a certain value, above which it did not increase. Our study revealed the monitored parameters of the COP to be sensitive to the support surface size manipulations. The results of the study provide an important source for clinical and research use of the body sway measurements. Key pointsTesting static balance with body sway related center of pressure (COP) parameters;Testing sensitivity of COP sub-components to manipulations of the stance position;Analytical approach to the study of COP parameters that enable the insight to the frequency/amplitude and direction dependency relationships;Adding to the basic knowledge of static balance which can be applied to testing and training routines. PMID- 24149638 TI - Longitudinal Study in 3,000 m Male Runners: Relationship between Performance and Selected Physiological Parameters. AB - The purpose of the present study was to analyze longitudinal changes in 3,000 m running performance and the relationship with selected physiological parameters. Eighteen well-trained male middle-distance runners were measured six times (x3 per year) throughout two consecutive competitive seasons. The following parameters were measured on each occasion: maximal oxygen uptake (VO2max), running economy (RE), velocity at maximal oxygen uptake (vVO2max), velocity at 4mmol L(-1) blood lactate concentration (V4), and performance velocity (km.h(-1)) in 3,000 m time trials. Values ranged from 19.59 to 20.16 km.h(-1), running performance; 197 to 207 mL.kg(-1).km(-1). RE; 17.2 to 17.7 km.h(-1), V4; 67.1 to 72.5 mL.kg(-1).min(-1), VO2max; and 19.8 to 20.2 km.h(-1), vVO2max. A hierarchical linear model was used to quantify longitudinal relationships between running performance and selected physiological variables. Running performance decreased significantly over time, between each time point the decrease in running velocity was 0.06 km.h(-1). The variables that significantly explained performance changes were V4 and vVO2max. Also, vVO2max and V4 were the measures most strongly correlated with performance and can be used to predict 3,000 m race velocity. The best prediction formula for 3,000 m running performance was: y = 0.646 + 0.626x + 0.416z (R(2)=0.85); where y = V3,000 m velocity (km.h(-1)), x = V4 (km.h(-1)) and z = vVO2max (km.h(-1)). The high predictive power of vVO2max and V4 suggest that both coaches and athletes should give attention to improving these two physiological variables, in order to improve running performance. Key pointsV4 and vVO2max are the most important physiological variables to explain longitudinal changes in 3000 m running performance;3000 m running performance prediction is better if one uses both V4 and vVO2max in the same formula: y = 0.646 + 0.626x + 0.416z; R(2)=0.85, where y is the Vrace (km/h), x is V4 (km/h) and z is vVO2max (km/h).The V4 and vVO2max can be used for training control purposes. PMID- 24149639 TI - Modification of agility running technique in reaction to a defender in rugby union. AB - Three-dimensional kinematic analysis examined agility running technique during pre-planned and reactive performance conditions specific to attacking ball carries in rugby union. The variation to running technique of 8 highly trained rugby union players was compared between agility conditions (pre-planned and reactive) and also agility performance speeds (fast, moderate and slow). Kinematic measures were used to determine the velocity of the centre of mass (COM) in the anteroposterior (running speed) and mediolateral (lateral movement speed) planes. The position of foot-strike and toe-off was also examined for the step prior to the agility side- step (pre-change of direction phase) and then the side-step (change of direction phase). This study demonstrated that less lateral movement speed towards the intended direction change occurred during reactive compared to pre-planned conditions at pre-change of direction (0.08 +/- 0.28 m.s( 1) and 0.42 +/- 0.25 m.s(-1), respectively) and change of direction foot-strikes (0.25 +/- 0.42 m.s(-1) and 0.69 +/- 0.43 m.s(-1), respectively). Less lateral movement speed during reactive conditions was associated with greater lateral foot displacement (44.52 +/- 6.10% leg length) at the change of direction step compared to pre-planned conditions (41.35 +/- 5.85%). Importantly, the anticipation abilities during reactive conditions provided a means to differentiate between speeds of agility performance, with faster performances displaying greater lateral movement speed at the change of direction foot- strike (0.52 +/- 0.34 m.s(-1)) compared to moderate (0.20 +/- 0.37 m.s(-1)) and slow ( 0.08 +/- 0.31 m.s(-1)). The changes to running technique during reactive conditions highlight the need to incorporate decision-making in rugby union agility programs. Key pointsChanges to running technique occur when required to make a decision.Fast agility performers use different stepping strategies in reactive conditions.Decision-making must be incorporated in agility training programs. PMID- 24149640 TI - Effects of Low-Intensity Cycle Training with Restricted Leg Blood Flow on Thigh Muscle Volume and VO2MAX in Young Men. AB - Concurrent improvements in aerobic capacity and muscle hypertrophy in response to a single mode of training have not been reported. We examined the effects of low intensity cycle exercise training with and without blood flow restriction (BFR) on muscle size and maximum oxygen uptake (VO2max). A group of 19 young men (mean age +/- SD: 23.0 +/- 1.7 years) were allocated randomly into either a BFR training group (n=9, BFR-training) or a non-BFR control training group (n=10, CON training), both of which trained 3 days/wk for 8 wk. Training intensity and duration were 40% of VO2max and 15 min for the BFR-training group and 40% of VO2max and 45 min for the CON-training group. MRI-measured thigh and quadriceps muscle cross-sectional area and muscle volume increased by 3.4-5.1% (P < 0.01) and isometric knee extension strength tended to increase by 7.7% (p < 0.10) in the BFR-training group. There was no change in muscle size (~0.6%) and strength (~1.4%) in the CON-training group. Significant improvements in VO2max (6.4%) and exercise time until exhaustion (15.4%) were observed in the BFR-training group (p < 0.05) but not in the CON-training group (-0.1 and 3. 9%, respectively). The results suggest that low-intensity, short-duration cycling exercise combined with BFR improves both muscle hypertrophy and aerobic capacity concurrently in young men. Key pointsConcurrent improvements in aerobic capacity and muscle hypertrophy in response to a single mode of training have not been reported.In the present study, low-intensity (40% of VO2max) cycle training with BFR can elicit concurrent improvement in muscle hypertrophy and aerobic capacity. PMID- 24149641 TI - Validity of a Commercial Linear Encoder to Estimate Bench Press 1 RM from the Force-Velocity Relationship. AB - The aim of this study was to assess the validity and accuracy of a commercial linear encoder (Musclelab, Ergotest, Norway) to estimate Bench press 1 repetition maximum (1RM) from the force - velocity relationship. Twenty seven physical education students and teachers (5 women and 22 men) with a heterogeneous history of strength training participated in this study. They performed a 1 RM test and a force - velocity test using a Bench press lifting task in a random order. Mean 1 RM was 61.8 +/- 15.3 kg (range: 34 to 100 kg), while 1 RM estimated by the Musclelab's software from the force-velocity relationship was 56.4 +/- 14.0 kg (range: 33 to 91 kg). Actual and estimated 1 RM were very highly correlated (r = 0.93, p<0.001) but largely different (Bias: 5.4 +/- 5.7 kg, p < 0.001, ES = 1.37). The 95% limits of agreement were +/-11.2 kg, which represented +/-18% of actual 1 RM. It was concluded that 1 RM estimated from the force-velocity relationship was a good measure for monitoring training induced adaptations, but also that it was not accurate enough to prescribe training intensities. Additional studies are required to determine whether accuracy is affected by age, sex or initial level. Key pointsSome commercial devices allow to estimate 1 RM from the force-velocity relationship.These estimations are valid. However, their accuracy is not high enough to be of practical help for training intensity prescription.Day-to-day reliability of force and velocity measured by the linear encoder has been shown to be very high, but the specific reliability of 1 RM estimated from the force-velocity relationship has to be determined before concluding to the usefulness of this approach in the monitoring of training induced adaptations. PMID- 24149642 TI - Preexercise urine specific gravity and fluid intake during one-hour running in a thermoneutral environment - a randomized cross-over study. AB - Urine specific gravity is often used to assess hydration status. Athletes who are hypohydrated prior to exercise tend to ingest more fluid during the exercise, possibly to compensate for their pre exercise fluid deficit. The purpose of this study was to evaluate the effect of additional fluid intake on fluid balance and gastrointestinal tract comfort during 1h running in a thermoneutral environment when athletes followed their habitual fluid and dietary regimes. Sixteen men and sixteen women ingested a 6% carbohydrate-electrolyte solution immediately prior to exercise and then every 15 minutes during two runs, with a consumption rate of 2 mL.kg(-1) (LV, lower volume) or 3 mL.kg(-1) (HV, higher volume) body mass. Urine specific gravity and body mass changes were determined before and after the tests to estimate hydration status. During exercise subjects verbally responded to surveys inquiring about gastrointestinal symptoms, sensation of thirst and ratings of perceived exertion. Plasma glucose, heart rate and blood pressure were also evaluated. Men had higher preexercise urine specific gravity than women (1.025 vs. 1.016 g.mL(-1) HV; and 1.024 vs. 1.017 g.mL(-1) LV) and greater sweat loss (1.21 +/- 0.27 L vs. 0.83 +/- 0.21 L HV; and 1.18 +/- 0.23 L vs. 0.77 +/- 0.17 LV). Prevalence of gastrointestinal discomfort increased after 45 min. No significant differences on heart rate, rate of perceived exertion, blood pressure or glycemia was observed with the additional fluid intake. From these results it appears that additional fluid intake reduces body mass loss and thirst sensation. When compared to the men, however, preexercise euhydration was more common in women and an increased fluid intake increases the risk of body mass gain and gastrointestinal discomfort. Key pointsThere seems to be a wide variability in pre-exercise hydration status between male and female and efforts aimed at educating athletes about the importance of pregame hydration must be emphasized.The fluid ingestion during running exercise in a moderate environment reduces body mass loss and thirst sensation, but an increased fluid intake at rates to match the fluid loss might raise the risk of body mass gain in women during prolonged activities.Individual gastric tolerance and familiarization with fluid replacement should be taken into account when providing athletes with strategies for hydration during exercise. PMID- 24149643 TI - Alterations of kinetic characteristics in step up and over test in patients with anterior cruciate ligament deficiency. AB - The purpose of this study is to investigate the alterations of kinetic characteristics in the step up/over test in patients with acute and chronic anterior cruciate ligament (ACL) deficiency. Twenty acute, twenty chronic ACL deficient (ACLD) patients, and forty healthy controls participated in this study. The step up/over test was performed on a clinical force platform system to obtain the following variables: movement time, lift-up index and impact index. The percentages of the indexes from the stepping leg and time of step-up and swing- over were further calculated. These variables were examined statistically by using mixed repeated measure analysis of variance to reveal the differences between groups and between limbs. Smaller lift-up forces and longer swing-over time in both ACLD groups than those in the control group were found. One exception was the lift-up index in the affected side condition of the acute ACLD group, which was not significantly different from the controls. A reduced contribution to the impact index from the affected stepping leg was also found in the acute ACLD group. The acute ACLD group showed no significant change in their step-up strategy at the affected limbs, but they may have a poorer eccentric control of the affected knees on the step and thus put a larger portion of loading onto the unaffected landing leg. Our results indicated the lift-up index, swing-over time and load- distributing strategy at impact may be important parameters in monitoring functional recovery in patients with ACL deficiency. The detected alterations in these parameters could be used as a reference to design proper rehabilitation exercises for these patients. Key pointsThe lift-up index and the time of swing-over could be important parameters for indentifying functional impairments in patients with ACL deficiency.The differences between limbs were found only in the acute ACLD group with a larger lift-up index and smaller load-distribution at impact on the affected limb.The step up/over test on the clinical force platform system could be helpful in providing a reference to design proper rehabilitation exercise and to monitor the recovery of the functional ability in patients with ACL deficiency. PMID- 24149644 TI - Portuguese Coaches' Perceptions of and Preferences for Knowledge Sources Related to their Professional Background. AB - The purpose of this study was to analyse Portuguese coaches' perceptions of, and preferences for, knowledge sources as related to professional background; namely academic education level, coach education level and coaching experience. The study's participants comprised 336 Portuguese coaches from twenty-two sports. A questionnaire was used to identify coaches' demographic characteristics and representations about their preferred sources of coaching knowledge. MANOVA using Tukey's HSD test was used to compare groups. The results highlighted that coaches perceived that coaching knowledge is built from a broad range of sources from personal coaching and playing experiences to more explicit formal, informal and non-formal learning situations. Results indicated that the coaches ascribed more importance to experiential sources such as working with experts, learning by doing, interacting with peer coaches and attending informal seminars and clinics, than to the formal learning situations provided by the national coaching certification programs. Differences, however, were found in that coaches who had a greater background within higher education (physical) and sport valued informal and non-formal learning sources more than did coaches who were defined as not coming from an academic background. The findings point to the importance of developing new learning, experientially-based, opportunities within the Portuguese context, where curricula content continues to be delivered via didactic means. Key pointsCoaches recognized that learning is obtained from a broad range of sources of coaching knowledge and each source has a particular role in the development of a coach.Experiential guided sources reached more importance to coaches as working with experts, learning by doing, attending seminars/clinics outside of the formal system and interaction with peers were the most acknowledged.The only source that is related to formal learning, national certification programs, was recognized as the less importance than all informal and non-formal learning situations.The profile of the source of coaching knowledge showed to be stable among coaches as only the academic education level differentiated the coaches' perceptions. PMID- 24149645 TI - Study of day, month and season pedometer-determined variability of physical activity of high school pupils in the czech republic. AB - Long-term day-to-day monitoring of physical activity (PA) has not been undertaken in adolescents despite PA declines rapidly during adolescence. This study monitored the school year-round pedometer-determined PA of pupils attending high school in the Czech Republic. We assessed their PA levels; appraised the school year-round variability of their PA; and, assessed the associations between their PA levels and weekdays/weekends; months; seasons; and physical education (PE) lessons at school. We observed the PA levels of 10 girls and 2 boys (aged 16.0 +/ 0.7 years). Each pupil wore an unsealed pedometer (Omron HJ-105) on the right side of the waist continuously for one year, and recorded steps/day and daily behaviour (e.g. after-school PA, PE lesson) into an activity diary. In total, participants recorded step counts for 2,979 person- days (82.0% of a possible 3,628 person-days). We used the Missing Values Analysis EM function of SPSS to estimate step values that were missing from the dataset. The sample's mean daily step count was 14,727 +/- 6,612 steps/day, and repeated ANOVA showed differences in steps/day across the days of the week (p < 0.0001), months (p < 0.0001) and seasons (p < 0.0001). The mean number of steps/day for weekdays (15,733 +/- 6,354) was higher (p < 0.0001) than weekends values (12,196 +/- 6,574), and was higher for days with PE lesson (17,280 +/- 5,988) than for days without PE lesson (15,569 +/- 6,318) (p < 0.0001). The total contribution of PE class (90 minutes) to pupils' daily PA was 10.0% additional steps per PE day. In conclusion, this study contributes to understanding the day-to-day PA variability of adolescent pupils across the school year. Across all months and seasons, pupils achieved notably more steps on weekdays than on weekends; and on PE days than on non-PE days. Research is required to assess these findings for school pupils in other countries. Key pointsPedometer appears to be suitable for long-term monitoring of physical activity in adolescents.Day of the week, month and season are significant factors in pedometer-determined day-to-day variability of physical activity of adolescent pupils.Across all months and seasons, pupils achieved notably more steps on weekdays than on weekends, with Sunday being the least active day.Regular PE lessons contribute considerably to the total physical activity levels in adolescent pupils. The increase in steps/day on days with PE is relatively constant throughout the school year regardless of month, season and the content of PE lessons. PMID- 24149646 TI - Warming-Up Affects Performance and Lactate Distribution between Plasma and Red Blood Cells. AB - Warming-up (WU) is a widely used preparation for training and competition. However, little is known about the potential mechanisms of WU on performance and on the lactate distribution in the blood compartment. The purpose of the present study was to investigate whether different WU procedures affect performance and lactate distribution between plasma and red blood cells (RBCs) after maximal exercise. At three different occasions eleven subjects performed one 30 s maximal effort exercise on a cycle ergometer. Before each exercise, subjects warmed up at different intensities: 1. no WU (NWU); 2. extensive WU (EWU); 3. intensive WU (IWU). Blood samples were taken under resting conditions, after WU, and in 1 minute intervals during recovery to determine lactate concentrations [LA] in whole blood ([LA]WB), plasma ([LA]plasma) and erythrocytes ([LA]RBC). Mean power output was +58 Watt (EWU) and +60 Watt (IWU) higher compared to NWU. For each WU condition [LA]plasma and [LA]RBC differed significantly at any time point, showing greater [LA]plasma compared to [LA]RBC. The maximal effort exercise caused a rapid decrease of the [LA]RBC/[LA]plasma ratio. [LA]RBC reached the peak 3-5 minutes later than [LA]plasma depending on the WU condition. The initial increments in [LA]RBC were 10-16% lower after IWU compared to NWU and EWU. The lower increment of [LA]RBC after IWU might be due to a "higher preloading" with lactate before exercise, causing a smaller initial [LA] gradient between plasma and RBCs. It seems that the influx decreases with increasing intracellular [LA]. Another possibility one could speculate about is, that the extracellular increase in [LA] inhibits the outflux of lactate produced by the RBC itself. This inhibited export of lactate from RBCs may lead to an intracellular lactate accumulation. But the relatively fast increase in [LA]RBC and other investigations partly contradicts this possibility. Key pointsWarm-up significantly improves performance during 30 s maximal effort exercise.No differences in performance were found between extensive and intensive warm up.Warm-up and maximal effort exercise affects the lactate distribution between plasma and RBC.Lactate influx into RBC decreases with increasing intracellular lactate concentrations. PMID- 24149647 TI - Accuracy of the Polar S810i(TM) Heart Rate Monitor and the Sensewear Pro Armband(TM) to Estimate Energy Expenditure of Indoor Rowing Exercise in Overweight and Obese Individuals. AB - Accurately assessing the energy expenditure (EE) of different types of physical activity is important for exercise prescription in obese individuals. The aim of this study was to examine the accuracy of the Polar S810i Heart Rate Monitor and SenseWear Pro Armband (SWA) for estimating energy expenditure (EE) during indoor rowing versus indirect calorimetry (IC). 43 overweight and obese adults (16 men, 27 women, BMI = 31.2 +/- 3.7) participated in the study. Within a week after a maximal incremental test on a rowing ergometer, EE was assessed with Polar S810i, SWA and IC during two different intensities of rowing exercises (at 50% VO2max and 70% VO2max) on a Concept II ergometer. Data were analyzed with Pearson's product moment correlations and repeated measures ANOVA. Post hoc multiple comparisons were performed using the Bonferroni test. Bland-Altman plots were created to assess the agreement between the EE estimates and IC measurements. At 50% VO2max, Polar S810i and SWA significantly overestimated EE by 0.5 +/- 0.50 kcal.min(-1) (p < 0.001) and by 0.9 +/- 0.92 kcal.min(-1) (p < 0.001), respectively. At 70% VO2max, no significant differences were found between the SWA and IC, and between Polar S810i and IC measurements. Bland-Altman plots showed good agreements between the measured EE and estimates by Polar S810i and SWA at 70% VO2max. At 50% VO2max, there was a poor agreement between SWA and IC measurements. There were high correlations among three methods at both intensities (r = 0.82 to r = 0.95). In conclusion, Polar S810i and SWA showed reasonable concordance with IC for measuring EE of the moderate intensity exercise but not the lower intensity exercise on indoor rowing in the participants of this study. Polar S810i and SWA might be useful to assess EE during indoor rowing for overweight and obese individuals who try to manage their body weight, but it is necessary to develop exercise and population specific algorithms to enhance the accuracy of SWA to estimate energy expenditure during various intensities of physical exercises. Key pointsPolar S810i and SWA when compared to the indirect calorimetry, provide reasonable estimates of energy expenditure on rowing ergometer at the moderate exercise intensity, but not at the low exercise intensity.The monitor of the Concept II Model D rowing ergometer significantly overestimated the energy expenditure during low and moderate intensity exercises. However there was a moderate correlation between EE estimates of this device and indirect calorimetry measurements. PMID- 24149648 TI - Emotional and cognitive changes during and post a near fatal heart attack and one year after: a case study. AB - This case study reports on changes in emotions before and during an unexpected heart rate in a young, apparently healthy male with a life-long history of exercise in the absence of family history of heart problems. He completed the Brunel Mood Scale (Terry et al. , 2003) to assess emotions before, during, and after the heart attack, and also describing his thoughts during these periods. Results indicate he experienced unpleasant emotions in the build up to the heart attack, feelings he attributed at the time to frustration to achieve fitness goals. He maintained an exercise regime prior to having a heart attack, a finding consistent with previous research suggesting that early diagnosis, although vital for survival, is not likely to be identified among seemingly healthy individuals. During the heart attack, he experienced a rapid emotional change characterised by a rapid increase in anger coupled with thoughts of needing to survive. The intensity of emotions and regulation strategies employed before and during the heart attack provide insight this experience, and we suggest future research should investigate emotional change during adverse conditions. Key pointsThe present case study details emotions experienced and attempts to regulate these emotions before, during and post a heart attack. Unpleasant emotions experienced before the heart were attributed to lack of progress toward fitness goals, a perception that is plausible as he was a regular exerciser.Early identification of heart attack is critical as "Time is Muscle" (Whyte et al., 2009) and therefore even people perceived to be at low risk should consider the possibility of such an eventuality, and seek medical treatment early in the process. PMID- 24149649 TI - Use of Death Certificates to Identify Tuberculosis-Related Deaths in Washington State. AB - CONTEXT: Death certificates are routinely used to estimate tuberculosis (TB) mortality rates. The validity of International Classification of Diseases, Tenth Revision (ICD-10) codes and text cause of death data for this purpose is uncertain. OBJECTIVE: To evaluate the accuracy of ICD-10 coded and text cause of death data in identifying TB-related deaths in Washington State. DESIGN: Cross sectional descriptive study comparing TB-related deaths detected through Washington State death certificates to TB-related deaths identified in the Washington State TB registry during 2009-2010. MAIN OUTCOME MEASURE(S): Sensitivity and positive predictive value of ICD-10 coded and text cause of death definitions in identifying TB-related deaths compared to the TB registry. RESULTS: All methods for identifying TB-related deaths using death certificate data overestimated the number of TB-related deaths compared to the tuberculosis registry. The positive predictive value ranged from 22% for a TB ICD-10 code as an underlying or multiple cause of death to 56% for TB listed in the direct cause of death text field. Seventeen (33%) of 51 subjects assigned with a TB ICD-10 code as an underlying or multiple cause of death had no evidence of TB on the death certificate and were not present in the TB registry. CONCLUSIONS: Death certificates were not highly predictive of TB-related deaths. Use of the direct cause of death text field was the most accurate method to identify a TB-related death when using death certificates. Specific ICD-10 coding algorithms may misclassify subjects as having died from TB. PMID- 24149650 TI - Estimating genome-wide heterozygosity: effects of demographic history and marker type. AB - Heterozygosity-fitness correlations (HFCs) are often used to link individual genetic variation to differences in fitness. However, most studies examining HFCs find weak or no correlations. Here, we derive broad theoretical predictions about how many loci are needed to adequately measure genomic heterozygosity assuming different levels of identity disequilibrium (ID), a proxy for inbreeding. We then evaluate the expected ability to detect HFCs using an empirical data set of 200 microsatellites and 412 single nucleotide polymorphisms (SNPs) genotyped in two populations of bighorn sheep (Ovis canadensis), with different demographic histories. In both populations, heterozygosity was significantly correlated across marker types, although the strength of the correlation was weaker in a native population compared with one founded via translocation and later supplemented with additional individuals. Despite being bi-allelic, SNPs had similar correlations to genome-wide heterozygosity as microsatellites in both populations. For both marker types, this association became stronger and less variable as more markers were considered. Both populations had significant levels of ID; however, estimates were an order of magnitude lower in the native population. As with heterozygosity, SNPs performed similarly to microsatellites, and precision and accuracy of the estimates of ID increased as more loci were considered. Although dependent on the demographic history of the population considered, these results illustrate that genome-wide heterozygosity, and therefore HFCs, are best measured by a large number of markers, a feat now more realistically accomplished with SNPs than microsatellites. PMID- 24149651 TI - Replicated high-density genetic maps of two great tit populations reveal fine scale genomic departures from sex-equal recombination rates. AB - Linking variation in quantitative traits to variation in the genome is an important, but challenging task in the study of life-history evolution. Linkage maps provide a valuable tool for the unravelling of such trait-gene associations. Moreover, they give insight into recombination landscapes and between-species karyotype evolution. Here we used genotype data, generated from a 10k single nucleotide polymorphism (SNP) chip, of over 2000 individuals to produce high density linkage maps of the great tit (Parus major), a passerine bird that serves as a model species for ecological and evolutionary questions. We created independent maps from two distinct populations: a captive F2-cross from The Netherlands (NL) and a wild population from the United Kingdom (UK). The two maps contained 6554 SNPs in 32 linkage groups, spanning 2010 cM and 1917 cM for the NL and UK populations, respectively, and were similar in size and marker order. Subtle levels of heterochiasmy within and between chromosomes were remarkably consistent between the populations, suggesting that the local departures from sex equal recombination rates have evolved. This key and surprising result would have been impossible to detect if only one population was mapped. A comparison with zebra finch Taeniopygia guttata, chicken Gallus gallus and the green anole lizard Anolis carolinensis genomes provided further insight into the evolution of avian karyotypes. PMID- 24149652 TI - Coestimation of recombination, substitution and molecular adaptation rates by approximate Bayesian computation. AB - The estimation of parameters in molecular evolution may be biased when some processes are not considered. For example, the estimation of selection at the molecular level using codon-substitution models can have an upward bias when recombination is ignored. Here we address the joint estimation of recombination, molecular adaptation and substitution rates from coding sequences using approximate Bayesian computation (ABC). We describe the implementation of a regression-based strategy for choosing subsets of summary statistics for coding data, and show that this approach can accurately infer recombination allowing for intracodon recombination breakpoints, molecular adaptation and codon substitution rates. We demonstrate that our ABC approach can outperform other analytical methods under a variety of evolutionary scenarios. We also show that although the choice of the codon-substitution model is important, our inferences are robust to a moderate degree of model misspecification. In addition, we demonstrate that our approach can accurately choose the evolutionary model that best fits the data, providing an alternative for when the use of full-likelihood methods is impracticable. Finally, we applied our ABC method to co-estimate recombination, substitution and molecular adaptation rates from 24 published human immunodeficiency virus 1 coding data sets. PMID- 24149653 TI - The evolution of novelty in conserved genes; evidence of positive selection in the Drosophila fruitless gene is localised to alternatively spliced exons. AB - There has been much debate concerning whether cis-regulatory or coding changes are more likely to produce evolutionary innovation or adaptation in gene function, but an additional complication is that some genes can dramatically diverge through alternative splicing, increasing the diversity of gene function within a locus. The fruitless gene is a major transcription factor with a wide range of pleiotropic functions, including a fundamental conserved role in sexual differentiation, species-specific morphology and an important influence on male sexual behaviour. Here, we examine the structure of fruitless in multiple species of Drosophila, and determine the patterns of selective constraint acting across the coding region. We found that the pattern of selection, estimated from the ratio of non-synonymous to synonymous substitutions, varied considerably across the gene, with most regions of the gene evolutionarily conserved but with several regions showing evidence of divergence as a result of positive selection. The regions that showed evidence of positive selection were found to be localised to relatively consistent regions across multiple speciation events, and are associated with alternative splicing. Alternative splicing may thus provide a route to gene diversification in key regulatory loci. PMID- 24149654 TI - Genetic consequences of habitat fragmentation during a range expansion. AB - We investigate the effect of habitat fragmentation on the genetic diversity of a species experiencing a range expansion. These two evolutionary processes have not been studied yet, at the same time, owing to the difficulties of deriving analytic results for non-equilibrium models. Here we provide a description of their interaction by using extensive spatial and temporal coalescent simulations and we suggest guidelines for a proper genetic sampling to detect fragmentation. To model habitat fragmentation, we simulated a two-dimensional lattice of demes partitioned into groups (patches) by adding barriers to dispersal. After letting a population expand on this grid, we sampled lineages from the lattice at several scales and studied their coalescent history. We find that in order to detect fragmentation, one needs to extensively sample at a local level rather than at a landscape level. This is because the gene genealogy of a scattered sample is less sensitive to the presence of genetic barriers. Considering the effect of temporal changes of fragmentation intensities, we find that at least 10, but often >100, generations are needed to affect local genetic diversity and population structure. This result explains why recent habitat fragmentation does not always lead to detectable signatures in the genetic structure of populations. Finally, as expected, long-distance dispersal increases local genetic diversity and decreases levels of population differentiation, efficiently counteracting the effects of fragmentation. PMID- 24149655 TI - Landscape features and helminth co-infection shape bank vole immunoheterogeneity, with consequences for Puumala virus epidemiology. AB - Heterogeneity in environmental conditions helps to maintain genetic and phenotypic diversity in ecosystems. As such, it may explain why the capacity of animals to mount immune responses is highly variable. The quality of habitat patches, in terms of resources, parasitism, predation and habitat fragmentation may, for example, trigger trade-offs ultimately affecting the investment of individuals in various immunological pathways. We described spatial immunoheterogeneity in bank vole populations with respect to landscape features and co-infection. We focused on the consequences of this heterogeneity for the risk of Puumala hantavirus (PUUV) infection. We assessed the expression of the Tnf-alpha and Mx2 genes and demonstrated a negative correlation between PUUV load and the expression of these immune genes in bank voles. Habitat heterogeneity was partly associated with differences in the expression of these genes. Levels of Mx2 were lower in large forests than in fragmented forests, possibly due to differences in parasite communities. We previously highlighted the positive association between infection with Heligmosomum mixtum and infection with PUUV. We found that Tnf-alpha was more strongly expressed in voles infected with PUUV than in uninfected voles or in voles co-infected with the nematode H. mixtum and PUUV. H. mixtum may limit the capacity of the vole to develop proinflammatory responses. This effect may increase the risk of PUUV infection and replication in host cells. Overall, our results suggest that close interactions between landscape features, co-infection and immune gene expression may shape PUUV epidemiology. PMID- 24149656 TI - Phylogeographic and population genetic analyses reveal Pleistocene isolation followed by high gene flow in a wide ranging, but endangered, freshwater mussel. AB - Freshwater organisms of North America have had their contemporary genetic structure shaped by vicariant events, especially Pleistocene glaciations. Life history traits promoting dispersal and gene flow continue to shape population genetic structure. Cumberlandia monodonta, a widespread but imperiled (IUCN listed as endangered) freshwater mussel, was examined to determine genetic diversity and population genetic structure throughout its range. Mitochondrial DNA sequences and microsatellite loci were used to measure genetic diversity and simulate demographic events during the Pleistocene using approximate Bayesian computation (ABC) to test explicit hypotheses explaining the evolutionary history of current populations. A phylogeny and molecular clock suggested past isolation created two mtDNA lineages during the Pleistocene that are now widespread. Two distinct groups were also detected with microsatellites. ABC simulations indicated the presence of two glacial refugia and post-glacial admixture of them followed by simultaneous dispersal throughout the current range of the species. The Ouachita population is distinct from others and has the lowest genetic diversity, indicating that this is a peripheral population of the species. Gene flow within this species has maintained high levels of genetic diversity in most populations; however, all populations have experienced fragmentation. Extirpation from the center of its range likely has isolated remaining populations due to the geographic distances among them. PMID- 24149657 TI - Home-loving boreal hare mitochondria survived several invasions in Iberia: the relative roles of recurrent hybridisation and allele surfing. AB - Genetic introgression from a resident species into an invading close relative can result from repeated hybridisation along the invasion front and/or allele surfing on the expansion wave. Cases where the phenomenon is massive and systematic, such as for hares (genus Lepus) in Iberia, would be best explained by recurrent hybridisation but this is difficult to prove because the donor populations are generally extinct. In the Pyrenean foothills, Lepus europaeus presumably replaced Lepus granatensis recently and the present species border is parallel to the direction of invasion, so that populations of L. granatensis in the contact zone represent proxies of existing variation before the invasion. Among three pairs of populations sampled across this border, we find less differentiation of mitochondrial DNA (mtDNA) across than along it, as predicted under recurrent hybridisation at the invasion front. Using autosomal microsatellite loci and X- and Y-linked diagnostic loci, we show that admixture across the border is quasi absent, making it unlikely that lack of interspecific mtDNA differentiation results from ongoing gene flow. Furthermore, we find that the local species ranges are climatically contrasted, making it also unlikely that ongoing ecology driven movement of the contact account for mtDNA introgression. The lack of mtDNA differentiation across the boundary is mostly due to sharing of mtDNA from a boreal species currently extinct in Iberia (Lepus timidus) whose mitochondria have thus remained in place since the last deglaciation despite successive invasions by two other species. Home-loving mitochondria thus witness past species distribution rather than ongoing exchanges across stabilised contact zones. PMID- 24149658 TI - A codon-optimized bacterial antibiotic gene used as selection marker for stable nuclear transformation in the marine red alga Pyropia yezoensis. AB - Marine macroalgae play an important role in marine coastal ecosystems and are widely used as sea vegetation foodstuffs and for industrial purposes. Therefore, there have been increased demands for useful species and varieties of these macroalgae. However, genetic transformation in macroalgae has not yet been established. We have developed a dominant selection marker for stable nuclear transformation in the red macroalga Pyropia yezoensis. We engineered the coding region of the aminoglycoside phosphotransferase gene aph7" from Streptomyces hygroscopicus to adapt codon usage of the nuclear genes of P. yezoensis. We designated this codon-optimized aph7" gene as PyAph7. After bombarding P. yezoensis cells with plasmids containing PyAph7 under the control of their endogenous promoter, 1.9 thalli (or individuals) of hygromycin-resistant strains were isolated from a 10-mm square piece of the bombarded thallus. These transformants were stably maintained throughout the asexual life cycle. Stable expression of PyAph7was verified using Southern blot analysis and genomic PCR and RT-PCR analyses. PyAph7 proved to be a new versatile tool for stable nuclear transformation in P. yezoensis. PMID- 24149660 TI - Comparison of different passive knee extension torque-angle assessments. AB - Previous studies have used isokinetic dynamometry to assess joint torques and angles during passive extension of the knee, often without reporting upon methodological errors and reliability outcomes. In addition, the reliability of the techniques used to measure passive knee extension torque-angle and the extent to which reliability may be affected by the position of the subjects is also unclear. Therefore, we conducted an analysis of the intra- and inter-session reliability of two methods of assessing passive knee extension: (A) a 2D kinematic analysis coupled to a custom-made device that enabled the direct measurement of resistance to stretch and (B) an isokinetic dynamometer used in two testing positions (with the non-tested thigh either flexed at 45 degrees or in the neutral position). The intra-class correlation coefficients (ICCs) of torque, the slope of the torque-angle curve, and the parameters of the mathematical model that were fit to the torque-angle data for the above conditions were measured in sixteen healthy male subjects (age: 21.4 +/- 2.1 yr; BMI: 22.6 +/- 3.3 kg m(-2); tibial length: 37.4 +/- 3.4 cm). The results found were: (1) methods A and B led to distinctly different torque-angle responses; (2) passive torque-angle relationship and stretch tolerance were influenced by the position of the non-tested thigh; and (3) ICCs obtained for torque were higher than for the slope and for the mathematical parameters that were fit to the torque-angle curve. In conclusion, the measurement method that is used and the positioning of subjects can influence the passive knee extension torque-angle outcome. PMID- 24149659 TI - Parameters and efficiency of direct gene disruption by zinc finger nucleases in medaka embryos. AB - Zinc finger nucleases (ZFNs) can generate targeted gene disruption (GD) directly in developing embryos of zebrafish, mouse and human. In the fish medaka, ZFNs have been attempted on a transgene. Here, we developed procedures and parameters for ZFN-mediated direct GD on the gonad-specifically expressed gsdf locus in medaka. A pair of ZFNs was designed to target the first exon of gsdf and their synthetic mRNAs were microinjected into 1-cell stage embryos. We reveal dose dependent survival rate and GD efficiency. In fry, ZFN mRNA injection at 10 ng/MUl led to a GD efficiency of 30 %. This value increased up to nearly 100 % when the dose was enhanced to 40 ng/MUl. In a typical series of experiments of ZFN mRNA injection at 10 ng/MUl, 420 injected embryos developed into 94 adults, 4 of which had altered gsdf alleles. This leads to a GD efficacy of ~4 % in the adulthood. Sequencing revealed a wide variety of subtle allelic alterations including additions and deletions of 1~18 bp in length in ZFN-injected samples. Most importantly, one of the 4 adults examined was capable of germline transmission to 15.2 % of its F1 progeny. Interestingly, ontogenic analyses of the allelic profile revealed that GD commenced early in development, continued during subsequent stages of development and in primordia for different adult organs of the three germ layers. These results demonstrate the feasibility and- for the first time to our knowledge--the efficacy of ZFN-mediated direct GD on a chromosomal gene in medaka embryos. PMID- 24149663 TI - Electroacupuncture: applications in the treatment of chronic nonhealing wounds. AB - Maximizing the effectiveness of any wound treatment requires that normal wound healing dynamics are appreciated. In considering adjuvant wound therapies, the clinical evidence supporting a therapy must be fully understood. The biological changes associated with electroacupuncture can have a positive effect on wound healing, although limited clinical data are available. PMID- 24149664 TI - Tissue destruction classification systems. AB - Assessing the level of tissue destruction in wounds can be a confusing challenge. This important task is frequently accompanied by questions and the need for clarification to accurately classify the level of damage seen in wounds. The purpose of this article was to present several known classification systems to help clarify this issue for the clinician. PMID- 24149665 TI - Pressure ulcer treatment in pediatric patients. AB - OBJECTIVE: To assess pressure ulcer (PrU) treatment in Swiss hospitalized pediatric patients and to determine whether there are differences in PrU treatment, according to demographic characteristics of the patients. DESIGN: A descriptive multicenter point prevalence study was conducted in June 2009 in all German-speaking pediatric hospitals in Switzerland. SETTING: All hospitalized patients from birth up to 17 years or younger in 14 Swiss pediatric hospitals, including all pediatric departments, were assessed. PATIENTS: A total of 412 patients participated in this study. MAIN OUTCOME MEASURES: The instrument and method of the Dutch National Prevalence Measurement of Care Problems were used. MAIN RESULTS: Thirty-five percent of the patients had a PrU. Almost all of these PrUs (94.1%) were of category 1. The most severe PrUs occurred in patients older than 8 years. Age of the patient and department were the only characteristics that significantly influenced the occurrence of PrU categories 2 to 4. Pressure ulcer categories 2 to 4 were mostly covered with hydrocolloid or polyurethane foam dressings. No pediatric-specific guideline regarding PrU treatment is used in the involved hospitals. CONCLUSION: Most patients had category 1 PrUs, so appropriate prevention to decrease any further trauma in these patients was necessary. Severe PrUs (categories 2-4) are mostly limited to older pediatric (aged >8 years) patients with chronic conditions or after surgery intervention. A PrU treatment guideline adapted for pediatric needs is recommended. PMID- 24149667 TI - Meaningful reports drive process improvement. PMID- 24149666 TI - Best practices for the management of foot ulcers in people with diabetes. AB - Care of people with diabetic foot ulcers requires a systematic approach following the wound bed preparation paradigm and the existing best practice recommendations. The purpose of this article is to summarize key evidence and recommendations regarding prevention and management of diabetic foot ulcers that can be translated into practice. PMID- 24149668 TI - Guided fracture of films on soft substrates to create micro/nano-feature arrays with controlled periodicity. AB - While the formation of cracks is often stochastic and considered undesirable, controlled fracture would enable rapid and low cost manufacture of micro/nanostructures. Here, we report a propagation-controlled technique to guide fracture of thin films supported on soft substrates to create crack arrays with highly controlled periodicity. Precision crack patterns are obtained by the use of strategically positioned stress-focusing V-notch features under conditions of slow application of strain to a degree where the notch features and intrinsic crack spacing match. This simple but robust approach provides a variety of precisely spaced crack arrays on both flat and curved surfaces. The general principles are applicable to a wide variety of multi-layered materials systems because the method does not require the careful control of defects associated with initiation-controlled approaches. There are also no intrinsic limitations on the area over which such patterning can be performed opening the way for large area micro/nano-manufacturing. PMID- 24149669 TI - Battery life of portable home ventilators: effects of ventilator settings. AB - BACKGROUND: The battery life (BL) of portable home ventilator batteries is reported by manufacturers. The aim of this study was to evaluate the effects of ventilator mode, breathing frequency, PEEP, and leaks on the BL of 5 commercially available portable ventilators. METHODS: The effects of the ventilator mode (volume controlled-continuous mandatory ventilation [VC-CMV] vs pressure support ventilation [PSV]), PEEP 5 cm H2O, breathing frequency (10, 15, and 20 breaths/min), and leaks during both volume-targeted ventilation and PSV on the BL of 5 ventilators (Elisee 150, Monnal T50, PB560, Vivo 50, and Trilogy 100) were evaluated. Each ventilator was ventilated with a test lung at a tidal volume of 700 ml and an inspiratory time of 1.2 s in the absence of leaks. RESULTS: Switching from PSV to VC-CMV or the addition of PEEP did not significantly change ventilator BL. The increase in breathing frequency from 10 to 20 breaths/min decreased the BL by 18 +/- 11% (P = .005). Leaks were associated with an increase in BL during the VC-CMV mode (18 +/- 20%, P = .04) but a decrease in BL during the PSV mode (-13 +/- 15%, P = .04). CONCLUSIONS: The BL of home ventilators depends on the ventilator settings. BL is not affected by the ventilator mode (VC CMV or PSV) or the addition of PEEP. BL decreases with an increase in breathing frequency and during leaks with a PSV mode, whereas leaks increase the duration of ventilator BL during VC-CMV. PMID- 24149670 TI - Longitudinal evaluation of compressor/nebulizer performance. AB - BACKGROUND: Inhaled medications are the mainstay of treatment for maintenance of lung health in patients with cystic fibrosis (CF). Compressor/nebulizer units are used an average of 100-120 min/d by patients with CF. Each compressor/nebulizer has unique flow/pressure characteristics that affect particle size distribution and drug output rate. Few data are available regarding longitudinal performance of compressor/nebulizers. We hypothesized that their use over a 24-wk period under conditions similar to those of patients with CF would affect their performance. METHODS: Four new units of compressor/reusable nebulizers from 3 brands (Pari Vios/Pari LC Plus, Pulmo-Aide 5650D/Viox, and Inspiration Elite/SideStream Plus) commonly used by patients with CF were tested. Compressor/nebulizers were operated for 1 h twice daily 5 d/wk for 24 wk. Compressor flow/pressure characteristics were measured every 6 wk. Maximal flow was recorded without and with the nebulizer (MF and MF/NEB, respectively). Pressure was recorded at zero flow (MP) and at MF/NEB (P/NEB). Particle size distribution, inhaled mass (IM), and IM in respirable range were evaluated at baseline and every 12 wk. RESULTS: Vios had statistically significant declines in MP and P/NEB at each measurement compared with baseline (45.8 and 32.6 psi for MP and 16.7 and 14.3 psi for P/NEB at wk 0 and 24, respectively, P < .05), but other compressors did not. MF and MF/NEB were stable over time but significantly varied among brands. Vios had the greatest slope of flow/pressure relationship (Vios > Pulmo-Aide > Inspiration Elite). Two Vios units stopped working at wk 11 and 24, respectively. All compressors maintained baseline IM, IM in respirable range, and aerosol characteristics. CONCLUSIONS: Long-term use of compressor/nebulizers in a regimen similar to that of patients with CF affected their performance. Pari Vios was the most affected brand, with declines in MP and P/NEB and 2 units that stopped working. Measurement of MF and MF/NEB could help identify compressors that are likely to fail. PMID- 24149671 TI - Unexplained persistent dyspnea in a young woman with eosinophilic angiocentric fibrosis. AB - Eosinophilic angiocentric fibrosis (EAF) is a rare inflammatory disease that primarily involves the nose and sinuses. Involvement of the eye orbit and larynx has also been described. However, it is very rare for this disease to involve the lower respiratory tract and cause dyspnea. We describe a rare case of EAF involving the lower respiratory tract with airway narrowing. A 29-year-old female with a 7-year history of nasal obstruction presented with unexplained persistent dyspnea. EAF was diagnosed via endoscopic biopsy of an irregular mucosal lesion in the posterior wall of the right maxillary sinus. Chest computed tomography and bronchoscopy showed a diffuse inflammatory narrowing of the airway in the tracheobronchial trees. EAF can affect lower respiratory tracts with airway narrowing that can be characterized by dyspnea. We must consider narrowing of the lower respiratory tracts in patients with EAF complaining of unexplained persistent dyspnea. PMID- 24149672 TI - Physical training and noninvasive ventilation in COPD patients: a meta-analysis. AB - BACKGROUND: Exercise training improves both exercise tolerance and quality of life in patients with COPD. The intensity of exercise training is crucial to achieve a true physiologic effect. However, in COPD patients, exertional dyspnea and leg fatigue mean that the patient cannot maintain intensity of training for enough time to yield a physiologic training effect. The use of noninvasive ventilation (NIV) support has been proposed as an alternative strategy to improve exercise tolerance and respiratory and cardiovascular performances. The first aim of our meta-analysis was to evaluate exercise training with NIV in terms of physiologic effects after the completion of a pulmonary rehabilitation program. The second aim was to investigate the dose-response relationship between physical improvement and training intensity. METHODS: Literature research was performed using MEDLINE, Embase, and CINAHL. Meta-analysis and meta-regressions were performed using random effects models. RESULTS: Eight studies provided a proper description of a training schedule in stable COPD patients. A similar effect between NIV and placebo was observed for the outcomes considered despite differences between studies. However, subjects experienced a relevant and statistically significant improvement after rehabilitation for almost all of the outcomes considered. Heart rate (6 beats/min [95% CI 0.94-11.01], P = .02), work load (9.73 W [95% CI 3.78-15.67], P < .001), and oxygen consumption (242.11 mL/min [95% CI 154.93-329.9], P < .001) significantly improved after training. Improvements in heart rate and work load were significantly correlated to training intensity. CONCLUSIONS: Given the small number of available studies, the small sample sizes, and the complete absence of power calculation, we think that this topic deserves a more in-depth investigation. Randomized clinical trials with larger sample sizes based on statistical power calculations and designed to investigate the effect of training duration and intensity on rehabilitation are needed to confirm results in this important field. PMID- 24149673 TI - Reversible pre-capillary pulmonary hypertension due to dasatinib. AB - Pulmonary arterial hypertension and secondary pleural effusion have been reported in association with long-term therapy with the multi-tyrosine kinase inhibitor dasatinib, approved for the treatment of chronic myeloid leukemia. Here, we present the case of a 50-year-old man, diagnosed with chronic myeloid leukemia in August 2003, who developed pulmonary arterial hypertension after > 4 years of treatment with dasatinib. The complete remission of pulmonary arterial hypertension following dasatinib discontinuation suggests an etiological role of the drug in its development, although the administration of sildenafil may have played a therapeutic role. PMID- 24149674 TI - More and better should be done to guarantee evidence-based management of ADHD in children across Europe. PMID- 24149676 TI - Preparation of hollow nickel silicate nanospheres for separation of His-tagged proteins. AB - Hollow nickel silicate nanospheres (NiSiO3 NSs) with hierarchical shells were hydrothermally synthesized by using silica spheres as a template. The NiSiO3 NSs have an average diameter of 250 nm with a shell thickness of 50 nm, and the hierarchical shell consists of a large number of sheets. By taking advantage of the high affinity of Ni(2+) toward histidine-tagged (His-tagged) proteins, hollow NiSiO3 NSs can be used to enrich and separate His-tagged proteins directly from a mixture of lysed cells. Results indicated that the hollow NiSiO3 NSs presented negligible nonspecific protein adsorption and a high protein binding ability with a high binding capacity of 13.2 mmol g(-1). Their specificity and affinity toward His-tagged proteins remained after recycling 5 times. The hollow NiSiO3 NSs are especially suitable for rapid purification of His-tagged proteins. PMID- 24149678 TI - Regioselective synthesis of oxepinones and azepinones by gold-catalyzed cycloisomerization of functionalyzed cyclopropyl alkynes. AB - A regioselective synthesis of oxepinones and azepinones in good to excellent yields from alkynylcyclopropanecarboxylic acid derivatives is described. This novel cycloisomerization cascade process consists of a nucleophilic addition followed by a cyclopropane ring-opening, where both donor and acceptor groups are required as substituents of the cyclopropane ring. PMID- 24149677 TI - Interaction of microbes with mucus and mucins: recent developments. AB - Due to the recent rapid expansion in our understanding of the composition of the gut microflora and the consequences of altering that composition the question of how bacteria colonise mucus layers and interact with components of mucus, such as mucin, is now receiving widespread attention. Using a combination of mucus secreting cells, and a novel mucin microarray platform containing purified native mucins from different sources we recently demonstrated that two gastrointestinal pathogens, Helicobacter pylori and Campylobacter jejuni, colonise mucus by different mechanisms. This result emphasizes the potential for even closely related bacteria to interact with mucus in divergent ways to establish successful infection. Expanding the use of the mucin arrays described in the study to other microorganisms, both pathogenic and commensal, should lead to the discovery of biologically important motifs in bacterial-host interactions and complement the use of novel in vitro cell models, such as mucus secreting cell lines. PMID- 24149680 TI - Indian students' perspectives on obesity and school-based obesity prevention: a qualitative examination. AB - Childhood obesity has recently been reported as a growing problem in low- and middle-income countries. One potential prevention strategy is to apply effective obesity prevention approaches from the United States and/or other Western countries into programs that can be implemented in developing countries such as India. The purpose of this study was to explore Indian students' perceptions of social-contextual factors related to obesity and whether they perceived a role for school-based obesity prevention. This study was conducted as a first step in a model to translate interventions from one culture to another. A total of 183 fourth- and fifth-grade students of middle socioeconomic status participated in focus group discussions. Analyses were guided by the essential principles of qualitative research and informed by social cognitive and social ecological theories. Results yielded five relevant themes: (a) student health behavior knowledge, (b) parental influence on health behavior, (c) school influence on health behavior, (d) media influence on health behavior, and (e) contexts for health promotion intervention. We found that students had moderate knowledge related to health behaviors (i.e., food intake and physical activity); that parents, schools, and the media are all important contributors to healthy and unhealthy behavior; and that schools can play an important role in the prevention of obesity. Results suggest that Indian middle socioeconomic status students are already moderately aware of the health benefits to nutritious food intake and physical activity, but parents, schools, and the media can influence unhealthy behaviors. PMID- 24149681 TI - Comparison of active and electrostimulated recovery strategies after fatiguing exercise. AB - The purpose of this study was to compare an electrostimulated to an active recovery strategy after a submaximal isometric fatiguing exercise. Nineteen healthy men completed three sessions (separated by at least 4 weeks) which included a knee extensors provocation exercise consisting of 3 sets of 25 isometric contractions. Contraction intensity level was fixed respectively at 60%, 55% and 50% of previously determined maximal voluntary contraction for the first, second and third sets. This provocation exercise was followed by either an active (AR) recovery (25 min pedaling on a cycle ergometer), an electrostimulated (ESR) recovery (25-min continuous and non-tetanic (5 Hz) stimulation of the quadriceps) or a strictly passive recovery (PR). Peak torques of knee extensors and subjective perception of muscle pain (VAS, 0-10) were evaluated before (pre ex), immediately after the provocation exercise (post-ex), after the recovery period (post-rec), as well as 75 minutes (1h15) and one day (24h) after the exercise bout. Time course of peak torque was similar among the different recovery modes: ~ 75% of initial values at post-ex, ~ 90% at post-rec and at 1h15. At 24h, peak torque reached a level close to baseline values (PR: 99.1 +/- 10.7%, AR: 105.3 +/- 12.2%, ESR: 104.4 +/- 10.5%). VAS muscle pain scores decreased rapidly between post-ex and post-rec (p < 0.001); there were no significant differences between the three recovery modes (p = 0.64). In conclusion, following a submaximal isometric knee extension exercise, neither electrostimulated nor active recovery strategies significantly improved the time course of muscle function recovery. Key pointsThree sets of submaximal isometric contractions at 60%, 55% and 50% of MVC induced an early fatigue without DOMS but did not lead to exhaustion.In comparison with passive recovery, active and electrostimulated recovery did not lead to significantly higher MVC torques 24h after the exercise bout.No significant differences were demonstrated between the effects of passive, active and electrostimulated recoveries on muscle pain after repeated submaximal isometric contractions. PMID- 24149682 TI - Time Course Change of IGF1/Akt/mTOR/p70s6k Pathway Activation in Rat Gastrocnemius Muscle During Repeated Bouts of Eccentric Exercise. AB - The purpose of this study was to examine whether insulin-like growth factor (IGF 1) and Akt/mTOR/p70S6K pathway activity is altered by chronic eccentric exercise in rat medial gastrocnemius muscle. Male Wistar rats (n = 24) were randomly assigned to 1 of the 2 groups: eccentric exercise (ECC) group or sham-operated control (CON) group. Rats in the ECC group were trained every second day for 10 days (5 sessions in total) or 20 days (10 sessions in total). After either 5 or 10 exercise sessions, muscle specimens were dissected and weighed. The mRNA expression of IGF-1 and its variant, mechano growth factor (MGF), was evaluated using real time reverse transcriptase-polymerase chain reaction (RT-PCR). Tissue concentrations of Akt (P), mTOR (P), and p70S6K (P) were measured by using western blot analysis. The medial gastrocnemius muscle mass of the ECC group did not show any significant difference after 5 exercise sessions, whereas the muscle mass increased significantly after 10 exercise sessions with a concomitant increase in the cross-sectional area of muscle fibers (p < 0.05). The expression of IGF-1 mRNA and the tissue concentrations of Akt (P) and p70S6K (P) after 10 exercise sessions was significantly higher than those of the age-matched controls and the rats that received 5 exercise sessions. The expression of MGF mRNA in both ECC5S and ECC10S were significantly higher than that in each period-matched control (p < 0.01). The tissue concentration of mTOR (P) after 10 sessions showed a significant increase when compared with period-matched controls (p < 0.01). These results suggest that activation of the IGF-1/Akt/mTOR/p70S6K signaling pathway becomes dominant in the later phase of chronic exercise, when significant muscular hypertrophy is observed. Key pointsWe confirmed that the rat muscular exercise model using originally-developed equipment increased the wet mass of the medial gastrocnemius muscle and cross-sectional areas of muscle fibres in 10 sessions (20 days) but not in 5 sessions (10days).We clarified that the increases of muscle mass and CSA of muscle fibers were accompanied by IGF-1 mRNA expression, the phosphorylated Akt, mTOR, and p70S6K.These results suggest that muscular hypertrophy in our model was achieved after 10 sessions of exercise and associated with the activation of IGF-1/Akt/mTOR/p70S6K signal pathway. PMID- 24149683 TI - Heart rate variability before and after cycle exercise in relation to different body positions. AB - The purpose of this study was to assess the effect of three different body positions on HRV measures following short-term submaximal exercise. Thirty young healthy males performed submaximal cycling for five minutes on three different occasions. Measures of HRV were obtained from 5-min R to R wave intervals before the exercise (baseline) and during the last five minutes of a 15 min recovery (post-exercise) in three different body positions (seated, supine, supine with elevated legs). Measures of the mean RR normal-to-normal intervals (RRNN), the standard deviation of normal-to-normal intervals (SDNN), the root mean square of successive differences (RMSSD) and the low-frequency (LF) and the high-frequency (HF) spectral power were analyzed. Post-exercise RRNN, RMSSD were significantly higher in the two supine positions (p < 0. 01) compared with seated body position. Post-exercise ln LF was significantly lower in the supine position with elevated legs than in the seated body position (p < 0.05). No significant difference was found among the three different body positions for post-exercise ln HF (p > 0.05). Post-exercise time domain measures of HRV (RRNN, SDNN, RMSSD) were significantly lower compared with baseline values (p < 0.01) regardless body position. Post-exercise ln LF and ln HF in all three positions remained significantly reduced during recovery compared to baseline values (p < 0.01). The present study suggests that 15 minutes following short-term submaximal exercise most of the time and frequency domain HRV measures have not returned to pre exercise values. Modifications in autonomic cardiac regulation induced by body posture present at rest remained after exercise, but the post-exercise differences among the three positions did not resemble the ones established at rest. Key pointsWhether different body positions may enhance post-exercise recovery of autonomic regulation remains unclear.The absence of restoration of HRV measures after 15 minutes of recovery favor the existence of modifying effects of exercise on mechanisms underlying heart regulation.On the basis of discrepancies in HRV measures in different body positions pre- and post-exercise we argue that the pace of recovery of cardiac autonomic regulation is dependent on body posture. PMID- 24149684 TI - Effects of caffeine on exercise performance in sedentary females. AB - The purpose of the study was to examine the effect of caffeine ingestion on total work, average power, oxygen consumption (VO2), respiratory exchange ratio (RER), ratings of perceived exertion (RPE), heart rate (HR) and energy expenditure (kJ) during stationary cycling at a standardised power output, as well as during a set time period where participants were required to cycle as fast as they could. Ten healthy, sedentary, female, non- regular caffeine users completed 15 min of stationary cycling at a standardised power output equating to 65% HRmax (Phase A), followed by 10 min of stationary cycling where they were required to cycled as fast as they could (Phase B) after ingesting 6.0 mg.kg(-1) of caffeine or placebo 60 min prior to exercise. VO2 and energy expenditure were significantly higher at the end of Phase A (p = 0.008 and p = 0.011, respectively). All other variables examined in Phase A were similar between trials. In Phase B, there were no significant differences found for any variable assessed. While caffeine ingestion resulted in significant increases in VO2 and energy expenditure during steady-state exercise, it did not improve cycling performance during a 10 min trial where participants were required to cycle as fast as they could. Key pointsA 6.0 mg.kg(-1) dose of caffeine did not improve work done (J.kg(-1)) or mean power (W) during 10 min of self-paced stationery cycling in sedentary female participants.A 6.0 mg.kg(-1) dose of caffeine significantly increased VO2 and energy expenditure (kJ) during 15 min of steady-state stationery cycling in sedentary female participants.A 6.0 mg.kg(-1) dose of caffeine did not significantly affect RPE, RER or HR during 15 min of steady-state cycling or 10 min of cycling performed as fast as the participant could achieve, when compared to placebo, in sedentary female participants. PMID- 24149685 TI - The relative age effect in youth soccer players from Spain. AB - The purpose of this study was to identify the existence of Relative Age Effect (RAE) at youth level in both elite and amateur Spanish soccer clubs, and also to carry out an analysis providing with information on how this effect has evolved in recent years. We have obtained information on the youth teams of the 20 clubs belonging to the Spanish Professional Football League (LFP) in two separate seasons (2005-2006 and 2008-2009) as well as data on five youth academies belonging to amateur clubs. The collected data revealed an over- representation of players born in the first months of the selection year in all groups of analysis (Elite 2005-2006, Elite 2008-2009 and Amateurs), although only the Elite groups showed significant variations in birth-date distribution in relation to the Spanish population. The results showed a reduction in RAE from the 2005-2006 season to the 2008-2009 season. The following variables - playing position, the number of years each player has spent in their specific age group and the category of the team at each club were shown not to have influence on the extent of RAE. Key pointsThere was RAE in all groups analyzed, although only the Elite groups showed significant variations in birth-date distribution in relation to the general population.RAE is more evident in the Elite groups than in the Amateur probably because of the detection process, which is more thorough in the Elite groups.Playing position, number of years in their specific age group and category of the team did not have any influence on the extent of RAE.Any attempts to prevent RAE should be based on a stable sport policy and the implication of all the stakeholders in the system. All of them should think in the development of a player as a long-term project. PMID- 24149686 TI - Testing of tactical performance in youth elite soccer. AB - This is a twofold study with the goals of evaluating tactical oriented game test situations for 12-13-year old highly-talented soccer players and to analyze dynamic, intra-individual developments of the players. A cross-sectional design was carried in study 1, using game test situations to measure specific tactics and creative performance for 195 expert players. The results from five evaluation criteria show that both diagnostic instruments can be used for recording football specific creativity and game intelligence in talented young players. They produced tactical indicators that can be described as objective and valid, exhibit a sufficient degree of differentiation and are easy to record. Study 2 uses a longitudinal design to present a dynamic performance diagnostic tool for analyzing intra-individual improvements of German Soccer Foundation talents according to football-specific creativity and game intelligence. The results with respect to divergent tactical thinking clearly show that very different change processes were observed in the German Soccer Foundation players. Finally, the practical implications for the training process are discussed on the basis of both studies. Key pointsWith game test situations it is possible to assess tactical performance as game intelligence and creativity objective, valid, with a sufficient degree of differentiation, and economically.The results with respect to game intelligence and creativity show that very different change processes were observed in the German Soccer Foundation players dependend on the bases (trainers).Current literature on tactics for school sports as well as for children's, youth and high performance soccer at the club level should place much more emphasis on individual and group-tactical requirements in soccer. PMID- 24149687 TI - The acute effects of back squats on vertical jump performance in men and women. AB - The aim of the present study was to investigate the acute effects of performing back squats on subsequent performance during a series of vertical jumps in men and women. Twelve men and 12 women were tested on three separate occasions, the first of which was used to determine their 1-repetition maximum (1-RM) parallel back squat. Following this, subjects performed a potentiation and a control treatment in a counterbalanced order. The potentiation treatment culminated with subjects performing parallel back squats with a load equivalent to 70% 1- RM for three repetitions, following which they performed one countermovement vertical jump (CMJ) for maximal height every three minutes for a total of 10 jumps. During the control treatment, subjects performed only the CMJs. Jump height (JH) and vertical stiffness (VStiff) were calculated for each jump from the vertical force signal recorded from a force platform. There were no significant changes in JH or VStiff following the treatments and no significant differences in the responses between men and women (p > 0.05). Correlations between normalized 1-RM back squat load and the absolute change in JH and VStiff were small to moderate for both men and women, with most correlations being negative. Large variations in response to the back squats were noted in both men and women. The use of resistance exercises performed prior to a series of vertical jumps can result in improvements in performance in certain individuals, although the gains tend to be small and dependent upon the mechanical variable measured. There does not seem to be any differences between men and women in the response to dynamic potentiation protocols. Key pointsSubstantial individual responses were noted in both men and women in response to the PAP protocol used in the present study.The choice of dependent variable influences the ef-ficacy of the PAP protocol, with JH and VStiff demonstrating disparate responses in individual sub-jects.Such individual responses may render such PAP protocols impractical for strength and conditioning practitioners as the protocols are likely to require in-dividualizing to each athlete. PMID- 24149688 TI - Women and Men in Sport Performance: The Gender Gap has not Evolved since 1983. AB - Sex is a major factor influencing best performances and world records. Here the evolution of the difference between men and women's best performances is characterized through the analysis of 82 quantifiable events since the beginning of the Olympic era. For each event in swimming, athletics, track cycling, weightlifting and speed skating the gender gap is fitted to compare male and female records. It is also studied through the best performance of the top 10 performers in each gender for swimming and athletics. A stabilization of the gender gap in world records is observed after 1983, at a mean difference of 10.0% +/- 2.94 between men and women for all events. The gender gap ranges from 5.5% (800-m freestyle, swimming) to 18.8% (long jump). The mean gap is 10.7% for running performances, 17.5% for jumps, 8.9% for swimming races, 7.0% for speed skating and 8.7% in cycling. The top ten performers' analysis reveals a similar gender gap trend with a stabilization in 1982 at 11.7%, despite the large growth in participation of women from eastern and western countries, that coincided with later- published evidence of state-institutionalized or individual doping. These results suggest that women will not run, jump, swim or ride as fast as men. Key pointsSex is a major factor influencing best performances and world records.A stabilization of the gender gap in world records is observed after 1983, at a mean difference of 10.0% +/- 2.94 between men and women for all events.The gender gap ranges from 5.5% (800-m freestyle, swimming) to 36.8% (weight lifting).The top ten performers' analysis reveals a similar gender gap trend with a stabilization in 1982 at 11.7%.Results suggest that women will not run, jump, swim or ride as fast as men. PMID- 24149689 TI - Metabolic and cardiovascular responses to upright cycle exercise with leg blood flow reduction. AB - The purpose of this study was to examine the metabolic and cardiovascular response to exercise without (CON) or with (BFR) restricted blood flow to the muscles. Ten young men performed upright cycle exercise at 20, 40, and 60% of maximal oxygen uptake, VO2max in both conditions while metabolic and cardiovascular parameters were determined. Pre-exercise VO2 was not different between CON and BFR. Cardiac output (Q) was similar between the two conditions as a 25% reduction in stroke volume (SV) observed in BFR was associated with a 23% higher heart rate (HR) in BFR compared to CON. As a result rate-pressure product (RPP) was higher in the BFR but there was no difference in mean arterial pressure (MAP) or total peripheral resistance (TPR). During exercise, VO2 tended to increase with BFR (~10%) at each workload. Q increased in proportion to exercise intensity and there were no differences between conditions. The increase in SV with exercise was impaired during BFR; being ~20% lower in BFR at each workload. Both HR and RPP were significantly greater at each workload with BFR. MAP and TPR were greater with BFR at 40 and 60% VO2max. In conclusion, the BFR employed impairs exercise SV but central cardiovascular function is maintained by an increased HR. BFR appears to result in a greater energy demand during continuous exercise between 20 and 60% of control VO2max; probably indicated by a higher energy supply and RPP. When incorporating BFR, HR and RPP may not be valid or reliable indicators of exercise intensity. Key pointsBlood flow reduction (BFR) employed impairs stroke volume (SV) during exercise, but central cardiovascular function is maintained by an increased heart rate (HR).BFR appears to result in a greater energy demand during continuous exercise between 20 and 60% of control VO2max;Probably indicated by a higher energy supply (VO2) and rate-pressure product (HR x systolic blood pressure). PMID- 24149690 TI - Motivational cluster profiles of adolescent athletes: an examination of differences in physical-self perception. AB - The primary purpose of the present study was to identify motivational profiles of adolescent athletes using cluster analysis in non-Western culture. A second purpose was to examine relationships between physical self-perception differences of adolescent athletes and motivational profiles. One hundred and thirty six male (Mage = 17.46, SD = 1.25 years) and 80 female adolescent athletes (Mage = 17.61, SD = 1.19 years) from a variety of team sports including basketball, soccer, volleyball, and handball volunteered to participate in this study. The Sport Motivation Scale (SMS) and Physical Self-Perception Profile (PSPP) were administered to all participants. Hierarchical cluster analysis revealed a four cluster solution for this sample: amotivated, low motivated, moderate motivated, and highly motivated. A 4 x 5 (Cluster x PSPP Subscales) MANOVA revealed no significant main effect of motivational clusters on physical self-perception levels (p > 0.05). As a result, findings of the present study showed that motivational types of the adolescent athletes constituted four different motivational clusters. Highly and moderate motivated athletes consistently scored higher than amotivated athletes on the perceived sport competence, physical condition, and physical self-worth subscales of PSPP. This study identified motivational profiles of competitive youth-sport participants. Key pointsHighly motivated athletes have a tendency to perceive themselves competent in psychomotor domains as compared to the amotivated athletesAs the athletes feel more competent in psychomotor domain, they are more intrinsically motivated.The information about motivational profiles of adolescent athletes could be used for developing strategies and interventions designed to improve the strength and quality of sport participants' motivation. PMID- 24149691 TI - Differences in Physical Fitness and Cardiovascular Function Depend on BMI in Korean Men. AB - We investigated the associations between cardiovascular function and both body mass index and physical fitness in Korean men. The subjects were 2,013 men, aged 20 to 83 years, who visited a health promotion center for a comprehensive medical and fitness test during 2006-2009. The WHO's Asia-Pacific Standard Report definition of BMI was used in this study. Fitness assessment of cardiorespiratory endurance, muscular strength, muscular endurance, flexibility, power, agility, and balance were evaluated by VO2max (ml/kg/min), grip strength (kg), sit-ups (reps/min), sit and reach (cm), vertical jump (cm), side steps (reps/30s), and standing on one leg with eyes closed (sec), respectively. For cardiovascular function, we evaluated systolic blood pressure (SBP), diastolic blood pressure (DBP), resting heart rate (RHR), double product (DP), and vital capacity. There were significant decreases in cardiorespiratory endurance (p < 0.001), power (p < 0.001), and balance (p < 0.001), and increases in muscular strength (p < 0.001). Further, cardiovascular function, including SBP (p < 0.001), DBP (p < 0.001), double product (p < 0.001), and vital capacity (p=0.006) appeared to be lower for the obesity group. We conclude that an obese person exhibits lower fitness level and weaker cardiovascular function than a normal person. Key pointsThe obese group had a lower fitness level, including cardiorespiratory endurance, power, and balance.Obese group demonstrated an increase in muscular strength.Obese group had higher blood pressure and weaker cardiovascular function, including DP and vital capacity, than the normal group. PMID- 24149692 TI - The calciotropic hormone response to omega-3 supple-mentation during long-term weight-bearing exercise training in post menopausal women. AB - The purpose of this study was to examine the effects of ingestion of omega-3 (n 3) and aerobic exercise intervention on the calcium regulating hormones in healthy postmenopausal women. To this end, 56 healthy sedentary postmenopausal women with mean age 57.7 +/- 3.5 yrs participated in this study. Participants were randomly divided into exercise plus supple-ment (E+S; n = 14), exercise (E; n = 14), supplement (S; n = 14) and control (Con, n = 14) groups. The subjects in E+S and E groups performed aerobic exercise training (walking and jog-ging) up to 65% of exercise HRmax, three times a week for 16 weeks. Subjects in E+S and S groups were asked to consume 1000 mg/d omega-3 for 16 weeks. The blood ionized Calcium (Ca(+2)), Parathyroid hormone (PTH), estrogen and Calcitonin (CT) were measured before and after 16 weeks of exercise training. Results indicated that consuming 1000 mg.day(-1) omega-3 during 16 weeks and or the aerobic exercise, significantly increased CT (p = 0.001) in E+S, E and S groups and significantly decreased PTH (p = 0.001) levels in E+S and E groups, also significantly increased estrogen (p = 0.024) levels in E+S and E groups, but had no significant effects on blood Ca(+2) (p = 0.619) levels. The results of present study demonstrate that omega-3 in combination with regular aerobic exercise training have significant effects on serum CT, estrogen and PTH in non-athletic post menopausal women, suggesting that participating in moderate intensity weight bearing exercise and incorporating sources of omega-3 in the diet a possible intervention to help slow the loss of bone that occurs following menopause. Key pointsLong-term weight-bearing exercise was shown to prove positive effects on bone metabolism.Serum calciotropic hormone levels and Ca(+2) can be affected by exercise intensity as well as dura-tion.There is a good relationship between dietary omega-3 (n-3) and bone metabolism in post-menopausal women.Omega-3 in combination with long-term weight-bearing exercise training has significant effects on serum calciotropic hormone levels in non-athlete post-menopausal women. PMID- 24149693 TI - Autonomic nervous activity and lipid oxidation postexercise with capsaicin in the humans. AB - This study evaluated the synergistic effects of acute exercise with capsaicin (200mg) upon the restoration of cardiac autonomic functions and depolarization- repolarization interval as well as substrate oxidation. Nine healthy males [21.9(0.8) yrs] volunteered for this study. Cardiac autonomic activity, metabolic responses, and the ECG QT intervals were continuously measured during 5 min at rest and postexercise recovery after 30 min exercise at 50% VO2max on a stationary ergometer with placebo (ECON) or capsaicin intake (ECAP), and no exercise control (NCON) were randomized. Results indicated that the HF power reflecting parasympathetic activity significantly returned to the baseline much faster during ECAP than ECON trial during postexercise [122.1 (23.2) vs. 60.2 (11.7) %, p < 0.05]. The ECAP trial significantly decreased RQ [0.79(0.02) vs. 0.85 (0.03), p < 0.05] with significantly greater fat oxidation [69.3 (6.0) vs. 49.4 (10.8) %, p < 0.05] in comparison to NCON trial during 120 min postexercise recovery without any adverse effects on cardiac electrical stability as determined by trigger-averaged ECG QT interval analyses. We suggest that capsaicin before the exercise may contribute to the improvement of cardio protective functions and metabolic responses as one of the beneficial supplements accelerating faster restoration of autonomic activity and enhanced lipolysis during postexercise recovery without any adverse effects on cardiac electrical stability. Key pointsCapsaicin before exercise may contribute to the improvement of cardio-protective functions as one of the beneficial supplements accelerating faster restoration of autonomic activityCapsaicin before exercise enhanced lipolysis during postexercise recovery periodCapsaicin intake does not influence cardiac electrical stability during recovery period. PMID- 24149694 TI - Caffeine attenuates acute growth hormone response to a single bout of resistance exercise. AB - The purpose of this study was to investigate the effects of caffeine consume on substrate metabolism and acute hormonal responses to a single bout of resistance exercise (RE). Ten resistance-trained men participated in this study. All subjects performed one repetition maximum (1RM) test and then performed two protocols: caffeine (CAF, 6 mg.kg(-1)) and control (CON) in counter balanced order. Subjects performed RE (8 exercises, 3 sets of 10 repetitions at 75% of 1RM) after caffeine or placebo ingestion one hour prior to RE. Blood samples collected prior to treatment ingestion (pre-60), immediately prior to RE (pre exe), and 0, 15, 30 min post to RE (P0, P15, P30) for analysis of insulin, testosterone, cortisol, growth hormone, glucose, free fatty acid and lactic acid. Each experiment was separated by seven days. In this study, statistical analysis of a two-way analysis of variance (treatment by time) with repeated measures was applied. After ingesting caffeine, the concentrations of free fatty acid (pre- exe, P0, P15, P30) in CAF were significantly higher than CON (p < 0.05). Additionally, the responses of GH (P0, P15, P30) in CAF were significantly lower than CON (p < 0.05), whereas the concentrations of insulin, testosterone and cortisol were not different between CAF and CON (p < 0.05) after RE. The results of this study indicated that caffeine ingestion prior to RE might attenuate the response of GH. This effect might be caused by the elevation in blood FFA concentration at the beginning of RE. Key pointsCaffeine ingestion may attenuate the response of GH to a single bout of resistance exercise.The depression of GH response may be caused by the elevation in serum FFA concentration at the beginning of resistance exercise.Caffeine ingestion before resistance exercise may not alert the concentration of cortisol and testosterone. PMID- 24149695 TI - The effect of core exercises on transdiaphragmatic pressure. AB - Abdominal exercises, such as sit ups and leg lifts, are used to enhance strength of the core muscles. An overlooked aspect of abdominal exercises is the compression the abdomen, leading to increased diaphragmatic work. We hypothesized that core exercises would produce a variety of transdiaphragmatic pressures. We also sought to determine if some of the easy exercises would produce pressures sufficient for a training stimulus to the diaphragm. We evaluated the effect of 13 different abdominal exercises, ranging in difficulty, on transdiaphragmatic pressure (Pdi), an index of diaphragmatic activity. Six healthy subjects, aged 22 to 53, participated. Each subject was instrumented with two balloon-tipped catheters to obtain gastric and esophageal pressures, from which Pdi was calculated. Prior to initiating the exercises, each subject performed a maximal inspiratory pressure (MIP) maneuver. Resting Pdi was also measured. The exercises were performed from least to most difficult, with five repetitions each. There was a significant difference between the exercises and the MIP Pdi, as well as between the exercises and resting Pdi (p < 0.001). The exercises stratified into three Pdi levels. Seven of the exercises yielded Pdi >= 50% of the Pdi during the MIP maneuver, which may provide a training stimulus to the diaphragm if used as a regular exercise. The Pdi measurements also provide insight into diaphragm recruitment during different core exercises, and may aid in the design of exercises to improve diaphragm strength and endurance. Key pointsPlease provide 3 5 bullet points of the study.The study examined the effect of different core exercises of varying difficulty on activation of the diaphragm.We found that the exercises yielded different pressures, some of which were greater than 50% of the pressures generated during a maximal inspiratory maneuver.The difficulty of the exercise was not always correlated with the magnitude of the pressure.Some of these exercises should be easy enough for subjects in rehabilitation programs to perform and still generate high enough pressures to help strengthen the diaphragm. PMID- 24149696 TI - Frontal plane knee moments in golf: effect of target side foot position at address. AB - Golf has the potential to keep people active well into their later years. Injuries to the target side knee have been reported in golfers, yet no mechanisms for these injuries have been proposed. The loads on the knee during the golf swing may be insufficient to cause acute injury, yet they may be a factor in the progression of overuse/degenerative conditions; therefore, research developing swing modifications that may alter loading of the knee is warranted. It has been suggested that the proper golf set-up position has the target-side foot externally rotated but no reasoning for this modification has been provided. Frontal plane knee moments have been implicated in many knee pathologies. Therefore, this study used a 3-dimensional link segment model to quantify the frontal plane knee moments during the golf swing in a straight (STR) and externally rotated (EXT) target-side foot position. Subjects were 7 collegiate golfers and knee moments were compared between conditions using repeated measures T-tests. The golf swing knee moment magnitudes were also descriptively compared to those reported for two athletic maneuvers (drop jump landing, side-step cutting) and activities of daily living (gait, stair ascent). The EXT condition decreased the peak knee adduction moment as compared to the STR condition; however, foot position had no effect on the peak knee abduction moment. Also, the magnitude of the knee adduction moments during the two activities of daily living were 9-33% smaller than those experienced during the two different golfing conditions. The drop jump landing and golf swing knee moments were of similar magnitude (STR= - 5%, EXT= + 8%); however, the moments associated with side- step cutting were 50-71% larger than those on the target side knee during the golf swing. The loading of the target side knee during the golf swing may be a factor in the development and progression of knee pathologies and further research should examine ways of attenuating these loads through exercise and swing modifications. Key pointsAn externally rotated front foot position at address would be recommended for those with medial knee pathology in the target side limb.There is a large valgus moment on the target side knee during the golf swing that is not decreased with external rotation of the foot at address.The potential of the knee moments on the target side limb to lead to knee pathologies in golfers needs to be further investigated. PMID- 24149697 TI - Analysis of the vertical ground reaction forces and temporal factors in the landing phase of a countermovement jump. AB - In most common bilateral landings of vertical jumps, there are two peak forces (F1 and F2) in the force-time curve. The combination of these peak forces and the high frequency of jumps during sports produce a large amount of stress in the joints of the lower limbs which can be determinant of injury. The aim of this study was to find possible relationships between the jump height and F1 and F2, between F1 and F2 themselves, and between F1, F2, the time they appear (T1 and T2, respectively) and the length of the impact absorption phase (T). Thirty semi professional football players made five countermovement jumps and the highest jump of each player was analyzed. They were instructed to perform the jumps with maximum effort and to land first with the balls of their feet and then with their heels. All the data were collected using a Kistler Quattro Jump force plate with a sample rate of 500 Hz. Quattro Jump Software, v.1.0.9.0., was used. There was neither significant correlation between T1 and F1 nor between T1 and F2. There was a significant positive correlation between flight height (FH) and F1 (r = 0.584, p = 0.01) but no significant correlation between FH and F2. A significant positive correlation between F1 and T2 (r = 0.418, p < 0.05) and a significant negative correlation between F2 and T2 (r = -0.406, p < 0.05) were also found. There is a significant negative correlation between T2 and T (r = -0. 443, p < 0.05). T1 has a little effect in the impact absorption process. F1 increases with increasing T2 but F2 decreases with increasing T2. Besides, increasing T2, with the objective of decreasing F2, makes the whole impact absorption shorter and the jump landing faster. Key pointsIn the landing phase of a jump there are always sev-eral peak forces. The combination of these peaks forces and the high frequency of jumps during sports produces a large amount of stress in the joints of the lower limbs which can be determinant of injury.In the most common two footed landings usually appear two peak forces (F1 and F2) in the force-time curve and the second one is usually related to injury's risk. In this article it is shown that increasing the time F2 appears decrease F2.Increasing landing times could be counterproductive with respect to the goals of the sport. In this article it is shown that increasing the time F2 appears makes, however, the whole impact absorption shorter in du-ration. PMID- 24149698 TI - Game-Related Statistics that Discriminated Winning, Drawing and Losing Teams from the Spanish Soccer League. AB - The aim of the present study was to analyze men's football competitions, trying to identify which game-related statistics allow to discriminate winning, drawing and losing teams. The sample used corresponded to 380 games from the 2008-2009 season of the Spanish Men's Professional League. The game-related statistics gathered were: total shots, shots on goal, effectiveness, assists, crosses, offsides commited and received, corners, ball possession, crosses against, fouls committed and received, corners against, yellow and red cards, and venue. An univariate (t-test) and multivariate (discriminant) analysis of data was done. The results showed that winning teams had averages that were significantly higher for the following game statistics: total shots (p < 0.001), shots on goal (p < 0.01), effectiveness (p < 0.01), assists (p < 0.01), offsides committed (p < 0.01) and crosses against (p < 0.01). Losing teams had significantly higher averages in the variable crosses (p < 0.01), offsides received (p < 0. 01) and red cards (p < 0.01). Discriminant analysis allowed to conclude the following: the variables that discriminate between winning, drawing and losing teams were the total shots, shots on goal, crosses, crosses against, ball possession and venue. Coaches and players should be aware for these different profiles in order to increase knowledge about game cognitive and motor solicitation and, therefore, to evaluate specificity at the time of practice and game planning. Key pointsThis paper increases the knowledge about soccer match analysis.Give normative values to establish practice and match objectives.Give applications ideas to connect research with coaches' practice. PMID- 24149699 TI - The effects of regular aerobic exercise on renal functions in streptozotocin induced diabetic rats. AB - Diabetic nephropathy is a feared complication of diabetes since it can lead to end-stage renal failure and also it is a risk factor of cardiovascular disease. The important clinical problems caused by diabetic nephropathy are proteinuria and decreased renal function. Exercise is a cornerstone of diabetes management, along with diet and medication. Since acute exercise causes proteinuria and decreases glomerular filtration rate, the effect of exercise on diabetic nephropathy is controversial. The aim of this study was to investigate the effect of regular aerobic exercise on microalbuminuria and glomerular filtration rate in diabetic rats. Moderate diabetes was induced by streptozotocin (45 mg/kg IV) in rats and an aerobic exercise- training program on a treadmill was carried out for 8 weeks. Four groups of rats; control sedentary (CS), control exercise (CE), diabetic sedentary (DS) and diabetic exercise (DE) were included in the study. Blood glucose levels were determined from the plasma samples taken at the end of 4 weeks of stabilization period and 8 weeks of training program. Creatinine clearance (CCr) and microalbuminuria (MA) levels were determined to evaluate renal functions. The analyzed data revealed that regular aerobic exercise: 1) significantly decreased the plasma glucose level of the DE group compared to the DS group (p < 0.05), 2) significantly decreased the microalbuminuria level of the DE group compared to those of DS group (p < 0.01), 3) significantly decreased the creatinine clearance levels of the DE and CE groups compared to those of CS group (p < 0.05). The results of this study suggest that despite of decreasing creatinine clearance, regular submaximal aerobic exercise has a preventive effect on development of microalbuminuria and thus may retard nephropathy in diabetic rats. Key pointsRegular submaximal aerobic exercise can facilitate the control of blood glucose level in diabetic rats.Streptozotocin induced diabetes may cause microalbuminuria and regular submaximal aerobic exercise may have a preventive effect on renal functions. PMID- 24149700 TI - Does combined dry land strength and aerobic training inhibit performance of young competitive swimmers? AB - THE AIM OF THE CURRENT STUDY WAS TWOFOLD: (i) to examine the effects of eight weeks of combined dry land strength and aerobic swimming training for increasing upper and lower body strength, power and swimming performance in young competitive swimmers and, (ii) to assess the effects of a detraining period (strength training cessation) on strength and swimming performance. The participants were divided into two groups: an experimental group (eight boys and four girls) and a control group (six boys and five girls). Apart from normal practice sessions (six training units per week of 1 h and 30 min per day), the experimental group underwent eight weeks (two sessions per week) of strength training. The principal strength exercises were the bench press, the leg extension, and two power exercises such as countermovement jump and medicine ball throwing. Immediately following this strength training program, all the swimmers undertook a 6 week detraining period, maintaining the normal swimming program, without any strength training. Swimming (25 m and 50 m performances, and hydrodynamic drag values), and strength (bench press and leg extension) and power (throwing medicine ball and countermovement jump) performances were tested in three moments: (i) before the experimental period, (ii) after eight weeks of combined strength and swimming training, and (iii) after the six weeks of detraining period. Both experimental and control groups were evaluated. A combined strength and aerobic swimming training allow dry land strength developments in young swimmers. The main data can not clearly state that strength training allowed an enhancement in swimming performance, although a tendency to improve sprint performance due to strength training was noticed. The detraining period showed that, although strength parameters remained stable, swimming performance still improved. Key pointsThis study investigated the effect of dry land strength training on sprint performance in young competitive swimmers.A combined strength and aerobic swimming training allow dry land strength developments in young swimmers.The main data can not clearly state that strength training allowed an enhancement in swimming performance, although a tendency to improve sprint performance due to strength training was noticed.The detraining period showed that, although strength parameters remained stable, swimming performance still improved. PMID- 24149701 TI - Intensity and timing in life of recreational physical activity in relation to breast cancer risk among pre- and postmenopausal women. AB - Regular recreational physical activity has been found to be associated with a decrease in breast cancer risk in women in the majority of epidemiologic studies, but research findings are inconsistent regarding the intensity of activity and timing in life. To address these issues the relations of moderate and vigorous intensity recreational physical activity during ages 14-20, 21-34, 35-50, and over age 50 years to pre- and postmenopausal breast cancer risk were examined. A case-control study of 858 women, with histological confirmation of invasive breast cancer, and 1085 controls, free of any cancer diagnosis, all subjects aged 28-79 years was conducted in the Region of Western Pomerania (Poland). Physical activity was assessed using a self-administered questionnaire with questions on type of activity, duration, frequency, and intensity for each type of activity. Odds ratios (OR) and 95% confidence intervals (CI) of breast cancer associated with physical activity were calculated using unconditional logistic regression. Vigorous physical activity at ages 14-20 and 21-34 years lowered breast cancer risk by at least 35% in premenopausal women and by at least 51% in postmenopausal women for the highest versus lowest quartiles of the activity. The risk was also reduced in postmenopausal women who reported on average more than 1.74 hours per week of vigorous intensity recreational activity in ages >50 years (OR = 0.58; 95%CI = 0.27-0.97; P for trend = 0.013). For moderate activity the relationships remained statistically significant only in postmenopausal women active during ages 14- 20 years. The results indicate also a plausible risk reduction among premeno-pausal women. These results support the hypothesis that recrea-tional activity, particularly done early in life, is associated with a decrease in the invasive breast cancer risk in postmenopausal women. Among premenopausal women, only vigorous forms of activity may significantly decrease the risk. Key pointsRecreational physical activity of vigorous intensity during ages 14-20 and 21-34 years protect against breast cancer regardless of menopausal status.Vigorous recreational physical activity at ages >50 years was also associated with reduced postmeno-pausal breast cancer risk.The risk reduction was also observed among post-menopausal women engaged in recreational physical activity of moderate intensity at ages 14-20 years. PMID- 24149702 TI - Interactive effects of team cohesion on perceived efficacy in semi-professional sport. AB - The present study examined the relationships among cohesion, self-efficacy, coaches' perceptions of their players' efficacy at the individual level and athletes' perceptions of their teammates' efficacy. Participants (n = 76) recruited from four semi- professional soccer and basketball teams completed cohesiveness and efficacy questionnaires who. Data were analyzed through a correlational methodology. Results indicated significant correlations between self-efficacy and task cohesion and social cohesion. Regression analysis results suggest task cohesion positively related to coaches and teammate's perception of efficacy. These results have implications for practitioners in terms of the importance of team building to enhance team cohesion and feelings of efficacy. Key pointsThis paper increases the knowledge about soccer and basketball match analysis.Give normative values to establish practice and match objectives.Give applications ideas to connect research with coaches' practice. PMID- 24149703 TI - Effects of warm-up on vertical jump performance and muscle electrical activity using half-squats at low and moderate intensity. AB - The purpose of this study was to determine the effects of a specific warm-up using half-squats at low and moderate intensity on vertical jump performance and electromyographic activity of the thigh muscles. The subjects were 26 men who were divided into a low intensity group (LIG; n = 13) and a moderate intensity group (MIG; n = 13). The LIG performed a specific warm-up protocol that included the explosive execution of half-squats with loads 25 and 35% of the one repetition maximum (1RM) and the MIG with loads 45 and 65% of the 1RM. The two groups performed a countermovement jump (CMJ) before and three minutes after the specific warm-up protocols. During the concentric phase of the CMJ a linear encoder connected to an A/D converter interfaced to a PC with a software for data acquisition and analysis allowed the calculation of average mechanical power. The electromyographic (EMG) activity of the vastus lateralis (VL), vastus medialis (VM) and rectus femoris (RF) were recorded during the concentric phase of the jumps. The average quadriceps (Qc) activity (mean value of the VL, VM and RF) was also calculated. A two way ANOVA (protocols X time) with repeated measures on the second factor was used to analyze the data. Following the specific warm-up procedure both groups improved (p <= 0.05) CMJ performance and mechanical power by 3.5% and 6.3%, respectively, with no differences observed between the two groups. EMG activity of the Qc and VL increased (p <= 0.05) for both groups by 5.9% and 8.5%, respectively. It is concluded that the use of a specific warm-up that includes half-squats, performed explosively with low to moderate intensity, improves CMJ performance. This may be due to increased muscle activation as evaluated by the surface EMG. Key pointsThe inclusion of two sets of explosively performed half squats with low to moderate loads in the warm up procedure elicited an acute performance en-hancement.The performance was enhanced regardless of the load used in the warm-up.The performance enhancement is accompanied by a greater electromyographic activity of the knee extensors muscles. PMID- 24149704 TI - Cycling efficiency in trained male and female competitive cyclists. AB - The aim of this study was to examine differences in cycling efficiency between competitive male and female cyclists. Thirteen trained male (mean +/- SD: 34 +/- 8 yr, 74.1 +/- 6.0 kg, Maximum Aerobic Power (MAP) 414 +/- 40 W, VO2max 61.3 +/- 5.4 ml.kg(-1).min(-1)) and 13 trained female (34 +/- 9 yr, 60.1 +/- 5.2 kg, MAP 293 +/- 22 W, VO2max 48.9 +/- 6.1 ml.kg(-1).min(-1)) competitive cyclists completed a cycling test to ascertain their gross efficiency (GE). Leg and lean leg volume of all cyclists was also measured. Calculated GE was significantly higher in female cyclists at 150W (22.5 +/- 2.1 vs 19.9 +/- 1. 8%; p < 0.01) and 180W (22.3 +/- 1.8 vs 20.4 +/- 1.5%; p = 0.01). Cadence was not significantly different between the groups (88 +/- 6 vs 91 +/- 5 rev.min(-1)). Lean leg volume was significantly lower for female cyclists (4.04 +/- 0.5 vs 5.51 +/- 0.8 dm(3); p < 0.01) and was inversely related to GE in both groups at 150 and 180W (r = 0.59 and -0.58; p < 0.05). Lean leg volume was shown to account for the differences in GE between the males and females. During an "unloaded "pedalling condition, male cyclists had a significantly higher O2 cost than female cyclists (1.0 +/- 0.1 vs 0.7 +/- 0.1 L.min(-1); p < 0.01), indicative of a greater non propulsive cost of cycling. These results suggest that differences in efficiency between trained male and female cyclists can be partly accounted for by sex specific variation in lean leg volume. Key pointsDifferences in GE exist between male and female cyclists.Males have a higher oxygen cost of "unloaded "cycling, as predicted by the intercept of the O2 cost-power output relationshipThis suggests that in addition to work rate, leg volume/mass may be an important determinant of observed differences in oxygen cost and therefore GE, between male and female competitive cyclists. PMID- 24149705 TI - Cell damage, antioxidant status, and cortisol levels related to nutrition in ski mountaineering during a two-day race. AB - The aim of this study was to measure the effect of nutrition on cell damage, antioxidant enzymes, and cortisol during a two-day ski mountaineering competition. Twenty-one male skiers participated in the study. Creatine kinase (CK), aspartate aminotransferase (AST), alanine aminotransferase (ALT), gamma glutamyl transpeptidase (GGT), lactate dehydrogenase (LDH), alkaline phosphatase (AP), cortisol and C-reactive protein (CRP), glutathione peroxidase (GPx) and reductase activities (GR) and C-reactive protein (CRP) levels, total antioxidant status, and cortisol levels were measured in serum the day before and immediately after the race. Their diet was also analysed during the competition. Enzymes and cortisol levels significantly increased after the competition. CK and LDH and cortisol levels were negatively correlated to total energy, protein, and fat intake. Intake of vitamin A, B1, B2, B6 and niacin was negatively correlated to LDH and AP. A negative correlation was also found between CK activity and Na, Fe, and Zn intake. Cortisol levels were negatively correlated to the intake of vitamins C, B1 and B2, and niacin. A positive correlation was found between serum GPx and intake of energy, carbohydrates, proteins, A and B vitamins, and folic acid. Skiers with the lowest nutrient intake during the competition were the ones who showed greater cell damage and lower antioxidant enzyme activity and cortisol levels, which may impair performance and also cause injuries and accidents. Particularly, skiers should have high intakes of total energy, macronutrients, vitamins A and B, Na, Zn, and Fe in order to decrease the deleterious effect of strenuous exercise. Key pointsA two-day ski mountaineering race produced muscle cell damage and oxidative stress and an increase in cortisol levels.There was a marked insufficient intake of carbohydrates which has been shown to affect performanceThose skiers with lowest nutrient intake showed greater cell damage, lower antioxidant activity and higher cortisol levels.Nutrition should be carefully monitored and assessed in order to minimize the mentioned blood changes to avoid fatigue, injuries and also accidents in this type of sport; particularly when skiers must carry their own food. PMID- 24149706 TI - Psychological factors as predictors of injuries among senior soccer players. A prospective study. AB - It is reported that between 65-91% of elite soccer players in Sweden have at least one injury per year. Several studies define different physiological and psychological factors affecting athletic injury-risk. A number of models contain proposals that specify relationships between psychological factors and an increased athletic injury-risk. Examples include Williams and Andersen's stress injury model and Johnson and Ivarsson's empirical model of injury risk factors which proposes that factors such as trait anxiety and ineffective coping skills are influential. The purpose of this study was to examine the relationship between (a) personality factors, b) coping variables, and (c) stress and injury risk. Participants were 48 male soccer players from 3 Swedish teams ranging in age from 16 to 36 years (M = 22 years). Participants completed 5 questionnaires: Football Worry Scale, Swedish universities Scales of Personality, Life Events Survey for Collegiate Athletes, Daily Hassle Scale and Brief COPE. Information on injuries was collected by athletic trainers of the teams over 3-months. Results suggest injury was significantly predicted by 4 personality trait predictors: somatic trait anxiety, psychic trait anxiety, stress susceptibility, and trait irritability. Collectively, the predictors self-blame and acceptance could explain 14.6% of injury occurrence. More injuries were reported among players who score high in daily hassles. These results support previous findings. Recommendations are given for both the athletes and the trainers on working to prevent sport injuries. Key pointsA number of psychological factors, such as high stress levels and ineffective coping could increase the injury risk among athletes.The two coping factors, self - blame and acceptance could together explain 14.6 % of injury occurrence.Results of the current study suggest that the factors; somatic trait anxiety, psychic trait anxiety, stress susceptibility and trait irritability could increase injury risk among soccer players.Suggestion for future research is to investigate how daily hassles affects injury risk among soccer players in larger samples and on premiership levels. Moreover, to investigate the effects of a preventive intervention designs for a representative sample of soccer players. PMID- 24149707 TI - Biological and genetic factors regulating natural competence in a bacterial plant pathogen. AB - For naturally competent bacteria, spatially structured growth can provide an environment for enhanced horizontal gene transfer through transformation and recombination. DNA is often present in the extracellular environment, such as in the extracellular matrix of biofilms, and the lysis of a single cell can result in high local DNA concentrations. Xylella fastidiosa is a naturally competent plant pathogen that typically lives in a surface-attached state, yet previous work characterizing the competence of this organism was conducted with planktonic cells in liquid environments. Here, we show that transformation and recombination efficiencies are two to three orders of magnitude higher for cells grown on solid compared with liquid media, with maximum recombination efficiencies of about 10( 3). Cells were highly competent throughout their exponential growth phase, with no significant change in recombination efficiencies until population growth rates began to slow. Mutations in type IV pili, competency-related, and cell-cell signalling genes significantly impacted the ability of X. fastidiosa to acquire and incorporate DNA. Because X. fastidiosa is highly competent when growing in a surface-attached state, as it does within its insect vectors and host plants, recombination of naturally transformed DNA could be a significant route by which horizontal gene transfer occurs in natural environments. PMID- 24149708 TI - The prevalence and origin of exoprotease-producing cells in the Bacillus subtilis biofilm. AB - Biofilm formation by the Gram-positive bacterium Bacillus subtilis is tightly controlled at the level of transcription. The biofilm contains specialized cell types that arise from controlled differentiation of the resident isogenic bacteria. DegU is a response regulator that controls several social behaviours exhibited by B. subtilis including swarming motility, biofilm formation and extracellular protease (exoprotease) production. Here, for the first time, we examine the prevalence and origin of exoprotease-producing cells within the biofilm. This was accomplished using single-cell analysis techniques including flow cytometry and fluorescence microscopy. We established that the number of exoprotease-producing cells increases as the biofilm matures. This is reflected by both an increase at the level of transcription and an increase in exoprotease activity over time. We go on to demonstrate that exoprotease-producing cells arise from more than one cell type, namely matrix-producing and non-matrix producing cells. In toto these findings allow us to add exoprotease-producing cells to the list of specialized cell types that are derived during B. subtilis biofilm formation and furthermore the data highlight the plasticity in the origin of differentiated cells. PMID- 24149709 TI - Cdkn1b overexpression in adult mice alters the balance between genome and tissue ageing. AB - Insufficient cell proliferation has been suggested as a potential cause of age related tissue dysgenesis in mammals. However, genetic manipulation of cell cycle regulators in the germ lines of mice results in changes in animal size but not progeroid phenotypes. Here we increase levels of the cyclin-dependent kinase inhibitor Cdkn1b (p27kip1) in adult mice through doxycycline-inducible expression and show this results in reduced cell proliferation in multiple tissues. The mice undergo changes resembling ageing even in the absence of an elevated DNA damage response or evidence of senescent cells, suggesting an altered balance between genetic and tissue ageing. In contrast, suppressing cell proliferation by doxycycline treatment of neonates retards growth, but the onset of degenerative changes is delayed during the period of reduced body mass. These results support the hypothesis that many of the most recognizable features of mammalian ageing can result from an imbalance between cell production and the mass of tissue that must be maintained. PMID- 24149710 TI - The heroic role of the caregiver in oncology: a photojournalistic report. PMID- 24149711 TI - Thiazolodinediones and cancer: duplicate publication bias? PMID- 24149712 TI - In reply. PMID- 24149716 TI - International Association of Endocrine Surgeons: the origin. PMID- 24149718 TI - Chronological improvement in survival following rectal cancer surgery: a large scale, single-center study. PMID- 24149717 TI - Patterns of structural recurrence in papillary thyroid cancer. AB - BACKGROUND: Papillary thyroid carcinoma (PTC) is uncommonly associated with tumor related mortality, although local recurrence can be a frequent and difficult problem. This study was conducted to clarify the pattern of structural locoregional recurrence in PTC. MATERIAL AND METHOD: A retrospective cohort study of patients undergoing surgical intervention for PTC was undertaken. Data were collected from a comprehensive thyroid cancer database maintained within a single tertiary referral center. The primary outcome measure was cancer recurrence requiring surgical intervention. Secondary outcome measures were site of recurrence, time to recurrence, and risk factors for recurrence. RESULTS: In the period 1980-2013, 1,183 patients with PTC were included in the study. The overall rate of structural recurrence requiring reoperative surgery was 7.9 %. The median time to reoperation was 31 months. Younger age, male gender, large primary tumor diameter, and number of positive lymph nodes at initial presentation were all significantly associated with disease recurrence. The lateral compartments (levels I, II, III, IV, V) were involved almost twice as frequently as the central compartment (level VI) (67 vs 32 %, P < 0.01). The distribution of recurrences was level I (1 %), level II (12 %), level III (18 %), level IV (18 %), level V (17 %), level VI (32 %), level VII (2 %). CONCLUSIONS: In a center with a liberal approach to central compartment lymph node dissection for PTC, the lateral neck compartment is the most common site of structural recurrence requiring reoperative surgery. PMID- 24149719 TI - Short-term free-fall landing causes reduced bone size and bending energy in femora of growing rats. AB - The purpose of this study was to determine the effects of a mechanical loading course (short-term free-fall landing) on femoral geometry and biomechanical properties in growing rats. Thirty-two female Wistar rats (7-week-old) were randomly assigned to three groups: L30 (n = 11), L10 (n = 11) and CON (n = 10) groups. Animals in the L10 and L30 groups were subjected to a 5-day free-fall landing program in which animals were dropped from a height of 40cm 10 and 30 times per day, respectively. Landing ground reaction force (GRF) was measured on the 1(st) and 5(th) days of landing training. All animals were subjected to two fluorescent labeling injections on the days before and after the 5-day landing training. Three days after the last labeling injection, animals were sacrificed under deep anesthesia. Methods of dynamic histomorphometry, tissue geometry and tissue biomechanical measurements were used to investigate the response in femora. A significant decrease in peak GRF in the hind-limb was shown from day 1 to day 5. No significant difference was shown among groups in dynamic histomorphometry. Biomechanical property analyses showed significantly lower maximal energy and post-yield energy in the L10 and L30 groups as compared to the CON group (p < 0.05). Moreover, geometric measurements revealed that cross sectional cortical areas and thicknesses were significantly lower in landing groups than in the CON group. Short-term (5-day) free-fall landing training resulted in minor compromised long bone tissue, as shown by reduced bending energy and cortical bone area but not in other mechanical properties or tissue measurements (e.g. weights and length) of growing female rats. Further studies would be valuable to investigate whether this compromised bone material represents the existence of a latency period in the adaptation of bone material to external mechanical loading. Key pointsShort-term free-fall landing causes compromised bone material as shown by reduced post-yield energy in long bones of rodents.The results of the current study suggest the existence of unsettled bone material after a short-term mechanical loading regime.The connection of the present animal study to the stress fractures occurring in young athletes needs to be clarified. PMID- 24149720 TI - Participation Motivation and Student's Physical Activity among Sport Students in Three Countries. AB - The main aim of this study was to examine the differences in motivation to participate in sport activities among sports students from three different countries. On a sample of 390 sports students from Slovenia, Croatia and Germany we studied what motivates an interest in being sports active. The sample was stratified across the choice to attend table tennis lessons at all three institutions and all students have completed the Participation Motivation Questionnaire (PMQ). The results revealed that the latent structure of the types of sports students' motives consisted of six factors (sport action with friend, popularity, fitness & health, social status, sports events, relaxation through sports). We also found significant sex differences in motivation to participate in sport activities for all sports students from the three different countries. We did not find relevant age-based differences among the students, and this is the only initial hypothesis that we can reject. Key pointsThe potential implications of the result can be in better understanding the relationship between different motivational orientations - in particular, extrinsic motivation - and sport motivation among school-aged individuals.In the context of Self Determination Theory, students can be encouraged in developing more autonomous orientations for sport activity, rather than controlled and impersonal, especially in certain countries.Significant factors of differences have been found in motivation to participate in sport activities among sports students from three different countries and also some significant sex differences have been found in motivation to participate in sport activities for all sports students. PMID- 24149721 TI - The effects of tai chi chuan combined with vibration training on balance control and lower extremity muscle power. AB - The aim of this study was to determine whether performing Tai Chi Chuan on a customized vibration platform could enhance balance control and lower extremity muscle power more efficiently than Tai Chi Chuan alone in an untrained young population. Forty-eight healthy young adults were randomly assigned to the following three groups: a Tai Chi Chuan combined with vibration training group (TCV), a Tai Chi Chuan group (TCC) or a control group. The TCV group underwent 30 minutes of a reformed Tai Chi Chuan program on a customized vibration platform (32 Hz, 1 mm) three times a week for eight weeks, whereas the TCC group was trained without vibration stimuli. A force platform was used to measure the moving area of a static single leg stance and the heights of two consecutive countermovement jumps. The activation of the knee extensor and flexor was also measured synchronously by surface electromyography in all tests. The results showed that the moving area in the TCV group was significantly decreased by 15.3%. The second jump height in the TCV group was significantly increased by 8.14%, and the activation of the knee extensor/flexor was significantly decreased in the first jump. In conclusion, Tai Chi Chuan combined with vibration training can more efficiently improve balance control, and the positive training effect on the lower extremity muscle power induced by vibration stimuli still remains significant because there is no cross-interaction between the two different types of training methods. Key pointsEight weeks of Tai Chi Chuan combined with vibration training can more efficiently improve balance control for an untrained young population.The positive training effect on the lower extremity muscle power induced by vibration stimuli during Tai Chi Chuan movements still remains significant because of SSC mechanism.Combining Tai Chi Chuan with vibration training is more efficient and does not decrease the overall training effects due to a cross-interaction of each other. PMID- 24149722 TI - Artificial intelligence in sports on the example of weight training. AB - The overall goal of the present study was to illustrate the potential of artificial intelligence (AI) techniques in sports on the example of weight training. The research focused in particular on the implementation of pattern recognition methods for the evaluation of performed exercises on training machines. The data acquisition was carried out using way and cable force sensors attached to various weight machines, thereby enabling the measurement of essential displacement and force determinants during training. On the basis of the gathered data, it was consequently possible to deduce other significant characteristics like time periods or movement velocities. These parameters were applied for the development of intelligent methods adapted from conventional machine learning concepts, allowing an automatic assessment of the exercise technique and providing individuals with appropriate feedback. In practice, the implementation of such techniques could be crucial for the investigation of the quality of the execution, the assistance of athletes but also coaches, the training optimization and for prevention purposes. For the current study, the data was based on measurements from 15 rather inexperienced participants, performing 3-5 sets of 10-12 repetitions on a leg press machine. The initially preprocessed data was used for the extraction of significant features, on which supervised modeling methods were applied. Professional trainers were involved in the assessment and classification processes by analyzing the video recorded executions. The so far obtained modeling results showed good performance and prediction outcomes, indicating the feasibility and potency of AI techniques in assessing performances on weight training equipment automatically and providing sportsmen with prompt advice. Key pointsArtificial intelligence is a promising field for sport-related analysis.Implementations integrating pattern recognition techniques enable the automatic evaluation of data measurements.Artificial neural networks applied for the analysis of weight training data show good performance and high classification rates. PMID- 24149723 TI - Using bench press load to predict upper body exercise loads in physically active individuals. AB - This study investigated whether loads for assistance exercises of the upper body can be predicted from the loads of the bench press exercise. Twenty-nine physically active collegiate students (age: 22.6 +/- 2.5; weight training experience: 2.9 +/- 2.1 years; estimated 1RM bench press: 54.31 +/- 14.60 kg; 1RM: body weight ratio: 0.80 +/- 0.22; BMI: 22.7 +/- 2.1 kg.m(-2)) were recruited. The 6RM loads for bench press, barbell bicep curl, overhead dumbbell triceps extension, hammer curl and dumbbell shoulder press were measured. Test retest reliability for the 5 exercises as determined by Pearson product moment correlation coefficient was very high to nearly perfect (0.82-0.98, p < 0.01). The bench press load was significantly correlated with the loads of the 4 assistance exercises (r ranged from 0.80 to 0.93, p < 0.01). Linear regression revealed that the bench press load was a significant (R(2) range from 0.64 to 0.86, p < 0.01) predictor for the loads of the 4 assistance exercises. The following 6RM prediction equations were determined: (a) Hammer curl = Bench press load (0.28) + 6.30 kg, (b) Barbell biceps curl = Bench press load (0.33) + 6.20 kg, (c) Overhead triceps extension = Bench press load (0.33) - 0.60 kg, and (d) Dumbbell shoulder press = Bench press load (0.42) + 5.84 kg. The difference between the actual load and the predicted load using the four equations ranged between 6.52% and 8.54%, such difference was not significant. Fitness professionals can use the 6RM bench press load as a time effective and accurate method to predict training loads for upper body assistance exercises. Key pointsThe bench press load was significantly correlated with the loads of the 4 assistance exercises.No significant differences were found between the actual load and the predicted load in the four equations.6RM bench press load can be a time effective and accurate method to predict training loads for upper body assistance exercises. PMID- 24149724 TI - Effects of High-Intensity Endurance Exercise on Epidermal Barriers against Microbial Invasion. AB - For athletes, preventing infectious disease on skin is important. Examination measurement of epidermal barriers could provide valuable information on the risk of skin infections. The aim of this study was to determine the effects of high intensity endurance exercise on epidermal barriers. Six healthy adult males (age; 22.3 +/- 1.6 years) performed bicycle exercise at 75%HRmax for 60 min from 18:30 to 19:30. Skin surface samples were measured 18:30 (pre), 19:30 (post), 20:30 (60 min), and 21:30 (120 min). Secretory immunoglobulin A (SIgA) and human beta defensin 2 (HBD-2) concentrations were measured using an enzyme-linked immunosorbent assay (ELISA). SIgA concentration at pre was significantly higher than at post, 60 min and 120 min (p < 0.05). HBD-2 concentration at post and 120 min was significantly higher than at pre (p < 0. 05). Moisture content of the stratum corneum was significantly higher at post than at pre, 60 min, and 120 min (p < 0.05). On the chest, moisture content of the stratum corneum was significantly lower at 120 min than at pre (p < 0.05). The number of staphylococci was significantly higher at post than at pre (p < 0.05), and tended to be higher at 60 min than at pre on the chest (p = 0. 08). High-intensity endurance exercise might depress the immune barrier and physical barrier and enhance the risk of skin infection. On the other hand, the biochemical barrier increases after exercise, and our findings suggest that this barrier might supplement the compromised function of other skin barriers. Key pointsThe immune barrier and physical barrier might be depressed and the risk of skin infection might be enhanced by high-intensity endurance exercise.The biochemical barrier increases after high-intensity endurance exercise and might supplement the compromised function of other skin barriers.We recommend that athletes maintain their skin surface in good condition, for example, by showering immediately after sports activities and using moisturizers. PMID- 24149725 TI - Exercise training improves cardiovascular autonomic activity and attenuates renal damage in spontaneously hypertensive rats. AB - Experiments were performed to determine the influence of exercise training by swimming on cardiovascular autonomic control and renal morphology in spontaneously hypertensive rats (SHR) and Wystar-Kyoto (WKY) rats. Sedentary normotensive (SN), trained normotensive (TN), sedentary hypertensive (SH), and trained hypertensive (TH) rats were included in this study. Arterial pressure (AP), heart rate (HR), means of power spectral analysis of HR (HRV) and systolic AP variability (SAPV) were recorded in baseline conditions. Following, the HR baroreflex and autonomic tonus control were assessed. At the end, all animals were euthanized and their kidneys were excised to evaluate renal damage. Resting bradycardia was observed in TH and TN rats compared with their respective sedentary animals (p < 0.05). Exercise training attenuated AP in TH vs. SH (p < 0.001). The LF component of HRV and SAPV were lower in TH than SH (p < 0.05). The LF/HF relation was lower in TH than SH and SN (p < 0.05). TN and TH rats showed a sympathetic tonus reduction in comparison to SN and SH rats (p < 0.001). The TH presented an increased vagal tonus compared to SH (p < 0.05). Exercise training improved baroreflex control of HR in TH group versus SH (p < 0.05). The TH showed a lower number of sclerotic glomeruli compared to SH (p < 0.005). The exercise training decrease the glomerular indexes in TN and TH (p < 0.05). Further analysis showed a significant correlation between sympathetic nervous activity and AP levels (p < 0.05). A positive association was also found between sympathetic nervous activity and glomerular index (p < 0.05). Therefore, the exercise training reduces AP and attenuates renal damage. In addition, the attenuation of renal injury was associated with lower sympathetic activity. These findings strongly suggest that exercise training may be a therapeutic tool for improving structure and renal function in hypertensive individuals. Key pointsEndurance training.Decrease of the sympathetic activity.Attenuation of renal injury.Decrease of blood pressure in SHR. PMID- 24149726 TI - Effects of body mass-based squat training in adolescent boys. AB - The purpose of this study was to determine the effects of body mass-based squat training on body composition, muscular strength and motor fitness in adolescent boys. Ninety-four boys (13.7 +/- 0.6 yrs, 1.60 +/- 0.09 m, 50.2 +/- 9.6 kg) participated in this study and were randomly assigned to training (n = 36) or control (n = 58) groups. The training group completed body mass-based squat exercise training (100 reps/day, 45 sessions) for 8 weeks. Body composition and muscle thickness at the thigh anterior were determined by a bioelectrical impedance analyzer and ultrasound apparatus, respectively. Maximal voluntary knee extension strength and sprint velocity were measured using static myometer and non-motorized treadmill, respectively. Jump height was calculated using flight time during jumping, which was measured by a matswitch system. The 8-wk body mass based squat training significantly decreased percent body fat (4.2%) and significantly increased the lean body mass (2.7%), muscle thickness (3.2%) and strength of the knee extensors (16.0%), compared to control group. The vertical jump height was also significantly improved by 3.4% through the intervention. The current results indicate that body mass-based squat training for 8 weeks is a feasible and effective method for improving body composition and muscular strength of the knee extensors, and jump performance in adolescent boys. Key pointsAn 8-wk body mass-based squat exercise training decreased percent body fat in adolescent boys.The body mass-based squat exercise training increased muscle size and strength capability of the knee extensors in adolescent boys.The squat exercise training improves vertical jump height in adolescent boys. PMID- 24149727 TI - The effect of court location and available time on the tactical shot selection of elite squash players. AB - No previous research in squash has considered the time between shots or the proximity of the ball to a wall, which are two important variables that influence shot outcomes. The aim of this paper was to analyse shot types to determine the extent to which they are played in different court areas and a more detailed analysis to determine whether the time available had an influence on the shot selected. Ten elite matches, contested by fifteen of the world's top right handed squash players (age 27 +/- 3.2, height 1.81 +/- 0.06 m, weight 76.3 +/- 3.7 kg), at the men's World Team Championships were processed using the SAGIT/Squash tracking system with shot information manually added to the system. Results suggested that shot responses were dependent upon court location and the time between shots. When these factors were considered repeatable performance existed to the extent that one of two shots was typically played when there was limited time to play the shot (< 1.20s). For example, it was clear that when players did not have a lot of time to hit the ball (low time i.e. < 1.06s, and mid time i.e. 1.06 - 1.20s) in the front left corner close to the side wall, the crosscourt lob was used frequently (44.30% and 36.31% respectively) whereas when there was more time this shot was seldom used (13.64%). Consequently variant and invariant behaviour were shown to exist in elite squash although for the first time it was suggested that the availability of time to play a shot contributed to which of these behaviours was evident. This analysis could be extended by adopting a case study approach to see how individual differences in strategy and tactics affect shot selections. Key pointsPrevious research has suggested that a playing strategy, elements decided in advance of the match, may be evident for elite players by examining court location and preceding shot type, however these parameters alone are unlikely to be sufficient predictors.At present there is no known analysis in squash, or indeed in any of the racket sports, that has quantified the time available to respond to different shot types. An understanding of the time interval between shots and the movement characteristics of the player responding to different shots according to the court positions might facilitate a better understanding of the dynamics that determine shot selection.Some elements of a general playing strategy were evident e.g. predominately hitting to the back left of the court, but tactical differences in shot selection were also evident on the basis of court location and time available to play a shot. PMID- 24149728 TI - The Effects of Pre- and Post-Exercise Whey vs. Casein Protein Consumption on Body Composition and Performance Measures in Collegiate Female Athletes. AB - Two of the most popular forms of protein on the market are whey and casein. Both proteins are derived from milk but each protein differs in absorption rate and bioavailability, thus it is possible that each type of protein may contribute differently to the adaptations elicited through resistance training. Therefore, the purpose of this study was to investigate the potential effects of ingestion of two types of protein in conjunction with a controlled resistance training program in collegiate female basketball players. Sixteen NCAA Division III female basketball players were matched according to body mass and randomly assigned in a double-blind manner to consume 24 g whey protein (WP) (N = 8, 20.0 +/- 1.9 years, 1.58 +/- 0.27 m, 66. 0 +/- 4.9 kg, 27.0 +/- 4.9 %BF) or 24 g casein protein (CP) (N = 8, 21.0 +/- 2.8 years, 1.53 +/- 0.29 m, 68.0 +/- 2.9 kg, 25.0 +/- 5.7 %BF) immediately pre- and post-exercise for eight weeks. Subjects participated in a supervised 4-day per week undulating periodized training program. At 0 and 8 weeks, subjects underwent DXA body composition analysis, and at 0 and 8 weeks underwent one repetition maximum (1RM) strength, muscle endurance, vertical jump, 5-10-5 agility run, and broad jump testing sessions. Data were analyzed using repeated measures ANOVA, and presented as mean +/- SD changes from baseline after 60 days. No significant group x time interaction effects were observed among groups in changes in any variable (p > 0.05). A significant time effect was observed for body fat (WP: -2.0 +/- 1.1 %BF; CP: -1.0 +/- 1.6 %BF, p < 0.001), lean mass (WP: 1.5 +/- 1.0 kg; CP: 1. 4 +/- 1.0 kg, p < 0.001), fat mass (WP: 1.3 +/- 1.2 kg; CP: -0.6 +/- 1.4 kg, p < 0.001), leg press 1RM (WP: 88.7 +/- 43.9 kg; CP: 90.0 +/- 48.5 kg, p < 0.001), bench press 1RM (WP: 7.5 +/- 4.6 kg; CP: 4.3 +/- 4.5 kg, p = 0.01), vertical jump (WP: 4.1 +/- 1.8 cm; CP: 3.5 +/- 7.6 cm, p < 0.001), 5-10-5 (WP: -0.3 +/- 0.2 sec; CP: -0.09 +/- 0.42 sec, p < 0.001), and broad jump (WP: 10.4 +/- 6.6 cm; CP: 12. 9 +/- 7.1 cm, p < 0.001). The combination of a controlled undulating resistance training program with pre- and post-exercise protein supplementation is capable of inducing significant changes in performance and body composition. There does not appear to be a difference in the performance- enhancing effects between whey and casein proteins. Key pointsFemales can experience and increase in performance makers from consuming protein after resistance training.Females can have a decreased body fat composition when ingesting protein with daily resistance training and conditioning.There was no significant difference in performance markers between whey and casein. PMID- 24149729 TI - Lumbar corsets can decrease lumbar motion in golf swing. AB - Swinging a golf club includes the rotation and extension of the lumbar spine. Golf-related low back pain has been associated with degeneration of the lumbar facet and intervertebral discs, and with spondylolysis. Reflective markers were placed directly onto the skin of 11young male amateur golfers without a previous history of back pain. Using a VICON system (Oxford Metrics, U.K.), full golf swings were monitored without a corset (WOC), with a soft corset (SC), and with a hard corset (HC), with each subject taking 3 swings. Changes in the angle between the pelvis and the thorax (maximum range of motion and angular velocity) in 3 dimensions (lumbar rotation, flexion-extension, and lateral tilt) were analyzed, as was rotation of the hip joint. Peak changes in lumbar extension and rotation occurred just after impact with the ball. The extension angle of the lumbar spine at finish was significantly lower under SC (38 degrees ) or HC (28 degrees ) than under WOC (44 degrees ) conditions (p < 0.05). The maximum angular velocity after impact was significantly smaller under HC (94 degrees /sec) than under SC (177 degrees /sec) and WOC (191 degrees /sec) conditions, as were the lumbar rotation angles at top and finish. In contrast, right hip rotation angles at top showed a compensatory increase under HC conditions. Wearing a lumbar corset while swinging a golf club can effectively decrease lumbar extension and rotation angles from impact until the end of the swing. These effects were significantly enhanced while wearing an HC. Key pointsRotational and extension forces on the lumbar spine may cause golf-related low back painWearing lumbar corsets during a golf swing can effectively decrease lumbar extension and rotation angles and angular velocity.Wearing lumbar corsets increased the rotational motion of the hip joint while reducing the rotation of the lumbar spine. PMID- 24149730 TI - Reliability and Validity of a New Test of Change-of-Direction Speed for Field Based Sports: the Change-of-Direction and Acceleration Test (CODAT). AB - Field sport coaches must use reliable and valid tests to assess change-of direction speed in their athletes. Few tests feature linear sprinting with acute change- of-direction maneuvers. The Change-of-Direction and Acceleration Test (CODAT) was designed to assess field sport change-of-direction speed, and includes a linear 5-meter (m) sprint, 45 degrees and 90 degrees cuts, 3- m sprints to the left and right, and a linear 10-m sprint. This study analyzed the reliability and validity of this test, through comparisons to 20-m sprint (0-5, 0 10, 0-20 m intervals) and Illinois agility run (IAR) performance. Eighteen Australian footballers (age = 23.83 +/- 7.04 yrs; height = 1.79 +/- 0.06 m; mass = 85.36 +/- 13.21 kg) were recruited. Following familiarization, subjects completed the 20-m sprint, CODAT, and IAR in 2 sessions, 48 hours apart. Intra class correlation coefficients (ICC) assessed relative reliability. Absolute reliability was analyzed through paired samples t-tests (p <= 0.05) determining between-session differences. Typical error (TE), coefficient of variation (CV), and differences between the TE and smallest worthwhile change (SWC), also assessed absolute reliability and test usefulness. For the validity analysis, Pearson's correlations (p <= 0.05) analyzed between-test relationships. Results showed no between-session differences for any test (p = 0.19-0.86). CODAT time averaged ~6 s, and the ICC and CV equaled 0.84 and 3.0%, respectively. The homogeneous sample of Australian footballers meant that the CODAT's TE (0.19 s) exceeded the usual 0.2 x standard deviation (SD) SWC (0.10 s). However, the CODAT is capable of detecting moderate performance changes (SWC calculated as 0.5 x SD = 0.25 s). There was a near perfect correlation between the CODAT and IAR (r = 0.92), and very large correlations with the 20-m sprint (r = 0.75-0.76), suggesting that the CODAT was a valid change-of-direction speed test. Due to movement specificity, the CODAT has value for field sport assessment. Key pointsThe change-of-direction and acceleration test (CODAT) was designed specifically for field sport athletes from specific speed research, and data derived from time-motion analyses of sports such as rugby union, soccer, and Australian football. The CODAT features a linear 5-meter (m) sprint, 45 degrees and 90 degrees cuts and 3-m sprints to the left and right, and a linear 10-m sprint.The CODAT was found to be a reliable change-of-direction speed assessment when considering intra-class correlations between two testing sessions, and the coefficient of variation between trials. A homogeneous sample of Australian footballers resulted in absolute reliability limitations when considering differences between the typical error and smallest worthwhile change. However, the CODAT will detect moderate (0.5 times the test's standard deviation) changes in performance.The CODAT correlated with the Illinois agility run, highlighting that it does assess change-of-direction speed. There were also significant relationships with short sprint performance (i.e. 0-5 m and 0-10 m), demonstrating that linear acceleration is assessed within the CODAT, without the extended duration and therefore metabolic limitations of the IAR. Indeed, the average duration of the test (~6 seconds) is field sport-specific. Therefore, the CODAT could be used as an assessment of change-of-direction speed in field sport athletes. PMID- 24149731 TI - Effects of a 12 Week SAQ Training Programme on Agility with and without the Ball among Young Soccer Players. AB - The purpose of this study was to determine the effects of a 12 week conditioning programme involving speed, agility and quickness (SAQ) training and its effect on agility performance in young soccer players. Soccer players were randomly assigned to two groups: experimental group (EG; n = 66, body mass: 71.3 +/- 5.9 kg; body height: 1.77 +/- 0.07 m) and control group (CG; n = 66, body mass: 70.6 +/- 4.9 kg; body height: 1.76 +/- 0.06 m). Agility performance was assessed using field tests: Slalom; Slalom with ball; Sprint with 90 degrees turns; Sprint with 90 degrees turns with ball; Sprint with 180 degrees turns; Sprint with backward and forward running; Sprint 4 x 5 m. Statistically significant improvements (p < 0.05) between pre and post training were evident for almost all measures of agility, with and without the ball, with the exception being the Sprint with backward and forward running. This suggests that SAQ training is an effective way of improving agility, with and without the ball, for young soccer players and can be included in physical conditioning programmes. Key pointsSAQ training appears to be an effective way of improving agility with and without the ball in young soccer playersSoccer coaches could use this training during pre-season and in season trainingCompared with pre-training, there was a statistically significant improvement in all but one measure of agility, both with and without the ball after SAQ training. PMID- 24149732 TI - Reliability of the Woodway Curve(TM) Non-Motorized Treadmill for Assessing Anaerobic Performance. AB - A curved treadmill offers a practical method of assessing anaerobic power by enabling unrestricted running motion and greater sport specificity. The purpose of this research was to determine reliability of a curved treadmill (cTM) sprint test and to compare performance measures to the traditional Wingate anaerobic power test (WAnT) performed on a cycle ergometer. Thirty-two recreationally active men and women (22.4 +/- 2.8 yrs; 1.73 +/- 0.08 m; 74. 2 +/- 13.2 kg) performed four familiarization trials on cTM, followed by two randomly assigned experimental trials consisting of one 30-second maximum effort on either cTM or WAnT. Each trial was separated by at least 48 hours. Repeated measures analysis of variance (ANOVA), interclass correlations (ICC), standard error of measurement (SEM), and minimal differences (MD) were used to determine reliability of familiarization trials on cTM, and Pearson product moment correlations were calculated to compare cTM and WAnT. ANOVA results showed significant differences (p < 0.05) during the four familiarization trials. Post hoc analysis showed significant differences (p < 0. 05) between the first two trials. Familiarization trials 3 and 4 showed a high reliability for each performance variable (distance: ICC2,1 = 0.969, %SEM = 2.645, p = 0.157; mean velocity: ICC2,1 = 0. 969, %SEM = 2.622, p = 0.173; peak velocity: ICC2,1 = 0.966, %SEM = 3.142, p = 0.033; mean power: ICC2,1 = 0.940, %SEM = 4.140, p = 0.093; and peak power: ICC2,1 = 0.887, %SEM = 11.244, p = 0.669). Participants elicited an average peak power of 1050.4 +/- 338.5 Watts on cTM and 1031.4 +/- 349.8 Watts on WAnT. Pearson product moment coefficients indicated high correlations between peak power, mean power, and peak velocity (r = 0.75, p < 0.001; r = 0.84, p < 0.001; and r = 0.76, p < 0. 001, respectively) derived from cTM and WAnT. In conclusion, results suggest that after two familiarization trials, cTM is a reliable sprint test for recreationally active men and women. In addition, there are strong relationships between cTM and WAnT in assessing anaerobic performance. Key pointsThe Woodway Curve 3.0(TM) is a non-motorized treadmill utilizing a curved platform which allows individuals to simulate an unrestricted sprint test in a laboratory setting, offering a practical and sport specific method of assessing anaerobic power.The curved treadmill provides a reliable sprint test for recreationally active men and women.There are strong relationships between the curved treadmill and cycle ergometer in assessing anaerobic performance. PMID- 24149733 TI - Training at the optimum power zone produces similar performance improvements to traditional strength training. AB - The purpose of this study was to test if substituting a regular maximum strength oriented training regimen by a power-oriented one at the optimal power load in the first phase of a traditional periodization produces similar performance improvements later on into the training period. Forty five soldiers of the Brazilian brigade of special operations with at least one year of army training experience were divided into a control group (CG - n = 15, 20.18 +/- 0.72 yrs, 1.74 +/- 0.06 m, 66.7 +/- 9.8 kg, and 1RM/weight ratio = 1.14 +/- 0.12), a traditional periodization group (TG - n = 15, 20.11 +/- 0.7 yrs, 1.72 +/- 0.045 m, 63.1 +/- 3.6 kg, and 1RM/weight ratio = 1.21 +/- 0.16); and a maximum-power group (MPG - n = 15, 20.5 +/- 0.6 yrs, 1.73 +/- 0.049m, 67.3 +/- 9.8 kg, 1RM/weight ratio = 1.20 +/- 0.14). Maximum strength (26.2% and 24.6%), CMJ height (30.8% and 39.1%) and sprint speed (11.6% and 14.5%) increased significantly (p < 0.05) and similarly for the MPG and TG, respectively, from pre- to post assessments. Our data suggests that a power training regimen may be used in the initial phase of the training cycle without impairing performance later on into the training period. Key pointsTraining at the optimal power zone during two mesocycles of a traditional periodization did not hamper strength, speed and power performance improvements.Additional research is required in order to find out if longer periods of training at optimal power zone are capable of producing similar performance improvements to traditional strength training regimen. PMID- 24149734 TI - Evaluating Australian football league player contributions using interactive network simulation. AB - This paper focuses on the contribution of Australian Football League (AFL) players to their team's on-field network by simulating player interactions within a chosen team list and estimating the net effect on final score margin. A Visual Basic computer program was written, firstly, to isolate the effective interactions between players from a particular team in all 2011 season matches and, secondly, to generate a symmetric interaction matrix for each match. Negative binomial distributions were fitted to each player pairing in the Geelong Football Club for the 2011 season, enabling an interactive match simulation model given the 22 chosen players. Dynamic player ratings were calculated from the simulated network using eigenvector centrality, a method that recognises and rewards interactions with more prominent players in the team network. The centrality ratings were recorded after every network simulation and then applied in final score margin predictions so that each player's match contribution-and, hence, an optimal team-could be estimated. The paper ultimately demonstrates that the presence of highly rated players, such as Geelong's Jimmy Bartel, provides the most utility within a simulated team network. It is anticipated that these findings will facilitate optimal AFL team selection and player substitutions, which are key areas of interest to coaches. Network simulations are also attractive for use within betting markets, specifically to provide information on the likelihood of a chosen AFL team list "covering the line ". Key pointsA simulated interaction matrix for Australian Rules football players is proposedThe simulations were carried out by fitting unique negative binomial distributions to each player pairing in a sideEigenvector centrality was calculated for each player in a simulated matrix, then for the teamThe team centrality measure adequately predicted the team's winning marginA player's net effect on margin could hence be estimated by replacing him in the simulated side with another player. PMID- 24149735 TI - Ground reaction forces and loading rates associated with parkour and traditional drop landing techniques. AB - Due to the relative infancy of Parkour there is currently a lack of empirical evidence on which to base specific technique instruction upon. The purpose of this study was to compare the ground reaction forces and loading rates involved in two Parkour landing techniques encouraged by local Parkour instructors and a traditional landing technique recommended in the literature. Ten male participants performed three different drop landing techniques (Parkour precision, Parkour roll, and traditional) onto a force plate. Compared to the traditional technique the Parkour precision technique demonstrated significantly less maximal vertical landing force (38%, p < 0.01, ES = 1.76) and landing loading rate (54%, p < 0.01, ES = 1.22). Similarly, less maximal vertical landing force (43%, p < 0.01, ES = 2.04) and landing loading rate (63%, p < 0.01, ES = 1.54) were observed in the Parkour roll technique compared to the traditional technique. It is unclear whether or not the Parkour precision technique produced lower landing forces and loading rates than the Parkour roll technique as no significant differences were found. The landing techniques encouraged by local Parkour instructors such as the precision and roll appear to be more appropriate for Parkour practitioners to perform than a traditional landing technique due to the lower landing forces and loading rates experienced. Key pointsParkour precision and Parkour roll landings were found to be safer than a traditional landing technique, resulting in lower maximal vertical forces, slower times to maximal vertical force and ultimately lesser loading rates.Parkour roll may be more appropriate (safer) to utilize than the Parkour precision during Parkour landing scenarios.The Parkour landing techniques investigated n this study may be beneficial for landing by non-Parkour practitioners in everyday life. PMID- 24149736 TI - Effects of Strength vs. Ballistic-Power Training on Throwing Performance. AB - The purpose of the present study was to investigate the effects of 6 weeks strength vs. ballistic-power (Power) training on shot put throwing performance in novice throwers. Seventeen novice male shot-put throwers were divided into Strength (N = 9) and Power (n = 8) groups. The following measurements were performed before and after the training period: shot put throws, jumping performance (CMJ), Wingate anaerobic performance, 1RM strength, ballistic throws and evaluation of architectural and morphological characteristics of vastus lateralis. Throwing performance increased significantly but similarly after Strength and Power training (7.0-13.5% vs. 6.0-11.5%, respectively). Muscular strength in leg press increased more after Strength than after Power training (43% vs. 21%, respectively), while Power training induced an 8.5% increase in CMJ performance and 9.0 - 25.8% in ballistic throws. Peak power during the Wingate test increased similarly after Strength and Power training. Muscle thickness increased only after Strength training (10%, p < 0.05). Muscle fibre Cross Sectional Area (fCSA) increased in all fibre types after Strength training by 19 26% (p < 0.05), while only type IIx fibres hypertrophied significantly after Power training. Type IIx fibres (%) decreased after Strength but not after Power training. These results suggest that shot put throwing performance can be increased similarly after six weeks of either strength or ballistic power training in novice throwers, but with dissimilar muscular adaptations. Key pointsBallistic-power training with 30% of 1RM is equally effective in increasing shot put performance as strength training, in novice throwers, during a short training cycle of six weeks.In novice shot putters with relatively low initial muscle strength/mass, short-term strength training might be more important since it can increase both muscle strength and shot put performance.The ballistic type of power training resulted in a significant increase of the mass of type IIx muscle fibres and no change in their proportion. Thus, this type of training might be used effectively during the last weeks before competition, when the strength training load is usually reduced, in order to increase muscle power and shot put performance in novice shot putters. PMID- 24149737 TI - Effect of different rest intervals, between sets, on muscle performance during leg press exercise, in trained older women. AB - The purpose of this study was to assess the effect of different rest intervals (RI) between sets on number of repetitions, sustainability of repetitions, and total volume during a leg press exercise. Seventeen resistance-trained older women (68.0 +/- 5.9 years, 71. 2 +/- 11.7 kg, 1.58 +/- 0.07 m) participated in the study. All participants performed three sets to voluntary exhaustion, with loads that corresponded to 15 maximum repetitions, in two experimental sessions (that ranged from 48 to 72 hours apart). In each session, one of two RI (one minute: RI-1 and three minute: RI-3) was tested, employing a randomized and counterbalanced design. For both RI, significant reductions (p < 0.05) were observed in the number of repetitions and sustainability of repetitions, from the first to the second and third sets. Differences (p < 0.05) between the RI also were observed in the two final sets. The total volume for the RI-3 session was statistically higher (29.4%, p < 0.05) as compared to the RI-1 session. The length of the RI between sets influenced the number of repetitions, sustainability of repetitions, and total volume. The longer RI should be used, therefore, when the goal of training is to increase the total volume. Key pointsThis study examined the influence of rest intervals, between sets, on muscle performance during leg press exercise, in trained older women.When multiple sets were performed to voluntary exhaustion, neither short and long rest interval (1 and 3 minutes, respectively) promoted the sustainability of repetitions in subsequent sets.A longer rest interval seems to be necessary for a higher number of repetitions in subsequent sets, and with increase in time of tension and total volume. PMID- 24149738 TI - A pilot study on the effects of magnesium supplementation with high and low habitual dietary magnesium intake on resting and recovery from aerobic and resistance exercise and systolic blood pressure. AB - The effects of magnesium supplementation on blood pressure (BP) have been studied for over 25 years and results have been inconsistent. Blood pressure reductions in randomized studies have varied from 12 mmHg reductions to no reduction. The objective of this pilot intervention was to investigate the effect of magnesium supplementation on systolic blood pressure whilst resting and during recovery from aerobic and resistance exercise and on performance. A further objective was to see whether the effect of a high vs low habitual dietary magnesium intake affected these results. Sixteen male volunteers were randomly assigned to either a 300 mg.d(-1) magnesium oxide supplementation (MO) or a control group (CG) for 14 days. Resting blood pressure (BP) and heart rate (HR) were measured before subjects performed a maximal 30 minute cycle, immediately followed by three x 5 second isometric bench press, both at baseline and after the intervention. Blood pressure and heart rate were recorded immediately post exercise and after five minutes recovery. A 3 day food diary was recorded for all subjects to measure dietary magnesium intake. At the end of the intervention, the supplemented group, had a reduction in mean resting systolic BP by 8.9 mmHg (115.125 +/- 9.46 mmHg, p = 0.01) and post exercise by 13 mmHg (122.625 +/- 9. 88 mmHg, p = 0.01). Recovery BP was 11.9 mmHg lower in the intervention group compared to control (p = 0.006) and HR decreased by 7 beats per minute in the experimental group (69.0 +/- 11.6 bpm, p = 0. 02). Performance indicators did not change within and between the groups. Habitual dietary magnesium intake affected both resting and post exercise systolic BP and the subsequent effect of the magnesium supplementation. These results have an implication in a health setting and for health and exercise but not performance. Key pointsMagnesium supplementation will have an effect on resting and recovery systolic blood pressure with aerobic exercise.Magnesium supplementation will have an effect on resting and recovery systolic blood pressure with resistance exercise.Magnesium supplementation did not have an effect on performance indicators.A low habitual dietary magnesium intake will negatively affect blood pressure.A high habitual dietary magnesium intake will impact on the effect of magnesium supplementation. PMID- 24149739 TI - Comparative evaluation of two skiing simulators as functional training devices for recreational skiers. AB - The aims of this study were to examine two ski simulators, Skimagic and Skier's Edge, and to evaluate their efficacy as functional training devices for skiers. Vertical ground reaction forces, knee flexion angle kinematics and muscles activity were recorded on these devices and compared with those measured in similar condition while skiing on snow. Five ski instructors performed three randomized testing sessions (snow, Skimagic and Skier's Edge). During the testing sessions, vertical ground reaction forces were recorded by means of pressure insoles in synchronisation with a portable data logger that collected values of knee flexion-extension and EMG activation of rectus femoris and vastus medialis. EMG activations and ground reaction forces measured while skiing on simulators were lower than on snow. Although less overall EMG activation was present on the simulators, the pattern of EMG activity was closer to real snow on Skimagic than on Skiers' Edge. Results of the present study suggested that the two devices are not effectively applicable for strength training. However, based on the recorded EMG patterns, the Skimagic treadmill is potentially suitable to act as a functional training device for recreational skiers provided that an increase of speed and slope on Skimagic could induce a closer matching of the studied biomechanical parameters with the snow skiing conditions. Key pointsEMG activation and ground reaction forces were lower on both simulators with respect to snow.Both simulators were not able to provide an effective contribution to strength development for skiers.In term of functional training Skier's Edge showed a predominance of concentric action over eccentric which is in contrast with competitive skiing.Skimagic treadmill could be potentially suitable to act as a functional training device for recreational skiers only if an increase of speed and slope will induce a closer matching of the studied biomechanical parameters with the snow skiing conditions. PMID- 24149740 TI - Mechanisms for triceps surae injury in high performance front row rugby union players: a kinematic analysis of scrummaging drills. AB - The front row of a rugby union scrum consists of three players. The loose head prop, hooker and tight head prop. The objective of this study was to determine if known biomechanical risk factors for triceps surae muscle injury are exhibited in the lower limb of front row players during contested scrummaging. Eleven high performance front row rugby union players were landmarked bilaterally at the posterior superior iliac spine (PSIS), greater trochanter, lateral femoral epicondyle, midline of the calcaneus above the plantar aspect of the heel, midline lower leg 5cm and 20cm proximal to the lateral malleolus, at the axis of subtalar joint, lateral malleolus, and head of the fifth metatarsal. Players were video recorded during a series of 2 on 1 live scrummaging drills. Biomechanical three dimensional analysis identified large angular displacements, and increased peak velocities and accelerations at the ankle joint during attacking scrummaging drill techniques when in the stance phase of gait. This places the triceps surae as increased risk of injury and provides valuable information for training staff regarding injury prevention and scrum training practices for front row players. Key pointsFront rowers exhibited patterns of single leg weight bearing, in a position of greater ankle plantar flexion and knee extension at toe off during scrummaging, which is a risk position for TS injury.Front rowers also exhibited greater acceleration at the ankle, knee, and hip joints, and greater changes in ankle ROM from toe strike to toe off during attacking scrum drills.These reported accelerations and joint displacements may be risk factors for TS injury, as the ankle is accelerating into plantar flexion at final push off and the muscle is shortening from an elongated state. PMID- 24149741 TI - Intermittent versus Continuous Incremental Field Tests: Are Maximal Variables Interchangeable? AB - The aim of the present study was to compare physiological responses derived from an incremental progressive field test with a constant speed test i.e. intermittent versus continuous protocol. Two progressive maximum tests (Carminatti's test (T-CAR) and the Vameval test (T-VAM)), characterized by increasing speed were used. T-CAR is an intermittent incremental test, performed as shuttle runs; while T-VAM is a continuous incremental test performed on an athletic track. Eighteen physically active, healthy young subjects (21.9 +/- 2.0 years; 76.5 +/- 8.6 kg, 1.78 +/- 0.08 m, 11.2 +/- 5.4% body fat), volunteered for this study. Subjects performed four different maximum test sessions conducted in the field: two incremental tests and two time to exhaustion tests (TTE) at peak test velocities (PV). No significant differences were found for PV (T-CAR = 15.6 +/- 1.2; T-VAM = 15.5 +/- 1.3 km.h(-1)) and maximal HR (T-CAR = 195 +/- 11; T- VAM = 194 +/- 14 bpm). During TTE, there were no significant differences for HR (TTET-CAR and TTET-VAM = 192 +/- 12 bpm). However, there was a significant difference in TTE (p = 0.04) (TTET-CAR = 379 +/- 84, TTET-VAM = 338 +/- 58 s) with a low correlation (r = 0.41). The blood lactate concentration measured at the end of the TTE tests, showed no significant difference (TTET-CAR = 13.2 +/- 2.4 vs. TTET-VAM = 12.9 +/- 2.4 mmol.l(-1)). Based on the present findings, it is suggested that the maximal variables derived from T-CAR and T-VAM can be interchangeable in the design of training programs. Key pointsT-CAR is an intermittent shuttle run test that predicts the maximal aerobic speed with accuracy, hence, test results could be interchangeable with continuous straight line tests.T-CAR provides valid field data for evaluating aerobic fitness.In comparison with T-VAM, T-CAR may be a more favourable way to prescribe intermittent training using a shuttle-running protocol. PMID- 24149742 TI - Analysis of Relationships between the Level of Errors in Leg and Monofin Movement and Stroke Parameters in Monofin Swimming. AB - The aim of this study was to analyze the error structure in propulsive movements with regard to its influence on monofin swimming speed. The random cycles performed by six swimmers were filmed during a progressive test (900m). An objective method to estimate errors committed in the area of angular displacement of the feet and monofin segments was employed. The parameters were compared with a previously described model. Mutual dependences between the level of errors, stroke frequency, stroke length and amplitude in relation to swimming velocity were analyzed. The results showed that proper foot movements and the avoidance of errors, arising at the distal part of the fin, ensure the progression of swimming speed. The individual stroke parameters distribution which consists of optimally increasing stroke frequency to the maximal possible level that enables the stabilization of stroke length leads to the minimization of errors. Identification of key elements in the stroke structure based on the analysis of errors committed should aid in improving monofin swimming technique. Key pointsThe monofin swimming technique was evaluated through the prism of objectively defined errors committed by the swimmers.The dependences between the level of errors, stroke rate, stroke length and amplitude in relation to swimming velocity were analyzed.Optimally increasing stroke rate to the maximal possible level that enables the stabilization of stroke length leads to the minimization of errors.Propriety foot movement and the avoidance of errors arising at the distal part of fin, provide for the progression of swimming speed.The key elements improving monofin swimming technique, based on the analysis of errors committed, were designated. PMID- 24149743 TI - Time of day - effects on motor coordination and reactive strength in elite athletes and untrained adolescents. AB - OBJECTIVES: the issue of time-of-day effects on performance is crucial when considering the goal of reaching peak results in sport disciplines. The present study was designed to examine time-of-day effects in adolescents on motor coordination, assessed with Hirtz's battery and neuromuscular components of strength, evaluated with reactive strength tests. METHODS: forty-two elite female gymnasts, aged 13.3 +/- 0.5 years (Mean +/- SD), were recruited for the study. Fifty healthy female students (aged 12.8 +/- 1.7 years) served as the control group. All participants underwent the testing sessions over two days at two different times of day in a randomized order. RESULTS: Oral temperature was measured at the two times of the day and a significant diurnal variation (p < 0.01) in both groups was found. MANOVA revealed significant group differences in the overall tests (p < 0.01). The gymnast group showed no significant differences in the coordination tests with respect to the time of day, but significant differences were observed for reactive strength as assessed with the vertical jump tests (p < 0.01). Gyamnasts attained better results in the evening in the reactive strength tests [flight time (F1.90 = 17.322 p < 0.01) and ground contact time (F1.90 = 8.372; p < 0.01) of the hopping test]. CONCLUSION: the temperature effect was more evident in the reactive strength tests and orientation test, especially in the gymnast group in which this effect added to their usual training time effect. The time-since-awakening influenced coordination performances in complex tasks more than reaction strength tests in simple tasks. The main outcome of the study was that we did not observe time-of-day effects on coordination skills in elite gymnasts and in untrained adolescents. The time of day in which athletes usually trained these skills could influence these results. Key pointsThe results obtained in this study suggested that the best time to perform a particular task depends specifically on the nature of the task, the precise size of the cognitive load and the level of practice of the participants.In the field of practice, it is incumbent for coaches to organise sports selection based on reactive strength, using the morning hours for untrained adolescents, when alertness and the benefits of sleeping could improve performance. Evening hours, conversely, should be used for elite gymnasts who specifically train at that time (specific "temporal training effect").These study results cannot give indications about the best time of the day to organize selection tests based on coordination skills. PMID- 24149744 TI - Performance level affects the dietary supplement intake of both individual and team sports athletes. AB - Dietary supplement (DS) intake is high in elite level athletes, however few studies have investigated the impact that the performance level of the athletes has on supplementation intake in individual and team sports. The purpose of the study was to determine and compare the DS intake among individual and team sport athletes of various performance levels. A total of 2845 participants (athletes: 2783, controls: 62) between the ages of 11 and 44 years old participated in the study. A 3-page questionnaire was developed to assess the intake of DS. Athletes were categorized based on participation in individual (n = 775) and team sports (n = 2008). To assess the effect of performance level in supplementation intake, athletes were categorized based on training volume, participation in the national team, and winning at least one medal in provincial, national, international or Olympic games. Overall, 37% of all athletes of various performance levels reported taking at least one DS in the last month. A higher prevalence of DS intake was reported in individual (44%) compared to team sport athletes (35%) (p < 0.001). Athletes of high performance level reported greater DS intake compared to lower performance athletes. Males reported a significantly greater prevalence of DS intake compared to females. The most popular supplement reported was amino acid preparation with the main reason of supplementation being endurance improvements. In conclusion, performance level and type of sport appear to impact the DS practices of male and female athletes. These findings should be validated in other populations. Key points37% of Mediterranean athletes of various sports and levels have reported taking dietary supplements.The performance level of the athletes affects the dietary supplementation intake.Athletes in individual sports appear to have a higher DS intake compared to team sport athletes.Male athletes appear to take more dietary supplements compared to female athletes. PMID- 24149745 TI - Effect of the volume of fluid ingested on urine concentrating ability during prolonged heavy exercise in a hot environment. AB - This study examined the effect of the volume of fluid ingested on urine concentrating ability during prolonged heavy exercise in a hot environment at low levels of dehydration. Seven healthy males performed 105 min of intermittent cycle exercise at 70% maximum oxygen uptake (32 degrees C, 60% relative humidity) while receiving no fluid ingestion (NF), voluntary fluid ingestion (VF), partial fluid ingestion equivalent to one-half of body mass loss (PF), and full fluid ingestion equivalent to body mass loss (FF). Fluid (5 degrees C, 3.4% carbohydrate, 10.5 mmol.L(-1) sodium) was ingested just before commencing exercise and at 15, 33, 51, 69, and 87 min of exercise, and the total amount of fluid ingested in PF and FF was divided into six equal volumes. During exercise, body mass loss was 2.2 +/- 0.2, 1.1 +/- 0.5, 1.1 +/- 0.2, and 0.1 +/- 0.2% in NF, VF, PF, and FF, respectively, whereas total sweat loss was about 2% of body mass in each trial. Subjects in VF ingested 719 +/- 240 ml of fluid during exercise; the volume of fluid ingested was 1.1 +/- 0.4% of body mass. Creatinine clearance was significantly higher and free water clearance was significantly lower in FF than in NF during exercise. Urine flow rate during exercise decreased significantly in NF. There were significant decreases in creatinine and osmolar clearance and was a significant increase in free water clearance during exercise in NF and VF. Creatinine clearance decreased significantly and free water clearance increased significantly during exercise in PF. There was no statistical change in urinary indices of renal function during exercise in FF. The findings suggest that full fluid ingestion equivalent to body mass loss has attenuated the decline in urine concentrating ability during prolonged heavy exercise in a hot environment at low levels of dehydration. Key pointsDuring prolonged heavy exercise in a hot environment at low levels of dehydration, fluid ingestion equivalent to body mass loss results in no changes in urinary indices of renal function.Fluid ingestion equivalent to body mass loss can attenuate the decline in urine concentrating ability during exercise.Ad libitum or voluntary fluid ingestion is ineffective in reducing the decline in urine concentrating ability during exercise. PMID- 24149746 TI - Effects of heat stress and sex on pacing in marathon runners. AB - Recent research suggests that women tend to exhibit less of a precipitous decline in run velocity during the latter stages of a marathon than men when the covariates of age and run time are controlled for. The purpose of this study was to examine this sex effect with the added covariate of heat stress on pacing, defined as the mean velocity of the last 12.2 km divided by the mean velocity of the first 30 km. A secondary purpose of this investigation was to compare the pacing profiles of the elite men and women runners and the pacing profiles of the elite and nonelite runners. Subjects included 22,990 men and 13,233 women runners from the 2007 and 2009 Chicago marathons for which the mean ambient temperatures were 26.67 degrees C and 2.77 degrees C, respectively. Each 5-km split time was measured via an electronic chip worn on the participants' shoe. Multiple regression analysis indicated that age, sex, heat stress, and overall finish time (p < 0.01 for each) were simultaneous independent elements of pacing. Nonelite women were consistently better pacers than nonelite men in both marathons, and this sex difference was magnified from cold to warm race temperatures. No difference (p < 0.05) in pacing was found between elite men and women runners. Elite men and women had enhanced pacing over their nonelite counterparts. In hotter temperatures, coaches of novice runners should advise their athletes to implement a slower initial velocity to maintain or increase running velocity later in the race. PMID- 24149747 TI - Accuracy and reliability of GPS devices for measurement of sports-specific movement patterns related to cricket, tennis, and field-based team sports. AB - The aim of this study was to determine the accuracy and reliability of 5, 10, and 15 Hz global positioning system (GPS) devices. Two male subjects (mean +/- SD; age, 25.5 +/- 0.7 years; height, 1.75 +/- 0.01 m; body mass, 74 +/- 5.7 kg) completed 10 repetitions of drills replicating movements typical of tennis, cricket, and field-based (football) sports. All movements were completed wearing two 5 and 10 Hz MinimaxX and 2 GPS-Sports 15 Hz GPS devices in a specially designed harness. Criterion movement data for distance and speed were provided from a 22-camera VICON system sampling at 100 Hz. Accuracy was determined using 1 way analysis of variance with Tukey's post hoc tests. Interunit reliability was determined using intraclass correlation (ICC), and typical error was estimated as coefficient of variation (CV). Overall, for the majority of distance and speed measures, as measured using the 5, 10, and 15 Hz GPS devices, were not significantly different (p > 0.05) to the VICON data. Additionally, no improvements in the accuracy or reliability of GPS devices were observed with an increase in the sampling rate. However, the CV for the 5 and 15 Hz devices for distance and speed measures ranged between 3 and 33%, with increasing variability evident in higher speed zones. The majority of ICC measures possessed a low level of interunit reliability (r = -0.35 to 0.39). Based on these results, practitioners of these devices should be aware that measurements of distance and speed may be consistently underestimated, regardless of the movements performed. PMID- 24149748 TI - Muscle activation during various hamstring exercises. AB - The dorsal muscles of the lower torso and extremities have often been denoted the "posterior chain." These muscles are used to support the thoracic and lumbar spine and peripheral joints, including the hip, knee, and ankle on the dorsal aspect of the body. This study investigated the relative muscle activity of the hamstring group and selected surrounding musculature during the leg curl, good morning, glute-ham raise, and Romanian deadlift (RDL). Twelve healthy, weight trained men performed duplicate trials of single repetitions at 85% 1-repetition maximum for each lift in random order, during which surface electromyography and joint angle data were obtained. Repeated measures analysis of variance across the 4 exercises was performed to compare the activity from the erector spinae (ES), gluteus medius (GMed), semitendinosus (ST), biceps femoris (BF), and medial gastrocnemius (MGas). Significant differences (p <= 0.05) were noted in eccentric muscle activity between exercise for the MGas (p < 0.027), ST (p < 0.001), BF (p < 0.001), and ES (p = 0.032), and in concentric muscle activity, for the ES (p < 0.001), BF (p = 0.010), ST (p = 0.009), MGas (p < 0.001), and the GMed (p = 0.018). Bonferroni post hoc analysis revealed significant pairwise differences during eccentric actions for the BF, ST, and MGas. Post hoc analysis also revealed significant pairwise differences during concentric actions for the ES, BF, ST, MGas, and GMed. Each of these showed effect sizes that are large or greater. The main findings of this investigation are that the ST is substantially more active than the BF among all exercises, and hamstring activity was maximized in the RDL and glute-ham raise. Therefore, athletes and coaches who seek to maximize the involvement of the hamstring musculature should consider focusing on the glute-ham raise and RDL. PMID- 24149749 TI - The effects of elapsed time after warm-up on subsequent exercise performance in a cold environment. AB - Athletes often compete in cold environments and may face delays because of weather or race logistics between performance of a warm-up and the start of the race. This study sought to determine, (a) whether a delay after warm-up affects subsequent time trial (TT) performance and (b) if exposure to a cold environment has an additive effect. We hypothesized that after a warm-up, 30 minutes of rest in a cold environment would negatively affect subsequent rowing and running performance. In a temperate (temp; 24 degrees C) or cold (cold; 5 degrees C) environment, 5 rowers (33 +/- 10 years; 83 +/- 12 kg) and 5 runners (23 +/- 2 years; 65 +/- 8 kg) performed a 15-minute standardized warm-up followed by a 5- or 30-minute rest and then performed a 2-km rowing or 2.4 km running TT. The 5 minute rest following warm-up in the temperate environment (5Temp) served as the control trial to which the other experimental trials (5Cold; 30Temp; and 30Cold) were compared. Heart rate, lactate, and esophageal (Tes) and skin (Tsk) temperatures were measured throughout. Postrest and post-TT, Tes, and Tsk were lowest in the 30Cold trials. The greatest decrement in TT performance vs. 5Temp occurred in 30Cold (-4.0%; difference of 20 seconds). This difference is considered to have practical importance, as it was greater than the reported day to-day variation for events of this type. We conclude that longer elapsed time following warm-up, combined with cold air exposure, results in potentially important reductions in exercise performance. Athletes should consider the appropriate timing of warm-up. In addition, performance may be preserved by maintaining skin and core temperatures following a warm-up, via clothing or other means. PMID- 24149751 TI - Kinematic and kinetic improvements associated with action observation facilitated learning of the power clean in Australian footballers. AB - This study investigated the effectiveness of action observation (AO) on facilitating learning of the power clean technique (kinematics) compared with traditional strength coaching methods and whether improvements in performance (kinetics) were associated with an improvement in lifting technique. Fifteen subjects (age, 20.9 +/- 2.3 years) with no experience in performing the power clean exercise attended 12 training and testing sessions over a 4-week period. Subjects were assigned to 2 matched groups, based on preintervention power clean performance and performed 3 sets of 5 repetitions of the power clean exercise at each training session. Subjects in the traditional coaching group (TC; n = 7) received the standard coaching feedback (verbal cues and physical practice), whereas subjects in the AO group (n = 8) received similar verbal coaching cues and physical practice but also observed a video of a skilled model before performing each set. Kinematic data were collected from video recordings of subjects who were fitted with joint center markings during testing, whereas kinetic data were collected from a weightlifting analyzer attached to the barbell. Subjects were tested before intervention, at the end of weeks 2 and 3, and at after intervention at the end of week 4. Faster improvements (3%) were observed in power clean technique with AO-facilitated learning in the first week and performance improvements (mean peak power of the subject's 15 repetitions) over time were significant (p < 0.001). In addition, performance improvement was significantly associated (R = 0.215) with technique improvements. In conclusion, AO combined with verbal coaching and physical practice of the power clean exercise resulted in significantly faster technique improvements and improvement in performance compared with traditional coaching methods. PMID- 24149752 TI - The influence of the time of day on core temperature and lower body power output in elite rugby union sevens players. AB - Core temperature typically displays a low circadian in the morning before peaking later in the day, and these changes occur within small physiological ranges. Body temperature plays an important role in physical performance, and some athletes may be required to train and compete in both the morning and evening. However, the influence of the circadian change in body temperature and its influence on physical performance in elite athletes are unclear. This study examined the effects of the time of day on core temperature and lower body power output in elite rugby union sevens players. Sixteen elite rugby union sevens players completed morning (in AM) countermovement jump and core temperature (Tcore) measurement, which were then repeated later the same day (in PM). Countermovement jump was processed for peak power output (PPO). Data were analyzed using paired samples t-test and Pearson's product moment correlation and are presented in mean +/- SD. Tcore significantly increased from AM to PM (AM, 36.92 +/- 0.23 vs. PM, 37.18 +/- 0.18 degrees C; P < 0.001) with PPO significantly increasing from AM to PM in all 16 players (AM, 5248 +/- 366 vs. PM, 5413 +/- 361 W; P < 0.001). The delta change in Tcore (0.26 +/- 0.13 degrees C) and PPO (164 +/- 78 W) was significantly related (r = 0.781; P < 0.001). In conclusion, small circadian changes in core temperature can influence physical performance in elite athletes. Coaches should seek to use strategies, which may raise morning body temperature to offset the circadian low in the morning. PMID- 24149753 TI - Combining normobaric hypoxia with short-term resistance training has no additive beneficial effect on muscular performance and body composition. AB - The aim of this study was to determine the effects of short-term resistance training combined with systemic hypoxia on muscular performance and body composition. Eighteen resistance-untrained men (21.3 +/- 2.0 years, 172.7 +/- 5.5 cm, 67.3 +/- 9.7 kg) were matched and assigned to 2 experimental groups: performing 6 weeks of squat exercise training under normobaric hypoxia (H, FiO2 = 15%) or normoxia (N). In both groups, subjects performed 3 weekly sessions (a total of 18 sessions) of 3 sets of back squat at 10-repetition maximum with 2 minutes of rest between sets. Dynamic, isometric, and isokinetic leg strength and body composition were measured under normoxia before and after resistance training. Squat 1 repetition maximum (1RM) improved significantly (p <= 0.05) after resistance training in both H and N groups (88.9 +/- 16.9 to 109.4 +/- 17.0 kg and 90.0 +/- 12.2 to 105.6 +/- 13.3 kg, respectively). However, there were no changes in maximal isometric and isokinetic leg strength, lean body mass, and fat mass after the resistance training in both groups. In addition, no significant differences were observed between H and N groups in squat 1RM, maximal isometric and isokinetic leg strength, and body composition. The major findings of this study suggest that short-term resistance training performed under normobaric hypoxia has no additive beneficial effect on muscular performance and body composition. In practical terms, our data suggest that the use of systemic hypoxia during short-term resistance training is not a viable method to further enhance muscular performance and body composition in previously resistance untrained men. PMID- 24149754 TI - The Effects of Running Speed on Ground Reaction Forces and Lower Limb Kinematics During Single-Leg Stop Movement. AB - The purpose of this study was to investigate the effects of running speed on both ground reaction forces (GRFs) and lower limb kinematics during the deceleration phase of the single-leg stop movement. With 7 male university students participating in this study, each subject accelerated forwards at 3 approach speeds (2.50, 2.75, and 3.00 m.s), and stopped with the right leg landing on the force plate. Kinematic data were recorded from a lateral view using 1 high-speed camera. The result was that all subjects indicated the same stopping pattern, and 3 peaks of the resultant GRF were observed. The first peak (P1) appeared before full foot-ground contact, and the time to peak from initial foot contact to P1 was significantly shorter with increasing approach speeds (p <= 0.05). The second (P2) and third (P3) peaks were observed after full foot-ground contact, and the resultant GRF at P3 and the posterior GRF at P2 and P3 were significantly greater with increasing approach speeds (p <= 0.05). The hip flexion and the planter flexion angles at each peak were larger with increasing approach speeds (p <= 0.05). However, there was no significant difference in the vertical GRF, range of motion, and angular velocity of hip, knee, and ankle joints when comparing different approach speeds. This study suggests that to improve the stop movement strategy under faster approach speeds, it is important to increase the magnitude of posterior GRF and the hip and ankle flexion angles under increasing speeds. PMID- 24149755 TI - An investigation of motivational variables in CrossFit facilities. AB - CrossFit is a growing fitness trend in the United States; however, little systematic research has addressed specific motivational principles within this unique exercise environment. The purpose of the study was to explore the influence of gender and membership time on perceptions of motivational climate and goals within the CrossFit environment. Specifically, people may set goals related to self-improvement (i.e., mastery) or focus on their performance in comparison to others (i.e., performance). Motivational climate refers to an individual's perception of being encouraged to focus on either mastery or performance goals from CrossFit trainers. A total of 144 members (88 females; 56 males) completed questionnaires to assess participants' perceptions of CrossFit goal structures and perceptions of the motivational climate encouraged by the trainer within their CrossFit box. Results indicated a significant main effect for gender on preferred goals (p <= 0.05), with males reporting higher levels of performance approach goals and females reporting higher levels of master avoidance goals. Participants who reported shorter membership times were found to have significantly higher mastery-related goals than individuals who reported longer membership times (p <= 0.05). The results from the study suggest that practitioners should consider how perceptions of the motivational climate and goals in group-based exercise settings such as CrossFit may vary based on demographic variables, and that these differences may impact how to most effectively motivate, encourage, and instruct group members, particularly with regard to helping members set goals that most effectively address their approach to the CrossFit regimen. PMID- 24149756 TI - Trunk extensor and flexor strength capacity in healthy young elite athletes aged 11-15 years. AB - Differences in trunk strength capacity because of gender and sports are well documented in adults. In contrast, data concerning young athletes are sparse. The purpose of this study was to assess the maximum trunk strength of adolescent athletes and to investigate differences between genders and age groups. A total of 520 young athletes were recruited. Finally, 377 (n = 233/144 M/F; 13 +/- 1 years; 1.62 +/- 0.11 m height; 51 +/- 12 kg mass; training: 4.5 +/- 2.6 years; training sessions/week: 4.3 +/- 3.0; various sports) young athletes were included in the final data analysis. Furthermore, 5 age groups were differentiated (age groups: 11, 12, 13, 14, and 15 years; n = 90, 150, 42, 43, and 52, respectively). Maximum strength of trunk flexors (Flex) and extensors (Ext) was assessed in all subjects during isokinetic concentric measurements (60 degrees .s(-1); 5 repetitions; range of motion: 55 degrees ). Maximum strength was characterized by absolute peak torque (Flexabs, Extabs; N.m), peak torque normalized to body weight (Flexnorm, Extnorm; N.m.kg(-1) BW), and Flexabs/Extabs ratio (RKquot). Descriptive data analysis (mean +/- SD) was completed, followed by analysis of variance (alpha = 0.05; post hoc test [Tukey-Kramer]). Mean maximum strength for all athletes was 97 +/- 34 N.m in Flexabs and 140 +/- 50 N.m in Extabs (Flexnorm = 1.9 +/- 0.3 N.m.kg(-1) BW, Extnorm = 2.8 +/- 0.6 N.m.kg(-1) BW). Males showed statistically significant higher absolute and normalized values compared with females (p < 0.001). Flexabs and Extabs rose with increasing age almost 2-fold for males and females (Flexabs, Extabs: p < 0.001). Flexnorm and Extnorm increased with age for males (p < 0.001), however, not for females (Flexnorm: p = 0.26; Extnorm: p = 0.20). RKquot (mean +/- SD: 0.71 +/- 0.16) did not reveal any differences regarding age (p = 0.87) or gender (p = 0.43). In adolescent athletes, maximum trunk strength must be discussed in a gender- and age-specific context. The Flexabs/Extabs ratio revealed extensor dominance, which seems to be independent of age and gender. The values assessed may serve as a basis to evaluate and discuss trunk strength in athletes. PMID- 24149757 TI - The physiology of judo-specific training modalities. AB - Understanding the physiological response to the most common judo training modalities may help to improve the prescription and monitoring of training programs. This review is based on search results using the following terms: "judo," "judo and training," "judo and physiology," "judo and specific exercises," and "judo and combat practice." Uchi-komi (repetitive technical training) is a specific judo exercise that can be used to improve aerobic and anaerobic fitness. Effort to pause ratio, total session duration, number and duration of individual sets, and the type of technique can be manipulated to emphasize specific components of metabolism. "Nage-komi" (repetitive throwing training) can also be used to improve aerobic and anaerobic fitness, depending on the format of the training session. "Randori" (combat or fight practice; sparring) is the training modality most closely related to actual judo matches. Despite the similarities, the physiological demands of randori practice are not as high as observed during real competitive matches. Heart rate has not shown to be an accurate measure of training intensity during any of the previously mentioned judo training modalities. High-volume, high-intensity training programs often lead judo athletes to experience overtraining-related symptoms, with immunosuppression being one of the most common. In conclusion, judo training and judo-specific exercise should be manipulated to maximize training response and competitive performance. PMID- 24149759 TI - Olympic preparation in Brazilian judo athletes: description and perceived relevance of training practices. AB - The aim of this study was to describe the training routines used by judo athletes and their perception concerning the relevance, effort made, concentration needed, and pleasure obtained during the training sessions conducted 6 months before their Olympic participation and to compare with medal winners and other competitors in these aspects. Sixty-one Olympic Brazilian judo athletes (men = 39; women = 22), representing 66.3% of all Brazilian participants in this Olympic sport (from 1964 to 2008), including 10 medal winners (9 men and 1 woman) answered a questionnaire concerning their training routines. Mann-Whitney and Student's t-test for independent samples were used. Judo medalists and nonmedalists in the Olympic Games did not differ in: (a) the age when they started to practice and to compete in judo, (b) the age when they competed in the Olympic Games, (c) hours of training per week and per training session and the number of training sessions per day in their preparation for this event, (d) frequency and time spent for performing judo-specific and general exercises and their perceived relevance, effort, pleasure, and concentration for these activities performed during the preparation for the Olympic Games. The only differences found were the groundwork (ne-waza) randori practice, which was less frequently performed by medal winners, and perceived relevance attributed to this activity, which was considered less relevant by the medal winners compared with nonmedal winners. Thus, judo Olympic medal winners and nonmedalists did not differ in many training aspects in the final phase of their preparation to the Olympic Games. PMID- 24149760 TI - Body composition and bone mineral density of national football league players. AB - The purpose of the present study was to examine the body composition of National Football League (NFL) players before the start of the regular season. Four hundred eleven NFL players were measured for height, weight and lean, fat, and bone mass using dual-energy x-ray absorptiometry (DXA). Subjects were categorized by their offensive or defensive position for comparison. On average, positions that mirror each other (i.e., offensive lineman [OL] vs. defensive lineman [DL]) have very similar body composition. Although OL had more fat mass than DL, they were similar in total and upper and lower lean mass. Linebackers (LB) and running backs (RB) were similar for all measures of fat and lean mass. Tight ends were unique in that they were similar to RB and LB on measures of fat mass; however, they had greater lean mass than both RB and LB and upper-body lean mass that was similar to OL. Quarterbacks and punters/kickers were similar in fat and lean masses. All positions had normal levels of bone mineral density. The DXA allowed us to measure differences in lean mass between arms and legs for symmetry assessments. Although most individuals had similar totals of lean mass in each leg and or arms, there were outliers who may be at risk for injury. The data presented demonstrate not only differences in total body composition, but also show regional body composition differences that may provide positional templates. PMID- 24149761 TI - The effects of interday rest on adaptation to 6 weeks of plyometric training in young soccer players. AB - The purpose of this study was to determine the effects of short-term plyometric training interposed with 24 or 48 hours of rest between training sessions on explosive and endurance adaptations in young soccer players. A total of 166 players, between 10 and 17 years of age, were randomly divided into 3 groups: a control group (CG; n = 55) and 2 plyometric training groups with 24 hours (PT24; n = 54) and 48 hours (PT48; n = 57) of rest between training sessions. Before and after intervention, players were measured in squat jump, countermovement jump, 20 (RSI20) cm drop jump reactive strength index, broad long jump, 20-m sprint time, 10 * 5-m agility time, 20-m multistage shuttle run test, and sit-and-reach test. The plyometric training program was applied during 6 weeks, 2 sessions per week, with a load from 140 to 260 jumps per session, replacing some soccer-specific drills. After intervention, the CG did not show significant performance changes. PT24 and PT48 groups showed a small-to-moderate significant improvement in all performance tests (p < 0.001), with no differences between treatments. Although it has been recommended that plyometric drills should not be conducted on consecutive days, the study shows that plyometric training applied twice weekly on consecutive or nonconsecutive days results in similar explosive and endurance adaptations in young male soccer players. PMID- 24149762 TI - Effects of sprint and plyometrics training on field sport acceleration technique. AB - The mechanisms for speed performance improvement from sprint training and plyometrics training, especially relating to stance kinetics, require investigation in field sport athletes. This study determined the effects of sprint training and plyometrics training on 10-m sprint time (0-5, 5-10, and 0-10 m intervals), step kinematics (step length and frequency, contact and flight time), and stance kinetics (first, second, and last contact relative vertical [VF, VI], horizontal [HF, HI], and resultant [RF, RI] force and impulse; resultant ground reaction force angle [RFtheta]; ratio of horizontal to resultant force [RatF]) during a 10-m sprint. Sixteen male field sport athletes were allocated into sprint training (ST) and plyometrics training (PT) groups according to 10-m sprint time; independent samples t-tests (p <= 0.05) indicated no between-group differences. Training involved 2 sessions per week for 6 weeks. A repeated measures analysis of variance (p <= 0.05) determined within- and between-subject differences. Both groups decreased 0-5 and 0-10 m time. The ST group increased step length by ~15%, which tended to be greater than step length gains for the PT group (~7%). The ST group reduced first and second contact RFtheta and RatF, and second contact HF. Second contact HI decreased for both groups. Results indicated a higher post-training emphasis on VF production. Vertical force changes were more pronounced for the PT group for the last contact, who increased or maintained last contact VI, RF, and RI to a greater extent than the ST group. Sprint and plyometrics training can improve acceleration, primarily through increased step length and a greater emphasis on VF. PMID- 24149763 TI - Foot strike pattern and gait changes during a 161-km ultramarathon. AB - Foot strike pattern has not been examined during ultramarathons where fatigue or avoidance of impact might have greater effect on foot strike and other gait parameters than in shorter events. In this study, video analysis from 3 level sites at a 161-km ultramarathon was used to: (a) examine changes in foot strike pattern, stride rate, and stride length; (b) determine if foot strike pattern is related to performance; and (c) ascertain if post-race blood creatine phosphokinase (CK) concentrations differ by foot strike pattern. Rear-foot strike (RFS) prevalence was 79.9, 89.0, and 83.9% at 16.5, 90.3, and 161.1 km, respectively. There was a significant distance effect observed between the 90.3 and 161.1-km site for stride rate (p < 0.05) and across all distances for stride length (p < 0.0001), but stride rate and length were stable among the top 20 finishers. There was no effect (p = 0.3) of foot strike pattern on performance. However, top 20 finishers had greater use (p = 0.02) of a non-RFS pattern at 161.1 km than the remaining finishers. There was a trend toward greater post-race blood CK values among non-RFS runners compared with RFS runners, reaching significance at the 90.3 km site (p < 0.05). Thus, the increased RFS prevalence by race midpoint was likely because of greater muscular demands of non-RFS patterns as supported by the higher post-race blood CK concentrations among non RFS runners. Faster runners maintained higher stride rates and lengths throughout the race and made greater use of a non-RFS pattern at the end of the race compared with the slower finishers. PMID- 24149764 TI - Validation of the Loughborough Soccer Passing Test in young soccer players. AB - The aim of this study was to examine the validity and reliability of the Loughborough Soccer Passing Test (LSPT) in adolescent soccer players. Eighty seven players, aged 14-17 years, were recruited according to their playing level: elite (n = 44), sub-elite (n = 22), and non-elite (n = 21). Two attempts of the LSPT were performed at baseline. Players then completed 10 attempts over 3 weeks to familiarize themselves with the test. Subsequently, 2 main trials, separated by 1 week, were performed; the mean of the 2 attempts was recorded as the performance score. After familiarization, the performance scores showed significant differences (p < 0.01) between elite (40.3 +/- 8.3 seconds), sub elite (58.1 +/- 10.2 seconds), and non-elite players (66.6 +/- 11.7 seconds). There was low-to-moderate reliability between trials with sub-elite (r = 0.35, p < 0.05) and non-elite players (r = 0.47, p < 0.05), but very good for elite players (r = 0.96, p < 0.05). Scores at baseline were better (p < 0.05) for elite players (51.0 +/- 9.3 seconds) compared with sub-elite (60.8 +/- 8.2 seconds) and non-elite players (69.0 +/- 11.1 seconds). The LSPT seems to be a valid and reliable protocol to assess differences in soccer skill performance in adolescent players and can distinguish players according to their playing level. The LSPT was able to distinguish different abilities without players undergoing any familiarization with the test, thus enabling it to be used for talent identification purposes. PMID- 24149765 TI - A comparison of linear speed, closed-skill agility, and open-skill agility qualities between backcourt and frontcourt adult semiprofessional male basketball players. AB - The measurement of fitness qualities relevant to playing position is necessary to inform basketball coaching and conditioning staff of role-related differences in playing groups. To date, sprinting and agility performance have not been compared between playing positions in adult male basketball players. Therefore, the purpose of this study was to describe and compare linear speed, closed-skill agility, and open-skill agility qualities between backcourt (point guard and shooting guard positions) and frontcourt (small forward, power forward, and center positions) semiprofessional basketball players. Six backcourt (mean +/- SD: age, 24.3 +/- 7.9 years; stature, 183.4 +/- 4.0 cm; body mass, 85.5 +/- 12.3 kg; VO2max, 51.9 +/- 4.8 ml.kg(-1).min(-1)) and 6 frontcourt (mean +/- SD: age, 27.5 +/- 5.5 years; stature, 194.4 +/- 7.1 cm; body mass, 109.4 +/- 8.8 kg; VO2max, 47.1 +/- 5.0 ml.kg(-1).min(-1)) adult male basketball players completed 20-m sprint, closed-skill agility, and open-skill agility performance tests. Magnitude-based inferences revealed that backcourt players (5 m, 1.048 +/- 0.027 seconds; 10 m, 1.778 +/- 0.048 seconds; 20 m, 3.075 +/- 0.121 seconds) possessed likely quicker linear sprint times than frontcourt players (5 m, 1.095 +/- 0.085 seconds; 10 m, 1.872 +/- 0.127 seconds; 20 m, 3.242 +/- 0.221 seconds). Conversely, frontcourt players (1.665 +/- 0.096 seconds) held possible superior closed-skill agility performance than backcourt players (1.613 +/- 0.111 seconds). In addition, unclear positional differences were apparent for open skill agility qualities. These findings indicate that linear speed and change of direction speed might be differently developed across playing positions. Furthermore, position-related functions might similarly depend on the aspects of open-skill agility performance across backcourt and frontcourt players. Basketball coaching and conditioning staff should consider the development of position-targeted training drills to improve speed, agility, and cognitive qualities in players. PMID- 24149766 TI - The influence of professional status on maximal and rapid isometric torque characteristics in elite soccer referees. AB - The purpose of this study was to examine the effectiveness of maximal and rapid isometric torque characteristics of the posterior muscles of the hip and thigh and lower-body power to discriminate between professional status in full-time and part-time professional soccer referees. Seven full-time (mean +/- SE: age = 36 +/ 2 years; mass = 82 +/- 4 kg; and height = 179 +/- 3 cm) and 9 part-time (age = 34 +/- 2 years; mass = 84 +/- 2 kg; and height = 181 +/- 2 cm) professional soccer referees performed 2 isometric maximal voluntary contractions (MVCs) of the posterior muscles of the hip and thigh. Peak torque (PT) and absolute and relative rate of torque development (RTD) were calculated from a torque-time curve that was recorded during each MVC. Lower-body power output was assessed through a vertical jump test. Results indicated that the rapid torque characteristics were greater in the full-time compared with the part-time referees for absolute RTD (p = 0.011) and relative RTD at 1/2 (p = 0.022) and 2/3 (p = 0.033) of the normalized torque-time curve. However, no differences were observed for PT (p = 0.660) or peak power (Pmax, p = 0.149) between groups. These findings suggest that rapid torque characteristics of the posterior muscles of the hip and thigh may be sensitive and effective measures for discriminating between full-time and part-time professional soccer referees. Strength and conditioning coaches may use these findings to help identify professional soccer referees with high explosive strength-related capacities and possibly overall refereeing ability. PMID- 24149767 TI - The effects of COREPOWER machine training versus home-based core training on golfers' physical fitness and sport performance. AB - The purpose of this study was to determine the effects of a 36 session COREPOWER machine training intervention and those of a 36 session home-based core training intervention programme on golfers' physical fitness and sport specific performance. It was hypothesised that both modalities will improve on golf related fitness aspects. Subjects comprised of experienced golfers and were randomly divided into a machine group (M: n = 51) and a home group (H: n = 50). The following variables were measured both pre- and post-intervention: lower back flexibility (sit & reach), muscle endurance (sit-ups and push-ups), muscle strength (wall-squats and back dynamometer), cardio-respiratory fitness (3 minute step-test), balance (Biodex Balance System), club head speed and carry distance (Flightscope). The Wilcoxon and Mann-Whitney signed-rank test was used to compare pre and post-intervention measurements within each group with significance set at p < 0.05. An ANCOVA analyses was also run as well as Pearson Product Moment correlations. Results portrayed that with the exception of cardiorespiratory fitness, all variables in both groups showed significant (p<0.05) improvement post intervention. Push-ups (p = 0.000; ?17.03%; d = 0.92) and driver carry distance (p = 0.000; ?30.30%; d = 0.40) showed the greatest percentage improvement post intervention within group M, while sit-ups (p = 0.000; ?14.41%; d = 0.77) and push-ups (p = 0.000; ?12.52%; d = 0.90) showed the greatest percentage improvement within group H. Lower back strength holds significant correlation to golf performance. Thus both modalities, the COREPOWER machine training and the home-based manual core training were equally effective in improving selected fitness components; however the machine was more effective in improving golf performance parameters. These observations can be applied to golfers in addition to their usual golfing activities as well as to other sport populations as this study formed an evidence base for core training. PMID- 24149768 TI - Effects of 8-week in-season plyometric training on upper and lower limb performance of elite adolescent handball players. AB - We hypothesized that replacement of a part of the normal in-season regimen of top level adolescent handball players by an 8-week biweekly course of lower and upper limb plyometric training would enhance characteristics important to competition, including peak power output (Wpeak), jump performance, muscle volume, and ball throwing velocity. Study participants (23 men, age: 17.4 +/- 0.5 years, body mass: 79.9 +/- 11.5 kg, height: 1.79 +/- 6.19 m, body fat: 13.8 +/- 2.1%) were randomly assigned between controls (C; n = 11) and an experimental group (E, n = 12). Measures preintervention and postintervention included force-velocity ergometer tests for upper (Wupper peak) and lower limbs (Wlower peak), force platform determinations of squat jump (SJ) and countermovement jump (CMJ) characteristics (jump height, maximal force, initial velocity, and average power), video filming of sprint velocities (first step [V1S], first 5 m [V5m], and 25-30 m [Vmax]), and anthropometric estimates of leg muscle volume. E showed gains relative to C in Wupper peak and Wlower peak (p < 0.01 and p < 0.001), SJ (height p < 0.01; force p <= 0.05), CMJ (height p < 0.01; force p < 0.01 and relative power p <= 0.05), and sprint velocities (p < 0.001 for V1S, V5m, and Vmax). E also showed increases in leg and thigh muscle volumes (p < 0.001), but arm muscle volumes did not differ from control. We conclude that introduction of biweekly plyometric training into the standard regimen improved components important to handball performance, particularly explosive actions, such as sprinting, jumping, and ball throwing velocity. PMID- 24149769 TI - Electrically controlled membranes exploiting Cassie-Wenzel wetting transitions. AB - We report electrically controlled membranes which become permeable when an electrical field is exerted on a droplet deposited on the membrane. Micro-porous polycarbonate membranes are obtained with the breath-figures assembly technique, using micro-scaled stainless steel gauzes as supports. The membranes demonstrate pronounced Cassie-Baxter wetting. Air cushions trapped by the droplet prevent water penetration through the membrane. We demonstrate two possibilities for controlling the permeability of the membrane, namely contact and non-contact scenarios. When an electrical field is exerted on a droplet deposited on the membrane, the triple-line is de-pinned and the wetting transition occurs in the non-contact scheme. Thus, the membrane becomes permeable. The contact scheme of the permeability control is based on the electrowetting phenomenon. PMID- 24149772 TI - Signal recovery in imaging photoplethysmography. AB - Imaging photoplethysmography is an emerging technique for the extraction of biometric information from people using video recordings. The focus is on extracting the cardiac heart rate of the subject by analysing the luminance of the colour video signal and identifying periodic components. Advanced signal processing is needed to recover the information required. In this paper, independent component analysis (ICA), principal component analysis, auto- and cross-correlation are investigated and compared with respect to their effectiveness in extracting the relevant information from video recordings. Results obtained are compared with those recorded by a modern commercial finger pulse oximeter. It is found that ICA produces the most consistent results. PMID- 24149770 TI - Body mass index and incident hospitalisation for cardiovascular disease in 158 546 participants from the 45 and Up Study. AB - OBJECTIVE: To investigate the relationship between fine gradations in body mass index (BMI) and risk of hospitalisation for different types of cardiovascular disease (CVD). DESIGN, SUBJECTS AND METHODS: The 45 and Up Study is a large-scale Australian cohort study initiated in 2006. Self-reported data from 158 546 individuals with no history of CVD were linked prospectively to hospitalisation and mortality data. Hazard ratios (HRs) of incident hospitalisation for specific CVD diagnoses in relation to baseline BMI categories were estimated using Cox regression, adjusting for age, sex, region of residence, income, education, smoking, alcohol intake and health insurance status. RESULTS: There were 9594 incident CVD admissions over 583 100 person-years among people with BMI>=20 kg m( 2), including 3096 for ischaemic heart disease (IHD), 1373 for stroke, 411 for peripheral vascular disease (PVD) and 320 for heart failure. The adjusted HR of hospitalisation for all CVD diagnoses combined increased significantly with increasing BMI (P(trend) <0.0001)). The HR of IHD hospitalisation increased by 23% (95% confidence interval (95% CI): 18-27%) per 5 kg m(-2) increase in BMI (compared to BMI 20.0-22.49 kg m(-2), HR (95% CI) for BMI categories were: 22.5 24.99=1.25 (1.08-1.44); 25-27.49=1.43 (1.24-1.65); 27.5-29.99=1.64 (1.42-1.90); 30-32.49=1.63 (1.39-1.91) and 32.5-50=2.10 (1.79-2.45)). The risk of hospitalisation for heart failure showed a significant, but nonlinear, increase with increasing BMI. No significant increase was seen with above-normal BMI for stroke or PVD. For other specific classifications of CVD, HRs of hospitalisation increased significantly with increasing BMI for: hypertension; angina; acute myocardial infarction; chronic IHD; pulmonary embolism; non-rheumatic aortic valve disorders; atrioventricular and left bundle-branch block; atrial fibrillation and flutter; aortic aneurysm; and phlebitis and thrombophlebitis. CONCLUSION: The risk of hospitalisation for a wide range of CVD subtypes increases with relatively fine increments in BMI. Obesity prevention strategies are likely to benefit from focusing on bringing down the mean BMI at the population level, in addition to targeting those with a high BMI. PMID- 24149773 TI - [Integrated care for depressive disorders]. AB - BACKGROUND: According to the special report of the Advisory Council on the Assessment of Developments in the Health Care Sector, the termination of contracts on integrated care (IC) in accordance with S140a-d of the Social Act V (SGB V) was mostly due to high costs and volume expansion by services providers (physicians). However, there is still limited knowledge about the medical and economic impact of projects of integrated care, as such projects were on the one hand not primarily designed with a scientific evaluation in mind and on the other hand health insurance agencies usually do not evaluate data for scientific reasons. AIM: In Aachen the IC project "Integrated Care in Mental Health" ran between 2006 and 2011. During that time a total of 3,408 patients with depressive disorders were treated across institutional and trans-sectoral borders according to the national clinical practice guidelines and S3 guidelines on unipolar depression. This study was initiated in an attempt to describe and evaluate the clinical success of treatment. RESULTS: This study evaluated the outcome of the clinical treatment provided but due to the lack of available data on the economic impact of the project, the study contribution is limited to non-economic aspects. By comparing various clinical parameters it could be shown that scores in certain patient-reported clinical scales, such as the Hamilton rating scale for depression, and the WHO-5 well-being index as well as on the clinician-reported clinical global impression (CGI) improved in a statistically significant manner over time compared to initial assessments. Due to the lack of data on an appropriate comparison cohort of patients any comparative statements concerning the superiority of the treatment of depressive disorders outside an integrated care project remains hypothetical and preliminary. CONCLUSION: This study revealed the limitations of a naturalistic study in an IC setting and showed that without adequate funding a satisfactory evaluation that fulfills scientific criteria seems to be impossible. PMID- 24149774 TI - Feasibility study of gemcitabine plus docetaxel in advanced or recurrent uterine leiomyosarcoma and undifferentiated endometrial sarcoma in Japan. AB - BACKGROUND: Uterine leiomyosarcoma (LMS) and undifferentiated endometrial sarcoma (UES) are rare, aggressive malignancies. Both are treated similarly; however, few chemotherapy agents are effective. Recently, the combination of gemcitabine (900 mg/m(2), days 1 and 8) plus docetaxel (100 mg/m(2), day 8) with granulocyte colony-stimulating factor (G-CSF, 150 MUg/m(2), days 9-15) has been shown to have activity in LMS. In Japan, neither prophylactic G-CSF at a dose of 150 MUg/m(2) nor docetaxel at a dose of 100 mg/m(2) are approved for use. For this reason, we evaluated the combination of 900 mg/m(2) gemcitabine plus 70 mg/m(2) docetaxel regimen without prophylactic G-CSF support in advanced or recurrent LMS and UES in Japanese patients. METHODS: Eligible women with advanced or recurrent LMS and UES were treated with 900 mg/m(2) gemcitabine on days 1 and 8, plus 70 mg/m(2) docetaxel on day 8, every 3 weeks. The primary endpoint was overall response rate, defined as a complete or partial response. RESULTS: Of the eleven women enrolled, 10 were evaluated for a response. One complete response and 2 partial responses were observed (30 %) with an additional 4 (40 %) having stable disease. Mean progression-free survival was 5.4 months (range 1.3-24.8 months), and overall survival was 14 months (range 5.3-38.4 months). Grade 4 neutropenia was the major toxicity (50 %). The median number of cycles was 5 (range 2-18). Twenty two cycles (44 %) employed G-CSF. CONCLUSION: The gemcitabine plus docetaxel regimen without prophylactic G-CSF support was tolerable and highly efficacious in Japanese patients with advanced or recurrent LMS and UES. PMID- 24149775 TI - Correlation of IDH1/2 mutation with clinicopathologic factors and prognosis in anaplastic gliomas: a report of 203 patients from China. AB - PURPOSE: Isocitrate dehydrogenase (IDH) gene mutation is one of the most exciting new advances in these years. It has been reported that IDH gene frequently altered in grade II and grade III gliomas. We aimed to identify the mutation frequency of IDH genes in Chinese anaplastic glioma patients, the association of IDH gene mutation with other clinical and molecular pathological features and the prognostic value of it. METHODS: We performed polymerase chain reaction-based IDH gene mutation detection in 203 anaplastic glioma patients from China. RESULTS: A total of 108 and 3 patients harbored IDH1 and IDH2 gene mutation, respectively. And there was a higher proportion of MGMT promoter methylation, frontal lobe location, and better outcome and lower proportion of temporal location in IDH mutated samples. There were hardly any significant association between protein expression level of well-known markers and IDH mutation. Anaplastic oligoastrocytoma and anaplastic astrocytoma patients with IDH gene mutation showed similar prognosis with anaplastic oligodendroglioma patients with wild type IDH gene. CONCLUSIONS: IDH gene mutation is a good prognostic marker and a potential substratification factor for anaplastic glioma patients. PMID- 24149776 TI - Prognostic nutritional index predicts outcomes of malignant pleural mesothelioma. AB - PURPOSE: Nutritional status has been associated with long-time outcomes in cancer patients. We investigated whether the prognostic nutritional index (PNI), an indicator of nutritional status, affects overall survival in patients with malignant pleural mesothelioma (MPM). METHODS: We enrolled 121 patients with histologically confirmed MPM, who had successfully undergone biopsy by medical thoracoscopy in this study. Demographic, clinical and laboratory data were collected retrospectively. The PNI was calculated as 10* serum albumin value (g/dl) + 0.005 * total lymphocyte count (per mm(3)) in peripheral blood. Univariate and multivariate analyses were used to identify prognostic factors. RESULTS: Mean pretreatment PNI was 44.6. PNI was significantly associated with age (P = 0.031), smoking habits (P = 0.039) and weight loss (P = 0.029). Survival analysis showed PNI to be an independent prognostic factor in MPM. Patients with lower PNIs (PNI < 44.6) had greater risk of death than those with higher PNIs (PNI >= 44.6; hazard ratio: 2.290; 95 % confidence interval: 1.415-3.706; P = 0.001). These analyses were adjusted for patient age, gender, smoking habits, dyspnea, chest pain, weight loss, primary site of tumor, histology, platinum based systemic chemotherapy, hospital and stage. CONCLUSIONS: Pretreatment PNI is a novel independent prognostic factor in MPM. PMID- 24149778 TI - The social-psychological outcomes of martial arts practise among youth: a review. AB - Martial arts involvement among the youth has been described in controversial terms. Studies regarding the effects of martial arts practise on youth show contrasting images. While some refer to enhanced personal and social opportunities for those that participate, others warn against increased levels of aggressiveness and antisocial behavior among its participants. The aim of the present review is to provide, firstly, an overview of the major findings of studies concerning the social-psychological outcomes of martial arts practise. Secondly, the limitations of those studies are discussed. From more than 350 papers, collected during a two-year lasting literature study, 27 papers met all criteria to be included in this study. This review revealed that even though a considerable amount of research on social-psychological outcomes of martial arts practise has been conducted over the years, to date, it has not brought clarity in the existing duality regarding the possible effects of martial arts involvement. It is proposed that a better understanding can be provided if specific influential factors are taken into account in future research (i.e., participants' characteristics, type of guidance, social context and structural qualities of the sport). Key pointsMany common beliefs exist about the positive and negative outcomes of martial arts practise.Studies regarding the effects of martial arts practise on youth show contrasting images.Several influential factors have to be taken into account when examining the social-psychological outcomes of martial arts practise. PMID- 24149777 TI - Chromatin remodeling by the small RNA machinery in mammalian cells. AB - Chromatin states, quite different from changes in DNA sequence, can impact fundamental cellular processes such as determination of cell identity and development of disease. However, how chromatin states are established and regulated remain to be fully elucidated. In several lower eukaryotes, the small RNA machinery comprised of small RNA and its partners, the Argonaute proteins, is known to play important roles in the establishment of heterochromatin and silencing of repetitive sequences. In mammalian cells, however, the nuclear function of the small RNA machinery is largely unknown. Emerging evidence suggests that components of the small RNA pathway interact with chromatin to regulate nuclear events, including gene transcription and alternative splicing. In addition, these endogenous mechanisms are being exploited to target specific genomic loci for manipulation of gene expression and splicing events. In this review, I summarize current understanding of chromatin remodeling by small RNAs in mammalian cells and highlight recent efforts to map genome-wide interactions between RNAi-related factors and chromatin. PMID- 24149779 TI - Markers of inflammation, endothelial activation and autoimmunity in adolescent female gymnasts. AB - High levels of physical activity have been linked to benefits in cardiovascular and bone health by affecting, in part, changes in proinflammatory profile. Therefore, we have aimed to assess the effects of intensive training on markers of inflammation, endothelial activation and auto-immunity in the absence of the potential confounding effects of incident atherosclerosis. The subjects comprised 25 competitive gymnasts and 19 healthy sedentary adolescent females, aged 8-17 years. Serum soluble intercellular adhesion molecule 1 (sICAM-1), high sensitivity C-reactive protein (hsCRP), heat shock protein 27 (Hsp27) and Hsp27 antibody titres were measured by ELISAs in a sample of adolescent girls who were either physically active (competitive gymnasts) or sedentary. The association between age, body mass index (BMI), dietary intake, serum hsCRP, sICAM-1 and Hsp27 antigen and antibody titres were determined. The mean serum sICAM-1 concentrations were significantly higher in the gymnasts compared to the sedentary females (0.29 +/- 0.02 versus 0.23 +/- 0.01 mg.L(-1), p < 0.01). In contrast serum hsCRP concentrations were substantially lower in the gymnasts compared to the sedentary adolescent females (0.49 +/- 0.03 versus 1.38 +/- 0.19 mg.L(-1), p < 0.001). Differences remained significant after adjustment for anthropometric factors. We also found that serum Hsp27 antigen concentrations were determined by dietary saturated fat intake (p < 0.001), and antibody titres to Hsp27 were determined by dietary PUFA (p < 0.001) after adjustment for BMI. Our findings show that young female gymnasts have an altered profile of inflammatory markers and endothelial activation compared to their less physically active peers. Key pointsResults showed that adolescent young female gymnasts have an altered serum inflammatory markers and endothelial activation, compared to their less physically active peers.Physical activities improved immune system.Differences in these biochemical data kept significant after adjustment for body weight and height. PMID- 24149780 TI - Development of body composition, hormone profile, physical fitness, general perceptual motor skills, soccer skills and on-the-ball performance in soccer specific laboratory test among adolescent soccer players. AB - The aim of the present study was to examine the development of on-the-ball skills in soccer-specific laboratory test and to examine how traditional measures of body composition, hormone profile, physical fitness, general perceptual motor skills and soccer skills were related to performance measured in open skill environment among 10, 12, and 14-year-old regional male soccer players (n = 12/group). The measured variables were height, weight, fat, muscle mass, testosterone, 10m sprint, agility, counter movement jump, peripheral awareness, Eye- Hand-Foot coordination, passing skill, dribbling skill and on-the-ball skills (performance time and passing accuracy) in soccer-specific laboratory test. A significant main effect by age was found in all measured variables except in fat, in peripheral awareness and in passing accuracy. In discriminant analysis 63.9% (lambda = 0.603, F = 4.600, p < 0.01) of the players were classified correctly based on physical fitness and general perceptual motor skills into three ability groups originally classified with performance time in soccer specific laboratory test. Correlation co- efficient analysis with-in age groups revealed that variables associated with performance time in soccer-specific laboratory test were peripheral awareness (r = 0.72, p < 0.01) in 10-year-olds; testosterone (r = -0.70, p < 0.05), dribbling skill (r = 0.73, p < 0.01) and passing skill (r = 0.73, p < 0.01) in 12-year-olds; agility (r = 0.79, p < 0.01), counter movement jump (r = - 0.62, p < 0.01), dribbling skill (r = 0.80, p < 0.01) and passing skill (r = 0.58, p < 0. 05) in 14-year olds. Corresponding relationships with passing accuracy were weight (r = 0.59, p < 0.05), fat (r = 0.66, p < 0.05), 10m sprint (r = 0.71, p < 0.01) and countermovement jump (r = 0.64, p < 0.05) in 10-year-olds; Eye-Hand-Foot coordination (r = 0.63, p < 0.05) in 14-year- olds. The relationship between soccer-specific anticipation time and performance time in soccer- specific laboratory test was significant only in the 14-year-old age group (r = 0.76, p < 0.01). To conclude, on-the-ball skill performance in soccer-specific laboratory test improved with age and it seemed that soccer-specific perceptual skills became more and general perceptual motor skills less important with age in soccer-specific laboratory test. Key pointsPhysical fitness characteristics and general perceptual motor skills predicted performance time of the open skill soccer-specific laboratory test in the group of 10-14 year-old regional soccer players.Before puberty the players were able to compensate weaker soccer-specific skills with better general physical performance abilities.Soccer-specific skills became more important with age and at the age of 14 the players were not able to compensate soccer-specific skills with general physical performance abilities.Beside basic ball-handling skills it also important to recognize the importance of soccer-specific perceptual skills (anticipation and reaction) as a part of successful soccer performance. PMID- 24149781 TI - Effect of exercise intensity on differentiated and undifferentiated ratings of perceived exertion during cycle and treadmill exercise in recreationally active and trained women. AB - The purpose of the study is to examine the effect of aerobic exercise intensity on components of the differentiated perceived exertion model in young women performing weight bearing and non-weight bearing aerobic exercise. Subjects were 18-25 yr old women who were recreationally active (n = 19; VO2max = 33.40 ml.kg( 1).min(-1)) and trained (N = 22; VO2max = 43.3 ml.kg(-1).min(-1)). Subjects underwent two graded exercise tests (GXT) on a treadmill and bike which were separated by 48 hours. RPE-Overall, -Legs, and -Chest, as well as oxygen uptake (VO2) and heart rate were recorded each minute. Individual regression analyses were used to identify RPE-Overall,-Legs, and -Chest at 40, 60, 80% VO2max/peak. Separate two factor (site (3) x intensity (3)) ANOVAs with repeated measures on site and intensity were computed for each training status. Furthermore, RPE responses were also examined with a one factor (site (3)) within subject ANOVA with repeated measure on site at the ventilatory breakpoint. For both the recreationally active and trained groups no significant differences were observed for RPE-Overall, -Legs, and -Chest during treadmill exercise. However, for cycling exercise results indicated that RPE-Legs was significantly greater at all exercise intensities than RPE-Overall and RPE-Chest for trained subjects while for recreationally active subjects RPE-Legs was only significantly higher at the highest exercise intensity. Responses at the ventilatory breakpoint during cycle exercise indicated that RPE-Legs was significantly greater than RPE-Chest and RPE Overall for trained subjects but not for recreationally active subjects. Signal dominance was not observed at an intensity equivalent to the ventilatory breakpoint during treadmill exercise in either of the groups. In recreationally active and trained females signal dominance was demonstrated only during cycling exercise, but not during treadmill exercise. Signal integration could not be demonstrated during cycling and treadmill exercise at various intensities. Key pointsRPE is a valid tool to track relative exercise intensity and can be applied as differentiated and undifferentiated responses regardless of training status.RPE-Legs dominated the signal response in trained women during cycling exercise.RPE-Legs, -Chest, and -Overall did not differ significantly in trained and recreationally active women during treadmill exercise.RPE-Legs and -Chest contribute equally to the formation of RPE-Overall during cycling and treadmill exercise. PMID- 24149782 TI - The influence of weight loss on anaerobic threshold in obese women. AB - Obesity is associated with decreased physical activity. The aim of the study was to assess the anaerobic threshold in obese and normal weight women and to analyse the effect of weight-reduction therapy on the determined thresholds. PATIENTS AND METHODS: 42 obese women without concomitant disease (age 30.5 +/- 6.9y; BMI 33.6 +/- 3.7 kg.m(-2)) and 19 healthy normal weight women (age 27.6 +/- 7.0y; BMI 21.2 +/- 1.9 kg.m(-2)) performed cycle ergometer incremental ramp exercise test up to exhaustion. The test was repeated in 19 obese women after 12.3 +/- 4.2% weight loss. The lactate threshold (LT) and the ventilatory threshold (VT) were determined. Obese women had higher lactate (expressed as oxygen consumption) and ventilator threshold than normal weight women. The lactate threshold was higher than ventilatory one both in obese and normal weight women (1.11 +/- 0.21 vs 0.88 +/- 0.18 L.min(-1), p < 0.001; 0.94 +/- 0.15 vs 0.79 +/- 0.23 L.min(- 1), p < 0.01, respectively). After weight reduction therapy neither the lactate nor the ventilatory threshold changed significantly. The results concluded that; 1. The higher lactate threshold noted in obese women may be related to the increased fat acid usage in metabolism. 2. Both in obese and normal weight women lactate threshold appears at higher oxygen consumption than ventilatory threshold. 3. The obtained weight reduction, without weight normalisation was insufficient to cause significant changes of lactate and ventilatory thresholds in obese women. Key pointsResults showed that adolescent young female gymnasts have an altered serum inflammatory markers and endothelial activation, compared to their less physically active peers.Physical activities improved immune system.Differences in these biochemical data kept significant after adjustment for body weight and height. PMID- 24149783 TI - The relation between mild leg-length inequality and able-bodied gait asymmetry. AB - The causes of able-bodied gait asymmetries are unclear. Mild (< 3 cm) leg-length inequality (LLI) may be one cause of these asymmetries; however, this idea has not been thoroughly investigated. The purpose of this study was to investigate the nature of the relationship between LLI and able-bodied gait asymmetries. We hypothesized that subjects (n = 26) with relatively large LLI, quantified radiographically, would display less symmetrical gait than subjects with relatively small LLI. Gait asymmetries for joint kinematics and joint kinetics were determined using standard gait analysis procedures. Symmetry coefficients were used to quantify bilateral gait symmetry for sagittal-plane hip, knee, and ankle joint angles, moments, and powers. A Pearson product-moment correlation coefficient (r) was used to evaluate the relationship between LLI and the aforementioned symmetry coefficients. Also, these symmetry coefficients were compared between subjects with relatively small LLI (LLI < 1 cm; n = 19) and relatively large LLI (LLI >= 1 cm; n = 7). Statistically significant relationships were observed between LLI and the symmetry coefficient for knee joint moment (r = -0.48) and power (r = -0.51), and ankle joint moment (r = 0.41) and power (r = -0.42). Similarly, subjects with relatively large LLI exhibited significantly lower symmetry coefficients for knee joint moment (p = 0.40) and power (p = 0.35), and ankle joint moment (p = 0.40) and power (p = 0.22) than subjects with relatively small LLI. Degree of bilateral symmetry for knee and ankle joint kinetics appears to be related to LLI in able- bodied gait. This finding supports the idea that LLI is one cause of able-bodied gait asymmetries. Other factors, however, are also likely to contribute to these gait asymmetries; these may include other morphological asymmetries as well as asymmetrical neuromuscular input to the lower limb muscles. Key pointsModerate negative relationships were observed between mild limb-length inequality and gait symmetry for knee and ankle moment and power.Subjects with relatively large mild limb-length inequality (between 1.0 and 2.3 cm) exhibited significantly less symmetrical gait for knee and ankle joint moment and power than subjects with relatively small mild limb-length inequality (< 1 cm).These results indicate that the degree of symmetry for knee and ankle joint kinetics appears to be related to mild limb-length inequality in able-bodied gait.These results further our understanding of normal human walking and provide important background information for future studies on gait pathology associated with mild limb-length inequality. PMID- 24149784 TI - Cardiorespiratory characteristics and cholesterol responses to a single session of heavy leg press exercise. AB - The effect of resistance exercise on blood lipids is not clear yet. The purpose of this study was to examine the cholesterol responses to a heavy resistance leg press exercise emphasizing on the eccentric movement 24 and 48 hours following exercise and to quantify the cardiorespiratory responses of the exercise bout in an attempt to clarify the exercise characteristics that may be responsible for the effects of heavy resistance exercise on blood lipids. Nine healthy, untrained male volunteers aged 27.2 +/- 1.1 yrs (76.2 +/- 2.5 kg, 1.79 +/- 0.02 m) performed a session of heavy RE emphasizing on the eccentric movement consisting of eight sets of inclined leg presses at six repetition maximum with 3-min rest intervals. Venous blood samples were obtained at rest (control) and 24 and 48 hours following exercise. Average VO2 at rest was 4.0 +/- 0.4 ml.min(-1).kg(-1), during exercise 19.6 +/- 0.2 ml.min(-1).kg(-1) and during the 180 sec recovery period between sets 12.5 +/- 0.2 ml.min(-1).kg(-1). RER values decreased with the progression of the exercise and were significantly lower during the last four sets compared with the first four sets of the exercise session. Resting heart rate was 67 +/- 2 bpm, and maximum heart rate during exercise was 168 +/- 1 bpm. Serum creatine kinase was significantly elevated on day 1 (1090 +/- 272 U.L(-1), p < 0.03) and peaked on day 2 (1230 +/- 440 U.L(-1) p < 0. 01). Total cholesterol, HDL cholesterol and calculated LDL cholesterol concentration did not change significantly following with exercise. This protocol of heavy resistance exercise has no effect on TC or cholesterol sub-fraction concentration 24 and 48 hours following exercise which may be due to the low energy expenditure of the exercise and/or to the gender of the participants. Key pointsRepeated sets of heavy resistance exercise significantly increase oxygen uptake both during exercise and the following recovery period.Even though exercise was of low volume (8 sets x 6 repetitions) the elevated oxygen uptake during the rest intervals in combination with the total exercise session duration (26 min) resulted in aerobic energy expenditure that is equivalent to low to moderate intensity cycling.Leg press resistance exercise emphasizing on the eccentric movement that caused muscle damage had no effect on total cholesterol, HDL-C and LDL-C during the two days following exercise in young healthy male subjects. PMID- 24149785 TI - Foot and lower limb diseases in runners: assessment of risk factors. AB - The present study analyzed the impact of the running style and the morphologic and functional characteristics of the foot on the incidence of non-traumatic foot and lower limb disorders in runners. From January 2004 to December 2008, we prospectively examined 166 runners, both recreational and competitive, involved in various running specialities, from three athletics clubs in Northern Italy. They were 86 males and 80 females, with a mean age of 31.1 +/- 12.2 years. We considered non-traumatic foot and lower limb diseases reported during the follow up period, which resulted in a minimum sport rest of two weeks. The incidence of these diseases was examined with respect to general characteristics, type of activity, foot morphology, running style. 59% of athletes reported one or more diseases. The most common were plantar fasciitis (31% of athletes) and Achilles tendinopathies (24%). Overall, the more prone to injuries were males (60.9% of cases), competitive runners (70.9%), middle-distance runners (51.7%), and those using spike shoes (80.3%). Age, body weight and height were not important predictors of running injuries in general. Considering the morphological characteristics of the foot, the most prone to injury were the varus hindfoot (87.5% of cases) and the cavus arch (71.4%). In conclusion, a deep knowledge of the factors predisposing runners to specific diseases, often chronic and highly debilitating for the athlete, may allow implementing effective therapeutic measures. Key pointsExamination of 166 runners during a period of five years of activity.The incidence of these diseases was examined with respect to general characteristics, type of activity, foot morphology, running style.59% of athletes reported one or more diseases. The most common were plantar fascitis (31% of athletes) and Achilles tendinopathies (24%).Overall, the more prone to injuries were males (60.9% of cases), competitive runners (70.9%), middle-distance runners (51.7%), and those using spike shoes (80.3%).Age, body weight and height were not important predictors of running injuries in general.The most prone to injury were the varus hindfoot (87.5% of cases) and the cavus arch (71.4%). PMID- 24149786 TI - Assessment of Movement Skill Performance in Preschool Children: Convergent Validity Between MOT 4-6 and M-ABC. AB - The purpose was to determine the level of agreement between the Motoriktest fur Vier- bis Sechsjahrige Kinder [MOT 4-6] and the Movement Assessment Battery for Children [M-ABC]. 48 preschool children participated in the study (Mean age = 5 years, 6 months, SD = 3 months). There was high classification agreement (90%) between both tests. A Kappa correlation coefficient (0.67) provided moderately strong support for convergent validity. Less agreement was shown in identification of motor difficulties (58%). This was reflected by lower correlation coefficients on the fine movement cluster and test item level. The MOT 4-6 showed values within the range of similar movement skill performance assessment protocols. Because of its specific focus it may be of meaningful value to assess movement skill competence in typically developing preschool children (ages 4 to 6). Key pointsThe Motoriktest fur Vier- bis Sechsjahrige Kinder (MOT 4 6) showed values within the range of similar motor performance tests. Because of its specific focus it may be of great value to assess movement skill competence in typically developing preschool children (ages 4 to 6).Children's movement skill competence can be expressed as a single composite score. The results from this study also support the use of composite scores that include functional categorization (e.g. locomotion, object control and stability). PMID- 24149787 TI - The effect of achievement goals on moral attitudes in young athletes. AB - The purpose of the study is to assess the hypothesis that achievement goal orientations will predict sportpersonship attitudes among young athletes, namely that task orientation will predict socially positive attitudes and ego orientation will predict socially negative attitudes. For hundred and eighty two athletes, aged 13 to 16 years completed the Portuguese versions of the Task and Ego Orientation in Sport Questionnaire (TEOSQp) and of the Sports Attitudes Questionnaire (SAQp). Bivariate correlations were used to examine the relationships between TEOSQp and SAQp. Afterwards, relationships between ego orientation and score agreement in cheating and gamesmanship as well as task orientation and score agreement in convention and commitment were examined through EQS (version 5.7). For the estimation of the model, the maximum likelihood method was used. A matrix correlation between the variables (task orientation, ego orientation, cheating, gamesmanship, convention and commitment) showed positive correlations between task orientation and convention (r = 0.29, p < 0.01) and commitment (r = 0. 40, p < 0.01). Ego orientation appeared to be positively correlated with cheating (r = 0.30, p < 0.01) and gamesmanship (r = 0.33, p < 0.01), and negatively with convention (r = -0.16, p < 0.01).The fit of the model was evaluated using the CFI (0.97) and SRMR (0.04). The hypothesized model was confirmed. Task and ego orientations produced a significant effect on prosocial attitudes and on antisocial attitudes, respectively. Task-oriented goals in youth sport programs can represent a relevant framework for promoting prosocial attitudes and consequentely increment the effectiveness of educational interventions. Key pointsSport seems to be an important component of daily physical activity in children and adolescents and its importance is often viewed as positive.Literature suggests that a high task orientation has a positive link with moral variables and a high ego orientation is likely to promote inappropriate behaviours.Task orientation will predict pro-social sport attitudes, and to assess the hypothesis that ego orientation will predict anti social sport attitudes among young athletes.It is possible to suggest a pattern in which the self-referenced achievement goals can promote the expression of sportspersonship attitudesEnvironmental factors can be more influential than dispositional orientations when it comes to sportspersonship. PMID- 24149788 TI - Swimming enhances bone mass acquisition in growing female rats. AB - Growing bones are most responsive to mechanical loading. We investigated bone mass acquisition patterns following a swimming or running exercise intervention of equal duration, in growing rats. We compared changes in bone mineral properties in female Sprague Dawley rats that were divided into three groups: sedentary controls (n = 10), runners (n = 8) and swimmers (n = 11). Runners and swimmers underwent a six week intervention, exercising five days per week, 30min per day. Running rats ran on an inclined treadmill at 0.33 m.s(-1), while swimming rats swam in 25(0)C water. Dual energy X-ray absorptiometry scans measuring bone mineral content (BMC), bone mineral density (BMD) and bone area at the femur, lumbar spine and whole body were recorded for all rats before and after the six week intervention. Bone and serum calcium and plasma parathyroid hormone (PTH) concentrations were measured at the end of the 6 weeks. Swimming rats had greater BMC and bone area changes at the femur and lumbar spine (p < 0.05) than the running rats and a greater whole body BMC and bone area to that of control rats (p < 0.05). There were no differences in bone gain between running and sedentary control rats. There was no significant difference in serum or bone calcium or PTH concentrations between the groups of rats. A swimming intervention is able to produce greater beneficial effects on the rat skeleton than no exercise at all, suggesting that the strains associated with swimming may engender a unique mechanical load on the bone. Key pointsA six week swimming intervention is able to produce greater osteogenic effects on the rat skeleton than no exercise.A daily treadmill running intervention does not attenuate a rats propensity to run voluntarily at night. PMID- 24149789 TI - Determination of an Optimal Threshold Value for Muscle Activity Detection in EMG Analysis. AB - It is commonly agreed that one needs to use a threshold value in the detection of muscle activity timing in electromyographic (EMG) signal analysis. However, the algorithm for threshold determination lacks an agreement between the investigators. In this study we aimed to determine a proper threshold value in an incremental cycling exercise for accurate EMG signal analysis. Nine healthy recreationally active male subjects cycled until exhaustion. EMG recordings were performed on four low extremity muscle groups; gastrocnemius lateralis (GL), gastrocnemius medialis (GM), soleus (SOL) and vastus medialis (VM). We have analyzed our data using three different threshold levels: 25%, 35% and 45% of the mean RMS EMG value. We compared the appropriateness of these threshold values using two criteria: (1) significant correlation between the actual and estimated number of bursts and (2) proximity of the regression line of the actual and estimated number of bursts to the line of identity. It had been possible to find a significant correlation between the actual and estimated number of bursts with the 25, 35 and 45% threshold values for the GL muscle. Correlation analyses for the VM muscle had shown that the number of bursts estimated with the 35% threshold value was found to be significantly correlated with the actual number of bursts. For the GM muscle, it had been possible to predict the burst number by using either the 35% or 45% threshold value and for the SOL muscle the 25% threshold value was found as the best predictor for actual number of burst estimation. Detailed analyses of the actual and estimated number of bursts had shown that success of threshold estimation may differ among muscle groups. Evaluation of our data had clearly shown that it is important to select proper threshold values for correct EMG signal analyses. Using a single threshold value for different exercise intensities and different muscle groups may cause misleading results. Key pointsalpha priori accepted threshold value may cause erroneous results in EMG analysis.Using a single threshold value for different exercise intensities and different muscle groups may cause misleading results.The investigators may need to use different threshold selection strategies for different workloads.The investigators have to justify the choice of threshold selection with valid arguments before detailed EMG signal analyses. PMID- 24149790 TI - Regular exercise participation mediates the affective response to acute bouts of vigorous exercise. AB - Physical inactivity is a leading factor associated with cardiovascular disease and a major contributor to the global burden of disease in developed countries. Subjective mood states associated with acute exercise are likely to influence future exercise adherence and warrant further investigation. The present study examined the effects of a single bout of vigorous exercise on mood and anxiety between individuals with substantially different exercise participation histories. Mood and anxiety were assessed one day before an exercise test (baseline), 5 minutes before (pre-test) and again 10 and 25 minutes post exercise. Participants were 31 university students (16 males, 15 females; Age M = 20), with 16 participants reporting a history of regular exercise with the remaining 15 reporting to not exercise regularly. Each participant completed an incremental exercise test on a Monark cycle ergometer to volitional exhaustion. Regular exercisers reported significant post-exercise improvements in mood and reductions in state anxiety. By contrast, non-regular exercisers reported an initial decline in post-exercise mood and increased anxiety, followed by an improvement in mood and reduction in anxiety back to pre-exercise levels. Our findings suggest that previous exercise participation mediates affective responses to acute bouts of vigorous exercise. We suggest that to maximise positive mood changes following exercise, practitioners should carefully consider the individual's exercise participation history before prescribing new regimes. Key pointsPrevious exercise participation mediates the affective response to acute bouts of vigorous exercise.Regular exercisers respond positively to acute bouts of vigorous physical activity, reporting less state anxiety and fatigue, and more vigour.Non-regular exercisers respond with an initial reduction in positive mood states, followed by a rebound to baseline levels 25 minutes post exercise.To maximise positive post-exercise mood states, especially among novice exercisers, practitioners should carefully consider previous exercise participation when prescribing new exercise regimes. PMID- 24149791 TI - Reliability of a contact and non-contact simulated team game circuit. AB - Most team sports are characterised by repeated short maximal sprint efforts interspersed with longer periods of active recovery or rest. Although a variety of testing protocols have been devised to simulate these activity patterns under controlled conditions, a common limitation is the lack of 'body contact' to simulate the tackling efforts seen in contact sports. Therefore, the purpose of this study was to assess the reliability of a simulated team game protocol with and without 'contact'. Eleven male, team-sport athletes (mean +/- SD; age 22 +/- 2 yr; BMI 23.0 +/- 1.7 kg.m(-2)) completed four separate testing trials; two 'non contact' trials (NCON) and two 'contact' (CON) trials of a simulated game to determine the reliability of a range of team sport performance indicators including repeated 15-m sprint time, vertical jump height, heart rate response and ratings of perceived exertion (RPE). The team game protocol involved four sets of 15-min of intermittent running around a circuit replicating the movement patterns observed in team sports, either with or without simulated contact. Within-subject reliability of each performance measure was determined by expressing the typical error of measurement as the coefficient of variation, as well as determining intra-class correlations. Both CON and NCON produced reliable results for a variety of team sport performance indicators including repeated 15 m sprint time, vertical jump height, heart rate response and RPE. Repeated sprint and jump performance declined over time throughout the simulated game (p < 0.05), while heart rate and RPE increased. There was no difference in these performance measures between CON and NCON protocols. As such, these simulated game protocols provide reliable options for assessing team game performance parameters in response to training or other interventions under controlled conditions. Key pointsA variety of protocols have been devised to simulate the activity patterns of team sports.The protocol used in the current study is unique in that it includes an aspect of 'contact', which has been lacking from previous protocols.Both the 'contact' and 'non-contact' protocols tested appear reliable for assessing team game performance parametersThese protocols provide a reliable option for assessing team game performance parameters for both contact and non contact sports. PMID- 24149792 TI - Key factors and timing patterns in the tennis forehand of different skill levels. AB - The main purpose of the present study was to quantify and compare selected kinematic variables and their timing during the tennis forehand of different skill levels. An eight-camera 400 Hz, Vicon motion analysis system recorded kinematic data of six ATP- professionals (elite) and seven high performance (HP) players when shots were played cross court and down the line. Timing of the maximum angles, linear and angular velocities was measured prior to and after impact. A total of twelve strokes per subject were analyzed from the beginning to the end of horizontal racquet movement. Significant differences (p < 0.01) and large effect sizes were observed between elite and HP players in the timing of maximum pelvis (-0.075 +/- 0.008 vs. -0.093 +/- 0.012 s) and trunk angular velocities (-0.057 +/- 0.004 vs. -0.075 +/- 0.011 s) before impact. The elite group showed a tendency (p < 0.05) towards higher peak horizontal shoulder (3.0 +/- 0.4 vs. 2.5 +/- 0.4 m.s(-1)) and racquet velocities (33.1 +/- 2.4 vs. 31.1 +/ 1.9 m.s(-1)) compared to the HP players. Depending on the situation (cross court vs. down the line), different peak hip, racquet and separation angles were found for both groups. Similar peak values were detected between groups for maximum angular velocities and displacement of key variables that had been selected for analysis. The findings of this study can be vital for successful player development, improved performance or injury prevention. The later occurrence of maximum angular pelvis and trunk rotations were the main reasons for the tendency towards higher horizontal shoulder and racquet velocities in the elite group. Key pointsDifferent timing of maximum angular pelvis and trunk rotations separated the elite from the high performance players.The elite group tended to reach higher horizontal shoulder and racquet velocities than the high performance group.In addition to maximum angular velocities, maximum racquet, shoulder, and hip alignment angles were similar between groups.To improve the forehand performance level of their athletes, coaches should focus on proper pelvis and trunk rotation. PMID- 24149793 TI - Monitoring of lower limb comfort and injury in elite football. AB - The aim of the study was to examine the relation between lower limb comfort scores and injury and to measure the responsiveness of a lower limb comfort index (LLCI) to changes over time, in a cohort of professional footballers. Lower limb comfort was recorded for each individual using a comfort index which assessed the comfort status of five anatomical segments and footwear. Specifically we tested the extent to which comfort zones as measured by the LLCI were related to injury measured as time loss events. The hypothesis for the study was that poor lower limb comfort is related to time loss events (training or match day). A total of 3524 player weeks of data was collected from 182 professional athletes encompassing three codes of football (Australian Rules, Rugby league, Rugby Union). The study was conducted during football competition periods for the respective football leagues and included a period of pre- season training. The results of regression indicated that poor lower limb comfort was highly correlated to injury (R(2) =0.77) and accounted for 43.5 time loss events/ 1000hrs football exposure. While poor comfort was predictive of injury 47% of all time loss events it was not statistically relevant (R(2) =0.18). The results indicate lower limb comfort can be used to assess the well-being of the lower limb; poor comfort is associated with injury, and the LLCI has good face validity and high criterion-related validity for the relationship between comfort and injury. Key pointsComfort as a method to determine the well-being of athletes has a role in injury management.A lower limb comfort index is a mechanism by which lower limb comfort can be evaluated.Poor lower limb comfort is associated with injury in professional football.The use of a comfort as a marker of athlete health has practical and clinical relevance to sports medicine professionals managing musculoskeletal injury. PMID- 24149794 TI - Game related statistics which discriminate between winning and losing under-16 male basketball games. AB - The aim of the present study was to identify the game-related statistics which discriminate between winning and losing teams in under-16 years old male basketball games. The sample gathered all 122 games in the 2004 and 2005 Under-16 European Championships. The game-related statistics analysed were the free-throws (both successful and unsuccessful), 2- and 3-points field-goals (both successful and unsuccessful) offensive and defensive rebounds, blocks, assists, fouls, turnovers and steals. The winning teams exhibited lower ball possessions per game and better offensive and defensive efficacy coefficients than the losing teams. Results from discriminant analysis were statistically significant and allowed to emphasize several structure coefficients (SC). In close games (final score differences below 9 points), the discriminant variables were the turnovers (SC = 0.47) and the assists (SC = 0.33). In balanced games (final score differences between 10 and 29 points), the variables that discriminated between the groups were the successful 2-point field-goals (SC = -0.34) and defensive rebounds (SC = -0. 36); and in unbalanced games (final score differences above 30 points) the variables that best discriminated both groups were the successful 2-point field goals (SC = 0.37). These results allowed understanding that these players' specific characteristics result in a different game-related statistical profile and helped to point out the importance of the perceptive and decision making process in practice and in competition. Key pointsThe players' game-related statistical profile varied according to game type, game outcome and in formative categories in basketball.The results of this work help to point out the different player's performance described in U-16 men's basketball teams compared with senior and professional men's basketball teams.The results obtained enhance the importance of the perceptive and decision making process in practice and in competition. PMID- 24149796 TI - Conversions of Mn oxides to nanolayered Mn oxide in electrochemical water oxidation at near neutral pH, all to a better catalyst: catalyst evolution. AB - Here, for the first time, it is reported that some Mn oxides after a few hours convert to a nanolayered Mn oxide when the compounds are used as water-oxidizing catalysts in a water electrolysis device at near neutral pH and in the presence of LiClO4. The new nanolayered Mn oxide is more active than other Mn oxides toward water oxidation. This result is very important for artificial photosynthetic systems that use Mn oxides as water-oxidizing catalysts. PMID- 24149795 TI - Mechanisms of the anterior cruciate ligament injury in sports activities: a twenty-year clinical research of 1,700 athletes. AB - The mechanisms of anterior cruciate ligament (ACL) injuries are still inconclusive from an epidemiological standpoint. An epidemiological approach in a large sample group over an appropriate period of years will be necessary to enhance the current knowledge of the ACL injury mechanism. The objective of the study was to investigate the ACL injury occurrence in a large sample over twenty years and demonstrate the relationships between the ACL injury occurrence and the dynamic knee alignment at the time of the injury. We investigated the activity, the injury mechanism, and the dynamic knee alignment at the time of the injury in 1,718 patients diagnosed as having the ACL injuries. Regarding the activity at the time of the injury, "competition "was the most common, accounting for about half of all the injuries. The current result also showed that the noncontact injury was the most common, which was observed especially in many female athletes. Finally, the dynamic alignment of "Knee-in & Toe- out "(i.e. dynamic knee valgus) was the most common, accounting for about half. These results enhance our understanding of the ACL injury mechanism and may be used to guide future injury prevention strategies. Key pointsWe investigated the situation of ACL injury occurrence, especially dynamic alignments at the time of injury, in 1,718 patients who had visited our institution for surgery and physical therapy for twenty years.Our epidemiological study of the large patient group revealed that "knee-in & toe-out "alignment was the most frequently seen at the time of the ACL injury.From an epidemiological standpoint, we need to pay much attention to avoiding "Knee-in & Toe-out "alignment during sports activities. PMID- 24149797 TI - Unexpected reactivity and mechanism of carboxamide activation in bacterial N linked protein glycosylation. AB - The initial glycan transfer in asparagine-linked protein glycosylation is catalysed by the integral membrane enzyme oligosaccharyltransferase (OST). Here we study the mechanism of the bacterial PglB protein, a single-subunit OST, using chemically synthesized acceptor peptide analogues. We find that PglB can glycosylate not only asparagine but also glutamine, homoserine and the hydroxamate Asp(NHOH), although at much lower rates. In contrast, N-methylated asparagine or 2,4-diaminobutanoic acid (Dab) are not glycosylated. We find that of the various peptide analogues, only asparagine- or Dab-containing peptides bind tightly to PglB. Glycopeptide products are unable to bind, providing the driving force of product release. We find no suitably positioned residues near the active site of PglB that can activate the acceptor asparagine by deprotonation, making a general base mechanism unlikely and leaving carboxamide twisting as the most likely mechanistic proposal for asparagine activation. PMID- 24149798 TI - cis-Resveratrol produces anti-inflammatory effects by inhibiting canonical and non-canonical inflammasomes in macrophages. AB - Resveratrol, a natural phenolic compound found in red grapes and wine, exists as cis and trans isomers. Recent studies have shown that trans-resveratrol possesses anti-inflammatory, anti-oxidant, anti-carcinogenic, anti-tumor and immunomodulatory properties. However, it remains unclear whether cis-resveratrol may exhibit similar activities. The objective of the present study was to examine the effects of cis- and trans-resveratrol on the production of pro-inflammatory cytokines and mediators in human macrophages. We examined the possibility that cis- and trans-resveratrol may affect cytokine secretion by modulating inflammasomes, intracellular multi-protein complexes, the assembly of which leads to caspase-1 activation and secretion of active IL-1beta by macrophages. Our results show that pre-treatment of macrophages with cis-resveratrol not only reduces pro-IL-1beta production and IL-1beta secretion, but also suppresses ATP induced transcription and activation of caspase-1 and caspase-4. Notably, cis resveratrol inhibits the expression of the purinergic receptor, P2X(7)R, and the endoplasmic reticulum stress marker, Glc-regulated protein 78, but also reduces reactive oxygen species production. Moreover, cis-resveratrol attenuates cyclooxygenase-2 expression and prostaglandin E2 production. cis-Resveratrol also decreases the phosphorylation of p38 MAPK and expression of the c-Jun protein. These results indicate that cis-resveratrol produces anti-inflammatory effects by inhibiting both the canonical and non-canonical inflammasomes, and associated pathways in human macrophages. PMID- 24149800 TI - Mechanics and learning practices associated with the tennis forehand: a review. AB - The forehand ranks closely behind the serve in importance in the sport of tennis. Yet, while the serve has been the focus of a litany of research reviews, the literature describing forehand stroke production has not been reviewed as extensively. The purposes of this article are therefore to review the research describing the mechanics of the forehand and then to appraise that research alongside the coach-led development of the stroke. The consensus of this research supports the importance of axial rotation of the pelvis, trunk, shoulder horizontal adduction and internal rotation as the primary contributors to the development of racket speed in the forehand. The relationship between grip style and racket velocity is similarly well established. However, it is also clear that there remains considerable scope for future research to longitudinally examine the inter-relationships between different teaching methodologies, equipment scaling and forehand mechanics. Key PointsSports biomechanics has played a key role in assisting tennis coaches to understand the mechanical characteristics of the forehand.Research has confirmed the largely positive role of modified courts and balls in increasing the technical proficiency, number and success of forehand shots of beginner children.Suggested research directions include prospective or longitudinal studies into the inter-relationships of different teaching methodologies, equipment scaling and forehand mechanics. PMID- 24149799 TI - Nutrition for tennis: practical recommendations. AB - Tennis is a pan-global sport that is played year-round in both hemispheres. This places notable demands on the physical and psychological preparation of players and included in these demands are nutritional and fluid requirements both of training and match- play. Thus, the purpose of this article is to review nutritional recommendations for tennis. Notably, tennis players do not excel in any particular physiological or anthropometric characteristic but are well adapted in all areas which is probably a result of the varied nature of the training demands of tennis match play. Energy expenditures of 30.9 +/- 5.5 and 45.3 +/- 7.3 kJ.min(-1) have been reported in women and men players respectively regardless of court surface. Tennis players should follow a habitually high carbohydrate diet of between 6-10 g.kg(-1).d(-1) to ensure adequate glycogen stores, with women generally requiring slightly less than men. Protein intake guidelines for tennis players training at a high intensity and duration on a daily basis should be ~1.6 g.kg(-1).d(-1) and dietary fat intake should not exceed 2 g.kg(-1).d(-1). Caffeine in doses of 3 mg.kg(-1) provides ergogenic benefit when taken before and/or during tennis match play. Depending on environmental conditions, sweat rates of 0.5 to and over 5 L.hr(-1) and sodium losses of 0.5 - 1.8 g have been recorded in men and women players. 200 mL of fluid containing electrolytes should be consumed every change-over in mild to moderate temperatures of < 27 degrees C but in temperatures greater than 27 degrees C players should aim for <= 400 mL. 30-60 g.hr(-1) of carbohydrate should be ingested when match play exceeds 2 hours. Key PointsTennis players should follow a habitually high carbohydrate diet of between 6-10 g.kg(-1) to ensure adequate glycogen stores, with women generally requiring slightly less than men. Protein intake guidelines for tennis players training at a high intensity and duration on a daily basis should be ~1.6 g.kg(-1).d(-1). Dietary fat intake should not exceed 2 g.kg(-1).d(-1).Caffeine in doses of 3 mg.kg(-1) can provide ergogenic benefit when taken before and/or during tennis match play.200 mL of fluid containing electrolytes should be consumed every change-over in mild to moderate temperatures of < 27 degrees C but in temperatures greater than 27 degrees C players should aim for >= 400 mL.30-60 g.hr(-1) of carbohydrate should be ingested when match play exceeds 2 hours.During periods of travel, specific dietary requirements can be communicated with agencies and hotels prior to arrival and in the event that suitably nutritious foods are not available in the host country, players can bring or send non-perishable foods and goods where customs and quarantine laws allow. PMID- 24149801 TI - Effects of a 6-week junior tennis conditioning program on service velocity. AB - This study examined the effects of a 6-week strength-training program on serve velocity in youth tennis players. Thirty competitive healthy and nationally ranked male junior tennis players (13 years of age) were randomly and equally divided into control and training groups. The training group performed 3 sessions (60-70 min) weekly for 6 weeks, comprising core strength, elastic resistance and medicine ball exercises. Both groups (control and training) also performed a supervised stretching routine at the end of each training session, during the 6 week intervention. Service velocity, service accuracy and shoulder internal/external rotation were assessed initially and at the end of the 6-week conditioning program for both, control and training groups. There was a significant improvement in the serve velocity for the training group (p = 0. 0001) after the intervention, whereas in the control group there were no differences between pre and post-tests (p = 0.29). Serve accuracy was not affected in the training group (p = 0.10), nor in the control group (p = 0.15). Shoulder internal/external rotation ROM significantly improved in both groups, training (p = 0.001) and control (p = 0.0001). The present results showed that a short- term training program for young tennis players, using minimum equipment and effort, can result in improved tennis performance (i.e., serve velocity) and a reduction in the risk of a possible overuse injury, reflected by an improvement in shoulder external/internal range of motion. Key PointsA short-term training program for young tennis players, using minimum equipment and effort, can result in improved tennis performance and a reduction in the risk of a possible overuse injury, reflected by an improvement in shoulder external/internal range of motionA combination of core stabilization, elastic resistance exercises, and upper body plyometric exercises (i.e., medicine ball throws), focussing on the primary muscle groups and stabilizers involved in tennis specific movement patterns, could be appropriate for development tennis playersStretching exercises are recommended in the cool-down phase following matches or training sessions. PMID- 24149802 TI - Effects of the tennis tournament on players' physical performance, hormonal responses, muscle damage and recovery. AB - The purpose of this study was to examine changes in selected physiological and performance variables of male tennis players (n=8) during a 3-day tennis tournament and the following 2-day recovery period. Each player played three two hour tennis matches. The following measurements were taken: blood samples for serum testosterone T, cortisol C, creatinekinase CK, performance tests of maximal isometric leg press MVC and maximal rate of force development RFD, 5m run 5m, 5 leap 5l, counter movement jump CMJ and serve velocity S and DOMS questionnaire. During the games at 40 and 80 minutes the following tests were made: blood sample, MVC, 5m, CMJ and S. Both MVC and RFD were before the 2(nd) and 3(rd) match significantly lower than before the 1(st) match (p < 0.02) and remained reduced after 1 to 2 days of recovery. Serum C was significantly higher than the baseline value before each match (p < 0.05) and after 40 minutes of playing (p < 0.03). Serum T elevated from the baseline during every match at T40 (p < 0.02). CK elevated during the whole tournament peaking after the 3rd match. After one rest day CK was still significantly higher than the baseline value. Upper and lower body DOMS were elevated significantly but remained above the baseline after one rest day. The tennis tournament leads to reduced MVC and RFD, increased muscle damage and soreness and reduced recovery. It seems that a tennis tournament causes such a heavy speed strength load for the legs in addition to muscle damage that the recovery of explosive attributes of leg extensor muscles is impaired after two days of rest after the tournament. Serum cortisol and testosterone concentration elevated before and during the tennis match, but the outcome of the tennis match is difficult to predict using C or/and T levels before, during or after the match. Key PointsThe tennis tournament impairs player's MVC and RFD, increases muscle damage and soreness and reduces recovery.One day of rest after the tennis tournament is insufficient to recover explosive attributes of leg extensor muscles.Serum cortisol and testosterone concentration elevated before and during tennis match.The result of the tennis match is difficult to predict using cortisol or/and testosterone levels before, during or after the match. PMID- 24149803 TI - Do high blood hepcidin concentrations contribute to low ferritin levels in young tennis players at the end of tournament season? AB - The purpose of the present study was to verify whether impaired iron metabolism in young athletes is a consequence of an excessive workload during the tournament season. Low levels of ferritin (under 25 ug.L(-1)) have been frequently observed in young tennis players. We considered this finding to be related to the high intensity workload or to insufficient rest, which both trigger a strong immune response. Groups of male, well-trained young tennis players (16 +/- 0.9 years old, average of 10-year training experience) and a control peer group participated in this study. The research consisted of two examination sessions (March and September 2010). Blood samples were collected to determine haematological and immunological parameters. Additionally, body composition and physical capacity were assessed. In both periods of the study, the trained groups were characterised by low levels of ferritin, but also elevated levels of pro- inflammatory cytokine IL-1beta. Moreover, an inverse correlation between IL-1beta and blood ferritin was observed. Additionally, an increased concentration of the iron homeostasis regulator hepcidin was found in blood samples (mean 71 ng.ml( 1); range from 48 to 100 ng.ml(-1)). We concluded that the pro- inflammatory cytokine IL-1beta, most likely induced by an extensive workload during the tournament season, was responsible for the low level of ferritin in young, professional athletes. Key PointsThe first research demonstrating low grade inflammation-induced iron deficiency to be associated with elevated blood hepcidin levels in young tennis athletes.Evaluation of immunological response after the complete tournament season in young male tennis players.Conclusion to introduce the assessment of hepcidin to monitor trainings as well as symptoms of overreaching more effectively.Research providing practical information for coaches that changes in diet and modifications in workloads applied in physical training could be more effective than iron supplementation in iron deficient athletes. PMID- 24149804 TI - Joint Kinetics to Assess the Influence of the Racket on a Tennis Player's Shoulder. AB - This study aimed at investigating the influence of three rackets on shoulder net joint moments, power and muscle activity during the flat tennis serve under field conditions. A 6-camera Eagle((r)) motion analysis system, operating at 256 Hz, captured racket and dominant upper limb kinematics of the serve in five tennis players under three racket conditions (A: low mass, high balance and polar moment, B: low three moments of inertia, and C: high mass, swingweight and twistweight). The electromyographic activity of six trunk and arm muscles was simultaneously recorded. Shoulder net joint moments and power were computed by 3D inverse dynamics. The results showed that greater shoulder joint power and internal/external rotation peak moments were found to accelerate and decelerate racket A in comparison with the racket C. Moreover, serving with the racket A resulted in less activity in latissimus dorsi muscle during the acceleration phase, and biceps brachii muscle during the follow-through phase when compared with racket C. These initial findings encourage studying the biomechanical measurements to quantify the loads on the body during play in order to reduce them, and then prevent shoulder injuries. Racket specifications may be a critical point for coaches who train players suffering from shoulder pain and chronic upper limb injuries should be considered in relation to the racket specifications of the players. Key PointsLight racket required more joint power than heavy one to achieve similar post impact ball velocity.Serving with a light racket resulted in higher shoulder internal and external rotation moments than using a heavy one for similar performance.Chronic shoulder pain should encourage coaches to check for potentially inappropriate racket specifications of their players. PMID- 24149805 TI - The relationships between simulated tennis performance and biomarkers for nitric oxide synthesis. AB - Tennis performance requires a good aerobic endurance and recovering capacity. Nitric oxide (NO) is a gas which is not only a vasodilator and antioxidant but it also regulates the use of oxygen and glucose. The aim of this study was to examine the relationships between simulated tennis performance test (PT) and NOx (sum of nitrate+nitrite) levels and lactate elimination speed (LES). Twenty well trained male tennis players with game levels of ITN 4 (International Tennis Number) and lower (mean +/- SD; age 22.9 +/- 2.6 yrs; height 1.82 +/- 0.06 m and mass 75.7 +/- 8.0 kg) participated in the study. Participants performed three 4 min bouts and a 2-min continuous groundstroke against balls projected from a tennis ball machine at speeds of 50, 55, 62 and 70 km.h(-1). After this exercise, subjects were given a 20 min passive rest. After each period and at during the recovery phase; plasma NOx, glucose (GLU) and lactate (LA) levels were determined. LES was calculated during passive recovery. GLU, LA and heart rate (HR) showed a linear increase in comparison to the values in the previous step while PT decreased significantly. Following each period NOx and glucose levels increased independently, but their decreasing rates in recovery phase were related (r = 0.470, p < 0.05). The successive increase in NOx and GLU parameters between the third and the forth periods was significant (p < 0.05). Only in the third period was there a significant relation between PT and NOx (r = 0.494; p < 0.05). In the present study, no significant relationship was found between PT and GLU, LA levels and LES. No significant correlation was found between simulated tennis performance and blood NOx levels. However the addition of loads like those in the third period in tennis trainings can be beneficial for performance in trained tennis players. It is recommended that the relationships between tennis performance with NOx and GLU are studied during a real tennis match. Key PointsIn a sport like tennis which lasts 2-6 hours and has short rests, performance depends on the player's capacity to perform the intensive exercise intermittently. Therefore, recovering potential is important in tennis.In none of the periods of this study were the expected (significant) relations observed of the athletes. Therefore, it can be claimed that LA increase, LA elimination and aerobic endurance do not play a significant role in the performance and the decrease in performance in this exercise model. PMID- 24149806 TI - Movement characteristics of elite tennis players on hard courts with respect to the direction of ground strokes. AB - Previous studies of movement characteristics in tennis have considered the effect of playing surface but have assumed that playing strategies are simply determined by the surface as opposed to being under an individual's control. This study considered the selection of cross court or down the line ground strokes as being indicative of playing strategy and measured the outcome of playing these shots in terms of the opponent's movements. Matches (N = 8) at the 2011 ATP tournament 500 Valencia were recorded and analysed using SAGIT, a computer vision tracking system that allowed both players' movements to be tracked automatically, albeit with operator supervision. The data was split into (N = 188) games for analysis purposes and these lasted a median 174.24 seconds with active time (ball in play) a median proportion of 34.89% (IQR = 10.64%) of total time. During the active time losers of games tended to cover less distance (median = 80.17 m), move quicker (median = 1.38 m.s(-1)), spend more time in the defensive zones (median = 14.24 s) and less in the offensive zones (median = 44.74 s). These results suggested that game winners tended to dominate game losers, forcing them to exhibit behaviors typically associated with a defensive strategy. Defensive and offensive strategy are not well defined currently and future investigations should consider movements in relation to individual shots, in particular their velocities, at the rally level and by different individuals to better understand successful performance. Key PointsDuring the active time losers of games covered less distance, moved quicker, spend more time in the defensive zones and less in the offensive zones.These results suggested that game winners tended to dominate game losers, forcing them to exhibit behaviors typically associated with a defensive strategy.There are no differences between the proportion of cross court shots and down the line shots played by game winners and game losers.Future research should consider individual shots at the rally level to better understand successful performance and ultimately strategy. PMID- 24149807 TI - Exercise training-induced changes in inflammatory mediators and heat shock proteins in young tennis players. AB - Heat shock proteins (Hsp) represent proteins' groups, whose protective function, may be induced by heat, reactive oxygen species, cytokines etc. We evaluated blood levels of Hsp27 and Hsp70, and their relation to skeletal muscle damage and inflammation in young tennis players before and after the conditioning camp. Blood samples were collected directly after tournament season, 3-day rest and 14 day conditioning camp that followed. Hydrogen peroxide (H2O2) demonstrated the highest concentration directly after tournament season, which significantly decreased at camp's end. The pro-inflammatory cytokines IL-1beta and TNFalpha decreased, whereas anti-inflammatory cytokines IL-6 and IL-10 increased after 3d rest and 14d camp. Hsp27 increased after 3d rest and remained so after 14d camp, while Hsp70 decreased from baseline to camp's completion. Hsp27 and Hsp70 correlated significantly with H2O2, IL-1beta and TNFalpha. Muscle damage, observed as creatine kinase (CK) activity changes, increased after 14d camp similarly to Hsp27 and anti-inflammatory cytokines IL-6 and IL-10. Obtained data allows to conclude that decrease of Hsp27 and increase in pro-inflammatory cytokines could be a good indicator of overreaching. Reverse tendencies in these proteins may verify accuracy of conditioning camp. Finally, this training program caused an increase in the anti-inflammatory cytokines concentrations, improving individual status of recovery. Key PointsThe study demonstrating low grade inflammation-induced by the tournament season in young tennis player.Three days of active rest stimulated the anti-inflammatory response via rise of Hsp27 and anti-inflammatory cytokine IL-10.Observed decrease of blood Hsp70 may support mental recovery.Thirteen-day appropriate training program led to maintaining an immunological response balance. PMID- 24149808 TI - Sport nutrition and doping in tennis: an analysis of athletes' attitudes and knowledge. AB - Nutrition and doping issues are rarely studied in the sport of tennis. The aims of this investigation were to determine knowledge on doping (KD) and knowledge on sport nutrition (KSN), and corresponding socio-demographic-, sport-, and sport nutrition- and doping-factors among an international sample of high-level tennis players of both sexes (43 females; 22 years old on average). In the first phase of the investigation, the KSN and KD questionnaires were studied for their reliability and validity. The consumption of NS is found to be very high, with almost of all the females and 80% of the males using NS at least occasionally. The athletes showed a low tendency regarding future doping usage, although most of them are convinced that doping does exist in tennis. Since athletes declared that their coaches are their main source of information about NS and doping, future studies should investigate what coaches actually know about such problems. KSN has been found to be protective against potential doping behavior in the future. Males are found to be more prone to doping than females. Therefore, in order to prevent doping behavior in tennis we strongly suggest intensive educational programs on sports nutrition and doping-related problems. Key PointsThe incidence of nutritional supplementation use among the tennis players is found to be very high, especially among the females.Although most of the subjects are of the opinion that the doping behavior is present in tennis circuit, we have found a low tendency regarding future doping usage, and high levels of athletes' trust in their coaches with regard to nutritional supplementation and doping.There are indices that the knowledge about nutrition is protective factor against potential doping behavior. It clearly reinforces the need to include a wide educational program on sports nutrition in tennis, but also in other sports. PMID- 24149809 TI - The effect of moderate and high-intensity fatigue on groundstroke accuracy in expert and non-expert tennis players. AB - Exploring the effects of fatigue on skilled performance in tennis presents a significant challenge to the researcher with respect to ecological validity. This study examined the effects of moderate and high-intensity fatigue on groundstroke accuracy in expert and non-expert tennis players. The research also explored whether the effects of fatigue are the same regardless of gender and player's achievement motivation characteristics. 13 expert (7 male, 6 female) and 17 non expert (13 male, 4 female) tennis players participated in the study. Groundstroke accuracy was assessed using the modified Loughborough Tennis Skills Test. Fatigue was induced using the Loughborough Intermittent Tennis Test with moderate (70%) and high-intensities (90%) set as a percentage of peak heart rate (attained during a tennis-specific maximal hitting sprint test). Ratings of perceived exertion were used as an adjunct to the monitoring of heart rate. Achievement goal indicators for each player were assessed using the 2 x 2 Achievement Goals Questionnaire for Sport in an effort to examine if this personality characteristic provides insight into how players perform under moderate and high intensity fatigue conditions. A series of mixed ANOVA's revealed significant fatigue effects on groundstroke accuracy regardless of expertise. The expert players however, maintained better groundstroke accuracy across all conditions compared to the novice players. Nevertheless, in both groups, performance following high-intensity fatigue deteriorated compared to performance at rest and performance while moderately fatigued. Groundstroke accuracy under moderate levels of fatigue was equivalent to that at rest. Fatigue effects were also similar regardless of gender. No fatigue by expertise, or fatigue by gender interactions were found. Fatigue effects were also equivalent regardless of player's achievement goal indicators. Future research is required to explore the effects of fatigue on performance in tennis using ecologically valid designs that mimic more closely the demands of match play. Key PointsGroundstroke accuracy under moderate-intensity fatigue is equivalent to performance at rest.Groundstroke accuracy declines significantly in both expert (40.3% decline) and non-expert (49.6%) tennis players following high-intensity fatigue.Expert players are more consistent, hit more accurate shots and fewer out shots across all fatigue intensities.The effects of fatigue on groundstroke accuracy are the same regardless of gender and player's achievement goal indicators. PMID- 24149810 TI - The variability of the serve toss in tennis under the influence of artificial crosswind. AB - This study was made to analyze the variability and stability of the serve toss in tennis, on the x (side-to-side), y (back-to-front) and z (vertical) axes, with 12 experienced players under the influence of crosswind (induced aerodynamic flow) produced by an industrial ventilator. The players were analyzed individually after serving at maximum speed and accuracy to the intersection point of the centre line and service line ("T "point). The results allow us to conclude that the experienced players tend to stabilize the vertical dimension of the service (z axis). Additionally, this study confirms the invariability of the player height ratio: height of impact (1:1.5) in experienced players even when constrained by the "artificial crosswind. "Given the above, the vertical dimension of the tennis serve is assumed as a constant feature, which is guaranteed in the remaining varying dimensions (y and x axes) of the ball toss. Thus, the variability should be seen as part of the solution and not as something to be avoided by players and coaches. Key PointsAnalysis of the tennis serve variability under the effect of artificial crosswindTwelve experienced tennis players performed a set of 20 free serves (without wind constraints), and four other sets of 20 serves under different practice conditions (with different crosswind intensities)The players tend to stabilize in the z axis and vary in the y- (back-to-front) and x-axes (side-to-side) during the ball toss tennis serve in all the practice conditions (with and without crosswind)THE MAINTENANCE OF A PLAYER HEIGHT RATIO: impact height of approximately 1:1.5 in experienced players, even when constrained by "artificial crosswind". PMID- 24149811 TI - Tennis training sessions as a rehabilitation instrument for patients after acute myocardial infarction. AB - The aims of this study were to measure the effects of a cardiac rehabilitation program based on a modification of a sport (tennis) on quality of life, on various laboratory test parameters and on an exercise stress test, and to determine if the results of this novel activity are equivalent to those of traditional programs (i.e., the use of the bicycle ergometer). The sample consisted of 79 patients with a low-risk acute coronary syndrome. They were divided into three groups: two experimental groups and one control group. One of the experimental groups used the bicycle ergometer as its main physical activity, whereas the other received training in a modified form of tennis lesson. By the end of the 3-month program, triglycerides, cholesterol LDL, cholesterol HDL, (-25 mg.dl(-1) and 32.3 mg.dl(-1) final, and 15.7 mg.dl(-1) and 23.3 mg.dl(-1) LDL final, respectively) and exercise capacity improved significantly (by 1.1 metabolic equivalents (METs) and 1.2 METs, respectively), in both experimental groups. We conclude that the application of a comprehensive cardiac rehabilitation program in patients with low-risk acute coronary syndrome based on a program of modified tennis improves exercise tolerance and metabolic parameters, as well as certain physical characteristics that reduce cardiovascular risk. Key PointsCardiac rehabilitation of low risk patients with acute coronary syndrome based on a program of modified tennis produces an improvement in quality of life, lipid profiles and in exercise toleranceA cardiac rehabilitation program based on a modification of tennis produces favourable changes in various anthropometric parameters related to the reduction of cardiovascular riskThe development of programs of cardiac rehabilitation based on modified versions of various sports would advantage the adherence to physical exercise. PMID- 24149812 TI - The effects of scaling tennis equipment on the forehand groundstroke performance of children. AB - The modifications that have taken place within youth sports have made games, such as basketball, soccer, or tennis, easier for children to play. The purpose of this study was to determine the effects low compression (LC) tennis balls and scaled tennis courts had on the forehand groundstroke performance of children. The forehand groundstroke performances of eight subjects' (8.10 +/- 0.74 yrs) using LC tennis balls were measured on a scaled tennis court and standard compression balls (SC) on a standard court. Forehand groundstroke performance was assessed by the ForeGround test which measures Velocity Precision Success Index (VPS) and Velocity Precision Index (VP). Participants attempted three different forehand rally patterns on two successive days, using LC balls on the 18.3m court one day and SC balls on the 23.8m court the other. When using LC balls, participants' recorded higher overall VPS performance scores (p < 0.001) for each non-error stroke as well as higher VP scores (p = 0.01). The results of this study confirmed that the use of modified balls and modified court size may increase the control, velocity and overall success rate of the tennis forehand groundstroke of children. Key PointsThis study observed the effects of modified tennis balls and court had on the forehand groundstroke performance in children.Modified ball compression and modified court size can increase control, velocity and overall success of tennis performance.Children will have more success learning the game of tennis using modified equipment than using standard equipment. PMID- 24149813 TI - Motor imagery and tennis serve performance: the external focus efficacy. AB - There is now ample evidence that motor imagery (MI) contributes to enhance motor performance. Previous research also demonstrated that directing athletes' attention to the effects of their movements on the environment is more effective than focusing on the action per se. The present study aimed therefore at evaluating whether adopting an external focus during MI contributes to enhance tennis serve performance. Twelve high-level young tennis players were included in a test-retest procedure. The effects of regular training were first evaluated. Then, players were subjected to a MI intervention during which they mentally focused on ball trajectory and specifically visualized the space above the net where the serve can be successfully hit. Serve performance was evaluated during both a validated serve test and a real match. The main results showed a significant increase in accuracy and velocity during the ecological serve test after MI practice, as well as a significant improvement in successful first serves and won points during the match. Present data therefore confirmed the efficacy of MI in combination of physical practice to improve tennis serve performance, and further provided evidence that it is feasible to adopt external attentional focus during MI. Practical applications are discussed. Key PointsMotor imagery contributes to enhance tennis serve performance.Data provided evidence of the benefits of adopting an external focus of attention during imagery.Results showed significant improvement in successful first serves and won points during a real match. PMID- 24149814 TI - Pelvic rotation and lower extremity motion with two different front foot directions in the tennis backhand groundstroke. AB - When a tennis player steps forward to hit a backhand groundstroke in closed stance, modifying the direction of the front foot relative to the net may reduce the risk of ankle injury and increase performance. This study evaluated the relationship between pelvic rotation and lower extremity movement during the backhand groundstroke when players stepped with toes parallel to the net (Level) or with toes pointed towards the net (Net). High school competitive tennis players (eleven males and seven females, 16.8 +/- 0.8 years, all right- handed) performed tennis court tests comprising five maximum speed directional runs to the court intersection line to hit an imaginary ball with forehand or backhand swings. The final backhand groundstroke for each player at the backcourt baseline was analyzed. Pelvic rotation and lower extremity motion were quantified using 3D video analysis from frontal and sagittal plane camera views reconstructed to 3D using DLT methods. Plantar flexion of ankle and supination of the front foot were displayed for both Net and Level groups during the late phase of the front foot step. The timings of the peak pelvis rotational velocity and peak pelvis rotational acceleration showed different pattern for Net and Level groups. The peak timing of the pelvis rotational velocity of the Level group occurred during the late phase of the step, suggesting an increase in the risk of inversion ankle sprain and a decrease in stroke power compared to the Net group. Key PointsRegarding the movement of the forefoot, the Net group and the Level group showed a pattern of supination-pronation-supination during the front stepping foot contact phase (FSFCP). However, the Level group showed only supination of various degrees during FSFCP.For the Net group, the maximum angular velocity of pelvis occurred in the early phase of FSFCP before impact; however, for the Level group, the maximum angular velocity of pelvis occurred in the latter phase of FSFCP after impact.The Level group players showed a potentially higher risk of inversion ankle sprain during the latter stage of FSFCP as pelvic rotation reached maximum angular velocity.The Net group may have a more effective kinetic chain during backhand groundstrokes, which ultimately enhances performance. PMID- 24149815 TI - On the gender effects of handedness in professional tennis. AB - The aim of this study was to explore the effects of the gender variable in relation to other player and match characteristics on the advantage possessed by left-handed professional tennis players over their right-handed rivals. The data include 16 732 male tennis players and 16 432 female tennis players who played 438 937 and 415 346 matches, respectively, in the period from 1968 to the end of 2011. The results revealed that the advantage of left-handed professional tennis players is higher in males compared to females. The inverse impact of player and match quality on the left- handers' advantage was clearly confirmed. On the contrary, it seems that the type of court surface does not directly imply this advantage. To obtain an overview on the individual level, directed and weighted networks of tennis matches in both gender categories were constructed. Applying network analytic methods and the PageRank algorithm, the best left and right handed players in the Open Era of tennis were identified. The top three ranked left-handed players in the male and female categories were found to be far more consistent in their ranks achieved against left and right-handed opponents compared to their right-handed counterparts. Key PointsThe advantage of left handed professional tennis players over their right-handed opponents is higher in males compared to females.The quality of player and match is inversely proportional to the advantage of left-handers against their right-handed counterparts.On the contrary, it seems that the type of court surface does not directly imply this advantage.When the tennis talent appears in left-handers it is likely to be an outstanding one, particularly in the female category. PMID- 24149816 TI - Tournament Structure and Success of Players Based on Location in Men's Professional Tennis. AB - This article discusses the relationship between success of professional male tennis players according to the country and world region from which they originate and the professional tournament structure in men's tennis in that world region and country. The success of a country or world region was defined by the number of players in the top 300 ATP rankings and was calculated for seven time periods between 1975 and 2008. The results showed the correlations between the total number of top 300 ranked players, the total number of tournaments, and the annual tournament prize money of the specific country. The correlations were nearly perfect in the 1975-1990 period (r = 0.93-0.95; p < 0.01) but only high in the 2005-2008 period (r = 0.60-0.64; p < 0.01), suggesting that the association between the number of top 300 ranked tennis players and professional tournaments, while still significant, is in decline. These data should inform the policy and investment decisions of regional and national federations, particularly as they relate to domestic professional tennis tournament structures and to explore opportunities to include professional tournaments of neighbour countries in their player's development programs. Key PointsThis paper observes relation changes between the total number of players, total number of ATP tournaments and total annual prize money in particular continents from 1975 to 2008.The correlation between the tennis success, total number of tournaments and total annual prize money in tournaments was highest from 1975 to 1989 and was gradually decreasing from 1990 to 2008.The leading tennis countries organise over 20 ATP tournaments and entry professional tournaments per year. Tennis less developed countries very often is using the competition systems of the most successful tennis countries.Indications are that tennis will continue to become increasingly global and that this trend may be unlikely to reverse. PMID- 24149817 TI - Paying patients with psychosis to improve adherence. PMID- 24149818 TI - Palm oil taxes and cardiovascular disease mortality in India: economic epidemiologic model. AB - OBJECTIVE: To examine the potential effect of a tax on palm oil on hyperlipidemia and on mortality due to cardiovascular disease in India. DESIGN: Economic epidemiologic model. MODELING METHODS: A microsimulation model of mortality due to myocardial infarction and stroke among Indian populations was constructed, incorporating nationally representative data on systolic blood pressure, total cholesterol, tobacco smoking, diabetes, and cardiovascular event history, and stratified by age, sex, and urban/rural residence. Household expenditure data were used to estimate the change in consumption of palm oil following changes in oil price and the potential substitution of alternative oils that might occur after imposition of a tax. A 20% excise tax on palm oil purchases was simulated over the period 2014-23. MAIN OUTCOME MEASURES: The model was used to project future mortality due to myocardial infarction and stroke, as well as the potential effect of a tax on food insecurity, accounting for the effect of increased food prices. RESULTS: A 20% tax on palm oil purchases would be expected to avert approximately 363,000 (95% confidence interval 247,000 to 479,000) deaths from myocardial infarctions and strokes over the period 2014-23 in India (1.3% reduction in cardiovascular deaths) if people do not substitute other oils for reduced palm oil consumption. Given estimates of substitution of palm oil with other oils following a 20% price increase for palm oil, the beneficial effects of increased polyunsaturated fat consumption would be expected to enhance the projected reduction in deaths to as much as 421,000 (256,000 to 586,000). The tax would be expected to benefit men more than women and urban populations more than rural populations, given differential consumption and cardiovascular risk. In a scenario incorporating the effect of taxation on overall food expenditures, the tax may increase food insecurity by <1%, resulting in 16,000 (95% confidence interval 12,000 to 22,000) deaths. CONCLUSIONS: Curtailing palm oil intake through taxation may modestly reduce hyperlipidemia and cardiovascular mortality, but with potential distributional consequences differentially benefiting male and urban populations, as well as affecting food security. PMID- 24149819 TI - Should people at low risk of cardiovascular disease take a statin? PMID- 24149820 TI - GMC and vulnerable doctors: too blunt an instrument? PMID- 24149821 TI - What are we spending on the English NHS? PMID- 24149822 TI - Which is the best medical school? PMID- 24149823 TI - US endocrinologists release "choose wisely" list. PMID- 24149825 TI - Regulatory T cells and COPD. AB - While the innate immune system has long been implicated in the pathogenesis of COPD, a role for the acquired immune system is less well studied. The increasing recognition that COPD shares features with autoimmune disease has led to interest in a potential role for regulatory T cells, which are intimately involved in the control of autoimmunity. The suggestion that regulatory T cell numbers are increased in patients with COPD may indicate their dysfunction or resistance to suppression by target cells. Investigation of regulatory T cells may therefore be of importance in understanding the inflammation and tissue damage that occurs in patients with COPD who cease smoking. PMID- 24149826 TI - SKUP3 trial: comment. PMID- 24149827 TI - Does extensive genotyping and nasal potential difference testing clarify the diagnosis of cystic fibrosis among patients with single-organ manifestations of cystic fibrosis? AB - BACKGROUND: The phenotypic spectrum of cystic fibrosis (CF) has expanded to include patients affected by single-organ diseases. Extensive genotyping and nasal potential difference (NPD) testing have been proposed to assist in the diagnosis of CF when sweat testing is inconclusive. However, the diagnostic yield of extensive genotyping and NPD and the concordance between NPD and the sweat test have not been carefully evaluated. METHODS: We evaluated the diagnostic outcomes of genotyping (with 122 mutations included as disease causing), sweat testing and NPD in a prospectively ascertained cohort of undiagnosed patients who presented with chronic sino-pulmonary disease (RESP), chronic/recurrent pancreatitis (PANC) or obstructive azoospermia (AZOOSP). RESULTS: 202 patients (68 RESP, 42 PANC and 92 AZOOSP) were evaluated; 17.3%, 22.8% and 59.9% had abnormal, borderline and normal sweat chloride results, respectively. Only 17 (8.4%) patients were diagnosable as having CF by genotyping. Compared to sweat testing, NPD identified more patients as having CF (33.2%) with fewer borderline results (18.8%). The level of agreement according to kappa statistics (and the observed percentage of agreement) between sweat chloride and NPD in RESP, PANC and AZOOSP subjects was 'moderate' (65% observed agreement), 'poor' (33% observed agreement) and 'fair' (28% observed agreement), respectively. The degree of agreement only improved marginally when subjects with borderline sweat chloride results were excluded from the analysis. CONCLUSIONS: The diagnosis of CF or its exclusion is not always straightforward and may remain elusive even with comprehensive evaluation, particularly among individuals who present at an older age with single-organ manifestations suggestive of CF. PMID- 24149828 TI - The Clinical COPD Questionnaire: response to pulmonary rehabilitation and minimal clinically important difference. AB - BACKGROUND: The Clinical COPD Questionnaire (CCQ) is a simple 10-item, health related quality of life questionnaire (HRQoL) with good psychometric properties. However, little data exists regarding the responsiveness of the CCQ to pulmonary rehabilitation (PR) or the minimal clinically important difference (MCID). The study aims were to assess the responsiveness of the CCQ to PR, to compare the responsiveness of the CCQ to other HRQoL questionnaires and to provide estimates for the MCID. METHODS: The CCQ, St George's Respiratory Questionnaire (SGRQ), Chronic Respiratory Questionnaire (CRQ) and COPD Assessment Test (CAT) were measured in 261 patients with COPD before and after outpatient PR. Pre to post PR changes and Cohen's effect size were calculated. Changes in CCQ were compared with changes in other HRQoL questionnaires. Using an anchor-based approach and receiver operating characteristic (ROC) curves, the CCQ change cutoffs that identified patients achieving the known MCID for other health status questionnaires with PR were identified. RESULTS: The CCQ, SGRQ, CRQ and CAT all significantly improved with PR with an effect size of -0.39, -0.33, 0.62 and 0.25, respectively. CCQ change correlated significantly with change in SGRQ, CRQ and CAT (r=0.48, -0.56, 0.54, respectively; all p<0.001). ROC curves consistently identified a CCQ change cutoff of -0.4 as the best discriminating value to identify the MCID for the SGRQ, CRQ and CAT (area under curve: 0.71, 0.75 and 0.77, respectively; all p<0.001). CONCLUSIONS: The CCQ is responsive to PR with an estimated clinically important improvement of -0.4 points. The CCQ is a practical alternative to more time-consuming measures of HRQoL. PMID- 24149829 TI - Linking genotype to phenotype on beads: high throughput selection of peptides with biological function. AB - Although peptides are well recognised biological molecules in vivo, their selection from libraries is challenging because of relative low affinity whilst in linear conformation. We hypothesized that multiplexed peptides and DNA on the surface of beads would provide a platform for enhanced avidity and the selection of relevant peptides from a library (ORBIT bead display). Using human immunodeficiency virus (HIV-1) gp120 as a target, we identify peptides that inhibit HIV-1 replication in vitro through blocking of protein:protein interaction with the co-receptor CCR5. The bead display approach has many potential applications for probing biological systems and for drug lead development. PMID- 24149830 TI - Transcardiac retrograde transvenous embolization of proximally occluded pulmonary arteriovenous malformation. AB - PURPOSE: To report a novel transcardiac retrograde transvenous coil embolization of inadequately proximally occluded pulmonary arteriovenous malformation (AVM). METHODS: Pulmonary AVM in the right A4 segment in an 8-year-old boy with hereditary hemorrhagic telangiectasia was initially treated by proximal occlusion of the feeding artery with coils. 6 years later, recurrent AVM caused dyspnea on exertion. The A4 AVM was reperfused by many collaterals from local pulmonary arteries. Via the Brockenbrough procedure, an 8F-long sheath was introduced from right atrium to left atrium. A 7F balloon catheter was then coaxially introduced into right middle pulmonary vein. Then a microcatheter was introduced retrogradely from pulmonary vein to pulmonary artery through the recurrent AVM. RESULTS: The venous sac and the distal arterial segment of the A4 AVM were successfully embolized with detachable coils. The A4 AVM was completely occluded. No adverse effects were observed, and dyspnea on exertion disappeared. CONCLUSION: This novel transcardiac retrograde transvenous embolization is useful for inadequately treated pulmonary AVM with proximal feeding artery occlusion. PMID- 24149831 TI - Stereotactic radiofrequency ablation for liver tumors in inherited metabolic disorders. AB - PURPOSE: Both glycogen storage disease type Ia (GSD Ia) and tyrosinemia type I (TYR I) are inherited metabolic disorders that can be complicated by formation of liver adenomas in juvenile/young adult age and/or development of hepatocellular carcinoma. We describe the first application of stereotactic radiofrequency ablation (SRFA) in focal lesions in three patients with inherited metabolic disorders affecting the liver. METHODS: SRFA was applied for removal of single large liver adenomas in a 22-year-old woman and a 20-year-old man with GSD Ia and of a suspicious lesion in a 16-year-old girl with TYR I with alpha-fetoprotein (AFP) elevation. RESULTS: SRFA was successful. Large scars were avoided, and in the TYR I patient, elevated AFP values promptly returned to normal. CONCLUSION: The SRFA technique is a good alternative to surgical resection of focal liver lesions and could greatly help patients with inherited metabolic disorders with liver involvement, including focal liver lesions and potential malignancy. PMID- 24149832 TI - Hepatocellular carcinomas within the Milan criteria: predictors of histologic necrosis after drug-eluting beads transarterial chemoembolization. AB - PURPOSE: To evaluate pathologic, imaging, and technical predictors of therapy response in patients with hepatocellular carcinoma (HCC) within the Milan criteria undergoing doxorubicin drug-eluting beads transarterial chemoembolization (DEB-TACE) before orthotopic liver transplantation (OLT). METHODS: This prospective study included consecutive patients with HCC who underwent DEB-TACE before OLT. Tumor histologic necrosis on liver explants was utilized as the standard of reference to categorize treated HCCs as group 1 (>50 % necrosis) or group 2 (<=50 % necrosis). DEB-TACE technique, histological factors, and imaging evaluation utilizing the modified Response Evaluation Criteria in Solid Tumors (mRECIST) were compared between groups 1 and 2. RESULTS: Twenty-seven HCCs were identified in 23 patients. Group 1 comprised 18 HCCs (mean necrosis 86.2 %). Group 2 comprised 9 HCCs (mean necrosis 31.1 %). The mean time between the last DEB-TACE session and the OLT was 112 days. Lesion size was significantly larger in group 1 (mean 3.2 cm; 95 % confidence interval 2.55-3.85) than in group 2 (mean 2.1 cm; 95 % confidence interval 1.79-2.48) (p = 0.030). Group 1 also demonstrated a higher frequency of encapsulated lesions when compared to group 2 (78 % vs. 22 %; p = 0.0027). A significant linear correlation was found between the quantification of necrosis by imaging and pathology (p = 0.0011) using the mRECIST, with a poorer correlation index in group 2. CONCLUSION: Larger and encapsulated HCCS are associated with a higher percentage of necrosis. A significant linear correlation between the amount of necrosis by imaging and pathology was encountered when mRECIST was utilized. PMID- 24149833 TI - Cationic oligo-p-phenylene ethynylenes form complexes with surfactants for long term light-activated biocidal applications. AB - Cationic oligo-p-phenylene ethynylenes are highly effective light-activated biocides that deal broad-spectrum damage to a variety of pathogens, including bacteria. A potential problem arising in the long-term usage of these compounds is photochemical breakdown, which nullifies their biocidal activity. Recent work has shown that these molecules complex with oppositely-charged surfactants, and that the resulting complexes are protected from photodegradation. In this manuscript, we determine the biocidal activity of an oligomer and a complex formed between it and sodium dodecyl sulfate. The complexes are able to withstand prolonged periods of irradiation, continuing to effectively kill both Gram negative and Gram-positive bacteria, while the oligomer by itself loses its biocidal effectiveness quickly in the presence of light. In addition, damage and stress responses induced by these biocides in both E. coli and S. aureus are discussed. This work shows that complexation with surfactants is a viable method for long-term light-activated biocidal applications. PMID- 24149834 TI - A possible structural basis behind the pathogenic role of apolipoprotein E hereditary mutations associated with lipoprotein glomerulopathy. AB - Single amino acid mutations in apolipoprotein E (apoE) have been associated with the development of the rare kidney disease lipoprotein glomerulopathy (LPG). Although the genetic linkage to disease development is well established, the mechanism of pathogenesis is largely unknown, limiting therapeutic insight. Here, we summarize current knowledge in the field and focus on the possible effects of LPG-associated mutations on the structure of apoE. Recent findings have suggested that mutation-induced folding perturbations in apoE lead to structural destabilization and aggregation, effects that may underlie lipoprotein thrombi accumulation in the glomerulus, a hallmark of LPG. The recognition that structural destabilization may underlie the association between apoE mutations and LPG can be key for development of new innovative treatments for this rare disease. PMID- 24149835 TI - Topics in lipoprotein glomerulopathy: an overview. AB - Here, we introduce four topics in lipoprotein glomerulopathy (LPG). To date, approximately 150 cases of LPG have been reported worldwide. Recently two groups studied hot spots of APOE-Sendai and APOE-Kyoto, the representative variants of LPG, in narrow areas of Japan and China, respectively. They suggest that both variants have descended through a founder effect. APOE-Sendai and APOE-Kyoto cause different transformations of apolipoproteins aggregating lipoproteins and resulting in lipoprotein thrombi within the glomerulus. Moreover, the macrophage impairment in LPG may provide another mechanism for lipoprotein thrombi in which massive lipoproteins accumulate in the glomerulus without foam cells. On the other hand, the administration of fibrate with the intensive control of triglyceride and apolipoprotein E particularly from the early phase will ameliorate LPG and prevent renal dysfunction. PMID- 24149836 TI - Lysosomal acid lipase and lipophagy are constitutive negative regulators of glucose-stimulated insulin secretion from pancreatic beta cells. AB - AIMS/HYPOTHESIS: Lipolytic breakdown of endogenous lipid pools in pancreatic beta cells contributes to glucose-stimulated insulin secretion (GSIS) and is thought to be mediated by acute activation of neutral lipases in the amplification pathway. Recently it has been shown in other cell types that endogenous lipid can be metabolised by autophagy, and this lipophagy is catalysed by lysosomal acid lipase (LAL). This study aimed to elucidate a role for LAL and lipophagy in pancreatic beta cells. METHODS: We employed pharmacological and/or genetic inhibition of autophagy and LAL in MIN6 cells and primary islets. Insulin secretion following inhibition was measured using RIA. Lipid accumulation was assessed by MS and confocal microscopy (to visualise lipid droplets) and autophagic flux was analysed by western blot. RESULTS: Insulin secretion was increased following chronic (>= 8 h) inhibition of LAL. This was more pronounced with glucose than with non-nutrient stimuli and was accompanied by augmentation of neutral lipid species. Similarly, following inhibition of autophagy in MIN6 cells, the number of lipid droplets was increased and GSIS was potentiated. Inhibition of LAL or autophagy in primary islets also increased insulin secretion. This augmentation of GSIS following LAL or autophagy inhibition was dependent on the acute activation of neutral lipases. CONCLUSIONS/INTERPRETATION: Our data suggest that lysosomal lipid degradation, using LAL and potentially lipophagy, contributes to neutral lipid turnover in beta cells. It also serves as a constitutive negative regulator of GSIS by depletion of substrate for the non lysosomal neutral lipases that are activated acutely by glucose. PMID- 24149837 TI - Increased expression of miR-187 in human islets from individuals with type 2 diabetes is associated with reduced glucose-stimulated insulin secretion. AB - AIMS/HYPOTHESIS: Type 2 diabetes is characterised by progressive beta cell dysfunction, with changes in gene expression playing a crucial role in its development. MicroRNAs (miRNAs) are post-transcriptional regulators of gene expression and therefore alterations in miRNA levels may be involved in the deterioration of beta cell function. METHODS: Global TaqMan arrays and individual TaqMan assays were used to measure islet miRNA expression in discovery (n = 20) and replication (n = 20) cohorts from individuals with and without type 2 diabetes. The role of specific dysregulated miRNAs in regulating insulin secretion, content and apoptosis was subsequently investigated in primary rat islets and INS-1 cells. Identification of miRNA targets was assessed using luciferase assays and by measuring mRNA levels. RESULTS: In the discovery and replication cohorts miR-187 expression was found to be significantly increased in islets from individuals with type 2 diabetes compared with matched controls. An inverse correlation between miR-187 levels and glucose-stimulated insulin secretion (GSIS) was observed in islets from normoglycaemic donors. This correlation paralleled findings in primary rat islets and INS-1 cells where overexpression of miR-187 markedly decreased GSIS without affecting insulin content or apoptotic index. Finally, the gene encoding homeodomain-interacting protein kinase-3 (HIPK3), a known regulator of insulin secretion, was identified as a direct target of miR-187 and displayed reduced expression in islets from individuals with type 2 diabetes. CONCLUSIONS/INTERPRETATION: Our findings suggest a role for miR-187 in the blunting of insulin secretion, potentially involving regulation of HIPK3, which occurs during the pathogenesis of type 2 diabetes. PMID- 24149838 TI - Incidence of type 1 diabetes in Norway among children aged 0-14 years between 1989 and 2012: has the incidence stopped rising? Results from the Norwegian Childhood Diabetes Registry. AB - AIMS/HYPOTHESIS: Our study aimed to describe the incidence of type 1 diabetes in children below 15 years of age in Norway during the period 1989-2012 and to assess the regional variation during 2004-2012. We further set out to estimate the completeness of ascertainment in the Norwegian Childhood Diabetes Registry (NCDR). METHODS: Incident cases of type 1 diabetes were registered in the NCDR and incidence rates were modelled using Poisson regression. Ascertainment for 2005-2008 was estimated using capture-recapture methodology by using data from the Norwegian Prescription Database (NorPD), a nationwide register established in 2004, which included insulin prescribed and dispensed at pharmacies to individual patients. Population data were obtained from Statistics Norway. RESULTS: Observed incidence rates for 1989-2012 suggested three distinct time segments: in 1989 1996, the average incidence rate was 22.6 per 100,000 person-years (95% CI 21.4, 23.7); in 1996-2004, the average incidence rate was 28.4 per 100,000 person-years (95% CI 27.3, 29.6); and from 2004 to 2012, the average incidence rate per 100,000 person-years was 32.7 (95% CI 31.5, 34.0). After adjustment for age and sex, the estimated change per year was 1.8% for 1989-1996 (95% CI -0.07, 3.6; p = 0.059), 3.4% for 1996-2004 (95% CI 2.2, 4.7; p < 0.0001) and 0.3% for 2004-2012 (95% CI -0.9, 1.6; p = 0.64). The highest incidence was in the age group 10-14 years for both sexes. A significant regional variation in incidence was observed (p < 0.001). Completeness of ascertainment in the NCDR was estimated to be 91%. CONCLUSIONS/INTERPRETATION: The previously observed increase in incidence of type 1 diabetes has levelled off and remained essentially constant at 32.7 per 100,000 person-years during 2004-2012. There is a significant variation in type 1 diabetes incidence within Norway. PMID- 24149840 TI - Adverse effects of near current-electrode placement in non-invasive bio-impedance measurements. AB - A major problem confronting application of impedance techniques to studies of disease is the extraction of intrinsic properties of the tissue from the measured impedances, which unavoidably involve geometric factors as well. Amongst the foremost are the sizes and locations of the measuring electrode arrays, and this paper addresses one of these, the location of current injecting electrodes. Tetrapolar impedance measurements on a 17.5 cm segment of the thigh gave R and X values three to four times larger when the current injecting electrodes were placed 2.5 cm from the sensing electrodes than when very distant placement was used. The frequency dependences of R and X were affected as well, though the X versus R plots still showed virtually perfect depressed-center semicircles, as in the Cole model. R(f) and X(f) for the set of contiguous 2.5 cm wide sub-segments show that these behaviors can be explained by a combination of the transverse orientation of current flow lines near the injecting electrodes and the anisotropy of the resistivity associated with the bundled fiber structure of muscle tissue. The measured impedance was found to be a separable function of geometric and intrinsic tissue variables, but far more complicated than is implicit in the usual cylindrical models. The results also suggest that many full and segmental body composition studies in the literature may be prone to substantial errors due to too close placement of the current injecting electrodes. PMID- 24149839 TI - MS/MS-based networking and peptidogenomics guided genome mining revealed the stenothricin gene cluster in Streptomyces roseosporus. AB - Most (75%) of the anti-infectives that save countless lives and enormously improve quality of life originate from microbes found in nature. Herein, we described a global visualization of the detectable molecules produced from a single microorganism, which we define as the 'molecular network' of that organism, followed by studies to characterize the cellular effects of antibacterial molecules. We demonstrate that Streptomyces roseosporus produces at least four non-ribosomal peptide synthetase-derived molecular families and their gene subnetworks (daptomycin, arylomycin, napsamycin and stenothricin) were identified with different modes of action. A number of previously unreported analogs involving truncation, glycosylation, hydrolysis and biosynthetic intermediates and/or shunt products were also captured and visualized by creation of a map through MS/MS networking. The diversity of antibacterial compounds produced by S. roseosporus highlights the importance of developing new approaches to characterize the molecular capacity of an organism in a more global manner. This allows one to more deeply interrogate the biosynthetic capacities of microorganisms with the goal to streamline the discovery pipeline for biotechnological applications in agriculture and medicine. This is a contribution to a special issue to honor Chris Walsh's amazing career. PMID- 24149841 TI - A universal TaqMan-based RT-PCR protocol for cost-efficient detection of small noncoding RNA. AB - Several methods for the detection of RNA have been developed over time. For small RNA detection, a stem-loop reverse primer-based protocol relying on TaqMan RT-PCR has been described. This protocol requires an individual specific TaqMan probe for each target RNA and, hence, is highly cost-intensive for experiments with small sample sizes or large numbers of different samples. We describe a universal TaqMan-based probe protocol which can be used to detect any target sequence and demonstrate its applicability for the detection of endogenous as well as artificial eukaryotic and bacterial small RNAs. While the specific and the universal probe-based protocol showed the same sensitivity, the absolute sensitivity of detection was found to be more than 100-fold lower for both than previously reported. In subsequent experiments, we found previously unknown limitations intrinsic to the method affecting its feasibility in determination of mature template RISC incorporation as well as in multiplexing. Both protocols were equally specific in discriminating between correct and incorrect small RNA targets or between mature miRNA and its unprocessed RNA precursor, indicating the stem-loop RT-primer, but not the TaqMan probe, triggers target specificity. The presented universal TaqMan-based RT-PCR protocol represents a cost-efficient method for the detection of small RNAs. PMID- 24149842 TI - The molecular recognition of kink-turn structure by the L7Ae class of proteins. AB - L7Ae is a member of a protein family that binds kink-turns (k-turns) in many functional RNA species. We have solved the X-ray crystal structure of the near consensus sequence Kt-7 of Haloarcula marismortui bound by Archaeoglobus fulgidus L7Ae at 2.3-A resolution. We also present a structure of Kt-7 in the absence of bound protein at 2.2-A resolution. As a result, we can describe a general mode of recognition of k-turn structure by the L7Ae family proteins. The protein makes interactions in the widened major groove on the outer face of the k-turn. Two regions of the protein are involved. One is an alpha-helix that enters the major groove of the NC helix, making both nonspecific backbone interactions and specific interactions with the guanine nucleobases of the conserved G * A pairs. A hydrophobic loop makes close contact with the L1 and L2 bases, and a glutamate side chain hydrogen bonds with L1. Taken together, these interactions are highly selective for the structure of the k-turn and suggest how conformational selection of the folded k-turn occurs. PMID- 24149843 TI - HAMR: high-throughput annotation of modified ribonucleotides. AB - RNA is often altered post-transcriptionally by the covalent modification of particular nucleotides; these modifications are known to modulate the structure and activity of their host RNAs. The recent discovery that an RNA methyl-6 adenosine demethylase (FTO) is a risk gene in obesity has brought to light the significance of RNA modifications to human biology. These noncanonical nucleotides, when converted to cDNA in the course of RNA sequencing, can produce sequence patterns that are distinguishable from simple base-calling errors. To determine whether these modifications can be detected in RNA sequencing data, we developed a method that can not only locate these modifications transcriptome wide with single nucleotide resolution, but can also differentiate between different classes of modifications. Using small RNA-seq data we were able to detect 92% of all known human tRNA modification sites that are predicted to affect RT activity. We also found that different modifications produce distinct patterns of cDNA sequence, allowing us to differentiate between two classes of adenosine and two classes of guanine modifications with 98% and 79% accuracy, respectively. To show the robustness of this method to sample preparation and sequencing methods, as well as to organismal diversity, we applied it to a publicly available yeast data set and achieved similar levels of accuracy. We also experimentally validated two novel and one known 3-methylcytosine (3mC) sites predicted by HAMR in human tRNAs. Researchers can now use our method to identify and characterize RNA modifications using only RNA-seq data, both retrospectively and when asking questions specifically about modified RNA. PMID- 24149844 TI - Novel small Cajal-body-specific RNAs identified in Drosophila: probing guide RNA function. AB - The spliceosomal small nuclear RNAs (snRNAs) are modified post-transcriptionally by introduction of pseudouridines and 2'-O-methyl modifications, which are mediated by box H/ACA and box C/D guide RNAs, respectively. Because of their concentration in the nuclear Cajal body (CB), these guide RNAs are known as small CB-specific (sca) RNAs. In the cell, scaRNAs are associated with the WD-repeat protein WDR79. We used coimmunoprecipitation with WDR79 to recover seven new scaRNAs from Drosophila cell lysates. We demonstrated concentration of these new scaRNAs in the CB by in situ hybridization, and we verified experimentally that they can modify their putative target RNAs. Surprisingly, one of the new scaRNAs targets U6 snRNA, whose modification is generally assumed to occur in the nucleolus, not in the CB. Two other scaRNAs have dual guide functions, one for an snRNA and one for 28S rRNA. Again, the modification of 28S rRNA is assumed to take place in the nucleolus. These findings suggest that canonical scaRNAs may have functions in addition to their established role in modifying U1, U2, U4, and U5 snRNAs. We discuss the likelihood that processing by scaRNAs is not limited to the CB. PMID- 24149846 TI - Synthesis, structural, photophysical and electrochemical studies of various d metal complexes of btp [2,6-bis(1,2,3-triazol-4-yl)pyridine] ligands that give rise to the formation of metallo-supramolecular gels. AB - 2,6-Bis(1,2,3-triazol-4-yl)pyridine (btp) is a terdentate binding motif that is synthesised modularly via the CuAAC reaction. Herein, we present the synthesis of ligands 1 and 2 and the investigation of the coordination chemistry, photophysical behaviour and electrochemistry of complexes of these with a number of d-metal ions (e.g. Ru(II), Ir(III), Ni(II) and Pt(II)). The X-ray crystal structures of ligand 1 and the complexes [Ru.2(2)](PF6)Cl, [Ni.1(2)](PF6)Cl and [Ir.1Cl3] are also presented. All of the complexes displayed non-classical triazolyl C-H...Cl(-) hydrogen bonding. All but one complex showed no metal-based luminescence at room temperature, while all of the Pt(ii) complexes displayed luminescence at 77 K. The electrochemistry of the Ru(II) complexes was also studied and these complexes were found to have higher oxidation potentials than analogous compounds. The redox behaviour of [RuL2](2+) complexes with both 1 and 2 was nearly identical, while [Ru.1Cl2(DMSO)] was oxidised at significantly lower potential. We also show that the Ru(II) complex of 2, [Ru.2(2)](PF6)Cl, gave rise to the formation of a metallo-supramolecular gel, the morphology of which was studied using scanning electron and helium ion microscopy. PMID- 24149845 TI - Overlapping and distinct functions of CstF64 and CstF64tau in mammalian mRNA 3' processing. AB - mRNA 3' processing is dynamically regulated spatially and temporally. However, the underlying mechanisms remain poorly understood. CstF64tau is a paralog of the general mRNA 3' processing factor, CstF64, and has been implicated in mediating testis-specific mRNA alternative polyadenylation (APA). However, the functions of CstF64tau in mRNA 3' processing have not been systematically investigated. We carried out a comprehensive characterization of CstF64tau and compared its properties to those of CstF64. In contrast to previous reports, we found that both CstF64 and CstF64tau are widely expressed in mammalian tissues, and their protein levels display tissue-specific variations. We further demonstrated that CstF64 and CstF64tau have highly similar RNA-binding specificities both in vitro and in vivo. CstF64 and CstF64tau modulate one another's expression and play overlapping as well as distinct roles in regulating global APA profiles. Interestingly, protein interactome analyses revealed key differences between CstF64 and CstF64tau, including their interactions with another mRNA 3' processing factor, symplekin. Together, our study of CstF64 and CstF64tau revealed both functional overlap and specificity of these two important mRNA 3' processing factors and provided new insights into the regulatory mechanisms of mRNA 3' processing. PMID- 24149847 TI - Transvaginal organ extraction: potential for broad clinical application. AB - BACKGROUND: Natural orifice transluminal endoscopic surgery procedures have evolved over the past few years. A transvaginal approach is a promising alternative for intraperitoneal procedures. Our objective was to evaluate the safety and feasibility of transvaginal organ extraction. METHODS: This institutional review board-approved protocol involved retrospective review of an ongoing prospective study. Female subjects who presented to our hospital for elective cholecystectomy, appendectomy, or sleeve gastrectomy were offered participation in the study. Eligible patients met the following criteria: age between 18 and 75, diagnosis of gallbladder disease, acute appendicitis, or morbid obesity who desired surgical treatment. A hybrid transvaginal natural orifice approach was used in this series. RESULTS: Thirty-four women underwent transvaginal organ extraction between September 2007 and January 2012. The mean age was 40 +/- 12.1 years (range 23-63 years). The mean body mass index was 27 +/ 6.4 kg/m(2) (range 16-43 kg/m(2)). All patients had an American Society of Anesthesiologists classification of two or below. The mean operative time for cholecystectomy, appendectomy, and sleeve gastrectomy was 90, 71, and 135 min, respectively. There were no conversions to open operation and no intraoperative complications. The mean hospital stay was 2 days for all cases. Patients were followed for a mean of 24 months (range 1-61 months). There were two pregnancies and two successful vaginal deliveries. Six patients (18 %) had minor complaints of spotting or heavy menses in the immediate postoperative period that resolved with conservative measures. There were no abdominal wall complications. There were no long-term complications and no mortalities. CONCLUSIONS: This initial experience suggests that this surgical approach is safe, does not increase length of stay, and has no long-term vaginal complications. Given this attractive profile, a transvaginal approach may prove to be a superior mode of organ extraction, although randomized studies and long-term follow-up are needed. PMID- 24149848 TI - Minimally invasive surgery for serosa-positive gastric cancer (pT4a) in patients with preoperative diagnosis of cancer without serosal invasion. AB - BACKGROUND: Although surgeons normally use minimally invasive surgery (MIS) for patients with early gastric cancer, in Korea and Japan the procedure is also indicated for serosa-negative tumors. Serosal invasion is regarded to be a potential risk factor for peritoneal dissemination as a result of the effect of pneumoperitoneum and tumor manipulation during the operation. We compared operative outcomes between MIS and conventional open surgery for serosa-involved advanced gastric cancer patients who had a preoperative diagnosis of cancer without serosal invasion. METHODS: A total of 61 patients (39 patients treated by MIS and 22 by open surgery) treated between 2003 and 2009 who were first diagnosed preoperatively as serosa negative on the basis of computed tomography, endoscopy, and endoscopic ultrasound but then diagnosed as serosa positive upon final pathology were studied. We retrospectively compared recurrence and survival between the two treatment groups. RESULTS: Clinicopathologic characteristics, clinical stage, extent of surgery, and short-term operative outcome did not differ between the groups. 5-year overall survival (73.5 vs. 67.5 %, p = 0.518, respectively) and disease-free survival (67.8 vs. 54.2 %, p = 0.296, respectively) were comparable between the MIS and open surgery groups. There were recurrences in 12 patients in the MIS group and 11 patients in the open surgery group, with a median follow-up period of 64 months. Recurrence patterns did not differ between the groups; moreover, MIS did not increase peritoneal recurrences compared to open surgery (42.0 vs. 54.5 %, p = 0.537, respectively). In multivariate analyses, the type of surgery was not an independent prognostic factor. CONCLUSIONS: Similar survival and recurrence patterns were observed in advanced gastric cancer patients preoperatively diagnosed as serosa negative who were treated either by MIS or open surgery. MIS may be safely applied in patients with serosa-positive tumors. PMID- 24149849 TI - Systematic review and meta-analysis of endoscopic submucosal dissection versus transanal endoscopic microsurgery for large noninvasive rectal lesions. AB - BACKGROUND: For almost 30 years, transanal endoscopic microsurgery (TEM) has been the mainstay treatment for large rectal lesions. With the advent of endoscopic submucosal dissection (ESD), flexible endoscopy has aimed at en bloc R0 resection of superficial lesions of the digestive tract. This systematic review and meta analysis compared the safety and effectiveness of ESD and full-thickness rectal wall excision by TEM in the treatment of large nonpedunculated rectal lesions preoperatively assessed as noninvasive. METHODS: A systematic review of the literature published between 1984 and 2010 was conducted (Registration no. CRD42012001882). Data were integrated with those from the original databases requested from the study authors when needed. Pooled estimates of the proportions of patients with en bloc R0 resection, complications, recurrence, and need for further treatment in the ESD and TEM series were compared using random-effects single-arm meta-analysis. RESULTS: This review included 11 ESD and 10 TEM series (2,077 patients). The en bloc resection rate was 87.8 % (95 % confidence interval [CI] 84.3-90.6) for the ESD patients versus 98.7 % (95 % CI 97.4-99.3 %) for the TEM patients (P < 0.001). The R0 resection rate was 74.6 % (95 % CI 70.4-78.4 %) for the ESD patients versus 88.5 % (95 % CI 85.9-90.6 %) for the TEM patients (P < 0.001). The postoperative complications rate was 8.0 % (95 %, CI 5.4-11.8 %) for the ESD patients versus 8.4 % (95 % CI 5.2-13.4 %) for the TEM patients (P = 0.874). The recurrence rate was 2.6 % (95 % CI 1.3-5.2 %) for the ESD patients versus 5.2 % (95 % CI 4.0-6.9 %) for the TEM patients (P < 0.001). Nevertheless, the rate for the overall need of further abdominal treatment, defined as any type of surgery performed through an abdominal access, including both complications and pathology indications, was 8.4 % (95 % CI 4.9-13.9 %) for the ESD patients versus 1.8 % (95 % CI 0.8-3.7 %) for the TEM patients (P < 0.001). CONCLUSIONS: The ESD procedure appears to be a safe technique, but TEM achieves a higher R0 resection rate when performed in full-thickness fashion, significantly reducing the need for further abdominal treatment. PMID- 24149850 TI - Simulation-based training improves the operative performance of totally extraperitoneal (TEP) laparoscopic inguinal hernia repair: a prospective randomized controlled trial. AB - BACKGROUND: Laparoscopic surgery has an important role to play in the care of patients with inguinal hernias, but the procedure is difficult to learn. This study aimed to assess whether training to proficiency using a novel laparoscopic inguinal hernia repair (LIHR) simulation curriculum improved operating room (OR) performance. METHODS: For this study, 17 surgical residents [postgraduate years (PGYs) 2-5] participated in a didactic LIHR course and then were randomized to a training (T) or a control (C, standard residency) group. Performance of totally extraperitoneal (TEP) LIHR in the OR at baseline and after the study was measured using the Global Operative Assessment of Laparoscopic Skills-Groin Hernia (GOALS GH). RESULTS: Of the 17 residents, 14 (5 T and 9 C) completed their final evaluations. The two groups showed no differences in terms of LIHR experience. The baseline GOALS-GH scores in the OR were similar (T 14.8; range 12.8-16.8 vs. C 13.6; range 12.3-14.8; P = 0.20). The mean number of training sessions needed to achieve proficiency was 4.8 (range 4.4-5.2), and the mean total training time was 109 min (range 61.9-149.1 min). After training, OR performance improved in the T group by 3.4 points (range 2.0-4.8 points; P = 0.002), whereas no significant change was seen in the C group [1.2; (range -1.1 to 3.6; P = 0.27)]. The final total GOALS-GH scores showed a trend toward better performance in the T group than in the C group [18.2; (range 14.9-21.5) vs. 14.8; (range 12.4-17.1); P = 0.06). CONCLUSIONS: This study demonstrated the skills required for transfer of LIHR to the OR using a low-cost procedure-specific simulator. Residents who trained to proficiency on the McGill Laparoscopic Inguinal Hernia Simulator (MLIHS) showed greater skill improvement than their colleagues who did not. These results provide evidence supporting the use of simulation to teach and assess LIHR. PMID- 24149851 TI - Management of upper intestinal leaks using an endoscopic vacuum-assisted closure system (E-VAC). AB - BACKGROUND: Esophageal perforations and postoperative leakage of esophagogastrostomy are considered to be life-threatening conditions due to the development of mediastinitis and consecutive sepsis. Vacuum-assisted closure (VAC), a well-established treatment method for superficial infected wounds, is based on a negative pressure applied to the wound via a vacuum-sealed sponge. Endoluminal VAC (E-VAC) therapy is a novel method, and experience with its esophageal application is limited. METHODS: This retrospective study summarizes the experience of a center with a high volume of upper gastrointestinal surgery using E-VAC therapy for patients with leakages of the esophagus. The study investigated 14 patients who had esophageal defects treated with E-VAC. Three patients had a spontaneous defect; two patients had an iatrogenic defect; and nine patients had a postoperative esophageal defect. RESULTS: The average duration of application was 12.1 days, and an average of 3.9 E-VAC systems were used. For 6 of the 14 patients, E-VAC therapy was combined with the placement of self-expanding metal stents. Complete restoration of the esophageal defect was achieved in 12 (86 %) of the 14 patients. Two patients died due to prolonged sepsis. CONCLUSION: This report demonstrates that E-VAC therapy adds an additional treatment option for partial esophageal wall defects. The combination of E-VAC treatment and endoscopic stenting is a successful novel procedure for achieving a high closure rate. PMID- 24149852 TI - Design and validation of an assessment tool for open surgical procedures. AB - BACKGROUND: Laparoscopy is currently the gold standard for cholecystectomy. Recent literature suggests surgical trainees have limited exposure to open cholecystectomy, which may result in suboptimal performance in the event of conversion. Furthermore, most training and assessment models are designed for laparoscopic cholecystectomy, with limited opportunities for open simulator training. The present study's purpose was to design an inexpensive model for open cholecystectomy and to validate a performance assessment tool. METHODS: The simulator comprises a porcine liver and gallbladder in a mock human abdomen with silicon skin. The assessment tool utilizes inexpensive infrared (IR) cameras to provide tracking of participant hand motions. Eleven novice general surgery trainees (<20 cholecystectomies) and five expert surgeons (>100 cholecystectomies) completed an open cholecystectomy using the simulator. Procedures were recorded and assessed by a blinded evaluator using a global rating scale. Tracking data analysis was based on number of movements and total path length. RESULTS: Novices (t = 36.18 min) completed the procedure significantly slower than did experts (t = 19.53 min) (Mann-Whitney test U = 20, p < 0.05) and had significantly more hand movements (Mann-Whitney test U = 20, p < 0.05). Analysis of the total global rating scale scores showed a significant difference between novice (14/35) and expert (24/35) performance in all categories (Mann-Whitney test U = 58, p < 0.05). CONCLUSION: The present model presents a realistic, low-cost tool for training and assessment of procedural skills in open cholecystectomy. The study demonstrated the validity of the IR tracking device as an objective assessment tool for open surgical skills training. Future training should incorporate this low-cost, highly effective training device into surgical curricula. PMID- 24149853 TI - Laparoscopic pudendal nerve decompression and transposition combined with omental flap protection of the nerve (Istanbul technique): technical description and feasibility analysis. AB - BACKGROUND: We aimed in this study to investigate the efficacy of laparoscopic pudendal nerve decompression and transposition (LaPNDT) in the treatment of chronic pelvic pain due to pudendal neuralgia. Pudendal nerve entrapment (PNE) between the sacrospinous and sacrotuberous ligaments is the most frequent etiology. We describe the technical details, feasibility, and advantages of a laparoscopic approach in patients with PNE. METHODS: Consecutive patients (n = 27) with a diagnosis of PNE underwent LaPNDT with omental flap protection in an effort to prevent re-fibrosis around the nerve in the long term. The degree of pain and pain impact were evaluated pre- and postoperatively using the visual analog pain scale (VAS) and the Impact of Symptoms and Quality of Life. RESULTS: The mean (+/- standard deviation [SD]) follow-up of the 27 patients was 6.8 +/- 4.2 months; 16 of the 27 were followed-up for more than 6 months. The mean (SD) operation time was 199.4 +/- 36.1 (155-300) min, and the mean estimated blood loss was 39.7 ml. All patients were ambulated on the first postoperative day, and the mean (SD) hospitalization time was 2.1 +/- 1.0 (1-6) days. The mean VAS scores of 27, 23, 16, and 6 patients were 1.5, 1.4, 1.6, and 2.0, postoperatively, at the first, third, sixth, and twelfth months (p < 0.0001). A more than reduction in VAS score (>80 %) was achieved in 13 of the 16 patients (81.2 %) who were followed-up for more than 6 months. CONCLUSIONS: LaPNDT seems a feasible surgical modality for cautiously selected patients with PNE. In addition, using an omental flap for protection of the nerve is one of the most important technical advantages of laparoscopy. As a minimally invasive surgery, the laparoscopic approach can be technically feasible, with its promising preliminary results in the treatment of PNE. With further analysis, in the future it may open new frontiers for pudendal nerve neuromodulation as a new treatment modality in some intractable functional problems of the genitourinary tract. PMID- 24149854 TI - Effect of transoral incisionless fundoplication on reflux mechanisms. AB - OBJECTIVES: Transoral incisionless fundoplication (TIF) is a new endoscopic treatment option for gastroesophageal reflux disease (GERD). The mechanisms underlying the anti-reflux effect of this new procedure have not been studied. We therefore conducted this explorative study to evaluate the effect of TIF on reflux mechanisms, focusing on transient lower esophageal sphincter relaxations (TLESRs) and esophagogastric junction (EGJ) distensibility. METHODS: GERD patients (N = 15; 11 males, mean age 41 years, range 23-66), dissatisfied with medical treatment were studied before and 6 months after TIF. We performed 90-min postprandial combined high-resolution manometry and impedance-pH monitoring and an ambulatory 24-h pH-impedance monitoring. EGJ distensibility was evaluated using an endoscopic functional luminal imaging probe before and directly after the procedure. RESULTS: TIF reduced the number of postprandial TLESRs (16.8 +/- 1.5 vs. 9.2 +/- 1.3; p < 0.01) and the number of postprandial TLESRs associated with reflux (11.1 +/- 1.6 vs. 5.6 +/- 0.6; p < 0.01), but the proportion of TLESRs associated with reflux was unaltered (67.6 +/- 6.9 vs. 69.9 +/- 6.3 %). TIF also led to a decrease in the number and proximal extent of reflux episodes and an improvement of acid exposure in the upright position; conversely, TIF had no effect on the number of gas reflux episodes. EGJ distensibility was reduced after the procedure (2.4 +/- 0.3 vs. 1.6 +/- 0.2 mm(2)/mmHg; p < 0.05). CONCLUSIONS: TIF reduced the number of postprandial TLESRs, the number of TLESRs associated with reflux and EGJ distensibility. This resulted in a reduction of the number and proximal extent of reflux episodes and improvement of acid exposure in the upright position. The anti-reflux effect of TIF showed to be selective for liquid-containing reflux only, thereby preserving the ability of venting gastric air. PMID- 24149855 TI - Delayed closure of open abdomen in septic patients is facilitated by combined negative pressure wound therapy and dynamic fascial suture. AB - INTRODUCTION: The aim of this prospective controlled trial was the definition of the optimal timepoint for delayed closure after negative pressure wound therapy (NPWT) in the treatment of the open abdomen (OA) in septic patients after abdominal surgery. The delayed closure of the abdominal wall after abdominal NPWT treatment is often problematic due to the lateralization of the fascial edge leading to unfavorably high tensile forces of the adapting sutures in the midline. We present the results of an innovative combination of NPWT with a new fascial-approximation technique using dynamic fascial sutures (DFS) and delayed closure of the abdominal wall. METHODS: Eighty-seven patients subjected to OA therapy following surgery for secondary peritonitis were treated with NPWT and DFS. In all patients, a running suture of elastic vessel loops was used to approximate fascial edges. This procedure was continued for the duration of NPWT until final closure of the abdomen with running suture in 55 patients (63.2 %) and interrupted suture technique in eight patients (9.2 %). An anterior component separation was performed in seven patients. RESULTS: Delayed closure was achieved in 68 patients (78.2 %) after 12.6 days [mean (SD) 25.1 (2-204)] days and 4.3 re operations [mean (SD) 6.0 (1-43)]. Fifteen (17.2 %) superficial and two (2.3 %) deep wound infections occurred. In three (3.4 %) cases, entero-atmospheric fistulas had to be treated. We recorded no technique-specific complications. Four (5.9 %) incisional hernia were detected in a mean follow-up of 40.5 months (16 65). Mortality rate was 55.2 %. CONCLUSION: Using a new technique combining NPWT and DFS in the treatment of the OA, the delayed closure of the fascial edges by running suture can be achieved and the number of re-operations can be kept low. The technique was safe and led to a low incidence of incisional hernias. Extensive abdominal wall reconstruction was seldom required. PMID- 24149857 TI - Gastrointestinal stromal tumors of the stomach: the role of laparoscopic resection. Single-centre experience of 38 cases. AB - INTRODUCTION: Laparoscopic resection is considered the gold standard of treatment only for small gastric gastrointestinal stromal tumor (GIST). MATERIALS AND METHODS: Between January 2004 and September 2012, 38 consecutive gastric GISTs were operated on by laparoscopic approach, without conversions. Thirty-five cases were primary GISTs and three were bleeding GISTs with hepatic metastases non responding to conservative therapy treated by emergency surgery. RESULTS: Median tumor size was 3.63 cm (1.8-17 cm). In two cases tumor size was <2 cm, between 2 and 5 cm in 26 cases, between 5 and 10 cm in eight cases, and >10 cm in two cases. In two cases, localization was in the cardia, fundus in ten cases, lesser curve in 11 cases, greater curve in 12 cases, and antrum in three cases. We performed 24 wedge resections, eight transgastric resections and six antrectomies. An Endo-GIATM was used in 25 cases, and a manual laparoscopic reconstruction with extramucosal suture was performed in 13 cases. No postoperative mortality and morbidity was observed. The routine use of laparoscopy allowed us to perform resections in 100 % of cases, even in those where preoperative imaging suggested an open approach according to the current guidelines. CONCLUSIONS: The use of a pre-resection endobag avoids spillage and seeding, thus increasing the possibility of resection. In conclusion, we consider the laparoscopic approach as mandatory in all cases, always considering the possibility of converting to the open technique when necessary. PMID- 24149856 TI - Long-term outcome of laparoscopic versus open liver resection for hepatocellular carcinoma: a case-controlled study with propensity score matching. AB - BACKGROUND: Laparoscopic liver resection (LR) for hepatocellular carcinoma (HCC) is usually applied to superficial and left-side small lesions. Therefore, well designed comparative studies about the results of LR versus open liver resection (OR) for HCC are difficult and still uncommon. The aim of this study was to compare the perioperative and long-term oncologic outcomes of LR versus OR for HCC between well-matched patient groups. METHODS: Between January 2000 and March 2012, 205 patients (43 with intent-to-treat with LR, 162 OR) underwent primary liver resection of less than three segments for HCC in our center. To select a comparison group, propensity score matching (PSM) was used at 1:1 ratio with covariates of baseline characteristics, including tumor characteristics. Outcomes were compared between the matched groups. RESULTS: The two groups were well balanced by PSM and 29 patients were matched respectively. In LR, there was more non-anatomical resection (65.5 vs. 34.5 %; p = 0.012), less postoperative ascites (0.0 vs. 17.2 %; p = 0.025), and shorter hospital stay (7.69 +/- 2.94 vs. 13.38 +/- 7.37 days; p < 0.001). With the exception of these, there were no significant differences in perioperative and long-term outcomes. The 1-, 3- and 5-year survivals were 100, 100 and 92.2 % in LR, and 96.5, 92.2 and 87.7 % in OR (p = 0.267), respectively. The 1-, 3- and 5-year disease-free survivals were 81.7, 61.7 and 54.0 % in LR, and 78.6, 60.9 and 40.1 % in OR, respectively (p = 0.929). CONCLUSIONS: The outcome of LR for HCC was technically feasible and safe in selected patients, and LR showed similar perioperative and long-term oncologic outcomes when compared with OR matched with PSM. PMID- 24149859 TI - Expert opinion: computed tomography versus magnetic resonance imaging for young adults with congenital heart disease. PMID- 24149858 TI - Functional interplay between Aurora B kinase and Ssu72 phosphatase regulates sister chromatid cohesion. AB - Cohesins establish cohesion between replicated sister chromatids and are maintained as a multiprotein complex on chromosome arms until they are phosphorylated by mitotic kinases, such as Aurora B and Plk1. However, the mechanics of how the phosphorylation and dephosphorylation of cohesin subunits by kinases and phosphatases, respectively, leads to the dissociation of the cohesin complex from chromosomes remain unclear. Here we report that Aurora B kinase directly interacts with and phosphorylates Ssu72, a new cohesin-binding phosphatase, at Ser 19 in vitro and in vivo. The Aurora B-mediated phosphorylation of Ssu72 causes the structural modification of Ssu72 protein, downregulates phosphatase activity and triggers the ubiquitin-dependent degradation of Ssu72. Overexpression of the Aurora B-mediated phosphomimetic mutant of Ssu72 prevents maintainance chromosome arm cohesion. These results provide evidence that Aurora B kinase directly targets Ssu72 phosphatase for regulation of sister chromatid cohesion during early mitosis. PMID- 24149860 TI - Adult congenital heart disease: a practical approach. AB - Adults with congenital heart disease (CHD) represent an increasing population both because anomalies that might have remained undiagnosed in the past are now being diagnosed later in life on imaging and because significant therapeutic advances have resulted in survival to adulthood of patients with complex CHD. In this article, we discuss simple and common complex congenital anomalies that are encountered in general practice including their incidence, associations, and expected postoperative appearances. We will describe an approach to segmental anatomy and situs evaluation and details of some of the common vascular anomalies, simple shunts, and complex CHDs to refine the imaging strategies and diagnostic acumen of radiologists interested in CHD who may not be practicing in specialized adult CHD centers. Key imaging appearances on chest radiography, protocoling tips for answering clinically relevant questions on computed tomography and magnetic resonance imaging, and the specific imaging appearances and common complications related to long-standing CHD in the adult and complications of treatment are reviewed for each entity. PMID- 24149861 TI - Iterative image reconstruction and its role in cardiothoracic computed tomography. AB - Revolutionary developments in multidetector-row computed tomography (CT) scanner technology offer several advantages for imaging of cardiothoracic disorders. As a result, expanding applications of CT now account for >85 million CT examinations annually in the United States alone. Given the large number of CT examinations performed, concerns over increase in population-based risk for radiation-induced carcinogenesis have made CT radiation dose a top safety concern in health care. In response to this concern, several technologies have been developed to reduce the dose with more efficient use of scan parameters and the use of "newer" image reconstruction techniques. Although iterative image reconstruction algorithms were first introduced in the 1970s, filtered back projection was chosen as the conventional image reconstruction technique because of its simplicity and faster reconstruction times. With subsequent advances in computational speed and power, iterative reconstruction techniques have reemerged and have shown the potential of radiation dose optimization without adversely influencing diagnostic image quality. In this article, we review the basic principles of different iterative reconstruction algorithms and their implementation for various clinical applications in cardiothoracic CT examinations for reducing radiation dose. PMID- 24149862 TI - Malpractice suits in chest radiology: an evaluation of the histories of 8265 radiologists. AB - PURPOSE: The aim of this study was to present rates of claims, causes of error, percentage of cases resulting in a judgment, and average payments made by radiologists in chest-related malpractice cases in a survey of 8265 radiologists. MATERIALS AND METHODS: The malpractice histories of 8265 radiologists were evaluated from the credentialing files of One-Call Medical Inc., a preferred provider organization for computed tomography/magnetic resonance imaging in workers' compensation cases. RESULTS: Of the 8265 radiologists, 2680 (32.4%) had at least 1 malpractice suit. Of those who were sued, the rate of claims was 55.1 per 1000 person years. The rate of thorax-related suits was 6.6 claims per 1000 radiology practice years (95% confidence interval, 6.0-7.2). There were 496 suits encompassing 48 different causes. Errors in diagnosis comprised 78.0% of the causes. Failure to diagnose lung cancer was by far the most frequent diagnostic error, representing 211 cases or 42.5%. Of the 496 cases, an outcome was known in 417. Sixty-one percent of these were settled in favor of the plaintiff, with a mean payment of $277,230 (95% confidence interval, 226,967-338,614). CONCLUSIONS: Errors in diagnosis, and among them failure to diagnose lung cancer, were by far the most common reasons for initiating a malpractice suit against radiologists related to the thorax and its contents. PMID- 24149863 TI - Monod sign. PMID- 24149864 TI - Bronchial stump aspergillosis. PMID- 24149865 TI - Imaging of a case of disseminated Mycobacterium avium complex infection. PMID- 24149869 TI - Effects of Combined Creatine Plus Fenugreek Extract vs. Creatine Plus Carbohydrate Supplementation on Resistance Training Adaptations. AB - The purpose of this study was to evaluate the effects of combined creatine and fenugreek extract supplementation on strength and body composition. Forty- seven resistance trained men were matched according to body weight to ingest either 70 g of a dextrose placebo (PL), 5 g creatine/70 g of dextrose (CRD) or 3.5 g creatine/900 mg fenugreek extract (CRF) and participate in a 4-d/wk periodized resistance-training program for 8-weeks. At 0, 4, and 8-weeks, subjects were tested on body composition, muscular strength and endurance, and anaerobic capacity. Statistical analyses utilized a separate 3X3 (condition [PL vs. CRD vs. CRF] x time [T1 vs. T2 vs. T3]) ANOVAs with repeated measures for all criterion variables (p <= 0.05). No group x time interaction effects or main effects (p > 0.05) were observed for any measures of body composition. CRF group showed significant increases in lean mass at T2 (p = 0.001) and T3 (p = 0.001). Bench press 1RM increased in PL group (p = 0.050) from T1-T3 and in CRD from T1-T2 (p = 0. 001) while remaining significant at T3 (p < 0.001). CRF group showed a significant increase in bench press 1RM from T1-T2 (p < 0.001), and also increased from T2-T3 (p = 0.032). Leg press 1RM significantly increased at all time points for PL, CRD, and CRF groups (p < 0.05). No additional between or within group changes were observed for any performance variables and serum clinical safety profiles (p > 0.05). In conclusion, creatine plus fenugreek extract supplementation had a significant impact on upper body strength and body composition as effectively as the combination of 5g of creatine with 70g of dextrose. Thus, the use of fenugreek with creatine supplementation may be an effective means for enhancing creatine uptake while eliminating the need for excessive amounts of simple carbohydrates. Key pointsFenugreek plus creatine supplementation may be a new means of increasing creatine uptake.Creatine plus fenugreek seems to be just as effective as the classic creatine plus carbohydrate ingestion in terms of stimulating training adaptations.This is the first study to our knowledge that has combined fenugreek with creatine supplementation in conjunction with a resistance training program. PMID- 24149868 TI - Current opinions on tendinopathy. AB - Tendinopathy is characterized by pain in the tendon and impaired performance sometimes associated with swelling of the tendon. Its diagnosis is usually clinical but ultrasonography and magnetic resonance imaging can refine the diagnosis. Tendinopathy is highly prevalent and is one of the most frequently self reported musculoskeletal diseases in physical workers and sports people. Nevertheless, it is very difficult to carry out general epidemiologic studies on tendinopathy because of the varying sports cultures and sports habits in different countries. The aetiology of tendinopathy seems to be multi-factorial, involving intrinsic and extrinsic factors. The role of inflammation is still debated but the absence of inflammatory cells does not mean that inflammatory mediators are not implicated. Different theories have been advanced to explain pain and chronicity mechanisms, but these mechanisms remain largely unknown. "Conventional "treatments are generally employed empirically to fight pain and inflammation but they do not modify the histological structure of the tendon. However, these treatments are not completely satisfactory and the recurrence of symptoms is common. Currently, eccentric training remains the treatment of choice for tendinopathy, even though some studies are contradictory. Moreover, many interesting new treatments are now being developed to treat tendinopathy, but there is little evidence to support their use in clinical practice. Key pointsThe word "tendinopathy "is the correct term for the clinical diagnosis of pain accompanied by impaired performance, and sometimes swelling in the tendon.The aetiology of tendinopathy seems to be a multi-factorial process, involving promoting factors that are intrinsic or extrinsic, working either alone or in combination.US (with color Doppler) and MRI are usually prescribed when tendinopathy is unresponsive to treatment and entails lingering symptoms.Eccentric training is currently considered to be the most efficient treatment for tendinopathy; nevertheless, in order to be effective, this treatment needs specific modalities: slow speed, low intensity and gradual intensification, with minimum 20 to 30 sessions of exercises often being needed.Many interesting new treatments are now being developed to treat tendinopathy, but currently there is little evidence to support their use in clinical practice. PMID- 24149870 TI - Effect of a pre-workout energy supplement on acute multi-joint resistance exercise. AB - The effect of a pre-workout energy supplement on acute multi- joint resistance exercise was examined in eight resistance-trained college-age men. Subjects were randomly provided either a placebo (P) or a supplement (S: containing caffeine, taurine, glucuronolactone, creatine, beta-alanine, and the amino acids; leucine, isoleucine, valine, glutamine and arginine) 10 minutes prior to resistance exercise. Subjects performed 4 sets of no more than 10 repetitions of either barbell squat or bench press at 80% of their pre-determined 1 repetition- maximum (1RM) with 90 seconds of rest between sets. Dietary intake 24 hours prior to each of the two training trials was kept constant. Results indicate that consuming the pre-workout energy drink 10 minutes prior to resistance exercise enhances performance by significantly increasing the number of repetitions successfully performed (p = 0.022) in S (26.3 +/- 9.2) compared to P (23.5 +/- 9.4). In addition, the average peak and mean power performance for all four sets was significantly greater in S compared to P (p < 0.001 and p < 0.001, respectively). No differences were observed between trials in subjective feelings of energy during either pre (p = 0.660) or post (p = 0.179) meaures. Similary, no differences between groups, in either pre or post assessments, were observed in subjective feelings of focus (p = 0.465 and p = 0.063, respectively), or fatigue (p = 0.204 and p = 0.518, respectively). Results suggest that acute ingestion of a high-energy supplement 10 minutes prior to the onset of a multi-joint resistance training session can augment training volume and increase power performance during the workout. Key pointsConsumption of a pre-workout energy supplement containing caffeine, taurine, glucuronolactone, creatine, beta alanine, and amino acids consumed 10 minutes prior to a bout of resistance exercise enhances the total number of repetitions performed during the exercise bout.Power outputs for each repetition during the workout were significantly greater when using the supplement compared to placebo.Ingestion of supplement did not have any significant effect on subjective measures of fatigue, energy and focus. PMID- 24149871 TI - Comparison of rowing on a concept 2 stationary and dynamic ergometer. AB - Biomechanical and physiological responses to rowing 1000 m at a power output equivalent to a 2000 m race were compared in 34 collegiate rowers (17 women, 17 men) rowing on a stationary and dynamic Concept 2 ergometer. Stroke ratio, peak handle force, rate of force development, impulse, and respiratory exchange ratio decreased by 15.7, 14.8, 10.9, 10.2 and 1.9%, respectively, on the dynamic ergometer. In contrast, percent time to peak force and stroke rate increased by 10.5 and 12.6%, respectively, during dynamic ergometry; the changes in stroke rate and impulse were greater for men than women. Last, VO2 was 5.1% higher and efficiency 5. 3% lower on the dynamic ergometer for men. Collegiate rowers used higher stoke rates and lower peak stroke forces to achieve a similar power output while rowing at race pace on the dynamic ergometer, which may have increased the cardiopulmonary demand and possibly reduced force production in the primary movers. Differences were more pronounced in males than females; this dichotomy may be more due to dynamic ergometer familiarity than sex. Key pointsWhen rowing at a constant power output, all rowers used higher stroke rates and lower stroke forces on the Concept 2 Dynamic ergometer as compared to the Concept 2 Stationary ergometer.When rowing at a constant power output, cardiopulmonary demand was higher for all rowers, as measured by heart rate, on the Concept 2 Dynamic ergometer as compared to the Concept 2 Stationary ergometer.When rowing at a constant power output, efficiency was lower for male rowers on the Concept 2 Dynamic ergometer as compared to the Concept 2 Stationary ergometer. PMID- 24149872 TI - Interplay of different contextual motivations and their implications for exercise motivation. AB - The aim of this study was to analyze the interaction between different contextual motivations and exercise motivation. The sample consisted of 449 exercisers aged between 16 and 53 years. Questionnaires were used to measure the satisfaction of basic psychological needs, self-determined motivation and the autotelic experience during exercise. The level of self-determined motivation regarding health, leisure and interpersonal relationships was also measured. The results of the structural equation modeling demonstrated that basic psychological needs and self-determined motivations about health and leisure positively predicted the self-determined motivation to exercise. Moreover, the self-determined motivation to exercise positively predicted the autotelic experience. The model was invariant across age, although some gender differences were found. Specifically, the self-determined motivation towards health in men did not significantly predict the self-determined motivation to exercise. These results represent to evaluate the role that other contextual motivations play in exercise motivation. Key pointsSelf-determined motivations about health and leisure positively predicted exercise motivation.Motivation in interpersonal relationships did not relate to exercise motivation.Relationships were invariant across age, although some gender differences were found. Self-determined motivation towards health in men did not significantly predict self-determined motivation to exercise, whereas leisure motivation played a major role in explaining this variable. PMID- 24149873 TI - The effects of exercise on food intake and hunger: relationship with acylated ghrelin and leptin. AB - This study investigated the effects of a long bout of aerobic exercise on hunger and energy intake and circulating levels of leptin and acylated ghrelin. Ten healthy male subjects undertook two, 4 h trials in a randomized crossover design. In the exercise trial subjects ran for 105 min at 50% of maximal oxygen uptake and the last 15 min at 70% of maximal oxygen uptake followed by a 120 min rest period. In the control trial, subjects rested for 4 h. Subjects consumed a buffet test meal at 180 min during each trial. Hunger ratings, acylated ghrelin, leptin, glucose and insulin concentrations were measured at 0, 1, 2, 3 and 4 h. No differences were found at baseline values for hunger, acylated ghrelin, leptin, insulin and glucose for both trials (p > 0.05). The estimated energy expenditure of the exercise trial was 1550 +/- 136 kcal. Exercise did not change subsequent absolute energy intake, but produced a significant decrease (p < 0.05) in relative energy intake. A two-way ANOVA revealed a significant (p < 0. 05) interaction effect for hunger and acylated ghrelin. In conclusion, this exercise regimen had a positive effect on reducing appetite which is related to reduced acylated ghrelin responses over time. This finding lends support for a role of exercise in weight management. Key pointsPhysical exercise is a strategy used to counteract obesity, since it lowers the energetic balance by increasing energy expenditure. However, because any energy expended in exercise elevates the intensity of hunger and drives food consumption, it is pertinent to ask how effective exercise could be in helping people to lose weight or to prevent weight gain.The effects of exercise on hunger sensations and food intake are fairly controversial and depend on the intensity and duration of exercise.120 min prolonged treadmill exercise with mix intensity, temporarily decreased hunger sensations, acylated ghrelin and relative energy intake.Variations in exercise intensity should theoretically be a useful means of weight loss. PMID- 24149874 TI - Effects of Combined Foot/Ankle Electromyostimulation and Resistance Training on the In-Shoe Plantar Pressure Patterns during Sprint in Young Athletes. AB - Several studies have already reported that specific foot/ankle muscle reinforcement strategies induced strength and joint position sense performance enhancement. Nevertheless the effects of such protocols on sprint performance and plantar loading distribution have not been addressed yet. The objective of the study is to investigate the influence of a 5-wk foot/ankle strength training program on plantar loading characteristics during sprinting in adolescent males. Sixteen adolescent male athletes of a national training academy were randomly assigned to either a combined foot/ankle electromyostimulation and resistance training (FAST) or a control (C) group. FAST consisted of foot medial arch and extrinsic ankle muscles reinforcement exercises, whereas C maintained their usual training routine. Before and after training, in-shoe loading patterns were measured during 30-m running sprints using pressure sensitive insoles (right foot) and divided into nine regions for analysis. Although sprint times remained unchanged in both groups from pre- to post- training (3.90 +/- 0.32 vs. 3.98 +/- 0.46 s in FAST and 3.83 +/- 0.42 vs. 3.81 +/- 0.44 s in C), changes in force and pressure appeared from heel to forefoot between FAST and C. In FAST, mean pressure and force increased in the lateral heel area from pre- to post- training (67.1 +/- 44.1 vs. 82.9 +/- 28.6 kPa [p = 0.06]; 25.5 +/- 17.8 vs. 34.1 +/- 14.3 N [p = 0.05]) and did not change in the medial forefoot (151.0 +/- 23.2 vs. 146.1 +/- 30.0 kPa; 142.1 +/- 29.4 vs. 136.0 +/- 33.8; NS). Mean area increased in FAST under the lateral heel from pre- to post- (4.5 +/- 1.3 vs. 5.7 +/- 1.6 cm(2) [p < 0.05]) and remained unchanged in C (5.5 +/- 2.8 vs. 5.0 +/- 3.0 cm(2)). FAST program induced significant promising lateral and unwanted posterior transfer of the plantar loads without affecting significantly sprinting performance. Key pointsWe have evaluated the effects of a foot/ankle strength training program on sprint performance and on related plantar loading characteristics in teenage athletes, and this have not been examined previously.Our results showed no significant pre- to post- changes in sprint performance.This study revealed initially a lateral transfer and secondly a posterior transfer of the plantar loads after the foot/ankle strength training program. PMID- 24149875 TI - DHA- Rich Fish Oil Improves Complex Reaction Time in Female Elite Soccer Players. AB - Omega-3 fatty acids (n-3) has shown to improve neuromotor function. This study examined the effects of docosahexaenoic acid (DHA) on complex reaction time, precision and efficiency, in female elite soccer players. 24 players from two Spanish female soccer Super League teams were randomly selected and assigned to two experimental groups, then administered, in a double-blind manner, 3.5 g.day( 1) of either DHA-rich fish oil (FO =12) or olive oil (OO = 12) over 4 weeks of training. Two measurements (pre- and post-treatment) of complex reaction time and precision were taken. Participants had to press different buttons and pedals with left and right hands and feet, or stop responding, according to visual and auditory stimuli. Multivariate analysis of variance displayed an interaction between supplement administration (pre/post) and experimental group (FO/OO) on complex reaction time (FO pre = 0.713 +/- 0.142 ms, FO post = 0.623 +/- 0.109 ms, OO pre = 0.682 +/- 1.132 ms, OO post = 0.715 +/- 0.159 ms; p = 0.004) and efficiency (FO pre = 40.88 +/- 17.41, FO post = 57.12 +/- 11.05, OO pre = 49.52 +/- 14.63, OO post = 49. 50 +/- 11.01; p = 0.003). It was concluded that after 4 weeks of supplementation with FO, there was a significant improvement in the neuromotor function of female elite soccer players. Key pointsThe results obtained from the study suggest that supplementation with DHA produced perceptual motor benefits in female elite athletes.DHA could be a beneficial supplement in sports where decision making and reaction time efficiency are of importance. PMID- 24149876 TI - Effect of taurine supplementation on the alterations in amino Acid content in skeletal muscle with exercise in rat. AB - Taurine included abundantly in skeletal muscle, particularly in the slow-twitch fibers, enhances exercise performance. However, the exact mechanisms for this effect have been unclear. The present study investigated the influence of taurine supplementation on amino acids profile in skeletal muscles as one of mechanisms in the enhancement of exercise performance induced by taurine. In the rats that received taurine solution, amino acids concentrations were comprehensively quantified in two portions with different fiber compositions in the fast-twitch fiber dominant (FFD) gastrocnemius muscle after 2 weeks, and in the gastrocnemius and additional other FFD muscles, liver, and plasma with exhausted exercise after 3 weeks. In the FFD muscles after 2 weeks, a common phenomenon that decreased concentrations of threonine (-16%), serine (-15~-16%), and glycine (-6~-16%) were observed, and they are categorized in the pyruvate precursors for hepatic gluconeogenesis rather than biosynthesis, polar, and side-chain structures. The decreases in the three amino acids were significantly emphasized after an additional week of taurine supplementation in the FFD muscles (p values in three amino acids in these tissues were less than 0.001-0.05), but not in the liver and plasma, accompanied with significantly increase of running time to exhaustion (p <0.05). In contrast, the three amino acids (threonine and serine; p < 0.05, glycine; p < 0.01) and alanine (p < 0.01) in the liver were significantly decreased and increased, respectively, following the exhaustive exercise. In conclusion, the taurine-induced reductions of these amino acids in skeletal muscle might be one of the mechanisms which underpin the enhancement of exercise performance by taurine. Key pointsTaurine ingestion significantly decreased certain amino acids in skeletal muscles accompanied with enhanced exercise performance.The decreased amino acids in common were threonine, serine, and glycine, but not alanine; pyruvate precursor for gluconeogenesis.The alteration of three amino acids in muscles was maintained after exhausted exercise.The muscular alterations of them might be one of taurine-induced roles on exercise performance. PMID- 24149877 TI - Effect of phlebodium decumanum on the immune response induced by training in sedentary university students. AB - Exercise training is considered a good model to provoke different degrees of immune dysfunction affecting physical performance and some physiological responses related to oxidative stress and low grade inflammation. Phlebodium decumanum is a polypodiaceae may induce shown immunomodulating effects, specifically directed to the release of proinflammatory cytokines by macrophages in response to various stimuli, as reported different in vitro studies. The aim of this study was to evaluate the modulating effect of phlebodium decumanum, on the immune response induced by physical exercise. Thirty-one subjects (males only) were randomly divided into two groups: Group PD (n = 18); age: 22.1 +/- 1.81, weight 74.21 +/- 8.74 kg) that was treated with phlebodium decumanum; Group P (n = 13); age: 22.5 +/- 1.63, weight 78 +/- 12.5 kg) that was treated with a placebo. Before and after one month training program performed by both groups (three times a week), the following performance parameters and immune response variables were measured: Dynamic Maximum Force; Interval-Training; Tennis test; pro-inflammatory (TNF , IL6) and anti-inflammatory (TNFalpha-IIrs, IL1-ra) cytokines levels. Data were statistically analyzed with Mann- Whitney U test and Wilcoxon paired test (p < 0.05). Statistically significant differences were recorded within groups before and after the training program. PD group showed a significant improvement in the performance parameters (Strength Muscle Test: dorsal: p < 0.002; deltoids: p < 0.03; and pectorals: p < 0.07; Interval Training: p < 0.06; Tennis Test: p < 0.02). Cytokine levels resulted in a more positive profile in the PD group rather than in the P group, in which higher levels of IL-6 (p < 0.02) and a reduction of TNF-IIrs (p < 0.003) and IL1-ra (p < 0.03) were recorded. In this study the use of phlebodium decumanum demonstrated beneficial effects in the modulation of the immune response during physical performance. Key pointsPracticing sport or physical activity of medium-high intensity three times a week during 4 weeks induces changes in immune response indicators levels;The assumption of phlebodium decumanum induced a reduction in pro-inflammatory cytokines levels and a higher concentration of anti-inflammatory cytokines.Anti-inflammatory cytokines have a protective and modulating effect on the immune response. PMID- 24149878 TI - Selective activation of the rectus abdominis muscle during low-intensity and fatiguing tasks. AB - In order to understand the potential selective activation of the rectus abdominis muscle, we conducted two experiments. In the first, subjects performed two controlled isometric exercises: the curl up (supine trunk raise) and the leg raise (supine bent leg raise) at low intensity (in which only a few motor units are recruited). In the second experiment, subjects performed the same exercises, but they were required to maintain a certain force level in order to induce fatigue. We recorded the electromyographic (EMG) activities of the lower and upper portions of the rectus abdominis muscle during the exercises and used spatial-temporal and frequency analyses to describe muscle activation patterns. At low-intensity contractions, the ratio between the EMG intensities of the upper and lower portions during the curl up exercise was significantly larger than during the leg raise exercise (p = 0.02). A cross-correlation analysis indicated that the signals of the abdominal portions were related to each other and this relation did not differ between the tasks (p = 0.12). In the fatiguing condition, fatigue for the upper portion was higher than for the lower portion during the curl up exercise (p = 0.008). We conclude that different exercises evoked, to a certain degree, individualized activation of each part of the rectus abdominis muscle, but different portions of the rectus abdominis muscle contributed to the same task, acting like a functional unit. These results corroborate the relevance of varying exercise to modify activation patterns of the rectus abdominis muscle. Key pointsSelective activation of the rectus abdominis muscle is possible because this muscle has different portions (which can have different motor fibers in series) which can be innervated by different nerves as well as by a common nerve branch.Changes in body position and exercise intensity cre-ate different demands for the different portions of the rectus abdominis muscle.Exercise variation seems to be valid to modify the activation patterns of the rectus abdominis muscle. PMID- 24149879 TI - Effects of whole-body vibration on resistance training for untrained adults. AB - Although resistance training (RT) combined with whole-body vibration (WBV) is becoming increasingly popular among untrained adults, the additional effects of WBV on muscle fitness are still not well understood. The aim of the present study was to evaluate the effects of WBV on muscle strength, muscle power, muscle endurance, and neuromuscular activities compared with the identical RT without WBV. Thirty-three individuals (6 males and 27 females; 22-49 years old) were randomly assigned to a training program using slow-velocity RT coupled with WBV (RT- WBV group, n = 17) or an identical exercise program without WBV (RT group, n = 16). Participants performed eight exercises per 60 min session on a vibration platform (RT-WBV group, frequency, 35 Hz; amplitude, 2 mm) twice weekly for seven weeks. To evaluate the effects of WBV, the maximal isometric and isokinetic knee extension strength, maximal isometric lumbar extension strength, countermovement jump, and the number of sit-ups were measured before and after the trial. Significantly higher increases were observed in the maximal isometric and concentric knee extension strength (p = 0.02, p = 0.04 , respectively), and maximal isometric lumbar extension strength at 60 degrees of trunk flexion (p = 0.02) in the RT-WBV group (+36.8%, +38.4%, +26.4%, respectively) in comparison to the RT group (+16.5%, +12.8%, +14.3%, respectively). A significant difference was also observed between the RT-WBV group (+8.4%) and the RT group (+4.7%) in the countermovement jump height (p = 0.02). In conclusion, the results suggest that significant additional increases in maximal isometric and concentric knee extension and lumbar extension strength, and countermovement jump height can be achieved by incorporating WBV into a slow-velocity RT program during the initial stage of regular RT in untrained healthy adults. Key pointsA randomized controlled trial was conducted to investigate the effects of slow velocity resistance training combined with whole-body vibration on maximal muscle strength, power, muscle endurance, and neuromuscular activities in healthy untrained individuals.Resistance training program for lower extremities and trunk muscles were performed twice weekly for 7 weeks.A 7 weeks slow velocity resistance training program with whole-body vibration significantly increased maximal isometric knee extension and lumbar extension strength and power in healthy untrained individuals. PMID- 24149880 TI - Legs and trunk muscle hypertrophy following walk training with restricted leg muscle blood flow. AB - We examined the effect of walk training combined with blood flow restriction (BFR) on the size of blood flow-restricted distal muscles, as well as, on the size of non-restricted muscles in the proximal limb and trunk. Nine men performed walk training with BFR and 8 men performed walk training alone. Training was conducted two times a day, 6 days/wk, for 3 wk using five sets of 2-min bouts (treadmill speed at 50 m/min), with a 1-min rest between bouts. After walk training with BFR, MRI-measured upper (3.8%, P < 0.05) and lower leg (3.2%, P < 0. 05) muscle volume increased significantly, whereas the muscle volume of the gluteus maximus (-0.6%) and iliopsoas (1.8%) and the muscle CSA of the lumber L4 L5 (-1.0) did not change. There was no significant change in muscle volume in the walk training alone. Our results suggest that the combination of leg muscle blood flow restriction with slow walk training elicits hypertrophy only in the distal blood flow restricted leg muscles. Exercise intensity may be too low during BFR walk training to increase muscle mass in the non- blood flow restricted muscles (gluteus maximus and other trunk muscles). Key pointsPrevious studies of blood flow restricted walk training have focused solely on thigh muscles distal to pressure cuffs placed on the upper most portion of the proximal thigh.In the current study, both proximal and distal muscles were evaluated following the combination of walk training with leg blood flow restriction (BFR). Muscle hypertrophy only occurred in the thigh and lower leg, which were the blood flow restricted muscles examined.No significant change was observed in the non restricted trunk muscles following 3 weeks of twice-daily BFR walk training. PMID- 24149881 TI - May I curse a referee? Swear words and consequences. AB - The purpose of this study was to determine whether male and female soccer (football) referees would execute the Laws of the Game despite players' verbal abuse. Law 12 (Fouls and misconduct) instructs the referees as to how they should react when a player, substitute or substituted player expresses a swear word. The player should be issued a red card. Referees (n = 113) were presented with 28 swear words and asked how they would respond if this situation occurred in a real game (red card, yellow/blue card [blue cards are used in juvenile games, player leaves field of game for 10 minutes], admonition, no reaction). The selected words were divided into categories (such as pertaining to intelligence or sexual abuse) indicating different degrees of insult. Approximately half of the referees would have responded to players saying swear words in a game by issuing a red card (55.7% red card, 25.2% yellow/blue card, 12.1% admonition, and 7.0% no reaction). The response was independent of the referees' qualification and experience. It was found that the insulting content of a swear word determines the referee's decision. Referees would apply Law 12 only in one half of the cases, depending on the insulting content. The findings are discussed in the context of game management. Key pointsLack of consistency in referees' response to a verbal offence.Referees' qualification as well as the duration of serving as a referee did not influence the effect.The insulting content is crucial for a red card. PMID- 24149882 TI - Assessing inter-effort recovery and change of direction ability with the 30-15 intermittent fitness test. AB - The aim of the present study was to propose a new and simple field assessment of inter-effort recovery and change of direction (COD) ability based on performance during the 30-15 Intermittent Fitness Test (30-15IFT, an intermittent, incremental shuttle-run test) using three different protocols. Forty team-sport players (22 +/- 2 years) performed either (group A; n = 16) the original 30-15IFT and two modified versions, one without a rest period (i.e. continuous run, 30 15IFT-CONT) and one without COD (30-15IFT-LINE), or (group B; n = 24) the original 30-15IFT and a modified version with more COD (28-m shuttle instead of 40-m, 30- 15IFT-28m). Heart rate (HR), blood lactate concentration ([La]b), rating of perceived exertion (RPE) and maximal running speed were recorded for all tests. There was no statistical difference in either maximal HR (A: p = 0.07 and B: p = 0.94) or RPE (A: p = 0.10 and B: p = 0.97) between tests. Compared with the 30-15IFT (12.3 +/- 2.5, p < 0.01) and 30-15IFT-LINE (11.3 +/- 2.6, p = 0.07, ES = 0.61), [La]b was lower for 30-15IFT-CONT (9.6 +/- 3.3 mmol.L(-1)). Compared with 30-15IFT, maximal running speed was higher for 30-15IFT-LINE (103.1 +/- 1.7%, p < 0.001) and lower for 30-15IFT-CONT (93.2 +/- 1.4%, p < 0.001), while it was similar for 30-15IFT-28m (99.7 +/- 3.6%, p = 0.62). Maximal speeds reached after the four tests were significantly but not perfectly correlated (r = 0.74 to 95, all p < 0.001). Present results show that differences in the maximal running speed reached following different versions of the 30-15IFT can be used by coaches to isolate and evaluate inter- effort recovery (i.e. 30-15IFT vs. 30 15IFT-CONT) and COD (i.e., 30-15IFT vs. 30-15IFT-LINE) abilities in the field. Additionally, COD ability as evaluated here appears to be independent of shuttle length. Key pointsThe comparison of the maximal running speed reached at the original 30-15IFT with these reached at two modified protocols (i.e., 30-15IFT CONT and 30-15IFT-LINE ) enables a simple and field-based assess-ment of between efforts recovery and COD abilities during high-intensity runs.These data can be used by coaches to complete the physical profiling of each player, which could high-light the need for specific training interventions. PMID- 24149883 TI - Spinal posture of thoracic and lumbar spine and pelvic tilt in highly trained cyclists. AB - The aim of this study was to evaluate sagittal thoracic and lumbar spinal curvatures and pelvic tilt in elite and master cyclists when standing on the floor, and sitting on a bicycle at three different handlebar-hand positions. A total of 60 elite male cyclists (mean age: 22.95 +/- 3.38 years) and 60 master male cyclists (mean age: 34.27 +/- 3.05 years) were evaluated. The Spinal Mouse system was used to measure sagittal thoracic and lumbar curvature in standing on the floor and sitting positions on the bicycle at three different handlebar-hand positions (high, medium, and low). The mean values for thoracic and lumbar curvatures and pelvic tilt in the standing position on the floor were 48.17 +/- 8.05 degrees , -27.32 +/- 7.23 degrees , and 13.65 +/- 5.54 degrees , respectively, for elite cyclists and 47.02 +/- 9.24 degrees , -25.30 +/- 6.29 degrees , and 11.25 +/- 5.17 degrees for master cyclists. A high frequency of thoracic hyperkyphosis in the standing position was observed (58.3% in elite cyclists and 53.3% in master cyclists), whereas predominately neutral values were found in the lumbar spine (88.3% and 76.7% in elite and master cyclists, respectively). When sitting on the bicycle, the thoracic curve was at a lower angle in the three handlebar-hand positions with respect to the standing position on the floor in both groups (p < 0.01). The lumbar curve adopted a kyphotic posture. In conclusion, cyclists present a high percentage of thoracic hyperkyphotic postures in standing positions on the floor. However, thoracic hyperkyphosis is not directly related to positions adopted on the bicycle. Key pointsThis study evaluated thoracic and lumbar spinal curvatures and pelvic tilt in elite and master cyclists while standing and sitting on the bicycle.Elite and master cyclists showed a high frequency of thoracic hyperkyphosis and neutral lumbar lordosis in standing.Cyclists adopted a significantly lower thoracic kyphosis on the bicycle at the three handlebar positions analysed (upper, middle and lower handlebars) than in standing posture. The lumbar spine showed a kyphotic posture.The high percentage of standing thoracic hyperkyphosis in both groups of cyclists may be related to factors other than the specific posture adopted while cycling. Lumbar kyphosis on the bicycle may not affect the sagittal configuration of the lumbar spine in standing. PMID- 24149884 TI - Energy expenditure and habitual physical activities in adolescent sprint athletes. AB - This study aimed to assess total energy expenditure (TEE) and specific habitual physical activities in adolescent sprint athletes. Two methods used to estimate TEE, an activity diary (AD) and SenseWear armband (SWA), were compared. Sixteen athletes (6 girls, 10 boys, mean age 16.5 +/- 1.6 yr) simultaneously wore a SWA and completed an AD and food diary during one week. Basal energy expenditure as given by the SWA when taken off was corrected for the appropriate MET value using the AD. TEE as estimated by the AD and SWA was comparable (3196 +/- 590 kcal and 3012 +/- 518 kcal, p = 0.113) without day-to-day variations in TEE and energy expended in activities of high intensity. Daily energy intake (2569 +/- 508 kcal) did not match TEE according to both the AD and SWA (respectively p < 0.001 and p = 0.007). Athletes were in a supine position for a longer time on weekend days than on week days and slept longer on Sundays. Athletes reported a longer time of high-intensive physical activities in the AD than registered by the SWA on 4 out of 7 days. In addition to specific sprint activities on 3 to 7 days per week, 11 out of 16 athletes actively commuted to school where they participated in sports once or twice per week. The AD and the SWA are comparable in the estimation of TEE, which appears realistic and sustainable. The SWA offers an appropriate and objective method in the assessment of TEE, sleeping and resting in adolescent athletes on the condition that detailed information is given for the times the armband is not worn. The AD offers activity specific information but relies on the motivation, compliance and subjectivity of the individual, especially considering high-intensive intermittent training. Key pointsThe activity diary and Sensewear armband provide comparable estimates of TEE in adolescent sprint athletes.A high inter-individual variation was observed in time spent in high intensity physical activities, advocating an individual based assessment when coaching athletes.The activity diary is useful when detailed information on specific physical activities is desired. The Sensewear armband offers objective information on sleeping, resting, and physical activity duration.Wearing the Sensewear combined with reporting on activities when the Sensewear is not worn and when doing specific activities of interest results in more complete information. PMID- 24149885 TI - Heart rate recovery after submaximal exercise in four different recovery protocols in male athletes and non-athletes. AB - The effects of different recovery protocols on heart rate recovery (HRR) trend through fitted heart rate (HR) decay curves were assessed. Twenty one trained male athletes and 19 sedentary male students performed a submaximal cycle exercise test on four occasions followed by 5 min: 1) inactive recovery in the upright seated position, 2) active (cycling) recovery in the upright seated position, 3) supine position, and 4) supine position with elevated legs. The HRR was assessed as the difference between the peak exercise HR and the HR recorded following 60 seconds of recovery (HRR60). Additionally the time constant decay was obtained by fitting the 5 minute post-exercise HRR into a first-order exponential curve. Within- subject differences of HRR60 for all recovery protocols in both groups were significant (p < 0. 001) except for the two supine positions (p > 0.05). Values of HRR60 were larger in the group of athletes for all conditions (p < 0.001). The time constant of HR decay showed within-subject differences for all recovery conditions in both groups (p < 0.01) except for the two supine positions (p > 0.05). Between group difference was found for active recovery in the seated position and the supine position with elevated legs (p < 0.05). We conclude that the supine position with or without elevated legs accelerated HRR compared with the two seated positions. Active recovery in the seated upright position was associated with slower HRR compared with inactive recovery in the same position. The HRR in athletes was accelerated in the supine position with elevated legs and with active recovery in the seated position compared with non-athletes. Key pointsIn order to return to a pre-exercise value following exercise, heart rate (HR) is mediated by changes in the autonomic nervous system but the underlying mechanisms governing these changes are not well understood.Even though HRR is slower with active recovery, lactate elimination after high intensity exercise might be more important for athletes than the de cline of heart rate.Lying supine during recovery after exercise may be an effective means of transiently restoring HR and vagal modulation and a safe position for prevention of syncope. PMID- 24149886 TI - Field-based pre-cooling for on-court tennis conditioning training in the heat. AB - The present study investigated the effects of pre-cooling for on- court, tennis specific conditioning training in the heat. Eight highly-trained tennis players performed two on-court conditioning sessions in 35 degrees C, 55% Relative Humidity. Sessions were randomised, involved either a pre-cooling or control session, and consisted of 30-min of court- based, tennis movement drills. Pre cooling involved 20-min of an ice-vest and cold towels to the head/neck and legs, followed by warm-up in a cold compression garment. On-court movement distance was recorded by 1Hz Global Positioning Satellite (GPS) devices, while core temperature, heart rate and perceptual exertion and thermal stress were also recorded throughout the session. Additionally, mass and lower-body peak power during repeated counter-movement jumps were measured before and after each session. No significant performance differences were evident between conditions, although a moderate-large effect (d = 0.7-1.0; p > 0.05) was evident for total (2989 +/- 256 v 2870 +/- 159m) and high-intensity (805 +/- 340 v 629 +/- 265m) distance covered following pre-cooling. Further, no significant differences were evident between conditions for rise in core temperature (1.9 +/- 0.4 v 2. 2 +/- 0.4 degrees C; d > 0.9; p > 0.05), although a significantly smaller change in mass (0.9 +/- 0.3 v 1. 3 +/- 0.3kg; p < 0.05) was present following pre-cooling. Perceived thermal stress and exertion were significantly lower (d > 1.0; p < 0.05) during the cooling session. Finally, lower-body peak power did not differ between conditions before or after training (d < 0.3; p > 0.05). CONCLUSIONS: Despite trends for lowered physiological load and increased distances covered following cooling, the observed responses were not significantly different or as explicit as previously reported laboratory-based pre-cooling research. Key pointsPre-cooling did not significantly enhance training performance or reduce physiological load for tennis training in the heat, although trends indicate some benefits for both.Pre-cooling can reduce perceptual strain of on-court tennis training in the heat to improve perceptual load of training sessions.Court-side pre-cooling may not be of sufficient volume to invoke large physiological changes. PMID- 24149887 TI - Gene response of the gastrocnemius and soleus muscles to an acute aerobic run in rats. AB - Genes can be activated or inhibited by signals within the tissues in response to an acute bout of exercise. It is unclear how a particular aerobic exercise bout may influence two muscles with similar actions to the activity. Therefore, the purposes of this investigation was to determine the gene response of selected genes involved in the "stress" response of the gastrocnemius (fast-twitch) and soleus (slow-twitch) muscles to a single two hour aerobic exercise bout in female Sprague-Dawley Rats at the 1 hour time point after the exercise. Exercised rats were run (n=8) for 2 hours at 20 m.min(-1) and one hour after the completion of the bout had their soleus (S) and gastrocnemius (G) muscles removed. Age and timed matched sedentary control rats had both S and G muscles removed also. RNA was isolated from all muscles. Real-time PCR analysis was performed on the following genes: NFkappaB, TNFalpha, and Atf3. GAPDH was used as the housekeeping gene for both muscles. S muscle showed more genes altered (n = 52) vs G (n = 26). NFkappaB gene expression was 0.83 +/- 0.14 in the exercised S but was + 1.36 +/- 0.58 in the exercised G and was not significantly different between the muscles. TNFalpha was altered 1.30 +/- 0. 34 in the exercised S and 1.36 +/- 0.71 in the exercised G and was not significantly different between the muscles. The gene Atf3 was significantly altered at 4.97 +/- 1.01 in the exercised S, while it was not significantly altered in the exercised G (0.70 +/- 0.55). This study demonstrates that an acute bout of aerobic exercise can alter gene expression to a different extent in both the S and G muscles. It is highly likely that muscle recruitment was a factor which influenced the gene expression in theses muscles. It is interesting to note that some genes were similarly activated in these two muscles but other genes may demonstrate a varied response to the same exercise bout depending on the type of muscle. Key pointsThe soleus (primarily slow twitch) and the gastrocnemius (primarily fast type) do not respond the same to a given exercise bout.There are gene transcription differences in stress genes between the 2 muscles.The results of exercise studies should be carefully viewed as the muscle used in measurements may not provide an adequate representation of all skeletal muscles. PMID- 24149888 TI - ACTN3 R577X Polymorphism and Neuromuscular Response to Resistance Training. AB - The R577X polymorphism at the ACTN3 gene has been associated with muscle strength, hypertrophy and athletic status. The X allele, which is associated with the absence of ACTN3 protein is supposed to impair performance of high force/velocity muscle contractions. The purpose of the present study was to investigate the association of the R577X polymorphism with the muscle response to resistance training in young men. One hundred forty one men performed two resistance training sessions per week for 11 weeks. Participants were tested for 1RM bench press, knee extensors peak torque, and knee extensors muscle thickness at baseline and after the training period. Genotyping was conducted using de DdeI restriction enzyme. Genotype distribution was 34.4% for RR, 47% for RX and 18.6% for the XX genotype. According to the results, the R577X polymorphism at the ACTN3 gene is not associated with baseline muscle strength or with the muscle strength response to resistance training. However, only carriers of the R allele showed increases in muscle thickness in response to training. Key pointsACTN3 Genotype distribution in the present study was similar to others populations (34.4% for RR, 47% for RX, and 18.6% for the XX).The R577X polymorphism at the ACTN3 gene is not associated with baseline muscle strength or with the muscle strength response to resistance training.It appears that the R allele carriers respond better to muscle thickness gains in response to training. PMID- 24149889 TI - Effects of music interventions on emotional States and running performance. AB - The present study compared the effects of two different music interventions on changes in emotional states before and during running, and also explored effects of music interventions upon performance outcome. Volunteer participants (n = 65) who regularly listened to music when running registered online to participate in a three-stage study. Participants attempted to attain a personally important running goal to establish baseline performance. Thereafter, participants were randomly assigned to either a self-selected music group or an Audiofuel music group. Audiofuel produce pieces of music designed to assist synchronous running. The self-selected music group followed guidelines for selecting motivating playlists. In both experimental groups, participants used the Brunel Music Rating Inventory-2 (BMRI-2) to facilitate selection of motivational music. Participants again completed the BMRI-2 post- intervention to assess the motivational qualities of Audiofuel music or the music they selected for use during the study. Results revealed no significant differences between self-selected music and Audiofuel music on all variables analyzed. Participants in both music groups reported increased pleasant emotions and decreased unpleasant emotions following intervention. Significant performance improvements were demonstrated post intervention with participants reporting a belief that emotional states related to performance. Further analysis indicated that enhanced performance was significantly greater among participants reporting music to be motivational as indicated by high scores on the BMRI-2. Findings suggest that both individual athletes and practitioners should consider using the BMRI-2 when selecting music for running. Key pointsListening to music with a high motivational quotient as indicated by scores on the BMRI-2 was associated with enhanced running performance and meta-emotional beliefs that emotions experienced during running helped performance.Beliefs on the effectiveness of music intended to alter emotions were associated with high scores on the BMRI-2.Runners seeking to use music as an emotion regulating strategy should consider using the BMRI-2 as an effective means by which to identify potentially motivating tracks. PMID- 24149891 TI - Boolean operations mediated by an ion-pair receptor of a multi-readout molecular logic gate. AB - A heteroditopic BODIPY dye that performs all basic Boolean operations with a cation (K(+)) and an anion (F(-)) as inputs and absorption, transmission and fluorescence as outputs is described. The molecular logic gate can also act as a digital comparator between the inputs. PMID- 24149890 TI - Short Durations of Static Stretching when Combined with Dynamic Stretching do not Impair Repeated Sprints and Agility. AB - This study aimed to compare the effect of different static stretching durations followed by dynamic stretching on repeated sprint ability (RSA) and change of direction (COD). Twenty-five participants performed the RSA and COD tests in a randomized order. After a 5 min aerobic warm up, participants performed one of the three static stretching protocols of 30 s, 60 s or 90 s total duration (3 stretches x 10 s, 20 s or 30 s). Three dynamic stretching exercises of 30 s duration were then performed (90 s total). Sit-and-reach flexibility tests were conducted before the aerobic warm up, after the combined static and dynamic stretching, and post- RSA/COD test. The duration of static stretching had a positive effect on flexibility with 36.3% and 85.6% greater sit-and-reach scores with the 60 s and 90 s static stretching conditions respectively than with the 30 s condition (p <= 0.001). However there were no significant differences in RSA and COD performance between the 3 stretching conditions. The lack of change in RSA and COD might be attributed to a counterbalancing of static and dynamic stretching effects. Furthermore, the short duration (<= 90 s) static stretching may not have provided sufficient stimulus to elicit performance impairments. Key pointsThe duration of combined static and dynamic stretching had a positive effect on flexibility with 36.3% and 85.6% greater sit and reach scores with the 60 s and 90 s static stretching conditions respectively than with the 30 s condition (p <= 0.001).No significant differences in RSA and COD between the 3 stretching conditions.The lack of change in RSA and COD might be attributed to a counterbalancing of static and dynamic stretching effects.The short duration (<= 90 s) static stretching may not have provided sufficient stimulus to elicit performance impairments. PMID- 24149892 TI - Status report: Middle East respiratory syndrome. PMID- 24149894 TI - A hybrid solar cell fabricated using amorphous silicon and a fullerene derivative. AB - Hybrid solar cells, based on organic and inorganic semiconductors, are a promising way to enhance the efficiency of solar cells because they make better use of the solar spectrum and are straightforward to fabricate. We report on a new hybrid solar cell comprised of hydrogenated amorphous silicon (a-Si:H), [6,6] phenyl-C71-butyric acid methyl ester ([71]PCBM), and poly-3,4 ethylenedioxythiophene poly styrenesulfonate (PEDOT:PSS). The properties of these PEDOT:PSS/a-Si:H/[71]PCBM devices were studied as a function of the thickness of the a-Si:H layer. It was observed that the open circuit voltage and the short circuit current density of the device depended on the thickness of the a-Si:H layer. Under simulated one sun AM 1.5 global illumination (100 mW cm(-2)), a power conversion efficiency of 2.84% was achieved in a device comprised of a 274 nm-thick layer of a-Si:H; this is the best performance achieved to date for a hybrid solar cell made of amorphous Si and organic materials. PMID- 24149893 TI - Mesenchymal stem cells enhance autophagy and increase beta-amyloid clearance in Alzheimer disease models. AB - Current evidence suggests a central role for autophagy in Alzheimer disease (AD), and dysfunction in the autophagic system may lead to amyloid-beta (Abeta) accumulation. Using in vitro and in vivo AD models, the present study investigated whether mesenchymal stem cells (MSCs) could enhance autophagy and thus exert a neuroprotective effect through modulation of Abeta clearance In Abeta-treated neuronal cells, MSCs increased cellular viability and enhanced LC3 II expression compared with cells treated with Abeta only. Immunofluorescence revealed that MSC coculture in Abeta-treated neuronal cells increased the number of LC3-II-positive autophagosomes that were colocalized with a lysosomal marker. Ultrastructural analysis revealed that most autophagic vacuoles (AVs) in Abeta treated cells were not fused with lysosomes, whereas a large portion of autophagosomes were conjoined with lysosomes in MSCs cocultured with Abeta treated neuronal cells. Furthermore, MSC coculture markedly increased Abeta immunoreactivity colocalized within lysosomes and decreased intracellular Abeta levels compared with Abeta-treated cells. In Abeta-treated animals, MSC administration significantly increased autophagosome induction, final maturation of late AVs, and fusion with lysosomes. Moreover, MSC administration significantly reduced the level of Abeta in the hippocampus, which was elevated in Abeta-treated mice, concomitant with increased survival of hippocampal neurons. Finally, MSC coculture upregulated BECN1/Beclin 1 expression in AD models. These results suggest that MSCs significantly enhance autolysosome formation and clearance of Abeta in AD models, which may lead to increased neuronal survival against Abeta toxicity. Modulation of the autophagy pathway to repair the damaged AD brain using MSCs would have a significant impact on future strategies for AD treatment. PMID- 24149895 TI - Evolution of the techniques used in studying associative olfactory learning and memory in adult Drosophila in vivo: a historical and technical perspective. AB - Drosophila melanogaster behavioral mutants have been isolated in which the ability to form associative olfactory memories has been disrupted primarily by altering cyclic adenosine monophosphate signal transduction. Unfortunately, the small size of the fruit fly and its neurons has made the application of neurobiological techniques typically used to investigate the physiology underlying these behaviors daunting. However, the realization that adult fruit flies could tolerate a window in the head capsule allowing access to the central structures thought to be involved plus the development of genetically expressed reporters of neuronal function has allowed a meteoric expansion of this field over the last decade. This review attempts to summarize the evolution of the techniques involved from the first use of a window to access these brain areas thought to be involved in associative olfactory learning and memory, the mushroom bodies and antennal lobes, to the current refinements which allow both high resolution multiphoton imaging and patch clamping of identified neurons while applying the stimuli used in the behavioral protocols. This area of research now appears poised to reveal some very exciting mechanisms underlying behavior. PMID- 24149898 TI - Suitability of FIFA's "The 11" Training Programme for Young Football Players - Impact on Physical Performance. AB - There is a paucity of evidence regarding the use of injury prevention programmes for preadolescents participating in sport. "The 11 "injury prevention programme was developed by FIFA's medical research centre (F-MARC) to help reduce the risk of injury in football players aged 14 years and over. The aim of this study was to determine the suitability and effectiveness of "The 11 "for younger football players. Twenty-four [12 experimental (EXP), 12 control (CON)] young football players (age 10.4 +/- 1.4 yr) participated. The EXP group followed "The 11 "training programme 5 days per week, for 6 weeks, completing all but one of the 10 exercises. Prior to, and after the intervention, both EXP and CON groups performed a battery of football-specific physical tests. Changes in performance scores within each group were compared using independent t-tests (p <= 0.05). Feedback was also gathered on the young players' perceptions of "The 11". No injuries occurred during the study in either group. Compliance to the intervention was 72%. Measures of leg power (3 step jump and counter-movement jump) increased significantly (3.4 and 6.0% respectively, p < 0.05). Speed over 20 m improved by 2% (p < 0.05). Most players considered "The 11 "beneficial but not enjoyable in the prescribed format. Given the observed improvements in the physical abilities and the perceived benefits of "The 11", it would appear that a modified version of the programme is appropriate and should be included in the training of young football players, for both physical development and potential injury prevention purposes, as well as to promote fair play. To further engage young football players in such a programme, some modification to "The 11 "should be considered. Key pointsChildren who participate in recreational and competitive sports, especially football, are susceptible to injury.There is a need for the design and assessment of injury prevention programmes for children.The 11 "improves essential physical performance characteristics and has the potential to reduce the risk of injury.It may be prudent to implement a 'child-friendly' version of "The 11", to enhance long-term programme adherence and to ensure progressive physical development of players. PMID- 24149897 TI - A review of stature, body mass and maximal oxygen uptake profiles of u17, u20 and first division players in brazilian soccer. AB - Investigations in the physiological demands of soccer have identified that a significant percentage of energy production in match performance is provided through the aerobic pathways. It is therefore important to assess maximal oxygen uptake (VO2Max) of players in order to evaluate their aerobic fitness status and optimize their physical conditioning. However, it is also important to consider the variation of (VO2Max) profiles for soccer players, with differences having been identified in terms of playing position as well as playing style. This paper reviews the academic literature between 1996 and 2006 and reports on the methodologies employed and the values obtained for stature, body mass and (VO2Max) profiles of soccer players of different positions in professional Brazilian clubs at U-17, U-20 and First Division levels. Indirect measurements accounted for the majority of tests conducted at U-17 (70%) and U-20 (84.6%) levels whereas at First Division level almost half of the (VO2Max) evaluations were performed by direct measurements (47.8%). The mean (VO2Max) profiles obtained for outfield players in U-17 was 56.95 +/- 3.60 ml.kg(-1).min(-1), 58.13 +/- 3.21 ml.kg(-1).min(-1) for U-20 players and 56.58 +/- 5.03 ml.kg(-1).min(-1) for First Division players. In Brazil, the U-20 players appear to have highest VO2Max values, however the profiles reported for all outfield positions in U-17 and First Division levels are often lower than those reported for the same category of players from other countries. This may be a reflection of the style of play used in Brazilian soccer. This is further emphasized by the fact that the playing position with the highest VO2Max values was the external defenders whereas most findings from studies performed in European soccer indicate that midfielders require the highest VO2Max values. Key pointsPhysical and physiological differences exist between Brazilian soccer and European soccer.Players in Brazil appear to be shorter in stature, similar in body mass and have a lower overall aerobic capacity to their European equivalentsIn Brazil, there seems to be a physical development phase for players at U-20 level which prepares them for the demands at First Division level. PMID- 24149899 TI - Energy expenditure and intensity of physical activity in soccer referees during match-play. AB - The aim of this study was to determine the caloric expenditure and the intensity of physical activities performed by official soccer referees during a match expressed in Metabolic Equivalent (METs). The physical activity of referees accredited by CBF (Brazilian Confederation of Soccer) was video-recorded during twenty-nine official games of Parana Championship (Brasil), Series A and B of the 2005/2006. Computerized video analysis was used to determine the time spent in 6 locomotor activities (standing still, walking, jogging, backwards running, running and sprint). The frequency and duration of each activity were recorded and these data were utilized to calculate the distance covered by the referee. Energy expenditure values were estimated, utilizing specific equations, from the time players spent in each motor activity. The referees observed in this study had a mean age of 38.9 +/- 3.8 years, body mass of 86.1 +/- 7.1 kg, stature of 1.80 +/- 0.07 m and a body mass index of 26.5 +/- 0.6 kg.m(-2). During match play, referees covered an average distance of 9155.4 +/- 70.3 meters (8411 - 9765), with a mean energy expenditure of 734.7 +/- 65 kcal. This energy expenditure was significantly reduced in the second half: 359.9 +/- 6.3 vs 374.7 +/- 6.6 kcal (p = 0.006), and averaged to be moderate energy intensity (5 METs) with predominant utilization of the aerobic energy system. In total, during 67% of match-play the intensity was equal or lower than 3.8 METs and in 33% it was higher than 9.8 METs. The pattern of movement observed in the present study confirms that soccer refereeing may be considered as a highly intermittent exercise mode. The high to low-intensity activity ratio may be defined as 1:7.1. In conclusion, referees officiating in professional soccer matches in Brazil should perform a physical conditioning regime that provides the stamina required at this level and consume appropriate and adequate nutrition to meet the energetic demands for match-play. Key pointsIn order to elaborate a diet that sufficiently restores the athlete's energy expenditure during training and/or competition, the first step would be to measure energy expenditure during activity.We observed that during officials matches soccer referees perform physical aerobic activities of low and moderate intensity, and present a significant decline in energy expenditure between the first and second half.The pattern of movement observed in the present report confirms that soccer referees, like players undertake intermittent type exercise.Nutritional habits of soccer referees must be adapted to their daily physical activities, short training periods and moderate energy intensity physical activity, on average, during match refereeing. PMID- 24149900 TI - Ventilation Behavior in Trained and Untrained Men During Incremental Test: Evidence of one Metabolic Transition Point. AB - This study aimed to describe and compare the ventilation behavior during an incremental test utilizing three mathematical models and to compare the feature of ventilation curve fitted by the best mathematical model between aerobically trained (TR) and untrained (UT) men. Thirty five subjects underwent a treadmill test with 1 km.h(-1) increases every minute until exhaustion. Ventilation averages of 20 seconds were plotted against time and fitted by: bi-segmental regression model (2SRM); three-segmental regression model (3SRM); and growth exponential model (GEM). Residual sum of squares (RSS) and mean square error (MSE) were calculated for each model. The correlations between peak VO2 (VO2PEAK), peak speed (SpeedPEAK), ventilatory threshold identified by the best model (VT2SRM) and the first derivative calculated for workloads below (moderate intensity) and above (heavy intensity) VT2SRM were calculated. The RSS and MSE for GEM were significantly higher (p < 0.01) than for 2SRM and 3SRM in pooled data and in UT, but no significant difference was observed among the mathematical models in TR. In the pooled data, the first derivative of moderate intensities showed significant negative correlations with VT2SRM (r = -0.58; p < 0.01) and SpeedPEAK (r = -0.46; p < 0.05) while the first derivative of heavy intensities showed significant negative correlation with VT2SRM (r = -0. 43; p < 0.05). In UT group the first derivative of moderate intensities showed significant negative correlations with VT2SRM (r = -0.65; p < 0.05) and SpeedPEAK (r = -0.61; p < 0.05), while the first derivative of heavy intensities showed significant negative correlation with VT2SRM (r= -0.73; p< 0.01), SpeedPEAK (r = -0.73; p < 0.01) and VO2PEAK (r = -0.61; p < 0.05) in TR group. The ventilation behavior during incremental treadmill test tends to show only one threshold. UT subjects showed a slower ventilation increase during moderate intensities while TR subjects showed a slower ventilation increase during heavy intensities. Key pointsThe increase of ventilation during incremental exercise tends to show only one metabolic transition point.The presence of a threshold process or a continuous process in ventilation during incremental exercise seems to be only a methodological matter.The ventilatory efficiency can be employed to distinguish trained than untrained subjects once this index is associated with aerobic parameters. When analyzed the whole curve, trained subjects show a better ventilatory efficiency at heavy intensities and untrained subjects show a better ventilatory efficiency at moderate intensities. PMID- 24149901 TI - Red blood cell and whole blood glutathione redox status in endurance-trained men following a ski marathon. AB - The aim of the present study was to evaluate the changes in glutathione redox ratio (GSSG.GSH(-1)) in red blood cells (RBCs) and whole blood in well-trained men following a ski marathon. 16 male subjects (27.0 +/- 4.7 yrs, 1.81 +/- 0.06 m, 77.6 +/- 9.6 kg, VO2max 66.2 +/- 5.7 ml.kg(-1).min(-1)) were examined before the competition (pre- COMP), after the competition (post-COMP) and during an 18 hour recovery period (RECOV). There was a slight decrease in reduced glutathione (GSH) in blood and in RBCs in post-COMP. During RECOV, the GSH level in blood was reduced, the GSH level in RBCs was significantly elevated (a statistically significant difference as compared to the pre-COMP level). The post-COMP GSSG.GSH(-1) in full blood did not increase significantly, but its increase was statistically significant during the 18-hour recovery period. During the post COMP and RECOV, the GSSG.GSH(-1) in RBCs slightly decreased in comparison with the pre-COMP. Vitamin C concentration in serum increased in post-COMP (49% vs. pre- COMP) and decreased to the baseline level during RECOV. In conclusion, our data show that acute exercise slightly increases the GSSG.GSH(-1) in whole blood, while GSSG.GSH(-1) in RBCs significantly decreases. Thus, exercise-related changes in the non-enzymatic components of the glutathione system (GSSG and GSH) in whole blood and RBCs are not identical. Key pointsThe glutathione system is a principal cellular non-enzymic antioxidant system in the organism. Long-term or high-intensity exercise may lead to a decreased level of reduced glutathione (GSH), and thereby increase the glutathione redox ratio (GSSG.GSH(-1)).Limited data are available about the glutathione redox (GSSG.GSH(-1)) status measured simultaneously in red blood cells (RBCs) and blood concerning acute high intensity exercise.Acute high-intensity exercise slightly increases the GSSG.GSH( 1) in whole blood, while GSSG.GSH(-1) significantly decreases in RBCs.Our descriptive data show that exercise-induced changes in the non-enzymatic glutathione system seem to be more effective in RBCs and may prevent the damages resulting from reactive oxygen species during exercise. PMID- 24149902 TI - Ankle taping does not impair performance in jump or balance tests. AB - This study aimed to investigate the influence of prophylactic ankle taping on two balance tests (static and dynamic balance) and one jump test, in the push off and the landing phase. Fifteen active young subjects (age: 21.0 +/- 4.4 years) without previous ankle injuries volunteered for the study. Each participant performed three tests in two different situations: with taping and without taping. The tests were a counter movement jump, static balance, and a dynamic posturography test. The tests and conditions were randomly performed. The path of the center of pressures was measured in the balance tests, and the vertical ground reaction forces were recorded during the push-off and landing phases of the counter movement jump. Ankle taping had no influence on balance performance or in the push off phase of the jump. However, the second peak vertical force value during the landing phase of the jump was 12% greater with ankle taping (0.66 BW, 95% CI -0.64 to 1.96). The use of prophylactic ankle taping had no influence on the balance or jump performance of healthy young subjects. In contrast, the taped ankle increased the second peak vertical force value, which could be related to a greater risk of injury produced by the accumulation of repeated impacts in sports where jumps are frequently performed. Key pointsAnkle taping has no influence on balance performance.Ankle taping does not impair performance during the push-off phase of the jump.Ankle taping could increase the risk of injury during landings by increasing peak forces. PMID- 24149903 TI - A Multi-Stage Ultra-Endurance Run over 1,200 KM Leads to a Continuous Accumulation of Total Body Water. AB - We determined whether ultra-runners in a multi-stage ultra- endurance run lose body mass, fat mass, skeletal muscle mass or total body water in a descriptive field study at the 'Deutschlandlauf' 2007 a 1,200 km run within 17 consecutive days with 10 male non-professional Caucasian ultra-runners (mean +/- SD, 43.8 +/- 6.2 years, 73.8 +/- 6.0 kg body mass, 1.77 +/- 0.05 m body height, BMI 23.3 +/- 1.8 kg.m(-2)). Body mass, fat mass, skeletal muscle mass, lean body mass and percent total body water were determined using bioelectrical impedance analysis and the anthropometric method before the race and after each stage. In addition, urinary specific gravity was measured in order to quantify hydration status. Fat mass (bioelectrical impedance analysis) decreased by 3.9 kg (p < 0.05), skeletal muscle mass (anthropometric method) decreased by 2.0 kg (p < 0.05) whereas percent total body water increased by 6.1 % (p < 0.05) by the end of the race. Ultra-runners in a multi-stage ultra-endurance event over 1,200 km, with 17 consecutive stages, showed a cumulative increase in percent total body water, a decrease in skeletal muscle mass and a decrease in fat mass, depending upon the method used. We presume that the eccentric component of running leads to damage of skeletal muscle, leading to rhabdomyolysis, with impaired renal function. Key pointsUltra-runners in a multi-stage ultra-endurance run over 1,200 km in 17 consecutive stages suffered a decrease in fat mass, skeletal muscle mass and an increase in total body water, whereas overall body mass showed no change. PMID- 24149904 TI - Capsaicin supplementation fails to modulate autonomic and cardiac electrophysiologic activity during exercise in the obese: with variants of UCP2 and UCP3 polymorphism. AB - We investigated the effects of capsaicin supplementation (150mg) on alterations of autonomic nervous system (ANS) activity associated with adverse effects of cardiac depolarization-repolarization intervals during aerobic exercise in obese humans. Nine obese males (26.1 +/- 1.5 yrs) volunteered between study designed. The cardiac ANS activities evaluated by means of heart rate variability of power spectral analysis and cardiac QT interval were continuously measured during 5-min rest and 30-min exercise at 50% of maximal ventilation threshold (50%VTmax) on stationary ergometer with placebo (CON) or capsaicin (CAP) oral administration chosen at random. The uncoupling protein (UCP) 2 and UCP 3 genetic variants of the subjects were analyzed by noninvasive genotyping method from collecting buccal mucosa cells. The results indicated that there were no significant differences in cardiac ANS activities during rest and exercise between CON and CAP trials. Although no significant difference, A/A allele of UCP2 polymorphism showed a reduced sympathetic nervous system (SNS) index activity compared to G/G + G/A allele during exercise intervention in our subjects. On the other hand, the data on cardiac QT interval showed no significant difference, indicating that oral administration of capsaicin did not cause any adverse effect on cardiac depolarization-repolarization. In conclusion, our results suggest that capsaicin supplementation 1 h before exercise intervention has no effect on cardiac ANS activities and cardiac electrical stability during exercise in obese individuals. Further studies should also consider genetic variants for exercise efficacy against obesity. Key pointsObese individuals possess reduced cardiac autonomic nervous activities, especially sympathetic nervous activity associated with thermogenesis induced by capsaicin.Lower sympathetic nervous activity may associate with -866 G/A variants of UCP2 polymorphism.Capsaicin ingestion, however, may consider as a safe nutrient-aid with no adverse effects of cardiac electrical stability. PMID- 24149905 TI - The effect of different corrective feedback methods on the outcome and self confidence of young athletes. AB - This experiment investigated the effects of three corrective feedback methods, using different combinations of correction, or error cues and positive feedback for learning two badminton skills with different difficulty (forehand clear - low difficulty, backhand clear - high difficulty). Outcome and self-confidence scores were used as dependent variables. The 48 participants were randomly assigned into four groups. Group A received correction cues and positive feedback. Group B received cues on errors of execution. Group C received positive feedback, correction cues and error cues. Group D was the control group. A pre, post and a retention test was conducted. A three way analysis of variance ANOVA (4 groups X 2 task difficulty X 3 measures) with repeated measures on the last factor revealed significant interactions for each depended variable. All the corrective feedback methods groups, increased their outcome scores over time for the easy skill, but only groups A and C for the difficult skill. Groups A and B had significantly better outcome scores than group C and the control group for the easy skill on the retention test. However, for the difficult skill, group C was better than groups A, B and D. The self confidence scores of groups A and C improved over time for the easy skill but not for group B and D. Again, for the difficult skill, only group C improved over time. Finally a regression analysis depicted that the improvement in performance predicted a proportion of the improvement in self confidence for both the easy and the difficult skill. It was concluded that when young athletes are taught skills of different difficulty, different type of instruction, might be more appropriate in order to improve outcome and self confidence. A more integrated approach on teaching will assist coaches or physical education teachers to be more efficient and effective. Key pointsThe type of the skill is a critical factor in determining the effectiveness of the feedback types.Different instructional methods of corrective feedback could have beneficial effects in the outcome and self-confidence of young athletesInstructions focusing on the correct cues or errors increase performance of easy skills.Positive feedback or correction cues increase self-confidence of easy skills but only the combination of error and correction cues increase self confidence and outcome scores of difficult skills. PMID- 24149906 TI - The kinetics and stiffness characteristics of the lower extremity in older adults during vertical jumping. AB - The purpose of this study was to examine the modulating effects of age on lower limb stiffness and net muscle joint activity degeneration when performing a functional activity involving SSC. Seven young males and seven older males were recruited as subjects for this study. A high-speed camera and a force plate were synchronized to collect the biomechanical parameters. The kinetic parameters were calculated with the inverse dynamics process. The stiffness of lower limbs was calculated with the spring-mass model. The Student's t-test was used to test the differences of two age groups. Statistical significance was set at alpha = 0.05. The present research showed that the older group produced a smaller peak net muscle joint moment at hip and knee. There were no differences in leg stiffness, hip stiffness, and ankle stiffness between the two age groups. Knee stiffness was smaller in the older group. In elderly adults, reduced muscle strength in the lower limbs, especially in the hip and knee, and reduced stiffness of the knee, influence the basic functions of human life and increase the risk of injury. Differences in lower extremity kinetics and stiffness in elderly adults during SSC movement may have implications for new preventive measures. Key pointsThe present research showed that the older group reduced muscle strength in the lower limbs, especially in the hip and knee, and reduced stiffness of the knee, influence the basic functions of human life and increase the risk of injury.There were no differences in leg stiffness, hip stiffness, and ankle stiffness between the two age groups.Older subjects maintain hip angular stiffness by decreasing joint angles in order to protect the joint and to increase stability during movement.In elderly adults, insufficient angular stiffness of the knee joint may increase the risk of knee injury during a functional activity involving SSC. PMID- 24149907 TI - The effects of cold whirlpool on power, speed, agility, and range of motion. AB - The purpose was to determine if cold whirlpool treatment decreases functional performance equally regardless of gender. A secondary aim was to determine if there is a gradual increase in functional performance across time. Twenty-one college-aged subjects volunteered to participate in this study and were required to perform four measures of functional performance including: counter movement vertical jump, T-test, 36.58-meter dash (40-yard), and active range of motion of the ankle. Participants were treated with a 20 minute, 10 degree Celsius cold whirlpool following the pre-test of a given functional performance measure. Participants demonstrated significant decreases in counter movement vertical jump, T-test, and 40-yard dash performance immediately following treatment. Vertical jump performance remained impaired for at least 32 minutes. While both the T-test and 40-yard dash were affected for 7 and 22 minutes post- treatment, respectively. Participants also demonstrated significant decreases in peak power and average power immediately after and for 32 minutes post-treatment. Dorsiflexion was significantly decreased 7 and 12 minutes following treatment. There were no differences for plantar flexion, inversion, or eversion. These data suggest functional performance was affected immediately following and for up to 32 minutes after cold whirlpool treatment. It was also evident that there is a gradual performance increase for each measure of functional performance across time. Therefore, the consequences should be carefully considered before returning athletes to activity following cold whirlpool treatment. Key pointsCryotherapy is a common and highly effective modality in treating acute and chronic athletic injuries.The results indicated that cold whirlpool does have an immediate and subsequent effect on functional performance.Understanding how cold whirlpool adversely affects functional performance allows clinicians to continue using this modality before vigorous athletic activity. PMID- 24149908 TI - The role of active muscle mass on exercise-induced cardiovascular drift. AB - The purpose of this study was to examine the role of active muscle mass on cardiovascular drift (CVdrift) during prolonged exercise. Twelve subjects with peak oxygen uptake (VO2peak) of 3.52 +/- 0.52 L.min(-1) (mean +/- SD) cycled for 55 min with 80 revolutions per minute with either two legs (2-legged) or one leg (1-legged). Oxygen uptake was at 60% of VO2peak throughout the 2-legged trial and at half of this value in 1- legged condition. Cardiac output (CO-CO2 rebreathing), heart rate (HR) and quadriceps integrated electromyographic activity (iEMG) were higher (p < 0.01) during 2-legged than 1- legged exercise. Changes in stroke volume from 20 to 50 min of exercise were greater in 2-legged than in 1-legged (?SV: -20.8 +/- 0.8 vs. -13.3 +/- 1.3 ml.beat(-1), p < 0.05). Similarly, changes in heart rate (?HR) were +18.5 +/- 0.8 and +10.7 +/- 1.0 beats.min(-1), in 2-legged and 1-legged, respectively (p < 0.01). Calculated blood volume changes declined significantly in 2-legged exercise (?BV: -4.25 +/- 0.43%, p < 0.05). Sympathetic activation as indicated by the ratio of low and high frequency in spectral analysis of HR (LF HF(-1) ratio) was higher in 2 legged than in 1- legged trial (p < 0.05). At the end of exercise, CO had a tendency to decrease from 20(th) min in 2-legged (changes in CO = -0.92 +/- 0.3 L.min(-1), p = 0.07), whereas it was maintained in 1- legged cycling (?CO = -0.15 +/- 0.2 L.min(-1), p = 0.86). Multiple regression analysis showed that HR rise and blood volume decline were predictors of SV drop whereas heart rate increase was explained by rectal temperature and magnitude of muscle mass activation, as indicated by iEMG (p < 0.05) in 2-legged cycling. In conclusion, apart from the well-known factors of thermal status and blood volume decline, it seems that muscle mass involved plays also a role on the development of CVdrift. Key pointsThe magnitude of the participated muscle mass plays a critical role for the development of cardiovascular drift, when the oxygen consumption per leg is the same.Apart from thermal status and blood volume decline, central command plays a role on cardiovascular regulation during steady state exercise performed with large muscle mass. PMID- 24149909 TI - Athlete's Retention of a Coach's Instruction Before a Judo Competition. AB - The aim of the present study was to analyze the instruction of the Judo coach immediately before the competition, in the process of preparation for the fights, looking to (1) study the coherency between the information which the coach transmits and that which the athlete retains; (2) identify the correlation between the coherency, the extension and the number of ideas conveyed by the coach; (3) determine if the retention varies in relation to variables such as the form and nature of the information, as well as the gender and practice category of the athletes. The participants were 11 coaches and 58 athletes of 3 categories: under- 15, under-17 and under-20, of both genders. One hundred and sixteen (116) instructional episodes were observed, which corresponds to four hundred and six (406) information units convoyed by the coaches. The coaches' instructions given before the competition were recorded in an audio and video register. After the coaches' instruction, the athletes were approached by the investigator and an interview was accomplished. To determine if the retention varies in relation to form and nature of the information and gender and practice category of the athletes, the non-parametric statistics, U de Mann-Whitney and Kruskal- Wallis, was used. Correlation of Spearman was applied to verify the degree of association between the coherency, the extension and the number of ideas conveyed by the coach. The results showed that a substantial part of the information was not retained by the athletes and the information coherency was inversely related to the number of transmitted ideas. The coaches were, mainly, prescriptive and the form of the information was not important for the retention of the information. Gender was a differentiated variable as the girls showed more coherency in the retained ideas in relation to the ideas transmitted by the coach. Key pointsThe instructions given by the coach are optimized if the athletes retain and understand them well and should be carefully analyzed by researchers and coaches.The ratio between the number of concordant ideas between coach and athlete (coherency) increased when the number of ideas decreased which raises the question of the adequacy of the instructional strategies used by coach.The prescriptive information showed that athletes were able to express a larger number of ideas in fewer words (larger density) while the combined information caused athletes to use more words to reproduce what the coach said.Gender was a differentiated variable as the girls showed more coherency in the retained ideas in relation to the ideas transmitted by the coach. These results indicate a possible tendency for girls to be more attentive when the coach is emitting information. However, to confirm this assumption more research is needed. PMID- 24149910 TI - Low handicap golfers generate more torque at the shoe-natural grass interface when using a driver. AB - The aim was to determine the rotational torque occurring at the shoe-natural grass interface during golf swing performance with different clubs, and to determine the influence of handicap and golf shoe design. Twenty-four golfers (8 low 0-7; 8 medium 8-14; and 8 high 15+) performed 5 shots with a driver, 3-iron and 7-iron when 3 shoes were worn: a modern 8 mm metal 7-spike shoe, an alternative 7-spike shoe and a flat soled shoe. Torque was measured at the front and back foot by grass covered force platforms in an outdoor field. Torque at the shoe- natural turf interface was similar at the front foot when using a driver, 3 iron and 7-iron with maximum mean torque (Tzmax 17-19 Nm) and torque generation in the entire backswing and downswing approximately 40 Nm. At the back foot, torque was less than at the front foot when using the driver, 3-iron and 7-iron. At the back foot Tzmax was 6-7 Nm, and torque generation was 10-16 Nm, with a trend for greater torque generation when using the driver rather than the irons. The metal spike shoe allowed significantly more back foot torque generation when using a driver than a flat- soled shoe (p < 0.05). There was no significant difference between the metal and alternative spike shoes for any torque measure (p > 0.05), although back foot mean torques generated tended to be greater for the metal spike shoe. The golf shot outcomes were similar for low, medium and high handicappers in both metal and alternative spike shoes (metal: 87%; 76%; 54%; alternative: 85%; 74%; 54% respectively). The better, low handicap golfers generated significantly more back foot torque (metal spike: 18.2 Nm; alternative: 15.8 Nm; p < 0.05) when using a driver. Further research should consider back foot shoe-grass interface demands during driver usage by low handicap and lighter body-weight golfers. Key pointsShoe to natural turf torque generation is an important component in performing a golf swing with a driver club.Torque at the shoe to natural turf interface was similar at the front foot when using a driver, 3-iron and 7-iron with Tzmax (17-19 Nm approx) and torque generation in the entire backswing and downswing of 40 Nm.Torque at the back foot was less than at the front foot when using the driver, 3-iron and 7-iron; Tzmax was 6-7 Nm, and torque generation 10-16 Nm with a trend to be greater when the driver was used.Low handicap golfers generated significantly more torque at the back foot than the medium or high handicappers (P<0.05) when using a driver.The metal spike shoe on natural turf allowed significantly more torque generation at the back foot than a flat-soled golf shoe when using a driver. Results have implications for golf shoe design. PMID- 24149911 TI - Recovery of bone mineral density and fertility in a former amenorrheic athlete. AB - Inadequate dietary intake and prolonged amenorrhea in women athletes can lead to bone loss, particularly at the spine, which may be irreversible. This report presents the case of a woman endurance runner, followed prospectively over 6 years after presenting with the female athlete triad. Bone mineral density (BMD) and body composition were assessed by dual-energy X-ray absorptiometry. At baseline, lumbar spine (LS), total hip and total body (TB) BMD Z-scores were 2.2, -0.5 and -0.3 respectively. At 6 years, following a recovery plan of cognitive behavioural therapy (CBT), weight gain, improved dietary intake and reduced training load, the athlete regained menstrual function and BMD. LS, TB and hip BMD Z-scores improved to -0.6, -0.1 and 0.1 respectively. Restoration of fertility was indicated by pregnancy, following only 4 months of regular menstruation. This case report suggests that bone density and fertility may not be completely jeopardised in formerly amenorrheic and osteopenic athletes, providing recovery through diet, weight gain, and return of menstruation is achieved within the third decade. Longitudinal studies tracking bone changes in women with amenorrhea and low BMD are required and would have important implications for the treatment of the female athlete triad. Key pointsPeak bone mass and fertility may not be completely jeopardised in women athletes providing recovery is attained in the third decade.Recovery from the Female Athlete Triad in this case involved weight gain, improved diet and a return of menstruation, and appeared to be encouraged by cognitive behavioural therapy (CBT).Further longitudinal studies are warranted to inform on prognosis and to aid in the identification of strategies for recovery from the Triad. PMID- 24149912 TI - Intracranial hemorrhage pattern in the patients with factor XIII deficiency. AB - Intracranial hemorrhage (ICH) is one of the most severe and life-threatening manifestations occurring in the patients with factor XIII (F XIII) deficiency. The aim of this study was to describe the ICH pattern in the patients suffering from F XIII deficiency. In this case series, we investigated 38 patients with severe F XIII deficiency in south of Iran from January to May 2012. ICH pattern, neurologic complications, efficacy of treatment, and incidence of recurrence were reported. The site of ICH was intraparenchymal in 35 patients (92.1 %), subdural in 2 patients (5.2 %), and epidural hemorrhage in 1 patient (2.6 %). Besides, neurologic complications occurred in 21 patients (55.2 %), including locomotor disability in 8, psychological impairment in 7, mental disorders in 5, speech impairment in 4, and visual impairment in 2. Prophylaxis was started with a dose of 10 IU/kg Fibrogammin every 4-6 weeks for all the patients, except for one. All the patients on prophylaxis showed good response without any episodes of recurrence, except for one. The most frequent site of ICH in our patients was intraparenchymal. It seems that long-term prophylactic treatment with a dose of 10 IU/kg Fibrogammin could be effective in the prevention of CNS bleeding in the patients with F XIII deficiency. Moreover, all the patients with severe F XIII deficiency even without severe bleeding symptoms are recommended to undergo prophylactic treatment. PMID- 24149913 TI - Primary myelofibrosis: when the clone manifests with Rh phenotype splitting. PMID- 24149914 TI - Efficacy of the hypomethylating agents as frontline, salvage, or consolidation therapy in adults with acute myeloid leukemia (AML). AB - The hypomethylating agents (HAs), azacitidine and decitabine, have emerged as an alternative to initial and salvage therapy in patients with acute myeloid leukemia (AML). Little is known about how AML responds to hypomethylating agents after standard therapy, and the activity of these agents in a real-world setting is not well studied. We retrospectively examined data for 75 consecutive AML patients at Wake Forest from 2002 to 2011 treated with HAs either as first-line (n = 34), salvage (n = 28), or consolidation (n = 13) therapy. We collected data on age, gender, race, Charlson comorbidity index (CCI), cytogenetics, type of treatment, complete remission (CR), complete remission with incomplete count recovery (CRi), and survival. Statistical analysis was performed using Kaplan Meier estimates and Cox proportional hazards models. Frontline response rate (CR + CRi) was 26.5 %, and median overall survival (OS) was 3.4 months (95 % CI 1.3 7.4), with 18 % alive at 1 year. In the salvage cohort, the response rate was significantly lower compared to frontline (3.6 versus 26.5 %, p = 0.017). Despite the reduced response, OS from time of HA treatment was longer than frontline at 8.2 months (CI 4.8-10.3). In the consolidation cohort, OS was 13.8 months (CI 8.0 21.6) with one patient in remission more than 30 months from diagnosis. These data suggest that prior cytotoxic therapy decreases marrow response rates to HAs but not survival. Furthermore, use of hypomethylating agents for consolidation resulted in a median overall survival over 1 year in a cohort of older patients. This suggests that hypomethylating agents have activity in all phases of AML treatment. PMID- 24149916 TI - An investigation of electron-phonon coupling via phonon dispersion measurements in graphite using angle-resolved photoelectron spectroscopy. AB - Electron-phonon coupling (EPC) plays an important role in solid state physics. Here, we demonstrate an experimental method that enables investigation of the elemental processes of the indirect transition, in which EPC participates in photoexcitation in solids, by resolving the energy and momentum of phonons and electrons simultaneously. For graphite, we used angle-resolved photoelectron spectroscopy to observe electron emission at the Gamma-point being scattered from the K-point by a phonon. Energy conservation during phonon emission implies that the step-like structure in the spectrum is near the Fermi level, and angle resolved measurements revealed phonon dispersions that contribute to EPC because of parallel momentum conservation. The observed phonon branch depends on the photon energy, i.e., the final photoexcitation state; this dependency is partly explained by the selection rule, which is determined by the electron state symmetry for the initial, intermediate, and final states and the phonon. PMID- 24149915 TI - Selection on haemagglutinin imposes a bottleneck during mammalian transmission of reassortant H5N1 influenza viruses. AB - The emergence of human-transmissible H5N1 avian influenza viruses poses a major pandemic threat. H5N1 viruses are thought to be highly genetically diverse both among and within hosts; however, the effects of this diversity on viral replication and transmission are poorly understood. Here we use deep sequencing to investigate the impact of within-host viral variation on adaptation and transmission of H5N1 viruses in ferrets. We show that, although within-host genetic diversity in haemagglutinin (HA) increases during replication in inoculated ferrets, HA diversity is dramatically reduced upon respiratory droplet transmission, in which infection is established by only 1-2 distinct HA segments from a diverse source virus population in transmitting animals. Moreover, minor HA variants present in as little as 5.9% of viruses within the source animal become dominant in ferrets infected via respiratory droplets. These findings demonstrate that selective pressures acting during influenza virus transmission among mammals impose a significant bottleneck. PMID- 24149917 TI - Rapid response of breast cancer to neoadjuvant intramammary testosterone anastrozole therapy: neoadjuvant hormone therapy in breast cancer. AB - OBJECTIVE: Experimental and clinical data support the inhibitory effect of testosterone on breast tissue and breast cancer. However, testosterone is aromatized to estradiol, which exerts the opposite effect. The aim of this study was to determine the effect of testosterone, combined with the aromatase inhibitor anastrozole, on a hormone receptor positive, infiltrating ductal carcinoma in the neoadjuvant setting. METHODS: To determine clinical response, we obtained serial ultrasonic measurements and mammograms before and after therapy. Three combination implants-each containing 60 mg of testosterone and 4 mg of anastrozole-were placed anterior, superior, and inferior to a 2.4-cm tumor in the left breast. Three additional testosterone-anastrozole implants were again placed peritumorally 48 days later. RESULTS: By day 46, there was a sevenfold reduction in tumor volume, as measured on ultrasound. By week 13, we documented a 12-fold reduction in tumor volume, demonstrating a rapid logarithmic response to intramammary testosterone-anastrozole implant therapy, equating to a daily response rate of 2.78% and a tumor half-life of 23 days. Therapeutic systemic levels of testosterone were achieved without elevation of estradiol, further demonstrating the efficacy of anastrozole combined with testosterone. CONCLUSIONS: This novel therapy, delivered in the neoadjuvant setting, has the potential to identify early responders and to evaluate the effectiveness of therapy in vivo. This may prove to be a new approach to both local and systemic therapies for breast cancer in subgroups of patients. In addition, it can be used to reduce tumor volume, allowing for less surgical intervention and better cosmetic oncoplastic results. PMID- 24149918 TI - Inverse correlation between the standard deviation of R-R intervals in supine position and the simplified menopausal index in women with climacteric symptoms. AB - OBJECTIVE: Disturbance of autonomic nervous activity has been thought to play a role in the climacteric symptoms of postmenopausal women. This study was therefore designed to investigate the relationship between autonomic nervous activity and climacteric symptoms in postmenopausal Japanese women. METHODS: The autonomic nervous activity of 40 Japanese women with climacteric symptoms and 40 Japanese women without climacteric symptoms was measured by power spectral analysis of heart rate variability using a standard hexagonal radar chart. The scores for climacteric symptoms were determined using the simplified menopausal index. RESULTS: Sympathetic excitability and irritability, as well as the standard deviation of mean R-R intervals in supine position, were significantly (P < 0.01, 0.05, and 0.001, respectively) decreased in women with climacteric symptoms. There was a negative correlation between the standard deviation of mean R-R intervals in supine position and the simplified menopausal index score. The lack of control for potential confounding variables was a limitation of this study. CONCLUSIONS: In climacteric women, the standard deviation of mean R-R intervals in supine position is negatively correlated with the simplified menopausal index score. PMID- 24149919 TI - Cognitive-behavior therapy for menopausal symptoms (hot flushes and night sweats): moderators and mediators of treatment effects. AB - OBJECTIVE: Cognitive-behavior therapy (CBT) has been found in recent randomized controlled trials (MENOS1 and MENOS2) to reduce the impact of hot flushes and night sweats (HFNS). In the MENOS2 trial, group CBT was found to be as effective as self-help CBT in reducing the impact of HFNS. This study investigates for whom and how CBT works for women in the MENOS2 trial. METHODS: This study performed a secondary analysis of 140 women with problematic HFNS who were recruited to the MENOS2 trial: 48 were randomly assigned to group CBT, 47 were randomly assigned to self-help CBT, and 45 were randomly assigned to usual care. Self-report questionnaires were completed at baseline, 6 weeks postrandomization, and 26 weeks postrandomization. Potential moderators and mediators of treatment effects on the primary outcome-hot flush problem rating-were examined using linear mixed effects models and path analysis, respectively. RESULTS: CBT was effective at reducing HFNS problem rating regardless of age, body mass index, menopause status, or psychological factors at baseline. Fully reading the manual in the self-help CBT arm and completing most homework assignments in the group CBT arm were related to greater improvement in problem rating at 6 weeks. The effect of CBT on HFNS problem rating was mediated by changes in cognitions (beliefs about coping/control of hot flushes, beliefs about night sweats and sleep) but not by changes in mood. CONCLUSIONS: These findings suggest that CBT is widely applicable for women having problematic HFNS, regardless of sociodemographic or health-related factors, and that CBT works mainly by changing the cognitive appraisal of HFNS. PMID- 24149921 TI - Effects of walking on the preservation of bone mineral density in perimenopausal and postmenopausal women: a systematic review and meta-analysis. AB - OBJECTIVE: This study aims to critically evaluate the effects of a walking intervention on bone mineral density (BMD) in perimenopausal and postmenopausal women and to identify the optimal duration of this walking exercise intervention. METHODS: Two independent reviewers assessed for eligibility randomized and nonrandomized controlled trials evaluating the effects of walking on BMD in perimenopausal and postmenopausal women. Heterogeneity, potential publication bias, and the quality of the included trials were assessed. RESULTS: Ten trials were eligible for inclusion. A meta-analysis of trials assessing lumbar spine BMD showed no significant effects (weighted mean difference [WMD] [fixed effects], 0.01 g/cm(2); 95% CI, -0.00 to 0.02; P = 0.05) regardless of the length of the intervention duration. BMD at the femoral neck increased after long intervention durations (6 mo to 1-2 y), although no significant effect could be seen when all trials assessing femoral neck BMD were taken into account (WMD [fixed effects], 0.01 g/cm(2); 95% CI, -0.00 to 0.01; P = 0.07). The effects of walking on the radius and whole body were not significant (WMD [random effects], -0.01 g/cm; 95% CI, -0.06 to 0.04; P = 0.71; and WMD [fixed effects], 0.04 g/cm(2); 95% CI, -0.00 to 0.08; P = 0.06, respectively). CONCLUSIONS: Walking as a singular exercise therapy has no significant effects on BMD at the lumbar spine, at the radius, or for the whole body in perimenopausal and postmenopausal women, although significant and positive effects on femoral neck BMD in this population are evident with interventions more than 6 months in duration. PMID- 24149920 TI - Does bone loss begin after weight loss ends? Results 2 years after weight loss or regain in postmenopausal women. AB - OBJECTIVE: Short-term weight loss is accompanied by bone loss in postmenopausal women. The longer-term impact of weight loss on bone in reduced overweight/obese women compared with women who regained their weight was examined in this study using a case-control design. METHODS: Postmenopausal women (N = 42; mean [SD] body mass index, 28.3 [2.8] kg/m; mean [SD] age, 60.7 [5.5] y) were recruited 2 years after the start of a 6-month weight loss trial; those who maintained their weight (weight loss maintainer [WL-M] group) were matched to a cohort of women who regained their weight (weight loss regainer [WL-R] group). Serum hormones and bone markers were measured in a subset. Bone mineral density (BMD) at the femoral neck, trochanter, spine, radius, and total body, and soft-tissue composition were taken at baseline, 0.5 years, and 2 years. RESULTS: During weight loss, both groups lost 9.3% (3.4%) of body weight, with no significant difference between the groups. After weight loss, weight change was -0.1% (2.7%) and 6.0% (3.3%) in the WL-M (n = 22) and WL-R (n = 20) groups, respectively. After 2 years, both groups lost BMD at the femoral neck and trochanter (P <= 0.01), whereas only the WL-M group reduced BMD at the 1/3 radius (P < 0.001). There was greater BMD loss at the trochanter (-6.8% [5.7%]) and 1/3 radius (-4.5% [3.3%]) in the WL-M group compared with the WL-R group after 2 years. Multiple linear regression showed that change in leg fat mass (but not trunk fat) contributed to trochanter BMD loss (P < 0.05). CONCLUSIONS: After 2 years, there is no BMD recovery of weight reduction-induced bone loss, irrespective of weight regain. These data suggest that the period after weight loss may be an important point in time to prevent bone loss for those who maintain weight and those who regain weight. PMID- 24149923 TI - Outcome and sexual function after transobturator tape procedure versus tension free vaginal tape SECUR: a randomized controlled trial. AB - OBJECTIVE: This study aims to compare efficacy, safety, and sexual function between inside-out transobturator tape (TVT-O) and tension-free vaginal tape SECUR (TVT-S) procedures for stress urinary incontinence (SUI) treatment. METHODS: Ninety-four women without concomitant pelvic organ prolapse repairs were randomly allocated to undergo TVT-O or TVT-S procedure. Demographic data, intraoperative and postoperative complications, and surgical outcomes were analyzed. Patients completed the Chinese version of the Incontinence Impact Questionnaire Short Form and the Pelvic Organ Prolapse/Urinary Incontinence Sexual Function Questionnaire Short Form (PISQ-12) before surgical operation and on follow-up after surgical operation. RESULTS: There were no significant differences in cure rates between the two groups at 12 and 24 months of follow up. Hematomas occurred in two patients in the TVT-O group. Urinary retention and de novo urinary urgency were similar in both groups. Operative time was significantly shorter for patients in the TVT-S group (P < 0.05), and postoperative groin/thigh pain was higher (P < 0.05) in the TVT-O group. In both groups, Incontinence Impact Questionnaire Short Form scores improved significantly after surgical operation (P < 0.001). Compared with a mean (SD) score of 33.9 (4.5) postoperatively (12 mo), the total PISQ-12 score before surgical operation was 30.9 (6.5), representing a significant difference (P = 0.021) in the TVT-S group. There was no significant difference in PISQ-12 scores before and after the TVT-O procedure. CONCLUSIONS: The two techniques seem to be equally effective for SUI treatment. However, TVT-O results in a higher rate of groin/thigh pain and longer operative time. TVT-S can improve quality of life and sexual function in women with SUI. PMID- 24149922 TI - Is there evidence that estrogen therapy promotes weight maintenance via effects on leptin? AB - OBJECTIVE: Leptin, a hormone secreted by adipocytes, plays a crucial role in regulating energy balance. Estrogen, like leptin, reduces food intake and adiposity while increasing energy expenditure in animals and humans of both sexes through its actions on the central nervous system. We reviewed the literature for studies of the effects of exogenously administered estrogen on serum leptin concentrations and adiposity in women. METHODS: Using PubMed/Medline, we searched for studies of hormone therapy that enrolled healthy postmenopausal women. Studies were further evaluated to determine if leptin and adiposity were monitored both at baseline and throughout a treatment period of at least 2 months. RESULTS: Twenty articles met inclusion criteria. We found no consistent effects of exogenous estrogen on serum leptin concentrations, adiposity, or weight gain. CONCLUSIONS: Despite suggestive data from animal studies, the current literature does not provide compelling evidence that estrogen therapy attenuates weight gain, alters circulating leptin levels, or improves leptin action in postmenopausal women. PMID- 24149924 TI - Menopause after a history of intrahepatic cholestasis of pregnancy. AB - OBJECTIVE: Intrahepatic cholestasis of pregnancy is a hormone-provoked disorder that fades quickly after parturition. The aim of this study was to establish whether a history of intrahepatic cholestasis of pregnancy reduces the use of hormone therapy for menopausal symptoms and, irrespective of hormone therapy, whether intrahepatic cholestasis is associated with other health aspects after menopause. METHODS: In 2010, questionnaires were sent to a cohort of women who delivered in Tampere University Hospital, Finland, from 1969 to 1988. The study population comprised postmenopausal women with a history of intrahepatic cholestasis of pregnancy (n = 189) and their controls (n = 416). The main outcome measures were the use of hormone therapy and other means of alleviating menopausal symptoms, and the diseases the women reported. RESULTS: There were no differences in the use of hormone therapy between the two groups. Of the diseases reported, breast cancer, hepatobiliary diseases, and hypothyroidism were more frequent among women with a history of intrahepatic cholestasis of pregnancy, whereas cardiac arrhythmia was less frequent. With respect to other diseases, there were no differences. CONCLUSIONS: A history of intrahepatic cholestasis of pregnancy does not reduce the use of hormone therapy. However, when physicians prescribe hormone therapy for these women, a history of intrahepatic cholestasis of pregnancy calls for attention in view of its association with gallstones. PMID- 24149925 TI - Randomized controlled trial of whole soy and isoflavone daidzein on menopausal symptoms in equol-producing Chinese postmenopausal women. AB - OBJECTIVE: Dietary supplements containing soy or isoflavones are widely used as alternatives to hormone therapy. However, their efficacy is still inconclusive, and limited data on equol producers are available. The aim of this study was to examine the effect of whole soy (soy flour) or purified daidzein (one major soy isoflavone and the precursor of equol) on menopausal symptoms in equol-producing postmenopausal women, a population most likely to benefit from soy intervention. METHODS: This is a 6-month parallel-group, double-blind, randomized, placebo controlled trial. Two hundred seventy equol-producing prehypertensive Chinese postmenopausal women were randomized to one of three treatment groups: 40 g of soy flour (whole soy group), 40 g of low-fat milk powder + 63 mg of daidzein (daidzein group), or 40 g of low-fat milk powder (placebo group) daily, each given as a solid beverage for 6 months. Changes in menopausal symptoms were assessed by a validated and structured symptom checklist at baseline and 6 months. RESULTS: Two hundred fifty-three participants completed the study according to protocol. Urinary isoflavones indicated good compliance with the interventions. Baseline menopausal symptoms were comparable among the three study groups. Intention-to-treat analysis indicated that there was no significant difference in the 6-month changes or percent changes in the total number of menopausal symptoms, in the five dimensions of symptoms, and in the frequencies of individual symptoms among the three treatment groups. CONCLUSIONS: Whole soy and purified daidzein have no significant effect on alleviation of menopausal symptoms among equol-producing postmenopausal women with prehypertension. PMID- 24149926 TI - Oxidative stress contributes to large elastic arterial stiffening across the stages of the menopausal transition. AB - OBJECTIVE: It is unclear how changes in ovarian hormones during the menopausal transition contribute to age-associated arterial stiffening. We sought to evaluate differences in arterial stiffness and the role of oxidative stress across the stages of the menopausal transition in healthy women. METHODS: Arterial stiffness (carotid artery compliance and ultrasound) was measured during immediate infusions of saline (control) and ascorbic acid (experimental model to immediately decrease oxidative stress) in 97 healthy women (22-70 y) classified as premenopausal (n = 24; mean [SD] age, 33 [7] y), early perimenopausal (n = 21; 49 [3] y) or late perimenopausal (n = 21; 50 [4] y), or postmenopausal (n = 31; 57 [5] y). RESULTS: Basal carotid artery compliance was different among the groups (P < 0.001). Mean [SD] compliance was highest in premenopausal women (1.31 [0.25] mm/mm Hg * 10), with progressive decrements in perimenopausal (early perimenopausal, 0.98 [0.31] mm/mm Hg * 10; late perimenopausal, 0.90 [0.25] mm/mm Hg * 10) and postmenopausal (0.75 [0.24] mm/mm Hg * 10) women. Ascorbic acid infusion improved compliance in late perimenopausal (15% [18%] increase, P = 0.001) and postmenopausal (17% [26%] increase, P = 0.002) women but not in early perimenopausal or premenopausal women. CONCLUSIONS: Arterial stiffening worsens across the stages of the menopausal transition in healthy women. This seems to be mediated, in part, by oxidative stress, particularly during the late perimenopausal and postmenopausal periods. It remains uncertain whether this is specifically caused by loss of ovarian function or aging. PMID- 24149927 TI - Lifetime endogenous reproductive factors and severe depressive symptoms in postmenopausal women: findings from the E3N cohort. AB - OBJECTIVE: This study aims to identify reproductive factors associated with severe depressive symptoms (SDS) in postmenopausal women and to determine whether a past psychological disorder (PPD) and the timing of first-onset PPD in relation to menopause modify associations. METHODS: Lifetime reproductive characteristics and PPD were obtained from 51,088 postmenopausal women of the E3N cohort study. The Center for Epidemiologic Studies--Depression Scale (CES-D) was used to assess SDS. Multivariate logistic regression models were performed to estimate the risk of SDS overall and according to the presence and timing of first-onset PPD (before the final menstrual period, in early postmenopause, or in late postmenopause). RESULTS: Women with irregular cycles were at increased risk for SDS (odds ratio [OR], 1.35; 95% CI, 1.19-1.53), except when PPD occurred in early postmenopause (OR, 1.08; 95% CI, 0.74-1.57). Parity was inversely associated with the risk of SDS (P < 0.001), whereas decreasing age at first full-term pregnancy increased the risk of SDS with PPD (P < 0.001) and increasing age at last full term pregnancy increased the risk of SDS without PPD (P = 0.012). Age at final menstrual period (per 2-y increment) was associated with a decreased risk of SDS with postmenopausal (especially late postmenopausal) PPD (OR, 0.82; 95% CI, 0.80 0.85) but with an increased risk of SDS when PPD occurred before the final menstrual period (OR, 1.15; 95% CI, 1.12-1.19). Artificial menopause increased the risk of SDS with PPD before the final menstrual period (OR, 1.40; 95% CI, 1.18-1.66), whereas menopausal symptoms were associated with SDS across all categories. CONCLUSIONS: Associations between endogenous reproductive factors and SDS may vary according to the presence of PPD and the timing of first-onset PPD. Further studies are warranted. PMID- 24149928 TI - Menopause across cultures: clinical considerations. AB - Although many clinicians are aware of cross-cultural variation in the frequency of hot flash reports at midlife, they may underestimate the extent to which the meaning of menopause, as well as attitudes toward treatment, varies across populations. Likewise, variations in symptom frequency may influence help-seeking behavior. This Practice Pearl offers guidance regarding the issues pertinent to the midlife care of patients from diverse cultures and ethnicities. PMID- 24149929 TI - Unfinished business! PMID- 24149930 TI - Phase 3 randomized controlled study of gastroretentive gabapentin for the treatment of moderate-to-severe hot flashes in menopause. AB - OBJECTIVE: The goal of this study was to evaluate the efficacy and safety of gastroretentive gabapentin (G-GR) for the treatment of moderate-to-severe menopausal hot flashes. METHODS: The primary endpoints of this randomized, placebo-controlled study of G-GR (600 mg am/1,200 mg pm) were the mean daily frequency and severity of hot flashes at weeks 4 and 12. Secondary endpoints included Patients' Global Impression of Change, Clinicians' Global Impression of Change, and daily sleep interference at week 24. RESULTS: Six hundred women with 7 or more moderate-to-severe hot flashes/day enrolled; 66.2% completed 24 weeks of treatment. At weeks 4 and 12, G-GR-treated women experienced significantly greater reductions in mean hot flash frequency and severity than placebo-treated women (frequency: week 4, -1.7, P < 0.0001; week 12, -1.14, P = 0.0007; severity: week 4, -0.21, P < 0.0001; week 12, -0.19, P = 0.012). Similar reductions were maintained up to week 24. On the Patient Global Impression of Change, more women receiving G-GR than placebo were "much" or "very much" improved (week 12: 58% vs 44%, P = 0.0008; week 24: 76% vs 55%, P < 0.0001). G-GR significantly reduced sleep interference compared with placebo at week 12 (P = 0.0056) and week 24 (P = 0.0084). Approximately 5% more women taking G-GR withdrew because of adverse events (G-GR/placebo, 16.7%/11.5%). The most common adverse events were dizziness (12.7%/3.4%), headache (9.3%/8.1%), and somnolence (6.0%/2.7%); incidences dropped to sustained low levels after a few weeks. CONCLUSIONS: G-GR is a modestly effective nonhormone therapy option for the treatment of moderate-to severe hot flashes due to menopause and is well tolerated with titration. PMID- 24149932 TI - Elevated CNS inflammation in patients with preclinical Alzheimer's disease. AB - Alzheimer's disease (AD) is a progressive, neurodegenerative disease that may involve inflammatory responses in the central nervous system (CNS). Our objective was to determine whether patients with amnestic mild cognitive impairment (aMCI), a preclinical stage of AD, have inflammatory characteristics similar to patients with multiple sclerosis (MS), a known CNS inflammatory disease. The frequency of lymphocytes and levels of pro-inflammatory cytokines in the cerebrospinal fluid of aMCI patients was comparable to MS patients or patients at high risk to develop MS. Thus, brain inflammation occurs early at the preclinical stage of AD and may have an important role in pathology. PMID- 24149931 TI - The oxygen paradox of neurovascular coupling. AB - The coupling of cerebral blood flow (CBF) to neuronal activity is well preserved during evolution. Upon changes in the neuronal activity, an incompletely understood coupling mechanism regulates diameter changes of supplying blood vessels, which adjust CBF within seconds. The physiologic brain tissue oxygen content would sustain unimpeded brain function for only 1 second if continuous oxygen supply would suddenly stop. This suggests that the CBF response has evolved to balance oxygen supply and demand. Surprisingly, CBF increases surpass the accompanying increases of cerebral metabolic rate of oxygen (CMRO2). However, a disproportionate CBF increase may be required to increase the concentration gradient from capillary to tissue that drives oxygen delivery. However, the brain tissue oxygen content is not zero, and tissue pO2 decreases could serve to increase oxygen delivery without a CBF increase. Experimental evidence suggests that CMRO2 can increase with constant CBF within limits and decreases of baseline CBF were observed with constant CMRO2. This conflicting evidence may be viewed as an oxygen paradox of neurovascular coupling. As a possible solution for this paradox, we hypothesize that the CBF response has evolved to safeguard brain function in situations of moderate pathophysiological interference with oxygen supply. PMID- 24149933 TI - Blood glutamate scavenging as a novel neuroprotective treatment for paraoxon intoxication. AB - Organophosphate-induced brain damage is an irreversible neuronal injury, likely because there is no pharmacological treatment to prevent or block secondary damage processes. The presence of free glutamate (Glu) in the brain has a substantial role in the propagation and maintenance of organophosphate-induced seizures, thus contributing to the secondary brain damage. This report describes for the first time the ability of blood glutamate scavengers (BGS) oxaloacetic acid in combination with glutamate oxaloacetate transaminase to reduce the neuronal damage in an animal model of paraoxon (PO) intoxication. Our method causes a rapid decrease of blood Glu levels and creates a gradient that leads to the efflux of the excess brain Glu into the blood, thus reducing neurotoxicity. We demonstrated that BGS treatment significantly prevented the peripheral benzodiazepine receptor (PBR) density elevation, after PO exposure. Furthermore, we showed that BGS was able to rescue neurons in the piriform cortex of the treated rats. In conclusion, these results suggest that treatment with BGS has a neuroprotective effect in the PO intoxication. This is the first time that this approach is used in PO intoxication and it may be of high clinical significance for the future treatment of the secondary neurologic damage post organophosphates exposure. PMID- 24149936 TI - A floating macro/mesoporous crystalline anatase TiO2 ceramic with enhanced photocatalytic performance for recalcitrant wastewater degradation. AB - A macro/mesoporous anatase TiO2 ceramic floating photocatalyst has been successfully synthesized using highly thermally stable mesoporous TiO2 powder as a precursor, followed by a camphene-based freeze-casting process and high temperature calcinations. The ceramics are characterized in detail by X-ray diffraction, Raman spectra, scanning electron microscopy, transmission electron microscopy and N2 adsorption-desorption isotherms. The results indicate that the TiO2 ceramics present hierarchical macro/mesoporous structures, which maintain high porosity and high compressive strength at the optimal sintering temperature of 800 degrees C. The ordered mesoporous TiO2 network still possesses high thermal stability and inhibits the anatase-to-rutile phase transformation during calcinations. The obtained ceramics exhibit good adsorptive and photocatalytic activity for the degradation of octane and rhodamine B, and the total organic carbon removal ratio is up to 98.8% and 98.6% after photodegradation for 3 h, respectively. The roles of active species in the photocatalytic process are compared using different types of active species scavengers, and the degradation mechanism is also proposed. Furthermore, the ceramics are recyclable, and no clear changes are observed after ten cycles. In addition, the ceramics are also active in the photodegradation of phenol, thiobencarb, and atrazine. Therefore, these novel floating photocatalysts will have wide applications, including the removal of floating organic pollutants from the wastewater surfaces or the removal of soluble organic pollutants from wastewater. PMID- 24149934 TI - Effects of negative air ions on oxygen uptake kinetics, recovery and performance in exercise: a randomized, double-blinded study. AB - Limited research has suggested that acute exposure to negatively charged ions may enhance cardio-respiratory function, aerobic metabolism and recovery following exercise. To test the physiological effects of negatively charged air ions, 14 trained males (age: 32 +/- 7 years; VO2max: 57 +/- 7 mL min(-1) kg(-1)) were exposed for 20 min to either a high-concentration of air ions (ION: 220 +/- 30 * 10(3) ions cm(-3)) or normal room conditions (PLA: 0.1 +/- 0.06 * 10(3) ions cm( 3)) in an ionization chamber in a double-blinded, randomized order, prior to performing: (1) a bout of severe-intensity cycling exercise for determining the time constant of the phase II VO2 response (tau) and the magnitude of the VO2 slow component (SC); and (2) a 30-s Wingate test that was preceded by three 30-s Wingate tests to measure plasma [adrenaline] (ADR), [nor-adrenaline] (N-ADR) and blood [lactate] (B(Lac)) over 20 min during recovery in the ionization chamber. There was no difference between ION and PLA for the phase II VO2 tau (32 +/- 14 s vs. 32 +/- 14 s; P = 0.7) or VO2 SC (404 +/- 214 mL vs 482 +/- 217 mL; P = 0.17). No differences between ION and PLA were observed at any time-point for ADR, N-ADR and B(Lac) as well as on peak and mean power output during the Wingate tests (all P > 0.05). A high-concentration of negatively charged air ions had no effect on aerobic metabolism during severe-intensity exercise or on performance or the recovery of the adrenergic and metabolic responses after repeated-sprint exercise in trained athletes. PMID- 24149937 TI - Insulated skin temperature as a measure of core body temperature for individuals wearing CBRN protective clothing. AB - This study assessed the validity of insulated skin temperature (Tis) to predict rectal temperature (Tre) for use as a non-invasive measurement of thermal strain to reduce the risk of heat illness for emergency service personnel. Volunteers from the Police, Fire and Rescue, and Ambulance Services performed role-related tasks in hot (30 degrees C) and neutral (18 degrees C) conditions, wearing service specific personal protective equipment. Insulated skin temperature and micro climate temperature (Tmc) predicted Tre with an adjusted r(2) = 0.87 and standard error of the estimate (SEE) of 0.19 degrees C. A bootstrap validation of the equation resulted in an adjusted r(2) = 0.85 and SEE = 0.20 degrees C. Taking into account the 0.20 degrees C error, the prediction of Tre resulted in a sensitivity and specificity of 100% and 91%, respectively. Insulated skin temperature and Tmc can be used in a model to predict Tre in emergency service personnel wearing CBRN protective clothing with an SEE of 0.2 degrees C. However, the model is only valid for Tis over 36.5 degrees C, above which thermal stability is reached between the core and the skin. PMID- 24149938 TI - Solvatochromism of pyranine-derived photoacids. AB - Photoacidity is frequently found in aromatic alcohols where the equilibrium dissociation constant increases by some orders of magnitude upon electronic excitation. In this study we investigated the solvatochromism of a family of recently synthesized super-photoacids and their methylated counterparts based on pyrene. The chemical similarity of these molecules on the one hand and their differing photoacidity with pKa* values between -0.8 and -3.9 on the other allow for gaining insights into the mechanisms contributing to excited-state proton transfer. Three different solvent scales, namely Lippert-Mataga, Kamlet-Taft and Catalan, were independently employed in this study and gave consistent results. We found the strongest correlation of the excited-state acidity with the dipolarity of the excited state, pem ranging from -1775 cm(-1) to -2500 cm(-1), and a concomitant change in the permanent dipole moment of roughly 14 Debye. Spectral changes due to varying basicity of the solvent, which probes the conjugated property of the solute, are found to be less indicative of the graduation of excited-state acidity, i.e. bem values between -700 and -1200 cm( 1). The solvent acidity is the only parameter with a distinct influence on the electronic spectra of the deprotonated species. The low values of aem ~ 400 cm( 1), which are 3-4* smaller than aabs and aexc, indicate the low basicity of these species in the excited state. Triggered by semiempirical theoretical calculations, the energetic splitting between the two lowest excited states could be related to the excited-state acidity and points to alterations in the electronic mixing of locally excited and charge-transfer states, caused by the substituents. Differences between the threefold negatively charged pyranine and the new neutral photoacids are also discussed. PMID- 24149940 TI - Cyclist drag in team pursuit: influence of cyclist sequence, stature, and arm spacing. AB - In team pursuit, the drag of a group of cyclists riding in a pace line is dependent on several factors, such as anthropometric characteristics (stature) and position of each cyclist as well as the sequence in which they ride. To increase insight in drag reduction mechanisms, the aerodynamic drag of four cyclists riding in a pace line was investigated, using four different cyclists, and for four different sequences. In addition, each sequence was evaluated for two arm spacings. Instead of conventional field or wind tunnel experiments, a validated numerical approach (computational fluid dynamics) was used to evaluate cyclist drag, where the bicycles were not included in the model. The cyclist drag was clearly dependent on his position in the pace line, where second and subsequent positions experienced a drag reduction up to 40%, compared to an individual cyclist. Individual differences in stature and position on the bicycle led to an intercyclist variation of this drag reduction at a specific position in the sequence, but also to a variation of the total drag of the group for different sequences. A larger drag area for the group was found when riding with wider arm spacing. Such numerical studies on cyclists in a pace line are useful for determining the optimal cyclist sequence for team pursuit. PMID- 24149941 TI - Reading Performance of Young Adults With ADHD Diagnosed in Childhood. AB - OBJECTIVE: To study reading performance of young adults with ADHD and its relation with executive functioning. METHOD: Thirty young adults with a childhood diagnosis of ADHD and 30 with normal development (ND) were compared on reading accuracy, fluency, and comprehension. Furthermore, ADHD with reading disabilities (ADHD+RD) and ADHD without reading disabilities (ADHD-RD) subgroups were compared using self-report and informant-report versions of the Behavior Rating Inventory of Executive Function-Adult version (BRIEF-A). RESULTS: Adults with ADHD obtained significantly worse results than the ND adults on reading speed, responses to literal questions, and a cloze test. Although the comparison of the ADHD+RD and ADHD-RD groups did not show significant differences on the BRIEF-A subscales, the ADHD+RD group surpassed the critical percentile (85) on more subscales, with working memory and metacognition especially affected. CONCLUSION: The findings point out that reading should be assessed in individuals with ADHD as part of their evaluation to design effective early interventions. PMID- 24149939 TI - Multiple cytoskeletal pathways and PI3K signaling mediate CDC-42-induced neuronal protrusion in C. elegans. AB - Rho GTPases are key regulators of cellular protrusion and are involved in many developmental events including axon guidance during nervous system development. Rho GTPase pathways display functional redundancy in developmental events, including axon guidance. Therefore, their roles can often be masked when using simple loss-of-function genetic approaches. As a complement to loss-of-function genetics, we constructed a constitutively activated CDC-42(G12V) expressed in C. elegans neurons. CDC-42(G12V) drove the formation of ectopic lamellipodial and filopodial protrusions in the PDE neurons, which resembled protrusions normally found on migrating growth cones of axons. We then used a candidate gene approach to identify molecules that mediate CDC-42(G12V)-induced ectopic protrusions by determining if loss of function of the genes could suppress CDC-42(G12V). Using this approach, we identified 3 cytoskeletal pathways previously implicated in axon guidance, the Arp2/3 complex, UNC-115/abLIM, and UNC-43/Ena. We also identified the Nck-interacting kinase MIG-15/NIK and p21-activated kinases (PAKs), also implicated in axon guidance. Finally, PI3K signaling was required, specifically the Rictor/mTORC2 branch but not the mTORC1 branch that has been implicated in other aspects of PI3K signaling including stress and aging. Our results indicate that multiple pathways can mediate CDC-42-induced neuronal protrusions that might be relevant to growth cone protrusions during axon pathfinding. Each of these pathways involves Rac GTPases, which might serve to integrate the pathways and coordinate the multiple CDC-42 pathways. These pathways might be relevant to developmental events such as axon pathfinding as well as disease states such as metastatic melanoma. PMID- 24149942 TI - Empirically Determined, Psychopathological Subtypes in Children With ADHD. AB - OBJECTIVE: The aim of this study was to empirically determine subgroups of ADHD defined by specific patterns of psychopathology. METHOD: A clinical sample of 223 children with ADHD, aged 5 to 14 years, was examined with the Child Behavior Checklist (CBCL). In addition, comorbid psychiatric disorders, psychosocial risk factors, and socioeconomic status were assessed. RESULTS: Cluster analysis of CBCL subscales yielded a solution with four distinct subgroups. While "externalizers" showed a high rate of comorbid oppositional defiant disorder (ODD) and conduct disorder (CD), "obsessive-compulsives" exhibited thought problems, low rates of comorbid CD, and high symptoms of inattention. "High psychiatric symptom carriers" had high rates of familial risk factors, acute life events, comorbid ODD, and CD. "Low psychiatric symptom carriers" also scored low in all other variables studied. CONCLUSION: Children with ADHD can be divided into four subgroups according to their CBCL-based psychopathology, and these subgroups differ in their risk factor profiles. PMID- 24149943 TI - Evaluation of the QTc prolongation potential of a monoclonal antibody, siltuximab, in patients with monoclonal gammopathy of undetermined significance, smoldering multiple myeloma, or low-volume multiple myeloma. AB - PURPOSE: A phase 1 study evaluated the QTc prolongation potential of siltuximab, a chimeric, anti-interleukin-6 mAb, in patients with monoclonal gammopathy of undetermined significance (MGUS), smoldering multiple myeloma (SMM), or low volume MM. METHODS: Patients with baseline QTcF and QTcB <= 500 ms, QRS < 100 ms, PR < 200 ms and no significant cardiac disease received siltuximab 15 mg/kg q3w, the highest dosage used in clinical studies, for 4 cycles. Twelve-lead ECGs obtained at multiple time points pre- and post-infusion at cycles 1 and 4 were evaluated by central cardiology laboratory. No effect on QTc interval was concluded if the upper limit of least square (LS) mean 90 % CI for QTc change from baseline at each time point was <20 ms. RESULTS: An effect on QTc prolongation was ruled out, as the upper bound of 90 % CI was <10 ms at each time point in 27 evaluable patients (13 MGUS, 13 SMM, 1 low-volume MM) with no differences between disease types. Maximum mean QTc increase from baseline occurred 3 h after cycle 1 infusion (QTcF = 3.2 [LS mean 90 % CI -0.01, 6.45] ms; QTcB = 2.7 [-0.69, 6.14] ms). At all other time points, mean QTcF and QTcB increase from baseline was <=1.5 ms and upper bound 90 % CI was <=5.1 ms. Twenty patients had mostly low-grade AEs, including nausea, fatigue (20 % each); thrombocytopenia, headache (each 13 %); dyspnea, leukopenia, neutropenia, paresthesia, abnormal hepatic function, URTI (each 10 %). Three MGUS patients achieved 50 % M-protein reduction. There was no association between siltuximab pharmacokinetics and QTc interval. CONCLUSIONS: Siltuximab did not affect the QTc interval. Overall safety was similar to other single-agent siltuximab studies. PMID- 24149944 TI - Midazolam as a phenotyping probe to predict sunitinib exposure in patients with cancer. AB - PURPOSE: Patients treated with sunitinib show substantial inter-patient variability in drug exposure (~30-40 %), which is largely unexplained. Since sunitinib is metabolized by cytochrome P450(CYP)3A4, variability in the activity of this enzyme may explain a considerable proportion of this inter-patient variability. Midazolam is widely used as a phenotyping probe to assess CYP3A4 activity. The objective of this study was to prospectively evaluate the relationship between midazolam and sunitinib exposure. Additionally, the correlation between sunitinib trough levels and exposure and the influence of sunitinib on midazolam exposure was determined. METHODS: Thirteen patients treated with sunitinib in a 4 weeks "on"-2 weeks "off" regimen received twice 7.5 mg midazolam; once with and once without sunitinib. Steady-state sunitinib, its active metabolite SU12662 and midazolam exposures were determined. RESULTS: A significant correlation between midazolam exposure (AUC(0-7h)) and steady-state sunitinib and sunitinib + SU12662 exposure (AUC(0-24h)) was found (p = 0.006 and p = 0.0018, respectively); midazolam exposure explained 51 and 41 % of the inter patient variability in sunitinib and sunitinib + SU12622 exposure. Furthermore, C trough was highly correlated (r(2) = 0.94) with sunitinib AUC(0-24h). Sunitinib decreased midazolam exposure with 24 % (p = 0.034). CONCLUSION: Midazolam exposure is highly correlated with sunitinib exposure and explains a large proportion of the observed inter-patient variability in sunitinib pharmacokinetics. Consequently, midazolam could be used to identify patients that are at risk of under- or overtreatment, respectively, at the start of sunitinib therapy. Moreover, sunitinib and sunitinib + SU12662 trough levels are highly correlated with drug exposure and can thus be used in clinical practice to individualize sunitinib therapy. The decrease in midazolam exposure by sunitinib needs further investigation. PMID- 24149946 TI - Training-level induced changes in blood parameters response to on-water rowing races. AB - The study investigated blood markers allowing discriminating physiological responses to on-water rowing races, notably regarding training volume of athletes and race duration. College (COL) and national (NAT) rowers performed a 1000- or 2000-m race. Capillary blood samples obtained before and post-race allowed an analysis of a wide range of serum parameters. COL rowers had a lower rowing experience and training volume than NAT. Races induced a higher lactate concentration increase in NAT compared to COL (10.45 +/- 0.45 vs 13.05 +/- 0.60; p 1/4 0.001). Race distance (2000 vs. 1000 m) induced a higher increase in fatty acids (0.81 +/- 0.31 vs +0.67 +/- 0. 41; p 1/4 0.05) and triglycerides concentration in NAT (0.33 +/- 0.07 vs 0.15 +/- 0.09; p 1/4 0.01), but remained comparable between NAT and COL for the 1000-m races. Amino acids concentrations increased in NAT (0.19 +/- 0.03, p 1/4 0.01), but urea concentration increased only for NAT rowers having performed the 2000-m race (0.72 +/- 0.22, p 1/4 0.05). Transferrin concentration decreased after the 2000-m race (-0.60 +/- 0.25, p 1/4 0.05), and concentration changes of haptoglobin differed between NAT2000 (tendency to be reduced) and COL (tendency to by enhanced) (p 1/4 0.05). Our results confirmed that the training level in rowing is associated with higher glycolysis utilization during maximal 1000- and 2000-m exercise and no difference for similarly trained subjects at these two distances. Our study also demonstrated that a 2000-m race could initiate fatty and amino-acid metabolisms in highly trained subjects. Therefore, these changes in blood parameter responses to a characteristic rowing exercise highlighted the importance of monitoring the physiological effects of training in sporting conditions and according to individual characteristics. Key pointsRowing races despite their short duration could initiate fatty and amino-acids metabolisms.Effects of maximal exercise on metabolic blood parameters depend on individual capabilities, suggesting that the effects of exercise or training on a given blood parameter may be monitored relatively to individual maximal concentrations rather than by inter-individual comparison.High training level may lead to marked disruption of homeostasis which could be easily reversed by high recovery capabilities. PMID- 24149947 TI - Relationships between muscle fatigue characteristics and markers of endurance performance. AB - The aim of this study was to examine the relationship of a range of in-vivo whole muscle characteristics to determinants of endurance performance. Eleven healthy males completed a cycle ergometer step test to exhaustion for the determination of the lactate threshold, gross mechanical efficiency, peak power and VO2max. On two separate occasions, contractile and fatigue characteristics of the quadriceps femoris were collected using a specially designed isometric strength-testing chair. Muscle fatigue was then assessed by stimulating the muscle for 3 minutes. Force, rate of force development and rates of relaxation were calculated at the beginning and end of the 3 minute protocol and examined for reliability and in relation to lactate threshold, VO2max, gross mechanical efficiency and peak power. Muscle characteristics, rate of force development and relaxation rate were demonstrated to be reliable measures. Force drop off over the 3 minutes (fatigue index) was related to lactate threshold (r = -0.72 p 1/4 0.01) but not to VO2max. The rate of force development related to the peak power at the end of the cycle ergometer test (r = -0.75 p 1/4 0.01). Rates of relaxation did not relate to any of the performance markers. We found in-vivo whole muscle characteristics, such as the fatigue index and rate of force development, relate to specific markers of peripheral, but not to central, fitness components. Our investigation suggests that muscle characteristics assessed in this way is reliable and could be feasibly utilised to further our understanding of the peripheral factors underpinning performance. Key pointsParticipants with a high lactate threshold displayed greater fatigue resistance in the electrical stimulation test.Muscle performance characteristics relate to specific components of endurance performance.The electrical stimulation protocol could be a useful technique, alongside other established measures, when constructing a physiological profile of a participant. PMID- 24149948 TI - Impact of diet, exercise end diet combined with exercise programs on plasma lipoprotein and adiponectin levels in obese girls. AB - We studied the effect of three programs, diet restriction (D), individualized exercise training (E) at the maximal lipid oxidation point (LIPOXmax) and diet combined with exercise (D+E), on body mass, plasma lipoprotein and adiponectin levels in obese girls. Eighteen obese adolescents girls aged 12-14 years were studied. A longitudinal intervention was carried out, consisting of a two-month diet (D; -500 kcal.day-1), of individualized exercise (E; 4 days/week, 90 min.day 1) and of diet combined with exercise (D+E). Body mass, body mass index (BMI), body fat mass, waist circumference, substrate crossover point, LIPOXmax point, homeostasis model assessment (HOMA-IR) index, fasting levels of lipids and circulatory adiponectin, were measured in all subjects before and after the program. In subjects of the D+E group, body mass, BMI, body fat mass, waist circumference, HOMA-IR, low-density lipoprotein cholesterol (LDL-C) and total cholesterol / high-density lipoprotein cholesterol (TC/HDL-C) ratio were significantly lower, and HDL-C and adiponectin were higher after the program than that of subjects in the D or E groups. Diet/exercise improved the ability to oxidize lipids during exercise (crossover point: + 18.5 +/- 3.4 of % Wmax; p < 0.01 and fat oxidation rate at LIPOXmax: + 89.7 +/- 19.7 mg.min(-1); p < 0.01). In the D+E group, significant correlations were found between changes in body mass and adiponectin and between changes in the TC/HDL-C ratio and LIPOXmax. These findings show that the combined program of diet restriction and individualized exercise training at the LIPOXmax point is necessary to simultaneously improve body mass loss, adiponectin levels, as well as metabolic parameters, in obese girls. Key pointsDiet combined with exercise training improved body composition, adiponectin levels and metabolic parameters in obese girls.Diet only decreases body mass and LDL-C without improving fat oxidation and HDL- C.Individualized exercise training at LIPOXmax point improved the HDL-C and the circulatory adiponectin levels with any change of LDL-C and body composition. PMID- 24149949 TI - Psychophysiological responses in the pre-competition period in elite soccer players. AB - This study investigated pre-competition physiological and psychological states of eighteen elite soccer players. Salivary cortisol was assessed during a non- training day and before three league games. Affective states (unpleasant and pleasant, somatic and transactional emotions) were evaluated using the Tension and Effort-Stress Inventory before the three league games. Participants formed 2 groups, 11 starters and 7 non-starters, depending on the starting list established by the coach. All players reported more intense pleasant transactional and somatic emotions than unpleasant ones prior to all games (p < 0.05), and relatively stable profiles of these psychological responses were observed across the three league games. However, salivary cortisol levels increased during pre-game for all players in comparison with the non- training day (p < 0.001). This anticipatory rise was only related to unpleasant somatic emotions (p < 0.001). This demonstrates that cortisol can be used as an index of emotional response to competition. Key pointsElite athletes perceive the participation to competition as a challenging situation as they experience more pleasant emotions than unpleasant ones in the pre-competition period. This profile is relatively stable across three league games, which is possibly due to the athletes' experience at this level.Participation to competition lead to anticipatory acute response of cortisol in the pre-competition period, which potentially prepares the athlete to perform.These responses are not related to status player (e.g., starter versus non-starter)Physiological stress (e.g. anticipatory rise in cortisol concentrations) is related to negative somatic emotions.Cortisol may constitute a measure of emotional response in pre competition period. PMID- 24149950 TI - Discrepancy between training, competition and laboratory measures of maximum heart rate in NCAA division 2 distance runners. AB - A percentage of either measured or predicted maximum heart rate is commonly used to prescribe and measure exercise intensity. However, maximum heart rate in athletes may be greater during competition or training than during laboratory exercise testing. Thus, the aim of the present investigation was to determine if endurance-trained runners train and compete at or above laboratory measures of 'maximum' heart rate. Maximum heart rates were measured utilising a treadmill graded exercise test (GXT) in a laboratory setting using 10 female and 10 male National Collegiate Athletic Association (NCAA) division 2 cross-country and distance event track athletes. Maximum training and competition heart rates were measured during a high-intensity interval training day (TR HR) and during competition (COMP HR) at an NCAA meet. TR HR (207 +/- 5.0 b.min(-1); means +/- SEM) and COMP HR (206 +/- 4 b.min(-1)) were significantly (p < 0.05) higher than maximum heart rates obtained during the GXT (194 +/- 2 b.min(-1)). The heart rate at the ventilatory threshold measured in the laboratory occurred at 83.3 +/- 2.5% of the heart rate at VO2 max with no differences between the men and women. However, the heart rate at the ventilatory threshold measured in the laboratory was only 77% of the maximal COMP HR or TR HR. In order to optimize training induced adaptation, training intensity for NCAA division 2 distance event runners should not be based on laboratory assessment of maximum heart rate, but instead on maximum heart rate obtained either during training or during competition. Key pointsA percentage of maximum heart rate is commonly used to prescribe and measure exercise intensity. However, maximum heart rate may be greater during competition or training than during laboratory exercise testing.Heart rates during training and competition were significantly higher than maximum heart rates obtained during laboratory exercise testing.To optimize training-induced adaptation, training intensity for NCAA division 2 distance event runners should not be based on laboratory assessment of maximum heart rate, but instead on maximum heart rate measure obtained either during training or during competition. PMID- 24149951 TI - Validity of critical frequency test for measuring table tennis aerobic endurance through specific protocol. AB - The aim of this study was to validate critical frequency specific test (critf) for the estimation of the aerobic endurance in table tennis players. METHODS: Eight male international-level table tennis players participated of this study. Specific tests were applied by using a mechanical ball thrower to control the intensity of the exercise. The critf was determined by applying three or four series of exercises to exhaustion (Tlim). The critf was evaluated by using lactate steady state test (90, 100, and 106 % of critf intensity). The other specific test was an incremental protocol used to determine the anaerobic threshold (AnTBI) and the onset of blood lactate accumulation (OBLA) using a ball thrower. RESULTS: The critf (39.87 +/- 3.31 balls.min(-1)) was not significantly different among AnTBI (48.11 +/- 7.36 balls.min(- 1)) and OBLA3.5 (49.36 +/- 12.04 balls.min(-1)) frequencies and it was correlated with AnTBI parameter (r = 0.78). At frequencies of the 90 and 100% of critf a dynamic equilibrium was verified in lactate concentration between the eighth and twentieth minutes. However, this dynamic equilibrium was not found at 106% intensity. CONCLUSION: The data indicate that in table tennis the critf model can be used for measuring the aerobic endurance. Key pointsIn table tennis is need the use of a specific protocol for evaluation of the aerobic endurance.The critical frequency test in table tennis seems to represent the intensity of maximal equilibrium of lactatemia.The critical frequency test can be used for measuring table tennis aerobic endurance through specific protocol. PMID- 24149952 TI - Muscle activation during low-intensity muscle contractions with varying levels of external limb compression. AB - The purpose was to investigate muscle activation during low- intensity muscle contractions with various levels of external limb compression to reduce muscle perfusion/outflow. A series of unilateral elbow flexion muscle contractions (30 repetitive contractions followed by 3 sets x 15 contractions) was performed at 20% of 1RM with varying levels of external compression (0 (without compression), 98, 121, and 147 mmHg external compression) around the upper arm. Electromyography (EMG) signals were recorded from surface electrodes placed on the biceps brachii muscle and analyzed for integrated EMG (iEMG). Maximal voluntary isometric contraction (MVC) decreased similarly during the control (0 mmHg) and 98 mmHg external compression bout (~18%); the decline in MVC with 121 and 147 mmHg external compression was significantly greater (~37%). Muscle activation increased progressively throughout the contraction bout with each level of external compression, but iEMG was significantly greater during 147 mmHg external compression. In conclusion, low-intensity muscle contractions performed with external compression of 147 mmHg appears to alter muscle perfusion/outflow leading to increased muscle activation without decrements in work performed during the contraction bout. Key pointsLow-intensity muscle contractions with external compression are maintained by greater neural activation.It appears there is optimal external compression pressure for increased muscle activation without exaggerated fatigue.External compression per arm circumference was related to the neuromuscular response and fatigue. PMID- 24149953 TI - Effects of the menstrual cycle on expiratory resistance during whole body exercise in females. AB - Our objective was to determine if the menstrual cycle affected expiratory resistance developed during progressive incremental exercise in females. Eleven females (age = 19.7 +/- 1.1 yr., body mass = 58.9 +/- 8.8 Kg, height = 1.65 +/- 0.3 m) gave consent to participate in the study. Participants were studied during the follicular (day 7 +/- 2 days following onset of menses) and luteal (day 21 +/ 2 days following onset of menses) phases of their menstrual cycle. The expiratory resistance was significantly higher during the follicular phase at maximal workload versus the luteal phase (1.0 +/- 0.06 cm H2O/L/sec vs. 0.9 +/- 0.07 cm H2O/L/sec.: p1/4 0.05). No other differences were found in expiratory resistance, oxygen uptake or maximal heart rate during exercise. Results showed that the increase in expiratory resistance during the follicular phase of the menstrual cycle may be contributing to the changes in the pulmonary system of females as reported by other authors. Key pointsDuring maximal exercise there was a significantly larger expiratory resistance during the follicular phase versus luteal phase of the female subjects menstrual cycle.Fluctuation in hormones (especially progesterone and/ or oestrogen) may contribute to changes in expiratory resistance.The increased expiratory resistance may be a contributing factor to the increased occurrence of expiratory flow limitation in female subjects. PMID- 24149954 TI - Position-specific deficit of joint position sense in ankles with chronic functional instability. AB - The present study was aimed to test a hypothesis that individuals with functional ankle instability (FAI) underestimate the joint angle at greater plantarflexion and inversion. Seventeen males with unilateral FAI and 17 controls (males without FAI) consented for participation in this IRB-approved, case-control study. Using a passive reproduction test, we assessed ankle joint position sense (JPS) for test positions between 30 and -10 degrees plantarflexion with an inclement of 10 degrees with or without 20 degrees inversion at each plantarflexion angle. The constant error (CE) was defined as the value obtained by subtracting the true angle of a test position from the corresponding perceived angle. At plantarflexed and inverted test positions, the CE values were smaller in negative with greater in the FAI group than in the control group. That is, in the FAI group, the FAI group underestimated the true plantarflexion angle at combined 30 degrees plantarflexion and 20 degrees inversion. We conclude that the ankle with FAI underestimate the amount of plantarflexion, which increases the chance of reaching greater planterflexion and inversion than patients' intention at high risk situations of spraining such as landing. Key pointsJoint position sense (JPS) of the ankle with functional ankle instability was investigated utilizing a passive reproduction test.The FAI group demonstrated greater error of the joint position than the control group only when the ankle was positioned at combined inversion and plantarflexion.The FAI group underestimated plantarflexion angle when the ankle was placed at combined inversion and plantarflexion. PMID- 24149955 TI - Changes in rowing technique over a routine one hour low intensity high volume training session. AB - High volume low intensity training sessions such as one hour rowing ergometer sessions are frequently used to improve the fitness of elite rowers. Early work has suggested that technique may decline over this time period. This study sought to test the hypothesis that "elite rowers can maintain technique over a one hour rowing ergometer session". An electromagnetic device, in conjunction with a load cell, was used to assess rowing technique in terms of force generation and spinal kinematics in six male elite sweep oarsmen (two competed internationally and the remainder at a club senior level). All subjects performed one hour of rowing on a Concept II indoor rowing ergometer using a stroke rate of 18-20 strokes per minute and a heart rate ranging between 130-150 beats per minute, following a brief 5 minute warm- up. Recordings of rowing technique and force were made every 10 minutes. The elite group of rowers were able to sustain their rowing technique and force parameters over the hour session. Subtle changes in certain parameters were observed including a fall in force output of approximately 10N after the first seven minutes of rowing, and a change in leg compression of three degrees at the end of the one hour rowing piece which corresponded with a small increase in anterior rotation of the pelvis. However, it is unclear if such changes reflect a "warm-up" effect or if they are indicative of early signs of fatigue. These findings suggest that low intensity high volume ergometer rowing sessions do not have a detrimental effect on the technique of a group of experienced and highly trained rowers. Key pointsElite rowers do not demonstrate changes in rowing kinematics over and hour rowing piece.Rowers require an adequate warm-up to establish their technique. PMID- 24149956 TI - Effect of an on-sight lead on the physiological and psychological responses to rock climbing. AB - Rock climbing is a multi-discipline activity that encompasses forms such as bouldering, top roping and lead climbing on natural and artificial climbing surfaces. A major focus of research has been explanation of physiological functioning. More recent research indicates that anxiety levels are elevated for less experienced climbers and in response to lead climbing ascents. Research regarding the demands of rock climbing has placed a lesser focus on the interaction of psychological and physiological factors. The objective of this study was to examine the effects of an on-sight lead climb on the physiological and psychological demands of the climb in comparison with a subsequent lead climb. Ten intermediate level climbers volunteered to complete the two climbing trials, on-sight lead climb (OSLC) and second lead climb (LC2). Climb time, lactate concentrations (baseline, pre climb, post climb and 15 min post climb), heart rate (1 min pre climb, peak HR, 1 min post climb and average climb across the duration of the climb), oxygen consumption, pre climb anxiety (CSAI-2R) were assessed for each climber for both trials. Results indicated that there were significant differences in self reported pre climb somatic and cognitive anxiety (t(9) = 2.79, p = 0.01, t(9) = 1.94, p = 0.043), climb time (t(9) = 3.07, p = 0.0052) and post climb lactate concentrations between the climbs (t(9) = 2.58, p = 0.015). These results indicate that psychological as well as physiological stress impact upon the response to rock climbing. The higher anxiety levels associated with an OSLC are likely to have influenced the physiological responses for the intermediate climbers in this study. Future studies should take into account the type of climbing, experience of climbers and the number of ascents as well as taking into account the interaction between physiological and psychological factors in response to rock climbing. Key pointsFor intermediate climbers, there are significant differences in physiological and psychological responses to on-sight lead and subsequent lead climb.There was an increased psychological and physiological load for leading a climb for the first time (on sight).These results indicate that the type of climbing should be taken into account when interpreting results from climbing studies with intermediate or recreational climbers. PMID- 24149957 TI - Anthropometric, gait and strength characteristics of kenyan distance runners. AB - This study intended to take a biomechanical approach to understand the success of Kenyan distance runners. Anthropometric, gait and lower extremity strength characteristics of six elite Kenyan distance runners were analyzed. Stride frequency, relative stride length and ground contact time were measured at five running speeds (3.5 - 5.4 m/s) using a motion capture system. Isometric knee extension and flexion torques were measured at six angles and hamstrings and quadriceps (H:Q) ratios at three angular velocities were determined using an isokinetic dynamometer. These runners were characterized by a low body mass index (20.1 +/- 1.8 kg.m(- 2)), low percentage body fat (5.1 +/- 1.6%) and small calf circumference (34.5 +/- 2.3 cm). At all running speeds, the ground contact time was shorter (p 1/4 0.05) during right (170 - 212 ms) compared to left (177 - 220 ms) foot contacts. No bilateral difference was observed in other gait or strength variables. Their maximal isometric strength was lower than other runners (knee extension: 1.4 - 2.6 Nm.kg(-1), knee flexion: 1.0 - 1.4 Nm.kg(-1)) but their H:Q ratios were higher than athletes in other sports (1.03 +/- 0.51 at 60(o)/s, 1.44 +/- 0.46 at 120(o)/s, 1.59 +/- 0.66 at 180(o)/s). The slim limbs of Kenyan distance runners may positively contribute to performance by having a low moment of inertia and thus requiring less muscular effort in leg swing. The short ground contact time observed may be related to good running economy since there is less time for the braking force to decelerate forward motion of the body. These runners displayed minor gait asymmetry, though the difference may be too small to be practically significant. Further investigations are needed to confirm whether the bilateral symmetry in strength and high H:Q ratios are related to genetics, training or the lack of injuries in these runners. Key pointsThis is the first study in the literature to analyze the biomechanical characteristics of elite Kenyan distance runners, potentially providing insight into their success in distance running.Their slim limbs may positively contribute to performance by having a low moment of inertia and thus requiring less muscular effort in leg swing.Overall, short ground contact time was observed with the right leg shorter than the left leg. This may be related to good running economy since there is less time for the braking force to decelerate forward motion of the body.These runners displayed symmetry in strength between the left and right legs and possessed high hamstrings to quadriceps ratios compared to athletes in other sports. PMID- 24149958 TI - Changes in EEG during graded exercise on a recumbent cycle ergometer. AB - Previous studies have shown changes in brain activity as a result of exercise; however, few studies have examined changes during exercise. The purpose of this study was to examine brain activity during a graded exercise test. Twenty male participants performed a graded exercise test on a recumbent cycle ergometer. Exercise intensity was set initially at 50W and was increased by 50W every 2 minutes until volitional fatigue was reached. Electroencephalography (EEG) was measured prior to the onset of exercise, during the last minute of each stage of exercise, immediately post-exercise, and 10 minutes into recovery. EEG was recorded from 8 scalp sites leading to analysis of alpha 1, alpha 2, beta 1, beta 2, and theta activities. Expired air was collected and analyzed for ventilation rate (VE), VO2, % of peak VO2, and Respiratory Exchange Ratio (RER). No differences were seen in EEG between the hemispheres of the brain. There was, however, a significant increase in brain activity across the spectrum occurring at 200 W through immediately post-exercise. Brain activity returned to pre- exercise levels by 10 minutes post. VO2, % of peak VO2 and RER increased linearly with exercise intensity. VE increased linearly through 200 W; however, a disproportionate increase was seen in VE from 200 W to peak exercise. The results of this investigation demonstrate that brain activity may be related to exercise intensity. Future research will want to examine how these changes in brain activity influence affective, perceptual and cognitive changes often associated with exercise. Efforts will also need to be made to determine if changes in brain activity during exercise are mediated by central (within the brain) or peripheral mechanisms. Key pointsEEG can be recorded during exercise.Brain EEG activity increases during exercise and may be related to exercise intensity.Brain EEG activity returns to resting levels quickly after the cessation of exercise. PMID- 24149959 TI - Pronounced muscle deoxygenation during supramaximal exercise under simulated hypoxia in sprint athletes. AB - The purpose of this study was to determine whether acute hypoxia alters the deoxygenation level in vastus lateralis muscle during a 30 s Wingate test, and to compare the muscle deoxygenation level between sprint athletes and untrained men. Nine male track sprinters (athletic group, VO2max 62.5 +/- 4.1 ml/kg/min) and 9 healthy untrained men (untrained group, VO2max 49.9 +/- 5.2 ml.kg(-1).min(-1)) performed a 30 s Wingate test under simulated hypoxic (FIO2 = 0.164 and PIO2 = 114 mmHg) and normoxic conditions. During the exercise, changes in oxygenated hemoglobin (OxyHb) in the vastus lateralis were measured using near infrared continuous wave spectroscopy. Decline in OxyHb, that is muscle deoxygenation, was expressed as percent change from baseline. Percutaneous arterial oxygen saturation (SpO2), oxygen uptake (VO2), and ventilation (VE) were measured continuously. In both groups, there was significantly greater muscle deoxygenation, lower SpO2, lower peakVO2, and higher peakVE during supramaximal exercise under hypoxia than under normoxia, but no differences in peak and mean power output during the exercise. Under hypoxia, the athletic group experienced significantly greater muscle deoxygenation, lower SpO2, greater decrement in peakVO2 and increment in peakVE during the exercise than the untrained group. When the athletic and untrained groups were pooled, the increment of muscle deoxygenation was strongly correlated with lowest SpO2 in the 30 s Wingate test under hypoxia. These results suggest that acute exposure to hypoxia causes a greater degree of peripheral muscle deoxygenation during supramaximal exercise, especially in sprint athletes, and this physiological response would be explained mainly by lower arterial oxygen saturation. Key pointsThe deoxygenation trends in the vastus lateralis muscle during 30 s Wingate test in track sprinters and untrained men under simulated hypoxic and normoxic conditions was investigated using near infrared spectroscopy.Acute hypoxia caused a greater degree of peripheral muscle deoxygenation than normoxia, whereas there were no changes in performance such as power output during 30 s Wingate test.Sprint athletes show a greater degree of peripheral muscle deoxygenation during 30 s Wingate test in hypoxia when compared with untrained subjects.A larger difference in muscle deoxygenation between hypoxia and normoxia is accompanied by lowest SpO2 at the 30 s Wingate test in hypoxia. PMID- 24149960 TI - The effect of stimulus anticipation on the interpolated twitch technique. AB - The objective of this study was to investigate the effect of expected and unexpected interpolated stimuli (IT) during a maximum voluntary contraction on quadriceps force output and activation. Two groups of male subjects who were either inexperienced (MI: no prior experience with IT tests) or experienced (ME: previously experienced 10 or more series of IT tests) received an expected or unexpected IT while performing quadriceps isometric maximal voluntary contractions (MVCs). Measurements included MVC force, quadriceps and hamstrings electromyographic (EMG) activity, and quadriceps inactivation as measured by the interpolated twitch technique (ITT). When performing MVCs with the expectation of an IT, the knowledge or lack of knowledge of an impending IT occurring during a contraction did not result in significant overall differences in force, ITT inactivation, quadriceps or hamstrings EMG activity. However, the expectation of an IT significantly (p 1/4 0.0001) reduced MVC force (9.5%) and quadriceps EMG activity (14.9%) when compared to performing MVCs with prior knowledge that stimulation would not occur. While ME exhibited non-significant decreases when expecting an IT during a MVC, MI force and EMG activity significantly decreased 12.4% and 20.9% respectively. Overall, ME had significantly (p 1/4 0.0001) higher force (14.5%) and less ITT inactivation (10.4%) than MI. The expectation of the noxious stimuli may account for the significant decrements in force and activation during the ITT. Key pointsA single orientation session may not be adequate for a valid estimation of muscle activation using the ITT.The expectation of an electrical stimulation whether delivered or not can impair performance.The validity of the ITT for estimating the extent of full muscle activation must be viewed with caution, since the expectation of IT discomfort may inhibit the individual's ability to exert maximum force, especially with inexperienced participants. PMID- 24149961 TI - Peak fat oxidation rate during walking in sedentary overweight men and women. AB - The aim of this study was to determine the relative exercise intensity that elicits maximal fat oxidation during walking in inactive and overweight men and women and evaluate any possible sex differences. Forty six healthy, sedentary, overweight men (age: 36.3 +/- 1.3 years, body fat: 28.8 +/- 0.8%, n = 28, mean +/ SE) and women (age: 36.6 +/- 1.8 years, body fat: 37.1 +/- 0.8%, n = 18) participated in the study. Fat oxidation was calculated from expired air analysis using indirect calorimetry during an incremental treadmill walking test. Peak fat oxidation rate (PFO) was higher in men compared to women (0.31 +/- 0.02 vs. 0.20 +/- 0.02 g.min(-1); p < 0.001), but this difference disappeared when PFO was scaled per kg fat-free mass (4. 36 +/- 0.23 vs. 3.99 +/- 0.37 mg.kg fat free mass(-1).min(-1)). Also, the relative exercise intensity at which PFO occurred was similar for men and women and corresponded to 40.1 +/- 1.8 and 39. 5 +/- 2.3% of maximal oxygen uptake (VO2max) and 60.0 +/- 1.4 and 57.8 +/- 1.4% of maximal heart rate, respectively. The walking speed corresponding to PFO was 5.5 +/- 0.2 and 5.0 +/- 0.1 km.h(-1) for men and women, respectively. Regression analysis showed that sex, FFM and VO2max were significant predictors of PFO expressed in g.min(-1) (adjusted R(2) = 0.48, p = 0.01). However when PFO was scaled per kg FFM, only a small part of the variance was explained by VO2max (adjusted R(2) = 0.12, p < 0.05). In conclusion, peak fat oxidation rate and the corresponding relative exercise intensity were similar in male and female overweight and sedentary individuals, but lower compared to those reported for leaner and/or physically active persons. Walking at a moderate speed (5.0-5.5 km.h(-1)) may be used as a convenient way to exercise at an intensity eliciting peak fat oxidation in overweight individuals. Key pointsPeak fat oxidation rate scaled per kg fat free mass and the corresponding relative exercise intensity are similar in male and female overweight and sedentary individuals, but lower compared to those reported for leaner and/or physically active persons.Walking at a moderate speed (5.0-5.5 km.h(-1)) may be used as a convenient way to exercise at an intensity eliciting peak fat oxidation in overweight individuals.The relationship between %HRmax and %VO2max in overweight individuals is different from that reported for normal-weight adults and should be taken into account to optimize exercise intensity using heart rate in obese individuals.Due to the low intensity corresponding to peak fat oxidation in overweight and sedentary persons and the inter-individual differences, exercise intensity for health benefits should be prescribed following individual testing. PMID- 24149962 TI - Validation of a new portable metabolic system during an incremental running test. AB - We tested a new portable metabolic system, the Jaeger Oxycon Mobile (OM) at a range of running speeds. Six subjects carried out, in random order, two incremental tests on a treadmill, one of them using the OM, and the other using the Jaeger Oxycon Pro (OP). There are systematic errors in the measurements of oxygen consumption (VO2) and respiratory exchange ratio (RER) with the OM. Production of CO2 (VCO2) tends to be overestimated by the OM, although the differences are not significant. Ventilation (VE) showed very similar values in both analyzers. Data of VO2 and RER were corrected with a regression equation which minimised the differences among the devices. The portable metabolic system OM makes systematic errors in measurements of VO2 and RER which can be adjusted with a regression analysis to obtain data comparable to those obtained by fixed systems. Key pointsPortable metabolic systems are frequently used to explore various physiological ventilatory variables in field tests.There are systematic errors in the measurements of oxygen consumption (VO2) and respiratory exchange ratio (RER) with the Jaeger Oxycon Mobile (OM) portable metabolic systemProduction of CO2 (VCO2) tends to be overestimated by the OMData of VO2 and RER can be corrected with a regression equationThe portable metabolic system OM makes systematic errors in measurements of VO2 and RER which can be adjusted with a regression analysis to obtain data comparable to those obtained by fixed systems. PMID- 24149963 TI - Evaluation of work place group and internet based physical activity interventions on psychological variables associated with exercise behavior change. AB - The purpose of this research was to compare group-based and internet-based physical activity interventions in terms of desirability, participant characteristics, exercise self-efficacy, and barrier self-efficacy. Pretest questionnaires were completed prior to voluntary enrollment into either of the ten-week physical activity interventions. Both interventions were based on Social Cognitive Theory and the Transtheoretical Model. Interventions were followed with posttest questionnaires. Results demonstrated that the internet intervention attracted more participants, but only the group-based participants showed significant increases in exercise and barrier self-efficacy. At pretest, participants who selected the internet intervention were significantly lower in life and job satisfaction than those who selected the group intervention. Results suggest that traditional group-based exercise interventions are helpful for improving cognitions associated with exercise behavior change (e.g., exercise self-efficacy) and that the internet intervention may help employees who fall into an "unhappy employee "typology. Key pointsGroup-based physical activity interventions are capable of improving exercise self-efficacy and barrier self efficacy.At pretest, participants who selected the internet physical activity intervention were significantly lower in job and life satisfaction than those who selected the group-intervention.While the internet intervention attracted more participants, the group-based physical activity intervention was more successful at changing cognitions associated with successful exercise behavior change. PMID- 24149964 TI - 3D Reconstruction of Phalangeal and Metacarpal Bones of Male Judo Players and Sedentary Men by MDCT Images. AB - This study has been performed to reveal hand bone peculiarities of elite male judoists by comparing their phalangeal and metacarpal bones with those of sedentary men on the basis of biometric ratio of the bones by means of three dimensional (3D) reconstruction of multidetector computed tomography (MDCT) images. For this purpose, the axial images of the right and left hands of 8 elite male judo players (mean age: 22.0 +/- 2.9 years, mean weight: 64.0 +/- 4.9 kg) and 8 sedentary men (mean age: 26.0 +/- 2.8 years, mean weight: 69.0 +/- 3.6 kg) were obtained from MDCT. After semi-automatic segmentation and manual editing, the tracings of bone surfaces were stacked and overlaid to be reconstructed as the 3D images by the 3D program. All biometrical measurements of the reconstructed images of the bones were automatically calculated by this program to analyze statistically. This study showed that the differences between biometric ratios of judoist and sedentary men's hand bones were significant contrary to null hypothesis which was established as there is no difference between biometric hand bone ratios of these men of both groups. Therefore null hypothesis was rejected. Author suggests that intense clutching actions practised in judo sports can most probably lead to some hand bone proliferations. 3D reconstructed results belonging to the judo players and sedentary men help orthopaedists to diagnose pathological formations related to hand bones of judoists and may be used for anatomical education in medicine faculties, respectively. We hope that the results from the biometric and reconstructive techniques carried out in this work will contribute to the present knowledge on judoist and shed light on the future studies on sports medicine related to skeletal structure of other sportsmen. Key pointsImage processing of hands of sedentary man and male judo players.3D models of hands of those men by using MDCT images.The results from those models compared in terms of volume, surface areas, and length changes for all individual hand bones. PMID- 24149965 TI - Acute effects of pre-event lower limb massage on explosive and high speed motor capacities and flexibility. AB - The aim of this study was to examine the acute effects of pre- performance lower limb massage after warm-up on explosive and high-speed motor capacities and flexibility. Twenty-four physically active healthy Caucasian male subjects volunteered to participate in this study. All subjects were from a Physical Education and Sport Department in a large university in Turkey. The study had a counterbalanced crossover design. Each of the subjects applied the following intervention protocols in a randomised order; (a) massage, (b) stretching, and (c) rest. Before (pre) and after (post) each of the interventions, the 10 meter acceleration (AS), flying start 20 meter sprint (FS), 30 meter sprint from standing position (TS), leg reaction time (LR), vertical jump (VJ) and sit & reach (SR) tests were performed. A Wilcoxon's signed rank test was used to compare before and after test values within the three interventions (massage, stretching and rest). The data showed a significant worsening, after massage and stretching interventions, in the VJ, LR (only in stretching intervention), AS and TS tests (p < 0.05), and significant improvement in the SR test (p < 0.05). In contrast, the rest intervention led only to a significant decrement in TS performance (p < 0.05). In conclusion, the present findings suggest that performing 10 minute posterior and 5 minute anterior lower limb Swedish massage has an adverse effect on vertical jump, speed, and reaction time, and a positive effect on sit and reach test results. Key pointsPerforming 10 minute posterior and 5 minute anterior lower limb Swedish massages has an adverse affect on vertical jump, speed, and reaction time and a positive effect on sit and reach test results.According to the present results, long duration massage should not be recommended for warm-ups.Larger subject pools are needed to verify these events. PMID- 24149966 TI - Stress fracture of the ulna in a break-dancer. AB - Break dancing is a popular activity in teenagers and is associated with severe trauma to bones and tissues. We report the first known case of a break dancer with an ulnar stress fracture. Such injuries occur in a variety of sports due to substantial stress on the ulna and repetitive excessive rotation of the forearm. In this study we describe a patient who experienced an ulnar stress fracture during break dancing training. The diagnosis was established by history and physical examination. Initial radiographic findings were negative. However, radiographs taken 3 months after initial presented revealed callus formation over the ulnar shaft. This suggested that readjustment is required in break dancing training protocols. It is important to increase awareness of this injury among physicians to expedite the diagnosis and to prevent the possibility of conversion to an overt fracture in the future. Key pointsStress fractures should not be ignored when the patient changes exercise loading.A thoroughly detailed clinical history, physical examination, and plain radiographs were used diagnostically in this clinical case.The best methods for the treatment of stress fractures include readjustment training protocols to prevent conversion to overt fractures. PMID- 24149967 TI - Evaluation of three pneumothorax size quantification methods on digitized chest X ray films using medical-grade grayscale and consumer-grade color displays. AB - This study focused on the effects of pneumothorax size quantification in digital radiology environments when a quantification method is selected according to the radiologist's criteria. The objective of this study was to assess the effects of factors, including the radiologist (with different experience), displays (medical grade and consumer-grade displays), or display calibration, on the Rhea, Collins, and Light quantification methods. This study used a factorial design with 76 cases, including 16 pneumothorax cases observed by six radiologists on three displays with and without the DICOM standard calibration. The gold standard was established by two radiologists by using computed tomography. Analysis of variance (ANOVA) was performed on the pneumothorax sizes. For the three quantifications methods, none of the evaluated factors were significant. We conclude that radiologists, displays, and calibration do not significantly affect the quantification of pneumothorax size in different digital radiology environments. PMID- 24149968 TI - Clinical social networking--a new revolution in provider communication and delivery of clinical information across providers of care? AB - The adoption of social media technologies appears to enhance clinical outcomes through improved communications as reported by Bacigalupe (Fam Syst Heal 29(1):1 14, 2011). The ability of providers to more effectively, directly, and rapidly communicate among themselves as well as with patients should strengthen collaboration and treatment as reported by Bacigalupe (Fam Syst Heal 29(1):1-14, 2011). This paper is a case study in one organization's development of an internally designed and developed social technology solution termed "Unite." The Unite system combines social technologies' features including push notifications, messaging, community groups, and user lists with clinical workflow and applications to construct dynamic provider networks, simplify communications, and facilitate clinical workflow optimization. Modeling Unite as a social technology may ease adoption barriers. Developing a social network that is integrated with healthcare information systems in the clinical space opens the doors to capturing and studying the way in which providers communicate. The Unite system appears to have the potential to breaking down existing communication paradigms. With Unite, a rich set of usage data tied to clinical events may unravel alternative networks that can be leveraged to advance patient care. PMID- 24149969 TI - Hopping transport through defect-induced localized states in molybdenum disulphide. AB - Molybdenum disulphide is a novel two-dimensional semiconductor with potential applications in electronic and optoelectronic devices. However, the nature of charge transport in back-gated devices still remains elusive as they show much lower mobility than theoretical calculations and native n-type doping. Here we report a study of transport in few-layer molybdenum disulphide, together with transmission electron microscopy and density functional theory. We provide direct evidence that sulphur vacancies exist in molybdenum disulphide, introducing localized donor states inside the bandgap. Under low carrier densities, the transport exhibits nearest-neighbour hopping at high temperatures and variable range hopping at low temperatures, which can be well explained under Mott formalism. We suggest that the low-carrier-density transport is dominated by hopping via these localized gap states. Our study reveals the important role of short-range surface defects in tailoring the properties and device applications of molybdenum disulphide. PMID- 24149970 TI - Maternal risk factors associated with increased dioxin concentrations in breast milk in a hot spot of dioxin contamination in Vietnam. AB - This study looked to identify determinants of exposure to dioxin in breast milk from breast-feeding women in a hot spot of dioxin exposure in Vietnam. Breast milk was collected from 140 mothers 1 month after delivery. The risk factors investigated included length of residency, drinking of well water and the frequency of animal food consumption. Cluster analysis was performed to identify dietary patterns of fish and meat portions, fish variety and egg variety. Residency, age and parity were clearly associated with increased dioxin levels. Drinking well water and the consumption of marine crab and shrimps were related to higher levels of furans in breast milk. The consumption of quail eggs also appeared to be associated with increased levels of some dioxin isomers in this area. Some mothers who ate no or less meat than fish and mothers who consumed more freshwater fish than marine fish had lower levels of dioxins in their breast milk. However, the type of water and the eating habits of mothers contributed only partly to the increased dioxin levels in their breast milk; the length of residency was the most important risk factor associated with increased dioxin body burdens of mothers. PMID- 24149972 TI - Genetic revelation of hexavalent chromium toxicity using Caenorhabditis elegans as a biosensor. AB - The interaction of heavy metals such as hexavalent chromium, Cr (VI) with the environment drastically influences living organisms leading to an ecological imbalance. Caenorhabditis elegans, a saprophytic nematode having 60-80% homology with human genes offers a distinct advantage to be used as a biosensor for the appraisal of heavy metal-induced environmental toxicity and risk monitoring. The present study examines the toxicity effects of K2Cr2O7 as Cr (VI) on stress related gene expression and morphometric parameters of C. elegans under in vitro conditions to identify genetic markers for environmental pollution. Alterations in growth and modified gene expression were observed in Cr (VI)-exposed N2 worms. The 24-h median lethal concentration for Cr (VI) was observed as 158.5 mgl(-1). Use of the responses of stress-related gene expression suggests that C. elegans can be used as an efficient biosensor for figuring out the precise route of Cr (VI)-induced environmental toxicity in a quick, simple, and inexpensive manner. PMID- 24149971 TI - Personal care product use and urinary phthalate metabolite and paraben concentrations during pregnancy among women from a fertility clinic. AB - Parabens and phthalates are potential endocrine disruptors frequently used in personal care/beauty products, and the developing fetus may be sensitive to these chemicals. We measured urinary butyl-paraben (BP), methyl-paraben, propyl paraben, mono-n-butyl phthalate (MBP), and monoethyl phthalate (MEP) concentrations up to three times in 177 pregnant women from a fertility clinic in Boston, MA. Using linear mixed models, we examined the relationship between self reported personal care product use in the previous 24 h and urinary paraben and phthalate metabolite concentrations. Lotion, cosmetic, and cologne/perfume use were associated with the greatest increases in the molar sum of phthalate metabolite and paraben concentrations, although the magnitude of individual biomarker increases varied by product used. For example, women who used lotion had BP concentrations 111% higher (95% confidence interval (CI): 41%, 216%) than non-users, whereas their MBP concentrations were only 28% higher (CI: 2%, 62%). Women using cologne/perfume had MEP concentrations 167% (CI: 98%, 261%) higher than non-users, but BP concentrations were similar. We observed a monotonic dose response relationship between the total number of products used and urinary paraben and phthalate metabolite concentrations. These results suggest that questionnaire data may be useful for assessing exposure to a mixture of chemicals from personal care products during pregnancy. PMID- 24149973 TI - The effects of perchlorate, nitrate, and thiocyanate on free thyroxine for potentially sensitive subpopulations of the 2001-2002 and 2007-2008 National Health and Nutrition Examination Surveys. AB - Among women with urinary iodine concentration <100 MUg/l in the 2001-2002 National Health and Nutrition Examination Survey (NHANES), urinary perchlorate was associated with significant changes in thyroid stimulating hormone and total thyroxine (T4). Although perchlorate, nitrate, and thiocyanate all potentially act to inhibit iodide uptake, free T4 was not found to be associated with exposure to these chemicals in the same data. Fetuses of pregnant mothers with iodine deficiency are thought to be a sensitive subpopulation for perchlorate exposure, but the potential associations between free T4 and exposure to these chemicals among pregnant mothers in NHANES 2001-2002 and 2007-2008 have not been specifically evaluated to date. This study investigates the potential associations between urinary perchlorate, nitrate, and thiocyanate and serum free T4 in individuals with low urinary iodine levels and pregnant women. Multivariate regression models of free T4 were conducted and included urinary perchlorate, nitrate, thiocyanate, and covariates known to have an impact on the thyroid (anti thyroid peroxidase (TPO) antibodies, age, race/ethnicity, body mass index, and hours of fasting). Meta-analyses were also conducted on non-pregnant and on pregnant women from the two survey cycles. Urinary nitrate was associated with serum free T4 in non-pregnant women of NHANES 2001-2002 who had urinary iodine >=100 MUg/l. In the meta-analysis, urinary perchlorate, nitrate, and thiocyanate were significant predictors of serum free T4 in non-pregnant women. No association was found in men and pregnant women. TPO antibodies were significant predictors of free T4 among non-pregnant women only when the models included urinary perchlorate, nitrate, or thiocyanate. Risk assessment for perchlorate exposure should consider co-exposure to nitrate and thiocyanate. PMID- 24149974 TI - An evaluation of metrics for assessing maternal exposure to agricultural pesticides. AB - We evaluate the use of three different exposure metrics to estimate maternal agricultural pesticide exposure during pregnancy. Using a geographic information system-based method of pesticide exposure estimation, we combine data on crop density and specific pesticide application amounts/dates to create the three exposure metrics. For illustration purposes, we create each metric for a North Carolina cohort of pregnant women, 2003-2005, and analyze the risk of congenital anomaly development with a focus on metric comparisons. Based on the results, and the need to balance data collection efforts/computational efficiency with accuracy, the metric which estimates total chemical exposure using application dates based on crop-specific earliest planting and latest harvesting information is preferred. Benefits and drawbacks of each metric are discussed and recommendations for extending the analysis to other states are provided. PMID- 24149975 TI - Serum TCDD and TEQ concentrations among Seveso women, 20 years after the explosion. AB - The Seveso Women's Health Study (SWHS) is a historical cohort study of the female population residing near Seveso, Italy, on 10 July 1976, when a chemical explosion resulted in the highest known residential exposure to 2,3,7,8 tetrachlorodibenzo-p-dioxin (TCDD). Individual TCDD concentration was measured in serum collected near the time of the explosion, and in 1996, we collected adequate blood for TCDD and total dioxin toxic equivalent (TEQ) measurement. Polychlorinated dibenzo-p-dioxins, dibenzofurans, and biphenyls were measured in 1996 serum for a sample (n=225, 23%) of the SWHS cohort and WHO 2005 TEQs were calculated. We examined characteristics that predict 1996 TCDD concentrations and estimated TCDD elimination half-life over the 20-year period since the explosion. Median lipid-adjusted TCDD and total TEQ concentrations in 1996 serum were 7.3 and 26.2 p.p.t., respectively. Initial 1976 TCDD and age at explosion were the strongest predictors of 1996 TCDD. The TCDD elimination half-life was 7.1 years for women older than 10 years in 1976, but was shorter in those who were younger. Twenty years after the explosion, TCDD concentrations in this SWHS sample, the majority of who were children in 1976, remain elevated relative to background. These data add to the limited data available on TCDD elimination half-life in children. PMID- 24149977 TI - Adjacent segment disease after anterior cervical discectomy and fusion in a large series. AB - BACKGROUND: Adjacent segment disease (ASD) development is known to occur after anterior cervical discectomy and fusion (ACDF). OBJECTIVE: To study the relationship between index ACDF levels and the location of ASD development (above/below), as well as the effect of fusion length on ASD development. METHODS: We report 888 patients who underwent ACDF for cervical spondylosis over a twenty-year period at a single institution. Of these patients, 108 had re-do surgery due to symptomatic ASD. Patients were followed for an average of 92.4 +/- 52.6 months after the index ACDF. RESULTS: In agreement with previous ACDF case series, we found the highest rates of cervical spinal degenerative disease requiring surgery at C5/C6, followed by C6/C7. Interestingly, neither the inherent location of index ACDF nor the length of instrumented arthrodesis appeared to correlate with the propensity to develop ASD. However, patients were more likely to develop ASD above the index level of fusion. This was true even for patients undergoing a second revision surgery due to recurrent ASD. Importantly, our data are consistent with existing in vitro biomechanical data in cadaveric spines. CONCLUSION: We describe in detail the location and length of arthrodesis for index ACDFs, as well as first and second revision fusion surgeries in one of the largest Western cohorts in the literature. Our findings support the theory that iatrogenically introduced stress and instability at adjacent spinal segments contribute to the pathogenesis of ASD. PMID- 24149976 TI - Sex-related differences in fractional flow reserve-guided treatment. AB - BACKGROUND: Sex-specific differences affect the evaluation, treatment, and prognosis of coronary artery disease. We tested the hypothesis that long-term outcomes of fractional flow reserve (FFR)-guided percutaneous coronary intervention (PCI) are different between women and men. METHODS AND RESULTS: Consecutive 1090 patients, referred for PCI and undergoing FFR measurements at the Mayo Clinic between October 2002 and December 2009, were included in this registry study. Clinical events were compared between the sexes during a median follow-up of 50.9 months. Of all patients, women had higher FFR adjusted by visual coronary stenosis than men (P=0.03). The Kaplan-Meier percent of major adverse cardiac events at 5 years was 35% in women and 38% in men (P=0.54). Interestingly, in patients undergoing PCI with an FFR <0.75, the incidence of death or myocardial infarction was significantly higher in women than in men (hazard ratio, 2.16; 95% confidence interval, 1.04-4.51; P=0.04). Moreover, compared with patients with FFR >0.80, deferral of PCI for those with FFR between 0.75 and 0.80 was associated with an increased rate of major adverse cardiac events, particularly death or myocardial infarction in women (hazard ratio, 3.25; 95% confidence interval, 1.56-6.74; P=0.002) and revascularization in men (hazard ratio, 2.66; 95% confidence interval, 1.66-4.54; P<0.001). CONCLUSIONS: Long-term outcome differs between women and men undergoing FFR-guided PCI. Our data suggest that the sex-based treatment strategy is necessary to further optimize prognosis of patients with coronary artery disease. PMID- 24149978 TI - Safety of staged epilepsy surgery in children. AB - BACKGROUND: Surgical resection of epileptic foci relies on accurate localization of the epileptogenic zone, often achieved by subdural and depth electrodes. Our epilepsy center has treated selected children with poorly localized medically refractory epilepsy with a staged surgical protocol, with at least 1 phase of invasive monitoring for localization and resection of epileptic foci. OBJECTIVE: To evaluate the safety of staged surgical treatments for refractory epilepsy among children. METHODS: Data were retrospectively collected, including surgical details and complications of all patients who underwent invasive monitoring. RESULTS: A total of 161 children underwent 200 admissions including staged procedures (>1 surgery during 1 hospital admission), and 496 total surgeries. Average age at surgery was 7 years (range, 8 months to 16.5 years). A total of 250 surgeries included resections (and invasive monitoring), and 189 involved electrode placement only. The cumulative total number of surgeries per patient ranged from 2 to 10 (average, 3). The average duration of monitoring was 10 days (range, 1-30). There were no deaths. Follow-up ranged from 1 month to 10 years. Major complications included unexpected new permanent mild neurological deficits (2%/admission), central nervous system or bone flap infections (1.5%/admission), intracranial hemorrhage, cerebrospinal fluid leak, and a retained strip (each 0.5%/admission). Minor complications included bone absorption (5%/admission), positive surveillance sub-/epidural cultures in asymptomatic patients (5.5%/admission), noninfectious fever (5%/admission), and wound complications (3%/admission). Thirty complications necessitated additional surgical treatment. CONCLUSION: Staged epilepsy surgery with invasive electrode monitoring is safe in children with poorly localized medically refractory epilepsy. The rate of major complications is low and appears comparable to that associated with other elective neurosurgical procedures. PMID- 24149979 TI - In reply: Is there a contribution of anesthesia to the outcome of the SAMMPRIS trial? PMID- 24149980 TI - Synthesis of closo- and nido-biscarboranes with rigid unsaturated linkers as precursors to linear metallacarborane-based molecular rods. AB - Several biscarborane-type derivatives of 8-iodo-1,2-dicarba-closo-dodecaborane (1), suitable as the precursors of linear metallacarborane-based molecular rods, were prepared. The synthesized closo-compounds contained two carborane moieties connected through a rigid linear unsaturated linker. The linkers were based on ethynylene and para-phenylene fragments and their combinations. The deboronation of all reported closo-compounds was selective and afforded nido-products with open pentagonal faces on opposite sides of the molecule, parallel to each other and perpendicular to the main molecular axis. All of the closo and nido products were characterized by a variety of physical methods (NMR, HRMS, IR). The structures of closo-carboranes 3, 6, 9, and 14 and nido-carboranes 15 and 17 were established by X-ray diffraction. PMID- 24149981 TI - Wireless powered capsule endoscopy for colon diagnosis and treatment. AB - This paper presents a wireless power transfer system integrated with an active locomotion and biopsy module in an endoscopic capsule for colon inspection. The capsule, which can move automatically, is designed for non-invasive biopsy and visual inspection of the intestine. To supply enough power for multiple functions and ensure safety for the human body, the efficiency of the current power transmission system needs to be improved. To take full advantage of the volume in the capsule body, a novel structure of receiving coils wound on a multi-core of MnZn ferrite hollow cylinder was used; with this new core, the efficiency increased to more than 7.98%. Up to 1.4 W of dc power can be delivered to the capsule as it travels along the gastrointestinal tract. Three micro motors were integrated for pumping, anchoring, locomotion and biopsy. A user interface and RF communication enables the operator to drive the capsule in an intuitive manner. To gauge the efficacy of the wireless power supply in a simulated real-world application, the biopsy and locomotion capabilities of the device were successfully tested in a slippery, soft tube and gut environment in vitro. PMID- 24149982 TI - Influence of the tyrosine environment on the second harmonic generation of iturinic antimicrobial lipopeptides at the air-water interface. AB - The second harmonic generation (SHG) response at the air-water interface from the tyrosine-containing natural iturinic cyclo-lipopeptides mycosubtilin, iturin A and bacillomycin D is reported. It is shown that this response is dominated by the single tyrosine residue present in these molecules owing to the large first hyperpolarizability arising from the non-centrosymmetric aromatic ring structure of this amino acid. The SHG response of these iturinic antibiotics is also compared to the response of surfactin, a cyclo-lipopeptide with a similar l,d amino acid sequence but lacking a tyrosine residue, and PalmATA, a synthetic linear lipopeptide possessing a single tyrosine residue but lacking the amino acid sequence structuring the cycle of the iturinic antibiotics. From the light polarization analysis of the SHG response, it is shown that the tyrosine local environment is critical in defining the SHG response of these peptides at the air water interface. Our results demonstrate that tyrosine, similar to tryptophan, can be used as an endogenous molecular probe of peptides and proteins for SHG at the air-water interface, paving the way for SHG studies of other tyrosine containing bioactive molecules. PMID- 24149983 TI - Diagnosing celiac disease in patients with a history of lymphoma: factors that matter. AB - OBJECTIVE: The aim of this study was to identify pitfalls in establishing the diagnosis of celiac disease (CD) in patients with a history of lymphoma. METHODS: A total of 103 patients with a history of lymphoma had anti-tissue transglutaminase antibodies (atTGA) and their class A, G, and M immunoglobulin (IgA, IgG) levels determined. Patients with atTGA positivity underwent enterobiopsy and CD-associated HLA locus testing. RESULTS: The mean age of patients was 55 ( +/- 13.5) years. The predominant lymphoma types included B-type non-Hodgkin's lymphoma (B-NHL, 66 %), T-type NHL (8 %), and Hodgkin's lymphoma (26 %). Serological positivity was documented in 3.9 % of cases; one patient had the diagnosis of CD confirmed by enterobiopsy. In 11 patients (10.7 %), IgA levels were decreased to a various extent; of these patients, 10 were shown to have also their IgG levels decreased. The median time from follow-up to blood collection was 58 (32-104) months. The decrease in immunoglobulin levels correlated with a more advanced stage of the tumor (Ann Arbor III-IV) at the time of diagnosis [1.4 (0.9-2.0) g/l versus 2.4 (1.5-3.0) g/l for IgA, p = 0.0001; and 9.4 (7.2-11.5) g/l versus 11.2 (10.3-12.3) g/l for IgG, p = 0.001] and older age [65 (54-72) years versus 55 (44-61) years for IgA, p = 0.04; and 69 (59-74) years versus 53 (43-61) years for IgG, p = 0.0001]. Rituximab therapy in B-NHL patients had no effect on the subsequent incidence of decreased IgA levels. CONCLUSION: Reduced IgA and IgG levels represent important factors contributing to the low detection rate of serological screening for CD in patients with a history of lymphoma. PMID- 24149984 TI - Totally endoscopic congenital heart surgery compared with the traditional heart operation in children. AB - OBJECTIVE: Totally endoscopic surgery compared with the conventional heart operation in children is described in this article to find a preferable treatment for congenital heart diseases. METHODS: Between May 2000 and December 2007, 708 children with congenital heart disease were divided into two groups: endoscopic group and conventional group. For the endoscopic group, all children underwent total endoscopic procedures with peripheral cardiopulmonary bypass, transthoracic aortic cross-clamp, and antegrade cardioplegia, whereas for the conventional group, all children were operated in traditional way. Three 1-2-cm intercostal ports in the right chest were used for access in the endoscopic group. The intrathoracic part of the operation was performed completely under two dimensional video, using conventional instruments. Directly closureed of the atrial septal defect was performed in 74 cases, patch closureed of the atrial septal defect in 48 cases, directly closureed of the ventricular septal defect in 158 cases, patch closureing of the ventricular septal defect in 116 cases. For the conventional group, all operations were done with traditional median sternotomy. Directed closureing of the atrial septal defect was performed in 38 cases, patch closed of the atrial septal defect in 56 cases, directly closureed of the ventricular septal defect in 76 cases, patch closureed of the ventricular septal defect in 142 cases. RESULTS: There was no hospital mortality in both groups. For the endoscopic group, operations were performed successfully in 390 (98.5 %) patients, enlarging a port to a 5-cm incision in 4 children. Reoperation was necessary in two children, and no conversion to median sternotomy incision was necessary. The mean duration of operation was 132 +/- 48 min, and cardiopulmonary bypass and aortic cross-clamp times were 54 +/- 16 min and 25 +/- 8 min, respectively. Major postoperative complications occurred in nine (2.3 %, p < 0.05) cases. For the conventional group, all children were operated by median sternotomy, and the mean duration of operation was 118 +/- 41 min (p < 0.05); cardiopulmonary bypass and aortic cross-clamp times were 51 +/- 13 min and 21 +/- 6 min (p < 0.05), respectively. Major postoperative complications occurred in 16 (5.1 %) cases. Also, the intensive care unit stay time (8.3 +/- 2.8 h versus 8.9 +/- 2.9 h, p < 0.01), postoperative drainage (120 +/- 21 ml versus 433 +/- 140 ml, p < 0.05), and hospital time (8.6 +/- 1.8 days versus 11.5 +/- 1.9 days, p < 0.05) were statistically different. CONCLUSIONS: Totally endoscopic closed chest congenital heart surgery in children was feasible and safe. The results were similar or even superior to the traditional operations due to the decreased use of blood products and shortened hospital time. Degree of satisfaction with cosmetic result and postoperative comfort were very high. Therefore, endoscopic surgery will become a new popular choice for some congenital heart disease patients in the future. PMID- 24149985 TI - 2013 Research Award. AB - The winner of the "Best Original Research Paper in Cancer Nursing" Award for 2013 is "Effects of an Internet Support System to Assist Cancer Patients in Reducing Symptom Distress: A Randomized Controlled Trial" by Cornelia M. Ruland, PhD. PMID- 24149986 TI - A regional approach to understanding farmer suicide rates in Queensland. AB - PURPOSE: Elevated suicide rates among farmers have been observed across a number of countries, including Australia. However, studies on farmer suicide have typically treated farmers as a homogenous group, and have predominately been focussed at a national level. This overlooks potential variability in suicide rates (and, by extension, contributory factors) within different groups of farmers (for example, different age groups), as well as across different geographical locations. METHODS: Using a unique data source, the Queensland Suicide Register, the current study examined variation in farmer suicide rates by age, sex, and location within Queensland. RESULTS: Although farmer suicide rates varied substantially across different regions of Queensland, no significant associations were found between rates of farmer and non-farmer suicide, or between the proportion of farmers in a region and farmer suicide rates. CONCLUSIONS: This suggests that farmer suicide may be characterised by unique combinations of occupational and location-related effects that are likely to vary substantially within and between different regions, and provides caution against treating farmer suicide as a homogenous phenomenon. The highest rates of farmer suicide were observed among younger farmers (aged 18-34 years), highlighting a need for targeted suicide prevention initiatives for this group. PMID- 24149987 TI - Epac-inhibitors: facts and artefacts. AB - cAMP is a universal second messenger. Its signalling is mediated by protein kinase A, Epac and certain types of ion channels in mammalians. cAMP signalling is involved in many physiological processes ranging from vision to the control of insulin secretion, pacemaker activity and gene transcription and therefore selective pharmacological interference is of medical interest. Whereas selective inhibitors of PKA and selective activators of Epac are well established, no inhibitors of Epac were available until recently. Here the action of four of the novel Epac inhibitors was analysed by biophysical means. ESI-05 is confirmed as a selective inhibitor of Epac2. No direct action of Brefeldin A on Epac could be demonstrated. ESI-09 and HJC0197 were found to act as chemicals with general protein denaturing properties and do not act on Epac selectively. PMID- 24149989 TI - Surgery outperforms other treatment options for obesity, finds analysis. PMID- 24149988 TI - The accumulation of misfolded proteins in the mitochondrial matrix is sensed by PINK1 to induce PARK2/Parkin-mediated mitophagy of polarized mitochondria. AB - Defective mitochondria exert deleterious effects on host cells. To manage this risk, mitochondria display several lines of quality control mechanisms: mitochondria-specific chaperones and proteases protect against misfolded proteins at the molecular level, and fission/fusion and mitophagy segregate and eliminate damage at the organelle level. An increase in unfolded proteins in mitochondria activates a mitochondrial unfolded protein response (UPR(mt)) to increase chaperone production, while the mitochondrial kinase PINK1 and the E3 ubiquitin ligase PARK2/Parkin, whose mutations cause familial Parkinson disease, remove depolarized mitochondria through mitophagy. It is unclear, however, if there is a connection between those different levels of quality control (QC). Here, we show that the expression of unfolded proteins in the matrix causes the accumulation of PINK1 on energetically healthy mitochondria, resulting in mitochondrial translocation of PARK2, mitophagy and subsequent reduction of unfolded protein load. Also, PINK1 accumulation is greatly enhanced by the knockdown of the LONP1 protease. We suggest that the accumulation of unfolded proteins in mitochondria is a physiological trigger of mitophagy. PMID- 24149991 TI - Capturing three-dimensional in vivo lumbar intervertebral joint kinematics using dynamic stereo-X-ray imaging. AB - Availability of accurate three-dimensional (3D) kinematics of lumbar vertebrae is necessary to understand normal and pathological biomechanics of the lumbar spine. Due to the technical challenges of imaging the lumbar spine motion in vivo, it has been difficult to obtain comprehensive, 3D lumbar kinematics during dynamic functional tasks. The present study demonstrates a recently developed technique to acquire true 3D lumbar vertebral kinematics, in vivo, during a functional load lifting task. The technique uses a high-speed dynamic stereo-radiography (DSX) system coupled with a volumetric model-based bone tracking procedure. Eight asymptomatic male participants performed weight-lifting tasks, while dynamic X ray images of their lumbar spines were acquired at 30 fps. A custom-designed radiation attenuator reduced the radiation white-out effect and enhanced the image quality. High resolution CT scans of participants' lumbar spines were obtained to create 3D bone models, which were used to track the X-ray images via a volumetric bone tracking procedure. Continuous 3D intervertebral kinematics from the second lumbar vertebra (L2) to the sacrum (S1) were derived. Results revealed motions occurring simultaneously in all the segments. Differences in contributions to overall lumbar motion from individual segments, particularly L2 L3, L3-L4, and L4-L5, were not statistically significant. However, a reduced contribution from the L5-S1 segment was observed. Segmental extension was nominally linear in the middle range (20%-80%) of motion during the lifting task, but exhibited nonlinear behavior at the beginning and end of the motion. L5-S1 extension exhibited the greatest nonlinearity and variability across participants. Substantial AP translations occurred in all segments (5.0 +/- 0.3 mm) and exhibited more scatter and deviation from a nominally linear path compared to segmental extension. Maximum out-of-plane rotations (<1.91 deg) and translations (<0.94 mm) were small compared to the dominant motion in the sagittal plane. The demonstrated success in capturing continuous 3D in vivo lumbar intervertebral kinematics during functional tasks affords the possibility to create a baseline data set for evaluating the lumbar spinal function. The technique can be used to address the gaps in knowledge of lumbar kinematics, to improve the accuracy of the kinematic input into biomechanical models, and to support development of new disk replacement designs more closely replicating the natural lumbar biomechanics. PMID- 24149990 TI - Efficacy of EMLA cream phonophoresis comparison with ultrasound therapy on myofascial pain syndrome of the trapezius: a single-blind, randomized clinical study. AB - The aim of this study is to investigate whether eutectic mixture of local anesthetics (EMLA) cream phonophoresis superior to conventional US over the trigger points (TPs) in terms of improvements of pain, range of motion and disability in myofascial pain syndrome (MPS). Fifty patients (42 female, 8 male) diagnosed with MPS were included in the study. Patients were randomly assigned into two treatment groups including phonophoresis (PH) group (n = 25) and ultrasound (US) group (n = 25). PH group received EMLA cream phonophoresis (2.5 % lidocaine, 2.5 % prilocaine); US group received conventional ultrasound therapy over the all active TPs on trapezius muscle for 10 min a day for 15 sessions. Outcome measures were performed before the treatment course and at the end of a 15-session course of treatment. Student T, Mann-Whitney U, chi-square and Wilcoxon tests were used for statistical analysis. At the end of the therapy, there was statistically significant decrease in both PH group and US group in terms of number of trigger point (NTP) (p = 0.001, p = 0.029), pain intensity on movement (p = 0.001 vs. 0.002) and right/left cervical lateral ROMs (p = 0.001/p = 0.001, p = 0.009/p = 0.020) relative to baseline. The NTP decrease in PH group was significantly higher than that in US group (1.84 +/- 1.46 vs. 0.72 +/- 1.45; p = 0.01). Pain intensity at rest (p = 0.001) and NPDI scores (p = 0.001) were statistically improvement in only PH group. EMLA cream phonophoresis is more effective than conventional ultrasound therapy in terms of pain and associated neck disability, and it seems the complementary treatment option for MPS. PMID- 24149992 TI - Physiological responses of elite junior Australian rules footballers during match play. AB - Australian Football (AF) is Australia's major football code. Despite research in other football codes, to date, no data has been published on the physiological responses of AF players during match play. Fifteen athletes (17.28 +/- 0.76 yrs) participated in four pre-season matches, sanctioned by Australian Football League (AFL) Victoria, investigating Heart Rate (HR), Blood Lactate (BLa), Core Temperature (Tcore), and Hydration status. Match HR was measured continuously using HR monitors. BLa was measured via finger prick lancet at the end of each quarter of play. Tcore was measured by use of ingestible temperature sensor and measured wirelessly at the end of each quarter of play. Hydration status was measured using refractometry, measuring urine specific gravity, and body weight pre and post-match. Environmental conditions were measured continuously during matches. Results of HR responses showed a high exertion of players in the 85-95% maximum HR range. Elevated mean BLa levels, compared to rest, were observed in all players over the duration of the matches (p = 0.007). Mean Tcore rose 0.68 degrees C between start and end of matches. Mean USG increased between 0.008 g/ml (p = 0.001) with mean body weight decreasing 1.88 kg (p = 0.001). This study illustrates physiological responses in junior AF players playing in the heat as well as providing physiological data for consideration by AF coaching staff when developing specific training programs. Continued research should consider physiological measurements under varying environments, and at all playing levels of AF, to ascertain full physiological responses during AF matches. Key pointsSpecific conditioning sessions for junior athletes should include high intensity bouts; greater than 85% of heart rate maximum zone.Football anaerobic conditioning activities (e.g. sprint training) should be randomised throughout training sessions to replicate demands of the game (e.g. training in a fatigued state).Coaches and fitness staff should provide education and player management strategies for fluid replacement at key opportunities (pre-match, formal breaks and substation on and off the field) during matches. PMID- 24149993 TI - Profile of position movement demands in elite junior Australian rules footballers. AB - This study investigated the positional movement patterns in elite junior Australian Football (AF). Thirty players (17.1 +/- 0.9 years) participating in this study were tracked over seven home games of the regular 2006 Victorian junior (Under 18) league season. Using lapsed-time video analysis, each position for an entire match was videotaped on three separate occasions over the course of the season. Data analysed included the number of individual efforts, duration and frequency of efforts; distance and percentage time for the classifications of standing, walking jogging, running and sprinting. Results showed that the midfield position travelled the greatest distance (4173 +/- 238 m per quarter; p < 0.05; ES = .94) whilst the full forward/full back travelled the least (2605 +/- 348 m per quarter, p < 0.05, ES = 1.21). For all positions, walking or jogging accounted for the greatest number of efforts (45-55%), conversely running and sprinting accounted for 5-13% of match efforts. The majority of efforts across all classifications were between 0-3.99 s. The data from this study provides further evidence that AF is an intermittent sport characterised by high intensity movements separated by low intensity movements at a ratio of one high intensity effort every 12-40 s. However, careful interpretation of the data is required when training junior AF players for specific positions, given the specific group studied. Key pointsTraining for Australian Football should incorporate repeated sprint bouts rather than long continuous running that reflect the characteristics of the sport.Specialised positional training (involving distances and repetitions) can be prescribed to prepare junior athletes for specialist roles in senior level Australian Football.Differences between elite junior and senior Australian football provides further evidence to coaches that junior athletes should not be trained as adults. PMID- 24149994 TI - Relationships between physical education students' motivational profiles, enjoyment, state anxiety, and self-reported physical activity. AB - The purpose of this study was to analyze motivational profiles based on the self determination theory (Deci and Ryan, 2000) and how these profiles are related to physical education students' enjoyment, state anxiety, and physical activity. The participants, 429 sixth grade students (girls = 216; boys = 213) completed SMS, Sport Enjoyment Scale, PESAS, and Physical Activity Scale. Cluster analyses identified two motivational profiles: 1) the "High motivation profile", in which the students had high intrinsic and extrinsic motivation, and low levels of amotivation, and 2) the "Low motivation profile", in which the students had low intrinsic and extrinsic motivation, and low levels of amotivation. The students in the first cluster enjoyed physical education more and were physically more active. The results revealed that students may be motivated towards physical education lessons both intrinsically and extrinsically, and still experience enjoyment in physical education. Key pointsTWO MOTIVATIONAL PROFILES WERE REVEALED: 1) the "High motivation profile", in which the students had high intrinsic and extrinsic motivation, and low levels of amotivation, and 2) the "Low motivation profile", in which the students had low intrinsic and extrinsic motivation, and low levels of amotivation.The students in the first profile enjoyed physical education more and were physically more active than the students in the second profile.Moreover, the representatives of the "High motivation profile "experienced greater anxiety toward physical education than the representatives of the "Low motivation profile"These findings raised an interesting question whether students engaging in physical education benefit more from the presence of both self-determined and non-self-determined forms of motivation, or are the benefits higher if students are primarily self-determined? PMID- 24149995 TI - Association between sarcopenia-related phenotypes and aerobic capacity indexes of older women. AB - The purpose of the present study was to examine the association between fat-free mass (FFM), quadriceps strength and sarcopenia with aerobic fitness indexes of elderly women. A total of 189 volunteers (66.7 +/- 5.46 years) underwent aerobic capacity measurement through a symptom-limited cardiopulmonary exercise test to determine their individual ventilatory thresholds (VT) and peak oxygen uptake (VO2 peak). Quadriceps muscle strength was assessed using an isokinetic dynamometer. Also, dual energy X-ray absorptiometry was used to assess FFM and cutoff values were used to classify subjects as sarcopenic or nonsarcopenic. Correlations, student t-test and analysis of variance were used to examine the data. Both FFM and quadriceps strength variables were positively and significantly correlated with the measured aerobic capacity indexes. These results were observed for peak exercise as well as for ventilatory thresholds. Individuals classified as sarcopenic presented significantly lower muscle strength and (VO2 peak) when compared to nonsarcopenic. It can be concluded that FFM and quadriceps strength are significantly related to aerobic capacity indexes in older women, and that besides presenting lower quadriceps strength, women classified as sarcopenic have lower peak oxygen consumption. Taken together, the present results indicate that both FFM and strength play a role in the age related decline of aerobic capacity. Key pointsMaximal aerobic capacity, generally expressed as peak oxygen consumption (VO2 peak), declines with advancing age and this process is associated with an increased risk for cardiovascular diseases.Also, the aging process is associated with a progressive loss of muscle mass and strength and this phenomenon has been referred to as Sarcopenia. Sarcopenia has been described in both elderly men and women and has been linked to multiple negative clinical outcomes.The present study provide evidence that muscle-related phenotypes are associated with aerobic capacity of older individuals, thus suggesting that sarcopenia explains in part the decline in aerobic fitness observed with advancing age. PMID- 24149996 TI - Quantification of the impaired cardiac output response to exercise in heart failure: application of a non-invasive device. AB - An impaired cardiac output (CO) response to exercise is a hallmark of chronic heart failure (CHF), and the degree to which CO is impaired is related to the severity of CHF and prognosis. However, practical methods for obtaining cardiac output during exercise are lacking, and what constitutes and impaired response is unclear. Forty six CHF patients and 13 normal subjects underwent cardiopulmonary exercise testing (CPX) while CO and other hemodynamic measurements at rest and during exercise were obtained using a novel, non-invasive, bioreactance device based on assessment of relative phase shifts of electric currents injected across the thorax, heart rate and ventricular ejection time. An abnormal cardiac output response to exercise was defined as achieving <= 95% of the confidence limits of the slope of the relationship between CO and oxygen uptake (VO2). An impaired CO slope identified patients with more severe CHF as evidenced by a lower peak VO2, lower peak CO, heightened VE/VCO2 slope, and lower oxygen uptake efficiency slope. CO can be estimated during exercise using a novel bioreactance technique; patients with an impaired response to exercise exhibit reduced exercise capacity and inefficient ventilation typical of more severe CHF. Non- invasive measurement of cardiac performance in response to exercise provides a simple method of identifying patients with more severe CHF and may complement the CPX in identifying CHF patients at high risk. Key pointsNon-invasive measurement of cardiac output during exercise is feasible in patients with heart failure.Impairment in the CO response to exercise identifies heart failure patients with more severe disease, lower exercise capacity and inefficient ventilation.Non-invasive measurement of cardiac performance during exercise has potentially important applications for the functional and prognostic assessment of patients with heart failure. PMID- 24149997 TI - Home advantage in high-level volleyball varies according to set number. AB - The aim of the present study was to identify the probability of winning each Volleyball set according to game location (home, away). Archival data was obtained from 275 sets in the 2005 Men's Senior World League and 65,949 actions were analysed. Set result (win, loss), game location (home, away), set number (first, second, third, fourth and fifth) and performance indicators (serve, reception, set, attack, dig and block) were the variables considered in this study. In a first moment, performance indicators were used in a logistic model of set result, by binary logistic regression analysis. After finding the adjusted logistic model, the log-odds of winning the set were analysed according to game location and set number. The results showed that winning a set is significantly related to performance indicators (Chisquare(18)=660.97, p<0.01). Analyses of log odds of winning a set demonstrate that home teams always have more probability of winning the game than away teams, regardless of the set number. Home teams have more advantage at the beginning of the game (first set) and in the two last sets of the game (fourth and fifth sets), probably due to facilities familiarity and crowd effects. Different game actions explain these advantages and showed that to win the first set is more important to take risk, through a better performance in the attack and block, and to win the final set is important to manage the risk through a better performance on the reception. These results may suggest intra game variation in home advantage and can be most useful to better prepare and direct the competition. Key pointsHome teams always have more probability of winning the game than away teams.Home teams have higher performance in reception, set and attack in the total of the sets.The advantage of home teams is more pronounced at the beginning of the game (first set) and in two last sets of the game (fourth and fifth sets) suggesting intra-game variation in home advantage.Analysis by sets showed that home teams have a better performance in the attack and block in the first set and in the reception in the third and fifth sets. PMID- 24149999 TI - Accountability systems and instructional approaches in youth volleyball training. AB - The purpose of this study was to examine accountability systems operating in youth volleyball training sessions and to understand how those systems vary according to the instructional tasks and the nature of the information provided by coaches. Additionally, the interactive effect of the players' age group on accountability systems and instructional tasks will be inspected. Twenty-eight youth volleyball coaches (for under 14s and under 18s) were observed, one training session each. Systematic observation strategies were used to describe and analyse task presentation and task structure during practice. Results convey that the accountability systems implemented by coaches were mainly implicit and governed by opportunity rather than explicit performance criteria imparted in task presentation. Remarks on the quality of performance only occurred during ongoing practice. More often than not coaches showed no reaction when athletes did not accomplish the tasks, failing to convey consequential expectancy-demand monitoring messages. The instructional approach was predominantly composed of informing tasks, of technical nature and general information, which can reflect a technique and generalist coach profile. These results indicate the presence of weak and ambiguous accountability system, also corroborated by positive correlations of extending tasks with the category without exigency task presentation as well as with no reaction to unaccomplished tasks. There were no notorious differences in accountability behaviours between players' age group. Key pointsAccountability systems implemented by coaches were mainly implicit and governed by opportunity rather than explicit performance criteria imparted in task presentation. Only during practice, coaches remark the performance quality, followed by participation/effort.The instructional approach was predominantly composed of informing tasks, of technical nature and general information, which can reflect a technique and generalist coach profile.In general, coaches did not differentiate accountability behaviours according to the players' age group. PMID- 24149998 TI - Combined strength and endurance training in competitive swimmers. AB - A combined intervention of strength and endurance training is common practice in elite swimming training, but the scientific evidence is scarce. The influences between strength and endurance training have been investigated in other sports but the findings are scattered. Some state the interventions are negative to each other, some state there is no negative relationship and some find bisected and supplementary benefits from the combination when training is applied appropriately. The aim of this study was to investigate the impact of a combined intervention among competitive swimmers. 20 subjects assigned to a training intervention group (n = 11) or a control group (n = 9) from two different teams completed the study. Anthropometrical data, tethered swimming force, land strength, performance in 50m, 100m and 400m, work economy, peak oxygen uptake, stroke length and stroke rate were investigated in all subjects at pre- and post test. A combined intervention of maximal strength and high aerobic intensity interval endurance training 2 sessions per week over 11 weeks in addition to regular training were used, while the control group continued regular practice with their respective teams. The intervention group improved land strength, tethered swimming force and 400m freestyle performance more than the control group. The improvement of the 400m was correlated with the improvement of tethered swimming force in the female part of the intervention group. No change occurred in stroke length, stroke rate, performance in 50m or 100m, swimming economy or peak oxygen uptake during swimming. Two weekly dry-land strength training sessions for 11 weeks increase tethered swimming force in competitive swimmers. This increment further improves middle distance swimming performance. 2 weekly sessions of high- intensity interval training does not improve peak oxygen uptake compared with other competitive swimmers. Key pointsTwo weekly sessions of dry land strength training improves the swimming force.Two weekly sessions of high-intensity endurance training did not cause improved endurance capacity.It may seem that dry land strength training can improve middle distance performance. PMID- 24150000 TI - Effects of small-sided games on physical conditioning and performance in young soccer players. AB - The purpose of this study was to examine, first, the movement actions performed during two different small-sided games and, second, their effects on a series of field endurance and technical tests. Thirty-four young soccer players (age: 13 +/ 0.9 yrs; body mass: 62.3 +/- 15.1 kg; height: 1.65 +/- 0.06 m) participated in the study. Small-sided games included three-a-side (3 versus 3 players) and six-a side (6 versus 6 players) games consisting of 10 bouts of 4 min duration with 3 min active recovery between bouts. Soccer player performance was evaluated using five field tests: a) 30m sprint, b) throw-in for distance, c) Illinois Agility Test, d) dribbling the ball and e) horizontal jump before, in the middle and after the implementation of both game situations. Heart rate was monitored during the entire testing session. Each game was also filmed to measure soccer movements within the game. The ANOVA analysis indicated that the three-a- side games displayed significantly higher heart rate values compared with the six-a-side games (p < 0.05). The number of short passes, kicks, tackles, dribbles and scoring goals were significantly higher during the three-a-side compared with the six-a-side game condition (p < 0. 05) while players performed more long passes and headed the ball more often during the six-a-side (p < 0.05). After the three a-side games, there was a significant decline in sprint and agility performance (p < 0.05), while after both game conditions significant alterations in the throw in and the horizontal jump performance were observed (p < 0.05). The results of the present study indicated that three-a-side games provide higher stimulus for physical conditioning and technical improvement than six-a-side games and their use for training young soccer players is recommended. Key pointsThree-a-side games display higher HR compared with six-a-side games.In the three-a-side games players performed more short passes, kicks, dribbles, tackles and scored more goals compared with the six-a-side games.Impairment in endurance and field test performance was observed mainly after three-a-side games.The use of the three-a side games to develop physical fitness and technique in young soccer players is recommended. PMID- 24150001 TI - Comparison of Lactate Threshold, Glucose, and Insulin Levels Between OLETF and LETO Rats After All-Out Exercise. AB - Otsuka Long-Evans Tokushima Fatty (OLETF) rats are an animal model for obesity and Non Insulin Dependent Diabetes Mellitus by hyperphagia. The lactate threshold (LT) is used to determinate aerobic capacity and exercise intensity in individuals. The purpose of this study was to determine whether velocity at the LT (VLT), glucose, and insulin levels of OLETF differs from Long-Evans Tokushima (LETO) rats after all-out exercise on treadmill running. In the results, we found that VLT level of OLETF rats (17.8 +/- 1.39 m.min(-1)) was significantly lower than that of the LETO rats (20.5 +/- 1.33 m.min(-1)). The blood glucose levels immediately after all-out exercise increased in OLETF (from 7.23 +/- 0.36 to 9.38 +/- 1.77 mmol.L(-1)) and decreased in LETO rats (from 6.36 +/- 0.27 to 4.42 +/- 0.71 mmol.L(-1)), and the insulin level was decreased in both the OLETF (from 34.4 +/- 7.7 to 20.13 +/- 8.63 uU.mL(-1)) and LETO (from 15.29 +/- 2.6 to 5.72 +/ 1.49 uU.mL(-1)) rats immediately after the all-out exercise, but the difference was not significant. Our results suggest that the different VLT, blood glucose and insulin levels should be considered to compensate for the differences between the OLETF and LETO rats. Moreover, the VLT will be a useful reference for the future studies on exercise training of OLETF rats. Key pointsThe VLT of OLETF was significantly lower than that of LETO rats.The changes of the blood lactate levels from rest to all-out exercise showed significant difference between OLETF and LETO rats.The result of low VLT in the OLETF compared to LETO rats implies that the application of relatively low exercise intensity is suitable for OLETF rats.The different VLT should be recognized to compensate for the differences between the OLETF and LETO rats. PMID- 24150002 TI - Effect of rest interval length on the volume completed during upper body resistance exercise. AB - The purpose of the current study was to compare the workout volume (sets x resistance x repetitions per set) completed during two upper body resistance exercise sessions that incorporated 1 minute versus 3 minute rest intervals between sets and exercises. Twelve trained men completed two experimental sessions that consisted of 5 upper body exercises (i.e. barbell bench press, incline barbell bench press, pec deck flye, barbell lying triceps extension, triceps pushdown) performed for three sets with an 8-RM load. The two experimental sessions differed only in the length of the rest interval between sets and exercises; one session with a 1-minute and the other session with a 3 minute rest interval. The results demonstrated that for each exercise, significantly greater workout volume was completed when resting 3 minutes between sets and exercises (p < 0.05). These results indicate that during a resistance exercise session, if sufficient time is available, resting 3 minutes between sets and exercises allows greater workout volume for the upper body exercises examined. Key pointsThe length of the rest interval between sets is an important variable when designing a resistance exercise program and may vary depending on the characteristic being emphasized (i.e. maximal strength, hypertrophy, localized muscular endurance, power).Although acknowledged, this variable is rarely monitored precisely in field settings.Previous studies that examined rest interval lengths from 1 to 5 minutes between sets for single exercises demonstrated significant differences in repetition performance and the exercise volume completed.There is a need for further research to compare the workout volume (sets x resistance x repetitions per set) completed over an entire resistance exercise session with different rest intervals between sets.The results of the current study indicate that during a resistance exercise session, if sufficient time is available, resting 3 minutes between sets and exercises allows greater workout volume for the upper body exercises examined. PMID- 24150003 TI - Effects of the administration of feedback on performance of the bmx cycling gate start. AB - The aim of the present study was to determine the effect of the administration of external feedback (FB) on the time used to execute the gate start skill in BMX cycling discipline. The sample used was n = 6 riders from the Spanish national team (19.3 +/- 2.1 years). An intragroup experimental design with repeated measures was used to compare the evolution of the skill developed by the participants before and after treatment, as well as the degree of retention of the possible learning. The results showed that there were no significant differences between the 2 first pre-test sessions (PRE), nor between any of the other treatment, post-test or re-test sessions (TREAT, POS and RET, respectively). Nevertheless, significant differences were observed between either of the PRE sessions and any of the TREAT, POS or RET sessions (p <= 0.028), showing a significant reduction of the time needed to perform this skill after TREAT (1.264 +/- 0.045 ms in PRE, 1.047 +/- 0.019 ms in POS, and 1.041 +/- 0.021 ms in RET). In conclusion, the use of audiovisual FB and cognitive training of the skill can result in a significant improvement in the execution of the gate start in BMX reducing the time to develop the task. Key pointsThis work provides a practical application of many studies developed around teaching-learning technique in sport. In those studies this kind of applications were suggested as necessary.All the recent theories are applied in the real sport context, and using elite athletes.A successful program is proposed to be used by coaches and athletes just following a few simple guidelines, and this can be a really useful tool to follow. PMID- 24150004 TI - Arm vs. Combined Leg and Arm Exercise: Blood Pressure Responses and Ratings of Perceived Exertion at the Same Indirectly Determined Heart Rate. AB - Pre-participation screening is very important for prescribing and practising exercise safely. The aim of this study was to investigate both ratings of perceived exertion (RPE) and blood pressure responses in two different types of exercises with matching duration and indirectly determined working heart rate (HR). Participants were 23 male students, who were generally healthy but sedentary. The time course of their RPE and blood pressure during a 50- minute work-out session on an arm crank ergometer and a cross trainer were compared. RM ANOVA showed both a higher RPE (p < 0.001) and diastolic blood pressure (DBP) (p < 0.001) response to the arm exercise that were shown significantly correlated (r = 0.883; p = 0.008). Linear regression analysis (p = 0.001) confirmed the ability to predict the time course of DBP by knowing the RPE on the arm crank ergometer. Even if people use the recommended relative intensity, the HR method is not always safe for health without pre-participation screening because exercise characteristics can negatively influence physiological responses. The HR method could be substituted by the RPE method. Key pointsArm Crank Ergometer elicits a higher diastolic blood pressure response respect to Cross Trainer when people exercise at the same heart rate.Arm Crank Ergometer elicits a higher ratings of perceived exertion respect to Cross trainer when people exercise at the same heart rate.Indirect determined working heart rate is not always safe even if the theoretical intensity is that recommended for health.Rating of perceived exertion method should be used instead of heart rate method to avoid the dangerous physiological responses observed. PMID- 24150005 TI - Angiotensin-converting enzyme genotype affects skeletal muscle strength in elite athletes. AB - Previous studies have associated angiotensin-converting enzyme (ACE) D allele with variability in the skeletal muscle baseline strength, though conclusions have been inconsistent across investigations. The purpose of this study was to examine the possible association between ACE genotype and skeletal muscle baseline strength in elite male and female athletes involved in different event expertise. A group of 58 elite athletes, designated as Olympic candidates, were studied: 35 swimmers (19 males and 16 females, 18.8 +/- 3.2 years) and 23 triathletes (15 males and 8 females, 18.7 +/- 3.0 years). The athletes were classified as: short (<= 200m) and middle (400m to 1500m) distance athletes, respectively. For each subject the grip strength in both hands was measure using an adjustable mechanical hand dynamometer. The maximum height in both squat jump (SJ) and counter movement jump (CMJ) were also assessed, using a trigonometric carpet (Ergojump Digitime 1000; Digitest, Jyvaskyla, Finland). DNA extraction was obtained with Chelex 100((r)) and genotype determination by PCR-RFLP methods. Both males and females showed significantly higher right grip strength in D allele carriers compared to II homozygote's. We found that allelic frequency differs significantly by event distance specialization in both genders (p < 0.05). In fact, sprinter D allele carriers showed the superior scores in nearly all strength measurements (p < 0.05), in both genders. Among endurance athletes, the results also demonstrated that female D allele carriers exhibited the higher performance right grip and CMJ scores (p < 0.05). In conclusion, the ACE D allele seems associated with skeletal muscle baseline strength in elite athletes, being easily identified in females. Key pointsDD homozygote's and D allele carriers from both genders shows significantly higher right grip strength.Right grip strength remains significantly higher in the D allele carrier's female endurance group.Female's D allele carriers exhibited the higher performance counter movement jump scores.ACE genotype effects in skeletal-muscle strength are diverse by gender, being easily identified in females. PMID- 24150006 TI - Effects of fatigue on frontal plane knee motion, muscle activity, and ground reaction forces in men and women during landing. AB - Women tear their Anterior Cruciate Ligament (ACL) 2-8 times more frequently than men. Frontal plane knee motion can produce a pathological load in the ACL. During a state of fatigue the muscles surrounding the knee joint may lose the ability to protect the joint during sudden deceleration while landing. The purpose of this study was to investigate the effects of fatigue and gender on frontal plane knee motion, EMG amplitudes, and GRF magnitudes during drop- jump landing. Pretest posttest comparison group design was used. Twenty-six volunteers (14 women; 12 Men; Mean +/- standard deviation age = 24.5 +/- 2.7 yrs; height = 1.73 +/- 0.09 m; mass = 74.3 +/- 11.8 kg) participated in the study. Knee frontal plane ranges of motion and positions, ground reaction force peak magnitudes, and surface EMG RMS amplitudes from five lower extremity muscles (vastus medialis, vastus lateralis, medial hamstring, lateral hamstring, and lateral gastrocnemius) were obtained during the landing phase of a drop-jump. MANOVA and ANOVA indicated that peak GRF significantly (p < 0.05; 2.50 +/- 0.75 BW vs. 2.06 +/- 0.93 BW) decreased during fatigued landings. No other variables exhibited a fatigue main effect, although there was a significant (p < 0.05) fatigue by gender interaction for the frontal plane range of motion from initial contact to max knee flexion variable. Follow-up analyses failed to reveal significant gender differences at the different levels of fatigue for this variable. Additionally, no variables exhibited a significant gender main effect. Single subject analysis indicated that fatigue significantly altered frontal plane knee motion, peak GRF, and EMG in some subjects and the direction of differences varied by individual. Fatigue altered some aspects of landing performance in both men and women, but there were no gender differences. Additionally, both group and single subject analyses provided valuable but different information about factors representing neuromuscular control during drop-jump landing. Key pointsFatigue reduces ground reaction forces in both men and women during drop-jump landings.There was no significant difference in frontal plane knee kinematics between men and women when they were fatigued.Men and women did show differences in frontal plane knee kinematics in the fatigued state compared to the pre-fatigued state and the increased motion was in the valgus direction and varus direction.Single subject analysis shows that both women and men exhibit characteristics that may predispose them to ACL injury. PMID- 24150007 TI - Exercise-induced arterial adaptations in elite judo athletes. AB - The purpose of this study was to examine exercise-induced arterial adaptations in elite Judo male and female athletes. 27 male Judo athletes (age 24.06 +/- 2 years), 11 female Judoka (age 24.27 +/- 1 years), 27 sedentary healthy men (age 24.01 +/- 2 years) and 11 women (age 24.21 +/- 1 years) participated in the current study. The examined vessels included brachial, radial, ulnar, popliteal, anterior and posterior tibial arteries. The experimental parameters were recorded with the use of Duplex ultrasound at rest. Diastolic diameter and blood mean flow velocity of the examined arteries in Judo athletes were found to be both significantly increased (p < 0.05) compared to the findings of the control groups. In male Judo athletes the brachial (p < 0.001), radial (p < 0.001), and anterior tibial artery (p < 0.001) presented the highest difference on the diastolic diameter, compared with the control male group. In female Judo athletes, ulnar (p < 0.001), radial (p < 0.001), and brachial (p < 0.001) arteries illustrated the highest diastolic diameter. The highest blood mean flow velocity was recorded in ulnar (p < 0.001) and popliteal arteries (p < 0.001) of the Judo athletes groups. Recording differences between the two genders, male participants presented larger arteries than females. Conclusively, Judo has been found to be a highly demanding physical sport, involving upper and lower limbs leading to significant arterial adaptations. Obtaining vascular parameters provide a useful tool to the medical team, not only in the direction of enhancement of the efficacy of physical training, but in unknown so far parameters that may influence athletic performance of both male and female elite Judokas. Key pointsJudo athletes demonstrated a general homogenous increase of the arterial functionality of the upper and lower limbs compared to the control groups.Diastolic diameter found to be significantly increased in male and female Judo athletes, highlighting the effects of exercise training on the vascular system.Judo athletes had had statistically significant increase of the blood mean flow velocity in all examined arteries, compared with the relevant control group.The current study underscores the impact of Judo training on the structure and the function of the arterial system.Clinically, the increased arterial parameters in elite Judo athletes may be essential elements for improved athletic performance.Sports medicine practitioners should give special concern to the vascular functionality for several physiological and medical tests. PMID- 24150008 TI - A motivational music and video intervention improves high-intensity exercise performance. AB - Music and video are utilised by recreational gym users to enhance their exercise experience. Music and video have not been investigated for their combined ergogenic effect during high intensity exercise. To induce fatigue, this study was performed in warm (~26 degrees C), moist conditions (~50%RH). Six, non acclimated, male participants took part in the study. Each participant completed three 30-minute exercise bouts on a motorised treadmill under three counterbalanced conditions on separate days: control (CON), motivational music plus video intervention (M), non-motivational intervention (NM). They completed a warm-up (5 km.h(-1) [5 minutes], 9km.h(-1) [10 minutes]) followed by a maximal effort run (15 minutes). Participants did not receive any feedback of time elapsed, distance run or speed. MEASURES: Distance covered (metres), heart rate, blood lactate accumulation (B(lac)) and ratings of perceived exertion (RPE). Participants in the M condition ran significantly further than in the NM (M: 3524 [388]metres; NM: 3110 [561]metres; CON: 3273 [458]metres) and CON conditions, accumulated more B(lac), but did not increase their peak RPE rating (p < 0.05). The M intervention improved tolerance of high intensity exercise in warm conditions. It was proposed that a change in attentional processing from internal (physical sensations) to external perspective (music and video) may have facilitated this improvement. These findings have strong implications for improving health, fitness and engagement in gym-based exercise programs. Key pointsThe study examined the ergogenic effect of a motivational (M) video and music intervention on high-intensity exercise performance in comparison to a non motivational (NM) condition and a control (CON).PARTICIPANTS IN THE M CONDITION RAN SIGNIFICANTLY FURTHER THAN IN THE NM (M: 3524 [388]metres; NM: 3110 [561]metres; CON: 3273 [458]metres) and CON conditions, accumulated more B(lac), but did not increase their peak RPE rating (p < 0.05).It was proposed that a change in attentional processing from internal (physical sensations) to external perspective (music and video) may have facilitated this improvement.These findings have strong implications for improving health, fitness and engagement in gym-based exercise programs. PMID- 24150009 TI - Gender differences in sport injury risk and types of inju-ries: a retrospective twelve-month study on cross-country skiers, swimmers, long-distance runners and soccer players. AB - This twelve months survey compared injury risk and injury types by genders (312 females, 262 males) in 15- to 35-year-old cross-country skiers, swimmers, long- distance runners and soccer players. More male than female athletes reported at least one acute injury (44% vs. 35%, p < 0.05), and more male than female runners reported at least one overuse injury (69% vs. 51%, p < 0.05). When the incidence of acute and overuse injuries both separately and combined was calculated per 1000 training hours, per 1000 competition hours and all exposure hours combined we found no gender differences in either of these comparisons. After adjustment for sport event males were at increased risk for posterior thigh overuse injuries compared to females (relative risk (RR) 5.8, 95% confidence interval (CI) 1.3 to 26.4, p < 0.05) while females were at increased risk for overuse injuries in the ankle compared to males (RR 3.1, 95% CI 1.0 to 9.3, p < 0.05). After adjustment for exposure time (injuries/1000 exposure hours) significance of the difference between the sexes in overuse injury to the ankle persisted (female 0.11 vs. male 0.02 injuries/1000 exposure hours, p < 0.05). Six athletes had an anterior cruciate ligament (ACL) injury, of whom four were female soccer players. After combining all reported acute and overuse ankle and knee injuries, the proportion of athletes with such injury was higher in the female compared to male soccer players (75% and 54% respectively; p < 0.05), but no difference was found in such injuries when calculated per 1000 exposure hours. In conclusion, we found some gender differences in sport-related injuries, but most of these differences seemed to be explained at least in part by differences in the amount of training. Key pointsOnly a few sport injury studies have compared in-jury rates between the sexesOverall gender-related risk for acute and overuse injuries in top-level athletes between the sexes was smallSome gender differences in the specific anatomical locations of injuries as well as in specific injuries in sports were foundSome of these differences seem to be explained by the differences in the amount of training. PMID- 24150010 TI - The difference in respiratory and blood gas values during recovery after exercise with spontaneous versus reduced breathing frequency. AB - Extrapolation from post-exercise measurements has been used to estimate respiratory and blood gas parameters during exercise. This may not be accurate in exercise with reduced breathing frequency (RBF), since spontaneous breathing usually follows exercise. This study was performed to ascertain whether measurement of oxygen saturation and blood gases immediately after exercise accurately reflected their values during exercise with RBF. Eight healthy male subjects performed an incremental cycling test with RBF at 10 breaths per minute. A constant load test with RBF (B10) was then performed to exhaustion at the peak power output obtained during the incremental test. Finally, the subjects repeated the constant load test with spontaneous breathing (SB) using the same protocol as B10. Pulmonary ventilation (VE), end-tidal oxygen (PETO2), and carbon dioxide pressures (PETCO2) and oxygen saturation (SaO2) were measured during both constant load tests. The partial pressures of oxygen (PO2) and carbon dioxide (PCO2) in capillary blood were measured during the last minute of exercise, immediately following exercise and during the third minute of recovery. At the end of exercise RBF resulted in lower PETO2, SaO2 and PO2, and higher PETCO2 and PCO2 when compared to spontaneous breathing during exercise. Lower SaO2 and PETO2 were detected only for the first 16s and 20s of recovery after B10 compared to the corresponding period in SB. There were no significant differences in PO2 between SB and B10 measured immediately after the exercise. During recovery from exercise, PETCO2 remained elevated for the first 120s in the B10 trial. There were also significant differences between SB and B10 in PCO2 immediately after exercise. We conclude that RBF during high intensity exercise results in hypoxia; however, due to post-exercise hyperpnoea, measurements of blood gas parameters taken 15s after cessation of exercise did not reflect the changes in PO2 and SaO2 seen during exercise. Key pointsIn some sports, the environment is inappropriate for direct measurement of respiratory and blood gas parameters during exercise. To overcome this problem, extrapolation from post-exercise measurements has often been used to estimate changes in respiratory and blood gas parameters during exercise.The possibility of hypoxia and hypercapnia during exercise with reduced breathing frequency has been tested by measuring capillary blood sampled after the exercise.Reduced breathing frequency during high intensity exercise results in hypoxia; however, due to marked post-exercise hyperventilation, measurements of blood gas parameters taken 15 s after the cessation of exercise did not yield any changes in these parameters.Despite hyperventilation during recovery, hypercapnia could be detected by measuring blood gas parameters within 15 s after the exercise with reduced breathing frequency. PMID- 24150011 TI - Effects of Consecutive Basketball Games on the Game-Related Statistics that Discriminate Winner and Losing Teams. AB - The aim of the present study was to identify the game-related statistics that discriminated basketball winning and losing teams in each of the three consecutive games played in a condensed tournament format. The data were obtained from the Spanish Basketball Federation and included game-related statistics from the Under-20 league (2005-2006 and 2006-2007 seasons). A total of 223 games were analyzed with the following game-related statistics: two and three-point field goal (made and missed), free-throws (made and missed), offensive and defensive rebounds, assists, steals, turnovers, blocks (made and received), fouls committed, ball possessions and offensive rating. Results showed that winning teams in this competition had better values in all game-related statistics, with the exception of three point field goals made, free-throws missed and turnovers (p >= 0.05). The main effect of game number was only identified in turnovers, with a statistical significant decrease between the second and third game. No interaction was found in the analysed variables. A discriminant analysis allowed identifying the two-point field goals made, the defensive rebounds and the assists as discriminators between winning and losing teams in all three games. Additionally to these, only the three-point field goals made contributed to discriminate teams in game three, suggesting a moderate effect of fatigue. Coaches may benefit from being aware of this variation in game determinant related statistics and, also, from using offensive and defensive strategies in the third game, allowing to explore or hide the three point field-goals performance. Key pointsOverall team performances along the three consecutive games were very similar, not confirming an accumulated fatigue effect.The results from the three-point field goals in the third game suggested that winning teams were able to shoot better from longer distances and this could be the result of exhibiting higher conditioning status and/or the losing teams' exhibiting low conditioning in defense. PMID- 24150012 TI - Effect of the rotor crank system on cycling performance. AB - The aim of this study was to evaluate the impact of a novel crank system on laboratory time-trial cycling performance. The Rotor system makes each pedal independent from the other so that the cranks are no longer fixed at 180 degrees . Twelve male competitive but non-elite cyclists (mean +/- s: 35 +/- 7 yr, Wmax = 363 +/- 38 W, VO2peak = 4.5 +/- 0.3 L.min(-1)) completed 6-weeks of their normal training using either a conventional (CON) or the novel Rotor (ROT) pedal system. All participants then completed two 40.23-km time-trials on an air-braked ergometer, one using CON and one using ROT. Mean performance speeds were not different between trials (CON = 41.7 km.h(-1) vs. ROT = 41.6 km.h(-1), P > 0.05). Indeed, the pedal system used during the time-trials had no impact on any of the measured variables (power output, cadence, heart rate, VO2, RER, gross efficiency). Furthermore, the ANOVA identified no significant interaction effect between main effects (Time-trial crank system*Training crank system, P > 0.05). To the authors' knowledge, this is the first study to examine the effects of the Rotor system on endurance performance rather than endurance capacity. These results suggest that the Rotor system has no measurable impact on time-trial performance. However, further studies should examine the importance of the Rotor 'regulation point' and the suggestion that the Rotor system has acute ergogenic effects if used infrequently. Key pointsThe Rotor crank system does not improve gross efficiency in well-trained cyclists.The Rotor crank system has no measurable impact on laboratory 40.23-km time-trial performance.A 6-week period of familiarisation does not increase the effectiveness of the Rotor crank system. PMID- 24150014 TI - The nephrotoxicity risk in rats subjected to heavy muscle activity. AB - When the body is exposed to insults, the kidneys exhibit adaptive changes termed renal cytoresistance, characterized by cholesterol accumulation in the membranes of the tubule cells. However, heavy muscle activity has not yet been accepted as one of the stressors that could lead to cytoresistance. In order to study the renal functional characteristics of animals exposed to heavy muscle activity, rats were subjected to exhaustive treadmill exercise for 5 days and their data was compared to those of sedentary controls. It was found that in exercised rats, blood lactate, muscle citrate synthase and proximal tubule peroxynitrite levels were all elevated, suggesting the presence of oxidative stress in the proximal tubule segments. However, mean arterial pressure, renal blood flow, glomerular filtration rate, fractional excretion of sodium and potassium, and organic anion excretion remained normal. Despite unchanged blood cholesterol levels, cholesterol loading in the proximal tubule segments, especially the free form, and decreased lactate dehydrogenase release from cytoresistant proximal tubule segments indicated the development of renal cytoresistance. However, this resistance did not seem to have protected the kidneys as expected because organic anion accumulation associated with glycosuria and proteinuria, in addition to the elevated urinary cholesterol levels, all imply the presence of an impaired glomerular permeability and reabsorption in the proximal tubule cells. Therefore, we suggest that in response to heavy muscle activity the tubular secretion may remain intact, although cytoresistance in the proximal tubule cells may affect the tubular reabsorptive functions and basolateral uptake of substances. Thus, this differential sensitivity in the cytoresistance should be taken into account during functional evaluation of the kidneys. Key pointsThe cholesterol loading and decreased LDH release from PTSs isolated from exhausted rats indicate the heavy muscle activity induced renal cytoresistance.Heavy muscle activity-induced renal cytoresistance did not preserve the kidney functions.Organic anion accumulation as well as failure in the absorptive capacity of the tubule cells suggest the presence of some biochemical changes and elevated vulnerability of kidneys against nephrotoxic agents in rats subjected to heavy muscle activity. PMID- 24150013 TI - Grape extract improves antioxidant status and physical performance in elite male athletes. AB - Excessive physical exercise overproduces reactive oxygen species. Even if elite sportsmen increase their antioxidant status by regular physical training, during the competition period, this improvement is not sufficient to limit free radical production which could be detrimental to the body. The aim of this randomized, double-blind, placebo controlled, and crossover study on 20 elite sportsmen (handball = 10, basketball = 5, sprint = 4, and volleyball = 1) during the competition period was to determine if the consumption of a grape extract (GE; Vitis vinifera L.) was able to improve the parameters related to (i) anti oxidative status and oxidative stress and (ii) physical performance. Specific biomarkers of antioxidant capacity, oxidative stress, skeletal cell muscle damage, and other general biomarkers were determined in plasma and urine before (D0) and after one month (D30) of placebo or GE supplementation (400mg.d(-1)). Effort tests were conducted using the Optojump((r)) system, which allows determining the total physical performance (EnRJ45), explosive power (RJ110), and fatigue (RJL5). The plasma ORAC value was not modified in the placebo group; however, GE increased the ORAC value compared to the placebo at D30 (14 966+/-335 vs 14 242+/-339 dumol Teq.L(-1); p < 0.05). The plasma FRAP value was significantly reduced in the placebo group, but not in the GE group. Therefore, GE limited the reduction of FRAP compared to the placebo at D30 (1 053.7+/-31.5 vs 993.7+/-26.7 umol Teq.L(-1); p < 0.05). Urinary isoprostane values were increased in the placebo group, but were not modified in the GE group. Consequently, GE limited the production of isoprostanes compared to the placebo at D30 (1.24+/-0.12 vs 1.26+/-0.13 ng.mg(-1) creatinine; p < 0.05). GE administration, compared to the placebo at D30, reduced the plasmatic creatine phosphokinase concentration (CPK, 695.7+/-177.0 vs 480.0+/-81.1 IU.L(-1), p = 0.1) and increased hemoglobin levels (Hb, 14.5+/-0.2 vs 14.8+/-0.2 vs g.dL(-1), p < 0.05), suggesting that GE administration might protect cell damage during exercise. The high variability between sport disciplines did not permit to observe the differences in the effort test. Analyzing each individual group, handball players increased their physical performance by 24% (p < 0.05) and explosive power by 6.4% (p = 0.1) after GE supplementation compared to the placebo. Further analyses showed that CPK and Hb were the only biomarkers correlated with the increase in performance. In conclusion, GE ameliorates the oxidative stress/antioxidant status balance in elite athletes in the competition period, and enhances performance in one category of sportsmen (handball). Our results suggest that the enhancement in performance might be caused by the protective action of GE during physical exercise. These findings encourage conducting further studies to confirm the efficacy and mechanisms of action of GE on elite and occasional athletes. Key pointsGrape extract consumption improves the oxidative stress/antioxidant status balance in sportsmen.Grape extract consumption enhances physical performance in one category of sportsmen (Handball).The performance enhancement might be caused by the protective action of grape extract during physical exercise. PMID- 24150015 TI - Niche separation of sympatric macaques, Macaca assamensis and M. mulatta, in limestone habitats of Nonggang, China. AB - Comparative studies of sympatric species are essential in understanding those species' behavioral and ecological adaptations as well as the mechanisms that can reduce resource competition enough to allow coexistence. We collected data on diet, activity budget and habitat use from two sympatric macaque species, the Assamese macaque (Macaca assamensis) and the rhesus macaque (M. mulatta), in a limestone seasonal rainforest of Nonggang Nature Reserve, southwestern Guangxi, China. Our results show that the two sympatric macaques differ in diet, activity budget, and habitat use: (1) out of the 131 plant species that were used by both macaque species as food over the year, only 15 plant species (11 %) were shared. Rhesus macaques used more plant species as major foods, and had higher dietary diversity and evenness indexes than Assamese macaques. (2) Assamese macaques fed predominantly on leaves, whereas rhesus macaques fed more selectively on fruits. The rhesus macaques' diet varied according to season, and was significantly correlated to season fluctuation in fruit availability. (3) Assamese macaques devoted more time to resting, and less time to feeding than rhesus macaques (4) Assamese macaques were present mostly on the cliff, and tended to stay on the ground, whereas rhesus macaques were present mostly on the hillside, and showed preference to lower and middle canopy. The observed differences in diet and habitat use between the two macaque species represent behavioral patterns enabling their coexistence. PMID- 24150016 TI - Rb1 family mutation is sufficient for sarcoma initiation. AB - It is thought that genomic instability precipitated by Rb1 pathway loss rapidly triggers additional cancer gene mutations, accounting for rapid tumour onset following Rb1 mutation. However, recent whole-genome sequencing of retinoblastomas demonstrated little genomic instability, but instead suggested rapid epigenetic activation of cancer genes. These results raise the possibility that loss of the Rb1 pathway, which is a hallmark of cancers, might be sufficient for cancer initiation. Yet, mutation of the Rb1 family or inactivation of the Rb1 pathway in primary cells has proven insufficient for tumour initiation. Here we demonstrate that traditional nude mouse assays impose an artificial anoikis and proliferation barrier that prevents Rb1 family mutant fibroblasts from initiating tumours. By circumventing this barrier, we show that primary fibroblasts with only an Rb1 family mutation efficiently form sarcomas in nude mice, and a Ras ZEB1-Akt pathway then causes transition of these tumours to an invasive phenotype. PMID- 24150018 TI - Transcending politics to promote women's health. PMID- 24150019 TI - Transcending politics to promote women's health. PMID- 24150020 TI - Transcending politics to promote women's health. PMID- 24150021 TI - In reply. PMID- 24150022 TI - Oral contraceptive pills as primary prevention for ovarian cancer: a systematic review and meta-analysis. PMID- 24150023 TI - In reply. PMID- 24150027 TI - Hypertension in pregnancy. Report of the American College of Obstetricians and Gynecologists' Task Force on Hypertension in Pregnancy. PMID- 24150028 TI - ACOG Committee Opinion No. 577: Understanding and using the U.S. Selected Practice Recommendations for Contraceptive Use, 2013. AB - The U.S. Selected Practice Recommendations for Contraceptive Use, 2013 (U.S. SPR), issued by the Centers for Disease Control and Prevention is a companion piece to the Centers for Disease Control and Prevention's U.S. Medical Eligibility Criteria for Contraceptive Use, 2010. The U.S. Medical Eligibility Criteria for Contraceptive Use, 2010, provides guidance for which contraceptive methods are safe for women with selected characteristics and medical conditions, whereas the U.S. SPR offers guidance on how to use these methods most effectively. The American College of Obstetricians and Gynecologists endorses the U.S. SPR and encourages its use by Fellows; providers should always consider the specific clinical situation when applying these guidelines to individual clinical care. PMID- 24150029 TI - ACOG CommitteeOpinion No. 578: Elective surgery and patient choice. AB - Acknowledgment of the importance of patient autonomy and increased patient access to information, such as information on the Internet, has prompted more patient generated requests for surgical interventions not traditionally recommended. Depending on the context, acceding to a request for a surgical option that is not traditionally recommended can be ethical. Decisions about acceding to patient requests for nontraditional surgical interventions should be based on strong support for patients' informed preferences and values; understood in the context of an interpretive conversation; and consistent with considerations of safety, cost-effectiveness, and attention to effects on the health care system of expanded choice. Physicians should make sure that their counseling about specific risks and benefits is based on current evidence. After the physician has provided information and careful counseling, the patient and physician will often reach a mutually acceptable decision. If the patient and physician cannot reach an agreement, then referral or second opinion may be appropriate. PMID- 24150030 TI - ACOG Committee Opinion No 579: Definition of term pregnancy. AB - In the past, the period from 3 weeks before until 2 weeks after the estimated date of delivery was considered "term," with the expectation that neonatal outcomes from deliveries in this interval were uniform and good. Increasingly, however, research has shown that neonatal outcomes, especially respiratory morbidity, vary depending on the timing of delivery within this 5-week gestational age range. To address this lack of uniformity, a work group was convened in late 2012, which recommended that the label "term" be replaced with the designations early term (37 0/7 weeks of gestation through 38 6/7 weeks of gestation), full term (39 0/7 weeks of gestation through 40 6/7 weeks of gestation), late term (41 0/7 weeks of gestation through 41 6/7 weeks of gestation), and postterm (42 0/7 weeks of gestation and beyond) to more accurately describe deliveries occurring at or beyond 37 0/7 weeks of gestation. The American College of Obstetricians and Gynecologists and the Society for Maternal-Fetal Medicine endorse and encourage the uniform use of the work group's recommended new gestational age designations by all clinicians, researchers, and public health officials to facilitate data reporting, delivery of quality health care, and clinical research. PMID- 24150032 TI - Regional airway obstruction in cystic fibrosis determined by electrical impedance tomography in comparison with high resolution CT. AB - Electrical impedance tomography (EIT) is able to deliver regional information to assess the airway obstruction in patients with cystic fibrosis (CF). In the present study, regional obstruction in CF patients measured by EIT was compared with high resolution computed tomography (HRCT). Five CF patients were routinely scheduled for HRCT examination. EIT measurements were performed on these patients +/-2 months during a standard pulmonary function test. The weighted Brody score derived from HRCT, which considers bronchiectasis, mucus plugging, peribronchial thickening, parenchymal opacity and hyperinflation, was calculated from the CT scans acquired at the location of EIT electrodes +/-5 cm. Ratios of maximum expiratory flows at 25% and 75% of vital capacity (MEF25/MEF75) with respect to relative impedance change were calculated for regional areas in EIT images. Regional airway obstruction identified in the MEF25/MEF75 maps was similar to that found in CT. Median values of MEF25/MEF75 and weighted Brody score were highly correlated (r(2) = 0.83, P < 0.05). We found that regional obstruction measured by EIT is reliable and may be used as an additional clinical examination tool for CF patients. PMID- 24150033 TI - The first bismuth-NHC complexes. AB - The synthesis, isolation and crystallographic characterization of the first N heterocyclic carbene adducts of bismuth is reported, by direct reaction of the Dipp2NHC (Dipp = 2,6-diisopropylphenyl) or (i)Pr2(Me2)NHC with BiCl3. This represents the last non-radioactive element from groups 13-17 for which an NHC element fragment remained unreported. PMID- 24150034 TI - Photosynthesis of Quercus suber is affected by atmospheric NH3 generated by multifunctional agrosystems. AB - Montados are evergreen oak woodlands dominated by Quercus species, which are considered to be key to biodiversity conservation and ecosystem services. This ecosystem is often used for cattle breeding in most regions of the Iberian Peninsula, which causes plants to receive extra nitrogen as ammonia (NH(3)) through the atmosphere. The effect of this atmospheric NH(3) (NH(3atm)) on ecosystems is still under discussion. This study aimed to evaluate the effects of an NH(3atm) concentration gradient downwind of a cattle barn in a Montado area. Leaves from the selected Quercus suber L. trees along the gradient showed a clear influence of the NH(3) on delta(13)C, as a consequence of a strong limitation on the photosynthetic machinery by a reduction of both stomatal and mesophyll conductance. A detailed study of the impact of NH(3atm) on the photosynthetic performance of Q. suber trees is presented, and new mechanisms by which NH(3) affects photosynthesis at the leaf level are suggested. PMID- 24150035 TI - Effects of temperature and water deficit on cambial activity and woody ring features in Picea mariana saplings. AB - Increase in temperature under the projected future climate change would affect tree growth, including the physiological mechanisms related to sapling responses, which has been examined recently. The study investigated the plant water relations, cambial activity and wood formation in black spruce saplings [Picea mariana (Mill.) B.S.P.] subjected to water deficit and warming. Four-year-old saplings growing in three greenhouses were submitted to different thermal conditions: T0, with a temperature equal to the external air temperature; and T + 2 and T + 5, with temperatures set at 2 and 5 K higher than T0, respectively. We also submitted saplings to two irrigation regimes and studied the effects of a water deficit of 32 days in May-June. We evaluated plant water relations, cambial activity, wood formation and anatomical characteristics from May to October 2010. Lower needle physiology rates were observed during water deficit, with 20-day suspension of irrigation, but after re-watering, non-irrigated saplings attained the same values as irrigated ones in all thermal conditions. Significant differences between irrigation regimes were detected in cambial activity at the end of the water deficit and after resumption of irrigation. Under warmer conditions, the recovery of non-irrigated saplings was slower than T0 and they needed from 2 to 4 weeks to completely restore cambial activity. No significant differences in wood anatomy were observed between irrigation regimes, but there was a sporadic effect on wood density under warming. During wood formation, the warmer conditions combined with water deficit increased sapling mortality by 5 and 12.2% for T + 2 and T + 5, respectively. The black spruce saplings that survived were more sensitive to water availability, and the restoration of cambial activity was slower at temperatures higher than T0. Our results suggest that black spruce showed a plastic response to intense water deficit under warming, but this would compromise their survival. PMID- 24150037 TI - Examining the source behind Sherpa mountain fitness. PMID- 24150036 TI - Surgical techniques for spinopelvic reconstruction following total sacrectomy: a systematic review. AB - PURPOSE: To identify all available reconstruction methods for a total sacrectomy. Secondarily, we aimed to evaluate outcomes based on different interventions. METHODS: We searched PubMed to identify sacral resections for tumors requiring internal fixation for stabilization. Demographic information, fixation techniques and postoperative outcomes were abstracted. RESULTS: Twenty-three publications (43 patients) met inclusion criteria from an initial search of 856 (kappa 0.93). Mean age was 37 years and follow-up was 33 months. Fixation methods included a combination of spinopelvic fixation (SPF), posterior pelvic ring fixation (PPRF), and/or anterior spinal column fixation (ASCF). For the purposes of analysis, patients were segregated based on whether they received ASCF. Postoperative complications including wound/instrument infections, GI or vascular complications were reported at a higher rate in the non-ASCF group (1.63 complications/patient vs. 0.7 complications/patient). Instrument failure was seen in 5 (16.1 %) out of the 31 patients with reported outcomes. Specifically, 1 out of 8 patients (12.5 %) with ASCF compared with 4 out of 23 patients (17.4 %) without ASCF had hardware failure. At final follow-up, 35 of 39 patients were ambulating. CONCLUSION: While surgical treatment of primary sacral tumors remains a challenge, there have been advances in reconstruction techniques following total sacrectomy. SPF has shifted from intrapelvic rod and hook constructs to pedicle and iliac screw-rod systems for improved rigidity. PPRF and ASCF have adapted for deficiencies in the posterior ring and anterior column. A trend toward a lower rate of hardware failure emerged in the group utilizing anterior spinal column support. Despite a more involved reconstruction with ASCF, surgical complications such as infection rates and blood loss were lower compared to the group without ASCF. While we cannot definitively say one system is superior to the other, based on the data gleaned from this systematic review, it is our opinion that incorporation of ASCF in reconstructing the spinopelvic junction may lead to improved outcomes. However, most importantly, we recommend that the treating surgeon operate on patients requiring a total sacrectomy based on his or her level of comfort, as these cases can be extremely challenging even among experts. PMID- 24150038 TI - Reconciling phylodynamics with epidemiology: the case of dengue virus in southern Vietnam. AB - Coalescent methods are widely used to infer the demographic history of populations from gene genealogies. These approaches-often referred to as phylodynamic methods-have proven especially useful for reconstructing the dynamics of rapidly evolving viral pathogens. Yet, population dynamics inferred from viral genealogies often differ widely from those observed from other sources of epidemiological data, such as hospitalization records. We demonstrate how a modeling framework that allows for the direct fitting of mechanistic epidemiological models to genealogies can be used to test different hypotheses about what ecological factors cause phylodynamic inferences to differ from observed dynamics. We use this framework to test different hypotheses about why dengue serotype 1 (DENV-1) population dynamics in southern Vietnam inferred using existing phylodynamic methods differ from hospitalization data. Specifically, we consider how factors such as seasonality, vector dynamics, and spatial structure can affect inferences drawn from genealogies. The coalescent models we derive to take into account vector dynamics and spatial structure reveal that these ecological complexities can substantially affect coalescent rates among lineages. We show that incorporating these additional ecological complexities into coalescent models can also greatly improve estimates of historical population dynamics and lead to new insights into the factors shaping viral genealogies. PMID- 24150039 TI - Massive habitat-specific genomic response in D. melanogaster populations during experimental evolution in hot and cold environments. AB - Experimental evolution in combination with whole-genome sequencing (evolve and resequence [E&R]) is a promising approach to define the genotype-phenotype map and to understand adaptation in evolving populations. Many previous studies have identified a large number of putative selected sites (i.e., candidate loci), but it remains unclear to what extent these loci are genuine targets of selection or experimental noise. To address this question, we exposed the same founder population to two different selection regimes-a hot environment and a cold environment-and quantified the genomic response in each. We detected large numbers of putative selected loci in both environments, albeit with little overlap between the two sets of candidates, indicating that most resulted from habitat-specific selection. By quantifying changes across multiple independent biological replicates, we demonstrate that most of the candidate SNPs were false positives that were linked to selected sites over distances much larger than the typical linkage disequilibrium range of Drosophila melanogaster. We show that many of these mid- to long-range associations were attributable to large segregating inversions and confirm by computer simulations that such patterns could be readily replicated when strong selection acts on rare haplotypes. In light of our findings, we outline recommendations to improve the performance of future Drosophila E&R studies which include using species with negligible inversion loads, such as D. mauritiana and D. simulans, instead of D. melanogaster. PMID- 24150040 TI - Plant expansins in bacteria and fungi: evolution by horizontal gene transfer and independent domain fusion. AB - Horizontal gene transfer (HGT) has been described as a common mechanism of transferring genetic material between prokaryotes, whereas genetic transfers from eukaryotes to prokaryotes have been rarely documented. Here we report a rare case of HGT in which plant expansin genes that code for plant cell-wall loosening proteins were transferred from plants to bacteria, fungi, and amoebozoa. In several cases, the species in which the expansin gene was found is either in intimate association with plants or is a known plant pathogen. Our analyses suggest that at least two independent genetic transfers occurred from plants to bacteria and fungi. These events were followed by multiple HGT events within bacteria and fungi. We have also observed that in bacteria expansin genes have been independently fused to DNA fragments that code for an endoglucanase domain or for a carbohydrate binding module, pointing to functional convergence at the molecular level. Furthermore, the functional similarities between microbial expansins and their plant xenologs suggest that these proteins mediate microbial plant interactions by altering the plant cell wall and therefore may provide adaptive advantages to these species. The evolution of these nonplant expansins represents a unique case in which bacteria and fungi have found innovative and adaptive ways to interact with and infect plants by acquiring genes from their host. This evolutionary paradigm suggests that despite their low frequency such HGT events may have significantly contributed to the evolution of prokaryotic and eukaryotic species. PMID- 24150042 TI - Acupuncture and related techniques in ambulatory anesthesia. AB - PURPOSE OF REVIEW: Along with a growing awareness of quality in healthcare, has come a focus on postanesthetic morbidities, which still remain challenging in our daily practice of anesthesia. Acupuncture and related techniques (acustimulation) are often suggested to be adequate treatments with low cost and minimal adverse effects. This review focuses on the current evidence and applicability of these techniques for use in ambulatory anesthesia. RECENT FINDINGS: Trials exploring the effects of acustimulation may produce ambiguous results and sometimes be difficult to evaluate. Controversies still remain as to the clinical relevance. Recent trials suggest that acustimulation may prevent postoperative pain, nausea and vomiting. There are also promising results for the use of the techniques in reducing preoperative anxiety, postoperative shivering and emergence delirium. SUMMARY: Pharmacological drug treatment may be only partially effective and produce an adverse event. Research suggests that acustimulation may alleviate postoperative morbidities, although the body of evidence of the effect is equivocal. The treatments are easy to perform, and adverse events and costs are minimal. It may be profitable to implement this beneficial treatment to asmbulatory patients. PMID- 24150041 TI - Critical evaluation of auditory event-related potential deficits in schizophrenia: evidence from large-scale single-subject pattern classification. AB - Event-related potential (ERP) deficits associated with auditory oddball and click conditioning paradigms are among the most consistent findings in schizophrenia and are discussed as potential biomarkers. However, it is unclear to what extend these ERP deficits distinguish between schizophrenia patients and healthy controls on a single-subject level, which is of high importance for potential translation to clinical routine. Here, we investigated 144 schizophrenia patients and 144 matched controls with an auditory click-conditioning/oddball paradigm. P50 and N1 gating ratios as well as target-locked N1 and P3 components were submitted to conventional general linear models and to explorative machine learning algorithms. Repeated-measures ANOVAs revealed significant between-group differences for the oddball-locked N1 and P3 components but not for any gating measure. Machine learning-assisted analysis achieved 77.7% balanced classification accuracy using a combination of target-locked N1 and P3 amplitudes as classifiers. The superiority of machine learning over repeated-measures analysis for classifying schizophrenia patients was in the range of about 10% as quantified by receiver operating characteristics. For the first time, our study provides large-scale single-subject classification data on auditory click conditioning and oddball paradigms in schizophrenia. Although our study exemplifies how automated inference may substantially improve classification accuracy, our data also show that the investigated ERP measures show comparably poor discriminatory properties in single subjects, thus illustrating the need to establish either new analytical approaches for these paradigms or other paradigms to investigate the disorder. PMID- 24150043 TI - The neighborhood where you live is a risk factor for stroke. AB - BACKGROUND: The excess stroke mortality in the southeastern states of the United States (stroke-belt states) is well known; however, the factors associated with this pattern have not been fully elucidated. We measured the contribution of several demographic factors by analyzing stroke mortality data (2005-2009) at the census block group (BG) level in the state of Arkansas. METHODS AND RESULTS: Census BGs were used as proxies for neighborhoods. BGs were stratified using 5 census measures: poverty (percent of population below federal poverty level), population density (population per square mile), education (percent of population aged >25 years who did not graduate from high school), population mobility (percent of population who resided at the same address 1 year ago), and the percent of non-Hispanic blacks (percent of population that is black). Generalized additive models were used to estimate the variation in stroke mortality among BGs and to assess the impact of different demographic variables. From 2005 to 2009, there were 8930 stroke deaths in Arkansas. There was considerable variation in the relative risk even between adjacent BGs within a single county. The geographically weighted regression analyses indicated that 4.5% to 9% of deviance in stroke mortality among BGs could be explained by poverty, education, population density, and population mobility. Race/ethnicity (non-Hispanic blacks) explains <2% of the deviance in stroke mortality among BGs. CONCLUSIONS: Our study shows that primordial risk factors such as poverty and education drive disparities in stroke mortality among neighborhoods in Arkansas. PMID- 24150044 TI - Dynamic prediction modeling approaches for cardiac surgery. AB - BACKGROUND: The calibration of several cardiac clinical prediction models has deteriorated over time. We compare different model fitting approaches for in hospital mortality after cardiac surgery that adjust for cross-sectional case mix in a heterogeneous patient population. METHODS AND RESULTS: Data from >300 000 consecutive cardiac surgery procedures performed at all National Health Service and some private hospitals in England and Wales between April 2001 and March 2011 were extracted from the National Institute for Cardiovascular Outcomes Research clinical registry. The study outcome was in-hospital mortality. Model approaches included not updating, periodic refitting, rolling window, and dynamic logistic regression. Covariate adjustment was made in each model using variables included in the logistic European System for Cardiac Operative Risk Evaluation model. The association between in-hospital mortality and some variables changed with time. Notably, the intercept coefficient has been steadily decreasing during the study period, consistent with decreasing observed mortality. Some risk factors, such as operative urgency and postinfarct ventricular septal defect, have been relatively stable over time, whereas other risk factors, such as left ventricular function and surgery on the thoracic aorta, have been associated with lower risk relative to the static model. CONCLUSIONS: Dynamic models or periodic model refitting is necessary to counteract calibration drift. A dynamic modeling framework that uses contemporary and available historic data can provide a continuously smooth update mechanism that also allows for inferences to be made on individual risk factors. Better models that withstand the effects of time give advantages for governance, quality improvement, and patient-level decision making. PMID- 24150045 TI - eComment. Is overgrowth of costal cartilages the unique cause of pectus deformities? PMID- 24150046 TI - eComment. Dilemma of the costal cartilage overgrowth in chest wall deformities. PMID- 24150047 TI - eComment. Incidence of patient-prosthesis mismatch in patients with a Perceval S valve. PMID- 24150048 TI - eComment. Is adventitial dissection enough as a simple and effective way to reduce radial artery spasm? PMID- 24150049 TI - eComment. Genetics and delirium after heart surgery. PMID- 24150050 TI - eComment. Delirium after cardiac surgery: incidence and risk factors. PMID- 24150051 TI - eComment. Postoperative delirium in elderly cardiac surgery patients. PMID- 24150052 TI - eComment. Risk factors for delirium after cardiac and peripheral vascular surgery. PMID- 24150053 TI - eComment. Negative effect of delirium beyond the immediate postoperative period. PMID- 24150054 TI - eComment. Is surgery still worthwhile as compared to stereotactic ablative radiotherapy or CyberKnife in high-risk surgical patients with Stage I non-small cell-lung cancer? PMID- 24150055 TI - eComment. Transcatheter heart valve in the pulmonary position. PMID- 24150056 TI - eComment. Post-sternotomy mediastinitis management: negative pressure is the key. PMID- 24150057 TI - eComment. Stroke rate after surgical myocardial revascularization. PMID- 24150058 TI - e-Comment: conducting meta-analyses of off-pump versus on-pump coronary artery bypass surgery: where we stand. PMID- 24150059 TI - eComment. Mini-partial heart autotransplantation for atrial fibrillation and mitral valve surgery. PMID- 24150060 TI - eComment: partial cardiac autotransplantation with a concomitant mitral valve, aortic valve replacement and tricuspid plasty. PMID- 24150062 TI - Outcomes of Stay Strong, Stay Healthy in community settings. AB - Loss of muscle strength, flexibility, and balance are strong predictors of falls in the elderly. OBJECTIVES: The goal of this research was to investigate the effectiveness of a 10-week, strength-based exercise program delivered by Extension professionals. METHODS: Matched pair t tests were used to compare differences in five measures of fitness collected from 808 participants (mean age = 65.4 years) at the start and finish of the exercise program. RESULTS: Following programming, participants significantly improved strength, flexibility, and balance. DISCUSSION: Results indicate that an evidence-based program can be translated into a community Extension program that is able to improve the fitness level of seniors. PMID- 24150063 TI - Severity of fall-based injuries, fear of falling, and activity restriction: sex differences in a population-based sample of older Canadian adults. AB - OBJECTIVES: Little is known about how different fall-based injuries relate to fear of falling and activity restriction, and if these relationships differ between sexes. We explored fear of falling and activity restriction in individuals who have experienced fall-based injuries. METHODS: A total of 16,369 older adults from the Canadian Community Health Survey reported their worst fall based injury, whether they experience fear of falling, and whether they restrict activities from fear of falling. RESULTS: Females had greater odds of fear of falling than males. Only females who experienced a fracture or head injury had increased odds of fear of falling and only females who experienced a head injury had increased odds of restricting activities compared with females who fell without injury. DISCUSSION: Only severe fall-based injuries are associated with fear of falling and activity restriction, and this relationship is unique to females. Sex differences warrant further investigation and suggest a need for targeted interventions. PMID- 24150064 TI - The CASZ1/Egfl7 transcriptional pathway is required for RhoA expression in vascular endothelial cells. AB - Vertebrate development depends on the formation of a closed circulatory loop consisting of intricate networks of veins, arteries, and lymphatic vessels. The coordinated participation of multiple molecules including growth factors, transcription factors, extracellular matrix proteins, and regulators of signaling such as small GTPases is essential for eliciting the desired cellular behaviors associated with vascular assembly and morphogenesis. We have recently demonstrated that a novel transcriptional pathway involving activation of the Epidermal Growth Factor-like Domain 7 (Egfl7) gene by the transcription factor CASTOR (CASZ1) is required for blood vessel assembly and lumen morphogenesis. Furthermore, this transcriptional network promotes RhoA expression and subsequent GTPase activity linking transcriptional regulation of endothelial gene expression to direct physiological outputs associated with Rho GTPase signaling, i.e., cell adhesion and cytoskeletal dynamics. Here we will discuss our studies with respect to our current understanding of the mechanisms underlying regulation of RhoA transcription, protein synthesis, and activity. PMID- 24150065 TI - Concerns regarding hair cortisol as a biomarker of chronic stress in exercise and sport science. AB - Hair cortisol has the potential to fill the methodological void of long-term cortisol assessment while becoming a widely accepted measure in biopsychology. This review critically examines the applicability and relevance of hair cortisol measurement specifically within the field of exercise and sport science. Current measures of the HPA axis only cover a brief time period, whereas hair cortisol is a unique, non-invasive means to capture long- term cortisol secretion. Studies have shown that individuals who have elevated cortisol secretion (e.g. due to diseases associated with a disturbed activation of the HPA axis or exposure to stressful life events) reveal increased hair cortisol. By contrast, only weak correlations exist between hair cortisol and perceived stress, and the direction of the relationship between hair cortisol levels and mental disorders is unclear. Acute exercise, however, results in increased levels of cortisol that eventually is reflected in higher levels of cortisol in hair samples and studies have shown that exercise intensity is related to hair cortisol level. Thus, elevated hair cortisol levels found among regular exercisers are not necessarily pathological. Thus, one should practice caution when associating athletes' elevated hair cortisol with poor mental health or disease. Hair cortisol analysis can contribute to a more complete understanding of how long-term cortisol elevation mediates stress-related effects on the health and performance of recreational exercisers and elite athletes. Nevertheless, it is crucial for exercise and sport scientists to consider whether their research questions can be adequately addressed, given that regular intense exercise results in substantially augmented hair cortisol levels. PMID- 24150066 TI - The influence of external perturbations on running kinematics and muscle activity before and after accommodation. AB - In the current study, the running pattern of the lower extremity was examined while being perturbed through tubes attached between the ankles and the lower back to analyze influences on the running pattern variability before and after a varied running intervention. 3D-kinematics, joint coupling and electromyography (EMG), as well as their variability, were analyzed in ten healthy male participants during treadmill running (10.5 km.h(-1)). Pre- and post-tests each consisted of 2 x 30 min treadmill running (one with and one without tubes). The results showed major acute effects on EMG and kinematics, as well as joint coordination variability, due to the constraints (p < 0.05). After the intervention, a process of normalization of most kinematic and EMG parameters occurred; however, EMG variability, kinematic variability and joint coordination variability were reduced during tube running below normal running level (p < 0.05). The findings further indicate rapid kinematic adaptations while muscle activity appears to require longer practice to adapt. The constraint serves to acutely increase variability, but may lead to reduced variability when applied for a longer period of time. PMID- 24150067 TI - Alteration of muscle function after electrical stimulation bout of knee extensors and flexors. AB - The purpose was to study the effects on muscle function of an electrical stimulation bout applied unilaterally on thigh muscles in healthy male volunteers. One group (ES group, n = 10) received consecutively 100 isometric contractions of quadriceps and 100 isometric contractions of hamstrings (on-off ratio 6-6 s) induced by neuromuscular electrical stimulations (NMES). Changes in muscle torque, muscle soreness (0-10 VAS), muscle stiffness and serum creatine kinase (CK) activity were assessed before the NMES exercise (pre-ex) as well as 24h (d+1), 48h (d+2) and 120h (d+5) after the bout. A second group (control group, n = 10) were submitted to the same test battery than the ES group and with the same time-frame. The between-group comparison indicated a significant increase in VAS scores and in serum levels of CK only in the ES group. In the ES group, changes were more pronounced in hamstrings than in quadriceps and peaked at d+2 (quadriceps VAS scores = 2.20 +/- 1.55 a.u. (0 at pre-ex); hamstrings VAS scores = 3.15 +/- 2.14 a.u. (0 at pre-ex); hip flexion angle = 62 +/- 5 degrees (75 +/- 6 degrees at pre-ex); CK activity = 3021 +/- 2693 IU.l(-1) (136 +/- 50 IU.l(-1) at pre-ex)). The results of the present study suggested the occurrence of muscle damage that could have been induced by the peculiar muscle recruitment in NMES and the resulting overrated mechanical stress. The sensitivity to the damaging effects of NMES appeared higher in the hamstrings than in quadriceps muscles. PMID- 24150068 TI - Acute effects of static stretching, dynamic exercises, and high volume upper extremity plyometric activity on tennis serve performance. AB - The purpose of this study was to compare the acute effects of static stretching; dynamic exercises and high volume upper extremity plyometric activity on tennis serve performance. Twenty-six elite young tennis players (15.1 +/- 4.2 years, 167.9 +/- 5.8 cm and 61.6 +/- 8.1 kg) performed 4 different warm-up (WU) routines in a random order on non-consecutive days. The WU methods consisted of traditional WU (jogging, rally and serve practice) (TRAD); traditional WU and static stretching (TRSS); traditional WU and dynamic exercise (TRDE); and traditional WU and high volume upper extremity plyometric activity (TRPLYP). Following each WU session, subjects were tested on a tennis serve ball speed test. TRAD, TRSS, TRDE and TRPLYO were compared by repeated measurement analyses of variance and post-hoc comparisons. In this study a 1 to 3 percent increase in tennis serve ball speed was recorded in TRDE and TRPLYO when compared to TRAD (p< 0.05). However, no significant change in ball speed performance between TRSS and TRAD. (p> 0.05). ICCs for ball speed showed strong reliability (0.82 to 0.93) for the ball speed measurements.The results of this study indicate that dynamic and high volume upper extremity plyometric WU activities are likely beneficial to serve speed of elite junior tennis players. PMID- 24150069 TI - Differences between the Vastus Lateralis and Gastrocnemius Lateralis in the Assessment Ability of Breakpoints of Muscle Oxygenation for Aerobic Capacity Indices During an Incremental Cycling Exercise. AB - In recent years, breakpoints (Bp) of muscle oxygenation have been measured in local muscles using near infrared spectroscopy (NIRS) to assess (predict) systemic aerobic capacity indices [lactate threshold (LT), gas exchange threshold (GET) and maximal oxygen uptake (VO2peak)]. We investigated muscular differences in the assessment (predictive) ability of the Bp of muscle oxygenation for aerobic capacity indices during incremental cycling exercise on the aerobic capacity indices. Thirty-one active college students were recruited for an incremental cycling exercise test, during which NIRS muscle oxygenation in the vastus lateralis (VL) and gastrocnemius lateralis (GL), blood lactate concentration and cardiopulmonary variables were measured simultaneously in a multi-modality approach. A linear regression model was used to analyse the relationship between the Bp of the muscle oxygenation index (OI) and the systemic aerobic capacity indices. The Bp of the muscle OI in both the VL (BpVL) and GL (BpGL) were significantly correlated with the aerobic capacity indices. Additionally, the BpVL had a better goodness-of-fit [higher coefficient of determination (R(2), p < 0.001) and lower root mean squared error (RMSE, p < 0.03)] in the linear regressions and occurred earlier than the BpGL. In conclusion, both the BpVL and the BpGL could be measured by NIRS to assess the systemic aerobic capacity indices; however, there were muscular differences in the assessment ability of the Bp of muscle oxygenation. PMID- 24150070 TI - Analysis of motivational profiles of satisfaction and importance of physical education in high school adolescents. AB - The purpose of this study was to analyze the motivational profiles of satisfaction with and importance of physical education in high school students and its relation with gender and the practice of sport. The sample comprised 2002 students aged from 12 to 19 who completed the Sport Motivation Scale (Nunez et al., 2006), the Sport Satisfaction Instrument (Baena-Extremera et al., 2012) and the Importance of Physical Education Scale (Moreno et al., 2009). Descriptive analyzes, correlations between the scales, a cluster analysis for profiles, and a MANOVA were conducted to examine differences by gender. Three clusters (profiles) were identified. The first profile identified was "moderate" motivation (n = 463) and was associated with boys who practice physical activity for less than 3 hours per week. The second profile identified was "low" motivation (n = 545) and was associated mainly with girls who practice physical activity for less than 3 hours per week. And lastly the third profile identified was "high" motivation (n = 910), which was found to be greater in boys who practiced physical exercise for more than 3 hours a week. PMID- 24150071 TI - The impact of a sports vision training program in youth field hockey players. AB - The aim of this study was to investigate whether a sports vision training program improves the visual performance of youth male field hockey players, ages 12 to 16 years, after an intervention of six weeks compared to a control group with no specific sports vision training. The choice reaction time task at the D2 board (Learning Task I), the functional field of view task (Learning Task II) and the multiple object tracking (MOT) task (Transfer Task) were assessed before and after the intervention and again six weeks after the second test. Analyzes showed significant differences between the two groups for the choice reaction time task at the D2 board and the functional field of view task, with significant improvements for the intervention group and none for the control group. For the transfer task, we could not find statistically significant improvements for either group. The results of this study are discussed in terms of theoretical and practical implications. Key pointsPerceptual training with youth field hockey playersCan a sports vision training program improve the visual performance of youth male field hockey players, ages 12 to 16 years, after an intervention of six weeks compared to a control group with no specific sports vision training?The intervention was performed in the "VisuLab" as DynamicEye((r)) SportsVision Training at the German Sport University Cologne.We ran a series of 3 two-factor univariate analysis of variance (ANOVA) with repeated measures on both within subject independent variables (group; measuring point) to examine the effects on central perception, peripheral perception and choice reaction time.The present study shows an improvement of certain visual abilities with the help of the sports vision training program. PMID- 24150072 TI - Effects of unstable shoes on energy cost during treadmill walking at various speeds. AB - In recent years, shoes having rounded soles in the anterior-posterior direction have been commercially introduced, which are commonly known as unstable shoes (US). However, physiological responses during walking in US, particularly at various speeds, have not been extensively studied to date. The purpose of this study was to investigate the effect of wearing unstable shoes while walking at low to high speeds on the rate of perceived exertion (RPE), muscle activation, oxygen consumption (VO2), and optimum speed. Healthy male adults wore US or normal walking shoes (WS), and walked at various speeds on a treadmill with no inclination. In experiment 1, subjects walked at 3, 4, 5, 6, and 7 km.h(-1) (duration, 3 min for all speeds) and were recorded on video from the right sagittal plane to calculate the step length and cadence. Simultaneously, electromyogram (EMG) was recorded from six different thigh and calf muscles, and the integrated EMG (iEMG) was calculated. In experiment 2, RPE, heart rate and VO2 were measured with the walking speed being increased from 3.6 to 7.2 km.h(-1) incrementally by 0.9 km.h(-1) every 6 min. The optimum speed, defined by the least oxygen cost, was calculated from the fitted quadratic relationship between walking speed and oxygen cost. Wearing US resulted in significantly longer step length and lower cadence compared with WS condition at any given speed. For all speeds, iEMG in the medial gastrocnemius and soleus muscles, heart rate, and VO2 were significantly higher in US than WS. However, RPE and optimum speed (US, 4.75 +/- 0.32 km.h(-1); WS, 4. 79 +/- 0.18 km.h(-1)) did not differ significantly between the two conditions. These results suggest that unstable shoes can increase muscle activity of lower legs and energy cost without influencing RPE and optimum speed during walking at various speeds. PMID- 24150073 TI - Influence of endurance exercise on the risk of pneumonia and Fever in leukemia and lymphoma patients undergoing high dose chemotherapy. A pilot study. AB - Pneumonia and fever are common side effects of high dose chemotherapy (HDC). The positive influence of physical activity on physiological and psychological parameters in cancer patients has been demonstrated in several studies. In this non-randomized controlled pilot study we investigated the infection and pneumonia risk in 36 high dose chemotherapy patients undergoing a supervised endurance exercise program. 18 patients exercised for at least 3 weeks, starting with initiation of chemotherapy. These patients in the intervention group were compared with 18 patients who were matched by disease (leukemia/lymphoma), sex, age, risk factors, therapy protocols and did not take part in the exercise intervention. Leukemia and lymphoma groups were evaluated separately. In the leukemia group significant higher pneumonia rates could be observed in the control group (p = 0.040) when compared to the intervention group. Further an almost significantly higher risk (p = 0.061) of developing a pneumonia and fever was detected in the control group. In this pilot study, we gained first important positive experiences in possibly preventing pneumonias and fever through endurance training. Due to the non-randomized study design and small sample size the results are limited yet not irrelevant. RCTs with larger sample sizes are necessary to prove these findings. PMID- 24150074 TI - Field based reliability and validity of the bioharnessTM multivariable monitoring device. AB - The BioharnessTM device is designed for monitoring physiological variables in free-living situations but has only been proven to be reliable and valid in a laboratory environment. Therefore, this study aimed to determine the reliability and validity of the BioharnessTM using a field based protocol. Twenty healthy males participated. Heart rate (HR), breathing frequency (BF) and accelerometry (ACC) were assessed by simultaneous measurement of two BioharnessTM devices and a test-retest of a discontinuous incremental walk-jog-run protocol (4 - 11 km.h( 1)) completed in a sports hall. Adopted precision of measurement devices were; HR: Polar T31 (Polar Electro), BF: Spirometer (Cortex Metalyser), ACC: Oxygen expenditure (Cortex Metalyser). For all data, precision of measurement reported good relationships (r = 0.61 to 0.67, p < 0.01) and large Limits of Agreement for HR (>79.2 b.min(-1)) and BF (>54.7 br.min(-1)). ACC presented excellent precision (r = 0.94, p < 0.01). Results for HR (r= ~0.91, p < 0.01: CV <7.6) and ACC (r > 0.97, p < 0.01; CV <14.7) suggested these variables are reliable. BF presented more variable data (r = 0.46-0.61, p < 0.01; CV < 23.7). As velocity of movement increased (>8 km.h(-1)) data became more erroneous. A data cleaning protocol removed gross errors in the data analysis and subsequent reliability and validity statistics improved across all variables. In conclusion, the BioharnessTM HR and ACC variables have demonstrated reliability and validity in a field setting, though data collected at higher velocities should be treated with caution. Measuring human physiological responses in a field based environment allows for more ecologically valid data to be collected and devices such as the BioharnessTM could be used by exercise professionals to begin to further investigate this area. PMID- 24150075 TI - Effect of creatine supplementation on muscle damage and repair following eccentrically-induced damage to the elbow flexor muscles. AB - We investigated effects of creatine (Cr) supplementation (CrS) on exercise induced muscle damage. Untrained males and females (N = 27) ages 18-25, with no CrS history in the past 4 months, were randomly assigned to CrS (creatine and carbohydrate) (n = 9), placebo (P) (carbohydrate only) (n = 9), or control (C) (no supplements) groups (n = 9). Participants followed a 5-day Cr loading protocol of 40 g.day(-1), divided for 5 days prior to exercise, reduced to 10 g g.day(-1) for 5 days following exercise. Testing consisted of 5 maximal isometric contractions at 90 arm flexion with the preferred arm on a CYBEX NORM dynamometer, assessed prior to, immediately following, and 24, 48, 72, and 96 hours post muscle-damaging procedures. Damage was induced to the elbow flexor muscles using 6 sets of 10 eccentric contractions at 75 degrees /sec, 90 degrees /sec and 120 degrees /sec. Participants were asked to rate their muscle soreness on a scale of 1-10. Data was analyzed using repeated-measures ANOVA, with an alpha of 0.05. No significant differences were found between muscle force loss and rate of recovery or muscle soreness between groups over the 96 hr recovery period (p > 0.05). Across all 3 experimental groups an initial decrease in force was observed, followed by a gradual recovery. Significant differences were found between baseline and all others times (p = 0.031,0 .022, 0.012, 0.001 respectively), and between the 48 hour and 96 hour time periods (p = 0.034). A weak negative correlation between subjectively rated muscle soreness and mean peak isometric force loss (R(2) = 0.0374 at 96 hours), suggested that muscle soreness and muscle force loss may not be directly related. In conclusion, 5 days of Cr loading, followed by a Cr maintenance protocol did not reduce indices of muscle damage or speed recovery of upper body muscles following eccentrically induced muscle damage. PMID- 24150076 TI - Acute effects of three different circuit weight training protocols on blood lactate, heart rate, and rating of perceived exertion in recreationally active women. AB - Interval and circuit weight training are popular training methods for maximizing time-efficiency, and are purported to deliver greater physiological benefits faster than traditional training methods. Adding interval training into a circuit weight-training workout may further enhance the benefits of circuit weight training by placing increased demands upon the cardiovascular system. Our purpose was to compare acute effects of three circuit weight training protocols 1) traditional circuit weight training, 2) aerobic circuit weight training, and 3) combined circuit weight-interval training on blood lactate (BLA), heart rate (HR), and ratings of perceived exertion (RPE). Eleven recreationally active women completed 7 exercise sessions. Session 1 included measurements of height, weight, estimated VO2max, and 13 repetition maximum (RM) testing of the weight exercises. Sessions 2-4 were held on non-consecutive days for familiarization with traditional circuit weight training (TRAD), aerobic circuit weight training (ACWT), and combined circuit weight-interval training (CWIT) protocols. In sessions 5-7, TRAD, ACWT, and CWIT were performed in a randomized order >= 72 hr apart for measures of BLA, HR, and RPE at pre-exercise and following each of three mini-circuit weight training stations. Repeated-measures ANOVAs yielded significant interactions (p < 0.05) in BLA, HR, and RPE. Combined circuit weight interval training (CWIT) produced higher BLA (7.31 +/- 0.37 vs. TRAD: 3.99 +/- 0.26, ACWT: 4.54 +/- 0.31 mmol.L(-1)), HR (83.51 +/- 1.18 vs. TRAD: 70.42 +/- 1.67, ACWT: 74.13 +/- 1.43 beats.min(-1)) and RPE (8.14 +/- 0.41 vs. TRAD: 5.06 +/- 0.43, ACWT: 6.15 +/- 0.42) at all measures. Aerobic circuit weight training (ACWT) elicited greater RPE than traditional circuit weight training (TRAD) at all measures. Including combined circuit weight-interval training (CWIT) workouts into exercise programming may enhance fitness benefits and maximize time efficiency more so than traditional circuit training methods. PMID- 24150077 TI - Acute effects of two different warm-up protocols on flexibility and lower limb explosive performance in male and female high level athletes. AB - This study examined the effects of two different warm-up protocols on lower limb power and flexibility in high level athletes. Twenty international level fencers (10 males and 10 females) performed two warm-up protocols that included 5-min light jogging and either short (15s) or long (45s) static stretching exercises for each of the main leg muscle groups (quadriceps, hamstrings and triceps surae), followed by either 3 sets of 3 (short stretching treatment), or 3 sets of 5 tuck jumps (long stretching treatment), in a randomized crossover design with one week between treatments. Hip joint flexion was measured with a Lafayette goniometer before and after the 5-min warm-up, after stretching and 8 min after the tuck jumps, while counter movement jump (CMJ) performance was evaluated by an Ergojump contact platform, before and after the stretching treatment, as well as immediately after and 8 minutes after the tuck jumps. Three way ANOVA (condition, time, gender) revealed significant time (p < 0.001) and gender (p < 0.001) main effects for hip joint flexion, with no interaction between factors. Flexibility increased by 6. 8 +/- 1.1% (p < 0.01) after warm-up and by another 5.8 +/- 1.6% (p < 0.01) after stretching, while it remained increased 8 min after the tuck jumps. Women had greater ROM compared with men at all time points (125 +/- 8 degrees vs. 94 +/- 4 degrees p<0.01 at baseline), but the pattern of change in hip flexibility was not different between genders. CMJ performance was greater in men compared with women at all time points (38.2 +/- 1.9 cm vs. 29.8 +/- 1.2 cm p < 0.01 at baseline), but the percentage of change CMJ performance was not different between genders. CMJ performance remained unchanged throughout the short stretching protocol, while it decreased by 5.5 +/- 0.9% (p < 0.01) after stretching in the long stretching protocol However, 8 min after the tuck jumps, CMJ performance was not different from the baseline value (p = 0.075). In conclusion, lower limb power may be decreased after long periods of stretching, but performance of explosive exercises may reverse this phenomenon. PMID- 24150078 TI - Scapular contribution for the end-range of shoulder axial rotation in overhead athletes. AB - The aim of this study was to analyze the relative contribution of the scapular motion on the extreme range-of-motion of shoulder external and internal rotation, in overhead athletes. An electromagnetic tracking device (Flock of Birds) was used to record humeral and scapular kinematics. The dominant arm of 26 male subjects (13 athletes and 13 non-athletes) was studied while subjects actively reached end-range of internal and external rotation. Humeral and scapular angles were calculated and compared across groups by means of a t-test for independent samples. A bivariate correlation approach was used to describe the relationship between humeral angles and scapular variables. The range-of-motion of the thoracohumeral angles, during shoulder external rotation was significantly less (p < 0.05) on the athletes group, athletes also positioned their dominant scapula more retracted and posteriorly tilted. A positive correlation was found between glenohumeral angles and scapular tilt (r = 0.6777; p < 0.05). Concerning internal rotation; athletes showed significantly greater (highest) thoracohumeral angles (p < 0.05). Scapula assumed a position more in retraction and anterior tilt. Based on these findings, it is suggested that differences found in athletes seem to reveal an eventual shoulder adaptation to the throwing mechanics. PMID- 24150079 TI - Comparison of temporal parameters of swimming rescue elements when performed using dolphin and flutter kick with fins - didactical approach. AB - The aim of this study was an analysis of the time required to swim to a victim and tow them back to shore, while perfoming the flutter-kick and the dolphin-kick using fins. It has been hypothesized that using fins while using the dolphin-kick when swimming leads to reduced rescue time. Sixteen lifeguards took part in the study. The main tasks performed by them, were to approach and tow (double armpit) a dummy a distance of 50m while applying either the flutter-kick, or the dolphin kick with fins. The analysis of the temporal parameters of both techniques of kicking demonstrates that, during the approach to the victim, neither the dolphin (tmean = 32.9s) or the flutter kick (tmean = 33.0s) were significantly faster than the other. However, when used for towing a victim the flutter kick (tmean = 47.1s) was significantly faster when compared to the dolphin-kick (tmean = 52.8s). An assessment of the level of technical skills in competitive swimming, and in approaching and towing the victim, were also conducted. Towing time was significantly correlated with the parameter that linked the temporal and technical dimensions of towing and swimming (difference between flutter kick towing time and dolphin-kick towing time, 100m medley time and the four swimming strokes evaluation). No similar interdependency has been discovered in flutter kick towing time. These findings suggest that the dolphin-kick is a more difficult skill to perform when towing the victim than the flutter-kick. Since the hypothesis stated was not confirmed, postulates were formulated on how to improve dolphin-kick technique with fins, in order to reduce swimming rescue time. PMID- 24150080 TI - Test-retest reliability of the aerobic power index submaximal exercise test in cancer patients. AB - The purpose of this study was to investigate the reliability of the Aerobic Power Index (API) submaximal cardiorespiratory exercise test, as well as associated variables of oxygen uptake (ml.kg(-1).min(-1)) and ratings of perceived exertion (RPE) in cancer patients who are generally unable to complete maximal or lengthy aerobic fitness tests. Twenty male and female participants (11 male; 9 female) aged between 18 and 70 y (mean = 53.28 +/- 11. 82 y) were recruited with medical consent within 4 weeks of completing chemotherapy treatment for a lymphohaematopoietic cancer (LHC). Of the twenty recruited participants' 2 were excluded from analysis due to disease relapse or complications unrelated to testing occurring within the month following testing. Intra-class correlation coefficient (ICC) scores for power output (W.kg(-1)) and oxygen uptake (ml.kg( 1).min(-1)) were highly reliable (R1 = 0.96 and 0.96, respectively) and the ICC for RPE was moderately reliable (R1 = 0.83). Technical error of measurement results for power output (W.kg(-1)), oxygen uptake (ml.kg(-1).min(-1)) and RPE were 0.11W.kg(-1), 1.18 ml.kg(-1).min(-1) and 1.0 respectively. A Pearson's product-moment correlation demonstrated a strong relationship between power output (W.kg(-1)) and oxygen uptake (ml.kg(-1).min(-1)) for both trials (r = 0.93 and 0.89, respectively). Results demonstrate that the API test is a highly reliable protocol for use with a LHC population and can be considered a clinically feasible, safe and tolerable exercise test. PMID- 24150081 TI - In Vivo Kinematics of the Anterior Cruciate Ligament Deficient Knee During Wide Based Squat Using a 2D/3D Registration Technique. AB - Anterior cruciate ligament (ACL) deficiency increases the risk of early osteoarthritis (OA). Studies of ACL deficient knee kinematics would be important to reveal the disease process and therefore to find mechanisms which would potentially slow OA progression. The purpose of this study was to determine if in vivo kinematics of the anterior cruciate ligament deficient (ACLD) knee during a wide-based squat activity differ from kinematics of the contralateral intact knee. Thirty-three patients with a unilateral ACLD knee consented to participate in this institutional review board approved study with the contralateral intact knee serving as the control. In vivo knee kinematics during the wide-based squat were analyzed using a 2D/3D registration technique utilizing CT-based bone models and lateral fluoroscopy. Comparisons were performed using values between 0 and 100 degrees flexion both in flexion and extension phases of the squat activity. Both the ACLD and intact knees demonstrated increasing tibial internal rotation with knee flexion, and no difference was observed in tibial rotation between the groups. The tibia in the ACLD knee was more anterior than that of the contralateral knees at 0 and 5 degrees flexion in both phases (p < 0.05). Tibiofemoral medial contact points of the ACLD knees were more posterior than that of the contralateral knees at 5, 10 and 15 degrees of knee flexion in the extension phase of the squat activity (p < 0.05). Tibiofemoral lateral contact points of the ACLD knees were more posterior than that of the contralateral knees at 0 degrees flexion in the both phases (p < 0.05). The kinematics of the ACLD and contralateral intact knees were similar during the wide-based squat except at the low flexion angles. Therefore, we conclude the wide-based squat may be recommended for the ACLD knee by avoiding terminal extension. PMID- 24150082 TI - Comparison of the shake weight((r)) modality exercises when compared to traditional dumbbells. AB - Individuals are continuously looking for faster, more efficient methods with which to develop physical fitness. This has led to the development of products and programs marketed towards increasing physical fitness in minimal time. The Shake Weight((r)) (SW) has been advertised to increase muscular strength among other factors in less time than traditional weightlifting. The purpose of this study was to compare the electromyographic (EMG) muscle activity of the SW to a traditional dumbbell (DB) performing the same exercises. Twelve men (22.9 +/- 1.6 years) and 13 women (23.0 +/- 1.9 years) volunteered to participate in this study. Subjects performed the chest shake (CS), biceps shake (BS), and triceps shake (TS) using the SW and DW. Maximal voluntary isometric contractions (MVIC) were exhibited for all muscles. EMG activity was recorded for the pectoralis major (PM), triceps brachii (TB), biceps brachii (BB), anterior deltoid (AD), trapezius (TR), and rectus abdominus (RA) and compared to detect differences between modalities. EMG activity for each muscle group was reported as a percentage of each subject's individual MVIC. A repeated measures ANOVA revealed no significant differences between the SW and DB modalities during each exercise for all muscles except the BB (p < 0.05). During the CS exercise muscle activity was significantly greater for DB in the BB muscle when compared to the SW mode (50.8 +/- 28.9%; 35.8 +/- 30.8%). The SW did not have any advantage over the DB for any exercise, nor for any muscle group. Further, no muscle group during any of the SW trials exhibited an MVIC over 60%, the level necessary to increase muscular strength. PMID- 24150083 TI - Magnetic versus electrical stimulation in the interpolation twitch technique of elbow flexors. AB - The study compared peripheral magnetic with electrical stimulation of the biceps brachii m. (BB) in the single pulse Interpolation Twitch Technique (ITT). 14 healthy participants (31+/-7 years) participated in a within-subjects repeated measures design study. Single, constant-current electrical and magnetic stimuli were delivered over the motor point of BB with supramaximal intensity (20% above maximum) at rest and at various levels of voluntary contraction. Force measurements from right elbow isometric flexion and muscle electromyograms (EMG) from the BB, the triceps brachii m. (TB) and the abductor pollicis brevis m. (APB) were obtained. The twitch forces at rest and maximal contractions, the twitch force-voluntary force relationship, the M-waves and the voluntary activation (VA) of BB between magnetic and electrical stimulation were compared. The mean amplitude of the twitches evoked at MVC was not significantly different between electrical (0.62 +/- 0.49 N) and magnetic (0.81 +/- 0.49 N) stimulation (p > 0.05), and the maximum VA of BB was comparable between electrical (95%) and magnetic (93%) stimulation (p > 0. 05). No differences (p >0.05) were revealed in the BB M-waves between electrical (13.47 +/- 0.49 mV.ms) and magnetic (12.61 +/- 0.58 mV.ms) stimulation. The TB M-waves were also similar (p > 0.05) but electrically evoked APB M-waves were significantly larger than those evoked by magnetic stimulation (p < 0.05). The twitch-voluntary force relationship over the range of MVCs was best described by non-linear functions for both electrical and magnetic stimulation. The electrically evoked resting twitches were consistently larger in amplitude than the magnetically evoked ones (mean difference 3.1 +/- 3.34 N, p < 0.05). Reduction of the inter-electrodes distance reduced the twitch amplitude by 6.5 +/- 6.2 N (p < 0.05). The fundamental similarities in voluntary activation assessment of BB with peripheral electrical and magnetic stimulation point towards a promising new application of peripheral magnetic stimulation as an alternative to the conventional ITT for the assessment of BB voluntary activation. PMID- 24150084 TI - Effects of prolonged endurance exercise on vascular endothelial and inflammation markers. AB - Systemic inflammation has been found in association with vascular endothelial function for clinical implications including exercise-induced pathology. However, information on the relationship between the exercise-related inflammatory responses and endothelial function is limited. This study aimed to investigate the effects of prolonged endurance exercise on the expression of selected soluble adhesion molecules and inflammatory markers. Twenty-four middle-aged males participating in a 308 km ultra-marathon were recruited in this study. Venous blood was collected at baseline, 100 km, 200 km, and 308 km for the analysis of sVCAM-1, sE-selectin, leukocytes, hs-CRP, CK, and TNF-alpha. Significant increases of sVCAM-1, sE-selectin, and leukocytes were observed at 100 km. sVCAM 1 had the greatest significant increase at 100 km. In addition, sVCAM-1 was significantly associated with the running speed and leukocytes. sE-selectin was significantly associated with leukocytes, hs-CRP, TNF-alpha, and CK. Delayed rises in hs-CRP and CK were observed at 200 km. TNF-alpha fluctuated throughout the race with a significant increase at 308 km. Delayed onset of hs-CRP and continuously increased sE-selectin suggest anti-inflammatory responses to suppress pro-inflammatory markers such as TNF-alpha. Prolonged repetition of muscle contraction may have released delayed CK and significant rise in TNF-alpha toward the end of the race. The present study demonstrated an activation of the surrogate markers of endothelial dysfunction in relationship to exercise intensity and leukocyte trafficking without a significant activation of the inflammatory responses. Thus, alteration of the endothelium may be related to increased blood flow and shear stress put upon the endothelium in response to increased oxygen demand on the heart. PMID- 24150085 TI - Effects of electrostimulation and plyometric training program combination on jump height in teenage athletes. AB - The purpose of this study was to examine the effects of eight-week (2 days/week) training periods of plyometric exercises (PT) and neuromuscular electrostimulation (EMS) on jump height in young athletes. Squat jump (SJ), counter movement jump (CMJ) and drop jump (DJ) were performed to assess the effects of the training protocols 98 athletes (100 & 200m and 100m & 110m hurdles) voluntarily took part in this study, 51 males (52%) and 47 females (48%), 17.91 +/- 1.42 years old, and 5.16 +/- 2.56 years of training experience. The participants were randomly assigned to four different groups according to the frequency and the timing of the stimulation. Analysis of covariance was used to analyze the effects of every training program on jump height. Our findings suggest that compared to control (Plyometrics (PT) only), the combination of 150Hz EMS + PT simultaneously combined in an 8 week (2days/week) training program, we could observe significant jump height improvements in the different types of strength: explosive, explosive-elastic, and explosive-elastic-reactive. The combination of PT after <= 85 Hz EMS did not show any jump height significant increase in sprinters. In conclusion, an eight week training program (with just two days per week) of EMS combined with plyometric exercises has proven useful for the improvement of every kind of vertical jump ability required for sprint and hurdles disciplines in teenage athletes. PMID- 24150086 TI - Reliability and validity of physiological data obtained within a cycle-run transition test in age-group triathletes. AB - This study examined the validity and reliability of a sequential "Run-Bike-Run" test (RBR) in age-group triathletes. Eight Olympic distance (OD) specialists (age 30.0 +/- 2.0 years, mass 75.6 +/- 1.6 kg, run VO2max 63.8 +/- 1.9 ml. kg(-1). min(-1), cycle VO2peak 56.7 +/- 5.1 ml. kg(-1). min(-1)) performed four trials over 10 days. Trial 1 (TRVO2max) was an incremental treadmill running test. Trials 2 and 3 (RBR1 and RBR2) involved: 1) a 7-min run at 15 km. h(-1) (R1) plus a 1-min transition to 2) cycling to fatigue (2 W. kg(-1) body mass then 30 W each 3 min); 3) 10-min cycling at 3 W. kg(-1) (Bsubmax); another 1-min transition and 4) a second 7-min run at 15 km. h(-1) (R2). Trial 4 (TT) was a 30-min cycle - 20 min run time trial. No significant differences in absolute oxygen uptake (VO2), heart rate (HR), or blood lactate concentration ([BLA]) were evidenced between RBR1 and RBR2. For all measured physiological variables, the limits of agreement were similar, and the mean differences were physiologically unimportant, between trials. Low levels of test-retest error (i.e. ICC <0.8, CV<10%) were observed for most (logged) measurements. However [BLA] post R1 (ICC 0.87, CV 25.1%), [BLA] post Bsubmax (ICC 0.99, CV 16.31) and [BLA] post R2 (ICC 0.51, CV 22.9%) were least reliable. These error ranges may help coaches detect real changes in training status over time. Moreover, RBR test variables can be used to predict discipline specific and overall TT performance. Cycle VO2peak, cycle peak power output, and the change between R1 and R2 (deltaR1R2) in [BLA] were most highly related to overall TT distance (r = 0.89, p < 0. 01; r = 0.94, p < 0.02; r = 0.86, p < 0.05, respectively). The percentage of TR VO2max at 15 km. h(-1), and deltaR1R2 HR, were also related to run TT distance (r = -0.83 and 0.86, both p < 0.05). PMID- 24150087 TI - Higher Cardiorespiratory Fitness in Older Trained Women is Due to Preserved Stroke Volume. AB - Previous literature has shown that sedentary older women rely on peripheral adaptations to improve cardiorespiratory fitness with endurance training i.e. they show minimal increases in central parameters (cardiac output, Q) in response to endurance training. The purpose of this study therefore was to determine whether endurance trained older women were able to preserve maximal exercise Q and were characterized by a high stroke volume (SV) when compared to physically inactive older women. Trained (n = 7) and untrained (n = 1 0) women attended two maximal and one submaximal laboratory session. Breath-by-breath analysis was conducted using mass spectrometry and Q was assessed using acetylene open circuit inert gas wash-in. Multivariate analysis of variance and paired samples t-tests were used to determine between and within group differences. Trained women had a significantly higher VO2max (37.5 vs. 24.1 ml(-1).kg.min(-1)) compared to untrained women. There were no differences for peripheral oxygen extraction (VO2/Q) at either submaximal or maximal work rates; however trained women had a significantly higher SV at maximal (119.3 vs. 94.6 ml) exercise compared to untrained women. In both trained and untrained women, SV did not rise significantly between submaximal and maximal exercise. CONCLUSION: Highly fit, endurance trained older women are able to preserve central parameters of VO2max. Peripheral oxygen extraction is similar between older trained and untrained women. PMID- 24150088 TI - Efficacy of home-based kinesthesia, balance & agility exercise training among persons with symptomatic knee osteoarthritis. AB - The purpose of this study was to determine the efficacy of a home-based kinesthesia, balance and agility (KBA) exercise program to improve symptoms among persons age >= 50 years with knee osteoarthritis (OA). Forty-four persons were randomly assigned to 8-weeks, 3 times per week KBA, resistance training (RT), KBA + RT, or Control. KBA utilized walking agility exercises and single-leg static and dynamic balancing. RT used elastic resistance bands for open chain lower extremity exercises. KBA + RT performed selected exercises from each technique. Control applied inert lotion daily. Outcomes included the OA specific WOMAC Index of Pain, Stiffness, and Physical Function (PF), community activity level, exercise self-efficacy, self-report knee stability, and 15m get up & go walk (GUG). Thirty-three participants [70.7 (SD 8.5) years] completed the trial. Analysis of variance comparing baseline, mid-point, and follow-up measures revealed significant (p < 0.05) improvements in WOMAC scores among KBA, RT, KBA + RT, and Control, with no differences between groups. However, Control WOMAC improvements peaked at mid-point, whereas improvement in the exercise conditions continued at 8-weeks. There were no significant changes in community activity level. Only Control improved exercise self-efficacy. Knee stability was improved in RT and Control. GUG improved in RT and KBA+RT. These results indicate that KBA, RT, or a combination of the two administered as home exercise programs are effective in improving symptoms and quality of life among persons with knee OA. Control results indicate a strong placebo effect in the short term. A combination of KBA and RT should be considered as part of the rehabilitation program, but KBA or RT alone may be appropriate for some patients. Studies with more statistical power are needed to confirm or refute these results. Patient presentation, preferences, costs, and convenience should be considered when choosing an exercise rehabilitation approach for persons with knee OA. PMID- 24150089 TI - The contribution of "resting" body muscles to the slow component of pulmonary oxygen uptake during high-intensity cycling. AB - Oxygen uptake (VO2) kinetics during moderate constant-workrate (WR) exercise (>lactate-threshold (thetaL)) are well described as exponential. AbovethetaL, these kinetics are more complex, consequent to the development of a delayed slow component (VO2sc), whose aetiology remains controversial. To assess the extent of the contribution to the VO2sc from arm muscles involved in postural stability during cycling, six healthy subjects completed an incremental cycle-ergometer test to the tolerable limit for estimation of thetaL and determination of peak VO2. They then completed two constant-WR tests at 90% of thetaL and two at 80% of ? (difference between thetaL and VO2peak). Gas exchange variables were derived breath-by-breath. Local oxygenation profiles of the vastus lateralis and biceps brachii muscles were assessed by near-infrared spectroscopy, with maximal voluntary contractions (MVC) of the relevant muscles being performed post exercise to provide a frame of reference for normalising the exercise-related oxygenation responses across subjects. Above supra-thetaL, VO2 rose in an exponential-like fashion ("phase 2), with a delayed VO2sc subsequently developing. This was accompanied by an increase in [reduced haemoglobin] relative to baseline (?[Hb]), which attained 79 +/- 13 % (mean, SD) of MVC maximum in vastus lateralis at end-exercise and 52 +/- 27 % in biceps brachii. Biceps brachii ?[Hb] was significantly correlated with VO2 throughout the slow phase. In contrast, for sub- L exercise, VO2 rose exponentially to reach a steady state with a more modest increase in vastus lateralis ?[Hb] (30 +/- 11 %); biceps brachii ?[Hb] was minimally affected (8 +/- 2 %). That the intramuscular O2 desaturation profile in biceps brachii was proportional to that for VO2sc during supra-thetaL cycle ergometry is consistent with additional stabilizing arm work contributing to the VO2sc. PMID- 24150090 TI - Trapezoid stress fracture in an international shot-putter: a case report. AB - Trapezoid fractures are relatively rare upper limb fractures. The case report of a trapezoid stress fracture in the dominant hand of a 22 year old international standard shot-putter is presented. PMID- 24150091 TI - Phase equilibrium in Mg-Cu-Y. AB - Magnesium-based bulk metallic glasses (BMG) have potential in applications ranging from biomedical to sports equipment and the Mg-Cu-Y system offers some of the most promising alloys. Phase relations and ternary solubility of the binary and ternary compounds of this system have been experimentally investigated. The Isothermal section of Mg-Cu-Y system at 673 K for the entire composition range has been constructed. Phase relations in the Cu-rich (>66 at.% Cu) region of the Mg-Cu-Y system has been determined for the first time. The homogeneity range of three ternary compounds has been determined. Solidifications behavior of several key alloys have been discussed based on the differential scanning calorimetry (DSC) experiments and thermodynamic calculations. Extensive analysis of the DSC curves has been carried out to relate them to the corresponding phase transformation reactions and temperatures. Some of the most promising metallic glass forming regions have been analyzed using thermodynamic calculations. PMID- 24150092 TI - Spatiotemporal and time-frequency analysis of functional near infrared spectroscopy brain signals using independent component analysis. AB - Functional near infrared spectroscopy (fNIRS) is a noninvasive method to capture brain activities according to the measurements of changes in both oxyhemoglobin and deoxyhemoglobin concentrations. However, fNIRS recordings are the hemodynamic signals that come from the latent neural sources that are spatially and temporally mixed across the brain. The purpose of this work is to extract the temporal and frequency characteristics as well as the spatial activation patterns in the brains using independent component analysis (ICA). In this study, the filtered fNIRS recordings were processed and the time-frequency and spatiotemporal domain independent components (ICs) were identified by ICA. We found that multiple task-related components can be separated by ICA in time frequency domain, and distinct spatial patterns of brain activity can be derived from ICs that are well correlated with the specific neural events, such as finger tapping tasks. PMID- 24150093 TI - Determination of optical properties by interstitial white light spectroscopy using a custom fiber optic probe. AB - We demonstrate interstitial recovery of absorption and scattering coefficients using a custom optical probe and a Monte Carlo (MC)-based recovery algorithm. The probe consists of six side-firing spectroscopy fibers contained in a 1.1-mm outer diameter cladding, with each fiber having a different axial and angular position on the probe. Broadband white light is delivered by one of the fibers and is detected steady-state by the remaining fibers. These spatially and spectrally resolved data are analyzed using a MC-based fitting algorithm in order to extract the local optical properties. The technique was verified in tissue-simulating phantoms consisting of Intralipid-20% as a scatterer and either manganese meso tetra (4-sulfanatophenyl) porphine or intact human erythrocytes as an absorber. Absorption coefficients were recovered with a mean error of 9% and scattering coefficients were recovered with a mean error of 19%, whereas the hemoglobin oxygen saturation was recovered with a mean error of 12%. These results demonstrate the feasibility of optical property recovery for situations in which surface-contact spectroscopy is not a possibility, and where only a single probe can be inserted into the tissue. PMID- 24150094 TI - A constitutively active form of a durum wheat Na+/H+ antiporter SOS1 confers high salt tolerance to transgenic Arabidopsis. AB - The SOS signaling pathway has emerged as a key mechanism in preserving the homeostasis of Na+ and K+ under saline conditions. We have recently identified and functionally characterized, by complementation studies in yeast, the gene encoding the durum wheat plasma membrane Na+/H+ antiporter (TdSOS1). To extend these functional studies to the whole plant level, we complemented Arabidopsis sos1-1 mutant with wild-type TdSOS1 or with the hyperactive form TdSOS1?972 and compared them to the Arabidopsis AtSOS1 protein. The Arabidopsis sos1-1 mutant is hypersensitive to both Na+ and Li+ ions. Compared with sos1-1 mutant transformed with the empty binary vector, seeds from TdSOS1 or TdSOS1?972 transgenic plants had better germination under salt stress and more robust seedling growth in agar plates as well as in nutritive solution containing Na+ or Li+ salts. The root elongation of TdSOS1?972 transgenic lines was higher than that of Arabidopsis sos1-1 mutant transformed with TdSOS1 or with the endogenous AtSOS1 gene. Under salt stress, TdSOS1?972 transgenic lines showed greater water retention capacity and retained low Na+ and high K+ in their shoots and roots. Our data showed that the hyperactive form TdSOS1?972 conferred a significant ionic stress tolerance to Arabidopsis plants and suggest that selection of hyperactive alleles of the SOS1 transport protein may pave the way for obtaining salt-tolerant crops. PMID- 24150095 TI - Isoperistaltic left colic graft interposition via a retrosternal approach for esophageal reconstruction in patients with a caustic stricture: mortality, morbidity, and functional results. AB - PURPOSE: To report our results of treating esophageal caustic stricture with an isoperistaltic left colic graft interposed via a retrosternal route. METHODS: We reviewed 70 patients who underwent substernal left colon interposition, performed retrosternally, for an esophageal caustic stricture, between January, 1999 and December, 2011. RESULTS: The median operative time in this series was 3 h. A pharyngoplasty was performed in 10 patients (14.28 %), the thoracic inlet was found to be enlarged in 33 patients (47.1 %), and posterior cologastric anastomosis was performed in 58 patients (82.8 %). Two patients (2.8 %) died. Minor and major postoperative complications developed in 28 patients (40 %), including graft ischemia in 2 (2.8 %) and cervical anastomotic leakage in 14 (20 %). Five patients (7.14 %) developed a cervical anastomotic stricture. The functional results were satisfactory. CONCLUSION: Retrosternal isoperistaltic left colic transplant interposition is an excellent long-term replacement for an esophageal caustic stricture. If performed by experienced surgeons, this procedure is effective for esophageal reconstruction. PMID- 24150096 TI - Hepatopancreatoduodenectomy with arterial reconstruction for extrahepatic cholangiocarcinoma with celiac axis obstruction: report of a case. AB - We report a case of successful right hepatectomy plus pancreatoduodenectomy (Rt HPD) with arterial reconstruction for extrahepatic bile duct carcinoma with obstruction of the celiac axis in a 76-year-old man. Obstruction of the celiac axis resulted in arterial blood supply to the upper abdominal organs coming from the pancreatic head arcade. The patient underwent arterial reconstruction before the Rt-HPD to maintain the blood supply from the pancreatic head arcade for as long as possible. His postoperative course was uneventful and he was well with no sign of recurrence when last seen, 64 months after surgery. To our knowledge, this is the first description of this modified HPD with arterial reconstruction. Thus, rational surgical planning based on careful preoperative assessment would expand the indications for HPD, even for patients with celiac axis obstruction requiring arterial reconstruction. PMID- 24150098 TI - Comparison of the Limberg flap and bilateral gluteus maximus advancing flap following oblique excision for the treatment of pilonidal sinus disease. AB - PURPOSE: This study was performed to compare the use of a bilateral gluteus maximus advancing flap (BGMAF) following oblique incision, which was recently described for the surgical treatment of sacrococcygeal pilonidal sinus (SPS) disease, with the widely used Limberg flap (LF) technique following a rhomboid incision. METHODS: A total of 105 patients treated for SPS were evaluated retrospectively. The patients were evaluated in terms of their age, body mass index, symptoms, length of the operation, complications, postoperative hospital stay, time to return to work, postoperative cosmetic satisfaction and recurrence rate. RESULTS: Fifty-six of the patients were treated with BGMAF, while 49 were treated with LF. The mean follow-up was 20.5 +/- 5.4 months. The mean length of the operation, hospital stay and time to return to work were shorter, while the cosmetic satisfaction score was higher in the BGMAF group compared to the LF group. There was no statistically significant difference between the groups for the other criteria. CONCLUSION: The BGMAF appears to be superior to the LF in terms of the length of the operation, time to return to work and degree of cosmetic satisfaction. It is preferable for sinuses not to require wide excision, while the LF is more appropriate for sinuses with a large post-excision defect. PMID- 24150097 TI - Clinical implications of the LINE-1 methylation levels in patients with gastrointestinal cancer. AB - Epigenetic alterations, such as DNA methylation, histone modification and the loss of genome imprinting, are important indicators of human carcinogenesis. DNA methylation is a fundamental epigenetic process that modulates the gene expression levels. In cancer cells, DNA methylation may be altered in two principle ways: global DNA hypomethylation and site-specific CpG island promoter hypermethylation. Long interspersed element-1 (LINE-1 or L1) is a repetitive DNA retrotransposon that duplicates via a copy-and-paste genetic mechanism. Since LINE-1 constitutes a substantial portion (approximately 17 %) of the human genome, the extent of LINE-1 methylation is regarded to be a surrogate marker of global DNA methylation. Measuring the level of LINE-1 methylation using pyrosequencing technology has emerged as a cost-effective and high-throughput method for assessing the global DNA methylation status. In some types of gastrointestinal (GI) cancers, LINE-1 hypomethylation is strongly associated with a poor prognosis, supporting its potential role as a prognostic marker. In addition, the LINE-1 methylation level may prove to be a useful clinical biomarker for assessing the risk of cancer or predicting the chemotherapeutic efficacy of treatment in patients with GI cancers. In this article, we summarize current knowledge regarding LINE-1 methylation and its clinical implications in GI cancers, including colorectal cancer, gastric cancer and esophageal cancer. PMID- 24150099 TI - Usefulness of endoscopic breast-conserving surgery for breast cancer. AB - PURPOSE: We compared the safety, invasiveness and cosmetic outcomes between endoscopic breast-conserving surgery (endoscopic group) and surgery under direct vision (direct vision group) for treating breast cancer. METHODS: We compared 100 cases of endoscopic surgery with 150 cases of direct vision surgery. The safety was evaluated in terms of the blood loss, length of the operation and presence or absence of complications, whereas the degree of invasiveness was assessed using preoperative and postoperative leukocyte counts, neutrophil counts, interleukin (IL-6) levels and fever. The cosmetic outcome was assessed on the basis of a breast evaluation by the medical staff and the patient's subjective satisfaction. RESULTS: In both groups, serious postoperative complications were absent. No significant differences were observed in the leukocyte counts, neutrophil counts, IL-6 level or fever between the groups. An evaluation of the cosmetic outcomes by the staff showed a more favorable breast size, breast shape and scar condition in the endoscopic group. A significantly higher level of patient satisfaction was also observed in the endoscopic group. Postoperative local recurrence was absent. CONCLUSIONS: The endoscopic approach showed comparable safety and invasiveness, and provided better postoperative cosmetic outcomes than direct vision surgery. Our results suggest that endoscopic breast-conserving surgery is a potentially useful surgical method for the treatment of breast cancer. PMID- 24150100 TI - Chiral silicon Lewis acids having a pentacoordinate stereogenic silicon center: 29Si NMR studies and application to asymmetric Diels-Alder reactions. AB - The (29)Si NMR studies of chiral pentacoordinate silyl triflimides having a stereogenic center at silicon have revealed that a chiral silicon center is highly configurationally unstable. Such configurational instability has an enormously beneficial effect on the diastereo- and enantioselectivity of the catalytic asymmetric Diels-Alder reaction. PMID- 24150101 TI - Width of abnormal ganglion cell complex area determined using optical coherence tomography to predict glaucoma. AB - PURPOSES: We examined the relationships of ganglion cell complex (GCC) parameters determined on spectral-domain optical coherence tomography (SD-OCT), especially the width of abnormal areas, and its ability to detect various stages of glaucoma. METHODS: OCT parameters of glaucomatous and normal eyes were determined with the RTVue SD-OCT. Widths of abnormal GCC areas marked by either red or yellow on the OCT significance map were quantified with image J software. The relationships between the abnormal GCC area and other GCC parameters [thickness, focal loss volume (FLV), and global loss volume (GLV)] and the peripapillary retinal nerve fiber layer (RNFL) thickness were determined using regression analyses. The potential of using the GCC and RNFL parameters to discriminate between glaucomatous and normal eyes was examined using the area under the curve (AUC) of receiver operating characteristics (ROC). RESULTS: One hundred and eighteen glaucomatous eyes and 45 normal control eyes were studied. Nonlinear models best described the relationships between abnormal GCC area and other GCC parameters. Scatter plots showed changes in the average thickness of the GCC and RNFL, and the average sizes of the GLV preceded changes of abnormal areas of the GCC. The width of the abnormal areas on the GCC thickness map was comparable with other parameters for diagnosing glaucoma. CONCLUSIONS: OCT thickness parameters appeared to decrease faster than the area parameter at the initial stage of glaucoma. The sizes of abnormal areas of the GCC were the most pertinent parameters for detecting glaucoma. PMID- 24150102 TI - A novel neutral organic electron donor with record half-wave potential. AB - Tricyclic donor 26 has been prepared and is the most reducing neutral ground state organic molecule known, with an oxidation potential 260 mV more negative than the previous record. Cyclic voltammetry shows that a 2-electron reversible redox process occurs in DMF as solvent at -1.46 V vs. Ag/AgCl. PMID- 24150103 TI - Clinical profile of Alzheimer's disease: is the age of the patient a decisive factor? Results of the INFLUENCE study. AB - Epidemiological and clinical studies suggest that dementia patients aged >= 85 years are biologically different from those aged 65-84. This study aimed to assess whether patients (>85 years) have a distinct sociodemographic and clinical profile. Older patients had lower educational achievements, different carer relationships, and were more likely to take memantine/concomitant treatments and be institutionalized. Differences were observed with respect to concomitant disease/other risk factors (depression, dyslipidemia, cardiovascular disease, hypertension). Oldest patients had greater impairment (more severe Global Deterioration Scale stage, lower Mini-Mental State Examination scores). Greater concomitant drug use and younger carers associated with older patients suggest higher management and social costs. PMID- 24150104 TI - Rosiglitazone prevents amyloid-beta oligomer-induced impairment of synapse formation and plasticity via increasing dendrite and spine mitochondrial number. AB - Rosiglitazone has been known to attenuate neurodegeneration in Alzheimer's disease (AD), but the underlying mechanisms remain to be fully elucidated. In this study, living-cell image, immunocytochemistry, and electrophysiology were used to examine the effects of soluble amyloid-beta protein (Abeta) oligomers and rosiglitazone on the synapse formation, plasticity, and mitochondrial distribution in cultured neurons. Incubation of hippocampal cultures with amyloid beta (Abeta)42 oligomers (0.5 MUM) for 3 h significantly decreased dendritic filopodium and synapse density. Pretreatment with rosiglitazone (0.5-5 MUM) for 24 h prevented the Abeta42-induced loss of dendritic filopodium and synapse in a dose-dependent manner. However, neither Abeta42 oligomer nor rosiglitazone has a significant effect on the velocity and length of dendritic filopodia. Electrophysiological recording showed that acute exposure of slices with 0.5 MUM Abeta42 oligomers impaired hippocampal long-term potentiation (LTP). Pre incubation of hippocampal slices with rosiglitazone significantly attenuated the Abeta42-induced LTP deficit, which depended on rosiglitazone concentrations (1-5 MUM) and pretreatment period (1-5 h). The beneficial effects of rosiglitazone were abolished by the peroxisome proliferator-activated receptor gamma (PPARgamma) specific antagonist, GW9662. Moreover, the mitochondrial numbers in the dendrite and spine were decreased by Abeta42 oligomers, which can be prevented by rosiglitazone. In conclusion, our data suggested that rosiglitazone prevents Abeta42 oligomers-induced impairment via increasing mitochondrial numbers in the dendrite and spine, improving synapse formation and plasticity. This process is most likely through the PPARgamma-dependent pathway and in concentration and time dependent manners. The study provides novel insights into the mechanisms for the protective effects of rosiglitzone on AD. PMID- 24150105 TI - Metabolic correlates of Rey auditory verbal learning test in elderly subjects with memory complaints. AB - We evaluated the brain metabolic correlates of main indexes of a widely used word list learning test, the Rey Auditory Verbal Memory Test (RAVLT), in a group of elderly subjects with memory complaints. Fifty-four subjects (age: 72.02 +/- 7.45; Mini-Mental State Examination (MMSE) score: 28.9 +/- 1.24) presenting at a memory clinic complaining of memory deficit, but not demented, and thirty controls (age: 71.87 +/- 7.08; MMSE score: 29.1 +/- 1.1) were included. Subjects with memory complaints included both patients with (amnestic mild cognitive impairment, aMCI) and without (subjective memory complaints, SMC) impairment on memory tests. All subjects underwent 18F-fluorodeoxyglucose positron emission tomography (FDG-PET), analyzed with statistical parametric. Patients with aMCI but not those with SMC showed the expected posterior cingulate-precuneus and parietal hypometabolism as compared to controls. Correlation was determined for between four indexes of the RAVLT and brain metabolism. The results show a significant correlation between the delayed recall score and metabolism in posterior cingulate gyrus of both hemispheres and in left precuneus, as well as between a score of long-term percent retention and metabolism in left posterior cingulate gyrus, precuneus, and orbitofrontal areas. These correlations survived correction for age, education, and MMSE score. No correlation was found between immediate or total recall scores and glucose metabolism. These data show the relevant role of posterior cingulate-precuneus and orbitofrontal cortices in retention and retrieval of de-contextualized verbal memory material in a group of elderly subjects with memory complaints and shed light on the topography of synaptic dysfunction in these subjects, overlapping that found in the earliest stages of Alzheimer-type neurodegeneration. PMID- 24150106 TI - Coconut oil attenuates the effects of amyloid-beta on cortical neurons in vitro. AB - Dietary supplementation has been studied as an approach to ameliorating deficits associated with aging and neurodegeneration. We undertook this pilot study to investigate the effects of coconut oil supplementation directly on cortical neurons treated with amyloid-beta (Abeta) peptide in vitro. Our results indicate that neuron survival in cultures co-treated with coconut oil and Abeta is rescued compared to cultures exposed only to Abeta. Coconut oil co-treatment also attenuates Abeta-induced mitochondrial alterations. The results of this pilot study provide a basis for further investigation of the effects of coconut oil, or its constituents, on neuronal survival focusing on mechanisms that may be involved. PMID- 24150107 TI - Anesthetics and its impact on the brain and Alzheimer's disease. PMID- 24150108 TI - Can a bacterial endotoxin be a key factor in the kinetics of amyloid fibril formation? AB - Data found in literature have reported that bacterial endotoxins may be involved in the inflammatory and pathological processes associated with amyloidosis and Alzheimer's disease (AD). In fact, it has been observed that the chronic infusion of the bacterial lipopolysaccharide, the outer cell wall component of Gram negative bacteria, into the fourth ventricle of rats reproduces many of the inflammatory and pathological features seen in the brain of AD patients. In this context, a key player in the pathogenesis of AD is the amyloid-beta peptide (Abeta) that is capable of aggregating in fibrils that represent the main component of amyloid plaques. These deposits that accumulate among brain cells are indeed one of the hallmarks of AD. This aggregation in fibrils seems to correlate with Abeta toxic effects. However, recent data have shown that amyloid fibril formation not only results in toxic aggregates but also provides biologically functional molecules; such amyloids have been identified on the surface of fungi and bacteria. The aim of this work was to gain insight into the influence of bacterial endotoxins on Abeta fibrillogenesis; factors that influence fibril formation may be important for Abeta toxic potential. Following three days of incubation at 37 degrees C, Abeta was organized in compact fibrils and the in vitro Abeta fibrillogenesis was potentiated by the Escherichia coli endotoxin. This suggests the importance of infectious events in the pathogenesis of AD and proposes a new aspect related to the putative pathological factors that can be implicated in the mechanisms involved in Abeta25-35 fibrillogenesis. PMID- 24150109 TI - Tau proteins harboring neurodegeneration-linked mutations impair kinesin translocation in vitro. AB - We tested the hypothesis that mutant tau proteins that cause neurodegeneration and dementia differentially alter kinesin translocation along microtubules (MTs) relative to normal tau in vitro. We employed complementary in vitro motility assays using purified recombinant kinesin, purified recombinant tau, and purified bovine brain alpha:beta tubulin to isolate interactions among these components without any contribution by cellular regulatory mechanisms. We found that kinesin translocates slower along MTs assembled by any of three independent tau mutants (4-repeat P301L tau, 4-repeat DeltaN296 tau, and 4-repeat R406W tau) relative to its translocation rate along MTs assembled by normal, 4-repeat wild type (WT) tau. Moreover, the R406W mutation exhibited isoform specific effects; while kinesin translocation along 4-repeat R406W tau assembled MTs is slower than along MTs assembled by 4-repeat WT tau, the R406W mutation had no effect in the 3 repeat tau context. These data provide strong support for the notion that aberrant modulation of kinesin translocation is a component of tau-mediated neuronal cell death and dementia. Finally, we showed that assembling MTs with taxol before coating them with mutant tau obscured effects of the mutant tau that were readily apparent using more physiologically relevant MTs assembled with tau alone, raising important issues regarding the use of taxol as an experimental reagent and novel insights into therapeutic mechanisms of taxol action. PMID- 24150110 TI - Regional differences in white matter breakdown between frontotemporal dementia and early-onset Alzheimer's disease. AB - BACKGROUND: White matter abnormalities have been associated with both behavioral variant frontotemporal dementia (bvFTD) and Alzheimer's disease (AD). OBJECTIVE: Using MRI diffusion tensor imaging (DTI) measures, we compared white matter integrity between patients with bvFTD and those with early-onset AD and correlated these biomarkers with behavioral symptoms involving emotional blunting. METHODS: We studied 8 bvFTD and 12 AD patients as well as 12 demographically-matched healthy controls (NCs). Using four DTI metrics (fractional anisotropy, axial diffusivity, radial diffusivity, and mean diffusivity), we assessed the frontal lobes (FWM) and genu of the corpus callosum (GWM), which are vulnerable late-myelinating regions, and a contrasting early myelinating region (splenium of the corpus callosum). The Scale for Emotional Blunting Scale (SEB) was used to assess emotional functioning of the study participants. RESULTS: Compared to AD patients and NCs, the bvFTD subjects exhibited significantly worse FWM and GWM integrity on all four DTI metrics sensitive to myelin and axonal integrity. In contrast, AD patients showed a numerical trend toward worse splenium of the corpus callosum integrity than bvFTD and NC groups. Significant associations between SEB ratings and GWM DTI measures were demonstrated in the combined bvFTD and AD sample. When examined separately, these relationships remained robust for the bvFTD group but not the AD group. CONCLUSIONS: The regional DTI alterations suggest that FTD and AD are each associated with a characteristic distribution of white matter degradation. White matter breakdown in late-myelinating regions was associated with symptoms of emotional blunting, particularly within the bvFTD group. PMID- 24150112 TI - Military contributions to modern trauma care. PMID- 24150111 TI - Autoimmune manifestations in the 3xTg-AD model of Alzheimer's disease. AB - BACKGROUND: Immune system activation is frequently reported in patients with Alzheimer's disease (AD). However, it remains unknown whether this is a cause, a consequence, or an epiphenomenon of brain degeneration. OBJECTIVE: The present study examines whether immunological abnormalities occur in a well-established murine AD model and if so, how they relate temporally to behavioral deficits and neuropathology. METHODS: A broad battery of tests was employed to assess behavioral performance and autoimmune/inflammatory markers in 3xTg-AD (AD) mice and wild type controls from 1.5 to 12 months of age. RESULTS: Aged AD mice displayed severe manifestations of systemic autoimmune/inflammatory dise6ase, as evidenced by splenomegaly, hepatomegaly, elevated serum levels of anti nuclear/anti-dsDNA antibodies, low hematocrit, and increased number of double negative T splenocytes. However, anxiety-related behavior and altered spleen function were evident as early as 2 months of age, thus preceding typical AD-like brain pathology. Moreover, AD mice showed altered olfaction and impaired "cognitive" flexibility in the first 6 months of life, suggesting mild cognitive impairment-like manifestations before general learning/memory impairments emerged at an older age. Interestingly, all of these features were present in 3xTg-AD mice prior to significant amyloid-beta or tau pathology. CONCLUSION: The results indicate that behavioral deficits in AD mice develop in parallel with systemic autoimmune/inflammatory disease. These changes antedate AD-like neuropathology, thus supporting a causal link between autoimmunity and aberrant behavior. Consequently, 3xTg-AD mice may be a useful model in elucidating the role of immune system in the etiology of AD. PMID- 24150113 TI - Therapeutic targeting of the mitochondrial dysfunction in septic acute kidney injury. AB - PURPOSE OF REVIEW: Acute kidney injury (AKI) is a common and serious complication of severe sepsis. No targeted therapies exist for sepsis-associated AKI, suggesting a pressing need for elucidation of the underlying pathogenic mechanisms. RECENT FINDINGS: Emerging studies of human and experimental septic AKI kidneys have affirmed the longstanding observation that cell death in the tubule is uncommon despite often severe impairment of filtration. Rather than cell death, there appears to be widespread sublethal injury to tubular epithelial mitochondria. These organelles efficiently harness energy through controlled oxidation of metabolic fuels, they house pro-apoptotic proteins, and they produce reactive oxygen species. Derangement in one or more of these functions may contribute to the large reduction in renal function in septic AKI despite only scant cell death. In experimental septic AKI, molecular markers of mitochondrial biogenesis and function - whose renal expression dips during injury - rebound to normal levels as kidney function improves. Results from knockout mice suggest that restoration of mitochondrial function within the nephron may be critical to functional recovery. SUMMARY: Recent findings from human and experimental septic AKI studies strongly implicate the mitochondrion as an important target for sublethal kidney injury. Stimulating the natural pathways through which mitochondrial function is normally recovered following sepsis represents a promising strategy for the development of novel therapies. PMID- 24150114 TI - An update on adding docosahexaenoic acid (DHA) and arachidonic acid (AA) to baby formula. AB - Human milk is the ideal food providing optimal nutrition for healthy term infants. Its complex lipid composition is critical for infant growth and serves as a golden standard for baby formula development. Docosahexaenoic acid (C22:6 n- 3, DHA) and arachidonic acid (C20:4 n- 6, AA) are the two major long chain polyunsaturated fatty acids (PUFAs) in human milk. In humans, they are fundamental components of the cell membrane and play an important role in neurite growth and signal transmission. Their importance for both preterm and term infants has been demonstrated by various clinical trials. DHA and AA supplementation shows desirable influences on visual and cognitive development in early life and is additionally associated with potential benefits on later health. Further clinical data revealed that supplementing both DHA and AA instead of DHA alone during infancy is important to deliver the optimal outcome. In this review, we summarize current research and scientific evidence of DHA and AA on baby development. PMID- 24150115 TI - Use of the nasal sidewall island inversion flap for single-stage ala nasi reconstruction: a report of 103 consecutive cases. AB - BACKGROUND: Alar reconstruction can be challenging, and numerous solutions for reconstructing this potentially difficult area have been proposed. The authors' preferred solution is an island inversion flap based on the superior alar artery. METHODS: The authors performed a retrospective review of the medical notes and photographs of 103 consecutive patients who underwent alar reconstruction with the nasal sidewall island inversion flap. Patient demographics and complications were recorded. When they were available, postoperative photographs (>2 months postoperatively) were rated by three plastic surgeons using a Likert scale together with a rating guide to determine the aesthetic outcome. RESULTS: Between 1998 and 2012, the authors performed 103 island inversion flaps. Mean patient age was 59 years (range, 23 to 85 years). Eighteen (17 percent) of 103 patients had defects extending beyond the ala. There were no flap losses and seven cases of superficial epidermolysis. Revision surgery was performed in three cases. In 48 of 103 cases, postoperative photographs (>2 months postoperatively) were available for aesthetic assessment. The aesthetic results were rated as "good" to "excellent" in more than 70 percent of cases (range, 73 to 85 percent) by the three plastic surgeons. CONCLUSIONS: The nasal sidewall island inversion flap is a reliable and versatile flap for alar reconstruction. It can consistently produce good to excellent aesthetic results in a single-stage operation. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, IV. PMID- 24150116 TI - Analysis of fat graft metabolic adaptation and vascularization using positron emission tomography-computed tomographic imaging. AB - BACKGROUND: Fat tissue transfer is commonly used for different soft-tissue defects in surgery. The immediate result of these operations is often good, but the long-term result is unfortunately unpredictable. The authors used an experimental model to evaluate the vascularization, survival, and metabolic changes after free fat transfer and the impact of proangiogenic therapy on these processes. METHODS: Fat was collected from the mouse epididymal region and placed into the subcutaneous tissue of the forehead. Fat grafts were treated with proangiogenic vascular endothelial growth factor (VEGF)-A (n = 9) or the control vector (n = 9). Metabolic activity and fat graft volume were investigated by positron emission tomography-computed tomography at 4 weeks and at 12 weeks. Histologic analysis was performed at 12 weeks. RESULTS: The glucose metabolism (fluorodeoxyglucose uptake) of the transferred epididymal fat was higher than in the epididymal fat before transplantation in both study groups (VEGF-A and control) and resembled that of normal subcutaneous fat. VEGF-A therapy enhanced the survival and capillary density of the transferred fat after surgery. CONCLUSIONS: Transfer of the metabolically inactive (epididymal) fat into a new environment modulated the metabolic activity of the fat grafts to resemble the situation in the recipient site. These novel findings support the clinical use of free fat grafts in various anatomical regions and tissue types. Proangiogenic VEGF-A therapy enhanced the vascularization and survival of the free fat grafts. PMID- 24150117 TI - Management of failed alveolar bone grafts: improved outcomes and decreased morbidity with allograft alone. AB - BACKGROUND: This study demonstrates the safety and efficacy of allograft alone in revision alveolar bone graft surgery. METHODS: A retrospective review of the authors' institution's alveolar bone graft experience (from 2004 to 2012) with open iliac crest bone graft, minimal-access iliac crest bone graft plus supplemental allograft, and revision allograft alone was performed. All patients (n = 47) were treated with alveolar fistula repair with primary closure. RESULTS: Group 1 patients (12 male, 10 female; average age, 10 years) received iliac crest bone graft alone; 17 had unilateral and five had bilateral clefts. Group 2 (eight male, six female; average age, 9 years) received an iliac crest bone graft plus allograft; six clefts were unilateral and eight were bilateral. Group 3 (six male, five female; average age, 13 years) received revision allograft alone; seven clefts were unilateral and four were bilateral. Average operative time/alveolus was shortest in group 3 compared with groups 1 and 2 (p < 0.0005). Average engraftment was better in group 3 than in group 1 (p < 0.001) and similar to that in group 2 (p < 0.079). Revision alveolar bone graft with allograft alone improved Enemark scores from 3.7 preoperatively to 1.0 postoperatively (p < 0.0001). Hospital stay was shortest in group 3 compared with groups 1 and 2 (p < 0.0001). Bone graft extrusion occurred in six patients (27.3 percent) in group 1, no complications occurred in group 2, and a single necrotic central incisor was lost at the time of revision bone grafting in group 3 (9.1 percent). CONCLUSION: Allograft alone is safe and effective and provides a reliable alternative when traditional alveolar bone graft with iliac crest bone graft has failed. CLINICAL QUESTIONS/LEVEL OF EVIDENCE: Therapeutic, III. PMID- 24150118 TI - Nerve gaps. AB - SUMMARY: Peripheral nerve injury is a significant problem affecting greater that 1 million people around the world each year and poses major challenges to the plastic and reconstructive surgeon. When primary nerve repair is not possible, several options for management of the nerve gap include a nerve autograft, nerve conduit, and acellular nerve allograft. For extensive and proximal nerve injuries, cellular nerve allografts and nerve transfers may be considered. This article reviews the indications and outcomes for each option, as in many cases more than one option may be acceptable. PMID- 24150119 TI - A patient-centered appraisal of outcomes following abdominal wall reconstruction: a systematic review of the current literature. AB - BACKGROUND: Published assessment tools have attempted to investigate patient centered outcomes after abdominal wall defect repairs, including quality-of-life measures, functional outcomes, pain assessment, and overall satisfaction scores; however, health-related quality of life following hernia repair remains unclear. METHODS: The MEDLINE, PubMed, and Cochrane databases were queried and 880 articles were identified. Of these, 22 met inclusion/exclusion criteria. Analysis included health-related quality-of-life metrics focusing on quality of life, pain, physical function, overall satisfaction with surgery, impact of component separation, use of synthetic or biologic mesh, and emotional sequelae of an abdominal wall defect and repair. RESULTS: Twenty-two studies were reviewed; the mean study size was 117.7 patients (range, 14 to 402 patients). Mean and median ventral hernia defect sizes were 104.5 cm and 71.5 cm, respectively. All studies reported open repairs using synthetic mesh. The Short Form-36 was used most often (11 of 22) in comparison to other assessment methods. Patients had global improvement in quality of life, functionality, impact on social function, and patient satisfaction. Hernia recurrence was found to have a major negative impact on quality of life. Midline repair improved overall pain and abdominal wall functionality in both presurgical patients and those with hernia recurrence. Component separation techniques appear to have a positive impact on global health related quality of life. CONCLUSIONS: Adopting an abdominal wall procedure specific quality-of-life assessment tool as the standard is strongly recommended to gain a comprehensive understanding of abdominal wall defects and repairs. The available literature in open abdominal wall repair suggests an improved quality of life. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, III. PMID- 24150120 TI - Surgical decompression of the great auricular nerve: a therapeutic option for neurapraxia following rhytidectomy. AB - BACKGROUND: Great auricular nerve injuries are the most frequent nerve injuries following rhytidectomy, occurring at a rate of 6 percent. Short-scar techniques may decrease visualization and increase the risk of injury/compression of the great auricular nerve. Recent reviews have identified that great auricular nerve injury can contribute to long-term paresthesias and allodynia in a majority of patients. Identification of this injury, with subsequent exploration, wide release, and decompression, should be performed. METHODS: Four patients with injury of the great auricular nerve were referred for persistent allodynia as a complication of short-scar rhytidectomy. Following confirmation of a Tinel sign over the great auricular nerve, each patient underwent subsequent exploration and neurolysis. RESULTS: Diagnosis of compression and suture impingement was confirmed at exploration, and extensive decompression was performed with care taken to protect the nerve from postoperative scar formation. All patients noted postoperative improvement in symptoms, with nearly complete resolution at 6 months. CONCLUSIONS: Minimally invasive techniques may impart increased risk of nerve injury in exchange for reduced scar length. In instances of great auricular nerve injury, progressive metabolic changes and increased vascular permeability allow for inflammatory cellular influx and fibrin deposition, compounding nerve dysfunction and symptomatic complaints. Noninvasive modalities may not alleviate complaints of pain and hyperesthesia, particularly in the event of suture compression. Persistent injuries can affect quality of life, with intrusive thoughts about symptoms, or an inability to perform grooming activities. Exploration and decompression of the great auricular nerve may offer a long-term solution for the patient with postrhytidectomy allodynia. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, V. PMID- 24150121 TI - Soft-tissue fillers in rhinoplasty. AB - SUMMARY: Soft-tissue fillers have been applied throughout the face; however, the literature has largely ignored the injection of fillers into the nasal anatomy. This Special Topic article reviews proper filler choice and injection technique for the nose based on the senior author's (R.J.R.) experience. Discussion includes indications for soft-tissue filler injection into the nose as well as specific technical pearls based on filler material, anatomic area, and potential complications. The application of soft-tissue fillers to rhinoplasty has certainly broadened the nasal surgeon's armamentarium. While major structural changes of the nose are best accomplished through surgical alteration of the osseocartilaginous framework, soft-tissue fillers offer an excellent method to augment areas or refine irregularities. These often subtle alterations require precise preinjection nasal analysis. PMID- 24150122 TI - Brava and autologous fat grafting for breast reconstruction after cancer surgery. AB - BACKGROUND: Although autologous fat grafting is widely accepted for breast reconstruction, its indications remain limited to minor contour deformities after reconstruction and small deformities after breast-conserving surgery. The authors describe a case series of total or nearly total breast reconstructions treated with the perioperative use of a vacuum-based external tissue expander (i.e., the Brava device) followed by autologous fat grafting. METHODS: The authors assessed the clinical outcomes and aesthetic results in six nonirradiated total mastectomy cases and eight severely deformed irradiated breast-conserving surgery cases. Total Brava wearing time and skin complications were also investigated. RESULTS: The number of fat grafting procedures required ranged from one to four, and the mean amount of fat grafted during each procedure was 256 cc (range, 150 to 400 cc). Postoperative fat lysis and cellulitis occurred in two cases (14.3 percent). Brava worked effectively for total mastectomy cases, and improvement in the total aesthetic score was significantly higher than that in the breast-conserving surgery cases. All patients wore the device for more than 8 hours/day. The most frequent skin complication was dermatitis [n = 11 (79 percent)], which occurred in all breast-conserving surgery cases. CONCLUSIONS: Brava was well tolerated by patients. Fat grafting with perioperative use of Brava is an alternative to total breast reconstruction in total mastectomy cases. However, for severely deformed breast-conserving surgery breasts treated with radiation therapy, the contracted skin was difficult to extend despite Brava use, and the results were less satisfactory. These cases also experienced a higher incidence of skin complications compared with the total mastectomy cases. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, IV. PMID- 24150123 TI - The anteromedial thigh free flap anatomy: a clinical, anatomical, and cadaveric study. AB - BACKGROUND: Perforator flaps have become the choice of most reconstructive surgeons because they have decreased donor-site morbidity. Among these flaps, the free anteromedial thigh flap has not yet become a first-choice flap because of the inconstant anatomy of its pedicle. This study aimed to describe the anatomy from different perspectives to highlight common patterns and simplify the flap's application in clinical cases. METHODS: The study started in 2004 and took 9 years to complete. It was performed on 12 clinical anteromedial thigh flap cases, 48 clinical cases of anterolateral thigh flap in which the vascular anatomy of the anteromedial thigh flap was studied, and 48 cadaver dissections. RESULTS: In "type of perforators," the authors found an almost total consistency between clinical cases (group 1) and dissections in patients (group 2) (chi = 0.164 and p = 0.92), whereas the cadaver dissections (group 3) were minimally homogeneous (chi = 13.7 and p = 0.0082). Then, taking into account the parameter "origin of perforators," they noticed the same trend with a clear alignment between the first two groups (chi = 1.84 and p = 0.87) and a strong inhomogeneity in relation to the third group (chi = 19.8 and p = 0.03). CONCLUSIONS: Anatomical study of the anteromedial thigh flap pedicle showed a marked variability that makes preoperative planning difficult, and thus more stressful to realize. This evidence confirms that the flap can be used as a second choice or simultaneously with the anterolateral thigh flap. In addition, the authors strongly suggest a preoperative radiological study to minimize the possible anatomical variabilities during surgery. PMID- 24150124 TI - Kernel approximate Bayesian computation in population genetic inferences. AB - Approximate Bayesian computation (ABC) is a likelihood-free approach for Bayesian inferences based on a rejection algorithm method that applies a tolerance of dissimilarity between summary statistics from observed and simulated data. Although several improvements to the algorithm have been proposed, none of these improvements avoid the following two sources of approximation: 1) lack of sufficient statistics: sampling is not from the true posterior density given data but from an approximate posterior density given summary statistics; and 2) non zero tolerance: sampling from the posterior density given summary statistics is achieved only in the limit of zero tolerance. The first source of approximation can be improved by adding a summary statistic, but an increase in the number of summary statistics could introduce additional variance caused by the low acceptance rate. Consequently, many researchers have attempted to develop techniques to choose informative summary statistics. The present study evaluated the utility of a kernel-based ABC method [Fukumizu, K., L. Song and A. Gretton (2010): "Kernel Bayes' rule: Bayesian inference with positive definite kernels," arXiv, 1009.5736 and Fukumizu, K., L. Song and A. Gretton (2011): "Kernel Bayes' rule. Advances in Neural Information Processing Systems 24." In: J. Shawe-Taylor and R. S. Zemel and P. Bartlett and F. Pereira and K. Q. Weinberger, (Eds.), pp. 1549-1557., NIPS 24: 1549-1557] for complex problems that demand many summary statistics. Specifically, kernel ABC was applied to population genetic inference. We demonstrate that, in contrast to conventional ABCs, kernel ABC can incorporate a large number of summary statistics while maintaining high performance of the inference. PMID- 24150125 TI - Abnormal hip physical examination findings in asymptomatic female soccer athletes. AB - PURPOSE: Examination of the hip provides information regarding risk for pre arthritic hip disorders, knee injuries, and low back pain. The purpose of this study was to report a hip screening examination of asymptomatic female soccer athletes and to test the hypothesis that these findings vary by competition experience. METHODS: Asymptomatic females from a youth soccer club, a college, and a professional team were evaluated. Passive hip range of motion, hip abduction strength, and hip provocative tests were assessed. Data were compared for the grade/middle school, high school, college, and professional athletes. RESULTS: One hundred and seventy-two athletes with a mean age of 16.7 +/- 5 years (range 10-30) participated. Professional athletes had less flexion (HF) for both hips (p < 0.0001) and less internal rotation (IR) for the preferred kicking leg (p < 0.05) compared to all other groups. Grade/middle school athletes had more external rotation in both hips as compared to all other groups (p < 0.0001). For the preferred kicking leg, collegiate athletes had less hip abduction strength as compared to other groups (p < 0.01). Positive provocative hip tests were found in 22 % of all players and 36 % of the professionals. In professionals, a positive provocative test was associated with ipsilateral decreased HF (p = 0.04). CONCLUSION: Asymptomatic elite female soccer athletes with the most competition experience had less bilateral hip flexion and preferred kicking leg IR than less experienced athletes. Positive provocative hip tests were found in 22 % of athletes. Future studies are needed to show whether these findings link to risk for intra-articular hip or lumbar spine and knee disorders. LEVEL OF EVIDENCE: III. PMID- 24150126 TI - Differential therapeutic effects of anti-VEGF-A antibody in different tumor models: implications for choosing appropriate tumor models for drug testing. AB - We previously reported that the host response to certain chemotherapies can induce primary tumor regrowth, angiogenesis, and even metastases in mice, but the possible impact of anti-VEGF-A therapy in this context has not been fully explored. We, therefore, used combinations of anti-VEGF-A with chemotherapy on various tumor models in mice, including primary tumors, experimental lung metastases, and spontaneous lung metastases of 4T1-breast and CT26-colon murine cancer cell lines. Our results show that a combined treatment with anti-VEGF-A and folinic acid/5-fluorouracil/oxaliplatin (FOLFOX) but not with anti-VEGF-A and gemcitabine/cisplatinum (Gem/CDDP) enhances the treatment outcome partly due to reduced angiogenesis, in both primary tumors and experimental lung metastases models. However, neither treatment group exhibited an improved treatment outcome in the spontaneous lung metastases model, nor were changes in endothelial cell numbers found at metastatic sites. As chemotherapy has recently been shown to induce tumor cell invasion, we tested the invasion properties of tumor cells when exposed to plasma from FOLFOX-treated mice or patients with cancer. While plasma from FOLFOX-treated mice or patients induced invasion properties of tumor cells, the combination of anti-VEGF-A and FOLFOX abrogated these effects, despite the reduced plasma VEGF-A levels detected in FOLFOX-treated mice. These results suggest that the therapeutic impact of antiangiogenic drugs varies in different tumor models, and that anti-VEGF-A therapy can block the invasion properties of tumor cells in response to chemotherapy. These results may implicate an additional therapeutic role for anti-VEGF-A when combined with chemotherapy. PMID- 24150127 TI - The metabolic demands of kayaking: a review. AB - Flat-water kayaking is one of the best-known competitive canoeing disciplines in Australia and across the European countries. From a stationary start, paddlers are required to paddle their kayaks with maximal effort along the length of the competing distance. The ultimate criterion of kayak performance is the time taken to paddle a designated competition distance. In flat-water racing, events are contested over 500 and 1000 metres. To approximate the ultimate criterion over these distances, the velocity of the kayak should be measured. Furthermore, other factors that affect performance, such as force, power, technique and aerobic fitness, would all provide a valuable insight to the success of the kayak paddler. Specific research performed examining the physiological demands on kayak paddlers demonstrate high levels of both aerobic power and anaerobic capacity. It is the purpose if this review to present the published physiological data relating to men's and women's kayaking. With a number of recent publications, a need for an updated review is necessary. The present review summarises recent data on anthropometrics, physiological characteristics of successful and unsuccessful kayak athletes and methods of physiological testing. Due to the fact that more data have been reported for male competitors than for their female counterparts, the demands of kayaking on male athletes will be the main focus for this review. The review also suggests areas for future research into flatwater kayaking performance. Understanding the physiological requirements of kayaking can assist coaches and athletes in a number of ways. During competition or training, such information is helpful in the selection of appropriate protocols and metabolic indices to monitor an athlete's performance improvements and assess an athlete's suitability for a particular race distance. Furthermore, it may aid the coach in the development of more specific training programs for their athletes. Key pointsFlat water kayaking is characterised by exceptional demands on upper body performance.When examining the oxygen consumption, it is notable that although a high value is attainable, they are not quite as high as other sporting events such as road cycling, rowing or running where lower body is dominant.Elite kayakers demonstrate superior aerobic and anaerobic quantities and have reported maximal oxygen consumptions of around 58 ml.kg(-1).min(-1) (4.7 L.min(-1)) and lactate values of around 12 mM during laboratory and on water testing. PMID- 24150128 TI - Temporal dynamics of acrobatic activity: an approach of elite athletes specious present. AB - The present study examined how "meaningful time "is constructed and used during acrobatic performance. To do so, six elite athletes (2 tumblers, 2 trampolinists, 2 acrobatic skiers) performed the same acrobatic move within the context of their respective sports. Their activity was described step-by-step using the data obtained from self- confrontation interviews linked to behaviour analysis based on video recordings. The descriptions, which identified the actions, feelings and thoughts of the athletes in relation to the unfolding time of their performance, were then compared. The results demonstrated that acrobatic performance can be divided into different periods that delineate meaningful time. Differences were observed in how the athletes organized activity (e.g. cognitive, physical) according to the specific sport. The results were interpreted as specific ways to use flight time. Key pointsElite acrobatic athletes' activities organize the unfolding of the performance by progressively informing the performers about the state of the evolving situation.The complexity of the activity involved for such acrobatic performances is reduced by a process of timed and situated organization.Athletes' activity consisted to display different jigs corresponding to a meaningful delineate specious present for efficient performance. PMID- 24150129 TI - Lack of agreement between gas exchange variables measured by two metabolic systems. AB - The purpose of this study was to assess the agreement and consistency between gas exchange variables measured by two online metabolic systems during an incremental exercise test. After obtaining local ethics approval and informed consent, 15 healthy subjects performed an incremental exercise test to volitional fatigue using the Bruce protocol. The Innocor (Innovision, Denmark) and CardiO2 (Medical Graphics, USA) systems were placed in series, with the Innocor mouthpiece attached to the pneumotach of the CardiO2. Metabolic data were analysed during the last 30 seconds of each stage and at peak exercise. There were non- significant differences (p > 0.05) between the two systems in estimation of oxygen consumption (VO2) and in minute ventilation (VE). Mean Cronbach's alpha for VO2 and VE were 0.88 and 0.92. The Bland-Altman analysis revealed that limits of agreement were -0.52 to 0.55 l.min(-1) for VO2, and -8.74 to 10.66 l.min(-1) for VE. Carbon dioxide production (VCO2) and consequently respiratory exchange ratio (RER) measured by the Innocor were significantly lower (p < 0.05) through all stages. The CardiO2 measured fraction of expired carbon dioxide (FeCO2) significantly higher (p < 0.05). The limits of agreement for VO2 and VE are wide and unacceptable in cardio-pulmonary exercise testing. The Innocor reported VCO2 systematically lower. Therefore the Innocor and CardiO2 metabolic systems cannot be used interchangeably without affecting the diagnosis of an individual patient. Results from the present study support previous suggestion that considerable care is needed when comparing metabolic data obtained from different automated metabolic systems. Key pointsThere is general concern regarding the limited knowledge available about the accuracy of a number of commercially available systems.Demonstrated limits of agreement between key gas exchange variables (oxygen consumption and minute ventilation) as measured by the two metabolic systems were wide and unacceptable in cardio-pulmonary exercise testing.Considerable care is needed when comparing metabolic data obtained from different automated metabolic systems. PMID- 24150130 TI - Peers' influence on exercise enjoyment: a self-determination theory approach. AB - The purpose of this research was to study the influence of motivational climate perceived in peers and basic psychological needs (competence, autonomy and relatedness) on self-determined motivation and enjoyment in exercise. A sample comprised of 394 non- competitive physical exercisers, 156 women and 238 men aged between 16 and 54 (M = 21.64, SD = 7. 18), completed the Motivational Climate Perceived in Peers Scale, Scale of Motivational Mediators in Physical Activity, Behavioural Regulation in Exercise Questionnaire-2 and Physical Activity Enjoyment Scale. A correlation analysis between the variables studied, a confirmatory factor analysis (CFA) and structural equation analysis were performed. The results showed that the task- involving peer motivational climate positively predicted the three basic psychological needs (competence, autonomy and relatedness). In turn, meeting the needs for competence and relatedness positively predicted self-determined motivation, which also positively predicted the enjoyment the exercisers had during the activity. There were no significant associations between the ego- involving peer motivational climate and psychological needs. A multisample analysis indicated that the model was invariant across age and degree of exercise involvement. This study reiterates the importance of increasing exercisers' self-determined motivation in order to obtain more enjoyment and to be more committed to the exercise. Therefore, it is essential to foster perceptions of competence, autonomy and relatedness by means of a task-involving climate. The findings provide evidence for the importance of peer motivational climate in sports motivation. Key pointsTask-involving peer motivational climate positively predicted the three basic psychological needs (competence, autonomy and relatedness). There were no significant associations between the ego-involving peer motivational climate and psychological needs.Needs for competence and relatedness positively predicted self-determined motivation.Self-determined motivation positively predicted enjoyment. PMID- 24150131 TI - Exertion during uphill, level and downhill walking with and without hiking poles. AB - This study examined the effects of poles when walking on the rate of perceived exertion (RPE), physiological and kinematics parameters, and upon the mean ratio between locomotor and respiratory rhythms. Twelve healthy male and female volunteers, aged 22 to 49 years old, completed on a motorized treadmill in a counterbalanced randomized order 12 walking trials for 10 min at an individually preferred walking speed, with three grades (horizontal level, uphill or downhill with a slope of 15%), with and without hiking poles and a load carriage of 15% of body mass. During all testing sessions, heart rate (HR), oxygen consumption (VO2), ventilation (VE), tidal volume (VT), breathing frequency (Bf), and stride frequency were recorded continuously during the last 5-min of each trial. At the end of each trial, subjects were asked to give RPE. Energy cost (EC) and VE increased significantly with the grade (-15% < 0% < +15%) and with the carrying load. VT was significantly less important with hiking poles, while Bf was significantly more elevated. VO2 and EC increased (p < 0.05) with the use of the hiking poles only during the downhill trials. No significant effect of poles was observed on HR, RPE, and preferred walking speed. The average ratio between the locomotor and respiratory frequencies was significantly influenced by the three experimental factors tested. There was a significant relationship between average ratio of leg movement per breath and EC of walking among all conditions (r = 0.83, n = 12). These results suggest that the use of the hiking poles had a significant influence on the respiratory and energetic responses only during downhill walking. Key pointsEnergetic cost, respiratory responses, stride rate, respiratory to cycle rate ratio were significantly influenced by the use of hiking poles according to the grade at self-selected walking speed.Hiking poles induced an increase in respiratory frequency, VE and energetic cost during downhill, while little changes were observed during level and uphill terrain.The original results obtained in downhill necessitate supplementary studies in the field in order to confirm these first tendencies on treadmill. PMID- 24150132 TI - The effects of interval feedback on the self-efficacy of netball umpires. AB - The present study used quantitative and qualitative methods to explore the relationship between interval feedback and self-efficacy toward umpiring netball games. Grade "A "level umpires (n = 7) provided feedback to umpires (n = 40) under two conditions; 1) interval feedback given at the end of one tournament game (after 14 minutes) and again at the end of a second consecutive game (after 28 minutes), and 2) feedback at the end of the game (after 28 minutes). Umpires in both conditions completed an Umpiring Self-Efficacy Questionnaire (USEQ) which was a 14-item measure designed to assess factors relevant to netball umpire performance. Participants completed the USEQ immediately before game one, during the interval, and after a second game. Umpires also completed a feedback questionnaire which enabled them to reflect on the feedback received. A repeated measures factorial (time x feedback condition) ANOVA indicated no significant interaction effect (F = 0.05, p > .05), and no main effect for condition (F = 0.06, p > .05) or time (F = 1.61, p > .05) for changes in self-efficacy. Although there were no significant effects, qualitative data alluded to aspects of feedback perceived to enhance umpire self-efficacy, thus identifying ways in which feedback might have a more consistent effect. Practical implications of the study in relation to verbal interval feedback are discussed. Key pointsInterval feedback may detract from umpires processing of information during a game.Interval feedback can enhance self-efficacy.Findings show that personal and situational factors interacted to determine the outcome of feedback.Feedback should be tailored for the needs of the individual and take into account situational factors, to enhance the possibility of accruing positive outcomes. PMID- 24150133 TI - Relationship between maximum shoulder external rotation angle during throwing and physical variables. AB - The amount of stress imposed on shoulder and elbow appears to be directly correlated with the degree of maximum shoulder external rotation (MER) during throwing motions. Therefore, identifying risk factors contributing to the increase of MER angle may help to decrease the throwing injuries occurrence in baseball players. The purpose of the present study was to demonstrate the correlation between MER and the kinematic variables at stride foot contact (SFC) during the early cocking phase, the passive range of motion (ROM), and the shoulder strength. The subjects were 40 high school baseball players. Each subject carried out five throwing tasks with his maximum effort. A three dimensional analysis was performed to obtain the MER, and the shoulder angles of external rotation (ER), extension and abduction at SFC in the early cocking phase. The ROM and muscle strength of the shoulder ER and internal rotation (IR) were also measured. Significant moderate linear correlations were found between the MER and the ER (r = -0.32, p = 0.04) at SFC, extension angle ( r= 0.35, p = 0.03) at SFC, IR strength (r = -0.30, p = 0.04) and passive ROM of ER (r = 0.46, p = 0.01). The shoulder IR and extension angles at SFC may determine the degree of the MER angle. Furthermore, weak IR muscle strength and excessive ROM of ER might be risk factors for shoulder and elbow injuries. The finding will enable us to establish better prevention and rehabilitation strategies for throwing injuries in baseball players. Key pointsIt has been reported that the amount of stress imposed on shoulder and elbow joints is correlated with the degree of maximum shoulder external rotation angle (MER) during throwing. Therefore, controlling MER within a normal range plays a key role in the prevention for throwing-related injuries in baseball players.Physical and biomechanical factors related to the degree of MER must be addressed to advance the current prevention and rehabilitation strategies for the shoulder and elbow injuries.The current finding demonstrated that there was a significant moderate leaner correlation between shoulder internal rotation angle at the initial foot contact in the early cocking phase and MER. PMID- 24150134 TI - Anaerobic capacity may not be determined by critical power model in elite table tennis players. AB - The aim of the present study was to verify the applicability of anaerobic work capacity (AWC) determined from the critical power model in elite table tennis players. Eight male international level table tennis players participated in the study. The tests undertaken were: 1) A critical frequency test used to determinate the anaerobic work capacity; 2) Wingate tests were performed using leg and arm ergometers. AWC corresponded to 99.5 +/- 29.1 table tennis balls. AWC was not related to peak (r = -0.25), mean (r = -0.02), relative peak (r = -0.49) or relative mean power (r = 0.01), nor fatigue index (r = -0.52) (Wingate leg ergometer). Similar correlations for peak (r = -0.34), mean (r = -0.04), relative peak (r = -0.49), relative mean power (r = -0.14) and peak blood lactate concentration (r = -0.08) were determined in the Wingate arm ergometer test. Based on these results the AWC determined by a modified critical power test was not a good index for measurement of anaerobic capacity in table tennis players. Key pointsAnaerobic work capacity (AWC) was not good index of anaerobic capacity in table tennis.AWC determined using the table tennis ergometer showed low correlations with the Wingate test measures for cycle and arm ergometry.A sport specific protocol is required for measuring anaerobic capacity in table tennis. PMID- 24150135 TI - Analysis of drafting effects in swimming using computational fluid dynamics. AB - The purpose of this study was to determine the effect of drafting distance on the drag coefficient in swimming. A k-epsilon turbulent model was implemented in the commercial code Fluent((r)) and applied to the fluid flow around two swimmers in a drafting situation. Numerical simulations were conducted for various distances between swimmers (0.5-8.0 m) and swimming velocities (1.6-2.0 m.s(-1)). Drag coefficient (Cd) was computed for each one of the distances and velocities. We found that the drag coefficient of the leading swimmer decreased as the flow velocity increased. The relative drag coefficient of the back swimmer was lower (about 56% of the leading swimmer) for the smallest inter-swimmer distance (0.5 m). This value increased progressively until the distance between swimmers reached 6.0 m, where the relative drag coefficient of the back swimmer was about 84% of the leading swimmer. The results indicated that the Cd of the back swimmer was equal to that of the leading swimmer at distances ranging from 6.45 to 8. 90 m. We conclude that these distances allow the swimmers to be in the same hydrodynamic conditions during training and competitions. Key pointsThe drag coefficient of the leading swimmer decreased as the flow velocity increased.The relative drag coefficient of the back swimmer was least (about 56% of the leading swimmer) for the smallest inter-swimmer distance (0.5 m).The drag coefficient values of both swimmers in drafting were equal to distances ranging between 6.45 m and 8.90 m, considering the different flow velocities.The numerical simulation techniques could be a good approach to enable the analysis of the fluid forces around objects in water, as it happens in swimming. PMID- 24150136 TI - Searching for criteria in evaluating the monofin swimming turn from the perspective of coaching and improving technique. AB - This study aims to analysise the selected kinematic parameters of the monofin swimming turn. The high complexity of performing turns is hindered by the large surface of the monofin, which disturbs control and sense of the body in water. A lack of objective data available on monofin swimming turns has resulted in field research connected with the specification of parameters needed for the evaluation of the technique. Therefore, turns observed in elite swimmers contain underlying conclusions for objective criteria, ensuring the highest level of coaching and the improving of turns in young swimmers. Six, high level, male swimmers participated in the study. The subject of the analysis was the fastest turn, from one out of three trial turns made after swimming a distance of 25 m. Images of the turns were collected from two cameras located under water in accordance with the procedures of the previous analyses of freestyle turns. The images were digitized and analysed by the SIMI((r))- Movement Analysis System. The interdependency of the total turn time and the remaining recorded parameters, constituted the basis for analysis of the kinematic parameters of five turn phases. The interdependency was measured using r- Pearson's correlation coefficients. The novel character of the subject covered in this study, forced interpretation of the results on the basis of turn analyses in freestyle swimming. The results allow for the creation of a diagram outlinig area of search for an effective and efficient monofin swimming turn mechanism. The activities performed from the moment of wall contact until the commencement of stroking seem to be crucial for turn improvement. A strong belief has resulted that, the correct monofin swimming turn, is more than just a simple consequence of the fastest performance of all its components. The most important criteria in evaluating the quality of the monofin swimming turn are: striving for the optimal extension of wall contact time, push-off time and glide time. Key pointsShort time and large surface of the monofin additionally hinders complexity of the turn performance by disturbance in sensing and controlling body in water. Availability of no objective data on monofin swimming turns resulted in research in the field connected with specifying parameters needed for the technique evaluation.Correct turn technique may help to improve swimming race results.The diagram constructed on the basis of the interdependency of the total turn time and the remaining recorded kinematic parameters should establish the areas of searching for mechanism of effective and efficient monofin swimming turn.The most crucial, from the coaching and improving point of view, seem to be activities which take place from the moment of feet wall contact till the first propulsive movements. Therefore, the high quality of the monofin swimming turn technique is not just a simple consequence of the fastest performance of all its component parts.THE MOST IMPORTANT CRITERIA OF THE QUALITY IN THE MONOFIN SWIMMING TURN TECHNIQUE ARE: striving for extending in the optimum scope of wall contact time, the time of the push-off phase and the glide time. PMID- 24150137 TI - Glenohumeral internal rotation deficit in the asymptomatic professional pitcher and its relationship to humeral retroversion. AB - The purpose of this study was to determine if glenohumeral internal rotation deficits (GIRD) exist in an asymptomatic population of professional pitchers, and to assess whether these changes are primarily a bony or soft tissue adaptation. Twenty three, active, asymptomatic professional (Major League Baseball) pitchers volunteered for the study. Clinical measures of glenohumeral ranges of motion, laxity, GIRD, as well as radiographic measures of humeral retroversion were taken by two independent orthopaedic surgeons. Data comparing side to side differences in range of motion, laxity, and humeral retroversion were analyzed for statistical significance using a paired t-test for continuous data and a Chi squared test for ordinal data, with a significance set at 0.05. Evaluations of statistical correlations between different measurement parameters were accomplished using a Pearson product moment correlation. We hypothesized GIRD will be positively correlated with humeral retroversion (HR) in the pitching arm. All clinical and radiographic measures were made in the field, at spring training, by physicians of both private and institutional based sports medicine practices. For the entire group, significant differences were exhibited for HR, external rotation at 90 degrees and internal rotation at 90 degrees , for dominant vs. non-dominant arms. GIRD of greater than 25 degrees was noted in 10/23 of pitchers. In this group, HR was significantly increased and correlated to GIRD. No such increase or correlation was noted for the non-GIRD group. GIRD is a common finding in asymptomatic professional pitchers, and is related to humeral retroversion. Thus internal rotation deficits should not be used as the sole screening tool to diagnose the disabled throwing shoulder. Key pointsGIRD is relatively common in asymptomatic baseball pitchers (35-43%).Large ranges (-45 to 5 degrees ) and a large standard deviation (+/-16 degrees ) were noted suggesting that GIRD is quite variable in this population.GIRD is a variable measure in the asymptomatic population, and therefore should not be used as sole proof for the disabled throwing shoulder. PMID- 24150138 TI - The effects of kinetic energy on concentric and eccentric isokinetic work. AB - This investigation examined inertial effects on work output during isokinetic concentric knee extension and eccentric knee flexion. Total work (Wtotal) included work due to kinetic energy (Wkin), with respect to gravity (Wgrav), and against the dynamometer (Wdyn). Eighteen resistance-trained participants (9 males, 9 females) performed maximal voluntary concentric (90, 150, 210, 270 deg/s) and eccentric (-150, -90, -30 deg/s) actions with the dominant leg. Differences between work measurement type (WMT), i.e., gravity-corrected work and Wtotal, were assessed. ANOVA (2 WMT x 2 mode x 2 gender x 4 speed) revealed significant main effects (p < 0. 05) for both factors concentrically but only for WMT eccentrically. It was concluded that the effect of kinetic energy during isokinetic leg extension may elicit differences in measurement where the associated error (Kerr) significantly increases with increasing velocity concentrically and decreases eccentrically. Key pointsTotal isokinetic work is underestimated by standard gravity corrected techniques.Standard gravity corrected work measurements overestimate isometric eccentric total work.The overestimation of isometric eccentric total work increases with greater angular velocity. PMID- 24150139 TI - Influence of gait manipulation on running economy in female distance runners. AB - The aim of this investigation was to determine if gait manipulation influences running economy. Following 30 minutes of accommodation to level treadmill running at 3.35 m.s(-1) and determination of VO2peak, nine female distance runners (age = 23.3 +/- 4.2 years; body mass = 57.5 +/- 5.2 kg; height = 1.64 +/- 0.10 m; body fat = 11.4 +/- 2.4 %; VO2peak = 54.9 +/- 4.1 ml.kg(-1).min(-1)) completed two treadmill running sessions. In each session, standing VO2 was measured and subjects ran for 6 minutes at 3.35 m.s(-1) under 4 randomly-selected conditions: a) normal running (NL), b) hands behind back (BK), c) hands on head (HD), and d) running with exaggerated vertical oscillation (VOSC). During the last 2 minutes of each running bout, samples of expired air were analyzed to determine oxygen uptake (VO2). Data obtained by averaging gross VO2 values across sessions indicated that VOSC (51.0 +/- 2.5 ml.kg(-1).min(-1)) and HD (46.1 +/- 2.0 ml.kg( 1).min(-1)) resulted in significantly (p < 0.05) elevated VO2 values compared to BK (43.9 +/- 2.4 ml.kg(-1).min(-1)) and NL (43.4 2.6 ml.kg(-1).min(-1)). VO2 measured during VOSC was also higher compared to HD. Viewed in concert, these results suggest that specific gait manipulations can produce marked decrements in running economy among trained female distance runners. Key pointsThis investigation demonstrates that specific biomechanical manipulations can produce substantive increases in the oxygen cost (VO2) of submaximal running in female distance runners.The magnitude of increases in VO2 reported in this study raises the intriguing possibility that meaningful improvements in running economy might be achieved by manipulating the gait of distance runners who exhibit specific aspects of running style that deviate markedly from the optimum. PMID- 24150140 TI - Pre, during, and post exercise anterior tibial compartment pressures in long distance runners. AB - The aim of the study was to assess pre, during, and postexercise compartment pressures in the anterior tibial compartment in asymptomatic long distance runners (5000 m) and recreational athletes. Forty-eight participants (n = 48, 24 females and 24 males) underwent the experimental procedures. The participants were assigned into 4 groups of 12 volunteers. Intracompartmental pressures measurements were recorded 1 minute before, at the 1(st) minute after the onset of exercise, and finally 5 minutes after the completion of the exercise on treadmill. The wick catheter technique was the method of choice for measuring intracompartmental pressure values. Post hoc analysis of the groups by measures interaction indicated that all pairwise comparisons among pre-test (1 minute before exercise), during-test (1(st) minute during exercise), and post-test measures (5 minutes after exercise) were statistically significant for male controls (p < .001), male athletes (p < .001), female controls (p < .001) and female athletes (p < .001). The results confirm the correlation between long distance runners and the increased risk of chronic exertional compartment syndrome (CECS) development. Key pointsCompartment syndrome is a condition characterised by increased intracompartmental pressures within inelastic fascia which surrounds muscular compartmentsInitial CECS symptomatology is not clear and increases graduallyAll the study participants presented the lowest intra compartment pressure values one minute before the beginning of exercise (at rest) with the highest value being recorded at the first minute of exercise.Control population had lower intra-compartment pressure than professional runners.One minute after the beginning of exercise control and athlete men group showed higher intra-compartment pressure than control and athlete women group, indicating a probable sex difference both for athletes and controls.Further studies on predisposing factors of CECS, such as increased intracompartmental pressure values in asymptomatic population is needed to establish the diagnosis in a proper time. PMID- 24150141 TI - The relationship between isometric and dynamic strength in college football players. AB - Previous research has demonstrated the importance of both dynamic and isometric maximal strength and rate of force development (RFD) in athletic populations. The purpose of this study was to examine the relationships between measures of isometric force (PF), RFD, jump performance and strength in collegiate football athletes. The subjects in this study were twenty-two men [(mean +/- SD):age 18.4 +/- 0.7 years; height 1.88 +/- 0.07 m; mass 107.6 +/- 22.9 kg] who were Division I college football players. They were tested for PF using the isometric mid thigh pull exercise. Explosive strength was measured as RFD from the isometric force time curve. The one repetition maximum (1RM) for the squat, bench press and power clean exercises were determined as measures of dynamic strength. The two repetition maximum (2RM) for the split jerk was also determined. Vertical jump height and broad jump was measured to provide an indication of explosive muscular power. There were strong to very strong correlations between measures of PF and 1RM (r = 0. 61 - 0.72, p < 0.05). The correlations were very strong between the power clean 1RM and squat 1RM (r = 0.90, p < 0.05). There were very strong correlations between 2RM split jerk and clean 1RM (r = 0.71, p < 0.05), squat 1RM (r = 0.71, p < 0.05), bench 1RM (r = 0.70, p < 0.05) and PF (r = 0.72, p < 0.05). There were no significant correlations with RFD. The isometric mid thigh pull test does correlate well with 1RM testing in college football players. RFD does not appear to correlate as well with other measures. The isometric mid thigh pull provides an efficient method for assessing isometric strength in athletes. This measure also provides a strong indication of dynamic performance in this population. Key pointsIn Division I college football players the isometric mid thigh pull test correlates well with 1RM testing.Rate of Force Development does not appear to be as closely related to dynamic and isometric strength in college football players.The isometric mid thigh pull provides a quick and efficient method for assessing isometric strength in athletes. PMID- 24150142 TI - Can Blood Gas and Acid-Base Parameters at Maximal 200 Meters Front Crawl Swimming be Different Between Former Competitive and Recreational Swimmers? AB - The aim of the present study was to ascertain whether maximal 200 m front crawl swimming strategies and breathing patterns influenced blood gas and acid-base parameters in a manner which gives advantage to former competitive swimmers in comparison with their recreational colleagues. Twelve former competitive male swimmers (the CS group) and nine recreational male swimmers (the RS group) performed a maximal 200 m front crawl swimming with self- selected breathing pattern. Stroke rate (SR) and breathing frequency (BF) were measured during the swimming test. Measures also included blood lactate concentration ([LA]) and parameters of blood acid-base status before and during the first minute after the swimming test. The CS group swam faster then the RS group. Both groups have similar and steady SR throughout the swimming test. This was not matched by similar BF in the CS group but matched it very well in the RS group (r = 0.89). At the beginning of swimming test the CS group had low BF, but they increased it throughout the swimming test. The BF at the RS group remained constant with only mirror variations throughout the swimming test. Such difference in velocity and breathing resulted in maintaining of blood Po2 from hypoxia and Pco2 from hypercapnia. This was similar in both groups. [LA] increased faster in the CS group than in the RS group. On the contrary, the rate of pH decrease remained similar in both groups. The former competitive swimmers showed three possible advantages in comparison to recreational swimmers during maximal 200 m front crawl swimming: a more dynamic and precise regulation of breathing, more powerful bicarbonate buffering system and better synchronization between breathing needs and breathing response during swimming. Key pointsTraining programs for competitive swimmers should promote adaptations to maximal efforts.Those adaptations should include high and maximal intensity swims with controlled breathing frequency (taking breath every fourth, fifth, sixth or eighth stroke cycle for front crawl swimming).Such training will improve breathing regulation in order to impose a better synchronization between breathing needs and breathing response during maximal swimming. PMID- 24150143 TI - The Role of Knee Positioning and Range-of-Motion on the Closed-Stance Forehand Tennis Swing. AB - This paper discusses the role of knee positioning and range-of- motion on the closed-stance forehand tennis swing. The analyses of tennis swing mechanics were performed using a computer model comprised of a full-body model of a human and an inertial model of a racket. The model was driven by subject forehand swings (16 female college-level subjects) recorded with a high-speed digital motion analysis system. The study discovered that both initial knee positioning and range-of motion were positively related to racket velocity and characteristic of more skilled players. The direct effects of knee positioning and range-of-motion on racket movement are minimal, however there are several indirect biomechanical effects on the forehand motion such as movement of the body mass center, work of the knee, hip and back joints, and the angular range-of-motion of the hips and torso. Some of these indirect effects were related to racket velocity and characteristic of more skilled players. Factors that influenced knee positioning and range-of-motion include years of playing, amount of coaching, and body style. Efforts to both increase and restrict the knee movements of the subjects resulted in substantially lower racket velocities (and other detrimental biomechanical effects) implying that there may be optimal knee positions and range-of-motion for a given subject. The most skilled subject exhibited a high degree of consistency of knee positioning and range-of-motion. This subject adjusted for varying ball height through modified initial knee positioning while maintaining fairly constant ranges-of-motion. Key pointsInitial knee positioning and range-of motion were positively related to racket velocity and characteristic of more skilled players for the closed stance forehand motion.Knee positioning and range of-motion had several indirect biomechanical effects on the forehand motion such as movement of the body mass center, work of the knee, hip and back joints, and the angular range-of-motion of the hips and torso.Efforts to both increase and restrict the knee movements resulted in substantially lower racket velocities implying that there may be optimal knee positions and range-of-motion for a given subject.The most skilled subject exhibited a high degree of consistency of knee positioning and range-of-motion. This subject adjusted for varying ball height through modified initial knee positioning while maintaining fairly constant ranges-of-motion. PMID- 24150144 TI - The Effects of Sodium Citrate Ingestion on Metabolism and 1500-m Racing Time in Trained Female Runners. AB - The purpose of the study was to assess the effects of sodium citrate ingestion on the metabolic response to exercise and performance in a 1500-m competitive run in trained female middle-distance runners in field conditions. Seventeen athletes (mean (+/- SD) aged 18.6 +/- 2.5 years, VO2max 55.2 +/- 7.6 ml.kg(-1).min(-1)) competed in two 1500-m races following ingestion of 0.4 g.kg(-1) body mass of sodium citrate (CIT) and placebo (PLC - 1.0% solution of NaCl). The two substances, CIT and PLC were administered in 800 ml of solution in a randomly assigned double-blind crossover manner. Capillary blood samples were analysed for lactate, glucose, haemoglobin and haematocrit before administering the solutions (baseline) as well as before and after both 1500-m races. The athletes' times for trials CIT and PLC were 321.4 +/- 26.4 and 317.4 +/- 22.5 s, respectively (p > 0.05). A greater relative increase in plasma volume after administering the experimental solution, an increased body mass (by 0.4 kg; p = 0.006) immediately before the race and a restrained increase in blood glucose concentration (by 2.5 +/- 1.2 mmol.l(-1) vs 3.4 +/- 0.8 mmol.l(-1); p = 0.002) during the race were observed in the CIT trial compared to the PLC. A significant relationship was observed between body mass of the subjects immediately before the race and performance time (r = 0.374; p = 0.029). There were no between-treatment differences in heart rate in any stage of the run or in blood lactate accumulation during the race (final concentration of lactate was 14.4 +/- 3.0 mmol.l(-1) and 13.4 +/- 2.5 mmol.l(-1) (p > 0.05) in the CIT and PLC trials, respectively). The results suggest that sodium citrate induces an increase in water retention before exercise and may modify carbohydrate metabolism in high intensity running, but does not improve performance in 1500-m competitive run in female middle-distance runners. Key pointsPrevious studies have found that sodium bicarbonate administration may enhance performance in male athletes in running distances of 400-1500 m.The use of sodium bicarbonate in competitive sports is limited because it induces gastrointestinal distress in many subjects.The limited data on the effects of sodium citrate ingestion on the metabolic response to exercise and performance suggest that it may have all the benefits of sodium bicarbonate without the associated negative side effects.We assessed the effects of sodium citrate ingestion on the metabolic response to exercise and performance in a 1500-m competitive run in trained young female middle-distance runners.The results suggest that sodium citrate induces an increase in water retention before exercise and may modify carbohydrate metabolism in high intensity running, but does not improve performance in 1500-m competitive run in female middle-distance runners. PMID- 24150145 TI - Aerobic Fitness Level Typical of Elite Athletes is not Associated With Even Faster VO2 Kinetics During Cycling Exercise. AB - The aim of this study was to address the question if the VO2 kinetics is further improved as the aerobic training status increases from trained to elite level athletes. Maximal oxygen uptake (VO2max), work-rate associated to VO2max (IVO2max) and VO2 kinetics of moderate (Mod) and maximal exercise (Max) were determined in fifty- five subjects. Then, they were assigned into three groups: low (LF), intermediate (IF) and high (HF) aerobic fitness level. In average, the VO2max of LF, IF and HF groups were, respectively, 36.0 +/- 3.1, 51.1 +/- 4.5 and 68.1 +/- 3.9 ml.kg.min(-1) (p <= 0.05 among each other). VO2 kinetics mean response time of both exercise intensities were significantly faster (p <= 0.05) in HF (Mod, 27.5 +/- 5.5 s; Max, 32.6 +/- 8.3 s) and IF (Mod, 25.0 +/- 3.1 s; Max, 42.6 +/- 10.4 s) when compared to LF (Mod, 35.7 +/- 7.9 s; Max: 57.8 +/- 17.8 s). We can conclude that VO2 kinetics is improved as the fitness level is increased from low to intermediate but not further improved as the aerobic fitness level increases from intermediate to high. Key pointsCurrently, it is reasonable to believe that the rate-limiting step of VO2 kinetics depends on exercise intensity.The well known physiological adaptations induced by endurance training are likely the most extreme means to overcome rate-limiting steps determining VO2 kinetics across exercise intensities.However, exercise adaptation leading individuals to the high-end of aerobic fitness level range (VO2max > 65 ml.kg.min-1) is not able to further improve VO2 kinetics during both, moderate and maximal intensity exercise. PMID- 24150146 TI - Volume of physical activity and injury occurrence in young basketball players. AB - Participation in organised, competitive physical activity by young athletes is increasing rapidly. This is concurrent with an increase in sporting injuries in the young population. This pilot study aimed to compare the weekly volume and types of physical activity in young basketball players injured and not injured during the season. Detailed physical activity and injury data were prospectively collected in 46 school-level basketball players aged 14 to 18 years. Participants completed physical activity logs which documented the type of physical activity undertaken, what the activity consisted of (i.e. training, competition) and the level at which it was played on a daily basis. Allied health staff completed a weekly injury form. Results showed that injured and uninjured athletes participated in a similar volume of total weekly physical activity over the season. However, injured athletes (p = 0.04) and athletes who specifically sustained overuse injuries (p = 0.01) participated in a greater amount of basketball refereeing than uninjured athletes. Based on these findings it was concluded that greater participation in running-type physical activity such as refereeing, as an addition to training and competition, may predispose the young basketball player to increased injury risk. Future research using larger sample sizes are required to further investigate the role of participation volume and type on injury occurrence in adolescent athletes. Key pointsBasketball players participating in larger amounts of running-type physical activity, in addition to regular training and competition, may be predisposed to overuse injuryFuture studies using larger sample sizes are required to investigate the precise volumes of physical activity that increase injury riskThis would assist in the development of participation guidelines to decrease the current injury rates observed in the young athletic population. PMID- 24150147 TI - Comparing the effects of various whole-body vibration accelerations on counter movement jump performance. AB - While it seems that whole body vibration (WBV) might be an effective modality to enhance physical performance, the proper prescription of WBV for performance enhancement remains unknown. The purpose of this study was to compare the immediate effect of various WBV accelerations on counter movement jump (CMJ) height, the duration of any effect, and differences between men and women. Forty four participants (33 men, 11 women) participated in no less than four CMJ familiarization sessions and completed all vibration sessions. Participants performed a pre-test (three maximal CMJs), followed randomly by one of five WBV accelerations; 1g (no-WBV control), 2.16g, 2.80g, 4.87g, and 5.83g. Participants performed three maximal CMJs immediately, five, and 10 minutes following each 45 sec WBV session. The mean of the three performances was used and calculated as a percentage of the pre-vibration mean value. A Repeated Measures Analysis of Variance (ANOVA; acceleration x time x gender) model was used to analyze the data. The two-way interactions of acceleration-gender (p = 0.033) and time-gender (p = 0.050) were significant. Women performed significantly better following the 2.80g (p = 0.0064) and 5.83g (p = 0. 0125) WBV sessions compared to the 1g (control) session. Men, however, did not experience performance enhancing effects following any of the vibration sessions. While significant differences did not occur between time in either gender, the effects of the 45 sec WBV session in women were transient, lasting approximately five minutes. During the prescription of WBV, gender should be considered given that the results of this study seem to indicate that men and women respond differently to WBV. The results of this study suggest that WBV might be a useful modality as applied during the pre-competition warm-up. Key pointsWBV accelerations of 2.80g (40 Hz, 2-4 mm) and 5.83g (50 Hz, 4 6 mm) seem to elicit a performance enhancement effect following short-duration (45 sec) exposure in untrained women.The performance enhancement effect of a short-duration is transient, lasting less than 10 minutes following exposure.Men and women might differ in their response to the WBV stimulus, as measured by countermovement jump. PMID- 24150148 TI - Echocardiographic parameters in athletes of different sports. AB - Competitive athletics is often associated with moderate left ventricular (LV) hypertrophy, and it has been hypothesized that training mode and type of exercise modulates long-term cardiac adaptation. The purpose of the study was to compare cardiac structure and function among athletes of various sports and sedentary controls. Standard transthoracic two-dimensional M-mode and Doppler echocardiography was performed at rest in Caucasian male canoe/kayak paddlers (n = 9), long distance runners (LDR, n = 18), middle distance runners (MDR, n = 17), basketball players (BP, n = 31), road cyclists (n = 8), swimmers (n = 10), strength/power athletes (n = 9) of similar age (range, 15 to 31 yrs), training experience (4 to 9 years), and age-matched healthy male sedentary controls (n = 15). Absolute interventricular septum (IVS) thickness and LV wall thickness, but not LV diameter, were greater in athletes than sedentary controls. Left ventricular mass of all athletes but relative wall thickness of only BP, swimmers, cyclists, and strength/power athletes were higher as compared with controls (p < 0.05). Among athletes, smaller IVS thickness was observed in MDR than BP, cyclists, swimmers or strength/power athletes, while LDR had higher body size-adjusted LV diameter as compared to BP, cyclists and strength/power athletes. In conclusion, relative LV diameter was increased in long distance runners as compared with basketball players, cyclists, and strength/power athletes. Basketball, road cycling, strength/power, and swimming training were associated with increased LV concentricity as compared with paddling or distance running. Key pointsThe type of cardiac hypertrophy seems to be only moderately exercise-specific.Long-distance runners develop larger left ventricular dilation as compared with basketball players, cyclists, and strength/power athletes.Myocardial wall thickening is triggered by different sporting activities that involve large muscle groups. PMID- 24150149 TI - Season-to-Season Variations of Physiological Fitness Within a Squad of Professional Male Soccer Players. AB - The purpose of this study was to examine season-to-season variations in physiological fitness parameters among a 1(st) team squad of professional adult male soccer players for the confirmatory purposes of identifying normative responses (immediately prior to pre-season training (PPS), mid-season (MID), and end-of-season (EOS)). Test-retest data were collected from a student population on the primary dependent variables of anaerobic threshold (AT) and maximal aerobic power (VO2 max) to define meaningful measurement change in excess of test retest technical error between test-to-test performances. Participants from a pool of 42 professional soccer players were tested over a set sequence of tests during the 3-year period: 1) basic anthropometry, 2) countermovement jump (CMJ) tests 3) a combined AT and VO2 max test. Over the 3-year period there were no test-to-test changes in mean VO2 max performance exceeding pre-defined limits of test agreement (mean of eight measures: 61.6 +/- 0.6 ml.kg(-1).min(-1)). In contrast, VO2 at AT was significantly higher at the MID test occasion in seasons 2 (+4.8%; p = 0.04, p < 0.05) and 3 (+6.8%; p = 0.03, p < 0.05). The CMJ tests showed a test-to-test improvement of 6.3% (best of 3 jumps) (p = 0.03, p < 0.05) and 10.3% (20-s sustained jumping test) (p = 0.007, p < 0.01) between PPS2 and MID2 and thereafter remained stable. Anthropometrics were unaffected. In summary, despite some personnel changes in the elite cohort between test-to-test occasions, VO2 max values did not vary significantly over the study which supports previous short-term observations suggesting a general 'elite' threshold of 60 ml.kg(-1) min. Interestingly, AT significantly varied where VO2 max was stable and these variations also coincided with on- and off-seasons suggesting that AT is a better indication of acute training state than VO2 max. Key pointsMaximal aerobic power remains fairly stable across inter- and intra-season measurements.Anaerobic threshold appears more sensitive of training state confirming our earlier observations.The professional players tended to attain optimal performances at the mid-season interval over the 3 seasons, presumably prior to the development of accumulative fatigue. PMID- 24150150 TI - Identification of placebo responsive participants in 40km laboratory cycling performance. AB - The placebo effect, a positive outcome resulting from the belief that a beneficial treatment has been received, is widely acknowledged but little understood. It has been suggested that placebo responsiveness, the degree to which an individual will respond to a placebo, might vary in the population. The study aimed to identify placebo-responsive participants from a previously published paper that examined the effects of caffeine and placebos on cycling performance. A quantitative model of placebo responsiveness was defined. 14 male participants were subsequently classified as either placebo responsive or non responsive. Interviews were conducted to corroborate these classifications. Secondary quantitative analyses of performance data were conducted to identify further placebo responses. Finally, the five factor model of personality was used to explore relationships between personality and placebo responsiveness. Overall, 5 of 14 participants were classified as placebo responsive. Performance data suggested that 2 participants were placebo responsive whilst 12 were not. Interview data corroborated experimental data for these participants and for 9 of the remainder, however it suggested that the remaining 3 had experienced placebo effects. Secondary quantitative analysis revealed that performance for these 3 participants, whilst no better than for non-responsive participants, was associated with substantially increased oxygen uptake in the 2 conditions in which participants believed caffeine had been administered (7.0% +/- 15.1; 95% confidence intervals -2.6 to 16.7, and 6.0% +/- 15.4; -3.9 to 15.9 respectively). Finally, data suggested that the personality factors of extroversion, agreeableness, openness and neuroticism may relate to placebo responding. Placebo effects such as pain tolerance and fatigue resistance might be experienced by a percentage of participants but might not always be manifest in objective measures of performance. Key pointsBeliefs can have both positive (placebo) and negative (nocebo) effectsPlacebo effects may be experienced both objectively and subjectivelyCertain personality traits may be related to placebo respondingA multi-method approach may best elucidate placebo effects in sport. PMID- 24150151 TI - Effect of heat preconditioning by microwave hyperthermia on human skeletal muscle after eccentric exercise. AB - The purpose of this study was to clarify whether heat preconditioning results in less eccentric exercise-induced muscle damage and muscle soreness, and whether the repeated bout effect is enhanced by heat preconditioning prior to eccentric exercise. Nine untrained male volunteers aged 23 +/- 3 years participated in this study. Heat preconditioning included treatment with a microwave hyperthermia unit (150 W, 20 min) that was randomly applied to one of the subject's arms (MW); the other arm was used as a control (CON). One day after heat preconditioning, the subjects performed 24 maximal isokinetic eccentric contractions of the elbow flexors at 30 degrees .s(-1) (ECC1). One week after ECC1, the subjects repeated the procedure (ECC2). After each bout of exercise, maximal voluntary contraction (MVC), range of motion (ROM) of the elbow joint, upper arm circumference, blood creatine kinase (CK) activity and muscle soreness were measured. The subjects experienced both conditions at an interval of 3 weeks. MVC and ROM in the MW were significantly higher than those in the CON (p < 0.05) for ECC1; however, the heat preconditioning had no significant effect on upper arm circumference, blood CK activity, or muscle soreness following ECC1 and ECC2. Heat preconditioning may protect human skeletal muscle from eccentric exercise-induced muscle damage after a single bout of eccentric exercise but does not appear to promote the repeated bout effect after a second bout of eccentric exercise. Key pointsThere have been few studies about the effects of heat preconditioning on muscle damage caused by eccentric exercise and the repeated bout effect after a second bout of eccentric exercise.Heat preconditioning with microwave hyperthermia may attenuate eccentric exercise-induced muscle damage.Heat preconditioning does not enhance the repeated bout effect. PMID- 24150152 TI - A Hypothesis: Could Portable Natural Grass be a Risk Factor for Knee Injuries? AB - Previous study has shown a likely link between increased shoe- surface traction and risk of knee Anterior Cruciate Ligament (ACL) injury. Portable natural grass systems are being used more often in sport, but no study to date has investigated their relative safety. By their nature, they must have high resistance to falling apart and therefore newly laid systems may be at risk of creating excessive shoe surface traction. This study describes two clusters of knee injuries (particularly non-contact ACL injuries), each occurring to players of one professional football team at single venue, using portable grass, in a short space of time. The first series included two ACL injuries, one posterolateral complex disruption and one lateral ligament tear occurring in two rugby league games on a portable bermudagrass surface in Brisbane, Australia. The second series included four non-contact ACL injuries over a period of ten weeks in professional soccer games on a portable Kentucky bluegrass/perennial ryegrass surface in Barcelona, Spain. Possible intrinsic risk factors are discussed but there was no common risk shared by the players. Although no measures of traction were made at the Brisbane venue, average rotational traction was measured towards the end of the injury cluster at Camp Nou, Barcelona, to be 48 Nm. Chance undoubtedly had a part to play in these clusters, but the only obvious common risk factor was play on a portable natural grass surface soon after it was laid. Further study is required to determine whether portable natural grass systems may exhibit high shoe-surface traction soon after being laid and whether this could be a risk factor for knee injury. Key pointsExcessive shoe-surface traction is a hypothesised risk factor for knee ligament injuries, including anterior cruciate ligament injuries.Portable natural grass systems (by their nature in order to prevent grass rolls or squares from falling apart) will tend to exhibit high resistance to tearing when first laid. This may lead to excessive shoe-surface traction.This dual case series describes two clusters of non-contact knee ligament injuries which occurred in circumstances of newly laid portable turf.Further research is warranted to undercover any link between non-contact knee ligament injuries and ground surfaces conditions. PMID- 24150159 TI - Exploring the molecular underpinnings of convergent evolution. PMID- 24150161 TI - Clarification of OLAW's position on rodent cage changes. PMID- 24150162 TI - The strange ways of the tammar wallaby. PMID- 24150163 TI - Ensure animal welfare. PMID- 24150164 TI - Euthanasia records for individual animals. PMID- 24150165 TI - Define record-keeping requirements. PMID- 24150166 TI - Keep organized records. PMID- 24150167 TI - Learning a new technique in your living room. PMID- 24150168 TI - Complicated urolithiasis in a Long Evans rat. PMID- 24150169 TI - Incidence of dental lesions in musk shrews (Suncus murinus) and their association with sex, age, body weight and diet. AB - Both wild and laboratory strains of the musk shrew (Suncus murinus) have a high incidence of periodontitis. The authors completed necropsy examinations in 51 shrews to identify dental lesions including tooth loss, mobility and fractures. Dental lesions were identified in significantly more females than males, and older animals were more likely to have lesions present. Shrews with one or more dental lesions weighed significantly less than those without lesions present. Dietary supplementation with mealworms did not significantly affect the incidence of dental lesions or the body weight of male or female shrews. The authors recommend routine body weight measurement as a simple, noninvasive method of detecting shrews with an increased likelihood of having dental lesions. PMID- 24150170 TI - Auditing laboratory rodent biosecurity programs. AB - A rodent biosecurity program that includes periodic evaluation of procedures used in an institution's vivarium can be used to ensure that best practices are in place to prevent a microbial pathogen outbreak. As a result of an ongoing comprehensive biosecurity review within their North American and European production facilities, the authors developed a novel biosecurity auditing process and worksheet that could be useful in other animal care and use operations. The authors encourage other institutions to consider initiating similar audits of their biosecurity programs to protect the health of their laboratory animals. PMID- 24150171 TI - An insurance policy (and more) for the animal care and use program. PMID- 24150172 TI - When the trade winds blow in our favor. PMID- 24150173 TI - Sharing her passion with others. AB - Tonja Marie Henze, MS, CMAR, RLATg, Facilities Coordinator, Division of Animal Resources, University of Illinois, Urbana, IL. Ms. Henze talks about the joys and challenges of her job and realizing the importance of speaking out about her passion for laboratory animal care. PMID- 24150175 TI - Genetic analysis of Ras genes in epidermal development and tumorigenesis. AB - Proliferation and differentiation of epidermal keratinocytes are tightly controlled to ensure proper development and homeostasis of the epidermis. The Ras family of small GTPases has emerged as a central node in the coordination of cell proliferation in the epidermis. Recent genetic evidence from mouse models has revealed that the intensity of Ras signaling modulates the proliferative capacity of epidermal keratinocytes. Interfering with Ras signaling either by combined elimination of the 3 Ras genes from the basal layer of the epidermis or by overexpression of dominant-negative Ras isoforms caused epidermal thinning due to hypoproliferation of keratinocytes. In contrast, overexpression of oncogenic Ras mutants in different epidermal cell layers led to hyperproliferative phenotypes including the development of papillomas and squamous cell carcinomas. Here, we discuss the value of loss- and gain-of-function studies in mouse models to assess the role of Ras signaling in the control of epidermal proliferation. PMID- 24150174 TI - Platelets protect from septic shock by inhibiting macrophage-dependent inflammation via the cyclooxygenase 1 signalling pathway. AB - Although it has long been known that patients with sepsis often have thrombocytopenia and that septic patients with severe thrombocytopenia have a poor prognosis and higher mortality, the role of platelets in the pathogenesis of sepsis is poorly understood. Here we report a protective role of platelets in septic shock. We show that experimental thrombocytopenia induced by intraperitoneal injection of an anti-glycoprotein Ibalpha monoclonal antibody increases mortality and aggravates organ failure, whereas transfusion of platelets reduces mortality in lipopolysaccharide-induced endotoxemia and a bacterial infusion mouse sepsis model. Plasma concentrations of proinflammatory cytokines TNF-alpha and IL-6 are elevated by thrombocytopenia and decreased by platelet transfusion in septic mice. Furthermore, we identify that platelets protect from septic shock by inhibiting macrophage-dependent inflammation via the COX1/PGE2/EP4-dependent pathway. Thus, these findings demonstrate a previously unappreciated role for platelets in septic shock and suggest that platelet transfusion may be effective in treating severely septic patients. PMID- 24150176 TI - Direct social support and long-term health among middle-aged and older adults with type 2 diabetes mellitus. AB - OBJECTIVES: This study examined whether or not direct social support is associated with long-term health among middle-aged and older adults with diabetes mellitus. METHOD: Direct social support was assessed at baseline (2003) for 1,099 adults with type 2 diabetes mellitus from the Health and Retirement Study. Self reported health status was examined at baseline and in 4 biennial survey waves (2003-2010). A series of ordinal logistic regression models examined whether or not the 7-item Diabetes Care Profile scale was associated with a subsequent change in health status over time. Additional analyses examined whether or not individual components of direct social support were associated with health status change. RESULTS: After adjusting for baseline covariates, greater direct social support as measured by the Diabetes Care Profile was associated with improved health outcomes over time; however, this trend was not significant (p = .06). The direct social support measures that were associated with improved health over follow-up were support for taking medicines (odds ratio [OR] = 1.22), physical activity (OR = 1.26), and going to health care providers (OR = 1.22; all p < .05). DISCUSSION: Interventions that specifically target improving specific aspects of diabetes social support may be more effective in improving long-term health than less targeted efforts. PMID- 24150177 TI - Widowhood and depressive symptoms among Korean elders: the role of social ties. AB - OBJECTIVES: This study examines the impact of social ties on the relationship between widowhood and depressive symptoms among the older Korean population. METHOD: Data were derived from the baseline survey of the Korean Longitudinal Study of Aging. The sample consisted of 1,953 men and 2,469 women aged >=60 years who were married and had at least 1 child. The 10-item Center for Epidemiological Studies Depression Scale was the outcome measure. Multiple linear regression was used to evaluate the influence of social ties as the mediators and moderators on the relationship between widowhood and depressive symptoms. RESULTS: The quality of relationship between women and their children accounted for 51.52% of the difference in depressive symptoms between married and widowed women, but only 11.36% between married and widowed men. The interaction of widowhood and the quality of relationships with children was significant only among men, and the interaction of this status and cohabitation with married children was significant only among women. DISCUSSION: The quality of relationship with children plays an important mediating role in the relationship between widowed status and depressive symptoms among Korean men and women elders. Cohabitation with children may buffer mental distress for such women, and qualitatively good relationships with children may be important as moderators for the mental health of older Korean men after bereavement. PMID- 24150178 TI - National stereotypes of older people's competence are related to older adults' participation in paid and volunteer work. AB - OBJECTIVES: Why are older people perceived as more competent in some countries relative to others? In the current study, we investigate the extent to which national variation in perceptions of older people's competence is systematically related to national variation in the extent to which older people participate in paid and volunteer work. METHOD: We used multilevel regression to analyze data from the European Social Survey and test the relationship between perceptions of older people's competence and older people's participation in paid and volunteer work across 28 countries. We controlled for a number of potentially confounding variables, including life expectancy as well as the gender ratio and average education of the older population in each country. We controlled for the average objective cognitive abilities of the older population in a subsample of 11 countries. RESULTS: Older people were perceived as more competent in countries in which more older people participated in paid or volunteer work, independent of life expectancy and the average education, gender makeup, and average cognitive abilities of the older population. DISCUSSION: The results suggest that older people's participation in paid and volunteer work is related to perceptions of older people's competence independent of older people's actual competence. PMID- 24150179 TI - Volunteer transitions and physical and psychological health among older adults in Taiwan. AB - OBJECTIVES: This study examines the relationship between transitions in volunteering activity and physical and psychological health outcomes among older adults in Taiwan. METHOD: We used 3 waves of a longitudinal survey from Taiwan (1999, 2003, and 2007) including 1,847 older adults aged 58-74. We categorized volunteer activity over time into 5 categories and used generalized estimating equations to examine the relationship between volunteer transition group membership and health outcomes. RESULTS: Approximately, 3% of older volunteers kept volunteering and 7% stopped or started their volunteering over time. Engaging in any volunteering, including continuous volunteering, discrete volunteering, active-to-inactive volunteering, and inactive-to-active volunteering, was significantly associated with better self-rated health and higher life satisfaction when compared with the nonvolunteering group. Only those in the continuous volunteer group and those who shifted from inactive-to-active volunteering showed a positive association with better physical function and less depression, compared with the nonvolunteering group. DISCUSSION: The results suggest that the positive relationship between volunteering and health may decline when older adults discontinue or withdraw from volunteering. More research is needed to explore the mechanism behind older people's desistance from, persistence in, and resumption of volunteer engagement. PMID- 24150186 TI - Huggable communication medium decreases cortisol levels. AB - Interpersonal touch is a fundamental component of social interactions because it can mitigate physical and psychological distress. To reproduce the psychological and physiological effects associated with interpersonal touch, interest is growing in introducing tactile sensations to communication devices. However, it remains unknown whether physical contact with such devices can produce objectively measurable endocrine effects like real interpersonal touching can. We directly tested this possibility by examining changes in stress hormone cortisol before and after a conversation with a huggable communication device. Participants had 15-minute conversations with a remote partner that was carried out either with a huggable human-shaped device or with a mobile phone. Our experiment revealed significant reduction in the cortisol levels for those who had conversations with the huggable device. Our approach to evaluate communication media with biological markers suggests new design directions for interpersonal communication media to improve social support systems in modern highly networked societies. PMID- 24150187 TI - Quantifying subjective assessment of sleep quality, quality of life and depressed mood in children with enuresis. AB - AIM: The aim of this study was to compare a group of children who has monosymptomatic nocturnal enuresis (MNE) with a healthy control group by assessing their depression scales, quality of life and sleep quality. METHODS: Hundred and one children with MNE and 38 healthy controls are included in the study, aged between 8 and 16 years old. All participants were performed the Pediatric Quality of Life Inventory (PedsQL 4.0), Depression Scale for Children (CES-DC) and The Pittsburgh Sleep Quality Index (PSQI) tests. The two groups were compared for their demographic factors and for the results of the tests above. RESULTS: There were no significant differences between the two groups according to age, gender and other demographic factors. Quality of life, depression and sleep quality scores implied worse health in the patient group. The PedsQL scores were assessed as 1,659.90 +/- 296.01 in the patient group and 1,818.42 +/- 227.92 in the control group (p = 0.001). The CES-DC scores were 11.74 +/- 6.11 in the patient group and 7.00 +/- 3.97 in the control group (p < 0.001). And the PSQI scores were 2.58 +/- 2.48 in the patient group, 1.15 +/- 1.10 in the control group (p < 0.001). Also in the patient group, there was a positive correlation between participants' ages and the PedsQL (p = 0.010; r = 0.256), the CES-DC (p = 0.000; r = 0.382), the PSQI (p = 0.000; r = 0.403) scores. The success parameters at school were significantly worse in the patient group (p = 0.05). CONCLUSION: All our findings show us that the children with nocturnal enuresis were affected negatively because of their disease; especially when they grow up the scores get worse health, so we suggest that treatment must be started at suitable age according to guidelines. PMID- 24150188 TI - Beneficial impact of early cranioplasty in patients with decompressive craniectomy: evidence from transcranial Doppler ultrasonography. AB - BACKGROUND: A cranioplasty (CP) is often performed after decompressive craniectomy (DC) for cosmetic and protective reasons; however, the timing of CP needs to be better evaluated to maximize beneficial outcomes and neurological recovery. OBJECTIVE: We investigated the effects and mechanisms of early CP compared to late CP on neurological recovery, from the perspective of cerebral blood flow (CBF). METHODS: This study retrospectively reviewed 43 patients undergoing early (<12 weeks) or late (>= 12 weeks) cranioplasty after DC. The CBF velocity was measured by transcranial Doppler ultrasonography and was analyzed prior to and after CP in every patient. Complications were recorded. RESULTS: The CBF velocity in the middle cerebral artery (MCA) ipsilateral to the CP was increased in both groups and was statistically different between groups (p < 0.05). On the contralateral side, however, the CBF in the MCA was increased in the early CP group, but not the late CP group. Change (expressed as delta, Delta) was defined as the difference in CBF velocity between pre- and postoperative status in the early and late CP groups. A statistically significant difference was detected in the Delta of MCA on the ipsilateral side between the early and late groups. There were no differences in the incidence of complications between groups. CONCLUSIONS: Our results show better post-DC improvements in the CBF of patients receiving CP < 12 weeks after DC, compared to those receiving CP >= 12 weeks after DC. Therefore, early CP has potential benefits for cerebral perfusion. PMID- 24150189 TI - A neurosurgical phantom-based training system with ultrasound simulation. AB - BACKGROUND: Brain tumor surgeries are associated with a high technical and personal effort. The required interactions between the surgeon and the technical components, such as neuronavigation, surgical instruments and intraoperative imaging, are complex and demand innovative training solutions and standardized evaluation methods. Phantom-based training systems could be useful in complementing the existing surgical education and training. METHODS: A prototype of a phantom-based training system was developed, intended for standardized training of important aspects of brain tumor surgery based on real patient data. The head phantom consists of a three-part construction that includes a reusable base and adapter, as well as a changeable module for single use. Training covers surgical planning of the optimal access path, the setup of the navigation system including the registration of the head phantom, as well as the navigated craniotomy with real instruments. Tracked instruments during the simulation and predefined access paths constitute the basis for the essential objective training feedback. RESULTS: The prototype was evaluated in a pilot study by assistant physicians at different education levels. They performed a complete simulation and a final assessment using an evaluation questionnaire. The analysis of the questionnaire showed the evaluation result as "good" for the phantom construction and the used materials. The learning effect concerning the navigated planning was evaluated as "very good", as well as having the effect of increasing safety for the surgeon before planning and conducting craniotomies independently on patients. CONCLUSIONS: The training system represents a promising approach for the future training of neurosurgeons. It aims to improve surgical skill training by creating a more realistic simulation in a non-risk environment. Hence, it could help to bridge the gap between theoretical and practical training with the potential to benefit both physicians and patients. PMID- 24150190 TI - Postmenopausal osteoporosis. AB - PURPOSE OF REVIEW: The aim of this study is to provide a thorough updated review of the diagnosis and treatment of postmenopausal osteoporosis. RECENT FINDINGS: There have been several important findings in the field of postmenopausal osteoporosis over the past 1-2 years. Fewer morphometric vertebral fractures were found in women treated for 6 years with zoledronic acid compared with those who stopped treatment after 3 years. Longer duration of bisphosphonate therapy is associated with a higher risk of atypical femur fractures. Combination therapy with teriparatide and denosumab appears to increase bone mineral density to a greater extent than either therapy alone in postmenopausal women at high risk for fracture. There are several novel therapies under investigation for the treatment of osteoporosis, which are in various stages of development. Nonadherence to osteoporosis therapies continues to be a major problem in clinical practice. SUMMARY: There are numerous effective pharmacologic treatment options for postmenopausal osteoporosis. Bisphosphonate drug holidays continue to be an area of significant debate. PMID- 24150191 TI - An update on the recent literature on sickle cell bone disease. AB - PURPOSE OF REVIEW: To summarize the findings of the recent publications on sickle cell bone disease (SBD). RECENT FINDINGS: Individuals with sickle cell disease (SCD) are living longer and develop progressive organ damage including SBD with age. Recent studies suggest alternative radiological diagnostics such as ultrasound and scintigraphy can detect and differentiate between different forms of SBD. MRI with or without diffusion-weighted sequences remains the gold standard. Case reports of cranio-orofacial SBD highlight the rarity of this presentation. Vitamin D deficiency is highly prevalent at all ages, but may not be an independent risk factor for avascular necrosis (AVN). Gene polymorphisms of the Annexin A gene may predict AVN in SCD. A recent study demonstrated reduced days with pain and improved physical activity quality of life following high-dose vitamin D therapy. The high rates of osteopenia and osteoporosis in SCD support the need for research addressing this rising public health problem. Lastly, results of total hip arthroplasty for AVN in SCD has improved significantly over time with the use of cementless prosthetic material and improved supportive care. SUMMARY: SBD remains poorly studied. Prospective randomized studies targeting predictors, diagnostics, prevention, and treatment options for SBD are sorely needed. PMID- 24150192 TI - Stroke volume variation in hepatic resection: a replacement for standard central venous pressure monitoring. AB - BACKGROUND: Central venous pressure (CVP) is the standard method of volume status evaluation during hepatic resection. CVP monitoring requires preoperative placement of a central venous catheter (CVC), which can be associated with increased time, cost, and adverse events. Stroke volume variation (SVV) is a preload index that can be used to predict an individual's fluid responsiveness through an existing arterial line. The purpose of this study was to determine if SVV is as safe and effective as CVP in measuring volume status during hepatic resection. METHODS: Two cohorts of 40 consecutive patients (80 total) were evaluated during hepatic resection between December 2010 and August 2012. The initial evaluation group of 40 patients had continuous CVP monitoring and SVV monitoring performed simultaneously to establish appropriate SVV parameters for hepatic resection. A validation group of 40 patients was then monitored with SVV alone to confirm the accuracy of the established SVV parameters. Type of hepatic resection, transection time, blood loss, complications, and additional operative and postoperative factors were collected prospectively. SVV was calculated using the FlotracTM/VigileoTM System. RESULTS: The evaluation group included 40 patients [median age 62 (29-82) years; median body mass index (BMI) 27.7 (16.5 40.6)] with 18 laparoscopic, 22 open, and 24 undergoing major (>=3 segments) hepatectomy. Median transection times were 43 (range 20-65) min, median blood loss 250 (range 20-950) cc, with no Pringle maneuver utilized. In this evaluation group, a CVP of -1 to 1 significantly correlated to a SVV of 18-21 (R (2) = 0.85, p < 0.001). The validation group included 40 patients [median age 61 (35-78) years; median BMI 28.1 (17-41.2)], with 24 laparoscopic, 16 open, and 33 undergoing major hepatectomy. Using a SVV goal of 18 to 21, median transection time was 55 (25-78) min, median blood loss of 255 (range 100-1,150) cc, again without the use of a Pringle maneuver. CONCLUSIONS: SVV can be used safely as an alternative to CVP monitoring during hepatic resection with equivalent outcomes in terms of blood loss and parenchymal transection time. Using SVV as a predictor of fluid status could prove to be advantageous by avoiding the need for CVC insertion and therefor eliminating the risk of CVC related complications in patients undergoing hepatic resection. PMID- 24150193 TI - More than 10-year follow-up after total en bloc spondylectomy for spinal tumors. AB - BACKGROUND: There are many reports of en bloc resection for spinal tumors. However, no studies have evaluated the clinical outcomes with follow-up exceeding 10 years after surgery. METHODS: We reviewed 82 patients who had undergone total en bloc spondylectomy (TES) before January 2002 and identified 29 (19 with primary tumors and 10 with metastatic tumors) who had survived for more than 10 years after surgery. We evaluated the clinical outcomes including patient-based outcomes using questionnaire. The questionnaire included subjective assessment of the results of TES and SF-36. RESULTS: Overall, 33 % of patients with metastases from kidney cancer and 25 % of those with metastases from thyroid cancer survived for more than 10 years after TES for solitary spinal metastases. Four patients with metastatic tumors had no evidence of disease at the time of survey. There were no tumor recurrences in any of the 23 patients who underwent TES as the primary surgery. No revision surgeries have been required as a result of instrumentation failure in any of the 29 patients. About 90 % of the patients were satisfied or very satisfied with the results of TES. The SF-36 results demonstrated that the both physical and mental health of patients with primary tumors was equivalent to those of healthy individuals, and the mental health of patients with metastatic tumors was almost similar to them. CONCLUSIONS: This study showed the long-term clinical outcomes after TES to be favorable. TES played an important role in the treatment strategy for spinal tumors including metastases. PMID- 24150194 TI - Germline SDHC mutation presenting as recurrent SDH deficient GIST and renal carcinoma. PMID- 24150195 TI - CRTC3-MAML2 fusion transcript in a bronchial mucoepidermoid carcinoma. PMID- 24150196 TI - Histopathological features associated with application of black salve to cutaneous lesions: a series of 16 cases and review of the literature. AB - AIMS: To document the histopathological features of self-treatment of cutaneous lesions with the escharotic agent black salve. METHODS: Retrospective review of cutaneous lesions treated with black salve retrieved from the files of four pathology practices in Western Australia and review of the published literature. RESULTS: 16 lesions from 11 patients who self administered black salve for the treatment of skin lesions were reviewed. Clinical diagnoses at the time of biopsy included scar, keloid scar, pseudomelanoma, basal cell carcinoma, squamous cell carcinoma and cutaneous necrosis. Histopathological features identified in our series included scarring, granulomatous inflammation, implanted foreign material, reactive stromal atypia and suppurative necrosis. Residual neoplasia was present in two of 16 cases, including a basal cell carcinoma and a melanocytic naevus. An additional 13 lesions in 10 patients were identified in the medical literature, including cases with poor cosmetic outcomes and cases of malignant tumours masked by uncontrolled escharotic treatment. CONCLUSIONS: Availability of black salve through easily accessible internet sites appears to be associated with persisting use of this agent for the self-management of cutaneous lesions. Awareness of the potential complications and range of histopathological features associated with self-administration of escharotic agents is of importance to dermatologists and histopathologists. PMID- 24150197 TI - Antioxidant and anticomplement functions of flavonoids extracted from Penthorum chinense Pursh. AB - Penthorum chinense Pursh is rich in flavonoids, which have strong antioxidant and anticomplement activities. In order to optimize their extraction conditions, various extraction parameters were chosen to identify their effects on flavonoids extraction. Single factor and Box-Behnken experimental designs consisting of 24 experimental runs and five replicates at zero point were applied to obtain the optimal extraction yield. The optimization conditions for flavonoids extraction were determined as follows: ethanol concentration 60.89%, extraction time 68.15 min, temperature 52.89 degrees C and liquid/solid ratio 19.70 : 1. The corresponding flavonoids content was 7.19%. The regression equation was found to fit well with the actual situation. Furthermore, the antioxidant activity (the free radical scavenging ability and ferric reducing/antioxidant power) and anticomplement ability of the flavonoids from P. chinense were determined. Results showed that the flavonoids of P. chinense displayed significant antioxidant and anticomplement activities. Its antioxidant activity can compete with ascorbic acid (Vc), whereas its anticomplement activity (IC50 = 111.6 MUg ml(-1)) surpassed the effect of heparin (IC50 = 399.7 MUg ml(-1)) which was used as the positive control, suggesting that P. chinense flavonoids and their related products could potentially be used as a promising natural agent in the treatment of humoral effector inflammation. PMID- 24150198 TI - Early differentiation between good and poor response to growth hormone therapy in short children born small for gestational age (SGA) to improve the outcome of poor responders. AB - OBJECTIVE: The aim of this study was to examine height-gain response in relation to predicted good or poor response during first-year low or high growth hormone (GH) dose in short prepubertal children born small for gestational age. PATIENTS AND METHODS: The OPTIMA (Optimization of GH Treatment in Short Children Born Small for Gestational Age Based on a Growth Prediction Model) randomised study evaluated 12-month height standard deviation score (SDS) changes in patients receiving GH dose: fixed high (FH; 0.067 mg/kg/day) or 0.035 mg/kg/day individually adjusted (IA) after 3 months according to the Cologne early growth prediction. RESULTS: Predicted 12-month height SDS gain was <0.75 for 21/89 FH dose patients, considered poor responders; 11/21 reached a 12-month height SDS gain of >=0.75. In IA-dose poor responders, increasing GH dose at 3 months maintained mean height velocity (HV), with 73.7% reaching a 12-month height SDS gain of >=0.75 vs. 73.8% in IA-dose good responders who continued on low GH dose, where mean HV decreased after the initial 3-month period. CONCLUSION: GH dose increase at 3 months in patients with predicted poor response maintained catch-up growth. Even when on FH dose, some patients did not achieve a good response. PMID- 24150199 TI - Plasma leptin and adiponectin concentrations correlate with cardiometabolic risk and systemic inflammation in healthy, non-obese children. AB - BACKGROUND: Plasma adipocytokines are associated with metabolic profile and cardiovascular risk in obese children. OBJECTIVE: To investigate the association of plasma leptin and adiponectin concentrations with cardiometabolic risk profile and systemic inflammation in non-obese children. SUBJECTS: We studied 170 healthy, non-obese children (86 males, mean age 10+/-2 years). METHODS: Children's current body mass index (BMI), plasma leptin and adiponectin concentrations, lipid profile, fasting plasma glucose and high sensitivity C reactive protein (hsCRP) were measured. RESULTS: After adjustment for age, gender and BMI, plasma leptin concentrations were positively associated with hsCRP (t=2.72, p=0.009) and fasting plasma glucose (t=4.27, p<0.0001); plasma adiponectin concentrations were negatively associated with hsCRP (t=-3.31, p=0.0016); and positively with high density lipoprotein cholesterol (t=2.32, p=0.02). Children in the highest quartile of leptin/adiponectin (L/A) ratio demonstrated significantly higher BMI, systolic blood pressure, hsCRP, triglycerides and fasting glucose and the lowest high density lipoprotein (HDL) compared to lower L/A ratio quartiles. CONCLUSIONS: Alterations in plasma leptin and adiponectin may help to reclassify non-obese children, detecting those with more unfavorable risk profiles independent of BMI status. PMID- 24150200 TI - Effect of micronutrient supplementation on height velocity of underprivileged girls in comparison with un-supplemented healthy controls. AB - The aim of this study was to investigate the effect of 1-year micronutrient supplementation on the height velocity of underprivileged premenarchal girls in comparison with the natural growth of apparently healthy girls from an affluent class. A 1-year cluster-randomisation intervention trial was conducted in 119 premenarchal girls (8-12 years) from two schools catering to the lower socioeconomic strata (LSES) in Pune, India. Three classes of age-matched girls were randomly allocated to any one of the three intervention groups: (i) Ca+MZn+D group (C1: zinc, 15 mg/day+multivitamins; calcium, 500 mg/day; vitamin D, 30,000 IU/3 months); (ii) Ca+D group (C2: calcium, 500 mg/day; vitamin D, 30,000 IU/3 months); and (iii) M+D group (C3: multivitamins; vitamin D, 30,000 IU/3 months). Height, weight, and Tanner stage were assessed at baseline and endline. A total of 119 age-matched, apparently healthy school girls from a higher socioeconomic group (HSES) were assessed for their growth after 1 year without any supplementation. At baseline, mean height-for-age Z-scores and weight-for-age Z scores by Indian references were >-2 in 99% of HSES girls and 28% of LSES girls had height-for-age Z-scores <-2. Post-intervention, increase in height-for-age Z scores adjusted for Tanner stage was significantly higher in the Ca+MZn+D group (0.32+/-0.06) than in the respective age-matched controls (C1 group) (-0.02+/ 0.05) (p<0.05) as well as in both the Ca+D group (0.18+/-0.06) and the M+D group (0.14+/-0.04) (p<0.05). After adjusting for Tanner stage, height velocity was significantly higher for the Ca+MZn+D group (6.7+/-0.4 cm/year) than for the M+D group (6.1+/-0.2), Ca+D group (5.6+/-0.5) as well as age-matched controls (C1 group) (5.0+/-0.3) (p<0.05). Supplementation with calcium+vitamin D, zinc and multivitamins may be effective in improving stature in underprivileged Indian premenarchal girls. PMID- 24150201 TI - Heterozygous GHR gene mutation in a child with idiopathic short stature. AB - Several monogenic defects have been reported to be associated with idiopathic short stature. Focusing on growth hormone receptor (GHR)-gene alterations, the heterozygosity of the same gene defect may be associated with a range of growth deficits. We found a heterozygous mutation (V144I) within exon 6 of the GHR gene in a patient with a low level of insulin-like growth factor I (IGF-I), normal level of GH, and severe short stature. Despite the lack of statistical difference, an overall tendency for reduced wt-GH-induction of GHR activation and Jak/Stat signalling in cells transiently expressing GHR-V144I alone or co expressing wt-GHR compared to cells expressing only wt-GHR was found when GH doses were increased. Our results suggest that, although GHR sequence variants are responsible for some functional alterations commonly observed in children with idiopathic short stature, these changes may not explain all the height deficits observed in these subjects. PMID- 24150202 TI - Permanent neonatal diabetes mellitus caused by a novel mutation in the KCNJ11 gene. AB - Mutations in the KCNJ11 gene are responsible for the majority of permanent neonatal diabetes mellitus (PNDM) cases. Some mutations in this gene, including p.Q52R, are associated with the developmental delay, epilepsy, neonatal diabetes (DEND) syndrome. We describe a patient with PNDM who had no neurological finding although she was determined to have a novel mutation (p.Q52L) in the same residue of the KCNJ11 as in the previously reported cases with DEND syndrome. This case suggests that not all Q52 mutations in the KCNJ11 gene are necessarily related to DEND syndrome. PMID- 24150203 TI - Molecular characterization of Chilean patients with a clinical diagnosis of Noonan syndrome. AB - BACKGROUND: Noonan syndrome (NS) is an autosomal dominant syndrome characterized by typical dysmorphic features, cardiac anomalies as well as postnatal growth retardation, and is associated with Ras-MAPK pathway gene mutations. The purpose of this study was to improve the diagnosis of Chilean patients with suspected NS through molecular analysis. METHODS: We screened 18 Chilean patients with a clinical diagnosis of NS for mutations in PTPN11 by high resolution melting (HRM) and subsequent sequencing. RESULTS: Three PTPN11 missense mutations were detected in 22% of analyzed patients. Of these, two (c.181G>A and c.1510A>G) were previously reported and one was the novel substitution c.328G>A (p.E110K) affecting the linker stretch between the N-SH2 and C-SH2 domains of SHP-2 protein. CONCLUSION: Molecular studies confirmed the clinical diagnosis of NS in 4 of 18 patients, which provided support for therapeutic decisions and improved genetic counseling for their families. PMID- 24150204 TI - Adiponectin serum concentrations in newborn at delivery appear to be of fetal origin. AB - OBJECTIVE: Adiponectin (APN) may play a role in adapting energy metabolism at the maternal-fetal unit. The aim of the study was to investigate the relationship between placental APN mRNA expression, maternal serum APN concentration and umbilical cord serum APN concentration in full-term healthy newborns. METHODS: Serum APN levels were compared in 46 samples (23 from healthy newborns; gestational age 37.0 to 41.5 weeks) and their mothers (n=23). The APN concentration was measured using enzyme linked immunosorbent assay (ELISA). We analyzed the mRNA expression profile of APN in 22 placenta tissue samples using real time polymerase chain reaction (RT-PCR). RESULTS: The highest APN serum concentrations were found in umbilical cord blood, these were significantly higher than maternal APN levels (mean concentration+/-SD; 38.48+/-12.8 vs. 6.6+/ 2.3 MUg/mL, p<0.001). Otherwise, there were no significant correlation between maternal APN and umbilical cord APN concentration. APN gene expression was very low and only found in 8 out of 22 placentas. There were no significant correlation between placental APN mRNA and umbilical cord serum APN or maternal serum APN concentration. Umbilical cord APN concentrations were positively associated with birth weight (r=0.535; p=0.012) and gestational age (r=0.559; p=0.013). Maternal APN concentration revealed a negative correlation between maternal body weight (r=-0.623; p=0.009) and body mass index (BMI) (r=-0.634; p=0.008) at delivery. Additionally, no significant correlation was found between newborn birth weight and maternal weight. CONCLUSIONS: This study suggests that high serum APN concentrations in umbilical cord blood are not regulated by placental APN mRNA gene expression. The high concentration of APN in cord blood is independent from maternal APN concentration, suggesting an important physiological role of APN and implicating that umbilical APN concentration reflects its exclusive production by fetal tissues. PMID- 24150205 TI - The effect of childhood obesity on cardiac functions. AB - Obesity is a metabolic disorder defined as excessive accumulation of body fat, which is made up of genetic, environmental, and hormonal factors and has various social, psychological, and medical complications. Childhood obesity is a major indicator of adult obesity. The aim of this study is to evaluate the cardiac functions via electrocardiography (ECG), echocardiography (ECHO), and treadmill test in childhood obesity. A patient group consisting of 30 obese children and a control group consisting of 30 non-obese children were included in the study. The age range was between 8 and 17 years. Anthropometric measurements, physical examination, ECG, ECHO, and treadmill test were done in all patients. P-wave dispersion (PD) was found to be statistically significantly high in obese patients. In ECHO analysis, we found that end-diastolic diameter, end-systolic diameter, left ventricle posterior wall thickness, and interventricular septum were significantly greater in obese children. In treadmill test, exercise capacity was found to be significantly lower and the hemodynamic response to exercise was found to be defective in obese children. Various cardiac structural and functional changes occur in childhood obesity and this condition includes important cardiovascular risks. PD, left ventricle end-systolic and end-diastolic diameter, left ventricle posterior wall thickness, interventricular septum thickness, exercise capacity, and hemodynamic and ECG measurements during exercise testing are useful tests to determine cardiac dysfunctions and potential arrhythmias even in early stages of childhood obesity. Early recognition and taking precautions for obesity during childhood is very important to intercept complications that will occur in adulthood. PMID- 24150206 TI - Molecular interactions of hemoglobin with resveratrol: potential protective antioxidant role and metabolic adaptations of the erythrocyte. AB - This article reports the role of resveratrol in the erythrocyte as a result of its interaction with hemoglobin and describes the effect of this interaction on the metabolism, the redox state, and the release of ATP. The drug crosses the erythrocyte membrane and binds to hemoglobin, altering its modulation and the release of ATP. Our study correlates the variation of the phosphorylation balance induced by resveratrol with the change in the intracellular concentration of ATP and with the decrease in ATP release from red blood cell and the consequent paracrine alteration on the vascular epithelium. Molecular docking calculations indicate larger specificity of binding for oxy-hemoglobin that correlates well with the stabilization of the R-quaternary structure and with the functional modulation of resveratrol on the protein. Finally, we locate a putative binding site at the central cavity of hemoglobin and characterize its key interacting residues with the drug. Computational results support the assumption that resveratrol may act as a protector agent against oxidative protein damage by interacting with hemoglobin. PMID- 24150207 TI - Lipid-lowering effect of molluscan (Katelysia opima) glycosaminoglycan (GAG) in hypercholesterolemic induced rats. AB - Identifying pharmacologically safe lipid-lowering 'deliverables' could potentiate therapeutic outcome for diet-induced atherogenesis. Accordingly, we investigated the potential of molluscan (Katelysia opima) glycosaminoglycan (GAG) in modulating the early lipid changes in atherogenesis. Wistar rats were fed a diet with (n=24) or without (n=6) hypercholesterolemic atherogenic CCT (rat chow supplemented with 4% cholesterol, 1% cholic acid, and 0.5% thiouracil) for 17 days. CCT-fed rates were (i) treated with isolated molluscan GAG (40 mg/kg/day, s.c.) for 10 days after the introduction of CCT diet, (ii) cotreated with GAG (40 mg/kg/day, s.c.) for 17 days, or (iii) treated with heparin (200 units/kg/day, s.c.) for 10 days after the introduction of CCT. The increases induced by CCT diet in the plasma levels of cholesterol, triglycerides, high-density lipoprotein, very-low-density lipoprotein, and low-density lipoprotein were completely attenuated with GAG treatment. Consistently, alterations induced by CCT diet in the levels of plasma lecithin cholesterol acyltransferase and lipoprotein lipase activities were restored to baseline levels with GAG treatment. Coherently, histology revealed a decrease associated with GAG treatment in the CCT-diet-induced foam cells (in aorta), tubular damages (kidney), and lipid accumulations (liver). Together, these results suggest that GAG may exert antiatherogenesis potential by significantly attenuating lipid modulations derived by a high-fat diet. Further, the data imply that the GAG extracts may comprehensively prevent hypercholesterolemia-associated tissue damage and could thus serve as a therapeutic deliverable for hypercholesterolemia. PMID- 24150208 TI - Development and validation of dried matrix spot sampling for the quantitative determination of amyloid beta peptides in cerebrospinal fluid. AB - BACKGROUND: The use of dried blood spots on filter paper is well documented as an affordable and practical alternative to classical venous sampling for various clinical needs. This technique has indeed many advantages in terms of collection, biological safety, storage, and shipment. Amyloid beta (Abeta) peptides are useful cerebrospinal fluid (CSF) biomarkers for Alzheimer disease diagnosis. However, Abeta determination is hindered by preanalytical difficulties in terms of sample collection and stability in tubes. METHODS: We compared the quantification of Abeta peptides (1-40, 1-42, and 1-38) by simplex and multiplex ELISA, following either a standard operator method (liquid direct quantification) or after spotting CSF onto dried matrix paper card. RESULTS: The use of dried matrix spot (DMS) overcame preanalytical problems and allowed the determination of Abeta concentrations that were highly commutable (Bland-Altman) with those obtained using CSF in classical tubes. Moreover, we found a positive and significant correlation (r2=0.83, Pearson coefficient p=0.0329) between the two approaches. CONCLUSIONS: This new DMS method for CSF represents an interesting alternative that increases the quality and efficiency in preanalytics. This should enable the better exploitation of Abeta analytes for Alzheimer's diagnosis. PMID- 24150209 TI - Corrected reports in laboratory medicine in a Chinese university hospital for 3 years. PMID- 24150210 TI - Extensive study of human insulin immunoassays: promises and pitfalls for insulin analogue detection and quantification. AB - BACKGROUND: Over the last few decades, new synthetic insulin analogues have been developed. Their measurement is of prime importance in the investigation of hypoglycaemia, but their quantification is hampered by variable cross-reactivity with many insulin assays. For clinical analysis, it has now become essential to know the potential cross-reactivity of analogues of interest. METHODS: In this work, we performed an extensive study of insulin analogue cross-reactivity using numerous human insulin immunoassays. We investigated the cross-reactivity of five analogues (lispro, aspart, glulisine, glargine, detemir) and two glargine metabolites (M1 and M2) with 16 commercial human insulin immunoassays as a function of concentration. RESULTS: The cross-reactivity values for insulin analogues or glargine metabolites ranged from 0% to 264%. Four assays were more specific to human insulin, resulting in negligible cross-reactivity with the analogues. However, none of the 16 assays was completely free of cross-reactivity with analogues or metabolites. The results show that analogue cross-reactivity, which varies to a large degree, is far from negligible, and should not be overlooked in clinical investigations. CONCLUSIONS: This study has established the cross-reactivity of five insulin analogues and two glargine metabolites using 16 immunoassays to facilitate the choice of the immunoassay(s) and to provide sensitive and specific analyses in clinical routine or investigation. PMID- 24150211 TI - Educating DNP students about critical appraisal and knowledge translation. AB - Consumers expect that health care providers will use the best evidence when assisting them in making decisions about treatment options. Nurses at all educational levels report that they lack knowledge to critically appraise research studies and the skills to effectively implement evidence-based practice (EBP) in their clinical settings. Organizational culture and management support of innovation are critical factors in the adoption of EBP. Doctor of Nursing Practice (DNP) graduates can have a pivotal role in the transfer of knowledge to practice, yet critical appraisal and EBP competencies for DNP and Master of Science in Nursing (MSN) students have not been well differentiated in nursing curricula. Also students' attitudes toward EBP, self-efficacy beliefs, utilization, and knowledge gaps are rarely evaluated before courses are designed. This article reports on the development of a DNP-level EBP course to help students evaluate and apply research findings to clinical practice. PMID- 24150212 TI - In real time: exploring nursing students' learning during an international experience. AB - Abstract Nursing education has increasingly turned to international learning experiences to educate students who are globally minded and aware of social injustices in local and global communities. To date, research with international learning experiences has focused on the benefits for the students participating, after they have completed the international experience. The purpose of this qualitative study was to explore how nursing students learn during the international experience. The sample consisted of eight nursing students who enrolled in an international learning experience, and data were collected in "real time" in Zambia. The students were observed during learning activities and were interviewed three times. Three major themes emerged from the thematic analysis: expectations shaped students' learning, engagement facilitated learning, and critical reflection enhanced learning. Implications are discussed, related to disrupting media representations of Africa that shape students' expectations, and educational strategies for transformative learning and global citizenship. PMID- 24150213 TI - The protonophore CCCP interferes with lysosomal degradation of autophagic cargo in yeast and mammalian cells. AB - Mitophagy is a selective pathway, which targets and delivers mitochondria to the lysosomes for degradation. Depolarization of mitochondria by the protonophore CCCP is a strategy increasingly used to experimentally trigger not only mitophagy, but also bulk autophagy. Using live-cell fluorescence microscopy we found that treatment of HeLa cells with CCCP caused redistribution of mitochondrially targeted dyes, including DiOC6, TMRM, MTR, and MTG, from mitochondria to the cytosol, and subsequently to lysosomal compartments. Localization of mitochondrial dyes to lysosomal compartments was caused by retargeting of the dye, rather than delivery of mitochondrial components to the lysosome. We showed that CCCP interfered with lysosomal function and autophagosomal degradation in both yeast and mammalian cells, inhibited starvation-induced mitophagy in mammalian cells, and blocked the induction of mitophagy in yeast cells. PARK2/Parkin-expressing mammalian cells treated with CCCP have been reported to undergo high levels of mitophagy and clearance of all mitochondria during extensive treatment with CCCP. Using correlative light and electron microscopy in PARK2-expressing HeLa cells, we showed that mitochondrial remnants remained present in the cell after 24 h of CCCP treatment, although they were no longer easily identifiable as such due to morphological alterations. Our results showed that CCCP inhibits autophagy at both the initiation and lysosomal degradation stages. In addition, our data demonstrated that caution should be taken when using organelle-specific dyes in conjunction with strategies affecting membrane potential. PMID- 24150214 TI - Gender-specific pleiotropic bone-muscle relationship in the elderly from a nationwide survey (KNHANES IV). AB - SUMMARY: The aim of this study was to examine the gender-specific association between sarcopenia and bone geometry/metabolic parameters. Low muscle mass was associated with greater deterioration of bone than in deterioration of glucose or lipid profiles. This bone-muscle relationship was more prominent in men than in women. INTRODUCTION: There are few studies that report on gender differences in the effects of low muscle mass on bone and metabolic parameters in elderly subjects. This study aimed to assess the gender-specific influence of muscle mass on bone and metabolic parameters. METHODS: A total of 2,264 participants (940 men and 1,324 women) whose age ranged from 65 to 92 years were analyzed using data from The Fourth Korea National Health and Nutrition Examination Surveys (2008 2009). We measured bone mineral density (BMD) and appendicular muscle mass using the dual-energy X-ray absorptiometry and also measured metabolic profiles. RESULTS: The age-related trend in bone and muscle coincided in men but not in women. Femoral neck (FN) and total hip (TH) BMD were highly correlated with muscle mass in both genders. However, in women, this correlation was not significant in the lumbar spine (LS). In addition, this positive correlation was stronger in the FN or TH than in the LS and was stronger in men than in women. Subjects with sarcopenia were at a higher risk for osteoporosis in the FN, TH, and LS in men, and in the TH and FN in women. The degree of association between muscle mass and metabolic profiles was relatively very weak. CONCLUSION: Bone muscle relationship was more prominent in men than in women. The gender differences in bone-muscle relationship may be helpful for the development of gender-specific preventive strategies in the elderly, especially in men. PMID- 24150215 TI - Targeted cancer exome sequencing reveals recurrent mutations in myeloproliferative neoplasms. AB - With the intent of dissecting the molecular complexity of Philadelphia-negative myeloproliferative neoplasms (MPN), we designed a target enrichment panel to explore, using next-generation sequencing (NGS), the mutational status of an extensive list of 2000 cancer-associated genes and microRNAs. The genomic DNA of granulocytes and in vitro-expanded CD3+T-lymphocytes, as a germline control, was target-enriched and sequenced in a learning cohort of 20 MPN patients using Roche 454 technology. We identified 141 genuine somatic mutations, most of which were not previously described. To test the frequency of the identified variants, a larger validation cohort of 189 MPN patients was additionally screened for these mutations using Ion Torrent AmpliSeq NGS. Excluding the genes already described in MPN, for 8 genes (SCRIB, MIR662, BARD1, TCF12, FAT4, DAP3, POLG and NRAS), we demonstrated a mutation frequency between 3 and 8%. We also found that mutations at codon 12 of NRAS (NRASG12V and NRASG12D) were significantly associated, for primary myelofibrosis (PMF), with highest dynamic international prognostic scoring system (DIPSS)-plus score categories. This association was then confirmed in 66 additional PMF patients composing a final dataset of 168 PMF showing a NRAS mutation frequency of 4.7%, which was associated with a worse outcome, as defined by the DIPSS plus score. PMID- 24150216 TI - Chemomodulation of sequential high-dose cytarabine by fludarabine in relapsed or refractory acute myeloid leukemia: a randomized trial of the AMLCG. AB - Chemomodulation of cytarabine by fludarabine has been attributed with a higher antileukemic efficacy, but randomized trials to address this question are rare. We therefore conducted a multicenter, randomized phase III study to evaluate the antileukemic efficacy of adding fludarabine to sequential high-dose cytarabine+idarubicin (SHAI) re-induction chemotherapy in relapsed or refractory acute myeloid leukemia (AML). Patients (n=326, of which 281 were evaluable) were randomly assigned to SHAI (cytarabine, 1 g/m(2) bid, days 1-2 and 8-9 (3 g/m(2) for patients <= 60 years with refractory AML or >= 2nd relapse); idarubicin 10 mg/m(2) daily, days 3-4 and 10-11) or F-SHAI (SHAI with fludarabine, 15 mg/m(2), 4 h before cytarabine). Although complete remission (CR) rates (35% SHAI and 44% F-SHAI) and overall survival did not differ between both regimens, fludarabine prolonged time to treatment failure from 2.04 to 3.38 months (median, P<0.05). Twenty-seven percent of patients proceeded to allogeneic stem cell transplantation, with a significantly higher number of patients in CR or incomplete remission in the F-SHAI group (22 vs 10%, P<0.01). In conclusion, fludarabine has a beneficial, although moderate, impact on the antileukemic efficacy of high-dose cytarabine-based salvage therapy for relapsed and refractory AML. PMID- 24150218 TI - Long-term response to lenalidomide in patients with newly diagnosed multiple myeloma. PMID- 24150217 TI - Extended survival and reduced risk of AML progression in erythroid-responsive lenalidomide-treated patients with lower-risk del(5q) MDS. AB - Lenalidomide is the approved treatment for patients with red blood cell (RBC) transfusion-dependent lower-risk myelodysplastic syndromes (MDS) and chromosome 5q deletion (del(5q)). We report the long-term outcomes (median follow-up 3.2 years) in patients treated with lenalidomide in the MDS-003 trial. RBC transfusion independence (TI) >= 8 weeks was achieved in 97 of 148 treated patients (65.5%), with a median response duration of 2.2 years. Partial or complete cytogenetic response was achieved by 63 of 88 evaluable patients (71.6%). Median overall survival (OS) was longer in patients achieving RBC-TI >= 8 weeks (4.3 vs 2.0 years in non-responders; P<0.0001) or cytogenetic response (4.9 vs 3.1 years in non-responders; P=0.010). Time to acute myeloid leukemia (AML) progression was longer in patients achieving RBC-TI >= 8 weeks or any cytogenetic response versus non-responders (P=0.001 and P=0.0002, respectively). In a landmark multivariate analysis, RBC-TI >= 8 weeks was associated with prolonged OS (P<0.001) and a trend toward reduced relative risk of AML progression (P=0.080). Among these lower-risk MDS patients with del(5q), lenalidomide was associated with prolonged RBC-TI and cytogenetic responses, which were linked to improved OS and reduced risk of AML progression. PMID- 24150219 TI - Use of the 46/1 haplotype to model JAK2(V617F) clonal architecture in PV patients: clonal evolution and impact of IFNalpha treatment. PMID- 24150220 TI - Induction of differential apoptotic pathways in multiple myeloma cells by class selective histone deacetylase inhibitors. PMID- 24150221 TI - Reprogramming of MLL-AF9 leukemia cells into pluripotent stem cells. AB - The 'Yamanaka factors' (Oct4, Sox2, Klf4 and c-Myc) are able to generate induced pluripotent stem (iPS) cells from different cell types. However, to what degree primary malignant cells can be reprogrammed into a pluripotent state has not been vigorously assessed. We established an acute myeloid leukemia (AML) model by overexpressing the human mixed-lineage leukemia-AF9 (MLL-AF9) fusion gene in mouse hematopoietic cells that carry Yamanaka factors under the control of doxycycline (Dox). On addition of Dox to the culture, the transplantable leukemia cells were efficiently converted into iPS cells that could form teratomas and produce chimeras. Interestingly, most chimeric mice spontaneously developed the same type of AML. Moreover, both iPS reprogramming and leukemia reinitiation paths could descend from the same leukemia-initiating cell. RNA-seq analysis showed reversible global gene expression patterns between these interchangeable leukemia and iPS cells on activation or reactivation of MLL-AF9, suggesting a sufficient epigenetic force in driving the leukemogenic process. This study represents an important step for further defining the potential interplay between oncogenic molecules and reprogramming factors during MLL leukemogenesis. More importantly, our reprogramming approach may be expanded to characterize a range of hematopoietic malignancies in order to develop new strategies for clinical diagnosis and treatment. PMID- 24150222 TI - Synchronized neural oscillations and the pathophysiology of Parkinson's disease. AB - PURPOSE OF THE REVIEW: Developments in functional neurosurgery for movement disorders and recent advances in electrophysiological techniques have allowed important insights into the role of oscillations in corticobasal ganglia circuits, both in health and in neurological disease states. Here we review recent developments in our understanding of how abnormally synchronized oscillatory activity within the corticobasal ganglia loop may play a key role in the pathophysiology of cognitive and motor phenotypes in Parkinson's disease. RECENT FINDINGS: Recent developments highlight the motor and non-motor roles of alpha, beta and gamma oscillations in the context of Parkinson's disease. They also emphasize the importance of oscillatory coupling between basal ganglia and cortex and draw attention to the importance of interactions between different frequency bands. SUMMARY: Oscillatory activities across multiple frequency bands and their cross-frequency interactions within spatially segregated loops of the basal ganglia-thalamo-cortical system may relate to distinct components of clinical impairment, both motor and non-motor. It is hoped that this characterization will lead to improved interventions like deep brain stimulation, tailored to specific components of clinical impairment and their associated spatial and spectral signatures. PMID- 24150223 TI - The association between immune activation and manic symptoms in patients with a depressive disorder. AB - Although recent studies have shown that immunological processes play an important role in the pathophysiology of mood disorders, immune activation may only be present in specific subgroups of patients. Our study aimed to examine whether immune activation was associated with (a) the presence of manic symptoms and (b) the onset of manic symptoms during 2 years of follow-up in depressed patients. Patients with a depressive disorder at baseline (N=957) and healthy controls (N=430) were selected from the Netherlands Study of Depression and Anxiety. Assessments included lifetime manic symptoms at baseline and two-year follow up, as well as C-reactive protein (CRP), interleukin-6 (IL-6) and tumor necrosis factor alpha (TNF-alpha) at baseline. Within depressed patients, immune activation was not related to the presence or absence of lifetime manic symptoms at baseline. However, CRP levels were strongly elevated in depressed men who developed manic symptoms compared with those who did not develop manic symptoms over 2 years (P<0.001, Cohen's d=0.89). IL-6 and TNF-alpha were also higher in depressed men with an onset of manic symptoms, but this association was not significant. However, we found that the onset of manic symptoms was particularly high in men with multiple elevated levels of inflammatory markers. Depressed men who developed manic symptoms during follow-up had increased immunological activity (especially CRP) compared with depressed men who did not develop manic symptoms. Further research should explore whether a treatment approach focusing on inflammatory processes may be more effective in this specific subgroup of depressed patients. PMID- 24150224 TI - Role of the ventral striatum in developing anorexia nervosa. AB - Functional imaging data in adult patients with anorexia nervosa (AN) support a dysfunctional signal in the ventral striatum as neural signature of AN. In the present study, development of this signal was investigated with the prediction that a characteristic pattern of ventral-striatal signalling will be shown in response to cues associated with food restriction that reflects the evolvement of starvation dependence over time. The signal was assessed in adolescent patients with AN, whose duration of illness was about five times shorter relative to the adult sample. During functional magnetic resonance imaging subjects were required to estimate weights of body images (underweight, normal weight, overweight) and to process each stimulus in a self-referring way. Relative to age-matched, young healthy controls, underweight stimuli were already associated with greater activity of the ventral striatum, and processing of normal-weight stimuli elicited already reduced signalling. Subjective preferences showed exactly the same pattern of results. Relative to adult AN, the present data reveal a developing dysfunctional signal that, if untreated, will essentially contribute to the maintenance of AN. We discuss putative mechanisms that may play a crucial role in the development of AN, and also deduce new hypotheses about the involvement of the midbrain dopamine system, of which illness-related alterations may contribute to the development of AN. PMID- 24150225 TI - Transcriptional regulation of the MET receptor tyrosine kinase gene by MeCP2 and sex-specific expression in autism and Rett syndrome. AB - Single nucleotide variants (SNV) in the gene encoding the MET receptor tyrosine kinase have been associated with an increased risk for autism spectrum disorders (ASD). The MET promoter SNV rs1858830 C 'low activity' allele is enriched in ASD, associated with reduced protein expression, and impacts functional and structural circuit connectivity in humans. To gain insight into the transcriptional regulation of MET on ASD-risk etiology, we examined an interaction between the methyl CpG-binding protein 2 (MeCP2) and the MET 5' promoter region. Mutations in MeCP2 cause Rett syndrome (RTT), a predominantly female neurodevelopmental disorder sharing some ASD clinical symptoms. MeCP2 binds to a region of the MET promoter containing the ASD-risk SNV, and displays rs1858830 genotype-specific binding in human neural progenitor cells derived from the olfactory neuroepithelium. MeCP2 binding enhances MET expression in the presence of the rs1858830 C allele, but MET transcription is attenuated by RTT-specific mutations in MeCP2. In the postmortem temporal cortex, a region normally enriched in MET, gene expression is reduced dramatically in females with RTT, although not due to enrichment of the rs1858830 C 'low activity' allele. We newly identified a sex based reduction in MET expression, with male ASD cases, but not female ASD cases compared with sex-matched controls. The experimental data reveal a prominent allele-specific regulation of MET transcription by MeCP2. The mechanisms underlying the pronounced reduction of MET in ASD and RTT temporal cortex are distinct and likely related to factors unique to each disorder, including a noted sex bias. PMID- 24150226 TI - Latrepirdine is a potent activator of AMP-activated protein kinase and reduces neuronal excitability. AB - Latrepirdine/Dimebon is a small-molecule compound with attributed neurocognitive enhancing activities, which has recently been tested in clinical trials for the treatment of Alzheimer's and Huntington's disease. Latrepirdine has been suggested to be a neuroprotective agent that increases mitochondrial function, however the molecular mechanisms underlying these activities have remained elusive. We here demonstrate that latrepirdine, at (sub)nanomolar concentrations (0.1 nM), activates the energy sensor AMP-activated protein kinase (AMPK). Treatment of primary neurons with latrepirdine increased intracellular ATP levels and glucose transporter 3 translocation to the plasma membrane. Latrepirdine also increased mitochondrial uptake of the voltage-sensitive probe TMRM. Gene silencing of AMPKalpha or its upstream kinases, LKB1 and CaMKKbeta, inhibited this effect. However, studies using the plasma membrane potential indicator DisBAC2(3) demonstrated that the effects of latrepirdine on TMRM uptake were largely mediated by plasma membrane hyperpolarization, precluding a purely 'mitochondrial' mechanism of action. In line with a stabilizing effect of latrepirdine on plasma membrane potential, pretreatment with latrepirdine reduced spontaneous Ca(2+) oscillations as well as glutamate-induced Ca(2+) increases in primary neurons, and protected neurons against glutamate toxicity. In conclusion, our experiments demonstrate that latrepirdine is a potent activator of AMPK, and suggest that one of the main pharmacological activities of latrepirdine is a reduction in neuronal excitability. PMID- 24150228 TI - Capsule-controlled selectivity of a rhodium hydroformylation catalyst. AB - Chemical processes proceed much faster and more selectively in the presence of appropriate catalysts, and as such the field of catalysis is of key importance for the chemical industry, especially in light of sustainable chemistry. Enzymes, the natural catalysts, are generally orders of magnitude more selective than synthetic catalysts and a major difference is that they take advantage of well defined cavities around the active site to steer the selectivity of a reaction via the second coordination sphere. Here we demonstrate that such a strategy also applies for a rhodium catalyst; when used in the hydroformylation of internal alkenes, the selectivity of the product formed is steered solely by changing the cavity surrounding the metal complex. Detailed studies reveal that the origin of the capsule-controlled selectivity is the capsule reorganization energy, that is, the high energy required to accommodate the hydride migration transition state, which leads to the minor product. PMID- 24150227 TI - Genetic and clinical factors predict lithium's effects on PER2 gene expression rhythms in cells from bipolar disorder patients. AB - Bipolar disorder (BD) is associated with abnormal circadian rhythms. In treatment responsive BD patients, lithium (Li) stabilizes mood and reduces suicide risk. Li also affects circadian rhythms and expression of 'clock genes' that control them. However, the extent to which BD, Li and the circadian clock share common biological mechanisms is unknown, and there have been few direct measurements of clock gene function in samples from BD patients. Hence, the role of clock genes in BD and Li treatment remains unclear. Skin fibroblasts from BD patients (N=19) or healthy controls (N=19) were transduced with Per2::luc, a rhythmically expressed, bioluminescent circadian clock reporter gene, and rhythms were measured for 5 consecutive days. Rhythm amplitude and period were compared between BD cases and controls with and without Li. Baseline period was longer in BD cases than in controls. Li 1 mM increased amplitude in controls by 36%, but failed to do so in BD cases. Li 10 mM lengthened period in both BD cases and controls. Analysis of clock gene variants revealed that PER3 and RORA genotype predicted period lengthening by Li, whereas GSK3beta genotype predicted rhythm effects of Li, specifically among BD cases. Analysis of BD cases by clinical history revealed that cells from past suicide attempters were more likely to show period lengthening with Li 1 mM. Finally, Li enhanced the resynchronization of damped rhythms, suggesting a mechanism by which Li could act therapeutically in BD. Our work suggests that the circadian clock's response to Li may be relevant to molecular pathology of BD. PMID- 24150229 TI - Postoperative infliximab and elemental diet combination in a case with diffuse, extensive jejunoileal Crohn's disease. PMID- 24150230 TI - Systematic review: anal and rectal changes after radiotherapy for prostate cancer. AB - PURPOSE: Pelvic radiotherapy may lead to changes of anorectal function resulting in incontinence-related complaints. The aim of this study was to systematically review objective findings of late anorectal physiology and mucosal appearance after irradiation for prostate cancer. METHODS: MEDLINE, EMBASE, and the Cochrane library were searched. Original articles in which anal function, rectal function, or rectal mucosa were examined >=3 months after EBRT for prostate cancer were included. RESULTS: Twenty-one studies were included with low to moderate quality. Anal resting pressures significantly decreased in 6 of the 9 studies including 277 patients. Changes of squeeze pressure and rectoanal inhibitory reflex were less uniform. Rectal distensibility was significantly impaired after EBRT in 7 of 9 studies (277 patients). In 4 of 9 studies on anal and in 5 of 9 on rectal function, disturbances were associated with urgency, frequent bowel movements or fecal incontinence. Mucosal changes as assessed by the Vienna Rectoscopy Score revealed telangiectasias in 73 %, congestion in 33 %, and ulceration in 4 % of patients in 8 studies including 346 patients, but no strictures or necrosis. Three studies reported mucosal improvement during follow-up. Telangiectasias, particularly multiple, were associated with rectal bleeding. Not all bowel complaints (30 %) were related to radiotherapy. CONCLUSIONS: Low to moderate quality evidence indicates that EBRT reduces anal resting pressure, decreases rectal distensibility, and frequently induces telangiectasias of rectal mucosa. Objective changes may be associated with fecal incontinence, urgency, frequent bowel movements, and rectal bleeding, but these symptoms are not always related to radiation damage. PMID- 24150231 TI - All-near-infrared multiphoton microscopy interrogates intact tissues at deeper imaging depths than conventional single- and two-photon near-infrared excitation microscopes. AB - The era of molecular medicine has ushered in the development of microscopic methods that can report molecular processes in thick tissues with high spatial resolution. A commonality in deep-tissue microscopy is the use of near-infrared (NIR) lasers with single- or multiphoton excitations. However, the relationship between different NIR excitation microscopic techniques and the imaging depths in tissue has not been established. We compared such depth limits for three NIR excitation techniques: NIR single-photon confocal microscopy (NIR SPCM), NIR multiphoton excitation with visible detection (NIR/VIS MPM), and all-NIR multiphoton excitation with NIR detection (NIR/NIR MPM). Homologous cyanine dyes provided the fluorescence. Intact kidneys were harvested after administration of kidney-clearing cyanine dyes in mice. NIR SPCM and NIR/VIS MPM achieved similar maximum imaging depth of ~100 MUm. The NIR/NIR MPM enabled greater than fivefold imaging depth (>500 MUm) using the harvested kidneys. Although the NIR/NIR MPM used 1550-nm excitation where water absorption is relatively high, cell viability and histology studies demonstrate that the laser did not induce photothermal damage at the low laser powers used for the kidney imaging. This study provides guidance on the imaging depth capabilities of NIR excitation-based microscopic techniques and reveals the potential to multiplex information using these platforms. PMID- 24150232 TI - Transient activation of hedgehog pathway rescued irradiation-induced hyposalivation by preserving salivary stem/progenitor cells and parasympathetic innervation. AB - PURPOSE: To examine the effects and mechanisms of transient activation of the Hedgehog pathway on rescuing radiotherapy-induced hyposalivation in survivors of head and neck cancer. EXPERIMENTAL DESIGN: Mouse salivary glands and cultured human salivary epithelial cells were irradiated by a single 15-Gy dose. The Hedgehog pathway was transiently activated in mouse salivary glands, by briefly overexpressing the Sonic hedgehog (Shh) transgene or administrating smoothened agonist, and in human salivary epithelial cells, by infecting with adenovirus encoding Gli1. The activity of Hedgehog signaling was examined by the expression of the Ptch1-lacZ reporter and endogenous Hedgehog target genes. The salivary flow rate was measured following pilocarpine stimulation. Salivary stem/progenitor cells (SSPC), parasympathetic innervation, and expression of related genes were examined by flow cytometry, salisphere assay, immunohistochemistry, quantitative reverse transcription PCR, Western blotting, and ELISA. RESULTS: Irradiation does not activate Hedgehog signaling in mouse salivary glands. Transient Shh overexpression activated the Hedgehog pathway in ductal epithelia and, after irradiation, rescued salivary function in male mice, which is related with preservation of functional SSPCs and parasympathetic innervation. The preservation of SSPCs was likely mediated by the rescue of signaling activities of the Bmi1 and Chrm1-HB-EGF pathways. The preservation of parasympathetic innervation was associated with the rescue of the expression of neurotrophic factors such as Bdnf and Nrtn. The expression of genes related with maintenance of SSPCs and parasympathetic innervation in female salivary glands and cultured human salivary epithelial cells was similarly affected by irradiation and transient Hedgehog activation. CONCLUSIONS: These findings suggest that transient activation of the Hedgehog pathway has the potential to restore salivary gland function after irradiation-induced dysfunction. PMID- 24150233 TI - Altered microenvironment promotes progression of preinvasive breast cancer: myoepithelial expression of alphavbeta6 integrin in DCIS identifies high-risk patients and predicts recurrence. AB - PURPOSE: This study investigated the functional and clinical significance of integrin alphavbeta6 upregulation in myoepithelial cells of ductal carcinoma in situ (DCIS). EXPERIMENTAL DESIGN: Archival samples of DCIS and DCIS with associated invasion (n = 532) were analyzed for expression of alphavbeta6 by immunohistochemistry and ability to predict recurrence and progression assessed in an independent, unique cohort of DCIS cases with long-term follow-up. Primary myoepithelial cells and myoepithelial cell lines, with and without alphavbeta6 expression, were used to measure the effect of alphavbeta6 on growth and invasion of tumor cell lines in vitro and in a xenograft mouse model. Involvement of TGFbeta signaling was established using mink lung epithelial cell (MLEC) assay and antibody inhibition, and expression and activation of matrix metalloproteinase (MMP)-9 established by Real Time-PCR and zymography. RESULTS: Expression of alphavbeta6 is significantly associated with progression to invasive cancer (P < 0.006) and with recurrence over a median follow-up of 114 months in a series of matched DCIS cases treated with local excision. We show that expression of alphavbeta6 drives myoepithelial cells to promote tumor cell invasion in vitro and enhances mammary tumor growth in vivo. The tumor-promoting effect of alphavbeta6-positive myoepithelial cells is dependent on TGFbeta-driven upregulation of MMP9 and can be abrogated by inhibiting this pathway. CONCLUSION: These findings indicate that altered myoepithelial cells in DCIS predict disease progression and recurrence and show that upregulation of alphavbeta6 on myoepithelial cells generates a tumor promoter function through TGFbeta upregulation of MMP-9. These data suggest that expression of alphavbeta6 may be used to stratify patients with DCIS. PMID- 24150234 TI - Abiraterone acetate in combination with prednisone for the treatment of patients with metastatic castration-resistant prostate cancer: U.S. Food and Drug Administration drug approval summary. AB - On December 10, 2012, the U.S. Food and Drug Administration granted full approval for a modified indication for abiraterone acetate (Zytiga tablets; Janssen Biotech, Inc.) in combination with prednisone for the treatment of patients with metastatic castration-resistant prostate cancer (mCRPC). The approval was based on clinical trial COU-AA-302, which randomly allocated asymptomatic or mildly symptomatic patients with chemotherapy-naive mCRPC and no visceral metastases to either abiraterone acetate plus prednisone (N = 546) or placebo plus prednisone (N = 542). The coprimary endpoints were radiographic progression-free survival (rPFS) and overall survival (OS). The median rPFS was 8.3 months in the placebo arm and had not yet been reached in the abiraterone acetate arm {HR, 0.43 [95% confidence interval (CI) 0.35-0.52]; P < 0.0001}. A prespecified interim analysis demonstrated an improvement in OS favoring the abiraterone acetate arm [HR, 0.79 (95% CI, 0.66-0.96)] but did not cross the O'Brien-Fleming boundary for statistical significance. Safety data confirmed the known adverse reaction profile of abiraterone acetate. Full approval was granted on the basis of a large magnitude of effect on rPFS, a favorable trend in OS, and internal consistency across multiple secondary endpoints and exploratory patient-reported pain data. This is the first drug approval for mCRPC to use rPFS as the primary endpoint. Importantly, this approval was granted in the context of a prior statistically significant OS benefit that formed the basis of the original April 28, 2011, approval of abiraterone acetate for patients with mCRPC who had received prior chemotherapy containing docetaxel. PMID- 24150235 TI - Genes upregulated in prostate cancer reactive stroma promote prostate cancer progression in vivo. AB - PURPOSE: Marked reactive stroma formation is associated with poor outcome in clinically localized prostate cancer. We have previously identified genes with diverse functions that are upregulated in reactive stroma. This study tests the hypothesis that expression of these genes in stromal cells enhances prostate cancer growth in vivo. EXPERIMENTAL DESIGN: The expression of reactive stroma genes in prostate stromal cell lines was evaluated by reverse transcriptase (RT) PCR and qRT-PCR. Genes were knocked down using stable expression of short-hairpin RNAs (shRNA) and the impact on tumorigenesis assessed using the differential reactive stroma (DRS) system, in which prostate stromal cell lines are mixed with LNCaP prostate cancer cells and growth as subcutaneous xenografts assessed. RESULTS: Nine of 10 reactive stroma genes tested were expressed in one or more prostate stromal cell lines. Gene knockdown of c-Kit, Wnt10B, Bmi1, Gli2, or COMP all resulted in decreased tumorigenesis in the DRS model. In all tumors analyzed, angiogenesis was decreased and there were variable effects on proliferation and apoptosis in the LNCaP cells. Wnt10B has been associated with stem/progenitor cell phenotype in other tissue types. Using a RT-PCR array, we detected downregulation of multiple genes involved in stem/progenitor cell biology such as OCT4 and LIF as well as cytokines such as VEGFA, BDNF, and CSF2 in cells with Wnt10B knockdown. CONCLUSIONS: These findings show that genes upregulated in prostate cancer-reactive stroma promote progression when expressed in prostate stromal cells. Moreover, these data indicate that the DRS model recapitulates key aspects of cancer cell/reactive stroma interactions in prostate cancer. PMID- 24150238 TI - In vitro biocompatibility and antibacterial efficacy of a degradable poly(L lactide-co-epsilon-caprolactone) copolymer incorporated with silver nanoparticles. AB - Silver nanoparticles (Ag-nps) are currently used as a natural biocide to prevent undesired bacterial growth in clothing, cosmetics and medical products. The objective of the study was to impart antibacterial properties through the incorporation of Ag-nps at increasing concentrations to electrospun degradable 50:50 poly(L-lactide-co-epsilon-caprolactone) scaffolds for skin tissue engineering applications. The biocompatibility of the scaffolds containing Ag-nps was evaluated with human epidermal keratinocytes (HEK); cell viability and proliferation were evaluated using Live/Dead and alamarBlue viability assays following 7 and 14 days of cell culture on the scaffolds. Significant decreases in cell viability and proliferation were noted for the 1.0 mg(Ag) g(scaffold)(-1) after 7 and 14 days on Ag-nps scaffolds. After 14 days, scanning electron microscopy revealed a confluent layer of HEK on the surface of the 0.0 and 0.1 mg(Ag) g(scaffold)(-1). Both 0.5 and 1.0 mg(Ag) g(scaffold)(-1) were capable of inhibiting both Gram positive and negative bacterial strains. Uniaxial tensile tests revealed a significant (p < 0.001) decrease in the modulus of elasticity following Ag-nps incorporation compared to control. These findings suggest that a scaffold containing between 0.5 and 1.0 mg(Ag) g(scaffold)(-1) is both biocompatible and antibacterial, and is suitable for skin tissue engineering graft scaffolds. PMID- 24150236 TI - Long noncoding RNAs as metazoan developmental regulators. AB - The study of long noncoding RNAs (lncRNAs) is still in its infancy with more putative RNAs identified than those with ascribed functions. Defined as transcripts that are longer than 200 nucleotides without a coding sequence, their numbers are on the rise and may well challenge protein coding transcripts in number and diversity. lncRNAs are often expressed at low levels and their sequences are frequently poorly conserved, making it unclear if they are transcriptional noise or bonafide effectors. Despite these limitations, inroads into their functions are being made and it is clear they make a contribution in regulating all aspects of biology. The early verdict on their activity, however, suggests the majority function as chromatin modifiers. A good proportion show a connection to disease highlighting their importance and the need to determine their function. The focus of this review is on lncRNAs which influence developmental processes which in itself covers a large range of known activities. PMID- 24150239 TI - A validation of two-dimensional in vivo regional strain computed from displacement encoding with stimulated echoes (DENSE), in reference to tagged magnetic resonance imaging and studies in repeatability. AB - Fast cine displacement encoding with stimulated echoes (DENSE) has comparative advantages over tagged MRI (TMRI) including higher spatial resolution and faster post-processing. This study computed regional radial and circumferential myocardial strains with DENSE displacements and validated it in reference to TMRI, according to American Heart Association (AHA) guidelines for standardized segmentation of regions in the left ventricle (LV). This study was therefore novel in examining agreement between the modalities in 16 AHA recommended LV segments. DENSE displacements were obtained with spatiotemporal phase unwrapping and TMRI displacements obtained with a conventional tag-finding algorithm. A validation study with a rotating phantom established similar shear strain between modalities prior to in vivo studies. A novel meshfree nearest node finite element method (NNFEM) was used for rapid computation of Lagrange strain in both phantom and in vivo studies in both modalities. Also novel was conducting in vivo repeatability studies for observing recurring strain patterns in DENSE and increase confidence in it. Comprehensive regional strain agreements via Bland Altman analysis between the modalities were obtained. Results from the phantom study showed similar radial-circumferential shear strains from the two modalities. Mean differences in regional in vivo circumferential strains were 0.01 +/- 0.09 (95% limits of agreement) from comparing the modalities and -0.01 +/- 0.07 from repeatability studies. Differences and means from comparison and repeatability studies were uncorrelated (p > 0.05) indicating no increases in differences with increased strain magnitudes. Bland-Altman analysis and similarities in regional strain distribution within the myocardium showed good agreements between DENSE and TMRI and show their interchangeability. NNFEM was also established as a common framework for computing strain in both modalities. PMID- 24150240 TI - Endophthalmitis caused by Achromobacter xylosoxidans after cataract surgery. AB - PURPOSE: To report Achromobacter xylosoxidans as a cause of both acute-onset and delayed-onset postoperative endophthalmitis after cataract surgery. METHODS: A noncomparative consecutive case series of patients with culture-proven A. xylosoxidans endophthalmitis between 1970 and 2012. Cataract surgery and intraocular lens placement were performed in all patients before endophthalmitis. Positive cultures were obtained from the vitreous, capsular bag, and/or the removed intraocular lens. RESULTS: The clinical diagnosis was confirmed in four patients with positive cultures. Two patients with endophthalmitis had a preliminary culture report of Pseudomonas species. In addition to receiving intravitreal antibiotics, all patients underwent capsulectomy and intraocular lens removal at the time of pars plana vitrectomy. Visual acuity at last follow up was 20/40 or better in 2 (50%) of the 4 patients, but the remaining 2 patients were 20/200 or worse. CONCLUSION: A. xylosoxidans may be a cause of acute, recurrent, and delayed-onset postoperative endophthalmitis after cataract surgery. Complete capsulectomy and intraocular lens removal can be considered in recurrent and recalcitrant patients. PMID- 24150241 TI - Macular telangiectasia--changes in macular pigment optical density during a 5 year follow-up. AB - PURPOSE: To quantitatively analyze the distribution of macular pigment (MP) over a period of 5 years and for monitoring progression of macular telangiectasia. METHODS: Macular pigment concentration (autofluorescence, excitation wavelengths: 488 and 514 nm) was determined at baseline and after 5 years in 43 eyes of 22 subjects (46-80 years; mean, 65.6 years; 10 men) participating in the macular telangiectasia project. RESULTS: Mean MP density at 0.5 degrees declined in the segment (one eighth of a circle) with the highest MP optical density (-0.04 density units; P= 0.015), where density units (DU), and also averaged in the 2 segments that divided segments with detectable MP from those in which MP was no longer detectable (-0.04 density units; P = 0.0005). In the first segment mentioned, 2 degrees values decreased to a lesser extent and not significantly. The diameter of MP loss expanded horizontally from 2.64 mm to 2.74 mm (P = 0.0001) but not vertically. Macular pigment density in the "halo" of peripheral MP at a mean of 5.44 degrees (4.53-6.21 degrees ) increased (+0.01 DU; P= 0.01). CONCLUSION: Five years of follow-up resulted in central (0.5 degrees ) reduction and peripheral (4.53-6.21 degrees ) accumulation of MP. Longer period of follow up may disclose significant changes in paracentral locations. The area of central MP loss expands in particular in a horizontal direction and less vertically. Centrifugal movement of MP during disease may explain our findings. PMID- 24150243 TI - Th2-type inflammation instructs inflammatory dendritic cells to induce airway hyperreactivity. AB - Dendritic cells (DCs) play critical roles in determining the fate of CD4+ T cells. Among DC sub-populations, monocyte-derived inflammatory DCs (iDCs) have been shown to play an important role in the induction of adaptive immune responses under inflammatory conditions. Although previous studies have shown that DCs have an indispensable role in the induction of allergic airway inflammation and airway hyperreactivity (AHR) in murine asthma models, the precise roles of iDCs in the asthmatic responses remain largely unknown. We show here that T(h)2 cell-mediated inflammation in murine asthma models induces the expression of some markers of alternatively activated macrophage such as arginase 1 and resistin-like molecule-alpha in iDCs by a mechanism depending on the intrinsic expression of STAT6. In contrast, T(h)1 cell-mediated inflammation induces iDCs to express TNF-alpha and inducible nitric oxide synthase (iNOS), markers of TNF-alpha- and iNOS-producing DCs. Moreover, we show that iDCs under a T(h)2 environment play an important role in the induction of AHR, independently of allergic airway inflammation. Our results thus indicate the importance of iDCs in the induction of AHR as downstream effector cells in T(h)2 cell-mediated asthmatic responses. PMID- 24150242 TI - Hypoxia-induced and A2A adenosine receptor-independent T-cell suppression is short lived and easily reversible. AB - Tissue hypoxia plays a key role in establishing an immunosuppressive environment in vivo by, among other effects, increasing the level of extracellular adenosine, which then signals through A2A adenosine receptor (A2AR) to elicit its immunosuppressive effect. Although the important role of the adenosine--A2AR interaction in limiting inflammation has been established, the current study revisited this issue by asking whether hypoxia can also exert its T-cell inhibitory effects even without A2AR. A similar degree of hypoxia-triggered inhibition was observed in wild-type and A2AR-deficient T cells both in vitro and, after exposure of mice to a hypoxic atmosphere, in vivo. This A2AR independent hypoxic T-cell suppression was qualitatively and mechanistically different from immunosuppression by A2AR stimulation. The A2AR-independent hypoxic immunosuppression strongly reduced T-cell proliferation, while IFN-gamma producing activity was more susceptible to the A2AR-dependent inhibition. In contrast to the sustained functional impairment after A2AR-mediated T-cell inhibition, the A2AR-independent inhibition under hypoxia was short lived, as evidenced by the quick recovery of IFN-gamma-producing activity upon re stimulation. These data support the view that T-cell inhibition by hypoxia can be mediated by multiple mechanisms and that both A2AR and key molecules in the A2AR independent T-cell inhibition should be targeted to overcome the hypoxia-related immunosuppression in infected tissues and tumors. PMID- 24150244 TI - Aryl hydrocarbon receptor plays protective roles in ConA-induced hepatic injury by both suppressing IFN-gamma expression and inducing IL-22. AB - The aryl hydrocarbon receptor (AhR), a ligand-activated nuclear transcription factor, is known to mediate the toxic and carcinogenic effects of various environmental pollutants, while AhR has been shown to protect animals from various types of tissue injury. ConA-induced hepatitis is known as a mouse model of acute liver injury. Here, we found a protective role of AhR in ConA-induced hepatitis. AhR is induced in the liver during ConA-induced hepatitis, and Ahr (-/ ) mice were highly sensitive to this model. Bone marrow chimera experiments indicate that Ahr (-/-) hematopoietic cells are responsible for hypersensitivity to ConA-induced hepatitis. We found that IFN-gamma from invariant NKT cells was up-regulated and IL-22 from innate lymphoid cells (ILCs) was abolished in Ahr (-/ ) mice. In addition, IL-22 production was still observed in Rag2 (-/-) mice but it was severely reduced in Ahr (-/-) Rag2 (-/-) mice. ConA-induced IL-22 production was also dependent on retinoic acid-related orphan receptor gammat. These results show that AhR has crucial protective roles in ConA-induced liver injury via promoting IL-22 production from ILCs and suppressing IFN-gamma expression from NKT cells. PMID- 24150245 TI - Early pathological alterations of lower lumbar cords detected by ultrahigh-field MRI in a mouse multiple sclerosis model. AB - Magnetic resonance imaging (MRI) is widely employed for the diagnosis of multiple sclerosis (MS). However, sometimes, the lesions found by MRI do not correlate with the neurological impairments observed in MS patients. We recently showed autoreactive T cells accumulate in the fifth lumbar cord (L5) to pass the blood brain barrier and cause inflammation in the central nervous system of experimental autoimmune encephalomyelitis (EAE) mice, an MS model. We here investigated this early event using ultrahigh-field MRI. T2-weighted image signals, which conform to the water content, increased in L4 and L5 during the development of EAE. At the same time, the sizes of L4 and L5 changed. Moreover, angiographic images of MRI showed branch positions of the blood vessels in the lower lumbar cords were significantly altered. Interestingly, EAE mice showed occluded and thickened vessels, particularly during the peak phase, followed by reperfusion in the remission phase. Additionally, demyelination regions of some MS patients had increased lactic acid content, suggesting the presence of ischemic events. These results suggest that inflammation-mediated alterations in the lower lumbar cord change the homeostasis of the spinal cord and demonstrate that ultrahigh-field MRI enables the detection of previously invisible pathological alterations in EAE. PMID- 24150246 TI - Ethnic and gender differences in HPV knowledge, awareness, and vaccine acceptability among White and Hispanic men and women. AB - The purpose of this study was to examine factors associated with human papillomavirus (HPV) knowledge and awareness, and HPV vaccination among White and Hispanic males and females. Differences in HPV knowledge, sources of information, vaccine awareness, vaccination status, and interest in vaccination were examined. A community sample was recruited from local health care clinics in a medium sized Midwestern city between May 2010 and December 2011. Participants (N = 507) were White (n = 243) and Hispanic, males (n = 202) and females between the ages of 15 30. Results indicate that White and female participants were significantly more likely to have heard of HPV, have higher levels of HPV knowledge, have been diagnosed with HPV, and be aware of the HPV vaccine for women. White and female participants were also more likely to have heard of HPV from their physician and were significantly more interested in receiving the HPV vaccine in the future. There was no effect of ethnicity on interest in the vaccine per a doctor's recommendation, however. Findings suggest that Whites and females have greater levels of HPV awareness and knowledge and that, while Hispanic participants are less likely than White participants to be told about the HPV vaccine from their provider, they may be equally receptive to such a recommendation. PMID- 24150248 TI - MitoPark mice, an animal model of Parkinson's disease, show enhanced prepulse inhibition of acoustic startle and no loss of gating in response to the adenosine A(2A) antagonist SCH 412348. AB - RATIONALE: Psychoses are debilitating side effects associated with current dopaminergic treatments for Parkinson's disease (PD). Prepulse inhibition (PPI), in which a non-startling stimulus reduces startle response to a subsequent startle-eliciting stimulus, is important in filtering out extraneous sensory stimuli. PPI deficits induced by dopamine agonists can model symptoms of psychosis. Adenosine A(2A) receptor antagonists, being developed as novel PD treatments, indirectly modulate dopamine signaling in the basal ganglia and may have an improved psychosis profile which could be detected using the PPI model. OBJECTIVES: The aims of this study is to characterize PPI in MitoPark mice, which exhibit progressive loss of dopamine signaling and develop a Parkinson-like motor phenotype, and assess standard and novel PD treatment effects on PPI in MitoPark mice, which more closely mimic the basal ganglia dopamine status of PD patients. RESULTS: MitoPark mice displayed enhanced PPI as dopamine tone decreased with age, consistent with studies in intact mice that show enhanced PPI in response to dopamine antagonists. Paradoxically, older MitoParks were more sensitive to PPI disruption when challenged with dopamine agonists such as apomorphine or pramipexole. Alternatively, SCH 412348, an adenosine A(2A) antagonist, did not disrupt PPI in MitoPark mice at doses that normalized hypoactivity. CONCLUSION: Use of MitoPark mice in the PPI assay to assess the potential for PD treatment to produce psychoses likely represents a more disease-relevant model. SCH 412348 does not differentially disrupt PPI as do dopamine agonists, perhaps indicative of an improved psychosis profile of adenosine A(2A) antagonists, even in PD patients with decreased dopamine tone in the basal ganglia. PMID- 24150247 TI - How the cerebral serotonin homeostasis predicts environmental changes: a model to explain seasonal changes of brain 5-HTT as intermediate phenotype of the 5 HTTLPR. AB - Molecular imaging studies with positron emission tomography have revealed that the availability of serotonin transporter (5-HTT) in the human brain fluctuates over the course of the year. This effect is most pronounced in carriers of the short allele of the 5-HTT promoter region (5-HTTLPR), which has in several previous studies been linked to an increased risk to develop mood disorders. We argue that long-lasting fluctuations in the cerebral serotonin transmission, which is regulated via the 5-HTT, are responsible for mediating responses to environmental changes based on an assessment of the expected "safety" of the environment; this response is obtained in part through serotonergic modulation of the hypothalamic-pituitary-adrenal (HPA) axis. We posit that the intermediate phenotype of the s-allele may properly be understood as mediating a trade-off, wherein increased responsiveness of cerebral serotonin transmission to seasonal and other forms of environmental change imparts greater behavioral flexibility, at the expense of increased vulnerability to stress. This model may explain the somewhat higher prevalence of the s-allele in some human populations dwelling at geographic latitudes with pronounced seasonal climatic changes, while this hypothesis does not rule out that genetic drift plays an additional or even exclusive role. We argue that s-allele manifests as an intermediate phenotype in terms of an increased responsiveness of the 5-HTT expression to number of daylight hours, which may serve as a stable surrogate marker of other environmental factors, such as availability of food and safety of the environment in populations that live closer to the geographic poles. PMID- 24150250 TI - The role of simulation training in obstetrics: a healthcare training strategy dedicated to performance improvement. AB - PURPOSE OF REVIEW: In this review, the role of simulation as a strategy for training and performance improvement is reviewed. The review is timely, as providing safe and high-quality healthcare is the goal of every healthcare system and soon reimbursement will be tied to quality measures. Simulation has emerged as a strategic approach that can result in improved quality and safety through training of individuals and teams, improvement in healthcare systems, and determination of competence. The rationale for this approach will be presented and discussed. RECENT FINDINGS: In this review, the recent literature that demonstrates the effectiveness of simulation in training of individuals, training of multidisciplinary teams, assessment of healthcare systems, and assessment of competence was reviewed. The literature that supports the role of simulation in improved patient outcomes was also reviewed. SUMMARY: There is a rapidly developing body of literature supporting the use of simulation in healthcare. Although research is still needed to demonstrate the effectiveness of simulation for evaluation, healthcare systems should develop strategies to implement and maintain simulation training. PMID- 24150249 TI - Cytokines plasma levels during antidepressant treatment with sertraline and transcranial direct current stimulation (tDCS): results from a factorial, randomized, controlled trial. AB - RATIONALE: The inflammatory hypothesis of depression states that increased levels of pro-inflammatory cytokines triggered by external and internal stressors are correlated to the acute depressive state. This hypothesis also suggests that pharmacotherapy partly acts in depression through anti-inflammatory effects. Transcranial direct current stimulation (tDCS) is a novel, promising, non invasive somatic treatment for depression, although its antidepressant mechanisms are only partly understood. OBJECTIVES: We explored the effects of tDCS and sertraline over the immune system during an antidepressant treatment trial. METHODS: In a 6-week, double-blind, placebo-controlled trial, 73 antidepressant free patients with unipolar depression were randomized to active/sham tDCS and sertraline/placebo (2 * 2 design). Plasma levels of several cytokines (IL-2, IL 4, IL-6, IL-10, IL-17a, IFN-gamma, and TNF-alpha) were determined to investigate the effects of the interventions and of clinical response on them. RESULTS: All cytokines, except TNF-alpha, decreased over time, these effects being similar across the different intervention-groups and in responders vs. non-responders. CONCLUSIONS: tDCS and sertraline (separately and combined) acute antidepressant effects might not specifically involve normalization of the immune system. In addition, being one of the first placebo-controlled trials measuring cytokines over an antidepressant treatment course, our study showed that the decrease in cytokine levels during the acute depressive episode could involve a placebo effect, highlighting the need of further placebo-controlled trials and observational studies examining cytokine changes during depression treatment and also after remission of the acute depressive episode. PMID- 24150251 TI - All strategies great and small. PMID- 24150252 TI - A liquid CO2-compatible hydrocarbon surfactant: experiment and modelling. AB - Surfactants soluble in liquid CO2 are rare and knowledge on interfacial and self assembly behaviour is fragmented. We found that polyoxyethylene (5) isooctylphenyl ether is interfacially active at the water-liquid CO2 interface. Water-liquid CO2 interfacial tension was measured at various surfactant concentrations at 50 bar and 283 K using the pendant drop method, and a CMC like cusp was observed at a surfactant concentration of ~50 mM in the bulk liquid CO2. This system was modelled applying the self-consistent field theory of Scheutjens and Fleer (SF-SCF). We use a free-volume approach, wherein the chemical potential of the vacancies was linked to the pressure and the molecules were described using a freely-jointed chain model on a united atom level. The model indicates that typically the water-vapour interface is wet by CO2. Interestingly, a window of partial wetting was identified at the water-vapour interface as a function of the chemical potential of the surfactant. The second-order nature of both wetting transitions is attributed to the close proximity to the critical point of the CO2 vapour system. Furthermore, the SF-SCF theory was used to study the self-assembly of the surfactant in bulk CO2 or water, focusing on the three-phase coexistence, that is at P/Psat = 1. Above ~40 mM in the CO2-rich phase, the theory indicates stable water swollen reverse micelles with an aggregation number of ~100. The analysis further shows the stability of compressible CO2-swollen surfactant bilayers in the bulk water phase at elevated surfactant concentrations. Finally it was found that the critical reverse micellar concentration (in liquid CO2) increases and the aggregation number decreases with increasing pressure. PMID- 24150253 TI - Enigmatic GPCR finds a stimulating drug. AB - GPR17 is an orphan G protein-coupled receptor involved in orchestration of oligodendrocyte differentiation and myelination in the central nervous system. In this issue of Science Signaling, Hennen et al. used a signaling pathway-unbiased screen to identify two small molecule activators of this receptor. One of these, MDL29951, was carried forward to illustrate GPR17-dependent activation of Galphai and Galphaq-promoted signaling pathways in cell lines expressing recombinant GPR17, whereas no effect was observed with previously proposed but dubitable agonists (uracil nucleotides and cysteinyl leukotrienes) of this receptor. Conversely, MDL29951 did not activate any of the known uracil or adenine nucleotide-activated P2Y receptors or cysteinyl leukotriene receptors. Galphai- and Galphaq-dependent signaling responses also were observed in primary rat oligodendrocytes in the presence of MDL29951. Moreover, MDL29951 diminished myelination in primary oligodendrocytes isolated from heterozygous mice but had no effect on myelination in oligodendrocytes from GPR17 knockout mice. Effects of a small-molecule GPR17 agonist observed during oligodendrocyte differentiation support the idea that development of antagonists of GPR17 is a rational goal for elaboration of pharmacotherapies in demyelinating diseases. PMID- 24150255 TI - Antidiabetic sulfonylureas and cAMP cooperatively activate Epac2A. AB - Sulfonylureas are widely used drugs for treating insulin deficiency in patients with type 2 diabetes. Sulfonylureas bind to the regulatory subunit of the pancreatic beta cell potassium channel that controls insulin secretion. Sulfonylureas also bind to and activate Epac2A, a member of the Epac family of cyclic adenosine monophosphate (cAMP)-binding proteins that promote insulin secretion through activation of the Ras-like guanosine triphosphatase Rap1. Using molecular docking simulation, we identified amino acid residues in one of two cyclic nucleotide-binding domains, cNBD-A, in Epac2A predicted to mediate the interaction with sulfonylureas. We confirmed the importance of the identified residues by site-directed mutagenesis and analysis of the response of the mutants to sulfonylureas using two assays: changes in fluorescence resonance energy transfer (FRET) of an Epac2A-FRET biosensor and direct sulfonylurea-binding experiments. These residues were also required for the sulfonylurea-dependent Rap1 activation by Epac2A. Binding of sulfonylureas to Epac2A depended on the concentration of cAMP and the structures of the drugs. Sulfonylureas and cAMP cooperatively activated Epac2A through binding to cNBD-A and cNBD-B, respectively. Our data suggest that sulfonylureas stabilize Epac2A in its open, active state and provide insight for the development of drugs that target Epac2A. PMID- 24150254 TI - Decoding signaling and function of the orphan G protein-coupled receptor GPR17 with a small-molecule agonist. AB - Replacement of the lost myelin sheath is a therapeutic goal for treating demyelinating diseases of the central nervous system (CNS), such as multiple sclerosis (MS). The G protein (heterotrimeric guanine nucleotide-binding protein) coupled receptor (GPCR) GPR17, which is phylogenetically closely related to receptors of the "purinergic cluster," has emerged as a modulator of CNS myelination. However, whether GPR17-mediated signaling positively or negatively regulates this critical process is unresolved. We identified a small-molecule agonist, MDL29,951, that selectively activated GPR17 even in a complex environment of endogenous purinergic receptors in primary oligodendrocytes. MDL29,951-stimulated GPR17 engaged the entire set of intracellular adaptor proteins for GPCRs: G proteins of the Galpha(i), Galpha(s), and Galpha(q) subfamily, as well as beta-arrestins. This was visualized as alterations in the concentrations of cyclic adenosine monophosphate and inositol phosphate, increased Ca2+ flux, phosphorylation of extracellular signal-regulated kinases 1 and 2 (ERK1/2), as well as multifeatured cell activation recorded with label-free dynamic mass redistribution and impedance biosensors. MDL29,951 inhibited the maturation of primary oligodendrocytes from heterozygous but not GPR17 knockout mice in culture, as well as in cerebellar slices from 4-day-old wild-type mice. Because GPCRs are attractive targets for therapeutic intervention, inhibiting GPR17 emerges as therapeutic strategy to relieve the oligodendrocyte maturation block and promote myelin repair in MS. PMID- 24150256 TI - Coffee and caffeine intake and incidence of type 2 diabetes mellitus: a meta analysis of prospective studies. AB - PURPOSE: Coffee and caffeine have been linked to type 2 diabetes mellitus (T2DM). A dose-response meta-analysis of prospective studies was conducted to assess the association between coffee and caffeine intake and T2DM incidence. METHODS: Pertinent studies were identified by a search of PubMed and EMBASE. The fixed- or random-effect pooled measure was selected based on between-study heterogeneity. Dose-response relationship was assessed by restricted cubic spline. RESULTS: Compared with the lowest level, the pooled relative risk (95 % CI) of T2DM was 0.71 (0.67-0.76) for the highest level of coffee intake (26 articles involving 50,595 T2DM cases and 1,096,647 participants), 0.79 (0.69-0.91) for the highest level of decaffeinated coffee intake (10 articles involving 29,165 T2DM cases and 491,485 participants) and 0.70 (0.65-0.75) for the highest level of caffeine intake (6 articles involving 9,302 T2DM cases and 321,960 participants). The association of coffee, decaffeinated coffee and caffeine intake with T2DM incidence was stronger for women than that for men. A stronger association of coffee intake with T2DM incidence was found for non-smokers and subjects with body mass index <25 kg/m(2). Dose-response analysis suggested that incidence of T2DM decreased by 12 % [0.88 (0.86-0.90)] for every 2 cups/day increment in coffee intake, 11 % [0.89 (0.82-0.98)] for every 2 cups/day increment in decaffeinated coffee intake and 14 % [0.86 (0.82-0.91)] for every 200 mg/day increment in caffeine intake. CONCLUSIONS: Coffee and caffeine intake might significantly reduce the incidence of T2DM. PMID- 24150259 TI - Cancer trials in New Zealand--patients are not the problem. PMID- 24150258 TI - Immune correlates of HIV exposure without infection in foreskins of men from Rakai, Uganda. AB - Human immunodeficiency virus (HIV) susceptibility is heterogenous, with some HIV exposed but seronegative (HESN) individuals remaining uninfected despite repeated exposure. Previous studies in the cervix have shown that reduced HIV susceptibility may be mediated by immune alterations in the genital mucosa. However, immune correlates of HIV exposure without infection have not been investigated in the foreskin. We collected sub-preputial swabs and foreskin tissue from HESN (n=20) and unexposed control (n=57) men undergoing elective circumcision. Blinded investigators assayed swabs for HIV-neutralizing IgA, innate antimicrobial peptides, and cytokine levels. Functional T-cell subsets from foreskin tissue were assessed by flow cytometry. HESN foreskins had elevated alpha-defensins (3,027 vs. 1,795 pg ml(-1), P=0.011) and HIV-neutralizing IgA (50.0 vs. 13.5% of men, P=0.019). Foreskin tissue from HESN men contained a higher density of CD3 T cells (151.9 vs. 69.9 cells mm(-2), P=0.018), but a lower proportion of these was Th17 cells (6.12 vs. 8.04% of CD4 T cells, P=0.007), and fewer produced tumor necrosis factor alpha (TNFalpha) (34.3 vs. 41.8% of CD4 T cells, P=0.037; 36.9 vs. 45.7% of CD8 T cells, P=0.004). A decrease in the relative abundance of susceptible CD4 T cells and local TNFalpha production, in combination with HIV-neutralizing IgA and alpha-defensins, may represent a protective immune milieu at a site of HIV exposure. PMID- 24150257 TI - DAMPs activating innate and adaptive immune responses in COPD. AB - Chronic obstructive pulmonary disease (COPD), a progressive lung disease characterized by sustained neutrophilic airway inflammation, is caused by chronic exposure to noxious stimuli, e.g., cigarette smoke. This chronic exposure can induce immunogenic cell death of structural airway cells, inducing the release of damage-associated molecular patterns (DAMPs). Levels of several DAMPs, including S100 proteins, defensins, and high-mobility group box-1 (HMGB1), are increased in extracellular lung fluids of COPD patients. As DAMPs can attract and activate immune cells upon binding to pattern recognition receptors, we propose that their release may contribute to neutrophilic airway inflammation. In this review, we discuss the novel role of DAMPs in COPD pathogenesis. Relevant DAMPs are categorized based on their subcellular origin, i.e. cytoplasm, endoplasmic reticulum, nucleus, and mitochondria. Furthermore, their potential role in the pathophysiology of COPD will be discussed. PMID- 24150260 TI - The new ICMJE recommendations. PMID- 24150261 TI - Summer weekend sun exposure and sunburn among a New Zealand urban population, 1994-2006. AB - AIM: To describe summer weekend sun exposure and sunburn experience, 1994-2006, among urban New Zealanders (15-69 years) by sex, age group, skin type and outdoor activity type. METHOD: A series of five telephone surveys undertaken in the summers of 1994, 1997, 1999-2000, 2002-3 and 2005-6 provided a sample of 6,195 respondents with usable data from five major cities (Auckland, Hamilton, Wellington, Christchurch and Dunedin). Respondents were administered a Computer Assisted Telephone Interview (CATI) questionnaire which sought sociodemographic information, sun exposure, and sunburn experience during the most recent weekend. RESULTS: Overall, 69% of the sample had spent at least 15 minutes outdoors between 11am and 4pm. Weekend sunburn was reported by 21%, and was more common among males, young adults and those with highly sun-sensitive skin than females, older adults and those with less sensitive skin. The head/face/neck was the body area most frequently and severely sunburned. Sunburn was associated with greater time spent outdoors and occurred most frequently during water-based (29%) and passive recreational activities (25%) and paid work (23%). CONCLUSIONS: Sun protection strategies could usefully be targeted not only towards at-risk population groups, but also towards those activities and contexts most strongly associated with potentially harmful sun exposure. PMID- 24150262 TI - PSA screening in New Zealand: total population results and general practitioners' current attitudes and practices. AB - AIMS: Prostate cancer is the second most common cancer among men in New Zealand. Prostate-specific antigen (PSA) as a screening tool for prostate cancer remains controversial. The aim was to determine the rate of PSA screening in New Zealand and to survey general practitioners' utility of PSA and their attitudes towards PSA screening. METHOD: A questionnaire was sent to 1000 general practitioners (GPs). In addition, a non-identifiable prospective audit of all registered New Zealand GPs' laboratory PSA tests was accessed for 2011. RESULTS: Of the 931,923 males older than 40 years, 267,037 had a PSA test performed (28.3%). This percentage peaked in the 65-75 age group (45%). 263 GP questionnaires were completed. 79% of all GPs would initiate discussion of PSA testing. The most common method of testing was at a time of another health need or check-up. CONCLUSION: The incidence of yearly PSA testing in the New Zealand male population over the age of 40 is 28%. GPs provide appropriate information for men to make an informed decision about PSA screening. There is an increasing population of GPs who will not initiate any discussion of PSA testing in their male patients. PMID- 24150263 TI - Communicating the location of potential skin neoplasms for excision between the referring and the operating doctor--an audit of skin lesion referrals in Whanganui, New Zealand. AB - AIM: The importance of correctly defining the location of potential skin cancer when surgical treatment may be required is self-evident. Clear communication is essential if the professional diagnosing potential skin cancer is not the same professional providing treatment. We aimed to assess the nature of the localising information provided in referrals to the local anaesthetic skin lesion theatre in our institution. METHODS: Information localising target lesions for new patients seen in our local anaesthetic skin excision theatre was recorded during a 2-month period April to May 2012 inclusive RESULTS: 100 patients were seen in our skin excision theatre during the study period; 16 patients were not able to identify the target skin lesion at the time they entered the operating theatre. The target lesion could not be determined from the referral text in 30/100 cases. Diagrams were provided in 19/100 cases. Photographs were provided in 3/100 cases. CONCLUSIONS: Pictorial and photographic means of communicating the location of suspicious lesions are under-utilised in our service. Relying on the patient or the referral text to correctly identify the lesion leaves considerable room for error. We suggest that photographic information for skin lesion referrals is adopted as a minimum standard. PMID- 24150264 TI - Diagnosing malignant pleural effusions: how do we compare? AB - INTRODUCTION: Accurate and prompt diagnosis of malignant pleural effusion (MPE) is important as patients with suspected MPE often wait for many days before the diagnosis is secure. AIMS: (1) To evaluate the diagnostic yield of pleural fluid cytology for patients admitted to Middlemore Hospital (MMH) in Auckland, New Zealand with MPE between 31 May 2010-1 June 2011. (2) To document the waiting time for cytology results to be made available and whether this contributed to length of stay. (3) To evaluate whether the volume of pleural fluid analysed contributed to diagnostic yield. METHODS: A retrospective audit of pleural fluid cytology results on 36 consecutive patients admitted to MMH with a pleural effusion which was subsequently proven to be due to malignancy. Data was obtained from hospital medical records and Web Eclair databases. RESULTS: 54.8% (17/31) of patients had positive pleural fluid cytology. Initial pleural fluid cytology was positive in 16 (51.6%). Only 4/15 patients with negative pleural fluid cytology had a repeat aspiration (1 was positive). Median cytology turnaround time was 6.72 days, range 2.23-43.06 days. Average length of stay (ALOS) was 7.78 days, range 1.11-20.8 days. Cytology turnaround times seem shorter for inpatients and when a diagnosis of cancer is unknown but the ALOS is longer if patients have negative initial cytology and when a diagnosis of cancer is uncertain. Samples >50mL appear to have a higher diagnostic yield compared to samples less than and equal to 50mL but this was not statistically significant (77.8% to 41.2%, p=0.08). CONCLUSION: Diagnostic yield from pleural fluid cytology at our hospital is comparable with other documented studies. ALOS appears to be influenced by a negative initial pleural fluid cytology and the uncertainty of diagnosis of cancer, not cytology turnaround time. The results suggest a more efficient diagnostic and treatment algorithm could be considered with emphasis on Day Stay investigation and treatment. PMID- 24150265 TI - Identifying lung cancer patients who may be eligible for epidermal growth factor receptor (EGFR) mutation testing. AB - AIM: To characterise patients with non-squamous, non-small cell lung cancer (NSCLC) diagnosed at Counties Manukau District Health Board (CMDHB; South Auckland, New Zealand) to estimate the number who may be eligible for EGFR mutation testing. METHODS: Retrospective review of clinical records of 206 patients diagnosed at CMDHB with primary lung cancer between 01/07/2011 and 30/06/2012 RESULTS: Of the 206 patients, 141 (68.4%) had non-squamous, non-small cell lung cancer (NSCLC). Of these 141 cases: 87 (62%) were adenocarcinomas; 73 (51.8%) were male; 78 (55.3%) were European, 16 (18.4%) were Pacific Islanders, 22 (15.4%) were Maori and 15 (10.7%) were Asian, with nine being from South East Asia; 28 (19.9%) had never smoked; 103 (73.0%) had advanced cancer (stage IIIA or more advanced); and 112 (79.4%) cases had an ECOG performance score of two or less. There were four patients with advanced adenocarcinoma who were South East Asian females and had never smoked, all of whom had an ECOG performance score of less than two. CONCLUSION: In a 1-year cohort of primary lung cancer patients, 68% had non-squamous, NSCLC and were potentially eligible for EGFR mutation testing. Patients with advanced stage, non-squamous NSCLC comprised half of all lung cancer patients. PMID- 24150266 TI - How to substantially increase recruitment in cancer trials in New Zealand. AB - Recruitment rates into cancer treatment trials are generally very low, both in New Zealand and internationally. This viewpoint article suggests that recruitment rates could be substantially increased by considering all patients newly diagnosed with cancer to be automatically eligible for randomisation if experimental treatments were available under study protocols for patients with their type of cancer. Patients randomised to be offered the experimental treatment would be approached for consent to receive it, whereas patients randomised not to be offered this treatment would continue to receive standard treatment (thus serving as the control group) and not be approached for consent. Routine adoption of this approach, known as "post-randomisation consent" or "pre randomisation", would require public consultation and "societal consent". While this proposal is not without significant challenges and potential disadvantages, an informed public discussion on the subject would seem worthwhile given the potential for increasing patient access to new cancer treatments and advancing medical science. PMID- 24150267 TI - The completeness of cancer treatment data on the National Health Collections. AB - The New Zealand Ministry of Health (MoH) maintains a number of National Collections, which contain data on diagnoses, procedures and service provision for patients. There are concerns that these collections may underestimate the provision of cancer treatment, but the extent to which this is true is largely unknown. In this brief report, we focus on the Auckland region to illustrate the extent to which the National Collections undercount receipt of surgery in patients with breast, colon or renal cancer, and receipt of chemo- and/or radiotherapy for breast cancer patients with regional extent of disease (all diagnosed 2006-2008). We collected treatment data from the National collections and augmented this with data from Cancer Centres, breast cancer registers, private hospitals and personal clinician databases. The National Collections were used to determine 'baseline' treatment data, and we then compared receipt of treatment to that observed on the augmented dataset. We found that the National Collections undercounted receipt of surgery by 13-19%, and receipt of chemo- or radiotherapy for breast cancer patients by 18% and 16% respectively. Our observations clearly point toward (1) a non-reporting private hospital 'effect' on surgery data completeness; and (2) underreporting of adjuvant therapy to the MoH by service providers. PMID- 24150268 TI - Cancer care coordinators: what are they and what will they cost? AB - Health care resources are scarce, and future funding increases are less likely than in the past; reorientation of health services to more efficient and effective delivery is as timely as ever. In this light, we consider the recent funding decision by the Government to provide $16 million over the next 4 years for cancer coordination nurses. While the intricacies of the role are still being defined, it is likely that cancer care coordinators could benefit patients in terms of access to and timeliness of care, and patient satisfaction. Our research into the role shows that many coordinating activities for cancer patients are already being done, but often in an ad hoc manner by a number of different personnel. Thus, we estimate that the likely 'true' incremental cost of cancer care coordinators is in fact relatively low when considered in opportunity cost terms because the cancer care coordinator will be able to free up time for other staff enabling them to provide care elsewhere in the health system and reduce tasks being unnecessarily repeated. The funding of cancer care coordinators is a great opportunity to improve the timeliness of care and improve the experience of patients through their cancer journey, but the success of these roles depends on the leadership provided, peer support, continual appraisal and the resources available. PMID- 24150269 TI - Differentiation between malignant melanoma and Spitz tumour has improved over the past decade due to modern pathological techniques. AB - A 10-year-old boy was diagnosed with a thick neurotropic melanoma of the lip in 2002. He is alive and well without evidence of disease recurrence 10 years later. We applied modern pathologic techniques to this lesion to highlight recent advances in melanoma diagnostics. PMID- 24150270 TI - Medical image. Purple urine bag syndrome. PMID- 24150271 TI - Iodine supplementation in pregnancy and breastfeeding: a New Zealand survey of user awareness. PMID- 24150272 TI - Hydrophilic tetracarboxy bacteriochlorins for photonics applications. AB - Bacteriochlorins absorb strongly in the near-infrared (NIR, 700-900 nm) region and hence are well suited for photophysical studies and photomedical applications, yet such endeavors heretofore have been largely limited by the intrinsic lipophilicity of the bacteriochlorin macrocycle. Here, a new molecular design is investigated wherein 3,5-dicarboxyphenyl units are appended to the beta pyrrolic positions of the bacteriochlorin. Use of the 3,5-aryl substitution motif places the carboxylic acid groups, which are anionic at neutral pH, above and below the plane of the bacteriochlorin macrocycle. A de novo synthesis has been employed to create five such bacteriochlorins, which uses as intermediates two new 2,12-dibromobacteriochlorin building blocks and a known 3,13 dibromobacteriochlorin. The aryl groups with protected carboxylate moieties were introduced by Suzuki coupling; subsequent deprotection afforded the hydrophilic bacteriochlorins. The latter were characterized by absorption and fluorescence spectroscopy in DMF and in aqueous phosphate buffer (pH 7). In most cases, comparable sharp emission (FWHM of ~25 nm) and modest fluorescence yields (0.060 0.11) were observed in aqueous phosphate buffer medium and in DMF. Aqueous solubility was examined by absorption spectral interrogation of samples over a 1000-fold concentration range with reciprocal change in pathlength (~0.5, 5, 50, and 500 MUM; 10, 1, 0.1, and 0.01 cm pathlength cuvettes). One hydrophilic bacteriochlorin was prepared that contains a single maleimido-terminated tether for bioconjugation; the tether was installed by the sequence of 15-bromination of the bacteriochlorin, Suzuki coupling, and DCC-mediated amide formation. The maleimido-bacteriochlorin was conjugated to a 48-residue cysteine-containing peptide analogue of a constituent from a bacterial photosynthetic light harvesting complex. Taken together, the results show a new molecular design and facile de novo synthetic route for obtaining hydrophilic bacteriochlorins including a bioconjugatable group if desired. PMID- 24150274 TI - Tracking mechanical wave propagation within tissue using phase-sensitive optical coherence tomography: motion artifact and its compensation. AB - We describe theoretical and experimental investigations of motion artifacts that can arise in the detection of shear wave propagating within tissue with phase sensitive optical coherence tomography. We find that the motion artifact is a combined product of sample surface motion and refractive index difference between sample and air, which cannot be neglected when estimating the tissue motion within tissue. A method of compensating the motion artifact is demonstrated, the results of which emphasize the need for surface motion compensation when measuring the mechanical response for elastography or other biomedical applications. PMID- 24150273 TI - High genome heterozygosity and endemic genetic recombination in the wheat stripe rust fungus. AB - Stripe rust, caused by Puccinia striiformis f. sp. tritici (Pst), is one of the most destructive diseases of wheat. Here we report a 110-Mb draft sequence of Pst isolate CY32, obtained using a 'fosmid-to-fosmid' strategy, to better understand its race evolution and pathogenesis. The Pst genome is highly heterozygous and contains 25,288 protein-coding genes. Compared with non-obligate fungal pathogens, Pst has a more diverse gene composition and more genes encoding secreted proteins. Re-sequencing analysis indicates significant genetic variation among six isolates collected from different continents. Approximately 35% of SNPs are in the coding sequence regions, and half of them are non-synonymous. High genetic diversity in Pst suggests that sexual reproduction has an important role in the origin of different regional races. Our results show the effectiveness of the 'fosmid-to-fosmid' strategy for sequencing dikaryotic genomes and the feasibility of genome analysis to understand race evolution in Pst and other obligate pathogens. PMID- 24150275 TI - Neuroimmunological function in parents of children suffering from cancer. AB - The main aim of this study is to evaluate the relationship between depression and immunological function in parents of children with cancer. Thirty-two parents participated in the study. The parents completed the following assessments: a list of major stressful events in a Hemato-Oncology ward, beck depression inventory II (BDI-II), posttraumatic diagnostic scale (PDS) and quality of life (QOL) questionnaire. A single blood sample was drawn from parents for evaluation of cortisol levels and lymphocyte cell subgroups. The parents were divided into two groups: Those who suffered from depression as defined by BDI-II cutoff score of 14 (depressed parents (DP), n = 7), and non-depressed parents (non-DP, n = 25). In parents of children with cancer the DP group had statistically significantly higher stressful event scores, dysfunction scores (from the PDS) and CD8 percentage compared to the non-DP group. QOL, CD4 percentage and CD4/CD8 ratio were significantly lower in the DP group. The BDI scores significantly positively correlated with events and dysfunctional scores, and significantly negatively correlated with QOL scores and CD4/CD8 ratio. High psychiatric morbidity was found in parents of children with cancer. The findings of altered immunity in DP provide further evidence that the physiological response to stress and depression may alter immune functions. PMID- 24150277 TI - Metabolic exploitation of the sialic acid biosynthetic pathway to generate site specifically labeled antibodies. AB - Lack of a universal site-specific conjugation methodology for antibodies limits their potential to be developed as tumor-specific imaging agents or targeted therapeutics. A potential mechanism for site-specific conjugation involves utilization of the conserved N-glycosylation site in the CH2 domain. We sought to develop an antibody with an altered azido-sugar at this site whereby site specific label could be added. The HB8059 hybridoma was cultured with peracetylated N-azidoacetlymannosamine (Ac4ManNAz). The resulting azido-sugar antibody was conjugated to phosphine-polyethylene glycol (PEG3)-biotin via a modified Staudinger reaction. Biochemical and functional characterization of the biotinylated antibody was performed. The azido-sugar antibody was also labeled with DyLight-650-Phosphine and injected into mice harboring pancreatic cancer xenografts. The tumors were dissected and imaged utilizing an IVIS fluorescent camera. The antibody was successfully produced in 100 MUM Ac4ManNAz. The biotinylated antibody demonstrated a 50 kDa heavy and 25 kDa light chain on sodium dodecyl sulfate-polyacrylamide gel electrophoresis, but demonstrated a single band at 50 kDa on western blot. Treatment with a N-linked glycosidase extinguished the band. Flow cytometry demonstrated antigen-specific binding of CA19-9-positive cells and the antibody localized to the antigen-positive tumor in vivo. We successfully produced an antibody with an azido-sugar at the conserved CH2 glycosylation site. We were able to utilize this azide to label the antibody with biotin or fluorescent label and demonstrate that the label is added in a site-specific manner to the heavy chain, N-linked glycosylation site. Finally, we demonstrated functionality of our antibody for in vitro and in vivo targeting of pancreatic cancer cells. PMID- 24150278 TI - Clinical and radiological long-term outcomes of anterior microforaminotomy for cervical degenerative disease. AB - STUDY DESIGN: A retrospective review. OBJECTIVE: To evaluate the long-term clinical and radiological results after anterior microforaminotomy (AMF), with details of postoperative degeneration. SUMMARY OF BACKGROUND DATA: AMF is an alternative procedure to treat unilateral cervical radiculopathy. Although previous clinical results are favorable, degeneration may occur after surgery. However, the details of this have not been proven. METHODS: A total of 154 AMF procedures in 135 patients were performed. Of these, 82 patients (97 AMF) had complete preoperative and minimum 3-year postoperative clinical outcomes data available for analysis. Radiological data were analyzed with picture achieving communication system images. Long-term clinical results were accessed by a questionnaire and telephone interviews. Clinical and radiological parameters were statistically analyzed. RESULTS: Spondylosis comprised 53.7%, disc herniation comprised 36%, and mixed comprised 10.3%. The mean age was 49 (range, 31-76) years. Operated levels were 1 level in 71 patients, 2 in 10, and 3 in 1. Reoperation was performed in 2 patients (2.4%). The mean follow-up was 6.1 years. A total of 90.3% achieved an excellent or good outcome. Visual analogue scale scores improved from 8.2 (6-10) to 2.9 (0-10), and neck disability index scores improved from 24.5 (7-46) to 6.7 (0-31) (P < 0.05). Eighty-one cases (83.5%) showed a decrease in disc height (DH), with 1 mm of the mean. The DH decrease was positively correlated with disc invasion (P < 0.01) and AMF diameter (P < 0.01). According to statistical analysis, the critical AMF diameter was 4.7 mm. Anterior spur formation occurred in 39 cases (40.2%). No radiological parameters affected the clinical outcome. CONCLUSION: AMF is a safe, effective procedure to treat unilateral cervical radiculopathy. Critical DH decreases may be the trigger of sequential degeneration. To preserve DH, disc invasion must be avoided, and AMF must be made as small as possible with exact removal of compressive lesion. LEVEL OF EVIDENCE: 4. PMID- 24150276 TI - Effects of dopamine receptor blockade on the intensity-response function of electroretinographic b- and d-waves in light-adapted eyes. AB - The effects of dopamine receptor blockade by sulpiride (D2-class antagonist) and sulpiride plus SCH 23390 (D1-class antagonist) on the V - log I function of the electroretinographic (ERG) b- and d-waves were investigated in light-adapted frog eyes. Sulpiride significantly decreased the absolute sensitivity of the b- and d waves. The amplitude of the both waves was diminished over the whole intensity range studied. A similar effect on the b-, but not d-wave amplitude was seen during the perfusion with sulpiride plus SCH 23390. The effect on the d-wave amplitude depended on stimulus intensity. The threshold of the d-wave was not significantly altered. The suprathreshold d-wave amplitude was enhanced at the lower stimulus intensities and remained unchanged at the higher ones. The results obtained indicate that the action of endogenous dopamine on the photopic ERG shows clear ON-OFF asymmetry. Participation of different classes of dopamine receptors is probably responsible for this difference. PMID- 24150280 TI - Ion-pairing chromatography on a porous graphitic carbon column coupled with time of-flight mass spectrometry for targeted and untargeted profiling of amino acid biomarkers involved in Candida albicans biofilm formation. AB - BACKGROUND: Candida albicans, the most common fungal pathogen related to colonization and biofilm formation on the surfaces of indwelling medical devices, shows high resistance to the most commonly used antifungal drugs. In this study, an ion-pairing chromatography-porous graphitic carbon column coupled with a time of-flight mass spectrometry (IP-PGC-TOF/MS) system was developed for targeted and untargeted profiling of metabolites involved in biofilm and planktonic growth of C. albicans. Using untargeted profiling analysis, 16 differential metabolites were screened and identified as potential biomarkers, most of which were amino acids or related compounds. Based on untargeted profiling analysis, targeted quantitative analysis of 22 amino acids was established and carefully evaluated using stable isotope-labeled internal standards. Among them, 9 amino acids that were not screened by untargeted profiling were further characterized as new biomarkers. Finally, a total of 25 potential biomarkers were screened using the combined targeted and untargeted strategy, among which 16 were characterized for the first time. Our results confirmed that amino acid metabolism and polyamine metabolism were at a high level in biofilms, except for some new biomarkers including ornithine, arginine and proline that were directly related to ornithine. Further experiments were carried out on the ornithine decarboxylase negative (spe1Delta) mutant, and the results showed that the consumption of ornithine for putrescine biosynthesis has a significant impact on biofilm formation and may prove to be a drug target for resolving drug resistance of C. albicans. This study provides a systematic view of changes in amino acid metabolism during C. albicans biofilm formation by a combination of targeted and untargeted profiling using an original IP-PGC-TOF/MS method. It is a feasible approach for characterizing subtle variations and screening novel biomarkers from the microbial metabolome. PMID- 24150281 TI - Sprouting and intussusceptive angiogenesis in postpneumonectomy lung growth: mechanisms of alveolar neovascularization. AB - In most rodents and some other mammals, the removal of one lung results in compensatory growth associated with dramatic angiogenesis and complete restoration of lung capacity. One pivotal mechanism in neoalveolarization is neovascularization, because without angiogenesis new alveoli can not be formed. The aim of this study is to image and analyze three-dimensionally the different patterns of neovascularization seen following pneumonectomy in mice on a sub micron-scale. C57/BL6 mice underwent a left-sided pneumonectomy. Lungs were harvested at various timepoints after pneumonectomy. Volume analysis by microCT revealed a striking increase of 143 percent in the cardiac lobe 14 days after pneumonectomy. Analysis of microvascular corrosion casting demonstrated spatially heterogenous vascular densitities which were in line with the perivascular and subpleural compensatory growth pattern observed in anti-PCNA-stained lung sections. Within these regions an expansion of the vascular plexus with increased pillar formations and sprouting angiogenesis, originating both from pre-existing bronchial and pulmonary vessels was observed. Also, type II pneumocytes and alveolar macrophages were seen to participate actively in alveolar neo angiogenesis after pneumonectomy. 3D-visualizations obtained by high-resolution synchrotron radiation X-ray tomographic microscopy showed the appearance of double-layered vessels and bud-like alveolar baskets as have already been described in normal lung development. Scanning electron microscopy data of microvascular architecture also revealed a replication of perialveolar vessel networks through septum formation as already seen in developmental alveolarization. In addition, the appearance of pillar formations and duplications on alveolar entrance ring vessels in mature alveoli are indicative of vascular remodeling. These findings indicate that sprouting and intussusceptive angiogenesis are pivotal mechanisms in adult lung alveolarization after pneumonectomy. Various forms of developmental neoalveolarization may also be considered to contribute in compensatory lung regeneration. PMID- 24150282 TI - Erratum. PMID- 24150283 TI - On-chip processing of particles and cells via multilaminar flow streams. AB - The processing of particles, cells, and droplets for reactions, analyses, labeling, and coating is an important aspect of many microfluidic workflows. However, performing multi-step processes is typically a laborious and time consuming endeavor. By exploiting the laminar nature of flow within microchannels, such procedures can benefit in terms of both speed and simplicity. This can be achieved either by manipulating the flow streams around the objects of interest, particularly for the localized perfusion of cells, or by manipulating the objects themselves within the streams via a range of forces. Here, we review the variety of methods that have been employed for performing such "multilaminar flow" procedures on particles, cells, and droplets. PMID- 24150284 TI - Supported nanohydroxyapatite on anodized titanium wire for solid-phase microextraction. AB - In this paper, a simple and versatile route was introduced to prepare solid-phase microextraction coatings on the chemically inert titanium wire. Titania nanotube array film can be created on metallic substrates by electrochemical anodization in fluoride-containing electrolytes and subsequently support various secondary reactions to prepare functional surfaces. In the present work, titania nanotube array-coated titanium wire was successfully modified by nanostructured hydroxyapatite by a simple solution-based in situ chemical deposition method. This coating has a high surface-to-volume ratio with a thickness of about 10 MUm. Extraction performance of the fiber was assessed on several polycyclic aromatic hydrocarbons in water solutions. The nanohydroxyapatite-coated fiber showed good precision (<7.4 %), low detection limits (1.79-4.89 ng/L), and wide linearity (0.1-200 MUg/L) under the selected conditions. The repeatability of fiber to fiber was 1.9-18.2 %. The new solid-phase microextraction fiber has a lifetime of over 150 extractions due to the hydroxyapatite nanoslices uniformly and strongly deposited on the wire surface. The environmental water sample was used to test the reliability of the solid-phase microextraction-gas chromatography method; some analytes were detected and quantified. PMID- 24150285 TI - A superconcentrated ether electrolyte for fast-charging Li-ion batteries. AB - We have found ultrafast Li(+) intercalation into graphite in a superconcentrated ether electrolyte, even exceeding that in a currently used commercial electrolyte. This discovery is an important breakthrough toward fast-charging Li ion batteries far beyond present technologies. PMID- 24150287 TI - Terahertz plasmonic waveguides created via 3D printing. AB - We demonstrate that 3D printing, commonly associated with the manufacture of large objects, allows for the fabrication of high quality terahertz (THz) plasmonic structures. Using a commercial 3D printer, we print a variety of structures that include abrupt out-of-plane bends and continuously varying bends. The waveguides are initially printed in a polymer resin and then sputter deposited with ~500 nm of Au. This thickness of Au is sufficient to support low loss propagation of surface plasmon-polaritons with minimal impact from the underlying layer, thereby demonstrating a useful approach for fabricating a broad range of plasmonic structures that incorporate complex geometries. Using THz time domain spectroscopy, we measure the guided-wave properties of these devices. We find that the propagation properties of the guided-wave modes are similar to those obtained in similar conventional metal-based waveguides, albeit with slightly higher loss. This additional loss is attributed to roughness associated with limitations that currently exist in commercial 3D printers. PMID- 24150288 TI - Image filtering in structured illumination microscopy using the Lukosz bound. AB - Various aspects of image filtering affect the final image quality in Structured Illumination Microscopy, in particular the regularization parameter and type of regularization function, the relative height of the side bands, and the shape of the apodization function. We propose an apodization filter without adjustable parameters based on the application of the Lukosz bound in order to guarantee a non-negative point spread function. Simulations of digital resolution charts and experimental data of chromatin structures and of actin filaments show artefact free reconstructions for a wide range of filter parameters. In general, a trade off is observed between sharpness and noise suppression. PMID- 24150286 TI - PP2A inhibition results in hepatic insulin resistance despite Akt2 activation. AB - In the liver, insulin suppresses hepatic gluconeogenesis by activating Akt, which inactivates the key gluconeogenic transcription factor FoxO1 (Forkhead Box O1). Recent studies have implicated hyperactivity of the Akt phosphatase Protein Phosphatase 2A (PP2A) and impaired Akt signaling as a molecular defect underlying insulin resistance. We therefore hypothesized that PP2A inhibition would enhance insulin-stimulated Akt activity and decrease glucose production. PP2A inhibitors increased hepatic Akt phosphorylation and inhibited FoxO1in vitro and in vivo, and suppressed gluconeogenesis in hepatocytes. Paradoxically, PP2A inhibition exacerbated insulin resistance in vivo. This was explained by phosphorylation of both hepatic glycogen synthase (GS) (inactivation) and phosphorylase (activation) resulting in impairment of glycogen storage. Our findings underline the significance of GS and Phosphorylase as hepatic PP2A substrates and importance of glycogen metabolism in acute plasma glucose regulation. PMID- 24150289 TI - A Nipkow disk integrated with Fresnel lenses for terahertz single pixel imaging. AB - We present a novel Nipkow disk design for terahertz (THz) single pixel imaging applications. A 100 mm high resistivity (rho~3k-10k Omega.cm) silicon wafer was used for the disk on which a spiral array of twelve 16-level binary Fresnel lenses were fabricated using photolithography and a dry-etch process. The implementation of Fresnel lenses on the Nipkow disk increases the THz signal transmission compared to the conventional pinhole-based Nipkow disk by more than 12 times thus a THz source with lower power or a THz detector with lower detectivity can be used. Due to the focusing capability of the lenses, a pixel resolution better than 0.5 mm is in principle achievable. To demonstrate the concept, a single pixel imaging system operating at 2.52 THz is described. PMID- 24150290 TI - Multi-level surface enhanced Raman scattering using AgOx thin film. AB - Ag nanostructures with surface-enhanced Raman scattering (SERS) activities have been fabricated by applying laser-direct writing (LDW) technique on silver oxide (AgOx) thin films. By controlling the laser powers, multi-level Raman imaging of organic molecules adsorbed on the nanostructures has been observed. This phenomenon is further investigated by atomic-force microscopy and electromagnetic calculation. The SERS-active nanostructure is also fabricated on transparent and flexible substrate to demonstrate our promising strategy for the development of novel and low-cost sensing chip. PMID- 24150291 TI - Design of thin infrared quarter-wave and half-wave plates using antenna-array sheets. AB - A thin quarter-wave plate and a half-wave plate are designed based on multiple antenna-array sheets (AAS). For transmission through cascaded antenna-array sheets, an equivalent transmission-line model is used. The interspacing dielectric is modeled as a transmission line with each AAS treated as a loaded shunt admittance. By utilizing this transmission-line model to treat the plates as a differential phase shifter between two orthogonal polarizations, a quarter wave plate can be designed with two AAS and a half-wave plate can be designed with three AAS. Both wave plates can achieve high transmission with the desired 90 degrees and 180 degrees phase difference between two orthogonal polarizations. PMID- 24150292 TI - Deformation of ultra-short laser pulses by optical systems for laser scanners. AB - Current experiments of processing glass with ultra-short laser pulses (< 1 ps) lead to scan angle depending processing results. This scan angle depending effect is examined by simulations of a common focusing lens for laser scanners. Due to dispersion, focusing lenses may cause pulse deformations and increase the pulse duration in the focal region. If the field angle of the incoming laser beam is variable, the pulse deformation may also vary as a function of the field angle. By ray tracing as well as wave optical simulations we investigate pulse deformations of optical systems for different scan angles. PMID- 24150293 TI - Method for optical inspection of nanoscale objects based upon analysis of their defocused images and features of its practical implementation. AB - A microscopic method to inspect isolated sub 100 nm scale structures made of silicon is presented. This method is based upon an analysis of light intensity distributions at defocused images obtained along the optical axis normal to the sample plane. Experimental measurements of calibrated lines (height 50 nm, length 100 MUm, and widths of 40-150 nm in 10 nm steps) on top of a monocrystalline silicon substrate are presented. Library of defocused images of calibrated lines is obtained experimentally and numerically with accordance to experimental setup parameters and measurements conditions. Processing of the measured defocused images and comparison with simulated ones from library allow one to distinguish between objects with a 10 nm change in width. It is shown that influence of optical system aberrations must be taken into account in order to achieve coincidence between simulation and measured results and increase accuracy of line width inspection accuracy. The limits of accuracy for object width measurements using this optical method are discussed. PMID- 24150294 TI - Nanoscale tensile stress approach for the direct writing of plasmonic nanostructures. AB - One- and two-dimensional plasmonic nanostructures can be fabricated using nanoscale tensile stress. A polymer layer, coated with a thin metal film, is exposed to an interference pattern produced by ultraviolet laser beams. Crosslinking is induced between the polymeric molecules located within the bright fringes. This process not only increases the refractive index but also reduces the polymer layer thickness. Corrugations occur on the continuous thin metal film due to the nanoscale stress in the polymer layer. Thus, a periodic nanostructure of area 3 * 3 mm and depth 50 nm is created both in the polymer and metal films with excellent homogeneity and reproducibility. This method enables direct writing of a large-area plasmonic nanostructure at low cost which can be used in the design of optoelectronic devices and sensors. PMID- 24150295 TI - Optical investigation of strong exciton localization in high Al composition AlxGa1-xN alloys. AB - The exciton localization in wurtzite AlxGa1-xN alloys with x varying from 0.41 to 0.63 has been studied by deep-ultraviolet photoluminescence (PL) spectroscopy and picosecond time-resolved PL spectroscopy. Obvious S-shape temperature dependence was observed indicating that the strong exciton localization can be formed in high Al composition AlxGa1-xN alloys. It was also found that the Al composition dependence of exciton localization energy of AlGaN alloys is inconsistent with that of the excitonic linewidth. We contribute the inconsistency to the strong zero-dimensional exciton localization. PMID- 24150296 TI - Metallic nanoparticle chains on dielectric waveguides: coupled and uncoupled situations compared. AB - We investigate the optical behaviors of metallic nanoparticle (MNP) chains supporting localized surface plasmon (LSP) for different distances between particles. MNPs are excited through the fundamental TE mode of a silicon waveguide. Finite difference time domain (FDTD) calculations and optical power transmission measurements reveal three different behaviors. For short distances between particles, dipolar coupling occurs, and the MNP chain behaves as a waveguide. For the longest distances, nanoparticles are uncoupled, and the MNP chain acts as a LSP Bragg grating. Finally, for intermediate distances, we observe one behavior at a time, i.e. dipolar coupling or LSP Bragg reflection. There is only a small range of wavelengths within which both behaviors can coexist. PMID- 24150297 TI - Optically controlled polarizer using a ladder transition for high speed Stokesmetric Imaging and Quantum Zeno Effect based optical logic. AB - We demonstrate an optically controlled polarizer at ~1323 nm using a ladder transition in a Rb vapor cell. The lower leg of the 5S(1/2),F = 1->5P(1/2),F = 1,2->6S(1/2),F = 1,2 transitions is excited by a Ti:Sapphire laser locked to a saturated absorption signal, representing the control beam. A tunable fiber laser at ~1323 nm is used to excite the upper leg of the transitions, representing the signal beam. When the control beam is linearly polarized, it produces an excitation of the intermediate level with a particular orientation of the angular momentum. Under ideal conditions, this orientation is transparent to the signal beam if it has the same polarization as the control beam and is absorbed when it is polarized orthogonally. We also present numerical simulations of the system using a comprehensive model which incorporates all the relevant Zeeman sub-levels in the system, and identify means to improve the performance of the polarizer. A novel algorithm to compute the evolution of large scale quantum system enabled us to perform this computation, which may have been considered too cumbersome to carry out previously. We describe how such a polarizer may serve as a key component for high-speed Stokesmetric imaging. We also show how such a polarizer, combined with an optically controlled waveplate, recently demonstrated by us, can be used to realize a high speed optical logic gate by making use of the Quantum Zeno Effect. Finally, we describe how such a logic gate can be realized at an ultra-low power level using a tapered nanofiber embedded in a vapor cell. PMID- 24150298 TI - One-dimensional transient radiative transfer by lattice Boltzmann method. AB - The lattice Boltzmann method (LBM) is extended to solve transient radiative transfer in one-dimensional slab containing scattering media subjected to a collimated short laser irradiation. By using a fully implicit backward differencing scheme to discretize the transient term in the radiative transfer equation, a new type of lattice structure is devised. The accuracy and computational efficiency of this algorithm are examined firstly. Afterwards, effects of the medium properties such as the extinction coefficient, the scattering albedo and the anisotropy factor, and the shapes of laser pulse on time-resolved signals of transmittance and reflectance are investigated. Results of the present method are found to compare very well with the data from the literature. For an oblique incidence, the LBM results in this paper are compared with those by Monte Carlo method generated by ourselves. In addition, transient radiative transfer in a two-Layer inhomogeneous media subjected to a short square pulse irradiation is investigated. At last, the LBM is further extended to study the transient radiative transfer in homogeneous medium with a refractive index discontinuity irradiated by the short pulse laser. Several trends on the time resolved signals different from those for refractive index of 1 (i.e. refractive index-matched boundary) are observed and analysed. PMID- 24150299 TI - Efficient decoy-state quantum key distribution with quantified security. AB - We analyse the finite-size security of the efficient Bennett-Brassard 1984 protocol implemented with decoy states and apply the results to a gigahertz clocked quantum key distribution system. Despite the enhanced security level, the obtained secure key rates are the highest reported so far at all fibre distances. PMID- 24150300 TI - Linear photonic frequency discriminator on As2S3-ring-on-Ti:LiNbO3 hybrid platform. AB - We report a photonic frequency discriminator built on the vertically integrated As2S3-ring-on-Ti:LiNbO3 hybrid platform. The discriminator consists of a Mach Zehnder interferometer (MZI) formed by the optical path length difference (OPD) between polarization modes of Ti-diffused waveguide on LiNbO3 substrate and a vertically integrated As2S3 race-track ring resonator on top of the substrate. The figures of merit of the device, enhancement of the signal-to-3rd order intermodulation distortion (IMD3) power ratio and corresponding 3rd order intercept point (IP3) over a traditional MZI, are demonstrated through device characterization. PMID- 24150301 TI - Gigabit close-proximity wireless connections supported by 60 GHz RoF links with low carrier suppression. AB - We present an experimental investigation of the 60 GHz optical carrier suppressed radio over fiber systems with less than 5 dB carrier suppression. As a case study, the 60 GHz RoF signal is generated using a 12.5 Gb/s commercially available Mach-Zehnder modulator biased at its minimum point. We report on error free transmission over 20 km of standard single mode fiber and 1 m of wireless distance. Furthermore, the efficiency of photonic RF generation depending on the value of carrier suppression is reported. We argue that transport of RoF signals with low carrier suppression assisted with simplified techniques of lightwave generation, baseband data modulation, and RF downconversion might be a promising enabling technology for fiber support of close-proximity wireless terminals. PMID- 24150302 TI - Double-layer Fano resonance photonic crystal filters. AB - We report ultra-compact surface-normal high-Q optical filters based on single- and double-layer stacked Fano resonance photonic crystal slabs on both Si and quartz substrates. A single layer photonic crystal filter was designed and a Q factor of 1,737 was obtained with 23 dB extinction ratio. With stacked double layer photonic crystal configuration, the optical filter Q can increase to over 10,000,000 in design. Double-layer filters with quality factor of 9,734 and extinction ratio of 8 dB were experimentally demonstrated, for a filter design with target Q of 22,000. PMID- 24150303 TI - Efficient continuous-wave self-Raman Yb:KGW laser with a shift of 89 cm-1. AB - We demonstrated a continuous-wave (CW) self-Raman laser with high conversion efficiency by using Yb:KGW as the Raman crystal. The first Stokes line of wavelength centered at 1095.2 nm with spectral bandwidth of 8 nm and the cascaded Raman conversion wavelength at 1109.5 nm with spectral bandwidth of 3.4 nm were observed with a Raman shift of 89 cm-1 with respect to the fundamental laser wavelength at 1085.0 nm with spectral bandwidth of 10 nm. The CW Raman output power of 1.7 W was attained under the diode pump power of 7.8 W which corresponds to the slope efficiency and the diode-to-Stokes optical conversion efficiency of 26.6% and 21.8%, respectively. PMID- 24150304 TI - Effects of crystallinity and point defects on optoelectronic applications of beta Ga2O3 epilayers. AB - This study evaluates the effect of crystallinity and point defects on time dependent photoresponsivity and the cathodoluminescence (CL) properties of beta Ga2O3 epilayers. A synchrotron high-resolution X-ray technique was used to understand the crystalline structure of samples. Rutherford backscattering spectroscopy was used to determine the net chemical composition of the samples to examine the type and ratio of their possible point defects. The results show that in functional time-dependent photoresponsivity of photodetectors based on beta Ga2O3 epilayers, point defects contribution overcomes the contribution of crystallinity. However, the crystalline structure affects the intensities and emission regions of CL spectra more than point defects. PMID- 24150305 TI - Hybrid distributed Raman amplification combining random fiber laser based 2nd order and low-noise LD based 1st-order pumping. AB - A configuration of hybrid distributed Raman amplification (H-DRA), that is formed by incorporating a random fiber laser (RFL) based 2nd-order pump and a low-noise laser-diode (LD) based 1st-order pump, is proposed in this paper. In comparison to conventional bi-directional 1st-order DRA, the effective noise figure (ENF) is found to be lower by amount of 0 to 4 dB due to the RFL-based 2nd-order pump, depending on the on-off gain, while the low-noise 1st-order Raman pump is used for compensating the worsened signal-to-noise ratio (SNR) in the vicinity towards the far end of the fiber and avoiding the potential nonlinear impact induced by excess injection of pump power and suppressing the pump-signal relative intensity noise (RIN) transfer. As a result, the gain distribution can be optimized along ultra-long fiber link, due to combination of the 2nd-order RFL and low-noise 1st order pumping, making the transmission distance be extended significantly. We utilized such a configuration to achieve ultra-long-distance distributed sensing based on Brillouin optical time-domain analysis (BOTDA). A repeater-less sensing distance record of up to 154.4 km with 5 m spatial resolution and ~ +/- 1.4 degrees C temperature uncertainty is successfully demonstrated. PMID- 24150306 TI - Laser-induced selective crosslinking for scaling the heterointerfacial domain in polymer blends. AB - Organic blends containing heterojunction structures at the interfacial phase have been applied extensively in organic optoelectronic devices to modify charge transfer, separation, and recombination processes. Scaling and controlling the transition domains at the hetero-interface are of crucial importance for deep insights into the involved physics and for architecturing the devices with improved performance. However, it is difficult to recognize and characterize these transition domains directly using the conventional microscopic techniques, in particular when different molecules are dissolved in the same solvent with equal solubility. In this work, we introduce a technique defined as laser-induced selective cross-linking to isolate the interfacial phase from other phases into a directly measurable practicity. Thus, the hetero-domains become visualized and directly measurable. Based on the insolubility of the selectively cross-linked molecules in organic solvents, a lift-off process may remove the uncross-linked or incompletely cross-linked molecules, so that the hetero-domain is more clearly visualized and more precisely measured. A transition domain in a scale of about 200 nm is resolved in the F8BT/PFB blend film between their respectively rich phases after the selective cross-linking of the F8BT molecules by a blue laser. Furthermore, hetero-crosslinking between F8BT and PFB molecules was also resolved by both microscopic and near-field spectroscopic investigations. PMID- 24150307 TI - A method for characterizing the stability of light sources. AB - We describe a method for measuring small fluctuations in the intensity of a laser source with a resolution of 10-4. The current signal generated by a PIN diode is passed to a front-end electronics that discriminates the AC from the DC components, which are physically separated and propagated along circuit paths with different gains. The gain long the AC signal path is set one order of magnitude larger than that along the DC signal path in such a way to optimize the measurement dynamic range. We then derive the relative fluctuation signal by normalizing the input-referred AC signal component to its input-referred DC counterpart. In this way the fluctuation of the optical signal waveform relative to the mean power of the laser is obtained. A "Noise-Scattering-Pattern method" and a "Signal-Power-Spectrum method" are then used to analyze the intensity fluctuations from three different solid-state lasers. This is a powerful tool for the characterization of the intensity stability of lasers. Applications are discussed. PMID- 24150308 TI - Transmission characteristics of a bidirectional transparent screen based on reflective microlenses. AB - A microlens array (MLA) based see-through, front projection screen, which can be used in direct projection head-up displays (HUD), color teleprompters and bidirectional interactive smart windows, is evaluated for various performance metrics in transmission mode. The screen structure consists of a partially reflective coated MLA buried between refractive-index-matched layers of epoxy as reported in Ref [1]. The reflected light is expanded by the MLA to create an eyebox for the user. The brightness gain of the screen can be varied by changing the numerical aperture of the microlenses. Thus, using high gain designs, a low power projector coupled with the screen can produce high-brightness and even 3D images as the polarization is maintained at the screen. The impact of the partially reflective coatings on the transmitted light in terms of resolution and modulation transfer function associated with the screen is studied. A condition similar to the Rayleigh criteria for diffraction-limited imaging is discussed for the microlens arrays and the associated coating layers. The optical path difference between the light transmitted from the center and the edges of each microlens caused by the reflective layer coatings should not exceed lambda/4. Furthermore, the crosstalk between the front and rear projected images is found to be less than 1.3%. PMID- 24150309 TI - Single shot speckle and coherence analysis of the hard X-ray free electron laser LCLS. AB - The single shot based coherence properties of hard x-ray pulses from the Linac Coherent Light Source (LCLS) were measured by analyzing coherent diffraction patterns from nano-particles and gold nanopowder. The intensity histogram of the small angle x-ray scattering ring from nano-particles reveals the fully transversely coherent nature of the LCLS beam with a number of transverse mode = 1.1. On the other hand, the speckle contrasts measured at a large wavevector yields information about the longitudinal coherence of the LCLS radiation after a silicon (111) monochromator. The quantitative agreement between our data and the simulation confirms a mean coherence time of 2.2 fs and a x-ray pulse duration of 29 fs. Finally the observed reduction of the speckle contrast generated by x-rays with pulse duration longer than 30 fs indicates ultrafast dynamics taking place at an atomic length scale prior to the permanent sample damage. PMID- 24150310 TI - Diode-pumped continuous wave tunable and graphene Q-switched Tm:LSO lasers. AB - We have investigated the lasing characteristics of Tm:LSO crystal in three operation regimes: continuous wave (CW), wavelength tunable and passive Q switching based on graphene. In CW regime, a maximum output power of 0.65 W at 2054.9 nm with a slope efficiency of 21% was achieved. With a quartz plate, a broad wavelength tunable range of 145 nm was obtained, corresponding to a FWHM of 100 nm. By using a graphene saturable absorber mirror, the passively Q-switched Tm:LSO laser produced pulses with duration of 7.8 MUs at 2030.8 nm under a repetition rate of 7.6 kHz, corresponding to pulse energy of 14.0 MUJ. PMID- 24150311 TI - 217 km long distance photon-counting optical time-domain reflectometry based on ultra-low noise up-conversion single photon detector. AB - We demonstrate a photon-counting optical time-domain reflectometry with 42.19 dB dynamic range using an ultra-low noise up-conversion single photon detector. By employing the long-wave pump technique and a volume Bragg grating, we achieve a noise equivalent power of -139.7 dBm/?Hz for our detector. We perform the OTDR experiments using a fiber of length approximate 217 km, and show that our system can identify defects along the entire fiber length in a measurement time of 13 minutes. PMID- 24150312 TI - High-flexibility optical encryption via aperture movement. AB - We present a new method using single-path beam-propagation-based imaging via aperture movement for optical encryption. The aperture is sequentially moved in the transverse domain, and a series of diffraction intensity patterns (i.e., ciphertexts) are correspondingly recorded during optical encryption. An iterative phase retrieval algorithm is applied for the decryption. It is illustrated that the proposed optical security system possesses several significant advantages, such as high flexibility and high security. The proposed optical security system also provides an effective channel to control information assignment and authentication. PMID- 24150313 TI - Non-iterative determination of pattern phase in structured illumination microscopy using auto-correlations in Fourier space. AB - The artefact-free reconstruction of structured illumination microscopy images requires precise knowledge of the pattern phases in the raw images. If this parameter cannot be controlled precisely enough in an experimental setup, the phases have to be determined a posteriori from the acquired data. While an iterative optimisation based on cross-correlations between individual Fourier images yields accurate results, it is rather time-consuming. Here I present a fast non-iterative technique which determines each pattern phase from an auto correlation of the respective Fourier image. In addition to improving the speed of the reconstruction, simulations show that this method is also more robust, yielding errors of typically less than lambda/500 under realistic signal-to-noise levels. PMID- 24150314 TI - Four-domain dual-combination operation invariance and time reversal symmetry of electromagnetic fields. AB - Current experimental investigations about time reversal (TR) electromagnetic (EM) fields always depended on TR mirror (TRM). However, EM fields can perform reversal operation invariance in four domains connected by Fourier Transform. A multiplication table and an appropriate operating figure about EM fields' invariance are derived to describe a series of dual combined operations in the four domains, in which there are at least 10 dual-combination operations different from current TRM operations which can equivalently actualize TR symmetry. Theoretically, centrosymmetric operations of spatial position vector and spatial spectrum vector may have the potential to promote different reversal mirrors. PMID- 24150315 TI - Laser-induced cooling of a Yb:YAG crystal in air at atmospheric pressure. AB - We report for the first time the experimental demonstration of optical cooling of a bulk crystal at atmospheric pressure. The use of a fiber Bragg grating (FBG) sensor to measure laser-induced cooling in real time is also demonstrated for the first time. A temperature drop of 8.8 K from the chamber temperature was observed in a Yb:YAG crystal in air when pumped with 4.2 W at 1029 nm. A background absorption of 2.9 * 10-4 cm-1 was estimated with a pump wavelength at 1550 nm. Simulations predict further cooling if the pump power is optimized for the sample's dimensions. PMID- 24150316 TI - Refraction effect in an in-plane-switching blue phase liquid crystal cell. AB - We develop a refraction model to analyze the electro-optic effects of an in-plane switching blue phase liquid crystal (IPS-BPLC) cell. Good agreement with experiment is obtained. Based on this model, we optimize the parameters affecting the electro-optics of IPS-BPLC, such as electrode dimension, saturated induced birefringence, saturation electric field, and cell gap. An IPS-BPLC with low operation voltage (<10V(rms)) and high transmittance (~80%) with single gamma curve can be achieved by optimizing the BPLC material and device structure. PMID- 24150317 TI - Fabry-Perot enhanced Faraday rotation in graphene. AB - We demonstrate that giant Faraday rotation in graphene in the terahertz range due to the cyclotron resonance is further increased by constructive Fabry-Perot interference in the supporting substrate. Simultaneously, an enhanced total transmission is achieved, making this effect doubly advantageous for graphene based magneto-optical applications. As an example, we present far-infrared spectra of epitaxial multilayer graphene grown on the C-face of 6H-SiC, where the interference fringes are spectrally resolved and a Faraday rotation up to 0.15 radians (9 degrees ) is attained. Further, we discuss and compare other ways to increase the Faraday rotation using the principle of an optical cavity. PMID- 24150318 TI - Doping concentration induced phase transition in Eu3+-doped beta-PbF2 nano particles. AB - Europium doped beta-PbF2 nano-particles with different doping concentration are prepared to investigate the site structure of Eu3+ dopants. It is concluded that the site symmetry of Eu3+ dopants in beta-PbF2 nano-particles lowers from O(h)to D(4h) with the increase of doping concentration. By X-ray diffraction analysis and photoluminescence spectroscopy study, a doping concentration induced phase transition from lowly doped cubic Pb3EuF9 to highly doped tetragonal PbEuF5 is detected. The intermediate phase of moderately doped nano-particles, which contains both phases mentioned above, is observed for the first time. Moreover, the temperature-dependent intermediate phase analysis suggests that the tetragonal phase is more stable than the cubic phase, which is also confirmed by the first-principle calculations. Our results suggest that the doping concentration induced phase transition in beta-PbF2 nano-particles can be used for understanding other Lanthanide-doped nano-particle systems. PMID- 24150319 TI - Partially scanned interferogram methodology applied to IASI for the retrieval of CO, CO2, CH4 and N2O. AB - The technique of partially scanned interferograms is applied to the retrieval of trace gases from Infrared Atmospheric Sounding Interferometer (IASI) observations. For the specific case of CO, CO2, CH4 and N2O, we show that this methodology allows us to retrieve trace gases column abundances at an unprecedented accuracy at the level of the single IASI footprint. The technique consists in transforming the IASI spectra back to the interferogram domain where we identify small regions that are mostly sensitive to single gas species. The retrieval is then performed by directly applying Least Squares estimation to these small segments of interferometric radiances. One of the main advantages of the technique is that it allows the efficient use of the information contained in all the IASI channels that are available in the absorption bands of a specific gas species. The retrieval technique has been applied to IASI radiances measured over the Mediterranean sea during the month of July 2010, one of the hottest months on record. Results have been validated against ground-based measurements. We have also carried out a comparison with Atmospheric Infrared Radiometer Sounder data and IASI retrievals obtained with usual variational approaches in the spectral domain. PMID- 24150320 TI - Phase-stabilization of the carrier-envelope-offset frequency of a SESAM modelocked thin disk laser. AB - We phase-stabilized the carrier-envelope-offset (CEO) frequency of a SESAM modelocked Yb:CaGdAlO4 (CALGO) thin disk laser (TDL) generating 90-fs pulses at a center wavelength of 1051.6 nm and a repetition rate of 65 MHz. By launching only 2% of its output power into a photonic crystal fiber, we generated a coherent octave-spanning supercontinuum spectrum. Using a standard f-to-2f interferometer for CEO detection, we measured CEO beats with 33 dB signal-to-noise ratio in 100 kHz resolution bandwidth. We achieved a tight lock of the CEO frequency at 26.18 MHz by active feedback to the pump current. The residual in-loop integrated phase noise is 120 mrad (1 Hz-1 MHz). This is, to our knowledge, the first CEO stabilized SESAM modelocked TDL. Our results show that a reliable lock of the CEO frequency can be achieved using standard techniques in spite of the strongly spatially multimode pumping scheme of TDLs. This opens the door towards fully stabilized low-noise frequency combs with hundreds of watts of average power from table-top SESAM modelocked thin disk oscillators. PMID- 24150321 TI - Scattering of multi-Gaussian Schell-model beams on a random medium. AB - Using the angular spectrum representation of plane waves, we investigate the scattering of multi-Gaussian Schell-model (MGSM) beams from a random medium within the accuracy of the first-order Born approximation. The far-zone properties, including the normalized spectral density and the spectral degree of coherence, are discussed. It is shown that the normalized spectral density and the spectral degree of coherence are influenced by the boundary of the beam profile (i.e., M), the transverse beam width, the correlation width of the source, and the properties of the scatterer. PMID- 24150322 TI - Stepwise synthesis of cubic Au-AgCdS core-shell nanostructures with tunable plasmon resonances and fluorescence. AB - Cubic Au-AgCdS core-shell nanostructures were synthesized through cation exchange method assisted by tributylphosphine (TBP) as a phase-transfer agent. Among intermediate products, Au-Ag core-shell nanocubes exhibited many high-order plasmon resonance modes related to the special cubic shape, and these plasmon bands red-shifted along with the increasing of particle size. The plasmon band of Au core first red-shifted and broadened at the step of Au-Ag2S and then blue shifted and narrowed at the step of Au-AgCdS. Since TBP was very crucial for the efficient conversion from Ag2S to CdS, we found that both absorption and fluorescence of the final products could be controlled by TBP. PMID- 24150323 TI - Correction of rotational inaccuracy in lateral shearing interferometry for freeform measurement. AB - A lateral shearing interferometer has an advantage over previous wavefront measuring interferometers since it requires no reference. Therefore the lateral shearing interferometer can be a powerful solution to measure a freeform surface. It, however, has some issues to be resolved before it can be implemented. One of them is the orthogonality problem between two shearing directions in LSI. Previous wavefront reconstruction algorithms assume that the shearing directions are perfectly orthogonal to each other and lateral shear is obtained simultaneously in the sagittal and tangential directions. For practical LSI, however, there is no way to guarantee perfect orthogonality between two shearing directions. Motivated by this, we propose a new algorithm that is able to compensate the rotational inaccuracy. The mathematical model is derived in this paper. Computer simulations and experiments are also displayed to verify our algorithm. PMID- 24150324 TI - Modal liquid crystal array of optical elements. AB - In this study, a novel liquid crystal array based on modal control principle is proposed and demonstrated. The advanced device comprises a six striped electrode structure that forms a configurable 2D matrix of optical elements. A simulation program based on the Frank-Oseen equations and modal control theory has been developed to predict the device electrooptic response, that is, voltage distribution, interference pattern and unwrapped phase. A low-power electronics circuit, that generates complex waveforms, has been built for driving the device. A combined variation of the waveform amplitude and phase has provided a high tuning versatility to the device. Thus, the simulations have demonstrated the generation of a liquid crystal prism array with tunable slope. The proposed device has also been configured as an axicon array. Test measurements have allowed us to demonstrate that electrooptic responses, simulated and empirical, are fairly in agreement. PMID- 24150326 TI - Tunable, continuous-wave, ultraviolet source based on intracavity sum-frequency generation in an optical parametric oscillator using BiB3O6. AB - We report a continuous-wave (cw) source of tunable radiation across 333-345 nm in the ultraviolet (UV) using bismuth triborate, BiB3O6 (BIBO) as the nonlinear gain material. The source is based on internal sum-frequency-generation (SFG) in a cw singly-resonant optical parametric oscillator (OPO) pumped at 532 nm. The compact tunable source employs a 30-mm-long MgO:sPPLT crystal as the OPO gain medium and a 5-mm-long BIBO crystal for intracavity SFG of the signal and pump, providing up to 21.6 mW of UV power at 339.7 nm, with >15 mW over 64% of the SFG tuning range. The cw OPO is also tunable across 1158-1312 nm in the idler, delivering as much as 1.7 W at 1247 nm, with >1W over 65% of the tuning range. The UV output at maximum power exhibits passive power stability better than 3.4% rms and frequency stability of 193 GHz over more than one minute. PMID- 24150325 TI - Analysis of cellular objects through diffraction images acquired by flow cytometry. AB - It was found that the diffraction images acquired along the side scattering directions with objects in a cell sample contain pattern variations at both the global and local scales. We show here that the global pattern variation is associated with the categorical size and morphological heterogeneity of the imaged objects. An automated image processing method has been developed to separate the acquired diffraction images into three types of global patterns. Combined with previously developed method for quantifying local texture pattern variations, the new method allows fully automated analysis of diffraction images for rapid and label-free classification of cells according to their 3D morphology. PMID- 24150327 TI - Precise shaping of laser light by an acousto-optic deflector. AB - We present a laser beam shaping method using acousto-optic deflection of light and discuss its application to dipole trapping of ultracold atoms. By driving the acousto-optic deflector with multiple frequencies, we generate an array of overlapping diffraction-limited beams that combine to form an arbitrary-shaped smooth and continuous trapping potential. Confinement of atoms in a flat-bottomed potential formed by a laser beam with uniform intensity over its central region confers numerous advantages over the harmonic confinement intrinsic to Gaussian beam dipole traps and many other trapping schemes. We demonstrate the versatility of this beam shaping method by generating potentials with large flat-topped regions as well as intensity patterns that compensate for residual external potentials to create a uniform background to which the trapping potential of experimental interest can be added. PMID- 24150328 TI - Performance improvement of transparent germanium-gallium-sulfur glass ceramic by gold doping for third-order optical nonlinearities. AB - Transparent chalcogenide glass ceramics were prepared by thermally treating gold doped germanium-gallium-sulfur glass. The gold, as nucleating agents, modified the crystallization process of the glass, resulting in the formation of nanocrystals belonging to a single alpha-Ga2S3 phase. The crystalline grains increased in number with the treatment duration while their size remained constant, leading to a high infrared transmittance of the glass ceramics. Z-scan measurements revealed the performance improvement of the alpha-Ga2S3 nanocrystals to third-order optical nonlinearities. PMID- 24150329 TI - Plane wave excitation-detection of non-resonant plasmons along finite-width graphene strips. AB - An approach to couple free-space waves and non-resonant plasmons propagating along graphene strips is proposed based on the periodic modulation of the graphene strip width. The solution is technologically very simple, scalable in frequency, and provides customized coupling angle and intensity. Moreover, the coupling properties can be dynamically controlled at a fixed frequency via the graphene electrical field effect, enabling advanced and flexible plasmon excitation-detection strategies. We combine a previously derived scaling law for graphene strips with leaky-wave theory borrowed from microwaves to achieve rigorous and efficient modeling and design of the structure. In particular we analytically derive its dispersion, predict its coupling efficiency and radiated field structure, and design strip configurations able to fulfill specific coupling requirements. The proposed approach and developed methods are essential to the recent and fundamental problem of the excitation-detection of non-resonant plasmons propagating along a continuous graphene strip, and could pave the way to smart all-graphene sensors and transceivers. PMID- 24150330 TI - Coherent digital demodulation of single-camera N-projections for 3D-object shape measurement: co-phased profilometry. AB - Fringe projection profilometry is a well-known technique to digitize 3 dimensional (3D) objects and it is widely used in robotic vision and industrial inspection. Probably the single most important problem in single-camera, single projection profilometry are the shadows and specular reflections generated by the 3D object under analysis. Here a single-camera along with N-fringe-projections is (digital) coherent demodulated in a single-step, solving the shadows and specular reflections problem. Co-phased profilometry coherently phase-demodulates a whole set of N-fringe-pattern perspectives in a single demodulation and unwrapping process. The mathematical theory behind digital co-phasing N-fringe-patterns is mathematically similar to co-phasing a segmented N-mirror telescope. PMID- 24150331 TI - Self-referenced characterization of femtosecond laser pulses by chirp scan. AB - We investigate a variant of the d-scan technique, an intuitive pulse characterization method for retrieving the spectral phase of ultrashort laser pulses. In this variant a ramp of quadratic spectral phases is applied to the input pulses and the second harmonic spectra of the resulting pulses are measured for each chirp value. We demonstrate that a given field envelope produces a unique and unequivocal chirp-scan map and that, under some asymptotic assumptions, both the spectral amplitude and phase of the measured pulse can be retrieved analytically from only two measurements. An iterative algorithm can exploit the redundancy of the information contained in the chirp-scan map to discard experimental noise, artifacts, calibration errors and improve the reconstruction of both the spectral intensity and phase. This technique is compared to two reference characterization techniques (FROG and SRSI). Finally, we perform d-scan measurements with a simple grating-pair compressor. PMID- 24150332 TI - Low drive voltage optical phase modulator with novel InGaAlAs/InAlAs multiple quantum-barrier based n-i-n heterostructure. AB - An optical phase modulator based on novel n-i-n InGaAlAs/InAlAs multiple-quantum barrier (MQBs) is proposed to reduce the waveguide loss and enhance the modulation efficiency. Efficient bias loading with low leakage current is realized by taking advantages of the large conduction band discontinuity in InGaAlAs/InAlAs heterostructure and high electron reflection by MQBs. Low optical transmission loss of 2.3 dB/cm and improved modulation performance with a voltage length product of 1.06 V?cm are demonstrated for TE mode at 1550 nm. The linear and quadratic electro-optic coefficients of the fabricated device are estimated to be 1.0 pm/V and 1.4 * 10-19 m2/V2, respectively. PMID- 24150333 TI - Femtosecond pulses from a modelocked integrated external-cavity surface emitting laser (MIXSEL). AB - Novel surface-emitting optically pumped semiconductor lasers have demonstrated >1 W modelocked and >100 W continuous wave (cw) average output power. The modelocked integrated external-cavity surface emitting laser (MIXSEL) combines the gain of vertical-external-cavity surface-emitting lasers (VECSELs) with the saturable absorber of a semiconductor saturable absorber mirror (SESAM) in one single semiconductor structure. This unique concept allows for stable and self-starting passive modelocking in a simple straight cavity. With quantum-dot based absorbers, record-high average output power was demonstrated previously, however the pulse duration was limited to 17 ps so far. Here, we present the first femtosecond MIXSEL emitting pulses with a duration as short as 620 fs at 4.8 GHz repetition rate and 101 mW average output power. The novel MIXSEL structure relies on a single low temperature grown quantum-well saturable absorber with a low saturation fluence and fast recovery dynamics. A detailed characterization of the key modelocking parameters of the absorber and the challenges for absorber integration into the MIXSEL structure are discussed. PMID- 24150334 TI - Compact dual-band circular polarizer using twisted Hilbert-shaped chiral metamaterial. AB - We propose a kind of chiral metamaterial inspired from the fractal concept. The Hilbert fractal perturbation in the twisted split ring resonator element results in compact metamaterial and breaking mirror symmetry, which readily forms chirality over triple bands. The discrepancy between co-polarization conversion and cross-polarization conversion over multiple bands can be explored for multifunctional devices. A multiband circular polarizer is then numerically and experimentally studied in the X band based on the bilayered twisted Hilbert resonator with mutual 90 degrees rotation. The ability of transforming linearly polarized incident waves to circularly polarized waves is unambiguously demonstrated with high conversion efficiency and large polarization extinction ratio of more than 20 dB across dual bands. Moreover, exceptionally strong optical activity and circular dichroism are also observed. PMID- 24150335 TI - High temperature stable PbS quantum dots. AB - For the fabrication of nanoparticle containing optical fibers by melt and draw technique, nanoparticle stability at high temperatures is a requirement. We report the synthesis of quantum dots at temperatures as high as 1000 degrees C, compatible with fiber drawing, stabilized for the first time by a prior low temperature heating step. It is observed that quantum dots formed by this two step heating leads to a better emission stability at high powers associated with a reversible phenomenon, making these nanomaterials suitable for further technological applications. PMID- 24150336 TI - Spectral variability of sea surface skylight reflectance and its effect on ocean color. AB - In this study, sea surface skylight spectral reflectance rho(lambda) was retrieved by means of the non-linear spectral optimization method and a bio optical model. The spectral variability of rho(lambda) was found to be mainly influenced by the uniformity of the incident skylight, and a model is proposed to predict the rho(lambda) spectral dependency based on skylight reflectance at 750 nm. It is demonstrated that using the spectrally variable rho(lambda), rather than a constant, yields an improved agreement between the above-water remote sensing reflectance R(rs)(lambda) estimates and concurrent profiling ones. The findings of this study highlight the necessity to re-process the relevant historical above-water data and update ocean color retrieval algorithms accordingly. PMID- 24150337 TI - Stress distribution around femtosecond laser affected zones: effect of nanogratings orientation. AB - Under certain exposure conditions, femtosecond lasers create nanogratings in the bulk of fused silica for which the orientation is governed by the laser polarization. Such nanostructure induces stress that affects optical and chemical properties of the material. Here, we present a method based on optical retardance measurement to quantify the stress around laser affected zones. Further, we demonstrate stress dependence on the nanogratings orientation and we show that the stress within single nanogratings lamellae can locally be as high as several gigapascals. PMID- 24150338 TI - Phase locking in a Nd:YVO4 waveguide laser array using Talbot cavity. AB - We demonstrated phase-locking in a laser-diode-array-pumped Nd:YVO4 laser array (15 emitters) using a Talbot cavity. The Nd:YVO4 slab crystal was coated by dielectric material for claddings and formed a planar waveguide for the vertical mode. To stabilize the horizontal array mode, periodical thermal lenses were generated by controlling the heat flow. The phase-locked waveguide array generated 1.65-W output power, while 2.02 W was available in a standard cavity. Two-peak supermode was demonstrated with the Talbot cavity and was converted to a single peak with a spatial light modulator. We also experimentally and numerically analyzed the characteristics of Talbot phase-locking. PMID- 24150339 TI - Field trial of automatic bias control scheme for optical IQ modulator and demodulator with directly detected 112 Gb/s DQPSK Signal. AB - When optical transceivers employing in-phase and quadrature (IQ) modulators and demodulator are used in real transmission systems, it is very important to search optimum bias points and to prevent bias drift from their optimal points due to of temperature variation, stress, or device aging. We demonstrate a simple and cost effective automatic bias control scheme for optical IQ modulator and demodulator based on RF power and peak voltage detection. The principle of control scheme and effects of bias voltage on monitoring parameters are presented. The dynamic performance of the control scheme, effects of optical signal-to-noise ratio (OSNR) of signal, and effects of temperature variation are also evaluated. For the evaluation of bias control scheme at real-environment, we implement the automatic bias control scheme in 112 Gb/s dual carrier-differential QPSK (DC DQPSK) transceiver, and investigate its long-term stability performances in a field transmission experiment over 797-km of installed fiber and ROADM. PMID- 24150340 TI - 3D-PSTD simulation and polarization analysis of a light pulse transmitted through a scattering medium. AB - A tridimensional pseudo-spectral time domain (3D-PSTD) algorithm, that solves the full-wave Maxwell's equations by using Fourier transforms to calculate the spatial derivatives, has been applied to determine the time characteristics of the propagation of electromagnetic waves in inhomogeneous media. Since the 3D simulation gives access to the full-vector components of the electromagnetic fields, it allowed us to analyse the polarization state of the scattered light with respect to the characteristics of the scattering medium and the polarization state of the incident light. We show that, while the incident light is strongly depolarized on the whole, the light that reaches the output face of the scattering medium is much less depolarized. This fact is consistent with our recently reported experimental results, where a rotation of the polarization does not preclude the restoration of an image by phase conjugation. PMID- 24150341 TI - Spectrally-spatial fourier-holography. AB - We propose a novel method to obtain non-lens holographic images of micro-objects in white light with diffraction limit quality, based on fourier-spectroscopy principles. We developed a simple method for numerical acquisition of digital holograms of micro-objects at any spectral component from the set of two dimensional interferograms, registered by fourier-spectrometer. In our experiments we used spectrally-spatial holographic fourier-spectrometer (SSHFS), equipped with supercontinuum light source and CCD camera for registration. Holographic images of several test objects acquired experimentally at different spectral components are presented. Visualization of local spatially-spectral inhomogeneities of micro-objects is discussed through the example of silver berry scaly hair sample. PMID- 24150342 TI - Influence of generalized focusing of few-cycle Gaussian pulses in attosecond pulse generation. AB - In contrast to the case of quasi-monochromatic waves, a focused optical pulse in the few-cycle limit may exhibit two independent curved wavefronts, associated with phase and group retardations, respectively. Focusing optical elements will generally affect these two wavefronts differently, thus leading to very different behavior of the pulse near focus. As limiting cases, we consider an ideal diffractive lens introducing only phase retardations and a perfect non-dispersive refractive lens (or a curved mirror) introducing equal phase and group retardations. We study the resulting diffraction effects on the pulse, finding both strong deformations of the pulse shape and shifts in the spectrum. We then show how important these effects can be in highly nonlinear optics, by studying their role in attosecond pulse generation. In particular, the focusing effects are found to affect substantially the generation of isolated attosecond pulses in gases from few-cycle fundamental optical fields. PMID- 24150343 TI - One dimensional spatial localization of polychromatic stationary wave-packets in normally dispersive media. AB - In this paper we illustrate how the localization of the stationary two dimensional solution of the propagation equation strongly depends on the features of its spatio-temporal spectral bandwidth. We especially investigate the role of the ultra-broad temporal support and of the spatial bandwidth of the spectrum on the high localization in one spatial dimension of "Bessel-like" or "blade-like" beams, quasi-stationarily propagating in normally dispersive materials, and potentially interesting for microfabrication applications. PMID- 24150344 TI - Femtosecond spatial pulse shaping at the focal plane. AB - Spatial shaping of ultrashort laser beams at the focal plane is theoretically analyzed. The description of the pulse is performed by its expansion in terms of Laguerre-Gaussian orthonormal modes. This procedure gives both a comprehensive interpretation of the propagation dynamics and the required signal to encode onto a spatial light modulator for spatial shaping, without using iterative algorithms. As an example, pulses with top-hat and annular spatial profiles are designed and their dynamics analyzed. The interference of top-hat pulses is also investigated finding potential applications in high precision pump-probe experiments (without using delay lines) and for the creation of subwavelength ablation patterns. In addition, a novel class of ultrashort pulses possessing non stationary orbital angular momentum is also proposed. These exotic pulses provide additional degrees of freedom that open up new perspectives in fields such as laser-matter interaction and micro-machining. PMID- 24150345 TI - The contribution of nonlocal electro-opto-thermal interaction to single molecule nonlinear Raman enhancement. AB - we develop a precise modelling where nonlocal electro-opto-thermal interactions are comprehensively included for the analysis of nonlinear Raman enhancement and plasmonic heating. An interaction enhancement factor G(IEF) is introduced to quantify the coupling between the electromagnetic field and the temperature field which is rarely considered in the estimation of Raman enhancement. For the case of isolated single nanosphere, G(IEF) can be up to ten, indicating a thermal origin which well explains the observed temperature rise, shortened blinking period, and the nonlinearly enhanced Raman cross-section. For the case of nanodimer, the suppression of plasmon heating was analyzed, demonstrating the great capability to mitigate biomolecular degradation and blinking. PMID- 24150346 TI - Manipulation of dark photonic angular momentum states via magneto-optical effect for tunable slow-light performance. AB - We propose a novel scheme in realizing tunable slow-light performance by manipulating dark photonic angular momentum states (PAMSs) in metamaterials via the magneto-optical effect. We show that by applying a static magnetic field B, some pairs of sharp transmission dips can be observed in the background transparency window of a complex metamaterial design. Each pair of transmission dips are related to the excitation of dark PAMSs with opposite topological charges -m and +m, with a lifted degeneracy due to the classic analogue of Zeeman effect. Nonreciprocal characteristics can be observed in the distributions of field amplitude and transverse energy flux. The performance of slow light, including the group index ng, its abnormal feature, the associated strong absorption and the dependence with B are also discussed. PMID- 24150347 TI - Experimental demonstration of using divergence cost-function in SPGD algorithm for coherent beam combining with tip/tilt control. AB - A novel approach of tip/tilt control by using divergence cost function in stochastic parallel gradient descent (SPGD) algorithm for coherent beam combining (CBC) is proposed and demonstrated experimentally in a seven-channel 2-W fiber amplifier array with both phase-locking and tip/tilt control, for the first time to our best knowledge. Compared with the conventional power-in-the-bucket (PIB) cost function for SPGD optimization, the tip/tilt control using divergence cost function ensures wider correction range, automatic switching control of program, and freedom of camera's intensity-saturation. Homemade piezoelectric-ring phase modulator (PZT PM) and adaptive fiber-optics collimator (AFOC) are developed to correct piston- and tip/tilt-type aberrations, respectively. The PIB cost function is employed for phase-locking via maximization of SPGD optimization, while the divergence cost function is used for tip/tilt control via minimization. An average of 432-MUrad of divergence metrics in open loop has decreased to 89 MUrad when tip/tilt control implemented. In CBC, the power in the full width at half maximum (FWHM) of the main lobe increases by 32 times, and the phase residual error is less than lambda/15. PMID- 24150348 TI - Single-camera microscopic stereo digital image correlation using a diffraction grating. AB - A simple, cost-effective but practical microscopic 3D-DIC method using a single camera and a transmission diffraction grating is proposed for surface profile and deformation measurement of small-scale objects. By illuminating a test sample with quasi-monochromatic source, the transmission diffraction grating placed in front of the camera can produce two laterally spaced first-order diffraction views of the sample surface into the two halves of the camera target. The single image comprising negative and positive first-order diffraction views can be used to reconstruct the profile of the test sample, while the two single images acquired before and after deformation can be employed to determine the 3D displacements and strains of the sample surface. The basic principles and implementation procedures of the proposed technique for microscopic 3D profile and deformation measurement are described in detail. The effectiveness and accuracy of the presented microscopic 3D-DIC method is verified by measuring the profile and 3D displacements of a regular cylinder surface. PMID- 24150349 TI - Corrections to the knife-edge based reconstruction scheme of tightly focused light beams. AB - The knife-edge method is an established technique for profiling light beams. It was shown, that this technique even works for tightly focused beams, if the material and geometry of the probing knife-edges are chosen carefully. Furthermore, it was also reported recently that this method fails, when the knife edges are made from pure materials. The artifacts introduced in the reconstructed beam shape and position depend strongly on the edge and input beam parameters, because the knife-edge is excited by the incoming beam. Here we show, that the actual beam shape and spot size of tightly focused beams can still be derived from knife-edge measurements for pure edge materials and different edge thicknesses by adapting the analysis method of the experimental data taking into account the interaction of the beam with the edge. PMID- 24150350 TI - Using optoacoustic imaging for measuring the temperature dependence of Gruneisen parameter in optically absorbing solutions. AB - Gruneisen parameter is a key temperature-dependent physical characteristic responsible for thermoelastic efficiency of materials. We propose a new methodology for accurate measurements of temperature dependence of Gruneisen parameter in optically absorbing solutions. We use two-dimensional optoacoustic (OA) imaging to improve accuracy of measurements. Our approach eliminates contribution of local optical fluence and absorbance. To validate the proposed methodology, we studied temperature dependence of aqueous cupric sulfate solutions in the range from 22 to 4 degrees C. Our results for the most diluted salt perfectly matched known temperature dependence for the Gruneisen parameter of water. We also found that Gruneisen-temperature relationship for cupric sulfate exhibits linear trend with respect to the concentration. In addition to accurate measurements of Gruneisen changes with temperature, the developed technique provides a basis for future high precision OA temperature monitoring in live tissues. PMID- 24150351 TI - Spontaneous picosecond pulse generation in a diode-pumped Nd:YAP laser. AB - We present the first observation, to the best of our knowledge, the spontaneous generation of picoseconds pulse trains in a diode-pumped Nd:YAP laser with gigahertz repetition rate. Spatially dependent temporal dynamics were experimentally observed. After theoretically reconstruct the experimental temporal-resolved patterns, we verify that the complicated spatially-dependent temporal dynamics were originated from simultaneous coherent locking combination of fundamental and several additional higher-order transverse modes. PMID- 24150352 TI - Photon-number squeezing with a noisy femtosecond fiber laser amplifier source using a collinear balanced detection technique. AB - We experimentally demonstrate photon-number squeezing at 1.55 MUm using a noisy erbium-doped fiber amplifier (EDFA). We employ a collinear balanced detection (CBD) technique, where the intensity noise at a specific radio frequency is canceled between two pulse trains. In spite of substantially large excess noise (>10 dB) in an EDFA due to amplified spontaneous emission, we successfully cancel the intensity noise and achieve a shot noise limit at a specific radio frequency with the CBD technique. We exploit two sets of fiber polarization interferometers to generate squeezed light and observe a maximal photon-number squeezing of -2.6 dB. PMID- 24150353 TI - Solar-Pumped TEM00 Mode Nd:YAG laser. AB - Here we show a significant advance in solar-pumped laser beam brightness by utilizing a 1.0 m diameter Fresnel lens and a 3 mm diameter Nd:YAG single-crystal rod. The incoming solar radiation is firstly focused by the Fresnel lens on a solar tracker. A large aspheric lens and a 2D-CPC concentrator are then combined to further compress the concentrated solar radiation along the thin laser rod within a V-shaped pumping cavity. 2.3 W cw TEM00 (M2 <= 1.1) solar laser power is finally produced, attaining 1.9 W laser beam brightness figure of merit, which is 6.6 times higher than the previous record. For multimode operation, 8.1 W cw laser power is produced, corresponding to 143% enhancement in collection efficiency. PMID- 24150354 TI - Mode multi/demultiplexer based on cascaded asymmetric Y-junctions. AB - A mode-(de)multiplexer with low loss and large spectral bandwidth is proposed. The device is designed by utilizing a structure with cascaded asymmetric Y junctions. By carefully controlling the widths of the wide and narrow arms of the Y-junctions, the fundamental mode of a narrow arm excites the higher-order mode of its stem in the multiplexing case, and a high-order mode of the stem separated from other lower-order modes evolves into the fundamental mode of the narrow arm in the demultiplexing case. As an example, a 1 * 4 mode-(de)multiplexer is analyzed by using the beam propagation method. Simulation results show the demultiplexed crosstalk is lower than -21.8 dB, under a common spectral bandwidth of 140 nm. The insertion loss is negligible. PMID- 24150355 TI - Integrated waveguide Bragg gratings for microwave photonics signal processing. AB - Integrated Microwave photonics (IMWP) signal processing using Photonic Integrated Circuits (PICs) has attracted a great deal of attention in recent years as an enabling technology for a number of functionalities not attainable by purely microwave solutions. In this context, integrated waveguide Bragg grating (WBG) devices constitute a particularly attractive approach thanks to their compactness and flexibility in producing arbitrarily defined amplitude and phase responses, by directly acting on coupling coefficient and perturbations of the grating profile. In this article, we review recent advances in the field of integrated WBGs applied to MWP, analyzing the advantages leveraged by an integrated realization. We provide a perspective on the exciting possibilities offered by the silicon photonics platform in the field of MWP, potentially enabling integration of highly-complex active and passive functionalities with high yield on a single chip, with a particular focus on the use of WBGs as basic building blocks for linear filtering operations. We demonstrate the versatility of WBG based devices by proposing and experimentally demonstrating a novel, continuously tunable, integrated true-time-delay (TTD) line based on a very simple dual phase shifted WBG (DPS-WBG). PMID- 24150356 TI - Complete Stokes polarimetry of magneto-optical Faraday effect in a terbium gallium garnet crystal at cryogenic temperatures. AB - We report the complete determination of the polarization changes caused in linearly polarized incident light due to propagation in a magneto-optically active terbium gallium garnet (TGG) single crystal, at temperatures ranging from 6.3 to 300 K. A 28-fold increase in the Verdet constant of the TGG crystal is seen as its temperature decreases to 6.3 K. In contrast with polarimetry of light emerging from a Faraday material at room temperature, polarimetry at cryogenic temperatures cannot be carried out using the conventional fixed polarizer analyzer technique because the assumption that ellipticity is negligible becomes increasingly invalid as temperature is lowered. It is shown that complete determination of light polarization in such a case requires the determination of its Stokes parameters, otherwise inaccurate measurements will result with negative implications for practical devices. PMID- 24150357 TI - A novel planar metamaterial design for electromagnetically induced transparency and slow light. AB - A novel planar plasmonic metamaterial for electromagnetically induced transparency and slow light characteristic is presented in this paper, which consists of nanoring and nanorod compound structures. Two bright modes in the metamaterial are induced by the electric dipole resonance inside nanoring and nanorod, respectively. The coupling between two bright modes introduces transparency window and large group index. By adjusting the geometric parameters of metamaterial structure, the transmittance of EIT window at 385 THz is about 60%, and the corresponding group index and Q factor can reach up to 1.2 * 103 and 97, respectively, which has an important application in slow-light device, active plasmonic switch, SERS and optical sensing. PMID- 24150358 TI - An all-fiber continuously time-dispersion-tuned picosecond optical parametric oscillator at 1 MUm region. AB - We report the experimental demonstration of a fully fiber-integrated picosecond optical parametric oscillator. The gain is provided by a 50-meters homemade photonic crystal fiber in the ring cavity. A time-dispersion-tuned technique is used to allow the oscillator to select the oscillating wavelength adaptively and synchronize with the pump pulse train. The output wavelength of the oscillator can be continuously tuned from 988 to 1046 nm and from 1085 to 1151 nm by adjusting the pump wavelength and the time-dispersion-tuned technique simultaneously. PMID- 24150359 TI - Analog nonlinear MIMO receiver for optical mode division multiplexing transmission. AB - The complexity and the power consumption of digital signal processing are crucial issues in optical transmission systems based on mode division multiplexing and coherent multiple-input multiple-output (MIMO) processing at the receiver. In this paper the inherent characteristic of spatial separation between fiber modes is exploited, getting a MIMO system where joint demultiplexing and detection is based on spatially separated photodetectors. After photodetection, one has a MIMO system with nonlinear crosstalk between modes. The paper shows that the nonlinear crosstalk can be dealt with by a low-complexity and non-adaptive detection scheme, at least in the cases presented in the paper. PMID- 24150360 TI - Self-amplitude and self-phase modulation of the charcoal mode-locked erbium-doped fiber lasers. AB - With the intra-cavity nano-scale charcoal powder based saturable absorber, the 455-fs passive mode-locking of an L-band erbium-doped fiber laser (EDFL) is demonstrated. The size reduction of charcoal nano-particle is implemented with a simple imprinting-exfoliation-wiping method, which assists to increase the transmittance up to 0.91 with corresponding modulation depth of 26%. By detuning the power gain from 17 to 21 dB and cavity dispersion from -0.004 to -0.156 ps2 of the EDFL, the shortening of mode-locked pulsewidth from picosecond to sub picosecond by the transformation of the pulse forming mechanism from self amplitude modulation (SAM) to the combining effect of self-phase modulation (SPM) and group delay dispersion (GDD) is observed. A narrower spectrum with 3-dB linewidth of 1.83-nm is in the SAM case, whereas the spectral linewidth broadens to 5.86 nm with significant Kelly sideband pair can be observed if the EDFL enters into the SPM regime. The mode-locking mechanism transferred from SAM to SPM/GDD dominates the pulse shortening procedure in the EDFL, whereas the intrinsic defects in charcoal nano-particle only affect the pulse formation at initial stage. The minor role of the saturable absorber played in the EDFL cavity with strongest SPM is observed. PMID- 24150361 TI - 10-Gbit/s direct modulation of a TO-56-can packed 600-MUm long laser diode with 2% front-facet reflectance. AB - A 600-MUm long-cavity laser diode with a front-facet reflectance of 2% is demonstrated as a colorless OC-192 transmitter for the future DWDM-PON, which is packed in a TO-56-can package of only 4-GHz frequency bandwidth but can be over bandwidth modulated with 10-Gbit/s non-return-to-zero data-stream. The coherent injection-locking successfully suppresses its side-mode intensity and noise floor level, which further improves its modulation throughput at higher frequencies. With increasing the coherent injection-locking power from -12 to -3 dBm, the side mode suppression ratio significantly increases from 39 to 50 dB, which also suppresses the frequency chirp from -12 to -4 GHz within a temporal range of 150 ps. The dense but weak longitudinal modes (with 0.6-nm spacing) in the long cavity laser diode suppresses to one single-mode in a 100-GHz wide DWDM channel for carrying the OC-192 data at 9.953 Gbit/s. Such an over-bandwidth modulated laser diode still exhibits an on/off extinction ratio of 6.68 dB and a signal-to noise ratio of 4.96 dB, which can provide a back-to-back receiving power sensitivity of -12.2 dBm at BER of 10-9. After 25-km DSF transmission of the OOK data-stream at a bit rate up to 10 Gbit/s, the receiving power sensitivity is 10.1 dBm at a requested BER of 10-9. PMID- 24150362 TI - Ultrabroadband supercontinuum and third-harmonic generation in bulk solids with two optical-cycle carrier-envelope phase-stable pulses at 2 MUm. AB - We report on the generation of ultrabroadband supercontinuum (SC) by filamentation of two optical-cycle, carrier-envelope phase-stable pulses at 2 MUm in fused silica, sapphire, CaF2 and YAG. The SC spectra extend from 450 nm to more than 2500 nm, and their particular shapes depend on dispersive properties of the materials. Prior to spectral super-broadening, we observe third-harmonic generation, which occurs in the condition of large phase and group velocity mismatch and consists of free and driven components. A double-peaked third harmonic structure coexists with the SC pulse as demonstrated by the numerical simulations and verified experimentally. The SC pulses have stable carrier envelope phase with short-term rms fluctuations of ~ 300 mrad, as simultaneously measured in YAG crystal by f-2f and f-3f interferometry, where the latter makes use of intrinsic third-harmonic generation. PMID- 24150363 TI - Measuring the scattering coefficient of turbid media from two-photon microscopy. AB - In this paper, we propose a new and simple method based on two-photon excitation fluorescence (TPEF) microscopy to measure the scattering coefficient u(s) of thick turbid media. We show, from Monte Carlo simulations, that u(s) can be derived from the axial profile of the ratio of the TPEF signals epi-collected by the confocal and the non-descanned ports of a scanning microscope, independently of the anisotropy factor g and of the absorption coefficient u(a) of the medium. The method is validated experimentally on tissue-mimicking optical phantoms, and is shown to have potential for imaging the scattering coefficient of heterogeneous media. PMID- 24150364 TI - Efficient curvilinear coordinate method for grating diffraction simulation. AB - The article presents a new method for rigorous simulation of the light diffraction on one-dimensional gratings. The method is capable to solve metal dielectric structures in linear time and consumed memory with respect to structure complexity. Exceptional performance and convergence for metal gratings are achieved by implementing a curvilinear coordinate transformation into the generalized source method previously developed for dielectric gratings. PMID- 24150365 TI - Complete analog control of the carrier-envelope-phase of a high-power laser amplifier. AB - In this work we demonstrate the development of a complete analog feedback loop for the control of the carrier-envelope phase (CEP) of a high-average power (20 W) laser operating at 10 kHz repetition rate. The proposed method combines a detection scheme working on a single-shot basis at the full-repetition-rate of the laser system with a fast actuator based either on an acousto-optic or on an electro-optic crystal. The feedback loop is used to correct the CEP fluctuations introduced by the amplification process demonstrating a CEP residual noise of 320 mrad measured on a single-shot basis. The comparison with a feedback loop operating at a lower sampling rate indicates an improvement up to 45% in the residual noise. The measurement of the CEP drift for different integration times clearly evidences the importance of the single-shot characterization of the residual CEP drift. The demonstrated scheme could be efficiently applied for systems approaching the 100 kHz repetition rate regime. PMID- 24150366 TI - A lateral optical equilibrium in waveguide-resonator optical force. AB - We consider the lateral optical force between a resonator and a waveguide, and study the possibility of an equilibrium that occurs solely from the optical force in such system. We prove analytically that a single-resonance system cannot give such an equilibrium in the resonator-waveguide force. We then show that two resonance systems can provide such an equilibrium. We provide an intuitive way to predict the existence of an equilibrium, and give numerical examples. PMID- 24150367 TI - Localized enhancement of electric field in tip-enhanced Raman spectroscopy using radially and linearly polarized light. AB - Finite-Difference Time-Domain (FDTD) calculations are used to characterize the electric field in the vicinity of a sharp silver or gold cone with an apex diameter of 10 nm. The simulations are utilized to predict the intensity and the distribution of the locally enhanced electric field in tip-enhanced Raman spectroscopy (TERS). A side-by-side comparison of the enhanced electric field induced by a radially and a linearly polarized light in both gap-mode and conventional TERS setup is performed. For this purpose, a radially polarized source is introduced and integrated into the FDTD modeling. Additionally, the optical effect of a thin protective layer of alumina on the enhancement of the electric field is investigated. PMID- 24150368 TI - Optical limiting effect and ultrafast saturable absorption in a solid PMMA composite containing porphyrin-covalently functionalized multi-walled carbon nanotubes. AB - A versatile solid Poly-methyl-methacrylate (PMMA) composite containing porphyrin covalently functionalized multi-walled carbon nanotubes (MWNTs-TPP) was prepared through free radical polymerization without additional dispersion stabilizer. Using nanosecond, femtosecond pulse Z-scan and degenerate femtosecond pump-probe techniques, we studied the optical limiting effect, ultrafast saturable absorption and transient differential transmission of the composite. Results show that the solid composite exhibits weaker optical limiting effects than that of the suspension at 532 nm under nanosecond pulse, due to the absence of nonlinear scattering mechanism. The composite also shows ultrafast saturable absorption with a relaxation time about 190 fs at 800 nm under femtosecond pulse due to band filling effect, comparably to the suspension. The versatile solid composite can be the candidate for uses in applications of ultrafast optical switching and mode locking element or optical limiter for nanosecond pulse. PMID- 24150369 TI - Lensless zoomable holographic projection using scaled Fresnel diffraction. AB - Projectors require a zoom function. This function is generally realized using a zoom lens module composed of many lenses and mechanical parts; however, using a zoom lens module increases the system size and cost, and requires manual operation of the module. Holographic projection is an attractive technique because it inherently requires no lenses, reconstructs images with high contrast and reconstructs color images with one spatial light modulator. In this paper, we demonstrate a lensless zoomable holographic projection. Without using a zoom lens module, this holographic projection realizes the zoom function using a numerical method, called scaled Fresnel diffraction which can calculate diffraction at different sampling rates on a projected image and hologram. PMID- 24150370 TI - Bleaching-corrected fluorescence microspectroscopy with nanometer peak position resolution. AB - Fluorescence microspectroscopy (FMS) with environmentally sensitive dyes provides information about local molecular surroundings at microscopic spatial resolution. Until recently, only probes exhibiting large spectral shifts due to local changes have been used. For filter-based experimental systems, where signal at different wavelengths is acquired sequentially, photostability has been required in addition. Herein, we systematically analyzed our spectral fitting models and bleaching correction algorithms which mitigate both limitations. We showed that careful analysis of data acquired by stochastic wavelength sampling enables nanometer spectral peak position resolution even for highly photosensitive fluorophores. To demonstrate how small spectral shifts and changes in bleaching rates can be exploited, we analyzed vesicles in different lipid phases. Our findings suggest that a wide range of dyes, commonly used in bulk spectrofluorimetry but largely avoided in microspectroscopy due to the above mentioned restrictions, can be efficiently applied also in FMS. PMID- 24150371 TI - Triple-layer Fabry-Perot absorber with near-perfect absorption in visible and near-infrared regime. AB - A simple absorber design which enables near-perfect absorption in the visible and near-infrared regions is presented. The absorber is an unpatterned metal/dielectric/metal triple-layer, e.g., a 20 nm-thick metal film as the top layer, a 250 nm-thick dielectric film as the middle layer, and a 200 nm-thick metal film as the bottom layer. It was found that the high-efficiency absorption at specific wavelengths is mainly due to the Fabry-Perot (FP) resonances in the dielectric middle layer which result in trapping of the resonant light in the middle layer and thus enhanced absorption efficiency. PMID- 24150372 TI - UV laser interaction with a fluorescent dye solution studied using pulsed digital holography. AB - A frequency tripled Q-switched Nd-YAG laser (wavelength 355 nm, pulse duration 12 ns) has been used to pump Coumarin 153 dye solved in ethanol. Simultaneously, a frequency doubled pulse (532 nm) from the same laser is used to probe the solvent perpendicularly resulting in a gain through stimulated laser induced fluorescence (LIF) emission. The resulting gain of the probe beam is recorded using digital holography by blending it with a reference beam on the detector. Two digital holograms without and with the pump beam were recorded. Intensity maps were calculated from the recorded digital holograms and used to calculate the gain of the probe beam due to the stimulated LIF. In addition numerical data of the local temperature rise was calculated from the corresponding phase maps using Radon inversion. It was concluded that about 15% of the pump beam energy is transferred to the dye solution as heat while the rest is consumed in the radiative process. The results show that pulsed digital holography is a promising technique for quantitative study of fluorescent species. PMID- 24150373 TI - Investigation of local strain distribution and linear electro-optic effect in strained silicon waveguides. AB - We present detailed investigations of the local strain distribution and the induced second-order optical nonlinearity within strained silicon waveguides cladded with a Si3N4 strain layer. Micro-Raman Spectroscopy mappings and electro optic characterization of waveguides with varying width w(WG) show that strain gradients in the waveguide core and the effective second-order susceptibility chi(2)(yyz) increase with reduced w(WG). For 300 nm wide waveguides a mean effective chi(2)(yyz) of 190 pm/V is achieved, which is the highest value reported for silicon so far. To gain more insight into the origin of the extraordinary large optical second-order nonlinearity of strained silicon waveguides numerical simulations of edge induced strain gradients in these structures are presented and discussed. PMID- 24150374 TI - Dynamic modulation of spatially structured polarization fields for real-time control of ultrafast laser-material interactions. AB - The polarization state of an ultrafast laser is dynamically controlled using two Spatial Light Modulators and additional waveplates. Consequently, four states of polarization, linear horizontal and vertical, radial and azimuthal, all with a ring intensity distribution, were dynamically switched at a frequency nu = 12.5 Hz while synchronized with a motion control system. This technique, demonstrated here for the first time, enables a remarkable level of real-time control of the properties of light waves and applied to real-time surface patterning, shows that highly controlled nanostructuring is possible. Laser ablation of Induced Periodic Surface Structures is used to directly verify the state of polarization at the focal plane. PMID- 24150377 TI - Terahertz magnetoplasmon energy concentration and splitting in Graphene PN Junctions. AB - Terahertz plasmons and magnetoplasmons propagating along electrically and chemically doped graphene p-n junctions are investigated. It is shown that such junctions support non-reciprocal magnetoplasmonic modes which get concentrated at the middle of the junction in one direction and split away from the middle of the junction in the other direction under the application of an external static magnetic field. This phenomenon follows from the combined effects of circular birefringence and carrier density non-uniformity. It can be exploited for the realization of plasmonic isolators. PMID- 24150376 TI - Image-inspired 3D multiphoton excited fabrication of extracellular matrix structures by modulated raster scanning. AB - Multiphoton excited photochemistry is a powerful 3D fabrication tool that produces sub-micron feature sizes. Here we exploit the freeform nature of the process to create models of the extracellular matrix (ECM) of several tissues, where the design blueprint is derived directly from high resolution optical microscopy images (e.g. fluorescence and Second Harmonic Generation). To achieve this goal, we implemented a new form of instrument control, termed modulated raster scanning, where rapid laser shuttering (10 MHz) is used to directly map the greyscale image data to the resulting protein concentration in the fabricated scaffold. Fidelity in terms of area coverage and relative concentration relative to the image data is ~95%. We compare the results to an STL approach, and find the new scheme provides significantly improved performance. We suggest the method will enable a variety of cell-matrix studies in cancer biology and also provide insight into generating scaffolds for tissue engineering. PMID- 24150378 TI - Fiber laser pumped high power mid-infrared laser with picosecond pulse bunch output. AB - We report a novel quasi-synchronously pumped PPMgLN-based high power mid-infrared (MIR) laser with picosecond pulse bunch output. The pump laser is a linearly polarized MOPA structured all fiberized Yb fiber laser with picosecond pulse bunch output. The output from a mode-locked seed fiber laser was directed to pass through a FBG reflector via a circulator to narrow the pulse duration from 800 ps to less than 50 ps and the spectral FWHM from 9 nm to 0.15 nm. The narrowed pulses were further directed to pass through a novel pulse multiplier through which each pulse was made to become a pulse bunch composing of 13 sub-pulses with pulse to pulse time interval of 1.26 ns. The pulses were then amplified via two stage Yb fiber amplifiers to obtain a linearly polarized high average power output up to 85 W, which were then directed to pass through an isolator and to pump a PPMgLN-based optical parametric oscillator via quasi-synchronization pump scheme for ps pulse bunch MIR output. High MIR output with average power up to 4 W was obtained at 3.45 micron showing the feasibility of such pump scheme for ps pulse bunch MIR output. PMID- 24150379 TI - Size-controllable nanopyramids photonic crystal selectively grown on p-GaN for enhanced light-extraction of light-emitting diodes. AB - Size-controllable p-GaN hexagonal nanopyramids (HnPs)-photonic crystal (PhC) structures were selectively grown on flat p-GaN layer for the elimination of total internal reflection of light-emitting diodes (LEDs). The LEDs with HnPs-PhC of 46.3% bottom fill factor (PhC lattice constant is 730 nm) showed an improved light output power by 99.9% at forward current of 350 mA compared to the reference LEDs with flat p-GaN layer. We confirmed the effect of HnPs-PhC with different bottom fill factors and the effect of nanopyramid-shaped and nanocolumn shaped PhC on the light-extraction of LEDs was also investigated by using three dimensional finite-difference time-domain simulations. PMID- 24150380 TI - Effects of current crowding on light extraction efficiency of conventional GaN based light-emitting diodes. AB - Current crowding effects (CCEs) on light extraction efficiency (LEE) of conventional GaN-based light-emitting diodes (LEDs) are analyzed through Monte Carlo ray-tracing simulation. The non-uniform radiative power distribution of the active layer of the Monte Carlo model is obtained based on the current spreading theory and rate equation. The simulation results illustrate that CCE around n-pad (n-CCE) has little effect on LEE, while CCE around p-pad (p-CCE) results in a notable LEE droop due to the significant absorption of photons emitted under p pad. LEE droop is alleviated by a SiO2 current blocking layer (CBL) and reflective p-pad. Compared to the conventional LEDs without CBL, the simulated LEE of LEDs with CBL at 20 A/cm2 and 70 A/cm2 is enhanced by 7.7% and 19.0%, respectively. It is further enhanced by 7.6% and 11.4% after employing a reflective p-pad due to decreased absorption. These enhancements are in accordance with the experimental results. Output power of LEDs with CBL is enhanced by 8.7% and 18.2% at 20 A/cm2 and 70 A/cm2, respectively. And the reflective p-pad results in a further enhancement of 8.9% and 12.7%. PMID- 24150381 TI - THz phase-contrast computed tomography based on Mach-Zehnder interferometer using continuous wave source: proof of the concept. AB - In this study, we propose a THz computed tomography (CT) method based on phase contrast, which retrieves the phase shift information at each data point through a phase modulation technique using a Mach-Zehnder interferometer with a continuous wave (CW) source. The THz CT is based on first-generation CT, which acquires a set of projections by translational and rotational scans using a thin beam. From the phase-shift projections, we reconstruct a spatial distribution of refractive indices in a cross section of interest. We constructed a preliminary system using a highly coherent CW THz source with a frequency of 0.54 THz to prove the concept and performed an imaging experiment using phantoms to investigate its imaging features such as artifact-immune imaging, quantitative measurement, and selective detection. PMID- 24150382 TI - Numerical characterization of an ultra-high NA coherent fiber bundle part II: point spread function analysis. AB - Straightforward numerical integration of the Rayleigh-Sommerfeld diffraction integral (R-SDI) remains computationally challenging, even with today's computational resources. As such, approximating the R-SDI to decrease the computation time while maintaining a good accuracy is still a topic of interest. In this paper, we apply an approximation for the R-SDI that is to be used to propagate the field exiting a Coherent Fiber Bundle (CFB) with ultra-high numerical aperture (0.928) of which we presented the design and modal properties in previous work. Since our CFB has single-mode cores with a diameter (550 nm) smaller than the wavelength (850 nm) for which the CFB was designed, we approximate the highly divergent fundamental modes of the cores with real Dirac delta functions. We find that with this approximation we can strongly reduce the computation time of the R-SDI while maintaining a good agreement with the results of the full R-SDI. Using this approximation, we first determine the Point Spread Function (PSF) for an 'ideal' output field exiting the CFB (identical amplitudes for cores on a perfect hexagonal lattice with the phase of each core determined by the appropriate spherical and tilted plane wave front). Next, we analyze the PSF when amplitude or phase noise is superposed onto this 'ideal' field. We find that even in the presence of these types of noise, the effect on the central peak of PSF is limited. From these types of noise, phase noise is found to have the biggest impact on the PSF. PMID- 24150383 TI - Wave optics theory and 3-D deconvolution for the light field microscope. AB - Light field microscopy is a new technique for high-speed volumetric imaging of weakly scattering or fluorescent specimens. It employs an array of microlenses to trade off spatial resolution against angular resolution, thereby allowing a 4-D light field to be captured using a single photographic exposure without the need for scanning. The recorded light field can then be used to computationally reconstruct a full volume. In this paper, we present an optical model for light field microscopy based on wave optics, instead of previously reported ray optics models. We also present a 3-D deconvolution method for light field microscopy that is able to reconstruct volumes at higher spatial resolution, and with better optical sectioning, than previously reported. To accomplish this, we take advantage of the dense spatio-angular sampling provided by a microlens array at axial positions away from the native object plane. This dense sampling permits us to decode aliasing present in the light field to reconstruct high-frequency information. We formulate our method as an inverse problem for reconstructing the 3-D volume, which we solve using a GPU-accelerated iterative algorithm. Theoretical limits on the depth-dependent lateral resolution of the reconstructed volumes are derived. We show that these limits are in good agreement with experimental results on a standard USAF 1951 resolution target. Finally, we present 3-D reconstructions of pollen grains that demonstrate the improvements in fidelity made possible by our method. PMID- 24150384 TI - High efficiency, monolithic fiber chirped pulse amplification system for high energy femtosecond pulse generation. AB - A novel monolithic fiber-optic chirped pulse amplification (CPA) system for high energy, femtosecond pulse generation is proposed and experimentally demonstrated. By employing a high gain amplifier comprising merely 20 cm of high efficiency media (HEM) gain fiber, an optimal balance of output pulse energy, optical efficiency, and B-integral is achieved. The HEM amplifier is fabricated from erbium-doped phosphate glass fiber and yields gain of 1.443 dB/cm with slope efficiency >45%. We experimentally demonstrate near diffraction-limited beam quality and near transform-limited femtosecond pulse quality at 1.55 um wavelength. With pulse energy >100 uJ and pulse duration of 636 fs (FWHM), the peak power is estimated to be ~160 MW. NAVAIR Public Release Distribution Statement A-"Approved for Public release; distribution is unlimited". PMID- 24150385 TI - Design and analysis of a silicon-based terahertz plasmonic switch. AB - In this paper, a novel terahertz (THz) plasmonic switch is designed and simulated. The device consists of a periodically corrugated n-type doped silicon wafer covered with a metallic layer. Surface plasmon propagation along the structure is controlled by applying a control voltage onto the metal. As will be presented, the applied voltage can effectively alter the width of the depletion layer appeared between the deposited metal and the semiconductor. In this manner, the conductivity of the silicon substrate can be successfully controlled due to the absence of free electrons at the depleted sections. Afterwards, the effectiveness of the proposed plasmonic switch is enhanced by implementing a p(++)-type doped well beneath the metallic indentation edges. Consequently, a P Intrinsic-N diode is formed which can manipulate the plasmon propagation by modifying the electron and hole densities inside the intrinsic area. The simulation results are explained very concisely by the help of scattering matrix formalism. Such a representation is essential as employing the switches in the design of complex plasmonic systems with many interacting parts. PMID- 24150386 TI - FDTD method for laser absorption in metals for large scale problems. AB - The FDTD method has been successfully used for many electromagnetic problems, but its application to laser material processing has been limited because even a several-millimeter domain requires a prohibitively large number of grids. In this article, we present a novel FDTD method for simulating large-scale laser beam absorption problems, especially for metals, by enlarging laser wavelength while maintaining the material's reflection characteristics. For validation purposes, the proposed method has been tested with in-house FDTD codes to simulate p-, s-, and circularly polarized 1.06 MUm irradiation on Fe and Sn targets, and the simulation results are in good agreement with theoretical predictions. PMID- 24150387 TI - Snapshot molecular imaging using coded energy-sensitive detection. AB - We demonstrate a technique for measuring the range-resolved coherent scatter form factors of different objects from a single snapshot. By illuminating the object with an x-ray pencil beam and placing a coded aperture in front of a linear array of energy-sensitive detector elements, we record the coherently scattered x-rays. This approach yields lateral, range, and momentum transfer resolutions of 1 mm, 5 mm, and 0.2 nm-1, respectively, which is sufficient for the distinguishing a variety of solids and liquids. These results indicate a path toward real-time volumetric molecular imaging for non-destructive examination in a variety of applications, including medical diagnostics, quality inspection, and security detection. PMID- 24150388 TI - Time-bin entangled photon pairs from spontaneous parametric down-conversion pumped by a cw multi-mode diode laser. AB - Generation of time-bin entangled photon pairs requires the use of the Franson interferometer which consists of two spatially separated unbalanced Mach-Zehnder interferometers through which the signal and idler photons from spontaneous parametric down-conversion (SPDC) are made to transmit individually. There have been two SPDC pumping regimes where the scheme works: the narrowband regime and the double-pulse regime. In the narrowband regime, the SPDC process is pumped by a narrowband cw laser with the coherence length much longer than the path length difference of the Franson interferometer. In the double-pulse regime, the longitudinal separation between the pulse pair is made equal to the path length difference of the Franson interferometer. In this paper, we propose another regime by which the generation of time-bin entanglement is possible and demonstrate the scheme experimentally. In our scheme, differently from the previous approaches, the SPDC process is pumped by a cw multi-mode (i.e., short coherence length) laser and makes use of the coherence revival property of such a laser. The high-visibility two-photon Franson interference demonstrates clearly that high-quality time-bin entanglement source can be developed using inexpensive cw multi-mode diode lasers for various quantum communication applications. PMID- 24150389 TI - Curved Yb:YAG waveguide lasers, fabricated by femtosecond laser inscription. AB - Straight and s-curve Yb(7%):YAG waveguides have been fabricated with the femtosecond laser writing technique. By employing a novel writing scheme an increase of the refractive index change could be achieved in comparison to waveguides written with the standard procedure. Straight waveguides, fabricated with this scheme, enabled highly efficient Ti:sapphire laser pumped waveguide lasers with slope efficiencies of 79% and output powers of more than 1 W. With slope efficiencies from 50% to 60% for the curved waveguide lasers with radii of curvature of R >= 20 mm the possibility of fs-laser written complex optical devices is demonstrated. PMID- 24150390 TI - Generation and confinement of microwave gas-plasma in photonic dielectric microstructure. AB - We report on a self-guided microwave surface-wave induced generation of ~60 MUm diameter and 6 cm-long column of argon-plasma confined in the core of a hollow core photonic crystal fiber. At gas pressure of 1 mbar, the micro-confined plasma exhibits a stable transverse profile with a maximum gas-temperature as high as 1300 +/- 200 K, and a wall-temperature as low as 500 K, and an electron density level of 1014 cm-3. The fiber guided fluorescence emission presents strong Ar+ spectral lines in the visible and near UV. Theory shows that the observed combination of relatively low wall-temperature and high ionisation rate in this strongly confined configuration is due to an unprecedentedly wide electrostatic space-charge field and the subsequent ion acceleration dominance in the plasma-to gas power transfer. PMID- 24150391 TI - Blue-green emitting microdisks using low-temperature-grown ZnO on patterned silicon substrates. AB - Zinc oxide (ZnO) as an extremely bright emitter is an attractive material for photonic devices. However, devices made of epitaxially grown ZnO are difficult to fabricate due to the lack of selective etching processes. Here, we demonstrate that by a low-temperature growth process on pre-patterned silicon dioxide (SiO2) microdisks (MDs) high quality ZnO resonators are created. The devices exhibit whispering gallery modes (WGMs) over the blue-green part of the visible spectrum with quality factors exceeding Q = 3500, which are among the highest values reported in this material system so far. By deposition of SiO2 capping layers we find an enhanced coupling of the spontaneous emission from the active medium into the MDs, observed by sharp WGMs up to a radial quantum number of N = 3. PMID- 24150392 TI - 85.7 MHz repetition rate mode-locked semiconductor disk laser: fundamental and soliton bound states. AB - Mode-locked optically pumped semiconductor disk lasers (SDLs) are in strong demand for applications in bio-medical photonics, chemistry, space communications and non-linear optics. However, the wider spread of SDLs was constrained as they are operated in high repetition rates above 200 MHz due to short carrier lifetimes in the semiconductors. Here we demonstrate experimentally and theoretically that it is possible to overcome the limitation of fast carrier relaxation and show significant reduction of repetition rate down to 85.7 MHz by exploiting phase-amplitude coupling effect. In addition, a low repetition rate SDL serves as a test-bed for bound soliton state previously unknown for semiconductor devices. The breakthrough to sub-100 MHz repetition rate will open a whole new window of development opportunities. PMID- 24150393 TI - Near-field recording on phase-change nanoparticles and reflective reproduction from nanoantenna utilizing plasmonic resonance for high-density optical memory. AB - For high-density optical memory system, near-field recording on a medium with phase-change nanoparticles and dual metal layers was proposed. A finite difference time domain (FDTD) analysis demonstrated that a combination of a nanoantenna with such a medium so as to enhance plasmonic resonance would enable effective recording with larger (~10 times) working distance (WD) than for a conventional medium. A reproduction method of detecting the intensity of the reflected wave from the nanoantenna was also proposed in the same setup as the recording. We found that plasmonic resonance induced in the nanoantenna was enhanced and the intensity of reflected light was also increased when the phase state of nanoparticle was crystalline. Since the sub-diffraction limited size of nanoantenna is larger than a nanoparticle, the detected signal intensity can be greatly improved. Calculated results showed that our proposed system and methods for recording and reproduction would have a potential to become effective solutions for terabyte-class optical memory system. PMID- 24150394 TI - Effect of the finishing oil of acrylic fibers in the optical rotation of the Raman scattered light. AB - Polarized Raman spectra have been obtained from polyacrylonitrile copolymers fibers with vinyl acetate Poly(AN-co-VA), and methyl acrylate Poly(AN-co-MA) with finishing and without finishing, in order to show the effect of the finishing in the optical rotation of the Raman scattered light. The polarized Raman spectra were used to calculate the depolarization ratios for both fibers. These values reveal that there is antisymmetric Raman scattering in the form of anomalous depolarization for some bands due to a dipolar interaction between the polar headgroup of the finishing with the polar nitrile group of the fiber causing changes in the orientation of fiber polymer chains, or pseudo antisymmetric Raman scattering due to planar hydrocarbons of the oil finishing which are optically active and are aligned when they are applied to the acrylic fibers during the spinning process. Although the finishing should not affect the physical or chemical properties of the fibers, in this work is shown that the finishing could introduce optical activity in the different wavenumbers of the Raman signal and this effect is proportional to the finishing content. According to the results obtained in this work, Raman polarized spectroscopy can provide an express method to identify acrylic fibers with finishing and without finishing agents. PMID- 24150395 TI - Displacement measurement using a wavelength-phase-shifting grating interferometer. AB - A grating interferometer based on the wavelength-modulated phase-shifting method for displacement measurements is proposed. A laser beam with sequential phase shifting can be accomplished using a wavelength-modulated light passing through an unequal-path-length optical configuration. The optical phase of the moving grating is measured by the wavelength-modulated phase-shifting technique and the proposed time-domain quadrature detection method. The displacement of the grating is determined by the grating interferometry theorem with the measured phase variation. Experimental results reveal that the proposed method can detect a displacement up to a large distance of 1 mm and displacement variation down to the nanometer range. PMID- 24150396 TI - Rotatable illusion media for manipulating terahertz electromagnetic waves. AB - Based on composite optical transformation, we propose a rotatable illusion media with positive permittivity and permeability to manipulate terahertz waves, and a new way to realize singular parameter-independent cloaks when the incident wave with a certain width propagates from specific incident directions. The fundamental mechanism of this kind of cloak is that the illusion media can be able to avoid the incident wave interacting with the objects. Comparing with traditional transformation-coordinate-based cloaks such as cylindrical-shaped cloaks, our cloaks are independent of singular material parameters. Furthermore, this type of rotatable illusion media can be applied to design tunable miniaturized high-directivity antenna (a small antenna array covered with the rotatable illusion media appears like a large one and meanwhile, the radiation directions of the small antenna array is tunable via this rotatable illusion media). Full wave simulations are performed to confirm these points. PMID- 24150397 TI - Heterogeneous lithium niobate photonics on silicon substrates. AB - A platform for the realization of tightly-confined lithium niobate photonic devices and circuits on silicon substrates is reported based on wafer bonding and selective oxidation of refractory metals. The heterogeneous photonic platform is employed to demonstrate high-performance lithium niobate microring optical resonators and Mach-Zehnder optical modulators. A quality factor of ~7.2 * 104 is measured in the microresonators, and a half-wave voltage-length product of 4 V.cm and an extinction ratio of 20 dB is measured in the modulators. PMID- 24150398 TI - Combined action of the bound-electron nonlinearity and the tunnel-ionization current in low-order harmonic generation in noble gases. AB - We study numerically low-order harmonic generation in noble gases pumped by intense femtosecond laser pulses in the tunneling ionization regime. We analyze the influence of the phase-mismatching on this process, caused by the generated plasma, and study in dependence on the pump intensity the origin of harmonic generation arising either from the bound-electron nonlinearity or the tunnel ionization current. It is shown that in argon the optimum pump intensity of about 100 TW/cm2 leads to the maximum efficiency, where the main contribution to low order harmonics originates from the bound-electron third and fifth order susceptibilities, while for intensities higher than 300 TW/cm2 the tunnel ionization current plays the dominant role. Besides, we predict that VUV pulses at 133 nm can be generated with relatively high efficiency of about 1.5 * 10-3 by 400 nm pump pulses. PMID- 24150399 TI - Photonic-crystal structures with polarized-wave-guiding property and their applications in the mid and far infrared wave bands. AB - Photonic crystal (PhC) structures with polarized-wave-guiding property (PhC polarization waveguides) are proposed, demonstrated and applied to construct several new kinds of compact and efficient micro polarization devices in the mid and far infrared wave bands, including TE polarizers, TM polarizers, TE-downward T-shaped polarization-beam splitters (PBSs), TM-downward T-shaped PBSs and lying T-shaped PBSs. Theoretical models for the operating mechanism of the structures are presented. The polarization devices built as applications of the PhC polarization waveguides are demonstrated by the finite-element method with the dispersion of materials being considered. Furthermore, optimized parameters are obtained by investigating the extinction ratio (EXR), the degree of polarization (DOP) and insertion loss. Moreover, structures based on PhC slabs derived from the 2D ones, together with woodpile PhC covers and substrates are suggested for the 3D version of the proposed devices for implementation. An example of the 3D version structures shows a performance as good as that of the 2D structure. The devices proposed have relatively wide ranges of operating wavelength. Meanwhile, they are very compact in their structures and convenient for connection or coupling of signals among different optical elements, so they have the potential for wide applications in mid-and-far infrared optical devices or circuits, which are useful in remote sensing, image and vision, positioning and communications with infrared waves. Furthermore, the principle can be applied to build polarizers and PBSs in other wave bands. PMID- 24150400 TI - Optical properties of excitons in metal-insulator-semiconductor nanowires. AB - The theoretical model for the metal-insulator-semiconductor nanowires is established and the optical properties are investigated. The linear absorption of the hybrid excitons, formed due to the exciton-plasmon interaction, shows obvious red shift on the magnitude of several meVs. The mechanism of the red shift is found to be the joint action of the increased excitonic binding energy attributed to the indirect Coulomb interaction and the decreased effective bandgap caused by the additional self-energy potential. The conclusion is also supported by the evolution of the absorption spectra with the adjustable structural parameters. PMID- 24150402 TI - A disappointing reform. PMID- 24150401 TI - Autophagy and oxidative stress in gliomas with IDH1 mutations. AB - IDH1 mutations in gliomas associate with longer survival. Prooxidant and antiproliferative effects of IDH1 mutations and its D-2-hydroxyglutarate (2-HG) product have been described in vitro, but inconsistently observed. It is also unclear whether overexpression of mutant IDH1 in wild-type cells accurately phenocopies the effects of endogenous IDH1-mutations on tumor apoptosis and autophagy. Herein we investigated the effects of 2-HG and mutant IDH1 overexpression on proliferation, apoptosis, oxidative stress, and autophagy in IDH1 wild-type glioma cells, and compared those results with patient-derived tumors. 2-HG reduced viability and proliferation of U87MG and LN18 cells, triggered apoptosis in LN18 cells, and autophagy in U87MG cells. In vitro studies and flank xenografts of U87MG cells overexpressing R132H IDH1 exhibited increased oxidative stress, including increases of both manganese superoxide dismutase (MnSOD) and p62. Patient-derived IDH1-mutant tumors showed no significant differences in apoptosis or autophagy, but showed p62 accumulation and actually trended toward reduced MnSOD expression. These data indicate that mutant IDH1 and 2-HG can induce oxidative stress, autophagy, and apoptosis, but these effects vary greatly according to cell type. PMID- 24150408 TI - Conjugated polymers: Long and winding polymeric roads. PMID- 24150409 TI - Cellular mechanosensing: Sharing the force. PMID- 24150410 TI - Material witness: Improving pore performance. PMID- 24150411 TI - Bioactive hydrogels: Lighting the way. PMID- 24150412 TI - Materials for drug delivery. PMID- 24150413 TI - Strategies for advancing cancer nanomedicine. PMID- 24150414 TI - Translating materials design to the clinic. PMID- 24150415 TI - Delivery materials for siRNA therapeutics. AB - RNA interference (RNAi) has broad potential as a therapeutic to reversibly silence any gene. To achieve the clinical potential of RNAi, delivery materials are required to transport short interfering RNA (siRNA) to the site of action in the cells of target tissues. This Review provides an introduction to the biological challenges that siRNA delivery materials aim to overcome, as well as a discussion of the way that the most effective and clinically advanced classes of siRNA delivery systems, including lipid nanoparticles and siRNA conjugates, are designed to surmount these challenges. The systems that we discuss are diverse in their approaches to the delivery problem, and provide valuable insight to guide the design of future siRNA delivery materials. PMID- 24150416 TI - Engineering synthetic vaccines using cues from natural immunity. AB - Vaccines aim to protect against or treat diseases through manipulation of the immune response, promoting either immunity or tolerance. In the former case, vaccines generate antibodies and T cells poised to protect against future pathogen encounter or attack diseased cells such as tumours; in the latter case, which is far less developed, vaccines block pathogenic autoreactive T cells and autoantibodies that target self tissue. Enormous challenges remain, however, as a consequence of our incomplete understanding of human immunity. A rapidly growing field of research is the design of vaccines based on synthetic materials to target organs, tissues, cells or intracellular compartments; to co-deliver immunomodulatory signals that control the quality of the immune response; or to act directly as immune regulators. There exists great potential for well-defined materials to further our understanding of immunity. Here we describe recent advances in the design of synthetic materials to direct immune responses, highlighting successes and challenges in prophylactic, therapeutic and tolerance inducing vaccines. PMID- 24150417 TI - Stimuli-responsive nanocarriers for drug delivery. AB - Spurred by recent progress in materials chemistry and drug delivery, stimuli responsive devices that deliver a drug in spatial-, temporal- and dosage controlled fashions have become possible. Implementation of such devices requires the use of biocompatible materials that are susceptible to a specific physical incitement or that, in response to a specific stimulus, undergo a protonation, a hydrolytic cleavage or a (supra)molecular conformational change. In this Review, we discuss recent advances in the design of nanoscale stimuli-responsive systems that are able to control drug biodistribution in response to specific stimuli, either exogenous (variations in temperature, magnetic field, ultrasound intensity, light or electric pulses) or endogenous (changes in pH, enzyme concentration or redox gradients). PMID- 24150420 TI - Acculturation and weight loss strategies among Latinas. AB - This study examined the relationship between indicators of acculturation and weight loss strategies among Latinas. Latinas residing in the United States longer had more experience with various weight loss strategies (r = 0.24, p = 0.05). Controlling for demographic factors and BMI, years of U.S. residence was related to whether increased physical activity (OR 1.18, 95% CI 1.01-1.39, p = 0.04) and reduced portion sizes (OR 1.39, 95% CI 1.02-1.91, p = 0.03) were used as strategies for weight loss. More English spoken at home was associated with use of reducing calories as a strategy for weight loss (OR 4.13, 95% CI 1.06 16.09, p = 0.04). Regardless of acculturation level, less empirically supported methods such as using herbal products and a girdle were more prevalent than commonly recommended methods such as using meal replacement products and commercial weight loss programs. Behavioral weight loss interventions for Latinas should consider acculturation to more effectively target subgroups, address cultural practices, and teach lifestyle-appropriate strategies. PMID- 24150418 TI - Macroscale delivery systems for molecular and cellular payloads. AB - Macroscale drug delivery (MDD) devices are engineered to exert spatiotemporal control over the presentation of a wide range of bioactive agents, including small molecules, proteins and cells. In contrast to systemically delivered drugs, MDD systems act as a depot of drug localized to the treatment site, which can increase drug effectiveness while reducing side effects and confer protection to labile drugs. In this Review, we highlight the key advantages of MDD systems, describe their mechanisms of spatiotemporal control and provide guidelines for the selection of carrier materials. We also discuss the combination of MDD technologies with classic medical devices to create multifunctional MDD devices that improve integration with host tissue, and the use of MDD technology in tissue-engineering strategies to direct cell behaviour. As our ever-expanding knowledge of human biology and disease provides new therapeutic targets that require precise control over their application, the importance of MDD devices in medicine is expected to increase. PMID- 24150422 TI - Root systems analysis branches out. PMID- 24150421 TI - Health care access and breast cancer screening among Latinas along the California Mexican border. AB - Latinas are more likely to exhibit late stage breast cancers at the time of diagnosis and have lower survival rates compared to white women. A contributing factor may be that Latinas have lower rates of mammography screening. This study was guided by the Behavioral Model of Health Services Use to examine factors associated with mammography screening utilization among middle-aged Latinas. An academic-community health center partnership collected data from community-based sample of 208 Latinas 40 years and older in the San Diego County who completed measures assessing psychosocial factors, health care access, and recent mammography screening. Results showed that 84.6 % had ever had a mammogram and 76.2 % of women had received a mammogram in the past 2 years. Characteristics associated with mammography screening adherence included a lower acculturation (OR 3.663) a recent physician visit in the past year (OR 6.304), and a greater confidence in filling out medical forms (OR 1.743), adjusting for covariates. Results demonstrate that an annual physical examination was the strongest predictor of recent breast cancer screening. Findings suggest that in this community, improving access to care among English-speaking Latinas and addressing health literacy issues are essential for promoting breast cancer screening utilization. PMID- 24150423 TI - Sequential induction of auxin efflux and influx carriers regulates lateral root emergence. AB - In Arabidopsis, lateral roots originate from pericycle cells deep within the primary root. New lateral root primordia (LRP) have to emerge through several overlaying tissues. Here, we report that auxin produced in new LRP is transported towards the outer tissues where it triggers cell separation by inducing both the auxin influx carrier LAX3 and cell-wall enzymes. LAX3 is expressed in just two cell files overlaying new LRP. To understand how this striking pattern of LAX3 expression is regulated, we developed a mathematical model that captures the network regulating its expression and auxin transport within realistic three dimensional cell and tissue geometries. Our model revealed that, for the LAX3 spatial expression to be robust to natural variations in root tissue geometry, an efflux carrier is required--later identified to be PIN3. To prevent LAX3 from being transiently expressed in multiple cell files, PIN3 and LAX3 must be induced consecutively, which we later demonstrated to be the case. Our study exemplifies how mathematical models can be used to direct experiments to elucidate complex developmental processes. PMID- 24150424 TI - An efficient in planta transformation of Jatropha curcas (L.) and multiplication of transformed plants through in vivo grafting. AB - An efficient and reproducible Agrobacterium-mediated in planta transformation was developed in Jatropha curcas. The various factors affecting J. curcas in planta transformation were optimized, including decapitation, Agrobacterium strain, pin pricking, vacuum infiltration duration and vacuum pressure. Simple vegetative in vivo cleft grafting method was adopted in the multiplication of transformants without the aid of tissue culture. Among the various parameters evaluated, decapitated plants on pin-pricking and vacuum infiltrated at 250 mmHg for 3 min with the Agrobacterium strain EHA 105 harbouring the binary vector pGA 492 was proved to be efficient in all terms with a transformation efficiency of 62.66%. Transgene integration was evinced by the GUS histochemical analysis, and the GUS positive plants were subjected to grafting. Putatively transformed J. curcas served as "Scion" and the wild type J. curcas plant severed as "Stock". There was no occurrence of graft rejection and the plants were then confirmed by GUS histochemical analysis, polymerase chain reaction (PCR) and Southern hybridization. Genetic stability of the grafted plants was evaluated by using randomly amplified polymorphic DNA (RAPD), marker which showed 100% genetic stability between mother and grafted plants. Thus, an efficient in planta transformation and grafting based multiplication of J. curcas was established. PMID- 24150426 TI - Effect of the successive steps of a cryopreservation protocol on the structural integrity of Rubia akane Nakai hairy roots. AB - In this work, we studied the impact of the successive steps of the droplet vitrification protocol technique employed for cryopreservation of Rubia akane hairy roots on the features of cortical, pericycle and endoderm cells of apical and central root segments, using histology techniques and combining qualitative and quantitative observations. In apical segments, plasmolysis (22-71 %, depending on cell type) was observed only after the loading treatment and did not increase after the following steps of the protocol. By contrast, in central segments, plasmolysis (39-45 %) was already observed after the sucrose pretreatment; it increased to 54-68 %, depending on cell type, after the loading treatment, but no further changes were noted after treatment with the vitrification solution. After liquid nitrogen exposure and unloading treatment, deplasmolysis was more rapid in apical segments, with cortical and pericycle cells having retrieved their original features. In central segments, only cortical cells had retrieved their original features and endoderm and pericycle cells were still highly plasmolysed. Nuclei were more strongly impacted by the cryopreservation protocol in central segments, where they displayed a highly condensed nucleoplasm from the loading treatment onwards and had not retrieved their original aspect after the unloading treatment. By contrast, nuclei had a much less condensed nucleoplasm in cells of apical segments, and they had retrieved their original aspect after the unloading treatment. PMID- 24150425 TI - The role of ascorbate in protein folding. AB - Ascorbate was linked to protein folding a long time ago. At the first level of this connection, it had been shown that ascorbate functions as an essential cofactor in the hydroxylation enzymes involved in collagen synthesis. Although the hydroxylation reactions catalyzed by the members of the prolyl 4-hydroxylase family are considered to be ascorbate dependent, the hydroxylation of proline alone does not need ascorbate. Prolyl 4-hydroxylases participate in two catalytic reactions: one in which proline residues are hydroxylated, while 2-oxoglutarate is decarboxylated and molecular oxygen is consumed. This reaction is ascorbate independent. However, in another reaction, prolyl 4-hydroxylases catalyze the decarboxylation of 2-oxoglutarate uncoupled from proline hydroxylation but still needing molecular oxygen. At this time, ferrous iron is oxidized and the protein is rendered catalytically inactive until reduced by ascorbate. At the second level of the connection, the oxidation and the oxidized form of ascorbate, dehydroascorbate, is involved in the formation of disulfide bonds of secretory proteins. The significance of the dehydroascorbate reductase activity of protein disulfide isomerase was debated because protein disulfide isomerase as a dehydroascorbate reductase was found to be too slow to be the major route for the reduction of dehydroascorbate (and formation of disulfides) in the endoplasmic reticulum lumen. However, very recently, low tissue ascorbate levels and a noncanonical scurvy were observed in endoplasmic reticulum thiol oxidase- and peroxiredoxin 4-compromised mice. This novel observation implies that ascorbate may be involved in oxidative protein folding and creates a link between the disulfide bond formation (oxidative protein folding) and hydroxylation. PMID- 24150427 TI - Assessment of cauda equina syndrome progression pattern to improve diagnosis. AB - STUDY DESIGN: Meta-analysis of individual patient data. OBJECTIVE: To date, the progression pattern of cauda equina syndrome (CES) has not been summarized. This study assessed individual patient data from CES cases, investigated the CES progression pattern to help clinicians provide timely diagnoses. SUMMARY OF BACKGROUND DATA: Because there were few randomized controlled trials about CES, our research was based on case reports of CES with detailed medical history. METHODS: We searched English literature regarding CES in the PubMed database. We included a total of 198 publications involving 264 cases that met the inclusion criteria. The occurrence order of symptoms was determined by reviewing patients' medical histories, and the progression pattern of CES was analyzed using sequential pattern mining. Finally, we summarized and reassessed the current timing of CES diagnosis. RESULTS: Result of sequential pattern mining demonstrated that the progression process of CES could be divided into 3 stages: early stage of CES (CESE), with bilateral peripheral nerve dysfunction characterized by progressive sensory-motor defects from unilateral to bilateral in lower extremities; incomplete CES, with reduction of sphincter functions; and CES in retention, with sphincter dysfunction. Among all the cases, 81.08% (180 cases) were diagnosed at the stage of incomplete CES or CES in retention, in which 99.4% (179 cases) had experienced CESE without being diagnosed. CONCLUSION: The characteristic progressive sensory-motor CESE defects in lower extremities marked CES onset. Instead of waiting for the onset of sphincter function abnormalities, CES should be diagnosed when the CESE symptoms manifest. PMID- 24150428 TI - Reoperation and revision rates of 3 surgical treatment methods for lumbar stenosis associated with degenerative scoliosis and spondylolisthesis. AB - STUDY DESIGN: Retrospective cohort analysis. OBJECTIVE: To compare early treatment failures, survivorship, and clinical outcomes of 3 procedures used to treat symptomatic lumbar spinal stenosis and degenerative deformity. SUMMARY OF BACKGROUND DATA: Symptomatic lumbar stenosis is commonly seen in association with degenerative deformity, often leading to more complex surgical treatment, with laminectomy and fusion, supplanting laminectomy alone. More recently, the interspinous process spacer (ISP), developed to treat straightforward spinal stenosis, has been used in patients with spinal deformity to limit morbidity, although no studies have compared outcomes in this patient population. METHODS: A retrospective cohort analysis of 90 consecutive patients, mean age 70 years, with 5-year mean follow-up (minimum, 2 yr), treated for stenosis with associated deformity with ISP device placement, laminectomy alone, or laminectomy and short segment fusion. Early failure was defined as return to the operating room for revision of the index level or adjacent segment within 2 years. A Kaplan-Meier survival analysis was performed, and clinical outcomes and patient satisfaction was assessed. RESULTS: Reoperation within 2 years was noted in 16.7% of patients treated for spinal stenosis and mild deformity. There was a significantly higher rate of same-level recurrence in the ISP group (33.3%), than the laminectomy (8.3%) and lami/fusion groups (0%) (P< 0.0001). Early reoperation due to adjacent segment pathology (ASP) was most common in the lami/fusion group (13.3%). Kaplan Meier analysis revealed lowest survival for the ISP group and highest survival in the laminectomy-alone group at 2 years (P= 0.043) and 5 years (P= 0.007). CONCLUSION: Early failure was significantly more common in patients treated with an ISP device for spinal stenosis and lumbar deformity, whereas reoperation due to symptomatic adjacent segment pathology was most common in patients treated with laminectomy and fusion. Laminectomy alone had the highest rate of survival. LEVEL OF EVIDENCE: 3. PMID- 24150429 TI - Biomechanical effect of transforaminal lumbar interbody fusion and axial interbody threaded rod on range of motion and S1 screw loading in a destabilized L5-S1 spondylolisthesis model. AB - STUDY DESIGN: A cadaveric lumbosacral spondylolytic spondylolisthesis model was used to evaluate the biomechanical function of 2 different interbody spacers. OBJECTIVE: To analyze and compare the reduction in pedicle screw strain and spine range of motion (ROM) between transforaminal lumbar interbody fusion (TLIF) and an axial interbody threaded rod (AxialITR) in a destabilized L5-S1 spondylolisthesis model. SUMMARY OF BACKGROUND DATA: Symptomatic spondylolytic spondylolisthesis is often treated with posterior instrumented fusion augmented by a variety of different interbody devices. Interbody spacers rely primarily on posterior instrumentation to stabilize the spine during fusion, but there may be advantages to the more rigid support offered by an anterior threaded rod. METHODS: Pure-moment flexibility testing was performed on L3-S1 cadaveric specimens in 4 conditions: (1) Intact, (2) L5-S1 pedicle screws (PS) + L5-S1 disc destabilization (DDS), (3) TLIF at L5-S1 + PS + DDS, and (4) AxialITR at L5-S1 + PS + DDS. Specimens were destabilized by performing a complete denucleation at L5 S1 and sectioning two-thirds of the annulus' width from anterior to posterior. The S1 PSs were instrumented with strain gauges to measure screw-bending moments and ROM was quantified with a noncontact camera system. RESULTS: S1 screw strains were highest with PS but were significantly reduced by 73% in flexion and 31% in extension with TLIF (P <= 0.004). AxialITR significantly reduced strain by 78% in flexion and 81% in extension (P <= 0.001). ROM was smallest with AxialITR in each test direction at 1.7 +/- 1.8 degrees in flexion-extension, 1.6 +/- 0.9 degrees in lateral bending and 1.3 +/- 0.8 degrees in torsion. CONCLUSION: This study demonstrated that ROM and S1 screw-bending moments were reduced with the use of AxialITR and TLIF. Although the TLIF and AxialITR both reduced strains and motion, the AxialITR provided a significant reduction in extension strain when compared with TLIF. LEVEL OF EVIDENCE: N/A. PMID- 24150430 TI - Revision spinal fusion in patients older than 75: is it worth the risks? AB - STUDY DESIGN: Retrospective clinical study of a prospective database. OBJECTIVE: This study aims to determine whether revision spinal fusion surgery is worthwhile in patients older than 75 from a risk-benefit perspective. SUMMARY OF BACKGROUND DATA: The benefits of spinal fusion in patients older than 65 is well documented. However, the clinical benefit to patients older than 75 of revision surgery, which often yields worse outcomes with higher complication rates, is uncertain. METHODS: Ninety-nine consecutive patients older than 75 with minimum 2-year follow-up underwent spinal fusion as either a primary (n = 58) or revision (n = 41) operation. Diagnoses were spondylolisthesis (n = 43), scoliosis (n = 28), kyphosis (n = 5), and other degenerative spinal disorders (n = 26). Outcomes were obtained prospectively by visual analogue scale (VAS) and Oswestry Disability Index (ODI) at preoperative, 1-year, 2-year, and latest follow-up. RESULTS: Revision patients had significantly worse scores compared with primary patients at all time intervals, for both VAS (preoperative: 6.4 vs. 5.8, 1 yr: 3.6 vs. 2.4, 2 yr: 4.7 vs. 2.5) and ODI (preoperative: 52.2 vs. 44.1, 1 yr: 37.3 vs. 25.6, 2 yr: 47.0 vs. 25.0). Both groups improved significantly at 1 year postoperatively. At 2 years, the results of revision surgery deteriorated (DeltaVAS: -1.7, DeltaODI: -5.2), whereas the benefits of primary procedures were maintained (DeltaVAS: -3.3, DeltaODI: -19.1). Complications were generally greater in the revision group and included revision surgery (8[19.5%] vs. 7[12.1%]), nonunion (2[4.9%] vs. 3[5.2%]), adjacent level fracture (4[9.8%] vs. 6[10.3%]), infection (6[14.7%] vs. 2[3.4%]), foot drop (0[0.0%] vs. 4[6.9%]), imbalance (4[9.8%] vs. 1[1.7%]), pulmonary failure (1[2.4%] vs. 1[1.7%]), and death (0[0.0%] vs. 1[1.7%]). CONCLUSION: Despite having worse initial ODI and VAS scores, revision patients older than 75 initially benefit as much as patients older than 75 undergoing primary operations. However, at 2 years, revision patients do not have a sustained benefit despite a higher complication rate. LEVEL OF EVIDENCE: 4. PMID- 24150431 TI - Reliability and validity of the French-Canadian version of the scoliosis research society 22 questionnaire in France. AB - STUDY DESIGN: Outcome study to determine the internal consistency, reproducibility, and concurrent validity of the French-Canadian version of the Scoliosis Research Society 22 (SRS-22 fcv) patient questionnaire in France. OBJECTIVE: To determine whether the SRS-22 fcv can be used in a population from France. SUMMARY OF BACKGROUND DATA: The SRS-22 has been translated and validated in multiple countries, notably in the French-Canadian language in Quebec, Canada. Use of SRS-22 fcv seems appropriate for evaluating adolescent idiopathic scoliosis in France. However, French-Canadian French is noticeably different from the French spoken in France, and no study has investigated the use of a French Canadian version of a health-quality questionnaire in another French population. METHODS: The methods used for validating the SRS-22 fcv in Quebec were adopted for use with a group of 200 adolescents with idiopathic scoliosis and 60 healthy adolescents in France. Reliability and reproducibility were measured by the Cronbach alpha and intraclass correlation coefficient (ICC), construct validity by factorial analysis, concurrent validity by the Short-Form of the survey, and discriminant validity by analysis of variance and multivariate linear regression. RESULTS: In France, the SRS-22 fcv showed good global internal consistency (Cronbach alpha = 0.87, intraclass correlation coefficient = 0.92), a coherent factorial structure, and high correlation coefficients between the SRS-22 fcv and Short-Form of the survey (P < 0.001). However, reliability and validity were slightly less than that for the instrument's original validation and the validation of the SRS-22 fcv in Quebec. These differences could be explained by language and cultural differences. CONCLUSION: The SRS-22 fcv is relevant for use in France, but further development and validation of a specific French questionnaire remain necessary to improve the assessment of functional outcomes of adolescents with scoliosis in France. LEVEL OF EVIDENCE: N/A. PMID- 24150432 TI - Do anchor density or pedicle screw density correlate with short-term outcome measures in adolescent idiopathic scoliosis surgery? AB - STUDY DESIGN: Retrospective review. OBJECTIVE: Determine if factors under surgeon control (anchor density or pedicle screw density) or those not under surgeon control (curve magnitude, levels requiring fusion, and curve flexibility) correlate with standard, short-term quality and outcome measures for adolescent idiopathic scoliosis. SUMMARY OF BACKGROUND DATA: Pedicle screw fixation has revolutionized posterior spinal instrumentation and fusion for adolescent idiopathic scoliosis and seems to provide greater radiographical coronal plane curve correction than less expensive constructs. Other clinically relevant improvements in outcome have been difficult to demonstrate. METHODS: Retrospective review of 119 posterior spinal instrumentation and fusion cases for adolescent idiopathic scoliosis by 4 surgeons at 1 institution. Average follow-up was 586.7 days. Outcome measures were main thoracic curve correction, complications, reoperations, infection, intensive care unit days, length of stay, estimated blood loss, transfusion, procedure time, implant charges, and total hospital charges. "Surgeon-dependent" variables were implant density (fixation/instrumented level) and pedicle coefficient (implant density * percentage of anchors that are pedicle screws). "Surgeon-independent" variables were main thoracic curve magnitude, main thoracic curve flexibility, and levels fused. Correlations were estimated using Pearson correlation coefficients. One way analysis of variance was used to estimate the effect of "type of surgeon" or "surgeon" on surgeon-dependent variables. RESULTS: Complications, reoperations, and infections did not correlate with surgeon-dependent or surgeon-independent variables. Main thoracic curve correction correlated strongly with curve flexibility (correlation coefficient [cc] = 0.4089, P < 0.0001). Surgeon independent variables were levels fused correlated significantly with procedure time (cc = 0.610, P < 0.001), hospital charges (cc = 0.309, P < 0.001), hospital length of stay (cc = 0.366 [P < 0.001]), implant charges (cc = 0.199, P < 0.047), and estimated blood loss (cc = 0.243, P < 0.013). Surgeon-dependent variables were implant density significantly correlated with implant charges (cc = 0.243, P < 0.015) and inversely with length of stay (cc = -0.236, P < 0.015). Pedicle coefficient was not significantly correlated with any outcome measure. CONCLUSION: Levels fused, a surgeon-independent variable, had the most consistently strong correlations with standard short-term quality indicators. With physician grading by payers largely dependent on easily measured outcomes from medical records, hospital and billing records, physicians need to be aware of the surgeon-dependent and surgeon-independent variables that may affect their outcomes and cost-effectiveness profile. LEVEL OF EVIDENCE: 3. PMID- 24150433 TI - Four- and five- level en bloc spondylectomy for malignant spinal tumors. AB - STUDY DESIGN: Retrospective study. OBJECTIVE: To report results of 4- and 5-level en bloc spondylectomy (EBS) in the treatment of malignant spinal tumors. SUMMARY OF BACKGROUND DATA: EBS is widely used to avoid local recurrence in the treatment of spinal malignant tumors. Four- and 5-level EBS are aggressive procedures associated with complications and morbidity. METHODS: We conducted a retrospective study of all patients treated with minimum 4-level EBS. Patient and surgical data were noted. Radiographs, magnetic resonance images, and computed tomographic scans were studied for local recurrence, graft, and instrumentation failures at subsequent follow-up. Type of excision was classified into intralesional, marginal, and wide margins. Complications were divided into major or minor and were further classified as intraoperative, early, and late postoperative. At the last follow-up, the patients were classified as alive with no evidence of local or systemic disease, alive with evidence of local or systemic disease or both, dead with evidence of local disease, or systemic disease or both, and dead without evidence of local and systemic disease. RESULTS: Nine patients were identified who required a minimum 4-level en bloc resection. Five males and 4 females. Average age was 41.66 years (11-66). There were 8 primary malignant tumors: 3 chordomas, 3 osteosarcomas, 1 chondrosarcoma, 1 primary lung tumor and 1 metastatic alveolar soft part sarcoma. Six were operated with 4-level en bloc and 3 with 5 levels. The mean surgical time was 713 minutes and estimated blood loss was 4.5 L. Mean follow-up was 27.7 months (8 84). At the last follow-up, 6 patients were alive with no evidence of local or systemic disease, 1 alive with evidence of systemic disease, 1 dead with evidence of local disease, or systemic disease or both, and 1 DNLS. Only 1 (11%) patient had a local recurrence. Three patients with Frankel D had full neurological recovery. Histopathological assessment showed marginal margins in 7 patients and wide in 2. There were 9 major and 9 minor complications in 7 patients. Five of 7 patients (71%) with complications, had fully recovered from their complications at the last follow-up. CONCLUSION: Multilevel EBS, can be offered to a patient to prevent local recurrence of disease. Even in experienced hands, the risks of intra- and postoperative complications are high (78%). However, most of the patients with complications, recovered completely (71%). Although the surgery itself may prove beneficial, patients should be well informed regarding the morbidity associated with it. LEVEL OF EVIDENCE: 4. PMID- 24150434 TI - Adjacent segment disease after anterior cervical discectomy and fusion: clinical outcomes after first repeat surgery versus second repeat surgery. AB - STUDY DESIGN: Retrospective clinical study. OBJECTIVE: To study the long-term effects of repeat cervical fusion after development of adjacent segment disease (ASD). SUMMARY OF BACKGROUND DATA: ASD is a well-recognized development after anterior cervical discectomy and fusion (ACDF). Although there are data on the development of ASD after ACDF, the incidence of ASD after repeat ACDF has not been well established. METHODS: We collected 888 consecutive patients who underwent ACDF for cervical degenerative disease during a 20-year period at a single institution. Patients were followed for an average of 94.0 +/- 78.1 months after the first ACDF. RESULTS: Of the 888 patients who underwent ACDF, 108 patients developed ASD, necessitating a second cervical fusion. Among these 108 patients, 27 patients later developed recurrent ASD, requiring a third cervical fusion. Thus, in this series, the incidence of ASD after ACDF is 12.2%, statistically increasing to 25% after a second cervical fusion (P = 0.0002). Notably, ASD occurred 47.0 +/- 44.9 months after the first ACDF and statistically decreased to 30.3 +/- 24.9 months after a second cervical fusion (P = 0.01). Of the 77 patients who underwent a second cervical fusion via an anterior approach, 23 developed recurrent ASD requiring a third cervical fusion. In contrast, of the 31 patients who had a posteriorly approached second cervical fusion, only 4 developed recurrent ASD requiring a third cervical fusion. CONCLUSION: We present a cohort of patients undergoing multiple sequential operations due to ASD during a 20-year period. In this series of 888 patients, the incidence of ASD development is lowest after the first ACDF. Patients who undergo a second cervical fusion develop ASD at both higher and faster rates. Moreover, patients who had a second cervical fusion via an anterior approach had a higher chance of developing recurrent ASD versus patients who had a posterior approach. LEVEL OF EVIDENCE: 3. PMID- 24150435 TI - Cost-effectiveness of total disc replacement versus multidisciplinary rehabilitation in patients with chronic low back pain: a Norwegian multicenter RCT. AB - STUDY DESIGN: Randomized clinical trial with 2-year follow-up. OBJECTIVE: To evaluate the cost-effectiveness of total disc replacement (TDR) versus multidisciplinary rehabilitation (MDR) in patients with chronic low back pain (CLBP). SUMMARY OF BACKGROUND DATA: The existing studies on CLBP report cost effectiveness of fusion surgery versus disc replacement and fusion versus rehabilitation. This study evaluated the cost-effectiveness of TDR versus MDR. METHODS: Between April 2004 and May 2007, 173 patients with CLBP (>1 yr) were randomized to TDR (n = 86) or MDR (n = 87). Treatment effects (Euro Qol 5D [EQ 5D] and Short Form 6D [SF-6D]) and relevant direct and indirect costs at 6 weeks and at 3, 6, 12, and 24 months after treatment were assessed. Gain in quality adjusted life years (QALYs) after 2 years was estimated. Cost-effectiveness was expressed as an incremental cost-effectiveness ratio. RESULTS: The mean QALYs gained (standard deviation) using EQ-5D was 1.29 (0.53) in the TDR group and 0.95 (0.52) in the MDR group, a significant difference of 0.34 (95% confidence interval 0.18-0.50). The mean total cost per patient in the TDR group was &OV0556;87,622 (58,351) compared with &OV0556;74,116 (58,237) in the MDR group, which was not significantly different (95% confidence interval: -4041 to 31,755). The incremental cost-effectiveness ratio for the TDR procedure varied from &OV0556;39,748 using EQ-5D (TDR cost-effective) to &OV0556;128,328 using SF-6D (TDR not cost-effective). The dropout rate was 20% (15% TDR group, 24% MDR group). Five patients moved from the MDR to the TDR group, whereas 9 patients randomized to TDR declined surgery. Using per-protocol analysis instead of intention-to-treat analysis indicated that TDR was not cost-effective, irrespective of the use of EQ-5D or SF-6D. CONCLUSION: In this study, TDR was cost-effective compared with MDR after 2 years when using EQ-5D for assessing QALYs gained and a willingness to pay of &OV0556;74,600 (kr500,000/QALY). TDR was not cost-effective when SF-6D was used; therefore, our results should be interpreted with caution. Longer follow-up is needed to accurately assess the cost-effectiveness of TDR. LEVEL OF EVIDENCE: 2. PMID- 24150436 TI - Sagittal balance and spinopelvic parameters after lateral lumbar interbody fusion for degenerative scoliosis: a case-control study. AB - STUDY DESIGN: Retrospective matched-cohort analysis. OBJECTIVE: To evaluate the change in radiographical parameters in patients undergoing interbody fusion and posterior instrumentation compared with posterior spine fusion (PSF) alone for degenerative scoliosis. SUMMARY OF BACKGROUND DATA: Little is known about the effect of lateral interbody fusion (LIF) on sagittal plane correction in the setting of degenerative scoliosis. We performed a retrospective study to investigate these changes compared with PSF. METHODS: Between 1997 and 2011, 33 patients had LIF at 181 levels between T8 and L5 vertebrae for the treatment of degenerative scoliosis (mean; 5 +/- 2 levels). Of those, 23 patients had additional anterior lumbar interbody fusion (ALIF) at 37 levels between L4 and S1 vertebrae (mean; 1.6 +/- 0.5 levels). A 1:1 matched control of patients who underwent PSF was performed. Patients were matched by age, sex, and diagnosis. Clinical and radiographical data were collected and compared between the matched cohorts. RESULTS: Lumbar lordosis (LL) was significantly restored in the LIF +/- ALIF compared with PSF cohort (44 degrees +/- 14 degrees vs. 36 degrees +/- 15 degrees , P = 0.02). The segmental LL over the 102 LIF levels significantly improved from 12 degrees +/- 10 degrees to 21 degrees +/- 13 degrees postoperatively (P < 0.0001). However, the change over the 37 ALIF levels was not significant (from 30 degrees +/- 15 degrees to 29 degrees +/- 9 degrees , P = 0.8). Sagittal plane alignment was improved in the LIF +/- ALIF compared with PSF cohort and trended toward but did not reach significance (3.8 +/- 3.2 cm vs. 6.2 +/- 5.7 cm, P = 0.09). Sacral slope was significantly higher in the LIF +/- ALIF compared with PSF cohort (33 degrees +/- 11 degrees vs. 28 degrees +/- 10 degrees , P = 0.03). Pelvic tilt was lower in the LIF +/- ALIF compared with PSF cohort and trended toward but did not reach significance (22 degrees +/- 10 degrees vs. 26 degrees +/- 10 degrees , P = 0.08). CONCLUSION: LL and sacral slope had mildly but statistically improved in the interbody fusion cohort compared with PSF cohort. Sagittal alignment and pelvic tilt trended toward but did not reach statistical significance. Segmental LL was improved at LIF levels more than at ALIF levels. LEVEL OF EVIDENCE: 3. PMID- 24150437 TI - Quality-of-life outcomes with minimally invasive transforaminal lumbar interbody fusion based on long-term analysis of 304 consecutive patients. AB - STUDY DESIGN: This was a prospective clinical study that took place in an outpatient spine clinic. OBJECTIVE: To demonstrate the short-/long-term outcomes from a large cohort of patients undergoing minimally invasive transforaminal lumbar interbody fusion (MITLIF). SUMMARY OF BACKGROUND DATA: Long-term prospective outcomes in patients undergoing minimally invasive spinal fusion for debilitating back pain has not been well studied. METHODS: Presenting diagnosis was determined from clinical findings and radiographical (radiograph, magnetic resonance image, computed tomographic scan) evaluations preoperatively. Patients were assessed with outcome measures preoperatively, and postoperatively at 2 weeks, 3 months, 6 months, 12 months, 24 months, and annually 2 to 7 years (mean follow-up: 47 mo) final follow-up. The rate of postoperative complications and reoperations at the initial level of MITLIF and adjacent level(s) were followed. Fusion rates were assessed blinded and independently by radiograph. RESULTS: Visual analogue scale scores decreased significantly from 7.0 preoperatively to 3.5 at mean 47-month follow-up. Oswestry Disability Index scores declined from 43.1 preoperatively to 28.2 at mean 47-month follow-up. Short-Form 36 mental component scores increased from 43.8 preoperatively to 49.7 at 47-month follow up. Short-Form 36 physical component scores increased from 30.6 preoperatively to 39.6 at 47-month follow-up (P < 0.05). CONCLUSION: This prospectively collected outcomes study shows long-term statistically significant clinical outcomes improvement after MITLIF in patients with clinically symptomatic spondylolisthesis and degenerative disc disease with or without stenosis. MITLIF resulted in a high rate of spinal fusion and very low rate of interbody fusion failure and/or adjacent segment disease requiring reoperation while reducing postoperative complications. LEVEL OF EVIDENCE: 3. PMID- 24150438 TI - Analysis of L5 incidence in normal population use of L5 incidence as a guide in reconstruction of lumbosacral alignment. AB - STUDY DESIGN: Cross-sectional study. OBJECTIVE: To establish a statistic model defining the relationship between L5 incidence (L5I) and pelvic incidence (PI) in normal population and to illustrate the importance of L5I in maintaining the normal sagittal profile of spine. SUMMARY OF BACKGROUND DATA: L5I was proposed for the evaluation of postoperative improvements in high-grade isthmic spondylolisthesis. It has been proven that a postoperative improvement in L5I was correlated with a better surgical outcome, indicating that the restoration of L5I is important in restoring normal sagittal balance and spinal morphology. METHODS: This retrospective study recruited 138 healthy volunteers, who were stratified into 2 groups according to age: adolescent group (13-18 yr) and adult group (19 35 yr). Parameters including PI, pelvic tilt, sacral slope, lumbar lordosis (LL), upper arc of the LL, lower arc of the LL, L5I, lumbosacral angle, and height of L5-S1 disc were measured on the long-cassette standing upright lateral radiographs of the spine and pelvis. The relations between all parameters were determined via the Pearson correlation coefficient (r). Linear regression was applied to model the relationship between PI and L5I. RESULTS: This study demonstrated significant correlation between L5I and PI with a coefficient of 0.818, and a formula based on linear regression was established to estimate the ideal L5I from PI as follows: L5I = 0.725 PI - 12.757. Pelvic tilt, sacral slope, lumbosacral angle, LL, lower arc of the LL, and height of L5-S1 disc were also found strongly correlated with L5I, whereas no correlation was found between upper arc of the LL and L5I. CONCLUSION: Strong correlations were found between L5I and spinopelvic parameters in healthy subjects, indicating that L5I was an important parameter in local lumbosacral alignment. Ideal postoperative L5I could be mathematically calculated by PI according to the formula as follows: L5I = 0.725 PI - 12.757, suggesting that calculated ideal L5I could be regarded as a guide in surgical decision making. LEVEL OF EVIDENCE: 3. PMID- 24150439 TI - Predictors for the progression of cervical lesion in rheumatoid arthritis under the treatment of biological agents. AB - STUDY DESIGN: Retrospective cohort analysis. OBJECTIVE: To clarify the effect of biological agents (BAs) on the development and progression of cervical lesions in patients with rheumatoid arthritis (RA) and to identify biomarkers that accurately predict disease progression. SUMMARY OF BACKGROUND DATA: The introduction of BAs changed the paradigm of RA treatment. However, their effects on cervical lesions in patients with RA have not been studied. METHODS: Ninety one subjects who had received BAs for 2 years or more were enrolled. Mean radiographical interval was 3.9 years. Disease activity was evaluated by disease activity score-C-reactive protein levels, and matrix metalloproteinase-3 levels. Cervical lesions were defined as an atlantodental interval more than 3 mm for atlantoaxial subluxation (AAS), Ranawat value less than 13 mm for vertical subluxation (VS), and anterior or posterior listhesis more than 2 mm for subaxial subluxation. Disease progression was defined radiographically as an increase in the atlantodental interval more than 2 mm for AAS, a decrease in both Ranawat and Redlund-Johnell values more than 2 mm for VS, and an increase in listhesis more than 2 mm for subaxial subluxation. We used multivariate regression techniques to assess predictors of disease progression. RESULTS: Baseline radiographical evaluation showed no pre-existing cervical lesion in 44 patients, AAS in 29, and VS in 18. Radiological progression occurred in 7% patients without baseline lesions, 79% in the AAS group, and 72% in the VS group. The incidence of progression was significantly lower in patients without lesions at baseline. Multivariate regression analysis demonstrated pre-existing cervical lesions, disease activity score-C-reactive protein levels at baseline and metalloproteinase-3 levels at final visit as good predictors of RA progression. CONCLUSION: BAs prevented de novo cervical lesions in patients with RA but failed to control progression in patients with pre-existing cervical lesions. Disease activity score-C-reactive protein levels at baseline were related to pre-existing joint destruction, and metalloproteinase-3 levels accurately predicted ongoing bone destruction during BA treatment. LEVEL OF EVIDENCE: 3. PMID- 24150441 TI - Therapist attitudes towards computer-based trainings. AB - Computer-based trainings are a promising avenue for increasing access to training in evidence-based practices. However, little is known about whether therapists are willing to use them. Results from a national survey of practicing therapists (N = 1,067) indicated that 26 % of therapists reported previously using a computer-based training and overall attitudes (as measured by the Computer-Based Training Attitudes Scale) were positive. Higher therapist computer fluency and greater openness to new treatments predicted positive attitudes. Therapists with more positive attitudes were more likely to have previously used a computer-based training. Implications are discussed. PMID- 24150440 TI - A retrospective quasi-experimental study of a transitional housing program for patients with severe and persistent mental illness. AB - Transitional housing programs aim to improve living skills and housing stability for tenuously housed patients with mental illness. 113 consecutive Transitional Housing Team (THT) patients were matched to 139 controls on diagnosis, time of presentation, gender and prior psychiatric hospitalisation and compared using a difference-in-difference analysis for illness acuity and service use outcomes measured 1 year before and after THT entry/exit. There was a statistically significant difference-in-difference favouring THT participants for bed days (mean difference in difference -20.76 days, SE 9.59, p = 0.031) and living conditions (HoNOS Q11 mean difference in difference -0.93, SE 0.23, p < 0.001). THT cost less per participant (I$14,024) than the bed-days averted (I$17,348). The findings of reductions in bed days and improved living conditions suggest that transitional housing programs can have a significant positive impact for tenuously housed patients with high inpatient service usage, as well as saving costs for mental health services. PMID- 24150444 TI - Untitled: Gonzalo Fonseca. PMID- 24150445 TI - Report reveals scope of US antibiotic resistance threat. PMID- 24150446 TI - Leaders in evidence-based medicine examine the path ahead. PMID- 24150447 TI - FDA: Increased HBV reactivation risk with ofatumumab or rituximab. PMID- 24150461 TI - Teaching value in academic environments: shifting the ivory tower. PMID- 24150462 TI - Physician education in addiction medicine. PMID- 24150463 TI - A piece of my mind. Shepard's prayer. PMID- 24150464 TI - Eliminating prevention counseling to improve HIV screening. PMID- 24150465 TI - Influenza vaccination in 2013-2014: achieving 100% participation. PMID- 24150466 TI - Effect of risk-reduction counseling with rapid HIV testing on risk of acquiring sexually transmitted infections: the AWARE randomized clinical trial. AB - IMPORTANCE: To increase human immunodeficiency virus (HIV) testing rates, many institutions and jurisdictions have revised policies to make the testing process rapid, simple, and routine. A major issue for testing scale-up efforts is the effectiveness of HIV risk-reduction counseling, which has historically been an integral part of the HIV testing process. OBJECTIVE: To assess the effect of brief patient-centered risk-reduction counseling at the time of a rapid HIV test on the subsequent acquisition of sexually transmitted infections (STIs). DESIGN, SETTING, AND PARTICIPANTS: From April to December 2010, Project AWARE randomized 5012 patients from 9 sexually transmitted disease (STD) clinics in the United States to receive either brief patient-centered HIV risk-reduction counseling with a rapid HIV test or the rapid HIV test with information only. Participants were assessed for multiple STIs at both baseline and 6-month follow-up. INTERVENTIONS: Participants randomized to counseling received individual patient centered risk-reduction counseling based on an evidence-based model. The core elements included a focus on the patient's specific HIV/STI risk behavior and negotiation of realistic and achievable risk-reduction steps. All participants received a rapid HIV test. MAIN OUTCOMES AND MEASURES: The prespecified outcome was a composite end point of cumulative incidence of any of the measured STIs over 6 months. All participants were tested for Neisseria gonorrhoeae, Chlamydia trachomatis, Treponema pallidum (syphilis), herpes simplex virus 2, and HIV. Women were also tested for Trichomonas vaginalis. RESULTS: There was no significant difference in 6-month composite STI incidence by study group (adjusted risk ratio, 1.12; 95% CI, 0.94-1.33). There were 250 of 2039 incident cases (12.3%) in the counseling group and 226 of 2032 (11.1%) in the information only group. CONCLUSION AND RELEVANCE: Risk-reduction counseling in conjunction with a rapid HIV test did not significantly affect STI acquisition among STD clinic patients, suggesting no added benefit from brief patient-centered risk reduction counseling. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01154296. PMID- 24150467 TI - Association between influenza vaccination and cardiovascular outcomes in high risk patients: a meta-analysis. AB - IMPORTANCE: Among nontraditional cardiovascular risk factors, recent influenzalike infection is associated with fatal and nonfatal atherothrombotic events. OBJECTIVES: To determine if influenza vaccination is associated with prevention of cardiovascular events. DATA SOURCES AND STUDY SELECTION: A systematic review and meta-analysis of MEDLINE (1946-August 2013), EMBASE (1947 August 2013), and the Cochrane Library Central Register of Controlled Trials (inception-August 2013) for randomized clinical trials (RCTs) comparing influenza vaccine vs placebo or control in patients at high risk of cardiovascular disease, reporting cardiovascular outcomes either as efficacy or safety events. DATA EXTRACTION AND SYNTHESIS: Two investigators extracted data independently on trial design, baseline characteristics, outcomes, and safety events from published manuscripts and unpublished supplemental data. High-quality studies were considered those that described an appropriate method of randomization, allocation concealment, blinding, and completeness of follow-up. MAIN OUTCOMES AND MEASURES: Random-effects Mantel-Haenszel risk ratios (RRs) and 95% CIs were derived for composite cardiovascular events, cardiovascular mortality, all-cause mortality, and individual cardiovascular events. Analyses were stratified by subgroups of patients with and without a history of acute coronary syndrome (ACS) within 1 year of randomization. RESULTS: Five published and 1 unpublished randomized clinical trials of 6735 patients (mean age, 67 years; 51.3% women; 36.2% with a cardiac history; mean follow-up time, 7.9 months) were included. Influenza vaccine was associated with a lower risk of composite cardiovascular events (2.9% vs 4.7%; RR, 0.64 [95% CI, 0.48-0.86], P = .003) in published trials. A treatment interaction was detected between patients with (RR, 0.45 [95% CI, 0.32-0.63]) and without (RR, 0.94 [95% CI, 0.55-1.61]) recent ACS (P for interaction = .02). Results were similar with the addition of unpublished data. CONCLUSIONS AND RELEVANCE: In a meta-analysis of RCTs, the use of influenza vaccine was associated with a lower risk of major adverse cardiovascular events. The greatest treatment effect was seen among the highest-risk patients with more active coronary disease. A large, adequately powered, multicenter trial is warranted to address these findings and assess individual cardiovascular end points. PMID- 24150469 TI - A persistent red crusted plaque on the back. PMID- 24150470 TI - Effect of oxytocin on placebo analgesia: a randomized study. PMID- 24150468 TI - Conjunctivitis: a systematic review of diagnosis and treatment. AB - IMPORTANCE: Conjunctivitis is a common problem. OBJECTIVE: To examine the diagnosis, management, and treatment of conjunctivitis, including various antibiotics and alternatives to antibiotic use in infectious conjunctivitis and use of antihistamines and mast cell stabilizers in allergic conjunctivitis. EVIDENCE REVIEW: A search of the literature published through March 2013, using PubMed, the ISI Web of Knowledge database, and the Cochrane Library was performed. Eligible articles were selected after review of titles, abstracts, and references. FINDINGS: Viral conjunctivitis is the most common overall cause of infectious conjunctivitis and usually does not require treatment; the signs and symptoms at presentation are variable. Bacterial conjunctivitis is the second most common cause of infectious conjunctivitis, with most uncomplicated cases resolving in 1 to 2 weeks. Mattering and adherence of the eyelids on waking, lack of itching, and absence of a history of conjunctivitis are the strongest factors associated with bacterial conjunctivitis. Topical antibiotics decrease the duration of bacterial conjunctivitis and allow earlier return to school or work. Conjunctivitis secondary to sexually transmitted diseases such as chlamydia and gonorrhea requires systemic treatment in addition to topical antibiotic therapy. Allergic conjunctivitis is encountered in up to 40% of the population, but only a small proportion of these individuals seek medical help; itching is the most consistent sign in allergic conjunctivitis, and treatment consists of topical antihistamines and mast cell inhibitors. CONCLUSIONS AND RELEVANCE: The majority of cases in bacterial conjunctivitis are self-limiting and no treatment is necessary in uncomplicated cases. However, conjunctivitis caused by gonorrhea or chlamydia and conjunctivitis in contact lens wearers should be treated with antibiotics. Treatment for viral conjunctivitis is supportive. Treatment with antihistamines and mast cell stabilizers alleviates the symptoms of allergic conjunctivitis. PMID- 24150471 TI - Contaminated methylprednisolone injections. PMID- 24150472 TI - Contaminated methylprednisolone injections--reply. PMID- 24150473 TI - Use of spinal injections for low back pain. PMID- 24150474 TI - Use of spinal injections for low back pain--reply. PMID- 24150475 TI - Risks associated with opioid use. PMID- 24150476 TI - Risks associated with opioid use. PMID- 24150477 TI - Risks associated with opioid use--reply. PMID- 24150480 TI - The ripening of fruits. PMID- 24150481 TI - JAMA patient page. Blood lipids. PMID- 24150482 TI - Assessment of endogenous, oral and inhaled steroid cross-reactivity in the Roche cortisol immunoassay. AB - BACKGROUND: Inhaled steroids are widely used for the treatment of asthma. Concerns over adrenal suppression when used at high doses or in combination with drugs such as ritonavir exist, requiring the measurement of serum cortisol. Herein, we investigate the cross-reactivity of the inhaled steroids betamethasone, fluticasone and beclomethasone in the Roche cortisol immunoassay, in addition to five other steroids. METHODS: Five replicates were produced from a serum pool for each of the eight steroids at a final concentration of 0.1 and 1 ug/mL. Each steroid was dissolved in 50% methanol, with 50% methanol of the same volume added to the control sample. The cross-reactivity of each steroid in the cortisol assay was calculated. RESULTS: There was no statistically or clinically significant cross-reactivity in the measurement of cortisol when fluticasone, beclomethasone or betamethasone were spiked at 0.1 and 1.0 ug/mL, except for beclomethasone at a concentration of 1 ug/mL (1490 nmol/L) with a cross reactivity of 1.6%, which is unlikely to be clinically significant. At both steroid concentrations investigated, prednisolone, 17-hydroxyprogesterone and 11 deoxycortisol exhibited statistically significant cross-reactivities that were greater than the least significant change of the assay (13.1%), whereas dexamethasone and metyrapone did not. Mean inter-assay precision was 1.5% (405 1586 nmol/L). CONCLUSION: The cross-reactivity of the inhaled steroids; betamethasone, fluticasone and beclomethasone in the Roche cortisol immunoassay are unlikely to be clinically significant at the concentrations found in patients on therapeutic doses. This will enable confident assessment of adrenal status in patients at risk of adrenal suppression. PMID- 24150483 TI - Performance measurements in diabetes care: the complex task of selecting quality indicators. AB - PURPOSE: To review the literature on the content and development of the sets of quality indicators used in studies on the quality of diabetes care in primary care settings. DATA SOURCES: The MEDLINE (Ovid), PubMed, PsychINFO, Embase and CINAHL databases were searched for relevant articles published up to January 2011. STUDY SELECTION: and data extraction We included studies on the quality of adult diabetes care, using quality indicators. We excluded studies focusing on the hospital setting, patient subgroups, specific components of diabetes care and specific outcomes. In total, 102 studies (including 102 sets and 1494 indicators) were analyzed by two independent reviewers, using the criteria of the National Quality Measures Clearinghouse and international guidelines to document the content and selection of the identified indicators. RESULTS OF DATA SYNTHESIS: Sets varied greatly in number, content and definitions of quality indicators. Most of the indicators concerned HbA1C, lipids, blood pressure, eye and foot examination and urinalysis. Few sets included indicators on lifestyle counseling, patient experiences, healthcare structure or access to healthcare providers. Seventy sets did not specify explicit selection criteria, and 19 of these did not report the sources of the indicators. CONCLUSIONS: Sets of quality indicators are diverse in number, content and definitions. This diversity reflects a lack of uniformity in the concept of diabetes care quality and hinders the interpretation of and comparison between quality assessments. Methodology regarding defining constructs such as the quality of diabetes care and indicator selection procedures is available and should be used more rigorously. PMID- 24150484 TI - Catalytic asymmetric aldol reactions in aqueous media--a 5 year update. AB - Asymmetric reactions in water and in aqueous solutions have become an area of fast growing interest recently. Although for a long time neglected as a medium for organic reactions, water has attracted attention as the most widely distributed solvent in the world. Indeed, water is the solvent used by nature for biological chemistry including aldol reactions being essential for glycolysis, gluconeogenesis and related processes. Consequently, artificial catalysts designed and used for aldol reactions in water can be promising for the synthesis of enantiopure molecules and are also important for the understanding of complex chemistry of life. This tutorial review summarizes recent developments in the area of aqueous asymmetric aldol reactions highlighting two fundamental directions--development of water compatible chiral Lewis acids and amine-based organocatalysts. PMID- 24150485 TI - High-throughput metabolomic approach revealed the acupuncture exerting intervention effects by perturbed signatures and pathways. AB - Metabolomics can capture global changes and the overall physiological status in biochemical networks and pathways in order to elucidate sites of perturbations. High-throughput metabolomics and acupuncturology have similar characteristics such as entirety, comprehensiveness and dynamic changes, and can identify potential candidates for acupuncture effects and provide valuable information towards understanding therapy mechanisms. Saliva has recently gained popularity as a potential tool for biomarker monitoring, as its composition may potentially reflect plasma metabolite levels and, therefore, may be used as an indicator of the physiological state. However, the underlying mechanism of acupuncture, remains largely unknown, which hinders its widespread use. Acupuncture would produce unique characterization of metabolic perturbations. In this study, UPLC/ESI-HDMS in high-accuracy mode coupled with pattern recognition analysis was carried out to investigate the mechanism and saliva metabolite biomarkers for acupuncture treatment at 'Zusanli' acupoint (ST-36) as a case study. Putative metabolite identifications for these ions were obtained through a mass-based database search. As a result, the top canonical pathways including phenylalanine metabolism, alanine, aspartate and glutamate metabolism, d-glutamine and d glutamate metabolism, and steroid hormone biosynthesis pathways were acutely perturbed. 26 differential metabolites were identified by chemical profiling, and may be useful to clarify the physiological basis and mechanism of ST-36. More importantly, network construction has led to the integration of metabolites associated with the multiple perturbation pathways. These results provide useful insights into biomarker discovery utilizing metabolomics as an efficient and cost effective platform. This study opens new possibilities for the selection of saliva as a source of metabolite biomarkers representative of specific disorders. PMID- 24150486 TI - Regulations guiding the interstate shipment of investigational product. AB - PURPOSE: Investigational drug services (IDSs) are often responsible for delivery of investigational product, whether to a study participant pursuant to a prescription or in bulk to another investigational study site. These deliveries must often cross state borders. For situations in which the study is not conducted under an investigational new drug application, these shipments are subject to the legislation of the receiving state. SUMMARY: Every state board of pharmacy in the United States was contacted in an effort to compile a single resource describing interstate investigational product shipping regulations for each state. The majority of the states require registration with their board of pharmacy for shipment of medication into the state. Some states will allow for exceptions and/or fee waiver in certain situations. Controlled substances also fall under the jurisdiction of the Drug Enforcement Administration, with additional constraints placed on their shipment by many states. CONCLUSION: Knowledge of state legislative requirements surrounding interstate shipment of investigational product is crucial for IDSs to maintain compliance with all regulations. This document provides an important framework for obtaining and interpreting this information. However, as legislation changes on a regular basis, current legislation should be reviewed prior to the commencement of interstate shipping. PMID- 24150487 TI - Regulatory authority approaches to deploying quality improvement standards to community pharmacies: insights from the SafetyNET-RX program. AB - BACKGROUND: Continuous quality improvement (CQI) programs provide an effective means to improve the safety and quality of community pharmacy practice. The role of formal support processes in ensuring the success of these CQI programs is explored in this research using the SafetyNET-Rx project. OBJECTIVE: The primary objectives of this research were to determine how knowledge of, and confidence in, mandated CQI standards differs among pharmacies with access to formal support mechanisms and those without and the challenges faced by both. METHODS: A survey questionnaire was mailed to 179 community pharmacies in Nova Scotia, Canada, in spring 2011. Quantitative results were analyzed using the Mann-Whitney U test for nonparametric data. Qualitative open-ended responses were analyzed using content analysis. RESULTS: Performing the Mann-Whitney U test indicated that a number of differences exist between the 2 groups with respect to: (1) staff knowledge of reporting quality-related events (QREs) to an anonymous database; (2) conducting annual pharmacy safety self-assessments; (3) confidence in meeting these 2 elements; and (4) documenting changes to address QREs. A number of challenges were identified by respondents through the open-ended questions. CONCLUSIONS: This research highlights the value of the active provision of formal support when developing standards related to quality improvement. PMID- 24150488 TI - Outcomes of 3-year-old children with hearing loss and different types of additional disabilities. AB - This research investigated the speech, language, and functional auditory outcomes of 119 3-year-old children with hearing loss and additional disabilities. Outcomes were evaluated using direct assessment and caregiver report. Multiple regressions revealed that type of additional disability and level of maternal education were significant predictors of language outcomes. Poorer outcomes were achieved in a combined group of children with autism, cerebral palsy, and/or developmental delay (DD) (Group A), compared with children with vision or speech output impairments, syndromes not entailing DD, or medical disorders (Group B). Better outcomes were associated with higher levels of maternal education. The association between better language outcomes and earlier cochlear implant switch on approached significance. Further regression analyses were conducted separately for children with different types of additional disabilities. Level of maternal education was the only significant predictor of outcomes for Group A children, whereas degree of hearing loss was the strongest predictor for children in Group B. The findings highlight the variable impact that different types of additional disabilities can have on language development in children with hearing loss. PMID- 24150489 TI - Spoken english language development among native signing children with cochlear implants. AB - Bilingualism is common throughout the world, and bilingual children regularly develop into fluently bilingual adults. In contrast, children with cochlear implants (CIs) are frequently encouraged to focus on a spoken language to the exclusion of sign language. Here, we investigate the spoken English language skills of 5 children with CIs who also have deaf signing parents, and so receive exposure to a full natural sign language (American Sign Language, ASL) from birth, in addition to spoken English after implantation. We compare their language skills with hearing ASL/English bilingual children of deaf parents. Our results show comparable English scores for the CI and hearing groups on a variety of standardized language measures, exceeding previously reported scores for children with CIs with the same age of implantation and years of CI use. We conclude that natural sign language input does no harm and may mitigate negative effects of early auditory deprivation for spoken language development. PMID- 24150490 TI - Microbial community dynamics in batch high-solid anaerobic digestion of food waste under mesophilic conditions. AB - Microbial community shifts, associated with performance data, were investigated in an anaerobic batch digester treating high-solid food waste under mesophilic conditions using, a combination of molecular techniques and chemical analysis methods. The batch process was successfully operated with an organic removal efficiency of 44.5% associated with a biogas yield of 0.82 L/g VSremoval. Microbial community structures were examined by denaturing gel gradient electrophoresis. Clostridium and Symbiobacterium organisms were suggested to be mainly responsible for the organic matter catabolism in hydrolysis and acidogenesis reactions. The dynamics of archaeal and methanogenic populations were monitored using real-time PCR targeting 16S rRNA genes. Methanosarcina was the predominant methanogen, suggesting that the methanogenesis took place mainly via an aceticlastic pathway. Hydrogenotrophic methanogens were also supported in high-solid anaerobic digestion of food waste through syntrophism with syntrophic bacterium. Microbial community shifts showed good agreement with the performance parameters in anaerobic digestion, implying the possibility of diagnosing a high solid anaerobic digestion process by monitoring microbial community shifts. On the other hand, the batch results could be relevant to the start-up period of a continuous system and could also provide useful information to set up a continuous operation. PMID- 24150491 TI - Tristetraprolin regulates prostate cancer cell growth through suppression of E2F1. AB - The transcription factor E2F1 is active during G1 to S transition and is involved in the cell cycle and progression. A recent study reported that increased E2F1 is associated with DNA damage and tumor development in several tissues using transgenic models. Here, we show that E2F1 expression is regulated by tristetraprolin (TTP) in prostate cancer. Overexpression of TTP decreased the stability of E2F1 mRNA and the expression level of E2F1. In contrast, inhibition of TTP using siRNA increased the E2F1 expression. E2F1 mRNA contains three AREs within the 3'UTR, and TTP destabilized a luciferase mRNA that contained the E2F1 mRNA 3'UTR. Analyses of point mutants of the E2F1 mRNA 3'UTR demonstrated that ARE2 was mostly responsible for the TTP-mediated destabilization of E2F1 mRNA. RNA EMSA revealed that TTP binds directly to the E2F1 mRNA 3'UTR of ARE2. Moreover, treatment with siRNA against TTP increased the proliferation of PC3 human prostate cancer cells. Taken together, these results demonstrate that E2F1 mRNA is a physiological target of TTP and suggests that TTP controls proliferation as well as migration and invasion through the regulation of E2F1 mRNA stability. PMID- 24150492 TI - Comparison of the organophosphorus hydrolase surface display using InaVN and Lpp OmpA systems in Escherichia coli. AB - The purpose of this study was to compare the ability of an engineered Escherichia coli to degrade chlorpyrifos (Cp) using an organophosphorus hydrolase enzyme by employing the Lpp-OmpA chimera and the N-terminal domain of the ice nucleation protein as anchoring motifs. Tracing of the expression location of the recombinant protein using SDS-PAGE showed the presentation of OPH by both anchors on the outer membrane. This is the first report on the presentation of OPH on the cell surface by Lpp-OmpA under the control of the T7 promoter. The results showed cell growth in the presence of Cp as the sole source of energy, without growth inhibition, and with higher whole-cell activity for both cells harboring plasmids pENVO and pELMO, at approximately 10,342.85 and 10,857.14 U/mg, respectively. Noticeably, the protein displayed by pELMO was lower than the protein displayed by pENVO. It can be concluded that Lpp-OmpA can display less protein, but more functional OPH protein. These results highlight the high potential, of both engineered bacteria, for use in the bioremediation of pesticide-contaminated sources in the environment. PMID- 24150493 TI - Secretory expression, functional characterization, and molecular genetic analysis of novel halo-solvent-tolerant protease from Bacillus gibsonii. AB - A novel protease gene from Bacillus gibsonii, aprBG, was cloned, expressed in B. subtilis, and characterized. High-level expression of aprBG was achieved in the recombinant strain when a junction was present between the promoter and the target gene. The purified recombinant enzyme exhibited similar N-terminal sequences and catalytic properties to the native enzyme, including high affinity and hydrolytic efficiency toward various substrates and a superior performance when exposed to various metal ions, surfactants, oxidants, and commercial detergents. AprBG was remarkably stable in 50% organic solvents and retained 100% activity and stability in 0-4 M NaCl, which is better than the characteristics of previously reported proteases. AprBG was most closely related to the high alkaline proteases of the subtilisin family with a 57-68% identity. The secretion and maturation mechanism of AprBG was dependent on the enzyme activity, as analyzed by site-directed mutagenesis. Thus, when taken together, the results revealed that the halo-solvent-tolerant protease AprBG displays significant activity and stability under various extreme conditions, indicating its potential for use in many biotechnology applications. PMID- 24150494 TI - Elucidation of the regulation of ethanol catabolic genes and ptsG using a glxR and adenylate cyclase gene (cyaB) deletion mutants of Corynebacterium glutamicum ATCC 13032. AB - The cyclic AMP receptor protein (CRP) homolog, GlxR, controls the expression of several genes involved in the regulation of diverse physiological processes in Corynebacterium glutamicum. In silico analysis has revealed the presence of glxR binding sites upstream of genes adhA, ald, and ptsG, encoding glucose-specific phosphotransferase system protein, alcohol dehydrogenase (ADH), and acetaldehyde dehydrogenase (ALDH), respectively. However, the involvement of the GlxR-cAMP complex on the expression of these genes has been explored only in vitro. In this study, the expressions of ptsG, adhA, and ald were analyzed in detail using an adenylate cyclase gene (cyaB) deletion mutant and glxR deletion mutant. The specific activities of ADH and ALDH were increased in both the mutants in glucose and glucose plus ethanol media, in contrast to the wild type. In accordance, the promoter activities of adhA and ald were derepressed in the cyaB mutant, indicating that glxR acts as a repressor of adhA. Similarly, both the mutants exhibited derepression of ptsG regardless of the carbon source. These results confirm the involvement of GlxR on the expression of important carbon metabolic genes; adhA, ald, and ptsG. PMID- 24150495 TI - Improved production of medium-chain-length polyhydroxyalkanoates in glucose-based fed-batch cultivations of metabolically engineered Pseudomonas putida strains. AB - One of the major challenges in metabolic engineering for enhanced synthesis of value-added chemicals is to design and develop new strains that can be translated into well-controlled fermentation processes using bioreactors. The aim of this study was to assess the influence of various fed-batch strategies in the performance of metabolically engineered Pseudomonas putida strains, Deltagcd and Deltagcd-pgl, for improving production of medium-chain-length polyhydroxyalkanoates (mcl-PHAs) using glucose as the only carbon source. First we developed a fed-batch process that comprised an initial phase of biomass accumulation based on an exponential feeding carbon-limited strategy. For the mcl PHA accumulation stage, three induction techniques were tested under nitrogen limitation. The substrate-pulse feeding was more efficient than the constant feeding approach to promote the accumulation of the desirable product. Nonetheless, the most efficient approach for maximum PHA synthesis was the application of a dissolved-oxygen-stat feeding strategy (DO-stat), where P. putida Deltagcd mutant strain showed a final PHA content and specific PHA productivity of 67% and 0.83 g.l(-1).h(-1), respectively. To our knowledge, this mcl-PHA titer is the highest value that has been ever reported using glucose as the sole carbon and energy source. Our results also highlighted the effect of different fed-batch strategies upon the extent of realization of the intended metabolic modification of the mutant strains. PMID- 24150496 TI - Dual role of acidic diacetate sophorolipid as biostabilizer for ZnO nanoparticle synthesis and biofunctionalizing agent against Salmonella enterica and Candida albicans. AB - In the present study, a yeast species isolated from CETP, Vellore, Tamilnadu was identified as Cryptococcus sp. VITGBN2 based on molecular techniques and was found to be a potent producer of acidic diacetate sophorolipid in mineral salt media containing vegetable oil as additional carbon source. The chemical structure of the purified biosurfactant was identified as acidic diacetate sophorolipid through GC-MS analysis. This sophorolipid was used as a stabilizer for synthesis of zinc oxide nanoparticles (ZON). The formation of biofunctionalized ZON was characterized using UV-visible spectroscopy, XRD, scanning electron microscopy (SEM), and Fourier transform infrared spectroscopy. The antimicrobial activities of naked ZON and sophorolipid functionalized ZON were tested based on the diameter of inhibition zone in agar well diffusion assay, microbial growth rate determination, protein leakage analysis, and lactate dehydrogenase assay. Bacterial pathogen Salmonella enterica and fungal pathogen Candida albicans showed more sensitivity to sophorolipid biofunctionalized ZON compared with naked ZON. Among the two pathogens, S. enterica showed higher sensitivity towards sophorolipid biofunctionalized ZON. SEM analysis showed that cell damage occurred through cell elongation in the case of S. enterica, whereas cell rupture was found to occur predominantly in the case of C. albicans. This is the first report on the dual role of yeastmediated sophorolipid used as a biostabilizer for ZON synthesis as well as a novel functionalizing agent showing antimicrobial property. PMID- 24150497 TI - Biofilm formation and antibiotic resistance in Salmonella Typhimurium are affected by different ribonucleases. AB - Biofilm formation and antibiotic resistance are important determinants for bacterial pathogenicity. Ribonucleases control RNA degradation and there is increasing evidence that they have an important role in virulence mechanisms. In this report, we show that ribonucleases affect susceptibility against ribosome targeting antibiotics and biofilm formation in Salmonella. PMID- 24150498 TI - Enzymatic synthesis of dithiolopyrrolone antibiotics using cell-free extract of Saccharothrix algeriensis NRRL B-24137 and biochemical characterization of two pyrrothine N-acyltransferases in this extract. AB - Saccharothrix algeriensis NRRL B-24137 produces naturally different dithiolopyrrolone derivatives. The enzymatic activity of pyrrothine N acyltransferase was determined to be responsible for the transfer of an acyl group from acyl-CoA to pyrrothine core. This activity was also reported to be responsible for the diversity of the dithiolopyrrolone derivatives. Based on this fact, nine dithiolopyrrolone derivatives were produced in vitro via the crude extract of Sa. algeriensis. Three of them have never been obtained before by natural fermentation: acetoacetyl-pyrrothine, hydroxybutyryl-pyrrothine, and dimethyl thiolutin (holomycin). Two acyltransferase activities, acetyltransferase and benzoyltransferase catalyzing the incorporation of linear and cyclic acyl groups to the pyrrothine core, respectively, were biochemically characterized in this crude extract. The first one is responsible for formation of acetyl pyrrothine and the second for benzoyl-pyrrothine. Both enzymes were sensitive to temperature changes: For example, the loss of acetyltransferase and benzoyltransferase activity was 53% and 80% respectively after pre-incubation of crude extract for 60 min at 20 degrees C. The two enzymes were more active in neutral and basal media (pH 7-10) than in the acidic one (pH 3-6). The optimum temperature and pH of acetyltransferase were 40 degrees C and 7, with a Km value of 7.9 MUM and a Vmax of 0.63 MUM/min when acetyl-CoA was used as limited substrate. Benzoyltransferase had a temperature and a pH optimum at 55 degrees C and 9, a Km value of 14.7 MUM, and a Vmax of 0.67 MUM/min when benzoyl- CoA was used as limited substrate. PMID- 24150499 TI - Identification of novel phytase genes from an agricultural soil-derived metagenome. AB - Environmental microorganisms are emerging as an important source of new enzymes for wide-scale industrial application. In this study, novel phytase genes were identified from a soil microbial community. For this, a function-based screening approach was utilized for the identification of phytase activity in a metagenomic library derived from an agricultural soil. Two novel phytases were identified. Interestingly, one of these phytases is an unusual histidine acid phosphatase family phytase, as the conserved motif of the active site of PhyX possesses an additional amino acid residue. The second phytase belongs to a new type, which is encoded by multiple open reading frames (ORFs) and is different to all phytases known to date, which are encoded by a single ORF. PMID- 24150500 TI - Immobilization and characterization of tannase from a metagenomic library and its use for removal of tannins from green tea infusion. AB - Tannase (Tan410) from a soil metagenomic library was immobilized on different supports, including mesoporous silica SBA-15, chitosan, calcium alginate, and amberlite IRC 50. Entrapment in calcium alginate beads was comparatively found to be the best method and was further characterized. The optimum pH of the immobilized Tan410 was shifted toward neutrality compared with the free enzyme (from pH 6.4 to pH 7.0). The optimum temperature was determined to be 45 degrees C for the immobilized enzyme and 30 degrees C for the free enzyme, respectively. The immobilized enzyme had no loss of activity after 10 cycles, and retained more than 90% of its original activity after storage for 30 days. After immobilization, the enzyme activity was only slightly affected by Hg(2+), which completely inhibited the activity of the free enzyme. The immobilized tannase was used to remove 80% of tannins from a green tea infusion on the first treatment. The beads were used for six successive runs resulting in overall hydrolysis of 56% of the tannins. PMID- 24150501 TI - Do head-on-trunk signals modulate disengagement of spatial attention? AB - Body schema is indispensable for sensorimotor control and learning, but whether it is associated with cognitive functions, such as allocation of spatial attention, remains unclear. Observations in patients with unilateral spatial neglect support this view, yet data from neurologically normal participants are inconsistent. Here, we investigated the influence of head-on-trunk positions (30 degrees left or right, straight ahead) on disengagement of attention in healthy participants. Five experiments examined the effects of valid or invalid cues on spatial shifts of attention using the Posner paradigm. Experiment 1 used a forced choice task. Participants quickly reported the location of a target that appeared left or right of the fixation point, preceded by a cue on the same (valid) or opposite side (invalid). Experiments 2, 3, and 4 also used valid and invalid cues but required participants to simply detect a target appearing on the left or right side. Experiment 5 used a speeded discrimination task, in which participants quickly reported the orientation of a Gabor. We observed expected influences of validity and stimulus onset asynchrony as well as inhibition of return; however, none of the experiments suggested that head-on-trunk position created or changed visual field advantages, contrary to earlier reports. Our results showed that the manipulations of the body schema did not modulate attentional processes in the healthy brain, unlike neuropsychological studies on neglect patients. Our findings suggest that spatial neglect reflects a state of the lesioned brain that is importantly different from that of the normally functioning brain. PMID- 24150502 TI - Explicit knowledge about the availability of visual feedback affects grasping with the left but not the right hand. AB - Previous research (Whitwell et al. in Exp Brain Res 188:603-611, 2008; Whitwell and Goodale in Exp Brain Res 194:619-629, 2009) has shown that trial history, but not anticipatory knowledge about the presence or absence of visual feedback on an upcoming trial, plays a vital role in determining how that feedback is exploited when grasping with the right hand. Nothing is known about how the non-dominant left hand behaves under the same feedback regimens. In present study, therefore, we compared peak grip aperture (PGA) for left- and right-hand grasps executed with and without visual feedback (i.e., closed- vs. open-loop conditions) in right-handed individuals under three different trial schedules: the feedback conditions were blocked separately, they were randomly interleaved, or they were alternated. When feedback conditions were blocked, the PGA was much larger for open-loop trials as compared to closed-loop trials, although this difference was more pronounced for right-hand grasps than left-hand grasps. Like Whitwell et al., we found that mixing open- and closed-loop trials together, compared to blocking them separately, homogenized the PGA for open- and closed-loop grasping in the right hand (i.e., the PGAs became smaller on open-loop trials and larger on closed-loop trials). In addition, the PGAs for right-hand grasps were entirely determined by trial history and not by knowledge of whether or not visual feedback would be available on an upcoming trial. In contrast to grasps made with the right hand, grasps made by the left hand were affected both by trial history and by anticipatory knowledge of the upcoming visual feedback condition. But these effects were observed only on closed-loop trials, i.e., the PGAs of grasps made with the left hand on closed-loop trials were smaller when participants could anticipate the availability of feedback on an upcoming trial (alternating trials) than when they could not (randomized trials). In contrast, grasps made with the left hand on open-loop trials exhibited the same large PGAs under all feedback schedules: blocked, random, or alternating. In other words, there was no evidence for homogenization. Taken together, these results suggest that in addition to the real-time demands of the task, such as the target's size and position and the availability of visual feedback, the initial (i.e., pre movement) programming of right-hand grasping relies on what happened on the previous trial, whereas the programming of left-hand grasping is more cognitively supervised and exploits explicit information about trial order to prepare for an upcoming trial. PMID- 24150503 TI - Impact of WHO recommendations to eliminate industrial trans-fatty acids from the food supply in Latin America and the Caribbean. AB - BACKGROUND: The World Health Organization (WHO) has deemed that there is enough evidence to recommend the elimination of industrially produced trans-fatty acids (TFA) from the food supply. This article evaluates government-led public health strategies in countries in Latin America and the Caribbean (LAC), and factors perceived to affect following WHO's recommendation to eliminate industrially produced TFA. METHODS: Descriptive, prospective multiple case studies integrated data from open-ended questionnaires to representatives of ministries of health, and systematic review of internal and publicly available documents in 13 LAC countries. FINDINGS: Overall, government efforts to follow WHO recommendations have not been well co-ordinated throughout the region. Evidence for this includes the lack of standardization of TFA definitions. For example, some countries exclude naturally occurring TFA from the definitions, whereas others leave the option open to their inclusion. As a consequence, the criteria for trans-free nutrient claims and labelling requirements are inconsistent across the region. Government-led strategies varied from banning or limiting TFA content in the food supply to voluntary labelling of TFA. The identified challenges to the implementation of policies to reduce TFA include the shortage of information on TFA content of diets and foods, consumer unawareness of TFA and lack of monitoring and surveillance. The identified enabling factors were intersectoral collaboration with industry, mandatory labelling regulation and international and national visibility of the topic, which facilitated reduction of TFA content. INTERPRETATION: A co-ordinated effort is required to achieve virtual elimination of all TFA in the region, as recommended by WHO. Standardization of the definition of TFA across the region would facilitate regulation, consumer education efforts and monitoring and surveillance efforts. Simultaneously, countries need to determine their level of exposure to TFA through the implementation of small surveys to assess blood TFA levels using blood spots, and the evaluation of TFA in fat sources that are commonly used. PMID- 24150504 TI - Dual practice by doctors working in South and East Asia: a review of its origins, scope and impact, and the options for regulation. AB - Health professionals often undertake private work whilst also employed by government. Such dual practice (DP) is found in both high-income and lower- and middle-income countries (LMIC) around the world, with varying degrees of tolerance. This review focuses on DP in South and East Asia in the context of the rapidly expanding mixed health systems in this region. Although good data are lacking, health service uptake in South and East Asia is increasing, particularly in the private sector. Appropriately regulated, DP can improve health service access, the range of services offered and doctors' satisfaction. By contrast, weakly regulated DP can negatively affect public health service access, quality, efficiency and equity, as doctors often pursue the balance of public and private work that maximizes their income and other benefits. The environment for regulation of DP is changing rapidly, with improved communications opportunities, increasing literacy and rising civil society, particularly in this region. Currently, the options for regulating DP include (1) those which restrict the opportunities for dual practitioners to prioritize income and other benefits over their responsibility to the public; these require a level of regulatory capacity often missing in LMIC governments; and (2) those which not only tolerate public sector doctors' private work but also encourage adequate health services for the general public. Growth of the private sector and weak regulation in South and East Asia increases the risk that dual practitioners will ignore the poor. Responsive and decentred regulation of doctors involving professional associations, civil society and other stakeholders is increasingly recommended. Moreover, as governments in LMIC strive for universal health coverage, market and financing opportunities for regulation of DP may arise, particularly involving insurers. This may also help to improve the current imbalance in the urban-rural distribution of doctors. PMID- 24150505 TI - Modeling protein-peptide recognition based on classical quantitative structure affinity relationship approach: implication for proteome-wide inference of peptide-mediated interactions. AB - Peptide-mediated interactions are crucial to a variety of functions in the living cell and are estimated to be involved in up to 40 % of all cellular processes. Fast and reliable inference of such interactions is fundamentally important for our understanding and, then, reconstruction of complete virtual interactomics involved in a specific cell, tissue or organism. In the current study, we performed structure-level characterization, modeling and prediction of protein peptide recognition specificity and stability in a high-throughput manner. To achieve this, the classical chemometrics methodology quantitative structure activity relationship (QSAR), which is traditionally applied to small-molecule entities such as drug compounds and environmental chemicals, was employed to statistically correlate structure features with binding affinities for a panel of structure-solved, affinity-known protein-peptide complexes compiled from the PDB database and literatures. In the standard QSAR procedure, various structural descriptors including physicochemical, geometrical and constitutional parameters that characterize diverse aspects of protein-peptide interaction property were derived from the biomacromolecular complex structure architecture, and these descriptors were then correlated with experimentally measured affinities by using the partial least squares (PLS) regression and Gaussian process (GP) in conjunction with genetic algorithm (GA) variable selection. The nonlinear GA/GP method was found to perform much well as compared to linear GA/PLS modeling, suggesting that the protein-peptide interaction system is highly complicated that may involve strong noise and interactive effect. The optimal GA/GP model revealed that the interface size and solvent effect play a critical role in protein peptide binding, and other properties such as peptide length and flexibility also contribute significantly to the binding. A further test on 2,018 human amphiphysin SH3 domain-binding peptides demonstrated that the purposed QSAR modeling procedure is very fast and effective, which can thus be readily used to perform proteome-wide inference of peptide-mediated interactions. PMID- 24150506 TI - Epoxidation of bromoallenes connects red algae metabolites by an intersecting bromoallene oxide--Favorskii manifold. AB - DMDO epoxidation of bromoallenes gives directly alpha,beta-unsaturated carboxylic acids under the reaction conditions. Calculated (omegaB97XD/6-311G(d,p)/SCRF = acetone) potential energy surfaces and (2)H- and (13)C-labeling experiments are consistent with bromoallene oxide intermediates which spontaneously rearrange via a bromocyclopropanone in an intersecting bromoallene oxide - Favorskii manifold. PMID- 24150507 TI - Point-of-Care Testing. PMID- 24150508 TI - Evolution of Point-of-Care Testing in Australia. AB - Currently no mandatory standards or guidelines exist for Point-of-Care Testing (PoCT) in Australia. In 2001, a report on the role and value of 'near patient testing' in general practice outlined work that was required to assist the Australian Government to decide how to manage PoCT. Phillips Fox reported that adoption of mandatory accreditation requirements was not justified by the level of risk associated with PoCT. If implemented appropriately, PoCT could be useful with frontline management of chronic disease, relieving stress on general practice and expanding the reach of pathology. Interim PoCT standards in general practice were developed by a Quality Use of Pathology committee, and formed an accreditation framework for the PoCT in General Practice Trial. This trial concluded that PoCT has a role in supporting the primary healthcare team to manage chronic disease patients. While results of the trial are still being considered, the potential impact of funding PoCT in general practice is being treated as part of the wider review of pathology funding currently taking place in Australia. Although Australia has local models from which to draw experience, it has yet to decide the quality framework it would adopt if it was to roll out PoCT in general practice. The quality framework that Australia adopts for PoCT must achieve high quality pathology results that enhance clinical care. PMID- 24150509 TI - i-STAT - Combining Chemistry and Haematology in PoCT. AB - Point-of-care testing (PoCT) is traditionally considered a branch or offshoot of clinical chemistry. The appearance on the market of small, light, inexpensive, multi-purpose, point-of-care analysers, which combine a number of widely differing analytes, has to some degree upset this paradigm. Such analysers, however, are invaluable in some clinical settings. Specialties other than clinical chemistry may have differing views on traditional test management, particularly with regard to quality control (QC), quality assurance (QA), and training. These views must be considered when designing an overall PoCT management plan. Test management issues should be resolved by taking the view that it is a 'point-of-care' test, and by looking at the specific test technology and method involved, rather than by just assuming it is a 'haematology' or a 'chemistry' test. Clinical users of a combined PoCT system are principally interested in the generation of good quality results. To avoid confusion, any advice given to clinical staff regarding their analysers should be clear, concise, and above all else, consistent. PMID- 24150510 TI - The Conduct of Quality Control and Quality Assurance Testing for PoCT Outside the Laboratory. PMID- 24150511 TI - Contribution of Industry to PoCT Implementation. PMID- 24150512 TI - A Practical Example of PoCT Working in the Community. PMID- 24150513 TI - Integrating PoCT into Clinical Care. AB - In South Australia, the Integrated Cardiovascular Clinical Network SA (iCCnet SA) is the provider which enacts the recommendations and policies of the state-wide cardiac clinical network working parties in rural and remote areas by developing appropriate clinical tools. Pathology tests play a significant role in contributing to best practice for patient diagnosis and management. As most South Australian country hospitals do not have timely access to pathology results, point-of-care testing (PoCT) for troponin and N-terminal pro-brain natriuretic peptide (NT-proBNP) has been integrated into clinical pathways for the management of possible acute coronary syndrome (ACS) and suspected heart failure patients respectively. Compared with control hospitals of similar size and resources, preliminary results from an iCCnet SA regional hospital showed improved patient outcomes for ACS: 30-day readmission rates were reduced from 10.4% to 4.2% (p = 0.03) and there was a corresponding trend in the reduction of in-hospital death rates from 15.8% to 9.8% (p = 0.1). The establishment of iCCnet SA has improved outcomes for rural patients presenting to hospital with symptoms suggestive of ACS by facilitating the uptake of evidence-based acute cardiac care. Implementation of PoCT equipment into clinical care requires a systematic approach that engages all stakeholders involved in patient care. Provider clinical networks, such as iCCnet SA, provide a structure for effective working relationships between health professionals. PoCT has been critical to the success of the network, but it needs to be implemented within an integrated system of care to produce optimal outcomes. PMID- 24150514 TI - The National QAAMS Program - A Practical Example of PoCT Working in the Community. AB - The Quality Assurance for Aboriginal and Torres Strait Islander Medical Services (QAAMS) Program is the largest and longest-standing national point-of-care testing (PoCT) program in Australia. With a focus on PoCT for diabetes management, it now operates in 115 Indigenous medical services and has been funded continuously by the Australian Government for 11 years. A recent independent evaluation of the QAAMS Program concluded that the program continues to meet best practice standards for Indigenous healthcare, diabetes management and PoCT. PMID- 24150515 TI - The Evidence to Support Point-of-Care Testing. AB - Point-of-care testing (PoCT) is now possible in many areas of clinical medicine. This review examines the evidence for its application in four areas: self monitoring; community testing primarily in the pharmacy; general practice; and the emergency department. In all of these areas except pharmacy, randomised controlled trials of PoCT versus central laboratory testing have been performed, with the results of some of these trials supporting the use of PoCT. Aside from providing evidence, these trials and other observational studies have provided valuable information about how PoCT should be conducted. In particular they have shown that adoption of the technology is often insufficient to achieve a benefit and in some cases a change of care process is also required. PMID- 24150517 TI - Regulatory sequences of the porcine THBD gene facilitate endothelial-specific expression of bioactive human thrombomodulin in single- and multitransgenic pigs. AB - BACKGROUND: Among other mismatches between human and pig, incompatibilities in the blood coagulation systems hamper the xenotransplantation of vascularized organs. The provision of the porcine endothelium with human thrombomodulin (hTM) is hypothesized to overcome the impaired activation of protein C by a heterodimer consisting of human thrombin and porcine TM. METHODS: We evaluated regulatory regions of the THBD gene, optimized vectors for transgene expression, and generated hTM expressing pigs by somatic cell nuclear transfer. Genetically modified pigs were characterized at the molecular, cellular, histological, and physiological levels. RESULTS: A 7.6-kb fragment containing the entire upstream region of the porcine THBD gene was found to drive a high expression in a porcine endothelial cell line and was therefore used to control hTM expression in transgenic pigs. The abundance of hTM was restricted to the endothelium, according to the predicted pattern, and the transgene expression of hTM was stably inherited to the offspring. When endothelial cells from pigs carrying the hTM transgene--either alone or in combination with an aGalTKO and a transgene encoding the human CD46-were tested in a coagulation assay with human whole blood, the clotting time was increased three- to four-fold (P<0.001) compared to wild-type and aGalTKO/CD46 transgenic endothelial cells. This, for the first time, demonstrated the anticoagulant properties of hTM on porcine endothelial cells in a human whole blood assay. CONCLUSIONS: The biological efficacy of hTM suggests that the (multi-)transgenic donor pigs described here have the potential to overcome coagulation incompatibilities in pig-to-primate xenotransplantation. PMID- 24150516 TI - Resting-state cortico-thalamic-striatal connectivity predicts response to dorsomedial prefrontal rTMS in major depressive disorder. AB - Despite its high toll on society, there has been little recent improvement in treatment efficacy for major depressive disorder (MDD). The identification of biological markers of successful treatment response may allow for more personalized and effective treatment. Here we investigate whether resting-state functional connectivity predicted response to treatment with repetitive transcranial magnetic stimulation (rTMS) to dorsomedial prefrontal cortex (dmPFC). Twenty-five individuals with treatment-refractory MDD underwent a 4-week course of dmPFC-rTMS. Before and after treatment, subjects received resting-state functional MRI scans and assessments of depressive symptoms using the Hamilton Depresssion Rating Scale (HAMD17). We found that higher baseline cortico-cortical connectivity (dmPFC-subgenual cingulate and subgenual cingulate to dorsolateral PFC) and lower cortico-thalamic, cortico-striatal, and cortico-limbic connectivity were associated with better treatment outcomes. We also investigated how changes in connectivity over the course of treatment related to improvements in HAMD17 scores. We found that successful treatment was associated with increased dmPFC-thalamic connectivity and decreased subgenual cingulate cortex caudate connectivity, Our findings provide insight into which individuals might respond to rTMS treatment and the mechanisms through which these treatments work. PMID- 24150518 TI - Silencing the glycerol-3-phosphate dehydrogenase gene in Saccharomyces cerevisiae results in more ethanol being produced and less glycerol. AB - Transcription of the gene coding for glycerol-3-phosphate dehydrogenase (GPD1) was repressed in an industrial strain of Saccharomyces cerevisiae using a silencing vector. A fusion fragment containing GPD1 and Kan MX genes was generated by overlap extension PCR, then, the vector, pYES2.0 GPD1/Kan MX, was constructed by inserting the fusion fragment into the S. cerevisiae plasmid, pYES2.0. pYES2.0 GPD1/Kan MX, was linearized by KpnI, transformed into S. cerevisiae using the PEG/LiAc/ssDNA method, and integrated into the S. cerevisiae chromosome. GPD1 silencing gave 20 % less glycerol-3-phosphate dehydrogenase activity, 19 % lower glycerol production, and 9.7 % higher ethanol production compared with the original strain. These findings further the development of industrial S. cerevisiae strains with improved ethanol production and reduced glycerol content for the efficient production of bio-ethanol. PMID- 24150519 TI - Past and future. Current drugs targeting HIV-1 integrase and reverse transcriptase-associated ribonuclease H activity: single and dual active site inhibitors. AB - Catalytic HIV type-1 (HIV-1) integrase (IN) and ribonuclease H (RNase H) domains belong to the polynucleotidyl transferase superfamily and are characterized by highly conserved motifs that coordinate two divalent Mg(2+) cations and are attractive targets for new antiviral agents. Several structural features of both domains are now available. Drugs targeting the HIV-1 IN are currently approved for anti-HIV therapy, while no drug targeting the HIV-1 RNase H function is yet available. This review describes HIV-1 IN and the RNase H function and structures, compounds targeting their active sites and dual inhibition as a new approach for drug development. PMID- 24150520 TI - Effect of lesion location on endometriotic adhesion and angiogenesis in SCID mice. AB - OBJECTIVE: To evaluate the effects of lesion location on adhesion and angiogenesis of transplanted endometriotic lesions in SCID mice. METHODS: Three groups of female SCID mice included intraperitoneal (i.p.) (n = 12), subcutaneous (s.c.) (n = 12), and mock surgery (control) (n = 12). At 2 weeks after ovariectomy, the mice were transplanted with eutopic endometrium from endometriosis patients either subcutaneously or sutured within the peritoneal, or underwent mock surgery. After 4 weeks, the mice were sacrificed to evaluate the adhesion and volume changes of the implanted lesions. Furthermore, semiquantitative immunohistochemical staining was performed to analyze expression of MMP-2 and TIMP-2 as adhesion makers, and vWF, VEGF, and HIF-1alpha as angiogenesis markers. RESULTS: Adhesion occurred in 9 of 12 mice in the i.p. group, 3 of 12 mice in the s.c. group, and 3 of 12 mice in the control group. Fisher's exact test showed that the difference of adhesion occurrence between i.p. and s.c. groups was statistically significant (p < 0.05). Graft volume changes were higher in the s.c. group than those in the i.p. group. MMP-2 expression was higher in the s.c. group than that in the i.p. group (p < 0.01). There was no significant difference of TIMP-2 expression between s.c. and i.p. groups. vWF, VEGF, and HIF-1alpha expression was significantly higher in the s.c. group than that in the i.p. group (p < 0.01). CONCLUSIONS: Lesion location might be involved in the pathological changes of endometriosis. The intraperitoneal location is related to endometriotic adhesion, whereas the subcutaneous location is related to the infiltration of endometriotic lesions. PMID- 24150521 TI - Determinants of alcohol cessation, reduction and no reduction during pregnancy. AB - PURPOSE: Despite public health initiatives targeting the harmful effects of alcohol exposure on fetal growth, 12 % of pregnant women report current alcohol use. For women who reported drinking alcohol prior to pregnancy, we examined several factors as predictors of three alcohol use patterns during the third trimester of pregnancy: cessation, reduction and no reduction. METHODS: Using the 2002-2009 Pregnancy Risk Assessment Monitoring System (PRAMS) dataset (311,428 records), a multinomial logistic regression model was constructed to compare alcohol risk by category: (1) cessation vs. reduction (2) no reduction vs. reduction. RESULTS: In this sample, 49.4 % drank alcohol before pregnancy. Among those who drank before pregnancy, ~87 % quit drinking during pregnancy, 6.6 % reduced, and about 6.4 % reported no reduction. Older women and those with higher education were more likely to reduce than quit their alcohol use. Conversely, women who were black or Hispanic, overweight, obese, or multiparas were more likely to quit than to reduce their prenatal alcohol consumption. Several stressors such as abuse during pregnancy increased their risk of not quitting or not reducing alcohol during the last trimester of pregnancy. CONCLUSIONS: Differentiating prenatal alcohol use patterns can inform the design of targeted interventions and public health policies to meet the Healthy People 2020 objective for achieving a national rate of 98.3 % alcohol abstinence during pregnancy. PMID- 24150522 TI - Liver resection and radiofrequency ablation of very early hepatocellular carcinoma cases (single nodule <2 cm): a single-center study. AB - AIM: The aim of our study was to compare the short-term and long-term outcomes of resection and radiofrequency ablation (RFA) in cases of very early hepatocellular carcinoma (HCC) (tumors<2 cm in diameter). PATIENTS AND METHODS: Between July 2003 and August 2008, 52 patients were diagnosed as very early HCC (<=2 cm), of whom 21 received a liver resection and 31 underwent RFA. We compared the baseline characteristics, the intraoperative data, and the recovery metrics between these two groups including postoperative complications and the 1-, 3-, and 5-year overall and tumor-free survival rates. RESULTS: No statistically significant differences were observed in the baseline characteristics between very early HCC patients allocated to the liver resection group and those in the RFA group. The liver function in the liver resection group was better than that of the RFA group with respect to the Child score (P=0.004), but not the model for end-stage liver disease score (P=0.066). More tumor targets were located in the center of the liver (compared with the periphery) in the RFA group (P=0.003). The RFA patients showed much shorter operative times, less blood loss, and had shorter hospital stays than the resection group but had a much higher overall cost (all P=0.000). The 1-, 3-, and 5-year overall survival rates were 95.2, 85.7, and 81.0%, respectively, for the liver resection group, and 93.5, 90.3, and 80.6%, respectively, for the RFA group (P=0.976). The 1-, 3-, and 5-year tumor-free survival rates were 90.5, 81.0, and 76.2%, respectively, in the resection group and 90.3, 83.9, and 71.0%, respectively, in the RFA group (P=0.830). CONCLUSION: With comparable short-term and long-term effects on overall survival and tumor recurrence rate and with a shorter operative time, less blood loss, and a shorter hospital stay, RFA should be considered as the first choice for the treatment for very early HCCs as it presents an efficacious and economic option. PMID- 24150523 TI - Overexpression of microRNA-183 in human colorectal cancer and its clinical significance. AB - AIM: MicroRNA-183 (miR-183) has been shown to play a potential oncogenic role in colon cancer. The aim of this study was to evaluate the expression of miR-183 in colorectal cancer (CRC) and its potential relevance to clinicopathological characteristics and patient survival. MATERIALS AND METHODS: Surgical specimens of cancer tissue and adjacent normal mucosa were obtained from 94 patients with CRC. The relative expression levels of miR-183 in the cancer and the normal adjacent mucosa were measured by quantitative real-time PCR. We analyzed their correlation with clinicopathological parameters and prognostic value. RESULTS: The relative expression levels of miR-183 were significantly higher in CRC tissues than in the normal adjacent mucosa (P<0.001), and a high expression of miR-183 correlated with advanced clinical stage (P=0.030), lymph node metastasis (P=0.012), and distant metastasis (P=0.049). Kaplan-Meier analysis indicated that patients with high miR-183 expression had a poor overall survival (P=0.002). Moreover, multivariate analysis showed that increased expression of miR-183 was an independent predictor of overall survival. CONCLUSION: The increased expression of miR-183 is closely related to advanced clinical stage, lymph node and distant metastases, and poor prognosis of CRC, indicating that miR-183 may serve as a predictive biomarker for the prognosis or the aggressiveness of CRC. PMID- 24150525 TI - Structural phase transition and photoluminescence properties of YF3 and YF3:Eu3+ under high pressure. AB - We investigate high-pressure induced phase transitions of YF3 and Eu-doped YF3 (YF3:Eu(3+)) by using the angular dispersive synchrotron X-ray diffraction technique at room temperature. It is found that the starting orthorhombic phase transforms into a new high-pressure phase which is identified as hexagonal structure in both YF3 and YF3:Eu(3+). The high-pressure structure of YF3 and YF3:Eu(3+) returned to the orthorhombic phase after release of pressure. The photoluminescence properties of YF3:Eu(3+) have also been studied under high pressure up to 25 GPa. The Eu(3+) ion luminescence lines of (5)D0->(7)F1,2,3,4 transition originating from the orthorhombic phase transform into another group of luminescence lines of hexagonal phase under high pressure, which reveals the pressure-induced structural transition of YF3:Eu(3+). The relative luminescence intensity ratio of (5)D0->(7)F2 to (5)D0->(7)F1 transitions of the Eu(3+) ions is found to increase with increasing pressure before phase transition and decrease after transition finished, indicating reducing and enhancing of the symmetry around the Eu(3+) ions, respectively. PMID- 24150526 TI - Configuration-controlled Au nanocluster arrays on inverse micelle nano-patterns: versatile platforms for SERS and SPR sensors. AB - Nanopatterned 2-dimensional Au nanocluster arrays with controlled configuration are fabricated onto reconstructed nanoporous poly(styrene-block-vinylpyridine) inverse micelle monolayer films. Near-field coupling of localized surface plasmons is studied and compared for disordered and ordered core-centered Au NC arrays. Differences in evolution of the absorption band and field enhancement upon Au nanoparticle adsorption are shown. The experimental results are found to be in good agreement with theoretical studies based on the finite-difference time domain method and rigorous coupled-wave analysis. The realized Au nanopatterns are exploited as substrates for surface-enhanced Raman scattering and integrated into Kretschmann-type SPR sensors, based on which unprecedented SPR-coupling-type sensors are demonstrated. PMID- 24150527 TI - Some unique features of polymer crystallisation. AB - Mono-lamellar single crystals in thin films provide suitable model systems for studying crystallisation of long chain polymers, making distinct differences with respect to small molecules visible. Due to the high viscosity of polymeric melts, transport toward the growth front is slow and the corresponding crystal growth can suitably be followed in time. Besides being able to investigate generic processes in controlling crystal morphology like epitaxial growth or growth front instabilities, thin film studies reveal unique features of polymer crystallisation. In particular, it is possible to observe a logarithmic spatio temporal evolution of the lamellar crystal thickness, caused by continuous rearrangements leading to regions of differing degrees of meta-stability within polymer single crystals. As a consequence of the kinetically determined lamellar thickness and the corresponding variations in melting temperature, polymer crystals allow for self-seeding, i.e., crystals can be re-grown from a melt which contains a few thermodynamically stable remnants of pre-existing crystals acting as seeds. Hence, when a single crystal is molten, all remnants have a unique orientation and thus also the crystals re-grown from these seeds. The logarithmic time-dependence of the variation in crystal thickness is reflected in a number of seeds decreasing exponentially with increasing seeding temperature. Despite their molecular complexity and some unique features, polymers proved to be valuable systems for detailed studies of crystal growth, allowing testing of theoretical concepts of morphology development. PMID- 24150528 TI - Designing functionalizable hydrogels through thiol-epoxy coupling chemistry. AB - A novel and modular strategy has been developed for the preparation of reactive and functionalized hydrogels. In this strategy, thiol-epoxy coupling chemistry was employed for the formation of a hydrophilic network. The hydroxyl groups, generated during the coupling process, were then engaged in anchoring a fluorescent probe to the hydrogel scaffold. PMID- 24150529 TI - A reduced national incidence of anogenital warts in young Danish men and women after introduction of a national quadrivalent human papillomavirus vaccination programme for young women--an ecological study. AB - In January 2009 the human papillomavirus (HPV) vaccine was included in the Danish childhood vaccination programme for girls aged 12 years. A catch-up programme for girls up to 16 years of age was started a couple of months earlier. Based on national register data, anogenital wart (AGW) incidences between January 2001 and December 2011 were estimated. We used chi2 analysis to identify significant trends in proportions of patients diagnosed with AGW in the period before and after inclusion of the HPV vaccine in the program. The development of chlamydia infections was included in this study as a proxy for possible behaviour changes that could affect the AGW incidence. Between 2008 and 2011, a 50% (95% CI 44-56) decrease in AGW incidence was seen among 15-19-year-old men (p = 0.041), from 5.2 to 2.6/1,000. Among women, a 67% (95% CI 63-72) decrease from 11.7 to 3.8/1,000 was seen (p < 0.0001). The decline in frequency of AGW in young Danish women seems to result from the high coverage of the HPV vaccination programme and young men probably benefit from herd immunity. PMID- 24150530 TI - Target-stimulated metallic HgS nanostructures on a DNA-based polyion complex membrane for highly efficient impedimetric detection of dissolved hydrogen sulfide. AB - Target-stimulated metallic HgS nanostructures formed on the DNA-based polyion complex (PIC) membrane were for the first time utilized as an efficient scheme for impedimetric detection of hydrogen sulfide (H2S) by coupling insoluble precipitation with sensitivity enhancement. PMID- 24150531 TI - Reliability and validity of television food advertising questionnaire in Malaysia. AB - Interventions to counter the influence of television food advertising amongst children are important. Thus, reliable and valid instrument to assess its effect is needed. The objective of this study was to determine the reliability and validity of such a questionnaire. The questionnaire was administered twice on 32 primary schoolchildren aged 10-11 years in Selangor, Malaysia. The interval between the first and second administration was 2 weeks. Test-retest method was used to examine the reliability of the questionnaire. Intra-rater reliability was determined by kappa coefficient and internal consistency by Cronbach's alpha coefficient. Construct validity was evaluated using factor analysis. The test retest correlation showed moderate-to-high reliability for all scores (r = 0.40*, p = 0.02 to r = 0.95**, p = 0.00), with one exception, consumption of fast foods (r = 0.24, p = 0.20). Kappa coefficient showed acceptable-to-strong intra-rater reliability (K = 0.40-0.92), except for two items under knowledge on television food advertising (K = 0.26 and K = 0.21) and one item under preference for healthier foods (K = 0.33). Cronbach's alpha coefficient indicated acceptable internal consistency for all scores (0.45-0.60). After deleting two items under Consumption of Commonly Advertised Food, the items showed moderate-to-high loading (0.52, 0.84, 0.42 and 0.42) with the Scree plot showing that there was only one factor. The Kaiser-Meyer-Olkin was 0.60, showing that the sample was adequate for factor analysis. The questionnaire on television food advertising is reliable and valid to assess the effect of media literacy education on television food advertising on schoolchildren. PMID- 24150532 TI - Patient- and physician-related risk factors for hyperkalaemia in potassium increasing drug-drug interactions. AB - PURPOSE: Hyperkalaemia due to potassium-increasing drug-drug interactions (DDIs) is a clinically important adverse drug event. The purpose of this study was to identify patient- and physician-related risk factors for the development of hyperkalaemia. METHODS: The risk for adult patients hospitalised in the University Hospital Zurich between 1 December 2009 and 31 December 2011 of developing hyperkalaemia was correlated with patient characteristics, number, type and duration of potassium-increasing DDIs and frequency of serum potassium monitoring. RESULTS: The 76,467 patients included in this study were prescribed 8,413 potentially severe potassium-increasing DDIs. Patient-related characteristics associated with the development of hyperkalaemia were pulmonary allograft [relative risk (RR) 5.1; p < 0.0001), impaired renal function (RR 2.7; p < 0.0001), diabetes mellitus (RR 1.6; p = 0.002) and female gender (RR 1.5; p = 0.007). Risk factors associated with medication were number of concurrently administered potassium-increasing drugs (RR 3.3 per additional drug; p < 0.0001) and longer duration of the DDI (RR 4.9 for duration >=6 days; p < 0.0001). Physician-related factors associated with the development of hyperkalaemia were undetermined or elevated serum potassium level before treatment initiation (RR 2.2; p < 0.001) and infrequent monitoring of serum potassium during a DDI (interval >48 h: RR 1.6; p < 0.01). CONCLUSION: Strategies for reducing the risk of hyperkalaemia during potassium-increasing DDIs should consider both patient- and physician-related risk factors. PMID- 24150533 TI - Risk of hypertension with regorafenib in cancer patients: a systematic review and meta-analysis. AB - BACKGROUND: Regorafenib is a novel multikinase inhibitor approved for use in metastatic colorectal cancer (mCRC) and locally advanced gastrointestinal stromal tumors (GISTs). Hypertension is one of the major adverse events of this agent, but to date the incidence and risk of hypertension with regorafenib have not been systematically investigated. We have conducted a systematic review and meta analysis of published clinical trials to determine its overall incidence and risk. METHODS: PubMed, Web of Science and abstracts presented at the American Society of Clinical Oncology annual meetings were searched to identify relevant studies published up to September 9, 2013. Eligible studies were prospective phase II or III clinical trials using regorafenib in cancer patients with data on hypertension available. The incidence and relative risk (RR) of hypertension were calculated using a random-effects model. RESULTS: Data from a total of 1,069 patients (regorafenib n = 750; controls n = 319) from five clinical trials were included for analysis. The overall incidence of all-grade and high-grade hypertension were 44.4 % [95 % confidence interval (CI) 30.8-59.0 %) and 12.5 % (95 % CI 5.2-27.1 %), respectively. The use of regorafenib in cancer patients was associated with a significantly increased risk of all-grade (RR 3.76, 95 % CI 2.35-5.99) and high-grade (RR, 8.39, 95 % CI 3.10-22.71) hypertension. The risk might vary with tumor types (P = 0.000). CONCLUSIONS: Patients with cancer receiving regorafenib have a significantly higher risk of developing hypertension. Close monitoring and appropriate management of this hypertension are strongly recommended. PMID- 24150534 TI - Precise size evaluation of extraocular muscles using fat-suppressed fast T1 weighted gradient-recalled echo imaging and multiple gaze fixation targets. AB - PURPOSE: We studied the feasibility of the precise size measurement of extraocular muscles using fast magnetic resonance imaging sequences and gaze fixation targets. MATERIALS AND METHODS: We recruited 20 healthy volunteers and optimized fat-suppressed fast T1-weighted gradient-recalled echo (FS T1-GRE) and single-shot fast spin-echo (SSFSE) imaging for evaluating extraocular muscles. With each eye at 40 degrees abduction and adduction, we scanned the short-axis plane at the maximum diameter of the bilateral lateral and medial rectus muscles and measured the maximal cross-sectional area of the muscles during extension and contraction. We evaluated interobserver reproducibility and variability between the size measurements using the two MR sequences and the measurement reproducibility using FS T1-GRE imaging. RESULTS: The interobserver reproducibility in the muscle size measurements using FS T1-GRE and SSFSE imaging was excellent (r = 0.93-0.94) and moderate to good (r = 0.54-0.75), respectively. The interobserver variability was less with FS T1-GRE than SSFSE imaging (p < 0.01). The reproducibility of the size measurement using FS T1-GRE was good to excellent (r = 0.78-0.92). CONCLUSION: FS T1-GRE imaging with the subject staring at each of multiple targets is useful for evaluating precisely the size of extraocular muscles. PMID- 24150538 TI - Ready to pass the baton. PMID- 24150537 TI - Septal penetration in iodine-123 metaiodobenzylguanidine cardiac sympathetic imaging using a medium-energy collimator. AB - BACKGROUND: Septal penetration of high-energy photons affects the estimation of the heart-to-mediastinum (H/M) ratio in cardiac (123)I-metaiodobenzylguanidine (MIBG) imaging, and the use of a medium-energy (ME) collimator has been shown to improve quantitative accuracy. We investigated the effect of septal penetration on the estimation of H/M ratios using an ME collimator. METHODS AND RESULTS: Point sources of (99m)Tc and (123)I were imaged using various collimators, which indicated that the effect of high-energy photons with the ME collimator was relatively small but larger than that with the high-energy (HE) collimator. Four hours after (123)I-MIBG injection, 20 patients underwent planar anterior chest imaging by different methods in succession. The ME collimator gave lower H/M ratios (mean 2.52) than the HE collimator (2.57), indicating influence of septal penetration in the ME collimator; however, the difference was limited. Although narrowing the energy window from 20% (2.51) to 15% (2.54) increased the H/M ratios in imaging with the ME collimator, the difference was quite limited. CONCLUSIONS: Septal penetration affects the estimation of the H/M ratios using an ME collimator; however, this influence is small and would not have clinical significance. PMID- 24150539 TI - Effects of perceived support from mothers, fathers, and teachers on depressive symptoms during the transition to middle school. AB - The transition to middle school can be a significant stressor for young adolescents, leading to increases in depression for those who are vulnerable. The current study examined how perceived support from mothers, fathers, and teachers independently and interactively predicted developmental patterns of depressive symptoms during adolescents' transition to middle school, and gender differences in these effects of social support. Four timepoints of data were collected from 1,163 participants (48.5 % boys) enrolled in an ethnically diverse suburban middle school in the Midwest between 1.25 and 20.50 months after these participants entered the 7th grade. The results from growth curve modeling indicated that levels of depressive symptoms decreased over time for boys but remained stable for girls during the developmental period examined. There is also evidence that support from mothers, fathers, and teachers independently and inversely predicted levels of depressive symptoms at the beginning of the 7th grade, and support from both mothers and fathers predicted changes in these symptoms. Effects of mothers' support and teachers' support, but not the effect of fathers' support, remained significant in reducing levels of depressive symptoms at 20.50 months from middle school entry. Furthermore, the protective effect of mothers' support was stronger for girls than for boys. Finally, mothers' support interacted with fathers' support and teachers' support to predict levels of depressive symptoms. Specifically, the protective effect of mothers' support was more salient when fathers' support was low, and vice versa. In contrast, support from mothers and teachers had an amplifying, synergistic effect. PMID- 24150540 TI - The role of goal representations, cultural identity, and dispositional optimism in the depressive experiences of American Indian youth from a Northern Plains tribe. AB - American Indian researchers and scholars have emphasized the importance of identifying variables that promote resilience and protect against the development of psychopathology in American Indian youth. The present study examined the role of self-regulation, specifically goal characteristics (i.e., goal self-efficacy, goal specificity, intrinsic vs. extrinsic motivation, and goal conflict) and dispositional optimism, as well as cultural identity and self-reported academic grades in the depressive experiences of American Indian youth from a North American plains tribe. One hundred and sixty-four participants (53% female) completed measures of goal representations, cultural identity, dispositional optimism, academic performance, and depressive symptoms. Results supported a model in which higher goal self-efficacy, American Indian cultural identity, grade point average, and dispositional optimism each significantly predicted fewer depressive symptoms. Moreover, grade point average and goal self-efficacy had both direct and indirect (through dispositional optimism) relationships with depressive symptoms. Our findings underscore the importance of cognitive self regulatory processes and cultural identity in the depressive experiences for these American Indian youth and may have implications for youth interventions attempting to increase resiliency and decrease risk for depressive symptoms. PMID- 24150541 TI - Comparing patterns and predictors of immigrant offending among a sample of adjudicated youth. AB - Research on immigration and crime has only recently started to consider potential heterogeneity in longitudinal patterns of immigrant offending. Guided by segmented assimilation and life course criminology frameworks, this article advances prior research on the immigration-crime nexus in three ways: using a large sample of high-risk adjudicated youth containing first and second generation immigrants; examining longitudinal trajectories of official and self reported offending; and merging segmented assimilation and life course theories to distinguish between offending patterns. Data come from the Pathways to Desistance study containing detailed offending and socio-demographic background information on 1,354 adolescents (13.6 % female; n = 1,061 native-born; n = 210 second generation immigrants; n = 83 first generation immigrants) as they transition to young adulthood (aged 14-17 at baseline). Over 84 months we observe whether patterns of offending, and the correlates that may distinguish them, operate differently across immigrant generations. Collectively, this study offers the first investigation of whether immigrants, conditioned on being adjudicated, are characterized by persistent offending. Results show that first generation immigrants are less likely to be involved in serious offending and to evidence persistence in offending, and appear to be on a path toward desistance much more quickly than their peers. Further, assimilation and neighborhood disadvantage operate in unique ways across generational status and relate to different offending styles. The findings show that the risk for persistent offending is greatest among those with high levels of assimilation who reside in disadvantaged contexts, particularly among the second generation youth in the sample. PMID- 24150542 TI - Prosocial behavior as a protective factor for children's peer victimization. AB - A majority of peer victimization research focuses on its associations with negative outcomes, yet efforts to understand possible protective factors that may mitigate these negative outcomes also require attention. The present study was an investigation of the potential moderating effect of prosocial behaviors on loneliness for youth who are peer victimized. Participants were fourth and fifth grade students (511 total; 49 % boys) who were primarily European American (43.4 %) and Hispanic (48.2 %). Structural Equation Modeling was used to test the interaction of prosocial behavior and peer victimization (relational and overt forms) on loneliness 1 year later. The results indicated that prosocial behavior significantly moderated the relationship between peer victimization (for the relational form only) and loneliness while controlling for levels of perceived peer support. A multi-group comparison by gender further indicated the moderation was significant for boys only. Potential implications for intervention/prevention efforts focused on developing children's prosocial skills as a possible protective factor for relationally victimized youth are discussed. PMID- 24150543 TI - Laryngeal sensation and pharyngeal delay time after (chemo)radiotherapy. AB - The objective of the study was to evaluate the association between changes in laryngeal sensation and initiation of swallowing reflex or swallowing function before and after (chemo)radiotherapy. A prospective study was conducted in a tertiary referral university hospital. Thirteen patients who received (chemo)radiotherapy for treatment of laryngeal or hypopharyngeal cancer were included. Laryngeal sensation was evaluated at the tip of the epiglottis before and 1, 3 months, and 1 year after (chemo)radiotherapy. Videofluoroscopy was performed at the same time. Quantitative determinations included changes in laryngeal sensation, computed analysis of pharyngeal delay time, the distance and velocity of hyoid bone movement during the phase of hyoid excursion, and pharyngeal residue rate (the proportion of the bolus that was left as residue in the pharynx at the first swallow). Laryngeal sensation significantly deteriorated 1 month after (chemo)radiotherapy, but there was a tendency to return to pretreatment levels 1 year after treatment. Neither pharyngeal delay time nor displacement of the hyoid bone changed significantly before and after (chemo)radiotherapy. In addition, there was no significant difference in the mean velocity of hyoid bone movement and the amount of stasis in the pharynx at the first swallow before and after (chemo)radiotherapy. After (chemo)radiotherapy, laryngeal sensation deteriorated. But, in this study, videofluoroscopy showed that swallowing reflex and function were maintained. PMID- 24150544 TI - Central auditory processing and word discrimination in patients with multiple sclerosis. AB - Many multiple sclerosis (MS) patients with normal pure tone threshold suffer from difficulties in their hearing especially speech perception in background noise, which is possibly because of incompetence of central auditory processing in this group. Three audiologic tests including gap in noise test (GIN), duration pattern sequence test (DPST) and word discrimination score (WDS) were used for comparing a number of aspects of central auditory processing between patients with MS and normal subjects. Approximate threshold and percent of correct answers in GIN test, percent of correct answers in DPST test and monosyllabic discrimination in WDS test were obtained through cross-sectional non-invasive study conducted on 26 subjects with relapsing-remitting multiple sclerosis who had mean age of 28.9 (SD 4.1) years, and 26 18-40-year-old ones with normal hearing and mean age of 27.7 (SD 5.2). Results of this study demonstrate increased approximate threshold and reduction of percent of correct answers obtained from GIN test in patients with multiple sclerosis (Pv = 0.0001). Furthermore in patients with MS, the average of correct answers in DPST was lower than normal subjects and finally performance of MS subjects in WDS test in quiet environment was correlated with GIN threshold (r = -/624, Pr = /003). Results of the present study showed that patients with MS had defect in aspects of central auditory processing consisting of temporal resolution, auditory pattern and the memory for auditory task and difficulty in discrimination of speech in noisy environment that are related to the involvement of central nervous system. PMID- 24150545 TI - Primary amyloid goiter mimicking rapid growing thyroid malignancy. AB - Amyloid accumulation in the thyroid gland leading to a clinically detectable mass, known as amyloid goiter, is a rare condition associated with primary amyloidosis. Moreover, a localized primary amyloid goiter involving only the thyroid gland is rarer still. Here, we report a patient with a localized primary amyloid goiter that had grown rapidly, causing dysphagia and dyspnea on exercise, and confused us with malignancy such as anaplastic carcinoma. After surgery, no further symptoms occurred. A diagnosis of amyloid goiter was established on microscopic examination. In patients with a rapidly enlarging thyroid gland presenting with dysphagia, dyspnea, or hoarseness, amyloid goiter and malignancy should both be suspected, even when systemic amyloidosis is not suspected. PMID- 24150546 TI - Factors predictive of outcome following primary total laryngectomy for advanced squamous cell carcinoma. AB - The increasing use of primary chemoradiation (CRT) for laryngeal squamous cell carcinoma (SCC) means that historical surgical data sets are not representative of the modern laryngectomy patient. We analyse a contemporary total laryngectomy (TL) cohort to identify factors predictive of outcome. This is a retrospective consecutive case note review in a UK tertiary referral centre. Demographic, staging, treatment and outcome data were collected. Oncological outcomes are expressed using the Kaplan-Meier method. The log-rank test was used for univariate analysis and cox regression for multivariate analysis. Sixty consecutive patients between 2003 and 2010 underwent primary TL, 28 including partial pharyngectomy. Median age was 61 years and mean follow-up was 24 months (1-78 months). Thirty six patients died during the study period, 24 of their disease. Of the disease-specific deaths, two occurred peri-operatively, four from local, two from regional and 18 from distant disease [two patients had simultaneous local and distant recurrence (DR)]. Five-year overall survival, disease-specific survival, loco-regional recurrence-free survival and distant recurrence-free survival (DRFS) were 36, 51, 87, 62 %, respectively. Of 17 parameters analysed, pN-stage, extra-capsular spread, a non-cohesive tumour front, thyroid infiltration and involvement of level 6 were significant predictors of disease-specific survival (DSS) on univariate analysis. pN > 1 and the presence of adverse histological features were found to be independent predictors of DSS and DRFS on multivariate analysis. Neither was significantly associated with loco-regional recurrence-free survival. Around half of patients who undergo TL for stage IV SCC will die of disease within 5 years, with most deaths attributable to DR. Surgery provides excellent loco-regional control but patients, especially those with advanced nodal disease and/or adverse histological features, should be thoroughly screened for occult distant disease. Level of evidence 4. PMID- 24150547 TI - Effects of the depth of anesthesia on distortion product otoacoustic emissions. AB - To analyze the effects of the depth of anesthesia on inner ear function measured with distortion product otoacoustic emissions (DPOAEs) at 2f 1 - f 2. Thirty patients who underwent tonsillectomy under general anesthesia (GA) were included. Patients were assigned randomly to one of two groups: group 1 (n = 15) received propofol, group 2 (n = 15) sevoflurane as anesthetic agent. The sedation level was assessed by the bispectral index system. DPOAE measurements were performed before premedication (T 1), 5 min after premedication (T 2), 3 min after induction of general anesthesia (T 3) and every 10 min (T 4, T 5) thereafter until the end of surgery at about 23 min post-anesthetic induction, while sedation levels were obtained starting at the beginning until the end of anesthesia. After premedication, both blood oxygen saturation and heart rate decreased. Following induction of anesthesia systolic and diastolic blood pressure decreased, while, as expected, the level of sedation increased. Analyzing the propofol and sevoflurane group separately, both groups showed comparable overall courses of DPOAE levels at higher frequencies (2.8 kHz p = 0.310, 4 kHz p = 0.193, 6 kHz p = 0.269, 8 kHz p = 0.223) and no changes of DPOAE levels compared with baseline values were observed. At T5 the 1 kHz DPOAE level increased in the propofol group and slightly decreased in the sevoflurane group (p < 0.001). While the 1.4 kHz DPOAE level in the propofol group did not change over time the 1.4 kHz DPOAE level decreased in the sevoflurane group (baseline to T 4 p = 0.045; Baseline to T 5 p = 0.004). While overall there were different courses between these two groups in the 2 kHz DPOAE level, in the post hoc analysis only a tendency in the change from baseline to T 4 could be observed (p = 0.082). These results indicate that while the amplitudes of certain DPOAEs were influenced by GA, the depth of anesthesia had no effect on this measure of cochlear function in clinical routine. Therefore, DPOAE measurements in sedation and during GA are useful but the effect of anesthetic agents on DPOAE levels needs to be taken into account when analyzing the test. PMID- 24150548 TI - A novel mutation of DNAH5 in chronic rhinosinusitis and primary ciliary dyskinesia in a Chinese family. AB - The genetic factors underlying the pathogenesis of chronic rhinosinusitis (CRS) remains unclear. We herein identified four related subjects with CRS and primary ciliary dyskinesia (PCD) from geographically disperse Chinese Han communities and performed exome capture and sequencing of one affected individual and unaffected parents. We found a novel mutation in DNAH5 (c. 8030G>A) in CRS and PCD which was different from those attributed to cystic fibrosis and a defect of cilia motility in a Chinese family through exome capture and sequencing. Our findings showed that c. 8030G>A of DNAH5 may be implicated as the disease-causing gene of CRS and PCD in this Chinese family, which may expand the understanding of clinicians on the pathogenesis of CRS. Moreover, the identification of this novel mutation in DNAH5 indirectly indicates that exome capture and sequencing are beneficial in the genetic research of midget consanguinity families. PMID- 24150549 TI - Bilateral ground reaction forces and joint moments for lateral sidestepping and crossover stepping tasks. AB - Racquet sports have high levels of joint injuries suggesting the joint loads during play may be excessive. Sports such as badminton employ lateral sidestepping (SS) and crossover stepping (XS) movements which so far have not been described in terms of biomechanics. This study examined bilateral ground reaction forces and three dimensional joint kinetics for both these gaits in order to determine the demands of the movements on the leading and trailing limb and predict the contribution of these movements to the occurrence of overuse injury of the lower limbs. A force platform and motion-analysis system were used to record ground reaction forces and track marker trajectories of 9 experienced male badminton players performing lateral SS, XS and forward running tasks at a controlled speed of 3 m.s(-1) using their normal technique. Ground reaction force and kinetic data for the hip, knee and ankle were analyzed, averaged across the group and the biomechanical variables compared. In all cases the ground reaction forces and joint moments were less than those experienced during moderate running suggesting that in normal play SS and XS gaits do not lead to high forces that could contribute to increased injury risk. Ground reaction forces during SS and XS do not appear to contribute to the development of overuse injury. The distinct roles of the leading and trailing limb, acting as a generator of vertical force and shock absorber respectively, during the SS and XS may however contribute to the development of muscular imbalances which may ultimately contribute to the development of overuse injury. However it is still possible that faulty use of these gaits might lead to high loads and this should be the subject of future work. Key pointsGround reaction forces and joint moments during lateral stepping are smaller in magnitude than those experienced during moderate running.Force exposure in SS and XS gaits in normal play does not appear to contribute to the development of overuse injuryThe leading and trailing limbs perform distinct roles, acting as a generator of vertical force and shock absorber respectively.This distinct contribution may contribute to the development of muscular imbalances which may ultimately contribute to the development of overuse injury. PMID- 24150550 TI - Proximal and distal factors associated with dropout versus maintained participation in organized sport. AB - The purpose of this study was to investigate a large number of determinants of sport dropout among French adolescents, in order to reveal proximal and distal factors of dropout. 261 current and 106 dropout athletes (M = 14.6) participated to the study. The data were collected by a questionnaire assessing demographic information, athletes' perceptions on their experience, their parents, teammates and coach. t-tests revealed that current and former athletes were distinct on numerous variables. A discriminant function analysis showed three proximal predictors of sport dropout (perceived value of the activity, satisfaction, parents' investment). Subsequent regression analyses showed that perceived value was positively predicted by perceived competence, the value of the activity for teammates, coach's investment, and negatively by conflicts of interest and goal conflict with teammates; satisfaction was positively predicted by the coach's mastery climate, but negatively predicted by conflicts of interest and goal conflict with teammates and with the coach; parents investment was negatively predicted by the goal conflicts with them. This study permitted to discriminate between proximal and more distal psychological antecedents of the dropout behaviour. It brings information relative to the possible targets of interventions aiming at preventing dropout from organized sport. Key pointsGeographical, financial and time constraints did not predict dropout from organized sport.The value of the activity, the level of satisfaction of the athlete, and the perceived parental investment, were identified as proximal predictors of maintained participation.Athletes' perceptions about themselves (perceived competence, conflict of interest) or their coach (investment, climate, goal conflicts), peers (value, goal conflicts) or parents (goal conflicts), seem to act as distal factors. PMID- 24150551 TI - Can the curriculum be used to estimate critical velocity in young competitive swimmers? AB - The aims of the present study were to assess critical velocity using the swimmer curriculum in front crawl events and to compare critical velocity to the velocity corresponding to a 4 mmol.l(-1) of blood lactate concentration and to the velocity of a 30 min test. The sample included 24 high level male swimmers ranged between 14 and 16 years old. For each subject the critical velocity, the velocity corresponding to a 4 mmol.l(-1) of blood lactate concentration and the mean velocity of a 30 min test were determined. The critical velocity was also estimated by considering the best performance of a swimmer over several distances based on the swimmer curriculum. Critical velocity including 100, 200 and 400 m events was not different from the velocity of 4 mmol.l(-1) of blood lactate concentration. Critical velocity including all the swimmer events was not different from the velocity of a 30 min test. The assessment of critical velocity based upon the swimmer curriculum would therefore seem to be a good approach to determine the aerobic ability of a swimmer. The selection of the events to be included in critical velocity assessment must be a main concern in the evaluation of the swimmer. Key pointsCritical velocity using 100, 200 and 400 m events was not different from the velocity of 4 mmol.l(-1) of blood lactate concentration.Critical velocity using all the swimmer events was not different from the velocity of a 30 min test.The assessment of critical velocity based upon the swimmer curriculum seemed to be a good approach to determine the aerobic capacity of a swimmer.The decision on the events to be analysed must be a main concern in the evaluation of the swimmer critical velocity. PMID- 24150552 TI - Effect of the shoulder position on the biceps brachii emg in different dumbbell curls. AB - Incline Dumbbell Curl (IDC) and Dumbbell Preacher Curl (DPC) are two variations of the standard Dumbbell Biceps Curl (DBC), generally applied to optimize biceps brachii contribution for elbow flexion by fixing shoulder at a specific angle. The aim of this study is to identify changes in the neuromuscular activity of biceps brachii long head for IDC, DPC and DBC exercises, by taking into account the changes in load moment arm and muscle length elicited by each dumbbell curl protocol. A single cycle (concentric-eccentric) of DBC, IDC and DPC, was applied to 22 subjects using a submaximal load of 40% estimated from an isometric MVC test. The neuromuscular activity of biceps brachii long head was compared by further partitioning each contraction into three phases, according to individual elbow joint range of motion. Although all protocols elicited a considerable level of activation of the biceps brachii muscle (at least 50% of maximum RMS), the contribution of this muscle for elbow flexion/extension varied among exercises. The submaximal elbow flexion (concentric) elicited neuro muscular activity up to 95% of the maximum RMS value during the final phase of IDC and DBC and 80% for DPC at the beginning of the movement. All exercises showed significant less muscle activity for the elbow extension (eccentric). The Incline Dumbbell Curl and the classical Dumbbell Biceps Curl resulted in similar patterns of biceps brachii activation for the whole range of motion, whereas Dumbbell Preacher Curl elicited high muscle activation only for a short range of elbow joint angle. Key pointsThe Incline Dumbbell Curl and the Dumbbell Biceps Curl resulted in a considerable neuromuscular effort throughout the whole elbow range of motion.The Incline Dumbbell Curl and the Dumbbell Biceps Curl may be preferable for the improvement of biceps brachii force in training programs. PMID- 24150553 TI - Effects of three feedback conditions on aerobic swim speeds. AB - THE PURPOSE OF THIS STUDY WAS TWOFOLD: (a) to develop an underwater chronometer capable to provide feedback while the athlete is swimming, as well as being a control tool for the coach, and (b) to analyse its feedback effect on swim pace control compared with feedback provided by the coach and with no feedback, in 25 m and 50 m swimming pools. 30 male swimmers of national level volunteer to participate. Each swimmer swam 3 x 200 m at aerobic speed (AS) and 3 x 200 m just under the anaerobic threshold speed (AnS), each swam repetition with a different feedback condition: chronometer, coach and without feedback. Results (a) validate the chronometer system developed and (b) show that swimmers pace control is affected by the type of feedback provided, the swim speed elected and the size of the swimming pool. Key pointsProviding concurrent feedback to swimmers improves theis swimming pace control.It is more important to provide feedback to control swim pace when the swimming pool is 50m long.Technological development as this chronometer system, could offload coach work, so coach can focus its time and attention on other performance aspects or other swimmers.Technological developments are more accepted by coaches when they don't interfere on swimmers execution, that is, whet it is not necessary to implement the swimmer with cables and apparatus. PMID- 24150554 TI - Survey of short-term oral corticosteroid administration by orthopaedic physicians in college and high school athletes. AB - The use of oral corticosteroid (OCS) drugs is advocated because of their potent anti-inflammatory effects. They also possess many potential adverse effects. No study has assessed physician prescribing practices of OCS therapy in high school (HS) or college (COL) athletes. This paper reports the prescribing patterns of sports medicine physicians who used short-term OCS therapy and to describe associated complications in HS and COL athletes within a 24- month period. An internet link to a descriptive epidemiology survey was included in an e-mail to all members of the Arthroscopy Association of North America and the American Orthopaedic Society for Sports Medicine. Descriptive statistics and correlation analysis were used to examine responses. Total response rate was 32% (615/1,928). Sixty-six percent of the physicians indicated prescribing OCS to both groups of athletes, while 29% reported prescribing OCS to COL athletes and 5% to HS athletes for musculoskeletal injuries. Physicians who prescribed multiple OCS regimens to the same athlete within the same season (P = 0.01) and physicians who prescribed OCS to the skeletally immature athlete (P = 0.009) reported more complications than other physicians. Among the 412 physicians who did not prescribe OCS in the treatment of athletic induced musculoskeletal injury, 251 (61%) cited a risk of developing medical complications as the primary reason for avoiding use. The reported number of medical complications was low with no cases of avascular necrosis reported for the 2-year recall period. Orthopaedic surgeons who treated athletic induced musculoskeletal injuries with a short-term course of oral corticosteroids reported that high school and college athletes benefited with few medical complications. Key pointsThirty-four percent of orthopaedic sports medicine physicians we surveyed reported prescribing a short-term course of oral corticosteroids for the treatment of an athletic-related musculoskeletal injury within the previous 24 months of answering the survey.The orthopaedic surgeons who treated athletic induced musculoskeletal injuries with a short-term course of OCS reported the high school and college athletes benefited from OCS treatment with few medical complications.Short-term oral corticosteroid use in multiple regimens in the same athlete and in the skeletally immature athlete may pose an increased risk of medical complication. PMID- 24150555 TI - Effects of sodium bicarbonate ingestion on swim performance in youth athletes. AB - The purpose of this study was to evaluate the effect of oral administration of sodium bicarbonate (300 mg.kg(-1) b.w.) on swim performance in competitive, (training experience of 6.6 +/- 0.6 years) youth, (15.1 +/- 0.6 years) male swimmers. The subjects completed a test trial, in a double blind fashion, on separate days, consisting of 4 x 50m front crawl swims with a 1(st) minute passive rest interval twice, on two occasions: after ingestion of bicarbonate or placebo, 72 hours apart, at the same time of the day. Blood samples were drawn from the finger tip three times during each trial; upon arrival to the laboratory, 60 min after ingestion of placebo or the sodium bicarbonate solution and after the 4 x 50m test, during the 1st min of recovery. Plasma lactate concentration, blood pH, standard bicarbonate and base excess were evaluated. The total time of the 4 x 50 m test trial improved from 1.54.28 to 1.52.85s, while statistically significant changes in swimming speed were recorded only during the first 50m sprint (1.92 vs. 1.97 m.s(-1), p < 0.05). Resting blood concentration of HCO(-) 3 increased following the ingestion of sodium bicarbonate from 25.13 to 28.49 mM (p < 0.05). Sodium bicarbonate intake had a statistically significant effect on resting blood pH (7.33 vs. 7.41, p < .05) as well as on post exercise plasma lactate concentration (11.27 vs. 13.06 mM, p < 0.05)). Collectively, these data demonstrate that the ingestion of sodium bicarbonate in youth athletes is an effective buffer during high intensity interval swimming and suggest that such a procedure can be used in youth athletes to increase training intensity as well as swimming performance in competition at distances from 50 to 200 m. Key pointsSodium bicarbonate is an effective ergogenic aid, also in youth athletes.Sodium bicarbonate intake improves swimming sprint performance.Sodium bicarbonate intake increases resting blood pH and bicarbonate level. PMID- 24150556 TI - Effects of voluntary wheel running on satellite cells in the rat plantaris muscle. AB - This study investigated the effects of voluntary wheel running on satellite cells in the rat plantaris muscle. Seventeen 5-week-old male Wistar rats were assigned to a control (n = 5) or training (n = 12) group. Each rat in the training group ran voluntarily in a running-wheel cage for 8 weeks. After the training period, the animals were anesthetized, and the plantaris muscles were removed, weighed, and analyzed immunohistochemically and biochemically. Although there were no significant differences in muscle weight or fiber area between the groups, the numbers of satellite cells and myonuclei per muscle fiber, percentage of satellite cells, and citrate synthase activity were significantly higher in the training group compared with the control group (p < 0.05). The percentage of satellite cells was also positively correlated with distance run in the training group (r = 0.61, p < 0.05). Voluntary running can induce an increase in the number of satellite cells without changing the mean fiber area in the rat plantaris muscle; this increase in satellite cell content is a function of distance run. Key pointsThere is no study about the effect of voluntary running on satellite cells in the rat plantaris muscle.Voluntary running training causes an increase of citrate synthase activity in the rat plantaris muscle but does not affect muscle weight and mean fiber area in the rat plantaris muscle.Voluntary running can induce an increase in the number of satellite cells without hypertrophy of the rat plantaris muscle. PMID- 24150557 TI - Hydrodynamic analysis of different thumb positions in swimming. AB - The aim of the present study was to analyze the hydrodynamic characteristics of a true model of a swimmer hand with the thumb in different positions using numerical simulation techniques. A three-dimensional domain was created to simulate the fluid flow around three models of a swimmer hand, with the thumb in different positions: thumb fully abducted, partially abducted, and adducted. These three hand models were obtained through computerized tomography scans of an Olympic swimmer hand. Steady-state computational fluid dynamics analyses were performed using the Fluent((r)) code. The forces estimated in each of the three hand models were decomposed into drag and lift coefficients. Angles of attack of hand models of 0 degrees , 45 degrees and 90 degrees , with a sweep back angle of 0 degrees were used for the calculations. The results showed that the position with the thumb adducted presented slightly higher values of drag coefficient compared with thumb abducted positions. Moreover, the position with the thumb fully abducted allowed increasing the lift coefficient of the hand at angles of attack of 0 degrees and 45 degrees . These results suggested that, for hand models in which the lift force can play an important role, the abduction of the thumb may be better, whereas at higher angles of attack, in which the drag force is dominant, the adduction of the thumb may be preferable. Key pointsNumerical simulation techniques can provide answers to problems which have been unobtainable using experimental methods.The computer tomography scans allowed the creation of a complete and true digital anatomic model of a swimmer hand.The position with the thumb adducted presented slightly higher values of drag coefficient than the positions with the thumb abducted.The position with the thumb fully abducted allowed increasing the lift coefficient of the hand at angles of attack of 0 and 45 degrees.For hand positions in which the lift force can play an important role the abduction of the thumb may be better whereas at higher angles of attack, in which the drag force is dominant, the adduction of the thumb may be preferable for swimmers. PMID- 24150558 TI - Serum IGF-I and hormonal responses to incremental exercise in athletes with and without left ventricular hypertrophy. AB - We investigated the response of insulin-like growth factor (IGF- I), insulin-like growth factor binding protein-3 (IGFBP-3) and some hormones, i.e., testosterone (T), growth hormone (GH), cortisol (C), and insulin (I), to maximal exercise in road cyclists with and without diagnosed left ventricular hypertrophy. M-mode and two-dimensional Doppler echocardiography was performed in 30 professional male endurance athletes and a group of 14 healthy untrained subjects using a Hewlett Packard Image Point HX ultrasound system with standard imaging transducers. Echocardiography and an incremental physical exercise test were performed during the competitive season. Venous blood samples were drawn before and immediately after the maximal cycling exercise test for determination of somatomedin and hormonal concentrations. The basal concentration of IGF-I was statistically higher (p < 0.05) in athletes with left ventricular muscle hypertrophy (LVH) when compared to athletes with a normal upper limit of the left ventricular wall (LVN) (p < 0.05) and to the control group (CG) (p < 0.01). The IGF-I level increased significantly at maximal intensity of incremental exercise in CG (p < 0.01), LVN (p < 0.05) and LVH (p < 0.05) compared to respective values at rest. Long-term endurance training induced an increase in resting (p < 0.01) and post-exercise (p < 0.05) IGF-I/IGFBP-3 ratio in athletes with LVH compared to LVN. The testosterone (T) level was lower in LVH at rest compared to LVN and CG groups (p < 0.05). These results indicate that resting serum IGF-I concentration were higher in trained subjects with LVH compared to athletes without LVH. Serum IGF- I/IGFBP-3 elevation at rest and after exercise might suggest that IGF-I act as a potent stimulant of left ventricular hypertrophy in chronically trained endurance athletes. Key pointsIn sports training athletes engaged in the same training regimen acquired different stages of cardiac hypertrophy.Physical exercise had a significant effect on serum insulin-like growth factor - I concentration depending on maximal oxygen uptake during endurance exercise.Athletes with clinically diagnosed physiological left ventricular hypertrophy had higher resting serum insulin-like growth factor - I concentration compared to those without left ventricular hypertrophy and sedentary subjects.Increased insulin like growth factor - I release during long-term training seems to significantly contribute to sports-specific functional adaptation of the left ventricle. PMID- 24150559 TI - Familiarization, reliability, and comparability of a 40-m maximal shuttle run test. AB - The aims of this study were to examine familiarization and reliability associated with a 40-m maximal shuttle run test (40-m MST), and to compare performance measures from the test with those of a typical unidirectional multiple sprint running test (UMSRT). 12 men and 4 women completed four trials of the 40-m MST (8 * 40-m; 20 s rest periods) followed by one trial of a UMSRT (12 * 30-m; repeated every 35 s); with seven days between trials. All trials were conducted indoors and performance times were recorded via twin-beam photocells. Significant between trial differences in mean 40-m MST times were indicative of learning effects between trials 1 and 2. Test-retest reliability across the remaining trials as determined by coefficient of variation (CV) and intraclass correlation coefficient (ICC) revealed: a) very good reliability for measures of fastest and mean shuttle time (CV = 1.1 - 1.3%; ICC = 0.91 - 0.92); b) good reliability for measures of blood lactate (CV = 10.1 - 23.9%; ICC = 0.74 - 0.82) and ratings of perceived exertion (CV = 5.3 - 7.6%; ICC = 0.79 - 0.84); and c) poor reliability for measures of fatigue (CV = 38.7%; ICC = 0.59). Comparisons between performance indices of the 40-m MST and the UMSRT revealed significant correlations between all measures, except pre-test blood lactate concentration (r = 0. 47). Whilst the 40-m MST does not appear to provide more information than can be gleaned from a typical UMSRT, following the completion of a familiarization trial, the 40-m MST provides an alternative and, except for fatigue measures, reliable means of evaluating repeated sprint ability. Key pointsTests of multiple sprint performance are a popular means of evaluating repeated sprint ability.Multiple sprint tests incorporating changes of direction may be more ecologically valid than unidirectional protocols.The 40-m maximal shuttle run test is a reliable way of evaluating repeated sprint ability following the completion of one familiarization trial.The 40-m maximal shuttle run test shows no clear advantage over a standard unidirectional multiple sprint test. PMID- 24150560 TI - Physical activity patterns and estimated daily energy expenditures in normal and overweight tunisian schoolchildren. AB - Our aim was to test the normality of physical activity patterns and energy expenditures in normal weight and overweight primary school students. Heart rate estimates of total daily energy expenditure (TEE), active energy expenditure (AEE), and activity patterns were made over 3 consecutive school days in healthy middle-class Tunisian children (46 boys, 44 girls, median age (25(th)-75(th)) percentile, 9.2 (8.8-9.9) years. Our cross-section included 52 students with a normal body mass index (BMI) and 38 who exceeded age-specific BMI limits. TEE, AEE and overall physical activity level (PAL) were not different between overweight children and those with a normal BMI [median values (25(th)-75(th)) 9.20 (8.20-9.84) vs. 8.88 (7.42-9.76) MJ/d; 3.56 (2.59-4.22) vs. 3.85 (2.77-4.78) MJ/d and 1.74 (1.54-2.04) vs. 1.89 (1.66-2.15) respectively]. Physical activity intensities (PAI) were expressed as percentages of the individual's heart rate reserve (%HRR). The median PAI for the entire day (PAI24) and for the waking part of day (PAIw) were lower in overweight than in normal weight individuals [16.3 (14.2-18.9) vs. 20.6 (17.9-22.3) %HRR, p < 0.001) and 24.8 (21.6-28.9) vs.26.2 (24.5-30.8) %HRR, p < 0.01], respectively. Overweight children allocated more of their day to sedentary pursuits [385 (336-468) vs 297 (235-468) min/d, p < 0.001], and less time to moderate physical activity [381(321-457) vs. 460 (380 534) min/d, p < 0.01]. Nevertheless, because of the greater energy cost of a given task, total and active daily energy expenditure did not differ from those with a normal BMI. Key pointsThe physical activity intensity for the entire day (PAI24) and for the waking part of day (PAIw) were lower in overweight than in normal weight individuals.However, because the energy cost of activity is greater in those who are overweight, they do not differ in total energy expenditure or in active energy expenditure.Normal children spend more time in moderate activity and less time in sedentary pursuits than overweight children. PMID- 24150561 TI - Short and longer-term effects of creatine supplementation on exercise induced muscle damage. AB - The purpose of this investigation was to determine if creatine supplementation assisted with reducing the amount of exercise induced muscle damage and if creatine supplementation aided in recovery from exercise induced muscle damage. Two groups of subjects (group 1 = creatine; group 2 = placebo) participated in an eccentric exercise protocol following 7 and 30 days of creatine or placebo supplementation (20 g.d(-1) for 7 d followed by 6g.d(-1) for 23 d = 30 d). Prior to the supplementation period, measurements were obtained for maximal dynamic strength, maximal isometric force, knee range of motion, muscle soreness, and serum levels of creatine kinase (CK) and lactate dehydrogenase (LDH). Following 7 days of creatine supplementation, on day 8, subjects began consuming 6 g.d(-1) of creatine for 23 days. Additionally on days 8 and 31, subjects performed an eccentric exercise protocol using the knee extensors to induce muscle damage. Indirect markers of muscle damage, including maximal isometric force, knee range of motion, muscle soreness, and serum levels of CK and LDH, were collected at 12, 24, and 48 hours following each exercise bout. The results indicated that acute bouts of creatine have no effect on indirect markers of muscle damage for the acute (7 days) bout. However, maximal isometric force was greater for the creatine group versus placebo for the chronic (30 days) bout. This suggests that the ergogenic effect of creatine following 30 days of supplementation may have a positive impact on exercise induced muscle damage. Key pointsEccentric muscle actions highly associated with exercise induced muscle damage.Creatine supplementation has ergogenic effect to increase protein synthesis.Creatine supplementation does not attenuate exercise induced muscle damage with short term supplementation (7 days).Increased maximal isometric force seen with creatine supplementation after 30 days following exercise induced muscle damage.Ergogenic effect of creatine supplementation may contribute to reduced exercise induced muscle damage. PMID- 24150562 TI - A randomised placebo-exercise controlled trial of Kung Fu training for improvements in body composition in overweight/obese adolescents: the "Martial Fitness" study. AB - The purpose of the study was to investigate if Chinese martial arts (Kung Fu, KF) might be effective for improving body composition, as well as being an appealing form of physical activity for inexperienced, sedentary, overweight/obese adolescents. Twenty subjects (age: 13.3 +/- 1.8 y; BMI percentile: 98.6(86.5 - 99.8); 60% girls) were randomly-assigned to the supervised KF or placebo (Tai Chi, TC) control group 3 d.wk(-1) for 6 months. We assessed body composition, including total and regional fat and lean mass, total and regional bone mineral density (BMD), percent lean and fat mass, body mass index and waist circumference, at baseline and after 6 months of training using anthropometry and dual-energy X-ray absorptiometry (DXA). Habitual physical activity and dietary intake were recorded as covariates via self-report at each time-point. As expected due to natural growth, significant increases in height, weight, total and lumbar BMD, and lean mass were seen in the cohort over time, with a trend for increased whole body fat mass, with no difference between groups. By contrast, percent fat and android fat mass via DXA did not increase in either group over time. The absence of a similar expected increase in central adiposity over 6 months could indicate a positive effect of participation in both programs on the metabolically critical abdominal adiposity in this cohort. Further research in this area is warranted to determine ways to increase uptake and compliance, and to see if longer-term martial arts training not only maintains, but improves abdominal fat mass and related metabolic health indices in overweight/ obese adolescents. Key pointsParticipation in our martial arts trial attenuated the increases in body fat mass expected due to growth in our overweight/obese adolescent group.All subjects allocated to the Kung Fu intervention were satisfied with their Kung Fu training, in contrast to our placebo-exercise (Tai Chi) subjects, suggesting that this form of exercise is worth investigating further for adherence and efficacy.This was the first randomized, placebo exercise controlled trial to be conducted, examining the effects of martial arts training alone on body composition in sedentary overweight/obese adolescents. Larger, longer-term trials are required to confirm our findings. PMID- 24150563 TI - Difference in the magnitude of muscle damage between elbow flexors and knee extensors eccentric exercises. AB - The aim of this study was to investigate the difference in the magnitude of muscle damage between maximal eccentric exercises of the elbow flexors (EF) and knee extensors (KE). Twelve sedentary male volunteers participated in the study. Range of motion (ROM), isometric peak torque (IPT), delayed onset of muscle soreness (DOMS), creatine kinase activity (CK), and myoglobin concentration (Mb) were evaluated before, immediately after, and on the 1(st) , 2(nd), 3(rd) , and 7(th) days following exercise. Total work (TW) during exercises was recorded and corrected by muscle volume (TWc). TWc was greater (p < 0.01) for EF [24 (2) joule.cm-3] than for KE [7 (0.4) joule.cm(-3)]. Increases in CK on the 2(nd) , 3(rd) , and 7(th) days (p < 0.01) and increases in Mb on the 1(st) , 2(nd) , 3(rd) , and 7(th) days were significantly (p<0.01) larger for EF than for KE. The decline in IPT was greater (p < 0.05- 0.01) for EF at all test occasions compared with KE. The results of this study demonstrate that the magnitude of muscle damage is greater and the recovery is slower following maximal eccentric exercise of the EF than of the KE for sedentary males. Key pointsThe magnitude of muscle damage is greater and the recovery is slower following maximal eccentric exercise of the EF than of the KE for sedentary males.This may be because of the higher total eccentric work per muscle unit in elbow flexors. PMID- 24150564 TI - A comparison of the sit-and-reach test and the back-saver sit-and-reach test in university students. AB - This study compares the forward reach score, spine and pelvis postures, and hamstring criterion-related validity (concurrent validity) between the sit-and reach test (SR) and the back-saver sit-and-reach test (BS). Seventy-six men (mean age +/- SD: 23.45 +/- 3.96 years) and 67 women (mean age +/- SD: 23.85 +/- 5.36 years) were asked to perform three trials of SR, BS left (BSl), right (BSr), and passive straight leg raise (PSLR) right and left (hamstring criterion measure) in a randomized order. The thoracic, lumbar, and pelvis angles (measured with a Uni level inclinometer) and forward reach scores were recorded once the subjects reached forward as far as possible without flexing the knees. A repeated measure ANOVA was performed followed by Bonferroni's post hoc test. Pearson correlation coefficients were used to define the relationships between SR and BS scores with respect to PSLR. In both men and women, the thoracic angle in BS was significantly greater than in SR (p<0.016). However, no significant differences were found between the tests in lumbar angle, pelvic angle, and forward reach scores. The concurrent validity of the forward reach score as a measure of hamstring extensibility was moderate in women (0.66 0. 76) and weak to moderate in men (0.51 0.59). The concurrent validity was slightly higher in SR than in BS, although no significant differences between the correlation values were observed. There were significant differences in the thoracic angle between the SR and BS, but not in the forward reach score. There was no difference in concurrent validity between the two tests. However, the traditional SR was preferred because it reached better concurrent validity than the BS. Key pointsPrevious studies have analyzed the validity of sit-and-reach and back-saver sit-and-reach tests as criterion measures of hamstring muscle extensibility. The differences in the position of lower limbs between both the tests could influence the spinal and pelvic angles and forward reach score.Forward reach scores, lumbar and pelvic angles showed no significant differences between the tests, while lower thoracic angle was found in the sit-and-reach. However relatively large changes in thoracic angle were required to be confident true difference had occurred.The sit and-reach test is the preferred test over the back-saver sit-and-reach as measure of hamstring muscle extensibility. The concurrent validity of sit-and-reach and back-saver sit-and-reach in men is compromised, and hence, other tests should be considered to evaluate the hamstring extensibility. PMID- 24150565 TI - Possible relationship of folic Acid supplementation and improved flow-mediated dilation in premenopausal, eumenorrheic athletic women. AB - The purpose of this study was to determine if six weeks of folic acid supplementation would improve brachial artery endothelial-dependent flow-mediated dilation in eumenorrheic female runners with previously normal serum folate levels. This was a prospective, double-blinded, randomized pilot study with convenience sampling. Sixteen eumenorrheic subjects who were not taking birth control pills and who ran at least 20 miles/week were randomly assigned to 10 mg/day of folic acid supplementation or placebo for at least 6 weeks. Serum folate levels and brachial artery measurements were made during the early follicular phase of the menstrual cycle, in a sedentary state, following an 8 hour fast; a standard ultrasound technique was used. The brachial artery vasodilator response to reactive hyperemia was similar between the folic acid (6.6% +/- 0.8%, mean +/- SE) and placebo groups (6.5% +/- 0.7%) at baseline. After six weeks, there was a significantly higher change in flow-mediated dilation for the folic acid group (3.5% +/- 0.6%) compared to the placebo group (0.1% +/- 0.2%) (p = 0.01). Serum folate levels also increased significantly in the folic acid group following six weeks of folic acid supplementation. This study demonstrates that brachial artery flow-mediated dilation improves significantly in eumenorrheic female runners with previously normal serum folate levels after 6 weeks of supplementation with folic acid. Key pointsFolic acid improves FMD in eumenorrheic runners.Folic acid improves FMD in women runners. PMID- 24150566 TI - Self-reported versus diagnosed stress fractures in norwegian female elite athletes. AB - The aim of this study was to determine the prevalence of self- reported versus diagnosed stress fractures in female elite athletes and non-athletic controls. A random sample of Norwegian elite athletes from the national teams, aged 13-39 years (n = 186) and a random sample of non-athletic controls (n = 145) in the same age group participated in the study. The athletes represented a junior- or senior team, or a recruiting squad for one of these teams, in one of 46 different sports/events. A higher percentage of athletes self-reported stress fractures (14.0%) compared to those diagnosed with stress fractures (8.1%) (p < 0.001). Six controls self- reported stress fractures, but none of them were diagnosed with stress fractures. These results indicate that self-reporting of stress fractures has low validity. This finding has important implications for further research on stress fractures in athletes. Key pointsThis study is the first to compare self reported and diagnosed stress fractures in the total population of elite athletes representing all kinds of sports.The results indicate that self-reporting of stress fractures has low validity in both athletes and non-athletic controls, and other measurement methods should be considered when evaluating possible stress fractures.Based on our results, stress fractures seem to be a sport-related injury. PMID- 24150567 TI - Relationships between accelerometer-assessed physical activity and health in children: impact of the activity-intensity classification method. AB - It is unknown whether relationships detected between physical activity intensity and health differ according to accelerometer thresholds used [sample-specific thresholds (SSTs), published thresholds (PTs) or the individualized activity related time equivalent (ArteACC)]. SSTs were developed through ActiGraph calibration in 52 boys, aged 8-10 years. The boys subsequently wore an ActiGraph for seven days. SSTs, PTs and ArteACC for moderate (MPA) and vigorous (VPA) activity were applied. Waist circumference (WC), peak oxygen consumption (VO2peak) and blood pressure were assessed. After applying SSTs, 48.9% of boys achieved 60+ minutes of daily MVPA, compared with 8.5% with PTs and 100% with ArteACC. MPA and VPA were correlated with WC and VO2peak, regardless of whether PTs or SSTs were used (WC: MPA r = -0.37 to -0.43; VO2peak: r = 0.34 to 0.39, p < 0.05). With ArteACC, only VPA was correlated with WC (r = -0.39, p < 0.01) and VO2peak (r = 0.35, p < 0.05). Relationships with blood pressure were statistically non-significant. Although estimates of the quantity of activity differed according to thresholds used, relationships detected with health were consistent regardless of whether SSTs or PTs were employed. There was no advantage of using SSTs or individualized thresholds. Researchers are encouraged to use PTs to ensure greater comparability between studies. Key pointsStandardized accelerometer intensity thresholds for evaluating children's physical activity do not exist, therefore determining whether relationships between activity and health differ when using different thresholds is of interest.Although prevalence estimates differ according to the choice of accelerometer intensity threshold, relationships detected between activity and various health outcomes in boys are similar, providing the moderate threshold is at least equivalent to an average brisk walk (i.e., >= 4 METs).Standardization of thresholds between samples should not impact on relationships determined with health and would allow comparability of prevalence estimates. PMID- 24150568 TI - A palmar fracture-dislocation of the proximal interphalangeal joint of the middle finger caused by bowling: a case report. AB - During bowling, a twenty year old man could not pull out his middle finger from the ball in release and injured his finger. X-ray revealed a palmar fracture- dislocation of the PIP joint. We manipulated the PIP joint, but a gap remained at the fracture site on the X-ray after reduction. Surgical treatment was performed with a screw. Postoperatively, the middle finger was fixed with a splint for two weeks, and then active range of motion exercises were started. One year after the operation, the fracture had healed with a congruous joint surface, and the patient had full range of motion in the middle finger with no difficulties in activities of daily living. The etiology of a palmar fracture-dislocation of the PIP joint is still controversial, but we suggested the mechanism of the fracture dislocation was caused by a shearing force to the middle phalangeal base from a dorsal direction. The main cause of the current injury was the poor fit between the middle finger and the hole of the bowling ball. Bowling is a popular and safe sport, but we should be aware of unexpected hand injuries related to bowling which may occur, especially in players at a recreational level. Key pointsWe presented a palmar fracture-dislocation of the PIP joint in a middle finger that occured while bowling.We discussed the mechanism and suggested the main cause of the injury was the poor fit between the middle finger and the hole of the bowling ball.We advised that while bowling is recognized as a safe sport, due to its popularity we should be aware of unexpected hand injuries which may occur, especially in players at a recreational level. PMID- 24150569 TI - The impact of ionic mercury on antioxidant defenses in two mercury-sensitive anaerobic bacteria. AB - While the toxicological effects of mercury (Hg) are well studied in mammals, little is known about the mechanisms of toxicity to bacterial cells lacking an Hg resistance (mer) operon. We determined that Shewanella oneidensis MR-1 is more sensitive to ionic mercury [Hg(II)] under aerobic conditions than in fumarate reducing conditions, with minimum inhibitory concentrations of 0.25 and 2 MUM respectively. This increased sensitivity in aerobic conditions is not due to increased import, as more Hg is associated with cellular material in fumarate reducing conditions than in aerobic conditions. In fumarate reducing conditions, glutathione may provide protection, as glutathione levels decrease in a dose dependent manner, but this does not occur in aerobic conditions. Hg(II) does not change the redox state of thioredoxin in MR1 in either fumarate reducing conditions or aerobic conditions, although thioredoxin is oxidized in Geobacter sulfurreducens PCA in response to Hg(II) treatment. However, treatment with 0.5 MUM Hg(II) increases lipid peroxidation in aerobic conditions but not in fumarate reducing conditions in MR-1. We conclude that the enhanced sensitivity of MR-1 to Hg(II) in aerobic conditions is not due to differences in intracellular responses, but due to damage at the cell envelope. PMID- 24150570 TI - Changes in neural circuitry regulating response-reversal learning and Arc mediated consolidation of learning in rats with methamphetamine-induced partial monoamine loss. AB - Methamphetamine (METH)-induced neurotoxicity results in long-lasting depletions of monoamines and changes in basal ganglia function. We previously reported that rats with METH-induced neurotoxicity no longer engage dorsomedial striatum during a response-reversal learning task, as their performance is insensitive to acute disruption of dorsomedial striatal function by local infusion of an N-methyl-D aspartate receptor antagonist or an antisense oligonucleotide against the activity-regulated cytoskeleton-associated (Arc) gene. However, METH-pretreated rats perform the task as well as controls. Therefore, we hypothesized that the neural circuitry involved in the learning had changed in METH-pretreated rats. To test this hypothesis, rats were pretreated with a neurotoxic regimen of METH or with saline. After 3-5 weeks, rats were trained on the reversal-learning task and in situ hybridization for Arc was performed. A significant correlation between Arc expression and performance on the task was found in nucleus accumbens shell of METH-, but not saline-, pretreated rats. Consistent with the idea that the correlation between Arc expression in a brain region and behavioral performance implicates that brain region in the learning, infusion of an antisense oligonucleotide against Arc into the shell impaired consolidation of reversal learning in METH-, but not saline-, pretreated rats. These findings provide novel evidence suggesting that METH-induced neurotoxicity leads to a shift from dorsal to ventral striatal involvement in the reversal-learning task. Such reorganization of neural circuitry underlying learning and memory processes may contribute to impaired cognitive function in individuals with METH-induced neurotoxicity or others with striatal dopamine loss, such as patients with Parkinson's disease. PMID- 24150572 TI - Differential interference contrast microscopy imaging of micrometer-long plasmonic nanowires. AB - We report polarization- and wavelength-sensitive differential interference contrast (DIC) images and intensities of 2 MUm-long gold nanowires. The feasibility and usefulness of the gold nanowires as optical sensors and probes in biological systems are demonstrated through combining with a DIC microscope. PMID- 24150573 TI - Caregivers' perceptions of the therapeutic benefits of drug treatments for dementia. AB - BACKGROUND AND AIMS: To collect opinions, perceptions, and expectations on the therapeutic benefits of drug treatment for dementia and the impact on the care of the patient in a large sample of caregivers. Only few studies deal with this topic in a small number of participants. METHODS: This used an ad-hoc online questionnaire to collect the opinions of caregivers of patients with dementia and assess their expectations and perceptions of the therapeutic benefits of drug treatments. The questionnaire was accessible for nearly 4 months on the Federazione Alzheimer Italia website and had three sections: (1) information on the patient with dementia; (2) information on the caregiver's perception of the therapeutic benefits of drug treatments; (3) information on caregivers. To evaluate the relationship between the caregiver's expectations of the therapeutic benefits of dementia treatments and some characteristics of the patients and the caregivers, we used the Chi-square test. RESULTS: During the access time, 439 questionnaires were filled, and 369 were validated for inclusion in the analysis; of these, 329 also had information on caregivers. The expectations of drug treatment effects were not statistically significantly influenced by any variables considered about the patients or the caregivers. Caregivers' beliefs about the effectiveness of dementia treatment, their expectations and changes in their lives were clear. CONCLUSIONS: This study addresses a gap in knowledge about caregivers' experiences and their views of drug treatments, and highlights the need for a pharmaceutical treatment that helps to resolve the symptoms and outcomes of dementia. PMID- 24150571 TI - Altered interhemispheric and temporal lobe white matter microstructural organization in severe chronic schizophrenia. AB - Diffusion MRI investigations in schizophrenia provide evidence of abnormal white matter (WM) microstructural organization as indicated by reduced fractional anisotropy (FA) primarily in interhemispheric, left frontal and temporal WM. Using tract-based spatial statistics (TBSS), we examined diffusion parameters in a sample of patients with severe chronic schizophrenia. Diffusion MRI data were acquired on 19 patients with chronic severe schizophrenia and 19 age- and gender matched healthy controls using a 64 gradient direction sequence, (b=1300 s/mm(2)) collected on a Siemens 1.5T MRI scanner. Diagnosis of schizophrenia was determined by Diagnostic and Statistical Manual for Mental Disorders 4th Edition (DSM-IV) Structured Clinical Interview for DSM disorder (SCID). Patients were treatment resistance, having failed to respond to at least two antipsychotic medications, and had prolonged periods of moderate to severe positive or negative symptoms. Analysis of diffusion parameters was carried out using TBSS. Individuals with chronic severe schizophrenia had significantly reduced FA with corresponding increased radial diffusivity in the genu, body, and splenium of the corpus callosum, the right posterior limb of the internal capsule, right external capsule, and the right temporal inferior longitudinal fasciculus. There were no voxels of significantly increased FA in patients compared with controls. A decrease in splenium FA was shown to be related to a longer illness duration. We detected widespread abnormal diffusivity properties in the callosal and temporal lobe WM regions in individuals with severe chronic schizophrenia who have not previously been exposed to clozapine. These deficits can be driven by a number of factors that are indistinguishable using in vivo diffusion-weighted imaging, but may be related to reduced axonal number or packing density, abnormal glial cell arrangement or function, and reduced myelin. PMID- 24150574 TI - Adipocyte-fatty acid binding protein and non-alcoholic fatty liver disease in the elderly. AB - BACKGROUND: Adipocyte-fatty acid binding protein (A-FABP) is an intracellular lipid transporter that mediates metabolically triggered inflammation, and it is associated with insulin resistance, atherogenic dyslipidemia, and cardiovascular risk. AIMS: The aim of this study was to evaluate A-FABP behavior in elderly people, and especially its association with liver steatosis at abdominal ultrasound. METHOD: Cross-sectional study of two cohort of individuals with and without steatosis, with assessment of several clinical and laboratory variables. Prospective evaluation of liver steatosis remodeling after six years of follow up. One hundred and fifty-six subjects aged over 65 years were enrolled. RESULTS: Serum A-FABP positively correlated with body fat percentage, total cholesterol, serum triglycerides and erythrocyte sedimentation rate. Unlike expected, high A FABP levels were associated with absence of liver steatosis, while there was no evidence of association with steatosis grade changes after 6 years of follow-up. CONCLUSION: Among individuals aging more than 65 years included in the study, A FABP was inversely associated with liver steatosis. It can be argued, that still uncovered mechanisms modify A-FABP behavior in elderly people, especially its association with multifactorial diseases. PMID- 24150575 TI - Predictive effects of muscle strength after hospitalization in old patients. AB - BACKGROUND AND AIMS: Frailty is a common situation that often influences clinical outcomes, disability or institutionalization. The present study aims to evaluate the weight of hand grip strength (HGS) reduction in terms of death or re hospitalizations, at 3-month and 1-year follow-up. METHODS: Observational study performed on hospitalized patients aged 65 years or more. The HGS was measured twice: at hospital admission and discharge. The statistical analysis was performed using SPSS, version 18 for Windows. The chi (2) test was used to evaluate the relationship between HGS and different variables. Three-month and 1 year survival and hospital re-admissions have been analyzed using Kaplan-Meier's curves. The analyses have been adjusted for age and gender. RESULTS: A total of 201 hospitalized patients have been recruited. Of them, 76 were males. The mean age was 81.79 +/- 7.409 years. Of all the patients enrolled, 66.2 and 45.3 % did not show any impairment performing activities of daily living and instrumental activities of daily living, respectively. Moreover, patients were not cognitively impaired [SPMSQ (short portable mental status questionnaire ) m +/- SD = 1.47 +/- 0.794]. At 3-month follow-up patients with strength reduction had a relative risk of death more than seven times higher than the others (p = 0.047). Same results were observed at 1-year follow-up (95 % CI = 1.85-9.84; p = 0.000). There was no significant relationship between HGS and hospital re-admissions. CONCLUSIONS: Effects of strength reduction occurring during a period of hospitalization could produce effects even after hospitalization itself. This increases the relevance of maintaining usual physical performance of patients even during hospitalization. PMID- 24150576 TI - Gene Silencing in Skin After Deposition of Self-Delivery siRNA With a Motorized Microneedle Array Device. AB - Despite the development of potent siRNAs that effectively target genes responsible for skin disorders, translation to the clinic has been hampered by inefficient delivery through the stratum corneum barrier and into the live cells of the epidermis. Although hypodermic needles can be used to transport siRNA through the stratum corneum, this approach is limited by pain caused by the injection and the small volume of tissue that can be accessed by each injection. The use of microneedle arrays is a less painful method for siRNA delivery, but restricted payload capacity limits this approach to highly potent molecules. To address these challenges, a commercially available motorized microneedle array skin delivery device was evaluated. This device combines the positive elements of both hypodermic needles and microneedle array technologies with little or no pain to the patient. Application of fluorescently tagged self-delivery (sd)-siRNA to both human and murine skin resulted in distribution throughout the treated skin. In addition, efficient silencing (78% average reduction) of reporter gene expression was achieved in a transgenic fluorescent reporter mouse skin model. These results indicate that this device effectively delivers functional sd-siRNA with an efficiency that predicts successful clinical translation.Molecular Therapy-Nucleic Acids (2013) 2, e129; doi:10.1038/mtna.2013.56; published online 22 October 2013. PMID- 24150577 TI - HIV Tat Domain Improves Cross-correction of Human Galactocerebrosidase in a Gene- and Flanking Sequence-dependent Manner. AB - Krabbe disease is a devastating neurodegenerative lysosomal storage disorder caused by a deficiency of beta-galactocerebrosidase (GALC). Gene therapy is a promising therapeutic approach for Krabbe disease. As the human brain is large and it is difficult to achieve global gene transduction, the efficacy of cross correction is a critical determinant of the outcome of gene therapy for this disease. We investigated whether HIV Tat protein transduction domain (PTD) can improve the cross-correction of GALC. Tat-PTD significantly increased (~6-fold) cross-correction of GALC through enhanced secretion and uptake in a cell-culture model system. The effects of Tat-PTD were gene and flanking amino acids dependent. Tat-fusion increased the secretion of alpha-galactosidase A (alpha-gal A), but this did not improve its cross-correction. Tat-fusion did not change either secretion or uptake of beta-glucocerebrosidase (GC). Tat-PTD increased GALC protein synthesis, abolished reactivity of GC to the 8E4 antibody, and likely reduced mannose phosphorylation in all these lysosomal enzymes. This study demonstrated that Tat-PTD can be useful for increasing cross-correction efficiency of lysosomal enzymes. However, Tat-PTD is not a mere adhesive motif but possesses a variety of biological functions. Therefore, the potential beneficial effect of Tat-PTD should be assessed individually on each lysosomal enzyme.Molecular Therapy-Nucleic Acids (2013) 2, e130; doi:10.1038/mtna.2013.57; published online 22 October 2013. PMID- 24150578 TI - MOD(MDG4)-64.2 protein, isoform of MOD(MDG4) loci, directly interacts with the Tweedle protein family of Drosophila melanogaster. PMID- 24150579 TI - Structure functional analysis of the vole Nanog 5' regulatory region. PMID- 24150580 TI - Rate of alternative electron transport in arabidopsis mitochondria affects the expression of the glutamate dehydrogenase gene gdh2. PMID- 24150581 TI - Accumulation of changes in the genome of shallot virus X persisting in vegetatively reproduced plants. PMID- 24150582 TI - Cloning and sequence analysis of cDNA encoding a new short form of rat acid chitinase. PMID- 24150583 TI - Polyethyleneimine-coated magnetic nanoparticles for cell labeling and modification. PMID- 24150584 TI - Biological activity of lipophilic derivatives of peptide 562-572 of rat luteinizing hormone receptor. PMID- 24150585 TI - Alteration of the catalytic properties of divinyl ether synthase as a result of substitutions of unique amino acids. PMID- 24150586 TI - Oxidative modification of fibrinogen molecules. PMID- 24150587 TI - Analysis of genome-wide contacts of forum terminus in Drosophila S2 cells. PMID- 24150588 TI - Insulin affects reproduction and juvenile hormone metabolism under normal and stressful conditions in Drosophila females. PMID- 24150589 TI - A recessive mutation causing oogenesis disruption found in the third chromosome of D. melanogaster strain Zvenigorod. PMID- 24150590 TI - Signaling effects of substrate stimulation of nNOS in rat soleus after eccentric exercise. PMID- 24150591 TI - Synthetic applications of arylboronic acid via an aryl radical transfer pathway. AB - The transition-metal-catalyzed functionalization of arylboronic acids is the most powerful tool for the formation of carbon-carbon and carbon-heteroatom bonds in modern organic synthesis. These transformations are generally considered to proceed via organometallic intermediates generated by transmetalation from the boronic acids. Interestingly, there is a novel recognition that arylboronic acids can serve as aryl radical precursors via oxidative carbon-boron bond cleavage in recent years. Manganese(III) acetate, Ag(I)/persulfate and iron(II or III)/persulfate catalytic systems have been shown to be effective for this transformation. In this review, recent advances in this new area are highlighted and their mechanisms are also discussed. PMID- 24150592 TI - C70-carboxyfullerenes as efficient antioxidants to protect cells against oxidative-induced stress. AB - Oxidative stress induced by excessive production of reactive oxygen species (ROS) has been implicated in the etiology of many human diseases. Acquiring a highly efficient antioxidant with good biocompatibility is of significance in eliminating the deleterious effect induced by the oxidative stress. Herein, we address our efforts on investigating the cytoprotective effect of carboxyfullerenes on H2O2-injured cells. Meanwhile, the uptake and intracellular location of carboxyfullerenes were studied. The results show that C70 carboxyfullerenes (dimalonic acid C70 fullerene (DF70) and trimalonic acid C70 fullerene (TF70)) exhibit an obviously protective effect against oxidative stress on C2C12 cells at concentrations as low as 2.5 MUmol L(-1), whereas C60 carboxyfullerenes (dimalonic acid C60 fullerene (DF60) and quadri-malonic acid C60 fullerene (QF60)) show a protective effect at relatively higher concentration (40 MUmol L(-1)). The molecular structure of carboxyfullerenes and the physiological state of cells play an important role in the different cytoprotective capability. Further study reveals that DF70 and TF70 could enter into cells and mainly localize into the lysosome, which possibly involves the protective mechanism by stabilizing lysosome. The use of a significantly low concentration of C70-carboxyfullerene as the antioxidative agent will benefit the therapeutic approaches aiming at alleviating ROS-induced injuries such as muscle disorder and arthritis. PMID- 24150593 TI - Antibody-drug conjugates: targeting melanoma with cisplatin encapsulated in protein-cage nanoparticles based on human ferritin. AB - A novel antibody-drug conjugate (ADC) was synthesized incorporating ferritin based nanoparticles. An average of three molecules of monoclonal antibody (mAb) Ep1 to the human melanoma-specific antigen CSPG4 were conjugated to a single ferritin cage encapsulating about 50 cisplatin molecules (HFt-Pt-Ep1). The HFt-Pt Ep1 nanoparticle had an estimated molecular size of about 900 kD and 33 nm, and flow cytometry demonstrated specific binding to a CSPG4(+) melanoma cell line, but not to a CSPG4(-) breast carcinoma cell line. As compared to the cisplatin containing ferritin nanoparticle alone (HFt-Pt), which inhibited thymidine incorporation more efficiently in breast carcinoma than melanoma cells, the mAb derivatized HFt-Pt-Ep1 nanoparticle had a 25-fold preference for the latter. A similar preference for melanoma was observed upon systemic intravenous administration of HFt-Pt-Ep1 to nude mice xenotransplanted with pre-established, palpable melanoma and breast carcinoma tumors. Thus, we have been able to determine precise combinations and stoichiometric relationships between mAbs and nanoparticle protein cages, whereby the latter lose their tropism for ubiquitously distributed cellular receptors, and acquire instead remarkably lineage-selective binding. HFt-Pt-Ep1 is therefore an interesting model to improve the therapeutic index of antiblastic therapy in a tumor such as melanoma, which at its advanced stages is totally refractory to mono- and combination chemotherapy. PMID- 24150594 TI - Comet assay in reconstructed 3D human epidermal skin models--investigation of intra- and inter-laboratory reproducibility with coded chemicals. AB - Reconstructed 3D human epidermal skin models are being used increasingly for safety testing of chemicals. Based on EpiDermTM tissues, an assay was developed in which the tissues were topically exposed to test chemicals for 3h followed by cell isolation and assessment of DNA damage using the comet assay. Inter laboratory reproducibility of the 3D skin comet assay was initially demonstrated using two model genotoxic carcinogens, methyl methane sulfonate (MMS) and 4 nitroquinoline-n-oxide, and the results showed good concordance among three different laboratories and with in vivo data. In Phase 2 of the project, intra- and inter-laboratory reproducibility was investigated with five coded compounds with different genotoxicity liability tested at three different laboratories. For the genotoxic carcinogens MMS and N-ethyl-N-nitrosourea, all laboratories reported a dose-related and statistically significant increase (P < 0.05) in DNA damage in every experiment. For the genotoxic carcinogen, 2,4-diaminotoluene, the overall result from all laboratories showed a smaller, but significant genotoxic response (P < 0.05). For cyclohexanone (CHN) (non-genotoxic in vitro and in vivo, and non-carcinogenic), an increase compared to the solvent control acetone was observed only in one laboratory. However, the response was not dose related and CHN was judged negative overall, as was p-nitrophenol (p-NP) (genotoxic in vitro but not in vivo and non-carcinogenic), which was the only compound showing clear cytotoxic effects. For p-NP, significant DNA damage generally occurred only at doses that were substantially cytotoxic (>30% cell loss), and the overall response was comparable in all laboratories despite some differences in doses tested. The results of the collaborative study for the coded compounds were generally reproducible among the laboratories involved and intra-laboratory reproducibility was also good. These data indicate that the comet assay in EpiDermTM skin models is a promising model for the safety assessment of compounds with a dermal route of exposure. PMID- 24150595 TI - Mechanistic insights into the cytotoxicity and genotoxicity induced by glycidamide in human mammary cells. AB - Acrylamide (AA) is a well-known industrial chemical classified as a probable human carcinogen. Benign and malignant tumours at different sites, including the mammary gland, have been reported in rodents exposed to AA. This xenobiotic is also formed in many carbohydrate-rich foods prepared at high temperatures. For this reason, AA is an issue of concern in terms of human cancer risk. The epoxide glycidamide (GA) is thought to be the ultimate genotoxic AA metabolite. Despite extensive experimental and epidemiological data focused on AA-induced breast cancer, there is still lack of information on the deleterious effects induced by GA in mammary cells. The work reported here addresses the characterisation and modulation of cytotoxicity, generation of reactive oxygen species, formation of micronuclei (MN) and quantification of specific GA-DNA adducts in human MCF10A epithelial cells exposed to GA. The results show that GA significantly induces MN, impairs cell proliferation kinetics and decreases cell viability at high concentrations by mechanisms not involving oxidative stress. KU55933, an inhibitor of ataxia telangiectasia mutated kinase, enhanced the cytotoxicity of GA (P < 0.05), supporting a role of this enzyme in regulating the repair of GA induced DNA lesions. Moreover, even at low GA levels, N7-GA-Gua adducts were generated in a linear dose-response manner in MCF10A cells. These results confirm that human mammary cells are susceptible to GA toxicity and reinforce the need for additional studies to clarify the potential correlation between dietary AA exposure and breast cancer risk in human populations. PMID- 24150597 TI - Capsule commentary on Yoong et al., a cross-sectional study examining Australian general practitioners' identification of overweight and obese patients. PMID- 24150596 TI - Measurement of choroid plexus perfusion using dynamic susceptibility MR imaging: capillary permeability and age-related changes. AB - INTRODUCTION: The cerebrospinal fluid (CSF) plays a major role in the physiology of the central nervous system. The continuous turnover of CSF is mainly attributed to the highly vascularized choroid plexus (CP) located in the cerebral ventricles which represent a complex interface between blood and CSF. We propose a method for evaluating CP functionality in vivo using perfusion MR imaging and establish the age-related changes of associated parameters. METHODS: Fifteen patients with small intracranial tumors were retrospectively studied. MR Imaging was performed on a 3T MR Scanner. Gradient-echo echo planar images were acquired after bolus injection of gadolinium-based contrast agent (CA). The software developed used the combined T1- and T2-effects. The decomposition of the relaxivity signals enables the calculation of the CP capillary permeability (K2). The relative cerebral blood volume (rCBV), mean transit time (MTT), and signal slope decrease (SSD) were also calculated. RESULTS: The mean permeability K2 of the extracted CP was 0.033+/-0.18 s(-1). K2 and SSD significantly decreased with subject's age whereas MTT significantly increased with subject's age. No significant correlation was found for age-related changes in rCBV and rCBF. CONCLUSION: The decrease in CP permeability is in line with the age-related changes in CSF secretion observed in animals. The MTT increase indicates significant structural changes corroborated by microscopy studies in animals or humans. Overall, DSC MR-perfusion enables an in vivo evaluation of the hemodynamic state of CP. Clinical applications such as neurodegenerative diseases could be considered thanks to specific functional studies of CP. PMID- 24150598 TI - The haemodynamic cascade. PMID- 24150599 TI - Copper binding promotes the interaction of cisplatin with human copper chaperone Atox1. AB - Cu(I) binding promotes the platination of Atox1, although cisplatin binds to the copper coordination sites. In addition, Cu(I) binding enhances the competition of Atox1 with DTT in the reaction of cisplatin. These results indicate that cuprous ions could regulate the cellular trafficking of cisplatin. PMID- 24150600 TI - In vitro myoblast motility models: investigating migration dynamics for the study of skeletal muscle repair. AB - Skeletal muscle repair requires the migration of myoblasts (activated satellite cells) both to the injury site and then within the wound to facilitate cellular alignment in preparation for differentiation, fusion and eventual healing. Along this journey, the cells encounter a range of soluble and extracellular matrix factors which regulate their movement and ultimately determine how successful the repair process will be. Sub-optimal migration can lead to a number of scenarios, including reduced myoblast numbers entering the wound, poor alignment and insufficient differentiation to correctly repair the damage. It is therefore critical that all aspects of myoblast migration are understood, particularly in response to the changing growth and matrix factor profile prevalent following skeletal muscle injury. Since 1962, when Boyden first introduced his chemotactic chamber, numerous in vitro migration assays have been developed to mimic the wound more closely. These have increased in complexity to account for the complex micro-environment found in vivo during muscle repair and include a range of modified cell exclusion, chemotactic and three-dimensional assays. This review describes and discusses these advances and highlights the importance they have in expanding our understanding of myoblast migration dynamics. PMID- 24150601 TI - Increased lung cancer risk among patients with pneumococcal pneumonia: a nationwide population-based cohort study. AB - BACKGROUND: The possible effects of pneumonia on subsequent lung cancer have been reported, but no relevant publications have focused on the association between pneumococcal pneumonia and lung cancer. The purpose of this study was to perform a nationwide population-based cohort study to investigate the risk of lung cancer after pneumococcus infection. METHODS: This nationwide population-based cohort study was based on data obtained from the Taiwan National Health Insurance Database. In total, 22,034 pneumococcal pneumonia patients and 88,136 controls, matched for age and sex, were recruited for the study from 1997 to 2010. RESULTS: The incidence rate of lung cancer (28.2 per 1,000 person-years) was significantly higher in pneumococcal pneumonia patients than in controls (8.7 per 1,000 person years; incidence rate ratio, 3.25; 95 % confidence interval, 3.09-3.42; p < 0.001). Cox proportional hazards regression analysis showed a hazard ratio of 4.24 (95 % confidence interval, 3.96-4.55) for the pneumococcal pneumonia cohort after adjustment for age, gender, and comorbidities. CONCLUSIONS: Pneumococcal pneumonia is associated with an increased risk of lung cancer. Thus, physicians should remain aware of this association when assessing patients with pneumococcal pneumonia. PMID- 24150602 TI - 3D printing of biomimetic microstructures for cancer cell migration. AB - To understand the physical behavior and migration of cancer cells, a 3D in vitro micro-chip in hydrogel was created using 3D projection printing. The micro-chip has a honeycomb branched structure, aiming to mimic 3D vascular morphology to test, monitor, and analyze differences in the behavior of cancer cells (i.e. HeLa) vs. non-cancerous cell lines (i.e. 10 T1/2). The 3D Projection Printing system can fabricate complex structures in seconds from user-created designs. The fabricated microstructures have three different channel widths of 25, 45, and 120 microns wide to reflect a range of blood vessel diameters. HeLa and 10 T1/2 cells seeded within the micro-chip were then analyzed for morphology and cell migration speed. 10 T1/2 cells exhibited greater changes in morphology due to channel size width than HeLa cells; however, channel width had a limited effect on 10 T1/2 cell migration while HeLa cancer cell migration increased as channel width decreased. This physiologically relevant 3D cancer tissue model has the potential to be a powerful tool for future drug discoveries and cancer migration studies. PMID- 24150603 TI - Model of pore formation in a single cell in a flow-through channel with micro electrodes. AB - Microfluidic channels with embedded micro-electrodes are of growing use in devices that aim to electroporate single cells. In this article we present an analysis of pore evolution in a single cell passing by two planar electrodes that are separated by a nano-gap. The cell experiences an electric field that changes in time, as it goes over the electrodes in the channel. The nano-gap between the electrodes enhances the electric field's strength in the micro-channel, thus enabling the use of low potential difference between the electrodes. By computing the electric field on the surface of the cell we can calculate the pore density, as predicted by the model described by Krassowska and Filev (Biophys. J. 92(2):404-417, 2007). The simulation presented in this article is a useful tool for planning and executing experiments of single-cell electroporation in flow through devices. We demonstrate how different parameters, such as cell size and the size of the gap between the electrodes, change the pore density and show how electroporation between micro-electrodes on the same plane is different from conventional electroporation between facing electrodes. PMID- 24150604 TI - Irisin stimulates browning of white adipocytes through mitogen-activated protein kinase p38 MAP kinase and ERK MAP kinase signaling. AB - The number and activity of brown adipocytes are linked to the ability of mammals to resist body fat accumulation. In some conditions, certain white adipose tissue (WAT) depots are readily convertible to a ''brown-like'' state, which is associated with weight loss. Irisin, a newly identified hormone, is secreted by skeletal muscles into circulation and promotes WAT "browning" with unknown mechanisms. In the current study, we demonstrated in mice that recombinant irisin decreased the body weight and improved glucose homeostasis. We further showed that irisin upregulated uncoupling protein-1 (UCP-1; a regulator of thermogenic capability of brown fat) expression. This effect was possibly mediated by irisin induced phosphorylation of the p38 mitogen-activated protein kinase (p38 MAPK) and extracellular signal-related kinase (ERK) signaling pathways. Inhibition of the p38 MAPK by SB203580 and ERK by U0126 abolished the upregulatory effect of irisin on UCP-1. In addition, irisin also promoted the expression of betatrophin, another newly identified hormone that promotes pancreatic beta-cell proliferation and improves glucose tolerance. In summary, our data suggest that irisin can potentially prevent obesity and associated type 2 diabetes by stimulating expression of WAT browning-specific genes via the p38 MAPK and ERK pathways. PMID- 24150605 TI - SH2B1 in beta-cells regulates glucose metabolism by promoting beta-cell survival and islet expansion. AB - IGF-1 and insulin promote beta-cell expansion by inhibiting beta-cell death and stimulating beta-cell proliferation, and the phosphatidylinositol (PI) 3 kinase/Akt pathway mediates insulin and IGF-1 action. Impaired beta-cell expansion is a risk factor for type 2 diabetes. Here, we identified SH2B1, which is highly expressed in beta-cells, as a novel regulator of beta-cell expansion. Silencing of SH2B1 in INS-1 832/13 beta-cells attenuated insulin- and IGF-1 stimulated activation of the PI 3-kinase/Akt pathway and increased streptozotocin (STZ)-induced apoptosis; conversely, overexpression of SH2B1 had the opposite effects. Activation of the PI 3-kinase/Akt pathway in beta-cells was impaired in pancreas-specific SH2B1 knockout (PKO) mice fed a high-fat diet (HFD). HFD-fed PKO mice also had increased beta-cell apoptosis, decreased beta-cell proliferation, decreased beta-cell mass, decreased pancreatic insulin content, impaired insulin secretion, and exacerbated glucose intolerance. Furthermore, PKO mice were more susceptible to STZ-induced beta-cell destruction, insulin deficiency, and hyperglycemia. These data indicate that SH2B1 in beta-cells is an important prosurvival and proproliferative protein and promotes compensatory beta cell expansion in the insulin-resistant state and in response to beta-cell stress. PMID- 24150606 TI - OATP1B3 is expressed in pancreatic beta-islet cells and enhances the insulinotropic effect of the sulfonylurea derivative glibenclamide. AB - Organic anion transporting polypeptide OATP1B3 is a membrane-bound drug transporter that facilitates cellular entry of a variety of substrates. Most of the previous studies focused on its hepatic expression and function in hepatic drug elimination. In this study, we report expression of OATP1B3 in human pancreatic tissue, with the abundance of the transporter localized in the islets of Langerhans. Transport studies using OATP1B3-overexpressing MDCKII cells revealed significant inhibition of the cellular uptake of the known substrate cholecystokinin-8 in the presence of the insulinotropic antidiabetes compounds tolbutamide, glibenclamide, glimepiride, and nateglinide and identified glibenclamide as a novel substrate of OATP1B3. Sulfonylurea derivatives exert their insulinotropic effect by binding to the SUR1 subunit of the KATP channels inducing insulin secretion in beta-cells. Here, we show that transient overexpression of human OATP1B3 in a murine beta-cell line (MIN6)-which exhibits glucose and glibenclamide-sensitive insulin secretion-significantly enhances the insulinotropic effect of glibenclamide without affecting glucose-stimulated insulin secretion. Taken together, our data provide evidence that the drug transporter OATP1B3 functions as a determinant of the insulinotropic effect of glibenclamide on the tissue level. Changes in transport activity based on drug drug interactions or genetic variability may therefore influence glibenclamide efficacy. PMID- 24150607 TI - Autoantigen-induced focusing of Vbeta13+ T cells precedes onset of autoimmune diabetes in the LEW.1WR1 rat. AB - The earliest events leading to autoimmune type 1 diabetes (T1D) are not known in any species. A T-cell receptor (TCR)-variable region, TCR-Vbeta13, is required for susceptibility to autoimmune diabetes in rats, and selective depletion of Vbeta13(+) T cells with an allele-specific monoclonal antibody prevents disease in multiple rat strains. To investigate the role of Vbeta13 early in diabetes, we examined islet T-cell transcripts in susceptible (LEW.1WR1) and resistant (LEW.1W and Wistar Furth) strains induced with polyinosinic:polycytidylic acid. Vbeta13(+) T cells displayed antigenic focusing in LEW.1WR1 islets 5 days postinduction and were characterized by a substantial decrease in complementarity determining region 3 diversity. This occurred prior to significant islet T-cell accumulation (day 7) or frank diabetes (days 10-14). Vbeta13(+) transcripts increased in LEW.1WR1 islets during diabetes progression, but not in resistant rats. We also analyzed transcript clonality of rat TCR-Valpha5, an ortholog of the dominant TCR-Valpha chain found on insulin B:9-23-reactive T cells in nonobese diabetic rat islets. We observed clonal expansion of Valpha5(+) transcripts in prediabetic LEW.1WR1 islets, suggesting that rat Valpha5 is also an important component of islet autoantigen recognition. These data provide additional evidence that genome-encoded TCR sequences are important determinants of genetic susceptibility to T1D. PMID- 24150608 TI - Small-molecule inhibitors of PKR improve glucose homeostasis in obese diabetic mice. AB - Obesity and metabolic diseases appear as clusters, often featuring high risk for insulin resistance and type 2 diabetes, and constitute a major global health problem with limited treatment options. Previous studies have shown that double stranded RNA-dependent kinase, PKR, plays an important role in the nutrient/pathogen-sensing interface, and acts as a key modulator of chronic metabolic inflammation, insulin sensitivity, and glucose homeostasis in obesity. Recently, pathological PKR activation was also demonstrated in obese humans, strengthening its prospects as a potential drug target. Here, we investigate the use of two structurally distinct small-molecule inhibitors of PKR in the treatment of insulin resistance and type 2 diabetes in cells and in a mouse model of severe obesity and insulin resistance. Inhibition of PKR reduced stress induced Jun NH2-terminal kinase activation and insulin receptor substrate 1 serine phosphorylation in vitro and in vivo. In addition, treatment with both PKR inhibitors reduced adipose tissue inflammation, improved insulin sensitivity, and improved glucose intolerance in mice after the establishment of obesity and insulin resistance. Our findings suggest that pharmacologically targeting PKR may be an effective therapeutic strategy for the treatment of insulin resistance and type 2 diabetes. PMID- 24150609 TI - A meta-analysis of the association between angiotensin-converting enzyme insertion/ deletion gene polymorphism and the risk of overweight/obesity. AB - BACKGROUND AND OBJECTIVE: The association between angiotensin-converting enzyme insertion/deletion (ACE I/D) gene polymorphism and the risk of overweight/obesity remains controversial. A meta-analysis was conducted to evaluate the association between ACE I/D gene polymorphism and overweight/obesity susceptibility. METHOD: All eligible studies were included in this meta-analysis by searching PubMed, Embase and Cochrane databases through April 2013 according to a predefined criteria. RESULTS: Fourteen case-control studies including 3371 cases and 4490 controls were recruited for the analysis of the association between ACE I/D gene polymorphism and overweight/obesity susceptibility. A significant association was observed between DD genotype and overweight/obesity risk in overall populations and Africans (p=0.014 and 0.010, respectively). D allele was associated with the risk of overweight/ obesity in Africans (p=0.026). However, II genotype might not be a protective factor against overweight/obesity risk in overall populations, Africans, Caucasians and Asians. CONCLUSIONS: DD genotype is a risk factor for the overweight/obesity susceptibility in overall populations, particularly in Africans. D allele is a risk factor for the overweight/obesity susceptibility in Africans. Further larger studies are needed to confirm our findings. PMID- 24150610 TI - The insertion-deletion polymorphism of the ACE gene is associated with increased blood pressure in women at the end of pregnancy. AB - INTRODUCTION: Malfunctioning of the cardiovascular system during pregnancy may be responsible for adverse effects on the 'mother-fetus' system. The cardiovascular system of a pregnant woman develops adaptation to the increased load. Angiotensin converting enzyme (ACE) is known to play an important role in the adaptation. The present study was designed to investigate whether the insertion-deletion (I/D) polymorphism of the ACE gene is associated with the level of arterial blood pressure in women before and during pregnancy. MATERIALS AND METHODS: The level of blood pressure was measured in 591 Russian women (Central Russia) before and during (37-40 weeks term) pregnancy. The women were divided into three groups which were hypertensive, hypotensive, and normotensive according to blood pressure level. Genotyping of the ACE I/D polymorphism was performed using polymerase chain reaction (PCR) and amplified fragment length polymorphism assay. RESULTS: Women with genotype DD showed the highest blood pressure level both during and at the end of pregnancy (p<0.05). The highest frequencies of allele D and genotype DD were found in pregnant women in the hypertensive group. CONCLUSIONS: The deletion variant of the ACE gene is associated with high blood pressure level at the end of pregnancy. PMID- 24150611 TI - Angiotensin-converting enzyme insertion/deletion polymorphism associated with allergic rhinitis susceptibility: evidence from 1410 subjects. AB - BACKGROUND AND OBJECTIVE: Whether the insertion/deletion (I/D) polymorphism of the angiotensin-converting enzyme (ACE) gene increases susceptibility to allergic rhinitis (AR) is still undetermined. Therefore, this meta-analysis was performed to systematically assess the possible association between them. METHODS: The OVID, Medline, Embase, Web of Science, CNKI and Wangfang databases were searched to identify the eligible studies focusing on the association between ACE I/D polymorphism and susceptibility to AR. RESULTS: A total of 1410 subjects from six studies were subjected to meta-analysis. In the overall analysis, ACE I/D polymorphism had a statistically significant association with increased AR risk under all genetic models (p<0.05). In the subgroup analysis by ethnicity, significant elevated AR risks were associated with ACE I/D polymorphism in Asians under all genetic models (p<0.05) and in Caucasians under under allele contrast, homozygous comparison and recessive models (p<0.05). In the subgroup analysis by age, ACE I/D polymorphism was associated with significant elevated risks of AR in adults (p<0.05) but not in children (p>0.05) under all genetic models. CONCLUSIONS: The ACE I/D polymorphism may be a risk factor for AR and studies with large sample size and representative population are warranted to verify this finding. PMID- 24150613 TI - Attitudes of medical students, clinicians and sports scientists towards exercise counselling. AB - We compared the amount of exercise undertaken by medical students, clinicians, and sport scientists with the National Australian Physical Activity (NAPA) Guidelines. A second aim was to compare attitudes to exercise counselling as preventive medicine between university- and clinic-based professionals. The research setting was a university medical school and a sports science sports medicine centre. A 20-item questionnaire was completed by 216 individuals (131 medical students, 43 clinicians and 37 sports scientists). Self-reported physical activity habits, exercise counselling practices and attitudes towards preventive medicine were assessed. The physical activity undertaken by most respondents (70%) met NAPA Guidelines. General practitioners had significantly lower compliance rates with NAPA Guidelines than other professionals. More than half of clinicians and medical students (54%) were less active now compared with levels of activity undertaken prior to graduate training. Most physicians (68%) reported they sometimes discuss physical activity with patients. In contrast, the majority of non-medically qualified respondents (60%) said they never discuss physical activity with their doctor. Most respondents (70%) had positive attitudes to exercise counselling. Sports scientists and respondents who were highly active in childhood had more positive attitudes to exercise counselling than others. Health professionals in this study were more active than the general population, however healthy exercise habits tend to deteriorate after the commencement of medical training. Despite the important role of doctors in health promotion, the degree of exercise counselling to patients is low. Key pointsThe rate of exercise counselling by doctors to patients is lowSports physicians and scientists have substantially more positive attitudes to exercise counselling than clinicians and medical studentsMedical schools have a responsibility to promote physical activity of students and improve training in exercise counselling. PMID- 24150612 TI - 50 years of allosteric interactions: the twists and turns of the models. AB - The concept of indirect or 'allosteric' interaction between topographically distinct sites, and the subsequent 1965 Monod-Wyman-Changeux (MWC) model for the conformational change mediating them, arose around 50 years ago. Many classic regulatory proteins (including haemoglobin, Asp transcarbamylase and nicotinic acetylcholine receptor) follow the central paradigm of the MWC model, which has been expanded and challenged as a result of novel technologies. Importantly, the concept of allosteric interaction has aided our understanding of human diseases and drug design. PMID- 24150614 TI - The Effect of Omega-3 Fatty Acid Supplementation on the Inflammatory Response to eccentric strength exercise. AB - Omega-3 fatty acids (omega-3) have anti-inflammatory properties. However, it is not known if omega-3 supplementation attenuates exercise-induced inflammation. We tested the hypothesis that omega-3 supplementation reduces inflammation that is induced by eccentric arm curl exercise. Healthy adult men and women (n=11; 35 +/- 10 y) performed eccentric biceps curls on two occasions, once after 14d of dietary omega-3 restriction (control trial) and again after 7d of 3,000 mg/d omega-3 supplementation (omega-3 trial). Before and 48 h after eccentric exercise, signs of inflammation was assessed by measuring soreness ratings, swelling (arm circumference and arm volume), and temperature (infrared skin sensor). Arm soreness increased (p < 0.0001) in response to eccentric exercise; the magnitude of increase in soreness was 15% less in the omega-3 trial (p = 0.004). Arm circumference increased after eccentric exercise in the control trial (p = 0.01) but not in the omega-3 trial (p = 0.15). However, there was no difference between trials (p = 0.45). Arm volume and skin temperature did not change in response to eccentric exercise in either trial. These findings suggest that omega-3 supplementation decreases soreness, as a marker of inflammation, after eccentric exercise. Based on these findings, omega-3 supplementation could provide benefits by minimizing post-exercise soreness and thereby facilitate exercise training in individuals ranging from athletes undergoing heavy conditioning to sedentary subjects or patients who are starting exercise programs or medical treatments such as physical therapy or cardiac rehabilitation. Key pointsDietary supplementation with omega-3 fatty acids has been shown to reduce inflammation in numerous inflammatory diseases such as rheumatoid arthritis, inflammatory bowel disease, and Chrohn's disease.Although strenuous exercise is known to cause acute increases in inflammation, it is not clear if omega-3 fatty acid supplementation attenuates this adverse response to exercise.Our research demonstrates that 3000 mg.d-1 omega-3 fatty acid supplementation minimizes the severe, delayed-onset muscle soreness that results from strenuous eccentric strength exercise.This information, along with a plethora of information showing that omega-3 fatty acid supplementation has other health benefits, demonstrates that a readily available over the counter nutritional supplement (i.e. omega-3 fatty acids) reduces delayed-onset soreness caused by strenuous strength exercise.This information has obvious relevance to athletic populations but also to other groups such as physical therapy patients and newly admitted cardiac rehabilitation patients, as muscle soreness, if left unchecked, can slow the progress in adapting to a new exercise program.Furthermore, as inflammation is known to be involved in the pathogenesis if numerous diseases, including heart disease, cancer, and diabetes, it is likely prudent for individuals to use inflammation-attenuating interventions, such as omega-3 supplementation, to keep inflammatory responses to physical activity at a minimum. PMID- 24150615 TI - Influence of Intramuscular Application of Autologous Conditioned Plasma on Systemic Circulating IGF-1. AB - Platelet-rich plasma (PRP) to increase levels of platelets and growth factors has been used for the treatment of sports injuries suggesting to improve healing and regeneration. This method offers some potential especially for elite athletes. However, the insulin like growth factor-1 (IGF-1) is prohibited by the World Anti Doping Agency and, in addition, there may be a possible link between increased levels of IGF-1 and cancer risk. Aim of the study was to evaluate a systemic increase of IGF-1 after local intramuscular administration of PRP in young healthy moderately trained male subjects. Blood samples were drawn and PRP preparation was performed by means of centrifugation. Enriched plasma was injected into the gluteus muscle. Venous blood was collected and serum prepared before as well as after 0.5, 3 and 24 hours after PRP administration. IGF-1 analysis was performed applying an ELISA test kit. No significant systemic increase of mean IGF-1 was found after the PRP injection. Only one subject showed an increase after 24 h, but all IGF-1 values were found within reference limits. We conclude that a single intramuscular application of PRP does not significantly increase systemic IGF-1 levels. Therefore, a single application of PRP is safe with respect to systemic IGF-1 response and cancer risk and this should be allowed for treatment of muscle injuries in elite athletes. Key pointsThere is no increase of systemic IGF-1 levels after a single local intramuscular administration of PRP.Professional athletes and non-athletes alike can benefit from such a treatment option for muscle injuries and related sports injuries without an increased risk of cancer.More studies are warranted to provide definitive evidence to guide surgeon's decision making regarding the appropriate use for PRP products. PMID- 24150616 TI - Exploring the organizational effect of prenatal testosterone upon the sporting brain. AB - The 2D:4D ratio is a putative marker for prenatal testosterone and has the potential to explain variations in sport performance. To date there has been little research into the association between sporting performance, digit ratio and psychological variables. This study examined the relationship between 2D:4D and mental toughness, optimism, goal orientations, aggression, coping style and their association with sporting achievement. A post facto design was adopted. Participants consisted of an opportunity sample of 122 sports people: male (n =60) and female (n = 62) from a university in North East England. Following informed consent, a Vernier Caliper was used to measure digit ratio hand scans. Participants completed self-reports measures including, the Alternative Psychological Performance Inventory (Golby et al., 2008), Sport Mental Toughness Questionnaire (Sheard et al., 2009), Life Orientation Test-Revised (Scheier et al., 1994), Buss-Perry aggression (Buss-Perry, 1992) and 30 item coping style questionnaire (Joseph et al., 1995). MANOVA revealed significant gender differences in 2D:4D with males demonstrating lower ratios (Manning, 2002). The 2D:4D was found to differentiate eleven of the seventeen measured variables, including mental toughness scores (p < 0.001) and varying levels of sporting achievement i.e. international/national, regional and school levels (p< 0.001). Specifically, this difference was significant when comparing the highest (international/national) and lowest (leisure/school) groups. Perhaps there is a threshold for prenatal testosterone's influence upon sporting ability. Further research is necessary to examine the subtle differences between competitors involved in different achievement levels. It is proposed that high prenatal levels of testosterone may contribute to the development of increased mental toughness, optimism, ego/task goal orientations in individuals, and hence aptitude towards sport. Findings lend support for the tentative claim that mental toughness may be partially biologically predetermined. Theoretical and practical implications are considered, along with limitations of the current study. Key pointsIncreased prenatal testosterone exposure was associated with successful sport performance. There is a need to further consider psychological aspects related to sport performance and their potential relationship with 2D:4D.Mental toughness variables, optimism, goal orientation, hostility and coping style are related to levels of 2:4D.Perhaps with further substantiation, 2D:4D could provide a supporting objective measure, to complement existing psychometric instruments. PMID- 24150617 TI - Comparison of the Traditional, Swing, and Chicken Wing Volleyball Blocking Techniques in NCAA Division I Female Athletes. AB - In volleyball, blocking is highly correlated with team success. The identification of specific techniques that produce a more successful block would be helpful knowledge for coaches and players. This study compared the traditional, swing, and "chicken wing" blocking techniques in combination with the running step footwork pattern in order to determine which technique enabled athletes to perform a more effective block. High-speed videography (7 cameras, Vicon Motion Analysis System) was used to capture the blocking movements of thirteen female NCAA Division I athletes (age = 19.4 +/- 1.19 years, height = 1.82 +/- 0.08 m, mass = 70.63 +/- 7.96 kg, and years of participation at the collegiate level = 2.23 +/- 1.17 years). Each player was familiar with each blocking technique. Reflective markers were placed on the players and in randomized order the players performed 3 blocking trials of each technique. The following dependent variables were assessed: The time it took the athletes to get off the ground and get their hands above (vertically) the net was calculated. The distance the hand reached over the net or hand penetration (displacement between the net and finger in the anterior and vertical planes) was also measured. Lastly, jump height was calculated. Repeated measures ANOVA and post-hoc comparisons were done (alpha = 0.05). There was no significant difference in the main effect for time to get off the ground (p > 0.05). There was a significant difference in the time to get the hands above the net (p < 0.05). The swing block was best for jump height (p <.001) and hand penetration (p < 0.05). These results can help coaches and players decide which blocking technique will benefit them most as a blocking team and as individual blockers. Key pointsThe swing blocking technique resulted in greater jump heights and increased hand penetration, relative to the traditional and chicken wing blocking techniques.The chicken wing blocking technique resulted in greater jump heights and increased hand penetration, relative to the traditional blocking technique.THE TRADITIONAL BLOCKING TECHNIQUE DOES NOT APPEAR TO PROVIDE ANY COMPETITIVE ADVANTAGE RELATED TO THE VARIABLES OBSERVED DURING THIS STUDY: (1) duration spent getting off of the ground and placing hands over the net, (2) jump height, and (3) hand penetration magnitude. PMID- 24150618 TI - Why do they engage in such hard programs? The search for excellence in youth basketball. AB - Excellent performance in sport has a strong positive relationship with the accumulated hours of practice. The specialization years are seen as a decisive moment to lift the skill level, athletic readiness and commitment but the selection and orientation of talent has been strongly dependent of biological and motor variables. The purpose of this study is to describe the achievement and motivation variables that can explain the belonging to an elite competitive level of young basketball players. Eighty-two basketball players under 16 years fulfilled the WOFO Questionnaire (Spence and Helmreich, 1983), and an adapted version of the DPMQ (De Bruin, Rikers and Schmidt, 2007). Forty players (mean age 15. 8 +/- 0.96) were engaged in high performance centres and forty-two (mean age 15.6 +/- 1.01) played in national level clubs. A decision tree and a random forest analysis between elite and national level players were performed. The most discriminant variable was Will to Excel, with 85,2% true positives in elite or national level. Mastery and competitiveness did not enter the final model. The will to reach excellence in performance can be considered as a condition to engage in more specialized and demanding practice. The assessment of the path to expertise only through motor variables or through the accumulated hours of deliberate practice is limited and can lead to mistaken identification or orientation of young sport talents. The use of a more comprehensive model is needed. Key pointsExcellent performance in sport has a strong positive relationship with the accumulated hours of practice.It seems reasonable that if the young athletes are better selected, have better training conditions and practice and compete more time with better teammates and opponents, the chance of becoming competent adult athletes is greater.A self orientation to excellence may play a crucial role in persistence in practice, in order to achieve higher standards in competition.The specific motivation that underpins participation at different levels and help the coaches to be sensitive to non-biological or non functional variables, leading to a better knowledge and caring of the adolescents they teach.The assessment of the path to expertise only through motor variables or through the accumulated hours of deliberate practice is limited and can lead to mistaken identification or orientation of young sport talents. PMID- 24150619 TI - Game location and team quality effects on performance profiles in professional soccer. AB - Home advantage in team sports has an important role in determining the outcome of a game. The aim of the present study was to identify the soccer game- related statistics that best discriminate home and visiting teams according to the team quality. The sample included all 380 games of the Spanish professional men's league. The independent variables were game location (home or away) and the team quality. Teams were classified into four groups according to their final ranking at the end of the league. The game-related statistics registered were divided into three groups: (i) variables related to goals scored; (ii) variables related to offense and (iii) variables related to defense. A univariate (t-test and Mann Whitney U) and multivariate (discriminant analysis) analysis of data was done. Results showed that home teams have significantly higher means for goal scored, total shots, shots on goal, attacking moves, box moves, crosses, offsides committed, assists, passes made, successful passes, dribbles made, successful dribbles, ball possession, and gains of possession, while visiting teams presented higher means for losses of possession and yellow cards. In addition, the findings of the current study confirm that game location and team quality are important in determining technical and tactical performances in matches. Teams described as superior and those described as inferior did not experience the same home advantage. Future research should consider the influence of other confounding variables such as weather conditions, game status and team form. Key pointsHome teams have significantly higher figures for attack indicators probably due to facilities familiarity and crowd effects.The teams' game-related statistics profile varied according to game location and team quality.Teams described as superior and those described as inferior did not experience the same home advantage. PMID- 24150620 TI - A low-cost contact system to assess load displacement velocity in a resistance training machine. AB - This study sought to determine the validity of a new system for assessing the displacement and average velocity within machine-based resistance training exercise using the Chronojump System. The new design is based on a contact bar and a simple, low-cost mechanism that detects the conductivity of electrical potentials with a precision chronograph. This system allows coaches to assess velocity to control the strength training process. A validation study was performed by assessing the concentric phase parameters of a leg press exercise. Output time data from the Chronojump System in combination with the pre established range of movement was compared with data from a position sensor connected to a Biopac System. A subset of 87 actions from 11 professional tennis players was recorded and, using the two methods, average velocity and displacement variables in the same action were compared. A t-test for dependent samples and a correlation analysis were undertaken. The r value derived from the correlation between the Biopac System and the contact Chronojump System was >0.94 for all measures of displacement and velocity on all loads (p < 0.01). The Effect Size (ES) was 0.18 in displacement and 0.14 in velocity and ranged from 0.09 to 0.31 and from 0.07 to 0.34, respectively. The magnitude of the difference between the two methods in all parameters and the correlation values provided certain evidence of validity of the Chronojump System to assess the average displacement velocity of loads in a resistance training machine. Key pointsThe assessment of speed in resistance machines is a valuable source of information for strength training.Many commercial systems used to assess velocity, power and force are expensive thereby preventing widespread use by coaches and athletes.The system is intended to be a low-cost device for assessing and controlling the velocity exerted on each repetition in any resistance training machine.The system could be easily adapted in any vertical displacement barbell exercise. PMID- 24150621 TI - Pre-Workout Carbohydrate Supplementation does not Affect Measures of Selfassessed Vitality and Affect in College Swimmers. AB - Beneficial effects of dietary carbohydrate (CHO) on physical and psychological parameters have been demonstrated in athletes. Because affect, or mood, can predict athletic performace, the main objective of this study was to determine the effect of pre-workout CHO on affect in swimmers. College swimmers (n = 37) participated in a randomized crossover experiment of the effects of a pre-workout CHO supplement on vitality and affect. Subjects consumed a CHO supplement or placebo for two days before morning practice. After each morning practice, swimmers completed measures of affect and feelings of vitality. Pearson correlations were performed to describe relationships among variables. Differences in means between the CHO and placebo conditions were determined by paired t-tests. Independent t-tests were used to determine differences in variables between the highest and lowest tertiles of breakfast consumption frequency. All statistical analyses were performed using SAS 9.1.3 (Cary, NC) and statistical signficance was set at alpha = 0.05. There were no significant differences in affect or feelings of vitality between the CHO supplement and placebo conditions (all p >= 0.15). Our results do not support a beneficial effect of CHO supplementation before morning swim practice on affect or feelings of vitality in swimmers. Key pointsPre-workout carbohydrate did not affect post workout measures of vitality or affect in collegiate swimmers.Avoidance of feeling nauseous/ill' and 'lack of time' were the most frequent reasons reported by swimmers for forgoing breakfast before morning swim practice.A longer trial of carbohydrate supplementation is needed to verify if there is indeed no effect of pre-workout carbohydrate on post-workout measures of vitality or affect in swimmers. PMID- 24150622 TI - Exercise x BCAA Supplementation in Young Trained Rats: What are their Effects on Body Growth? AB - The purpose of this study was to evaluate whether Branched-chain amino acids (BCAAs) supplementation had any beneficial effects on growth and metabolic parameters of young rats submitted to chronic aerobic exercise. Thirty-two young rats (age: 21-d) were randomly assigned to four experimental groups (n = 8): Supplemented Trained (Sup/Ex), Control Trained (Ctrl/Ex), Supplemented Sedentary (Sup/Sed) and Control Sedentary (Ctrl/Sed). The trained groups underwent a five week swimming protocol and received supplemented (45 mg BCAA/body weight/day) or control ration. Trained animals presented a lower body length and a higher cartilage weight, regardless of supplementation. Physical activity was responsible for a substantial reduction in proteoglycan synthesis in cartilage tissue, and BCAA supplementation was able to attenuate this reduction and also to improve glycogen stores in the liver, although no major differences were found in body growth associated to this supplementation. Key pointsCartilage proteoglycan synthesis was dramatically reduced in trained animals as a whole.BCAA supplementation augmented liver glycogen stores and reduced proteolysis in our experimental conditionsTrained animals receiving BCAA supplementation featured increased proteoglycan synthesis compared to sedentary ones, probably because BCAA may have attenuated the negative effects of exercise on cartilage development.BCAA supplementation was not capable of neutralizing directly the negative effects of long-term physical training and lower food intake in young male rats on body growth. PMID- 24150623 TI - Characteristics of maximum performance of pedaling exercise in recumbent and supine positions. AB - To determine the characteristics of maximum pedaling performance in the recumbent and supine positions, maximum isokinetic leg muscle strength was measured in eight healthy male subjects during pedaling at three velocities (300 degrees /s, 480 degrees /s, and 660 degrees /s), and maximum incremental tests were performed for each position. The maximum isokinetic muscle strength in the recumbent position was 210.0 +/- 29.2 Nm at 300 degrees /s, 158.4 +/- 19.8 Nm at 480 degrees /s, and 110.6 +/- 13.2 at 660 degrees /s. In contrast, the muscle strength in the supine position was 229.3 +/- 36.7 Nm at 300 degrees /s, 180. 7 +/- 20.3 Nm at 480 degrees /s, and 129.6 +/- 14.0 Nm at 660 degrees /s. Thus, the maximum isokinetic muscle strength showed significantly higher values in the supine position than in the recumbent position at all angular velocities. The knee and hip joint angles were measured at peak torque using a goniometer; the knee joint angle was not significantly different between both positions, whereas the hip joint angle was greater in the supine position than in the recumbent position (Supine position: 137.3 +/- 9. 33 degree at 300 degrees /s, 140.0 +/- 11.13 degrees at 480 degrees /s, and 141.0 +/- 9.61 degrees at 660 degrees /s. Recumbent position: 99.5 +/- 12.21 degrees at 300 degrees /s, 101.6 +/- 12.29 degrees at 480 degrees /s, and 105.8 +/- 14.28 degrees at 660 degrees /s). Peak oxygen uptake was higher in the recumbent position (50.3 +/- 4.43 ml.kg(-1).min( 1)) than in the supine position (48.7 +/- 5.10 ml.kg(-1).min(-1)). At maximum exertion, the heart rate and whole-body rate of perceived exertion (RPE) were unaffected by position, but leg muscle RPE was higher in the supine position (19.5 +/- 0.53 than in the recumbent position (18.8 +/- 0.71). These results suggest that the supine position is more suitable for muscle strength exertion than the recumbent position, and this may be due to different hip joint angles between the positions. On the contrary, the endurance capacity was higher in the recumbent position than in the supine position. Since leg muscle RPE was higher in the supine position than in the recumbent position, it was suggested that different burdens imposed on active muscles in both positions exerted an impact on the result of the endurance capacity. Key pointsIsokinetic maximal peak torque measured in this study during pedaling showed higher values in the supine position than in the recumbent position at all angular velocities.Maximum oxygen uptake as evaluated by maximum incremental testing showed higher values in the recumbent position than in the supine position.No significant changes in the angle of peak torque for the knee joint or hip joint were observed in either the recumbent or supine position even at an increased angular velocity. These observations indicate the effectiveness of a cycle-type muscle strength assessment device for evaluating leg muscle strength. PMID- 24150624 TI - Effects of high intensity training by heart rate or power in recreational cyclists. AB - Technological advances in interval training for cyclists have led to the development of both heart rate (HR) monitors and powermeters (PM). Despite the growing popularity of PM use, the superiority of PM-based training has not been established. The aim of the present study was to investigate the relative effectiveness of HR-based versus PM-based interval training on 20 km time trial (20km TT), lactate threshold (LT) power, and peak aerobic capacity (VO2max) in recreational cyclists. Participants (n =20; M age=33.9, SD =13) completed a baseline 20km TT to establish their VO2max and LT and were then randomly assigned to either HR-determined or PM-determined training sessions. Over a period of up to 5 weeks participants completed 7.2 (+/- 1.1) interval training sessions at their specific LT for their respective interval training method. Repeated measures analyses of variances (ANOVAs) showed that both HR-based and PM-based training groups significantly improved their LT power (F(1,16) = 28., p < 0.01, eta(2) = 0.63) and 20km TT time (F(1,16) = 4.92, p = 0.04, eta(2) = 0.24) at posttest, showing a 17 watt increase (9.8%) and a near 3-and-a-half minute improvement (7.8%) in 20km TT completion time. There were no significant group (HR vs. PM) x time (baseline vs. posttest) interactions for 20km TT completion time, LT power, or VO2max ratings. Our results coincide with the literature supporting the effectiveness of interval training for endurance athletes. Furthermore, our findings indicate that there is no empirical evidence for the superiority of any single type of device in the implementation of interval training. This study indicates that there are no noticeable advantages to using PM to increase performance in the average recreational cyclist, suggesting that low cost HR monitor are equally capable as training devices. Key pointsInterval training improves performance for recreational cyclists as measure by changes in lactate threshold watts and 20km time trial timeNo evidence of superiority of either heart monitor training and power meter trainingLow cost heart rate monitors are equally capable as training devices. PMID- 24150626 TI - Postural control after a prolonged treadmill run at individual ventilatory and anaerobic threshold. AB - The objective of the study was to verify whether young males' balance was affected by 30min prolonged treadmill running (TR) at individual ventilatory (IVT) and anaerobic (IAT) thresholds in recovery time. The VO2max, IAT and IVT during an incremental TR were determined. Mean displacement amplitude (Acp) and velocity (Vcp) of center of pressure were recorded before (pre) and after (0min post; 5min post; and 10min post) prolonged TR at IAT and IVT, through posturographic trials performed with eyes open (EO) and closed (EC). Significant differences between IVT and IAT for Vcp, between EO and EC for Acp and Vcp, were observed. The IAT induced higher destabilizing effect when postural trials were performed with EC. The IVT intensity produced also a destabilizing effect on postural control immediately after exercise. An impairment of postural control after prolonged treadmill running exercise at IVT and IAT intensity was showed. However, destabilizing effect on postural control disappeared within 10min after IAT intensity and within 5min after IVT intensity. Key pointsTo verify whether young males' balance was affected by 30min prolonged treadmill running at individual ventilatory and anaerobic thresholds in recovery time.Mean displacement amplitude and velocity of foot pressure center were recorded before and after prolonged treadmill running at individual ventilatory and anaerobic thresholds, through posturographic trials performed with eyes open and closed.Destabilizing effect on postural control disappeared within 10min post individual anaerobic threshold, and within 5min post individual ventilatory threshold. PMID- 24150627 TI - Monocular and binocular vision in the performance of a complex skill. AB - The goal of this study was to investigate the role of binocular and monocular vision in 16 gymnasts as they perform a handspring on vault. In particular we reasoned, if binocular visual information is eliminated while experts and apprentices perform a handspring on vault, and their performance level changes or is maintained, then such information must or must not be necessary for their best performance. If the elimination of binocular vision leads to differences in gaze behavior in either experts or apprentices, this would answer the question of an adaptive gaze behavior, and thus if this is a function of expertise level or not. Gaze behavior was measured using a portable and wireless eye-tracking system in combination with a movement-analysis system. Results revealed that gaze behavior differed between experts and apprentices in the binocular and monocular conditions. In particular, apprentices showed less fixations of longer duration in the monocular condition as compared to experts and the binocular condition. Apprentices showed longer blink duration than experts in both, the monocular and binocular conditions. Eliminating binocular vision led to a shorter repulsion phase and a longer second flight phase in apprentices. Experts exhibited no differences in phase durations between binocular and monocular conditions. Findings suggest, that experts may not rely on binocular vision when performing handsprings, and movement performance maybe influenced in apprentices when eliminating binocular vision. We conclude that knowledge about gaze-movement relationships may be beneficial for coaches when teaching the handspring on vault in gymnastics. Key pointsSkills in gymnastics are quite complex and the athlete has to meet temporal and spatial constraints to perform these skills adequately. Visual information pickup is thought to be integral in complex skill performance. However, there is no compelling evidence on the role of binocular vision in complex skill performance.The study reveals, that apprentices optimize their gaze behavior and their movement behavior when binocular vision is eliminated, whereas experts gaze behavior and movement behavior is uninfluenced by eliminating binocular vision.We state, that binocular vision is not necessary for experts to perform to their best. However, eliminating binocular vision could be part of an optimization strategy for apprentices, which could in turn be transferred to new training programs. PMID- 24150625 TI - Daily Physical Activity and Physical Fitness in 11-to 15-year-old Trained and Untrained Turkish Boys. AB - The aims of this study were to assess levels and patterns of physical activity (PA) in relation to age and regular sport activity, and to examine its relationship to physical fitness in trained and untrained boys. One hundred forty seven 11-to 15- year-old boys (73 trained and 74 untrained) participated in this study. Trained boys, comprised of 26 soccer, 25 handball and 22 volleyball players, had been training regularly for at least one year. The intensity, duration and frequency of PA were assessed from four complete days of heart rate monitoring with 15-seconds sampling intervals. Aerobic fitness was assessed by determining peakVO2 with a portable breath-by-breath gas analyzer (Cosmed K4b(2)) and the running speeds at fixed lactate concentrations during an incremental running test. Anaerobic fitness was evalu-ated with the Wingate Anaerobic Test. Skinfold thicknesses from eight sites and Tanner stages of pubic hair were also obtained. Based on 15-s heart rate data, instead of continuous activity, multiple short bouts of moderate and vigorous PA, lasting up to one minute, were characteristic of daily PA patterns of both trained and untrained boys. PA levels of trained boys were higher than untrained boys (p < 0.01) and the levels of PA decreased with age and maturation in both groups (p < 0.05). Daily PA variables were related to body fatness in both groups (p < 0.05), but the relationships were not consistent in the trained group. Daily PA variables were also related to aerobic fitness in the untrained group (p < 0.05) and these relationships were somewhat better with vigorous PA, whereas in the trained group, none of the PA variables were related to any of the aerobic fitness indices (p > 0.05). No relationship was observed between PA variables and anaerobic fitness in either group (p> 0.05). It seems that such relationships may somewhat depend on the fitness level of the subjects. Key pointsPA levels of trained boys were higher than untrained boys and the levels of PA decreased with age and maturation in both groups.Based on the 15-s HR data, instead of continuous activity, multiple short bouts of moderate and vigorous PA, lasting up to one minute, were characteristic of daily PA patterns of both trained and untrained boys.Daily PA variables were related to aerobic fitness in the untrained group and these relationships were somewhat better with vigorous PA (>70% HRR), whereas in the trained group, none of the PA variables were related to any of the aerobic fitness indices.Neither peak nor mean power values were related to any of the daily PA variables in both trained and untrained groups. PMID- 24150628 TI - Evaluating a computer based skills acquisition trainer to classify badminton players. AB - The aim of the present study was to compare the statistical ability of both neural networks and discriminant function analysis on the newly developed SATB program. Using these statistical tools, we identified the accuracy of the SATB in classifying badminton players into different skill level groups. Forty-one participants, classified as advanced, intermediate, or beginner skilled level, participated in this study. Results indicated neural networks are more effective in predicting group membership, and displayed higher predictive validity when compared to discriminant analysis. Using these outcomes, in conjunction with the physiological and biomechanical variables of the participants, we assessed the authenticity and accuracy of the SATB and commented on the overall effectiveness of the visual based training approach to training badminton athletes. Key pointsNeural networks are more effective in predicting group membership and displayed higher predictive validity when compared to discriminant analysis.These results provide implications for coaches and trainers of badminton to implement visual based training methods into their own training program.Predicting shot type was more successful that predicting location placement. This suggests implications for training badminton player's judgement of shuttlecock trajectory. PMID- 24150629 TI - Influence of opposition on ball velocity in the handball jump throw. AB - The purpose of the present study was to investigate the influence of different degrees of opposition on ball velocity in the jump throw in elite, amateur and adolescent team handball players. Thus, one hundred and nineteen elite, amateur and under 18 team handball players performed jump throws under three different conditions: 1) without opposition, 2) with the opposition of the goalkeeper and 3) with the opposition of the goalkeeper and a defensive player. The degree of opposition was found to have a negative effect on ball velocity in all three groups (p < 0.001). Furthermore, the level of competition had a positive effect on ball velocity (p < 0.001). However, no interaction was found between the level of competition and the degree of opposition on ball velocity (p = 0.178). The findings of this study indicate that an increase of external stimuli probably influences throwing kinematics and thereby maximal ball velocity. However, experience does not seem to be a factor that can reduce the influence of these external stimuli. Key pointsThe degree of opposition had a negative effect upon ball throwing velocity in elite, amateur and adolescent handball players in the jump throw.It indicated that an increase of external stimuli influences the execution of throwing.Experience does not seem to be a factor that can reduce the influence of these external stimuli. PMID- 24150630 TI - Physiological Responses to On-Court vs Running Interval Training in Competitive Tennis Players. AB - The aim of this study was to compare heart rate (HR), blood lactate (LA) and rate of perceived exertion (RPE) responses to a tennis-specific interval training (i.e., on-court) session with that of a matched-on-time running interval training (i.e., off-court). Eight well-trained, male (n = 4) and female (n = 4) tennis players (mean +/- SD; age: 16.4 +/- 1.8 years) underwent an incremental test where peak treadmill speed, maximum HR (HRmax) and maximum oxygen uptake (VO2max) were determined. The two interval training protocols (i.e., off- court and on court) consisted of 4 sets of 120 s of work, interspersed with 90 s rest. Percentage of HRmax (95.9 +/- 2.4 vs. 96.1 +/- 2.2%; p = 0.79), LA (6.9 +/- 2.5 vs. 6.2 +/- 2.4 mmol.L(-1); p = 0.14) and RPE (16.7 +/- 2.1 vs. 16.3 +/- 1.8; p = 0.50) responses were similar for off-court and on-court, respectively. The two interval training protocols used in the present study have equivalent physiological responses. Longitudinal studies are still warranted but tennis specific interval training sessions could represent a time-efficient alternative to off-court (running) interval training for the optimization of the specific cardiorespiratory fitness in tennis players. Key pointsOn-court interval training protocol can be used as an alternative to running interval trainingTechnical/tactical training should be performed under conditions that replicate the physical and technical demands of a competitive matchDuring the competitive season tennis on-court training might be preferred to off-court training. PMID- 24150631 TI - VO2 Off Transient Kinetics in Extreme Intensity Swimming. AB - Inconsistencies about dynamic asymmetry between the on- and off- transient responses in oxygen uptake are found in the literature. Therefore, the purpose of this study was to characterize the oxygen uptake off-transient kinetics during a maximal 200-m front crawl effort, as examining the degree to which the on/off regularity of the oxygen uptake kinetics response was preserved. Eight high level male swimmers performed a 200-m front crawl at maximal speed during which oxygen uptake was directly measured through breath-by-breath oxymetry (averaged every 5 s). This apparatus was connected to the swimmer by a low hydrodynamic resistance respiratory snorkel and valve system. RESULTS: The on- and off-transient phases were symmetrical in shape (mirror image) once they were adequately fitted by a single-exponential regression models, and no slow component for the oxygen uptake response was developed. Mean (+/- SD) peak oxygen uptake was 69.0 (+/- 6.3) mL.kg(-1).min(-1), significantly correlated with time constant of the off- transient period (r = 0.76, p < 0.05) but not with any of the other oxygen off transient kinetic parameters studied. A direct relationship between time constant of the off-transient period and mean swimming speed of the 200-m (r = 0.77, p < 0.05), and with the amplitude of the fast component of the effort period (r = 0.72, p < 0.05) were observed. The mean amplitude and time constant of the off transient period values were significantly greater than the respective on- transient. In conclusion, although an asymmetry between the on- and off kinetic parameters was verified, both the 200-m effort and the respectively recovery period were better characterized by a single exponential regression model. Key pointsThe VO2 slow component was not observed in the recovery period of swimming extreme efforts;The on and off transient periods were better fitted by a single exponential function, and so, these effort and recovery periods of swimming extreme efforts are symmetrical;The rate of VO2 decline during the recovery period may be due to not only the magnitude of oxygen debt but also the VO2peak obtained during the effort period. PMID- 24150632 TI - Kinematic analysis of line-out throwing in elite international rugby union. AB - The rugby union line-out is a key aspect of game play and involves players from both teams contesting for the ball after it has been thrown in from the side line. Successful lines-out throws require the ball to be delivered accurately to the hands of a jumping and/or lifted team mate (approximately 3-3.5 m off the ground) over distances of between 5- 18 m. Previous research has suggested considerable inter and intra-individual differences in the throwing techniques of international level players. Accordingly, this project investigated the interrelationships between accuracy and the line-out throwing characteristics of three elite international rugby players, and then analyzed whether these changed for throws over increasing length. Three-dimensional (3D) data were developed from video footage (50 Hz) of three elite international subjects for 30 throws over three distances (6 m, 10 m, and 15 m). Results showed notable differences between subjects in many variables at each of the key throw phases. However, several variables such as the degree of trunk flexion at the end of the backswing and at ball release, coupled with elbow flexion angle at ball release remained constant as throw length increased. All subjects exhibited high levels of consistency in movement patterns across all throw lengths. Findings indicated that these high performance line-out throwers shared several common characteristics that will provide useful guides in the development of training programs. Key pointsA key aspect of this research was the assessment of throwing accuracy using a functional throwing task that mimicked normal performance.Although individual differences in throwing technique occurred, several technical aspects of the throw were common to each of these elite international players.Subjects tended to be extremely consistent in the way they positioned the ball at the end of the backswing, and had very consistent elbow (flexion) and shoulder (flexion and abduction) angles at both the end of the backswing and at ball release.In addition, throwers kept the trunk close to upright during the throw with minimal trunk flexion or extension regardless of throw distance.To throw for longer distances participants tended to increase the involvement of the legs. PMID- 24150633 TI - Effects of vibration training and detraining on balance and muscle strength in older adults. AB - The purpose of this study was to analyze the effects of 2 days/week versus 4 days/week of Whole Body Vibration (WBV) during eight weeks of WBV training on health-related quality of life (SF-36), balance and lower body strength, as well as short-term detraining (3 weeks) on balance and lower body strength among older adults. Thirty-four older adults were randomly assigned to a control group (Control; n = 11) or to one of the vibration training groups: WBV 2 days/week (WBV_2d; n = 11) or WBV 4 days/week (WBV_4d; n = 12). The WBV groups exercised for 8 weeks, following 3 weeks of detraining. Lower body strength increased significantly (p < 0.05) for both groups, WBV_2d and WBV_4d, after 8-week training. A significant reduction in strength was observed following 3 weeks of detraining only in WBV_2d group (p < 0.05). All variables of the SF-36 and the balance test did not change after intervention in any group. 2 days/week and 4 days/week of WBV during 8 weeks showed the same improvements on muscle strength. 3 weeks of detraining did not reverse the gains in strength made during 32 sessions of WBV. Key points2 days and 4 days per week of WBV training during 8 weeks showed the same improvements on muscle strength.3 weeks of detraining did not reverse the gains in strength made during 32 sessions of WBV exercise.3 weeks of detraining did reverse the gains in strength made during 16 sessions of WBV exercise. PMID- 24150634 TI - The acute effects of varying strength exercises bouts on 5Km running. AB - This study investigated if there were acute interference effects of strength exercises on subsequent continuous and intermittent 5Km aerobic exercises. Eleven physically active males (23.1 +/- 3.1 yrs, 1.75 +/- 0.07 m, 70.5 +/- 8.8 kg, and 58.2 +/- 8.3 VO2max) performed the following experimental sessions: A) 5 sets of 5 RM on the leg press followed by a 5km run performed continuously (average velocity of the first and second ventilatory thresholds, vDelta50), B) 5 sets of 5 RM on the leg press followed by a 5km run performed intermittently (1 min run at the vVO2max : 1 min of rest); C) 2 sets of 15 RM on the leg press followed by a 5km continuous run; and D) 2 sets of 15 RM on the leg press followed by a 5km intermittent run. Heart rate, blood lactate concentration, rate of perceived exertion, and VO2 at the first and the fifth km were considered for statistical purposes. There were no significant effects of both strength bouts on any of the variables associated with endurance performance (p > 0.05). It seems that both maximum and strength endurance bouts do not acutely impair aerobic performance. Key pointsResidual acute peripheral fatigue does not seem to be the only cause in the interference effect observed during concurrent training regimens.Peripheral fatigue mechanisms of running such as lactate concentration are not altered by prior lower volume strength exercises.Strength and strength endurance exercises performed before a running bout do not seem to impair the performance in the latter. PMID- 24150635 TI - A practical model of low-volume high-intensity interval training induces performance and metabolic adaptations that resemble 'all-out' sprint interval training. AB - Recently, a novel type of high-intensity interval training known as sprint interval training has demonstrated increases in aerobic and anaerobic performance with very low time commitment. However, this type of training program is unpractical for general populations. The present study compared the impact of a low-volume high-intensity interval training to a "all-out" sprint interval training. Twenty-four active young males were recruited and randomized into three groups: (G1: 3-5 cycling bouts ? 30-s all-out with 4 min recovery; G2: 6- 10 cycling bouts ? 125% Pmax with 2 min recovery) and a non-trained control group. They all performed a VO2max test, a time to exhaustion at Pmax (Tmax) and a Wingate test before and after the intervention. Capillary blood lactate was taken at rest, 3, and 20 min after the Wingate trial. Training was performed 3 sessions per week for 4 weeks. In G1, significant improvements (p < 0.05) following training were found in VO2max (9.6%), power at VO2max (12.8%), Tmax (48.4%), peak power output (10.3%) and mean power output (17.1%). In G2, significant improvements following training were found in VO2max (9.7%), power at VO2max (16.1%), Tmax (54.2%), peak power output (7.4%; p < 0.05), but mean power output did not change significantly. Blood lactate recovery (20(th) min) significantly decreased in G1 and G2 when compared with pre-testing and the CON group (p < 0.05). In conclusion, the results of the current study agree with earlier work demonstrating the effectiveness of 30-s all-out training program to aerobic and anaerobic adaptations. Of substantial interest is that the low volume high intensity training provides similar results but involves only half the intensity with double the repetitions. Key pointsGiven the markedly lower training volume in the training groups, our results suggest that intense interval training is indeed a time-efficient strategy to induce rapid metabolic and performance adaptations.The results demonstrate that a practical low-volume HIT program is effective for improving metabolic and performance adaptations that resemble many of the same performance gains occurred in all-out SIT protocol. PMID- 24150636 TI - Influence of type of muscle contraction and gender on postactivation potentiation of upper and lower limb explosive performance in elite fencers. AB - The purpose of this study was to evaluate the postactivation potentiation (PAP) effect of isometric and plyometric contractions on explosive performance of the upper and the lower limbs in male and female elite athletes. Thirteen male and ten female international level fencers performed four protocols of either isometric (3 sets of 3 sec) or plyometric (3 sets of 5 repetitions) bench and leg press, in a within subject randomized design. Before and immediately after the PAP treatment and following 4, 8, 12 min, explosive performance was measured by performing a countermovement jump (CMJ) or a bench press throw. Statistical analysis revealed significant time effect for peak leg power during the CMJ (p < 0.001) only for men, with values after the isometric PAP treatment being lower than baseline at the 8 and 12 min time points (by 7.5% (CI95% = 3.9-11.2%) and 8.7% (CI95% = 6.0-11.5%, respectively), while after the plyometric PAP treatment peak leg power remained unchanged. A significant negative correlation was found between leg strength (as expressed by 1-RM leg press performance) and the change in peak leg power between baseline and after 12 min of recovery only in male fencers (r = -0.55, p < 0.05), suggesting that stronger individuals may show a greater decrease in peak leg power. Based on the above results we conclude that lower body power performance in international level fencers may be negatively affected after isometric contractions and thus they should be advised against using isometric exercises to induce PAP with the protocol prescribed in the present study. Furthermore, gender and strength level must be considered in the practical application of PAP. Key pointsSignificantly lower values for peak power of the legs were noted in men at 8 and 12 min of recovery in response to the PAP protocol used in this studyThere is some evidence to suggest that stronger individuals may have a greater and longer lasting fatigue that may actually result in a decrease rather than increase of performance after a PAP protocolFencers should be advised to avoid the use of isometric exercises in warm up routines to augment explosive performance. PMID- 24150637 TI - Oxygen uptake kinetics during incremental- and decremental-ramp cycle ergometry. AB - The pulmonary oxygen uptake (VO2) response to incremental-ramp cycle ergometry typically demonstrates lagged-linear first-order kinetics with a slope of ~10-11 ml.min(-1).W(-1), both above and below the lactate threshold (thetaL), i.e. there is no discernible VO2 slow component (or "excess" VO2) above thetaL. We were interested in determining whether a reverse ramp profile would yield the same response dynamics. Ten healthy males performed a maximum incremental -ramp (15-30 W.min(-1), depending on fitness). On another day, the work rate (WR) was increased abruptly to the incremental maximum and then decremented at the same rate of 15-30 W.min(-1) (step-decremental ramp). Five subjects also performed a sub-maximal ramp-decremental test from 90% of thetaL. VO2 was determined breath by-breath from continuous monitoring of respired volumes (turbine) and gas concentrations (mass spectrometer). The incremental-ramp VO2-WR slope was 10.3 +/ 0.7 ml.min(-1).W(-1), whereas that of the descending limb of the decremental ramp was 14.2 +/- 1.1 ml.min(-1).W(-1) (p < 0.005). The sub-maximal decremental ramp slope, however, was only 9. 8 +/- 0.9 ml.min(-1).W(-1): not significantly different from that of the incremental-ramp. This suggests that the VO2 response in the supra-thetaL domain of incremental-ramp exercise manifest not actual, but pseudo, first-order kinetics. Key pointsThe slope of the decremental-ramp response is appreciably greater than that of the incremental.The response dynamics in supra-thetaL domain of the incremental-ramp appear not to manifest actual first-order kinetics.The mechanisms underlying the different dynamic response behaviour for incremental and decremental ramps are presently unclear. PMID- 24150638 TI - The application of biomechanics to penalty corner drag-flick training: a case study. AB - The penalty corner is one of the most important game situations in field hockey with one third of all goals resulting from this tactical situation. The aim of this study was to develop and apply a training method, based on previous studies, to improve the drag- flick skill on a young top-class field hockey player. A young top-class player exercised three times per week using specific drills over a four week period. A VICON optoelectronic system (Oxford Metrics, Oxford, UK) was employed to capture twenty drag-flicks, with six cameras sampling at 250 Hz, prior and after the training period. In order to analyze pre- and post-test differences a dependent t-test was carried out. Angular velocities and the kinematic sequence were similar to previous studies. The player improved (albeit not significantly) the angular velocity of the stick. The player increased front foot to the ball at T1 (p < 0.01) and the drag-flick distances. The range of motion from the front leg decreased from T1 to T6 after the training period (p < 0.01). The specific training sessions conducted with the player improved some features of this particular skill. This article shows how technical knowledge can help with the design of training programs and whether some drills are more effective than others. Key pointsThis article adds information about the drag flick kinematics.This article adds information about how to train the drag flick.The drag-flick is the most efficient technique shooting for goal after a penalty corner. PMID- 24150640 TI - Preparation and reactivity of a dinitrogen-bridged dimolybdenum-tetrachloride complex. AB - A dinitrogen-bridged dimolybdenum-tetrachloride complex is prepared and reduced with Super-Hydride (LiBHEt3) to afford the corresponding dimolybdenum-dinitrogen complex together with the formation of molecular dihydrogen. This reaction proceeds via the ligand exchange of the coordinated dihydrogen generated in situ with molecular dinitrogen. PMID- 24150642 TI - The changes in metabolism of the regulatory brain protein NAP-22 at the early stages of postnatal ontogeny in spontaneous hypertensive and WKY rats born to females fed with calcium-deficient diet. PMID- 24150643 TI - Effect of hindlimb unloading on myelinated fibers in the mouse lumbar spinal cord. PMID- 24150644 TI - Location of pattern-recognizing and vanilloid receptors in the nerve plexuses of the rat intestine. PMID- 24150645 TI - Effect of prenatal infection of mice with bacterial endotoxin on the migration of neurons producing gonadotropin-releasing hormone. PMID- 24150646 TI - Cyclooxygenase and lipoxygenase inhibitors modulate the Glutoxim and Molixan effects on the intracellular Ca2+ concentration in macrophages. PMID- 24150647 TI - The use of olfaction by the Russian desman (Desmana moschata L.) during underwater swimming. PMID- 24150648 TI - The role of the insulin signaling pathway in the control of the Drosophila sexual dimorphism with respect to thermal stress resistance. PMID- 24150649 TI - Stevioside increases the resistance of winter wheat to low temperatures and heavy metals. PMID- 24150650 TI - New findings of unique preserved fossil mammals in the permafrost of Yakutia. PMID- 24150651 TI - The first finding of a frozen Holocene bison (Bison priscus Bojanus, 1827) carcass in Chukotka. PMID- 24150652 TI - Population dynamics of the pulmonate mollusk Lymnaea stagnalis under the conditions of prolonged reproduction by self-fertilization. PMID- 24150653 TI - The role of the TLR-dependent signaling pathway in the mechanism of phagocyte protection by exogenous heat shock protein HSP70 from the endotoxin action. PMID- 24150654 TI - A new reference gene, Ef1A, for quantitative real-time PCR assay of the starfish Asterias rubens pyloric ceca. PMID- 24150655 TI - Cell death of L-929 cells induced by cytotoxic complex Tag7-Hsp70 is analogous to the death of the same cells induced by TNF-alpha. AB - The identification and studying the molecular bases of functioning of new cytotoxic agents finds an important implication in developing drugs for fighting with tumors. While investigating the cytotoxic action of protein complex Tag7 Hsp70 which was opened in our laboratory previously we found that Tag7-Hsp70 demonstrated the same specificity in regard to different tumor target cells as it was for classical cytokine TNF-alpha. L-929 cells and Jurkat cells appeared to be good targets representing up to 30% of dead cells within a population and HeLa cells--bad targets representing less than 5% of dead cells after 20 h of incubation with either of the cytotoxic agents. While investigating the action of either TNF-alpha or Tag7-Hsp70 on L-929 cells we detected two peaks of death: after 3 h and after 20 h. For both cytotoxic agents we observed the first, smaller (13-15%), peak to be eliminated after the addition of caspase inhibitor YVAD-CHO and the second, greater (25-30%), peak to become even bigger in presence of caspase inhibitor. Probably, protein complex Tag7-Hsp70 interacts like TNF alpha with a receptor on the surface of tumor cells that results in triggering two alternative mechanisms of programmed cell death: apoptosis and necroptosis. PMID- 24150656 TI - Model of structuring the stem cell niche in shoot apical meristem of Arabidopsis thaliana. PMID- 24150657 TI - Exogenous heat shock protein HSP70 modulates lipopolysaccharide-induced macrophage activation. PMID- 24150658 TI - The pathways of silver nanoparticles formation by Mycobacterium smegmatis. PMID- 24150659 TI - Mesoporous ZnCo2O4 nanoflakes with bifunctional electrocatalytic activities toward efficiencies of rechargeable lithium-oxygen batteries in aprotic media. AB - This study reports the successful synthesis of ternary spinel-based ZnCo2O4 nanoflakes (NFs) with mesoporous architectures via the combination of a urea assisted hydrothermal reaction with calcination in an air atmosphere. Owing to their favorable mesostructures and desirable bifunctional oxygen reduction and evolution activities, the resulting mesoporous ZnCo2O4 NFs yielded stable cyclability at a cut-off capacity of 500 mA h gcarbon(-1) in the case of aprotic Li-O2 batteries. PMID- 24150660 TI - Randomized comparison between the combination of acetaminophen and ibuprofen and each constituent alone for analgesia following tonsillectomy in children. AB - PURPOSE: Combined acetaminophen and ibuprofen may be more effective than either constituent alone for pain in adults. The combination was compared with the individual constituents for analgesia following tonsillectomy in children. METHODS: One hundred and fifty-two children (6-14 yr) undergoing tonsillectomy were randomized to receive either combination acetaminophen (48 mg.kg(-1).day( 1)) and ibuprofen (24 mg.kg(-1).day(-1)) or the same doses of acetaminophen alone or ibuprofen alone, every six hours for 48 hr. The primary outcome measure was a time-corrected area under the curve (AUCt) calculated from assessments on a 100 mm visual analogue scale (with Wong Baker FACES((r)) as anchors). At each assessment the children rated pain while at rest and on swallowing at multiple time points over the study duration. Secondary outcome measures were a global pain rating, requirement for rescue analgesia, sleep disturbance, and frequency of adverse events. RESULTS: The mean [standard error of the mean (SEM)] AUCt values at rest were; combination 29.6 (1.9), acetaminophen 30.4 (2.0), ibuprofen 34 (1.9). The mean (SEM) AUCt values on swallowing were; combination 39.1 (2.0), acetaminophen 39.9 (2.0), ibuprofen 43.7 (1.9). The mean (95% confidence interval) differences in AUCt values between groups on swallowing were: combination vs acetaminophen -0.9 (-6.2 to 4.5); combination vs ibuprofen -4.6 ( 9.9 to 0.67) and at rest were: combination vs acetaminophen -0.81 (-6.11 to 4.48); combination vs ibuprofen -4.37 (-9.62 to 0.88). Differences between groups were not clinically important for the pain scores, similarly for the secondary outcomes. CONCLUSION: The combination of ibuprofen and acetaminophen was not superior to its individual components in the regimen studied in this pediatric population undergoing tonsillectomy. The study was registered with the Australia New Zealand Clinical Trial Registry (ACTRN12607000005459) on January 4, 2007. PMID- 24150661 TI - Systematic review of outcome measures of walking training using electromechanical and robotic devices in patients with stroke. AB - OBJECTIVE: The aim of this systematic review was to identify appropriate selection criteria of clinical scales for future trials, starting from those most commonly reported in the literature, according to their psychometric properties and International Classification of Functioning, Disability and Health (ICF) domains. DATA SOURCES: A computerized literature research of articles was conducted in MEDLINE, EMBASE, CINALH, PubMed, PsychINFO and Scopus databases. STUDY SELECTION: Clinical trials evaluating the effects of electromechanical and robot-assisted gait training trials in stroke survivors. DATA EXTRACTION: Fifteen independent authors performed an extensive literature review. DATA SYNTHESIS: A total of 45 scales was identified from 27 studies involving 966 subjects. The most commonly used outcome measures were: Functional Ambulation Category (18 studies), 10-Meter Walking Test (13 studies), Motricity Index (12 studies), 6 Minute Walking Test (11 studies), Rivermead Mobility Index (8 studies) and Berg Balance Scale (8 studies). According to the ICF domains 1 outcome measure was categorized into Body Function and Structure, 5 into Activity and none into Participation. CONCLUSION: The most commonly used scales evaluated the basic components of walking. Future studies should also include instrumental evaluation. Criteria for scale selection should be based on the ICF framework, psychometric properties and patient characteristics. PMID- 24150662 TI - A mapping study on physical activity in stroke rehabilitation: establishing the baseline. AB - OBJECTIVE: To establish physical activity level, environment and social interaction in routine stroke rehabilitation practice. DESIGN: Prospective observational study using behavioural mapping. METHODS: Patients at 4 hospital stroke rehabilitation units in Sweden at least 7 days post-stroke were observed over 1 week-day at 10 min intervals between 08.00 h and 17.00 h. At each observation, physical activity, location and people present were ascertained. RESULTS: Patients (n = 104) had a mean age of 70.3 (standard deviation (SD) 14.4) years. Median time since stroke was 19 (range 7-142) days. Patients were alone for 52% of the day, during this time 7% was spent in standing/walking activities. While with a physiotherapist patients were standing/walking for 43% of the time. Using median regression it was found that the median percentage of time spent in standing/walking was associated with gait independence and age. Gait independence increased the median percentage of time spent in standing/walking by 16.5% (95% confidence interval (CI) 12.1-20.9, p < 0.001), while an increase of 1 year of age reduced the median percentage of time spent in standing/walking by 0.16% (95% CI -0.31 to -0.01, p < 0.05). CONCLUSION: Patients had low levels of physical activity and social interaction. This study suggests that there is a huge potential to increase patients' activity level and augment social interaction above current levels. PMID- 24150663 TI - Temporal variation and morphologic characteristics of J-waves in patients with early repolarisation syndrome. AB - OBJECTIVE: Electrocardiographic markers identifying malignant forms of early repolarisation (ER) from ER of normal variants are of prime clinical importance. We compared the ECG parameters of ER patterns in patients with early repolarisation syndrome (ERS) proximate to the ventricular fibrillation (VF) episodes, remote from the events and those with normal controls with ER. DESIGN: A retrospective, case-control study. SETTING: University hospital. PATIENTS: This study included 12 patients with ERS and 36 age-matched, gender-matched controls with ER. MAIN OUTCOME MEASURES: Dynamic change of J-wave. RESULTS: The highest amplitude of J-wave, sum of the J-wave amplitudes or the number of leads with ER showed a dramatic change during the perievent period. J-wave amplitudes (2.0+/ 1.3 vs 4.0+/-1.7, p=0.004) and the number of leads with ER (3.3+/-1.7 vs 5.3+/ 2.0, p=0.021) were significantly higher around the time of VF. In particular, the characteristic morphology of 'giant' (wide, >80 ms) J-waves were observed during the perievent period in 5/12 patients with ERS. However, there were no significant differences in the electrocardiographic parameters of ER pattern remote from VF events between the patients with ERS and normal control subjects with ER. CONCLUSIONS: Although the extent of and amplitude of J-wave or ST segment elevation (STE) increased significantly around VF episodes, the electrocardiographic parameters of ER remote from VF episodes were not significantly different from those of normal controls. The narrow time window of these ECG changes limits early detection of ER patients at risk of developing VF or sudden cardiac death. PMID- 24150664 TI - Influenza and ischaemic heart disease: research challenges and future directions. PMID- 24150665 TI - Massive cement pulmonary embolism during percutaneous vertebroplasty. PMID- 24150666 TI - Claim that primary care provides in excess of 80% NHS activity is wrong. PMID- 24150667 TI - We need to ask "what is the purpose of research?". PMID- 24150668 TI - Medical journal editors and publication bias. PMID- 24150669 TI - Red Bull meets the Australian dietary guidelines. PMID- 24150670 TI - Is the Iraqi birth defects report believable? PMID- 24150671 TI - Suicides in Greece: a light at the end of the tunnel. PMID- 24150672 TI - Simple solutions to Strongyloides stercoralis infection. PMID- 24150673 TI - Sequential analysis shows that beta blockade in non-cardiac surgery is ineffective and may even be harmful. PMID- 24150674 TI - Ignoring the basic courtesies of consultation. PMID- 24150675 TI - Doctors' name badges are important. PMID- 24150676 TI - Effect of commonly prescribed drugs on incidence of gout. PMID- 24150677 TI - Time to consider the best way to plan for single rooms. PMID- 24150678 TI - The elephant in the single room debate: keeping patients active. PMID- 24150679 TI - Children thrive on companionship, not single rooms. PMID- 24150680 TI - Risk of inpatient falls is increased with single rooms. PMID- 24150681 TI - US group suggests way to boost access to trial data while preventing misuse. PMID- 24150682 TI - Revision of Helsinki declaration aims to prevent exploitation of study participants. PMID- 24150683 TI - Doctors' leaders question L2bn estimated cost to NHS of caring for visitors. PMID- 24150684 TI - Household income directly affects children's development, research shows. PMID- 24150685 TI - Effect of Fontan fenestration on regional venous oxygen saturation during exercise: further insights into Fontan fenestration closure. AB - Fontan fenestration closure is a topic of great debate. The body of data regarding the risks and benefits of fenestration closure is limited yet growing. Previous studies have demonstrated that Fontan patients have less exercise capacity than those with normal cardiovascular anatomy. Differences also have been noted within various subgroups of Fontan patients such as whether Fontan is fenestrated or not. This study aimed to compare trends in regional oxygen saturations using near-infrared spectroscopy (NIRS) in patients with Fontan circulations during ramping exercise to further delineate differences between patients with and without a fenestration. It was hypothesized that Fontan patients with fenestrations have better exercise times, higher absolute regional oxygen venous saturations, and smaller arteriovenous differences than Fontan patients without fenestrations. For this study, 50 consecutive Fontan patients and 51 consecutive patients with normal cardiovascular anatomy were recruited. Placement of NIRS probes was performed to obtain regional oxygen saturations from the brain and the kidney. Readings were obtained at 1-min intervals during rest, exercise, and recovery. A standard Bruce protocol was used with a 5-min recovery period. Absolute regional tissue oxygenation values (rSO2) and arterial-venous oxygen saturation differences (AVDO2) calculated as arterial oxygen saturation (SPO2)--rSO2 for normal versus Fontan patients and for fenestrated versus unfenestrated Fontan patients were compared using independent t tests. When normal and Fontan patients were compared, the Fontan patients had a significantly shorter duration of exercise (9.3 vs 13.2 min; p < 0.001). No statistically significant difference in rSO2 change or AVDO2 was evident at the time of peak exercise, at 2 min into the recovery, or at 5 min into the recovery. A small oxygen debt also was paid back to the brain in the Fontan patients after exercise, as evidenced by a narrower AVDO2 than at baseline. The comparison of Fontan patients with and without fenestration showed no statistically significant difference in exercise time, rSO2 change, or AVDO2. The Fontan patients were noted to have shorter exercise times than the normal patients and also appeared to have an alteration in postexertional regional blood flow. However, when the various Fontan subtypes were compared by presence or absence of a fenestration, no significant differences were noted with regard to change in regional oxygen saturation or arteriovenous oxygen saturation. Thus, for patients with Fontan physiology, closure of the fenestration does not seem to have an impact on the dynamics of regional oxygen extraction during exercise or recovery. PMID- 24150686 TI - Accuracy of Doppler-derived indices in predicting pulmonary vascular resistance in children with pulmonary hypertension secondary to congenital heart disease with left-to-right shunting. AB - This study aimed to evaluate the accuracy of Doppler echocardiography-derived indices in children with pulmonary hypertension secondary to congenital heart disease with left-to-right shunting. Doppler-derived indices including the acceleration time corrected (AcTc), deceleration time corrected, deceleration index, peak velocity, heart-rate-corrected inflection time (InTc), and a new index (the acceleration slope [Acc = peak flow velocity/AcTc]) were measured from the pulmonary artery (PA) systolic flow curve before and after 100 % oxygen administration in the main, left, and right PAs of 33 children. The acquired data were compared between low and high pulmonary vascular resistance (PVR) groups and between responders and nonresponders to the vasoreactivity test. The AcTc values differed significantly between the low and high PVR groups before and after oxygen administration in the main (P = 0.032 and <0.001, respectively), right (P = 0.011 and <0.001, respectively), and left (P < 0.001 and <0.001, respectively) PAs. The AcTc cutoff point in the main PA was 3.44 before oxygen administration (81% sensitivity and 91% specificity). The InTc in the main PA and its changes differed significantly between the low and high PVR groups before and after oxygen administration and between the responders and nonresponders (P = 0.016, 0.046, and 0.021, respectively). The velocity changes of the PA in the main PA differed significantly between the responders and nonresponders to oxygen administration (P < 0.001). The Acc and its changes differed significantly between the low and high PVR groups after oxygen administration and between the responders and nonresponders to oxygen administration (P = 0.044 and 0.006, respectively). Doppler echocardiographic examination using PA systolic flow indices in addition to PA reactivity testing is a promising technique for assessing PVR in children with congenital heart disease. PMID- 24150687 TI - Characterization and differentiation potential of rabbit mesenchymal stem cells for translational regenerative medicine. AB - Mesenchymal stem cells (MSCs) derived from the adult bone marrow are multipotent stem cells that can give rise to lineages of bone, cartilage, muscle, fat, and others. The rabbit is a common preclinical model used for cardiovascular and orthopaedic applications. MSCs derived from the rabbit whole bone marrow are routinely investigated in these models for regenerative medicine applications. However, rabbit MSCs (rbMSCs) have not been extensively characterized in terms of immunophenotypic characteristics and differentiation potential and more specifically, in comparison to human MSCs (hMSCs). This study examined rbMSCs' surface antigens as well as their multipotent differentiation potential. In addition, the transduction efficiency of rbMSCs using a lentiviral vector with red fluorescent protein (RFP) as a method for labeling the cells for in vitro and in vivo use was also examined. RbMSCs were positive for CD44 and CD29 and negative for CD45 and CD14, which is similar to hMSCs, but rbMSCs did not express CD90. RbMSCs also expressed the pluripotent transcription factor, Sox2. The rbMSCs at early passages differentiated along the osteoblastic, chondrocytic, and adipocytic lineages. However, quantitative analyses demonstrated lower levels of differentiation markers for rabbit cells as compared to human cells. Transduction efficiency of 90.5% was observed for rbMSC transfected with RFP. Transduced cells also retained their osteogenic potential, but proliferation was reduced in comparison to nontransduced cells. This study demonstrates that MSCs isolated from the rabbit bone marrow have differences from human cells and should be considered when using rbMSCs in preclinical models for MSC regenerative medicine or tissue engineering strategies. PMID- 24150689 TI - Electroclinical progression of subtle generalized convulsive status epilepticus: description of a case. PMID- 24150688 TI - Discrete gait characteristics are associated with m.3243A>G and m.8344A>G variants of mitochondrial disease and its pathological consequences. AB - Mitochondrial disease is complex and variable, making diagnosis and management challenging. The situation is complicated by lack of sensitive outcomes of disease severity, progression, contributing pathology and clinical efficacy. Gait is emerging as a sensitive marker of pathology; however, to date, no studies have quantified gait in mitochondrial disease. In this cross-sectional study, we quantified gait characteristics in 24 patients with genetically confirmed mitochondrial disease (m.3243A>G and m.8344A>G) and 24 controls. Gait was measured using an instrumented walkway according to a predefined model with five domains hypothesised to reflect independent features of the neural control of gait in mitochondrial disease, including: pace (step velocity and step length); rhythm (step time); variability (step length and step time variability); asymmetry (step time asymmetry); and postural stability (step width, step width variability and step length asymmetry). Gait characteristics were compared with respect to controls and genotype. Additional measures of disease severity, pathophysiology and imaging were also compared to gait to verify the validity of gait characteristics. Discrete gait characteristics differed between controls and mitochondrial disease groups, even in relatively mildly affected patients harbouring the m.3243A>G mutation. The pattern of gait impairment (increased variability and reduced postural control) was supported by significant associations with measures of disease severity, progression, pathophysiology and radiological evidence of cerebellar atrophy. Discrete gait characteristics may help describe functional deficits in mitochondrial disease, enhance measures of disease severity and pathology, and could be used to document treatment effects of novel therapies. PMID- 24150690 TI - Supporting pregnant Aboriginal and Torres Strait Islander women to quit smoking: views of antenatal care providers and pregnant indigenous women. AB - To assess support for 12 potential smoking cessation strategies among pregnant Australian Indigenous women and their antenatal care providers. Cross-sectional surveys of staff and women in antenatal services providing care for Indigenous women in the Northern Territory and New South Wales, Australia. Respondents were asked to indicate the extent to which each of a list of possible strategies would be helpful in supporting pregnant Indigenous women to quit smoking. Current smokers (n = 121) were less positive about the potential effectiveness of most of the 12 strategies than the providers (n = 127). For example, family support was considered helpful by 64 % of smokers and 91 % of providers; between 56 and 62 % of smokers considered advice and support from midwives, doctors or Aboriginal Health Workers likely to be helpful, compared to 85-90 % of providers. Rewards for quitting were considered helpful by 63 % of smokers and 56 % of providers, with smokers rating them more highly and providers rating them lower, than most other strategies. Quitline was least popular for both. This study is the first to explore views of pregnant Australian Indigenous women and their antenatal care providers on strategies to support smoking cessation. It has identified strategies which are acceptable to both providers and Indigenous women, and therefore have potential for implementation in routine care. Further research to explore their feasibility in real world settings, uptake by pregnant women and actual impact on smoking outcomes is urgently needed given the high prevalence of smoking among pregnant Indigenous women. PMID- 24150691 TI - Peripheral blood CD56(bright) NK cells respond to stem cell factor and adhere to its membrane-bound form after upregulation of c-kit. AB - CD56(bright) NK cells express receptors for IL-2, IL-7, IL-15, and SCF. We found that human peripheral blood CD56(bright) NK cells responded to IL-2, IL-7, IL-15 by phosphorylating STAT-5, ERK, and Akt but did not respond to SCF. However, CD56(bright) NK cells in culture upregulated c-kit transcription three to fourfold, which led to a steady increase in c-kit and a concomitant acquisition of responsiveness to SCF. After 44 h, CD56(bright) NK cells had upregulated c-kit approximately 20-fold and phosphorylated ERK and Akt in response to SCF concentrations well below levels present in plasma. CD56(bright) NK cells cultured in IL-15 maintained c-kit transcription/expression at ex vivo levels and did not become responsive to SCF. Furthermore, SCF-responsive, CD56(bright) c kit(high) NK cells swiftly downregulated c-kit and stopped responding to SCF after IL-15 stimulation. However, commitment of CD56(bright) NK cells to a c-kit negative, SCF-unresponsive state did not occur, as after 5 days of culture, withdrawal of IL-15 restored c-kit to maximal levels and reestablished SCF responsiveness. CD56(bright) NK cells that had upregulated c-kit firmly adhered to COS cells transfected with the membrane form of SCF. Furthermore, SCF signaling significantly increased the capacity of CD56(bright) NK cells to degranulate. Collectively, our data suggest that c-kit on human CD56(bright) NK cells is a functional receptor that is downregulated in peripheral blood, possibly to render CD56(bright) NK cells unresponsive to the SCF therein. PMID- 24150692 TI - An integrative model of subcortical auditory plasticity. AB - In direct conflict with the concept of auditory brainstem nuclei as passive relay stations for behaviorally-relevant signals, recent studies have demonstrated plasticity of the auditory signal in the brainstem. In this paper we provide an overview of the forms of plasticity evidenced in subcortical auditory regions. We posit an integrative model of auditory plasticity, which argues for a continuous, online modulation of bottom-up signals via corticofugal pathways, based on an algorithm that anticipates and updates incoming stimulus regularities. We discuss the negative implications of plasticity in clinical dysfunction and propose novel methods of eliciting brainstem responses that could specify the biological nature of auditory processing deficits. PMID- 24150693 TI - Phenotypic and genomic characterization of the Antarctic bacterium Gillisia sp. CAL575, a producer of antimicrobial compounds. AB - Microorganisms from Antarctica have evolved particular strategies to cope with cold. Moreover, they have been recently reported as producers of antimicrobial compounds, which inhibit the growth of other bacteria. In this work we characterized from different viewpoints the Gillisia sp. CAL575 strain, a psychrotrophic bacterium that produces microbial volatile organic compounds involved in the growth inhibition of Burkholderia cepacia complex members. Sequencing and analysis of the whole genome of Gillisia sp. CAL575 revealed that it includes genes that are involved in secondary metabolite production, adaptation to cold conditions, and different metabolic pathways for the production of energy. All these features make Gillisia sp. CAL575 a possible tool for biotechnology. PMID- 24150694 TI - Perchlorate and halophilic prokaryotes: implications for possible halophilic life on Mars. AB - In view of the finding of perchlorate among the salts detected by the Phoenix Lander on Mars, we investigated the relationships of halophilic heterotrophic microorganisms (archaea of the family Halobacteriaceae and the bacterium Halomonas elongata) toward perchlorate. All strains tested grew well in NaCl based media containing 0.4 M perchlorate, but at the highest perchlorate concentrations, tested cells were swollen or distorted. Some species (Haloferax mediterranei, Haloferax denitrificans, Haloferax gibbonsii, Haloarcula marismortui, Haloarcula vallismortis) could use perchlorate as an electron acceptor for anaerobic growth. Although perchlorate is highly oxidizing, its presence at a concentration of 0.2 M for up to 2 weeks did not negatively affect the ability of a yeast extract-based medium to support growth of the archaeon Halobacterium salinarum. These findings show that presence of perchlorate among the salts on Mars does not preclude the possibility of halophilic life. If indeed the liquid brines that may exist on Mars are inhabited by salt-requiring or salt tolerant microorganisms similar to the halophiles on Earth, presence of perchlorate may even be stimulatory when it can serve as an electron acceptor for respiratory activity in the anaerobic Martian environment. PMID- 24150696 TI - Highly luminescent S, N co-doped graphene quantum dots with broad visible absorption bands for visible light photocatalysts. AB - A facile hydrothermal synthesis route to N and S, N co-doped graphene quantum dots (GQDs) was developed by using citric acid as the C source and urea or thiourea as N and S sources. Both N and S, N doped GQDs showed high quantum yield (78% and 71%), excitation independent under excitation of 340-400 nm and single exponential decay under UV excitation. A broad absorption band in the visible region appeared in S, N co-doped GQDs due to doping with sulfur, which alters the surface state of GQDs. However, S, N co-doped GQDs show different color emission under excitation of 420-520 nm due to their absorption in the visible region. The excellent photocatalytic performance of the S, N co-doped GQD/TiO2 composites was demonstrated by degradation of rhodamine B under visible light. The apparent rate of S, N:GQD/TiO2 is 3 and 10 times higher than that of N:GQD/TiO2 and P25 TiO2 under visible light irradiation, respectively. PMID- 24150697 TI - Stereocontrolled synthesis of the oxathiabicyclo[3.3.1]nonane core structure of tagetitoxin. AB - Tagetitoxin is an unusually densely functionalized natural product, consisting of an unprecedented oxathiabicyclo[3.3.1]nonane ring system possessing acetate, phosphate, amide, carboxylic acid, and amine groups with six contiguous asymmetric centers. A fully functionalized core structure of tagetitoxin was synthesized from tri-O-acetyl-D-galactal in a highly stereoselective manner. PMID- 24150695 TI - Distribution of microcystin-LR to testis of male Sprague-Dawley rats. AB - Microcystins (MCs) are a group of cyclic heptapeptide toxins produced by naturally freshwater cyanobacteria. Among more than 90 identified analogues of microcystins, microcystin-LR (MC-LR) is the most abundant and toxic. Our previous investigations indicated that MC-LR displays male reproductive toxicity, but the target of MC-LR in testes remains unclear. To this end, the present study is designed to elucidate whether microcystin-LR could be distributed to testes and explore the target cells in testes. In the in vivo study, male Sprague-Dawley rats were injected intraperitoneally with MC-LR at a dose of 300 MUg/kg per day for 6 days. MC-LR was detected in testes, mainly within seminiferous tubules, which was further validated by Western blot. The concentrations of MC-LR were determined by LC-MS analysis, with a result of 0.0252 +/- 0.0037 and 0.0056 +/- 0.0012 MUg/g dry weight in liver and testis respectively. In the in vitro study, Primary cultured spermatogonia, Sertoli cells and Leydig cells were exposed to MC LR respectively, and MC-LR was observed to enter spermatogonia and Sertoli cells, but not Leydig cells. These results suggested that the reproductive toxicity of MC-LR were induced by its distribution in testis. Spermatogonia and Sertoli cells are important target cells. PMID- 24150698 TI - [Rheumatoid arthritis: lower work loss during treatment with biologicals?--Modern treatment principles reduce work loss in rheumatoid arthritis]. PMID- 24150699 TI - [Off-label drug prescriptions among outpatient children and adolescents in Germany--a database analysis]. AB - BACKGROUND: Due to lack of respective studies children often receive medication that is applied beyond the approved indication. The consequence of this off-label use is often an increased risk of unexpected and undesirable side effects. This study deals with the amount of off-label drug prescriptions among children and adolescents receiving outpatient treatment in Germany. The aim is to outline age , gender-, region-, and insurance specific differences and to determine risk factors for an off-label prescription. METHODS: This is a retrospective study that has been conducted by means of the IMS Patient Database Disease Analyzer for the year 2010 considering three therapy classes (analgesics, antibiotics and antidepressants). The evaluation of the risk factors for an off-label prescription resulted from a multivariate logistic regression. Age- and dose specific prescriptions were analyzed but not indication-specific prescriptions. RESULTS: In total 189,285 children and adolescents with analgesics-, 147,089 with antibiotics-, and 15,405 with antidepressants prescriptions were identified. The percentage of patients with off-label prescriptions amounted to 0.9 % for analgesics, 2.5 % for antibiotics and 8.5 % for antidepressants. The off-label prescriptions made by general practitioners were significantly higher than those made by pediatricians and child psychiatrists. The number of off-label prescriptions in country sides was higher than in cities. In eastern states more off-label prescriptions were made than in western states of Germany. CONCLUSION: The study shows that outpatient treatment of children and adolescents occurs widely with drugs corresponding to age and dosage. Off-label prescriptions not conform to indication were not determined. However, off-label drug use should be reduced further for outpatient treatment to ensure a safe and low-risk medical treatment for children and adolescents. PMID- 24150700 TI - [Extracorporeal membrane oxygenation as bridge to recovery in infarction-related refractory right heart failure]. AB - HISTORY AND CLINICAL FINDINGS: We present a 41-year-old man with cardiac arrest in need of cardiopulmonary resuscitation (CPR) with the diagnosis of a posterior wall infarction, who was hospitalized in our cardiac centre. INVESTIGATIONS: The cardiac catheterization showed a thrombotic obstruction of the right coronary artery. After percutaneous coronary revascularization a hemodynamically stable situation could be achieved and the patient was admitted to the intensive care unit (ICU). TREATMENT AND CLINICAL COURSE: The patient became again hemodynamically unstable and a CPR was required. Based on the acute right heart failure with therapy refractory cardiogenic shock we decided within our heart team for an extra corporeal membrane oxygenation (ECMO) applied during CPR in the ICU. The extracorporeal support was needed for three days. Seven days after the emergency cardiac catheterization the patient was extubated and transferred to our intermediate care. CONCLUSION: Extracorporeal life support is feasible und effective for bridging therapy in patients with acute ischemic right heart failure with refractory cardiogenic shock and successful reperfusion therapy. PMID- 24150701 TI - [Rapid progressive glomerulonephritis as a nephrological emergency--case 8/2013]. AB - HISTORY AND ADMISSION FINDINGS: We report on a 53-year-old female patient who was admitted to hospital with fever, dyspnoea and arthralgias that was followed by diarrhoea and anuria. Upon respiratory deterioration she was referred to our hospital. INVESTIGATIONS: Urine analysis revealed an active urine sediment and kidney ultrasound showed hyperechoic renal parenchyma. Chest x-ray revealed widespread bilateral opacifications that were further investigated by bronchoscopy. A renal biopsy was performed due to an active urine sediment. DIAGNOSIS, TREATMENT AND COURSE: The patient suffered from pneumonia induced by pulmonary congestion and a newly acquired influenza infection. Histological examination of the kidney biopsy revealed an extracapillary proliferative IgA glomerulonephritis. After stabilization of the pulmonary situation and commencing hemodialysis, immunosuppressive therapy was started including cyclophosphamid. CONCLUSIONS: A rapid-progressive glomerulonephritis represents a nephrological emergency leading to acute kidney injury and dysfunction of other organs. PMID- 24150702 TI - [83-year-old patient with gait ataxia, dementia and incontinence]. PMID- 24150703 TI - [Importance and evidence of regular physical activity for prevention and treatment of diseases]. AB - A sedentary lifestyle has been shown to have negative effects on morbidity and mortality. In contrast, a large number of prospective cohort studies on the effects of regular physical activity demonstrated positive effects. Therefore, physical training is today an essential part of prevention and therapy in internal medicine. This review is based on literature research in meta-analysis and review papers. Regular physical exercise or training is a significant and evidence-based part of prevention and therapy of diseases such as heart, cardiovascular and lung diseases, diabetes mellitus, renal disease and cancer. Evidence of training effects is mostly high grade. Physical activity or exercise training is indicated in many diseases as medicine--similar as a drug. It is applied after acute treatment as a component of the standard drug therapy. There is a non-linear dose-response effect, psychological aspects and some side-effects need to be considered.In conclusion, physical exercise acts as a highly efficient drug, and should be used in many diseases. Training recommendations refer to the kind, the duration, the intensity, the frequency and the increase of training. PMID- 24150704 TI - [Treatment recommendations for alcohol dependence--comparison of German and international guidelines]. AB - In order to identify relevant recommendations for the treatment of alcohol dependent adults a systematic guideline research was conducted on national and international guideline providers. The research showed differences between German and international guidelines in terms of the treatment goal and the resulting treatment recommendations. In Germany, abstinence is the only accepted treatment goal. An alcohol reduction in terms of harm reduction is recommended by one guideline as an intermediate goal. The recommended treatment options include intensive inpatient measures such as detoxification and alcohol withdrawal. Further outpatient treatment of alcohol dependency is not recommended by German guidelines. International guidelines also recommend abstinence as the goal for all patients. Beyond, the reduction of alcohol consumption is recommended as a possible treatment goal under certain conditions if abstinence not (yet) is possible. Thereby the treatment goal should be set individually considering the patient's feasibility and wishes. Besides abstinence also the reduction of alcohol consumption leads to an improvement of health. Therefore patients aiming for this goal should also be supported. Furthermore, the inclusion of patient's wishes in the goal setting leads to better treatment outcomes. Therefore, an extension of goal setting and treatment recommendations towards the reduction of alcohol consumption seems reasonable for Germany. Furthermore, the adaption to the state of international guidelines seems reasonable. PMID- 24150705 TI - Letter to the editor: Mean platelet volume and diabetic retinopathy. PMID- 24150706 TI - Diagnosis of subretinal neovascularization associated with idiopathic juxtafoveal retinal telangiectasia - fluorescein angiography versus spectral-domain optical coherence tomography. AB - BACKGROUND: To compare ability of fluorescein angiography (FFA) and spectral domain optical coherence tomography (SD-OCT) to diagnose subretinal neovascularization (SRNV) secondary to idiopathic juxtafoveal retinal telangiectasia (IJRT) type 2A. METHODS: Two masked observers evaluated FFA and SD OCT images separately to diagnose the presence of SRNV in 65 eyes of 36 patients. A third masked observer diagnosed SRNV on color fundus photo. Presence of SRNV on color fundus photo was defined as presence of subretinal hemorrhage, thickening of retina, and/or visible membrane at the macula. Presence of SRNV on FFA was defined when there was hyperfluorescence in early phase with increase in intensity and size in the late phase; presence of membrane, large irregular lesion, hypofluorescence due to subretinal haemorrhage. SRNV on SD-OCT was defined as the presence of thickening of the retinal pigment epithelium choriocapillaris complex with or without intraretinal fluid or subretinal fluid and associated with intraretinal hyperreflective area with retinal thickening. RESULTS: Interobserver agreement (Kappa) for diagnosis of SRNV on FFA and SD-OCT was 0.373 (95 % CI, 0.106-0.617) and 0.775 (95 % CI, 0.612-0.899) respectively. The sensitivity and specificity of FFA were 52.3 % and 70.0 % respectively. With regard to SD-OCT, the sensitivity and specificity were 72.7 % and 64.1 % respectively in reference to color photograph. The negative predictive value (NPV) of SD-OCT (80.6 %) was higher than FFA (73.7 %). When we considered only the presence of subretinal hemorrhage on color photograph as a confirmed diagnosis of SRNV and compared the diagnostic ability of FFA and SD-OCT, we found that the FFA had poor sensitivity (58.3 %) but a better specificity (71.8 %) than SD-OCT, which had sensitivity of 75 % and specificity of 64 % (Tables 1 and 2). However, the negative predictive value (NPV) of SD-OCT (89.29 %) was slightly better than FFA (84.85 %). CONCLUSION: Interobserver agreement between the observers was better for SD-OCT than for FFA in making the diagnosis of SRNV. SD OCT is a better diagnostic modality than FFA for ruling out the presence of SRNV. PMID- 24150708 TI - Comparison of diagnostic accuracy between multidetector computed tomography and virtual histology intravascular ultrasound for detecting optical coherence tomography-derived fibroatheroma. AB - Histopathological studies have reported that optical coherence tomography (OCT) can accurately detect fibroatheroma that is involved in not only culprit lesion of acute coronary syndrome but also no-reflow phenomenon after percutaneous coronary intervention. Studies have demonstrated superiority of OCT in plaque characterization and interruption of arterial wall component. At current, multidetector computed tomography (MDCT) and virtual histology intravascular ultrasound (VH-IVUS) are considered as alternative imaging devices for coronary plaque characterization. This study aimed to compare the diagnostic accuracy for detecting fibroatheroma between MDCT and VH-IVUS using OCT as the reference standard. Forty-three lesions from 27 patients assessed by MDCT, VH-IVUS, and OCT were included in this study. Fibroatheroma was defined by OCT as a signal-poor region with a fast signal drop-off and little or no signal backscattering within the lesion. From 43 lesions, OCT revealed 21 fibroatheromas. Ring-like sign assessed by MDCT and positive remodeling assessed by IVUS were more frequently observed in OCT-fibroatheroma than non-OCT-fibroatheroma. The remodeling index of OCT-fibroatheroma assessed by MDCT and IVUS were higher than those of non-OCT fibroatheroma. The sensitivity, specificity, positive predict values, negative predict values and accuracy of ring-like sign by MDCT and VH-IVUS for detecting OCT-fibroatheroma were 43, 95, 90, 64, 70 % and 71, 45, 56, 63, 58 %, respectively. Our results suggest that both accuracies of MDCT and VH-IVUS to detect OCT-fibroatheroma are insufficient. We need to apply appropriate device for searching vulnerable plaque. PMID- 24150707 TI - A dose-response meta-analysis of dietary lutein and zeaxanthin intake in relation to risk of age-related cataract. AB - BACKGROUND: Lutein and zeaxanthin are thought to have beneficial effects on protecting the lens against cataract formation, but findings from epidemiologic studies have been inconsistent. We aimed to conduct a meta-analysis of prospective cohort studies to examine the association between dietary lutein and zeaxanthin intake and risk of age-related cataract (ARC). METHODS: We systematically searched MEDLINE, EMBASE, Web of Science, and Cochrane Library databases up to March 2013. Reference lists from retrieved articles were also reviewed. The adjusted relative risks (RRs) from each study were extracted to calculate a pooled estimate with its 95 % confidence interval (CI). The dose response relationships were assessed by using generalized least-squares trend estimation. RESULTS: Six prospective cohort studies were identified involving 4,416 cases and 41,999 participants. For the comparison between the highest and the lowest categories of dietary lutein and zeaxanthin intake, significant inverse association were found for nuclear cataract (RR: 0.75; 95 % CI: 0.65, 0.85), but not for cortical cataract (RR: 0.85; 95 % CI: 0.53, 1.17) and for posterior subcapsular cataract (RR: 0.77; 95 % CI: 0.40, 1.13). Dose-response analysis showed that every 300 MUg/d increment in dietary lutein and zeaxanthin intake was associated with a 3 %, 1 %, or 3 % reduction in the risk of nuclear cataract (RR: 0.97; 95 % CI: 0.94, 0.99), cortical cataract (RR: 0.99; 95 % CI: 0.95, 1.02), or posterior subcapsular cataract (RR: 0.97; 95 % CI: 0.93, 1.01) respectively. CONCLUSIONS: Dietary lutein and zeaxanthin intake is associated with a reduced risk of ARC, especially nuclear cataract in a dose-response manner, indicating a beneficial effect of lutein and zeaxanthin in ARC prevention. PMID- 24150709 TI - A Five-Year Follow-Up on the Role of Educational Support in Preventing Dropout From Upper Secondary Education in Finland. AB - In this longitudinal study, we investigated the role of word reading and mathematical difficulties measured in 9th grade as factors for receiving educational support for learning in upper secondary education in Grades 10 to 12 (from ages 16 to 19) and furthermore as predictors of dropout from upper secondary education within 5 years after compulsory education. In addition, we studied the role of school achievement in Grades 9 and 11 in this prediction. The participants of this study were members of one age group of 16-year-old ninth graders (N = 595, females 302, males 293) in a midsized Finnish city, who were followed for 5 years after completing compulsory education. The path model results, where the effects of gender, educational track, and SES were controlled, showed, first, that students with academic learning difficulties received educational support for learning particularly in the 11th grade. Second, academic learning difficulties directly affected school achievement in the 9th grade, but no longer in the 11th grade. Third, mathematical difficulties directly predicted dropout from upper secondary education, and difficulties in both word reading and mathematics had an indirect effect through school achievement in Grades 9 and 11 on dropout. PMID- 24150710 TI - [Abdominal compartment syndrome]. AB - Abdominal compartment syndrome is defined as a pathological elevation of intraabdominal pressure associated with significant organ dysfunction and failure. Organ dysfunction mainly affects the renal, pulmonary, cardiac, gastrointestinal, and central nervous system. A high level of suspicion for this condition and early identification of patients at risk are mandatory for the successful management of abdominal compartment syndrome, which includes conservative and operative strategies. PMID- 24150711 TI - [Gastrointestinal bleeding in cardiological patients]. AB - Oral anticoagulation and antiplatelet therapy are risk factors for gastrointestinal (GI) bleeding. GI bleeding-especially lower GI bleeding-seems to be associated with a poorer outcome. With the introduction of dabigatrane and rivaroxaban, difficulties in the management of bleeding complications arose. Thus, the goal of the authors was to establish a standard operating procedure (SOP) for the treatment of severe GI bleeding associated with rivaroxaban, dabigatrane, and antiplatelet therapy. Bleeding complications during phenprocoumon treatment should be treated with prothrombin complex concentrates and vitamin K1. Dabigatrane elimination is highly dependent to the renal function. The measurement of drug concentrations of dabigatrane and rivaroxaban is useful to indicate an increased risk of bleeding complications. Severe bleeding associated with dabigatrane or rivaroxaban therapy should trigger prothrombin complex therapy, whereby in cases with severe bleeding associated with antiplatelet therapy platelet transfusion should be initiated. Low-dose aspirin should be continued after 24 h. PMID- 24150713 TI - The effect of size and sex on PCB and PAH concentrations in crab Portunus pelagicus. AB - Polychlorinated biphenyl and polycyclic aromatic hydrocarbon concentrations in the hepatopancreas of blue swimming crab (Portunus pelagicus) from the north Persian Gulf were measured. In addition, the relationships between crab size (carapace width) and polychlorinated biphenyl (PCB) and polycyclic aromatic hydrocarbon (PAH) levels in hepatopancreas were investigated by linear regression analysis. Among the PCBs, congeners 110 and 153 were the most frequent and abundant. The results showed that, except in a few cases, significant relationships between PCB and PAH levels and crab size were positive. Comparison between male and female indicated that the average PCB16, 44, 153, and acenaphthylene, acenaphthene, and anthracene concentrations in hepatopancreas of male crab were found to be significantly higher than those found in the female crab. PMID- 24150712 TI - Lack of liver injury in Wistar rats treated with the combination of isoniazid and rifampicin. AB - Isoniazid (INH) can cause serious idiosyncratic liver injury. An animal model would greatly facilitate mechanistic studies, but it is essential that the mechanism in the model be similar to the liver injury that can occur in humans. We attempted to replicate a previous study in which Wistar rats treated with INH and rifampicin (RMP) developed liver injury, which was promising because of its delayed onset similar to the liver injury that can occur in humans. Wistar rats were treated with either a high dose of INH (150 mg/kg/day) or a combination of INH and RMP (75 mg/kg/day and 50 mg/kg/day, respectively) for up to 4 weeks. However, we did not observe any liver injury or evidence of an inflammatory infiltrate as had been reported; rather, we observed an increase in CTLA4 positive cells in the cervical lymph nodes as well as a decrease in serum CXCL1 and MCP-1. In short, we were unable to reproduce a previously reported model of delayed onset INH-induced liver injury in Wistar rats. PMID- 24150714 TI - Groundwater phosphorus in forage-based landscape with cow-calf operation. AB - Forage-based cow-calf operations may have detrimental impacts on the chemical status of groundwater and streams and consequently on the ecological and environmental status of surrounding ecosystems. Assessing and controlling phosphorus (P) inputs are, thus, considered the key to reducing eutrophication and managing ecological integrity. In this paper, we monitored and evaluated P concentrations of groundwater (GW) compared to the concentration of surface water (SW) P in forage-based landscape with managed cow-calf operations for 3 years (2007-2009). Groundwater samples were collected from three landscape locations along the slope gradient (GW1 10-30% slope, GW2 5-10% slope, and GW3 0-5% slope). Surface water samples were collected from the seepage area (SW 0% slope) located at the bottom of the landscape. Of the total P collected (averaged across year) in the landscape, 62.64% was observed from the seepage area or SW compared with 37.36% from GW (GW1 = 8.01%; GW2 = 10.92%; GW3 = 18.43%). Phosphorus in GW ranged from 0.02 to 0.20 mg L(-1) while P concentration in SW ranged from 0.25 to 0.71 mg L(-1). The 3-year average of P in GW of 0.09 mg L(-1) was lower than the recommended goal or the Florida's numeric nutrients standards (NNS) of 0.12 mg P L(-1). The 3-year average of P concentration in SW of 0.45 mg L(-1) was about fourfold higher than the Florida's NNS value. Results suggest that cow-calf operation in pasture-based landscape would contribute more P to SW than in the GW. The risk of GW contamination by P from animal agriculture production system is limited, while the solid forms of P subject to loss via soil erosion could be the major water quality risk from P. PMID- 24150715 TI - Short-term effects of visitor trampling on macroinvertebrates in karst streams in an ecotourism region. AB - In order to evaluate the potential risks of human visitation on macroinvertebrate communities in streams, we investigated the effect of trampling using two short term experiments conducted in a Brazilian ecotourism karst region. We asked three questions: (a) Does trampling increase the drift rate of aquatic macroinvertebrates and organic matter? (b) Does trampling change the macroinvertebrate community organization? (c) If trampling alters the community structure, is a short time (5 days, a between weekends interval - peaks of tourism activities) sufficient for community restructuring? Analysis of variance of richness, total abundance, abundance of the most abundant genus (e.g., Simothraulopsis and Callibaetis), and community composition showed that trampling immediately affects macroinvertebrate community and that the intervals between the peaks of visitation (5 days) are not sufficient to complete community restructuring. Considering that bathing areas receive thousands of visitors every year and that intervals of time without visitation are nearly nonexistent, we suspect that the negative effects on the macroinvertebrate community occur in a cumulative way. Finally, we discuss some simple procedures that could potentially be used for reducing trampling impacts in lotic environments. PMID- 24150717 TI - Sudden cardiac arrest during sports. PMID- 24150716 TI - Biosorption kinetics of heavy metals by leaf biomass of Jatropha curcas in single and multi-metal system. AB - Biosorption of Cu(2+), Zn(2+), and Cr(6+) from aqueous solutions by leaf biomass of Jatropha curcas was investigated as a function of biomass concentration, initial metal ion concentration, contact time, and pH of the solution systematically. The aim of this study was to optimize biosorption process and find out a suitable kinetic model for the metal removal in single and multi-metal system. The experimental data were analyzed using two sorption kinetic models, viz., pseudo-first- and pseudo-second-order equations, to determine the best fit equation for the biosorption of metal ions Cu(2+), Zn(2+), and Cr(6+) onto the leaf biomass of J. curcas in different metal systems. The experimental data fitted well the pseudo-second-order equation and provided the best correlation for the biosorption process. The findings of the present investigation revealed that J. curcas leaf biomass was an eco-friendly and cost-effective biosorbent for the removal of heavy metal ions from wastewater. PMID- 24150718 TI - Stabilized Wittig olefination for bioconjugation. AB - Stabilized Wittig olefination holds great potential as a bioconjugation reaction. We demonstrate that the reaction of stabilized phosphorus ylides (or phosphonium salts) with aryl aldehydes is sufficiently robust to be used for live cell affinity isolation and fluorescence tagging of a protein, FKBP12. PMID- 24150719 TI - A method for highly efficient catalytic immobilisation of glucose oxidase on the surface of silica. AB - A simple, mild and convenient method has been developed for catalytic immobilisation of glucose oxidase (GOx), chemically modified to contain pendant methallylsilyl groups, on an untreated silica surface. PMID- 24150720 TI - High redox and performance stability of layered SmBa(0.5)Sr(0.5)Co(1.5)Cu(0.5)O(5+delta) perovskite cathodes for intermediate temperature solid oxide fuel cells. AB - Cobalt-containing cathodes often encounter problems such as high thermal expansion coefficients (TEC) and poor stability, making them unsuitable for practical use as cathode materials for intermediate-temperature solid oxide fuel cells (IT-SOFCs). This study focuses on the effects of Cu doping in the Co site of SmBa0.5Sr0.5Co2O5+delta in terms of structural characteristics, electrical properties, electrochemical performance, redox properties, and performance stability as an IT-SOFC cathode material. The TEC value of a SmBa0.5Sr0.5Co1.5Cu0.5O5+delta (SBSCCu50) sample is 12.8 * 10(-6) K(-1), which is lower than that (13.7 * 10(-6) K(-1)) of a SmBa0.5Sr0.5Co2O5+delta (SBSCO) sample at 700 degrees C. SBSCCu50 showed higher redox stability at lower p(O2) and a more stable cell power output while retaining desirable electrochemical performance, as compared with SBSCO. SBSCCu50 displayed reduced TEC values and enhanced redox and performance stability, as well as satisfactory electrical properties and electrochemical performance under typical fuel cell operating conditions. The results indicate that SBSCCu50 is a promising material as a cathode for IT-SOFCs. PMID- 24150721 TI - Criteria for definition of a complex abdominal wall hernia. AB - PURPOSE: A clear definition of "complex (abdominal wall) hernia" is missing, though the term is often used. Practically all "complex hernia" literature is retrospective and lacks proper description of the population. There is need for clarification and classification to improve patient care and allow comparison of different surgical approaches. The aim of this study was to reach consensus on criteria used to define a patient with "complex" hernia. METHODS: Three consensus meetings were convened by surgeons with expertise in complex abdominal wall hernias, aimed at laying down criteria that can be used to define "complex hernia" patients, and to divide patients in severity classes. To aid discussion, literature review was performed to identify hernia classification systems, and to find evidence for patient and hernia variables that influence treatment and/or prognosis. RESULTS: Consensus was reached on 22 patient and hernia variables for "complex" hernia criteria inclusion which were grouped under four categories: "Size and location", "Contamination/soft tissue condition", "Patient history/risk factors", and "Clinical scenario". These variables were further divided in three patient severity classes ('Minor', 'Moderate', and 'Major') to provide guidance for peri-operative planning and measures, the risk of a complicated post operative course, and the extent of financial costs associated with treatment of these hernia patients. CONCLUSION: Common criteria that can be used in defining and describing "complex" (abdominal wall) hernia patients have been identified and divided under four categories and three severity classes. Next step would be to create and validate treatment algorithms to guide the choice of surgical technique including mesh type for the various complex hernias. PMID- 24150723 TI - Global longitudinal strain in patients with suspected heart failure and a normal ejection fraction: does it improve diagnosis and risk stratification? AB - Many patients have clinical, structural or bio-marker evidence of heart failure (HF) but a normal left ventricular ejection fraction (LVEF; HeFNEF). Measurement of global longitudinal strain (GLS) may add diagnostic and prognostic information. Patients with symptoms suggesting heart failure and LVEF >=50% were studied: 76 had no substantial cardiac dysfunction (left atrial diameter (LAD) <40 mm and amino-terminal pro-brain natriuretic peptide (NTproBNP) <400 ng/l); 99 had "possible HeFNEF" (LAD >=40 mm or NTproBNP >=400 ng/l); and 138 had "definite HeFNEF" (LAD >=40 mm and NTproBNP >=400 ng/L). Mean LVEF was 58% in each subgroup. Patients with definite HeFNEF were older, more likely to have atrial fibrillation, had more symptoms and signs of fluid retention, were more likely to have right ventricular dysfunction and had higher pulmonary pressures than other groups. Mean GLS (SD) was less negative in patients with definite HeFNEF (-13.6 (3.0)% vs. possible HeFNEF: -15.2 (3.1)% vs. no substantial cardiac dysfunction: 15.9 (2.4)%; p < 0.001). GLS was -19.1 (2.1)% in 20 controls. During a median follow up of 647 days, cardiovascular death or an unplanned hospitalisation for heart failure occurred in 62 patients. In univariable analysis, GLS but not LVEF predicted events. However, in a multi-variable analysis, only urea, NTproBNP, left atrial volume, inferior vena cava diameter and atrial fibrillation independently predicted adverse outcome. GLS is abnormal in patients who have other evidence of HeFNEF, is associated with a worse prognosis in this population but is not a powerful independent predictor of outcome. PMID- 24150726 TI - Genetic diversity and bottleneck studies in endangered Bhutia and Manipuri pony breeds. AB - For studying the genetic diversity and bottleneck problem in Bhutia and Manipuri pony breeds of India, we analysed DNA samples of 34 Bhutia and 50 Manipuri, true to breed, ponies using 47 polymorphic microsatellite markers. All the microsatellites were observed to be highly polymorphic in nature in both Bhutia and Manipuri breeds with mean no. of alleles as 8.702 +/- 0.0493 and 8.416 +/- 0.0548 respectively. Genetic diversity values in terms of heterozygosity values within individual breeds were also high with very low inbreeding (Fis 0.102 and 0.055 in Bhutia and Manipuri ponies, respectively). Number of alleles in both the populations together ranged from 3 to 18 with an average of 10.851 +/- 1.583 per locus. The mean effective number of alleles was observed to 5.34 +/- 0.253. All loci except ASB017 and HTG004 showed high values of allele richness (>5.0). The mean observed and expected heterozygosities were 0.7159 +/- 0.022, 0.7986 +/- 0.011 (Levene's) and 0.7936 +/- 0.011 (Nei's), respectively. The high mean values of heterozygosity indicated the presence of high genetic diversity in both the pony populations. The overall mean value of within-population inbreeding estimates (Fis) was low (0.101 +/- 0.023) indicating low to moderate level of inbreeding. Bottleneck studies revealed that no recent bottleneck problem has taken place in both the populations. Both pony populations were found to be in mutation drift equilibrium. The study reveals that both the pony breeds have high diversity and timely action needs to be taken to conserve them. PMID- 24150727 TI - Epidemiology of proximal femoral fractures in South Korea. AB - We determined the incidence of femoral neck, intertrochanteric, and subtrochanteric fractures and compared the demographic characteristics of each fracture group in the Korean population. PURPOSE: All proximal femur fractures (femoral neck, intertrochanteric, and subtrochanteric fracture) have been considered to have similar demographics and to be related with osteoporosis. However, there has been lack of comparison with demographics of each fracture. Our purposes were to determine the incidences of femoral neck, intertrochanteric, and subtrochanteric fracture and to compare the demographic characteristics of each fracture group in the Korean population. METHODS: We assessed the demographic characteristics of proximal femoral fractures (femoral neck, intertrochanteric, and subtrochanteric) in the entire Korean population in 2010 by accessing nationwide data from the Health Insurance Review Assessment Service (HIRA). After proper identification using International Classification of Diseases, 10th revision (ICD-10) codes, we calculated absolute number and age- and gender-specific incidence rates for each proximal femoral fracture group. RESULTS: The incidences of femoral neck, intertrochanteric, and subtrochanteric fractures were 29.3, 26.8, and 2.0 per 100,000 persons, respectively. In a population of over 60-year-old individuals, the incidences of hip fracture (femoral neck and intertrochanteric fracture) in men and women were 260.0 and 527.0 per 100,000 persons, and the incidences of subtrochanteric fracture in men and women were 7.2 and 13.2 per 100,000 persons. The incidences of subtrochanteric fractures insensibly increased, while the incidences of femoral neck and intertrochanteric fractures exponentially increased with aging. CONCLUSIONS: The demographic characteristic patterns of the patients with subtrochanteric fractures were not similar to those of patients with femoral neck and intertrochanteric fractures, which are typically categorized as osteoporosis related fractures. PMID- 24150725 TI - The MTR 2756A>G polymorphism and maternal risk of birth of a child with Down syndrome: a case-control study and a meta-analysis. AB - Methionine synthase (MTR) is required for the conversion of homocysteine (hcy) to methionine in the one-carbon metabolic pathway. Previous studies investigating a common MTR 2756A>G polymorphism as a maternal risk factor for the birth of a child with Down syndrome (DS) are conflicting and limited by small case-control cohorts, and its contribution to circulating hcy levels is still debated. We performed a large case-control study and a meta-analysis of the literature to further address the role of MTR 2756A>G as a maternal risk factor for the birth of a child with DS. 286 mothers of a DS child (MDS) and 305 control mothers of Italian origin were included in the case-control study. Genotyping was performed by means of PCR/RFLP technique. Data on circulating levels of hcy, folates, and vitamin B12 were available for 189 MDS and 194 control mothers. The meta analysis of previous and present data involved a total of 8 studies (1,171 MDS and 1,402 control mothers). Both the case-control study and the meta-analysis showed no association of MTR 2756A>G with the maternal risk of birth of a child with DS (OR = 1.15; 95 % CI 0.85-1.55, and OR = 1.08; 95 % CI 0.93-1.25, respectively), even after stratification of the overall data available for the meta-analysis into ethnic groups. No association of the studied polymorphism with circulating levels of hcy, folates, and vitamin B12 was observed. Present data do not support a role for MTR 2756A>G as independent maternal risk factor for a DS birth. PMID- 24150728 TI - Perinatal HIV testing among African American, Caucasian, Hmong and Latina women: exploring the role of health-care services, information sources and perceptions of HIV/AIDS. AB - Perinatal HIV transmission disproportionately affects African American, Latina and potentially Hmong women in the United States. Understanding racially and ethnically diverse women's perceptions of and experiences with perinatal health care, HIV testing and HIV/AIDS may inform effective health communications to reduce the risk of perinatal HIV transmission among disproportionate risk groups. We used a qualitative descriptive research design with content analysis of five focus groups of African American, Caucasian, Hmong and Latina women of reproductive age with low socioeconomic status distinguished by their race/ethnicity or HIV status. A purposive stratified sample of 37 women shared their health-care experiences, health information sources and perceptions of HIV testing and HIV/AIDS. Women's responses highlighted the importance of developing and leveraging trusted provider and community-based relationships and assessing a woman's beliefs and values in her sociocultural context, to ensure clear, consistent and relevant communications. Perinatal health communications that are culturally sensitive and based on an assessment of women's knowledge and understanding of perinatal health and HIV/AIDS may be an effective tool for health educators addressing racial and ethnic disparities in perinatal HIV transmission. PMID- 24150729 TI - Thin film MnGe grown on Si(111). AB - MnGe has been grown as a thin film on Si(111) substrates by molecular beam epitaxy. A 10 A layer of MnSi was used as the seed layer in order to establish the B20 crystal structure. Films of a thickness between 45 and 135 A have been prepared and structurally characterized using reflection high-energy electron diffraction, atomic force microscopy and x-ray diffraction. These studies provided evidence that MnGe forms in the cubic B20 crystal structure as islands exhibit a very smooth surface. The islands become larger with increasing film thickness. A magnetic characterization reveals that the ordering temperature of MnGe thin films is enhanced compared to that for bulk material. The properties of the helical magnetic structure obtained from magnetization and magnetoresistivity measurements are compared with those of films of the related compound MnSi. The much stronger Dzyaloshinskii-Moriya interaction in MnGe results in a higher rigidity of the spin helix. PMID- 24150731 TI - Endoscopic bilateral stenting of malignant hilar bile duct obstruction using novel partially covered self-expandable metal stents. PMID- 24150730 TI - [Evaluation of tolerance of zidovudine-lamivudine-nevirapine combination in HIV 1 patients in Fann Teaching Hospital in Dakar]. AB - We conducted a study to evaluate the tolerance of the zidovudine (AZT), lamivudine (3TC) and nevirapine (NVP) combination regimen in HIV-1 patients by a descriptive analytical retrospective study of all HIV-1 patients receiving AZT 3TC-NVP combination between 2008 and 2011. Seventy patients were included. Two thirds of the patients presented at least one side effect (44 cases). The digestive disorders (15 cases) and neuropsychiatric (14 cases) were the most frequent. Epigastralgia (20%), headaches (20%) and arthralgias (13%) were main side effects. A maculo-papular exanthema was noted in three cases. During the follow-up, five patients presented with anemia. No patient presented hepatic cytolysis due to NVP. All the patients followed for more than six months presented a side effect against 29.7% when the duration of treatment was equal to or less than 6 months (p=10(-5)). Most of the side effects due to the association AZT/3TC/NVP are minor. The evaluation of the clinical and biological tolerance must be maintained during all the follow-up. PMID- 24150732 TI - Radiofrequency ablation of Barrett's esophagus using an overtube. PMID- 24150733 TI - Endoscopic ultrasound-guided drainage of giant liver abscess associated with transgastric migration of a self-expandable metallic stent. PMID- 24150734 TI - Double-balloon enteroscopy-ERCP rendezvous technique. PMID- 24150736 TI - Hematoperitoneum after small-bowel spiral enteroscopy. PMID- 24150735 TI - A safe technique using clips for covered self-expandable metal stent placement during endoscopic ultrasound-guided hepaticogastrostomy. PMID- 24150737 TI - Neuroendocrine tumor of the extrahepatic bile duct: a tumor in an unusual site visualized by cholangioscopy. PMID- 24150738 TI - Effects of environmental factors on MSP21-25 aggregation indicate the roles of hydrophobic and electrostatic interactions in the aggregation process. AB - Merozoite surface protein 2 (MSP2), one of the most abundant proteins on the merozoite surface of Plasmodium falciparum, is recognized to be important for the parasite's invasion into the host cell and is thus a promising malaria vaccine candidate. However, mediated mainly by its conserved N-terminal 25 residues (MSP21-25), MSP2 readily forms amyloid fibril-like aggregates under physiological conditions in vitro, which impairs its potential as a vaccine component. In addition, there is evidence that MSP2 exists in aggregated forms on the merozoite surface in vivo. To elucidate the aggregation mechanism of MSP21-25 and thereby understand the behavior of MSP2 in vivo and find ways to avoid the aggregation of relevant vaccine in vitro, we investigated the effects of agitation, pH, salts, 1 anilinonaphthalene-8-sulfonic acid (ANS), trimethylamine N-oxide dihydrate (TMAO), urea, and sub-micellar sodium dodecyl sulfate (SDS) on the aggregation kinetics of MSP21-25 using thioflavin T (ThT) fluorescence. The results showed that MSP21-25 aggregation was accelerated by agitation, while repressed by acidic pHs. The salts promoted the aggregation in an anion nature-dependent pattern. Hydrophobic surface-binding agent ANS and detergent urea repressed MSP21-25 aggregation, in contrast to hydrophobic interaction strengthener TMAO, which enhanced the aggregation. Notably, sub-micellar SDS, contrary to its micellar form, promoted MSP21-25 aggregation significantly. Our data indicated that hydrophobic interactions are the predominant driving force of the nucleation of MSP21-25 aggregation, while the elongation is controlled mainly by electrostatic interactions. A kinetic model of MSP21-25 aggregation and its implication were also discussed. PMID- 24150739 TI - Effect of distal sugars and interglycosidic linkage on the N-glycoprotein linkage region conformation: synthesis and X-ray crystallographic investigation of beta-1 N-alkanamide derivatives of cellobiose and maltose as disaccharide analogs of the conserved chitobiosylasparagine linkage. AB - The linkage region constituents, 2-deoxy-2-acetamido-beta-D-glucopyranose (GlcNAc) and L-asparagine (Asn) are conserved in the N-glycoproteins of all eukaryotes. Elucidation of the structure and conformation of the linkage region of glycoproteins is important to understand the presentation and dynamics of the carbohydrate chain at the protein/cell surface. Earlier crystallographic studies using monosaccharide models and analogs of N-glycoprotein linkage region have shown that the N-glycosidic torsion, phiN, is more influenced by the structural variation in the sugar part than that of the aglycon moiety. To access the influence of distal sugar as well as interglycosidic linkage (alpha or beta) on the N-glycosidic torsion angles, cellobiosyl and maltosyl alkanamides have been synthesized and structural features of seven of these analogs have been characterized by X-ray crystallography. Comparative analysis of the seven disaccharide analogs with the reported monosaccharide analogs showed that the phiN value of cellobiosyl analogs deviate ~9 degrees with respect to GlcbetaNHAc. In the case of maltosyl analogs, deviation is more than 18 degrees . These deviations indicate that the N-glycosidic torsion is influenced by addition of distal sugar as well as with respect to inter glycosidic linkage (alpha or beta); it is less influenced by changes occurring at the aglycon. The chi2 value of alkanamide derived from glucose, cellobiose and maltose exhibit a large range of variations (from 1.6 degrees to -109.9 degrees ). This large span of chi2 value suggests the greater degree of rotational freedom around C1'-C2' bond which is restricted in GlcNAc alkanamides. The present finding explicitly proved the importance of molecular architecture in the N-glycoproteins linkage region to maintain the linearity, planarity and rigidity. These factors are necessary for N glycan to serve role in inter- as well as intramolecular carbohydrate-protein interactions. PMID- 24150740 TI - Mesoporous titanium zirconium oxide nanospheres with potential for drug delivery applications. AB - Mesoporous titanium zirconium (TiZr) oxide nanospheres with variable Ti to Zr ratios were synthesized using sol-gel chemistry followed by solvothermal treatment. These oxide nanospheres exhibited similar diameters (~360 nm), high surface areas (from 237 +/- 2 to 419 +/- 4 m(2) g(-1)), and uniform pore diameters (~3.7 nm). Three drugs, ibuprofen, dexamethasone, and erythromycin, were loaded into the TiZr oxide nanospheres. The TiZr oxide nanospheres exhibited a high loading capacity, up to 719 mg g(-1), and sustained release profiles in phosphate buffered saline (PBS) at pH 7.4. The mesoporous TiZr oxide nanospheres also exhibited hydrolytic stability, as evidenced by the retention of the integrity of the mesostructures after drug release in PBS for 21 days. PMID- 24150741 TI - Structure-activity relationship studies of the aromatic positions in cyclopentapeptide CXCR4 antagonists. AB - The cyclopentapeptide CXCR4 antagonist FC131 (cyclo(-Arg(1)-Arg(2)-2-Nal(3) Gly(4)-D-Tyr(5)-), 2; 2-Nal = 3-(2-naphthyl)alanine) represents an excellent starting point for development of novel drug-like ligands with therapeutic potential in HIV, cancer, stem-cell mobilization, inflammation, and autoimmune diseases. While the structure-activity relationships for Arg(1), Arg(2), and Gly(4) are well established, less is understood about the roles of the aromatic residues 2-Nal(3) and D-Tyr(5). Here we report further structure-activity relationship studies of these two positions, which showed that (i) the distal aromatic ring of the 2-Nal(3) side chain is required in order to maintain high potency and (ii) replacement of D-Tyr(5) with conformationally constrained analogues results in significantly reduced activity. However, a simplified analogue that contained Gly instead of D-Tyr(5) was only 13-fold less potent than 2, which means that the D-Tyr(5) side chain is dispensable. These findings were rationalized based on molecular docking, and the collective structure-activity data for the cyclopentapeptides suggest that appropriately designed Arg(2)-2 Nal(3) dipeptidomimetics have potential as CXCR4 antagonists. PMID- 24150742 TI - Multicomponent synthesis of unnatural pyrrolizidines using 1,3-dipolar cycloaddition of proline esters. AB - The synthesis of unnatural pyrrolizidines has been studied using a multicomponent domino process involving proline or 4-hydroxyproline esters, an aldehyde and a dipolarophile. The formation of the iminium salt promotes the 1,3-dipolar cycloaddition affording highly substituted pyrrolizidines under mild conditions and high regio- and diastereoselectivities. PMID- 24150743 TI - A thymosin beta15-like peptide promotes intersegmental myotome extension in the chicken embryo. AB - Beta-thymosins constitute a group of small actin-sequestering peptides. These highly conserved peptides are involved in cytoskeleton dynamics and can influence different cell properties such as motility, substrate adhesion, shape and chemotaxis. As a marker for tumour metastasis, the mammalian thymosin beta15 is believed to have an important diagnostic relevance in cancer prognosis, although little is known about its physiological function. In order to study the role of thymosin beta15(avian) in embryogenesis, we cloned the chicken and quail orthologues of thymosin beta15 and used the chicken as a model for vertebrate development. Avian thymosin beta15, the first known non-mammalian thymosin beta15 like gene, encodes a peptide that possesses a cysteine at position one after the methionine which is a significant difference compared to its mammalian counterparts. Thymosin beta15(avian) expression starts at an early stage of development. The expression pattern changes rapidly with development and differs from that of the related thymosin beta4 gene. The most prominent expression domain is seen in developing muscles of limbs and trunk. Gain-of-function experiments revealed that thymosin beta15(avian) has a function in normal myotome development. Ectopic over-expression of thymosin beta15(avian) leads to premature elongation of myotome cells trespassing segment borders. We conclude that thymosin beta15(avian) has a still undescribed function in promoting myocyte elongation. PMID- 24150744 TI - The molecular basis of the specificity and cross-reactivity of the NeuN epitope of the neuron-specific splicing regulator, Rbfox3. AB - Ever since its description and the generation of its defining antibody some 20 years ago, NeuN (Neural Nuclei) has been an invaluable tool for developmental neuroscientist sand neuropathologists to identify neurons and follow their normal or malignant development [corrected].The recent identification of the splicing factor Rbfox3 as the molecule constituting the genuine NeuN epitope has opened up a novel perspective on NeuN immunostaining and its interpretation. Here, we briefly review these recent developments, and we provide a series of data that allow to rationalize the specificity of the NeuN/A60 antibody on aldehyde-fixed tissues on the one hand, and its cross-reactivity with Synapsin I and R3hdm2 on Western blots on the other. We argue that rather than being considered as a mere marker for mature neurons, Rbfox3-mediated NeuN/A60 immunoreactivity may provide a window onto neuronal biology. Specifically, we hypothesize that the phosphorylation-dependent antigenicity of the Rbfox3/NeuN epitope should allow to visualize neuronal physiology realized through Rbfox3, including splicing, on the single-cell level. PMID- 24150745 TI - Validation of the revised International Criteria for Behcet's Disease (ICBD) in Iran. AB - The first internationally agreed criteria for Behcet's disease were the International Study Group (ISG) criteria. It had very high specificity, but lacked good sensitivity, missing an important subset of patients. The International Criteria for Behcet's Disease (ICBD) were created in 2006 to overcome this lack of sensitivity. It was revised in 2010. The objective of this study was to evaluate the performance of the revised International Criteria for Behcet's Disease (rICBD) in Iran. In this study, the ISG and ICBD were evaluated and compared to the rICBD. All patients from the Behcet's Disease Registry (7,011) and controls (5,226), up to March 2013, entered the study. The diagnosis was clinical, by expert opinion. Sensitivity, specificity, and accuracy were calculated for ISG, ICBD, and rICBD. A 95% confidence interval (95%CI) was calculated for percentages. For ISG, the sensitivity was 77.5% (95%CI = 76.5 78.5). It was 98.3% for ICBD (95%CI = 98.0-98.6) and 96.8% for rICBD (95%CI = 96.4-97.2). Specificity was 99.2% (95%CI = 99.0-99.4) for ISG, 96.2% for ICBD (95%CI = 95.7-96.7), and 97.2% for rICBD (95%CI = 96.8-97.6). Accuracy was 86.7% (95%CI = 86.1-87.3) for ISG, 97.4% for ICBD (95%CI = 97.1-97.7), and 97.0% for rICBD (95%CI = 96.7-97.3). In Iranian patients, ICBD has 20.8% and rICBD 19.3% higher sensitivity than ISG. Although the specificity was lower than ISG by 3% for ICBD and 2% for rICBD, the accuracy was higher respectively by 10.7 and 10.3%. ICBD has by far better performance than ISG. The difference was even more prominent in Iranian patients than for the ICBD cohort of patients and controls. PMID- 24150746 TI - Prevalence of psoriatic arthritis in psoriasis patients according to newer classification criteria. AB - The aim of this study is to determine the prevalence of psoriatic arthritis (PsA) according to CASPAR criteria, ASAS peripheral and axial SpA criteria, and New York criteria for AS. The first 100 patients consecutively attending a psoriasis dermatology clinic were assessed. Demographic and clinical data were collected; all patients were questioned and examined for joint manifestations. Rheumatoid factor and radiographies of hands, feet, cervical spine, and pelvis for sacroiliac joints were obtained. X-rays were read independently by two experienced observers in blind fashion. Patients with objective joint manifestations, both axial and peripheral, were evaluated for fulfillment of CASPAR, ASAS peripheral and axial, and New York criteria. Median age 48 years; 93 % of patients had psoriasis vulgaris and 56 % nail involvement. Seventeen patients had peripheral arthritis as follows: nine mono/oligoarticular and eight polyarthritis. Median arthritis duration was 8 years. Seventeen percent of patients fulfilled CASPAR and ASAS peripheral criteria, 6 % New York, and 5 % ASAS axial criteria. Patients who met CASPAR criteria showed a significantly higher psoriasis duration compared to those without arthritis (M 16 vs. 10 years, p = 0.02), and a higher frequency of nail involvement (88.2 vs. 49.4 %, p = 0.003). Five patients (29.4 %) fulfilled ASAS axial criteria; all of them had peripheral involvement as follows: mono/oligoarticular in three patients and polyarticular in two. Patients with peripheral and axial involvement presented a significantly higher frequency of erythrodermic psoriasis compared to the other patients (35.3 vs. 1.2 %, p = 0.0006 and 80 vs. 16.7 %, p = 0.02). Prevalence of PsA, for CASPAR and ASAS peripheral criteria, was of 17 %. Five percent of patients met ASAS axial criteria, while 6 % met New York criteria. Worth noting, few patients without signs or symptoms of arthritis had radiological changes, both axial and peripheral, precluding a proper classification. PMID- 24150747 TI - Patient co-payment and adherence to statins: a review and case studies. AB - PURPOSE: This study aims to review the international literature about whether there is an association between co-payment and statin adherence, and to present case studies to illustrate the impact of a reduction in patient co-payment associated with generic drugs on improving therapy adherence. METHODS: Studies that examined the impact of patient co-payment on statin adherence were identified in PubMed, Cochrane Central Register of Controlled Trials and EconLit up to January 2013. A standardized data extraction form was completed for each included study, collecting information about country, sample, setting, adherence measure, design, results about the impact of co-payment on statin adherence, and methodological quality. Two cases from the outpatient clinic of one the authors (PRS) were added. RESULTS: The literature supported a statistically significant negative association between co-payment and statin adherence. This association appeared to be influenced by the absolute level of co-payments, the size of the co-payment change, whether co-payment increases or decreases, the time horizon over which the impact of a co-payment change is examined, the type of drug for which co-payment changes (e.g. generic or branded drug), the availability of alternative drugs and switching behaviour. Two case studies illustrated that cost issues are important to patients and that patient adherence to statin therapy improved following a switch to generic statins. CONCLUSIONS: Current studies have demonstrated that statin adherence is influenced by co-payment and a range of patient, physician and pharmacy characteristics. Nevertheless, the power of these models to explain the variation in adherence remains limited. PMID- 24150748 TI - Toward an integrated software platform for systems pharmacology. AB - Understanding complex biological systems requires the extensive support of computational tools. This is particularly true for systems pharmacology, which aims to understand the action of drugs and their interactions in a systems context. Computational models play an important role as they can be viewed as an explicit representation of biological hypotheses to be tested. A series of software and data resources are used for model development, verification and exploration of the possible behaviors of biological systems using the model that may not be possible or not cost effective by experiments. Software platforms play a dominant role in creativity and productivity support and have transformed many industries, techniques that can be applied to biology as well. Establishing an integrated software platform will be the next important step in the field. PMID- 24150750 TI - Cytoplasmic genetic variation and extensive cytonuclear interactions influence natural variation in the metabolome. AB - Understanding genome to phenotype linkages has been greatly enabled by genomic sequencing. However, most genome analysis is typically confined to the nuclear genome. We conducted a metabolomic QTL analysis on a reciprocal RIL population structured to examine how variation in the organelle genomes affects phenotypic variation. This showed that the cytoplasmic variation had effects similar to, if not larger than, the largest individual nuclear locus. Inclusion of cytoplasmic variation into the genetic model greatly increased the explained phenotypic variation. Cytoplasmic genetic variation was a central hub in the epistatic network controlling the plant metabolome. This epistatic influence manifested such that the cytoplasmic background could alter or hide pairwise epistasis between nuclear loci. Thus, cytoplasmic genetic variation plays a central role in controlling natural variation in metabolomic networks. This suggests that cytoplasmic genomes must be included in any future analysis of natural variation. DOI: http://dx.doi.org/10.7554/eLife.00776.001. PMID- 24150751 TI - Effects of treadmill exercise on neural stem cells, cell proliferation, and neuroblast differentiation in the subgranular zone of the dentate gyrus in cyclooxygenase-2 knockout mice. AB - Cyclooxygenase-2 (COX-2) function has been implicated in a number of physiological processes, including inflammatory responses, synaptic transmission, and synaptic plasticity in the brain. However, the specific role of COX-2 in exercise-induced neurogenesis is still debatable. Here, we assessed the role of COX-2 in exercise-induced plasticity by comparing COX-2 knockout mice to wild type control littermates. We investigated the number of neural stem cells, and the degree of cell proliferation and neuronal differentiation in COX-2 knockout and its wild-type mice that either exercised or remained inactive. Wild-type and COX-2 knockout mice were put on a treadmill and were either sedentary or were forced to run 1 h/day for five consecutive days at a pace of 10-12 m/min for 5 weeks. Loss of COX-2 expression in the knockout mice was confirmed with two measures: (1) COX immunolabeling in the hippocampus, and (2) the identification of abnormal kidney development using hematoxylin and eosin staining, including subcapsular glomerular hypoplasia and hypertrophy of the deeper cortical glomeruli. Compared to wild-type mice, COX-2 knockout mice exhibited a significant reduction in the neural stem cells (nestin-positive cells), cell proliferation (Ki67-positive cells), and neuroblast differentiation (doublecortin positive cells). In contrast, exercise significantly increased the neural stem cells, cell proliferation, and neuroblast differentiation in both the wild-type and COX-2 knockout mice although the NeuN-immunoreactive neurons were similar in all groups. Expression of phosphorylated cAMP-response element binding protein was decreased in knockout mice. Exercise increased its expression in the subgranular zone of the dentate gyrus in both wild-type and knockout mice. These results suggest that the COX-2 pathway is one of important factors on neural stem cells, cell proliferation and neuroblast differentiation in sedentary mice. The ability of exercise to increase these types of neural plasticity, regardless of COX-2 signaling, suggests that the effects of exercise on neural stem cells, cell proliferation, and neuroblast differentiation are induced via a pathway that is independent of COX-2. PMID- 24150752 TI - Early over-expression of GRP receptors in prostatic carcinogenesis. AB - BACKGROUND: The GRP receptor shows high over-expression in prostatic adenocarcinoma and high grade PIN, but low expression in normal prostate glands. This represents the molecular basis for GRP receptor imaging of prostate cancer with radioactive compounds. However, a focal, high density GRP receptor expression can be observed in hitherto uncharacterized prostate glands. METHODS: GRP receptors were quantitatively measured with in vitro receptor autoradiography using 125I-Tyr4 -bombesin in samples from 115 prostates. On successive tissue sections, 125I-Tyr4 -bombesin autoradiography was compared with H&E staining and MIB-1 and 34betaE12 immunohistochemistry. RESULTS: On one hand, it was confirmed that GRP receptors were expressed in adenocarcinoma and high grade PIN in high density and high incidence (77% and 73%, respectively), but in normal prostate glands in low density and low frequency (18%). On the other hand, a novel and intriguing observation was the existence of focal non-invasive prostate glands with high GRP receptor density, characterized by low grade nuclear atypia and increased proliferation, compatible with lower grade PIN. There was a significant GRP receptor density gradient (P <= 0.005), increasing from normal prostate glands (mean relative optical density, ROD, of 125I-Tyr4 -bombesin binding: 0.17) over atypical glands without increased MIB-1 labeling (0.28) and atypical glands with increased MIB-1 expression (0.44) to high grade PIN and adenocarcinoma (0.64 and 0.58, respectively). CONCLUSIONS: GRP receptor over-expression may be a novel, specific marker of early prostatic neoplastic transformation, arising in low grade PIN, and progressively increasing during malignant progression. This should be considered when interpreting in vivo GRP receptor imaging in males. PMID- 24150753 TI - Primary mast cell disorders in children. AB - Mastocytosis arises from clonal mast cell expansion and the resultant accumulation of mast cells in cutaneous and sometimes extracutaneous tissues. Recent studies have demonstrated that c-kit mutations seem to be more prevalent in pediatric mastocytosis than previously assumed, but what determines disease evolution and severity in the individual patient remains elusive. For the large majority of children, mastocytosis is a self-limited cutaneous disease that spontaneously regresses before they reach adult age. Rarely, children develop systemic disease progression that is the hallmark of adult-onset disease. Therefore, invasive diagnostic testing, including performing a bone marrow biopsy, is not routinely recommended and usually reserved for children that present with signs of systemic involvement and persistently elevated serum tryptase levels. Despite its often-transient nature and limited skin involvement, some children experience challenging disease-associated symptoms due to spontaneous or trigger-induced mast cell degranulation. Anticipation of and preparation for potential complications can in many instances avoid symptomatic exacerbations. Proper symptomatic treatment and supportive care can often improve the child's quality of life. Cytoreductive therapy is usually not indicated given the natural history of spontaneous disease resolution. PMID- 24150755 TI - Intravitreally transplanted dental pulp stem cells promote neuroprotection and axon regeneration of retinal ganglion cells after optic nerve injury. AB - PURPOSE: To investigate the potential therapeutic benefit of intravitreally implanted dental pulp stem cells (DPSCs) on axotomized adult rat retinal ganglion cells (RGCs) using in vitro and in vivo neural injury models. METHODS: Conditioned media collected from cultured rat DPSCs and bone marrow-derived mesenchymal stem cells (BMSCs) were assayed for nerve growth factor (NGF), brain derived neurotrophic factor (BDNF), and neurotrophin-3 (NT-3) secretion using ELISA. DPSCs or BMSCs were cocultured with retinal cells, with or without Fc-TrK inhibitors, in a Transwell system, and the number of surviving betaIII-tubulin+ retinal cells and length/number of betaIII-tubulin+ neurites were quantified. For the in vivo study, DPSCs or BMSCs were transplanted into the vitreous body of the eye after a surgically induced optic nerve crush injury. At 7, 14, and 21 days postlesion (dpl), optical coherence tomography (OCT) was used to measure the retinal nerve fiber layer thickness as a measure of axonal atrophy. At 21 dpl, numbers of Brn-3a+ RGCs in parasagittal retinal sections and growth-associated protein-43+ axons in longitudinal optic nerve sections were quantified as measures of RGC survival and axon regeneration, respectively. RESULTS: Both DPSCs and BMSCs secreted NGF, BDNF, and NT-3, with DPSCs secreting significantly higher titers of NGF and BDNF than BMSCs. DPSCs, and to a lesser extent BMSCs, promoted statistically significant survival and neuritogenesis/axogenesis of betaIII tubulin+ retinal cells in vitro and in vivo where the effects were abolished after TrK receptor blockade. CONCLUSIONS: Intravitreal transplants of DPSCs promoted significant neurotrophin-mediated RGC survival and axon regeneration after optic nerve injury. PMID- 24150754 TI - Retinal nerve fiber layer thickness in a population of 12-year-old children in central China measured by iVue-100 spectral-domain optical coherence tomography: the Anyang Childhood Eye Study. AB - PURPOSE: To study the distribution of peripapillary retinal nerve fiber layer (RNFL) thickness in a population of 12-year-old children in central China using iVue-100 spectral-domain optical coherence tomography (SD-OCT). METHODS: Twelve year-old students (n = 2105) from four randomly selected middle schools in Anyang, China, participated in the study. Each child underwent ocular examinations, including optical biometry, cycloplegic autorefraction, and SD-OCT (iVue-100). Glaucoma optic nerve head scan was performed to measure RNFL thickness. Only the children with a signal strength index higher than 45 were included in the analyses. Multivariate analyses were performed to examine the association of RNFL with demographic variables (e.g., sex, age, and body mass index [BMI]) and ocular variables (e.g., axial length and refractive error). RESULTS: Optical coherence tomography scans of adequate quality were available for 1955 children (92.9%). The mean (SD) RNFL thickness was 103.08 (9.01) MUm, with the mean (SD) thickest RNFL in the inferior quadrant (129.34 [14.90] MUm), followed by the superior (126.19 [15.24] MUm), temporal (82.98 [10.57] MUm), and nasal (73.82 [13.89] MUm) quadrants. The RNFL was thicker with shorter axial length (beta = -1.53, P < 0.0001) and with higher hyperopia (beta = 0.90, P < 0.0001). Girls had slightly thicker average RNFL thickness than boys (P < 0.0001). The RNFL thickness had no significant correlation with age or BMI. CONCLUSIONS: This study establishes normative peripapillary RNFL values of 12 year-old Chinese children as measured by iVue-100 SD-OCT. The RNFL thickness decreased significantly with increasing axial length and higher myopia. PMID- 24150756 TI - Mechanisms of neuroprotection by glucose in rat retinal cell cultures subjected to respiratory inhibition. AB - PURPOSE: Previous experiments have demonstrated that short-term hyperglycemia in rats renders the retina resistant to subsequent metabolic insults. The present study aimed to elucidate putative mechanisms involved in this protective response. METHODS: Retinal cultures comprising neurons and glia were treated with the mitochondrial complex I inhibitor, rotenone, at a range of concentrations, for up to 24 hours. In some cases, glucose or the alternative energy substrates, pyruvate or lactate, and/or inhibitors of glycolysis or the pentose phosphate pathway (PPP) were also applied. Cell viability was assessed using complementary techniques: immunocytochemistry, immunoblotting, cytotoxicity assay, and TUNEL. Cellular levels of ATP, reactive oxygen species (ROS), and nicotinamide adenine dinucleotide phosphate (NAD[P]H) were also assessed. RESULTS: Rotenone caused the preferential loss of neurons from retinal cultures in a concentration-dependent manner; glial cells were also affected, but only at a higher concentrations (10 MUM). Cell loss was by apoptosis, and was preceded by a reduction of both cellular ATP and NAD(P)H levels and an increase in the production of ROS. Glucose counteracted the detrimental effects of rotenone. This involved a reduction in ROS levels and an increase in the cellular ATP/NAD(P)H ratio. The protective effect of glucose was partially reversed by either PPP or glycolysis inhibition. CONCLUSIONS: Glucose rescued cultured rat retinal cells from rotenone-induced toxicity. Glucose acted via both the PPP and the glycolytic pathway, maintaining cellular ATP and NAD(P)H levels and reducing ROS production. These data have implications for treatment of retinal diseases that involve metabolic compromise to neurons. PMID- 24150757 TI - Identifying distinct risk factors for vision-specific distress and depressive symptoms in people with vision impairment. AB - PURPOSE: To determine the relative importance and associated risk factors of vision-specific distress and depressive symptoms in people with visual impairments. METHODS: In this cross-sectional study, 162 adult patients with visual acuity less than 6/12 were interviewed using telephone-administered questionnaires. Vision-specific distress was assessed with the emotional well being scale of the Impact of Vision Impairment Questionnaire. Depressive symptoms were assessed with the Patient Health Questionnaire-9. Other measures including vision-specific functioning, coping, and social support were also assessed. Multiple regression and commonality analysis were used to determine the relative contribution of factors explaining variance in vision-specific distress and depressive symptoms. RESULTS: Vision-specific distress and depressive symptoms were strongly associated. Vision-specific functioning (betas = 0.47, P < 0.001), avoidant coping (betas = -0.32, P < 0.001), social coping efficacy (betas = 0.17, P = 0.001), and depressive symptoms (betas = 0.18, P = 0.006) were significant determinants of vision-specific distress. Vision-specific functioning accounted for 37.7% of the unique variance in this model. Vision-specific distress was an important risk factor for depression, accounting for 36.6% of the unique variance in depressive symptoms. CONCLUSIONS: Vision-specific distress is related to a person's ability to manage the practical and social challenges of vision impairment. Further work is required to distinguish vision-specific distress and depression and to examine what interventions are best to target vision-specific distress. PMID- 24150758 TI - Association between ZIC2, RASGRF1, and SHISA6 genes and high myopia in Japanese subjects. AB - PURPOSE: We investigated the association of genetic variations, which were identified recently in a large-scale genome-wide association study (GWAS) to confer risk of refractive error and common myopia in Caucasians, with high myopia in Japanese subjects. METHODS: The 5 single-nucleotide polymorphisms (SNPs) from the 5 genes TOX, RDH5, ZIC2, RASGRF1, and SHISA6, were genotyped in 1339 unrelated highly myopic Japanese patients and 3248 healthy Japanese participants in the Nagahama Study. In addition, genotypes were compared between high myopia patients without choroidal neovascularization (CNV) and patients with myopic CNV. RESULTS: Significant associations between rs8000973 near ZIC2 (P = 7.16 * 10( 7)), rs4778879 in RASGRF1 (P = 3.40 * 10(-7)), and rs2969180 in SHISA6 (P = 0.033) and high myopia were observed. Odds ratios (95% confidence intervals) were 1.33 (1.19-1.49), 0.78 (0.71-0.86), and 1.11 (1.01-1.22) for the rs8000973 C allele, rs4778879 A allele, and rs2969180 G allele, respectively. The effect of the rs2969180 allele G contrasted with that observed in the original report, whereas the effect of the other 2 SNPs agreed. Further analysis using controls with -1.0 diopter (D) <= spherical equivalent <= +1.0 D showed a significant association between ZIC2 and RASGRF1, but not SHISA6. Among the patients with high myopia, 516 had myopic CNV in either eye, while 823 patients did not have myopic CNV in eyes. No evaluated genes showed a significant association with the development of myopic CNV. CONCLUSIONS: ZIC2 and RASGRF1 are susceptibility genes, not only for common myopia, but also for high myopia. PMID- 24150759 TI - Functional outcome in subretinal electronic implants depends on foveal eccentricity. AB - PURPOSE: An active microelectronic subretinal implant, developed to replace the photoreceptive function in hereditary degenerations of the outer retina, has been applied in a pilot and clinical study in patients with end-stage retinal degeneration. METHODS: The study population comprised 20 blind patients, all of whom lost vision as result of a hereditary retinal disease. An active visual implant was placed surgically within the subretinal space of each patient: subfoveal placement in eight patients (group 1) and parafoveal placement in 12 (group 2). Standardized low-vision tests, including light perception, light localization, movement detection, grating acuity, and visual acuity by Landolt C rings, were used under masked, randomized implant-OFF and implant-ON conditions. For the chip-mediated vision functional results of both subject groups were compared. RESULTS: Three of 20 patients were excluded from analysis because of surgical or technical implant issues. Among patients with nonfoveal placement of the implant, 80% could perceive light, 10% recognized location, and 10% correctly distinguished stripe patterns up to a resolution of 0.33 cycles/degree. No nonfoveal placement patient passed the motion or Landolt C-ring tests. When the implant was placed subfoveally, 100% of patients could perceive light and determine light localization, 75% could resolve motion up to 35 degrees /s, 88% correctly distinguished stripe patterns up to a resolution of 3.3 cycles/degree, and 38% passed a Landolt C-ring test with a decimal visual acuity of up to 20/546 (logMAR 1.43). CONCLUSIONS: Subfoveal placement of active subretinal visual implants allows superior measurable outcomes compared to para- or nonfoveal placement locations. (ClinicalTrials.gov numbers, NCT01024803, NCT00515814.). PMID- 24150760 TI - ITE, a novel endogenous nontoxic aryl hydrocarbon receptor ligand, efficiently suppresses EAU and T-cell-mediated immunity. AB - PURPOSE: Ligands for aryl hydrocarbon receptor (AHR), such as dioxins, are highly toxic. One such ligand, TCDD, was found to exert potent immunosuppressive capacities in mice developing pathogenic autoimmune processes, including EAU, but its toxicity makes it unusable for humans. A recently identified endogenous AHR ligand, ITE, is also immunosuppressive, but is nontoxic and could therefore be useful for therapy in humans. Here, we tested ITE for its capacity to inhibit EAU and related immune responses. METHODS: EAU was induced in B10.A mice by immunization with interphotoreceptor retinoid-binding protein (IRBP; 40 MUg) in CFA. Treatment with ITE was by daily intraperitoneal injection of 0.2 mg. Disease severity was assessed by both fundoscopy and histological examination. Draining lymph node cells were tested for proliferation by thymidine uptake and for cytokine production and release by ELISA. In addition, the intracellular expression of cytokines and Foxp3 was determined by flow cytometry. Serum antibodies were measured by ELISA. RESULTS: Treatment with ITE efficiently inhibited the development of EAU in mice, as well as the cellular immune responses against IRBP and PPD. ITE treatment inhibited the expansion of both Th1 and Th17 subpopulations, as well as their release of the signature cytokines, IFN gamma and IL-17. The treatment moderately increased, however, the proportion of Foxp3 expressing T-regulatory cells. Antibody production was not affected by the treatment. CONCLUSIONS: ITE, an endogenous AHR ligand, efficiently inhibits EAU development and related cellular immune responses. Being nontoxic, ITE may be considered for treatment of pathogenic immunity in humans. PMID- 24150761 TI - The association between visual field defect severity and fear of falling in primary open-angle glaucoma. AB - PURPOSE: To determine if glaucomatous visual field defect severity is associated with fear of falling. METHODS: This is a cross-sectional study. A total of 387 consecutive subjects with POAG were enrolled in this study along with 293-ocular disease-free control subjects, who were screened at the same institutions. We defined mild POAG as MD of -6 dB or better, moderate POAG as MD of -6 to -12 dB, and severe POAG as MD of -12 dB or worse in the better eye. All participants were requested to answer a questionnaire on fear of falling. Associations between POAG severity and the prevalence of fear of falling were evaluated with the Cochran Armitage trend test. Multivariable factors including age-adjusted odds ratios (ORs) for the prevalence of fear of falling and 95% confidence intervals (CIs) were evaluated with logistic regression models. RESULTS: The prevalence of fear of falling was 35/293 (11.9%) in the control group, 38/313 (12.1%) in the mild POAG group, 12/48 (25.0%) in the moderate POAG group, and 6/26 (23.1%) in the severe POAG group, and the trend was statistically significant (P = 0.028 Cochran Armitage trend test). The adjusted ORs for prevalence in the mild, moderate, and severe POAG groups compared with that in the control group were 1.44 (95% CI: 0.83-2.51), 2.33 (95% CI: 1.00-5.44), and 4.06 (95% CI: 1.39-11.90), respectively. CONCLUSIONS: Among patients with POAG, the severity of visual field defects is associated with fear of falling. (http://www.umin.ac.jp/ctr/index.htm number, UMIN000005574.). PMID- 24150763 TI - The effects of retinoic acid on human corneal stromal keratocytes cultured in vitro under serum-free conditions. AB - PURPOSE: Retinoic acid (RA) is a metabolite of vitamin A that plays a fundamental role in the development and function of the human eye. The purpose of this study was to investigate the effects of RA on the phenotype of corneal stromal keratocytes maintained in vitro for extended periods under serum-free conditions. METHODS: Keratocytes isolated from human corneas were cultured up to 21 days in serum-free media supplemented with RA or DMSO vehicle. The effects of RA and of its removal after treatment on cell proliferation and morphology were evaluated. In addition, the expression of keratocyte markers was quantified at the transcriptional and protein levels by quantitative PCR and immunoblotting or ELISA, respectively. Furthermore, the effects of RA on keratocyte migration were tested using scratch assays. RESULTS: Keratocytes cultured with RA up to 10 * 10( 6) M showed enhanced proliferation and stratification, and reduced mobility. RA also promoted the expression of keratocyte-characteristic proteoglycans, such as keratocan, lumican, and decorin, and increased the amounts of collagen type-I in culture while significantly reducing the expression of matrix metalloproteases 1, 3, and 9. RA effects were reversible, and cell phenotype reverted to that of control after removal of RA from media. CONCLUSIONS: Retinoic acid was shown to control the phenotype of human corneal keratocytes cultured in vitro by regulating cell behavior and extracellular matrix composition. These findings contribute to our understanding of corneal stromal biology in health and disease, and may prove useful in optimizing keratocyte cultures for applications in tissue engineering, cell biology, and medicine. PMID- 24150764 TI - A microcontact printing induced supramolecular self-assembled photoactive surface for patterning polymer brushes. AB - A facile and robust strategy for creating micropatterned polymer brushes via the combination of a micro-contact printing (MUCP) induced supramolecular self assembled photoactive surface with subsequent self-initiated photografting and photopolymerization (SIPGP) is reported. The results contribute to polymeric functionalization on a wide range of hydroxylated surfaces or graphene based materials. PMID- 24150762 TI - Morphology and topography of retinal pericytes in the living mouse retina using in vivo adaptive optics imaging and ex vivo characterization. AB - PURPOSE: To noninvasively image retinal pericytes in the living eye and characterize NG2-positive cell topography and morphology in the adult mouse retina. METHODS: Transgenic mice expressing fluorescent pericytes (NG2, DsRed) were imaged using a two-channel, adaptive optics scanning laser ophthalmoscope (AOSLO). One channel imaged vascular perfusion with near infrared light. A second channel simultaneously imaged fluorescent retinal pericytes. Mice were also imaged using wide-field ophthalmoscopy. To confirm in vivo imaging, five eyes were enucleated and imaged in flat mount with conventional fluorescent microscopy. Cell topography was quantified relative to the optic disc. RESULTS: We observed strong DsRed fluorescence from NG2-positive cells. AOSLO revealed fluorescent vascular mural cells enveloping all vessels in the living retina. Cells were stellate on larger venules, and showed banded morphology on arterioles. NG2-positive cells indicative of pericytes were found on the smallest capillaries of the retinal circulation. Wide-field SLO enabled quick assessment of NG2-positive distribution, but provided insufficient resolution for cell counts. Ex vivo microscopy showed relatively even topography of NG2-positive capillary pericytes at eccentricities more than 0.3 mm from the optic disc (515 +/- 94 cells/mm(2) of retinal area). CONCLUSIONS: We provide the first high resolution images of retinal pericytes in the living animal. Subcellular resolution enabled morphological identification of NG2-positive cells on capillaries showing classic features and topography of retinal pericytes. This report provides foundational basis for future studies that will track and quantify pericyte topography, morphology, and function in the living retina over time, especially in the progression of microvascular disease. PMID- 24150765 TI - Estrogen inhibits RANKL-induced osteoclastic differentiation by increasing the expression of TRPV5 channel. AB - The inhibitor effect of estrogen on osteoclasts differentiation is very important in the etiology of estrogen protecting the adult skeleton against bone loss. However, the precise molecular events underlying the effect of estrogen on osteoclasts differentiation are not known. Recent studies implicated an important role of transient receptor potential vanilloid 5 (TRPV5) in osteoclast differentiation and bone resorption. Furthermore, some studies have confirmed that estrogen is involved in the regulation of calcium ion (Ca(2+)) influx in many cells via TRPV5 channel. Therefore, we hypothesize that TRPV5 channel may be implicated in the process of estrogen-inhibited osteoclastogenesis and bone resorption. Western blot, quantitative real-time PCR, tartrate-resistant acid phosphatase (TRAP) staining, and pit formation assay were employed to investigate the role of TRPV5 in estrogen decreasing osteoclast differentiation and bone resorption. We found that the expression of TRPV5 is significantly down-regulated during estrogen deficiency-induced osteoclastogenesis. Furthermore, TRAP staining and pit formation assay showed that the depletion of TRPV5 significantly blocks the inhibitor effects of estrogen on osteoclasts differentiation and bone resorption activity. Further studies confirmed that estrogen regulates the expression of TRPV5 channel via estrogen receptor. Based on these results above, we can draw conclusion that TRPV5 may contribute to the process of estrogen inhibited osteoclastogenesis and bone resorption activity. PMID- 24150766 TI - [New WHO described CNS tumor entities]. PMID- 24150767 TI - [Post-traumatic hematoma sternal hematoma with malignancy signs -- difficulties in the differential diagnosis]. PMID- 24150769 TI - [Omission of mammography screening as a gross treatment error]. PMID- 24150771 TI - Application of PINS radiofrequency pulses to reduce power deposition in RARE/turbo spin echo imaging of the human head. AB - PURPOSE: To explore the use of PINS radiofrequency (RF) pulses to reduce RF power deposition in multiband/simultaneous multislice imaging with the RARE/turbo spin echo (TSE) sequence at 3T and 7T. METHODS: A PINS-TSE sequence was implemented and combined with blipped CAIPI to improve the reconstruction of superposed slices. Whole brain imaging of healthy volunteers was performed at both 3T and 7T using a 32-channel coil for signal reception. RESULTS: A considerable reduction in power deposition was achieved compared with a standard sequence of the manufacturer. At 3T, the reduction in specific absorption rate (SAR) made short pulse repetition times (TRs) possible, however, in order to obtain a good T2 contrast, it is advisable to maintain TR while extending the echo train length. At 7T, whole brain coverage with a spatial resolution of 1 * 1 * 2 mm(3) was achieved in an acquisition time of 150 s. Furthermore, it could be shown that pulse sequences that use PINS pulses do not suffer from having additional magnetization transfer contrast. CONCLUSION: PINS RF pulses combined with multiband imaging reduce SAR sufficiently to enable routine TSE imaging at 7T within clinically acceptable acquisition times. In general, the combination of multiband imaging with PINS RF pulses represents a method to reduce total RF power deposition. PMID- 24150772 TI - Adoptive cytotoxic T lymphocyte therapy triggers a counter-regulatory immunosuppressive mechanism via recruitment of myeloid-derived suppressor cells. AB - Complex interactions among multiple cell types contribute to the immunosuppressive milieu of the tumor microenvironment. Using a murine model of adoptive T-cell immunotherapy (ACT) for B16 melanoma, we investigated the impact of tumor infiltrating cells on this complex regulatory network in the tumor. Transgenic pmel-1-specific cytotoxic T lymphocytes (CTLs) were injected intravenously into tumor-bearing mice and could be detected in the tumor as early as on day 1, peaking on day 3. They produced IFN-gamma, exerted anti-tumor activity and inhibited tumor growth. However, CTL infiltration into the tumor was accompanied by the accumulation of large numbers of cells, the majority of which were CD11b(+) Gr1(+) myeloid-derived suppressor cells (MDSCs). Notably, CD11b(+) Gr1(int) Ly6G(-) Ly6C(+) monocytic MDSCs outnumbered the CTLs by day 5. They produced nitric oxide, arginase I and reactive oxygen species, and inhibited the proliferation of antigen-specific CD8(+) T cells. The anti-tumor activity of the adoptively-transferred CTLs and the accumulation of MDSCs both depended on IFN gamma production on recognition of tumor antigens by the former. In CCR2(-/-) mice, monocytic MDSCs did not accumulate in the tumor, and inhibition of tumor growth by ACT was improved. Thus, ACT triggered counter-regulatory immunosuppressive mechanism via recruitment of MDSCs. Our results suggest that strategies to regulate the treatment-induced recruitment of these MDSCs would improve the efficacy of immunotherapy. PMID- 24150773 TI - [From preemptive to preventive analgesia]. PMID- 24150775 TI - [Neuromuscular monitoring]. AB - The effect of muscle relaxants varies among people and the extent, the duration and recovery from the neuromuscular block varies. Clinical tests cannot determine the effect of muscle relaxants which is only possible with neuromuscular monitoring. The relaxometry procedure measures the muscular response to electrical stimulation of the corresponding motor nerve and the adductor pollicis muscle is mostly used; however, this muscle is not representative for other muscle groups, such as the muscles of the larynx and diaphragm. The muscles of the larynx and diaphragm are more resistant against nondepolarizing muscle relaxants than the adductor pollicis muscle. The train of four (TOF) is used at the beginning of surgery for monitoring of the optimal time for tracheal intubation; moreover, the TOF is used during surgery for monitoring of the muscle blockade and at the end of surgery for monitoring recovery. Monitoring of deep muscular blockades, however, is only possible with the posttetanic count (PTC) when there are no TOF counts. The PTC allows repetition and higher doses of muscle relaxants during abdominal surgery; therefore, conditions for surgery are optimal and cumulation of muscle relaxants is avoided. PMID- 24150776 TI - Feasibility and potential of in utero foetal membrane-derived cell transplantation. AB - Cells isolated from foetal membranes of human term placenta display multiple properties, including some features of stem/progenitor cells, together with immunomodulatory actions and the ability to secrete bioactive soluble factors. Whilst such properties support the potential applicability of these cells in transplantation settings aimed at regenerating/repairing tissues in adults, theoretically, using these cells in prenatal treatment strategies may also be achievable. To assess the feasibility of a foetal membrane-derived cell-based therapeutic treatment during foetal development, we firstly addressed the question of whether in utero transplantation using these cells was possible. To this end, we assessed postnatal microchimerism after transplantation of amniotic membrane-derived cells (a mixture of both mesenchymal stromal/stem cells and epithelial cells) in foetal sheep. Transplantation was performed with or without human umbilical cord blood mononuclear cells and chorionic membrane-derived mesenchymal stromal/stem cells, and was followed by a postnatal booster cell injection. Lambs were euthanized 2-4 months postnatally and their organs/tissues were analysed for microchimerism through detection of human DNA. Human DNA was found in almost all tissues of all of the lambs, with the seemingly random appearance of human cells in some of the analysed tissues suggesting long-term human microchimerism and donor cell migration after in utero/postnatal booster xenotransplation. Differences in microchimerism tissue distribution between animals transplanted with different cell types are discussed. This pilot study adds to ongoing efforts by different investigators to explore the potential of in utero cellular transplantation, and warrants further investigation of using foetal membrane-derived cells for prenatal cell therapies. PMID- 24150777 TI - The effect of non-growth factors on chondrogenic differentiation of mesenchymal stem cells. AB - Chondrogenic differentiation of mesenchymal stem cells (MSCs) in vitro usually requires the presence of growth factors in the culture condition. But many cost effect methods can successfully fulfill this without addition of these cytokines. This article focuses upon the effect of non-growth factors on the chondrogenic differentiation of MSCs and the concise introduction of the potential mechanism of these methods. PMID- 24150778 TI - Effects of BG-12 (dimethyl fumarate) on health-related quality of life in patients with relapsing-remitting multiple sclerosis: findings from the CONFIRM study. AB - Multiple sclerosis (MS) has a significant impact on health-related quality of life (HRQoL) with symptoms adversely affecting many aspects of everyday living. BG-12 (dimethyl fumarate) demonstrated significant efficacy in the phase III studies DEFINE and CONFIRM in patients with relapsing-remitting MS. In CONFIRM, HRQoL was worse in patients with greater disability at baseline, and who relapsed during the study, and improved with BG-12 treatment. Mean Short Form-36 Physical Component Summary scores for BG-12 increased over 2 years and scores for placebo decreased. Coupled with clinical and neuroradiological benefits, these HRQoL results further support BG-12 as an effective oral treatment for relapsing MS. PMID- 24150779 TI - Quality of life outcomes with BG-12 (dimethyl fumarate) in patients with relapsing-remitting multiple sclerosis: the DEFINE study. AB - BACKGROUND: Oral BG-12 (dimethyl fumarate), approved for the treatment of the relapsing forms of MS, has demonstrated clinical efficacy with an acceptable safety profile in the Phase III "Determination of the Efficacy and Safety of Oral Fumarate in Relapsing-Remitting Multiple Sclerosis (RRMS)" (DEFINE) and "Comparator and an Oral Fumarate in RRMS" (CONFIRM) studies. OBJECTIVES: To evaluate the health-related quality of life (HRQoL) impairment that is associated with RRMS and to assess the effects of BG-12 on HRQoL in the DEFINE study. METHODS: Patients with RRMS were randomized to BG-12 240 mg twice (BID) or three times (TID) daily, or placebo, for 2 years. HRQoL was assessed by the Short Form 36 (SF-36), global assessment of well-being visual analog scale and the EuroQol 5D. RESULTS: In the 1237 patients from DEFINE, HRQoL impairment was greatest in patients who had higher disability scores and in those who had experienced relapse. Change in SF-36 physical component summary scores during 2 years' treatment significantly favored BG-12 over placebo (both doses: p < 0.001). We saw similar benefits in other measures of functioning and general well-being as early as Week 24. These benefits were maintained during the study. CONCLUSIONS: Our results add to evidence for a negative impact of RRMS on HRQoL and they demonstrate the benefits of BG-12 on HRQoL measures, which coupled with significant clinical efficacy, further support its use as a new treatment for RRMS. PMID- 24150780 TI - The influence of loading intensity on muscle-tendon unit behavior during maximal knee extensor stretch shortening cycle exercise. AB - Tendon stiffness increases as the magnitude and rate of loading increases, according to its viscoelastic properties. Thus, under some loading conditions tendons should become exceptionally stiff and act almost as rigid force transducers. Nonetheless, observations of tendon behavior during multi-joint sprinting and jumping tasks have shown that tendon strain increases whilst muscle strain decreases as the loading intensity increases. The purpose of the current study was to examine the influence of external loading intensity on muscle-tendon unit (MTU) behavior during a high-speed single-joint, stretch-shortening cycle (SSC) knee extension task. Eighteen men (n = 9) and women (n = 9) performed single-leg, maximum intensity SSC knee extensions at loads of 20, 60 and 90% of their one repetition maximum. Vastus lateralis fascicle length (L(f)) and velocity (v(f)) as well as MTU (L(MTU)) and tendinous tissue (L(t)) length were measured using high-speed ultrasonography (96 Hz). Patellar tendon force (F(t)) and rate of force development (RFDt) were estimated using inverse dynamics. Results showed that as loading intensity increased, concentric joint velocity and shortening v f decreased whilst F t and RFDt increased, but no significant differences were observed in eccentric joint velocity or peak L(MTU) or L(f). In addition, the tendon lengthened significantly less at the end of the eccentric phase at heavier loads. This is the first observation that tendon strain decreases significantly during a SSC movement as loading intensity increases in vivo, resulting in a shift in the tendon acting as a power amplifier at light loads to a more rigid force transducer at heavy loads. PMID- 24150781 TI - Assessment of extracellular dehydration using saliva osmolality. AB - INTRODUCTION: When substantial solute losses accompany body water an isotonic hypovolemia (extracellular dehydration) results. The potential for using blood or urine to assess extracellular dehydration is generally poor, but saliva is not a simple ultra-filtrate of plasma and the autonomic regulation of salivary gland function suggests the possibility that saliva osmolality (Sosm) may afford detection of extracellular dehydration via the influence of volume-mediated factors. PURPOSE: This study aimed to evaluate the assessment of extracellular dehydration using Sosm. In addition, two common saliva collection methods and their effects on Sosm were compared. METHODS: Blood, urine, and saliva samples were collected in 24 healthy volunteers during paired euhydration and dehydration trials. Furosemide administration and 12 h fluid restriction were used to produce extracellular dehydration. Expectoration and salivette collection methods were compared in a separate group of eight euhydrated volunteers. All comparisons were made using paired t-tests. The diagnostic potential of body fluids was additionally evaluated. RESULTS: Dehydration (3.1 +/- 0.5% loss of body mass) decreased PV (-0.49 +/- 0.12 L; -15.12 +/- 3.94% change), but Sosm changes were marginal (<10 mmol/kg) and weakly correlated with changes in absolute or relative PV losses. Overall diagnostic accuracy was poor (AUC = 0.77-0.78) for all body fluids evaluated. Strong agreement was observed between Sosm methods (Expectoration: 61 +/- 10 mmol/kg, Salivette: 61 +/- 8 mmol/kg, p > 0.05). CONCLUSIONS: Extracelluar dehydration was not detectable using plasma, urine, or saliva measures. Salivette and expectoration sampling methods produced similar, consistent results for Sosm, suggesting no methodological influence on Sosm. PMID- 24150782 TI - Effects of probiotics supplementation on gastrointestinal permeability, inflammation and exercise performance in the heat. AB - PURPOSE: This study aimed to investigate the effects of multi-strain probiotics supplementation on gastrointestinal permeability, systemic markers of inflammation and running performance when exercising in the heat. METHODS: Ten male runners were randomized to 4 weeks of daily supplementation with a probiotics capsule (45 billion CFU of Lactobacillus, Bifidobacterium and Streptococcus strains) or placebo, separated by a washout period (double-blind, cross-over trial). After each treatment, the runners exercised to fatigue at 80% of their ventilatory threshold at 35 degrees C and 40% humidity. To assess gastrointestinal permeability, runners ingested lactulose and rhamnose before exercise and post-exercise urine was collected to measure sugar concentrations. Venous blood samples were collected before, immediately after and 1 h after exercise, and core temperature was monitored during exercise. RESULTS: Probiotics supplementation significantly increased run time to fatigue (min:s 37:44 +/- 2:42 versus 33:00 +/- 2:27; P = 0.03, d = 0.54). Average core temperature during exercise was similar between trials (probiotic 38.1 +/- 0.2 degrees C, placebo 38.1 +/- 0.1 degrees C; P = 0.77, d = 0.13). Serum lipopolysaccharide concentration increased post-exercise (P < 0.001), while there was a moderate to large reduction in pre-exercise (d = 0.70) and post-exercise (d = 1.24) concentration following probiotics supplementation. Plasma concentrations of IL 6, IL-10 and IL-1ra increased after exercise (P < 0.01), but there was no significant difference between trials (P > 0.05). There was a small to moderate reduction (d = 0.35) in urine lactulose:rhamnose and a small reduction (d = 0.25) in symptoms of gastrointestinal discomfort following probiotics supplementation (both P = 0.25). CONCLUSION: Four weeks of supplementation with a multi-strain probiotic increased running time to fatigue in the heat. Further studies are required to elucidate the exact mechanisms for this performance benefit. PMID- 24150783 TI - Importance of optic flow for postural stability of male and female young adults. AB - PURPOSE: A feedback control process based on self-motion perception contributes to postural stability; however, little is known about the visual modulation of postural muscles. The aim of this study was to investigate the effect of optic flow stimuli, presented full field, in the peripheral and foveal visual field, on muscular activation. Then, we assessed the correlation between optic flow, muscle activity and body sway in male and female subjects. METHODS: We used surface electromyography (EMG) and stabilometry on 24 right-handed young adults. We recorded the bilateral activation of tibialis anterior, gastrocnemius medialis, biceps femoris and vastus medialis. EMG and center of pressure (COP) signals were acquired simultaneously. EMG signal amplitude was computed as root mean square normalized by baseline. RESULTS: We found a significant effect for muscles, gender and an interaction effect of muscle by gender (ANOVA, p < 0.001). Results showed different postural alignments in males and females. The COP spatial variability during peripheral stimuli was generally reduced. The prevalent direction of oscillation evoked by peripheral stimuli was clustered, while foveal and random stimuli induced distributed and randomized directions. Also for muscle activity, we found gender differences in the prevalent oscillation distributions evoked by optic flow. CONCLUSION: Visual stimuli always evoke an excitatory input on postural muscles, but the stimulus structure produces different postural effects. Peripheral optic flow stimuli stabilize postural sway, while random and foveal optic flow provoke larger sway variability similar to those evoked in the absence of visual stimulation. PMID- 24150784 TI - Acute passive vibration reduces arterial stiffness and aortic wave reflection in stroke survivors. AB - PURPOSE: Impaired leg arterial stiffness (pulse wave velocity, PWV) and vasodilatory function are found after stroke. Acute passive vibration (PV) decreases leg PWV (legPWV) and pressure wave reflection (aortic augmentation index, aAIx) in healthy men. Our objective was to evaluate the effects of acute PV on aAIx and PWV in the paretic and non-paretic sides in stroke survivors. METHODS: Eleven stroke survivors (4 females) were randomized to either no-PV (control) or PV (25 Hz and 2 mm amplitude) trials on two separated visits. Following 20 min of supine rest with legs on a vibration platform, blood pressure, PWV, and aAIx were gathered before 10 continuous minutes of control or PV. Measurements were repeated at post-5, post-15, and post-30 min after control or PV. RESULTS: LegPWV and brachial-ankle PWV (baPWV, systemic stiffness) in paretic and non-paretic sides along with aAIx were significantly (P < 0.05) decreased from baseline at post-5 min after PV compared with control. At post-15 min, paretic and non-paretic legPWV remained significantly lower than baseline, but only non-paretic legPWV was different from control. We noted correlations between changes in paretic legPWV and changes in paretic baPWV (r = 0.47, P = 0.028) and aAIx (r = 0.51, P = 0.017) at post-5 min. CONCLUSIONS: Acute PV applied to the legs of stroke survivors reduces systemic arterial stiffness and aortic wave reflection due to a reduction in leg arterial stiffness, which last longer in the non-paretic than in the paretic leg. PMID- 24150785 TI - Assessment of calf muscle fatigue during submaximal exercise using transcranial magnetic stimulation versus transcutaneous motor nerve stimulation. AB - PURPOSE: Few studies have assessed the time-dependent response of fatigue (i.e., loss of force) during submaximal exercise without the use of maximum contractions. There is unexplored potential in the use of the superimposed muscle twitch (SIT), evoked by transcranial magnetic stimulation (TMS) or motor nerve stimulation (MNS), to assess fatigue during voluntary submaximal contractions. For the human triceps surae muscles, there are also no data on TMS-evoked twitches. METHODS: To optimise the TMS stimulus for assessment of fatigue, we first tested the effects of TMS power (40, 55, 70, 85, 100% max) on SIT force during contractions (0-100% MVC in 10% increments) in six subjects. Then, we compared SIT responses (TMS and MNS) during submaximal contractions and MVCs (all at 60 s intervals) during a continuous protocol of intermittent contractions (30% MVC) consisting of consecutive 5 min periods of baseline, fatigue (ischaemia) and recovery. RESULTS: For TMS, SIT force increased as a diminishing function of TMS power (P < 0.05), the relationships between SIT force and the force of voluntary contraction at all TMS powers were parabolic, and SIT force was maximised at ~20 40% MVC. During intermittent contractions, MVC and SIT forces were stable during baseline, decreased similarly during ischaemia by 40-50% (P < 0.05), and recovered similarly to baseline values (P > 0.05) before the end of the protocol. CONCLUSION: TMS can be used to evoke twitches during submaximal contractions of the human calf muscle and, along with MNS, used to assess fatigue during submaximal exercise. PMID- 24150786 TI - Functional effects of sequence variations in the E6 and E2 genes of human papillomavirus 16 European and Asian variants. AB - Sequence variations within the genome of human papillomavirus (HPV) type 16 have been reported in different ethnic populations, with some evidence suggesting that non-European variants may confer higher oncogenic potential. HPV16 European (EUR) and Asian (As) variants were identified previously as two major variants in cervical cancer from Anyang, China. The evolutionary analysis of these variants revealed that several important sequence variations in the E6 and E2 genes were under positive selection pressure. The aim of this study was to evaluate the effects of these variations on E6 and E2 functions regarding p53 degradation and transcription regulation of the long control region (LCR). By Western blot analysis, a similar ability to degrade p53 was observed among EUR E6, As E6, EUR E6-L83V and As E6-E113D. A rare variation, EUR E6-R10G, was found to shorten the half-life of p53 more efficiently than the other variations. Unlike EUR E2 acting as a transcriptional activator or a repressor at different concentrations, As E2 showed a dose-dependent repression of LCR activity, about twofold stronger than EUR E2 in the luciferase reporter assays. Furthermore, the site-directed mutagenesis revealed that E232K, which is a linked variation in the hinge region of As E2, was responsible for its enhanced repression ability. Collectively, these data indicate the altered functions of HPV16 E6 and E2 by certain variations, which may influence the potential of viral carcinogenesis. PMID- 24150787 TI - Expression and prognostic role of SKIP in human breast carcinoma. AB - Ski-interacting protein (SKIP) is a nuclear hormone receptor-interacting cofactor, interactions with the proto-oncogene Ski, appears to modulate a number of signalling pathways involved in control of cell proliferation and differentiation, and may play a critical role in oncogenesis. In the present study, to investigate the potential roles of SKIP in breast cancer, expression patterns, interaction and the correlation with clinical/prognostic factors of SKIP and Ki-67 were examined among patients with breast cancer. Immunohistochemistry and Western blot analysis were performed for SKIP in 85 breast carcinoma samples. The data were correlated with clinicopathological features. The univariate and multivariate survival analyses were also performed to determine their prognostic significance. We found that SKIP was over expressed in breast carcinoma as compared with the adjacent normal tissues. High expression of SKIP was positively associated with histological grade (P = 0.01) and Ki-67 (P = 0.004). Univariate analysis showed that SKIP expression was associated with a poor prognosis (P = 0.006). While in vitro, following release of breast cancer cell lines from serum starvation, the expression of SKIP was up-regulated, whereas p27 was down-regulated. In addition, we employed small interfering RNA (siRNA) technique to knock down SKIP expression and observed it effects on MDA-MB 231 cells growth. SKIP depletion by siRNA inhibited cell proliferation, blocked S phase and decreased cyclin A and cyclin B levels. On the basis of these results, we suggested that SKIP overexpression was involved in the pathogenesis of breast cancer, which might serve as a future target for breast cancer. PMID- 24150788 TI - Applications of biofilms in bioremediation and biotransformation of persistent organic pollutants, pharmaceuticals/personal care products, and heavy metals. AB - In this review, the strategies being employed to exploit the inherent durability of biofilms and the diverse nutrient cycling of the microbiome for bioremediation are explored. Focus will be given to halogenated compounds, hydrocarbons, pharmaceuticals, and personal care products as well as some heavy metals and toxic minerals, as these groups represent the majority of priority pollutants. For decades, industrial processes have been creating waste all around the world, resulting in contaminated sediments and subsequent, far-reaching dispersal into aquatic environments. As persistent pollutants have accumulated and are still being created and disposed, the incentive to find suitable and more efficient solutions to effectively detoxify the environment is even greater. Indigenous bacterial communities are capable of metabolizing persistent organic pollutants and oxidizing heavy metal contaminants. However, their low abundance and activity in the environment, difficulties accessing the contaminant or nutrient limitations in the environment all prevent the processes from occurring as quickly as desired and thus reaching the proposed clean-up goals. Biofilm communities provide among other things a beneficial structure, possibility for nutrient, and genetic exchange to participating microorganisms as well as protection from the surrounding environment concerning for instance predation and chemical and shear stresses. Biofilms can also be utilized in other ways as biomarkers for monitoring of stream water quality from for instance mine drainage. The durability and structure of biofilms together with the diverse array of structural and metabolic characteristics make these communities attractive actors in biofilm-mediated remediation solutions and ecosystem monitoring. PMID- 24150789 TI - Effects of roxithromycin on ammonia-oxidizing bacteria and nitrite-oxidizing bacteria in the rhizosphere of wheat. AB - In a pot-cultural experiment, the impact of the antibiotic roxithromycin (ROX) addition was assessed on the diversities of microbial structure and function communities, especially involved in ammonia and nitrite oxidation in wheat rhizosphere soil with and without the addition of earthworms. The abundances of ammonia-oxidizing bacteria (AOB), nitrite-oxidizing bacteria (NOB), and total bacteria were surveyed by the quantitative PCR. The quantities of total bacteria, AOB, and NOB with earthworms were higher than those without earthworms because of the synergistic effect. ROX inhibited the growth of AOB in all treatments, although the quantities of AOB were in a light increase in medium and heavy polluted treatments compared with that in the light polluted treatments. Different from AOB, the quantities of NOB were lowest in light polluted treatments, but the quantities of NOB were rapidly increased in medium and heavy polluted treatments compared with that in the control. These results indicated that the application of ROX principally had a negative effect on nitrification performance by affecting the abundances and relative ratios of both AOB and NOB in soil communities, which affected the N cycle in an agricultural ecosystem. According to the metabolic diversities evaluated by the biologic assay, the tendency of metabolic diversities was quite contrary to the quantities of NOB in all treatments and showed the contrast growing relation of autotrophic and heterotrophic bacteria under ROX pollution pressure in agricultural ecosystems. PMID- 24150790 TI - A simple method for cleaning graphene surfaces with an electrostatic force. PMID- 24150791 TI - Electrophoretic deposition polymerization of diacetylenes with tunable structure. AB - Serial novel chiral polydiacetylenes (PDAs) are efficiently prepared at room temperature by the controllable electrophoretic deposition of diacetylenes with tunable structure as designed from easily available starting materials. The colorimetrically reversible properties of PDAs in the range between 25 and 85 degrees C are influenced by the different amino acid moiety in the PDAs as anticipated. The PDA containing aromatic ring is much better for the colorimetrically reversible properties, while irreversible thermochromism is displayed for the PDA with the structure of the longer methylene units in the main chain of amino acid moiety. PMID- 24150793 TI - In memorium: Roy A.E. Bakay, MD. PMID- 24150792 TI - Acquisition of resistant microorganisms and infections in HIV-infected patients admitted to the ICU. AB - Whether critically ill human immunodeficiency virus (HIV)-infected patients are at risk of acquiring nosocomial infections and resistant or potentially resistant microorganisms (RPRMs) remains to be clarified. The aim was to compare the acquisition of RPRMs, infections and mortality in critically ill HIV-infected and non-infected patients. An observational, prospective cohort study of patients admitted to a medical intensive care unit (ICU) was undertaken. Swabbing of nares, pharynx and rectum, and culture of respiratory secretions were obtained within 48 h of admission and thrice weekly thereafter. Clinical samples were obtained as deemed necessary by the attending physician. Clinical variables, severity scores on admission and exposures during ICU stay were collected. Logistic regression was used to evaluate ICU mortality. Out of the 969 included patients, 64 (6.6%) were HIV-infected. These patients had a higher Acute Physiology and Chronic Health Evaluation (APACHE) II score on admission (19.5 +/- 6.6 vs. 21.1 +/- 5.4, p = 0.02), stayed longer in the care unit and were more exposed to several invasive devices and antibiotics. There were no differences in the rate of acquisition of RPRMs and the only difference in ICU-acquired infections was a significantly higher incidence of catheter-related bacteraemia (3% vs. 9%, p = 0.03). The ICU-related mortality was similar in both groups (14% vs. 16%, p = 0.70) and in HIV-infected patients, it tended to be associated with a lower CD4 cell count (p = 0.06). Despite a longer ICU stay, critically ill HIV infected patients did not show a higher rate of RPRMs acquisition. The rate of ICU-acquired infection was similar between HIV-infected and non-infected patients, except for catheter-related bacteraemia, which was higher in the HIV infected population. Mortality was similar in both groups. PMID- 24150794 TI - Synthesis of terminal uranium(IV) disulfido and diselenido compounds by activation of elemental sulfur and selenium. AB - Rare stakes: Terminal uranium(IV) disulfido and diselenido compounds, Tp*2U(E2) (E=S, Se), were synthesized by the activation of elemental chalcogens. Structural, spectroscopic, computational and magnetic studies of these species establish their tetravalency and highly polarized U-E bonds. PMID- 24150795 TI - 5alpha-reductase type 3 enzyme in benign and malignant prostate. AB - BACKGROUND: Currently available 5alpha-reductase inhibitors are not completely effective for treatment of benign prostate enlargement, prevention of prostate cancer (CaP), or treatment of advanced castration-recurrent (CR) CaP. We tested the hypothesis that a novel 5alpha-reductase, 5alpha-reductase-3, contributes to residual androgen metabolism, especially in CR-CaP. METHODS: A new protein with potential 5alpha-reducing activity was expressed in CHO-K1 cellsandTOP10 E. coli for characterization. Protein lysates and total mRNA were isolated from preclinical and clinical tissues. Androgen metabolism was assessed using androgen precursors and thin layer chromatography or liquid chromatography tandem mass spectrometry. RESULTS: The relative mRNA expression for the three 5alpha reductase enzymes in clinical samples of CR-CaP was 5alpha-reductase-3 ? 5alpha reductase-1> 5alpha-reductase-2. Recombinant 5alpha-reductase-3 protein incubations converted testosterone, 4-androstene-3,17-dione (androstenedione) and 4-pregnene-3,20-dione (progesterone) to dihydrotestosterone, 5alpha-androstan 3,17-dione, and 5alpha-pregnan-3,20-dione, respectively. 5alpha-Reduced androgen metabolites were measurable in lysates from androgen-stimulated (AS) CWR22 and CR CWR22 tumors and clinical specimens of AS-CaP and CR-CaP pre-incubated with dutasteride (a bi-specific inhibitor of 5alpha-reductase-1 and 2). CONCLUSION: Human prostate tissues contain a third 5alpha-reductase that was inhibited poorly by dutasteride at high androgen substrate concentration in vitro, and it may promote DHT formation in vivo, through alternative androgen metabolism pathways when testosterone levels are low. PMID- 24150798 TI - Panoscopic structures by hierarchical cascade self-assembly of inorganic surfactants with magnetic heads containing dysprosium ions. AB - Magnetic moustaches: Inorganic surfactants (I-SURFs) with head groups containing Dy(3+) undergo a hierarchical self-organization cascade controlled by magnetic interactions. The resulting aggregates are shaped like dumbbells with frayed, moustache-like ends. PMID- 24150797 TI - Gas and the microbiome. AB - Humans are host to trillions of microbial colonizers that contribute significantly to human health and disease. Advances in sequencing and other technologies have facilitated dramatic advances in our knowledge of the types and number of organisms colonizing different areas of the body, and while our knowledge of the roles played by the different bacteria, fungi, and archaea has increased dramatically, there remains much to uncover. The microbes that colonize the human gut contribute to vitamin biosynthesis, immune modulation, and the breakdown of otherwise indigestible foods for nutrient harvest. Bacteria and archaea produce various gases as by-products of fermentation, and it is becoming increasingly understood that these gases have both direct and indirect effects on the gut, and may also be used as diagnostic markers, e.g., hydrogen production as measured by breath testing can be used to diagnose bacterial overgrowth. In this article, we review the roles and effects of hydrogen (H2), methane (CH4) and hydrogen sulfide (H2S) in the human gut. PMID- 24150801 TI - [Oesophageal GIST at the left tracheobronchial angle: resection with right-sided VATS]. AB - OBJECTIVE: The vast majority of submucosal oesophageal tumours are leiomyomas. Gastrointestinal stromal tumours (GIST) account for only one percent of all gastrointestinal malignancies, whereby an oesophageal location represents a medical rarity. Although surgical resection is the gold standard, the optimal procedure remains a matter of debate. Conventional oesophageal resection is the most common therapeutic choice to ensure complete removal with an appropriate safety margin and avoid dissemination of neoplastic cells. Anyhow, occasional case reports about enucleation of oesophageal GIST have been published. This video paper for the first time describes the use of right-sided video-assisted thoracoscopic surgery (VATS) as a technique to enucleate an oesophageal GIST within the left tracheobronchial angle. INDICATION: A 68-year-old male patient was evaluated for recurrent haemoptysis and dysphagia and diagnosed with a 1.4 cm sized oesophageal tumour at the left tracheobronchial angle. CT scan showed a submucosal location without signs of invasive growth. After conducting endosonography we suspected a leiomyoma and performed minimally invasive enucleation with right-sided VATS. METHOD: Employing independent lung ventilation the patient was put into a left lateral position. Four trocars were applied. After incision of the mediastinal pleura the tumour was localised with intraoperative gastroscopy and diaphanoscopy. By mobilisation of the oesophagus and transection of the azygous vein it was possible to bluntly dissect the mass from surrounding oesophageal muscular fibres and safely extract it with a specimen bag. After removal of the thoracic drainage on the first postoperative day the patient was discharged the day after. The further course was uneventful. Histological work-up showed a GIST pT1cN0M0 R0 with a Ki-67 index less than 1 % (UICC I). After 10 months of follow-up the patient is recurrence-free and shows no symptoms. CONCLUSION: Enucleation of a locally limited oesophageal GIST by right-sided VATS is a feasible and safe surgical procedure with dramatically reduced invasiveness compared to conventional open oesophageal resections. PMID- 24150802 TI - [Vascular surgical/medical topics 2013--sustained, well-developed scientific journalism and unabated scientific interest]. PMID- 24150799 TI - Selective TBK1/IKKi dual inhibitors with anticancer potency. AB - Increasing evidence suggests that the noncanonical IKKs play critical roles in tumor genesis and development, leading to the notion that noncanonical IKKs may be good targets for cancer therapy. Here, we demonstrate that although TBK1 is not overexpressed or constitutively activated in some tumor cells, targeting IKKi induces the activation of TBK1. Therefore, simultaneously targeting both kinases is necessary to efficiently suppress tumor cell proliferation. We show that three TBK1/IKKi dual inhibitors, which are based on a structurally rigid 2-amino-4-(3' cyano-4'-pyrrolidine)phenyl-pyrimidine scaffold, potently inhibit cell viability in human breast, prostate and oral cancer cell lines. Treatment with these TBK1/IKKi dual inhibitors significantly impairs tumor development in xenograft and allograft mouse models. The anticancer function of these inhibitors may be partially due to their suppression of TBK1/IKKi-mediated AKT phosphorylation and VEGF expression. Most importantly, these TBK1/IKKi dual inhibitors have drug-like properties including low molecular weight, low cytochrome P450 inhibition and high metabolic stability. Therefore, our studies provide proof of concept for further drug discovery efforts that may lead to novel strategies and new therapeutics for the treatment of human cancer. PMID- 24150803 TI - [Carbon dioxide angiography in EVAR: basic principles, indications and limitations]. AB - Compared to open surgery, endovascular aneurysm repair has shown superior results in terms of morbidity and mortality. Therefore the 2011 published Practical Guidelines for Abdominal Aortic Aneurysm Repair (EVAR) demand an individual evaluation of every patient concerning an EVAR solution. To reduce the risk of contrast-associated complications such as severe allergic reactions hyperthyroidism or contrast-induced nephropathy with permanent loss of renal function, the use of carbon dioxide should be considered for every case. The imaging software solutions are part of the modern angiography technique and the imaging quality of CO2 angiography is equivalent or even better as compared to conventional angiography when the patient is appropriately prepared and positioned. PMID- 24150804 TI - [Multiresistant pathogens--a challenge for clinicians]. AB - Gram-negative pathogens are currently isolated frequently in invasive nosocomial infections and give rise to major therapeutic problems due to their resistance pattern. Metaanalyses of randomised controlled studies have demonstrated that an antibiotic combination treatment is not indicated in many cases. However, in critically ill patients (septic shock) and also in immunocompromised patients with previous intensive care as well as broad spectrum antibiotic treatment, a combination of antibiotics is recommended. This therapy should be based on the source of the infection, on local resistance data, on antibiotic pretreatment, on basic diseases of the patient and on current liver and renal functions. The start of therapy should be as fast as possible after collection of optimal materials for microbiological analysis. Dosage of selected antibiotics should be based on rational pharmacokinetic and pharmacodynamic parameters. A de-escalation of antibiotics is strongly recommended in all international guidelines based on the microbiological results and the clinical response of the patient. New antibiotics or therapeutic strategies against multiresistant Gram-negative pathogens will not be available in the next 5 to 10 years; therefore, it is absolute mandatory to use the currently still effective antibiotics, like carbapenems and polymyxins, very rationally and restrictively. PMID- 24150805 TI - [Increasingly individualised therapeutic options in the rare isolated aneurysm of the iliac artery--vascular surgical versus image-guided endovascular intervention]. AB - BACKGROUND: Isolated aneurysms of the iliac artery are rare but in case of rupture potentially life-threatening. AIM, PATIENTS AND METHODS: The aim of this systematic, clinical, prospective observational study was to retrospectively evaluate prospectively collected perioperative data obtained in consecutive patients with an isolated iliac artery aneurysm with regard to the diagnostic and therapeutic management including the outcome characterised by periinterventional morbidity, lethality, and overall survival over an intermediate time course of the follow-up. RESULTS: From 01/01/2002 to 03/31/2013, overall 35 patients with an isolated iliac artery aneurysm were diagnosed (females, n = 3 [8.6 %]; mean age, 70 [46-83] years). The mean hospital stay was 13 days. There were 24 aneurysms at the common iliac artery (AIC; 69 %), 8 at the internal iliac artery (AII; 23 %) and 3 at the external iliac artery (AIE; 9 %). Three patients (9 %) with an aneurysmatic rupture were admitted. The therapeutic options comprised: 12 patients underwent open resection and subsequent implantation of a prosthesis (34 %), 17 individuals were treated with an endovascular repair (49 %); 5 cases were managed with a "wait and see" policy (14 %). There was no lethality among the elective interventions whereas the lethality of emergency cases was 33 % (n = 1). Subdividing the patients treated with open surgery versus endovascular repair indicates significant differences of the preoperative characteristics, e.g., of the proportions of AIC in the distribution of aneurysmatic sites (75 % vs. 59 %; p = 0.007) reflecting the differential indication. CONCLUSIONS: Isolated iliac artery aneurysms can be approached with open surgery or with an endovascular repair depending on elective or emergency circumstances. In addition, clinical status of the patient and personal experience need to be taken into account. Depending on aneurysmatic site, extension, combination with accompanying findings and implantation sites at the proximal and distal sites of the aneurysm, the less invasive and less traumatic image-guided radiological approach can provide acceptable therapeutic success with regard to the sufficient exclusion of the aneurysm and can be increasingly used according to the individual patient and his/her findings. PMID- 24150806 TI - [Management of shunt thrombosis]. AB - INTRODUCTION: The shunt thrombosis is the most frequent complication of dialysis shunts in haemodialysis patients. Morphological reasons are the main causes of shunt occlusion. A critical evaluation of this aspect is presented on the basis of our own experience. PATIENTS AND METHODS: A retrospective study investigated our own procedure of 136 operations between 2007 and 2011 on occluded haemodialysis shunts of the arm. The patient population comprised 49 thrombosed Cimino shunts, 64 PTFE and 23 occluded venous shunts for haemodialysis within a period of four weeks. The thrombosed PTFE shunts showed a recurrence rate of 48 %. There was a maximum of 9 previous operations on renewed occluded shunts. For the patency rates, the reocclusions and the intraoperative abandoning of the shunt were added. Preoperative duplex and angiography were performed on average in 20 % all of the cases. RESULTS: All of the occluded Cimino shunts were treated successfully by thrombectomy in addition to a new anastomosis (38 out of 49, 78 %). The thrombosed PTFE loops for thrombectomy alone in 6 of 11 cases (54 %) and with additive corrections of the anastomosis showed in conclusion a patency rate of 64 % (16 out of 25). A complete new shunt reconstruction of the occluded PTFE shunts was necessary in 14 cases (22 %) and achieved patency rate of 85 %. For the venous loops anastomosis corrections were successful in 8 of 11 cases (72 %). The complete new shunt reconstructions, over bypass procedures or graft interpositions showed the best statistically significant results (chi2 = 3.9; p < 0.05) in comparison to the other procedures. Concerning time management both the day Monday and the weekend were troublesome. CONCLUSION: The creation of a new anastomosis is the preferred method in the treatment of an occluded Cimino shunt. The sole thrombectomy and correction of the venous anastomosis is often insufficient. The most important aspect in cases of occluded PTFE loops is a completely new shunt reconstruction including interposition and over bypass. The need to perform the operations in good time is obvious, but not necessary in every case at night. PMID- 24150807 TI - [Comments: interventional revascularisation of acute and subacute occlusions with the Rotarex device]. PMID- 24150808 TI - 21st Congress of International Association of Surgeons, Gastroenterologists and Oncologists in Tokyo, 2011. PMID- 24150809 TI - [14th Surgical "Erzgebirg" Symposium--Congress Report]. PMID- 24150810 TI - [Patient safety, error avoidance and error management--a report on highlights and important impulses of the Annual Congress of the Thuringian Society of Surgeons 2012]. PMID- 24150813 TI - H2S-mediated thermal and photochemical methane activation. AB - Sustainable, low-temperature methods for natural gas activation are critical in addressing current and foreseeable energy and hydrocarbon feedstock needs. Large portions of natural gas resources are still too expensive to process due to their high content of hydrogen sulfide gas (H2S) mixed with methane, deemed altogether as sub-quality or "sour" gas. We propose a unique method of activation to form a mixture of sulfur-containing hydrocarbon intermediates, CH3SH and CH3SCH3 , and an energy carrier such as H2. For this purpose, we investigated the H2S-mediated methane activation to form a reactive CH3SH species by means of direct photolysis of sub-quality natural gas. Photoexcitation of hydrogen sulfide in the CH4 + H2S complex resulted in a barrierless relaxation by a conical intersection to form a ground-state CH3SH + H2 complex. The resulting CH3SH could further be coupled over acidic catalysts to form higher hydrocarbons, and the resulting H2 used as a fuel. This process is very different from conventional thermal or radical-based processes and can be driven photolytically at low temperatures, with enhanced control over the conditions currently used in industrial oxidative natural gas activation. Finally, the proposed process is CO2 neutral, as opposed to the current industrial steam methane reforming (SMR). PMID- 24150811 TI - DNA modifications and neurological disorders. AB - Mounting evidence has recently underscored the importance of DNA methylation in normal brain functions. DNA methylation machineries are responsible for dynamic regulation of methylation patterns in discrete brain regions. In addition to methylation of cytosines in genomic DNA (5-methylcytosine; 5mC), other forms of modified cytosines, such as 5-hydroxymethylcytosine, 5-formylcytosine, and 5 carboxylcytosine, can potentially act as epigenetic marks that regulate gene expression. Importantly, epigenetic modifications require cognate binding proteins to read and translate information into gene expression regulation. Abnormal or incorrect interpretation of DNA methylation patterns can cause devastating consequences, including mental illnesses and neurological disorders. Although DNA methylation was generally considered to be a stable epigenetic mark in post-mitotic cells, recent studies have revealed dynamic DNA modifications in neurons. Such reversibility of 5mC sheds light on potential mechanisms underlying some neurological disorders and suggests a new route to correct aberrant methylation patterns associated with these disorders. PMID- 24150814 TI - Tuberculosis: a missed opportunity for early diagnosis at the front line? AB - INTRODUCTION: The incidence of tuberculosis (TB) has increased over the last two decades. Many patients with TB preferentially access healthcare via the emergency department (ED) prediagnosis, presenting an early opportunity for diagnosis. METHODS: We looked at the number of patients who presented to ED in the 3 months prior to TB notification, and their outcomes. RESULTS: 42% of all notifications had accessed ED prior to notification. The majority were hospitalised, with a proportion of these patients previously attending ED only to be discharged. 37% of patients were discharged from ED with many having TB symptoms, and only a minority referred onto TB clinic. CONCLUSIONS: The ED is often the first contact that urban TB patients have with healthcare. Healthcare professionals should ensure this diagnosis is not missed in high incidence areas as it has significant clinical and infection control consequences. PMID- 24150812 TI - Epigenetics of Alzheimer's disease and frontotemporal dementia. AB - This article will review the recent advances in the understanding of the role of epigenetic modifications and the promise of future epigenetic therapy in neurodegenerative dementias, including Alzheimer's disease and frontotemporal dementia. PMID- 24150815 TI - Identification of auxotrophic mutants of the yeast Kluyveromyces marxianus by non homologous end joining-mediated integrative transformation with genes from Saccharomyces cerevisiae. AB - The isolation and application of auxotrophic mutants for gene manipulations, such as genetic transformation, mating selection and tetrad analysis, form the basis of yeast genetics. For the development of these genetic methods in the thermotolerant fermentative yeast Kluyveromyces marxianus, we isolated a series of auxotrophic mutants with defects in amino acid or nucleic acid metabolism. To identify the mutated genes, linear DNA fragments of nutrient biosynthetic pathway genes were amplified from Saccharomyces cerevisiae chromosomal DNA and used to directly transform the K. marxianus auxotrophic mutants by random integration into chromosomes through non-homologous end joining (NHEJ). The appearance of transformant colonies indicated that the specific S. cerevisiae gene complemented the K. marxianus mutant. Using this interspecific complementation approach with linear PCR-amplified DNA, we identified auxotrophic mutations of ADE2, ADE5,7, ADE6, HIS2, HIS3, HIS4, HIS5, HIS6, HIS7, LYS1, LYS2, LYS4, LYS9, LEU1, LEU2, MET2, MET6, MET17, TRP3, TRP4 and TRP5 without the labour-intensive requirement of plasmid construction. Mating, sporulation and tetrad analysis techniques for K. marxianus were also established. With the identified auxotrophic mutant strains and S. cerevisiae genes as selective markers, NHEJ-mediated integrative transformation with PCR-amplified DNA is an attractive system for facilitating genetic analyses in the yeast K. marxianus. PMID- 24150818 TI - [Tinea barbae profunda by Arthroderma benhamiae. A diagnostic challenge]. AB - Dermatomycoses due to pets and farm animals are often a clinical and diagnostic challenge for dermatologists. A 24-year-old man presented with inflammatory skin changes on his cheeks and chin. Because of negative fungal culture and the clinical appearance of a highly inflammatory process, our first diagnosis was a bacterial pyoderma. Polymerase chain reaction (PCR) identified Arthroderma benhamiae in both the patient and his guinea pig. A. benhamiae is a zoophilic dermatophyte which belongs to the Trichophyton mentagrophytes-complex. The fungus is acquired from guinea pigs and causes highly inflammatory forms of tinea. PCR based diagnostics are quick and simple tools to identify this pathogen, so that suitable antimycotic therapy can be initiated quickly. PMID- 24150819 TI - [Off-label use]. PMID- 24150816 TI - Evolutionary analysis of HBV "S" antigen genetic diversity in Iranian blood donors: a nationwide study. AB - The genetic diversity of the HBV S gene has a significant impact on the prophylaxis and treatment of hepatitis B infection. The effect of selective pressure on this genetic alteration has not yet been studied in Iranian blood donors. To explore HBV evolution and to analyze the effects and patterns of hepatitis B surface antigen (HBsAg) mutations on blood screening assays, 358 Iranian blood donors diagnosed as asymptomatic HBV carriers were enrolled in this nationwide study. Large S and partial S genes were amplified and sequenced. HBV (sub) genotypes and synonymous and nonsynonymous mutations were investigated. The impact of naturally occurring mutations on HBsAg ELISA results was explored. Phylogenetic analyses revealed that isolated strains were of genotype D. The dominant subgenotype/subtype was D1/ayw2. Deletions and naturally occurring stop codons in the pre-S1 and major hydrophilic region (MHR) were identified. In total, 32.8% of the studied strains harbored 195 single or multiple mutations in the MHR, the majority of which were located at the first loop of the "a determinant" domain. The ayw2 subtype showed a significant effect on the ELISA signal/cut-off value and carried fewer mutations in the MHR. Nonsynonymous/synonymous substitution value indicated that negative selection was the dominant evolutionary force in the HBV S gene. This nationwide study revealed that mutation frequency of HBsAg among Iranian blood donors was much higher than previous reports from the different local regions. These findings regarding the significant differences in reactivity of ELISA among different subtypes of HBV and its correlation with the number of mutations at the MHR will be valuable to public health authorities. PMID- 24150820 TI - [Appropriate off-label prescription in practice]. AB - BACKGROUND: More than 2,000 different types of disease entities are treated in dermatology. Even for some of the more commonly occurring diseases there is no explicitly approved medication. Further limitations in the approval status can be found for skin diseases in children and adolescents, in pregnancy and with multiple comorbidities. Therefore, for medical and ethical reasons in many dermatological treatment situations prescription of medications off label is necessary. Against the background of the difficult formal and legal framework conditions for off-label prescription, knowledge of the regulations on off-label use is essential for dermatologists. METHODEN: The presented data were taken from the essential sources of the social security statutes V (SGB V), pharmaceutical guidelines and legal texts on jurisprudence of off-label use. RESULTS: There are no standardized regulations on off-label use for dermatological diseases in Germany. Only a few indications and pharmaceuticals have as yet been included in the processing procedure by the Federal Joint Committee. The large proportion of the necessary treatment in off-label use refers to the jurisprudence, in particular the Federal Social Court. According to this an off-label use can be justified in exceptional cases, and from the sociolegal perspective can even be demanded by patients, if the existing indications represent a serious life threatening disease or one which permanently reduces the quality of life, a suitable therapy under approved conditions is not available and there is a well founded prospect of successful treatment. For appropriate prescription in off label use it is necessary to carry out an appropriate and thorough evaluation and documentation of previous treatment and of the degree of suffering on the side of the patient and to have knowledge of the international literature on studies involving the selected substance. Off-label use is involved in approximately 5 15% of necessary pharmaceutical prescriptions in dermatology and affects some 30 drugs and several hundred indications in routine treatment. Currently the CVderm is constructing a databank for dermatology called E-skin for simplification of off-label use in dermatology (http://www.arzneimittelleitfaden.de). CONCLUSION: Prescriptions for off-label use are an integral component of qualified dermatological treatment. Despite regulatory and legal hurdles off-label use can be implemented with knowledge of the juridical and formal conditions. PMID- 24150821 TI - [Off-label use and G-BA. Legal framework for off-label use]. AB - Off-label use of medicinal products, i.e. beyond their submitted, tested and approved indications, lies between 30 and 90%--depending on the indication. In dermatology, off-label use is of special importance, for even guideline-endorsed standard therapeutic approaches for common dermatological diseases like atopic eczema, psoriasis, or malignant melanoma are to some extent not licensed for these indications. In addition, many of the approximately 5000 dermatological diseases have a low prevalence. For many such orphan diseases, there are no approved drugs, and it is not feasible that licensing studies will be performed for these indications within a foreseeable time. A reliable legal framework for the reimbursement of medicinal products that are used off-label is essential both for patients and to allow physicians to choose the most adequate therapy. Therefore, off-label use expert groups have been convened by the Federal Ministry of Health (BMG) in order to improve patient care. So far this new and innovative approach has not provided any reasonable improvement for many patients with dermatological diseases whose treatment can only be off-label since a comprehensive evaluation of all off-label indications is not possible. The following statement of the former Federal Minister of Health, U. Schmidt, is particularly true for dermatological therapy: "Good oncologic care also requires a good drug treatment--especially in the outpatient setting. The use of drugs which are not or not yet approved for this indication is often required here". Federal Minister of Health, Ulla Schmidt, 25th German Cancer Congress, 10 March 2002, Berlin. PMID- 24150822 TI - ["With all suitable means". Off-label-use and public statutory employers' liability insurance]. AB - In Germany, responsibility for treatment of occupational diseases lies with the public statutory employers' liability insurances (SELI). According to their legal obligation SELI have to ascertain cure--wherever possible--"with all suitable means". Thus, dermatologists treating patients with occupational dermatoses are required to deliver the best possible therapy, which, according to the current scientific knowledge, may in some cases be off-label. For example, in occupational contact dermatitis a number of scientifically promising topical and systemic drugs are not yet licensed for this indication. Off-label prescribing is not prohibited and there are no laws limiting physician flexibility in such prescribing. SELI also allows the use of off-label drugs. The goals of optimal treatment or effective prevention of occupational disease determine the measures which can be employed. Off-label use is approved for occupational skin diseases when the medication is required for cure or prevention and its use meets generally accepted medical standards. In these cases, SELI will cover off-label drug prescriptions. However, detailed patient counseling and informed consent are mandatory. PMID- 24150823 TI - [Off-label use of alitretinoin]. AB - Oral alitretinoin (9-cis retinoic acid) is an endogenous retinoid related to vitamin A. Studies have shown that oral alitretinoin is effective and well tolerated in the treatment of severe chronic hand eczema, so that it is approved for this indication. This review summarizes new studies and clinical experience on the off-label use of alitretinoin. PMID- 24150824 TI - [Off-label indications for topical tacrolimus]. AB - The topical calcineurin antagonist tacrolimus plays an important role in the treatment of different forms of eczema because of its favorable risk profile. In addition, different off-label indications have been clinically tested where tacrolimus ointment has achieved clinical improvement. This article discusses off label treatment of vitiligo, seborrheic dermatitis, steroid rosacea, perioral dermatitis, rosacea and lichen sclerosus. PMID- 24150825 TI - [Off-label use of infliximab]. AB - Tumor necrosis factor alpha (TNFalpha) is a pro-inflammatory cytokine and a key mediator of inflammation. Several TNFalpha antagonists have been used therapeutically. One of them, infliximab, is a chimeric monoclonal antibody with anti-TNFalpha activity. Numerous studies have shown TNFalpha antagonists to be effective in treating psoriasis--particularly severe resistant forms--and arthritis. Additionally, several case reports and studies showing the effects of TNFalpha on new dermatologic indications have been published. The intention of this review is to summarize the new off-label uses of infliximab according to published data. PMID- 24150826 TI - [Spironolactone in dermatological treatment. On and off label indications]. AB - There are no currently FDA/EMEA-approved dermatologic indications for spironolactone and its off-label uses are, among others, female acne, female pattern hair loss, hidradenitis suppurativa or hirsutism. The rationale behind these relays on the mechanism of action of spironolactone which interferes with the hormone-controlled sebum and sweat gland secretion and with androgen stimulated hair growth. The average dose used by the dermatologits is 50-100 mg daily. It should not be used in pregnant and lactating women and it is not used in men due to the risk of feminization. Although further studies to assess its efficacy and safety are necessary, currently spironolactone is regarded as a useful tool in the dermatologic treatment armamentarium. PMID- 24150827 TI - [Syphilis. Part 1: Introduction, pathology and clinical aspects]. AB - In Germany more than 3,500 people become infected with syphilis annually. As elsewhere in Western Europe there is a low level endemicity with a concentration among population subgroups with high rates of partner exchange, such as men who have sex with other men. In Germany after initially reduced numbers of cases, the incidence rate has increased after the turn of the millennium. In 2011 the incidence reached 4.5 cases per 100,000 inhabitants, which is the highest incidence since the introduction of the Infection Protection Act of 2001. Syphilis, like other sexually transmitted infections and diseases with its manifold clinical manifestations and complex diagnostics, is a large global problem for public health systems. The recent resurgence of syphilis presents a challenge for all physicians but particularly for dermatologists and venereologists because the skin and adjacent mucous membranes are initially affected. Rapid diagnosis, differential diagnosis, consequent treatment and monitoring can cure the disease. Prevention of misdiagnosis is essential otherwise severe, sometimes fatal cardiovascular complications, neurosyphilis and transfer to unborn and newborn children can occur. The synergy of syphilis and sexually transmitted human immunodeficiency virus (HIV) is of special importance. Syphilis together with genital herpes and other sexually transmitted genital and oral ulcers is an important pacemaker for HIV. PMID- 24150828 TI - Stretchable polymeric multielectrode array for conformal neural interfacing. AB - A highly stretchable neural interface of concurrent robust electrical and mechanical properties is developed with a conducting polymer film as the sole conductor for both the electrodes and the leads. This neural interface offers the benefits of conducting polymer electrodes in a demanding stretchable format, including low electrode impedance and high chargeinjection capacity, due to the large electroactive surface area of the electrode. PMID- 24150829 TI - Muckle-Wells cryopyrinopathy: complex phenotyping and response to therapy in a new multiplex kindred. AB - Muckle-Wells syndrome (MWS) is a member of the cryopyrin-associated periodic syndrome family of auto-inflammatory diseases, originally described as a triad of urticaria, sensorineural deafness and amyloidosis. IL-1 blockade is a proven therapy for MWS. The clinical, laboratory and genotypic characteristics of a novel kindred of five individuals with Muckle-Wells syndrome are described. Response to IL-1 blockade therapy in the proband was evaluated. All five affected family members experienced symptoms of multi-organ inflammation. Lead time between symptom onset and diagnosis was approximately 30 years in the proband. Fever was not a universal feature in all affected family members. Anti-IL-1 therapy in the proband resulted in improvements in patient-reported symptoms, inflammatory markers, auditory acuity and reversal of her infertility. Muckle Wells syndrome is a rare, multisystem, auto-inflammatory syndrome. Delay in diagnosis prevents effective treatment. We propose reversal of infertility to be among the potential benefits of IL-1 inhibition in this disease. PMID- 24150830 TI - Condylus tertius with atlanto-axial rotatory fixation: an unreported association. AB - The "condylus tertius" or the "third occipital condyle" is an embryological remnant of the proatlas sclerotome. Anatomically, it is attached to the basion and often articulates with the anterior arch of the atlas and the odontoid apex; hence, it is also called the "median occipital condyle". It is a rare anomaly of the cranio-vertebral junction (CVJ) that can lead to instability and compression of important surrounding neurovascular structures. We report a case of a 16-year old boy who presented with suboccipital neck pain, torticollis and right sided hemiparesis. Plain radiographs revealed an increased atlanto-dental interspace (ADI) with a retroflexed odontoid. Open mouth view showed asymmetry of the articular processes of the atlas with respect to the dens. Computed tomography (CT) of the CVJ delineated the third occipital condyle. Furthermore, on dynamic CT study, a type 3 atlanto-axial rotatory fixation (AARF) was clearly demonstrated. Magnetic resonance imaging (MRI) of the CVJ revealed severe right sided spinal cord compression by the retroflexed and rightward deviated dens. It also revealed disruption of the left alar and transverse ligaments. The patient was treated with 8 weeks of cranial traction and reasonable alignment was obtained. This was followed by C1-C2 lateral mass screw fixation and C1-C2 interlaminar wiring to maintain the alignment. A review of the literature did not reveal any cases of condylus tertius associated with non-traumatic AARF. An accurate knowledge of the embryology and imaging features of this rare CVJ anomaly is useful in the prompt diagnosis and management of such patients. PMID- 24150831 TI - Madura foot: two case reports, review of the literature, and new developments with clinical correlation. AB - "Madura foot" or pedal mycetoma is a rare destructive infection of the skin and subcutaneous tissues of the foot, progressing to involve muscle and bone. The infection can be caused by both bacteria and fungi. Infection typically follows traumatic implantation of bacteria or fungal spores, which are present in soil or on plant material. Clinically, this entity can be difficult to diagnose and can have an indolent and progressive course. Early diagnosis is important to prevent patient morbidity and mortality. We present two cases of pedal mycetoma, review the literature, review new developments in diagnosis, and discuss magnetic resonance imaging (MRI) features of this unusual entity. PMID- 24150832 TI - Fibromyxoid pseudotumor of the ligamentum teres treated with fresh osteochondral allograft. AB - Intra-articular tumors and tumor-like conditions of the hip are rare. When they occur, they can interrupt normal articular congruency, leading to pain and joint dysfunction. If these conditions result in large osteochondral defects, they pose challenging reconstructive problems in young patients. We describe a case of a 29 year-old man who presented with a 2-year history of right hip pain. Advanced imaging demonstrated an expansile lesion in the region of his ligamentum teres (LT), eroding a significant portion of his femoral head and expanding the cotyloid fossa. He was treated with surgical hip dislocation, excision of the lesion, and femoral head reconstruction with fresh osteochondral (OC) allograft transplantation via press-fit technique. Histologic examination of the mass showed a benign fibromyxoid pseudotumor. Although non-neoplastic masses have been described in almost all organ systems, to our knowledge this is the first description of this entity affecting the native hip joint. It is only the second description of using press-fit OC allografting in the femoral head. This case adds to the body of literature defining symptomatic LT pathology that may benefit from surgical management. It underscores the need to study the ligament further, as the ability to diagnose and treat intra-articular hip pathology has improved with modern imaging and methods of open and arthroscopic hip surgery. PMID- 24150833 TI - Synthesis and bonding in carbene complexes of an unsymmetrical dilithio methandiide: a combined experimental and theoretical study. AB - Herein, we report the preparation of a new unsymmetrical, bis(thiophosphinoyl) substituted dilithio methandiide and its application for the synthesis of zirconium- and palladium-carbene complexes. These complexes were found to exhibit remarkably shielded (13)C NMR shifts, which are much more highfield-shifted than those of "normal" carbene complexes. DFT calculations were performed to determine the origin of these observations and to distinguish the electronic structure of these and related carbene complexes compared with the classical Fischer and Schrock-type complexes. Various methods show that these systems are best described as highly polarized Schrock-type complexes, in which the metal-carbon bond possesses more electrostatic contributions than in the prototype Schrock systems, or even as "masked" methandiides. As such, geminal dianions represent a kind of "extreme" Schrock-type ligands favoring the ionic resonance structure M(+)-CR2(-) as often used in textbooks to explain the nucleophilic nature of Schrock complexes. PMID- 24150834 TI - Clinical presentation and differential diagnosis of dementia with Lewy bodies: a review. AB - BACKGROUND: Dementia with Lewy bodies is one of the most prevalent dementia diagnoses. However, differential diagnosis between dementia with Lewy bodies, Alzheimer's disease, and Parkinson's disease with dementia can still be very difficult given the overlap in neuropathology, clinical presentation, cognitive, and neuroanatomical changes. METHOD: A literature review of dementia with Lewy bodies, Alzheimer's disease, and Parkinson's disease with dementia was conducted using PubMed. RESULTS AND IMPLICATIONS: Accurate diagnosis of dementia with Lewy bodies is crucial in order to more accurately predict the progression of the disease and negative side effects from pharmacological treatment. The differences and similarities between dementia with Lewy bodies, Alzheimer's disease, and Parkinson's disease with dementia are highlighted in order to aid clinicians in differential diagnosis. PMID- 24150835 TI - Pharmacokinetics of dalfampridine extended release 7.5-mg tablets in healthy subjects and individuals with mild and moderate renal impairment: an open-label study. AB - Dalfampridine extended release tablets (D-ER; prolonged-release fampridine in Europe) are available to improve walking in patients with multiple sclerosis (MS). D-ER is mainly renally eliminated; the approved 10-mg twice daily dose is contraindicated in the United States in patients with moderate or severe renal impairment. This study evaluated single-dose and steady-state pharmacokinetics of a 7.5-mg dose of D-ER in healthy subjects (n = 13) and subjects with mild (n = 17) and moderate (n = 12) renal impairment. D-ER plasma concentrations were consistently higher in subjects with renal impairment relative to healthy individuals with a significant (P < .0001) inverse linear relationship between creatinine clearance and drug exposure. Steady-state AUC0-12 among healthy subjects, 167.0 +/- 55.3 ng h/mL, increased 74% and 151% with mild and moderate renal impairment, respectively. The overall incidence of adverse events was 61.5%, 47.1%, and 33.3% in healthy subjects, and subjects with mild and moderate renal impairment, respectively, and for treatment-related adverse events the rates were 0%, 17.6%, and 8.3%, respectively. The most common adverse events were headache, dizziness, and arthralgia. The pharmacokinetics of D-ER 7.5-mg twice daily in subjects with mild renal impairment was comparable to 10-mg twice daily in patients with MS who had normal renal function. Exposure was significantly higher in moderate renal impairment. PMID- 24150836 TI - Improved molecular tools for sugar cane biotechnology. AB - Sugar cane is a major source of food and fuel worldwide. Biotechnology has the potential to improve economically-important traits in sugar cane as well as diversify sugar cane beyond traditional applications such as sucrose production. High levels of transgene expression are key to the success of improving crops through biotechnology. Here we describe new molecular tools that both expand and improve gene expression capabilities in sugar cane. We have identified promoters that can be used to drive high levels of gene expression in the leaf and stem of transgenic sugar cane. One of these promoters, derived from the Cestrum yellow leaf curling virus, drives levels of constitutive transgene expression that are significantly higher than those achieved by the historical benchmark maize polyubiquitin-1 (Zm-Ubi1) promoter. A second promoter, the maize phosphonenolpyruvate carboxylate promoter, was found to be a strong, leaf preferred promoter that enables levels of expression comparable to Zm-Ubi1 in this organ. Transgene expression was increased approximately 50-fold by gene modification, which included optimising the codon usage of the coding sequence to better suit sugar cane. We also describe a novel dual transcriptional enhancer that increased gene expression from different promoters, boosting expression from Zm-Ubi1 over eightfold. These molecular tools will be extremely valuable for the improvement of sugar cane through biotechnology. PMID- 24150837 TI - Evaluation of the incidence and risk of hypoglycemic coma associated with selection of basal insulin in the treatment of diabetes: a Finnish register linkage study. AB - OBJECTIVE: Long-acting basal insulin analogs have demonstrated positive effects on the balance between effective glycemic control and risk of hypoglycemia versus neutral protamine Hagedorn (NPH) insulin in randomized controlled trials. Evidence of severe hypoglycemic risk with insulin detemir, insulin glargine, or NPH insulin is presented from a nationwide retrospective database study. RESEARCH DESIGN AND METHODS: Data from hospital and secondary healthcare visits due to hypoglycemic coma from 75 682 insulin-naive type 1 or 2 diabetes patients initiating therapy with NPH insulin, insulin glargine, or insulin detemir in Finland between 2000 and 2009 were analyzed. Incidence rates with 95% confidence intervals (CIs) were calculated using Poisson regression. Hazard ratios were estimated using Cox's regression with adjustments for relevant background variables. RESULTS: The adjusted risk of hospital/secondary healthcare visits due to the first severe hypoglycemic event was 21.7% (95% CI 9.6-32.1%, p < 0.001) lower for insulin detemir and 9.9% (95% CI 1.5-17.6%, p = 0.022) lower for insulin glargine versus NPH insulin. Risk of hypoglycemic coma recurrence was 36.3% (95% CI 8.9-55.5%, p = 0.014) lower for detemir and 9.5% but not significantly (95% CI -10.2 to 25.7%, p = 0.318) lower for glargine versus NPH insulin. Risk of all hypoglycemic coma events was 30.8% (95% CI 16.2-42.8%, p value <0.001) lower for detemir and 15.6% (95% CI 5.1-25.0%, p-value 0.005) lower for glargine versus NPH. Insulin detemir had a significantly lower risk for first (13.1% lower [p = 0.034]), recurrent (29.6% lower [p = 0.021]), and all (17.9% lower [p = 0.016]) severe hypoglycemic events than insulin glargine. CONCLUSIONS: There were considerable differences in risk of hospitalization or secondary healthcare visits due to hypoglycemic coma between basal insulin treatments in real-life clinical practice. PMID- 24150838 TI - Exploring quality in gradient copolymers. AB - Quality of gradient copolymers is evaluated by atomic force microscopy (AFM) and correlated with molecular weight distribution (MWD) values. ARGET ATRP is employed with decreasing levels of catalyst concentrations to generate copolymers with increasing M-w/M-n values. The copolymers are transformed into molecular bottlebrushes to enable imaging and analysis of individual molecules by AFM. The average height (cross-sectional) profile of all bottlebrushes agrees with the instantaneous composition (ICHEMA-TMS ) of the analogous copolymer backbone, as determined by (1) H NMR. The copolymer synthesized with 500 ppm of catalyst exhibits more narrow distributions of both brush height and backbone length when analyzed as a bottlebrush by AFM. Correspondingly, the copolymers synthesized with lower catalyst concentrations yield bottlebrushes with broader height and length distribution. These results establish MWD values as an excellent trait to assess quality within gradient copolymers. PMID- 24150839 TI - Does the nose know? An update on MRSA decolonization strategies. AB - Colonization with methicillin-resistant Staphylococcus aureus (MRSA) is an important step in the pathogenesis of active infection and is a key factor in the epidemiology of MRSA infection. Decolonization of patients found to have MRSA carriage may be of value in certain patient populations, especially those undergoing elective surgery. However, the most commonly used agent for decolonization, mupirocin, comes with a considerable risk of resistance if widely employed. Recent studies of other novel agents for decolonization show promise, but further research is necessary. This review focuses on the pathogenesis from MRSA colonization to infection, identifies the risk factors for colonization, and summarizes decolonization strategies, including novel approaches that may have a role in decreasing MRSA disease burden. PMID- 24150840 TI - Finding the missing link: disulfide-containing proteins via a high-throughput proteomics approach. AB - Top-down proteomics have recently started to gain attention as a novel method to provide insight into the structure of proteins in their native state, specifically the number and location of disulfide bridges. However, previous techniques still relied on complex and time-consuming protein purification and reduction reactions to yield useful information. In this issue of Proteomics, Zhao et al. (high-throughput screening of disulfide-containing proteins in a complex mixture, Proteomics 2013, 13, 3256-3260) devise a clever and rapid method for high-throughput determination of disulfides in proteins via reduction by tris(2-carboxyethyl)phosphine. Their work provides the foundation necessary to undertake more complex experiments in biological samples. PMID- 24150841 TI - Soluble CD23 measurement by CBA: a convenient and reliable quantification method in chronic lymphocytic leukemia. AB - The soluble form of the transmembrane glycoprotein CD23 corresponding to the low affinity receptor for the immunoglobulin E (sCD23) is found in the serum of patients with chronic lymphocytic leukemia (CLL). In this disease, an increase in sCD23 level is predictive of poor prognosis at diagnosis as well as during clinical outcome. Quantification of sCD23 is classically performed by enzyme linked immunosorbent assay (ELISA), a method not routinely used in hematology laboratories. Our aim was to apply cytometric bead array (CBA) technology to measure sCD23 levels. We tested 420 serum samples, 360 from patients and 60 from healthy volunteers. We selected three pairs of monoclonal antibodies recognizing the CD23 molecule that were tested in various conditions of temperature, centrifugation, washing, or chemical supplementation. Satisfactory performances in terms of repeatability (CV: 5%) and reproducibility (CV: 6%) were obtained with the selected pair of antibodies, with a threshold of positivity at 6 ng/mL. CBA and ELISA techniques were correlated with a Spearman coefficient at 0.99. The reproducibility and reliability of the sCD23 CBA assay were confirmed, with a Spearman coefficient at 0.99 in a series of 23 CLL patients and 13 controls tested in two laboratories equipped with different cytometers and using different lots of CBA reagents. Data obtained with serum and plasma samples were correlated with a Spearman coefficient at 0.99. Our study validates a simple method that allows the clinicians to benefit from an indicator of prognosis at the diagnosis as well as a marker of the evolution of CLL disease. PMID- 24150842 TI - A novel method for measuring acetabular cup deformation in cadavers. AB - Press-fit acetabular shells are subject to compressive loading conditions upon insertion during surgery. These conditions may result in deformation of the shell, potentially adversely affecting the performance of any liner fitted within it. This technical note describes the method used to measure acetabular shell deformation in a cadaver study using an optical GOM ATOS Triple Scan system. Six custom-made titanium acetabular shells were scanned prior to and immediately following insertion into three cadavers (one shell per acetabulum). A three dimensional colour map was created for each shell, and cross sections were taken at the rim to determine the maximum diametrical deformation. Values of between 30 and 150 um were recorded, with the results suggesting a size-dependent response. PMID- 24150843 TI - Quinolone-resistant Escherichia coli from the faecal microbiota of healthy volunteers after ciprofloxacin exposure are highly adapted to a commensal lifestyle. AB - OBJECTIVES: Quinolone-resistant Escherichia coli (QREC) primarily emerge in commensal bacteria under selective pressure. The aim of this work was to investigate the characteristics of QREC from the faecal microbiota after quinolone exposure, as they remain largely unknown. METHODS: Forty-eight healthy volunteers received ciprofloxacin from day 1 to day 14. QREC were detected in stools from 14 subjects at day 42. QREC were compared in terms of genetic background, metabolic properties, stress resistance and intestinal colonization abilities with quinolone-susceptible E. coli (QSEC) from the same 14 individuals and from 29 volunteers who remained QREC-free. RESULTS: QREC always belonged to a single clone for a given volunteer and to restricted phylogenetic groups. QREC carried significantly more iron capture systems than QSEC. Maximum growth rates in minimal medium with gluconate, general stress regulator RpoS activity assessed by iodine staining and resistance to oxidative and acid stresses were significantly higher for QREC than for QSEC. In a mouse colonization model, QREC efficiently colonized the intestine microbiota despite the presence of QSEC competitors. At day 42, QREC and QSEC faecal counts from the 14 volunteers were comparable except in three subjects where only QREC could be detected. CONCLUSIONS: These results suggest that QREC do not have a fitness cost, probably as a result of genetic co-selection, but are highly adapted to a commensal lifestyle. They may not be eliminated easily from the faecal microbiota from healthy subjects once selected. PMID- 24150844 TI - Evolution of methicillin-resistant Staphylococcus aureus towards increasing resistance. AB - OBJECTIVES: To elucidate the evolutionary history of Staphylococcus aureus clonal complex (CC) 8, which encompasses several globally distributed epidemic lineages, including hospital-associated methicillin-resistant S. aureus (MRSA) and the highly prevalent community-associated MRSA clone USA300. METHODS: We reconstructed the phylogeny of S. aureus CC8 by mutation discovery at 112 genetic housekeeping loci from each of 174 isolates, sampled on five continents between 1957 and 2008. The distribution of antimicrobial resistance traits and of diverse mobile genetic elements was investigated in relation to the isolates' phylogeny. RESULTS: Our analyses revealed the existence of nine phylogenetic clades within CC8. We identified at least eight independent events of methicillin resistance acquisition in CC8 and dated the origin of a methicillin-resistant progenitor of the notorious USA300 clone to the mid-1970s. Of the S. aureus isolates in our collection, 88% carried plasmidic rep gene sequences, with up to five different rep genes in individual isolates and a total of eight rep families. Mapping the plasmid content onto the isolates' phylogeny illustrated the stable carriage over decades of some plasmids and the more volatile nature of others. Strikingly, we observed trends of increasing antibiotic resistance during the evolution of several lineages, including USA300. CONCLUSIONS: We propose a model for the evolution of S. aureus CC8, involving a split into at least nine phylogenetic lineages and a subsequent series of acquisitions and losses of mobile genetic elements that carry diverse virulence and antimicrobial resistance traits. The evolution of MRSA USA300 towards resistance to additional antibiotic classes is of major concern. PMID- 24150845 TI - Fluorescent-ligand-mediated screening of G-quadruplex structures using a DNA microarray. PMID- 24150846 TI - Transcriptional activation of TFEB/ZKSCAN3 target genes underlies enhanced autophagy in spinobulbar muscular atrophy. AB - Spinobulbar muscular atrophy (SBMA) is an inherited neuromuscular disorder caused by the expansion of a CAG repeat encoding a polyglutamine tract in exon 1 of the androgen receptor (AR) gene. SBMA demonstrates androgen-dependent toxicity due to unfolding and aggregation of the mutant protein. There are currently no disease modifying therapies, but of increasing interest for therapeutic targeting is autophagy, a highly conserved cellular process mediating protein quality control. We have previously shown that genetic manipulations inhibiting autophagy diminish skeletal muscle atrophy and extend the lifespan of AR113Q knock-in mice. In contrast, manipulations inducing autophagy worsen muscle atrophy, suggesting that chronic, aberrant upregulation of autophagy contributes to pathogenesis. Since the degree to which autophagy is altered in SBMA and the mechanisms responsible for such alterations are incompletely defined, we sought to delineate autophagic status in SBMA using both cellular and mouse models. Here, we confirm that autophagy is induced in cellular and knock-in mouse models of SBMA and show that the transcription factors transcription factor EB (TFEB) and ZKSCAN3 operate in opposing roles to underlie these changes. We demonstrate upregulation of TFEB target genes in skeletal muscle from AR113Q male mice and SBMA patients. Furthermore, we observe a greater response in AR113Q mice to physiological stimulation of autophagy by both nutrient starvation and exercise. Taken together, our results indicate that transcriptional signaling contributes to autophagic dysregulation and provides a mechanistic framework for the pathologic increase of autophagic responsiveness in SBMA. PMID- 24150847 TI - Exome sequencing and functional analyses suggest that SIX6 is a gene involved in an altered proliferation-differentiation balance early in life and optic nerve degeneration at old age. AB - Primary open-angle glaucoma (POAG) is a hereditary neurodegenerative disease, characterized by optic nerve changes including increased excavation, notching and optic disc hemorrhages. The excavation can be described by the vertical cup-disc ratio (VCDR). Previously, genome-wide significant evidence for the association of rs10483727 in SIX1-SIX6 locus with VCDR and subsequent POAG was found. Using 1000 genomes-based imputation of four independent population-based cohorts in the Netherlands, we identified a missense variant rs33912345 (His141Asn) in SIX6 associated with VCDR (Pmeta = 7.74 * 10(-7), n = 11 473) and POAG (Pmeta = 6.09 * 10(-3), n = 292). Exome sequencing analysis revealed another missense variant rs146737847 (Glu129Lys) also in SIX6 associated with VCDR (P = 5.09 * 10(-3), n = 1208). These two findings point to SIX6 as the responsible gene for the previously reported association signal. Functional characterization of SIX6 in zebrafish revealed that knockdown of six6b led to a small eye phenotype. Histological analysis showed retinal lamination, implying an apparent normal development of the eye, but an underdeveloped lens, and reduced optic nerve diameter. Expression analysis of morphants at 3 dpf showed a 5.5-fold up regulation of cdkn2b, a cyclin-dependent kinase inhibitor, involved in cell cycle regulation and previously associated with VCDR and POAG in genome-wide association studies (GWASs). Since both six6b and cdkn2b play a key role in cell proliferation, we assessed the proliferative activity in the eye of morphants and found an alteration in the proliferative pattern of retinal cells. Our findings in humans and zebrafish suggest a functional involvement of six6b in early eye development, and open new insights into the genetic architecture of POAG. PMID- 24150850 TI - [Lung cancer screening - where are we in 2013?]. AB - Lung cancer is one of the leading causes of death in Europe and the USA. A relatively good prognosis is limited to those patients in whom the tumor is detected at an early stage. As clinical symptoms of lung cancer are a late finding in the natural course of the disease, most of the patients are diagnosed at an advanced tumor stage when palliative care remains the only therapeutic option. For this reason, early diagnosis of lung cancer might save lives. The National Lung Screening Trial (NLST), in the U. S. A., provided evidence that screening with low-dose CT (LD-CT) is able to reduce lung cancer mortality by 20.0 %. The encouraging results of the NLST, however, could not be confirmed by the preliminary results of ongoing European trials. Even if the European trials are able to confirm a reduction in lung cancer mortality by LD-CT, a number of important questions must be answered before the implementation of nationwide screening programs. First of all, the population that might benefit from CT lung cancer screening has to be defined precisely. Furthermore, guidelines have to be established about how to manage screening participants with detected lung nodules, as the vast majority of these pulmonary nodules will prove to be benign. This review article summarizes the results of the NLST and the initial data from the European screening trials, and will discuss some of the major open questions in lung cancer screening with CT. PMID- 24150848 TI - Characterization of a DAPI-RIT-DAPI system for gas-phase ion/molecule and ion/ion reactions. AB - The discontinuous atmospheric pressure interface (DAPI) has been developed as a facile means for efficiently introducing ions generated at atmospheric pressure to an ion trap in vacuum [e.g., a rectilinear ion trap (RIT)] for mass analysis. Introduction of multiple beams of ions or neutral species through two DAPIs into a single RIT has been previously demonstrated. In this study, a home-built instrument with a DAPI-RIT-DAPI configuration has been characterized for the study of gas-phase ion/molecule and ion/ion reactions. The reaction species, including ions or neutrals, can be introduced from both ends of the RIT through the two DAPIs without complicated ion optics or differential pumping stages. The primary reactant ions were isolated prior to reaction and the product ions were mass analyzed after controlled reaction time period. Ion/molecule reactions involving peptide radical ions and proton-transfer ion/ion reactions have been carried out using this instrument. The gas dynamic effect due to the DAPI operation on internal energy deposition and the reactivity of peptide radical ions has been characterized. The DAPI-RIT-DAPI system also has a unique feature for allowing the ion reactions to be carried out at significantly elevated pressures (in 10(-1) Torr range), which has been found to be helpful to speed up the reactions. The viability and flexibility of the DAPI-RIT-DAPI system for the study of gas-phase ion reactions have been demonstrated. PMID- 24150851 TI - [The new classification of lung adenocarcinoma]. AB - The new, interdisciplinary IASLC/ATS/ERS classification of lung adenocarcinoma has achieved a considerable impact since its publication in the year 2011. It separates tumours into preinvasive, minimally invasive and invasive subtypes. The preinvasive lesions atypical, adenomatous hyperplasia (AAH) and adenocarcinoma in situ (AIS) together with the minimally invasive adenocarcinoma (MIA), have an excellent prognosis after complete resection with 100 % survival. It enables a reproducible tumour grading by the determination of the predominant histological growth pattern which could be confirmed in several follow-up studies. Thereby the mixed subtype was eliminated which formerly represented about 80 % of all adenocarcinomas. Similarly, the terms bronchioloalveolar adenocarcinoma and bronchioloalveolar tumour growth were eliminated because they represented several distinct entities, specifically the in-situ lesions AAH and ACIS as well as the non-in-situ/invasive tumours like minimally invasive adenocarcinoma, lepidic predominant adenocarcinoma (LPA) and invasive mucinous adenocarcinoma (IMA). Although the classification is based on data from tumour resections it accommodates the fact that most tumours are diagnosed on biopsies and cytological specimens and includes recommendations for an efficient work-up to preserve tissue for molecular testing. Furthermore, the morphological analysis may provide hints for molecular changes including mutations with therapeutic relevance that may enable targeted molecular diagnostics. This review presents essentials facts of the new classification that will be part of the next WHO classification of lung tumors and its follow-up publications. PMID- 24150852 TI - [Stereotactic body radiotherapy for malignant nodules in the lung]. AB - Stereotactic body radiotherapy (SBRT) is a method for the highly precise application of percutaneous high dose radiotherapy of extracranial targets in a limited number of treatment fractions. Due to the excellent local control rates, SBRT is now well established in limited stage lung tumours. In medically inoperable patients SBRT is the method of choice, in high-risk patients and patients who refuse resection, the current literature recommends SBRT as a reasonable therapeutic option. An analysis of the SBRT working group of the German Society for Radiation Oncology showed that the treatment results in Germany are well comparable to international data. The limitations of SBRT lie in the treatment of tumours in the direct neighbourhood of so-called "serial" normal tissues, which is due to the risk of severe late effects of high dose radiation. Therefore these patients should be treated by SBRT, if at all, in the context of respective clinical studies. PMID- 24150853 TI - [Pulmonary artery chemoembolization--from bench to bedside]. AB - Locoregional approaches for inoperable lung metastases described in the literature are limited to isolated lung perfusion (ILP). A lot of experimental studies show feasibility and good oncological response with low toxicity. However, clinical applications are rare--probably due to the invasiveness of the procedure in a palliative aim. Recently chemoembolisation of the lung in a small animal model was performed and compared to isolated lung perfusion and intravenous therapy. Using a simultaneous unilateral injection of degradable starch microspheres and carboplatin into the pulmonary artery, temporary reversible embolization at the capillary and arteriolar level has been achieved. Chemoembolization was superior to intravenous chemotherapy and had a response comparable to that of isolated lung perfusion in the solitary lung metastasis model. It was not associated with early toxicity and the long-term effect on lung parenchyma was similar to those of intravenous therapy and isolated lung perfusion. Since only a third of the normal intravenous cytostatic dose is used in chemoembolization, the general side effects are thus not a limiting factor. In the large-animal model, the new method can be performed interventionally via a pulmonary catheter without changing the circulation relevantly. After 6 months no chronic injury was seen. First clinical applications show that the procedure was well tolerated in patients with unresectable metastases. PMID- 24150854 TI - [VATS lobectomy--a standard procedure in the therapy for stage I non-small cell lung cancer?]. AB - Even though VATS lobectomy has been practised since 1991 in stage I of non-small cell lung cancer (NSCLC), it was not being considered equivalent to conventional lobectomy due to considerable doubts in terms of safety and oncological permissibility. This study describes our experience and an evaluation of the systematic establishment of lobectomy by means of video-assisted thoracic surgery (VATS) as standard treatment of NSCLC in stage I, which serves as an alternative to conventional surgery. For this purpose, 42 NSCLC patients in stage I, undergoing a conventional lobectomy in 2010 (group I), were retrospectively compared to 30 patients in the same tumour stage (group II) who were treated in 2011 using VATS lobectomy. The comparison of these two groups was drawn regarding operation time, number of resected lymph nodes, required analgesics, duration of drainage, rate of postoperative complications and length of hospital stay. Although VATS lobectomy requires a longer operation time of approximately 30 minutes, it shows significant advantages in reference to postoperative need of analgesics, duration of drainage and complications after surgery. Furthermore, the amount of resected lymph nodes was comparable in both groups. Therefore, VATS lobectomy constitutes an essential extension for the operative management in a lung cancer centre. Our results show that this new method is not only of equal, but of superior value compared to conventional lobectomy. Our experience and recent data in the literature illustrate that VATS lobectomy will play a decisive role in therapy for NSCLC in stage I, potentially even in stages II and IIIA. PMID- 24150855 TI - [Pulmonary metastasectomy: an analysis of technical and oncological outcomes in 301 patients with a focus on laser resection]. AB - BACKGROUND: Resection of lung metastasis is an important component in the therapy of patients with metastatic solid tumours. The aim of this analysis was to compare the technical and oncological outcomes of laser-assisted pulmonary metastasectomy with those of standard resection techniques such as electrocautery and stapling. PATIENTS/MATERIAL AND METHODS: We retrospectively analysed all patients who had undergone curative intended pulmonary metastasectomy in our department between January 2005 and June 2010. Follow-up was accomplished by visits in the outpatient department of our medical centre or by questionnaires of the primary physicians. RESULTS: 301 patients were identified. In 62 patients (20.6 %) the Nd-YAG laser was used for resection. Despite a significantly higher number of resected lesions in the laser-assisted resection group in comparison to the group with wedge and anatomic resections (median: 7.0 vs. 2.0; p < 0.01), there was no significant difference in surgical and overall morbidity except for a higher rate of pneumonia (11.3 vs. 2.9 %; p < 0.01). Follow-up was completed for 85.4 % of the patients. After a median follow-up of 27.2 months (range: 2.3 to 60.6 months) 42.5 % of the patients suffered from recurrence and 29.2 % had died. Mean disease-free interval was 12.9 months (range: 0 to 60.6 months). Although a higher number of metastases was resected in the laser group, we did not see a significant correlation between surgical technique and long-term survival (p < 0.8). Regression analysis confirmed the number of metastases to be a significant factor influencing survival (p < 0.02), but subgroup analysis of laser-assisted resections no longer showed significance in respect to the number of metastases. CONCLUSION: The number of metastases has an influence on prognosis but seems to be of secondary importance, particularly if complete technical resectability with the aid of the laser is given. PMID- 24150856 TI - [The Zentralblatt fur Chirurgie continues to evolve as a publication medium of the German Society of Thoracic Surgery]. PMID- 24150857 TI - [Radical pleurectomy and hyperthermic intrathoracic chemotherapy for treatment of thymoma with pleural spread]. AB - INTRODUCTION: Patients with pleural thymoma spread (Masaoka stage IV a) should be treated within a multimodal treatment regime. However, the extent of local surgical resection to achieve optimal tumour control remains controversial. PATIENTS AND METHODS: Prospective analysis between September 2008 and April 2013 of all patients with a Masaoka stage IV a thymoma, who underwent radical pleurectomy/decortication (P/D) followed by hyperthermic intrathoracic chemotherapy (HITHOC). RESULTS: A total of 11 patients (male n = 7; mean age 46.5 +/- 11.4 years) with a primary stage IV a thymoma (n = 3) or thymoma with pleural relapse (n = 8) were included after successful transsternal thymoma resection. WHO histological classification was: B1 n = 1, B2 n = 6, B3 n = 3 and C n = 1. A radical P/D (5/11; 45 %) was extended with resection of the pericardium and diaphragm in 6/11 (55 %) patients. After surgical resection (91 % complete macroscopic R0/R1-resection) the HITHOC with cisplatin (100 mg/m2 body surface area (BSA) n = 7; 150 mg/m2 BSA n = 4) was performed for one hour at 42 degrees C. Operative revision was necessary in two patients (chylo- and hematothorax) with one patient also requiring temporary renal replacement therapy due acute renal failure (cisplatin 150 mg/m2 BSA). 30-day mortality was 0 %. Local recurrence (pulmonary n = 1, paravertebral n = 2) was documented in 3/10 (30 %) patients after R0/R1 resection. After a mean follow-up of 23 months the overall median survival was 27 months and 82 % (9/11) patients are still alive at the end of the study period. CONCLUSIONS: Masaoka stage IV a thymoma could be safely treated with lung-sparing radical P/D and HITHOC with cisplatin in a multimodality treatment regime. Early results with respect to recurrence and survival are encouraging, but further studies are warranted and we have to await long-term results. PMID- 24150859 TI - [The small lung nodule: dealing with a frequent radiological finding]. AB - Small pulmonary nodules less than 10 mm in size are frequently found by multidetector CT in high-risk patients. The risk of malignancy is rather low. The individual cancer risk, the radiological appearance and the presence or absence of growth are guides towards the indication for invasive procedures. A risk adjusted algorithm should avoid unnecessary invasive procedures without missing a lung cancer. PMID- 24150860 TI - Bacterial surface display of endoglin by antigen 43 induces antitumor effectiveness via bypassing immunotolerance and inhibition of angiogenesis. AB - Various angiogenesis-related self-molecules have been considered to be therapeutic targets. However, the direct use of self-molecules as vaccines is not recommended because of the inherent ability of the host to develop immune tolerance. Antigen 43 (Ag43) is a surface protein found in E. coli and contains an alpha and a beta subunits, which contains multiple T epitopes in alpha subunit. Here we construct a novel Ag43 surface display system (Ag43 system) to express Ag43 chimeric proteins to disrupt immune tolerance against self molecules. The Ag43 system was constructed from an Escherichia coli strain Tan109, derived from JM109, in which the Ag43 gene was deleted and a recombinant plasmid (pETAg43') expressing a partial Ag43 gene was introduced. The extracellular domain of angiogenesis-related endoglin gene was then subcloned into plasmid pETAg43', resulting in a recombinant plasmid pETAg43'/END(e) which was then used to transform Tan109 for protein expression. We found that Ag43 and endoglin chimeric protein (Ag43'/END(e) ) was expressed on the bacterial surface. The chimeric protein could be separated from the bacterial surface by heating to 60 degrees C and yet retain activity. We used Ag43'/END(e) as a protein vaccine and found that it could disrupt immune tolerance against endoglin by inducing significant antitumor activities and inhibit angiogenesis in several tumor models without significant side effects. These data suggest that Ag43'/END(e) chimeric protein is a potential model vaccine for active tumor immunotherapy, and that Ag43 system could be an effective tool for novel vaccine preparation to break immune tolerance to other angiogenesis-related self-molecules for cancer therapy. PMID- 24150861 TI - The effect of CXCR4 silencing on epithelial-mesenchymal transition related genes in glioma U87 cells. AB - The epithelial-mesenchymal transition (EMT) of tumor cells is deemed to be closely associated with tumor metastasis. CXCR4 has been proved to play an important role in the process of tumor metastasis. This study illustrates the function and expression of CXCR4 silencing and the EMT related genes in the human glioma cell line U87. The results showed that CXCR4 silencing could inhibit the cell invasive and adhesion potentials, expression of N-cadherin, vimentin, beta catenin, TGF-beta1, p-Smad2, and p-Akt, and the activity of transcription factors NF-kappaB, AP-1, Snail, and twist. Meanwhile, CXCR4 silencing could also up regulate the expression of E-cadherin, indicating that silencing of CXCR4 expression can inhibit the expression of EMT related genes in U87 cells. The study would provide a potential theoretical basis for the further exploration of the role of CXCR4 in human glioma. PMID- 24150862 TI - Influence of nanosecond pulsed laser irradiance on the viability of nanoparticle loaded cells: implications for safety of contrast-enhanced photoacoustic imaging. AB - Photoacoustic imaging, a promising new diagnostic medical imaging modality, can provide high contrast images of molecular features by introducing highly absorbing plasmonic nanoparticles. Currently, it is uncertain whether the absorption of low fluence pulsed light by plasmonic nanoparticles could lead to cellular damage. In our studies we have shown that low fluence pulsed laser excitation of accumulated nanoparticles at low concentration does not impact cell growth and viability, while we identify thresholds at which higher nanoparticle concentrations and fluences produce clear evidence of cell death. The results provide insights for improved design of photoacoustic contrast agents and for applications in combined imaging and therapy. PMID- 24150863 TI - The role of socially prescribed perfectionism in the link between perceived racial discrimination and African American adolescents' depressive symptoms. AB - Research examining the social origins of perfectionism has focused on negative evaluative experiences in the family, with less attention to negative social evaluations in other contexts and situations relevant for African American adolescents. The experience of racial discrimination is common for African American youth, and may trigger maladaptive perfectionistic beliefs if the youth perceive that they do not meet others' standards (socially prescribed perfectionism) or internalize discriminatory messages. Thus, the present study examined longitudinal associations among racial discrimination, socially prescribed perfectionism, and depressive symptoms among a community sample of urban and predominantly low income African American adolescents (n = 492; 46.7 % female). In each of grades 7, 8 and 9, participants reported their experiences with racial discrimination, perfectionistic beliefs, and depressive symptoms. Analyses revealed that experiences with racial discrimination in grade 7 were associated with socially prescribed perfectionism in grade 8 which, in turn, was linked with depressive symptoms in grade 9. Results suggest that prospective associations between the experience of racial discrimination and depressive symptoms are due, in part, to increased socially prescribed perfectionism. Implications for interventions targeting depression in African American are discussed. PMID- 24150865 TI - Cortical and subcortical brain atrophy in Parkinson's disease with visual hallucination. AB - BACKGROUND: The aim of this study was to investigate the cortical and subcortical brain structures in Parkinson's disease (PD) with visual hallucination (VH), and to elucidate the association between the proposed hypothesis of VH in PD and regional brain volume changes. METHODS: We used 3T magnetic resonance imaging (MRI) and voxel-based morphometry (VBM) to investigate the brain structures of PD patients with VH (PD-VH; n = 13) and PD patients without VH (PD-C; n = 13). RESULTS: The PD-VH patients showed significant cortical atrophy compared to the PD-C patients in the bilateral dorsolateral prefrontal cortex, left rostral region of the prefrontal cortex, left ventral section of the cingulate cortex, bilateral primary visual cortex, and secondary visual cortex including the left inferior occipital gyrus, right lingual cortex, right supramarginal gyrus, and left fusiform gyrus. Significant subcortical atrophic changes were observed in the white matter of the right parahippocampal gyrus, the bilateral posterior part of the cingulate gyrus, the left lingual gyrus, and the right middle occipital gyrus. CONCLUSIONS: VH in PD can occur due to distinctive neuroanatomical involvement. PMID- 24150864 TI - Socioeconomic status and child mental health: the role of parental emotional well being and parenting practices. AB - This study examined the role of parental emotional well-being and parenting practices as mediators of the association between familial socioeconomic status (SES) and child mental health problems. The sample included 2,043 5th-7th graders (50.7 % female) participating in the second wave of the Bergen Child Study. Children completed the Strengths and Difficulties Questionnaire, parents reported family economy and education level, emotional well-being (measured with the Everyday Feelings Questionnaire), and the use of negative disciplinary and affirmative parenting practices (measured using the Family Life Questionnaire). Path analyses were conducted to examine the associations between SES and externalizing and internalizing problems. Results supported a model where family economy was associated with externalizing problems through parental emotional well-being and parenting practices, whereas maternal education level was associated with externalizing problems through negative discipline. The direct association between paternal education level and externalizing problems was not mediated by parenting. For internalizing problems, we found both direct associations with family economy and indirect associations with family economy through parental emotional well-being and parenting. The results suggest that parental emotional well-being and parenting practices are two potential mechanisms through which low socioeconomic status is associated with child mental health problems. PMID- 24150866 TI - Safrole suppresses murine myelomonocytic leukemia WEHI-3 cells in vivo, and stimulates macrophage phagocytosis and natural killer cell cytotoxicity in leukemic mice. AB - Many anticancer drugs are obtained from phytochemicals and natural products. However, some phytochemicals have mutagenic effects. Safrole, a component of Piper betle inflorescence, has been reported to be a carcinogen. We have previously reported that safrole induced apoptosis in human oral cancer cells in vitro and inhibited the human oral tumor xenograft growth in vivo. Until now, there is no information addressing if safrole promotes immune responses in vivo. To evaluate whether safrole modulated immune function, BALB/c mice were intraperitoneally injected with murine myelomonocytic WEHI-3 leukemia cells to establish leukemia and then were treated with or without safrole at 4 and 16 mg/kg. Animals were sacrificed after 2 weeks post-treatment with safrole for examining the immune cell populations, phagocytosis of macrophages and the natural killer (NK) cells' cytotoxicity. Results indicated that safrole increased the body weight, and decreased the weights of spleen and liver in leukemic mice. Furthermore, safrole promoted the activities of macrophages phagocytosis and NK cells' cytotoxicity in leukemic mice when compared with untreated leukemic mice. After determining the cell marker population, we found that safrole promoted the levels of CD3 (T cells), CD19 (B cells) and Mac-3 (macrophages), but it did not affect CD11b (monocytes) in leukemic mice. In conclusion, safrole altered the immune modulation and inhibited the leukemia WEHI-3 cells in vivo. PMID- 24150867 TI - Protective effect of lycopene on oxidative stress and antioxidant status in Cyprinus carpio during cypermethrin exposure. AB - The aim of this study was to investigate the ameliorative properties of lycopene against the toxic effects of cypermethrin (CYP) by examining oxidative damage markers such as lipid peroxidation and the antioxidant defense system components in carp (Cyprinus carpio). The fish were divided into seven groups of 10 fish each and received the following treatments: group 1, no treatment; group 2, orally administered corn oil; group 3, oral lycopene (10 mg/kg body weight); group 4, exposure to 0.202 MUg/L CYP; group 5, exposure to 0.202 MUg/L CYP plus oral administration of 10 mg/kg lycopene; group 6, exposure to 0.404 MUg/L CYP; and group 7, exposure to 0.404 MUg/L CYP plus oral administration of 10 mg/kg lycopene. Treatment was continued for 28 days, and at the end of this period, blood and tissue (liver, kidney, and gill) samples were collected. Levels of malondialdehyde (MDA) and reduced glutathione (GSH) as well as superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GSH-Px) activities were determined in blood and tissues for measurement of oxidant-antioxidant status. MDA level, as an index of lipid peroxidation, increased in blood and tissues. Antioxidant enzyme activities in blood and tissues were modified in CYP groups compared with controls. Administration of lycopene ameliorated these parameters. The present results suggest that administration of lycopene might alleviate CYP-induced oxidative stress. PMID- 24150868 TI - Prenatal exposure to permethrin influences vascular development of fetal brain and adult behavior in mice offspring. AB - Pyrethroids are one of the most widely used classes of insecticides and show neurotoxic effects that induce oxidative stress in the neonatal rat brain. However, little is still known about effects of prenatal exposure to permethrin on vascular development in fetal brain, central nervous system development, and adult offspring behaviors. In this study, the effects of prenatal exposure to permethrin on the development of cerebral arteries in fetal brains, neurotransmitter in neonatal brains, and locomotor activities in offspring mice were investigated. Permethrin (0, 2, 10, 50, and 75 mg/kg) was orally administered to pregnant females once on gestation day 10.5. The brains of permethrin-treated fetuses showed altered vascular formation involving shortened lengths of vessels, an increased number of small branches, and, in some cases, insufficient fusion of the anterior communicating arteries in the area of circle of Willis. The prenatal exposure to permethrin altered neocortical and hippocampus thickness in the mid brain and significantly increased norepinephrine and dopamine levels at postnatal day 7 mice. For spontaneous behavior, the standing ability test using a viewing jar and open-field tests showed significant decrease of the standing ability and locomotor activity in male mice at 8 or 12 weeks of age, respectively. The results suggest that prenatal exposure to permethrin may affect insufficient development of the brain through alterations of vascular development. PMID- 24150869 TI - Fullerene-sp2-iminosugar balls as multimodal ligands for lectins and glycosidases: a mechanistic hypothesis for the inhibitory multivalent effect. AB - Concerted functioning of lectins and carbohydrate-processing enzymes, mainly glycosidases, is essential in maintaining life. It was commonly assumed that the mechanisms by which each class of protein recognizes their cognate sugar partners are intrinsically different: multivalency is a characteristic feature of carbohydrate-lectin interactions, whereas glycosidases bind to their substrates or substrate-analogue inhibitors in monovalent form. Recent observations on the glycosidase inhibitory potential of multivalent glycomimetics have questioned this paradigm and led to postulate an inhibitory multivalent effect. Here the mechanisms at the origin of this phenomenon have been investigated. A D-gluco configured sp(2)-iminosugar glycomimetic motif, namely 1-amino-5N,6O oxomethylydenenojirimycin (1N-ONJ), behaving, simultaneously, as a ligand of peanut agglutinin (PNA) lectin and as an inhibitor of several glycosidases, has been identified. Both the 1N-ONJ-lectin- and 1N-ONJ-glycosidase-recognition processes have been found to be sensitive to multivalency, which has been exploited in the design of a lectin-glycosidase competitive assay to explore the implication of catalytic and non-glycone sites in enzyme binding. A set of isotropic dodecavalent C60-fullerene-sp(2)-iminosugar balls incorporating matching or mismatching motifs towards several glycosidases (inhitopes) was synthesized for that purpose, thereby preventing differences in binding modes arising from orientational preferences. The data supports that: 1) multivalency allows modulating the affinity and selectivity of a given inhitope towards glycosidases; 2) multivalent presentation can switch on the inhibitory capacity for some inhitope-glycosidase pairs, and 3) interactions of the multivalent inhibitors with non-glycone sites is critical for glycosidase recognition. The ensemble of results point to a shift in the binding mode on going from monovalent to multivalent systems: in the first case a typical ''key-lock'' model involving, essentially, the high-affinity active site can be assumed, whereas in the second, a lectin-like behavior implying low-affinity non-glycone sites probably operates. The differences in responsiveness to multivalency for different glycosidases can then be rationalized in terms of the structure and accessibility of the corresponding carbohydrate-binding regions. PMID- 24150870 TI - Perioperative infection in the patient with rheumatic disease. AB - The risk of infection accompanies the benefits of surgery. Immunomodulatory chronic illnesses may increase the risk of surgical infections. Surgical patients with rheumatologic illness need close preoperative assessment regarding their infection risks (fixed and modifiable), which vary on the basis of the proposed procedure, specific rheumatologic illness, and underlying comorbidities. Modification of the medication regimens in the preoperative period may decrease risk and enhance healing. Intraoperative antisepsis and antibiotic prophylaxis remain critical in this patient population. Postoperative fevers within 3 days of surgery are usually noninfectious but require vigilance and attention. The principles of surgical infection reduction are not different in the rheumatologic and general patient populations, but best practice depends on expertise in caring for patients with these illnesses. PMID- 24150872 TI - Facile synthesis of magnetic metal organic frameworks for the enrichment of low abundance peptides for MALDI-TOF MS analysis. AB - In this work, core-shell magnetic metal organic framework (MOF) microspheres were successfully synthesized by coating magnetite particles with mercaptoacetic acid and subsequent reactions with ethanol solutions of Cu(OAc)2 and benzene-1,3,5 tricarboxylic acid (designated as H3 btc) alternately. The resulting Fe3 O4 @[Cu3 (btc)2 ] possess strong magnetic responsiveness. We applied the novel nanocomposites in the enrichment of low-concentration standard peptides, peptides in MYO and BSA tryptic digests and in human urine in combination with MALDI-TOF MS analysis for the first time. In addition, the Cu3 (btc)2 MOF shells exhibit strong affinity to peptides, thus providing a rapid and convenient approach to the concentration of low-abundance peptides. Notably, peptides at an extremely low concentration of 10 pM could be detected by MALDI-TOF MS after enrichment with the magnetic MOF composites. In brief, the facile synthesis and efficient enrichment process of the Fe3 O4 @[Cu3 (btc)2 ] microspheres make them promising candidates for the isolation of peptides in even complex biological environments. PMID- 24150871 TI - Animal models of scleroderma: current state and recent development. AB - Systemic sclerosis (SSc) is a multisystem connective tissue disease characterized by three cardinal features: immunological abnormalities, vasculopathy, and fibrosis of skin and certain internal organs. Although several animal models recapitulating selected aspects of SSc have been reported, the absence of models fulfilling the full clinical picture of SSc has hindered progress in the development and testing of therapy for this disease. In recent years, three new inducible animal models have revealed the critical importance of reactive oxygen species, angiotensin II, and the combination of DNA topoisomerase I immunization and IL-6 induction in fibrosis of SSc. In addition, two genetic animal models have revealed the potential involvement of transcription factors, Fra-2 and Fli1, in the fibrosis and vasculopathy of SSc. These new animal models provide important insights into specific pathological processes of SSc and novel therapeutic targets that may lead to more effective treatment of this incurable disease. PMID- 24150873 TI - Radical thiol-yne chemistry on diphenylacetylene: selective and quantitative addition enabling the synthesis of hyperbranched poly(vinyl sulfide)s. AB - A powerful variation of traditional radical thiol-yne reaction with diphenylacetylene (DPA)-based starting materials leading to the quantitative and selective formation of the corresponding vinyl sulfides is reported. A variety of different thiols are shown to undergo reaction with DPA and the influence of their structure on reactivity is studied. The results obtained from the model reactions are then used to guide the efficient synthesis of hyperbranched poly(vinyl sulfide) (hb-PVS) systems by employing a dithiol and a trialkyne in an A2 + B3 approach. The polymers obtained show excellent solubility in common organic solvents and exhibit high refractive indices (e.g., 1.70 at 589 nm). The combined ease of processability and potential for cross-linking make these materials very interesting for applications, such as coatings for optical devices. The selective mono-addition thiol-yne reaction on DPA serves not only as a synthetic method for the preparation of PVS but could also be applied to the general modification of acetylene-containing materials. PMID- 24150874 TI - Calendar time-specific propensity score analysis for observational data: a case study estimating the effectiveness of inhaled long-acting beta-agonist on asthma exacerbations. AB - PURPOSE: Propensity scores (PS) are frequently used in observational studies. PS are usually estimated over the entire study period without consideration of the effect of changing patterns of the included variables over time. This study sought to compare PS estimated using the entire study period (conventional PS) and PS estimated for specific periods (calendar time-specific PS (CTS-PS)), and to determine whether there are differences in estimated treatment effects using these approaches. METHODS: We conducted a claims data analysis. Asthmatic patients who received an asthma controller during 1997-2008 were included. Exposed patients were those who received an inhaled long-acting beta-2 agonist. Conventional PS used the entire period to estimate a PS for individuals. CTS-PS approach divided the study period into 1-year periods and estimated PS separately for each period. Each individual had two PS. Both PS approaches were used to estimate adjusted hazard ratio (HR) for asthma exacerbations using Cox proportional hazard models. RESULTS: A total of 288,518 patients with an average age of 11.9 +/- 5.8 years were included. The difference between conventional PS and CTS-PS in each period ranged from -0.213 to 0.098. The adjusted HR of conventional PS-matched cohort was 1.20 (95%CI: 1.18-1.22), whereas the estimate for the CTS-PS-matched cohort was 1.24 (95%CI: 1.23-1.37). CONCLUSION: Focusing on a specific year, there was a difference between conventional PS estimated versus CTS-PS for that year. However, there was minimal effect of CTS-PS on the observed treatment effects compared with conventional PS approach. PMID- 24150875 TI - Commentary on Crowley et al.'s research priorities for economic analysis of prevention. AB - Economic theory provides a textbook ideal for how to conduct efficiency analysis that determines optimal resource allocation. The real world is not, however, an ideal place. This article suggests that common sense should be allowed to temper zealous commitment to textbook ideals. The spirit and the process of economic evaluation may be as important as the "final answer" expressed as a summary statistic. PMID- 24150876 TI - Do the Cambridge Neuropsychological Test Automated Battery episodic memory measures discriminate amnestic mild cognitive impairment? AB - OBJECTIVE: Although visual recognition memory and visuospatial paired associates learning has been shown to be impaired in amnestic mild cognitive impairment (aMCI), the sensitivity and specificity of the visual memory tests used to identify aMCI are not well defined. The current study attempted to analyze the sensitivity and specificity of three visual episodic memory tests (Pattern Recognition Memory [PRM], Delayed Matching to Sample [DMS], and Paired Associated Learning [PAL]) from the CANTAB, in differentiating aMCI patients from control healthy participants. METHODS: Seventy seven aMCI patients and 85 cognitive normal controls aged over 50 years performed the PRM, DMS, and PAL tests. Univariate and multivariate logistic regression and receiver operating characteristic curve analyses were used to study the relationships between aMCI and visual memory measures. RESULTS: The three Cambridge Neuropsychological Test Automated Battery measures significantly predicted aMCI. The optimal predictive model combined the total percent correct responses for PRM and DMS with the PAL total errors (six shapes adjusted), with a sensitivity of 72%, specificity of 83%, and achieved predictive accuracy of 80%. CONCLUSION: Visual episodic memory tasks such as those involved in the PRM, DMS, and PAL tests (included in the Cambridge Neuropsychological Test Automated Battery) may sensitively discriminate aMCI patients from normal controls. These tests may be useful for correct diagnosis of aMCI. PMID- 24150877 TI - Respiratory syncytial virus detection in cells and clinical samples by using three new monoclonal antibodies. AB - Acute respiratory infections caused by the respiratory syncytial virus (RSV) are important health burdens that affect infants worldwide. RSV is also an important cause of morbidity and disease in adults, which causes enormous economic losses. At the present time, RSV infection is diagnosed by immunofluorescence, test pack and/or PCR, obtaining better results with PCR than with any other technique. The production of new monoclonal antibodies (mAbs) capable of detecting RSV in clinical samples is necessary to generate better and faster diagnosis tools for RSV. In this study, three new mAbs, directed against the RSV N and M2-1 proteins, were evaluated for the detection of RSV in clinical samples. Nasopharyngeal swabs were obtained from: 27 RSV-positive patients; 15 human metapneumovirus (hMPV) positive patients; and 6 healthy controls. To evaluate RSV presence in these samples, clinical samples and RSV-infected cells were tested by Enzyme-Linked ImmunoSorbent Assay (ELISA), flow cytometry, immunofluorescence, and dot-blot assays. Specificity and sensitivity were determined for each mAb by using purified RSV antigens and antigens from different viruses. Infected cells and clinical samples tested with the three new mAbs resulted positive by immunofluorescence, ELISA, flow cytometry, and dot blot. No false positives were obtained in samples infected with other respiratory virus (hMPV) or from healthy controls. These results suggest that these new anti-RSV mAbs can be considered for the rapid and reliable detection of RSV on infected cells and clinical specimens by multiple immunological approaches. PMID- 24150880 TI - MIL-53(Fe): a metal-organic framework with intrinsic peroxidase-like catalytic activity for colorimetric biosensing. PMID- 24150881 TI - Mesoporous silica and organosilica films templated by nanocrystalline chitin. AB - Liquid crystalline phases can be used to impart order into inorganic solids, creating materials that mimic natural architectures. Herein, mesoporous silica and organosilica films with layered structures and high surface areas have been templated by nanocrystalline chitin. Aqueous suspensions of spindle-shaped chitin nanocrystals were prepared by sequential deacetylation and hydrolysis of chitin fibrils isolated from king crab shells. The nanocrystalline chitin self-assembles into a nematic liquid-crystalline phase that has been used to template silica and organosilica composites. Removal of the chitin template by either calcination or sulfuric-acid-catalyzed hydrolysis gave mesoporous silica and ethylene-bridged organosilica films. The large, crack-free mesoporous films have layered structures with features that originate from the nematic organization of the nanocrystalline chitin. PMID- 24150882 TI - Chemical etiology of nucleic acid structure: the pentulofuranosyl oligonucleotide systems: the (1'->3')-beta-L-ribulo, (4'->3')-alpha-L-xylulo, and (1'->3')-alpha L-xylulo nucleic acids. AB - Under potentially prebiotic scenarios, ribose (pentose), the component of RNA is formed in meager amounts, as opposed to ribulose and xylulose (pentuloses). Consequently, replacement of ribose in RNA, with pentulose sugars, gives rise to prospective oligonucleotide candidates that are potentially prebiotic structural variants of RNA that could be formed by the same type of chemical pathways that gave rise to RNA from ribose. The potentially natural alternative (1'->3')-ribulo oligonucleotides and (4'->3')- and (1'->3')-xylulo oligonucleotides consisting of adenine and thymine were synthesized and found to exhibit no self-pairing or cross-pairing with RNA. This signifies that even though pentulose sugars may have been abundant in a prebiotic scenario, the pentulose nucleic acids (NAs), if and when formed, would not have been competitors of RNA, or interfered with the emergence of RNA as a functional informational system. The reason for the lack of base pairing in pentulose NA highlights the contrasting and central role played by the furanosyl ring in RNA and pentulose NA, enabling and optimizing the base pairing in RNA, while impeding it in pentulose NA. PMID- 24150883 TI - Ultrathin shell double emulsion templated giant unilamellar lipid vesicles with controlled microdomain formation. AB - A microfluidic approach is reported for the high-throughput, continuous production of giant unilamellar vesicles (GUVs) using water-in-oil-in-water double emulsion drops as templates. Importantly, these emulsion drops have ultrathin shells; this minimizes the amount of residual solvent that remains trapped within the GUV membrane, overcoming a major limitation of typical microfluidic approaches for GUV fabrication. This approach enables the formation of microdomains, characterized by different lipid compositions and structures within the GUV membranes. This work therefore demonstrates a straightforward and versatile approach to GUV fabrication with precise control over the GUV size, lipid composition and the formation of microdomains within the GUV membrane. PMID- 24150886 TI - The contextual action relationship between a tool and its action recipient modulates their joint perception. AB - Facilitatory effects have been noted between tools and the objects that they act upon (their "action recipients") across several paradigms. However, it has not been convincingly established that the motor system is directly involved in the joint visual processing of these object pairings. Here, we used the attentional blink (AB) paradigm to demonstrate privileged access to perceptual awareness for tool-action recipient object pairs and to investigate how motor affordances modulate their joint processing. We demonstrated a reduction in the size of the AB that was greater for congruent tool-action recipient pairings (e.g., hammer nail) than for incongruent pairings (e.g., scissors-nail). Moreover, the AB was reduced only when action recipients followed their associated tool in the temporal sequence, but not when this order was reversed. Importantly, we also found that the effect was sensitive to manipulations of the motor congruence between the tool and the action recipient. First, we observed a greater reduction in the AB when the tool and action recipient were correctly aligned for action than when the tool was rotated to face away from the action recipient. Second, presenting a different tool as a distractor between the tool and action recipient target objects removed any benefit seen for congruent pairings. This was likely due to interference from the motor properties of the distractor tool that disrupted the motor synergy between the congruent tool and action recipient targets. Overall, these findings demonstrate that the contextual motoric relationship between tools and their action recipients facilitates their visual encoding and access to perceptual awareness. PMID- 24150884 TI - Face and object discrimination in autism, and relationship to IQ and age. AB - The current study tested fine discrimination of upright and inverted faces and objects in adolescents with Autism Spectrum Disorder (ASD) as compared to age- and IQ-matched controls. Discrimination sensitivity was tested using morphed faces and morphed objects, and all stimuli were equated in low-level visual characteristics (luminance, contrast, spatial frequency make-up). Participants with ASD exhibited slight, non-significant impairments in discrimination sensitivity for faces, yet significantly enhanced discrimination sensitivity for objects. The ASD group also showed a protracted development of face and object inversion effects. Finally, for ASD participants, face sensitivity improved with increasing IQ while object sensitivity improved with age. By contrast, for controls, face sensitivity improved with age, but neither face nor object sensitivity was influenced by IQ. These findings suggest that individuals with ASD follow a qualitatively different path in the development of face and object processing abilities. PMID- 24150885 TI - The "Eye Avoidance" Hypothesis of Autism Face Processing. AB - Although a growing body of research indicates that children with autism spectrum disorder (ASD) exhibit selective deficits in their ability to recognize facial identities and expressions, the source of their face impairment is, as yet, undetermined. In this paper, we consider three possible accounts of the autism face deficit: (1) the holistic hypothesis, (2) the local perceptual bias hypothesis and (3) the eye avoidance hypothesis. A review of the literature indicates that contrary to the holistic hypothesis, there is little evidence to suggest that individuals with autism do perceive faces holistically. The local perceptual bias account also fails to explain the selective advantage that ASD individuals demonstrate for objects and their selective disadvantage for faces. The eye avoidance hypothesis provides a plausible explanation of face recognition deficits where individuals with ASD avoid the eye region because it is perceived as socially threatening. Direct eye contact elicits a increased physiological response as indicated by heightened skin conductance and amygdala activity. For individuals with autism, avoiding the eyes is an adaptive strategy, however, this approach interferes with the ability to process facial cues of identity, expressions and intentions, exacerbating the social challenges for persons with ASD. PMID- 24150887 TI - One "Both" Sex"es": Observations, suppositions, and airy speculations on fetal sex anatomy in British scientific literature, 1794-1871. AB - The hegemony of the two-sex paradigm in the European scientific imagination and wider culture did not automatically equate to the hegemony of two discrete genders. In fact, two sexes facilitated a variety of gender choices: two singular and a number of double or otherwise intersexed (most commonly referred to as "hermaphrodite" or "bisexual" in its anatomical sense). This article explores some key British medical and allied scientific texts, with reference to associated Continental literature, as a means of illustrating the complexity of the two-sex paradigm and the unexpected transformation of gender possibilities that it helped produce through the early and middle decades of the nineteenth century. Discourses surrounding the first direct observations of the earliest development of fetal urinogenital anatomy were pivotal. The prevailing view that the incipient embryo was sexually undifferentiated (a paragon of the one-sex paradigm) was challenged by the Edinburgh anatomist Robert Knox, initially as he sought to bolster his professional reputation at the height of the Burke and Hare "body-snatching" scandal. Knox suggested that every embryo began life in an essentially dual-sexed state, an individual's sex anatomy depending on the greater or lesser development of component female and male structures. Greater clarification on the contested status of the homology-hermaphrodite distinction was achieved with the discovery of the early co-existence of the excretory duct of the Wolffian body (mesonephric duct) and the Mullerian duct (paramesonephric duct), an observation that made anatomical bisexuality difficult to ignore. The nineteenth-century's greatest champion of primordial hermaphroditism was Charles Darwin who was pivotal in phylogenizing the principle and establishing the premise that (in his own words) "Every man & woman is hermaphrodite," a foundation stone of late-nineteenth-century sexology. PMID- 24150888 TI - Discovery of chemotherapy-associated ovarian cancer antigens by interrogating memory T cells. AB - According to the immunogenic cell death hypothesis, clinical chemotherapy treatments may result in CD8(+) and CD4(+) T-cell responses against tumor cells. To discover chemotherapy-associated antigens (CAAs), T cells derived from ovarian cancer (OC) patients (who had been treated with appropriate chemotherapy protocols) were interrogated with proteins isolated from primary OC cells. We screened for immunogenicity using two-dimensional electrophoresis gel-eluted OC proteins. Only the selected immunogenic antigens were molecularly characterized by mass-spectrometry-based analysis. Memory T cells that recognized antigens associated with apoptotic (but not live) OC cells were correlated with prolonged survival in response to chemotherapy, supporting the model of chemotherapy induced apoptosis as an adjuvant of anti-tumor immunity. The strength of both memory CD4(+) and CD8(+) T cells producing either IFN-gamma or IL-17 in response to apoptotic OC antigens was also significantly greater in Responders to chemotherapy than in nonresponders. Immunogenicity of some of these antigens was confirmed using recombinant proteins in an independent set of patients. The T cell interrogation system represents a strategy of reverse tumor immunology that proposes to identify CAAs, which may then be validated as possible prognostic tumor biomarkers or cancer vaccines. PMID- 24150890 TI - Efficacy of revision surgery for the dislocating total hip arthroplasty: report from a large community registry. AB - BACKGROUND: Historically, achieving stability for the unstable total hip arthroplasty (THA) with revision surgery has been achieved inconsistently. Most of what we know about this topic comes from reports of high-volume surgeons' results; the degree to which these results are achieved in the community is largely unknown, but insofar as most joint replacements are done by community surgeons, the issue is important. QUESTIONS/PURPOSES: We used a community joint registry to determine: (1) the frequency of repeat revision after surgery to treat the unstable THA; (2) what surgical approaches to this problem are in common use in the community now; (3) are there differences in repeat revision frequency that vary by approach used; and (4) has the frequency of repeat revision decreased over time as surgical technique and implant options have evolved? METHODS: We reviewed 6801 primary THAs performed in our community joint registry over the last 20 years. One hundred eighteen patients (1.7%) with a mean age of 67 years were revised within the registry for instability/dislocation. Failure was defined as a return to the operating room for rerevision surgery for instability. Minimum followup was 2 years (average, 9.4 years; range, 2-20 years) with six patients having incomplete followup. The frequency of rerevisions was calculated and compared using Pearson's chi-square test. Cumulative rerevision rates were calculated using the Kaplan-Meier method and types of revision procedures were compared using the log-rank test. RESULTS: The initial revision procedure was successful in 108 patients (92%); 10 patients underwent repeat surgery for recurrent dislocation after their initial revision surgery. The most frequently performed procedure was revision of the head and liner only (35 of 118 [30%]); constrained devices were used in 19% (22 of 118) of the procedures. There was no difference in the cumulative rerevision rates for instability or dislocation by type of revision procedure performed. Six of 22 constrained liners were rerevised for varying indications. There was no difference in frequency of repeat revision for instability between those patients revised for THAs performed before 2003 and those managed more recently. CONCLUSIONS: Revision surgery for unstable THA is successfully managed in the community with a variety of surgical interventions. Identifying the reason for dislocation and addressing the source remain paramount. Constrained liners should be used with caution; although typically used in the most problematic settings, rerevision for a variety of failure modes remains troublesome. LEVEL OF EVIDENCE: Level III, therapeutic study. See Guidelines for Authors for a complete description of levels of evidence. PMID- 24150892 TI - Boron nitride nanotubes and primary human osteoblasts: in vitro compatibility and biological interactions under low frequency ultrasound stimulation. AB - In this paper we investigated a novel and non-invasive approach for an endogenous osteoblast stimulation mediated by boron nitride nanotubes (BNNTs). Specifically, following the cellular uptake of the piezoelectric nanotubes, cultures of primary human osteoblasts (hOBs) were irradiated with low frequency ultrasound (US), as a simple method to apply a mechanical input to the cells loaded with BNNTs. This in vitro study was aimed at investigating the main interactions between hOBs and BNNTs and to study the effects of the 'BNNTs + US' stimulatory method on the osteoblastic function and maturation.A non-cytotoxic BNNT concentration to be used in vitro with hOB cultures was established. Moreover, investigation with transmission electron microscopy/electron energy loss spectroscopy (TEM/EELS) confirmed that BNNTs were internalized in membranal vesicles. The panel of investigated osteoblastic markers disclosed that BNNTs were capable of fostering the expression of late-stage bone proteins in vitro, without using any mineralizing culture supplements. In our samples, the maximal osteopontin expression, with the highest osteocalcin and Ca(2+) production, in the presence of mineral matrix with nodular morphology, was observed in the samples treated with BNNTs + US. In this group was also shown a significantly enhanced synthesis of TGF-beta1, a molecule sensitive to electric stimulation in bone. Finally, gene deregulations of the analyzed osteoblastic genes leading to depletive cellular effects were not detected. Due to their piezoelectricity, BNNT-based therapies might disclose advancements in the treatment of bone diseases. PMID- 24150889 TI - Long-term (8 year) outcomes and predictors of major adverse cardiac events after full metal jacket drug-eluting stent implantation. AB - OBJECTIVES: We examined long-term outcomes and predictors of major adverse cardiac events after the full metal jacket (FMJ) stent implantation. BACKGROUND: The FMJ procedure has been used to treat diffuse coronary artery disease (CAD), but long-term outcomes remain unknown. METHODS: The study population consisted of 347 consecutive patients (352 lesions) who had been treated for de novo diffuse CAD with FMJ stents (stent length >= 60 mm). RESULTS: The mean age was 61.0 +/- 10.1 years, and the stent length was 71.9 +/- 13.7 mm. The procedural success rate was 97.7%. Major in-hospital complications (one death and two acute stent thromboses) occurred in three patients (0.7%). The median follow-up was 101 months (interquartile range, 95-108 months). During follow-up, there were 60 deaths (33 cardiac), 20 myocardial infarctions, and 94 revascularizations. Definite stent thrombosis occurred in 12 patients. The event-free survival rate for cardiac death, cardiac death/myocardial infarction, or cardiac death/myocardial infarction/target lesion revascularization was 90.5 +/- 1.6, 85.8 +/- 1.9, and 71.6 +/- 2.5% at 8 years, respectively. Left ventricular dysfunction (ejection fraction < 45%) was an independent predictor of cardiac death (OR: 4.88; 95% CI: 1.81-13.13; P = 0.002). Left ventricular dysfunction and a stent length > 80 mm were significantly related to cardiac death/myocardial infarction. Likewise, a stent length > 80 mm was an independent predictor of cardiac death/myocardial infarction/target lesion revascularization (OR: 2.45; 95% CI: 1.16-5.19; P = 0.019). CONCLUSION: Long-term outcomes appear favorable after FMJ procedures, and left ventricular dysfunction and a stent length > 80 mm are major predictors of major adverse cardiac events. These findings might be useful in identifying the most suitable treatments for patients with very diffuse CAD. (c) 2013 Wiley Periodicals, Inc. PMID- 24150893 TI - Highly enantioselective decarboxylative Mannich reaction of malonic acid half oxyesters with cyclic trifluoromethyl ketimines: synthesis of beta-amino esters and anti-HIV drug DPC 083. PMID- 24150894 TI - Sex and ESR1 genotype may influence the response to treatment with donepezil and rivastigmine in patients with Alzheimer's disease. AB - BACKGROUND: Many factors could be responsible for the different response to treatment with the cholinesterase inhibitors (ChEIs) donepezil and rivastigmine in Alzheimer's disease (AD) patients. Sex and the variants of the estrogen receptor alpha (ESR1) gene are reported to modulate AD susceptibility or the course of the disease. The aim of the present study was to verify whether patient's sex and ESR1 genotype could influence the response to ChEI treatment, as there is evidence that estrogens affect cholinergic system functioning. METHODS: Two ESR1 intronic polymorphisms (PvuII, rs2234693; XbaI, rs9340799) were examined in 184 AD patients: 157 were receiving treatment with donepezil or rivastigmine and 27 were receiving no treatment. Cognitive status was assessed using the mini mental state examination at four time points (1, 3, 9, and 15 months into therapy). RESULTS: Among the patients under treatment with either ChEI, the women responded more markedly than the men. As compared with the untreated patients, the effects of treatment were statistically significant for both donepezil and rivastigmine. A significant effect of ESR1 genotypes was observed for the donepezil-treated patients, among which those carrying at least one copy of P and X alleles showed a significantly lower cognitive decline than the noncarriers. CONCLUSIONS: The present data seem to confirm a sex-related influence on treatment, as the women seemed to be more sensitive to therapy and to have experienced less cognitive decline. ESR1 may be another gene contributing to interindividual variability in response to treatment with ChEIs. PMID- 24150895 TI - Chemically induced magnetism in atomically precise gold clusters. AB - Comparative theoretical and experimental investigations are reported into chemically induced magnetism in atomically-precise, ligand-stabilized gold clusters Au25 , Au38 and Au55 . The results indicate that [Au25 (PPh3 )10 (SC12 H25 )5 Cl2 ](2+) and Au38 (SC12 H25 )24 are diamagnetic, Au25 (SC2 H4 Ph)18 is paramagnetic, and Au55 (PPh3 )12 Cl6 , is ferromagnetic at room temperature. Understanding the magnetic properties resulting from quantum size effects in such atomically precise gold clusters could lead to new fundamental discoveries and applications. PMID- 24150899 TI - Photodynamic chiral molecular switches with thermal stability: from reflection wavelength tuning to handedness inversion of self-organized helical superstructures. AB - A good turn: Three compounds that bear two axially chiral bridged binaphthyl units were developed as photodynamic chiral dopants for nematic liquid crystals. For compounds with suitable bridge lengths, a change in the dihedral angle induced a switch of the binaphthyl units from the cisoid to the transoid form upon UV irradiation, which led to an inversion of the handedness of the helices. PMID- 24150898 TI - Assessment of cellularity, genomic DNA yields, and technical platforms for BRAF mutational testing in thyroid fine-needle aspirate samples. AB - BACKGROUND: BRAF mutation V600E (substitution Val600Glu) is a molecular signature for papillary thyroid carcinoma (PTC). Testing for BRAF mutation is clinically useful in providing prognostic prediction and facilitating accurate diagnosis of PTC in thyroid fine-needle aspirate (FNA) samples. METHODS: This study assessed the correlation of cellularity with DNA yield and compared 2 technical platforms with different sensitivities in detection of BRAF mutation in cytologic specimens. Cellularity was evaluated based on groups of 10+ cells on a ThinPrep slide: 1+ (1-5 groups), 2+ (6-10 groups), 3+ (11-20 groups), and 4+ (> 20 groups). Genomic DNA was extracted from residual materials of thyroid FNAs after cytologic diagnosis. RESULTS: Approximately 49% of thyroid FNA samples had low cellularity (1-2+). DNA yield is proportionate with increased cellularity and increased nearly 4-fold from 1+ to 4+ cellularity in cytologic samples. When applied to BRAF mutational assay, using a cutoff of 6 groups of follicular cells with 10+ cells per group, 96.7% of cases yielded enough DNA for at least one testing for BRAF mutation. Five specimens (11.6%) with lower cellularity did not yield sufficient DNA for duplicate testing. Comparison of Sanger sequencing to allele-specific polymerase chain reaction methods shows the latter confers better sensitivity in detection of BRAF mutation, especially in limited cytologic specimens with a lower percentage of malignant cells. CONCLUSIONS: This study demonstrates that by using 6 groups of 10+ follicular cells as a cutoff, nearly 97% of thyroid FNA samples contain enough DNA for BRAF mutational assay. Careful selection of a molecular testing system with high sensitivity facilitates the successful conduction of molecular testing in limited cytologic specimens. Cancer (Cancer Cytopathol) 2014;122:114-22 (c) 2013 American Cancer Society. PMID- 24150896 TI - Effective delivery of large genes to the retina by dual AAV vectors. AB - Retinal gene therapy with adeno-associated viral (AAV) vectors is safe and effective in humans. However, AAV's limited cargo capacity prevents its application to therapies of inherited retinal diseases due to mutations of genes over 5 kb, like Stargardt's disease (STGD) and Usher syndrome type IB (USH1B). Previous methods based on 'forced' packaging of large genes into AAV capsids may not be easily translated to the clinic due to the generation of genomes of heterogeneous size which raise safety concerns. Taking advantage of AAV's ability to concatemerize, we generated dual AAV vectors which reconstitute a large gene by either splicing (trans-splicing), homologous recombination (overlapping), or a combination of the two (hybrid). We found that dual trans-splicing and hybrid vectors transduce efficiently mouse and pig photoreceptors to levels that, albeit lower than those achieved with a single AAV, resulted in significant improvement of the retinal phenotype of mouse models of STGD and USH1B. Thus, dual AAV trans splicing or hybrid vectors are an attractive strategy for gene therapy of retinal diseases that require delivery of large genes. PMID- 24150900 TI - Synthesis, crystal structure and photophysical properties of pyrene-helicene hybrids. AB - Synthesis of helically chiral aromatics resulting from fusion of pyrene and [4]- or [5]helicene has been accomplished using photoredox catalysis employing a Cu based sensitizer as the key step. Photocyclisation experiments for the synthesis of the target compounds were carried out in batch and using continuous flow strategies. The solid-state structures, UV/Vis absorption spectra and fluorescence spectra of the pyrene-helicene hybrids were investigated and compared to that of the parent [5]helicene to discern the effects of merging a pyrene moiety within a helicene skeleton. The studies demonstrated that pyrene helicene hybrids adopt co-planar or stacked arrangements in the solid state, in contrast to the solid-state structure of the parent [5]helicene. The UV/Vis and fluorescence spectra of the pyrene-helicene hybrids exhibited strong red-shifts when compared to the parent [5]helicene. DFT calculations suggest that the strategy of extending the pi surface in the y axis of the helicenes increased their HOMO levels while also decreasing their LUMO levels, resulting in significantly reduced band gaps. PMID- 24150901 TI - Simultaneous monitoring of intracellular ATP and oxygen levels in chondrogenic differentiation using a dual-color bioluminescence reporter. AB - A number of assay methods which measure cellular metabolic activity have only measured intracellular ATP levels because it has been speculated that ATP production and oxygen consumption are obligatorily coupled to each other under normal conditions. However, there exist many cases in which ATP production and oxygen consumption are uncoupled. Therefore, measurement of only intracellular ATP levels has a limit for understanding the overall metabolic states during various cellular functions. Here, we report a novel system for simultaneously monitoring intracellular ATP and oxygen levels using a red-emitting Phrixothrix hirtus luciferase (PxRe) and a blue-emitting Renilla luciferase (Rluc). Using this system, we monitored the dynamic changes in both intracellular ATP and oxygen levels during chondrogenesis. We found that the oxygen level oscillated at twice the frequency of ATP in chondrogenesis and the oxygen oscillations have an antiphase mode to the ATP oscillations; we also found an independent mode for the ATP oscillations. This result indicates that both mitochondrial and non mitochondrial respiration oscillate and thus play a role in chondrogenesis. This dual-color monitoring system is useful for studying metabolic regulations that underlie diverse cellular processes. PMID- 24150902 TI - Genetic attributes of blood-derived subtype-C HIV-1 tat and env in India and neurocognitive function. AB - Genetic elements in HIV-1 subtype B tat and env are associated with neurotoxicity yet less is known about other subtypes. HIV-1 subtype C tat and env sequences were analyzed to determine viral genetic elements associated with neurocognitive impairment in a large Indian cohort. Population-based sequences of HIV-1 tat (exon 1) and env (C2-V3 coding region) were generated from blood plasma of HIV infected patients in Pune, India. Participants were classified as cognitively normal or impaired based on neuropsychological assessment. Tests for signature residues, positive and negative selection, entropy, and ambiguous bases were performed using tools available through Los Alamos National Laboratory (http://www.hiv.lanl.gov) and Datamonkey (http://www.datamonkey.org). HIV-1 subtype C tat and env sequences were analyzed for 155 and 160 participants, of which 34-36% were impaired. Two signature residues were unique to impaired participants in exon 1 of tat at codons 29 (arginine) and 68 (proline). Positive selection was noted at codon 29 among normal participants and at codon 68 in both groups. The signature at codon 29 was also a signature for low CD4+ (<200 cells/mm(3)) counts but remained associated with impairment after exclusion of those with low CD4+ counts. No unique genetic signatures were noted in env. In conclusion, two signature residues were identified in exon 1 of HIV-1 subtype C tat that were associated with neurocognitive impairment in India and not completely accounted for by HIV disease progression. These signatures support a linkage between diversifying selection in HIV-1 subtype C tat and neurocognitive impairment. PMID- 24150903 TI - Schizophrenia and emotional rubbernecking. AB - Orienting toward emotionally salient information can be adaptive, as when danger needs to be avoided. Consistent with this idea, research has shown that emotionally valenced information draws attention more so than does neutral information in healthy individuals. However, at times this tendency is not adaptive, and it may distract the individual from goals. People with schizophrenia (PSZ), though they frequently show deficits in attentional control, have also been shown to exhibit diminished recognition of and attention to emotional information. In the present study, we investigated how the presentation of emotionally salient information affected performance on a working memory task for PSZ and healthy controls (HC). We found that although hit rates were equal to those of HCs for PSZ, the PSZ made fewer false alarms-resulting in overall better performance-than did the HCs. Deficits in emotional processing in PSZ appear to provide an advantage to them in situations in which salient emotional information competes with active cognitive goals. PMID- 24150904 TI - Computational analysis of local membrane properties. AB - In the field of biomolecular simulations, dynamics of phospholipid membranes is of special interest. A number of proteins, including channels, transporters, receptors and short peptides are embedded in lipid bilayers and tightly interact with phospholipids. While the experimental measurements report on the spatial and/or temporal average membrane properties, simulation results are not restricted to the average properties. In the current study, we present a collection of methods for an efficient local membrane property calculation, comprising bilayer thickness, area per lipid, deuterium order parameters, Gaussian and mean curvature. The local membrane property calculation allows for a direct mapping of the membrane features, which subsequently can be used for further analysis and visualization of the processes of interest. The main features of the described methods are highlighted in a number of membrane systems, namely: a pure dimyristoyl-phosphatidyl-choline (DMPC) bilayer, a fusion peptide interacting with a membrane, voltage-dependent anion channel protein embedded in a DMPC bilayer, cholesterol enriched bilayer and a coarse grained simulation of a curved palmitoyl-oleoyl-phosphatidyl-choline lipid membrane. The local membrane property analysis proves to provide an intuitive and detailed view on the observables that are otherwise interpreted as averaged bilayer properties. PMID- 24150905 TI - Performance of a new thermostable mannanase in breaking guar-based fracturing fluids at high temperatures with little premature degradation. AB - A new thermostable beta-1,4-mannanase (DtManB) cloned from Dictyoglomus thermophilum CGMCC 7283 showed the maximum activity towards hydroxypropyl guar gum at 80 degrees C, with a half-life of 46 h. DtManB exhibited good compatibility with various additives of fracturing fluid, retaining more than 50 % activity in all the cases tested. More importantly, premature degradation could be alleviated significantly when using DtManB as breaker, because at 27 and 50 degrees C it displayed merely 3.7 and 18.5 % activities compared to those at 80 degrees C. In a static test, 0.48 mg DtManB could break 200 mL borax cross-linked fracturing fluid dramatically at 80 degrees C, and merely 18 mPa s of the viscosity was detected even after the broken fluid was cooled down and only 161.4 mg L(-1) of the residue was left after the enzymatic reaction. All these positive features demonstrate the great potential of this mannanase as a new enzyme breaker for application in enhanced recovery of petroleum oil. PMID- 24150906 TI - A two-step, one-pot enzymatic method for preparation of duck egg white protein hydrolysates with high antioxidant activity. AB - Biocatalytic hydrolysis reactions were designed for preparation of bioactive hydrolysate of duck egg white protein (DEWP) employing two enzymes in one pot. Firstly, the fresh DEWP was thermal treated at 95 degrees C, for 40 min at pH 10, to effectively deactivate enzyme inhibitors thus facilitating the following two-step enzymatic hydrolysis. Compared with single-enzyme processes, the two step enzymatic procedures showed much higher reaction efficiency. The first enzymatic step (in the presence of Alcalase or hydrolase SEEP) allowed to hydrolyze DEWP with degree of hydrolysis (DH) of 8.8-10% and soluble peptide yield (SEP) of 60.5-70.2% in a short period (4 h). The second enzymatic step (in the presence of Trypsin or Alcalase) gave a further degradation of DEWP with DH and SEP being more than 26.2% and 90.4%, respectively. The final hydrolysates exhibited high antioxidant activity in an evident DH dependent manner. The hydrolysates achieved by sequential addition of the proteinase SEEP and Alcalase at DH value 21% gave the highest antioxidant activity, which was mainly ascribed to the changes in the amino acid compositions that the contents of some key amino acids and total hydrophobic amino acids were significantly improved by the enzymatic hydrolysis. PMID- 24150907 TI - The importance of contextual factors and age in association with anxiety and depression in Black breast cancer patients. AB - OBJECTIVES: Limited research exists on correlates of psychosocial distress in Black breast cancer patients. The goals of the study were to describe the prevalence of distress (anxiety and depression) in Black women with breast cancer and to examine the influence of demographic, clinical, contextual (e.g., self efficacy, medical mistrust), and process of care factors (e.g., patient satisfaction) on women's level of anxiety and depression. METHODS: Eighty-two Black women diagnosed with invasive non-metastatic breast cancer were interviewed by phone. Collected data included demographic, clinical, contextual, and process of care factors. Bivariate correlations were used to examine relationships between those variables. Multiple linear regressions were used to examine predictors of anxiety and depression. RESULTS: About one-third of the women (32%) met cut-off thresholds for distress. Medical mistrust and positive attitude had significant influences on anxiety levels, whereas age and positive attitude were determinants of levels of depression. Participants with higher medical mistrust reported more anxiety (r = .379; p < .001) and depression (r = .337; p = .002), whereas women with higher self-efficacy reported less anxiety (r = -.401; p < .001) and depression (r = -.427; p < .001). Age was inversely related to both anxiety and depression (r = -.224; r = -.296, respectively; p < .05). CONCLUSIONS: Findings support national recommendations for routine distress screening in the delivery of cancer care particularly in younger Black patients. Interventions targeted to boost self-efficacy or reduce medical mistrust through enhanced patient-provider interactions may decrease psychological distress. Psychosocial needs of younger patients warrant particular attention. PMID- 24150911 TI - Scientists (of the world) behave! PMID- 24150910 TI - Trajectories of quality of life in early-stage dementia: individual variations and predictors of change. AB - BACKGROUND: Little evidence is available about how quality of life (QoL) changes as dementia progresses. OBJECTIVES: We explored QoL trajectories over a 20-month period and examined what predicted change in QoL. METHOD: Fifty-one individuals with a diagnosis of Alzheimer's, vascular or mixed dementia (people with dementia (PwD)) participating in the Memory Impairment and Dementia Awareness Study rated their QoL using the QoL-Alzheimer's Disease Scale at baseline and at 20-month follow-up. PwD also rated their mood and quality of relationship with the carer. In each case, the carer rated his or her level of stress and perceived quality of relationship with the PwD. RESULTS: There was no change in mean QoL score. Nearly one-third of PwD rated QoL more positively at 20-month follow-up and nearly one third rated QoL more negatively. These changes could be regarded as reliable in one-quarter of the sample. Participants taking acetylcholinesterase-inhibiting medication at baseline were more likely to show a decline in QoL score. There were no other significant differences between those whose scores increased, decreased or stayed the same on any demographic or disease-related variables, or in mood or perceived quality of relationship with the carer. Whereas baseline QoL score was the strongest predictor of QoL at 20 months, the quality of relationship with the carer as perceived by the PwD was also independently a significant predictor. CONCLUSIONS: There is a degree of individual variation in QoL trajectories. Use of acetylcholinesterase-inhibiting medication appears linked to decline in QoL score, whereas positive relationships with carers play an important role in maintaining QoL in early-stage dementia. PMID- 24150912 TI - CD138 (syndecan-1) expression in health and disease. AB - CD138 (syndecan-1, Sdc-1) is a member of the syndecan family that comprises heparan sulfate proteoglycans. CD138 is significant for cell-cell and cell-matrix interactions. In adult human tissues, CD138 is predominantly expressed in epithelial cells and plasmacytes. CD138 immunoexpression is altered in a wide spectrum of benign inflammatory, infectious and fibrotic diseases (colitis, allergic contact dermatitis, fibrosis of various organs, etc) and diabetes mellitus type II. Furthermore, CD138 is involved in molecular pathways that are deregulated during carcinogenesis and are related to cell proliferation, apoptosis, angiogenesis, tumour invasion and metastasis. CD138 tumour cell and stromal immunoexpression is modified in various types of cancer, and is frequently correlated with clinico-pathological parameters and patients' prognosis. The soluble form of CD138 may be used as a prognostic serum biomarker with promising results in respiratory tract carcinomas. CD138 plays a crucial role in carcinogenesis and is an attractive target for anticancer treatment with heparanase inhibitors and anti-CD138 antibodies for immunotherapy. PMID- 24150908 TI - Tracking motor impairments in the progression of Huntington's disease. AB - The Unified Huntington's Disease Rating Scale is used to characterize motor impairments and establish motor diagnosis. Little is known about the timing of diagnostic confidence level categories and the trajectory of motor impairments during the prodromal phase. Goals of this study were to estimate the timing of categories, model the prodromal trajectory of motor impairments, estimate the rate of motor impairment change by category, and provide required sample size estimates for a test of efficacy in clinical trials. In total, 1010 gene-expanded participants from the Neurobiological Predictors of Huntington's Disease (PREDICT HD) trial were analyzed. Accelerated failure time models were used to predict the timing of categories. Linear mixed effects regression was used to model the longitudinal motor trajectories. Age and length of gene expansion were incorporated into all models. The timing of categories varied significantly by gene expansion, with faster progression associated with greater expansion. For the median expansion, the third diagnostic confidence level category was estimated to have a first occurrence 1.5 years before diagnosis, and the second and first categories were estimated to occur 6.75 years and 19.75 years before diagnosis, respectively. Motor impairments displayed a nonlinear prodromal course. The motor impairment rate of change increased as the diagnostic confidence level increased, with added acceleration for higher progression scores. Motor items can detect changes in motor impairments before diagnosis. Given a sufficiently high progression score, there is evidence that the diagnostic confidence level can be used for prodromal staging. Implications for Huntington's disease research and the planning of clinical trials of efficacy are discussed. PMID- 24150913 TI - X-ray spectroscopic verification of the active species in iron-catalyzed cross coupling reactions. PMID- 24150914 TI - Histone post-translational modifications in preimplantation mouse embryos and their role in nuclear architecture. AB - In mammals, epigenetic modifications are globally rearranged after fertilization, when gametes fuse to form the embryo. While gametes carry special epigenetic signatures and a unique nuclear organization, they attain embryo-specific patterns after fertilization. This "reprogramming" is promoted by intimate contact between the parental inherited genomes and the oocyte cytoplasm over the first cell cycles of development. Although the mechanisms of this reprogramming remain poorly understood, it appears that the particular epigenetic landscape established after fertilization is essential for further development. This review looks at histone post-translational modifications, focusing on their functions in chromatin organization and their role in nuclear architecture during mouse embryonic development. Epigenetic changes linked to the use of assisted reproductive technologies are also considered. PMID- 24150915 TI - Chirality induction by formation of assembled structures based on anion responsive pi-conjugated molecules. AB - Anion-responsive pi-conjugated compounds having chiral alkyl chains were synthesized. Circular dichroism (CD) and circularly polarized luminescence (CPL) were observed in the solution-state assemblies of the chiral anion receptors and those of their anion complexes as salts of a planar triazatriangulenium cation. The CD and CPL spectral patterns of the ion-pair-based assemblies were completely opposite to those of the anion-free assemblies, and this suggests that anion binding and subsequent ion pairing change the chirality of the assembly modes. PMID- 24150916 TI - Numerical modelling of plasticity induced by transcranial magnetic stimulation. AB - We use neural field theory and spike-timing dependent plasticity to make a simple but biophysically reasonable model of long-term plasticity changes in the cortex due to transcranial magnetic stimulation (TMS). We show how common TMS protocols can be captured and studied within existing neural field theory. Specifically, we look at repetitive TMS protocols such as theta burst stimulation and paired-pulse protocols. Continuous repetitive protocols result mostly in depression, but intermittent repetitive protocols in potentiation. A paired pulse protocol results in depression at short ( < ~ 10 ms) and long ( > ~ 100 ms) interstimulus intervals, but potentiation for mid-range intervals. The model is sensitive to the choice of neural populations that are driven by the TMS pulses, and to the parameters that describe plasticity, which may aid interpretation of the high variability in existing experimental results. Driving excitatory populations results in greater plasticity changes than driving inhibitory populations. Modelling also shows the merit in optimizing a TMS protocol based on an individual's electroencephalogram. Moreover, the model can be used to make predictions about protocols that may lead to improvements in repetitive TMS outcomes. PMID- 24150917 TI - The policy chicken and the science egg. Has applied ecology failed the transgenic crops debate? AB - Ecology has a long history of research relevant to and impacting on real-world issues. Nonetheless problems of communication remain between policy-makers and scientists because they tend to work at different levels of generality (policy deals with broad issues, science prefers specific questions), and complexity (policy-makers want simple answers, ecologists tend to offer multi-factorial solutions) and to different timescales (policy-makers want answers tomorrow, ecologists always seem to want more time). These differences are not unique to the debate about the cultivation of transgenic crops. Research on gene flow is used to illustrate how science and policy are intimately bound together in a value-laden, iterative and messy process unlike that characterised by the 'encounter problem-do science-make policy' model. It also demonstrates how the gap between science and policy is often characterised by value-laden language. Scientists involved in ERA for transgenic crops may find their engagement with policy- and decision-makers clouded by misunderstanding about what one should expect from the other. Not the least of these, that science can define harm, is explored in a discussion of the U.K. Farm Scale Evaluations of herbicide-tolerant GM crops. The varied responses to these extensive trials highlight the problems of linking specific scientific experiments with broad policy objectives. The problems of applied ecology in the transgenic crops debate are not unique but may differ from other areas of environmental policy in the intense politicisation of the debate, the emphasis on assessment of risk and the particularly broad policy objectives. PMID- 24150918 TI - GM crops, the environment and sustainable food production. AB - Today, over 7.1 billion people rely on the earth's resources for sustenance, and nearly a billion people are malnourished, their minds and bodies unable to develop properly. Globally, population is expected to rise to more than 9 billion by 2050. Given the combined pressures of human population growth, the rapidly growing desire for increased levels of consumption, and the continued use of inappropriate technologies, it is not surprising that humans are driving organisms to extinction at an unprecedented rate. Many aspects of the sustainable functioning of the natural world are breaking down in the face of human-induced pressures including our individual and collective levels of consumption and our widespread and stubborn use of destructive technologies. Clearly, agriculture must undergo a redesign and be better and more effectively managed so as to contribute as well as possible to feeding people, while at the same time we strive to lessen the tragic loss of biodiversity and damage to all of its productive systems that the world is experiencing. For GM crops to be part of the solution, biosafety assessments should not be overly politically-driven or a burdensome impedance to delivering this technology broadly. Biosafety scientists and policy makers need to recognize the undeniable truth that inappropriate actions resulting in indecision also have negative consequences. It is no longer acceptable to delay the use of any strategy that is safe and will help us achieve the ability to feed the world's people. PMID- 24150919 TI - Diffusion MRI in the diagnosis of parkinsonism and tremor. PMID- 24150920 TI - In vivo volumetric photoacoustic molecular angiography and therapeutic monitoring with targeted plasmonic nanostars. AB - Photoacoustic (PA) imaging promises deeper tissue penetration while maintaining rich optical contrast as compared to other high resolution optical imaging techniques. In this report, a near-infrared pulse laser serves as the excitation source, and 128 ultrasonic transducers are spirally distributed on a hemispherical surface to receive PA signals for three-dimensional (3D) image reconstruction. With these attributes, the unique modality produces an isotropic and homogeneous spatial resolution (~200 MUm) with penetration depth of centimeters. Cyclic Arg-Gly-Asp (RGD) peptides conjugated plasmonic gold nanostars (RGD-GNS) are designed to specifically target over-expressed integrin alpha(v)beta3 on tumor neovasculature, enabling highly sensitive angiography and photothermal therapy (PTT). After the administration of RGD-GNS, tumor angiogenesis is clearly imaged with enhanced contrast, and the growth of tumor is effectively inhibited by PTT after laser irradiation. This study suggest that the PA angiography with plasmonic RGD-GNS can be applied as a triple functional platform for tumor diagnosis, PTT, and treatment monitoring. This PA technique offers deeper imaging depth with homogeneous resolution over existing optical imaging techniques for early diagnosis of tumor angiogenesis as well as on-the spot nanotherapeutic evaluation. PMID- 24150921 TI - The adaptation of the Affective Norms for English Words (ANEW) for Italian. AB - We developed affective norms for 1,121 Italian words in order to provide researchers with a highly controlled tool for the study of verbal processing. This database was developed from translations of the 1,034 English words present in the Affective Norms for English Words (ANEW; Bradley & Lang, 1999) and from words taken from Italian semantic norms (Montefinese, Ambrosini, Fairfield, & Mammarella, Behavior Research Methods, 45, 440-461, 2013). Participants evaluated valence, arousal, and dominance using the Self-Assessment Manikin (SAM) in a Web survey procedure. Participants also provided evaluations of three subjective psycholinguistic indexes (familiarity, imageability, and concreteness), and five objective psycholinguistic indexes (e.g., word frequency) were also included in the resulting database in order to further characterize the Italian words. We obtained a typical quadratic relation between valence and arousal, in line with previous findings. We also tested the reliability of the present ANEW adaptation for Italian by comparing it to previous affective databases and performing split half correlations for each variable. We found high split-half correlations within our sample and high correlations between our ratings and those of previous studies, confirming the validity of the adaptation of ANEW for Italian. This database of affective norms provides a tool for future research about the effects of emotion on human cognition. PMID- 24150922 TI - The "hands together" method of nonsterile scalpel blade mounting and removal. AB - Scalpels are utilized by many different user groups for such purposes as medical procedures and dissection. Injuries caused by scalpels are a potential risk for scalpel users, and include injuries that may occur while mounting and removing the scalpel blade. Between 10% and 20% of all scalpel injuries in education and healthcare settings are reported to occur while scalpel blades are being mounted or removed. At present there are few published or "best practice" demonstrations of safe technique for scalpel blade mounting and removal. This brief article outlines a variation of the procedure for scalpel blade mounting and removal. It includes strategies developed to minimize risk or injury for the scalpel user, including providing a stable base for the hands and arms so as to prevent unnecessary large amplitude movements that may lead to injury of the scalpel user or a third party. Such a technique may promote scalpel safety, contribute to the development of "best practice" scalpel use, and help decrease injuries that may be caused while mounting or removing scalpel blades. PMID- 24150923 TI - Selenium, zinc, and copper plasma levels in patients with schizophrenia: relationship with metabolic risk factors. AB - The aim of this study was to determine the plasma selenium (Se), copper (Cu), and zinc (Zn) levels and to evaluate their possible association with metabolic syndrome (MetS) components in patients with schizophrenia. The study group consisted of 60 patients with schizophrenia and 60 sex- and age-matched healthy controls. Anthropometric measurements, blood pressure, and biochemical analysis of fasting blood were performed in all subjects. Patients with schizophrenia had significantly higher plasma Cu concentrations compared with controls (0.97 +/- 0.31 vs. 0.77 +/- 0.32 mg/L, p = 0.001). The plasma Cu concentration showed a positive correlation with plasma glucose and diastolic blood pressure in the patient groups (r s = 0.263, p < 0.05 and r s = 0.272, p < 0.05, respectively). The plasma Se level correlated positive with MetS score (r s = 0.385, p < 0.01), waist circumference (r s = 0.344, p < 0.05), plasma glucose (r s = 0.319, p < 0.05), and triglyceride concentrations (r s = 0.462, p < 0.001) in patients with schizophrenia. Plasma Zn did not correlate with any of the MetS components. These results suggest that alterations in plasma Cu and Se levels in medicated patients with schizophrenia could be associated with metabolic risk factors. PMID- 24150924 TI - Comparative efficacies of fluoxetine and paroxetine in major depression across varying acute-phase treatment periods: a meta-analysis. AB - INTRODUCTION: Previous studies have shown that varying acute-phase treatment periods of fluoxetine and paroxetine can result in varying antidepressive effects. We therefore did a meta-analysis to ascertain the efficacy of fluoxetine versus paroxetine for depression by varying acute-phase treatment periods. METHODS: PubMed, CCTR, Web of Science, Embase, CBM-disc, and CNKI were searched up to March 2013. The key search terms were "depression," "paroxetine," and "fluoxetine." No language restriction was imposed. RESULTS: We included 17 studies with 3,110 patients. Three treatment period subgroups were created: 6, 8/10, and 12 weeks. In the 6-week subgroup, paroxetine was more efficacious than fluoxetine (odds ratio [OR]: 0.74; P < 0.05). In the 8/10-week subgroup, two drugs displayed comparative efficacy (OR, 0.85; P > 0.05). In the 12-week subgroup, fluoxetine was more efficacious than paroxetine (OR: 1.25; P < 0.05). There were no significant differences in acceptability. Significant heterogeneity and potential publication bias did not exist. CONCLUSIONS: Patients' economic conditions, individual preference, and side effects of fluoxetine and paroxetine can be obstacles of successful treatment. Inappropriate acute-phase treatment, such as inadequate treatment periods, may result in pseudoresistance. Clinicians should take these information into consideration when prescribe fluoxetine or paroxetine for patients. Our results can aid clinicians in making an optimal treatment plan to increase odds of response. PMID- 24150925 TI - Risk of colorectal cancer and adenomas in the families of patients with adenomas: a population-based study in Utah. AB - BACKGROUND: Guidelines recommend that individuals with a first-degree relative (FDR) diagnosed with colorectal cancer (CRC) or advanced adenoma before age 60 years should undergo colonoscopy starting at age 40 years. The authors quantified the risk of adenomas and CRC in FDRs, second-degree relatives (SDRs), and third degree relatives (TDRs) of patients diagnosed with adenomas and advanced adenomas. METHODS: A population-based, retrospective, case-control study was performed of residents of the state of Utah aged 50 years to 80 years who underwent colonoscopy between 1995 and 2009 at Intermountain Healthcare or the University of Utah. Controls were selected from the population of colonoscopy patients who were free of adenomas or CRC and matched to each case based on sex and birth year. Colonoscopy results were linked with cancer and pedigree information from the Utah Population Database to investigate the familial aggregation of adenomas and CRC using Cox regression analysis. The unit of analysis was the relatives of cases and controls. RESULTS: Of 126,936 patients who underwent colonoscopy, 43,189 had adenomas and 5563 had advanced adenomas and defined the case population. An elevated risk of CRC was found in FDRs (relative risk [RR], 1.35; 95% confidence interval [95% CI], 1.25-1.46), SDRs (RR, 1.15; 95% CI, 1.07-1.23) of adenoma cases, and in FDRs of advanced adenoma cases (RR, 1.68; 95% CI, 1.29-2.18) compared with controls. Approximately 10% of CRCs diagnosed in relatives would have been missed if the current screening guidelines were strictly adhered to. CONCLUSIONS: Relatives of colonoscopy patients with adenomas and advanced adenomas appear to have a significantly elevated risk of developing colorectal neoplasia. These data should be considered when establishing CRC screening guidelines for individuals and their families. PMID- 24150926 TI - Hemagglutinin and neuraminidase genes of influenza B viruses circulating in Riyadh, Saudi Arabia during 2010-2011: evolution and sequence analysis. AB - Influenza viruses are known as continuing threats to human public health every year worldwide. Evolutionary dynamics of influenza B viruses in humans are in a unique progression having two lineages; B/Yam and B/Vic-like viruses, which are circulating simultaneously worldwide. There is a considerable lack of data on influenza B viruses circulating in Saudi Arabia. During the winter-spring season of 2010-2011, 80 nasopharyngeal aspirates were collected from hospitalized patients with flu-like symptoms in Riyadh. Screening of samples by one-step RT PCR identified three (3.8%) influenza B viruses. Sequencing of hemagglutinin (HA) and neuraminidase (NA) genes was performed to analyze influenza B viruses circulating in Riyadh as compared to the globally circulating strains. Several common and six unique amino acid substitutions were observed for both HA and NA genes of influenza B Saudi strains. Three unique substitutions (T182A, D196N, and K254R) were identified in HA gene of the B/Yam-like Riyadh strains. In NA gene, a unique common substitution (D53G) was found in all Riyadh strains, while two unique substitutions (L38P, G233R) were recognized only in B/Vic-like Riyadh strains. Riyadh strains were also found to contain N-glycosylation site in HA gene of both B/Vic and B/Yam lineages at positions 197-199 (NET) and 196-198 (NNK/DNK), respectively. The significance of these mutations on the antigenicity of both lineages is discussed herein. The unique changes observed in HA and NA genes of influenza B Riyadh strains support strongly the need for continuous surveillance and monitoring of new evolving strains that might pose threat to the Saudi community. PMID- 24150927 TI - Randomized, placebo-controlled study to assess the impact on QT/QTc interval of supratherapeutic doses of ceftazidime-avibactam or ceftaroline fosamil-avibactam. AB - Potential effects of supratherapeutic doses of intravenous (IV) ceftazidime avibactam and ceftaroline fosamil-avibactam on cardiac repolarization were assessed in a thorough QT/QTc study. This was a double-blind, randomized, placebo controlled, four-period crossover Phase I study (NCT01290900) in healthy males (n = 51). Subjects received, in randomized order and separated by >=3 days washout: single doses of IV ceftaroline fosamil 1,500 mg with avibactam 2,000 mg; IV ceftazidime 3,000 mg with avibactam 2,000 mg; oral moxifloxacin 400 mg (open label positive control); and IV placebo (saline). Least square mean and two-sided 90% confidence intervals (CI) for change from baseline in Fridericia-corrected QT interval (DeltaQTcF) for active treatments versus placebo were estimated at 10 time points over 24 hours. The upper bound of the two-sided 90% CI for placebo corrected DeltaQTcF did not exceed 10 milliseconds at any time point over 24 hours for ceftaroline fosamil-avibactam or ceftazidime-avibactam. The lower bound of the two-sided 90% CI for the difference between moxifloxacin and placebo in DeltaQTcF over 1-4 hours was >5 milliseconds, confirming assay sensitivity. Pharmacokinetics results confirmed achievement of supratherapeutic plasma concentrations. No safety concerns were raised. In conclusion, supratherapeutic doses of ceftaroline fosamil-avibactam or ceftazidime-avibactam were not associated with QT/QTc prolongation in this study population. PMID- 24150928 TI - CASP10 results compared to those of previous CASP experiments. AB - We compare results of the community efforts in modeling protein structures in the tenth CASP experiment, with those in earlier CASPs particularly in CASP5, a decade ago. There is a substantial improvement in template based model accuracy as reflected in more successful modeling of regions of structure not easily derived from a single experimental structure template, most likely reflecting intensive work within the modeling community in developing methods that make use of multiple templates, as well as the increased number of experimental structures available. Deriving structural information not obvious from a template is the most demanding as well as one of the most useful tasks that modeling can perform. Thus this is gratifying progress. By contrast, overall backbone accuracy of models appears little changed in the last decade. This puzzling result is explained by two factors--increased database size in some ways makes it harder to choose the best available templates, and the increased intrinsic difficulty of CASP targets as experimental work has progressed to larger and more unusual structures. There is no detectable recent improvement in template-free modeling, but again, this may reflect the changing nature of CASP targets. PMID- 24150929 TI - Cancer-related fatigue in breast cancer patients after surgery: a multicomponent model using partial least squares-path modeling. AB - OBJECTIVE: The aim of this study is to examine factors contributing to cancer related fatigue (CRF) in breast cancer patients who have undergone surgery. METHODS: Sixty women (mean age: 50.0) completed self-rated questionnaires assessing components of CRF, muscular and cognitive functions. Also, physiological and subjective data were gathered. Data were analyzed using partial least squares variance-based structural equation modeling in order to examine factors contributing to CRF after breast surgery. RESULTS: The tested model was robust in terms of its measurement quality (reliability and validity). According to the structural model results, emotional distress (beta = 0.59; p < 0.001), pain (beta = 0.23; p < 0.05), and altered vigilance (beta = 0.30; p < 0.05) were associated with CRF, accounting for 61% of the explained variance. Also, emotional distress (beta = 0.41; p < 0.05) and pain (beta = 0.40; p < 0.05) were related to low physical function and accounted for 41% of the explained variance. However, the relationship between low physical function and CRF was weak and nonsignificant (beta = 0.01; p > 0.05). CONCLUSION: Emotional distress, altered vigilance capacity, and pain are associated with CRF in postsurgical breast cancer. In addition, emotional distress and pain are related to diminished physical function, which, in turn, has no significant impact on CRF. The current model should be examined in subsequent phases of the treatment (chemotherapy and/or radiotherapy) when side effects are more pronounced and may lead to increased intensity of CRF and low physical function. PMID- 24150930 TI - The DEKA Arm: its features, functionality, and evolution during the Veterans Affairs Study to optimize the DEKA Arm. AB - BACKGROUND AND AIM: DEKA Integrated Solutions Corp. (DEKA) was charged by the Defense Advanced Research Project Agency to design a prosthetic arm system that would be a dramatic improvement compared with the existing state of the art. The purpose of this article is to describe the two DEKA Arm prototypes (Gen 2 and Gen 3) used in the Veterans Affairs Study to optimize the DEKA Arm. TECHNIQUE: This article reports on the features and functionality of the Gen 2 and Gen 3 prototypes discussing weight, cosmesis, grips, powered movements Endpoint, prosthetic controls, prosthetist interface, power sources, user notifications, troubleshooting, and specialized socket features; pointing out changes made during the optimization efforts. DISCUSSION: The DEKA Arm is available in three configurations: radial configuration, humeral configuration, and shoulder configuration. All configurations have six preprogrammed grip patterns and four wrist movements. The humeral configuration has four powered elbow movements. The shoulder configuration uses Endpoint Control to perform simultaneous multi-joint movements. Three versions of foot controls were used as inputs. The Gen 3 incorporated major design changes, including a compound wrist that combined radial deviation with wrist flexion and ulnar deviation with wrist extension, an internal battery for the humeral configuration and shoulder configuration, and embedded wrist display. CLINICAL RELEVANCE: The DEKA Arm is an advanced upper limb prosthesis, not yet available for commercial use. It has functionality that surpasses currently available technology. This manuscript describes the features and functionality of two prototypes of the DEKA Arm, the Gen 2 and the Gen 3. PMID- 24150931 TI - Longitudinal kinematic and kinetic adaptations to obstacle crossing in recent lower limb amputees. AB - BACKGROUND: Obstacle crossing is an important activity of daily living, necessary to avoid tripping or falling, although it is not fully understood how transtibial amputees adapt to performing this activity of daily living following discharge from rehabilitation. OBJECTIVES: The objective of this study was to investigate the longitudinal adaptations in obstacle crossing in transtibial amputees post discharge from rehabilitation. STUDY DESIGN: Longitudinal repeated measures. METHODS: Seven unilateral transtibial amputees crossed an obstacle 0.1m high positioned along a walkway while kinematic and kinetic data were recorded at 1, 3 and 6 months post-discharge. RESULTS: At 6 months post-discharge, walking velocity had increased (0.17 m.s(-1)) with most participants self-selecting an intact lead limb preference. During swing phase, peak knee flexion (p = 0.03) and peak knee power absorption (K4; p = 0.01) were greater with an intact versus affected lead limb preference. Having crossed the obstacle, intact limb peak ankle power generation in pre-swing (A2; p = 0.01) and knee power absorption (K3; p = 0.05) during stance phase were greater when compared to the affected limb. CONCLUSIONS: Obstacle crossing improved, although a greater reliance on intact limb function was highlighted. Results suggested that further improvements to locomotor performance may be obtained by increasing affected limb knee range of motion and concentric and eccentric strength of the knee extensors and flexors. CLINICAL RELEVANCE: The novel objective data from this study establish an understanding of how recent transtibial amputees adapt to performing obstacle crossing following discharge from rehabilitation. This allows for evidence-based clinical interventions to be developed, aimed at optimising biomechanical function, thus improving overall locomotor performance and perhaps subsequent quality of life. PMID- 24150932 TI - Extending the Stetter reaction with 1,6-acceptors. PMID- 24150933 TI - Synergistic effect of ketone and hydroperoxide in Bronsted acid catalyzed oxidative coupling reactions. PMID- 24150934 TI - The epigenetics of early development: inferences from stem cells. AB - Approximately 200 cell types and multiple tissues are established throughout the development of the zygote to an adult mammal. During this process, the cellular genome remains fixed, yet the transcriptome of each of the cell types become widely divergent. This review discusses the epigenetics of preimplantation embryos and the use of embryonic stem cells (ESCs) and epiblast stem cells (EpiSCs) as cell-culture models for the inner cell mass (ICM) and epiblast, respectively. Differential patterns of transcription are set up during development by the action of key transcription factors and epigenetics, which are involved in the establishment and maintenance of stable transcriptional states during development. In early embryos, for example, changes in the epigenome consist of alterations to the methylation of CpG dinucleotides and post translational modification of histones within chromatin. In addition, histone replacement occurs broadly in zygotes. The ICM of the blastocyst, on the other hand, has the amazing ability to contribute to every tissue and cell type present in the adult body. Therefore, ESCs are arguably the most important cell-culture model available to developmental biologists. The advantages and risks of using ESCs to model ICM pluripotency are therefore discussed. PMID- 24150935 TI - Multiple myeloma-associated hDIS3 mutations cause perturbations in cellular RNA metabolism and suggest hDIS3 PIN domain as a potential drug target. AB - hDIS3 is a mainly nuclear, catalytic subunit of the human exosome complex, containing exonucleolytic (RNB) and endonucleolytic (PIN) active domains. Mutations in hDIS3 have been found in ~10% of patients with multiple myeloma (MM). Here, we show that these mutations interfere with hDIS3 exonucleolytic activity. Yeast harboring corresponding mutations in DIS3 show growth inhibition and changes in nuclear RNA metabolism typical for exosome dysfunction. Construction of a conditional DIS3 knockout in the chicken DT40 cell line revealed that DIS3 is essential for cell survival, indicating that its function cannot be replaced by other exosome-associated nucleases: hDIS3L and hRRP6. Moreover, HEK293-derived cells, in which depletion of endogenous wild-type hDIS3 was complemented with exogenously expressed MM hDIS3 mutants, proliferate at a slower rate and exhibit aberrant RNA metabolism. Importantly, MM mutations are synthetically lethal with the hDIS3 PIN domain catalytic mutation both in yeast and human cells. Since mutations in PIN domain alone have little effect on cell physiology, our results predict the hDIS3 PIN domain as a potential drug target for MM patients with hDIS3 mutations. It is an interesting example of intramolecular synthetic lethality with putative therapeutic potential in humans. PMID- 24150936 TI - Evolution of CRISPR RNA recognition and processing by Cas6 endonucleases. AB - In many bacteria and archaea, small RNAs derived from clustered regularly interspaced short palindromic repeats (CRISPRs) associate with CRISPR-associated (Cas) proteins to target foreign DNA for destruction. In Type I and III CRISPR/Cas systems, the Cas6 family of endoribonucleases generates functional CRISPR-derived RNAs by site-specific cleavage of repeat sequences in precursor transcripts. CRISPR repeats differ widely in both sequence and structure, with varying propensity to form hairpin folds immediately preceding the cleavage site. To investigate the evolution of distinct mechanisms for the recognition of diverse CRISPR repeats by Cas6 enzymes, we determined crystal structures of two Thermus thermophilus Cas6 enzymes both alone and bound to substrate and product RNAs. These structures show how the scaffold common to all Cas6 endonucleases has evolved two binding sites with distinct modes of RNA recognition: one specific for a hairpin fold and the other for a single-stranded 5'-terminal segment preceding the hairpin. These findings explain how divergent Cas6 enzymes have emerged to mediate highly selective pre-CRISPR-derived RNA processing across diverse CRISPR systems. PMID- 24150937 TI - LoQAtE--Localization and Quantitation ATlas of the yeast proteomE. A new tool for multiparametric dissection of single-protein behavior in response to biological perturbations in yeast. AB - Living organisms change their proteome dramatically to sustain a stable internal milieu in fluctuating environments. To study the dynamics of proteins during stress, we measured the localization and abundance of the Saccharomyces cerevisiae proteome under various growth conditions and genetic backgrounds using the GFP collection. We created a database (DB) called 'LoQAtE' (Localizaiton and Quantitation Atlas of the yeast proteomE), available online at http://www.weizmann.ac.il/molgen/loqate/, to provide easy access to these data. Using LoQAtE DB, users can get a profile of changes for proteins of interest as well as querying advanced intersections by either abundance changes, primary localization or localization shifts over the tested conditions. Currently, the DB hosts information on 5330 yeast proteins under three external perturbations (DTT, H2O2 and nitrogen starvation) and two genetic mutations [in the chaperonin containing TCP1 (CCT) complex and in the proteasome]. Additional conditions will be uploaded regularly. The data demonstrate hundreds of localization and abundance changes, many of which were not detected at the level of mRNA. LoQAtE is designed to allow easy navigation for non-experts in high-content microscopy and data are available for download. These data should open up new perspectives on the significant role of proteins while combating external and internal fluctuations. PMID- 24150938 TI - GEISHA: an evolving gene expression resource for the chicken embryo. AB - GEISHA (Gallus Expression In Situ Hybridization Analysis; http://geisha.arizona.edu) is an in situ hybridization gene expression and genomic resource for the chicken embryo. This update describes modifications that enhance its utility to users. During the past 5 years, GEISHA has undertaken a significant restructuring to more closely conform to the data organization and formatting of Model Organism Databases in other species. This has involved migrating from an entry-centric format to one that is gene-centered. Database restructuring has enabled the inclusion of data pertaining to chicken genes and proteins and their orthologs in other species. This new information is presented through an updated user interface. In situ hybridization data in mouse, frog, zebrafish and fruitfly are integrated with chicken genomic and expression information. A resource has also been developed that integrates the GEISHA interface information with the Online Mendelian Inheritance in Man human disease gene database. Finally, the Chicken Gene Nomenclature Committee database and the GEISHA database have been integrated so that they draw from the same data resources. PMID- 24150939 TI - Mechanistic insights into the role of Hop2-Mnd1 in meiotic homologous DNA pairing. AB - The Hop2-Mnd1 complex functions with the DMC1 recombinase in meiotic recombination. Hop2-Mnd1 stabilizes the DMC1-single-stranded DNA (ssDNA) filament and promotes the capture of the double-stranded DNA partner by the recombinase filament to assemble the synaptic complex. Herein, we define the action mechanism of Hop2-Mnd1 in DMC1-mediated recombination. Small angle X-ray scattering analysis and electron microscopy reveal that the heterodimeric Hop2-Mnd1 is a V shaped molecule. We show that the protein complex harbors three distinct DNA binding sites, and determine their functional relevance. Specifically, the N terminal double-stranded DNA binding functions of Hop2 and Mnd1 co-operate to mediate synaptic complex assembly, whereas ssDNA binding by the Hop2 C-terminus helps stabilize the DMC1-ssDNA filament. A model of the Hop2-Mnd1-DMC1-ssDNA ensemble is proposed to explain how it mediates homologous DNA pairing in meiotic recombination. PMID- 24150940 TI - DECIPHER: database for the interpretation of phenotype-linked plausibly pathogenic sequence and copy-number variation. AB - The DECIPHER database (https://decipher.sanger.ac.uk/) is an accessible online repository of genetic variation with associated phenotypes that facilitates the identification and interpretation of pathogenic genetic variation in patients with rare disorders. Contributing to DECIPHER is an international consortium of >200 academic clinical centres of genetic medicine and >=1600 clinical geneticists and diagnostic laboratory scientists. Information integrated from a variety of bioinformatics resources, coupled with visualization tools, provides a comprehensive set of tools to identify other patients with similar genotype phenotype characteristics and highlights potentially pathogenic genes. In a significant development, we have extended DECIPHER from a database of just copy number variants to allow upload, annotation and analysis of sequence variants such as single nucleotide variants (SNVs) and InDels. Other notable developments in DECIPHER include a purpose-built, customizable and interactive genome browser to aid combined visualization and interpretation of sequence and copy-number variation against informative datasets of pathogenic and population variation. We have also introduced several new features to our deposition and analysis interface. This article provides an update to the DECIPHER database, an earlier instance of which has been described elsewhere [Swaminathan et al. (2012) DECIPHER: web-based, community resource for clinical interpretation of rare variants in developmental disorders. Hum. Mol. Genet., 21, R37-R44]. PMID- 24150941 TI - The double PHD finger domain of MOZ/MYST3 induces alpha-helical structure of the histone H3 tail to facilitate acetylation and methylation sampling and modification. AB - Histone tail modifications control many nuclear processes by dictating the dynamic exchange of regulatory proteins on chromatin. Here we report novel insights into histone H3 tail structure in complex with the double PHD finger (DPF) of the lysine acetyltransferase MOZ/MYST3/KAT6A. In addition to sampling H3 and H4 modification status, we show that the DPF cooperates with the MYST domain to promote H3K9 and H3K14 acetylation, although not if H3K4 is trimethylated. Four crystal structures of an extended DPF alone and in complex with unmodified or acetylated forms of the H3 tail reveal the molecular basis of crosstalk between H3K4me3 and H3K14ac. We show for the first time that MOZ DPF induces alpha-helical conformation of H3K4-T11, revealing a unique mode of H3 recognition. The helical structure facilitates sampling of H3K4 methylation status, and proffers H3K9 and other residues for modification. Additionally, we show that a conserved double glycine hinge flanking the H3 tail helix is required for a conformational change enabling docking of H3K14ac with the DPF. In summary, our data provide the first observations of extensive helical structure in a histone tail, revealing the inherent ability of the H3 tail to adopt alternate conformations in complex with chromatin regulators. PMID- 24150942 TI - Phosphorylation of a C-terminal auto-inhibitory domain increases SMARCAL1 activity. AB - SMARCAL1 promotes the repair and restart of damaged replication forks. Either overexpression or silencing SMARCAL1 causes the accumulation of replication associated DNA damage. SMARCAL1 is heavily phosphorylated. Here we identify multiple phosphorylation sites, including S889, which is phosphorylated even in undamaged cells. S889 is highly conserved through evolution and it regulates SMARCAL1 activity. Specifically, S889 phosphorylation increases the DNA stimulated ATPase activity of SMARCAL1 and increases its ability to catalyze replication fork regression. A phosphomimetic S889 mutant is also hyperactive when expressed in cells, while a non-phosphorylatable mutant is less active. S889 lies within a C-terminal region of the SMARCAL1 protein. Deletion of the C terminal region also creates a hyperactive SMARCAL1 protein suggesting that S889 phosphorylation relieves an auto-inhibitory function of this SMARCAL1 domain. Thus, S889 phosphorylation is one mechanism by which SMARCAL1 activity is regulated to ensure the proper level of fork remodeling needed to maintain genome integrity during DNA synthesis. PMID- 24150943 TI - Integrated omics study delineates the dynamics of lipid droplets in Rhodococcus opacus PD630. AB - Rhodococcus opacus strain PD630 (R. opacus PD630), is an oleaginous bacterium, and also is one of few prokaryotic organisms that contain lipid droplets (LDs). LD is an important organelle for lipid storage but also intercellular communication regarding energy metabolism, and yet is a poorly understood cellular organelle. To understand the dynamics of LD using a simple model organism, we conducted a series of comprehensive omics studies of R. opacus PD630 including complete genome, transcriptome and proteome analysis. The genome of R. opacus PD630 encodes 8947 genes that are significantly enriched in the lipid transport, synthesis and metabolic, indicating a super ability of carbon source biosynthesis and catabolism. The comparative transcriptome analysis from three culture conditions revealed the landscape of gene-altered expressions responsible for lipid accumulation. The LD proteomes further identified the proteins that mediate lipid synthesis, storage and other biological functions. Integrating these three omics uncovered 177 proteins that may be involved in lipid metabolism and LD dynamics. A LD structure-like protein LPD06283 was further verified to affect the LD morphology. Our omics studies provide not only a first integrated omics study of prokaryotic LD organelle, but also a systematic platform for facilitating further prokaryotic LD research and biofuel development. PMID- 24150944 TI - HRaP: database of occurrence of HomoRepeats and patterns in proteomes. AB - We focus our attention on multiple repeats of one amino acid (homorepeats) and create a new database (named HRaP, at http://bioinfo.protres.ru/hrap/) of occurrence of homorepeats and disordered patterns in different proteomes. HRaP is aimed at understanding the amino acid tandem repeat function in different proteomes. Therefore, the database includes 122 proteomes, 97 eukaryotic and 25 bacterial ones that can be divided into 9 kingdoms and 5 phyla of bacteria. The database includes 1,449,561 protein sequences and 771,786 sequences of proteins with GO annotations. We have determined homorepeats and patterns that are associated with some function. Through our web server, the user can do the following: (i) search for proteins with the given homorepeat in 122 proteomes, including GO annotation for these proteins; (ii) search for proteins with the given disordered pattern from the library of disordered patterns constructed on the clustered Protein Data Bank in 122 proteomes, including GO annotations for these proteins; (iii) analyze lengths of homorepeats in different proteomes; (iv) investigate disordered regions in the chosen proteins in 122 proteomes; (v) study the coupling of different homorepeats in one protein; (vi) determine longest runs for each amino acid inside each proteome; and (vii) download the full list of proteins with the given length of a homorepeat. PMID- 24150945 TI - Functional characterization of the common c.-32-13T>G mutation of GAA gene: identification of potential therapeutic agents. AB - Glycogen storage disease type II is a lysosomal storage disorder due to mutations of the GAA gene, which causes lysosomal alpha-glucosidase deficiency. Clinically, glycogen storage disease type II has been classified in infantile and late-onset forms. Most late-onset patients share the leaky splicing mutation c.-32-13T>G. To date, the mechanism by which the c.-32-13T>G mutation affects the GAA mRNA splicing is not fully known. In this study, we demonstrate that the c.-32-13T>G mutation abrogates the binding of the splicing factor U2AF65 to the polypyrimidine tract of exon 2 and that several splicing factors affect exon 2 inclusion, although the only factor capable of acting in the c.-32-13 T>G context is the SR protein family member, SRSF4 (SRp75). Most importantly, a preliminary screening using small molecules described to be able to affect splicing profiles, showed that resveratrol treatment resulted in a significant increase of normal spliced GAA mRNA, GAA protein content and activity in cells transfected with a mutant minigene and in fibroblasts from patients carrying the c-32-13T>G mutation. In conclusion, this work provides an in-depth functional characterization of the c.-32-13T>G mutation and, most importantly, an in vitro proof of principle for the use of small molecules to rescue normal splicing of c. 32-13T>G mutant alleles. PMID- 24150946 TI - Staphylococcus aureus protein SAUGI acts as a uracil-DNA glycosylase inhibitor. AB - DNA mimic proteins are unique factors that control the DNA binding activity of target proteins by directly occupying their DNA binding sites. The extremely divergent amino acid sequences of the DNA mimics make these proteins hard to predict, and although they are likely to be ubiquitous, to date, only a few have been reported and functionally analyzed. Here we used a bioinformatic approach to look for potential DNA mimic proteins among previously reported protein structures. From ~14 candidates, we selected the Staphylococcus conserved hypothetical protein SSP0047, and used proteomic and structural approaches to show that it is a novel DNA mimic protein. In Staphylococcus aureus, we found that this protein acts as a uracil-DNA glycosylase inhibitor, and therefore named it S. aureus uracil-DNA glycosylase inhibitor (SAUGI). We also determined and analyzed the complex structure of SAUGI and S. aureus uracil-DNA glycosylase (SAUDG). Subsequent BIAcore studies further showed that SAUGI has a high binding affinity to both S. aureus and human UDG. The two uracil-DNA glycosylase inhibitors (UGI and p56) previously known to science were both found in Bacillus phages, and this is the first report of a bacterial DNA mimic that may regulate SAUDG's functional roles in DNA repair and host defense. PMID- 24150947 TI - Structures of bacterial polynucleotide kinase in a Michaelis complex with GTP*Mg2+ and 5'-OH oligonucleotide and a product complex with GDP*Mg2+ and 5'-PO4 oligonucleotide reveal a mechanism of general acid-base catalysis and the determinants of phosphoacceptor recognition. AB - Clostridium thermocellum polynucleotide kinase (CthPnk), the 5' end-healing module of a bacterial RNA repair system, catalyzes reversible phosphoryl transfer from an NTP donor to a 5'-OH polynucleotide acceptor. Here we report the crystal structures of CthPnk-D38N in a Michaelis complex with GTP*Mg(2+) and a 5'-OH oligonucleotide and a product complex with GDP*Mg(2+) and a 5'-PO4 oligonucleotide. The O5' nucleophile is situated 3.0 A from the GTP gamma phosphorus in the Michaelis complex, where it is coordinated by Asn38 and is apical to the bridging beta phosphate oxygen of the GDP leaving group. In the product complex, the transferred phosphate has undergone stereochemical inversion and Asn38 coordinates the 5'-bridging phosphate oxygen of the oligonucleotide. The D38N enzyme is poised for catalysis, but cannot execute because it lacks Asp38-hereby implicated as the essential general base catalyst that abstracts a proton from the 5'-OH during the kinase reaction. Asp38 serves as a general acid catalyst during the 'reverse kinase' reaction by donating a proton to the O5' leaving group of the 5'-PO4 strand. The acceptor strand binding mode of CthPnk is distinct from that of bacteriophage T4 Pnk. PMID- 24150949 TI - A p-quinodimethane-bridged porphyrin dimer. AB - A p-quinodimethane (p-QDM)-bridged porphyrin dimer 1 has been prepared for the first time. An unexpected Michael addition reaction took place when we attempted to synthesize compound 1 by reaction of the cross-conjugated keto-linked porphyrin dimers 8a and 8b with alkynyl/aryl Grignard reagents. Alternatively, compound 1 could be successfully prepared by intramolecular Friedel-Crafts alkylation of the diol-linked porphyrin dimer 14 with concomitant oxidation in air. Compound 1 shows intense one-photon absorption (OPA, lambda(max)=955 nm, epsilon=45400 M(-1) cm(-1)) and a large two-photon absorption (TPA) cross-section (sigma((2))(max)=2080 GM at 1800 nm) in the near-infrared (NIR) region due to its extended pi-conjugation and quinoidal character. It also exhibits a short singlet excited-state lifetime of 25 ps. The cyclic voltammogram of 1 displays multiple redox waves with a small electrochemical energy gap of 0.86 eV. The ground-state geometry, electronic structure, and optical properties of 1 have been further studied by density functional theory (DFT) calculations and compared with those of the keto-linked dimer 8b. This research has revealed that incorporation of a p QDM unit into the porphyrin framework had a significant impact on its optical and electronic properties, leading to a novel NIR OPA and TPA chromophore. PMID- 24150948 TI - The natural anticancer compound rocaglamide selectively inhibits the G1-S-phase transition in cancer cells through the ATM/ATR-mediated Chk1/2 cell cycle checkpoints. AB - Targeting the cancer cell cycle machinery is an important strategy for cancer treatment. Cdc25A is an essential regulator of cycle progression and checkpoint response. Over-expression of Cdc25A occurs often in human cancers. In this study, we show that Rocaglamide-A (Roc-A), a natural anticancer compound isolated from the medicinal plant Aglaia, induces a rapid phosphorylation of Cdc25A and its subsequent degradation and, thereby, blocks cell cycle progression of tumor cells at the G1-S phase. Roc-A has previously been shown to inhibit tumor proliferation by blocking protein synthesis. In this study, we demonstrate that besides the translation inhibition Roc-A can induce a rapid degradation of Cdc25A by activation of the ATM/ATR-Chk1/Chk2 checkpoint pathway. However, Roc-A has no influence on cell cycle progression in proliferating normal T lymphocytes. Investigation of the molecular basis of tumor selectivity of Roc-A by a time resolved microarray analysis of leukemic vs. proliferating normal T lymphocytes revealed that Roc-A activates different sets of genes in tumor cells compared with normal cells. In particular, Roc-A selectively stimulates a set of genes responsive to DNA replication stress in leukemic but not in normal T lymphocytes. These findings further support the development of Rocaglamide for antitumor therapy. PMID- 24150950 TI - [Validation of the ice pack test in ophthalmoparesis due to myasthenia gravis]. AB - INTRODUCTION: Myasthenia gravis is an autoimmune disease of the neuromuscular junction that presents clinically as fluctuating weakness of skeletal muscles, as of the ocular region (myasthenia ocular). AIM: To demonstrate that the sensitivity and specificity of the ice pack test are high, in the differential diagnosis of palpebral ptosis and ophthalmoparesis for myasthenia gravis and myasthenia ocular. SUBJECTS AND METHODS: Observational, analytical, and non randomized study of 43 subjects, 21 with myasthenia gravis and 22 controls. All patients received a glove with ice on your upper eyelids affected for 2 minutes, after which we assessed the degree of improvement in palpebral ptosis and ophthalmoparesis. All patients had repetitive nerve stimulation study. RESULTS: We analyzed 36 patients, 18 patients with myasthenia gravis or myasthenia ocular and 18 controls. All patients had palpebral ptosis but ophthalmoparesis only 20 of them. Ice pack test for ophthalmoparesis showed a sensitivity of 83%, specificity 100%, positive predictive value (PPV) of 100% and negative predictive value (NPV) of 80% in the diagnosis of myasthenia gravis. Ice pack test for palpebral ptosis was determined a sensitivity of 89%, specificity 100%, PPV of 100% and NPV of 90%. For repetitive nerve stimulation was calculated a sensitivity of 61%, specificity of 83%, PPV of 79% and NPV of 68%. CONCLUSION: Ice pack test, both palpebral ptosis and ophthalmoparesis is a simple test, safe, cheap, fast and reliable to be used routinely in patients suspected of palpebral ptosis and/or ophthalmoparesis due to myasthenia gravis, and which has a high validity, safety, and reproducibility as a diagnostic test. PMID- 24150951 TI - [Relationship between memory complaints and memory performance, mood and sociodemographic variables in young adults]. AB - INTRODUCTION: Neurological consultations due to memory complaints have increased in recent years in both older and younger people. Few investigations have studied the variables related to memory complaints in young adults. AIM: To analyze, in a sample of young adults, the relationship between memory complaints and objective memory performance, depressive and anxiety symptoms, age, sex and level of studies. SUBJECTS AND METHODS: The study included 582 healthy workers, without cognitive impairment, aged 22-64 years. ASSESSMENT: Word List and Family Scenes of Wechsler Memory Scale-III, Memory Failures of Everyday Questionnaire (MFE) and Goldberg Anxiety and Depression Scale. RESULTS: We did not find any significant association between subjective assessment of memory and objective performance, both immediate and delayed in verbal and visual memory. Depression and anxiety had the highest correlation with MFE. The significant variables in the multiple regression analysis were: depression, with the largest effect size, age, college studies and sex. CONCLUSION: In young adults, those which had a greater perception of daily forgetfulness were not those with lesser memory performance. The most important variables involved in memory complaints were depression and anxiety. Younger people, people with college education and men reported less memory complaints. PMID- 24150952 TI - [Anti-N-methyl-D-aspartate (NMDA) receptor encephalitis: experience with six pediatric patients. Potential efficacy of methotrexate]. AB - INTRODUCTION. Anti-N-methyl-D-aspartate (NMDA) receptor encephalitis is a condition that is increasingly more frequently diagnosed in the paediatric age. Unlike adults, in many cases it is not associated to tumours and the most common initial manifestations in children are seizures and movement disorders, while in adults there is a predominance of psychiatric alterations. CASE REPORTS. We present six confirmed paediatric cases with antibodies against the subunit NR1 of the NMDA receptor in serum and cerebrospinal fluid. Five of the cases began with seizures as the initial clinical symptom prior to the development of the classical clinical features of this condition. In all cases, steroids were used as the first line of treatment, although these only brought about control over the manifestations in one of them; the other patients therefore required second line immunomodulators. All the patients received methotrexate as immunomodulator treatment to prevent relapses, and in all cases there was an improvement in the patients' situation. CONCLUSIONS. In our series of patients with anti-NMDA receptor encephalitis, none were associated with tumours. All of them were given methotrexate for at least one year and no adverse clinical or analytical events were observed; likewise, there were no neurological sequelae or relapses during treatment. Although it is a small series and it would be advisable to increase the number and time to progression, we see methotrexate as an excellent alternative immunomodulator treatment for this pathology. PMID- 24150953 TI - [Practical issues with the use of rivaroxaban]. AB - Rivaroxaban is an oral highly selective direct factor Xa inhibitor. Rivaroxaban is currently approved for the prevention of venous thromboembolism in adult patients undergoing elective hip or knee replacement surgery, for the treatment of deep vein thrombosis and pulmonary embolism and long-term secondary prevention of venous thromboembolism, and for stroke and systemic embolism prevention in patients with nonvalvular atrial fibrillation. Rivaroxaban has many advantages over vitamin K antagonists and this may facilitate its use in clinical practice. As a result, it is expected that new oral anticoagulants may change patient management strategies. On the other hand, rivaroxaban has some particularities that are necessary to know. The aim of this manuscript was to review the use of rivaroxaban not only in general population, but also in specific patients groups and clinical situations to achieve an optimal management with this drug in daily clinical practice. PMID- 24150955 TI - [Microdeletion 2q23.1 and syndromic findings]. PMID- 24150956 TI - [From theory to practice: spin labeling MRI]. PMID- 24150957 TI - [Visibility in neuropaediatrics]. PMID- 24150958 TI - SIMIFF study: Italian fungal registry of mold infections in hematological and non hematological patients. AB - PURPOSE: We compared the risk factors, the diagnostic tools and the outcome of filamentous fungal infections (FFIs) in hematological patients (HAEs) and non hematological patients (non-HAEs). METHODS: Prospective surveillance (2009-2011) of proven and probable FFIs was implemented in 23 Italian hospitals. RESULTS: Out of 232 FFIs, 113 occurred in HAEs and 119 in non-HAEs. The most frequent infection was invasive aspergillosis (76.1 % for HAEs, 56.3 % for non-HAEs), and the localization was principally pulmonary (83.2 % for HAEs, 74.8 % for non HAEs). Neutropenia was a risk factor for 89.4 % HAEs; the main underlying condition was corticosteroid treatment (52.9 %) for non-HAEs. The distribution of proven and probable FFIs was different in the two groups: proven FFIs occurred more frequently in non-HAEs, whereas probable FFIs were correlated with the HAEs. The sensitivity of the galactomannan assay was higher for HAEs than for non-HAEs (95.3 vs. 48.1 %). The overall mortality rate was 44.2 % among the HAEs and 35.3 % among the non-HAEs. The etiology influenced the patient outcomes: mucormycosis was associated with a high mortality rate (57.1 % for HAEs, 77.8 % for non-HAEs). CONCLUSIONS: The epidemiological and clinical data for FFIs were not identical in the HAEs and non-HAEs. The differences should be considered to improve the management of FFIs according to the patients' setting. PMID- 24150959 TI - The 2009 pandemic influenza A(H1N1) coincides with changes in the epidemiology of other viral pathogens causing acute respiratory tract infections in children. AB - BACKGROUND: In Germany, the outbreak of the novel pandemic 2009 influenza A(H1N1) virus A(H1N1)pdm09 caused a wave of high activity between November 2009 and January 2011. The aim of this study was to investigate the prevalence of 19 respiratory pathogens in children hospitalized for lower respiratory tract infections during the winter influenza seasons of 2009/2010 and 2010/2011 and to observe a possible impact of influenza A(H1N1)pdm09 on the epidemiology of other epidemic viruses. MATERIALS AND METHODS: Specimens were nasopharyngeal aspirates which had been collected from children admitted to the participating hospitals in the area of Mainz, Wiesbaden, and Kiel, Germany, with acute community-acquired lower respiratory tract infections. The specimens were subjected to a previously described multiplex reverse transcription PCR assay to detect the following microorganisms: enterovirus, influenza virus types A and B, respiratory syncytial virus (RSV), parainfluenzavirus types 1-4, adenovirus, Mycoplasma pneumoniae, Chlamydophila pneumoniae, rhinovirus, human metapneumovirus (hMPV), coronavirus OC43 and 229E, influenza A(H1N1)pdm09, Bordetella pertussis, Bordetella parapertussis, and Legionella pneumophila. RESULTS: A total of 3,998 clinical specimens were collected from July 2009 to March 2011, of which 296 were positive for A(H1N1)pdm09. An epidemic of seasonal influenza A or B was not observed in the 2009/2010 season, but a minor epidemic of seasonal influenza B was observed in January/February 2011. Influenza A(H1N1)pdm09 coincided with the absence of the seasonal influenza A of former years. The RSV and hMPV epidemics of 2009/2010 erupted several weeks later than expected based on data collected in the PID-ARI Network during the past 10 years, whereas in the 2010/2011 influenza season they occurred as expected. CONCLUSIONS: The emergence of the novel influenza A(H1N1)pdm09 virus may have been influenced the epidemiology of other epidemic viruses, such as the RSV and hMPV. No epidemic of seasonal influenza was observed in the 2009/2010 influenza season. PMID- 24150960 TI - Motor cortex acquires a pivotal role in levodopa-induced dyskinesia pathophysiology. PMID- 24150961 TI - Diagnosis and phylogenetic analysis of ovine pulmonary adenocarcinoma in China. AB - Ovine pulmonary adenocarcinoma (OPA) is a lung tumor of sheep caused by jaagsiekte sheep retrovirus (JSRV). OPA is common in sheep, and it is most commonly observed in China. Without preventative vaccines and serological diagnostic tools for assay of OPA, identification of JSRV based on reverse transcription polymerase chain reaction (RT-PCR) is very important for prevention and control measures for OPA in practice management. In this study, the diagnosis of OPA was made from analysis of clinical signs, pathological observations, JSRV like particle discovery, and RT-PCR of the target env gene. The phylogenetic analysis showed that the China Shandong (SD) strain studied in this article belonged to exogenous JSRV, and it was very similar to 92k3, which was isolated from sheep in the Kenya (Y18305). The current study reported a severe outbreak of OPA in Shandong Province, China. The observations could offer a comparative view of the env gene of JSRV. PMID- 24150962 TI - Effect of periodic pacemaker optimization on left atrial reverse remodeling in long-term cardiac resynchronization therapy. AB - PURPOSE: Few data exist about the effect of cardiac resynchronization therapy (CRT) on left atrial (LA) reverse remodeling and function, and whether echocardiographic (echo)-guide pacemaker optimization of atrioventricular and interventricular delays could beneficially affect LA reverse remodeling in long term CRT therapy. METHODS: Effect of periodic pacemaker optimization on LA reverse remodeling induced by CRT was analyzed in 113 consecutive patients (mean age, 60 +/- 11 years) and stratified according to periodic pacemaker optimization (group 1) and nonperiodic pacemaker optimization (group 2). Left atrial volumes index percent changes were assessed at every continuing 6-month follow-up visit. The primary endpoint was LA reverse remodeling. The secondary endpoint included left ventricular reverse remodeling and left ventricular ejection fraction. RESULTS: There is no significant difference of follow-up duration in subgroups (42.43 +/- 18.94 months in group 1 vs 37.76 +/- 20.24 months in group 2, p = 0.228). The responder's rate of subgroups showed similar after follow-up of 12 months (60.0 vs 53.2%, p = 0.483). After 24-month follow-up, the mean reduction of LAV index was similar in two groups (10.34 vs 7.53%, p = 0.257). The improvement effect of LA reverse remodeling induced by CRT was sustained during 24-month follow-up to the end of current study in periodic pacemaker optimization group. The degree of LAV index percent reduction was directly correlated to periodic pacemaker optimization at end of current analysis (17.13 vs 10.35%, p = 0.047). CONCLUSIONS: Periodic echo-guide pacemaker optimization of atrioventricular and interventricular delays plays a positive role on LA reverse remodeling in long-term CRT therapy. PMID- 24150963 TI - Internet communication of outpatients with Asperger's disorder or schizophrenia in Japan. AB - INTRODUCTION: There is insufficient information about the Internet usage of psychiatric patients. The aim of this study is to investigate the usage of Internet communication among subjects with Asperger's disorder (AD) or schizophrenia. METHODS: A questionnaire survey was carried out in Japan among 29 outpatients with AD, 32 outpatients with schizophrenia, and 97 age-matched normal volunteers. This study limited the participants to young male adults (20- to 39 year-olds) using the Internet. RESULTS: People with a diagnosis of AD prefer personal computers to mobile phones as their Internet terminal, have an inclination to use anonymous media, and tend to think that they can communicate more correctly through the Internet than face-to-face communication. People with a diagnosis of schizophrenia employ the Internet to a degree almost similar to controls, and tend to rely on unknown persons, but also sometimes feel hurt when communicating on the Internet. Moreover, their sensitivity to the risks of the Internet tends to decrease with the aggravation of their psychotic symptoms. DISCUSSION: It may be important to pay attention to the excessive use of some limited media by people with a diagnosis of AD. Providing people with a diagnosis of schizophrenia with sufficient information about the risks of the Internet is also important. PMID- 24150964 TI - C-Met in invasive breast cancer: is there a relationship with the basal-like subtype? AB - BACKGROUND: Basal-like (BL) breast cancer is an aggressive form of breast cancer with limited treatment options. Recent work has identified BL breast cancer as a biologically distinct form of triple-negative breast cancer, with a worse outlook. The receptor tyrosine kinase c-Met is a novel therapeutic target associated with reduced survival in breast cancer. Few studies have specifically addressed the association between c-Met and molecular subtype of breast cancer, yet this is a key consideration when selecting patients for clinical trials. The aim of this study is to evaluate c-Met expression in a large cohort of invasive breast cancers and in particular, its correlation with molecular subtype. METHODS: Immunohistochemistry for c-Met was performed and evaluated on 1274 invasive breast cancers using tissue microarray technology. The c-Met scores were correlated with molecular subtype, survival, and other standard clinicopathological prognostic factors. RESULTS: Multivariate logistic regression showed c-Met was independently associated with BL status (odds ratio=6.44, 95% confidence interval=1.74-23.78, P=.005). There was a positive correlation between c-Met and Her2 (P=.005) and an inverse correlation with tumor size (P<.001). C Met was an independent poor prognostic factor at Cox regression analysis in all subtypes (hazard ratio=1.85, 95% confidence interval=1.07-3.19, P=.027) and there was a trend toward reduced survival in BL tumors overexpressing c-Met, but this was not significant. CONCLUSIONS: C-Met is independently associated with BL breast cancer. In the future, patients with BL tumors should be included in clinical trials of anti-c-Met therapy. PMID- 24150965 TI - Post-mortem CT findings in a case of necrotizing cellulitis of the floor of the mouth (Ludwig angina). AB - Ludwig angina is a rare but potentially lethal infection of the submandibular space that can cause significant upper airway obstruction. We report a case of undiagnosed Ludwig angina that progressed rapidly to death. Ludwig angina was suspected after post-mortem computed tomography (PMCT) found swollen mylohyoid muscle with stranding in subcutaneous fat, thickening of deep fascia, and local lymphadenopathy. Subsequently, an autopsy revealed woody induration of the submental region and liquefactive necrosis of the mylohyoid muscle, confirming the diagnosis. It is likely that the dental abscess identified on PMCT was the source of infection. Multiple invasive medical procedures were performed on the subject by the ambulance crew prior to his death. PMCT assisted further in determining procedural success. PMID- 24150968 TI - Analysis of brazilin and protosappanin B in sappan lignum by capillary zone electrophoresis with acid barrage stacking. AB - A method was developed to determine brazilin and protosappanin B in natural products by CE after acid barrage stacking. The optimum conditions were as follows: a BGE of 20 mM sodium tetraborate (pH 9.2) containing 6% v/v of methanol, hydrodynamic injection (0.5 psi, 65 s) followed by hydrodynamic injection of 150 mM citric acid (pH 2.3; 0.5 psi, 22 s), and separated with +25 kV. Under these conditions, brazilin and protosappanin B were separated with a sample-to-sample time less than 13 min and detection limits of 0.28 MUg/mL and 0.15 MUg/mL, respectively. The applicability of the developed method was demonstrated by the detection of brazilin and protosappanin in methanol extract of sappan lignum. PMID- 24150969 TI - Stereotype threat can both enhance and impair older adults' memory. AB - Negative stereotypes about aging can impair older adults' memory via stereotype threat; however, the mechanisms underlying this phenomenon are unclear. In two experiments, we tested competing predictions derived from two theoretical accounts of stereotype threat: executive-control interference and regulatory fit. Older adults completed a working memory test either under stereotype threat about age-related memory declines or not under such threat. Monetary incentives were manipulated such that recall led to gains or forgetting led to losses. The executive-control-interference account predicts that stereotype threat decreases the availability of executive-control resources and hence should impair working memory performance. The regulatory-fit account predicts that threat induces a prevention focus, which should impair performance when gains are emphasized but improve performance when losses are emphasized. Results were consistent only with the regulatory-fit account. Although stereotype threat significantly impaired older adults' working memory performance when remembering led to gains, it significantly improved performance when forgetting led to losses. PMID- 24150971 TI - Temperature effects on the hydrodynamic radius of the intrinsically disordered N terminal region of the p53 protein. AB - Intrinsically disordered proteins (IDPs) are often characterized in terms of the hydrodynamic radius, Rh . The Rh of IDPs are known to depend on fractional proline content and net charge, where increased numbers of proline residues and increased net charge cause larger Rh . Though sequence and charge effects on the Rh of IDPs have been studied, the temperature sensitivity has been noted only briefly. Reported here are Rh measurements in the temperature range of 5-75 degrees C for the intrinsically disordered N-terminal region of the p53 protein, p53(1-93). Of note, the Rh of this protein fragment was highly sensitive to temperature, decreasing from 35 A at 5 degrees C to 26 A at 75 degrees C. Computer generated simulations of conformationally dynamic and disordered polypeptide chains were performed to provide a hypothesis for the heat-induced compaction of p53(1-93) structure, which was opposite to the heat-induced increase in Rh observed for a model folded protein. The simulations demonstrated that heat caused Rh to trend toward statistical coil values for both proteins, indicating that the effects of heat on p53(1-93) structure could be interpreted as thermal denaturation. The simulation data also predicted that proline content contributed minimally to the native Rh of p53(1-93), which was confirmed by measuring Rh for a substitution variant that had all 22 proline residues changed for glycine. PMID- 24150970 TI - General and practical carboxyl-group-directed remote C-H oxygenation reactions of arenes. PMID- 24150972 TI - Uvular injury during the perioperative period in patients undergoing general anesthesia. AB - OBJECTIVE: The purpose of this study was to evaluate the incidence and causes of uvular injury in the patients that received general anesthesia in the perioperative period. STUDY DESIGN: A 4-year retrospective review of cases of uvular injury and their resolution was conducted in adult patients who received general anesthesia at our institution. METHODS: An extensive review was conducted of the quality assurance (QA) database maintained by the Department of Anesthesiology at our tertiary academic medical center. The database was searched for cases of uvular injury that occurred in adult patients undergoing general anesthesia that between January 2007 and December 2010. The medical records of identified patients were then obtained to evaluate the presentation, treatment and ultimate resolution of injury. RESULTS: Ten cases of uvular injury were reported in the 28,788 general anesthetics conducted over a 3-year period in adult patients. This correlates to an incidence of 0.034%. Uvular injury occurred in mostly male patients (80%) during elective cases in the supine position. All cases were associated with endotracheal intubation. Additional objects, such as gastric tubes and esophageal temperature probes, were placed in the pharynx of 80% of these patients. Urologic procedures were associated with 50% of reported cases. Treatment ranged from observation to medical therapy. There were no permanent symptoms in any of the patients. CONCLUSION: Uvular injury is a relatively rare complication that occurs in patients during the perioperative period who receive general anesthesia. While endotracheal intubation is closely associated with this type of injury, further study is required to elucidate the mechanism and other associated etiologic factors. PMID- 24150973 TI - Pediatric palliative care: using miniature chairs to facilitate communication. AB - Good communication is essential but sometimes challenging in pediatric palliative care. We describe 3 cases whereby miniature chairs made of various materials and colors were used successfully to encourage communication among pediatric patients, family, and health care professionals. This chair-inspired model may serve as a simple tool to facilitate complex discussions and to enable self expression by children in the pediatric palliative care setting. PMID- 24150974 TI - Effect of human adipose tissue-derived mesenchymal-stem-cell bioactive materials on porcine embryo development. AB - Human adipose tissue-derived mesenchymal stem cells (hAT-MSCs) secrete bioactive materials that are beneficial for tissue repair and regeneration. In this study, we characterized human hAT-MSC bioactive material (hAT-MSC-BM), and examined the effect of hAT-MSC-BM on porcine embryo development. hAT-MSC-BM was enriched with several growth factors and cytokines, including fibroblast growth factor 2 (FGF2), vascular endothelial growth factor A (VEGFA), and interleukin 6 (IL6). Among the various concentrations and days of treatment tested, 10% hAT-MSC-BM treatment beginning on culture Day 4 provided the best environment for the in vitro growth of parthenogenetic porcine embryos. While the addition of 10% fetal bovine serum (FBS) increased the hatching rate and the total cell number of parthenogenetic porcine embryos compared with the control and hAT-MSC culture medium group, the best results were from the group cultured with 10% hAT-MSC-BM. Mitochondrial activity was also higher in the 10% hAT-MSC-BM-treated group. Moreover, the relative mRNA expression levels of development and anti-apoptosis genes were significantly higher in the 10% hAT-MSC-BM-treated group than in control, hAT-MSC culture medium, or 10% FBS groups, whereas the transcript abundance of an apoptosis gene was slightly lower. Treatment with 10% hAT-MSC-BM starting on Day 4 also improved the development rate and the total cell number of in vitro-fertilized embryos. This is the first report on the benefits of hAT-MSC BM in a porcine embryo in vitro culture system. We conclude that hAT-MSC-BM is a new, alternative supplement that can improve the development of porcine embryos during both parthenogenesis and fertilization in vitro. PMID- 24150975 TI - Transfer of chirality in the rhodium-catalyzed intramolecular [5+2] cycloaddition of 3-acyloxy-1,4-enynes (ACEs) and alkynes: synthesis of enantioenriched bicyclo[5.3.0]decatrienes. AB - Chiral bicycles: Enantioenriched bicyclo[5.3.0]decatrienes were prepared from readily available chiral 3-acyloxy-1,4-enynes (ACEs) for the first time. In most cases, the chirality of the ACEs could be transferred to the bicyclic products with high efficiency. Inversion of the configuration was observed, thus confirming the predictions of previous computational studies. PMID- 24150976 TI - Is the thrombus truly free-floating? A case report. AB - A free-floating thrombus in the left atrium is very rare in mitral stenosis. Such a thrombus can lead to sudden circulatory arrest and syncope or can cause severe cerebral or peripheral thromboembolic events. Clinical diagnosis is difficult, but left atrial thrombus should be suspected if patients with mitral stenosis and atrial fibrillation have intermittent or changing murmurs, emboli, or syncope. We describe the case of a patient with mild mitral stenosis under warfarin therapy, and a left atrial pedunculated thrombus discovered during the investigation for syncope attacks. PMID- 24150977 TI - Annexin A4-conferred platinum resistance is mediated by the copper transporter ATP7A. AB - Although platinum drugs are often used for the chemotherapy of human cancers, platinum resistance is a major issue and may preclude their use in some cases. We recently reported that enhanced expression of Annexin A4 (Anx A4) increases chemoresistance to carboplatin through increased extracellular efflux of the drug. However, the precise mechanisms underlying that chemoresistance and the relationship of Anx A4 to platinum resistance in vivo remain unclear. In this report, the in vitro mechanism of platinum resistance induced by Anx A4 was investigated in endometrial carcinoma cells (HEC1 cells) with low expression of Anx A4. Forced expression of Anx A4 in HEC1 cells resulted in chemoresistance to platinum drugs. In addition, HEC1 control cells were compared with Anx A4 overexpressing HEC1 cells in xenografted mice. Significantly greater chemoresistance to cisplatin was observed in vivo in Anx A4-overexpressing xenografted mice. Immunofluorescence analysis revealed that exposure to platinum drugs induced relocation of Anx A4 from the cytoplasm to the cellular membrane, where it became colocalized with ATP7A, a copper transporter also well known as a mechanism of platinum efflux. ATP7A expression suppressed by small interfering RNA had no effect on HEC1 control cells in terms of chemosensitivity to platinum drugs. However, suppression of ATP7A in Anx A4-overexpressing platinum-resistant cells improved chemosensitivity to platinum drugs (but not to 5-fluorouracil) to a level comparable to that of control cells. These results indicate that enhanced expression of Anx A4 confers platinum resistance by promoting efflux of platinum drugs via ATP7A. PMID- 24150978 TI - Ordered mesoporous Fe-porphyrin-like architectures as excellent cathode materials for the oxygen reduction reaction in both alkaline and acidic media. AB - Iron ORR: An ordered, mesoporous, Fe-porphyrin-like material was created through the nanocasting and pyrolysis of traditional Fe-N4 porphyrins. The resulting nonprecious metal electrocatalyst was used for the oxygen reduction reaction in both alkaline and acidic media. PMID- 24150979 TI - Intraoperative dopamine release during globus pallidus internus stimulation in Parkinson's disease. AB - BACKGROUND: It is still unclear whether dopamine (DA) levels correlate with Parkinson's disease (PD) severity or play a role in the mechanisms of high frequency stimulation (HFS). METHODS: We have used microdialysis to record pallidal DA in 5 patients with PD undergoing microelectrode-guided pallidotomy. RESULTS: We found that patients with more severe disease and, consequently, lower pallidal DA did poorly after pallidal lesions. In the operating room, 4 of 5 patients had a significant increase in DA levels during HFS (600%, on average). To test the hypothesis that DA was important for the effects of stimulation, we correlated the amelioration in rigidity observed in the operating room with pallidal DA release. Though rigidity was 56% better during stimulation, no correlation was found between such an improvement and DA release. CONCLUSIONS: These findings suggest that additional mechanisms not directly dependent on pallidal DA release may be involved in the clinical effects of HFS of the globus pallidus internus. PMID- 24150980 TI - Genetically engineered humanized mouse models for preclinical antibody studies. AB - The use of genetic engineering has vastly improved our capabilities to create animal models relevant in preclinical research. With the recent advances in gene editing technologies, it is now possible to very rapidly create highly tunable mouse models as needs arise. Here, we provide an overview of genetic engineering methods, as well as the development of humanized neonatal Fc receptor (FcRn) models and their use for monoclonal antibody in vivo studies. PMID- 24150981 TI - Metal leaching, acidity, and altitude confine benthic macroinvertebrate community composition in Andean streams. AB - Andean streams drain metal-rich bedrock and are subjected to an extreme altitude gradient, which may create highly selective conditions for life. The aim of the present study was to evaluate the combined effects of metals and altitude on benthic macroinvertebrate community composition in Andean streams. Metal-rich sites were characterized by high metal concentrations and low pH, and high altitude sites were characterized by high ultraviolet-B radiation and low concentrations of dissolved organic matter. Canonical correspondence analysis indicated that the patterns in faunal composition were best explained by metals followed by altitude, with dipterans and collembolans occurring mostly under harsh conditions of high altitude and high metal levels. Interaction between metals and altitude was most evident at metal-rich sites. It is suggested that in Andean streams, metal leaching from igneous rock and altitude may be important factors confining benthic macroinvertebrate communities, reducing their numbers and changing their composition toward specialized taxa. PMID- 24150982 TI - Single dose oral celecoxib for acute postoperative pain in adults. AB - BACKGROUND: This is an update of a review first published in The Cochrane Library in Issue 4, 2008, and updated in Issue 3, 2012. Celecoxib is a selective cyclo oxygenase-2 (COX-2) inhibitor usually prescribed for the relief of chronic pain in osteoarthritis and rheumatoid arthritis. Celecoxib is believed to be associated with fewer upper gastrointestinal adverse effects than conventional non-steroidal anti-inflammatory drugs (NSAIDs). Its effectiveness in acute pain was demonstrated in the earlier reviews. OBJECTIVES: To assess analgesic efficacy and adverse effects of a single oral dose of celecoxib for moderate to severe postoperative pain in adults. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, the Oxford Pain Database, and ClinicalTrials.gov. The most recent search was to 31 May 2013. SELECTION CRITERIA: We included randomised, double-blind, placebo-controlled trials (RCTs) of adults prescribed any dose of oral celecoxib or placebo for acute postoperative pain. DATA COLLECTION AND ANALYSIS: Two review authors assessed studies for quality and extracted data. We converted summed pain relief (TOTPAR) or pain intensity difference (SPID) into dichotomous information, yielding the number of participants with at least 50% pain relief over four to six hours. We used this to calculate the relative benefit (RB) and number needed to treat to benefit (NNT), for one patient to achieve at least 50% of maximum pain relief with celecoxib who would not have done so with placebo. We used information on use of rescue medication to calculate the proportion of participants requiring rescue medication and the weighted mean of the median time to use. MAIN RESULTS: Ten studies (1785 participants) met the inclusion criteria. The two new studies in this update had been identified in the earlier update, but data were not available. There remain three potentially relevant unpublished studies for which data are not available at this time.The NNT for celecoxib 200 mg and 400 mg compared with placebo for at least 50% of maximum pain relief over four to six hours was 4.2 (95% confidence interval (CI) 3.4 to 5.6) and 2.6 (95% CI 2.3 to 3.0) respectively. The median time to use of rescue medication was 6.6 hours with celecoxib 200 mg, 8.4 hours with celecoxib 400 mg, and 2.3 hours with placebo. The proportion of participants requiring rescue medication over 24 hours was 74% with celecoxib 200 mg, 63% for celecoxib 400 mg, and 91% for placebo. The NNT to prevent one patient using rescue medication was 4.8 (95% CI 3.5 to 7.7) and 3.5 (95% CI 2.9 to 4.6) for celecoxib 200 mg and 400 mg respectively. Adverse events were generally mild to moderate in severity, and were experienced by a similar proportion of participants in the celecoxib and placebo groups. One serious adverse event that was probably related to celecoxib was reported. AUTHORS' CONCLUSIONS: Single-dose oral celecoxib is an effective analgesic for postoperative pain relief. Indirect comparison suggests that the 400 mg dose has similar efficacy to ibuprofen 400 mg. PMID- 24150983 TI - Synthesis, characterization and cytocompatibility of a degradable polymer using ferric catalyst for esophageal tissue engineering. AB - This study focused on the synthesis, characterization and cytocompatibility of a biodegradable polymer by the cross-linking from poly(ethylene glycol-co-lactide) dimethacrylate (PLEGDMA), polyethylene glycol diacrylate (PEGDA) and N isopropylacrylamide, where PLEGDMA was synthesized by ring-opening oligomerization of poly(ethylene glycol) with different molecular weights (Mn = 400, 600, 1000, 2000 Da) and L-lactide using low toxic iron(III) acetylacetonate (Fe(acac)3) as the catalyst and subsequently being terminated with dimethacrylate. The product, PLEGDMA, was analyzed to confirm its chemistry using FTIR spectroscopy, (1)H NMR spectra and gel permeation chromatography etc. The thermodynamic properties, mechanical behaviors, surface hydrophilicity, degradability and cytotoxicity of the cross-linked product were evaluated by differential scanning calorimetry, tensile tests, contact angle measurements and cell cultures. The effects of reaction variables such as PEGDA content and reactants ratio were optimized to achieve a material with low glass transition temperature (Tg), high wettability and preferable mechanical characteristics. Using a tubular mould which has been patented in our group, a tubular scaffold with predetermined dimension and pattern was fabricated, which aims at guiding the growth and phenotype regulation of esophageal primary cells like fibroblast and smooth muscle cell towards fabricating tissue engineered esophagus in future. PMID- 24150984 TI - Photoactive hybrid gelators based on a luminescent inorganic [Cu4I4] cluster core. PMID- 24150985 TI - Characterization of a bacteriocin produced by Lactococcus lactis subsp. lactis CRL 1584 isolated from a Lithobates catesbeianus hatchery. AB - Lactococcus lactis CRL 1584 isolated from a Lithobates catesbeianus hatchery inhibits the growth of Citrobacter freundii (a bullfrog pathogen) and Listeria monocytogenes by a synergistic effect between lactic acid, hydrogen peroxide and a bacteriocin-like molecule. The chemical characterization of the bacteriocin in cell-free supernatants indicates that it has a proteinaceous nature. Hexadecane and ethyl acetate did not modify the bacteriocin activity, while 10 and 20 % (v/v) chloroform decreased the activity by 29 and 43 %, respectively. The antimicrobial peptide was heat stable since 85 % of residual activity was detected when neutralized supernatants were heated at 80 degrees C for 30 min. Moreover, no bacteriocin inactivation was observed when supernatants were kept at -20 degrees C for 3 months. The synthesis of the bacteriocin was associated with bacterial growth, highest production (2,100 AU/ml) being detected at the end of the exponential growth phase. At pH ranges of 5-6.5 and 5.0-5.5 the inhibitory molecule was stable when stored for 2 days at 4 and 25 degrees C, respectively. Moreover, it had a bactericidal effect on L. monocytogenes and the ultrastructural studies of pathogenic cells revealed clumping of the cytoplasmic material, increased periplasmic space and cell wall modifications. The deduced amino acid sequence of the bacteriocin was identical to nisin Z and the genetic determinants for its production are harbored in the chromosome. These results, described for the first time in L. lactis from a bullfrog hatchery, will increase knowledge of the bacteriocin under study with a view to its potential inclusion in probiotics for raniculture or biopreservatives. PMID- 24150986 TI - TWIST1 is a molecular marker for a poor prognosis in oral cancer and represents a potential therapeutic target. AB - BACKGROUND: Locoregional recurrence and distant metastases are ominous events in patients with advanced oral squamous cell carcinoma (OSCC). The objective of this study was to identify functional biomarkers that are predictive of OSCC progression to metastasis. METHODS: The expression profile of a network of epithelial-mesenchymal transition (EMT) genes was investigated in a large cohort of patients with progressive OSCC using a complimentary DNA microarray platform coupled to quantitative reverse transcriptase-polymerase chain reaction and immunohistochemical analyses. Therapeutic potential was investigated in vitro and in vivo using an orthotopic mouse model of metastatic OSCC growing in the tongue microenvironment. RESULTS: Among deregulated EMT genes, the Twist-related protein 1 (TWIST1) transcription factor and several of its regulated genes were significantly overexpressed across advanced stages of OSCC. This result was corroborated by the clinical observation that Twist1 up-regulation predicted the occurrence of lymph node and lung metastases as well as poor patient survival. In support of Twist1 as a driver of OSCC progression, the up-regulation of Twist1 was observed in cells isolated from patients with metastatic OSCC. The inhibition of Twist1 in these metastatic cells induced a potent inhibition of cell invasiveness in vitro as well as progression in vivo. CONCLUSIONS: The current results provide evidence for the prognostic value and therapeutic potential of a network of Twist genes in patients with advanced OSCC. PMID- 24150987 TI - A highly sensitive "turn-on" fluorescent sensor for the detection of human serum proteins based on the size exclusion of the polyacrylamide gel. AB - A highly sensitive "turn-on" fluorescent sensor based on the size exclusion of the polyacrylamide gel was developed for the on-gels detection of human serum proteins after PAGE. The possible mechanism of this fluorescence sensor was illustrated and validated by utilizing five kinds of colloidal silver nanoparticles with different particle size distribution and six kinds of polyacrylamide gels with different pore size. It was attributed to that silver nanoparticles (<5 nm in diameter) had been selectively absorbed into the gel and formed the small silver nanoclusters, resulting in the red fluorescence. Using this new technique for the detection of human serum proteins after PAGE, a satisfactory sensitivity was achieved and some relatively low-abundance proteins (e.g. zinc-alpha-2-glycoprotein), which are the significant proteinic markers of certain diseases can be easily detected, but not with traditional methods. Furthermore, it was also successfully applied to distinguish between serums from hepatoma patient and healthy people. As a new protein detection technique, the colloidal silver nanoparticles based "turn-on" fluorescent sensor offers a rapid, economic, low background, and sensitive way for direct detection of human serum proteins, showing available potential and significance in the development of nanobiotechnology and proteome research. PMID- 24150988 TI - Response to Fukuda et al. PMID- 24150990 TI - Proteomic analysis of striatum from MPTP-treated marmosets (Callithrix jacchus) with L-DOPA-induced dyskinesia of differing severity. AB - Marmosets rendered parkinsonian with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and treated with L-3,4-dihydroxyphenylalanine (L-DOPA) develop dyskinesia, but with differing degrees of severity. To provide insight into the molecular mechanisms responsible for the different level of dyskinesia to manifest in individual animals, proteins in striatum from MPTP-treated marmosets with different levels of L-DOPA-induced dyskinesia were separated by 2-dimensional (2 D) protein electrophoresis. Thirty-five differentially expressed proteins were identified by mass spectrometry and peptide mass fingerprinting, and comparative analysis found 10 were significantly increased and 3 had significantly reduced expression in animals with a high level of dyskinesia when compared to animals with a low incidence of dyskinesia. These proteins belonged to a range of functional classes, for example, molecular chaperones, metabolic enzymes and synaptic structural proteins. The findings of this study provide clues about the molecular mechanisms that cause dyskinesia to manifest and point towards potential novel targets for the development of therapeutic agents to prevent or treat established dyskinesia. PMID- 24150989 TI - Improvement in social deficits in autism spectrum disorders using a theatre based, peer-mediated intervention. AB - Social Emotional NeuroScience Endocrinology Theatre is a novel intervention program aimed at improving reciprocal social interaction in youth with autism spectrum disorder (ASD) using behavioral strategies and theatrical techniques in a peer-mediated model. Previous research using a 3-month model showed improvement in face perception, social interaction, and reductions in stress. The current study assessed a 2-week summer camp model. Typically developing peers were trained and paired with ASD youth (8-17 years). Social perception and interaction skills were measured before and after treatment using neuropsychological and parental measures. Behavioral coding by reliable, independent raters was conducted within the treatment context (theatre) and outside the setting (playground). Salivary cortisol levels to assess physiological arousal were measured across contexts (home, theatre, and playground). A pretest-posttest design for within-group comparisons was used, and prespecified pairwise comparisons were achieved using a nonparametric Wilcoxon signed-rank test. Significant differences were observed in face processing, social awareness, and social cognition (P < 0.05). Duration of interaction with familiar peers increased significantly over the course of treatment (P < 0.05), while engagement with novel peers outside the treatment setting remained stable. Cortisol levels rose on the first day of camp compared with home values yet declined by the end of treatment and further reduced during posttreatment play with peers. Results corroborate previous findings that the peer-mediated theatre program contributes to improvement in core social deficits in ASD using a short-term, summer camp treatment model. Future studies will explore treatment length and peer familiarity to optimize and generalize gains. PMID- 24150991 TI - Wound breakdown after middle cranial fossa craniotomy: an unusual complication after rhytidectomy. AB - Wound complications after middle cranial fossa craniotomy are rare. We describe a patient who underwent a left middle fossa craniotomy for resection of a small internal auditory canal tumor with subsequent development of wound breakdown and infection 1 week postoperatively. Prompting of the patient elicited a history of bilateral rhytidectomies. Wound debridement, hyperbaric oxygen therapy, dermal regeneration template placement, and prolonged antibiotic treatment were performed. Complete secondary intention healing occurred with an acceptable cosmetic outcome. Prior rhytidectomy scars must be identified and incorporated into the surgical planning prior to performing middle fossa craniotomy incisions. PMID- 24150992 TI - Beyond rheumatoid arthritis: the close association between interstitial cystitis and Sjogren's syndrome. PMID- 24150994 TI - 5th Joint Italian-German Purine Club Meeting : "fostering translational research on purines by Italian-German joint efforts". PMID- 24150995 TI - A normalization strategy for the analysis of plasma microRNA qPCR data in colorectal cancer. PMID- 24150996 TI - Colorectal cancer among first-degree relatives of individuals with adenomas: the risk is elevated, but now what? PMID- 24150993 TI - Role of immune-inflammatory and oxidative and nitrosative stress pathways in the etiology of depression: therapeutic implications. AB - Accumulating data have led to a re-conceptualization of depression that emphasizes the role of immune-inflammatory processes, coupled to oxidative and nitrosative stress (O&NS). These in turn drive the production of neuroregulatory tryptophan catabolites (TRYCATs), driving tryptophan away from serotonin, melatonin, and N-acetylserotonin production, and contributing to central dysregulation. This revised perspective better encompasses the diverse range of biological changes occurring in depression and in doing so provides novel and readily attainable treatment targets, as well as potential screening investigations prior to treatment initiation. We briefly review the role that immune-inflammatory, O&NS, and TRYCAT pathways play in the etiology, course, and treatment of depression. We then discuss the pharmacological treatment implications arising from this, including the potentiation of currently available antidepressants by the adjunctive use of immune- and O&NS-targeted therapies. The use of such a frame of reference and the treatment benefits attained are likely to have wider implications and utility for depression-associated conditions, including the neuroinflammatory and (neuro)degenerative disorders. PMID- 24150997 TI - Long-term efficacy and safety of fluphenazine in patients with Tourette syndrome. AB - OBJECTIVES: Haloperidol and pimozide are the only drugs currently approved by the U.S. Food and Drug Administration for treatment of Tourette syndrome (TS), but their potential side effects, which include tardive dyskinesia (TD), limit their use. METHODS: We performed a retrospective chart review of patients with TS treated with fluphenazine over a 26-year period. RESULTS: Among 268 patients with TS, fluphenazine was initiated at a mean age of 15.8 +/- 10.7 years (range, 4.1 70.2) and titrated to an optimal dose of 3.24 +/- 2.3 mg/day (range, 0.5-12.0), which was continued for an average of 2.6 +/- 3.2 years (range, 0.01-16.8). Marked to moderate improvement was noted in 211 (80.5%). The most common side effects included drowsiness, fatigue, or both, observed in 70 (26.1%) patients. There were no cases of TD. CONCLUSIONS: Fluphenazine appears to be safe and effective in the treatment of TS, and there were no cases of TD in this cohort treated up to 16.8 years. PMID- 24150998 TI - Computer-aided design, synthesis and validation of 2-phenylquinazolinone fragments as CDK9 inhibitors with anti-HIV-1 Tat-mediated transcription activity. AB - The activity of the cyclin-dependent kinase 9 (CDK9) is critical for HIV-1 Tat mediated transcription and represents a promising target for antiviral therapy. Here we present computational studies that, along with preliminary synthetic efforts, allowed us to identify and characterize a new class of nontoxic anti CDK9 chemotypes based on the 2-phenylquinazolinone scaffold. Inhibition of CDK9 translated into the ability to interfere selectively with Tat-mediated transactivation of the viral promoter and in the inhibition of HIV-1 reactivation from latently infected cells, with the most potent derivative 37 (2-(4 aminophenyl)-7-chloroquinazolin-4(3H)-one) showing an IC50 value of 4.0 MUM. Because the herein reported 2-phenylquinazolinones are merely fragments, they are largely optimizable, paving the way to derivatives with improved potency. PMID- 24150999 TI - The changed face of PTSD diagnosis. PMID- 24151000 TI - National estimates of exposure to traumatic events and PTSD prevalence using DSM IV and DSM-5 criteria. AB - Prevalence of posttraumatic stress disorder (PTSD) defined according to the American Psychiatric Association's Diagnostic and Statistical Manual fifth edition (DSM-5; 2013) and fourth edition (DSM-IV; 1994) was compared in a national sample of U.S. adults (N = 2,953) recruited from an online panel. Exposure to traumatic events, PTSD symptoms, and functional impairment were assessed online using a highly structured, self-administered survey. Traumatic event exposure using DSM-5 criteria was high (89.7%), and exposure to multiple traumatic event types was the norm. PTSD caseness was determined using Same Event (i.e., all symptom criteria met to the same event type) and Composite Event (i.e., symptom criteria met to a combination of event types) definitions. Lifetime, past-12-month, and past 6-month PTSD prevalence using the Same Event definition for DSM-5 was 8.3%, 4.7%, and 3.8% respectively. All 6 DSM-5 prevalence estimates were slightly lower than their DSM-IV counterparts, although only 2 of these differences were statistically significant. DSM-5 PTSD prevalence was higher among women than among men, and prevalence increased with greater traumatic event exposure. Major reasons individuals met DSM-IV criteria, but not DSM-5 criteria were the exclusion of nonaccidental, nonviolent deaths from Criterion A, and the new requirement of at least 1 active avoidance symptom. PMID- 24151001 TI - Finalizing PTSD in DSM-5: getting here from there and where to go next. AB - The process that resulted in the diagnostic criteria for posttraumatic stress disorder (PTSD) in the Diagnostic and Statistical Manual of Mental Disorders (5th ed.; DSM-5; American Psychiatric Association; ) was empirically based and rigorous. There was a high threshold for any changes in any DSM-IV diagnostic criterion. The process is described in this article. The rationale is presented that led to the creation of the new chapter, "Trauma- and Stressor-Related Disorders," within the DSM-5 metastructure. Specific issues discussed about the DSM-5 PTSD criteria themselves include a broad versus narrow PTSD construct, the decisions regarding Criterion A, the evidence supporting other PTSD symptom clusters and specifiers, the addition of the dissociative and preschool subtypes, research on the new criteria from both Internet surveys and the DSM-5 field trials, the addition of PTSD subtypes, the noninclusion of complex PTSD, and comparisons between DSM-5 versus the World Health Association's forthcoming International Classification of Diseases (ICD-11) criteria for PTSD. The PTSD construct continues to evolve. In DSM-5, it has moved beyond a narrow fear-based anxiety disorder to include dysphoric/anhedonic and externalizing PTSD phenotypes. The dissociative subtype may open the way to a fresh approach to complex PTSD. The preschool subtype incorporates important developmental factors affecting the expression of PTSD in young children. Finally, the very different approaches taken by DSM-5 and ICD-11 should have a profound effect on future research and practice. PMID- 24151002 TI - "I wouldn't start from here"--an alternative perspective on PTSD from the ICD-11: comment on Friedman (2013). AB - This commentary briefly summarizes some of the criticism directed at the diagnosis of posttraumatic stress disorder (PTSD) according to the Diagnostic and Statistical Manual of Mental Disorders (5th ed.) including the issues of complexity and comorbidity, and offers a rationale for attempting a simpler approach to diagnosis that can be used in minimally resourced, non-English speaking countries. Rather than describe comprehensively the features of PTSD, the World Health Organization in its upcoming edition of the International Classification of Diseases has opted to define a much smaller number of symptoms that will effectively discriminate PTSD from other related conditions. Parallel research on the two approaches to diagnosis promises to add greatly to our understanding of the condition. PMID- 24151003 TI - Applying an international perspective in defining PTSD and related disorders: comment on Friedman (2013). AB - We address the general perspective of the World Health Organization towards the classification process of the 11(th) revision of the International Classification of Diseases and Related Health Problems (ICD-11); give a short description of the ICD-11 proposals related to "disorders specifically associated with stress" and the differentiation between posttraumatic stress disorder, complex posttraumatic stress disorder, and prolonged grief disorder; and comment on the most important aim of classifying mental disorders-to provide the best treatments available. PMID- 24151004 TI - The DSM-5 got PTSD right: comment on Friedman (2013). AB - Friedman in his article in this issue describes the posttraumatic stress disorder (PTSD) diagnosis according to the Diagnostic and Statistical Manual of Mental Disorders (5th ed.; DSM-5) and provides considerable information about the process that resulted in the revisions, as well as how PTSD in the DSM-5 differs from proposals for PTSD in the International Classification of Mental Disorders and Related Health Problems (ICD-11). In this commentary, I argue that (a) the placement of PTSD in the DSM-5 category of Trauma and Stressor-Related Disorders is a major advance because it draws attention to the role of "nurture" when there is an overemphasis on "nature" by some; (b) the broader construct of PTSD in DSM 5 is justified because it includes clinically important problems and can be reliably diagnosed; and (c) the web surveys contributed substantially to the provision of data needed to support proposed changes. Concerns are raised about the proposed ICD-11 approach, and the case is presented that substantial evidence should be required before these proposed changes are made because they differ substantially from a DSM-5 PTSD diagnosis that has demonstrated reliability and validity. PMID- 24151005 TI - PTSD in the DSM-5: reply to Brewin (2013), Kilpatrick (2013), and Maercker and Perkonigg (2013). AB - The greater emphasis on scientific evidence and the high threshold for changing any criterion in the Diagnostic and Statistical Manual for Mental Disorders (4th ed., DSM-IV) probably account for many key differences between the DSM-5 and the International Classification of Diseases and Related Health Problems (11th ver.; ICD-11) with regard to diagnostic criteria for posttraumatic stress disorder (PTSD). Important questions about PTSD remain that can only be settled by future research. Additional research is also needed on subthreshold PTSD, a dissociative subtype described in the DSM-5; complex PTSD, included in the ICD-11; bereavement related disorders; and adjustment disorders. We can all look forward to such scientific advances to inform our ongoing efforts to develop the best diagnostic criteria for trauma- and stressor-related disorders. PMID- 24151006 TI - Micromachined silicon attenuated total reflectance infrared spectroscopy: an emerging detection method in micro/nanofluidics. AB - Microfluidics is an emerging field with various applications. In situ analysis of liquids inside microfluidic channels is an important research subject for any of these applications. On the other hand, attenuated total reflectance infrared spectroscopy (ATR-IR) is a strong surface detection method. Recently, there have been various attempts to use ATR-IR for detection of liquids inside microfluidic channels. Micromachined silicon ATR-IR (MUSi-ATR-IR) is an emerging analytical tool for micro/nanofluidics. This paper reviews MUSi-ATR-IR micro/nanofluidics detection devices and discusses the application fields, capabilities, advantages, and disadvantages of the method. PMID- 24151007 TI - Respiratory induced dynamic variations of stroke volume and its surrogates as predictors of fluid responsiveness: applicability in the early stages of specific critical states. AB - Respiratory induced dynamic variations of stroke volume and its surrogates are very sensitive and specific predictors of fluid responsiveness, but their use as targets for volume management can be limited. In a recent study, limiting factors were present in 53 % of surgical patients with inserted arterial line. In the intensive care unit (ICU) population the frequency is presumably higher, but the real prevalence is unknown. Our goal was to study the feasibility of dynamic variations guided initial volume resuscitation in specific critical states. We have performed a 5 year retrospective evaluation of patients admitted with diagnosis sepsis, polytrauma, after high risk surgery or cardiac arrest. Occurrence of major (sedation, mandatory ventilation and tidal volume, open chest and arrhythmias) and minor limiting factors (PEEP level, use of vasopressors and presence of arterial catheter) was screened within the first 24 h after admission. In the study period 1296 patients were hospitalized in our ICU with severe sepsis (n = 242), polytrauma (n = 561), after high risk surgery (n = 351) or cardiac arrest (n = 141). From these patients 549 (42.4 %) fulfilled all major criteria for applicability of dynamic variations. In our evaluation only limited number of patients admitted for polytrauma (51 %), sepsis (37 %), after cardiac arrest (39 %) or surgical procedure (33 %) fulfil all the major criteria for use of dynamic variations at the ICU admission. The prevalence was similar in patients with shock. Occurrence of minor factors can pose further bias in evaluation of these patients. General use of dynamic variations guided protocols for initial resuscitations seems not universally applicable. PMID- 24151008 TI - Local label learning (LLL) for subcortical structure segmentation: application to hippocampus segmentation. AB - Automatic and reliable segmentation of subcortical structures is an important but difficult task in quantitative brain image analysis. Multi-atlas based segmentation methods have attracted great interest due to their promising performance. Under the multi-atlas based segmentation framework, using deformation fields generated for registering atlas images onto a target image to be segmented, labels of the atlases are first propagated to the target image space and then fused to get the target image segmentation based on a label fusion strategy. While many label fusion strategies have been developed, most of these methods adopt predefined weighting models that are not necessarily optimal. In this study, we propose a novel local label learning strategy to estimate the target image's segmentation label using statistical machine learning techniques. In particular, we use a L1-regularized support vector machine (SVM) with a k nearest neighbor (kNN) based training sample selection strategy to learn a classifier for each of the target image voxel from its neighboring voxels in the atlases based on both image intensity and texture features. Our method has produced segmentation results consistently better than state-of-the-art label fusion methods in validation experiments on hippocampal segmentation of over 100 MR images obtained from publicly available and in-house datasets. Volumetric analysis has also demonstrated the capability of our method in detecting hippocampal volume changes due to Alzheimer's disease. PMID- 24151009 TI - Asymmetric palladium(II)-catalyzed cascade reaction giving quaternary amino succinimides by 1,4-addition and a Nef-type reaction. PMID- 24151010 TI - Rare-earth-metal alkylaluminates supported by N-donor-functionalized cyclopentadienyl ligands: C-H bond activation and performance in isoprene polymerization. AB - Homoleptic tetramethylaluminate complexes [Ln(AlMe4)3] (Ln=La, Nd, Y) reacted with HCp(NMe2) (Cp(NMe2) =1-[2-(N,N-dimethylamino)-ethyl]-2,3,4,5-tetramethyl cyclopentadienyl) in pentane at -35 degrees C to yield half-sandwich rare-earth metal complexes, [{C5 Me4CH2CH2NMe2 (AlMe3)}Ln(AlMe4)2]. Removal of the N-donor coordinated trimethylaluminum group through donor displacement by using an equimolar amount of Et2O at ambient temperature only generated the methylene bridged complexes [{C5Me4CH2CH2NMe(MU-CH2)AlMe3}Ln(AlMe4)] with the larger rare earth-metal ions lanthanum and neodymium. X-ray diffraction analysis revealed the formation of isostructural complexes and the C-H bond activation of one aminomethyl group. The formation of Ln(MU-CH2)Al moieties was further corroborated by (13)C and (1)H-(13)C HSQC NMR spectroscopy. In the case of the largest metal center, lanthanum, this C-H bond activation could be suppressed at 35 degrees C, thereby leading to the isolation of [(Cp(NMe2))La(AlMe4)2], which contains an intramolecularly coordinated amino group. The protonolysis reaction of [Ln(AlMe4)3] (Ln=La, Nd) with the anilinyl-substituted cyclopentadiene HCp(AMe2) (Cp(AMe2) =1-[1-(N,N-dimethylanilinyl)]-2,3,4,5 tetramethylcyclopentadienyl) at -35 degrees C generated the half-sandwich complexes [(Cp(AMe2))Ln(AlMe4)2]. Heating these complexes at 75 degrees C resulted in the C-H bond activation of one of the anilinium methyl groups and the formation of [{C5Me4C6H4NMe(MU-CH2)AlMe3}Ln(AlMe4)] through the elimination of methane. In contrast, the smaller yttrium metal center already gave the aminomethyl-activated complex at -35 degrees C, which is isostructural to those of lanthanum and neodymium. The performance of complexes [{C5Me4CH2CH2NMe(MU-CH2 )AlMe3}-Ln(AlMe4)], [(Cp(AMe2))Ln(AlMe4)2], and [{C5Me4C6H4NMe(MU CH2)AlMe3}Ln(AlMe4)] in the polymerization of isoprene was investigated upon activation with [Ph3C][B(C6F5)4], [PhNMe2 H][B(C6F5)4], and B(C6F5)3. The highest stereoselectivities were observed with the lanthanum-based pre-catalysts, thereby producing polyisoprene with trans-1,4 contents of up to 95.6 %. Narrow molecular weight distributions (Mw/Mn <1.1) and complete consumption of the monomer suggested a living-polymerization mechanism. PMID- 24151011 TI - Narrow-band ultraviolet B phototherapy versus broad-band ultraviolet B or psoralen-ultraviolet A photochemotherapy for psoriasis. AB - BACKGROUND: The most commonly used types of phototherapy for treating psoriasis are narrow-band ultraviolet B (NB-UVB); broad-band ultraviolet B (BB-UVB), which includes selective (delivering radiation with a wavelength range of 305 to 325 nm) and conventional BB-UVB (280 to 320 nm); and psoralen ultraviolet A photochemotherapy (oral or bath PUVA). There is substantial controversy regarding their efficacy when compared with each other. OBJECTIVES: To assess the effects of narrow-band ultraviolet B phototherapy versus broad-band ultraviolet B or psoralen ultraviolet A photochemotherapy for psoriasis. SEARCH METHODS: We searched the following databases up to August 2013: the Cochrane Skin Group Specialised Register, CENTRAL in The Cochrane Library (2013, Issue 7), MEDLINE (from 1946), and EMBASE (from 1974). We searched the following databases up to November 2012: CNKI (from 1974) and CBM (from 1978). We also searched trials registers and the OpenGrey database. SELECTION CRITERIA: We included all randomised controlled trials (RCTs) that compared NB-UVB phototherapy with BB-UVB or PUVA for treating psoriasis, which included chronic plaque psoriasis (CPP), guttate psoriasis (GP), and palmoplantar psoriasis (PPP). DATA COLLECTION AND ANALYSIS: Two review authors independently conducted the study selection, 'Risk of bias' assessment, and data extraction. MAIN RESULTS: We included 13 RCTs, with a total of 662 participants. We report the results of intention-to-treat analyses (ITT) here. Our primary outcomes of interest were as follows: Participant-rated global improvement, Percentage of participants reaching Psoriasis Area and Severity Index (PASI) 75 (which meant equal to or more than 75% reduction in PASI score), Withdrawal due to side-effects, and Clearance rate.In one RCT of NB-UVB compared with oral PUVA in participants with CPP, the difference in PASI 75 was not statistically significant (risk ratio (RR) 0.91, 95% confidence interval (CI) 0.63 to 1.32; N = 51; low quality). In three other RCTs of CPP, the clearance rates were inconsistent because in one, there was no difference between the groups (RR 1.01, 95% CI 0.91 to 1.12; N = 54), and in the other two, the clearance rates were statistically significantly in favour of oral PUVA: RR 0.66, 95% CI 0.47 to 0.93; N = 93 and RR 0.75, 95% CI 0.59 to 0.96; N = 100, respectively. Pooled data from these three studies indicated that withdrawals due to adverse events were not significantly different between either group (RR 0.71, 95% CI 0.20 to 2.54; N = 247; low quality).The evidence from the comparison of NB UVB with bath PUVA in terms of clearance rate for CPP was also inconsistent: Pooled data from two left-right body comparison RCTs found no significant difference between the NB-UVB and bath PUVA groups (RR 1.79, 95% CI 0.46 to 6.91; N = 92; low quality), while a parallel RCT favoured bath PUVA (RR 0.18, 95% CI 0.05 to 0.71; N = 36; low quality).In participants with PPP, one RCT found there were no significant differences between NB-UVB treated sides and topical PUVA treated sides in terms of clearance rate (RR 0.09, 95% CI 0.01 to 1.56; N = 50; low quality).Two RCTs found NB-UVB plus retinoid (re-NB-UVB) and PUVA plus retinoid (re-PUVA) had similar effects for treating people with CPP or GP in terms of clearance rate (RR 0.93, 95% CI 0.79 to 1.10; N = 90; low quality).One RCT in people with CPP found no significant differences between NB-UVB and selective BB-UVB in terms of clearance rate (RR 1.40, 95% CI 0.92 to 2.13; N = 100; low quality) and withdrawals due to adverse events (RR 3.00, 95% CI 0.32 to 27.87; N = 100; low quality).No studies reported our primary outcomes for NB-UVB compared with conventional BB-UVB. AUTHORS' CONCLUSIONS: Current evidence is very heterogeneous and needs to be interpreted with caution. The clearance rate between oral PUVA and NB-UVB is inconsistent among the included studies. Evidence regarding NB-UVB versus bath PUVA is also inconsistent. Re-NB-UVB and re-PUVA are similarly effective for treating people with CPP or GP. In practice, NB-UVB may be more convenient to use since exogenous photosensitiser is not required before phototherapy.NB-UVB is considered ineffective for PPP in clinical practice, and a small RCT did not detect a statistically significant difference between NB-UVB and topical PUVA for clearing PPP. NB-UVB seemed to be similar to selective BB UVB for clearing CPP.Larger prospective studies are needed to confirm the long term safety of NB-UVB. PMID- 24151013 TI - Patient reported outcomes in endoscopic and open transcervical treatment for Zenker's diverticulum. AB - OBJECTIVES/HYPOTHESIS: To compare long-term symptomatic outcomes between external transcervical (ET) and endoscopic stapling diverticulotomy (ESD) surgeries for Zenker's diverticulum. STUDY DESIGN: Retrospective review. METHODS: Patients undergoing surgery for Zenker's diverticulum surgery between 1998 and 2010 with at least 1 year follow-up were telephoned and questioned for dysphagia, choking, regurgitation, and halitosis based on a validated Gastrointestinal Quality-of Life Index. Symptom degree preoperatively and at phone call was assessed. Patients rated their overall postoperative symptoms as worsened, unchanged, improved, or completely resolved. RESULTS: A total of 96 patients were eligible for inclusion and 55 were successfully contacted. Of these, 24 underwent ESD and 31 had ET operations. Average follow-up time was significantly longer for the ET group than the ESD group (5.7 vs. 3.1 years respectively, P < 0.01). Gender, age at operation, diverticulum size, and preoperative symptom scores were not statistically different between the two groups. For both techniques, symptom scores showed significant improvement postoperatively (P < 0.01). A greater proportion of patients undergoing ET procedures reported their symptoms to be completely resolved or improved compared with the ESD group (93% vs. 67%, P = 0.015). Patients undergoing ET demonstrated a greater change or improvement in survey score compared to ESD patients (7.23 vs. 3.42, P = 0.014). CONCLUSION: Both the ET and ESD surgeries significantly benefit patients, regardless of diverticulum size. Long-term symptomatic outcomes between the two populations indicate that patients with ET procedures attain a greater degree of resolution of preoperative symptoms. PMID- 24151012 TI - Genetic effects on cerebellar structure across mouse models of autism using a magnetic resonance imaging atlas. AB - Magnetic resonance imaging (MRI) of autism populations is confounded by the inherent heterogeneity in the individuals' genetics and environment, two factors difficult to control for. Imaging genetic animal models that recapitulate a mutation associated with autism quantify the impact of genetics on brain morphology and mitigate the confounding factors in human studies. Here, we used MRI to image three genetic mouse models with single mutations implicated in autism: Neuroligin-3 R451C knock-in, Methyl-CpG binding protein-2 (MECP2) 308 truncation and integrin beta3 homozygous knockout. This study identified the morphological differences specific to the cerebellum, a structure repeatedly linked to autism in human neuroimaging and postmortem studies. To accomplish a comparative analysis, a segmented cerebellum template was created and used to segment each study image. This template delineated 39 different cerebellar structures. For Neuroligin-3 R451C male mutants, the gray (effect size (ES) = 1.94, FDR q = 0.03) and white (ES = 1.84, q = 0.037) matter of crus II lobule and the gray matter of the paraflocculus (ES = 1.45, q = 0.045) were larger in volume. The MECP2 mutant mice had cerebellar volume changes that increased in scope depending on the genotype: hemizygous males to homozygous females. The integrin beta3 mutant mouse had a drastically smaller cerebellum than controls with 28 out of 39 cerebellar structures smaller. These imaging results are discussed in relation to repetitive behaviors, sociability, and learning in the context of autism. This work further illuminates the cerebellum's role in autism. PMID- 24151014 TI - Abnormal expression pattern of Notch receptors, ligands, and downstream effectors in the dorsolateral prefrontal cortex and amygdala of suicidal victims. AB - Recent studies have associated alterations of neuronal plasticity in specific brain areas with suicidal behavior. The Notch signaling pathway plays a relevant role in the control of stem cell maintenance, cell migration, and neuronal plasticity. In the present study, the gene expression of the four Notch receptors (NOTCH1-4), the five canonical ligands (DLL1, DLL3, DLL4, JAGGED1, and JAGGED2), the two non-canonical ligands (DLK1 and DLK2), and the transcription factors (HES1, HEY1, and HEY2) were measured in the dorsolateral prefrontal cortex (DLPFC) and amygdala (AMY) of suicide victims (S; n = 13 males, with no clinical psychiatric history and non-treated with anxiolytic or antidepressant drugs) and their corresponding controls (C; n = 13 males) by real-time PCR. The results revealed a reduction of NOTCH2 and NOTCH1, NOTCH3, and NOTCH4 gene expression in the DLPFC and AMY of S compared with C, respectively. DLL1 levels were increased in the DLPFC and decreased in the AMY, whereas DLL4, JAGGED1, and JAGGED2 were significantly decreased in the regions analyzed. DLK1 was reduced in the AMY, whereas no changes were observed in the DLPFC and in DLK2 expression levels in any of the regions analyzed. HES1 was significantly reduced in both brain regions from S, whereas there were no significant changes in HEY1 and HEY2. This study provides evidence suggesting that the Notch signaling pathway could be a potential key target in the treatment of suicidal behaviors. PMID- 24151015 TI - Public belief that mentally ill people are violent: is the USA exporting stigma to the rest of the world? PMID- 24151016 TI - Religious conflicts of interest. PMID- 24151017 TI - Sevelamer carbonate lowers serum phosphorus effectively in haemodialysis patients: a randomized, double-blind, placebo-controlled, dose-titration study. AB - BACKGROUND: Hyperphosphataemia in patients with advanced chronic kidney disease (CKD) is associated with adverse outcomes, including vascular calcification and higher mortality rates. While phosphate lowering is an integral aspect of CKD management, the efficacy and safety of phosphate binders in a contemporary cohort of Chinese haemodialysis patients (who have different genetics and dietary patterns than other populations) has not been previously described. Moreover, sparse data are available on strategies for optimal dose titration when transitioning from a calcium-based to a polymer-based phosphate binder. METHODS: This randomized, double-blind, dose-titration study compared sevelamer carbonate (starting dose 800 mg three times daily) with placebo over 8 weeks' duration in Chinese CKD patients on haemodialysis. Patients were required to be using calcium based binders prior to study start. RESULTS: In all, 205 patients were randomized (sevelamer, n = 135; placebo, n = 70); mean age was 48.6 years, 61% were male and the mean time on dialysis was 4.4 years. The mean serum phosphorus decreased significantly in patients treated with sevelamer carbonate [change -0.69 +/- 0.64 mmol/L (-2.14 +/- 1.98 mg/dL)] but remained persistently elevated with placebo [change -0.06 +/- 0.57 mmol/L (-0.19 +/- 1.76 mg/dL)] (P < 0.0001). When compared with placebo, sevelamer carbonate treatment resulted in statistically significant greater mean reductions from baseline in serum total (-17.1 versus -3.3%) and low density lipoprotein cholesterol (-33.5 versus-7.6%) (P < 0.0001 for both). Sevelamer carbonate was well tolerated with 96% adherence compared with 97% adherence in the placebo arm. Overall, adverse events experienced by patients in the sevelamer carbonate and placebo treatment groups were similar and consistent with their underlying renal disease. CONCLUSIONS: This study demonstrated that hyperphosphataemia developed quickly following the cessation of phosphate binders and remained persistently elevated in end-stage CKD in the placebo-treated group. Gradually titrating up sevelamer carbonate from an initial dose of 2.4 g/day to an average daily dose of 7.1 +/- 2.5 g/day was well tolerated, safe and efficacious in contemporary Chinese haemodialysis patients. PMID- 24151018 TI - The Biobank of Nephrological Diseases in the Netherlands cohort: the String of Pearls Initiative collaboration on chronic kidney disease in the university medical centers in the Netherlands. AB - Despite advances in preventive therapy, prognosis in chronic kidney disease (CKD) is still grim. Clinical cohorts of CKD patients provide a strategic resource to identify factors that drive progression in the context of clinical care and to provide a basis for improvement of outcome. The combination with biobanking, moreover, provides a resource for fundamental and translational studies. In 2007, the Dutch government initiated and funded the String of Pearls Initiative (PSI), a strategic effort to establish infrastructure for disease-based biobanking in the University Medical Centres (UMCs) in the Netherlands, in a 4-year start-up period. CKD was among the conditions selected for biobanking, and this resulted in the establishment of the Biobank of Nephrological Diseases-NL (BIND-NL) cohort. Patients with CKD Stages 1-4 are eligible. The data architecture is designed to reflect routine care, with specific issues added for enrichment, e.g. questionnaires. Thus, the collected clinical and biochemical data are those required by prevailing guidelines for routine nephrology care, with a minimal dataset for all patients, and diagnosis-specific data for the diagnostic categories of primary and secondary glomerular disorders and adult dominant polycystic kidney disease, respectively. The dataset is supplemented by a biobank, containing serum, plasma, urine and DNA. The cohort will be longitudinally monitored, with yearly follow-up for clinical outcome. Future linking of the data to those from the national registries for renal replacement therapy is foreseen to follow the patients' lifeline throughout the different phases of renal disease and different treatment modalities. In the design of the data architecture, care was taken to ensure future exchangeability of data with other CKD cohorts by applying the data harmonization format of the Renal DataSHaPER, with a dataset based upon standardized indicator sets to facilitate collaboration with other CKD cohorts. Enrolment started in 2010, and over 2200 eligible patients have been enrolled in the different UMCs. Follow-up of enrolled patients has started, and enrolment will continue at a slower rate. The aggregation and standardization of clinical data and biosamples from large numbers of CKD patients will be a strategic resource not only for clinical and translational research, but also by its basis in routine clinical care for clinical governance and quality improvement projects. PMID- 24151019 TI - Renal prognosis a long time after renal biopsy on patients with diabetic nephropathy. AB - BACKGROUND: A new classification of diabetic nephropathy was reported by Tervaert et al., but the association between pathological findings and the clinical outcomes remains unclear. METHODS: Among 310 patients with diabetes mellitus who underwent renal biopsy from March 1985 to January 2010 and were confirmed to have diabetic nephropathy according to the Tervaert's classification, 205 patients were enrolled in this study. Cox proportional hazard regression analysis was used to calculate the hazard ratio (HR) and 95% confidence interval (CI) for death censored renal death. Each regression analysis employed two levels of multivariate adjustment. RESULTS: After adjustment for age, gender, estimated glomerular filtration rate, type of diabetes, urinary protein excretion, systolic blood pressure, body mass index, HbA1c, diabetic retinopathy and red blood cells in urinary sediment at the time of renal biopsy, compared with glomerular class IIA, the HRs for death-censored renal death of glomerular classes I, IIB, III and IV were 0.21 (95% CI: 0.04-1.25), 2.12 (0.89-5.04), 4.23 (1.80-9.90), and 3.27 (1.32-8.10), respectively. Also, compared with an interstitial fibrosis and tubular atrophy score 1 group, HRs for score 0 group, score 2 group and score 3 group were 0.08 (0.01-0.57), 2.17 (0.96-4.91), 4.78 (1.96-11.68), respectively. CONCLUSIONS: The progression of glomerular, tubulointerstitial and vascular lesions was associated with higher HRs for renal death. These results suggest the clinical utility of Tervaert's pathological classification. PMID- 24151021 TI - Re: Hanna-Mitchell AT, Wolf-Johnston AS, Barrick SR, et al. Effect of botulinum toxin A on urothelial-release of ATP and expression of SNARE targets within the urothelium. Neurourol Urodyn 2015;34:79-84. PMID- 24151020 TI - Cardiac function and tolerance to ischemia-reperfusion injury in chronic kidney disease. AB - BACKGROUND: Cardiac dysfunction is an independent risk factor of ischemic heart disease and mortality in chronic kidney disease (CKD) patients, yet the relationship between impaired cardiac function and tolerance to ischemia reperfusion (IR) injury in experimental CKD remains unclear. METHODS: Cardiac function was assessed in 5/6 ablation-infarction (AI) and sham male Sprague Dawley rats at 20 weeks of age, 8 weeks post-surgery using an isolated working heart system. This included measures taken during manipulation of preload and afterload to produce left ventricular (LV) function curves as well as during reperfusion following a 15-min ischemic bout. In addition, LV tissue was used for biochemical tissue analysis. RESULTS: Cardiac function was impaired in AI animals during preload and afterload manipulations. Cardiac functional impairments persisted post-ischemia in the AI animals, and 36% of AI animals did not recover sufficiently to achieve aortic overflow following ischemia (versus 0% of sham animals). However, for those animals able to withstand the ischemic perturbation, no difference was observed in percent recovery of post-ischemic cardiac function between groups. Urinary NOx (nitrite + nitrate) excretion was lower in AI animals and accompanied by reduced LV endothelial nitric oxide synthase and NOx. LV antioxidants superoxide dismutase-1 and -2 were reduced in AI animals, whereas glutathione peroxidase-1/2 as well as NADPH-oxidase-4 and H(2)O(2) were increased in these animals. CONCLUSIONS: Impaired cardiac function appears to predispose AI rats to poor outcomes following short-duration ischemic insult. These findings could be, in part, mediated by increased oxidative stress via nitric oxide dependent and -independent mechanisms. PMID- 24151022 TI - Cancer care for individuals with schizophrenia. AB - Individuals with schizophrenia are a vulnerable population that has been relatively neglected in health disparities research. Despite having an equivalent risk of developing most cancers, patients with schizophrenia are more likely to die of cancer than the general population. Cancer care disparities are likely the result of patient-, provider-, and systems-level factors and influenced by the pervasive stigma of mental illness. Individuals with schizophrenia have higher rates of health behaviors linked with cancer mortality including cigarette smoking. They also have significant medical comorbidity, are less likely to have up-to-date cancer screening, and may present at more advanced stages of illness. Patients with schizophrenia may be less likely to receive chemotherapy or radiotherapy, have more postoperative complications, and have less access to palliative care. However, opportunities exist for the interdisciplinary team, including medical, surgical, and radiation oncologists; psychiatrists; and primary care physicians, to intervene throughout the continuum of cancer care to promote survival and quality of life. This review summarizes data on overall and cancer-specific mortality for individuals with schizophrenia and reviews specific disparities across the cancer care continuum of screening, diagnosis, treatment, and end-of-life care. Using a case, the authors illustrate clinical challenges for this population including communication, informed consent, and risk of suicide, and provide suggestions for care. Finally, recommendations for research to address the disparities in cancer care for individuals with schizophrenia are discussed. Despite significant challenges, with collaboration between oncology and mental health teams, individuals with schizophrenia can receive high-quality cancer care. PMID- 24151023 TI - Prenatal diagnosis of Robinow syndrome: a case report. AB - Robinow syndrome, also known as fetal face syndrome, is a rare genetically heterogeneous condition characterized mainly by mesomelic limb shortening, facial malformations, and genital abnormalities. This report describes the sonographic findings in a case of autosomal-dominant Robinow syndrome diagnosed at 23.1 weeks' gestation, in a patient with no history of affected relatives. Here we describe the sonographic characteristics of this syndrome from the diagnosis until birth. The prenatal and postnatal findings, the differential diagnosis, and the prognosis of patients with this syndrome are discussed. (c) 2013 Wiley Periodicals, Inc. J Clin Ultrasound, 42:297-300, 2014. PMID- 24151024 TI - Aerosol and ozone observations during six cruise campaigns across the Mediterranean basin: temporal, spatial, and seasonal variability. AB - The Mediterranean basin, because of its semi-enclosed configuration, is one of the areas heavily affected by air pollutants. Despite implications on both human health and radiative budget involving an increasing interest, monitoring databases measuring air pollution directly over this area are yet relatively limited. Owing to this context, concentrations of fine (PM2.5) and coarse (PM2.5 10) particles along with other ancillary data, such as ozone levels and meteorological parameters, were measured during six cruise campaigns covering almost the whole Mediterranean basin. Elemental composition of both PM2.5 and PM2.5-10 was also determined to identify specific tracers for different classes of particles that can be found in the Mediterranean atmosphere. Outcomes resulting from the integration of a preliminary qualitative examination with a more quantitative analysis, based on receptor modelling, suggested that European continental influence, Saharan dust outbreaks, wildfire events, sea spray and fossil fuel combustion were the leading causes of the aerosol-ozone variations within the Mediterranean basin. Shipping emissions, consisting in both local harbours and maritime traffic across the basin, were also tested using the marker ratio of V/Ni. Peak values observed for coarse fraction have shown to be driven by the occurrence of African dust events. Considering the major influence of Continental pollution and wildfire events, the spatial variability resulted in larger fine particle concentrations and higher ozone levels over the Eastern Mediterranean side in comparison to the Western one. PMID- 24151025 TI - Evaluation of in situ catalysed hydrogen peroxide propagation (CHP) for phenanthrene and fluoranthene removals from soil and its associated impacts on soil functionality. AB - Extensive contamination of soils by highly recalcitrant contaminants such as polycyclic aromatic hydrocarbons (PAHs) is an environmental problem arising from rapid industrialisation. This work focusses on the remediation of soil contaminated with 3- and 4-aromatic ring PAHs (phenanthrene (PHE) and fluoranthene (FLUT)) through catalysed hydrogen peroxide propagation (CHP). In the present work, the operating parameters of the CHP treatment in packed soil column was optimised with central composite design (H2O2/soil 0.081, Fe(3+)/soil 0.024, sodium pyrophosphate (SP)/soil 0.024, pH of SP solution 7.73). The effect of contaminant aging on PAH removals was also investigated. Remarkable oxidative PAH removals were observed for the short aging and extended aging period (up to 86.73 and 70.61 % for PHE and FLUT, respectively). The impacts of CHP on soil biological, chemical and physical properties were studied for both spiked and aged soils. Overall, the soil functionality analyses after the proposed operating condition demonstrated that the values for soil respiration, electrical conductivity, pH and iron precipitation fell within acceptable limits, indicating the compatibility of the CHP process with land restoration. PMID- 24151026 TI - Antibacterial activity of silver nanoparticles grafted on stone surface. AB - Microbial colonization has a relevant impact on the deterioration of stone materials with consequences ranging from esthetic to physical and chemical changes. Avoiding microbial growth on cultural stones therefore represents a crucial aspect for their long-term conservation. The antimicrobial properties of silver nanoparticles (AgNPs) have been extensively investigated in recent years, showing that they could be successfully applied as bactericidal coatings on surfaces of different materials. In this work, we investigated the ability of AgNPs grafted to Serena stone surfaces to inhibit bacterial viability. A silane derivative, which is commonly used for stone consolidation, and Bacillus subtilis were chosen as the grafting agent and the target bacterium, respectively. Results show that functionalized AgNPs bind to stone surface exhibiting a cluster disposition that is not affected by washing treatments. The antibacterial tests on stone samples revealed a 50 to 80 % reduction in cell viability, with the most effective AgNP concentration of 6.7 MUg/cm(2). To our knowledge, this is the first report on antimicrobial activity of AgNPs applied to a stone surface. The results suggest that AgNPs could be successfully used in the inhibition of microbial colonization of stone artworks. PMID- 24151027 TI - Enhanced bioaccumulation of pentachlorophenol in carp in the presence of multi walled carbon nanotubes. AB - The impact of suspended particles on the bioavailability of pollutants has long been a controversial topic. In this study, adsorption of pentachlorophenol (PCP) onto a natural suspended particulate matter (SPM) and multi-walled carbon nanotubes (MWCNTs) was studied. Facilitated transports of PCP into carp by SPM and MWCNTs were evaluated by bioaccumulation tests exposing carp (Carassius auratus red var.) to PCP-contaminated water in the presence of SPM and MWCNTs, respectively. Desorption of PCP on SPM and MWCNTs in simulated digested fluids was also investigated. The results demonstrate that MWCNTs (K F = 7.99 * 10(4)) had a significantly stronger adsorption capacity for PCP than the SPM (K F = 19.0). The presence of SPM and MWCNTs both improved PCP accumulation in the carp during the 21 days of exposure, and the 21 days PCP concentration in the carp was enhanced by 25.9 and 12.8 % than that without particles, respectively. The enhancement in bioaccumulation by MWCNTs was less than that by the SPM. Considerably more PCP was accumulated in the viscera of the fish (BCF = 519495 for SPM and 148955 for MWCNTs), and the difference in PCP concentrations between different tissues became greater with particles. PCP desorption in the simulated digestive fluids was faster than that in the background solution. Compared to MWCNTs-bound PCP, more SPM-bound PCP was desorbed, and K F of desorption for SPM was at least 4 orders of magnitude higher than that for MWCNTs, which can explain the greater enhancement in bioaccumulation in the presence of SPM. Particle-bound pollutants might pose more risk than pollutants alone. PMID- 24151028 TI - Precipitation softening: a pretreatment process for seawater desalination. AB - Reduction of membrane fouling in reverse osmosis systems and elimination of scaling of heat transfer surfaces in thermal plants are a major challenge in the desalination of seawater. Precipitation softening has the potential of eliminating the major fouling and scaling species in seawater desalination plants, thus allowing thermal plants to operate at higher top brine temperatures and membrane plants to operate at a reduced risk of fouling, leading to lower desalinated water costs. This work evaluated the use of precipitation softening as a pretreatment step for seawater desalination. The effectiveness of the process in removing several scale-inducing materials such as calcium, magnesium, silica, and boron was investigated under variable conditions of temperature and pH. The treatment process was also applied to seawater spiked with other known fouling species such as iron and bacteria to determine the efficiency of removal. The results of this work show that precipitation softening at a pH of 11 leads to complete elimination of calcium, silica, and bacteria; to very high removal efficiencies of magnesium and iron (99.6 and 99.2 %, respectively); and to a reasonably good removal efficiency of boron (61 %). PMID- 24151029 TI - Excellent performance of few-layer borocarbonitrides as anode materials in lithium-ion batteries. AB - Borocarbonitrides (BxCyNz) with a graphene-like structure exhibit a remarkable high lithium cyclability and current rate capability. The electrochemical performance of the Bx Cy Nz materials, synthesized by using a simple solid-state synthesis route based on urea, was strongly dependent on the composition and surface area. Among the three compositions studied, the carbon-rich compound B0.15C0.73N0.12 with the highest surface area showed an exceptional stability (over 100 cycles) and rate capability over widely varying current density values (0.05-1 A g(-1)). B0.15C0.73N0.12 has a very high specific capacity of 710 mA h g(-1) at 0.05 A g(-1) . With the inclusion of a suitable additive in the electrolyte, the specific capacity improved drastically, recording an impressive value of nearly 900 mA h g(-1) at 0.05 A g(-1) . It is believed that the solid electrolyte interphase (SEI) layer at the interface of BxCyNz and electrolyte also plays a crucial role in the performance of the BxCyNz . PMID- 24151030 TI - Phytotherapy of opioid dependence and withdrawal syndrome: a review. AB - Development of tolerance and dependence is a major problem associated with opioid treatment. Withdrawal syndrome is common between medical and illicit users of these agents. Phytomedicine has shown promise in the treatment of this complicated psychosomatic condition. In this study, the effects of plant extracts and active components on morphine dependence and withdrawal syndrome are discussed. Proper keywords were used to search through PubMed, Google Scholar, and SciVerse, as well as two local scientific databases, www.iranmedex.com and www.SID.com. All relevant results (original articles, meeting abstracts, patents, etc.) published from 2000 to 2013 were chosen for final review. A total of 35 plant species were studied on this subject. Plants from Lamiaceae, Ranunculaceae, and Apiaceae families were especially effective. A few studies were carried out on human subjects and the rest in animal models. Opioid dependence and withdrawal syndrome remain an intimidating challenge. Nonetheless, plants and their derivatives are suitable sources for their treatment. Although there are several plants shown to be effective in animal models, few clinical studies are available. PMID- 24151031 TI - Rapid simultaneous determination of twelve major components in Pien Tze Huang by ultra-performance liquid chromatography coupled with triple quadrupole mass spectrometry. AB - An efficient method using ultra-performance LC coupled with triple quadrupole MS was developed for the rapid determination of 12 major active components in Pien Tze Huang (PZH), a well-known traditional Chinese formula. Chromatographic separation was achieved on a Waters XBridge BEH RP18 column (50 mm * 2.1 mm id, 1.7 MUm) with a gradient mobile phase (A: 0.1% aqueous formic acid and B: acetonitrile with 0.1% formic acid) at a flow rate of 0.8 mL/min. The chromatographic peaks of 12 components were identified by comparing their retention time and MS data with the related reference compounds. Multiple reaction monitoring was employed for the quantitative analysis. Ten batches of PZH were analyzed with a good linear regression relationship (r, 0.9987-0.9995), intraday precisions (RSD, 2.05-4.80%), interday precisions (RSD, 1.99-4.98%), repeatability (RSD, 2.21-4.20%), stability (RSD, 3.52-4.81%), and recovery (95.63 104.80%). By using this established method, the present study offered highly sensitive, specific, and speedy determination of 12 major components, which promoted the quality control investigation of PZH greatly. PMID- 24151032 TI - Subthalamic nucleus and striatum: the red and green signals to regulate the traffic of basal ganglia circuitry. PMID- 24151034 TI - Vibrational circular dichroism discrimination of diastereomeric cedranol acetates. AB - The reliability of vibrational circular dichroism (VCD) spectroscopy to discriminate four diastereomeric cedranol acetates 1-4 by means of their absolute configuration is examined. The usage of CompareVOA software to quantify comparisons of the measured infrared (IR) and VCD spectra with the corresponding simulated spectra at the B3LYP/DGDZVP and B3PW91/DGDZVP levels of theory for each diastereomer enabled the B3PW91 functional to be qualified as superior to the B3LYP functional for vibrational calculations of 1-4. Analogously, a set of quantitative VCD spectra cross-comparisons of 1-4 unambiguously distinguished the diastereomers using B3PW91 and failed using B3LYP. Remarkably, quantitative IR spectra cross-comparisons of 1-4 using B3PW91 or B3LYP functionals demonstrated that the achiral spectroscopic IR technique is not able to distinguish cedranol acetate diastereomers. VCD comparisons using anisotropy g-factor values of bands in the 1550-950 cm(-1) region of the spectra were of aid to facilitate visual spectra matching for each diastereomer. PMID- 24151033 TI - Resveratrol Interferes with Fura-2 Intracellular Calcium Measurements. AB - Resveratrol, a naturally occurring polyphenol found in some fruits and especially in grapes, has been reported to provide diverse health benefits. Resveratrol's mechanism of action is the subject of many investigations, and some studies using the ratiometric calcium indicator Fura-2 suggest that it modulates cellular calcium responses. In the current study, contradictory cellular calcium responses to resveratrol applied at concentrations exceeding 10 MUM were observed during in vitro imaging studies depending on the calcium indicator used, with Fura-2 indicating an increase in intracellular calcium while Fluo-4 and the calcium biosensor YC3.60 indicated no response. When cells loaded with Fura-2 were treated with 100 MUM resveratrol, excitation at 340 nm resulted in a large intensity increase at 510 nm, but the expected concurrent decline with 380 nm excitation was not observed. Pre-treatment of cells with the calcium chelator BAPTA-AM did not prevent a rise in the 340/380 ratio when resveratrol was present, but it did prevent an increase in 340/380 when ATP was applied, suggesting that the resveratrol response was an artifact. Cautious data interpretation is recommended from imaging experiments using Fura-2 concurrently with resveratrol in calcium imaging experiments. PMID- 24151035 TI - Single dose oral dexibuprofen [S(+)-ibuprofen] for acute postoperative pain in adults. AB - BACKGROUND: This review is an update of a previously published review in The Cochrane Database of Systematic Reviews Issue 3, 2009 on single dose oral dexibuprofen (S(+)-ibuprofen) for acute postoperative pain in adults.Dexibuprofen is a non-steroidal anti-inflammatory drug (NSAID) licensed for use in rheumatic disease and other musculoskeletal disorders in the UK, and widely available in other countries worldwide. It is an active isomer of ibuprofen. This review sought to evaluate the efficacy and safety of oral dexibuprofen in acute postoperative pain, using clinical studies in patients with established pain, and with outcomes measured primarily over four to six hours, using standard methods. This type of study has been used for many decades to establish that drugs have analgesic properties. OBJECTIVES: To assess the efficacy and adverse effects of single dose oral dexibuprofen for acute postoperative pain using methods that permit comparison with other analgesics evaluated in standardised studies using almost identical methods and outcomes. SEARCH METHODS: Searches were run for the original review in 2009 and subsequent searches have been run in August 2013. We did not find any new published studies as a result of the updated search.We searched for randomised studies of dexibuprofen in acute postoperative pain in MEDLINE, EMBASE, and CENTRAL (The Cochrane LIbrary), and for clinical trial reports and synopses of published and unpublished studies from Internet sources. SELECTION CRITERIA: Randomised, double blind, placebo-controlled clinical studies of oral dexibuprofen for relief of acute postoperative pain in adults. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed study quality and extracted data. We extracted pain relief or pain intensity data and converted it into the dichotomous outcome of number of participants with at least 50% pain relief over four to six hours, from which relative risk and number needed to treat to benefit (NNT) were calculated. Numbers of participants using rescue medication over specified time periods, and time to use of rescue medication, were sought as additional measures of efficacy. We collected information on adverse events and withdrawals. MAIN RESULTS: New data were identified for this update in one unpublished trial synopsis (BR1160 1995) in addition to the single study (Dionne 1998) that was included in the original review. In both studies dexibuprofen gave high levels of response, with 51/96 (53%) participants experiencing at least 50% pain relief with dexibuprofen 200 mg and 35/50 (70%) with dexibuprofen 400 mg, compared with 75/147 (51%) with racemic ibuprofen 400 mg, and 12/62 (13%) with placebo. The numbers of participants was too small to calculate NNTs with any meaning. The median time to additional analgesic use was greater than four hours for all active therapies, but about two hours for placebo.Adverse events were generally of mild or moderate intensity and consistent with events normally associated with anaesthesia and surgery. There were no serious adverse events or deaths.Additional data did not alter the conclusions from the earlier review. AUTHORS' CONCLUSIONS: The information from these two studies in acute postoperative pain suggested that dexibuprofen may be a useful analgesic, but at doses not very different from racemic ibuprofen, for which considerably more evidence exists. PMID- 24151036 TI - Zwitterionic moieties from the Huisgen reaction: a case study with amphiphilic dendritic assemblies. AB - Supramolecular nano-assemblies that reduce nonspecific interactions with biological macromolecules, such as proteins, are of great importance for various biological applications. Recently, zwitterionic materials have been shown to reduce nonspecific interactions with biomolecules, owing both to their charge neutrality and their ability to form a strong hydration layer around zwitterions via electrostatic interactions. Here, new triazole-based zwitterionic moieties are presented that are incorporated as the hydrophilic functionalities in facially amphiphilic dendrons. The amphiphilic zwitterionic dendrons spontaneously self-assemble in aqueous solutions forming micelle-type aggregates, which were confirmed by DLS, TEM, and fluorescence techniques. The structural and functional characteristics of the zwitterionic dendrons are also compared with the corresponding charge-neutral PEG-based dendrons and anionic carboxylate-based dendrons. Surface-charge measurements, temperature sensitivity and evaluation of interactions of these assemblies with proteins form the bases for these comparisons. PMID- 24151037 TI - Catalytic enantioselective synthesis of functionalized tropanes reveals novel inhibitors of hedgehog signaling. AB - Dipolar cycloaddition: A highly efficient copper(I)-catalyzed enantioselective [3+2] cycloaddition reaction of 1,3-fused cyclic azomethine ylides and nitroalkenes has been developed. This method provides access to functionalized tropane scaffolds with several quaternary and tertiary stereocenters in a single step under mild reaction conditions. PMID- 24151038 TI - Vascular tissue engineering: from in vitro to in situ. AB - Blood vessels transport blood to deliver oxygen and nutrients. Vascular diseases such as atherosclerosis may result in obstruction of blood vessels and tissue ischemia. These conditions require blood vessel replacement to restore blood flow at the macrocirculatory level, and angiogenesis is critical for tissue regeneration and remodeling at the microcirculatory level. Vascular tissue engineering has focused on addressing these two major challenges. We provide a systematic review on various approaches for vascular graft tissue engineering. To create blood vessel substitutes, bioengineers and clinicians have explored technologies in cell engineering, materials science, stem cell biology, and medicine. The scaffolds for vascular grafts can be made from native matrix, synthetic polymers, or other biological materials. Besides endothelial cells, smooth muscle cells, and fibroblasts, expandable cells types such as adult stem cells, pluripotent stem cells, and reprogrammed cells have also been used for vascular tissue engineering. Cell-seeded functional tissue-engineered vascular grafts can be constructed in bioreactors in vitro. Alternatively, an autologous vascular graft can be generated in vivo by harvesting the capsule layer formed around a rod implanted in soft tissues. To overcome the scalability issue and make the grafts available off-the-shelf, nonthrombogenic vascular grafts have been engineered that rely on the host cells to regenerate blood vessels in situ. The rapid progress in the field of vascular tissue engineering has led to exciting preclinical and clinical trials. The advancement of micro /nanotechnology and stem cell engineering, together with in-depth understanding of vascular regeneration mechanisms, will enable the development of new strategies for innovative therapies. PMID- 24151039 TI - Effects of tibolone on osteoarthritis in ovariectomized rats: association with nociceptive pain behaviour. AB - BACKGROUND: To investigate the role of the synthetic steroid tibolone in the progression of osteoarthritis (OA) and in nociceptive behaviour in an experimental rat model of OA and ovariectomy (OVX)-induced osteoporosis. METHODS: OA was induced in Wistar rats by anterior cruciate ligament transection (ACLT) of the right knee. Osteoporosis was induced by bilateral OVX. Groups of animals were subjected to ACLT, OVX, sham or OVX + ACLT. In addition, two groups were subjected to OVX + ACLT surgeries and were orally administered 0.1 or 0.5 mg tibolone every other day for 14 consecutive weeks, starting 6 weeks after surgery. Nociceptive behaviours (secondary mechanical allodynia and weight bearing distribution of the hind paws) were analysed prior to and every 3 weeks after surgery up to 24 weeks. At 24 weeks, histopathological studies were performed on the cartilage and synovial membranes of the knee joints, and bone metabolism was assessed by measuring serum concentrations of calcium, phosphorus and alkaline phosphatase. RESULTS: Rats undergoing ACLT or OVX + ACLT surgeries showed obvious OA changes in the joints. Animals subjected to ACLT + OVX and treated with tibolone had significantly less cartilage degeneration and synovitis and showed improved nociceptive tests compared with animals undergoing ACLT + OVX surgeries alone. OVX increased the severity of the ACLT-induced OA changes. There was a significant increase in serum alkaline phosphatase in the tibolone-treated ACLT + OVX groups. CONCLUSIONS: Treatment with tibolone attenuated the development of OA, concomitantly reduced nociception and increased serum alkaline phosphatase in ACLT + OVX rats. PMID- 24151040 TI - The lungs as anatomical reservoirs of HIV infection. AB - Failure of antiretroviral therapy to eradicate HIV, even in individuals who suppress the virus to undetectable levels, is a consequence of persistent infection in latently infected cells and within anatomical reservoirs. Support for the notion that the lungs are distinct anatomical reservoirs of HIV comes from a spectrum of studies that have documented different levels of HIV within the lungs compared with the peripheral blood. Different HIV variants have also been found within these two compartments, including variants with distinct antiretroviral resistance mutations. Given that macrophages are long-lived cellular reservoirs of HIV because of their resistance to apoptosis, HIV can persist for prolonged periods within alveolar macrophages that are abundant within the lungs. Furthermore, the large number of cells in close proximity within the lungs provides fertile grounds for cell-to-cell spread of HIV. Distinct immunological pressures in the lungs compared with the peripheral blood likely account for differences in HIV levels within these two compartments in addition to the finding of different variants within these regions. Furthermore, coinfections and tobacco may serve as local stimuli to induce further HIV replication within the lungs. Herein, we review the evidence supporting the notion that lungs are important reservoirs of HIV infection, and we discuss various factors influencing HIV burden within these reservoirs. PMID- 24151042 TI - Commentary on the role of expert opinion in developing evidence-based guidelines. AB - Evidence-based clinical practice guidelines (CPGs) help guide busy practitioners in clinical decision making. CPGs are evidence-based in that recommendations are based on available knowledge derived from published clinical trials. The challenges presented by the tasks of finding, assessing, interpreting, and assembling the information in these reports are herculean. Missing or imperfect evidence may lead to the publication of suboptimal guidelines, even when the other components of the development process have been flawlessly performed. This commentary highlights the requirement that expert opinion must be explicitly recognized by CPG authoring groups when the published evidence is missing or inadequate. PMID- 24151041 TI - Association between sarcopenia and the risk of serious infection among adults undergoing liver transplantation. AB - Although sarcopenia (muscle loss) is associated with increased mortality after liver transplantation, its influence on other complications is less well understood. We examined the association between sarcopenia and the risk of severe posttransplant infections among adult liver transplant recipients. By calculating the total psoas area (TPA) on preoperative computed tomography scans, we assessed sarcopenia among 207 liver transplant recipients. The presence or absence of a severe posttransplant infection was determined by a review of the medical chart. The influence of posttransplant infections on overall survival was also assessed. We identified 196 episodes of severe infections among 111 patients. Fifty-six patients had more than 1 infection. The median time to the development of an infection was 27 days (interquartile range = 13-62 days). When the patients were grouped by TPA tertiles, patients in the lowest tertile had a greater than 4-fold higher chance of developing a severe infection in comparison with patients in the highest tertile (odds ratio = 4.6, 95% confidence interval = 2.25-9.53). In a multivariate analysis, recipient age (hazard ratio = 1.04, P = 0.02), pretransplant TPA (hazard ratio = 0.38, P < 0.01), and pretransplant total bilirubin level (hazard ratio = 1.05, P = 0.02) were independently associated with the risk of developing severe infections. Patients with severe posttransplant infections had worse 1-year survival than patients without infections (76% versus 92%, P = 0.003). In conclusion, among patients undergoing liver transplantation, a lower TPA was associated with a heightened risk for posttransplant infectious complications and mortality. Future efforts should focus on approaches for assessing and mitigating vulnerability in patients undergoing transplantation. PMID- 24151043 TI - SEOM clinical guidelines for the management of metastatic breast cancer 2013. AB - Patients with metastatic breast cancer should be offered comprehensive and personalized medical attention including, but not limited to, psychosocial, supportive and symptom-related interventions. A large number of treatment options are available and several prognostic and predictive factors are useful to identify the best therapeutic options individually. PMID- 24151044 TI - Differentiation and interaction of tibial versus spinal nerve stimulation for micturition control in the rat. AB - AIMS: To determine time course of the bladder inhibitory response to unilateral or bilateral stimulation of the tibial nerve (TN) and spinal nerve (SN) as well as the interaction of stimulation at these two sites. METHODS: In anesthetized female rats, a wire electrode was placed under either one or both of the TN or L6 SN. A cannula was placed into the bladder via the urethra. Saline infusion induced bladder rhythmic contraction (BRC). RESULTS: Compared to SN neuromodulation, TN neuromodulation is less efficacious. The first 5-min stimulation at three times motor threshold on the SN and TN decreased the BRC frequency to 9% and 69% of controls, respectively. In contrast to SN stimulation, bilateral TN neuromodulation is not more effective than unilateral and sustained TN stimulation results in an apparent desensitization of the bladder response. If a 15-min TN stimulation was applied, BRCs were shutdown only during the first 5 min of stimulation. If a 5-min stimulation, using sufficient current to abolish BRC, is repeated, at least 20 min between stimulations was required in order for the responses to the first and second stimulations to be equivalent. Finally, stimulation of the TN combined with SN never produced a significantly greater effect than TN or SN stimulation alone. CONCLUSIONS: Based on the current experiments, it would appear that SN neuromodulation of bladder activity is preferable to TN stimulation and there is no evidence to suggest that stimulation at both sites would offer a therapeutic advantage over spinal stimulation alone. PMID- 24151045 TI - Factors associated with breast and cervical cancer screening in Korea: data from a national community health survey. AB - This study investigated factors associated with breast and cervical cancer screening using data from a nationwide community survey. A nationwide cross sectional study was performed in all 253 administrative districts of Korea. The breast and cervical cancer screening rate was negatively associated with the obesity (beta = -2.91, 95% confidence interval [CI] = -4.73 to -1.03; beta = 1.93, 95% CI = -3.43 to -0.43), positively associated with the European Quality of Life-5 Dimensions scale (beta =2.53, 95% CI = 0.24 to 4.81; beta = 2.51, 95% CI = 0.68 to 4.34). Moreover, higher alcohol consumption rate was negatively related to screening rates for breast cancer, while areas with higher proportion of diabetes were found to have higher screening rates. Area with higher rate of osteoarthritis had a lower screening rate for cervical cancer. This study showed breast and cervical cancer screening was associated with particular area characteristics. This ecological approach is thought to be a major complement to measures of health attributes. PMID- 24151046 TI - GKN2 contributes to the homeostasis of gastric mucosa by inhibiting GKN1 activity. AB - Gastrokine 1 (GKN1) plays an important role in maintaining gastric mucosa integrity. Here, we investigated whether gastrokine 2 (GKN2) contributes to the homeostasis of gastric epithelial cells by regulating GKN1 activity. We analyzed cell viability, proliferation, and death in AGS cells transfected with GKN1, GKN2, GKN1 plus GKN2 using MTT, BrdU incorporation, and apoptosis assays, respectively. In addition, the expression levels of the cell cycle- and apoptosis related proteins, miR-185, DNMT1, and EZH2 were determined. We also compared the expression of GKN1, GKN2, and CagA in 50 non-neoplastic gastric mucosae and measured GKN2 expression in 169 gastric cancers by immunohistochemistry. GKN2 inhibited anti-proliferative and pro-apoptotic activities, miR-185 induction, and anti-epigenetic modifications of GKN1. There was a positive correlation between GKN1 and GKN2 expression (P = 0.0074), and the expression of GKN1, but not GKN2, was significantly lower in Helicobacter pylori CagA-positive gastric mucosa (P = 0.0013). Interestingly, ectopic GKN1 expression in AGS cells increased GKN2 mRNA and protein expression in a time-dependent manner (P = 0.01). Loss of GKN2 expression was detected in 126 (74.6%) of 169 gastric cancers by immunohistochemical staining and was closely associated with GKN1 expression and differentiation of gastric cancer cells (P = 0.0002 and P = 0.0114, respectively). Overall, our data demonstrate that in the presence of GKN2, GKN1 loses its ability to decrease cell proliferation, induce apoptosis, and inhibit epigenetic alterations in gastric cancer cells. Thus, we conclude that GKN2 may contribute to the homeostasis of gastric epithelial cells by inhibiting GKN1 activity. PMID- 24151047 TI - Highly emissive luminogens based on imidazo[1,2-a]pyridine for electroluminescent applications. AB - A search for novel organic luminogens led us to design and synthesize some N fused imidazole derivatives based on imidazo[1,2-a]pyridine as the core and arylamine and imidazole as the peripheral groups. The fluorophores were synthesized through a multicomponent cascade reaction (A(3) coupling) of a heterocyclic azine with an aldehyde and alkyne, followed by Suzuki coupling and a multicomponent cyclization reaction. All of the compounds exhibited interesting photophysical responses, especially arylamine-containing derivatives, which displayed strong positive solvatochromism in the emission spectra that indicated a more polar excited state owing to an efficient charge migration from the donor arylamine to the imidazo[1,2-a]pyridine acceptor. The quantum yields ranged from 0.2 to 0.7 and depended on the substitution pattern, most notably that based on the donor group at the C2 position. Moreover, the influence of general and specific solvent effects on the photophysical properties of the fluorophores was discussed with four-parameter Catalan and Kamlet-Taft solvent scales. The excellent thermal, electrochemical, and morphological stability of the compounds was explored by cyclic voltammetry, thermogravimetric analysis, and AFM methods. Furthermore, to understand the structure, bonding, and band gap of the molecules, DFT calculations were performed. The performance of the electroluminescence behavior of the imidazo[1,2-a]pyridine derivative was investigated by fabricating a multilayer organic light-emitting diode with a configuration of ITO/NPB (60 nm)/EML (40 nm)/BCP (15 nm)/Alq3 (20 nm)/LiF (0.5 nm)/Al(100 nm) (ITO=indium tin oxide, EML=emissive layer, BCP=2,9-dimethyl-4,7-diphenyl-1,10-phenanthroline, Alq3 =tris(8-hydroxyquinolinato)aluminum), which exhibited white emission with a turn-on voltage of 8 V and a brightness of 22 cd m(-2). PMID- 24151048 TI - Breathing effect in a cobalt phosphonate upon dehydration/rehydration: a single crystal-to-single-crystal study. AB - Two cobalt phosphonates, [Co2(2,2'-bpy)2(H2O)(pbtcH)] (1) and [Co2(H2O)(pbtcH)(phen)2] (2; pbtcH5=5-phosphonatophenyl-1,2,4-tricarboxylic acid, 2,2'-bpy=2,2'-bipyridine, phen=1,10-phenanthroline), with layer structures are reported. Compound 1 contains O-C-O and O-P-O bridged tetramers of Co4, which are further connected by pbtcH(4-) units to form a layer. In compound 2, the cobalt tetramers made up of water-bridged Co2 dimers and O-P-O linkages are connected into a layer by pbtcH(4-) units. Upon dehydration, compounds 1 and 2 experience single-crystal-to-single-crystal (SC-SC) structural transformations to form [Co2(2,2'-bpy)2(pbtcH)] (1 a) and [Co2(pbtcH)(phen)2] (2 a), respectively. The process is reversible in each case. Notably, a breathing effect is observed for 1, accompanied by pore opening and closing due to the reorientation of the coordinated 2,2'-bpy molecules. The transformation was also monitored by in situ IR measurements. Magnetic studies reveal that antiferromagnetic interactions are mediated between the magnetic centers in compounds 1 and 1 a, whereas ferromagnetic interactions are dominant in compound 2. PMID- 24151049 TI - Minimum set of cytochromes P450 for reconstituting the biosynthesis of camalexin, a major Arabidopsis antibiotic. AB - Bringing it all together: The missing key step in the biosynthesis of camalexin was uncovered by in vitro biochemical characterization. The coupling of Trp- and Cys-derived fragments through C?S bond formation is promoted by an unusual cytochrome P450 CYP71A13. The in vitro reconstitution of the camalexin biosynthesis (left) from Trp and Cys was achieved using just three cytochromes P450. IAN=indole-3-acetonitrile. PMID- 24151051 TI - Multi-level quantum Monte Carlo wave functions for complex reactions: the decomposition of alpha-hydroxy-dimethylnitrosamine. AB - We present here several novel features of our recently proposed Jastrow linear generalized valence bond (J-LGVB) wave functions, which allow a consistently accurate description of complex potential energy surfaces (PES) of medium-large systems within quantum Monte Carlo (QMC). In particular, we develop a multilevel scheme to treat different regions of the molecule at different levels of the theory. As prototypical study case, we investigate the decomposition of alpha hydroxy-dimethylnitrosamine, a carcinogenic metabolite of dimethylnitrosamine (NDMA), through a two-step mechanism of isomerization followed by a retro-ene reaction. We compute a reliable reaction path with the quadratic configuration interaction method and employ QMC for the calculation of the electronic energies. We show that the use of multideterminantal wave functions is very important to correctly describe the critical points of this PES within QMC, and that our multilevel J-LGVB approach is an effective tool to significantly reduce the cost of QMC calculations without loss of accuracy. As regards the complex PES of alpha hydroxy-dimethylnitrosamine, the accurate energies computed with our approach allows us to confirm the validity of the two-step reaction mechanism of decomposition originally proposed within density functional theory, but with some important differences in the barrier heights of the individual steps. PMID- 24151050 TI - HCVAD plus imatinib or dasatinib in lymphoid blastic phase chronic myeloid leukemia. AB - BACKGROUND: Chronic myeloid leukemia (CML) may progress to blast phase (BP) at the rate of 1% to 1.5% per year. With the use of single-agent tyrosine kinase inhibitors, median overall survival ranges between 7 and 11 months. METHODS: The outcome was analyzed for 42 patients with lymphoid BP-CML who were treated with hyperfractionated cyclophosphamide, vincristine, Adriamycin, dexamethasone (HCVAD) plus imatinib or dasatinib. RESULTS: Complete hematological response was achieved in 90% of patients, complete cytogenetic remission in 58%, and complete molecular remission in 25%. Flow cytometry minimal residual disease negativity was achieved by 42% of evaluable patients after induction. Eighteen patients received allogeneic stem cell transplant (SCT) while in first complete hematological response. Median remission duration was 14 months and was longer among SCT recipients (P = .01) on multivariate analysis. Median overall survival was 17 months (range, 7-27 months) and was longer among SCT recipients (P < .001) and patients treated with dasatinib (P = .07) on multivariate analysis. Although a high rate of hematologic toxicity (100%) and infectious complications (59%) were observed, the related rate of treatment discontinuation was low (7% and 9%, respectively). CONCLUSIONS: HCVAD combined with tyrosine kinase inhibitors is an effective regimen for the management of BP-CML, particularly when followed by allogeneic SCT. PMID- 24151052 TI - Rapid identification and comparative analysis of the chemical constituents and metabolites of Phellodendri amurensis cortex and Zhibai dihuang pill by ultra performance liquid chromatography with quadrupole TOF-MS. AB - Zhibai dihuang pill is a famous traditional Chinese medicine formula containing the herbal medicine Phellodendri amurensis cortex. In this work, an integrative pattern recognition approach including principal component analysis and orthogonal partial least squared discriminant analysis based on ultra-performance liquid chromatography coupled to MS was successfully applied for the rapid discovery of natural compounds from herbal medicines. In a 24 min analysis, 93 compounds were identified or tentatively characterized from Zhibai dihuang pill based on their fragmentation behaviors, 23 of which were from Phellodendri amurensis cortex. A total of 26 metabolites in plasma were identified from Phellodendri amurensis cortex in Zhibai dihuang pill formula, among them, 12 prototypes and 14 metabolites through metabolic pathways of demethylation, methylation, hydrolysis, sulfate conjugation, and glucuronide conjugation, which were seven metabolites more than that of the single drug, suggesting the importance of the compatibility of traditional Chinese medicine. The present study provided important structural information on the metabolism of Zhibai dihuang pill. Furthermore, the results of this work have demonstrated the feasibility of ultra-performance liquid chromatography coupled to MS for the rapid and reliable characterization of metabolites from herbal medicines. Based on these results, this method could be a novel approach for identifying potentially bioactive components in other traditional Chinese medicines. PMID- 24151053 TI - Focused ultrasound thalamotomy improves essential tremor. PMID- 24151054 TI - Evaluating the health literacy burden of Canada's public advisories: a comparative effectiveness study on clarity and readability. AB - BACKGROUND: Significant knowledge gaps exist related to evaluating health product risk communication effectiveness in a regulatory setting. To this end, Health Canada is assessing methods to evaluate the effectiveness of their health product risk communications in an attempt to identify best practices. OBJECTIVE: We examined the health literacy burden of Public Advisories (PAs) before and after implementation of a new template. We also compared two methods for their usefulness and applicability in a regulatory setting. METHODS: Suitability assessment of materials (SAM) and readability tests were run by three independent evaluators on 46 PAs (14 "Pre-format change" and 32 "Post-format change"). These tests provided adequacy scores for various health literacy elements and corresponding scholastic grades. RESULTS: PAs using the new template scored better, with an average increase of 18 percentage points (p < 0.001), on the SAM test. All of the 46 PAs evaluated were rated as "requiring a college/university education comprehension level" using readability tests. Results among readability tests were comparable. CONCLUSION: Improvements made to Health Canada's PA template had a measurable, positive effect on reducing the health literacy burden, based on the SAM results. A greater focus on the use of plain language would likely add to this effect. The SAM test emerged as a robust, reliable, and informative health literacy tool to assess risk messages and identify further improvement efforts. Regulators, industry, and public sector organizations involved in communicating health product risk information should consider the use of this test as a best practice to evaluate health literacy burden. PMID- 24151055 TI - A genetic counselor's guide to using next-generation sequencing in clinical practice. AB - Advances in next-generation sequencing (NGS) and rapid reductions in cost have increased the use of such technologies in research and clinical practice. However, many barriers exist to translating NGS for routine clinical use, including issues related to the interpretation of results, and the potential to find results that are secondary or incidental to the specific application of NGS. Nonetheless, NGS has become sufficiently affordable to be offered by several clinical laboratories, and increasingly it is becoming an attractive and viable option for clinicians and patients. This article reviews current NGS technologies, highlighting the information genetic counselors need to know to make informed-decisions about utilizing NGS in the clinic, and underscoring the impact of this new testing modality on the practice of genetic counseling. PMID- 24151056 TI - An in vitro and molecular informatics study to evaluate the antioxidative and beta-hydroxy-beta-methylglutaryl-CoA reductase inhibitory property of Ficus virens Ait. AB - The present study is initially intended to evaluate antioxidant and beta-hydroxy beta-methylglutaryl-CoA reductase (HMGR) inhibitory property of Ficus virens Ait., first by in vitro analyses followed by a corroboratory molecular informatics study. Our results show that of all the sequentially extracted fraction of F. virens bark and leaves extract, F. virens bark methanol extract exhibits strong radical scavenging, antioxidant and oxidative DNA damage protective activity, which is well correlated with its total phenolic content. In addition, F. virens bark methanol extract, which is non-cytotoxic, significantly and non-covalently inhibit the HMGR activity (IC50 = 3.45 +/- 0.45 ug/ml) in comparison with other extracts. The mechanistic aspect of this inhibition activity is authenticated by molecular docking study of bioactive compounds as revealed from gas chromatography-mass spectrometry data, with HMGR. The analysis for the first time indicates that quinic acid (DeltaG: -8.11 kcal/mol) and paravastatin (DeltaG: -8.22 kcal/mol) exhibit almost same binding energy, while other compounds also showed good binding energy, suggesting that quinic acid alone or in combination with other major bioactive compound is probably responsible for HMGR inhibitory property of the extract and plausibly can be used in in vivo system for the management, prevention, and alleviation of hypercholesterolemia as well as hypercholesterolemia-induced oxidative stress. PMID- 24151057 TI - Ultrasound-guided thrombin injection in the treatment of iatrogenic arterial pseudoaneurysms: single-center experience. AB - The aim of this study was to assess the safety and efficacy of ultrasound-guided percutaneous thrombin injection for the treatment of postcatheterization arterial pseudoaneurysms. We evaluated retrospectively 82 consecutive subjects treated with percutaneous ultrasound-guided thrombin injection of postcatheterization femoral (n = 79), brachial (n = 2), and radial (n = 1) pseudoaneurysms from January 2006 to April 2012. Pseudoaneurysm size, thrombin dose, and therapy outcome were documented. All pseudoaneurysm sacs were thrombosed with a single injection. The overall primary success rate (complete sac thrombosis) was 92.7%. A 30-day Doppler ultrasound follow-up showed a 100% procedural success. There were no complications. PMID- 24151058 TI - Problems encountered in managing of hCG findings in Spanish football. PMID- 24151059 TI - Reply: To PMID 23813604. PMID- 24151060 TI - CSF dynamic analysis of a predictive pulsatility-based infusion test for normal pressure hydrocephalus. AB - Disturbed cerebrospinal fluid (CSF) dynamics are part of the pathophysiology of normal pressure hydrocephalus (NPH) and can be modified and treated with shunt surgery. This study investigated the contribution of established CSF dynamic parameters to AMP(mean), a prognostic variable defined as mean amplitude of cardiac-related intracranial pressure pulsations during 10 min of lumbar constant infusion, with the aim of clarifying the physiological interpretation of the variable. AMP(mean) and CSF dynamic parameters were determined from infusion tests performed on 18 patients with suspected NPH. Using a mathematical model of CSF dynamics, an expression for AMP(mean) was derived and the influence of the different parameters was assessed. There was high correlation between modelled and measured AMP(mean) (r = 0.98, p < 0.01). Outflow resistance and three parameters relating to compliance were identified from the model. Correlation analysis of patient data confirmed the effect of the parameters on AMP(mean) (Spearman's rho = 0.58-0.88, p < 0.05). Simulated variations of +/-1 standard deviation (SD) of the parameters resulted in AMP(mean) changes of 0.6-2.9 SD, with the elastance coefficient showing the strongest influence. Parameters relating to compliance showed the largest contribution to AMP(mean), which supports the importance of the compliance aspect of CSF dynamics for the understanding of the pathophysiology of NPH. PMID- 24151061 TI - Upper aero-digestive tract lymphomas presenting as polypoidal/pedunculated lesions: case report and review of literature. AB - AIM: To describe a case of diffuse large B cell lymphoma (DLBCL) presenting as a pedunculated/polypoidal mass in upper aero-digestive tract and to review pertinent literature. METHODS: Using Pubmed advanced search, case reports and literature were reviewed for this condition. RESULTS: A 16 year old female presented with history of shortness of breath when lying down, voice change, progressing odynophagia and feeling of throat lump. Direct visualization showed flower like pedunculated mass, attached to the left lateral oropharyngeal wall. Excision of this mass showed DLBCL and no disease anywhere. She received four cycles of Rituximab + CHOP and is disease-free for 4 years. Only 21 cases of pedunculated upper aero-digestive tract lymphomas have been reported in literature. Median age 53 years (16-90 years), males 80 %, females 20 %, localized disease (65 %). Common sites were endobronchial polypoid lesion (7 cases), nasal polyps (7), nasopharyngeal polyps (2), nose and paranasal sinus (1), laryngeal polyp (2) and one each as gum, esophagus and oropharyngeal (current case) polyp. Pathology showed aggressive lymphoma in 94 %. CONCLUSION: DLBCL as an extranodal pedunculated lesion in the oropharynx is very rare. Careful pathological evaluation is essential for these lesions for proper diagnosis. PMID- 24151062 TI - Extensive HPV-related carcinoma in situ of the upper aerodigestive tract with 'nonkeratinizing' histologic features. AB - Over the past several decades, it has become clear that human papillomavirus (HPV) is important for the development and progression of many head and neck squamous cell carcinomas, particularly those arising in the oropharyngeal tonsillar crypts. Yet, our understanding of HPV's role in premalignant squamous lesions remains relatively poor. This is in part because premalignant lesions of the oropharyngeal tonsillar crypt tissue, where most HPV-related carcinomas arise, are difficult if not impossible to identify. Recent evidence does suggest a role for HPV in a subset of premalignant lesions of the surface epithelium, especially the oral cavity, despite the rarity of HPV-related invasive squamous cell carcinomas at this site. Furthermore, these HPV-related oral cavity dysplasias appear to have unique, bowenoid histologic features described as 'basaloid' with full-thickness loss of squamous maturation, mitotic figures and apoptosis throughout. Here, we present a unique case of an HPV-related premalignant lesion (squamous cell carcinoma in situ) extensively involving the surface epithelium of the oral cavity, oropharynx and larynx that had 'nonkeratinizing' histologic features typical of HPV-related invasive squamous cell carcinoma. This case was strongly p16 positive by immunohistochemistry and harbored transcriptionally active HPV as demonstrated by E6/E7 RNA in situ hybridization. Furthermore, the patient had an excellent response to radiation treatment. PMID- 24151063 TI - Synthesis and evaluation of two coumarin-type derivatization reagents for fluorescence detection of chiral amines and chiral carboxylic acids. AB - The synthesis of two fluorescent coumarin-type chiral derivatization agents (4 and 11) is reported. A chiral side chain was introduced at position 7 of the coumarin via Mitsunobu reaction. The two coumarins bear in this side chain either a free amino group or a carboxyl group, making them useful for further transformations. Conjugates of chiral prototype drugs with 4 or 11 were prepared by amide coupling of the analyte's carboxyl group to the reagent's amine group, or vice versa. The separation of seven diastereomeric conjugates through achiral high-performance liquid chromatography (HPLC) on a common C18 column is demonstrated. PMID- 24151065 TI - Aromatase inhibitors for uterine fibroids. AB - BACKGROUND: Uterine fibroids, also called uterine leiomyomas or myomas, are the most common benign tumours in women of reproductive age. Albeit generally benign, uterine fi broids can have a major impact on women's health and quality of life by contributing to abnormal uterine bleeding and causing pelvic pressure symptoms (such as increased urinary frequency, pelvic pain and constipation). Traditional treatments for symptomatic fi broids include a variety of surgical techniques. However, because of the high recurrence rate, as well as possible pain and infertility caused by the formation of postoperative adhesions, this approach may not be advisable. Safer and more effective medical therapy has long been awaited. Both in vitro studies and clinical trials have suggested that use of the aromatase inhibitors (AIs), a class of anti-oestrogens, might inhibit fi broid growth, thereby eliminating the need for surgery. OBJECTIVES: To evaluate the effectiveness and safety of aromatase Inhibitors (AIs) in women with uterine fibroids. SEARCH METHODS: We searched the following databases (from inception to August 21, 2013): Cochrane Menstrual Disorders and Subfertility Group Specialised Register, Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library), MEDLINE, EMBASE, CINAHL and PsycINFO. In addition, the reference lists of included trials were searched, and experts in the field were contacted. SELECTION CRITERIA: Randomised controlled trials (RCTs) in women of reproductive age comparing the effects of any AI versus placebo, no treatment or any medical treatment/surgery were included. DATA COLLECTION AND ANALYSIS: Selection of eligible trials, assessment of trial quality and data extraction were performed independently by two review authors. If data were available, we planned to calculate odds ratios (ORs) for analysis of dichotomous data and mean differences for continuous data, with 95% confidence intervals (CIs). MAIN RESULTS: Only one trial involving 70 participants was included. This trial did not report our primary review outcome (relief of symptoms of fibroids). The only secondary review outcomes reported by this trial were adverse effects (hot flushes) and reduction in fibroid size. Significantly fewer women reported hot flushes in the letrozole group than in the GnRHa group (0/33 vs 26/27, P < 0.05). Use of letrozole reduced fibroid volume by 46% and use of a gonadotrophin-releasing hormone (GnRH) agonist (GnRHa) by 32% after 12 weeks of treatment; these proportions were not significantly different. The included trial did not report data on fibroid volume in a form that permitted calcuation of an odds ratio. Morevoer it was unblinded and included only 60/70 women in analysis. AUTHORS' CONCLUSIONS: Evidence is insufficient to support the use of AI drugs in the treatment of women with uterine fibroids. PMID- 24151064 TI - Electrophysiological characterization of spinal neuron sensitization by elevated calcium channel alpha-2-delta-1 subunit protein. AB - BACKGROUND: Voltage-gated calcium channel alpha2 delta1 subunit is the binding site for gabapentin, an effective drug in controlling neuropathic pain states including thermal hyperalgesia. Hyperalgesia to noxious thermal stimuli in both spinal nerve-ligated (SNL) and voltage-gated calcium channel alpha2 delta1 overexpressing transgenic (Tg) mice correlates with higher alpha2 delta1 levels in dorsal root ganglia and dorsal spinal cord. In this study, we investigated whether abnormal synaptic transmission is responsible for thermal hyperalgesia induced by elevated alpha2 delta1 expression in these models. METHODS: Behavioural sensitivities to thermal stimuli were test in L4 SNL and sham mice, as well as in alpha2 delta1 Tg and wild-type mice. Miniature excitatory (mEPSC) and inhibitory (mIPSC) post-synaptic currents were recorded in superficial dorsal spinal cord neurons from these models using whole-cell patch clamp slice recording techniques. RESULTS: The frequency, but not amplitude, of mEPSC in superficial dorsal horn neurons was increased in SNL and alpha2 delta1 Tg mice, which could be attenuated by gabapentin dose dependently. Intrathecal alpha2 delta1 antisense oligodeoxynucleotide treatment diminished increased mEPSC frequency and gabapentin's inhibitory effects in elevated mEPSC frequency in the SNL mice. In contrast, neither the frequency nor the amplitude of mIPSC was altered in superficial dorsal horn neurons from the SNL and alpha2 delta1 Tg mice. CONCLUSIONS: Our findings support a role of peripheral nerve injury-induced alpha2 delta1 in enhancing pre-synaptic excitatory input onto superficial dorsal spinal cord neurons that contributes to nociception development. PMID- 24151066 TI - Reduction of oxidative stress may play a role in the anti-inflammatory effect of the novel herbal formulation in a rat model of hydrochloric acid-induced cystitis. AB - AIMS: We investigated the effect of the multi-herbal medicine, WSY-1075 in an animal model of hydrochloric acid (HCl)-induced cystitis. METHODS: Rats were randomly assigned to three groups: sham-operated (control), HCl-induced only (HC), and HC treated with WSY-1075 (HC + WT). Oral administration of either distilled water (control, HC) or WSY-1075 (400 mg/kg) was continued for 4 weeks. In HC and HC + WT groups, cystitis was induced with 0.4 M HCl beginning on the 22nd day. Rats in each group underwent cystometrography, and bladders were examined for evidence of inflammation and oxidative stress. RESULTS: Treatment with WSY-1075 decreased the frequency of urination and reduced inflammation of the bladder tissue in a rat model of HCl-induced cystitis. Compared with the control group, the HC group showed severe chronic inflammatory and fibrosis signs, and the inflammatory grades significantly decreased following WSY-1075 treatment in the HC-WT group. The HC + WT group showed a markedly decreased expression of pro-inflammatory cytokines compared to the HC group. The level of malondialdehyde was significantly greater in the HC group compared to the control group, and it was significantly reduced in the treated (HC + WT) group. The levels of superoxide dismutase increased in the HC + WT group, which confirmed the anti-oxidant effect of WSY-1075. CONCLUSIONS: We suggest that reduction of oxidative stress may play a role in this anti-inflammatory effect. PMID- 24151068 TI - Problematic internet use in childhood and youth: evolution of a 21st century affliction. AB - OBJECTIVE: To describe the emergence of, and myriad issues pertaining to, problematic internet use in childhood and youth. In this overview and appraisal of a uniquely 21st century affliction, the focus is on youth and less on young adult perspectives. CONCLUSIONS: We employed relevant literature-search methodology though EMBASE, Psychinfo and Web of Science, utilising the key terms of PIU, internet addiction and youth mental health, and present a selection of the pioneering and important research developments both nationally and internationally. We focused on the literature from the past 10 years, but we also included relevant early developments in the field going back to the 1990s. We also made reference, where appropriate, to major considerations of relevance to the general public, where these were reported in reputable international news and media organisations. The authors utilised common internet search engines to access these news reports. It was found that the complex, novel and at times controversial concept of 'problematic internet use' (PIU)--often popularly dubbed 'internet addiction'--has attracted much public, media and research interest, particularly over the past decade. In common with many other afflictions that have a prominent 'pop-cultural' component, often the commentary and debate has been polarising, unclear and sensationalist. At times, more light than heat appears to be generated. PMID- 24151067 TI - Three-dimensional hemodynamics in intracranial aneurysms: influence of size and morphology. AB - PURPOSE: To use four-dimensional (4D)-flow MRI for the comprehensive in vivo analysis of hemodynamics and its relationship to size and morphology of different intracranial aneurysms (IA). We hypothesize that different IA groups, defined by size and morphology, exhibit different velocity fields, wall shear stress, and vorticity. MATERIALS AND METHODS: The 4D-flow MRI (spatial resolution = 0.99-1.8 * 0.78-1.46 * 1.2-1.4 mm(3) , temporal resolution = 44-48 ms) was performed in 19 IAs (18 patients, age = 55.4 +/- 13.8 years) with saccular (n = 16) and fusiform (n = 3) morphology and different sizes ranging from small (n = 8; largest dimension = 6.2 +/- 0.4 mm) to large and giant (n = 11; 25 +/- 7 mm). Analysis included quantification of volumetric spatial-temporal velocity distribution, vorticity, and wall shear stress (WSS) along the aneurysm's 3D surface. RESULTS: The 4D-flow MRI revealed distinct hemodynamic patterns for large/giant saccular aneurysms (Group 1), small saccular aneurysms (Group 2), and large/giant fusiform aneurysms (Group 3). Saccular IA (Groups 1, 2) demonstrated significantly higher peak velocities (P < 0.002) and WSS (P < 0.001) compared with fusiform aneurysms. Although intra-aneurysmal 3D velocity distributions were similar for Group 1 and 2, vorticity and WSS was significantly (P < 0.001) different (increased in Group 1 by 54%) indicating a relationship between IA size and hemodynamics. Group 3 showed reduced velocities (P < 0.001) and WSS (P < 0.001). CONCLUSION: The 4D flow MRI demonstrated the influence of lesion size and morphology on aneurysm hemodynamics suggesting the potential of 4D-flow MRI to assist in the classification of individual aneurysms. PMID- 24151069 TI - Molecular mechanism of GTPase activation at the signal recognition particle (SRP) RNA distal end. AB - The signal recognition particle (SRP) RNA is a universally conserved and essential component of the SRP that mediates the co-translational targeting of proteins to the correct cellular membrane. During the targeting reaction, two functional ends in the SRP RNA mediate distinct functions. Whereas the RNA tetraloop facilitates initial assembly of two GTPases between the SRP and SRP receptor, this GTPase complex subsequently relocalizes ~100 A to the 5',3'-distal end of the RNA, a conformation crucial for GTPase activation and cargo handover. Here we combined biochemical, single molecule, and NMR studies to investigate the molecular mechanism of this large scale conformational change. We show that two independent sites contribute to the interaction of the GTPase complex with the SRP RNA distal end. Loop E plays a crucial role in the precise positioning of the GTPase complex on these two sites by inducing a defined bend in the RNA helix and thus generating a preorganized recognition surface. GTPase docking can be uncoupled from its subsequent activation, which is mediated by conserved bases in the next internal loop. These results, combined with recent structural work, elucidate how the SRP RNA induces GTPase relocalization and activation at the end of the protein targeting reaction. PMID- 24151070 TI - Cross-talk between site-specific transcription factors and DNA methylation states. AB - DNA methylation, which occurs predominantly at CpG dinucleotides, is a potent epigenetic repressor of transcription. Because DNA methylation is reversible, there is much interest in understanding the mechanisms by which it can be regulated by DNA-binding transcription factors. We discuss several models that, by incorporating sequence motifs, CpG density, and methylation levels, attempt to link the binding of a transcription factor with the acquisition or loss of DNA methylation at promoters and distal regulatory elements. Additional in vivo genome-wide characterization of transcription factor binding patterns and high resolution DNA methylation analyses are clearly required for stronger support of each model. PMID- 24151071 TI - Interactome analysis reveals ezrin can adopt multiple conformational states. AB - Ezrin, a member of the ezrin-radixin-moesin family (ERM), is an essential regulator of the structure of microvilli on the apical aspect of epithelial cells. Ezrin provides a linkage between membrane-associated proteins and F-actin, oscillating between active/open and inactive/closed states, and is regulated in part by phosphorylation of a C-terminal threonine. In the open state, ezrin can bind a number of ligands, but in the closed state the ligand-binding sites are inaccessible. In vitro analysis has proposed that there may be a third hyperactivated form of ezrin. To gain a better understanding of ezrin, we conducted an unbiased proteomic analysis of ezrin-binding proteins in an epithelial cell line, Jeg-3. We refined our list of interactors by comparing the interactomes using quantitative mass spectrometry between wild-type ezrin, closed ezrin, open ezrin, and hyperactivated ezrin. The analysis reveals several novel interactors confirmed by their localization to microvilli, as well as a significant class of proteins that bind closed ezrin. Taken together, the data indicate that ezrin can exist in three different conformational states, and different ligands "perceive" ezrin conformational states differently. PMID- 24151072 TI - Regulation of 130-kDa smooth muscle myosin light chain kinase expression by an intronic CArG element. AB - The mylk1 gene encodes a 220-kDa nonmuscle myosin light chain kinase (MLCK), a 130-kDa smooth muscle MLCK (smMLCK), as well as the non-catalytic product telokin. Together, these proteins play critical roles in regulating smooth muscle contractility. Changes in their expression are associated with many pathological conditions; thus, it is important to understand the mechanisms regulating expression of mylk1 gene transcripts. Previously, we reported a highly conserved CArG box, which binds serum response factor, in intron 15 of mylk1. Because this CArG element is near the promoter that drives transcription of the 130-kDa smMLCK, we examined its role in regulating expression of this transcript. Results show that deletion of the intronic CArG region from a beta-galactosidase reporter gene abolished transgene expression in mice in vivo. Deletion of the CArG region from the endogenous mylk1 gene, specifically in smooth muscle cells, decreased expression of the 130-kDa smMLCK by 40% without affecting expression of the 220 kDa MLCK or telokin. This reduction in 130-kDa smMLCK expression resulted in decreased phosphorylation of myosin light chains, attenuated smooth muscle contractility, and a 24% decrease in small intestine length that was associated with a significant reduction of Ki67-positive smooth muscle cells. Overall, these data show that the CArG element in intron 15 of the mylk1 gene is necessary for maximal expression of the 130-kDa smMLCK and that the 130-kDa smMLCK isoform is specifically required to regulate smooth muscle contractility and small intestine smooth muscle cell proliferation. PMID- 24151073 TI - Gas7b (growth arrest specific protein 7b) regulates neuronal cell morphology by enhancing microtubule and actin filament assembly. AB - Neurons undergo several morphological changes as a part of normal neuron maturation process. Alzheimer disease is associated with increased neuroproliferation and impaired neuronal maturation. In this study, we demonstrated that Gas7b (growth arrest specific protein 7b) expression in a neuronal cell line, Neuro 2A, induces cell maturation by facilitating formation of dendrite-like processes and/or filopodia projections and that Gas7b co localizes with neurite microtubules. Molecular analysis was performed to evaluate whether Gas7b associates with actin filaments and microtubules, and the data revealed two novel roles of Gas7b in neurite outgrowth: we showed that Gas7b enhances bundling of several microtubule filaments and connects microtubules with actin filaments. These results suggest that Gas7b governs neural cell morphogenesis by enhancing the coordination between actin filaments and microtubules. We conclude that lower neuronal Gas7b levels may impact Alzheimer disease progression. PMID- 24151074 TI - Proinflammatory cytokine tumor necrosis factor (TNF)-like weak inducer of apoptosis (TWEAK) suppresses satellite cell self-renewal through inversely modulating Notch and NF-kappaB signaling pathways. AB - Satellite cell self-renewal is an essential process to maintaining the robustness of skeletal muscle regenerative capacity. However, extrinsic factors that regulate self-renewal of satellite cells are not well understood. Here, we demonstrate that TWEAK cytokine reduces the proportion of Pax7(+)/MyoD(-) cells (an index of self-renewal) on myofiber explants and represses multiple components of Notch signaling in satellite cell cultures. The number of Pax7(+) cells is significantly increased in skeletal muscle of TWEAK knock-out (KO) mice compared with wild-type in response to injury. Furthermore, Notch signaling is significantly elevated in cultured satellite cells and in regenerating myofibers of TWEAK-KO mice. Forced activation of Notch signaling through overexpression of the Notch1 intracellular domain (N1ICD) rescued the TWEAK-mediated inhibition of satellite cell self-renewal. TWEAK also activates the NF-kappaB transcription factor in satellite cells and inhibition of NF-kappaB significantly improved the number of Pax7(+) cells in TWEAK-treated cultures. Furthermore, our results demonstrate that a reciprocal interaction between NF-kappaB and Notch signaling governs the inhibitory effect of TWEAK on satellite cell self-renewal. Collectively, our study demonstrates that TWEAK suppresses satellite cell self renewal through activating NF-kappaB and repressing Notch signaling. PMID- 24151075 TI - Monopolar spindle 1 (MPS1) kinase promotes production of closed MAD2 (C-MAD2) conformer and assembly of the mitotic checkpoint complex. AB - MPS1 kinase is an essential component of the spindle assembly checkpoint (SAC), but its functioning mechanisms are not fully understood. We have shown recently that direct interaction between BUBR1 and MAD2 is critical for assembly and function of the human mitotic checkpoint complex (MCC), the SAC effector. Here we report that inhibition of MPS1 kinase activity by reversine disrupts BUBR1-MAD2 as well as CDC20-MAD2 interactions, causing premature activation of the anaphase promoting complex/cyclosome. The effect of MPS1 inhibition is likely due to reduction of closed MAD2 (C-MAD2), as expressing a MAD2 mutant (MAD2(L13A)) that is locked in the C conformation rescued the checkpoint defects. In the presence of reversine, exogenous C-MAD2 does not localize to unattached kinetochores but is still incorporated into the MCC. Contrary to a previous report, we found that sustained MPS1 activity is required for maintaining both the MAD1.C-MAD2 complex and open MAD2 (O-MAD2) at unattached kinetochores to facilitate C-MAD2 production. Additionally, mitotic phosphorylation of BUBR1 is also affected by MPS1 inhibition but seems dispensable for MCC assembly. Our results support the notion that MPS1 kinase promotes C-MAD2 production and subsequent MCC assembly to activate the SAC. PMID- 24151076 TI - Phosphatidylinositol phosphate 5-kinase Igammai2 in association with Src controls anchorage-independent growth of tumor cells. AB - A fundamental property of tumor cells is to defy anoikis, cell death caused by a lack of cell-matrix interaction, and grow in an anchorage-independent manner. How tumor cells organize signaling molecules at the plasma membrane to sustain oncogenic signals in the absence of cell-matrix interactions remains poorly understood. Here, we describe a role for phosphatidylinositol 4-phosphate 5 kinase (PIPK) Igammai2 in controlling anchorage-independent growth of tumor cells in coordination with the proto-oncogene Src. PIPKIgammai2 regulated Src activation downstream of growth factor receptors and integrins. PIPKIgammai2 directly interacted with the C-terminal tail of Src and regulated its subcellular localization in concert with talin, a cytoskeletal protein targeted to focal adhesions. Co-expression of PIPKIgammai2 and Src synergistically induced the anchorage-independent growth of nonmalignant cells. This study uncovers a novel mechanism where a phosphoinositide-synthesizing enzyme, PIPKIgammai2, functions with the proto-oncogene Src, to regulate oncogenic signaling. PMID- 24151077 TI - Reactivation of fetal splicing programs in diabetic hearts is mediated by protein kinase C signaling. AB - Diabetic cardiomyopathy is one of the complications of diabetes that eventually leads to heart failure and death. Aberrant activation of PKC signaling contributes to diabetic cardiomyopathy by mechanisms that are poorly understood. Previous reports indicate that PKC is implicated in alternative splicing regulation. Therefore, we wanted to test whether PKC activation in diabetic hearts induces alternative splicing abnormalities. Here, using RNA sequencing we identified a set of 22 alternative splicing events that undergo a developmental switch in splicing, and we confirmed that splicing reverts to an embryonic pattern in adult diabetic hearts. This network of genes has important functions in RNA metabolism and in developmental processes such as differentiation. Importantly, PKC isozymes alpha/beta control alternative splicing of these genes via phosphorylation and up-regulation of the RNA-binding proteins CELF1 and Rbfox2. Using a mutant of CELF1, we show that phosphorylation of CELF1 by PKC is necessary for regulation of splicing events altered in diabetes. In summary, our studies indicate that activation of PKCalpha/beta in diabetic hearts contributes to the genome-wide splicing changes through phosphorylation and up-regulation of CELF1/Rbfox2 proteins. These findings provide a basis for PKC-mediated cardiac pathogenesis under diabetic conditions. PMID- 24151078 TI - Binding of G-quadruplexes to the N-terminal recognition domain of the RNA helicase associated with AU-rich element (RHAU). AB - Polynucleotides containing consecutive tracts of guanines can adopt an intramolecular G-quadruplex structure where multiple planar tetrads of hydrogen bound guanines stack on top of each other. Remodeling of G-quadruplexes impacts numerous aspects of nucleotide biology including transcriptional and translational control. RNA helicase associated with AU-rich element (RHAU), a member of the ATP-dependent DEX(H/D) family of RNA helicases, has been established as a major cellular quadruplex resolvase. RHAU contains a core helicase domain responsible for ATP binding/hydrolysis/helicase activity and is flanked on either side by N- and C-terminal extensions. The N-terminal extension is required for quadruplex recognition, and we have previously demonstrated complex formation between this domain and a quadruplex from human telomerase RNA. Here we used an integrated approach that includes small angle x-ray scattering, nuclear magnetic resonance spectroscopy, circular dichroism, and dynamic light scattering methods to demonstrate the recognition of G-quadruplexes by the N terminal domain of RHAU. Based on our results, we conclude that (i) quadruplex from the human telomerase RNA and its DNA analog both adopt a disc shape in solution, (ii) RHAU53-105 adopts a defined and extended conformation in solution, and (iii) the N-terminal domain mediates an interaction with a guanine tetrad face of quadruplexes. Together, these data form the foundation for understanding the recognition of quadruplexes by the N-terminal domain of RHAU. PMID- 24151079 TI - miR-125a-5p regulates differential activation of macrophages and inflammation. AB - Macrophage activation is a central event in immune responses. Macrophages undergoing classical activation (M1 macrophages) are proinflammatory, whereas alternatively activated macrophages (M2 macrophages) are generally anti inflammatory. miRNAs play important regulatory roles in inflammatory response. However, the manner in which miRNAs regulate macrophage activation in response to different environmental cues has not been well defined. In this study, we found that M-BMM macrophages (M2) express greater levels of miR-125a-5p than do GM-BMM macrophages (M1). Stimulation of macrophages through TLR2 and TLR4 but not through TLR3 enhanced miR-125a-5p expression. Up-regulation of miR-125a-5p after TLR2/4 activation requires the adaptor MYD88 but not TRIF. Overexpression of miR 125a-5p diminished M1 phenotype expression induced by LPS but promoted M2 marker expression induced by IL-4. In contrast, knockdown of miR-125a-5p promoted M1 polarization and diminished IL-4-induced M2 marker expression. We found that miR 125a-5p targets KLF13, a transcriptional factor that has an important role in T lymphocyte activation and inflammation. KLF13 knockdown had similar effects on M1 activation as did miR-125a-5p overexpression. In addition, miR-125a-5p regulates phagocytic and bactericidal activities of macrophages. Our data suggest that miR 125a-5p has an important role in suppressing classical activation of macrophages while promoting alternative activation. PMID- 24151080 TI - Slippery substrates impair ATP-dependent protease function by slowing unfolding. AB - ATP-dependent proteases are responsible for most energy-dependent protein degradation across all species. Proteases initially bind an unstructured region on a substrate and then translocate along the polypeptide chain, unfolding and degrading protein domains as they are encountered. Although this process is normally processive, resulting in the complete degradation of substrate proteins to small peptides, some substrates are released prematurely. Regions of low sequence complexity within the substrate such as the glycine-rich region (GRR) from p105 or glycine-alanine repeats (GAr) from the EBNA1 (Epstein-Barr virus nuclear antigen-1) protein, can trigger partial degradation and fragment release. Loss of processivity could be due to inability to hold on to the substrate (faster release) or inability to unfold and degrade a substrate domain (slower unfolding). I previously showed that the GRR slows domain unfolding by the proteasome (Kraut, D. A., Israeli, E., Schrader, E. K., Patil, A., Nakai, K., Nanavati, D., Inobe, T., and Matouschek, A. (2012) ACS Chem. Biol. 7, 1444-1453). In contrast, a recently published study concluded that GArs increase the rate of substrate release from ClpXP, a bacterial ATP-dependent protease (Too, P. H., Erales, J., Simen, J. D., Marjanovic, A., and Coffino, P. (2013) J. Biol. Chem. 288, 13243-13257). Here, I show that these apparently contradictory results can be reconciled through a reanalysis of the ClpXP GAr data. This reanalysis shows that, as with the proteasome, low complexity sequences in substrates slow their unfolding and degradation by ClpXP, with little effect on release rates. Thus, despite their evolutionary distance and limited sequence identity, both ClpXP and the proteasome share a common mechanism by which substrate sequences regulate the processivity of degradation. PMID- 24151081 TI - MicroRNA-200b stimulates tumour growth in TGFBR2-null colorectal cancers by negatively regulating p27/kip1. AB - Colorectal cancer (CRC) remains the most common malignancy worldwide. TGF-beta1 is often overexpressed in late stages of colorectal carcinogenesis and promotes tumour growth and metastasis. Several reports have verified that the loss of functional TGFBRII expression contributed to escape the tumour suppressor activity of TGF-beta1 and that the epithelial-to-mesenchymal transition (EMT) responded to TGF-beta1 involved in tumour invasion and metastasis. However, the mechanisms by which TGF-beta1 confers a growth advantage to TGFBRII-null colorectal cancer cells have not been elucidated. MicroRNAs (miRNAs) are post transcriptional inhibitory regulators of gene expression that act by directly binding complementary mRNA and are key determinants of cancer initiation and progression. In this study, we revealed a role for miR-200b in colorectal cancer. MiR-200b was highly expressed in TGFBRII-null tumour tissues and colorectal cancer cell lines and positively correlated with cell proliferation in tumour tissues and cell lines. In contrast, decreasing the miR-200b level in TGFBRII null cells suppressed cell proliferation and cell cycle progression. Furthermore, in vivo studies also suggested a stimulating effect of miR-200b on TGFBRII-null cell-derived xenografts. CDKN1B (p27/kip1) and RND3 (RhoE) have miR-200b binding sequences within their 3' untranslated regions and were confirmed to be direct targets of miR-200b using fluorescent reporter assays. Meanwhile, CDKN1B (p27/kip1) played a role in miR-200b-stimulated TGFBR-null CRC. This study suggests that miR-200b plays a tumour-promoting role by targeting CDKN1B (p27/kip1) in CRCs. PMID- 24151082 TI - Transition-metal-free synthesis of N-(1-alkenyl)imidazoles by potassium phosphate promoted addition reaction of alkynes to imidazoles. AB - The addition reaction of alkynes to N-heterocycles by simply heating in DMSO with potassium phosphate is reported. Good yields with high stereoselectivity could be achieved for a range of substrates. The scope is quite general for both amines and phenylacetylenes. In addition, internal alkynes and alpha-bromostyrene were also examined in this reaction. This process is efficient and useful for the synthesis of (Z)-N-(1-alkenyl)imidazoles and related Z products. Thus, the reaction is useful because of the importance of the imidazole scaffold. PMID- 24151083 TI - Surfactant hydrogels for the dispersion of carbon-nanotube-based catalysts. AB - Novel hydrogel phases based on positively charged and zwitterionic surfactants, namely, N-[p-(n-dodecyloxybenzyl)]-N,N,N-trimethylammonium bromide (pDOTABr) and p-dodecyloxybenzyldimethylamine oxide (pDOAO), which combine pristine carbon nanotubes (CNTs), were obtained, thus leading to stable dispersions and enhanced cross-linked networks. The composite hydrogel featuring a well-defined nanostructured morphology and an overall positively charged surface was shown to efficiently immobilise a polyanionic and redox-active tetraruthenium-substituted polyoxometalate (Ru4POM) by complementary charge interactions. The resulting hybrid gel has been characterised by electron microscopy techniques, whereas the electrostatic-directed assembly has been monitored by means of fluorescence spectroscopy and zeta-potential tests. This protocol offers a straightforward supramolecular strategy for the design of novel aqueous-based electrocatalytic soft materials, thereby improving the processability of CNTs while tuning their interfacial decoration with multiple catalytic domains. Electrochemical evidence confirms that the activity of the catalyst is preserved within the gel media. PMID- 24151084 TI - Alternative delivery systems for agents to treat acute agitation: progress to date. AB - Psychomotor agitation is often associated with aggression. It is important to identify agitation early and achieve results quickly in order to prevent aggressive behavior. Strategies may include verbal de-escalation techniques, reduced stimulation, medications, or a combination of approaches. Historically, pharmacological treatments for agitation have been delivered using oral and intramuscular formulations. Although the types of medication available have not changed dramatically, different formulations have been developed recently to aid in treating this difficult condition. This paper will detail some of the newer, more novel formulations used to deliver medications to treat agitation. Formulations to be described include orally disintegrating tablets, sublingual, buccal and intranasal forms, as well as an inhalation form. Each form has a unique purpose and will aid in treatment of different populations at different levels of agitation. Of note, of the medication formulations to be discussed, only inhaled loxapine is FDA approved for acute agitation in schizophrenia and bipolar disorder and no medications are approved for 'agitation' outside of a specific disease state. The orally disintegrating tablets of olanzapine, risperidone, and aripiprazole are swallowed and enter the circulation via the portal system. They do not have a more rapid onset of action than the standard oral tablets but are useful for patients that might otherwise divert the medication. The sublingual, buccal and intranasal formulations include asenapine and midazolam. Absorption by this route is more rapid and avoids first-pass metabolism. Finally, inhaled loxapine enters the alveoli and appears quickly in the arterial circulation. All of these novel formulations require at least some cooperation but have the potential to prevent escalation and improve the experience of patients and could be considered when negotiation is possible. PMID- 24151085 TI - Relationships among affective factors and preferred engagement in science-related activities. AB - This study investigated how affective factors impact participation in science learning using structural equation modeling. Using a dataset from Taiwan, a model was obtained that showed the relationships among science-related interest, enjoyment, self-efficacy, self-concept, competency, leisure time engagement, and future interest in science. The paths relating to engagement and future interest were much stronger for interest and enjoyment than for self-efficacy and self concept. There was no significant path between science competency and future science interest or engagement. The results suggest that the affective and cognitive pathways to scientific competency are divergent and that they might be differentially activated by different contexts and activities. This indicates that school science educators might wish to reconsider the merit of overemphasizing achievement in comparison to interest. Finally, the results suggest that the development of science competency per se may not be the best way to ensure public engagement and understanding of science. PMID- 24151086 TI - An international comparative public health analysis of sex trafficking of women and girls in eight cities: achieving a more effective health sector response. AB - Sex trafficking, trafficking for the purpose of forced sexual exploitation, is a widespread form of human trafficking that occurs in all regions of the world, affects mostly women and girls, and has far-reaching health implications. Studies suggest that up to 50 % of sex trafficking victims in the USA seek medical attention while in their trafficking situation, yet it is unclear how the healthcare system responds to the needs of victims of sex trafficking. To understand the intersection of sex trafficking and public health, we performed in depth qualitative interviews among 277 antitrafficking stakeholders across eight metropolitan areas in five countries to examine the local context of sex trafficking. We sought to gain a new perspective on this form of gender-based violence from those who have a unique vantage point and intimate knowledge of push-and-pull factors, victim health needs, current available resources and practices in the health system, and barriers to care. Through comparative analysis across these contexts, we found that multiple sociocultural and economic factors facilitate sex trafficking, including child sexual abuse, the objectification of women and girls, and lack of income. Although there are numerous physical and psychological health problems associated with sex trafficking, health services for victims are patchy and poorly coordinated, particularly in the realm of mental health. Various factors function as barriers to a greater health response, including low awareness of sex trafficking and attitudinal biases among health workers. A more comprehensive and coordinated health system response to sex trafficking may help alleviate its devastating effects on vulnerable women and girls. There are numerous opportunities for local health systems to engage in antitrafficking efforts while partnering across sectors with relevant stakeholders. PMID- 24151087 TI - Feasibility of deep-inspiration breath-hold PET/CT with short-time acquisition: detectability for pulmonary lesions compared with respiratory-gated PET/CT. AB - OBJECTIVES: Deep-inspiration breath-hold (DIBH) PET/CT with short-time acquisition and respiratory-gated (RG) PET/CT are performed for pulmonary lesions to reduce the respiratory motion artifacts, and to obtain more accurate standardized uptake value (SUV). DIBH PET/CT demonstrates significant advantages in terms of rapid examination, good quality of CT images and low radiation exposure. On the other hand, the image quality of DIBH PET is generally inferior to that of RG PET because of short-time acquisition resulting in poor signal-to noise ratio. In this study, RG PET has been regarded as a gold standard, and its detectability between DIBH and RG PET studies was compared using each of the most optimal reconstruction parameters. METHODS: In the phantom study, the most optimal reconstruction parameters for DIBH and RG PET were determined. In the clinical study, 19 cases were examined using each of the most optimal reconstruction parameters. RESULTS: In the phantom study, the most optimal reconstruction parameters for DIBH and RG PET were different. Reconstruction parameters of DIBH PET could be obtained by reducing the number of subsets for those of RG PET in the state of fixing the number of iterations. In the clinical study, high correlation in the maximum SUV was observed between DIBH and RG PET studies. The clinical result was consistent with that of the phantom study surrounded by air since most of the lesions were located in the low pulmonary radioactivity. CONCLUSION: DIBH PET/CT may be the most practical method which can be the first choice to reduce respiratory motion artifacts if the detectability of DIBH PET is equivalent with that of RG PET. Although DIBH PET may have limitations in suboptimal signal-to-noise ratio, most of the lesions surrounded by low background radioactivity could provide nearly equivalent image quality between DIBH and RG PET studies when each of the most optimal reconstruction parameters was used. PMID- 24151088 TI - Temperature-controlled ultrasound- and vortex-assisted liquid-liquid microextraction combined with GC for the determination of the concentrations of organophosphorus pesticides in beverage samples. AB - The aim of this work was to develop temperature-controlled ultrasound- and vortex assisted liquid-liquid microextraction as a fast and efficient approach for the extraction of nine organophosphorus pesticides in beverage samples followed by GC with flame photometric detection analysis. The combination of ultrasonication and vortexing were used to assist the microextraction, and the use of a dispersion solvent was avoided. Several variables that could potentially affect the extraction efficiency, namely, the type and volume of extraction solvent, sequence, and time of ultrasonication and vortexing, ultrasonication bath temperature and ionic strength were optimized. Under optimum conditions, the calibration graphs were linear over the range of 0.5-200 MUg/L. The LOD (S/N = 3) was between 0.01 and 0.05. The optimized method exhibited a good precision level with RSD values between 4.5 and 9.8%. The enrichment factors for the nine organophosphorus pesticides were between 224 and 339. Four beverage samples were successfully analyzed using the proposed method. PMID- 24151089 TI - A streamlined strategy for aglycone assembly and glycosylation. AB - Multipurpose sugars: Carbohydrate-derived silane reagents are utilized as the reductant for nickel-catalyzed aldehyde-alkyne reductive coupling reactions and as the glycosyl donor for subsequent intramolecular glycosylation. The approach enables the assembly of the carbon-carbon framework and stereochemical features of an aglycone while simultaneously establishing the site of glycosylation. PMID- 24151091 TI - Gray matter atrophy and freezing of gait in Parkinson's disease: Is the evidence black-on-white? AB - OBJECTIVES: The pathophysiology underlying freezing of gait (FOG) in Parkinson's disease (PD) is poorly understood. We tested whether gray matter (GM) atrophy contributes to FOG in PD. METHODS: Voxel-based morphometry quantified GM atrophy in 106 patients who were classified as freezers (n = 30) or nonfreezers (n = 76). Well-matched smaller subgroups were also studied. Balance, gait, and cognitive function were assessed, and we evaluated the relationship between GM, FOG severity, and symptoms associated with FOG. RESULTS: GM was significantly reduced in the inferior parietal lobe and angular gyrus in the matched freezers (n = 22), compared to nonfreezers (n = 22; P < 0.015, cluster-level corrected). In the entire cohort, FOG severity was related to bilateral caudate volumes. CONCLUSIONS: GM atrophy in cortical (i.e., parietal lobe and angular gyrus) and subcortical areas (i.e., caudate) are related to FOG. Disparities among the existing findings suggest that inferences regarding specific brain regions should be made with caution. PMID- 24151090 TI - HER-2/neu gene amplification in relation to expression of HER2 and HER3 proteins in patients with esophageal adenocarcinoma. AB - BACKGROUND: Human epidermal growth factor receptor 2 (HER2) is a therapeutic target in patients with esophageal adenocarcinoma (EAC), with gene amplification used as a selection criterion for treatment, although to the authors' knowledge the concordance between amplification and HER2 protein expression remains undefined in EAC. Furthermore, the association between HER2 and its interacting partner, human epidermal growth factor receptor 3 (HER3), is unknown yet appears to be of potential therapeutic relevance. METHODS: Patients with untreated EACs (N = 673) were analyzed for HER2 amplification and polysomy 17 by fluorescence in situ hybridization in parallel with immunohistochemistry (IHC) (IHC scores of 0 1+, 2+, and 3+). Amplification was defined as HER2/CEP17 >= 2. HER3 expression by IHC was analyzed in randomly selected cases (n = 224). IHC and fluorescence in situ hybridization results were compared using least squares linear regression. RESULTS: Overall, 17% of the EACs (116 of 673 EACs) were HER2-amplified with an amplification frequency that was highest among IHC3+ cases (89%) and declined among IHC2+ cases (13%) and IHC0 to IHC1+ cases (4%). Among HER2-amplified cases, the level of amplification increased linearly with HER2 membranous expression (HER2/CEP17 ratio: 7.9 in IHC3+ and 5.5 in IHC2+ vs 2.8 in IHC0 to IHC1+ [P < .0001]), with 14% of amplified tumors demonstrating absent/faint expression (IHC0 to IHC1+). Polysomy 17 was not found to be associated with HER2 expression. Cytoplasmic HER3 expression was detected in 87% of tumors (195 of 224 tumors) and was found to be significantly associated with better differentiation (P < .0001). Stepwise increases in HER3 expression were associated with higher HER2 expression levels (P = .0019). CONCLUSIONS: Levels of HER2 protein expression and amplification were found to be linearly associated and highly concordant. Among amplified tumors with absent/faint expression, the level of amplification was low. Frequent expression of HER3 suggests its relevance as a therapeutic target, and its significant association with HER2 supports ongoing efforts to inhibit HER2/HER3 in patients with EAC. PMID- 24151092 TI - Fast low-angle shot diffusion tensor imaging with stimulated echo encoding in the muscle of rabbit shank. AB - In the past, spin-echo (SE) echo planar imaging(EPI)-based diffusion tensor imaging (DTI) has been widely used to study the fiber structure of skeletal muscles in vivo. However, this sequence has several shortcomings when measuring restricted diffusion in small animals, such as its sensitivity to susceptibility related distortions and a relatively short applicable diffusion time. To address these limitations, in the current work, a stimulated echo acquisition mode (STEAM) MRI technique, in combination with fast low-angle shot (FLASH) readout (turbo-STEAM MRI), was implemented and adjusted for DTI in skeletal muscles. Signal preparation using stimulated echoes enables longer effective diffusion times, and thus the detection of restricted diffusion within muscular tissue with intracellular distances up to 100 um. Furthermore, it has a reduced penalty for fast T2 muscle signal decay, but at the expense of 50% signal loss compared with a SE preparation. Turbo-STEAM MRI facilitates high-resolution DTI of skeletal muscle without introducing susceptibility-related distortions. To demonstrate its applicability, we carried out rabbit in vivo measurements on a human whole-body 3 T scanner. DTI parameters of the shank muscles were extracted, including the apparent diffusion coefficient, fractional anisotropy, eigenvalues and eigenvectors. Eigenvectors were used to calculate maps of structural parameters, such as the planar index and the polar coordinates theta and phi of the largest eigenvector. These parameters were compared between three muscles. theta and phi showed clear differences between the three muscles, reflecting different pennation angles of the underlying fiber structures. Fiber tractography was performed to visualize and analyze the architecture of skeletal pennate muscles. Optimization of tracking parameters and utilization of T2 -weighted images for improved muscle boundary detection enabled the determination of additional parameters, such as the mean fiber length. The presented results support the applicability of turbo-STEAM MRI as a promising method for quantitative DTI analysis and fiber tractography in skeletal muscles. PMID- 24151093 TI - Occupational injury among hospital patient-care workers: what is the association with workplace verbal abuse? AB - OBJECTIVE: To test the association between workplace abuse exposure and injury risk among hospital workers. We hypothesized that exposed workers would have higher injury rates than unexposed workers. METHODS: Survey of direct-care workers (n = 1,497) in two hospitals. Exposure to workplace abuse was assessed through self-report; occupational injury reports were extracted from employee records. We tested associations between non-physical workplace violence and injury using log-binomial regression and multilevel modeling. RESULTS: Adjusted prevalence ratio (PR) for injury associated with being yelled at was 1.52 (95% CI 1.19, 1.95); for experiencing hostile/offensive gestures 1.43 (1.11, 1.82); and for being sworn at 1.41 (1.09, 1.81). In analyses by injury subtypes, musculoskeletal injuries were more strongly associated with abuse than were acute traumatic injuries. Associations operated on group and individual levels and were most consistently associated with abuse perpetrated by patients. CONCLUSION: Exposure to workplace abuse may be a risk factor for injuries among hospital workers. PMID- 24151094 TI - Intravenous lobular capillary hemangioma occurring in the cephalic vein of a 39 year-old adult. AB - Intravenous lobular capillary hemangiomas are extremely uncommon and mostly occur in the veins of the neck and upper extremities. Here, we report the clinical and sonographic features of an intravenous lobular capillary hemangioma localized in the right cephalic vein, and we discuss its pathologic findings and differential diagnoses. PMID- 24151095 TI - Emotion regulation predicts anxiety over a five-year interval: a cross-lagged panel analysis. AB - BACKGROUND: Emotion regulation (ER) deficits have been linked to symptoms of anxiety in cross-sectional studies. However, the direction of the relationship between ER and anxiety symptom severity (ASS) is unclear. METHODS: In order to clarify the relationship between ER skills and ASS symptoms, we assessed skills and symptoms in 131 individuals twice over a 5-year interval. Cross-lagged panel analyses were conducted to test whether ER skills were a significant predictor of subsequent ASS or vice versa. Additionally, we explored whether specific ER skills differed in regard to the strength of prospective associations with subsequent ASS. RESULTS: ER skills negatively predicted subsequent ASS over and above the effects of baseline ASS (whereas anxiety symptoms did not predict subsequent ER deficits). Acceptance, tolerance, and willingness to confront had the strongest prospective effects on lower subsequent ASS. CONCLUSIONS: General ER skills may play an important role in the development and maintenance of anxiety disorders. PMID- 24151096 TI - Longitudinal changes in MRI markers in a reversible unilateral ureteral obstruction mouse model: preliminary experience. AB - PURPOSE: To evaluate longitudinal changes in renal oxygenation and diffusion measurements in a model of reversible unilateral ureteral obstruction (rUUO) which has been shown to induce chronic renal functional deficits in a strain dependent way. C57BL/6 mice show higher degree of functional deficit compared with BALB/c mice. Because hypoxia and development of fibrosis are associated with chronic kidney diseases and are responsible for progression, we hypothesized that MRI measurements would be able to monitor the longitudinal changes in this model and will show strain dependent differences in response. Here blood oxygenation level dependent (BOLD) and diffusion MRI measurements were performed at three time points over a 30 day period in mice with rUUO. MATERIALS AND METHODS: The studies were performed on a 4.7T scanner with the mice anesthetized with isoflurane before UUO, 2 and 28 days postrelease of 6 days of obstruction. RESULTS: We found at the early time point (~2 days after releasing the obstruction), the relative oxygenation in C57Bl/6 mice were lower compared with BALB/c. Diffusion measurements were lower at this time point and reached statistical significance in BALB/c CONCLUSION: These methods may prove valuable in better understanding the natural progression of kidney diseases and in evaluating novel interventions to limit progression. PMID- 24151097 TI - Source-specific social support and circulating inflammatory markers among white collar employees. AB - BACKGROUND: Despite known beneficial effects of social support on cardiovascular health, the pathway through which sources of support (supervisor, coworkers, family/friends) influence inflammatory markers is not completely understood. PURPOSE: We investigated the independent and moderating associations between social support and inflammatory markers. METHODS: A total of 137 male white collar employees underwent a blood draw for measurement of high-sensitive C reactive protein (hs-CRP), interleukin-6 (IL-6), tumor necrosis factor alpha (TNF alpha), monocyte and leukocyte counts, and completed a questionnaire on social support. RESULTS: Multivariable linear regression analyses controlling for covariates revealed that supervisor support was inversely associated with IL-6 (beta = -0.24, p < 0.01) while coworker support was marginally associated with TNF-alpha (beta = -0.16, p < 0.10). Support from family/friends was not associated with inflammatory markers. CONCLUSION: Social support from the immediate supervisor may be a potential mechanism through which social support exerts beneficial effects on inflammatory markers in working men. PMID- 24151098 TI - A new enantioselective synthesis of the anticonvulsant drug pregabalin (Lyrica) based on a hydrolytic kinetic resolution method. AB - A practical and efficient enantioselective synthesis of the anticonvulsant drug pregabalin is described for the first time using Jacobsen's hydrolytic kinetic resolution of a terminal epoxide as a key step and a source of chirality. PMID- 24151099 TI - A novel protocol for molecularly imprinted polymer filaments online coupled to GC MS for the determination of androgenic steroids in urine. AB - An online system that can perform dynamic microextraction, on-coating derivatization and desorption, and subsequent GC-MS analysis with a large-volume injection was developed. A derivatization cell as the conjunction of the online system was developed for the online extraction and derivatization. To evaluate the feasibility of the online system, methyltestosterone molecularly imprinted polymer filaments (MIPFs) were prepared for the selective online extraction of five androgenic steroids, namely, methyltestosterone, testosterone, epitestosterone, nandrolone, and metandienone. Under the optimized conditions, the detection limits of testosterone and epitestosterone were 0.09 and 0.12 MUg/L, respectively, which were under the minimum required performance limits between 2 and 10 MUg/L from the World Anti-Doping Agency. The detection limits of the other three androgenic steroids were varied from 0.04 to 0.18 MUg/L. Finally, the MIPFs-GC-MS method was applied for the determination of androgenic steroids in urine, and satisfactory recovery (78.0-96.9%) and reproducibility (3.2-8.9%) were obtained. The proposed online coupling system offers an attractive alternative for hyphenation to GC instruments and could also be extended to other adsorptive materials. PMID- 24151100 TI - Evolution and human sexuality. AB - The aim of this review is to put core features of human sexuality in an evolutionary light. Toward that end, I address five topics concerning the evolution of human sexuality. First, I address theoretical foundations, including recent critiques and developments. While much traces back to Darwin and his view of sexual selection, more recent work helps refine the theoretical bases to sex differences and life history allocations to mating effort. Second, I consider central models attempting to specify the phylogenetic details regarding how hominin sexuality might have changed, with most of those models honing in on transitions from a possible chimpanzee-like ancestor to the slightly polygynous and long-term bonded sociosexual partnerships observed among most recently studied hunter-gatherers. Third, I address recent genetic and physiological data contributing to a refined understanding of human sexuality. As examples, the availability of rapidly increasing genomic information aids comparative approaches to discern signals of selection in sexuality-related phenotypes, and neuroendocrine studies of human responses to sexual stimuli provide insight into homologous and derived mechanisms. Fourth, I consider some of the most recent, large, and rigorous studies of human sexuality. These provide insights into sexual behavior across other national samples and on the Internet. Fifth, I discuss the relevance of a life course perspective to understanding the evolution of human sexuality. Most research on the evolution of human sexuality focuses on young adults. Yet humans are sexual beings from gestation to death, albeit in different ways across the life course, and in ways that can be theoretically couched within life history theory. PMID- 24151101 TI - Options for independent bladder management in patients with spinal cord injury and hand function prohibiting intermittent catheterization. AB - AIMS: Choosing the appropriate bladder management strategy for the spinal cord injury patient with neurogenic bladder and hand function prohibitive of self catheterization (urethral or stomal) catheterization is complex and based on limited literature. We have catalogued the available data in this review. METHODS: A literature review was conducted on external sphincterotomy, suprapubic tube, ileal conduit, and ileovesicostomy between 1994 and 2012. Articles on neurogenic bladder focused primarily on spinal cord injury were included. Important aspects of each technique, patient selection, urologic events, and quality of life are described. CONCLUSION: The available literature consists primarily of level 3 data. Patient reported outcomes were rarely measured. External sphincterotomy is a good option for males who are candidates for an external catheter and who wish to avoid a complicated reconstruction-most will need re-operations for failure. Suprapubic tube is an option in both genders. Complaints usually involve urine leakage and urinary tract infection, which typically resolve with conservative measures. There is some evidence to support patient satisfaction. Ileal conduit is an option for all patients with quadriplegia, offering continuous drainage and absence of foreign material. Many providers and patients will choose more conservative options first. The ileovesicostomy is best applied to small bladders with severe overactivity. The "reversibility" of this procedure makes it attractive to those not interested in an ileal conduit and who have had complications from prolonged suprapubic tube placement. The authors conclude with recommendations for future research, most importantly more standard reporting of objective data. PMID- 24151102 TI - Initial stages in the formation of Cu2ZnSn(S,Se)4 nanoparticles. PMID- 24151103 TI - Adult attachment anxiety: using group therapy to promote change. AB - Group therapy can facilitate changes for members with greater attachment anxiety who tend to struggle with negative self-perceptions, difficulties regulating emotions, poor reflective functioning, and compromised interpersonal relationships. A clinical example of a therapy group with members who had elevated attachment anxiety and who were diagnosed with binge eating disorder demonstrates how attachment theory can be applied to group treatment. The clinical material from the beginning, middle, and end of group is presented to highlight how attachment anxiety influences members' emotional reactions and behaviors in the group, how group factors facilitate change, and how the leader fosters the development of a secure base within the group. Pre- to posttreatment outcomes indicate positive changes in binge eating, depressive symptoms, and attachment avoidance and anxiety. To facilitate change in individuals with greater attachment anxiety, group therapists may foster a secure base in the group through group cohesion, which will facilitate down regulation of emotions, better reflective functioning, and relationships that are less preoccupied with loss and more secure. PMID- 24151104 TI - Creation of circularly polarized luminescence from an achiral polyfluorene derivative through complexation with helix-forming polysaccharides: importance of the meta-linkage chain for helix formation. AB - A circularly polarized luminescence (CPL) material has been created by polymer polymer complexation between a helix-forming polysaccharide, schizophyllan (SPG), and a meta-phenylene-linked polyfluorene derivative (mPFS). Computational modeling revealed that mPFS can adopt a helical structure although a conventional polyfluorene derivative with a para-phenylene linkage tends to enjoy a rigid rodlike conformation. Our detailed experimental examination showed that mPFS forms a chiral nanowire complex through cohelix formation with SPG. We have found, as expected, that this cohelical complex emits highly efficient CPL even in an aqueous solution. The appearance of the high CPL property is due to 1) a high quantum yield of the fluorene unit and 2) immobilization of the helically twisted conformation of mPFS in an isolated manner through cohelix formation with SPG. One can propose, therefore, that the SPG/mPFS complex acts as a new high performance CPL material with a solvent-dispersible nanowire structure. PMID- 24151105 TI - Association of E-selectin gene polymorphism and serum PAPP-A with carotid atherosclerosis in end-stage renal disease. AB - BACKGROUND: Atherosclerotic vascular disease represents a significant cause of morbidity and mortality in patients with end-stage renal disease (ESRD). The endothelium plays a crucial role in vascular inflammation. E-selectin is exclusively expressed on activated endothelial cells and is upregulated following an inflammatory response and oxidative stress, while serum pregnancy-associated plasma protein-A (PAPP-A) concentrations are related to the presence and stability of carotid atherosclerotic plaques. OBJECTIVE: The aim of this study was to investigate whether there is an association between SELE rs5355C>T gene polymorphism, serum PAPP-A level and the presence of carotid atherosclerosis in ESRD patients. SUBJECTS AND METHODS: Seventy subjects were recruited into this study; 40 ESRD patients [age (mean +/- SD) 43.42 +/- 13.94 years] and 30 age- and gender-matched healthy individuals assigned to the control group. Polymerase chain reaction-restriction fragment length polymorphism was performed for the analysis of SELE rs5355C>T gene polymorphism, while serum PAPP-A concentrations were measured using electro-chemiluminescence immunoassay. Routine laboratory tests were measured on an automated chemistry analyzer. Carotid ultrasonographic studies were performed by a bilateral high-resolution B-mode ultrasound. RESULTS: There was no significant relationship between the SELE rs5355C>T gene polymorphism and ESRD incidence. Serum PAPP-A levels were significantly higher in ESRD patients compared with controls [median (interquartile range) 5.8 (5.1-11.6) and 5.1 (4.1-6.7), respectively; p = 0.005]. Serum PAPP-A correlated positively with urea, creatinine, systolic and diastolic blood pressure (DBP). Serum PAPP-A showed a statistically significant increase in SELE rs5355TT versus CC in both patients and controls. There was no association on comparing right intima-media thickness (IMT), left IMT, right cross-sectional area (CSA) and left CSA with the CC, CT and TT genotypes of SELE rs5355C>T. No correlation between serum PAPP-A with each of the above-mentioned carotid doppler findings was observed. There was a statistically significant increase in DBP in TT genotype carriers when compared with CC genotype carriers (p = 0.009). Serum PAPP-A levels were higher in hypertensive ESRD patients when compared with normotensive ESRD patients. There was a statistically significant decrease in high-density lipoprotein cholesterol (HDL-C) in TT genotype carriers when compared with CT genotype carriers in the whole study group (p = 0.003). Serum PAPP-A correlated negatively with HDL-C. CONCLUSION: The lack of a direct association between SELE rs5355C>T gene polymorphism, serum PAPP-A level and IMT suggests that their hypothesized association with carotid atherosclerosis might reflect an indirect mechanism of SELE rs5355C>T gene polymorphism and serum PAPP-A with cardiovascular risk factors such as blood pressure and HDL-C rather than a direct effect on the vasculature. PMID- 24151106 TI - Fluctuations in cognition and alertness vary independently in dementia with Lewy bodies. AB - Fluctuations in mental status are 1 of the core diagnostic criteria for dementia with Lewy bodies (DLB) and are thought to reflect variability in daytime alertness. Previous attempts to study fluctuations have been limited to caregiver reports, observer rating scales, short segments of electroencephalography, or motor-dependent, reaction time tests. Concordance among such measures is often poor, and fluctuations remain difficult to quantify. We compared fluctuations in cognition and alertness in patients with DLB (n = 13) and idiopathic Parkinson's disease (PD) (n = 64), a condition associated with deficits in daytime alertness. We systematically and repeatedly collected cognitive and physiologic measures during a 48-hour inpatient protocol in a sound-attenuated sleep laboratory in a geriatric hospital. Cognitive fluctuations were analyzed using coefficients of variation (COVs) derived from performance on a bedside examination familiar to clinicians (digit span). Alertness fluctuations were assessed objectively using COVs from the polysomnographically-based Maintenance of Wakefulness Test. Despite predictably lower mean digit span performances, DLB patients demonstrated significantly greater cognitive fluctuations than PD patients (P < 0.001), even when groups were matched on general cognitive impairment. There were no group differences in alertness fluctuations, although DLB patients were less alert than PD patients not receiving dopaminergics. The prevailing assumption that fluctuations in cognition in DLB are reflected in fluctuations in daytime alertness was not supported by objective, physiological measurements. Fluctuating mental status in DLB patients can be detected with repeated administration of a simple bedside exam that can be adapted to a clinic setting. PMID- 24151108 TI - Experiences of intimacy among people with bladder exstrophy. AB - Previous research investigating the psychosocial and psychosexual impact of living with the complex genitourinary condition bladder exstrophy has been limited in scope and methodological quality. However, the limited evidence suggests that people with bladder exstrophy commonly encounter difficulties that might negatively impact their experiences of intimacy. We conducted an interpretative phenomenological analysis to explore intimacy in 6 participants aged 16 to 56 years. Participants discussed how their parents and later they themselves concealed their health condition. This concealment was associated with feeling safe and protected, yet shameful. Participants also discussed developing intimate knowledge of their own emerging identity while developing intimacy with others, as well as the importance of sharing the experience of bladder exstrophy with others in the development of intimate relationships. We discuss the findings in relation to theoretical issues of concealment, shame, attachment, psychosocial development, intimacy, and chronic illness. PMID- 24151109 TI - Towards the non-invasive assessment of MHC genotype in wild primates: analysis of wild Assamese macaque MHC-DRB from fecal samples. AB - The major histocompatibility complex (MHC) plays an important role in the immune response and may thus crucially affect an individual's fitness, relevant also for studies on evolutionary ecology and wildlife conservation. Detailed knowledge on the genomic organization, polymorphism and diversity of the MHC has a narrow taxonomic focus though and among macaques is only available for rhesus and long tailed macaques-the species most commonly kept for biomedical research. The lack of data on wild populations is largely due to the difficulty of obtaining blood or tissue samples necessary for genotyping approaches. Here, we aimed at analyzing MHC-DRB from non-invasively collected fecal samples in wild Assamese macaques (Macaca assamensis), utilizing the MHC-DRB-STR (D6S2878) microsatellite marker. Due to the fecal DNA source incomplete genotypes occurred, which may be improved in the future by method refinement. We detected 28 distinct DRB-STR lengths in 43 individuals with individual genotypes containing 1-9 MHC-DRB-STRs and defined four haplotypes segregating between families in Mendelian fashion. Our results indicate that variability and diversity of MHC-DRB in Assamese macaques is comparable to that of other macaque species and importantly, that fecal samples can be used for non-invasive analysis of MHC genes after refinement of the applied methods, opening a number of opportunities for MHC research on natural populations. PMID- 24151110 TI - A case of gallbladder perforation detected by sonography after a blunt abdominal trauma. AB - Gallbladder (GB) perforation is a very rare posttraumatic abdominal injury. It is potentially life-threatening, and good outcome requires early diagnosis. We present a case of isolated posttraumatic GB perforation in which the precise sonographic (US) diagnosis led us to apply proper management. Color Doppler US showed a clear to-and-fro flow signal passing through the perforation site, and contrast-enhanced US confirmed the presence of a small defect in the GB wall. When examining posttraumatic patients, the possibility of GB perforation must be kept in mind. Color Doppler US and contrast-enhanced US are the examinations of choice to detect the perforation site and show bile movement through the perforation. PMID- 24151111 TI - Predictors of significant worsening of patient-reported fatigue over a 1-month timeframe in ambulatory patients with common solid tumors. AB - BACKGROUND: Understanding the determinants of fatigue worsening may help distinguish between different fatigue phenotypes and inform clinical trial designs. METHODS: Patients with invasive cancer of the breast, prostate, colon/rectum, or lung were enrolled from multiple sites. At enrollment during an outpatient visit and 4 or 5 weeks later, patients rated their symptoms on a numerical rating scale from zero to 10. A 2-point change on that scale was considered clinically significant for a change in fatigue. Effects of demographic and clinical factors on patient-reported fatigue were examined using logistic regression models. RESULTS: In total, 3123 patients were enrolled at baseline, and 3032 patients could be analyzed for fatigue change. At baseline, 23% of patients had no fatigue, 35% had mild fatigue, 25% had moderate fatigue, and 17% had severe fatigue. Key parameters in a model of fatigue worsening included fatigue at baseline (odds ratio [OR], 0.75), disease status (OR, 1.99), performance status (OR, 1.38), history of depression (OR, 1.28), patient perception of bother because of comorbidity (OR, 1.26), and treatment exposures, including recent cancer treatment (OR, 1.77) and receipt of corticosteroids (OR, 1.37). The impact of sex was examined only in patients with colorectal and lung cancer, and it was a significant factor, with men most likely to experience worsening of fatigue (OR, 1.46). CONCLUSIONS: Predictors of fatigue worsening included multiple factors that were difficult to modify, including the baseline fatigue level, sex, disease status, performance status, recent cancer treatment, bother because of comorbidity, and history of depression. Future fatigue prevention and treatment trial designs should account for key predictors of worsening fatigue. PMID- 24151112 TI - Investigation of the chemomarkers correlated with flower colour in different organs of Catharanthus roseus using NMR-based metabolomics. AB - INTRODUCTION: Flower colour is a complex phenomenon that involves a wide range of secondary metabolites of flowers, for example phenolics and carotenoids as well as co-pigments. Biosynthesis of these metabolites, though, occurs through complicated pathways in many other plant organs. The analysis of the metabolic profile of leaves, stems and roots, for example, therefore may allow the identification of chemomarkers related to the final expression of flower colour. OBJECTIVE: To investigate the metabolic profile of leaves, stems, roots and flowers of Catharanthus roseus and the possible correlation with four flower colours (orange, pink, purple and red). METHODS: (1) H-NMR and multivariate data analysis were used to characterise the metabolites in the organs. RESULTS: The results showed that flower colour is characterised by a special pattern of metabolites such as anthocyanins, flavonoids, organic acids and sugars. The leaves, stems and roots also exhibit differences in their metabolic profiles according to the flower colour. Plants with orange flowers featured a relatively high level of kaempferol analogues in all organs except roots. Red-flowered plants showed a high level of malic acid, fumaric acid and asparagine in both flowers and leaves, and purple and pink flowering plants exhibited high levels of sucrose, glucose and 2,3-dihydroxy benzoic acid. High concentrations of quercetin analogues were detected in flowers and leaves of purple-flowered plants. CONCLUSIONS: There is a correlation between the metabolites specifically associated to the expression of different flower colours and the metabolite profile of other plant organs and it is therefore possible to predict the flower colours by detecting specific metabolites in leaves, stems or roots. This may have interesting application in the plant breeding industry. PMID- 24151113 TI - Acute carotid stenting for treatment of stuttering transient ischemic attacks after recent carotid endarterectomy. AB - Carotid endarterectomy (CEA) is the established standard to treat occlusive extracranial atherosclerotic carotid disease. Complications of CEA must be recognized and dealt with efficiently due to the potentially catastrophic neurologic sequelae. A 67-year-old African American man was transferred from an outside hospital for an acute stroke. He had initially presented with a small right frontal subcortical infarct and had undergone a right CEA 2 days prior to transfer. He had a fluctuating examination with left-sided hemiplegia to slight hemiparesis and inconsistent neglect. Head CT demonstrated a watershed infarct of the right hemisphere. CT angiography demonstrated high grade stenosis at the distal aspect of the CEA anastomosis. He was promptly taken for angiography and underwent acute stenting of the right internal carotid artery. This case demonstrates that carotid artery stenting is a safe management strategy for the treatment of complications associated with failed distal anastomosis during CEA. PMID- 24151114 TI - Mechanical thrombectomy with the Solitaire stent: is there a learning curve in achieving rapid recanalization times? AB - METHODS: In acute ischemic stroke, good outcome following successful recanalization is time dependent. In patients undergoing endovascular therapy at our institution, recanalization times with the Solitaire stent were retrospectively evaluated to assess for the presence of a learning curve in achieving rapid recanalization. METHODS: We reviewed patients who presented to our stroke center and achieved successful recanalization with the Solitaire stent exclusively. Time intervals were calculated (CT to angiography arrival, angiography arrival to groin puncture, groin puncture to first deployment, and deployment to recanalization) from time stamped images and angiography records. Patients were divided into three sequential groups, with overall CT to recanalization time and subdivided time intervals compared. RESULTS: 83 patients were treated with the Solitaire stent from May 2009 to February 2012. Recanalization (Thrombolyis in Cerebral Infarction score 2A) occurred in 75 (90.4%) patients. CT to recanalization demonstrated significant improvement over time, which was greatest between the first 25 and the most recent 25 cases (161 94 min; p<0.01). The maximal contribution to this was from improvements in first stent deployment to recanalization time (p=0.001 between the first and third groups), with modest contributions from moving patients from CT to the angiography suite faster (p=0.02 between the first and third groups) and from groin puncture to first stent deployment (p=0.02 between the first and third groups). CONCLUSIONS: There is a learning curve involved in the efficient use of the Solitaire stent in endovascular acute stroke therapy. Along with improvements in patient transfer to angiography and improved efficiency with intracranial access, mastering this device contributed significantly towards reducing recanalization times. PMID- 24151115 TI - Spinal cord stimulators in an outpatient interventional neuroradiology practice. AB - PURPOSE: Spinal cord stimulation is a known modality for the treatment of chronic back and neck pain. Traditionally, spine surgeons and pain physicians perform the procedures. We report our experience in performing neuromodulation procedures in an outpatient interventional neuroradiology practice. METHODS: A retrospective analysis of medical records of all trial and permanent implantation patients over a period of 4 years was performed. 45 patients (32 men) of median age 47 years were included in the study. The primary diagnoses were 23 cases of failed back or neck surgery syndrome, 12 cases of spinal stenosis, 4 cases of axial pain, 3 cases with reflex sympathetic dystrophy, 1 case of peripheral vascular disease, 1 case of phantom limb and 1 case of post-concussion syndrome. RESULTS: Thirty-four trials were performed in an outpatient clinic while 11 trials were performed in hospital outpatient settings. Trial periods were 3-7 days. 27 patients (60%) who reported >=50% pain relief underwent a permanent implantation. An interventional neuroradiologist performed 17 implantations, while spine surgeons performed 10 implantations. 23 implants were epidural (19 lumbar and 4 cervical) and four implants were subcutaneous. During the follow-up period, three patients had infections (13%) and required removal of the device and two cases (8%) reported lead migration. CONCLUSIONS: Neuromodulation procedures can be performed safely in an outpatient interventional radiology setting. Although the infection rate was relatively higher in this study population, the other complication rates and trial-to-implant ratio are similar to published data. PMID- 24151116 TI - Recanalization of acute carotid stent occlusion using Penumbra 4Max aspiration catheter: technical report and review of rescue strategies for acute carotid stent occlusion. AB - Carotid artery stenting (CAS) has become a widely used treatment for carotid artery stenosis, especially in high-risk patients. Acute in-stent and distal protection device occlusion are potentially catastrophic complications of this procedure. Previously described rescue strategies have included administration of antiplatelet agents (eg, abciximab) with/without thrombolytics and removal of the filter. Here we describe the successful resolution of in-stent occlusion by mechanical thrombolysis using the Penumbra 4Max aspiration catheter. Distal flow was subsequently restored with minimal residual stenosis. The patient did not suffer any consequent neurological deficits. The different strategies that could be used in this critical situation are reviewed. PMID- 24151117 TI - Diagnostic yield of delayed neurovascular imaging in patients with subarachnoid hemorrhage, negative initial CT and catheter angiograms, and a negative 7 day repeat catheter angiogram. AB - PURPOSE: The yield of delayed neurovascular imaging in patients with subarachnoid hemorrhage (SAH), negative initial CT and catheter angiograms (CT angiography (CTA), DSA), and negative 7 day repeat DSA is not well understood. Our aim was to determine the yield of delayed neurovascular imaging for the detection of causative vascular lesions in this clinical scenario. METHODS: We retrospectively examined the yield of delayed CTA and DSA for the detection of causative vascular lesions in patients presenting to our institution with SAH, negative initial CTA and DSA examinations, and a negative 7 day repeat DSA during a 6.5 year period. Two neuroradiologists evaluated the non-contrast CTs to determine the SAH pattern, and the delayed CTAs and DSAs to assess for the presence of a causative vascular lesion. RESULTS: 39 patients were included: 23 men (59%) and 16 women (41%), mean age 55.5 years (range 33-75). 25 patients had diffuse SAH (64.1%), 12 had perimesencephalic SAH (30.8%), and two had peripheral sulcal SAH (5.1%). The delayed neurovascular examination was CTA in 30 patients (76.9%) and DSA in nine patients (23.1%). Mean time to delayed CTA or DSA was 34.9 days (median 34, range 14-69 days). Delayed CTA demonstrated a causative vascular lesion in two patients (5.1%, one small internal carotid artery aneurysm and one small pontine arteriovenous malformation), both with diffuse SAH (yield 8%). CONCLUSIONS: Delayed neurovascular imaging is valuable in the evaluation of patients with diffuse SAH who have negative initial CTA and DSA examinations and a negative 7 day repeat DSA, demonstrating a causative vascular lesion in 8% of patients. PMID- 24151119 TI - Assessment of nonischemic fibrosis in hypertrophic cardiomyopathy: comparison of gadopentetate dimeglumine and gadobenate dimeglumine for enhanced cardiovascular magnetic resonance imaging. AB - PURPOSE: To compare whether the higher relaxivity contrast agent gadobenate is superior for the identification of nonischemic late gadolinium enhancement (LGE) in hypertrophic cardiomyopathy (HCM) compared to standard relaxivity agents such as gadopentetate. MATERIALS AND METHODS: Fifteen patients with HCM and positive LGE based on routine cardiac magnetic resonance (CMR) with 0.2 mmol/kg gadopentetate were enrolled. Each patient thereafter underwent a second enhanced CMR exam with 0.2 mmol/kg gadobenate using the same CMR protocol. LGE was assessed in a short axis stack acquired after contrast administration using an inversion recovery gradient echo sequence. Two independent blinded readers quantified LGE by manual planimetry. The signal intensities of injured myocardium, remote myocardium, left ventricular cavity, and air were measured in identical locations using anatomical landmarks and dedicated software. The signal to-noise ratio (SNR) and contrast-to-noise ratio (CNR) were calculated. RESULTS: No adverse events related to contrast administration occurred. Gadobenate dimeglumine showed a higher SNR of injured myocardium (45.4 +/- 24.0 vs. 31.1 +/- 16.6, P = 0.002) and a higher CNR between remote and injured myocardium (37.6 +/- 25.0 vs. 26.5 +/- 17.6, P = 0.006) compared to gadopentetate dimeglumine. The amount of LGE (based on the same postprocessing criteria and definitions) was higher with gadobenate dimeglumine (12.7 +/- 8.5 g vs. 9.4 +/- 5.6 g, P = 0.005). There was no difference in intra- and interobserver variability between gadopentetate dimeglumine and gadobenate dimeglumine. CONCLUSION: CMR with the high relaxivity contrast agent gadobenate dimeglumine reveals significantly more tissue with LGE in patients with HCM. PMID- 24151120 TI - Upregulation of the long non-coding RNA HOTAIR promotes esophageal squamous cell carcinoma metastasis and poor prognosis. AB - Recent studies of the individual functionalities of long non-coding RNAs (lncRNAs) in the development and progression of cancer have suggested that HOX transcript antisense RNA (HOTAIR) is capable of reprogramming chromatin organization and promoting cancer cell metastasis. In order to ascertain the expression pattern of the lncRNA HOTAIR and assess its biological role in the development and progression of esophageal squamous cell carcinoma (ESCC), HOTAIR expression in ESCC tissues and adjacent noncancerous tissues were collected from 78 patients and measured by real-time reverse transcription-polymerase chain reaction (RT-PCR). HOTAIR correlation with clinicopathological features and prognosis was also analyzed. Suppression of HOTAIR using siRNA treatment was performed in order to explore its role in tumor progression. Notably elevated HOTAIR expression levels were observed in cancerous tissues compared to adjacent noncancerous tissues (96%, P < 0.01), showing a high correlation with cancer metastasis (P < 0.01), elevated TNM (2009) stage classification (P < 0.01), and lowered overall survival rates (P = 0.003). Multivariate analysis revealed that HOTAIR expression (P = 0.003) is also an independent prognostic factor for comparison of TNM stage (P = 0.024) and lymph node metastasis (P = 0.010). Furthermore, in vitro assays of the ESCC cell line KYSE30 demonstrated that knockdown of HOTAIR reduced cell invasiveness and migration while increasing the response of cells to apoptosis. Thus, HOTAIR is a novel molecule involved in both ESCC progression and prognosis. Full elucidation of HOTAIR functionality relevant to ESCC may open avenues for the use of lncRNAs in identification of novel drug targets and therapies for ESCC and other prevalent cancers. PMID- 24151118 TI - Peril and pleasure: an rdoc-inspired examination of threat responses and reward processing in anxiety and depression. AB - As a step toward addressing limitations in the current psychiatric diagnostic system, the National Institute of Mental Health recently developed the Research Domain Criteria (RDoC) to stimulate integrative research-spanning self-report, behavior, neural circuitry, and molecular/genetic mechanisms-on core psychological processes implicated in mental illness. Here, we use the RDoC conceptualization to review research on threat responses, reward processing, and their interaction. The first section of the manuscript highlights the pivotal role of exaggerated threat responses-mediated by circuits connecting the frontal cortex, amygdala, and midbrain-in anxiety, and reviews data indicating that genotypic variation in the serotonin system is associated with hyperactivity in this circuitry, which elevates the risk for anxiety and mood disorders. In the second section, we describe mounting evidence linking anhedonic behavior to deficits in psychological functions that rely heavily on dopamine signaling, especially cost/benefit decision making and reward learning. The third section covers recent studies that document negative effects of acute threats and chronic stress on reward responses in humans. The mechanisms underlying such effects are unclear, but the fourth section reviews new optogenetic data in rodents indicating that GABAergic inhibition of midbrain dopamine neurons, driven by activation of the habenula, may play a fundamental role in stress-induced anhedonia. In addition to its basic scientific value, a better understanding of interactions between the neural systems that mediate threat and reward responses may offer relief from the burdensome condition of anxious depression. PMID- 24151123 TI - An update for human blood plasma pretreatment for optimized recovery of low molecular-mass peptides prior to CE-MS and SPE-CE-MS. AB - Protein precipitation and centrifugal filtration are well-established methods for concentrating and purifying peptides with a low relative molecular mass (Mr) from human blood plasma before proteomic and peptidomic studies using high-performance separation techniques, but there is little information on peptide recoveries. Here, we evaluate acetonitrile precipitation followed by a range of centrifugal filtration conditions for the analysis of low Mr peptides in human blood plasma before CE-MS and SPE coupled online to CE-MS. Three opioid peptides were used as model compounds, that is, dynorphin A 1-7, endomorphin 1, and methionine enkephalin and 3, 10, and 30 K Mr cut-off cellulose acetate filters (Amicon(r) Ultra-0.5) and 10 K Mr cut-off polyethersulfone filters (Vivaspin(r) 500) were studied. Unexpectedly, recoveries and repeatability were only optimum after passivating the 10 K Mr cut-off cellulose acetate filters with PEG to avoid peptide adsorption on the inner walls of the plastic sample reservoir. PMID- 24151122 TI - Achilles tendon ruptures. AB - The incidence of acute Achilles tendon ruptures is on the rise. This is thought to be due to the increasing number of middle-aged persons participating in athletic and/or strenuous activity. Ruptures of the Achilles tendon can be severely debilitating, with deficits seen years after the initial incident. Also, these injuries can have substantial socioeconomic impacts regardless of the treatment selected. Debate continues over the optimal treatment of Achilles tendon ruptures, especially the argument whether to treat patients nonoperatively or surgically. Newer evidence shows that functional rehabilitation, including early weight-bearing, should be an integral part of successful treatment of acute Achilles ruptures. Further research is needed to further investigate the ideal treatment and rehabilitation protocols. PMID- 24151124 TI - Efficient access to enantiopure gamma4-amino acids with proteinogenic side-chains and structural investigation of gamma4-Asn and gamma4-Ser in hybrid peptide helices. AB - Hybrid peptides composed of alpha- and beta-amino acids have recently emerged as new class of peptide foldamers. Comparatively, gamma- and hybrid gamma-peptides composed of gamma(4) -amino acids are less studied than their beta-counterparts. However, recent investigations reveal that gamma(4)-amino acids have a higher propensity to fold into ordered helical structures. As amino acid side-chain functional groups play a crucial role in the biological context, the objective of this study was to investigate efficient synthesis of gamma(4)-residues with functional proteinogenic side-chains and their structural analysis in hybrid peptide sequences. Here, the efficient and enantiopure synthesis of various N- and C-terminal free-gamma(4)-residues, starting from the benzyl esters (COOBzl) of N-Cbz-protected (E)-alpha,beta-unsaturated gamma-amino acids through multiple hydrogenolysis and double-bond reduction in a single-pot catalytic hydrogenation is reported. The crystal conformations of eight unprotected gamma(4)-amino acids (gamma(4)-Val, gamma(4)-Leu, gamma(4)-Ile, gamma(4)-Thr(OtBu), gamma(4)-Tyr, gamma(4)-Asp(OtBu), gamma(4)-Glu(OtBu), and gamma-Aib) reveals that these amino acids adopted a helix favoring gauche conformations along the central C(gamma) C(beta) bond. To study the behavior of gamma(4)-residues with functional side chains in peptide sequences, two short hybrid gamma-peptides P1 (Ac-Aib-gamma(4) Asn-Aib-gamma(4)-Leu-Aib-gamma(4)-Leu-CONH2 ) and P2 (Ac-Aib-gamma(4)-Ser-Aib gamma(4)-Val-Aib-gamma(4)-Val-CONH2 ) were designed, synthesized on solid phase, and their 12-helical conformation in single crystals were studied. Remarkably, the gamma(4) -Asn residue in P1 facilitates the tetrameric helical aggregations through interhelical H bonding between the side-chain amide groups. Furthermore, the hydroxyl side-chain of gamma(4)-Ser in P2 is involved in the interhelical H bonding with the backbone amide group. In addition, the analysis of 87 gamma(4) residues in peptide single-crystals reveal that the gamma(4)-residues in 12 helices are more ordered as compared with the 10/12- and 12/14-helices. PMID- 24151125 TI - Clinical management of patients with hypertension and high cardiovascular risk: main results of an Italian survey on blood pressure control. AB - INTRODUCTION: Hypertension management and control still represents a major clinical challenge for physicians, as well as for National Health Care Systems, since high blood pressure (BP) levels in treated uncontrolled outpatients are related to a persistently increased risk of cardiovascular (CV) events. The Italian Society of Hypertension (SIIA) has prompted several educational interventions for improving BP control in Italy. AIM: To evaluate clinical attitudes and preferences of large community sample of both specialized physicians and general practitioners, included in an educational program, endorsed by SIIA and aimed at improving interventions for achieving better BP control in Italy. METHODS: A predefined questionnaire, which included a main body with 17 questions and 15 specific items (3-4 questions for each item), was anonymously administered to a large community sample of physicians who have practice in managing outpatients with hypertension and high CV risk profile. Both specialized physicians and general practitioners, distributed throughout the whole Italian territory, have been included in this educational program. Data were reported into a computerised spreadsheet and centrally analysed. Confidentiality of the data were guaranteed during each phase of the study. RESULTS: From a total of 64 questions, 557 physicians (478 male, mean age 54.2 +/ 7.1 years, average age of medical activity 28.0 +/- 8.1 years), among which 261 (46.9 %) specialised physicians and 296 (53.1 %) general practitioners, provided 60,713 answers to the survey questionnaire. Physicians devote time and effort for achieving the recommended BP targets (<140/90 and <130/80 mmHg in high risk subgroups), yet they reported a very high rate of BP control (about 70 %). Concomitant presence of diabetes, cardiac and renal organ damage (35-50 %), as well as comorbidities (20-35 %), is reported to be high and able to impact on antihypertensive treatment's efficacy. Appropriate BP assessment is also viewed as a key tool for verifying effectiveness of a given drug therapy. Beyond non pharmacological options, ACE inhibitors and ARBs were considered to most useful, effective and well tolerated options to start and maintain antihypertensive treatment, thus adding diuretics or calcium-channel blockers if needed. Direct renin inhibitors was considered to be effective in difficult to treat hypertension and to provide sustained antihypertensive efficacy. CONCLUSIONS: With the well-known limitations of an observational, cross-sectional survey, in which a predefined questionnaire was administered to physicians rather than collecting data from medical databases, this study provides useful and updated information on attitudes and preferences, as well as on difficulties and troubles for physicians when managing outpatients with hypertension and high CV risk profile in Italy. PMID- 24151126 TI - Delayed gastric emptying in Parkinson's disease. AB - Gastrointestinal symptoms are evident in all stages of Parkinson's disease (PD). Most of the gastrointestinal abnormalities associated with PD are attributable to impaired motility. At the level of the stomach, this results in delayed gastric emptying. The etiology of delayed gastric emptying in PD is probably multifactorial but is at least partly related to Lewy pathology in the enteric nervous system and discrete brainstem nuclei. Delayed gastric emptying occurs in both early and advanced PD but is underdetected in routine clinical practice. Recognition of delayed gastric emptying is important because it can cause an array of upper gastrointestinal symptoms, but additionally it has important implications for the absorption and action of levodopa. Delayed gastric emptying contributes significantly to response fluctuations seen in people on long-term l dopa therapy. Neurohormonal aspects of the brain-gut axis are pertinent to discussions regarding the pathophysiology of delayed gastric emptying in PD and are also hypothesized to contribute to the pathogenesis of PD itself. Ghrelin is a gastric-derived hormone with potential as a therapeutic agent for delayed gastric emptying and also as a novel neuroprotective agent in PD. Recent findings relating to ghrelin in the context of PD and gastric emptying are considered. This article highlights the pathological abnormalities that may account for delayed gastric emptying in PD. It also considers the wider relevance of abnormal gastric pathology to our current understanding of the etiology of PD. PMID- 24151127 TI - Metacognitive judgments-of-learning in adolescents with autism spectrum disorder. AB - This study investigated metacognitive monitoring abilities in adolescents with autism spectrum disorder in two experiments using the judgment-of-learning paradigm. Participants were asked to predict their future recall of unrelated word pairs during the learning phase. Experiment 1 compared judgments-of-learning made immediately after learning and judgments-of-learning made after a delay. We found that both groups overestimated their memory performance but that overall there were no group differences in judgment-of-learning accuracy. Additionally, both groups displayed the standard delayed judgment-of-learning effect (yielding greater judgment accuracy in delayed compared to immediate judgments), suggesting that both groups were able to use appropriate information in making their judgments-of-learning. Experiment 2 assessed whether adolescents with autism spectrum disorder could regulate their study time according to their judgments-of learning using a self-paced learning procedure. Results showed that both groups spent more time learning items given lower judgments-of-learning. Finally, Experiment 2 showed that judgments-of-learning and study time varied according to item difficulty in both groups. As a whole, these findings demonstrate that adolescents with autism spectrum disorder can accurately gauge their memory performance while learning new word associations and use these skills to control their study time at learning. PMID- 24151128 TI - The coherence of autism. AB - There is a growing body of opinion that we should view autism as fractionable into different, largely independent sets of clinical features. The alternative view is that autism is a coherent syndrome in which principal features of the disorder stand in intimate developmental relationship with each other. Studies of congenitally blind children offer support for the latter position and suggest that a source of coherence in autism is restriction in certain forms of perceptually dependent social experience. PMID- 24151129 TI - Awareness about autism among school teachers in Oman: a cross-sectional study. AB - Children with special needs such as those with autism spectrum disorder have been recorded as ostracized and stigmatized in many parts of the world. Little is known about whether such negative views are present among mainstream teachers in Oman. A cross-sectional study was conducted to evaluate school teachers' awareness about autism spectrum disorder in an urban region in Oman. A total of 164 teachers were randomly enrolled from five schools. Misconceptions about autism spectrum disorder were found to be common among mainstream teachers in the country. We posit that such lack of awareness was likely to be rooted with sociocultural patterning as well as conflicting views often "spun" by the scientific community and mass media. Enlightened views toward children with autism spectrum disorder should be presented to Omani teachers to overcome misconceptions and negative attitudes toward children with autism spectrum disorder. PMID- 24151130 TI - Carotenoid supplementation enhances reproductive success in captive strawberry poison frogs (Oophaga pumilio). AB - Amphibians are currently experiencing the most severe declines in biodiversity of any vertebrate, and their requirements for successful reproduction are poorly understood. Here, we show that supplementing the diet of prey items (fruit flies) with carotenoids has strong positive effects on the reproduction of captive strawberry poison frogs (Oophaga pumilio), substantially increasing the number of metamorphs produced by pairs. This improved reproduction most likely arose via increases in the quality of both the fertilized eggs from which tadpoles develop and trophic eggs that are fed to tadpoles by mothers. Frogs in this colony had previously been diagnosed with a Vitamin A deficiency, and this supplementation may have resolved this issue. These results support growing evidence of the importance of carotenoids in vertebrate reproduction and highlight the nuanced ways in which nutrition constrains captive populations. PMID- 24151131 TI - Insensitive nitrogen-rich materials incorporating the nitroguanidyl functionality. AB - A new class of nitroguanidyl-functionalized nitrogen-rich materials derived from 1,3,5-triazine and 1,2,4,5-tetrazine was synthesized through reactions between N nitroso-N'-alkylguanidines and the hydrazine derivatives of 1,3,5-triazine or 1,2,4,5-tetrazine. These compounds were fully characterized using multinuclear NMR and IR spectroscopies, elemental analysis, and differential scanning calorimetry (DSC). The heats of formation for all compounds were calculated with Gaussian 03 and then combined with experimental densities to determine the detonation pressures (P) and velocities (Dv) of the energetic materials. Interestingly, some of the compounds exhibit an energetic performance (P and Dv) comparable to that of RDX, thus holding promise for application as energetic materials. PMID- 24151135 TI - Twin reversed arterial perfusion sequence presenting as intrauterine cyst. PMID- 24151134 TI - Involvement and targeted intervention of dysregulated Hedgehog signaling in osteosarcoma. AB - BACKGROUND: During development, the Hedgehog pathway plays important roles regulating the proliferation and differentiation of chondrocytes, providing a template for growing bone. In this study, the authors investigated the components of dysregulated Hedgehog signaling as potential therapeutic targets for osteosarcoma. METHODS: Small-molecule agonists and antagonists that modulate the Hedgehog pathway at different levels were used to investigate the mechanisms of dysregulation and the efficacy of Hedgehog blockade in osteosarcoma cell lines. The inhibitory effect of a small-molecule Smoothened (SMO) antagonist, IPI-926 (saridegib), also was examined in patient-derived xenograft models. RESULTS: An inverse correlation was identified in osteosarcoma cell lines between endogenous glioma-associated oncogene 2 (GLI2) levels and Hedgehog pathway induction levels. Cells with high levels of GLI2 were sensitive to GLI inhibition, but not SMO inhibition, suggesting that GLI2 overexpression may be a mechanism of ligand independent activation. In contrast, cells that expressed high levels of the Hedgehog ligand gene Indian hedgehog (IHH) and the target genes patched 1 (PTCH1) and GLI1 were sensitive to modulation of both SMO and GLI, suggesting ligand dependent activation. In 2 xenograft models, active autocrine and paracrine, ligand-dependent Hedgehog signaling was identified. IPI-926 inhibited the Hedgehog signaling interactions between the tumor and the stroma and demonstrated antitumor efficacy in 1 of 2 ligand-dependent models. CONCLUSIONS: The current results indicate that both ligand-dependent and ligand-independent Hedgehog dysregulation may be involved in osteosarcoma. It is the first report to demonstrate Hedgehog signaling crosstalk between the tumor and the stroma in osteosarcoma. The inhibitory effect of IPI-926 warrants additional research and raises the possibility of using Hedgehog pathway inhibitors as targeted therapeutics to improve treatment for osteosarcoma. PMID- 24151133 TI - Nucleus of the solitary tract in the C57BL/6J mouse: Subnuclear parcellation, chorda tympani nerve projections, and brainstem connections. AB - The nucleus of the solitary tract (NST) processes gustatory and related somatosensory information rostrally and general viscerosensory information caudally. To compare its connections with those of other rodents, this study in the C57BL/6J mouse provides a subnuclear cytoarchitectonic parcellation (Nissl stain) of the NST into rostral, intermediate, and caudal divisions. Subnuclei are further characterized by NADPH staining and P2X2 immunoreactivity (IR). Cholera toxin subunit B (CTb) labeling revealed those NST subnuclei receiving chorda tympani nerve (CT) afferents, those connecting with the parabrachial nucleus (PBN) and reticular formation (RF), and those interconnecting NST subnuclei. CT terminals are densest in the rostral central (RC) and medial (M) subnuclei; less dense in the rostral lateral (RL) subnucleus; and sparse in the ventral (V), ventral lateral (VL), and central lateral (CL) subnuclei. CTb injection into the PBN retrogradely labels cells in the aforementioned subnuclei; RC and M providing the largest source of PBN projection neurons. Pontine efferent axons terminate mainly in V and rostral medial (RM) subnuclei. CTb injection into the medullary RF labels cells and axonal endings predominantly in V at rostral and intermediate NST levels. Small CTb injections within the NST label extensive projections from the rostral division to caudal subnuclei. Projections from the caudal division primarily interconnect subnuclei confined to the caudal division of the NST; they also connect with the area postrema. P2X2 -IR identifies probable vagal nerve terminals in the central (Ce) subnucleus in the intermediate/caudal NST. Ce also shows intense NADPH staining and does not project to the PBN. PMID- 24151136 TI - Automatic prebent customized prosthesis for pectus excavatum minimally invasive surgery correction. AB - Pectus excavatum is the most common deformity of the thorax. A minimally invasive surgical correction is commonly carried out to remodel the anterior chest wall by using an intrathoracic convex prosthesis in the substernal position. The process of prosthesis modeling and bending still remains an area of improvement. The authors developed a new system, i3DExcavatum, which can automatically model and bend the bar preoperatively based on a thoracic CT scan. This article presents a comparison between automatic and manual bending. The i3DExcavatum was used to personalize prostheses for 41 patients who underwent pectus excavatum surgical correction between 2007 and 2012. Regarding the anatomical variations, the soft tissue thicknesses external to the ribs show that both symmetric and asymmetric patients always have asymmetric variations, by comparing the patients' sides. It highlighted that the prosthesis bar should be modeled according to each patient's rib positions and dimensions. The average differences between the skin and costal line curvature lengths were 84 +/- 4 mm and 96 +/- 11 mm, for male and female patients, respectively. On the other hand, the i3DExcavatum ensured a smooth curvature of the surgical prosthesis and was capable of predicting and simulating a virtual shape and size of the bar for asymmetric and symmetric patients. In conclusion, the i3DExcavatum allows preoperative personalization according to the thoracic morphology of each patient. It reduces surgery time and minimizes the margin error introduced by the manually bent bar, which only uses a template that copies the chest wall curvature. PMID- 24151137 TI - Comparative study of normal and sensitive skin aerobic bacterial populations. AB - The purpose of this study was to investigate if the sensitive skin syndrome, a frequent skin disorder characterized by abnormal painful reactions to environmental factors in the absence of visible inflammatory response, could be linked to a modification in the skin bacterial population. A total of 1706 bacterial isolates was collected at the levels of the forehead, cheekbone, inner elbow, and lower area of the scapula on the skin of normal and sensitive skin syndrome-suffering volunteers of both sexes and of different ages. Among these isolates, 21 strains were randomly selected to validate in a first step the Matrix-Assisted Laser Desorption/Ionization (MALDI)-Biotyper process as an efficient identification tool at the group and genus levels, by comparison to API((r)) strips and 16S ribosomal RNA gene sequencing identification techniques. In a second step, identification of the skin microbiota isolates by the MALDI Biotyper tool allowed to pinpoint some differences in terms of bacterial diversity with regard to the collection area, and the volunteer's age and gender. Finally, comparison of the skin microbiota from normal and sensitive skin syndrome-suffering volunteers pointed out gender-related variations but no detectable correlation between a phylum, a genus or a dominant bacterial species and the sensitive skin phenotype. This study reveals that there is no dysbiosis of aerobic cultivable bacteria associated with the sensitive skin syndrome and further demonstrates that the MALDI-Biotyper is a powerful technique that can be efficiently employed to the study of cultivable human skin bacteria. To our knowledge, this is the first study focusing on bacteria in the sensitive skin syndrome. These results are of potential importance for pharmaceutical and cosmetic industries, which are looking for new strategies to treat this multiparametric disorder. PMID- 24151138 TI - Simulation from a known Cox MSM using standard parametric models for the g formula. AB - It is routinely argued that, unlike standard regression-based estimates, inverse probability weighted (IPW) estimates of the parameters of a correctly specified Cox marginal structural model (MSM) may remain unbiased in the presence of a time varying confounder affected by prior treatment. Previously proposed methods for simulating from a known Cox MSM lack knowledge of the law of the observed outcome conditional on the measured past. Although unbiased IPW estimation does not require this knowledge, standard regression-based estimates rely on correct specification of this law. Thus, in typical high-dimensional settings, such simulation methods cannot isolate bias due to complex time-varying confounding as it may be conflated with bias due to misspecification of the outcome regression model. In this paper, we describe an approach to Cox MSM data generation that allows for a comparison of the bias of IPW estimates versus that of standard regression-based estimates in the complete absence of model misspecification. This approach involves simulating data from a standard parametrization of the likelihood and solving for the underlying Cox MSM. We prove that solutions exist and computations are tractable under many data-generating mechanisms. We show analytically and confirm in simulations that, in the absence of model misspecification, the bias of standard regression-based estimates for the parameters of a Cox MSM is indeed a function of the coefficients in observed data models quantifying the presence of a time-varying confounder affected by prior treatment. We discuss limitations of this approach including that implied by the 'g-null paradox'. PMID- 24151139 TI - Smokers' and nonsmokers' beliefs about harmful tobacco constituents: implications for FDA communication efforts. AB - INTRODUCTION: Legislation requires the U.S. Food and Drug Administration (FDA) to release information to the public about harmful constituents in tobacco and tobacco smoke. To inform these efforts, we sought to better understand how smokers and nonsmokers think about tobacco constituents. METHODS: In October 2012, 300 U.S. adults aged 18-66 years completed a cross-sectional Internet survey. The questions focused on 20 harmful tobacco constituents that the FDA has prioritized for communicating with the public. RESULTS: Most participants had heard of 7 tobacco constituents (ammonia, arsenic, benzene, cadmium, carbon monoxide, formaldehyde, and nicotine), but few participants had heard of the others (e.g., acrolein). Few participants correctly understood that many constituents were naturally present in tobacco. Substances that companies add to cigarette tobacco discouraged people from wanting to smoke more than substances that naturally occur in cigarette smoke (p < .001). Ammonia, arsenic, carbon monoxide, and formaldehyde being in cigarettes elicited the most discouragement from smoking. Constituents elicited greater discouragement from wanting to smoke if respondents were nonsmokers (beta = -.34, p < .05), had negative images of smokers (i.e., negative smoker prototypes; beta = .19, p < .05), believed constituents are added to tobacco (beta = .14, p < .05), or were older (beta = .16, p < .05). CONCLUSIONS: Our study found low awareness of most tobacco constituents, with greater concern elicited by additives. Efforts to communicate health risks of tobacco constituents should consider focusing on ones that elicited the most discouragement from smoking. PMID- 24151140 TI - Cigarette smoking as an expression of independence and freedom among inmates in a tobacco-free prison in the United States. AB - INTRODUCTION: Most adults report initiation of cigarette smoking during adolescence, a time also marked by developmental striving for independence and freedom. Tobacco use may retain its association with independence and/or freedom into adulthood. This association may contribute to continued tobacco use and/or increased risk of relapse to smoking among some individuals. This study examines the relationship between cigarette smoking and perceptions of independence and freedom among inmates in a tobacco-free prison in the northeastern United States. METHODS: Questionnaires administered to 247 male and female inmates 6 weeks prior to scheduled prison release assessed demographics, smoking history, nicotine dependence, attitudes toward smoking, and plans for tobacco use or abstinence after prison release. Perceptions of smoking as an expression of independence and freedom were measured using 2 items. Smoking was assessed 3 weeks postrelease. RESULTS: Constructs of freedom and independence were correlated but did not overlap completely. Both constructs were negatively associated with plans for smoking abstinence after prison release, and with perceived costs of continued smoking. Number of cigarettes smoked postrelease and perception of the pros of smoking were associated with freedom, but not independence. CONCLUSIONS: Associations of smoking as an expression of freedom and independence may negatively influence plans for renewed smoking after a forced abstinence. Additional research is needed to determine the degree to which these 2 constructs predict smoking behavior and whether they can be used to improve interventions for incarcerated smokers. PMID- 24151141 TI - Predictors of completion of exposure therapy in OEF/OIF veterans with posttraumatic stress disorder. AB - BACKGROUND: Despite large-scale dissemination and implementation efforts of evidence-based psychotherapy to veterans from Operation Enduring/Iraqi Freedom (OEF/OIF), little is known regarding the factors that contribute to the successful completion of these treatments in this high-risk population. The present study investigated predictors of treatment completion during a standardized exposure-based psychotherapy for PTSD. METHODS: Ninety-two OEF/OIF combat veterans enrolled in a randomized controlled trial for an eight session exposure-based psychotherapy for PTSD. All participants completed structured clinical interviews and several background and symptom questionnaires. Of the initial 92 participants, 28% of the sample (n = 26) discontinued treatment prior to completion of the trial. RESULTS: Predictors of discontinuation of treatment were assessed with a hierarchical logistic regression. Disability status was positively associated with treatment discontinuation, and postdeployment social support was negatively associated with discontinuation. In contrast to previous findings, other factors, such as age and PTSD symptomatology, were not identified as significant predictors. CONCLUSIONS: The present study suggested that disability status at the start of treatment increases the risk for treatment discontinuation whereas increased social support buffers against discontinuation. Together, these findings highlight the importance of increased assessment and early intervention when these factors are present to potentially reduce treatment discontinuation and improve treatment outcomes in OEF/OIF veterans with PTSD. PMID- 24151142 TI - Quantification of abdominal aortic aneurysm wall enhancement with dynamic contrast-enhanced MRI: feasibility, reproducibility, and initial experience. AB - PURPOSE: To investigate the feasibility and reproducibility of dynamic contrast enhanced MRI (DCE-MRI) to quantify abdominal aortic aneurysm (AAA) vessel wall enhancement dynamics which may reflect the amount of wall microvasculature. AAA vessel wall microvasculature has been linked with aneurysm progression and rupture. MATERIALS AND METHODS: Thirty patients with AAA underwent DCE-MRI at 1.5 Tesla. Enhancement dynamics of the aneurysm wall were quantified in regions-of interest (ROIs) in the vessel wall by calculating the transfer constant (K(trans) ) using pharmacokinetic modeling and the area-under-gadolinium-curve (AUC). To assess reproducibility, 10 patients were imaged twice on different occasions. ROIs were drawn by two independent observers. The intraclass correlation coefficients (ICC) and coefficients of variation (CV) were determined to investigate intra-, interobserver, and interscan variability. RESULTS: Twenty eight analyzable MR examinations were included for pharmacokinetic analysis after excluding two examinations due to severe motion artifacts. Intra-, interobserver, and interscan variability for K(trans) were small (all ICC > 0.90, CV < 14%) as well as for AUC measurements (all ICC > 0.88, CV < 23%). CONCLUSION: Quantitative analysis of AAA vessel wall enhancement dynamics with DCE-MRI is feasible and reproducible. PMID- 24151143 TI - The use and acceptance of Other Scientifically Relevant Information (OSRI) in the U.S. Environmental Protection Agency (EPA) Endocrine Disruptor Screening Program. AB - The U.S. Environmental Protection Agency (EPA) Endocrine Disruptor Screening Program (EDSP) currently relies on an initial screening battery (Tier 1) consisting of five in vitro and six in vivo assays to evaluate a chemical's potential to interact with the endocrine system. Chemical companies may request test waivers based on Other Scientifically Relevant Information (OSRI) that is functionally equivalent to data gathered in the screening battery or that provides information on a potential endocrine effect. Respondents for 47 of the first 67 chemicals evaluated in the EDSP submitted OSRI in lieu of some or all Tier 1 tests, seeking 412 waivers, of which EPA granted only 93. For 20 of the 47 chemicals, EPA denied all OSRI and required the entire Tier 1 battery. Often, the OSRI accepted was either identical to data generated by the Tier 1 assay or indicated a positive result. Although identified as potential sources of OSRI in EPA guidance, Part 158 guideline studies for pesticide registration were seldom accepted by EPA. The 93 waivers reduced animal use by at least 3325 animals. We estimate 27,731 animals were used in the actual Tier 1 tests, with additional animals being used in preparation for testing. Even with EPA's shift toward applying 21st-century toxicology tools to screening of endocrine disruptors in the future, acceptance of OSRI will remain a primary means for avoiding duplicative testing and reducing use of animals in the EDSP. Therefore, it is essential that EPA develop a consistent and transparent basis for accepting OSRI. PMID- 24151144 TI - Improved oral bioavalability of mebudipine upon administration in PhytoSolve and Phosal-based formulation (PBF). AB - The aim of this investigation was to examine the efficacy of PhytoSolve and Phosal-based formulation (PBF) to enhance the oral bioavailability of mebudipine, which is a poorly water-soluble calcium channel blocker. The solubility of mebudipine in various oils was determined. PhytoSolve was prepared with a medium chain triglyceride (MCT) oil (20%), soybean phospholipids (5%), and a 70% fructose solution (75%). The influence of the weight ratio of Phosal 50PG to glycerol in PBF on the mean globule size was studied with dynamic light scattering. The optimized formulation was evaluated for robustness toward dilution, transparency, droplet size, and zeta potential. The in vivo oral absorption of different mebudipine formulations (PhytoSolve, PBF, oily solution, and suspension) were evaluated in rats. The optimized PBF contained Phosal 50PG/glycerol in a 6:4 ratio (w/w). The PBF and PhytoSolve formulations were miscible with water in any ratio and did not demonstrate any phase separation or drug precipitation over 1 month of storage. The mean particle size of PhytoSolve and PBF were 138.5 +/- 9.0 and 74.4 +/- 2.5 nm, respectively. The in vivo study demonstrated that the oral bioavailability of PhytoSolve and PBF in rats was significantly higher than that of the other formulations. The PhytoSolve and PBF formulations of mebudipine are found to be more bioavailable compared with suspension and oily solutions during an in vivo study in rats. These formulations might be new alternative carriers that increase the oral bioavailability of poorly water-soluble molecules, such as mebudipine. PMID- 24151145 TI - Habitual street food intake and subclinical carotid atherosclerosis. AB - Street food (SF) is defined as out-of-home food consumption, and generally consists of energy-dense meals rich in saturated fats and poor in fibers, vitamins and antioxidants. Though SF consumption may have unfavorable metabolic and cardiovascular effects, its possible association with atherosclerosis has not been considered. The association between habitual SF consumption and asymptomatic carotid atherosclerosis, defined as the presence of plaques and/or increased intima-media thickness, was therefore investigated. One thousand thirty-five randomly selected adult participants without known diabetes and atherosclerotic cardiovascular diseases were cross-sectionally investigated in Palermo, Italy. Each participant answered a food frequency questionnaire and underwent high resolution ultrasonographic evaluation of both carotid arteries. Laboratory blood measurements were obtained in a subsample of 541 participants. A score of SF consumption was obtained by categorizing each of ten SFs consumed more or less than once a month. Participants were divided into three classes based on the tertiles of SF score distribution. Age, gender distribution, body mass index (BMI), prevalence of hypertension and of clinically silent carotid atherosclerosis (I tertile 20.8 %, II tertile 19.7 %, III tertile 19.0 %; P = 0.85) were not significantly different among the three groups. Clinically silent carotid atherosclerosis was independently associated with age, gender and hypertension. The score of SF consumption was significantly correlated with BMI (r = 0.10; P = 0.04), uric acid (r = 0.16; P = 0.002) and high-density lipoproteins-cholesterol (r = -0.13; P = 0.009) blood concentrations. In conclusion, this study suggests that SF consumption is not associated with clinically silent carotid atherosclerosis. However, given the association of SF consumption with other cardiovascular risk factors, caution requires that this category of food should be limited in patients at high cardiovascular risk. PMID- 24151147 TI - Development and impact of an intervention to boost recruitment in a multicenter pediatric randomized clinical trial. AB - OBJECTIVES: Our primary objective was to develop and evaluate an intervention to increase recruitment in a multicenter pediatric randomized clinical trial (RCT). Our secondary objective was to assess the impact beyond 120 days. METHODS: The study was conducted at 17 academic centers participating in a pediatric RCT. The intervention consisted of utilizing a recruitment assessment tool at a site visit or teleconference with key site personnel. RESULTS: We found a significant increase in the number of individuals enrolled for all 17 sites at 120 days postintervention (mean = 1.12 per site; median = 1 per site; 95% confidence interval = 1-2; P = .04). No significant differences were apparent beyond the first 120 days postintervention. CONCLUSIONS: Successful recruitment in RCTs is essential to the quality, generalizability, and cost-effectiveness of clinical research. Implementation of this recruitment intervention may effectively increase recruitment in RCTs. Beyond the first 120 days postintervention, repeated interventions may be required. What is new? Despite general and pediatric-specific challenges to recruitment in RCTs, a paucity of evidence exists on effective recruitment strategies or assessment tools to reliably enhance recruitment. We developed a recruitment intervention for use in RCTs that enables clinical researchers to enhance recruitment. PMID- 24151148 TI - Current research on transcultural psychiatry in the Anglophone Caribbean: epistemological, public policy, and epidemiological challenges. AB - In this article, we review recent research on mental health in the Caribbean. Three major themes emerge: (a) the effects of colonialism on the Caribbean psyche; (b) decolonization of psychiatric public policy, including innovative treatment approaches, deinstitutionalization, and community and policy responses to mental health issues; and (c) the nature and epidemiology of psychiatric pathology among contemporary Caribbean people, with particular focus on migration, genetic versus social causation of psychosis and personality disorders, and mechanisms of resilience and social capital. Caribbean transcultural psychiatry illustrates the principles of equipoise unique to developing countries that protect the wellness and continued survival of postcolonial Caribbean people. PMID- 24151146 TI - Reg4-induced mitogenesis involves Akt-GSK3beta-beta-Catenin-TCF-4 signaling in human colorectal cancer. AB - Upregulation of regenerating gene 4 (Reg4) is observed in many human gastrointestinal malignancies including colorectal cancer (CRC). We previously reported a Reg4-mediated induction of epidermal growth factor receptor-Akt-AP1 signaling regulating CRC cell apoptosis. However, the role of Reg4 in the regulation of CRC cell division is poorly understood. This study tests the hypothesis that Reg4 induces Akt-GSK3beta-beta-Catenin-TCF-4 signaling to regulate CRC cell division. In vitro models of human CRC were used to determine the role of Reg4 in regulation of CRC cell division. Cell cycle studies demonstrated that Reg4 treatment significantly decreased CRC cell number in G1 phase and increased in G2 phase. Subsequently Reg4 significantly increased the mitotic index of CRC cells. As assessed by real-time RT-PCR and Western blot analyses, Reg4 significantly increased the expression of cell cycle regulatory genes Cyclin D1 and D3, and associated Cyclin-dependent kinases (CDK4 and CDK6). Reg4-mediated increase in these genes involved a pathway that included an induced Akt activity by increasing phosphorylation of Thr308 and Ser473, a reduced glycogen synthase kinase 3beta (GSK-3beta) activity by increasing phosphorylation of Ser9, an induced nuclear translocation of beta-Catenin by decreasing phosphorylation of Ser33/37/Thr41, and an increased TCF-4 transcriptional activity. Furthermore, antagonism of Reg4-signaling using Reg4-specific mAbs (2H6 and 3E5) and Akt inhibitor significantly decreased, whereas agonism using GSK 3beta antagonist (SB216763) significantly increased mitotic index and proliferation of CRC cells. These results identify Reg4 as a key regulator of the CRC cell division and proliferation, hence a potential target of human CRC treatment. PMID- 24151150 TI - Study of enantioselectivity on an immobilized amylose carbamate stationary phase under subcritical fluid chromatography. AB - In this paper, we describe the enantiomeric separation of a chiral alcohol under subcritical fluid chromatography conditions using a 3 MUm particle size bonded amylose carbamate stationary phase. Linear and branched alcohols were used as polar modifiers in CO2. The studies with linear alcohols showed a decrease in selectivity factor as the number of carbons in the linear chain increased. For branched alcohols, as the bulk of substituents at the alpha carbon atom increases the separation factor decreases. Thermodynamic studies showed that in the presence of the alcohols studies, except methanol and ethanol, a positive DeltaDeltaS was observed. Molecular mechanics simulation brought more insights into the mechanism of enantiomeric separation on this stationary phase under subcritical fluid chromatography. PMID- 24151151 TI - Addition of organometallic reagents to chiral N-methoxylactams: enantioselective syntheses of pyrrolidines and piperidines. AB - Enantioselective iridium-catalyzed allylic substitutions were used to prepare N allyl hydroxamic acid derivatives that were suitable for ring-closing metathesis, giving N-methoxylactams. Reactions of these derivatives with Grignard or organolithium compounds gave hemiaminals, which could be reduced diastereoselectively via acyliminium intermediates to give cis-piperidines or cis pyrrolidines with substituents in the 2,6- or 2,5-positions, respectively. In addition, compounds with a quaternary carbon center could be synthesized by corresponding reactions with potassium cyanide/AcOH. The procedures were applied in the syntheses of alkaloids (-)-209D and (+)-prosophylline. PMID- 24151152 TI - DICER1 mutations in an adolescent with cervical embryonal rhabdomyosarcoma (cERMS). PMID- 24151153 TI - High resolution myocardial first-pass perfusion imaging with extended anatomic coverage. AB - PURPOSE: To evaluate and to compare Parallel Imaging and Compressed Sensing acquisition and reconstruction frameworks based on simultaneous multislice excitation for high resolution contrast-enhanced myocardial first-pass perfusion imaging with extended anatomic coverage. MATERIALS AND METHODS: The simultaneous multislice imaging technique MS-CAIPIRINHA facilitates imaging with significantly extended anatomic coverage. For additional resolution improvement, equidistant or random undersampling schemes, associated with corresponding reconstruction frameworks, namely Parallel Imaging and Compressed Sensing can be used. By means of simulations and in vivo measurements, the two approaches were compared in terms of reconstruction accuracy. Comprehensive quality metrics were used, identifying statistical and systematic reconstruction errors. RESULTS: The quality measures applied allow for an objective comparison of the frameworks. Both approaches provide good reconstruction accuracy. While low to moderate noise enhancement is observed for the Parallel Imaging approach, the Compressed Sensing framework is subject to systematic errors and reconstruction induced spatiotemporal blurring. CONCLUSION: Both techniques allow for perfusion measurements with a resolution of 2.0 * 2.0 mm(2) and coverage of six slices every heartbeat. Being not affected by systematic deviations, the Parallel Imaging approach is considered to be superior for clinical studies. PMID- 24151154 TI - Reply to myelosuppression after frontline fludarabine, cyclophosphamide, and rituximab in patients with chronic lymphocytic leukemia: analysis of persistent and new-onset cytopenia. PMID- 24151155 TI - Opposite latitudinal gradients in projected ocean acidification and bleaching impacts on coral reefs. AB - Coral reefs and the services they provide are seriously threatened by ocean acidification and climate change impacts like coral bleaching. Here, we present updated global projections for these key threats to coral reefs based on ensembles of IPCC AR5 climate models using the new Representative Concentration Pathway (RCP) experiments. For all tropical reef locations, we project absolute and percentage changes in aragonite saturation state (Omegaarag) for the period between 2006 and the onset of annual severe bleaching (thermal stress >8 degree heating weeks); a point at which it is difficult to believe reefs can persist as we know them. Severe annual bleaching is projected to start 10-15 years later at high-latitude reefs than for reefs in low latitudes under RCP8.5. In these 10-15 years, Omegaarag keeps declining and thus any benefits for high-latitude reefs of later onset of annual bleaching may be negated by the effects of acidification. There are no long-term refugia from the effects of both acidification and bleaching. Of all reef locations, 90% are projected to experience severe bleaching annually by 2055. Furthermore, 5% declines in calcification are projected for all reef locations by 2034 under RCP8.5, assuming a 15% decline in calcification per unit of Omegaarag. Drastic emissions cuts, such as those represented by RCP6.0, result in an average year for the onset of annual severe bleaching that is ~20 years later (2062 vs. 2044). However, global emissions are tracking above the current worst-case scenario devised by the scientific community, as has happened in previous generations of emission scenarios. The projections here for conditions on coral reefs are dire, but provide the most up to-date assessment of what the changing climate and ocean acidification mean for the persistence of coral reefs. PMID- 24151156 TI - Iterative antimicrobial candidate selection from informed d-/l-Peptide dimer libraries. AB - Growing resistance to antibiotics, as well as newly emerging pathogens, stimulate the investigation of antimicrobial peptides (AMPs) as therapeutic agents. Here, we report a new library design concept based on a stochastic distribution of natural AMP amino acid sequences onto half-length synthetic peptides. For these compounds, a non-natural motif of alternating D- and L-backbone stereochemistry of the peptide chain predisposed for beta-helix formation was explored. Synthetic D-/L-peptides with permuted half-length sequences were delineated from a full length starter sequence and covalently recombined to create two-dimensional compound arrays for antibacterial screening. Using the natural AMP magainin as a seed sequence, we identified and iteratively optimized hit compounds showing high antimicrobial activity against Gram-positive and Gram-negative bacteria with low hemolytic activity. Cryo-electron microscopy characterized the membrane associated mechanism of action of the new D-/L-peptide antibiotics. PMID- 24151157 TI - Alanine aminotransferase and metabolic syndrome in adolescents: the Korean National Health and Nutrition Examination Survey Study. AB - WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT: Adolescent NAFLD has increased in parallel with obesity. Elevated serum ALT level is a surrogate marker for NALFD. Increased ALT levels are closely related to NAFLD and metabolic syndrome. WHAT THIS STUDY ADDS: Increased ALT within normal range are associated with an increased risk of metabolic syndrome. All of the five components of metabolic syndrome were associated with high ALT within normal range. By elevation of ALT, the prevalence of metabolic syndrome increased in obese adolescents and normal weight adolescents as well. BACKGROUND/AIMS: The potential interactions between alanine aminotransferase (ALT) and components of metabolic syndrome (MetS) have not been fully investigated in healthy adolescents. This study investigated the impact of a mild ALT elevation on the risks of MetS in healthy Korean adolescents. METHODS: From the Korean National Health and Nutrition Examination Surveys 1998-2009, the data of 5026 adolescents aged 10-18 years (2604 boys and 2422 girls) were analysed. Individuals who had ALT levels equal or more than 40 IU L(-1) were excluded. RESULTS: Subjects in the upper ALT tertile had higher mean values of body mass index (BMI), homeostasis model assessment-insulin resistance and prevalence of MetS than subjects in the lower tertile. The risk of each five components of MetS was significantly higher than subjects in the lower tertile. Compared with the subjects in the lower ALT tertile, the prevalence of MetS was higher in the upper tertile among obese adolescents (44.6-50.7% vs. 31.2 40.0%) as well as normal-weight adolescents (5.2-7.7% vs. 2.7-3.2%). Subjects in the upper ALT tertile were at a higher risk of MetS than those in the lower tertile (odds ratio [OR] = 1.95 for boys, OR = 2.00 for girls) after controlling for age and BMI. CONCLUSIONS: A high serum ALT within normal range increased the risk of all the components of MetS. The prevalence of MetS increased with the elevation of obesity level, and it increased further with the elevation of ALT tertile. Thus, serum ALT levels in addition to BMI might be useful as a marker for early detection of MetS. PMID- 24151159 TI - Rare sequence variants in ANO3 and GNAL in a primary torsion dystonia series and controls. AB - BACKGROUND: Rare autosomal-dominant mutations in ANO3 and GNAL have been recently shown to represent novel genetic factors underlying primary torsion dystonia (PTD) with predominantly craniocervical involvement. METHODS: We used high resolution melting to screen all exons of ANO3 and GNAL for rare sequence variants in a population of 342 German individuals with mainly sporadic PTD and 376 general population controls. RESULTS: We identified 2 novel missense variants in ANO3 (p.Ile833Val and p.Gly973Arg) and 1 novel missense variant in GNAL (p.Val146Met) in three different nonfamilial cases. Variant carriers presented with adult-onset dystonia involving the neck and/or face. In controls, 3 rare ANO3 missense variants (p.Tyr235Cys, p.Asn256Ser, and p.Pro893Leu) but no rare nonsynonymous GNAL variants were present. CONCLUSIONS: GNAL variants seem to be a rare cause of PTD in our mainly sporadic German sample. Low frequency missense variants in ANO3 occur in both cases and controls, warranting further assessment of this gene in PTD pathogenesis. PMID- 24151158 TI - Neurogenesis in the lamprey central nervous system following spinal cord transection. AB - After spinal cord transection, lampreys recover functionally and axons regenerate. It is not known whether this is accompanied by neurogenesis. Previous studies suggested a baseline level of nonneuronal cell proliferation in the spinal cord and rhombencephalon (where most supraspinal projecting neurons are located). To determine whether cell proliferation increases after injury and whether this includes neurogenesis, larval lampreys were spinally transected and injected with 5-bromo-2&prime-deoxyuridine (BrdU) at 0-3 weeks posttransection. Labeled cells were counted in the lesion site, within 0.5 mm rostral and caudal to the lesion, and in the rhombencephalon. One group of animals was processed in the winter and a second group was processed in the summer. The number of labeled cells was greater in winter than in summer. The lesion site had the most BrdU labeling at all times, correlating with an increase in the number of cells. In the adjacent spinal cord, the percentage of BrdU labeling was higher in the ependymal than in nonependymal regions. This was also true in the rhombencephalon but only in summer. In winter, BrdU labeling was seen primarily in the subventricular and peripheral zones. Some BrdU-labeled cells were also double labeled by antibodies to glial-specific (antikeratin) as well as neuron-specific (anti-Hu) antigens, indicating that both gliogenesis and neurogenesis occurred after spinal cord transection. However, the new neurons were restricted to the ependymal zone, were never labeled by antineurofilament antibodies, and never migrated away from the ependyma even at 5 weeks after BrdU injection. They would appear to be cerebrospinal fluid-contacting neurons. PMID- 24151160 TI - Open fourth ventricle prior to 20 weeks' gestation: a benign finding? AB - OBJECTIVE: To evaluate the role of the brainstem-vermis (BV) angle in the diagnosis of fetal posterior fossa abnormalities at 15-18 weeks' gestation. METHODS: We examined retrospectively three-dimensional (3D) ultrasound volumes acquired at 15-18 gestational weeks in fetuses with normal posterior fossa (controls) and in those with cystic posterior fossa. Whether the fourth ventricle appeared open posteriorly in axial views was noted and the BV angle was measured. A detailed follow-up was obtained in all cases. RESULTS: Of the 139 controls, 46 cases were excluded because of inadequate quality of the 3D volumes. Of the 93 remaining normal fetuses, 84 (90.3%) had a closed fourth ventricle and a BV angle < 20 degrees , whereas 9/93 (9.7%) had an open fourth ventricle and a BV angle between 20 degrees and 37 degrees . The study group of 11 fetuses included seven with Dandy-Walker malformation and four with Blake's pouch cyst. In abnormal cases as a whole, the BV angle was significantly increased compared with that in controls (P < 0.0001). However, fetuses with Blake's pouch cyst and normal fetuses with an open fourth ventricle had strikingly similar sonograms: the BV angle was between 20 degrees and 37 degrees and the fourth ventricle appeared open only when viewed using a more steeply angulated scanning plane than that of the standard transcerebellar plane; in fetuses with Dandy-Walker malformation the fourth ventricle was widely open posteriorly, even in the standard transcerebellar view, and the BV angle was > 45 degrees , significantly increased compared both with that in normal fetuses (P < 0.0001) and with that in fetuses with Blake's pouch cyst (P = 0.004). CONCLUSION: An open fourth ventricle is found in about 10% of normal fetuses at 15-18 weeks' gestation. Measurement of the BV angle is useful in such cases, as a value >= 45 degrees is associated with a very high risk of severe posterior fossa malformation. PMID- 24151161 TI - Twice-weighted multiple interval estimation of a marginal structural model to analyze cost-effectiveness. AB - Cost-effectiveness analysis is an important tool that can be applied to the evaluation of a health treatment or policy. When the observed costs and outcomes result from a nonrandomized treatment, making causal inference about the effects of the treatment requires special care. The challenges are compounded when the observation period is truncated for some of the study subjects. This paper presents a method of unbiased estimation of cost-effectiveness using observational study data that is not fully observed. The method-twice-weighted multiple interval estimation of a marginal structural model-was developed in order to analyze the cost-effectiveness of treatment protocols for advanced dementia residents living nursing homes when they become acutely ill. A key feature of this estimation approach is that it facilitates a sensitivity analysis that identifies the potential effects of unmeasured confounding on the conclusions concerning cost-effectiveness. PMID- 24151162 TI - Speciation, adsorption and determination of chromium(III) and chromium(VI) on a mesoporous surface imprinted polymer adsorbent by combining inductively coupled plasma atomic emission spectrometry and UV spectrophotometry. AB - In the present study, a Cr(III)-imprinted polymer (Cr(III)-IIP) was prepared by an easy one-step sol-gel reaction with a surface imprinting technique on the support of silica mesoporous material. A new SPE method for the speciation, separation, preconcentration, and determination of Cr(III) and Cr(VI) by inductively coupled plasma atomic emission spectrometry and UV on the mesoporous imprinted polymer adsorbent was developed. The structure of the imprinted polymer was characterized by Fourier transform infrared spectroscopy, X-ray powder diffraction, transmission electron microscopy, and nitrogen adsorption-desorption isotherms. The adsorption kinetics, thermodynamics behavior, and recognition ability toward Cr(III) on Cr(III)-IIP and nonimprinted polymer were compared. The results showed that Cr(III)-IIP had higher selectivity and nearly a two times larger Langmuir adsorption capacity (38.50 mg/g) than that of NIP. The proposed method has been successfully applied in the determination and speciation of chromium in natural water samples with satisfactory results. PMID- 24151163 TI - Reversible layer-by-layer deposition on solid substrates inspired by mussel byssus cuticle. AB - The protective coating on mussel (Mytilus galloprovincialis) byssus has attracted considerable research interest because of its excellent mechanical properties such as hardness and extensibility. These special properties are known to be highly related with specific interactions between mussel foot protein-1 and metal ions. In particular, the complexation between catechols in mfp-1 and iron(III) has been identified as a key interaction. This finding has given opportunities for pursuing promising applications. Herein, we report that emulating the properties of the mussel byssus cuticle provides an important platform for developing reversible layer-by-layer (LbL) deposition, an advanced technique for surface modification. LbL films were constructed on solid substrates by sequential immersion of substrates into solutions containing iron(III) and catecholic compounds. The thickness of the LbL films was effectively controlled by increasing the immersion steps, and the reversibility of the LbL deposition was demonstrated by addition of a chelating agent. PMID- 24151171 TI - Ifosfamide chemotherapy and nonconvulsive status epilepticus: case report and review of the literature. AB - We present a patient with peritoneal carcinosarcoma who was treated with the alkylating agent ifosfamide and experienced a rapid decline in mental status. Electroencephalogram (EEG) displayed generalized periodic epileptiform discharges, which raised suspicion for nonconvulsive status epilepticus (NCSE). Following administration of midazolam, the patient's clinical condition and EEG improved. We review the 8 documented cases of ifosfamide-induced NCSE, and demonstrate the similarity in clinical features when compared with ifosfamide neurotoxicity that is not classified as NCSE. EEG findings suggesting an ictal pattern are subtle and heterogeneous, but they are essential for a diagnosis. Since it is unlikely that EEGs are uniformly obtained in instances of ifosfamide neurotoxicity, many cases of NCSE may go unrecognized. PMID- 24151172 TI - Psychometric properties of the resourcefulness scale among caregivers of persons with autism spectrum disorder. AB - Caregiving for children with autism spectrum disorder (ASD) can be very costly to caregivers' well-being. Resourcefulness interventions have shown increases in positive health outcomes. However, before delivering the intervention, there should be a reliable and a valid measure to test resourcefulness. The psychometric properties of the Resourcefulness Scale (RS) have not been examined among ASD caregivers. This study examined the psychometrics of the 28-item RS in a convenience sample of 204 ASD caregivers. A Cronbach's alpha of .91 showed the internal consistency of the RS. Construct validity was supported by the emergence of two dimensions of resourcefulness (personal and social) in a confirmatory factor analysis and by substantial intercorrelations between the two subscales (r = .48, p < .001). Findings suggested the reliability and validity of RS among ASD caregivers, which is a necessary step toward implementing resourcefulness interventions to help ASD caregivers to deal with their stress and improve their quality of life. PMID- 24151173 TI - A unified model for estimating and testing familial aggregation. AB - Investigations of familial aggregation of disease can provide important clues for genetic mechanisms, and many such studies have been published in the epidemiological literature using various statistical methods. We developed a unified model for familial risk by extending a Cox regression model to enable estimation of the detailed effects of kinship. By appropriate parameterisation of the model, we show how the risks to all specific first-degree kinships can be estimated and formally compared using simple interaction terms and how the model can be extended to accommodate higher-degree relatives. The correlation due to observations from family members and from the potential for repeated observations is accommodated by a robust sandwich variance estimator or a bootstrap estimate. Hazard ratios for different kinships are formally compared using a robust Wald test. We illustrate the method with applications to studies of adult leukemia and non-Hodgkin's lymphoma in the Swedish population and display our results on a pedigree diagram. Our estimates are consistent with published work that used simpler stratified methods, and our model enabled the detection of a number of statistically significant effects of kinship. The recognition of such kindred specific disease risk could be a first step in the design of more informative genetic biomarker studies. PMID- 24151174 TI - Myelosuppression after frontline fludarabine, cyclophosphamide, and rituximab in patients with chronic lymphocytic leukemia: analysis of persistent and new-onset cytopenia. PMID- 24151176 TI - Copper-catalyzed aerobic oxidative C-H functionalization of substituted pyridines: synthesis of imidazopyridine derivatives. AB - A novel, efficient, and practical method for the synthesis of imidazopyridine derivatives has been developed through the copper-catalyzed aerobic oxidative C-H functionalization of substituted pyridines with N-(alkylidene)-4H-1,2,4-triazol-4 amines. The procedure occurs by cleavage of the N-N bond in the N-(alkylidene)-4H 1,2,4-triazol-4-amines and activation of an aryl C-H bond in the substituted pyridines. This is the first example of the preparation of imidazopyridine derivatives by using pyridines as the substrates by transition-metal-catalyzed C H functionalization. This method should provide a novel and efficient strategy for the synthesis of other nitrogen heterocycles. PMID- 24151175 TI - Crosslinking of collagen scaffolds promotes blood and lymphatic vascular stability. AB - The low stiffness of reconstituted collagen hydrogels has limited their use as scaffolds for engineering implantable tissues. Although chemical crosslinking has been used to stiffen collagen and protect it against enzymatic degradation in vivo, it remains unclear how crosslinking alters the vascularization of collagen hydrogels. In this study, we examine how the crosslinking agents genipin and 1 ethyl-3-(3-dimethylaminopropyl) carbodiimide alter vascular stability and function in microfluidic type I collagen gels in vitro. Under moderate perfusion (~10 dyn/cm(2) shear stress), tubes of blood endothelial cells (ECs) exhibited indistinguishable stability and barrier function in untreated and crosslinked scaffolds. Surprisingly, under low perfusion (~5 dyn/cm(2) shear stress) or nearly zero transmural pressure, microvessels in crosslinked scaffolds remained stable, while those in untreated gels rapidly delaminated and became poorly perfused. Similarly, tubes of lymphatic ECs under intermittent flow were more stable in crosslinked gels than in untreated ones. These effects correlated well with the degree of mechanical stiffening, as predicted by analysis of fracture energies at the cell-scaffold interface. This work demonstrates that crosslinking of collagen scaffolds does not hinder normal EC physiology; instead, crosslinked scaffolds promote vascular stability. Thus, routine crosslinking of scaffolds may assist in vascularization of engineered tissues. PMID- 24151177 TI - Accuracy and precision of no instrument is guaranteed: a reply to Rosenstock et al. PMID- 24151178 TI - Systematic review and meta-analysis of performance of second-trimester nasal bone assessment in detection of fetuses with Down syndrome. AB - OBJECTIVE: To review systematically the literature on diagnostic tests and performance of second-trimester sonographic assessment of nasal bone (NB) in identifying fetuses affected by Down syndrome. METHODS: A search of studies involving screening tests for NB evaluation and measurements was carried out in the main international bibliographic databases (MEDLINE, EMBASE and CINAHL). Those considered to be relevant were then subjected to critical reading, following Critical Appraisal Skills Programme (CASP) criteria, by at least three independent observers. All data were extracted and tabulated by two independent investigators. A statistical synthesis of sensitivity, specificity and likelihood ratios was performed using specific software (Meta-DiSc). RESULTS: From an initial list of 852 articles referring to ultrasound markers for Down syndrome, 207 relevant papers were selected. Following exclusions, 21 studies were included in the quantitative synthesis. The pooled estimates of positive and negative likelihood ratios were 40.08 (95% CI, 18.10-88.76) and 0.71 (95% CI, 0.64-0.79), respectively, for absent NB and 15.15 (95% CI, 8.15-28.16) and 0.47 (95% CI, 0.34 0.64), respectively, for hypoplastic NB. No relevant differences were found between the various means of defining nasal hypoplasia (multiples of the median (MoM) or percentiles). The biparietal diameter/nasal bone length (BPD/NBL) ratio showed somewhat higher sensitivity but lower specificity with a threshold effect. CONCLUSIONS: NB absence or hypoplasia show high specificity and low but acceptable sensitivity in identifying fetuses with Down syndrome. Screening performance is better with NB measurements as a function of MoM or percentiles rather than as the BPD/NBL ratio. Classification of women into various risk groups for Down syndrome does not affect diagnostic performance. PMID- 24151179 TI - Addition of amino acid moieties to lapatinib increases the anti-cancer effect via amino acid transporters. AB - Anti-cancer agents delivered to cancer cells often show multi-drug resistance (MDR) due to expulsion of the agents. One way to address this problem is to increase the accumulation of anti-cancer agents in cells via amino acid transporters. Thus, val-lapatinib and tyr-lapatinib were newly synthesized by adding valine and tyrosine moieties, respectively, to the parent anti-cancer agent lapatinib without stability issues in rat plasma. Val-lapatinib and tyr lapatinib showed enhanced anti-cancer effects versus the parent lapatinib in various cancer cell lines, including human breast cancer cells (MDA-MB-231, MCF7) and lung cancer cells (A549), but not in non-cancerous MDCK-II cells. A glutamine uptake study revealed that both val-lapatinib and tyr-lapatinib, but not the parent lapatinib, inhibited glutamine transport in MDA-MB-231 and MCF7 cells, suggesting the involvement of amino acid transporters. In conclusion, val lapatinib and tyr-lapatinib have enhanced anti-cancer effects, likely due to an increased uptake of the agents into cancer cells via amino acid transporters. The present data suggest that amino acid transporters may be an effective drug delivery target to increase the uptake of anti-cancer agents, leading to one method of overcoming MDR in cancer cells. PMID- 24151180 TI - Towards functional orthogonalisation of protein complexes: individualisation of GroEL monomers leads to distinct quasihomogeneous single rings. AB - The essential molecular chaperonin GroEL is an example of a functionally highly versatile cellular machine with a wide variety of in vitro applications ranging from protein folding to drug release. Directed evolution of new functions for GroEL is considered difficult, due to its structure as a complex homomultimeric double ring and the absence of obvious molecular engineering strategies. In order to investigate the potential to establish an orthogonal GroEL system in Escherichia coli, which might serve as a basis for GroEL evolution, we first successfully individualised groEL genes by inserting different functional peptide tags into a robustly permissive site identified by transposon mutagenesis. These peptides allowed fundamental aspects of the intracellular GroEL complex stoichiometry to be studied and revealed that GroEL single-ring complexes, which assembled in the presence of several functionally equivalent but biochemically distinct monomers, each consist almost exclusively of only one type of monomer. At least in the case of GroEL, individualisation of monomers thus leads to individualisation of homomultimeric protein complexes, effectively providing the prerequisites for evolving an orthogonal intracellular GroEL folding machine. PMID- 24151181 TI - Multisource ascertainment of Huntington disease in Canada: prevalence and population at risk. AB - There is uncertainty surrounding the accuracy of prevalence estimates for Huntington's disease (HD). The aims of this study were to provide a best estimate of the prevalence and population at risk for HD in the province of British Columbia (BC), Canada, in 2012. HD patients with a clinical and/or genetic diagnosis of HD and individuals at risk for HD were ascertained from multiple sources. Clinical and genetic data were obtained from all available medical, social service, and genetic testing records. Six hundred and thirty-one HD patients and 3,763 individuals at 25% or 50% risk for HD were identified. Prevalence of HD was estimated at 13.7 per 100,000 (95% confidence interval [CI]: 12.6-14.8 per 100,000) in the general population, and 17.2 per 100,000 (95% CI: 15.8-18.6 per 100,000) in the Caucasian population. The population at 25% to 50% risk was estimated at 81.6 per 100,000 (95% CI: 79.0-84.2 per 100,000) individuals. These figures suggest there may be up to 4,700 individuals affected with HD and 14,000 at 50% risk for HD in Canada as well as up to 43,000 individuals affected with HD and 123,000 at 50% risk for HD in the United States. This is the first direct assessment of HD epidemiology in Canada in over three decades. These findings suggest that underascertainment may have led to previous underestimates of prevalence, namely, in Caucasian populations, and will aid in the planning of appropriate resource allocation and service delivery for the HD community. PMID- 24151183 TI - Development of a molecularly imprinted polymer for prometryne clean-up in the environment. AB - Molecularly imprinted polymers (MIPs) are prepared on the surface of modified silica gel using prometryne as a template, methacrylic acid as the functional monomer, ethylene glycol dimethacrylate as a crosslinker, and 2,2 azobisisobutyronitrile as an initiator. The structure of the MIPs was characterized using SEM and FTIR spectroscopy. The selectivity of the MIPs for the template molecule prometryne was proven by adsorption experiments. Highly selective SPE cartridges of MIP particles were developed and an optimized prometryne procedure was developed for the enrichment and clean-up of prometryne residues in water, soil, and wheat samples. The concentrations of prometryne in the samples were analyzed by HPLC. The average recoveries of prometryne spiked for water at 0.05~0.8 mg/L were 101.47-106.65% and the RSD was 2.63-4.71%. The average recoveries of prometryne spiked for soil at 0.05~0.8 mg/L were 87.34 94.91% with the RSD being 2.77-8.41%. The average recoveries of prometryne spiked for wheat plant at 0.2~2.0 mg/kg were 91.04-97.76% with the RSD being 6.53 10.69%. The method developed here can be regenerated and repeatedly used more than two dozen times. PMID- 24151182 TI - Semiautomated analysis of carotid artery wall thickness in MRI. AB - PURPOSE: To develop a semiautomatic method based on level set method (LSM) for carotid arterial wall thickness (CAWT) measurement. MATERIALS AND METHODS: Magnetic resonance imaging (MRI) of diseased carotid arteries was acquired from 10 patients. Ground truth (GT) data for arterial wall segmentation was collected from three experienced vascular clinicians. The semiautomatic variational LSM was employed to segment lumen and arterial wall outer boundaries on 102 MR images. Two computer-based measurements, arterial wall thickness (WT) and arterial wall area (AWA), were computed and compared with GT. Linear regression, Bland-Altman, and bias correlation analysis on WT and AWA were applied for evaluating the performance of the semiautomatic method. RESULTS: Arterial wall thickness measured by radial distance measure (RDM) and polyline distance measure (PDM) correlated well between GT and variational LSM (r = 0.83 for RDM and r = 0.64 for PDM, P < 0.05). The absolute arterial wall area bias between LSM and three observers is less than 10%, suggesting LSM can segment arterial wall well compared with manual tracings. The Jaccard Similarity (Js ) analysis showed a good agreement for the segmentation results between proposed method and GT (Js 0.71 +/- 0.08), the mean curve distance for lumen boundary is 0.34 +/- 0.2 mm between the proposed method and GT, and 0.47 +/- 0.2 mm for outer wall boundary. CONCLUSION: The proposed LSM can generate reasonably accurate lumen and outer wall boundaries compared to manual segmentation, and can work similar to a human reader. However, it tends to overestimate CAWT and AWA compared to the manual segmentation for arterial wall with small area. PMID- 24151184 TI - The synergies of microorganisms enlightened - convergent approaches to delineating coinfections. PMID- 24151185 TI - 25th anniversary article: The evolution of electronic skin (e-skin): a brief history, design considerations, and recent progress. AB - Human skin is a remarkable organ. It consists of an integrated, stretchable network of sensors that relay information about tactile and thermal stimuli to the brain, allowing us to maneuver within our environment safely and effectively. Interest in large-area networks of electronic devices inspired by human skin is motivated by the promise of creating autonomous intelligent robots and biomimetic prosthetics, among other applications. The development of electronic networks comprised of flexible, stretchable, and robust devices that are compatible with large-area implementation and integrated with multiple functionalities is a testament to the progress in developing an electronic skin (e-skin) akin to human skin. E-skins are already capable of providing augmented performance over their organic counterpart, both in superior spatial resolution and thermal sensitivity. They could be further improved through the incorporation of additional functionalities (e.g., chemical and biological sensing) and desired properties (e.g., biodegradability and self-powering). Continued rapid progress in this area is promising for the development of a fully integrated e-skin in the near future. PMID- 24151186 TI - Advanced glycation end products in degenerative nucleus pulposus with diabetes. AB - Diabetes mellitus (DM) has been clinically proved as a risk factor of disc degeneration, and the accumulation of advanced glycation end products (AGEs) is known to be potentially involved in diabetes. The purpose of this study is to investigate the effect of AGEs in the degeneration process of diabetic nucleus pulposus (NP) in rats and humans. Diabetic NP cells from rat coccygeal discs were treated with different concentrations of AGEs (0, 50, and 100 ug/ml) for 3 days, and mRNA expressions of MMP-2 and RAGE were measured by real-time RT-PCR. In addition, conditioned medium from NP cells was used to analyze protein expression of MMP-2 activity and ERK by gelatin zymography and Western blot. These experiments were repeated using human intervertebral disc samples. The immunohistochemical expression of AGEs was significantly increased in diabetic discs. In response to AGEs, an increase of MMP-2, RAGE, and ERK at both mRNA and protein expression levels was observed in diabetic NP cells. The findings suggest that AGEs and DM are associated with disc degeneration in both species. Hyperglycemia in diabetes enhances the accumulation of AGEs in the NP and triggers disc degeneration. PMID- 24151187 TI - On the joint use of propensity and prognostic scores in estimation of the average treatment effect on the treated: a simulation study. AB - Propensity and prognostic score methods seek to improve the quality of causal inference in non-randomized or observational studies by replicating the conditions found in a controlled experiment, at least with respect to observed characteristics. Propensity scores model receipt of the treatment of interest; prognostic scores model the potential outcome under a single treatment condition. While the popularity of propensity score methods continues to grow, prognostic score methods and methods combining propensity and prognostic scores have thus far received little attention. To this end, we performed a simulation study that compared subclassification and full matching on a single estimated propensity or prognostic score with three approaches combining the estimated propensity and prognostic scores: full matching on a Mahalanobis distance combining the estimated propensity and prognostic scores (FULL-MAHAL); full matching on the estimated prognostic propensity score within propensity score calipers (FULL PGPPTY); and subclassification on an estimated propensity and prognostic score grid with 5 * 5 subclasses (SUBCLASS(5*5)). We considered settings in which one, both, or neither score model was misspecified. The data generating mechanisms varied in the degree of linearity and additivity in the true treatment assignment and outcome models. FULL-MAHAL and FULL-PGPPTY exhibited strong to superior performance in root mean square error terms across all simulation settings and scenarios. Methods combining propensity and prognostic scores were no less robust to model misspecification than single-score methods even when both score models were incorrectly specified. Our findings support the joint use of propensity and prognostic scores in estimation of the average treatment effect on the treated. PMID- 24151188 TI - Biodegradable sodium alginate-based semi-interpenetrating polymer network hydrogels for antibacterial application. AB - A series of biodegradable, semi-interpenetrating polymer network (semi-IPN) hydrogels were synthesized from a combination of carbohydrate polymer and sodium alginate (NaAlg) with acrylamide and dimethyl aminoethyl methacrylate, and crosslinked with N,N-methylenebisacrylamide via radical redox polymerization. The cytocompatibility of the hydrogels with respect to their monomers and semi-IPN hydrogels was evaluated in vitro using cultures of mouse fibroblast cell lines. This study allowed the entrapment of silver nanoparticles (NPs) into semi-IPN hydrogel networks by the in situ reduction of Ag(+) ions using NaBH4 as a reducing agent. UV-visible spectroscopy confirmed the formation of silver NPs in the semi-IPN hydrogel matrix. The formation of silver NPs was also confirmed from a themogravimetric analysis weight loss difference between hydrogel and silver nanocomposite as 32%. The morphology and structure of the AgNPs present in the hydrogel networks were examined by scanning electron microscopy. Transmission electron microscopy revealed silver NPs with a size of ~5 nm. The silver nanocomposite hydrogel exhibited good antibacterial activity against both gram positive (Staphylococcus aureus) and gram negative (Escherichia coli) bacteria. These results suggest that the hydrogel can be applied as wound dressings and for water purification purposes. PMID- 24151189 TI - Identification of human cytochrome P450 enzymes involved in the hepatic and intestinal biotransformation of 20(S)-protopanaxadiol. AB - 20(S)-Protopanaxadiol (aPPD), a ginseng sapogenin, has been shown to be a promising anti-cancer compound and anti-depressant agent. Although the bacterial biotransformation of ginsenosides has been studied thoroughly, few have reported on the cytochrome P450 (P450) mediated metabolism of aPPD. Taken orally, aPPD must first undergo absorption and metabolism in the intestine before further metabolism in the liver. The present study investigated the comparative biotransformation profile of aPPD in human intestinal microsomes (HIM) and human liver microsomes (HLM) and characterized the human P450 enzymes involved in aPPD metabolism. Three major monooxygenated metabolites and five minor dioxygenated metabolites were identified as the predominant products in aPPD incubations with HIM and HLM using liquid chromatography-mass spectrometry. Reaction phenotyping studies were performed with a panel of specific P450 chemical inhibitors, antibody inhibition and human recombinant P450 enzymes. Ketoconazole, a CYP3A inhibitor, blocked the formation of oxygenated metabolites of aPPD in both HIM and HLM in a concentration dependent manner. Among the human recombinant P450 enzymes assayed, CYP3A4 exhibited the highest activity towards aPPD oxidative metabolite formation, followed by CYP3A5. In summary, the results have shown that aPPD is extensively metabolized by HIM and the metabolite profile following in vitro incubations is similar in HIM and HLM. CYP3A4 and CYP3A5 isoforms are the predominant enzymes responsible for oxygenation of aPPD in HIM and HLM. The characterization of aPPD as a CYP3A substrate may facilitate better prediction of drug-herb interactions when aPPD is taken concomitantly with other therapeutic agents. PMID- 24151190 TI - Fetoscopic cord transection for treatment of monoamniotic twin reversed arterial perfusion sequence. PMID- 24151191 TI - Does prescribed burning result in biotic homogenization of coastal heathlands? AB - Biotic homogenization due to replacement of native biodiversity by widespread generalist species has been demonstrated in a number of ecosystems and taxonomic groups worldwide, causing growing conservation concern. Human disturbance is a key driver of biotic homogenization, suggesting potential conservation challenges in seminatural ecosystems, where anthropogenic disturbances such as grazing and burning are necessary for maintaining ecological dynamics and functioning. We test whether prescribed burning results in biotic homogenization in the coastal heathlands of north-western Europe, a seminatural landscape where extensive grazing and burning has constituted the traditional land-use practice over the past 6000 years. We compare the beta-diversity before and after fire at three ecological scales: within local vegetation patches, between wet and dry heathland patches within landscapes, and along a 470 km bioclimatic gradient. Within local patches, we found no evidence of homogenization after fire; species richness increased, and the species that entered the burnt Calluna stands were not widespread specialists but native grasses and herbs characteristic of the heathland system. At the landscapes scale, we saw a weak homogenization as wet and dry heathland patches become more compositionally similar after fire. This was because of a decrease in habitat-specific species unique to either wet or dry habitats and postfire colonization by a set of heathland specialists that established in both habitat types. Along the bioclimatic gradient, species that increased after fire generally had more specific environmental requirements and narrower geographical distributions than the prefire flora, resulting in a biotic 'heterogenisation' after fire. Our study demonstrates that human disturbance does not necessarily cause biotic homogenization, but that continuation of traditional land-use practices can instead be crucial for the maintenance of the diversity and ecological function of a seminatural ecosystem. The species that established after prescribed burning were heathland specialists with relatively narrow geographical ranges. PMID- 24151193 TI - A pictorial essay on fetal rabbit anatomy using micro-ultrasound and magnetic resonance imaging. AB - INTRODUCTION: With this pictorial essay, we aimed to provide gestational age specific reference ranges of relevant fetal structures using micro-ultrasound, as well as its correlation with postmortem MRI and whole body sections. MATERIAL AND METHODS: Time-mated pregnant rabbits (n = 24) were assessed once at various gestational ages in the second half of pregnancy (15, 17, 21 to 23, 25 to 28, and 30 to 31 days; term = 31 days). We obtained biometric data, together with Doppler flow patterns in the ductus venosus, umbilical artery and umbilical vein. After euthanasia, micro-ultrasound images were compared with images obtained by 9.4 Tesla MRI and whole body paraffin sections at 15, 23, 26, and 28 days. RESULTS: We constructed biometric normative curves, which showed a significant correlation with gestational age. The pulsatility index (PI) in the umbilical artery decreased with gestation (PI = 5.746-0.2969(GA) + 0.004931(GA)(2) ; R(2) = 0.30), whereas pulsatility index for veins (PIV) in the ductus venosus remained constant (median PIV = 0.82 (0.60-1.12)). In this report, we provide an anatomical atlas of fetal thoracic development using both micro-ultrasound and MRI. CONCLUSION: We describe anatomical fetal leporine development as can be visualized by micro-ultrasound and MR imaging. The reported reference ranges may be useful for researchers using the fetal rabbit model. PMID- 24151192 TI - Striatal dopamine D1-like receptor binding is unchanged in primary focal dystonia. AB - BACKGROUND: Multiple studies have demonstrated decreases in striatal D2-like (D2, D3) radioligand binding in primary focal dystonias. Although most investigations have focused on D2-specific receptors (D2R), a recent study suggests that the decreased D2-like binding may be due to a D3-specific (D3R) abnormality. However, only limited data exist on the role of D1-specific receptors (D1R) and the D1R mediated pathways within basal ganglia in dystonia. Metabolic positron emission tomography (PET) data in primary generalized dystonia suggest resting state over activity in the D1R-mediated direct pathway, leading to excessive disinhibition of motor cortical areas. This work investigated whether striatal D1-like receptors are affected in primary focal dystonias. METHODS: Striatal-specific (caudate and putamen) binding of the D1-like radioligand [(11)C]NNC 112 was measured using PET in 19 patients with primary focal dystonia (cranial, cervical, or arm) and 18 controls. RESULTS: No statistically significant difference was detected in striatal D1-like binding between the two groups. The study had 91% power to detect a 20% difference, indicating that false-negative results were unlikely. CONCLUSIONS: Because [(11)C]NNC 112 has high affinity for D1-like receptors, very low affinity for D2-like receptors, and minimal sensitivity to endogenous dopamine levels, we conclude that D1-like receptor binding is not impaired in these primary focal dystonias. PMID- 24151194 TI - Limited sinus tarsi approach for intra-articular calcaneus fractures. AB - BACKGROUND: Operative treatment of calcaneal fractures has a historically high rate of wound complications, so the most optimal operative approach has been a topic of investigation. This study reviews the radiographic and clinical outcomes of the use of the sinus tarsi approach for operative fixation of these fractures with attention to the rate of infection and restoration of angular measurements. METHODS: The radiographs and charts of 20 patients with 22 calcaneal fractures were reviewed to assess for restoration of angular and linear dimensions of the calcaneus as well as time to radiographic union. Secondary outcome measures included the rate of postoperative infection, osteomyelitis, revision surgeries, and nonunion. RESULTS: We found a statistically significant restoration of Bohler's angle and calcaneal width. Three of the 22 cases had a superficial wound infection. One patient had revision surgery for symptomatic hardware removal. There were no events of osteomyelitis, deep infection, malunion, or nonunion. CONCLUSION: We found that the sinus tarsi approach yielded similar outcomes to those reported in the literature. LEVEL OF EVIDENCE: Level IV, retrospective case series. PMID- 24151195 TI - Poly(hydroxyethyl methacrylate)-based composite cryogel with embedded macroporous cellulose beads for the separation of human serum immunoglobulin and albumin. AB - A novel super-macroporous monolithic composite cryogel was prepared by embedding macroporous cellulose beads into poly(hydroxyethyl methacrylate) cryogel. The cellulose beads were fabricated by using a microchannel liquid-flow focusing and cryopolymerization method, while the composite cryogel was prepared by cryogenic radical polymerization of the hydroxyethyl methacrylate monomer with poly(ethylene glycol) diacrylate as cross-linker together with the cellulose beads. After graft polymerization with (vinylbenzyl)trimethylammonium chloride, the composite cryogel was applied to separate immunoglobulin-G and albumin from human serum. Immunoglobulin-G with a mean purity of 83.2% and albumin with a purity of 98% were obtained, indicating the composite cryogel as a promising chromatographic medium in bioseparation for the isolation of important bioactive proteins like immunoglobulins and albumins. PMID- 24151196 TI - Gallium induces the production of virulence factors in Pseudomonas aeruginosa. AB - The novel antimicrobial gallium is a nonredox iron III analogue with bacteriostatic and bactericidal properties, effective for the treatment of Pseudomonas aeruginosa in vitro and in vivo in mouse and rabbit infection models. It interferes with iron metabolism, transport, and presumably its homeostasis. As gallium exerts its antimicrobial effects by competing with iron, we hypothesized that it ultimately will lead cells to an iron deficiency status. As iron deficiency promotes the expression of virulence factors in vitro and promotes the pathogenicity of P. aeruginosa in animal models, it is anticipated that treatment with gallium will also promote the production of virulence factors. To test this hypothesis, the reference strain PA14 and two clinical isolates from patients with cystic fibrosis were exposed to gallium, and their production of pyocyanin, rhamnolipids, elastase, alkaline protease, alginate, pyoverdine, and biofilm was determined. Gallium treatment induced the production of all the virulence factors tested in the three strains except for pyoverdine. In addition, as the Ga-induced virulence factors are quorum sensing controlled, co-administration of Ga and the quorum quencher brominated furanone C-30 was assayed, and it was found that C-30 alleviated growth inhibition from gallium. Hence, adding both C-30 and gallium may be more effective in the treatment of P. aeruginosa infections. PMID- 24151197 TI - Concerted electron/proton transfer mechanism in the oxidation of phenols by laccase. AB - This study aimed to assess structural requirements in the enzyme/substrate interactions that are responsible for tuning the enzymatic reactivity. To better assess the role of the aspartic residue in the substrate-binding pocket of basidiomycete-type laccases, we compared the catalytic efficiency of wild-type enzymes to that of a mutant in which carboxylic acid residue Asp206 was changed to alanine. Oxidation efficiency towards phenolic substrates by laccases of Trametes villosa, Trametes versicolor and a T. versicolor D206A mutant was studied at two pH values. By the Hammett approach and Marcus analysis, we obtained unambiguous evidence that the oxidation takes place by a concerted electron/proton transfer (EPT) mechanism, and that at pH 5 (optimum pH for enzyme activity) the phenolic proton is transferred to Asp206 during the concerted electron/proton transfer process. PMID- 24151198 TI - The family of ferrocene-stabilized silylium ions: synthesis, 29Si NMR characterization, Lewis acidity, substituent scrambling, and quantum-chemical analyses. AB - The purpose of this systematic experimental and theoretical study is to deeply understand the unique bonding situation in ferrocene-stabilized silylium ions as a function of the substituents at the silicon atom and to learn about the structure parameters that determine the (29)Si NMR chemical shift and electrophilicity of these strong Lewis acids. For this, ten new members of the family of ferrocene-stabilized silicon cations were prepared by a hydride abstraction reaction from silanes with the trityl cation and characterized by multinuclear (1)H and (29)Si NMR spectroscopy. A closer look at the NMR spectra revealed that additional minor sets of signals were not impurities but silylium ions with substitution patterns different from that of the initially formed cation. Careful assignment of these signals furnished experimental proof that sterically less hindered silylium ions are capable of exchanging substituents with unreacted silane precursors. Density functional theory calculations provided mechanistic insight into that substituent transfer in which the migrating group is exchanged between two silicon fragments in a concerted process involving a ferrocene-bridged intermediate. Moreover, the quantum-chemical analysis of the (29)Si NMR chemical shifts revealed a linear relationship between delta((29)Si) values and the Fe...Si distance for subsets of silicon cations. An electron localization function and electron localizability indicator analysis shows a three-center two-electron bonding attractor between the iron, silicon, and C'(ipso) atoms, clearly distinguishing the silicon cations from the corresponding carbenium ions and boranes. Correlations between (29)Si NMR chemical shifts and Lewis acidity, evaluated in terms of fluoride ion affinities, are seen only for subsets of silylium ions, sometimes with non-intuitive trends, indicating a complicated interplay of steric and electronic effects on the degree of the Fe...Si interaction. PMID- 24151199 TI - 25th anniversary article: progress in chemistry and applications of functional indigos for organic electronics. AB - Indigo and its derivatives are dyes and pigments with a long and distinguished history in organic chemistry. Recently, applications of this 'old' structure as a functional organic building block for organic electronics applications have renewed interest in these molecules and their remarkable chemical and physical properties. Natural-origin indigos have been processed in fully bio-compatible field effect transistors, operating with ambipolar mobilities up to 0.5 cm(2) /Vs and air-stability. The synthetic derivative isoindigo has emerged as one of the most successful building-blocks for semiconducting polymers for plastic solar cells with efficiencies > 5%. Another isomer of indigo, epindolidione, has also been shown to be one of the best reported organic transistor materials in terms of mobility (~2 cm(2) /Vs) and stability. This progress report aims to review very recent applications of indigoids in organic electronics, but especially to logically bridge together the hereto independent research directions on indigo, isoindigo, and other materials inspired by historical dye chemistry: a field which was the root of the development of modern chemistry in the first place. PMID- 24151201 TI - Diagnostic performance of diffusion-weighted MR imaging in detecting acute appendicitis in children: comparison with conventional MRI and surgical findings. AB - PURPOSE: To determine the value of diffusion-weighted MRI for the diagnosis of acute appendicitis in children. MATERIALS AND METHODS: Forty-five consecutive patients with a clinical diagnosis of acute appendicitis underwent abdominal MRI; 39 were operated on for acute appendicitis. First, the diffusion-weighted imaging (DWI) alone was reviewed, followed by conventional MRI alone, and then conventional MRI and DWI were reviewed by two observers within a consensus. The surgical findings were compared with the MRI. Sensitivity, specificity, and accuracy were calculated for DWI, conventional MRI, and combined DWI and conventional MRI for the depiction of acute appendicitis. RESULTS: A combination of DWI and conventional MRI was the most sensitive and the most accurate, with corresponding sensitivity and accuracy of 0.92 and 0.92, respectively. Using DWI alone the sensitivity and accuracy was found to be 0.78 and 0.77, respectively. Using conventional MRI alone, sensitivity of 0.81 and accuracy of 0.82 was found for the consensus of the two observers. CONCLUSION: The use of combination of DWI and conventional MRI is a valuable technique in the diagnosis of acute appendicitis in children. PMID- 24151200 TI - Whole exome sequencing identifies variation in CYB5A and RNF10 associated with adiposity and type 2 diabetes. AB - OBJECTIVE: Few coding variants in genes associated with type 2 diabetes (T2D) have been identified, and the underlying physiologic mechanisms whereby susceptibility genes influence T2D risk are often unknown. The objective of this study was to identify coding variation that increases risk for T2D via an effect on a pre-diabetic trait. METHODS: Whole exome sequencing was done in 177 Pima Indians. Selected variants (N = 345) were genotyped in 555 subjects characterized for body fatness, glucose disposal rates during a clamp, acute insulin response to glucose, and 2-h plasma glucose concentrations during an OGTT, and were also genotyped in up to 5,880 subjects with longitudinal measures of BMI. Variants associated with quantitative traits were assessed for association with T2D in 7,667 subjects. RESULTS: rs7238987 in CYB5A associated with body fatness (P = 7.0 * 10(-6) ). This SNP and a novel SNP in RNF10 also associated with maximum recorded BMI (P = 6.2 * 10(-7) and P = 7.2 * 10(-4) ) and maximum childhood BMI z score (P = 5.9 * 10(-4) and P = 8.5 * 10(-7) ). The BMI increasing alleles increased the risk for T2D (P = 0.01; OR = 1.13 [1.03-1.24] and 9.5 * 10(-3) ; OR = 1.49 [1.10-2.02]). CONCLUSIONS: CYB5A, which has a role in stearyl-CoA desaturase activity, and RNF10, with an unknown role in weight regulating pathways, associated with adiposity and nominally increased the risk for T2D in American Indians. PMID- 24151202 TI - Reproducibility of phase rotation STEAM at 3T: focus on glutathione. AB - PURPOSE: The purpose of this study was to determine the reproducibility of a very short echo time (TE) phase rotation stimulated echo acquisition mode (STEAM) sequence at 3T with a focus on the detection of glutathione. METHODS: Ten healthy subjects were scanned on two separate visits. Spectra were acquired from voxels placed in the anterior and posterior cingulates. Reproducibility was assessed using mean coefficients of variation (CVs) and mean absolute differences (ADs), and reliability was assessed using standard error of measurement (SEM) and intraclass correlations (ICCs). Phantoms containing glutathione and metabolites with overlapping resonances were scanned to test the validity of glutathione quantification. RESULTS: Excellent reproducibility as illustrated by CVs <=8.3% and ADs <=11.6% for both regions was obtained for glutathione and other commonly reported metabolites. Reproducibility measures for gamma-aminobutyric acid and glutamine were good overall with CVs ranging from 6.4%-10.5% and ADs ranging from 8.6%-15.5% for both regions. Glutathione absolute and relative reliability were very good (SEMs <=9.9%) and fair (ICCs = 0.42-0.51), respectively. Phantom studies demonstrated the ability to accurately detect glutathione from other metabolites with overlapping resonances with great precision (R(2) = 0.99). CONCLUSION: A very short TE phase rotation STEAM sequence proved reproducible for metabolites difficult to quantify but important for the study of psychiatric and neurological illness. PMID- 24151203 TI - A mutable albino allele in rice reveals that formation of thylakoid membranes requires the SNOW-WHITE LEAF1 gene. AB - Active DNA transposons are important tools for gene functional analysis. The endogenous non-autonomous transposon, nDart1-0, in rice (Oryza sativa L.) is expected to generate various transposon-insertion mutants because nDart1-0 elements tend to insert into genic regions under natural growth conditions. We have developed a specific method (nDart1-0-iPCR) for efficient detection of nDart1-0 insertions and successfully identified the SNOW-WHITE LEAF1 (SWL1) gene in a variegated albino (swl1-v) mutant obtained from the nDart1-promoted rice tagging line. The variegated albino phenotype was caused by insertion and excision of nDart1-0 in the 5'-untranslated region of the SWL1 gene predicted to encode an unknown protein with the N-terminal chloroplast transit peptide. SWL1 expression was detected in various rice tissues at different developmental stages. However, immunoblot analysis indicated that SWL1 protein accumulation was strictly regulated in a tissue-specific manner. In the swl1 mutant, formations of grana and stroma thylakoids and prolamellar bodies were inhibited. This study revealed that SWL1 is essential for the beginning of thylakoid membrane organization during chloroplast development. Furthermore, we provide a developmental perspective on the nDart1-promoted tagging line to characterize unidentified gene functions in rice. PMID- 24151204 TI - Strigolactone and cytokinin act antagonistically in regulating rice mesocotyl elongation in darkness. AB - Strigolactones (SLs) are a group of phytohormones that control plant growth and development including shoot branching. Previous studies of the phenotypes of SL related rice (Oryza sativa) dwarf (d) mutants demonstrated that SLs inhibit mesocotyl elongation by controlling cell division. Here, we found that the expression of cytokinin (CK)-responsive type-A RESPONSE REGULATOR (RR) genes was higher in d10-1 and d14-1 mutants than in the wild type. However, CK levels in mesocotyls of the d mutants were not very different from those in the wild type. On the other hand, application of a synthetic CK (kinetin) enhanced mesocotyl elongation in the d mutants and the wild type. d10-1 and d14-1 mesocotyls were more sensitive to CK than wild-type mesocotyls, suggesting that the up-regulation of the CK-responsive type-A RR genes and the higher elongation of mesocotyls in the d mutants are mainly due to the increased sensitivity of the d mutants to CK. Co-treatment with kinetin and a synthetic SL (GR24) confirmed the antagonistic functions of SL and CK on mesocotyl elongation. OsTCP5, which encodes a transcription factor belonging to the cell division-regulating TCP family, was also regulated by SL and CK and its expression was negatively correlated with mesocotyl length. These findings suggest that OsTCP5 contributes to the SL- and CK-controlled mesocotyl elongation in darkness. PMID- 24151205 TI - Epigenetic changes accompany developmental programmed cell death in tapetum cells. AB - The tapetum, the nursing tissue inside anthers, undergoes cellular degradation by programmed cell death (PCD) during late stages of microspore-early pollen development. Despite the key function of tapetum, little is known about the molecular mechanisms regulating this cell death process in which profound nuclear and chromatin changes occur. Epigenetic features (DNA methylation and histone modifications) have been revealed as hallmarks that establish the functional status of chromatin domains, but no evidence on the epigenetic regulation of PCD has been reported. DNA methylation is accomplished by DNA methyltransferases, among which DNA methyl transferase 1 (MET1) constitutes one of the CG maintenance methyltransferase in plants, also showing de novo methyltransferase activity. In this work, the changes in epigenetic marks during the PCD of tapetal cells have been investigated by a multidisciplinary approach to reveal the dynamics of DNA methylation and the pattern of expression of MET1 in relation to the main cellular changes of this PCD process which have also been characterized in two species, Brassica napus and Nicotiana tabacum. The results showed that tapetum PCD progresses with the increase in global DNA methylation and MET1 expression, epigenetic changes that accompanied the reorganization of the nuclear architecture and a high chromatin condensation, activity of caspase 3-like proteases and Cyt c release. The reported data indicate a relationship between the PCD process and the DNA methylation dynamics and MET1 expression in tapetal cells, suggesting a possible new role for the epigenetic marks in the nuclear events occurring during this cell death process and providing new insights into the epigenetic control of plant PCD. PMID- 24151206 TI - Synthesis and characterization of a noncytotoxic, X-ray opaque polyurethane containing iodinated hydroquinone bis(2-hydroxyethyl) ether as chain extender for biomedical applications. AB - An iodinated urethane polymer that does not require addition of X-ray attenuating additives to impart X-ray opacity was synthesized and characterized for biomedical applications. A new X-ray opaque diiodo compound, namely, 2,2'-(2,5 diiodobenzene-1,4-diyl)bis(oxy)diethanol (DBD), was synthesized by iodinating hydroquinone bis(2-hydroxyethyl) ether and this compound was used as chain extender during polyurethane synthesis so that X-ray opacity could be imparted to the polymer formed. X-ray opaque polyurethane (XPU) was synthesized by reacting 1,6-diisocyanatohexane with poly(hexamethylene carbonate)diol and DBD. X-ray opacity of XPU was measured with a fluoroscopy machine using BaSO4 -filled polyurethane as controls. Radiographic images showed that XPU sample had X-ray opacity equivalent to 15 wt % BaSO4-filled polymer. In vivo imaging in a rabbit model showed that the material could be readily distinguishable from bones. XPU was found to be hemocompatible and noncytotoxic to L929 fibroblast cell lines. Optical transparency measurements using ultraviolet-visible spectrophotometer showed that XPU transmitted 85% of visible light. PMID- 24151207 TI - Population-based meta-analysis of furosemide pharmacokinetics. AB - Furosemide is a loop diuretic frequently used to treat fluid overload conditions such as hepatic cirrhosis and congestive heart failure (CHF). A population-based meta-analysis approach in NONMEM(r) was used to develop a PK model characterizing the time-course of furosemide in plasma and excretion into the urine for healthy subjects and fluid overload patients. Furosemide PK data from healthy subjects receiving 80 mg of oral furosemide were supplemented with additional individual and aggregate plasma concentration and urinary excretion versus time data from the literature after intravenous (i.v.) or oral furosemide administration (10-500 mg) to healthy subjects or fluid overload patients. A three-compartment model with zero-order input following i.v. administration (or first-order absorption using a Weibull function after oral administration) and first-order elimination best described furosemide PK. A covariate analysis identified creatinine clearance (CL(CR)) as a statistically significant predictor of renal clearance (CL(R)), with a population mean CL(R) of 4.67, 3.11, 1.95 and 1.17 l/h for a subject with normal renal function (CL(CR) = 120 ml/min) or mild (CL(CR) = 80 ml/min), moderate (CL(CR) = 50 ml/min) or severe (CLCR = 30 ml/min) renal impairment. Oral bioavailability was 59.1% and non-renal clearance was 2.02 l/h. A PC-VPC and other model diagnostics demonstrated that the population PK model can reasonably predict the rate of urinary furosemide excretion over time using dosing history and commonly available demographic data, allowing for convenient assessment of PK-PD relationships for furosemide when given alone or in combination with other agents used to treat fluid overload conditions. PMID- 24151208 TI - 'Stained-glass' sign for placental mesenchymal dysplasia. PMID- 24151209 TI - Chemoselective oxime reactions in proteins and peptides by using an optimized oxime strategy: the demise of levulinic acid. PMID- 24151210 TI - Human antibody responses to pneumococcal surface protein A and capsular polysaccharides during acute and convalescent stages of invasive disease in adult patients. AB - The IgG antibody responses to pneumococcal surface protein A (PspA) and capsular polysaccharides in acute and convalescent-phase sera from 10 adult patients with invasive pneumococcal disease were analysed. The relatedness between the strains were characterized by capsular serotyping (1, 4, 7F, 9V, 12F and 19F), multilocus sequence typing (MLST) and sequencing of the gene coding for PspA. Immunoblotting with the patient's own infecting strain used as whole cell antigen revealed strong antibody responses to PspA in 4 of 10 patients. Two of these patients showed cross reactivity of PspA antibodies within PspA families 1 and 2 by ELISA measurements with recombinant PspA proteins. Using ELISA, we found increased levels of capsular-specific antibodies during convalescent phase in 9 of 10 patients. All patients, except one, revealed low antibody levels in their acute phase sera. The binding of serum antibodies to live pneumococci using the patient's own infective strain was measured by flow cytometry. The antibodies binding to the live pneumococci corresponded to the serotype-specific polysaccharides by ELISA. Low antibody-binding activities to their infective strain in the acute serum may explain why they were not protected. PMID- 24151211 TI - Multifunctional plasmonic nanorattles for spectrum-guided locoregional therapy. AB - Locoregional death of cancer cells (in vitro) is induced by ablation of plasmonic nanorattles combined with triggered release of a chemotherapeutic drug from the nanorattles. Completion of the therapy process is indicated by a "Raman signal flip" between the two reporters of the surface-enhanced Raman scattering (SERS) probe. The nanorattles enable targeted delivery of payload and simultaneous monitoring of the payload release and the therapy process. PMID- 24151212 TI - Divergent responses of fire to recent warming and drying across south-eastern Australia. AB - The response of fire to climate change may vary across fuel types characteristic of differing vegetation types (i.e. litter vs. grass). Models of fire under climatic change capture these differing potential responses to varying degrees. Across south-eastern Australia, an elevation in the severity of weather conditions conducive to fire has been measured in recent decades. We examined trends in area burned (1975-2009) to determine if a corresponding increase in fire had occurred across the diverse range of ecosystems found in this part of the continent. We predicted that an increase in fire, due to climatic warming and drying, was more likely to have occurred in moist, temperate forests near the coast than in arid and semiarid woodlands of the interior, due to inherent contrasts in the respective dominant fuel types (woody litter vs. herbaceous fuels). Significant warming (i.e. increased temperature and number of hot days) and drying (i.e. negative precipitation anomaly, number of days with low humidity) occurred across most of the 32 Bioregions examined. The results were mostly consistent with predictions, with an increase in area burned in seven of eight forest Bioregions, whereas area burned either declined (two) or did not change significantly (nine) in drier woodland Bioregions. In 12 woodland Bioregions, data were insufficient for analysis of temporal trends in fire. Increases in fire attributable mostly to warming or drying were confined to three Bioregions. In the remainder, such increases were mostly unrelated to warming or drying trends and therefore may be due to other climate effects not explored (e.g. lightning ignitions) or possible anthropogenic influences. Projections of future fire must therefore not only account for responses of different fuel systems to climatic change but also the wider range of ecological and human effects on interactions between fire and vegetation. PMID- 24151214 TI - Movement disorders in women: a review. AB - The field of women's health developed based on the recognition that there are important sex-based differences regarding several aspects of medical illnesses. We performed a literature review to obtain information about differences between women and men for neurological movement disorders. We identified important differences in prevalence, genetics, clinical expression, course, and treatment responses. In addition, we found that female life events, including menstruation, pregnancy, breast feeding, menopause, and medications prescribed to women (such as oral contraceptives and hormone-replacement therapy), have significant implications for women with movement disorders. Understanding this biological sex specific information can help improve the quality and individualization of care for women with movement disorders and may provide insights into neurobiological mechanisms. PMID- 24151213 TI - Rapid preparative separation of six bioactive compounds from Gentiana crassicaulis Duthie ex Burk. using microwave-assisted extraction coupled with high-speed counter-current chromatography. AB - A rapid method combining microwave-assisted extraction (MAE) and high-speed counter-current chromatography (HSCCC) was applied for preparative separation of six bioactive compounds including loganic acid (I), isoorientin-4'-O-glucoside (II), 6'-O-beta-d-glucopyranosyl gentiopicroside (III), swertiamarin (IV), gentiopicroside (V), sweroside (VI) from traditional Tibetan medicine Gentiana crassicaulis Duthie ex Burk. MAE parameters were predicted by central composite design response surface methodology. That is, 5.0 g dried roots of G. crassicaulis were extracted with 50 mL 57.5% aqueous ethanol under 630 W for 3.39 min. The extract (gentian total glycosides) was separated by HSCCC with n butanol/ethyl acetate/methanol/1% acetic acid water (7.5:0.5:0.5:3.5, v/v/v/v) using upper phase mobile in tail-to-head elution mode. 16.3, 8.8, 12., 25.1, 40.7, and 21.8 mg of compounds I-VI were obtained with high purities in one run from 500 mg of original sample. The purities and identities of separated components were confirmed using HPLC with photo diode array detection and quadrupole TOF-MS and NMR spectroscopy. The study reveals that response surface methodology is convenient and highly predictive for optimizing extraction process, MAE coupled with HSCCC could be an expeditious method for extraction and separation of phytochemicals from ethnomedicine. PMID- 24151216 TI - Reactivity of yttrium carboxylates toward alkylaluminum hydrides. AB - Yttrocene-carboxylate complex [Cp*2Y(OOCAr(Me))] (Cp*=C5Me5, Ar(Me) =C6H2Me3 2,4,6) was synthesized as a spectroscopically versatile model system for investigating the reactivity of alkylaluminum hydrides towards rare-earth-metal carboxylates. Equimolar reactions with bis-neosilylaluminum hydride and dimethylaluminum hydride gave adduct complexes of the general formula [Cp*2Y(MU OOCAr(Me))(MU-H)AlR2] (R=CH2SiMe3, Me). The use of an excess of the respective aluminum hydride led to the formation of product mixtures, from which the yttrium aluminum-hydride complex [{Cp*2Y(MU-H)AlMe2(MU-H)AlMe2(MU-CH3)}2] could be isolated, which features a 12-membered-ring structure. The adduct complexes [Cp*2Y(MU-OOCAr(Me))(MU-H)AlR2] display identical (1)J(Y,H) coupling constants of 24.5 Hz for the bridging hydrido ligands and similar (89)Y NMR shifts of delta= 88.1 ppm (R=CH2SiMe3) and delta=-86.3 ppm (R=Me) in the (89)Y DEPT45 NMR experiments. PMID- 24151215 TI - Early therapy assessment of combined anti-DR5 antibody and carboplatin in triple negative breast cancer xenografts in mice using diffusion-weighted imaging and (1)H MR spectroscopy. AB - PURPOSE: To assess the early response of triple-negative breast-cancer (TNBC) following TRA-8 and carboplatin therapy using DWI and MRS in 2LMP and SUM159 mouse models. MATERIALS AND METHODS: Four groups (n = 5/group) of each model were untreated or treated with carboplatin, TRA-8, and combination, respectively. DWI and MRS were applied on 0, 3, and 7 days after therapy initiation, and all tumors were collected thereafter for terminal deoxynucleotidyl transferase mediated dUTP nick end labeling (TUNEL) staining. The changes in intratumoral apparent diffusion coefficient (ADC) and fat-water ratios (FWRs) were compared with tumor volume changes and apoptotic cell densities. RESULTS: Mean ADC values of 2LMP and SUM159 tumors significantly increased 4 +/- 4% and 37 +/- 11% during 7 days of combination therapy, respectively, as compared to control groups (P < 0.05). Similarly, mean FWRs of 2LMP and SUM159 tumors significantly increased 102 +/- 30% and 126 +/- 52%, respectively, for 7 days of combined treatment (P < 0.05). The changes of the mean ADC values for 3 days (or FWRs for 7 days) were linearly proportional to either the mean volume changes or apoptotic cell densities in both models. CONCLUSION: DWI and MRS assessed the early tumor response to TRA-8 and carboplatin in TNBC mouse models. PMID- 24151218 TI - Feasibility of semiautomated MR volumetry using gadoxetic acid-enhanced MRI at hepatobiliary phase for living liver donors. AB - PURPOSE: To assess the feasibility of semiautomated MR volumetry using gadoxetic acid-enhanced MRI at the hepatobiliary phase compared with manual CT volumetry. METHODS: Forty potential live liver donor candidates who underwent MR and CT on the same day, were included in our study. Semiautomated MR volumetry was performed using gadoxetic acid-enhanced MRI at the hepatobiliary phase. We performed the quadratic MR image division for correction of the bias field inhomogeneity. With manual CT volumetry as the reference standard, we calculated the average volume measurement error of the semiautomated MR volumetry. We also calculated the mean of the number and time of the manual editing, edited volume, and total processing time. RESULTS: The average volume measurement errors of the semiautomated MR volumetry were 2.35% +/- 1.22%. The average values of the numbers of editing, operation times of manual editing, edited volumes, and total processing time for the semiautomated MR volumetry were 1.9 +/- 0.6, 8.1 +/- 2.7 s, 12.4 +/- 8.8 mL, and 11.7 +/- 2.9 s, respectively. CONCLUSION: Semiautomated liver MR volumetry using hepatobiliary phase gadoxetic acid-enhanced MRI with the quadratic MR image division is a reliable, easy, and fast tool to measure liver volume in potential living liver donors. PMID- 24151217 TI - Readiness redefined: a behavioral task during screening predicted 1-year weight loss in the look AHEAD study. AB - OBJECTIVE: Predicting outcome in weight loss trials from baseline characteristics has proved difficult. Readiness to change is typically measured by self-report. METHODS: Performance of a behavioral task, completion of food records, from the screening period in the Look AHEAD study (n = 549 at four clinical centers) was assessed. Completeness of records was measured by the number of words and Arabic numerals (numbers) recorded per day, the number of eating episodes per day, and days per week where physical activity was noted. The primary outcome was weight loss at one year. RESULTS: In univariable analysis, both the number of words recorded and the number of numbers recorded were associated with greater weight loss. In multivariable analysis, individuals who recorded 20-26, 27-33, and >=34 words per day lost 9.12%, 11.40%, and 12.08% of initial weight, compared to 8.98% for individuals who recorded less than 20 words per day (P values of 0.87, 0.008, and <0.001, respectively, compared to <20 words per day). CONCLUSIONS: Participants who kept more detailed food records at screening lost more weight after 1 year than individuals who kept sparser records. The use of objective behavioral screening tools may improve the assessment of weight loss readiness. PMID- 24151219 TI - On the maxillary nerve. AB - The trigeminal, the fifth cranial nerve of vertebrates, represents the rostralmost component of the nerves assigned to pharyngeal arches. It consists of the ophthalmic and maxillomandibular nerves, and in jawed vertebrates, the latter is further divided into two major branches dorsoventrally. Of these, the dorsal one is called the maxillary nerve because it predominantly innervates the upper jaw, as seen in the human anatomy. However, developmentally, the upper jaw is derived not only from the dorsal part of the mandibular arch, but also from the premandibular primordium: the medial nasal prominence rostral to the mandibular arch domain. The latter component forms the premaxillary region of the upper jaw in mammals. Thus, there is an apparent discrepancy between the morphological trigeminal innervation pattern and the developmental derivation of the gnathostome upper jaw. To reconcile this, we compared the embryonic developmental patterns of the trigeminal nerve in a variety of gnathostome species. With the exception of the diapsid species studied, we found that the maxillary nerve issues a branch (nasopalatine nerve in human) that innervates the medial nasal prominence derivatives. Because the trigeminal nerve in cyclostomes also possesses a similar branch, we conclude that the vertebrate maxillomandibular nerve primarily has had a premandibular branch as its dorsal element. The presence of this branch would thus represent the plesiomorphic condition for the gnathostomes, implying its secondary loss within some lineages. The branch for the maxillary process, more appropriately called the palatoquadrate component of the maxillary nerve (V(2)), represents the apomorphic gnathostome trait that has evolved in association with the acquisition of an upper jaw. PMID- 24151220 TI - The Coulter principle: Imaginary origins. PMID- 24151221 TI - Paramagnetic relaxation of long-lived coherences in solution NMR. AB - Long-lived coherences (LLCs) are known to have lifetimes much longer than transverse magnetization or single quantum coherences (SQCs). The effect of paramagnetic ions on the relaxation of LLCs is not known. This is particularly important, as LLCs have potential applications in various fields like analytical NMR, in vivo NMR and MR imaging methods. We study here the behaviour of LLCs in the presence of paramagnetic relaxation agents. The stepwise increase in the concentration of the metal ion is followed by measuring various relaxation rates. The effect of paramagnetic ions is analysed in terms of the external random field's contribution to the relaxation of two coupled protons in 2,3,6 trichlorobenzaldehyde. The LLCs relax faster than ordinary SQCs in the presence of paramagnetic ions of varying character. This is explained on the basis of an increase in the contribution of the external random field to relaxation due to a paramagnetic relaxation mechanism. Comparison is also made with ordinary Zeeman relaxation rates like R1, R2, R1rho and also with rate of relaxation of long lived states RLLS which are known to be less sensitive to paramagnetically induced relaxation. Also, the extent of correlation of random fields at two proton sites is studied and is found to be strongly correlated with each other. The obtained correlation constant is found to be independent of the nature of added paramagnetic impurities. PMID- 24151222 TI - Defining enthesitis in spondyloarthritis by ultrasound: results of a Delphi process and of a reliability reading exercise. AB - OBJECTIVE: To standardize ultrasound (US) in enthesitis. METHODS: An initial Delphi exercise was undertaken to define US-detected enthesitis and its core components. These definitions were subsequently tested on static images taken from spondyloarthritis patients in order to evaluate their reliability. RESULTS: Excellent agreement (>80%) was obtained for including hypoechogenicity, increased thickness of the tendon insertion, calcifications, enthesophytes, erosions, and Doppler activity as core elementary lesions of US-detected enthesitis. US definitions were subsequently obtained for each elementary component. On static images, the intraobserver reliability showed a high degree of variability for the detection of elementary lesions, with kappa coefficients ranging from 0.13-1. The interobserver kappa values were variable, with the lowest kappa coefficient for enthesophytes (0.24) and the highest coefficient for Doppler activity at the enthesis (0.63). CONCLUSION: This is the first consensus-based US definition of enthesitis and its elementary components and the first step performed to ensure a higher degree of homogeneity and comparability of results between studies and in daily clinical work. PMID- 24151223 TI - Do ICF core sets for low back pain include patients' self-reported activity limitations because of back problems? AB - PURPOSE: The aim of this study was to investigate content validity of the International Classification of Functioning, Disability and Health (ICF) Core Sets for low back pain (LBP), by examining whether common activities reported as difficult to perform are included in the Core Sets. METHODS: A cross-sectional design was used. Ninety-eight patients with long-lasting back pain (>3 months) between 18 and 65 years of age were consecutively recruited from a Multidisciplinary Outpatient Spine Clinic. Difficulties with daily life and work task activities because of back pain were examined by asking the patients two questions: 1) can you specify activities that are difficult to perform because of your back pain? and 2) are there specific work tasks that you are unable to do because of your back pain? Two raters independently classified the written responses according to the ICF Core Sets' component Activities and Participation. RESULTS: Activities and work tasks were linked to 15 of 29 categories (52%) in the Comprehensive Core Set, and 9 of 12 (75%) in the Brief Core Set, and the initial agreement between the two raters in coding the answers according to the Core Sets was (83%, k = 0.80) and (93%, k = 0.9), respectively, before consensus was reached. CONCLUSIONS: The Comprehensive Core Set for LBP to a large degree contains daily life and work-related activities frequently reported as difficult to perform by patients with long-lasting LBP. The categories, however, are very broad and do not provide specified descriptions of the most frequently reported activity limitations such as sitting, standing and walking. The Brief Core Set does not include categories for frequently reported activities such as pulling/pushing and leisure/recreation activities. ICF Core Sets for LBP seem suitable for obtaining a gross overview of the patients' functional limitations, but do not give sufficient information from a therapeutic point of view. PMID- 24151224 TI - Fabrication of cysteine-responsive biomimetic single nanochannels by a thiol-yne reaction strategy and their application for sensing in urine samples. AB - A photoinitiated thiol-yne click reaction strategy is used to fabricate a novel responsive biomimetic nanochannel platform. It displays a selective response for Cys by way of covalent bond formation on the channel surface. This system can be applied for Cys sensing with high specificity and non-interference performance in complex matrices and human urine samples. PMID- 24151225 TI - An efficient strategy for the extraction and purification of lignans from Schisandra chinensis by a combination of supercritical fluid extraction and high speed counter-current chromatography. AB - An efficient strategy for extracting and separating five lignans from Schisandra chinensis (Turcz.) Baill has been developed using supercritical fluid extraction (SFE) and high-speed counter-current chromatography (HSCCC) in the present study. First, the extraction was performed by a preparative SFE system under 15 MPa of pressure at 36 degrees C for 4 h. Then, the SFE extract was successfully separated and purified by HSCCC with a two-phase solvent system composed of n hexane/ethyl acetate/methanol/water (6:4:5:5, 6:4:6:4, 6:4:8:2, v/v) in a stepwise elution mode. The fractions were analyzed by HPLC, and the chemical structures of the products were identified by ESI-MS and 1H NMR spectroscopy. As a result, a total of 12.5 mg of schisandrin at 98.0% purity, 7.1 mg of gomisin A at 98.1% purity, 1.8 mg of schisantherin B at 93.3% purity, 4.4 mg of deoxyschisandrin at 92.9% purity, and 6.8 mg of gamma-schisandrin at 89.1% purity were obtained from 300 mg crude extract in a one-step purification. PMID- 24151227 TI - Aerobic oxidative coupling between carbon nucleophiles and allylic alcohols: a strategy to construct beta-(hetero)aryl ketones and aldehydes through hydrogen migration. AB - Wacker heck of a reaction: A highly efficient Pd(II) -catalyzed intermolecular oxidative-coupling reaction is reported, inspired by the fundamental Heck and Wacker processes. The (hetero)aryl-PdX species, originating from C?H activation step or desulfonyl hydrazides, coupled with allylic alcohols by using oxygen as the sole oxidant. PMID- 24151226 TI - Piperlongumine inhibits NF-kappaB activity and attenuates aggressive growth characteristics of prostate cancer cells. AB - BACKGROUND: Elevated NF-kappaB activity has been previously demonstrated in prostate cancer cell lines as hormone-independent or metastatic characteristics develop. We look at the effects of piperlongumine (PL), a biologically active alkaloid/amide present in piper longum plant, on the NF-kappaB pathway in androgen-independent prostate cancer cells. METHODS: NF-kappaB activity was evaluated using Luciferase reporter assays and Western blot analysis of p50 and p65 nuclear translocation. IL-6, IL-8, and MMP-9 levels were assessed using ELISA. Cellular adhesion and invasiveness properties of prostate cancer cells treated with PL were also assessed. RESULTS: NF-kappaB DNA-binding activity was directly down-regulated with increasing concentrations of PL, along with decreased nuclear translocation of p50 and p65 subunits. Expression of IL-6, IL 8, MMP-9, and ICAM-1 was attenuated, and a decrease of cell-to-matrix adhesion and invasiveness properties of prostate cancer cells were observed. CONCLUSIONS: PL-mediated inhibition of NF-kappaB activity decreases aggressive growth characteristics of prostate cancer cells in vitro. PMID- 24151228 TI - Effect of dietary fatty acids on metabolic rate and nonshivering thermogenesis in golden hamsters. AB - Hibernating rodents prior to winter tend to select food rich in polyunsaturated fatty acids (PUFA). Several studies found that such diet may positively affect their winter energy budget by enhancing torpor episodes. However, the effect of composition of dietary fatty acids (FA) on metabolism of normothermic heterotherms is poorly understood. Thus we tested whether diets different in FA composition affect metabolic rate (MR) and the capacity for nonshivering thermogenesis (NST) in normothermic golden hamsters (Mesocricetus auratus). Animals were housed in outdoor enclosures from May 2010 to April 2011 and fed a diet enriched with PUFA (i.e., standard food supplemented weekly with sunflower and flax seeds) or with saturated and monounsaturated fatty acids (SFA/MUFA, standard food supplemented with mealworms). Since diet rich in PUFA results in lower MR in hibernating animals, we predicted that PUFA-rich diet would have similar effect on MR of normothermic hamsters, that is, normothermic hamsters on the PUFA diet would have lower metabolic rate in cold and higher NST capacity than hamsters supplemented with SFA/MUFA. Indeed, in winter resting metabolic rate (RMR) below the lower critical temperature was higher and NST capacity was lower in SFA/MUFA-supplemented animals than in PUFA-supplemented ones. These results suggest that the increased capacity for NST in PUFA-supplemented hamsters enables them lower RMR below the lower critical temperature of the thermoneural zone. PMID- 24151229 TI - Assessment of fetal cardiomyopathy in early-stage twin-twin transfusion syndrome: comparison between commonly reported cardiovascular assessment scores. AB - OBJECTIVES: To assess the relationship between commonly reported fetal cardiomyopathy scoring systems in early-stage twin-twin transfusion syndrome (TTTS). METHODS: We reviewed retrospectively 100 cases of Quintero Stages I and II TTTS referred to our center for evaluation from 2008 to 2010. The cases were divided into groups of 25, representing each of four grades of TTTS cardiomyopathy as assessed by Cincinnati stage: no cardiomyopathy, Stage IIIa, Stage IIIb and Stage IIIc. Spearman correlation (rs ) was calculated between the Children's Hospital of Philadelphia (CHOP) score, cardiovascular profile score (CVPS), Cincinnati stage and myocardial performance index (MPI). RESULTS: There was a weak correlation between the Cincinnati stage and the CHOP score (rs = 0.36) and CVPS (rs = -0.39), while correlation was strong between the CHOP score and CVPS (rs = -0.72). MPI elevation was concordant with Cincinnati stage more frequently (82% of cases) than were ventricular hypertrophy (43%) or atrioventricular valve regurgitation (28%). 51% of fetuses with minimally elevated CHOP score (0-1) and 48% of fetuses with minimally depressed CVPS (9-10) had significant elevation (Z-score >= +3) in right ventricular or left ventricular MPI. CONCLUSIONS: MPI has a strong influence on grading the severity of fetal cardiomyopathy using the Cincinnati stage among fetuses with mild TTTS. Furthermore, significant elevation of the MPI is common among fetuses with mild disease as assessed by the CHOP score and CVPS. These differences should be understood when assessing and grading cardiomyopathy in TTTS, particularly in early (Quintero Stages I and II) disease. PMID- 24151230 TI - Running apraxia as a presenting symptom of neuronal ceroid lipofuscinosis 6. PMID- 24151231 TI - Navigator artifact reduction in three-dimensional late gadolinium enhancement imaging of the atria. AB - PURPOSE: Navigator-gated three-dimensional (3D) late gadolinium enhancement (LGE) imaging demonstrates scarring following ablation of atrial fibrillation. An artifact originating from the slice-selective navigator-restore pulse is frequently present in the right pulmonary veins (PVs), obscuring the walls and making quantification of enhancement difficult. We describe a simple sequence modification to greatly reduce or remove this artifact. METHODS: A navigator gated inversion-prepared gradient echo sequence was modified so that the slice selective navigator-restore pulse was delayed in time from the nonselective preparation (NAV-restore-delayed). Both NAV-restore-delayed and conventional 3D LGE acquisitions were performed in 11 patients and the results compared. RESULTS: One patient was excluded due to severe respiratory motion artifact in both NAV restore-delayed and conventional acquisitions. Moderate to severe artifact was present in 9 of the remaining 10 patients using the conventional sequence and was considerably reduced when using the NAV-restore-delayed sequence (ostial PV to blood pool ratio, 1.7 +/- 0.5 versus 1.1 +/- 0.2, respectively [P < 0.0001]; qualitative artifact scores, 2.8 +/- 1.1 versus 1.2 +/- 0.4, respectively [P < 0.001]). While navigator signal-to-noise ratio was reduced with the NAV-restore delayed sequence, respiratory motion compensation was unaffected. CONCLUSIONS: Shifting the navigator-restore pulse significantly reduces or eliminates navigator artifact. This simple modification improves the quality of 3D LGE imaging and potentially aids late enhancement quantification in the atria. PMID- 24151232 TI - BRCA1-mediated inflammation and growth activated & inhibited transition mechanisms between no-tumor hepatitis/cirrhotic tissues and HCC. AB - To understand breast cancer 1 early onset (BRCA1)-mediated inflammation and growth activated and inhibited transition mechanisms between no-tumor hepatitis/cirrhotic tissues (HBV or HCV infection) and human hepatocellular carcinoma (HCC), BRCA1-activated different complete (all no positive correlation, Pearson correlation coefficient <0.25) and uncomplete (partly no positive correlation except BRCA1, Pearson <0.25) networks were identified in higher HCC compared with lower no-tumor hepatitis/cirrhotic tissues (HBV or HCV infection) from the corresponding BRCA1-stimulated (Pearson >=0.25) or inhibited (Pearson <= 0.25) overlapping molecules of Pearson and GRNInfer, respectively. This result was verified by the corresponding scatter matrix. As visualized by GO, KEGG, GenMAPP, BioCarta, and disease database integration, we proposed mainly that BRCA1-stimulated different complete network was involved in BRCA1 activation with integral to membrane killer cell lectin-like receptor C to nucleus interferon regulatory factor 5-induced inflammation, whereas the corresponding inhibited network participated in BRCA1 repression with matrix roundabout axon guidance receptor homolog 1 to plasma membrane versican-induced growth in lower no-tumor hepatitis/cirrhotic tissues (HBV or HCV infection). However, BRCA1-stimulated network contained BRCA1 activation with endothelium-specific to lysosomal transmembrane and carbamoyl synthetase to tastin, histone cluster and cyclin induced growth, whereas the corresponding inhibited different complete network included BRCA1 repression with ovalbumin, thyroid stimulating hormone beta and Hu antigen C to cytochrome P450 to transducin-induced inflammation in higher HCC. Our BRCA1 different networks were verified by BRCA1-activated or -inhibited complete and uncomplete networks within and between no-tumor hepatitis/cirrhotic tissues (HBV or HCV infection) or (and) HCC. PMID- 24151233 TI - Group specific vein-atlasing: an application for analyzing the venous system under normal and multiple sclerosis conditions. AB - PURPOSE: To create a group-specific vein-atlas based on healthy control subjects to visualize the average venous system under normal conditions and to compare the venous volume portion in multiple sclerosis (MS) lesions with that atlas. MATERIALS AND METHODS: Susceptibility-weighted imaging (SWI), as well as T1 weighted imaging, was performed at 7 Tesla on nine healthy controls and nine age matched MS patients. Automatic vein segmentation was performed on SWI data. The vessel segmentation results of the healthy controls were nonlinearly transformed into a model space, and subsequently averaged to create the vein-atlas. Thirteen normal-appearing white matter (NAWM) regions and 18 MS lesions were manually segmented in the patient data, and were used to calculate the venous volume portion in individual patient data and in corresponding regions within the vein atlas. RESULTS: The vein-atlas illustrates the average venous network of the control group. The venous volume portion in MS lesions was significantly higher (P < 0.05) compared with the corresponding regions in the vein-atlas. NAWM regions did not differ significantly (P > 0.05) from corresponding atlas regions. CONCLUSION: The developed vein-atlas shows the average venous system of a specific population and allows, therefore, the evaluation of the venous system of individual subjects. PMID- 24151234 TI - Comparable flow cytometry data can be obtained with two types of instruments, Canto II, and Navios. A GEIL study. AB - Flow cytometry (FC) instruments settings classically rely on local establishment of photomultipliers (PMT) voltages adapted to the measurements expected to be performed. In the era of multiparameter FC (MFC), it appears more and more desirable that comparable patterns of fluorescence are obtained in different settings. This relies on a harmonization of settings between instruments. Although this has been shown to be feasible within a given brand of flow cytometers, little information is available about broader comparisons in a given center or in a multicenter fashion. Here, we report a two-phase series of experiments first performed between a Canto II (BD Biosciences) and a Navios (Beckman Coulter) instruments in the same center. PMT values adjusted on the reference instrument (RI) Canto II were used to establish target values for PMT settings on the paired Navios practice instrument (PI). This allowed to show the good correlation of all but peaks 1 and 2 of Rainbow((r)) beads between RI and PI. Using 4- or 8-color stained leukocytes, the similitude of the settings was further confirmed. A complex set of matrices was then established between five centers all equipped with both instruments. Using Bland & Altman difference comparisons for median fluorescence values, it was shown that using either Rainbow beads or CD16 stained polymorphonuclears to set-up target values on the RI CantoII, highly superimposable results could be obtained on all 9 PI. The latter were obtained using Rainbow beads or Compbeads((r)) for comparisons. In summary, this two-phase study demonstrates the feasibility of different methods allowing for a robust harmonization of settings for MFC. PMID- 24151235 TI - Highly transparent and conductive ZnO: Al thin films from a low temperature aqueous solution approach. PMID- 24151236 TI - Cooperatively enhanced receptors for biomimetic molecular recognition. AB - The concept of preorganization suggests that organizing a receptor around its guest during binding is detrimental, because the cost of conformational change is assumed to be paid out of the binding energy. Although this concept has historically guided the synthesis of a great many synthetic hosts, in recent years, chemists have begun to synthesize receptors that resemble proteins in their cooperative conformational changes. Such changes could enhance the host guest interactions, in particular if the binding of the guest triggers previously unengaged noncovalent interactions within the host. These hosts, referred to as cooperatively enhanced receptors, corroborate with their biological counterparts to support the approach of creating high-affinity receptors through the combined strategies of cooperativity and preorganization. Solvents, often the invisible participants of any solution-based supramolecular process, should be properly considered in the design of synthetic receptors, whether preorganized or cooperatively enhanced. PMID- 24151237 TI - Reply: To PMID 23983044. PMID- 24151238 TI - Selectivity analysis of single binder assays used in plasma protein profiling. AB - The increasing availability of antibodies toward human proteins enables broad explorations of the proteomic landscape in cells, tissues, and body fluids. This includes assays with antibody suspension bead arrays that generate protein profiles of plasma samples by flow cytometer analysis. However, antibody selectivity is context dependent so it is necessary to corroborate on-target detection over off-target binding. To address this, we describe a concept to directly verify interactions from antibody-coupled beads by analysis of their eluates by Western blots and MS. We demonstrate selective antibody binding in complex samples with antibodies toward a set of chosen proteins with different abundance in plasma and serum, and illustrate the need to adjust sample and bead concentrations accordingly. The presented approach will serve as an important tool for resolving differential protein profiles from antibody arrays within plasma biomarker discoveries. PMID- 24151239 TI - Novel bioactive amino-functionalized cellulose nanofibers. AB - Amino-cellulose-based nanofibers are prepared by electrospinning of blended solutions of 6-deoxy-6-trisaminoethyl-amino (TEAE) cellulose and polyvinyl alcohol (PVA). The TEAE cellulose with a degree of substitution of 0.67 is synthesized via a nucleophilic displacement reaction starting from cellulose-p toluenesulfonic acid ester. Several solution characteristics such as polymer concentration, electrical conductivity, and surface tension as well as setup parameters are investigated to optimize the ability of nanofiber formation. These parameters are evaluated using the rheological studies of the solutions. The nanofibers obtained are characterized by scanning electron microscopy (SEM) and show a high antimicrobial activity against Staphylococcus aureus and Klebsiella pneumoniae. PMID- 24151240 TI - Photocontrolled self-assembly of a bis-azobenzene-containing alpha-amino acid. PMID- 24151241 TI - Executive functions and driving in people with Parkinson's disease. PMID- 24151242 TI - S49G and R389G polymorphisms of the beta1-adrenergic receptor influence signaling via the cAMP-PKA and ERK pathways. AB - Two functionally important beta1-adrenergic receptor (beta1AR) polymorphisms have been identified. The R389G polymorphism influences coupling to the Gs-cAMP pathway. R(389)-beta1ARs display enhanced activation of cAMP/PKA; they provide short-term inotropic support but also cause a predisposition to cardiomyopathic decompensation. A second S49G polymorphism is implicated in the evolution of heart failure, but the mechanism remains uncertain. This study shows that position 49 and 389 polymorphisms function in a coordinate manner to influence agonist-dependent cAMP/PKA and ERK responses. cAMP/PKA and ERK responses are more robust in HEK293 cells that heterologously overexpress G(49)-beta1ARs, compared with S(49)-beta1ARs. However, this phenotype is most obvious on a G(389)-beta1AR background; the more robust agonist-dependent cAMP/PKA and ERK responses in R(389)-beta1AR cells effectively obscure the effect of the S49G polymorphism. We also show that isoproterenol (Iso) and carvedilol activate ERK via a similar EGFR independent mechanism in cells expressing various beta1AR haplotypes. However, Iso activates ERK via an Src-independent pathway, but carvedilol-dependent ERK activation requires Src. Since the S49G polymorphism has been linked to changes in beta1AR trafficking, we examined whether beta1AR polymorphisms influence partitioning to lipid raft membranes. Biochemical fractionation studies show that all four beta1AR variants are recovered in buoyant flotillin-enriched membranes; the distinct signaling phenotypes of the different beta1AR variants could not be attributed to any gross differences in basal compartmentalization to lipid raft membranes. The allele-specific differences in beta1AR signaling phenotypes identified in this study could underlie interindividual differences in responsiveness to beta-blocker therapy and clinical outcome in heart failure. PMID- 24151243 TI - ENU mutation mapped to a distal region of chromosome 11 is a major determinant of bone size. AB - Using a phenotype driven n-ethyl-nitrosourea (ENU) screen in growth hormone deficient mice, we have identified a mutant (named 14104) that exhibited a smaller bone size. Phenotype measurements by microcomputed tomography revealed that mutant mice exhibited a 43 and 34% reduction in tissue area and bone area, respectively at the femur middiaphysis. Dynamic histomorphometry revealed a 30 and 15% lower bone formation rate at the periosteal and endosteal surface, respectively. Breaking strength of the femur was reduced by 30% in the mutant mice. To determine if the 14104 locus is involved in a mechanical loading signaling pathway, the skeletal anabolic response to tibia axial loading was evaluated. The increase in trabecular response in the loaded region was severely compromised by the 14014 mutation. To identify the location of mutation, we performed linkage analysis using 62 polymorphic markers in the B6-DBA/2J F2 mice. The genome-wide linkage analysis identified the location of the mutation to a 72 to 83 cM region on chromosome 11 with peak logarithm of the odds scores of 15 for periosteal circumference at marker D11mit338. Sequence analysis revealed no mutation in the coding region of 11 potential candidate genes. Based on these data and published data on the skeletal phenotype of genes in this region, we concluded that the 109-119 Mb region of chromosome 11 harbors a bone size gene that regulates periosteal bone formation. The mutant strain developed in this study provides an important tool to identify a novel mechanosensitive gene that determines bone size during postnatal development. PMID- 24151244 TI - Identification of KCNJ11 as a functional candidate gene for bovine meat tenderness. AB - The potassium inwardly rectifying channel, subfamily J, member 11 (KCNJ11) gene was investigated as a candidate for meat tenderness based on the effects reported on muscle for KCNJ11 gene knockout in rat models and its position in a quantitative trait locus (QTL) for meat tenderness in the bovine genome. Sequence variations in the KCNJ11 gene were described by sequencing six amplified fragments, covering almost the entire gene. We identified single nucleotide polymorphisms (SNP) and validated them by different approaches, taking advantage of simultaneous projects that are being developed with the same Nelore population. By sequencing the KCNJ11 in Nelore steers representing extreme phenotypes for Warner-Bratzler shear force (WBSF), it was possible to identify 22 SNPs. We validated two of the identified markers by genotyping the whole population (n = 460). Analysis of association between genotypes and WBSF values revealed a significant additive effect of a SNP at different meat aging times (P <= 0.05). In addition, an association between the expression levels of KCNJ11 and WBSF was found, with lower expression levels of KCNJ11 associated with more tender meat (P <= 0.05). The results showed that the KCNJ11 gene is a candidate mapped to a QTL for meat tenderness previously identified on BTA15 and may be useful to identify animals with genetic potential to produce tender meat. The effect of KCNJ11 observed on muscle is potentially due to changes in activity of KATP channels, which in turn influence the flow of potassium in the intracellular space, allowing establishment of the membrane potential necessary for muscle contraction. PMID- 24151245 TI - Genome-wide analysis of the rat colon reveals proximal-distal differences in histone modifications and proto-oncogene expression. AB - Since disease susceptibility of the intestine exhibits an anatomical bias, we propose that the chromatin landscape, especially the site-specific epigenetic differences in histone modification patterns throughout the colonic longitudinal axis, contributes to the differential incidence of site-specific pathology. To test this hypothesis, we assessed the chromatin structure associated with gene expression profiles in the rat proximal and distal colon by globally correlating chromatin immunoprecipitation next-generation sequencing analysis (ChIP-Seq) with mRNA transcription (RNA-Seq) data. Crypts were isolated from the proximal and distal colonic regions from rats maintained on a semipurified diet, and mRNA gene expression profiles were generated by RNA-Seq. The remaining isolated crypts were formaldehyde-cross-linked and chromatin immunoprecipitated with antibodies against H3K4me3, H3K9me3, and RNA polymerase II. Globally, RNA-Seq results indicate that 9,866 genes were actively expressed, of which 540 genes were differentially expressed between the proximal and distal colon. Gene ontology analysis indicates that crypt location significantly affected both chromatin and transcriptional regulation of genes involved in enterocyte movement, lipid metabolism, lymphatic development, and immune cell trafficking. Gene function analysis indicates that the PI3-kinase signaling pathway was regulated in a site specific manner, e.g., proto-oncogenes, JUN, FOS, and ATF, were upregulated in the distal colon. Middle and long noncoding RNAs (lncRNAs) were also detected in the colon, including select lncRNAs formerly only detected in the rat nervous system. In summary, distinct combinatorial patterns of histone modifications exist in the proximal versus distal colon. These site-specific differences may explain the differential effects of chemoprotective agents on cell transformation in the ascending (proximal) and descending (distal) colon. PMID- 24151247 TI - Rapid isotropic resolution cartilage assessment using radial alternating repetition time balanced steady-state free-precession imaging. AB - PURPOSE: To compare a balanced steady-state free-precession sequence with a radial k-space trajectory and alternating repetition time fat suppression (Radial ATR) with other currently used fat-suppressed 3D sequences for evaluating the articular cartilage of the knee joint at 3.0T. MATERIALS AND METHODS: Radial-ATR, fast spin-echo (FSE-Cube), gradient recall-echo acquired in the steady-state (GRASS), and spoiled gradient recall-echo (SPGR) sequences with similar voxel volumes and identical scan times were performed at 3.0T on both knee joints of five volunteers. Signal-to-noise ratio (SNR) and contrast-to-noise ratio (CNR) measurements were performed for all sequences using a double acquisition method and compared using Mann-Whitney Wilcoxon tests. Radial-ATR sequences with 0.3 mm and 0.4 mm isotropic resolution were also performed on the knee joints of seven volunteers and three patients with osteoarthritis. RESULTS: Average SNR values for cartilage, synovial fluid, and bone marrow were 54.7, 153.3, and 12.9, respectively, for Radial ATR, 30.8, 44.1, and 1.9, respectively, for FSE-Cube, 13.3, 46.9, and 3.3, respectively, for GRASS, and 19.1, 8.1, and 2.1, respectively, for SPGR. Average CNR values between cartilage and synovial fluid and between cartilage and bone marrow were 98.6 and 41.8, respectively, for VIPR ATR, 13.4 and 28.8, respectively, for FSE-Cube, 33.6 and 10.0, respectively, for GRASS, and 11.0 and 16.9, respectively, for SPGR. Radial-ATR had significantly higher (P < 0.001) cartilage, synovial fluid, and bone marrow SNR and significantly higher (P < 0.01) CNR between cartilage and synovial fluid and between cartilage and bone marrow than FSE-Cube, GRASS, and SPGR. Radial-ATR provided excellent visualization of articular cartilage at high isotropic resolution with no image degradation due to off-resonance banding artifacts. CONCLUSION: Radial-ATR had superior SNR efficiency to other fat-suppressed 3D cartilage imaging sequences and produced high isotropic resolution images of the knee joint which could be used for evaluating articular cartilage at 3.0T. PMID- 24151246 TI - Noninvasive MRI measurement of the absolute cerebral blood volume-cerebral blood flow relationship during visual stimulation in healthy humans. AB - PURPOSE: The relationship between cerebral blood volume (CBV) and cerebral blood flow (CBF) underlies blood oxygenation level-dependent functional MRI signal. This study investigates the potential for improved characterization of the CBV CBF relationship in humans, and examines sex effects as well as spatial variations in the CBV-CBF relationship. METHODS: Healthy subjects were imaged noninvasively at rest and during visual stimulation, constituting the first MRI measurement of the absolute CBV-CBF relationship in humans with complete coverage of the functional areas of interest. RESULTS: CBV and CBF estimates were consistent with the literature, and their relationship varied both spatially and with sex. In a region of interest with stimulus-induced activation in CBV and CBF at a significance level of the P < 0.05, a power function fit resulted in CBV = 2.1 CBF(0.32) across all subjects, CBV = 0.8 CBF(0.51) in females and CBV = 4.4 CBF(0.15) in males. Exponents decreased in both sexes as ROIs were expanded to include less significantly activated regions. CONCLUSION: Consideration for potential sex-related differences, as well as regional variations under a range of physiological states, may reconcile some of the variation across literature and advance our understanding of the underlying cerebrovascular physiology. PMID- 24151248 TI - Tumor heterogeneity makes AML a "moving target" for detection of residual disease. AB - Detection of minimal residual disease is recognized as an important post-therapy risk factor in acute myeloid leukemia patients. Two most commonly used methods for residual disease monitoring are real-time quantitative polymerase chain reaction and multiparameter flow cytometry. The results so far are very promising, whereby it is likely that minimal residual disease results will enable to guide future post-remission treatment strategies. However, the leukemic clone may change between diagnosis and relapse due to the instability of the tumor cells. This instability may already be evident at diagnosis if different subpopulations of tumor cells coexist. Such tumor heterogeneity, which may be reflected by immunophenotypic, molecular, and/or cytogenetic changes, can have important consequences for minimal residual disease detection, since false negative results can be expected to be the result of losses of aberrancies used as minimal residual disease markers. In this review the role of such changes in minimal residual disease monitoring is explored. Furthermore, possible causes of tumor instability are discussed, whereby the concept of clonal selection and expansion of a chemotherapy-resistant subpopulation is highlighted. Accordingly, detailed knowledge of the process of clonal evolution is required to improve both minimal residual disease risk stratification and patient outcome. PMID- 24151249 TI - Carotid intima-media thickness as a novel inflammatory marker in psoriasis: comment on the article by Lin et al. PMID- 24151250 TI - Nanostructured conducting polymers as intelligent implant surface: fabricated on biomedical titanium with a potential-induced reversible switch in wettability. AB - Conducting polypyrrole (PPy) nanotube arrays, nanotube networks and irregular films are deposited on biomedical titanium. By in situ application of weak periodic potentials, the nanostructured conducting polymers undergo a reversible switch in wettability, which is a redox process of dopant molecules (as hydrophilic groups) immobilized and de-immobilized on the surface of the conducting polymers. PMID- 24151251 TI - Differential label-free quantitative proteomic analysis of avian eggshell matrix and uterine fluid proteins associated with eggshell mechanical property. AB - Eggshell strength is a crucial economic trait for table egg production. During the process of eggshell formation, uncalcified eggs are bathed in uterine fluid that plays regulatory roles in eggshell calcification. In this study, a label free MS-based protein quantification technology was used to detect differences in protein abundance between eggshell matrix from strong and weak eggs (shell matrix protein from strong eggshells and shell matrix protein from weak eggshells) and between the corresponding uterine fluids bathing strong and weak eggs (uterine fluid bathing strong eggs and uterine fluid bathing weak eggs) in a chicken population. Here, we reported the first global proteomic analysis of uterine fluid. A total of 577 and 466 proteins were identified in uterine fluid and eggshell matrix, respectively. Of 447 identified proteins in uterine fluid bathing strong eggs, up to 357 (80%) proteins were in common with proteins in uterine fluid bathing weak eggs. Similarly, up to 83% (328/396) of the proteins in shell matrix protein from strong eggshells were in common with the proteins in shell matrix protein from weak eggshells. The large amount of common proteins indicated that the difference in protein abundance should play essential roles in influencing eggshell strength. Ultimately, 15 proteins mainly relating to eggshell matrix specific proteins, calcium binding and transportation, protein folding and sorting, bone development or diseases, and thyroid hormone activity were considered to have closer association with the formation of strong eggshell. PMID- 24151252 TI - An anionic microporous polymer network prepared by the polymerization of weakly coordinating anions. PMID- 24151253 TI - Dysregulation of the axonal trafficking of nuclear-encoded mitochondrial mRNA alters neuronal mitochondrial activity and mouse behavior. AB - Local translation of nuclear-encoded mitochondrial mRNAs is essential for mitochondrial activity, yet there is little insight into the role that axonal trafficking of these transcripts play in neuronal function and behavior. Previously, we identified a 38 nucleotide stem-loop structure (zipcode) in the 3' untranslated region of the Cytochrome C oxidase IV (COXIV) mRNA that directs the transport of a reporter mRNA to the axon of superior cervical ganglion neurons (SCG). Overexpression of a chimeric reporter mRNA with the COXIV zipcode competed with the axonal trafficking of endogenous COXIV mRNA, and led to attenuated axon growth in SCG neurons. Here, we show that exogenous expression of the COXIV zipcode in cultured SCG neurons also results in the reduction of local ATP levels and increases levels of reactive oxygen species (ROS) in the axon. We took advantage of this "competition" phenotype to investigate the in vivo significance of axonal transport of COXIV mRNA. Toward this end, we generated transgenic mice expressing a fluorescent reporter fused to COXIV zipcode under a forebrain specific promoter. Immunohistological analyses and RT-PCR analyses of RNA from the transgenic mouse brain showed expression of the reporter in the deep layer neurons in the pre-frontal and frontal cortex. Consistent with the in vitro studies, we observed increased ROS levels in neurons of these transgenic animals. A battery of behavioral tests on transgenic mice expressing the COXIV zipcode revealed an "anxiety-like" behavioral phenotype, suggesting an important role for axonal trafficking of nuclear-encoded mitochondrial mRNAs in neuronal physiology and animal behavior. PMID- 24151255 TI - Involvement of nuclear JAK2 signaling in AG490-induced apoptosis of gastric cancer cells. AB - Although JAK2 inhibitors can result in antitumor activity against various tumors, some tumors have showed insensitivity or resistance to the inhibitors. To investigate the possible mechanisms underlying responses of gastric cancer (GC) cells to AG490, a specific JAK2 inhibitor, human GC cell lines SGC7901 and AGS were used. AG490 did not significantly induce apoptosis in SGC7901 cells, but it did in AGS cells. Interestingly, in SGC7901 cells, AG490 led to increased nuclear translocation of total JAK2 proteins, accompanied with initial inactivation but later reactivation of JAK2. However, in AGS cells, AG490 led to decreased nuclear localization of total JAK2 proteins, accompanied with sustained inactivation of JAK2. Moreover, silencing of human homolog of Drosophila Hairy and enhancer of split (Hes) 1 with siRNA partly blocked AG490-induced nuclear translocation of JAK2, and enhanced AG490-induced apoptosis in SGC7901 cells. The results collectively suggested that nuclear JAK2 signaling pathway may act as an escape way from JAK2 inhibitors in some GC cells. PMID- 24151256 TI - Profound methyl effects in drug discovery and a call for new C-H methylation reactions. AB - The methyl group is one of the most commonly occurring carbon fragments in small molecule drugs. This simplest alkyl fragment appears in more than 67 % of the top selling drugs of 2011 and can modulate both the biological and physical properties of a molecule. This Review focuses on so-called magic methyl effects on binding potency, where the seemingly mundane change of C?H to C?Me improves the IC50 value of a drug candidate more than 100-fold. This discussion is followed by a survey of recent advances in synthetic chemistry that allow the direct methylation of C(sp(2) )?H and C(sp(3) )?H bonds. It is our hope that the relevance of the meager methyl group to drug discovery as presented herein will inspire reports on new C?H methylation reactions. PMID- 24151257 TI - A reverse supply chain can enhance waste management programmes. PMID- 24151254 TI - Early illness features associated with mortality in the juvenile idiopathic inflammatory myopathies. AB - OBJECTIVE: Because juvenile idiopathic inflammatory myopathies (IIMs) are potentially life-threatening systemic autoimmune diseases, we examined risk factors for juvenile IIM mortality. METHODS: Mortality status was available for 405 patients (329 with juvenile dermatomyositis [DM], 30 with juvenile polymyositis [PM], and 46 with juvenile connective tissue disease-associated myositis [CTM]) enrolled in nationwide protocols. Standardized mortality ratios (SMRs) were calculated using US population statistics. Cox regression analysis was used to assess univariable associations with mortality, and random survival forest (RSF) classification and Cox regression analysis were used for multivariable associations. RESULTS: Of 17 deaths (4.2% overall mortality), 8 (2.4%) were in juvenile DM patients. Death was related to the pulmonary system (primarily interstitial lung disease [ILD]) in 7 patients, gastrointestinal system in 3, and multisystem in 3, and of unknown etiology in 4 patients. The SMR for juvenile IIMs overall was 14.4 (95% confidence interval [95% CI] 12.2-16.5) and was 8.3 (95% CI 6.4-10.3) for juvenile DM. The top mortality risk factors in the univariable analysis included clinical subgroup (juvenile CTM, juvenile PM), antisynthetase autoantibodies, older age at diagnosis, ILD, and Raynaud's phenomenon at diagnosis. In multivariable analyses, clinical subgroup, illness severity at onset, age at diagnosis, weight loss, and delay to diagnosis were the most important predictors from RSF; clinical subgroup and illness severity at onset were confirmed by multivariable Cox regression analysis. CONCLUSION: Overall mortality was higher in juvenile IIM patients, and several early illness features were identified as risk factors. Clinical subgroup, antisynthetase autoantibodies, older age at diagnosis, and ILD are also recognized as mortality risk factors in adult myositis. PMID- 24151258 TI - Is this the era of consensus? PMID- 24151259 TI - Intention-to-treat analyses for interventional studies. PMID- 24151260 TI - Reflections on current methods for evaluating skills during joint replacement surgery: a scoping review. AB - Valid and reliable techniques for assessing performance are essential to surgical education, especially with the emergence of competency-based frameworks. Despite this, there is a paucity of adequate tools for the evaluation of skills required during joint replacement surgery. In this scoping review, we examine current methods for assessing surgeons' competency in joint replacement procedures in both simulated and clinical environments. The ability of many of the tools currently in use to make valid, reliable and comprehensive assessments of performance is unclear. Furthermore, many simulation-based assessments have been criticised for a lack of transferability to the clinical setting. It is imperative that more effective methods of assessment are developed and implemented in order to improve our ability to evaluate the performance of skills relating to total joint replacement. This will enable educators to provide formative feedback to learners throughout the training process to ensure that they have attained core competencies upon completion of their training. This should help ensure positive patient outcomes as the surgical trainees enter independent practice. PMID- 24151261 TI - Proceedings of the International Consensus on Periprosthetic Joint Infection. AB - Louis Pasteur once said that: "Fortune favours the prepared mind." As one of the great scientists who contributed to the fight against infection, he emphasised the importance of being prepared at all times to recognise infection and deal with it. Despite the many scientific discoveries and technological advances, such as the advent of antibiotics and the use of sterile techniques, infection continues to be a problem that haunts orthopaedic surgeons and inflicts suffering on patients. The medical community has implemented many practices with the intention of preventing infection and treating it effectively when it occurs. Although high-level evidence may support some of these practices, many are based on little to no scientific foundation. Thus, around the world, there is great variation in practices for the prevention and management of periprosthetic joint infection. This paper summaries the instigation, conduct and findings of a recent International Consensus Meeting on Surgical Site and Periprosthetic Joint Infection. PMID- 24151262 TI - The blood supply to the femoral head after posterior fracture/dislocation of the hip, assessed by CT angiography. AB - The femoral head receives blood supply mainly from the deep branch of the medial femoral circumflex artery (MFCA). In previous studies we have performed anatomical dissections of 16 specimens and subsequently visualised the arteries supplying the femoral head in 55 healthy individuals. In this further radiological study we compared the arterial supply of the femoral head in 35 patients (34 men and one woman, mean age 37.1 years (16 to 64)) with a fracture/dislocation of the hip with a historical control group of 55 hips. Using CT angiography, we identified the three main arteries supplying the femoral head: the deep branch and the postero-inferior nutrient artery both arising from the MFCA, and the piriformis branch of the inferior gluteal artery. It was possible to visualise changes in blood flow after fracture/dislocation. Our results suggest that blood flow is present after reduction of the dislocated hip. The deep branch of the MFCA was patent and contrast-enhanced in 32 patients, and the diameter of this branch was significantly larger in the fracture/dislocation group than in the control group (p = 0.022). In a subgroup of ten patients with avascular necrosis (AVN) of the femoral head, we found a contrast-enhanced deep branch of the MFCA in eight hips. Two patients with no blood flow in any of the three main arteries supplying the femoral head developed AVN. PMID- 24151263 TI - Improving pre-operative planning for complex total hip replacement with a Rapid Prototype model enabling surgical simulation. AB - Pre-operative planning for total hip replacement (THR) is challenging in hips with severe acetabular deformities, including those with a hypoplastic acetabulum or severe defects and in the presence of arthrodesis or ankylosis. We evaluated whether a Rapid Prototype (RP) model, which is a life-sized reproduction based on three-dimensional CT scans, can determine the feasibility of THR and provide information about the size and position of the acetabular component in severe acetabular deformities. THR was planned using an RP model in 21 complex hips in five men (five hips) and 16 women (16 hips) with a mean age of 47.7 years (24 to 70) at operation. An acetabular component was implanted successfully and THR completed in all hips. The acetabular component used was within 2 mm of the predicted size in 17 hips (80.9%). All of the acetabular components and femoral stems had radiological evidence of bone ingrowth and stability at the final follow-up, without any detectable wear or peri-prosthetic osteolysis. The RP model allowed a simulated procedure pre-operatively and was helpful in determining the feasibility of THR pre-operatively, and to decide on implant type, size and position in complex THRs. PMID- 24151264 TI - Metal-on-metal hip resurfacing compared with 28-mm diameter metal-on-metal total hip replacement: a randomised study with six to nine years' follow-up. AB - A total of 219 hips in 192 patients aged between 18 and 65 years were randomised to 28-mm metal-on-metal uncemented total hip replacements (THRs, 107 hips) or hybrid hip resurfacing (HR, 112 hips). At a mean follow-up of eight years (6.6 to 9.3) there was no significant difference between the THR and HR groups regarding rate of revision (4.0% (4 of 99) vs 5.8% (6 of 104), p = 0.569) or re-operation rates without revision (5.1% (5 of 99) vs 2.9% (3 of 104), p = 0.428). In the THR group one recurrent dislocation, two late deep infections and one peri-prosthetic fracture required revision, whereas in the HR group five patients underwent revision for femoral head loosening and one for adverse reaction to metal debris. The mean University of California, Los Angeles activity scores were significantly higher in HR (7.5 (sd 1.7) vs 6.9 (sd 1.7), p = 0.035), but similar mean Western Ontario and McMaster Universities Osteoarthritis Index scores were obtained (5.8 (sd 9.5) in HR vs 5.1 (sd 8.9) in THR, p = 0.615) at the last follow-up. Osteolysis was found in 30 of 81 THR patients (37.4%), mostly in the proximal femur, compared with two of 83 HR patients (2.4%) (p < 0.001). At five years the mean metal ion levels were < 2.5 MUg/l for cobalt and chromium in both groups; only titanium was significantly higher in the HR group (p = 0.001). Although revision rates and functional scores were similar in both groups at mid-term, long-term survival analysis is necessary to determine whether one procedure is more advantageous than the other. PMID- 24151265 TI - Adverse peri-operative outcomes following elective total hip replacement in diabetes mellitus: a systematic review and meta-analysis of cohort studies. AB - Total hip replacement (THR) has been shown to be a cost-effective procedure. However, it is not risk-free. Certain conditions, such as diabetes mellitus, are thought to increase the risk of complications. In this study we have evaluated the prevalence of diabetes mellitus in patients undergoing THR and the associated risk of adverse operative outcomes. A meta-analysis and systematic review were conducted according to the guidelines of the meta-analysis of observational studies in epidemiology. Inclusion criteria were observational studies reporting the prevalence of diabetes in the study population, accompanied by reports of at least one of the following outcomes: venous thromboembolic events; acute coronary events; infections of the urinary tract, lower respiratory tract or surgical site; or requirement for revision arthroplasty. Altman and Bland's methods were used to calculate differences in relative risks. The prevalence of diabetes mellitus was found to be 5.0% among patients undergoing THR, and was associated with an increased risk of established surgical site infection (odds ratio (OR) 2.04 (95% confidence interval (CI) 1.52 to 2.76)), urinary infection (OR 1.43 (95% CI 1.33 to 1.55)) and lower respiratory tract infections (OR 1.95 (95% CI 1.61 to 2.26)). Diabetes mellitus is a relatively common comorbidity encountered in THR. Diabetic patients have a higher rate of developing both surgical site and non-surgical site infections following THR. PMID- 24151267 TI - Meeting increased demand for total knee replacement and follow-up: determining optimal follow-up. AB - The strain on clinic and surgeon resources resulting from a rise in demand for total knee replacement (TKR) requires reconsideration of when and how often patients need to be seen for follow-up. Surgeons will otherwise require increased paramedical staff or need to limit the number of TKRs they undertake. We reviewed the outcome data of 16 414 primary TKRs undertaken at our centre to determine the time to re-operation for any reason and for specific failure mechanisms. Peak risk years for failure were determined by comparing the conditional probability of failure, the number of failures divided by the total number of TKRs cases, for each year. The median times to failure for the most common failure mechanisms were 4.9 years (interquartile range (IQR) 1.7 to 10.7) for femoral and tibial loosening, 1.9 years (IQR 0.8 to 3.9) for infection, 3.1 years (IQR 1.6 to 5.5) for tibial collapse and 5.6 years (IQR 3.4 to 9.3) for instability. The median time to failure for all revisions was 3.3 years (IQR 1.2 to 8.5), with an overall revision rate of 1.7% (n = 282). Results from our patient population suggest that patients be seen for follow-up at six months, one year, three years, eight years, 12 years, and every five years thereafter. Patients with higher pain in the early post-operative period or high body mass index (>= 41 kg/m(2)) should be monitored more closely. PMID- 24151266 TI - The effect of the Oxford uncemented medial compartment arthroplasty on the bone mineral density and content of the proximal tibia. AB - We studied the bone mineral density (BMD) and the bone mineral content (BMC) of the proximal tibia in patients with a well-functioning uncemented Oxford medial compartment arthroplasty using the Lunar iDXA bone densitometer. Our hypothesis was that there would be decreased BMD and BMC adjacent to the tibial base plate and increased BMD and BMC at the tip of the keel. There were 79 consecutive patients (33 men, 46 women) with a mean age of 65 years (44 to 84) with a minimum two-year follow-up (mean 2.6 years (2.0 to 5.0)) after unilateral arthroplasty, who were scanned using a validated standard protocol where seven regions of interest (ROI) were examined and compared with the contralateral normal knee. All had well-functioning knees with a mean Oxford knee score of 43 (14 to 48) and mean Knee Society function score of 90 (20 to 100), showing a correlation with the increasing scores and higher BMC and BMD values in ROI 2 in the non-implanted knee relative to the implanted knee (p = 0.013 and p = 0.015, respectively). The absolute and percentage changes in BMD and BMC were decreased in all ROIs in the implanted knee compared with the non-implanted knee, but this did not reach statistical significance. Bone loss was markedly less than reported losses with total knee replacement. There was no significant association with side, although there was a tendency for the BMC to decrease with age in men. The BMC was less in the implanted side relative to the non-implanted side in men compared with women in ROI 2 (p = 0.027), ROI 3 (p = 0.049) and ROI 4 (p = 0.029). The uncemented Oxford medial compartment arthroplasty appears to allow relative preservation of the BMC and BMD of the proximal tibia, suggesting that the implant acts more physiologically than total knee replacement. Peri-prosthetic bone loss is an important factor in assessing long-term implant stability and survival, and the results of this study are encouraging for the long-term outcome of this arthroplasty. PMID- 24151268 TI - A prediction model for length of stay after total and unicompartmental knee replacement. AB - Early and accurate prediction of hospital length-of-stay (LOS) in patients undergoing knee replacement is important for economic and operational reasons. Few studies have systematically developed a multivariable model to predict LOS. We performed a retrospective cohort study of 1609 patients aged >= 50 years who underwent elective, primary total or unicompartmental knee replacements. Pre operative candidate predictors included patient demographics, knee function, self reported measures, surgical factors and discharge plans. In order to develop the model, multivariable regression with bootstrap internal validation was used. The median LOS for the sample was four days (interquartile range 4 to 5). Statistically significant predictors of longer stay included older age, greater number of comorbidities, less knee flexion range of movement, frequent feelings of being down and depressed, greater walking aid support required, total (versus unicompartmental) knee replacement, bilateral surgery, low-volume surgeon, absence of carer at home, and expectation to receive step-down care. For ease of use, these ten variables were used to construct a nomogram-based prediction model which showed adequate predictive accuracy (optimism-corrected R(2) = 0.32) and calibration. If externally validated, a prediction model using easily and routinely obtained pre-operative measures may be used to predict absolute LOS in patients following knee replacement and help to better manage these patients. PMID- 24151269 TI - The long-term outcome of uncemented Low Contact Stress total knee replacement in patients with rheumatoid arthritis: results at a mean of 22 years. AB - We reviewed the long-term clinical and radiological results of 63 uncemented Low Contact Stress (LCS) total knee replacements (TKRs) in 47 patients with rheumatoid arthritis. The mean age of the patients at the time of surgery was 69 years (53 to 81). At a mean follow-up of 22 years (20 to 25), 12 patients were alive (17 TKRs), 27 had died (36 TKRs), and eight (ten TKRs) were lost to follow up. Revision was necessary in seven patients (seven TKRs, 11.1%) at a mean of 12.1 years (0 to 19) after surgery. In the surviving ten patients who had not undergone revision (15 TKRs), the mean Oxford knee score was 30.2 (16 to 41) at a mean follow-up of 19.5 years (15 to 24.7) and mean active flexion was 105 degrees (90 degrees to 150 degrees ). The survival rate was 88.9% at 20 years (56 of 63) and the Kaplan-Meier survival estimate, without revision, was 80.2% (95% confidence interval 37 to 100) at 25 years. PMID- 24151270 TI - The outcome of total ankle replacement: a systematic review and meta-analysis. AB - We performed a systematic review and meta-analysis of modern total ankle replacements (TARs) to determine the survivorship, outcome, complications, radiological findings and range of movement, in patients with end-stage osteoarthritis (OA) of the ankle who undergo this procedure. We used the methodology of the Cochrane Collaboration, which uses risk of bias profiling to assess the quality of papers in favour of a domain-based approach. Continuous outcome scores were pooled across studies using the generic inverse variance method and the random-effects model was used to incorporate clinical and methodological heterogeneity. We included 58 papers (7942 TARs) with an interobserver reliability (Kappa) for selection, performance, attrition, detection and reporting bias of between 0.83 and 0.98. The overall survivorship was 89% at ten years with an annual failure rate of 1.2% (95% confidence interval (CI) 0.7 to 1.6). The mean American Orthopaedic Foot and Ankle Society score changed from 40 (95% CI 36 to 43) pre-operatively to 80 (95% CI 76 to 84) at a mean follow-up of 8.2 years (7 to 10) (p < 0.01). Radiolucencies were identified in up to 23% of TARs after a mean of 4.4 years (2.3 to 9.6). The mean total range of movement improved from 23 degrees (95% CI 19 to 26) to 34 degrees (95% CI 26 to 41) (p = 0.01). Our study demonstrates that TAR has a positive impact on patients' lives, with benefits lasting ten years, as judged by improvement in pain and function, as well as improved gait and increased range of movement. However, the quality of evidence is weak and fraught with biases and high quality randomised controlled trials are required to compare TAR with other forms of treatment such as fusion. PMID- 24151271 TI - The effect of a Galeazzi fracture on the strength of pronation and supination two years after surgical treatment. AB - The aim of this study was to determine the effect of a Galeazzi fracture on the strength of pronation and supination at a mean of two years after surgical treatment. The strength of pronation and supination was measured in varying rotational positions of the forearm of ten male patients (mean age 38.9 years (21 to 64)) who had undergone plate fixation for a Galeazzi fracture. The stability of the distal radioulnar joint was assessed, and a clinical assessment using the quick-Disabilities of the Arm Shoulder and Hand (quickDASH) questionnaire and patient-related wrist examination (PRWE) scores was undertaken. In addition, the strength of pronation and supination was measured in a male control group of 42 healthy volunteers (mean age 21.8 years (18 to 37)). The mean absolute loss of strength of supination in the injured compared with the non-injured arm throughout all ranges of forearm rotation was 16.1 kg (sem 5.3), corresponding to a relative loss of 12.5% (95% confidence interval (CI) 3.6 to 21.4). For the strength of pronation, the mean loss was 19.1 kg (sem 4.5), corresponding to a relative loss of 27.2% (95% CI 14.2 to 40.1). Loss of strength of supination following a Galeazzi fracture correlated with poor quickDASH (p = 0.03) and PRWE scores (p < 0.01). Loss of strength of pronation (27.2%), and of supination (12.5%) in particular, after a Galeazzi fracture is associated with worse clinical scores, highlighting the importance of supination of the forearm in function of the upper limb. PMID- 24151272 TI - An investigation of the effect of AlloMatrix bone graft in distal radial fracture: a prospective randomised controlled clinical trial. AB - The osteoinductive properties of demineralised bone matrix have been demonstrated in animal studies. However, its therapeutic efficacy has yet to be proven in humans. The clinical properties of AlloMatrix, an injectable calcium-based demineralised bone matrix allograft, were studied in a prospective randomised study of 50 patients with an isolated unstable distal radial fracture treated by reduction and Kirschner (K-) wire fixation. A total of 24 patients were randomised to the graft group (13 men and 11 women, mean age 42.3 years (20 to 62)) and 26 to the no graft group (8 men and 18 women, mean age 45.0 years (17 to 69)). At one, three, six and nine weeks, and six and 12 months post-operatively, patients underwent radiological evaluation, assessments for range of movement, grip and pinch strength, and also completed the Disabilities of Arm, Shoulder and Hand questionnaire. At one and six weeks and one year post-operatively, bone mineral density evaluations of both wrists were performed. No significant difference in wrist function and speed of recovery, rate of union, complications or bone mineral density was found between the two groups. The operating time was significantly higher in the graft group (p = 0.004). Radiologically, the reduction parameters remained similar in the two groups and all AlloMatrix extraosseous leakages disappeared after nine weeks. This prospective randomised controlled trial did not demonstrate a beneficial effect of AlloMatrix demineralised bone matrix in the treatment of this category of distal radial fractures treated by K-wire fixation. PMID- 24151273 TI - Radial extracorporeal shock-wave therapy in patients with chronic rotator cuff tendinitis: a prospective randomised double-blind placebo-controlled multicentre trial. AB - The aim of this study was to determine the effect of radial extracorporeal shock wave therapy (rESWT) on patients with chronic tendinitis of the rotator cuff. This was a randomised controlled trial in which 82 patients (mean age 47 years (24 to 67)) with chronic tendinitis diagnosed clinically were randomly allocated to a treatment group who received low-dose rESWT (three sessions at an interval 10 to 14 days, 2000 pulses, 0.11 mJ/mm(2), 8 Hz) or to a placebo group, with a follow-up of six months. The patients and the treating orthopaedic surgeon, who were both blinded to the treatment, evaluated the results. A total of 44 patients were allocated to the rESWT group and 38 patients to the placebo group. A visual analogue scale (VAS) score for pain, a Constant-Murley (CMS) score and a simple shoulder test (SST) score significantly improved in both groups at three and six months compared with baseline (all p <= 0.012). The mean VAS was similar in both groups at three (p = 0.43) and six months (p = 0.262). Also, the mean CMS and SST scores were similar in both groups at six months (p = 0.815 and p = 0.834, respectively). It would thus seem that low-dose rESWT does not reduce pain or improve function in patients chronic rotator cuff tendinitis compared with placebo treatment. PMID- 24151274 TI - Surgical treatment of severe congenital thoracolumbar kyphosis through a single posterior approach. AB - A combined anterior and posterior surgical approach is generally recommended in the treatment of severe congenital kyphosis, despite the fact that the anterior vascular supply of the spine and viscera are at risk during exposure. The aim of this study was to determine whether the surgical treatment of severe congenital thoracolumbar kyphosis through a single posterior approach is feasible, safe and effective. We reviewed the records of ten patients with a mean age of 11.1 years (5.4 to 14.1) who underwent surgery either by pedicle subtraction osteotomy or by vertebral column resection with instrumented fusion through a single posterior approach. The mean kyphotic deformity improved from 59.9 degrees (45 degrees to 110 degrees ) pre-operatively to 17.5 degrees (3 degrees to 40 degrees ) at a mean follow-up of 47.0 months (29 to 85). Spinal cord monitoring was used in all patients and there were no complications during surgery. These promising results indicate the possible advantages of the described technique over the established procedures. We believe that surgery should be performed in case of documented progression and before structural secondary curves develop. Our current strategy after documented progression is to recommend surgery at the age of five years and when 90% of the diameter of the spinal canal has already developed. PMID- 24151275 TI - A reliable measurement for identifying a lumbosacral transitional vertebra with a solid bony bridge on a single-slice midsagittal MRI or plain lateral radiograph. AB - The purpose of this study was to devise a simple but reliable radiological method of identifying a lumbosacral transitional vertebra (LSTV) with a solid bony bridge on sagittal MRI, which could then be applied to a lateral radiograph. The vertical mid-vertebral angle (VMVA) and the vertical anterior vertebral angle (VAVA) of the three most caudal segments of the lumbar spine were measured on MRI and/or on a lateral radiograph in 92 patients with a LSTV and 94 controls, and the differences per segment (Diff-VMVA and Diff-VAVA) were calculated. The Diff VMVA of the two most caudal vertebrae was significantly higher in the control group (25 degrees (sd 8) than in patients with a LSTV (type 2a+b: 16 degrees (SD 9), type 3a+b: -9 degrees (SD 10), type 4: -5 degrees (SD 7); p < 0.001). A Diff-VMVA of <= +10 degrees identified a LSTV with a solid bony bridge (type 3+4) with a sensitivity of 100% and a specificity of 89% on MRI and a sensitivity of 94% and a specificity of 74% on a lateral radiograph. A sensitivity of 100% could be achieved with a cut-off value of 28 degrees for the Diff-VAVA, but with a lower specificity (76%) on MRI than with Diff-VMVA. Using this simple method (Diff-VMVA <= +10 degrees ), solid bony bridging of the posterior elements of a LSTV, and therefore the first adjacent mobile segment, can be easily identified without the need for additional imaging. PMID- 24151276 TI - Corail uncemented hemiarthroplasty with a Cathcart head for intracapsular hip fractures. AB - The National Institute for Health and Clinical Excellence (NICE) guidelines from 2011 recommend the use of cemented hemi-arthroplasty for appropriate patients with an intracapsular hip fracture. In our institution all patients who were admitted with an intracapsular hip fracture and were suitable for a hemi arthroplasty between April 2010 and July 2012 received an uncemented prosthesis according to our established departmental routine practice. A retrospective analysis of outcome was performed to establish whether the continued use of an uncemented stem was justified. Patient, surgical and outcome data were collected on the National Hip Fracture database. A total of 306 patients received a Cathcart modular head on a Corail uncemented stem as a hemi-arthroplasty. The mean age of the patients was 83.3 years (SD 7.56; 46.6 to 94) and 216 (70.6%) were women. The mortality rate at 30 days was 5.8%. A total of 46.5% of patients returned to their own home by 30 days, which increased to 73.2% by 120 days. The implant used as a hemi-arthroplasty for intracapsular hip fracture provided satisfactory results, with a good rate of return to pre-injury place of residence and an acceptable mortality rate. Surgery should be performed by those who are familiar with the design of the stem and understand what is required for successful implantation. PMID- 24151277 TI - Effect of early administration of alendronate after surgery for distal radial fragility fracture on radiological fracture healing time. AB - This multicentre prospective clinical trial aimed to determine whether early administration of alendronate (ALN) delays fracture healing after surgical treatment of fractures of the distal radius. The study population comprised 80 patients (four men and 76 women) with a mean age of 70 years (52 to 86) with acute fragility fractures of the distal radius requiring open reduction and internal fixation with a volar locking plate and screws. Two groups of 40 patients each were randomly allocated either to receive once weekly oral ALN administration (35 mg) within a few days after surgery and continued for six months, or oral ALN administration delayed until four months after surgery. Postero-anterior and lateral radiographs of the affected wrist were taken monthly for six months after surgery. No differences between groups was observed with regard to gender (p = 1.0), age (p = 0.916), fracture classification (p = 0.274) or bone mineral density measured at the spine (p = 0.714). The radiographs were assessed by three independent assessors. There were no significant differences in the mean time to complete cortical bridging observed between the ALN group (3.5 months (SE 0.16)) and the no-ALN group (3.1 months (SE 0.15)) (p = 0.068). All the fractures healed in the both groups by the last follow-up. Improvement of the Quick-Disabilities of the Arm, Shoulder and Hand (QuickDASH) score, grip strength, wrist range of movement, and tenderness over the fracture site did not differ between the groups over the six-month period. Based on our results, early administration of ALN after surgery for distal radius fracture did not appear to delay fracture healing times either radiologically or clinically. PMID- 24151278 TI - Reverse shoulder replacement after resection of the proximal humerus for bone tumours. AB - We investigated the functional outcome in patients who underwent reverse shoulder replacement (RSR) after removal of a tumour of the proximal humerus. A total of 16 patients (ten women and six men) underwent this procedure between 1998 and 2011 in our hospital. Five patients died and one was lost to follow-up. Ten patients were available for review at a mean follow-up of 46 months (12 to 136). Eight patients had a primary and two patients a secondary bone tumour. At final follow up the mean range of active movement was: abduction 78 degrees (30 degrees to 150 degrees ); flexion 98 degrees (45 degrees to 180 degrees ); external rotation 32 degrees (10 degrees to 60 degrees ); internal rotation 51 degrees (10 degrees to 80 degrees ). The mean Musculoskeletal Tumor Society score was 77% (60% to 90%) and the mean Toronto Extremity Salvage Score was 70% (30% to 91%). Two patients had a superficial infection and one had a deep infection and underwent a two-stage revision procedure. In two patients there was loosening of the RSR; one dislocated twice. All patients had some degree of atrophy or pseudo-atrophy of the deltoid muscle. Use of a RSR in patients with a tumour of the proximal humerus gives acceptable results. PMID- 24151279 TI - Oral versus intravenous tranexamic acid in enhanced-recovery primary total hip and knee replacement: results of 3000 procedures. AB - In our department we use an enhanced recovery protocol for joint replacement of the lower limb. This incorporates the use of intravenous tranexamic acid (IVTA; 15 mg/kg) at the induction of anaesthesia. Recently there was a national shortage of IVTA for 18 weeks; during this period all patients received an oral preparation of tranexamic acid (OTA; 25 mg/kg). This retrospective study compares the safety (surgical and medical complications) and efficacy (reduction of transfusion requirements) of OTA and IVTA. During the study period a total of 2698 patients received IVTA and 302 received OTA. After adjusting for a range of patient and surgical factors, the odds ratio (OR) of receiving a blood transfusion was significantly higher with IVTA than with OTA (OR 0.48 (95% confidence interval 0.26 to 0.89), p = 0.019), whereas the safety profile was similar, based on length of stay, rate of readmission, return to theatre, deep infection, stroke, gastrointestinal bleeding, myocardial infarction, pneumonia, deep-vein thrombosis and pulmonary embolism. The financial benefit of OTA is L2.04 for a 70 kg patient; this is amplified when the cost saving associated with significantly fewer blood transfusions is considered. Although the number of patients in the study is modest, this work supports the use of OTA, and we recommend that a randomised trial be undertaken to compare the different methods of administering tranexamic acid. PMID- 24151280 TI - Current concepts of the management of anterior cruciate ligament injuries in children. AB - Recent reports have suggested an increase in the number of anterior cruciate ligament (ACL) injuries in children, although their true incidence is unknown. The prognosis of the ACL-deficient knee in young active individuals is poor because of secondary meniscal tears, persistent instability and early-onset osteoarthritis. The aim of surgical reconstruction is to provide stability while avoiding physeal injury. Techniques of reconstruction include transphyseal, extraphyseal or partial physeal sparing procedures. In this paper we review the management of ACL tears in skeletally immature patients. PMID- 24151281 TI - Ponseti casting for club foot - above- or below-knee?: A prospective randomised clinical trial. AB - We undertook a randomised clinical trial to compare treatment times and failure rates between above- and below-knee Ponseti casting groups. Eligible children with idiopathic clubfoot, treated using the Ponseti method, were randomised to either below- or above-knee plaster of Paris casting. Outcome measures were total treatment time and the occurrence of failure, defined as two slippages or a treatment time above eight weeks. A total of 26 children (33 feet) were entered into the trial. The above-knee group comprised 17 feet in 13 children (ten boys and three girls, median age 13 days (1 to 40)) and the below-knee group comprised 16 feet in 13 children (ten boys and three girls, median age 13 days (5 to 20)). Because of six failures (37.5%) in the below-knee group, the trial was stopped early for ethical reasons. The rate of failure was significantly higher in the below-knee group (p = 0.039). The median treatment times of six weeks in the below-knee and four weeks in the above-knee group differed significantly (p = 0.01). This study demonstrates that the use of a below-knee plaster of Paris cast in conjunction with the Ponseti technique leads to unacceptably high failure rates and significantly longer treatment times. Therefore, this technique is not recommended. PMID- 24151282 TI - Effects of commonly used medications on bone tissue mineralisation in SaOS-2 human bone cell line: an in vitro study. AB - We analysed the effects of commonly used medications on human osteoblastic cell activity in vitro, specifically proliferation and tissue mineralisation. A list of medications was retrieved from the records of patients aged > 65 years filed in the database of the largest health maintenance organisation in our country (> two million members). Proliferation and mineralisation assays were performed on the following drugs: rosuvastatin (statin), metformin (antidiabetic), metoprolol (beta-blocker), citalopram (selective serotonin reuptake inhibitor [SSRI]), and omeprazole (proton pump inhibitor (PPI)). All tested drugs significantly stimulated DNA synthesis to varying degrees, with rosuvastatin 5 ug/ml being the most effective among them (mean 225% (SD 20)), compared with metformin 10 ug/ml (185% (SD 10)), metoprolol 0.25 ug/ml (190% (SD 20)), citalopram 0.05 ug/ml (150% (sd 10)) and omeprazole 0.001 ug/ml (145% (SD 5)). Metformin and metoprolol (to a small extent) and rosuvastatin (to a much higher extent) inhibited cell mineralisation (85% (SD 5)). Our results indicate the need to evaluate the medications prescribed to patients in terms of their potential action on osteoblasts. Appropriate evaluation and prophylactic treatment (when necessary) might lower the incidence and costs associated with potential medication-induced osteoporosis. PMID- 24151283 TI - Response to: YaDeau JT, Goytizolo EA, Padgett DE, et al. Analgesia after total knee replacement: local infiltration versus epidural combined with a femoral nerve blockade. PMID- 24151285 TI - Exam corner--November 2013. AB - The FRCS (Tr & Orth) examination has three components: MCQs, Vivas and Clinical Examination. The Vivas are further divided into five sections comprising Basic Science, Adult Pathology, Hands, Children's Orthopaedics and Trauma. The Clinical Examination section is divided into upper- and lower-limb cases. The aim of this section in the Journal is to focus specifically on the trainees preparing for the exam and to cater to all the sections of the exam every month. The vision is to complete the cycle of all relevant exam topics (as per the syllabus) in four years. PMID- 24151286 TI - Injectable 3D hydrogel scaffold with tailorable porosity post-implantation. AB - Since rates of tissue growth vary significantly between tissue types, and also between individuals due to differences in age, dietary intake, and lifestyle related factors, engineering a scaffold system that is appropriate for personalized tissue engineering remains a significant challenge. In this study, a gelatin-hydroxyphenylpropionic acid/carboxylmethylcellulose-tyramine (Gtn-HPA/CMC Tyr) porous hydrogel system that allows the pore structure of scaffolds to be altered in vivo after implantation is developed. Cross-linking of Gtn-HPA/CMC-Tyr hydrogels via horseradish peroxidase oxidative coupling is examined both in vitro and in vivo. Post-implantation, further alteration of the hydrogel structure is achieved by injecting cellulase enzyme to digest the CMC component of the scaffold; this treatment yields a structure with larger pores and higher porosity than hydrogels without cellulase injection. Using this approach, the pore sizes of scaffolds are altered in vivo from 32-87 MUm to 74-181 MUm in a user-controled manner. The hydrogel is biocompatible to COS-7 cells and has mechanical properties similar to those of soft tissues. The new hydrogel system developed in this work provides clinicians with the ability to tailor the structure of scaffolds post-implantation depending on the growth rate of a tissue or an individual's recovery rate, and could thus be ideal for personalized tissue engineering. PMID- 24151287 TI - Birth defects after early pregnancy use of antithyroid drugs: a Danish nationwide study. AB - INTRODUCTION: Hyperthyroidism in pregnant women should be adequately treated to prevent maternal and fetal complications, but teratogenic effects of antithyroid drug (ATD) treatment have been described. Evidence is still lacking in regard to the safety and choice of ATD in early pregnancy. OBJECTIVE: Our objective was to determine to which degree the use of methimazole (MMI)/carbimazole (CMZ) and propylthiouracil (PTU) in early pregnancy is associated with an increased prevalence of birth defects. METHODS: This Danish nationwide register-based cohort study included 817 093 children live-born from 1996 to 2008. Exposure groups were assigned according to maternal ATD use in early pregnancy: PTU (n = 564); MMI/CMZ (n = 1097); MMI/CMZ and PTU (shifted in early pregnancy [n = 159]); no ATD (ATD use, but not in pregnancy [n = 3543]); and nonexposed (never ATD use [n = 811 730]). Multivariate logistic regression was used to estimate adjusted odds ratio (OR) with 95% confidence interval (95% CI) for diagnosis of a birth defect before 2 years of age in exposed versus nonexposed children. RESULTS: The prevalence of birth defects was high in children exposed to ATD in early pregnancy (PTU, 8.0%; MMI/CMZ, 9.1%; MMI/CMZ and PTU, 10.1%; no ATD, 5.4%; nonexposed, 5.7%; P < .001). Both maternal use of MMI/CMZ (adjusted OR = 1.66 [95% CI 1.35-2.04]) and PTU (1.41 [1.03-1.92]) and maternal shift between MMI/CMZ and PTU in early pregnancy (1.82 [1.08-3.07]) were associated with an increased OR of birth defects. MMI/CMZ and PTU were associated with urinary system malformation, and PTU with malformations in the face and neck region. Choanal atresia, esophageal atresia, omphalocele, omphalomesenteric duct anomalies, and aplasia cutis were common in MMI/CMZ-exposed children (combined, adjusted OR = 21.8 [13.4-35.4]). CONCLUSIONS: Both MMI/CMZ and PTU were associated with birth defects, but the spectrum of malformations differed. More studies are needed to corroborate results in regard to early pregnancy shift from MMI/CMZ to PTU. New ATD with fewer side effects should be developed. PMID- 24151288 TI - Screening for gestational diabetes: a systematic review and meta-analysis. AB - CONTEXT: Gestational diabetes mellitus (GDM) is defined as any degree of hyperglycemia with first recognition during pregnancy. The optimal time to screen for GDM that would maximize the yield and benefits remains unclear. OBJECTIVE: Our objective was to appraise the evidence regarding screening for GDM (accuracy, correlation with adverse outcomes, and harms). DATA SOURCES: We searched Ovid Medline, OVID EMBASE, OVID Cochrane Library, Web of Science, Scopus, PsycInfo, and CINAHL through May 2011. STUDY SELECTION: We included randomized controlled trials and observational studies that enrolled pregnant woman who were evaluated using different GDM screening tests. DATA EXTRACTION: Two reviewers working independently abstracted the data. RESULTS: We did not find any randomized controlled trials of GDM screening that measured feto-maternal outcomes. A 1-hour 50-g glucose challenge test with a cutoff point at 140 mg/dL was the most commonly used screening method. The results of this test were statistically associated with feto-maternal outcomes (P < .001), even though only 11% of individuals with a positive test (according to Carpenter and Coustan criteria) developed GDM. Positive Carpenter and Coustan criteria were associated with macrosomia (odds ratio [OR] = 2.4, 95% confidence interval [CI] = 1.9-3.1, P < .001) and gestational hypertension (OR = 1.7, CI = 1.3-2.1, P < .001). Positive National Diabetes Data Group criteria were also associated with macrosomia (OR = 3.2, CI = 2.3-4.4, P < .001) and gestational hypertension (OR = 2.1, CI = 1.6 2.8, P < .001). CONCLUSIONS: Indirect evidence supports the use of contemporary screening tests for GDM to identify pregnancies at increased risk of adverse feto maternal outcomes. It also suggests that use of these tests will place some women under unnecessary treatment for GDM. PMID- 24151289 TI - Glucose targets in pregnant women with diabetes: a systematic review and meta analysis. AB - BACKGROUND: Glucose-lowering treatments are used during pregnancy to reduce the risk for complications in the mother and offspring, yet treatment targets have not been established. OBJECTIVE: Our objective was to appraise and summarize the available evidence regarding the association between different blood glucose targets during pregnancy and fetal and maternal outcomes. METHODS: We searched Medline, EMBASE, Cochrane Library, Web of Science, Scopus, PsycInfo, and CINAHL through May 2011 for randomized trials and observational studies that enrolled women with diabetes during pregnancy and reported planned or achieved glucose targets. We used random-effects meta-regression models to estimate the odds ratio for the association of outcomes of interest and glucose targets. When possible, we adjusted for diabetes type, trimester, and diabetes treatment. RESULTS: We included 34 studies enrolling 9433 women. The studies had moderate to high risk of bias due to evidence of reporting bias and insufficient adjustment for important covariates, particularly maternal body mass index. A fasting glucose target of <90 mg/dL was the most commonly reported and the one most strongly associated with reduced risk of macrosomia (odds ratio = 0.53, 95% confidence interval = 0.31-0.90, P = .02) for women with gestational diabetes during the third trimester. For type 1 and type 2 diabetes, and for pre- and postprandial targets, data were sparse and inconclusive. CONCLUSIONS: Evidence warranting very low confidence in the estimates suggests that a fasting glucose target of <90 mg/dL is associated with a lower risk of macrosomia and other outcomes of different importance in women with gestational diabetes. Whether this target can be extrapolated to women with pregestational diabetes or whether targets above or below this threshold offer a better benefit/risk balance remains unclear. PMID- 24151291 TI - Cystic apocrine hyperplasia is the most common finding in MRI detected breast lesions. AB - MRI of the breast is an increasingly employed modality for breast imaging due to its relatively high sensitivity for the detection of breast carcinoma. Cumulative data indicate that MRI of the breast has relatively higher sensitivity, but lower specificity than mammography. However, data regarding the diagnostic yield for particular types of breast lesions detected via breast MRI remain scant. Over a 3.5-year period, we evaluated histological findings of 192 needle core biopsies of MRI detected breast lesions. In this series, the positive predictive value of MRI detected lesions for breast carcinoma was 20%. Invasive carcinoma was diagnosed in 16/192 (8%) and in situ carcinoma in 22/192 (11%). The most commonly detected histological finding was cystic apocrine hyperplasia (19%), a benign entity. PMID- 24151292 TI - A mediator of singlet oxygen responses in Chlamydomonas reinhardtii and Arabidopsis identified by a luciferase-based genetic screen in algal cells. AB - All cells produce reactive oxygen species (ROS) as by-products of their metabolism. In addition to being cytotoxic, ROS act as regulators of a wide range of developmental and physiological processes. Little is known about the molecular mechanisms underlying the perception of ROS and initiation of cellular responses in eukaryotes. Using the unicellular green alga Chlamydomonas reinhardtii, we developed a genetic screen for early components of singlet oxygen signaling. Here, we report the identification of a small zinc finger protein, methylene blue sensitivity (MBS), that is required for induction of singlet oxygen-dependent gene expression and, upon oxidative stress, accumulates in distinct granules in the cytosol. Loss-of-function mbs mutants produce singlet oxygen but are unable to fully respond to it at the level of gene expression. Knockout or knockdown of the homologous genes in the higher plant model Arabidopsis thaliana results in mutants that are hypersensitive to photooxidative stress, whereas overexpression produces plants with elevated stress tolerance. Together, our data indicate an important and evolutionarily conserved role of the MBS protein in ROS signaling and provide a strategy for engineering stress-tolerant plants. PMID- 24151290 TI - Diagnosis and treatment of polycystic ovary syndrome: an Endocrine Society clinical practice guideline. AB - OBJECTIVE: The aim was to formulate practice guidelines for the diagnosis and treatment of polycystic ovary syndrome (PCOS). PARTICIPANTS: An Endocrine Society appointed Task Force of experts, a methodologist, and a medical writer developed the guideline. EVIDENCE: This evidence-based guideline was developed using the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) system to describe both the strength of recommendations and the quality of evidence. CONSENSUS PROCESS: One group meeting, several conference calls, and e mail communications enabled consensus. Committees and members of The Endocrine Society and the European Society of Endocrinology reviewed and commented on preliminary drafts of these guidelines. Two systematic reviews were conducted to summarize supporting evidence. CONCLUSIONS: We suggest using the Rotterdam criteria for diagnosing PCOS (presence of two of the following criteria: androgen excess, ovulatory dysfunction, or polycystic ovaries). Establishing a diagnosis of PCOS is problematic in adolescents and menopausal women. Hyperandrogenism is central to the presentation in adolescents, whereas there is no consistent phenotype in postmenopausal women. Evaluation of women with PCOS should exclude alternate androgen-excess disorders and risk factors for endometrial cancer, mood disorders, obstructive sleep apnea, diabetes, and cardiovascular disease. Hormonal contraceptives are the first-line management for menstrual abnormalities and hirsutism/acne in PCOS. Clomiphene is currently the first-line therapy for infertility; metformin is beneficial for metabolic/glycemic abnormalities and for improving menstrual irregularities, but it has limited or no benefit in treating hirsutism, acne, or infertility. Hormonal contraceptives and metformin are the treatment options in adolescents with PCOS. The role of weight loss in improving PCOS status per se is uncertain, but lifestyle intervention is beneficial in overweight/obese patients for other health benefits. Thiazolidinediones have an unfavorable risk-benefit ratio overall, and statins require further study. PMID- 24151293 TI - A comprehensive mutational analysis of the Arabidopsis resistance protein RPW8.2 reveals key amino acids for defense activation and protein targeting. AB - The Arabidopsis thaliana resistance to powdery mildew8.2 (RPW8.2) protein is specifically targeted to the extrahaustorial membrane (EHM) encasing the haustorium, or fungal feeding structure, where RPW8.2 activates broad-spectrum resistance against powdery mildew pathogens. How RPW8.2 activates defenses at a precise subcellular locale is not known. Here, we report a comprehensive mutational analysis in which more than 100 RPW8.2 mutants were functionally evaluated for their defense and trafficking properties. We show that three amino acid residues (i.e., threonine-64, valine-68, and aspartic acid-116) are critical for RPW8.2-mediated cell death and resistance to powdery mildew (Golovinomyces cichoracearum UCSC1). Also, we reveal that two arginine (R)- or lysine (K) enriched short motifs (i.e., R/K-R/K-x-R/K) make up the likely core EHM-targeting signals, which, together with the N-terminal transmembrane domain, define a minimal sequence of 60 amino acids that is necessary and sufficient for EHM localization. In addition, some RPW8.2 mutants localize to the nucleus and/or to a potentially novel membrane that wraps around plastids or plastid-derived stromules. Results from this study not only reveal critical amino acid elements in RPW8.2 that enable haustorium-targeted trafficking and defense, but also provide evidence for the existence of a specific, EHM-oriented membrane trafficking pathway in leaf epidermal cells invaded by powdery mildew. PMID- 24151296 TI - Ethanolamide oxylipins: new players in seedling development. PMID- 24151294 TI - The importance of cardiolipin synthase for mitochondrial ultrastructure, respiratory function, plant development, and stress responses in Arabidopsis. AB - Cardiolipin (CL) is the signature phospholipid of the mitochondrial inner membrane. In animals and yeast (Saccharomyces cerevisiae), CL depletion affects the stability of respiratory supercomplexes and is thus crucial to the energy metabolism of obligate aerobes. In eukaryotes, the last step of CL synthesis is catalyzed by CARDIOLIPIN SYNTHASE (CLS), encoded by a single-copy gene. Here, we characterize a cls mutant in Arabidopsis thaliana, which is devoid of CL. In contrast to yeast cls, where development is little affected, Arabidopsis cls seedlings are slow developing under short-day conditions in vitro and die if they are transferred to long-day (LD) conditions. However, when transferred to soil under LD conditions under low light, cls plants can reach the flowering stage, but they are not fertile. The cls mitochondria display abnormal ultrastructure and reduced content of respiratory complex I/complex III supercomplexes. The marked accumulation of tricarboxylic acid cycle derivatives and amino acids demonstrates mitochondrial dysfunction. Mitochondrial and chloroplastic antioxidant transcripts are overexpressed in cls leaves, and cls protoplasts are more sensitive to programmed cell death effectors, UV light, and heat shock. Our results show that CLS is crucial for correct mitochondrial function and development in Arabidopsis under both optimal and stress conditions. PMID- 24151295 TI - The R2R3-MYB transcription factors MYB14 and MYB15 regulate stilbene biosynthesis in Vitis vinifera. AB - Plant stilbenes are phytoalexins that accumulate in a small number of plant species, including grapevine (Vitis vinifera), in response to biotic and abiotic stresses and have been implicated in many beneficial effects on human health. In particular, resveratrol, the basic unit of all other complex stilbenes, has received widespread attention because of its cardio-protective, anticarcinogenic, and antioxidant properties. Although stilbene synthases (STSs), the key enzymes responsible for resveratrol biosynthesis, have been isolated and characterized from several plant species, the transcriptional regulation underlying stilbene biosynthesis is unknown. Here, we report the identification and functional characterization of two R2R3-MYB-type transcription factors (TFs) from grapevine, which regulate the stilbene biosynthetic pathway. These TFs, designated MYB14 and MYB15, strongly coexpress with STS genes, both in leaf tissues under biotic and abiotic stress and in the skin and seed of healthy developing berries during maturation. In transient gene reporter assays, MYB14 and MYB15 were demonstrated to specifically activate the promoters of STS genes, and the ectopic expression of MYB15 in grapevine hairy roots resulted in increased STS expression and in the accumulation of glycosylated stilbenes in planta. These results demonstrate the involvement of MYB14 and MYB15 in the transcriptional regulation of stilbene biosynthesis in grapevine. PMID- 24151297 TI - Ethanolamide oxylipins of linolenic acid can negatively regulate Arabidopsis seedling development. AB - N-Acylethanolamines (NAEs) are fatty-acid derivatives with potent biological activities in a wide range of eukaryotic organisms. Polyunsaturated NAEs are among the most abundant NAE types in seeds of Arabidopsis thaliana, and they can be metabolized by either fatty acid amide hydrolase (FAAH) or by lipoxygenase (LOX) to low levels during seedling establishment. Here, we identify and quantify endogenous oxylipin metabolites of N-linolenoylethanolamine (NAE 18:3) in Arabidopsis seedlings and show that their levels were higher in faah knockout seedlings. Quantification of oxylipin metabolites in lox mutants demonstrated altered partitioning of NAE 18:3 into 9- or 13-LOX pathways, and this was especially exaggerated when exogenous NAE was added to seedlings. When maintained at micromolar concentrations, NAE 18:3 specifically induced cotyledon bleaching of light-grown seedlings within a restricted stage of development. Comprehensive oxylipin profiling together with genetic and pharmacological interference with LOX activity suggested that both 9-hydroxy and 13-hydroxy linolenoylethanolamides, but not corresponding free fatty-acid metabolites, contributed to the reversible disruption of thylakoid membranes in chloroplasts of seedling cotyledons. We suggest that NAE oxylipins of linolenic acid represent a newly identified, endogenous set of bioactive compounds that may act in opposition to progression of normal seedling development and must be depleted for successful establishment. PMID- 24151298 TI - Cell growth defect factor1/chaperone-like protein of POR1 plays a role in stabilization of light-dependent protochlorophyllide oxidoreductase in Nicotiana benthamiana and Arabidopsis. AB - Angiosperms require light for chlorophyll biosynthesis because one reaction in the pathway, the reduction of protochlorophyllide (Pchlide) to chlorophyllide, is catalyzed by the light-dependent protochlorophyllide oxidoreductase (POR). Here, we report that Cell growth defect factor1 (Cdf1), renamed here as chaperone-like protein of POR1 (CPP1), an essential protein for chloroplast development, plays a role in the regulation of POR stability and function. Cdf1/CPP1 contains a J-like domain and three transmembrane domains, is localized in the thylakoid and envelope membranes, and interacts with POR isoforms in chloroplasts. CPP1 can stabilize POR proteins with its holdase chaperone activity. CPP1 deficiency results in diminished POR protein accumulation and defective chlorophyll synthesis, leading to photobleaching and growth inhibition of plants under light conditions. CPP1 depletion also causes reduced POR accumulation in etioplasts of dark-grown plants and as a result impairs the formation of prolamellar bodies, which subsequently affects chloroplast biogenesis upon illumination. Furthermore, in cyanobacteria, the CPP1 homolog critically regulates POR accumulation and chlorophyll synthesis under high-light conditions, in which the dark-operative Pchlide oxidoreductase is repressed by its oxygen sensitivity. These findings and the ubiquitous presence of CPP1 in oxygenic photosynthetic organisms suggest the conserved nature of CPP1 function in the regulation of POR. PMID- 24151301 TI - Sodium in plants: perception, signalling, and regulation of sodium fluxes. AB - Although not essential for most plants, sodium (Na(+)) can be beneficial to plants in many conditions, particularly when potassium (K(+)) is deficient. As such it can be regarded a 'non-essential' or 'functional' nutrient. By contrast, the many salinized areas around the globe force plants to deal with toxicity from high levels of Na(+) in the environment and within tissues. Progress has been made in identifying the relevant membrane transporters involved in the uptake and distribution of Na(+). The latter is important in the context of mitigating salinity stress but also for the optimization of Na(+) as an abundantly available functional nutrient. In both cases plants are likely to require mechanism(s) to monitor Na(+) concentration, possibly in multiple compartments, to regulate gene expression and transport activities. Extremely little is known about whether such mechanisms are present and if so, how they operate, either at the cellular or the tissue level. This paper gives an overview of the regulatory and potential sensing mechanisms that pertain to Na(+), in both the context of salt stress and Na(+) as a nutrient. PMID- 24151300 TI - The family of Peps and their precursors in Arabidopsis: differential expression and localization but similar induction of pattern-triggered immune responses. AB - In Arabidopsis thaliana, the endogenous danger peptides, AtPeps, have been associated with plant defences reminiscent of those induced in pattern-triggered immunity. AtPeps are perceived by two homologous receptor kinases, PEPR1 and PEPR2, and are encoded in the C termini of the PROPEP precursors. Here, we report that, contrary to the seemingly redundant AtPeps, the PROPEPs fall at least into two distinct groups. As revealed by promoter-beta-glucuronidase studies, expression patterns of PROPEP1-3, -5, and -8 partially overlapped and correlated with those of the PEPR1 and -2 receptors, whereas those of PROPEP4 and -7 did not share any similarities with the former. Moreover, bi-clustering analysis indicated an association of PROPEP1, -2, and -3 with plant defence, whereas PROPEP5 expression was related to patterns of plant reproduction. In addition, at the protein level, PROPEPs appeared to be distinct. PROPEP3::YFP (fused to yellow fluorescent protein) was present in the cytosol, but, in contrast to previous predictions, PROPEP1::YFP and PROPEP6::YFP localized to the tonoplast. Together with the expression patterns, this could point to potentially non-redundant roles among the members of the PROPEP family. By contrast, their derived AtPeps, including the newly reported AtPep8, when applied exogenously, provoked activation of defence-related responses in a similar manner, suggesting a high level of functional redundancy between the AtPeps. Taken together, our findings reveal an apparent antagonism between AtPep redundancy and PROPEP variability, and indicate new roles for PROPEPs besides plant immunity. PMID- 24151299 TI - Evidence for a role of chloroplastic m-type thioredoxins in the biogenesis of photosystem II in Arabidopsis. AB - Chloroplastic m-type thioredoxins (TRX m) are essential redox regulators in the light regulation of photosynthetic metabolism. However, recent genetic studies have revealed novel functions for TRX m in meristem development, chloroplast morphology, cyclic electron flow, and tetrapyrrole synthesis. The focus of this study is on the putative role of TRX m1, TRX m2, and TRX m4 in the biogenesis of the photosynthetic apparatus in Arabidopsis (Arabidopsis thaliana). To that end, we investigated the impact of single, double, and triple TRX m deficiency on chloroplast development and the accumulation of thylakoid protein complexes. Intriguingly, only inactivation of three TRX m genes led to pale-green leaves and specifically reduced stability of the photosystem II (PSII) complex, implying functional redundancy between three TRX m isoforms. In addition, plants silenced for three TRX m genes displayed elevated levels of reactive oxygen species, which in turn interrupted the transcription of photosynthesis-related nuclear genes but not the expression of chloroplast-encoded PSII core proteins. To dissect the function of TRX m in PSII biogenesis, we showed that TRX m1, TRX m2, and TRX m4 interact physically with minor PSII assembly intermediates as well as with PSII core subunits D1, D2, and CP47. Furthermore, silencing three TRX m genes disrupted the redox status of intermolecular disulfide bonds in PSII core proteins, most notably resulting in elevated accumulation of oxidized CP47 oligomers. Taken together, our results suggest an important role for TRX m1, TRX m2, and TRX m4 proteins in the biogenesis of PSII, and they appear to assist the assembly of CP47 into PSII. PMID- 24151303 TI - Glutamate signalling in roots. AB - As a signalling molecule, glutamate is best known for its role as a fast excitatory neurotransmitter in the mammalian nervous system, a role that requires the activity of a family of ionotropic glutamate receptors (iGluRs). The unexpected discovery in 1998 that Arabidopsis thaliana L. possesses a family of iGluR-related (GLR) genes laid the foundations for an assessment of glutamate's potential role as a signalling molecule in plants that is still in progress. Recent advances in elucidating the function of Arabidopsis GLR receptors has revealed similarities with iGluRs in their channel properties, but marked differences in their ligand specificities. The ability of plant GLR receptors to act as amino-acid-gated Ca(2+) channels with a broad agonist profile, combined with their expression throughout the plant, makes them strong candidates for a multiplicity of amino acid signalling roles. Although root growth is inhibited in the presence of a number of amino acids, only glutamate elicits a specific sequence of changes in growth, root tip morphology, and root branching. The recent finding that the MEKK1 gene is a positive regulator of glutamate sensitivity at the root tip has provided genetic evidence for the existence in plants of a glutamate signalling pathway analogous to those found in animals. This short review will discuss the most recent advances in understanding glutamate signalling in roots, considering them in the context of previous work in plants and animals. PMID- 24151302 TI - Proteomics profiling reveals novel proteins and functions of the plant stigma exudate. AB - Proteomic analysis of the stigmatic exudate of Lilium longiflorum and Olea europaea led to the identification of 51 and 57 proteins, respectively, most of which are described for the first time in this secreted fluid. These results indicate that the stigmatic exudate is an extracellular environment metabolically active, participating in at least 80 different biological processes and 97 molecular functions. The stigma exudate showed a markedly catabolic profile and appeared to possess the enzyme machinery necessary to degrade large polysaccharides and lipids secreted by papillae to smaller units, allowing their incorporation into the pollen tube during pollination. It may also regulate pollen-tube growth in the pistil through the selective degradation of tube-wall components. Furthermore, some secreted proteins were involved in pollen-tube adhesion and orientation, as well as in programmed cell death of the papillae cells in response to either compatible pollination or incompatible pollen rejection. Finally, the results also revealed a putative cross-talk between genetic programmes regulating stress/defence and pollination responses in the stigma. PMID- 24151304 TI - Inhibition of nitrogen fixation in symbiotic Medicago truncatula upon Cd exposure is a local process involving leghaemoglobin. AB - Leguminous biological nitrogen fixation (BNF) is very sensitive to environmental fluctuations. It is still contentious how BNF is regulated under stress conditions. The local or systemic control of BNF and the role played by reactive oxygen species (ROS) in such regulation have still not been elucidated completely. Cadmium, which belongs to the so-called heavy metals, is one of the most toxic substances released into the environment. The mechanisms involved in Cd toxicity are still not completely understood but the overproduction of ROS is one of its characteristic symptoms. In this work, we used a split-root system approach to study nodule BNF and the antioxidant machinery's response to the application of a mild Cd treatment on one side of a nodulated Medicago truncatula root system. Cd induced the majority of nodule antioxidants without generating any oxidative damage. Cd treatment also provoked BNF inhibition exclusively in nodules directly exposed to Cd, without provoking any effect on plant shoot biomass or chlorophyll content. The overall data suggest that the decline in BNF was not due to a generalized breakdown of the plant but to control exerted through leghaemoglobin/oxygen availability, affecting nitrogenase function. PMID- 24151306 TI - IDA: a peptide ligand regulating cell separation processes in Arabidopsis. AB - In contrast to animals, plants continuously produce new organs, such as leaves, flowers, and lateral roots (LRs), and may shed organs that have served their purpose. In the model plant Arabidopsis thaliana the peptide INFLORESCENCE DEFICIENT IN ABSCISSION (IDA) signals through the leucine-rich repeat-receptor like kinases (LRR-RLKs) HAESA (HAE), and HAESA-LIKE2 (HSL2) to control the abscission of floral organs after pollination. Recent work from other plant species indicates that this signalling system is conserved and could regulate leaf abscission in soybean and tomato. Abscission is a cell separation process involving the breakdown of cell walls between adjacent files of abscission zone (AZ) cells at the base of organs to be shed. The emergence of new lateral root primordia (LRP), initiated deep inside the root under the influence of the phytohormone auxin, is similarly dependent on cell wall dissolution to separate cells in the overlying tissues. It has been shown that this process also requires IDA, HAE, and HSL2. The receptors are redundant in function during floral organ abscission, but during lateral root emergence (LRE) they are differentially involved in regulating cell wall remodelling (CWR) genes. An overview is given here of the similarities and differences of IDA signalling during floral organ abscission and LRE. PMID- 24151305 TI - In vitro binding of Sorghum bicolor transcription factors ABI4 and ABI5 to a conserved region of a GA 2-OXIDASE promoter: possible role of this interaction in the expression of seed dormancy. AB - The precise adjustment of the timing of dormancy release according to final grain usage is still a challenge for many cereal crops. Grain sorghum [Sorghum bicolor (L.) Moench] shows wide intraspecific variability in dormancy level and susceptibility to pre-harvest sprouting (PHS). Both embryo sensitivity to abscisic acid (ABA) and gibberellin (GA) metabolism play an important role in the expression of dormancy of the developing sorghum grain. In previous works, it was shown that, simultaneously with a greater embryo sensitivity to ABA and higher expression of SbABA-INSENSITIVE 4 (SbABI4) and SbABA-INSENSITIVE 5 (SbABI5), dormant grains accumulate less active GA4 due to a more active GA catabolism. In this work, it is demonstrated that the ABA signalling components SbABI4 and SbABI5 interact in vitro with a fragment of the SbGA 2-OXIDASE 3 (SbGA2ox3) promoter containing an ABA-responsive complex (ABRC). Both transcription factors were able to bind the promoter, although not simultaneously, suggesting that they might compete for the same cis-acting regulatory sequences. A biological role for these interactions in the expression of dormancy of sorghum grains is proposed: either SbABI4 and/or SbABI5 activate transcription of the SbGA2ox3 gene in vivo and promote SbGA2ox3 protein accumulation; this would result in active degradation of GA4, thus preventing germination of dormant grains. A comparative analysis of the 5'-regulatory region of GA2oxs from both monocots and dicots is also presented; conservation of the ABRC in closely related GA2oxs from Brachypodium distachyon and rice suggest that these species might share the same regulatory mechanism as proposed for grain sorghum. PMID- 24151307 TI - Deciphering genetic diversity and inheritance of tomato fruit weight and composition through a systems biology approach. AB - Integrative systems biology proposes new approaches to decipher the variation of phenotypic traits. In an effort to link the genetic variation and the physiological and molecular bases of fruit composition, the proteome (424 protein spots), metabolome (26 compounds), enzymatic profile (26 enzymes), and phenotypes of eight tomato accessions, covering the genetic diversity of the species, and four of their F1 hybrids, were characterized at two fruit developmental stages (cell expansion and orange-red). The contents of metabolites varied among the genetic backgrounds, while enzyme profiles were less variable, particularly at the cell expansion stage. Frequent genotype by stage interactions suggested that the trends observed for one accession at a physiological level may change in another accession. In agreement with this, the inheritance modes varied between crosses and stages. Although additivity was predominant, 40% of the traits were non-additively inherited. Relationships among traits revealed associations between different levels of expression and provided information on several key proteins. Notably, the role of frucktokinase, invertase, and cysteine synthase in the variation of metabolites was highlighted. Several stress-related proteins also appeared related to fruit weight differences. These key proteins might be targets for improving metabolite contents of the fruit. This systems biology approach provides better understanding of networks controlling the genetic variation of tomato fruit composition. In addition, the wide data sets generated provide an ideal framework to develop innovative integrated hypothesis and will be highly valuable for the research community. PMID- 24151308 TI - Jasmonic acid and glucose synergistically modulate the accumulation of glucosinolates in Arabidopsis thaliana. AB - The interplay of plant hormones and glucose (Glu) in regulating glucosinolate accumulation in Arabidopsis thaliana was investigated in this study. Glucose induced glucosinolate biosynthesis was enhanced significantly by the addition of jasmonic acid (JA), whereas the synergistic effect of salicylic acid (SA) and Glu was less obvious. The enhanced glucosinolate accumulation is associated with elevated expression of genes in glucosinolate biosynthetic pathway, as well as the transcription factors involved in their regulation, such as MYB28, MYB29, MYB34, and MYB122. The induction of indolic and aliphatic glucosinolates after treatment with JA and Glu in JA-insensitive mutants, coi1, jar1, and jin1, was compromised. Moreover, the effect of JA and Glu on glucosinolate contents was dramatically reduced in Glu-insensitive mutants, rgs1-2 and abi5-7. These results indicate a crosstalk between JA and Glu signalling in the regulation of glucosinolate biosynthesis. JA signalling, RGS1 (the putative membrane receptor of Glu signalling), and ABI5, are involved in the synergistic effect of JA and Glu on glucosinolate accumulation. PMID- 24151309 TI - The global transmission network of HIV-1. AB - Human immunodeficiency virus type 1 (HIV-1) is pandemic, but its contemporary global transmission network has not been characterized. A better understanding of the properties and dynamics of this network is essential for surveillance, prevention, and eventual eradication of HIV. Here, we apply a simple and computationally efficient network-based approach to all publicly available HIV polymerase sequences in the global database, revealing a contemporary picture of the spread of HIV-1 within and between countries. This approach automatically recovered well-characterized transmission clusters and extended other clusters thought to be contained within a single country across international borders. In addition, previously undescribed transmission clusters were discovered. Together, these clusters represent all known modes of HIV transmission. The extent of international linkage revealed by our comprehensive approach demonstrates the need to consider the global diversity of HIV, even when describing local epidemics. Finally, the speed of this method allows for near-real-time surveillance of the pandemic's progression. PMID- 24151310 TI - HIV-1 transmission networks in a small world. PMID- 24151317 TI - Recent advances in humanized mice: accelerating the development of an HIV vaccine. AB - Recent advances in the development of humanized mice hold great promise to advance our understanding of protective immunity to human immunodeficiency virus (HIV) infection and to aid in the design of an effective HIV vaccine. This supplement of the Journal of Infectious Diseases summarizes work in the humanized mouse model presented at an HIV Humanized Mouse workshop in Boston, Massachusetts, in November 2012, including recent advances in the development of humanized mice, the trafficking of human immune cells following mucosal HIV transmission, the role of immune activation and Toll-like receptor agonists in the control of HIV, the induction and efficacy of HIV-specific cellular and humoral immune responses, and the preclinical modeling of novel anti-HIV therapeutics. Many gaps remain in our understanding of how to design an effective HIV vaccine and novel therapeutics to eliminate the viral reservoir. Promising early results from studies in humanized mice suggest great potential and enthusiasm for this model to accelerate these critical areas of HIV research. PMID- 24151318 TI - Overcoming current limitations in humanized mouse research. AB - Immunodeficient mice engrafted with human cells and tissues have provided an exciting alternative to in vitro studies with human tissues and nonhuman primates for the study of human immunobiology. A major breakthrough in the early 2000s was the introduction of a targeted mutation in the interleukin 2 (IL-2) receptor common gamma chain (IL2rg(null)) into mice that were already deficient in T and B cells. Among other immune defects, natural killer (NK) cells are disrupted in these mice, permitting efficient engraftment with human hematopoietic cells that generate a functional human immune system. These humanized mouse models are becoming increasingly important for preclinical studies of human immunity, hematopoiesis, tissue regeneration, cancer, and infectious diseases. In particular, humanized mice have enabled studies of the pathogenesis of human specific pathogens, including human immunodeficiency virus type 1, Epstein Barr virus, and Salmonella typhi. However, there are a number of limitations in the currently available humanized mouse models. Investigators are continuing to identify molecular mechanisms underlying the remaining defects in the engrafted human immune system and are generating "next generation" models to overcome these final deficiencies. This article provides an overview of some of the emerging models of humanized mice, their use in the study of infectious diseases, and some of the remaining limitations that are currently being addressed. PMID- 24151319 TI - BLT humanized mice as model to study HIV vaginal transmission. AB - The majority of human immunodeficiency virus type 1 (HIV-1) infections occur by sexual exposure, and vaginal transmission accounts for more than half of all newly acquired infections. Studies of vaginal transmission of simian immunodeficiency virus to nonhuman primates (NHPs) have suggested an important role for immune cell trafficking in the establishment of infection as well is in the process of viral dissemination. However, NHP models do not permit the study of HIV transmission and dissemination. The improvement of humanized mouse models with robust human immune cell reconstitution of the female genital tract renders these mice susceptible to intravaginal HIV infection. Thus humanized mouse models of HIV vaginal infection will allow the study of the mechanisms involved in HIV transmission and dissemination in vivo. PMID- 24151320 TI - Intravital microscopy in BLT-humanized mice to study cellular dynamics in HIV infection. AB - Humanized mouse models have, over the past few years, seen dramatic improvements, including the colonization of both lymphoid and nonlymphoid tissues with all major immune cell lineages, the development of T cells with human major histocompatibility complex restriction, and the ability to mount functional adaptive immune responses to human pathogens, as documented in some instances. This has greatly increased the range of questions related to the biology of human immunodeficiency virus (HIV) infection that can be usefully addressed through experimental approaches utilizing small animal models. Among these approaches is in vivo imaging, and specifically multiphoton intravital microscopy (MP-IVM), which allows for the investigation of dynamic biological processes at cellular and subcellular resolution in the tissues of live animals. We have recently begun to use MP-IVM in lymph nodes of humanized mice in order to examine HIV infectious spread in vivo at the tissue and cellular level. Here, we provide a short perspective on the close link between the patterns of immune cell migration and the mechanisms of viral dissemination, and summarize the results of our initial studies. PMID- 24151321 TI - Immune activation and the role of TLRs and TLR agonists in the pathogenesis of HIV-1 infection in the humanized mouse model. AB - Immune activation plays a critical role in HIV-1 pathogenesis, but the pathways that are responsible for HIV-1-associated immune activation are not well understood. Recent advances in the development of a humanized mouse model for HIV 1 infection might provide new approaches to study the mechanisms of HIV-1 associated immune activation, and to test interventions aimed at reducing HIV-1 pathogenesis. PMID- 24151322 TI - HIV-specific CD8+ T-cell immunity in humanized bone marrow-liver-thymus mice. AB - CD8(+) T-cell responses play a critical role in the control of human immunodeficiency virus (HIV) infection, and recent vaccine studies in nonhuman primates now demonstrate the ability of T cells to prevent the early dissemination of simian immunodeficiency virus and perhaps clear residual infection. Recent advances in humanized mouse models, in particular the humanized bone marrow-liver-thymus (BLT) mouse model, show promise in their ability not only to support sustained infection with HIV, but also to recapitulate human HIV specific immunity. The availability of a small-animal model with which to study human-specific immune responses to HIV would greatly facilitate the elucidation of mechanisms of immune control, as well as accelerate the iterative testing of promising vaccine candidates. Here we discuss data from our recent study detailing the composition and efficacy of HIV-specific CD8(+) T-cell responses in humanized BLT mice that was recently presented at a Harvard Center for AIDS Research symposium on humanized mouse models for HIV vaccine design. PMID- 24151323 TI - Humoral immunity in humanized mice: a work in progress. AB - Humanized mice historically have not been good models of human humoral immunity induced by either infection or immunization. However, newer versions of humanized mice generated in severely immunodeficient mice with a targeted disruption of the IL2Rgammac gene have recently been reported to produce antigen-specific class switched human antibodies, with some demonstrating neutralizing activities. Here we review the growing ability of humanized mice to support the study of human humoral immune responses, discussing the current and future potential of these models as well as their current limitations. PMID- 24151325 TI - The potential for Bayesian compressive sensing to significantly reduce electron dose in high-resolution STEM images. AB - The use of high-resolution imaging methods in scanning transmission electron microscopy (STEM) is limited in many cases by the sensitivity of the sample to the beam and the onset of electron beam damage (for example, in the study of organic systems, in tomography and during in situ experiments). To demonstrate that alternative strategies for image acquisition can help alleviate this beam damage issue, here we apply compressive sensing via Bayesian dictionary learning to high-resolution STEM images. These computational algorithms have been applied to a set of images with a reduced number of sampled pixels in the image. For a reduction in the number of pixels down to 5% of the original image, the algorithms can recover the original image from the reduced data set. We show that this approach is valid for both atomic-resolution images and nanometer-resolution studies, such as those that might be used in tomography datasets, by applying the method to images of strontium titanate and zeolites. As STEM images are acquired pixel by pixel while the beam is scanned over the surface of the sample, these postacquisition manipulations of the images can, in principle, be directly implemented as a low-dose acquisition method with no change in the electron optics or the alignment of the microscope itself. PMID- 24151324 TI - Pre-clinical modeling of CCR5 knockout in human hematopoietic stem cells by zinc finger nucleases using humanized mice. AB - Genetic strategies to block expression of CCR5, the major co-receptor of human immunodeficiency virus type 1 (HIV-1), are being developed as anti-HIV therapies. For example, human hematopoietic stem/precursor cells (HSPC) can be modified by the transient expression of CCR5-targeted zinc finger nucleases (ZFNs) to generate CCR5-negative cells, which could then give rise to HIV-resistant mature CD4(+) T cells following transplantation into patients. The safety and anti-HIV effects of such treatments can be evaluated by transplanting ZFN-treated HSPC into immunodeficient mice, where the extent of human cell engraftment, lineage differentiation and anti-HIV activity arising from the engineered HSPC can be examined. In this way, humanized mice are providing a powerful small animal model for pre-clinical studies of novel anti-HIV therapies. PMID- 24151326 TI - Effects of exercise dose and type during breast cancer chemotherapy: multicenter randomized trial. AB - BACKGROUND: Exercise improves physical functioning and symptom management during breast cancer chemotherapy, but the effects of different doses and types of exercise are unknown. METHODS: A multicenter trial in Canada randomized 301 breast cancer patients to thrice-weekly supervised exercise during chemotherapy consisting of either a standard dose of 25 to 30 minutes of aerobic exercise (STAN; n = 96), a higher dose of 50 to 60 minutes of aerobic exercise (HIGH; n = 101), or a combined dose of 50 to 60 minutes of aerobic and resistance exercise (COMB; n = 104). The primary endpoint was physical functioning assessed by the Medical Outcomes Survey-Short Form (SF)-36. Secondary endpoints were other physical functioning scales, symptoms, fitness, and chemotherapy completion. All statistical tests were linear mixed model analyses, and the P values were two sided. RESULTS: Follow-up assessment of patient-reported outcomes was 99.0%. Adjusted linear mixed-model analyses showed that neither HIGH (+0.8; 95% confidence interval [CI] = -0.8 to 2.4; P = .30) nor COMB (+0.5; 95% CI = -1.1 to 2.1; P = .52] were superior to STAN for the primary outcome. In secondary analyses not adjusted for multiple comparisons, HIGH was superior to STAN for the SF-36 physical component summary (P = .04), SF-36 bodily pain (P = .02), and endocrine symptoms (P = .02). COMB was superior to STAN for endocrine symptoms (P = .009) and superior to STAN (P < .001) and HIGH (P < .001) for muscular strength. HIGH was superior to COMB for the SF-36 bodily pain (P = .04) and aerobic fitness (P = .03). No differences emerged for body composition or chemotherapy completion. CONCLUSIONS: A higher volume of aerobic or combined exercise is achievable and safe during breast cancer chemotherapy and may manage declines in physical functioning and worsening symptoms better than standard volumes. PMID- 24151328 TI - Is physician employment by health systems an answer? PMID- 24151327 TI - Effect of medical oncologists' attitudes on accrual to clinical trials in a community setting. AB - PURPOSE: Oncology clinical trials (OCTs) are crucial in evaluating new cancer treatments, but only 2% to 3% of US adult patients with cancer enter OCTs. This study assessed barriers to participation in clinical trials among oncologists in a large integrated health care delivery system with an active clinical trials program. Although many studies have identified major physician barriers to enrollment, few have examined how these barriers affect actual trial accrual. METHODS: Using information from a mailed survey, we examined the effect of oncologists' attitudes, beliefs, experiences, sociodemographic factors, and practice characteristics on clinical trial accrual in the 2 years following the survey. We identified relationships between these variables and subsequent clinical trial accrual using correlations and mixed effects models. RESULTS: A construct combining questions that assessed oncologist attitudes, beliefs, and experiences substantially influenced OCT enrollment (r = .51; P < .0001). This construct included awareness of open clinical trials and specific eligible patients, as well as the practice of initiating a discussion about OCTs with most eligible patients. This broad concept of awareness had the greatest correlation with enrollment and mediated the effect on enrollment of other values and beliefs, such as welcoming a patient's initiation of a trial discussion and valuing the support of research nurses and coordinators. CONCLUSION: Even in a health care setting with an active clinical trials program, substantial research personnel, infrastructure support, and widespread access to trials among oncologists and patients, oncologists' participation remains quite variable. Oncologist values, beliefs, and awareness of clinical trials play an important role in OCT accrual. PMID- 24151329 TI - Using quality oncology practice initiative metrics for physician incentive compensation. AB - PURPOSE: To demonstrate the use of American Society of Clinical Oncology (ASCO) Quality Oncology Practice Initiative (QOPI) measures as part of a financial incentive plan for an academic health center-based hematology-oncology division. METHODS: An 11-member QOPI-certified hematology-oncology division participated in a pilot variable compensation (VC) plan with group-specific targets selected based on prior below-average performance. Twenty percent of overall VC was linked to success in two QOPI categories: completion of treatment summaries within 90 days of end of chemotherapy and assessment of patients' emotional well-being by second office visit. Three tiers of achievement were set for each goal. A formula combining VC goals into year-end payout was driven by three levels of percent base salary: 8%, 12%, and 24%, with probability of achievement of each goal of 90%, 50%, and 10%, respectively. Practice leadership was educated about QOPI acceptance in the oncology community. RESULTS: The division participated in QOPI during spring and fall 2012. With systems-based improvements, 40.54% of medical records audited had treatment summaries, resulting in achievement of tier III compensation. Documentation of emotional well-being increased, yielding 63% of patient cases compliant; however, the national benchmark concurrently improved, making this insufficient to achieve tier I. CONCLUSION: QOPI metrics can be used as a quality incentive for oncologists in a VC plan. Non-oncologists can appreciate the strength of QOPI as a quality tool. The combination of a QOPI program through ASCO and use of various QOPI metrics can drive continuous improvement in an oncology group. PMID- 24151330 TI - The cannabis conundrum. PMID- 24151332 TI - Transcript processing and export kinetics are rate-limiting steps in expressing vertebrate segmentation clock genes. AB - Sequential production of body segments in vertebrate embryos is regulated by a molecular oscillator (the segmentation clock) that drives cyclic transcription of genes involved in positioning intersegmental boundaries. Mathematical modeling indicates that the period of the clock depends on the total delay kinetics of a negative feedback circuit, including those associated with the synthesis of transcripts encoding clock components [Lewis J (2003) Curr Biol 13(16):1398 1408]. Here, we measure expression delays for three transcripts [Lunatic fringe, Hes7/her1, and Notch-regulated-ankyrin-repeat-protein (Nrarp)], that cycle during segmentation in the zebrafish, chick, and mouse, and provide in vivo measurements of endogenous splicing and export kinetics. We show that mRNA splicing and export are much slower than transcript elongation, with the longest delay (about 16 min in the mouse) being due to mRNA export. We conclude that the kinetics of mRNA and protein production and destruction can account for much of the clock period, and provide strong support for delayed autorepression as the underlying mechanism of the segmentation clock. PMID- 24151333 TI - Wnt/Rspondin/beta-catenin signals control axonal sorting and lineage progression in Schwann cell development. AB - During late Schwann cell development, immature Schwann cells segregate large axons from bundles, a process called "axonal radial sorting." Here we demonstrate that canonical Wnt signals play a critical role in radial sorting and assign a role to Wnt and Rspondin ligands in this process. Mice carrying beta-catenin loss of-function mutations show a delay in axonal sorting; conversely, gain-of function mutations result in accelerated sorting. Sorting deficits are accompanied by abnormal process extension, differentiation, and aberrant cell cycle exit of the Schwann cells. Using primary cultured Schwann cells, we analyze the upstream effectors, Wnt and Rspondin ligands that initiate signaling, and downstream genetic programs that mediate the Wnt response. Our analysis contributes to a better understanding of the mechanisms of Schwann cell development and fate decisions. PMID- 24151334 TI - Dynamics of dendritic spines in the mouse auditory cortex during memory formation and memory recall. AB - Long-lasting changes in synaptic connections induced by relevant experiences are believed to represent the physical correlate of memories. Here, we combined chronic in vivo two-photon imaging of dendritic spines with auditory-cued classical conditioning to test if the formation of a fear memory is associated with structural changes of synapses in the mouse auditory cortex. We find that paired conditioning and unpaired conditioning induce a transient increase in spine formation or spine elimination, respectively. A fraction of spines formed during paired conditioning persists and leaves a long-lasting trace in the network. Memory recall triggered by the reexposure of mice to the sound cue did not lead to changes in spine dynamics. Our findings provide a synaptic mechanism for plasticity in sound responses of auditory cortex neurons induced by auditory cued fear conditioning; they also show that retrieval of an auditory fear memory does not lead to a recapitulation of structural plasticity in the auditory cortex as observed during initial memory consolidation. PMID- 24151335 TI - Developmental bias in the evolution of phalanges. AB - Evolutionary theory has long argued that the entrenched rules of development constrain the range of variations in a given form, but few empirical examples are known. Here we provide evidence for a very deeply conserved skeletal module constraining the morphology of the phalanges within a digit. We measured the sizes of phalanges within populations of two bird species and found that successive phalanges within a digit exhibit predictable relative proportions, whether those phalanges are nearly equal in size or exhibit a more striking gradient in size from large to small. Experimental perturbations during early stages of digit formation demonstrate that the sizes of the phalanges within a digit are regulated as a system rather than individually. However, the sizes of the phalanges are independent of the metatarsals. Temporal studies indicate that the relative sizes of the phalanges are established at the time of initial cell condensation. Measurements of phalanges across species from six major taxonomic lineages showed that the same predictable range of variants is conserved across vast taxonomic diversity and evolutionary time, starting with the very origins of tetrapods. Although in general phalangeal variations fall within a range of nearly equal-sized phalanges to those following a steep large-to-small gradient, a novel derived condition of excessive elongation of the distal-most phalanges has evolved convergently in multiple lineages, for example under selection for grasping rather than walking or swimming. Even in the context of this exception, phalangeal variations observed in nature are a small subset of potential morphospace. PMID- 24151338 TI - Using an Option Grid in shared decision making. PMID- 24151337 TI - Understanding the role of mitochondria in the pathogenesis of chronic pain. AB - Chronic pain is a major public health problem. Mitochondria play important roles in a myriad of cellular processes and mitochondrial dysfunction has been implicated in multiple neurological disorders. This review aims to provide an insight into advances in understanding of the role of mitochondrial dysfunction in the pathogenesis of chronic pain. The results show that the five major mitochondrial functions (the mitochondrial energy generating system, reactive oxygen species generation, mitochondrial permeability transition pore, apoptotic pathways and intracellular calcium mobilisation) may play critical roles in neuropathic and inflammatory pain. Therefore, protecting mitochondrial function would be a promising strategy to alleviate or prevent chronic pain states. Related chronic inflammatory and neuropathic pain models, as well as the spectral characteristics of current fluorescent probes to detect mitochondria in pain studies, are also discussed. PMID- 24151339 TI - Circular permutated red fluorescent proteins and calcium ion indicators based on mCherry. AB - Red fluorescent indicators for calcium ion (Ca(2+)) are preferable, relative to blue-shifted alternatives, for biological imaging applications due to the lower phototoxicity, lower autofluorescent background and deeper tissue penetration associated with longer wavelength light. Accordingly, we undertook the development of a genetically encoded Ca(2+) indicator based on the popular and widely utilized Discosoma-derived red fluorescent protein, mCherry. Starting from a promising but dimly fluorescent circular permutated variant of mCherry, we first engineered a 13-fold brighter variant (cp196V1.2) through directed evolution. This bright cp196V1.2 was then used as the scaffold for creation of eight distinct libraries of potential Ca(2+) indicators via permutation at different sites within the 7th and 10th beta-strands, and fusion of calmodulin and M13 to the new termini. Screening of these libraries led to the conclusion that, consistent with previous investigations of homologous fluorescent proteins, the 146-145 site in beta-strand 7 is the most promising permutation site for construction of useful Ca(2+) indicators. Further rounds of directed evolution ultimately led to an indicator that exhibits a 250% change in intrinsic brightness in response to Ca(2+) and an exceptionally high affinity (Kd = 6 nM) for Ca(2+). PMID- 24151336 TI - What is a representative brain? Neuroscience meets population science. AB - The last decades of neuroscience research have produced immense progress in the methods available to understand brain structure and function. Social, cognitive, clinical, affective, economic, communication, and developmental neurosciences have begun to map the relationships between neuro-psychological processes and behavioral outcomes, yielding a new understanding of human behavior and promising interventions. However, a limitation of this fast moving research is that most findings are based on small samples of convenience. Furthermore, our understanding of individual differences may be distorted by unrepresentative samples, undermining findings regarding brain-behavior mechanisms. These limitations are issues that social demographers, epidemiologists, and other population scientists have tackled, with solutions that can be applied to neuroscience. By contrast, nearly all social science disciplines, including social demography, sociology, political science, economics, communication science, and psychology, make assumptions about processes that involve the brain, but have incorporated neural measures to differing, and often limited, degrees; many still treat the brain as a black box. In this article, we describe and promote a perspective--population neuroscience--that leverages interdisciplinary expertise to (i) emphasize the importance of sampling to more clearly define the relevant populations and sampling strategies needed when using neuroscience methods to address such questions; and (ii) deepen understanding of mechanisms within population science by providing insight regarding underlying neural mechanisms. Doing so will increase our confidence in the generalizability of the findings. We provide examples to illustrate the population neuroscience approach for specific types of research questions and discuss the potential for theoretical and applied advances from this approach across areas. PMID- 24151340 TI - Evidence-based laboratory medicine. PMID- 24151341 TI - From evidence to best practice in laboratory medicine. AB - Laboratory tests offer value if they provide benefit to patients at acceptable costs. Laboratory testing is one of the most widely used diagnostic interventions supporting medical decisions, yet evidence demonstrating its value and impact on health outcomes is limited. This contributes to wide variations in test utilisation including underdiagnosis, overdiagnosis and misdiagnosis, which may impact the quality and the clinical- and cost-effectiveness of care and patient safety. Therefore implementing evidence into the care of patients is a moral and social imperative to laboratory professionals and all health care staff. This review investigates the reasons research does not get into practice, or only does with a very long delay. Apart from reviewing the common barriers to implementation, it also discusses the drivers of inappropriate test utilisation. By reviewing the theoretical and practical aspects of implementation science, recommendations are made for approaches that are thought to be most effective and that can be adopted to close the gap between evidence and practice, and to facilitate evidence-based laboratory medicine. Passive dissemination of the evidence and educational interventions are insufficient and do not offer sustainable solutions. A multifaceted and individualised implementation strategy, including individually tailored academic detailing, reminder systems, clinical decision support systems, feedback on performance, and participation of doctors and laboratory professionals in quality improvement activities addressing test selection and interpretation and in clinical audits, has greater potential for success. Examples of these initiatives at the laboratory and clinical interface are provided with links to valuable resources. PMID- 24151342 TI - Economic Evidence and Point-of-Care Testing. AB - Health economics has been an established feature of the research, policymaking, practice and management in the delivery of healthcare. However its role is increasing as the cost of healthcare begins to drive changes in most healthcare systems. Thus the output from cost effectiveness studies is now being taken into account when making reimbursement decisions, e.g. in Australia and the United Kingdom. Against this background it is also recognised that the health economic tools employed in healthcare, and particularly the output from the use of these tools however, are not always employed in the routine delivery of services. One of the notable consequences of this situation is the poor record of innovation in healthcare with respect to the adoption of new technologies, and the realisation of their benefits. The evidence base for the effectiveness of diagnostic services is well known to be limited, and one consequence of this has been a very limited literature on cost effectiveness. One reason for this situation is undoubtedly the reimbursement strategies employed in laboratory medicine for many years, simplistically based on the complexity of the test procedure, and the delivery as a cost-per-test service. This has proved a disincentive to generate the required evidence, and little effort to generate an integrated investment and disinvestment business case, associated with care pathway changes. Point-of-care testing creates a particularly challenging scenario because, on the one hand, the unit cost-per-test is larger through the loss of the economy of scale offered by automation, whilst it offers the potential of substantial savings through enabling rapid delivery of results, and reduction of facility costs. This is important when many health systems are planning for complete system redesign. We review the literature on economic assessment of point-of-care testing in the context of these developments. PMID- 24151343 TI - HbA1c as a Diagnostic Test for Diabetes Mellitus - Reviewing the Evidence. AB - The evidence base in support of HbA1c as a diagnostic test for diabetes mellitus is focused on predicting a clinical outcome, considered to be the pinnacle of the Stockholm Hierarchy applied to reference intervals and clinical decision limits. In the case of diabetes, the major outcome of interest is the long term microvascular complications for which a large body of data has been accumulated, leading to the endorsement of HbA1c for diagnosis in many countries worldwide, with some variations in cut-offs and testing strategies. PMID- 24151344 TI - Monitoring in clinical biochemistry. AB - Monitoring tests form an increasing proportion of the workload in clinical biochemistry and biochemists can help by providing clinicians with information about the variability and precision of tests, the time frame for pharmacodynamic stabilisation after a treatment change, and the frequency of testing. This paper outlines the phases of monitoring, and how to decide if monitoring is beneficial, which test to use for monitoring, when a change in the test result indicates a need for the change in treatment and the length of testing intervals. We conclude with some recommendations for biochemists for future areas of research and advice that can be given to clinicians. PMID- 24151345 TI - On-the-Job Evidence-Based Medicine Training for Clinician-Scientists of the Next Generation. AB - Clinical scientists are at the unique interface between laboratory science and frontline clinical practice for supporting clinical partnerships for evidence based practice. In an era of molecular diagnostics and personalised medicine, evidence-based laboratory practice (EBLP) is also crucial in aiding clinical scientists to keep up-to-date with this expanding knowledge base. However, there are recognised barriers to the implementation of EBLP and its training. The aim of this review is to provide a practical summary of potential strategies for training clinician-scientists of the next generation. Current evidence suggests that clinically integrated evidence-based medicine (EBM) training is effective. Tailored e-learning EBM packages and evidence-based journal clubs have been shown to improve knowledge and skills of EBM. Moreover, e-learning is no longer restricted to computer-assisted learning packages. For example, social media platforms such as Twitter have been used to complement existing journal clubs and provide additional post-publication appraisal information for journals. In addition, the delivery of an EBLP curriculum has influence on its success. Although e-learning of EBM skills is effective, having EBM trained teachers available locally promotes the implementation of EBM training. Training courses, such as Training the Trainers, are now available to help trainers identify and make use of EBM training opportunities in clinical practice. On the other hand, peer-assisted learning and trainee-led support networks can strengthen self directed learning of EBM and research participation among clinical scientists in training. Finally, we emphasise the need to evaluate any EBLP training programme using validated assessment tools to help identify the most crucial ingredients of effective EBLP training. In summary, we recommend on-the-job training of EBM with additional focus on overcoming barriers to its implementation. In addition, future studies evaluating the effectiveness of EBM training should use validated outcome tools, endeavour to achieve adequate power and consider the effects of EBM training on learning environment and patient outcomes. PMID- 24151347 TI - Looking Down or Looking Up: Status and Subjective Well-Being among Asian and Latino Immigrants in the United States. AB - Foundational theories of international migration rest on the assumption that immigrants maintain reference groups in their country of origin even after settling in a new place, while the transnationalism perspective suggests that immigrants maintain a dual frame of reference. This paper uses the nationally representative National Latino and Asian American Survey to test the location of immigrants' reference groups. I find that the relationship between various measures of subjective social standing and subjective well-being suggests that immigrants maintain simultaneous reference groups in both the United States and the country of origin, supporting transnational theories, and refuting earlier theories. PMID- 24151346 TI - Family Histories and Multiple Transitions Among Homeless Young Adults: Pathways to Homelessness. AB - This study explored the early family histories of homeless young adults, the types and number of transitions they experienced, and their pathways to the street. Intensive qualitative interviews were audio taped and transcribed with 40 homeless young adults 19 to 21 years of age in the Midwest. Findings show that family backgrounds were generally characterized by substance use, child maltreatment, and witnessing violence, all of which provide social context for understanding why so many of these young people opted to leave home in search of an alternative living situation. The current findings also reveal that while some young adults ran away from home as adolescents, others were "pushed out" (i.e., told to leave), or removed by state agencies. Current study findings illustrate that young adults' trajectories are marked by multiple living arrangements such as home, foster care, detention facility, and drug rehabilitation. Overall, study results show that young adults' family histories place them on trajectories for early independence marked by multiple transitions and numerous living situations, culminating in a lack of a permanent residence to call home. PMID- 24151348 TI - Floating Choices: A Generational Perspective on Intentions of Rural-Urban Migrants in China. AB - Using data from a 2005 Survey of rural-urban migrants in Shenzhen, this paper investigates intentions of two groups of migrants. We use the birth years from 1970 to 1980 as a reasonable range of dividing lines to separate the two groups. For each year we divide the sample into those born before that year and those born in or after that year. These are referred to as the old and the new generation, respectively. Three possible development trajectories are considered: settling in cities, returning home to seek a nonagricultural job, and returning home to farm. We find that members of the new generation have stronger desires to do non-farm work, and returning to seek a nonagricultural job has become the most important planned trajectory for this generation. Sharp differences exist between the two generations in the reasons that underlie their intentions. For the old generation, conditions such as age, family responsibility, and type of job are important determinants of intentions, while other conditions such as initial migration motives, social capital, and socioeconomic conditions of origin areas are important for the intentions of the new generation. Thus the new generation is more likely to view migration as a form of investment with the accumulation of human capital and social capital. Those migrants from the old generation who have higher education levels also intend to seek non-farm jobs. However, because of the combined effects of life cycle and the market transition in China, these intentions are not as strong as those of the new generation. We discuss economic and policy implications of our findings. PMID- 24151349 TI - Epidermal growth factor receptor and metastatic colorectal cancer: insights into target therapies. AB - Colorectal cancer (CRC) has high incidence and mortality worldwide. In 2012, CRC was the second most prevalent cancer among males (9%) and the third among females (8%). In recent decades, standard chemotherapies protocols combining 5 fluorouracil, leucovorin, irinotecan and oxaliplatin were important for improve survival in this set of patients. Further, biological drugs throughout epidermal growth factor receptor (EGFR) pathways showed interesting results in metastatic disease (mCRC) control when in association to standard chemotherapy regimens. Cetuximab and panitumumab are two cornerstones for mCRC treatment and are both approved in Europe and United States based on previous results phase III trials. This paper will briefly summarize those anti-EGFR therapies framework in mCRC and discusses some issues in this regard. PMID- 24151350 TI - Pain in chronic pancreatitis: managing beyond the pancreatic duct. AB - Chronic pancreatitis (CP) continues to be a clinical challenge. Persistent or recurrent abdominal pain is the most compelling symptom that drives patients to seek medical care. Unfortunately, in spite of using several treatment approaches in the clinical setting, there is no single specific treatment modality that can be earmarked as a cure for this disease. Traditionally, ductal hypertension has been associated with causation of pain in CP; and patients are often subjected to endotherapy and surgery with a goal to decompress the pancreatic duct. Recent studies on humans (clinical and laboratory based) and experimental models have put forward several mechanisms, including neuroimmune alterations, which could be responsible for pain. This might explain the partial or no response to single modality treatment in a significant proportion of patients. The current review discusses the recent concepts of pain generation in CP and evidence based therapeutic approaches (other than ductal decompression) to handle persistent or recurrent pain. We focus primarily on parenchymal and neural components; and discuss the role of antioxidants and the existing controversies, drugs that interfere with neural transmission, pancreatic enzyme supplementation, celiac neurolysis, and pancreatic resection procedures. The review concludes with the treatment approach that we follow at our institute. PMID- 24151352 TI - Hepatectomy for bile duct injuries: when is it necessary? AB - Iatrogenic bile duct injuries (IBDI) are still a challenge for surgeons. The most frequently, they are caused by laparoscopic cholecystectomy which is one of the commonest surgical procedure in the world. Endoscopic techniques are recommended as initial treatment of IBDI. When endoscopic treatment is not effective, surgery is considered. Different surgical biliary reconstructions are performed in most patients in IBDI. Roux-Y hepaticojejunostomy is the commonest biliary reconstruction for IBDI. In some patients with complex IBDI, hepatectomy is required. Recently, Li et al analyzed the factors that had led to hepatectomy for patients with IBDI after laparoscopic cholecystectomy (LC). Authors concluded that hepatectomy might be necessary to manage early or late complications after LC. The study showed that proximal IBDI (involving hepatic confluence) and IBDI associated with vascular injuries were the two independent risk factors of hepatectomy in this series. Authors distinguished two main groups of patients that require liver resection in IBDI: those with an injury-induced liver necrosis necessitating early intervention, and those in whom liver resection is indicated for treatment of liver atrophy following long-term cholangitis. In this commentary, indications for hepatectomy in patients with IBDI are discussed. Complex biliovascular injuries as indications for hepatectomy are presented. Short- and long-term results in patients following liver resection for IBDI are also discussed. Hepatectomy is not a standard procedure in surgical treatment of IBDI, but in some complex injuries it should be considered. PMID- 24151353 TI - Right hepatic lobe living donation: a 12 years single Italian center experience. AB - Mini invasive techniques are taking over conventional open liver resections in the setting of left lateral segmentectomy for living liver donation, and hydride procedure are being implemented for the living related right hepatectomy. Our center routinely performs laparoscopic left lateral segmentectomy for pediatric recipient and has been the first in the Europe performing an entirely robotic right hepatectomy. Great emphasis is posed on living donor safety which is the first priority during the entire operation, then the most majority of our procedures are still conventional open right hepatectomy (RHLD), defined as removal of a portion of liver corresponding to Couinaud segments 5-8, in order to obtain a graft for adult to adult living related liver transplant. During this 10 years period some changes, herein highlighted, have occurred to our surgical techniques. This study reports the largest Italian experience with RHLD, focused on surgical technique evolution over a 10 years period. Donor safety must be the first priority in right-lobe living-related donation: the categorization of complications of living donors, specially, after this "highly sensitive" procedure, reflects the need for prompt and detailed reports. PMID- 24151351 TI - Liver elastography, comments on EFSUMB elastography guidelines 2013. AB - Recently the European Federation of Societies for Ultrasound in Medicine and Biology Guidelines and Recommendations have been published assessing the clinical use of ultrasound elastography. The document is intended to form a reference and to guide clinical users in a practical way. They give practical advice for the use and interpretation. Liver disease forms the largest section, reflecting published experience to date including evidence from meta-analyses with shear wave and strain elastography. In this review comments and illustrations on the guidelines are given. PMID- 24151354 TI - Quality of care delivered to hospitalized inflammatory bowel disease patients. AB - Hospitalized patients with inflammatory bowel disease (IBD) are at high risk for morbidity, mortality, and health care utilization costs. While the literature on trends in hospitalization rates for this disease is conflicting, there does appear to be significant variation in the delivery of care to this complex group, which may be a marker of suboptimal quality of care. There is a need for improvement in identifying patients at risk for hospitalization in an effort to reduce admissions. Moreover, appropriate screening for a number of hospital acquired complications such as venous thromboembolism and Clostridium difficile infection is suboptimal. This review discusses areas of inpatient care for IBD patients that are in need of improvement and outlines a number of potential quality improvement initiatives such as pay-for-performance models, quality improvement frameworks, and healthcare information technology. PMID- 24151355 TI - Quality improvement in pediatric inflammatory bowel disease: moving forward to improve outcomes. AB - In recent years, pediatric health care has embraced the concept of quality improvement to improve patient outcomes. As quality improvement efforts are implemented, network collaboration (where multiple centers and practices implement standardized programs) is a popular option. In a collaborative network, improvement in the conduct of structural, process and outcome quality measures can lead to improvements in overall health, and benchmarks can be used to assess and compare progress. In this review article, we provided an overview of the quality improvement movement and the role of quality indicators in this movement. We reviewed current quality improvement efforts in pediatric inflammatory bowel disease (IBD), as well as other pediatric chronic illnesses. We discussed the need to standardize the development of quality indicators used in quality improvement networks to assess medical care, and the validation techniques which can be used to ensure that process indicators result in improved outcomes of clinical significance. We aimed to assess current quality improvement efforts in pediatric IBD and other diseases, such as childhood asthma, childhood arthritis, and neonatal health. By doing so, we hope to learn from their successes and failures and to move the field forward for future improvements in the care provided to children with IBD. PMID- 24151356 TI - Interventions and targets aimed at improving quality in inflammatory bowel disease ambulatory care. AB - Over the past decade, there has been increasing focus on improving the quality of healthcare delivered to patients with chronic diseases, including inflammatory bowel disease. Inflammatory bowel disease is a complex, chronic condition with associated morbidity, health care costs, and reductions in quality of life. The condition is managed primarily in the outpatient setting. The delivery of high quality of care is suboptimal in several ambulatory inflammatory bowel disease domains including objective assessments of disease activity, the use of steroid sparing agents, screening prior to anti-tumor necrosis factor therapy, and monitoring thiopurine therapy. This review outlines these gaps in performance and provides potential initiatives aimed at improvement including reimbursement programs, quality improvement frameworks, collaborative efforts in quality improvement, and the use of healthcare information technology. PMID- 24151357 TI - Personalizing therapies for gastric cancer: molecular mechanisms and novel targeted therapies. AB - Globally, gastric cancer is the 4(th) most frequently diagnosed cancer and the 2(nd) leading cause of death from cancer, with an estimated 990000 new cases and 738000 deaths registered in 2008. In the advanced setting, standard chemotherapies protocols acquired an important role since last decades in prolong survival. Moreover, recent advances in molecular therapies provided a new interesting weapon to treat advanced gastric cancer through anti-human epidermal growth factor receptor 2 (HER2) therapies. Trastuzumab, an anti-HER2 monoclonal antibody, was the first target drug in the metastatic setting that showed benefit in overall survival when in association with platinum-5-fluorouracil based chemotherapy. Further, HER2 overexpression analysis acquired a main role in predict response for trastuzumab in this field. Thus, we conducted a review that will discuss the main points concerning trastuzumab and HER2 in gastric cancer, providing a comprehensive overview of molecular mechanisms and novel trials involved. PMID- 24151359 TI - Irritable bowel syndrome and organic diseases: a comparative analysis of esophageal motility. AB - AIM: To assess the esophageal motility in patients with irritable bowel syndrome (IBS) and to compare those with patients with autoimmune disorders. METHODS: 15 patients with IBS, 22 with systemic lupus erythematosus (SLE) and 19 with systemic sclerosis (SSc) were prospectively selected from a total of 115 patients at a single university centre and esophageal motility was analysed using standard manometry (Mui Scientific PIP-4-8SS). All patients underwent esophago-gastro duodenoscopy before entering the study so that only patients with normal endoscopic findings were included in the current study. All patients underwent a complete physical, blood biochemistry and urinary examination. The grade of dysphagia was determined for each patient in accordance to the intensity and frequency of the presented esophageal symptoms. Furthermore, disease activity scores (SLEDAI and modified Rodnan score) were obtained for patients with autoimmune diseases. Outcome parameter: A correlation coefficient was calculated between amplitudes, velocity and duration of the peristaltic waves throughout esophagus and patients' dysphagia for all three groups. RESULTS: There was no statistical difference in the standard blood biochemistry and urinary analysis in all three groups. Patients with IBS showed similar pathologic dysphagia scores compared to patients with SLE and SSc. The mean value of dysphagia score was in IBS group 7.3, in SLE group 6.73 and in SSc group 7.56 with a P-value > 0.05. However, the manometric patterns were different. IBS patients showed during esophageal manometry peristaltic amplitudes at the proximal part of esophagus greater than 60 mmHg in 46% of the patients, which was significant higher in comparison to the SLE (11.8%) and SSc-Group (0%, P = 0.003). Furthermore, IBS patients showed lower mean resting pressure of the distal esophagus sphincter (Lower esophageal sphincter, 22 mmHg) when compared with SLE (28 mmHg, P = 0.037) and SSc (26 mmHg, P = 0.052). 23.5% of patients with SLE showed amplitudes greater as 160 mmHg in the distal esophagus (IBS and SSc: 0%) whereas 29.4% amplitudes greater as 100 mmHg in the middle one (IBS: 16.7%, SSc: 5.9% respectively, P = 0.006). Patients with SSc demonstrated, as expected, in almost half of the cases reduced peristalsis or even aperistalsis in the lower two thirds of the esophagus. SSc patients demonstrated a negative correlation coefficient between dysphagia score, amplitude and velocity of peristaltic activity at middle and lower esophagus [r = -0.6, P < 0.05]. CONCLUSION: IBS patients have comparable dysphagia-scores as patients with autoimmune disorders. The different manometric patterns might allow differentiating esophageal symptoms based on IBS from other organic diseases. PMID- 24151358 TI - New insights in bilirubin metabolism and their clinical implications. AB - Bilirubin, a major end product of heme breakdown, is an important constituent of bile, responsible for its characteristic colour. Over recent decades, our understanding of bilirubin metabolism has expanded along with the processes of elimination of other endogenous and exogenous anionic substrates, mediated by the action of multiple transport systems at the sinusoidal and canalicular membrane of hepatocytes. Several inherited disorders characterised by impaired bilirubin conjugation (Crigler-Najjar syndrome type I and type II, Gilbert syndrome) or transport (Dubin-Johnson and Rotor syndrome) result in various degrees of hyperbilirubinemia of either the predominantly unconjugated or predominantly conjugated type. Moreover, disrupted regulation of hepatobiliary transport systems can explain jaundice in many acquired liver disorders. In this review, we discuss the recent data on liver bilirubin handling based on the discovery of the molecular basis of Rotor syndrome. The data show that a substantial fraction of bilirubin conjugates is primarily secreted by MRP3 at the sinusoidal membrane into the blood, from where they are subsequently reuptaken by sinusoidal membrane bound organic anion transporting polypeptides OATP1B1 and OATP1B3. OATP1B proteins are also responsible for liver clearance of bilirubin conjugated in splanchnic organs, such as the intestine and kidney, and for a number of endogenous compounds, xenobiotics and drugs. Absence of one or both OATP1B proteins thus may have serious impact on toxicity of commonly used drugs cleared by this system such as statins, sartans, methotrexate or rifampicin. The liver blood cycling of conjugated bilirubin is impaired in cholestatic and parenchymal liver diseases and this impairment most likely contributes to jaundice accompanying these disorders. PMID- 24151360 TI - Diabetic neuropathy: an evaluation of the use of quercetin in the cecum of rats. AB - AIM: To investigate the effect of quercetin supplementation on the myenteric neurons and glia in the cecum of diabetic rats. METHODS: Total preparations of the muscular tunic were prepared from the ceca of twenty-four rats divided into the following groups: control (C), control supplemented with quercetin (200 mg/kg quercetin body weight) (CQ), diabetic (D) and diabetic supplemented with quercetin (DQ). Immunohistochemical double staining technique was performed with HuC/D (general population)/nitric oxide synthase (nNOS), HuC-D/S-100 and VIP. Density analysis of the general neuronal population HuC/D-IR, the nNOS-IR (nitrergic subpopulation) and the enteric glial cells (S-100) was performed, and the morphometry and the reduction in varicosity population (VIP-IR) in these populations were analyzed. RESULTS: Diabetes promoted a significant reduction (25%) in the neuronal density of the HuC/D-IR (general population) and the nNOS IR (nitrergic subpopulation) compared with the C group. Diabetes also significantly increased the areas of neurons, glial cells and VIP-IR varicosities. Supplementation with quercetin in the DQ group prevented neuronal loss in the general population and increased its area (P < 0.001) and the area of nitrergic subpopulation (P < 0.001), when compared to C group. Quercetin induced a VIP-IR and glial cells areas (P < 0.001) in DQ group when compared to C, CQ and D groups. CONCLUSION: In diabetes, quercetin exhibited a neuroprotective effect by maintaining the density of the general neuronal population but did not affect the density of the nNOS subpopulation. PMID- 24151361 TI - Full robot-assisted gastrectomy with intracorporeal robot-sewn anastomosis produces satisfying outcomes. AB - AIM: To evaluate the feasibility and safety of full robot-assisted gastrectomy with intracorporeal robot hand-sewn anastomosis in the treatment of gastric cancer. METHODS: From September 2011 to March 2013, 110 consecutive patients with gastric cancer at the authors' institution were enrolled for robotic gastrectomies. According to tumor location, total gastrectomy, distal or proximal subtotal gastrectomy with D2 lymphadenectomy was fully performed by the da Vinci Robotic Surgical System. All construction, including Roux-en-Y jejunal limb, esophagojejunal, gastroduodenal and gastrojejunal anastomoses were fully carried out by the intracorporeal robot-sewn method. At the end of surgery, the specimen was removed through a 3-4 cm incision at the umbilicus trocar point. The details of the surgical technique are well illustrated. The benefits in terms of surgical and oncologic outcomes are well documented, as well as the failure rate and postoperative complications. RESULTS: From a total of 110 enrolled patients, radical gastrectomy could not be performed in 2 patients due to late stage disease; 1 patient was converted to laparotomy because of uncontrollable hemorrhage, and 1 obese patient was converted due to difficult exposure; 2 patients underwent extra-corporeal anastomosis by minilaparotomy to ensure adequate tumor margin. Robot-sewn anastomoses were successfully performed for 12 proximal, 38 distal and 54 total gastrectomies. The average surgical time was 272.52 +/- 53.91 min and the average amount of bleeding was 80.78 +/- 32.37 mL. The average number of harvested lymph nodes was 23.1 +/- 5.3. All specimens showed adequate surgical margin. With regard to tumor staging, 26, 32 and 46 patients were staged as I, II and III, respectively. The average hospitalization time after surgery was 6.2 d. One patient experienced a duodenal stump anastomotic leak, which was mild and treated conservatively. One patient was readmitted for intra-abdominal infection and was treated conservatively. Jejunal afferent loop obstruction occurred in 1 patient, who underwent re-operation and recovered quickly. CONCLUSION: This technique is feasible and can produce satisfying postoperative outcomes. It is also convenience and reliable for anastomoses in gastrectomy. Full robotic hand-sewn anastomosis may be a minimally invasive technique for gastrectomy surgery. PMID- 24151362 TI - HER2 in gastric cancer: comparative analysis of three different antibodies using whole-tissue sections and tissue microarrays. AB - AIM: To compare the performance of three commercially available anti-human epidermal growth factor receptor 2 (HER2) antibodies in whole-tissue sections and tissue microarrays (TMAs) of a series of gastric tumors. METHODS: We present a comparative analysis of three anti-HER2 antibodies (HercepTest, 4B5 and SP3) using TMA and whole-tissue sections prepared from the same paraffin blocks of 199 gastric adenocarcinomas operated upon between January 2004 and December 2008 at a Brazilian cancer hospital. The data on the patients' age, sex, the anatomical location of the tumor and the Lauren's histological classification were collected from clinical and pathological records. The immunohistochemical (IHC) results were examined by two pathologists and the cases were classified as positive (3+), equivocal (2+) and negative (0 or 1+), according to the criteria of the IHC scoring system of gastric cancer. TMAs and whole-tissue sections were evaluated separately and independently. All cases yielding discordant IHC results and/or scored as 2+ were subjected to dual-color in situ hybridization in order to determine the final HER2 status. Besides determining the sensitivity and predictive value for HER2-positive status, we measured the accuracy of each antibody by calculating the area under the receiver operating characteristic (ROC) curve. The agreement between the results obtained using the TMAs and those obtained using the whole-tissue sections was assessed by means of Kappa coefficient. RESULTS: Intratumoral heterogeneity of HER2 expression was observed with all antibodies. HER2-positive expression (3+) in the whole-tissue sections was observed in 23 cases (11.6%) using the 4B5 antibody, in 18 cases (9.1%) using the SP3 antibody and in 10 cases (5.1%) using the HercepTest antibody. In the TMAs, 11 positive cases (5.6%) were identified using SP3 antibody, 9 (4.6%) using the 4B5 antibody and 6 (3%) using the HercepTest antibody. The sensitivity using whole-tissue sections and TMA, respectively, was 95.2% and 42.9% with 4B5, 90.5% and 66.7% with SP3 and 47.6% and 42.9% with HercepTest. The accuracy, calculated from the area under the ROC curve, using whole-tissue sections and TMA, respectively, was 0.91 and 0.79 by 4B5, 0.86 and 0.80 by SP3 and 0.73 and 0.71 by HercepTest. The concordance of the results obtained using whole-tissue sections and TMA was 97.4% (Kappa 0.75) using HercepTest, 85.6% (Kappa 0.56) using SP3 and 84.1% (Kappa 0.38) using 4B5. CONCLUSION: The use of the 4B5 antibody on whole tissue sections was the most accurate IHC method for evaluating HER2 expression in gastric adenocarcinoma. PMID- 24151363 TI - Emergency admissions due to swallowed foreign bodies in adults. AB - AIM: To study a retrospective analysis of patients who presented to the emergency departments (ED) with complaints related to foreign body ingestions. METHODS: Patients older than 16 years of age who presented to the ED between January 1(st) and December 31(st) of 2010 with complaints related to swallowed foreign bodies were identified from electronic health records and patient charts. RESULTS: A total of 100 patients presented with a complaint of foreign body ingestion during the study period. Overall, an X-ray was performed on 75 patients, and a fiberoptic evaluation was performed on 45 patients. A foreign body was detected in 46 (46%) patients. The diagnostic yield of the X-ray was 27 (36%) out of 75 patients, while the diagnostic yield of the fiberoptic evaluations was 21 (47%) out of 45 patients. The detected foreign bodies were mostly located in the esophagus (17 out of 46 foreign bodies detected). When the types of ingested foreign bodies were evaluated, 52 (52%) patients reported ingesting food, and 19 (19%) patients reported swallowing pins. An X-ray was performed on 33 patients with accidental food ingestions but yielded a positive result in only two cases. In 12 out of 21 patients with accidental food ingestion who underwent fiberoptic evaluation, the foreign material was detected and removed. CONCLUSION: Plain radiography is helpful in the localization of radiopaque swollen foreign bodies, while fiberoptic methods are useful as both diagnostic and therapeutic tools, regardless of radiopacity. PMID- 24151364 TI - Nonalcoholic fatty liver disease is associated with coronary artery disease in Koreans. AB - AIM: To investigate whether nonalcoholic fatty liver disease (NAFLD) affects coronary artery disease (CAD) and identify candidate mediators. METHODS: Patients who underwent coronary angiography were consecutively recruited. The patients were classified into four groups by coronary artery stenosis: A, insignificant; B, one-vessel disease; C, two-vessel disease; and D, three-vessel disease. Abdominal ultrasonography was performed to determine the presence of a fatty liver and categorize by grade: 0, no evidence; 1, mild; 2, moderate; and 3, severe. We measured not only known CAD risk factors, but also serum insulin, HOMA index, adiponectin, interleukin-6, tumor necrosis factor-alpha and high sensitivity C-reactive protein levels. RESULTS: Of the 134 patients who met the inclusion criteria, 82 (61.2%) had ultrasonographically diagnosed NAFLD. Among the 46 patients with CAD, 37 (80.4%) had evidence of a fatty liver. The two groups (A vs B-D) were significantly different in terms of age, total cholesterol, triglycerides, low-density lipoprotein levels and fatty liver. Coronary artery stenosis was strongly associated with fatty liver in a grade dependent manner (P = 0.025). In binary logistic regression, NAFLD was a significant independent predictor of CAD (P = 0.03, OR = 1.685; 95%CI: 1.051 2.702). Among the candidate mediators, the serum adiponectin level showed a trend toward lowering based on CAD progression (P = 0.071). CONCLUSION: NAFLD is an independent risk factor for CAD in a grade-dependent manner. Moreover, adiponectin might be related to the pathogenesis of NAFLD. PMID- 24151365 TI - Diet of patients after pouch surgery may affect pouch inflammation. AB - AIM: To investigate the diet of pouch patients compared to healthy controls, and to correlate pouch patients' diet with disease behavior. METHODS: Pouch patients were recruited and prospectively followed-up at the Comprehensive Pouch Clinic at the Tel Aviv Sourasky Medical Center. Pouch behavior was determined based on clinical, endoscopic and histological criteria. Healthy age- and sex-matched volunteers were selected from the "MABAT" Israeli Nutrition and Public Health Governmental Study and served as the control group. All the participants completed a 106-item food frequency questionnaire categorized into food groups and nutritional values based on those used in the United States Department of Agriculture food pyramid and the Israeli food pyramid. Data on Dietary behavior, food avoidance, the use of nutritional supplements, physical activity, smoking habits, and body-mass index (BMI) were also obtained. Pouch patients who had familial adenomatous polyposis (n = 3), irritable pouch syndrome (n = 4), or patients whose pouch surgery took place less than one year previously (n = 5) were excluded from analysis. RESULTS: The pouch patients (n = 80) consumed significantly more from the bakery products food group (1.2 +/- 1.4 servings/d vs 0.6 +/- 1.1 servings/d, P < 0.05) and as twice as many servings from the oils and fats (4.8 +/- 3.4 servings/d vs 2.4 +/- 2 servings/d, P < 0.05), and the nuts and seeds food group (0.3 +/- 0.6 servings/d vs 0.1 +/- 0.4 servings/d, P < 0.05) compared to the controls (n = 80). The pouch patients consumed significantly more total fat (97.6 +/- 40.5 g/d vs 84.4 +/- 39 g/d, P < 0.05) and fat components [monounsaturated fatty acids (38.4 +/- 16.4 g/d vs 30 +/- 14 g/d, P < 0.001), and saturated fatty acids (30 +/- 15.5 g/d vs 28 +/- 14.1 g/d, P < 0.00)] than the controls. In contrast, the pouch patients consumed significantly fewer carbohydrates (305.5 +/- 141.4 g/d vs 369 +/- 215.2 g/d, P = 0.03), sugars (124 +/- 76.2 g/d vs 157.5 +/- 90.4 g/d, P = 0.01), theobromine (77.8 +/- 100 mg/d vs 236.6 +/- 244.5 mg/d, P < 0.00), retinol (474.4 +/- 337.1 MUg/d vs 832.4 +/- 609.6 MUg/d, P < 0.001) and dietary fibers (26.2 +/- 15.4 g/d vs 30.7 +/- 14 g/d, P = 0.05) than the controls. Comparisons of the food consumption of the patients without (n = 23) and with pouchitis (n = 45) showed that the former consumed twice as many fruit servings as the latter (3.6 +/- 4.1 servings/d vs 1.8 +/- 1.7 servings/d, respectively, P < 0.05). In addition, the pouchitis patients consumed significantly fewer liposoluble antioxidants, such as cryptoxanthin (399 +/- 485 MUg/d vs 890.1 +/- 1296.8 MUg/d, P < 0.05) and lycopene (6533.1 +/- 6065.7 MUg/d vs 10725.7 +/- 10065.9 MUg/d, P < 0.05), and less vitamin A (893.3 +/- 516 MUg/d vs 1237.5 +/- 728 MUg/d, P < 0.05) and vitamin C (153.3 +/- 130 mg/d vs 285.3 +/- 326.3 mg/d, P < 0.05) than the patients without pouchitis. The mean BMI of the pouchitis patients was significantly lower than the BMI of the patients with a normal pouch: 22.6 +/- 3.2 vs 27 +/- 4.9 (P < 0.001). CONCLUSION: Decreased consumption of antioxidants by patients with pouchitis may expose them to the effects of inflammatory and oxidative stress and contribute to the development of pouchitis. PMID- 24151366 TI - Consumption of spicy foods and the prevalence of irritable bowel syndrome. AB - AIM: To explore the association between consumption of spicy foods and prevalence of irritable bowel syndrome (IBS) among Iranian adults. METHODS: In this cross sectional study, data from 4763 Iranian adult participants were used. Consumption of spicy foods was estimated using a dietary habits questionnaire that included a question on spicy foods consumption: "how frequently do you use spicy foods (pepper, curry, ginger, cinnamon and turmeric) during a week?" Participants could respond to the question by choosing one of these choices: never, 1-3 times, 4-6 times, 7-9 times, or more than 10 times per week. A modified Persian version of the Rome III questionnaire was used to determine the prevalence of IBS. RESULTS: IBS was prevalent in 21.7% (18.6% of men and 24.1% of women) of the study population. After controlling for potential confounders including dietary behaviors, those consuming spicy foods >= 10 times per week were 92% more likely to have IBS compared with those who never consumed spicy foods (OR = 1.92; 95%CI: 1.23-3.01, P trend < 0.01). The association remained significant even after taking lactose intolerance into account (OR = 1.85; 95%CI: 1.18-2.90, P trend < 0.01). Stratified analysis by gender revealed that the association between consumption of spicy foods and IBS was not significant in men; however, a significant association was found among women after taking potential cofounders, including meal regularity and lactose intolerance, into account. Women who consumed spicy foods >= 10 times per week were two times more likely to have IBS compared with those who never consumed spicy foods (OR = 2.03; 95%CI: 1.09-3.77, P trend = 0.02). CONCLUSION: Consumption of spicy foods is directly associated with IBS, particularly in women. Further, prospective studies are warranted to (1) examine this association in other populations; and (2) evaluate whether dietary interventions, for example a reduction in spice consumption, would improve IBS symptoms. PMID- 24151367 TI - Midterm outcome of stapled transanal rectal resection for obstructed defecation syndrome: a single-institution experience in China. AB - AIM: To assess midterm results of stapled transanal rectal resection (STARR) for obstructed defecation syndrome (ODS) and predictive factors for outcome. METHODS: From May 2007 to May 2009, 75 female patients underwent STARR and were included in the present study. Preoperative and postoperative workup consisted of standardized interview and physical examination including proctoscopy, colonoscopy, anorectal manometry, and defecography. Clinical and functional results were assessed by standardized questionnaires for the assessment of constipation constipation scoring system (CSS), Longo's ODS score, and symptom severity score (SSS), incontinence Wexner incontinence score (WS), quality of life Patient Assessment of Constipation-Quality of Life Questionnaire (PAC-QOL), and patient satisfaction visual analog scale (VAS). Data were collected prospectively at baseline, 12 and 30 mo. RESULTS: The median follow-up was 30 mo (range, 30-46 mo). Late postoperative complications occurred in 11 (14.7%) patients. Three of these patients required procedure-related reintervention (one diverticulectomy and two excision of staple granuloma). Although the recurrence rate was 10.7%, constipation scores (CSS, ODS score and SSS) significantly improved after STARR (P < 0.0001). Significant reduction in ODS symptoms was matched by an improvement in the PAC-QOL and VAS (P < 0.0001), and the satisfaction index was excellent in 25 (33.3%) patients, good in 23 (30.7%), fairly good in 14 (18.7%), and poor in 13 (17.3%). Nevertheless, the WS increased after STARR (P = 0.0169). Incontinence was present or deteriorated in 8 (10.7%) patients; 6 (8%) of whom were new onsets. Univariate analysis revealed that the occurrence of fecal incontinence (preoperative, postoperative or new-onset incontinence; P = 0.028, 0.000, and 0.007, respectively) was associated with the success of the operation. CONCLUSION: STARR is an acceptable procedure for the surgical correction of ODS. However, its impact on symptomatic recurrence and postoperative incontinence may be problematic. PMID- 24151368 TI - A new endoscopic ultrasonography image processing method to evaluate the prognosis for pancreatic cancer treated with interstitial brachytherapy. AB - AIM: To develop a fuzzy classification method to score the texture features of pancreatic cancer in endoscopic ultrasonography (EUS) images and evaluate its utility in making prognosis judgments for patients with unresectable pancreatic cancer treated by EUS-guided interstitial brachytherapy. METHODS: EUS images from our retrospective database were analyzed. The regions of interest were drawn, and texture features were extracted, selected, and scored with a fuzzy classification method using a C++ program. Then, patients with unresectable pancreatic cancer were enrolled to receive EUS-guided iodine 125 radioactive seed implantation. Their fuzzy classification scores, tumor volumes, and carbohydrate antigen 199 (CA199) levels before and after the brachytherapy were recorded. The association between the changes in these parameters and overall survival was analyzed statistically. RESULTS: EUS images of 153 patients with pancreatic cancer and 63 non-cancer patients were analyzed. A total of 25 consecutive patients were enrolled, and they tolerated the brachytherapy well without any complications. There was a correlation between the change in the fuzzy classification score and overall survival (Spearman test, r = 0.616, P = 0.001), whereas no correlation was found to be significant between the change in tumor volume (P = 0.663), CA199 level (P = 0.659), and overall survival. There were 15 patients with a decrease in their fuzzy classification score after brachytherapy, whereas the fuzzy classification score increased in another 10 patients. There was a significant difference in overall survival between the two groups (67 d vs 151 d, P = 0.001), but not in the change of tumor volume and CA199 level. CONCLUSION: Using the fuzzy classification method to analyze EUS images of pancreatic cancer is feasible, and the method can be used to make prognosis judgments for patients with unresectable pancreatic cancer treated by interstitial brachytherapy. PMID- 24151369 TI - Ectopic liver: different manifestations, one solution. AB - Developmental abnormalities are rare in the liver. This study presents two case reports of ectopic liver. The first case was a 31-year-old male with clinical indication for laparoscopic appendectomy. Laparoscopy identified a perforated appendix and an unknown tumorous lesion in the ligamentum hepato umbilicalis. The patient underwent a laparoscopic appendectomy, intraoperative lavage of the peritoneal cavity, and extirpation of the lesion in the ligamentum hepato umbilicalis. Histopathological examination of the excised tumor revealed that it comprised liver tissue with fibrinous changes. The tumor was completely separate from the liver with no connection. It was classified as an ectopic liver. No further therapy was required. The second case was a 59-year-old male with a tumor on the upper pole of the spleen, incidentally diagnosed in an ultrasound examination. The biopsy raised suspicion of hepatocellular carcinoma. A positron emission tomography-computed tomography examination revealed accumulation of F-18 fluorodeoxyglucose only in the tumor. The patient underwent a splenectomy with a resection and reconstruction of diaphragm. After the hepatocellular carcinoma was confirmed, adjuvant therapy (sorafenib) was initialized. The operations and postoperative recoveries were uncomplicated in both cases. Despite the low incidence of ectopic liver and rare complications, it is necessary to maintain awareness of this possibility. The potential malignancy risk for ectopic liver tissue is the basis for radical surgical removal. Therapy for hepatocellular carcinoma in an ectopic liver follows the same guidelines as those followed for treating the "mother" liver. PMID- 24151370 TI - A case of a duodenal duplication cyst presenting as melena. AB - Duodenal duplication cysts are benign rare congenital anomalies reported mainly in the pediatric population, but seldom in adults. Symptoms depend on the type and location and can present as abdominal pain, distension, dysphagia or dyspepsia. They have been reported to be responsible for duodenal obstruction, pancreatitis and, in rare cases, gastrointestinal bleeding. We present a case of a duodenal duplication cyst in a 43-year-old man presenting as melena. Initial gastroduodenoscopy and colonoscopy did not reveal any bleeding focus. However, the patient began passing melena after 3 d, with an acute decrease in hemoglobin levels. Subsequent studies revealed a duplication cyst in the second portion of the duodenum which was surgically resected. Histology revealed a duodenal duplication cyst consisting of intestinal mucosa. There was no further bleeding and the patient recovered completely. In rare cases, duodenal duplication cysts might cause gastrointestinal bleeding and should be included in the differential diagnosis. PMID- 24151371 TI - Simultaneous intrahepatic and subgaleal hemorrhage in antiphospholipid syndrome following anticoagulation therapy. AB - Warfarin is a widely used anticoagulant. Interindividual differences in drug response, a narrow therapeutic range and the risk of bleeding render warfarin difficult to use clinically. An 18-year-old woman with antiphospholipid syndrome received long-term warfarin therapy for a recurrent deep vein thrombosis. Six years later, she developed right flank pain. We diagnosed intrahepatic and subgaleal hemorrhages secondary to anticoagulation therapy. After stopping oral anticoagulation, a follow-up computed tomography showed improvement in the hemorrhage. After restarting warfarin because of a recurrent thrombosis, the intrahepatic hemorrhage recurred. We decided to start clopidogrel and hydroxychloroquine instead of warfarin. The patient has not developed further recurrent thrombotic or bleeding episodes. Intrahepatic hemorrhage is a very rare complication of warfarin, and our patient experienced intrahepatic and subgaleal hemorrhage although she did not have any risk factors for bleeding or instability of the international normalized ratio control. PMID- 24151372 TI - Ileal duplication mimicking intestinal intussusception: a congenital condition rarely reported in adult. AB - Intestinal duplication is an uncommon congenital condition in young adults. A 25 year-old man complained of chronic, intermittent abdominal pain for 3 years following previous appendectomy for the treatment of suspected appendicitis. Abdominal discomfort and pain, suggestive of intestinal obstruction, recurred after operation. A tubular mass was palpable in the right lower quadrant. Computed tomography enterography scan identified suspicious intestinal intussusception, while Tc-99m pertechnetate scintigraphy revealed a cluster of strip-like abnormal radioactivity in the right lower quadrant. On exploratory laparotomy, a tubular-shaped ileal duplication cyst was found arising from the mesenteric margin of the native ileal segment located 15 cm proximal to the ileocecal valve. Ileectomy was performed along with the removal of the duplication disease, and the end-to-end anastomosis was done to restore the gastrointestinal tract continuity. Pathological examination showed ileal duplication with ectopic gastric mucosa. The patient experienced an eventless postoperative recovery and remained asymptomatic within 2 years of postoperative follow-up. PMID- 24151373 TI - Plastic tube-assisted gastroscopic removal of embedded esophageal metal stents: a case report. AB - A patient with stent embedding after placement of an esophageal stent for an esophagobronchial fistula was treated with an ST-E plastic tube inserted into the esophagus to the upper end of the stent using gastroscopy. The gastroscope was guided into the esophagus through the ST-E tube, and an alligator forceps was inserted into the esophagus through the ST-E tube alongside the gastroscope. Under gastroscopy, the stent wire was grasped with the forceps and pulled into the ST-E tube. When resistance was met during withdrawal, the gastroscope was guided further to the esophageal section where the stent was embedded. Biopsy forceps were guided through a biopsy hole in the gastroscope to the embedded stent to remove silicone membranes and connection threads linking the Z-shaped wire mesh. While the lower section of the Z-shaped stent was fixed by the biopsy forceps, the alligator forceps were used to pull the upper section of the metal wire until the Z-shaped metal loops elongated. The wire mesh of the stent was then removed in stages through the ST-E tube. Care was taken to avoid bleeding and perforation. Under the assistance of an ST-E plastic tube, an embedded esophageal metal stent was successfully removed with no bleeding or perforation. The patient experienced an uneventful recovery after surgery. Plastic tube assisted gastroscopic removal of embedded metal stents can be minimally invasive, safe, and effective. PMID- 24151374 TI - Strategies to reduce pulmonary complications after esophagectomy. AB - Esophagectomy, the surgical removal of all or part of the esophagus, is a surgical procedure that is associated with high morbidity and mortality. Pulmonary complications are an especially important postoperative problem. Therefore, many perioperative strategies to prevent pulmonary complications after esophagectomy have been investigated and introduced in daily clinical practice. Here, we review these strategies, including improvement of patient performance and technical advances such as minimally invasive surgery that have been implemented in recent years. Furthermore, interventions such as methylprednisolone, neutrophil elastase inhibitor and epidural analgesia, which have been shown to reduce pulmonary complications, are discussed. Benefits of the commonly applied routine nasogastric decompression, delay of oral intake and prophylactic mechanical ventilation are unclear, and many of these strategies are also evaluated here. Finally, we will discuss recent insights and new developments aimed to improve pulmonary outcomes after esophagectomy. PMID- 24151375 TI - Risk prediction of hepatitis B virus-related hepatocellular carcinoma in the era of antiviral therapy. AB - Chronic hepatitis B (CHB)-related hepatocellular carcinoma (HCC) is a major health problem in Asian-Pacific regions. Antiviral therapy reduces, but does not eliminate the risk of HCC. It would be a heavy financial burden in most low and middle economic countries if all CHB patients received antiviral therapy and HCC surveillance. Thus, there is a need for accurate risk prediction to assist prognostication, decisions on the need for antiviral therapy and HCC surveillance. A few well-established risk factors for HCC, namely advanced age, male gender, high viral load, cirrhosis etc., are the core components of three HCC risk scores: CU-HCC, GAG-HCC and REACH-B scores. These 3 scores were confirmed to be accurate in predicting HCC up to 10 years in treatment-naive patients. Their validity and applicability have recently been demonstrated in a large cohort of entecavir treatment patients. A decrease in risk scores after antiviral therapy translates to a lower risk of HCC. These findings support the application of HCC risk scores in all CHB patients. Different levels of care and different intensities of HCC surveillance should be offered according to the risk profile of patients. Patients at risk of HCC should undergo regular HCC surveillance, even when they are receiving antiviral treatment. PMID- 24151376 TI - Gastroesophageal reflux disease: Update on inflammation and symptom perception. AB - Although gastroesophageal reflux disease (GERD) is a common disorder in Western countries, with a significant impact on quality of life and healthcare costs, the mechanisms involved in the pathogenesis of symptoms remain to be fully elucidated. GERD symptoms and complications may result from a multifactorial mechanism, in which acid and acid-pepsin are the important noxious factors involved. Prolonged contact of the esophageal mucosa with the refluxed content, probably caused by a defective anti-reflux barrier and luminal clearance mechanisms, would appear to be responsible for macroscopically detectable injury to the esophageal squamous epithelium. Receptors on acid-sensitive nerve endings may play a role in nociception and esophageal sensitivity, as suggested in animal models of chronic acid exposure. Meanwhile, specific cytokine and chemokine profiles would appear to underlie the various esophageal phenotypes of GERD, explaining, in part, the genesis of esophagitis in a subset of patients. Despite these findings, which show a significant production of inflammatory mediators and neurotransmitters in the pathogenesis of GERD, the relationship between the hypersensitivity and esophageal inflammation is not clear. Moreover, the large majority of GERD patients (up to 70%) do not develop esophageal erosions, a variant of the condition called non-erosive reflux disease. This summary aims to explore the inflammatory pathway involved in GERD pathogenesis, to better understand the possible distinction between erosive and non-erosive reflux disease patients and to provide new therapeutic approaches. PMID- 24151377 TI - Proton pump inhibitor resistance, the real challenge in gastro-esophageal reflux disease. AB - Gastro-esophageal reflux disease (GERD) is one of the most prevalent chronic diseases. Although proton pump inhibitors (PPIs) represent the mainstay of treatment both for healing erosive esophagitis and for symptom relief, several studies have shown that up to 40% of GERD patients reported either partial or complete lack of response of their symptoms to a standard PPI dose once daily. Several mechanisms have been proposed as involved in PPIs resistance, including ineffective control of gastric acid secretion, esophageal hypersensitivity, ultrastructural and functional changes in the esophageal epithelium. The diagnostic evaluation of a refractory GERD patients should include an accurate clinical evaluation, upper endoscopy, esophageal manometry and ambulatory pH impedance monitoring, which allows to discriminate non-erosive reflux disease patients from those presenting esophageal hypersensitivity or functional heartburn. Treatment has been primarily based on doubling the PPI dose or switching to another PPI. Patients with proven disease, not responding to PPI twice daily, are eligible for anti-reflux surgery. PMID- 24151378 TI - Gastro-esophageal reflux disease and obesity, where is the link? AB - The confluence between the increased prevalence of gastro-esophageal reflux disease (GERD) and of obesity has generated great interest in the association between these two conditions. Several studies have addressed the potential relationship between GERD and obesity, but the exact mechanism by which obesity causes reflux disease still remains to be clearly defined. A commonly suggested pathogenetic pathway is the increased abdominal pressure which relaxes the lower esophageal sphincter, thus exposing the esophageal mucosal to gastric content. Apart from the mechanical pressure, visceral fat is metabolically active and it has been strongly associated with serum levels of adipo-cytokines including interleukin-6 and tumor necrosis factor alpha, which may play a role in GERD or consequent carcinogenesis. This summary is aimed to explore the potential mechanisms responsible for the association between GERD and obesity, and to better understand the possible role of weight loss as a therapeutic approach for GERD. PMID- 24151379 TI - Concepts of oxidative stress and antioxidant defense in Crohn's disease. AB - Oxygen free radical and lipid peroxides (oxidative stress) are highly reactive and represent very damaging compounds. Oxidative stress could be a major contributing factor to the tissue injury and fibrosis that characterize Crohn's disease. An imbalance between increased reactive oxygen species levels and decreased antioxidant defenses occurs in Crohn's patients. Decreased blood levels of vitamins C and E and decreased intestinal mucosal levels of CuZn superoxide dismutase, glutathione, vitamin A, C, E, and beta-carotene have been reported for Crohn's patients. Increased levels of proinflammatory cytokines, such as interleukin-1 and -8 and tumor necrosis factor, have been detected in inflammatory bowel disease. Oxidative stress significantly increased the production of neutrophils, chemokines, and interleukin-8. These effects were inhibited by antioxidant vitamins and arachidonic acid metabolite inhibitors in human intestinal smooth muscle cells isolated from the bowels of Crohn's disease patients. The main pathological feature of Crohn's disease is an infiltration of polymorphonuclear neutrophils and mononuclear cells into the affected part of the intestine. Activated neutrophils produce noxious substances that cause inflammation and tissue injury. Due to the physiological and biochemical actions of reactive oxygen species and lipid peroxides, many of the clinical and pathophysiological features of Crohn's disease might be explained by an imbalance of increased reactive oxygen species and a net decrease of antioxidant molecules. This review describes the general concepts of free radical, lipid peroxide and antioxidant activities and eventually illustrates their interferences in the development of Crohn's strictures. PMID- 24151380 TI - Current position of ALPPS in the surgical landscape of CRLM treatment proposals. AB - The Authors summarize problems, criticisms but also advantages and indications regarding the recent surgical proposal of associating liver partition and portal vein ligation (PVL) for staged hepatectomy (ALPPS) for the surgical management of colorectal liver metastases. Looking at published data, the technique, when compared with other traditional and well established methods such as PVL/portal vein embolisation (PVE), seems to give real advantages in terms of volumetric gain of future liver remnant. However, major concerns are raised in the literature and some questions remain unanswered, preliminary experiences seem to be promising. The method has been adopted all over the world over the last 2 years, even if oncological long-term results remain unknown, and benefit for patients is questionable. No prospective studies comparing traditional methods (PVE, PVL or classical 2 staged hepatectomy) with ALPPS are available to date. Technical reinterpretations of the original method were also proposed in order to enhance feasability and increase safety of the technique. More data about morbidity and mortality are also expected. The real role of ALPPS is, to date, still to be established. Large clinical studies, even if, for ethical reasons, in well selected cohorts of patients, are expected to better define the indications for this new surgical strategy. PMID- 24151381 TI - Pleiotrophin promotes perineural invasion in pancreatic cancer. AB - Perineural invasion (PNI) in pancreatic cancer is an important cause of local recurrence, but little is known about its mechanism. Pleiotrophin (PTN) is an important neurotrophic factor. It is of interest that our recent experimental data showed its involvement in PNI of pancreatic cancer. PTN strongly presents in the cytoplasm of pancreatic cancer cells, and high expression of PTN and its receptor may contribute to the high PNI of pancreatic cancer. Correspondingly, PNI is prone to happen in PTN-positive tumors. We thus hypothesize that, as a neurite growth-promoting factor, PTN may promote PNI in pancreatic cancer. PTN is released at the time of tumor cell necrosis, and binds with its high-affinity receptor, N-syndecan on pancreatic nerves, to promote neural growth in pancreatic cancer. Furthermore, neural destruction leads to a distorted neural homeostasis. Neurons and Schwann cells produce more N-syndecan in an effort to repair the pancreatic nerves. However, the abundance of N-syndecan attracts further PTN positive cancer cells to the site of injury, creating a vicious cycle. Ultimately, increased PTN and N-syndecan levels, due to the continuous nerve injury, may promote cancer invasion and propagation along the neural structures. Therefore, it is meaningful to discuss the relationship between PTN/N-syndecan signaling and PNI in pancreatic cancer, which may lead to a better understanding of the mechanism of PNI in pancreatic cancer. PMID- 24151382 TI - Effects of integrin-targeted photodynamic therapy on pancreatic carcinoma cell. AB - AIM: To investigate the effects of photodynamic therapy with quantum dots arginine-glycine-aspartic acid (RGD) probe as photosensitizer on the proliferation and apoptosis of pancreatic carcinoma cells. METHODS: Construction of quantum dots-RGD probe as photosensitizer for integrin-targeted photodynamic therapy was accomplished. After cells were treated with photodynamic therapy (PDT), the proliferation of SW1990 cells were measured by methyl thiazolyl tetrazolium assay. Morphologic changes, cell cycle retardance and apoptosis were observed under fluoroscope and flow cytometry. The expression of myeloid cell leukemia-1 (Mcl-1), protein kinase B (Akt) and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) mRNA were detected by reverse transcription polymerase chain reaction. The amount of reactive oxygen species were also evaluated by fluorescence probe. RESULTS: The photodynamic therapy with quantum dots-RGD probe as photosensitizer significantly inhibited cell proliferation (P < 0.01). Apoptotic cells and morphologic changes could be found under optical microscope. The FCM revealed PDT group had more significant cell apoptosis rate compared to control cells (F = 130.617, P < 0.01) and cell cycle G0/G1 and S retardance (P < 0.05) compared to control cells. The expression of Mcl-1 and Akt mRNA were down-regulated, while expression of TRAIL mRNA was up-regulated after cells treated with PDT. PDT group had more significant number of cells producing reactive oxygen species compared to control cells (F = 3262.559, P < 0.01). CONCLUSION: The photodynamic therapy with quantum dots-RGD probe as photosensitizer significantly inhibits cell proliferation and increases apoptosis in SW1990 cells. PMID- 24151383 TI - Characteristics and prognosis of gastric cancer in patients aged >= 70 years. AB - AIM: To elucidate the prognostic value of age for gastric cancer and identify the optimal treatment for elderly gastric cancer patients. METHODS: We enrolled 920 patients with gastric cancer who underwent gastrectomy between January 2003 and December 2007 in our center. Patients were categorized into three groups: younger group (age < 50 years), middle-aged group (50-69 years), and elderly group (>= 70 years). Clinicopathological features were compared among the three groups and potential prognostic factors were analyzed. The log-rank test was used to assess statistical differences between curves. Independent prognostic factors were identified by the Cox proportional hazards regression model. Stratified analysis was used to investigate the impact of age on survival at each stage. Cancer specific survival was also compared among the three groups by excluding deaths due to reasons other than gastric cancer. We analyzed the potential prognostic factors for patients aged >= 70 years. Finally, the impact of extent of lymphadenectomy and postoperative chemotherapy on survival for each age group was evaluated. RESULTS: In the elderly group, there was a male predominance. At the same time, cancers of the upper third of the stomach, differentiated type, and less-invasive surgery were more common than in the younger or middle-aged groups. Elderly patients were more likely to have advanced tumor-node-metastasis (TNM) stage and larger tumors, but less likely to have distant metastasis. Although 5 year overall survival (OS) rate specific to gastric cancer was not significantly different among the three groups, elderly patients demonstrated a significantly lower 5-year OS rate than the younger and middle-aged patients (elderly vs middle aged vs younger patients = 22.0% vs 36.6% vs 38.0%, respectively). In the TNM stratified analysis, the differences in OS were only observed in patients with II and III tumors. In multivariate analysis, only surgical margin status, pT4, lymph node metastasis, M1 and sex were independent prognostic factors for elderly patients. The 5-year OS rate did not differ between elderly patients undergoing D1 and D2 lymph node resection, and these patients benefited little from chemotherapy. CONCLUSION: Age >= 70 years was an independent prognostic factor for gastric cancer after gastrectomy. D1 resection is appropriate and postoperative chemotherapy is possibly unnecessary for elderly patients with gastric cancer. PMID- 24151384 TI - Computed tomography findings of pneumatosis and portomesenteric venous gas in acute bowel ischemia. AB - AIM: To use more representative sample size to evaluate whether computed tomography (CT) scan evidence of the concomitant presence of pneumatosis and portomesenteric venous gas is a predictor of transmural bowel necrosis. METHODS: Data from 208 patients who were referred for a diagnosis of bowel ischemia were retrospectively reviewed. Only patients who underwent a surgical intervention following a diagnosis of bowel ischemia who also had a post-operative histological confirmation of such a diagnosis were included. Patients were split into two groups according to the presence of histological evidence of transmural bowel ischemia (case group) or partial bowel ischemia (control group). CT images were reviewed for findings of ischemia, including mural thickening, pneumatosis, bowel distension, portomesenteric venous gas and arterial or venous thrombi. RESULTS: A total of 248 subjects who underwent surgery for bowel ischemia were identified. Among the 208 subjects enrolled in our study, transmural bowel necrosis was identified in 121 subjects (case group), and partial bowel necrosis was identified in 87 subjects (control group). Based on CT findings, including mural thickening, bowel distension, pneumatosis, pneumatosis plus portomesenteric venous gas and presence of thrombi or emboli, there were no significant differences between the case and control groups. The concomitant presence of pneumatosis and porto-mesenteric venous gas showed an odds ratio of 1.95 (95%CI: 0.491-7.775, P = 0.342) for the presence of transmural necrosis. The presence of pneumatosis plus porto-mesenteric venous gas exhibited good specificity (83%) but low sensitivity (17%) in the identification of transmural bowel infarction. Accordingly, the positive and negative predictive values were 60% and 17%, respectively. CONCLUSION: Although pneumatosis plus porto-mesenteric venous gas is associated with bowel ischemia, we have demonstrated that their co-occurrence cannot be used as diagnostic signs of transmural necrosis. PMID- 24151385 TI - Prevalence of Helicobacter pylori virulence genotypes among children in Eastern Turkey. AB - AIM: To identify the virulence genotypes of Helicobacter pylori (H. pylori) if present in children in Eastern Turkey and if those genotypes are mostly associated with severe clinical presentations. METHODS: A total of 49 H. pylori positive Turkish children (42 with antral nodularity and 7 with peptic ulcer) who underwent upper gastrointestinal endoscopy with abdominal symptoms during the period from March 2011 to September 2012 were enrolled in this study. Antral nodularity was diagnosed endoscopically by two of the authors. We determined for the presence of cagA, vacA, cagE, iceA and babA2 genotypes of H. pylori isolates in DNA obtained directly from frozen gastric biopsy samples by polymerase chain reaction test using specific primers. RESULTS: Of the 49 H. pylori isolates studied, 61.2%, 91.8%, 22.4%, 28.6%, 57.1% and 40.8% were positive for the cagA, vacA s1, cagE, iceA1, iceA2 and babA2 genes, respectively. We showed that the most common vacA subtype was s1a (79.6%). However, the s2 gene was found less frequently with an isolation rate of 8.2% of the H. pylori isolates. The genotypes iceA2 and vacA s1m2 were the most frequently found types in children with antral nodularity. In addition, the genotypes iceA1, babA2 and vacA s1m1 were found in similar ratios in all the H. pylori isolates obtained from children with peptic ulcer. The genotypes vacA s2m1 and s1c were not observed in any of isolates studied. CONCLUSION: This study showed that vacA s1m2, cagA and iceA2 were the most common genotypes, and no association between antral nodularity and genotypes was observed. PMID- 24151386 TI - Bariatric surgery and diabetes remission: sleeve gastrectomy or mini-gastric bypass? AB - AIM: To investigate the weight loss and glycemic control status [blood glucose, hemoglobin A1c (HbA1c) and hypoglycaemic treatment]. METHODS: The primary risk factor for type 2 diabetes is obesity, and 90% of all patients with type 2 diabetes are overweight or obese. Although a remarkable effect of bariatric surgery is the profound and durable resolution of type 2 diabetes clinical manifestations, little is known about the difference among various weight loss surgical procedures on diabetes remission. Data from patients referred during a 3 year period (from January 2009 to December 2011) to the University of Naples "Federico II" diagnosed with obesity and diabetes were retrieved from a prospective database. The patients were split into two groups according to the surgical intervention performed [sleeve gastrectomy (SG) and mini-gastric bypass (MGB)]. Weight loss and glycemic control status (blood glucose, HbA1c and hypoglycaemic treatment) were evaluated. RESULTS: A total of 53 subjects who underwent sleeve gastrectomy or mini-gastric bypass for obesity and diabetes were screened for the inclusion in this study. Of these, 4 subjects were excluded because of surgical complications, 7 subjects were omitted because young surgeons conducted the operations and 11 subjects were removed because of the lack of follow-up. Thirty-one obese patients were recruited for this study. A total of 15 subjects underwent SG (48.4%), and 16 underwent MGB (51.6%). After adjusting for various clinical and demographic characteristics in a multivariate logistic regression analysis, high hemoglobin A1c was determined to be a negative predictor of diabetes remission at 12 mo (OR = 0.366, 95%CI: 0.152-0.884). Using the same regression model, MGB showed a clear trend toward higher diabetes remission rates relative to SG (OR = 3.780, 95%CI: 0.961-14.872). CONCLUSION: Although our results are encouraging regarding the effectiveness of mini-gastric bypass on diabetes remission, further studies are needed to provide definitive conclusions in selecting the ideal procedure for diabetes remission. PMID- 24151387 TI - No evidence of HPV DNA in esophageal squamous cell carcinoma in a population of Southern Brazil. AB - AIM: To investigate the association between human papillomavirus (HPV) and esophageal squamous cell carcinoma (ESCC) in southern Brazil. METHODS: We studied 189 esophageal samples from 125 patients from three different groups: (1) 102 biopsies from 51 patients with ESCC, with one sample from the tumor and another from normal esophageal mucosa distant from the tumor; (2) 50 esophageal biopsies from 37 patients with a previous diagnosis of head and neck squamous cell carcinoma (HNSCC); and (3) 37 biopsies from esophageal mucosa with normal appearance from 37 dyspeptic patients, not exposed to smoking or alcohol consumption. Nested-polymerase chain reaction (PCR) with the MY09/11 and GP5/6 L1 primers was used to detect HPV L1 in samples fixed in formalin and stored in paraffin blocks. All PCR reactions were performed with a positive control (cervicovaginal samples), with a negative control (Human Genomic DNA) and with a blank reaction containing all reagents except DNA. We took extreme care to prevent DNA contamination in sample collection, processing, and testing. RESULTS: The histological biopsies confirmed the diagnosis of ESCC in 52 samples (51 from ESCC group and 1 from the HNSCC group) and classified as well differentiated (12/52, 23.1%), moderately differentiated (27/52, 51.9%) or poorly differentiated (7/52, 13.5%). One hundred twenty-eight esophageal biopsies were considered normal (51 from the ESCC group, 42 from the HNSCC group and 35 from dyspeptic patients). Nine had esophagitis (7 from the HNSCC and 2 from dyspeptic patients). Of a total of 189 samples, only 6 samples had insufficient material for PCR analysis: 1 from mucosa distant from the tumor in a patient with ESCC, 3 from patients with HNSCC and 2 from patients without cancer. In 183 samples (96.8%) GAPDH, G3PDH and/or beta-globin were amplified, thus indicating the adequacy of the DNA in those samples. HPV DNA was negative in all the 183 samples tested: 52 with ESCC, 9 with esophagitis and 122 with normal esophageal mucosa. CONCLUSION: There was no evidence of HPV infection in different ESCC from southern Brazil. PMID- 24151388 TI - Effects of 5-HT2B, 5-HT3 and 5-HT4 receptor antagonists on gastrointestinal motor activity in dogs. AB - AIM: To study the effects of 5-hydroxytryptamine (5-HT) receptor antagonists on normal colonic motor activity in conscious dogs. METHODS: Colonic motor activity was recorded using a strain gauge force transducer in 5 dogs before and after 5 HT2B, 5-HT3 and 5-HT4 receptor antagonist administration. The force transducers were implanted on the serosal surfaces of the gastric antrum, terminal ileum, ileocecal sphincter and colon. Test materials or vehicle alone was administered as an intravenous bolus injection during a quiescent period of the whole colon in the interdigestive state. The effects of these receptor antagonists on normal gastrointestinal motor activity were analyzed. RESULTS: 5-HT2B, 5-HT3 and 5-HT4 receptor antagonists had no contractile effect on the fasting canine terminal ileum. The 5-HT3 and 5-HT4 receptor antagonists inhibited phase III of the interdigestive motor complex of the antrum and significantly inhibited colonic motor activity. In the proximal colon, the inhibitory effect was dose dependent. Dose dependency, however, was not observed in the distal colon. The 5-HT2B receptor antagonist had no contractile effect on normal colonic motor activity. CONCLUSION: The 5-HT3 and 5-HT4 receptor antagonists inhibited normal colonic motor activity. The 5-HT2B receptor antagonist had no contractile effect on normal colonic motor activity. PMID- 24151389 TI - Colonic diverticulitis with comorbid diseases may require elective colectomy. AB - AIM: To investigate the comorbid disease could be the predictors for the elective colectomy in colonic diverticulitis. METHODS: A retrospective chart review of 246 patients with colonic diverticulitis admitted between 2000 and 2008 was conducted, and 19 patients received emergent operation were identified and analyzed. Data were collected with regard to age, sex, albumin level on admission, left or right inflammation site, the history of recurrent diverticulitis, preoperative comorbidity, smoking habits, medication, treatment policy, morbidity, and mortality. Preoperative comorbid diseases included cardiovascular disease, diabetes, pulmonary disease, peptic ulcer disease, gouty arthritis, and uremia. Medications in use included non-steroidal anti inflammatory drugs, acetylsalicylic acid (Aspirin), and corticosteroids. Univariate and multivariate logistic regression analyses were performed to identify the relevant risk factors correlating to colectomy. RESULTS: The mean age of the 246 patients was 69.5 years (range, 24-94 years). Most diverticulitis could be managed with conservative treatment (n = 227, 92.3%), and urgent colectomy was performed in 19 patients (7.7%). There were three deaths in the surgical group and four deaths in the nonsurgical group. The overall mortality rate in the study was 1.7% among patients with conservative treatment and 15.7% among patients undergoing urgent colectomy. Multiple logistic regression analysis indicated that comorbidities were risk factors for urgent colectomy for diverticulitis. CONCLUSION: To avoid high mortality and morbidity related to urgent colectomy, we suggest that patients with colonic diverticulitis and comorbid diseases may require elective colectomy. PMID- 24151390 TI - Anisodamine accelerates spontaneous passage of single symptomatic bile duct stones <= 10 mm. AB - AIM: To investigate the rate of spontaneous passage of single and symptomatic common bile duct (CBD) stones <= 10 mm in diameter in 4 wk with or without a 2-wk course of anisodamine. METHODS: A multicenter, randomized, placebo-controlled trial was undertaken. A total of 197 patients who met the inclusion criteria were enrolled. Ninety-seven patients were assigned randomly to the control group and the other 100 to the anisodamine group. The anisodamine group received intravenous infusions of anisodamine (10 mg every 8 h) for 2 wk. The control group received the same volume of 0.9% isotonic saline for 2 wk. Patients underwent imaging studies and liver-function tests every week for 4 wk. The rate of spontaneous passage of CBD stones was analyzed. RESULTS: The rate of spontaneous passage of CBD stones was significantly higher in the anisodamine group than that in the control group (47.0% vs 22.7%). Most (87.2%, 41/47) stone passages in the anisodamine group occurred in the first 2 wk, and passages in the control group occurred at a comparable rate each week. Factors significantly increasing the possibility of spontaneous passage by univariate logistic regression analyses were stone diameter (< 5 mm vs >= 5 mm and <= 10 mm) and anisodamine therapy. Multivariate logistic regression analyses revealed that these two factors were significantly associated with spontaneous passage. CONCLUSION: Two weeks of anisodamine administration can safely accelerate spontaneous passage of single and symptomatic CBD stones <= 10 mm in diameter, especially for stones < 5 mm. PMID- 24151391 TI - Salvage irrigation-suction in gracilis muscle repair of complex rectovaginal and rectourethral fistulas. AB - AIM: To evaluate the efficacy of gracilis muscle transposition and postoperative salvage irrigation-suction in the treatment of complex rectovaginal fistulas (RVFs) and rectourethral fistulas (RUFs). METHODS: Between May 2009 and March 2012, 11 female patients with complex RVFs and 8 male patients with RUFs were prospectively enrolled. Gracilis muscle transposition was undertaken in all patients and postoperative wound irrigation-suction was performed in patients with early leakage. Efficacy was assessed in terms of the success rate and surgical complications. SF-36 quality of life (QOL) scores and Wexner fecal incontinence scores were compared before and after surgery. RESULTS: The fistulas healed in 14 patients after gracilis muscle transposition; the initial healing rate was 73.7%. Postoperative leakage occurred and continuous irrigation-suction of wounds was undertaken in 5 patients: 4 healed and 1 failed, and postoperative fecal diversions were performed for the patient whose treatment failed. At a median follow-up of 17 mo, the overall healing rate was 94.7%. Postoperative complications occurred in 4 cases. Significant improvement was observed in the quality outcomes framework scores (P < 0.001) and Wexner fecal incontinence scores (P = 0.002) after the successful healing of complex RVFs or RUFs. There was no significant difference in SF-36 QOL scores between the initial healing group and irrigation-suction-assisted healing group. CONCLUSION: Gracilis muscle transposition and postoperative salvage wound irrigation-suction gained a high success rate in the treatment of complex RVFs and RUFs. QOL and fecal incontinence were significantly improved after the successful healing of RVFs and RUFs. PMID- 24151392 TI - Role of ABCG2 expression driven by cisplatin in platinum-containing chemotherapy for gastric cancer. AB - AIM: To investigate the relationship between increases in expression time of ABCG2 mRNA driven by cisplatin and efficacy of platinum-containing chemotherapy for gastric cancer. METHODS: Tumor specimens and normal control tissues were collected from 78 patients with gastric cancer treated from January 2008 to December 2011. Fresh tumor tissue obtained from the surgically resected specimens was tested within 6 h. Polymerase chain reaction products were run on 2% agarose gels and analyzed under ultraviolet light after ethidium bromide staining. Increases in ABCG2 mRNA expression time were assessed after cancer cells were incubated with cisplatin, and were divided into terciles and compared in relation to clinical outcomes. RESULTS: Among groups classified by expression time of ABCG2 mRNA, no significant differences in baseline clinical characteristics and pathological findings were detected. The median overall time was 14.2 (95%CI: 9.7 18.6), 11.4 (95%CI: 6.3-16.5) and 8.1 (95%CI: 5.4-10.8) in patients with low, intermediate and high increases in ABCG2 mRNA expression times (P < 0.05), respectively. Median survival associated with performance status and tumor node metastasis (TNM) stage showed a similar trend, with longer survival and higher risk for mortality associated with lower performance status score and TNM stage. In a multivariate analysis for survival with Cox proportional-hazards model, increased ABCG2 mRNA expression time was an independent predictor for overall survival. Overall survival was longer with increased ABCG2 mRNA expression times <= 0.71 than increased ABCG2 mRNA expression times > 0.71, with a hazard ratio for death of 0.855 (95%CI: 0.615-0.962, P = 0.038). CONCLUSION: Increased ABCG2 mRNA expression time driven by cisplatin is associated with survival of gastric cancer patients, and this may help modify the therapeutic strategies. PMID- 24151393 TI - Expression and significance of Musashi-1 in gastric cancer and precancerous lesions. AB - AIM: To investigate expression of stem cell marker Musashi-1 (Msi-1) in relationship to tumorigenesis and progression of intestinal-type gastric cancer (GC). METHODS: Endoscopic biopsy specimens and surgical specimens were obtained, including 54 cases of intestinal-type GC, 41 high-grade intraepithelial neoplasia, 57 low-grade intraepithelial neoplasia, 31 intestinal metaplasia, and 36 normal gastric mucosa. Specimens were fixed in 10% paraformaldehyde, conventionally dehydrated, embedded in paraffin, and sliced in 4-MUm-thick serial sections. Two-step immunohistochemical staining was used to detect Msi-1 and proliferating cell nuclear antigen (PCNA) expression. Correlation analysis was conducted between Msi-1 and PCNA expression. The relationship between Msi-1 expression and clinicopathological parameters of GC was analyzed statistically. RESULTS: There were significant differences in Msi-1 and PCNA expression in different pathological tissues (chi2 = 15.37, P < 0.01; chi2 = 115.36, P < 0.01). Msi-1 and PCNA-positive cells were restricted to the isthmus of normal gastric glands. Expression levels of Msi-1 and PCNA in intestinal metaplasia were significantly higher than in normal mucosa (U = 392.0, P < 0.05; U = 40.50, P < 0.01), whereas there was no significant difference compared to low or high-grade intraepithelial neoplasia. Msi-1 and PCNA expression in intestinal-type GC was higher than in high-grade intraepithelial neoplasia (U = 798.0, P < 0.05; U = 688.0, P < 0.01). There was a significantly positive correlation between Msi-1 and PCNA expression (r(s) = 0.20, P < 0.01). Msi-1 expression in GC tissues was correlated with their lymph node metastasis and tumor node metastasis stage (chi2 = 12.62, P < 0.01; chi2 = 11.24, P < 0.05), but not with depth of invasion and the presence of distant metastasis. CONCLUSION: Msi-1-positive cells may play a key role in the early events of gastric carcinogenesis and may be involved in invasion and metastasis of GC. PMID- 24151394 TI - Can eradication rate of gastric Helicobacter pylori be improved by killing oral Helicobacter pylori? AB - AIM: To evaluate the influence of oral Helicobacter pylori (H. pylori) on the success of eradication therapy against gastric H. pylori. METHODS: A total of 391 patients with dyspepsia were examined for H. pylori using the saliva H. pylori antigen test (HPS), 13C-urea breath test (UBT), gastroscopy, and gastric mucosal histopathological detection. Another 40 volunteers without discomfort were subjected to HPS and 13C-UBT, and served as the control group. The 233 patients who were (13C-UBT+ were enrolled in this study and divided into 4 groups. Patients who were HPS- and 13C-UBT+ (n = 53) received triple therapy alone. Those who were both HPS+ and 13C-UBT+ (n = 180) were randomly divided into 3 groups: (1) the O+G+t group which received triple therapy alone (n = 53); (2) the O+G+tm group which received both triple therapy and mouthrinse treatment (n = 65); and (3) the O+G+tmp group which received triple therapy, mouthrinse, and periodontal treatment (n = 62). The HPS and 13C-UBT were continued for 4 wk after completion of treatment, and the eradication rate of gastric H. pylori and the prevalence of oral H. pylori in the 4 groups were then compared. RESULTS: The eradication rates of gastric H. pylori in the O-G+t group, the O+G+tm group, and the O+G+tmp group were 93.3%, 90.0%, and 94.7% respectively; all of these rates were higher than that of the O+G+t group (78.4%) [O-G+t group vs O+G+t group (P = 0.039); O+G+tm group vs O+G+t group (P = 0.092); O+G+tmp group vs O+G+t group (P = 0.012); O+G+tm group vs O-G+t group (P = 0.546); O+G+tmp group vs O-G+t group (P = 0.765); O+G+tm group vs O+G+tmp group (P = 0.924)]. The eradication of gastric H. pylori was significantly improved using the combination of triple therapy, mouthrinse, and periodontal treatment. The eradication rates of gastric H. pylori in the peptic ulcer group, chronic atrophic gastritis group and control group were higher than in the duodenitis group and the superficial gastritis group. The prevalence rates of oral H. pylori in the O-G+t group, O+G+t group, O+G+tm group and O+G+tmp group following treatment were 0%, 76.5%, 53.3%, and 50.9%, respectively [O-G+t group vs O+G+t group (P < 0.0001); O+G+tm group vs O+G+t group (P = 0.011); O+G+tmp group vs O+G+t group (P = 0.006); O+G+tm group vs O G+t group (P < 0.0001); O+G+tmp group vs O-G+t group (P < 0.0001); O+G+tm group vs the O+G+tmp group (P = 0.790)]. Both mouthrinse and periodontal treatment significantly reduced the prevalence of oral H. pylori. CONCLUSION: Mouthrinse treatment alone or combined with periodontal treatment can, to some extent, reduce the prevalence of oral H. pylori and improve the eradication rate of gastric H. pylori. PMID- 24151395 TI - Importance of b value in diffusion weighted imaging for the diagnosis of pancreatic cancer. AB - AIM: To investigate the use of multi-b-value diffusion-weighted imaging in diagnosing pancreatic cancer. METHODS: We retrospectively analyzed 33 cases of pancreatic cancer and 12 cases of benign pancreatic tumors at the Second Affiliated Hospital of Kunming Medical University from December 2008 to January 2011. The demographic characteristics, clinical presentation, routine magnetic resonance imaging and diffusion weighted imaging (DWI) features with different b values were reviewed. Continuous data were expressed as mean +/- SD. Comparisons between pancreatic cancer and benign pancreatic tumors were performed using the Student's t test. A probability of P < 0.05 was considered statistically significant. RESULTS: Thirty-three patients with pancreatic cancer were identified. The mean age at diagnosis was 60 +/- 5.6 years. The male: female ratio was 21:12. Twenty cases were confirmed by surgical resection and 13 by biopsy of metastases. T1 weighted images demonstrated a pancreatic head mass in 16 patients, a pancreatic body mass in 10 cases, and a pancreatic tail mass with pancreatic atrophy in 7 cases. Eight patients had hepatic metastases, 13 had invasion or envelopment of mesenteric vessels, 4 had bone metastases, and 8 had lymph node metastases. DWI demonstrated an irregular intense mass with unclear margins. Necrotic tissue demonstrated an uneven low signal. A b of 1100 s/mm2 was associated with a high intensity signal with poor anatomical delineation. A b of 700 s/mm2 was associated with apparent diffusion coefficients (ADCs) that were useful in distinguishing benign and malignant pancreatic tumors (P < 0.05). b values of 50, 350, 400, 450 and 1100 s/mm2 were associated with ADCs that did not differentiate the two tumors. CONCLUSION: Low b value images demonstrated superior anatomical details when compared to high b value images. Tumor tissue definition was high and contrast with the surrounding tissues was good. DWI was useful in diagnosing pancreatic cancer. PMID- 24151396 TI - Macrophage migration inhibitory factor gene polymorphisms in inflammatory bowel disease: an association study in New Zealand Caucasians and meta-analysis. AB - AIM: To investigate the association of macrophage migration inhibitory factor (MIF) promoter polymorphisms with inflammatory bowel disease (IBD) risk. METHODS: One thousand and six New Zealand Caucasian cases and 540 Caucasian controls were genotyped for the MIF SNP -173G > C (rs755622) and the repeat polymorphism CATT5 8 (rs5844572) using a pre-designed TaqMan SNP assay and capillary electrophoresis, respectively. Data were analysed for single site and haplotype association with IBD risk and phenotype. Meta-analysis was employed, to assess cumulative evidence of association of MIF -173G > C with IBD. All published genotype data for MIF -173G > C in IBD were identified using PubMed and subsequently searching the references of all PubMed-identified studies. Imputed genotypes for MIF -173G > C were generated from the Wellcome Trust Case Control Consortium (and National Institute of Diabetes and Digestive and Kidney Diseases). Separate meta-analyses were performed on Caucasian Crohn's disease (CD) (3863 patients, 6031 controls), Caucasian ulcerative colitis (UC) (1260 patients, 1987 controls), and East Asian UC (416 patients and 789 controls) datasets using the Mantel-Haenszel method. The New Zealand dataset had 93% power, and the meta-analyses had 100% power to detect an effect size of OR = 1.40 at alpha = 0.05, respectively. RESULTS: In our New Zealand dataset, single-site analysis found no evidence of association of MIF polymorphisms with overall risk of CD, UC, and IBD or disease phenotype (all P values > 0.05). Haplotype analysis found the CATT5/-173C haplotype occurred at a higher frequency in New Zealand controls compared to IBD patients (0.6 vs 0.01; P = 0.03, OR = 0.22; 95%CI: 0.05 0.99), but this association did not survive bonferroni correction. Meta-analysis of our New Zealand MIF -173G > C data with data from seven additional Caucasian datasets using a random effects model found no association of MIF polymorphisms with CD, UC, or overall IBD. Similarly, meta-analysis of all published MIF -173G > C data from East Asian datasets (416 UC patients, 789 controls) found no association of this promoter polymorphism with UC. CONCLUSION: We found no evidence of association of MIF promoter polymorphisms with IBD. PMID- 24151398 TI - Aberrant celio-mesenteric supply of the splenic flexure: provoking a bleed. AB - Lower gastrointestinal hemorrhage presents a common indication for hospitalization and account for over 300,000 admissions per year in the United States. Multimodality imaging is often required to aid in localization of the hemorrhage prior to therapeutic intervention if endoscopic treatment fails. Imaging includes computer tomography angiography, red blood cell tagged scintigraphy and conventional angiography, with scintigraphy being the most sensitive followed by computer tomography angiography. Aberrant celio-mesenteric supply occurs in 2% of the population; however failure to identify this may result in failed endovascular therapy. Computer tomography angiography is sensitive for arterial hemorrhage and delineates the anatomy, allowing the treating physician to plan an endovascular approach. If at the time of conventional angiography, the active bleed is not visualized, but the site of bleeding has been identified on computer tomography angiography, provocative angiography can be utilized in order to stimulate bleeding and subsequent targeted treatment. We describe a case of lower gastrointestinal hemorrhage at the splenic flexure supplied by a celio-mesenteric branch in a patient and provocative angiography with tissue plasminogen activator utilized at the time of treatment to illicit the site of hemorrhage and subsequent treatment. PMID- 24151397 TI - Effects of entecavir and lamivudine for hepatitis B decompensated cirrhosis: meta analysis. AB - AIM: To compare the effects of entecavir (ETV) and lamivudine (LAM) for the treatment of hepatitis B decompensated cirrhosis using a meta-analysis. METHODS: We conducted a literature search for all eligible studies published prior to May 30, 2013 using PUBMED, MEDLINE, EMBASE, the China National Knowledge Infrastructure (CNKI), the VIP database, the Wanfang database and the Cochrane Controlled Trial Register. Randomized controlled trials (RCTs) comparing ETV with LAM for the treatment of hepatitis B decompensated cirrhosis were included. The data were analyzed with Review Manager Software 5.0.2. We used RR as an effect measure, and reported its 95%CI. The meta-analysis was performed using either a fixed-effect or random-effect model, based on the absence or presence of significant heterogeneity. Two reviewers assessed the risk of bias and extracted data independently and in duplicate. The analysis was executed using the main outcome parameters including hepatitis B virus (HBV) DNA undetectability, HBV DNA level, hepatitis B e antigen (HBeAg) seroconversion, alanine aminotransferase (ALT) level, albumin level, total bilirubin (TBIL) level, prothrombin time activity (PTA) level, Child-Turcotte-Pugh (CTP) score, mortality, drug resistance, and adverse reactions. Meta-analysis of the included trials and subgroup analyses were conducted to examine the association between pre-specified characteristics and the therapeutic effects of the two agents. RESULTS: Thirteen eligible trials (873 patients in total) were included and evaluated for methodological quality and heterogeneity. Of these studies, all had baseline comparability, 12 of them reported baseline values of the two treatment groups in detail. Following various treatment durations (12, 24, 36, 48 and > 48 wk), both ETV and LAM significantly reduced HBV DNA level, however, reductions were greater in the ETV group (MD = -0.66, 95%CI: -0.83-0.50, P < 0.00001), (MD = -0.93, 95%CI: -1.36-0.51, P < 0.0001), (MD = -1.4, 95%CI: -1.78-1.01, P < 0.00001), (MD = -1.18, 95%CI: -1.90-0.46, P = 0.001), (MD = -0.14, 95%CI: -0.17-0.11, P < 0.00001, respectively). At 12, 24 and 48 wk of treatment, ETV had a significant effect on the rate of HBV DNA undetectability (RR = 1.55, 95%CI: 1.22-1.99, P = 0.0004), (RR = 1.25, 95%CI: 1.13-1.38, P < 0.0001), (RR = 1.2, 95%CI: 1.10-1.32, P < 0.0001, respectively). Although HBeAg seroconversion in the ETV group was more pronounced than that in the LAM group at 24 wk (27.90% vs 26.19%) and 48 wk (31.52% vs 25.00%) of treatment, there was no statistically significant difference between them (RR = 1.49, 95%CI: 0.98-2.28, P = 0.07), (RR = 1.27, 95%CI: 0.98-1.65, P = 0.07, respectively). Following various treatment durations, both the ETV group and the LAM group showed significantly improved liver function (ALT, AIB, TBIL, PTA and CTP levels) and reduced mortality (ETV 6.37%, LAM 7.89%). The effects in the ETV group (0.33%) were statistically lower than those in the LAM group (14.33%) regarding the rate of drug-resistance (RR = 0.1, 95%CI: 0.04-0.24, P <= 0.00001). In addition, no severe adverse reactions were observed in the two treatment groups. CONCLUSION: ETV and LAM significantly improved liver function and reduced mortality. Both drugs produced similar serological responses, and were safe and well tolerated. However, ETV resulted in a better virological response and lower drug-resistance, but is more expensive. PMID- 24151399 TI - A rare case of primary choriocarcinoma in the sigmoid colon. AB - Primary colorectal choriocarcinoma is an extremely rare neoplasm and is usually associated with a poor prognosis. Only 13 cases of colorectal choriocarcinoma have previously been reported. There is no standard chemotherapeutic regimen for this tumor type. A 68-year-old man presented with melena and was diagnosed with sigmoid colonic adenocarcinoma with multiple liver metastases. He underwent a laparoscopic sigmoidectomy. Pathology revealed choriocarcinoma with a focal component of moderately differentiated adenocarcinoma of colon origin. Based on the collagen gel droplet-embedded culture drug sensitivity test (CD-DST) results, mFOLFOX6 and bevacizumab were administered, which suppressed aggressive tumor growth for 4 mo. The patient died 9 mo after the initial diagnosis. Our study results suggest that the standard chemotherapy regimen for colorectal cancer might have suppressive effects against primary colorectal choriocarcinoma. Moreover, CD-DST may provide, at least in part, therapeutic insight for the selection of appropriate antitumor agents for such patients. PMID- 24151400 TI - Diagnosis and treatment of benign multicystic peritoneal mesothelioma. AB - Benign multicystic peritoneal mesothelioma (BMPM) is a rare cystic mesothelial lesion that occurs predominantly in reproductive aged women. A 56-year-old Caucasian male was admitted to our surgical department with a chief complaint of a painful mass in his right lower abdomen for almost 2 years. The physical examination revealed a palpable painful mass. Computed tomography demonstrated an irregular, cystic tumor in his right lower abdomen. There was no obvious capsule or internal septations. No enhancement after intravenous administration of contrast was noted. An exploratory laparotomy was performed, and a multicystic tumor and adherent to the caecum was noted. The walls of the cysts were thin and smooth, filled with clear fluid, and very friable. An en bloc resection of the tumor, including appendix and caecum, was performed. Histological examination revealed multiple cysts lined with flattened simple epithelial cells, and the capsule walls of the cysts were composed of fibrous tissue. Immunohistochemical analysis documented positive expression of mesothelial cells and calretinin. The final diagnosis was BMPM. The patient was well at 6-mo follow-up. BMPM is exceedingly rare lesion. A complete resection of the tumor is required. The diagnosis of BMPM is based on pathological analysis. PMID- 24151401 TI - Laparoscopic transduodenal local resection of periampullary neuroendocrine tumor: a case report. AB - Studies on laparoscopic transduodenal local resection have not been readily available. Only three cases have been reported in the English-language literature. We describe herein a case of 25-year-old woman with periampullary neuroendocrine tumor (NET). Endoscopic ultrasonography revealed a duodenal papilla mass originated from the submucosa and close to the ampulla. The periampullary tumor was successfully managed with laparoscopic transduodenal local resection without any procedure-related complications. Pathological examination showed a NET (Grade 2) with negative margin. The patient was followed up for six months without signs of recurrence. This case suggests that laparoscopic transduodenal local resection is a feasible procedure in selected patients with periampullary tumor. PMID- 24151402 TI - Positron emission tomography/computerized tomography in the evaluation of primary non-Hodgkin's lymphoma of prostate. AB - Primary malignant lymphoma of the prostate is exceedingly rare. Here we report a case of a 65-year-old man who presented with increased urinary frequency, urinary urgency, and urinary incontinence for two years. Benign prostatic hypertrophy was suspected at primary impression. Ultrasound revealed a hypoechoic lesion of the prostate. The total serum prostate-specific antigen was within normal range. Positron emission tomography/computerized tomography (PET/CT) showed a hypermetabolic prostatic lesion. Prostate biopsy was consistent with a non germinal center diffuse large B cell lymphoma. There was complete remission of the prostatic lesion following six cycles of chemotherapy as shown on the second PET/CT imaging. 18F-fluoro-deoxy glucose PET/CT is not only a complement to conventional imaging, but also plays a significant role in the diagnosis and evaluation of treatment response of prostatic lymphoma. PMID- 24151403 TI - Women in dentistry: A perspective on major universities in Saudi Arabia. Part 1: Historical background. AB - As the works of females have been present in many fields of our lives, the history mentions little trace of these facts. The field of dentistry was among these professions. This paper will review the presence of dental practice by women world wide and will present a review of dentistry in Saudi Arabia. PMID- 24151404 TI - Rehabilitation of the edentulous mandible with implant-supported overdenture using ball attachments and healing abutments: A case report. AB - For many years, osseointegrated implant-supported overdentures have been used in the rehabilitation of the edentulous lower jaw with excellent results. In this report, additional implants with healing abutments were applied posterior to mental foramen on each side was used to achieve additional support to the overdenture. PMID- 24151405 TI - The use of mini-implants in en masse retraction for the treatment of bimaxillary dentoalveolar protrusion. AB - This case report describes the treatment of a 22-year-old girl who had incompetent lips with severe bimaxillary dentoalveolar protrusion. The treatment of choice for such patients is usually extraction of four first premolars and retraction of the anterior teeth. To maintain the extraction space, maximum anchorage is required. Mini-implants were used to provide maximum anchorage for obtaining a good facial profile. PMID- 24151406 TI - Correction of a severely rotated maxillary central incisor with the Whip device. AB - OBJECTIVE: The aim of this case report was to introduce an appliance that can be used for correcting severe rotation of anterior teeth in pre-adolescent children. APPLIANCE DESIGN AND TESTING: This is a case report of an 11-year-old Iranian boy with a mixed dentition Class I malocclusion defined by a severe rotation of upper left central incisor and a mesiodens between the centrals. The supernumerary tooth was first extracted, and then a Whip device including removable appliance, a cantilever spring and bonded tube on rotated tooth was inserted into his mouth. After 8 months, the upper left central incisor was orthodontically brought into proper alignment. Circumferential supracrestal fibrotomy was done next to overcorrection of the tooth and one week after surgery, the device was removed and the retention was started. CONCLUSION: The whip device, a removable appliance can be very effective for correcting severe rotation of anterior teeth. PMID- 24151407 TI - Papillon-Lefevre syndrome: A case report. AB - Papillon-Lefevre syndrome (PLS) is a rare autosomal recessive disorder of keratinization, characterized by palmoplantar hyperkeratosis, periodontal involvement and precocious loss of dentition. The purpose of this report was to describe the case of an 18-year-old girl who presented to the out patient department of Navodaya Dental College and Hospital, Raichur, Karnataka, India, with the chief complaint of multiple loss of teeth. Her gingiva appeared erythematous, edematous and bled readily on probing, and the teeth were mobile. Hyperkeratosis of palms and soles were found. These findings are consistent with Papillon-Lefevre syndrome. The clinical presentation, differential diagnosis, complications and management of this syndrome are discussed. PMID- 24151409 TI - Achondroplasia: Craniofacial manifestations and considerations in dental management. AB - Achondroplasia is the most common form of skeletal dysplasia dwarfism that manifests with stunted stature and disproportionate limb shortening. Achondroplasia is of dental interest because of its characteristic craniofacial features which include relative macrocephaly, depressed nasal bridge and maxillary hypoplasia. Presence of large head, implanted shunt, airway obstruction and difficulty in head control require special precautions during dental management. Craniofacial manifestations and considerations in dental management are presented in 11-year-old female patient with achondroplasia. PMID- 24151408 TI - The elastomers for complete denture impression: A review of the literature. AB - This article reviews the current trends in materials used for complete denture impression. Peer-reviewed articles, published in English and in French between 1954 and 2007, were identified through a MEDLINE search (Pubmed and Elsevier) and a hand search of relevant textbooks and annual publications. Emphasis was made on the characteristics of the elastomers, their manipulation, the different techniques used, and the quality of the impression obtained. The combination of excellent physical properties, handling characteristics, and unlimited dimensional stability assures the popularity of these impression materials. PMID- 24151410 TI - The Saudi Dental Journal's mission for the Saudi Dental Society. PMID- 24151411 TI - Lateral cephalometric norms for Saudi adults: A meta-analysis. AB - Orthodontic diagnosis and treatment planning require careful evaluation of the patient's cephalometric values and comparison to known population cephalometric means or norms. Despite the availability of several published studies on Saudi cephalometric norms, Caucasian norms are still referred to when Saudi patients are treated. To reach a consensus between these studies and to establish more accurately cephalometric norms for Saudis, a meta-analysis of the relevant literature was performed. Electronic database (PubMed), Saudi Dental Journal and Master theses were searched for studies reporting cephalometric values of normal male and female Saudi adults with numerical data and 8 studies with a total sample size of 485 met the inclusion criteria. A meta-analysis with results from these studies was completed. The combined mean estimates and SD of common cephalometric measurements were calculated. The data included in this comprehensive meta-analysis were compared with Caucasian norms and results indicated that Saudis have distinct cephalometric features. Saudis tend to have slightly more convex profiles and more proclined incisors than the Caucasians. These findings confirm the previously published results and should serve as more accurate reference values that were drawn from a large sample size. PMID- 24151412 TI - Apical surgery: A review of current techniques and outcome. AB - Apical surgery is considered a standard oral surgical procedure. It is often a last resort to surgically maintain a tooth with a periapical lesion that cannot be managed with conventional endodontic (re-)treatment. The main goal of apical surgery is to prevent bacterial leakage from the root-canal system into the periradicular tissues by placing a tight root-end filling following root-end resection. Clinicians are advised to utilize a surgical microscope to perform apical surgery to benefit from magnification and illumination. In addition, the application of microsurgical techniques in apical surgery, i.e., gentle incision and flap elevation, production of a small osteotomy, and the use of sonic- or ultrasonic driven microtips, will result in less trauma to the patient and faster postsurgical healing. A major step in apical surgery is to identify possible leakage areas at the cut root face and subsequently to ensure adequate root-end filling. Only a tight and persistent apical obturation will allow periapical healing with good long-term prognosis. The present paper describes current indications, techniques and outcome of apical surgery. PMID- 24151413 TI - Class II malocclusion treatment using combined Twin Block and fixed orthodontic appliances - A case report. AB - The effect of the Twin Block functional orthodontic appliances is mostly dento alveolar with small skeletal effect. There are certain clinical indications where functional appliances can be used successfully in class II malocclusion e.g. in a growing patient. The use of these appliances is greatly dependent on the patient's compliance and they simplify the fixed appliance phase. In this case, a 13-year old adolescent was treated with Twin Block appliance followed by fixed appliance to detail the occlusion. The design and treatment effects were demonstrated in this case report. PMID- 24151414 TI - To publish or not to publish, that is the question. PMID- 24151415 TI - Adverse effects of orthodontic treatment: A clinical perspective. AB - Orthodontic treatment is associated with a number of adverse effects, such as root resorption, pain, pulpal changes, periodontal disease, and temporomandibular dysfunction (TMD). Orthodontists should be aware of these effects and associated risk factors. Risk factors linked to root resorption include the duration of treatment, length, and shape of the root, trauma history, habits, and genetic predisposition. PMID- 24151416 TI - Surgical treatment of keratocystic odontogenic tumour: A review article. AB - KCOT is one of the most aggressive odontogenic cysts with a high recurrence rate, this was explained histopathologically as it typically shows a thin, friable wall, which is often difficult to enucleate from the bone in one piece, and have small satellite cysts within the fibrous wall. Multiple surgical approaches were introduced including decompression, marsupilization, enucleation with or without adjunct (Carnoy's solution, enucleation) and resection. Depending on other studies KCOT can be conservatively treated with enucleation and application of Carnoy's solution or cryotherapy. This can be used specially in the large lesions that when treated with resection, the continuity of the jaw will be interrupted. This technique shows comparable results to other more aggressive techniques. PMID- 24151417 TI - Orthodontic treatment of an anterior openbite with the aid of corticotomy procedure: Case report. AB - This case report illustrates the orthodontic treatment combined with the corticotomy technique in an adult patient to accelerate tooth movement and shorten the treatment time. The patient was a 22-year-old woman with an anterior open bite and flared and spaced upper and lower incisors. First, fixed orthodontic appliances (bidimensional edgewise brackets) were bonded, and a week later buccal and lingual corticotomy with alveolar augmentation procedure in the maxillary arch from the first molar to the contralateral first molar, and from canine to canine in the mandibular arch was performed. Orthodontic therapy proceeded with frequent activation of the appliances to retract the incisors every 2 weeks. The total treatment time was 5 months and no adverse effects were observed at the end of active treatment. The addition of the decortication procedure to the conventional orthodontic therapy decreased the duration of treatment significantly. Successful closure of the anterior open bite with adequate overbite and interdigitation of the teeth were achieved. PMID- 24151418 TI - Mandibular brown tumor as the first manifestation of primary hyperparathyroidism: A case report. AB - Patients with primary hyperparathyroidism (brown tumor) are usually asymptomatic and clinical presentation of the tumor in the jaws is rarely the first sign of the disease. We report a 45-year-old female patient who presented with a mandibular swelling as the first sign of the disease. PMID- 24151419 TI - The future is not ours to see? With data, yes! PMID- 24151420 TI - The use of regenerative techniques in apical surgery: A literature review. AB - Apical surgery has become a standard of care for tooth maintenance if conventional endodontic retreatment is not possible or associated with risks. However, in certain situations, the outcome of apical surgery may be compromised due to the extent or location of the periapical or periradicular lesions. The present review article including clinical and experimental studies reports and discusses the outcome of regenerative techniques (RT) in conjunction with apical surgery, with regard to the type of periradicular lesions: APICAL LESIONS: The majority of studies have shown no benefit for healing in test sites treated with RT compared to control sites treated without RT. The use of a radio-opaque bone filler/substitute may even compound the radiographic interpretation of periapical healing. Currently, the use of RT for lesions <10 mm limited to the apical area is not warranted. THROUGH-AND-THROUGH LESIONS: All reviewed studies demonstrated a better outcome for test sites with RT compared to the control sites without RT; hence the use of RT for treatment of tunnel lesions in apical surgery is recommended. APICO-MARGINAL LESIONS: All clinical studies assessed cohorts without controls, and, therefore, no firm conclusion about the benefit of RT for treatment of apico-marginal lesions in conjunction with apical surgery can be drawn. However, the experimental animal studies have shown that healing of teeth with apico-marginal lesions appears to benefit from RT. PMID- 24151421 TI - Necrotizing fasciitis in association with Ludwig's angina - A case report. AB - A 28 year old male diabetic patient developed Ludwig's angina which subsequently evolved into cervicofacial necrotizing fasciitis. The differential characteristic of Ludwig's angina and cervicofacial necrotizing fasciitis, as it relates to this rare presentation is discussed. The clinical and radiological features, pathophysiology, diagnosis and the management that resulted in a successful outcome are presented. PMID- 24151422 TI - Intraoral venous malformation with phleboliths. AB - The most common type of vascular malformation is the venous malformation and these are occasionally associated with phleboliths. We report a case of a 45 year old woman with intraoral venous malformation with phleboliths. PMID- 24151424 TI - Automatic identification of algal community from microscopic images. AB - A good understanding of the population dynamics of algal communities is crucial in several ecological and pollution studies of freshwater and oceanic systems. This paper reviews the subsequent introduction to the automatic identification of the algal communities using image processing techniques from microscope images. The diverse techniques of image preprocessing, segmentation, feature extraction and recognition are considered one by one and their parameters are summarized. Automatic identification and classification of algal community are very difficult due to various factors such as change in size and shape with climatic changes, various growth periods, and the presence of other microbes. Therefore, the significance, uniqueness, and various approaches are discussed and the analyses in image processing methods are evaluated. Algal identification and associated problems in water organisms have been projected as challenges in image processing application. Various image processing approaches based on textures, shapes, and an object boundary, as well as some segmentation methods like, edge detection and color segmentations, are highlighted. Finally, artificial neural networks and some machine learning algorithms were used to classify and identifying the algae. Further, some of the benefits and drawbacks of schemes are examined. PMID- 24151423 TI - On Crowd-verification of Biological Networks. AB - Biological networks with a structured syntax are a powerful way of representing biological information generated from high density data; however, they can become unwieldy to manage as their size and complexity increase. This article presents a crowd-verification approach for the visualization and expansion of biological networks. Web-based graphical interfaces allow visualization of causal and correlative biological relationships represented using Biological Expression Language (BEL). Crowdsourcing principles enable participants to communally annotate these relationships based on literature evidences. Gamification principles are incorporated to further engage domain experts throughout biology to gather robust peer-reviewed information from which relationships can be identified and verified. The resulting network models will represent the current status of biological knowledge within the defined boundaries, here processes related to human lung disease. These models are amenable to computational analysis. For some period following conclusion of the challenge, the published models will remain available for continuous use and expansion by the scientific community. PMID- 24151425 TI - Human Retrovirus Codon Usage from tRNA Point of View: Therapeutic Insights. AB - The purpose of this study was to investigate the balance between transfer ribonucleic acid (tRNA) supply and demand in retrovirus-infected cells, seeking the best targets for antiretroviral therapy based on the hypothetical tRNA Inhibition Therapy (TRIT). Codon usage and tRNA gene data were retrieved from public databases. Based on logistic principles, a therapeutic score (T-score) was calculated for all sense codons, in each retrovirus-host system. Codons that are critical for viral protein translation, but not as critical for the host, have the highest T-score values. Theoretically, inactivating the cognate tRNA species should imply a severe reduction of the elongation rate during viral mRNA translation. We developed a method to predict tRNA species critical for retroviral protein synthesis. Four of the best TRIT targets in HIV-1 and HIV-2 encode Large Hydrophobic Residues (LHR), which have a central role in protein folding. One of them, codon CUA, is also a TRIT target in both HTLV-1 and HTLV-2. Therefore, a drug designed for inactivating or reducing the cytoplasmatic concentration of tRNA species with anticodon TAG could attenuate significantly both HIV and HTLV protein synthesis rates. Inversely, replacing codons ending in UA by synonymous codons should increase the expression, which is relevant for DNA vaccine design. PMID- 24151427 TI - Vernix caseosa peritonitis after vaginal delivery. AB - INTRODUCTION: Vernix caseosa peritonitis (VCP) is a very unusual complication caused by inflammatory response to amniotic fluid spilled into the maternal peritoneal cavity. Twenty-seven cases have been reported, and all occurred after cesarean section. CASE PRESENTATION: We present a case of VCP following vaginal delivery; this may be the first case reported after vaginal delivery. Mrs. A, 28 years old, gravida 3, para 2, with one previous cesarean section, was admitted at 41 weeks gestation in active labor. Vacuum extraction was performed to deliver a healthy male baby, 4.410 kg, Apgar scores 7, 8. She developed fever, acute abdominal pain, and distension about 3 hours after delivery. A diagnosis of acute abdomen was made. Laparotomy was performed and it revealed neither uterine scar rupture nor other surgical emergencies, but 500 mL of turbid fluid and some cheesy material on the serosal surface of all viscera. Biopsies were taken. She had a course of antibiotics and her recovery was complete. Histology of the peritoneal fluid and tissue biopsy resulted in a diagnosis of VCP. CONCLUSION: Clinical diagnosis of peritonitis due to vernix caseosa should be considered in patients presenting postpartum with an acute abdomen after vaginal delivery. PMID- 24151426 TI - Elevated Norepinephrine may be a Unifying Etiological Factor in the Abuse of a Broad Range of Substances: Alcohol, Nicotine, Marijuana, Heroin, Cocaine, and Caffeine. AB - A wide range of commonly abused drugs have effects on the noradrenergic neurotransmitter system, including alterations during acute intoxication and chronic use of these drugs. It is not established, however, that individual differences in noradrenergic signaling, which may be present prior to use of drugs, predispose certain persons to substance abuse. This paper puts forth the novel hypothesis that elevated noradrenergic signaling, which may be raised largely due to genetics but also due to environmental factors, is an etiological factor in the abuse of a wide range of substances, including alcohol, nicotine, marijuana, heroin, cocaine, and caffeine. Data are reviewed for each of these drugs comprising their interaction with norepinephrine during acute intoxication, long-term use, subsequent withdrawal, and stress-induced relapse. In general, the data suggest that these drugs acutely boost noradrenergic signaling, whereas long term use also affects this neurotransmitter system, possibly suppressing it. During acute withdrawal after chronic drug use, noradrenergic signaling tends to be elevated, consistent with the observation that norepinephrine lowering drugs such as clonidine reduce withdrawal symptoms. Since psychological stress can promote relapse of drug seeking in susceptible individuals and stress produces elevated norepinephrine release, this suggests that these drugs may be suppressing noradrenergic signaling during chronic use or instead elevating it only in reward circuits of the brain. If elevated noradrenergic signaling is an etiological factor in the abuse of a broad range of substances, then chronic use of pharmacological agents that reduce noradrenergic signaling, such as clonidine, guanfacine, lofexidine, propranolol, or prazosin, may help prevent or treat drug abuse in general. PMID- 24151428 TI - The role of nutraceuticals in the management of autism. AB - Autism and related disorders are increasingly prevalent behavioral syndromes of impaired verbal and nonverbal communication and socialization owing to neurodevelopmental abnormalities. The most recent estimate for the prevalence of autistic disorders is about 1% on a global scale. Etiology of autism is multifactorial and multidimensional that makes therapeutic intervention even harder. Heterogeneity of genetic factors, oxidative stress, autoimmune mechanism, and epigenetic mechanisms complicate the nature of pathogenesis of the disease. Nutraceutical approach to treat this disease is a promising strategy, especially in some areas, it is more attractive than others. This review critically analyzes the roles of vitamins and cofactors, dietary modifications and gut abnormalities, probiotics and prebiotics, phytochemicals, and environmental factors in order to determine the state of evidence in nutraceutical-based autism management practices. This article presents a systematic review of randomized- and placebocontrolled trials to examine the evidence supports the use of autism nutraceu10.1016/j.jsps.2012.10.001ticals. The results will be discussed in the light of all relevant evidence generated from other clinical and exploratory studies. PMID- 24151429 TI - Body mass index and binocular vision skills. AB - INTRODUCTION: Body Mass Index (BMI) is of increasing interest to eye care practitioners. Associations have recently been proven between high BMI and several diseases affecting the eyes, including AMD, intracranial hypertension, optic disc cupping, and glaucoma. The symptoms of dizziness and vertigo have also been associated with high BMI. However, to these authors' knowledge, there has been no study performed comparing BMI to binocular function. METHODS: In this analytical-descriptive study, 119 randomly selected young subjects had their BMI measured, along with refractive error, dissociated phoria, near point of convergence, vergence ranges and facility, and stereopsis. RESULTS: In most situations, the subjects classified as normal and overweight, based on their BMI had better performance than those classified as underweight or obese. The worst binocular performance was found in underweight subjects. The one-way ANOVA showed only statistically significant differences between mean of near point of convergence and vergence facility, in different states of BMI. CONCLUSION: Unlike most ocular diseases that are adversely affected by higher BMI values, most binocular vision skills are adversely affected by lower BMI values. The possible reasons for this are discussed. PMID- 24151430 TI - The effects of protein solubility on the RNA Integrity Number (RIN) for recombinant Escherichia coli. AB - High quality, intact messenger RNA (mRNA) is required for DNA microarray and reverse transcriptase polymerase chain reaction analysis and is generally obtained from total RNA isolations. The most widely recognized measure of RNA integrity is the RNA Integrity Number (RIN) obtained from the Agilent Bioanalyzer, as it provides sizing, quantification, and quality control measures. This work describes comparisons of the RIN values obtained for recombinant E. coli. Uninduced recombinant E. coli cultures were examined, as well as induced cultures that produced either a soluble or insoluble recombinant protein. The uninduced cultures and the induced cultures producing soluble protein had higher RIN values than the induced cultures producing insoluble protein. These lower RIN values for E. coli producing the insoluble protein indicate that cellular degradation of the ribosomal RNA species is the likely cause of the lower RIN values. As the use of DNA microarrays and other gene expression tools increase in usage in the industrial recombinant protein production community, these results suggest the need for further studies to determine acceptable RIN ranges for gene expression analysis and effects of various culture conditions on RIN values for recombinant E. coli. PMID- 24151431 TI - Immunostaining of p16(INK4a)/Ki-67 and L1 capsid protein on liquid-based cytology specimens obtained from ASC-H and LSIL-H cases. AB - BACKGROUND: Atypical squamous cell cannot exclude high-grade squamous intraepithelial lesion (ASC-H) and low-grade intraepithelial lesion cannot exclude high-grade squamous intraepithelial lesion (LSIL-H) are ambiguous diagnostic entities for the prediction of high-grade cervical lesion. Objective and reproducible tests for predicting high-grade cervical lesions are needed to reduce unnecessary colposcopic referrals or follow-ups. OBJECTIVE: We aimed to identify an adequate set of adjunctive markers to predict cervical intraepithelial neoplasia grade 2+ (CIN2+) in residual liquid-based cytology specimens (LBCS). METHODS: We conducted p16 (INK4a)/Ki-67 and L1 capsid protein immunostaining and human papillomavirus (HPV) DNA typing on 56 LBCS diagnosed with ASC-H or LSIL-H, all of which were subjected to histologic confirmation or follow-up cytologic examination. RESULTS: Positivity for p16 (INK4a)/Ki-67 was associated with a histology of CIN2+ (P=0.047) and CIN3+ (P=0.002). Negativity for L1 capsid protein was associated with CIN2+ confirmed at follow-up (P=0.02).Positivity for high-risk HPV (HR-HPV) was associated with CIN2+ confirmed at follow-up (P=0.036) and a histology of CIN2+ (P=0.037). The sensitivity, specificity, positive predictive value, and negative predictive value for predicting follow-up CIN2+ were 76.2%, 51.4%, 48.5%, and 78.3%, respectively, for p16 (INK4a)/Ki-67 immunostaining; 95.2%, 34.3%, 46.5%, and 92.3%, respectively, for L1 capsid protein; and 66.7%, 67.7%, 54.5%, and 77.8%, respectively, for HR-HPV. The classification and regression tree analysis showed that the combined results of p16 (INK4a)/Ki-67 andL1 capsid protein immunostaining and the HR-HPV test, conducted sequentially, correctly classified 81.8% of samples (27/33)in the prediction of a histology of CIN2 + in ASC-H or LSIL-H. For determination of the histology of cervical intraepithelial neoplasia grade 3+ (CIN3+)in ASC-H or LSIL-H, we found that the combined results of p16 (INK4a)/Ki-67 and L1 capsid protein immunostaining correctly classified 78.8% (26/33) of samples. CONCLUSIONS: p16(INK4a)/Ki-67 and L1 capsid protein immunostaining and HR-HPV testing of residual LBCS diagnosed with ASC-H or LSIL-H are useful objective biomarkers for predicting CIN2+. Immunostaining for p16(INK4a)/Ki-67 and L1 capsid protein are sufficient to predict CIN3+. PMID- 24151432 TI - A comparative study on morphochemical properties and osteogenic cell differentiation within bone graft and coral graft culture systems. AB - The objective of this study was to compare the morphological and chemical composition of bone graft (BG) and coral graft (CG) as well as their osteogenic differentiation potential using rabbit mesenchymal stem cells (rMSCs) in vitro. SEM analysis of BG and CG revealed that the pores in these grafts were interconnected, and their micro-CT confirmed pore sizes in the range of 107-315 um and 103-514 um with a total porosity of 92% and 94%, respectively. EDS analysis indicated that the level of calcium in CG was relatively higher than that in BG. FTIR of BG and CG confirmed the presence of functional groups corresponding to carbonyl, aromatic, alkyl, and alkane groups. XRD results revealed that the phase content of the inorganic layer comprised highly crystalline form of calcium carbonate and carbon. Atomic force microscopy analysis showed CG had better surface roughness compared to BG. In addition, significantly higher levels of osteogenic differentiation markers, namely, alkaline phosphatase (ALP), Osteocalcin (OC) levels, and Osteonectin and Runx2, Integrin gene expression were detected in the CG cultures, when compared with those in the BG cultures. In conclusion, our results demonstrate that the osteogenic differentiation of rMSCs is relatively superior in coral graft than in bone graft culture system. PMID- 24151433 TI - Interaction of RAS activation and lipid disorders accelerates the progression of glomerulosclerosis. AB - BACKGROUND: The activation of the renin-angiotensin system (RAS) and lipid disorders are major risk factors in progressive chronic kidney disease. This study aimed to investigate the potential synergistic mechanisms of RAS activation and lipid disorders that contribute to glomerulosclerosis. MATERIALS AND METHODS: Human renal mesangial cells (HMCs) were treated with 10(-7) mol/L angiotensin II (Ang II) or with 30 MUg/ml cholesterol and 1 MUg/ml 25-hydroxycholesterol (lipid loading) for 24 hours. Lipid accumulation in the cells was evaluated by Oil Red O staining and intracellular cholesterol quantitative assays. The gene and protein expression of molecules in the low-density lipoprotein receptor (LDLr) pathway, the RAS family, and the extracellular matrix were examined by real-time polymerase chain reaction and Western blotting. The translocation of sterol regulatory element-binding protein (SREBP) cleavage activating protein (SCAP), which escorts SREBP-2 from the endoplasmic reticulum (ER) to the Golgi, was examined by immunofluorescent staining. RESULTS: Ang II increased lipid droplet accumulation in HMCs. Further analysis revealed that Ang II increased the mRNA and protein expression of LDLr, SCAP, and SREBP-2. This increase was correlated with an enhanced translocation of the SCAP/SREBP-2 complex from the ER to the Golgi in HMCs that was induced by Ang II, thereby activating LDLr gene transcription. Interestingly, lipid loading increased the mRNA and protein expression of angiotensinogen, Ang II, renin, angiotensin-converting enzyme, angiotensin II type 1 receptor, and type 2 receptor in HMCs with increased mRNA and protein expression of collagen I, alpha-smooth muscle actin, and fibronectin. CONCLUSIONS: This study demonstrates that the interaction of RAS activation and lipid disorders accelerates the progression of glomerulosclerosis. PMID- 24151434 TI - Risk factors for invasive pulmonary aspergillosis and hospital mortality in acute on-chronic liver failure patients: a retrospective-cohort study. AB - BACKGROUND: Invasive pulmonary aspergillosis (IPA) in acute-on-chronic liver failure (ACLF) patients is associated with a high mortality. But the clinical characteristics of and the risk factors for IPA among patients with ACLF remains unclear. This study was aimed at assessing clinical manifestation, the risk factors and antifungal medications for as well as the mortality due to IPA in ACLF patients at the First Affiliated Hospital, College of Medicine, Zhejiang University. PATIENTS AND METHODS: Patients with ACLF who were diagnosed with proven or probable IPA by clinical and laboratory parameters from 1 December 2008 to 1 May 2012 were retrospectively evaluated to determine the risk factors for IPA and the clinical outcomes. The follow-up ended on 30 July 2012. Multivariate analysis was performed to identify the risk factors for mortality and the development of IPA. RESULTS: In total, 787 patients with ACLF were enrolled, and 39 of these patients developed IPA. Thirty seven of these 39 patients died in spite of treatment with antifungal drugs. Controls included 48 patients who did not have a pulmonary infection. The survival rate of patients with IPA was significantly lower than that of those without IPA. IPA was found to be independently associated with age (p = 0.021), encephalopathy (p = 0.002), and steroid use (p = 0.000). There was significant difference in the prognosis between the patients treated with either voriconazole or itraconazole and those without antifungal treatment. CONCLUSIONS: Patients with ACLF and IPA have a high mortality rate. Patients with ACLF who present with encephalopathy should avoid steroids, as they increase the mortality rate. Azoles may prolong the survival time. PMID- 24151435 TI - Incidence, clinical, microbiological features and outcome of bloodstream infections in patients undergoing hemodialysis. AB - OBJECTIVES: Infection is a common cause of death among hemodialysis patients. The study investigated incidence, risk factors, clinical features and outcome of bloodstream infections (BSIs) in haemodialysis patients. METHODS: The records of haemodialysis patients from 1999 to 2005 were reviewed. Risk factors were investigated by multivariate analysis. RESULTS: There were identified 148 bacteremic episodes, in 102 patients. The BSI rate was 0.52 per 1000 patient days. Of the 148 episodes, 34 occurred in patients with permanent fistulae (0.18/1000 patient-days); 19 in patients with grafts (0.39/1000 patient-days); 28 in patients with permanent tunneled central catheters (1.03/1000 patient-days); and 67 in those with temporary-catheter (3.18/1000 patient-days). With fistula as reference, the BSI ratio was 1.84 with arteriovenous graft (P=.029), 4.85 with permanent central venous catheter (P<.001), and 14.88 with temporary catheter (P <.001). Catheter related were 41 episodes (28%). Gram positive organism were responsible for 96 episodes (65%), with S. aureus ( 55%) the most frequent, followed by S. epidermidis (26%) and Gram-negative for 36 (23%), with E. coli (39%) the most frequent. Infection was polymicrobial in 14 (9.5%). Diabetes (p<0.001), low serum albumin (p=0.040) and low hemoglobin (p<0.001) were significant risk factors. During hospitalization 18 patients (18%) died. Septic shock (p<0.001) and polymicrobial infection (p=0.041) were associated with in hospital mortality. CONCLUSION: The risk of BSI in patients undergoing hemodialysis is related to the catheter type and vascular access. Septic shock and polymicrobial infection predispose to unfavourable outcome. PMID- 24151436 TI - Mammalian sperm fertility related proteins. AB - Infertility is an important aspect of human and animal reproduction and still presents with much etiological ambiguity. As fifty percent of infertility is related to the male partner, molecular investigations on sperm and seminal plasma can lead to new knowledge on male infertility. Several comparisons between fertile and infertile human and other species sperm proteome have shown the existence of potential fertility markers. These proteins have been categorized into energy related, structural and other functional proteins which play a major role in sperm motility, capacitation and sperm-oocyte binding. The data from these studies show the impact of sperm proteome studies on identifying different valuable markers for fertility screening. In this article, we review recent development in unraveling sperm fertility related proteins. PMID- 24151437 TI - Dynamic changes of clinical features that predict the prognosis of acute-on chronic hepatitis B liver failure: a retrospective cohort study. AB - OBJECTIVE: The natural history of acute-on-chronic hepatitis B liver failure (ACHBLF) is complex and highly variable. However, the global clinical characteristics of this entity remain ill-defined. We aimed to investigate the dynamic patterns of the natural progression as well as their impact on the outcomes of ACHBLF. METHODS: The clinical features and disease states were retrospectively investigated in 54 patients with ACHBLF at the China South Hepatology Center. The clinical and laboratory profiles including hepatic encephalopathy (HE), hepatorenal syndrome (HRS), and spontaneous bacterial peritonitis (SBP) were evaluated. The disease state estimated by the model for end-stage liver disease (MELD) score and the dynamic patterns during the clinical course of ACHBLF were extrapolated. RESULTS: Twenty-two patients died during the 3-month follow-up period (40.74%). The patients were predominantly male (88.89%). Baseline characteristics showed that there were significant differences in only hepatitis B virus (HBV) DNA levels and platelet count between the deceased and surviving patients (P=0.014 and P=0.012, respectively). Other baseline characteristics were similar in both groups. The dynamic state of the MELD score gradually increased from an initial hepatic flare until week 4 of ACHBLF progression. There were notable changes of the dynamic state of the MELD score at two time points (week 2 and week 4) during ACHBLF progression. The MELD scores were significantly greater in the death group (24.80 +/- 2.99) than in the survival group (19.49+/-1.96, P<0.05) during the clinical course of ACHBLF; the MELD scores of the survival group began to decrease from week 4, while they continued to rise and eventually decreased as more patients died. The gradients of the ascent and descent stages could predict exactly the severity and prognosis of ACHBLF. CONCLUSIONS: The natural progression of ACHBLF could be divided approximately into four stages including ascent, plateau, descent, and convalescence stages according to different trends of liver failure progression, respectively. Thus, the special patterns of the natural progression of ACHBLF may be regarded as a significant predictor of the 3-month mortality of ACHBLF. PMID- 24151438 TI - Dose adjustment strategy of cyclosporine A in renal transplant patients: evaluation of anthropometric parameters for dose adjustment and C0 vs. C2 monitoring in Japan, 2001-2010. AB - The optimal use and monitoring of cyclosporine A (CyA) have remained unclear and the current strategy of CyA treatment requires frequent dose adjustment following an empirical initial dosage adjusted for total body weight (TBW). The primary aim of this study was to evaluate age and anthropometric parameters as predictors for dose adjustment of CyA; and the secondary aim was to compare the usefulness of the concentration at predose (C0) and 2-hour postdose (C2) monitoring. An open label, non-randomized, retrospective study was performed in 81 renal transplant patients in Japan during 2001-2010. The relationships between the area under the blood concentration-time curve (AUC0-9) of CyA and its C0 or C2 level were assessed with a linear regression analysis model. In addition to age, 7 anthropometric parameters were tested as predictors for AUC0-9 of CyA: TBW, height (HT), body mass index (BMI), body surface area (BSA), ideal body weight (IBW), lean body weight (LBW), and fat free mass (FFM). Correlations between AUC0 9 of CyA and these parameters were also analyzed with a linear regression model. The rank order of the correlation coefficient was C0 > C2 (C0; r=0.6273, C2; r=0.5562). The linear regression analyses between AUC0-9 of CyA and candidate parameters indicated their potential usefulness from the following rank order: IBW > FFM > HT > BSA > LBW > TBW > BMI > Age. In conclusion, after oral administration, C2 monitoring has a large variation and could be at high risk for overdosing. Therefore, after oral dosing of CyA, it was not considered to be a useful approach for single monitoring, but should rather be used with C0 monitoring. The regression analyses between AUC0-9 of CyA and anthropometric parameters indicated that IBW was potentially the superior predictor for dose adjustment of CyA in an empiric strategy using TBW (IBW; r=0.5181, TBW; r=0.3192); however, this finding seems to lack the pharmacokinetic rationale and thus warrants further basic and clinical investigations. PMID- 24151439 TI - The relation of the level of serum anti-TF, -Tn and -alpha-Gal IgG to survival in gastrointestinal cancer patients. AB - OBJECTIVE: To evaluate the relation of the level of serum anti-TF, -Tn and alphaGal carbohydrate antibodies to survival in gastrointestinal cancer patients. METHODS: The level of anti-TF (Thomsen-Friedenreich antigen), -Tn and -alphaGal IgG was analysed in the serum of patients with gastric (n = 83) and colorectal (n = 51) cancers in the long-term follow-up, using ELISA with polyacrylamide glycoconjugates. To evaluate overall survival and the risk of death, the Kaplan Meier method and the Cox proportional hazards model were used in the univariate analysis of patients groups. RESULTS: A significantly better survival was observed: (1) in patients with an increased level of anti-TF antibodies (all, stage III, T2-4, N1-2 and G3; P = 0.004-0.038, HR = 0.16-0.46); and (2) in patients with an increased level of anti-Tn antibodies (G1-2 tumors; P = 0.034 0.042, HR = 0.34-0.47). A significantly worse survival was observed in gastrointestinal, gastric and colorectal groups with an increased level of serum anti-alphaGal antibodies. This association depended on the patho-morphology of tumors (all, stages I-II, III, T2-4, N0, N1-2 and G1-2; P = 0.006-0.048, HR = 1.99-2.33). In the combined assessment of the anti-TF and -alphaGal antibodies level of the whole gastrointestinal group (n = 53), P = 0.002, HR = 0.25, 95% CI 0.094-0.655. In the follow-up, the survival time was shorter in patients whose level of anti-alphaGal antibodies rose (P = 0.009-0.040, HR = 2.18-4.27). The level of anti-TF antibodies inversely correlated with neutrophil/lymphocyte ratio (NLR, r = - 0.401, P = 0.004, n = 49). Patients with a higher level of anti alphaGal antibodies and NLR values demonstrated a significantly worse survival (P = 0.009, HR = 2.98, n = 48). CONCLUSIONS: The preoperative levels of anti-TF, -Tn and -alphaGal antibodies and their dynamics are of prognostic significance. The method for the determination of circulating anti-carbohydrate antibodies may be a useful supplement in clinical outcome assessment. PMID- 24151440 TI - Type and location of placenta previa affect preterm delivery risk related to antepartum hemorrhage. AB - PURPOSE: To evaluate whether type and location of placenta previa affect risk of antepartum hemorrhage-related preterm delivery. METHODS: We retrospectively studied 162 women with singleton pregnancies presenting placenta previa. Through observation using transvaginal ultrasound the women were categorized into complete or incomplete placenta previa, and then assigned to anterior and posterior groups. Complete placenta previa was defined as a placenta that completely covered the internal cervical os, with the placental margin >2 cm from the os. Incomplete placenta previa comprised marginal placenta previa whose margin adjacent to the internal os and partial placenta previa which covered the os but the margin situated within 2 cm of the os. Maternal characteristics and perinatal outcomes in complete and incomplete placenta previa were compared, and the differences between the anterior and the posterior groups were evaluated. RESULTS: Antepartum hemorrhage was more prevalent in women with complete placenta previa than in those with incomplete placenta previa (59.1% versus 17.6%), resulting in the higher incidence of preterm delivery in women with complete than in those with incomplete placenta previa [45.1% versus 8.8%; odds ratio (OR) 8.51; 95% confidence interval (CI) 3.59-20.18; p < 0.001]. In complete placenta previa, incidence of antepartum hemorrhage did not significantly differ between the anterior and the posterior groups. However, gestational age at bleeding onset was lower in the anterior group than in the posterior group, and the incidence of preterm delivery was higher in the anterior group than in the posterior group (76.2% versus 32.0%; OR 6.8; 95% CI 2.12-21.84; p = 0.002). In incomplete placenta previa, gestational age at delivery did not significantly differ between the anterior and posterior groups. CONCLUSION: Obstetricians should be aware of the increased risk of preterm delivery related to antepartum hemorrhage in women with complete placenta previa, particularly when the placenta is located on the anterior wall. PMID- 24151441 TI - Immunohistochemical evaluation of neuroreceptors in healthy and pathological temporo-mandibular joint. AB - AIM: A study was performed on the articular disk and periarticular tissues of the temporo-mandibular joint (TMJ) with immunohistochemical techniques to give evidence to the presence of neuroreceptors (NRec) in these sites. METHODS: The study was carried out on tissue samples obtained from 10 subjects without TMJ disease and from 7 patients with severe TMJ arthritis and arthrosis. We use antibodies directed against following antigens: Gliofibrillary Acidic Protein (GFAP), Leu-7, Myelin Basic Protein (MBP), Neurofilaments 68 kD (NF), Neuron Specific Enolase (NSE), S-100 protein (S-100) and Synaptophysin (SYN). RESULTS: This study revealed that Ruffini's-like, Pacini's-like and Golgi's-like receptors can be demonstrated in TMJ periarticular tissues and that free nervous endings are present in the subsynovial tissues but not within the articular disk. We observed elongated cytoplamic processes of chondrocytes that demonstrated strong S-100 immunoreactivity but they were unreactive with all other antibodies. These cytoplamic processes were more abundant and thicker in the samples obtained from patients with disease TMJ. CONCLUSION: The results of this study confirm that different Nrec are detectable in TMJ periarticular tissues but they are absent within the articular disk. In the latter site, only condrocytic processes are evident, especially in diseased TMJ, and they might have been confused with nervous endings in previous morphological studies. Nevertheless the absence of immunoreactivity for NF, NSE and SYN proves that they are not of neural origin. PMID- 24151442 TI - Incidence and predictors of radial artery occlusion associated transradial catheterization. AB - In this study, we sought to assess the incidence and predictors of radial artery occlusion (RAO), which is a significant complication of transradial cardiac catheterization. We prospectively evaluated the results of 106 patients who underwent coronary angiography and percutaneous coronary intervention (PCI) via the transradial approach (TRA). At the 3(rd) h of intervention, the radial artery was checked by palpation; color doppler ultrasonography was performed at the 24(th) h. Fluoroscopy duration, procedure success, and complications of the radial artery were recorded. The procedure was successfully completed in all patients. RAO was detected in eight female and two male patients. In terms of RAO, there was a statistically significant difference between males and females (p=0.019). Other parameters did not show a significant correlation with RAO. Altough did not have any effect on procedural success, eight patients developed transient radial artery spasm. Gender was not associated with radial arterial spasms (p=0.19). TRA in the diagnosis and treatment of coronary artery disease has shown high procedural success and low complication rates; it addition, it presents a low economic burden. It should be used widely and be involved in the routine cardiology residency program. PMID- 24151443 TI - Prevention of pleural adhesions by bioactive polypeptides - a pilot study. AB - OBJECTIVE: Postoperative pleural adhesions lead to major problems in repeated thoracic surgery. To date, no antiadhesive product has been proven clinically effective. Previous studies of differently charged polypeptides, poly-L-lysine (PL) and poly-L-glutamate (PG) have shown promising results reducing postoperative abdominal adhesions in experimental settings. This pilot study examined the possible pleural adhesion prevention by using the PL+PG concept after pleural surgery and its possible effect on key parameters; plasmin activator inhibitor-1 (PAI-1) and tissue growth factor beta 1 (TGFb) in the fibrinolytic process. METHODS: A total of 22 male rats were used in the study, one control group (n=10) and one experimental group (n=12). All animals underwent primary pleural surgery, the controls receiving saline in the pleural cavity and the experimental group the PL+PG solution administered by spray. The animals were evaluated on day 7. Macroscopic appearance of adhesions was evaluated by a scoring system. Histology slides of the adhesions and pleural biopsies for evaluation of PAI-1 and TGFb1 were taken on day 7. RESULTS: A significant reduction of adhesions in the PL+PG group (p<0.05) was noted at day 7 both regarding the length and severity of adhesions. There were no significant differences in the concentration of PAI-1 and TGFb1 when comparing the two groups. CONCLUSIONS: PL+PG may be used to prevent pleural adhesions. The process of fibrinolysis, and fibrosis was though not affected after PLPG administration. PMID- 24151444 TI - The high diversity of MRSA clones detected in a university hospital in istanbul. AB - BACKGROUND: To characterize the methicillin-resistant Staphylococcus aureus (MRSA) clones present in Istanbul, 102 MRSA isolates collected during a 5-year period at the Istanbul Medical Faculty Hospital were characterized using microarray analysis and phenotypic resistance profiles. METHODS: Resistance to methicillin was detected with a cefoxitin disk diffusion assay and confirmed with a MRSA-agar and MRSA detection kit. Antimicrobial susceptibility testing was performed by a disk diffusion assay and interpreted according to the 2012 guidelines of the Antibiogram Committee of the French Society for Microbiology. Decreased susceptibility to glycopeptides was confirmed using the population analysis profile-area under the curve (PAP-AUC) method. The presence of the mecA gene was detected by polymerase chain reaction. Bacterial DNA was extracted according to the manufacturer's recommended protocol using commercial extraction kits. Strains were extensively characterized using the DNA microarray. RESULTS: Isolates were grouped into six clonal complexes. The most frequently detected clone was the Vienna/Hungarian/Brazilian clone (ST239-MRSA-III), which accounted for 53.9% of the isolates. These isolates were resistant to multiple antibiotics, particularly penicillin, tetracycline, rifampicin, kanamycin, tobramycin, gentamicin, levofloxacin, erythromycin, lincomycin and fosfomycin. Furthermore, three isolates were detected by population analysis profile as heterogeneous vancomycin-intermediate S. aureus (hVISA). The UK-EMRSA-15 clone (ST22-MRSA-IV PVL negative) was detected in 9.8% of the isolates and was mainly susceptible to all anti-staphylococcal antibiotics. Seven isolates (6.9%) were positive for PVL genes and were assigned to the CC80-MRSA-IV clone (European CA-MRSA clone, three isolates), ST8-MRSA-IV clone (USA300 clone, two isolates, one ACME-positive) or ST22-MRSA-IV clone ("Regensburg EMRSA" clone, two isolates). All other clones were detected in one to six isolates and corresponded to well-known clones (e.g., Pediatric clone, Dublin EMRSA clone, WA MRSA-54/63, WA MRSA-1/57). CONCLUSIONS: This work highlighted both the high prevalence of ST239-MRSA-III clone and the large diversity of the other MRSA clones detected in a university hospital in Istanbul. PMID- 24151445 TI - TNF-alpha -857C>T genotype is predictive of clinical response after treatment with definitive 5-fluorouracil/cisplatin-based chemoradiotherapy in Japanese patients with esophageal squamous cell carcinoma. AB - BACKGROUND: Genotypes of tumor necrosis factor alpha (TNF-alpha) and its surface receptors, TNFRSF1A and TNFRSF1B, have been examined in terms of the progression, metastasis, clinical efficacy, and prognosis of various cancers; however, little is known about their effects on clinical outcome in patients with esophageal squamous cell carcinoma (ESCC). In this study, TNF-alpha and TNFRSF1A genotypes were retrospectively evaluated in terms of predicting clinical response, long term survival, and severe acute toxicities in 46 male Japanese ESCC patients treated with definitive 5-fluorouracil (5-FU)/cisplatin (CDDP)-based chemoradiotherapy (CRT). METHODS: A course consisted of the continuous infusion of 5-FU at 400 mg/m(2)/day for days 1-5 and 8-12, the infusion of CDDP at 40 mg/m(2)/day on days 1 and 8, and radiation at 2 Gy/day on days 1-5, 8-12, and 15 19, with a second course being repeated after a 2-week interval. The TNF-alpha 1031T>C (rs1799964), -863C>A (rs1800630), -857C>T (rs1799724), -308G>A (rs1800629), -238G>A (rs361525), TNFRSF1A -609G>T (rs4149570), and 36A>G (rs767455) genotypes were evaluated. RESULTS: The TNF-alpha -857C>T genotype was found to be predictive of clinical response, i.e., complete response or not (P = 0.010, Fisher's exact test), but had no effect on long-term survival (CC(-857) vs. CT(-857) + TT(-857), P = 0.072, Fisher's exact test, P = 0.070, Log-rank test). CONCLUSIONS: The TNF-alpha -857C>T genotype was found to be predictive of clinical response and was more likely to predict long-term survival in Japanese ESCC patients receiving definitive 5-FU/CDDP-based CRT. Further clinical investigations with a larger number of patients or experiments in vitro should be performed to assess the predictive value of this genotype following CRT. PMID- 24151446 TI - An anti-infection tissue-engineered construct delivering vancomycin: its evaluation in a goat model of femur defect. AB - A tissue-engineered construct (TEC) has previously been used for treating bone defects due to its strong osteogenic capability. However, transplantation of a TEC involves an open surgery that can cause infection. To overcome the potential risk of infection after TEC transplantation, we designed a system for the controlled release of antibiotics using fibrin gel-coated vancomycin alginate beads (FG-Vanco-AB) that can supply sustained antibiotics at the graft site. A TEC with FG-Vanco-AB was transplanted into critically sized bone defects of the right femur in a goat. As a control, the TEC without FG-Vanco-AB was transplanted into the left femur defect of the same goat. The breakpoint sensitivity of vancomycin for S. aureus (5 mg/L) was used as a known standard. Study results showed that the duration of time with vancomycin concentrations greater than 5 mg/L in the right graft site, blood, and left graft site were 28 days, 7 days, and 2 days, respectively. The bioactivity regarding vancomycin release was analysed by antibiotic disc diffusion. The vancomycin concentration was decreased from the centre of the graft to both ends of the femur. Radionuclide bone imaging showed no significant difference between the right and left TECs at either 28 or 56 days post-operation. Computed tomography and histological observation showed both sides' bone defects were healed by TEC at 112 days post-operation, and there was no significant difference in computed tomography value. These results suggest that FG-Vanco-AB in transplanted bone provided the ability to kill bacteria in local bone tissue while not interfering with the process of bone reconstruction and wound healing. PMID- 24151447 TI - Scavenger receptor class B type 1 gene rs5888 single nucleotide polymorphism and the risk of coronary artery disease and ischemic stroke: a case-control study. AB - BACKGROUND: Our previous studies have showed that the rs5888 single nucleotide polymorphism (SNP) in Scavenger receptor class B type 1 (SCARB1) gene is associated with serum lipid levels in the general Chinese populations. The present study was undertaken to detect the associations between rs5888 SNP and the risk of coronary artery disease (CAD) and ischemic stroke (IS). METHODS: A total of 1,716 unrelated subjects (CAD, 601; IS, 533; and healthy controls, 582) were included in this study. Genotyping of the rs5888 SNP were determined by polymerase chain reaction and restriction fragment length polymorphism. RESULTS: The genotypic frequencies of SCARB1 rs5888 SNP were different between CAD patients and controls, the subjects with TT genotype had high risk of CAD (OR = 1.76, P = 0.038 for TT vs. CC; and OR = 1.75, P = 0.036 for TT vs. CC/CT). There was no significant association between genotypes and the risk of IS. Further analysis showed that the subjects with TT genotype in the total population had lower levels of high-density lipoprotein cholesterol than the subjects with CC/CT genotypes (P < 0.05), the subjects with TT genotype in controls but not in CAD or IS patients had higher levels of serum LDL-C and ApoB than those with CC genotype (P < 0.05 for each). CONCLUSIONS: The present study suggests that the SCARB1 rs5888 SNP influences serum lipid levels, and is associated with the risk of CAD. PMID- 24151448 TI - Genetic confirmation of the role of sulfopyruvate decarboxylase in coenzyme M biosynthesis in Methanococcus maripaludis. AB - Coenzyme M is an essential coenzyme for methanogenesis. The proposed biosynthetic pathway consists of five steps, of which the fourth step is catalyzed by sulfopyruvate decarboxylase (ComDE). Disruption of the gene comE by transposon mutagenesis resulted in a partial coenzyme M auxotroph, which grew poorly in the absence of coenzyme M and retained less than 3% of the wild type level of coenzyme M biosynthesis. Upon coenzyme M addition, normal growth of the mutant was restored. Moreover, complementation of the mutation with the wild type comE gene in trans restored full growth in the absence of coenzyme M. These results confirm that ComE plays an important role in coenzyme M biosynthesis. The inability to yield a complete CoM auxotroph suggests that either the transposon insertion failed to completely inactivate the gene or M. maripaludis possesses a promiscuous activity that partially complemented the mutation. PMID- 24151451 TI - Mapping impervious surface area in the Brazilian Amazon using Landsat Imagery. AB - Impervious surface area (ISA) is an important parameter related to environmental change and socioeconomic conditions, and has been given increasing attention in the past two decades. However, mapping ISA using remote sensing data is still a challenge due to the variety and complexity of materials comprising ISA and the limitations of remote sensing data spectral and spatial resolution. This paper examines ISA mapping with Landsat Thematic Mapper (TM) images in urban and urban rural landscapes in the Brazilian Amazon. A fractional-based method and a per pixel based method were used to map ISA distribution, and their results were evaluated with QuickBird images based on the 2010 Brazilian census at the sector scale of analysis for examining the mapping performance. This research showed that the fraction-based method improved the ISA estimation, especially in urban rural frontiers and in a landscape with a small urban extent. Large errors were mainly located at the sites having ISA proportions of 0.2-0.4 in a census sector. Calibration with high spatial resolution data is valuable for improving Landsat based ISA estimates. PMID- 24151452 TI - The Mental Health Impact of Computer and Internet Training on a Multi-ethnic Sample of Community-Dwelling Older Adults: Results of a Pilot Randomised Controlled Trial. AB - INTRODUCTION: We preliminarily explored the effects of computer and internet training in older age and attempted to address the diversity gap in the ethnogeriatric literature, given that, in our study's sample, only one-third of the participants self-identified as White. The aim of this investigation was to compare two groups - the control and the experimental conditions - regarding theme 1) computer attitudes and related self-efficacy, and theme 2) self-esteem and depressive symptomatology. METHODS: Sixty non-institutionalized residents of Los Angeles County (mean age +/- SD: 69.12 +/- 10.37 years; age range: 51-92) were randomly assigned to either the experimental group (n=30) or the waitlist/control group (n=30). The experimental group was involved in 6 weeks of one-on-one computer and internet training for one 2-hour session per week. The same training was administered to the control participants after their post-test. Outcome measures included the four variables, organized into the two aforementioned themes. RESULTS: There were no significant between-group differences in either post-test computer attitudes or self-esteem. However, findings revealed that the experimental group reported greater computer self efficacy, compared to the waitlist/control group, at post-test/follow-up [F(1,56)=28.89, p=0.001, eta2 =0.01]. Additionally, at the end of the computer and internet training, there was a substantial and statistically significant decrease in depression scores among those in the experimental group when compared to the waitlist/control group [F(1,55)=9.06, p<0.004, eta2 =0.02]. CONCLUSIONS: There were significant improvements in favour of the experimental group in computer self-efficacy and, of noteworthy clinical relevance, in depression, as evidenced by a decreased percentage of significantly depressed experimental subjects from 36.7% at baseline to 16.7% at the end of our intervention. PMID- 24151449 TI - Protein adaptations in archaeal extremophiles. AB - Extremophiles, especially those in Archaea, have a myriad of adaptations that keep their cellular proteins stable and active under the extreme conditions in which they live. Rather than having one basic set of adaptations that works for all environments, Archaea have evolved separate protein features that are customized for each environment. We categorized the Archaea into three general groups to describe what is known about their protein adaptations: thermophilic, psychrophilic, and halophilic. Thermophilic proteins tend to have a prominent hydrophobic core and increased electrostatic interactions to maintain activity at high temperatures. Psychrophilic proteins have a reduced hydrophobic core and a less charged protein surface to maintain flexibility and activity under cold temperatures. Halophilic proteins are characterized by increased negative surface charge due to increased acidic amino acid content and peptide insertions, which compensates for the extreme ionic conditions. While acidophiles, alkaliphiles, and piezophiles are their own class of Archaea, their protein adaptations toward pH and pressure are less discernible. By understanding the protein adaptations used by archaeal extremophiles, we hope to be able to engineer and utilize proteins for industrial, environmental, and biotechnological applications where function in extreme conditions is required for activity. PMID- 24151453 TI - Novel antibacterial activity of lactococcus lactis subspecies lactis z11 isolated from zabady. AB - The purpose of this study was to select and characterize a probiotic bacterium with distinctive antimicrobial activities. In this respect, Lactococcus lactis subspecies lactis Z11 (L. lactis Z11) isolated from Zabady (Arabian yoghurt) inhibited other strains of lactic acid bacteria and some food-born pathogens including Listeria monocytogenes, Bacillus cereus and staphylococcus aureus. The inhibitory activity of cell free supernatant (CFS) of L. lactis Z11 isolated from zabady was lost by proteolytic enzymes, heat resistant. Consequently, the active substance(s) of CFS was characterized as a bacteriocin. This bacteriocin has been shown to consist of protein but has no lipidic or glucidic moieties in its active molecule. Its activity was stable in the pH range 2.0 to 7.0 and was not affected by organic solvents. The L. lactis Z11 bacteriocin was produced in CFS throughout the mide to the late exponential phase of growth of the producer organism and maximum bacteriocin production was obtained at initial pH 6.5 at incubation temperature of about 30 degrees C. PMID- 24151454 TI - A toolbox for real-time subject-independent and subject-dependent classification of brain states from fMRI signals. AB - There is a recent increase in the use of multivariate analysis and pattern classification in prediction and real-time feedback of brain states from functional imaging signals and mapping of spatio-temporal patterns of brain activity. Here we present MANAS, a generalized software toolbox for performing online and offline classification of fMRI signals. MANAS has been developed using MATLAB, LIBSVM, and SVMlight packages to achieve a cross-platform environment. MANAS is targeted for neuroscience investigations and brain rehabilitation applications, based on neurofeedback and brain-computer interface (BCI) paradigms. MANAS provides two different approaches for real-time classification: subject dependent and subject independent classification. In this article, we present the methodology of real-time subject dependent and subject independent pattern classification of fMRI signals; the MANAS software architecture and subsystems; and finally demonstrate the use of the system with experimental results. PMID- 24151456 TI - Female hippocampal estrogens have a significant correlation with cyclic fluctuation of hippocampal spines. AB - Synaptic plasticity of the female hippocampus may cyclically fluctuate across the estrous cycle. The spine density fluctuation had been explained by fluctuation of plasma estradiol (E2) and progesterone (PROG), with the assumption that these steroids penetrate into the hippocampus. Recently, however, we demonstrated that male hippocampal levels of sex steroids are much higher than those in plasma, suggesting a weak contribution of plasma steroids to the spine density. By combination of mass-spectrometric analysis with HPLC-purification and picolinoyl derivatization of hippocampal sex steroids, we determined the accurate concentration of E2 and PROG at four stages of plasma estrous cycle including Proestrus (Pro), Estrus (Est), Diestrus 1 (D1), and Diestrus 2 (D2). Hippocampal levels of E2 and PROG showed cyclic fluctuation with a peak at Pro for E2 and at D1 for PROG, having a positive correlation with the plasma estrous cycle. All these sex steroid levels are much higher in the hippocampus than in plasma. Even after ovariectomy a significant levels of E2 and PROG were observed in the hippocampus. The total spine density showed higher values at Pro and D1, and lower values at Est and D2, having a good correlation with the peak levels of hippocampal E2 or PROG. We also examined fluctuation of the head diameter of spines. Interestingly, mRNA expression level of steroidogenic enzymes (P450arom and 17beta-HSD, etc.) and sex-steroid receptors did not significantly change across the estrous cycle. Therefore, the fluctuation of total hippocampal PROG (equal to sum of hippocampus-synthesized PROG and plasma PROG) may be originated from the contribution of cyclic change in plasma PROG, which can induce the fluctuation of total hippocampal E2, since steroid conversion activity of hippocampus might be nearly the same across the estrus cycle. PMID- 24151457 TI - Can laptops be left inside passenger bags if motion imaging is used in X-ray security screening? AB - This paper describes a study where a new X-ray machine for security screening featuring motion imaging (i.e., 5 views of a bag are shown as an image sequence) was evaluated and compared to single view imaging available on conventional X-ray screening systems. More specifically, it was investigated whether with this new technology X-ray screening of passenger bags could be enhanced to such an extent that laptops could be left inside passenger bags, without causing a significant impairment in threat detection performance. An X-ray image interpretation test was created in four different versions, manipulating the factors packing condition (laptop and bag separate vs. laptop in bag) and display condition (single vs. motion imaging). There was a highly significant and large main effect of packing condition. When laptops and bags were screened separately, threat item detection was substantially higher. For display condition, a medium effect was observed. Detection could be slightly enhanced through the application of motion imaging. There was no interaction between display and packing condition, implying that the high negative effect of leaving laptops in passenger bags could not be fully compensated by motion imaging. Additional analyses were carried out to examine effects depending on different threat categories (guns, improvised explosive devices, knives, others), the placement of the threat items (in bag vs. in laptop) and viewpoint (easy vs. difficult view). In summary, although motion imaging provides an enhancement, it is not strong enough to allow leaving laptops in bags for security screening. PMID- 24151455 TI - microRNAs in nociceptive circuits as predictors of future clinical applications. AB - Neuro-immune alterations in the peripheral and central nervous system play a role in the pathophysiology of chronic pain, and non-coding RNAs - and microRNAs (miRNAs) in particular - regulate both immune and neuronal processes. Specifically, miRNAs control macromolecular complexes in neurons, glia and immune cells and regulate signals used for neuro-immune communication in the pain pathway. Therefore, miRNAs may be hypothesized as critically important master switches modulating chronic pain. In particular, understanding the concerted function of miRNA in the regulation of nociception and endogenous analgesia and defining the importance of miRNAs in the circuitries and cognitive, emotional and behavioral components involved in pain is expected to shed new light on the enigmatic pathophysiology of neuropathic pain, migraine and complex regional pain syndrome. Specific miRNAs may evolve as new druggable molecular targets for pain prevention and relief. Furthermore, predisposing miRNA expression patterns and inter-individual variations and polymorphisms in miRNAs and/or their binding sites may serve as biomarkers for pain and help to predict individual risks for certain types of pain and responsiveness to analgesic drugs. miRNA-based diagnostics are expected to develop into hands-on tools that allow better patient stratification, improved mechanism-based treatment, and targeted prevention strategies for high risk individuals. PMID- 24151458 TI - Identification of neural connectivity signatures of autism using machine learning. AB - Alterations in interregional neural connectivity have been suggested as a signature of the pathobiology of autism. There have been many reports of functional and anatomical connectivity being altered while individuals with autism are engaged in complex cognitive and social tasks. Although disrupted instantaneous correlation between cortical regions observed from functional MRI is considered to be an explanatory model for autism, the causal influence of a brain area on another (effective connectivity) is a vital link missing in these studies. The current study focuses on addressing this in an fMRI study of Theory of-Mind (ToM) in 15 high-functioning adolescents and adults with autism and 15 typically developing control participants. Participants viewed a series of comic strip vignettes in the MRI scanner and were asked to choose the most logical end to the story from three alternatives, separately for trials involving physical and intentional causality. The mean time series, extracted from 18 activated regions of interest, were processed using a multivariate autoregressive model (MVAR) to obtain the causality matrices for each of the 30 participants. These causal connectivity weights, along with assessment scores, functional connectivity values, and fractional anisotropy obtained from DTI data for each participant, were submitted to a recursive cluster elimination based support vector machine classifier to determine the accuracy with which the classifier can predict a novel participant's group membership (autism or control). We found a maximum classification accuracy of 95.9% with 19 features which had the highest discriminative ability between the groups. All of the 19 features were effective connectivity paths, indicating that causal information may be critical in discriminating between autism and control groups. These effective connectivity paths were also found to be significantly greater in controls as compared to ASD participants and consisted predominantly of outputs from the fusiform face area and middle temporal gyrus indicating impaired connectivity in ASD participants, particularly in the social brain areas. These findings collectively point toward the fact that alterations in causal connectivity in the brain in ASD could serve as a potential non-invasive neuroimaging signature for autism. PMID- 24151459 TI - Attention and multisensory integration of emotions in schizophrenia. AB - The impairment of multisensory integration in schizophrenia is often explained by deficits of attentional selection. Emotion perception, however, does not always depend on attention because affective stimuli can capture attention automatically. In our study, we specify the role of attention in the multisensory perception of emotional stimuli in schizophrenia. We evaluated attention by interference between conflicting auditory and visual information in two multisensory paradigms in patients with schizophrenia and healthy participants. In the first paradigm, interference occurred between physical features of the dynamic auditory and visual stimuli. In the second paradigm, interference occurred between the emotional content of the auditory and visual stimuli, namely fearful and sad emotions. In patients with schizophrenia, the interference effect was observed in both paradigms. In contrast, in healthy participants, the interference occurred in the emotional paradigm only. These findings indicate that the information leakage between different modalities in patients with schizophrenia occurs at the perceptual level, which is intact in healthy participants. However, healthy participants can have problems with the separation of fearful and sad emotions similar to those of patients with schizophrenia. PMID- 24151460 TI - Repeating with the right hemisphere: reduced interactions between phonological and lexical-semantic systems in crossed aphasia? AB - Knowledge on the patterns of repetition amongst individuals who develop language deficits in association with right hemisphere lesions (crossed aphasia) is very limited. Available data indicate that repetition in some crossed aphasics experiencing phonological processing deficits is not heavily influenced by lexical-semantic variables (lexicality, imageability, and frequency) as is regularly reported in phonologically-impaired cases with left hemisphere damage. Moreover, in view of the fact that crossed aphasia is rare, information on the role of right cortical areas and white matter tracts underpinning language repetition deficits is scarce. In this study, repetition performance was assessed in two patients with crossed conduction aphasia and striatal/capsular vascular lesions encompassing the right arcuate fasciculus (AF) and inferior frontal occipital fasciculus (IFOF), the temporal stem and the white matter underneath the supramarginal gyrus. Both patients showed lexicality effects repeating better words than non-words, but manipulation of other lexical-semantic variables exerted less influence on repetition performance. Imageability and frequency effects, production of meaning-based paraphrases during sentence repetition, or better performance on repeating novel sentences than overlearned cliches were hardly ever observed in these two patients. In one patient, diffusion tensor imaging disclosed damage to the right long direct segment of the AF and IFOF with relative sparing of the anterior indirect and posterior segments of the AF, together with fully developed left perisylvian white matter pathways. These findings suggest that striatal/capsular lesions extending into the right AF and IFOF in some individuals with right hemisphere language dominance are associated with atypical repetition patterns which might reflect reduced interactions between phonological and lexical-semantic processes. PMID- 24151461 TI - Processing speed training increases the efficiency of attentional resource allocation in young adults. AB - Cognitive training has been shown to improve performance on a range of tasks. However, the mechanisms underlying these improvements are still unclear. Given the wide range of transfer effects, it is likely that these effects are due to a factor common to a wide range of tasks. One such factor is a participant's efficiency in allocating limited cognitive resources. The impact of a cognitive training program, Processing Speed Training (PST), on the allocation of resources to a set of visual tasks was measured using pupillometry in 10 young adults as compared to a control group of a 10 young adults (n = 20). PST is a well-studied computerized training program that involves identifying simultaneously presented central and peripheral stimuli. As training progresses, the task becomes increasingly more difficult, by including peripheral distracting stimuli and decreasing the duration of stimulus presentation. Analysis of baseline data confirmed that pupil diameter reflected cognitive effort. After training, participants randomized to PST used fewer attentional resources to perform complex visual tasks as compared to the control group. These pupil diameter data indicated that PST appears to increase the efficiency of attentional resource allocation. Increases in cognitive efficiency have been hypothesized to underlie improvements following experience with action video games, and improved cognitive efficiency has been hypothesized to underlie the benefits of PST in older adults. These data reveal that these training schemes may share a common underlying mechanism of increasing cognitive efficiency in younger adults. PMID- 24151462 TI - Learning to modulate one's own brain activity: the effect of spontaneous mental strategies. AB - Using neurofeedback (NF), individuals can learn to modulate their own brain activity, in most cases electroencephalographic (EEG) rhythms. Although a large body of literature reports positive effects of NF training on behavior and cognitive functions, there are hardly any reports on how participants can successfully learn to gain control over their own brain activity. About one third of people fail to gain significant control over their brain signals even after repeated training sessions. The reasons for this failure are still largely unknown. In this context, we investigated the effects of spontaneous mental strategies on NF performance. Twenty healthy participants performed either a SMR (sensorimotor rhythm, 12-15 Hz) based or a Gamma (40-43 Hz) based NF training over ten sessions. After the first and the last training session, they were asked to write down which mental strategy they have used for self-regulating their EEG. After the first session, all participants reported the use of various types of mental strategies such as visual strategies, concentration, or relaxation. After the last NF training session, four participants of the SMR group reported to employ no specific strategy. These four participants showed linear improvements in NF performance over the ten training sessions. In contrast, participants still reporting the use of specific mental strategies in the last NF session showed no changes in SMR based NF performance over the ten sessions. This effect could not be observed in the Gamma group. The Gamma group showed no prominent changes in Gamma power over the NF training sessions, regardless of the mental strategies used. These results indicate that successful SMR based NF performance is associated with implicit learning mechanisms. Participants stating vivid reports on strategies to control their SMR probably overload cognitive resources, which might be counterproductive in terms of increasing SMR power. PMID- 24151463 TI - A unified view on weakly correlated recurrent networks. AB - The diversity of neuron models used in contemporary theoretical neuroscience to investigate specific properties of covariances in the spiking activity raises the question how these models relate to each other. In particular it is hard to distinguish between generic properties of covariances and peculiarities due to the abstracted model. Here we present a unified view on pairwise covariances in recurrent networks in the irregular regime. We consider the binary neuron model, the leaky integrate-and-fire (LIF) model, and the Hawkes process. We show that linear approximation maps each of these models to either of two classes of linear rate models (LRM), including the Ornstein-Uhlenbeck process (OUP) as a special case. The distinction between both classes is the location of additive noise in the rate dynamics, which is located on the output side for spiking models and on the input side for the binary model. Both classes allow closed form solutions for the covariance. For output noise it separates into an echo term and a term due to correlated input. The unified framework enables us to transfer results between models. For example, we generalize the binary model and the Hawkes process to the situation with synaptic conduction delays and simplify derivations for established results. Our approach is applicable to general network structures and suitable for the calculation of population averages. The derived averages are exact for fixed out-degree network architectures and approximate for fixed in degree. We demonstrate how taking into account fluctuations in the linearization procedure increases the accuracy of the effective theory and we explain the class dependent differences between covariances in the time and the frequency domain. Finally we show that the oscillatory instability emerging in networks of LIF models with delayed inhibitory feedback is a model-invariant feature: the same structure of poles in the complex frequency plane determines the population power spectra. PMID- 24151464 TI - Single-unit activities during epileptic discharges in the human hippocampal formation. AB - Between seizures the brain of patients with epilepsy generates pathological patterns of synchronous activity, designated as interictal epileptiform discharges (ID). Using microelectrodes in the hippocampal formations of 8 patients with drug-resistant temporal lobe epilepsy, we studied ID by simultaneously analyzing action potentials from individual neurons and the local field potentials (LFPs) generated by the surrounding neuronal network. We found that ~30% of the units increased their firing rate during ID and 40% showed a decrease during the post-ID period. Surprisingly, 30% of units showed either an increase or decrease in firing rates several hundred of milliseconds before the ID. In 4 patients, this pre-ID neuronal firing was correlated with field high frequency oscillations at 40-120 Hz. Finally, we observed that only a very small subset of cells showed significant coincident firing before or during ID. Taken together, we suggested that, in contrast to traditional views, ID are generated by a sparse neuronal network and followed a heterogeneous synchronization process initiated over several hundreds of milliseconds before the paroxysmal discharges. PMID- 24151465 TI - The Cerebral Blood Flow Biomedical Informatics Research Network (CBFBIRN) database and analysis pipeline for arterial spin labeling MRI data. AB - Arterial spin labeling (ASL) is a magnetic resonance imaging technique that provides a non-invasive and quantitative measure of cerebral blood flow (CBF). After more than a decade of active research, ASL is now emerging as a robust and reliable CBF measurement technique with increased availability and ease of use. There is a growing number of research and clinical sites using ASL for neuroscience research and clinical care. In this paper, we present an online CBF Database and Analysis Pipeline, collectively called the Cerebral Blood Flow Biomedical Informatics Research Network (CBFBIRN) that allows researchers to upload and share ASL and clinical data. In addition to serving the role as a central data repository, the CBFBIRN provides a streamlined data processing infrastructure for CBF quantification and group analysis, which has the potential to accelerate the discovery of new scientific and clinical knowledge. All capabilities and features built into the CBFBIRN are accessed online using a web browser through a secure login. In this work, we begin with a general description of the CBFBIRN system data model and its architecture, then devote the remainder of the paper to the CBFBIRN capabilities. The latter part of our work is divided into two processing modules: (1) Data Upload and CBF Quantification Module; (2) Group Analysis Module that supports three types of analysis commonly used in neuroscience research. To date, the CBFBIRN hosts CBF maps and associated clinical data from more than 1,300 individual subjects. The data have been contributed by more than 20 different research studies, investigating the effect of various conditions on CBF including Alzheimer's, schizophrenia, bipolar disorder, depression, traumatic brain injury, HIV, caffeine usage, and methamphetamine abuse. Several example results, generated by the CBFBIRN processing modules, are presented. We conclude with the lessons learned during implementation and deployment of the CBFBIRN and our experience in promoting data sharing. PMID- 24151466 TI - Synaptic membrane rafts: traffic lights for local neurotrophin signaling? AB - Lipid rafts, cholesterol and lipid rich microdomains, are believed to play important roles as platforms for the partitioning of transmembrane and synaptic proteins involved in synaptic signaling, plasticity, and maintenance. There is increasing evidence of a physical interaction between post-synaptic densities and post-synaptic lipid rafts. Localization of proteins within lipid rafts is highly regulated, and therefore lipid rafts may function as traffic lights modulating and fine-tuning neuronal signaling. The tyrosine kinase neurotrophin receptors (Trk) and the low-affinity p75 neurotrophin receptor (p75(NTR)) are enriched in neuronal lipid rafts together with the intermediates of downstream signaling pathways, suggesting a possible role of rafts in neurotrophin signaling. Moreover, neurotrophins and their receptors are involved in the regulation of cholesterol metabolism. Cholesterol is an important component of lipid rafts and its depletion leads to gradual loss of synapses, underscoring the importance of lipid rafts for proper neuronal function. Here, we review and discuss the idea that translocation of neurotrophin receptors in synaptic rafts may account for the selectivity of their transduced signals. PMID- 24151467 TI - Comparison of the effects of erythropoietin and anakinra on functional recovery and gene expression in a traumatic brain injury model. AB - The goal of this study was to compare the effects of two inflammatory modulators, erythropoietin (EPO) and anakinra, on functional recovery and brain gene expression following a cortical contusion impact (CCI) injury. Dosage regimens were designed to provide serum concentrations in the range obtained with clinically approved doses. Functional recovery was assessed using both motor and spatial learning tasks and neuropathological measurements conducted in the cortex and hippocampus. Microarray-based transcriptional profiling was used to determine the effect on gene expression at 24 h, 72 h, and 7 days post-CCI. Ingenuity Pathway Analysis was used to evaluate the effect on relevant functional categories. EPO and anakinra treatment resulted in significant changes in brain gene expression in the CCI model demonstrating acceptable brain penetration. At all three time points, EPO treatment resulted in significantly more differentially expressed genes than anakinra. For anakinra at 24 h and EPO at 24 h, 72 h, and 7 days, the genes in the top 3 functional categories were involved in cellular movement, inflammatory response and cell-to-cell signaling. For EPO, the majority of the genes in the top 10 canonical pathways identified were associated with inflammatory and immune signaling processes. This was true for anakinra only at 24 h post-traumatic brain injury (TBI). The immunomodulation effects of EPO and anakinra did not translate into positive effects on functional behavioral and lesion studies. Treatment with either EPO or anakinra failed to induce significant beneficial effects on recovery of function or produce any significant effects on the prevention of injury induced tissue loss at 30 days post-injury. In conclusion, treatment with EPO or anakinra resulted in significant effects on gene expression in the brain without affecting functional outcome. This suggests that targeting these inflammatory processes alone may not be sufficient for preventing secondary injuries after TBI. PMID- 24151468 TI - Brain-imaging during an isometric leg extension task at graded intensities. AB - Imaging the brain during complex and intensive movements is challenging due to the susceptibility of brain-imaging methods for motion and myogenic artifacts. A few studies measured brain activity during either single-joint or low-intensity exercises; however, the cortical activation state during larger movements with increases up to maximal intensity has barely been investigated so far. Eleven right-handed volunteers (22-45 years in age) performed isometric leg extensions with their right leg at 20, 40, 60, 80, and 100% of their maximal voluntary contraction. Contractions were hold for 20 s respectively. Electroencephalographic (EEG) and electromyographic (EMG) activity was recorded. Standardized low-resolution brain electromagnetic tomography (sLORETA) was used to localize the cortical current density within the premotor (PMC), primary motor (M1), primary somatosensory (S1) and somatosensory association cortex (SAC). ANOVA was used for repeated measures for comparison of intensities and between the left and right hemispheres. The quality of the EEG signal was satisfying up to 80% intensity. At 100% half of the participants were not able to keep their neck and face muscles relaxed, leading to myogenic artifacts. Higher contralateral vs. ipsilateral hemispheric activity was found for the S1, SAC and, PMC. M1 possessed higher ipsilateral activity. The highest activity was localized in the M1, followed by S1, PMC, and SAC. EMG activity and cortical current density within the M1 increased with exercise intensity. EEG recordings during bigger movements up to submaximal intensity (80%) are possible, but maximal intensities are still hard to investigate when subjects contracted their neck and face muscles at the same time. Isometric contractions mainly involve the M1, whereas the S1, PMC, and SAC seem not to be involved in the force output. Limitations and recommendations for future studies are discussed. PMID- 24151469 TI - Dual targeting of peroxisomal proteins. AB - Cellular compartmentalization into organelles serves to separate biological processes within the environment of a single cell. While some metabolic reactions are specific to a single organelle, others occur in more than one cellular compartment. Specific targeting of proteins to compartments inside of eukaryotic cells is mediated by defined sequence motifs. To achieve multiple targeting to different compartments cells use a variety of strategies. Here, we focus on mechanisms leading to dual targeting of peroxisomal proteins. In many instances, isoforms of peroxisomal proteins with distinct intracellular localization are encoded by separate genes. But also single genes can give rise to differentially localized proteins. Different isoforms can be generated by use of alternative transcriptional start sites, by differential splicing or ribosomal read-through of stop codons. In all these cases different peptide variants are produced, of which only one carries a peroxisomal targeting signal. Alternatively, peroxisomal proteins contain additional signals that compete for intracellular targeting. Dual localization of proteins residing in both the cytoplasm and in peroxisomes may also result from use of inefficient targeting signals. The recent observation that some bona fide cytoplasmic enzymes were also found in peroxisomes indicates that dual targeting of proteins to both the cytoplasm and the peroxisome might be more widespread. Although current knowledge of proteins exhibiting only partial peroxisomal targeting is far from being complete, we speculate that the metabolic capacity of peroxisomes might be larger than previously assumed. PMID- 24151470 TI - Association of frontal gray matter volume and cerebral perfusion in heroin addiction: a multimodal neuroimaging study. AB - Structure and function are closely related in the healthy human brain. In patients with chronic heroin exposure, brain imaging studies have identified long lasting changes in gray matter (GM) volume. More recently, we showed that acute application of heroin in dependent patients results in hypoperfusion of fronto temporal areas compared with the placebo condition. However, the relationship between structural and cerebral blood flow (CBF) changes in heroin addiction has not yet been investigated. Moreover, it is not known whether there is any interaction between the chronic structural changes and the short and long-term effects on perfusion caused by heroin. Using a double-blind, within-subject design, heroin or placebo (saline) was administered to 14 heroin-dependent patients from a stable heroin-assisted treatment program, in order to observe acute short-term effects. Arterial spin labeling (ASL) was used to calculate perfusion quantification maps in both treatment conditions, while Voxel-Based Morphometry (VBM) was conducted to calculate regional GM density. VBM and ASL data were used to calculate homologous correlation fields by Biological Parametric Mapping (BPM) and a whole-brain Pearson r correlation. We correlated each perfusion condition (heroin and placebo) separately with a VBM sample that was identical for the two treatment conditions. It was assumed that heroin associated perfusion is manifested in short-term effects, while placebo associated perfusion is more related to long-term effects. In order to restrict our analyses to fronto-temporal regions, we used an explicit mask for our analyses. Correlation analyses revealed a significant positive correlation in frontal areas between GM and both perfusion conditions (heroin and placebo). Heroin-associated perfusion was also negatively correlated with GM in the inferior temporal gyrus on both hemispheres. These findings indicate that, in heroin-dependent patients, low GM volume is positively associated with low perfusion within frontal regions. PMID- 24151472 TI - Testing process predictions of models of risky choice: a quantitative model comparison approach. AB - This article presents a quantitative model comparison contrasting the process predictions of two prominent views on risky choice. One view assumes a trade-off between probabilities and outcomes (or non-linear functions thereof) and the separate evaluation of risky options (expectation models). Another view assumes that risky choice is based on comparative evaluation, limited search, aspiration levels, and the forgoing of trade-offs (heuristic models). We derived quantitative process predictions for a generic expectation model and for a specific heuristic model, namely the priority heuristic (Brandstatter et al., 2006), and tested them in two experiments. The focus was on two key features of the cognitive process: acquisition frequencies (i.e., how frequently individual reasons are looked up) and direction of search (i.e., gamble-wise vs. reason wise). In Experiment 1, the priority heuristic predicted direction of search better than the expectation model (although neither model predicted the acquisition process perfectly); acquisition frequencies, however, were inconsistent with both models. Additional analyses revealed that these frequencies were primarily a function of what Rubinstein (1988) called "similarity." In Experiment 2, the quantitative model comparison approach showed that people seemed to rely more on the priority heuristic in difficult problems, but to make more trade-offs in easy problems. This finding suggests that risky choice may be based on a mental toolbox of strategies. PMID- 24151473 TI - Neural correlates of the numerical distance effect in children. AB - In number comparison tasks, the performance is better when the distance between the numbers to compare increases. It has been shown that this so-called numerical distance effect (NDE) decreases with age but the neuroanatomical correlates of these age-related changes are poorly known. Using functional magnetic resonance imaging (fMRI), we recorded the brain activity changes in children aged from 8 to 14 years while they performed a number comparison task on pairs of Arabic digits and a control color comparison task on non-numerical symbols. On the one hand, we observed developmental changes in the recruitment of frontal regions and the left intraparietal sulcus (IPS), with lower activation as age increased. On the other hand, we found that a behavioral index of selective sensitivity to the NDE was positively correlated with higher brain activity in a right lateralized occipito temporo-parietal network including the IPS. This leads us to propose that the left IPS would be engaged in the refinement of cognitive processes involved in number comparison during development, while the right IPS would underlie the semantic representation of numbers and its activation would be mainly affected by the numerical proximity between them. PMID- 24151471 TI - Treatment approaches for interoceptive dysfunctions in drug addiction. AB - There is emerging evidence that individuals with drug addiction have dysfunctions in brain systems that are important for interoceptive processing, which include, among others, the insular and the anterior cingulate cortices. These individuals may not be expending sufficient neural resources to process perturbations of the interoceptive state but may exert over-activation of these systems when processing drug-related stimuli. As a consequence, insufficient detection and processing of interoceptive state changes may result in inadequate anticipation and preparation to adapt to environmental challenges, e.g., adapt to abstinence in the presence of withdrawal symptoms. Here, we integrate interoceptive dysfunction in drug-addicted individuals, with the neural basis for meditation and exercise to develop a heuristic to target the interoceptive system as potential treatments for drug addiction. First, it is suggested that mindfulness based approaches can modulate both interoceptive function and insular activation patterns. Second, there is an emerging literature showing that the regulation of physical exercise in the brain involves the insula and anterior cingulate cortex and that intense physical exercise is associated with a insula changes that may provide a window to attenuate the increased interoceptive response to drug related stimuli. It is concluded that the conceptual framework of interoceptive dysfunctions in drug addiction and the experimental findings in meditation and exercise provide a useful approach to develop new interventions for drug addiction. PMID- 24151475 TI - Uncovering phenotypes of poor-pitch singing: the Sung Performance Battery (SPB). AB - Singing is as natural as speaking for humans. Increasing evidence shows that the layman can carry a tune (e.g., when asked to sing a well-known song or to imitate single pitches, intervals and short melodies). Yet, important individual differences exist in the general population with regard to singing proficiency. Some individuals are particularly inaccurate or imprecise in producing or imitating pitch information (poor-pitch singers), thus showing a variety of singing phenotypes. Unfortunately, so far there is not a standard set of tasks for assessing singing proficiency in the general population, allowing to uncover and characterize individual profiles of poor-pitch singing. Different tasks and analysis methods are typically used in various experiments, making the comparison of the results across studies arduous. To fill this gap we propose here a new tool for assessing singing proficiency (the Sung Performance Battery, SPB). The SPB starts from the assessment of participants' vocal range followed by five tasks: (1) single-pitch matching, (2) pitch-interval matching, (3) novel-melody matching, (4) singing from memory of familiar melodies (with lyrics and on a syllable), and (5) singing of familiar melodies (with lyrics and on a syllable) at a slow tempo indicated by a metronome. Data analysis via acoustical methods provides objective measures of pitch accuracy and precision in terms of absolute and relative pitch. The SPB has been tested in a group of 50 occasional singers. The results indicate that the battery is useful for characterizing proficient singing and for detecting cases of inaccurate and/or imprecise singing. PMID- 24151474 TI - Effects of arginine vasopressin on musical working memory. AB - Previous genetic studies showed an association between variations in the gene coding for the 1a receptor of the neuro-hormone arginine vasopressin (AVP) and musical working memory (WM). The current study set out to test the influence of intranasal administration (INA) of AVP on musical as compared to verbal WM using a double blind crossover (AVP-placebo) design. Two groups of 25 males were exposed to 20 IU of AVP in one session, and 20 IU of saline water (placebo) in a second session, 1 week apart. In each session subjects completed the tonal subtest from Gordon's "Musical Aptitude Profile," the interval subtest from the "Montreal Battery for Evaluation of Amusias (MBEA)," and the forward and backward digit span tests. Scores in the digit span tests were not influenced by AVP. In contrast, in the music tests there was an AVP effect. In the MBEA test, scores for the group receiving placebo in the first session (PV) were higher than for the group receiving vasopressin in the first session (VP) (p < 0.05) with no main Session effect nor Group * Session interaction. In the Gordon test there was a main Session effect (p < 0.05) with scores higher in the second as compared to the first session, a marginal main Group effect (p = 0.093) and a marginal Group * Session interaction (p = 0.88). In addition we found that the group that received AVP in the first session scored higher on scales indicative of happiness, and alertness on the positive and negative affect scale, (PANAS). Only in this group and only in the music test these scores were significantly correlated with memory scores. Together the results reflect a complex interaction between AVP, musical memory, arousal, and contextual effects such as session, and base levels of memory. The results are interpreted in light of music's universal use as a means to modulate arousal on the one hand, and AVP's influence on mood, arousal, and social interactions on the other. PMID- 24151476 TI - Emotional sounds modulate early neural processing of emotional pictures. AB - In our natural environment, emotional information is conveyed by converging visual and auditory information; multimodal integration is of utmost importance. In the laboratory, however, emotion researchers have mostly focused on the examination of unimodal stimuli. Few existing studies on multimodal emotion processing have focused on human communication such as the integration of facial and vocal expressions. Extending the concept of multimodality, the current study examines how the neural processing of emotional pictures is influenced by simultaneously presented sounds. Twenty pleasant, unpleasant, and neutral pictures of complex scenes were presented to 22 healthy participants. On the critical trials these pictures were paired with pleasant, unpleasant, and neutral sounds. Sound presentation started 500 ms before picture onset and each stimulus presentation lasted for 2 s. EEG was recorded from 64 channels and ERP analyses focused on the picture onset. In addition, valence and arousal ratings were obtained. Previous findings for the neural processing of emotional pictures were replicated. Specifically, unpleasant compared to neutral pictures were associated with an increased parietal P200 and a more pronounced centroparietal late positive potential (LPP), independent of the accompanying sound valence. For audiovisual stimulation, increased parietal P100 and P200 were found in response to all pictures which were accompanied by unpleasant or pleasant sounds compared to pictures with neutral sounds. Most importantly, incongruent audiovisual pairs of unpleasant pictures and pleasant sounds enhanced parietal P100 and P200 compared to pairings with congruent sounds. Taken together, the present findings indicate that emotional sounds modulate early stages of visual processing and, therefore, provide an avenue by which multimodal experience may enhance perception. PMID- 24151477 TI - The meaning of additive reaction-time effects: some misconceptions. PMID- 24151478 TI - Affect-related synesthesias: a prospective view on their existence, expression and underlying mechanisms. AB - The literature on developmental synesthesia has seen numerous sensory combinations, with surprisingly few reports on synesthesias involving affect. On the one hand, emotion, or more broadly affect, might be of minor importance to the synesthetic experience (e.g., Sinke et al., 2012). On the other hand, predictions on how affect could be relevant to the synesthetic experience remain to be formulated, in particular those that are driven by emotion theories. In this theoretical paper, we hypothesize that a priori studies on synesthesia involving affect will observe the following. Firstly, the synesthetic experience is not merely about discrete emotion processing or overall valence (positive, negative) but is determined by or even altered through cognitive appraisal processes. Secondly, the synesthetic experience changes temporarily on a quantitative level according to (i) the affective appraisal of the inducing stimulus or (ii) the current affective state of the individual. These hypotheses are inferred from previous theoretical and empirical accounts on synesthesia (including the few examples involving affect), different emotion theories, crossmodal processing accounts in synesthetes, and non-synesthetes, and the presumed stability of the synesthetic experience. We hope that the current review will succeed in launching a new series of studies on "affective synesthesias." We particularly hope that such studies will apply the same creativity in experimental paradigms as we have seen and still see when assessing and evaluating "traditional" synesthesias. PMID- 24151479 TI - Residual fMRI sensitivity for identity changes in acquired prosopagnosia. AB - While a network of cortical regions contribute to face processing, the lesions in acquired prosopagnosia are highly variable, and likely result in different combinations of spared and affected regions of this network. To assess the residual functional sensitivities of spared regions in prosopagnosia, we designed a rapid event-related functional magnetic resonance imaging (fMRI) experiment that included pairs of faces with same or different identities and same or different expressions. By measuring the release from adaptation to these facial changes we determined the residual sensitivity of face-selective regions-of interest. We tested three patients with acquired prosopagnosia, and all three of these patients demonstrated residual sensitivity for facial identity changes in surviving fusiform and occipital face areas of either the right or left hemisphere, but not in the right posterior superior temporal sulcus. The patients also showed some residual capabilities for facial discrimination with normal performance on the Benton Facial Recognition Test, but impaired performance on more complex tasks of facial discrimination. We conclude that fMRI can demonstrate residual processing of facial identity in acquired prosopagnosia, that this adaptation can occur in the same structures that show similar processing in healthy subjects, and further, that this adaptation may be related to behavioral indices of face perception. PMID- 24151480 TI - Dynamics of decision-making: from evidence accumulation to preference and belief. PMID- 24151481 TI - Processing bimodal stimuli: integrality/separability of color and orientation. AB - We examined how two distinct stimulus features, orientation and color, interact as contributions to global stimulus dissimilarity. Five subjects rated dissimilarity between pairs of bars (N = 30) varying in color (four cardinal hues, plus white) and orientation (six angles at 30 degrees intervals). An exploratory analysis with individual-differences multidimensional scaling (MDS) resulted in a 5D solution, with two dimensions required to accommodate the circular sequence of the angular attribute, and red-green, blue-yellow and achromatic axes for the color attribute. Weights of the orientation subspace relative to the color subspace varied among the subjects, from a 0.32:0.61 ratio to 0.53:0.44, emphasis shifting between color and orientation. In addition to Euclidean metric, we modeled the interaction of color and orientation using Minkowski power metrics across a range of Minkowski exponents p, including the city-block (p = 1), Euclidean (p = 2) and Dominance metric (p -> infinity) as special cases. For averaged data, p ~ 1.3 provided the best fit, i.e., intermediate between separable and integral features. For individual subjects, however, the metric exponent varied significantly from p = 0.7 to p = 3.1, indicating a subject-specific rule for combining color and orientation, as in Tversky and Gati's variable-weights model. No relationship was apparent between dimensional weights and individual p exponents. Factors affecting dimensional integrality are discussed, including possible underlying neural mechanisms where the interaction of the low-level vision attributes orientation and color might shift between uncorrelated (p = 1) or correlated (p >= 2) forms. PMID- 24151483 TI - Writing superiority in cued recall. AB - In list learning paradigms with free recall, written recall has been found to be less susceptible to intrusions of related concepts than spoken recall when the list items had been visually presented. This effect has been ascribed to the use of stored orthographic representations from the study phase during written recall (Kellogg, 2001). In other memory retrieval paradigms, by contrast, either better recall for modality-congruent items or an input-independent writing superiority effect have been found (Grabowski, 2005). In a series of four experiments using a paired associate learning paradigm we tested (a) whether output modality effects on verbal recall can be replicated in a paradigm that does not involve the rejection of semantically related intrusion words, (b) whether a possible superior performance for written recall was due to a slower response onset for writing as compared to speaking in immediate recall, and (c) whether the performance in paired associate word recall was correlated with performance in an additional episodic memory recall task. We observed better written recall in the first half of the recall phase, irrespective of the modality in which the material was presented upon encoding. An explanation for this effect based on longer response latencies for writing and hence more time for memory retrieval could be ruled out by showing that the effect persisted in delayed response versions of the task. Although there was some evidence that stored additional episodic information may contribute to the successful retrieval of associate words, this evidence was only found in the immediate response experiments and hence is most likely independent from the observed output modality effect. In sum, our results from a paired associate learning paradigm suggest that superior performance for written vs. spoken recall cannot be (solely) explained in terms of additional access to stored orthographic representations from the encoding phase. Our findings rather suggest a general writing-superiority effect at the time of memory retrieval. PMID- 24151482 TI - The role of oxytocin in familiarization-habituation responses to social novelty. AB - Stress or arousal responses to novel social contexts ease off when individuals get familiar with the social context. In the present study we investigated whether oxytocin is involved in this process of familiarization-habituation as oxytocin is known to increase trust and decrease anxiety. Fifty-nine healthy female subjects took part in the same experimental procedure in two sessions separated by 4 weeks. In the first (novelty) session state trust scores were significantly positively correlated with salivary oxytocin levels while in the second (familiarity) session state trust scores were significantly negatively correlated with salivary oxytocin levels. In a path model oxytocin was associated with increased trust in the novelty session and trust was associated with decreased oxytocin levels in the familiarity session. The results are consistent with the idea that oxytocin decreases stress-to-novelty responses by promoting familiarization to novel social contexts. PMID- 24151484 TI - Erratum: Cutaneous rabbit "hops toward a light: unimodal and cross-modal causality on the skin". PMID- 24151485 TI - Seeing the forest through the trees: improving decision making on the Iowa gambling task by shifting focus from short- to long-term outcomes. AB - INTRODUCTION: The present study sought to examine two methods by which to improve decision making on the Iowa Gambling Task (IGT): inducing a negative mood and providing additional learning trials. METHOD: In the first study, 194 undergraduate students [74 male; M age = 19.44 (SD = 3.69)] were randomly assigned to view a series of pictures to induce a positive, negative, or neutral mood immediately prior to the IGT. In the second study, 276 undergraduate students [111 male; M age = 19.18 (SD = 2.58)] completed a delay discounting task and back-to-back administrations of the IGT. RESULTS: Participants in an induced negative mood selected more from Deck C during the final trials than those in an induced positive mood. Providing additional learning trials resulted in better decision making: participants shifted their focus from the frequency of immediate gains/losses (i.e., a preference for Decks B and D) to long-term outcomes (i.e., a preference for Deck D). In addition, disadvantageous decision making on the additional learning trials was associated with larger delay discounting (i.e., a preference for more immediate but smaller rewards). CONCLUSIONS: The present results indicate that decision making is affected by negative mood state, and that decision making can be improved by increasing the number of learning trials. In addition, the current results provide evidence of a relationship between performance on the IGT and on a separate measure of decision making, the delay discounting task. Moreover, the present results indicate that improved decision making on the IGT can be attributed to shifting focus toward long-term outcomes, as evidenced by increased selections from advantageous decks as well as correlations between the IGT and delay discounting task. Implications for the assessment of decision making using the IGT are discussed. PMID- 24151486 TI - Sleep-Dependent Synaptic Down-Selection (II): Single-Neuron Level Benefits for Matching, Selectivity, and Specificity. AB - In a companion paper (1), we used computer simulations to show that a strategy of activity-dependent, on-line net synaptic potentiation during wake, followed by off-line synaptic depression during sleep, can provide a parsimonious account for several memory benefits of sleep at the systems level, including the consolidation of procedural and declarative memories, gist extraction, and integration of new with old memories. In this paper, we consider the theoretical benefits of this two-step process at the single-neuron level and employ the theoretical notion of Matching between brain and environment to measure how this process increases the ability of the neuron to capture regularities in the environment and model them internally. We show that down-selection during sleep is beneficial for increasing or restoring Matching after learning, after integrating new with old memories, and after forgetting irrelevant material. By contrast, alternative schemes, such as additional potentiation in wake, potentiation in sleep, or synaptic renormalization in wake, decrease Matching. We also argue that, by selecting appropriate loops through the brain that tie feedforward synapses with feedback ones in the same dendritic domain, different subsets of neurons can learn to specialize for different contingencies and form sequences of nested perception-action loops. By potentiating such loops when interacting with the environment in wake, and depressing them when disconnected from the environment in sleep, neurons can learn to match the long-term statistical structure of the environment while avoiding spurious modes of functioning and catastrophic interference. Finally, such a two-step process has the additional benefit of desaturating the neuron's ability to learn and of maintaining cellular homeostasis. Thus, sleep-dependent synaptic renormalization offers a parsimonious account for both cellular and systems level effects of sleep on learning and memory. PMID- 24151489 TI - Integrative neuro-endocrine pathways in the control of reproduction in lamprey: a brief review. AB - The gonadotropin-releasing hormone (GnRH) system is well known as the main regulator of reproductive physiology in vertebrates. It is also part of a network of brain structures and pathways that integrate information from the internal and external milieu and coordinate the adaptive behavioral and physiological responses to social and reproductive survival needs. In this paper we review the state of knowledge of the GnRH system in relation to the behavior, external, and internal factors that control reproduction in one of the oldest lineage of vertebrates, the lampreys. PMID- 24151487 TI - Tangles, Toxicity, and Tau Secretion in AD - New Approaches to a Vexing Problem. AB - When the microtubule (MT)-associated protein tau is not bound to axonal MTs, it becomes hyperphosphorylated and vulnerable to proteolytic cleavage and other changes typically seen in the hallmark tau deposits (neurofibrillary tangles) of tau-associated neurodegenerative diseases (tauopathies). Neurofibrillary tangle formation is preceded by tau oligomerization and accompanied by covalent crosslinking and cytotoxicity, making tangle cytopathogenesis a natural central focus of studies directed at understanding the role of tau in neurodegenerative disease. Recent studies suggest that the formation of tau oligomers may be more closely related to tau neurotoxicity than the presence of the tangles themselves. It has also become increasingly clear that tau pathobiology involves a wide variety of other cellular abnormalities including a disruption of autophagy, vesicle trafficking mechanisms, axoplasmic transport, neuronal polarity, and even the secretion of tau, which is normally a cytosolic protein, to the extracellular space. In this review, we discuss tau misprocessing, toxicity and secretion in the context of normal tau functions in developing and mature neurons. We also compare tau cytopathology to that of other aggregation-prone proteins involved in neurodegeneration (alpha synuclein, prion protein, and APP). Finally, we consider potential mechanisms of intra- and interneuronal tau lesion spreading, an area of particular recent interest. PMID- 24151488 TI - Local Renin-Angiotensin system in the reproductive system. AB - The renin-angiotensin system (RAS) is well known as regulator of electrolytes and blood pressure. Besides this function, there are numerous studies supporting the idea of a local tissue RAS. This system controls the local activity of the different RAS family members, especially of the functional proteins Angiotensin II and Angiotensin (1-7). Those antagonistically acting proteins have been described to be expressed in different organ systems including the human reproductive tract. Therefore, this local RAS has been suspected to be involved in the control and regulation of physiological and pathological conditions in the female reproduction tract. This review of the available literature summarizes the physiological influence of the RAS on the follicular development, ovarian angiogenesis, and placental- and uterine function. In addition, in the second part the role of the RAS concerning ovarian- and endometrial cancer becomes elucidated. This section includes possible novel therapeutic strategies via inhibition of RAS-mediated tumor growth and angiogenesis. Looking at a very complex system of agonistic and antagonistic tissue factors, it may be supposed that the RAS in the female reproduction tract will be of rising scientific interest in the upcoming years. PMID- 24151490 TI - Epstein-Barr virus-driven lymphomagenesis in the context of human immunodeficiency virus type 1 infection. AB - Epstein-Barr virus (EBV) is a ubiquitous human gamma-herpes virus which establishes a life-long asymptomatic infection in immunocompetent hosts. In human immunodeficiency virus type 1 (HIV-1) infected patients, the impaired immunosurveillance against EBV may favor the development of EBV-related diseases, ranging from lymphoproliferative disorders to B cell non-Hodgkin's lymphomas (NHL). Antiretroviral therapy (ART) has significantly modified the natural course of HIV-1 infection, resulting in decreased HIV-1 plasmaviremia, increased CD4 lymphocytes, and decreased opportunistic infections, indicating a restoration of immune functions. However, the impact of ART appears to be less favorable on EBV related malignancies than on other AIDS-defining tumors, such as Kaposi's sarcoma, and NHL remains the most common cancer during the ART era. EBV-driven tumors are associated with selective expression of latent oncogenic proteins, but uncontrolled lytic cycle with virus replication and/or reactivation may favor cell transformation, at least in the early phases. Several host's factors may promote EBV reactivation and replication; besides immunodepression, inflammation/chronic immune stimulation may play an important role. Microbial pathogen-associated molecular patterns and endogenous damage-associated molecular patterns, through Toll-like receptors, activate the immune system and may promote EBV reactivation and/or polyclonal expansion of EBV-infected cells. A body of evidence suggests that chronic immune stimulation is a hallmark of HIV-1 pathogenesis and may persist even in ART-treated patients. This review focuses on lymphomagenesis driven by EBV both in the context of the natural history of HIV-1 infection and in ART-treated patients. Understanding the mechanisms involved in the expansion of EBV-infected cells is a premise for the identification of prognostic markers of EBV-associated malignancies. PMID- 24151491 TI - Relationship between gene responses and symptoms induced by Rice grassy stunt virus. AB - Rice grassy stunt virus (RGSV) is a serious threat to rice production in Southeast Asia. RGSV is a member of the genus Tenuivirus, and it induces leaf yellowing, stunting, and excess tillering on rice plants. Here we examined gene responses of rice to RGSV infection to gain insight into the gene responses which might be associated with the disease symptoms. The results indicated that (1) many genes related to cell wall synthesis and chlorophyll synthesis were predominantly suppressed by RGSV infection; (2) RGSV infection induced genes associated with tillering process; (3) RGSV activated genes involved in inactivation of gibberellic acid and indole-3-acetic acid; and (4) the genes for strigolactone signaling were suppressed by RGSV. These results suggest that these gene responses to RGSV infection account for the excess tillering specific to RGSV infection as well as other symptoms by RGSV, such as stunting and leaf chlorosis. PMID- 24151492 TI - Interleukin 35: a key mediator of suppression and the propagation of infectious tolerance. AB - The importance of regulatory T cells (Tregs) in balancing the effector arm of the immune system is well documented, playing a central role in preventing autoimmunity, facilitating graft tolerance following organ transplantation, and having a detrimental impact on the development of anti-tumor immunity. These regulatory responses use a variety of mechanisms to mediate suppression, including soluble factors. While IL-10 and TGF-beta are the most commonly studied immunosuppressive cytokines, the recently identified IL-35 has been shown to have potent suppressive function in vitro and in vivo. Furthermore, not only does IL 35 have the ability to directly suppress effector T cell responses, it is also able to expand regulatory responses by propagating infectious tolerance and generating a potent population of IL-35-expressing inducible Tregs. In this review, we summarize research characterizing the structure and function of IL-35, examine its role in disease, and discuss how it can contribute to the induction of a distinct population of inducible Tregs. PMID- 24151493 TI - Co-Receptor CD8-Mediated Modulation of T-Cell Receptor Functional Sensitivity and Epitope Recognition Degeneracy. AB - The interaction between T-cell receptors (TCRs) and peptide epitopes is highly degenerate: a TCR is capable of interacting productively with a wide range of different peptide ligands, involving not only cross-reactivity proper (similar epitopes elicit strong responses), but also polyspecificity (ligands with distinct physicochemical properties are capable of interacting with the TCR). Degeneracy does not gainsay the fact that TCR recognition is fundamentally specific: for the vast majority of ligands, the functional sensitivity of a given TCR is virtually null whereas this TCR has an appreciable functional sensitivity only for a minute fraction of all possible ligands. Degeneracy can be described mathematically as the probability that the functional sensitivity, of a given TCR to a randomly selected ligand, exceeds a set value. Variation of this value generates a statistical distribution that characterizes TCR degeneracy. This distribution can be modeled on the basis of a Gaussian distribution for the TCR/ligand dissociation energy. The kinetics of the TCR and the MHCI molecule can be used to transform this underlying Gaussian distribution into the observed distribution of functional sensitivity values. In the present paper, the model is extended by accounting explicitly for the kinetics of the interaction between the co-receptor and the MHCI molecule. We show that T-cells can modulate the level of degeneracy by varying the density of co-receptors on the cell surface. This could allow for an analog of avidity maturation during incipient T-cell responses. PMID- 24151494 TI - Role of adipokines signaling in the modulation of T cells function. AB - The field that links immunity and metabolism is rapidly expanding. Apparently non immunological disorders such as obesity and type 2 diabetes have been linked to immune dysregulation, suggesting that metabolic alterations can be induced by or be consequence of an altered self-immune tolerance. In this context, adipose tissue produces and releases a variety of pro-inflammatory and anti-inflammatory factors, termed "adipokines," which can be considered as the bridge between obesity-related exogenous factors, such as nutrition and lifestyle, and the molecular events leading to metabolic syndrome, inflammatory, and/or autoimmune conditions. In obesity, increased production of most adipokines impacts on multiple functions such as appetite and energy balance, modulation of immune responses, insulin sensitivity, angiogenesis, blood pressure, lipid metabolism, and so on. This report aims to discuss some of the recent topics of adipocytokine research and their related signaling pathways, that may be of particular importance as could lead to effective therapeutic strategies for obesity associated diseases. PMID- 24151495 TI - Eradication of HIV and Cure of AIDS, Now and How? AB - Recent studies have highlighted the importance of eradication of human immunodeficiency virus (HIV) and cure of acquired immunodeficiency syndrome (AIDS). However, a pivotal point that the patient immunity controls HIV reactivation after highly active anti-retroviral therapy [HAART or combination anti-retroviral therapy (cART)] remains less well addressed. In spite of the fact that both innate and adaptive immunities are indispensable and numerous cells participate in the anti-HIV immunity, memory CD4 T-cells are indisputably the key cells organizing all immune actions against HIV while being the targets of HIV. Here we present a view and multidisciplinary approaches to HIV/AIDS eradication and cure. We aim at memory CD4 T-cells, utilizing the stem cell properties of these cells to reprogram an anti-HIV memory repertoire to eliminate the viral reservoir, toward achieving an AIDS-free world. PMID- 24151496 TI - Humoral Immune Response to AAV. AB - Adeno-associated virus (AAV) is a member of the family Parvoviridae that has been widely used as a vector for gene therapy because of its safety profile, its ability to transduce both dividing and non-dividing cells, and its low immunogenicity. AAV has been detected in many different tissues of several animal species but has not been associated with any disease. As a result of natural infections, antibodies to AAV can be found in many animals including humans. It has been shown that pre-existing AAV antibodies can modulate the safety and efficacy of AAV vector-mediated gene therapy by blocking vector transduction or by redirecting distribution of AAV vectors to tissues other than the target organ. This review will summarize antibody responses against natural AAV infections, as well as AAV gene therapy vectors and their impact in the clinical development of AAV vectors for gene therapy. We will also review and discuss the various methods used for AAV antibody detection and strategies to overcome neutralizing antibodies in AAV-mediated gene therapy. PMID- 24151497 TI - Association Analysis of IL10, TNF-alpha, and IL23R-IL12RB2 SNPs with Behcet's Disease Risk in Western Algeria. AB - OBJECTIVE: We have conducted the first study of the association of interleukin (IL)-10, tumor necrosis factor alpha (TNF-alpha), and IL23R-IL12RB2 region single nucleotide polymorphisms (SNPs) with Behcet's disease (BD) in Western Algeria. METHODS: A total of 51 BD patients and 96 unrelated controls from West region of Algeria were genotyped by direct sequencing for 11 SNPs including 2 SNPs from the IL10 promoter [c.-819T > C (rs1800871), c.-592A > C (rs1800872)], 6 SNPs from the TNF-alpha promoter [c.-1211T > C (rs1799964), c.-1043C > A (rs1800630), c.-1037C > T (rs1799724), c.-556G > A (rs1800750), c.-488G > A (rs1800629), and c.-418G > A (rs361525)], and 3 SNPs from the IL23R-IL12RB2 region [g.67747415A > C (rs12119179), g.67740092G > A (rs11209032), and g.67760140T > C (rs924080)]. RESULTS: The minor alleles c.-819T and c.-592A were significantly associated with BD [odds ratio (OR) = 2.18; 95% confidence interval (CI) 1.28-3.73, p = 0.003]; whereas, there was weaker association between TNF-alpha promoter SNPs or IL23R IL12RB2 region and disease risk. CONCLUSION: Unlike the TNF-alpha and the IL23R IL12RB2 region SNPs, the two IL10 SNPs were strongly associated with BD. The 819T, and -592A alleles and the -819TT, -819CT, and -592AA and -592CA genotypes seem to be highly involved in the risk of developing of BD in the population of Western Algeria. PMID- 24151498 TI - The major thylakoid protein kinases STN7 and STN8 revisited: effects of altered STN8 levels and regulatory specificities of the STN kinases. AB - Thylakoid phosphorylation is predominantly mediated by the protein kinases STN7 and STN8. While STN7 primarily catalyzes LHCII phosphorylation, which enables LHCII to migrate from photosystem (PS) II to PSI, STN8 mainly phosphorylates PSII core proteins. The reversible phosphorylation of PSII core proteins is thought to regulate the PSII repair cycle and PSII supercomplex stability, and play a role in modulating the folding of thylakoid membranes. Earlier studies clearly demonstrated a considerable substrate overlap between the two STN kinases, raising the possibility of a balanced interdependence between them at either the protein or activity level. Here, we show that such an interdependence of the STN kinases on protein level does not seem to exist as neither knock-out nor overexpression of STN7 or STN8 affects accumulation of the other. STN7 and STN8 are both shown to be integral thylakoid proteins that form part of molecular supercomplexes, but exhibit different spatial distributions and are subject to different modes of regulation. Evidence is presented for the existence of a second redox-sensitive motif in STN7, which seems to be targeted by thioredoxin f. Effects of altered STN8 levels on PSII core phosphorylation, supercomplex formation, photosynthetic performance and thylakoid ultrastructure were analyzed in Arabidopsis thaliana using STN8-overexpressing plants (oeSTN8). In general, oeSTN8 plants were less sensitive to intense light and exhibited changes in thylakoid ultrastructure, with grana stacks containing more layers and reduced amounts of PSII supercomplexes. Hence, we conclude that STN8 acts in an amount dependent manner similar to what was shown for STN7 in previous studies. However, the modes of regulation of the STN kinases appear to differ significantly. PMID- 24151499 TI - New insights into the genetic mechanism of IQ in autism spectrum disorders. AB - Autism spectrum disorders (ASD) comprise a number of underlying sub-types with various symptoms and presumably different genetic causes. One important difference between these sub-phenotypes is IQ. Some forms of ASD such as Asperger's have relatively intact intelligence while the majority does not. In this study, we explored the role of genetic factors that might account for this difference. Using a case-control study based on IQ status in 1657 ASD probands, we analyzed both common and rare variants provided by the Autism Genome Project (AGP) consortium via dbGaP (database of Genotypes and Phenotypes). We identified a set of genes, among them HLA-DRB1 and KIAA0319L, which are strongly associated with IQ within a population of ASD patients. PMID- 24151500 TI - Potential long non-coding RNAs to be considered as biomarkers or therapeutic targets in gastric cancer. PMID- 24151501 TI - Immunosenescence is associated with altered gene expression and epigenetic regulation in primary and secondary immune organs. AB - Deterioration of the immune system (immunosenescence) with age is associated with an increased susceptibility to infection, autoimmune disease and cancer, and reduced responsiveness to vaccination. Immunosenescence entails a reduced supply of naive T cells from the thymus and increased specialization of peripheral T cell clones. Both thymic involution and peripheral T cell homeostasis are thought to involve cellular senescence. In order to analyze this at the molecular level, we studied gene expression profiles, epigenetic status, and genome stability in the thymus and spleen of 1-, 4-, and 18-month-old Long Evans rats. In the thymus, altered gene expression, DNA and histone H3K9 hypomethylation, increased genome instability, and apoptosis were observed in 18-month-old animals compared to 1- and 4-month-old animals. In the spleen, alterations in gene expression and epigenetic regulation occurred already by the age of 4 months compared to 1 month and persisted in 18-month-old compared to 1-month-old rats. In both organs, these changes were accompanied by the altered composition of resident T cell populations. Our study suggests that both senescence and apoptosis may be involved in altered organ function. PMID- 24151502 TI - Evaluation of Antidiabetic Activity of Hydroalcoholic Extract of Cestrum nocturnum Leaves in Streptozotocin-Induced Diabetic Rats. AB - Objective. To investigate antidiabetic activity of hydroalcoholic extract of Cestrum nocturnum leaves in Wistar rats. Method. Cestrum nocturnum leaves extract in hydroalcoholic solution were prepared by Soxhletation method and stored in refrigerator at 4 degrees C for two days before use. Wistar rats were made diabetic by a single dose of streptozotocin (150 mg/kg i.p.). Hydroalcoholic leaves extract of Cestrum nocturnum was screened for antidiabetic activity and given to the STZ-induced diabetic rats at a concentration of 200 mg/kg and 400 mg/kg of body weight in different groups of 6 diabetic rats each orally once a day for 15 days. Metformin is also given to another group to support the result at a dose of 10 mg/kg of body weight orally once a day for 15 days. Blood glucose levels and body weights of rats were measured on 0, 5, 7, and 15th days. Results. Oral administration of the extracts for 15 days caused a significant (P < 0.01) reduction in blood glucose levels in diabetic rats. The body weight of diabetic animals was also improved after daily administration of extracts. The extract also improved other altered biochemical parameters associated with diabetes. Also the changes in food intake, water intake, and weight of internal organs were also restored to normal by the prolonged effect of extract treatment. PMID- 24151503 TI - Ureteroscopic laser treatment of upper urinary tract urothelial cell carcinomas: can a tumour free status be achieved? AB - Introduction. In cases of anatomic or functional single kidney with urothelial tumours of the upper urinary tract, the endoscopic laser ablation has proven efficacious. Based on the knowledge that low-grade, low-stage upper tract transitional cell carcinomas rarely progress to invasive lesions, indications for endoscopic laser ablation have expanded to include patients with bilateral functioning kidneys and low-grade tumours. The question that remains to be answered is whether endoscopic laser ablation has the ability to completely eradicate upper urinary tract tumours. Methods. We performed in 25 patients in a period of 11 years 288 ureteroscopies and, if needed, laser ablation of upper urinary tract tumours in imperative indication. Results. In 32% of the patients the cancer remained even after several laser sessions. 64% of patients were tumour free after one or more laser sessions but remained clear only for the next 3 months. Only 1 patient was tumour free for a period of 68 months after 1 session of laser treatment. The procedure had low complication rates. Conclusion. The laser technology and the introduction of small diameter semirigid and flexible ureteroscopes made ablation of upper urinary tract tumours possible and safe. Nevertheless a complete resection of the carcinomas is rarely possible. PMID- 24151504 TI - Delirium in Australian hospitals: a prospective study. AB - Objectives. Australian data regarding delirium in older hospitalized patients are limited. Hence, this study aimed to determine the prevalence and incidence of delirium among older patients admitted to Australian hospitals and assess associated outcomes. Method. A prospective observational study (n = 493) of patients aged >=70 years admitted to four Australian hospitals was undertaken. Trained research nurses completed comprehensive geriatric assessments using standardized instruments including the Confusion Assessment Method to assess for delirium. Nurses also visited the wards daily to assess for incident delirium and other adverse outcomes. Diagnoses of dementia and delirium were established through case reviews by independent physicians. Results. Overall, 9.7% of patients had delirium at admission and a further 7.6% developed delirium during the hospital stay. Dementia was the most important predictor of delirium at (OR = 3.18, 95% CI: 1.65-6.14) and during the admission (OR = 4.82; 95% CI: 2.19 10.62). Delirium at and during the admission predicted increased in-hospital mortality (OR = 5.19, 95% CI: 1.27-21.24; OR = 31.07, 95% CI: 9.30-103.78). Conclusion. These Australian data confirm that delirium is a common and serious condition among older hospital patients. Hospital clinicians should maintain a high index of suspicion for delirium in older patients. PMID- 24151505 TI - Outpatients' perspectives on problems and needs related to female genital mutilation/cutting: a qualitative study from somaliland. AB - Aim. To explore female outpatients' perspectives on problems related to female genital mutilation/cutting (FGM/C) and their views on information, care, and counseling. Setting. An FGM/C support center at a maternity clinic in Hargeisa, Somaliland. Methods. A qualitative, descriptive study, using content analysis of seven semistructured interviews with female outpatients. Results. All participants had been ignorant of the etiology of their FGM/C-related complications and hesitant to seek care. All had undergone infibulation but did not wish the same for their daughters. In recent years they had learnt through religious leaders and media campaigns that infibulation was unapproved by Islam. A less severe FGM/C type, "Sunna," was more accepted; however, few could define what "Sunna" meant. Condemning and ridiculing attitudes against uncircumcised women prevailed in their community. Conclusions. New ideas and concepts related to FGM/C enter the common discourse in the Somali society while traditional norms and values still prevail. Religion was shown to have a strong impact on FGM/C practices and beliefs. Interventions aiming to raise awareness of health consequences of all types of FGM/C, as well as where to seek care for complications, are needed in Somaliland. Involvement of religious leaders in anti FGM/C programs is essential. PMID- 24151506 TI - Delayed pneumocephalus-induced cranial neuropathy. AB - Pneumocephalus is a common occurrence after cranial surgery, with patients typically remaining asymptomatic from a moderate amount of intracranial air. Postsurgical pneumocephalus rarely causes focal neurological deficits; furthermore, cranial neuropathy from postsurgical pneumocephalus is exceedingly uncommon. Only 3 cases have been previously reported that describe direct cranial nerve compression from intracranial air resulting in an isolated single cranial nerve deficit. The authors present a patient who developed dysconjugate eye movements from bilateral oculomotor nerve palsy. Direct cranial nerve compression occurred as a result of postoperative pneumocephalus in the interpeduncular cistern. The isolated cranial neuropathy gradually recovered as the intracranial air was reabsorbed. PMID- 24151507 TI - Coagulopathy and Extremely Elevated PT/INR after Dabigatran Etexilate Use in a Patient with End-Stage Renal Disease. AB - Introduction. Dabigatran is an oral direct thrombin inhibitor which has been approved for prophylaxis of stroke in patients with atrial fibrillation. The use of dabigatran etexilate increased rapidly due to many benefits. However, questions have been raised constantly regarding the safety of dabigatran etexilate. Case. A 58-year-old Caucasian male with a history of recurrent paroxysmal atrial fibrillation status after pacemaker and end-stage renal disease on hemodialysis came to the Emergency Department with the complaint of severe epistaxis. He had been started on dabigatran 150 mg twice a day about 4 months ago as an outpatient by his cardiologist. His prothrombin time (PT) was 63 seconds with international normalized ratio (INR) of 8.8 and his activated partial thromboplastin time (aPTT) was 105.7 seconds. Otherwise, all labs were unremarkable including the liver function test. Dabigatran was stopped immediately. His INR and aPTT trended downward, reaching normal levels 5 days after admission. Conclusion. Dabigatran is contraindicated in patients with severe kidney insufficiency as it is predominantly excreted via the kidney (~80%). Elderly patients over 75 and patients with chronic renal impairment should be carefully evaluated before starting dabigatran. Despite studies showing only mild increase in aPTT and PT/INR in patients receiving dabigatran, close monitoring may be reasonable in patients with renal insufficiency. PMID- 24151508 TI - Pulmonary embolism as the first manifestation of multiple myeloma. AB - Multiple myeloma is considered a hypercoagulable state due to several mechanisms such as the increased IL-6 and immunoglobulins production, the defective fibrinolytic mechanism, and the acquired resistance to activated protein C that are involved in the pathogenesis and clinical futures of the disease. We describe a case of a female patient who presented to the hospital with pulmonary embolism as the first manifestation of the hypercoagulability of multiple myeloma. PMID- 24151509 TI - Multifocal Breast Cancer in Young Women with Prolonged Contact between Their Breasts and Their Cellular Phones. AB - Breast cancer occurring in women under the age of 40 is uncommon in the absence of family history or genetic predisposition, and prompts the exploration of other possible exposures or environmental risks. We report a case series of four young women-ages from 21 to 39-with multifocal invasive breast cancer that raises the concern of a possible association with nonionizing radiation of electromagnetic field exposures from cellular phones. All patients regularly carried their smartphones directly against their breasts in their brassieres for up to 10 hours a day, for several years, and developed tumors in areas of their breasts immediately underlying the phones. All patients had no family history of breast cancer, tested negative for BRCA1 and BRCA2, and had no other known breast cancer risks. Their breast imaging is reviewed, showing clustering of multiple tumor foci in the breast directly under the area of phone contact. Pathology of all four cases shows striking similarity; all tumors are hormone-positive, low intermediate grade, having an extensive intraductal component, and all tumors have near identical morphology. These cases raise awareness to the lack of safety data of prolonged direct contact with cellular phones. PMID- 24151510 TI - Chronic lymphocytic leukemia involving the breast parenchyma, mimicker of invasive breast cancer: differentiation on breast MRI. AB - Leukemic involvement of the breast is rare, particularly involvement by chronic lymphocytic leukemia (CLL). While concurrent invasive ductal carcinoma and CLL manifesting as a collision tumor in the breast is extremely rare, this association (CLL and carcinoma) has been described in other organs. We report here a case of a 58-year-old woman with concurrent invasive ductal carcinoma and CLL and describe the imaging features of CLL, particularly the differentiation on MRI. PMID- 24151511 TI - Behcet's Disease, Associated Large Vessel Thrombosis, and Coexistent Thrombophilia: A Distinct Nosological Entity? AB - Behcet's disease (BD) represents a multisystemic disorder that combines features of immune-mediated diseases and autoinflammatory disorders. Even though it is recognized that every type or size of vessel can be affected in this disease, there is an inability to describe a coherent model that sufficiently explains the predilection of certain patients with BD for manifesting severe large vessel thrombosis. The inconsistent epidemiologic data and the complex genetic background of BD, along with the controversy of multiple international studies regarding the coexistence of thrombophilia in patients with BD and large vessel thrombosis, make us think that a percentage of these patients may actually suffer from a distinct clinical entity. The stimulus for this concept arose from the clinical observation of three male patients who were admitted to our clinic due to extended vena cava thrombosis. On the occasion of those clinically and laboratory resembling cases, we performed a literature review concerning the epidemiology of BD, associated thrombosis, and coexistent thrombophilic factors, in order to present some evidence, which sustains our hypothesis that certain patients with large vessel thrombosis, who share features of BD and coexistent thrombophilia, should actually be further investigated for the possibility of suffering from a distinct nosological entity. PMID- 24151512 TI - Osseointegrated supported prosthesis and interdisciplinary approach for prosthodontic rehabilitation of a young patient with ectodermal dysplasia. AB - Anhidrotic ectodermal dysplasia is a triad of hypodontia or anodontia, hypotrichosis, and hypohydrosis, associated with other problems that result from the defective development of structures of ectodermal origin (Freire-Maia, Pinheiro (1988)). Early and extensive dental treatment is needed keeping in mind the effect on the craniofacial growth. Due to rapid growth of the jaws, the patients are rehabilitated using removable prostheses (Tarjan et al. (2005)). Hence for a young patient in this case report, the placement of endosseous osseointegrated implants was delayed till adulthood. Finally a definitive fixed tooth-supported and osseointegrated implant supported fixed partial denture therapy was used to rehabilitate the patient satisfactorily after she had completed her growth (Sweeney et al. (2005)). A review of the current literature relevant to several aspects of syndromic hypodontia, patient selection, and implant planning is discussed. PMID- 24151513 TI - p53/p21 Pathway involved in mediating cellular senescence of bone marrow-derived mesenchymal stem cells from systemic lupus erythematosus patients. AB - Our and other groups have found that bone marrow-derived mesenchymal stem cells (BM-MSCs) from systemic lupus erythematosus (SLE) patients exhibited senescent behavior and are involved in the pathogenesis of SLE. Numerous studies have shown that activation of the p53/p21 pathway inhibits the proliferation of BM-MSCs. The aim of this study was to determine whether p53/p21 pathway is involved in regulating the aging of BM-MSCs from SLE patients and the underlying mechanisms. We further confirmed that BM-MSCs from SLE patients showed characteristics of senescence. The expressions of p53 and p21 were significantly increased, whereas levels of Cyclin E, cyclin-dependent kinase-2, and phosphorylation of retinoblastoma protein were decreased in the BM-MSCs from SLE patients and knockdown of p21 expression reversed the senescent features of BM-MSCs from SLE patients. Our results demonstrated that p53/p21 pathway played an important role in the senescence process of BM-MSCs from SLE. PMID- 24151514 TI - Upregulated microRNA-155 expression in peripheral blood mononuclear cells and fibroblast-like synoviocytes in rheumatoid arthritis. AB - OBJECTIVE: This study was to screen for the miRNAs differently expressed in peripheral blood mononuclear cells (PBMC) of RA, to further identify the expression of miR-155 in RA PBMC and fibroblast-like synoviocytes (FLS), and to evaluate the function of miR-155 in RA-FLS. METHODS: Microarray was used to screen for differentially expressed miRNAs in RA PBMC. miR-155 expression in PBMC and FLS of RA were identified by real-time PCR. Enforced overexpression and downexpression of miR-155 were used to investigate the function of miR-155 in RA FLS. Expression of IKBKE which was previously identified as the actual target of miR-155 was examined by Western blot and real-time PCR in RA-FLS. RESULTS: miR 155 levels were increased in both PBMC and FLS of RA and could be induced by TNF- alpha . Upregulation of miR-155 decreased MMP-3 levels and suppressed proliferation and invasion of RA-FLS. Inverse relationship between the expressions of miR-155 and the MMPs production-related protein IKBKE was found. CONCLUSION: An inflammatory milieu may alter miRNA expression profiles in rheumatoid arthritis. miR-155 is upregulated in RA-FLS, and it may be a protective factor against the inflammatory effect in part by attenuating expression of IKBKE. PMID- 24151515 TI - Recent advances in the pathogenesis of autoimmune hair loss disease alopecia areata. AB - Alopecia areata is considered to be a cell-mediated autoimmune disease, in which autoreactive cytotoxic T cells recognize melanocyte-associated proteins such as tyrosinase. This review discusses recent advances in the understanding of the pathogenesis of alopecia areata, focusing on immunobiology and hormonal aspects of hair follicles (HFs). The HF is a unique "miniorgan" with its own immune and hormonal microenvironment. The immunosuppressive milieu of the anagen hair bulb modulated by immunosuppressive factors is known as "hair follicle immune privilege." The collapse of the hair follicle immune privilege leads to autoimmune reactions against hair follicle autoantigens. Alopecia areata is sometimes triggered by viral infections such as influenza that causes excess production of interferons (IFN). IFN- gamma is one of the key factors that lead to the collapse of immune privilege. This paper reviews the interactions between the endocrine and immune systems and hair follicles in the pathogenesis of alopecia areata. PMID- 24151517 TI - Systemic and nonrenal adverse effects occurring in renal transplant patients treated with mTOR inhibitors. AB - The mammalian target of rapamycin inhibitors (mTOR-I), sirolimus and everolimus, are immunosuppressive drugs largely used in renal transplantation. The main mechanism of action of these drugs is the inhibition of the mammalian target of rapamycin (mTOR), a regulatory protein kinase involved in lymphocyte proliferation. Additionally, the inhibition of the crosstalk among mTORC1, mTORC2, and PI3K confers the antineoplastic activities of these drugs. Because of their specific pharmacological characteristics and their relative lack of nephrotoxicity, these inhibitors are valid option to calcineurine inhibitors (CNIs) for maintenance immunosuppression in renal transplant recipients with chronic allograft nephropathy. However, as other immunosuppressive drugs, mTOR-I may induce the development of several adverse effects that need to be early recognized and treated to avoid severe illness in renal transplant patients. In particular, mTOR-I may induce systemic nonnephrological side effects including pulmonary toxicity, hematological disorders, dysmetabolism, lymphedema, stomatitis, cutaneous adverse effects, and fertility/gonadic toxicity. Although most of the adverse effects are dose related, it is extremely important for clinicians to early recognize them in order to reduce dosage or discontinue mTOR I treatment avoiding the onset and development of severe clinical complications. PMID- 24151516 TI - The role of T helper (TH)17 cells as a double-edged sword in the interplay of infection and autoimmunity with a focus on xenobiotic-induced immunomodulation. AB - Extensive research in recent years suggests that exposure to xenobiotic stimuli plays a critical role in autoimmunity induction and severity and that the resulting response would be exacerbated in individuals with an infection-aroused immune system. In this context, heavy metals constitute a prominent category of xenobiotic substances, known to alter divergent immune cell responses in accidentally and occupationally exposed individuals, thereby increasing the susceptibility to autoimmunity and cancer, especially when accompanied by inflammation-triggered persistent sensitization. This perception is learned from experimental models of infection and epidemiologic studies and clearly underscores the interplay of exposure to such immunomodulatory elements with pre- or postexposure infectious events. Further, the TH17 cell subset, known to be associated with a growing list of autoimmune manifestations, may be the "superstar" at the interface of xenobiotic exposure and autoimmunity. In this review, the most recently established links to this nomination are short-listed to create a framework to better understand new insights into TH17's contributions to autoimmunity. PMID- 24151519 TI - LMW heparin prevents increased kidney expression of proinflammatory mediators in (NZBxNZW)F1 mice. AB - We have previously demonstrated that continuous infusion of low molecular weight (LMW) heparin delays autoantibody production and development of lupus nephritis in (NZBxNZW)F1 (B/W) mice. In this study we investigated the effect of LMW heparin on renal cytokine and chemokine expression and on nucleosome-mediated activation of nucleosome-specific splenocytes. Total mRNA extracted from kidneys of heparin-treated or -untreated B/W mice was analysed by qPCR for the expression of several cytokines, chemokines, and Toll-like receptors. Splenocytes taken from B/W mice were stimulated with nucleosomes with or without the presence of heparin. Splenocyte cell proliferation as thymidine incorporation and the expression of costimulatory molecules and cell activation markers were measured. Heparin treatment of B/W mice reduced the in vivo expression of CCR2, IL1 beta , and TLR7 compared to untreated B/W mice. Nucleosome-induced cell proliferation of splenocytes was not influenced by heparin. The expression of CD80, CD86, CD69, CD25, CTLA-4, and TLR 2, 7, 8, and 9 was upregulated upon stimulation by nucleosomes, irrespective of whether heparin was added to the cell culture or not. In conclusion, treatment with heparin lowers the kidney expression of proinflammatory mediators in B/W mice but does not affect nucleosomal activation of splenocytes. PMID- 24151518 TI - The role of p38 MAPK in the aetiopathogenesis of psoriasis and psoriatic arthritis. AB - The pathogenetic mechanisms responsible for the induction of immune-mediated disorders, such as psoriasis, remain not well characterized. Molecular signaling pathways are not well described in psoriasis, as well as psoriatic arthritis, which is seen in up to 40% of patients with psoriasis. Signaling pathway defects have long been hypothesized to participate in the pathology of psoriasis, yet their implication in the altered psoriatic gene expression still remains unclear. Emerging data suggest a potential pathogenic role for mitogen activated protein kinases p38 (p38 MAPK) extracellular signal-regulated kinase 1/2 (ERK1/2), and c Jun N-terminal kinase (JNK) in the development of psoriasis. The data are still limited, though, for psoriatic arthritis. This review discusses the current data suggesting a crucial role for p38 MAPK in the pathogenesis of these disorders. PMID- 24151520 TI - The role of IL-33 in rheumatic diseases. AB - Interleukin-33 (IL-33), a novel member of IL-1 family, has been recently implicated in several inflammatory and autoimmune diseases. IL-33 can be produced by various types of tissues and cells and induce gene expression of Th2 associated cytokines via binding to the orphan receptor ST2. By promoting Th2 type immune response, IL-33 plays important roles in the allergy, whereas its function in autoimmune diseases attracts more attention. Recent studies reported the correlation of IL-33 with rheumatic diseases, and most of them found that the IL-33 expression levels were consistent with disease activity and development. Furthermore, evidence has indicated that IL-33-related treatment may ameliorate the pathogenic conditions and attenuate disease progression of those rheumatic diseases. Therefore, elucidation of the roles of IL-33 in rheumatic diseases would be beneficial to understand the pathogenesis and therapy of these diseases. In this paper, we will summarize the roles of IL-33 in the rheumatic diseases. PMID- 24151521 TI - Repeated-Doses Toxicity Study of the Essential Oil of Hyptis martiusii Benth. (Lamiaceae) in Swiss Mice. AB - Hyptis martiusii Benth. (Lamiaceae) is found in abundance in Northeastern Brazil where it is used in traditional medicine to treat gastric disorders. Since there are no studies reporting the toxicity and safety profile of this species, we investigated repeated-doses toxicity of the essential oil of Hyptis martiusii (EOHM). Swiss mice of both sexes were orally treated with EOHM (100 and 500 mg/kg) for 30 days, and biochemical, hematological, and morphological parameters were determined. No toxicity signs or deaths were recorded during the treatment with EOHM. The body weight gain was not affected, but there was an occasional variation in water and food consumption among mice of both sexes treated with both doses. The hematological and biochemical profiles did not show significant differences except for a decrease in the MCV and an increase in albumin, but these variations are within the limits described for the species. The microscopic analysis showed changes in liver, kidneys, lungs, and spleen; however, these changes do not have clinical relevance since they varied among the groups, including the control group. The results indicate that the treatment of repeated doses with the essential oil of Hyptis martiusii showed low toxicity in mice. PMID- 24151522 TI - A robust algorithm for optimisation and customisation of fractal dimensions of time series modified by nonlinearly scaling their time derivatives: mathematical theory and practical applications. AB - Standard methods for computing the fractal dimensions of time series are usually tested with continuous nowhere differentiable functions, but not benchmarked with actual signals. Therefore they can produce opposite results in extreme signals. These methods also use different scaling methods, that is, different amplitude multipliers, which makes it difficult to compare fractal dimensions obtained from different methods. The purpose of this research was to develop an optimisation method that computes the fractal dimension of a normalised (dimensionless) and modified time series signal with a robust algorithm and a running average method, and that maximises the difference between two fractal dimensions, for example, a minimum and a maximum one. The signal is modified by transforming its amplitude by a multiplier, which has a non-linear effect on the signal's time derivative. The optimisation method identifies the optimal multiplier of the normalised amplitude for targeted decision making based on fractal dimensions. The optimisation method provides an additional filter effect and makes the fractal dimensions less noisy. The method is exemplified by, and explained with, different signals, such as human movement, EEG, and acoustic signals. PMID- 24151523 TI - Fluid structural analysis of human cerebral aneurysm using their own wall mechanical properties. AB - Computational Structural Dynamics (CSD) simulations, Computational Fluid Dynamics (CFD) simulation, and Fluid Structure Interaction (FSI) simulations were carried out in an anatomically realistic model of a saccular cerebral aneurysm with the objective of quantifying the effects of type of simulation on principal fluid and solid mechanics results. Eight CSD simulations, one CFD simulation, and four FSI simulations were made. The results allowed the study of the influence of the type of material elements in the solid, the aneurism's wall thickness, and the type of simulation on the modeling of a human cerebral aneurysm. The simulations use their own wall mechanical properties of the aneurysm. The more complex simulation was the FSI simulation completely coupled with hyperelastic Mooney-Rivlin material, normal internal pressure, and normal variable thickness. The FSI simulation coupled in one direction using hyperelastic Mooney-Rivlin material, normal internal pressure, and normal variable thickness is the one that presents the most similar results with respect to the more complex FSI simulation, requiring one-fourth of the calculation time. PMID- 24151524 TI - Comparative analysis of mass spectral similarity measures on peak alignment for comprehensive two-dimensional gas chromatography mass spectrometry. AB - Peak alignment is a critical procedure in mass spectrometry-based biomarker discovery in metabolomics. One of peak alignment approaches to comprehensive two dimensional gas chromatography mass spectrometry (GC*GC-MS) data is peak matching based alignment. A key to the peak matching-based alignment is the calculation of mass spectral similarity scores. Various mass spectral similarity measures have been developed mainly for compound identification, but the effect of these spectral similarity measures on the performance of peak matching-based alignment still remains unknown. Therefore, we selected five mass spectral similarity measures, cosine correlation, Pearson's correlation, Spearman's correlation, partial correlation, and part correlation, and examined their effects on peak alignment using two sets of experimental GC*GC-MS data. The results show that the spectral similarity measure does not affect the alignment accuracy significantly in analysis of data from less complex samples, while the partial correlation performs much better than other spectral similarity measures when analyzing experimental data acquired from complex biological samples. PMID- 24151526 TI - Exact analytical solution of the peristaltic nanofluids flow in an asymmetric channel with flexible walls and slip condition: application to the cancer treatment. AB - In the cancer treatment, magnetic nanoparticles are injected into the blood vessel nearest to the cancer's tissues. The dynamic of these nanoparticles occurs under the action of the peristaltic waves generated on the flexible walls of the blood vessel. Studying such nanofluid flow under this action is therefore useful in treating tissues of the cancer. In this paper, the mathematical model describing the slip peristaltic flow of nanofluid was analytically investigated. Exact expressions were deduced for the temperature distribution and nano-particle concentration. In addition, the effects of the slip, thermophoresis, and Brownian motion parameters on the temperature and nano-particle concentration profiles were discussed and further compared with other approximate results in the literatures. In particular, these results have been obtained at the same values of the physical examined parameters that was considered in Akbar et al., "Peristaltic flow of a nanofluid with slip effects," 2012. The results reveal that remarkable differences are detected between the exact current results and those approximately obtained in the literatures for behaviour of the temperature profile and nano-particles concentration. Accordingly, the current analysis and results are considered as optimal and therefore may be taken as a base for any future comparisons. PMID- 24151525 TI - Identification of DNA-binding proteins using support vector machine with sequence information. AB - DNA-binding proteins are fundamentally important in understanding cellular processes. Thus, the identification of DNA-binding proteins has the particularly important practical application in various fields, such as drug design. We have proposed a novel approach method for predicting DNA-binding proteins using only sequence information. The prediction model developed in this study is constructed by support vector machine-sequential minimal optimization (SVM-SMO) algorithm in conjunction with a hybrid feature. The hybrid feature is incorporating evolutionary information feature, physicochemical property feature, and two novel attributes. These two attributes use DNA-binding residues and nonbinding residues in a query protein to obtain DNA-binding propensity and nonbinding propensity. The results demonstrate that our SVM-SMO model achieves 0.67 Matthew's correlation coefficient (MCC) and 89.6% overall accuracy with 88.4% sensitivity and 90.8% specificity, respectively. Performance comparisons on various features indicate that two novel attributes contribute to the performance improvement. In addition, our SVM-SMO model achieves the best performance than state-of-the-art methods on independent test dataset. PMID- 24151527 TI - The robotic lumbar spine: dynamics and feedback linearization control. AB - The robotic lumbar spine (RLS) is a 15 degree-of-freedom, fully cable-actuated robotic lumbar spine which can mimic in vivo human lumbar spine movements to provide better hands-on training for medical students. The design incorporates five active lumbar vertebrae and the sacrum, with dimensions of an average adult human spine. It is actuated by 20 cables connected to electric motors. Every vertebra is connected to the neighboring vertebrae by spherical joints. Medical schools can benefit from a tool, system, or method that will help instructors train students and assess their tactile proficiency throughout their education. The robotic lumbar spine has the potential to satisfy these needs in palpatory diagnosis. Medical students will be given the opportunity to examine their own patient that can be programmed with many dysfunctions related to the lumbar spine before they start their professional lives as doctors. The robotic lumbar spine can be used to teach and test medical students in their capacity to be able to recognize normal and abnormal movement patterns of the human lumbar spine under flexion-extension, lateral bending, and axial torsion. This paper presents the dynamics and nonlinear control of the RLS. A new approach to solve for positive and nonzero cable tensions that are also continuous in time is introduced. PMID- 24151528 TI - Feasibility of Energy Dispersive X-Ray Fluorescence Determination of Gold in Soft Tissue for Clinical Applications. AB - The feasibility of using EDXRF for a rapid quantitative analysis of gold in tumor tissue has been investigated. The protocol described here demonstrates that sample biopsies can be analyzed in as little as 8 hours, with minimal sample preparation. Samples were prepared by drying a 35 MUL aliquot of tissue dissolved in KOH in a standard EDXRF cup on a Prolene(r) support, producing a thin sample. Calibration curves of XRF peak intensity (CPS/mA) to the gold concentration (0-50 PPM) were prepared for liver, tumor, and a mix of tissue types. A linear regression demonstrated an R2 correlation of 0.93. Analysis of experimental samples showed that gold accumulation in tumors (5.8-41.3 PPM) was in agreement with previous studies, where samples were processed using INAA or ICP-MS. This report provides guidance for elemental analysis of gold in tissue in a shorter time span, showing potential for its use in a clinical setting. PMID- 24151529 TI - Sensitivity of Quantified Intracranial Aneurysm Geometry to Imaging Modality. AB - The objective of this study is to assess the sensitivity of intracranial aneurysm geometry to the modality of imaging. Four imaging modalities-3D rotational angiography (3DRA), computed tomography angiography (CTA), contrast enhanced magnetic resonance angiography (CE-MRA), and time-of-flight magnetic resonance angiography (TOF-MRA)-were assessed using data from a flow phantom and human subjects. A silicone flow phantom of the head and neck arteries with a 10 mm ACOM aneurysm was imaged using all four modalities under steady flow conditions. Three human subjects with mid to large sized intracranial aneurysm who had a 3DRA scan and one of CTA, CE-MRA, or TOF-MRA performed within a day were also studied. The aneurysm and contiguous vasculature were segmented for all available scans and geometric measures of their size (5 indices) and shape (6 indices) were estimated and compared. Visually, the size and shape of segmented 3D models of the aneurysms were similar across scan modalities for both the human subjects and the flow phantom. Consequently, the computed indices were consistent across modalities in the key morphometric indices. In conclusion, quantified indices of 3D geometry of the mid to large sized intracranial aneurysms investigated in this small study population are not sensitive to scanning modality. PMID- 24151530 TI - Musicality Correlates With Sociability and Emotionality in Williams Syndrome. AB - Williams Syndrome (WS) is a neurogenetic developmental disorder characterized by peaks and valleys of cognitive abilities. One peak that has been understudied is the affinity that many individuals with WS have toward music. It remains unknown whether their high levels of musical interest, skill and expressivity are related to their sociable personality or their verbal intelligence. We examined the relationships between musicality (musical interest, creativity and expressivity), sociability (social-emotionality, social approach) and language comprehension in WS and typically developing (TD) controls. Findings suggest that emotion expressivity through music in WS may be linked to their sensitivity and responsivity to emotions of others, whereas general interest in music may be related to greater linguistic capacity in TD individuals. Musicality and sociability may be more closely related in WS relative than in typical development; implications for future interventions for this neurodevelopmental condition will be discussed. PMID- 24151532 TI - Ephrin b2 receptor and microsatellite status in lymph node-positive colon cancer survival. AB - BACKGROUND: Ephrin B2 receptor (EphB2) is a target of the canonical wnt pathway implicated in colorectal carcinogenesis, and its down-regulation may be associated with adverse prognosis. We evaluated its prognostic value in resected colon cancer stratified by microsatellite status and other clinicopathologic characteristics. METHODS: We identified all cases of resected stage III colon cancer from 1995 to 2009 managed in the Capital Health district of Nova Scotia. Tissue microarrays were constructed and immunohistochemistry (IHC) for tumor EphB2 staining assigned into quartiles. Microsatellite status was evaluated by IHC for MutL homolog 1 (MLH1) and MutS homolog 2 (MSH2). Microsatellite stable tumors were defined as both MLH1/MSH2 (+/+); tumors staining otherwise were classified with microsatellite instability (MSI-H). Primary and secondary outcomes were disease-free survival (DFS) and overall survival (OS), respectively. RESULTS: We identified 159 cases with sufficient tissue for microarray analysis having a median follow-up of 3.47 years (range, 0.14-14). Median age was 61, 52% were male, 40% had an event, and 29% died. MSI-H was present in 18 (13%). Univariate analysis of EphB2 expression on DFS and OS showed a hazard ratio (HR) of 2.00 (P = .01) and 2.14 (P = .03), respectively. Multivariate analysis of EphB2 expression on DFS and OS showed an HR of 2.24 and 2.23, respectively, with tumor IHC <= 50%. CONCLUSIONS: In this cohort, decreased EphB2 expression was an independent prognostic factor for recurrence and death and may have prognostic relevance in tumors with MSI-H. However, this would require prospective validation in a larger study. PMID- 24151533 TI - Mutational Analysis of Circulating Tumor Cells Using a Novel Microfluidic Collection Device and qPCR Assay. AB - Circulating tumor cells (CTCs) provide a readily accessible source of tumor material from patients with cancer. Molecular profiling of these rare cells can lead to insight on disease progression and therapeutic strategies. A critical need exists to isolate CTCs with sufficient quantity and sample integrity to adapt to conventional analytical techniques. We present a microfluidic platform (IsoFlux) that uses flow control and immunomagnetic capture to enhance CTC isolation. A novel cell retrieval mechanism ensures complete transfer of CTCs into the molecular assay. Improved sensitivity to the capture antigen was demonstrated by spike-in experiments for three cell lines of varying levels of antigen expression. We obtained spike-in recovery rates of 74%, 75%, and 85% for MDA-MB-231 (low), PC3 (middle), and SKBR3 (high) cell lines. Recovery using matched enumeration protocols and matched samples (PC3) yielded 90% and 40% recovery for the IsoFlux and CellSearch systems, respectively. In matched prostate cancer samples (N = 22), patients presenting more than four CTCs per blood draw were 95% and 36% using IsoFlux and CellSearch, respectively. An assay for detecting KRAS mutations was described along with data from patients with colorectal cancer, of which 87% presented CTCs above the assay's limit of detection (four CTCs). The CTC KRAS mutant rate was 50%, with 46% of patients displaying a CTC KRAS mutational status that differed from the previously acquired tissue biopsy data. The microfluidic system and mutation assay presented here provide a complete workflow to track oncogene mutational changes longitudinally with high success rates. PMID- 24151531 TI - Metronomic chemotherapy: possible clinical application in advanced hepatocellular carcinoma. AB - Hepatocellular carcinoma (HCC) is a hypervascular highly angiogenic tumor usually associated with liver cirrhosis. Vascular endothelial growth factor plays a critical role in vascular development in HCC. In contrast to the treatment of early-stage HCC, the treatment options for advanced HCC are limited and prognosis is often poor, which contributes to this tumor type being the third leading cause of cancer-related deaths worldwide. Metronomic chemotherapy, which was originally designed to inhibit angiogenesis, involves low-dose chemotherapeutic agents administered in a frequent regular schedule with no prolonged breaks and minimizes severe toxicities. We reviewed the potential effects and impact of metronomic chemotherapy in preclinical studies with HCC models and in patients with advanced HCC, especially when combined with a molecular targeted agent. Metronomic chemotherapy involves multiple mechanisms that include antiangiogenesis and antivasculogenesis, immune stimulation by reducing regulatory T cells and inducing dendritic cell maturation, and possibly some direct tumor cell targeting effects, including the cancer stem cell subpopulation. The total number of preclinical studies with HCC models shows impressive results using metronomic chemotherapy-based protocols, especially in conjunction with molecular targeted agents. Four clinical trials and two case reports evaluating metronomic chemotherapy for HCC indicate it to be a safe and potentially useful treatment for HCC. Several preclinical and clinical HCC studies suggest that metronomic chemotherapy may become an alternative type of chemotherapy for advanced unresectable HCC and postsurgical adjuvant treatment of HCC. PMID- 24151534 TI - Exposure to ACEI/ARB and beta-Blockers Is Associated with Improved Survival and Decreased Tumor Progression and Hospitalizations in Patients with Advanced Colon Cancer. AB - BACKGROUND: Advanced colon cancer is associated with weight loss and decreased survival. Studies suggest that angiotensin and beta-adrenergic blockade decrease colon cancer progression and ameliorate weight loss. This study aims to determine whether exposure to beta-adrenoceptor blockers (BBs), angiotensin-converting enzyme inhibitors (ACEIs), or angiotensin receptor blockers (ARBs) is associated with decreased mortality, tumor progression, number of hospitalizations, or weight loss in colorectal cancer. METHODS: Retrospective chart review included patients with advanced colorectal cancer. Survival, stage, hospitalization, cancer progression, cancer treatment, and body weight history were collected. RESULTS: Two hundred sixty-two of 425 new stage III to IV colorectal cancer cases reviewed met the study criteria. Those exposed to ACEI/ARB, BB, or both were more likely to have diabetes, hypertension, and stage III colorectal cancer. Adjusting for age, presence of hypertension and diabetes, and stage, ACEI/ARB + BB exposure was associated with decreased mortality compared to unexposed individuals [hazard ratio (HR) = 0.5, confidence interval (CI) = 0.29-0.85; Cox regression, P = .01]. Fewer total and cancer-related hospitalizations and decreased cancer progression in the ACEI/ARB + BB group versus the unexposed group (HR = 0.59, CI = 0.36-0.99, P = .047) were seen. Exposure did not affect weight changes; furthermore, body weight changes from both prediagnosis and at diagnosis to 6, 12, 18, and 24 months postdiagnosis predicted survival. CONCLUSIONS: We have observed an association between exposure to a combination of ACEI/ARB + BB and increased survival, decreased hospitalizations, and decreased tumor progression in advanced colorectal cancer. Future studies will be needed to replicate these results and generalize them to broader populations. Determination of causality will require a randomized controlled trial. PMID- 24151535 TI - Common fusion transcripts identified in colorectal cancer cell lines by high throughput RNA sequencing. AB - Colorectal cancer (CRC) is the third most common cancer disease in the Western world, and about 40% of the patients die from this disease. The cancer cells are commonly genetically unstable, but only a few low-frequency recurrent fusion genes have so far been reported for this disease. In this study, we present a thorough search for novel fusion transcripts in CRC using high-throughput RNA sequencing. From altogether 220 million paired-end sequence reads from seven CRC cell lines, we identified 3391 candidate fused transcripts. By stringent requirements, we nominated 11 candidate fusion transcripts for further experimental validation, of which 10 were positive by reverse transcription polymerase chain reaction and Sanger sequencing. Six were intrachromosomal fusion transcripts, and interestingly, three of these, AKAP13-PDE8A, COMMD10-AP3S1, and CTB-35F21.1-PSD2, were present in, respectively, 18, 18, and 20 of 21 analyzed cell lines and in, respectively, 18, 61, and 48 (17%-58%) of 106 primary cancer tissues. These three fusion transcripts were also detected in 2 to 4 of 14 normal colonic mucosa samples (14%-28%). Whole-genome sequencing identified a specific genomic breakpoint in COMMD10-AP3S1 and further indicates that both the COMMD10 AP3S1 and AKAP13-PDE8A fusion transcripts are due to genomic duplications in specific cell lines. In conclusion, we have identified AKAP13-PDE8A, COMMD10 AP3S1, and CTB-35F21.1-PSD2 as novel intrachromosomal fusion transcripts and the most highly recurring chimeric transcripts described for CRC to date. The functional and clinical relevance of these chimeric RNA molecules remains to be elucidated. PMID- 24151536 TI - Diffusion-Weighted MRI as a Biomarker of Tumor Radiation Treatment Response Heterogeneity: A Comparative Study of Whole-Volume Histogram Analysis versus Voxel-Based Functional Diffusion Map Analysis. AB - RATIONALE: Treatment of glioblastoma (GBM) remains challenging due in part to its histologic intratumoral heterogeneity that contributes to its overall poor treatment response. Our goal was to evaluate a voxel-based biomarker, the functional diffusion map (fDM), as an imaging biomarker to detect heterogeneity of tumor response in a radiation dose escalation protocol using a genetically engineered murine GBM model. EXPERIMENTAL DESIGN: Twenty-four genetically engineered murine GBM models [Ink4a-Arf(-/-)/Pten(loxp/loxp)/Ntv-a RCAS/PDGF(+)/Cre(+)] were randomized in four treatment groups (n = 6 per group) consisting of daily doses of 0, 1, 2, and 4 Gy delivered for 5 days. Contrast enhanced T1-weighted and diffusion-weighted magnetic resonance imaging (MRI) scans were acquired for tumor delineation and quantification of apparent diffusion coefficient (ADC) maps, respectively. MRI experiments were performed daily for a week and every 2 days thereafter. For each animal, the area under the curve (AUC) of the percentage change of the ADC (AUCADC) and that of the increase in fDM values (AUCfDM+) were determined within the first 5 days following therapy initiation. RESULTS: Animal survival increased with increasing radiation dose. Treatment induced a dose-dependent increase in tumor ADC values. The strongest correlation between survival and ADC measurements was observed using the AUCfDM+ metric (R (2) = 0.88). CONCLUSION: This study showed that the efficacy of a voxel based imaging biomarker (fDM) was able to detect spatially varying changes in tumors, which were determined to be a more sensitive predictor of overall response versus whole-volume tumor measurements (AUCADC). Finally, fDM provided for visualization of treatment-associated spatial heterogeneity within the tumor. PMID- 24151537 TI - The Effect of Molecular Weight, PK, and Valency on Tumor Biodistribution and Efficacy of Antibody-Based Drugs. AB - Poor drug delivery and penetration of antibody-mediated therapies pose significant obstacles to effective treatment of solid tumors. This study explored the role of pharmacokinetics, valency, and molecular weight in maximizing drug delivery. Biodistribution of a fibroblast growth factor receptor 4 (FGFR4) targeting CovX-body (an FGFR4-binding peptide covalently linked to a nontargeting IgG scaffold; 150 kDa) and enzymatically generated FGFR4 targeting F(ab)2 (100 kDa) and Fab (50 kDa) fragments was measured. Peak tumor levels were achieved in 1 to 2 hours for Fab and F(ab)2 versus 8 hours for IgG, and the percentage injected dose in tumors was 0.45%, 0.5%, and 2.5%, respectively, compared to 0.3%, 2%, and 6% of their nontargeting controls. To explore the contribution of multivalent binding, homodimeric peptides were conjugated to the different sized scaffolds, creating FGFR4 targeting IgG and F(ab)2 with four peptides and Fab with two peptides. Increased valency resulted in an increase in cell surface binding of the bivalent constructs. There was an inverse relationship between valency and intratumoral drug concentration, consistent with targeted consumption. Immunohistochemical analysis demonstrated increased size and increased cell binding decreased tumor penetration. The binding site barrier hypothesis suggests that limited tumor penetration, as a result of high-affinity binding, could result in decreased efficacy. In our studies, increased target binding translated into superior efficacy of the IgG instead, because of superior inhibition of FGFR4 proliferation pathways and dosing through the binding site barrier. Increasing valency is therefore an effective way to increase the efficacy of antibody-based drugs. PMID- 24151538 TI - mRNA Expression Profiles for Prostate Cancer following Fractionated Irradiation Are Influenced by p53 Status. AB - We assessed changes in cell lines of varying p53 status after various fractionation regimens to determine if p53 influences gene expression and if multifractionated (MF) irradiation can induce molecular pathway changes. LNCaP (p53 wild-type), PC3 (p53 null), and DU145 (p53 mutant) prostate carcinoma cells received 5 and 10 Gy as single-dose (SD) or MF (0.5 Gy x 10, 1 Gy x 10, and 2 Gy x 5) irradiation to simulate hypofractionated and conventionally fractionated prostate radiotherapies, respectively. mRNA analysis revealed 978 LNCaP genes differentially expressed (greater than two-fold change, P < .05) after irradiation. Most were altered with SD (69%) and downregulated (75%). Fewer PC3 (343) and DU145 (116) genes were induced, with most upregulated (87%, 89%) and altered with MF irradiation. Gene ontology revealed immune response and interferon genes most prominently expressed after irradiation in PC3 and DU145. Cell cycle regulatory (P = 9.23 x 10(-73), 14.2% of altered genes, nearly universally downregulated) and DNA replication/repair (P = 6.86 x 10(-30)) genes were most prominent in LNCaP. Stress response and proliferation genes were altered in all cell lines. p53-activated genes were only induced in LNCaP. Differences in gene expression exist between cell lines and after varying irradiation regimens that are p53 dependent. As the duration of changes is >=24 hours, it may be possible to use radiation-inducible targeted therapy to enhance the efficacy of molecular targeted agents. PMID- 24151539 TI - (18)F-FDG Is a Surrogate Marker of Therapy Response and Tumor Recovery after Drug Withdrawal during Treatment with a Dual PI3K/mTOR Inhibitor in a Preclinical Model of Cisplatin-Resistant Ovarian Cancer. AB - AIM: Targeting the phosphoinositide 3-kinase (PI3K)/mammalian target of rapamycin (mTOR) pathway is a potential means of overcoming chemoresistance in ovarian cancer. We investigated the capability of (18)F-fluororodeoxyglucose ((18)F-FDG) small-animal positron emission tomography (SA-PET) to predict the effects of a dual PI3K/mTOR inhibitor (BEZ-235) in a cisplatin-resistant ovarian cancer model. METHODS: In a first experiment, nude rats bearing subcutaneous SKOV3 tumors received BEZ-235 for 3 days given alone or after paclitaxel and were compared to controls (either untreated or that were given the excipients of paclitaxel and BEZ-235). SA-PET was performed at baseline, on day 3, and day 7. In a second experiment aiming at further exploring the kinetics of (18)F-FDG tumor uptake during the first 48 hours following drug cessation, untreated controls were compared to rats receiving BEZ-235, which were imaged at baseline, on day 3, on day 4, and on day 5. SA-PET results were compared to cell proliferation assessment (Ki-67), PI3K/mTOR downstream target expression studies (pAKT and phospho-eukaryotic translation initiation factor 4E-binding protein 1), and apoptosis evaluation (cleaved caspase-3). RESULTS: In the first experiment, BEZ 235, compared to untreated controls, induced a marked decrease in (18)F-FDG uptake on day 3, which was correlated to a significant decrease in cell proliferation and to a significant PI3K/mTOR pathway inhibition. No tumor necrosis or apoptosis occurred. Four days following treatment cessation, tumor recovery (in terms of PI3K/mTOR inhibition and cell proliferation) occurred and was identified by (18)F-FDG SA-PET. Paclitaxel plus BEZ-235 showed results similar to BEZ-235 alone. In the second experiment, PI3K/mTOR pathways exhibited partial recovery as early as 24 hours following treatment cessation, but both (18)F-FDG SA-PET and cell proliferation remained unchanged. CONCLUSIONS: (18)F FDG SA-PET is a surrogate marker of target inhibition during treatment with BEZ 235 and predicts tumor recovery 4 days after drug withdrawal, but not during the first 48 hours following drug cessation, when a lag between PI3K/mTOR pathway recovery and metabolic recovery is observed. (18)F-FDG SA-PET could be used for therapy monitoring of PI3K/mTOR inhibitors, but our results also raise questions regarding the potential impact of the delay between PET imaging and the last drug intake on the accuracy of FDG imaging. PMID- 24151540 TI - Colon Macrophages Polarized by Commensal Bacteria Cause Colitis and Cancer through the Bystander Effect. AB - Intestinal commensal bacteria have recently been shown to trigger macrophages to produce diffusible clastogens (or chromosome-breaking factors) through a bystander effect (BSE) that mediates DNA damage and induces chromosomal instability in neighboring cells. Colon macrophages appear central to colon carcinogenesis and BSE through the expression of tumor necrosis factor-alpha (TNF alpha) and cyclooxygenase-2 (COX-2). The former induces netrin-1, a regulator of intestinal epithelial cell apoptosis, and the latter generates trans-4-hydroxy-2 nonenal (4-HNE), an endogenous mutagen. To test whether colon macrophages are key effectors for BSE, we depleted these cells in interleukin-10 knockout mice colonized with Enterococcus faecalis using encapsulated liposomal clodronate (ELC), a bisphosphonate that causes macrophage apoptosis. We observed that E. faecalis polarizes colon macrophages to an M1 phenotype. In addition, depleting these cells suppressed COX-2 and TNF-alpha, blocked the formation of 4-HNE protein adducts, and inhibited up-regulation of netrin-1-all markers for BSE. Finally, treatment with ELC prevented colitis, beta-catenin activation, and cancer formation. These results show that selected human commensals can polarize colon macrophages to the M1 phenotype and, when activated, serve as the key effector for bacterial-induced BSE. Our findings suggest that depleting M1 polarized macro-phages is a mechanism for the chemopreventive activity of bisphosphonates and that it represents a new strategy for preventing colon cancer induced by intestinal commensals. PMID- 24151542 TI - Erratum. AB - [This corrects the article on p. 394 in vol. 6.]. PMID- 24151541 TI - The Microenvironment of Cervical Carcinoma Xenografts: Associations with Lymph Node Metastasis and Its Assessment by DCE-MRI. AB - Poor disease-free and overall survival rates in locally advanced cervical cancer are associated with a tumor micro-environment characterized by extensive hypoxia, interstitial hypertension, and high lactate concentrations. The potential of gadolinium diethylenetriamine pentaacetic acid-based dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) in assessing the microenvironment and microenvironment-associated aggressiveness of cervical carcinomas was investigated in this preclinical study. CK-160 and TS-415 cervical carcinoma xenografts were used as tumor models. DCE-MRI was carried out at 1.5 T, and parametric images of K (trans) and v e were produced by pharmacokinetic analysis of the DCE-MRI series. Pimonidazole was used as a marker of hypoxia. A Millar catheter was used to measure tumor interstitial fluid pressure (IFP). The concentrations of glucose, adenosine triphosphate (ATP), and lactate were measured by induced metabolic bioluminescence imaging. High incidence of lymph node metastases was associated with high hypoxic fraction and high lactate concentration in CK-160 tumors and with high IFP and high lactate concentration in TS-415 tumors. Low K (trans) was associated with high hypoxic fraction, low glucose concentration, and high lactate concentration in tumors of both lines and with high incidence of metastases in CK-160 tumors. Associations between v e and microenvironmental parameters or metastatic propensity were not detected in any of the tumor lines. Taken together, this preclinical study suggests that K (trans) is a potentially useful biomarker for poor outcome of treatment in advanced cervical carcinoma. The possibility that K (trans) may be used to identify patients with cervical cancer who are likely to benefit from particularly aggressive treatment merits thorough clinical investigations. PMID- 24151543 TI - Potential Antibacterial Targets in Bacterial Central Metabolism. AB - The emerging antibiotic resistant bacteria and their abilities for rapid evolution have pushed the need to explore alternative antibiotics less prone to drug resistance. In this study, we employed methicillin/multidrug-resistant Staphylococcus aureus (MRSA) as a model bacterial system to initiate novel antibiotic development. An in silico identification of drug targets in MRSA 252 strain and MRSA Mu50 strain respectively was described. The identified potential targets were classified according to their known or putative functions. We discovered that a class of essential non-human homologous, central metabolic enzymes falls into the scope of potential drug targets for two reasons: 1) the identified targets either do not have human counterparts or use alternative catalytic mechanisms. Based on major differences in active site structure and catalytic mechanism, an inhibitor of such a bacterial enzyme can be designed which will not inhibit its human cousin. 2) attacking bacterial energy-making machinery bypasses the usual drug resistance sites, paving the road to multi faceted approaches to combat antibiotic resistance. PMID- 24151544 TI - Conceptual metaphorical mapping in chimpanzees (Pan troglodytes). AB - Conceptual metaphors are linguistic constructions. Such a metaphor is humans' mental representation of social rank as a pyramidal-like structure. High-ranked individuals are represented in higher positions than low-ranked individuals. We show that conceptual metaphorical mapping between social rank and the representational domain exists in our closest evolutionary relatives, the chimpanzees. Chimpanzee participants were requested to discriminate face identities in a vertical arrangement. We found a modulation of response latencies by the rank of the presented individual and the position on the display: a high ranked individual presented in the higher and a low-ranked individual in the lower position led to quicker identity discrimination than a high-ranked individual in the lower and a low-ranked individual in the higher position. Such a spatial representation of dominance hierarchy in chimpanzees suggests that a natural tendency to systematically map an abstract dimension exists in the common ancestor of humans and chimpanzees. DOI:http://dx.doi.org/10.7554/eLife.00932.001. PMID- 24151545 TI - Stochastic homeostasis in human airway epithelium is achieved by neutral competition of basal cell progenitors. AB - Lineage tracing approaches have provided new insights into the cellular mechanisms that support tissue homeostasis in mice. However, the relevance of these discoveries to human epithelial homeostasis and its alterations in disease is unknown. By developing a novel quantitative approach for the analysis of somatic mitochondrial mutations that are accumulated over time, we demonstrate that the human upper airway epithelium is maintained by an equipotent basal progenitor cell population, in which the chance loss of cells due to lineage commitment is perfectly compensated by the duplication of neighbours, leading to "neutral drift" of the clone population. Further, we show that this process is accelerated in the airways of smokers, leading to intensified clonal consolidation and providing a background for tumorigenesis. This study provides a benchmark to show how somatic mutations provide quantitative information on homeostatic growth in human tissues, and a platform to explore factors leading to dysregulation and disease. DOI:http://dx.doi.org/10.7554/eLife.00966.001. PMID- 24151546 TI - Multiple interfaces between a serine recombinase and an enhancer control site specific DNA inversion. AB - Serine recombinases are often tightly controlled by elaborate, topologically defined, nucleoprotein complexes. Hin is a member of the DNA invertase subclass of serine recombinases that are regulated by a remote recombinational enhancer element containing two binding sites for the protein Fis. Two Hin dimers bound to specific recombination sites associate with the Fis-bound enhancer by DNA looping where they are remodeled into a synaptic tetramer competent for DNA chemistry and exchange. Here we show that the flexible beta-hairpin arms of the Fis dimers contact the DNA binding domain of one subunit of each Hin dimer. These contacts sandwich the Hin dimers to promote remodeling into the tetramer. A basic region on the Hin catalytic domain then contacts enhancer DNA to complete assembly of the active Hin tetramer. Our results reveal how the enhancer generates the recombination complex that specifies DNA inversion and regulates DNA exchange by the subunit rotation mechanism. DOI:http://dx.doi.org/10.7554/eLife.01211.001. PMID- 24151548 TI - Sex Differences in Associations of Depressive Symptoms with Cardiovascular Risk Factors and Metabolic Syndrome among African Americans. AB - Young to middle-aged women usually have notably lower rates of cardiovascular disease (CVD) than their male counterparts, but African American women lack this advantage. Their elevated CVD may be influenced by sex differences in associations between depressed mood and CVD risk factors. This cross-sectional study examined whether relations between scores on the Center for Epidemiologic Studies-Depression (CES-D) scale and a spectrum of CVD risk factors varied by sex among African Americans (n = 1076; ages 30-64) from the Healthy Aging in Neighborhoods of Diversity across the Life Span (HANDLS) study. Sex-stratified multiple regressions and logistic regressions were conducted. Among women, CES-D scores correlated positively with systolic blood pressure and waist-to-hip ratio (P's < .05), but inversely with high-density lipoprotein cholesterol (HDL-C) (P < .01). Women had twice the odds for metabolic syndrome if CES-D scores >=16 and had a >=14% increase in odds of hypertension, abdominal obesity, and low HDL-C with each 5-unit increase in CES-D scores. Among men, CES-D scores correlated positively with high-sensitivity C-reactive protein (P < .05), and odds of hypertension increased by 21% with each 5-unit increase in CES-D scores. Depressive symptoms may promote premature CVD risk in African Americans, at least in part, via CVD risk factors and prevalent metabolic syndrome, particularly in African American women. PMID- 24151549 TI - Total knee arthroplasty considerations in rheumatoid arthritis. AB - The definitive treatment for advanced joint destruction in the late stages of rheumatoid arthritis can be successfully treated with total joint arthroplasty. Total knee arthroplasty has been shown to be a well-proven modality that can provide pain relief and restoration of mobility for those with debilitating knee arthritis. It is important for rheumatologists and orthopedic surgeons alike to share an understanding of the special considerations that must be addressed in this unique population of patients to ensure success in the immediate perioperative and postoperative periods including specific modalities to maximize success. PMID- 24151550 TI - Low-Fat Nondairy Minidrink Containing Plant Stanol Ester Effectively Reduces LDL Cholesterol in Subjects with Mild to Moderate Hypercholesterolemia as Part of a Western Diet. AB - The cholesterol-lowering efficacy of plant stanol ester (STAEST) added to fat- or milk-based products is well documented. However, their efficacy when added to nondairy liquid drinks is less certain. Therefore, we have investigated the cholesterol-lowering efficacy of STAEST added to a soymilk-based minidrink in the hypercholesterolemic subjects. In a randomized, double-blind, placebo-controlled parallel study, the intervention group (n = 27) consumed 2.7 g/d of plant stanols as the ester in soymilk-based minidrink (65 mL/d) with the control group (n = 29) receiving the same drink without added plant stanols once a day with a meal for 4 weeks. Serum total, LDL, and non-HDL cholesterol concentrations were reduced by 8.0, 11.1, and 10.2% compared with controls (P < 0.05 for all). Serum plant sterol concentrations and their ratios to cholesterol declined by 12-25% from baseline in the STAEST group while the ratio of campesterol to cholesterol was increased by 10% in the controls (P < 0.05 for all). Serum precursors of cholesterol remained unchanged in both groups. In conclusion, STAEST-containing soymilk-based low-fat minidrink consumed once a day with a meal lowered LDL and non-HDL cholesterol concentrations without evoking any side effects in subjects consuming normal Western diet. The clinical trial registration number is NCT01716390. PMID- 24151551 TI - Therapeutic strategies for high-dose vasopressor-dependent shock. AB - There is no consensual definition of refractory shock. The use of more than 0.5 mcg/kg/min of norepinephrine or epinephrine to maintain target blood pressure is often used in clinical trials as a threshold. Nearly 6% of critically ill patients will develop refractory shock, which accounts for 18% of deaths in intensive care unit. Mortality rates are usually greater than 50%. The assessment of fluid responsiveness and cardiac function can help to guide therapy, and inotropes may be used if hypoperfusion signs persist after initial resuscitation. Arginine vasopressin is frequently used in refractory shock, although definite evidence to support this practice is still missing. Its associations with corticosteroids improved outcome in observational studies and are therefore promising alternatives. Other rescue therapies such as terlipressin, methylene blue, and high-volume isovolemic hemofiltration await more evidence before use in routine practice. PMID- 24151552 TI - Using the delphi approach to identify priority areas for health visiting practice in an area of deprivation. AB - Families with children living in areas of high deprivation face multiple health and social challenges, and this high level of need has impacts on the work of health practitioners working in such areas. All families in the UK with children under five years have access to health visiting services, and health visitors have a key role in mitigating the effects of deprivation by addressing health needs through evidence based practice. This paper reports the first stage of a project in Tower Hamlets, London, an area of significant deprivation, which aims to develop an evidence-based toolkit to support health visitors in their practice with families. The first stage used a modified Delphi process to identify the priority health needs of families in the area between June and July 2012. The three-stage Delphi process involved 25 people: four health visitors, four other members of the health visiting service, and 17 representatives of other services working with families. A focus group event was followed by a second event where individuals completed a questionnaire ranking the 27 priorities identified in the first event. The consultation process concluded with participants completing a second questionnaire, by email, confirming or changing their prioritisation of the topics. PMID- 24151553 TI - Neuropathology and animal models of autism: genetic and environmental factors. AB - Autism is a heterogeneous behaviorally defined neurodevelopmental disorder. It is defined by the presence of marked social deficits, specific language abnormalities, and stereotyped repetitive patterns of behavior. Because of the variability in the behavioral phenotype of the disorder among patients, the term autism spectrum disorder has been established. In the first part of this review, we provide an overview of neuropathological findings from studies of autism postmortem brains and identify the cerebellum as one of the key brain regions that can play a role in the autism phenotype. We review research findings that indicate possible links between the environment and autism including the role of mercury and immune-related factors. Because both genes and environment can alter the structure of the developing brain in different ways, it is not surprising that there is heterogeneity in the behavioral and neuropathological phenotypes of autism spectrum disorders. Finally, we describe animal models of autism that occur following insertion of different autism-related genes and exposure to environmental factors, highlighting those models which exhibit both autism-like behavior and neuropathology. PMID- 24151555 TI - Nearest-neighbor interactions and their influence on the structural aspects of dipeptides. AB - In this theoretical study, the role of the side chain moiety of C-terminal residue in influencing the structural and molecular properties of dipeptides is analyzed by considering a series of seven dipeptides. The C-terminal positions of the dipeptides are varied with seven different amino acid residues, namely. Val, Leu, Asp, Ser, Gln, His, and Pyl while their N-terminal positions are kept constant with Sec residues. Full geometry optimization and vibrational frequency calculations are carried out at B3LYP/6-311++G(d,p) level in gas and aqueous phase. The stereo-electronic effects of the side chain moieties of C-terminal residues are found to influence the values of Phi and Omega dihedrals, planarity of the peptide planes, and geometry around the C7 alpha-carbon atoms of the dipeptides. The gas phase intramolecular H-bond combinations of the dipeptides are similar to those in aqueous phase. The theoretical vibrational spectra of the dipeptides reflect the nature of intramolecular H-bonds existing in the dipeptide structures. Solvation effects of aqueous environment are evident on the geometrical parameters related to the amide planes, dipole moments, HOMOLUMO energy gaps as well as thermodynamic stability of the dipeptides. PMID- 24151556 TI - Accuracy of implant placement utilizing customized patient instrumentation in total knee arthroplasty. AB - Customized patient instrumentation (CPI) combines preoperative planning with customized cutting jigs to position and align implants during total knee arthroplasty (TKA). We compared postoperative implant alignment of patients undergoing surgery with CPI to traditional TKA instrumentation for accuracy of implant placement. Twenty-five consecutive TKAs using CPI were analyzed. Preoperative CT scans of the lower extremities were segmented using a computer program. Limb alignment and mechanical axis were computed. Virtual implantation of computer-aided design models was done. Postoperative coronal and sagittal view radiographs were obtained. Using 3D image-matching software, relative positions of femoral and tibial implants were determined. Twenty-five TKAs implanted using traditional instrumentation were also analyzed. For CPI, difference in alignment from the preoperative plan was calculated. In the CPI group, the mean absolute difference between the planned and actual femoral placements was 0.67 degrees in the coronal plane and 1.2 degrees in the sagittal plane. For tibial alignment, the mean absolute difference was 0.9 degrees in the coronal plane and 1.3 degrees in the sagittal plane. For traditional instrumentation, difference from ideal placement for the femur was 1.5 degrees in the coronal plane and 2.3 degrees in the sagittal plane. For the tibia, the difference was 1.8 degrees in the coronal plane. CPI achieved accurate implant positioning and was superior to traditional TKA instrumentation. PMID- 24151554 TI - Epigenetics and autism. AB - This review identifies mechanisms for altering DNA-histone interactions of cell chromatin to upregulate or downregulate gene expression that could serve as epigenetic targets for therapeutic interventions in autism. DNA methyltransferases (DNMTs) can phosphorylate histone H3 at T6. Aided by protein kinase C beta 1, the DNMT lysine-specific demethylase-1 prevents demethylation of H3 at K4. During androgen-receptor-(AR-) dependent gene activation, this sequence may produce AR-dependent gene overactivation which may partly explain the male predominance of autism. AR-dependent gene overactivation in conjunction with a DNMT mechanism for methylating oxytocin receptors could produce high arousal inputs to the amygdala resulting in aberrant socialization, a prime characteristic of autism. Dysregulation of histone methyltransferases and histone deacetylases (HDACs) associated with low activity of methyl CpG binding protein-2 at cytosine-guanine sites in genes may reduce the capacity for condensing chromatin and silencing genes in frontal cortex, a site characterized by decreased cortical interconnectivity in autistic subjects. HDAC1 inhibition can overactivate mRNA transcription, a putative mechanism for the increased number of cerebral cortical columns and local frontal cortex hyperactivity in autistic individuals. These epigenetic mechanisms underlying male predominance, aberrant social interaction, and low functioning frontal cortex may be novel targets for autism prevention and treatment strategies. PMID- 24151557 TI - Chemical modification of polysaccharides. AB - This review covers methods for modifying the structures of polysaccharides. The introduction of hydrophobic, acidic, basic, or other functionality into polysaccharide structures can alter the properties of materials based on these substances. The development of chemical methods to achieve this aim is an ongoing area of research that is expected to become more important as the emphasis on using renewable starting materials and sustainable processes increases in the future. The methods covered in this review include ester and ether formation using saccharide oxygen nucleophiles, including enzymatic reactions and aspects of regioselectivity; the introduction of heteroatomic nucleophiles into polysaccharide chains; the oxidation of polysaccharides, including oxidative glycol cleavage, chemical oxidation of primary alcohols to carboxylic acids, and enzymatic oxidation of primary alcohols to aldehydes; reactions of uronic-acid based polysaccharides; nucleophilic reactions of the amines of chitosan; and the formation of unsaturated polysaccharide derivatives. PMID- 24151558 TI - Trismus pseudocamptodactyly syndrome: a sporadic cause of trismus. AB - Trismus pseudocamptodactyly syndrome is a very rare autosomal dominant inherited disorder characterized by the inability to completely open the mouth (trismus) and the presence of abnormally short tendon units causing the fingers to curve (camptodactyly). Early diagnosis and management of this condition is important to prevent facial deformities in the patient. Reporting such a case is important as case reports are one of the sources of data for calculating the prevalence of rare diseases. Here, we report a case of trismus pseudocamptodactyly syndrome in an eight-year-old boy with a brief review of the literature. PMID- 24151559 TI - Multiple hamartoma syndrome with characteristic oral and cutaneous manifestations. AB - Aim. To present a case of Cowden's syndrome and emphasize the importance of continued cancer surveillance in these patients. Cowden syndrome is an inherited autosomal dominant trait with incomplete penetrance and a range of expressivity. It is characterized by multiple hamartomas and neoplasms. Mucocutaneous features include trichilemmomas, oral mucosal papillomatosis, acral keratosis, and palmoplantar keratosis. Here, we report a case of Cowdens syndrome of a 30-year old female patient who came with a complaint of multiple growths in the oral cavity of a three-month duration. On examination, multiple skin-colored, flat topped papules over her forehead and right malar bone and multiple papillomatous papules involving all the mucosal surfaces intraorally were observed. This syndrome is associated with the development of several types of malignancies, especially breast carcinoma and thyroid carcinoma, which is why early recognition and regular and vigilant surveillance of individuals with the syndrome are important. PMID- 24151560 TI - Dental Treatments under the General Anesthesia in a Child with Keratitis, Ichthyosis, and Deafness Syndrome. AB - KID syndrome is a rare genodermatosis characterized by keratitis, ichthyosis, and sensorineural deafness. Although the dermatological, ophthalmologic, and sensorineural defects are emphasized in the literature, oral and dental evaluations are so superficial. In this case report, dental and oral symptoms of a three year and five months old boy with KID syndrome, suffering severe Early Childhood Caries (s-ECC) and dental treatments done under General Anesthesia (GA) were reported. PMID- 24151561 TI - Idiopathic orofacial granulomatosis with varied clinical presentation. AB - Orofacial granulomatosis is a granulomatous disease of orofacial region, which can occur for a variety of reasons. The clinical features are highly variable and sometimes so insidious that signs and symptoms are not frequently severe to cause alarm. The lips are most commonly involved with persistent/recurrent swelling. The medical history is very important as Crohn's disease and sarcoidosis can present oral manifestation. Other causes like mycobacterial infection, foreign body reaction, fungal infection, and allergy were excluded with further investigation to establish diagnosis. Here and we report a case of orofacial granulomatosis with a review of the literature. PMID- 24151562 TI - Successful treatment of localized pemphigus foliaceus with topical pimecrolimus. AB - We report the case of successful treatment of a 79-year-old male patient with recurrent pemphigus foliaceus with pimecrolimus cream 1% once daily for 40 days. The patient initially presented with localized lesions on the scalp and nose area and was treated with systemic corticosteroids. At his fourth relapse within a period of 16 months, he refused any systemic treatment. Pimecrolimus cream was suggested to him as an alternative option. PMID- 24151563 TI - Acute Hemolysis in the Emergency Department: Think about Clostridium perfringens! AB - Clostridium perfringens (CP) gives several clinical settings, from an asymptomatic to a massive intravascular hemolysis. We report a case of fatal intravascular hemolysis due to CP septicemia having a hepatic supposed starting point in the emergency department. Like in many cases, the diagnosis was made when patient had already gone into shock and died. The CP septicemia often complicated the course of the digestive or genital pathologies. The alpha toxin can damage the structural integrity of the red cell membrane by means of a phospholipase activity. Nevertheless, a massive intravascular hemolysis arises only rarely in this septicemia, only from 7 to 15% of the cases. The emergency physician has to think about this complication in case of hemoglobinuria and/or signs of hemolysis associated with a septic syndrome. An immediate antibiotic treatment adapted as well as the symptomatic treatment of the spread intravascular coagulation could improve the survival of these patients. PMID- 24151564 TI - TSH-Secreting Pituitary Macroadenoma in a Girl with Lingual Thyroid. AB - Patients with long-standing hypothyroid are, in some cases, reported to develop pituitary gland hyperplasia due to loss of feedback inhibition of thyroxine in hypothalamus-the condition of which typically regresses after thyroxine replacement. Herein, a 15-year-old girl-with long-standing untreated lingual hypothyroid-presents with a pathologically proven TSH pituitary macroadenoma and bilateral large ovarian cysts. Although MR imaging may differentiate between hyperplasia and macroadenoma of the pituitary gland, pathological examination is still a cornerstone to correct diagnosis. PMID- 24151565 TI - Anal canal duplication in an 11-year-old-child. AB - Anal canal duplication (ACD) is the least frequent digestive duplication. Symptoms are often absent but tend to increase with age. Recognition is, however, important as almost half of the patients with ACD have concomitant malformations. We present the clinical history of an eleven-year-old girl with ACD followed by a review of symptoms, diagnosis, treatment, and prognosis based on all the reported cases in English literature. PMID- 24151566 TI - Persistent mosaicism for 12p duplication/triplication chromosome structural abnormality in peripheral blood. AB - We present a rare case of mosaicism for a structural abnormality of chromosome 12 in a patient with phenotypic features of Pallister-Killian syndrome. A six-month old child with dysmorphic features, exotropia, hypotonia, and developmental delay was mosaic for both a normal karyotype and a cell line with 12p duplication/triplication in 25 percent of metaphase cells. Utilization of fluorescence in situ hybridization (FISH) identified three copies of probes from the end of the short arm of chromosome 12 (TEL(12p13) locus and the subtelomere (12p terminal)) on the structurally abnormal chromosome 12. Genome-wide SNP array analysis revealed that the regions of duplication and triplication were of maternal origin. The abnormal cell line in our patient was present at 25 percent at six months and 19 months of age in both metaphase and interphase cells from peripheral blood, where typically the isochromosome 12p is absent in the newborn. This may suggest that the gene(s) resulting in a growth disadvantage of abnormal cells in peripheral blood of patients with tetrasomy 12p may not have the same influence when present in only three copies. PMID- 24151567 TI - Clinical, Cytogenetic, and Biochemical Analyses of a Family with a t(3;13)(q26.2;p11.2): Further Delineation of 3q Duplication Syndrome. AB - Chromosomal abnormalities that result in genomic imbalances are a major cause of congenital and developmental anomalies. Partial duplication of chromosome 3q syndrome is a well-described condition, and the phenotypic manifestations include a characteristic facies, microcephaly, hirsutism, synophrys, broad nasal bridge, congenital heart disease, genitourinary disorders, and mental retardation. Approximately 60%-75% of cases are derived from a balanced translocation. We describe a family with a pure typical partial trisomy 3q syndrome derived from a maternal balanced translocation t(3;13)(q26.2;p11.2). As the chromosomal rearrangement involves the short arm of an acrocentric chromosome, the phenotype corresponds to a pure trisomy 3q26.2-qter syndrome. There are 4 affected individuals and several carriers among three generations. The report of this family is relevant because there are few cases of pure duplication 3q syndrome reported, and the cases described here contribute to define the phenotype associated with the syndrome. Furthermore, we confirmed that the survival until adulthood is possible. This report also identified the presence of glycosaminoglycans in urine in this family, not related to the chromosomal abnormality or the phenotype. PMID- 24151568 TI - Oncogenic brain metazoan parasite infection. AB - Multiple observations suggest that certain parasitic infections can be oncogenic. Among these, neurocysticercosis is associated with increased risk for gliomas and hematologic malignancies. We report the case of a 71-year-old woman with colocalization of a metazoan parasite, possibly cysticercosis, and a WHO grade IV neuroepithelial tumor with exclusively neuronal differentiation by immunohistochemical stains (immunopositive for synaptophysin, neurofilament protein, and Neu-N and not for GFAP, vimentin, or S100). The colocalization and temporal relationship of these two entities suggest a causal relationship. PMID- 24151569 TI - A Rare Case of Immune Reconstitution Inflammatory Syndrome Development in an Immunocompromised Patient with Progressive Multifocal Leukoencephalopathy and Multicentric Castleman's Disease. AB - Immune reconstitution inflammatory syndrome (IRIS) development in HIV with preexistent progressive multifocal leukoencephalopathy (PML) has been extensively studied. PML-IRIS typically manifests clinically as new or worsening neurologic symptoms in conjunction with enlarging CNS lesions and occurs in approximately 10 20 percent of HIV-infected patients with PML who begin HAART. Likewise, Multicentric Castleman's Disease (MCD), a rare malignant lymphoproliferative disorder, has a strong and well-known association with HIV. Our case provides a rare instance of PML-IRIS in combination with MCD in an HIV-positive individual. The combination of all three diseases has never been reported in the literature. Both MCD and PML were present during initial determination of HIV infection in our patient and their disease courses were altered during the subsequent development of IRIS. PMID- 24151570 TI - Recurrent ectopic pregnancy in the tubal remnant after salpingectomy. AB - We present two cases of ectopic pregnancy located within the remnant tube following ipsilateral salpingectomy. This particular pathology is rare and yet has significant consequences for the patient, with mortality rates 10-15 times higher than other ectopic pregnancies. It demonstrates that salpingectomy does not exclude ectopic pregnancy on the ipsilateral side. We suggest careful clinical consideration and bring attention to the current surgical technique. PMID- 24151571 TI - Late occurring ectopic pregnancy in a posthysterectomy patient. AB - The incidence of ectopic pregnancy after hysterectomy is extremely rare with only 56 cases reported in the medical literature. Due to its rare occurrence, this diagnosis may not be initially considered when such a patient presents with abdominopelvic pain. It is an important diagnosis to keep in mind since a delay in diagnosis may lead to death. The case presented below describes this extremely unusual diagnosis of an ectopic pregnancy which occurred six years after a supracervical hysterectomy. PMID- 24151572 TI - Fungal Keratitis Caused by Drechslera spp. Treated with Voriconazole: A Case Report. AB - Objective. To present a case of Drechslera spp. keratitis treated with topical Voriconazole. Method. A case report. Results. A 52-year-old diabetic male presented with a one-week history of foreign body sensation of the left eye, self medicated with Neomycin, Polymyxin B, and Dexamethasone eye drops, and was diagnosed to have bacterial conjunctivitis, which was treated with Levofloxacin drops. The patient developed a corneal opacity after 2 days and was initially seen with a visual acuity of counting fingers on the left eye, with a 3 mm central corneal ulcer with feathery borders. No hypopyon was noted. The right eye had a visual acuity of 20/20 and had unremarkable findings. Corneal scraping of the ulcer showed no organisms on Gram and Giemsa stain. Cultures were positive for Drechslera spp. and patient was started on Natamycin drops every 15 minutes, Atropine drops 3* a day, and Levofloxacin was continued every 4 hours. The ulcer increased to 4 mm, the infiltrates became deeper involving the midstroma, and there was appearance of a 2 mm hypopyon. Natamycin was shifted to Voriconazole eye drops every 15 minutes. There was note of a decrease in the size of the ulcer and clearing of the infiltrates with the new treatment regimen. Final visual acuity after 29 days of treatment was 20/40 with note of a slight corneal haze in the area of the previous ulcer. Conclusion. Voriconazole may be safe and effective in the treatment of Drechslera keratitis. There was no perforation and there was immediate decrease in the size of the ulcer. This is the first known case of Drechslera keratitis treated with Voriconazole eye drops in the Philippines. PMID- 24151573 TI - Emergency closed reduction of a c4/5 fracture dislocation with complete paraplegia resulting in profound neurologic recovery. AB - Introduction. Cervical spinal cord injuries due to traumatic fractures are associated with persistent neurological deficits. Although clinical evidence is weak, early decompression, defined as <24-72 h, has been frequently proposed. Animal studies show better outcomes after early decompression within one hour or less, which can hardly ever be achieved in clinical practice. Case Presentation. A 37-year-old patient was hospitalized after being hit by a shying horse. After diagnosis of C4/5 fracture dislocation and complete paraplegia, she was intubated and sedated with deep relaxation. Emergency reduction was performed at approximately 120 minutes after trauma. Subsequently, a standard anterior decompression, discectomy, and fusion were carried out. She was then transferred to a specialized rehabilitation hospital. Her neurologic function improved from AIS grade A on admission to grade B postoperatively and grade D after four months of rehabilitation. One year after the accident, she was ambulatory without walking aids and restarted horse riding. Discussion and Conclusion. Rarely in clinical practice, decompression of the spine canal can be performed as early as in this case. This case highlights the potential benefit of utmost early reduction in cervical fracture dislocations with compression of the spinal cord. PMID- 24151574 TI - Intra-Articular Giant Heterotopic Ossification following Total Knee Arthroplasty for Charcot Arthropathy. AB - Although the Charcot arthropathy may be associated with serious complications, total knee arthroplasty (TKA) is the preferred choice of treatment by patients. This case report presents an 80-year-old man with intra-articular giant heterotopic ossification following loosening of femoral and tibial implants and femoral condylar fracture. He had undergone TKA because of Charcot neuropathy seven years ago and had been doing well since. Immediately after a left knee sprain, he became unable to walk. Because he had developed a skin ulcer on his left calf where methicillin-resistant Staphylococcus aureus was detected, we postponed revision surgery until the ulcer was completely healed. While waiting, intra-articular bony fragments grew larger and formed giant heterotopic ossified masses. Eventually, the patient underwent revision surgery, and two major ossified masses were carefully and successfully extirpated. It should be noted that intra-articular heterotopic giant ossification is a significant complication after TKA for neuropathic arthropathy. PMID- 24151575 TI - Toward a Molecular Classification of Colorectal Cancer: The Role of MGMT. AB - O(6)-methylguanine DNA methyltransferase (MGMT) is a DNA repair enzyme with the ability to protect cells from DNA mutations by removing alkyl groups from the O(6) position of guanine. Colon mucosa is exposed to the direct effects of environmental carcinogens and therefore maintaining a proficient DNA repair system is very important to stay protected against DNA mutagenesis. Loss of MGMT expression is almost exclusively associated with methylation of CpG islands in the MGMT gene promoter region which is found in approximately 40% of colorectal cancers. The role of MGMT loss in colorectal tumorigenesis is complex but numerous studies have documented methylation of this gene even in the normal appearing mucosa as well as in aberrant crypt foci, suggesting that MGMT methylation can be regarded as an early event or "field defect" in colon cancer neoplasia. The focus of this perspective is the role of MGMT in different pathways of colorectal carcinogenesis as well as the implication of this molecule in treatment decisions in colorectal cancer patients. PMID- 24151576 TI - Managing iron supply during the infection cycle of a flea borne pathogen, Bartonella henselae. AB - Bartonella are hemotropic bacteria responsible for emerging zoonoses. Most Bartonella species appear to share a natural cycle that involves an arthropod transmission, followed by exploitation of a mammalian host in which they cause long-lasting intra-erythrocytic bacteremia. Persistence in erythrocytes is considered an adaptation to transmission by bloodsucking arthropod vectors and a strategy to obtain heme required for Bartonella growth. Bartonella genomes do not encode for siderophore biosynthesis or a complete iron Fe(3+) transport system. Only genes, sharing strong homology with all components of a Fe(2+) transport system, are present in Bartonella genomes. Also, Bartonella genomes encode for a complete heme transport system. Bartonella must face various environments in their hosts and vectors. In mammals, free heme and iron are rare and oxygen concentration is low. In arthropod vectors, toxic heme levels are found in the gut where oxygen concentration is high. Bartonella genomes encode for 3-5 heme binding proteins. In Bartonella henselae heme-binding proteins were shown to be involved in heme uptake process, oxidative stress response, and survival inside endothelial cells and in the flea. In this report, we discuss the use of the heme uptake and storage system of B. henselae during its infection cycle. Also, we establish a comparison with the iron and heme uptake systems of Yersinia pestis used during its infection cycle. PMID- 24151577 TI - Apoptosis in C. elegans: lessons for cancer and immunity. PMID- 24151578 TI - Extensive differences in antifungal immune response in two Drosophila species revealed by comparative transcriptome analysis. AB - The innate immune system of Drosophila is activated by ingestion of microorganisms. D. melanogaster breeds on fruits fermented by Saccharomyces cerevisiae, whereas D. virilis breeds on slime flux and decaying bark of tree housing a variety of bacteria, yeasts, and molds. In this study, it is shown that D. virilis has a higher resistance to oral infection of a species of filamentous fungi belonging to the genus Penicillium compared to D. melanogaster. In response to the fungal infection, a transcriptome profile of immune-related genes was considerably different between D. melanogaster and D. virilis: the genes encoding antifungal peptides, Drosomycin and Metchnikowin, were highly expressed in D. melanogaster whereas, the genes encoding Diptericin and Defensin were highly expressed in D. virilis. On the other hand, the immune-induced molecule (IM) genes showed contrary expression patterns between the two species: they were induced by the fungal infection in D. melanogaster but tended to be suppressed in D. virilis. Our transcriptome analysis also showed newly predicted immune-related genes in D. virilis. These results suggest that the innate immune system has been extensively differentiated during the evolution of these Drosophila species. PMID- 24151579 TI - Extending the serum half-life of G-CSF via fusion with the domain III of human serum albumin. AB - Protein fusion technology is one of the most commonly used methods to extend the half-life of therapeutic proteins. In this study, in order to prolong the half life of Granulocyte colony stimulating factor (G-CSF), the domain III of human serum albumin (3DHSA) was genetically fused to the N-terminal of G-CSF. The 3DHSA G-CSF fusion gene was cloned into pPICZ alpha A along with the open reading frame of the alpha -factor signal under the control of the AOX1 promoter. The recombinant expression vector was transformed into Pichia pastoris GS115, and the recombinant strains were screened by SDS-PAGE. As expected, the 3DHSA-G-CSF showed high binding affinity with HSA antibody and G-CSF antibody, and the natural N-terminal of 3DHSA was detected by N-terminal sequencing. The bioactivity and pharmacokinetic studies of 3DHSA-G-CSF were respectively determined using neutropenia model mice and human G-CSF ELISA kit. The results demonstrated that 3DHSA-G-CSF has the ability to increase the peripheral white blood cell (WBC) counts of neutropenia model mice, and the half-life of 3DHSA-G CSF is longer than that of native G-CSF. In conclusion, 3DHSA can be used to extend the half-life of G-CSF. PMID- 24151580 TI - Exercise trajectories of women from entry to a 6-month cardiac rehabilitation program to one year after discharge. AB - BACKGROUND: Physical activity is associated with reduced mortality and morbidity. Cardiac rehabilitation (CR) is an effective intervention for patients with cardiovascular disease (CVD). Unfortunately, women are less likely to engage in, or sustain, regular physical activity. Objectives were to (1) describe women's guidelines-based levels of physical activity during and after CR and (2) determine the physical activity trajectories of women from entry to CR to one year after CR. METHODS AND RESULTS: A prospective, longitudinal study of 203 women with CVD enrolled in a 6-month CR program. Physical activity was measured using the Godin Leisure Time Exercise Questionnaire (LSI), focusing on moderate strenuous activity. Data were analyzed using latent class growth analysis (LCGA) and logistic regression. Mean scores on the LSI showed women to be "active" at all follow-up points. LCGA revealed a two-class model, respectively, called "inactive relapsers" and "moderately active relapsers." Predictors of the "moderately active relapsers" class were employment status and diagnosis of myocardial infarction. CONCLUSIONS: Women achieved the recommended physical activity levels by the end of CR and sustained them until one year after CR. LCGA allowed us to determine the class trajectories associated with moderate-strenuous activity and, from these, to identify implications for targeted intervention. PMID- 24151581 TI - Factors influencing women's decision to participate or not in a surgical randomised controlled trial for surgical treatment of female stress urinary incontinence. AB - The study aims to explore the potentially influential factors affecting women's decision to accept/decline participation in surgical randomised trial using a novel acceptance/refusal questionnaire (ARQ). All women who were eligible to participate in SIMS-RCT were asked to complete the relevant section (acceptance/refusal) of the ARQ. Women reported its degree of relevance for their decision on a six-point Likert scale (0 = highly irrelevant, 5 = highly relevant). 135 (98%) and 31 (70%) women completed the acceptance and refusal sections of the ARQ, respectively. The most influencing factor in women's acceptance was the anticipation of "potential personal benefit"; percentage of relevance (POR) was 91.9%, followed by interest in helping others by "supporting innovative medical research"; POR was 87.7%. Most influencing factor in refusal for participation was "do not have time for follow-up"; POR was 56.8%, followed by "do not like the concept of randomisation"; POR was 54.4%. In conclusion, this study identifies the most influential factors relevant to women decision-making whether or not to participate in RCTs assessing surgical interventions for female stress urinary incontinence (SUI). A number of factors leading to refusal of participation are potentially correctable leading to better recruitment rates in future RCTs. PMID- 24151582 TI - Chronic heat stress inhibits immune responses to H5N1 vaccination through regulating CD4+ CD25+ Foxp3+ Tregs. AB - Chronic heat stress (CHS) is known to have negative impacts on the immune responses in animals and increases their susceptibility to infections including the highly pathogenic avian influenza virus H5N1. However, the role of regulatory T cells (Tregs) in CHS immunosuppression remains largely undefined. In this study, we demonstrated a novel mechanism by which CHS suppressed both Th1 and Th2 immune responses and dramatically decreased the protective efficacy of the formalin-inactivated H5N1 vaccine against H5N1 influenza virus infection. This suppression was found to be associated with the induced generation of CD4+ CD25+ Foxp3+ Tregs and the increased secretions of IL-10 and TGF- beta in CD4+ T cells. Adoptive transfer of the induced Tregs also suppressed the protective efficacy of formalin-inactivated H5N1 virus immunization. Collectively, this study identifies a novel mechanism of CHS immunosuppression mediated by regulating CD4+ CD25+ Foxp3+ Tregs. PMID- 24151584 TI - New optical methods for liveness detection on fingers. AB - This paper is devoted to new optical methods, which are supposed to be used for liveness detection on fingers. First we describe the basics about fake finger use in fingerprint recognition process and the possibilities of liveness detection. Then we continue with introducing three new liveness detection methods, which we developed and tested in the scope of our research activities--the first one is based on measurement of the pulse, the second one on variations of optical characteristics caused by pressure change, and the last one is based on reaction of skin to illumination with different wavelengths. The last part deals with the influence of skin diseases on fingerprint recognition, especially on liveness detection. PMID- 24151585 TI - Estimation of the lateral ventricles volumes from a 2D image and its relationship with cerebrospinal fluid flow. AB - PURPOSE: This work suggests a fast estimation method of the lateral ventricles volume from a 2D image and then determines if this volume is correlated with the cerebrospinal fluid flow at the aqueductal and cerebral levels in neurodegenerative diseases. MATERIALS AND METHODS: Forty-five elderly patients suffering from Alzheimer's disease (19), normal pressure hydrocephalus (13), and vascular dementia (13) were involved and underwent anatomical and phase contrast MRI scans. Lateral ventricles and stroke volumes were assessed on anatomical and phase contrast scans, respectively. A common reference plane was used to calculate the lateral ventricles' area on 2D images. RESULTS: The largest volumes were observed in hydrocephalus patients. The linear regression between volumes and areas was computed, and a strong positive correlation was detected (R2 = 0.9). A derived equation was determined to represent the volumes for any given area. On the other hand, no significant correlations were detected between ventricles and stroke volumes (R2 <= 0.15). CONCLUSION: Lateral ventricles volumes are significantly proportional to the 2D reference section area and could be used for patients' follow-up even if 3D images are unavailable. The cerebrospinal fluid fluctuations in brain disorders may depend on many physiological parameters other than the ventricular morphology. PMID- 24151583 TI - Application of universal stress proteins in probing the dynamics of potent degraders in complex terephthalate metagenome. AB - The culture-independent strategies to study microbial diversity and function have led to a revolution in environmental genomics, enabling fundamental questions about the distribution of microbes and their influence on bioremediation to be addressed. In this research we used the expression of universal stress proteins as a probe to determine the changes in degrading microbial population from a highly toxic terephthalate wastewater to a less toxic activated sludge bioreactor. The impact of relative toxicities was significantly elaborated at the levels of genus and species. The results indicated that 23 similar prokaryotic phyla were represented in both metagenomes irrespective of their relative abundance. Furthermore, the following bacteria taxa Micromonosporaceae, Streptomyces, Cyanothece sp. PCC 7822, Alicyclobacillus acidocaldarius, Bacillus halodurans, Leuconostoc mesenteroides, Lactococcus garvieae, Brucellaceae, Ralstonia solanacearum, Verminephrobacter eiseniae, Azoarcus, Acidithiobacillus ferrooxidans, Francisella tularensis, Methanothermus fervidus, and Methanocorpusculum labreanum were represented only in the activated sludge bioreactor. These highly dynamic microbes could serve as taxonomic biomarkers for toxic thresholds related to terephthalate and its derivatives. This paper, highlights the application of universal stress proteins in metagenomics analysis. Dynamics of microbial consortium of this nature can have future in biotechnological applications in bioremediation of toxic chemicals and radionuclides. PMID- 24151586 TI - CADe system integrated within the electronic health record. AB - The latest technological advances and information support systems for clinics and hospitals produce a wide range of possibilities in the storage and retrieval of an ever-growing amount of clinical information as well as in detection and diagnosis. In this work, an Electronic Health Record (EHR) combined with a Computer Aided Detection (CADe) system for breast cancer diagnosis has been implemented. Our objective is to provide to radiologists a comprehensive working environment that facilitates the integration, the image visualization, and the use of aided tools within the EHR. For this reason, a development methodology based on hardware and software system features in addition to system requirements must be present during the whole development process. This will lead to a complete environment for displaying, editing, and reporting results not only for the patient information but also for their medical images in standardised formats such as DICOM and DICOM-SR. As a result, we obtain a CADe system which helps in detecting breast cancer using mammograms and is completely integrated into an EHR. PMID- 24151587 TI - Effects of estrogen fluctuation during the menstrual cycle on the response to stretch-shortening exercise in females. AB - The aim of this study was to investigate whether variation in estrogen levels during the menstrual cycle influences susceptibility to exercise-induced muscle damage after stretch-shortening cycle exercise. Physically active women (n = 18; age = 20.2 +/- 1.7 yr) participated in this research. The subjects performed one session of 100 maximal drop jumps on day 1 or 2 of the follicular phase and another identical session on day 1 or 2 of the ovulatory phase; the order of the sessions was randomized. Quadriceps femoris muscle peak torque evoked by electrical stimulation and maximal voluntary contraction, muscle pain, and CK activity were measured before and at various times up to 72 h after exercise. It was found that the high estrogen level during the ovulatory phase might be related to an earlier return to baseline muscle strength after strenuous stretch shortening cycle exercise in that phase compared with the follicular phase. The estrogen effect appears to be highly specific to the damaged site because the differences in most EIMD markers (CK, soreness, and low-frequency fatigue) between the two menstrual cycle phases were small. PMID- 24151588 TI - Discoloration of indigo carmine using aqueous extracts from vegetables and vegetable residues as enzyme sources. AB - Several vegetables and vegetable residues were used as sources of enzymes capable to discolor indigo carmine (IC), completely or partially. Complete discoloration was achieved with aqueous extracts of green pea seeds and peels of green pea, cucumber, and kohlrabi, as well as spring onion leaves. The source of polyphenol oxidase (PPO), pH, time, and aeration is fundamental for the discoloration process catalyzed by PPO. The PPO present in the aqueous extract of green pea seeds was able to degrade 3,000 ppm of IC at a pH of 7.6 and magnetic stirring at 1,800 rpm in about 36 h. In addition, at 1,800 rpm and a pH of 7.6, this extract discolored 300 ppm of IC in 1:40 h; in the presence of 10% NaCl, the discoloration was complete in 5:50 h, whereas it was completed in 4:30 h with 5% NaCl and 2% laundry soap. PMID- 24151589 TI - Effects of neuromuscular electrical stimulation combined with exercises versus an exercise program on the pain and the function in patients with knee osteoarthritis: a randomized controlled trial. AB - OBJECTIVES: To investigate the effect of 8 weeks of NMES + Ex (neuromuscular electrical stimulation combined with exercises) on pain and functional improvement in patients with knee osteoarthritis (OA) compared to exercise (Ex) alone. DESIGN: Randomized controlled trial. SETTING: A specialty outpatient clinic. PARTICIPANTS: Patients (N = 100; women = 86, men = 14; age range, 50-75 years) with knee OA. INTERVENTIONS: Participants were randomly assigned to NMES + Ex or Ex group. OUTCOME MEASURES: Numerical Rating Scale 0 to 10 (NRS) and the Timed Up and Go (TUG) test were the primary outcomes. The secondary outcomes used were the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC). RESULTS: Following the interventions, a statistically significant improvement in both groups was observed in all outcomes assessed. For the comparison between the groups, no statistically significant difference was found between the NMES + Ex and the Ex groups in NRS (P = 0.52), TUG test (P = 0.12), and aspects of WOMAC: pain (P = 0.26), function (P = 0.23), and stiffness (P = 0.63). CONCLUSION: THE addition of NMES to exercise did not improve the outcomes assessed in knee OA patients. This study was registered at the Australian Clinical Trials Registry (ACTRN012607000357459). PMID- 24151590 TI - In-vivo effect of andrographolide on alveolar bone resorption induced by Porphyromonas gingivalis and its relation with antioxidant enzymes. AB - Alveolar bone resorption is one of the most important facts in denture construction. Porphyromonas gingivalis (Pg) causes alveolar bone resorption, and morphologic measurements are the most frequent methods to identify bone resorption in periodontal studies. This study has aimed at evaluating the effect of Andrographolide (AND) on alveolar bone resorption in rats induced by Pg. 24 healthy male Sprague Dawley rats were divided into four groups as follows: normal control group and three experimental groups challenged orally with Pg ATCC 33277 five times a week supplemented with 20 mg/kg and 10 mg/kg of AND for twelve weeks. Alveolar bones of the left and right sides of the mandible were assessed by a morphometric method. The bone level, that is, the distance from the alveolar bone crest to cementumenamel junction (CEJ), was measured using 6.1 : 1 zoom stereomicroscope and software. AND reduced the effect of Pg on alveolar bone resorption and decreased the serum levels of Hexanoyl-Lysine (HEL); furthermore the reduced glutathione/oxidised glutathione (GSH/GSSG) ratio in AND treated groups (10 and 20 mg/kg) significantly increased when compared with the Pg group (P < 0.05). We can conclude that AND suppresses alveolar bone resorption caused by Pg in rats. PMID- 24151591 TI - Pharmacokinetics and bioequivalence evaluation of cyclobenzaprine tablets. AB - The purpose of this study was to investigate cyclobenzaprine pharmacokinetics and to evaluate bioequivalence between two different tablet formulations containing the drug. An open, randomized, crossover, single-dose, two-period, and two sequence design was employed. Tablets were administered to 23 healthy subjects after an overnight fasting and blood samples were collected up to 240 hours after drug administration. Plasma cyclobenzaprine was quantified by means of an LC MS/MS method. Pharmacokinetic parameters related to absorption, distribution, and elimination were calculated. Cyclobenzaprine plasma profiles for the reference and test products were similar, as well as absorption pharmacokinetic parameters AUC (reference: 199.4 ng * h/mL; test: 201.6 ng * h/mL), Cmax (reference: 7.0 ng/mL; test: 7.2 ng/mL), and T(max) (reference: 4.5 h; test: 4.6 h). Bioequivalence was evaluated by means of 90% confidence intervals for the ratio of AUC (93%-111%) and C(max) (93%-112%) values for test and reference products, which were within the 80%-125% interval proposed by FDA. Cyclobenzaprine pharmacokinetics can be described by a multicompartment open model with an average rapid elimination half-life (t(1/2)beta) of 3.1 hours and an average terminal elimination half-life (t(1/2)gamma) of 31.9 hours. PMID- 24151592 TI - The investigation of tramadol dependence with no history of substance abuse: a cross-sectional survey of spontaneously reported cases in Guangzhou City, China. AB - The study was to survey and assess the drug dependence and abuse potential of tramadol with no history of substance abuse. Subjects of tramadol dependence with no prior history of substance abuse were surveyed by interview. Physical dependence of tramadol was assessed using 10 items opiate withdrawal scale (OWS), and psychological dependence was assessed by Addiction Research Center Inventory Chinese Version (ARCI-CV). Twenty-three male subjects (the median age was 23.4 +/ 4.1 years) referred to the addiction unit in Medical Hospital of Guangzhou with tramadol abuse problems were included in this cross-sectional study. The control group included 87 heroin addicts, 60 methamphetamine (MA) abusers, and 50 healthy men. The scores of OWS of tramadol were 0.83-2.30; the mean scores of identifying euphoric effects-MBG, sedative effects-PCAG, and psychotomimetic effects-LSD of ARCI were 8.96 +/- 3.08, 6.52 +/- 3.25, and 6.65 +/- 2.50, respectively, F = 4.927, P < 0.001. Scores of MBG scale in tramadol did not differ from those in heroin and MA groups (P > 0.05) but were higher than those in healthy men (P < 0.05). Tramadol with no history of substance abuse has a clear risk of producing high abuse potential under the long-term infrequent abuse and the high doses. PMID- 24151595 TI - Trypanosoma evansi and surra: a review and perspectives on transmission, epidemiology and control, impact, and zoonotic aspects. AB - This paper reviews the transmission modes of Trypanosoma evansi. Its worldwide distribution is attributed to mechanical transmission. While the role of tabanids is clear, we raise questions on the relative role of Haematobia sp. and the possible role of Stomoxys sp. in delayed transmission. A review of the available trypanocidal drugs and their efficacy in various host species is useful for understanding how they interact in disease epidemiology, which is complex. Although there are similarities with other mechanically transmitted trypanosomes, T. evansi has a more complex epidemiology due to the diversity of its hosts and vectors. The impact of clinical and subclinical disease is difficult to establish. A model was developed for buffaloes in the Philippines, which could be transferred to other places and livestock systems. Since Trypanosoma evansi was reported in humans, further research is required to investigate its zoonotic potential. Surra remains a potentially emerging disease that is a threat to Australia, Spain, and France. A number of questions about the disease have yet to be resolved. This brief review of the basic knowledge of T. evansi suggests that there is renewed interest in the parasite, which is spreading and has a major economic impact. PMID- 24151596 TI - Comparative gene expression profiling in human cumulus cells according to ovarian gonadotropin treatments. AB - In in vitro fertilization cycles, both HP-hMG and rFSH gonadotropin treatments are widely used to control human follicle development. The objectives of this study are (i) to characterize and compare gene expression profiles in cumulus cells (CCs) of periovulatory follicles obtained from patients stimulated with HP hMG or rFSH in a GnRH antagonist cycle and (ii) to examine their relationship with in vitro embryo development, using Human Genome U133 Plus 2.0 microarrays. Genes that were upregulated in HP-hMG-treated CCs are involved in lipid metabolism (GM2A) and cell-to-cell interactions (GJA5). Conversely, genes upregulated in rFSH-treated CCs are implicated in cell assembly and organization (COL1A1 and COL3A1). Interestingly, some genes specific to each gonadotropin treatment (NPY1R and GM2A for HP-hMG; GREM1 and OSBPL6 for rFSH) were associated with day 3 embryo quality and blastocyst grade at day 5, while others (STC2 and PTX3) were related to in vitro embryo quality in both gonadotropin treatments. These genes may prove valuable as biomarkers of in vitro embryo quality. PMID- 24151597 TI - A sensitive chemotaxis assay using a novel microfluidic device. AB - Existing chemotaxis assays do not generate stable chemotactic gradients and thus- over time--functionally measure only nonspecific random motion (chemokinesis). In comparison, microfluidic technology has the capacity to generate a tightly controlled microenvironment that can be stably maintained for extended periods of time and is, therefore, amenable to adaptation for assaying chemotaxis. We describe here a novel microfluidic device for sensitive assay of cellular migration and show its application for evaluating the chemotaxis of smooth muscle cells in a chemokine gradient. PMID- 24151593 TI - Nephrolithiasis: molecular mechanism of renal stone formation and the critical role played by modulators. AB - Urinary stone disease is an ailment that has afflicted human kind for many centuries. Nephrolithiasis is a significant clinical problem in everyday practice with a subsequent burden for the health system. Nephrolithiasis remains a chronic disease and our fundamental understanding of the pathogenesis of stones as well as their prevention and cure still remains rudimentary. Regardless of the fact that supersaturation of stone-forming salts in urine is essential, abundance of these salts by itself will not always result in stone formation. The pathogenesis of calcium oxalate stone formation is a multistep process and essentially includes nucleation, crystal growth, crystal aggregation, and crystal retention. Various substances in the body have an effect on one or more of the above stone forming processes, thereby influencing a person's ability to promote or prevent stone formation. Promoters facilitate the stone formation while inhibitors prevent it. Besides low urine volume and low urine pH, high calcium, sodium, oxalate and urate are also known to promote calcium oxalate stone formation. Many inorganic (citrate, magnesium) and organic substances (nephrocalcin, urinary prothrombin fragment-1, osteopontin) are known to inhibit stone formation. This review presents a comprehensive account of the mechanism of renal stone formation and the role of inhibitors/promoters in calcium oxalate crystallisation. PMID- 24151598 TI - Diversity and antimicrobial properties of lactic acid bacteria isolated from rhizosphere of olive trees and desert truffles of Tunisia. AB - A total of 119 lactic acid bacteria (LAB) were isolated, by culture-dependant method, from rhizosphere samples of olive trees and desert truffles and evaluated for different biotechnological properties. Using the variability of the intergenic spacer 16S-23S and 16S rRNA gene sequences, the isolates were identified as the genera Lactococcus, Pediococcus, Lactobacillus, Weissella, and Enterococcus. All the strains showed proteolytic activity with variable rates 42% were EPS producers, while only 10% showed the ability to grow in 9% NaCl. In addition, a low rate of antibiotic resistance was detected among rhizospheric enterococci. Furthermore, a strong antibacterial activity against plant and/or pathogenic bacteria of Stenotrophomonas maltophilia, Pantoea agglomerans, Pseudomonas savastanoi, the food-borne Staphylococcus aureus, and Listeria monocytogenes was recorded. Antifungal activity evaluation showed that Botrytis cinerea was the most inhibited fungus followed by Penicillium expansum, Verticillium dahliae, and Aspergillus niger. Most of the active strains belonged to the genera Enterococcus and Weissella. This study led to suggest that environmental-derived LAB strains could be selected for technological application to control pathogenic bacteria and to protect food safety from postharvest deleterious microbiota. PMID- 24151600 TI - A novel closed-chest porcine model of chronic ischemic heart failure suitable for experimental research in cardiovascular disease. AB - Cardiac pathologies are among the leading causes of mortality and morbidity in industrialized countries, with myocardial infarction (MI) representing one of the major conditions leading to heart failure (HF). Hitherto, the development of consistent, stable, and reproducible models of closed-chest MI in large animals, meeting the clinical realism of a patient with HF subsequent to chronic ischemic necrosis, has not been successful. We hereby report the design and ensuing application of a novel porcine experimental model of closed-chest chronic ischemia suitable for biomedical research, mimicking post-MI HF. We also emphasize the key procedural steps involved in replicating this unprecedented model, from femoral artery and vein catheterization to MI induction by permanent occlusion of the left anterior descending coronary artery through superselective deployment of platinum-nylon coils, as well as endomyocardial biopsy sampling for histologic analysis and cell harvesting. Our model could indeed represent a valuable contribution and tool for translational research, providing precious insights to understand and overcome the many hurdles concerning, and currently quenching, the preclinical steps mandatory for the clinical translation of new cardiovascular technologies for personalized HF treatments. PMID- 24151601 TI - A study on user authentication methodology using numeric password and fingerprint biometric information. AB - The prevalence of computers and the development of the Internet made us able to easily access information. As people are concerned about user information security, the interest of the user authentication method is growing. The most common computer authentication method is the use of alphanumerical usernames and passwords. The password authentication systems currently used are easy, but only if you know the password, as the user authentication is vulnerable. User authentication using fingerprints, only the user with the information that is specific to the authentication security is strong. But there are disadvantage such as the user cannot change the authentication key. In this study, we proposed authentication methodology that combines numeric-based password and biometric based fingerprint authentication system. Use the information in the user's fingerprint, authentication keys to obtain security. Also, using numeric-based password can to easily change the password; the authentication keys were designed to provide flexibility. PMID- 24151599 TI - Androgen signaling disruption during fetal and postnatal development affects androgen receptor and connexin 43 expression and distribution in adult boar prostate. AB - To date, limited knowledge exists regarding the role of the androgen signaling during specific periods of development in the regulation of androgen receptor (AR) and connexin 43 (Cx43) in adult prostate. Therefore, in this study we examined mRNA and protein expression, and tissue distribution of AR and Cx43 in adult boar prostates following fetal (GD20), neonatal (PD2), and prepubertal (PD90) exposure to an antiandrogen flutamide (50 mg/kg bw). In GD20 and PD2 males we found the reduction of the luminal compartment, inflammatory changes, decreased AR and increased Cx43 expression, and altered localization of both proteins. Moreover, enhanced apoptosis and reduced proliferation were detected in the prostates of these animals. In PD90 males the alterations were less evident, except that Cx43 expression was markedly upregulated. The results presented herein indicate that in boar androgen action during early fetal and neonatal periods plays a key role in the maintenance of normal phenotype and functions of prostatic cells at adulthood. Furthermore, we demonstrated that modulation of Cx43 expression in the prostate could serve as a sensitive marker of hormonal disruption during different developmental stages. PMID- 24151602 TI - Role of Rheum Polysaccharide in the cytokines produced by peripheral blood monocytes in TLR4 mediated HLA-B27 associated AAU. AB - PURPOSE: To evaluate the effect of a traditional Chinese medicine, Rheum Polysaccharide (RP), on the in vitro production of tumor necrosis factor alpha (TNF- alpha ) and interleukin-10 (IL-10) by lipopolysaccharide- (LPS-)stimulated human monocytes from HLA-B27 associated acute anterior uveitis patients of convalescence stage. METHOD: PBMC samples were isolated from 10 HLA-B27 associated acute anterior uveitis, incubated, respectively, and divided into 4 groups as follows: (1) controls, PBS was added in final concentration of 1 mg.L 1, (2) stimulated by LPS, LPS was added in final concentration of 1 mg.L-1, (3) stimulated by LPS + HTA125, 30 minutes before the adding of LPS in final concentration of 1 mg.L-1, the final concentration of 5 mg.L-1 of the HTA125 was added, and (4) stimulated by LPS + RP, 30 minutes before the adding of LPS in final concentration 1 mg.L-1, the final concentration 100 mg.L-1 of the RP was added. Supernatants were used to quantify the amounts of TNF- alpha and IL-10 released in time course using enzyme-linked immunosorbent assay (ELISA). RESULT: After stimulated by lps, the concentrations of TNF- alpha and IL-10 in culture supernatants of patients are significantly higher than control group at all time points (P < 0.01). Blockage of TLR-4 by HTA125 can decrease the production of TNF alpha and IL-10 compared with lps group (P < 0.01, except at 4 h group of IL 10). Concentration of TNF- alpha and IL-10 also decreases in the LPS + RP group (P < 0.01) but not so significantly as in the LPS + HTA125 group. CONCLUSION: As anti-TLR4 monoclonal antibodies, rheum Polysaccharide can also inhibit the secretion of cytokines produced by monocytes from HLA-B27 positive AAU patients of convalescence stage. PMID- 24151603 TI - Compression of the inferior vena cava in bowel obstruction. AB - INTRODUCTION: We investigated whether (a) the inferior vena cava (IVC) is compressed in bowel obstruction and (b) some tracts are more compressed than others. METHODS: Two groups of abdominal computed tomography (CT) examinations were collected retrospectively. Group O (N = 69) scans were positive for bowel obstruction, group C (N = 50) scans were negative for diseases. IVC anteroposterior and lateral diameters (APD, LAD) were assessed at seven levels. RESULTS: In group C, IVC section had an elliptic shape (APD/LAD: .76 +/- .14), the area of which increased gradually from 1.9 (confluence of the iliac veins) to 3.1 cm2/m2 of BSA (confluence of the hepatic veins) with a significant narrowing in the hepatic section. In group O, bowel obstruction caused a compression of IVC (APD/LAD: .54 +/- .17). Along its course, IVC section area increased from 1.3 to 2.5 cm2/m2. At ROC curve analysis, an APD/LAD ratio lower than 0.63 above the confluence of the iliac veins discriminated between O and C groups with sensitivity of 74% and specificity of 96%. CONCLUSIONS: Bowel obstruction caused a compression of IVC, which involved its entire course except for the terminal section. APD/LAD ratio may be useful to monitor the degree of compression. PMID- 24151604 TI - Locally applied valproate enhances survival in rats after neocortical treatment with tetanus toxin and cobalt chloride. AB - PURPOSE: In neocortical epilepsies not satisfactorily responsive to systemic antiepileptic drug therapy, local application of antiepileptic agents onto the epileptic focus may enhance treatment efficacy and tolerability. We describe the effects of focally applied valproate (VPA) in a newly emerging rat model of neocortical epilepsy induced by tetanus toxin (TeT) plus cobalt chloride (CoCl2). METHODS: In rats, VPA (n = 5) or sodium chloride (NaCl) (n = 5) containing polycaprolactone (PCL) implants were applied onto the right motor cortex treated before with a triple injection of 75 ng TeT plus 15 mg CoCl2. Video-EEG monitoring was performed with intracortical depth electrodes. RESULTS: All rats randomized to the NaCl group died within one week after surgery. In contrast, the rats treated with local VPA survived significantly longer (P < 0.01). In both groups, witnessed deaths occurred in the context of seizures. At least 3/4 of the rats surviving the first postoperative day developed neocortical epilepsy with recurrent spontaneous seizures. CONCLUSIONS: The novel TeT/CoCl2 approach targets at a new model of neocortical epilepsy in rats and allows the investigation of local epilepsy therapy strategies. In this vehicle-controlled study, local application of VPA significantly enhanced survival in rats, possibly by focal antiepileptic or antiepileptogenic mechanisms. PMID- 24151605 TI - Effect of C/N ratio and media optimization through response surface methodology on simultaneous productions of intra- and extracellular inulinase and invertase from Aspergillus niger ATCC 20611. AB - The study is to identify the extraction of intracellular inulinase (exo- and endoinulinase) and invertase as well as optimization medium composition for maximum productions of intra- and extracellular enzymes from Aspergillus niger ATCC 20611. From two different methods for extraction of intracellular enzymes, ultrasonic method was found more effective. Response surface methodology (RSM) with a five-variable and three-level central composite design (CCD) was employed to optimize the medium composition. The effect of five main reaction parameters including sucrose, yeast extract, NaNO3, Zn+2, and Triton X-100 on the production of enzymes was analyzed. A modified quadratic model was fitted to the data with a coefficient of determination (R2) more than 0.90 for all responses. The intra extracellular inulinase and invertase productions increased in the range from 16 to 8.4 times in the optimized medium (10% (w/v) sucrose, 2.5% (w/v) yeast extract, 2% (w/v) NaNO3, 1.5 mM (v/v) Zn+2, and 1% (v/v) Triton X-100) by RSM and from around 1.2 to 1.3 times greater than in the medium optimized by one-factor at-a-time, respectively. The results of bioprocesses optimization can be useful in the scale-up fermentation and food industry. PMID- 24151606 TI - Direct evaluation of L-DOPA actions on neuronal activity of Parkinsonian tissue in vitro. AB - Physiological and biochemical experiments in vivo and in vitro have explored striatal receptor signaling and neuronal excitability to posit pathophysiological models of Parkinson's disease. However, when therapeutic approaches, such as dopamine agonists, need to be evaluated, behavioral tests using animal models of Parkinson's disease are employed. To our knowledge, recordings of population neuronal activity in vitro to assess anti-Parkinsonian drugs and the correlation of circuit dynamics with disease state have only recently been attempted. We have shown that Parkinsonian pathological activity of neuronal striatal circuits can be characterized in in vitro cerebral tissue. Here, we show that calcium imaging techniques, capable of recording dozens of neurons simultaneously with single cell resolution, can be extended to assess the action of therapeutic drugs. We used L-DOPA as a prototypical anti-Parkinsonian drug to show the efficiency of this proposed bioassay. In a rodent model of early Parkinson's disease, Parkinsonian neuronal activity can be returned to control levels by the bath addition of L-DOPA in a reversible way. This result raises the possibility to use calcium imaging techniques to measure, quantitatively, the actions of anti Parkinsonian drugs over time and to obtain correlations with disease evolution and behavior. PMID- 24151607 TI - Antileukotriene reverts the early effects of inflammatory response of distal parenchyma in experimental chronic allergic inflammation. AB - AIMS: Compare the effects of montelukast or dexamethasone in distal lung parenchyma and airway walls of guinea pigs (GP) with chronic allergic inflammation. METHODS: GP have inhaled ovalbumin (OVA group-2x/week/4weeks). After the 4th inhalation, GP were treated with montelukast or dexamethasone. After 72 hours of the 7th inhalation, GP were anesthetised, and lungs were removed and submitted to histopathological evaluation. RESULTS: Montelukast and dexamethasone treatments reduced the number of eosinophils in airway wall and distal lung parenchyma compared to OVA group (P < 0.05). On distal parenchyma, both treatments were effective in reducing RANTES, NF- kappa B, and fibronectin positive cells compared to OVA group (P < 0.001). Montelukast was more effective in reducing eotaxin positive cells on distal parenchyma compared to dexamethasone treatment (P < 0.001), while there was a more expressive reduction of IGF-I positive cells in OVA-D group (P < 0.001). On airway walls, montelukast and dexamethasone were effective in reducing IGF-I, RANTES, and fibronectin positive cells compared to OVA group (P < 0.05). Dexamethasone was more effective in reducing the number of eotaxin and NF- kappa B positive cells than Montelukast (P < 0.05). CONCLUSIONS: In this animal model, both treatments were effective in modulating allergic inflammation and remodeling distal lung parenchyma and airway wall, contributing to a better control of the inflammatory response. PMID- 24151608 TI - Coating with autologous plasma improves biocompatibility of mesh grafts in vitro: development stage of a surgical innovation. AB - PURPOSE: To investigate mesh coating modalities with autologous blood components in a recently developed in vitro test system for biocompatibility assessment of alloplastic materials. MATERIALS AND METHODS: Seven different mesh types, currently used in various indications, were randomly investigated. Meshes were coated prior to cultivation with autologous peripheral blood mononuclear cells (PBMCs), platelets, and blood plasma. Pretreated meshes were incubated over 6 weeks in a minced tissue assay, representative for fibroblasts, muscle cells, and endothelial cells originating from 10 different patients. Adherence of those tissues on the meshes was microscopically investigated and semiquantitatively assessed using a previously described scoring system. RESULTS: Coating with peripheral blood mononuclear cells did not affect the adherence score, whereas coating with platelets and blood plasma increased the score suggesting improved biocompatibility in vitro. The previous ranking of native meshes remained consistent after coating. CONCLUSION: Plasma coating of meshes improves their biocompatibility score in a novel in vitro test system. PMID- 24151609 TI - TNF alpha mediated IL-6 secretion is regulated by JAK/STAT pathway but not by MEK phosphorylation and AKT phosphorylation in U266 multiple myeloma cells. AB - IL-6 and TNF alpha were significantly increased in the bone marrow aspirate samples of patients with active multiple myeloma (MM) compared to those of normal controls. Furthermore, MM patients with advanced aggressive disease had significantly higher levels of IL-6 and TNF alpha than those with MM in plateau phase. TNF alpha increased interleukin-6 (IL-6) production from MM cells. However, the detailed mechanisms involved in signaling pathways by which TNF alpha promotes IL-6 secretion from MM cells are largely unknown. In our study, we found that TNF alpha treatments induce MEK and AKT phosphorylation. TNF alpha stimulated IL-6 production was abolished by inhibition of JAK2 and IKK beta or by small interfering RNA (siRNA) targeting TNF receptors (TNFR) but not by MEK, p38, and PI3K inhibitors. Also, TNF alpha increased phosphorylation of STAT3 (ser727) including c-Myc and cyclin D1. Three different types of JAK inhibitors decreased the activation of the previously mentioned pathways. In conclusion, blockage of JAK/STAT-mediated NF- kappa B activation was highly effective in controlling the growth of MM cells and, consequently, an inhibitor of TNF alpha -mediated IL-6 secretion would be a potential new therapeutic agent for patients with multiple myeloma. PMID- 24151611 TI - Risk assessment of heavy metals pollution in agricultural soils of siling reservoir watershed in Zhejiang Province, China. AB - Presence of heavy metals in agriculture soils above the permissible limit poses threats to public health. In this study, concentrations of seven metals were determined in agricultural soils from Yuhang county, Zhejiang, China. Multivariate statistical approaches were used to study the variation of metals in soils during summer and winter seasons. Contamination of soils was evaluated on the basis of enrichment factor (EF), geoaccumulation index (I(geo)), contamination factor (C(f)), and degree of contamination (C(deg)). Heavy metal concentrations were observed higher in winter as compared to summer season. Cr and Cd revealed random distribution with diverse correlations in both seasons. Principal component analysis and cluster analysis showed significant anthropogenic intrusions of Zn, Cd, Pb, Cr, and Cu in the soils. Enrichment factor revealed significant enrichment (EF > 5) of Zn, Cd, and Pb, whereas geoaccumulation index and contamination factor exhibited moderate to high contamination for Zn, Cr, Cd, and Pb. In light of the studied parameters, permissible limit to very high degree of contamination (C(deg) > 16) was observed in both seasons. PMID- 24151612 TI - Association of urban slum residency with infant mortality and child stunting in low and middle income countries. AB - This study aimed to (i) examine the contextual influences of urban slum residency on infant mortality and child stunting over and above individual and household characteristics and (ii) identify factors that might modify any adverse effects. We obtained data from Demographic and Health Surveys conducted in 45 countries between 2000 and 2009. The respondents were women (15-49 years) and their children (0-59 months). Results showed that living in a slum neighborhood was associated with infant mortality (OR = 1.34, 95% CI = 1.15-1.57) irrespective of individual and household characteristics and this risk was attenuated among children born to women who had received antenatal care from a health professional (OR = 0.79, 95% CI = 0.63-0.99). Results also indicated that increasing child age exacerbated the risk for stunting associated with slum residency (OR = 1.19, 95% CI = 1.16-1.23). The findings suggest that improving material circumstances in urban slums at the neighborhood level as well as increasing antenatal care coverage among women living in these neighborhoods could help reduce infant mortality and stunted child growth. The cumulative impact of long-term exposure to slum neighborhoods on child stunting should be corroborated by future studies. PMID- 24151613 TI - Cerebral activation during von Frey filament stimulation in subjects with endothelin-1-induced mechanical hyperalgesia: a functional MRI study. AB - Endothelin-1 (ET-1) is an endogenously expressed potent peptide vasoconstrictor. There is growing evidence that ET-1 plays a role in the pain signaling system and triggers overt nociception in humans. The underlying neuronal pathways are still a matter of great debate. In the present study, we applied an intradermal ET-1 sensitization model to induce mechanical hyperalgesia in healthy subjects. Functional magnetic resonance imaging (fMRI) was used to tease out the cortical regions associated with the processing of ET-1-induced punctate hyperalgesia, as compared to a nonnoxious mechanical stimulation of the contralateral arm. Von Frey hair testing revealed the presence of increased responsiveness to punctate stimulation in all subjects. Activational patterns between nonpainful control stimulation and hyperalgesic stimulation were compared. Two major observations were made: (1) all cortical areas that showed activation during the control stimulation were also present during hyperalgesic stimulation, but in addition, some areas showed bilateral activation only during hyperalgesic stimulation, and (2) some brain areas showed significantly higher signal changes during hyperalgesic stimulation. Our findings suggest that injection of ET-1 leads to a state of punctate hyperalgesia, which in turn causes the activation of multiple brain regions. This indicates that ET-1 activates an extended neuronal pathway. PMID- 24151614 TI - Alkaline phosphatase: the next independent predictor of the poor 90-day outcome in alcoholic hepatitis. AB - AIM: Determination of risk factors relevant to 90-day prognosis in AH. Comparison of the conventional prognostic models such as Maddrey's modified discriminant function (mDF) and Child-Pugh-Turcotte (CPT) score with newer ones: the Glasgow Alcoholic Hepatitis Score (GAHS); Age, Bilirubin, INR, Creatinine (ABIC) score, Model for End-Stage Liver Disease (MELD), and MELD-Na in the death prediction. PATIENTS AND METHODS: The clinical and laboratory variables obtained at admission were assessed. The mDF, CPT, GAHS, ABIC, MELD, and MELD-Na scores' different areas under the curve (AUCs) and the best threshold values were compared. Logistic regression was used to assess predictors of the 90-day outcome. RESULTS: One hundred sixteen pts fulfilled the inclusion criteria. Twenty (17.4%) pts died and one underwent orthotopic liver transplantation (OLT) within 90 days of follow up. No statistically significant differences in the models' performances were found. Multivariate logistic regression identified CPT score, alkaline phosphatase (AP) level higher than 1.5 times the upper limit of normal (ULN), and corticosteroids (CS) nonresponse as independent predictors of mortality. CONCLUSIONS: The CPT score, AP > 1.5 ULN, and the CS nonresponse had an independent impact on the 90-day survival in AH. Accuracy of all studied scoring systems was comparable. PMID- 24151610 TI - Polymorphisms in the human cytochrome P450 and arylamine N-acetyltransferase: susceptibility to head and neck cancers. AB - The occurrence of head and neck cancer (HNC) is associated with smoking and alcohol drinking. Tobacco smoking exposes smokers to a series of carcinogenic chemicals. Cytochrome P450 enzymes (CYP450s), such as CYP1A1, CYP1B1, and CYP2D6, usually metabolize carcinogens to their inactive derivatives, but they occasionally convert the chemicals to more potent carcinogens. In addition, via CYP450 (CYP2E1) oxidase, alcohol is metabolized to acetaldehyde, a highly toxic compound, which plays an important role in carcinogenesis. Furthermore, two N acetyltransferase isozymes (NATs), NAT1 and NAT2, are polymorphic and catalyze both N-acetylation and O-acetylation of aromatic and heterocyclic amine carcinogens. Genetic polymorphisms are associated with a number of enzymes involved in the metabolism of carcinogens important in the induction of HNC. It has been suggested that such polymorphisms may be linked to cancer susceptibility. In this paper, we select four cytochrome P450 enzymes (CYP1A1, CYP1BA1, CYP2D6, and CYP2E1), and two N-acetyltransferase isozymes (NAT1 and NAT2) in order to summarize and analyze findings from the literature related to HNC risk by focusing on (i) the interaction between these genes and the environment, (ii) the impact of genetic defect on protein activity and/or expression, and (iii) the eventual involvement of race in such associations. PMID- 24151616 TI - Novel spectrophotometric method for the quantitation of urinary xanthurenic acid and its application in identifying individuals with hyperhomocysteinemia associated with Vitamin B6 deficiency. AB - A novel spectrophotometric method for the quantification of urinary xanthurenic acid (XA) is described. The direct acid ferric reduction (DAFR) procedure was used to quantify XA after it was purified by a solid-phase extraction column. The linearity of proposed method extends from 2.5 to 100.0 mg/L. The method is precise, yielding day-to-day CVs for two pooled controls of 3.5% and 4.6%, respectively. Correlation studies with an established HPLC method and a fluorometric procedure showed correlation coefficients of 0.98 and 0.98, respectively. Interference from various urinary metabolites was insignificant. In a small-scale screening of elderly conducted at Penghu county in Taiwan (n = 80), we were able to identify a group of twenty individuals having hyperhomocysteinemia (>15 MU mole/L). Three of them were found to be positive for XA as analyzed by the proposed method, which correlated excellently with the results of the activation coefficient method for RBC's AST/B6 functional test. These data confirm the usefulness of the proposed method for identifying urinary XA as an indicator of vitamin B6 deficiency-associated hyperhomocysteinemic condition. PMID- 24151615 TI - The role of osteoimmunology in periodontal disease. AB - Periodontal disease is a pathological condition that involves inflammation of the tooth supporting structures. It occurs in response to the presence of bacterial plaque on the tooth structure. The host defense system, including innate and adaptive immunity, is responsible for combating the pathologic bacteria invading the periodontal tissue. Failure to eradicate the invading pathogens will result in a continuous state of inflammation where inflammatory cells such as lymphocytes, PMNs, and macrophages will continue to produce inflammatory mediators in an effort to destroy the invaders. Unfortunately, these inflammatory mediators have a deleterious effect on the host tissue as well as foreign microbes. One of the effects of these mediators on the host is the induction of matrix degradation and bone resorption through activation of proteases and other inflammatory mediators that activate osteoclasts. PMID- 24151618 TI - Preexisting high expression of matrix metalloproteinase-2 in tunica media of saphenous vein conduits is associated with unfavorable long-term outcomes after coronary artery bypass grafting. AB - INTRODUCTION: Migration of the smooth muscle cells (SMCs) to the tunica media in the saphenous vein (SV) transplants is facilitated by matrix metalloproteinases (MMPs). The aim of this study was to identify any associations between expression of MMP-2 or endogenous tissue inhibitors (TIMP-2 and TIMP-3) in the SV segments and late failure of the SV grafts. METHODS: Two hundred consecutive patients with a mean age of 63.1 +/- 8.9 years who underwent primary isolated venous CABG were examined. Patients were retrospectively split into two subgroups, with the SV graft disease (SVGD (+); n = 47) or without it (SVGD (-); n = 153). In the SV segments, immunohistochemical analysis of the expression of the MMP-2, TIMP-2, and -3 was performed. RESULTS: In the SVGD (+) patients, tissue expression of MMP 2 was stronger, whereas that of both TIMPs was weaker than in the SVGD (-) patients. In majority of the SV segments obtained from the SVGD (-) individuals, a balance in MMP and TIMP expressions was found, whereas an upregulation of MMP-2 expression was usually noted in the SVGD (+) subjects. CONCLUSION: The strong expression of MMP-2 accompanied by reduced immunostaining of both TIMPs is associated with the development of the SV graft disease and unfavorable CABG outcomes. PMID- 24151619 TI - Cancer morbidity in rheumatoid arthritis: role of estrogen metabolites. AB - Estrogen metabolites have been implicated in rheumatoid arthritis (RA) and cancer, although the mechanism remains unestablished. Some estrogen metabolites, which are used for the assessment of cancer risk, play an important role in RA. The pathways by which malignancies associated with RA remain elusive. Possible mechanism involves enzymatic or nonenzymatic oxidation of estrogen into catecholestrogen metabolites through semiquinone and quinone redox cycle to produce free radicals that can cause DNA modifications. Modifications of DNA alter its immunogenicity and trigger various immune responses leading to elevated levels of cancer and RA antibodies. However, the role of different estrogen metabolites as a mediator of immune response cannot be ruled out in various immune-related diseases. PMID- 24151617 TI - Breath tests in respiratory and critical care medicine: from research to practice in current perspectives. AB - Today, exhaled nitric oxide has been studied the most, and most researches have now focused on asthma. More than a thousand different volatile organic compounds have been observed in low concentrations in normal human breath. Alkanes and methylalkanes, the majority of breath volatile organic compounds, have been increasingly used by physicians as a novel method to diagnose many diseases without discomforts of invasive procedures. None of the individual exhaled volatile organic compound alone is specific for disease. Exhaled breath analysis techniques may be available to diagnose and monitor the diseases in home setting when their sensitivity and specificity are improved in the future. PMID- 24151620 TI - An experimental approach for selecting appropriate rodent diets for research studies on metabolic disorders. AB - Diverse high energy diets have been utilized to precipitate obesity and related metabolic disorders in rodent models, though the dietary intervention has not absolutely been standardized. The present study established usage of a customized semipurified normal control diet (NCD) and high fat diet (HFD), for research studies on diet-induced metabolic disorders in albino rats. Male Wistar rats were fed with normal pellet diet (NPD) or customized NCDs I, II, III or HFDs I, II, III for 12 weeks and parameters, namely, body weight, visceral adiposity, serum triglycerides, cholesterol, and glucose were evaluated to select an appropriate NCD and HFD. The selected HFD was further evaluated for induction of fatty liver, whilst type 2 diabetes (T2D) induction was confirmed in HFD and streptozotocin (STZ) induced diabetes model in Wistar rats. Amongst different diets tested, NCD I and HFD-I were selected, since NCD-I exhibited close resemblance to NPD, whereas HFD-I induced metabolic alterations, particularly obesity and dyslipidemia consistently. Moreover, HFD-I elevated terminal hepatic lipids, while HFD-I/STZ treatment augmented insulin resistance index and serum glucose levels significantly indicating effective induction of fatty liver and T2D, respectively. Therefore, customized semipurified NCD-I and HFD-I can be recommended for research studies on diet-induced metabolic disorders in albino Wistar rats. PMID- 24151621 TI - 2-Hour postload serum glucose levels and maternal blood pressure as independent predictors of birth weight in "appropriate for gestational age" neonates in healthy nondiabetic pregnancies. AB - INTRODUCTION: Increased neonatal birth weight (NBW), often associated with diabetic pregnancies, is a recognized indicator of childhood obesity and future metabolic risk. Predictors of NBW in healthy non-diabetic pregnancies are not yet established. Here, we investigated the association of maternal parameters of healthy non-diabetic mothers with NBW of their "appropriate-for-gestational age" neonates. METHODS: The study involved 36 healthy mother/infant pairs. Examined parameters included NBW, maternal age, first and last trimester (BMI), weight gain, fasting serum lipids and glucose, 2-hour postload glucose levels and blood pressure. RESULTS: Postload-glucose levels were significantly higher in mothers of heavier neonates. ANOVA results indicated that 15% increase in postload glucose levels corresponded to more than 0.5 Kg increase in NBW in the third tertile. NBW correlated positively with postload glucose levels, and negatively with systolic blood pressure. Regression analysis showed that the main predictors of NBW were postload-glucose levels (B = 0.455, P = 0.003), followed by systolic blood pressure (B = -0.447, P = 0.004), together predicting 31.7% NBW variation. CONCLUSION: This study highlights that increased maternal postload sugar levels and blood pressure, within the normal range, highly predicts NBW of healthy mothers. These findings may provide focus for early dietary intervention measures to avoid future risks to the mother and baby. PMID- 24151622 TI - Gastric stump cancer: more than just another proximal gastric cancer and demanding a more suitable TNM staging system. AB - BACKGROUND: Considerable controversy persists about the biological behavior of gastric stump cancer (GSC). The aim of this study is to clarify if this cancer is just another proximal gastric cancer or if it emerges as a distinctive clinicopathologic entity. METHODS: This review of a prospectively collected gastric cancer database identified 73 patients with GSC in a single institution between January 1980 and June 2012 and compared them with 328 patients with proximal gastric cancer (PGC) and 291 patients with esophagogastric junction cancer (EGJC). RESULTS: Patients with GSC were predominantly males. Eighty-three percent of GSC penetrated the subserosal or the serosal layers. The median number of lymph nodes retrieved in GSC patients was significantly lower than in PGC patients or in EGJC patients. Cumulative survival curves were not different between GSC, PGC, or EGJC patients. Unlike that observed in PGC and in EGJC, no significant differences in cumulative survival according to the TNM staging system were observed in GSC cases. CONCLUSIONS: The outcome of patients with GSC displayed significant differences when compared to those with other proximal gastric cancers concerning the lack of survival association with the TNM staging system. Therefore a more suitable staging system should be designed for these unique cancers. PMID- 24151623 TI - Study of microRNAs related to the liver regeneration of the whitespotted bamboo shark, Chiloscyllium plagiosum. AB - To understand the mechanisms of liver regeneration better to promote research examining liver diseases and marine biology, normal and regenerative liver tissues of Chiloscyllium plagiosum were harvested 0 h and 24 h after partial hepatectomy (PH) and used to isolate small RNAs for miRNA sequencing. In total, 91 known miRNAs and 166 putative candidate (PC) miRNAs were identified for the first time in Chiloscyllium plagiosum. Through target prediction and GO analysis, 46 of 91 known miRNAs were screened specially for cellular proliferation and growth. Differential expression levels of three miRNAs (xtr-miR-125b, fru-miR 204, and hsa-miR-142-3p_R-1) related to cellular proliferation and apoptosis were measured in normal and regenerating liver tissues at 0 h, 6 h, 12 h, and 24 h using real-time PCR. The expression of these miRNAs showed a rising trend in regenerative liver tissues at 6 h and 12 h but exhibited a downward trend compared to normal levels at 24 h. Differentially expressed genes were screened in normal and regenerating liver tissues at 24 h by DDRT-PCR, and ten sequences were identified. This study provided information regarding the function of genes related to liver regeneration, deepened the understanding of mechanisms of liver regeneration, and resulted in the addition of a significant number of novel miRNAs sequences to GenBank. PMID- 24151624 TI - 7,8-Dihydroxyflavone suppresses oxidative stress-induced base modification in DNA via induction of the repair enzyme 8-oxoguanine DNA glycosylase-1. AB - The modified guanine base 8-oxoguanine (8-oxoG) is abundantly produced by oxidative stress, can contribute to carcinogenesis, and can be removed from DNA by 8-oxoguanine DNA glycosylase-1 (OGG1), which acts as an 8-oxoG glycosylase and endonuclease. This study investigated the mechanism by which 7,8-dihydroxyflavone (DHF) inhibits oxidative stress-induced 8-oxoG formation in hamster lung fibroblasts (V79-4). DHF significantly reduced the amount of 8-oxoG induced by hydrogen peroxide (H2O2) and elevated the levels of OGG1 mRNA and protein. DHF increased the binding of nuclear factor erythroid 2-related factor 2 (Nrf2) to antioxidant response element sequences in the upstream promoter region of OGG1. Moreover, DHF increased the nuclear levels of Nrf2, small Maf proteins, and the Nrf2/small Maf complex, all of which are decreased by H2O2 treatment. Likewise, the level of phosphorylated Akt, which activates Nrf2, was decreased by H2O2 treatment but restored by DHF treatment. The levels of OGG1 and nuclear translocation of Nrf2 protein were decreased upon treatment with PI3K inhibitor or Akt inhibitor, and DHF treatment did not restore OGG1 and nuclear Nrf2 levels in these inhibitor-treated cells. Furthermore, PI3K and Akt inhibitors abolished the protective effects of DHF in cells undergoing oxidative stress. These data indicate that DHF induces OGG1 expression via the PI3K-Akt pathway and protects cells against oxidative DNA base damage by activating DNA repair systems. PMID- 24151625 TI - Role of color Doppler imaging in early diagnosis and prediction of progression in glaucoma. AB - This longitudinal and prospective study analyzes the ability of orbital blood flow measured by color Doppler imaging (CDI) to predict glaucoma progression in patients with glaucoma risk factors. Patients with normal perimetry but having glaucoma risk factors and patients in the initial phase of glaucoma were prospectively included in the study and divided, after a five-year follow-up, into two groups: "Progression" and "No Progression" based on the changes in the Moorfields regression analysis (MRA) classification of Heidelberg retina tomograph (HRT). An orbital CDI was performed in all patients and the parameters obtained were correlated with changes in HRT. A logistic discrimination function (LDF) was calculated for ophthalmic artery (OA) and central retinal artery (CRA) parameters. Receiver operating characteristics curves (ROC) were used to assess the usefulness of LDFs to predict glaucomatous progression. A total of 71 eyes were included. End-diastolic velocity, time-averaged velocity, and resistive index in the OA and CRA were significantly different (P < 0.05) between the Progression and No Progression groups. The area under the ROC curves calculated for both LDFs was of 0.695 (OA) and 0.624 (CRA). More studies are needed to evaluate the ability of CDI to perform early diagnosis and to predict progression in glaucoma in eyes. PMID- 24151627 TI - Stem cell therapy in bladder dysfunction: where are we? And where do we have to go? AB - To date, stem cell therapy for the bladder has been conducted mainly on an experimental basis in the areas of bladder dysfunction. The therapeutic efficacy of stem cells was originally thought to be derived from their ability to differentiate into various cell types. Studies about stem cell therapy for bladder dysfunction have been limited to an experimental basis and have been less focused than bladder regeneration. Bladder dysfunction was listed in MESH as "urinary bladder neck obstruction", "urinary bladder, overactive", and "urinary bladder, neurogenic". Using those keywords, several articles were searched and studied. The bladder dysfunction model includes bladder outlet obstruction, cryoinjured, diabetes, ischemia, and spinal cord injury. Adipose derived stem cells (ADSCs), bone marrow stem cells (BMSCs), and skeletal muscle derived stem cells (SkMSCs) are used for transplantation to treat bladder dysfunction. The main mechanisms of stem cells to reconstitute or restore bladder dysfunction are migration, differentiation, and paracrine effects. The aim of this study is to review the stem cell therapy for bladder dysfunction and to provide the status of stem cell therapy for bladder dysfunction. PMID- 24151628 TI - The assessment of Proteus mirabilis susceptibility to ceftazidime and ciprofloxacin and the impact of these antibiotics at subinhibitory concentrations on Proteus mirabilis biofilms. AB - Rods of the Proteus genus are commonly isolated from patients, especially from the urinary tracts of the catheterised patients. The infections associated with biomaterials are crucial therapeutic obstacles, due to the bactericidal resistance of the biofilm. The aim of this study was to assess the susceptibility of P. mirabilis planktonic forms to ciprofloxacin and ceftazidime, the ability to form biofilm, and the impact of chosen sub-MIC concentrations of these antibiotics on biofilm at different stages of its formation. The research included 50 P. mirabilis strains isolated from wounds and the urinary tracts from patients of the University Hospital No. 1 in Bydgoszcz. The assessment of susceptibility to ciprofloxacin and ceftazidime was conducted using micromethods. The impact of sub-MIC concentrations of the chosen antibiotics on the biofilm was measured using the TTC method. The resistance to ciprofloxacin was confirmed for 20 strains (40.0%) while to ceftazidime for 32 (64.0%) of the tested P. mirabilis strains. All of the tested strains formed biofilm: 24.0% weakly, 26.0% moderately, and 50.0% strongly. It was determined that ciprofloxacin and ceftazidime caused eradication of the biofilm. Moreover, the connection between origin of the strains, biofilm maturity level, and resistance to antibiotics was proved. PMID- 24151629 TI - Anti-inflammatory activity of bioaccessible fraction from Eryngium foetidum leaves. AB - Eryngium foetidum (EF) has long been used as a medicinal plant and culinary spice in tropical regions. Phytochemicals in its leaves have been proposed to be responsible for the anti-inflammatory and antioxidant activities. The present study used in vitro digestion coupled with Caco-2 cells to assess such activities. Caco-2 cells were incubated with aqueous fraction from simulated digestion (bioaccessible fraction) of EF leaves with/without bile extract prior to stimulation with interleukin-1 beta (IL-1beta). Monocyte chemoattractant protein-1 (MCP-1) and IL-8 in culture media and the intracellular reactive oxygen species (ROS) were measured. Approximately 24% beta-carotene and 35% lutein of leaves were present in the aqueous fraction. The transfer of caffeic and chlorogenic acids to the aqueous fraction was 76%-81%, while that of kaempferol was 48%. Prior incubation of Caco-2 cells with the bioaccessible fraction suppressed IL-1beta activated IL-8 and MCP-1 by 33%, but the fraction lacking mixed micelles decreased IL-8 and MCP-1 levels only by 11%. The pretreatment of Caco-2 cells with the bioaccessible fraction of EF reduced ROS by 34%; the fraction lacking mixed micelles decreased ROS by 28%. These data suggest that bioactive compounds partitioning in mixed micelles play a significant role to suppress the proinflammatory insult but with a modest antioxidant effect. PMID- 24151630 TI - Efficacy and safety of docetaxel plus oxaliplatin and capecitabine in the first line treatment of advanced gastric adenocarcinoma. AB - OBJECTIVE: To evaluate the efficacy and safety of docetaxel plus oxaliplatin and capecitabine (DOX) in the first line treatment of advanced gastric adenocarcinoma. METHODS: A total of 37 patients were enrolled into this study, and they received DOX regimen (docetaxel 75 mg/m2 and oxaliplatin 130 mg/m2 intravenous infusion on day 1, and capecitabine 1000 mg/m2 orally twice daily on d1-14); treatment was repeated every 3 weeks. RESULTS: All 37 patients were assessable for evaluation. The numbers of patients with complete response (CR), partial responses (PR), stable disease (SD), and progressive disease (PD) were 1, 10, 23, and 3, respectively. The objective response rate (ORR) was 29.7%, with the disease control rate (DCR) of 91.9%. Median progression-free survival (mPFS) and overall survival (mOS) were 197 days and 364 days, respectively. The most common grade 3/4 toxicities were hematological toxicities. The most common grade 3/4 nonhematological toxicities were fatigue, nausea, vomiting, anorexia, diarrhea, and hand-foot syndrome. CONCLUSION: The DOX regimen demonstrated a promising efficacy as the first line regimen in treating advanced gastric cancer patients with good performance status, the toxicities were tolerated and controllable. Large-scale clinical observation is necessary to get further evidence. PMID- 24151632 TI - High-conjugation-efficiency aqueous CdSe quantum dots. AB - Quantum dots (QDs) are photoluminescent nanoparticles that can be directly or indirectly coupled with a receptor such as an antibody to specifically image a target biomolecule such as an antigen. Recent studies have shown that QDs can be directly made at room temperature and in an aqueous environment (AQDs) with 3 mercaptopropionic acid (MPA) as the capping ligand without solvent and ligand exchange typically required by QDs made by the organic solvent routes (OQDs). In this study, we have synthesized CdSe AQDs and compared their conjugation efficiency and imaging efficacy with commercial carboxylated OQDs in HT29 colon cancer cells using a primary antibody-biotinylated secondary antibody streptavidin (SA) sandwich. We showed that the best imaging condition for AQDs occurred when one AQD was bound with 3 +/- 0.3 SA with a nominal SA/AQD ratio of 4 corresponding to an SA conjugation efficiency of 75 +/- 7.5%. In comparison, for commercial CdSe-ZnS OQDs to achieve 2.7 +/- 0.4 bound SAs per OQD for comparable imaging efficacy a nominal SA/OQD ratio of 80 was needed corresponding to an SA conjugation efficiency of 3.4 +/- 0.5% for CdSe-ZnS OQDs. The more than 10 times better SA conjugation efficiency of the CdSe AQDs as compared to that of the CdSe-ZnS OQDs was attributed to more capping molecules on the AQD surface as a result of the direct aqueous synthesis. More capping molecules on the AQD surface also allowed the SA-AQD conjugate to be stable in cell culture medium for more than three days without losing their staining capability in a flowing cell culture medium. In contrast, SA-OQD conjugates aggregated in cell culture medium and in phosphate buffer saline solution over time. PMID- 24151631 TI - Cystic echinococcosis in a single tertiary care center in Rome, Italy. AB - BACKGROUND: Cystic echinococcosis (CE) is a chronic, clinically complex, and neglected disease. Its prevalence in Italy, a country of medium to high endemicity, remains poorly defined, as notification has long ceased to be mandatory. METHODS: We set up a retrospective cohort study involving all CE patients followed at our institute between January 2005 and December 2012. Demographical and clinical features were recorded and analyzed. RESULTS: CE was found in 28 patients (64.3%), mostly Italians from the central regions (50%), followed by subjects from the islands (33.3%) and Southern Italy (16.7%). Their median age was 45 years (IQR: 38.5-66.5), with Eastern Europeans being significantly younger (28 years, IQR: 19-39) than other patients (P <= 0.0001). A total of 149 cysts, mostly with hepatic localization (96%), were described. Based on the WHO classification, the cysts were mainly small (80.5%) and active (CE1 (73.8%); CE2 (7.4%)). Active cysts were more common in Eastern Europeans (85.7%) than Italians (66.7%). CONCLUSION: Our data confirm CE occurrence in Italy. We emphasize the importance to have a national CE registry, opportunely recently introduced. This is essential to assess CE prevalence in this country, implement appropriate control measures, and improve patient management. PMID- 24151633 TI - Glucose selective surface plasmon resonance-based bis-boronic acid sensor. AB - Saccharides - a versatile class of biologically important molecules - are involved in a variety of physiological and pathological processes, but their detection and quantification is challenging. Herein, surface plasmon resonance and self-assembled monolayers on gold generated from bis-boronic acid bearing a thioctic acid moiety, whose intramolecular distance between the boronic acid moieties is well defined, are shown to detect d-glucose with high selectivity, demonstrating a higher affinity than other saccharides probed, namely d galactose, d-fructose and d-mannose. PMID- 24151634 TI - A bis-boronic acid modified electrode for the sensitive and selective determination of glucose concentrations. AB - A bis-boronic acid modified electrode for the sensitive and selective determination of glucose concentrations has been developed. The electrochemical characteristics of the sensor with added saccharides were investigated using cyclic voltammetry (CV) and electrochemical impedance spectroscopy (EIS). The bis boronic acid modified electrode was both sensitive and selective for glucose. PMID- 24151635 TI - Fluorogenic probes using 4-substituted-2-nitrobenzenesulfonyl derivatives as caging groups for the analysis of human glutathione transferase catalyzed reactions. AB - We have synthesized a series of 4-substituted-2-nitrobenzene-sulfonyl compounds for caged fluorogenic probes and conducted a Hammett plot analysis using the steady-state kinetic parameters. The results revealed that the glutathione transferase (GST) alpha catalyzed reaction was dependent on the sigma value in the same way as the non-enzymatic reaction, whereas the dependence of the sigma value of the GST mu and pi was not as pronounced as that of GST alpha. PMID- 24151636 TI - Mid-infrared spectroscopy for gases and liquids based on quantum cascade technologies. AB - In this paper we present two compact, quantum cascade laser absorption spectroscopy based, sensors developed for trace substance detection in gases and liquids. The gas sensor, in its most integrated version, represents the first system combining a quantum cascade laser and a quantum cascade detector. Furthermore, it uses a toroidal mirror cell with a volume of only 40 cm(3) for a path length of up to 4 m. The analytical performance is assessed by the measurements of isotope ratios of CO2 at ambient abundance. For the (13)CO2/(12)CO2 isotope ratio, a measurement precision of 0.20/00 is demonstrated after an integration time of 600 s. For the liquid sensor, a microfluidic system is used to extract cocaine from saliva into a solvent (PCE) transparent in the mid-infrared. This system is bonded on top of a Si/Ge waveguide and the concentration of cocaine in PCE is measured through the interaction of the evanescent part of the waveguide optical mode and the solvent flowing on top. A detection limit of <100 MUg mL(-1) was achieved with this system and down to 10 MUg mL(-1) with a simplified, but improved system. PMID- 24151637 TI - Inhibition of type I interferon signalling prevents TLR ligand-mediated proteinuria. AB - The mechanisms by which inflammation or autoimmunity causes proteinuric kidney disease remain elusive. Yet proteinuria is a hallmark and a prognostic indicator of kidney disease, and also an independent risk factor for cardiovascular morbidity and mortality. Podocytes are an integral component of the kidney filtration barrier and podocyte injury leads to proteinuria. Here we show that podocytes, which receive signals from the vascular space including circulating antigens, constitutively express TLR1-6 and TLR8. We find that podocytes can respond to TLR ligands including staphylococcal enterotoxin B (SEB), poly I:C, or lipopolysaccharide (LPS) with pro-inflammatory cytokine release and activation of type I interferon (IFN) signalling. This in turn stimulates podocyte B7-1 expression and actin remodelling in vitro and transient proteinuria in vivo. Importantly, the treatment of mice with a type I IFN receptor-blocking antibody (Ab) prevents LPS-induced proteinuria. These results significantly extend our understanding of podocyte response to immune stimuli and reveal a novel mechanism for infection- or inflammation-induced transient proteinuria. Dysregulation or aberrant activation of this response may result in persistent proteinuria and progressive glomerular disease. In summary, the inhibition of glomerular type I IFN signalling with anti-IFN Abs may be a novel therapy for proteinuric kidney diseases. PMID- 24151638 TI - Abstracts of the American Society of Plastic Surgeons' Annual Meeting. October 11 15, 2013. San Diego, California, USA. PMID- 24151639 TI - Abstracts of ECTRIMS (Congress of the European Committee for Treatment and Research in Multiple Sclerosis) 2013. October 2-5, 2013. Copenhagen, Denmark. PMID- 24151640 TI - Abstracts of the 24th Great Wall International Congress of Cardiology, Asia Pacific Heart Congress 2013, International Congress of Cardiovascular Prevention and Rehabilitation 2013. October 10-13, 2013. Beijing, China. PMID- 24151641 TI - Reply to Haeseker: Value of controlled scientific experiments to resolve critical uncertainties regarding Snake River salmon survival. PMID- 24151642 TI - Abstracts of the 78th Annual Scientific Meeting of the American College of Gastroenterology. October 11-16, 2013. San Diego, California, USA. PMID- 24151643 TI - Abstracts of the 83rd Annual Meeting of the American Thyroid Association Meeting. October 16-20, 2013. San Juan, Puerto Rico. PMID- 24151644 TI - Reply: To PMID 22976235. PMID- 24151645 TI - Abstracts of ECIM 2013, the 12th European Congress on Internal Medicine. October 2-5, 2013. Prague, Czech Republic. PMID- 24151646 TI - [Leonardo da Vinci -- a life devoted to science]. PMID- 24151647 TI - Folic acid supplementation for rheumatoid arthritis patients on methotrexate: the good gets better. PMID- 24151648 TI - Calling time on intravenous immunoglobulin for preterm infants? PMID- 24151649 TI - [Correction with respect to MP Manns, 50 years Hepatology - From therapeutic nihilism for targeted therapy. Z Gastroenterol 2013; 51: 363-370]. PMID- 24151650 TI - [Correction of Prof. Dr. U. Leuschner]. PMID- 24151651 TI - Mycobacterium abscessus scleritis following intravitreous injection of bevacizumab. PMID- 24151652 TI - In reply. PMID- 24151653 TI - In reply. PMID- 24151654 TI - "Pure" primary large cell neuroendocrine carcinoma of the urinary bladder. Author reply. PMID- 24151655 TI - [Addiction medicine: more doctors needed for medical supervision of opioid replacement therapy]. PMID- 24151656 TI - [I. Molecular targeting therapy and immunotherapy]. PMID- 24151657 TI - [II.Current status of peptide vaccine for lung cancer]. PMID- 24151658 TI - [III. Immunotherapy for lung cancer]. PMID- 24151659 TI - [IV.Clinical trial of immunotherapy for lung cancer]. PMID- 24151660 TI - [Endoscopic papillary balloon dilatation vs. endoscopic sphincteropapillotomy for common bile duct stones: a meta analysis]. AB - OBJECTIVE: To evaluate the safety and efficacy between endoscopic papillary balloon dilatation (EPBD) and endoscopic sphincteropapillotomy ( EST) for common bile duct stones using meta-analysis method. METHODS: Randomizd controlled trials comparing EPBD with EST for common bile duct stones and published from January 1990 to July 2012 were recruited. This meta-analysis was conducted to estimate short-term and long-term complications. Fixed random effect model or random effect model was established to analyze the data. RESULTS: Twelve randomizd controlled trials were included in this analysis. These studies included 1865 patients, 925 of them were treated with EPBD and 940 were treated with EST. The analysis of basic characteristics of these included studies showed that: compared to EST, patients in the EPBD group were younger (OR = -1.16, 95% CI: -1.49 to 0.84, P = 0.00), while in two groups, there were no significant difference (P > 0.05) in gender proportion, average size of stones, number of gallstones, previous cholecystectomy, the number of merged duodenal diverticulum, common bile duct diameter, the total follow-up time. Also, compared to EST, the overall stone clearance in the EPBD group was lower (OR = 0.64, 95% CI: 0.42 to 0.96, P = 0.03), pancreatitis incidence was higher (OR = 2.67, 95% CI: 1.61 to 4.43, P = 0.00), incidence of bleeding (OR = 0.12, 95% CI: 0.04 to 0.34, P = 0.00), acute cholecystitis (OR= 0.39, 95% CI: 0.18 to 0.84, P = 0.02), total long-term complication rate (OR = 0.53, 95% CI: 0.36 to 0.77, P = 0.01), stone recurrence rate more than a year were lower (OR= 0.48, 95% CI: 0.26 to 0.90, P = 0.02). While in two groups, there were no significant difference (P > 0.05) in the stone removal on 1 '' attempt, the total near-term complications and acute cholangitis. CONCLUSIONS: On the basis of lower rates of bleeding, EPBD seems to be preferred strategy over EST for endoscopic remove of common bile duct stones in patients who have coagulopathy. Although stone recurrence rate more than a year of EPBD is lower, but the overall stone clearance rate is lower and the risk of pancreatitis is higher than that of EST. PMID- 24151661 TI - Authors' response. PMID- 24151662 TI - Diagnosis and management of motor vehicle trauma in children: an evidence-based review. AB - Injuries from motor vehicle crashes are the leading cause of mortality in children aged 5 years and older in the United States. This review discusses common injuries in children after motor vehicle trauma and examines the evidence regarding the evaluation and treatment of pediatric patients involved in motor vehicle crashes. Both prehospital and emergency department care are discussed along with a differential diagnosis of the injuries most commonly seen in motor vehicle crashes. The various options for imaging modalities are also discussed in this review. A critical appraisal of the existing guidelines for the management of motor vehicle trauma and for the use of appropriate child-safety restraints is presented. Emergency clinicians will be able to use the patient's history and physical examination findings along with knowledge of common injuries to determine the most appropriate workup and treatment of pediatric patients who present with motor vehicle trauma. PMID- 24151663 TI - [Folie a deux: a nosographic question or just a shared madness?]. AB - Folie a deux was described by Lasegue and Falret in 1877. The concept evolved thus giving rise to different variants of the same reported phenomenon. Taking a clinical case as an example, a review of the nosological definition of shared psychotic disorder was performed. Limitations were found in its descriptions of the subtypes of this unique clinical picture. In this paper we evaluate if its argument has real implications for the purpose of establishing a diagnosis and performing a definite therapeutic approach. PMID- 24151665 TI - [Out-of-the-hospital scenarios of mental health in children and youth: a panorama of experiences in the metropolitan area]. PMID- 24151664 TI - [Association between acute coronary events and psychosocial risk factors: vital exhaustion, anxiety and anger in an Argentinian population. A correlation study between risks factors]. AB - OBJECTIVE: To study the association between vital exhaustion, anxiety and anger with acute coronary event; second, determine whether they are associated with each other, and third, if the joint interaction of two or more factors increases the risk for coronary event. METHOD: We conducted a case-control study with 165 patients, both sexes, between 35 and 75 years, 90 patients with acute ischemic coronary event and 75 controls hospitalized with an acute event of non-ischemic cardiac causes. RESULTS: Statistically significant differences between the control group and the ischemic coronary group for vital exhaustion was found (OR = 3.0 (1.6-5.5) p < 0.001 (chi2)). Psychosocial risk factors are associated each with p < 0.001: anxiety and vital exhaustion (Spearman Rho = 0.58), anger and vital exhaustion (Spearman Rho = 0.41) and anxiety and anger (Spearman Rho = 0.38). The simultaneous presence of vital exhaustion and anxiety increases the probability of an acute ischemic coronary event (p < 0.01). CONCLUSIONS: In this study we found a significative association between vital exhaustion and acute ischemic coronary event, psychosocial risk factors are associated with each other and simultaneous presence of vital exhaustion and anxiety increases the probability of an acute ischemic coronary event. PMID- 24151666 TI - [Teenagers and crime: a dark day of justice]. AB - The methods of intervention and/or treatment of children/teenagers under 18 years old who are accused or found guilty of crimes are analyzed taking into consideration multidisciplinary intervention tools, especially those including any kind of 'psy' outpatient care. These programs, which are usually deployed in the social milieu, involve a conflictive junction between the fields of Law and Mental Health. It shall be required to review the different social responses to such children and teenagers and the current state of legal discussions in order to reflect upon the singular inclusion of the therapeutic approach to these complex contexts, where the 'socio-educational' aspect has occupied a substantial position. PMID- 24151667 TI - [Jakaira project: the adolescent parents as authors and actors of their own future]. AB - The purpose of the following paper is to present a project developed within the framework of collaboration between two foundations, Fundacion Kaleidos (Argentina) and Children Action (Switzerland). The aim of this project is to developed diverse programs to support and empower adolescent mothers and fathers as well as their children. Adolescents whose rights are very often not respected and who find themselves alone having to confront the negative prejudices of the adults around them regarding the parenthood, which they now face. The objectives of the programs are as follows: the promotion of the well-being of the adolescents and the development of a personal project around education or work, the promotion of early child development of their infants, to address the problems around gender inequality and the promotion of an intersectional network between distinct sectors of society (public, private and NGO). By means of an integral program, we aim to tackle the diverse aspects of the lives of the adolescents in question and their children. Their rights and their environment are key to developing the maximum potential of each individual and their families. PMID- 24151668 TI - [Community mental health networks and doors at a Health and Community Center (CeSAC No 24) in the south of the Autonomous City of Buenos Aires (CABA)]. AB - The history of the Health and Community Center (CeSAC) No 24 began 21 years ago in the Ramon Carrillo district, in Villa Soldati neighborhood. This is a marginal urban area in the south of the CABA with a population with urgent needs. The work started with a group of professionals dealing with primary care practices, and it continues up to the present. The goal of our community mental health project is the creation of spaces for prevention and well-being including art in all its expressions, with the active participation of neighbors in the coordination of many activities. Through the symbolic opening of doors and making networks visible, we opened the CeSAC to universities, scientific societies, foundations, NGOs, neighbor committees, neighborhood boards, human rights organizations, formal and informal education centers, cultural centers, churches, community radios, in order to show the vital movements of the community, as we -as a team- are an integral part of it. Our spaces, workshops and programs are a collective socio-historical construction that achieves milestones such as thinking, thinking of us, getting together and achieving the participation from the community and the continuous training for everybody working and living in Soldati. The decentralization and democratization trend, and the heterarchical management of our organization favors the possibility of catalyzing the wishes, motivations and efforts of the healthcare team, neighbors and network nodes, thus benefiting the creative work that turns a dream into a hopeful reality. PMID- 24151669 TI - ["Debris" public policies and exclusion. Their effects on subjective constitution]. AB - The following paper formulates a critical and conceptual analysis based on a territorial experience. It is enshrined in the field of mental health, understood as the collection of practices and problems aiming at addressing subjectivity, that is, they are inseparable from social and health practices. Some of the causes and effects of exclusion in subjective constitution become problems when institutional, group, community and individual interventions -always of a singular nature- take place. The existing relationship between public policies and population appears in the very core of an intervention or consultation; we, as professionals, are a part of it. People living in conditions of poverty often feel alien to traditional healthcare settings and they end up excluding such facilities from their resources. We will work on childhood and adolescence, as they are constituent stages in history, and the ways in which such history develops in situations with social exclusion. Some of such ways are paco (cocaine paste), violence, conflict with the law or ignorance of it. These are singular ways, but they involve a common and recurring mark related to rejection, neglect and subjective de-structuring. This is what I will refer to as debris hereafter. Lastly, the reconstruction of a Social Other and an approach based on the bond will be emphasized. This will also allow for a social bond, and the building of a care mechanism, which through transference may accommodate an individual who could make certain requests. PMID- 24151670 TI - [Open space of Non-Profit Organization La Casona de los Barriletes. Support program for youth in the process of being discharged from shelter facilities]. AB - On this paper we outline a work program called Outpatient Therapeutic Family Space (Open Space) of the Non-Profit Organization La Casona de los Barriletes, whose goals consist of supporting youth going through discharge processes from shelter facilities in the Autonomous City of Buenos Aires (CABA) where they were admitted or residing, and contributing with the consolidation of social inclusion processes. After a brief inspection of the history of the institution from where this program is developed, we explain a group of conceptual themes that help us focus on the problems, and we develop notions such as vulnerability, mental condition/disorder/disease, and health/illness/care process. Based on these definitions, we describe areas for the development of multidimensional interventions from an interdisciplinary team, aiming at developing cross institution and cross-sector coordination allowing for the construction of community reference networks for youth accompanied by their families or affective referents. Later on we analyze certain factors that operate as stimuli and obstacles in this task. Lastly, we present several considerations based on the revision of the work carried out. PMID- 24151671 TI - [Expanding the boundaries of clinics. Development of a community mental health program for children and teenagers from a rights perspective in the City of Buenos Aires]. AB - There are forms of severe suffering in contemporary life that are not accommodated within the mechanisms offered by the mental health care system or that are not described on diagnostics handbooks, which need an appropriate response. This paper deals with the development of a community mental health program that provided care to children and teenagers with severe mental disorders and with a significant subjective suffering in the City of Buenos Aires from 2006 until the beginning of 2012. Pursuant to international standards in force in terms of mental health and human rights, this community, collective and territorial mental health practice suggested an inter-discipline and cross-sector approach that took into consideration the multi-dimension of social health determiners to provide comprehensive care. In order to offer a reply to fragmentation and the repeated traumas to which a large number of these children and teenagers have been exposed to, the program designed individual clinical community strategies for each child or teenager, based on a network of continuous and reliable institutional supports. Conceived from a psychoanalytical approach, this praxis intended to benefit subjectification processes and the building of social bonds aiming at preventing the growing trends of administering medication and admitting children and teenagers as patients in mental health facilities. PMID- 24151673 TI - [First National Conference on the abandoned and delinquent child. Colonia Hogar Ricardo Gutierrez, Buenos Aires]. PMID- 24151672 TI - [Rescue and memory. Lanfranco Ciampi and the abandoned and delinquent child]. PMID- 24151674 TI - Introduction to a special grouping of papers from the 2012 A&WMA International Specialty Conference, Aerosol and Atmospheric Optics: Visibility and Air Pollution. PMID- 24151675 TI - Measurement of light scattering in an urban area with a nephelometer and PM2.5 FDMS TEOM monitor: accounting for the effect of water. AB - The US. Environmental Protection Agency (EPA) has proposed a new secondary standard based on visibility in urban areas. The proposed standard will be based on light extinction, calculated from 24-hr averaged measurements. It would be desirable to base the standard on a shorter averaging time to better represent human perception of visibility This could be accomplished by either an estimation of extinction from semicontinuous particulate matter (PM) data or direct measurement of scattering and absorption. To this end we have compared 1-hr measurements of fine plus coarse particulate scattering using a nephelometer along with an estimate of absorption from aethalometer measurements. The study took place in Lindon, UT, during February and March 2012. The nephelometer measurements were corrected for coarse particle scattering and compared to the Filter Dynamic Measurement System (FDMS) tapered element oscillating microbalance monitor (TEOM) PM2.5 measurements. The two measurements agreed with a mass scattering coefficient of 3.3 +/- 0.3 m2/g at relative humidity below 80%. However at higher humidity, the nephelometer gave higher scattering results due to water absorbed by ammonium nitrate and ammonium sulfate in the particles. This particle-associated water is not measured by the FDMS TEOM. The FDMS TEOM data could be corrected for this difference using appropriate IMPROVE protocols if the particle composition is known. However a better approach may be to use a particle measurement system that allows for semicontinuous measurements but also measures particle bound water Data are presented from a 2003 study in Rubidoux, CA, showing how this could be accomplished using a Grimm model 1100 aerosol spectrometer or comparable instrument. PMID- 24151676 TI - Characterization of secondary aerosol and its extinction effects on visibility over the Pearl River Delta Region, China. AB - Aerosol samples collected from July 2007 to March 2008 were used to obtain major aerosol constituents in an urban location in the Pearl River Delta Region (PRD), China. The minimum organic carbon (OC)/elemental carbon (EC) ratio was used to calculate the primary and secondary organic carbon and the extinction effect of the secondary aerosol on visibility was estimated. As indicated in the analysis, the mass of secondary aerosol takes up 50% of the total mass of PM2.5; the OC/EC ratio is larger than 2 and there are significant characteristics of secondary aerosol generation; the levels of secondary OC are comparable with those of sulfate; and there is obvious enrichment of secondary aerosol on more polluted days. In a dry environment, the extinction weight is 59% for the secondary aerosol, while it is as high as 82% if the environment is highly humid (relative humidity [RH] = 95%). The hygroscopic growth of the aerosol can reduce visibility greatly; the secondary aerosol shares much larger quotas on more polluted days. For the Pearl River Delta (PRD), secondary aerosol and carbonaceous aerosol, especially secondary organic carbon (SOC), are a very acute problem; the study of the generating mechanism and sources for secondary aerosol is the key to the effort of controlling visibility in this region. The equation set forth in IMPROVE experiments can only be referenced but is not applicable to evaluate the extinction effect of individual aerosol components on visibility in the PRD region. PMID- 24151677 TI - Atmospheric black carbon in PM2.5 in Indonesian cities. AB - Samples of airborne particulate matter were collected at several cities in Indonesia: Bandung, Jakarta, Palangka Raya, Serpong, and Yogyakarta, from January through December 2011. The samples were collected once a week using a Gent stacked filter unit sampler in two size fractions of 2.5 microm (fine, PM2.5) and 2.5 to 10 microm (coarse, PM2.5-10). Black carbon was measured using an EEL smoke stain reflectometer The average of PM2.5 during the sampling period for Bandung, Jakarta, Palangka Raya, Serpong, and Yogyakarta sites was 18.35, 16.50, 7.74, 16.68, and 8.78 microg/m3, respectively. The average of BC for Bandung, Jakarta, Palangka Raya, Serpong and Yogyakarta was 3.05, 3.37, 3.19, 2.51, and 2.20 microg/m3, respectively. The ratio of the 24-hr BC concentration compared to the PM2.5 concentrations showed that BC comprises about 17-45% of the fine particulate matter collected at all sites. The average percentage of BC in PM2.5 concentrations in Bandung, Jakarta, Palangka Raya, Serpong, and Yogyakarta was 18, 22, 45, 17, and 26%, respectively. Bandung and Jakarta compared with Yogyakarta showed higher concentrations of PM2.5 and BC, which indicated pollution occurring in Bandung and Jakarta is more intense than in Yogyakarta, while the maximum of BC concentration and the percentage of BC in PM2.5 in Palangka Raya were 6.04 microg/m3 and 75%, respectively This higher BC concentration than the other cities was due to the forest fires that occurred frequently during the sampling period. The contributions of BC source in these cities were also analyzed to ascertain the local sources of BC. IMPLICATIONS: BC in PM2.5 was monitored over the period of January-December 2011 in several big cities in Indonesia to provide quantitative information on BC concentrations and contributions to PM2.5 and for comparison among these cities and with other Asian countries. This study supports the national air quality monitoring projects. The results of black carbon concentrations in these areas indicate source contributions from local sources such as forest fire, biomass burning, and vehicle emissions. PMID- 24151678 TI - Characterization and source identification of airborne particulate loadings at receptor site-classes of Lagos Mega-City, Nigeria. AB - Size segregated suspended particulate matter (PM2.5 and PM2.5-10) were collected using Gent low-volume air sampler at four different receptor site-classes in Lagos Mega City, Nigeria. The particulate mass loading was quantified and the concentration was analyzed to examine the pattern and variation from one receptor site-class to another. The PM2.5/PM10 ratio varied among the site-classes with the residential and marine sites having the least and highest ratio of 0.31 +/- 0.13 and 0.49 +/- 0.17 respectively. Particulate loading was higher on weekdays than on weekends (by a factor of about 1.5) in all but the marine site-class.The mean PM2.5/PM10 ratio is 0.41 +/- 0.15, which suggests that traffic emission is not the principal source of the Particulate Matter (PM). The INAA assay of the particulates detected ten elements: As, Br, Ce, K, La, Mo, Na, Sb, Sm and Zn. Except for Br, Mo and Sb, the detected elements were more pronounced in the coarse-fractioned filter Principal Component Factor Analysis (PCFA) of the detected elements identified some common sources (traffic-related, traffic emission, sea-salt and industrial emission) for both PM fractions at the four receptor site-classes. PMID- 24151679 TI - Biomass burning contribution to ambient air particulate levels at Navrongo in the Savannah zone of Ghana. AB - The concentrations of airborne particulate matter (PM) in Navrongo, a town in the Sahel Savannah Zone of Ghana, have been measured and the major sources have been identified. This area is prone to frequent particulate pollution episodes due to Harmattan dust and biomass burning, mostly from annual bushfires. The contribution of combustion emissions, particularly from biomass and fossil fuel, to ambient air particulate loadings was assessed. Sampling was conducted from February 2009 to February 2010 in Navrongo. Two Gent samplers were equipped to collect PM10 in two size fractions, coarse (PM10-2.5) and fine (PM2.5). Coarse particles are collected on a coated, 8-microm-pore Nuclepore filter. Fine particle samples were sampled with 47-mm-diameter Nuclepore and quartz filters. Elemental carbon (EC) and organic carbon (OC) concentrations were determined from the quartz filters using thermal optical reflectance (IMPROVE/TOR) methods. Elements were measured on the fine-particle Nuclepore filters using energy dispersive x-ray fluorescence. The average PM2.5 mass concentration obtained at Navrongo was 32.3 microg/m. High carbonaceous concentrations were obtained from November to March, the period of Harmattan dust and severe bush fires. Total carbon was found to contribute approximately 40% of the PM2.5 particulate mass. Positive matrix factorization (PMF) suggested six major sources contributing to the PM2.5 mass. They are two stroke engines, gasoline emissions, soil dust, diesel emissions, biomass burning, and resuspended soil dust. Biomass combustion (16.0%) was identified as second most important source next to soil dust at Navrongo. PMID- 24151680 TI - Identification of haze-creating sources from fine particulate matter in Dhaka aerosol using carbon fractions. AB - Fine particulate matter (PM2.5) samples were simultaneously collected on Teflon and quartz filters between February 2010 and February 2011 at an urban monitoring site (CAMS2) in Dhaka, Bangladesh. The samples were collected using AirMetrics MiniVol samplers. The samples on Teflon filters were analyzed for their elemental composition by PIXE and PESA. Particulate carbon on quartz filters was analyzed using the IMPROVE thermal optical reflectance (TOR) method that divides carbon into four organic carbons (OC), pyrolized organic carbon (OP), and three elemental carbon (EC) fractions. The data were analyzed by positive matrix factorization using the PMF2 program. Initially, only total OC and total EC were included in the analysis and five sources, including road dust, sea salt and Zn, soil dust, motor vehicles, and brick kilns, were obtained. In the second analysis, the eight carbon fractions (OC1, OC2, OC3, OC4, OP, EC1, EC2, EC3) were included in order to ascertain whether additional source information could be extracted from the data. In this case, it is possible to identify more sources than with only total OC and EC. The motor vehicle source was separated into gasoline and diesel emissions and a fugitive Pb source was identified. Brick kilns contribute 7.9 microg/m3 and 6.0 microg/m3 of OC and EC, respectively, to the fine particulate matter based on the two results. From the estimated mass extinction coefficients and the apportioned source contributions, soil dust, brick kiln, diesel, gasoline, and the Pb sources were found to contribute most strongly to visibility degradation, particularly in the winter. PMID- 24151681 TI - Long-term trends and characteristics of visibility in two megacities in southwest China: Chengdu and Chongqing. AB - Visibility is a good indicator of air quality because it reflects the combined influences of atmospheric pollutants and synoptic processes. Trends in visibility and relationships with various factors in Chengdu and Chongqing, two megacities in southwest China, were analyzed using daily data from National Climatic Data Center and the Air Pollution Index (API) of the Ministry of Environmental Protection of China. Average annual visibility during the period of 1973-2010 was 8.1 +/- 3.9 in Chengdu and 6.2 +/- 4.3 km in Chongqing. PM10 dominates the reported primary pollutants in both cities, although concentrations have decreased from a high of 127.9 and 150 microg m3 before 2005 to 100.4 and 93.5 microg m(-3) in Chengdu and Chongqing, respectively. Low average visibility and extremely high levels of PM10 were observed in winter, whereas relative humidity had irregular and weak seasonal variations. Visibility in both cities has deteriorated in comparison to the 1960s and 1970s, mostly due-to the elevation of optical depth caused by anthropogenic pollution. Correlations and principal component analysis (PCA) were undertaken to determine the key factors affecting visibility. Visibility was only moderately correlated with PM10. In Chengdu, visibility displayed weak correlations with various factors, whereas visibility in Chongqing was most strongly related to relative humidity due to the atmospheric particulates in the region containing more hygroscopic components. PCA results further confirmed that high relative humidity and low wind speed increased the occurrence of low visibility events under high PM10 concentrations. Temperature and pressure, as indicators of weather systems, also played important roles in affecting visibility. Mathematical models of visibility prediction indicated that wind speed had the largest coefficients among all meteorological factors, and reductions in PM10 concentration only led to minor improvements in visibility. PMID- 24151682 TI - Field study and source attribution for PM2.5 and PM10 with resulting reduction in concentrations in the neighborhood north of the Houston Ship Channel based on voluntary efforts. AB - When annual average PM2.5 (fine particulate matter sized 2.5 microns and less) data for 2005 became available in April 2006 and the 3-yr average PM2.5 concentration in an area just north of the Houston Ship Channel reached 15.0 microg/m3, the Texas Commission on Environmental Quality (TCEQ) initiated daily collection of quartz fiber as well as Teflon PM2.5 filter samples for chemical speciation analysis. The purpose of the chemical speciation analysis was to use the speciation data, together with meteorological data and hourly TEOM (tapered element oscillating microbalance) PM2.5 mass data, to identify the causes of the high PM2.5 concentrations affecting the monitoring site and the neighborhood. The ultimate purpose was to target emission reduction efforts to sources contributing to the high measured PM2.5 concentrations. After a year of data collection, it was recognized that a specific source, unpaved driveways and loading areas along the Ship Channel and dirt tracked onto Clinton Drive, the main artery running east-west north of the Ship Channel, were the primary cause for the Clinton Drive site's measuring PM2.5 concentrations significantly higher than other sites in Houston. The source characterization and remediation steps that have led to sustained reduced concentrations are described in this paper. PMID- 24151683 TI - Summary and analysis of approaches linking visual range, PM2.5 concentrations, and air quality health impact indices for wildfires. AB - Several U.S. state and tribal agencies and other countries have implemented a methodology developed in the arid intermountain western U.S. where short-term (1- to 3-hr) particulate matter (PM) with aerodynamic diameters less than 2.5 microm (PM2.5) concentrations are estimated from an observed visual range (VR) measurement. This PM2.5 concentration estimate is then linked to a public health warning scale to inform the public about potential health impacts from smoke from wildfire. This methodology is often used where monitoring data do not exist (such as many rural areas). This work summarizes the various approaches, highlights the potential for wildfire smoke impact messaging conflicts at state and international borders, and highlights the need to define consistent short-term health impact category breakpoint categories. Is air quality "unhealthy" when 1- to 3-hr PM2.5 is > or = 139 microg/m3 as specified in the Wildfire Smoke, A Guide for Public Health Officials? Or is air quality unhealthy when 1- to 3-hr PM2.5 is > or = 88.6 microg/m3 as specified in the Montana categorizations? This work then examines the relationship between visual range and PM2.5 concentrations using data from the Interagency Monitoring of PROtected Visual Environments (IMPROVE) program and the IMPROVE extinction coefficient (beta ext) equation to simulate an atmosphere dominated by smoke for sites in the arid intermountain western U.S. and great plains. This was accomplished by rearranging the beta ext equation to solve for organic mass as a function of VR. The results show that PM2.5 and VR are related by PM2.5 = 622 * VR(-0.98) with a correlation of 0.99 and that at low VR values (<10 km) a small change in VR results in a large change in PM2.5 concentrations. The results also show that relative humidity and the presence of hygroscopic pollutants from sources other than fire can change the VR/PM2.5 relationships, especially at PM2.5 concentrations less than approximately 90 microg/m3. PMID- 24151684 TI - Influence of photolysis on multispectral photoacoustic measurement of nitrogen dioxide concentration. AB - Multispectral photoacoustic instruments are commonly used to measure aerosol and nitrogen dioxide (NO2) light absorption coefficients to determine the radiation budget of the atmosphere. Here a new photoacoustic system is developed to explore the effect of photolysis on the measured signal in a multispectral photoacoustic spectrometer In this system, a 405-nm laser is used primarily as light source for photolysis. Additionally, a well-overlapped 532-nm laser, modulated at the resonant frequency of the photoacoustic instrument, is used to probe the NO2 concentration. As a result, the photolysis effect at 405 nm can be observed by the photoacoustic instrument through the 532-nm laser. This work determines an 11% reduction of the photoacoustic signal caused by the photolysis effect for typical conditions, which needs to be taken into account when calibrating multispectral photoacoustic spectrometers with NO2. PMID- 24151685 TI - Estimating surface visibility at Hong Kong from ground-based LIDAR, sun photometer and operational MODIS products. AB - Hong Kong's surface visibility has decreased in recent years due to air pollution from rapid social and economic development in the region. In addition to deteriorating health standards, reduced visibility disrupts routine civil and public operations, most notably transportation and aviation. Regional estimates of visibility solved operationally using available ground and satellite-based estimates of aerosol optical properties and vertical distribution may prove more effective than standard reliance on a few existing surface visibility monitoring stations. Previous studies have demonstrated that such satellite measurements correlate well with near-surface optical properties, despite these sensors do not consider range-resolved information and indirect parameterizations necessary to solve relevant parameters. By expanding such analysis to include vertically resolved aerosol profile information from an autonomous ground-based lidar instrument, this work develops six models for automated assessment of surface visibility. Regional visibility is estimated using co-incident ground-based lidar, sun photometer visibility meter and MODerate-resolution maging Spectroradiometer (MODIS) aerosol optical depth data sets. Using a 355 nm extinction coefficient profile solved from the lidar MODIS AOD (aerosol optical depth) is scaled down to the surface to generate a regional composite depiction of surface visibility. These results demonstrate the potential for applying passive satellite depictions of broad-scale aerosol optical properties together with a ground-based surface lidar and zenith-viewing sun photometer for improving quantitative assessments of visibility in a city such as Hong Kong. PMID- 24151686 TI - APPROVED: 2014 accreditation and certification decision rules. PMID- 24151687 TI - Keeping the balance. Requirements for relative humidity in anesthetizing locations. PMID- 24151688 TI - Joint Commission releases speak up campaign on adult depression. New brochure answers questions and provides education. PMID- 24151689 TI - Dealing with peer-review: what is reasonable and what is not? PMID- 24151690 TI - How does care coordination provided by registered nurses "fit" within the organisational processes and professional relationships in the general practice context? AB - AIM: The aim of this study was to develop understanding about how a registered nurse-provided care coordination model can "fit" within organisational processes and professional relationships in general practice. BACKGROUND: In this project, registered nurses were involved in implementation of registered nurse-provided care coordination, which aimed to improve quality of care and support patients with chronic conditions to maintain their care and manage their lifestyle. METHOD: Focus group interviews were conducted with nurses using a semi-structured interview protocol. Interpretive analysis of interview data was conducted using Normalization Process Theory to structure data analysis and interpretation. RESULTS: Three core themes emerged: (1) pre-requisites for care coordination, (2) the intervention in context, and (3) achieving outcomes. Pre-requisites were adequate funding mechanisms, engaging organisational power-brokers, leadership roles, and utilising and valuing registered nurses' broad skill base. To ensure registered nurse-provided care coordination processes were sustainable and embedded, mentoring and support as well as allocated time were required. Finally, when registered nurse-provided care coordination was supported, positive client outcomes were achievable, and transformation of professional practice and development of advanced nursing roles was possible. CONCLUSION: Registered nurse provided care coordination could "fit" within the context of general practice if it was adequately resourced. However, the heterogeneity of general practice can create an impasse that could be addressed through close attention to shared and agreed understandings. Successful development and implementation of registered nurse roles in care coordination requires attention to educational preparation, support of the individual nurse, and attention to organisational structures, financial implications and team member relationships. PMID- 24151691 TI - Culturally and linguistically diverse general practitioners' utilisation of practice nurses. AB - BACKGROUND: Practice nurses are primarily employed by general practitioners, however little is known about the barriers to practice nurse employment from the perspective of general practitioners (GPs). AIM: This paper seeks to explore solo, culturally and linguistically diverse (CALD) general practitioners' perceptions of the practice nurse role, and to identify the barriers and facilitators of these doctors employing nurses within their practice. METHODS: A descriptive study, using semi-structured interviews, was conducted from July to August 2010. Participants were CALD GPs working as solo practitioners who were members of a Division of General Practice in South Western Sydney. Quantitative data were analysed using descriptive statistics and qualitative data were analysed using thematic analysis. RESULTS: The response rate was 51%, however no demographic differences were identified between responders and non-responders. The majority of participants (73%) agreed that practice nurses could perform vital sign measurements or spirometry. Fewer participants (52-63%) believed practice nurses could perform breast checks, pap smears, or assessment of medication regimes. Perceived barriers to employing a practice nurse included lack of space or equipment, legal implications, lack of a specific job description and language communication issues. Participants identified the need for greater financial rebates, assistance with training practice nurses and assistance with business modelling as facilitators to practice nurse employment. CONCLUSION: The feasibility of practice nurse employment in practices with solo, culturally and linguistically diverse general practitioners remains a challenge that needs further exploration. Employment of practice nurses may be a viable option for younger practitioners who have a desire to work in collaborative multidisciplinary models. PMID- 24151692 TI - Teaching and learning innovations for postgraduate education in nursing. AB - This paper begins with a literature review of blended learning approaches, including the creation of learning spaces in the online environment and the model of community of inquiry and collaborative learning promoted by Garrison and others. This model, comprising of three elements including 'social presence', 'cognitive presence' and 'teaching presence', guides academics in the development and delivery of quality programs designed to enhance each student's experience of their course. The second part of this paper is the application of blended learning for the Deakin University Master of Nursing Practice (Nurse Practitioner), including a range of online independent learning activities, Elluminate Live use (a real time online program) and on-campus contact with students. The application of these flexible and innovative online modalities offered in this course, have been designed to promote quality learning experiences for students around their employment commitments and lifestyle factors. As an off-campus course, the Master of Nursing Practice (Nurse Practitioner) presents as a more flexible option for nurses residing in various parts of Australia. The three core elements of the model of community of inquiry and collaborative learning by Garrison and others have been integrated through online teaching and learning access and face-to-face contact for one day in two trimesters of the academic year. The success of blended learning approaches are underpinned by effective communication and interactions between both academics and students. PMID- 24151693 TI - Effectiveness of video information on coronary angiography patients' outcomes. AB - BACKGROUND: Coronary angiography is a widely used invasive procedure for diagnosis of coronary artery diseases. The patients benefit from information about an invasive diagnostic procedure. OBJECTIVES: The aim of this study was to evaluate the effects of two educational methods (video information vs. verbal information) on the level of satisfaction, comfort, tolerability and on the heart rate and blood pressure of patients undergoing coronary angiography. METHODS: A randomized controlled trial design was employed in this study. 128 patients candidate for coronary angiography were randomly assigned to experimental (n = 64) and control (n = 64) groups. The data were collected from January to April 2009. The experimental group watched an informative video about the procedure of coronary angiography as well as pre- and post-angiography care, while the control group received only routine verbal education by nurses. Heart rate and blood pressure were obtained at baseline and after educational intervention. The levels of comfort, satisfaction, and tolerability were measured after the procedure. Statistical analysis was done using SPSS soft ware (Version, 11.5). RESULTS: The experimental group showed a statistically significant decrease in the heart rate and blood pressure after the educational intervention compared to the control group (P < .001). The patients in the experimental group had significantly higher levels of comfort, satisfaction, and tolerability than the control group (P < .001). CONCLUSIONS: Patients' education using an informative video before coronary angiography can effectively maximize the patients' outcome. The results of this study confirm the usefulness of video information prior to an invasive coronary angiography procedure. PMID- 24151694 TI - Examination of socio-demographics and job satisfaction in Australian registered nurses. AB - BACKGROUND: The results of the few studies found investigating relationships between sociodemographic variables and job satisfaction in nurses are mixed. Nevertheless some evidence exists which indicates that some socio-demographic variables are related to nurses' job satisfaction. Moreover reports indicate that job satisfaction is Linked to the retention of nurses. Relationships between socio-demographics and job satisfaction of Australian nurses are examined in the current study. AIM: To examine relationships between socio-demographic factors and job satisfaction and identify if these factors predicted job satisfaction Levels in Australian nurses. METHODS: A cross sectional survey was conducted of 2000 Australian registered nurses who were at the time members of an industrial and professional organisation. The nurses were randomised and stratified according to gender and were asked to answer questions on a socio-demographic questionnaire developed by the researcher. RESULTS: The majority of respondents showed positive job satisfaction scores. Pearson's correlation coefficients (r) found the covariates age, years of experience and years in current job were all moderately to highly positively correlated with each other (all r > 0.40, p < 0.001), however there were no significant interactions between these covariates and Job Satisfaction. Multivariable analysis found significant positive relationships existed between job satisfaction, specialty area and health sector. CONCLUSIONS: Specialty area and health sector showed significant associations with job satisfaction in nurses. These variables should be considered by governments, nursing, organisational leaders and policy makers when developing future policies and strategies aimed at retention. These variables should be investigated further in relation to nursing job satisfaction. PMID- 24151695 TI - Intervening to improve quality and safety of care for the obese in an orthopaedic unit: a collaborative action-oriented quality improvement project in a Magnet recognised facility. AB - PURPOSE OF STUDY: Our study aimed to identify and address impediments to nursing staff providing safe and quality care for obese patients on the orthopaedic unit of a medium sized medical/surgical acute care Magnet Recognised hospital using a participatory action oriented quality improvement methodology. MAIN FINDINGS: Both registered nurses and assistants-in-nursing indicated that placing a blue 'B' Magnet on the patients' room door as a way of identifying the patient as an obese patient ('B' for bariatric) was the most helpful and practical intervention. This was followed by the intervention of using at least three staff to roll a patient and use of two slide sheets for the larger patients with a BMI greater than 30 or weight greater than 100 kg. PRINCIPAL CONCLUSIONS: Collaborative participatory action-oriented quality improvement methods can engage staff at all levels in positive change to health service delivery in order to enhance the quality and safety of care for both patients and staff. Our project demonstrated that simple but effective interventions in the care of obese patients are readily adopted by staff who have had the opportunity to be involved in their development, implementation and evaluation. PMID- 24151696 TI - Palliative care needs of terminally ill people living alone: a service provider perspective. AB - BACKGROUND: Community-based palliative care services face challenges in meeting the needs of terminally ill clients who live alone without a primary caregiver. Yet, there is a dearth of literature on the perceptions of health service providers (HSPs) regarding the care needs and possible management options to assist this growing group to remain at home. OBJECTIVE: This paper investigated the support needs of people living alone with a terminal illness from a service provider perspective. DESIGN: In depth semi-structured interviews were conducted with nine HSPs from community based services in three Australian states. RESULTS: Four main themes emerged: care challenges, differences in care provision, appropriate approaches to care and essentials for an effective service such as 24 h care, cost-free provision of personal alarm systems, supported and coordinated housekeeping services, funded respite care and financial care packages. HSPs expressed a respect for the autonomy and independence of the clients, yet felt pressured to ensure that safe and attentive care was possible. HSPs recognised the central importance of maintaining the independence and autonomy of palliative care clients living alone. CONCLUSIONS: This study is the first in-depth account of what HSPs perceive they need to effectively look after home alone dying clients. The study provided directions to inform service planning for this growing and challenging population group regarding adequate and timely services that will lead to more complying with the clients' wishes, more care being delivered at home, a reduction in hospitalisations, a better quality of life and a capacity to die at home. PMID- 24151697 TI - Perceptions of clinical safety climate of the multicultural nursing workforce in Saudi Arabia: a cross-sectional survey. AB - PURPOSE: The purpose of this study is to explore the safety climate perceptions of the multicultural nursing workforce, and to investigate the influence of diversity of the multicultural nursing workforce on clinical safety in a large tertiary hospital in Saudi Arabia. BACKGROUND: Working in a multicultural environment is challenging. Each culture has its own unique characteristics and dimensions that shape the language, lifestyle, beliefs, values, customs, traditions, and patterns of behaviour, which expatriate nurses must come to terms with. However, cultural diversity in the health care environment can potentially affect the quality of care and patient safety. METHOD: A mixed-method case study (survey, interview and document analysis) was employed. A primary study phase entailed the administration of the Safety Climate Survey (SCS). A population sampling strategy was used and 319 nurses participated, yielding a 76.8% response rate. Descriptive and inferential statistics (Kruskal-Wallis test) were used to analyse survey data. RESULTS: The data revealed the nurses' perceptions of the clinical safety climate in this multicultural environment was unsafe, with a mean score of 3.9 out of 5. No significant difference was found between the age groups, years of nursing experience and their perceptions of the safety climate in this context. A significant difference was observed between the national background categories of nurses and perceptions of safety climate. CONCLUSION: Cultural diversity within the nursing workforce could have a significant influence on perceptions of clinical safety. These findings have the potential to inform policy and practice related to cultural diversity in Saudi Arabia. PMID- 24151698 TI - How nurses cope with occupational stress outside their workplaces. AB - Nursing is acknowledged as a stressful occupation, and the negative impact of high stress levels have been widely researched. Less attention has been paid to methods for coping with stress. The researchers conducted a study to explore and identify how nurses cope with work-related stress away from their work environments. Six focus groups were conducted with 38 nurses, including nursing directors, nurse unit managers, and ward nurses from a wide range of clinical areas. From the interview material, 11 coping strategies were identified: drinking alcohol, smoking, using the staff social club, using social networking websites, exercising, family activities, home-based activities, outdoor activities, avoiding people, displacement, and sleep. Although several adaptive strategies appear in this list (e.g., exercising, home-based activities), some nurses were using unhealthy behaviours to cope with work-related stress (e.g., drinking alcohol, smoking, displacement). This study clearly demonstrates the value of using qualitative approaches to understanding how nurses cope with stress. Knowledge produced locally, such as that generated for the hospital in this study, should serve as the foundation for organisational strategies to enhance the health of nurses. PMID- 24151699 TI - Complementary health therapies: moving towards an integrated health model. PMID- 24151700 TI - Complementary health therapies: moving towards an integrated health model. PMID- 24151701 TI - BJN beats austerity fatigue. PMID- 24151702 TI - Care closer to home: the role of district nurses. PMID- 24151703 TI - Anxiety and depression in care homes in Malta and Australia: Part 1. AB - This cross-sectional comparative study, conducted in two phases, assessed the levels of and factors contributing towards anxiety and depression in older people in residential homes in Malta and Australia. A mixed-method approach was adopted and the cognitive theory of stress and coping (Lazarus and Folkman, 1984) guided the study. Maltese residents were recruited from four church-run homes in Malta and Australia and two state residences in Malta. Response rates were high, with phase 1 at 94.48% (n = 137; mean age = 72.8 years) and phase 2 at 89.4%, (n = 42, mean age = 71.9 years). All the residents were mobile, were Roman Catholics and had lived in the homes for at least 6 months. In phase 1, quantitative data was collected using a demographic questionnaire and the hospital anxiety and depression scale. Normal ranges of anxiety and depression were found (anxiety: mean = 3.53-4.35; depression: mean = 2.67-4.72). No significant differences were found in anxiety and depression between countries, demographic characteristics and some other variables. The only significant difference lay in depression by mobility (F = 5.263; P = 0.006; df = 2), with wheelchair users scoring the highest mean (mean = 6.77; SD = 5.847; P = 0.007). Mobility was linked to functional abilities, which appeared to control anxiety and depression. Recommendations are made for rehabilitation and cross-cultural longitudinal research to investigate other influencing variables such as spirituality and caring relationships. PMID- 24151704 TI - Does honey have place in stoma care. PMID- 24151705 TI - Medication adherence in Parkinson's. AB - Parkinson's is a complex degenerative disease which affects both motor and non motor function and as such requires regular reassessment and collaboration between the patient and the healthcare team to achieve optimal outcomes. Complex medication regimes are often prescribed to manage symptoms; however, issues such as compliance, adherence and concordance need to be considered. The Parkinson's Nurse Specialist plays a central role in understanding patient needs and ability to manage medication regimes. The nurse has a fundamental function in achieving optimal medication adherence throughout the disease trajectory. PMID- 24151706 TI - The benefits of disposable surgical equipment. PMID- 24151707 TI - Supporting adherence and improving quality of life in haemophilia care. PMID- 24151708 TI - Enhancing adolescent care. PMID- 24151709 TI - OPSITE Flexifix Gentle: preventing breakdown in vulnerable skin. AB - For decades, the intact skin of patients has been at risk of damage from exposure to pressure or friction from devices used to support their treatment while in hospital. Device-related skin injury is a common cause of skin breakdown in the acute hospital environment. The use of clinical devices exposes patients to repetitive friction and light pressure that, if not recognised early, can lead to skin breakdown. Compounding this challenge of protecting skin is the use of adhesive tape that can cause skin stripping. A new dressing product called OPSITE Flexifix Gentle (OFG) is now available on the market. This product may support friction relief in these critical areas and prevent skin stripping and pressure ulcer formation while maintaining moisture balance and a healthy skin environment. This product focus outlines the clinical benefits from this silicone based film roll. The performance of the product on a 34-bed cardiothoracic intensive care unit will be reviewed through three case studies. PMID- 24151710 TI - Self-management in chronic oedema. AB - The number of people living with long-term conditions in the UK is increasing. This is putting an immense strain on already stretched health and social care resources. Government strategies are aimed at encouraging and supporting self management of these conditions. Self-management of chronic oedema has always been a key aspect of care planning for this patient group. This article focuses on how nurses can encourage and support self-management in chronic oedema. PMID- 24151711 TI - RCN issues red alert to the nursing profession. PMID- 24151712 TI - Nurses must be more confident in assessing Gillick competence. AB - The recent measles outbreak in south west Wales saw mass immunisation of children who had not received both doses of the measles, mumps and rubella (MMR) vaccine. The most difficult target group to immunise proved to be children in the 14-17 year age group, due in primarily to the reliance on parental consent for the immunisation instead of the child's consent under the rule in Gillick. For future mass immunisation programmes with this age group to be successful, nurses must be more confident in assessing Gillick competence and allow the child to consent to the vaccination. In this article the author considers the requirements for Gillick competence and highlights the factors nurses must consider when determining whether a child is competent to give consent to treatment. PMID- 24151713 TI - The use of the Mental Capacity Act Deprivation of Liberty Safeguards. PMID- 24151714 TI - Advancing practice: from staff nurse to nurse consultant. Part 12: Series summary. PMID- 24151715 TI - Developing the recognition and response skills of student nurses. AB - Acute deteriorations in health occur in all healthcare settings. Every health professional must therefore have the knowledge and skills to recognise and respond effectively to acute illness, in order to avert further deterioration. It is widely acknowledged that a robust understanding of physiological observations, in addition to effective interpretation and clinical decision-making skills, is required for this task (Odell et al, 2009; Steen, 2010). A significant amount of work has been undertaken in one higher education institution (HEI) to ensure that theoretical preparation adequately equips nurses for this aspect of their role. However, it would appear from this evaluative study that some barriers may exist that prevent this essential theoretical knowledge from being embedded into clinical practice. This gap in transformational knowledge is important to highlight as there is an increasingly urgent need for these skills if acutely ill patients are to be successfully rescued (The National Confidential Enquiry into Patient Outcome and Death (NCEPOD), 2005; 2009; 2012; National Institute for Health and Care Excellence (NICE), 2007 Department of Health (DH), 2009). The dissolution of barriers that prevent the development of effective recognition and response skills is an important task for all those involved in acute care education, in both HEI and clinical settings. PMID- 24151716 TI - Industry and clinician: collaboration is key. PMID- 24151717 TI - Pressure ulcer prevention: making a difference across a health authority? AB - Pressure ulcers (PUs), their cause and prevention have been discussed in the literature for many decades. Their prevention and management has been the core of a tissue viability nurse's daily clinical and strategic workload. The important point to acknowledge is that not all PUs can be prevented but it is believed most of them can and all preventative measures must be implemented and evaluated. Initial efforts focused on establishing a baseline of incidence and prevalence. More recently, the Department of Health has proposed that PUs could be eliminated in 95% of all NHS patients and incentivised the measurement of PUs and other harms by use of the NHS Safety Thermometer through the introduction of a new initiative. A research company was commissioned to explore which communications interventions would be effective in helping health professionals to prevent and treat PUs. A campaign was subsequently set in motion to educate and inform clinical staff on the cause and prevention of PUs. PMID- 24151718 TI - Antimicrobial dressings: the three As. PMID- 24151719 TI - Ankle brachial pressure index of normal, healthy, younger adults. AB - Doppler ultrasound and ankle brachial pressure index (ABPI) calculations are used in the assessment of lower limb vascularity, specifically to determine arterial deficiency. ABPI is important as it is used as an indicator when deciding management options for the treatment of leg ulceration. This study aimed to investigate the range of ABPI measurement, using Doppler ultrasound and sphygmomanometry in 36 young healthy adults aged 18-55 years. The findings show a mean ABPI in the left leg of 1.19 and a mean ABPI of 1.17 in the right leg which, while within the normal range, are consistently in the upper range and significantly higher than the acknowledged 'normal' midpoint of 1.0. It would appear that younger people will have ABPIs within the upper aspect of the normal range and well above the established norm of 1.0. PMID- 24151720 TI - Irene Anderson. PMID- 24151721 TI - Chronic wounds: management of healing and wellbeing. AB - This article discusses the impact of living with a chronic wound including the individual's wellbeing and the need for clinicians to consider the complex and often challenging factors that can help or hinder the patient experience. Patient engagement in the care planning process is an important consideration in promoting concordance (Gray et al, 2011). When choosing a dressing regimen, clinical decision-making should be based on holistic assessment and include the patient's perspective, expectations and attitudes (Dowsett, 2008). Living with a chronic wound can have a significant impact on both the physical and psychological health of an individual and patients may suffer from multiple effects including reduced mobility, pain, poor nutrition and depression. Management plans that have been informed by patient feedback and are sensitive to their concerns can only serve to promote concordance and partnership and achieve a positive experience even when healing is not the endpoint. PMID- 24151722 TI - Reducing pressure damage: care bundles and collaborative learning. AB - Reduction of hospital-acquired pressure ulcers is a patient and nursing priority. Although evidence-based interventions to prevent such ulcers are well known, reducing this healthcare burden has proven consistently difficult. Via case studies, this article describes how a bundle approach to pressure ulcer prevention may be adapted for use within different clinical areas. It illustrates how collaborative learning may facilitate the spread of improvement work across a health board and build improvement skills within nursing. PMID- 24151723 TI - Can you be bothered? PMID- 24151724 TI - Are you "into" your patients? PMID- 24151725 TI - Focus on: Removable prosthodontics. PMID- 24151726 TI - Celebrating 30 years of service to the profession. Interview by Damon Adams. PMID- 24151727 TI - Confronting controversial issues in dental implant therapy, part 2. PMID- 24151728 TI - Small-diameter implant placement: a case report. PMID- 24151729 TI - Duplicating the posterior extension of an existing denture. PMID- 24151730 TI - Six ways to improve a patient's health and your profits. PMID- 24151731 TI - Endodontic predictability: "what matters"? PMID- 24151732 TI - Sealing endodontic access cavities. PMID- 24151733 TI - Use of high translucency zirconia in the aesthetic zone. PMID- 24151734 TI - Role for CAD/CAM in forensics? PMID- 24151735 TI - Far, far away land: palliative care as a human right. PMID- 24151736 TI - The 2013 EAPC World Congress. PMID- 24151737 TI - Constipation in palliative care: treatment options and considerations for individual patient management. AB - Constipation is an all too common symptom in palliative care patients and may be associated with a range of severe issues and experiences. Its effects on patients contribute to both physical and psychological scarring during a very distressing stage of life not only for the patient but also for their caregivers. It is during this time that, too often, the complexity of managing the condition moves the locus of control away from the patient toward the health professionals. This article considers a number of different treatment options and facets of individual management that may enable patients to move the locus of control back to a position of joint management by patients, caregivers, and health professionals. PMID- 24151738 TI - The media critique of the Liverpool Care Pathway: some implications for nursing education. AB - End-of-life care pathways are championed around the globe as tools that might be used to enhance the quality of care at the very end of a person's life. This paper examines recent negative media discourse in the UK about the Liverpool Care Pathway for the Dying Patient (LCP). This media coverage may have had damaging effects, but it has also served to highlight inappropriate and even suboptimal end-of-life care. While recognising the pervading influence of organisational structures and cultures, some implications for initial and ongoing education of nurses are identified. PMID- 24151739 TI - The perspectives of bereaved family members on their experiences of support in palliative care. AB - AIM: To explore family members' supportive interactions in palliative care and the emotional experiences that they associate with these interactions. METHODS: Qualitative individual interviews were performed with bereaved family members recruited from an urban palliative care service in Sweden. The interviews were analysed using inductive qualitative content analysis. RESULTS: Five categories of supportive interactions with staff members were linked with emotional consequences: informational support, supportive encounters, professional focus of staff, a supportive environment, and bereavement support. Having a dialogue with family members nurtured certainty and security, supportive encounters gave a warm and comforting feeling, and bereavement support contributed to feelings of strength. Environmental factors contributed to dignity. CONCLUSION: Supportive interactions with staff and within a home-like environment help to build resilience if tailored to the family member's own needs. PMID- 24151740 TI - Evaluating a self-directed palliative care learning package for rural aged care workers: a pilot study. AB - AIM: To evaluate the effectiveness of a self-directed learning package in increasing palliative care knowledge and confidence for aged care workers in Rural New South Wales, Australia. METHOD: Participants piloted a palliative care self-directed learning package and completed pre- and post-package knowledge and confidence questionnaires with a 6-month follow-up. The data was then analysed via paired two-tailed T-tests. RESULTS: There was a statistically significant mean increase in knowledge and confidence after completion of the self-directed learning package. Knowledge but not confidence increases were retained after 6 months. CONCLUSION: Self-directed learning packages can play a part in increasing knowledge and confidence in palliative care for rural aged care workers. Questions remain regarding the role of ongoing support, education, and mentoring. PMID- 24151741 TI - Developing evidence-informed decision making in a hospice: an evaluation of organisational readiness. AB - INTRODUCTION: Multiprofessional home care and hospice teams should play a part in evidence-informed decision making. AIMS: To assess organisational readiness to adopt evidence-informed decision making in a hospice in England. DESIGN: A mixed methods approach was used. Clinical staff were surveyed regarding their attitudes to and skills in using evidence, and senior managers completed an organisation based self-assessment tool recording the readiness of the organisation to embrace an evidence-informed focus. RESULTS: 81% of the staff completed the survey. Staff were committed to the principles of evidence-informed decision making, but overall lacked the necessary knowledge and skills. Information obtained from the management self-assessment highlighted that a priority was to develop an evidence informed decision-making culture focusing on education, training, and policy development. CONCLUSION: The process used in this evaluation may be applicable to other areas of health care when assessing an organisation's readiness to incorporate evidence-informed decision making into policy and procedure. PMID- 24151742 TI - Using action research to investigate and improve hospice staff participation in workplace education. AB - Finding ways to make good quality education available to all staff in an expanding and increasingly busy hospice organisation is a real challenge. Constantly providing learning opportunities that are then poorly attended owing to the pressure of work is equally disappointing, and leads to questions of cost effectiveness. An action research project was undertaken to investigate the reasons for low attendance rates at learning events in one hospice. Having identified time and conflict with patient need as major issues, a second cycle of research using literature review and a survey methodology was conducted to find a contemporary and innovative solution to this problem in an attempt to establish a vibrant learning culture. As a result a virtual learning environment--ORACLE (Online Research and Care Learning Environment)--was created to augment the face to-face sessions and provide staff with access to appropriate learning materials 24 hours per day, 365 days per year.Although unique to this organisation, ORACLE has potential application to any other work environment. PMID- 24151743 TI - Surgical treatment of advanced ovarian cancer. AB - BACKGROUND: The classical treatment for advanced ovarian cancer (OC) consists of a optimal cytoreductive surgery (when the postoperative residual tumor is under 1 cm.), followed by adjuvant chemotherapy based on platinum or paclitaxel derivatives. The 5-year survival rate in case of advanced OC with secondary peritoneal carcinomatosis (PC) is below 25%. The treatment of PC (interpreted as a local-regional disease and not as a systemic disease) is based on an aggressive surgical act (a full or maximal cytoreduction without residual tumor), followed by local chemotherapy or hypertermic intraperitoneal chemotherapy. This is a retrospective study which reassesses the surgical treatment of advanced OC within the period January 2004 - December 2010 in the Center of General Surgery and Liver Transplantation within Fundeni Institute. METHODS: In the period January 2004 - December 2010 in the Center of General Surgery and Liver Transplantation within Fundeni Institute were operated 405 patients with advanced ovarian cancer. In 105 patients (25.9%) intraperitoneal chemotherapy with Cisplatin was performed. RESULTS: Overal survival was calculated for a subsample of 297 patients, for whom it was possible to properly ensure the follow-up, being of 43 months in the patients with intraperitoneal chemotherapy (p = 0.02) and 37 months in the patients without intraperitoneal chemotherapy. CONCLUSIONS: The maximal cytoreduction associating IPCH is an aggressive multidisciplinary therapeutic approach in advanced OC, reserved for difficult cases, considered in the past without solution. In properly selected cases, this shows a clear increase in survival rate. PMID- 24151744 TI - Selective or radical surgical strategy in functional autonomy of the thyroid in endemic areas. AB - BACKGROUND: The purpose of the research is to compare two surgical methods in the treatment of functional autonomy of the thyroid regarding postsurgical complications and functional results. METHODS: 212 patients were examined- divided into two groups. Group 1 (n = 148)--in which selective thyroid resection have been done and Group 2 (n = 64)--in which radical resection have been undertaken. RESULTS: For both groups the following postoperative complications have been determined: In 4 (1.8%) patients transitory recurrent palsy is determined and in 1 (0.5%) patient-permanent recurrent palsy. The frequency of the transitory hypoparathyroidism is 7.5% (n = 16) and that of the permanent hypoparathyroidism is 0%. 148 patients from the two groups were followed up with respect to the functional results obtained at the eight postsurgical week and from 1 to 7 years after the operation. In the selective group (eight postsurgical week) 3 from the patients were with hyperthyroidism and 4 with hypothyroidism. From 1 to 7 years after the operation the following functional results have been determinated: in 7 patients relapse of the hyperthyroidism, in 8 patients new hypothyroidism and in 3 patients- morphological recurrence In radically operated patients the frequency of the postsurgical hypothyroidism during the 8 postsurgical week was 50% (n = 26). For the period from 1 to 7 years after the operation the following functional results were observed: 1 patient with relapse of hypothyroidism, 11 patients with new hypothyroidism. Not one morphological recurrence was observed. CONCLUSIONS: The residual and recurrent hyperthyroidism are related to the insufficient extent of resection. A functionally confirmed surgical strategy has been imposed in the endemic areas striving to remove all nodular structures at the same preserving the normal thyroid tissue. PMID- 24151745 TI - Video-assisted thyroid resections in the treatment of papillary thyroid carcinoma. AB - One of the challenges of the minimally invasive video-assisted thyroid resections is their application for the surgical treatment of papillary thyroid carcinoma. AIM: To present our experience with the use of video-assisted thyroid resections with harmonic scalpel in the surgical treatment of patients with papillary thyroid carcinoma. MATERIAL AND METHODS: 259 patients with thyroid nodules were operated in our Clinic for a five-year period--from 2008 to 2013--via a video assisted technique. Thyroid carcinoma was found in 53 patients (46 female patients and seven male patients, aged 18 to 52 years). The patients were selected according to the established criteria, developed and adopted in our Clinic. The resection was performed using endoscopic harmonic scalpel (Ultracision CS-14C; produced by Ethicon Endo-Surgery Care). The surgical incision length, extent of surgery, duration of operative time, type and incidence of complications (intraoperative and postoperative), period of hospital stay, and safety and radicality of the surgical procedure were examined. RESULTS: The length of the surgical incision was from 1.5 to 2.5 cm in all operated patients. The tumor size varied from 0.5 to 2.0 cm. Papillary carcinoma was found in 42 patients and follicular variant of papillary thyroid carcinoma--in eleven patients. Minimally invasive video-assisted thyroidectomy (MIVAT), using harmonic scalpel and 5 mm optics, was performed in 42 patients and video-assisted lobectomy with near-total resection of the contralateral lobe was performed in the remaining eleven patients. Lymph node micrometastases in the central cervical compartment were found in four patients. Draining of thyroid gland bed was performed in three patients. Transient hypocalcemia was found in one patient. All patients were discharged within the first 24 postoperative hours. CONCLUSION: Our results confirm that, if the criteria for selection of patients are followed, the video-assisted thyroid resections with harmonic scalpel have a place in the surgical treatment of selected patients with papillary thyroid carcinoma. PMID- 24151746 TI - Planning augmentation mammaplasty of breast asymmetries. AB - The article presents a modern approach to planning augmentation mammoplasty of breast asymmetries. The preoperative planning includes anthropomorphic measurements to assess the breast anatomy; selection of suitable implants based on mathematical calculations; choice of operative technique that best suits the individual characteristics of the patient. Preoperative planning was done in 220 cases of women with breast asymmetries requesting augmentation mammoplasty during the period 2000-2011. Augmentation alone, augmentation with simultaneous mastopexy, and augmentation with reconstruction of the breast base are performed. The postoperative results obtained shape, volume and symmetry, are monitored during regular postoperative examinations. The significance of preoperative planning in augmentation mammoplasty of breast asymmetries is discussed. PMID- 24151747 TI - Pain affecting procedures in non-resectable pancreatic carcinoma. AB - Pancreatic cancer is third most common cancer of the gastrointestinal tract in Bulgaria, accouting for 11, 6% in 2008. The leading symptom in patients with pancreatic cancer is the pain. The pain can be related with neoplasms and their metastasis. We should use all kind of resourses for pain relief: conventional drugs (according to the three steps strategy of WHO), interventional or surgical procedures. AIM: To present the interventional and surgical techniques in our practice and to share our experience for pain control in patients with nonresectable pancreatic cancer to improve their quality of life. MATERIAL: In a seven year period (2004-2011) we performed 59 thoracoscopic splanhnicectomies/30- bilateral/ 4 intraoperative resections of celiac ganglion, 25 CT--control celiac plexus neurolysis and 90 cases pain relief with epidural analgesia. Concerning the quality of life we applied a questionnaire of a spannish medical center " City of Hope" adapted for patients with cancer and the level of pain with visual analogue scale VAS. RESULTS: The long-term duration of the pain relief technique depends on applied technic, of cancer invasion and of the technic itself. The technique with the longest effect are the intraoperative celiac ganglion removal and the bilateral thoracoscopic splanhnicectomy. On the other hand the shortest effect we report the celiac plexus neurolysis, and the epudural analgesia. These data are in correlation with the reduction of the pain shown using VAS thus improving the quality of life. CONCLUSIONS: The surgical and interventional methods for control of cancer pain have their own collocation improving the quality of life of these patients. New strategies for the pain control are need in the future. PMID- 24151748 TI - Surgical treatment of symptomatic and ruptured abdominal aortic aneurysms. AB - Despite the increased volume of patients undergoing selective reconstruction on the occasion of abdominal aortic aneurysms (AAA) in the last decades, the number of patients with rupture of abdominal aortic aneurysms (RAAA) is not significantly decreased. RAAA is catastrophic and life-threatening condition. It remains a challenge to every practitioner. To optimize the surgical practice we studied the literature for the treatment of symptomatic and rupture aneurysm of the abdominal aorta. PMID- 24151749 TI - En bloc laparoscopic sigmoidectomy, left adnexectomy, small bowel loop and piece of urinary bladder resection for advanced sigmoid tumor. AB - The laparoscopic surgery of colon increasingly replaces the conventional surgery of colon on a global and regional scale. Many randomized studies demonstrate the advantages with regard to the shorter postoperative hospital stay, faster recovery, and identical results of the indexes of survival and frequency of relapses. The en bloc resection in cases of locally advanced colon cancer is the most secure method for achieving of R0 resection . The growth of the tumoral mass towards the adjacent structures manifests with histological tumor invasion in approximately 50% of the cases. The cases of laparoscopic en bloc resection for the treatment of colorectal cancer, which are described in the literature, increase. In this report we present a clinical case of substenotic sigmoid colon cancer and perioperative finding of infiltration towards a small intestinal loop and part of the urinary bladder, as well as towards the left uterine tube and the left adnex. In the case of this patient laparoscopic en bloc resection of the tumor formation was performed according to the so called "laparoscopic no touch technique". Approximately 15-20% of the cases of colorectal cancer are still in T4 stage, with involvement of the adjacent organs (1), despite the advance of the examination methods. CLINICAL CASE: A 67 year old female was admitted to the hospital for a substenotic sigmoid colon lesion, syndrome of anemia, resulted adenocarcinoma at colonoscopy. Endoscopy showed an endoluminal tumor at 25 cm from the anal margin and preoperative work-up did not evidence any secondary lesions or invasion of other organs. METHODS: Four abdominal trocars were placed. The laparoscopic exploration of the abdominal cavity showed the presence of a colic mass with suspected invasion of a small bowel loop and part of the urinary bladder, the left uterine tube, and the left ovary. The tumor formation was dissected en bloc with resection of the left uterine tube and ovary, the urinary bladder, and a small bowel loop. Colorectal anastomosis with laparoscopic manual technique was performed. The anastomosis was tested for leak-tightness. The specimen was removed by enlargenemt of the 5 mm. suprapubic trocar. RESULTS: The mean operative time was 285 minutes with blood loss of 300 ml. Patient was discharged on Postoperative Day 5. The histological result verified tumoral invasion towards the urinary bladder, the small bowel, and the ovary. The final staging according to the TNM classification is pT4N0Mx. CONCLUSION: The en bloc laparoscopic resection for the treatment of sigmoid colon cancer, engaging the adjacent organs, is indicated and feasible, with surgical results, comparable with a conventional surgical intervention at the same volume. PMID- 24151750 TI - Embolization of anomalous vessels in tumor formation. AB - Embolotherapy or embolization has rapidly developed in recent years and now represents an integral part of interventional radiology practice. Embolotherapy is defined as the percutaneous endovascular application of one or more of a variety of agents or materials to accomplish vascular occlusion. Embolization has grown dramatically in scope and complexity over the past three decades, and with this growth, there is now a need to define standards for those practicing in this field, including: appropriate training with monitoring of outcomes; provision of pre-, intra-, and postprocedure patient care; and performance of the technical aspects of the procedure. We present 58 patients from clinic of Vascular Surgery and Angiology at "St. Ekaterina" University Hospital. After four abnormal nutrition artery embolization in two consecutive procedure due to recurrences formation of adrenal tumor. PMID- 24151751 TI - Health-related quality of life following isolated aortic valve surgery: is earlier intervention better? AB - BACKGROUND AND AIM OF THE STUDY: The study aim was to determine the health related quality of life (HRQL) in conjunction with clinical outcomes following aortic valve replacement (AVR) surgery. In these times of healthcare change, quality measures of the success of a procedure go beyond clinical outcomes, with patient reports of HRQL considered important. METHODS: All patients who had undergone AVR surgery were followed prospectively through the authors' valve registry and the local Society of Thoracic Surgery (STS) database. The HRQL (Short-Form 12 and Minnesota Living with Heart Failure Questionnaire) was collected preoperatively, and at six and 12 months after surgery. RESULTS: Since 2005, a total of 459 patients have undergone isolated AVR surgery. The mean age, ejection fraction and STS risk score were 65.8 +/- 13.6 years, 57.7 +/- 11.0%, and 2.8 +/- 3.5 (range: 0.4-47.9), respectively. The median (IQR) length of hospital stay was 5 (3-7) days. Compared to the STS national norms, all clinical outcomes were excellent. A Kaplan-Meier analysis showed the two year cumulative survival as 92.0%. After 12 months the physical and mental HRQL had improved significantly, surpassing age and heart disease norms (p < 0.001 and p = 0.02, respectively). Multivariate analysis determined that a higher 12-month physical HRQL was predicted by a lower STS risk score (B = -1.3, p < 0.001) and a lower perioperative morbidity (B = -5.5, p = 0.02) after adjustment for baseline HRQL, age, and gender. In a subset of patients classified as 'symptomatic', as determined by higher MLHF scores, the HRQL scores were increased to age norms and surpassed the heart disease norms. CONCLUSION: Patients who undergo AVR can expect excellent clinical and HRQL outcomes, with greater benefits the earlier the surgery is carried out. The tracking of HRQL is valuable in understanding the success of a procedure from the patients' perspective. PMID- 24151752 TI - Prevention and management of potential adverse events during transapical aortic valve replacement. AB - BACKGROUND AND AIM OF THE STUDY: Transapical transcatheter aortic valve replacement (TAVR) is a new minimally invasive technique with a known risk of unexpected intra-procedural complications. Nevertheless, the clinical results are good and the limited amount of procedural adverse events confirms the usefulness of a synergistic surgical/anesthesiological management in case of unexpected emergencies. METHODS: A review was made of the authors' four-year database and other available literature to identify major and minor intra-procedural complications occurring during transapical TAVR procedures. All implants were performed under general anesthesia with a balloon-expandable Edwards Sapien stent valve, and followed international guidelines on indications and techniques. RESULTS: Procedural success rates ranged between 94% and 100%. Life-threatening apical bleeding occurred very rarely (0-5%), and its incidence decreased after the first series of implants. Stent-valve embolization was also rare, with a global incidence ranging from 0-2%, with evidence of improvement after the learning curve. Rates of valve malpositioning ranged from 0% to < 3%, whereas the risk of coronary obstruction ranged from 0% to 3.5%. Aortic root rupture and dissection were dramatic events reported in 0-2% of transapical cases. Stent valve malfunction was rarely reported (1-2%), whereas the valve-in-valve bailout procedure for malpositioning, malfunctioning or severe paravalvular leak was reported in about 1.0-3.5% of cases. Sudden hemodynamic management and bailout procedures such as valve-in-valve rescue or cannulation for cardiopulmonary bypass were more effective when planned during the preoperative phase. CONCLUSION: Despite attempts to avoid pitfalls, complications during transapical aortic valve procedures still occur. Preoperative strategic planning, including hemodynamic status management, alternative cannulation sites and bailout procedures, are highly recommended, particularly during the learning curve of this technique. PMID- 24151753 TI - Clinical factors associated with classical symptoms of aortic valve stenosis. AB - BACKGROUND AND AIM OF THE STUDY: The recognition of clinical symptoms is critical to a therapeutic strategy for aortic valve stenosis (AS). It was hypothesized that AS symptoms might have multiple causes; hence, a study was conducted to investigate the factors that separately influence the classic symptoms of dyspnea, angina and syncope in AS. METHODS: The medical records of 170 consecutive patients with AS (> or = moderate grade) were reviewed. A multivariate logistic regression analysis was used to evaluate the hemodynamic and clinical factors that separately influence the development of three clinical symptoms: dyspnea (defined as NYHA class > or = 2), angina, and syncope. RESULTS: The most common symptom was dyspnea (47.1%), followed by angina (12.4%) and syncope (4.7%). The factors associated with dyspnea were a higher e' ratio (p = 0.04) and peak aortic valve velocity (p = 0.01). Only the severity of AS was associated with syncope. The presence of hypertension was associated with angina (p = 0.04). Moreover, coronary angiography was performed in 59 patients before aortic valve replacement and revealed coronary stenosis (> 50% diameter stenosis) in 11/16 patients (69%) that had angina. The presence of coronary stenosis was significantly associated with angina (p = 0.02). The development of dyspnea, angina or syncope was influenced by different factors in AS. CONCLUSION: Dyspnea and syncope were mainly associated with AS severity, and diastolic dysfunction also influenced dyspnea. In contrast, angina was mainly related to the presence of coronary stenosis rather than to AS severity. These factors should be considered when, selecting a therapeutic strategy for AS patients in the modern era. PMID- 24151754 TI - Upper 'J' ministernotomy versus full sternotomy: an easier approach for aortic valve reoperation. AB - BACKGROUND AND AIM OF THE STUDY: Aortic valve replacement (AVR) after previous cardiac surgery is usually associated with an increased risk profile. The study aim was to compare the outcome after AVR through an upper 'J' ministernotomy compared to a standard full sternotomy approach in a redo operation. METHODS: A total of 90 patients who underwent reoperative AVR at the authors' institution between October 2007 and January 2012 was retrospectively reviewed. Of these patients, 46 had patent bypass grafts and 44 previously had heart valve replacement or repair. Sixteen patients had endocarditis as the etiology, and 14 had prosthetic valve endocarditis. Of the 90 patients operated on, a minimally invasive upper 'J' ministernotomy was performed in 38, and a full median sternotomy in 52. The median age was 76 years (25th percentile 68.25 years; 75th percentile 79.25 years) for the minimally invasive group, and 73.5 (25th percentile 68 years; 75th percentile 78.75 years) for the full sternotomy group (p = 0.945). No statistically significant differences in terms of body mass index (p = 0.987), left ventricular ejection fraction (p = 0.544) and EuroSCORE (p = 0.162) were found between the two groups. Intraoperative data and postoperative outcomes, in terms of intensive care unit stay, blood loss, transfusions and sternal complications were analyzed. RESULTS: All patients underwent AVR. The median (IQR) cardiopulmonary bypass and cross-clamp times were respectively 67 (28) min and 51 (28) min for the minimally invasive group, and 72 (47) min and 53.5 (28) min for the full sternotomy group (p = 0.686 and p = 0.993). The postoperative ventilation time was significantly less in ministernotomy patients (median 6 versus 8.5 h; p = 0.027). One patient affected by endocarditis died in the minimally invasive group (mortality rate 2.6%). Hospital mortality in the traditional group was 3/52 (5.8%). CONCLUSION: Minimally invasive aortic valve surgery reoperation through an upper 'J' sternotomy proved to be at least as safe as the standard procedure in terms of hospital morbidity and mortality rates. PMID- 24151755 TI - Logistic EuroSCORE I risk analysis in aortic valve reoperations after bioprosthetic replacement. AB - BACKGROUND AND AIM OF THE STUDY: The aim was to evaluate the early and long-term results of redo-aortic valve replacement (AVR) for dysfunctioning bioprostheses, according to the type of bioprosthesis failure. The performance of the EuroSCORE in predicting operative mortality was addressed. METHODS: A retrospective analysis was performed of 164 patients who had undergone redo-AVR at the authors' institution. All data were collected prospectively. The type of bioprosthesis failure was categorized as either structural valve dysfunction (SVD), non structural vale dysfunction (NSVD), or infective endocarditis (IE). The logistic EuroSCORE I was obtained, and a formal analysis of its predictive performance was conducted. RESULTS: The mean logistic EuroSCORE was 26.3 +/- 20.6%, while the observed operative mortality was 10.6%. The EuroSCORE overestimated mortality in all subgroups of indication; operative mortality was higher among the NSVD (14.7%) and IE (13.9%) groups, and lower among SVD patients (8.5%). The performance of the EuroSCORE in predicting mortality was better in SVD patients, and worse in NSVD patients (areas under the ROC curve of 0.857 and 0.751, respectively). Only patient-related factors independently predicted the operative mortality (logistic regression). The SVD patients displayed a significantly better long-term survival compared to NSVD and IE patients. Patient-related factors were seen to be the determinants of long-term survival. CONCLUSION: Redo AVR can be performed with good early and long-term results, despite a high predicted risk. The logistic EuroSCORE I globally overestimates the risk, and its performance varies considerably according to the indication for redo-AVR. Therefore, it should not be used to determine the application of valve-in-valve procedures. The type of indication for redo-AVR (SVD, NSVD, IE) defines three different profiles of patients having distinctive early and long-term behaviors. PMID- 24151756 TI - Incidence and impact of prosthesis-patient mismatch after transcatheter aortic valve implantation. AB - BACKGROUND AND AIM OF THE STUDY: The study aim was to investigate the incidence of patient-prosthesis mismatch (PPM) with new catheter valves, and its influence on the patients' clinical state. At present, few echocardiographic data are available on the incidence and impact of PPM with the CoreValve and Sapien prostheses for transcatheter aortic valve implantation (TAVI). METHODS: The reliability of effective orifice area (EOA) measurements was assured by awaiting an interval of six months after TAVI. Of 256 survivors after TAVI, 149 complete echocardiographic data sets were available for the assessment of the indexed EOA (iEOA). In total, 106 CoreValve prostheses and 43 Sapien prostheses were implanted in this high-risk cohort (mean age 81 +/- 6 years, mean logistic EuroSCORE 20 +/- 13%). RESULTS: The overall incidence of PPM (iEOA < 0.85 cm2/m2) was 61%. Patients with a larger body surface area were more likely to develop PPM (p = 0.001), while the prosthesis type, native annulus diameter, preoperative EOA, gender and prosthesis size had no influence. The mean aortic gradient was significantly higher in patients with PPM. A reduction in the left ventricular end-diastolic diameter was seen in all patients, without significant differences between groups. There were no differences in postoperative NYHA class or self assessed health state between patients with or without PPM. CONCLUSION: PPM was common after TAVI in the presented cohort, presumably because the native calcium masses narrow the outflow area available for blood flow. As expected for low gradients, there was no impairment of left ventricular dimension regression or clinical state of the patients, even if severe PPM was present. Based on the presented data, it is assumed that PPM might be less relevant in TAVI patients. PMID- 24151757 TI - Sclerostin as a potential novel biomarker for aortic valve calcification: an in vivo and ex-vivo study. AB - BACKGROUND AND AIM OF THE STUDY: Sclerostin is a key negative regulator of bone formation. It was hypothesized that sclerostin might also play a potential role in the development of aortic valve calcification (AVC). The study aim was to evaluate serum sclerostin levels in patients with different degrees of AVC compared to a healthy control group, and to investigate local sclerostin expression in explanted calcified and non-calcified aortic valves. METHODS: A prospective cross-sectional study was performed in 115 patients (mean age 74 +/- 7 years) with echocardiographically proven AVC. Sclerostin serum levels were measured using ELISA and compared to values obtained from a healthy control population. For quantification of AVC, all patients of the study cohort underwent non-contrast-enhanced dual-source computed tomography (DSCT). Immunohistochemistry (IHC) staining for sclerostin and mRNA sclerostin expression was analyzed in 10 calcified aortic valves and 10 non-calcified age-matched control valves. RESULTS: Patients with AVC showed significantly higher sclerostin serum levels as compared to healthy controls (0.94 +/- 0.45 versus 0.58 +/- 0.26 ng/ml, p < 0.001). A significant correlation between sclerostin serum levels and Agatston AVC scores as assessed by DSCT was observed (r = 0.62, p < 0.001) in the study cohort. IHC revealed positive sclerostin staining in nine calcified valves, in contrast to negative staining for sclerostin in all non-calcified valves. Quantitative real-time PCR confirmed the increased sclerostin expression on mRNA level, with a significant up-regulation of sclerostin mRNA (fold change 150 +/- 52, p < 0.001) expression being shown in calcified aortic valves compared to non calcified control valves. Co-staining experiments revealed that sclerostin expressing cells co-express the major osteogenic transcription factor Runx2 and the extracellular matrix protein osteocalcin. CONCLUSION: Patients with AVC showed increased sclerostin serum levels compared to a healthy reference population, and it was revealed that the severity of AVC may be linked to increased sclerostin serum levels. Moreover, the PCR and staining data demonstrated an increased sclerostin expression in parallel to prototypic markers of osteogenic transdifferentiation, indicating a role of sclerostin in the valvular calcification process. PMID- 24151758 TI - Mid-term echocardiographic comparison of chordal preservation method of mitral valve replacement in patients with mitral stenosis. AB - BACKGROUND AND AIM OF THE STUDY: The efficacy of chordal-preserved mitral valve replacement (MVR) on left ventricular function was investigated in patients with mitral stenosis. METHODS: Eighty patients (25 males, 55 females; mean age 64.5 +/ 8.7 years) with pure mitral stenosis who underwent MVR between January 1999 and May 2008 were studied retrospectively. Of these patients, 20 had total chordal preserved MVR (group I), 36 had posterior leaflet-preserved MVR (group II), and 24 had MVR without chordal preservation (group III). Echocardiographic assessments were performed preoperatively and at four years postoperatively. RESULTS: Both, preoperatively and intraoperatively, there were no significant differences between the three groups. Mid-term echocardiography showed significant improvements in the left ventricular ejection fraction (LVEF) of the chordal preservation groups (group I, 55 +/- 12% to 60 +/- 7%, p = 0.017; group II, 56 +/-10% to 61 +/- 8%, p = 0.025), whereas the LVEF was significantly decreased after non-chordal-preserved MVR (group III, 56 +/- 7% to 49 +/- 11%, p = 0.036). Furthermore, the non-chordal preservation group demonstrated a significant increase in left ventricular volumes (end-diastolic volume, from 92 +/- 15 ml/m2 to 107 +/- 23 ml/m2, p = 0.005, end-systolic volume, from 43 +/- 7 ml/m2 to 58 +/- 20 ml/m2, p < 0.001) and a spherical change in left ventricular geometry (sphericity index, from 1.6 +/- 0.2 to 1.3 +/- 0.2, p < 0.001). CONCLUSION: Chordal preservation during MVR resulted in an improved ejection performance and the maintenance of left ventricular volume in mitral stenosis. However, these hemodynamic advantages were similar after total chordal preservation and posterior leaflet preservation. PMID- 24151759 TI - Mitral valve repair versus replacement in patients with rheumatic heart disease. AB - BACKGROUND AND AIM OF THE STUDY: Rheumatic fever is still the main cause of valve disease in developing countries. The study aim was to investigate the appropriateness of mitral valve repair in adult patients with rheumatic heart disease (RHD). METHODS: A systematic literature retrieval was performed for all clinical trials comparing the outcomes of mitral valve repair and replacement for RHD in PubMed, EMBASE and the Cochrane Library. Studies were excluded if they lacked a direct comparison of repair versus replacement. The primary outcomes were 30-day and long-term (> 5 years) survival. Secondary outcomes were postoperative complications and reoperation rates. Standard meta-analysis techniques were used. RESULTS: A total of seven studies was included. When comparing mitral valve repair (MVP) to mitral valve replacement (MVR), the summary odds ratio for 30-day mortality was 0.54 (95% confidence interval (CI) 0.34-0.86; p = 0.009), and the summary hazard ratio (HR) for long-term mortality was 0.62 (95% CI 0.45-0.85; p = 0.003). Other than the benefits of better survival rates, the risk of postoperative complications (cardiac death, bleeding or thromboembolic complications) was also lower in the repair group (HR 0.63; 95% CI 0.47-0.84; p = 0.002). A significantly higher reoperation rate was observed among patients with mitral valve repair (HR 1.85; 95% CI 1.41-2.43; p < 0.01). CONCLUSION: Mitral valve repair provides better short-term and long-term event free survival for rheumatic patients. With an acceptable reoperation rate, MVP is also more beneficial by avoiding troublesome lifelong anticoagulation. Thus, whenever possible, MVP should be attempted in patients with RHD. PMID- 24151760 TI - Investigation of the suitability of decellularized porcine pericardium in mitral valve reconstruction. AB - BACKGROUND AND AIM OF THE STUDY: Autologous and glutaraldehyde-treated xenogeneic and homogeneic pericardium has been used extensively in mitral valve repair, but there are a number of limitations associated with its use. These include calcification, limited durability and lack of in vivo regeneration with glutaraldehyde-treated xenografts, as well as the sacrifice of the patient's own pericardium in the case of repair with autologous pericardium. The study aim was to investigate the suitability of decellularized porcine pericardium for heterotopic repair of the mitral valve leaflets, and its potential to regenerate through endogenous cell repopulation in vivo, or in vitro cell seeding prior to implantation. METHODS: Fresh porcine anterior and posterior mitral valve leaflets, together with fresh and decellularized porcine pericardium, were tested histologically, biochemically and biomechanically to investigate potential similarities and differences between the different types of tissue. Subsequently, the decellularized pericardial scaffolds were tested both in terms of biocompatibility, using contact and extract cytotoxicity assays, and in terms of regenerative capacity through porcine mesenchymal stem cell (pMSC) seeding. RESULTS: Histological examination of fresh pericardium and leaflets showed the typical trilaminar and quadlaminar structures of the two tissues, respectively. No cell remnants were observed in the decellularized pericardium, whereas the histoarchitecture of the collagen, elastin and glycosaminoglycan (GAG) matrix appeared well preserved. Significant differences were found in the GAG and hydroxyproline contents and the biomechanics between the leaflet and the pericardial groups. No indication of cytotoxicity was observed with the decellularized pericardial scaffolds. The optimum cell seeding density of pMSCs was 1 x 10(5) cells per cm2, which represented the lowest density at which the cells were capable of repopulating the scaffold by migrating through its full thickness. CONCLUSION: Porcine mitral valve leaflets and porcine fresh/decellularized pericardium shared similar histoarchitectures, but had different biochemical compositions and biomechanics. Decellularized pericardium was shown to be an optimum material for cell repopulation, delivering the necessary biological and biomechanical cues to seeded or migrating cells, and representing a plausible scaffold option for the regeneration of the mitral leaflets in vitro or in vivo, respectively. PMID- 24151762 TI - Textile heart valve prosthesis: from fabric design criteria to early in-vivo performances. AB - BACKGROUND AND AIM OF THE STUDY: Percutaneous aortic valve implantation has become an alternative technique to surgical valve replacement in patients at high risk for open-chest surgery. Biological valve tissue is, however, a fragile material when folded for small-diameter catheter insertion purposes. Textile polyester is a less fragile material, and could be an alternative replacement for the valve leaflets. The dynamic performances obtained in vitro with a valve prosthesis made from textile have proven in previous studies to be satisfactory. However, as textile is a porous material the interaction processes between the fabric leaflet surfaces and living tissues remain unknown. The study aim was to discuss the fabric design criteria which are best suited to clinical application. METHODS: An appropriate design provided strength, limited porosity and low bulk to the fabric, which was particularly suited for small-diameter catheter insertion purposes. The in-vivo behavior of a non-coated polyester textile valve prototype was then studied in the mitral position in a sheep model. RESULTS: The results showed that limited tissue ingrowth occurred, and Ca deposits tended to stiffen the fabric leaflets after a two-month implantation period, which was not compatible with the survival of the animal. CONCLUSION: The initial results obtained with this non-coated polyester textile valve confirmed that this revolutionary fabric is worthy of further investigation. PMID- 24151761 TI - Long-term outcomes of early surgery for asymptomatic severe chronic mitral regurgitation. AB - BACKGROUND AND AIM OF THE STUDY: The long-term outcomes of early surgery in patients with asymptomatic severe chronic mitral regurgitation (MR) and the impact of preoperative left ventricular dysfunction, atrial fibrillation (AF) and/or pulmonary hypertension (PH) on outcomes in this patient group, were evaluated. METHODS: Between 1992 and 2007, a total of 212 patients (mean age 50 +/- 15 years) with asymptomatic severe chronic degenerative MR underwent early mitral valve surgery within 12 months after echocardiographic diagnosis at the authors' institution. Mitral valve repair was attempted in all cases. The mean follow up period was 82 +/- 36 months. The patients were allocated to two groups; 111 with preoperative left ventricular dysfunction, AF and/or PH (group A), and 101 patients without those findings (group B). The outcomes were compared using univariate and multivariate analyses. RESULTS: Mitral valve repair was performed successfully in 211 patients (99.5%). The operative mortality was 0.5% (1/212). The 10-year actuarial survivals were 97.3% in all patients, 95.1% in group A, and 100% in group B. The 10-year cardiac adverse event-free rates (cardiac death, mitral valve reoperation or readmission with congestive heart failure) were 94.7% in all patients, 92.7% in group A, and 96.2% in group B. The seven-year freedom rates from recurrent MR were 93.1% in all patients, 90.0% in group A, and 97.0% in group B. In comparative analyses, group A had poorer late outcomes than group B, although the differences were not statistically significant. The multivariate analysis failed to show that preoperative left ventricular dysfunction, AF and/or PH were significantly associated with late cardiac adverse event (HR: 2.1, 95% CI: 0.4 to 10.8; p = 0.392). CONCLUSION: Early surgery for asymptomatic chronic MR demonstrated excellent early and late outcomes. The study results failed to confirm that preoperative left ventricular dysfunction, AF and/or PH were significantly associated with adverse outcomes of early mitral valve surgery in this patient group. PMID- 24151763 TI - Porcine models of non-bacterial thrombotic endocarditis (NBTE) and infective endocarditis (IE) caused by Staphylococcus aureus: a preliminary study. AB - BACKGROUND AND AIM OF THE STUDY: Non-bacterial thrombotic endocarditis (NBTE) and, in particular, infective endocarditis (IE), are serious and potentially life threatening diseases. An increasingly important agent of human IE is Staphylococcus aureus, which typically causes an acute endocarditis with high mortality. The study aim was to evaluate the pig as a model for non-bacterial as well as S. aureus-associated endocarditis, as these models would have several advantages compared to other laboratory animal models. METHODS: Fourteen animals underwent surgery with placement of a plastic catheter in the left side of the heart. Six of the pigs did not receive a bacterial inoculation and were used to study the development of NBTE. The remaining eight pigs were inoculated intravenously once or twice with S. aureus, 10(5)-10(7) cfu/kg body weight. Two bacterial strains were used: S54F9 (porcine) and NCTC8325-4 (human). Clinical examination, echocardiography and bacterial blood cultures were used to diagnose and monitor the development of endocarditis. Animals were euthanized at between two and 15 days after catheter placement, and tissue samples were collected for bacteriology and histopathology. RESULTS: Pigs inoculated with 10(7) cfu/kg of S. aureus strain S54F9 developed clinical, echocardiographic and pathologic signs of IE. All other pigs, except one, developed NBTE. Serial blood cultures withdrawn after inoculation were positive in animals with IE, and negative in all other animals. CONCLUSION: S. aureus endocarditis was successfully induced in pigs with an indwelling cardiac catheter after intravenous inoculation of 10(7) cfu/kg of S. aureus strain S54F9. The model simulates typical pathological, clinical and diagnostic features seen in the human disease. Furthermore, NBTE was induced in all but one of the pigs without IE. Thus, the pig model can be used in future studies of the pathogenesis, diagnosis and therapy of NBTE and S. aureus endocarditis. PMID- 24151764 TI - True external diameter better predicts hemodynamic performance of bioprosthetic aortic valves than the manufacturers' stated size. AB - BACKGROUND AND AIM OF THE STUDY: Currently, there is no universal standard for sizing bioprosthetic aortic valves. Hence, a standardized comparison was performed to clarify this issue. METHODS: Every size of four commercially available bioprosthetic aortic valves marketed in the United States (Biocor Supra; Mosaic Ultra; Magna Ease; Mitroflow) was obtained. Subsequently, custom sizers were created that were accurate to 0.0025 mm to represent aortic roots 18 mm through 32 mm, and these were used to measure the external diameter of each valve. Using the effective orifice area (EOA) and transvalvular pressure gradient (TPG) data submitted to the FDA, a comparison was made between the hemodynamic properties of valves with equivalent manufacturer stated sizes and valves with equivalent measured external diameters. RESULTS: Based on manufacturer size alone, the valves at first seemed to be hemodynamically different from each other, with Mitroflow valves appearing to be hemodynamically superior, having a large EOA and equivalent or superior TPG (p < 0.05). However, Mitroflow valves had a larger measured external diameter than the other valves of a given numerical manufacturer size. Valves with equivalent external diameters were then compared, regardless of the stated manufacturer sizes. For truly equivalently sized valves (i.e., by measured external diameter) there was no clear hemodynamic difference. There was no statistical difference in the EOAs between the Biocor Supra, Mosaic Ultra, and Mitroflow valves, and the Magna Ease valve had a statistically smaller EOA (p < 0.05). On comparing the mean TPG, the Biocor Supra and Mitroflow valves had statistically equivalent gradients to each other, as did the Mosaic Ultra and Magna Ease valves. CONCLUSION: When comparing valves of the same numerical manufacturer size, there appears to be a difference in hemodynamic performance across different manufacturers' valves according to FDA data. However, comparing equivalently measured valves eliminates the differences between valves produced by different manufacturers. PMID- 24151765 TI - Gal-knockout bioprostheses exhibit less immune stimulation compared to standard biological heart valves. AB - BACKGROUND AND AIM OF THE STUDY: Current biological heart valves (BHVs) contain the major xenogeneic antigen Gal. Recipient anti-Gal antibody binding to such an implanted BHV may contribute to valve degeneration. The study aim was to compare, by implantation in non-human primates, the immune consequences of BHVs from Gal positive wild-type (WT) pigs and those from alpha-galactosyltransferase knockout (GTKO) pigs. METHODS: Recipients were immunized prior to implant with keyhole limpet hemocyanin (KLH) conjugated to alphaGal to match the anti-Gal levels and isotypes found in humans. Stented glutaraldehyde-fixed BHVs from WT (n = 4) and GTKO (n = 3) pigs were commercially manufactured and implanted in the mitral position in non-human primates. Recipients were treated with enoxaparin (1 mg/kg b.i.d.) for five weeks which was tapered, and then discontinued. Serum antibody levels to Gal and KLH were measured using ELISA. RESULTS: Overall anti-Gal and anti-KLH antibody levels were decreased in both WT and GTKO BHV recipients after implantation. Serum anti-Gal IgG levels in GTKO BHV recipients fell rapidly within one month, matching the loss of anti-KLH reactivity. There was no significant difference in retention of anti-KLH antibody between the groups. WT BHV recipients retained significantly elevated levels of anti-Gal IgG during the first year post implant. Area under the curve analysis showed that anti-Gal IgG was significantly increased in the WT BHV group compared to GTKO BHV recipients (p < 0.01). CONCLUSION: Persistent and significantly (p < 0.01) elevated levels of anti-Gal IgG were observed in WT but not GTKO BHV non-human primate recipients, and indicated a continuing BHV-specific immune stimulation to the alphaGal antigen. These data support the hypothesis that the clinical use of Gal positive xenogeneic bioprosthetic materials can induce an anti-Gal antibody response. Bioprosthetic devices prepared from GTKO pig tissue would eliminate immune stimulation to this major xenoreactive antigen, which may reduce the potential of immune-mediated injury and degeneration. PMID- 24151767 TI - Circulating plasma and platelet 5-hydroxytryptamine in carcinoid heart disease: a pilot study. AB - BACKGROUND AND AIM OF THE STUDY: Carcinoid heart disease (CaHD) is a rare form of valvular heart disease in patients with carcinoid syndrome (CS). The role of 5 hydroxytryptamine (5-HT) in the pathogenesis of CaHD is unclear. The study aim was to evaluate the association between platelet 5-HT (5-HTplt) and plasma 5-HT (5-HTpls) and valvular dysfunction. METHODS: Twelve patients with CaHD, 18 with CS and 10 'normal' subjects were recruited. Patients with CaHD underwent cardiac catheterization and echocardiography. 5-HTplt and 5-HTpls was sampled in blood from the femoral vein, right and left ventricle, and left antecubital fossa vein. RESULTS: Levels of 5-HTpls and 5-HTplt were significantly higher in patients with CaHD (median 5-HTpls 325 nmol/l and 5-HTplt 18.9 nmol/10(9) platelets) and CS (median 5-HTpls 155 nmol/l and 5-HTplt 16.4 nmol/10(9) platelets) when compared to healthy controls (median 5-HTpls 9 nmol/l and 5-HTplt 3.7 nmol/10(9) platelets; p < 0.0001 and p = 0.003, respectively). There was a significant increase in 5-HTplt and 5-HTpls between the femoral vein and right heart (p = 0.007 and p = 0.0002, respectively). There was no significant difference in 5 HTplt or 5-HTpls between the right and left side of the heart, irrespective of the presence of a patent foramen ovale or of left-sided CaHD. CONCLUSION: Plasma and platelet 5-HT levels are elevated in patients with CaHD. Despite exposure to similar levels of intracardiac plasma and platelet 5-HT, the development of valve dysfunction is heterogeneous. This suggests that individual heart valves have a susceptibility to the development of valvular dysfunction which is not related solely to plasma or platelet 5-HT levels. PMID- 24151766 TI - Presence of valvular calcification predicts the response to cinacalcet: data from the ADVANCE study. AB - BACKGROUND AND AIM OF THE STUDY: Cardiac valve calcification (CVC) and coronary artery calcification (CAC) appear to be linked pathogenetically, and both are associated with a poor prognosis among patients with chronic kidney disease on dialysis (CKD-5D). Little is known, however, about factors that affect the progression of CVC and CAC. METHODS: A post-hoc analysis was performed of the ADVANCE study to assess whether patients with CVC are more prone to CAC progression, and whether CVC predicts the response to different treatments for secondary hyperparathyroidism. RESULTS: Subjects were randomized to treatment with either cinacalcet and low doses of vitamin D analogs or larger, varying doses of vitamin D. Among 235 subjects, aortic valve or mitral valve calcification was detected in 108 (46%) and 118 (50%), respectively; 69 subjects (29%) had calcification of both valves. CVC was associated both with baseline CAC and CAC progression (p < 0.05). Subjects with aortic valve calcification who were treated with cinacalcet and low doses of vitamin D experienced less progression of CAC than subjects given larger, varying doses of vitamin D (adjusted OR: 0.26; 95% CI: 0.10, 0.64). This effect was greater in subjects with larger CAC burden at baseline. CONCLUSION: The study findings suggest that CVC is a predictor of CAC progression and, potentially, of greater cardiovascular vulnerability. Treatment with cinacalcet combined with low doses of vitamin D slowed the progression of CAC compared to therapy using larger, varying doses of vitamin D. PMID- 24151768 TI - Prooxidant-antioxidant balance and cardiac function in patients with cardiovascular disease following cardiac surgery. AB - BACKGROUND AND AIM OF THE STUDY: Cardiopulmonary bypass (CPB) is used during on pump coronary artery bypass grafting (CABG) and heart valvular replacement surgery, and is associated with the induction of oxidative stress. The aim of the study was to assess the association between indices of cardiac function and prooxidant-antioxidant balance (PAB) values in patients undergoing valve replacement surgery and on-or off-pump CABG. METHODS: Data were obtained from 44, 33, and 41 patients undergoing off-pump CABG, on-pump CABG, and valve replacement surgery, respectively. The PAB values were measured 24 h before and after the operative procedure, and at the time of discharge. Echocardiography was performed before surgery and before discharge. RESULTS: The changes in E/E', end-diastolic volume, end-systolic volume, left ventricular diastolic and systolic diameter were significantly related to baseline PAB values. In the valve replacement group, neither baseline nor changes in PAB values were associated with echocardiographic measurements. Also, neither off-pump nor on-pump CABG were significantly different in inducing oxidative stress (p = 0.596). When PAB values were measured in CABG patients, there was a significant difference in values between the three time points (p = 0.013). In the valve replacement group, PAB values were not significantly different between the preoperative and postoperative samples. CONCLUSION: The inverse association between the level of oxidative stress and cardiac function measurement may indicate that high levels of oxidative stress may be a predictor of the deterioration of cardiac function in CABG patients. However, in valvular heart disease patients the serum PAB value was not associated with changes in cardiac function. Levels of oxidative stress, as assessed by the PAB assay, were not significantly different for patients undergoing surgery with or without CPB. PMID- 24151769 TI - Prognostic variables for clinical outcomes in valvular heart disease patients with moderate to severe secondary tricuspid regurgitation. AB - BACKGROUND AND AIM OF THE STUDY: Secondary tricuspid regurgitation (STR) is frequently seen in cardiology practice. Currently, few data are available on the prognostic variables associated with moderate or severe STR on death and progression to valve surgery. Hence, the study aim was to identify these prognostic variables. METHODS: In this retrospective study, patients with at least moderate STR were identified from an ongoing database and followed until death, any valvular heart surgery, or the end of the study. Clinical and echocardiographic variables including age, gender, coronary artery disease, device implantation (defibrillator or pacemaker), pulmonary disease, left ventricular ejection fraction, right ventricular size, right ventricular systolic pressure (RVSP), STR severity and concomitant valve disease were recorded. End points were death and valve surgery. RESULTS: The average age of the 92 study participants was 68 +/- 16 years. During a mean follow up of 43 +/- 24 months, there were 13 deaths (14%) and 12 surgeries (13%). In multivariate analysis, both an elevated RVSP and device implantation were significant predictors of death (p = 0.0038 and 0.0487, respectively). Only an elevated RVSP was predictive of surgery (p = 0.05) and surgery-free survival (p = 0.0005). A RVSP > 48 mmHg had a hazard ratio of 3.93 (p = 0.0012) and a high diagnostic accuracy for predicting death, with an area under the receiver operating characteristic curve of 0.73. CONCLUSION: In patients with valvular heart disease and at least moderate STR, an elevated RVSP of at least 48 mmHg was associated with significantly increased mortality and decreased surgery-free survival. PMID- 24151770 TI - Pulmonary valve-sparing technique in patient with tetralogy of Fallot and anomalous coronary artery crossing the infundibulum. AB - A 15-month-old girl who presented at birth with tetralogy of Fallot and was followed after an echocardiographic diagnosis of an anomalous origin of the right coronary artery from the left anterior descending coronary artery, crossing the right ventricular infundibulum very close to the pulmonary valve annulus, was scheduled for repair. At surgery, after routine trans-atrial/trans-pulmonary repair, the pulmonary valve (PV) was balloon-dilated through the right ventricular outflow tract (RVOT) up to a 'normal size' PV annulus, based on the patient's body surface area. Two-dimensional echocardiography at discharge revealed an adequate relief of the RVOT obstruction, with a normal-sized PV annulus and a competent PV. In this subset of patients, this technique can be considered an additional surgical strategy to avoid the use of conduits. PMID- 24151771 TI - Corynebacterium striatum: an emerging nosocomial drug-resistant endocardial pathogen. AB - Endocarditis due to Corynebacterium striatum has been rarely reported. A 78-year old patient developed pacemaker endocarditis caused by multidrug-resistant C. striatum, complicated by vertebral osteomyelitis and epidural abscess. Daptomycin therapy successfully eradicated the bacteremia and metastatic infection. A review of the English literature on this emerging nosocomial, multidrug-resistant pathogen is included. PMID- 24151772 TI - Reoperative reimplantation procedure after previous remodeling in a patient with Marfan syndrome. AB - A 43-year-old man with Marfan syndrome presented with recurrent aortic root dilatation and aortic regurgitation at ten years after a remodeling (Yacoub) procedure. Herein is described a reoperative valve-sparing procedure employing the reimplantation technique (David procedure) used in the treatment of this patient. PMID- 24151773 TI - Successful transcatheter valve-in-valve implantation in a small deteriorated aortic valve bioprosthesis. AB - Increased life expectancy and improvement in clinical outcome following surgery has led to an increasing number of elderly patients with a history of prior aortic valve replacement (AVR). As a consequence, a considerable number of patients may require reintervention due to a dysfunctional bioprosthesis with structural valve deterioration (SVD). Transcatheter aortic valve implantation (TAVI) has become an established surgical alternative in patients with aortic stenosis and severe comorbidities. For those patients requiring reoperation, the 'valve-in-valve' concept has been described. Here, the case is reported of a patient with a very small Sorin Soprano 18 bioprosthesis with SVD who underwent a reintervention with the transapical valve-in-valve technique. The implantation was uneventful, with no residual paravalvular leakage and a low mean transprosthetic gradient. The valve-in-valve procedure may represent a feasible alternative for redo AVR in patients with a very small, structurally deteriorated bioprosthesis. PMID- 24151774 TI - Sutureless Medtronic 3f Enable aortic valve replacement in a heavily calcified aortic root. AB - The case is reported of a surgical aortic valvular stenosis with a severely calcified ascending aortic root in a 76-year-old woman. The morphology and size of the aortic annulus were unsuitable for transcatheter aortic valve implantation (TAVI); thus, surgery was scheduled. Aortic calcifications allowed a transverse aortotomy 4 cm superior to the sinotubular junction, with a remote endoaortic view of the valve. A Medtronic 3f Enable sutureless bioprosthesis was then implanted after aortic annular decalcification. Sutureless bioprostheses are new tools that promise to reduce technical difficulties and cross-clamp times in minimally invasive aortic valve replacement surgery. In addition, sutureless techniques may have other possible advantages in special circumstances requiring full sternotomy access, such as in the present case. PMID- 24151775 TI - Congenital discrete subaortic stenosis in pregnancy: case report and literature review. AB - Today's growing numbers of pregnant patients with congenital heart defects presents challenges for cardiologists treating adult patients. The case is presented of a 19-year-old woman who was admitted with a threatened miscarriage in the third trimester and was diagnosed with an incomplete atrioventricular canal, cleft mitral valve with severe regurgitation, and severe congenital subaortic stenosis caused by a subaortic membrane. She was managed conservatively, delivered via cesarean section, and then underwent surgical repair of all defects with good outcome. Here, a review is provided of the literature on the natural course, complications, and treatment strategies of subaortic stenosis, together with a summary of recommendations for the management of the condition. PMID- 24151776 TI - Biodegradable annuloplasty ring two years after implantation: first histological demonstration in human mitral annulus. AB - Although biodegradable annuloplasty rings have been used in clinics for almost a decade for mitral and/or tricuspid annuloplasty, the fate of the ring at the histological level has not been demonstrated in humans to date. The mitral annulus of a 39-year-old patient who underwent heart transplantation almost two years after annuloplasty was subjected to histological evaluation to demonstrate the mitral annular structures and consequences of biodegradable ring annuloplasty. On examination, the ring was shown to have completely degraded, and a fibrous band had formed in the posterior mitral annulus. No signs of residual calcification were observed. Neighboring structures such as circumflex artery and the great cardiac vein were intact. It can be concluded that the biodegradable annuloplasty ring is completely degraded in humans after implantation, leaving a fibrous band behind to support the posterior annulus. The risk of circumflex artery and great cardiac vein injury may not be considerable if the correct implantation technique is used. PMID- 24151777 TI - Second-generation functionalized medium-chain-length polyhydroxyalkanoates: the gateway to high-value bioplastic applications. AB - Polyhydroxyalkanoates (PHAs) are biodegradable biocompatible polyesters, which accumulate as granules in the cytoplasm of many bacteria under unbalanced growth conditions. Medium-chain-length PHAs (mcl-PHAs), characterized by C6-C14 branched monomer chains and typically produced by Pseudomonas species, are promising thermoelastomers, as they can be further modified by introducing functional groups in the side chains. Functionalized PHAs are obtained either by feeding structurally related substrates processed through the beta-oxidation pathway, or using specific strains able to transform sugars or glycerol into unsaturated PHA by de novo fatty-acid biosynthesis. Functionalized mcl-PHAs provide modified mechanical and thermal properties, and consequently have new processing requirements and highly diverse potential applications in emergent fields such as biomedicine. However, process development and sample availability are limited due to the toxicity of some precursors and still low productivity, which hinder investigation. Conversely, improved mutant strains designed through systems biology approaches and cofeeding with low-cost substrates may contribute to the widespread application of these biopolymers. This review focuses on recent developments in the production of functionalized mcl-PHAs, placing particular emphasis on strain and bioprocess design for cost-effective production. PMID- 24151778 TI - Association between Pseudonocardia symbionts and Atta leaf-cutting ants suggested by improved isolation methods. AB - Fungus-growing ants associate with multiple symbiotic microbes, including Actinobacteria for production of antibiotics. The best studied of these bacteria are within the genus Pseudonocardia, which in most fungus-growing ants are conspicuously visible on the external cuticle of workers. However, given that fungus-growing ants in the genus Atta do not carry visible Actinobacteria on their cuticle, it is unclear if this genus engages in the symbiosis with Pseudonocardia. Here we explore whether improving culturing techniques can allow for successful isolation of Pseudonocardia from Atta cephalotes leaf-cutting ants. We obtained Pseudonocardia from 9 of 11 isolation method/colony component combinations from all 5 colonies intensively sampled. The most efficient technique was bead-beating workers in phosphate buffer solution, then plating the suspension on carboxymethylcellulose medium. Placing these strains in a fungus growing ant-associated Pseudonocardia phylogeny revealed that while some strains grouped with clades of Pseudonocardia associated with other genera of fungus growing ants, a large portion of the isolates fell into two novel phylogenetic clades previously not identified from this ant-microbe symbiosis. Our findings suggest that Pseudonocardia may be associated with Atta fungus-growing ants, potentially internalized, and that localizing the symbiont and exploring its role is necessary to shed further light on the association. PMID- 24151779 TI - In vitro interaction between Bacillus megaterium strains and Caco-2 cells. AB - To further our understanding of the virulence potential of Bacillus megaterium strains, cell association and invasion assays were conducted in vitro by infecting human enterocytes (Caco-2 cells) with 53 strains of this bacterium isolated from honey. Two series of experiments were performed: (i) necrosis and cell detachment assays with the supernatants of bacterial culture filtrates from 16-h cultures and (ii) adhesion/invasion assays in which cultured enterocytes incubated with bacteria from 3-h cultures were resuspended in Dulbecco's modified Eagle's medium and chloramphenicol. The detachment of Caco-2 cells was evaluated by staining the cells with crystal violet. Necrosis was assessed by fluorescence microscopy of cells labeled with propidium iodide. Association (adhesion plus invasion) was determined by plate counts and invasion in an aminoglycoside protection assay. The results showed that spent culture supernatants detached and necrotized Caco-2 cells in a strain-dependent manner. Seven out of 53 B. megaterium filtered culture supernatants caused complete cell detachment. Suspensions of these same bacterial strains adhered and invaded enterocytes in 2 h infection experiments. To our knowledge, this is the first report on the interaction between B. megaterium and intestinal epithelial Caco-2 cells. PMID- 24151780 TI - A novel bleb-dependent polysaccharide export system in nitrogen-fixing Azotobacter vinelandii subjected to low nitrogen gas levels. AB - The alginate biofilm-producing bacterium Azotobacter vinelandii aerobically fixes nitrogen by oxygen-sensitive nitrogenases. Here we investigated the bacterial response to nitrogen/oxygen gas mixtures. A. vinelandii cells were cultured in nitrogen-free minimal media containing gas mixtures differing in their ratios of nitrogen and oxygen. The bacteria did not grow at oxygen concentrations >75% but grew well in the presence of 5% nitrogen/25% oxygen. Growth of wild-type and alginate-deficient strains when cultured with 50% oxygen did not differ substantially, indicating that alginate is not required for the protection of nitrogenases from oxygen damage. In response to decreasing nitrogen levels, A. vinelandii produced greater amounts of alginate, accompanied by the formation of blebs on the cell surface. The encystment of vegetative cells occurred in tandem with the release of blebs and the development of a multilayered exine. Immunoelectron microscopy using anti alginate-antibody revealed that the blebs contained alginate molecules. By contrast, alginate-deficient mutants could not form blebs. Taken together, our data provide evidence for a novel bleb-dependent polysaccharide export system in A. vinelandii that is activated in response to low nitrogen gas levels. PMID- 24151781 TI - Low virus to prokaryote ratios in the cold: benthic viruses and prokaryotes in a subpolar marine ecosystem (Hornsund, Svalbard). AB - The density and spatial distribution of benthic viruses and prokaryotes in relation to biotic and abiotic factors were investigated in sediment cores collected in Hornsund, a permanently cold fjord on the West coast of Svalbard, Norway. The cores were obtained from the mouth of the fjord to the central basin, along a longitudinal transect. The results of our analyses showed lower densities of viruses (0.2 x 10(8) to 5.4 x 10(8) virus-like particles/g) and lower virus-to prokaryote ratios (0.2-0.6, with the exception of the uppermost layer in the central basin, where the ratio was about 1.2) at the study site than generally found in the temperate areas, despite the relatively high organic matter content in subpolar sediments. Variations in benthic viral and prokaryote abundances along gradients of particle sedimentation rates, phytopigment concentrations, and macrobenthic species composition together suggested the influence of particle sedimentation and macrobenthic bioturbation on the abundance and spatial distribution ofprokaryotes and viruses in cold habitats. PMID- 24151782 TI - Dark fermentation: isolation and characterization of hydrogen-producing strains from sludges. AB - To improve bacterial hydrogen production, ten hydrogen-producing strains belonging to Clostridium spp. were isolated from various sludges under low vacuum. Hydrogenogenesis by dark fermentation in batch cultures of these strains was optimal at about 35 degrees C and an initial pH of 6.5, which for all strains gradually dropped to ca. pH 4 during the fermentation. Clostridium roseum H5 and C. diolis RT2 had the highest hydrogen yields per total substrate (120 ml H2/g initial COD). Substrate consumption alone by C. beijerinckii UAM and C. diolis RT2 reached 573 and 475 ml H2/g consumed COD, respectively. Butyric acid fermentation was predominant, with butyrate and acetate as the major by-products and propionate, ethanol, and lactate as secondary metabolites. The acetate:butyrate ratios and fermentation pathways varied depending on the strains and environmental conditions. Hydrogenogenesis was studied in greater detail in C. saccharobutylicum H1. In butyric acid fermentation by this representative strain, acetoacetate was detected as an intermediate metabolite. Hydrogenogenesis was also analyzed in an enrichment culture, which behaved similarly to the axenic cultures. PMID- 24151783 TI - The challenges of scientific publishing. PMID- 24151784 TI - The origins of BASCD and the specialty of dental public health: some personal memories. PMID- 24151785 TI - Oral health education and disease prevention in primary dental care: insight from a pilot intervention targeting children aged 0-7 years in northeast England. AB - This paper outlines a number of issues arising from a primary-care and community based oral health education (OHE) and disease prevention pilot targeting children aged 0-7 years in County Durham and Darlington during a six month period in 2011 12. The paper highlights the key practical challenges experienced by the NHS dental practices that provided OHE predominantly in community venues and the issues arising for those involved in managing the pilot on a day to day basis. Finally, the paper suggests potential solutions and learning points for dental public health practitioners. The work described in this paper relates to three relevant dental public health competencies: strategy development and implementation; strategic leadership and collaborative working for health and oral health improvement. PMID- 24151786 TI - Caries prevalence in 12-year-old children from Germany: results of the 2009 national survey. AB - OBJECTIVE: In 2009, complementary epidemiological studies were conducted in 16 German states. DESIGN: A 2009 cross-sectional oral health survey of children aged 12 years with 5% samples selected using a two-stage random sampling procedure. SUBJECTS: A random selection of 30,943 12-year-olds were examined in schools. METHOD: DMFT and fissure sealants were recorded following WHO criteria. Caries was diagnosed at the caries into dentine threshold (D3) using the visual method without radiography or fibre-optic transillumination. Statistical evaluation was performed using the software SPSS (v12.0). RESULTS: The proportion of children across Germany with caries experience was 31%. The mean DMFT score was 0.72 and the average Significant Caries Index (SiC) was 2.29. The results showed a wide variation among the different federal states, with mean regional DMFT values ranging from 0.56 to 1.06. Compared to the results obtained in 2004, caries prevalence and caries experience decreased distinctly in this age group. The mean DMFT score for 12-year-olds dropped from 2.44 to 0.72 between 1994 and 2009. The mean DMFT scores were 72.7% lower at the end of the observation period than a few years after the introduction of extensive caries prevention measures in Germany. The mean number of fissure sealed teeth ranged between 2.24 and 3.04. CONCLUSION: The decrease in caries prevalence observed between 1994 and 2004 continued between 2004 and 2009, although once again inequalities in oral health between federal states were observed. PMID- 24151787 TI - Longitudinal register study of attendance frequencies in public and private dental services in Finland. AB - OBJECTIVE: The Public Dental Service (PDS) in Finland was recently opened to all adults. According to annual statistics, 75% of children and 51% of adults made dental attendances in 2008. This study aimed to survey the frequency of dental attendance across three years and compared attendance frequencies between age groups and treatment sectors. METHODS: Data from municipal databases and the reimbursement register of the Social Insurance Institution were collected on all who had attended the PDS (733,000) or the private sector (473,000) in 2008 and they were retrospectively followed from 2008 to 2006. RESULTS: Most children had attended the PDS in each year (57.4%) or in two of the three years (32.2%). Most working aged (57.3%) and elderly (69.1%) were annual attenders in the private sector. In addition, 27.1% of the former and 19.8% of the latter had attended in two of the three years. Attending in one year only was unusual. In the PDS, adult annual attendance was uncommon (31.9%), and adult attenders were fairly evenly distributed over the three categories, attending in one, two or all three years. CONCLUSIONS: Annual or biannual attendances seemed to be the norm among children in the PDS and adults in the private sector. Adults in the PDS showed irregular attendance patterns probably partly due to scarcity of resources for recall patients in the PDS. PMID- 24151788 TI - The geographic distribution of patients seeking emergency dental care at the Royal Dental Hospital of Melbourne, Australia. AB - BACKGROUND: Little detail is known about the geographical catchment areas covered by dental hospitals, with no previous Australian studies of this kind. The aim of this study was to assess the geographical distribution of public dental emergency patients and their socioeconomic status to define catchment zones for a dental hospital. METHODS: All patients requesting emergency dental care at the Royal Dental Hospital Melbourne, meeting the inclusion criteria, in calendar years 2006 and 2010 were included in the sample. Geographic information systems tools were used to locate and link each patient address to the socioeconomic data. RESULTS: For both 2006 and 2010 95% of the patients were living within 50km of the hospital. In 2006, most of the patients seeking care lived within a 15km radius of the dental hospital whilst in 2010 that distance increased somewhat. Patients from areas with similar socioeconomic status living more than 10km away from the hospital had poorer access to dental emergency treatment. CONCLUSIONS: The hospital had a surprisingly large catchment zone that overlapped those of smaller community-based clinics. PMID- 24151789 TI - Using GIS to analyse dental practice distribution in Indiana, USA. AB - OBJECTIVE: Dentistry across the globe faces significant workforce issues with mal distribution at most levels of analysis being a substantial issue. This study was the first to apply high resolution Geographic Information Systems (GIS) tools to map every private dental practice in the State of Indiana against a backdrop of population demographics. The hypothesis tested in the study is that there is an even density distribution of dental practices across Indiana. METHOD: Adult population data were obtained from the United States Census of Population and divided by census tracts. The physical address for each dental practice in Indiana was collated from a comprehensive web-based search and the two datasets were integrated using GIS tools. RESULT: The whole adult population of Indiana (5 million) was distributed across 1,511 census tracts. Across these tracts a total of 2,096 separate private general dental practices were distributed. There were a total of 679 tracts (45%) without a dental practice while 2.5% of tracts had 8 or more practices. CONCLUSION: The practice to population ratio (1:2,384) for the whole State was not significantly different for those living within 50km (31 miles) or 25km (15 miles) of the seven major city centers, and mean personal income (by residency location) did not appear to significantly influence practice location. PMID- 24151790 TI - Oral health care services utilisation in the adult US population: Medical Expenditure Panel Survey 2006. AB - OBJECTIVES: To estimate the proportion of dental visits and to explore determinants of oral health care service (OHCS) utilisation among US civilian non institutionalised adults. METHODS: Cross-sectional data from the 2006 Medical Expenditure Panel Survey (MEPS) were used to analyse adults' self-reported dental visits across potential risk factors (n = 22,721). MEPS uses a complex sample design including stratification, clustering, multiple stages of selection, and disproportionate sampling. These survey design complexities were taken into account for analysis in this study. The analysis was performed in SAS 9.2 and used chi-square tests and binary logistic regression. RESULTS: MEPS (2006) represented approximately 222 million non-institutionalised US adults. 42% (weighted) of this population reported a dental visit in the past 12 months. Dental visit numbers were observed to increase with age, with the 55-64-year-olds approximately 44% more likely than the 18-24-year olds to have visited the dentist in the past year. Hispanics were 48% less likely to report a dental visit compared to Non-Hispanic Whites. Respondents with public- or no- dental insurance were less likely to report a dental visit than persons with private dental coverage. CONCLUSIONS: Under half the US adult civilian non-institutionalised population reported a dental visit during 2006. To help address utilisation disparities, creative initiatives and systemic approaches aimed at groups currently utilising OHCS less often could be an important step towards oral health equity. PMID- 24151791 TI - Dental infections increase the likelihood of hospital admissions among adult patients with sickle cell disease. AB - THE OBJECTIVE: To determine if dental infections increase the likelihood of hospital admission among adult patients with sickle cell disease (SCD). BASIC RESEARCH DESIGN: Cross-sectional analysis of data from the Nationwide Emergency Department Sample (NEDS) pooled for the years 2006 through 2008. Prevalence ratios (PR) for the effects of interest were estimated using Poisson regression with robust estimates of the variance. PARTICIPANTS: Adults, aged 18 and over, diagnosed with SCD using ICD-9-CM codes excluding participants discharged with a code for sickle cell trait. MAIN OUTCOME MEASURE: Emergency department (ED) visit disposition, dichotomised to represent whether or not the ED visit ended in admission versus being treated and released. RESULTS: Among patients having a sickle cell crisis, those with dental infections were 72% more likely to be admitted compared to those not having dental infections (PR = 1.72, 95% CI 1.58 1.87). No association was observed among adult SCD patients not having a sickle crisis event. Based on preliminary data from this analysis, prevention of dental infection among patients with SCD could result in an estimated cost saving of $2.5 million dollars per year. CONCLUSIONS: Having a dental infection complicated by a sickle cell crisis significantly increases the likelihood of hospital admission among adult SCD patients presenting to the ED. PMID- 24151792 TI - Preschool teachers as agents of oral health promotion: an intervention study in Sri Lanka. AB - BACKGROUND: According to National Oral Health Survey reports and research, Early Childhood Caries has been identified as a serious public health problem in Sri Lanka. More than 65% of preschool-aged children have dental decay and only 2% of them have had treatment. With proper interventions and commitment from public health personnel and responsible community leaders this should be a largely preventable disease. METHODS: An intervention study was conducted among preschool teachers in the District of Colombo, Sri Lanka, to assess their influence on oral health promotion in the school environment. All the available 52 preschools and all 72 teachers registered under a local government authority were involved in the study. Preschools were divided into intervention group and control group based on geographically defined areas. The intervention included training preschool teachers using a manual covering health education, health promotion, incorporation of oral-health-friendly activities into the preschool curriculum, and hands-on experience of oral examination. Pre- and post- assessments were conducted with a 6 month interval. RESULTS: After 6 months, the median oral health knowledge score of the intervention group improved from 55 to 72 (p = 0.005) and the mean score for oral health related practices from 32 to 35 (p = 0.032). The variables: oral-health-friendly preschool environment (p = 0.02), availability of brushing facilities (p = 0.005) and availability of information, education and communication materials related to oral health (p = 0.004) were significantly different between the two groups after 6 months. CONCLUSION: Oral health promotion activities can be effectively instilled in a pre-school environment by the education of teachers. PMID- 24151793 TI - Oral health literacy and information sources among adults in Tehran, Iran. AB - OBJECTIVE: To assess oral health literacy level and oral health information of Iranian adults in Tehran, and to determine the factors related to oral health literacy. BASIC RESEARCH DESIGN: A cross-sectional population study. PARTICIPANTS: A random sample of 1,031 adults in Tehran, Iran. METHODS: Oral health literacy was measured using an oral health adult literacy questionnaire (OHL-AQ). Variation in use of information sources by socio-economic and demographic background was estimated by odds ratios. A multiple linear regression model served to determine predictor factors of OHL-AQ scores controlling for characteristics of the subjects and number of information sources. RESULTS: The mean OHL-AQ score was 10.5 (sd 3.0). Women (p < 0.001), younger (p < 0.001), and better educated participants (p < 0.001) had higher OHL-AQ scores. The most common sources of oral health information were dentists (52.6%), and TV/Radio (49.5%). According to the regression model, females (p = 0.001), high educational level (p < 0.001), and use of multiple information sources (two sources p = 0.01, three sources or more p = 0.002) were the main predictor factors of OHL-AQ scores. CONCLUSIONS: The average oral health literacy level of Iranian adults was low. Disseminating evidence-based oral health care information from multiple sources including TV/radio, dentists, and other health professionals in different settings should improve public oral health literacy. PMID- 24151794 TI - Child oral health-related quality of life (COHQoL), enamel defects of the first permanent molars and caries experience among children in Western Australia. AB - Published reports suggest that children with enamel defects, especially where enamel is missing or breaking down, experience considerable discomfort and are generally more fearful of dental treatment. However, children's oral health related quality of life in relation to enamel defects has not been reported. The aim of this study was to examine the association between oral health-related quality of life among children (COHQoL) with enamel defects of the first permanent molars and deciduous caries experience. METHODS: Children attending pre primary schools in metropolitan Perth, Western Australia, were recruited and classified for enamel defects using the modified Developmental Defects of Enamel index. Caries experience of deciduous molars and canines was also recorded. Parents completed a child oral health-related quality of life questionnaire. Data were analysed using Kruskal-Wallis, Spearman's rank correlation, chi-square, multiple linear regression and ordered logistic regression to test the factors for their influence on the COHQoL. RESULTS: From the 550 children assessed (mean age 7.2 years) 522 COHQoL questionnaires were returned. Mean COHQoL score was 8.9 (sd 8.8). Bivariate tests showed no association of COHQoL with enamel defect status of the first permanent molars. COHQoL was associated with dmft (mean dmft 1.96, sd 2.62). Higher caries experience children had poorer reported oral health related quality of life. CONCLUSION: The presence of enamel defects in the first permanent molars did not affect the children's oral health-related quality of life. PMID- 24151795 TI - Oral health-related quality of life in non-syndromic cleft lip and/or palate patients: a systematic review. AB - THE OBJECTIVE: To evaluate oral health-related quality of life (OHRQoL) in non syndromic patients with cleft lip and/or palate (CLP), in comparison to a general non-cleft population. BASIC RESEARCH DESIGN: Systematic review. A literature search was conducted to identify papers reporting on OHRQoL in cleft samples. Only studies with suitable control groups were included. From each included paper were extracted the study and sample characteristics and results. MAIN OUTCOME MEASURES: OHRQoL score. RESULTS: Three papers were chosen according to the preset inclusion and exclusion criteria. All used an OHRQoL generic patient-reported questionnaire with evidence of a development and validation process, with responses recorded on a five-point scale. The results could not be combined for the purposes of meta-analysis due to lack of standardisation. In 2 of the 3 studies, the OHRQoL was found to be significantly lower in the cleft than in the non-cleft samples (in patients 8-18 or 18-65 years of age). The third study, based on a relatively small sample size, could not detect significant differences between cleft and non-cleft individuals. CONCLUSIONS: Based on the results of the few studies included in the present systematic review, non-syndromic patients with CLP tend to have a lower OHRQoL than a general non-cleft population. This seems to hold true both for children and adults. PMID- 24151796 TI - Localized photoelectrochemistry on a tungsten oxide-iron oxide thin film material library. AB - A WO3-Fe2O3 thin film combinatorial library was fabricated using a vapor phase co deposition method followed by a combined thermal annealing and oxidation process. The scanning electron microscopy (SEM) analysis of the library microstructure combined with X-ray diffraction (XRD) investigations suggested that alpha-Fe2O3 grains preferentially grow from boundaries of domains, containing finer grains of WO3 and Fe2WO6, forming filiform networks on the surface. The surface density of the hematite networks depends on the amount of Fe present in the library. Photocurrents measured at different applied biases using Photo Electrochemical Scanning Droplet Cell Microscopy (PE-SDCM) were analyzed and mapped along the entire compositional spread. A distinctive photocurrent peak was detected at 21.9 atom % Fe, and its appearance was correlated to the higher amount of hematite present in the library at this specific composition together with a specific WO3 crystallographic orientation ((222) orthorhombic or (400) monoclinic). This finding is confirmed by qualitative and quantitative XPS surface analysis at the photocurrent peak position in the material library. Thus the enhancement of the photocurrent cannot be exclusively attributed to certain surface modifications since only hematite was found on the library surface at the peak composition. PMID- 24151797 TI - Future roles of pharmacogenomic testing and biomarkers in psychiatry. PMID- 24151798 TI - The value of drug and metabolite concentration in blood as a biomarker of psychopharmacological therapy. AB - Desirable and undesirable effects of a drug are related to its concentration at various sites of actions. For many psychotropic drugs, it has been shown that drug concentration in brain correlates with concentration in blood. The latter is also an available estimate of clearance and bioavailability. Its monitoring enables identification of multiple factors that have an impact on clinical outcomes, especially uncertain compliance and pharmacokinetic peculiarities. For this review we analysed for antidepressants if drug concentration in blood can be used as biomarker for psychopharmacological treatment. Systematic review of the literature revealed for new and old antidepressant drugs that drug and metabolite concentrations in blood are measures of the pharmacokinetic phenotype and related differentially to occupancy of primary target structures, therapeutic effects and unwanted anticholinergic, cardiac and other side effects. Drug concentration in blood can therefore be used as biomarker in clinical practice to guide psychopharmacological treatment with established antidepressant drugs. Monitoring of drug concentration is suitable to improve efficacy and safety of the pharmacotherapy, especially in elderly patients who require complex pharmacological therapies. PMID- 24151800 TI - Complexities of CYP2D6 gene analysis and interpretation. AB - Cytochrome P450 2D6 (CYP2D6) plays an important role in the metabolism and bioactivation of about 25% of clinically used drugs including many antidepressants, antipsychotics and opioids. CYP2D6 activity is highly variably ranging from no activity in so-called poor metabolizers to ultrarapid metabolism at the other end of the extreme of the activity distribution. A large portion of this variability can be explained by the highly polymorphic nature of the CYP2D6 gene locus for which > 100 variants and subvariants identified to date. Allele frequencies vary markedly between ethnic groups; some have exclusively or predominantly only been observed in certain populations. Pharmacogenetic testing holds the promise of individualizing drug therapy by identifying patients with CYP2D6 diplotypes that puts them at an increased risk of experiencing dose related adverse events or therapeutic failure. Inferring a patient's CYP2D6 metabolic capacity, or phenotype, however, is a challenging task due to the complexity of the CYP2D6 gene locus. Allelic variation includes SNPs, small insertions and deletions, gene copy number variation and rearrangements with CYP2D7, a highly related non-functional gene. This review provides a summary of the intricacies of CYP2D6 variation and genotype analysis, knowledge that is invaluable for the translation of genotype into clinically useful information. PMID- 24151799 TI - Clinical validity of cytochrome P450 metabolism and serotonin gene variants in psychiatric pharmacotherapy. AB - Adverse events, response failures and medication non-compliance are common in patients receiving medications for the treatment of mental illnesses. A systematic literature review assessed whether pharmacokinetic (PK) or pharmacodynamic (PD) responses to 26 commonly prescribed antipsychotic and antidepressant medications, including efficacy or side effects, are associated with nucleotide polymorphisms in eight commonly studied genes in psychiatric pharmacotherapy: CYP2D6, CYP2C19, CYP2C9, CYP1A2, CYP3A4, HTR2C, HTR2A, and SLC6A4. Of the 294 publications included in this review, 168 (57%) showed significant associations between gene variants and PK or PD outcomes. Other studies that showed no association often had insufficient control for confounding variables, such as co-medication use, or analysis of medications not substrates of the target gene. The strongest gene-outcome associations were for the PK profiles of CYP2C19 and CYP2D6 (93% and 90%, respectively), for the PD associations between HTR2C and weight gain (57%), and for SLC6A4 and clinical response (54%), with stronger SLC6A4 response associations for specific drug classes (60-83%). The preponderance of evidence supports the validity of analyzing nucleotide polymorphisms in CYP and pharmacodynamic genes to predict the metabolism, safety, or therapeutic efficacy of psychotropic medications commonly used for the treatment of depression, schizophrenia, and bipolar illness. PMID- 24151801 TI - Towards the implementation of CYP2D6 and CYP2C19 genotypes in clinical practice: update and report from a pharmacogenetic service clinic. AB - Genetic testing may help to improve treatment outcomes in order to avoid non response or severe side effects to psychotropic medication. Most robust data have been obtained for gene variants in CYP2D6 and CYP2C19 enzymes for antipsychotics and antidepressant treatment. We reviewed original articles indexed in PubMed from 2008-2013 on CYP2D6 and CYP2C19 gene variants and treatment outcome to antidepressant or antipsychotic medication. We have started providing CYP2D6 and CYP2C19 genotype information to physicians and conducted a survey where preliminary results are reported. Studies provided mixed results regarding the impact of CYP2D6 and CYP2C19 gene variation on treatment response. Plasma levels were mostly found associated with CYP metabolizer status. Higher occurrence/severity of side effects were reported in non-extensive CYP2D6 or CYP2C19 metabolizers. Results showed that providing genotypic information is feasible and generally well accepted by both patients and physicians. Although currently available studies are limited by small sample sizes and infrequent plasma drug level assessment, research to date indicates that CYP2D6 and CYP2C19 testing may be beneficial particularly for non-extensive metabolizing patients. In summary, clinical assessment of CYP2D6 and CYP2C19 metabolizer status is feasible, well accepted and optimizes drug treatment in psychiatry. PMID- 24151802 TI - Value of genetic and epigenetic testing as biomarkers of response to antidepressant treatment. AB - Major depressive disorder (MDD) is one of the most prevalent and disabling psychiatric disorders worldwide and therefore an important public health priority. The selection process of antidepressant treatment is primarily guided by trial and error, and the outcomes with current antidepressant strategies are disappointing. The biological background of the disease is heterogeneous with presumably multiple biological systems involved. With the aim to individualize antidepressant treatment, multiple candidate gene and a few genome-wide association studies have been performed, but so far with very limited success. To address the dynamic changes of depressive symptoms and their response to treatment, recent studies focus on epigenetic mechanisms, as these are modulated by environmental stimuli and adaptive to different stages of the disorder. In the present paper, after a brief summary of the most important results from pharmacogenetic studies in MDD, we comment on the current and potential future value of genetic testing as a biomarker of response to antidepressant treatment. The new and exciting field of epigenetic mechanisms in antidepressant drug treatment will be presented in the second part of this review. PMID- 24151803 TI - Gene expression: biomarker of antidepressant therapy? AB - While antidepressant therapy is an essential treatment of major depression, a substantial group of treated patients do not respond to therapy, or suffer from severe side effects. Moreover, the time of onset of the clinical improvement is often delayed. Antidepressants as currently available usually enhance serotonergic, noradrenergic and dopaminergic neurotransmission and may contribute to the inadequate remission rates for major depression. Therefore biomarkers enabling the identification of subgroups of patients and also finding unprecedented targets would provide the basis for personalized medication and thus improve treatment efficacy and reduce side effects. Several pharmacogenetic studies on antidepressant treatment response using single nucleotide polymorphism (SNPs) mapping have been performed but provided only modest findings. Therefore the analysis of gene expression to integrate genomic activity and environmental effects promises a new approach to cope with the complexity of factors influencing antidepressant treatment. Here gene expression studies focusing on candidate genes and genome-wide approaches using RNA derived from peripheral blood cells are reviewed. The most promising findings exist for hypothalamic pituitary-adrenal (HPA) axis, inflammation and neuroplasticity related genes. However, straightforward translation into tailored treatment is still unlikely. Contradictory results limit the clinical use of the findings. Future studies are necessary, which could include functional analysis and consider gene-environment interactions. PMID- 24151804 TI - Cytokines as biomarkers in depressive disorder: current standing and prospects. AB - The frequently observed co-occurrence of depressive disorders and inflammatory diseases suggests a close connection between the nervous and the immune systems. Increased pro-inflammatory and type 1 cytokines, such as interleukin (IL)-1, tumour necrosis factor (TNF)-alpha and interferon (IFN)-gamma, appear to be an important link. Cytokines are synthesized by immune cells in the blood and peripheral tissues and by glial cells in the central nervous system (CNS). Evidence suggests that the blood-brain barrier (BBB) is permeable to cytokines and immune cells, and that afferent nerves, e.g. the vagus nerve, mediate the communication between peripheral inflammatory processes and CNS. Cytokines such as IL-1beta, TNF-alpha and IFN-gamma seem to contribute to the pathophysiology of depression by activating monoamine reuptake, stimulating the hypothalamic pituitary-adrenocortical (HPA) axis and decreasing production of serotonin due to increased activity of indolamine-2,3-dioxygenase (IDO). However, critical appraisal of these hypotheses is required, because cytokine elevation is not specific to depression. Moreover, several effective antidepressants such as amitriptyline and mirtazapine have been shown to increase cytokine production. When applying immunomodulatory therapies, these drugs may increase the risk of specific side effects such as infections or interact with antidepressant drugs on important functions of the body such as the coagulation system. PMID- 24151805 TI - EEG biomarkers in major depressive disorder: discriminative power and prediction of treatment response. AB - Major depressive disorder (MDD) has high population prevalence and is associated with substantial impact on quality of life, not least due to an unsatisfactory time span of sometimes several weeks from initiation of treatment to clinical response. Therefore extensive research focused on the identification of cost effective and widely available electroencephalogram (EEG)-based biomarkers that not only allow distinguishing between patients and healthy controls but also have predictive value for treatment response for a variety of treatments. In this comprehensive overview on EEG research on MDD, biomarkers that are either assessed at baseline or during the early course of treatment and are helpful in discriminating patients from healthy controls and assist in predicting treatment outcome are reviewed, covering recent decades up to now. Reviewed markers include quantitative EEG (QEEG) measures, connectivity measures, EEG vigilance-based measures, sleep-EEG-related measures and event-related potentials (ERPs). Further, the value and limitations of these different markers are discussed. Finally, the need for integrated models of brain function and the necessity for standardized procedures in EEG biomarker research are highlighted to enhance future research in this field. PMID- 24151806 TI - Neuroimaging as a potential biomarker to optimize psychiatric research and treatment. AB - Complex, polygenic phenotypes in psychiatry hamper our understanding of the underlying molecular pathways and mechanisms of many diseases. The unknown aetiology, together with symptoms which often show a large variability both across individuals and over time and also tend to respond comparatively slowly to medication, can be a problem for patient treatment and drug development. We argue that neuroimaging has the potential to improve psychiatric treatment in two ways. First, by reducing phenotypic complexity, neuroimaging intermediate phenotypes can help to identify disease-related genes and can shed light into the biological mechanisms of known risk genes. Second, quantitative neuroimaging markers - reflecting the spectrum of impairment on a brain-based level - can be used as a more sensitive, reliable and immediate treatment response biomarker. In the end, enhancing both our understanding of the pathophysiology of psychiatric disorders and the prediction of treatment success could eventually optimise current therapy plans. PMID- 24151807 TI - Sleep as a biomarker for depression. AB - Sleep is a complex biological process that involves cyclic changes of brain activity. The smooth transition between wakefulness and sleep and cyclic succession of sleep stages depend on the function of numerous neurotransmitters that reciprocally influence each other. For this reason sleep is a very sensitive biomarker of brain functioning. This article provides an overview of sleep changes in depression, mechanisms involved in sleep regulation and pathophysiology underlying depression, studies on sleep as a biomarker for depression, effects of antidepressants on sleep EEG, and studies in depression with the use of quantitative sleep EEG analysis. Research on sleep in depression has provided several valuable biomarkers that are related to increased risk for depression, show worsening during depressive episode, and are related to treatment outcome and relapse risk during remission phase. Among many sleep parameters, increased REM density and diminished delta sleep ratio deserve special interest. Sleep studies are also an important research tool for antidepressant drug development. However, due to sensitivity of sleep parameters to pharmacological interventions, the patients have to be investigated before the start of pharmacological treatment or after washout from the antidepressant drug, to obtain reliable data on disease-related biological processes from polysomnography. PMID- 24151809 TI - Feedback in clinical education, part II: Approved clinical instructor and student perceptions of and influences on feedback. AB - CONTEXT: Approved Clinical Instructors (ACIs; now known as preceptors) are expected to provide feedback to athletic training students (ATSs) during clinical education experiences. Researchers in other fields have found that clinical instructors and students often have different perceptions of actual and ideal feedback and that several factors may influence the feedback exchanges between instructors and students. However, understanding of these issues in athletic training education is minimal. OBJECTIVE: To investigate the current characteristics and perceptions of and the influences on feedback exchanges between ATSs and ACIs. DESIGN: Qualitative study. SETTING: One entry-level master's degree program accredited by the Commission on Accreditation of Athletic Training Education. PATIENTS OR OTHER PARTICIPANTS: Four ACIs and 4 second-year ATSs. DATA COLLECTION AND ANALYSIS: Individual, semistructured interviews were conducted with participants and integrated with field notes and observations for analysis. We used the constant comparative approach to inductively analyze data and develop codes and categories. Member checking, triangulation, and peer debriefing were used to promote trustworthiness of the study. RESULTS: Participants described that feedback plays an important role in clinical education and has several purposes related to improving performance. The ACIs and ATSs also discussed several preferred characteristics of feedback. Participants identified 4 main influences on their feedback exchanges, including the ACI, the ATS, personalities, and the learning environment. CONCLUSIONS: The ACIs and ATSs had similar perceptions of ideal feedback in addition to the actual feedback that was provided during their clinical education experiences. Most of the preferences for feedback were aligned with recommendations in the literature, suggesting that existing research findings are applicable to athletic training clinical education. Several factors influenced the feedback exchanges between ACIs and ATSs, which clinical education coordinators should consider when selecting clinical sites and training ACIs. PMID- 24151810 TI - Invalid performance and the ImPACT in national collegiate athletic association division I football players. AB - CONTEXT: Immediate Post-Concussion Assessment and Cognitive Testing (ImPACT) is a computerized cognitive test battery commonly used for concussion evaluation. An important aspect of these procedures is baseline testing, but researchers have suggested that many users do not use validity indices to ensure adequate effort during testing. No one has examined the prevalence of invalid performance for college football players. OBJECTIVE: To examine the prevalence of invalid scores on ImPACT testing. DESIGN: Cross-sectional study. SETTING: National Collegiate Athletic Association Division I university. PATIENTS OR OTHER PARTICIPANTS: A total of 159 athletes (age = 20.3 +/- 1.41 years; range = 17.8-23.7 years) from a Division I collegiate football team participated. INTERVENTION(S): An informational intervention regarding the importance of concussion testing to promote safety was administered before testing for the most recent season. MAIN OUTCOME MEASURE(S): We examined preseason ImPACT testing data across a 3-year period (total assessments = 269). Based on invalid and sandbagging indices denoted by the ImPACT manual, protocols were examined to indicate how many invalid indices each athlete had. RESULTS: A total of 27.9% (n = 75) of assessments were suggestive of invalid scores, with 4.1% (n = 11) suggesting invalid responding only, 17.5% (n = 47) indicating "sandbagging" only, and 6.3% (n = 17) showing both invalid and sandbagging responding. The informational intervention did not reduce the prevalence of invalid responding. CONCLUSIONS: These findings highlight the need for further information about the ImPACT validity indices and whether they truly reflect poor effort. Future work is needed to identify practices to reliably target and reduce invalid responding. PMID- 24151811 TI - Unprecedented nitronyl nitroxide bridged 3d-4f complexes: structure and magnetic properties. AB - Two novel 2p-3d-4f compounds, {Ln(hfac)3[Cu(hfac)2]3(NITPhPyrim)2} [Ln = Gd (1), Dy (2)], have been obtained by reacting phenyl pyrimidyl nitronyl nitroxide with Cu(hfac)2 and Ln(hfac)3. These two compounds are the first examples of two dimensional 3d-4f complexes bridged by nitronyl nitroxide radicals. Overall ferromagnetic behaviors were observed in both compounds. PMID- 24151812 TI - Del-1 overexpression in endothelial cells increases vascular density in tissue engineered implants containing endothelial cells and adipose-derived mesenchymal stromal cells. AB - We used a combination of strategies to stimulate the vascularization of tissue engineered constructs in vivo including a modular approach to build larger tissues from individual building blocks ("modules") mixed together. Each building block included vascular cells by design; modules were submillimeter-sized collagen gels with an outer layer of endothelial cells (ECs), and with embedded adipose-derived mesenchymal stromal cells (adMSCs) to support EC survival and blood vessel maturation in vivo. We transduced the ECs that coat the modules with a lentiviral construct to overexpress the angiogenic extracellular matrix (ECM) protein Developmental endothelial locus-1 (Del-1). Upon injection of modules in a subcutaneous SCID/Bg mouse model, there was an increase in the number of blood vessels for implants with ECs transduced to overexpress Del-1 compared with control implants (with enhanced green fluorescent protein [eGFP]-transduced ECs) over the 21-day duration of the study. The greatest difference between Del-1 and eGFP implants and the highest number of blood vessels were observed 7 days after transplantation. The day-7 Del-1 implants also had increased SMA+ staining compared with control, suggesting increased blood vessel maturation through recruitment of SMA+ smooth muscle cells or pericytes to stabilize the newly formed blood vessels. Perfusion studies (microcomputed tomography, ultrasound imaging, and systemic injection of fluorescent UEA-1 or dextran) showed that some of the newly formed blood vessels (both donor derived and host derived, in both Del-1 and eGFP implants) were perfused and connected to the host vasculature as early as 7 days after transplantation, and at later time points as well. Nevertheless, perfusion of the implants was limited in some cases, suggesting that further improvements are necessary to normalize the vasculature at the implant site. PMID- 24151814 TI - MC4R rs17782313 gene polymorphism was associated with glycated hemoglobin independently of its effect on BMI in Japanese: the Shimane COHRE study. AB - BACKGROUND: Type 2 diabetes (T2D) is among the leading public health problems in Japan, and glycated hemoglobin (HbA1c) can be used to screen the population for T2D. Gene polymorphisms, known to be associated with obesity, may predispose individuals to T2D. Rs17782313 the melanocortin 4 receptor (MC4R) has shown one of the strongest associations with body mass index (BMI). We conducted a study to investigate whether rs17782313 (TT versus TC + CC) was associated with HbA1c. METHOD: We conducted a cross-sectional study including 1142 Japanese adults (446 men: 64.9 +/- 14.4 years and 696 women: 66.7 +/- 12.3 years). MC4R rs17782313 was genotyped using fast real-time polymerase chain reaction. RESULTS: TC + CC genotype group showed significantly greater BMI (p = 0.039) and HbA1c (p = 0.001) than TT genotype group after adjustment for gender, age and, for HbA1c, BMI. Further analysis using linear regression analysis confirmed that the effect of MC4R rs17782313 on HbA1c (beta = 0.08; p = 0.003) was independent of the effect age, gender, BMI, low density lipoprotein cholesterol, homeostasis model assessment of insulin resistance and of beta cell function. This significant independent association was similarly noticed in non-obese (beta = 2.82; p = 0.005) subgroups. CONCLUSION: MC4R rs17782313 was associated with obesity and could confer a certain susceptibility to T2D that could be independent of its pro obesity effect. PMID- 24151815 TI - Immunohistochemical analysis of KBA.62 in 18 neurothekeomas: a potential marker for differentiating neurothekeoma, but a marker that may lead to confusion with melanocytic tumors. AB - BACKGROUND: Neurothekeoma represents a neoplasm of uncertain histogenesis that often occurs on the head and neck of younger individuals. Distinguishing neurothekeoma from other tumors, particularly malignancies such as melanoma, can be difficult given the variable presence of nuclear atypia, mitoses and extension into fat or skeletal muscle. KBA.62 represents an anti-melanoma monoclonal antibody that marks approximately 93% of melanomas. This study sought to evaluate KBA.62 expression in neurothekeomas, both as means of affirming the diagnosis and as a potential confounding factor in excluding a melanocytic process. METHODS: Eighteen neurothekeomas from 17 patients were analyzed by light microscopy and immunohistochemistry. Immunohistochemistry was performed with KBA.62, S100 and CD10 antibodies. The diagnosis of neurothekeoma was confirmed by at least two dermatopathologists. RESULTS: All cases showed similar light microscopic and immunohistochemical features. With the exception of two cases, cells expressed CD10 and exhibited morphologic features consistent with neurothekeoma. All 18 cases were S100 immunonegative. The epithelioid cells of all neurothekeomas were KBA.62 immunopositive, including both of two neurothekeomas occurring in the same patient. CONCLUSIONS: In this study 100% of neurothekeomas tested were KBA.62 positive, admittedly to varying degrees, suggesting the utility of this reagent as being supportive of the diagnosis of neurothekeoma. PMID- 24151816 TI - Can we predict sudden cardiac death in long-term survivors of atrial switch surgery for transposition of the great arteries? AB - OBJECTIVE: This study aims to identify predictors of sudden cardiac death (SCD) in patients with transposition of the great arteries (TGA) who have undergone atrial baffle surgery with the Mustard or Senning operation. BACKGROUND: Patients with TGA and previous atrial baffle surgery are known to be at increased risk of SCD. Despite this, indications for insertion of an implantable cardiac defibrillator for primary prevention have not been established. METHODS: Eighty nine patients with a diagnosis of TGA and previous Mustard or Senning repair were identified. Medical records were reviewed for SCD, aborted SCD, implantation of cardiac defibrillator (ICD), and use of cardiac medications. Clinically significant events (heart failure admissions, documented arrhythmias, and insertion of a pacemaker) were ascertained, and results of echocardiograms were explored. RESULTS: There were five SCDs in our population, and five patients underwent a primary prevention ICD insertion, with no subsequent sustained ventricular arrhythmia or aborted SCD. Patients who suffered SCD had undergone surgery at an older age (median 53 months vs. 14 months) in a slightly earlier era (median year of operation 1971 vs. 1975). Atrial arrhythmias requiring treatment were documented in 100% of the SCD and in 29% of the no SCD patients. CONCLUSIONS: Criteria for insertion of primary prevention implantable cardiac defibrillators postatrial baffle surgery remain to be established. In the SCD subgroup, surgery at an older age, earlier era of surgical repair, and history of atrial arrhythmia appear to convey an increased risk of sudden death. PMID- 24151817 TI - Predicting goal achievement during stroke rehabilitation for Medicare beneficiaries. AB - PURPOSE: Few studies have investigated the ability of treatment teams to predict functional improvement and whether an association between predicted goals and discharge function in patients with stroke exists. This study investigated goal prediction during stroke rehabilitation delivered in inpatient rehabilitation facilities (IRF) and the factors associated with goal prediction. METHODS: A serial, cross-sectional design analyzing the Medicare IRF Patient Assessment Instrument dataset. The sample included 179 479 admissions for stroke aged over 65 years in 968 IRFs. Generalized estimating equations (GEE) controlled for facility cluster effects were used for analysis of time trends for length of stay (LOS), predicted Functional Independence Measure (FIM) scores, discharge FIM scores and predicted-discharge difference FIM scores (goal FIM scores minus discharge FIM scores). GEE models were employed to determine the correlation between predicted FIM and discharge FIM scores and factors associated with goal achievement. RESULTS: Mean LOS, predicted FIM scores and discharge FIM scores decreased 1.8 d, 2.2 points and 3.6 points, respectively, while predicted discharge difference FIM scores increased 1.3 points. Discharge goals were not met 78.9% of the time. After controlling for patient characteristics, each predicted FIM point was associated with 0.6 discharge FIM points (p < 0.0001). Factors associated with not meeting or exceeding goals were: age (odds ratio; OR = 0.997), African Americans (OR = 0.905), number of comorbidities (OR = 0.970), number of complications (OR = 0.932) and right brain stroke (OR = 0.869). Factors associated with meeting or exceeding goals were: LOS (OR = 1.03), admission FIM score (OR = 1.02) and females (OR = 1.05). CONCLUSIONS: Trends for lower goals and lower discharge function occurred over time. A correlation existed between predicted FIM scores and discharge FIM scores. Patient factors were associated with goal achievement. IMPLICATIONS FOR REHABILITATION: Using the Functional Independence Measure, rehabilitation teams set lower goals for stroke rehabilitation in inpatient rehabilitation facilities during first 5.5 years of the IRF-PAI dataset. Discharge FIM scores also trended lower and fell at faster rate than goal FIM scores. Teams' goal FIM scores averaged nearly 12 points higher than discharge FIM scores, and over 75% of patients did not reach goals for the rehabilitation stay. Factors associated with meeting or exceeding goals were: length of stay, admission FIM scores and being a female. Factors associated with not meeting or exceeding goals were: age, number of comorbidities and complications, having a right-brain stroke and being African American. PMID- 24151818 TI - Dysarthria and dysphagia are highly prevalent among various types of neuromuscular diseases. AB - PURPOSE: Patients with a neuromuscular disease (NMD) can present with dysarthria and/or dysphagia. Literature regarding prevalence rates of dysarthria and dysphagia is scarce. The purpose of this study was to determine prevalence rates, severity and co-presence of dysarthria and dysphagia in adult patients with NMD. METHOD: Two groups of adult patients with NMD were included: 102 consecutive outpatients (the "unselected cohort") and 118 consecutive patients who were referred for multidisciplinary assessment (the "selected cohort"). An experienced speech-language pathologist examined each patient in detail. RESULTS: The pooled prevalence of dysarthria was 46% (95% CI: 36.5-55.9) and 62% (95% CI: 53.3-70.8) in the unselected and selected cohorts, respectively. The pooled prevalence of dysphagia was 36% (95% CI: 27.1-45.7) and 58% (95% CI: 49.4-67.2) in the unselected and selected cohorts, respectively. There was a modest but significant association between the presence of dysarthria and dysphagia (rs = 0.40; p < 0.01). Although the dysphagia was generally mild, dysarthria was moderate to severe in 15% of the dysarthric patients. CONCLUSION: The prevalence rates of dysarthria and dysphagia among patients with various types of NMD are high. Physicians should therefore be aware of this prevalence and consider referring NMD patients to a speech-language pathologist. IMPLICATONS OF REHABILITATION: Both dysarthria and dysphagia are highly prevalent among patients with neuromuscular diseases; moreover, although often mild, these disorders can occur relatively early in the course of the disease. Clinicians should routinely check for signs and symptoms related to dysarthria and/or dysphagia in patients who present with a neuromuscular disease, preferably using standardised instruments. PMID- 24151819 TI - Applications of the International Classification of Functioning, Disability and Health in goal-setting practices in healthcare. AB - PURPOSE: While evidence exists to support the adoption of collaborative goal setting in healthcare, some clinicians feel that it is not feasible. This article proposes that the development of a standardized collaborative goal-setting approach using the framework and classification system of the International Classification of Functioning, Disability and Health (ICF) could address these feasibility issues. It is the objective of this article to understand the extent to which the ICF has been integrated into current goal-setting literature in order to assess its potential use in a standardized collaborative goal-setting approach. METHODS: A scoping review of the literature published in English since 2001 was conducted in EMBASE, Medline and CINAHL. Articles were included in this review if they integrated the ICF into goal-setting practices in any healthcare discipline. RESULTS: Nineteen articles were included in this review. Analysis of these articles revealed that the ICF has been integrated into goal-setting practices. The benefits associated with this integration suggest that integrating the ICF into goal-setting practices can standardize collaborative goal-setting. CONCLUSION: Evidence from this scoping review supports the use of the ICF in healthcare goal-setting practices because it provides clinicians and patients with specific steps to follow when attempting to set goals collaboratively. IMPLICATIONS FOR REHABILITATION: Collaborative goal-setting. Collaborative goal setting involves patients working with their clinicians to develop health outcome goals together and is a fundamental component of patient-centered care. Some rehabilitation disciplines have yet to fully embrace collaborative goal-setting due to feasibility issues. This article proposes that the integration of the International Classification of Functioning, Disability and Health (ICF) into goal-setting practices could standardize collaborative goal-setting in a way that would address these feasibility issues. PMID- 24151820 TI - A scoping review of 10 years of published literature on community-based rehabilitation. AB - PURPOSE: To identify the characteristics of peer-reviewed literature on community based rehabilitation (CBR) in low- and middle-income countries published in English from 2003 to 2012. METHODS: This scoping review involved a systematic search of electronic databases using specific keyword/subject heading combinations. Journal articles were included if they were published in English, used "CBR" as related to rehabilitation with persons with disabilities and not limited to high-income countries (HICs). Data were charted according to both pre determined and emergent categories. A subset of articles was charted by two reviewers to ensure reliability of variables. RESULTS: A total of 114 articles were included. Fifty-two articles presented empirical research and 49 were published in one of two journals. The articles represented CBR activity in 26 specific countries, although only two of these were in Europe and only one was in the Americas. Authors were predominantly affiliated at universities and in HICs. CONCLUSIONS: This scoping review identified and characterized a large pool of literature on CBR, facilitating its incorporation into research and practice. Future research should examine the engagement of persons with disabilities in creating CBR literature, and analysis of literature in languages other than English. Implications for Rehabilitation Community-based rehabilitation (CBR) has been promoted as a rehabilitation strategy of choice in low- and middle-income countries (LMICs), but it has been critiqued for lack of an evidence base. A large number (114) of peer-reviewed articles were published on CBR between 2003 and 2012. Just under half of these articles (45%) presented empirical research, indicating that the evidence base for CBR is growing but will benefit from continued, rigorous inquiry. Furthermore, researchers from LMICs appear to be largely under-represented in published CBR research, flagging the need to support LMIC partners to share their CBR research in peer-reviewed journals. PMID- 24151821 TI - Negative control glucose dependent mediated by the PreS2 region on the translation efficiency of the reporter Sh-bleomycin gene in Saccharomyces cerevisiae. AB - Saccharomyces cerevisiae is able to sense and respond to environmental changes such as the availability of carbon sources. In a previous work, we showed that the expression of the PreS2-S gene of HBV in yeast was negatively regulated at the translational level dependent of glucose. In this study, we show that the S mRNA is detected in the polysomes indicating its active translation, while the PreS2-S mRNA was mainly found in monosomes. Moreover, we used the gene reporter assay based on Zeocin resistance, to better characterize the PreS2 region responsible for this control. Two chimeric genes composed of the N- and C terminal part of the PreS2 fused to the Sh-bleomycin gene conferring the resistance to Zeocin were expressed in yeast. We found that the strain expressing the N-terminal part of the PreS2 was sensitive to Zeocin on rich medium with 2% glucose. In contrast, the strain harbouring the C-terminal part of the PreS2 fused to the Sh-bleomycin grew on Zeocin, indicating that the Sh-bleomycin mRNA is efficiently translated, subsequently conferring resistance to Zeocin. Our data suggest the establishment of a translational control via the N-terminal part of the PreS2 mediated by the presence of 2% glucose in the media. PMID- 24151822 TI - Diversity of influences on infant feeding strategies in women living with HIV in Cape Town, South Africa: a mixed methods study. AB - OBJECTIVE: To explore influences on infant feeding intentions and practices in women living with HIV in South Africa. METHODS: Structured questionnaires were completed by 207 pregnant women and 203 post-partum women in Cape Town, South Africa. Concurrently, 34 semi-structured, qualitative interviews explored the influences on infant feeding strategies in women living with HIV. RESULTS: Overall, 50% (104) of pregnant women intended to breastfeed and 22% (45) of post partum women ever breastfed. Women who breastfed or intended to breastfeed were significantly more likely to have running water in their homes, to have formal housing and to receive advice in support of breastfeeding. Advice from clinic staff was the strongest predictor of breastfeeding [adjusted relative odds (ARO) in pregnant women: 6.87; 95% confidence interval (CI): 2.67, 17.66; ARO in post partum women: 4.04; 95% CI: 1.60, 10.19]. Other important influences included previous infant feeding experiences, desires to protect the infant from HIV and involvement of other care providers. Many women also noted that breastfeeding was not feasible due to work commitments and highlighted concerns around the discontinuation of the free provision of infant formula. CONCLUSION: These results suggest that women living with HIV balance complex influences in deciding on their preferred infant feeding strategies. This underscores the need for extensive provider, patient and community education to ensure consistent messaging, while allowing for adaptation to the circumstances of individual mothers. PMID- 24151823 TI - Type 2 diabetes mellitus and hypothyroidism: the possible influence of metformin therapy. AB - AIMS: To evaluate the frequency with which hypothyroidism is associated with Type 2 diabetes, to examine gender and ethnic group differences, and to assess the possible impact of metformin therapy. To compare the prevalence of hypothyroidism in a cohort of people with Type 2 diabetes with a previously published cohort of people with Type 1 diabetes from the same centre. METHOD: We randomly surveyed the records of 922 people with Type 2 diabetes (576 men and 342 women) to identify diagnoses of hypothyroidism, based on current thyroxin replacement therapy (with previous biochemical confirmation). Four subjects had secondary hypothyroidism after radio-iodine therapy for primary hyperthyroidism and were excluded from the analysis. The prevalence of primary hypothyroidism was documented in the remaining 918 subjects. We assessed the association of metformin therapy with hypothyroidism. RESULTS: The overall prevalence of primary hypothyroidism was 11.8% (women: 22.5%; men: 5.4%, P < 0.001) in subjects with Type 2 diabetes. Inter-ethnic differences were noted, with the highest prevalence among white subjects. The prevalence of hypothyroidism was lower in subjects with Type 2 diabetes who were receiving metformin therapy (P < 0.01), and this difference was greater when assessing those who developed primary hypothyroidism after starting metformin therapy (P < 0.001) CONCLUSIONS: Our results support a relatively close association between diabetes and hypothyroidism. Hypothyroidism was more common in the cohort of white subjects than in other ethnic groups. The use of metformin therapy in people with Type 2 diabetes was associated with a significantly lower prevalence of diagnosed hypothyroidism. PMID- 24151824 TI - Dimensional changes in soft tissues around dental implants following free gingival grafting: an experimental study in dogs. AB - OBJECTIVE: To study the buccal dimensional tissue changes at oral implants following free gingival grafting, with or without including the keratin layer, performed at the time of implant installation into alveolar mucosa. MATERIAL AND METHODS: The mandibular premolars and first molars were extracted bilaterally in six Beagle dogs. In the right side of the mandible (Test), flaps were first elevated, and the buccal as well as part of the lingual masticatory mucosa was removed. An incision of the periosteum at the buccal aspect was performed to allow the flap to be coronally repositioned. Primary wound closure was obtained. In the left side, the masticatory (keratinized) mucosa was left in situ, and no sutures were applied (Control). After 3 months of healing, absence of keratinized mucosa was confirmed at the test sites. Two recipient sites were prepared at each side of the mandible in the region of the third and fourth premolars. All implants were installed with the shoulder placed flush with the buccal alveolar bony crest, and abutments were connected to allow a non-submerged healing. Two free gingival mucosal grafts were harvested from the buccal region of the maxillary canines. One graft was left intact (gingival mucosal graft), while for the second, the epithelial layer was removed (gingival connective tissue graft). Subsequently, the grafts were fixed around the test implants in position of the third and fourth premolars, respectively. After 3 months, the animals were euthanized and ground sections obtained. RESULTS: Similar bony crest resorption and coronal extension of osseointegration were found at test and control sites. Moreover, similar dimensions of the peri-implant soft tissues were obtained at test and control sites. CONCLUSIONS: The increase in the alveolar mucosal thickness by means of a gingival graft affected the peri-implant marginal bone resorption and soft tissue recession around implants. This resulted in outcomes that were similar to those at implants surrounded by masticatory mucosa, indicating that gingival grafting in the absence of keratinized mucosa around implants may reduce the resorption of the marginal crest and soft tissue recession. PMID- 24151825 TI - Publishing data from failed cytogenetic assays- what can we learn? PMID- 24151826 TI - Mechanistic evaluation of substrate inhibition kinetics observed from aldehyde oxidase-catalyzed reactions. AB - While most enzyme-catalyzed reactions are adequately described by Michaelis Menten kinetics, Aldehyde Oxidase (AOX) metabolism might exhibit atypical kinetics due to possible substrate inhibition. Ignoring this phenomenon may lead to erroneous estimates of kinetic parameters and over simplification of the enzyme mechanism. In this study, in vitro metabolism data for 3 AOX substrates exhibiting varying degrees of substrate inhibition were analyzed with the following kinetic models: A) Michaelis-Menten (naive) model; B) Substrate inhibition (empirical) model; and C) Twobinding site (mechanistic) model. The application of this mechanistic model is a novel interpretation for kinetic analysis of AOX metabolism whereby substrate can presumably bind to two enzymes' active site(s). Unlike the other models, this mechanistic model quantitatively captures the degree of substrate inhibition observed. Analysis by this model showed: A) All tested substrates have simultaneous access to the metabolic and inhibitory site of the enzyme with Ks (binding affinity for inhibitory site) greater (1.3- to 28-fold) than Km (binding affinity for metabolic site); B) Dissociation constants for binding of a second substrate in either the productive and nonproductive enzyme conformations decreased with factor alpha ranging from 2.58 to 15.6 between compounds; and C) In addition, a drastic decrease (from 64% 98%) in the metabolism rates between compounds was exhibited by factor beta (ranging from 0.02-0.36). Overall, the mechanistic two-binding site model best fitted the experimental data. Moreover, the observed differences between kinetic parameters generated by these models highlight the importance of appropriate model selection to adequately fit the substrate inhibition kinetics of AOX metabolism. PMID- 24151827 TI - Effects of obesity induced by high-fat diet on the pharmacokinetics of atazanavir in rats. AB - We studied the effects of obesity on the pharmacokinetics of atazanavir (ATV) using a rat model of high-fat diet-induced obesity (obese rats). The areas under the plasma concentration-time curves for intravenous bolus, oral, and intraportal administration of ATV in obese rats were significantly greater than the corresponding values in control rats. Total plasma clearance of ATV after intravenous bolus injection in the obese rats (0.80 +/- 0.07 L/h/kg) was approximately half of that in the control rats (1.55 +/- 0.18 L/h/kg). Furthermore, ATV concentration in the plasma-unbound fraction of the obese rats (4.2% +/- 2.6%) was significantly lower than that in the control rats (14.2% +/- 2.3%). Such differences may result in changes in ATV distribution from the systemic circulation to peripheral or central tissues, and the pharmacological effects of ATV may therefore be reduced in obese patients. Moreover, hepatic extraction in the obese rats (13.5% +/- 1.6%) was approximately 62% of that in the controls (21.9% +/- 0.96%). These results suggest that hepatic metabolism decreased and that dosing regimens should be carefully evaluated in obese patients. Therefore, in obese patients, it is necessary to pay careful attention to therapeutic drug monitoring data, and the use of specific dosing regimens, as well as that of monitoring system for liver fat accumulation are recommended. PMID- 24151828 TI - Current therapy in sarcoidosis, the role of existing drugs and future medicine. AB - Sarcoidosis is a systemic, granulomatous disease that can affect multiple organs and has a variable clinical course. Corticosteroids (e.g. prednisone) remain the mainstay of therapy in sarcoidosis since their first use in this disease in the 1950s. A second-line therapeutic is often added to the treatment regimen in case of intolerable side effects, inefficacy or prolonged use of steroids. Methotrexate is considered by many to be the first choice drug in second-line therapeutics of sarcoidosis. Other often used second-line drugs are azathioprine and leflunomide. No large trials comparing different treatment options have been performed in sarcoidosis. In patients with severe disease who do not respond well to first and second-line therapy, biologicals such as infliximab can be promising. In this review, we provide a complete overview of all currently available therapeutic strategies in sarcoidosis. In addition, the gaps in current literature on sarcoidosis treatment were depicted to underline the importance of research in this mostly empiric field of medicine. Furthermore we highlight future medicine in sarcoidosis with emphasis on the role of personalised medicine. PMID- 24151829 TI - Recovery of stress response coincides with responsiveness to voluntary exercise after traumatic brain injury. AB - We have recently shown that there is a heightened stress response after a mild traumatic brain injury (TBI) during the first 2 post-injury weeks. This corresponds to the same post-injury period when exercise does not increase brain derived neurotrophic factor (BDNF) and autonomic dysfunction becomes evident with exercise. Here we determined stress and autonomic responses to voluntary and forced exercise at a post-injury time window when exercise has been found to elicit beneficial effects. Rats underwent a mild fluid percussion injury and were exercised at post-injury days 28-32 and 35-39. Cardiac and temperature autonomic function were evaluated. Hippocampal tissue was obtained immediately after exercise for analysis of BDNF. In contrast to the sub-acute period, corticosterone and adrenocorticotropic hormone responses to exercise were normalized in the TBI group. Irrespective of injury, forced exercise markedly stimulated the corticotrophic axis and did not increase BDNF. BDNF levels were increased with voluntary exercise in all animals. Rats exposed to forced exercise had lower activity levels during periods of non-exercise. This effect was more pronounced in the TBI rats. Cardiac and temperature autonomic responses to delayed exercise also recuperated. Rats with TBI that underwent forced exercise, however, had higher core body temperatures during experimental manipulations, thus suggesting that exposure to a potent stressor facilitates responsiveness to environmental stimulations. PMID- 24151830 TI - Therapy of H7N9 pneumonia: current perspectives. PMID- 24151831 TI - Inadequate research on methicillin-resistant Staphylococcus aureus risk among postpartum women. PMID- 24151833 TI - HIV-1 genetic variation and drug resistance development. AB - Up until 10 years ago, basic and clinical HIV-1 research was mainly performed on HIV-1 subtype B that predominated in resource-rich settings. Over the past decade, HIV-1 care and therapy has been scaled up substantially in Latin America, Africa and Asia. These regions are largely dominated by non-B subtype infections, and especially the African continent is affected by the HIV pandemic. Insight on the potency of antiviral drugs and regimens as well as on the emergence of drug resistance in non-B subtypes was lacking triggering research in this field, also partly driven by the introduction and spreading of HIV-1 non-B subtypes in Europe. The scope of this article was to review and discuss the state-of-the-art on the impact of HIV-1 genetic variation on the in vitro activity of antiviral drugs and in vivo response to antiviral therapy; as well as on the in vitro and in vivo emergence of drug resistance. PMID- 24151834 TI - Clostridium difficile surveillance: harnessing new technologies to control transmission. AB - Clostridium difficile surveillance allows outbreaks of cases clustered in time and space to be identified and further transmission prevented. Traditionally, manual detection of groups of cases diagnosed in the same ward or hospital, often followed by retrospective reference laboratory genotyping, has been used to identify outbreaks. However, integrated healthcare databases offer the prospect of automated real-time outbreak detection based on statistically robust methods, and accounting for contacts between cases, including those distant to the ward of diagnosis. Complementary to this, rapid benchtop whole genome sequencing, and other highly discriminatory genotyping, has the potential to distinguish which cases are part of an outbreak with high precision and in clinically relevant timescales. These new technologies are likely to shape future surveillance. PMID- 24151835 TI - Enhanced cytotoxicity of optimized liposomal genistein via specific induction of apoptosis in breast, ovarian and prostate carcinomas. AB - Clinical use of genistein against cancer is limited by its extremely low aqueous solubility, poor bioavailability and pharmacokinetics. Based on structural analogy with steroidal compounds, liposomal vehicle compositions were designed and optimized for maximum incorporation of genistein's flavonoid structure. Model conventional and stealth liposomes of genistein (GenLip)--incorporating unsaturated phospholipids and cholesterol--have demonstrated enhanced drug solubilization (over 350-folds > aqueous drug solution), shelf-life stability, and extended release profile. Owing to effective cellular delivery, preservation of genistein's antioxidant activity was confirmed through marked neutralization of peroxides via GenLip, in both quantitative and microscopic fluorescent-probe oxidation assays. Furthermore, significant broad-spectrum anticancer efficacy of GenLip, in murine and human cancer cell lines (p < 0.05-0.001), was achieved in a concentration and time-dependent manner--approx. 5-7 lower IC50 values versus all non-incorporated drug controls. Indicative of key pro-apoptotic activity, GenLip produced DNA laddering, with 1/3 of free drug solution content, and resulted in the highest induction level of P53-independent apoptotic pathway markers, compared to all treatments, in our assays (namely, mitochondrial polarization, and caspase-3/7 enzymes). Our proof-of-principle pharmaceutical design of genistein-loaded liposomes shows optimal loading capacity and physico-chemical properties, which improved cellular delivery and specific pro-apototic effectiveness of incorporated drug, against various cancers. PMID- 24151836 TI - Association study of glucocorticoid receptor genetic polymorphisms with efficacy of glucocorticoids in systemic lupus erythematosus: a prospective cohort study. AB - The response to glucocorticoids (GCs) for patients with systemic lupus erythematosus (SLE) is characterized by wide interindividual variability, with a significant number of patients who have no response. We analyzed whether genetic polymorphisms within glucocorticoid receptor (GR) gene are related to variability in the efficacy of GCs in Chinese population with SLE. A cohort of 220 patients with SLE was studied. These patients were treated with GCs (prednisone) for 12 weeks. The efficacy of GCs was measured with the scores on SLE disease activity index (SLEDAI). Patients were classified into two groups (sensitive and insensitive) according to their response to GCs. Polymorphisms of GR gene were genotyped by using multiplex SNaPshot method. A total of 212 patients (96.4%) were included in the final data analyses. Of these patients, 110 patients were considered sensitive to GCs, and 102 patients were considered insensitive to GCs. Eighteen tag single nucleotide polymorphisms (SNPs) of GR gene were selected. Significant associations were seen for rs4912905 (dominant model: crude OR = 0.410, 95%CI = 0.233-0.722, p = 0.002; adjusted OR = 0.419, 95%CI = 0.233-0.754, p = 0.004), rs17100234 (dominant model: crude OR = 0.521, 95%CI = 0.282-0.963, p = 0.038; adjusted OR = 0.520, 95%CI = 0.279-0.970, p = 0.040) and rs7701443 (recessive model: crude OR = 2.736, 95%CI = 1.183-6.331, p = 0.019; adjusted OR = 2.639, 95%CI = 1.116-6.239, p = 0.027) in GR gene, but not for other polymorphisms (p > 0.05). The results of the present study suggest that GR genetic polymorphisms may play a major role in the efficacy of GCs in Chinese population with SLE. PMID- 24151837 TI - Measurement techniques for respiratory tract deposition of airborne nanoparticles: a critical review. AB - Determination of the respiratory tract deposition of airborne particles is critical for risk assessment of air pollution, inhaled drug delivery, and understanding of respiratory disease. With the advent of nanotechnology, there has been an increasing interest in the measurement of pulmonary deposition of nanoparticles because of their unique properties in inhalation toxicology and medicine. Over the last century, around 50 studies have presented experimental data on lung deposition of nanoparticles (typical diameter<=100 nm, but here<=300 nm). These data show a considerable variability, partly due to differences in the applied methodologies. In this study, we review the experimental techniques for measuring respiratory tract deposition of nano-sized particles, analyze critical experimental design aspects causing measurement uncertainties, and suggest methodologies for future studies. It is shown that, although particle detection techniques have developed with time, the overall methodology in respiratory tract deposition experiments has not seen similar progress. Available experience from previous research has often not been incorporated, and some methodological design aspects that were overlooked in 30-70% of all studies may have biased the experimental data. This has contributed to a significant uncertainty on the absolute value of the lung deposition fraction of nanoparticles. We estimate the impact of the design aspects on obtained data, discuss solutions to minimize errors, and highlight gaps in the available experimental set of data. PMID- 24151839 TI - New polymorph of InVO4: a high-pressure structure with six-coordinated vanadium. AB - A new wolframite-type polymorph of InVO4 is identified under compression near 7 GPa by in situ high-pressure (HP) X-ray diffraction (XRD) and Raman spectroscopic investigations on the stable orthorhombic InVO4. The structural transition is accompanied by a large volume collapse (DeltaV/V = -14%) and a drastic increase in bulk modulus (from 69 to 168 GPa). Both techniques also show the existence of a third phase coexisting with the low- and high-pressure phases in a limited pressure range close to the transition pressure. XRD studies revealed a highly anisotropic compression in orthorhombic InVO4. In addition, the compressibility becomes nonlinear in the HP polymorph. The volume collapse in the lattice is related to an increase of the polyhedral coordination around the vanadium atoms. The transformation is not fully reversible. The drastic change in the polyhedral arrangement observed at the transition is indicative of a reconstructive phase transformation. The HP phase here found is the only modification of InVO4 reported to date with 6-fold coordinated vanadium atoms. Finally, Raman frequencies and pressure coefficients in the low- and high-pressure phases of InVO4 are reported. PMID- 24151838 TI - Control of perfusable microvascular network morphology using a multiculture microfluidic system. AB - The mechanical and biochemical microenvironment influences the morphological characteristics of microvascular networks (MVNs) formed by endothelial cells (ECs) undergoing the process of vasculogenesis. The objective of this study was to quantify the role of individual factors in determining key network parameters in an effort to construct a set of design principles for engineering vascular networks with prescribed morphologies. To achieve this goal, we developed a multiculture microfluidic platform enabling precise control over paracrine signaling, cell-seeding densities, and hydrogel mechanical properties. Human umbilical vein endothelial cells (HUVECs) were seeded in fibrin gels and cultured alongside human lung fibroblasts (HLFs). The engineered vessels formed in our device contained patent, perfusable lumens. Communication between the two cell types was found to be critical in avoiding network regression and maintaining stable morphology beyond 4 days. The number of branches, average branch length, percent vascularized area, and average vessel diameter were found to depend uniquely on several input parameters. Importantly, multiple inputs were found to control any given output network parameter. For example, the vessel diameter can be decreased either by applying angiogenic growth factors--vascular endothelial growth factor (VEGF) and sphingosine-1-phsophate (S1P)--or by increasing the fibrinogen concentration in the hydrogel. These findings introduce control into the design of MVNs with specified morphological properties for tissue-specific engineering applications. PMID- 24151840 TI - Synthesis and evaluation of a photoactive probe with a multivalent carbohydrate for capturing carbohydrate-lectin interactions. AB - Lectins are ubiquitous carbohydrate-binding proteins of nonimmune origin that are characterized by their specific recognition of defined monosaccharide or oligosaccharide structures. However, the use of carbohydrates to study lectin has been restricted by the weak binding affinity and noncovalent character of the interaction between carbohydrates and lectin. In this report, we designed and synthesized a multifunctional photoaffinity reagent composed of a trialkyne chain, a masked latent amine group, and a photoreactive 3-trifluoromethyl-3 phenyl-diazirine group in high overall yield. Two well-defined chemistries, Huisgen-Sharpless click chemistry and amide bond coupling, were the key steps for installing the multivalent character and tag in our designed photoaffinity probe. The photolabeling results demonstrated that the designed probe selectively labeled the target lectin, RCA120 ( Ricinus communis Agglutinin), in an E. coli lysate and an asialoglycoprotein receptor (ASGP-R) on intact HepG2 cell membranes. Moreover, the probe also enabled the detection of weak protein-protein interactions between RCA120 and ovalbumin (OVA). PMID- 24151843 TI - Elotuzumab: a novel anti-CS1 monoclonal antibody for the treatment of multiple myeloma. AB - INTRODUCTION: While conventional therapies are associated with high response rates in patients with newly diagnosed multiple myeloma, the development of drug resistance remains an issue, and effective therapy for relapsed and refractory patients represents a major clinical unmet need. AREAS COVERED: We reviewed the published data regarding the development and clinical investigation of a CS1 targeted monoclonal antibody, elotuzumab , for the potential treatment of multiple myeloma. Preclinical pharmacological data, along with clinical efficacy, safety, and tolerability of elotuzumab alone and in combination, are summarized. EXPERT OPINION: Elotuzumab, in combination with lenalidomide, demonstrated a remarkably high overall response rate in Phase I and II studies. Additionally, the improvements observed in progression-free survival suggested important superiority over lenalidomide/dexamethasone alone, with a similar tolerability profile. While elotuzumab is associated with a higher incidence of infusion reactions, these can be effectively mitigated with appropriate premedication. The high activity of the elotuzumab/lenalidomide combination is now being further investigated in randomized Phase III trials. Elotuzumab represents an exciting future potential treatment option for patients with multiple myeloma, including those with relapsed and refractory disease, as well as in the induction and post transplant maintenance settings, and possibly even for early therapy in patients with high-risk smoldering myeloma. PMID- 24151844 TI - Robust, reliable and resilient: designing molecular tuberculosis tests for microscopy centers in developing countries. PMID- 24151845 TI - Molecular biomarkers in 2013. PMID- 24151847 TI - The FilmArray(r) respiratory panel: an automated, broadly multiplexed molecular test for the rapid and accurate detection of respiratory pathogens. AB - The FilmArray Respiratory Panel (RP) (BioFire(TM) Diagnostics, Inc., Salt Lake City, UT, USA) is the first multiplex molecular panel cleared by the US FDA for the detection of both bacterial and viral respiratory pathogens in nasopharygeal swabs. The FilmArray RP targets 20 pathogens including 17 viruses and subtypes and three bacteria, and is performed with minimal sample manipulation. The FilmArray RP has a fully automated sample-to-answer workflow with a turn-around time of approximately 1 h. The reported sensitivity and specificity of the assay ranges from 80 to 100 and 100%, respectively, with the sensitivity for the adenovirus as low as 46%. A new version of the FilmArray RP assay (version 1.7) with improved sensitivity for the adenovirus was released in 2013. The performance characteristics and simplified workflow have allowed its implementation in a wide range of laboratories. The FilmArray RP has changed the diagnostic landscape and will have a significant impact on the care of patients with respiratory tract infection. PMID- 24151848 TI - New cancer diagnostics and therapeutics from a ninth 'hallmark of cancer': symmetric self-renewal by mutated distributed stem cells. AB - A total of eight cellular alterations associated with human carcinogenesis have been framed as the 'hallmarks of cancer'. This representation overlooks a ninth hallmark of cancer: the requirement for tumor-originating distributed stem cells to shift sufficiently from asymmetric to symmetric self-renewal kinetics for attainment of the high cell production rate necessary to form clinically significant tumors within a human lifespan. Overlooking this ninth hallmark costs opportunities for discovery of more selective molecular targets for development of improved cancer therapeutics and missing cancer stem cell biomarkers of greater specificity. Here, the biological basis for the ninth hallmark of cancer is considered toward highlighting its importance in human carcinogenesis and, as such, its potential for revealing unique molecules for targeting cancer diagnostics and therapeutics. PMID- 24151849 TI - Molecular biomarkers of neurodegeneration. AB - Neuronal dysfunction and degeneration are central events of a number of major diseases with significant unmet need. Neuronal dysfunction may not necessarily be the result of cell death, but may also be due to synaptic damage leading to impaired neuronal cell signaling or long-term potentiation. Once degeneration occurs, it is unclear whether axonal or synaptic loss comes first or whether this precedes neuronal cell death. In this review we summarize the pathophysiology of four major neurodegenerative diseases; Alzheimer's disease, Parkinson's disease, multiple sclerosis and amyotrophic lateral sclerosis (Lou Gehrig's disease) For each of these diseases, we describe how biochemical biomarkers are currently understood in relation to the pathophysiology and in terms of neuronal biology, and we discuss the clinical and diagnostic utility of these potential tools, which are at present limited. We discuss how markers may be used to drive drug development and clinical practice. PMID- 24151850 TI - Novel fluorescent microarray platforms: a case study in neurodegenerative disorders. AB - This review focuses on the fluorescent protein microarrays applied to neurodegenerative disorders, a major health problem in our aging society. Biomarker discovery studies and work on new diagnostic tests are both included. Three platforms are described: antibody planar microarrays, comprising an array of well-defined antibodies for the simultaneous capture of biomarkers; antigen planar microarrays in which proteins, peptides or small molecules are immobilized and probed with biological samples to chase specific antibodies; and bead-based array platforms, which are flow cytometry-based methods in which capture molecules are coupled to fluorescent microspheres, facilitating the simultaneous quantification of several analytes. PMID- 24151851 TI - Achieving molecular diagnostics for Lyme disease. AB - Early Lyme disease is often difficult to diagnose. Left untreated, symptoms can last for many years leading to chronic health problems. Serological tests for the presence of antibodies that react to Borrelia burgdorferi antigens are generally used to support a clinical diagnosis. Due to the biologically delayed antibody response, serology is negative in many patients in the initial 3 weeks after infection and a single test cannot be used to demonstrate active disease, although certain specialized tests provide strong correlation. Because of these limitations there exists a need for better diagnostics for Lyme disease that can detect Borrelia genomic material at the onset of symptoms. PMID- 24151852 TI - Skinomics: past, present and future for diagnostic microarray studies in dermatology. AB - Easily accessible, skin was among the first targets analyzed using 'omics' and dermatology embraced the approaches very early. Microarrays have been used to define disease markers, identify transcriptional changes and even trace the course of treatment. Melanoma and psoriasis have been explored using microarrays. Particularly noteworthy is the multinational mapping of psoriasis susceptibility loci. The transcriptional changes in psoriasis have been identified using hundreds of biopsies. Epidermal keratinocytes have been studied because they respond to UV light, infections, inflammatory and immunomodulating cytokines, toxins and so on. Epidermal differentiation genes are being characterized and are expressed in human epidermal stem cells. Exciting discoveries defining human skin microbiomes have opened a new field of research with great medical potential. Specific to dermatology, the non-invasive skin sampling for microarray studies, using tape stripping, has been developed; it promises to advance dermatology toward 'omics' techniques directly applicable to the personalized medicine of the future. PMID- 24151853 TI - Sub-optimal efficacy of ivermectin against Parascaris equorum in foals on three Thoroughbred stud farms in the Manawatu region of New Zealand. AB - AIM: To ascertain whether resistance was present in Parascaris equorum to the macrocyclic lactone anthelmintic ivermectin, using faecal egg count reduction tests. METHODS: Thirty-nine foals aged between 11 and 28 weeks on three Thoroughbred stud farms (Farms A; n=20, B; n=5 and C; n=14) were treated with ivermectin (Day 0) and faecal egg counts (FEC) were monitored before and for 21 (Farms A and B) or 14 (Farm C) days after treatment. On Farms A and B, the foals were treated with a macrocyclic lactone/benzimidazole/praziquantel combination on Day 21 and FEC assessed on Day 35. The three farms were all in the Manawatu region in the southern half of New Zealand's North Island. RESULTS: Of the 39 foals, 15 were not shedding P. equorum eggs on the day they were treated with ivermectin, but all 15 did so post-treatment. The FEC on Farms A and B showed no evidence of a reduction at any time between Day 7 and 21; egg output increased steadily over this period. Following combination treatment FEC were reduced by 94% on farm A and 100% on Farm B. On Farm C, there was a 69% reduction in P. equorum FEC on Day 14. Twelve of the 14 foals on Farm C were shedding strongylid eggs on Day 0 and on Day 14 FEC were reduced by 84%. CONCLUSIONS: Without comparison to untreated control animals, these results do not allow a reliable estimation of the exact level of efficacy of ivermectin against P. equorum, but they nevertheless show that, within the farms studied, ivermectin no longer achieved a complete kill of egg-laying adults and that foals treated with this drug may continue to shed considerable numbers of eggs after treatment. The results also indicate that ivermectin had sub-optimal efficacy against strongylid nematodes on one of the farms. PMID- 24151854 TI - Preliminary analysis of mortality associated with rituximab use in autoimmune diseases. AB - Normal antibodies and pathogenic autoantibodies are produced by B-cells and plasma cells. Rituximab is a chimeric monoclonal antibody that targets the CD20 molecule on cells that express them on their surface and kills them. Rituximab has been increasingly used to treat several autoimmune diseases. Studies on fatal outcomes associated with rituximab therapy are lacking. A comprehensive and detailed analysis in which the multiple factors that could contribute to a fatal outcome in all the autoimmune diseases in which rituximab has been used would be cumbersome, lack uniformity and would prove difficult in making certain definitive conclusions and comparisons, but more importantly it would not allow to provide specific precautions and recommendations to prevent mortality. Hence, autoimmune mucocutaneous blistering diseases (AMBD) were used as model to study fatal outcomes in patients treated with rituximab between 2000 and 2013, using uniform 13 criteria. Fatal outcomes were found in 14 patients with autoimmune blistering diseases out of 134 patients (10.4%). Patients died due to infections (75%), gastrointestinal (17%) and cardiac events (8%). Causes of death were reported in 101 patients with other autoimmune diseases out of 4320 with a mortality rate of 2.4%. Among them, 44 patients (43.6%) died from infections. A statistical analysis of the data demonstrated that a statistically significant higher mortality rate was observed in patients with AMBD compared to patients with other autoimmune diseases. Similarly, a statistically significant higher rate of death due to infections was reported in patients with AMBD compared to patients with other autoimmune diseases. Use of systemic corticosteroids and immunosuppressive agents as concomitant therapy with rituximab enhanced immunosuppression. In many patients, B-cells were depleted for prolonged periods, even after clinical recovery was observed. Although its main action is depletion of B-cells, rituximab has a significant impact on the immune and inflammatory systems, directly and indirectly and thus enhances susceptibility to infection. These preliminary data suggests that physicians using rituximab to treat autoimmune diseases should monitor their patients closely, especially their B cell levels until they return to normal, be vigilant for possible sources of infection, and be aware of potential fatal outcomes. PMID- 24151855 TI - Nanoscale contact-radius determination by spectral analysis of polymer roughness images. AB - In spite of the long history of atomic force microscopy (AFM) imaging of soft materials such as polymers, little is known about the detailed effect of a finite tip size and applied force on the imaging performance on such materials. Here we exploit the defined scaling of roughness amplitudes on amorphous polymer films to determine the transfer function imposed by the imaging tip. The finite indentation of the nanometer-scale tip into the comparatively soft polymer surface leads to a finite contact area, which in turn effectively acts as a moving average filter for the surface roughness. In the power spectral density (PSD), this leads to an attenuation of the roughness amplitudes related to the Airy pattern known from light diffraction of a circular aperture. This transfer function is affected by the roughness-induced local modulation of the tip height and contact area, which is studied by performing simulations of the polymer roughness and the imaging process. We find that for typical polymer parameters and sharp tips the contact radius of the tip-sample contact can be recovered from the roughness spectrum. We experimentally verify and demonstrate the method by measuring the nanoscale contact radius as a function of applied load and travel distance on a highly cross-linked model polymer. The data are consistent with the Johnson-Kendall-Roberts (JKR) contact model and verifies its applicability at the nanometer scale. Using the model, quantitative values of the elastic sample parameters can be determined. PMID- 24151857 TI - Perceived professional gains of master's level students following a person-of-the therapist training program: a retrospective content analysis. AB - The Person-of-the-Therapist Training (POTT) is a program designed to facilitate clinicians' ability to consciously and purposefully use themselves at the moment of contact with their clients in order to connect, assess, and intervene effectively. This qualitative study explored the experiences of 54 master's-level students who were enrolled in an accredited marriage and family therapy program in the United States and examined their perceived professional gains following a 9-month POTT course. Content analysis of trainees' reflections which they wrote at the end of the training revealed 6 primary themes: (a) increased awareness, (b) emotions, (c) improved clinical work, (d) humanity and woundedness, (e) meta awareness, and (f) factors that contributed to the learning process. Findings suggest that key outcomes of this training curriculum are congruent with its stated goals. Clinical and training recommendations are additionally provided. Video Abstract. PMID- 24151856 TI - Picomolar inhibitors of HIV reverse transcriptase featuring bicyclic replacement of a cyanovinylphenyl group. AB - Members of the catechol diether class are highly potent non-nucleoside inhibitors of HIV-1 reverse transcriptase (NNRTIs). The most active compounds yield EC50 values below 0.5 nM in assays using human T-cells infected by wild-type HIV-1. However, these compounds such as rilpivirine, the most recently FDA-approved NNRTI, bear a cyanovinylphenyl (CVP) group. This is an uncommon substructure in drugs that gives reactivity concerns. In the present work, computer simulations were used to design bicyclic replacements for the CVP group. The predicted viability of a 2-cyanoindolizinyl alternative was confirmed experimentally and provided compounds with 0.4 nM activity against the wild-type virus. The compounds also performed well with EC50 values of 10 nM against the challenging HIV-1 variant that contains the Lys103Asn/Tyr181Cys double mutation in the RT enzyme. Indolyl and benzofuranyl analogues were also investigated; the most potent compounds in these cases have EC50 values toward wild-type HIV-1 near 10 nM and high-nanomolar activities toward the double-variant. The structural expectations from the modeling were much enhanced by obtaining an X-ray crystal structure at 2.88 A resolution for the complex of the parent 2-cyanoindolizine 10b and HIV-1 RT. The aqueous solubilities of the most potent indolizine analogues were also measured to be ~40 MUg/mL, which is similar to that for the approved drug efavirenz and ~1000-fold greater than for rilpivirine. PMID- 24151858 TI - Longitudinal pilot-study of Sustained Attention to Response Task and P300 in manifest and pre-manifest Huntington's disease. AB - BACKGROUND: Earlier research has found cross-sectional attentional control deficits in manifest Huntington's disease (HD) using neuropsychological testing combined with simultaneous P300 registration. In the current pilot-study, we investigate attentional control in pre-manifest and manifest HD over a 3-year follow-up period. METHOD: Five manifest HD (MHD), 9 pre-manifest HD (PMHD), and 12 control subjects were included. Sustained Attention to Response task (SART) and P300 registration resulted in number of errors, reaction time (RT), and P300 amplitude and latency. RT change patterns surrounding No-go trials were also investigated. Within-subject differences were tested using paired-samples t-tests and between-group results with ANCOVA on delta scores (follow-up--baseline scores). RESULTS: Manifest HD made more errors and were slower than controls and PMHD. Longitudinally, MHD showed an overall RT increase and a specific slowing on trials preceding a correct No-go trial (within-group effects). The latter was also seen in PMHD. P300 latency prolongation was found for controls on No-go and for MHD on Go trials. On specific trials surrounding both correct and incorrect No-go trials, MHD became significantly slower over time than controls and PMHD (between-group effects). CONCLUSIONS: Over 3-years, MHD subjects became slower on the SART and showed a prolongation of P300 latency on specific SART trials. Specific slowing of performance over time was also seen in PMHD, suggestive of compensatory mechanisms in this group. PMID- 24151862 TI - Control of the charge distribution and modulation of the class II-III transition in weakly coupled Mo2-Mo2 systems. AB - Three novel dimolybdenum dimers [Mo2(DAniF)3]2(MU-OSCC6H4CSO), [Mo2(DAniF)3]2(MU O2CC6H4CS2), and [Mo2(DAniF)3]2(MU-S2CC6H4CS2) (DAniF = N,N'-di(p anisyl)formamidinate) have been synthesized and characterized by single-crystal X ray diffractions. Together with the terephthalate analogue, the four compounds, denoted as [O2-O2], [OS-OS], [S2-S2], and [O2-S2], have similar molecular skeletons and Mo2...Mo2 separations (~12 A), but varying sulfur contents or symmetry. The singly oxidized complexes [O2-O2](+), [OS-OS](+), [S2-S2](+), and [O2-S2](+) display characteristic intervalence transition absorption bands in the near- and mid-IR regions, with differing band energy, intensity, and shape. Applying the geometrical length of the bridging group "-CC6H4C-" (5.8 A) as the effective electron transfer distance, calculations from the Mulliken-Hush equation yield electronic coupling matrix elements (H(ab)) in the range 600-900 cm(-1). Significantly, this series presents a transition from electron localization to "almost-delocalization" as the carboxylate groups of the bridging ligand are successively thiolated. In terms of Robin-Day's scheme, [S2-S2](+) is best described as an intermediate between Class II and III, while [O2-O2](+) and [OS-OS](+) belong to Class II. It is unusual that the Class II-III transition occurs in such a weakly coupled system (H(ab) < 1000 cm(-1)). This is attributed to the d(delta)-p(pi) conjugation between the Mo2 center and bridging ligand. By electrochemical and spectroscopic methods, the internal energy difference for [O2 S2](+) is determined to be 2250 +/- 80 cm(-1), which controls the charge distribution of the cation radical. The experimental results and theoretical analyses illustrate that the unsymmetrical geometry leads to unbalanced electronic configurations and asymmetrical redox and optical behaviors. PMID- 24151863 TI - Nonionizing photoacoustic cystography with near-infrared absorbing gold nanostructures as optical-opaque tracers. AB - AIM: The objectives of this study were to demonstrate nonionizing photoacoustic tomography (PAT) of bladders with near-infrared absorbing gold nanocages (GNCs) as an optical-turbid tracer and to investigate the fate of GNCs after photoacoustic imaging. MATERIALS & METHODS: The rats' bladders were visualized using PAT after transurethral injection of 2-nM GNCs. The fate of GNCs in the bladders was investigated. Spectroscopic PAT was applied to identify GNC-filled bladders in vivo and study biodistribution ex vivo. RESULTS: Rats' bladders filled with GNCs were successfully imaged using a PAT system. The photoacoustic amplitude was enhanced by approximately 2240%. Both in vivo and ex vivo PAT results reveal that no accumulation of GNCs in the bladder and kidney was observed, and were validated with inductively coupled plasma mass spectrometry. CONCLUSION: The PAT with transurethral injection of GNCs provides two crucial safety features for clinical translation: no radiation exposure and no long-term heavy metal accumulation. PMID- 24151864 TI - Serum ferritin level is higher in poorly controlled patients with type 2 diabetes and people without diabetes, aged over 55 years. AB - AIMS: Diabetes mellitus has been increasing in Mongolia. There is also growing concern about the relationship between iron stores and the severity of type 2 diabetes. In this study, we aimed to evaluate serum ferritin level among Mongolian individuals with and without diabetes. METHODS: Of 254 participants, a total of 99 previously diagnosed patients with type 2 diabetes and the same numbers of subjects without diabetes were enrolled and invited to a physical examination (BMI, central obesity, blood pressure) and fasting blood tests (fasting blood glucose, HbA1c , serum ferritin, C-reactive protein, aspartate aminotransferase, alanine transferase). RESULTS: Serum ferritin was higher in the patients with type 2 diabetes compared with the control group without diabetes, with a significant difference in the female groups (341.6 +/- 67.2 and 159.1 +/- 36.8 ng/ml respectively, P = 0.019). Of the patients with type 2 diabetes, 43.4% had hyperferritinaemia, and 21.2% of the individuals without diabetes had hyperferritinaemia. In the group with type 2 diabetes, serum ferritin level was significantly higher in the group of women whose HbA1c was >= 53 mmol/mol (7.0%) compared with the other group of women whose HbA1c was < 53 mmol/mol (7.0%) (562.1 +/- 122.1 and 220.5 +/- 78.7 ng/ml respectively, P = 0.025). We also found that the subjects without diabetes, aged over 55 years, are at risk of increased serum ferritin. CONCLUSION: Poorly controlled patients with type 2 diabetes and people without diabetes of over 55 years of age are likely to be at a higher risk of developing hyperferritinaemia. Thus, regular assessments of serum ferritin might be important for those who are at risk of hyperferritnaemia for prevention and an early intervention. PMID- 24151865 TI - Immunophenotypic shift of CD4 and CD8 antigen expression in primary cutaneous T cell lymphomas: a clinicopathologic study of three cases. AB - Primary cutaneous T-cell lymphomas (CTCL) comprise a heterogeneous group of neoplasms with diverse clinical behavior. Mycosis fungoides (MF) is the most common type of CTCL. Immunophenotypical shift during progression of the disease is a rare event and its significance is unknown. We present three primary CTCL cases that showed an immunophenotypical shift and poor prognosis. Conventional hematoxylin/eosin and immunohistochemical-stained sections were examined in all the cases. Molecular analysis for rearrangement of the T-cell receptor (TCR) gene was performed in two cases. One case was classified as MF, while the other two lacked epidermotropism, and were considered primary cutaneous peripheral T-cell lymphoma (PTCL), NOS. Two cases were CD3+/CD4+ and one case was CD3+/CD8+ at diagnosis. The first two patients suffered many relapses and eventually, new CTCL lesions with a CD3+/CD8+ phenotype were observed. Both cases revealed identical clonal TCR rearrangements on the initial and late lesions, supporting the interpretation of a single clonal proliferation with different phenotypes. The third case progressed with skin recurrences and pulmonary lesions with a predominant CD3+/CD4+/CD8- phenotype. All cases manifested poor prognosis and two patients died of lymphoma. Immunophenotypical shift between CD4 and CD8 in CTCL seems to be a rare phenomenon that may be associated with disease progression. PMID- 24151866 TI - Synthesis of novel 2,3,4-trisubstituted-oxazolidine derivatives and in vitro cytotoxic evaluation. AB - We have previously reported the discovery of cytotoxic and pro-apoptotic hit compound 1,1-dimethylethyl (S)- 2,2-dimethyl-4-[(3-nitrophenoxy)methyl]-3 oxazolidinecarboxylate 1 against leukemia cells. In the present work we describe the synthesis of 25 derivatives of this hit varying the substituent at ring or stereochemistry of the oxazolidine ring and evaluated them against human cancer cells lines. Six compounds exerted significant activity against HL60 promyelocytic leukemia cells with IC50 in low micromolar range (4-18 MUM) and three compounds displayed activity against MDA-MB231 breast cancer cells (25-37 MUM). In vitro cytotoxicity on normal cells PBMC (human peripheral blood mononuclear cells) was also evaluated. Compounds 7e (p-NO2, S) and 7m (p-COOCH3, S) showed good antiproliferative activity against HL60 (4 and 5 MUM) and MDA MB231 (37 and 25 MUM) without affecting lymphocyte proliferation in PBMC, indicating low toxicity to normal cells. Besides, compound 7e induced DNA fragmentation on about 100% of HL60 cells at 50 MUM. In this case, it was more potent than 7m and lead 1. This indicated that compound 7e has a great pro apoptotic potential. PMID- 24151867 TI - EasyClone: method for iterative chromosomal integration of multiple genes in Saccharomyces cerevisiae. AB - Development of strains for efficient production of chemicals and pharmaceuticals requires multiple rounds of genetic engineering. In this study, we describe construction and characterization of EasyClone vector set for baker's yeast Saccharomyces cerevisiae, which enables simultaneous expression of multiple genes with an option of recycling selection markers. The vectors combine the advantage of efficient uracil excision reaction-based cloning and Cre-LoxP-mediated marker recycling system. The episomal and integrative vector sets were tested by inserting genes encoding cyan, yellow, and red fluorescent proteins into separate vectors and analyzing for co-expression of proteins by flow cytometry. Cells expressing genes encoding for the three fluorescent proteins from three integrations exhibited a much higher level of simultaneous expression than cells producing fluorescent proteins encoded on episomal plasmids, where correspondingly 95% and 6% of the cells were within a fluorescence interval of Log10 mean +/- 15% for all three colors. We demonstrate that selective markers can be simultaneously removed using Cre-mediated recombination and all the integrated heterologous genes remain in the chromosome and show unchanged expression levels. Hence, this system is suitable for metabolic engineering in yeast where multiple rounds of gene introduction and marker recycling can be carried out. PMID- 24151869 TI - The impact of pregnancy on the accuracy and delay in diagnosis of acute appendicitis. AB - OBJECTIVE: To determine the accuracy and the delay in diagnosis of presumed acute appendicitis in pregnancy. METHODS: Pregnant women undergoing appendectomy for presumed acute appendicitis were compared to non-pregnant age-matched women in a 3:1 ratio undergoing appendectomy in a tertiary medical center from 2001 to 2012. RESULTS: Out of 1618 women who underwent appendectomy during the study period, 81 (4.2%) were pregnant who were compared to 243 age-matched non-pregnant women. There was a significantly shorter interval between admission to the hospital and surgery and shorter surgery length (10.2 versuss 15.7 h, 1.2 +/- 0.4 versus 1.4 +/- 0.5 h, respectively, p < 0.001) in the pregnant group with similar rates of negative appendectomy (19.8% versus 21.8%, respectively, p = 0.86). The positive and negative predictive values of ultrasonography (US) for the diagnosis of acute appendicitis were 88.2% and 100%, and 92.9% and 57.1%, among the pregnant and the non-pregnant group, respectively. In multivariate analysis, early gestational age was found to be independently associated with higher rate of accurate US results (OR = 0.92, 95% CI 0.85-0.99, p = 0.39). CONCLUSION: Pregnant women undergoing appendectomy have shorter admission to surgery interval and surgical length with similar negative appendectomy rates compared to non-pregnant women. Ultrasound is an accurate tool for the diagnosis of acute appendicitis during pregnancy, especially during early gestation. PMID- 24151868 TI - Beyond the mitochondrion: cytosolic PINK1 remodels dendrites through protein kinase A. AB - The subcellular compartmentalization of kinase activity allows for regulation of distinct cellular processes involved in cell differentiation or survival. The PTEN-induced kinase 1 (PINK1), which is linked to Parkinson's disease, is a neuroprotective kinase localized to cytosolic and mitochondrial compartments. While mitochondrial targeting of PINK1 is important for its activities regulating mitochondrial homeostasis, the physiological role of the cytosolic pool of PINK1 remains unknown. Here, we demonstrate a novel role for cytosolic PINK1 in neuronal differentiation/neurite maintenance. Over-expression of wild-type PINK1, but not a catalytically inactive form of PINK1(K219M), promoted neurite outgrowth in SH-SY5Y cells and increased dendritic lengths in primary cortical and midbrain dopaminergic neurons. To identify the subcellular pools of PINK1 involved in promoting neurite outgrowth, we transiently transfected cells with PINK1 constructs designed to target PINK1 to the outer mitochondrial membrane (OMM PINK1) or restrict PINK1 to the cytosol (DeltaN111-PINK1). Both constructs blocked cell death associated with loss of endogenous PINK1. However, transient expression of DeltaN111-PINK1, but not of OMM-PINK1 or DeltaN111-PINK1(K219M), promoted dendrite outgrowth in primary neurons, and rescued the decreased dendritic arborization of PINK1-deficient neurons. Mechanistically, the cytosolic pool of PINK1 regulated neurite morphology through enhanced anterograde transport of dendritic mitochondria and amplification of protein kinase A-related signaling pathways. Our data support a novel role for PINK1 in regulating dendritic morphogenesis. PMID- 24151870 TI - Autoantibodies to neuronal antigens in children with new-onset seizures classified according to the revised ILAE organization of seizures and epilepsies. AB - PURPOSE: Potentially pathogenic autoantibodies are found increasingly in adults with seizure disorders, including focal seizures and those of unknown cause. In this study, we investigated a cohort of children with new-onset seizures to see whether there were autoantibodies and the relationship to any specific seizure or epilepsy type. METHODS: We prospectively recruited 114 children (2 months to 16 years) with new-onset seizures presenting between September 2009 and November 2011, as well as 65 controls. Patients were clinically assessed and classified according to the new International League Against Epilepsy (ILAE) organization of seizures and epilepsies classification system. Sera were tested for autoantibodies to a range of antigens, blind to the clinical and classification details. KEY FINDINGS: Eleven (9.7%) of 114 patients were positive for one or more autoantibodies compared to 3 of 65 controls (4.6%, p = ns). Patients had antibodies to the voltage-gated potassium channel (VGKC) complex (n = 4), contactin-associated protein-like 2 (CASPR2) (n = 3), N-methyl-d-aspartate receptors (NMDARs) (n = 2), or VGKC-complex and NMDAR (n = 2). None had antibodies to glutamic acid decarboxylase, contactin-2, or to glycine, 2-amino-3 (3-hydroxy-5-methyl-4-isoxazolyl) propionic acid (AMPA), or gamma-aminobutyric acid B receptors. Ten of these 11 patients were classified as having epilepsy according to the new ILAE organization of seizures and epilepsy. Although, there were no significant differences in the demographic and clinical features between antibody-positive and antibody-negative patients, the classification of "unknown cause" was higher in the antibody positive (7/10; 70%) compared with the antibody negative subjects (23/86; 26.7%; p = 0.0095, Fisher's exact test). Furthermore, four of these seven patients with epilepsy (57.1%) were classified as having predominantly focal seizures compared with 12 of the 86 antibody-negative patients (13.9%; p = 0.015). SIGNIFICANCE: Because autoantibodies were more frequent in pediatric patients with new-onset epilepsy of "unknown cause," often with focal epilepsy features, this group of children may benefit most from autoantibody screening and consideration of immune therapy. PMID- 24151871 TI - In vitro and in vivo antileishmanial and trypanocidal studies of new N-benzene- and N-naphthalenesulfonamide derivatives. AB - We report in vivo and in vitro antileishmanial and trypanocidal activities of a new series of N-substituted benzene and naphthalenesulfonamides 1-15. Compounds 1 15 were screened in vitro against Leishmania infantum , Leishmania braziliensis , Leishmania guyanensis , Leishmania amazonensis , and Trypanosoma cruzi . Sulfonamides 6e, 10b, and 10d displayed remarkable activity and selectivity toward T. cruzi epimastigotes and amastigotes. 6e showed significant trypanocidal activity on parasitemia in a murine model of acute Chagas disease. Moreover, 6e, 8c, 9c, 12c, and 14d displayed interesting IC50 values against Leishmania spp promastigotes as well as L. amazonensis and L. infantum amastigotes. 9c showed excellent in vivo activity (up to 97% inhibition of the parasite growth) in a short-term treatment murine model for acute infection by L. infantum. In addition, the effect of compounds 9c and 14d on tubulin as potential target was assessed by confocal microscopy analysis applied to L. infantum promastigotes. PMID- 24151872 TI - Qualitative and quantitative analysis of phenolics in Tetrastigma hemsleyanum and their antioxidant and antiproliferative activities. AB - The phenolic profiles of Tetrastigma hemsleyanum leaf extracts by different solvents (80% methanol, ethyl acetate and hexane) and their antioxidant and antiproliferative activities were investigated. Thirteen phenolic compounds (3 caffeoylquinic acid, 5-caffeoylquinic acid, 1-caffeoylquinic acid, 5-p coumaroylquinic acid, isoorientin-2"-O-rhamnoside, isoorientin, orientin-2"-O rhamnoside, orientin, 1-p-coumaroylquinic acid, vitexin-2"-O-rhamnoside, isovitexin-2"-O-rhamnoside, vitexin and isovitexin) were identified in T. hemsleyanum leaves for the first time, and six of them were quantified using a combination of LC-QTOF-MS and LC-QqQ-MS techniques. It was found that 80% methanol extract exhibited the highest antioxidant activities (DPPH, 3.32 mmol of Trolox/g DW; ABTS, 1.38 mmol of Trolox/g DW; FRAP, 1.85 mmol of FeSO4/g DW), while the hexane extract had the lowest (1.23, 0.43 and 0.13, respectively). Total phenolic contents (TPC) of various extracts of T. hemsleyanum leaves ranged from 28.95 to 275.71 mg of GAE/g DW. Also, total antioxidant activities as evaluated by ABTS, FRAP and DPPH assays were correlated well with TPC. In addition, 80% methanol extract provided antiproliferative activity on HepG2 cells (IC50 = 524 MUg/mL). This paper provides a complete picture of phenolics in T. hemsleyanum leaves and relates them to their antioxidant and antiproliferative activities. PMID- 24151873 TI - Prevalence and diversity of Escherichia coli isolated from a barley trial supplemented with bulky organic soil amendments: green compost and bovine slurry. AB - A barley field trial supplemented with bulky organic soil amendments, municipal compost or bovine slurry was sampled for Escherichia coli to test the hypothesis that E. coli isolated from the soil or from barley plants were derived from bovine slurry. A qualitative analysis showed that a total of 12% of the bulk soil cores and 16% of harvested grain samples yielded E. coli. The strongest association for positive detection of E. coli from soil was with time of year and for slurry-treated plots, with irrigation. However, E. coli were detected in plots from all treatment types and not exclusively associated with bovine slurry. Phylogroup, plasmid profiling and population genetics analysis (multilocus sequence typing) revealed extensive genetic diversity. Identical sequence types for slurry and soil isolates were detected, indicative of direct transfer into the soil, although not frequently. Host interaction assays with selected isolates showed a variation in the ability to colonize barley roots, but not in interactions with bovine cells. The work has implications in appropriate use of E. coli as a faecal indicator as isolates were widespread and diverse, reinforcing the view that some are a natural part of the microflora in agricultural systems. SIGNIFICANCE AND IMPACT OF THE STUDY: Faecal deposition is considered to be the main process that introduces Escherichia coli into soil, giving rise to their use as a faecal indication species and the potential for cycling pathogens in agricultural systems. We found that bovine slurry was not the main source of E. coli in a barley trial and a high degree of diversity was present in the collection. The findings support the hypothesis that the population structure of E. coli in secondary habitats is shaped by the environment and highlight the drawbacks of its use as a faecal indicator species. PMID- 24151874 TI - Stem cells as a potential therapy for necrotizing enterocolitis. AB - INTRODUCTION: Necrotizing enterocolitis (NEC) is a severe gastrointestinal disease of neonates, especially those born prematurely, that remains an important cause of morbidity and mortality. Although current treatments such as inotropes, antibiotics and ventilation are supportive, there is an urgent need for novel therapies that specifically target the affected intestine. AREAS COVERED: We briefly introduce the disease and the effects on intestinal epithelia. We provide a brief description of amniotic fluid stem (AFS) cells, and then describe some recent data in which AFS cells were beneficial in an animal model of NEC and a potential mechanism is described. The effects of AFS cells are compared with data on bone marrow mesenchymal stem cells. The potential implications of these findings for therapy are discussed. EXPERT OPINION: The current data are promising and demonstrate that stem cells do have an effect in rodent models of NEC. However, the short timescale, limited ability for longitudinal evaluation and uncertain clinical relevance of these models means that there are considerable challenges to be overcome before attempting stem cell therapy in clinical trials. Nevertheless, these data open up novel areas of research into a prevention or therapy for this devastating disease. PMID- 24151875 TI - Responsiveness of muscle size and strength to physical training in very elderly people: a systematic review. AB - The purpose of this review was to determine whether very elderly muscle (>75 years) hypertrophies in response to physical training. The databases MEDLINE; EMBASE; CINAHL Plus and SPORTDiscus were systematically literature searched with reference lists of all included studies and relevant reviews. Controlled trials (inactive elderly control group) involving healthy elderly participants over 75 years participating in an intervention complying with an established definition of physical training were included. Data extraction and quality assessment were performed using the PEDro scale. Data analysis was performed on muscle size and strength using RevMan (software version 5.1). Four studies were included of which four of four measured changes in gross muscle size. Training induced increases in muscle size from 1.5%-15.6% were reported in three of four studies, and one of four studies reported a decrease in muscle size (3%). The greatest gain in muscle mass was observed in a study of whole body vibration training. Meta-analysis of three studies found an increase of thigh muscle cross-sectional area (mean difference 2.31 cm(2) or 0.2%, 95% confidence interval (CI): 0.62 to 4.00; P = 0.008) and muscle strength (standardized mean difference 1.04, 95% CI: 0.65 to 1.43; P < 0.001). Physical training when delivered as resistance training has the ability to elicit hypertrophy and increase muscle strength in very elderly muscle. PMID- 24151876 TI - The molecular identification of Streptococcus equi subsp. equi strains isolated within New Zealand. AB - AIMS: To identify Streptococcus equi subsp. equi (S. equi) by PCR analysis and obtain isolates by culture, in order to investigate the strains of S. equi infecting horses within New Zealand. METHODS: A diagnostic PCR, based on the amplification of the seeI gene for S. equi, was used on 168 samples submitted from horses with and without clinical signs of strangles. Samples were also processed and cultured on selective media for the isolation of beta-haemolytic colonies. In addition, the hypervariable region of the seM gene of S. equi was amplified and then sequenced for strain typing purposes. RESULTS: Of the 168 samples, 35 tested positive for S. equi using PCR. Thirty-two confirmed samples were from horses with a clinical diagnosis of strangles and three were from horses where clinical information was unavailable. Only 22/35 (63%) confirmed S. equi samples were successfully isolated following culture. Strain typing demonstrated that two novel seM alleles of S. equi were found in New Zealand with SeM-99 strains being restricted to the North Island while SeM-100 strains were found in both North and South Islands. CONCLUSIONS: The application of PCR for the laboratory confirmation of strangles allowed for a rapid and sensitive identification of S. equi. Moreover, seM typing revealed that within the samples examined two strains of S. equi co-circulated within the North Island of New Zealand but only one strain in the South Island. CLINICAL RELEVANCE: PCR reduces the time required to obtain laboratory confirmation of strangles compared with culture methods. It also has greater sensitivity in detecting S. equi infections, which is of particular importance in the detection of carrier animals which normally shed low numbers of bacteria. Additionally, seM molecular typing can differentiate between bacterial strains, assisting in the monitoring of local strains of S. equi subsp. equi causing disease. PMID- 24151878 TI - Synthesis, antioxidant, anticancer and antiviral activities of novel quinoxaline hydrazone derivatives and their acyclic C-nucleosides. AB - The present investigation describes the synthesis of a new series of aldehydo sugar-N-(3-phenylquinoxalin-2- yl)hydrazones 3a-d and their acyclic C-nucleoside analogs, 1-(4-phenyl-[1,2,4]triazolo[4,3-a]quinoxalin-1-yl)alditols 7ad by using 2-hydrazino-3-phenylquinoxaline 1 as key intermediate. The synthesized compounds were screened for their antioxidant activities by 2,2'-azino-bis(3 ethylbenzothiazoline-6-sulfonic acid) (ABTS) radical cation scavenging method. Compounds 3d and 7a, showed potent scavenging activities against ABTS(+) radicals and were found to be the most potent antioxidants described in this study. Out of the synthesized compounds, compounds 3d and 7a were selected by the National Cancer Institute for evaluation of their in vitro anticancer activity. Results revealed that compounds 3d and 7a exhibited non-selective broad spectrum activity against all cancer cell lines between 10(-6) to 10(-5) molar concentrations. Compound 3d showed the highest sensitivity against leukemia cell line HL-60 (TB) with GI50 of 5.15 uM, while compound 7a showed the highest sensitivity against ovarian cancer cell lines IGROV1 and OVCAR-4 with GI50 of 14.5 and 16.0 MUM, respectively. In addition, compounds 3d and 7a showed TGI values of 72.2 and 96.3 uM, respectively against ovarian cancer cell line OVCAR-4. Furthermore, the target compounds were tested for antiviral activity against Herpes Simplex virus type-1 (HSV-1) using plaque reduction infectivity assay. The results indicated that compounds 3a-d and 7a exhibited very weak antiviral activity in comparison to Aphidicolin as a positive control. PMID- 24151877 TI - Co-administration of betulinic acid and methamphetamine causes toxicity to dopaminergic and serotonergic nerve terminals in the striatum of late adolescent rats. AB - Psychostimulant methamphetamine (METH) is toxic to striatal dopaminergic and serotonergic nerve terminals in adult, but not in the adolescent, brain. Betulinic acid (BA) and its derivatives are promising anti-HIV agents with some toxic properties. Many METH users, particularly young men, are HIV-positive; therefore, they might be treated with BA or its derivative for HIV infection. It is not known whether BA, or any of its derivatives, are neurotoxic in combination with METH in the adolescent brain. The present study investigated the effects of BA and binge METH in the striatum of late adolescent rats. BA or METH alone did not decrease the levels of dopaminergic or serotonergic markers in the striatum whereas BA and METH together decreased these markers in a BA dose-dependent manner. BA+METH also caused decreases in the levels of mitochondrial complex I in the same manner; BA alone only slightly decreased the levels of this enzyme in striatal synaptosomes. BA or METH alone increased cytochrome c. METH alone decreased parkin, increased complex II and striatal BA levels. These results suggest that METH in combination with BA can be neurotoxic to striatal dopaminergic and serotonergic nerve terminals in the late adolescent brain via mitochondrial dysfunction and parkin deficit. We report a synergistic neurotoxicity of betulinic acid (BA) and methamphetamine (METH) to monoaminergic terminals in the striatum of male late adolescent rats. BA contribution to the neurotoxicity is decreasing mitochondrial complex I whereas METH contribution is decreasing parkin and increasing brain concentration of BA. We propose that clinical use of BA in young male METH users can be neurotoxic. PMID- 24151879 TI - The discovery of novel histone lysine methyltransferase G9a inhibitors (part 1): molecular design based on a series of substituted 2,4-diamino-7- aminoalkoxyquinazoline by molecular-docking-guided 3D quantitative structure activity relationship studies. AB - Protein lysine methyltransferase G9a, which catalyzes methylation of lysine 9 of histone H3 (H3K9) and lysine 373 (K373) of p53, is overexpressed in human cancers. This suggests that small molecular inhibitors of G9a might be attractive antitumor agents. Herein we report our efforts on the design of novel G9a inhibitor based on the 3D quantitative structure-activity relationship (3D-QSAR) analysis of a series of 2,4-diamino-7-aminoalkoxyquinazolineas G9a inhibitors. The 3D-QSAR model was generated from 47 compounds using docking based molecular alignment. The best predictions were obtained with CoMFA standard model (q2 =0.700, r2 = 0.952) and CoMSIA model combined with steric, electrostatic, hydrophobic, hydrogen bond donor and acceptor fields (q2 = 0.724, r2 =0.960). The structural requirements for substituted 2,4-diamino-7-aminoalkoxyquinazoline for G9a inhibitory activity can be obtained by analysing the COMSIA plots. Based on the information, six novel follow-up analogs were designed. PMID- 24151880 TI - Mechanism of recruitment and activation of the endosome-associated deubiquitinase AMSH. AB - AMSH, a deubiquitinating enzyme (DUB) with exquisite specificity for Lys63-linked polyubiquitin chains, is an endosome-associated DUB that regulates sorting of activated cell-surface signaling receptors to the lysosome, a process mediated by the members of the endosomal sorting complexes required for transport (ESCRT) machinery. Whole-exome sequencing of DNA samples from children with microcephaly capillary malformation (MIC-CAP) syndrome identified recessive mutations encoded in the AMSH gene causatively linked to the disease. Herein, we report a number of important observations that significantly advance our understanding of AMSH within the context of the ESCRT machinery. First, we performed mutational and kinetic analysis of the putative residues involved in diubiquitin recognition and catalysis with a view of better understanding the catalytic mechanism of AMSH. Our mutational and kinetic analysis reveals that recognition of the proximal ubiquitin is imperative for the linkage specificity and catalytic efficiency of the enzyme. The MIC-CAP disease mutation, Thr313Ile, yields a substantial loss of catalytic activity without any significant change in the thermodynamic stability of the protein, indicating that its perturbed catalytic activity is the basis of the disease. The catalytic activity of AMSH is stimulated upon binding to the ESCRT-0 member STAM; however, the precise mechanism and its significance are not known. On the basis of a number of biochemical and biophysical analyses, we are able to propose a model for activation according to which activation of AMSH is allowed by facile, simultaneous binding to two ubiquitin groups in a polyubiquitin substrate, one by the catalytic domain of the DUB (binding to the distal ubiquitin) and the other (the proximal ubiquitin) by the ubiquitin interacting motif (UIM) from STAM. Such a mode of binding would stabilize the ubiquitin chain in a productive orientation, resulting in an enhancement of the activity of the enzyme. These data together provide a mechanism for understanding the recruitment and activation of AMSH at ESCRT-0, providing biochemical and biophysical evidence that supports a role for AMSH when it is recruited to the initial ESCRT complex: it functions to facilitate the transfer of ubiquitinated receptors (cargo) from one ESCRT member to the next by disassembling the polyubiquitin chain while leaving some ubiquitin groups still attached to the cargo. PMID- 24151881 TI - Synthesis, structure, luminescent, and magnetic properties of carbonato-bridged Zn(II)2Ln(III)2 complexes [(MU4-CO3)2{Zn(II)L(n)Ln(III)(NO3)}2] (Ln(III) = Gd(III), Tb(III), Dy(III); L(1) = N,N'-bis(3-methoxy-2-oxybenzylidene)-1,3 propanediaminato, L(2) = N,N'-bis(3-ethoxy-2-oxybenzylidene)-1,3 propanediaminato). AB - Carbonato-bridged Zn(II)2Ln(III)2 complexes [(MU4 CO3)2{Zn(II)L(n)Ln(III)(NO3)}2].solvent were synthesized through atmospheric CO2 fixation reaction of [Zn(II)L(n)(H2O)2].xH2O, Ln(III)(NO3)3.6H2O, and triethylamine, where Ln(III) = Gd(III), Tb(III), Dy(III); L(1) = N,N'-bis(3 methoxy-2-oxybenzylidene)-1,3-propanediaminato, L(2) = N,N'-bis(3-ethoxy-2 oxybenzylidene)-1,3-propanediaminato. Each Zn(II)2Ln(III)2 structure possessing an inversion center can be described as two di-MU-phenoxo-bridged {Zn(II)L(n)Ln(III)(NO3)} binuclear units bridged by two carbonato CO3(2-) ions. The Zn(II) ion has square pyramidal coordination geometry with N2O2 donor atoms of L(n) and one oxygen atom of a bridging carbonato ion at the axial site. Ln(III) ion is coordinated by nine oxygen atoms consisting of four from the deprotonated Schiff-base L(n), two from a chelating nitrate, and three from two carbonate groups. The temperature-dependent magnetic susceptibilities in the range 1.9-300 K, field-dependent magnetization from 0 to 5 T at 1.9 K, and alternating current magnetic susceptibilities under the direct current bias fields of 0 and 1000 Oe were measured. The magnetic properties of the Zn(II)2Ln(III)2 complexes are analyzed on the basis of the dicarbonato-bridged binuclear Ln(III)-Ln(III) structure, as the Zn(II) ion with d(10) electronic configuration is diamagnetic. ZnGd1 (L(1)) and ZnGd2 (L(2)) show a ferromagnetic Gd(III)-Gd(III) interaction with J(Gd-Gd) = +0.042 and +0.028 cm(-1), respectively, on the basis of the Hamiltonian H = -2J(Gd-Gd)SGd1.SGd2. The magnetic data of the Zn(II)2Ln(III)2 complexes (Ln(III) = Tb(III), Dy(III)) were analyzed by a spin Hamiltonian including the crystal field effect on the Ln(III) ions and the Ln(III)-Ln(III) magnetic interaction. The Stark splitting of the ground state was so evaluated, and the energy pattern indicates a strong easy axis (Ising type) anisotropy. Luminescence spectra of Zn(II)2Tb(III)2 complexes were observed, while those of Zn(II)2Dy(III)2 were not detected. The fine structure assignable to the (5)D4 -> (7)F6 transition of ZnTb1 and ZnTb2 is in good accord with the energy pattern from the magnetic analysis. The Zn(II)2Ln(III)2 complexes (Ln(III) = Tb(III), Dy(III)) showed an out-of-phase signal with frequency-dependence in alternating current susceptibility, indicative of single molecule magnet. Under a dc bias field of 1000 Oe, the signals become significantly more intense and the energy barrier, Delta/kB, for the magnetic relaxation was estimated from the Arrhenius plot to be 39(1) and 42(8) K for ZnTb1 and ZnTb2, and 52(2) and 67(2) K for ZnDy1 and ZnDy2, respectively. PMID- 24151882 TI - Incidence and predictors of hospitalization for tendon rupture in type 2 diabetes: the Fremantle diabetes study. AB - AIMS: To determine the incidence and predictors of tendon ruptures requiring hospitalization of representative patients with type 2 diabetes. METHODS: A total of 1296 patients from the longitudinal observational Fremantle Diabetes Study, Phase I, and 5159 de-identified age- and sex-matched control subjects without diabetes from the same urban area were studied. The patients' mean (sd) age was 64.0 (11.3) years and 48.6% of them were male. Their median (interquartile range) diabetes duration was 4.0 (1.0-9.0) years. The main outcome assessed was any tendon rupture requiring hospitalization in the Fremantle Diabetes Study subjects and the matched control subjects. Independent predictors of spontaneous ruptures in the patients from the Fremantle Diabetes Study were assessed using Cox proportional hazards modelling. RESULTS: The incidence rate ratio for any tendon rupture requiring hospitalization in patients vs control subjects was 1.44 (95% CI 1.10-1.87; P = 0.005). Independent predictors of spontaneous ruptures in patients were BMI [hazard ratio 1.05 (95% CI 1.002-1.10] for 1 kg/m2 increase; P = 0.010] and alcohol consumption [hazard ratio 1.52 (95% CI 1.11-2.09) for ?1 standard drink/day increase; P = 0.010]. Adjustment of the incidence rate ratio for overall rupture requiring hospitalization for these variables using the BMI and alcohol consumption data from the contemporary Australian general population suggested it could be as high as 1.84. CONCLUSIONS: There is a greater risk of tendon rupture requiring hospitalization in people with type 2 diabetes. Alcohol consumption and adiposity are potentially modifiable risk factors of spontaneous ruptures in patients with diabetes. PMID- 24151883 TI - Apolipoprotein E derived peptides inhibit the pro-inflammatory effect of lysophosphatidylcholine. AB - Apolipoprotein-derived peptides have emerged as a potential candidate for the treatment of various inflammatory disease conditions. These peptides bind to pro inflammatory lipids and inhibit their inflammatory functions. Lysophosphatidylcholine (LPC) is a potent pro-inflammatory lipid and increased level of circulating LPC plays a major role in various acute and chronic inflammatory conditions. In this report we examined the effect of peptides derived from the C-terminal domain of human apolipoprotein E on the properties of LPC. Our results show that the peptides (E8, E10 and E11) bind to LPC and inhibit LPC-induced up-regulation of pro-inflammatory markers in human leukocytes. The results suggest that these peptides can be used as an anti-inflammatory agent in inflammatory conditions in which increased level of LPC is a culprit. PMID- 24151884 TI - Medical negligence. An overview of legal theory and neurosurgical practice: duty of care. AB - A working knowledge of the legal principles of medical negligence is helpful to neurosurgeons. It helps them to act in a "reasonable, responsible and logical" manner, that is a practice that is consistent with the surgical practice of their peers. This article will review and explain the relevant medical law in relation to duty of care with illustrative neurosurgical cases. PMID- 24151900 TI - Transepithelial elimination in sarcoidosis: a frequent finding. AB - BACKGROUND: Transepithelial elimination is a process by which dermal materials are expelled through an active epithelial-dermal connective tissue interaction. It has been described as a regular or sporadic occurrence in a variety of dermatologic conditions, including sarcoidosis. OBSERVATION: Our patient demonstrated a rare presentation of sarcoidosis involving the genital region, with histopathologic evidence of transepithelial elimination of granulomas. This prompted us to conduct the first case series documenting the frequency of transepithelial elimination in sarcoidosis. METHODS: Slides of skin biopsies from patients (n = 50) with cutaneous sarcoidosis from the University of Alabama at Birmingham were evaluated for transepithelial elimination. Transepithelial elimination was defined as epithelial channel formation with a sarcoidal-type granuloma completely surrounded by squamous epithelium on the section examined. RESULTS: Transepithelial elimination was found in 9 of 50 cases (18%). CONCLUSION: This is the first report of transepithelial elimination in a lesion of sarcoidosis localized to the vulvar area, and one of only six reports in the English literature documenting cutaneous sarcoidosis with histopathologic evidence of transepithelial elimination. These reports are reviewed herein. Surprisingly, the results from this case series indicate that transepithelial elimination is more common in cutaneous sarcoidosis than one may surmise from the current literature. PMID- 24151899 TI - Postoperative pain control using continuous i.m. bupivacaine infusion plus patient-controlled analgesia compared with epidural analgesia after major hepatectomy. AB - OBJECTIVES: There is debate concerning the best mode of delivery of analgesia following liver resection, with continuous i.m. infusion of bupivacaine (CIB) plus patient-controlled i.v. analgesia (PCA) suggested as an alternative to continuous epidural analgesia (CEA). This study compares these two modalities. METHODS: A total of 498 patients undergoing major hepatectomy between July 2004 and July 2011 were included. Group 1 received CIB + PCA (n = 429) and Group 2 received CEA (n = 69). Groups were analysed on baseline patient and surgical characteristics. Primary endpoints were pain severity scores and total opioid consumption. Secondary endpoints were pain management failures, need for rescue medication, postoperative (opioid-related) morbidity and hospital length of stay (LoS). RESULTS: In both groups pain was well controlled and >70% of patients had no or minimal pain on PoDs 1 and 2. The numbers of patients experiencing severe pain were similar in both groups: PoD 1 at rest: 0.3% in Group 1 and 0% in Group 2 (P = 1.000); PoD 1 on movement: 8% in Group 1 and 2% in Group 2 (P = 0.338); PoD 2 at rest: 0% in Group 1 and 2% in Group 2 (P = 0.126), and PoD 2 on movement: 5% in Group 1 and 5% in Group 2 (P = 1.000). Although the CIB + PCA group required more opioid rescue medication on PoD 0 (53% versus 22%; P < 0.001), they used less opioids on PoDs 0-3 (P <= 0.001), had lower morbidity (26% versus 39%; P = 0.018), and a shorter LoS (7 days versus 8 days; P = 0.005). CONCLUSIONS: The combination of CIB + PCA provides pain control similar to that provided by CEA, but facilitates lower opioid consumption after major hepatectomy. It has the potential to replace epidural analgesia, thereby avoiding the occurrence of rare but serious complications. PMID- 24151901 TI - Automated hippocampal segmentation in patients with epilepsy: available free online. AB - PURPOSE: Hippocampal sclerosis, a common cause of refractory focal epilepsy, requires hippocampal volumetry for accurate diagnosis and surgical planning. Manual segmentation is time-consuming and subject to interrater/intrarater variability. Automated algorithms perform poorly in patients with temporal lobe epilepsy. We validate and make freely available online a novel automated method. METHODS: Manual hippocampal segmentation was performed on 876, 3T MRI scans and 202, 1.5T scans. A template database of 400 high-quality manual segmentations was used to perform automated segmentation of all scans with a multi-atlas-based segmentation propagation method adapted to perform label fusion based on local similarity to ensure accurate segmentation regardless of pathology. Agreement between manual and automated segmentations was assessed by degree of overlap (Dice coefficient) and comparison of hippocampal volumes. KEY FINDINGS: The automated segmentation algorithm provided robust delineation of the hippocampi on 3T scans with no more variability than that seen between different human raters (Dice coefficients: interrater 0.832, manual vs. automated 0.847). In addition, the algorithm provided excellent results with the 1.5T scans (Dice coefficient 0.827), and automated segmentation remained accurate even in small sclerotic hippocampi. There was a strong correlation between manual and automated hippocampal volumes (Pearson correlation coefficient 0.929 on the left and 0.941 on the right in 3T scans). SIGNIFICANCE: We demonstrate reliable identification of hippocampal atrophy in patients with hippocampal sclerosis, which is crucial for clinical management of epilepsy, particularly if surgical treatment is being contemplated. We provide a free online Web-based service to enable hippocampal volumetry to be available globally, with consequent greatly improved evaluation of those with epilepsy. PMID- 24151902 TI - Actin - a biosensor that determines cell fate in yeasts. AB - The decision to proliferate, to activate stress response mechanisms or to initiate cell death lies at the heart of the maintenance of a healthy cell population. Within multicellular and colony-forming single-celled organisms, such as yeasts, the functionality of cellular compartments that connect signalling to cell fate must be maintained to maximise adaptability and survival. The actin cytoskeleton is involved in processes such as the regulation of membrane microcompartments, receptor internalisation and the control of master regulatory GTPases, which govern cell decision-making. This affords the actin cytoskeleton a central position within cell response networks. In this sense, a functional actin cytoskeleton is essential to efficiently connect information input to response at the level of the cell. Recent research from fungal, plant and mammalian cells systems has highlighted that actin can trigger apoptotic death in cells that become incompetent to respond to environmental cues. It may also be the case that this property has been appropriated by microorganisms competing for niche environments within a human host. Here, we discuss the research that has been carried out in yeast that links actin to signalling processes and cell fate that supports its role as a biosensor. PMID- 24151903 TI - Insights of biosimilars through SWOT analysis. PMID- 24151904 TI - TMEM16A/B associated CaCC: structural and functional insights. AB - Calcium-activated chloride channels (CaCCs) play fundamental roles in numerous physiological processes. Transmembrane proteins 16A and 16B (TMEM16A/B) were identified to be the best molecular identities of CaCCs to date. This makes molecular investigation of CaCCs become possible. This review discusses the latest findings of TMEM16A/B associated CaCCs, the calcium and voltage dual dependence,the reorganization of Ca(2+)-binding site, the mechanisms of direct or indirect activation, the structure-functional relationship, and the possible stereoscopic structure. TMEM16A and other members of the family are associated with several kinds of cancers and other chloride channelopathies. An understanding of TMEM16 associated channel proteins will shed some light on their role in oncology and in pharmacology development. PMID- 24151905 TI - Etiology and morphology of carditis: experiences from a single center in China. AB - OBJECTIVE: To investigate the type of cardiac mucosa and its relationship with age and gender of the participants and to determine the coincidence of endoscopic and pathological diagnosis of carditis as well as its etiology. METHODS: The data of 70 patients with carditis (the carditis group) and 30 individuals with endoscopically normal-appearing cardiac mucosa (the control group), including their baseline characteristics and histopathological findings, were reviewed. Their Helicobacter pylori (H. pylori) status was also reviewed. RESULTS: Three main types of cardiac mucosa: mucous, oxyntic and mixed types, were found in 45.0%, 40.0% and 15.0% of all the participants, respectively. The distribution of these types was related to the age of the participants but not to their gender. Moderate to severe mucosal inflammation was detected in 60.0% (18/30) of the control group. The etiologies of cardiac inflammation were H. pylori infection and gastroesophageal reflux disease (GERD). For antral H. pylori-negative participants, cardiac mucosal inflammation was correlated with esophageal mucosal inflammation (P < 0.05), while for those with antral H. pylori infection it was associated with antral mucosal inflammation (P < 0.01). CONCLUSIONS: The distribution of different cardiac mucosal types was related to the participants' age. Normal-appearing cardiac mucosa under endoscopy might present with histopathologically moderate to severe cardiac inflammation. The etiologies of cardiac inflammation were H. pylori infection and GERD. Different causes of carditis may result in the different histological performance of the cardia. PMID- 24151906 TI - Selective NO trapping in the pores of chain-type complex assemblies based on electronically activated paddlewheel-type [Ru2(II,II)]/[Rh2(II,II)] dimers. AB - The design of porous materials that undergo selective adsorption of a specific molecule is a critical issue in research on porous coordination polymers or metal organic frameworks. For the purpose of the selective capture of molecules possessing an electron-acceptor character such as nitric oxide (NO), one dimensional chain compounds possessing a high donor character have been synthesized using 4-chloroanisate-bridged paddlewheel-type dimetal(II, II) complexes with M = Ru and Rh and phenazine (phz) as the chain linker: [M2(4-Cl-2 OMePhCO2)4(phz)].n(CH2Cl2) (M = Ru, 1; Rh, 2). These compounds are isostructural and are composed of chains with a [-{M2}-phz-] repeating unit and CH2Cl2 occupying the void space between the chains. Compounds 1 and 2 change to a new phase (1-dry and 2-dry) upon evacuating the crystallization solvent (CH2Cl2) and almost lose their pores in the drying process: no void space in 1-dry and 31.8 A(3), corresponding to 2.9% of the cell volume, in 2-dry. Nevertheless, the compounds show a unique gas accommodation ability. Accompanied by a structural transformation (i.e., the first gate-opening) at low pressures of <10 kPa, both compounds show a typical physisorption isotherm for O2 (90 K) and CO2 (195 K), with the adsorption amount of ca. 2-4 gas molecules per [M2] unit. In addition, the adsorption isotherm for NO (121 K) involves the first gate-opening followed by a second gate-opening anomaly at NO pressures of ~52 kPa for 1-dry and ~21 kPa for 2-dry. At the first gate-opening, the absorbed amount of NO is ca. 4 molecules per [M2] unit, and then it reaches 8.4 and 6.3 for 1-dry and 2-dry, respectively, at 95 kPa. Only the isotherm for NO exhibits hysteresis in the desorption process, and some of the NO molecules are trapped in pores even after evacuating at 121 K, although it recovers to the original dried sample on heating to room temperature. The adsorbed NO molecules accrue a significant electron donation from the host framework even in the [Rh2] derivative, indicating that such simple porous compounds with electron-donor characteristics are useful for the selective adsorption of NO. PMID- 24151907 TI - Flavor of cold-hardy grapes: impact of berry maturity and environmental conditions. AB - Since the arrival on the market of high-quality cold-hardy grape varieties, northern winemaking has been developing tremendously in countries traditionally unsuited for grape and wine production. Cold-hardy grapes are mainly interspecific hybrids of Vitis vinifera with Vitis labrusca and Vitis riparia , making their chemical composition distinct from that of V. vinifera varieties traditionally used for winemaking and therefore limiting the use of current knowledge about V. vinifera varieties in the assessment of grape maturity. Consequently, to evaluate the flavor development of cold-hardy grapes in the province of Quebec, Canada, the ripening of Frontenac and Marquette berries in two vineyards located in the southwest (SW) and northeast (NE) areas of the province, starting at the beginning of veraison, was studied. Quality attributes, phenolic compounds, and aroma profiles showed significant changes during maturation. Although full maturity was reached for both Frontenac and Marquette in the SW vineyard (1380 accumulated growing degree days, based on 10 degrees C), the accumulation of 1035 growing degree days was not sufficient to fully ripen Frontenac and Marquette in the NE vineyard. Principal component analysis showed different ripening patterns for the two studied locations. The longer veraison in the SW vineyard resulted in higher quality attributes and higher flavor development for both Frontenac and Marquette. Under the colder conditions in the NE vineyard, metabolite accumulation was driven primarily by berry growth, and flavor development was limited. Besides growing degree days and technological parameters (total soluble solids, pH, titratable acidity), which provide significant guidelines for maturity assessment in cold climate, phenolic maturity may be followed by the accumulation of hydroxycinnamic esters and flavonoids, although the impact of these compound classes on quality remains to be determined in cold-climate wines. In both Frontenac and Marquette, aromatic maturity was best assessed using the ratio of cis-3-hexenol to trans-2-hexenal, which showed a constant decrease until maturity. Interestingly, a shift in C6 compound profile, illustrated by the progression of the sum of C6 compounds respectively produced from linoleic (C18:2; hexanal and 1-hexanol) and alpha-linolenic (C18:3; trans-2 hexenol and cis-3-hexenol) acids occurred during ripening, with alpha-linolenic acid (C18:3) degradation products decreasing in both varieties as maturation approached. At harvest, aroma profiles of both Frontenac and Marquette were dominated by C6 compounds (hexanal, trans-2-hexenal, 1-hexanol, cis-3-hexenol, and hexanoic acid), acetic acid, beta-damascenone, and 2-phenylethanol, with Marquette additionally showing significant levels of monoterpenes (linalool, geraniol, and alpha-citral) and 1-octen-3-ol. PMID- 24151908 TI - Identification and characterization of the geranylgeranyl diphosphate synthase in Deinococcus radiodurans. AB - Deinococcus radiodurans strain R1 utilizes multiple antioxidants including a unique carotenoid, deinoxanthin, to fight again oxidative stress. Most of the enzymes involved in the deinoxanthin biosynthetic pathway have been identified. However, the enzyme catalysing the synthesis of geranylgeranyl diphosphate (GGPP), which is a precursor of carotenoid biosynthesis, has yet to be identified. Two putative isoprenyl diphosphate synthases (IPPS) homologues (DR1395 and DR932) were screened out by analysis of conserved amino acid regions, and their biochemical functions were investigated. Gene mutation, gene expression in Escherichia coli and analysis of carotenoid products were used to investigate the functions of these candidates. The results suggested that DR1395 encodes the protein for GGPP synthesis. Site-directed mutant analysis indicated that the amino acid composition of and around the first aspartate-rich motif is vital for GGPP synthase function. SIGNIFICANCE AND IMPACT OF THE STUDY: Deinococcus radiodurans strain R1 produces a unique carotenoid product, deinoxanthin, as an antioxidant. In this study, DR1395 was identified as the gene encoding geranylgeranyl diphosphate synthase (GGPPS) for entrance to deinoxanthin biosynthesis in D. radiodurans. Moreover, site-directed mutagenesis studies on DR1395 identified the effect of amino acid composition of the aspartate-rich motif on the production of this carotenoid. This study demonstrated the entrance step in the deinoxanthin biosynthetic pathway. These results can be useful in genetic engineering strategies for deinoxanthin production including enhancement of GGPPS gene expression in D. radiodurans. PMID- 24151909 TI - Nicotinamide treatment reduces the levels of oxidative stress, apoptosis, and PARP-1 activity in Abeta(1-42)-induced rat model of Alzheimer's disease. AB - The underlying mechanisms of Alzheimer's Disease (AD) are still unclear. It is suggested that poly(ADP-ribose) polymerase-1 (PARP-1) overactivation can cause neuroinflammation and cell death. In this study we searched the effects of nicotinamide (NA), endogenous PARP-1 inhibitor, on oxidative stress, apoptosis, and the regulation of PARP-1 and nuclear factor kappa B (NF-kappaB) in amyloid beta peptide (1-42) (Abeta(1-42))-induced neurodegeneration. Sprague-Dawley rats were divided into four groups as control, Abeta(1-42), Abeta(1-42) + NA(100 and 500 mg/kg). All groups were stereotaxically injected bilaterally into the hippocampus with Abeta(1-42) or saline. After surgery NA administrations were made intraperitoneally (ip) for 7 days. In order to investigate the effects of Abeta(1-42) and NA, protein carbonyls, lipid peroxidation, reactive oxygen species (ROS) production, glutathione (GSH) levels, activities of antioxidant enzymes (catalase, superoxide dismutase, glutathione peroxidase), mitochondrial function, mRNA and protein levels of PARP-1, NF-kappaB, p53, Bax, and Bcl-2 were measured in specific brain regions such as cortex and hippocampus. Abeta(1-42) treatment only increased the oxidative stress parameters and caused decline in antioxidant enzyme activities, mitochondrial function, and GSH levels. Also, overexpression of PARP-1, NF-kappaB, p53, Bax, and the decreased levels of Bcl-2 were observed in Abeta(1-42)-treated group. NA treatments against Abeta(1-42) upregulated Bcl-2 and downregulated PARP-1, NF-kappaB, p53, and Bax levels. NA treatments also decreased the oxidative stress parameters and elevated antioxidant enzyme activities, GSH levels, and mitochondrial function against Abeta(1-42) treatment. These data suggest that NA may have a therapeutic potential in neurodegenerative processes due to the decreased levels of oxidative stress, apoptosis, and PARP-1 activity. PMID- 24151910 TI - Naturally occurring antimicrobial peptide OH-CATH30 selectively regulates the innate immune response to protect against sepsis. AB - Sepsis, which is a systemic inflammatory response that follows a bacterial infection, has a high mortality rate and limited therapeutic options. Here we show that the antimicrobial peptide OH-CATH30, which naturally occurs in snake, selectively regulates the innate immune response to protect mice from lethal sepsis. The administration of OH-CATH30 significantly improves the survival rate of mice infected by antibiotic-susceptible and -resistant pathogens, including Escherichia coli , Pseudomonas aeruginosa , and Staphylococcus aureus . OH-CATH30 selectively up-regulates the production of chemokines and cytokines without harmful immune response. Recruitment of monocytes, macrophages, and neutrophils to the infection site is pivotal to the protective capacity of OH-CATH30. Furthermore, the alternative activation of the innate immune response by OH CATH30 depends on p38 mitogen-activated protein kinase signaling. Taken together, our study demonstrates that OH-CATH30, a naturally occurring antimicrobial peptide, selectively stimulates the innate immune response to protect against sepsis. PMID- 24151911 TI - Elevated liver enzymes are related to progression to impaired glucose tolerance in Japanese men. AB - AIMS: To investigate whether the elevation of liver enzymes is associated with the progression from normal to impaired glucose tolerance. METHODS: A historical cohort study was conducted in 594 male workers at public schools, who had normal glucose tolerance at baseline. The progression to impaired glucose tolerance and impaired fasting glycaemia during a mean follow-up of 3.1 years was measured using an oral glucose tolerance test. RESULTS: Overall, 141 (23.7%) subjects developed impaired glucose tolerance and 68 (11.4%) subjects developed impaired fasting glycaemia, 23 of whom had combined impaired fasting glycaemia/impaired glucose tolerance. The incidence of impaired glucose tolerance increased significantly with increasing quartiles of serum aspartate aminotransferase, alanine aminotransferase and gamma-glutamyltransferase (P for trend <0.01). In Cox proportional hazards regression analysis, after adjusting for comprehensive risk factors, including plasma glucose levels, BMI and homeostatic model assessment of insulin resistance, the risk of progression to impaired glucose tolerance was significantly higher in the highest quartile of alanine aminotransferase than in the lowest quartile (hazard ratio 2.5; 95% CI 1.1-5.7). A significant association between alanine aminotransferase and the progression to impaired glucose tolerance was found after further adjustments for other liver enzymes or after the sample was limited to those with BMI < 25.0 kg/m(2) or with fasting plasma glucose < 5.5 mmol/l. CONCLUSIONS: A higher level of alanine aminotransferase was independently associated with progression from normal to impaired glucose tolerance in Japanese men. The elevation of alanine aminotransferase may be a change that occurs early in the evolution of diabetes. PMID- 24151912 TI - Physical performance and short-term mortality in very old Mexican Americans. AB - BACKGROUND/STUDY CONTEXT: Physical performance measures have been found to be strong predictors of adverse outcomes in aging populations. Few studies have examined the predictive ability of physical performance measures exclusively within populations of the very old. This study explores the predictive ability of the Short Physical Performance Battery (SPPB) and its three subcomponents-a timed walk, balance test, and repeated timed chair stands-on mortality in a sample of Mexican Americans aged 75 and older. METHODS: Logistic regression analyses were used with data from the Hispanic Established Population for the Epidemiological Study of the Elderly (Hispanic EPESE), to investigate the relationship between timed walk, balance test, repeated timed chair stands, and the SPPB and mortality over a 21/2-year period. RESULTS: The authors find that being unable to complete the timed walk, the balance test, and repeated timed chair stands, or unable to complete any of the SPPB was significantly associated with mortality over 21/2 years. CONCLUSION: These findings indicate that physical performance measures may be less predictive of short-term mortality in very old Mexican Americans than previously thought. More research is needed to understand this relationship. PMID- 24151913 TI - Individual differences in task-specific paired associates learning in older adults: the role of processing speed and working memory. AB - BACKGROUND/STUDY CONTEXT: The role of processing speed and working memory was investigated in terms of individual differences in task-specific paired associates learning in a sample of older adults. Task-specific learning, as distinct from content-oriented item-specific learning, refers to gains in performance due to repeated practice on a learning task in which the to-be learned material changes over trials. METHODS: Learning trajectories were modeled within an intensive repeated-measures design based on participants obtained from an opt-in Internet-based sampling service (M(age) = 65.3, SD = 4.81). Participants completed an eight-item paired associates task daily over a 7-day period. RESULTS: Results indicated that a three-parameter hyperbolic model (i.e., initial level, learning rate, and asymptotic performance) best described learning trajectory. After controlling for age-related effects, both higher working memory and higher processing speed had a positive effect on all three learning parameters. CONCLUSION: These results emphasize the role of cognitive abilities for individual differences in task-specific learning of older adults. PMID- 24151915 TI - Explicit (semantic) memory for music in patients with mild cognitive impairment and early-stage Alzheimer's disease. AB - BACKGROUND/STUDY CONTEXT: Explicit memory for music was investigated by using a new test with 24 existing and 3 newly composed pieces. METHODS: Ten patients with mild cognitive impairment (MCI) and 10 patients with early stage of Alzheimer's disease (AD) were compared with 23 healthy subjects, in terms of verbal memory of music by the identification of familiar music excerpts and the discrimination of distortion and original timbre of musical excerpts. RESULTS: MCI and Alzheimer's patients showed significantly poorer performances in tasks requiring verbal memory of musical excerpts than the healthy participants. For discrimination of musical excerpts, MCI and AD patients surprisingly performed significantly better than the healthy comparison subjects. CONCLUSION: Our results support the notion of a specialized memory system for music. PMID- 24151914 TI - Qualitative neuropsychological measures: normative data on executive functioning tests from the Framingham offspring study. AB - BACKGROUND/STUDY CONTEXT: Studies have found that executive functioning is affected early in the pathophysiological processes associated with Alzheimer's disease and vascular dementia. There also exists a range of functioning on executive tasks during normal aging. Although qualitative data are commonly utilized in clinical practice for evaluating subtle changes in cognitive functioning and diagnostic discernment, it is not clear whether error responses used in clinical practice are also evident as normative behavior. METHODS: As part of an extensive battery of neuropsychological tests, executive functioning measures (i.e., Trail Making Test Part B, Similarities and Verbal Fluency tests) were administered via standardized administration prescript. Regression analyses were used to determine associations between vascular aging indices and qualitative performance measures. Descriptive statistics are included for 1907 cognitively normal individuals. RESULTS: Results suggest that although qualitative errors do occur, they are relatively infrequent within a presumably cognitively normal sample. Error commission rates on executive functioning tests are significantly associated with both age and education. CONCLUSION: Provided is a baseline profile of errors committed on tests of executive function across a range of age and educational levels. The normative data sets are included, stratified by age and educational achievement, for which to compare qualitative test performance of clinical and research populations. PMID- 24151916 TI - Perceived duration of emotional events: evidence for a positivity effect in older adults. AB - BACKGROUND/STUDY CONTEXT: Arousal and negative affect modulate the effect of emotion on the subjective experience of the passage of time. Given that older adults are less aroused by negative emotional stimuli, and report lower levels of negative affect, compared with younger adults, the present study examined whether the effect of emotion on time perception differed in older and younger adults. METHODS: Participants performed a temporal bisection task for emotional (i.e., angry, sad, happy) and neutral facial expressions presented at varying temporal intervals. RESULTS: Older adults perceived the duration of both positive and threatening events longer than neutral events, whereas younger adults only perceived threatening events longer than neutral events. CONCLUSION: The results, which are partially consistent with the positivity effect of aging postulated by the socioemotional selectivity theory, are the first to show how the effect of emotion on perceived duration affects older adults, and support previous research indicating that only threatening events prolong perceived duration in younger adults. PMID- 24151917 TI - Work Ability Index in Israeli hospital nurses: applicability of the adapted questionnaire. AB - BACKGROUND/STUDY CONTEXT: The Work Ability Index (WAI) questionnaire is widely used for evaluation of the work ability of workers. This is the first application of the validated Hebrew version of this questionnaire to Israeli nurses in order to evaluate factors affecting their work ability. METHODS: A cross-sectional study was conducted among 515 nurses from two general hospitals in Israel (87.3% female). RESULTS: A significant negative correlation was found between the WAI score and age, years in current job, and number of reported diagnoses. The most frequently reported illnesses (as diagnosed by a physician) were musculoskeletal disorders, endocrine/metabolic diseases, and cardiovascular diseases. Agreement between illnesses as diagnosed by a physician and as self-reported by nurses was low, especially with respect to mental/emotional stress, (kappa statistics = 16.4%, p < .001). CONCLUSIONS: Mean WAI score found in Israeli hospital nurses is relatively high as compared with that of European nurses. It gradually decreases with age. The WAI questionnaire enables the early identification of those nurses with compromised work ability and who are in need of assistance in order to prevent early retirement. As retirement age is currently advancing, keeping elderly workers in the workforce is of prime importance. PMID- 24151919 TI - Pharmacokinetics of drugs in mutant Nagase analbuminemic rats and responses to select diuretics. AB - OBJECTIVES: To report (1) the pharmacokinetics of drugs that are mainly metabolized via hepatic cytochrome P450s (CYPs) or mainly excreted via the urine and bile, (2) the mechanism for the urinary excretion of drugs (such as glomerular filtration or renal active secretion or re-absorption), and (3) the diuretic effect of some loop diuretics in mutant Nagase analbuminaemic rats (NARs), an animal model for human familial analbuminaemia based on the pharmacokinetics of drugs reported in the literatures. KEY FINDINGS: In NARs, the changes in the time-averaged non-renal clearances (CL(NR)s) of drugs that are mainly metabolized via CYPs were explained in terms of changes in the hepatic intrinsic clearance (mainly because of changes in CYPs), free (unbound) fractions of drugs in the plasma (fp) and hepatic blood-flow rate (QH) depending on the hepatic excretion ratios of drugs. SUMMARY: The CL(NR) changes of drugs mainly metabolized via hepatic CYPs can be sufficiently explained by the three earlier mentioned factors. The plasma albumin (furosemide) or globulin (azosemide, bumetanide and torasemide) binding affects their diuretic effects. PMID- 24151920 TI - Fruitful research: drug target discovery for neurodegenerative diseases in Drosophila. AB - INTRODUCTION: Although vertebrate model systems have obvious advantages in the study of human disease, invertebrate organisms have contributed enormously to this field as well. The conservation of genome structure and physiology among organisms poses unexpected peculiarities, and the redundancy in certain gene families or the presence of polymorphisms that can slightly alter gene expression can, in certain instances, bring invertebrate systems, such as Drosophila, closer to humans than mice and vice versa. This necessitates the analysis of disease pathways in multiple model organisms. AREAS COVERED: The author highlights findings from Drosophila models of neurodegenerative diseases that have occurred in the past few years. She also highlights and discusses various molecular, genetic and genomic tools used in flies, as well as methods for generating disease models. Finally, the author describes Drosophila models of Alzheimer's, Parkinson's tri-nucleotide repeat diseases, and Fragile X syndrome and summarizes insights in disease mechanisms that have been discovered directly in fly models. EXPERT OPINION: Full genome genetic screens in Drosophila can lead to the rapid identification of drug target candidates that can be subsequently validated in a vertebrate system. In addition, the Drosophila models of neurodegeneration may often show disease phenotypes that are absent in equivalent mouse models. The author believes that the extensive contribution of Drosophila to both new disease drug target discovery, in addition to target validation, makes them indispensible to drug discovery and development. PMID- 24151921 TI - Use of a large multiparent wheat mapping population in genomic dissection of coleoptile and seedling growth. AB - Identification of alleles towards the selection for improved seedling vigour is a key objective of many wheat breeding programmes. A multiparent advanced generation intercross (MAGIC) population developed from four commercial spring wheat cultivars (cvv. Baxter, Chara, Westonia and Yitpi) and containing ca. 1000 F(2) -derived, F(6:7) RILs was assessed at two contrasting soil temperatures (12 and 20 degrees C) for shoot length and coleoptile characteristics length and thickness. Narrow-sense heritabilities were high for coleoptile and shoot length (h(2) = 0.68-0.70), indicating a strong genetic basis for the differences among progeny. Genotypic variation was large, and distributions of genotype means were approximately Gaussian with evidence for transgressive segregation for all traits. A number of significant QTL were identified for all early growth traits, and these were commonly repeatable across the different soil temperatures. The largest negative effects on coleoptile lengths were associated with Rht-B1b ( 8.2%) and Rht-D1b (-10.9%) dwarfing genes varying in the population. Reduction in coleoptile length with either gene was particularly large at the warmer soil temperature. Other large QTL for coleoptile length were identified on chromosomes 1A, 2B, 4A, 5A and 6B, but these were relatively smaller than allelic effects at the Rht-B1 and Rht-D1 loci. A large coleoptile length effect allele (a = 5.3 mm at 12 degrees C) was identified on chromosome 1AS despite the relatively shorter coleoptile length of the donor Yitpi. Strong, positive genetic correlations for coleoptile and shoot lengths (r(g) = 0.85-0.90) support the co-location of QTL for these traits and suggest a common physiological basis for both. The multiparent population has enabled the identification of promising shoot and coleoptile QTL despite the potential for the confounding of large effect dwarfing gene alleles present in the commercial parents. The incidence of these alleles in commercial wheat breeding programmes should facilitate their ready implementation in selection of varieties with improved establishment and early growth. PMID- 24151922 TI - Characterizing impulsivity profile in patients with obsessive-compulsive disorder. AB - OBJECTIVE: Impulsivity represents a key dimension in obsessive-compulsive disorder (OCD), in relation to outcome and course. It can be assessed through the Barratt Impulsiveness Scale (BIS), which explores three main areas: attentional, motor, and nonplanning. Present study was aimed to assess level of impulsivity in a sample of OCD patients, in comparison with healthy controls, using the BIS. METHODS: Seventy-five OCD outpatients, 48 of them having psychiatric comorbidities and 70 healthy controls, were assessed through the BIS, and their scores were analyzed using Student's t-test for independent samples, on the basis of demographic and clinical characteristics. RESULTS: BIS total scores were significantly higher (P: 0.01) in patients compared to controls, with no difference between pure and comorbid patients. Attentional impulsivity scores were significantly higher than controls in patients with pure (P < 0.001) and comorbid OCD (P < 0.001), without differences among them. Patients with multiple OC phenotypes showed higher, though statistically non significant, total and attentional scores, compared to single phenotype patients. In addition, patients with comorbid major depressive disorder had higher, though statistically non significant, total and attentional scores, compared to patients with comorbid bipolar disorder, generalized anxiety disorder, and other disorders. CONCLUSIONS: Present findings showed higher impulsivity levels in OCD patients versus controls, particularly in the attentional area, and ultimately suggest a potential cognitive implication. PMID- 24151923 TI - Increased co-morbidity of depression and post-traumatic stress disorder symptoms and common risk factors in intensive care unit survivors: a two-year follow-up study. AB - OBJECTIVE: To investigate the long-term psychological impact of intensive care unit (ICU) hospitalization, as well as to establish risk factors which successfully discriminate patients at higher risk. METHODS: The Medical Outcomes Study Short Form Survey (SF-36), the Center for Epidemiologic Studies for Depression (CES-D), and the Davidson Trauma Scale (DTS) questionnaires were obtained from 48 ICU survivors who were also interviewed and self-reported on several acknowledged risk factors. RESULTS: A high co-morbidity between depression and post-traumatic stress disorder (PTSD) cases was observed. Both CES D and DTS scores correlated negatively with the SF-36 mental health subscale scores; although a causative relation cannot be attributed to this finding, it indicates a potential negative impact of depression and PTSD symptoms on the patients' quality of life even at 18- to 24-month post-ICU. The most important risk factor associated with a long-term impact on quality of life, depression and PTSD was lifetime history of any psychiatric disorder. CONCLUSIONS: During ICU admissions efforts should be made towards identifying and psychologically supporting those patients with a previous history of a psychiatric disease, as they are at considerably higher risk of suffering from the long-term psychological sequelae of ICU admission. PMID- 24151924 TI - Metabolic and mechanical involvement of arms and legs in simulated double pole skiing. AB - We evaluated arm and leg work rate and metabolism during double pole ergometer skiing. Thermodilution arm and leg blood flow was determined together with the arterial to venous difference for oxygen, while the work rate was assessed in eight male recreational skiers [24 (SD 7) years]. When work rate increased from 82 (SE 4) to 117 (7) W, leg power increased by 43% (enhanced vertical force and displacement of the body). The elbow angle tended to increase [from 71 (11.3) degrees to 75 (10.9) degrees ; P = 0.07] and arm oxygen uptake increased by 20 (5)% [from 0.65 (0.07) to 0.78 (0.08) L/min; P < 0.05] because two-arm blood flow increased [from 5.4 (0.6) to 6.3 (0.7) L/min; P < 0.05] with no significant change in oxygen extraction [from 59 (2.3)% to 60 (1.9)%] accompanied with net arm lactate and potassium release. In contrast, two-leg blood flow [from 5.8 (0.5) to 8.0 (0.5) L/min] and oxygen extraction [from 67 (1.3)% to 75 (1.5)%] increased (P < 0.05), resulting in a 53 (8)% increase in leg oxygen uptake [from 0.82 (0.06) to 1.24 (0.07) L/min; P < 0.05]. In conclusion, during double poling on an ergometer, arm muscle metabolism and work rate increase only marginally and an increase in work intensity is covered mainly by the leg muscles. PMID- 24151925 TI - Self-assembly of complex salts of cationic surfactants and anionic-neutral block copolymers. Dispersions with liquid-crystalline internal structure. AB - We report the synthesis of complex salts made from the cationic surfactant dodecyltrimethylammonium and diblock copolymers poly(acrylic acid)-block poly(acrylamide) of different molecular weights. In water, the complex salts self assemble into stable hierarchical aggregates with a dense core and a diffuse shell. In contrast to earlier reports, the surfactant/polymer aggregates exhibit a liquid crystalline structure of Pm3n cubic symmetry. The crystal structure is analogous to that obtained with homopolymer. Size and aggregation numbers were estimated from a combination of light and small-angle X-ray scattering experiments. It is found that the size of the aggregates decreases with increasing diblock asymmetry. The complex salt methodology presents many advantages, among which to be insensitive to the preparation conditions and to the mixing pathway. PMID- 24151926 TI - Efficacy of four lining materials in sandwich technique to reduce microleakage in class II composite resin restorations. AB - OBJECTIVES: The aim of the present study was to evaluate the effect of four different sandwich techniques on gingival microleakage of Class II direct composite resin restorations. MATERIALS AND METHODS: Fifty sound human premolars were selected and randomly divided into five groups (n=10). Class II box only cavities were prepared in one of the proximal surfaces of each tooth with a gingival margin located approximately 0.5 mm below the cemento-enamel junction. Group A (control) was restored incrementally with composite resin (Tetric Ceram). Groups B, C, D, and E were restored with the sandwich technique using a compomer (Compoglass F), flowable composite resin (Tetric Flow), self-cure composite resin (Degufill SC), or resin modified glass ionomer (Fuji II LC), respectively. After thermal-load cycling, the specimens were immersed in 0.5% basic fuschin for 24 hours. Dye penetration (10(-1) mm) was detected using a sectioning technique. Data were analyzed with repeated measurements and Duncan test at alpha=0.05. RESULTS: The least amount of microleakage was detected in the incremental group (1.28 +/- 0.98). The sandwich technique using resin modified glass ionomer (7.99 +/- 9.57) or compomer (4.36 +/- 1.78) resulted in significantly more leakage than did the sandwich technique using flowable (1.50 +/- 1.97) or self-cure composite (2.26 +/- 1.52). CONCLUSION: According to the results of this study, none of the four sandwich technique composite resin restorations used in this study could reduce gingival microleakage to a greater degree than the incremental technique. PMID- 24151927 TI - Interview: stabilization of biological assays: conventional versus new technology. Interview by Lauren Constable. AB - Miles Burrows speaks to Lauren Constable, Head of Commissioning Following completion of his PhD in Chemistry at Cardiff University (UK), Miles Burrows started his career at Amersham Biosciences (UK), predominately researching fluorescent reagents and the labeling of biological compounds. Following the acquisition of Amersham by GE Healthcare (UK), Burrows took on the role of R&D Technology Manager, leading a multifunctional team of chemists, biologists and industrial design engineers through new product introduction, research and product care projects. During this period, Burrows oversaw the launch of a custom assay stabilization service based on the well-established technology as used in GE Healthcare's Ready-To-GoTM product range. Since 2012 Burrows has been the Global Product Manager for custom molecular biology and fluorescent reagents for GE Healthcare Life Sciences. PMID- 24151928 TI - Dissipation of insecticidal Cry1Ac protein and its toxicity to nontarget aquatic organisms. AB - The widespread cultivation of Bacillus thuringiensis crops has raised public concerns on their risk to nontarget organisms. Persistence of Cry1Ac protein in soil, sediment and water and its toxicity to nontarget aquatic organisms were determined. The dissipation of Cry1Ac toxin was well described using first order kinetics, with the half-lives (DT50) ranging from 0.8 to 3.2, 2.1 to 7.6 and 11.0 to 15.8 d in soil, sediment and water, respectively. Microbial degradation played a key role in the dissipation of Cry1Ac toxin and high temperature accelerated the processes. Cry1Ac toxin was more toxic to the midge Chironomus dilutus than the amphipod Hyalella azteca, with the median lethal concentration (LC50) of C. dilutus being 155 ng/g dry weight and 201 ng/mL in 10-d sediment and 4-d water bioassays, respectively. While Cry1Ac toxin showed toxicity to the midges, risk of Bt proteins to aquatic nontarget organisms was limited because their environmentally relevant concentrations were much lower than the LC50s. PMID- 24151929 TI - Photocatalytic carbon disulfide production via charge transfer quenching of quantum dots. AB - Carbon disulfide, a potentially therapeutic small molecule, is generated via oxidative cleavage of 1,1-dithiooxalate (DTO) photosensitized by CdSe quantum dots (QDs). Irradiation of DTO-QD conjugates leads to lambda(irr) independent photooxidation with a quantum yield of ~4% in aerated pH 9 buffer solution that drops sharply in deaerated solution. Excess DTO is similarly decomposed, indicating labile exchange at the QD surfaces and a photocatalytic cycle. Analogous photoreaction occurs with the O-tert-butyl ester (t)BuDTO in nonaqueous media. We propose that oxidation is initiated by hole transfer from photoexcited QD to surface DTO and that these substrates are a promising class of photocleavable ligands for modifying QD surface coordination. PMID- 24151931 TI - Exploring the reactivity of N-alkynylated sulfoximines: [2 + 2]-cycloadditions. AB - To assess the potential of N-alkynylated sulfoximines as new (chiral) reagents for organic synthesis, their reactivity profile in numerous synthetic processes is under investigation. When reacted with ketenes, the alkynylated-sulfoximines undergo a [2 + 2]-cycloaddition process to afford sulfoximine-functionalized cyclobutenones in excellent yields. PMID- 24151930 TI - The impact of concordant and discordant comorbidities on patient-assessed quality of diabetes care. AB - OBJECTIVE: To examine the impact of concordant and discordant comorbidities on patients' assessments of providers' adherence to diabetes-specific care guidelines and quality of chronic illness care. RESEARCH DESIGN AND METHODS: A population-based survey of 3761 adults with type 2 diabetes, living in Queensland, Australia was conducted in 2008. Based on self-reports, participants were grouped into four mutually exclusive comorbid categories: none, concordant only, discordant only and both concordant and discordant. Outcome measures included patient-reported providers' adherence to guideline-recommended care and the Patient Assessment of Chronic Illness Care (PACIC), which measures care according to the Chronic Care Model. Analyses using the former measure included logistic regressions, and the latter measure included univariate analysis of variance, both unadjusted and adjusted for sampling region, gender, age, educational attainment, diabetes duration and treatment status. RESULTS: Having concordant comorbidities increased the odds of patient-reported providers' adherence for 7 of the 11 guideline-recommended care activities in unadjusted analyses. However, the effect remained significant for only two provider activities (reviews of medication and/or complications and blood pressure examinations) when adjusted. A similar pattern was found for the both concordant and discordant comorbidity category. The presence of discordant comorbidities influenced only one provider activity (blood pressure examinations). No association between comorbidity type and the overall PACIC score was found. CONCLUSIONS: Comorbidity type is associated with diabetes-specific care, but does not seem to influence broader aspects of chronic illness care directly. Providers need to place more emphasis on care activities which are not comorbidity-specific and thus transferable across different chronic conditions. PMID- 24151932 TI - Infrared multiple photon dissociation action spectroscopy of proton-bound dimers of cytosine and modified cytosines: effects of modifications on gas-phase conformations. AB - The gas-phase structures of proton-bound dimers of cytosine and modified cytosines and their d6-analogues generated by electrospray ionization are probed via infrared multiple photon dissociation (IRMPD) action spectroscopy and theoretical electronic structure calculations. The modified cytosines examined include the 5-methyl-, 5-fluoro-, and 5-bromo-substituted species. IRMPD action spectra of seven proton-bound dimers exhibit both similar and distinctive spectral features over the range of ~2600-3700 cm(-1). The IRMPD spectra of all of these proton-bound dimers are relatively simple, but exhibit obvious shifts in the positions of several bands that correlate with the properties of the substituent. The measured IRMPD spectra are compared to linear IR spectra calculated for the stable low-energy tautomeric conformations, determined at the B3LYP/6-31G* level of theory, to identify the conformations accessed in the experiments. Comparison of the measured IRMPD and calculated IR spectra indicates that only a single conformation, the ground-state structure, is accessed for all proton-bound homodimers, whereas the ground-state and a small population of the first-excited tautomeric conformations are accessed for all proton-bound heterodimers. In all cases, three hydrogen-bonding interactions in which the nucleobases are aligned in an antiparallel fashion analogous to that of the DNA i motif are responsible for stabilizing the base pairing. Thus, base modifications such as 5-methyl- and 5-halo-substitution of cytosine should not alter the structure of the DNA i-motif. PMID- 24151933 TI - Improved sake metabolic profile during fermentation due to increased mitochondrial pyruvate dissimilation. AB - Although the decrease in pyruvate secretion by brewer's yeasts during fermentation has long been desired in the alcohol beverage industry, rather little is known about the regulation of pyruvate accumulation. In former studies, we developed a pyruvate under-secreting sake yeast by isolating a strain (TCR7) tolerant to ethyl alpha-transcyanocinnamate, an inhibitor of pyruvate transport into mitochondria. To obtain insights into pyruvate metabolism, in this study, we investigated the mitochondrial activity of TCR7 by oxigraphy and (13) C-metabolic flux analysis during aerobic growth. While mitochondrial pyruvate oxidation was higher, glycerol production was decreased in TCR7 compared with the reference. These results indicate that mitochondrial activity is elevated in the TCR7 strain with the consequence of decreased pyruvate accumulation. Surprisingly, mitochondrial activity is much higher in the sake yeast compared with CEN.PK 113 7D, the reference strain in metabolic engineering. When shifted from aerobic to anaerobic conditions, sake yeast retains a branched mitochondrial structure for a longer time than laboratory strains. The regulation of mitochondrial activity can become a completely novel approach to manipulate the metabolic profile during fermentation of brewer's yeasts. PMID- 24151934 TI - beta-sheet structures and dimer models of the two major tyrocidines, antimicrobial peptides from Bacillus aneurinolyticus. AB - The structures of two major tyrocidines, antibiotic peptides from Bacillus aneurinolyticus, in an aqueous environment were studied using nuclear magnetic resonance spectroscopy, restrained molecular dynamics (MD), circular dichroism, and mass spectrometry. TrcA and TrcC formed beta-structures in an aqueous environment. Hydrophobic and hydrophilic residues were not totally separated into nonpolar and polar faces of the peptides, indicating that tyrocidines have low amphipathicity. In all the beta-structures, residues Trp(4)/Phe(4) and Orn(9) were on the same face. The ability of the peptides to form dimers in aqueous environment was studied by replica exchange MD simulations. Both peptides readily dimerize, and predominant complex structures were characterized through cluster analysis. The peptides formed dimers by either associating sideways or stacking on top of each other. Dimers formed through sideways association were mainly stabilized by hydrogen bonding, while the other dimers were stabilized by hydrophobic interactions. The ability of tyrocidine peptides to form different types of dimers with different orientations suggests that they can form larger aggregates, as well. PMID- 24151935 TI - Hypophosphatemia and sudden infant death syndrome (SIDS)--is ATP the link? PMID- 24151936 TI - The Hsp60 folding machinery is crucial for manganese superoxide dismutase folding and function. AB - Even though the deleterious effects of increased reactive oxygen species (ROS) levels have been implicated in a variety of neurodegenerative disorders, the triggering events that lead to the increased ROS and successive damages are still ill-defined. Mitochondria are the key organelles controlling the ROS balance, being their main source and also counteracting them by the action of the ROS scavenging system. Mitochondria, moreover, control the presence of ROS-damaged proteins by action of the protein quality control (PQC) system. One of its components is the mitochondrial chaperone Hsp60 assisting the folding of a subset of mitochondrial matrix proteins. Mutations in Hsp60 cause a late onset form of the neurodegenerative disease hereditary spastic paraplegia (SPG13). In this study, we aimed to address the molecular consequences of Hsp60 shortage. We here demonstrate that a heterozygous knockout Hsp60 model that recapitulates features of the human disease and exhibits increased oxidative stress in neuronal tissues. Moreover, we indicate that the increase of ROS is, at least in part, due to impaired folding of the manganese superoxide dismutase (MnSOD), a key antioxidant enzyme. We observed that the Hsp60 and MnSOD proteins interact. Based on these results, we propose that MnSOD is a substrate of the Hsp60 folding machinery and that under conditions of diminished availability of Hsp60, MnSOD is impaired in reaching the native state. This suggests a possible link between Hsp60-dependent PQC and the ROS scavenging systems that may have the function to increase ROS production under conditions of folding stress. PMID- 24151937 TI - Biomagnification of mercury in aquatic food webs: a worldwide meta-analysis. AB - The slope of the simple linear regression between log10 transformed mercury (Hg) concentration and stable nitrogen isotope values (delta(15)N), hereafter called trophic magnification slope (TMS), from several trophic levels in a food web can represent the overall degree of Hg biomagnification. We compiled data from 69 studies that determined total Hg (THg) or methyl Hg (MeHg) TMS values in 205 aquatic food webs worldwide. Hg TMS values were compared against physicochemical and biological factors hypothesized to affect Hg biomagnification in aquatic systems. Food webs ranged across 1.7 +/- 0.7 (mean +/- SD) and 1.8 +/- 0.8 trophic levels (calculated using delta(15)N from baseline to top predator) for THg and MeHg, respectively. The average trophic level (based on delta(15)N) of the upper-trophic-level organisms in the food web was 3.7 +/- 0.8 and 3.8 +/- 0.8 for THg and MeHg food webs, respectively. For MeHg, the mean TMS value was 0.24 +/- 0.08 but varied from 0.08 to 0.53 and was, on average, 1.5 times higher than that for THg with a mean of 0.16 +/- 0.11 (range: -0.19 to 0.48). Both THg and MeHg TMS values were significantly and positively correlated with latitude. TMS values in freshwater sites increased with dissolved organic carbon and decreased with total phosphorus and atmospheric Hg deposition. Results suggest that Hg biomagnification through food webs is highest in cold and low productivity systems; however, much of the among-system variability in TMS values remains unexplained. We identify critical data gaps and provide recommendations for future studies that would improve our understanding of global Hg biomagnification. PMID- 24151939 TI - Enterotoxin gene profiles of Staphylococcus aureus isolated from milk and dairy products in Italy. AB - Staphylococcal foodborne intoxication, occurring after consumption of staphylococcal enterotoxins (SEs) in food, is considered one of the most common forms of bacterial foodborne outbreaks worldwide. Milk and dairy products account for 5% of all the incriminated foods in staphylococcal outbreaks, referring to Europe. The distribution of genes encoding for enterotoxins in Staphylococcus aureus strains is highly variable, with some carried on stable regions of the chromosome and others carried on mobile genetic elements. The aim of this study was to analyse the distribution of genes encoding for SEs in Staph. aureus strains isolated from milk and dairy products. In the period from January 2010 to June 2011, a total of 1245 dairy samples (848 of raw milk and 397 of dairy products) were collected and analysed for detection of genes encoding for 11 SEs and SEls (SEA, SEB, SEC, SED, SEE, SEG, SEH, SEI, SER SElJ and SElP) according to the procedures of the Italian National Reference Laboratory for coagulase positive Staphylococci including Staph. aureus. Staphylococcus aureus strains were isolated in 481 (39%) samples. Of the 481 isolates of Staph. aureus tested, 255 (53%) were positive for one or more SE genes, and thirty-five different enterotoxin gene profiles were distinguished among the isolates. ser gene, found in 134 (28%) of the isolates, was the most frequent, followed by sed (25%) and selj genes (25%). The identification of new SEs increased the isolation frequency of enterotoxigenic staphylococci, thus suggesting that the pathogenic potential of Staph. aureus may be of greater importance than previously thought. Further studies are needed to quantify the expression of these new enterotoxins, and to assess their contribution to foodborne disease burden. SIGNIFICANCE AND IMPACT OF THE STUDY: The analyses targeted 11 staphylococcal enterotoxins genes and 35 different enterotoxin gene profiles were distinguished among the isolates. A total of 255 Staph. aureus isolates were positive for one or more SE genes while ser gene was the most prevalent. In 93% of the isolates bearing genes located on the enterotoxin gene cluster (n = 89), both seg and sei genes were present. PMID- 24151938 TI - Metabolic engineering of biomass for high energy density: oilseed-like triacylglycerol yields from plant leaves. AB - High biomass crops have recently attracted significant attention as an alternative platform for the renewable production of high energy storage lipids such as triacylglycerol (TAG). While TAG typically accumulates in seeds as storage compounds fuelling subsequent germination, levels in vegetative tissues are generally low. Here, we report the accumulation of more than 15% TAG (17.7% total lipids) by dry weight in Nicotiana tabacum (tobacco) leaves by the co expression of three genes involved in different aspects of TAG production without severely impacting plant development. These yields far exceed the levels found in wild-type leaf tissue as well as previously reported engineered TAG yields in vegetative tissues of Arabidopsis thaliana and N. tabacum. When translated to a high biomass crop, the current levels would translate to an oil yield per hectare that exceeds those of most cultivated oilseed crops. Confocal fluorescence microscopy and mass spectrometry imaging confirmed the accumulation of TAG within leaf mesophyll cells. In addition, we explored the applicability of several existing oil-processing methods using fresh leaf tissue. Our results demonstrate the technical feasibility of a vegetative plant oil production platform and provide for a step change in the bioenergy landscape, opening new prospects for sustainable food, high energy forage, biofuel and biomaterial applications. PMID- 24151940 TI - Association between lung capacity measurements and abnormal glucose metabolism: findings from the Crossroads study. AB - AIM: To examine the association between lung function and metabolic syndrome/Type 2 diabetes. METHODS: A total of 1454 adults from rural Victoria, Australia, from randomly selected households included in the Crossroads study, provided spirometric measurements including forced vital capacity, forced expiratory volume in 1 s, predicted percentage value of forced expiratory volume in 1 s and forced vital capacity predicted percentage value. Assessments also included HbA(1c), metabolic syndrome components and a 75-g oral glucose tolerance test. The area under the receiver-operating characteristic curves for waist circumference were compared with those for combinations of waist circumference and raw spirometric measures (forced vital capacity and forced expiratory volume in 1 s) for identifying metabolic syndrome or Type 2 diabetes. RESULTS: Partipants with a greater number of metabolic syndrome components were more likely to have reduced lung function, particularly if Type 2 diabetes was present: the predicted value of forced expiratory volume in 1 s decreased by 5-6% for participants with 2-4 metabolic syndrome components, and by 9% for those with Type 2 diabetes. The risk of metabolic syndrome or Type 2 diabetes was inversely associated with higher spirometry values (forced expiratory volume in 1 s percentage predicted value: odds ratio for 2-4 metabolic syndrome components 0.36 0.21 in women and 0.32-0.30 men; the odds ratio for Type 2 diabetes was 0.36 in women and 0.28 in men). Receiver-operating characteristic curve analysis for identifying metabolic syndrome and Type 2 diabetes revealed significant differences between the area under the receiver-operating characteristic curve with waist circumference alone and that for the combination of waist circumference with lung capacity measures. CONCLUSION: Pulmonary function is lower in people with metabolic syndrome and Type 2 diabetes. Spirometry variables are independent predictors of metabolic syndrome and Type 2 diabetes. PMID- 24151941 TI - Retrospective comparison of two peripheral lumbosacral plexus blocks in dogs undergoing pelvic limb orthopaedic surgery. AB - OBJECTIVES: To compare the lateral pre-iliac approach to the lumbar plexus combined with lumbar paravertebral sciatic nerve block, and the dorsal paravertebral approach to the lumbar plexus combined with sciatic nerve block in dogs. METHODS: Retrospective examination of case records of dogs that received the blocks and underwent pelvic limb orthopaedic surgery between 2010 and 2012. Success rate (intraoperative fentanyl consumption <2.1 ug/kg/hour), type and dose of local anaesthetic used, multiple of minimum alveolar concentration of volatile anaesthetic agent administered, incidence of intraoperative hypotension, postoperative methadone administration, postoperative contralateral limb paralysis and neurological complication at 6 weeks re-examination were analysed. RESULTS: Ninety-six and 95 records were retrieved in which lateral pre-iliac - lumbar paravertebral sciatic nerve and dorsal paravertebral - sciatic nerve were used, respectively. Success rates were 82.3% in lateral pre-iliac - lumbar paravertebral sciatic nerve and 74.7% in dorsal paravertebral - sciatic nerve groups. Bupivacaine, levobupivacaine and ropivacaine were used. Total local anaesthetic doses, intraoperative hypotension and postoperative methadone administered were similar between groups; minimum alveolar concentration multiple was significantly (P<0.001) lower in lateral pre-iliac - lumbar paravertebral sciatic nerve group. No neurological complications were noted. CLINICAL SIGNIFICANCE: Although success rates and perioperative analgesic requirements were not significantly different, the different exposure to anaesthetic agents suggests that the two techniques may not be equivalent. PMID- 24151942 TI - Current treatment approaches to osteoporosis - 2013. AB - The clinical diagnosis of osteoporosis has evolved over the past 20 years to emphasize the relationship between compromised bone strength and fracture susceptibility. The goal of treatment of osteoporosis is fracture prevention. The aging of the American population will place additional burdens on our healthcare system among which will be the need to treat and prevent the estimated increase in fracture rates projected over the next 10 years. There is a significant number of currently available bone strengthening medications used in the treatment of osteoporosis, and this report highlights the effects of these drugs on bone mineral density values and on the relative rates of fragility fractures when these drugs are compared to placebo in clinical trials of subjects with osteoporosis. Identifying those individuals most in need of immediate treatment to prevent fractures remains a challenge despite the use of fracture risk assessment tools, which assess bone mineral density and clinical parameters in order to define an individual's risk of fracture over a finite period of time. Newer tools that may help better define bone strength (resistance to fracture) include high resolution MRI and finite element analysis of the MRI generated images, and this technology and our experience with it is briefly reviewed in this report. There are a number of new classes of drugs in development for the treatment of osteoporosis, and the clinician is likely to have additional antiresorptive and anabolic agents as treatment options for this condition over the next few years. PMID- 24151943 TI - The year in gout: 2012-2013 - a walk through the 2012 ACR Gout Treatment Guidelines. AB - In 2012 the American College of Rheumatology (ACR) established its first-ever gout treatment guidelines. These guidelines address whom to treat, how to treat, and lifestyle and medication changes to make when treating patients with gout. In this manuscript, we review the ACR guidelines, with special attention to the issues of treating to target, and when and how to prevent attacks during urate- lowering therapy. Given that the quality of gout treatment in the USA is often suboptimal poor, these guidelines have the potential to improve the health of millions of gout sufferers in the USA and around the world. PMID- 24151944 TI - Juvenile idiopathic arthritis - what the clinician needs to know. AB - Juvenile idiopathic arthritis (JIA) includes several forms of chronic arthritis in childhood with no apparent cause. JIA is the most common rheumatic disease in children, and may result in pain, joint deformity, and growth im- pairment, with possible persistent active arthritis into adulthood. Prior treatment involved non specific agents, several with significant adverse effects. The recent use of biologics now provides target-specific therapy, which may be better tolerated. Through continued translational research and clinical trials, one better understands the biology mediating disease, with the hope of offering safer, more effective medicine, and potential cure. This review will outline the clinical features of JIA, as well as provide the latest updates in treatment. PMID- 24151945 TI - Immunogenicity - implications for rheumatoid arthritis treatment. AB - Biologic agents used to treat rheumatoid arthritis are in- trinsically immunogenic, as they represent complex proteins which are manufactured outside of the recipient of the drug. This is true for chimeric antibodies, humanized antibod- ies, and for fusion proteins. The emergence of antibodies against biologic agents (AAB) will influence both short and long-term efficacy of these agents and may also play a role in adverse events such as infusion reactions. For patients who fail an initial biologic agent or for those who initially respond but lose efficacy, knowledge of whether an AAB is present will allow the clinician to more effectively choose the best agent to which the patient can be switched. The pres- ence of rising ANA titers or antibodies to double stranded DNA may be a good marker for the emergence of AABs. Concurrent use of non biologic DMARDs at appropriate doses is critical to prevent the evolution of AABs and to ensure long-term efficacy of the biologic agent. PMID- 24151946 TI - Monotherapy in rheumatoid arthritis. AB - Therapeutic strategies for rheumatoid arthritis (RA) have evolved over time. Novel therapies have morphed in parallel to the ever-increasing understanding of RA pathogenesis, diagnosis and outcomes tools. For a century, the principal armamentarium was mainly composed by steroidal and non-steroidal anti inflammatories. Over the last 25 years, however, the concept of disease-modifying anti-rheumatic drugs (DMARDs) has made possible the notion that the natural history of RA could actually be altered. Since then, synthetic DMARDs particularly methotrexate (MTX) -have been used as monotherapy with significant success. This was followed by a revolutionary paradigm shift with the advent of anti-TNFalpha inhibitors and other "biologics" in the 1990s. Contemporary guidelines advocate for the use of a combina- tion therapy (i.e., MTX and a biologic) in aggressive RA cases given their proven additive effect. However, some patients are either intolerant to synthetic DMARDs or develop side effects that preclude their use. New data has recently emerged point- ing towards the potential for biologic monotherapy regimens in certain RA cases. This review will, therefore, describe the available evidence supporting the use of biologic DMARDs and the circumstances in which they are indicated. PMID- 24151947 TI - Treatment of systemic lupus erythematosus - 2013 update. AB - This 2013 update on the treatment of systemic lupus erythrematosus provides rationale for universal use of antimalarials even absent skin or joint manifestations, but chiefly focuses on the management options for refractory cutaneous, articular, and renal disease and current status of biologics; both FDA approved belimumab and off-label infliximab, rituximab, abatacept, and tociluzimab. A discussion of antiphospholipid syndrome secondary to lupus, specifically use of aspirin for asymptomatic patients, suggestions for catastrophic antibody syndrome, and potential roles for rituximab and eculizumab are provided. This review is a companion to an article published in this journal last year and in combination provides recommendations for standard care in routine cases of lupus as well as for the problematic, intractable patient. PMID- 24151948 TI - Treating to target in rheumatoid arthritis - challenges and opportunities. AB - The treat to target approach to managing therapy in rheumatoid arthritis was only just formally proposed in 2010, yet it is clearly here to stay. While the original recommendations were based on a limited set of published data, subsequent studies have explored the role of the treat to target approach in a variety of clinical settings and have confirmed its value. Despite this, additional data is needed, and challenges still remain in the widespread implementation of the treat to target strategy. Some of these challenges are at the patient level, some are at the physician level, and some are at the system level. The identification of these challenges is in itself an opportunity to improve the treat to target paradigm in order to maximize the outcomes of patients with rheumatoid arthritis. PMID- 24151949 TI - Willingness to pay for anterior cruciate ligament reconstruction. AB - The outcomes of ACL reconstructions in terms of patient satisfaction and function are well known. Most orthopaedic surgeons feel that Medicare and other payors do not reimburse enough for this surgery. The purpose of this study is to determine how much patients are willing to pay for this surgery and compare it to reimbursement rates. METHODS: We constructed a survey which described the function and limitations of an ACL deficient knee and the expected function of that knee after an ACL reconstruction. We then asked the volunteers how much they would be willing to pay for an ACL reconstruction if it were their knee. We also gathered data on the yearly earnings and Tegner activity level of the volunteers. In all, 143 volunteers completed the survey. We computed correlation coefficients between willingness to pay and both yearly earnings and Tegner activity level. RESULTS: The average amount that the volunteers were willing to pay for an ACL reconstruction was $4,867.00. There was no correlation between yearly earnings and willingness to pay. The correlation coefficient was 0.34. There was a weak correlation between Tegner activity level and willingness to pay. This correlation coefficient was 0.81. The Medicare allowable rate for ACL reconstruction (CPT 29888) in the geographic area of the study was $1,132.00. CONCLUSION: The data demonstrates that patients are willing to pay much more than traditional payors for ACL reconstruction. These payors undervalue the benefit of this surgery to the patient. There is increasing pressure on orthopaedic surgeons to not participate in insurance plans that reimburse poorly. This places an increasing financial burden on the patient. This study suggests that patients may be willing to pay more for their surgery than their insurance plan and accept more of this burden. PMID- 24151950 TI - Rapid mobilization decreases length-of-stay in joint replacement patients. AB - BACKGROUND: Physiotherapy after total joint replacement enhances postoperative recovery. Implementing a pathway to include earlier postoperative mobilization can reduce the hospital length-of-stay as well as cost. QUESTIONS: Does a rapid rehabilitation program con- sisting of physical therapy on the day of surgery affect the hospital length-of-stay on patients undergoing either total hip or total knee replacements? Is there a difference in the effectiveness of rapid rehabilitation between patients under- going Total Hip and Total Knee Replacements? Can these patients tolerate day of surgery physical therapy sessions? PATIENTS AND METHODS: Nine-hundred hip and knee arthro- plasty patients were divided into two groups for analysis. Group 1 participated in a rapid rehabilitation physical therapy program that began with physical therapists in the recovery room. Group 2 received a standard physical therapy protocol starting the day after surgery. Progression with rehabilitation was followed, and length of hospital stay between the two groups was compared. RESULTS: Total length-of stay was 3.9 days for the rapid rehabilitation group and was 4.4 days (p < 0.001) for the standard therapy group. We found the rapid rehabilitation group had a significantly shorter length-of-stay than patients who began therapy on postoperative day one. In addition to decreased length-of-stay, rapid rehabilitation also resulted in direct savings considering fewer hospital resources were utilized over the decreased time in-house. CONCLUSIONS: Rapid mobilization of total joint replacement patients in the recovery room can be accomplished safely and reduces the overall length of hospital stay for over 70 % of patients. PMID- 24151951 TI - Total knee arthroplasty in patients with a previous patellectomy. AB - Post-patellectomy patients represent a specific subgroup of patients that may develop arthritis and persistent knee pain and potentially require treatment with total knee arthroplasty. This article reviews the treatment and functional outcomes following total knee arthroplasty in patients with prior patellectomy. A case report is presented as an example of the clinical management of a post patellectomy patient with significant knee pain and disability treated with total knee arthroplasty. Emphasis will be placed in decision- making, specifically with the use of a posterior stabilized implant. In addition, postoperative strengthening of the quadriceps is essential to compensate for the lack of the patella and increase the success of total knee arthroplasty in this subgroup of patients. PMID- 24151952 TI - Delayed presentation of incidental durotomy. AB - Two case reports illustrate a delayed clinical presentation of incidental durotomy following surgical posterior decompression of the lumbar spine. The clinical presentation as well as radiographic imaging studies used in diagnosing this relatively rare surgical complication are discussed. Both nonoperative as well as surgical treatment alternatives are outlined. PMID- 24151953 TI - Characterization of warm saline-enhanced radiofrequency ablation lesions in the infarcted porcine ventricular myocardium. AB - BACKGROUND: Radiofrequency (RF) ablation of scar-mediated ventricular tachycardia is limited by the size of lesions achieved with conventional catheters. We examined the gross and histopathology characteristics of warm saline-enhanced radiofrequency (SERF) ablation delivered to left ventricular (LV) infarction scars via a novel catheter employing an extendable infusion needle electrode. METHODS AND RESULTS: Yorkshire pigs (n = 14) underwent LV infarction by left anterior descending artery balloon occlusion. After 4-6 weeks, baseline hemodynamic data were obtained and endocardial electroanatomic mapping was performed in 13 surviving animals. Following single, 40 Watt SERF ablations delivered endocardially to the center of infarctions, 4 were examined the same day (day 0). The rest underwent repeat measurements and were sacrificed at 1 week (n = 6), and at 4 weeks (n = 3). Average lesion depth and diameter were: 1.85 +/- 0.7 cm and 2.33 +/- 0.7 cm at day 0, 0.91 +/- 0.1 cm and 1.9 +/- 0.4 cm after 1 week, and 1.0 +/- 0.2 cm and 1.89 +/- 0.76 cm after 4 weeks, respectively. Histopathology at 1 week showed that ablation lesions covered 41 +/- 10.6% of the infarct area. SERF ablation lesions extended 100%, 90%, and 68% of the total wall thickness at day 0, 1 week, and 4 weeks, respectively. Hemodynamic parameters were unchanged. There were no myocardial wall perforations or aneurysms. CONCLUSION: SERF ablation within myocardial infarct tissue produced large, near transmural lesions, without evidence of myocardial perforation, wall thinning, or aneurysm formation. Ablations did not produce any negative hemodynamic effects in this small group of experiments. PMID- 24151954 TI - Optimization of novel indole-2-carboxamide inhibitors of neurotropic alphavirus replication. AB - Neurotropic alphaviruses, which include western equine encephalitis virus (WEEV) and Fort Morgan virus, are mosquito-borne pathogens that infect the central nervous system causing acute and potentially fatal encephalitis. We previously reported a novel series of indole-2-carboxamides as alphavirus replication inhibitors, one of which conferred protection against neuroadapted Sindbis virus infection in mice. We describe here further development of this series, resulting in 10-fold improvement in potency in a WEEV replicon assay and up to 40-fold increases in half-lives in mouse liver microsomes. Using a rhodamine123 uptake assay in MDR1-MDCKII cells, we were able to identify structural modifications that markedly reduce recognition by P-glycoprotein, the key efflux transporter at the blood-brain barrier. In a preliminary mouse PK study, we were able to demonstrate that two new analogues could achieve higher and/or longer plasma drug exposures than our previous lead and that one compound achieved measurable drug levels in the brain. PMID- 24151955 TI - Programmed death-1 expression in cutaneous B-cell lymphoma. AB - BACKGROUND: Numbers of programmed death-1 (PD-1) positive T cells have prognostic significance in some types of nodal B-cell lymphomas, but data on PD-1 expression in cutaneous B-cell lymphoma (CBCL) are few. In this study we determined the expression and distribution of PD-1 on neoplastic B cells and reactive T cells in skin sections from primary CBCLs. METHODS: By means of immunohistochemical staining, PD-1 expression was investigated in skin biopsies from 10 patients with primary cutaneous marginal zone lymphoma (PCMZL), 18 patients with primary cutaneous follicle center lymphoma (PCFCL) and 12 patients with primary cutaneous diffuse large B-cell lymphoma-leg type (PCDLBCL-LT). RESULTS: Neoplastic B cells were negative for PD-1 in all cases, except for two cases of PCDLBCL-LT. The frequency of PD-1(+) T cells was significantly higher in PCFCL than in PCMZL and PCDLBCL-LT, accounting for 20, 10 and 3% of the total number of infiltrating cells, and 60, 20 and 15% of the total number of CD3(+) T cells, respectively. CONCLUSIONS: PD-1 is rarely expressed by the neoplastic B cells in CBCL. High percentages of PD-1(+) T cells, particularly if found outside germinal centers, support a diagnosis of PCFCL. PMID- 24151956 TI - Do soccer and Zumba exercise improve fitness and indicators of health among female hospital employees? A 12-week RCT. AB - This randomized controlled study investigated the effectiveness of soccer and Zumba on fitness and health indicators in female participants recruited from a workplace. One hundred seven hospital employees were cluster-randomized to either a soccer group (SG), Zumba group (ZG), or control group (CG). Intervention effects for the two training groups were compared with CG. The training was conducted outside working hours as 2-3 1-h sessions per week for 12 weeks. Peak oxygen uptake (VO2peak ), fat percentage, fat mass, bone mineral content, and plasma osteocalcin were measured before and after the intervention period. Based on intention-to-treat-analyses, SG significantly improved the VO2peak relative to body mass (5%; P = 0.02) and decreased heart rate during 100-W cycle exercise (-7 bpm; P = 0.01), total body fat percentage (-1.1%; P = 0.002), and total body fat mass (-1.0 kg; P = 0.001) compared with CG. ZG significantly improved the VO2peak relative to body mass (5%; P = 0.03) and decreased total fat mass (-0.6 kg; P < 0.05) compared with CG. Plasma osteocalcin increased in SG (21%; P < 0.001) and ZG (10%; P = 0.01) compared with CG. The present study indicates that workplace initiated short-term soccer training as well as Zumba outside working hours may result in fitness and modest health benefits among female hospital employees. PMID- 24151957 TI - Bioinspired graphene nanopores with voltage-tunable ion selectivity for Na(+) and K(+). AB - Biological protein channels have many remarkable properties such as gating, high permeability, and selectivity, which have motivated researchers to mimic their functions for practical applications. Herein, using molecular dynamics simulations, we design bioinspired nanopores in graphene sheets that can discriminate between Na(+) and K(+), two ions with very similar properties. The simulation results show that, under transmembrane voltage bias, a nanopore containing four carbonyl groups to mimic the selectivity filter of the KcsA K(+) channel preferentially conducts K(+) over Na(+). A nanopore functionalized by four negatively charged carboxylate groups to mimic the selectivity filter of the NavAb Na(+) channel selectively binds Na(+) but transports K(+) over Na(+). Surprisingly, the ion selectivity of the smaller diameter pore containing three carboxylate groups can be tuned by changing the magnitude of the applied voltage bias. Under lower voltage bias, it transports ions in a single-file manner and exhibits Na(+) selectivity, dictated by the knock-on ion conduction and selective blockage by Na(+). Under higher voltage bias, the nanopore is K(+)-selective, as the blockage by Na(+) is destabilized and the stronger affinity for carboxylate groups slows the passage of Na(+) compared with K(+). The computational design of biomimetic ion-selective nanopores helps to understand the mechanisms of selectivity in biological ion channels and may also lead to a wide range of potential applications such as sensitive ion sensors, nanofiltration membranes for Na(+)/K(+) separation, and voltage-tunable nanofluidic devices. PMID- 24151958 TI - Antigen-specific tolerization approaches in multiple sclerosis. AB - INTRODUCTION: Inhibition of self-reactive T cells through induction of antigen specific immune tolerance holds the promise of effective treatment of autoimmune pathology with few side effects and preservation of normal immune functions. In multiple sclerosis (MS) several approaches have been tested already in clinical trials or are currently ongoing with the aim to inhibit myelin-reactive immune responses. AREAS COVERED: This article provides an overview of the recent and ongoing strategies to inhibit specific immune responses in MS, including different applications of myelin peptide-based approaches, T-cell vaccination, DNA vaccination and antigen-coupled cells. EXPERT OPINION: Despite difficulties in translation of antigen-specific therapies in MS, novel approaches have the potential to effectively induce immune tolerance and ameliorate the disease. To improve efficacy of treatments, future trials should include patients in the early phases of the disease, when the autoimmune response is predominant and immune reactivity still focused. The target antigens are not fully defined yet, and robust immunomonitoring assays should developed to provide mechanistic proof of concept in parallel to showing efficacy with respect to inhibiting inflammatory disease activity in the central nervous system (CNS). PMID- 24151959 TI - Incretins, amylin and other gut-brain axis hormones in children with coeliac disease. AB - BACKGROUND: Previous research indicated that coeliac disease (CD) is associated with type 1 diabetes mellitus (T1DM). However, the gut-brain axis peptide hormones secretion has not been evaluated so far in patients with CD prior to treatment initiation or under treatment, irrespective of patients having concomitant T1DM or not. The aim of the study was therefore to evaluate these gut hormones at the preprandial levels of patients with CD before and under treatment. METHODS: Of forty-seven CD children, 12 untreated (UCD), 22 treated with gluten-free diet (TCD) and 13 treated CD with coexisting T1DM (DCD), and 18 healthy controls (HC) were enrolled. Preprandial glucagon-like-peptide-1 (GLP-1), glucose-dependent-insulinotropic-polypeptide (GIP), active amylin, acylated ghrelin (AG), leptin, pancreatic polypeptide (PP) and peptide-tyrosine-tyrosine (PYY) were determined with hormone-map-array technology. RESULTS: We found in patients with CD compared with HC that the concentration of (i) GLP-1 was reduced remarkably in all patients with CD (P = 0.008), (ii) GIP was lower in patients with UCD (P = 0.008), (iii) amylin was remarkably reduced (P < 0.01) in all patients with CD, (iv) AG was significantly decreased in patients with DCD (P < 0.01), while (v) leptin, PP and PYY were not significantly different. GIP, GLP-1 and amylin levels correlated positively with insulin concentrations (P < 0.001, P = 0.004 and P < 0.01, respectively) in all patients. Amylin and GIP levels were strongly associated with triglycerides concentrations (P < 0.001, for both peptides) in children with CD. CONCLUSIONS: Our study revealed a different secretion pattern of gut-brain axis hormones in children with CD compared with HC. The alterations in the axis were more pronounced in children with both CD and T1DM. PMID- 24151960 TI - Antimicrobial use for symptom management in patients receiving hospice and palliative care: a systematic review. AB - BACKGROUND: Patients receiving hospice or palliative care often receive antimicrobial therapy; however the effectiveness of antimicrobial therapy for symptom management in these patients is unknown. OBJECTIVE: The study's objective was to systematically review and summarize existing data on the prevalence and effectiveness of antimicrobial therapy to improve symptom burden among hospice or palliative care patients. DESIGN: Systematic review of articles on microbial use in hospice and palliative care patients published from January 1, 2001 through June 30, 2011. MEASUREMENTS: We extracted data on patients' underlying chronic condition and health care setting, study design, prevalence of antimicrobial use, whether symptom response following antimicrobial use was measured, and the method for measuring symptom response. RESULTS: Eleven studies met our inclusion criteria in which prevalence of antimicrobial use ranged from 4% to 84%. Eight studies measured symptom response following antimicrobial therapy. Methods of symptom assessment were highly variable and ranged from clinical assessment from patients' charts to the Edmonton Symptom Assessment Scale. Symptom improvement varied by indication, and patients with urinary tract infections (two studies) appeared to experience the greatest improvement following antimicrobial therapy (range 67% to 92%). CONCLUSION: Limited data are available on the use of antimicrobial therapy for symptom management among patients receiving palliative or hospice care. Future studies should systematically measure symptom response and control for important confounders to provide useful data to guide antimicrobial use in this population. PMID- 24151961 TI - Development and validation of the Brief Assessment Scale for Caregivers in Chinese. AB - BACKGROUND: Chinese family caregivers in the United States experience high rates of burden. Studies in this population require culturally appropriate and valid instruments. OBJECTIVE: To adapt a Chinese version of the Brief Assessment Scale for Caregivers (BASC), a tool measuring positive and negative effects of caregiving. METHODS: New items for the Chinese adaptation were generated from the literature, an interdisciplinary professional group, and caregiver focus groups. The new items were translated into Chinese, added to the original 14-item BASC, then administered to caregivers in two surveys (n=205); participants also completed Chinese versions of the Caregiver Burden Inventory-Chinese (CBI-C), the Hospital Anxiety and Depression Scale (HADS), and the Katz Index for Activities of Daily Living. Item reduction and exploration of internal consistency, reliability and validity using correlational, exploratory, and confirmatory factor analysis were performed. RESULTS: Factor analysis and item-total correlations supported reduction in the number of new items. The final BASC Chinese (BASC-C) included 10 new items plus the 14 items from the original tool with an overall alpha coefficient of 0.79 for the 24-item scale. Three Chinese specific factors-cultural strain, decision-making strain, and emotional strain showed alpha coefficients of 0.69 to 0.79. Significant first order correlations were found between the BASC-C and previously validated measures (total BASC-C with HADS Anxiety [r=0.64, p<0.001], HADS Depression [r=0.60, p<0.001], and CBI-C [r=0.60, p<0.001]). Partial correlations indicated that the new Chinese items provided information supplemental to the original BASC. CONCLUSION: This study suggests that the BASC-C is a valid measure of caregiver burden among Chinese family caregivers. PMID- 24151962 TI - Rapid surface-biostructure interaction analysis using strong metal-based nanomagnets. AB - Nanomaterials are increasingly suggested for the selective adsorption and extraction of complex compounds in biomedicine. Binding of the latter requires specific surface modifications of the nanostructures. However, even complicated macromolecules such as proteins can afford affinities toward basic surface characteristics such as hydrophobicity, topology, and electrostatic charge. In this study, we address these more basic physical interactions. In a model system, the interaction of bovine serum albumin and amyloid beta 42 fibrillar aggregates with carbon-coated cobalt nanoparticles, functionalized with various polymers differing in character, was studied. The possibility of rapid magnetic separation upon binding to the surface represents a valuable tool for studying surface interactions and selectivities. We find that the surface interaction of Abeta 42 fibrillar aggregates is mostly hydrophobic in nature. Because bovine serum albumin (BSA) is conformationally adaptive, it is known to bind surfaces with widely differing properties (charge, topology, and hydrophobicity). However, the rate of tight binding (no desorption upon washing) can vary largely depending on the extent of necessary conformational changes for a specific surface. We found that BSA can only bind slowly to polyethylenimine-coated nanomagnets. Under competitive conditions (high excess BSA compared to that for beta 42 fibrillar aggregates), this effect is beneficial for targeting the fibrillar species. These findings highlight the possibility of selective extractions from complex media when advantageous basic physical surface properties are chosen. PMID- 24151963 TI - Gender differences in emotion recognition: Impact of sensory modality and emotional category. AB - Results from studies on gender differences in emotion recognition vary, depending on the types of emotion and the sensory modalities used for stimulus presentation. This makes comparability between different studies problematic. This study investigated emotion recognition of healthy participants (N = 84; 40 males; ages 20 to 70 years), using dynamic stimuli, displayed by two genders in three different sensory modalities (auditory, visual, audio-visual) and five emotional categories. The participants were asked to categorise the stimuli on the basis of their nonverbal emotional content (happy, alluring, neutral, angry, and disgusted). Hit rates and category selection biases were analysed. Women were found to be more accurate in recognition of emotional prosody. This effect was partially mediated by hearing loss for the frequency of 8,000 Hz. Moreover, there was a gender-specific selection bias for alluring stimuli: Men, as compared to women, chose "alluring" more often when a stimulus was presented by a woman as compared to a man. PMID- 24151966 TI - Can melanoma therapy change attitudes toward prevention and tanning? AB - Malignant melanoma is the most lethal skin cancer whose incidence is increasing worldwide. Important is knowledge of risk factors, early diagnosis, long-term follow-up on confirmed melanoma cases and prevention. In this study, we tested melanoma patients' attitudes toward solar radiation and perception of the value of follow-up. The present cross-sectional epidemiological study was carried out in a group of patients diagnosed with stage I and II of malignant melanoma (n = 124). They were monitored for at least 1 year. The research was carried out by anonymous questionnaire. The results revealed that the respondents welcomed the opportunity of follow-up care. Its benefits were said to outweigh the inconvenience of repeated checkups. However, the esthetic importance of a suntan was still considered quite high. Substantial reserve was found in the use of sunscreen. The need for wide public education and the protection against excessive contact with solar radiation is evident. Regular monitoring seems to be just as important. PMID- 24151965 TI - Cholesteryl ester species differently elevate plasma cholesterol in hamsters. AB - This study was to examine the effect of free cholesterol (C) and individual cholesteryl ester (CE) species, namely cholesteryl palmitate (CP), cholesteryl stearate (CS), cholesteryl oleate (CO), and cholesteryl linoleate (CL) on plasma total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), non-HDL-C, and triacylglycerols (TG) in hamsters. Results showed that addition of dietary CE species into diet at 0.1% differently raised plasma TC concentrations, with CO elevating plasma TC to 331 mg/dL, while CS raised plasma TC only to 220 mg/dL. It was found that CS was a poor substrate of pancreatic cholesterol esterase, while CO was a good substrate. The fecal analysis showed CS-fed hamsters had the highest fecal cholesterol concentration, while RT-PCR analysis found CS feeding was associated with down-regulations of intestinal Niemann-Pick C1 like 1 (NPC1L1) and acyl-CoA: cholesterol acyltransferase 2 (ACAT2) as well as microsomal triacylglycerol transport protein (MTP). It was therefore concluded that the plasma cholesterol-raising activity of CE species was partially governed by their hydrolysis rates in the intestine, and the relative low raising activity associated with CS was mediated by down-regulation of intestinal NPC1L1, ACAT2, and MTP. PMID- 24151964 TI - Substrate distortion contributes to the catalysis of orotidine 5'-monophosphate decarboxylase. AB - Orotidine 5'-monophosphate decarboxylase (ODCase) accelerates the decarboxylation of orotidine 5'-monophosphate (OMP) to uridine 5'-monophosphate (UMP) by 17 orders of magnitude. Eight new crystal structures with ligand analogues combined with computational analyses of the enzyme's short-lived intermediates and the intrinsic electronic energies to distort the substrate and other ligands improve our understanding of the still controversially discussed reaction mechanism. In their respective complexes, 6-methyl-UMP displays significant distortion of its methyl substituent bond, 6-amino-UMP shows the competition between the K72 and C6 substituents for a position close to D70, and the methyl and ethyl esters of OMP both induce rotation of the carboxylate group substituent out of the plane of the pyrimidine ring. Molecular dynamics and quantum mechanics/molecular mechanics computations of the enzyme-substrate complex also show the bond between the carboxylate group and the pyrimidine ring to be distorted, with the distortion contributing a 10-15% decrease of the DeltaDeltaG(?) value. These results are consistent with ODCase using both substrate distortion and transition-state stabilization, primarily exerted by K72, in its catalysis of the OMP decarboxylation reaction. PMID- 24151967 TI - Amending soils with phosphate as means to mitigate soil lead hazard: a critical review of the state of the science. AB - Ingested soil and surface dust may be important contributors to elevated blood lead (Pb) levels in children exposed to Pb contaminated environments. Mitigation strategies have typically focused on excavation and removal of the contaminated soil. However, this is not always feasible for addressing widely disseminated contamination in populated areas often encountered in urban environments. The rationale for amending soils with phosphate is that phosphate will promote formation of highly insoluble Pb species (e.g., pyromorphite minerals) in soil, which will remain insoluble after ingestion and, therefore, inaccessible to absorption mechanisms in the gastrointestinal tract (GIT). Amending soil with phosphate might potentially be used in combination with other methods that reduce contact with or migration of contaminated soils, such as covering the soil with a green cap such as sod, clean soil with mulch, raised garden beds, or gravel. These remediation strategies may be less expensive and far less disruptive than excavation and removal of soil. This review evaluates evidence for efficacy of phosphate amendments for decreasing soil Pb bioavailability. Evidence is reviewed for (1) physical and chemical interactions of Pb and phosphate that would be expected to influence bioavailability, (2) effects of phosphate amendments on soil Pb bioaccessibility (i.e., predicted solubility of Pb in the GIT), and (3) results of bioavailability bioassays of amended soils conducted in humans and animal models. Practical implementation issues, such as criteria and methods for evaluating efficacy, and potential effects of phosphate on mobility and bioavailability of co-contaminants in soil are also discussed. PMID- 24151968 TI - The role of in vitro gene expression profiling in particulate matter health research. AB - Exposure to particulate matter (PM) is consistently associated with increased morbidity and mortality rate. The mechanisms for these adverse health effects have been vigorously investigated for many years, but remain uncertain, in part due to the complex interactions between host and exposure. Over the past decade, the use of global gene expression profiling has increased to investigate molecular changes in an attempt to gain more insight into the complex mechanisms that underlie the adverse health effects induced by PM. These experiments have been performed mostly in cell cultures, in part due to the easy availability and maneuverability of different cell types. Whether or not the results obtained from these in vitro experiments are relevant to human exposure is unclear. In this study, cell culture studies were reviewed that used microarray technology to measure global gene expression in response to PM and the findings discussed in the context of global gene expression results obtained from animal and human exposure studies. Ten in vitro studies were identified from PubMed that reported global gene expression results in response to PM exposure. Despite difference in cell types, microarray platforms, incubation time, and PM sources and doses, these experiments showed commonality in the expression of genes and pathways, especially xenobiotic metabolism, oxidative stress, and inflammation. These gene expression profiles were consistent with results from animal and human controlled exposure experiments. The in vitro experiments also uncovered novel biological mechanisms that may be important in PM-induced health effects reported in epidemiological studies. Data indicate that in vitro microarray experiments complement animal and human exposure studies and allow the PM-associated health research to focus on the "toxic" components in PM and novel mechanisms, and may enhance risk assessment beyond the current mass-based standards. PMID- 24151971 TI - 'Prevalence and antimicrobial susceptibility of Listeria monocytogenes and methicillin-resistant Staphylococcus aureus strains from raw meat and meat products in Zaria, Nigeria. AB - The bacterial genera Listeria and Staphylococcus have been frequently isolated from food products and are responsible for a number of animal and human diseases. The aim of the study was to simultaneously isolate and characterize L. monocytogenes and Staphylococcus species from 300 samples of raw meat and meat products, to determine the susceptibility of the organisms to commonly used antimicrobial agents and to determine the presence of haemolysin A (hyl) virulence gene in L. monocytogenes and staphylococcal cassette chromosome mecA (SCCmec) gene in the Staph. aureus isolates using PCR. Of the 85 Listeria isolates tested, 12 L. monocytogenes were identified and tested for their sensitivity to 14 antimicrobial agents. All the 12 isolates (100%) were resistant to nine antimicrobial agents, but however sensitive to gentamicin. Only one isolate was found to harbour the hylA gene. Twenty-nine isolates were confirmed as Staph. aureus by the Microbact 12S identification system and were all presumptively identified as methicillin-resistant Staph. aureus species using oxacillin-resistant Staph. aureus basal medium (ORSAB). The 29 Staph. aureus isolates were tested for their sensitivity to 16 antimicrobial agents, and 11 were resistant to methicillin. None of the 11 Staph. aureus isolates harboured the methicillin resistance, mecA gene. SIGNIFICANCE AND IMPACT OF THE STUDY: Listeria monocytogenes and Staphylococcus aureus are important agents of foodborne diseases. Occurrence of these infectious agents was established in meat and meat products in Zaria, Nigeria. Majority of isolates obtained from this study, displayed multidrug resistance to commonly used antimicrobial agents, including methicillin resistance among the Staph. aureus isolates. The potential virulence of L. monocytogenes found in ready-to-eat food was documented by the carriage of hly A gene by one of the isolates. A different mechanism of methicillin resistance or different homologue of mec A gene may be circulating among Nigerian isolates. PMID- 24151973 TI - A diastereoselective oxa-Pictet-Spengler-based strategy for (+)-frenolicin B and epi-(+)-frenolicin B synthesis. AB - An efficient diastereoselective oxa-Pictet-Spengler reaction strategy was developed to construct benzoisochroman diastereomers. The utility of the reaction was demonstrated in the context of both the total synthesis of naturally occurring pyranonaphthoquinones (+)-frenolicin B and epi-(+)-frenolicin B as well as a range of frenolicin precursor analogs. The method is versatile and offers exquisite stereocontrol and, as such, offers a synthetic advance for the synthesis of pyranonaphthoquinone analogs. PMID- 24151974 TI - Recent developments in palifermin basic, pre-clinical and clinical research. PMID- 24151972 TI - Uncovering the determinants of a highly perturbed tyrosine pKa in the active site of ketosteroid isomerase. AB - Within the idiosyncratic enzyme active-site environment, side chain and ligand pKa values can be profoundly perturbed relative to their values in aqueous solution. Whereas structural inspection of systems has often attributed perturbed pKa values to dominant contributions from placement near charged groups or within hydrophobic pockets, Tyr57 of a Pseudomonas putida ketosteroid isomerase (KSI) mutant, suggested to have a pKa perturbed by nearly 4 units to 6.3, is situated within a solvent-exposed active site devoid of cationic side chains, metal ions, or cofactors. Extensive comparisons among 45 variants with mutations in and around the KSI active site, along with protein semisynthesis, (13)C NMR spectroscopy, absorbance spectroscopy, and X-ray crystallography, was used to unravel the basis for this perturbed Tyr pKa. The results suggest that the origin of large energetic perturbations are more complex than suggested by visual inspection. For example, the introduction of positively charged residues near Tyr57 raises its pKa rather than lowers it; this effect, and part of the increase in the Tyr pKa from the introduction of nearby anionic groups, arises from accompanying active-site structural rearrangements. Other mutations with large effects also cause structural perturbations or appear to displace a structured water molecule that is part of a stabilizing hydrogen-bond network. Our results lead to a model in which three hydrogen bonds are donated to the stabilized ionized Tyr, with these hydrogen-bond donors, two Tyr side chains, and a water molecule positioned by other side chains and by a water-mediated hydrogen-bond network. These results support the notion that large energetic effects are often the consequence of multiple stabilizing interactions rather than a single dominant interaction. Most generally, this work provides a case study for how extensive and comprehensive comparisons via site-directed mutagenesis in a tight feedback loop with structural analysis can greatly facilitate our understanding of enzyme active-site energetics. The extensive data set provided may also be a valuable resource for those wishing to extensively test computational approaches for determining enzymatic pKa values and energetic effects. PMID- 24151970 TI - Genomic resources notes accepted 1 August 2013-30 September 2013. AB - This article documents the public availability of raw transcriptome sequence data and 63,020 SNPs for the polar bear (Ursus maritimus). PMID- 24151976 TI - Immune cells: plastic players along colorectal cancer progression. AB - Inflammatory cells are involved in tumour initiation and progression. In parallel, the adaptive immune response plays a key role in fighting tumour growth and dissemination. The double-edged role of the immune system in solid tumours is well represented in colorectal cancer (CRC). The development and progression of CRC are affected by the interactions between the tumour and the host's response, occurring in a milieu named tumour microenvironment. The role of immune cells in human CRC is being unravelled and there is a strong interest in understanding their dynamics as to tumour promotion, immunosurveillance and immunoevasion. A better definition of immune infiltration would be important not only with respect to the 'natural history' of CRC, but in a clinically relevant perspective in the 21st century, with respect to its post-surgical management, including chemotherapy responsiveness. While it is becoming established that the amount of tumour-infiltrating lymphocytes influences the post-surgical progression of early stage CRC, the relevance of this immune parameter as to chemotherapy responsiveness remains to be clarified. Despite recent experimental work supporting the notion that infiltrating immune cells may influence chemotherapy mediated tumour cell death, tumour-infiltrating cells are not employed to identify patients who are more likely to benefit from adjuvant treatment. This review focuses on studies addressing the role of innate and adaptive immune cells along the occurrence and the progression of potentially curable CRC. PMID- 24151978 TI - Mitigating iodomethane emissions and iodide residues in fumigated soils. AB - Although long-regarded as an excellent soil fumigant for killing plant pests, methyl bromide (MeBr) was phased out in 2005 in the USA, because it can deplete the stratospheric ozone layer. Iodomethane (MeI) has been identified as an effective alternative to MeBr and is used in a number of countries for preplant pest control. However, MeI is highly volatile and potentially carcinogenic to humans if inhaled. In addition, iodide anions, a breakdown product of MeI, can build up in fumigated soils and potentially cause plant toxicity and contaminate groundwater via leaching. In order to overcome the above two obstacles in MeI application, a method is proposed to place reactive bags containing ammonium hydroxide solution (NH4OH) on the soil surface underneath an impermeable plastic film covering the fumigated area. Our research showed that using this approach, over 99% of the applied MeI was quantitatively transferred to iodide. Of all the resulting iodide, only 2.7% remained in the fumigated soil, and 97.3% was contained in the reactive bag that can be easily removed after fumigation. PMID- 24151977 TI - Telocytes express PDGFRalpha in the human gastrointestinal tract. AB - Telocytes (TC), a cell population located in the connective tissue of many organs of humans and laboratory mammals, are characterized by a small cell body and extremely long and thin processes. Different TC subpopulations share unique ultrastructural features, but express different markers. In the gastrointestinal (GI) tract, cells with features of TC were seen to be CD34-positive/c-kit negative and several roles have been proposed for them. Other interstitial cell types with regulatory roles described in the gut are the c-kit-positive/CD34 negative/platelet-derived growth factor receptor alpha (PDGFRalpha)-negative interstitial cells of Cajal (ICC) and the PDGFRalpha-positive/c-kit-negative fibroblast-like cells (FLC). As TC display the same features and locations of the PDGFRalpha-positive cells, we investigated whether TC and PDGFRalpha-positive cells could be the same cell type. PDGFRalpha/CD34, PDGFRalpha/c-kit and CD34/c kit double immunolabelling was performed in full-thickness specimens from human oesophagus, stomach and small and large intestines. All TC in the mucosa, submucosa and muscle coat were PDGFRalpha/CD34-positive. TC formed a three dimensional network in the submucosa and in the interstitium between muscle layers, and an almost continuous layer at the submucosal borders of muscularis mucosae and circular muscle layer. Moreover, TC encircled muscle bundles, nerve structures, blood vessels, funds of gastric glands and intestinal crypts. Some TC were located within the muscle bundles, displaying the same location of ICC and running intermingled with them. ICC were c-kit-positive and CD34/PDGFRalpha negative. In conclusion, in the human GI tract the TC are PDGFRalpha-positive and, therefore, might correspond to the FLC. We also hypothesize that in human gut, there are different TC subpopulations probably playing region-specific roles. PMID- 24151979 TI - Release of halide ions from the buried active site of the haloalkane dehalogenase LinB revealed by stopped-flow fluorescence analysis and free energy calculations. AB - Release of halide ions is an essential step of the catalytic cycle of haloalkane dehalogenases. Here we describe experimentally and computationally the process of release of a halide anion from the buried active site of the haloalkane dehalogenase LinB. Using stopped-flow fluorescence analysis and umbrella sampling free energy calculations, we show that the anion binding is ion-specific and follows the ordering I(-) > Br(-) > Cl(-). We also address the issue of the protonation state of the catalytic His272 residue and its effect on the process of halide release. While deprotonation of His272 increases binding of anions in the access tunnel, we show that the anionic ordering does not change with the switch of the protonation state. We also demonstrate that a sodium cation could relatively easily enter the active site, provided the His272 residue is singly protonated, and replace thus the missing proton. In contrast, Na(+) is strongly repelled from the active site containing the doubly protonated His272 residue. Our study contributes toward understanding of the reaction mechanism of haloalkane dehalogenase enzyme family. Determination of the protonation state of the catalytic histidine throughout the catalytic cycle remains a challenge for future studies. PMID- 24151980 TI - Ubiquinol supplementation protects against renal ischemia and reperfusion injury in rats. AB - Generation of toxic oxygen metabolites followed by oxidant- and inflammatory mediated tissue injury plays a crucial role in the pathogenesis of ischemia and reperfusion (IR). Ubiquinol, the reduced form of coenzyme Q10, is recognized for its potent antioxidant and anti-inflammatory properties in biological membranes. The present study was established to examine the possible protective effect of ubiquinol against renal IR injury. Groups of male Wistar rats were assigned into sham, ubiquinol, IR (45-min bilateral renal ischemia followed by 24-h reperfusion), and ubiquinol+ IR (ubiquinol 300 mg/kg given orally for 7 consecutive days before IR induction). Renal morphology, function, oxidative stress, and inflammatory markers were evaluated at the end of reperfusion. IR caused renal dysfunction as shown by significant increases in blood urea nitrogen, plasma creatinine, and a decrease in creatinine clearance. Light and electron microscopic examinations exhibited severe tubular damages and abnormal mitochondrial structure. IR-induced renal injuries were associated with significant increases in malondialdehyde, nitric oxide, tumor necrosis factor alpha, but decreases in antioxidant thiols and superoxide dismutase. Pretreatment with ubiquinol obviously attenuated all the changes caused by IR, whereas it had no considerable effect in the sham-operated rats. These findings indicate that supplementation of ubiquinol prior to IR incidence confers functional and morphological protection to the ischemic kidney by maintaining the redox balance and regulating the generation of inflammatory mediator. The outcomes suggest that ubiquinol may be a potential candidate to counteract organ dysfunction in conditions involving IR injury. PMID- 24151975 TI - Palifermin for the protection and regeneration of epithelial tissues following injury: new findings in basic research and pre-clinical models. AB - Keratinocyte growth factor (KGF) is a paracrine-acting epithelial mitogen produced by cells of mesenchymal origin, that plays an important role in protecting and repairing epithelial tissues. Pre-clinical data initially demonstrated that a recombinant truncated KGF (palifermin) could reduce gastrointestinal injury and mortality resulting from a variety of toxic exposures. Furthermore, the use of palifermin in patients with hematological malignancies reduced the incidence and duration of severe oral mucositis experienced after intensive chemoradiotherapy. Based upon these findings, as well as the observation that KGF receptors are expressed in many, if not all, epithelial tissues, pre-clinical studies have been conducted to determine the efficacy of palifermin in protecting different epithelial tissues from toxic injury in an attempt to model various clinical situations in which it might prove to be of benefit in limiting tissue damage. In this article, we review these studies to provide the pre-clinical background for clinical trials that are described in the accompanying article and the rationale for additional clinical applications of palifermin. PMID- 24151981 TI - Multivalent interactions of the SUMO-interaction motifs in RING finger protein 4 determine the specificity for chains of the SUMO. AB - RNF4 (RING finger protein 4) is a STUbL [SUMO (small ubiquitin-related modifier) targeted ubiquitin ligase] controlling PML (promyelocytic leukaemia) nuclear bodies, DNA double strand break repair and other nuclear functions. In the present paper, we describe that the sequence and spacing of the SIMs (SUMO interaction motifs) in RNF4 regulate the avidity-driven recognition of substrate proteins carrying SUMO chains of variable length. PMID- 24151982 TI - Controlled-frequency breath swimming improves swimming performance and running economy. AB - Respiratory muscle fatigue can negatively impact athletic performance, but swimming has beneficial effects on the respiratory system and may reduce susceptibility to fatigue. Limiting breath frequency during swimming further stresses the respiratory system through hypercapnia and mechanical loading and may lead to appreciable improvements in respiratory muscle strength. This study assessed the effects of controlled-frequency breath (CFB) swimming on pulmonary function. Eighteen subjects (10 men), average (standard deviation) age 25 (6) years, body mass index 24.4 (3.7) kg/m(2), underwent baseline testing to assess pulmonary function, running economy, aerobic capacity, and swimming performance. Subjects were then randomized to either CFB or stroke-matched (SM) condition. Subjects completed 12 training sessions, in which CFB subjects took two breaths per length and SM subjects took seven. Post-training, maximum expiratory pressure improved by 11% (15) for all 18 subjects (P < 0.05) while maximum inspiratory pressure was unchanged. Running economy improved by 6 (9)% in CFB following training (P < 0.05). Forced vital capacity increased by 4% (4) in SM (P < 0.05) and was unchanged in CFB. These findings suggest that limiting breath frequency during swimming may improve muscular oxygen utilization during terrestrial exercise in novice swimmers. PMID- 24151983 TI - Rapid prototyping of Fresnel zone plates via direct Ga(+) ion beam lithography for high-resolution X-ray imaging. AB - A significant challenge to the wide utilization of X-ray microscopy lies in the difficulty in fabricating adequate high-resolution optics. To date, electron beam lithography has been the dominant technique for the fabrication of diffractive focusing optics called Fresnel zone plates (FZP), even though this preparation method is usually very complicated and is composed of many fabrication steps. In this work, we demonstrate an alternative method that allows the direct, simple, and fast fabrication of FZPs using focused Ga(+) beam lithography practically, in a single step. This method enabled us to prepare a high-resolution FZP in less than 13 min. The performance of the FZP was evaluated in a scanning transmission soft X-ray microscope where nanostructures as small as sub-29 nm in width were clearly resolved, with an ultimate cutoff resolution of 24.25 nm, demonstrating the highest first-order resolution for any FZP fabricated by the ion beam lithography technique. This rapid and simple fabrication scheme illustrates the capabilities and the potential of direct ion beam lithography (IBL) and is expected to increase the accessibility of high-resolution optics to a wider community of researchers working on soft X-ray and extreme ultraviolet microscopy using synchrotron radiation and advanced laboratory sources. PMID- 24151984 TI - Esophago-pericardial fistula complicating atrial fibrillation ablation using a novel irrigated radiofrequency multipolar ablation catheter. PMID- 24151985 TI - The effect of diabetic neuropathy on foot bones: a systematic review and meta analysis. AB - AIMS: It is proposed that diabetic neuropathy may affect peripheral bone. Direct innervation of bone as well as neural control over its vascular supply and muscular influences may be affected by diabetes-induced peripheral neuropathies. Associated changes to bone may contribute to the occurrence of foot bone pathology in this population. This systematic review aims to examine the literature related to the effect of diabetic neuropathy on foot bones. METHODS: Studies examining relationships between neuropathy and indicators of bone health (e.g. bone mineral density) in populations with diabetes were sought. Relevant publications were obtained from searches in MEDLINE, CINAHL and Embase in the period up to March 2013. Meta-analysis was performed using a random effects model in the statistical package Stata version 12.1. RESULTS: Ten studies met the inclusion criteria and were included in the narrative synthesis. All studies were cross-sectional or case-control in design. Four of the 10 included studies found results indicating poorer bone health in those with diabetes and neuropathy compared with those with diabetes without neuropathy. Seven of the 10 studies were able to be included in a meta-analysis. The mean pooled effect was -0.36 (95% CI -0.76 to 0.04; P = 0.08), indicating a non-significant trend towards poorer bone health in those with diabetic neuropathy. CONCLUSIONS: We did not find a significant relationship between presence of neuropathy in those with diabetes and poorer peripheral bone health. However, methodological limitations of the included studies mean further research is required to investigate this theoretical relationship. PMID- 24151987 TI - Molecular similarity in medicinal chemistry. AB - Similarity is a subjective and multifaceted concept, regardless of whether compounds or any other objects are considered. Despite its intrinsically subjective nature, attempts to quantify the similarity of compounds have a long history in chemical informatics and drug discovery. Many computational methods employ similarity measures to identify new compounds for pharmaceutical research. However, chemoinformaticians and medicinal chemists typically perceive similarity in different ways. Similarity methods and numerical readouts of similarity calculations are probably among the most misunderstood computational approaches in medicinal chemistry. Herein, we evaluate different similarity concepts, highlight key aspects of molecular similarity analysis, and address some potential misunderstandings. In addition, a number of practical aspects concerning similarity calculations are discussed. PMID- 24151988 TI - Emulsifying and interfacial properties of vicilins: role of conformational flexibility at quaternary and/or tertiary levels. AB - Although the functionality of plant proteins (and soy proteins in particular) has been widely investigated in the last decades, the importance of conformational characteristics to their functionalities is still far away from being understood. The aim of the present work was to unravel the role of conformational flexibility at the quaternary and/or tertiary levels in the emulsifying and interfacial properties of phaseolin, an ideal vicilin (or 7S globulin) from red kidney bean. The conformational flexibility at quaternary and tertiary levels of phaseolin was modulated by urea with increasing concentrations from 0 to 8 M, as characterized by using dynamic light scattering (DLS), intrinsic fluorescence and derivative UV spectroscopy, and differential scanning calorimetry (DSC). The emulsifying and interfacial properties, including emulsifying ability, flocculated state of oil droplets (in fresh emulsions), emulsion stability against creaming, and adsorption dynamics at the oil-water interface, were characterized at a specific protein concentration of 0.5% (w/v). The results indicated that increasing the urea concentration resulted in a progressive dissociation of trimeric phaseolin molecules into monomeric subunits, and even a structural unfolding of dissociated subunits; the urea-induced conformational changes at quaternary and/or tertiary levels were reversible, and the molecules at high urea concentrations shared similar structural features to the "molten globule state". On the other hand, increasing the urea concentration progressively improved the emulsifying ability of the protein, and flocculated extent of oil droplets in the fresh emulsions, but led to a progressive decrease in interfacial protein concentration. The improvement of the emulsifying ability was not related to diffusion (during initial adsorption) and penetration at the interface, but highly dependent on ease of structural rearrangement of the adsorbed proteins. These observations clearly confirmed that the flexibility of phaseolin at quaternary and/or tertiary levels plays a vital role in its emulsifying ability, mainly through the way of affecting the ease of structural rearrangement of adsorbed proteins at the interface. The findings could provide an in-depth understanding of the importance of conformational flexibility for the emulsifying properties of oligomeric storage globulins, and thus are of great help to guide the modifications of the proteins for better emulsifying properties. PMID- 24151989 TI - Selectivity of antagonists for the Cys-loop native receptors for ACh, 5-HT and GABA in guinea-pig myenteric neurons. AB - The three most common Cys-loop receptors expressed by myenteric neurons are nACh, 5-HT3 and GABAA . To investigate the function of these proteins researchers have used channel inhibitors such as hexamethonium (antagonist of nACh receptors), ondansetron (antagonist of 5-HT3 receptors), picrotoxin and bicuculline (both antagonists of GABAA receptors). The aim of this study was to investigate the specificity of these inhibitors on Cys-loop receptors of primary cultured neurons obtained from the guinea-pig small intestine. The whole-cell configuration of the patch clamp techniques was used to record membrane currents induced by ACh (IACh ), 5-HT (I5-HT ) and GABA (IGABA ) in the absence and the presence of various concentrations of hexamethonium, ondansetron, picrotoxin or bicuculline. The three Cys-loop receptors present in enteric neurons are expressed independently and they do not cross-desensitized. Hexamethonium inhibited IACh without affecting I5-HT and IGABA . Ondansetron inhibited I5-HT and also IACh but did not affect IGABA . Picrotoxin and bicuculline inhibited I5-HT , IACh and IGABA with different potency, being the lowest potency on 5-HT3 receptors. All these inhibitory effects were concentration dependent and reversible. Our observations showed that except for hexamethonium, all other inhibitors used here show different degrees of selectivity, which has to be considered when these antagonists are used in experimental studies aimed to investigate the functions of these receptors. In particular, in tissues expressing nACh receptors because these are the targets of all other inhibitors used here. The low potency of picrotoxin and bicuculline to inhibit 5-HT3 receptors suggests that these receptors are heteromeric proteins. PMID- 24151991 TI - Pd-catalyzed enantioselective C-H iodination: asymmetric synthesis of chiral diarylmethylamines. AB - An enantioselective C-H iodination reaction using a mono-N-benzoyl-protected amino acid has been developed for the synthesis of chiral diarylmethylamines. The reaction uses iodine as the sole oxidant and proceeds at ambient temperature and under air. PMID- 24151990 TI - The effects of expectation disconfirmation on appraisal, affect, and behavioral intentions. AB - People's risk perceptions can have powerful effects on their outcomes, yet little is known about how people respond to risk information that disconfirms a prior expectation. We experimentally examined the affective, cognitive, and behavioral consequences of expectation disconfirmation in the context of risk perceptions. Participants were randomly assigned and then prompted toward either a high or low personal risk estimate regarding a fictitious health threat. All participants then received the same risk feedback, which presented either a negative disconfirmation experience (i.e., worse than expected) in the high-risk estimate condition or a positive disconfirmation experience (i.e., better than expected) in the low-risk estimate condition. Participants who experienced the negative disconfirmation reported stronger intentions to prevent the threat in the future compared to participants who experienced the positive disconfirmation. This effect was mediated by both disappointment about the risk feedback and perceptions of the severity of the threat. These findings have implications for risk communication, suggesting that the provision of objective risk information may improve or diminish the likelihood of behavior change depending on people's initial expectations and their emotional and cognitive reactions to the information. PMID- 24151992 TI - Characterization of BciB: a ferredoxin-dependent 8-vinyl-protochlorophyllide reductase from the green sulfur bacterium Chloroherpeton thalassium. AB - Two enzymes, BciA and BciB, are known to reduce the C-8 vinyl group of 8-vinyl protochlorophyllide, producing protochlorophyllide a, during the synthesis of chlorophylls and bacteriochlorophylls in chlorophototrophic bacteria. BciA from the green sulfur bacterium Chlorobaculum tepidum reduces the C-8 vinyl group using NADPH as the reductant. Cyanobacteria and some other chlorophototrophs have a second, nonhomologous type of 8-vinyl reductase, BciB, but the biochemical properties of this enzyme have not yet been described. In this study, the bciB gene of the green sulfur bacterium Chloroherpeton thalassium was expressed in Escherichia coli , and the recombinant protein was purified and characterized. Recombinant BciB binds a flavin adenine dinucleotide cofactor, and EPR spectroscopy as well as quantitative analyses of bound iron and sulfide suggest that BciB binds two [4Fe-4S] clusters, one of which may not be essential for the activity of the enzyme. Using electrons provided by reduced ferredoxin or dithionite, recombinant BciB was active and reduced the 8-vinyl moiety of the substrate, 8-vinyl protochlorophyllide, producing protochlorophyllide a. A structural model for BciB based on a recent structure for the FrhB subunit of F420-reducing [NiFe]-hydrogenase of Methanothermobacter marburgensis is proposed. Possible reasons for the occurrence and distribution of BciA and BciB among various chlorophototrophs are discussed. PMID- 24151993 TI - Gold-nanorod-based colorimetric and fluorescent approach for sensitive and specific assay of disease-related gene and mutation. AB - Sensitive and specific detection of disease-related gene and single nucleotide polymorphism (SNP) is of great importance in cancer diagnosis. Here, a colorimetric and fluorescent approach is described for detection of the p53 gene and SNP in homogeneous solution by using gold nanorods (GNRs) as both colorimetric probe and fluorescence quencher. Hairpin oligonucleotide was utilized as DNA probe to ensure highly sequence-specific detection of target DNA. In the presence of target DNA, the formation of DNA duplex greatly changed the electrostatic interaction between GNR and DNAs, leading to an obvious change in fluorescence and colorimetric response. The detection limit of fluorescent and colorimetric assay is 0.26 pM and 0.3 nM, respectively. Both fluorescence and colorimetric strategies were able to effectively discriminate complementary DNA from single-base mismatched DNA, which is meaningful for cancer diagnosis. More important, target DNA can be detected as low as 10 nM by the naked eye. Furthermore, transmission electron microscopy and fluorescence anisotropy measurements demonstrated that the color change as well as fluorescence quenching is ascribed to the DNA hybridization-induced aggregation of GNRs. Therefore, the assay provided a fast, sensitive, cost-effective, and specific sensing platform for detecting disease-related gene and SNP. PMID- 24151994 TI - Restricted pleiotropy facilitates mutational erosion of major life-history traits. AB - Radical shifts to new natural and human made niches can make some functions unneeded and thus exposed to genetic degeneration. Here we ask not about highly specialized and rarely used functions but those relating to major life-history traits, rate of growth, and resistance to prolonged starvation. We found that in yeast each of the two traits was visibly impaired by at least several hundred individual gene deletions. There were relatively few deletions affecting negatively both traits and likely none harming one but improving the other. Functional profiles of gene deletions affecting either growth or survival were strikingly different: the first related chiefly to synthesis of macromolecules whereas the second to maintenance and recycling of cellular structures. The observed pattern of gene indispensability corresponds to that of gene induction, providing a rather rare example of agreement between the results of deletion and expression studies. We conclude that transitions to new environments in which the ability to grow at possibly fastest rate or survive under very long starvation become practically unnecessary can result in rapid erosion of these vital functions because they are coded by many genes constituting large mutational targets and because restricted pleiotropy is unlikely to constrain this process. PMID- 24151996 TI - Limits to behavioral evolution: the quantitative genetics of a complex trait under directional selection. AB - Replicated selection experiments provide a powerful way to study how "multiple adaptive solutions" may lead to differences in the quantitative-genetic architecture of selected traits and whether this may translate into differences in the timing at which evolutionary limits are reached. We analyze data from 31 generations (n=17,988) of selection on voluntary wheel running in house mice. The rate of initial response, timing of selection limit, and height of the plateau varied significantly between sexes and among the four selected lines. Analyses of litter size and realized selection differentials seem to rule out counterposing natural selection as a cause of the selection limits. Animal-model analyses showed that although the additive genetic variance was significantly lower in selected than control lines, both before and after the limits, the decrease was not sufficient to explain the limits. Moreover, directional selection promoted a negative covariance between additive and maternal genetic variance over the first 10 generations. These results stress the importance of replication in selection studies of higher-level traits and highlight the fact that long-term predictions of response to selection are not necessarily expected to be linear because of the variable effects of selection on additive genetic variance and maternal effects. PMID- 24151997 TI - Selection biases the prevalence and type of epistasis along adaptive trajectories. AB - The contribution to an organism's phenotype from one genetic locus may depend upon the status of other loci. Such epistatic interactions among loci are now recognized as fundamental to shaping the process of adaptation in evolving populations. Although little is known about the structure of epistasis in most organisms, recent experiments with bacterial populations have concluded that antagonistic interactions abound and tend to deaccelerate the pace of adaptation over time. Here, we use the NK model of fitness landscapes to examine how natural selection biases the mutations that substitute during evolution based on their epistatic interactions. We find that, even when beneficial mutations are rare, these biases are strong and change substantially throughout the course of adaptation. In particular, epistasis is less prevalent than the neutral expectation early in adaptation and much more prevalent later, with a concomitant shift from predominantly antagonistic interactions early in adaptation to synergistic and sign epistasis later in adaptation. We observe the same patterns when reanalyzing data from a recent microbial evolution experiment. These results show that when the order of substitutions is not known, standard methods of analysis may suggest that epistasis retards adaptation when in fact it accelerates it. PMID- 24151995 TI - Outbreeding depression with low genetic variation in selfing Caenorhabditis nematodes. AB - Theory and empirical study produce clear links between mating system evolution and inbreeding depression. The connections between mating systems and outbreeding depression, whereby fitness is reduced in crosses of less related individuals, however, are less well defined. Here we investigate inbreeding and outbreeding depression in self-fertile androdioecious nematodes, focusing on Caenorhabditis sp. 11. We quantify nucleotide polymorphism for nine nuclear loci for strains throughout its tropical range, and find some evidence of genetic differentiation despite the lowest sequence diversity observed in this genus. Controlled crosses between strains from geographically separated regions show strong outbreeding depression, with reproductive output of F1s reduced by 36% on average. Outbreeding depression is therefore common in self-fertilizing Caenorhabditis species, each of which evolved androdioecious selfing hermaphroditism independently, but appears strongest in C. sp. 11. Moreover, the poor mating efficiency of androdioecious males extends to C. sp. 11. We propose that self fertilization is a key driver of outbreeding depression, but that it need not evolve as a direct result of local adaptation per se. Our verbal model of this process highlights the need for formal theory, and C. sp. 11 provides a convenient system for testing the genetic mechanisms that cause outbreeding depression, negative epistasis, and incipient speciation. PMID- 24151998 TI - Fruit evolution and diversification in campanulid angiosperms. AB - With increases in both the size and scope of phylogenetic trees, we are afforded a renewed opportunity to address long-standing comparative questions, such as whether particular fruit characters account for much of the variation in diversity among flowering plant clades. Studies to date have reported conflicting results, largely as a consequence of taxonomic scale and a reliance on potentially conservative statistical measures. Here we examine a larger and older angiosperm clade, the Campanulidae, and infer the rates of character transitions among the major fruit types, emphasizing the evolution of the achene fruits that are most frequently observed within the group. Our analyses imply that campanulids likely originated bearing capsules, and that all subsequent fruit diversity was derived from various modifications of this dry fruit type. We also found that the preponderance of lineages bearing achenes is a consequence of not only being a fruit type that is somewhat irreversible once it evolves, but one that also seems to have a positive association with diversification rates. Although these results imply the achene fruit type is a significant correlate of diversity patterns observed across campanulids, we conclude that it remains difficult to confidently and directly view this character state as the actual cause of increased diversification rates. PMID- 24152000 TI - Exploring the sociobiology of pyoverdin-producing Pseudomonas. AB - The idea that bacteria are social is a popular concept with implications for understanding the ecology and evolution of microbes. The view arises predominately from reasoning regarding extracellular products, which, it has been argued, can be considered "public goods." Among the best studied is pyoverdin-a diffusible iron-chelating agent produced by bacteria of the genus Pseudomonas. Here we report the de novo evolution of pyoverdin nonproducing mutants, genetically characterize these types and then test the appropriateness of the sociobiology framework by performing growth and fitness assays in the same environment in which the nonproducing mutants evolved. Our data draw attention to discordance in the fit between social evolution theory and biological reality. We show that pyoverdin-defective genotypes can gain advantage by avoiding the cost of production under conditions where the molecule is not required; in some environments pyoverdin is personalized. By exploring the fitness consequences of nonproducing types under a range of conditions, we show complex genotype-by environment interactions with outcomes that range from social to asocial. Together these findings give reason to question the generality of the conclusion that pyoverdin is a social trait. PMID- 24151999 TI - Seasonality maintains alternative life-history phenotypes. AB - Many organisms express discrete alternative phenotypes (polyphenisms) in relation to predictable environmental variation. However, the evolution of alternative life-history phenotypes remains poorly understood. Here, we analyze the evolution of alternative life histories in seasonal environments by using temperate insects as a model system. Temperate insects express alternative developmental pathways of diapause and direct development, the induction of a certain pathway affecting fitness through its life-history correlates. We develop a methodologically novel and holistic simulation model and optimize development time, growth rate, body size, reproductive effort, and adult life span simultaneously in both developmental pathways. The model predicts that direct development should be associated with shorter development time (duration of growth) and adult life span, higher growth rate and reproductive effort, smaller body size as well as lower fecundity compared to the diapause pathway, because the two generations divide the available time unequally. These predictions are consistent with many empirical data. Our analysis shows that seasonality alone can explain the evolution of alternative life histories. PMID- 24152002 TI - Modularity and rates of evolutionary change in a power-amplified prey capture system. AB - The dynamic interplay among structure, function, and phylogeny form a classic triad of influences on the patterns and processes of biological diversification. Although these dynamics are widely recognized as important, quantitative analyses of their interactions have infrequently been applied to biomechanical systems. Here we analyze these factors using a fundamental biomechanical mechanism: power amplification. Power-amplified systems use springs and latches to generate extremely fast and powerful movements. This study focuses specifically on the power amplification mechanism in the fast raptorial appendages of mantis shrimp (Crustacea: Stomatopoda). Using geometric morphometric and phylogenetic comparative analyses, we measured evolutionary modularity and rates of morphological evolution of the raptorial appendage's biomechanical components. We found that "smashers" (hammer-shaped raptorial appendages) exhibit lower modularity and 10-fold slower rates of morphological change when compared to non smashers (spear-shaped or undifferentiated appendages). The morphological and biomechanical integration of this system at a macroevolutionary scale and the presence of variable rates of evolution reveal a balance between structural constraints, functional variation, and the "roles of development and genetics" in evolutionary diversification. PMID- 24152003 TI - Coevolutionary feedbacks between family interactions and life history. AB - Families with parental care show a parent-offspring conflict over the amount of parental investment. To date, the resolution of this conflict was modeled as being driven by either purely within-brood or between-brood competition. In reality the partitioning of parental resources within- versus between-broods is an evolving life history trait, which can be affected by parent-offspring interactions. This coevolutionary feedback between life history and family interactions may influence the evolutionary process and outcome of parent offspring coadaptation. We used a genetic framework for a simulation model where we allowed parental parity to coevolve with traits that determine parental investment. The model included unlinked loci for clutch size, parental sensitivity, baseline provisioning, and offspring begging. The simulation showed that tight coadaptation of parent and offspring traits only occurred in iteroparous outcomes whereas semelparous outcomes were characterized by weak coadaptation. When genetic variation in clutch size was unrestricted in the ancestral population, semelparity and maximal begging with poor coadaptation evolved throughout. Conversely, when genetic variation was limited to iteroparous conditions, and/or when parental sensitivity was treated as an evolutionarily fixed sensory bias, coadapted outcomes were more likely. Our findings show the influence of a feedback between parity, coadaptation, and conflict on the evolution of parent-offspring interactions. PMID- 24152001 TI - Determinism in the diversification of Hispaniolan trunk-ground anoles (Anolis cybotes species complex). AB - The evolutionary processes that produce adaptive radiations are enigmatic. They can only be studied after the fact, once a radiation has occurred and been recognized, rather than while the processes are ongoing. One way to connect pattern to process is to study the processes driving divergence today among populations of species that belong to an adaptive radiation, and compare the results to patterns observed at a deeper, macroevolutionary level. We tested whether evolution is a deterministic process with similar outcomes during different stages of the adaptive radiation of Anolis lizards. Using a clade of terrestrial-scansorial lizards in the genus Anolis, we inferred the adaptive basis of spatial variation among contemporary populations and tested whether axes of phenotypic differentiation among them mirror known axes of diversification at deeper levels of the anole radiation. Nonparallel change associated with genetic divergence explains the vast majority of geographic variation. However, we found phenotypic variation to be adaptive as confirmed by convergence in populations occurring in similar habitats in different mountain ranges. Morphological diversification among populations recurs deterministically along two axes of diversification previously identified in the anole radiation, but the characters involved differ from those involved in adaptation at higher levels of anole phylogeny. PMID- 24152004 TI - Ecological constraints influence the emergence of cooperative breeding when population dynamics determine the fitness of helpers. AB - Cooperative breeding is a system in which certain individuals facilitate the production of offspring by others. The ecological constraints hypothesis states that ecological conditions deter individuals from breeding independently, and so individuals breed cooperatively to make the best of a bad situation. Current theoretical support for the ecological constraints hypothesis is lacking. We formulate a mathematical model that emphasizes the underlying ecology of cooperative breeders. Our goal is to derive theoretical support for the ecological constraints hypothesis using an ecological model of population dynamics. We consider a population composed of two kinds of individuals, nonbreeders (auxiliaries) and breeders. We suppose that help provided by an auxiliary increases breeder fecundity, but reduces the probability with which the auxiliary becomes a breeder. Our main result is a condition that guarantees success of auxiliary help. We predict that increasing the cost of dispersal promotes helping, in agreement with verbal theory. We also predict that increasing breeder mortality can either hinder helping (at high population densities), or promote it (at low population densities). We conclude that ecological constraints can exert influence over the evolution of auxiliary help when population dynamics are considered; moreover, that influence need not coincide with direct fitness benefits as previously found. PMID- 24152005 TI - Sex allocation adjustment to mating group size in a simultaneous hermaphrodite. AB - Sex allocation theory is considered as a touchstone of evolutionary biology, providing some of the best supported examples for Darwinian adaptation. In particular, Hamilton's local mate competition theory has been shown to generate precise predictions for extraordinary sex ratios observed in many separate-sexed organisms. In analogy to local mate competition, Charnov's mating group size model predicts how sex allocation in simultaneous hermaphrodites is affected by the mating group size (i.e., the number of mating partners plus one). Until now, studies have not directly explored the relationship between mating group size and sex allocation, which we here achieve in the simultaneously hermaphroditic flatworm Macrostomum lignano. Using transgenic focal worms with ubiquitous expression of green-fluorescent protein (GFP), we assessed the number of wild type mating partners carrying GFP+ sperm from these focal worms when raised in different social group sizes. This allowed us to test directly how mating group size was related to the sex allocation of focal worms. We find that the proportion of male investment initially increases with increasing mating group size, but then saturates as predicted by theory. To our knowledge, this is the first direct test of the mating group size model in a simultaneously hermaphroditic animal. PMID- 24152006 TI - Sex ratio and density affect sexual selection in a sex-role reversed fish. AB - Understanding how demographic processes influence mating systems is important to decode ecological influences on sexual selection in nature. We manipulated sex ratio and density in experimental populations of the sex-role reversed pipefish Syngnathus typhle. We quantified sexual selection using the Bateman gradient (betass'), the opportunity for selection (I), and sexual selection (Is), and the maximum standardized sexual selection differential (smax'). We also measured selection on body length using standardized selection differentials (s') and mating differentials (m'), and tested whether the observed I and Is differ from values obtained by simulating random mating. We found that I, Is, and s'max, but not betass', were higher for females under female than male bias and the opposite for males, but density did not affect these measures. However, higher density decreased sexual selection (m' but not s') on female length, but selection on body length was not affected by sex ratio. Finally, Is but not I was higher than expected from random mating, and only for females under female bias. This study demonstrates that both sex ratio and density affect sexual selection and that disentangling interrelated demographic processes is essential to a more complete understanding of mating behavior and the evolution of mating systems. PMID- 24152007 TI - Detecting range expansions from genetic data. AB - We propose a method that uses genetic data to test for the occurrence of a recent range expansion and to infer the location of the origin of the expansion. We introduce a statistic psi (the directionality index) that detects asymmetries in the 2D allele frequency spectrum of pairs of population. These asymmetries are caused by the series of founder events that happen during an expansion and they arise because low frequency alleles tend to be lost during founder events, thus creating clines in the frequencies of surviving low-frequency alleles. Using simulations, we show that psi is more powerful for detecting range expansions than both FST and clines in heterozygosity. We also show how we can adapt our approach to more complicated scenarios such as expansions with multiple origins or barriers to migration and we illustrate the utility of psi by applying it to a data set from modern humans. PMID- 24152008 TI - Consumer-resource interactions and the evolution of migration. AB - Theoretical studies have demonstrated that selection will favor increased migration when fitnesses vary both temporally and spatially, but it is far from clear how pervasive those theoretical conditions are in nature. Although consumer resource interactions are omnipresent in nature and can generate spatial and temporal variation, it is unknown even in theory whether these dynamics favor the evolution of migration. We develop a mathematical model to address whether and how migration evolves when variability in fitness is determined at least in part by consumer-resource coevolutionary interactions. Our analyses show that such interactions can drive the evolution of migration in the resource, consumer, or both species and thus supplies a general explanation for the pervasiveness of migration. Over short time scales, we show the direction of change in migration rate is determined primarily by the state of local adaptation of the species involved: rates increase when a species is locally maladapted and decrease when locally adapted. Our results reveal that long-term evolutionary trends in migration rates can differ dramatically depending on the strength or weakness of interspecific interactions and suggest an explanation for the evolutionary divergence of migration rates among interacting species. PMID- 24152009 TI - Size variation, growth strategies, and the evolution of modularity in the mammalian skull. AB - Allometry is a major determinant of within-population patterns of association among traits and, therefore, a major component of morphological integration studies. Even so, the influence of size variation over evolutionary change has been largely unappreciated. Here, we explore the interplay between allometric size variation, modularity, and life-history strategies in the skull from representatives of 35 mammalian families. We start by removing size variation from within-species data and analyzing its influence on integration magnitudes, modularity patterns, and responses to selection. We also carry out a simulation in which we artificially alter the influence of size variation in within-taxa matrices. Finally, we explore the relationship between size variation and different growth strategies. We demonstrate that a large portion of the evolution of modularity in the mammalian skull is associated to the evolution of growth strategies. Lineages with highly altricial neonates have adult variation patterns dominated by size variation, leading to high correlations among traits regardless of any underlying modular process and impacting directly their potential to respond to selection. Greater influence of size variation is associated to larger intermodule correlations, less individualized modules, and less flexible responses to natural selection. PMID- 24152010 TI - Correlated changes in occlusal pattern and diet in stem Murinae during the onset of the radiation of Old World rats and mice. AB - Adaptive radiations in mammals are sometimes associated with the emergence of key dental innovations facilitating food processing and masticatory movements. The dietary aspects of such innovations constitute an important focus in evolutionary biology. Murine rodents, which originated during middle Miocene, currently constitute the largest extant mammalian subfamily. Their adaptive radiation combines an original chewing motion with a peculiar occlusal pattern. The fossil record clearly establishes the timing of acquisitions of those innovations, and the aim of our study was to estimate the dietary changes associated with each of them. Fossil taxa phylogenetically closest to Murinae were investigated through the use of geographic information system applied on maps obtained from first upper molars digitized by X-ray synchrotron microtomography. This methodology enables estimation of quantitative topographic descriptors of the dietary specializations of the molar crown. The peculiar forwardly directed chewing motion acquired by stem Murinae may have been a key innovation allowing the invasion of an insectivorous dietary niche. The further radiation of crown Murinae coincides with the return to the plant-dominated omnivorous dietary niche of their distant ancestors through the acquisition of new morphological traits. The retention of the forwardly directed chewing motion by the crown Murinae could have become a competitive advantage in the context of a more generalist diet. PMID- 24152011 TI - The evolutionary history of cetacean brain and body size. AB - Cetaceans rival primates in brain size relative to body size and include species with the largest brains and biggest bodies to have ever evolved. Cetaceans are remarkably diverse, varying in both phenotypes by several orders of magnitude, with notable differences between the two extant suborders, Mysticeti and Odontoceti. We analyzed the evolutionary history of brain and body mass, and relative brain size measured by the encephalization quotient (EQ), using a data set of extinct and extant taxa to capture temporal variation in the mode and direction of evolution. Our results suggest that cetacean brain and body mass evolved under strong directional trends to increase through time, but decreases in EQ were widespread. Mysticetes have significantly lower EQs than odontocetes due to a shift in brain:body allometry following the divergence of the suborders, caused by rapid increases in body mass in Mysticeti and a period of body mass reduction in Odontoceti. The pattern in Cetacea contrasts with that in primates, which experienced strong trends to increase brain mass and relative brain size, but not body mass. We discuss what these analyses reveal about the convergent evolution of large brains, and highlight that until recently the most encephalized mammals were odontocetes, not primates. PMID- 24152012 TI - Why we are not dead one hundred times over. AB - The possibility of pervasive weak selection at tens or hundreds of millions of sites across the genome, suggested by recent studies of silent site DNA sequence variation and divergence, raises the problem of the survival of the population in the face of the large genetic load that may result. Two alternative resolutions of this problem are presented for populations where recombination is sufficiently frequent that different sites under selection evolve independently. One invokes weak stabilizing selection, of the magnitude compatible with abundant silent site variability. This can be shown to produce only a modest genetic load, due to the effectiveness of even weak stabilizing selection in keeping the trait mean close to the optimum. The other invokes soft selection, whereby individuals compete for a limiting resource whose abundance determines the absolute fitness of the population. Weak purifying selection at a large number of sites produces only a small variance in fitness among individuals within the population, due to the fact that most sites are fixed rather than polymorphic. Even when it produces a large genetic load, it is compatible with the observations on fitness variance when selection is soft. It may be very difficult to distinguish between these two possibilities. PMID- 24152013 TI - Pathogen life-history trade-offs revealed in allopatry. AB - Trade-offs in life-history traits is a central tenet in evolutionary biology, yet their ubiquity and relevance to realized fitness in natural populations remains questioned. Trade-offs in pathogens are of particular interest because they may constrain the evolution and epidemiology of diseases. Here, we studied life history traits determining transmission in the obligate fungal pathogen, Podosphaera plantaginis, infecting Plantago lanceolata. We find that although traits are positively associated on sympatric host genotypes, on allopatric host genotypes relationships between infectivity and subsequent transmission traits change shape, becoming even negative. The epidemiological prediction of this change in life-history relationships in allopatry is lower disease prevalence in newly established pathogen populations. An analysis of the natural pathogen metapopulation confirms that disease prevalence is lower in newly established pathogen populations and they are more prone to go extinct during winter than older pathogen populations. Hence, life-history trade-offs mediated by pathogen local adaptation may influence epidemiological dynamics at both population and metapopulation levels. PMID- 24152014 TI - Evolution of sprint speed in African savannah herbivores in relation to predation. AB - Predator-prey arms races are widely speculated to underlie fast speed in terrestrial mammals. However, due to lack of empirical testing, both the specificity of any evolutionary coupling between particular predator and prey species, and the relevance of alternative food-based hypotheses of speed evolution, remain obscure. Here I examine the ecological links between the sprint speed of African savannah herbivores, their vulnerability to predators, and their diet. I show that sprint speed is strongly predicted by the vulnerability of prey to their main predators; however, the direction of the link depends on the hunting style of the predator. Speed increases with vulnerability to pursuit predators, whereas vulnerability to ambush predators is associated with particularly slow speed. These findings suggest that differential vulnerability to specific predators can indeed drive interspecific variation in speed within prey communities, but that predator hunting style influences the intensity and consistency with which selection on speed is coupled between particular species. PMID- 24152015 TI - Surveillance cultures in pediatric allogeneic hematopoietic stem cell transplantation. AB - The value of surveillance cultures in predicting systemic infections and in guiding antimicrobial treatment is controversial. We investigated 57 pediatric allo-SCTs between 2007 and 2009. ALL (34), AML (5), and severe aplastic anemia (4) were the largest patient groups. Conditioning was TBI-based in 87% and 54% developed GVHD (21% grade III-IV). Of the 2594 weekly colonization samples, 24% were positive (fecal bacteria 86%, fecal fungi 16%, Clostridium difficile 16%; throat bacteria 17% and throat fungi 4%). Enterobacteria and enterococci were the most common fecal findings, staphylococci and streptococci in the throat. Of the bacterial stool samples pretransplant, 74% (mostly enterococci) were resistant to our first-line antibiotics (ceftazidime and cloxacillin). Candida species accounted for the majority of the fungal findings: 62% of the fecal and 78% in the throat. A total of 170 clinical infection episodes were recorded, and in 12 of these, the bacterial blood culture was positive. In 4/12 cases, the pathogen was detected in surveillance culture previously, leading to sensitivity and specificity of 33.3 and 47.4%, respectively. Positive predictive value of bacterial surveillance cultures was 0.9%. The antimicrobial treatment was changed in only five cases based on the surveillance culture results. Weekly surveillance cultures seldom provided clinical benefit and were not cost-effective. PMID- 24152016 TI - Diagnostic concordance rates in the subtyping of basal cell carcinoma by different dermatopathologists. AB - BACKGROUND: There are numerous subtypes of basal cell carcinoma (BCC). Defining the histopathologic subtype is an essential element in patient management, but there is little known data regarding interobserver precision in subtyping BCC. METHODS: We studied interobserver variance between six board-certified dermatopathologists who subtyped 100 BCCs in a blinded fashion. We used kappa statistic to calculate the concordance in suggested subtype by different dermatopathologists. Provided diagnoses were then re-categorized into low-risk and high-risk phenotypes, and kappa statistic for concordance on high-risk BCC was determined. RESULTS: The overall kappa statistic was 0.301, indicating fair agreement among the six observers. Superficial and fibroepithelial BCC had the highest individual kappa statistics. When subtypes were re-classified into a two tier system of high-risk and low-risk phenotypes, there was substantial interobserver agreement on high-risk BCC with a kappa statistic of 0.699. CONCLUSION: These results suggest only fair agreement among dermatopathologists on specific BCC subtypes, but substantial agreement on superficial, fibroepithelial and high-risk BCC growth patterns. A simplified classification system comprised of superficial, fibroepithelial, nodular and infiltrative subtypes would increase interobserver precision and facilitate clinical decision making. PMID- 24152018 TI - Paediatric male circumcision and penile hygiene: a Japanese mothers' view. AB - This paper analyses the views of 20 Japanese mothers concerning paediatric male circumcision and penile hygiene. In Japan, routine male circumcision has never been implemented for newborns and children, and adult males are mostly circumcised at aesthetic clinics. However, media reports indicate a trend of Japanese mothers willing to have their sons circumcised. In discussing penile hygiene and male circumcision, the construct of a 'sexual script' becomes relevant to understanding how linguistic and gender barriers made references to male genitalia and penile hygiene largely appear as 'vulgar' and 'unfeminine' in daily life conversations. Peers were often identified as the main source of information and only mothers who have struggled with their children's penile infections have learnt about male genital hygiene, a domain of knowledge largely transmitted by men. Male circumcision becomes a double-edged sword that could help prevent penile infections but also an embarrassing conversational topic that could elicit discrimination because most Japanese children are uncircumcised. PMID- 24152017 TI - Single-nucleotide polymorphism discovery in Leptographium longiclavatum, a mountain pine beetle-associated symbiotic fungus, using whole-genome resequencing. AB - Single-nucleotide polymorphisms (SNPs) are rapidly becoming the standard markers in population genomics studies; however, their use in nonmodel organisms is limited due to the lack of cost-effective approaches to uncover genome-wide variation, and the large number of individuals needed in the screening process to reduce ascertainment bias. To discover SNPs for population genomics studies in the fungal symbionts of the mountain pine beetle (MPB), we developed a road map to discover SNPs and to produce a genotyping platform. We undertook a whole genome sequencing approach of Leptographium longiclavatum in combination with available genomics resources of another MPB symbiont, Grosmannia clavigera. We sequenced 71 individuals pooled into four groups using the Illumina sequencing technology. We generated between 27 and 30 million reads of 75 bp that resulted in a total of 1, 181 contigs longer than 2 kb and an assembled genome size of 28.9 Mb (N50 = 48 kb, average depth = 125x). A total of 9052 proteins were annotated, and between 9531 and 17,266 SNPs were identified in the four pools. A subset of 206 genes (containing 574 SNPs, 11% false positives) was used to develop a genotyping platform for this species. Using this roadmap, we developed a genotyping assay with a total of 147 SNPs located in 121 genes using the Illumina((r)) Sequenom iPLEX Gold. Our preliminary genotyping (success rate = 85%) of 304 individuals from 36 populations supports the utility of this approach for population genomics studies in other MPB fungal symbionts and other fungal nonmodel species. PMID- 24152019 TI - Biomarkers in the assessment of acute and chronic kidney diseases in the dog and cat. AB - In both human and veterinary medicine, diagnosing and staging renal disease can be difficult. Measurement of glomerular filtration rate is considered the gold standard for assessing renal function but methods for its assessment can be technically challenging and impractical. The main parameters used to diagnose acute and chronic kidney disease include circulating creatinine and urea concentrations, and urine-specific gravity. However, these parameters can be insensitive. Therefore, there is a need for better methods to diagnose and monitor patients with renal disease. The use of renal biomarkers is increasing in human and veterinary medicine for the diagnosis and monitoring of acute and chronic kidney diseases. An ideal biomarker would identify site and severity of injury, and correlate with renal function, among other qualities. This article will review the advantages and limitations of renal biomarkers that have been used in dogs and cats, as well as some markers used in humans that may be adapted for veterinary use. In the future, measuring a combination of biomarkers will likely be a useful approach in the diagnosis of kidney disorders. PMID- 24152020 TI - Nedd4-2 (NEDD4L) controls intracellular Na(+)-mediated activity of voltage-gated sodium channels in primary cortical neurons. AB - Nedd4-2, a HECT (homologous with E6-associated protein C-terminus)-type ubiquitin protein ligase, has been implicated in regulating several ion channels, including Navs (voltage-gated sodium channels). In Xenopus oocytes Nedd4-2 strongly inhibits the activity of multiple Navs. However, the conditions under which Nedd4 2 mediates native Nav regulation remain uncharacterized. Using Nedd4-2-deficient mice, we demonstrate in the present study that in foetal cortical neurons Nedd4-2 regulates Navs specifically in response to elevated intracellular Na(+), but does not affect steady-state Nav activity. In dorsal root ganglia neurons from the same mice, however, Nedd4-2 does not control Nav activities. The results of the present study provide the first physiological evidence for an essential function of Nedd4-2 in regulating Navs in the central nervous system. PMID- 24152021 TI - Mass media campaign impacts influenza vaccine obtainment of university students. AB - OBJECTIVE: To describe the effectiveness of a mass media campaign in increasing the rate of college student influenza vaccine obtainment. PARTICIPANTS/METHODS: Students (N = 721) at a large southern university completed a survey between September 2011 and January 2012 assessing what flu clinic media sources were visualized and if they encouraged them to obtain vaccination. RESULTS: Nearly a 30% increase was seen in flu vaccination rates in Fall 2011 over Fall 2010. The main campus Web site portal was the most visualized media source among students. The majority of responses indicated that the source of information visualized had a moderate to strong influence over their decision to get vaccinated. CONCLUSIONS: Various communication channels should be utilized to increase influenza vaccination rate on a university campus. Use of mass media to influence college students to perceive, retain, and act on the message of obtaining the influenza vaccine did produce a noteworthy outcome. PMID- 24152022 TI - An examination of risky drinking behaviors and motivations for alcohol use in a college sample. AB - OBJECTIVE: The current study examined (1) drinking motives as a mediator of risky drinking behaviors (ie, pregaming and drinking games) and alcohol-related problems and (2) whether gender moderates the association between risky drinking behaviors and negative consequences. PARTICIPANTS: Participants (N = 368; 68% female) were drinkers aged 18 to 25. Data were collected from September to November 2010 and January to May 2011. METHODS: Participants completed measures regarding typical pregaming and drinking game alcohol consumption, drinking motives, and alcohol-related consequences. RESULTS: Social, coping, and enhancement motives partially explained relationships, with enhancement motives explaining the most variance for pregaming (31%) and drinking games (44%). Relationships between risky drinking and consequences were not moderated by gender. CONCLUSIONS: Drinking to enhance positive affect may be the most salient motivation for drinking related to pregaming and drinking games for college drinkers. Findings have implications for interventions tailored to students engaging in various heavy drinking practices. PMID- 24152023 TI - Cigarette smoking among Korean international college students in the United States. AB - OBJECTIVE AND PARTICIPANTS: This study explored (1) the prevalence of cigarette smoking among South Korean international college students in the United States, (2) differences in smoking between on- and off-campus living arrangements, and (3) predictors of an increase in smoking over time in the United States METHODS: An online survey was completed by 1,201 students at 52 4-year US universities (34% response rate). RESULTS: The overall smoking prevalence was 43.5%. The smoking rate (29.0%) of female students was higher than that (4%) of female college students in South Korea. Sex, living place, living situation, length of stay as a student in the United States, home smoking rules, campus-wide tobacco free policies, and levels of acculturative stress, anxiety, and depression were significantly associated with an increase in smoking (p < .05). CONCLUSIONS: Given the high smoking prevalence among the South Korean students on US college campuses, targeted prevention efforts for these students may be warranted. PMID- 24152024 TI - Compensatory weight control behaviors of women in emerging adulthood: associations between childhood abuse experiences and adult relationship avoidance. AB - OBJECTIVE: To examine correlates of compensatory weight control behaviors among women in transition between adolescence and adulthood. PARTICIPANTS: The authors recruited a sample of undergraduate women (N = 759) at a large northwestern university during the 2009-2010 academic year. METHODS: Logistic regression was used to assess relations among childhood abuse, psychosocial functioning, adult dating relationship factors, and women's endorsement of compensatory weight control behaviors. RESULTS: The final model reliably distinguished between participants who endorsed versus denied use of compensatory behaviors (chi(2)[5, N = 747] = 36.37, p < .001), with global psychosocial functioning and relationship avoidance accounting for the most variance. CONCLUSIONS: These findings illustrate the importance of considering childhood abuse histories and adult relationships while assessing young women's compensatory weight control behaviors. PMID- 24152025 TI - Perfectionism, anxiety, and depressive distress: evidence for the mediating role of negative automatic thoughts and anxiety sensitivity. AB - OBJECTIVE: This study assessed a mediational model in which negative automatic thoughts and anxiety sensitivity were hypothesized to mediate the relationship between perfectionism cognitions and depressive and anxiety symptoms. PARTICIPANTS: Participants were undergraduate students from an urban Canadian university. The data were collected from July 2009 to August 2010. METHODS: In a cross-sectional evaluation, 992 undergraduate participants completed questionnaires that assessed perfectionism cognitions, negative automatic thinking, anxiety sensitivity, and anxiety and depressive symptoms. RESULTS: Mediational analysis confirmed the role of anxiety sensitivity and negative automatic thoughts in mediating the association between perfectionistic cognitions, anxiety symptoms, and depressive distress. Furthermore, in line with previous studies, nearly a third of students displayed an elevated prevalence of anxiety and depressive symptoms. CONCLUSIONS: This study further clarified the associations and mediating relationships among mood states associated with perfectionism. PMID- 24152026 TI - Differences in sleep quality and health-related quality of life in young adults with allergies and asthma and their healthy peers. AB - OBJECTIVE: The current study examined the relationship between sleep quality and health-related quality of life (HRQOL). PARTICIPANTS: Participants were 501 undergraduate students with allergies (167), asthma + allergies (167), or with no history of a chronic illness (167) completed study measures from August 2011 to April 2012. METHODS: The undergraduate students completed questionnaires online as part of a larger study of psychosocial adjustment of young adults. RESULTS: Young adults with allergies and asthma + allergies reported significantly worse sleep quality and HRQOL than healthy peers. Additionally, those with allergies and asthma + allergies had significantly more sleep disturbances and used sleeping medication significantly more often in the previous month than healthy peers. CONCLUSIONS: These results highlight concerns regarding quality of life and sleep problems in an often-overlooked population. Importantly, sleep difficulties can result in difficulties in daily living and impairment in academic functioning. PMID- 24152027 TI - Parent conflict as a mediator between marianismo beliefs and depressive symptoms for Mexican American college women. AB - OBJECTIVE: The purpose of this study is to examine how marianismo is related to the depressive symptoms of Mexican American women with family conflict as a mediator. PARTICIPANTS: During January of 2010, 170 Mexican American women college students in a southern, Hispanic-serving institution were sampled. METHODS: A mediation analysis was conducted to determine if parent conflict mediates the relationship between marianismo values and depressive symptoms. RESULTS: Results from Barron and Kenny's(1) mediation analysis method, in conjunction with a Sobel(2) test indicated that parent conflict significantly mediated the relation between marianismo and depressive symptoms. CONCLUSION: Findings and implications of the mediation will be discussed for the mental health and treatment of Mexican American women college students. PMID- 24152029 TI - Measurement of ionic resonances in alkyl phenyl ketone cations via infrared strong field mass spectrometry. AB - Strong-field excitation of alkyl phenyl ketone molecules reveals an electronic resonance at 1370 nm in the radical cations upon measuring mass spectra as a function of excitation wavelength from 1240 to 1550 nm. The ratio of the benzoyl fragment ion to parent ion signal in acetophenone increases from 1:1.5 at 1240 nm excitation to 5:1 at 1370 nm (0.9 eV), and back to 1:1 at 1450 nm. Unlike acetophenone and propiophenone, the homologous molecules acetone and ethylbenzene exhibit no wavelength-dependent fragmentation patterns over the range from 1240 to 1550 nm, supporting the hypothesis that the electronic structure of the alkyl phenyl ketone cation enables the one-photon transition. Calculations on the acetophenone and propiophenone radical cations show the existence of a bright state, D2, 0.87 and 0.88 eV, respectively, above the ground-state D0 minimum. Calculations of the potential energy surfaces of the acetophenone radical cation suggest that a D2 -> D0 radiationless transition precedes dissociation on D0. Upon population transfer to the D2 surface, the wavepacket motion is directed toward a three-state conical intersection (D0/D1/D2) that facilitates the photodissociation by converting electronic to vibrational energy on the D0 surface. PMID- 24152030 TI - Asymmetric synthesis of chiral dihydrothiopyrans via an organocatalytic enantioselective formal thio [3 + 3] cycloaddition reaction with binucleophilic bisketone thioethers. AB - An unprecedented organocatalytic highly enantioselective approach to a 3,4 dihydro-2H-thiopyran scaffold with two contiguous stereogenic centers has been implemented through a formal thio [3 + 3] cycloaddition process involving a Michael-aldol condensation cascade sequence. Notably, a new class of binucleophilic bisketone thioethers is designed for the process. Furthermore, the fine-tuning of their reactivity enables the cascade process to proceed with highly regioselectively. PMID- 24152031 TI - Copper(II) complexes with 4-carbomethoxypyrrolidone functionalized PAMAM dendrimers: an EPR study. AB - The internal flexibility and interacting ability of PAMAM-dendrimers having 4 carbomethoxypyrrolidone-groups as surface groups (termed Gn-Pyr), which may be useful for biomedical purposes, and ion traps were investigated by analyzing the EPR spectra of their copper(II) complexes. Increasing amounts (with respect to the Pyr groups) of copper(II) gave rise to different signals constituting the EPR spectra at room and low temperature corresponding to different coordinations of Cu(2+) inside and outside the dendrimers. At low Cu(2+) concentrations, CuN4 coordination involving the DAB core is preferential for G3- and G5-Pyr, while G4 Pyr shows a CuN3O coordination. CuN2O2 coordination into the external dendrimer layer was also contributing to G3- and G4-Pyr spectra. The structures of the proposed copper-dendrimer complexes were also shown. G4-Pyr displays unusual binding ability toward Cu(II) ions. Mainly the remarkably low toxicity shown by G4-Pyr and its peculiar binding ability leads to a potential use in biomedical fields. PMID- 24152032 TI - Toward a life cycle-based, diet-level framework for food environmental impact and nutritional quality assessment: a critical review. AB - Supplying adequate human nutrition within ecosystem carrying capacities is a key element in the global environmental sustainability challenge. Life cycle assessment (LCA) has been used effectively to evaluate the environmental impacts of food production value chains and to identify opportunities for targeted improvement strategies. Dietary choices and resulting consumption patterns are the drivers of production, however, and a consumption-oriented life cycle perspective is useful in understanding the environmental implications of diet choices. This review identifies 32 studies that use an LCA framework to evaluate the environmental impact of diets or meals. It highlights the state of the art, emerging methodological trends and current challenges and limitations to such diet-level LCA studies. A wide range of bases for analysis and comparison (i.e., functional units) have been employed in LCAs of foods and diet; we conceptually map appropriate functional unit choices to research aims and scope and argue for a need to move in the direction of a more sophisticated and comprehensive nutritional basis in order to link nutritional health and environmental objectives. Nutritional quality indices are reviewed as potential approaches, but refinement through ongoing collaborative research between environmental and nutritional sciences is necessary. Additional research needs include development of regionally specific life cycle inventory databases for food and agriculture and expansion of the scope of assessments beyond the current focus on greenhouse gas emissions. PMID- 24152034 TI - Interactions between rotavirus and natural organic matter isolates with different physicochemical characteristics. AB - Interaction forces between rotavirus and Suwanee River natural organic matter (SRNOM) or Colorado River NOM (CRNOM) were studied by atomic force microscopy (AFM) in NaCl solutions and at unadjusted pH (5.7-5.9). Compared to CRNOM, SRNOM has more aromatic carbon and phenolic/carboxylic functional groups. CRNOM is characterized with aliphatic structure and considerable presence of polysaccharide moieties rich in hydroxyl functional groups. Strong repulsive forces were observed between rotavirus and silica or mica or SRNOM. The interaction decay length derived from the approaching curves for these systems involving rotavirus in high ionic strength solution was significantly higher than the theoretical Debye length. While no adhesion was observed for rotavirus and SRNOM, attraction was observed between CRNOM and rotavirus during approach and adhesion during retraction. Moreover, these adhesion forces decreased with increasing ionic strength. Interactions due to ionic hydrogen bonding between deprotonated carboxyl groups on rotavirus and hydroxyl functional groups on CRNOM were suggested as the dominant interaction mechanisms between rotavirus and CRNOM. PMID- 24152033 TI - Electromechanical effects of 1,25-dihydroxyvitamin d with antiatrial fibrillation activities. AB - INTRODUCTION: Treatment with 1,25-dihydroxyvitamin D (1,25[OH]2 D) has several cardiovascular benefits. 1,25[OH]2 D has direct cellular effects, but its effects on the atrium are not clear. We evaluated the effects of 1,25[OH]2 D on the atrial electrophysiology and atrial fibrillation (AF). METHODS: Conventional microelectrodes were used to record action potentials (APs) and contractility in isolated rabbit left atrium (LA) tissue preparations before and after the administration of 0.01, 0.1, and 1 nM 1,25[OH]2 D with and without rapid atrial pacing (RAP) and acetylcholine (5 mM)-induced AF. Surface ECG and intracardiac electrograms were recorded before and after the intravenous administration of 4 units/kg of 1,25[OH]2 D in heart failure (HF) rabbits (4 weeks after coronary artery ligation) with RAP and acetylcholine-induced AF. RESULTS: 1,25[OH]2 D dose dependently increased the AP duration in the LA, which was abolished by pretreatment with 0.1 MUM ryanodine. RAP and 5 mM acetylcholine-induced fewer (64.3% vs 100%, P < 0.05) AF occurrences in the presence (n = 14) of 1,25[OH]2 D than those (n = 14) in the absence of 1,25[OH]2 D. The LA treated with 1,25[OH]2 D (n = 9) had a slower maximal AF rate (10.9 +/- 2.4 Hz vs 13.3 +/- 2.7 Hz, P < 0.05) than the LA (n = 14) without 1,25[OH]2 D. Moreover, 1,25[OH]2 D caused a lower AF inducible percentage (11.0 +/- 1.9% vs 100 +/- 0%, P < 0.001) and a shorter duration (4 +/- 0.4 seconds vs 309 +/- 26 seconds, P < 0.001) with a prolonged LA 90% monophasic AP duration (94.1 +/- 0.2 milliseconds vs 98.5 +/- 0.1 milliseconds, P < 0.05) in 5 rabbits with HF. 1,25[OH]2 D did not prolong the QT interval or 90% of the AP duration in isolated Purkinje fibers. CONCLUSION: 1,25[OH]2 D has direct electromechanical effects on the LA and can prevent or terminate AF. PMID- 24152035 TI - Variants in the 1q21 risk region are associated with a visual endophenotype of autism and schizophrenia. AB - Deficits in sensitivity to visual stimuli of low spatial frequency and high temporal frequency (so-called frequency-doubled gratings) have been demonstrated both in schizophrenia and in autism spectrum disorder (ASD). Such basic perceptual functions are ideal candidates for molecular genetic study, because the underlying neural mechanisms are well characterized; but they have sometimes been overlooked in favor of cognitive and neurophysiological endophenotypes, for which neural substrates are often unknown. Here, we report a genome-wide association study of a basic visual endophenotype associated with psychological disorder. Sensitivity to frequency-doubled gratings was measured in 1060 healthy young adults, and analyzed for association with genotype using linear regression at 642 758 single nucleotide polymorphism (SNP) markers. A significant association (P = 7.9 * 10(-9) ) was found with the SNP marker rs1797052, situated in the 5'-untranslated region of PDZK1; each additional copy of the minor allele was associated with an increase in sensitivity equivalent to more than half a standard deviation. A permutation procedure, which accounts for multiple testing, showed that the association was significant at the alpha = 0.005 level. The region on chromosome 1q21.1 surrounding PDZK1 is an established susceptibility locus both for schizophrenia and for ASD, mirroring the common association of the visual endophenotype with the two disorders. PDZK1 interacts with N-methyl-d aspartate receptors and neuroligins, which have been implicated in the etiologies of schizophrenia and ASD. These findings suggest that perceptual abnormalities observed in two different disorders may be linked by common genetic elements. PMID- 24152036 TI - Multidimensional polypyrrole/iron oxyhydroxide hybrid nanoparticles for chemical nerve gas agent sensing application. AB - Multidimensional FeOOH nanoneedle-decorated hybrid polypyrrole nanoparticles (PFFs) were fabricated using dual-nozzle electrospray and heat stirring process. To decorate metal oxide nanoneedles on the polypyrrole (PPy) surface, metal oxide particle-decorated PPys (E_PPy) were fabricated as starting materials. The E_PPy particles were prepared by dual-nozzle electrospray because ferric ions (Fe(3+)) dispersed on the surface reacted with hydroxide (OH(-)) ions in the collector solution without aggregation of each particles. Multidimensional hybrid PFFs with maximized surface area were then formed by heat stirring reaction in the aqueous metal precursor contained solutions. The decoration morphology of the metal oxide nanoneedles could be controlled by precursor concentration in the aqueous solution. These multidimensional hybrid PPFs were applied to nerve gas agent (DMMP) chemical sensor at room temperature with excellent sensitivity. The minimum detectable level (MDL) of PFFs was as low as 0.1 ppb, which is higher than that for a chemical sensor based on hybrid materials. This is because the metal oxide nanoneedles increase surface area and affinity to DMMP vapor. PMID- 24152038 TI - A new trichothecene from Myrothecium roridum QDFE005, a symbiotic fungus isolated from Mactra chinensis. AB - A new trichothecene, 12'-episatratoxin H (1), together with three known analogs: roridin A (2), 16-hydroxyroridin E (3), and roridin E (4), was isolated from the culture broth of the symbiotic fungus Myrothecium roridum QDFE005, which was isolated from Mactra chinensis. Their structures were elucidated on the basis of spectroscopic methods, including 1D and 2D NMR (COSY, HMQC, and HMBC) techniques. Compound 1 exhibited significant cytotoxicity against the human tumor cell lines KB and HepG2 with IC50 values of 1.42 and 2.27 MUM, respectively. PMID- 24152037 TI - 'Cough-triggered' tuberculosis screening among adults with diabetes in Tanzania. AB - AIMS: Diabetes increases the risk of tuberculosis and the prevalence of diabetes is rising in tuberculosis-endemic regions such as sub-Saharan Africa. Resource appropriate strategies for tuberculosis case finding among African adults with diabetes are needed. The aims of this study were to determine prevalence of tuberculosis and evaluate one screening strategy among adult Tanzanians with diabetes. METHODS: In this prospective cohort study, we evaluated a 'cough triggered' strategy for tuberculosis case finding among adults with diabetes at our zonal hospital in Tanzania. All adults with diabetes and cough underwent further tuberculosis symptom assessment, and those with productive cough had sputum collected for microscopy and Mycobacterium tuberculosis culture. RESULTS: Between September 2011 and March 2012, 700 adults with diabetes attended our hospital. A total of 693 were enrolled, 121/693 (17.5%) had cough and 32/693 (4.6%) had at least two of the classic symptoms of tuberculosis. Of note, 87/121 (71.9%) of patients with cough could not produce sputum spontaneously. Nine patients were diagnosed with tuberculosis for a prevalence of 1299/100 000 (1.3%), sevenfold greater than the national average. CONCLUSIONS: Tuberculosis is common among Tanzanian adults with diabetes, but tuberculosis case finding is challenging because of the high prevalence of non-productive cough. This low cost, 'cough-triggered' tuberculosis case-finding strategy may serve as a reasonable first step for improving tuberculosis screening among adults with diabetes in sub-Saharan Africa. PMID- 24152039 TI - Importance of Crown Height Ratios in Dental Implants on the Fracture Strength of Different Connection Designs: An In Vitro Study. AB - PURPOSE: The aim of the present in vitro study was to assess the resistance to static fatigue of implants with different connections at various crown heights. MATERIALS AND METHODS: Sixty conical implants and 60 abutments were used with the smallest diameters available for each model. Three groups (n = 20) were established based on the implant connections: Morse taper O3.50 mm (group 1), external hexagon O3.50 mm (group 2), and internal hexagon O3.50 mm (group 3). Four crown heights were tested: h1 = 8 mm, h2 = 10 mm, h3 = 12 mm, and h4 = 14 mm. All groups were subjected to quasi-static loading at a 30 degrees angle to the implant axis in a universal testing machine. RESULTS: The mean fracture strengths for group 1 were 1524 N (h1 ), 1469 N (h2 ), 750 N (h3 ), and 729 N (h4 ). Those for group 2 were 1504 N (h1 ), 814 N (h2 ), 491 N (h3 ), and 325 N (h4 ). Those for group 3 were 1543 N (h1 ), 672 N (h2 ), 403 N (h3 ), and 390 N (h4 ). CONCLUSIONS: Resistance to loading decreases significantly with increasing crown height, and the connection design can affect the performance. PMID- 24152040 TI - Inspiration, collaboration, and cooperation in the PCMR community. PMID- 24152041 TI - Snowflake, albinism and conservation. PMID- 24152042 TI - Three BRNs are better than two. PMID- 24152043 TI - Flipping the phenotypic switch on a novel antimelanoma differentiation strategy. PMID- 24152044 TI - Overcoming melanoma drug resistance through metabolic targeting? PMID- 24152046 TI - Withanolide artifacts formed in methanol. AB - Methanol solutions of the main withanolides (6-8) naturally present in Physalis longifolia yielded five artificial withanolides (1-5), including three new compounds (1-3). Withanolides 1 and 2 were identified as intramolecular Michael addition derivatives, while withanolides 3-5 were the result of intermolecular Michael addition. A comprehensive literature investigation was conducted to identify potential withanolide Michael addition artifacts isolated from Solanaceous species to date. PMID- 24152047 TI - Structural basis for substrate specificity and mechanism of N-acetyl-D-neuraminic acid lyase from Pasteurella multocida. AB - N-Acetylneuraminate lyases (NALs) or sialic acid aldolases catalyze the reversible aldol cleavage of N-acetylneuraminic acid (Neu5Ac, the most common form of sialic acid) to form pyruvate and N-acetyl-d-mannosamine. Although equilibrium favors sialic acid cleavage, these enzymes can be used for high-yield chemoenzymatic synthesis of structurally diverse sialic acids in the presence of excess pyruvate. Engineering these enzymes to synthesize structurally modified natural sialic acids and their non-natural derivatives holds promise in creating novel therapeutic agents. Atomic-resolution structures of these enzymes will greatly assist in guiding mutagenic and modeling studies to engineer enzymes with altered substrate specificity. We report here the crystal structures of wild-type Pasteurella multocida N-acetylneuraminate lyase and its K164A mutant. Like other bacterial lyases, it assembles into a homotetramer with each monomer folding into a classic (beta/alpha)8 TIM barrel. Two wild-type structures were determined, in the absence of substrates, and trapped in a Schiff base intermediate between Lys164 and pyruvate, respectively. Three structures of the K164A variant were determined: one in the absence of substrates and two binary complexes with N acetylneuraminic acid (Neu5Ac) and N-glycolylneuraminic acid (Neu5Gc). Both sialic acids bind to the active site in the open-chain ketone form of the monosaccharide. The structures reveal that every hydroxyl group of the linear sugars makes hydrogen bond interactions with the enzyme, and the residues that determine specificity were identified. Additionally, the structures provide some clues for explaining the natural discrimination of sialic acid substrates between the P. multocida and Escherichia coli NALs. PMID- 24152048 TI - Development of a mouse model mimicking key aspects of a viral asthma exacerbation. AB - Viral respiratory tract infections are known triggers of asthma exacerbations in both adults and children. The current standard of care, inhaled CS (corticosteroids) and LABAs (long-acting beta2-adrenoceptor agonists), fails to prevent the loss of control that manifests as an exacerbation. In order to better understand the mechanisms underlying viral asthma exacerbations we established an in vivo model using the clinically relevant aeroallergen HDM (house dust mite) and the viral mimetic/TLR3 (Toll-like receptor 3) agonist poly(I:C). Poly(I:C) alone induced a similar neutrophilic inflammatory profile in the BAL (bronchoalveolar lavage) to that of HRV1b (human rhinovirus 1b) alone, accompanied by both elevated BAL KC (keratinocyte-derived chemokine) and IL-1beta (interleukin-1beta). When mice allergic to HDM were also challenged with poly(I:C) the neutrophilic inflammatory profile was exacerbated. Increased CD8(+) T-cell numbers, increased CD4(+) and CD8(+) cell activation and elevated KC and IL-1beta were observed. No increases in Th2 cytokines or the eosinophil chemoattractant CCL11 [chemokine (C-C motif) ligand 11], above those induced by HDM alone, were observed. The poly(I:C)-exacerbated neutrophilia did not translate into changes in AHR (airways hyper-responsiveness), indicating that in this model inflammation and AHR are two mechanistically independent events. To test the clinical relevance of this model CS sensitivity was assessed using prednisone, a synthetic oral CS used to manage exacerbations in asthmatic patients already on maximal doses of inhaled CS. The increased neutrophils, and accompanying cytokines/chemokines KC and IL-1beta induced by poly(I:C) challenge of HDM-sensitized and challenged mice were insensitive to oral prednisone therapy. In summary we have described a CS-resistant mouse model mimicking the key aspects of viral asthma exacerbation using the clinically relevant aeroallergen HDM and the viral mimic poly(I:C). This model may provide better understanding of disease mechanisms underlying viral exacerbations and could be used to build early confidence in novel therapeutic axes targeting viral asthma exacerbations in Th2 asthmatics. PMID- 24152049 TI - Sea urchin spines in the stratum corneum: an early finding related to trauma. AB - Penetrating trauma from sea urchin (Echinoidea) spines has been shown to cause numerous cutaneous reactions, ranging from initial pain that rapidly dissipates and resolves to chronic inflammation and formation of characteristic sea urchin granulomas. Many of these skin-colored or violaceous papules and nodules form weeks to months after injury, and may be surgically excised. Histopathologic examination commonly shows well-defined granulomas, the majority of which represent sarcoidal-type granulomas. Other microscopic patterns, such as foreign body reactions and chronic inflammation, have also been shown. Retained spine fragments are birefringent on polarized microscopic examination and are most likely found in the dermal layer. Herein, we describe a case of traumatic sea urchin cutaneous injury with a unique early cutaneous trauma reaction in a young male who lived in Hawaii. Histopathologic exam was significant for retained spines in the layer of the stratum corneum, but no signs of granulomatous inflammation were observed. This case report emphasizes the unique features of our case and reviews the common clinical and histopathologic features of sea urchin cutaneous reactions. PMID- 24152050 TI - More on spontaneous regression of chronic lymphocytic leukemia: two new cases and potential role of lamivudine in a further patient with advanced disease and hepatitis B virus infection. PMID- 24152051 TI - Catheter-related bloodstream infection due to Mycobacterium neoaurum in a patient with acute leukemia. PMID- 24152054 TI - Is the EEOC debating the right question concerning "voluntary" wellness programs? PMID- 24152053 TI - New algorithm for valganciclovir dosing in pediatric solid organ transplant recipients. AB - CMV infections are common after SOT. v-GCV is increasingly used in children. The aim of this study was to evaluate presently used dosing algorithms. Data from 104 pediatric SOT recipients (kidney, liver, and heart) aged 0.3-16.9 yr and receiving v-GCV once a day were used for model development and validation with the Pmetrics package for R. Monte Carlo simulations were performed to compare the probability of a GCV AUC 40-60 mg*h/L with the different algorithms across a range of ages, weights, and GFRs. GCV pharmacokinetics was well described by the non-parametric model. Clearance was dependent on GFR and Cockcroft-Gault estimates improved the model fit over Schwartz. Simulations showed that our new algorithm, where v-GCV dose is: Weight [kg]*(0.07*GFR [mL/min]+k), where k = 5 for GFR <= 30 mL/min, k = 10 for GFR > 30 mL/min and weight > 30 kg and k = 15 for GFR > 30 mL/min and weight <= 30 kg, outperformed the other algorithms. Thirty-three percent of all patients achieve an exposure above and 21% within the therapeutic window. We propose a simple algorithm for initial v-GCV dosing that standardizes plasma drug exposure better than current algorithms. Subsequent TDM is strongly suggested to achieve individual drug levels within the therapeutic window. PMID- 24152055 TI - Can chronic disease management programs for patients with type 2 diabetes reduce productivity-related indirect costs of the disease? Evidence from a randomized controlled trial. AB - The objective was to assess the impacts of diabetes self-management programs on productivity-related indirect costs of the disease. Using an employer's perspective, this study estimated the productivity losses associated with: (1) employee absence on the job, (2) diabetes-related disability, (3) employee presence on the job, and (4) early mortality. Data were obtained from electronic medical records and survey responses of 376 adults aged >=18 years who were enrolled in a randomized controlled trial of type 2 diabetes self-management programs. All study participants had uncontrolled diabetes and were randomized into one of 4 study arms: personal digital assistant (PDA), chronic disease self management program (CDSMP), combined PDA and CDSMP, and usual care (UC). The human-capital approach was used to estimate lost productivity resulting from 1, 2, 3, and 4 above, which are summed to obtain total productivity loss. Using robust regression, total productivity loss was modeled as a function of the diabetes self-management programs and other identified demographic and clinical characteristics. Compared to subjects in the UC arm, there were no statistically significant differences in productivity losses among persons undergoing any of the 3 diabetes management interventions. Males were associated with higher productivity losses (+$708/year; P<0.001) and persons with greater than high school education were associated with additional productivity losses (+$758/year; P<0.001). Persons with more than 1 comorbid condition were marginally associated with lower productivity losses (-$326/year; P=0.055). No evidence was found that the chronic disease management programs examined in this trial affect indirect productivity losses. PMID- 24152056 TI - Can health care organizations improve health behavior and treatment adherence? AB - Many Americans are failing to engage in both the behaviors that prevent and those that effectively manage chronic health conditions, including pulmonary disorders, cardiovascular conditions, diabetes, and cancer. Expectations that health care providers are responsible for changing patients' health behaviors often do not stand up against the realities of clinical care that include large patient loads, limited time, increasing co-pays, and restricted access. Organizations and systems that might share a stake in changing health behavior include employers, insurance payers, health care delivery systems, and public sector programs. However, although the costs of unhealthy behaviors are evident, financial resources to address the problem are not readily available. For most health care organizations, the return on investment for developing behavior change programs appears highest when addressing treatment adherence and disease self-management, and lowest when promoting healthy lifestyles. Organizational strategies to improve adherence are identified in 4 categories: patient access, provider training and support, incentives, and information technology. Strategies in all 4 categories are currently under investigation in ongoing studies and have the potential to improve self-management of many chronic health conditions. PMID- 24152057 TI - Leveraging effective clinical registries to advance medical care quality and transparency. AB - Policy makers, payers, and the general public are increasingly focused on health care quality improvement. Measuring quality requires robust data systems that collect data over time, can be integrated with other systems, and can be analyzed easily for trends. The goal of this project was to study effective tools and strategies in the design and use of clinical registries with the potential to facilitate quality improvement, value-based purchasing, and public reporting on the quality of care. The research team worked with an expert panel to define characteristics of effectiveness, and studied examples of effective registries in cancer, cardiovascular care, maternity, and joint replacement. The research team found that effective registries were successful in 1 or more of 6 key areas: data standardization, transparency, accuracy/completeness of data, participation by providers, financial sustainability, and/or providing feedback to providers. The findings from this work can assist registry designers, sponsors, and researchers in implementing strategies to increase the use of clinical registries to improve patient care and outcomes. PMID- 24152058 TI - Tunable asymmetric catalysis through ligand stacking in chiral rigid rods. AB - Chiral benzene-1,3,5-tricarboxamide (BTA) ligands, comprising one diphenylphosphino group and one or two remote chiral 1-methylheptyl side chains, were evaluated in the rhodium-catalyzed asymmetric hydrogenation of dimethyl itaconate. Despite the fact that the rhodium atom and the chiral center(s) are separated by more than 12 covalent bonds, up to 82% ee was observed. A series of control and spectroscopic experiments confirmed that the selectivity arises from the formation of chiral helical polymers by self-association of the BTA monomers through noncovalent interactions. The addition of a phosphine-free chiral BTA, acting as a comonomer for the chiral BTA ligands, increases the level of enantioselectivity (up to 88% ee). It illustrates how the selectivity of the reaction can be increased in a simple fashion by mixing two different BTA monomers. The concept was further probed by performing the same experiment with an achiral BTA ligand, i.e. a phosphine-functionalized BTA that contains two remote octyl side chains. It afforded an encouraging 31% ee, thus demonstrating the catalytically relevant transfer of chirality between the self-assembled units. It constitutes a unique example of the sergeants-and-soldiers principle applied to catalysis. PMID- 24152059 TI - Identification of phenolic compounds in plum fruits (Prunus salicina L. and Prunus domestica L.) by high-performance liquid chromatography/tandem mass spectrometry and characterization of varieties by quantitative phenolic fingerprints. AB - Plums (Prunus domestica L. and Prunus salicina L.) are edible fruits mostly consumed in America, China, and Europe. We have used LC-MS(n) to detect and characterize the phenolic compounds in plum varieties. Forty-one phenolics were detected comprising caffeoylquinic acids, feruloylquinic acid, p-coumaroylquinic acids, methyl caffeoylquinates, methyl p-coumaroylquinate, caffeoylshikimic acids, catechin, epicatechin, rutin, esculin, quercetin, quercetin-3-O-hexosides, dimeric proanthocyanidins, trimeric proanthocyanidins, caffeoyl-glucoside, feruloyl-glucoside, p-coumaroyl-glucoside, vanillic acid-glucosides, 3,4 dihydroxybenzoyl-glucoside, quercetin-3-O-pentosides, quercetin-3-O-rhamnoside, quercetin-pentoside-rhamnosides, and 3-p-methoxycinnamoylquinic acid. This is the first time when 3-p-methoxycinnamoylquinic acid is reported in nature. Chlorogenic acids and proanthocyanidins were the major phenolics present in plums. Furthermore, HPLC with DAD and chemical reaction detection was used to generate quantitative phenolic fingerprints from the fruit flesh of 33 plum varieties. The predominant compound was 3-caffeoylquinic acid in nearly all varieties studied; generally, however, the qualitative and quantitative profiles showed high diversity even among closely related progenies. PMID- 24152060 TI - Enhanced photovoltaic performance of semiconductor-sensitized ZnO-CdS coupled with graphene oxide as a novel photoactive material. AB - We report, for the first time, a ternary hybrid composite of ZnO, CdS, and graphene oxide (GO) as a one-coat paintable solution in performing the role of a photoanode for the semiconductor-sensitized solar cell, wherein hierarchical ZnO CdS heteroarrays are embedded onto the GO sheets. The photoconversion properties of the hybrid ternary-system-based photoanodes are evaluated in the photovoltaic devices having Pt and Ag as the counter electrodes with sulfide/polysulfide redox couple as the electrolyte. Power conversion efficiency (PCE) of ~2.82% has been achieved with a short-circuit current density (Jsc) of ~7.3 mA/cm(2), a maximum open-circuit voltage (Voc) of 703 mV, and a fill factor (FF) of 54% for the photovoltaic cell with Pt as a counter electrode. The identical hybrid photoanode against the Ag counter electrode resulted in the following values: PCE ~ 1.96%, Jsc ~ 5.7 mA/cm(2), Voc ~ 565 mV, and 63% FF. The band position proximity of CdS, ZnO, and GO in the proposed ternary system facilitates an efficient electronic interactions thereby promoting the electron transport within CdS-ZnO-GO. The hierarchically grown CdS nanorods over ZnO nanoparticle act as the sensitizer for ZnO, enhancing the visible light harvesting ability. The loading of 1.0 wt% of GO to ZnO-CdS results in enhanced separation of photogenerated electrons and holes within the photoactive layer, thereby improving the photovoltaic performance. The electronic interactions of GO to ZnO-CdS is evident from the drastic quenching of fluorescence, reduced exciton lifetime and Raman scattering measurements. In order to study the effect of GO in the photovoltaic performance, we have compared our result with the photoelectrical parameters of the devices fabricated using the binary ZnO-CdS composite as GO-free photoanodes. PMID- 24152061 TI - Power outage estimation for tropical cyclones: improved accuracy with simpler models. AB - In this article, we discuss an outage-forecasting model that we have developed. This model uses very few input variables to estimate hurricane-induced outages prior to landfall with great predictive accuracy. We also show the results for a series of simpler models that use only publicly available data and can still estimate outages with reasonable accuracy. The intended users of these models are emergency response planners within power utilities and related government agencies. We developed our models based on the method of random forest, using data from a power distribution system serving two states in the Gulf Coast region of the United States. We also show that estimates of system reliability based on wind speed alone are not sufficient for adequately capturing the reliability of system components. We demonstrate that a multivariate approach can produce more accurate power outage predictions. PMID- 24152062 TI - Increased commuting to school time reduces sleep duration in adolescents. AB - Active travel to school has been referred to as one way of increasing the level of daily physical exercise, but the actual impacts on student's general health are not clear. Recently, a possible association between active travel to school and the duration of sleep was suggested. Thus, the aim was of this study to investigate the associations between the type of transportation and travel time to school, the time in bed and sleepiness in the classroom of high school students. Information on sleeping habits and travel to school of 1126 high school students were analyzed, where 55.1% were girls with an average age of 16.24 (1.39) years old, in Santa Maria Municipality, Rio Grande do Sul, Brazil. Multiple linear regression and adjusted prevalence rates analyses were carried out. The frequency of active travel found was 61.8%. Associations between time in bed, sleepiness in the classroom and the type of transportation (active or passive) were not identified. Nevertheless, the time in bed was inversely associated with the travel time (p = 0.036) and with a phase delay. In the adjusted analysis, active travel was more incident for the students of schools in the suburbs (PR: 1.68; CI: 1.40-2.01) in comparison with the students of schools in the center. Therefore, longer trips were associated with a reduction of sleep duration of morning and night groups. Interventions concerning active travel to school must be carried out cautiously in order not to cause a reduction of the sleeping time. PMID- 24152063 TI - Relationship between time of day and periprocedural myocardial infarction after elective angioplasty. AB - OBJECTIVES: To test if the time of day significantly influences the occurrence of type 4A myocardial infarction in elective patients undergoing percutaneous coronary intervention (PCI). BACKGROUND: Recent studies have suggested an influence of circadian rhythms on myocardial infarction size and mortality among patients with ST-elevation myocardial infarction. The aim of the study is to investigate whether periprocedural myocardial infarction (PMI) is influenced by the time of day in elective patients undergoing PCI. METHODS: All consecutive patients undergoing elective PCI between 2007 and 2011 at our institutions with known post-interventional troponin were retrospectively included. Patients (n = 1021) were divided into two groups according to the starting time of the PCI: the morning group (n = 651) between 07:00 and 11:59, and the afternoon group (n = 370) between 12:00 and 18:59. Baseline and procedural characteristics as well as clinical outcome defined as the occurrence of PMI were compared between groups. In order to limit selection bias, all analyses were equally performed in 308 pairs using propensity score (PS) matching. RESULTS: In the overall population, the rate of PMI was statistically lower in the morning group compared to the afternoon group (20% vs. 30%, p < 0.001). This difference remained statistically significant after PS-matching (21% vs. 29%, p = 0.03). Multivariate analysis shows that being treated in the afternoon independently increases the risk for PMI with an odds ratio of 2.0 (95%CI: 1.1-3.4; p = 0.02). CONCLUSIONS: This observational PS-matched study suggests that the timing of an elective PCI influences the rate of PMI. PMID- 24152064 TI - Quantum dynamics study of vibrational excitation effects and energy requirement on reactivity for the O + CD4/CHD3 -> OD/OH + CD3 reactions. AB - A quantum reactive dynamics, six-degrees-of-freedom, time-dependent wave packet method is employed to study vibrational enhancement and energy requirement on reactivity of the O((3)P) + CD4/CHD3 -> OD/OH + CD3 reactions. The calculations show, for O + CD4, that all the vibrational excitations of CD4 enhance reactivity, which agrees with quasi-classical trajectory results. However, this finding contradicts the experimental observation where the bending excitation suppresses reactivity. The present study also reveals that translational energy, in general, is more effective to enhance reactivity than vibrational energy; however, at higher collision energy, vibrational energy is slightly more effective than translational energy. For O + CHD3, the stretching and bending excitations of CHD3 enhance the reaction, whereas the umbrella motion hinders reactivity. The calculated excitation functions agree well with experiments. PMID- 24152065 TI - Actinoranone, a cytotoxic meroterpenoid of unprecedented structure from a marine adapted Streptomyces sp. AB - The isolation and structure elucidation of a new meroterpenoid, actinoranone (1), produced by a marine bacterium closely related to the genus Streptomyces is reported. Actinoranone is composed of an unprecedented dihydronaphthalenone polyketide linked to a bicyclic diterpenoid. The stereochemistry of 1 was defined by application of the advanced Mosher's method and by interpretation of spectroscopic data. Actinoranone (1) is significantly cytotoxic to HCT-116 human colon cancer cells with an LD50 = 2.0 MUg/mL. PMID- 24152067 TI - Reduction in NO(x) emission trends over China: regional and seasonal variations. AB - We analyzed satellite observations of nitrogen dioxide (NO2) columns by the Ozone Monitoring Instrument (OMI) over China from 2005 to 2010 in order to estimate the top-down anthropogenic nitrogen oxides (NOx) emission trends. Since NOx emissions were affected by the economic slowdown in 2009, we removed one year of abnormal data in the analysis. The estimated average emission trend is 4.01 +/- 1.39% yr( 1), which is slower than the trend of 5.8-10.8% yr(-1) reported for previous years. We find large regional, seasonal, and urban-rural variations in emission trends. The average NOx emission trend of 3.47 +/- 1.07% yr(-1) in warm season (June-September) is less than the trend of 5.03 +/- 1.92% yr(-1) in cool season (October-May). The regional annual emission trends decrease from 4.76 +/- 1.61% yr(-1) in North China Plain to 3.11 +/- 0.98% yr(-1) in Yangtze River Delta and further down to -4.39 +/- 1.81% yr(-1) in Pearl River Delta. The annual emission trends of the four largest megacities, Shanghai, Beijing, Guangzhou, and Shenzhen are -0.76 +/- 0.29%, 0.69 +/- 0.27%, -4.46 +/- 1.22%, and -7.18 +/- 2.88% yr(-1), considerably lower than the regional averages or surrounding rural regions. These results appear to suggest that a number of factors, including emission control measures of thermal power plants, increased hydro-power usage, vehicle emission regulations, and closure or migration of high-emission industries, have significantly reduced or even reversed the increasing trend of NOx emissions in more economically developed megacities and southern coastal regions, but their effects are not as significant in other major cities or less economically developed regions. PMID- 24152066 TI - Engineered nanopore of Phi29 DNA-packaging motor for real-time detection of single colon cancer specific antibody in serum. AB - The ingenious design of the bacterial virus phi29 DNA packaging nanomotor with an elegant and elaborate channel has inspired its application for single molecule detection of antigen/antibody interactions. The hub of this bacterial virus nanomotor is a truncated cone-shaped connector consisting of 12 protein subunits. These subunits form a ring with a central 3.6-nm channel acting as a path for dsDNA to enter during packaging and to exit during infection. The connector has been inserted into a lipid bilayer. Herein, we reengineered an Epithelial Cell Adhesion Molecule (EpCAM) peptide into the C-terminal of nanopore as a probe to specifically detect EpCAM antibody (Ab) in nanomolar concentration at the single molecule level. The binding of Abs sequentially to each peptide probe induced stepwise blocks in current. The distinctive current signatures enabled us to analyze the docking and undocking kinetics of Ab-probe interactions and determine the Kd. The signal of EpCAM antibody can be discriminated from the background events in the presence of nonspecific antibody or serum. Our results demonstrate the feasibility of generating a highly sensitive platform for detecting antibodies at extremely low concentrations in the presence of contaminants. PMID- 24152068 TI - Linguistic validation of the 5D itching scale to Arabic in patients with end stage kidney disease. AB - BACKGROUND: Pruritus is one of the commonest skin complaints in end-stage kidney disease. Pruritus can be effectively managed if proper assessment is carried out to categorise its severity. The objective of this study is to test the reliability of an Arabic version of the 5D-Itching scale (5D-IS). METHOD: A self- administered Arabic version of the 5D-IS was tested for linguistic validation. Language validity of the tool was carried by using the forward/backward method. Internal consistency was tested using Cronbach's alpha and Spearman's rank. Factor analysis was performed to assess the content adequacy of the study tool. FINDINGS: A total of 151 patients completed the survey. The 5D-IS is mainly comprised of five domains that are used to assess the level of itching. The mean +/- SD 5-D score obtained in the study group was 12.7 +/- 5.3 with scores ranging between 6 and 25. Cronbach's alpha was 0.850 for the five domains of 5 D-IS. The reliability of five domain 5 D-IS indicates the practical applicability of the instrument with inter-correlation of 0.847 (p < 0.05). CONCLUSION: The 5D-IS was found to be a reliable tool for assessing itching in Arabic patients with uraemic pruritus. Due to its simplicity, this tool can easily be used by clinical staff to assess the severity of pruritus. PMID- 24152069 TI - The impact of the International Association of Diabetes and Pregnancy Study Groups (IADPSG) fasting glucose diagnostic criterion on the prevalence and outcomes of gestational diabetes mellitus in Han Chinese women. AB - AIMS: The International Association of Diabetes and Pregnancy Study Groups (IADPSG) proposed that a one-time value of fasting plasma glucose of 5.1 mmol/l or over at any time of the pregnancy is sufficient to diagnose gestational diabetes. We evaluated the repercussions of the application of this threshold in pregnant Han Chinese women. METHODS: This is a retrospective study of 5360 (72.3% of total) consecutively recruited pregnant Han Chinese women in one centre from 2008 to 2011. These women underwent a two-step gestational diabetes diagnostic protocol according to the previous American Diabetes Association criteria. The IADPSG fasting plasma glucose criterion was used to reclassify these 5360 women. The prevalence, clinical characteristics and obstetric outcomes were compared among the women classified as having gestational diabetes by the previous American Diabetes Association criteria (approximately 90% were treated), those reclassified as having gestational diabetes by the single IADPSG fasting plasma glucose criterion (untreated), but not as having gestational diabetes by the previous American Diabetes Association criteria, and those with normal glucose tolerance. RESULTS: There were 626 cases of gestational diabetes defined by the previous American Diabetes Association criteria (11.7%) and these cases were associated with increased risks of maternal and neonatal outcomes when compared with the women with normal glucose tolerance. With the IADPSG fasting plasma glucose criterion, another 1314 (24.5%) women were reclassified as having gestational diabetes. Gestational diabetes classified by the IADPSG fasting plasma glucose criterion was associated with gestational hypertension (P = 0.0094) and neonatal admission to nursery (P = 0.035) prior to adjustment for maternal age and BMI, but was no longer a predictor for adverse pregnancy outcomes after adjustment. CONCLUSION: The simple IADPSG fasting plasma glucose criterion increased the Chinese population with gestational diabetes by 200%. The increased population with gestational diabetes was not significantly associated with excess obstetric and neonatal morbidity. PMID- 24152071 TI - Dihaloiodoarenes: alpha,alpha-dihalogenation of phenylacetate derivatives. AB - A hypervalent iodine reagent-based alpha-carbonyl dihalogenation reaction is reported. Treating diazoacetate derivatives with either iodobenzene dichloride or iodotoluene difluoride results in gem-dichlorination or gem-difluorination products, respectively. The reaction is catalyzed by either Lewis acid or Lewis base activation of the aryl-lambda(3)-iodane (ArIX2) species and proceeds rapidly and chemoselectively to the desired gem-difunctionalized products in good to excellent yield. PMID- 24152070 TI - Three new ursane-type triterpenoids from the aerial parts of Isodon excisoides. AB - Three new ursane-type triterpenoids, 2alpha,3beta-dihydroxy-11alpha,12alpha-epoxy urs-28,13beta-olide (1), 2alpha,3beta,24-trihydroxy-11alpha,12alpha-epoxy-urs 28,13beta-olide (2), and 2alpha,3alpha,24-trihydroxy-11,20(30)-dien-urs-28,13beta olide (6), together with six known ursane-type triterpenoids (3-5, 7-9), were isolated from the EtOAc extract of the aerial parts of Isodon excisoides. Their structures were elucidated on the basis of 1D NMR and 2D NMR analyses as well as HRMS experiments. PMID- 24152072 TI - Electrophysiological characterization of uncoupled mutants of LacY. AB - In this study of the lactose permease of Escherichia coli (LacY), five functionally irreplaceable residues involved specifically in H(+) translocation (Arg302 and Glu325) or in the coupling between protonation and sugar binding (Tyr236, Glu269, and His322) were mutated individually or together with mutant Glu325 -> Ala. The wild type and each mutant were purified and reconstituted into proteoliposomes, which were then examined using solid-supported-membrane-based electrophysiology. Mutants Glu325 -> Ala or Arg302 -> Ala, in which H(+) symport is abolished, exhibit a weakly electrogenic rapid reaction triggered by sugar binding. The reaction is essentially absent in mutant Tyr236 -> Phe, Glu269 -> Ala, and His322 -> Ala, and each of these mutations blocks the electrogenic reaction observed in the Glu325 -> Ala mutant. The findings are consistent with the interpretation that the electrogenic reaction induced by sugar binding is due to rearrangement of charged residues in LacY and that this reaction is blocked by mutation of each member of the Tyr236/Glu269/His322 triad. In addition, further support is provided for the conclusion that deprotonation is rate limiting for downhill lactose/H(+) symport. PMID- 24152073 TI - Tribute to Peter G. Wolynes. PMID- 24152077 TI - Publications of Peter G. Wolynes. PMID- 24152074 TI - A scientific memoir. PMID- 24152078 TI - Regulation of hormonal responses of sweet pepper as affected by salinity and elevated CO2 concentration. AB - This study examines the extent to which the predicted CO2 -protective effects on the inhibition of growth, impairment of photosynthesis and nutrient imbalance caused by saline stress are mediated by an effective adaptation of the endogenous plant hormonal balance. Therefore, sweet pepper plants (Capsicum annuum, cv. Ciclon) were grown at ambient or elevated [CO2] (400 or 800 umol mol(-1)) with a nutrient solution containing 0 or 80 mM NaCl. The results show that, under saline conditions, elevated [CO2] increased plant dry weight, leaf area, leaf relative water content and net photosynthesis compared with ambient [CO2], whilst the maximum potential quantum efficiency of photosystem II was not modified. In salt stressed plants, elevated [CO2 ] increased leaf NO3(-) concentration and reduced Cl(-) concentration. Salinity stress induced ABA accumulation in the leaves but it was reduced in the roots at high [CO2], being correlated with the stomatal response. Under non-stressed conditions, IAA was dramatically reduced in the roots when high [CO2] was applied, which resulted in greater root DW and root respiration. Additionally, the observed high CK concentration in the roots (especially tZR) could prevent downregulation of photosynthesis at high [CO2], as the N level in the leaves was increased compared with the ambient [CO2], under salt-stress conditions. These results demonstrate that the hormonal balance was altered by the [CO2], which resulted in significant changes at the growth, gas exchange and nutritional levels. PMID- 24152079 TI - Intradiscal injection of fibrin sealant for the treatment of symptomatic lumbar internal disc disruption: results of a prospective multicenter pilot study with 24-month follow-up. AB - OBJECTIVE: Assess the safety and efficacy of intradiscal fibrin sealant in adults with chronic discogenic low back pain. DESIGN: Prospective, nonrandomized Food and Drug Administration approved pilot study. SETTING: Three centers in the United States. SUBJECTS: Fifteen adults with chronic, single, or contiguous two level lumbar discogenic pain confirmed through meticulous provocation discography. INTERVENTIONS: Volume- and pressure-controlled intradiscal delivery of BIOSTAT BIOLOGX((r)) Fibrin Sealant with the Biostat((r)) Delivery Device into symptomatic lumbar disc(s). OUTCOME MEASURES: Assessments were performed at baseline, 72 hours, and 1, 4, 13, 26, 52, and 104 weeks following intervention. Potential adverse events were evaluated with serial assessment of neurological status, radiographic, and magnetic resonance imaging (MRI). Efficacy measures included serial assessments of low back pain visual analog scale (VAS) measurements and the Roland-Morris Disability Questionnaire (RMDQ). RESULTS: Safety neurological assessments, X-ray, and MRI showed no significant changes. Adverse events were reported in nine subjects. Two instances of low back muscle spasm and one case of discitis were the only events considered related to the procedure or product. EFFICACY: Mean low back pain VAS scores (mm) decreased from 72.4 (95% confidence interval 64.6-80.3) at baseline to 31.7 (17.4-46.1), 35.4 (17.7-53.1), and 33.0 (16.3-49.6); mean RMDQ score improved from 15.2 (12.7-17.7) at baseline to 8.9 (5.3-12.5), 6.2 (3.4-9.1), and 5.6 (2.9-8.4) at 26, 52, and 104 weeks, respectively. CONCLUSION: Intradiscal injection of BIOSTAT BIOLOGX Fibrin Sealant with the Biostat Delivery Device appears safe and may improve pain and function in selected patients with discogenic pain. PMID- 24152080 TI - Evaluation of the EmbaGYNTM pelvic floor muscle stimulator in addition to Kegel exercises for the treatment of female stress urinary incontinence: a prospective, open-label, multicenter, single-arm study. AB - AIM: To assess the efficacy and safety of the EmbaGYNTM Pelvic Floor Exerciser, a battery-powered neuromuscular stimulation device with a vaginal, two-electrode stimulation probe in women with stress urinary incontinence. MATERIALS & METHODS: In this prospective, open-label, multicenter, single-arm study, patients with stress urinary incontinence (n = 83) underwent 12 weeks of treatment with EmbaGYN with Kegel exercises. RESULTS: At week 12, the mean number of incontinence episodes/day (primary end point) fell 56.2% (p = 0.152). A >=50% decrease from baseline in incontinence episodes was seen in 65.3% of subjects (p = 0.006). The mean number of incontinence pads/day fell 57.1% (p = 0.001). Mean 24- and 1-h in office urine loss declined 59.0% (p < 0.001) and 67% (p = 0.019), respectively. There was one nonserious device-related adverse event. CONCLUSION: EmbaGYN with Kegel exercises resulted in significant reductions in urine loss, incontinence pad use and improved incontinence-related quality of life, but did not have a significant effect on incontinence episodes/day. PMID- 24152081 TI - Parent report of child's health-related quality of life after a primary-care based weight management program. AB - BACKGROUND: Health-related quality of life (HRQoL) has been recognized as an important target and health outcome in obesity research. The current study aimed to examine HRQoL in overweight or obese children after a 10-week primary-care based weight management program, Parent-Led Activity and Nutrition for Healthy Living, in southern Appalachia. METHODS: Sixty-seven children (ages 5-12 years) and their caregivers were recruited from four primary care clinics, two of which were randomized to receive the intervention. Caregivers in the intervention groups received two brief motivational interviewing visits and four group sessions led by providers as well as four phone follow-ups with research staff. Caregivers completed the PedsQL and demographic questionnaires at baseline and at 3, 6, and 12 months postintervention. Child height and weight were collected to determine standardized BMI. RESULTS: Caregivers of children receiving the weight control intervention reported no statistically significant improvements in child total HRQoL, as compared to the control group, across the course of treatment (beta=0.178; 95% confidence interval, -0.681, 1.037; p=0.687). Additionally, no statistically significant improvements were found across other HRQoL domains. CONCLUSIONS: Future studies examining HRQoL outcomes in primary care may consider treatment dose as well as methodological factors, such as utilization of multiple informants and different measures, when designing studies and interpreting outcomes. PMID- 24152082 TI - Nonconsumptive predator-driven mortality causes natural selection on prey. AB - Predators frequently exert natural selection through differential consumption of their prey. However, predators may also cause prey mortality through nonconsumptive effects, which could cause selection if different prey phenotypes are differentially susceptible to this nonconsumptive mortality. Here we present an experimental test of this hypothesis, which reveals that nonconsumptive mortality imposed by predatory dragonflies causes selection on their damselfly prey favoring increased activity levels. These results are consistent with other studies of predator-driven selection, however, they reveal that consumption alone is not the only mechanism by which predators can exert selection on prey. Uncovering this mechanism also suggests that prey defensive traits may represent adaptations to not only avoid being consumed, but also for dealing with other sources of mortality caused by predators. Demonstrating selection through both consumptive and nonconsumptive predator mortality provides us with insight into the diverse effects of predators as an evolutionary force. PMID- 24152083 TI - Isolation, structure, and reactivity of an arylnickel(II) pivalate complex in catalytic C-H/C-O biaryl coupling. AB - We describe mechanistic studies of a C-H/C-O biaryl coupling of 1,3-azoles and aryl pivalates catalyzed by Ni(cod)2/dcype. This study not only supports a catalytic cycle consisting of C-O oxidative addition, C-H nickelation, and reductive elimination but also provides insight into the dramatic ligand effect in C-H/C-O coupling. We have achieved the first synthesis, isolation and structure elucidation of an arylnickel(II) pivalate, which is an intermediate in the catalytic cycle after oxidative addition of a C-O bond. Furthermore, kinetic studies and kinetic isotope effect investigations reveal that the C-H nickelation is the turnover-limiting step in the catalytic cycle. PMID- 24152085 TI - Shell structure of natural rubber particles: evidence of chemical stratification by electrokinetics and cryo-TEM. AB - The interfacial structure of natural rubber (NR) colloids is investigated by means of cryogenic transmission electron microscopy (cryo-TEM) and electrokinetics over a broad range of KNO3 electrolyte concentrations (4-300 mM) and pH values (1-8). The asymptotic plateau value reached by NR electrophoretic mobility (MU) in the thin double layer limit supports the presence of a soft (ion and water-permeable) polyelectrolytic type of layer located at the periphery of the NR particles. This property is confirmed by the analysis of the electron density profile obtained from cryo-TEM that evidences a ~2-4 nm thick corona surrounding the NR polyisoprene core. The dependence of MU on pH and salt concentration is further marked by a dramatic decrease of the point of zero electrophoretic mobility (PZM) from 3.6 to 0.8 with increasing electrolyte concentration in the range 4-300 mM. Using a recent theory for electrohydrodynamics of soft multilayered particles, this "anomalous" dependence of the PZM on electrolyte concentration is shown to be consistent with a radial organization of anionic and cationic groups across the peripheral NR structure. The NR electrokinetic response in the pH range 1-8 is indeed found to be equivalent to that of particles surrounded by a positively charged ~3.5 nm thick layer (mean dissociation pK ~ 4.2) supporting a thin and negatively charged outermost layer (0.6 nm in thickness, pK ~ 0.7). Altogether, the strong dependence of the PZM on electrolyte concentration suggests that the electrostatic properties of the outer peripheral region of the NR shell are mediated by lipidic residues protruding from a shell containing a significant amount of protein-like charges. This proposed NR shell interfacial structure questions previously reported NR representations according to which the shell consists of either a fully mixed lipid-protein layer, or a layer of phospholipids residing exclusively beneath an outer proteic film. PMID- 24152084 TI - Rab6 dependent post-Golgi trafficking of HSV1 envelope proteins to sites of virus envelopment. AB - Herpes simplex virus 1 (HSV1) is an enveloped virus that uses undefined transport carriers for trafficking of its glycoproteins to envelopment sites. Screening of an siRNA library against 60 Rab GTPases revealed Rab6 as the principal Rab involved in HSV1 infection, with its depletion preventing Golgi-to-plasma membrane transport of HSV1 glycoproteins in a pathway used by several integral membrane proteins but not the luminal secreted protein Gaussia luciferase. Knockdown of Rab6 reduced virus yield to 1% and inhibited capsid envelopment, revealing glycoprotein exocytosis as a prerequisite for morphogenesis. Rab6 dependent virus production did not require the effectors myosin-II, bicaudal-D, dynactin-1 or rabkinesin-6, but was facilitated by ERC1, a factor involved in linking microtubules to the cell cortex. Tubulation and exocytosis of Rab6 positive, glycoprotein-containing membranes from the Golgi was substantially augmented by infection, resulting in enhanced and targeted delivery to cell tips. This reveals HSV1 morphogenesis as one of the first biological processes shown to be dependent on the exocytic activity of Rab6. PMID- 24152086 TI - Pharmacokinetics and pharmacodynamics of intravenous and inhaled fluticasone furoate in healthy Caucasian and East Asian subjects. AB - AIM: The aim of the study was to evaluate the pharmacokinetics (PK) of inhaled and intravenous (i.v.) fluticasone furoate (FF) in healthy Caucasian, Chinese, Japanese and Korean subjects. METHOD: This was an open label, randomized, two way crossover study in healthy Caucasian, Chinese, Japanese and Korean subjects (n = 20 per group). Inhaled FF (200 MUg for 7 days, then 800 MUg for 7 days from a dry powder inhaler [DPI]) was administered in one treatment period and i.v.FF (250 MUg infusion) in the other. FF PK and serum cortisol (inhaled 200 MUg only) were compared between the ethnic groups using analysis of variance. P450 CYP3A4 activity and safety were also assessed. RESULTS: Ethnic differences in i.v. FF PK were accounted for by body weight differences. CYP3A4 activity was similar across the groups. Higher FF systemic exposure was seen following inhaled dosing in Chinese, Japanese and Korean subjects compared with Caucasian subjects. Absolute bioavailability was greater (36%-55%) in all East Asian groups than for Caucasian subjects following inhaled FF 800 MUg. Deconvolution analysis suggested inhaled FF resided in the lung of East Asian subjects longer than for Caucasians (time for 90% to be absorbed [t90]: 29.1-30.8 h vs. 21.4 h). In vitro simulation method predicted comparable delivered lung dose across ethnic groups. Serum cortisol weighted mean was similar between Caucasians and Chinese or Koreans, while in Japanese was on average 22% lower than in Caucasians. All FF treatments were safe and well tolerated. CONCLUSION: Modestly higher (<50%) FF systemic exposure seen in East Asian subjects following inhaled dosing was not associated with a clinically significant effect on serum cortisol, suggesting that a clinical dose adjustment in East Asian subjects is not required. PMID- 24152087 TI - Performance in working memory and attentional control is associated with the rs2180619 SNP in the CNR1 gene. AB - Individual differences in cognitive performance are partly dependent, on genetic polymporhisms. One of the single-nucleotide polymorphisms (SNP) of the CNR1 gene, which codes for cannabinoid receptor 1 (CB1R), is the rs2180619, located in a regulatory region of this gene (6q14-q15). The alleles of the rs2180619 are A > G; the G allele has been associated with addiction and high levels of anxiety (when the G allele interacts with the SS genotype of the 5-HTTLPR gene). However, GG genotype is observed also in healthy subjects. Considering G allele as risk for 'psychopathological conditions', it is possible that GG healthy subjects do not be addicted or anxious, but would have reduced performance, compared to AA subjects, in attentional control and working memory processing. One hundred and sixty-four healthy young Mexican-Mestizo subjects (100 women and 64, men; mean age: 22.86 years, SD=2.72) participated in this study, solving a task where attentional control and working memory were required. GG subjects, compared to AA subjects showed: (1) a general lower performance in the task (P = 0.02); (2) lower performance only when a high load of information was held in working memory (P = 0.02); and (3) a higher vulnerability to distractors (P = 0.03). Our results suggest that, although the performance of GG subjects was at normal levels, a lower efficiency of the endocannabinoid system, probably due to a lowered expression of CB1R, produced a reduction in the performance of these subjects when attentional control and working memory processing is challenged. PMID- 24152088 TI - What tissue does circumferential PV Isolation actually modulate? PMID- 24152089 TI - Enhanced threat detection in experienced riot police officers: cognitive evidence from the face-in-the-crowd effect. AB - We explored how varying levels of professional expertise in hostile crowd management could enhance threat detection capabilities as assessed by the face in the crowd paradigm. Trainee police officers and more experienced police officers specialized in, and having extensive experience with, riot control, were compared with participants with no experience in hostile crowd management on their search times and accuracy levels in detecting angry and happy face targets against a display of emotional and neutral distractor faces. The experienced officers relative to their trainee counterparts and nonpolice controls showed enhanced detection for threatening faces in both types of display along with a greater degree of inhibitory control over angry face distractors. These findings help to reinforce the ecological validity of the face in the crowd paradigm and provide a new theoretical link for the role of individual differences on the attentional processing of socially relevant stimuli. PMID- 24152090 TI - Enantioselective synthesis of cyclohepta[b]indoles: gram-scale synthesis of (S) SIRT1-inhibitor IV. AB - An enantioselective gram-scale synthesis of one of the most potent SIRT1 inhibitors has been accomplished by an unprecedented domino reaction sequence establishing the cyclohepta[b]indole core. This method was developed for application in natural product synthesis of a variety of indole alkaloids. PMID- 24152091 TI - First-episode types in bipolar disorder: predictive associations with later illness. AB - OBJECTIVE: Characteristics of initial illness in bipolar disorder (BD) may predict later morbidity. METHOD: We reviewed computerized clinical records and life charts of DSM-IV-TR BD-I or BD-II patients at affiliated mood-disorder centers to ascertain relationships of initial major illnesses to later morbidity and other clinical characteristics. RESULTS: Adult BD patient-subjects (N=1081; 59.8% BD-I; 58.1% women; 43% ever hospitalized) were followed 15.7+/-12.8 years after onsets ranking: depression (59%)>mania (13%)>psychosis (8.0%)>=anxiety (7.6%)>=hypomania (6.7%)>mixed states (5.5%). Onset types differed in clinical characteristics and strongly predicted later morbidity. By initial episode types, total time-ill ranked: mania>=hypomania>=mixed states>=psychosis>depression>anxiety. Depression was most prevalent long-term, overall; its ratio to mania-like illness (D/M, by per cent-time-ill) ranked by onset type: anxiety (4.75)>depression (3.27)>mixed states (1.39)>others (all<1.00). The MDI (mania or hypomania-depression-euthymia interval) course pattern was most common (34.4%) and associated with psychotic or manic onset; the depression before mania (DMI) pattern (25.0%) most often followed anxiety (38.8%), depression (30.8%), or mixed onsets (13.3%); both were predicted by initial mania depression sequences. CONCLUSION: First-lifetime illnesses and cycles predicted later morbidity patterns among BD patients, indicating value of early morbidity for prognosis and long-term planning. PMID- 24152092 TI - Hepatoprotection of noni juice against chronic alcohol consumption: lipid homeostasis, antioxidation, alcohol clearance, and anti-inflammation. AB - Chronic alcohol consumption leads to steatohepatitis and cirrhosis. Naturally fermented noni juice (NJ) contains polyphenols, polysaccharides, and some trace minerals. This study explored protective effects of NJ against chronic alcohol consumption. Mice were assigned randomly to one of the following groups: (1) control, control liquid diet and distilled water; (2) alcohol, alcohol liquid diet and distilled water; (3) Alc+NJ_1X, alcohol liquid diet and 5 mL NJ/kg BW; (4) Alc+NJ_2X, alcohol liquid diet and 10 mL NJ/kg BW; (5) Alc+NJ_3X, alcohol and 15 mL NJ/kg BW for 4 weeks. NJ decreased (p < 0.05) serum AST, ALT, and alcohol levels and liver lipids, as well as increased (p < 0.05) daily fecal lipid outputs in alcohol-diet fed mice. NJ supplementation not only down-regulated (p < 0.05) lipogenesis but also up-regulated (p < 0.05) fatty acid beta-oxidation in livers of alcohol-diet fed mice. NJ also accelerated alcohol clearance via increased (p < 0.05) hepatic ADH and ALDH activities. NJ increased (p < 0.05) hepatic TEAC and GSH levels but decreased (p < 0.05) TBARS value and TLR2/4, P38, ERK 1/2, NFkappaB P65, iNOS, COX-2, TNF-alpha, and IL-1beta expressions in alcohol-diet fed mice. NJ promotes hepatoprotection against alcohol-induced injury due to regulations of lipid homeostasis, antioxidant status, alcohol metabolism, and anti-inflammatory responses. PMID- 24152094 TI - Nanoscale resistive switching Schottky contacts on self-assembled Pt nanodots on SrTiO(3). AB - A nanoscale Schottky diode using Pt nanodisks on a Nb-doped SrTiO3 (Nb:STO) single crystal was fabricated, and resistive switching (RS) was demonstrated with conductive atomic force microscopy at ultrahigh vacuum. Pt disks with diameters on the order of 10 nm were formed using colloidal self-assembled patterns of silica nanospheres, followed by evaporation of the Pt layers on the Nb:STO single crystal. Here we show that the reproducible bipolar RS behavior of the nanoscale Pt/Nb:STO Schottky junction was achieved by utilizing local current-voltage spectroscopy. The conductance images, obtained simultaneously with topographic images, show the homogeneous current distribution of selected triangular-shaped Pt nanodisks during repetitive resistive switching between the high-resistance state (HRS) and low-resistance state (LRS). The endurance characteristics of the Pt/Nb:STO junction exhibit reliable switching behavior. These results suggest that the rectifying and resistive Pt/Nb:STO junction can be scaled down to the 10 nm range and their position can be controlled. PMID- 24152093 TI - OH-initiated heterogeneous oxidation of cholestane: a model system for understanding the photochemical aging of cyclic alkane aerosols. AB - Aerosols containing aliphatic hydrocarbons play a substantial role in the urban atmosphere. Cyclic alkanes constitute a large fraction of aliphatic hydrocarbon emissions originating from incomplete combustion of diesel fuel and motor oil. In the present study, cholestane (C27H48) is used as a model system to examine the OH-initiated heterogeneous oxidation pathways of cyclic alkanes in a photochemical flow tube reactor. Oxidation products are collected on filters and analyzed by a novel soft ionization two-dimensional gas chromatography/mass spectrometry technique. The analysis reveals that the first-generation functionalization products (cholestanones, cholestanals, and cholestanols) are the dominant reaction products that account for up to 70% by mass of the total speciated compounds. The ratio of first-generation carbonyls to alcohols is near unity at every oxidation level. Among the cholestanones/cholestanals, 55% are found to have the carbonyl group on the rings of the androstane skeleton, while 74% of cholestanols have the hydroxyl group on the rings. Particle-phase oxidation products with carbon numbers less than 27 (i.e., "fragmentation products") and higher-generation functionalization products are much less abundant. Carbon bond cleavage was found to occur only on the side chain. Tertiary-carbon alkoxy radicals are suggested to play an important role in governing both the distribution of functionalization products (via alkoxy radical isomerization and reaction with oxygen) and the fragmentation products (via alkoxy radical decomposition). These results provide new insights into the oxidation mechanism of cyclic alkanes. PMID- 24152095 TI - Templated self-assembly and local doping of molecules on epitaxial hexagonal boron nitride. AB - Using low-temperature scanning tunneling microscopy, we show that monolayer hexagonal boron nitride (h-BN) on Ir(111) acts as ultrathin insulating layer for organic molecules, while simultaneously templating their self-assembly. Tunneling spectroscopy experiments on cobalt phthalocyanine (CoPC) reveal narrow molecular resonances and indicate that the charge state of CoPC is periodically modulated by the h-BN moire superstructure. Molecules in the second layer show site selective adsorption behavior, allowing the synthesis of molecular dimers that are spatially ordered and inaccessible by usual chemical means. PMID- 24152096 TI - Resistant chronic myeloid leukemia beyond tyrosine-kinase inhibitor therapy: which role for omacetaxine? AB - The therapeutic armamentarium of chronic myeloid leukemia (CML) has been considerably improved after the introduction of first- and second-generation tyrosine-kinase inhibitors (TKIs). Accordingly, the natural history of the diseases has changed, and patients in complete molecular response now have the same life expectancy of their healthy coetaneous. Notwithstanding these results, ~ 20 - 30% of patients do not respond optimally to TKIs therapy, and most of these patients are potential candidates to progress toward the accelerated or blastic phase of the disease. Unfortunately, patients who become resistant to both first- and second-generation TKIs develop BCR-ABL kinase domain mutations, against which TKIs have extremely low cross-activity. In particular, none of the TKIs, with the exception of ponatinib, has significant activity against T315 mutation, which is estimated to be present in ~ 15 - 20% of patients carrying BCR ABL mutations. The use of omacetaxine mepesuccinate/homoharringtonine for the treatment of TKI-resistant CML patients regained interest due to its mechanism of action independent of binding to the ATP-binding pocket. Therefore, the activity of this compound is independent from the presence of BCR-ABL1 mutations, which makes it an attractive option for the treatment of CML patients after TKI failure. PMID- 24152097 TI - Quantifying groundwater's role in delaying improvements to Chesapeake Bay water quality. AB - A study has been undertaken to determine the time required for the effects of nitrogen-reducing best management practices (BMPs) implemented at the land surface to reach the Chesapeake Bay via groundwater transport to streams. To accomplish this, a nitrogen mass-balance regression (NMBR) model was developed and applied to seven watersheds on the Delmarva Peninsula. The model included the distribution of groundwater return times obtained from a regional groundwater flow (GWF) model, the history of nitrogen application at the land surface over the last century, and parameters that account for denitrification. The model was (1) able to reproduce nitrate concentrations in streams and wells over time, including a recent decline in the rate at which concentrations have been increasing, and (2) used to forecast future nitrogen delivery from the Delmarva Peninsula to the Bay given different scenarios of nitrogen load reduction to the water table. The relatively deep porous aquifers of the Delmarva yield longer groundwater return times than those reported earlier for western parts of the Bay watershed. Accordingly, several decades will be required to see the full effects of current and future BMPs. The magnitude of this time lag is critical information for Chesapeake Bay watershed managers and stakeholders. PMID- 24152098 TI - Isolation, identification, and media optimization of high-level cellulase production by Bacillus sp. BCCS A3, in a fermentation system using response surface methodology. AB - Cellulases are important glycosyl hydrolase enzymes, which break down cellulose to beta-glucose. They have been used widely in biotechnological processing such as bioethanol production. In this work we studied maximizing cellulase production by Bacillus sp. BCCS A3 using response surface methodology (RSM). A good result was attained with these conditions (% w/v): tryptone 0.1, Na2PO4 0.25, (NH4)2SO4 0.2, MgSO4 . 7H2O 0.005, CaCl2 0.005, KH2PO4 0.1, NaCl 0.1, sodium carboxymethylcellulose (CMC) 0.75, and pH 9. The cellulase activity in optimized medium was 49.80 U/ml. Moreover, high level of enzyme production was obtained by using fermentor system (50.30 U/ml). Thus, according to the obtained results, this statistical method provided quick identification and integration of key medium details for Bacillus sp. BCCS A3, leading to more cellulase production. PMID- 24152099 TI - Statistical optimization of alkaline protease production from brackish environment Bacillus sp. SKK11 by SSF using horse gram husk. AB - Protease production by Bacillus sp. SKK11 isolated from brackish environment was studied by solid-state fermentation with horse gram husk. Response surface methodology-based Box-Behnken design (BBD) was used to optimize the variables such as pH, maltose, and MgSO4. The BBD design analysis showed a reasonable adjustment of the quadratic model with the experimental data. Statistics-based contour and three-dimensional (3-D) plots were generated to evaluate the changes in the response surface and to understand the relationship between the enzyme yield and the culture conditions. The maximum yield of the enzyme was observed at pH 9.0. PMID- 24152100 TI - Development of genetically encoded fluorescent protein constructs of hyperthermophilic maltose-binding protein. AB - Circularly permuted green fluorescent protein (cGFP) was inserted into the hyperthermophilic maltose binding protein at two different locations. cGFP was inserted between amino acid residues 206 and 207, or fused to the N-terminal of maltose binding protein from Thermotoga maritima. The cloned DNA constructs were expressed in Escherichia coli cells, and purified by metal chelate affinity chromatography. Conformational change upon ligand binding was monitored by the increase in fluorescence intensity. Both of the fusion proteins developed significant fluorescence change at 0.5 mM maltose concentration, whereas their maltose binding affinities and optimum incubation times were different. Fluorescent biosensors based on mesophilic maltose binding proteins have been described in the literature, but there is a growing interest in biosensors based on thermostable proteins. Therefore, the developed protein constructs could be models for thermophilic protein-based fluorescent biosensors. PMID- 24152101 TI - Production of naringinase from a new soil isolate, Bacillus methylotrophicus: isolation, optimization and scale-up studies. AB - Five strains of naringin-degrading bacteria were isolated and found to be positive for extracellular naringinase activity. The one that showed highest activity in the selective medium was identified by 16S rRNA analysis as Bacillus methylotrophicus . The best combination of carbon-nitrogen source was determined by employing two-level full factorial analyses, comprising 24 experiments in shake flasks. Sucrose-yeast extract showed significant increase in naringinase activity (7.46 U/L) compared to the basal medium. Naringinase production was found to be inducible and naringin was found to be the best inducer among naringin, naringenin, hesperidin, and L-rhamnose. Inoculum size of 2% (v/v) and age of 48 hr favored naringinase and biomass production. Highest naringinase activity of 8 U/L was observed at the initial medium pH of 6. Response surface modeling was applied based on central composite design to determine the effects of three independent variables (sucrose, yeast extract, and naringin) and their mutual interactions. In total, 20 experiments were conducted and a statistical model was developed, which predicted naringinase production of 10.61 U/L. Subsequently, verification experiments were conducted and validity of the model was verified. Bioreactor studies conducted with the optimized medium showed an enzyme production of 12.05 U/L within 34 hr of fermentation. PMID- 24152102 TI - Influence of washing conditions on effective components of prothrombin complex concentrates. AB - In order to increase the yield of prothrombin complex concentrates (PCCs) and to reduce their associated thrombotic risks, the influence of washing conditions on the yield, purity, and balance of coagulation factors (FII, FVII, FIX, and FX), and inhibitor proteins (PC, PS, PZ, and AT [antithrombin]) in PCCs was investigated by orthogonal testing, in which three variables (sodium citrate, NaCl, and pH) and their three levels were selected. It was found that AT yield and purity were extraordinarily low, and at lower NaCl content, the general yield, purity, and balance were higher, lower, and better, respectively; however, the results became contrary at higher NaCl. Moreover, within the investigated levels, NaCl was the first determinant for the yield except AT and the purity except FVII, PC, PS, and AT. Sodium citrate was the first determinant for AT yield and FVII, PS, and AT purity. The yield except FII, PS, and AT decreased and the purity except PC increased with increase of sodium citrate content. Just for PC purity, pH was the first determinant. The effect with pH fluctuation on the yield and purity was characteristically unobvious. The outcome undoubtedly supplies the guidance to further improve PCCs. PMID- 24152103 TI - Production of human tissue plasminogen activator (tPA) in Cucumis sativus. AB - Tissue plasminogen activator (tPA) as a serine protease with 72 kD molecular mass and 527 amino acids plays an important role in the fibrinolytic system and the dissolution of fibrin clots in human body. The collective production of this drug in plants such as cucumber, one of the most important vegetables in the world, could reduce its production costs. In this study, after scrutiny of the appropriate regeneration of cucumber plant (Isfahan variety) on MS medium with naphthalene acetic acid hormone (NAA; 0/1 mg L-1) and benzyl amino purine hormone (BAP; 3 mg L-1) hormones, the cloned human tPA gene under the CaMV 35S promoter and NOS terminator into pBI121 plasmid was transferred into cotyledon explants by Agrobacterium tumefaciens strain LBA4404. Subsequent to the regeneration of inoculated explants on the selective medium, the persistence of tPA gene in recombinant plants was confirmed by polymerase chain reaction (PCR) with specific primers. To evaluate the tPA gene expression in transgenic plants, RNA was extracted and the tPA gene transcription was confirmed by reverse-transcription (RT) PCR. Followed the extraction of protein from the leaves of transgenic plants, the presence of tPA protein was confirmed by dot blot and sodium dodecyl sulfate (SDS) polyacrylamide gel electrophoresis (PAGE) analysis in order to survey the production of recombinant tPA protein. The enzyme-linked immunosorbent assay (ELISA) test was used for recombinant tPA protein level in transgenic cucumber plants. It was counted between 0.8 and 1%, and based on this, it was concluded that the presence of three expressions of regulatory factors (CaMV 35S, Kozak, NOS) and KDEL signal in the construct caused the increase of the tPA gene expression in cucumber plants. PMID- 24152104 TI - Purification and characterization of a thermostable extracellular phytase from Bacillus licheniformis PFBL-03. AB - Extracellular phytase from Bacillus licheniformis PFBL-03 was purified in three steps by using ammonium sulfate precipitation, ion-exchange chromatography on a DEAE Sephadex A-50 column, and gel filtration chromatography on Sephadex G-100. The single protein band on sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE) suggested that the enzyme was homogeneous. The molecular mass determined from SDS-PAGE was 36 kD. The enzyme yield was 10% while the purification fold was 39. The purified phytase exhibited optimum activity at 55 degrees C and was able to retain 55% of its original activity after 60 min of incubation at 80 degrees C. The purified enzyme had optimum pH of 6.0 and was stable over a pH range of 4.0 to 7.5. The kinetic parameters K(m) and V(max) of the purified phytase for sodium phytate were 4.7 mM and 49.01 umol/min. The activity of the enzyme was enhanced in the presence of Ca2+ but completely inhibited by Fe2+, Mn2+, and Cu2+. The exhibited characteristics of the purified phytase from Bacillus licheniformis PFBL-03 show that the enzyme has potential for applications in the animal feed industry. PMID- 24152105 TI - Optimization of affinity digestion for the isolation of cellulosomes from Clostridium thermocellum. AB - The affinity digestion process for cellulase purification consisting of binding to amorphous cellulose, and amorphous cellulose hydrolysis in the presence of dialysis (Morag et al., 1991), was optimized to obtain high activity recoveries and consistent protein recoveries in the isolation of Clostridium thermocellum cellulase. Experiments were conducted using crude supernatant prepared from C. thermocellum grown on either Avicel or cellobiose. While no difference was observed between Avicel-grown or cellobiose-grown cellulase in the adsorption step, differences were observed during the hydrolysis step. The optimal amorphous cellulose loading was found to be 3 mg amorphous cellulose per milligram supernatant protein. At this loading, 90-100% of activity in the crude supernatant was adsorbed. Twenty-four-hour incubation with the amorphous cellulose during the adsorption stage was found to result in maximal and stable adsorption of activity to the substrate. By fitting the adsorption data to the Langmuir model, an adsorption constant of 410 L/g and a binding capacity of 0.249 g cellulase/g cellulose were obtained. The optimal length of time for hydrolysis was found to be 3 hr for cellulase purified from Avicel cultures and 4 hr for cellulase purified from cellobiose cultures. These loadings and incubation times allowed for more than 85% activity recovery. PMID- 24152107 TI - Two new coumarins from the seeds of Solanum indicum. AB - Two new coumarins, (E)-2-(4-hydroxy-3-methoxybenzylidene)-5-methoxy-2H [1,4]dioxino[2,3-h]chromene-3,9-dione (indicumin E, 1) and 7-hydroxy-6,8 dimethoxy-3-(4'-hydroxy-3'-methoxyphenyl)-coumarin (2), together with two known coumarins isofraxidin (3) and fraxetin (4), were isolated from the Solanum indicum seeds. Their structures were established on the basis of 1D and 2D spectroscopic data. Compound 1 was the rarest coumarinolignoid known to date. PMID- 24152106 TI - Natural-like replication of an unnatural base pair for the expansion of the genetic alphabet and biotechnology applications. AB - We synthesized a panel of unnatural base pairs whose pairing depends on hydrophobic and packing forces and identify dTPT3-dNaM, which is PCR amplified with a natural base pair-like efficiency and fidelity. In addition, the dTPT3 scaffold is uniquely tolerant of attaching a propargyl amine linker, resulting in the dTPT3(PA)-dNaM pair, which is amplified only slightly less well. The identification of dTPT3 represents significant progress toward developing an unnatural base pair for the in vivo expansion of an organism's genetic alphabet and for a variety of in vitro biotechnology applications where it is used to site specifically label amplified DNA, and it also demonstrates for the first time that hydrophobic and packing forces are sufficient to mediate natural-like replication. PMID- 24152108 TI - Effect of alcohol chain length on the enzymatic resolution of racemic mandelic acid and kinetic study. AB - Asymmetric esterification of racemic mandelic acid (MA) was conducted in 1,2 dichloroethane using lipase Novozym 435 as catalyst. Different alcohols were screened for esterification to achieve high conversion and enantioselectivity. The results show that ethanol is the best alcohol substrate among tested alcohols, and long-chain alcohols show lower enantioselectivities. The effect of substrate concentrations on esterification with ethanol was studied, and the result indicates an alcohol inhibition. To examine the mechanism of the alcohol chain length effect, the ping-pong bi-bi mechanism with competitive alcohol inhibition was applied to build a model. By comparing the kinetic parameters of methanol, ethanol, butanol, heptanol, and octanol, it was found that both the Michaelis constant and the inhibition constant of alcohol increase with the increase in alcohol chain length, indicating that the balance between nucleophilicity and the inhibition effect is the possible reason for the highest conversion and enantioselectivity as shown by ethanol. PMID- 24152109 TI - Human serum transferrin: is there a link among autism, high oxalate levels, and iron deficiency anemia? AB - It has been previously suggested that large amounts of oxalate in plasma could play a role in autism by binding to the bilobal iron transport protein transferrin (hTF), thereby interfering with iron metabolism by inhibiting the delivery of iron to cells. By examining the effect of the substitution of oxalate for the physiologically utilized synergistic carbonate anion in each lobe of hTF, we sought to provide a molecular basis for or against such a role. Our work clearly shows both qualitatively (6 M urea gels) and quantitatively (kinetic analysis by stopped-flow spectrofluorimetry) that the presence of oxalate in place of carbonate in each binding site of hTF does indeed greatly interfere with the removal of iron from each lobe (in the absence and presence of the specific hTF receptor). However, we also clearly demonstrate that once the iron is bound within each lobe of hTF, neither anion can displace the other. Additionally, as verified by urea gels and electrospray mass spectrometry, formation of completely homogeneous hTF-anion complexes requires that all iron must first be removed and hTF then reloaded with iron in the presence of either carbonate or oxalate. Significantly, experiments described here show that carbonate is the preferred binding partner; i.e., even if an equal amount of each anion is available during the iron loading process, the hTF-carbonate complex is formed. PMID- 24152110 TI - Cell-type-dependent action potentials and voltage-gated currents in mouse fungiform taste buds. AB - Taste receptor cells fire action potentials in response to taste substances to trigger non-exocytotic neurotransmitter release in type II cells and exocytotic release in type III cells. We investigated possible differences between these action potentials fired by mouse taste receptor cells using in situ whole-cell recordings, and subsequently we identified their cell types immunologically with cell-type markers, an IP3 receptor (IP3 R3) for type II cells and a SNARE protein (SNAP-25) for type III cells. Cells not immunoreactive to these antibodies were examined as non-IRCs. Here, we show that type II cells and type III cells fire action potentials using different ionic mechanisms, and that non-IRCs also fire action potentials with either of the ionic mechanisms. The width of action potentials was significantly narrower and their afterhyperpolarization was deeper in type III cells than in type II cells. Na(+) current density was similar in type II cells and type III cells, but it was significantly smaller in non-IRCs than in the others. Although outwardly rectifying current density was similar between type II cells and type III cells, tetraethylammonium (TEA) preferentially suppressed the density in type III cells and the majority of non-IRCs. Our mathematical model revealed that the shape of action potentials depended on the ratio of TEA-sensitive current density and TEA-insensitive current one. The action potentials of type II cells and type III cells under physiological conditions are discussed. PMID- 24152111 TI - Foundational issues in risk assessment and risk management. AB - This is a perspective article on foundational issues in risk assessment and management. The aim is to discuss the needs, obstacles, and challenges for the establishment of a renewed, strong scientific foundation for risk assessment and risk management suited for the current and future technological challenges. The focus is on (i) reviewing and discussing the present situation and (ii) identifying how to best proceed in the future, to develop the risk discipline in the directions needed. The article provides some reflections on the interpretation and understanding of the concept of "foundations of risk assessment and risk management" and the challenges therein. One main recommendation is that different arenas and moments for discussion are needed to specifically address foundational issues in a way that embraces the many disciplinary communities involved (from social scientists to engineers, from behavioral scientists to statisticians, from health physicists to lawyers, etc.). One such opportunity is sought in the constitution of a novel specialty group of the Society of Risk Analysis. PMID- 24152113 TI - Ultrathin polymer films for transparent electrode applications prepared by controlled nucleation. AB - The vacuum vapor phase polymerization (VPP) technique is capable of producing conducting polymer films with conductivities up to 3400 S cm(-1). However, the method is not able to produce robust nano-thin films as required for transparent conducting electrode (TCE) applications. We show that with the addition of aprotic solvents or chelating agents to the oxidant mixture, it is possible to control the polymerization rate, and nucleation, in the VPP process. This provides the opportunity of altering the grain size and depositing conducting polymer films with a thickness of 16 to 200 nm with resulting optical transmission within the range 50-98% that are robust enough to endure the post polymerization processing steps. The figure of merit (FoM), which is used to quantify a film's suitability for TCE applications, results in values from 12 to 25. This result indicates that the nano-films outperform most of the previously reported graphene films and approaches the accepted industry standard for TCE applications. PMID- 24152114 TI - Rhodium-catalyzed enantioselective hydrogenation of beta-acylamino nitroolefins: a new approach to chiral beta-amino nitroalkanes. AB - An efficient and highly enantioselective catalytic asymmetric hydrogenation of beta-acylamino nitroolefins has been realized by using Rh-TangPhos as the catalyst. A series of beta-amino nitroalkane products, which are versatile intermediates in organic synthesis, were obtained with high yield and good enantioselectivity. PMID- 24152112 TI - Introgression in the Drosophila subobscura--D. Madeirensis sister species: evidence of gene flow in nuclear genes despite mitochondrial differentiation. AB - Species hybridization, and thus the potential for gene flow, was once viewed as reproductive mistake. However, recent analysis based on large datasets and newly developed models suggest that gene exchange is not as rare as originally suspected. To investigate the history and speciation of the closely related species Drosophila subobscura, D. madeirensis, and D. guanche, we obtained polymorphism and divergence data for 26 regions throughout the genome, including the Y chromosome and mitochondrial DNA. We found that the D. subobscura X/autosome ratio of silent nucleotide diversity is significantly smaller than the 0.75 expected under neutrality. This pattern, if held genomewide, may reflect a faster accumulation of beneficial mutations on the X chromosome than on autosomes. We also detected evidence of gene flow in autosomal regions, while sex chromosomes remain distinct. This is consistent with the large X effect on hybrid male sterility seen in this system and the presence of two X chromosome inversions fixed between species. Overall, our data conform to chromosomal speciation models in which rearrangements are proposed to serve as gene flow barriers. Contrary to other observations in Drosophila, the mitochondrial genome appears resilient to gene flow in the presence of nuclear exchange. PMID- 24152115 TI - First comparative evaluation of a new leukapheresis technology in non-cytokine stimulated donors. AB - BACKGROUND AND OBJECTIVES: Leukapheresis is an important source for mononuclear cells (MNCs) used in adoptive immunotherapies. Differences in the apheresis technology concerning physical conditions during cell separation and the optical detection system can affect the product's cellular content. MATERIALS AND METHODS: In a paired analysis, twenty healthy non-cytokine-stimulated donors underwent MNC collection at the Spectra Optia (Terumo BCT, Lakewood, CO, USA) and the COM.TEC (Fresenius Kabi, Bad Homburg, Germany) device. In twelve donors, apheresis was additionally performed with the Amicus (Fenwal Inc., Lake Zurich, IL, USA). Donor response to leukapheresis and product composition was compared. RESULTS: Mean yields of CD14+ (CD3+) cells were 1.64+/-0.70x10(9) (2.36+/ 0.96*10(9)) in the Spectra Optia, 1.45+/-0.50*10(9) (3.03+/-1.04*10(9)) in the COM.TEC and 1.20+/-0.37*10(9) (2.80+/-1.00*10(9)) in the Amicus products, respectively. The Spectra Optia collected significantly more CD14+ monocytes than the Amicus and significantly less CD3+ T cells than the COM.TEC (P=0.002 and P=0.021). Apheresis products of the Spectra Optia showed the significantly lowest red blood cell yields while the Amicus generated products with the significantly lowest platelet contents. CONCLUSIONS: Leukaphereses with the three devices resulted in almost equal total MNC yields. MNC products of the Spectra Optia and the Amicus could be used in preference for the monocyte enrichment by the Elutra system and the leukapheresis procedures could be also favourably applied in patients with low platelet counts. The COM.TEC is more efficient in monocyte and T-cell collection with the disadvantage of high residual non-target cell content in the products. PMID- 24152116 TI - Differential clinical characteristics and prognosis of patients with longstanding persistent atrial fibrillation presenting with recurrent atrial tachycardia versus recurrent atrial fibrillation after first ablation. AB - BACKGROUND: It is unknown if baseline characteristics and prognosis of patients with longstanding persistent (defined as history greater than 1 year) atrial fibrillation (LS-AF) differ among those with either recurrent atrial tachycardia (R-AT) or recurrent AF (R-AF) after first ablation. METHODS: In 222 consecutive LS-AF patients treated for R-AT or R-AF after first ablation, activation and entrainment mapping was used to identify R-AT mechanism and to guide the following ablation, and the ablation endpoints for all patients included complete pulmonary vein isolation, bidirectional block of lines, and disappearance of complex fractionated atrial electrograms. RESULTS: There were 102 patients in the R-AF group. LS-AF patients with R-AT as compared to R-AF had shorter AF duration and recurrence interval, smaller left atrium size and left ventricular end diastolic diameter, and less mitral and aortic regurgitation before first ablation. During follow-up (17.7 +/- 4.0 months) after R-AT/R-AF ablation, 78 LS AF patients developed recurrent atrial tachyarrhythmia, with lower overall and recurrence as AF in R-AT versus R-AF groups. CONCLUSIONS: LS-AF patients who develop R-AT versus R-AF after first ablation have more favorable baseline characteristics and prognosis. PMID- 24152117 TI - Predictors of painkiller dependence among people with pain in the general population. AB - OBJECTIVES: Self-medication with painkillers is widespread and increasing, and evidence about influences on painkiller dependence is needed to inform efforts to prevent and treat problem painkiller use. DESIGN: Online questionnaire survey. PARTICIPANTS: People in the general population who had pain and used painkillers in the last month (N = 112). MEASUREMENTS: Pain frequency and intensity, use of over-the-counter and prescription painkillers, risk of substance abuse (Screener and Opioid Assessment for Patients with Pain [SOAPP] scale), depression, anxiety, stress, alexithymia, pain catastrophizing, pain anxiety, pain self-efficacy, pain acceptance, mindfulness, self-compassion, and painkiller dependence (Leeds Dependence Questionnaire). RESULTS: In multiple regression, the independent predictors of painkiller dependence were prescription painkiller use (beta 0.21), SOAPP score (beta 0.31), and pain acceptance (beta -0.29). Prescription painkiller use mediated the influence of pain intensity. Alexithymia, anxiety, and pain acceptance all moderated the influence of pain. CONCLUSIONS: The people most at risk of developing painkiller dependence are those who use prescription painkillers more frequently, who have a prior history of substance-related problems more generally, and who are less accepting of pain. Based on these findings, a preliminary model is presented with three types of influence on the development of painkiller dependence: 1) pain leading to painkiller use, 2) risk factors for substance-related problems irrespective of pain, and 3) psychological factors related to pain. The model could guide further research among the general population and high-risk groups, and acceptance-based interventions could be adapted and evaluated as methods to prevent and treat painkiller dependence. PMID- 24152118 TI - Conformational analysis of 1-chloro- and 1-bromo-2-propanol. AB - The conformational isomerism of 1-chloro- (1) and 1-bromo-2-propanol (2) was theoretically and spectroscopically (NMR) analyzed. Conformers with the X-C-C-O (X = Cl and Br) fragment in the gauche orientation were found to be strongly prevalent both in the gas phase and solution, as analyzed by means of coupling constants in the diastereotopic methylene hydrogens. The gauche effect was calculated to be due to hyperconjugation rather than intramolecular X...HO hydrogen bond, indicating the rule of the stereochemical control in compounds with motifs (halohydrins) widely found in pharmaceutical and agrochemical products and intermediates. PMID- 24152119 TI - From 1D chain to 3D network: a new family of inorganic-organic hybrid semiconductors MO3(L)(x) (M = Mo, W; L = organic linker) built on perovskite-like structure modules. AB - MO3 (M = Mo, W) or VI-VI binary compounds are important semiconducting oxides that show great promise for a variety of applications. In an effort to tune and enhance their properties in a systematic manner we have applied a designing strategy to deliberately introduce organic linker molecules in these perovskite like crystal lattices. This approach has led to a wealth of new hybrid structures built on one-dimensional (1D) and two-dimensional (2D) VI-VI modules. The hybrid semiconductors exhibit a number of greatly improved properties and new functionality, including broad band gap tunability, negative thermal expansion, largely reduced thermal conductivity, and significantly enhanced dielectric constant compared to their MO3 parent phases. PMID- 24152120 TI - Breeding return times and abundance in capture-recapture models. AB - For many long-lived animal species, individuals do not breed every year, and are often not accessible during non-breeding periods. Individuals exhibit site fidelity if they return to the same breeding colony or spawning ground when they breed. If capture and recapture is only possible at the breeding site, temporary emigration models are used to allow for only a subset of the animals being present in any given year. Most temporary emigration models require the use of the robust sampling design, and their focus is usually on probabilities of annual survival and of transition between breeding and non-breeding states. We use lake sturgeon (Acipenser fulvescens) data from a closed population where only a simple (one sample per year) sampling scheme is possible, and we also wish to estimate abundance as well as sex-specific survival and breeding return time probabilities. By adding return time parameters to the Schwarz-Arnason version of the Jolly-Seber model, we have developed a new likelihood-based model which yields plausible estimates of abundance, survival, transition and return time parameters. An important new finding from investigation of the model is the overestimation of abundance if a Jolly-Seber model is used when Markovian temporary emigration is present. PMID- 24152121 TI - The Vps35 D620N mutation linked to Parkinson's disease disrupts the cargo sorting function of retromer. AB - The retromer is a trimeric cargo-recognition protein complex composed of Vps26, Vps29 and Vps35 associated with protein trafficking within endosomes. Recently, a pathogenic point mutation within the Vps35 subunit (D620N) was linked to the manifestation of Parkinson's disease (PD). Here, we investigated details underlying the molecular mechanism by which the D620N mutation in Vps35 modulates retromer function, including examination of retromer's subcellular localization and its capacity to sort cargo. We show that expression of the PD-linked Vps35 D620N mutant redistributes retromer-positive endosomes to a perinuclear subcellular localization and that these endosomes are enlarged in both model cell lines and fibroblasts isolated from a PD patient. Vps35 D620N is correctly folded and binds Vps29 and Vps26A with the same affinity as wild-type Vps35. While PD linked point mutant Vps35 D620N interacts with the cation-independent mannose-6 phosphate receptor (CI-M6PR), a known retromer cargo, we find that its expression disrupts the trafficking of cathepsin D, a CI-M6PR ligand and protease responsible for degradation of alpha-synuclein, a causative agent of PD. In summary, we find that the expression of Vps35 D620N leads to endosomal alterations and trafficking defects that may partly explain its action in PD. PMID- 24152122 TI - Preclinical pharmacokinetic characterization of 2-(4-(4-(5-(2-phenyl-5 (trifluoromethyl)oxazole-4-carboxamido)-1H-benzo[d]imidazol-2 yl)phenyl)cyclohexyl) acetic acid, a novel DGAT-1 inhibitor. AB - 1. A novel diacylglyceride acyltransferase-1 (DGAT-1) inhibitor, 2-(4-(4-(5-(2 phenyl-5-(trifluoromethyl) oxazole-4-carboxamido)-1H-benzo[d]imidazol-2 yl)phenyl)cyclohexyl) acetic acid (KR-69232), was synthesized for a potential therapeutic use against several metabolic disorders, such as obesity, insulin resistance, and type II diabetes, characterized by excessive triglycerides (TGs) in the blood. 2. The half-lives against phase I metabolism were measured as 75.3 +/- 20.9 min and over 120 min in rat and human liver microsomes, respectively. In Caco-2 cell monolayers, extremely low permeability (<0.13 * 10-6cm/s) was seen in the absorptive direction, predicting limited intestinal absorption of KR-69232. This compound was highly bound to rat and human plasma proteins (>99.8%). 3. With the intravenous administration of KR-69232 in rats (1, 2, and 5 mg/kg), non linear kinetics were observed at the highest dose, with significantly higher systemic clearance, higher volume of distribution, and lower dose-normalized AUC. Following oral administration, it exhibited low bioavailability (<10%) and was absorbed slowly (T(max), 3.8-5.2 h) over the dose range. We also confirmed that considerable KR-69232 remained in the intestine at T(max), demonstrating its limited absorption into the systemic circulation. PMID- 24152123 TI - Mapping genetic modifiers of survival in a mouse model of Dravet syndrome. AB - Epilepsy is a common neurological disorder affecting approximately 1% of the population. Mutations in voltage-gated sodium channels are responsible for several monogenic epilepsy syndromes. More than 800 mutations in the voltage gated sodium channel SCN1A have been reported in patients with generalized epilepsy with febrile seizures plus and Dravet syndrome. Heterozygous loss-of function mutations in SCN1A result in Dravet syndrome, a severe infant-onset epileptic encephalopathy characterized by intractable seizures, developmental delays and increased mortality. A common feature of monogenic epilepsies is variable expressivity among individuals with the same mutation, suggesting that genetic modifiers may influence clinical severity. Mice with heterozygous deletion of Scn1a (Scn1a(+/-) ) model a number of Dravet syndrome features, including spontaneous seizures and premature lethality. Phenotype severity in Scn1a(+/-) mice is strongly dependent on strain background. On the 129S6/SvEvTac strain Scn1a(+/-) mice exhibit no overt phenotype, whereas on the (C57BL/6J * 129S6/SvEvTac)F1 strain Scn1a(+/-) mice exhibit spontaneous seizures and early lethality. To systematically identify loci that influence premature lethality in Scn1a(+/-) mice, we performed genome scans on reciprocal backcrosses. Quantitative trait locus mapping revealed modifier loci on mouse chromosomes 5, 7, 8 and 11. RNA-seq analysis of strain-dependent gene expression, regulation and coding sequence variation provided a list of potential functional candidate genes at each locus. Identification of modifier genes that influence survival in Scn1a(+/-) mice will improve our understanding of the pathophysiology of Dravet syndrome and may suggest novel therapeutic strategies for improved treatment of human patients. PMID- 24152125 TI - Current uses of radiation therapy in patients with primary CNS lymphoma. AB - High-dose methotrexate (HD-MTX)-based chemotherapy is the current first-line therapy for primary CNS lymphoma. Whole-brain radiotherapy (WBRT) plays an important role in the management of primary CNS lymphoma and is indicated in patients with contraindication to chemotherapy, in patients with unusual histologic subtypes as curative treatment, as complementary therapy for patients failing to achieve complete remission after systemic chemotherapy and as salvage therapy for refractory or relapsing patients when systemic chemotherapy is no longer advisable. The two major pitfalls in WBRT use are transitory efficacy and neurotoxicity with deterioration of quality of life. Accordingly, WBRT administration as consolidation therapy in complete remission patients after first-line chemotherapy is controversial. In the present review, indications of WBRT will be outlined with emphasis on consolidation therapy, treatment-related neurotoxicity and efforts aimed at reducing toxicity. PMID- 24152124 TI - Febuxostat for treating allopurinol-resistant hyperuricemia in patients with chronic kidney disease. AB - BACKGROUND: Availability of the novel xanthine oxidase inhibitor febuxostat, which has multiple excretion pathways, enables investigation of the significance of serum uric acid control on renal function in patients with chronic kidney disease (CKD). METHODS: This was an exploratory, retrospective, observational study conducted at a single Japanese center. Serum uric acid concentrations and serum creatinine levels in the 6 months before and after the start of febuxostat treatment were collected for CKD patients switched from allopurinol after failing to achieve serum uric acid concentrations <=6.0 mg/dL. RESULTS: Evaluable data were available for 60 patients, 67% of whom had advanced CKD (eGFR <30 mL/min/1.73 m2). Mean dose of febuxostat was 15.9 (+/- 8) mg/day. Mean serum uric acid concentration decreased from 8.4 (+/-1.4) mg/dL at baseline to 6.2 (+/-1.2) mg/dL at 6 months; 47.5% of patients achieved a level <=6.0 mg/dL. The change from baseline in eGFR was positive at all time points during febuxostat treatment and the increase of 2.3 (+/-5.6) mL/min/1.73 m2 at 6 months was significant (p = 0.0027). Whereas the eGFR slope was negative during allopurinol treatment, it became positive after the switch to febuxostat. The change in eGFR slope before and after febuxostat treatment was significant for all patients (p < 0.01), for male patients (p < 0.05), and for patients with a baseline eGFR of <15 mL/min/1.73 m2 (p < 0.05). CONCLUSIONS: In patients with CKD, febuxostat reduces serum uric acid concentrations effectively and may suppress the progressive decline in renal function. PMID- 24152126 TI - Enhancing human-like collagen accumulation by deleting the major glucose transporter ptsG in recombinant Escherichia coli BL21. AB - Collagen has been proven to be a valuable biomedical material for many medical applications. Human-like collagen (HLC) is a novel important biomedical material with diverse medical applications. In this work, recombinant Escherichia coli BL21 3.7 ?ptsG was constructed, the characters of ptsG mutant strain were analyzed, and real-time quantitative polymerase chain reaction (PCR) was applied to investigate the effect of ptsG gene deletion on the transcriptional level of the phosphotransferase system (PTS) genes responsible for glucose transport. The HLC production and cell growth ability were 1.33- and 1.24-fold higher than those of its parent strain in the fermentation medium, respectively, and 1.16- and 1.17 fold in the modified minimal medium individually. The acetate accumulation decreased by 42%-56% compared to its parent strain in the fermentation medium, and 70%-87% in the modified minimal medium. The results of RT-qPCR showed that the transcriptional level of crr, ptsH, ptsI, and blgF in ptsG mutant all decreased dramatically, which inferred a decrease in the glucose uptake rate, but the transcriptional level of FruB and manX increased slightly, which demonstrated the activation of fructose- and mannose-specific transport pathways in the ptsG mutant. This study demonstrates that ptsG deletion is an effective strategy to reduce acetate accumulation and increase biomass and HLC production. PMID- 24152127 TI - Surface composition/organization of ionic liquids with Au nanoparticles revealed by high-sensitivity low-energy ion scattering. AB - High-sensitivity low-energy ion scattering (HS-LEIS) analysis was used to elucidate the outermost layer of both functionalized and non-functionalized imidazolium ionic liquids (ILs). The IL outermost layer is composed of all atoms of both cations and anions. The HS-LEIS analyses also allow for quantitative measurement of the thickness of IL overlayers on Au nanoparticles prepared by sputter deposition, which was shown to be a monolayer of ions, as predicted by density functional theory calculations. PMID- 24152128 TI - Temporal variation favors the evolution of generalists in experimental populations of Drosophila melanogaster. AB - In variable environments, selection should favor generalists that maintain fitness across a range of conditions. However, costs of adaptation may generate fitness trade-offs and lead to some compromise between specialization and generalization that maximizes fitness. Here, we evaluate the evolution of specialization and generalization in 20 populations of Drosophila melanogaster experimentally evolved in constant and variable thermal environments for 3 years. We developed genotypes from each population at two temperatures after which we measured fecundity across eight temperatures. We predicted that constant environments would select for thermal specialists and that variable environments would select for thermal generalists. Contrary to our predictions, specialists and generalists did not evolve in constant and spatially variable environments, respectively. However, temporal variation produced a type of generalist that has rarely been considered by theoretical models of developmental plasticity. Specifically, genotypes from the temporally variable selective environment were more fecund across all temperatures than were genotypes from other environments. These patterns suggest certain allelic effects and should inspire new directions for modeling adaptation to fluctuating environments. PMID- 24152129 TI - Pd(II)-catalyzed one-pot, three-step route for the synthesis of unsymmetrical acridines. AB - Unsymmetric acridines are synthesized via a one-pot amination/cyclization/aromatization reaction for the first time. With Pd(OAc)2-X Phos as the catalyst, a series of unsymmetric acridines are obtained in moderate to excellent yields (up to 99% yield). Meanwhile, the diphenylamine intermediate could be isolated, which is evidence of the domino process. PMID- 24152130 TI - Developing nurse educators' computer skills towards proficiency in nursing informatics. AB - The purpose of this paper is to assess nurse educators' competence development in nursing informatics (NI) and to compare their competence to the NI competence of other healthcare professionals. Electronic health records (EHR) have been in use for many years. However, the adoption of the nursing care plan finally made it possible for nurses in Finland to develop a model for structured documentation with nursing terminology. A total of n = 124 (n = 85 pre-test and n = 39 post test) participants from Universities of Applied Sciences (UAS), hospitals, hospitals' information management and health centres were surveyed with a e questionnaire designed to assess the development of their NI competences during the nursing documentation development project. The questionnaire included 145 structured questions and 6 open questions. Data analysis focused on classification and comparison of NI competences through data description and statistical parameters using figures and tables. The basic NI competences of the nurse educators were good at the end of project and the nurse educators had better information literacy and information management competences than other participants. The information retrieval skills varied greatly, but they improved evenly towards the end. The nurse educators mastered better evidence-based nursing and use of nursing process models in their work. PMID- 24152131 TI - Arsenic incorporation in synthetic struvite (NH4MgPO4.6H2O): a synchrotron XAS and single-crystal EPR study. AB - Struvite, a common biomineral and increasingly important fertilizer recovered from wastewater treatment plants, is capable of sequestering a wide range of heavy metals and metalloids, including arsenic. Inductively coupled plasma mass spectrometric (ICPMS) analyses and microbeam synchrotron X-ray fluororescence (MU SXRF) mapping show that struvite formed under ambient conditions contains up to 547 +/- 15 ppm As and that the uptake of As is controlled by pH. Synchrotron As K edge XANES spectra measured at 20 K show that As(5+) is the predominant oxidation state in struvite, irrespective of Na2HAsO4.7H2O or NaAsO2 as the source for As. Modeling of As K-edge EXAFS data suggest that local structural distortion associated with the substitution of As(5+) for P(5+) in struvite reaches up to 3.75 A. Single-crystal electron paramagnetic resonance (EPR) spectra of gamma-ray irradiated struvite disclose five [AsO3](2-) radicals and one [AsO4](2-) radical. These arsenic-centered oxyradicals are all readily attributed to form from diamagnetic [AsO4](3-) precursors during irradiation, providing further support for exclusive incorporation and local structural expansion beyond the first shell of As(5+) at the P site in struvite. PMID- 24152132 TI - Total antioxidant status and markers of oxidative stress in subjects with normal or impaired glucose regulation (IFG, IGT) in diabetic patients. AB - BACKGROUND: We investigated the ischemia-modified albumin (IMA), advanced oxidation protein products (AOPPs), prooxidants-antioxidants balance (PAB), and ferric reducing antioxidant power (FRAP) concentrations in patients with impaired fasting glucose (IFG), impaired glucose tolerance (IGT) and diabetes mellitus (DM) and compared the results to those of normoglycemic individuals at baseline and 2 hours after glucose loading. METHODS: An oral glucose tolerance test was performed on age-matched subjects (n = 110) with a body mass index (BMI) < 27 kg/m(2). Subjects were categorized as normoglycemic (n = 35), IFG (n = 25), IGT (n = 30) and DM (n = 20) according to the WHO criteria. The IMA, AOPP, PAB, FRAP concentrations were determined by colorimetric methods. RESULTS: At baseline, the AOPP concentrations were significantly higher in subjects with IFG and DM compared to normoglycemic subjects (p < 0.01 for all cases). The IFG, IGT and DM patients had a significantly higher IMA at baseline when compared with the normoglycemic individuals (p < 0.001 for all cases). The IMA in IFG subjects was significantly elevated (p < 0.05), while in DM patients, the IMA was significantly decreased (p < 0.001) after glucose loading with respect to baseline concentrations. Following glucose loading, the PAB was significantly decreased from baseline concentrations in normoglycemic individuals (p < 0.001) and in the IFG (p < 0.001) and IGT (p < 0.001) patients. CONCLUSION: In subjects with impaired glucose metabolism, the hyperglycemia is associated with increased IMA, AOPP and PAB concentrations. Increased IMA in subjects with IFG and decreased FRAP concentrations in subjects with IGT after glucose loading suggests that an increase in glucose concentrations can lead to tissue damage by increasing oxidative stress. PMID- 24152133 TI - The role of oral soft tissues in swallowing function: what can tongue pressure tell us? AB - Tongue pressure data taken from healthy subjects during normal oral activities such as mastication, speech and swallowing are providing us with new ways of understanding the role of the tongue in craniofacial growth and function. It has long been recognized that the sequential contact between the tongue and the palate plays a crucial role in the oropharyngeal phase of swallowing. However, because the focus of most research on intraoral pressure has been on the generation of positive pressure by the tongue on the hard palate and teeth, generation and coordination of absolute intraoral pressures and regional pressure gradients has remained unexplored. Ongoing research in our laboratory has uncovered highly variable individual pressure patterns during swallowing, which can nonetheless be divided into four stages: preparatory, primary propulsive, intermediate and terminal. These stages may further be sub-classified according to pressure patterns generated at the individual level as tipper or dipper patterns in the preparatory stage, roller or slapper in the primary propulsive and monophasic or biphasic during the intermediate stage. Interestingly, while an increase in bolus viscosity can result in significant changes to pressure patterns in some individuals, it has little effect in others. Highly individual responses to increased viscosity are also observed with swallowing duration. The above, together with other findings, have important implications for our understanding of the aetiology of widely differing conditions such as protrusive and retrusive malocclusions, dysphagia and sleep apnoea, as well as the development of novel food products. PMID- 24152134 TI - Concordance of studies for nodal staging is prognostic for worse survival in esophageal cancer. AB - Pretreatment clinical staging in esophageal cancer influences prognosis and treatment strategy. Current staging strategies utilize multiple imaging modalities, and often the results are contradictory. No studies have examined the implications of concordance of computed tomography (CT), positron emission tomography (PET), and endoscopic ultrasound (EUS) when used for the evaluation of nodal disease. The objective of this study was to determine if concordance of CT, PET, or EUS for nodal disease predicts worse overall survival. We reviewed 615 esophageal cancer patients with pretreatment CT, PET, and EUS that underwent esophagectomy for survival outcomes based on concordance of studies for nodal disease. Concordant N+ is defined as two or three studies positive for nodal disease; non-concordant N+ is defined as only one positive study. Node-positive disease by any study predicted shorter survival than node-negative disease (42% vs. 73% 5-year survival; P<0.001). Additionally, non-concordant N+ patients had shorter survival than N- patients (52% vs. 73% 5-year survival; P<0.001). Concordant N+ patients had shorter survival than non-concordant N+ patients (38- vs. 61-month median survival; P=0.017). There were no statistically significant differences in survival based on specific combinations of studies. When PET was disregarded, patients with both CT+ and EUS+ had shorter survival than patients with either CT+ or EUS+ (39- vs. 58-month median survival; P=0.029). Pretreatment CT, PET, or EUS concordance for node-positive disease predicts shorter overall survival in patients that undergo esophagectomy for esophageal cancer. Predicting survival in esophageal cancer should consider the synergistic capabilities of CT, PET, and EUS in evaluating nodal status. PMID- 24152135 TI - Toward disaster-resilient cities: characterizing resilience of infrastructure systems with expert judgments. AB - Resilient infrastructure systems are essential for cities to withstand and rapidly recover from natural and human-induced disasters, yet electric power, transportation, and other infrastructures are highly vulnerable and interdependent. New approaches for characterizing the resilience of sets of infrastructure systems are urgently needed, at community and regional scales. This article develops a practical approach for analysts to characterize a community's infrastructure vulnerability and resilience in disasters. It addresses key challenges of incomplete incentives, partial information, and few opportunities for learning. The approach is demonstrated for Metro Vancouver, Canada, in the context of earthquake and flood risk. The methodological approach is practical and focuses on potential disruptions to infrastructure services. In spirit, it resembles probability elicitation with multiple experts; however, it elicits disruption and recovery over time, rather than uncertainties regarding system function at a given point in time. It develops information on regional infrastructure risk and engages infrastructure organizations in the process. Information sharing, iteration, and learning among the participants provide the basis for more informed estimates of infrastructure system robustness and recovery that incorporate the potential for interdependent failures after an extreme event. Results demonstrate the vital importance of cross-sectoral communication to develop shared understanding of regional infrastructure disruption in disasters. For Vancouver, specific results indicate that in a hypothetical M7.3 earthquake, virtually all infrastructures would suffer severe disruption of service in the immediate aftermath, with many experiencing moderate disruption two weeks afterward. Electric power, land transportation, and telecommunications are identified as core infrastructure sectors. PMID- 24152136 TI - Methylation of structural components of the axoneme occurs during flagellar disassembly. AB - When Chlamydomonas cells resorb their flagella, seven polypeptides become asymmetrically dimethylated (aDMA) on arginine residues. Tandem mass spectrometry has identified these as radial spoke proteins 1, 2, 5, and 6; tektin, a structural component of the outer doublets; and flagellar-associated protein 172 (FAP172) (coiled-coil domain containing protein 40 (CCDC40)) and FAP250 (CCDC65), which are associated with inner arm dynein and the nexin-dynein regulatory complex. The enzyme protein arginine methyl transferase 1 (PRMT1), which generates aDMA residues, is a component of the flagellar matrix; antibodies to PRMT1 label full-length flagella in a punctate pattern along the length of the axoneme. During resorption, PRMT1 localization becomes enhanced at the flagellar tip, which is the site of the net disassembly of the flagellar axoneme, and gel shift assays indicate PRMT1 is phosphorylated under resorbing conditions. These data are consistent with a model in which a resorption signal activates one or more protein kinases, resulting in the up-regulation of the components of a protein methylation pathway resident in flagella. Methylation results in axonemal instability and/or enhances the interaction of axonemal polypeptides with intraflagellar transport particles, which then move disassembled components to the cell body for degradation or recycling. PMID- 24152137 TI - Paraplegia following thoracic and lumbar transforaminal epidural steroid injections: how relevant are particulate steroids? PMID- 24152139 TI - New eudesmane-type sesquiterpenoids from the processed rhizomes of Atractylodes macrocephala. AB - Two new eudesmane-type sesquiterpenoids, eudesma-4(15),7(11)-dien-8alpha,12-ether (atractylenother, 1) and 8alpha-hydroxyeudesma-4(15),7(11)-dien-8beta,12-olide (8 epiatractylenolide III, 2), and one new natural product named 4(R),15-epoxy-8beta hydroxyatractylenolide II (3), together with four known eudesmane-type sesquiterpenoid lactones, atractylenolides I, II, III, and IV, were isolated from the rhizome of Atractylodes macrocephala Koidz. processed with wheat bran. Their chemical structures were determined by the combination of 1D and 2D NMR analysis as well as mass spectrometry. PMID- 24152138 TI - Amyloid beta peptide-mediated neurotoxicity is attenuated by the proliferating microglia more potently than by the quiescent phenotype. AB - BACKGROUND: The specific role of microglia on Abeta-mediated neurotoxicity is difficult to assign in vivo due to their complicated environment in the brain. Therefore, most of the current microglia-related studies employed the isolated microglia. However, the previous in vitro studies have suggested either beneficial or destructive function in microglia. Therefore, to investigate the phenotypes of the isolated microglia which exert activity of neuroprotective or destructive is required. RESULTS: The present study investigates the phenotypes of isolated microglia on protecting neuron against Abeta-mediated neurotoxicity. Primary microglia were isolated from the mixed glia culture, and were further cultured to distinct phenotypes, designated as proliferating amoeboid microglia (PAM) and differentiated process-bearing microglia (DPM). Their inflammatory phenotypes, response to amyloid beta (Abeta), and the beneficial or destructive effects on neurons were investigated. DPM may induce both direct neurotoxicity without exogenous stimulation and indirect neurotoxicity after Abeta activation. On the other hand, PAM attenuates Abeta-mediated neurotoxicity through Abeta phagocytosis and/or Abeta degradation. CONCLUSIONS: Our results suggest that the proliferating microglia, but not the differentiated microglia, protect neurons against Abeta-mediated neurotoxicity. This discovery may be helpful on the therapeutic investigation of Alzheimer's disease. PMID- 24152140 TI - Morphine intake and the effects of naltrexone and buprenorphine on the acquisition of methamphetamine intake. AB - Some common genetic factors appear to influence risk for drug dependence across multiple drugs of abuse. In previous research, mice that were selectively bred for higher amounts of methamphetamine consumption, using a two-bottle choice methamphetamine drinking procedure, were found to be less sensitive to the locomotor stimulant effects of morphine and of the more selective MU-opioid receptor agonist fentanyl, compared to mice that were bred for low methamphetamine consumption. This suggested that MU-opioid receptor-mediated pathways may influence genetic risk for methamphetamine consumption. We hypothesized that these differences in opioid sensitivity would impact opioid intake in the methamphetamine drinking lines and that drugs with MU-opioid receptor activity would impact methamphetamine intake. Consumption of morphine was examined in 2, two-bottle choice studies, one that compared morphine to quinine consumption and another that used a saccharin fading procedure. Next, naltrexone (0, 0.5, 1, 2, 5, 10 and 20 mg/kg), a MU-opioid receptor antagonist, and buprenorphine (0, 1, 2 or 4 mg/kg), a MU-opioid receptor partial agonist, were each examined for their effects on the acquisition of methamphetamine consumption. Low methamphetamine drinking mice consumed more morphine compared to high methamphetamine drinking mice. Naltrexone did not alter methamphetamine consumption in either selected line; however, buprenorphine reduced methamphetamine intake in the high methamphetamine drinking line. These data show that greater sensitivity to opioids is associated with greater opioid intake and warrant further investigation of drugs with MU-opioid receptor-specific agonist activity in genetically determined differences in methamphetamine consumption. PMID- 24152141 TI - Knockout and humanized mice as suitable tools to identify enzymes metabolizing the human carcinogen aristolochic acid. AB - 1. Aristolochic acid I (AAI) is the predominant component in plant extract of Aristolochia genus that is involved in development of aristolochic acid nephropathy, Balkan endemic nephropathy and urothelial cancer. The diseases do not develop in all individuals exposed to AAI and patients exhibit different clinical outcomes. Differences in the activities of enzymes catalyzing the metabolism of AAI might be one of the reasons for this individual susceptibility. 2. Understanding which human enzymes are involved in reductive activation of AAI generating AAI-DNA adducts, and/or its detoxication to the O-demethylated metabolite, aristolochic acid Ia (AAIa), is necessary in the assessment of the susceptibility to this compound. 3. This review summarizes the results of the latest studies utilizing genetically engineered mouse models to identify which human and rodent enzymes catalyze the reductive activation of AAI to AAI-DNA adducts and its oxidative detoxication to AAIa in vivo. 4. The use of hepatic cytochrome P450 (Cyp) reductase null (HRN) mice, in which NADPH:Cyp oxidoreductase (Por) is deleted in hepatocytes, Cyp1a1((-/-)), Cyp1a2((-/-)) single-knockout, Cyp1a1/1a2((-/-)) double-knockout and CYP1A-humanized mice revealed that mouse and human CYP1A1 and 1A2, besides mouse NAD(P)H: quinone oxidoreductase, were involved in the activation of AAI but CYP1A1 and 1A2 also oxidatively detoxified AAI. PMID- 24152143 TI - Identification of high immunoreactive proteins from Streptococcus agalactiae isolates recognized by human serum antibodies. AB - The aim of the studies was to identify immunogenic proteins of Streptococcus agalactiae (group B streptococcus; GBS) isolates. Investigation of the immunoreactivity with human sera allowed us to determine major immunogenic proteins which might be potential candidates for the development of vaccine. For the study, we have selected 60 genetically different, well-characterized GBS clinical isolates. The proteins immunoreactivity with 24 human sera from patients with GBS infections, carriers, and control group without GBS was detected by SDS PAGE and Western blotting. As a result, some major immunogenic proteins were identified, of which four proteins with molecular masses of about 45 to 50 kDa, which exhibited the highest immunoreactivity features, were analyzed by LC-MS/MS. The proteins were identified by comparative analysis of peptides masses using MASCOT and statistical analysis. The results showed known molecules such as enolase (47.4 kDa), aldehyde dehydrogenase (50.6 kDa), and ones not previously described such as trigger factor (47 kDa) and elongation factor Tu (44 kDa). The preliminary results indicated that some GBS proteins that elicit protective immunity hold promise not only as components in a vaccine as antigens but also as carriers or adjuvants in polysaccharide conjugate vaccines, but more studies are needed. PMID- 24152142 TI - Short interfering RNA guide strand modifiers from computational screening. AB - Short interfering RNAs (siRNAs) are promising drug candidates for a wide range of targets including those previously considered "undruggable". However, properties associated with the native RNA structure limit drug development, and chemical modifications are necessary. Here we describe the structure-guided discovery of functional modifications for the guide strand 5'-end using computational screening with the high-resolution structure of human Ago2, the key nuclease on the RNA interference pathway. Our results indicate the guide strand 5'-end nucleotide need not engage in Watson-Crick (W/C) H-bonding but must fit the general shape of the 5'-end binding site in MID/PIWI domains of hAgo2 for efficient knockdown. 1,2,3-Triazol-4-yl bases formed from the CuAAC reaction of azides and 1-ethynylribose, which is readily incorporated into RNA via the phosphoramidite, perform well at the guide strand 5'-end. In contrast, purine derivatives with modified Hoogsteen faces or N2 substituents are poor choices for 5'-end modifications. Finally, we identified a 1,2,3-triazol-4-yl base incapable of W/C H-bonding that performs well at guide strand position 12, where base pairing to target was expected to be important. This work expands the repertoire of functional nucleotide analogues for siRNAs. PMID- 24152144 TI - Acute kidney injury due to tubular intraluminal monoclonal light chain crystals mimicking acute pyelonephritis. AB - Tubular intraluminal inflammatory cells may be seen in kidney biopsies of patients with pyelonephritis, cell-mediated transplant rejection, autoimmune tubulointerstitial nephritis, allergic reactions, or in association with monoclonal light chain casts. When casts in a native kidney are primarily composed of granulocytes, the cause is most commonly acute pyelonephritis due to an ascending bacterial urinary tract infection. We report a 57-year-old man with acute kidney injury and an intense intraluminal neutrophil response to monoclonal lambda light chain crystal containing casts. PMID- 24152145 TI - Right pulmonary artery sling in a single lung with bronchial isomerism. AB - Pulmonary artery slings are rare congenital anomalies seen only on the left side. The presence of right pulmonary artery (RPA) sling is extremely rare. We report a case of a RPA sling with a single lung associated with tracheal stenosis and its management. PMID- 24152146 TI - Facilitation allows plant coexistence in Cuban serpentine soils. AB - Serpentine soils represent stressful habitats where plants have to cope with heavy metals, moisture limitation and low nutrient availability. We propose that facilitation is an important mechanism structuring plant communities under such stressful conditions. Facilitation has been shown to generate the spatial association of species, forming discrete vegetation patches of phylogenetically distant species. We measured these spatial and phylogenetic signatures left by facilitation in a serpentine plant community of central Cuba. Our results show that seedlings preferentially grow under plants of different species, and that adults are significantly aggregated into vegetation patches. In these patches, adults tend to co-occur with distant relatives, ultimately forming phylogenetically diverse neighbourhoods. We discuss possible mechanisms explaining how species adapted to serpentine areas may be acting as nurses, reducing the stressful conditions for the establishment of other species. PMID- 24152147 TI - Nanoscale investigation of photoinduced hydrophilicity variations in anatase and rutile nanopowders. AB - The photoactive properties of TiO2 are employed to develop surfaces with self cleaning capabilities. Clearly, the fine-tuning of such surfaces for different applications relies on a holistic understanding of the different aspects that induce the self-cleaning behavior. Among those, the mechanisms responsible for the photoinduced surface alteration in the TiO2 allotropes are still not completely understood. In this study, TiO2 polymorphs nanopowders are investigated by combining the high spatial resolution observables of recently developed atomic force microscopy (AFM) based force spectroscopy techniques with diffuse reflection infrared Fourier transform spectroscopy (DRIFTS). Phase maps under irradiated and nonirradiated conditions for anatase and rutile suggest the existence of two distinct behaviors that are further discerned by energy analysis of amplitude and phase vs distance curves. Independently, surface analysis of anatase and rutile by means of DRIFTS spectroscopy reveals a readily distinguishable coexistence of dissociated water and molecular water on the two phases, confirming the stronger photoactivity of anatase. The peculiarity of the surface interaction under UV exposure is further investigated by reconstructing the force profiles between the oscillating AFM tip and the TiO2 phases with the attempt of gaining a better understanding of the mechanisms that cause the different hydrophilic properties in the TiO2 allotropes. PMID- 24152149 TI - Advancing the nutrition and early childhood development agenda: indicators and guidance. AB - The importance of early childhood development (ECD) is scientifically established and is increasingly recognized by governments and international organizations. However, progress in protecting and improving ECD is constrained by multisectoral influences on ECD, the multiple sectors and venues for delivering services, the lack of a common fiscal and policy space, and weak or fragmented data and monitoring systems. This paper describes two tools and strategies to strengthen multisectoral, system-wide policy environments for ECD. One is the Systems Approach for Better Education Results (SABER)-ECD framework for tracking progress toward an integrated ECD system. Developed by the World Bank, SABER-ECD assists governments and their partners to take stock of their existing ECD policies and programs, analyze strengths and areas for improvement using common metrics, and learn from international examples. The other tool is an Agenda-Setting and Commitments framework, based on research in global health and nutrition that can guide national-level actors in their advocacy and strategic efforts to strengthen the integrated ECD system. These represent practical and research-based tools to translate scientific evidence concerning ECD into effective and large-scale actions. PMID- 24152148 TI - First determination of the weak charge of the proton. AB - The Q(weak) experiment has measured the parity-violating asymmetry in ep elastic scattering at Q(2)=0.025(GeV/c)(2), employing 145 MUA of 89% longitudinally polarized electrons on a 34.4 cm long liquid hydrogen target at Jefferson Lab. The results of the experiment's commissioning run, constituting approximately 4% of the data collected in the experiment, are reported here. From these initial results, the measured asymmetry is A(ep)=-279+/-35 (stat) +/- 31 (syst) ppb, which is the smallest and most precise asymmetry ever measured in ep scattering. The small Q(2) of this experiment has made possible the first determination of the weak charge of the proton Q(W)(p) by incorporating earlier parity-violating electron scattering (PVES) data at higher Q(2) to constrain hadronic corrections. The value of Q(W)(p) obtained in this way is Q(W)(p)(PVES)=0.064+/-0.012, which is in good agreement with the standard model prediction of Q(W)(p)(SM)=0.0710+/ 0.0007. When this result is further combined with the Cs atomic parity violation (APV) measurement, significant constraints on the weak charges of the up and down quarks can also be extracted. That PVES+APV analysis reveals the neutron's weak charge to be Q(W)(n)(PVES+APV)=-0.975+/-0.010. PMID- 24152151 TI - Sniffing out steroid responsiveness in asthma using an electronic nose. PMID- 24152152 TI - Advances in our understanding of drug hypersensitivity. PMID- 24152153 TI - Multiple grass mixes as opposed to single grasses for allergen immunotherapy in allergic rhinitis. AB - Grass pollen allergy affects approximately 40% of allergic patients. Subcutaneous allergen immunotherapy (SCIT) is the only allergen-specific and disease-modifying treatment available. Currently available therapeutic vaccines for the treatment of grass pollen allergy are based on natural grass pollen extracts which are either made from pollen of one cross-reactive grass species or from several related grass species. Clinical studies have shown that SCIT performed with timothy grass pollen extract is effective for the treatment of grass pollen allergy. Moreover, it has been demonstrated that recombinant timothy grass pollen allergens contain the majority of relevant epitopes and can be used for SCIT in clinical trials. However, recent in vitro studies have suggested that mixes consisting of allergen extracts from several related grass species may have advantages for SCIT over single allergen extracts. Here, we review current knowledge regarding the disease-relevant allergens in grass pollen allergy, available clinical studies comparing SCIT with allergen extracts from timothy grass or from mixes of several related grass species of the Pooideae subfamily, in vitro cross-reactivity studies performed with natural allergen extracts and recombinant allergens and SCIT studies performed with recombinant timothy grass pollen allergens. In vitro and clinical studies performed with natural allergen extracts reveal no relevant advantages of using multiple grass mixes as opposed to single grass pollen extracts. Several studies analysing the molecular composition of natural allergen extracts and the molecular profile of patients' immune responses after SCIT with allergen extracts indicate that the major limitation for the production of a high quality grass pollen vaccine resides in intrinsic features of natural allergen extracts which can only be overcome with recombinant allergen-based technologies. PMID- 24152154 TI - Predicting steroid responsiveness in patients with asthma using exhaled breath profiling. AB - BACKGROUND: Exhaled breath contains disease-dependent volatile organic compounds (VOCs), which may serve as biomarkers distinguishing clinical phenotypes in asthma. Their measurement may be particularly beneficial in relation to treatment response. OBJECTIVE: Our aim was to compare the performance of electronic nose (eNose) breath analysis with previously investigated techniques (sputum eosinophils, exhaled nitric oxide (FeNO) and airway hyperresponsiveness) to discriminate asthma from controls and identify steroid responsiveness in steroid free patients. Trial registration ACTRN12613000038796. METHODS: Twenty-five patients with mild/moderate asthma had their inhaled steroid treatment discontinued until loss of control or 28 days. They were subsequently treated with oral prednisone 30 mg/day for 14 days. Steroid responsiveness was defined as an increase of either > 12% FEV1 or > 2 doubling doses PC20 AMP. Steroid-free assessment of sputum eosinophils, FeNO and exhaled breath VOCs were used to construct algorithms predicting steroid responsiveness. Performance characteristics were compared by ROC analysis. RESULTS: The eNose discriminated between asthma and controls (area under the curve = 0.766 +/- 0.14; P = 0.002) with similar accuracy to FeNO (0.862 +/- 0.12; P < 0.001) and sputum eosinophils (0.814 +/- 0.15; P < 0.001). Steroid responsiveness was predicted with greater accuracy by VOC-analysis (AUC = 0.883 +/- 0.16; P = 0.008) than FeNO (0.545 +/- 0.28; P = 0.751) or sputum eosinophils (0.610 +/- 0.29; P = 0.441). CONCLUSIONS AND CLINICAL RELEVANCE: Breath analysis by eNose can identify asthmatic patients and may be used to predict their response to steroids with greater accuracy than sputum eosinophils or FeNO. This implies a potential role for breath analysis in the tailoring of treatment for asthma patients. PMID- 24152155 TI - Cytokine responses of peripheral blood mononuclear cells to allergen do not identify asthma or asthma phenotypes. AB - BACKGROUND: Asthmatic patients are often differentiated based on their atopic status (atopic or nonatopic) and type of bronchitis (eosinophilic, neutrophilic, both, or neither). There is evidence supporting a central role for the T cell in asthma, but the role of allergen-induced T cell cytokines in driving disease in different asthma phenotypes remains unclear. OBJECTIVE: To investigate the hypothesis that peripheral blood mononuclear cells (PBMCs) from asthma patients with different phenotypes would react characteristically to a panel of common aeroallergens. METHODS: We incubated PBMCs from 41 asthma patients and 8 healthy controls with allergen and assessed PBMC proliferation by (3) H-thymidine incorporation and the production of the cytokines IL-5, IL-17A, IL-23, IL-10, and IFN-gamma by ELISA. RESULTS: No differences in PBMC proliferation or cytokine production were found in patients with asthma, compared with healthy controls, or between patients with different asthma phenotypes. CONCLUSIONS AND CLINICAL RELEVANCE: Peripheral blood mononuclear cell cytokine responses to allergen are not able to assist in the discrimination between disease state, atopic status, or type of bronchitis in asthma. PMID- 24152156 TI - VEGFA variants are associated with pre-school lung function, but not neonatal lung function. AB - BACKGROUND: Vascular endothelial growth factor (VEGF) is implicated in airway remodelling and asthma development. We studied VEGFA gene variants and plasma levels and the development of lung function, bronchial hyperresponsiveness and asthma in childhood. METHODS: We analysed 13 SNPs in the VEGFA gene in 411 children from the COPSAC2000 high-risk birth cohort. Asthma was diagnosed prospectively, and lung function measurements were obtained at birth and 6 years of age. Plasma VEGF levels were measured at 18 months of age. We used a Bonferroni adjusted significance level. Findings were replicated in the Prevention and Incidence of Asthma and Mite Allergy (PIAMA) birth cohort at age 8. RESULTS: At age six, three SNPs from the same linkage block were associated with FEV1 (rs699947, P = 1.31E-05), independent of asthma, and there were suggestive associations between FEV1/FVC ratio and rs833052 and maximal mid expiratory flow and rs6900017. Replication in the PIAMA cohort showed borderline association between FEV1 and rs699947 and significant meta-analysis result. SNPs upstream and nearby rs699947 were nominally associated with VEGF plasma levels. VEGF levels were not associated with asthmatic symptoms or lung function measures. CONCLUSIONS AND CLINICAL RELEVANCE: VEGF gene variants are associated with lung function at school age, but not at birth, suggesting a role of VEGF in post-natal lung function development. PMID- 24152157 TI - Allopurinol hypersensitivity is primarily mediated by dose-dependent oxypurinol specific T cell response. AB - BACKGROUND: Allopurinol is a main cause of severe cutaneous adverse reactions (SCAR). How allopurinol induces hypersensitivity remains unknown. Pre-disposing factors are the presence of the HLA-B*58:01 allele, renal failure and possibly the dose taken. OBJECTIVE: Using an in vitro model, we sought to decipher the relationship among allopurinol metabolism, HLA-B*58:01 phenotype and drug concentrations in stimulating drug-specific T cells. METHODS: Lymphocyte transformation test (LTT) results of patients who had developed allopurinol hypersensitivity were analysed. We generated allopurinol or oxypurinol-specific T cell lines (ALP/OXP-TCLs) from allopurinol naive HLA-B*58:01(+) and HLA-B*58:01( ) individuals using various drug concentrations. Their reactivity patterns were analysed by flow cytometry and (51) Cr release assay. RESULTS: Allopurinol allergic patients are primarily sensitized to oxypurinol in a dose-dependent manner. TCL induction data show that both the presence of HLA-B*58:01 allele and high concentration of drug are important for the generation of drug-specific T cells. The predominance of oxypurinol-specific lymphocyte response in allopurinol allergic patients can be explained by the rapid conversion of allopurinol to oxypurinol in vivo rather than to its intrinsic immunogenicity. OXP-TCLs do not recognize allopurinol and vice versa. Finally, functional avidity of ALP/OXP-TCL is dependent on both the induction dose and HLA-B*58:01 status. CONCLUSIONS AND CLINICAL RELEVANCE: This study establishes the important synergistic role of drug concentration and HLA-B*58:01 allele in the allopurinol or oxypurinol-specific T cell responses. Despite the prevailing dogma that Type B adverse drug reactions are dose independent, allopurinol hypersensitivity is primarily driven by oxypurinol-specific T cell response in a dose-dependent manner, particular in the presence of HLA-B*58:01 allele. PMID- 24152159 TI - Breastfeeding and introduction of complementary foods during infancy in relation to the risk of asthma and atopic diseases up to 10 years. AB - BACKGROUND: It has been hypothesized that changes in diet during early life may have contributed to the increase in childhood asthma and atopy. The long-term effect of the timing and content of infant feeding on the incidence of asthma and atopic diseases in children is unclear. OBJECTIVE: To investigate the associations between duration of breastfeeding and the timing of introduction of complementary foods during the first 6 months and parental-reported asthma, wheeze and atopic eczema up to 10 years of age. METHODS: Infant feeding practices (breastfeeding and introduction of complementary foods) of 1924 singleton children participating in the Study of Eczema and Asthma To Observe the influence of Nutrition (SEATON) birth cohort were prospectively collected up to 6 months with outcomes (wheeze, atopic eczema and asthma) being assessed at 1, 2, 5 and 10 years. Data were analysed using generalized estimating equations and discrete hazards models with adjustment for confounders. RESULTS: By 6 months, 59% and 35% of mothers had stopped exclusive and total breastfeeding, respectively. Although formula feeding was adversely associated with wheeze in the past 12 months (adjusted OR for no formula feeding: 070, 95% CI 0.50-0.97), and the introduction of biscuits/bread after 5 months of age adversely associated with atopic eczema (adjusted OR 1.34, 95% CI 1.06-1.69), these results lost their statistical significance after adjustment for multiple testing. Stratification of the results by the presence of eczema by 6 months of age and family atopic history did not substantially differ from the results of the whole study population. CONCLUSION AND CLINICAL RELEVANCE: Our results suggest that the nature of infant feeding during the first 6 months seems not to substantially influence the long-term risk of asthma and atopic diseases in children, nor in children at high risk of atopic disease because of a family history of atopic disease. PMID- 24152158 TI - Prevalence of IgE against neuromuscular blocking agents in hairdressers and bakers. AB - BACKGROUND: Allergic IgE-mediated reactions to neuromuscular blocking agents (NMBAs) are the main cause of immediate hypersensitivity reactions in anaesthesia; their predominant occurrence in the absence of previous exposure to NMBAs suggests a risk related to environmental exposure. OBJECTIVE: To investigate the prevalence of specific IgE to quaternary ammonium ions in two populations professionally exposed to quaternary ammonium compounds, in the north eastern France. METHODS: The study had a retrospective follow-up design whereby apprentices were assessed after their 2-year training period as apprentices. The professionally exposed hairdresser populations (n = 128) were compared with baker/pastry makers (n = 108) and 'non-exposed' matched control subjects (n = 379). RESULTS: We observed a 4.6-fold higher frequency of positive IgE against quaternary ammonium ions in hairdressers (HD), compared with baker/pastry makers (BP) and control (C) groups. The competitive inhibition of quaternary ammonium Sepharose radioimmunoassay (QAS-IgE RIA) with succinylcholine was significantly higher in HD, compared with BP and C groups, with inhibition percentage of 66.2 +/- 7.4, 39.7 +/- 6.0 and 43.8 +/- 9.9, respectively (P < 0.001). The specific IgE against quaternary ammonium ions recognized also two compounds widely used by hairdressers, benzalkonium chloride and polyquaternium-10, in competitive inhibition of IgE RIA. When considering the whole study population, hairdresser professional exposure and total IgE > 100 kU/L were the two significant predictors of IgE-sensitization against quaternary ammonium ions in the multivariate analysis of a model that included age, sex, professional exposure, increased concentration of total IgE (IgE > 100 kU/L) and positive IgE against prevalent allergens (Phadiatop((r)) ; P = 0.019 and P = 0.001, respectively). CONCLUSION AND CLINICAL RELEVANCE: The exposure to hairdressing professional occupational factors increases IgE-sensitization to NMBAs and quaternary ammonium ion compounds used in hairdressing. Besides the pholcodine hypothesis, our study suggests that repetitive exposure to quaternary ammonium compounds used in hairdressing is a risk factor for NMBAs sensitization. PMID- 24152160 TI - Proteinase-activated receptor-2 activation participates in allergic sensitization to house dust mite allergens in a murine model. AB - BACKGROUND: Many aeroallergens contain proteinase activity and are able to induce allergic sensitization when presented to mucosal surfaces. Some of these allergens activate proteinase-activated receptor-2 (PAR2 ). OBJECTIVE: To determine the role of PAR2 activation in a murine house dust mite (HDM) allergy model. METHODS: We sensitized and challenged PAR2 -deficient mice with HDM, and examined allergic outcomes compared to wild-type animals. To focus on the role of PAR2 in allergic sensitization, we administered a PAR2 blocking antibody to wild type animals during the sensitization phase and examined the outcomes immediately after sensitization or following subsequent allergen challenge. RESULTS: We found PAR2 -deficient mice sensitized and challenged with HDM failed to develop airway inflammation, did not produce HDM-specific IgG1 and had less IL-4 mRNA in the lungs than wild-type animals. Prevention of PAR2 activation during sensitization in wild-type mice diminished the levels of Th2 mediators, including IL-4, IL-5 and IL-13, in the lungs. Blocking PAR2 during the sensitization phase also led to decreased manifestations of allergic disease, including airway hyperresponsiveness (AHR) and airway inflammation following subsequent allergen challenge. HDM-induced proliferation of splenocytes obtained from animals sensitized in the presence of PAR2 antibody was reduced relative to those that did not receive antibody. The effect of PAR2 blockade could be transferred to naive mice through splenic CD4(+) T cells from sensitized mice. CONCLUSIONS AND CLINICAL RELEVANCE: PAR2 activation plays a key role during the sensitization phase of our HDM allergy model, leading to increased lung cytokine production and augmented lung reactivity. PAR2 activation is a common mechanism for sensitization to a wide variety of allergens and is therefore a potential pharmacological target to prevent allergy. PMID- 24152161 TI - Biochemical and immunological analysis of mould skin prick test solution: current status of standardization. AB - BACKGROUND: Sensitization prevalence to moulds reached from less than 10% in the general population to more than 25% in atopic and/or asthmatic subjects. To diagnose IgE-mediated mould sensitization, skin prick test (SPT) and specific IgE (sIgE) measurement are recommended. However, concordance of SPT and sIgE results is often less than 50% and standardization of the extracts is required to achieve reliable test results. OBJECTIVE: The aim of our study was to analyse mould SPT solutions (SPTs) with respect to quantity and quality of protein, antigen and human IgE-binding content as a prerequisite for further in vivo studies. METHODS: Commercial SPTs of Alternaria alternata, Aspergillus fumigatus, Cladosporium herbarum and Penicillium chrysogenum from six manufacturers as well as two in house extracts from Aspergillus versicolor were investigated. Protein-, antigen- and IgE-binding contents were quantified by Bradford assay, sandwich ELISA and IgE-ImmunoCAP-inhibition tests. Protein composition and IgE and IgG binding were analysed by SDS-PAGE and immunoblotting, respectively. RESULTS: Median protein concentrations were similar in all mould SPT extracts (90-110 MUg/mL). In contrast, antigen contents and IgE-binding capacity showed a high variability with median antigen values from 4 to 118 MUg/mL and IgE inhibition results between 30 to 95%. Whereas almost all SPTs of A. alternata and A. versicolor showed complete sIgE inhibition with mean values > 80%, only three extracts for A. fumigatus, two extracts for C. herbarum and none of the tested extracts for P. chrysogenum exceeded 50% sIgE reduction. Quantitative amounts of protein, antigenic and IgE-binding structures were not comparable with the quality of the corresponding protein or immunoblot pattern, with the exception of A. alternata SPTs. CONCLUSIONS AND CLINICAL RELEVANCE: Commercially available mould SPT extracts showed high variability raising the question of comparability and reliability of SPT results. Possible consequences for diagnostic test outcome will be investigated in the next step. PMID- 24152162 TI - The possible relevance of visual analogue scale in allergic patients. PMID- 24152164 TI - Insights into lipidomic perturbations in zebrafish tissues upon exposure to microcystin-LR and microcystin-RR. AB - This work represents the first study of its kind that was conducted to evaluate changes in lipid metabolic networks following a balneation exposure of adult zebrafish to MCLR (microcystin-leucine-arginine) and MCRR (microcystin-arginine arginine) at a sublethal dose (10 MUg L(-1)) for a period of 30 days. Following the exposure to MCLR and MCRR, gills, liver, intestine, and brain tissues were harvested for metabolite extraction. Extracted metabolites were detected using qTOF-LC-MS (time-of-flight-liquid chromatography-mass spectrometry). Metabolites were identified using Kegg pathways. The identified metabolites are shown on lipid biochemical maps to demonstrate major perturbations in the metabolic machinery. Results showed that most of the metabolic pathways under the lipid class were affected in different tissues of zebrafish following the exposure to MCLR and MCRR (10 MUg L(-1) for 30 days). The kind and flux of metabolic perturbations varied among different tissues of the organs after the exposure to MCLR and MCRR with the tissues of gills being the most affected. Among the various lipid pathways, cholesterol synthesis was affected significantly as observed from the highest number of perturbed metabolites in that pathway. Cholesterol is responsible for synthesis of steroid hormones and bile acids, which have been recognized as endocrine signaling molecules. Disruption in the synthesis of these compounds following MCLR/MCRR exposure suggests that MCs are capable of causing endocrine disruption among aquatic organisms even under sublethal conditions. Apart from cholesterol synthesis, various other metabolic pathways belonging to the class of essential fatty acids and lipid oxidation were also observed to be perturbed following a balneation exposure of zebrafish to MCLR/MCRR. PMID- 24152165 TI - Replication of results of genome-wide association studies on esophageal squamous cell carcinoma susceptibility loci in a Korean population. AB - Two recent genome-wide association studies have identified that the rs2274223 single-nucleotide polymorphism inphospholipase C epsilon 1 and the single nucleotide polymorphism rs13042395 in C20orf54 are involved in esophageal squamous cell carcinoma (ESCC) in Chinese populations. We hypothesized that genetic polymorphisms of phospholipase C epsilon 1 and C20orf54 are also associated with ESCC in a Korean population. The rs2274223 and rs13042395 genotyping was performed using high-resolution melting analysis. The rs2274223 GG genotype was significantly associated with an increased risk of ESCC (odds ratio [OR]=1.86, 95% confidence interval [CI]=1.08-3.25) compared with the rs2274223 AA genotype. The rs13042395 G allele showed a significantly decreased risk of ESCC in the younger age group (OR=0.71, 95% CI=0.52-0.97) and no significant association in the older group (OR=1.19, 95% CI=0.87-1.62). We observed that the rs2274223 polymorphism was associated with an increased risk of ESCC in this Korean case-control study and that age may modify the association between the rs13042395 polymorphism and the risk of ESCC. PMID- 24152166 TI - Hybrid incompatibility is acquired faster in annual than in perennial species of sunflower and tarweed. AB - Hybrid sterility is an important species barrier, especially in plants where hybrids can often form between divergent taxa. Here we explore how life history affects the acquisition of hybrid sterility in two groups in the sunflower family. We analyzed genetic distance and F1 pollen sterility for interspecific crosses in annual and perennial groups. We find that reproductive isolation is acquired in a steady manner and that annual species acquire hybrid sterility barriers faster than perennial species. Potential causes of the observed sterility pattern are discussed. PMID- 24152167 TI - Tools to covisualize and coanalyze proteomic data with genomes and transcriptomes: validation of genes and alternative mRNA splicing. AB - Direct links between proteomic and genomic/transcriptomic data are not frequently made, partly because of lack of appropriate bioinformatics tools. To help address this, we have developed the PG Nexus pipeline. The PG Nexus allows users to covisualize peptides in the context of genomes or genomic contigs, along with RNA seq reads. This is done in the Integrated Genome Viewer (IGV). A Results Analyzer reports the precise base position where LC-MS/MS-derived peptides cover genes or gene isoforms, on the chromosomes or contigs where this occurs. In prokaryotes, the PG Nexus pipeline facilitates the validation of genes, where annotation or gene prediction is available, or the discovery of genes using a "virtual protein" based unbiased approach. We illustrate this with a comprehensive proteogenomics analysis of two strains of Campylobacter concisus . For higher eukaryotes, the PG Nexus facilitates gene validation and supports the identification of mRNA splice junction boundaries and splice variants that are protein-coding. This is illustrated with an analysis of splice junctions covered by human phosphopeptides, and other examples of relevance to the Chromosome-Centric Human Proteome Project. The PG Nexus is open-source and available from https://github.com/IntersectAustralia/ap11_Samifier. It has been integrated into Galaxy and made available in the Galaxy tool shed. PMID- 24152168 TI - Heuristics structure and pervade formal risk assessment. AB - Lay perceptions of risk appear rooted more in heuristics than in reason. A major concern of the risk regulation literature is that such "error-strewn" perceptions may be replicated in policy, as governments respond to the (mis)fears of the citizenry. This has led many to advocate a relatively technocratic approach to regulating risk, characterized by high reliance on formal risk and cost-benefit analysis. However, through two studies of chemicals regulation, we show that the formal assessment of risk is pervaded by its own set of heuristics. These include rules to categorize potential threats, define what constitutes valid data, guide causal inference, and to select and apply formal models. Some of these heuristics lay claim to theoretical or empirical justifications, others are more back-of-the envelope calculations, while still more purport not to reflect some truth but simply to constrain discretion or perform a desk-clearing function. These heuristics can be understood as a way of authenticating or formalizing risk assessment as a scientific practice, representing a series of rules for bounding problems, collecting data, and interpreting evidence (a methodology). Heuristics are indispensable elements of induction. And so they are not problematic per se, but they can become so when treated as laws rather than as contingent and provisional rules. Pitfalls include the potential for systematic error, masking uncertainties, strategic manipulation, and entrenchment. Our central claim is that by studying the rules of risk assessment qua rules, we develop a novel representation of the methods, conventions, and biases of the prior art. PMID- 24152169 TI - Fluorescent biphenyl derivatives of phenylalanine suitable for protein modification. AB - In a recent study, we demonstrated that structurally compact fluorophores incorporated into the side chains of amino acids could be introduced into dihydrofolate reductase from Escherichia coli (ecDHFR) with minimal disruption of protein structure or function, even when the site of incorporation was within a folded region of the protein. The modified proteins could be employed for FRET measurements, providing sensitive monitors of changes in protein conformation. The very favorable results achieved in that study encouraged us to prepare additional fluorescent amino acids of potential utility for studying protein dynamics. Presently, we describe the synthesis and photophysical characterization of four positional isomers of biphenyl-phenylalanine, all of which were found to exhibit potentially useful fluorescent properties. All four phenylalanine derivatives were used to activate suppressor tRNA transcripts and incorporated into multiple positions of ecDHFR. All phenylalanine derivatives were incorporated with good efficiency into position 16 of ecDHFR and afforded modified proteins that consumed NADPH at rates up to about twice the rate measured for wild type. This phenomenon has been noted on a number of occasions previously and shown to be due to an increase in the off-rate of tetrahydrofolate from the enzyme, altering a step that is normally rate limiting. When introduced into sterically accessible position 49, the four phenylalanine derivatives afforded DHFRs having catalytic function comparable to wild type. The four phenylalanine derivatives were also introduced into position 115 of ecDHFR, which is known to be a folded region of the protein less tolerant of structural alteration. As anticipated, significant differences were noted in the catalytic efficiencies of the derived proteins. The ability of two of the sizable biphenyl phenylalanine derivatives to be accommodated at position 115 with minimal perturbation of DHFR function is attributed to rotational flexibility about the biphenyl bonds. PMID- 24152170 TI - Role of stoichiometry in the dimer-stabilizing effect of AMPA receptor allosteric modulators. AB - Protein dimerization provides a mechanism for the modulation of cellular signaling events. In alpha-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA) receptors, the rapidly desensitizing, activated state has been correlated with a weakly dimeric, glutamate-binding domain conformation. Allosteric modulators can form bridging interactions that stabilize the dimer interface. While most modulators can only bind to one position with a one modulator per dimer ratio, some thiazide-based modulators can bind to the interface in two symmetrical positions with a two modulator per dimer ratio. Based on small-angle X-ray scattering (SAXS) experiments, dimerization curves for the isolated glutamate-binding domain show that a second modulator binding site produces both an increase in positive cooperativity and a decrease in the EC50 for dimerization. Four body binding equilibrium models that incorporate a second dimer-stabilizing ligand were developed to fit the experimental data. The work illustrates why stoichiometry should be an important consideration during the rational design of dimerizing modulators. PMID- 24152171 TI - Tumor-associated edema in brain cancer patients: pathogenesis and management. AB - The long-term treatment of peritumoral edema remains a major challenge in clinical neuro-oncology. Steroids have been and will remain the backbone of any anti-edematous therapy because of their striking activity, convenient oral administration and also because of their cost-effectiveness. Their side effects, however, can compromise quality of life, particularly upon continuous administration. Therapeutic alternatives which may replace or - at least - help to reduce the steroid dose are limited. However, with the development of new agents such as corticorelin acetate, there is a hope that steroid-induced side effects can be delayed and reduced. The administration of anti-angiogenic agents with steroid-sparing effects, for example, bevacizumab, is limited due to their costs. Increased knowledge on boswellic acids and cyclooxygenase-2 inhibitors which are available for clinical application may help to exploit their anti-edema activity more efficiently in the future. PMID- 24152172 TI - Rhinophyma on the web. PMID- 24152173 TI - Beyond terrestrial biology: charting the chemical universe of alpha-amino acid structures. AB - alpha-Amino acids are fundamental to biochemistry as the monomeric building blocks with which cells construct proteins according to genetic instructions. However, the 20 amino acids of the standard genetic code represent a tiny fraction of the number of alpha-amino acid chemical structures that could plausibly play such a role, both from the perspective of natural processes by which life emerged and evolved, and from the perspective of human-engineered genetically coded proteins. Until now, efforts to describe the structures comprising this broader set, or even estimate their number, have been hampered by the complex combinatorial properties of organic molecules. Here, we use computer software based on graph theory and constructive combinatorics in order to conduct an efficient and exhaustive search of the chemical structures implied by two careful and precise definitions of the alpha-amino acids relevant to coded biological proteins. Our results include two virtual libraries of alpha-amino acid structures corresponding to these different approaches, comprising 121 044 and 3 846 structures, respectively, and suggest a simple approach to exploring much larger, as yet uncomputed, libraries of interest. PMID- 24152174 TI - The life history of Lactobacillus acidophilus as a probiotic: a tale of revisionary taxonomy, misidentification and commercial success. AB - Lactobacillus acidophilus is a commercially significant bacterial probiotic, originally isolated from the human gastrointestinal tract and designated Bacillus acidophilus in 1900. Throughout the development of methods to identify and characterise bacteria, L. acidophilus has undergone multiple taxonomic revisions and is now the type species of a phylogenetic subgroup in the highly diverse and heterogeneous Lactobacillus genus. As a result of the limitations of differentiating phenotypically similar species by morphological and biochemical means and revisionary nature of Lactobacillus taxonomy, the characterisation of L. acidophilus has struggled with misidentification and misrepresentation. In contrast, due to its global use as a probiotic supplement in functional foods, L. acidophilus sensu stricto is now one of the most well-characterised Lactobacillus species. Here, we establish the provenance of L. acidophilus strains, unpicking historical and current misidentifications of L. acidophilus, and reviewing the probiotic, genomic and physiological characteristics of this important Lactobacillus species. PMID- 24152175 TI - Endocarditis of the mitral valve posteromedial papillary muscle. AB - A 36-year-old intravenous drug abuser presented with an aortic root abscess and partial rupture of the posteromedial papillary muscle. Following aortic and mitral valve replacement, histological and microbiological analysis of the papillary muscle demonstrated methicillin-sensitive Staphylococcus aureus infection. PMID- 24152176 TI - Combinatorial synthesis of benzimidazole-azo-phenol derivatives as antifungal agents. AB - A chemically diverse library of benzimidazole-azo-phenol derivatives was efficiently prepared and screened for their antifungal activities against five phytopathogenic fungi. Some compounds exhibited potent antifungal activities. As compared with a commercially available agricultural fungicide, hymexazol, especially compound V-5 showed the most promising broad-spectrum antifungal activities against five phytopathogenic fungi. The EC50 values of V-5 against F. graminearum, A. solani, V. mali, B. cinerea, and C. lunata were 0.09, 0.08, 0.06, 0.07, and 0.11 MUmol/mL, respectively. PMID- 24152177 TI - Synthesis of 2-amino-4H-chromen-4-yl phosphonates [correction of phosphonats] via C-P bond formation catalyzed by nano-rods ZnO under solvent-free condition. AB - One-pot, three-component reactions of structurally diverse salicylaldehydes with malononitrile (or ethylcyanoacetate) and diethyl (or dimethyl) phosphate are carried out in the presence of nano-rods ZnO as an efficient catalyst for the synthesis of biologically interesting 2-amino-4H-chromen-4-yl phosphonate derivatives. The value of this method lies in its mild and environmentally benign reaction, simple procedure, good yields, and ease of handling. PMID- 24152178 TI - Classification of Aurora B kinase inhibitors using computational models. AB - Using Self-Organizing Map (SOM) and Support Vector Machine (SVM), four classification models were built to predict whether a compound is an active or weakly active inhibitor of Aurora B kinase. A dataset of 679 Aurora B kinase inhibitors was collected, and randomly split into a training set (278 active and 204 weakly active inhibitors) and a test set (109 active and 88 weakly active inhibitors). Based on 19 selected ADRIANA.Code descriptors and 135 MACCS fingerprints, all the four models showed a good prediction accuracy of over 87% on the test set. It benefited from the advantages of two different types of molecular descriptors in encoding structure information of compounds and characterizing the diversity of different inhibitors. Some molecular properties, such as hydrogen-bonding interactions and atom charge related descriptors were found to be important to the bioactivity of Aurora B kinase inhibitors. PMID- 24152179 TI - Society of Behavioral Sleep Medicine update-fall 2013. PMID- 24152180 TI - Putting the patient into patient-centered care. PMID- 24152183 TI - Nutrition and nurture in infancy and childhood. Abstracts of the Fourth International Interdisciplinary Conference Organized by Maternal & Infant Nutrition & Nurture Unit (MAINN), School of Health, University of Central Lancashire. June 10-12, 2013. Cumbria, United Kingdom. PMID- 24152184 TI - MiR-155 promotes proliferation of human breast cancer MCF-7 cells through targeting tumor protein 53-induced nuclear protein 1. AB - BACKGROUND: MiR-155 has emerged as an "oncomiR", which is the most significantly up-regulated miRNA in breast cancer. However, the mechanisms of miR-155 functions as an oncomiR are mainly unknown. In this study, the aims were to investigate the effects of miR-155 on cell proliferation, cell cycle, and cell apoptosis of ERalpha (+) breast cancer cells and to verify whether TP53INP1 (tumor protein 53 induced nuclear protein 1) is a target of miR-155, and tried to explore the mechanisms of miR-155 in this process. RESULTS: The expression of miR-155 is significantly higher in MCF-7 cells compared with MDA-MB-231 cells. Ectopic expression of TP53INP1 inhibits growth of MCF-7 cells by inducing cell apoptosis and inhibiting cell cycle progression. Overexpression of miR-155 increases cell proliferation and suppress cell apoptosis, whereas abrogating expression of miR 155 suppress cell proliferation and promotes cell apoptosis of MCF-7 cells. In addition, miR-155 negatively regulates TP53INP1 mRNA expression and the protein expression of TP53INP1, cleaved-caspase-3, -8, -9, and p21, and luciferase reporter reveals that TP53INP1 is targeted by miR-155. CONCLUSIONS: TP53INP1 is the direct target of miR-155. MiR-155, which is overexpressed in MCF-7 cells, contributes to proliferation of MCF-7 cells possibly through down-regulating target TP53INP1. PMID- 24152185 TI - Duloxetine Compared with Pregabalin for Diabetic Peripheral Neuropathic Pain Management in Patients with Suboptimal Pain Response to Gabapentin and Treated with or without Antidepressants: A Post Hoc Analysis. AB - OBJECTIVE: To examine the efficacy of duloxetine vs. pregabalin in the treatment for diabetic peripheral neuropathic pain (DPNP), comparing patient subgroups with and without concomitant antidepressant use. METHODS: This post hoc analysis assessed data from a randomized 12-week study that confirmed the noninferiority of duloxetine to pregabalin. In the previously published study, patients with DPNP with inadequate response to gabapentin were switched to duloxetine monotherapy, combination therapy of duloxetine plus gabapentin, or pregabalin monotherapy. Current, stable antidepressant use was allowed; 79 patients were concomitantly treated with antidepressants and 328 without antidepressants. In this post hoc analysis, improvement in the weekly mean of diary-based average daily pain ratings (numerical rating scale: 0-10) in antidepressant users and nonusers was analyzed using a longitudinal mixed-models repeated-measures (MMRM) analysis, including a test of the 3-way interaction (antidepressant subgroup by treatment by week) to assess whether the differences among treatment groups over 12 weeks differ between the antidepressant-use subgroups. RESULTS: The 3-way interaction was significant (P = 0.035), demonstrating that treatment-group differences in pain reduction over time differ between the subgroups. Among patients without antidepressant use, patients treated with duloxetine had significantly greater pain reduction than pregabalin at Week 4 and at each successive week up to the 12-week endpoint (-2.8 for duloxetine and -2.1 for pregabalin; P = 0.031); patients treated with duloxetine plus gabapentin had greater pain reduction than pregabalin at Weeks 2, 3, 5, and 7 to 9 (P <= 0.05) but not at endpoint (-2.4; P = 0.222). Among concomitant antidepressant users, no treatment-group differences were found. CONCLUSIONS: In patients with DPNP inadequately treated with gabapentin without the concomitant use of antidepressants, switching to duloxetine instead of pregabalin may provide better pain reduction. Conversely, in nonresponders to gabapentin who are concomitantly using an antidepressant, switching to duloxetine or pregabalin may provide similar pain reductions. PMID- 24152186 TI - An evaluation of operative self-assessment by UK postgraduate trainees. AB - BACKGROUND: Surgeons in training undertake procedure-based assessment (PBA) with their trainers. Time pressures limit when this occurs. Self-assessment would provide additional opportunities but requires evaluation of your own skills and knowledge. AIM: To investigate the validity of a self-assessment PBA in the operating theatre and evaluate learning needs and change in practice identified. METHODS: In a prospective study, postgraduate UK trainees performed a self assessment PBA after formally reflecting on appendicectomy surgery. Later, they performed their usual external assessment PBA on the same case and outcomes were compared. Learning outcomes were analysed independently by two trainers. RESULTS: There were 25 trainees (14 males), of age 29 years (25-33). They had performed a median of five previous appendicectomies (2-21) after a median three years of speciality training (range 1-4). There were no significant differences in global summary scores, trainee satisfaction or learning outcomes between external and self-assessment PBAs. Construct validity of the self-assessment PBA was demonstrated. The self-assessment PBA was more likely to identify non-technical skills. CONCLUSION: Our results suggest self-assessment PBA is valid for formative assessment. It identified a wide range of learning outcomes. Self assessment PBA would help trainees maximise every learning opportunity and practice self-assessment skills. PMID- 24152187 TI - Lessons learnt inform our approach to new antivascular endothelial growth factor treatments for neovascular age-related macular degeneration. PMID- 24152188 TI - Further cause for concern in childhood vision impairment. PMID- 24152189 TI - Control the wettability of poly(n-isopropylacrylamide-co-1-adamantan-1-ylmethyl acrylate) modified surfaces: the more Ada, the bigger impact? AB - Surface-initiated SET-LRP was used to synthesize polymer brush containing N isopropylacrylamide and adamantyl acrylate using Cu(I)Cl/Me6-TREN as precursor catalyst and isopropanol/H2O as solvent. Different reaction conditions were explored to investigate the influence of different parameters (reaction time, catalyst concentration, monomer concentration) on the polymerization. Copolymers with variable 1-adamantan-1-ylmethyl acrylate (Ada) content and comparable thickness were synthesized onto silicon surfaces. Furthermore, the hydrophilic and bioactive molecule beta-cyclodextrin-(mannose)7 (CDm) was synthesized and complexed with adamantane via host-guest interaction. The effect of adamantane alone and the effect of CDm together with adamantane on the wettability and thermoresponsive property of surface were investigated in detail. Experimental and molecular structure analysis showed that Ada at certain content together with CDm has the greatest impact on surface wettability. When Ada content was high (20%), copolymer-CDm surfaces showed almost no CDm complexed with Ada as the result of steric hindrance. PMID- 24152190 TI - Ion selective permeation through cellulose acetate membranes in forward osmosis. AB - Solute-solute interactions can have a dramatic impact on the permeation of solutes through dense polymeric membranes. In particular, understanding how solute-solute interactions can affect the design of osmotically driven membrane processes (ODMPs) is critical to the successful development of these emerging water treatment and energy generation processes. In this work, we investigate the influence that solute-solute interactions have on nitrate permeation through an asymmetric cellulose acetate forward osmosis membrane. A series of experiments that included systematic modifications to the cation paired with nitrate, the identity of the draw solute, and the solution pH were conducted. These experiments reveal that in the unique operating geometry of ODMPs, where solute containing solutions are present on both sides of the membrane, nitrate fluxes are significantly higher (>15 times in some cases) than predicted by existing models for solute permeation in ODMPs. The identity of the cation paired with nitrate influences the flux of nitrate; the identity of the cation in the draw solution does not affect the flux of nitrate; however, the identity of the anion in the draw solution has the most significant impact on the flux of nitrate. These results suggest that an ion exchange mechanism, which allows nitrate to switch rapidly with anions from the draw solution, is present when cellulose acetate based membranes are used in ODMPs. PMID- 24152192 TI - Resveratrol as a therapeutic agent for renal fibrosis induced by unilateral ureteral obstruction. AB - AIMS: Renal fibrosis is a common outcome of chronic kidney disease. This study was designed to examine the protective effects of resveratrol (RSV) against renal fibrosis induced by unilateral ureteral obstruction (UUO). We also attempted to elucidate the potential mechanism involved. METHODS: Mice were randomly divided into three groups: sham-operated, UUO, and UUO/RSV (20 mg.kg(-1).day(-1)). Histological changes were examined using periodic acid-Schiff and Masson's trichrome staining after 14 days. Superoxide dismutase (SOD), malondialdehyde (MDA), and 8-OHdG levels were determined using a commercially available kit. ICAM 1, TNF-alpha, and TGF-beta levels were measured using real-time PCR. Fibronectin levels were measured by western blot, and the Smad3 acetylation and Sirt1 were examined by immunoprecipitation and western blot. RESULTS: Our study showed that RSV treatment significantly attenuated renal injury including extracellular matrix deposition and tubulointerstitium damage. Renal cortical mRNA levels of ICAM-1, TNF-alpha, and TGF-beta, protein expression of fibronectin and Smad3 acetylation were significantly upregulated in the UUO group. However, treatment with RSV significantly decreased the expression of these proteins. Furthermore, RSV also decreased the levels of reactive oxygen species (ROS) including MDA and 8-OHdG, and increased the level of SOD, which protects cells against ROS damage. CONCLUSION: Our findings suggest that RSV treatment inhibits oxidative stress, Smad3 acetylation, and renal interstitial fibrosis. Therefore, RSV may have potential as a therapeutic target for the treatment of chronic kidney disease. PMID- 24152191 TI - Chemoproteomic discovery of cysteine-containing human short open reading frames. AB - The application of ribosome profiling and mass spectrometry technologies has recently revealed that the human proteome is larger than previously appreciated. Short open reading frames (sORFs), which are difficult to identify using traditional gene-finding algorithms, constitute a significant fraction of unknown protein-coding genes. Thus, experimental approaches to identify sORFs provide invaluable insight into the protein-coding potential of genomes. Here, we report an affinity-based approach to enrich and identify cysteine-containing human sORF encoded polypeptides (ccSEPs) from cells. This approach revealed 16 novel ccSEPs, each derived from an uncharacterized sORF, demonstrating its potential for discovering new genes. We validated expression of a SEP from its endogenous RNA, and demonstrated the specificity of our labeling approach using synthetic SEP. The discovery of additional human SEPs and their conservation indicate the potential importance of these molecules in biology. PMID- 24152193 TI - Rural Allied Health Scholarships: do they make a difference? AB - INTRODUCTION: The problem of recruiting and retaining a qualified rural and remote health workforce is well recognised and a number of strategies have been put in place to address this issue, including the use of bonded scholarship programs. However there is a paucity of evidence regarding the impact of scholarships on workforce outcomes particularly in relation to allied health professionals. This project involved a review of the Queensland Health Rural Scholarship Scheme (Allied Health) (QHRSS-AH) including impacts on those engaged with the scholarship program and for the funding organisation. Specifically this study aimed to examine the profile of the QHRSS-AH recipients from 2000 to 2010 including graduate recruitment outcomes and retention within the scholarship program. It also explored the influence of the QHRSS-AH on early career practice location decisions and the features of the scheme that influenced motivation to be involved as either a scholarship holder or manager, perceived barriers to employment of scholarship holders in rural or remote services, experiences of scholarship holders as new graduates in rural and remote services and views on support requirements. METHODS: A mixed methods study was conducted involving quantitative analysis of existing Queensland Health scholarship data and a qualitative study that used one-on-one, in-depth telephone interviews with 17 past or current scholarship holders and 11 managers of scholarship holders. RESULTS: Of the 146 participants, 69.2% had completed or were completing the service period (41.1% were post-bond and 28.1% were currently completing the service period). Of the remainder, 14.4% were still completing the study period, 2.7% had deferred the service period and 13.7% had broken service bonds. Scholarship holders and managers indicated support for scholarships. Key motivators for applying for a scholarship were financial and job security upon graduation, although the general appeal of and preference for rural practice was an underlying motivator. Regardless of receiving a scholarship, most scholarship recipients reported they would have gone into rural and remote practice. Professional and clinical support and supervision, supportive work environment and culture, mentoring and professional development are important for retention. New graduates need extra support to assist in the undergraduate-to-practice transition and both scholarship holders and managers emphasised the important role played by health services in having well defined, consistent, operational processes that orient and support new graduates particularly in relation to supervision, mentoring and professional development. CONCLUSION: Although scholarship holders and their managers support the rural scholarship program, aspects of the scholarships in their current form require consideration in light of current workforce supply and demand and changing professional structures within the organisation. While many scholarship holders felt well supported as a new graduate entering rural practice, others identified gaps in relation to their experiences and the support they received. Opportunities exist for more standardised approaches across all services to strengthen the support structures that are in place, particularly for new graduates. PMID- 24152194 TI - Romiplostim in children with chronic immune thrombocytopenia (ITP): the French experience. AB - A minority of children with chronic immune thrombocytopenia (ITP) require therapeutic intervention to prevent haemorrhagic risk. This retrospective national study evaluated romiplostim in childhood non-responsive or refractory chronic ITP. Between 2009 and 2012, 10 patients whose Buchanan score was 3-4 were treated with romiplostim. The median duration of thrombocytopenia was 1.9 years (0.8-15). The median duration of romiplostim treatment was 9 months (3-36). A response was observed in 5/10 patients (one complete, four partial). No serious adverse effect was noticed. The long-term benefit/risk balance of this innovative treatment is currently recorded by Centre de Reference National des Cytopenies Auto-immunes de l'Enfant. PMID- 24152195 TI - Elevated transglutaminase 2 activity is associated with hypoxia-induced experimental pulmonary hypertension in mice. AB - Previous studies in human patients and animal models have suggested that transglutaminase 2 (TG2) is upregulated in pulmonary hypertension (PH), a phenomenon that appears to be associated with the effects of serotonin (5 hydroxytryptamine; 5-HT) in this disease. Using chemical tools to interrogate and inhibit TG2 activity in vivo, we have shown that pulmonary TG2 undergoes marked post-translational activation in a mouse model of hypoxia-induced PH. We have also identified irreversible fluorinated TG2 inhibitors that may find use as non invasive positron emission tomography probes for diagnosis and management of this debilitating, lifelong disorder. Pharmacological inhibition of TG2 attenuated the elevated right ventricular pressure but had no effect on hypertrophy of the right ventricle of the heart. A longitudinal study of pulmonary TG2 activity in PH patients is warranted. PMID- 24152197 TI - Low-dose heparin for elective percutaneous coronary intervention. AB - OBJECTIVES: We evaluated the safety and efficacy of low-dose heparin (40 IU/kg) for elective percutaneous coronary intervention (PCI). BACKGROUND: Current guidelines recommend a 70-100 IU/kg bolus of heparin for elective PCI, but this dose may be associated with increased bleeding risk. Low-dose heparin may have an advantage in this regard, but has not been well studied. METHODS: From January 2008 to October 2012, 300 patients underwent elective transfemoral PCI and were treated with an initial bolus of 40 IU/kg of heparin at the UCLA Medical Center. Dual antiplatelet therapy with clopidogrel and aspirin was administered prior to or just after diagnostic coronary angiography. The primary end-point was the composite of cardiac death, myocardial infarction, urgent target vessel revascularization for ischemia, or major bleeding within 30 days after PCI. RESULTS: The mean activating clotting time was 233 +/- 28 seconds. The primary end-point occurred in 2.3%. The cardiac death rate was 0.3% but was not related to the PCI. The myocardial infarction rate was 1.3%. Urgent target vessel revascularization occurred in 1 patient (0.3%). The major bleeding rate was 0.3%. No stent thrombosis occurred. CONCLUSION: Using a lower dose of heparin with dual antiplatelet therapy is safe and is associated with a low bleeding risk after transfemoral PCI while providing suppression of ischemic events. This may also represent a cost savings compared with other antithrombotic strategies. A randomized clinical trial comparing low-dose heparin with bivalirudin in patients is required to determine the optimal anticoagulation strategy. PMID- 24152196 TI - Pharmacological inhibition of GSK-3 in a guinea pig model of LPS-induced pulmonary inflammation: I. Effects on lung remodeling and pathology. AB - BACKGROUND: Glycogen synthase kinase-3 (GSK-3) is a constitutively active kinase that regulates multiple signalling proteins and transcription factors involved in a myriad of cellular processes. The kinase acts as a negative regulator in beta catenin signalling and is critically involved in the smad pathway. Activation of both pathways may contribute to pulmonary features of chronic obstructive pulmonary disease (COPD). METHODS: In the present study, we investigated the effect of the selective GSK-3 inhibitor SB216763 on pulmonary pathology in a guinea pig model of lipopolysaccharide (LPS)-induced COPD. Guinea pigs were instilled intranasally with LPS or saline twice weekly for 12 weeks and pre treated with either intranasally instilled SB216763 or corresponding vehicle 30 min prior to each LPS/saline challenge. RESULTS: Repeated LPS exposures activated beta-catenin signalling, primarily in the airway epithelium and submucosa. LPS also induced pulmonary inflammation and tissue remodelling as indicated by inflammatory cell influx, increased pulmonary fibronectin expression and enhanced small airway collagen content. Inhibition of GSK-3 by SB216763 did not affect LPS induced inflammatory cell influx, but prevented the small airway remodelling and, unexpectedly, inhibited the activation of beta-catenin in vivo. LPS or SB216763 treatment had no effect on the airway smooth muscle content and alveolar airspace size. However, GSK-3 inhibition prevented LPS-induced right ventricle hypertrophy. CONCLUSIONS: Our findings indicate that GSK-3 inhibition prevents LPS-induced pulmonary pathology in guinea pigs, and that locally reduced LPS induced beta-catenin activation appears in part to underlie this effect. PMID- 24152198 TI - The role of gravity in the evolution of mammalian blood pressure. AB - Understanding of the factors involved in determining the level of central arterial blood pressure in mammals has been clouded by inappropriate allometric analyses that fail to account for phylogenetic relationships among species, and require pressure to approach 0 as body size decreases. The present study analyses systolic, mean arterial, and diastolic blood pressure in 47 species of mammal with phylogenetically informed techniques applied to two-parameter equations. It also sets nonlinear, three-parameter equations to the data to remove the assumption of the two-parameter power equation that the smallest animals must have negligible blood pressure. These analyses show that blood pressure increases with body size. Nonlinear analyses show that mean blood pressure increases from 93 mmHg in a 10 g mouse to 156 mmHg in a 4 tonne elephant. The scaling exponent of blood pressure is generally lower than, though not significantly different from, the exponent predicted on the basis of the expected scaling of the vertical distance between the head and the heart. This indicates that compensation for the vertical distance above the heart is not perfect and suggests that the pressure required to perfuse the capillaries at the top of the body may decrease in larger species. PMID- 24152199 TI - The neonatal lung--physiology and ventilation. AB - This review article focuses on neonatal respiratory physiology, mechanical ventilation of the neonate and changes induced by anesthesia and surgery. Optimal ventilation techniques for preterm and term neonates are discussed. In summary, neonates are at high risk for respiratory complications during anesthesia, which can be explained by their characteristic respiratory physiology. Especially the delicate balance between closing volume and functional residual capacity can be easily disturbed by anesthetic and surgical interventions resulting in respiratory deterioration. Ventilatory strategies should ideally include application of an 'open lung strategy' as well avoidance of inappropriately high VT and excessive oxygen administration. In critically ill and unstable neonates, for example, extremely low-birthweight infants surgery in the neonatal intensive care unit might be an appropriate alternative to the operating theater. Best respiratory management of neonates during anesthesia is a team effort that should involve a joint multidisciplinary approach of anesthetists, pediatric surgeons, cardiologists, and neonatologists to reduce complications and optimize outcomes in this vulnerable population. PMID- 24152200 TI - Further investigation of the blood characteristics of Australian Quoll (Dasyurus spp.) species. AB - BACKGROUND: The Eastern and Spotted-Tailed Quolls are "near threatened" Australian dasyurid marsupials that have undergone significant reduction in their geographic ranges in the past 200 years. Captive breeding and research colonies now exist, allowing further efforts to more fully understand the physiology of these carnivorous species. OBJECTIVES: The aims of the study were to provide a more detailed study of blood chemistry and differential WBC counts for Eastern and Spotted-Tailed Quolls, and to determine the influence by 3 biologic factors. METHODS: Blood samples were taken from conscious, captive, healthy Eastern Quolls. A small number of samples from Spotted-Tailed Quolls were also available and were included in the study for comparison. Blood chemistry and differential WBC counts were compared to determine season-, age-, and sex-related differences. RESULTS: For many of the analytes, blood chemistry results were comparable to other marsupial ranges, and no significant differences between sexes were detected (P > .05). Seasonal differences were determined for total bilirubin, glucose, creatinine, and potassium concentrations in the Eastern Quoll. Generally, higher concentrations of these analytes were observed in the summer; however, amylase activity was significantly higher in autumn (southern hemisphere). Eastern Quolls one year of age and younger had significantly (P < .05) higher ALP activities than older animals. CONCLUSIONS: The normal ranges determined in this study can be used to assess clinical health of quolls and will assist with captive management and future reintroduction programs to the wild. PMID- 24152201 TI - Nickel and cobalt release from jewellery and metal clothing items in Korea. AB - BACKGROUND: In Korea, the prevalence of nickel allergy has shown a sharply increasing trend. Cobalt contact allergy is often associated with concomitant reactions to nickel, and is more common in Korea than in western countries. OBJECTIVE: The aim of the present study was to investigate the prevalence of items that release nickel and cobalt on the Korean market. MATERIALS AND METHODS: A total of 471 items that included 193 branded jewellery, 202 non-branded jewellery and 76 metal clothing items were sampled and studied with a dimethylglyoxime (DMG) test and a cobalt spot test to detect nickel and cobalt release, respectively. RESULTS: Nickel release was detected in 47.8% of the tested items. The positive rates in the DMG test were 12.4% for the branded jewellery, 70.8% for the non-branded jewellery, and 76.3% for the metal clothing items. Cobalt release was found in 6.2% of items. Among the types of jewellery, belts and hair pins showed higher positive rates in both the DMG test and the cobalt spot test. CONCLUSION: Our study shows that the prevalence of items that release nickel or cobalt among jewellery and metal clothing items is high in Korea. PMID- 24152202 TI - Expression of an exogenous 1-aminocyclopropane-1-carboxylate deaminase gene in Mesorhizobium spp. reduces the negative effects of salt stress in chickpea. AB - Our goal was to study the symbiotic performance of two Mesorhizobium ciceri strains, transformed with an exogenous 1-aminocyclopropane-1-carboxylate deaminase gene (acdS), in chickpea plants under salinity stress. The EE-7 (salt sensitive) and G-55 (salt-tolerant) M. ciceri strains were transformed with an acdS gene present on plasmid pRKACC. Salinity significantly reduced the overall growth of plants inoculated with either wild-type strains. Although the growth of plants inoculated with either salt-sensitive or salt-tolerant strain was reduced under salinity, the salt-tolerant strain showed a higher ability to nodulate chickpea under salt stress compared with the salt-sensitive strain. The shoot dry weight was significantly higher in plants inoculated with the acdS-transformed salt-sensitive strain compared with the plants inoculated with the native strain in the presence of salt. The negative effects of salt stress were also reduced in nodulation when using acdS-transformed strains in comparison with the wild-type strains. Interestingly, by expressing the exogenous acdS gene, the salt-sensitive strain was able to induce nodules in the same extent as the salt-tolerant strain. Although preliminary, these results suggest that genetic modification of a Mesorhizobium strain can improve its symbiotic performance under salt stress and indicate that ACC deaminase can play an important role in facilitating plant rhizobium interaction under salinity conditions. PMID- 24152203 TI - Emotional-motivational barriers to blood donation among Togolese adults: a structural approach. AB - BACKGROUND: Although the number of blood donors has been rapidly increasing in Togo since 2003, it is nevertheless insufficient to cover the demand. OBJECTIVES: To increase needed blood donation in Togo, it is necessary to understand why most people are reluctant to do it. METHODS: A sample of 400 adult volunteers in Lome, mostly university educated, rated, on a scale of 0-10, the relevance to them of a comprehensive list of reasons that might deter people from donating blood. The ratings of 250 participants were subjected to factor analysis, and the resulting factorial structure was confirmed on the ratings of the other 150 participants. RESULTS: The resulting six factors were labelled (in order of their ratings of a representative sample of items): Lack of Courage and Lack of Information (mean 5.43 of 10), Concerns about the Use of Blood (4.72), Risk Aversion (4.37), Fear of Medical Settings (2.41), Conformity with Tradition (1.88) and Indifference to Others and Hostility to the Procedure (1.69). CONCLUSION: To increase blood donation, a public information campaign should address the emotional-motivational barriers found even in the most educated segment of Togolese society. PMID- 24152204 TI - Using random forest to model the domain applicability of another random forest model. AB - In QSAR, a statistical model is generated from a training set of molecules (represented by chemical descriptors) and their biological activities. We will call this traditional type of QSAR model an "activity model". The activity model can be used to predict the activities of molecules not in the training set. A relatively new subfield for QSAR is domain applicability. The aim is to estimate the reliability of prediction of a specific molecule on a specific activity model. A number of different metrics have been proposed in the literature for this purpose. It is desirable to build a quantitative model of reliability against one or more of these metrics. We can call this an "error model". A previous publication from our laboratory (Sheridan J. Chem. Inf. Model., 2012, 52, 814-823.) suggested the simultaneous use of three metrics would be more discriminating than any one metric. An error model could be built in the form of a three-dimensional set of bins. When the number of metrics exceeds three, however, the bin paradigm is not practical. An obvious solution for constructing an error model using multiple metrics is to use a QSAR method, in our case random forest. In this paper we demonstrate the usefulness of this paradigm, specifically for determining whether a useful error model can be built and which metrics are most useful for a given problem. For the ten data sets and for the seven metrics we examine here, it appears that it is possible to construct a useful error model using only two metrics (TREE_SD and PREDICTED). These do not require calculating similarities/distances between the molecules being predicted and the molecules used to build the activity model, which can be rate-limiting. PMID- 24152205 TI - Sensing small molecule interactions with lipid membranes by local pH modulation. AB - Herein, we utilized a label-free sensing platform based on pH modulation to detect the interactions between tetracaine, a positively charged small molecule used as a local anesthetic, and planar supported lipid bilayers (SLBs). The SLBs were patterned inside a flow cell, allowing for various concentrations of tetracaine to be introduced over the surface in a buffer solution. Studies with membranes containing POPC (1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine) yielded an equilibrium dissociation constant value of Kd = 180 +/- 47 MUm for this small molecule-membrane interaction. Adding cholesterol to the SLBs decreased the affinity between tetracaine and the bilayers, while this interaction tightened when POPE (1-hexadecanoyl-2-(9-Z-octadecenoyl)-sn-glycero-3 phosphoethanolamine) was added. Studies were also conducted with three negatively charged membrane lipids, POPG (1-palmitoyl-2-oleoyl-sn-glycero-3-phospho-(1'-rac glycerol) (sodium salt)), POPS (1-palmitoyl-2-oleoyl-sn-glycero-3-phospho-l serine (sodium salt)), and ganglioside GM1. All three measurements gave rise to a similar tightening of the apparent Kd value compared with pure POPC membranes. The lack of chemical specificity with the identity of the negatively charged lipid indicated that the tightening was largely electrostatic. Through a direct comparison with ITC measurements, it was found that the pH modulation sensor platform offers a facile, inexpensive, highly sensitive, and rapid method for the detection of interactions between putative drug candidates and lipid bilayers. As such, this technique may potentially be exploited as a screen for drug development and analysis. PMID- 24152206 TI - Glycemic control and insulin requirements in type 1 diabetic patients depending on the clinical characteristics at diabetes onset. AB - INTRODUCTION: The long-term prognosis of type 1 diabetes (T1DM) was evaluated in relation to the clinical characteristics at the time of diabetes onset. PATIENTS AND METHODS: We examined retrospectively the clinical and laboratory characteristics present at the time of diagnosis in 301 adult patients (187 men) consecutively admitted to hospital with T1DM onset and evaluated the clinical outcome of T1DM during 6 +/- 4.8 years following diagnosis. RESULTS: Women needed a greater insulin dose per kg of body weight over the first 2 years following diagnosis. Younger patients at diagnosis had greater insulin requirements during follow-up. Patients with at least one positive pancreatic antibody needed a greater insulin dose 2 years after diagnosis and developed poorer glycemic control during follow-up than patients with no detectable pancreatic antibodies at onset. Diabetic ketoacidosis at onset was associated with greater insulin requirements over the first 2 years of follow-up and with poorer glycemic control during the course of the illness. C-peptide levels at diagnosis correlated with insulin requirements during the first 2 years of follow-up. Patients with higher HbA1c levels at diagnosis had greater insulin requirements in the first year of follow-up. A correlation was found between the HbA1c levels at the consecutive years of follow-up. CONCLUSIONS: Female sex, younger age, humoral pancreatic autoimmunity, diabetic ketoacidosis, lower pancreatic reserve and higher HbA1c levels at onset could predict a poor long-term clinical outcome of T1DM in terms of insulin requirements and glycemic control. PMID- 24152207 TI - Synthesis, spectral, and structural studies of porphyrins having sterically hindered [eta(5)-CpCo(eta(4)-C4Ph4)] cobalt sandwich units at the meso positions. AB - Synthesis, spectral, and structural studies of the first examples of porphyrins substituted at the meso positions with sterically hindered eta(5)-CpCo(eta(4) C4Ph4) cobalt sandwich units are described. The novel dipyrromethane derived cobalt sandwich compound {eta(5)-[(C4H4N)2CH]C5H4}Co(eta(4)-C4Ph4) 1, as well as its parent aldehyde, eta(5)-[C5H4(CHO)]Co(eta(4)-C4Ph4), were used in the synthesis of porphyrins having one or two eta(5)-CpCo(eta(4)-C4Ph4) groups at their meso positions. 1,9-Diformyldipyrromethane derived eta(5)-CpCo(eta(4) C4Ph4) 2 was synthesized using dipyrromethane 1 under Vilsmeier conditions. A reaction of 2 with unsubstituted dipyrromethane under basic conditions in the presence of Pd(C6H5CN)2Cl2 yielded an A-type palladium coordinated porphyrin 3 [where A = eta(5)-CpCo(eta(4)-C4Ph4)]. A similar reaction of 2 with meso aryl and ferrocenyl-substituted dipyrromethanes yielded trans-AB type palladium coordinated porphyrins 4-6 [where A = eta(5)-CpCo(eta(4)-C4Ph4) and B = 4-tert butylphenyl 4, ferrocenyl 5, and pentafluorophenyl 6]. Reactions of 2 with 5 ferrocenyl dipyrromethane under the same reaction conditions in the presence of Ni(acac)2 and Zn(OAc)2 gave the trimetallic nickel(II) and zinc(II) complexed trans-AB type porphyrins 7 and 8 having both cobalt and iron sandwich units at the meso positions. Crystal structure of the Pd(II) porphyrin 5 and nickel(II) porphyrin 7 showed nonplanar structures having distinct ruffle type distortion of the porphyrin ring. Demetalation of the zinc(II) trans-AB type porphyrin 8 in the presence of trifluoroacetic acid gave the metal free base porphyrin 9. Reactions of the cobalt sandwich aldehyde [(eta(5)-C5H4(CHO)]Co(eta(4)-C4Ph4) with sterically hindered dipyrromethane derivatives under acid-catalyzed condensation reactions gave trans-A2B2 type porphyrins [where A = eta(5)-CpCo(eta(4)-C4Ph4) and B = pentafluorophenyl, 10 mesityl 11]. In contrast, reactions of [eta(5) C5H4(CHO)]Co(eta(4)-C4Ph4) with sterically unhindered meso-4-tert-butylphenyl dipyrromethane resulted in both AB3 12 and cis-A2B2 13 type porphyrins [where A = eta(5)-CpCo(eta(4)-C4Ph4) and B = (4-tert-butylphenyl] as a result of scrambling. The new porphyrin derivatives have been structurally characterized, and their spectral and electrochemical features were determined. PMID- 24152208 TI - Further characterization of the target of a potential aptamer biomarker for pancreatic cancer: cyclophilin B and its posttranslational modifications. AB - Posttranslational modifications on proteins can serve as useful biomarkers for disease. However, their discovery and detection in biological fluids is challenging. Aptamers are oligonucleotide ligands that demonstrate high affinity toward their target proteins and can discriminate closely related proteins with superb specificity. Previously, we generated a cyclophilin B aptamer (M9-5) that could discriminate sera from pancreatic cancer patients and healthy volunteers with high specificity and sensitivity. In our present work we further characterize the aptamer and the target protein, cyclophilin B, and demonstrate that the aptamer could discriminate between cyclophilin B expressed in human cells versus bacteria. Using mass-spectrometric analysis, we discovered post translational modifications on cyclophilin B that might be responsible for the M9 5 selectivity. The ability to distinguish between forms of the same protein with differing post-translational modifications is an important advantage of aptamers as tools for identification and detection of biomarkers. PMID- 24152209 TI - Relationship between Sensory Stimulation and Side Effects in Percutaneous Radiofrequency Treatment of the Trigeminal Ganglion. AB - INTRODUCTION: The objective of this study was to determine the efficacy of percutaneous radiofrequency (RF) treatment of the trigeminal ganglion for treating patients with trigeminal neuralgia, to determine which patients have a long-term benefit, and to evaluate the effect of RF parameters. METHODS: A retrospective study in 28 consecutive patients in combination with a follow-up questionnaire (n = 26, 93% response). RESULTS: An initial treatment effect of 89% was observed, 60% sustained at 12-month follow-up. Major side effects were hypesthesia (56%), dry eye (20%), and masseter muscle weakness (12%). A lower sensory stimulation threshold during treatment was associated with better patient satisfaction (P = 0.016), improved pain relief (P = 0.039), and trended toward more hypesthesia (P = 0.077). DISCUSSION: This low-volume study reported treatment effects in an older population that were similar to previous studies. Only a higher incidence of hypesthesia was detected by long-term follow-up. This study supported the high efficiency of RF treatment, but there was a high level of side effects. Most notable, low sensory stimulation was associated with increased hypesthesia, whereas higher stimulation levels yielded less effectiveness. Further investigation of an optimal sensory stimulation range for percutaneous RF treatment of the trigeminal ganglion was found to be warranted. PMID- 24152210 TI - COPD exacerbation frequency, pharmacotherapy and resource use: an observational study in UK primary care. AB - Chronic Obstructive Pulmonary Disease (COPD) management represents a significant health resource use burden. Understanding of current resource use, treatment strategies and outcomes can improve future COPD management, for patient benefit and to aid efficient service delivery. This study aimed to describe exacerbation frequency, pharmacotherapy and health resource use in COPD management in routine UK primary care. A retrospective, observational study using routine clinical records of 511 patients with COPD, was undertaken in 10 General Practices in England. Up to 3 years' patient data were collected and analysed. 75% (234/314) patients with mild-moderate COPD (>=50% predicted FEV1) received inhaled corticosteroids (ICS). 11% of patients (54/511) received ICS monotherapy. Mean (standard deviation) annual exacerbation frequency was 1.1 (1.2) in mild moderate, 1.7 (1.6) in severe (30-49% predicted FEV1) and 2.2 (2.0) in very severe (<30% predicted FEV1) COPD. 14% patients (69/511) had a mean exacerbation frequency of >=3/year ('frequent-exacerbators'); 9% (27/314) of patients with mild-moderate, 19% (27/145) with severe and 29% (15/52) with very severe COPD. 14% (10/69) of frequent-exacerbators failed to receive inhaled long-acting beta agonists (LABA), 25% (17/69) inhaled long-acting muscarinic antagonists (LAMA), and 12% ('/69) ICS. Frequent-exacerbators had a median of 6.67 primary care contacts/year, 1.0 secondary care visits/year and 21% were hospitalised for COPD/year. Inhaled therapy was frequently inappropriate, with over-use of ICS in patients with mild-moderate COPD. COPD exacerbations were associated with high health resource use and occurred at all levels of disease severity. COPD management strategies should encompass risk-stratification for both exacerbation frequency and physiological impairment. PMID- 24152211 TI - Comparing dynamic hyperinflation and associated dyspnea induced by metronome paced tachypnea versus incremental exercise. AB - Dynamic hyperinflation (DH) during exercise is associated with both dyspnea and exercise limitation in COPD. Metronome-paced tachypnoea (MPT) is a simple alternative for studying DH. We compared MPT with exercise testing (XT) as methods of provoking DH, and assessed their relationship with dyspnea. We studied 24 patients with moderate COPD (FEV1 59 +/- 9% predicted) after inhalation of ipratropium/salbutamol combination or placebo in a double-blind, crossover design. Inspiratory capacity (IC) was measured at baseline and after 30 seconds of MPT with breathing frequencies (fR) of 20, 30 and 40 breaths/min and metronome defined I:E ratios of 1:1 and 1:2, in random sequence, followed by incremental cycle ergometry with interval determinations of IC. DH was defined as a decline in IC from baseline (?IC) for both methods. Dyspnea was assessed using a Borg CR 10 scale. ?IC during MPT was greater with higher fR and I:E ratio of 1:1 versus 1:2, and less when patients were treated with bronchodilator rather than placebo (P = 0.032). DH occurred during 19 (40%) XTs, and during 35 (73%) tests using MPT. Eleven of 18 (61%) non-congruent XTs (where DH occurred on MPT but not XT) terminated before fR of 40 breaths/min was reached. Although greater during XT, the intensity of dyspnea bore no relationship to DH during either MPT and XT. MPT at 40 breaths/min and I:E of 1:1 elicits the greatest ?IC, and is a more sensitive method for demonstrating DH. The relationship between DH and dyspnea is complex and not determined by DH alone. PMID- 24152212 TI - Chronic obstructive pulmonary disease and asthma-patient characteristics and health impairment. AB - Abstract Background: Persons with chronic obstructive pulmonary disease (COPD) and/or asthma have great risk for morbidity. There has been sparse state-specific surveillance data to estimate the impact of COPD or COPD with concomitant asthma (overlap syndrome) on health-related impairment. METHODS: The North Carolina (NC) Behavioral Risk Factor Surveillance System (BRFSS) was used to assess relationships between COPD and asthma with health impairment indicators. Five categories [COPD, current asthma, former asthma, overlap syndrome, and neither] were defined for 24,073 respondents. Associations of these categories with health impairments (physical or mental disability, use of special equipment, mental or physical distress) and with co-morbidities (diabetes, coronary heart disease, stroke, arthritis, and high blood pressure) were assessed. RESULTS: Fifteen percent of NC adults reported a COPD and/or asthma history. The overall age adjusted prevalence of any self-reported COPD and current asthma were 5.6% and 7.6%, respectively; 2.4% reported both. In multivariable analyses, adults with overlap syndrome, current asthma only, and COPD only were twice as likely as those with neither disease to report health impairments (p < 0.05). Compared to those with neither disease, adults with overlap syndrome and COPD were more likely to have co-morbidities (p < 0.05). The prevalence of the five co-morbid conditions was highest in overlap syndrome; comparisons with the other groups were significant (p < 0.05) only for diabetes, stroke, and arthritis. CONCLUSIONS: The BRFSS demonstrates different levels of health impairment among persons with COPD, asthma, overlap syndrome, and those with neither disease. Persons reporting overlap syndrome had the most impairment and highest prevalence of co-morbidities. PMID- 24152213 TI - Reasons persons with COPD do not walk and relationship with daily step count. AB - BACKGROUND: Physical activity (PA) is significantly reduced in persons with COPD. Assessing reasons why persons with COPD do not engage in PA can guide development of effective interventions to promote PA. METHODS: We queried 102 participants with stable COPD about disease-related and general reasons why they do not walk more. The StepWatch Activity Monitor (Orthocare Innovations, Mountlake Terrace, WA, USA) assessed daily step count, a direct measure of PA. Regression models assessed daily step count by response categories, adjusting for age and FEV1 % predicted. RESULTS: Subjects had mean age 72 +/- 8 years and mean FEV1 1.48 +/- 0.55 L (52 +/- 19% predicted). COPD-related worries of becoming short of breath (SOB), needing to use inhalers, or oxygen level becoming low were endorsed by 31, 14, and 12 subjects, respectively. Controlling for age and FEV1% predicted, those who worried about becoming SOB walked an average of 1,329 fewer steps per day than those who did not worry (p = 0.020). Those who worried about needing to use inhalers walked an average of 1,806 fewer steps per day than those who did not worry (p = 0.016). Subjects who were the most motivated and confident walked significantly more than those who were the least motivated and confident. CONCLUSIONS: Presence of COPD-related reasons and lower motivation and confidence are associated with lower daily step count. Management of dyspnea and education about medication use during exercise, and strategies to increase motivation and confidence could facilitate walking in COPD. PMID- 24152214 TI - Quantifying the forces driving cell-cell adhesion in a fungal pathogen. AB - Owing to its ability to form biofilms on implanted medical devices, the fungal pathogen Candida albicans causes frequent infections in humans. A hallmark of C. albicans biofilms is the presence of two types of cells, budding yeast cells and growing hyphae, which are bound together and embedded in extracellular matrix material. Although cell-cell adhesion is critical to biofilm formation, architecture, and cohesion, we know little about the fundamental forces behind this interaction. Here, we use single-cell force spectroscopy to quantify the forces engaged in yeast-hyphae adhesion, focusing on the role of Als (agglutinin like sequence) proteins as prototypes of cell adhesion molecules. We show that adhesion between individual yeast and hyphal cells involves strong, short-range cohesive interactions (1.1 +/- 0.2 nN; 86 +/- 33 nm) and weak, long-range tether interactions (0.4 +/- 0.2 nN; 234 +/- 81 nm). Control experiments demonstrate that these interactions originate from cell surface proteins that are specific to C. albicans. Using mutant strains deficient for Als expression, we find that Als3 proteins, primarily expressed on the germ tube, play a key role in establishing strong cohesive adhesion. We suggest a model in which cohesive adhesion during biofilm formation originates from tight hydrophobic interactions between Als tandem repeat domains on adjacent cells. When subjected to force, the two interacting cell surfaces detach, but the cell bodies remain tethered through macromolecular extensions. Our results represent the first direct, noninvasive measurement of adhesion forces between interacting fungal cells and provide novel insights into the molecular origin of the cohesive strength of fungal biofilms. PMID- 24152215 TI - Effects of far-infrared irradiation on myofascial neck pain: a randomized, double blind, placebo-controlled pilot study. AB - OBJECTIVES: The objective of this study was to determine the relative efficacy of irradiation using a device containing a far-infrared emitting ceramic powder (cFIR) for the management of chronic myofascial neck pain compared with a control treatment. DESIGN: This was a randomized, double-blind, placebo-controlled pilot study. PARTICIPANTS: The study comprised 48 patients with chronic, myofascial neck pain. INTERVENTION: Patients were randomly assigned to the experimental group or the control (sham-treatment) group. The patients in the experimental group wore a cFIR neck device for 1 week, and the control group wore an inert neck device for 1 week. MAIN OUTCOME MEASUREMENT: Quantitative measurements based on a visual analogue scale (VAS) scoring of pain, a sleep quality assessment, pressure-pain threshold (PPT) testing, muscle tone and compliance analysis, and skin temperature analysis were obtained. RESULTS: Both the experimental and control groups demonstrated significant improvement in pain scores. However, no statistically significant difference in the pain scores was observed between the experimental and control groups. Significant decreases in muscle stiffness in the upper regions of the trapezius muscles were reported in the experimental group after 1 week of treatment. CONCLUSIONS: Short-term treatment using the cFIR neck device partly reduced muscle stiffness. Although the differences in the VAS and PPT scores for the experimental and control groups were not statistically significant, the improvement in muscle stiffness in the experimental group warrants further investigation of the long-term effects of cFIR treatment for pain management. PMID- 24152216 TI - The art of doing almost nothing: how a core Taijiquan principle can help us to understand turning points in therapeutic processes. AB - Health care professionals usually strive to reach turning points in therapeutic processes in order to help patients manage a problem or difficult situation. The professional aligns with the patient's needs through what can be described as "the art of doing almost nothing": listening, noticing, thinking, waiting, witnessing, and preventing harm. This process is similar to the Taijiquan principle of alignment illustrated in the yin-yang symbol taijitu. For both therapeutic process and Taijiquan, mastery is characterized through the phenomenon that the closer one gets to the turning point, the less visible are the practitioner's efforts in terms of observable action. PMID- 24152217 TI - Homogeneous and stereoselective copper(II)-catalyzed monohydration of methylenemalononitriles to 2-cyanoacrylamides. AB - A facile and efficient route for the homogeneous and highly stereoselective monohydration of substituted methylenemalononitriles to (E)-2-cyanoacrylamides catalyzed by copper(II) acetate monohydrate in acetic acid containing 2% water is described, and a mechanism is proposed. The protocol has proved to be suitable for the monohydration of dicyanobenzenes and 2-substituted malononitriles. PMID- 24152218 TI - hMICL and CD123 in combination with a CD45/CD34/CD117 backbone - a universal marker combination for the detection of minimal residual disease in acute myeloid leukaemia. AB - Real-time quantitative polymerase chain reaction (qPCR) has been extensively validated for the detection of minimal residual disease (MRD) in acute myeloid leukaemia (AML). Meanwhile, multicolour flow cytometry (MFC) has received less attention because the so-called leukaemia-associated immunophenotypes (LAIPs) are generally of lower sensitivity and specificity, and prone to change during therapy. To improve MRD assessment by MFC, we here evaluate the combination of human Myeloid Inhibitory C-type Lectin (hMICL, also termed C-type lectin domain family 12, member A, CLEC12A) and CD 123 (also termed interleukin-3 receptor alpha, IL3RA) in combination with CD34 and CD117 (KIT), as an MRD assay in pre clinical and clinical testing in 69 AML patients. Spiking experiments revealed that the assay could detect MRD down to 10(-4) in normal bone marrow with sensitivities equalling those of validated qPCR assays. Moreover, it provided at least one MFC MRD marker in 62/69 patients (90%). High levels of hMICL/CD123 LAIPs at the post-induction time-point were a strong prognostic marker for relapse in patients in haematological complete remission (P < 0.001). Finally, in post induction samples, hMICL/CD123 LAIPs were strongly correlated (r = 0.676, P = 0.0008) to applied qPCR targets. We conclude the hMICL/CD123-based MFC assay is a promising MRD tool in AML. PMID- 24152219 TI - Concurrent measures of fusion and transduction efficiency of primary CD34+ cells with human immunodeficiency virus 1-based lentiviral vectors reveal different effects of transduction enhancers. AB - Lentiviral vectors (LVs) are used for various gene transfer applications, notably for hematopoietic gene therapy, but methods are lacking for precisely evaluating parameters that control the efficiency of transduction in relation to the entry of vectors into target cells. We adapted a fluorescence resonance energy transfer based human immunodeficiency virus-1 fusion assay to measure the entry of nonreplicative recombinant LVs in various cell types, including primary human hematopoietic stem progenitor cells (HSPCs), and to quantify the level of transduction of the same initially infected cells. The assay utilizes recombinant LVs containing beta-lactamase (BLAM)-Vpr chimeric proteins (BLAM-LVs) and encoding a truncated form of the low-affinity nerve growth factor receptor (DeltaNGFR). After infection of target cells with BLAM-LVs, the vector entry rapidly leads to BLAM-Vpr release into the cytoplasm, which is measured by cleavage of a fluorescent substrate using flow cytometry. Parallel cultures of the same infected cells show transduction efficiency resulting from DeltaNGFR expression. This LV-based fusion/transduction assay is a dynamic and versatile tool, revealing, for instance, the postentry restrictions of LVs known to occur in cells of hematopoietic origin, especially human HSPCs. Furthermore, this BLAM LV assay allowed us to evaluate the effect of cytokine prestimulation of HSPCs on the entry step of LVs. The assay also shows that transduction enhancers such as Vectofusin-1 or Retronectin can partially relieve the postentry block, but their effects differ in how they promote LV entry. In conclusion, one such assay should be useful to study hematopoietic postentry restrictions directed against LVs and therefore should allow improvements in various LV-based gene therapy protocols. PMID- 24152220 TI - Ecological segregation in a small mammal hybrid zone: habitat-specific mating opportunities and selection against hybrids restrict gene flow on a fine spatial scale. AB - The degree to which closely related species interbreed is determined by a complex interaction of ecological, behavioral, and genetic factors. We examine the degree of interbreeding between two woodrat species, Neotoma bryanti and N. lepida, at a sharp ecological transition. We identify the ecological association of each genotypic class, assess the opportunity for mating between these groups, and test whether they have similar patterns of year-to-year persistence on our study site. We find that 13% of individuals have a hybrid signature but that the two parental populations and backcrosses are highly segregated by habitat type and use. Also, we find that adult hybrids are comparable to parental types in terms of year-to year persistence on our site but that, among juveniles, significantly fewer hybrids reach adulthood on site compared to their purebred counterparts. Our analyses show that this hybrid zone is maintained by occasional nonassortative mating coupled with hybrid fertility, but that these factors are balanced by lower apparent survival of juvenile hybrids and habitat-based preference or selection that limits heterospecific mating while promoting backcrossing to habitat-specific genotypes. This system presents a novel example of the role that sharp resource gradients play in reproductive isolation and the potential for genetic introgression. PMID- 24152221 TI - Asymmetric synthesis of QUINAP via dynamic kinetic resolution. AB - A palladium-catalyzed, atroposelective C-P coupling process has been developed for the asymmetric synthesis of QUINAP and its derivatives in high enantiomeric excess. Bromide, triflate (OTf) and 4-methanesulfonylbenzenesulfonate (OSs) precursors were studied, leading in the case of the triflate to a novel dynamic kinetic resolution involving isomerization of an arylpalladium intermediate. The operationally simple methods described in this communication afford these important ligands in good to high yields and selectivity using low catalyst loading (<=3 mol % Pd). PMID- 24152222 TI - A scalable, knowledge-based analysis framework for genetic association studies. AB - BACKGROUND: Testing for marginal associations between numerous genetic variants and disease may miss complex relationships among variables (e.g., gene-gene interactions). Bayesian approaches can model multiple variables together and offer advantages over conventional model building strategies, including using existing biological evidence as modeling priors and acknowledging that many models may fit the data well. With many candidate variables, Bayesian approaches to variable selection rely on algorithms to approximate the posterior distribution of models, such as Markov-Chain Monte Carlo (MCMC). Unfortunately, MCMC is difficult to parallelize and requires many iterations to adequately sample the posterior. We introduce a scalable algorithm called PEAK that improves the efficiency of MCMC by dividing a large set of variables into related groups using a rooted graph that resembles a mountain peak. Our algorithm takes advantage of parallel computing and existing biological databases when available. RESULTS: By using graphs to manage a model space with more than 500,000 candidate variables, we were able to improve MCMC efficiency and uncover the true simulated causal variables, including a gene-gene interaction. We applied PEAK to a case control study of childhood asthma with 2,521 genetic variants. We used an informative graph for oxidative stress derived from Gene Ontology and identified several variants in ERBB4, OXR1, and BCL2 with strong evidence for associations with childhood asthma. CONCLUSIONS: We introduced an extremely flexible analysis framework capable of efficiently performing Bayesian variable selection on many candidate variables. The PEAK algorithm can be provided with an informative graph, which can be advantageous when considering gene-gene interactions, or a symmetric graph, which simply divides the model space into manageable regions. The PEAK framework is compatible with various model forms, allowing for the algorithm to be configured for different study designs and applications, such as pathway or rare-variant analyses, by simple modifications to the model likelihood and proposal functions. PMID- 24152223 TI - Functional and structural alterations of peritoneum and secretion of fibrotic cytokines in rats caused by high glucose peritoneal dialysis solutions. AB - OBJECTIVE: To determine functional and structural alterations of peritoneum and fibrotic cytokines expression in peritoneal dialysis (PD) rats. METHODS: 28 Sprague-Dawley (S-D) rats were randomly divided into four groups and dialyzed with various solutions daily for four weeks: (1) no solution (CON group), (2) 0.9% Saline solution (NS group), (3) 1.5% Dianeal (LG group), (4) 4.25% Dianeal (HG group). Peritoneal equilibration tests, ultrafiltration function and effluent protein quantification were measured. Peritoneum morphology was studied and immunohistochemistry were performed for detection of transforming growth factor beta1 (TGF-beta1), connective tissue growth factor (CTGF), and fibronectin (FN) proteins. Reverse transcriptional-polymerase chain reaction was used to analyze the expression of TGF-beta1, CTGF mRNA. RESULTS: Administration of 4.25% Dianeal caused functional and structural changes of peritoneum, including protein loss through the transport process, decrease of peritoneal solute transport rate and ultrafiltration capacity. The collagen of peritoneum in the HG group was thicker than the other groups. The levels of CTGF, TGF-beta1, and FN proteins were significantly the highest in the HG group, followed by the LG group. The liner correlation analysis showed positive correlations between the levels of CTGF, TGF beta1, and FN proteins and the collagen thickness. The expression of TGF-beta1 and CTGF mRNA in the HG group were significantly higher than those in the other groups and were indicated positive correlation. CONCLUSION: Using high glucose peritoneal dialysis solutions in rats may not only lead to processing of peritoneal fibrosis, which is promoted by ectopic expression of TGF-beta1, but also increase the expression of CTGF. CTGF is an important fibrotic media of peritoneal fibrosis in PD rats. PMID- 24152224 TI - Evaluation of a blood group genotyping platform (BLOODchip((r)) Reference) in Japanese samples. AB - BACKGROUND: Blood-group genotyping arrays have been widely used in Caucasian and African American populations, but have not been thoroughly tested in Japanese subjects. AIM: To evaluate, using the BLOODchip((r)) Reference genotyping system, the concordance of previously typed samples with expected phenotypes and the coverage of the Japanese variants. METHODS: Blood samples from 100 Japanese donors were obtained. DNA was extracted with QIAsymphony (Qiagen, Hilden, Germany). Samples were typed by serological methods and processed with the BLOODchip((r)) . When a non-concordant result was identified, further sequencing by polymerase chain reaction-single specific primer (PCR-SSP) was performed. RESULTS: Concordance between systems was 98% (736/751), and 98.8% (742/751) if only non-software-related non-concordances were considered. In the ABO group, 6 'No Call' (NC, inability of the BLOODchip((r)) to assign a result) were ascribed to a variant of blood subtype A1 (A102; 467C>T), a common subtype in Asian populations, whereas three NC presented additional polymorphisms not contained in the BLOODchip((r)) (A102/A205, A102/O06 and A204/O02). In the RhD group, one discrepancy was correctly genotyped as RHD*1227A (Del phenotype) by the BLOODchip((r)) (phenotyped as partial D, RHD*DIVb). Another was phenotyped as D+ by the BLOODchip((r)) (phenotyped weak D by serology) and confirmed as RHD*D CE(2)-D heterozygous by sequencing. The 3 RhD NC can be solved by further software update. For RhCE, one discrepancy was correctly genotyped for both systems; however, only the BLOODchip((r)) was able to detect RHCE*CX allele. CONCLUSIONS: By programming the A102 ABO variant into the system software with the new allele combinations, the BLOODchip((r)) Reference is a suitable genotyping tool to be applied to Asian samples. PMID- 24152225 TI - Terra firma-forme dermatosis. PMID- 24152226 TI - Anti-depressive effect of polyphenols and omega-3 fatty acid from pomegranate peel and flax seed in mice exposed to chronic mild stress. AB - AIM: In this study polyphenols from pomegranate peel, and n-3 fatty acids with polyphenols from flax seed were evaluated for their anti depression properties in mice exposed to chronic mild stress (CMS). METHODS: A total of 40 mice initially trained to consume 2% sucrose solution for 3 weeks were then divided into five groups of eight each. The first group was the normal control, the remaining four groups were exposed to CMS but were force fed with either: 10 mL water per kg bodyweight per day; imipramine (a standard antidepressant) 15 mg kg bodyweight; 30 mg per kg bodyweight polyphenol equivalent extract from pomegranate peel; or 30 mg polyphenols per kg bodyweight with omega-3 fatty acids present, for 50 days. At the end, blood and brain were analyzed for various biomarkers of depression. RESULTS: The flax seed and imipramine groups had significantly increased sucrose consumption, decreased cortisol (blood), decreased epinephrine and norepinephrine concentration, decreased monoamine oxidase A and B activity, and decreased superoxide dismutase activity. Lipid peroxidation was completely inhibited. In contrast, pomegranate peel extract also completely inhibited lipid peroxidation in the brain, and reduced enzyme activity and hormone concentration but to a lesser extent than flax seed. CONCLUSION: Polyphenols from flax seed with omega-3 fatty acids were able to reduce all the CMS effects tested compared to polyphenols from pomegranate peel. PMID- 24152227 TI - Digital holographic microscopy: a quantitative label-free microscopy technique for phenotypic screening. AB - Digital Holographic Microscopy (DHM) is a label-free imaging technique allowing visualization of transparent cells with classical imaging cell culture plates. The quantitative DHM phase contrast image provided is related both to the intracellular refractive index and to cell thickness. DHM is able to distinguish cellular morphological changes on two representative cell lines (HeLa and H9c2) when treated with doxorubicin and chloroquine, two cytotoxic compounds yielding distinct phenotypes. We analyzed parameters linked to cell morphology and to the intracellular content in endpoint measurements and further investigated them with timelapse recording. The results obtained by DHM were compared with other optical label-free microscopy techniques, namely Phase Contrast, Differential Interference Contrast and Transport of Intensity Equation (reconstructed from three bright-field images). For comparative purposes, images were acquired in a common 96-well plate format on the different motorized microscopes. In contrast to the other microscopies assayed, images generated with DHM can be easily quantified using a simple automatized on-the-fly analysis method for discriminating the different phenotypes generated in each cell line. The DHM technology is suitable for the development of robust and unbiased image-based assays. PMID- 24152228 TI - Triethylene glycol bis(2-ethylhexanoate) - a new contact allergen identified in a spectacle frame. AB - BACKGROUND: Allergic reactions to spectacle frames are not unusual. A patient had a reproducible strong allergic patch test reaction to scrapings from the plastic material, and negative patch test results with available spectacle frame chemicals. OBJECTIVES: To identify the culprit allergen in this patient's spectacle frame. MATERIALS AND METHODS: An extract from the temple arms was analysed by gas chromatography mass spectrometry (GC-MS), and a major low molecular weight compound was detected. This compound was isolated by semi preparative high-performance liquid chromatography and identified by GC-MS and nuclear magnetic resonance spectroscopy. The purified compound was diluted in ethanol, and a dilution series was prepared for patch testing. RESULTS: Triethylene glycol bis(2-ethylhexanoate) was identified as the major compound in the extract. Patch testing of the patient proved that triethylene glycol bis(2 ethylhexanoate) was the causative allergen in the spectacle frame. Ten consecutive eczema patients tested as controls were negative. CONCLUSION: Triethylene glycol bis(2-ethylhexanoate) is a new, hitherto unreported contact allergen. PMID- 24152229 TI - Metabolic syndrome and C-reactive protein concentration as independent correlates of chronic kidney disease. AB - Inflammation is a common phenotype for cardiometabolic disorders. In this study, we attempted to investigate inter-relationships between metabolic syndrome (MetS), C-reactive protein (an inflammatory biomarker) and chronic kidney disease (CKD). We performed a cross-sectional analysis of data from a representative sample of 4425 Chinese adults in Taiwan. The MetS was defined by a unified criteria set by several major organizations. A CKD event was defined as an estimated glomerular filtration rate (eGFR) <60 mL/min per 1.73 m(2). Additionly, a CRP cutpoint of 3 mg/L was used to differentiate high and low CRP levels. Overall, 1000 participants had MetS, resulting in a prevalence rate of 22.6%. High CRP level was noted in 782 (17.6%) subjects. In addition, a total of 508 (11.5%) persons qualified as having CKD. Subjects with the MetS had 1.55-fold [95% confidence interval (CI), 1.03-2.32] increased odds of CKD compared with their counterparts without the MetS after multiple adjustments. In addition, there was a significantly graded relationship between increasing levels of serum CRP and prevalent CKD (p for trend = 0.001). Participants in the highest category of serum CRP had a significantly elevated odds of CKD as compared with those in the lowest category [odds ratio (OR), 1.60; 95% CI, 1.21-2.12]. However, there was no interaction in excess of additive scale between the presence of MetS and high CRP level (p = 0.83). These findings suggest that MetS and high CRP were independently associated with increased prevalence of CKD in Chinese adults. PMID- 24152230 TI - Characterization of a replication locus and formation of a higher-order complex between RepA protein and two inverted repeats in Streptomyces plasmid pSV1. AB - We identified the minimal locus of 163-kb plasmid pSV1 of Streptomyces violaceoruber for the replication in S. lividans. This locus comprised a repA gene and an upstream 407-bp sequence containing two inverted repeats (IR-III and IR-IV) within an iteron, an AT-rich region and a 300-bp noncoding sequence (NCS). RepA protein bound specifically to a 94-bp sequence covering the intact IR-III and IR-IV to form multimers of DNA/protein complexes, but was unable to bind specifically to the NCS and the promoter of repA gene. Interestingly, this 'bound' region also leaves eight 1-bp 'unbound' spacers at 7-11-9-11-9-11-9-11-8 bp intervals. RepA protein-protein interaction could form dimers or trimers in vitro. These results suggest that a higher-order complex between pSV1 RepA protein and the long inverted repeats may be formed during the initiation of plasmid replication. PMID- 24152231 TI - Baby steps on the road to HIV eradication. PMID- 24152232 TI - Dead man walking. AB - A year after seeing a physician for abdominal pain and obstipation and being told he couldn't be adequately evaluated without insurance, an uninsured man is diagnosed with metastatic colon cancer. Like thousands of other Americans, he will die for lack of insurance. PMID- 24152234 TI - Electronic structures and magnetism of SrFeO2 under pressure: a first-principles study. AB - We have studied the electronic structures and magnetism of SrFeO2 under pressure by first-principles calculations in the framework of density functional theory (DFT) with GGA+U and HSE06 hybrid functionals, respectively. The pressure-induced spin transition from S = 2 to S = 1 and the antiferromagnetic-ferromagnetic (AFM FM) transition observed in experiment are well reproduced by taking the site repulsion U and its pressure dependence into account. The electronic structure and its change with the pressure can be qualitatively understood in an ionic model together with the hybridization effects between the Fe 3d and O 2p states. It is found that the pressure leads to a change in Fe 3d electronic configuration from (d(z(2)))(2)(d(xz)d(yz))(2)(d(xy))(1)(d(x(2)-y(2)))(1) under ambient conditions to (d(z(2)))(2)(d(xz)d(yz))(3)(d(xy))(1)(d(x(2)-y(2)))(0) at high pressure. As a result, the spin state transits from S = 2 to S = 1 and both the antiferromagnetic intralayer Fe-O-Fe superexchange interaction and the interlayer Fe-Fe direction exchange coupling at ambient pressure become ferromagnetic at high pressure according to the Goodenough-Kanamori (G-K) rules. Additionally, our calculations predict another spin transition from S = 1 to S = 0 at pressures of about 220 GPa. PMID- 24152233 TI - Absence of detectable HIV-1 viremia after treatment cessation in an infant. AB - An infant born to a woman with human immunodeficiency virus type 1 (HIV-1) infection began receiving antiretroviral therapy (ART) 30 hours after birth owing to high-risk exposure. ART was continued when detection of HIV-1 DNA and RNA on repeat testing met the standard diagnostic criteria for infection. After therapy was discontinued (when the child was 18 months of age), levels of plasma HIV-1 RNA, proviral DNA in peripheral-blood mononuclear cells, and HIV-1 antibodies, as assessed by means of clinical assays, remained undetectable in the child through 30 months of age. This case suggests that very early ART in infants may alter the establishment and long-term persistence of HIV-1 infection. PMID- 24152235 TI - SILAC surrogates: rescue of quantitative information for orphan analytes in spike in SILAC experiments. AB - Super-stable isotope labeling by amino acids in cell culture (Super-SILAC) enables the sensitive and accurate analysis of complex biological tissue and tumor samples by comparison of light peptides observed in biological samples to heavy peptides from SILAC cell culture spike-ins. However, despite the use of multiple cell lines for Super-SILAC spike-in standards, the full protein and peptide profiles of biological samples are not completely represented in these internal standards, leading to orphan analytes for which sample to standard ratios cannot be calculated. This problem is exacerbated in some biological systems, such as muscle tissue, which lack adequate cell culture lines to reflect their complex and idiosyncratic protein profiles, resulting in up to 40% of peptide analytes without heavy cognates. Furthermore, these unquantified orphan analytes may be among the most biologically interesting and significant species, since their presence is not common to cell lines cultured in vitro. Here, we report on the development of a surrogate analysis strategy to interpolate quantitative relationships between peptide species, observed across multiple biological samples, which lack representation within the spike-in standards. The precision and accuracy of this method was assessed by replicate experiments in which surrogate-derived ratios from defined mixtures of spike-in SILAC standard and tissue lysate were compared against traditional SILAC ratios for species where both light and heavy peptide cognates were observed. We demonstrate the robustness of our SILAC surrogates strategy across a variety of murine tissues, including liver, spleen, brain, and muscle. Our approach increases the quantitative coverage and precision within a biological sample by rescuing previously intractable peptide species and applying additional evidence to improve the precision of existing quantifications. PMID- 24152237 TI - Surface processes on interstellar amorphous solid water: adsorption, diffusion, tunneling reactions, and nuclear-spin conversion. PMID- 24152238 TI - Fate of pathological prion (PrP(sc)92-138) in soil and water: prion-clay nanoparticle molecular dynamics. AB - Pathogenic prion protein scrapie (PrP(sc)) may contaminate soils for decades and remain in water in colloidal suspension, providing infection pathways for animals through the inhalation of ingested dust and soil particles, and drinking water. We used molecular dynamics simulations to understand the strong binding mechanism of this pathogenic peptide with clay mineral surfaces and compared our results to experimental works. We restricted our model to the moiety PrP(92-138), which is a portion of the whole PrP(sc) molecule responsible for infectivity and modeled it using explicit solvating water molecules in contact with a pyrophyllite cleavage plane. Pyrophyllite is taken as a model for common soil clay, but it has no permanent structural charge. However, partial residual negative charges occur on the cleavage plane slab surface due to a slab charge unbalance. The charge is isotropic in 2D and it was balanced with K(+) ions. After partially removing potassium ions, the peptide anchors to the clay surface via up to 10 hydrogen bonds, between protonated lysine or histidine residues and the oxygen atoms of the siloxane cavities. Our results provide insight to the mechanism responsible for the strong association between the PrP(sc) peptide and clay nanoparticles and the associations present in contaminated soil and water which may lead to the infection of animals. PMID- 24152239 TI - Ancestral character estimation under the threshold model from quantitative genetics. AB - Evolutionary biology is a study of life's history on Earth. In researching this history, biologists are often interested in attempting to reconstruct phenotypes for the long extinct ancestors of living species. Various methods have been developed to do this on a phylogeny from the data for extant taxa. In the present article, I introduce a new approach for ancestral character estimation for discretely valued traits. This approach is based on the threshold model from evolutionary quantitative genetics. Under the threshold model, the value exhibited by an individual or species for a discrete character is determined by an underlying, unobserved continuous trait called "liability." In this new method for ancestral state reconstruction, I use Bayesian Markov chain Monte Carlo (MCMC) to sample the liabilities of ancestral and tip species, and the relative positions of two or more thresholds, from their joint posterior probability distribution. Using data simulated under the model, I find that the method has very good performance in ancestral character estimation. Use of the threshold model for ancestral state reconstruction relies on a priori specification of the order of the discrete character states along the liability axis. I test the use of a Bayesian MCMC information theoretic criterion based approach to choose among different hypothesized orderings for the discrete character. Finally, I apply the method to the evolution of feeding mode in centrarchid fishes. PMID- 24152240 TI - A randomized, double-blind, placebo-controlled trial of duloxetine for the treatment of pain in patients with multiple sclerosis. AB - BACKGROUND: Patients with multiple sclerosis (MS) often report neuropathic pain (NP-MS). The purpose of this study was to assess the efficacy and tolerability of duloxetine as treatment for NP-MS. METHODS: In this study, 239 adults with NP-MS (duloxetine = 118, placebo = 121) were randomized to duloxetine 60 mg (30 mg for 1 week, then 60 mg for 5 weeks) or placebo once daily for a 6-week acute therapy phase, followed by a 12-week open-label extension phase (duloxetine 30 to 120 mg/day). Eligible patients had MS for >= 1 year and a score >= 4 on daily average pain intensity (API) ratings for >= 4 of 7 days immediately before randomization. Patients rated API daily on an 11-point numeric scale (0 [no pain] to 10 [worst possible pain]) in an electronic diary. The primary efficacy measure, change in weekly API ratings, was analyzed longitudinally with a mixed-model repeated measures analysis. Completion, reasons for discontinuation, and treatment emergent adverse event incidence were compared by Fisher's exact test. RESULTS: Duloxetine-treated patients had statistically greater mean improvement in API vs. placebo at Week 6 (-1.83 vs. -1.07, P = 0.001). Treatment completion did not significantly differ between groups. Discontinuation due to adverse events was statistically greater for duloxetine vs. placebo (13.6% vs. 4.1%, P = 0.012). Decreased appetite was reported significantly more often by duloxetine-treated patients (5.9% vs. 0%, P = 0.007). CONCLUSIONS: This study found analgesic efficacy of duloxetine for NP-MS. Duloxetine is not approved for treatment of this condition. The duloxetine safety profile of this study was consistent with the known profile in other patient populations. PMID- 24152242 TI - Compact representation of k-mer de Bruijn graphs for genome read assembly. AB - BACKGROUND: Processing of reads from high throughput sequencing is often done in terms of edges in the de Bruijn graph representing all k-mers from the reads. The memory requirements for storing all k-mers in a lookup table can be demanding, even after removal of read errors, but can be alleviated by using a memory efficient data structure. RESULTS: The FM-index, which is based on the Burrows Wheeler transform, provides an efficient data structure providing a searchable index of all substrings from a set of strings, and is used to compactly represent full genomes for use in mapping reads to a genome: the memory required to store this is in the same order of magnitude as the strings themselves. However, reads from high throughput sequences mostly have high coverage and so contain the same substrings multiple times from different reads. I here present a modification of the FM-index, which I call the kFM-index, for indexing the set of k-mers from the reads. For DNA sequences, this requires 5 bit of information for each vertex of the corresponding de Bruijn subgraph, i.e. for each different k-1-mer, plus some additional overhead, typically 0.5 to 1 bit per vertex, for storing the equivalent of the FM-index for walking the underlying de Bruijn graph and reproducing the actual k-mers efficiently. CONCLUSIONS: The kFM-index could replace more memory demanding data structures for storing the de Bruijn k-mer graph representation of sequence reads. A Java implementation with additional technical documentation is provided which demonstrates the applicability of the data structure (http://folk.uio.no/einarro/Projects/KFM-index/). PMID- 24152241 TI - Quantitative trait loci-dependent analysis of a gene co-expression network associated with Fusarium head blight resistance in bread wheat (Triticum aestivum L.). AB - BACKGROUND: Fusarium head blight (FHB) caused by Fusarium graminearum Schwabe is one of the most prevalent diseases of wheat (Triticum aestivum L.) and other small grain cereals. Resistance against the fungus is quantitative and more than 100 quantitative trait loci (QTL) have been described. Two well-validated and highly reproducible QTL, Fhb1 and Qfhs.ifa-5A have been widely investigated, but to date the underlying genes have not been identified. RESULTS: We have investigated a gene co-expression network activated in response to F. graminearum using RNA-seq data from near-isogenic lines, harboring either the resistant or the susceptible allele for Fhb1 and Qfhs.ifa-5A. The network identified pathogen responsive modules, which were enriched for differentially expressed genes between genotypes or different time points after inoculation with the pathogen. Central gene analysis identified transcripts associated with either QTL within the network. Moreover, we present a detailed gene expression analysis of four gene families (glucanases, NBS-LRR, WRKY transcription factors and UDP glycosyltransferases), which take prominent roles in the pathogen response. CONCLUSIONS: A combination of a network-driven approach and differential gene expression analysis identified genes and pathways associated with Fhb1 and Qfhs.ifa-5A. We find G-protein coupled receptor kinases and biosynthesis genes for jasmonate and ethylene earlier induced for Fhb1. Similarly, we find genes involved in the biosynthesis and metabolism of riboflavin more abundant for Qfhs.ifa-5A. PMID- 24152244 TI - 10(-7) m 17beta-oestradiol enhances odonto/osteogenic potency of human dental pulp stem cells by activation of the NF-kappaB pathway. AB - OBJECTIVES: Oestrogen has been proven to significantly enhance osteogenic potency, while oestrogen deficiency usually leads to impaired osteogenic differentiation of mesenchymal stem cells. However, little is known concerning direct effects of oestrogen on differentiation of human dental pulp stem cells (DPSCs). MATERIALS AND METHODS: In this study, human DPSCs were isolated and treated with 10(-7) m 17beta-oestradiol (E2). Alkaline phosphatase (ALP) assay and alizarin red staining were performed. RESULTS: Alkaline phosphatase and alizarin red showed that E2 treatment significantly enhanced ALP activity and mineralization ability of DPSCs, but had no effect on cell proliferation. Real time RT-PCR and western blot assay demonstrated that odonto/osteogenic markers (ALP, RUNX2/RUNX2, OSX/OSX, OCN/OCN and DSPP/DSP) were significantly upregulated in the cells after E2 treatment. Moreover, phosphorylation of cytoplasmic IkappaBalpha/P65 and expression of nuclear P65 were enhanced in a time-dependent manner following E2 treatment, suggesting activation of NF-kappaB signaling. Conversely, inhibition of the NF-kappaB pathway suppressed E2-mediated upregulation of odonto/osteogenic markers, indicating that the NF-kappaB pathway was pivotal for E2-mediated differentiation. CONCLUSION: These findings provide evidence that 10(-7) m 17beta-oestradiol promoted odonto/osteogenic differentiation of human DPSCs via activation of the NF-kappaB signaling pathway. PMID- 24152243 TI - Synthesis and anticancer activity of all known (-)-agelastatin alkaloids. AB - The full details of our enantioselective total syntheses of (-)-agelastatins A-F (1-6), the evolution of a new methodology for synthesis of substituted azaheterocycles, and the first side-by-side evaluation of all known (-) agelastatin alkaloids against nine human cancer cell lines are described. Our concise synthesis of these alkaloids exploits the intrinsic chemistry of plausible biosynthetic precursors and capitalizes on a late-stage synthesis of the C-ring. The critical copper-mediated cross-coupling reaction was expanded to include guanidine-based systems, offering a versatile preparation of substituted imidazoles. The direct comparison of the anticancer activity of all naturally occurring (-)-agelastatins in addition to eight advanced synthetic intermediates enabled a systematic analysis of the structure-activity relationship within the natural series. Significantly, (-)-agelastatin A (1) is highly potent against six blood cancer cell lines (20-190 nM) without affecting normal red blood cells (>333 MUM). (-)-Agelastatin A (1) and (-)-agelastatin D (4), the two most potent members of this family, induce dose-dependent apoptosis and arrest cells in the G2/M-phase of the cell cycle; however, using confocal microscopy, we have determined that neither alkaloid affects tubulin dynamics within cells. PMID- 24152246 TI - A tripodal ligand constructed from mesoionic carbene donors. AB - A tripodal ligand constructed solely from mesoionic carbene donors is reported. The donor strength of this ligand is lower than most imidazol-2-ylidene-based tris(carbene)borate ligands, as measured by IR spectroscopy of {NiNO}(10) and {Mn(CO)3}(+) derivatives. The attenuated donor strength is proposed to be due to the collective electron-withdrawing effect of the ligand's aryl substituents. PMID- 24152245 TI - Development and optimization of piperidyl-1,2,3-triazole ureas as selective chemical probes of endocannabinoid biosynthesis. AB - We have previously shown that 1,2,3-triazole ureas (1,2,3-TUs) act as versatile class of irreversible serine hydrolase inhibitors that can be tuned to create selective probes for diverse members of this large enzyme class, including diacylglycerol lipase-beta (DAGLbeta), a principal biosynthetic enzyme for the endocannabinoid 2-arachidonoylglycerol (2-AG). Here, we provide a detailed account of the discovery, synthesis, and structure-activity relationship (SAR) of (2-substituted)-piperidyl-1,2,3-TUs that selectively inactivate DAGLbeta in living systems. Key to success was the use of activity-based protein profiling (ABPP) with broad-spectrum and tailored activity-based probes to guide our medicinal chemistry efforts. We also describe an expanded repertoire of DAGL tailored activity-based probes that includes biotinylated and alkyne agents for enzyme enrichment coupled with mass spectrometry-based proteomics and assessment of proteome-wide selectivity. Our findings highlight the broad utility of 1,2,3 TUs for serine hydrolase inhibitor development and their application to create selective probes of endocannabinoid biosynthetic pathways. PMID- 24152247 TI - Relationship between thyroid nodules and non-functioning adrenal incidentalomas and their association with insulin resistance. AB - OBJECTIVE: The relationship between insulin resistance and thyroid nodules in patients with non-functional adrenal incidentalomas (AI) is not clearly understood. The aim of this study was to determine the frequency of thyroid nodules in AI patients, as well as to evaluate any possible associations with disorders of insulin resistance. METHODS: Patients diagnosed with a non functional AI were approached for inclusion in the study. Insulin resistance was evaluated using homeostasis model assessment (HOMA-IR). All participants were screened for the presence of thyroid nodule by ultrasonography, and fine needle aspiration biopsies were obtained from consenting subjects. RESULTS: One-hundred thirteen patients with AI and 152 age-, BMI- and gender-matched healthy controls were enrolled. AI patients had higher waist circumference and waist/hip ratio than the control group. Metabolic syndrome, hypertension and type 2 diabetes mellitus rates were significantly higher in AI patients. HOMA-IR was similar between the groups. At least one thyroid nodule was observed in 42 (27.6%) of the controls compared to 55 (48.7%) of AI patients (p < 0.001). The mean number of thyroid nodules in AI patients was significantly higher than the control subjects (2.4 +/- 0.9 versus 1.7 +/- 1.0, p = 0.008). Mean nodule volume was similar between AI patients and the controls. A correlation could not be established between adrenal tumor/thyroid nodule volumes and the number of thyroid nodules, HOMA-IR, waist circumference, waist/hip ratio, BMI and thyroid function tests. CONCLUSION: A higher prevalence of thyroid nodule and a higher number of thyroid nodules were determined in patients with AI compared to healthy controls. PMID- 24152248 TI - Skin viscoelasticity during hormone replacement therapy for climacteric ageing. AB - BACKGROUND: Climacteric ageing refers to the period of women's life centred by the perimenopause. This step of life is responsible for initiating skin atrophic withering and slackness responsible for changes in the viscoelasticity of the dermal connective tissue. Some women benefit from hormone replacement therapy (HRT) for controlling some unpleasant internal climacteric changes (osteoporosis, vasomotor instability, ...). OBJECTIVE: To investigate some corrective effects of HRT on the functional damages in the dermal tensile strength. PATIENTS AND METHODS: This study was performed on 200 healthy Caucasian women. In vivo skin viscoelasticity was assessed using the suction method. RESULTS: Skin distensibility and hysteresis appeared increased at menopause with or without HRT. By contrast, the biological elasticity significantly decreased out of HRT. CONCLUSION: Some drugs and cosmetics might attempt at improving such viscoelastic attributes of the skin at menopause. PMID- 24152249 TI - Combinatorial approach to improve photoelectrodes based on BiVO4. AB - The photoelectrochemical behavior of materials based on binary Bi-V oxides was investigated by preparing libraries of ternary metal oxides using high-throughput combinatorial inkjet printing of oxide precursors onto conductive glass substrates. Subsequent pyrolysis of the printed films, with addition of various levels of a third metal oxide precursor, produced libraries of metal oxides that were immersed under potential control into an electrolyte solution and evaluated for water photooxidation or photoreduction activity using a laser scanning technique to produce photocurrent images. It was found that the photoelectrolysis activity of the Bi-V oxides of various stoichiometries was best at a Bi/V ratio of 1 to 1 or the BiVO4 phase. The photocurrent generation of this phase was improved by the addition of various amounts of W, Cu, Fe, Mg, and Mn. Addition of W led to the largest increase in photocurrent of up to 18 times; however the electronic band gap was increased compared to that of unsubstituted BiVO4. PMID- 24152252 TI - Prognostic value of coronary flow reserve in asymptomatic moderate or severe aortic stenosis with preserved ejection fraction and nonobstructed coronary arteries. AB - AIM: Patients with moderate and severe aortic stenosis (AS) and without obstructive epicardial coronary disease have been shown to have an impairment of coronary flow reserve (CFR). We investigated the prognostic significance of CFR in predicting death during mid-to-long-term follow-up in asymptomatic patients with moderate/severe AS, preserved ejection fraction (EF), and with nonobstructed coronary arteries. METHOD AND RESULT: A total of 127 patients with moderate or severe AS (effective orifice area of 1.5 cm(2) or less), mean age 66 +/- 11 were enrolled in this prospective study. The median follow-up was 32 +/- 7 months. All patients had standard Doppler echo study, coronary angiography, and adenosine stress transthoracic Doppler echo for CFR measurement. Univariate analysis showed that diabetes mellitus, CFR, aortic valve area (AVA), maximal velocity (Vmax ), mean pressure gradient (Pmean ), energy loss index (ELI), aortic valve resistance (AVR), NT-proBNP, E/E', valvulo-arterial impedance (Zva ), and stroke work loss (SWL) were associated (P < 0.05) with death. Multivariable logistic regression analysis revealed that only Zva and CFR were independent predictors of death, with the CFR being the single strongest predictor (Table 2). Using receiver operating characteristics (ROC) analysis, the CFR value of 1.85 had the highest accuracy in predicting the death during mid-to-long-term follow-up (area under the curve; AUC 0.890, P = 0.009, sensitivity 96.3%, specificity 75%; 95% CI 0.287 0.946; Fig. 1). The Zva value of 5.52 Hg/mL per m had a sensitivity 70.0% and specificity 72.0% (AUC 0.766, 95% CI 0.587-0.946; P = 0.005). CONCLUSION: This study demonstrates that CFR has a prognostic value in patients with asymptomatic moderate or severe AS with preserved EF and nonobstructed coronary arteries. PMID- 24152253 TI - Race in virtual environments: competitive versus cooperative games with black or white avatars. AB - Often, virtual environments and video games have established goals, and to achieve them, users must either compete or cooperate with others. The common ingroup identity model predicts that individuals maintain multiple identities at any given time based on roles, demographics, and contextual factors, and that they interpret others based on similarity (i.e., perceived ingroup) or dissimilarity (i.e., perceived outgroup) to these identities. In this experiment, we manipulated two aspects of a virtual partner's identity-race and task collaboration-to determine how users would perceive others in a virtual world. White participants (N=99) played an anagram game competitively (outgroup) or cooperatively (ingroup) in a virtual environment with a black (outgroup) or white (ingroup) virtual partner. Contrary to hypotheses, performing either task led to more positive evaluations of black avatars than white avatars. PMID- 24152254 TI - Long-term response of neuropathic pain to intravenous immunoglobulin in relapsing diabetic lumbosacral radiculoplexus neuropathy. A case report. AB - Diabetic lumbosacral radiculoplexus neuropathy (DLRPN) is a rare painful peripheral neuropathic complication of diabetes mellitus. The clinical features of DLRPN include severe neuropathic pain, weakness, atrophy, and sensory loss in the lower limbs with asymmetrical distribution. Nerve ischemia due to inflammation and microvasculitis has been suggested as the pathophysiological mechanism for DLRPN. Analgesics and drugs for neuropathic pain often cannot achieve adequate pain control in DLRPN. Some reports suggest that intravenous immunoglobulin (IVIg) may reduce pain in DLRPN, but the mechanisms of this effect are unclear. We report a patient with relapsing DLRPN who was followed up for 8 years and whose pain improved after IVIg on nine occasions. We measured serum cytokines before and after IVIg; serum tumor necrosis factor alpha was increased when the patient reported pain and normalized after IVIg in parallel with pain improvement. Our data extend the notion that some types of pain, including peripheral neuropathic pain, may respond to IVIg and give some clue on the mechanism of this therapeutic effect. They are also consistent with the suggested role of the immune system in the pathophysiology of neuropathic pain and offer support to the hypothesis that cytokines may contribute to the pathogenesis of neuropathic pain. PMID- 24152255 TI - LOS oligosaccharide modification enhances dendritic cell responses to meningococcal native outer membrane vesicles expressing a non-toxic lipid A. AB - Outer membrane vesicles (OMV) are released by many bacteria, and contain immunogenic antigens in addition to harmful inflammatory factors, like lipopolysaccharides. Chemically detoxified OMV have been used in vaccines against Neisseria meningitidis (Nm); however, little is known about their interaction with antigen presenting cells. In this study, we investigated the interaction of Nm OMV with human dendritic cells (DC) to gain further understanding of their biological activity. We engineered a novel serogroup B Nm that is unencapsulated (siaD), expresses pentacylated lipid A (lpxL1), hence conferring reduced toxicity, and expresses an lgtB oligosaccharide structure designed to target OMV to DC via DC-SIGN. We show that the lgtB moiety is critical for internalization of NOMV by DC. Furthermore, the lgtB moiety significantly enhances DC maturation, IL-10 and IL-23 production in the presence of a pentacylated lipid A. While different DC phenotypes were observed for each NOMV, this had little effect on Th1 and Th2 cell differentiation; however, lgtBsignificantly increased Th17 cell expansion in the presence of pentacylated lipid A. We believe that lpxL1/lgtB NOMV should be considered further as a vaccine vector, particularly considering the importance of lgtB in antigen uptake and further human studies on antigen specific responses should be considered. PMID- 24152256 TI - Selective neuronal staining in tardigrades and onychophorans provides insights into the evolution of segmental ganglia in panarthropods. AB - BACKGROUND: Although molecular analyses have contributed to a better resolution of the animal tree of life, the phylogenetic position of tardigrades (water bears) is still controversial, as they have been united alternatively with nematodes, arthropods, onychophorans (velvet worms), or onychophorans plus arthropods. Depending on the hypothesis favoured, segmental ganglia in tardigrades and arthropods might either have evolved independently, or they might well be homologous, suggesting that they were either lost in onychophorans or are a synapomorphy of tardigrades and arthropods. To evaluate these alternatives, we analysed the organisation of the nervous system in three tardigrade species using antisera directed against tyrosinated and acetylated tubulin, the amine transmitter serotonin, and the invertebrate neuropeptides FMRFamide, allatostatin and perisulfakinin. In addition, we performed retrograde staining of nerves in the onychophoran Euperipatoides rowelli in order to compare the serial locations of motor neurons within the nervous system relative to the appendages they serve in arthropods, tardigrades and onychophorans. RESULTS: Contrary to a previous report from a Macrobiotus species, our immunocytochemical and electron microscopic data revealed contralateral fibres and bundles of neurites in each trunk ganglion of three tardigrade species, including Macrobiotus cf. harmsworthi, Paramacrobiotus richtersi and Hypsibius dujardini. Moreover, we identified additional, extra-ganglionic commissures in the interpedal regions bridging the paired longitudinal connectives. Within the ganglia we found serially repeated sets of serotonin- and RFamid-like immunoreactive neurons. Furthermore, our data show that the trunk ganglia of tardigrades, which include the somata of motor neurons, are shifted anteriorly with respect to each corresponding leg pair, whereas no such shift is evident in the arrangement of motor neurons in the onychophoran nerve cords. CONCLUSIONS: Taken together, these data reveal three major correspondences between the segmental ganglia of tardigrades and arthropods, including (i) contralateral projections and commissures in each ganglion, (ii) segmentally repeated sets of immunoreactive neurons, and (iii) an anteriorly shifted (parasegmental) position of ganglia. These correspondences support the homology of segmental ganglia in tardigrades and arthropods, suggesting that these structures were either lost in Onychophora or, alternatively, evolved in the tardigrade/arthropod lineage. PMID- 24152258 TI - Smoothing the way to high quality, safety, and economy. PMID- 24152257 TI - Bristol girls dance project (BGDP): protocol for a cluster randomised controlled trial of an after-school dance programme to increase physical activity among 11 12 year old girls. AB - BACKGROUND: Many children do not meet current UK physical activity (PA) guidelines. Girls are less active than boys throughout childhood, and the age related decline in PA, particularly from early adolescence, is steeper for girls than for boys. Dance is the favourite form of PA among UK secondary school aged girls. Delivering dance sessions after school could make a significant contribution to girls' PA. Therefore, after-school dance sessions may be an appropriate and cost-effective activity through which adolescent girls' PA levels can be increased. DESIGN: Two-arm cluster randomised control trial and economic evaluation conducted in 18 secondary schools across the greater Bristol area. All Year 7 girls in participating schools will receive a 'taster' dance session and subsequently be invited to participate in the project. There is space for up to 33 girls to participate in each school. Schools will be randomly assigned in equal numbers to intervention or control arms after baseline data has been collected. The nine intervention schools will receive a 20 week after-school dance-based intervention, consisting of 40 * 75 minute sessions, delivered by external dance instructors. Control schools will not receive the dance intervention. All measures will be assessed at baseline (time 0), at the end of the intervention period (time 1) and six months after the intervention has ended (time 2). Our primary interest is to determine the effectiveness and cost effectiveness of the intervention to affect the objectively-assessed (accelerometer) mean weekday minutes of moderate-to-vigorous PA (MVPA) accumulated by Year 7 girls one year after the baseline measurement (time 2). DISCUSSION: This paper describes the protocol for the Bristol Girls Dance Project cluster randomized controlled trial and economic evaluation, which is attempting to increase MVPA among Year 7 girls in UK secondary schools. TRIAL REGISTRATION: ISRCTN52882523. PMID- 24152259 TI - The debt of life--Thai lessons on a process-oriented ethical logic. PMID- 24152260 TI - Clinical findings for fungal infections caused by methylprednisolone injections. AB - BACKGROUND: Since September 18, 2012, public health officials have been investigating a large outbreak of fungal meningitis and other infections in patients who received epidural, paraspinal, or joint injections with contaminated lots of methylprednisolone acetate. Little is known about infections caused by Exserohilum rostratum, the predominant outbreak-associated pathogen. We describe the early clinical course of outbreak-associated infections. METHODS: We reviewed medical records for outbreak cases reported to the Centers for Disease Control and Prevention before November 19, 2012, from the six states with the most reported cases (Florida, Indiana, Michigan, New Jersey, Tennessee, and Virginia). Polymerase-chain-reaction assays and immunohistochemical testing were performed on clinical isolates and tissue specimens for pathogen identification. RESULTS: Of 328 patients without peripheral-joint infection who were included in this investigation, 265 (81%) had central nervous system (CNS) infection and 63 (19%) had non-CNS infections only. Laboratory evidence of E. rostratum was found in 96 of 268 patients (36%) for whom samples were available. Among patients with CNS infections, strokes were associated with an increased severity of abnormalities in cerebrospinal fluid (P<0.001). Non-CNS infections were more frequent later in the course of the outbreak (median interval from last injection to diagnosis, 39 days for epidural abscess and 21 days for stroke; P<0.001), and such infections developed in patients with and in those without meningitis. CONCLUSIONS: The initial clinical findings from this outbreak suggest that fungal infections caused by epidural and paraspinal injection of a contaminated glucocorticoid product can result in a broad spectrum of clinical disease, reflecting possible variations in the pathogenic mechanism and in host and exposure risk factors. (Funded by the Centers for Disease Control and Prevention.). PMID- 24152261 TI - HLA-B*13:01 and the dapsone hypersensitivity syndrome. AB - BACKGROUND: Dapsone is used in the treatment of infections and inflammatory diseases. The dapsone hypersensitivity syndrome, which is associated with a reported mortality of 9.9%, develops in about 0.5 to 3.6% of persons treated with the drug. Currently, no tests are available to predict the risk of the dapsone hypersensitivity syndrome. METHODS: We performed a genomewide association study involving 872 participants who had received dapsone as part of multidrug therapy for leprosy (39 participants with the dapsone hypersensitivity syndrome and 833 controls), using log-additive tests of single-nucleotide polymorphisms (SNPs) and imputed HLA molecules. For a replication analysis, we genotyped 24 SNPs in an additional 31 participants with the dapsone hypersensitivity syndrome and 1089 controls and performed next-generation sequencing for HLA-B and HLA-C typing at four-digit resolution in an independent series of 37 participants with the dapsone hypersensitivity syndrome and 201 controls. RESULTS: Genomewide association analysis showed that SNP rs2844573, located between the HLA-B and MICA loci, was significantly associated with the dapsone hypersensitivity syndrome among patients with leprosy (odds ratio, 6.18; P=3.84*10(-13)). HLA B*13:01 was confirmed to be a risk factor for the dapsone hypersensitivity syndrome (odds ratio, 20.53; P=6.84*10(-25)). The presence of HLA-B*13:01 had a sensitivity of 85.5% and a specificity of 85.7% as a predictor of the dapsone hypersensitivity syndrome, and its absence was associated with a reduction in risk by a factor of 7 (from 1.4% to 0.2%). HLA-B*13:01 is present in about 2 to 20% of Chinese persons, 1.5% of Japanese persons, 1 to 12% of Indians, and 2 to 4% of Southeast Asians but is largely absent in Europeans and Africans. CONCLUSIONS: HLA-B*13:01 was associated with the development of the dapsone hypersensitivity syndrome among patients with leprosy. (Funded by the National Natural Science Foundation of China and others.). PMID- 24152263 TI - Images in clinical medicine. Cold hands associated with scleroderma. PMID- 24152262 TI - Urologists' use of intensity-modulated radiation therapy for prostate cancer. AB - BACKGROUND: Some urology groups have integrated intensity-modulated radiation therapy (IMRT), a radiation treatment with a high reimbursement rate, into their practice. This is permitted by the exception for in-office ancillary services in the federal prohibition against self-referral. I examined the association between ownership of IMRT services and use of IMRT to treat prostate cancer. METHODS: Using Medicare claims from 2005 through 2010, I constructed two samples: one comprising 35 self-referring urology groups in private practice and a matched control group comprising 35 non-self-referring urology groups in private practice, and the other comprising non-self-referring urologists employed at 11 National Comprehensive Cancer Network centers matched with 11 self-referring urology groups in private practice. I compared the use of IMRT in the periods before and during ownership and used a difference-in-differences analysis to evaluate changes in IMRT use according to self-referral status. RESULTS: The rate of IMRT use by self-referring urologists in private practice increased from 13.1 to 32.3%, an increase of 19.2 percentage points (P<0.001). Among non-self referring urologists, the rate of IMRT use increased from 14.3 to 15.6%, an increase of 1.3 percentage points (P=0.05). The unadjusted difference-in differences effect was 17.9 percentage points (P<0.001). The regression-adjusted increase in IMRT use associated with self-referral was 16.4 percentage points (P<0.001). The rate of IMRT use by urologists working at National Comprehensive Cancer Network centers remained stable at 8.0% but increased by 33.0 percentage points among the 11 matched self-referring urology groups. The regression adjusted difference-in-differences effect was 29.3 percentage points (P<0.001). CONCLUSIONS: Urologists who acquired ownership of IMRT services increased their use of IMRT substantially more than urologists who did not own such services. Allowing urologists to self-refer for IMRT may contribute to increased use of this expensive therapy. (Funded by the American Society for Radiation Oncology.). PMID- 24152264 TI - Case records of the Massachusetts General Hospital. Case 33-2013. A 40-year-old woman with abdominal pain, weight loss, and anxiety about cancer. PMID- 24152265 TI - Radium-223 in prostate cancer. PMID- 24152266 TI - Radium-223 in prostate cancer. PMID- 24152267 TI - Semagacestat for treatment of Alzheimer's disease. PMID- 24152268 TI - Semagacestat for treatment of Alzheimer's disease. PMID- 24152269 TI - Semagacestat for treatment of Alzheimer's disease. PMID- 24152270 TI - Hospitalizations after a decade of pneumococcal vaccination. PMID- 24152271 TI - Hospitalizations after a decade of pneumococcal vaccination. PMID- 24152272 TI - Hospitalizations after a decade of pneumococcal vaccination. PMID- 24152273 TI - Effects of an estrogen receptor alpha variant. PMID- 24152274 TI - Effects of an estrogen receptor alpha variant. PMID- 24152275 TI - Acute high-altitude illnesses. PMID- 24152276 TI - Acute high-altitude illnesses. PMID- 24152277 TI - Acute high-altitude illnesses. PMID- 24152278 TI - Acute high-altitude illnesses. PMID- 24152279 TI - Acute high-altitude illnesses. PMID- 24152280 TI - Deficiency in complement factor B. PMID- 24152281 TI - Videos in clinical medicine. Technique for temporary pelvic stabilization after trauma. PMID- 24152282 TI - Images in clinical medicine. Dental implant in the ethmoid sinus. PMID- 24152283 TI - Translocation of cationic amphipathic peptides across the membranes of pure phospholipid giant vesicles. AB - The ability of amphipathic polypeptides with substantial net positive charges to translocate across lipid membranes is a fundamental problem in physical biochemistry. These peptides should not passively cross the bilayer nonpolar region, but they do. Here we present a method to measure peptide translocation and test it on three representative membrane-active peptides. In samples of giant unilamellar vesicles (GUVs) prepared by electroformation, some GUVs enclose inner vesicles. When these GUVs are added to a peptide solution containing a membrane impermeant fluorescent dye (carboxyfluorescein), the peptide permeabilizes the outer membrane, and dye enters the outer GUV, which then exhibits green fluorescence. The inner vesicles remain dark if the peptide does not cross the outer membrane. However, if the peptide translocates, it permeabilizes the inner vesicles as well, which then show fluorescence. We also measure translocation, simultaneously on the same GUV, by the appearance of fluorescently labeled peptides on the inner vesicle membranes. All three peptides examined are able to translocate, but to different extents. Peptides with smaller Gibbs energies of insertion into the membrane translocate more easily. Further, translocation and influx occur broadly over the same period, but with very different kinetics. Translocation across the outer membrane follows approximately an exponential rise, with a characteristic time of 10 min. Influx occurs more abruptly. In the outer vesicle, influx happens before most of the translocation. However, some peptides cross the membrane before any influx is observed. In the inner vesicles, influx occurs abruptly sometime during peptide translocation across the membrane of the outer vesicle. PMID- 24152284 TI - Association of metabolic syndrome with atypical features of depression in Japanese people. AB - AIM: It has been controversial whether metabolic syndrome (MetS) is associated with depression. We aimed to clarify the correlation between MetS and depression, considering atypical features of depression. METHODS: Participants were 1011 Japanese men aged 20-59 years. MetS was diagnosed according to criteria set by the International Diabetes Federation. Clinical interviews for major depressive disorder (MDD) employed the DSM-IV; MDD was classified into atypical and non atypical types. The prevalence of MetS was compared between the groups with no MDD, atypical depression, and non-atypical depression via trend analyses. Multiple logistic regression analyses examined the association of MetS with atypical depression and the features thereof. RESULTS: In total, 141 (14.0%) participants were diagnosed with MetS and 57 (5.6%) were diagnosed with MDD (14 had atypical and 43 had non-atypicalMDD). The prevalence of MetS was the highest in the group with atypical depression, followed by the non-atypical depression and no MDD groups, respectively, with a marginally significant trend (P = 0.07). The adjusted odds ratios of MetS associated with depression were 3.8 (95% confidence interval [CI] 1.1-13.2) for atypical depression and 1.6 (95% CI 0.7 3.6) for non-atypical depression. Among the five features of atypical depression, only hyperphagia was significantly related to MetS (odds ratio 2.7, 95% CI 1.8 4.1). CONCLUSION: There was a positive association between MetS and atypical depression, but not between MetS and non-atypical depression. Specifically, hyperphagia seems to be an important factor affecting the correlation between MetS and atypical depression. PMID- 24152286 TI - Hypothyroidism and cardiovascular disease: factors, mechanism and future perspectives. AB - Reduced function of the thyroid gland causes Hypothyroidism which is further attributed to defects in the secretion of thyroid hormones triiodothyronine (T3) and tetra-iodothyronine or thyroxine (T4). T3 and T4 hormones are not only known to regulate the rate of metabolism but also affect the growth and rate of function of many other systems in the body such as neuromuscular, gastrointestinal and cardiovascular system. Hypothyroidism patient usually show higher levels of total cholesterol, low-density lipoproteins (LDL), triglycerides, and other lipid molecules associated with heart disease. The question still remained to be addressed though is whether hypothyroidism affects heart and result in cardiovascular disease. The current review updates us with the recent progress in the hypothyroidism area especially in relation to its connecting link with the heart disease. The present study will further enhance our understanding of the intricacies involved in the secretion of thyroid hormones (T3 & T4) and thyroid stimulating hormone (TSH) subsequently affecting serum lipid levels. The study may help to dice-out cardiovascular risk factors associated with hypothyroidism so that effective measures could be taken prior to occurrence of coronary heart disease. PMID- 24152285 TI - Mass spectrometry-based quantitative proteomics for dissecting multiplexed redox cysteine modifications in nitric oxide-protected cardiomyocyte under hypoxia. AB - AIMS: Distinctive states of redox-dependent cysteine (Cys) modifications are known to regulate signaling homeostasis under various pathophysiological conditions, including myocardial injury or protection in response to ischemic stress. Recent evidence further implicates a dynamic interplay among these modified forms following changes in cellular redox environment. However, a precise delineation of multiplexed Cys modifications in a cellular context remains technically challenging. To this end, we have now developed a mass spectrometry (MS)-based quantitative approach using a set of novel iodoacetyl based Cys-reactive isobaric tags (irreversible isobaric iodoacetyl Cys-reactive tandem mass tag [iodoTMT]) endowed with unique irreversible Cys-reactivities. RESULTS: We have established a sequential iodoTMT-switch procedure coupled with efficient immunoenrichment and advanced shotgun liquid chromatography-MS/MS analysis. This workflow allows us to differentially quantify the multiple redox modified forms of a Cys site in the original cellular context. In one single analysis, we have identified over 260 Cys sites showing quantitative differences in multiplexed redox modifications from the total lysates of H9c2 cardiomyocytes experiencing hypoxia in the absence and presence of S-nitrosoglutathione (GSNO), indicative of a distinct pattern of individual susceptibility to S-nitrosylation or S-glutathionylation. Among those most significantly affected are proteins functionally implicated in hypoxic damage from which we showed that GSNO would protect. INNOVATION: We demonstrate for the first time how quantitative analysis of various Cys-redox modifications occurring in biological samples can be performed precisely and simultaneously at proteomic levels. CONCLUSION: We have not only developed a new approach to map global Cys-redoxomic regulation in vivo, but also provided new evidences implicating Cys-redox modifications of key molecules in NO-mediated ischemic cardioprotection. PMID- 24152287 TI - Mouse regenerating myofibers detected as false-positive donor myofibers with anti human spectrin. AB - Abstract Stem cell transplantation is being tested as a potential therapy for a number of diseases. Stem cells isolated directly from tissue specimens or generated via reprogramming of differentiated cells require rigorous testing for both safety and efficacy in preclinical models. The availability of mice with immune-deficient background that carry additional mutations in specific genes facilitates testing the efficacy of cell transplantation in disease models. The muscular dystrophies are a heterogeneous group of disorders, of which Duchenne muscular dystrophy is the most severe and common type. Cell-based therapy for muscular dystrophy has been under investigation for several decades, with a wide selection of cell types being studied, including tissue-specific stem cells and reprogrammed stem cells. Several immune-deficient mouse models of muscular dystrophy have been generated, in which human cells obtained from various sources are injected to assess their preclinical potential. After transplantation, the presence of engrafted human cells is detected via immunofluorescence staining, using antibodies that recognize human, but not mouse, proteins. Here we show that one antibody specific to human spectrin, which is commonly used to evaluate the efficacy of transplanted human cells in mouse muscle, detects myofibers in muscles of NOD/Rag1(null)mdx(5cv), NOD/LtSz-scid IL2Rgamma(null) mice, or mdx nude mice, irrespective of whether they were injected with human cells. These "reactive" clusters are regenerating myofibers, which are normally present in dystrophic tissue and the spectrin antibody is likely recognizing utrophin, which contains spectrin-like repeats. Therefore, caution should be used in interpreting data based on detection of single human-specific proteins, and evaluation of human stem cell engraftment should be performed using multiple human-specific labeling strategies. PMID- 24152289 TI - Characterization of novel single-variety oxygenated sesquiterpenoid hop oil fractions via headspace solid-phase microextraction and gas chromatography-mass spectrometry/olfactometry. AB - The volatile composition of novel varietal oxygenated sesquiterpenoid hop oil fractions ("spicy essences") was characterized by headspace solid-phase microextraction in combination with gas chromatography-mass spectrometry. Oxygenated sesquiterpenes represent the major chemical compound class, accounting for at least 65% of the total volatile fraction. In addition to oxygenated sesquiterpenes, spicy hop essences consist of several ketones, sesquiterpene and monoterpene hydrocarbons, and a relatively high number of unidentified compounds. On the basis of their relative composition, spicy hop essences can be fully differentiated according to their varietal origin. Multidimensional gas chromatography in combination with time-of-flight mass spectrometry on spicy hop essence cv. Spalter Select further demonstrated the enormous complexity of this particular hop oil fraction. The aromagram obtained via gas chromatography olfactometry comprised nine odor-active regions described in terms of "citrus", "green", "haylike", "earthy", "woody", and "spicy". 2-Undecanone, 2-tridecanone, gamma-cadinene, alpha-calacorene, calarene, humuladienone, caryolan-1-ol, caryophyllene oxide enantiomers, and humulene epoxide II are tentatively identified in the odor-active zones. PMID- 24152288 TI - iTRAQ-based protein profiling provides insights into the central metabolism changes driving grape berry development and ripening. AB - BACKGROUND: Grapevine (Vitis vinifera L.) is an economically important fruit crop. Quality-determining grape components such as sugars, acids, flavors, anthocyanins, tannins, etc., accumulate in the different grape berry development stages. Thus, correlating the proteomic profiles with the biochemical and physiological changes occurring in grape is of paramount importance to advance in our understanding of berry development and ripening processes. RESULTS: We report the developmental analysis of Vitis vinifera cv. Muscat Hamburg berries at the protein level from fruit set to full ripening. An iTRAQ-based bottom-up proteomic approach followed by tandem mass spectrometry led to the identification and quantitation of 411 and 630 proteins in the green and ripening phases, respectively. Two key points in development relating to changes in protein level were detected: end of the first growth period (7 mm-to-15 mm) and onset of ripening (15 mm-to-V100, V100-to-110). A functional analysis was performed using the Blast2GO software based on the enrichment of GO terms during berry growth. CONCLUSIONS: The study of the proteome contributes to decipher the biological processes and metabolic pathways involved in the development and quality traits of fruit and its derived products. These findings lie mainly in metabolism and storage of sugars and malate, energy-related pathways such as respiration, photosynthesis and fermentation, and the synthesis of polyphenolics as major secondary metabolites in grape berry. In addition, some key steps in carbohydrate and malate metabolism have been identified in this study, i.e., PFP-PFK or SuSy INV switches among others, which may influence the final sugar and acid balance in ripe fruit. In conclusion, some proteins not reported to date have been detected to be deregulated in specific tissues and developmental stages, leading to formulate new hypotheses on the metabolic processes underlying grape berry development. These results open up new lines to decipher the processes controlling grape berry development and ripening. PMID- 24152291 TI - Collagen scaffold for cartilage tissue engineering: the benefit of fibrin glue and the proper culture time in an infant cartilage model. AB - This study (i) developed a scaffold made of collagen I designed for hosting the autologous chondrocytes, (ii) focused on the optimization of chondrocytes seeding by the addition of the fibrin glue, and (iii) investigated the culture time for the ideal scaffold maturation in vitro. In the first part of the study, fresh chondrocytes were isolated from infant swine articular cartilage, and immediately seeded onto the collagen sponges either in medium or in fibrinogen in order to show the contribute of fibrin glue in cell seeding and survival into the scaffold. In the second part of the study, chondrocytes were first expanded in vitro and then resuspended in fibrinogen, seeded in collagen sponges, and cultured for 1, 3, and 5 weeks in order to identify the optimal time for the rescue of cell phenotype and for the scaffold maturation into a tissue with chondral properties. The histological and immunohistochemical data from the first part of the study (study with primary chondrocytes) demonstrated that the presence of fibrin glue ameliorated cell distribution and survival into the chondral composites. The second part of this work (study with dedifferentiated chondrocytes) showed that the prolongation of the culture to 3 weeks promoted a significant restoration of the cell phenotype, resulting in a composite with proper morphological features, biochemical composition, and mechanical integrity. In conclusion, this study developed a collagenic-fibrin glue scaffold that was able to support chondrocyte survival and synthetic activity in a static culture; in particular, this model was able to turn the engineered samples into a tissue with chondral-like properties when cultured in vitro for at least 3 weeks. PMID- 24152290 TI - Histone methylation mediates plasticity of human FOXP3(+) regulatory T cells by modulating signature gene expressions. AB - CD4(+) FOXP3(+) regulatory T (Treg) cells constitute a heterogeneous and plastic T-cell lineage that plays a pivotal role in maintaining immune homeostasis and immune tolerance. However, the fate of human Treg cells after loss of FOXP3 expression and the epigenetic mechanisms contributing to such a phenotype switch remain to be fully elucidated. In the current study, we demonstrate that human CD4(+) CD25(high) CD127(low/-) Treg cells convert to two subpopulations with distinctive FOXP3(+) and FOXP3(-) phenotypes following in vitro culture with anti CD3/CD28 and interleukin-2. Digital gene expression analysis showed that upon in vitro expansion, human Treg cells down-regulated Treg cell signature genes, such as FOXP3, CTLA4, ICOS, IKZF2 and LRRC32, but up-regulated a set of T helper lineage-associated genes, especially T helper type 2 (Th2)-associated, such as GATA3, GFI1 and IL13. Subsequent chromatin immunoprecipitation-sequencing of these subpopulations yielded genome-wide maps of their H3K4me3 and H3K27me3 profiles. Surprisingly, reprogramming of Treg cells was associated with differential histone modifications, as evidenced by decreased abundance of permissive H3K4me3 within the down-regulated Treg cell signature genes, such as FOXP3, CTLA4 and LRRC32 loci, and increased abundance of H3K4me3 within the Th2 associated genes, such as IL4 and IL5; however, the H3K27me3 modification profile was not significantly different between the two subpopulations. In conclusion, this study revealed that loss of FOXP3 expression from human Treg cells during in vitro expansion can induce reprogramming to a T helper cell phenotype with a gene expression signature dominated by Th2 lineage-associated genes, and that this cell type conversion may be mediated by histone methylation events. PMID- 24152292 TI - Thermosensitive liposomes for the delivery of gemcitabine and oxaliplatin to tumors. AB - The majority of ultrafast temperature sensitive liposome (uTSL) formulations reported in the literature deliver the highly membrane permeable drug, doxorubicin (DOX). Here we report on the study of the uTSL formulation, HaT (Heat activated cytoToxic, composed of the phospholipid DPPC and the surfactant Brij78) loaded with the water-soluble, but poorly membrane permeable anticancer drugs, gemcitabine (GEM) and oxaliplatin (OXA). The HaT formulation displayed ultrafast release of these drugs in response to temperature, whereas attempts with LTSL (Lyso-lipid Temperature Sensitive Liposome, composed of DPPC, MSPC, and DSPE-PEG) were unsuccessful. HaT-GEM and HaT-OXA both released >80% of the encapsulated drug within 2 min at 40-42 degrees C, with <5% drug leakage at 37 degrees C after 30 min in serum. The pharmacokinetic profile of both drugs was improved by formulating with HaT relative to the free drug, with clearance reduced by 50-fold for GEM and 3-fold for OXA. HaT-GEM and HaT-OXA both displayed improved drug uptake in the heated tumor relative to the unheated tumor (by 9-fold and 3-fold, respectively). In particular, HaT-GEM showed 25-fold improved delivery to the heated tumor relative to free GEM and significantly enhanced antitumor efficacy with complete tumor regression after a single dose of HaT-GEM. These data suggest that uTSL technology can also be used to deliver nonmembrane permeable drugs via an intravascular ultrafast release mechanism to great effect. PMID- 24152293 TI - English community pharmacists' experiences of using electronic transmission of prescriptions: a qualitative study. AB - BACKGROUND: The Electronic Prescription Service Release 2 (EPS2) in England has been designed to provide electronic transmission of digitally-signed prescriptions between primary care providers, with the intent on removing the large amounts of paper currently exchanged. As part of a wider evaluation of the EPS service, we wished to explore pharmacists' experience with the new system and their perceptions of its benefits and any associated problems. METHODS: We conducted semi-structured telephone interviews with community pharmacists using EPS2. We used a purposive sampling technique to obtain views from pharmacists working in pharmacies with a range of sizes and locations and to include both independent pharmacies and multiples. Interviews were transcribed verbatim and coded using grounded theory to identify the main factors that have influenced deployment and implementation in the eyes of respondents. QSR Nvivo was used as to aid in this process. RESULTS: It became apparent from the analysis that respondents perceived a wide range of advantages of EPS including improved safety, stock control, time management and improved relationships between pharmacy and General Practice staff. Respondents did not perceive a large difference in terms of work processes or development of their professional role. A large number of problems had been experienced in relation to both the technology itself and the way it was used by General Practices. It became apparent that work-around procedures had been developed for dealing with these issues but that not all these problems were perceived as having been addressed sufficiently at source. This sometimes had implications for the extent of EPS2 use and also limited some of the potential advantages of the EPS2 system, such as reduced effort in the management of prescription reimbursement. Respondents made suggestions for future improvements to EPS2. While interview data demonstrated that there were some feedback procedures in place, these were not regarded as being sufficient by the majority of respondents. CONCLUSIONS: Whilst pharmacists perceived a wide range of benefits of EPS, a large number of problems had been experienced. Despite these difficulties, no pharmacists expressed an overall negative view. PMID- 24152295 TI - Discovery and optimization of piperidyl-1,2,3-triazole ureas as potent, selective, and in vivo-active inhibitors of alpha/beta-hydrolase domain containing 6 (ABHD6). AB - alpha/beta-Hydrolase domain containing 6 (ABHD6) is a transmembrane serine hydrolase that hydrolyzes the endogenous cannabinoid 2-arachidonoylglycerol (2 AG) to regulate certain forms of cannabinoid receptor-dependent signaling in the nervous system. The full spectrum of ABHD6 metabolic activities and functions is currently unknown and would benefit from selective, in vivo-active inhibitors. Here, we report the development and characterization of an advanced series of irreversible (2-substituted)-piperidyl-1,2,3-triazole urea inhibitors of ABHD6, including compounds KT182 and KT203, which show exceptional potency and selectivity in cells (<5 nM) and, at equivalent doses in mice (1 mg kg(-1)), act as systemic and peripherally restricted ABHD6 inhibitors, respectively. We also describe an orally bioavailable ABHD6 inhibitor, KT185, that displays excellent selectivity against other brain and liver serine hydrolases in vivo. We thus describe several chemical probes for biological studies of ABHD6, including brain penetrant and peripherally restricted inhibitors that should prove of value for interrogating ABHD6 function in animal models. PMID- 24152296 TI - Relationships between age-related biochemical markers of bone turnover and OPG, TGF-beta1 and TGF-beta2 in native Chinese women. AB - Osteoprotegerin (OPG), transforming growth factor-beta1 (TGF-beta1) and TGF-beta2 are cytokines closely associated with bone metabolism. However, their association with bone turnover markers in native Chinese women remains unknown. The study aims to investigate the relationship between bone metabolism related cytokines including OPG, TGF-beta1, TGF-beta2 and bone turnover markers in native Chinese women. The cross-sectional study was conducted on 691 healthy Chinese women (20 80 years old). Levels of OPG, TGF-beta1, TGF-beta2, serum bone-specific alkaline phosphatase (BAP), osteocalcin (OC), cross-linked N-terminal telopeptides of type I collagen (sNTX), cross-linked C-terminal telopeptides of type I collagen (sCTX), urinary NTX (uNTX), urinary CTX (uCTX) and total urinary deoxypyridinoline (uDPD) were determined. The present study showed that OPG and TGF-beta2 had positive correlation with BAP, OC, uNTX, uCTX and uDPD, while TGF beta1 showed negative correlation with BAP, OC, sCTX, uNTX and uCTX, and most of the coefficients of partial correlation remained significant after adjustments for age and body mass index (BMI). Multiple linear regression stepwise analysis showed that OPG and TGF-beta2 were positive determinative factors for BAP, sCTX, uNTX and uCTX, which could explain 0.6-16.6% of the variation in these markers. TGF-beta1 was a negative determinative factor for BAP, OC, sCTX and uCTX, which could explain 0.7-7.3% of the variation in these markers. This study suggested that measuring bone turnover indicators and serum cytokines simultaneously might help evaluating changes in bone turnover rate caused by aging or menopause in women. PMID- 24152297 TI - Survival outcomes in patients with advanced non-small cell lung cancer treated with erlotinib: expanded access programme data from Belgium (the TRUST study). AB - Erlotinib has been shown to prolong progression-free (PFS) and overall survival (OS) in patients with advanced non-small cell lung cancer (NSCLC). We report here on effectiveness data on the subsample of 261 patients from 40 centres in Belgium involved in the TRUST study. Median age was 63 years. Most (69.0%) were male and current/former smokers (84.7%); with Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 or 1 (74.3%), stage IV disease (75.1%) and adenocarcinoma by histology (54.0%). Erlotinib was administered mainly as second- (47.1%) or third-line treatment (48.3%). Response rate was 6.5%; disease control rate 58.3%. Median PFS was 2.2 months. Better PS (P = 0.0384), stage IIIB disease (P = 0.0018) and presence of rash (P < 0.0001) were associated with longer PFS. OS rates at 1, 2 and 3 years were 26.4%, 10.9% and 6.4% respectively. Median OS was 5.9 months. Female gender (P = 0.007), better PS (P < 0.0001), stage IIIB disease (P = 0.0355) and presence of rash (P < 0.0001) were associated with longer OS. The findings confirm the therapeutic benefit of erlotinib in a broad range of patients in a sample from a country with a historically high lung cancer morbidity and mortality burden. Several determinants of PFS and OS are identified. PMID- 24152294 TI - The enzymes of human diphosphoinositol polyphosphate metabolism. AB - Diphospho-myo-inositol polyphosphates have many roles to play, including roles in apoptosis, vesicle trafficking, the response of cells to stress, the regulation of telomere length and DNA damage repair, and inhibition of the cyclin-dependent kinase Pho85 system that monitors phosphate levels. This review focuses on the three classes of enzymes involved in the metabolism of these compounds: inositol hexakisphosphate kinases, inositol hexakisphosphate and diphosphoinositol pentakisphosphate kinases and diphosphoinositol polyphosphate phosphohydrolases. However, these enzymes have roles beyond being mere catalysts, and their interactions with other proteins have cellular consequences. Through their interactions, the three inositol hexakisphosphate kinases have roles in exocytosis, diabetes, the response to infection, and apoptosis. The two inositol hexakisphosphate and diphosphoinositol-pentakisphosphate kinases influence the cellular response to phosphatidylinositol (3,4,5)-trisphosphate and the migration of pleckstrin homology domain-containing proteins to the plasma membrane. The five diphosphoinositol polyphosphate phosphohydrolases interact with ribosomal proteins and transcription factors, as well as proteins involved in membrane trafficking, exocytosis, ubiquitination and the proteasomal degradation of target proteins. Possible directions for future research aiming to determine the roles of these enzymes are highlighted. PMID- 24152298 TI - Asymmetric synthesis of 2-substituted oxetan-3-ones via metalated SAMP/RAMP hydrazones. AB - 2-Substituted oxetan-3-ones can be prepared in good yields and enantioselectivities (up to 84% ee) by the metalation of the SAMP/RAMP hydrazones of oxetan-3-one, followed by reaction with a range of electrophiles that include alkyl, allyl, and benzyl halides. Additionally, both chiral 2,2- and 2,4 disubstituted oxetan-3-ones can be made in high ee (86-90%) by repetition of this lithiation/alkylation sequence under appropriately controlled conditions. Hydrolysis of the resultant hydrazones with aqueous oxalic acid provides the 2 substituted oxetan-3-ones without detectable racemization. PMID- 24152299 TI - Multiple lesions of granular cell basal cell carcinoma: a case report. AB - Granular cell change in basal cell carcinoma (BCC) occurs rarely. Only 11 such cases have been reported; all of them were solitary nodular BCC. We report herein a case of multiple granular cell BCC with infundibulocystic features. The tumors presented as papules on the anterior neck of a 44-year-old female with a prior history of a well-differentiated squamous cell carcinoma (SCC) of the tongue and radiation involving the area in which BCC developed. Microscopically, the tumors were circumscribed small dermal nodules composed of epithelial cords with granular eosinophilic cytoplasm and entrapped infundibular keratocysts. Given the eosinophilic appearance of the tumor, history of SCC and the lesions multiplicity, the initial biopsy was first interpreted as metastatic SCC. The correct diagnosis of granular cell BCC was established upon rereview of the slides at a cancer center. Given the diagnostic controversy, immunohistochemical stains were performed. The tumor cells expressed Ber-EP4, CD63 (NKI/C3) and CD68. The tumors were compared to the prior SCC finding different morphologies. Extensive clinical evaluation showed no evidence of recurrent SCC. This report expands the clinicopathologic spectrum of granular cell variant of BCC and documents for the first time eruption of multiple such tumors in a localized area. PMID- 24152300 TI - Quality of screening with conventional Pap smear in Austria - a longitudinal evaluation. AB - BACKGROUND: In recent decades, the incidence of cervical cancer and cervical cancer mortality in Austria has declined by varying degrees. The Pap smear is to be considered a causal factor for this decline. METHODS: This longitudinal analysis is based on a data set of Pap smear assessments collected by the Committee for Quality Assurance of the Austrian Society of Cytology. Data from 15 laboratories participating in a voluntary self-monitoring program was analyzed for the time span 2004-2008. The data was analyzed in terms of smear quality and assessment quality.A rank-correlation-test for a monotonic trend analysis in the proportion of the three parameters Pap 0, "satisfactory, but limited/SBL", and Pap IIID/IV for the timespan 2004 to 2008 was carried out. RESULTS: For this study, we analyzed an average number of 730,000 smears per year over a five-year period. Specimens from all but two laboratories, i.e. < 2% of all smears, met the quality criterion for Pap 0 (Bethesda 2001 equivalent: Specimen processed and examined, but unsatisfactory for evaluation of epithelial abnormality), whilst only four laboratories, i.e. < 10% of all smears, reached the national requirement for smears classified as "satisfactory, but limited/SBL".When using the Pap IIID/IV ratio (LSIL: HSIL/AIS ratio) of 3:1 to 8:1 as a surrogate quality marker for the interpretation of smears, only five laboratories met this criterion during the survey period.The trend analysis indicated only that an increasing number of samples per year is correlated with an increased proportion of Pap 0 and "satisfactory, but limited/SBL" smears. CONCLUSIONS: Although participants get regular feedback about their results, no general improvements in smear taking or assessment were observed over the years, so mandatory quality management, including the possibility of sanctions, is suggested in order to reduce adverse health effects for women. PMID- 24152301 TI - Circulating lethal toxin decreases the ability of neutrophils to respond to Bacillus anthracis. AB - Polymorphonuclear leucocytes (PMNs) play a protective role during Bacillus anthracis infection. However, B. anthracis is able to subvert the PMN response effectively as evidenced by the high mortality rates of anthrax. One major virulence factor produced by B. anthracis, lethal toxin (LT), is necessary for dissemination in the BSL2 model of mouse infection. While human and mouse PMNs kill vegetative B. anthracis, short in vitro half-lives of PMNs have made it difficult to determine how or if LT alters their bactericidal function. Additionally, the role of LT intoxication on PMN's ability to migrate to inflammatory signals remains controversial. LF concentrations in both serum and major organs were determined from mice infected with B. anthracis Sterne strain at defined stages of infection to guide subsequent administration of purified toxin. Bactericidal activity of PMNs assessed using ex vivo cell culture assays showed significant defects in killing B. anthracis. In vivo PMN recruitment to inflammatory stimuli was significantly impaired at 24 h as assessed by real-time analysis of light-producing PMNs within the mouse. The observations described above suggest that LT serves dual functions; it both attenuates accumulation of PMNs at sites of inflammation and impairs PMNs bactericidal activity against vegetative B. anthracis. PMID- 24152302 TI - Immediate and extended effects of sodium lauryl sulphate exposure on stratum corneum natural moisturizing factor. AB - OBJECTIVES: Natural moisturizing factor (NMF) serves as the primary humectant of the stratum corneum (SC), principally comprised of hygroscopic amino acids and derivatives that absorb moisture. Barrier disruption has been shown to differentially affect the levels of specific NMF components, though the kinetics of NMF component restoration following disruption have not been examined. Here, we investigated the impact of barrier disruption caused by surfactant exposure on a subset of NMF components immediately following exposure and out to 10 days post exposure. METHODS: Volunteers wore patches containing either 1% w/v sodium lauryl sulphate (SLS) or distilled water on their forearms for 24 h. Measurements of transepidermal water loss, erythema, SC water content and a subset of SC NMF and lipid components were obtained at both sites before treatment, the day of patch removal, and 1, 2, 3, 6, and 10 days following treatment. RESULTS: Most measured NMF components decreased in response to SLS exposure. Exceptions were increases in lactate, ornithine and urea, and no difference in proline levels. In the days following exposure, reduced levels of several NMF components continued at the SLS site; however, all measured NMF components demonstrated equivalence to the vehicle control within 10 days. Histidine pH 7, lactate, ornithine and urea were the first to achieve levels equivalent to the vehicle control site, normalizing within 1 day after patch removal. CONCLUSION: Results imply that NMF components derived from sweat and urea cycling are least impacted by SLS exposure whereas NMF components derived from degradation of filaggrin and/or other S-100 proteins are most impacted. This implies the restoration of the processes responsible for S-100 protein processing into free amino acids takes several days to return to normal. Further examination of the enzymes involved in S-100 protein processing following barrier disruption would provide insight into the pathway(s) for NMF restoration during SC recovery. PMID- 24152303 TI - A comparative study of ribosomal proteins: linkage between amino acid distribution and ribosomal assembly. AB - BACKGROUND: Assembly of the ribosome from its protein and RNA constituents must occur quickly and efficiently in order to synthesize the proteins necessary for all cellular activity. Since the early 1960's, certain characteristics of possible assembly pathways have been elucidated, yet the mechanisms that govern the precise recognition events remain unclear.We utilize a comparative analysis to investigate the amino acid composition of ribosomal proteins (r-proteins) with respect to their role in the assembly process. We compared small subunit (30S) r protein sequences to those of other housekeeping proteins from 560 bacterial species and searched for correlations between r-protein amino acid content and factors such as assembly binding order, environmental growth temperature, protein size, and contact with ribosomal RNA (rRNA) in the 30S complex. RESULTS: We find r-proteins have a significantly high percent of positive residues, which are highly represented at rRNA contact sites. An inverse correlation between the percent of positive residues and r-protein size was identified and is mainly due to the content of Lysine residues, rather than Arginine. Nearly all r-proteins carry a net positive charge, but no statistical correlation between the net charge and the binding order was detected. Thermophilic (high-temperature) r proteins contain increased Arginine, Isoleucine, and Tyrosine, and decreased Serine and Threonine compared to mesophilic (lower-temperature), reflecting a known distinction between thermophiles and mesophiles, possibly to account for protein thermostability. However, this difference in amino acid content does not extend to rRNA contact sites, as the proportions of thermophilic and mesophilic contact residues are not significantly different. CONCLUSIONS: Given the significantly higher level of positively charged residues in r-proteins and at contact sites, we conclude that ribosome assembly relies heavily on an electrostatic component of interaction. However, the binding order of r-proteins in assembly does not appear to depend on these electrostatics interactions. Additionally, because thermophiles and mesophiles exhibit significantly different amino acid compositions in their sequences but not in the identities of contact sites, we conclude that this electrostatic component of interaction is insensitive to temperature and is not the determining factor differentiating the temperature sensitivity of ribosome assembly. PMID- 24152304 TI - Identifying the candidate genes involved in the calyx abscission process of 'Kuerlexiangli' (Pyrus sinkiangensis Yu) by digital transcript abundance measurements. AB - BACKGROUND: 'Kuerlexiangli' (Pyrus sinkiangensis Yu), a native pear of Xinjiang, China, is an important agricultural fruit and primary export to the international market. However, fruit with persistent calyxes affect fruit shape and quality. Although several studies have looked into the physiological aspects of the calyx abscission process, the underlying molecular mechanisms remain unknown. In order to better understand the molecular basis of the process of calyx abscission, materials at three critical stages of regulation, with 6000 * Flusilazole plus 300 * PBO treatment (calyx abscising treatment) and 50 mg.L-1GA3 treatment (calyx persisting treatment), were collected and cDNA fragments were sequenced using digital transcript abundance measurements to identify candidate genes. RESULTS: Digital transcript abundance measurements was performed using high-throughput Illumina GAII sequencing on seven samples that were collected at three important stages of the calyx abscission process with chemical agent treatments promoting calyx abscission and persistence. Altogether more than 251,123,845 high quality reads were obtained with approximately 8.0 M raw data for each library. The values of 69.85%-71.90% of clean data in the digital transcript abundance measurements could be mapped to the pear genome database. There were 12,054 differentially expressed genes having Gene Ontology (GO) terms and associating with 251 Kyoto Encyclopedia of Genes and Genomes (KEGG) defined pathways. The differentially expressed genes correlated with calyx abscission were mainly involved in photosynthesis, plant hormone signal transduction, cell wall modification, transcriptional regulation, and carbohydrate metabolism. Furthermore, candidate calyx abscission-specific genes, e.g. Inflorescence deficient in abscission gene, were identified. Quantitative real-time PCR was used to confirm the digital transcript abundance measurements results. CONCLUSIONS: We identified candidate genes that showed highly dynamic changes in expression during the calyx abscission process. These genes are potential targets for future functional characterization and should be valuable for exploration of the mechanisms of calyx abscission, and eventually for developing methods based on small molecule application to induce calyx abscission in fruit production. PMID- 24152305 TI - Association of candidate single nucleotide polymorphisms with somatic mutation of the epidermal growth factor receptor pathway. AB - BACKGROUND: Tumour growth in colorectal cancer and other solid cancers is frequently supported by activating mutations in the epidermal growth factor receptor (EGFR) signaling pathway (Patholog Res Int 2011:932932, 2011). Treatment of metastatic colorectal cancer with targeted anti-EGFR therapeutics such as cetuximab extends survival in only 25% of patients who test wild-type for KRAS, while the majority of patients prove resistant (J Clin Oncol 28(7):1254-1261, 2010).Prediction of cetuximab responsiveness for KRAS wild-type colorectal cancers is currently not well defined, and prognostic biomarkers would help tailor treatment to individual patients. Somatic mutation of the EGFR signalling pathway is a prevalent mechanism of resistance to cetuximab (Nature 486(7404):532 536, 2012). If the human genome harbours variants that influence susceptibility of the EGFR pathway to oncogenic mutation, such variants could also be prognostic for cetuximab responsiveness. METHODS: We assessed whether patient genetic variants may associate with somatic mutation of the EGFR signalling pathway. We combined tumour mutation data from the Cancer Genome Atlas with matched patient genetic data, and tested for germline variants that associate with somatic mutation of the EGFR pathway (including EGFR, KRAS, BRAF, PTEN and PIK3CA). RESULTS: Two single nucleotide polymorphisms (SNPs) located 90 kb upstream of the TERT oncogene associated with somatic mutation of the EGFR pathway beyond the threshold of genome-wide significance: rs7736074 (P = 4.64 * 10-9) and rs4975596 (P = 5.69 * 10-9). We show that allelic variants of rs7736074 and rs4975596 modulate TERT expression levels in multiple cancer types, and exhibit preliminary prognostic value for response to cetuximab. CONCLUSIONS: We have identified two germline SNPs that associate with somatic mutation of the EGFR pathway, and may be prognostic for cetuximab responsiveness. These variants could potentially contribute to a panel of prognostic biomarkers for assessing whether metastatic colorectal cancer patients are likely to derive benefit from cetuximab treatment. Genotyping of a large cohort of cetuximab-treated colorectal cancer patients is called for to further clarify the association. PMID- 24152307 TI - Evaluation of atrial electromechanical coupling times in hemodialysis patients. AB - BACKGROUND: There are no definite data about the atrial electromechanical coupling times (AEMCT) in patients with end stage renal failure (ESRF). The aim of this study was to investigate the AEMCT in ESRF patients without hypertension (HT) and diabetes mellitus. METHODS: The study population consisted of 47 normotensive, nondiabetic ESRF patients and 41 healthy age/gender-matched control subjects. The time intervals from the onset of P-wave on the surface electrocardiogram to the beginning of late diastolic A-wave (PA) were obtained from the lateral mitral annulus (PA-lateral, maximum AEMCT), septal annulus (PA septal), and tricuspid lateral annulus (PA-tricuspid). Time intervals were corrected according to the heart rate. The difference between PA-septal and PA tricuspid (right AEMCT), PA-lateral and PA-septal (left AEMCT), and PA-lateral and PA-tricuspid (inter AEMCT) were calculated. Corrected time intervals were used for calculations. RESULTS: Groups were similar for age (52 +/- 12.3 vs. 49.9 +/- 6 years, P > 0.05) and gender. Maximum (61 +/- 20 vs. 47 +/- 13 ms; P < 0.001) AEMCT was significantly higher in the patients compared with the control group, but septal and tricuspid EMCT were not different (P > 0.05). Both inter atrial (37 +/- 21 vs. 24 +/- 16 ms, P = 0.002) and left atrial (25 +/- 18 vs. 12 +/- 9 ms; P < 0.001) EMCT were significantly higher in patients when compared with the controls but intra-right atrial EMCT was not different. CONCLUSIONS: Atrial conduction parameters such as maximal EMCT, left atrial, and inter-atrial EMCTs were prolonged in ESRF patients. This prolongation is seen in ESRF patients even in the absence of factors that affect atrial coupling, such as HT. PMID- 24152306 TI - Epitope mapping of inhibitory antibodies targeting the C2 domain of coagulation factor VIII by hydrogen-deuterium exchange mass spectrometry. AB - BACKGROUND: The development of anti-factor VIII antibodies (inhibitors) is a significant complication in the management of patients with hemophilia A, leading to significant increases in morbidity and treatment cost. Using a panel of mAbs against different epitopes on FVIII, we have recently shown that epitope specificity, inhibitor kinetics and time to maximum inhibition are more important than inhibitor titer in predicting responses to FVIII and the combination of FVIII and recombinant FVIIa. In particular, a subset of high-titer inhibitors responded to high-dose FVIII, which would not be predicted on the basis of their inhibitor titer alone. Thus, the ability to quickly map the epitope spectrum of patient plasma with a clinically feasible assay may fundamentally change how clinicians approach the treatment of high-titer inhibitor patients. OBJECTIVES: To map the epitopes of anti-FVIII mAbs, three of which are classic inhibitors and one of which is a non-classic inhibitor, by the use of hydrogen-deuterium exchange coupled with mass spectrometry (HDX-MS). METHODS: The binding epitopes of four mAbs targeting the FVIII C2 domain were mapped with HDX-MS. RESULTS: The epitopes determined with HDX-MS are consistent with those obtained earlier through structural characterization and antibody competition assays. In addition, classic and non-classic inhibitor epitopes could be distinguished by the use of a limited subset of C2 domain-derived peptic fragments. CONCLUSION: Our results demonstrate the effectiveness and robustness of the HDX-MS method for epitope mapping, and suggest a potential role of rapid mapping of FVIII inhibitor epitopes in facilitating individualized treatment of inhibitor patients. PMID- 24152308 TI - Measuring the effectiveness of an audiological counseling program. AB - OBJECTIVE: Audiologists routinely observe patients struggle with psycho-emotional difficulties associated with hearing loss, yet are often underprepared to manage this vital aspect of patient care. For this reason, a workshop was developed for audiologists interested in expanding their counselling skills. Since one-time workshops typically do not result in changes in practice, this program adopted a distributed-over-time learning model, consisting of 20 hours of participation across six weeks. The extended nature of the program provided multiple opportunities to learn several counselling strategies, and apply and evaluate the effectiveness of these strategies in clinical settings. DESIGN: Learning objectives were assessed throughout the six-week program. However, at the conclusion of each program, it was unknown whether new knowledge carried over into sustained new skills. Therefore, we surveyed attendees six months after their program, to determine if the program had affected changes in their practice. STUDY SAMPLE: Twenty clinicians (response rate = 91%) participated in the survey. RESULTS: All respondents made some, and often many, changes in patient communication. They applied several counseling concepts to their work settings and reported positive changes in patient-clinician dynamics. CONCLUSION: Results suggest that a six-week program is effective in helping clinicians change their counseling skills within their practice. PMID- 24152309 TI - Development and validation of the Leuven intelligibility sentence test with male speaker (LIST-m). AB - OBJECTIVE: In addition to the LIST with a female speaker ( van Wieringen & Wouters, 2008 ), a new speech perception test with a male voice was developed and validated, for evaluating the intelligibility performance of cochlear implant (CI) users or severely hearing-impaired persons. DESIGN: Three experimental steps were carried out: (1) a perceptual optimization of the recorded materials, (2) an evaluation in normal-hearing (NH) listeners, and (3) a validation in CI-users. Measurements were performed both in quiet and in noise. STUDY SAMPLE: Forty-four NH subjects and six CI-users participated. RESULTS: After selecting the sentences with a similar intelligibility, the reference psychometric curve for NH listeners was determined, showing steep slopes for measurements in quiet (12.3%/dB) and in noise (18.7%/dB), similar to the LIST with female voice. The 38 lists of 10 sentences yielded equal scores, and the within-subject test-retest reliability was high (1.7 dB in quiet, 1.1 dB in noise). For the CI-users, parallel psychometric curves were found between the LIST with male and female voice. CONCLUSIONS: The LIST-m is a reliable and valid speech intelligibility test that can be used for CI-users, both in quiet and in noise. PMID- 24152311 TI - Die Brautbriefe: the Freud and Martha correspondence. PMID- 24152312 TI - Introduction: The Wolf Man's Rorschach. PMID- 24152313 TI - The Wolf Man's Rorschach. PMID- 24152314 TI - Rorschach protocol. PMID- 24152315 TI - The Wolf Man's Rorschach - part 2. PMID- 24152316 TI - Rorschach interpretation of Freud's "Wolf Man" at age 69. PMID- 24152317 TI - On the Rorschach protocol. PMID- 24152318 TI - Wolf Man: concluding commentary. PMID- 24152319 TI - When Freud headed for the East: aspects of a Chinese translation of his works. AB - Working on the basis of a resume of the Chinese translations to date of individual works by Sigmund Freud and critiques of these as secondary translations from the English, the particular difficulties of translating into a non-Indo-European language with an isolating and analytical writing system are presented. By way of introduction, reference is made to English and French language contributions to the issues of translation. PMID- 24152320 TI - The ego and the id revisited Freud and Damasio on the body ego/self. AB - Freud's statement in The Ego and the Id (1923) that the ego is first and foremost a bodily ego is well known. This paper tempts to clarify the premises underlying Freud's thesis. Particular attention is paid to Freud's investigation of internal perceptions. Freud argued that internal perceptions are more primordial than perceptions arising externally. In Freud's opinion the roots of the ego, the id, are to be found in body sensations and feelings, but he had to admit that very little was known about these sensations and feelings. Only much later was neuroscience in a position to offer evidence that feelings can be the direct perception of the internal state of the body. Damasio (2010) has recently suggested that the core of the self might be found in what he, like Freud, terms primordial feelings. Not only was Freud able to conceive of the ego as the perception and feeling of our own body but also to conceive of knowing the mental life of another by means of recreating the bodily state of another through imitation. PMID- 24152321 TI - Effects of parasitism on aphid nutritional and protective symbioses. AB - Insects often carry heritable symbionts that negotiate interactions with food plants or natural enemies. All pea aphids, Acyrthosiphon pisum, require infection with the nutritional symbiont Buchnera, and many are also infected with Hamiltonella, which protects against the parasitoid Aphidius ervi. Hamiltonella based protection requires bacteriophages called APSEs with protection levels varying by strain and associated APSE. Endoparasitoids, including A. ervi, may benefit from protecting the nutritional symbiosis and suppressing the protective one, while the aphid and its heritable symbionts have aligned interests when attacked by the wasp. We investigated the effects of parasitism on the abundance of aphid nutritional and protective symbionts. First, we determined strength of protection associated with multiple symbiont strains and aphid genotypes as these likely impact symbiont responses. Unexpectedly, some A. pisum genotypes cured of facultative symbionts were resistant to parasitism and resistant aphid lines carried Hamiltonella strains that conferred no additional protection. Susceptible aphid clones carried protective strains. qPCR estimates show that parasitism significantly influenced both Buchnera and Hamiltonella titres, with multiple factors contributing to variation. In susceptible lines, parasitism led to increases in Buchnera near the time of larval wasp emergence consistent with parasite manipulation, but effects were variable in resistant lines. Parasitism also resulted in increases in APSE and subsequent decreases in Hamiltonella, and we discuss how this response may relate to the protective phenotype. In summary, we show that parasitism alters the within-host ecology of both nutritional and protective symbioses with effects likely significant for all players in this antagonistic interaction. PMID- 24152322 TI - Spatial chaos and complexity in the intracellular space of cancer and normal cells. AB - BACKGROUND: One of the most challenging problems in biological image analysis is the quantification of the dynamical mechanism and complexity of the intracellular space. This paper investigates potential spatial chaos and complex behavior of the intracellular space of typical cancer and normal cell images whose structural details are revealed by the combination of scanning electron microscopy and focused ion beam systems. Such numerical quantifications have important implications for computer modeling and simulation of diseases. METHODS: Cancer cell lines derived from a human head and neck squamous cell carcinoma (SCC-61) and normal mouse embryonic fibroblast (MEF) cells produced by focused ion beam scanning electron microscopes were used in this study. Spatial distributions of the organelles of cancer and normal cells can be analyzed at both short range and long range of the bounded dynamical system of the image space, depending on the orientations of the spatial cell. A procedure was designed for calculating the largest Lyapunov exponent, which is an indicator of the potential chaotic behavior in intracellular images. Furthermore, the sample entropy and regularity dimension were applied to measure the complexity of the intracellular images. RESULTS: Positive values of the largest Lyapunov exponents (LLEs) of the intracellular space of the SCC-61 were obtained in different spatial orientations for both long-range and short-range models, suggesting the chaotic behavior of the cell. The MEF has smaller positive values of LLEs in the long range than those of the SCC-61, and zero vales of the LLEs in the short range analysis, suggesting a non-chaotic behavior. The intracellular space of the SCC-61 is found to be more complex than that of the MEF. The degree of complexity measured in the spatial distribution of the intracellular space in the diagonal direction was found to be approximately twice larger than the complexity measured in the horizontal and vertical directions. CONCLUSION: Initial findings are promising for characterizing different types of cells and therefore useful for studying cancer cells in the spatial domain using state-of-the-art imaging technology. The measures of the chaotic behavior and complexity of the spatial cell will help computational biologists gain insights into identifying associations between the oscillation patterns and spatial parameters of cells, and appropriate model for simulating cancer cell signaling networks for cancer treatment and new drug discovery. PMID- 24152324 TI - The glutamatergic hypothesis for Down syndrome: the potential use of N-methyl-D aspartate receptor antagonists to enhance cognition and decelerate neurodegeneration. AB - Down syndrome (DS) is the most common genetically defined cause of intellectual disability and accounts for over 50% of the cases of Alzheimer-type dementia in persons younger than 50 years of age. At present, no pharmacotherapy aimed at counteracting either the neurodevelopmental or the neurodegenerative component of this genetic disorder has been approved. Recent preclinical and clinical work on the N-methyl-D-aspartate (NMDA) receptor antagonist memantine give us some reason for optimism, at least in relation to the potential for a partial pharmacological improvement of hippocampus dependent memory deficits associated with DS. Here, we will review briefly the roles of NMDA receptors in health and disease, including the glutamatergic hypothesis for Alzheimer disease. Then, we will describe the basis for a glutamatergic hypothesis for DS, by reviewing the available preclinical evidence and assessing potential molecular mechanisms for NMDA receptor dysfunction in DS. A short description of the first two clinical trials of memantine in young and older adults with DS will follow. We will conclude by reviewing three caregiver reports from our recent clinical study and some lessons we have learned designing and conducting the first translational study in the field of DS to arise directly from experimental results in animal models. PMID- 24152323 TI - Artificial pancreas using a personalized rule-based controller achieves overnight normoglycemia in patients with type 1 diabetes. AB - OBJECTIVE: This study assessed the efficacy of a closed-loop (CL) system consisting of a predictive rule-based algorithm (pRBA) on achieving nocturnal and postprandial normoglycemia in patients with type 1 diabetes mellitus (T1DM). The algorithm is personalized for each patient's data using two different strategies to control nocturnal and postprandial periods. RESEARCH DESIGN AND METHODS: We performed a randomized crossover clinical study in which 10 T1DM patients treated with continuous subcutaneous insulin infusion (CSII) spent two nonconsecutive nights in the research facility: one with their usual CSII pattern (open-loop [OL]) and one controlled by the pRBA (CL). The CL period lasted from 10 p.m. to 10 a.m., including overnight control, and control of breakfast. Venous samples for blood glucose (BG) measurement were collected every 20 min. RESULTS: Time spent in normoglycemia (BG, 3.9-8.0 mmol/L) during the nocturnal period (12 a.m. 8 a.m.), expressed as median (interquartile range), increased from 66.6% (8.3 75%) with OL to 95.8% (73-100%) using the CL algorithm (P<0.05). Median time in hypoglycemia (BG, <3.9 mmol/L) was reduced from 4.2% (0-21%) in the OL night to 0.0% (0.0-0.0%) in the CL night (P<0.05). Nine hypoglycemic events (<3.9 mmol/L) were recorded with OL compared with one using CL. The postprandial glycemic excursion was not lower when the CL system was used in comparison with conventional preprandial bolus: time in target (3.9-10.0 mmol/L) 58.3% (29.1 87.5%) versus 50.0% (50-100%). CONCLUSIONS: A highly precise personalized pRBA obtains nocturnal normoglycemia, without significant hypoglycemia, in T1DM patients. There appears to be no clear benefit of CL over prandial bolus on the postprandial glycemia. PMID- 24152325 TI - Editorial: current strategies in targeting brain disorders. PMID- 24152326 TI - Future directions in the treatment of neuropathic pain: a review on various therapeutic targets. AB - Neuropathic pain is caused by structural lesion leading to functional abnormalities in central and peripheral nervous system. Neuropathic pain in itself is not always a disease, as it arises due to consequences of other diseases like diabetes, spinal cord injury, degenerative neuronal diseases and cancer. Current strategies of neuropathic pain treatment have provided relief to the patients to some extent, but complete cure is still a distant dream. In the future, it is hoped that a combination of new and improved pharmaceutical developments combined with careful clinical trials and increased understanding of neuroplasticity will lead to improved and effective pain management strategies leading to improved quality of life. In this review we have discussed various therapeutic targets of neuropathic pain and their pathophysiological mechanisms. Current status of drugs used for treatment of neuropathic pain have also been discussed in the review. PMID- 24152327 TI - Recent approaches for studying the role of glia. AB - A target-based approach has been used to develop novel drugs in many therapeutic fields. However, this approach remains suboptimal for drug discovery in brain disorders because the target identification in a brain disorder requires a hierarchical integration from in vitro cellular and functional tissue studies to animal models that sustain neuronal and glial complexity. Although glial cells comprise over half of the brain and play important roles in brain function and disease, the intracellular signaling of glial cells remains essentially unexplored. This is because the lack of optimal strategy to selectively activate or deactivate glial signaling has made it difficult to study glial roles. The recent development of approaches using mouse models and enabling the selective activation of cell signaling could be used to assess the role of glial cells in physiology and disease. This review presents how glial G- protein signaling contributes to brain disorders and how the role of glia is investigated. PMID- 24152328 TI - Regulatory triangle of neurodegeneration, adult neurogenesis and microRNAs. AB - MicroRNAs (miRNAs) have emerged as a new class of RNA molecules which are short in length, less in number but play bigger role in regulation of cellular events. miRNAs keep cellular homeostasis in tight control by fine tuning expression of protein coding genes at post-transcriptional level. Neurogenesis and neurodegeneration are two complex processes which are regulated by dynamic expression of regulatory proteins like transcription factors and signaling proteins. Evidences are accumulating that expression of miRNAs play major role in fate determination of neuronal cells undergoing neurogenesis or neurodegeneration. Neurodegeneration either induced by genetic factors or environmental chemicals results in development of neurodegenerative disorders like Parkinson's or Alzheimer's. With increasing acceptance of adult neurogenesis, it seems possible that inducing neurogenesis in adult brain can help in fighting with neurodegenerative disorders. Regulatory RNA molecules, like miRNAs are presenting them as potential therapeutic targets for inducing neurogenesis and controlling neurodegeneration. In the current review, we are exploring the link between neurodegeneration and adult neurogenesis regulation by focusing on miRNAs. PMID- 24152329 TI - Necroptosis: who knew there were so many interesting ways to die? AB - Conventional knowledge considered apoptosis as the sole form of programmed cell death during development, homeostasis and diseases, whereas necrosis was regarded as an unregulated and uncontrollable process. Recent revelations suggest that necrosis can also occur in a regulated, caspase-independent manner and shares characteristics with both necrosis and apoptosis. The major cell death processes namely apoptosis, autophagy and necrosis are interlinked and contain many common regulatory mechanisms. Mounting evidence indicates that necroptosis contributes to the pathogenesis of various diseases, including ischemic stroke, traumatic brain injury, neurodegenerative disorders and brain tumor. We present here an overview of the molecular mechanisms governing necroptosis and its connection with apoptosis and autophagy processes. Further, the necroptosis mechanisms underlying the neurodegeneration during ischemia reperfusion (I/R) injury are described, with an emphasis on the key proteins involved in this type of cell death. Knowledge regarding programmed cell death (PCD) with relevance to necroptosis may play a significant role in debilitating brain disorders. PMID- 24152331 TI - Editorial: pharmacological intervention for Down syndrome cognitive deficits: emerging drug targets. PMID- 24152330 TI - Insights on the neuromodulatory propensity of Selaginella (Sanjeevani) and its potential pharmacological applications. AB - Exploiting the potential of natural compounds to attenuate endogenous redox status to achieve neuroprotection is a novel concept in human disease therapy. This has necessitated a need to identify newer efficient phytochemicals possessing propensity to act on various biochemical therapeutic targets with low or no toxicity. Selaginella is a lithophytic pteridophyte which grows on constantly irrigated rocks in high altitude zones in different parts of the world. It is appraised to be "Sanjeevani" (the resurrection herb) based on its mythological reference in the Indian epic "Ramayana". Due to the presence of a unique disaccharide, trehalose, most species of Selaginella can survive severe drought conditions, maintaining the plant's structural stability and resurrect during rains. Several species of the genus are used in ethnic medicine for the therapy of jaundice, chronic trachitis, lung cancer, labor pain and wound healing. The major natural compounds in the genus Selaginella are characteristic flavonoid-dimers, called 'biflavonoids'. Although various biological effects of Selaginella have been documented in vitro, studies on its neuromodulatory properties are nonexisting despite the presence of potentially therapeutic biflavonoids. We have reviewed the existing literature on the possible pharmacological properties of Selaginella. Further, recent evidence gathered from our laboratory on the neuromodulatory propensity of S. delicatula employing in vivo models of chemically induced neurodegenerative diseases in rodents and Drosophila are discussed. Our findings point to a mechanism which modulates redox status and mitochondrial dysfunction suggesting their possible therapeutic use in oxidative stress-mediated neurodegenerative diseases including Parkinson's disease. PMID- 24152332 TI - DYRK1A: a potential drug target for multiple Down syndrome neuropathologies. AB - Down syndrome (DS), the most common genetic cause of intellectual disability, is caused by the trisomy of chromosome 21. MNB/DYRK1A (Minibrain/dual specificity tyrosine phosphorylation-regulated kinase 1A) has possibly been the most extensively studied chromosome 21 gene during the last decade due to the remarkable correlation of its functions in the brain with important DS neuropathologies, such as neuronal deficits, dendrite atrophy, spine dysgenesis, precocious Alzheimer's-like neurodegeneration, and cognitive deficits. MNB/DYRK1A has become an attractive drug target because increasing evidence suggests that its overexpression may induce DS-like neurobiological alterations, and several small-molecule inhibitors of its protein kinase activity are available. Here, we summarize the functional complexity of MNB/DYRK1A from a DS-research perspective, paying particular attention to the capacity of different MNB/DYRK1A inhibitors to reverse the neurobiological alterations caused by the increased activity of MNB/DYRK1A in experimental models. Finally, we discuss the advantages and drawbacks of possible MNB/DYRK1A-based therapeutic strategies that result from the functional, molecular, and pharmacological complexity of MNB/DYRK1A. PMID- 24152333 TI - Reducing GABAergic inhibition restores cognitive functions in a mouse model of Down syndrome. AB - Alterations in excitatory-inhibitory balance occur in Down syndrome and could be responsible for cognitive deficits observed through the life of all individuals carrying an extra copy of chromosome 21. Excess of inhibition in the adult could produce synaptic plasticity deficits that may be a primary mechanism contributing to learning and memory impairments. In this study we discuss pharmacological treatments that could potentially alleviate neuronal inhibition and have been tested in a mouse model of Down syndrome. gamma-aminobutyric acid (GABA) is the major inhibitory neurotransmitter in the mature central nervous system that binds to GABA-benzodiazepine receptors, opens a chloride channel and reduces neuronal excitability. These receptors have been extensively studied as targets for treatment of epilepsy, anxiety, sleep, cognitive disorders and the induction of sedation. Molecules that are either antagonists or inverse agonists of the GABA benzodiazepine receptors are able to reduce inhibitory GABAergic transmission. However modulating the excitatory-inhibitory balance towards increase of cognition without inducing seizures remains difficult particularly when using GABA antagonists. In this study we review data from the literature obtained using inverse agonists selective for the alpha5-subunit containing receptor. Such inverse agonists, initially developed as cognitive enhancers for treatment of memory impairments, proved to be very efficient in reversing learning and memory deficits in a Down syndrome mouse model after acute treatment. PMID- 24152334 TI - The Akt-mTOR pathway in Down's syndrome: the potential use of rapamycin/rapalogs for treating cognitive deficits. AB - An increasing amount of evidence suggests that the dysregulation of the Akt-mTOR (Akt-mammalian Target Of Rapamycin) signaling network is associated with intellectual disabilities, such as fragile X, tuberous sclerosis and Rett's syndrome. The Akt-mTOR pathway is involved in dendrite morphogenesis and synaptic plasticity, and it has been shown to modulate both glutamatergic and GABAergic synaptic transmission. We have recently shown that the AktmTOR pathway is hyperactive in the hippocampus of Ts1Cje mice, a model of Down's syndrome, leading to increased local dendritic translation that could interfere with synaptic plasticity. Rapamycin and rapalogs are specific inhibitors of mTOR, and some of these inhibitors are Food and Drug Administration-approved drugs. In this review, we discuss the molecular basis and consequences of Akt-mTOR hyperactivation in Down's syndrome, paying close attention to alterations in the molecular mechanisms underlying synaptic plasticity. We also analyze the pros and cons of using rapamycin/rapalogs for the treatment of the cognitive impairments associated with this condition. PMID- 24152335 TI - Changes in cesarean delivery rates by gestational age: United States, 1996-2011. AB - KEY FINDINGS: Data from the natality data file, national vital statistics system. After 12 years of consecutive increases, the preliminary cesarean delivery rate among singleton births was unchanged from 2009 to 2011 (31.3%). Cesarean delivery rates decreased more than 5% among births at 38 weeks of gestation, but increased 4% among births at 39 weeks. Decreases in cesarean delivery rates for births at 38 weeks occurred for non-Hispanic white, non-Hispanic black, and Hispanic women, as well as for all maternal age groups. Increases in cesarean delivery rates for births at 39 weeks occurred among non-Hispanic white, non-Hispanic black, and Hispanic women, as well as for all maternal age groups. The cesarean delivery rate at 38 weeks decreased in 30 states; the cesarean delivery rate at 39 weeks increased in 23 states. PMID- 24152336 TI - Higher preweaning mortality in free farrowing pens compared with farrowing crates in three commercial pig farms. AB - If loose-housed farrowing systems are to be an alternative to traditional farrowing crates, it is important that they can deliver the same production results as can be achieved in farrowing crates under commercial conditions. The aim of this study was to compare preweaning mortality in farrowing crates and free farrowing pens (FF-pens) within herds that had both systems. The study was conducted over 2 years in three commercial Danish herds that had FF-pens as well as traditional farrowing crates in their farrowing unit. Piglet mortality was analysed in two periods: before litter equalisation and after litter equalisation. Linear models were used to analyse effects of housing (crate or pen), herd (Herd A, B or C), parity (parities 1, 2, 3 to 4 or 5 to 8) as well as the effect of number of total born piglets on mortality before litter equalisation, and the effect of equalised litter size on piglet mortality after litter equalisation. All corresponding interactions were included in the models. Before litter equalisation piglet mortality was higher (P<0.001) in pens (13.7%) than in crates (11.8%). Similarly, piglet mortality after litter equalisation was higher in pens than in crates in all three herds, but the difference between pens and crates were dissimilar (P<0.05) in the different herds. In addition, piglet mortality, both before (P<0.001) and after litter equalisation (P<0.001), grew with increasing parity of the sows. Mortality before litter equalisation moreover increased with increasing number of total born piglets per litter (P<0.001), and mortality after equalisation increased when equalised litter size increased (P<0.001). No significant interactions were detected between housing and parity or housing and litter size for any of the analysed variables. In conclusion, there is knowledge how to design pens for free farrowing; but this study showed a higher preweaning mortality in the FF-pen. Nonetheless a noteworthy proportion of the sows in the FF-pens delivered results comparable to those farrowing in crates. This indicates that FF-pens are not yet a robust type of housing for farrowing sows. PMID- 24152337 TI - International developments in revenues and incomes of general practitioners from 2000 to 2010. AB - BACKGROUND: The remuneration system of General Practitioners (GPs) has changed in several countries in the past decade. The aim of our study was: to establish the effect of these changes on the revenues and income of GPs in the first decade of the 21st century. METHODS: Annual GP revenue and practice costs were collected from national institutes in the eight countries included in our study (Belgium, Denmark, Finland, France, Germany, The Netherlands, Sweden, The United Kingdom (UK)) from 2000-2010. The data were corrected for inflation and purchasing power. Data on the remuneration systems and changes herein were collected from the European Observatory Health Systems Reviews and country experts. RESULTS: Comprehensive changes in the remuneration system of GPs were associated with considerable changes in GP income. Incremental changes mainly coincided with a gradual increase in income after correction for inflation. Average GP income was higher in countries with a strong primary care structure. CONCLUSIONS: The gap between the countries where GPs have a lower income (Belgium, Sweden, France and Finland) and the countries where GPs have a higher income (Netherlands, Germany and the UK) continues to exist over time and appeared to be related to dimensions of primary care, such as governance and access. New payment forms, such as integrated care payment systems, and new health care professionals that are working for GPs, increasingly blur the line between practice costs and income, making it more and more important to clearly define expenditures on GPs, to remain sight on the actual income of GPs. PMID- 24152338 TI - In vitro and ex vivo evaluation of a multi-epitope heparinase vaccine for various malignancies. AB - Previous studies have indicated that heparanase (Hpa) might represent a candidate universal tumor-associated antigen. However, vaccine therapy targeting only one cytotoxic T lymphocyte (CTL) epitope is suboptimal in preventing cancer. In the present study, we designed heparanase multi-epitope vaccines to increase the immune response to standard single heparanase epitopes. The results showed that multi-epitope vaccines Hpa525 + 277 + 405 + 16 and Hpa8 + 310 + 315 + 363 induced higher Hpa-specific lysis of various cancer cells from different tissues in a HLA A2-restricted and heparanase-specific manner compared with the single epitope vaccines Hpa525, Hpa277, Hpa405, Hpa16, Hpa8, Hpa310, Hpa315 and Hpa363, both in vitro and ex vivo. Heparanase multi-epitope vaccines not only induced the heparanase-specific CTL to lyse tumor cells but also increased CTL secretion of interferon-gamma. However, these heparanase-specific CTL did not lyse heparanase expressing autologous lymphocytes and dendritic cells, which confirms the safety of these multi-epitope vaccines. Therefore, the present study provides theoretical evidence for the use of heparanase multi-epitope vaccines for clinical application. PMID- 24152339 TI - Bacterial versus fungal laccase: potential for micropollutant degradation. AB - Relatively high concentrations of micropollutants in municipal wastewater treatment plant (WWTP) effluents underscore the necessity to develop additional treatment steps prior to discharge of treated wastewater. Microorganisms that produce unspecific oxidative enzymes such as laccases are a potential means to improve biodegradation of these compounds. Four strains of the bacterial genus Streptomyces (S. cyaneus, S. ipomoea, S. griseus and S. psammoticus) and the white-rot fungus Trametes versicolor were studied for their ability to produce active extracellular laccase in biologically treated wastewater with different carbon sources. Among the Streptomyces strains evaluated, only S. cyaneus produced extracellular laccase with sufficient activity to envisage its potential use in WWTPs. Laccase activity produced by T. versicolor was more than 20 times greater, the highest activity being observed with ash branches as the sole carbon source. The laccase preparation of S. cyaneus (abbreviated LSc) and commercial laccase from T. versicolor (LTv) were further compared in terms of their activity at different pH and temperatures, their stability, their substrate range, and their micropollutant oxidation efficiency. LSc and LTv showed highest activities under acidic conditions (around pH 3 to 5), but LTv was active over wider pH and temperature ranges than LSc, especially at near-neutral pH and between 10 and 25 degrees C (typical conditions found in WWTPs). LTv was also less affected by pH inactivation. Both laccase preparations oxidized the three micropollutants tested, bisphenol A, diclofenac and mefenamic acid, with faster degradation kinetics observed for LTv. Overall, T. versicolor appeared to be the better candidate to remove micropollutants from wastewater in a dedicated post-treatment step. PMID- 24152341 TI - The Medical Council of India - change necessary, apprehensions persist. PMID- 24152342 TI - The murder of Dr Narendra Dabholkar: a fascist attack on rationalism. PMID- 24152340 TI - Inhibition of hepatitis C virus by the cyanobacterial protein Microcystis viridis lectin: mechanistic differences between the high-mannose specific lectins MVL, CV N, and GNA. AB - Plant or microbial lectins are known to exhibit potent antiviral activities against viruses with glycosylated surface proteins, yet the mechanism(s) by which these carbohydrate-binding proteins exert their antiviral activities is not fully understood. Hepatitis C virus (HCV) is known to possess glycosylated envelope proteins (gpE1E2) and to be potently inhibited by lectins. Here, we tested in detail the antiviral properties of the newly discovered Microcystis viridis lectin (MVL) along with cyanovirin-N (CV-N) and Galanthus nivalis agglutinin (GNA) against cell culture HCV, as well as their binding properties toward viral particles, target cells, and recombinant HCV glycoproteins. Using infectivity assays, CV-N, MVL, and GNA inhibited HCV with IC50 values of 0.6 nM, 30.4 nM, and 11.1 nM, respectively. Biolayer interferometry analysis demonstrated a higher affinity of GNA to immobilized recombinant HCV glycoproteins compared to CV-N and MVL. Complementary studies, including fluorescence-activated cell sorting (FACS) analysis, confocal microscopy, and pre- and post-virus binding assays, showed a complex mechanism of inhibition for CV-N and MVL that includes both viral and cell association, while GNA functions by binding directly to the viral particle. Combinations of GNA with CV-N or MVL in HCV infection studies revealed synergistic inhibitory effects, which can be explained by different glycan recognition profiles of the mainly high-mannoside specific lectins, and supports the hypothesis that these lectins inhibit through different and complex modes of action. Our findings provide important insights into the mechanisms by which lectins inhibit HCV infection. Overall, the data suggest MVL and CV-N have the potential for toxicity due to interactions with cellular proteins while GNA may be a better therapeutic agent due to specificity for the HCV gpE1E2. PMID- 24152343 TI - Trials and tribulations: an expose of the HPV vaccine trials by the 72nd Parliamentary Standing Committee Report. PMID- 24152344 TI - Dharma and medical ethics. AB - Despite the numerous policies, regulations and laws aimed at promoting and ensuring ethical practice in healthcare, ethical misconduct remains rampant. Perhaps something more is needed to encourage a genuine and sustained moral attitude and behaviour. To a casual reader, the regulations on ethics read merely as a list of do's and don'ts and their philosophical foundation is not clear. In actuality, morality is often grounded in philosophy. Traditionally, religious and theistic philosophies drove moral behaviour. However, this is changing due to the current trend of secularism. Hindu philosophies are among the oldest philosophies that are still thriving, and this article explores these philosophies and compares and contrasts them with some of the contemporary ethical theories to assess if they can add value to the field of medical ethics. The main theme of the article is dharma or righteous conduct, the concepts related to it and how these can have a bearing on the development of an ethical attitude and the practice of medical ethics. PMID- 24152345 TI - The big Cs of the informed consent form: compliance and comprehension. AB - The informed consent process is a shield which protects subjects from harms that may be caused by a scientific enquiry. Only a competent participant with a complete understanding of the trial can give informed consent. Although the content of a valid informed consent form has been established, the Drugs and Cosmetics (First Amendment) Rules, 2013 have stipulated that ICFs must fulfil the requirements of Appendix V of Schedule Y. We considered 50 ICFs and analysed whether they complied with Appendix V. Our analysis reveals a gloomy picture, with 70% of the ICFs deviating from the requirements of the law. We have identified the elements most commonly overlooked in the ICFs analysed. We recommend certain points which must be incorporated into ICFs to help participants better understand the trial. Our findings indicate that adequate action needs to be taken to ensure the protection of the rights of research participants. PMID- 24152346 TI - The relationship between ethical climate at work and job satisfaction among nurses in Tehran. AB - BACKGROUND: This study aimed to provide an understanding of the relationship between the ethical climate at the workplace and job satisfaction among nurses. METHODS: 210 nurses working in selected wards in the Tehran University of Medical Sciences were asked to fill out questionnaires on their work environment and level of job satisfaction. The data collection tools included a questionnaire to obtain demographic data, the Olson moral climate questionnaire and Minnesota job satisfaction questionnaire. The data were analysed using SPSS software version 14. RESULTS: We found a significant positive relationship between the ethical climate and the level of job satisfaction among the nurses. Among the demographic variables, the working shift, income level and type of duties allocated had a significant relationship with job satisfaction. CONCLUSION: Hospital managements should pay attention to the factors influencing job motivation among nurses, including the ethical climate of the work environment. PMID- 24152347 TI - "It all changed after Apollo": healthcare myths and their making in contemporary India. PMID- 24152348 TI - Ethics of "standard care" in randomised trials of screening for cervical cancer should not ignore scientific evidence and ground realities. PMID- 24152349 TI - Screening for cervical cancer revisited: understanding implementation research. PMID- 24152350 TI - Have scientists met their ethical responsibility towards research participants? PMID- 24152351 TI - Ethical issues in adapting new technologies for rapid diagnosis. PMID- 24152352 TI - Protection is not just about preventing disease: vaccine equity and ethics in the developing world. PMID- 24152353 TI - The H1N1 influenza pandemic: need for solutions to ethical problems. AB - The rapid spread of the novel influenza virus of H1N1 swine origin led to widespread fear, panic and unrest among the public and healthcare personnel. The pandemic not only tested the world's health preparedness, but also brought up new ethical issues which need to be addressed as soon as possible. This article highlights these issues and suggests ethical answers to the same. The main areas that require attention are the distribution of scarce resources, prioritisation of antiviral drugs and vaccines, obligations of healthcare workers, and adequate dissemination and proper communication of information related to the pandemic. It is of great importance to plan in advance how to confront these issues in an ethical manner. This is possible only if a comprehensive contingency plan is prepared with the involvement of and in consultation with all the stakeholders concerned. PMID- 24152354 TI - Medical regulation in India: an outsider's perspective. AB - This personal comment briefly describes the working of the General Medical Council, the medical regulator in the United Kingdom, with the aim of informing the discussion on how to regulate medical education and doctors' practice in India. Given that the ministry of health and family welfare is still debating the final constitution of the Medical Council of India, this paper is timely. PMID- 24152355 TI - Clinical trials in Sri Lanka: new Act at the behest of the pharmaceutical industry? PMID- 24152356 TI - Advancing physicians' skills versus safeguarding individual patient interests: an ethical dilemma. PMID- 24152357 TI - The medical trade. PMID- 24152358 TI - Breaking bad news in the paediatric ICU: need for ethical practice. PMID- 24152359 TI - Satpal Dang - a personal memoir. PMID- 24152360 TI - [A man with a swollen nipple]. AB - A 39-year-old man visited the dermatologist because of a swollen nipple since 2 months. The nipple area showed erythema, the mass was palpable. We found no swollen lymph nodes. After blood examination we made the diagnosis 'Borrelial lymphocytoma', a cutaneous manifestation of Lyme borreliosis. PMID- 24152361 TI - [Intermediate endpoints in clinical research]. AB - An intermediate variable such as blood pressure is part of the causal pathway of mechanisms to a clinical outcome, e.g. myocardial infarction. An intervention affects a clinical outcome through its effect on that intermediate variable. In studies designed to assess the effects of interventions an intermediate variable may be used as surrogate for clinical outcomes. Such an endpoint is also known as an intermediate endpoint. Intervention studies with intermediate endpoints are commonly performed in medical research to evaluate the effects of an intervention on clinical outcomes. Intervention studies with an intermediate endpoint are conducted in a smaller study population and with a shorter duration of follow-up than studies using clinical outcomes. An intermediate variable is not eligible as an intermediate endpoint when the intervention also affects other biological mechanisms that subsequently affect the clinical endpoint. Due to a smaller sample size and shorter study duration, side effects of intervention are more difficult to evaluate in studies with an intermediate endpoint than in studies with clinical endpoints. PMID- 24152362 TI - [Liver disorders in adults: ALT and AST]. AB - Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) are commonly used biomarkers for liver damage. As well as in liver tissue, AST is also present in cardiac and skeletal muscle and in erythrocytes, making ALT the most specific marker for liver damage. Here, we describe two patients with sustained increases in ALT and AST levels. The first patient is a 79-year-old woman who developed elevated serum transaminases shortly after having a myocardial infarction. The second patient, an obese 40-year-old woman presented with increased ALT and AST levels in the absence of physical symptoms. Notably, her father died of liver cirrhosis without a history of alcohol abuse. Based upon these case reports we discuss the differential diagnostic work-up of elevated serum transaminase levels. Furthermore, we explain monitoring, test performance, reference values and analytical pitfalls of these biomarkers. PMID- 24152363 TI - [The ICD in the terminal stage]. AB - ICDs are used to prevent sudden death caused by ventricular fibrillation. The number of patients with an ICD will keep growing. ICD shocks can severely disturb the dying process in terminally ill patients. Patients must be informed about this at the time of ICD implantation. The attending physician is responsible for proactive communication regarding deactivation when death is expected imminently. The decision to deactivate the ICD depends on personal wishes, and has proved to be difficult even if the patient has been well informed. Deactivation at home must be available so that severely ill patients do not need to travel to a hospital. PMID- 24152364 TI - [Home care in deprived districts: what is the role of material wealth?]. AB - OBJECTIVE: To examine if there is a higher uptake of home care among residents of deprived districts and to determine if this can be attributed to the lower levels of income and wealth of these residents. DESIGN: Retrospective, descriptive study. METHOD: The study focused on residents aged 50 and above. We obtained data on uptake of home care in 2007 from national care registries, which were combined with fiscal registry data on income and wealth. Postcode data were used to distinguish between 40 'deprived' districts and all other Dutch districts. RESULTS: In the deprived districts more residents received home care than in other districts. This difference was greatest among residents aged 50 to 69 years. After correction for age, sex and country of origin, the difference was substantial (odds ratio (OR): 1.31). After correction for differences in income this difference was halved (OR: 1.17).The difference was further strongly reduced after correction for wealth (OR: 1.06). In deprived districts there was a higher uptake of domestic care (OR: 1.12) but the inverse was true for personal care (OR: 0.95). The latter was most marked in residents aged 80 and above (OR: 0.88). CONCLUSION: The higher uptake of home care among residents of deprived districts can be attributed to low levels of income and wealth. In the Netherlands, changes in home care arrangements at national and local level should take into account people with financial problems and the districts in which they live. PMID- 24152365 TI - [Intersphincteric ligation of perianal fistula]. AB - Fistulotomy is inappropriate for patients with a high transsphincteric fistula, passing through the upper or middle third of the external anal sphincter, because this procedure requires division of a large part of the anal sphincter, with subsequent risk of fecal incontinence. Therefore, sphincter preserving procedures have been developed for the treatment of high transsphincteric fistulas, such as flap repair. In most hospitals, fistulotomy is still the treatment of choice for low transsphincteric fistula, passing through the lower third of the external anal sphincter. Although this procedure is considered simple and effective with a minimal risk of incontinence, data suggest that the risk of diminished fecal continence is not insignificant. Ligation of the intersphincteric fistula tract (LIFT) is a new sphincter preserving technique. This technique may be a sphincter preserving alternative for fistulotomy in low transsphincteric fistulas and for flap repair in high transsphincteric fistulas. PMID- 24152366 TI - [Choices for women at risk of hereditary breast cancer]. AB - In this article, we describe a woman diagnosed as being a BRCA1 mutation carrier at 32 years of age and a BRCA2 mutation carrier diagnosed at age 63 who each opted for MRI screening instead of a preventive mastectomy. In both women, breast cancer was detected by MRI: not visible on the mammogram, < 1 cm and node negative. Both women opted for breast-conserving treatment. We compare their screening strategies and therapy choices with those of a woman with a familial risk who was diagnosed with breast cancer at age 52. We also discuss the relevant literature. For BRCA1/2-mutation carriers, bilateral preventive oophorectomy, combined with either MRI screening or a bilateral preventive mastectomy, can contribute considerably to a better life expectancy. Both options are nearly equally effective. Breast-conserving treatment can be a safe choice for young BRCA1/2 mutation carriers despite a 40% risk of contralateral cancer within 10 years and possibly a higher risk of developing a second ipsilateral cancer. The contribution of mammography to early breast cancer detection is small for MRI screened BRCA1 carriers below 40 years of age; less than 10% according to the current literature. The high tumour growth rate and high breast cancer incidence in BRCA1/2 carriers above the age of 60 are arguments to screen more frequently than the current mammogram every 2 years. The optimal screening strategy for women with a familial risk either yearly MRI or mammogram - is still unknown and is being investigated in a randomized controlled trial (www.famrisc.nl). The age of onset of breast cancer is determined by both family history and risk group. If known, the ages of family members at diagnosis may assist in determining at what age preventive measures should be started for high-risk women. PMID- 24152367 TI - [Lifestyle-recommendations on weight loss in type 2 diabetes--useful, or not?]. AB - Weight loss is recommended for overweight or obese patients with type 2 diabetes on the basis of short-term studies, but the long-term effects of weight loss on cardiovascular disease are unknown. The recently published Look AHEAD (Action for health in diabetes) study investigated the 10-year effect of an intensive lifestyle intervention designed to achieve weight loss on cardiovascular morbidity and mortality among overweight or obese adults with type 2 diabetes. In this commentary, we discuss the results and clinical implications of this study. PMID- 24152368 TI - [A man with a crooked smile]. AB - A 51-year-old man had a paresis of the right side of the lower lip after carotic endarterectomy. The diagnosis was 'pressure neuropathy of the right ramus marginalis mandibulae' caused by the operation. This neuropathy is self limiting. PMID- 24152369 TI - Cytomegalovirus proctitis: a rare sexually transmitted disease. PMID- 24152370 TI - Training frontline mental health staff to deliver "low intensity" psychological therapy for psychosis: a qualitative analysis of therapist and service user views on the therapy and its future implementation. AB - BACKGROUND: Increasing access to evidence-based talking therapies for people with psychosis is a national health priority. We have piloted a new, "low intensity" (LI) CBT intervention specifically designed to be delivered by frontline mental health staff, following brief training, and with ongoing supervision and support. A pilot feasibility study has demonstrated significant improvement in service user outcomes. This study is a qualitative analysis of the experiences of the staff and service users taking part in the evaluation. AIMS: To evaluate the acceptability of the training protocol and the therapy, and to examine the factors promoting and restraining implementation. METHOD: All trained staff and service users completed a semi-structured interview that was transcribed and subjected to thematic analysis. RESULTS: Service users spoke about learning new skills and achieving their goals. Staff spoke about being able to use a brief, structured intervention to achieve positive outcomes for their clients. Both groups felt that longer, more sophisticated interventions were required to address more complex problems. The positive clinical outcomes motivated therapists to continue using the approach, despite organizational barriers. CONCLUSIONS: For both trained staff and service users, taking part in the study was a positive experience. Staff members' perceived skill development and positive reaction to seeing their clients improve should help to promote implementation. Work is needed to clarify whether and how more complex difficulties should be addressed by frontline staff. PMID- 24152371 TI - Is ABCC6 a genuine mitochondrial protein? AB - BACKGROUND: A recent article in Circulation Research suggests that the protein ABCC6, which when defective is responsible for pseudoxanthoma elasticum, an inherited condition with skin, eye and cardiovascular manifestations, is associated with dysfunction in mitochondria--Martin et al.: ABCC6 Localizes to the Mitochondria-Associated Membrane.Circ Res 2012, 111:516-520. We present complementary information based on a bioinformatics analysis, which was not performed in the article cited, to examine the suggestion that ABCC6 is localized to mitochondria. RESULTS: All the computational strategies and integrative approaches that constitute references in the field indicate that ABCC6 is localized outside of mitochondria. CONCLUSION: Our computational and integrative results, including both experimental and predictive data, show that there is no support in favor of the localization of ABCC6 in mitochondria. PMID- 24152372 TI - Screening for data clustering in multicenter studies: the residual intraclass correlation. AB - BACKGROUND: In multicenter studies, center-specific variations in measurements may arise for various reasons, such as low interrater reliability, differences in equipment, deviations from the protocol, sociocultural characteristics, and differences in patient populations due to e.g. local referral patterns. The aim of this research is to derive measures for the degree of clustering. We present a method to detect heavily clustered variables and to identify physicians with outlying measurements. METHODS: We use regression models with fixed effects to account for patient case-mix and a random cluster intercept to study clustering by physicians. We propose to use the residual intraclass correlation (RICC), the proportion of residual variance that is situated at the cluster level, to detect variables that are influenced by clustering. An RICC of 0 indicates that the variance in the measurements is not due to variation between clusters. We further suggest, where appropriate, to evaluate RICC in combination with R2, the proportion of variance that is explained by the fixed effects. Variables with a high R2 may have benefits that outweigh the disadvantages of clustering in terms of statistical analysis. We apply the proposed methods to a dataset collected for the development of models for ovarian tumor diagnosis. We study the variability in 18 tumor characteristics collected through ultrasound examination, 4 patient characteristics, and the serum marker CA-125 measured by 40 physicians on 2407 patients. RESULTS: The RICC showed large variation between variables: from 2.2% for age to 25.1% for the amount of fluid in the pouch of Douglas. Seven variables had an RICC above 15%, indicating that a considerable part of the variance is due to systematic differences at the physician level, rather than random differences at the patient level. Accounting for differences in ultrasound machine quality reduced the RICC for a number of blood flow measurements. CONCLUSIONS: We recommend that the degree of data clustering is addressed during the monitoring and analysis of multicenter studies. The RICC is a useful tool that expresses the degree of clustering as a percentage. Specific applications are data quality monitoring and variable screening prior to the development of a prediction model. PMID- 24152373 TI - Masculine attitudes of superiority deter men from accessing antiretroviral therapy in Dar es Salaam, Tanzania. AB - BACKGROUND: This article presents part of the findings from a larger study that sought to assess the role that gender relations play in influencing equity regarding access and adherence to antiretroviral therapy (ART). Review of the literature has indicated that, in Southern and Eastern Africa, fewer men than women have been accessing ART, and the former start using ART late, after HIV has already been allowed to advance. The main causes for this gender gap have not yet been fully explained. OBJECTIVE: To explore how masculinity norms limit men's access to ART in Dar es Salaam. DESIGN: This article is based on a qualitative study that involved the use of focus group discussions (FGDs). The study employed a stratified purposive sampling technique to recruit respondents. The study also employed a thematic analysis approach. RESULTS: Overall, the study's findings revealed that men's hesitation to visit the care and treatment clinics signifies the superiority norm of masculinity that requires men to avoid displaying weakness. Since men are the heads of families and have higher social status, they reported feeling embarrassed at having to visit the care and treatment clinics. Specifically, male respondents indicated that going to a care and treatment clinic may raise suspicion about their status of living with HIV, which in turn may compromise their leadership position and cause family instability. Because of this tendency towards 'hiding', the few men who register at the public care and treatment clinics do so late, when HIV-related signs and symptoms are already far advanced. CONCLUSION: This study suggests that the superiority norm of masculinity affects men's access to ART. Societal expectations of a 'real man' to be fearless, resilient, and emotionally stable are in direct conflict with expectations of the treatment programme that one has to demonstrate health promoting behaviour, such as promptness in attending the care and treatment clinic, agreeing to take HIV tests, and disclosing one's status of living with HIV to at least one's spouse or partner. Hence, there is a need for HIV control agencies to design community-based programmes that will stimulate dialogue on the deconstruction of masculinity notions. PMID- 24152374 TI - Antioxidant/prooxidant effects of alpha-tocopherol, quercetin and isorhamnetin on linoleic acid peroxidation induced by Cu(II) and H2O2. AB - The peroxidation of linoleic acid (LA) in the presence of copper(II) (Cu(II)) ions alone and with alpha-tocopherol (alpha-TocH) was investigated in aerated and incubated emulsions at 37 degrees C and pH 7. Additionally, the effects of quercetin (QR) and its O-methylated derivative, isorhamnetin (IR), as potential antioxidant protectors were studied in the (Cu(II) + TocH)-induced LA peroxidation system. Cu(II)-induced LA peroxidation followed pseudo-first-order kinetics with respect to primary (hydroperoxides) and secondary (aldehydes- and ketones-like) oxidation products, which were determined by ferric thiocyanate and thiobarbituric acid-reactive substances methods, respectively. As opposed to the concentration-dependent (at 0.6 and 10.0 uM) prooxidative action of alpha-TocH in the absence of QR and IR, the latter two compounds showed antioxidant effect over TocH. The peroxidation of LA in the presence of Cu(II)-H(2)O(2) combination alone and with TocH, QR and IR were also investigated in aerated and incubated emulsions, where the latter three compounds exhibited antioxidant effects. PMID- 24152376 TI - How did cause of death contribute to racial differences in life expectancy in the United States in 2010? AB - KEY FINDINGS: Data from the National Vital Statistics System, Mortality In 2010, life expectancy for the black population was 3.8 years lower than that of the white population. This difference was due to higher death rates for the black population for heart disease, cancer, homicide, diabetes, and perinatal conditions. Life expectancy for black males was 4.7 years lower than that of white males. This difference was due to higher death rates for black males for heart disease, homicide, cancer, stroke, and perinatal conditions. Life expectancy for black females was 3.3 years lower than that of white females. This difference was due to higher death rates for black females for heart disease, cancer, diabetes, perinatal conditions, and stroke. PMID- 24152377 TI - Comparison between landmark and surface-based three-dimensional analyses of facial asymmetry in adults. AB - BACKGROUND/OBJECTIVES: To collect the reference values for facial asymmetry in adults using landmark and surface-based three-dimensional analyses and to compare their diagnostic abilities. MATERIALS AND METHODS: Laser scans were taken from 85 British Caucasians, 29 males (23.9+/-5.7 years, range 19-44) and 56 females (28.1+/-9.5 years, range 19-54), students and staff of the Cardiff Dental Hospital, and three orthodontic patients with marked facial asymmetry. An asymmetry index (AI) was measured for 14 landmarks. The surface-to-surface average distance between the best-fit registered original and mirror scans (ADom) was measured for the whole face and six regions. Non-parametric descriptive statistics was used to obtain the reference values, and Mann-Whitney U-test was used for gender comparison. P values less than 0.05 were considered significant. Patients' values were compared to the reference values by calculating the corresponding percentiles. RESULTS: The lowest AI was found for 'pronasale' in males [median 0.1 (interquartile range 0.0-0.3) mm] and the highest for 'cheilion' [3.5 (2.4-5.0) mm] in females. The ADom for the whole face was 0.7 (0.5-0.9) mm in males and 0.6 (0.5-0.7) mm in females and regionally between 0.4 (0.3-0.6) mm and 0.8 (0.4-1.2) mm. In orthodontic patients, AI did not always reveal asymmetry in a particular coordinate plane, and surface-based analysis was favourable in regions underrepresented by landmarks. CONCLUSIONS: Facial asymmetry can be accurately quantified using landmark- and surface-based approaches. The latter offers a more comprehensive analysis of the face. PMID- 24152375 TI - The effects of vitamin D2 or D3 supplementation on glycaemic control and related metabolic parameters in people at risk of type 2 diabetes: protocol of a randomised double-blind placebo-controlled trial. AB - BACKGROUND: The global prevalence of type 2 diabetes is increasing. Effective strategies to address this public health challenge are currently lacking. A number of epidemiological studies have reported associations between low concentrations of 25-hydroxy vitamin D and the incidence of diabetes, but a causal link has not been established. We investigate the effect of vitamin D supplementation on the metabolic status of individuals at increased risk of developing type 2 diabetes. METHODS/DESIGN: In a randomised double-blind placebo controlled trial individuals identified as having a high risk of type 2 diabetes (non-diabetic hyperglycaemia or positive diabetes risk score) are randomised into one of three groups and given 4 doses of either placebo, or 100,000 IU Vitamin D2 (ergocalciferol) or 100,000 IU Vitamin D3 (cholecalciferol) at monthly intervals. The primary outcome measure is the change in glycated haemoglobin level between baseline and 4 months. Secondary outcome measures include blood pressure, lipid levels, apolipoproteins, highly sensitive C-reactive protein, parathyroid hormone (PTH) and safety of supplementation. and C-reactive protein. The trial is being conducted at two sites (London and Cambridge, U.K.) and a total of 342 participants are being recruited. DISCUSSION: Trial data examining whether supplementation of vitamin D improves glycaemic status and other metabolic parameters in people at risk of developing type 2 diabetes are sparse. This trial will evaluate the causal role of vitamin D in hyperglycaemia and risk of type 2 diabetes. Specific features of this trial include recruitment of participants from different ethnic groups, investigation of the relative effectiveness and safety of vitamin D2 and D3 and an evidence based approach to determination of the dose of supplementation. TRIAL REGISTRATION: EudraCT2009-011264-11; ISRCTN86515510. PMID- 24152378 TI - Effects of social disruption in elephants persist decades after culling. AB - BACKGROUND: Multi-level fission-fusion societies, characteristic of a number of large brained mammal species including some primates, cetaceans and elephants, are among the most complex and cognitively demanding animal social systems. Many free-ranging populations of these highly social mammals already face severe human disturbance, which is set to accelerate with projected anthropogenic environmental change. Despite this, our understanding of how such disruption affects core aspects of social functioning is still very limited. RESULTS: We now use novel playback experiments to assess decision-making abilities integral to operating successfully within complex societies, and provide the first systematic evidence that fundamental social skills may be significantly impaired by anthropogenic disruption. African elephants (Loxodonta africana) that had experienced separation from family members and translocation during culling operations decades previously performed poorly on systematic tests of their social knowledge, failing to distinguish between callers on the basis of social familiarity. Moreover, elephants from the disrupted population showed no evidence of discriminating between callers when age-related cues simulated individuals on an increasing scale of social dominance, in sharp contrast to the undisturbed population where this core social ability was well developed. CONCLUSIONS: Key decision-making abilities that are fundamental to living in complex societies could be significantly altered in the long-term through exposure to severely disruptive events (e.g. culling and translocation). There is an assumption that wildlife responds to increasing pressure from human societies only in terms of demography, however our study demonstrates that the effects may be considerably more pervasive. These findings highlight the potential long-term negative consequences of acute social disruption in cognitively advanced species that live in close-knit kin-based societies, and alter our perspective on the health and functioning of populations that have been subjected to anthropogenic disturbance. PMID- 24152379 TI - Management of challenging cases of patients with cancer-associated thrombosis including recurrent thrombosis and bleeding: guidance from the SSC of the ISTH: a rebuttal. PMID- 24152381 TI - Utilization of carboxymethyl chitosan in cosmetics. AB - Carboxymethyl chitosan is a chitosan derivative of the most intensively investigated due to its water solubility in wider pH range compared with the parent compound, thus extended its use in various applications. In this review, different preparation conditions, which resulting in the N- and O-carboxylated chitosan, diverse degree of substitution and water solubility are recapitulated. Five important features of carboxymethyl chitosan from recent studies, which are moisture absorption-retention, anti-microbial properties, antioxidant capacities, delivery system and emulsion stabilization, have been centred and emphasized for cosmetic utilization. Additionally, cytotoxicity information has been inclusively incorporated to ensure its safety in application. PMID- 24152380 TI - Psychosocial factors and mortality in women with early stage endometrial cancer. AB - OBJECTIVES: Psychosocial factors have previously been linked with survival and mortality in cancer populations. Little evidence is available about the relationship between these factors and outcomes in gynaecologic cancer populations, particularly endometrial cancer, the fourth most common cancer among women. This study examined the relationship between several psychosocial factors prior to surgical resection and risk of all-cause mortality in women with endometrial cancer. DESIGN: The study utilized a non-experimental, longitudinal design. METHODS: Participants were 87 women (Mage = 60.69 years, SDage = 9.12 years) who were diagnosed with T1N0-T3N2 endometrial cancer and subsequently underwent surgery. Participants provided psychosocial data immediately prior to surgery. Survival statuses 4-5 years post-diagnoses were abstracted via medical record review. Cox regression was employed for the survival analysis. RESULTS: Of the 87 women in this sample, 21 women died during the 4- to 5-year follow-up. Adjusting for age, presence of regional disease and medical comorbidity severity (known biomedical prognostic factors), greater use of an active coping style prior to surgery was significantly associated with a lower probability of all cause mortality, hazard ratio (HR) = 0.78, p = .04. Life stress, depressive symptoms, use of self-distraction coping, receipt of emotional support and endometrial cancer quality of life prior to surgery were not significantly associated with all-cause mortality 4-5 years following diagnosis. CONCLUSIONS: Greater use of active coping prior to surgery for suspected endometrial cancer is associated with lower probability of all-cause mortality 4-5 years post-surgery. Future research should attempt to replicate these relationships in a larger and more representative sample and examine potential behavioural and neuroendocrine/immune mediators of this relationship. STATEMENT OF CONTRIBUTION: What is already known on this subject? Psychosocial factors have previously been linked with clinical outcomes in a variety of cancer populations. With regards to gynecologic cancer, the majority of the research has been conducted in ovarian cancer and examines the protective role of social support in mortality outcomes. What does this study add? Demonstrates association between active coping during perioperative period and 5 year survival. Demonstrates psychosocial-survival relationship exists independent of biobehavioral factors. PMID- 24152382 TI - Directional asymmetry of facial and limb traits in horses and ponies. AB - Current published data on directional asymmetry (DA) in horses refer to racing Thoroughbreds. The aim of this study was to identify whether horses and ponies exhibit directionality of trait asymmetries. Eleven functional (limb) and four non-functional (facial) bilateral traits were measured on left and right sides in a cohort of 100 horses and ponies using callipers. The population was investigated as pooled data and as horse (withers height >148 cm) and pony (withers height <= 148 cm) sub-groups. Within the pooled data, functional traits were longer on the right for the third metacarpal (MCIII, 73%) and metatarsal (MTIII, 65%) bones and wider on the left for the forelimb proximal phalanx (54%), MCIII (40%), MTIII (51%) and hind limb proximal phalanx (55%). Dimensions of the intercarpal and tarsocrural joints were larger on the right side. Differences in DA were present between horses and ponies within non-functional traits, but not functional traits. The results suggest that DA within horses and ponies is more likely to be a species trait rather than one exclusive to racing as a result of pressures from directionally orientated training or from selective breeding strategies. PMID- 24152383 TI - Inheritance of equine sarcoid disease in Franches-Montagnes horses. AB - The mode of inheritance for susceptibility to equine sarcoid disease (ES) remains unknown. The objectives of this study were to analyse a large sample of the Franches-Montagnes (FM) horse population and investigate the heritability and mode of inheritance for susceptibility to ES. Horses were clinically examined for the presence of sarcoid tumours. A standardized examination protocol and client questionnaire were used and a pedigree- and subsequent segregation-analysis for the ES trait performed. To investigate the mode of inheritance, five models were evaluated and compared in a hierarchical way. The analyses reveal that variation in susceptibility to ES is best explained by a model incorporating polygenic variation. The possible effect of a major gene, such as specific equine leukocyte antigen alleles, is unlikely, but cannot be ruled-out entirely. The heritability of the phenotype on the observation scale for the trait 'affected with ES' was estimated to be 8%. A corrected value for the heritability on a liability scale was estimated at 21% and it is therefore possible to estimate breeding values for ES. The arguments against the practical implementation of an estimated breeding value in a multifactorial condition like ES are discussed. PMID- 24152384 TI - Evaluating traditional healers knowledge and practices related to HIV testing and treatment in South Africa. AB - BACKGROUND: In a context of inadequate human resources for health, this study investigated whether traditional healers have the knowledge and skill base which could be utilised to assist in the scaling up of HIV prevention and treatment services in South Africa. METHODS: Using a cross-sectional research design a total of 186 traditional healers from the Northern Cape province were interviewed. Responses on the following topics were obtained: socio-demographic characteristics; HIV training, experience and practices; and knowledge of HIV transmission, prevention and symptoms. Descriptive statistics and chi square tests were used to analyse the responses. RESULTS: Traditional healers' knowledge of HIV and AIDS was not as high as expected. Less than 50% of both trained and untrained traditional healers would treat a person they suspected of being HIV positive. However, a total of 167 (89%) respondents agreed using a condom can prevent HIV and a majority of respondents also agreed that having one sexual partner (127, 68.8%) and abstaining from sex can prevent HIV (145, 78.8%). Knowledge of treatment practices was better with statistically significant results being obtained. CONCLUSION: The results indicate that traditional healers could be used for prevention as well as referring HIV positive individuals for treatment. Traditional healers were enthusiastic about the possibility of collaborating with bio-medical practitioners in the prevention and care of HIV and AIDS patients. This is significant considering they already service the health needs of a large percentage of the South African population. However, further development of training programmes and materials for them on HIV and AIDS related issues would seem necessary. PMID- 24152385 TI - Propagation of tau pathology in Alzheimer's disease: identification of novel therapeutic targets. AB - Accumulation and aggregation of the microtubule-associated protein tau are a pathological hallmark of neurodegenerative disorders such as Alzheimer's disease (AD). In AD, tau becomes abnormally phosphorylated and forms inclusions throughout the brain, starting in the entorhinal cortex and progressively affecting additional brain regions as the disease progresses. Formation of these inclusions is thought to lead to synapse loss and cell death. Tau is also found in the cerebrospinal fluid (CSF), and elevated levels are a biomarker for AD. Until recently, it was thought that the presence of tau in the CSF was due to the passive release of aggregated tau from dead or dying tangle-bearing neurons. However, accumulating evidence from different AD model systems suggests that tau is actively secreted and transferred between synaptically connected neurons. Transgenic mouse lines with localized expression of aggregating human tau in the entorhinal cortex have demonstrated that, as these animals age, tau becomes mislocalized from axons to cell bodies and dendrites and that human tau-positive aggregates form first in the entorhinal cortex and later in downstream projection targets. Numerous in vitro and in vivo studies have provided insight into the mechanisms by which tau may be released and internalized by neurons and have started to provide insight into how tau pathology may spread in AD. In this review, we discuss the evidence for regulated tau release and its specific uptake by neurons. Furthermore, we identify possible therapeutic targets for preventing the propagation of tau pathology, as inhibition of tau transfer may restrict development of tau tangles in a small subset of neurons affected in early stages of AD and therefore prevent widespread neuron loss and cognitive dysfunction associated with later stages of the disease. PMID- 24152386 TI - Long-incubation-time gamma interferon release assays in response to purified protein derivative, ESAT-6, and/or CFP-10 for the diagnosis of Mycobacterium tuberculosis infection in children. AB - The diagnosis of childhood active tuberculosis (aTB) and latent Mycobacterium tuberculosis (M. tuberculosis) infection (LTBI) remains a challenge, and the replacement of tuberculin skin tests (TST) with commercialized gamma interferon (IFN-gamma) release assays (IGRA) is not currently recommended. Two hundred sixty six children between 1 month and 15 years of age, 214 of whom were at risk of recent M. tuberculosis infection and 51 who were included as controls, were prospectively enrolled in our study. According to the results of a clinical evaluation, TST, chest X ray, and microbiological assessment, each children was classified as noninfected, having LTBI, or having aTB. Long-incubation-time purified protein derivative (PPD), ESAT-6, and CFP-10 IGRA were performed and evaluated for their accuracy in correctly classifying the children. Whereas both TST and PPD IGRA were suboptimal for detecting aTB, combining the CFP-10 IGRA with a TST or with a PPD IGRA allowed us to detect all the children with aTB with a specificity of 96% for children who were positive for the CFP-10 IGRA. Moreover, the combination of the CFP-10 IGRA and PPD IGRA detected 96% of children who were eventually classified as having LTBI, but a strong IFN-gamma response to CFP-10 (defined as >500 pg/ml) was highly suggestive of aTB, at least among the children who were <3 years old. The use of long-incubation-time CFP-10 IGRA and PPD IGRA should help clinicians to quickly identify aTB or LTBI in young children. PMID- 24152387 TI - Efficient activation of human T cells of both CD4 and CD8 subsets by urease deficient recombinant Mycobacterium bovis BCG that produced a heat shock protein 70-M. tuberculosis-derived major membrane protein II fusion protein. AB - For the purpose of obtaining Mycobacterium bovis bacillus Calmette-Guerin (BCG) capable of activating human naive T cells, urease-deficient BCG expressing a fusion protein composed of Mycobacterium tuberculosis-derived major membrane protein II (MMP-II) and heat shock protein 70 (HSP70) of BCG (BCG-DHTM) was produced. BCG-DHTM secreted the HSP70-MMP-II fusion protein and effectively activated human monocyte-derived dendritic cells (DCs) by inducing phenotypic changes and enhanced cytokine production. BCG-DHTM-infected DCs activated naive T cells of both CD4 and naive CD8 subsets, in an antigen (Ag)-dependent manner. The T cell activation induced by BCG-DHTM was inhibited by the pretreatment of DCs with chloroquine. The naive CD8(+) T cell activation was mediated by the transporter associated with antigen presentation (TAP) and the proteosome dependent cytosolic cross-priming pathway. Memory CD8(+) T cells and perforin producing effector CD8(+) T cells were efficiently produced from the naive T cell population by BCG-DHTM stimulation. Single primary infection with BCG-DHTM in C57BL/6 mice efficiently produced T cells responsive to in vitro secondary stimulation with HSP70, MMP-II, and M. tuberculosis-derived cytosolic protein and inhibited the multiplication of subsequently aerosol-challenged M. tuberculosis more efficiently than did vector control BCG. These results indicate that the introduction of MMP-II and HSP70 into urease-deficient BCG may be useful for improving BCG for control of tuberculosis. PMID- 24152388 TI - Response to host density by the parasitoid Dolichogenidea tasmanica (Hymenoptera: Braconidae) and the influence of grapevine variety. AB - Natural enemies that respond to prey in a density-dependent manner may be able to quickly suppress pest populations before they reach economically damaging levels. Although it is primarily the combination of a natural enemy's functional response and a population numerical response that will influence the maximum number of pests attacked, other factors may influence a density-dependent response. We conducted large-scale field experiments, both artificially inoculating grapevines with larvae and using naturally occurring populations, to quantify and characterize the response of a parasitoid, Dolichogenidea tasmanica (Cameron) (Hymenoptera: Braconidae) to different densities of its host, the pest of grapevines, Epiphyas postvittana (Walker) (Lepidoptera: Tortricidae). We showed that the response of D. tasmanica to the density of E. postvittana was inversely density-dependent, and that the degree of parasitism was consistently and significantly higher in the grape variety Cabernet Sauvignon compared with Chardonnay. While the significant effect of variety on the degree of parasitism may provide an option for increasing the parasitism of E. postvittana by D. tasmanica, it also highlights how differences in host plant can influence trophic interactions. PMID- 24152390 TI - Abstracts of the 12th International Kidney Cancer Symposium. October 25-26, 2013. Chicago, Illinois, USA. PMID- 24152389 TI - A semi-parametric approach to estimate risk functions associated with multi dimensional exposure profiles: application to smoking and lung cancer. AB - BACKGROUND: A common characteristic of environmental epidemiology is the multi dimensional aspect of exposure patterns, frequently reduced to a cumulative exposure for simplicity of analysis. By adopting a flexible Bayesian clustering approach, we explore the risk function linking exposure history to disease. This approach is applied here to study the relationship between different smoking characteristics and lung cancer in the framework of a population based case control study. METHODS: Our study includes 4658 males (1995 cases, 2663 controls) with full smoking history (intensity, duration, time since cessation, pack-years) from the ICARE multi-centre study conducted from 2001-2007. We extend Bayesian clustering techniques to explore predictive risk surfaces for covariate profiles of interest. RESULTS: We were able to partition the population into 12 clusters with different smoking profiles and lung cancer risk. Our results confirm that when compared to intensity, duration is the predominant driver of risk. On the other hand, using pack-years of cigarette smoking as a single summary leads to a considerable loss of information. CONCLUSIONS: Our method estimates a disease risk associated to a specific exposure profile by robustly accounting for the different dimensions of exposure and will be helpful in general to give further insight into the effect of exposures that are accumulated through different time patterns. PMID- 24152391 TI - Combinatorial pharmacophore modeling of organic cation transporter 2 (OCT2) inhibitors: insights into multiple inhibitory mechanisms. AB - Organic cation transporter 2 (OCT2) is responsible for the entry step of many drugs in renal elimination, of which the changing activity may cause unwanted drug-drug interactions (DDIs). To develop drugs with favorable safety profile and provide instruction for rational clinical drug administration, it is of great interest to investigate the multiple mechanisms of OCT2 inhibition. In this study, we designed a combinatorial scheme to screen the optimum combination of pharmacophores from a pool of hypotheses established based on 162 OCT2 inhibitors. Among them, one single pharmacophore hypothesis represents a potential binding mode that may account for one unique inhibitory mechanism, and the obtained pharmacophore combination describes the multimechanisms of OCT2 inhibition. The final model consists of four individual pharmacophores, i.e., DHPR18, APR2, PRR5 and HHR4. Given a query ligand, it is considered as an inhibitor if it matches at least one of the hypotheses, or a noninhibitor if it fails to match any of four hypotheses. Our combinatorial pharmacophore model performs reasonably well to discriminate inhibitors and noninhibitors, yielding an overall accuracy around 0.70 for a test set containing 81 OCT2 inhibitors and 218 noninhibitors. Intriguingly, we found that the number of matched hypotheses was positively correlated with inhibition rate, which coincides with the pharmacophore modeling result of P-gp substrate binding. Further analysis suggested that the hypothesis PRR5 was responsible for competitive inhibition of OCT2, and other hypotheses were important for interaction between the inhibitor and OCT2. In light of the results, a hypothetical model for inhibiting transporting mediated by OCT2 was proposed. PMID- 24152392 TI - Decision making in stepped care: how do therapists decide whether to prolong treatment or not? AB - BACKGROUND: The efficiency of stepped care systems partly relies on systematic monitoring of patient outcomes and timely decisions to "step up" patients without any clear therapeutic gains to the next level of treatment. Qualitative evidence has suggested that this does not occur consistently, nor always congruently with clinical guidelines. AIMS: To investigate factors that influence psychological therapists' decisions to prolong or to conclude treatment in cases with little evidence of therapeutic gains. METHOD: Eighty-two clinicians in stepped care services completed questionnaires about the likelihood of "holding" non-improving patients in treatment, and factors associated with referrals and holding (FARAH Q). The factor structure, internal consistency and test-retest reliability of the measures was examined prior to assessing correlations between FARAH-Q items and likelihood of holding. RESULTS: A 4-factor solution indicated that clinicians' decision making is influenced by a complex interplay between beliefs, attitudes, subjective norms and self-efficacy. Correlational analysis indicated that holding is more likely to happen if there are perceived barriers to refer the patient for further treatment, if the therapist likes the patient and has a good therapeutic alliance, and if the therapist feels confident that s/he has the ability to achieve a positive outcome by prolonging treatment. CONCLUSIONS: Decisions to prolong or conclude treatment are not only influenced by evidence and guidelines, but also subjective beliefs, norms and attitudes. Understanding this decision making process is relevant to clinicians and supervisors interested in enhancing the efficiency of stepped care. PMID- 24152393 TI - [The dynamic mitochondria-nuclear redistribution of FKBP51 during the process of adipocyte differentiation is regulated by PKA]. AB - Glucocorticoids play an important role in adipogenesis via the glucocorticoid receptor (GR) that forms a heterocomplex with Hsp90-Hsp70 and a high molecular weight immunophilin FKBP51 or FKBP52. We have found that FKBP51 level of expression progressively increases, FKBP52 decreases, whereas Hsp90, Hsp70, and p23 remain unchanged when 3T3-L1 preadipocytes differentiate. Interestingly, FKBP51 translocates from mitochondria to the nucleus at the onset of adipogenesis. FKBP51 transiently concentrates in the nuclear lamina, at a time that this nuclear compartment undergoes its reorganization. FKBP51 nuclear localization is transient, after 48 h it cycles back to mitochondria. We found that the dynamic FKBP51 mitochondrial-nuclear shuttling is regulated by glucocorticoids and mainly on cAMP-PKA signaling since PKA inhibition by myristoilated-PKI, abrogated FKBP51 nuclear translocation induced by 3-isobutyl-1 methylxanthine (IBMX). It has been reported that PKA interacts with GR in a ligand dependent manner potentiating its transcriptional capacity. GR transcriptional capacity is reduced when cells are incubated in the presence of IBMX, forskolin or dibutyryl-cAMP, compounds that induced nuclear translocation of FKBP51, therefore PKA may exert a dual role in the control of GR. In summary, the presence of FKBP51 in the nucleus may be critical for GR transcriptional control, and possibly for the control of other transcription factors that are not members of the nuclear receptor family but are regulated by PKA signaling pathway, when transcription has to be strictly controlled to succeed in the acquisition of the adipocyte phenotype. PMID- 24152394 TI - [Toxic fungi in Buenos Aires City and surroundings]. AB - In Facultad de Ciencias Exactas y Naturales,Universidad de Buenos Aires there is a service called Servicio de Identificacion de Hongos Toxicos, directed by researchers of the Program of Medicinal Plants and Fungi Involved in Biological Degradation (PROPLAME-PRHIDEB, CONICET) that assist hospitals and other health establishments, identifying the different samples of fungi and providing information about their toxicity, so that patients can receive the correct treatment. The objective of the present study was to analyze all the cases received from 1985 to 2012. This analysis permitted the confection of a table identifying the most common toxic species. The information gathered revealed that 47% of the patients were under 18 years of age and had eaten basidiomes; the remaining 53% were adults who insisted that they were able to distinguish edible from toxic mushrooms. Chlorophyllum molybdites turned out to be the main cause of fungal intoxication in Buenos Aires, which is commonly confused with Macrolepiota procera, an edible mushroom. In the second place Amanita phalloides was registered, an agaric known to cause severe symptoms after a long period of latency (6-10 hours), and which can lead to hepatic failure even requiring a transplant to prevent severe internal injuries or even death, is not early and correctly treated. PMID- 24152395 TI - Pro-calcitonin and inflammation in chronic hemodialysis. AB - Procalcitonin (PCT) has emerged as a marker of infection, a frequent complication in hemodialysis (HD). We analyzed PCT levels in chronic non-acutely infected HD subjects, assessed its correlation with inflammatory and nutritional markers and propose a PCT reference value for non-infected HD patients. In an observational cross-sectional study, 48 chronic HD patients and 36 controls were analyzed. VARIABLES: age, gender, time on HD; diabetes; vascular access, PCT, C-reactive protein (CRP), albumin, malnutrition inflammatory score (MIS), hematocrit, leukocyte count, and body mass index (BMI). Subsequently, control (G1, n = 36, 43%) vs. non-infected patients (G2, n = 48, 57%) groups were compared. In control subjects (G1), age: 54.3 +/- 13.7 years, range (r): 30-81; males: 19 (53%); median PCT 0.034 ng/ml (r: 0.02-0.08); median CRP 0.80 mg/ dl (r: 0.36-3.9); p95 PCT level: 0.063 ng/ml. In G2, age: 60.2 +/- 15.2 years; males 32 (67%), time on HD: 27.0 +/- 24.4; diabetics: 19 (32%); median PCT: 0.26 ng/ml (r: 0.09-0.82); CRP: 1.1 mg/dl (r: 0.5-6.2); p95 PCT level: 0.8 ng/ml. In control subjects, PCT and CRP were significantly lower than in G2: PCT: 0.034 vs. 0.26 ng/ml, p = 0.0001; CRP: 0.8 vs. 1.1 mg/dl, p = 0.0004. PCT-CRP correlation in G2: p = 0.287, p = 0.048. PCT and CRP concentrations are elevated in chronic non-acutely infected HD subjects, independently of infection, diabetes and vascular access. A p95 PCT level of 0.8 ng/ml may be considered as the upper normal reference value in non-acutely infected HD subjects. The PCT cut-off level in HD is yet to be determined in HD. PMID- 24152396 TI - [Clinical-pathological features and gene profile in colorectal cancer]. AB - Colorectal cancer is the third most frequent cancer in men and the second most frequent in women, with a worldwide incidence of approximately 1.2 million new cases per year. Our primary objective was to study the relationship between clinical and histological features of individuals with colorectal cancer and the mutational status of codons 12 and 13 of the KRAS gene (7 validated mutations), in order to find a histopathological marker to mutated tumors. The secondary objective was to determine how many patients had additional mutations in codons 15 and 61 of the KRAS gene, and codon 600 of the BRAF gene, which could modify the tumor phenotype. Sixty individuals with colorectal cancer (30 wild-type subjects and 30 with validated mutations in codons 12 and 13 of the KRAS gene) were selected. Exons 2 and 3 of the KRAS gene, and exon 15 of the BRAF gene were amplified and sequenced. The data collected were reviewed by a descriptive, univariate and/or multivariate analysis, as appropriate. In conclusion, no relation was found between clinical and histological features of individuals with colorectal cancer and their mutational status for codons 12 and 13 of the KRAS gene. This suggests that those easily available data do not allow predicting the response to anti-EGFR therapy. In patients with advanced colorectal adenocarcinomas and KRAS wild-type status, further study of codon 600 of the BRAF gene could be required. PMID- 24152397 TI - [Coronary artery disease in patients with psoriasis]. AB - In previous reports, psoriasis was associated with an increased rate of coronary artery disease. These data has not been investigated in our population. We performed a cross-sectional study analyzing data from electronic medical records of a health system in Buenos Aires. We included all patients older than 18 years diagnosed with psoriasis between January 1, 2003 and July 31, 2011 and compared them with a control group. Controls were selected randomly by strata of age and sex from the same health system in a 2:1 ratio. We determined the prevalence of cardiovascular risk factors and coronary heart disease. We analyzed the association between psoriasis and coronary artery disease by both univariate and multivariate analyzes. In total, 3 833 subjects were included (1 286 with psoriasis and 2 547 controls). The prevalence of hypertension (50% vs. 38%, p < 0.001), smoking (25% vs. 17%, p < 0.001), diabetes (12% vs. 8%, p < 0.001) and coronary artery disease (4.98% vs. 3.06%, p = 0.003) were higher in the psoriasis group compared to controls. Regardless age and the presence or absence of diabetes, hypertension or smoking, there was a significant association between coronary artery disease and psoriasis (OR 1.48, CI95% 1.04-2.11, p = 0.03). In conclusion, in this population of Buenos Aires, psoriasis patients had a higher prevalence of diabetes, hypertension, smoking, and coronary artery disease. The association between psoriasis and coronary artery disease was independent of the risk factors explored. PMID- 24152398 TI - [Severe osteoporosis treatment with teriparatide]. AB - The primary objective of this retrospective study was to evaluate the treatment of severe osteoporosis with teriparatide (PTH) and to compare our results with those published in the literature. We included 46 patients, 42 women and four men, mean age: 69.15 +/- 9.43 years. Six patients were treatment naive and forty previously treated with bisphosphonates. Thirty-two patients had had 93 fractures of which 86 vertebral. Forty-six received PTH for 6 months, twenty-nine for 12 months and twenty completed the 18 months suggested. Bone mineral density (BMD) of the lumbar spine increased significantly at the first control performed at six months of treatment (p < 0.0001), and the femoral neck BMD reached a significant increase at the end of treatment (p = 0.002). Serum osteocalcin values significantly increased from the first month of treatment, followed by Beta crosslaps (beta-CTx, serum test) and bone-specific alkaline phosphatase, returning all the markers of bone turnover to baseline levels at 18 months. Serum and urinary calcium did not change significantly at any time, but 8 (17.9%) patients developed mild hypercalcemia and 3 (6.5%) asymptomatic hypercalciuria. The treatment was well tolerated and there were no serious adverse events requiring discontinuation. In conclusion, PTH is a safe and useful alternative for the treatment of primary severe osteoporosis. Our results agree with those previously reported in the literature. PMID- 24152399 TI - [Adverse events in 1395 infusions with different intravenous gammaglobulin products]. AB - The processes of isolation and sterilization of intravenous gamma globulin (IVIG) affect the end product characteristics and, therefore, its tolerability. Different products have different incidences of adverse reactions. The aim of this study was to quantify the immediate adverse events (AE) caused by the different IVIG preparations. We analyzed 1 395 infusions in 28 patients, with a median of 32.5 per subject (range 2-214), using six different IVIG preparations, with an average dose 40.3 +/- 8.3 g. One thousand and thirty-one infusions were analyzed retrospectively and 364 prospectively. Patients used a mean of 2.68 +/- 1.8 different IVIGs, with a median of 2 (range 1-6) per person. The number of trademarks used was related to the number of infusions received, r = 0.73. AE presented in 24 (2.3%) of 1 031 infusions retrospectively analyzed, affecting 11 of 23 patients enrolled, with a mean of 2.18 +/- 1.08 AE per subject. Of 24 patients and 364 infusions prospectively analyzed, AE were observed in 14 patients and in 32 (7.2%) procedures. Twenty-four (42.9%) of 56 AE were mild, 31 (55.5%) moderate and one (1.8%) severe. The infusion rate was 9.04 +/- 6 g/h for those presenting AE vs. 10.6 +/- 4.6 g/h for those who did not (p = 0.31, NS). The incidence, severity and proportion of patients with AE for each brand of IVIG were very different from each other. This information should be taken into account when selecting the IVIG to be used. PMID- 24152400 TI - [Cardiac surgery stratified by EuroSCORE. Long-term survival]. AB - The objective was to explore the usefulness of the logistic EuroSCORE to stratify the long-term survival curves in a sample of patients undergoing cardiac surgery. The 8-year survival of 390 patients undergoing cardiac surgery between 2003 and 2004 was analyzed, according to the basal value of the EuroSCORE, patients were classified into three risk groups: < 5%, 5-14.9% and > 15%. Eight-years Kaplan Meier's survival after coronary artery bypass grafting divided by the basal EuroSCORE was 83.5% for a basal risk < 5%, 65.2% for a basal risk 5 to 14.9% and 40.0% for a basal risk >15% (p = 0.000); whereas for valve or combined surgery it was 86.1%, 60.0% and 18.2% respectively (p = 0.0000). For all patients, ROC area was 0.759 (p = 0.000), for a EuroSCORE < 5% it was 0.689 (p = 0.002), between 5 and 14.9% it was 0.544 (p = 0.499) and for >15% it was 0.725 (p = 0.067). In conclusion, the logistic EuroSCORE allowed properly stratify the long-term survival curves in a sample of patients undergoing cardiac surgery, both the coronary and valve or combined surgery. Long-term results stratified by risk are a reasonable way to present late postoperative survival. PMID- 24152401 TI - [Scientific research in public health institutions of the City of Buenos Aires]. AB - Hospitals with academic activities offer better services to their patients. The Government of Buenos Aires City (GBAC) has an important network of health facilities, but there is little information regarding their academic activities. Our aim was to estimate the proportion of articles included in MEDLINE originated in GBAC hospitals, to evaluate their contribution regarding the whole country (Argentina), and to describe some characteristics of these papers. It is a cross sectional study based on a MEDLINE search, using the name of each of the 33 GBAC hospitals in the "affiliation" field. Among 22 million references, 1781 belonged to GBAC hospitals (4.4% of all references from Argentina); 66.5% were in English, 83.7% were related to humans, 30.1% were from the last 5 years, 8.3% included high level scientific evidence research (meta-analysis or randomized controlled trials), and 31.1% included research in children. Regarding the rest of the references from Argentina, those from GBAC hospitals included less papers in English (66.5% vs. 90.0%; OR: 0.22; p < 0.0001), less recent papers (30.1% vs. 34.6%; OR: 0.81; p < 0.0001), more research in humans (83.7% vs. 37.3%; OR: 8.65; p < 0.0001), more randomized controlled trials (8.0% vs. 2.8%; OR: 2,9; p < 0.0001), and more research in children (31.1% vs. 9.2%; OR: 4.44; p < 0.0001). GBAC hospitals contributed with 4.4% of references attributed to Argentina in MEDLINE. References from GBAC hospitals were less recent, and included more randomized controlled trials and research in children. PMID- 24152402 TI - [Masseter inhibitory reflex abnormality and brainstem lesion]. PMID- 24152403 TI - [Omental appendagitis]. PMID- 24152404 TI - [Health system and aboriginal communities in the province of Formosa, Argentina]. AB - The author comments her experience in the practice of medicine and public health among aborigines in Formosa, a long neglected province in northeast Argentina. Her experience goes through a span of 34 years, 11 in a small community in a far off region. The province has 530162 inhabitants, 43358 (6.5%) aborigines of the Wichi, Qom, and Pilaga ethnicities. Some particular public health problems of these aborigines are due to the great distance between communities and the regular medical assistance while others are related to cultural differences. The situation has gradually improved in the last 30 years due to government awareness in providing easy and close access to medical care, making the most of the abilities of local aborigines midwifes, teaching health assistants and conventional measures. The most apparent results are the decrease in infant mortality rates and the lower incidence of tuberculosis, with no deaths due to tuberculous meningitis since 1999. No less important was the opening of new opportunities for education and the teaching of both native and Spanish language in the schools retaining local customs. The changes have brought about new risks and challenges such as: traffic accidents involving youngsters riding motorcycles, alcoholism, obesity, diabetes (undiagnosed beforehand), high rate of adolescence pregnancy, and crisis of leadership within the communities. PMID- 24152405 TI - [Late onset Friedreich ataxia: clinical description of a family in Argentina]. AB - Friedreich Ataxia (FA) is the most common hereditary ataxia, caused by abnormal expansion of the GAA triplet of the first intron of the X25 gene on chromosome 9. Clinically it occurs in patients under the age of 25 and it is frequently associated with musculoskeletal, endocrine and myocardial disorders. Among their phenotypic variants there are patients starting their symptoms after the age of 25. The latter group is defined as late onset Freidreich ataxia (LOFA). The objective of this work is to present three siblings affected by late onset Friedreich ataxia. Their symptoms began between the ages of 32 and 34, with gait disturbance and dysarthria of cerebellar type, which worsened, thus becoming more evident in the course of 6-12 months. None had musculoskeletal or myocardial involvement. There was no family history of ataxia or other neurological disorders. Two of these patients underwent genetic study that showed abnormal expansion of GAA triplet confirming the diagnosis of FA. A magnetic resonance imaging (MRI) of the brain was performed. Proximal spinal cord atrophy, sparing cerebellar structures, was found in two of the cases and vermian atrophy associated with proximal spinal cord atrophy was observed in the third one. Molecular testing GAA expansions in the FA gene should be considered in cerebellar ataxia with dysarthria and loss of proprioception. PMID- 24152406 TI - [Small bowel intussusception and Vanek's tumor in an elderly woman]. AB - Inflammatory fibroid polyps are non-frequent benign lesions, described by Vanek in 1949, originated in the sub mucosa of the gastrointestinal tract. They have an uncertain origin and they are formed of fibroblastic and mesenchymal proliferations with an important eosinophilic proportion. Depending on where are they localized, could present different type of symptoms. The inflammatory fibroid polyps are one of the rare benign conditions causing intestinal intussusception in adults. We present the case of a 82 years old woman, who presented an intestinal intussusception due to an inflammatory fibroid polyp localized in the small bowel. PMID- 24152407 TI - [Agranulocytosis induced by levamisole in association to cocaine]. AB - Agranulocytosis in cocaine users is a worldwide recently recognized condition. It is due to the utilization as cutting agent of levamisole, an ancient antiparasitic and immunomodulator drug. We describe the case of a patient with agranulocytosis induced by levamisole in association to cocaine and we review clinical and biochemical characteristics of the clinical picture, as well as the management of these patients. We also analyze the reasons related to a more and more frequent practice, the addition of levamisole to cocaine. This is the first case described in our country, although it is probable that there are many not recognized or not described cases related to this pathology. PMID- 24152408 TI - [Pseudo-pituitary tumor and hypopituitarism secondary to a sphenoid sinus inverted papilloma]. AB - Inverted papilloma (IP) is a benign uncommon epithelial tumor, arising mostly from the lateral nasal wall. Though benign, this lesion is highly invasive into surrounding tissues and malignant transformation may occur. Primary IP of the sphenoid sinus and intracranial extension with dural invasion, even without histological evidence of malignancy, has only rarely been described. Hypopituitarism as a complication of this lesion has never been reported. We describe the case of a 59-year-old woman who was evaluated because of a 5-year history of severe headaches and abnormalities in the visual field. Magnetic resonance imaging (MRI) showed a 1.4 per 2.0 cm heterogeneous sellar lesion with suprasellar and sphenoid sinus extension, eroding the sellar floor with optic chiasm compression. Otolaryngologists gave her 16 mg/day of prednisone during approximately 3 months with a near total regression of the mass on MRI. The endocrine biochemical evaluation showed pituitary gonadal, thyroid and adrenal insufficiency. A new MRI showed growth of the tumor with obliteration of the sphenoid sinus. An endoscopic sinus biopsy revealed an IP, so a transnasal endoscopic sinus surgery was performed with complete resection evidenced by MRI a year later. PMID- 24152409 TI - [Obesity and metabolic syndrome in children and adolescents]. AB - Obesity and the metabolic syndrome are closely related to the cases of cardiovascular disease; they are usually regarded as belonging to the adult population but are seen with increasing frequency in children and adolescents. There is evidence that atherosclerotic lesions occur most often in young people with obesity. The factors involved in this pandemic are manifold and range from genetic-biological to cultural changes. The family and the environment in which the child develops play a key role in the adoption of habits related to diet and physical activity. This problem does not respect borders and cultures but all countries are being affected, even more those of middle-income. State and Society as a whole can play a role oriented to modify this environment. The restriction on sales of unhealthy food and the fight against the sedentary lifestyle are urgently needed to be applied. The impact that these disorders will have in terms of cardiovascular disease, has not yet reached its true dimension. PMID- 24152410 TI - [Guidelines for diagnosis, monitoring and treatment of Fabry disease]. AB - Fabry disease is an X-linked hereditary lysosomal storage disorder caused by deficiency of the enzyme alpha-galactosidase A. Knowledge about this disease, and its medical management, has made remarkable progress in the last decade, including the development of its specific treatment. This guide was developed by medical professionals from various specialties involved in the care of patients with Fabry disease. The discussion and analysis of the available scientific evidence, coupled with the experience of each of the participants, has allowed us to develop the concepts included in this guide in order to provide a useful tool for all professionals who care for patients with Fabry disease. PMID- 24152411 TI - [Annexins and recurrent pregnancy loss]. AB - Recurrent Pregnancy Loss (RPL) affects public health and directly compromises the quality of life of hundreds of women, with a detrimental effect on their physical and mental health. Approximately 50% of RPL are not associated to any of the currently known etiology and will be considered idiopathic. Recently, it has been demonstrated that the expression of annexin 5 (ANXA5), a protein found on the trophoblastic surface, plays a fundamental role in the development of pregnancy due to its immunomodulator and anticoagulant function at the placentary level. Some genetic haplotypes of ANXA5 are associated to alterations in the expression of this gene, such as haplotype M2 which is associated to a decrease in the expression of ANXA5. The presence of this haplotype is related to the following conditions occurring during pregnancy: RPL, foetal intrauterine growth restriction, low child weight at birth, preeclampsia and maternal pulmonary thromboembolism. This review describes the structure, function and genetic expression of ANXA5, as well as its possible implication in RPL. PMID- 24152412 TI - [A youthful heart with a youthful brain]. PMID- 24152413 TI - [Stress and resilience. Hans Selye and the reencounter of two cultures]. PMID- 24152414 TI - [The PSA and the risk of repeating the same mistakes]. PMID- 24152415 TI - [In response, more about the PSA]. PMID- 24152416 TI - Evidence for continuous glucose monitoring: sufficient for reimbursement? AB - Evidence for continuous glucose monitoring is mounting. Meta-analyses consistently show lowering of HbA1c , and the first trial reporting a reduction in severe hypoglycaemic events in patients with hypoglycaemia unawareness has recently been presented. The more recent trials studied larger numbers of patients and may have shown better results because of improved technology. The various combinations of pump and sensor, with automated bolus calculators and low glucose suspend features, make evaluation more challenging from a reimbursement point of view, but evidence seems convincing enough to justify reimbursement for selected patient groups, including those who have shown a substantial improvement in HbA1c during a trial period, and those with hypoglycaemia unawareness who encountered severe hypoglycaemia in the recent past. More data on cost-efficacy are needed. PMID- 24152417 TI - Efficacy of sorafenib in advanced renal cell carcinoma independent of prior treatment, histology or prognostic group. AB - AIM: To assess the response rate and safety of sorafenib in different subpopulations of patients with advanced renal cell carcinoma (RCC). METHODS: Single-arm open access trial. Key eligibility: advanced RCC with either clear cell or non-clear-cell histopathology; progression on prior systemic chemotherapy or treatment naive. Sorafenib was commenced at 400 mg twice daily continuously. RESULTS: A total 47 participants with metastatic RCC were treated with sorafenib. Overall, 1 participant experienced complete response, 6 (13%) had documented partial response (PR) and 29 (62%) had stable disease (SD) as the best response. Eight (17%) had non-clear-cell histopathology and five (10%) had sarcomatoid features. In the non-clear-cell histopathology cohort, five participants (62.5%) had SD. Twenty-three (49%) participants were treatment naive; of these, 1/23 showed CR, 5/23 experienced PR and 13/23 had SD (clinical benefit: 83%). Overall, 14 (30%) and 22 (47%) participants had high-risk status according to MSKCC (Memorial Sloan-Kettering Cancer Center) and Heng prognostic scores, respectively. In the MSKCC poor prognostic group (14 participants), one participant had CR, two participants showed PR and eight participants had SD (clinical benefit: 79%). In Heng poor prognostic group (22 participants), 1 participant experienced CR, 2 participants showed PR and 13 had SD (clinical benefit: 73%). Hand-foot syndrome (53%), rash (47%), fatigue (42%), nausea (40%), anorexia (34%) and diarrhea (32%) were the most common adverse events. CONCLUSIONS: This study confirms the efficacy and tolerability of sorafenib in a different spectrum of advanced RCC patients including non-clear-cell histology, poor prognostic status and as first-line treatment. PMID- 24152418 TI - Response to: 'Biologic discontinuation studies: a systematic review of methods' by van der Maas et al. PMID- 24152420 TI - Environmental tobacco smoke exposure in children aged 3-19 years with and without asthma in the United States, 1999-2010. AB - KEY FINDINGS: Data from the National Health and Nutrition Examination Survey, 1999-2010. From 1999 to 2010, the percentage of children without asthma exposed to environmental tobacco smoke (ETS) decreased from 57.3% to 44.2%, while children with asthma showed no change, with 57.9% exposed to ETS in 1999-2002 and 54.0% exposed in 2007-2010. In 2007-2010, a higher percentage of children with asthma were exposed to ETS than children without asthma. In 2007-2010, children with asthma were more likely to be exposed to ETS than children without asthma, if they were girls, Mexican American, aged 6-11 years, or had family income below 350% of the federal poverty guidelines. PMID- 24152419 TI - Increased function of pronociceptive TRPV1 at the level of the joint in a rat model of osteoarthritis pain. AB - OBJECTIVES: Blockade of transient receptor potential vanilloid 1 (TRPV1) with systemic antagonists attenuates osteoarthritis (OA) pain behaviour in rat models, but on-target-mediated hyperthermia has halted clinical trials. The present study investigated the potential for targeting TRPV1 receptors within the OA joint in order to produce analgesia. METHODS: The presence of TRPV1 receptors in human synovium was detected using western blotting and immunohistochemistry. In a rat model of OA, joint levels of an endogenous ligand for TRPV1, 12-hydroxy eicosatetraenoic acid (12-HETE), were quantified using liquid chromatography tandem mass spectrometry (LC-MS/MS). Effects of peripheral administration of the TRPV1 receptor antagonist JNJ-17203212 on afferent fibre activity, pain behaviour and core body temperature were investigated. Effects of a spinal administration of JNJ-17203212 on dorsal horn neuronal responses were studied. RESULTS: We demonstrate increased TRPV1 immunoreactivity in human OA synovium, confirming the diseased joint as a potential therapeutic target for TRPV1-mediated analgesia. In a model of OA pain, we report increased joint levels of 12-HETE, and the sensitisation of joint afferent neurones to mechanical stimulation of the knee. Local administration of JNJ-17203212 reversed this sensitisation of joint afferents and inhibited pain behaviour (weight-bearing asymmetry), to a comparable extent as systemic JNJ-17203212, in this model of OA pain, but did not alter core body temperature. There was no evidence for increased TRPV1 function in the spinal cord in this model of OA pain. CONCLUSIONS: Our data provide a clinical and mechanistic rationale for the future investigation of the therapeutic benefits of intra-articular administration of TRPV1 antagonists for the treatment of OA pain. PMID- 24152422 TI - Robust classification of motor imagery EEG signals using statistical time-domain features. AB - The tradeoff between computational complexity and speed, in addition to growing demands for real-time BMI (brain-machine interface) systems, expose the necessity of applying methods with least possible complexity. Willison amplitude (WAMP) and slope sign change (SSC) are two promising time-domain features only if the right threshold value is defined for them. To overcome the drawback of going through trial and error for the determination of a suitable threshold value, modified WAMP and modified SSC are proposed in this paper. Besides, a comprehensive assessment of statistical time-domain features in which their effectiveness is evaluated with a support vector machine (SVM) is presented. To ensure the accuracy of the results obtained by the SVM, the performance of each feature is reassessed with supervised fuzzy C-means. The general assessment shows that every subject had at least one of his performances near or greater than 80%. The obtained results prove that for BMI applications, in which a few errors can be tolerated, these combinations of feature-classifier are suitable. Moreover, features that could perform satisfactorily were selected for feature combination. Combinations of the selected features are evaluated with the SVM, and they could significantly improve the results, in some cases, up to full accuracy. PMID- 24152421 TI - Dose REduction strategy of subcutaneous TNF inhibitors in rheumatoid arthritis: design of a pragmatic randomised non inferiority trial, the DRESS study. AB - BACKGROUND: Preliminary, mostly uncontrolled studies suggest that dose reduction or discontinuation of tumour necrosis factor blockers can be achieved in a relevant proportion of patients with RA without loss of disease control. However, long term safety, cost effectiveness and feasibility in clinical practice remain uncertain. METHODS/DESIGN: This study is a 18-months pragmatic, non-inferiority, cost minimalisation, randomized controlled trial on dose reduction and discontinuation of the subcutaneous tumour necrosis factor (TNF) blockers adalimumab and etanercept in RA patients with low disease activity. 180 RA patients with low disease activity (DAS28 < 3.2 or clinical judgment of the rheumatologist) are randomized 2:1 to either increased spacing and eventually discontinuation after 6 months of the TNF blocker, and usual care. Implementation is done in routine daily care, using treat to target and feedback implementation in both treatment arms. The primary outcome is non-inferiority (NI margin 20%) in cumulative incidence of persistent (> 3 months) RA flare, according to a recently validated DAS28 based flare criterion (DAS28 change > 1.2, or DAS28 increase of 0.6 and current DAS28 >= 3.2). Secondary outcomes include mean disease activity, function, radiographic progression, safety and cost effectiveness. Cost per quality adjusted life year (QALY) differences between groups are expressed as a decremental cost effectiveness ratio (DCER), i.e. saved costs divided by (possible) loss in QALY. DISCUSSION: The design of this study targeted several clinical and methodological issues on TNF blocker dose de-escalation, including how to taper the TNF blockers, the satisfactory control condition, how to define flare, implementation in clinical practice, and the choice of the non-inferiority margin. Pragmatic cost minimalisation studies using non-inferiority designs and DCERs will become more mainstream as cost effectiveness in healthcare gains importance. TRIAL REGISTRATION: Dutch Trial Register NTR3216, The study has received ethical review board approval (number NL37704.091.11). PMID- 24152423 TI - Preclinical atherosclerosis and metabolic syndrome increase cardio- and cerebrovascular events rate: a 20-year follow up. AB - BACKGROUND: Intima-media thickness (IMT) is a validated marker of preclinical atherosclerosis and a predictor of cardiovascular events. PATIENTS: We studied a population of 529 asymptomatic patients (age 62 +/- 12.8 years), divided into two groups of subjects with and without Metabolic Syndrome (MetS). METHODS: All patients, at baseline, have had a carotid ultrasound evaluation and classified in two subgroups: the first one without atherosclerotic lesions and the second one with preclinical atherosclerosis (increased IMT or asymptomatic carotid plaque). Cardiovascular endpoints were investigated in a 20-years follow-up. RESULTS: There were 242 cardiovascular events: 144 among patients with MetS and 98 among in healthy controls (57.4% vs. 35.2%; P < 0.0001). 63 events occurred in patients with normal carotid arteries, while 179 events occurred in patients with preclinical atherosclerosis (31.8% vs. 54.1%; P < 0.0001). Of the 144 total events occurred in patients with MetS, 36 happened in the subgroup with normal carotid arteries and 108 in the subgroup with preclinical atherosclerosis (45% vs. 63.15%; P = 0.009). 98 events occurred in patients without MetS, of which 27 in the subgroup with normal carotid arteries and 71 in the subgroup with preclinical atherosclerosis (22.88% vs. 44.37%; P = 0.0003). In addition, considering the 63 total events occurred in patients without atherosclerotic lesions, 36 events were recorded in the subgroup with MetS and 27 events in the subgroup without MetS (45% vs. 22.88%; P = 0.0019). Finally, in 179 total events recorded in patients with preclinical carotid atherosclerosis, 108 happened in the subgroup with MetS and 71 happened in the subgroup without MetS (63.15% vs. 44.37%; P = 0.0009). The Kaplan-Meier function showed an improved survival in patients without atherosclerotic lesions compared with patients with carotid ultrasound alterations (P = 0.01, HR: 0.7366, CI: 0.5479 to 0.9904). CONCLUSIONS: Preclinical atherosclerosis leads to an increased risk of cardiovascular events, especially if it is associated with MetS. PMID- 24152425 TI - Impact of maximum speed on sprint performance during high-level youth female field hockey matches: female athletes in motion (FAiM) study. AB - The aim of this study was to examine the impact of maximum sprint speed on peak and mean sprint speed during youth female field hockey matches. Two high-level female field hockey teams (U-17, n = 24, and U-21, n = 20) were monitored during a 4-game international test series using global position system technology and tested for maximum sprint speed. Dependent variables were compared using a 3 factor ANOVA (age group, position, and speed classification); effect sizes (Cohen d) and confidence limits were also calculated. Maximum sprint speed was similar between age groups and positions, with faster players having greater speed than slower players (29.3 +/- 0.4 vs 27.2 +/- 1.1 km/h). Overall, peak match speed in youth female field hockey players reaches approximately 90% of maximum sprint speed. Absolute peak match speed and mean sprint speed during matches were similar among the age groups (except match 1) and positions (except match 2); however, peak match speed was greater for faster players in matches 3 and 4. No differences were observed in the relative proportion for mean sprint speeds for age groups or positions, but slower players consistently displayed similar relative mean sprint speeds by using a greater proportion of their maximum sprint speed. PMID- 24152424 TI - Evidence for factor IX-independent roles for factor XIa in blood coagulation. AB - BACKGROUND: Factor XIa is traditionally assigned a role in FIX activation during coagulation. However, recent evidence suggests this protease may have additional plasma substrates. OBJECTIVE: To determine whether FXIa promotes thrombin generation and coagulation in plasma in the absence of FIX, and to determine whether FXI-deficiency produces an antithrombotic effect in mice independently of FIX. METHODS: FXIa, FXIa variants and anti-FXIa antibodies were tested for their effects on plasma coagulation and thrombin generation in the absence of FIX, and for their effects on the activation of purified coagulation factors. Mice with combined FIX and FXI deficiency were compared with mice lacking either FIX or FXI in an arterial thrombosis model. RESULTS: In FIX-deficient plasma, FXIa induced thrombin generation, and anti-FXIa antibodies prolonged clotting times. This process involved FXIa-mediated conversion of FX and FV to their active forms. Activation of FV by FXIa required the A3 domain on the FXIa heavy chain, whereas activation of FX did not. FX activation by FXIa, unlike FIX activation, was not a calcium-dependent process. Mice lacking both FIX and FXI were more resistant to ferric chloride-induced carotid artery occlusion than FXI-deficient or FIX deficient mice. CONCLUSION: In addition to its predominant role as an activator of FIX, FXIa may contribute to coagulation by activating FX and FV. As the latter reactions do not require calcium, they may make important contributions to in vitro clotting triggered by contact activation. The reactions may be relevant to FXIa's roles in hemostasis and in promoting thrombosis. PMID- 24152427 TI - The inter-contact interval: a new measure to define frequent attenders in primary care. AB - BACKGROUND: Frequent attenders receive much attention in primary care research. Defining frequent attendance is crucial for an adequate view on this group of demanding patients. We aimed to develop a purely contact-based definition of "frequent attendance" and to apply it to real patients. METHODS: From electronic records of 123 general practices in Germany, patients' inter-contact intervals (ICI) between two consecutive doctor-patient-contacts were calculated in this retrospective observational study. ICI less than 7 days were labelled "frequent attendance", patients with 60% or more of such intervals "frequent attenders (new view)". In contrast, patients having at least 24 contacts per calendar year were considered "frequent attenders (traditional view)". Both groups were analysed in their diseases and demands, using multiple logistic regression. RESULTS: A total of 177,057 patients with at least 3 ICI in 1996 until 2006 yielded 4,408,033 ICI. One third were "short" ICI (less than 7 days), resulting in 19,759 (11.2%) frequent attenders (new). In contrast, 22,921 (12.9%) patients were frequent attenders (traditional). Compared to non-frequent attenders, frequent attenders (new) were more likely to have pneumonia (OR 1.66), stroke (OR 1.49), dementia (OR 1.46), or severe substance abuse (OR 1.44), also to need home visits or emergency attention. Frequent attenders (traditional) were more likely to have dementia (OR 2.76) or stroke (OR 2.06), and by far to need home visits (OR 5.43; all p < 0.001). CONCLUSIONS: A new measure, the interval in days of two consecutive face-to-face contacts (ICI), widens our perspective on frequent attenders in general practice. In many cases, their consultation behaviour and need for medical services seem to follow "disease logic". PMID- 24152426 TI - Diabetes impairs an interleukin-1beta-dependent pathway that enhances neurite outgrowth through JAK/STAT3 modulation of mitochondrial bioenergetics in adult sensory neurons. AB - BACKGROUND: A luminex-based screen of cytokine expression in dorsal root ganglia (DRG) and nerve of type 1 diabetic rodents revealed interleukin-1 (IL-1alpha) and IL-1beta to be significantly depressed. We, therefore, tested the hypothesis that impaired IL-1alpha and IL-1beta expression in DRG may contribute to aberrant axon regeneration and plasticity seen in diabetic sensory neuropathy. In addition, we determined if these cytokines could optimize mitochondrial bioenergetics since mitochondrial dysfunction is a key etiological factor in diabetic neuropathy. RESULTS: Cytokines IL-1alpha and IL-1beta were reduced 2-fold (p<0.05) in DRG and/or nerve of 2 and 5 month streptozotocin (STZ)-diabetic rats. IL-2 and IL-10 were unchanged. IL-1alpha and IL-1beta induced similar 2 to 3-fold increases in neurite outgrowth in cultures derived from control or diabetic rats (p<0.05). STAT3 phosphorylation on Tyr705 or Ser727 was depressed in DRG from STZ-diabetic mice and treatment of cultures derived from STZ-diabetic rats with IL-1beta for 30 min raised phosphorylation of STAT3 on Tyr705 and Ser727 by 1.5 to 2-fold (p<0.05). shRNA-based or AG490 inhibition of STAT3 activity or shRNA blockade of endogenous IL-1beta expression completely blocked neurite outgrowth. Cultured neurons derived from STZ-diabetic mice were treated for 24 hr with IL-1beta and maximal oxygen consumption rate and spare respiratory capacity, both key measures of bioenergetic fidelity that were depressed in diabetic compared with control neurons, were enhanced 2-fold. This effect was blocked by AG490. CONCLUSIONS: Endogenous synthesis of IL-1beta is diminished in nerve tissue in type 1 diabetes and we propose this defect triggers reduced STAT3 signaling and mitochondrial function leading to sup-optimal axonal regeneration and plasticity. PMID- 24152428 TI - Correlation of pre-veterinary admissions criteria, intra-professional curriculum measures, AVMA-COE professional competency scores, and the NAVLE. AB - Data consisting of preadmission criteria scores, annual and final cumulative grade point averages (GPAs), grades from individual professional courses, American Veterinary Medical Association Council on Education (AVMA-COE) Competency scores, annual class rank, and North American Veterinary Licensing Exam (NAVLE) scores were collected on all graduating DVM students at Kansas State University in 2009 and 2010. Associations among the collected data were compared by Pearson correlation. Pre-veterinary admissions criteria infrequently correlated with annual GPAs of Years 1-3, rarely correlated with the AVMA-COE Competencies, and never correlated with the annual GPA of Year 4. Low positive correlations occurred between the NAVLE and the Verbal Graduate Record Examination (GRE) (r=.214), Total GRE (r=.171), and the mean GPA of pre professional science courses (SGPA) (r=.236). Annual GPAs strongly correlated with didactic course scores. Annual GPAs and final class rank strongly correlated (mean r=-.849), and both strongly correlated with the NAVLE score (NAVLE: GPAs mean r=.628, NAVLE: final class rank r=-.714). Annual GPAs at the end of Years 1 4 weakly correlated or did not correlate with the AVMA-COE Competencies. The AVMA COE Competencies weakly correlated with scores earned in didactic courses of Years 1-3. AVMA-COE Competencies were internally consistent (mean r=.796) but only moderately correlated with performance on the NAVLE (mean r=.319). Low correlations between admissions criteria and outcomes indicate a need to reevaluate admission criteria as predictors of school success. If the NAVLE remains the primary discriminator for veterinary licensure (and the gateway to professional activity), then the AVMA-COE Competencies should be refined to better improve and reflect the NAVLE, or the NAVLE examination should change to reflect AVMA-COE Competencies. PMID- 24152429 TI - Finnish Children Healthy Eating Index (FCHEI) and its associations with family and child characteristics in pre-school children. AB - OBJECTIVE: The objective was to develop a Finnish Children Healthy Eating Index (FCHEI), to determine the relative validity of the index and to examine associations between the index and familial sociodemographic and lifestyle characteristics. DESIGN: Cross-sectional samples of children participating in a population-based birth cohort study in Finland. SETTING: Type I Diabetes Prediction and Prevention (DIPP) Study cohort. SUBJECTS: Three-day food records from 1-year-old (n 455), 3-year-old (n 471) and 6-year-old (n 713) children were completed between 2003 and 2005. RESULTS: Validity of the FCHEI was assessed by studying the associations between the FCHEI and nutrient intakes of the children. Among all age groups, intakes of SFA and sugars decreased across increasing quartiles of the FCHEI while intakes of PUFA, dietary fibre, vitamin D and vitamin E increased. Among 3- and 6-year-olds, being cared for at home was associated with the lowest FCHEI quartile (diet that deviates most from the recommendations). The lowest FCHEI quartile was also associated with residence in a semi-urban area among the 3-year-olds and low maternal education and smoking during pregnancy among the 6-year-olds. CONCLUSIONS: The FCHEI serves as a valid indicator of the quality of Finnish children's diet. Public health programmes aimed at improving the dietary behaviours of pre-school aged children should aim to improve the quality of food served at home. Families with history of lower parental education, maternal smoking during pregnancy or non-urban place of residence may require special attention. PMID- 24152430 TI - The antioxidant effects of the flavonoids rutin and quercetin inhibit oxaliplatin induced chronic painful peripheral neuropathy. AB - BACKGROUND: Oxaliplatin, the third-generation platinum compound, has evolved as one of the most important therapeutic agents in colorectal cancer chemotherapy. The main limiting factor in oxaliplatin treatment is painful neuropathy that is difficult to treat. This side effect has been studied for several years, but its full mechanism is still inconclusive, and effective treatment does not exist. Data suggest that oxaliplatin's initial neurotoxic effect is peripheral and oxidative stress-dependent. A spinal target is also suggested in its mechanism of action. The flavonoids rutin and quercetin have been described as cell-protecting agents because of their antioxidant, antinociceptive, and anti-inflammatory actions. We proposed a preventive effect of these agents on oxaliplatin-induced painful peripheral neuropathy based on their antioxidant properties. METHODS: Oxaliplatin (1 mg/kg, i.v.) was injected in male Swiss mice, twice a week (total of nine injections). The development of sensory alterations, such as thermal and mechanical allodynia, was evaluated using the tail immersion test in cold water (10 degrees C) and the von Frey test. Rutin and quercetin (25-100 mg/kg, i.p.) were injected 30 min before each oxaliplatin injection. The animals' spinal cords were removed for histopathological and immunohistochemical evaluation and malondialdehyde assay. RESULTS: Oxaliplatin significantly increased thermal and mechanical nociceptive response, effects prevented by quercetin and rutin at all doses. Fos immunostaining in the dorsal horn of the spinal cord confirmed these results. The oxidative stress assays mainly showed that oxaliplatin induced peroxidation in the spinal cord and that rutin and quercetin decreased this effect. The flavonoids also decreased inducible nitric oxide synthase and nitrotyrosine immunostaining in the dorsal horn of the spinal cord. These results suggest that nitric oxide and peroxynitrite are also involved in the neurotoxic effect of oxaliplatin and that rutin and quercetin can inhibit their effect in the spinal cord. We also observed the preservation of dorsal horn structure using histopathological analyses. CONCLUSIONS: Oxaliplatin induced painful peripheral neuropathy in mice, an effect that was prevented by rutin and quercetin. The mechanism of action of oxaliplatin appears to be, at least, partially oxidative stress-induced damage in dorsal horn neurons, with the involvement of lipid peroxidation and protein nitrosylation. PMID- 24152431 TI - What it means to be an adult child of a person with dementia. AB - The prevalence of dementia as a disease has increased worldwide with advancing age and growing population numbers, affecting whole families. However, most previous research does not separate the spouses or cohabitants from the adult children, but instead regards all next of kin involved in the everyday care of the person suffering from dementia as caregivers. This has made it difficult to find previous research regarding what it means to be an adult child of a person with dementia, and as such, the aim of this study is to explore that topic. The method used was narrative interviews analysed using phenomenological hermeneutics. Our comprehensive understanding showed that to be an adult child of a person with dementia means being burdened with the responsibility to act on behalf of the diseased parent despite a deep sense of grief and loss, which leads to frustration and despondence. The adult children's existence and reality are threatened not only by the loss of the parent but also by the possibility that one day they too may inherit the disease. This could be compared to a psychic crisis, which is defined as a situation that leads to radical changes in the afflicted person's relationship to life and reality, or, simply, "an upset in a steady state." The findings suggest that adult children of people with dementia are in need of support for a substantial period of time in order to adapt to the fact that they have lost a parent who is still alive. They also need information about the disease and the process of diagnosis and treatment to feel more a part of the process, as well as understand the behavior and needs of their parent. PMID- 24152432 TI - Combination of artificial neural network and genetic algorithm method for modeling of methylene blue adsorption onto wood sawdust from water samples. AB - The aim of this research was to develop a low price and environmentally friendly adsorbent with abundant of source to remove methylene blue (MB) from water samples. Sawdust solid-phase extraction coupled with high-performance liquid chromatography was used for the extraction and determination of MB. In this study, an experimental data-based artificial neural network model is constructed to describe the performance of sawdust solid-phase extraction method for various operating conditions. The pH, time, amount of sawdust, and temperature were the input variables, while the percentage of extraction of MB was the output. The optimum operating condition was then determined by genetic algorithm method. The optimized conditions were obtained as follows: 11.5, 22.0 min, 0.3 g, and 26.0 degrees C for pH of the solution, extraction time, amount of adsorbent, and temperature, respectively. Under these optimum conditions, the detection limit and relative standard deviation were 0.067 MUg L(-1) and <2.4%, respectively. The Langmuir and Freundlich adsorption models were applied to describe the isotherm constant and for the removal and determination of MB from water samples. PMID- 24152433 TI - Androgen receptor co-regulatory networks in castration-resistant prostate cancer. AB - Androgen and the androgen receptor (AR) are critical effectors of prostate cancer. Consequently, androgen deprivation therapy is typically employed as a first-line treatment for prostate cancer patients. While initial responses are generally positive, prostate tumors frequently recur and progress to a lethal form known as castration-resistant prostate cancer (CRPC). Recently, considerable effort has been directed toward elucidating the molecular mechanisms of CRPC. Results from both preclinical and clinical studies suggest that AR-mediated signaling persists and remains functionally important in CRPC despite the elimination of androgens. Understanding the role of this pathway in the development of resistance will therefore be critical to identify alternative diagnostic markers as well as more effective therapies for the treatment of CRPC. Using next-generation sequencing and other high-throughput approaches, numerous groups are beginning to identify the key differences in the transcriptional regulatory and gene expression programs between androgen-dependent and CRPC. A number of mechanisms have been proposed for the differences and these mostly involve alterations to components of the AR co-regulatory network. In this review, we summarize current knowledge on co-regulators of the AR and discuss their potential roles in CRPC. It is anticipated that a deeper understanding of these factors will undercover new targets that can assist in the diagnosis and treatment of CRPC. PMID- 24152434 TI - Microscale diffusion measurements and simulation of a scaffold with a permeable strut. AB - Electrospun nanofibrous structures provide good performance to scaffolds in tissue engineering. We measured the local diffusion coefficients of 3-kDa FITC dextran in line patterns of electrospun nanofibrous structures fabricated by the direct-write electrospinning (DWES) technique using the fluorescence recovery after photobleaching (FRAP) method. No significant differences were detected between DWES line patterns fabricated with polymer supplied at flow rates of 0.1 and 0.5 mL/h. The oxygen diffusion coefficients of samples were estimated to be ~92%-94% of the oxygen diffusion coefficient in water based on the measured diffusion coefficient of 3-kDa FITC-dextran. We also simulated cell growth and distribution within spatially patterned scaffolds with struts consisting of either oxygen-permeable or non-permeable material. The permeable strut scaffolds exhibited enhanced cell growth. Saturated depths at which cells could grow to confluence were 15% deeper for the permeable strut scaffolds than for the non permeable strut scaffold. PMID- 24152435 TI - Understanding the electronic structures and absorption properties of porphyrin sensitizers YD2 and YD2-o-C8 for dye-sensitized solar cells. AB - The electronic structures and excitation properties of dye sensitizers determine the photon-to-current conversion efficiency of dye sensitized solar cells (DSSCs). In order to understand the different performance of porphyrin dye sensitizers YD2 and YD2-o-C8 in DSSC, their geometries and electronic structures have been studied using density functional theory (DFT), and the electronic absorption properties have been investigated via time-dependent DFT (TDDFT) with polarizable continuum model for solvent effects. The geometrical parameters indicate that YD2 and YD2-o-C8 have similar conjugate length and charge transfer (CT) distance. According to the experimental spectra, the HSE06 functional in TDDFT is the most suitable functional for describing the Q and B absorption bands of porphyrins. The transition configurations and molecular orbital analysis suggest that the diarylamino groups are major chromophores for effective CT excitations (ECTE), and therefore act as electron donor in photon-induced electron injection in DSSCs. The analysis of excited states properties and the free energy changes for electron injection support that the better performance of YD2-o-C8 in DSSCs result from the more excited states with ECTE character and the larger absolute value of free energy change for electron injection. PMID- 24152436 TI - Effect of chain-extenders on the properties and hydrolytic degradation behavior of the poly(lactide)/poly(butylene adipate-co-terephthalate) blends. AB - Biodegradable poly(lactide)/poly(butylene adipate-co-terephthalate) (PLA/PBAT) blends were prepared by reactive blending in the presence of chain-extenders. Two chain-extenders with multi-epoxy groups were studied. The effect of chain extenders on the morphology, mechanical properties, thermal behavior, and hydrolytic degradation of the blends was investigated. The compatibility between the PLA and PBAT was significantly improved by in situ formation of PLA-co-PBAT copolymers in the presence of the chain-extenders, results in an enhanced ductility of the blends, e.g., the elongation at break was increased to 500% without any decrease in the tensile strength. The differential scanning calorimeter (DSC) results reveal that cold crystallization of PLA was enhanced due to heterogeneous nucleation effect of the in situ compatibilized PBAT domains. As known before, PLA is sensitive to hydrolysis and in the presence of PBAT and the chain-extenders, the hydrolytic degradation of the blend was evident. A three-stage hydrolysis mechanism for the system is proposed based on a study of weight loss and molecular weight reduction of the samples and the pH variation of the degradation medium. PMID- 24152437 TI - OsPOP5, a prolyl oligopeptidase family gene from rice confers abiotic stress tolerance in Escherichia coli. AB - The prolyl oligopeptidase family, which is a group of serine peptidases, can hydrolyze peptides smaller than 30 residues. The prolyl oligopeptidase family in plants includes four members, which are prolyl oligopeptidase (POP, EC3.4.21.26), dipeptidyl peptidase IV (DPPIV, EC3.4.14.5), oligopeptidase B (OPB, EC3.4.21.83), and acylaminoacyl peptidase (ACPH, EC3.4.19.1). POP is found in human and rat, and plays important roles in multiple biological processes, such as protein secretion, maturation and degradation of peptide hormones, and neuropathies, signal transduction and memory and learning. However, the function of POP is unclear in plants. In order to study POP function in plants, we cloned the cDNA of the OsPOP5 gene from rice by nested-PCR. Sequence analysis showed that the cDNA encodes a protein of 596 amino acid residues with Mw ~ 67.29 kD. In order to analyze the protein function under different abiotic stresses, OsPOP5 was expressed in Escherichia coli. OsPOP5 protein enhanced the tolerance of E. coli to high salinity, high temperature and simulated drought. The results indicate that OsPOP5 is a stress-related gene in rice and it may play an important role in plant tolerance to abiotic stress. PMID- 24152438 TI - Proteomic analysis identifies an NADPH oxidase 1 (Nox1)-mediated role for actin related protein 2/3 complex subunit 2 (ARPC2) in promoting smooth muscle cell migration. AB - A variety of vascular pathologies, including hypertension, restenosis and atherosclerosis, are characterized by vascular smooth muscle cell (VSMC) hypertrophy and migration. NADPH oxidase 1 (Nox1) plays a pivotal role in these phenotypes via distinct downstream signaling. However, the mediators differentiating these distinct phenotypes and their precise role in vascular disease are still not clear. The present study was designed to identify novel targets of VSMC Nox1 signaling using 2D Differential In-Gel Electrophoresis and Mass Spectrometry (2D-DIGE/MS). VSMC treatment with scrambled (Scrmb) or Nox1 siRNA and incubation with the oxidant hydrogen peroxide (H2O2; 50 uM, 3 h) followed by 2D-DIGE/MS on cell lysates identified 10 target proteins. Among these proteins, actin-related protein 2/3 complex subunit 2 (ARPC2) with no previous link to Nox isozymes, H2O2, or other reactive oxygen species (ROS), was identified and postulated to play an intermediary role in VSMC migration. Western blot confirmed that Nox1 mediates H2O2-induced ARPC2 expression in VSMC. Treatment with a p38 MAPK inhibitor (SB203580) resulted in reduced ARPC2 expression in H2O2-treated VSMC. Additionally, wound-healing "scratch" assay confirmed that H2O2 stimulates VSMC migration via Nox1. Importantly, gene silencing of ARPC2 suppressed H2O2-stimulated VSMC migration. These results demonstrate for the first time that Nox1-mediated VSMC migration involves ARPC2 as a downstream signaling target. PMID- 24152439 TI - Acidosis decreases c-Myc oncogene expression in human lymphoma cells: a role for the proton-sensing G protein-coupled receptor TDAG8. AB - Acidosis is a biochemical hallmark of the tumor microenvironment. Here, we report that acute acidosis decreases c-Myc oncogene expression in U937 human lymphoma cells. The level of c-Myc transcripts, but not mRNA or protein stability, contributes to c-Myc protein reduction under acidosis. The pH-sensing receptor TDAG8 (GPR65) is involved in acidosis-induced c-Myc downregulation. TDAG8 is expressed in U937 lymphoma cells, and the overexpression or knockdown of TDAG8 further decreases or partially rescues c-Myc expression, respectively. Acidic pH alone is insufficient to reduce c-Myc expression, as it does not decrease c-Myc in H1299 lung cancer cells expressing very low levels of pH-sensing G protein coupled receptors (GPCRs). Instead, c-Myc is slightly increased by acidosis in H1299 cells, but this increase is completely inhibited by ectopic overexpression of TDAG8. Interestingly, TDAG8 expression is decreased by more than 50% in human lymphoma samples in comparison to non-tumorous lymph nodes and spleens, suggesting a potential tumor suppressor function of TDAG8 in lymphoma. Collectively, our results identify a novel mechanism of c-Myc regulation by acidosis in the tumor microenvironment and indicate that modulation of TDAG8 and related pH-sensing receptor pathways may be exploited as a new approach to inhibit Myc expression. PMID- 24152440 TI - HuR-regulated mRNAs associated with nuclear hnRNP A1-RNP complexes. AB - Post-transcriptional regulatory networks are dependent on the interplay of many RNA-binding proteins having a major role in mRNA processing events in mammals. We have been interested in the concerted action of the two RNA-binding proteins hnRNP A1 and HuR, both stable components of immunoselected hnRNP complexes and having a major nuclear localization. Specifically, we present here the application of the RNA-immunoprecipitation (RIP)-Chip technology to identify a population of nuclear transcripts associated with hnRNP A1-RNPs as isolated from the nuclear extract of either HuR WT or HuR-depleted (KO) mouse embryonic fibroblast (MEF) cells. The outcome of this analysis was a list of target genes regulated via HuR for their association (either increased or reduced) with the nuclear hnRNP A1-RNP complexes. Real time PCR analysis was applied to validate a selected number of nuclear mRNA transcripts, as well as to identify pre-spliced transcripts (in addition to their mature mRNA counterpart) within the isolated nuclear hnRNP A1-RNPs. The differentially enriched mRNAs were found to belong to GO categories relevant to biological processes anticipated for hnRNP A1 and HuR (such as transport, transcription, translation, apoptosis and cell cycle) indicating their concerted function in mRNA metabolism. PMID- 24152441 TI - Angiotensin-converting enzymes play a dominant role in fertility. AB - According to the World Health Organization, infertility, associated with metabolic syndrome, has become a global issue with a 10%-20% incidence worldwide. An accumulating body of evidence has shown that the renin-angiotensin system is involved in the fertility problems observed in some populations. Moreover, alterations in the expression of angiotensin-converting enzyme-1, angiotensin converting enzyme-2, and angiotensin-converting enzyme-3 might be one of the most important mechanisms underlying both female and male infertility. However, as a pseudogene in humans, further studies are needed to explore whether the abnormal angiotensin-converting enzyme-3 gene could result in the problems of human reproduction. In this review, the relationship between angiotensin-converting enzymes and fertile ability is summarized, and a new procedure for the treatment of infertility is discussed. PMID- 24152442 TI - Cancer development, progression, and therapy: an epigenetic overview. AB - Carcinogenesis involves uncontrolled cell growth, which follows the activation of oncogenes and/or the deactivation of tumor suppression genes. Metastasis requires down-regulation of cell adhesion receptors necessary for tissue-specific, cell cell attachment, as well as up-regulation of receptors that enhance cell motility. Epigenetic changes, including histone modifications, DNA methylation, and DNA hydroxymethylation, can modify these characteristics. Targets for these epigenetic changes include signaling pathways that regulate apoptosis and autophagy, as well as microRNA. We propose that predisposed normal cells convert to cancer progenitor cells that, after growing, undergo an epithelial-mesenchymal transition. This process, which is partially under epigenetic control, can create a metastatic form of both progenitor and full-fledged cancer cells, after which metastasis to a distant location may occur. Identification of epigenetic regulatory mechanisms has provided potential therapeutic avenues. In particular, epigenetic drugs appear to potentiate the action of traditional therapeutics, often by demethylating and re-expressing tumor suppressor genes to inhibit tumorigenesis. Epigenetic drugs may inhibit both the formation and growth of cancer progenitor cells, thus reducing the recurrence of cancer. Adopting epigenetic alteration as a new hallmark of cancer is a logical and necessary step that will further encourage the development of novel epigenetic biomarkers and therapeutics. PMID- 24152443 TI - Crosstalk between delta opioid receptor and nerve growth factor signaling modulates neuroprotection and differentiation in rodent cell models. AB - Both opioid signaling and neurotrophic factor signaling have played an important role in neuroprotection and differentiation in the nervous system. Little is known about whether the crosstalk between these two signaling pathways will affect neuroprotection and differentiation. Previously, we found that nerve growth factor (NGF) could induce expression of the delta opioid receptor gene (Oprd1, dor), mainly through PI3K/Akt/NF-kappaB signaling in PC12h cells. In this study, using two NGF-responsive rodent cell model systems, PC12h cells and F11 cells, we found the delta opioid neuropeptide [D-Ala2, D-Leu5] enkephalin (DADLE) mediated neuroprotective effect could be blocked by pharmacological reagents: the delta opioid antagonist naltrindole, PI3K inhibitor LY294002, MAPK inhibitor PD98059, and Trk inhibitor K252a, respectively. Western blot analysis revealed that DADLE activated both the PI3K/Akt and MAPK pathways in the two cell lines. siRNA Oprd1 gene knockdown experiment showed that the upregulation of NGF mRNA level was inhibited with concomitant inhibition of the survival effects of DADLE in the both cell models. siRNA Oprd1 gene knockdown also attenuated the DADLE mediated neurite outgrowth in PC12h cells as well as phosphorylation of MAPK and Akt in PC12h and F11 cells, respectively. These data together strongly suggest that delta opioid peptide DADLE acts through the NGF-induced functional G protein coupled Oprd1 to provide its neuroprotective and differentiating effects at least in part by regulating survival and differentiating MAPK and PI3K/Akt signaling pathways in NGF-responsive rodent neuronal cells. PMID- 24152444 TI - The effect on proliferation and differentiation of cementoblast by using sclerostin as inhibitor. AB - Cementogenesis is of great importance for normal teeth root development and is involved in the repair process of root resorption caused by orthodontic treatment. As highly differentiated mesenchymal cells, cementoblasts are responsible for this process under the regulation of many endogenous agents. Among these molecules, sclerostin has been much investigated recently for its distinct antagonism effect on bone metabolism. Encoded by the sost gene, sclerostin is expressed in osteocytes and cementocytes of cellular cementum. it is still unclear. In the current study, we investigated the effects of sclerostin on the processes of proliferation and differentiation; a series of experiments including MTT, apoptosis examination, alkaline phosphatase (ALP) activity, gene analysis, and alizarin red staining were carried out to evaluate the proliferation and differentiation of cementoblasts. Protein expression including osteoprotegerin (OPG) and receptor activator of nuclear factor kappa B ligand (RANKL) were also checked to analyze changes in osteoclastogenesis. Results show that sclerostin inhibits cementoblasts proliferation and differentiation, and promotes osteoclastogenesis. Interestingly, the monoclonal antibody for sclerostin has shown positive effects on osteoporosis, indicating that it may facilitate cementogenesis and benefit the treatment of cementum related diseases. PMID- 24152445 TI - Identification of combined genetic determinants of liver stiffness within the SREBP1c-PNPLA3 pathway. AB - The common PNPLA3 (adiponutrin) variant, p.I148M, was identified as a genetic determinant of liver fibrosis. Since the expression of PNPLA3 is induced by sterol regulatory element binding protein 1c (SREBP1c), we investigate two common SREBP1c variants (rs2297508 and rs11868035) for their association with liver stiffness. In 899 individuals (aged 17-83 years, 547 males) with chronic liver diseases, hepatic fibrosis was non-invasively phenotyped by transient elastography (TE). The SREBP1c single nucleotide polymorphisms (SNPs) were genotyped using PCR-based assays with 5'-nuclease and fluorescence detection. The SREBP1c rs11868035 variant affected liver fibrosis significantly (p = 0.029): median TE levels were 7.2, 6.6 and 6.0 kPa in carriers of (TT) (n = 421), (CT) (n = 384) and (CC) (n = 87) genotypes, respectively. Overall, the SREBP1c SNP was associated with low TE levels (5.0-8.0 kPa). Carriers of both PNPLA3 and SREBP1c risk genotypes displayed significantly (p = 0.005) higher median liver stiffness, as compared to patients carrying none of these variants. The common SREBP1c variant may affect early stages of liver fibrosis. Our study supports a role of the SREBP1c-PNPLA3 pathway as a "disease module" that promotes hepatic fibrogenesis. PMID- 24152447 TI - Multivalent protein assembly using monovalent self-assembling building blocks. AB - Discotic molecules, which self-assemble in water into columnar supramolecular polymers, emerged as an alternative platform for the organization of proteins. Here, a monovalent discotic decorated with one single biotin was synthesized to study the self-assembling multivalency of this system in regard to streptavidin. Next to tetravalent streptavidin, monovalent streptavidin was used to study the protein assembly along the supramolecular polymer in detail without the interference of cross-linking. Upon self-assembly of the monovalent biotinylated discotics, multivalent proteins can be assembled along the supramolecular polymer. The concentration of discotics, which influences the length of the final polymers at the same time dictates the amount of assembled proteins. PMID- 24152449 TI - The Liverpool Care Pathway for the dying: what went wrong? PMID- 24152450 TI - Never the right time: advance care planning with frail and older people. PMID- 24152446 TI - Dietary polyunsaturated fatty acids and inflammation: the role of phospholipid biosynthesis. AB - The composition of fatty acids in the diets of both human and domestic animal species can regulate inflammation through the biosynthesis of potent lipid mediators. The substrates for lipid mediator biosynthesis are derived primarily from membrane phospholipids and reflect dietary fatty acid intake. Inflammation can be exacerbated with intake of certain dietary fatty acids, such as some omega 6 polyunsaturated fatty acids (PUFA), and subsequent incorporation into membrane phospholipids. Inflammation, however, can be resolved with ingestion of other fatty acids, such as omega-3 PUFA. The influence of dietary PUFA on phospholipid composition is influenced by factors that control phospholipid biosynthesis within cellular membranes, such as preferential incorporation of some fatty acids, competition between newly ingested PUFA and fatty acids released from stores such as adipose, and the impacts of carbohydrate metabolism and physiological state. The objective of this review is to explain these factors as potential obstacles to manipulating PUFA composition of tissue phospholipids by specific dietary fatty acids. A better understanding of the factors that influence how dietary fatty acids can be incorporated into phospholipids may lead to nutritional intervention strategies that optimize health. PMID- 24152451 TI - Organ donation in the UK: how general practice can help. PMID- 24152452 TI - Female genital mutilation: everyone's problem. PMID- 24152453 TI - Carbon footprint of patient journeys. PMID- 24152454 TI - Managing dyspepsia in primary care. PMID- 24152455 TI - Assisted dying. PMID- 24152456 TI - Sustainability in primary care. PMID- 24152457 TI - Persistent cough in children. PMID- 24152458 TI - Response to 'Repeat prescribing = hassle'. PMID- 24152459 TI - Future proofing primary care. PMID- 24152460 TI - Music: a better alternative than pain? PMID- 24152461 TI - Outside the box. PMID- 24152462 TI - Reflections on a research study about refugees and asylum seekers. PMID- 24152463 TI - Viewpoint. PMID- 24152464 TI - More than just Death in Venice: Irish Pavilion at the Venice Biennale. PMID- 24152465 TI - Graphic medicine: humanity in cartoon rats. PMID- 24152470 TI - Saul miller. PMID- 24152471 TI - Out-of-hours care. PMID- 24152472 TI - The role of patients. PMID- 24152473 TI - Arguing for more GP engagement in out-of-hours care. PMID- 24152474 TI - Pitfalls of GPs getting back directly into out-of-hours care. PMID- 24152475 TI - How primary and secondary care should work together. PMID- 24152476 TI - Community care of vulnerable older people: cause for concern. PMID- 24152477 TI - Sister Mary Joseph's nodule: an unusual but important physical finding characteristic of widespread internal malignancy. PMID- 24152478 TI - Autoimmune markers for the diagnosis of rheumatoid arthritis in primary care: primary care diagnostic technology update. PMID- 24152479 TI - Tips for GP trainees working in renal medicine. PMID- 24152480 TI - Do the elderly have a voice? Advance care planning discussions with frail and older individuals: a systematic literature review and narrative synthesis. AB - BACKGROUND: Recent years have seen marked improvements in end-of-life care, however concerns have been expressed that services are focused on the needs of patients with cancer. This review focuses on conversations about end-of-life care with frail and older people who have no main overriding diagnosis who are estimated to account for around 40% of deaths. AIM: To investigate the attitudes of the public and healthcare professionals to advance care planning discussions with frail and older people. DESIGN AND SETTING: Systematic literature review and narrative synthesis. METHOD: Articles that related to frail or older individuals and either advance care plans or discussions on end-of-life care were included. Studies of specific conditions or that focused on prognosis, capacity, or resuscitation decisions were excluded. RESULTS: While a significant minority of frail older individuals would find them unwelcome, the majority would appreciate the chance to discuss end-of-life care, yet most do not have this opportunity. Attitudes to the timing of these discussions were variable, but most perceived the risk of leaving them too late. Most doctors believed it was their professional responsibility to initiate discussions, but felt limited by time pressures and the absence of a precipitating event. A wide range of barriers were identified including the reluctance of family members to discuss end-of-life care, the passive expectation that someone else would decide on an individual's behalf, and significant uncertainty concerning future illness and decline. CONCLUSION: The marked disparity between the majority of older individuals who would like the opportunity to discuss their end-of-life care and the minority that currently have this opportunity raises important questions if the wishes of this large group in society are to be respected. The challenge is to find effective ways of encouraging dialogue and choice within the constraints of the current healthcare systems and personal circumstances. PMID- 24152481 TI - Palliative sedation in Dutch general practice from 2005 to 2011: a dynamic cohort study of trends and reasons. AB - BACKGROUND: Little is known about the quantity and reasons for use of palliative sedation in general practice. AIM: To gain more insight into the trends of and reasons for palliative sedation in Dutch general practice. DESIGN AND SETTING: Dynamic cohort study using registrations and questionnaire data of Dutch GPs. Method Data collected in the years from 2005 until 2011 in the Dutch Sentinel General Practice Network were analysed. Trends and reasons for use of palliative sedation were analysed using multilevel analyses to control for clustering of observations within general practices. RESULTS: From 2005-2011, 183 cases were reported from 56 general practices. The incidence of palliative sedation fluctuated between 33.7 per 100 000 patients in 2006 and 15.2 in 2011. No rise or decline during the period was observed. Palliative sedation was applied in 5.7% of all deaths and most frequently used in younger patients with cancer. The mean number of refractory symptoms was 2.6 (SD 1.2); pain (69.4%), dyspnoea (53.0%), and fear (39.3%). Patient involvement in decision making before the start of palliative sedation (87.4%) was less frequently present in patients suffering from cardiovascular or chronic obstructive pulmonary disease and in older patients compared to patients with cancer (P<0.05). Pending euthanasia requests were present in 20.8% of cases; the choice for palliative sedation in these cases was clearly motivated. CONCLUSION: Palliative sedation is performed in a small proportion of dying patients in Dutch general practice, without a rise or decline observed from 2005 to 2011. Patients with non-cancer diseases are less frequently involved in decision making than patients with cancer, possibly related to sudden deterioration. PMID- 24152482 TI - Opinions of the Dutch public on palliative sedation: a mixed-methods approach. AB - BACKGROUND: Palliative sedation is defined as deliberately lowering a patient's consciousness, to relieve intolerable suffering from refractory symptoms at the end of life. Palliative sedation is considered a last resort intervention in end of-life care that should not be confused with euthanasia. AIM: To inform healthcare professionals about attitudes of the general public regarding palliative sedation. design and setting: A cross-sectional survey among members of the Dutch general public followed by qualitative interviews. METHOD: One thousand nine hundred and sixty members of the general public completed the questionnaire, which included a vignette describing palliative sedation (response rate 78%); 16 participants were interviewed. RESULTS: In total, 22% of the responders indicated knowing the term 'palliative sedation'. Qualitative data showed a variety of interpretations of the term. Eighty-one per cent of the responders agreed with the provision of sedatives as described in a vignette of a patient with untreatable pain and a life expectancy of <1 week who received sedatives to alleviate his suffering. This percentage was somewhat lower for a patient with a life expectancy of <1 month (74%, P = 0.007) and comparable in the case where the physician gave sedatives with the aim of ending the patient's life (79%, P = 0.54). CONCLUSION: Most of the general public accept the use of palliative sedation at the end of life, regardless of a potential life-shortening effect. However, confusion exists about what palliative sedation represents. This should be taken into account by healthcare professionals when communicating with patients and their relatives on end-of-life care options. PMID- 24152483 TI - Providing general practice needs-based care for carers of people with advanced cancer: a randomised controlled trial. AB - BACKGROUND: Carers of patients with advanced cancer often have health and psychosocial needs, which are frequently overlooked. AIM: To meet the needs of carers through a GP consultation directed by a self-completed carer needs checklist. DESIGN AND SETTING: Randomised controlled trial in general practice with recruitment through specialist oncology clinics, in Brisbane, Australia. METHOD: Intervention was (a) carer-GP consultations directed by a self-completed checklist of needs at baseline and 3 months; and (b) a GP-Toolkit to assist GPs to address carer-identified needs. Control group received usual care. Outcome measures were intensity of needs, anxiety and depression, and quality of life. RESULTS: Total recruitment 392. Overall, no significant differences were detected in the number or intensity of need between groups. Compared to controls, intervention participants with baseline clinical anxiety showed improvements in mental wellbeing (P = 0.027), and those with baseline clinical depression had slower development of anxiety (P = 0.044) at 6 months. For those not anxious, physical wellbeing improved at 1 month (P = 0.040). Carers looking after patients with poor functional status had more physical needs (P = 0.037) at 1 month and more psychological and emotional needs at 3 months (P = 0.034). Those caring for less unwell patients showed improved mental wellbeing at 3 months (P = 0.022). CONCLUSION: The intervention did not influence the number or intensity of needs reported by carers of people with advanced cancer. There was limited impact in people with pre-existing clinical anxiety and depression. For the carer of those most severely affected by advanced cancer, it drew attention to the needs arising from the caregiving role. PMID- 24152484 TI - Employment loss during economic crisis and suicidal thoughts in Belgium: a survey in general practice. AB - BACKGROUND: The economic crisis of 2009 led to a wave of corporate reorganisations and bankruptcies, with many dismissals of employees. GPs were confronted with subsequent health consequences. AIM: To assess the possible relationship between losing one's job and having suicidal thoughts. DESIGN AND SETTING: A survey of patients aged 18-49 years recruited from GP practices in Belgium in Deurne (Flemish region) and La Louviere (Walloon region) from September to December 2010. Method Anonymous self-administered questionnaire. RESULTS: Of all eligible patients (n = 1818), 831 were offered the questionnaire and 377 completed it (45.4%). More than one in five had been confronted with employment loss in the past year (the responder or someone close losing their job). Almost one in ten had lost their job themselves in the past year. More than one in four had experienced suicidal thoughts and 11.7% had seriously considered ending their life in the past year. In the logistic regression analysis, the following characteristics showed a statistically significant relationship with having suicidal thoughts: being single (odds ratio [OR] = 4.8, 95% confidence interval [CI] = 1.7 to 13.8), not having satisfying social contacts (OR = 5.1, 95% CI = 1.6 to 16.2), having depressive complaints (OR = 18.4, 95% CI = 5.8 to 58.4), and having lost one's employment in the past year (OR = 8.8, 95% CI = 2.0 to 39.3). CONCLUSION: This study points to a statistically significant relationship between losing one's employment in the past year and having suicidal thoughts. It emphasises the important role of the GP in the continuous and reinforced assessment of suicidal risk in times of recession. PMID- 24152485 TI - Feasibility of detection and intervention for alcohol-related liver disease in the community: the Alcohol and Liver Disease Detection study (ALDDeS). AB - BACKGROUND: In the past 15 years mortality rates from liver disease have doubled in the UK. Brief alcohol advice is cost effective, but clinically meaningful reductions in alcohol consumption only occur in around 1 in 10 individuals. AIM: To provide evidence that detecting early liver disease in the community is feasible, practical, and that feedback of liver risk can increase the proportion of subjects reducing alcohol consumption. DESIGN AND SETTING: A community feasibility study in nine general practice sites in Hampshire. METHOD: Hazardous and harmful drinkers were identified by WHO AUDIT questionnaire and offered screening for liver fibrosis. RESULTS: In total, 4630 individuals responded, of whom 1128 (24%) hazardous or harmful drinkers were offered a liver fibrosis check using the Southampton Traffic Light (STL) test; 393 (38%) attended and test results were returned by post. The STL has a low threshold for liver fibrosis with 45 (11%) red, 157 (40%) amber, and 191 (49%) green results. Follow-up AUDIT data was obtained for 303/393 (77%) and 76/153 (50%) subjects with evidence of liver damage reduced drinking by at least one AUDIT category (harmful to hazardous, or hazardous to low risk) compared with 52/150 (35%, P<0.011) subjects without this evidence; in the subset of harmful drinkers patterns (AUDIT >15), 22/34 (65%) of STL positives, reduced drinking compared with 10/29 (35%, P<0.017) STL negatives. CONCLUSION: Detection of liver disease in the community is feasible, and feedback of liver risk may reduce harmful drinking. PMID- 24152486 TI - Alcohol consumption screening of newly-registered patients in primary care: a cross-sectional analysis. AB - BACKGROUND: Although screening and brief intervention is effective at reducing alcohol consumption in primary care and is recommended by guidelines, there are numerous barriers to its delivery. Screening newly-registered patients for alcohol-use disorders provides an opportunity for systematic collection of alcohol consumption data. AIM: To examine how alcohol screening data are recorded in primary care, the extent to which they are recorded, and whether reported levels of consumption differ from general population data. DESIGN AND SETTING: Cross-sectional analysis, with data collected from patients in the year after registration. METHOD: Data on alcohol consumption were collected from The Health Improvement Network (THIN) primary care database from patients aged >=18 years, newly registered with a general practice in 2007 to 2009, and compared with the Office for National Statistics Opinions (ONS Omnibus) survey. RESULTS: A total of 292 376 (76%) of the 382 609 newly-registered patients had entries for alcohol consumption (units a week, Read Codes for level of consumption, and/or screening test). Only 25 975 (9%) were recorded as completing a validated screening test, most commonly AUDIT/AUDIT-C (16 004, 5%) or FAST (9419, 3%). Alcohol-use disorders are underreported in primary care (for example, higher risk drinking 1% males, 0.5% females) in comparison with the Opinions survey (8% males, 7% females). conclusion: Alcohol screening data are collected from most patients within 1 year of registration with a GP practice; however, use of a validated screening test is rarely documented and alcohol-use disorders are underreported. Further efforts are needed to encourage or incentivise the use of validated tests to improve the quality of data collected. PMID- 24152489 TI - Up-regulation of miR-224 promotes cancer cell proliferation and invasion and predicts relapse of colorectal cancer. AB - BACKGROUND: MicroRNAs (miRNAs) are small, non-coding RNAs that can function as oncogenes or tumor suppressors in human cancer. Abnormally expressed miR-224 was found to play a fundamental role in several types of cancer. The aim of this study was to investigate the prognostic and biological values of miR-224 in colorectal cancer (CRC). METHODS: Quantitative RT-PCR (qRT-PCR) was used to evaluate expression levels of miR-224. The postoperative survival rate was analyzed with Kaplan-Meier method. The roles of miR-224 in cell proliferation, migration and invasion were analyzed with pre-miR-224 transfected cells. In addition, the regulation of SMAD4 by miR-224 was evaluated by qRT-PCR, Western blotting and luciferase reporter assays. RESULTS: In the present study, we demonstrated that miR-224 was significantly up-regulated in CRC tissue samples and associated with disease relapse and a relative poorer disease-free survival rate. Moreover, ectopic expression of miR-224 potently promoted tumor cell proliferation, migration and invasion in vitro. Furthermore, the over-expression of miR-224 in CRC cell lines decreased SMAD4 expression at the translational level and decreased SMAD4-driven luciferase-reporter activity. CONCLUSIONS: Our data suggest that miR-224 could play an oncogenic role in the cellular processes of CRC and represent a novel biomarker for tumor relapse of CRC patients. PMID- 24152491 TI - Occurrence of chronic lymphocytic leukemia in patients with chronic myelogenous leukemia. AB - Chronic lymphocytic leukemia (CLL) is the most common leukemia of adults in the western world and constitutes about 33% of all leukemia's. The incidence of CLL increases with age and are more common in older population. Chronic myeloid leukemia (CML) on the contrary occurs in both young adults and elderly and is a chronic myeloproliferative disease that originates from abnormal pluripotent stem cells and results in involvement of multiple hematopoietic lineages, but predominantly myeloid and less commonly lymphoid. Association between CLL and myeloid malignancies (CML, acute myeloid leukemia and MDS, myelodysplastic syndrome) is rare. In literature documenting CLL and CML in same patients, occur either simultaneously or CML is preceded by CLL. PMID- 24152487 TI - The causes of prescribing errors in English general practices: a qualitative study. AB - BACKGROUND: Few detailed studies exist of the underlying causes of prescribing errors in the UK. AIM: To examine the causes of prescribing and monitoring errors in general practice and provide recommendations for how they may be overcome. DESIGN AND SETTING: Qualitative interview and focus group study with purposive sampling of English general practices. METHOD: General practice staff from 15 general practices across three PCTs in England participated in a combination of semi-structured interviews (n = 34) and six focus groups (n = 46). Thematic analysis informed by Reason's Accident Causation Model was used. RESULTS: Seven categories of high-level error-producing conditions were identified: the prescriber, the patient, the team, the working environment, the task, the computer system, and the primary-secondary care interface. These were broken down to reveal various error-producing conditions: the prescriber's therapeutic training, drug knowledge and experience, knowledge of the patient, perception of risk, and their physical and emotional health; the patient's characteristics and the complexity of the individual clinical case; the importance of feeling comfortable within the practice team was highlighted, as well as the safety implications of GPs signing prescriptions generated by nurses when they had not seen the patient for themselves; the working environment with its extensive workload, time pressures, and interruptions; and computer-related issues associated with mis-selecting drugs from electronic pick-lists and overriding alerts were all highlighted as possible causes of prescribing errors and were often interconnected. CONCLUSION: Complex underlying causes of prescribing and monitoring errors in general practices were highlighted, several of which are amenable to intervention. PMID- 24152492 TI - Inhibiting valosin-containing protein suppresses osteosarcoma cell metastasis via AKT/nuclear factor of kappa B signaling pathway in vitro. AB - BACKGROUND AND AIM: The strategies of targeting valosin-containing protein (VCP) may have therapeutic potential for treating cancer metastasis. In this study, we aim to investigate the correlation of VCP protein expression in osteosarcoma (OS) tissues with pulmonary metastasis and its possible molecular mechanism. MATERIALS AND METHODS: Expression of VCP in 60 OS specimens was detected by immunohistochemistry (IHC) and the relationship with metastasis was analyzed. An artificial micro ribonucleic acid, targeting VCP, was performed to silence the expression of VCP in U2-OS cells. Cell mobility was detected by wound healing and Transwell assays. Western blot and real-time polymerase chain reaction were performed to investigate the expression of VCP in U2-OS cells. Furthermore, the protein of pAKT (phosphorylated serine/threonine protein kinase) and nuclear factor of kappa B protein 65 were measured by western blot to evaluate the effect of silencing VCP on AKT/nuclear factor of kappa B (NF-kB) signaling pathway. RESULTS: The results showed that the expression level of VCP protein in cases with pulmonary metastases was significantly higher than that in those without metastasis (P = 0.004). The invasion and migration of U2-OS cells were suppressed by silencing VCP. Furthermore, silencing VCP could down-regulate the phosphorylation of AKT and nuclear transfer of NF-kB. CONCLUSIONS: Our findings suggested that inhibition of VCP could suppress OS cells invasion and migration through down-regulating AKT/NF-kB signaling pathway. PMID- 24152493 TI - Assessment of non-invasive models for liver fibrosis in chronic hepatitis B virus related liver disease patients in resource limited settings. AB - CONTEXT: A total of 350 million individuals are affected by chronic hepatitis B virus infection world-wide. Historically, liver biopsy has been instrumental in adequately assessing patients with chronic liver disease. A number of non invasive models have been studied world-wide. AIM: The aim of this study is to assess the utility of non-invasive mathematical models of liver fibrosis in chronic hepatitis B (CHB). Indian patients in a resource limited setting using routinely performed non-invasive laboratory investigations. SETTINGS AND DESIGN: A cross-sectional study carried out at a tertiary care center. SUBJECTS AND METHODS: A total of 52 consecutive chronic liver disease patients who underwent percutaneous liver biopsy and 25 healthy controls were enrolled in the study. Routine laboratory investigations included serum aspartate aminotransferase (AST), Alanine aminotransferase (ALT), Gama glutamyl transpeptidase (GGT), total bilirubin, total cholesterol, prothrombin time and platelet count. Three non invasive models for namely aspartate aminotransferase to platelet ratio index (APRI), Fibrosis 4 (FIB-4) and Forn's index were calculated. Outcomes were compared for the assessment of best predictor of fibrosis by calculating the sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) of each index. STATISTICAL ANALYSIS USED: Medcalc online software and by Microsoft Excel Worksheet. Chi-square test was used for significance. P value < 0.05 was taken as significant. RESULTS: While the serum levels of AST, ALT and GGT were significantly higher in patients group as compare with the healthy controls (P < 0.01), the platelet counts were significantly lower in patient group as compared to the control group (P < 0.01). Mean value of all 3 indices were significantly higher in patients group as compare with the controls (P < 0.01). CONCLUSIONS: Out of the three indices, APRI index with a NPV of 95% appeared to be a better model for excluding significant liver fibrosis while FIB 4 with a PPV of 61% showed fair correlation with significant fibrosis. Thus, these two non-invasive models for predicting of liver fibrosis, namely APRI and FIB-4, can be utilized in combination as screening tools in monitoring of CHB patients, especially in resource limiting settings. PMID- 24152494 TI - The significance of microbiopsies in cytological smears. AB - BACKGROUND: The role of fine needle aspiration cytology (FNAC) in the diagnosis of malignant lesions is well documented. Conventionally obtained fine needle aspiration (FNA) smears frequently contain well preserved viable intact tissue fragments (microbiopsies). AIMS: The present study was aimed at evaluating the microbiopsies and carrying out further cyto-histopathologic correlation in order to assess what additional information they could provide. MATERIALS AND METHODS: A total of 116 FNA smears from clinically suspected malignant lesions were examined, of which 81 smears (70.0%) contained representative tissue fragments of the tumors. Histopathological details were available in 75 cases. Immunocytochemistry (ICC) was applied in selected smears as and when required. RESULTS: Tumors in which microbiopsies aided in diagnosis chiefly included soft tissue malignancies (12 cases), typed into malignant peripheral nerve sheath tumor, fibrosarcoma, spindle cell sarcoma and malignant melanoma; lung tumors (14 cases) classified as small cell carcinoma, large cell carcinoma, squamous carcinoma and adenocarcinoma; breast tumors (08 cases), typed into ductal, medullary and lobular carcinoma; and lymph node metastasis (19 cases) from primaries in lung, larynx and thyroid. The cyto-histopathologic concordance was raised from 81.2% in the absence of microbiopsies to 93.2% in their presence. CONCLUSIONS: FNA smears containing microbiopsies are of ample help in establishing firm diagnosis, tumor typing, and predicting possible primary sites in metastatic tumors which were not possible by cytology alone. Hence, this technique can be utilized to enhance the diagnostic accuracy of FNAC, if put into practice in evaluation of routine cytology smears, without increasing any financial burden on patients. PMID- 24152495 TI - Molecular and phenotypic expression of decorin as modulator of angiogenesis in human potentially malignant oral lesions and oral squamous cell carcinomas. AB - BACKGROUND: Decorin is an extracellular matrix, multifunctional small proteoglycan molecule in tumor stroma that has been shown to be modulator of angiogenesis. No clinical data is available so far on decorin expression and survival outcome of oral cancer. AIM: The aim of the present study was to examine molecular and phenotypic expression of two angiogenesis modulators viz. decorin and vascular endothelial growth factor-A (VEGF-A) in human potentially malignant oral lesions (PMOLs) and oral squamous cell carcinomas (OSCC) in relation to clinico-pathological variables and survival outcome. MATERIALS AND METHODS: Tissue biopsies were obtained from 72 PMOLs, 108 OSCC and 52 healthy controls. The PMOLs included cases of leukoplakias and oral submucous fibrosis. Immunohistochemistry was performed using antibodies against decorin, VEGF-A and CD-31. Messenger-ribonucleic acid (mRNA) expression was analyzed by using real time polymerase chain reaction. RESULTS: Cytoplasmic staining of decorin was observed in the basal layer of epithelium in 53 (73.61%) cases of PMOLs and in peritumoral stroma in 55 (50.92%) cases of OSCC. None of the cases showed nuclear expression of decorin. Decorin expression both at phenotypic and molecular level was found to be down-regulated from PMOLs to OSCC. Lymph node metastasis and reduced decorin expression independently correlated with overall survival in OSCC. VEGF-A expression had no significant impact on survival outcome. CONCLUSION: Micro vessel density and VEGF-A expression were significantly associated with reduced decorin expression in tumor stroma suggesting, decorin as angiogenic modulator in OSCC. Down-regulation of decorin expression and the presence of lymph node metastasis were adverse factor independently affecting overall survival in OSCC. PMID- 24152496 TI - Clinical and histopathological characteristics of cutaneous Leishmaniasis in Sanliurfa City of Turkey including Syrian refugees. AB - BACKGROUND: The aim of our study was to investigate the clinical and histopathological characteristics of cutaneous leishmaniasis (CL) in the city of Sanliurfa in Turkey, where Syrian refugees also reside. MATERIALS AND METHODS: At the Harran University Hospital outpatient clinics between 2012 and 2013, 54 CL cases, including 24 Syrian patients, underwent punch biopsy of the skin and/or a touch imprint. Patients in whom leishmania parasites were detected were included in the study. The clinical and histopathological data of the patients were obtained by a review of the patients' medical records. All the slides of each patient were re-evaluated histopathologically. RESULTS: Fifty-four cases (mean age; 17 +/- 12 years), consisting of 32 males (59.3%) and 22 females (40.7%), were examined. The most common site of involvement was the face (63%). The most common presentation was noduloulcerative lesions (57.4%). Histopathologically, the majority of the cases exhibited hyperkeratosis, follicular plugging of the epidermis, chronic inflammatory infiltration, leishmania amastigotes and non caseating granulomatous inflammation in the dermis. CONCLUSION: CL presents with a wide spectrum of expression, both clinically and histologically, and may mimic other inflammatory and neoplastic diseases. The diagnosis of CL relies on the identification of leishmania amastigotes in either a direct smear of the lesion or in a tissue section. PMID- 24152497 TI - A comparative study of Hasford score and Sokal index in prognostication of the novo chronic myeloid leukemia patients and a search for new prognostic markers. AB - INTRODUCTION: Chronic myeloid leukemia (CML) is a common myeloproliferative disorder. Based on clinical and hematological parameters, two prognostic scoring systems, i.e., Hasford and Sokal index scoring systems are available to predict survival duration of CML patients on imatinib therapy. AIMS AND OBJECTIVES: Our study's objective is to compare Hasford score with Sokal index for the prognostication of de novo CML patients on therapy and find out new prognostic markers. MATERIALS AND METHODS: This is a retrospective study. The study population comprised 66 patients who were followed up for 60 months. For each patient, at presentation, scoring was performed as per Hasford and Sokal index and Philadelphia chromosome analysis was carried out by conventional cytogenetics. Thereafter, hematological parameters were assessed 3 monthly and conventional cytogenetics was done yearly. RESULTS: Out of these 66 patients, the number of patients belonging to low, intermediate and high risk categories are 21, 33 and 12 respectively by Hasford score and 12, 32 and 22 respectively by Sokal index. Eight patients, who had been categorized into high risk group by Sokal index but intermediate risk group by Hasford score, have shown better survival possibility as monitored by hematological and cytogenetic parameters. Ten cases, categorized into intermediate risk group by Sokal index but low risk group by Hasford score, is doing well till date. CONCLUSIONS: This study shows that Hasford score predicts survival of the patients better than Sokal index. However, multicentric study over a large population is needed to give the final verdict. PMID- 24152498 TI - The effect of the alternative solutions to formaldehyde and xylene on tissue processing. AB - INTRODUCTION AND AIM: To assess the impact of new alternative solutions to formaldehyde and xylene on tissue processing, 13 different tissue processings were designed and performed on thirteen different tissues by using five different fixatives (formaldehyde, Glyo-Fixx(r), FineFix(r), Cell-block(r), Green-Fix(r)) and four different clearing agents (xylene, Sub-X(r), Bio-clear(r), Shandon Xylene Substitute(r)). MATERIALS AND METHODS: Hematoxylin and Eosine stained sections were compared by using qualitative histomorphological criterions. Histochemical and immunohistochemical (IHC) staining results were compared with qualitative and quantitative data obtained by a computer program, respectively. Tissue sections were tested for the availability of chromogenic in situ hybridization, deoxyribonucleic acid (DNA) and ribonucleic acid (RNA) extraction, and DNA quality by polymerase chain reaction. RESULTS: The quality of sections was well for all tissue processings. All alternative solutions were suitable for histochemistry. IHC staining results showed that alternative solutions that contain glyoxal as active agent need optimization for this application. The clearance of signals with chromogenic in situ hybridization were nearly same and well for all tissue samples. Furthermore, tissue processes that do not contain formaldehyde were found to be superior on preservation of nucleic acids. CONCLUSION: Formaldehyde-free fixatives and alternative clearing agents have potential in routine pathology and research to replace formaldehyde and xylene. PMID- 24152499 TI - Role of 30 kDa antigen of enteric bacterial pathogens as a possible arthritogenic factor in post-dysenteric reactive arthritis. AB - BACKGROUND: Reactive arthritis (ReA)/Reiter's syndrome (RS) may be caused as a sequel of infections caused by enteric bacterial pathogens, although the mechanisms through, which different pathogens cause similar disease are not clear. AIM: This study was done to look for the presence and role of any common bacterial antigen among the pathogens isolated from such patients. MATERIALS AND METHODS: A total of 51 patients of ReA and 75 controls (three groups of 25 subjects each: Group 1: Patients who did not develop arthritic complications within 3 months after bacillary dysentery/diarrhea; Group 2: Patients with other arthritic diseases and Group 3: Normal healthy subjects) were included. The isolated enteric pathogens were tested to detect the immunodominant antigens. RESULTS AND CONCLUSIONS: A common 30 kDa antigen was found to be specifically present among seven arthritogenic enteric bacterial strains belonging to three genera, Salmonella, Shigella and Hafnia. Post-dysenteric ReA patients' sera show higher levels of immunoglobulin G, immunoglobulin M and immunoglobulin A antibodies against this antigen as compared to the controls. Lymphocytes of ReA patients recognize this antigen, proliferate and produce interleukin-2 in response to this antigen more than the lymphocytes of controls. 30 kDa antigen may be a common arthritogenic factor associated with post-dysenteric ReA/RS. The association of Hafnia alvei with post-dysenteric ReA is described for the first time. Four cases of mycobacterial ReA had an association with this antigen, suggesting that the arthritogenic antigen of mycobacteria and enteric bacteria may be of a similar nature. PMID- 24152500 TI - Adhesion and virulence factor properties of Enterococci isolated from clinical samples in Iran. AB - INTRODUCTION: Enterococci rank among leading causes of nosocomial bacteremia, urinary tract infections and community acquired endocarditis. The aim of the present study was to investigate the presence of virulence factors in Enterococci strains isolated from clinical samples in Iranian Educational hospitals. METHODOLOGY: Presence of aggregation substance (asa), extracellular surface protein (esp), Enterococcus faecalis antigen A (efaA), adhesin of collagen from E. faecalis (ace), endocarditis and biofilm-associated pilli (ebp) as colonization factors and cytolysin (cyl), gelatinase (gel) and hyaloronidase (hyl) as secretary factors were investigated in isolates. A total of 201 clinical isolates of Enterococci were collected in 2009-2010 from eight educational hospitals. After deoxyribonucleic acid extraction, they were examined for presence of virulence factors by polymerase chain reaction. RESULTS: E. faecalis and Enterococcus faecium were isolated from 56.9% to 43.1%, respectively. Resistance to vancomycin and gentamicin were 33.8% and 83.9% in E. faecium isolates and 16.3% and 88.1% in E. faecalis isolates respectively. Colonization factors were found to be more prevalent in E. faecalis isolates and almost all isolates of E. faecalis had ace, ebp and efaA genes. Esp gene had a higher rate of distribution in Enterococci isolates (75.1%) in this study compared with previous studies. One of E. faecalis isolates contained hyl gene, but 38.8% of E. faecium isolates had it. Mutual exclusive were present between hyl and efaA in all E. faecium isolates and 69.7% of E. faecium hyl - positive isolates were esp positive. CONCLUSION: According to these results, virulence genes were more prevalent in E. faecalis isolates and E. faecalis had more potential pathogenesis for initiating an infection; however because of E. faeciums higher antibiotic resistance, we have been facing higher E. faecium infections in hospitalized patients. PMID- 24152501 TI - Detection of Candida albicans Sap2 in cancer patient serum samples by an indirect competitive enzyme-linked immunosorbent assay for the diagnosis of candidiasis. AB - BACKGROUND: The secreted aspartyl proteinases 2 (Sap2) of Candida albicans (C. albicans) is a potential marker of candididasis. It is a virulence factor associated with adherence and tissue invasion. AIM: In order to detect Sap2 in clinical sera, we developed an indirect competitive enzyme-linked immunosorbent assay (ELISA). MATERIALS AND METHODS: Polyclonal antibodies were produced for Sap2 by injecting Sap2 into a New Zealand White inbred rabbit. They could be used at a dilution exceeding 1:1200 in an indirect ELISA, and detected Sap2 concentration up to 1 ng/mL. RESULTS: Of the 286 cancer serum samples tested, 16.8% were found as candidiasis. The test was simple and economical to perform and had a level of sensitivity for detection of low-titer positive sera; thus, it may be proven to be of value in epidemiological studies on candidiasis. PMID- 24152502 TI - Lennert's lymphoma: clinicopathological profile of five cases. AB - BACKGROUND AND AIM: Lennert's lymphoma is a rare variant of peripheral T-cell lymphoma (PTCL) not otherwise specified (NOS) rich in epithelioid histiocytes. This study aims to analyze the clinical, morphologic, and immunophenotypic profile of cases of Lennert's lymphoma from our country and determines the utility of T-cell receptor (TCR) gene rearrangement in the diagnosis. MATERIALS AND METHODS: All cases diagnosed as Lennert's lymphoma during the period of January 2001 to August 2011 were included in this study. Hematoxylin and eosin (H and E) stained slides and immunohistochemistry results were analyzed and TCR gene rearrangement was performed. RESULTS: There were five cases of Lennert's lymphoma diagnosed in our institution during this period, which included two males and three females. All cases showed effacement of lymph node architecture by diffuse infiltration of small lymphoid T cells [CD3+, CD4+, CD8+, T-cell intracellular antigen 1 (TIA-1+), Granzyme B-] and clusters of epithelioid histiocytes throughout the lymph node and scattered large transformed cells (CD20-, CD30+, CD15-/+). TCR rearrangement was done in three cases by polymerase chain reaction (PCR) and showed the presence of a clonal T-cell population. CONCLUSIONS: Lennert's lymphoma constituted 0.11% of all non-Hodgkin lymphomas (NHLs) in our institution. Differentiation from classical Hodgkin's lymphoma is sometimes difficult by morphology and immunohistochemistry alone and TCR gene rearrangement was extremely useful in diagnosis. PMID- 24152503 TI - Differential diagnosis of cervical lymphadenitis mimicking malignancy due to tularemia: our experiences. AB - BACKGROUND: Tularemia is a disease caused by a Gram-negative coccobacillus Francisella tularensis. This bacterium may cause different types of clinical pictures owing to acquisition route and entrance site, such as ulceroglandular, oropharyngeal, glandular, pneumonic, typhoid and ocular forms. Oropharyngeal tularemia (OPT) is the most common form of tularemia in some regions. OPT may cause tonsillopharyngitis followed by cervical lymphadenopathies (LAPs). Without treatment LAP may persist for several months and may mimic other diseases causing cervical LAPs. MATERIALS AND METHODS: A total of six cases of OPT, five male and one female, between 21 and 31 years old, diagnosed serologically and clinically recorded in GATA Haydarpasa Training Hospital were included in this study. Detailed story including the region they lived for last 6 months, their occupation, family and neighborhood story with similar complaints were obtained. Patient data were also obtained from manually written patients files and electronical patient file system. Formalin fixed paraffin embedded tissue blocks of all biopsy material were submitted for polymerase chain reaction (PCR) study for F. tularensis. RESULTS: A total of six cases with head and neck mass following a story of tonsillopharyngitis admitted to different clinics including infectious diseases, ear-nose-throat and internal medicine in our tertiary care hospital. Physical examination revealed immobile, hard, conglomerated unilateral cervical lymphadenopathy in all cases. Histopathological examination revealed granulomatous inflammation in four cases. Acute suppurative inflammatory changes were also seen in two cases. Large necrotic areas mimicking casseifying necrosis were seen in two cases. PCR amplification of F. tularensis genom from isolated deoxyribonucleic acids was successful in five cases. CONCLUSION: Tularemia should be kept in mind in patients with tonsillopharyngitis not responding to penicillins and beta lactam antibiotics. Furthermore, persisting LAPs mimicking tumor with or without the story of previously experienced sore throat or tonsillopharyngitis in past few days or weeks should be evaluated for glandular or OPT. At this point, easily applicable serological tests such as tularemia micro-agglutination tests will confirm the diagnosis of OPT. However, if lymph node were already sampled to exclude especially malignancy or T cell lymphoma, tularemia PCR test may be used to make a certain diagnosis. PMID- 24152504 TI - Speciation of coagulase negative Staphylococcal isolates from clinically significant specimens and their antibiogram. AB - BACKGROUND: Despite their frequency as contaminants, coagulase-negative Staphylococci (CONS) have become important nosocomial pathogens, accounting for 9% of all nosocomial infections. These infections are difficult to treat because of the risk factors and the multiple drug resistance nature of these organisms. MATERIALS AND METHODS: One hundred and two consecutive CONS were isolated from various clinical samples like blood, pus, urine, urine catheter tip and gastric lavage. Most of the blood samples were from patients with risk factors (immunocompromised or on medical devices). After confirming the isolates as CONS, species-level identification was performed by simple, non-expensive conventional methods and antibiotic sensitivity testing was also carried out. RESULTS: Of 102 CONS isolates, 100 isolates could be identified to the species level. Among the 100 isolates, epidermidis was the most common species isolated, seen in 32%, followed by S. hemolyticus (18%), S. lugdunensis (12%), S. hominis (10%), S. saprophyticus (8%), S. capitis (6%), S. caprae (4%), S. xylosus (4%), S. cohni and S. warneri (3% each). In the present study, 56% of the isolates were methicillin-resistant CONS. Most of the isolates showed resistance to ampicillin and amoxyclav (89% each), followed by ceftriaxone (52%), cotrimoxazole (46%), cefotaxime (32%), gentamicin (25%), amikacin (21%). CONCLUSION: The increased pathogenic potential and multiple-drug resistance demonstrates the need to adopt simple, reliable and non-expensive methods for identifying and determining the antibiotic sensitivity of CONS. PMID- 24152505 TI - Evaluation of commercial boric acid containing vials for urine culture: low risk of contamination and cost effectiveness considerations. AB - BACKGROUND: Urine culture is a gold standard in the diagnosis of urinary tract infection. Clean catch midstream urine collection and prompt transportation is essential for appropriate diagnosis. Improper collection and delay in transportation leads to diagnostic dilemma. In developing countries, higher ambient temperatures further complicate the scenario. Here, we have evaluated the role of boric acid as a preservative for urine samples prior to culture in female patients attending outpatient department at our center. MATERIALS AND METHOD: Consecutive 104 urine samples were cultured simultaneously in plain uricol (Control-C) and boric acid containing tubes from Becton Dickinson urine culture kit (Boric acid group-BA). RESULTS: In the real-time evaluation, we found that in almost 57% (59/104) of the urine samples tested, it was more effective in maintaining the number of the organisms as compared to samples in the container without any preservative. Our in vitro study of simulated urine cultures revealed that urine samples could be kept up to 12 h before culture in the preservative without any inhibitory effect of boric acid. Though the use of boric acid kit may marginally increase the initial cost but has indirect effects like preventing delays in treatment and avoidance of false prescription of antibiotics. If the man-hours spent on repeat investigations are also taken into consideration, then the economic cost borne by the laboratory would also decrease manifold with the use of these containers. PMID- 24152506 TI - Prevalence of enterotoxin A and B genes in Staphylococcus aureus isolated from clinical samples and healthy carriers in Gorgan City, North of Iran. AB - BACKGROUND: Infections due to Staphylococcus aureus, a nosocomial and community acquired pathogen, is a major public health problem. Wide range of diseases caused by S. aureus from mild infections of the skin and soft tissue to life threatening diseases which is due to having several virulence factors such as enzymes, toxins and also enterotoxins. Enterotoxin A (SEA) and enterotoxin B (SEB) are superantigens and gastrointestinal toxins causing food poisoning. The sea and seb genes encode SEA and SEB, respectively. The goal of this study was determine the prevalence of sea and seb genes in S. aureus isolated from patients and healthy carriers in Gorgan city, north of Iran. MATERIALS AND METHODS: 170 isolates of S. aureus (95 from patients and 75 healthy carriers) were collected during 1 year. After identification and purification, DNA extraction was done by phenol - chloroform method. Amplification of sea and seb genes was done by specific primers and polymerase chain reaction method. RESULTS: Among the 170 isolates of S. aureus, 60.6% and 27.1% contained sea and seb genes, respectively. The frequencies of isolates containing sea and seb genes were 58.8% and 61.3%, respectively, in methicillin-resistant Staphylococcus aureus (MRSA) isolates and 23.5% and 28.6%, respectively, in methicillin-sensitive Staphylococcus aureus (MSSA) isolates which were not statistically significant. The frequency of these genes was not related to age, sex and source of isolation in the patients. CONCLUSION: This study showed that a high proportion of S. aureus isolates carried sea gene, whereas the frequency of seb gene in this region was predictable. PMID- 24152507 TI - Development and evaluation of flavi-immunoglobulin M capture enzyme-linked immunosorbent assay. AB - In this study, we report the evaluation of In-house flavi virus immunoglobulin M (IgM) capture enzyme-linked immunosorbent assay (ELISA), which can be used as a screening test to determine the infecting flavivirus serotype over the current serological methods. A panel of 88 sera (inclusive of well characterized dengue, Japanese Encephalitis (JE) and West Nile virus (WNV) positive and negative samples tested and confirmed by commercial kit) was used for evaluation of the kit. The sensitivity and specificity of the In-house capture assay versus the commercial kit for the sero-diagnosis of dengue was 100% and 87% respectively, for JE IgM, it was found to be 90% and 100% respectively, and for West Nile it was 87.5% and 90.9%. Based on the study, we concluded that this flavivirus serotyping ELISA provides rapid results and may be used as an accurate alternate to other serological tests for the specific diagnosis of flavivirus infections. PMID- 24152508 TI - Focal segmental glomerulosclerosis associated with maternally inherited diabetes and deafness: clinical pathological analysis. AB - Maternally inherited diabetes and deafness (MIDD), which is caused by an A to G substitution at position 3243 (m.3243A>G) in the transfer ribonucleic acid leucine gene, is characterized by diabetes and hearing loss. Patients with MIDD frequently have renal disease, which may precede the diagnosis of either diabetes or deafness or may be the sole manifestation of the m.3243A>G mutation. Recently, progressive renal failure was reported in adults, and a number of childhood cases of focal segmental glomerulosclerosis (FSGS) of MIDD have been reported. However, little is known about the glomerular lesions in FSGS in MIDD. In the present study, we reported two cases of FSGS associated with MIDD and studied the clinical features of the proband and her mother. PMID- 24152509 TI - Concomitant detection of biofilm and metallo-beta-lactamases production in gram negative bacilli. AB - Carbapenems are mainstay of treating serious multidrug resistant gram-negative biofilm-based infections. However, recent emergence of metallo-beta-lactamases (MbL) producing gram-negative bacilli in different parts of world may be related to gain of virulence factors associated with biofilm production. OBJECTIVES: To explore the association of MbL and biofilm production in various gram-negative bacilli. MATERIALS AND METHODS: In this study, 110 non-repetitive ceftazidime resistant gram-negative bacilli were evaluated for biofilm and MbetaL production. Biofilm forming ability of isolates obtained from various specimens was tested by the tube method. Disks of ceftazidime (30 MUg) and ceftazidime with ethylenediaminetetraacetic acid (30 MUg + 750 MUg, prepared in house) for MbetaL detection were used. Chi-square test was used to study the association between biofilm and MbetaL production. P value <0.05 was considered significant. RESULTS: 88 (80%) bacilli had shown biofilm producing ability. The association of biofilm and MbetaL was significant in cases of non-fermenters as compared to enterobacteriaceae members. CONCLUSION: The particular combination of virulence factors (biofilm and MbetaL) in bacteria may be a species specific effect which needs to be investigated at molecular level in detail. This may help in designing newer therapies based on interference with biofilm formation and thus countering clinical episodes of antibiotic resistance. PMID- 24152510 TI - Hepatic angiomyolipoma: a case report with diagnostic challenge. AB - Angiomyolipomas are rare benign tumors derived from perivascular epithelioid cells that occur frequently in kidney and rarely in the liver. We present a case of hepatic angiomyolipoma, with various clinical and radiological differential diagnoses. A 34-year-old male was found to have a palpable mass on the left side of the abdomen. Imaging showed heterogeneously enhancing mass lesion 15 cm Chi 7 cm, in the left lobe and segment 4 of the liver. Various benign and malignant diagnoses were entertained. The needle biopsy did not reveal any evidence of malignancy. Patient underwent resection of the lesion in view of the large size, which was diagnosed as angiomyolipoma. Angiomyolipoma is a benign tumor and accurate diagnosis is important to prevent overtreatment. Histology and immunohistochemistry may help in clinching the diagnosis, in proper clinical setting. PMID- 24152511 TI - Orbital solitary fibrous tumor with multinucleate giant cells: case report of an unusual finding in an uncommon tumor. AB - Solitary fibrous tumor (SFT) is a rare soft-tissue neoplasm which may occur at any site although it is more frequent in the pleura, mediastinum and lung. Orbital involvement by SFT is uncommon. Giant cells are extremely rare to be seen in a SFT and have been described to be immunoreactive for CD34. We present a case of orbital SFT with multinucleate giant cells expressing CD68 and lacking immunoreactivity for CD34. The differential diagnosis is discussed. PMID- 24152512 TI - Glomerulopathy in a patient with sarcocystis infestation. AB - To date, sarcocystis has been considered an asymptomatic infection in humans. Even though cases with glomerulonephritis have been reported in animals with sarcocystis, there have been no reports of a similar occurrence in humans. We report a case of acute proliferative glomerulonephritis and leukocytoclastic vasculitis in a patient with sarcocystis infestation. PMID- 24152513 TI - Nodular fasciitis: a diagnostic challenge. AB - Nodular fasciitis is a rare benign soft tissue tumor. The similarity in the cytological appearance of nodular fasciitis to that of pleomorphic adenoma makes it difficult to diagnose preoperatively that adds to its peculiarity. We report here a case of a middle-aged female with swelling in the neck that was diagnosed as pleomorphic adenoma on cytology. Surgical excision of the swelling was done and histopathological examination revealed it to be nodular fasciitis. This case is presented to highlight the challenge of correctly diagnosing nodular fasciitis. PMID- 24152514 TI - Hepatic metastasis with heterologous rhabdomyoblastic differentiation in a patient with gastrointestinal stromal tumor treated with imatinib. AB - Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors of the intestinal tract. In patients with locally advanced and/or metastatic GIST, the introduction of tyrosine kinase inhibitor, imatinib mesylate, has transformed the management of this previously untreatable neoplasm into a treatable entity. Approximately 80% of advanced metastatic GISTs respond to imatinib treatment. However, the majority of patients suffer disease progression at a median of 2 years due to drug resistance. Generally progressing GISTs retain their typical morphology. Herein, we report an extremely rare case of progressive metastatic GIST with heterologous rhabdomyoblastic differentiation after, imatinib mesylate treatment. We also review the relevant literature. PMID- 24152516 TI - Dermal duct tumor with prominent ductal and sebaceous differentiation. AB - Dermal duct tumor is a rare, benign tumor. Clinically, dermal duct tumor presents as a firm papule, plaque or nodule, particularly on the lower limbs or head and neck region. Dermal duct tumor is been classified as poroma. Poroma can have divergent differentiation, but showing prominent ductal and sebaceous differentiation is rare. We present a case of dermal duct tumor with prominent ductal and sebaceous differentiation arising in the scalp. A 45-year-old man with a painless slow-growing, elevated, brownish nodule on his scalp of 7-year duration was admitted to our hospital. Histopathology revealed dermal duct tumor. The neoplasm also showed prominent ductal and sebaceous differentiation. PMID- 24152515 TI - Unusual case of pulmonary renal syndrome with autopsy findings. AB - Scleroderma renal crises (SRC) is a serious complication of systemic sclerosis whose prognosis remains serious despite management with angiotensin-converting enzyme inhibitors, antihypertensives and dialysis. Pulmonary renal syndrome (PRS), characterised by diffuse alveolar hemorrhage (DAH) and SRC, is rare and carries a grave prognosis. This case report discusses the clinicopathological features of a 43-year-old male presenting with severe hypertension and rapidly progressive renal failure who subsequently developed DAH and died. The clinical course, exhaustive investigative work-up and autopsy findings led to a diagnosis of diffuse systemic sclerosis with PRS subcategorized into PRS with thrombotic microangiopathy. The index case came without a prior diagnosis of systemic sclerosis, thereby posing a serious diagnostic challenge and management issues. PMID- 24152518 TI - Chronic lymphocytic leukemia developing in a case of chronic myelogenous leukemia -accelerated phase: a rare case with review of the literature. AB - Chronic myelogenous leukemia (CML) and chronic lymphocytic leukemia (CLL) are two different and common hematological neoplasms. Their coexistence is rare, especially CLL developing in a patient of CML. Till date, only a few cases are reported and all had chronic myeloid leukemia - chronic phase earlier. We report the first case of CLL developing in a patient initially diagnosed in an accelerated phase of chronic myeloid leukemia. The clonality of both CML and CLL was proven by cytogenetic, molecular and flow cytometric studies. PMID- 24152517 TI - Placental site trophoblastic tumor in the pelvic wall: a case report and review of the literature. AB - Extra-uterine placental site trophoblastic tumor (PSTT) is extremely rare. To our knowledge, PSTT that occurs in the pelvic wall has not yet been reported. A 29 year-old woman presented with amenorrhea and irregular vaginal bleeding of 1 month. A solid tumor mass was detected by ultrasonography in the right pelvic wall. The tumor was comprised of large, polygonal tumor cells, with brisk mitosis and obvious vascular invasion. Immunohistochemical staining demonstrated that tumor cells were positive for human placental lactogen, CD146, cytokeratin, placental alkaline phosphatase, human chorionic gonadotropin were positive, the Ki-67 proliferative index was about 80%. The pathological diagnosis was PSTT. After the operation, the patient was treated with six cycles of etoposide, methotrexate, actinomycin, cyclophosphamide, and vincristine. The patient was followed for 18 months without recurrence. The report shows that extra-uterine PSTT is extremely rare and may have a good prognosis; surgical resection and adjuvant chemotherapy are good options. However, further experience to diagnose and cure this rare tumor is warranted. PMID- 24152519 TI - Pseudothrombocytopenia observed with ethylene diamine tetra acetate and citrate anticoagulants, resolved using 37 degrees C incubation and Kanamycin. AB - Pseudothrombocytopenia (PTP) is defined by falsely low platelet counts on automated analyzers caused by in vitro phenomena including large platelet aggregates in blood samples. Diagnosis and resolution of PTP is crucial as it can lead to unwarranted interventions. We discuss a case of PTP in a pre-surgical setting, which was resolved using 37 degrees C incubation and Kanamycin. PMID- 24152520 TI - Antibiotic pressure mediated selection of non-biofilm forming strain of Elizabethkingia meningosepticum causing fatal nosocomial meningitis in a term infant. AB - We describe a fatal case of hospital acquired meningitis in a term infant due to the antibiotic pressure mediated selection of Elizabethkingia meningosepticum. The antibiotics were administered for multi-drug resistant Acinetobacter baumannii infection. The strain was also phenotypically characterized for beta lactamase production, biofilm forming capability and resistance to in use disinfectants. PMID- 24152522 TI - A 1-year-old male child with recurrent respiratory infections since birth. PMID- 24152521 TI - Perinephric abscess caused by Fusarium chlamydosporum in an immunocompetent child: case report and identification of the morphologically atypical fungal strain. AB - Fusarium infections are important problem worldwide, cause a broad spectrum of infections in human including superficial infections as well as locally invasive and disseminated infections. We report a rare case of perinephric abscess caused by Fusarium chlamydosporum in a child who had a recent episode of pyelonephritis. This case illustrates the ever increasing spectrum of rare but offending pathogenic fungi in an immunocompetent host. Fungal infections should always be suspected in patients having one or the other underlying risk factor or who are unresponding to antibacterial therapy. Early diagnosis of infection with a specific pathogen may lead to changes in antifungal therapy and may be critical for an improved outcome. PMID- 24152524 TI - Angioleiomyoma of the kidney parenchyma. PMID- 24152523 TI - Ochrobactrum anthropi septicemia and pneumonia in a preterm, small for gestational age infant with multiple congenital anomalies. PMID- 24152525 TI - Adenomatoid tumor of adrenal gland: a rare case report. PMID- 24152526 TI - Pleomorphic hyalinizing angiectatic tumor exhibiting intricate branching vasculature: an interesting pattern in a rare tumor. PMID- 24152527 TI - An unusual cystic ovarian neoplasm. PMID- 24152528 TI - Primary peritoneal serous psammocarcinoma: a rare case. PMID- 24152529 TI - Primary cutaneous marginal zone lymphoma (PCMZL) presenting with heterochronous biclonal lesions. PMID- 24152530 TI - Ovarian sertoliform endometrioid carcinoma: a diagnostic dilemma. PMID- 24152531 TI - Double adenoma of the parathyroid: reinforcing the existence of this entity. PMID- 24152532 TI - Extragonadal GCT: a rare case report of sacrococcygeal pure yolk sac tumor. PMID- 24152533 TI - Diagnostic dilemma in a malignant cutaneous adnexal tumor. PMID- 24152534 TI - Nocardial mycetoma: re-infection with a different species at an unusual site--a rare case. PMID- 24152535 TI - Invasive intestinal myiasis in a young male presenting as fungating rectal mass: an unusual presentation. PMID- 24152536 TI - Physical activity and sedentary behavior among adults 60 years and older: New York City residents compared with a national sample. AB - This study describes moderate to vigorous physical activity (MVPA) and sedentary behavior among New York City (NYC) residents 60 years and older and compared with national United States' estimates. Adults aged 60 or older living in NYC (n = 760) were compared with similar aged adults from the National Health and Nutrition Examination Survey (NHANES; n = 2,451 adults). Both groups wore an ActiGraph accelerometer for one week. The NYC sample recorded 13.2, 23.8, and 37.8 mean min/day of MVPA and the NHANES sample recorded 10.6, 21.1, and 39.3, depending on the definition. Sedentary behavior averaged 9.6 hr/day for the NYC sample and 9.3 hr/day for the NHANES sample. The NYC sample spent a longer proportion of time in sedentary behavior and light activities, but more time in MVPA than the NHANES sample. Urbanicity may explain some of the differences between the two samples. PMID- 24152538 TI - Prescription sleep aid use among adults: United States, 2005-2010. AB - KEY FINDINGS: Data from the National Health and Nutrition Examination Survey, 2005-2010. About 4% of U.S. adults aged 20 and over used prescription sleep aids in the past month. The percentage of adults using a prescription sleep aid increased with age and education. More adult women (5.0%) used prescription sleep aids than adult men (3.1%). Non-Hispanic white adults were more likely to use sleep aids (4.7%) than non-Hispanic black (2.5%) and Mexican-American (2.0%) adults. Prescription sleep aid use varied by sleep duration and was highest among adults who sleep less than 5 hours (6.0%) or sleep 9 or more hours (5.3%). One in six adults with a diagnosed sleep disorder and one in eight adults with trouble sleeping reported using sleep aids. PMID- 24152537 TI - Incidence of unanticipated difficult airway using an objective airway score versus a standard clinical airway assessment: the DIFFICAIR trial - trial protocol for a cluster randomized clinical trial. AB - BACKGROUND: Pre-operative airway assessment in Denmark is based on a non-specific clinical assessment. Systematic, evidence-based and consistent airway assessment may reduce the incidence of unanticipated difficult airway management. By assessing multiple predictors for difficult airway management, the predictive value of the assessment increases. The Simplified Airway Risk Index (SARI) is a multivariate risk score for predicting difficult intubation.This study aims to compare the use of the SARI with a non-specified clinical airway assessment on predicting difficult intubation. Further, to compare the examination and registration of predictors for difficult mask ventilation with a non-specified clinical airway assessment on prediction of difficult mask ventilation. METHOD/DESIGN: We cluster-randomized 28 Danish departments of anaesthesia to airway assessment either by the SARI or by usual non-specific assessment. Data from patients' pre-operative airway assessment are registered in the Danish Anaesthesia Database. Objective scores for intubation and mask ventilation grade the severity of airway managements. The accuracy of predicting difficult intubation and mask ventilation is measured for each group. The primary outcome measure is the fraction of unanticipated difficult and easy intubation.The fraction of unanticipated difficult intubation in Denmark is 1.87%. With a stratified randomization, type 1 error risk of 5% and a power of 80%, 30 departments are required to detect or reject a 30% relative risk reduction equalling a number needed to treat of 180. Sample size estimation is adjusted for the study design and based on standards for randomization on cluster-level. With an average cluster size of 2,500 patients, 70,000 patients will be enrolled over a 1-year trial period. The database is programmed so that registration of the SARI and predictors for difficult mask ventilation are mandatory for the intervention group but invisible to controls. DISCUSSION: It is innovative to use a national clinical database as the basis for a randomized clinical trial. The method can serve as a precedent for implementation of evidence-based recommendations and database registration.The trial will forward understanding of how to predict and reduce unanticipated difficult airways and how to produce evidence-based recommendations for airway assessment and clinical database development. TRIAL REGISTRATION: (NCT01718561). PMID- 24152540 TI - Antimicrobial resistance in commensal Escherichia coli in veal calves is associated with antimicrobial drug use. AB - The aim of this study was to determine the association between farm management factors, including antimicrobial drug usage, and resistance in commensal Escherichia coli isolates from the faeces of white veal calves. Ninety E. coli isolates from one pooled sample per farm (n = 48) were tested for their phenotypical resistance against amoxicillin, tetracycline, cefotaxime, ciprofloxacin and trimethoprim/sulfamethoxazole (TMP/SMX). Logistic regression analysis revealed the following risk factors (P < 0.05); farmer wearing the same work clothes for several days [ciprofloxacin, odds ratio (OR) 2.6; tetracycline, OR 2.4], administration of trimethoprim-sulfonamide combinations (TMP/SMX, OR 3.0; amoxicillin, OR 3.1; tetracycline, OR 2.6), ?0.3 animal daily dosage per production cycle (ADD/pc), quinolones (ciprofloxacin, OR 2.8), ?1.3 ADD/pc, penicillins (ciprofloxacin, OR 3.3; tetracycline, OR 3.4), 20-40 ADD/pc, tetracyclines (tetracycline, OR 3.2) and >40 ADD/pc, tetracyclines (tetracycline, OR 13.1; amoxicillin, OR 6.5). In this study antimicrobial resistance in commensal E. coli was mainly associated with antimicrobial drug use. PMID- 24152539 TI - Interpreter-mediated diabetes consultations: a qualitative analysis of physician communication practices. AB - BACKGROUND: Patient-provider communication, in particular physicians' ability to listen to their patients, and support them in making difficult lifestyle changes, is an essential component of effective diabetes care. Clinical communication around diabetes can be especially challenging when language barriers are present, and may contribute to poor diabetes management and outcomes. Clinicians need to be aware of and address potential communication difficulties associated with interpreter-mediated consultations. The purpose of our study was to explore how physicians communicate in interpreter-mediated consultations with diabetic patients, and how their communication behaviors may impact diabetes communication and care. METHOD: We analyzed transcripts from 8 audio recorded, outpatient consultations at the Basel University Hospital general medicine outpatient clinic involving Turkish-speaking patients, German-speaking physicians, and Turkish German interpreters (both community interpreters and family members). RESULTS: Clinicians used closed questions when asking about symptoms and glucose control. When providing information and explanation, they spoke in long and complex speech turns. They often directed their speech to interpreters or became sidetracked by family members' questions or requests for information. Patients' participation in the consultation was minimal, and limited to brief answers to clinicians' questions. CONCLUSIONS: Clinicians need to be aware of common pitfalls that diminish patient-centeredness during interpreter-mediated consultations, and learn strategies to avoid them. Attention to established guidelines on triadic communication is recommended, as is hands-on training with interpreters. PMID- 24152541 TI - Accept or refuse? Factors influencing the decision-making of transplant surgeons who are offered a pancreas: results of a qualitative study. AB - BACKGROUND: Most offered pancreases are not transplanted. This study investigates the factors that inform and influence the transplant surgeon's decision to select an offered pancreas. METHODS: Semi-standardized interviews were conducted with 14 highly qualified transplant surgeons from all 14 German transplant centers performing > 5 pancreas transplantations per year. The interviews focused on medical and non-medical criteria on which the individual accept/refuse decision depends. Interviews were recorded, transcribed and underwent content analysis. RESULTS: The interviewees agreed upon certain main selection criteria, e.g. donor age, lab results, ICU stay. However, there was no consistency in judging these parameters, and clear cut-offs did not exist. The pancreas macroscopy is a pivotal factor, as well as knowing (and trusting) the donor surgeon. 3/14 surgeons reported that they had occasionally refused a pancreas because of staff shortage. Some interviewees followed a restrictive acceptance policy, whereas others preferred to accept almost any pancreas and inspect it personally before deciding. CONCLUSION: The assessment of medical donor characteristics is highly inconsistent. Both very cautious as well as very permissive acceptance policies may render the allocation process less efficient. A more standardized policy should be discussed. Finally, better training for donor surgeons seems advisable, in order to increase trust and thus pancreas utilization. PMID- 24152542 TI - Pediatric caregiver attitudes toward email communication: survey in an urban primary care setting. AB - BACKGROUND: Overall usage of email communication between patients and physicians continues to increase, due in part to expanding the adoption of electronic health records and patient portals. Unequal access and acceptance of these technologies has the potential to exacerbate disparities in care. Little is known about the attitudes of pediatric caregivers with regard to their acceptance of email as a means to communicate with their health care providers. OBJECTIVE: We conducted a survey to assess pediatric caregiver access to and attitudes toward the use of electronic communication modalities to communicate with health care providers in an urban pediatric primary care clinic. METHODS: Participants were pediatric caregivers recruited from an urban pediatric primary care clinic in Baltimore, Maryland, who completed a 35-item questionnaire in this cross-sectional study. RESULTS: Of the 229 caregivers who completed the survey (91.2% response rate), 171 (74.6%) reported that they use email to communicate with others. Of the email users, 145 respondents (86.3%) stated that they would like to email doctors, although only 18 (10.7%) actually do so. Among email users, African-American caregivers were much less likely to support the expanded use of email communication with health care providers (adjusted OR 0.34, 95% CI 0.14-0.82) as were those with annual incomes less than US $30,000 (adjusted OR 0.26, 95% CI 0.09-0.74). CONCLUSIONS: Caregivers of children have access to email and many would be interested in communicating with health care providers. However, African Americans and those in lower socioeconomic groups were much less likely to have positive attitudes toward email. PMID- 24152543 TI - Socio-economic disparities in Australian adolescents' eating behaviours. AB - OBJECTIVE: To assess the association between socio-economic position (SEP) and poor eating behaviours in a large representative sample of Australian secondary school students. DESIGN: Cross-sectional survey of students' vegetable, fruit, sugar-sweetened beverage and fast-food consumption assessed using validated instruments and collected via a web-based self-report format. SETTING: Secondary schools across all Australian states and territories. SUBJECTS: Secondary-school students (n 12 188; response rate: 54 %) aged 12-17 years participating in the 2009-10 National Secondary Students' Diet and Activity (NaSSDA) survey. RESULTS: Overall, 25 % of students reported consuming <=1 serving of vegetables/d and 29 % reported eating <=1 serving of fruit/d. Fourteen per cent of students reported drinking at least 1-2 cups of sugar-sweetened beverages/d while 9 % reported eating fast food >=3 times/week. After adjusting for other demographic factors, students of lower-SEP areas were more likely to report low intake of vegetables (F(4, 231) = 3.61, P = 0.007) and high frequency of consumption of sugar sweetened beverages (F(4, 231) = 8.41, P < 0.001) and fast food (F(4, 231) = 4.59, P = 0.001) compared with students of high-SEP neighbourhoods. A positive SEP association was found for fruit consumption among female students only (F(4, 231) = 4.20, P = 0.003). Those from lower-SEP areas were also more likely to engage in multiple poor eating behaviours (F(4, 231)=5.80, P < 0.001). CONCLUSIONS: Results suggest that socio-economic disparities in Australian adolescents' eating behaviours do exist, with students residing in lower-SEP neighbourhoods faring less well than those from high-SEP neighbourhoods. Reducing social inequalities in eating behaviours among young people should be a key consideration of future preventive strategies. PMID- 24152544 TI - TMS over V5 disrupts motion prediction. AB - Given the vast amount of sensory information the brain has to deal with, predicting some of this information based on the current context is a resource efficient strategy. The framework of predictive coding states that higher-level brain areas generate a predictive model to be communicated via feedback connections to early sensory areas. Here, we directly tested the necessity of a higher-level visual area, V5, in this predictive processing in the context of an apparent motion paradigm. We flashed targets on the apparent motion trace in-time or out-of-time with the predicted illusory motion token. As in previous studies, we found that predictable in-time targets were better detected than unpredictable out-of-time targets. However, when we applied functional magnetic resonance imaging-guided, double-pulse transcranial magnetic stimulation (TMS) over left V5 at 13-53 ms before target onset, the detection advantage of in-time targets was eliminated; this was not the case when TMS was applied over the vertex. Our results are causal evidence that V5 is necessary for a prediction effect, which has been shown to modulate V1 activity (Alink et al. 2010). Thus, our findings suggest that information processing between V5 and V1 is crucial for visual motion prediction, providing experimental support for the predictive coding framework. PMID- 24152545 TI - Less wiring, more firing: low-performing older adults compensate for impaired white matter with greater neural activity. AB - The reliable neuroimaging finding that older adults often show greater activity (over-recruitment) than younger adults is typically attributed to compensation. Yet, the neural mechanisms of over-recruitment in older adults (OAs) are largely unknown. Rodent electrophysiology studies have shown that as number of afferent fibers within a circuit decreases with age, the fibers that remain show higher synaptic field potentials (less wiring, more firing). Extrapolating to system level measures in humans, we proposed and tested the hypothesis that greater activity in OAs compensates for impaired white-matter connectivity. Using a neuropsychological test battery, we measured individual differences in executive functions associated with the prefrontal cortex (PFC) and memory functions associated with the medial temporal lobes (MTLs). Using event-related functional magnetic resonance imaging, we compared activity for successful versus unsuccessful trials during a source memory task. Finally, we measured white matter integrity using diffusion tensor imaging. The study yielded 3 main findings. First, low-executive OAs showed greater success-related activity in the PFC, whereas low-memory OAs showed greater success-related activity in the MTLs. Second, low-executive OAs displayed white-matter deficits in the PFC, whereas low memory OAs displayed white-matter deficits in the MTLs. Finally, in both prefrontal and MTL regions, white-matter decline and success-related activations occurred in close proximity and were negatively correlated. This finding supports the less-wiring-more-firing hypothesis, which provides a testable account of compensatory over-recruitment in OAs. PMID- 24152546 TI - Pre-diagnosis oophorectomy, estrogen therapy and mortality in a cohort of women diagnosed with breast cancer. AB - INTRODUCTION: Pre-diagnosis oophorectomy and estrogen therapy could impact mortality due to breast cancer and cardiovascular disease (CVD) among breast cancer survivors. Elective bilateral oophorectomy at the time of hysterectomy for benign conditions is not uncommon among US women. METHODS: We examined the association between pre-diagnosis total abdominal hysterectomy with bilateral salpingooophorectomy (TAHBSO) and both overall and cause-specific mortality in the Collaborative Breast Cancer Studies cohort. Medical history and prior estrogen use were collected during standardized telephone interviews. Vital status, including date and cause of death, was obtained by linkage with the National Death Index. Multivariate hazard ratios (HR) and 95% confidence intervals (CI) for cause-specific mortality were calculated using Cox proportional hazards regression. RESULTS: Seventeen percent (N = 1,778) of breast cancer survivors (mean age at diagnosis = 63.5) reported pre-diagnosis TAHBSO. During follow-up (mean = 9.5 years), 2,856 deaths occurred, including 1,060 breast cancer deaths and 459 CVD deaths. Breast cancer deaths occurred a median of 5.1 years after diagnosis; CVD deaths occurred further from diagnosis (median = 9.7 years). Women who reported pre-diagnosis TAHBSO had a 16% decrease in all cause mortality (HR = 0.84; 95% CI: 0.76, 0.92) compared to those with an intact uterus and ovaries. This overall decrease reflected a 27% lower breast cancer mortality among women who never used postmenopausal hormones (HR = 0.73; CI: 0.55, 0.96) and 43% lower CVD risk among women who reported using estrogen (HR = 0.57; CI: 0.39, 0.83) after TAHBSO. CONCLUSIONS: Information on prior TAHBSO and estrogen use can inform risk of death fromboth breast cancer and cardiovascular disease among breast cancer survivors. PMID- 24152547 TI - Structural and functional analysis of Utp23, a yeast ribosome synthesis factor with degenerate PIN domain. AB - During synthesis of yeast ribosome, a large complex, called the 90S pre-ribosome or the small subunit processome, is assembled on the nascent precursor rRNA and mediates early processing of 18S rRNA. The Utp23 protein and snR30 H/ACA snoRNA are two conserved components of 90S pre-ribosomes. Utp23 contains a degenerate PIN nuclease domain followed by a long C-terminal tail and associates specifically with snR30. Here, we report the crystal structure of the Utp23 PIN domain at 2.5-A resolution. The structure reveals a conserved core fold of PIN domain with degenerate active site residues, a unique CCHC Zn-finger motif, and two terminal extension elements. Functional sites of Utp23 have been examined with conservation analysis, mutagenesis, and in vivo and in vitro assays. Mutations in each of three cysteine ligands of zinc, although not the histidine ligand, were lethal or strongly inhibitory to yeast growth, indicating that the Zn-finger motif is required for Utp23 structure or function. The N-terminal helix extension harbors many highly conserved basic residues that mostly are critical for growth and in vitro RNA-binding activity of Utp23. Deletion of the C-terminal tail, which contains a short functionally important sequence motif, disrupted the interaction of Utp23 with snR30 and perturbed the pre-ribosomal association of Utp23. Our data establish a structural framework for dissecting Utp23 function in the assembly and dynamics of 90S pre-ribosomes. PMID- 24152549 TI - Evolutionary and ontogenetic changes in RNA editing in human, chimpanzee, and macaque brains. AB - Adenosine-to-inosine (A-to-I) substitutions are the most common type of RNA editing in mammals. A-to-I RNA editing is particularly widespread in the brain and is known to play important roles in neuronal functions. In this study we investigated RNA-editing changes during human brain development and maturation, as well as evolutionary conservation of RNA-editing patterns across primates. We used high-throughput transcriptome sequencing (RNA-seq) to quantify the RNA editing levels and assess ontogenetic dynamics of RNA editing at more than 8000 previously annotated exonic A-to-I RNA-editing sites in two brain regions- prefrontal cortex and cerebellum--of humans, chimpanzees, and rhesus macaques. We observed substantial conservation of RNA-editing levels between the brain regions, as well as among the three primate species. Evolutionary changes in RNA editing were nonetheless evident, with 40% of the annotated editing sites studied showing divergent editing levels among the three species and 16.5% of sites displaying statistically significant human-specific editing patterns. Across lifespan, we observed an increase of the RNA-editing level with advanced age in both brain regions of all three primate species. PMID- 24152548 TI - The central role of protein S12 in organizing the structure of the decoding site of the ribosome. AB - The ribosome decodes mRNA by monitoring the geometry of codon-anticodon base pairing using a set of universally conserved 16S rRNA nucleotides within the conformationally dynamic decoding site. By applying single-molecule FRET and X ray crystallography, we have determined that conditional-lethal, streptomycin dependence mutations in ribosomal protein S12 interfere with tRNA selection by allowing conformational distortions of the decoding site that impair GTPase activation of EF-Tu during the tRNA selection process. Distortions in the decoding site are reversed by streptomycin or by a second-site suppressor mutation in 16S rRNA. These observations encourage a refinement of the current model for decoding, wherein ribosomal protein S12 and the decoding site collaborate to optimize codon recognition and substrate discrimination during the early stages of the tRNA selection process. PMID- 24152550 TI - Genome-wide analysis of poly(A) site selection in Schizosaccharomyces pombe. AB - Polyadenylation of pre-mRNAs, a critical step in eukaryotic gene expression, is mediated by cis elements collectively called the polyadenylation signal. Genome wide analysis of such polyadenylation signals was missing in fission yeast, even though it is an important model organism. We demonstrate that the canonical AATAAA motif is the most frequent and functional polyadenylation signal in Schizosaccharomyces pombe. Using analysis of RNA-Seq data sets from cells grown under various physiological conditions, we identify 3' UTRs for nearly 90% of the yeast genes. Heterogeneity of cleavage sites is common, as is alternative polyadenylation within and between conditions. We validated the computationally identified sequence elements likely to promote polyadenylation by functional assays, including qRT-PCR and 3'RACE analysis. The biological importance of the AATAAA motif is underlined by functional analysis of the genes containing it. Furthermore, it has been shown that convergent genes require trans elements, like cohesin for efficient transcription termination. Here we show that convergent genes lacking cohesin (on chromosome 2) are generally associated with longer overlapping mRNA transcripts. Our bioinformatic and experimental genome-wide results are summarized and can be accessed and customized in a user-friendly database Pomb(A). PMID- 24152551 TI - SHAPE analysis of the 5' end of the Mason-Pfizer monkey virus (MPMV) genomic RNA reveals structural elements required for genome dimerization. AB - Earlier genetic and structural prediction analyses revealed that the packaging determinants of Mason Pfizer monkey virus (MPMV) include two discontinuous core regions at the 5' end of its genomic RNA. RNA secondary structure predictions suggested that these packaging determinants fold into several stem-loops (SLs). To experimentally validate this structural model, we employed selective 2' hydroxyl acylation analyzed by primer extension (SHAPE), which examines the flexibility of the RNA backbone at each nucleotide position. Our SHAPE data validated several predicted structural motifs, including U5/Gag long-range interactions (LRIs), a stretch of single-stranded purine (ssPurine)-rich region, and a distinctive G-C-rich palindromic (pal) SL. Minimum free-energy structure predictions, phylogenetic, and in silico modeling analyses of different MPMV strains revealed that the U5 and gag sequences involved in the LRIs differ minimally within strains and maintain a very high degree of complementarity. Since the pal SL forms a helix loop containing a canonical "GC" dyad, it may act as a RNA dimerization initiation site (DIS), enabling the virus to package two copies of its genome. Analyses of wild-type and pal mutant RNAs revealed that disruption of pal sequence strongly affected RNA dimerization. However, when in vitro transcribed trans-complementary pal mutants were incubated together showed RNA dimerization was restored authenticating that the pal loop (5'-CGGCCG-3') functions as DIS. PMID- 24152552 TI - Genome-wide identification of mRNAs associated with the protein SMN whose depletion decreases their axonal localization. AB - Spinal muscular atrophy is a neuromuscular disease resulting from mutations in the SMN1 gene, which encodes the survival motor neuron (SMN) protein. SMN is part of a large complex that is essential for the biogenesis of spliceosomal small nuclear RNPs. SMN also colocalizes with mRNAs in granules that are actively transported in neuronal processes, supporting the hypothesis that SMN is involved in axonal trafficking of mRNPs. Here, we have performed a genome-wide analysis of RNAs present in complexes containing the SMN protein and identified more than 200 mRNAs associated with SMN in differentiated NSC-34 motor neuron-like cells. Remarkably, ~30% are described to localize in axons of different neuron types. In situ hybridization and immuno-fluorescence experiments performed on several candidates indicate that these mRNAs colocalize with the SMN protein in neurites and axons of differentiated NSC-34 cells. Moreover, they localize in cell processes in an SMN-dependent manner. Thus, low SMN levels might result in localization deficiencies of mRNAs required for axonogenesis. PMID- 24152553 TI - Permissive Schwann cell graft/spinal cord interfaces for axon regeneration. AB - The transplantation of autologous Schwann cells (SCs) to repair the injured spinal cord is currently being evaluated in a clinical trial. In support, this study determined properties of spinal cord/SC bridge interfaces that enabled regenerated brainstem axons to cross them, possibly leading to improvement in rat hindlimb movement. Fluid bridges of SCs and Matrigel were placed in complete spinal cord transections. Compared to pregelled bridges of SCs and Matrigel, they improved regeneration of brainstem axons across the rostral interface. The regenerating brainstem axons formed synaptophysin(+) bouton-like terminals and contacted MAP2A(+) dendrites at the caudal interface. Brainstem axon regeneration was directly associated with glial fibrillary acidic protein (GFAP(+)) astrocyte processes that elongated into the SC bridge. Electron microscopy revealed that axons, SCs, and astrocytes were enclosed together within tunnels bounded by a continuous basal lamina. Neuroglycan (NG2) expression was associated with these tunnels. One week after injury, the GFAP(+) processes coexpressed nestin and brain lipid-binding protein, and the tips of GFAP(+)/NG2(+) processes extended into the bridges together with the regenerating brainstem axons. Both brainstem axon regeneration and number of GFAP(+) processes in the bridges correlated with improvement in hindlimb locomotion. Following SCI, astrocytes may enter a reactive state that prohibits axon regeneration. Elongation of astrocyte processes into SC bridges, however, and formation of NG2(+) tunnels enable brainstem axon regeneration and improvement in function. It is important for spinal cord repair to define conditions that favor elongation of astrocytes into lesions/transplants. PMID- 24152557 TI - Integrated metagenomic and metatranscriptomic analyses of microbial communities in the meso- and bathypelagic realm of north pacific ocean. AB - Although emerging evidence indicates that deep-sea water contains an untapped reservoir of high metabolic and genetic diversity, this realm has not been studied well compared with surface sea water. The study provided the first integrated meta-genomic and -transcriptomic analysis of the microbial communities in deep-sea water of North Pacific Ocean. DNA/RNA amplifications and simultaneous metagenomic and metatranscriptomic analyses were employed to discover information concerning deep-sea microbial communities from four different deep-sea sites ranging from the mesopelagic to pelagic ocean. Within the prokaryotic community, bacteria is absolutely dominant (~90%) over archaea in both metagenomic and metatranscriptomic data pools. The emergence of archaeal phyla Crenarchaeota, Euryarchaeota, Thaumarchaeota, bacterial phyla Actinobacteria, Firmicutes, sub phyla Betaproteobacteria, Deltaproteobacteria, and Gammaproteobacteria, and the decrease of bacterial phyla Bacteroidetes and Alphaproteobacteria are the main composition changes of prokaryotic communities in the deep-sea water, when compared with the reference Global Ocean Sampling Expedition (GOS) surface water. Photosynthetic Cyanobacteria exist in all four metagenomic libraries and two metatranscriptomic libraries. In Eukaryota community, decreased abundance of fungi and algae in deep sea was observed. RNA/DNA ratio was employed as an index to show metabolic activity strength of microbes in deep sea. Functional analysis indicated that deep-sea microbes are leading a defensive lifestyle. PMID- 24152558 TI - Purified brominated indole derivatives from Dicathais orbita induce apoptosis and cell cycle arrest in colorectal cancer cell lines. AB - Dicathais orbita is a large Australian marine gastropod known to produce bioactive compounds with anticancer properties. In this research, we used bioassay guided fractionation from the egg mass extract of D. orbita using flash column chromatography and identified fractions containing tyrindoleninone and 6 bromoisatin as the most active against colon cancer cells HT29 and Caco-2. Liquid chromatography coupled with mass spectrometry (LCMS) and 1H NMR were used to characterize the purity and chemical composition of the isolated compounds. An MTT assay was used to determine effects on cell viability. Necrosis and apoptosis induction using caspase/LDH assay and flow cytometry (PI/Annexin-V) and cell cycle analysis were also investigated. Our results show that semi-purified 6 bromoisatin had the highest anti-cancer activity by inhibiting cell viability (IC50 = ~100 uM) and increasing caspase 3/7 activity in both of the cell lines at low concentration. The fraction containing 6-bromoisatin induced 77.6% apoptosis and arrested 25.7% of the cells in G2/M phase of cell cycle in HT29 cells. Tyrindoleninone was less potent but significantly decreased the viability of HT29 cells at IC50 = 390 uM and induced apoptosis at 195 uM by increasing caspase 3/7 activity in these cells. This research will facilitate the development of these molluscan natural products as novel complementary medicines for colorectal cancer. PMID- 24152559 TI - Evaluation of passive samplers as a monitoring tool for early warning of Dinophysis toxins in shellfish. AB - From June 2006 to January 2007 passive samplers (solid phase adsorbing toxin tracking, SPATT) were tested as a monitoring tool with weekly monitoring of phytoplankton and toxin content (liquid chromatography-mass spectrometry, LC-MS) in picked cells of Dinophysis and plankton concentrates. Successive blooms of Dinophysis acuminata, D. acuta and D. caudata in 2006 caused a long mussel harvesting closure (4.5 months) in the Galician Rias (NW Spain) and a record (up to 9246 ng.g resin-week-1) accumulation of toxins in SPATT discs. Best fit of a toxin accumulation model was between toxin accumulation in SPATT and the product of cell densities by a constant value, for each species of Dinophysis, of toxin content (average) in picked cells. Detection of Dinophysis populations provided earlier warning of oncoming diarrhetic shellfish poisoning (DSP) outbreaks than the SPATT, which at times overestimated the expected toxin levels in shellfish because: (i) SPATT accumulated toxins did not include biotransformation and depuration loss terms and (ii) accumulation of toxins not available to mussels continued for weeks after Dinophysis cells were undetectable and mussels were toxin-free. SPATT may be a valuable environmental monitoring and research tool for toxin dynamics, in particular in areas with no aquaculture, but does not provide a practical gain for early warning of DSP outbreaks. PMID- 24152560 TI - Functional metabolomics uncovers metabolic alterations associated to severe oxidative stress in MCF7 breast cancer cells exposed to ascididemin. AB - Marine natural products are a source of promising agents for cancer treatment. However, there is a need to improve the evaluation of their mechanism of action in tumors. Metabolomics of the response to anti-tumor agents is a tool to reveal candidate biomarkers and metabolic targets. We used two-dimensional high resolution magic angle spinning proton-NMR spectroscopy-based metabolomics to investigate the response of MCF7 breast cancer cells to ascididemin, a marine alkaloid and lead molecule for anti-cancer treatment. Ascididemin induced severe oxidative stress and apoptosis within 48 h of exposure. Thirty-three metabolites were quantified. Metabolic response involved downregulation of glycolysis and the tricarboxylic acid cycle, and phospholipid metabolism alterations. Candidate metabolic biomarkers of the response of breast cancer cells to ascididemin were proposed including citrate, gluconate, polyunsaturated fatty acids, glycerophospho-choline and -ethanolamine. In addition, candidate metabolic targets were identified. Overall, the response to Asc could be related to severe oxidative stress and anti-inflammatory effects. PMID- 24152561 TI - Biosynthesis of polyunsaturated fatty acids in marine invertebrates: recent advances in molecular mechanisms. AB - Virtually all polyunsaturated fatty acids (PUFA) originate from primary producers but can be modified by bioconversions as they pass up the food chain in a process termed trophic upgrading. Therefore, although the main primary producers of PUFA in the marine environment are microalgae, higher trophic levels have metabolic pathways that can produce novel and unique PUFA. However, little is known about the pathways of PUFA biosynthesis and metabolism in the levels between primary producers and fish that are largely filled by invertebrates. It has become increasingly apparent that, in addition to trophic upgrading, de novo synthesis of PUFA is possible in some lower animals. The unequivocal identification of PUFA biosynthetic pathways in many invertebrates is complicated by the presence of other organisms within them. These organisms include bacteria and algae with PUFA biosynthesis pathways, and range from intestinal flora to symbiotic relationships that can involve PUFA translocation to host organisms. This emphasizes the importance of studying biosynthetic pathways at a molecular level, and the continual expansion of genomic resources and advances in molecular analysis is facilitating this. The present paper highlights recent research into the molecular and biochemical mechanisms of PUFA biosynthesis in marine invertebrates, particularly focusing on cephalopod molluscs. PMID- 24152563 TI - Identification of two novel anti-fibrotic benzopyran compounds produced by engineered strains derived from Streptomyces xiamenensis M1-94P that originated from deep-sea sediments. AB - The benzopyran compound obtained by cultivating a mangrove-derived strain, Streptomyces xiamenensis strain 318, shows multiple biological effects, including anti-fibrotic and anti-hypertrophic scar properties. To increase the diversity in the structures of the available benzopyrans, by means of biosynthesis, the strain was screened for spontaneous rifampicin resistance (Rif), and a mutated rpsL gene to confer streptomycin resistance (Str), was introduced into the S. xiamenensis strain M1-94P that originated from deep-sea sediments. Two new benzopyran derivatives, named xiamenmycin C (1) and D (2), were isolated from the crude extracts of a selected Str-Rif double mutant (M6) of M1-94P. The structures of 1 and 2 were identified by analyzing extensive spectroscopic data. Compounds 1 and 2 both inhibit the proliferation of human lung fibroblasts (WI26), and 1 exhibits better anti-fibrotic activity than xiamenmycin. Our study presents the novel bioactive compounds isolated from S. xiamenensis mutant strain M6 constructed by ribosome engineering, which could be a useful approach in the discovery of new anti-fibrotic compounds. PMID- 24152562 TI - Assessment of dual life stage antiplasmodial activity of british seaweeds. AB - Terrestrial plants have proven to be a prolific producer of clinically effective antimalarial drugs, but the antimalarial potential of seaweeds has been little explored. The main aim of this study was to assess the in vitro chemotherapeutical and prophylactic potential of the extracts of twenty-three seaweeds collected from the south coast of England against blood stage (BS) and liver stage (LS) Plasmodium parasites. The majority (14) of the extracts were active against BS of P. falciparum, with brown seaweeds Cystoseira tamariscifolia, C. baccata and the green seaweed Ulva lactuca being the most active (IC(50)s around 3 MUg/mL). The extracts generally had high selectivity indices (>10). Eight seaweed extracts inhibited the growth of LS parasites of P. berghei without any obvious effect on the viability of the human hepatoma (Huh7) cells, and the highest potential was exerted by U. lactuca and red seaweeds Ceramium virgatum and Halopitys incurvus (IC50 values 14.9 to 28.8 MUg/mL). The LS-active extracts inhibited one or more key enzymes of the malarial type-II fatty acid biosynthesis (FAS-II) pathway, a drug target specific for LS. Except for the red seaweed Halopitys incurvus, all LS-active extracts showed dual activity versus both malarial intracellular stage parasites. This is the first report of LS antiplasmodial activity and dual stage inhibitory potential of seaweeds. PMID- 24152564 TI - Red algal bromophenols as glucose 6-phosphate dehydrogenase inhibitors. AB - Five bromophenols isolated from three Rhodomelaceae algae (Laurencia nipponica, Polysiphonia morrowii, Odonthalia corymbifera) showed inhibitory effects against glucose 6-phosphate dehydrogenase (G6PD). Among them, the symmetric bromophenol dimer (5) showed the highest inhibitory activity against G6PD. PMID- 24152565 TI - Trypanocidal activity of marine natural products. AB - Marine natural products are a diverse, unique collection of compounds with immense therapeutic potential. This has resulted in these molecules being evaluated for a number of different disease indications including the neglected protozoan diseases, human African trypanosomiasis and Chagas disease, for which very few drugs are currently available. This article will review the marine natural products for which activity against the kinetoplastid parasites; Trypanosoma brucei brucei, T.b. rhodesiense and T. cruzi has been reported. As it is important to know the selectivity of a compound when evaluating its trypanocidal activity, this article will only cover molecules which have simultaneously been tested for cytotoxicity against a mammalian cell line. Compounds have been grouped according to their chemical structure and representative examples from each class were selected for detailed discussion. PMID- 24152567 TI - Effect of cilostazol addition or clopidogrel doubling on platelet function profiles in diabetic patients undergoing a percutaneous coronary intervention. AB - BACKGROUND: We investigated the pharmacodynamic effect of cilostazol addition (100 mg twice, Triple) or clopidogrel doubling (150 mg daily, Double) on standard dual antiplatelet therapy in type 2 diabetes mellitus (T2DM) patients with clopidogrel resistance undergoing a percutaneous coronary intervention. METHODS AND RESULTS: This was a prospective, randomized, cross-over platelet function study. Percent inhibition less than 20% was used as the cutoff value of clopidogrel resistance. After percutaneous coronary intervention, a total of 50 T2DM patients with clopidogrel resistance were assigned to receive cilostazol 100 mg twice daily or clopidogrel 150 mg daily for 28 days; afterwards, they received cross-over treatment for another 28 days. Eight patients were excluded because of side effects and follow-up loss. The platelet function test using VerifyNow was performed at three time points: at baseline (T0), 28 days after randomization (T1), and 28 days after cross-over treatment (T2).A total of 42 T2DM patients completed the study protocol. The clopidogrel resistance improved significantly following cilostazol addition or clopidogrel doubling treatment compared with baseline (52.9+/-27.0 in Triple, 45.4+/-16.8% in Double, P<0.001 in both). This effect continued after cross-over treatment (58.1+/-26.1 and 41.0+/-20.0%, respectively, both P<0.05). A head-to-head comparison between two groups showed a lower P2Y12 reaction unit (PRU) and higher percentage of platelet inhibition in the Triple than those in the Double group (PRU, 138.7+/-88.2 vs. 198.8+/-19.5, P=0.049; %platelet inhibition, 58.1+/-26.1 vs. 40.97+/-20.0, P=0.048). CONCLUSION: Adjunctive treatment with cilostazol in T2DM patients on standard dual antiplatelet therapy might be a more effective strategy for overcoming clopidogrel resistance than clopidogrel doubling treatment. PMID- 24152566 TI - Anti-inflammatory activities of natural products isolated from soft corals of Taiwan between 2008 and 2012. AB - This review reports details on the natural products isolated from Taiwan soft corals during the period 2008-2012 focusing on their in vitro and/or in vivo anti inflammatory activities. Chemical structures, names, and literature references are also reported. This review provides useful and specific information on potent anti-inflammatory marine metabolites for future development of immune-modulatory therapeutics. PMID- 24152568 TI - Triterpenoid saponins from the roots of Clematis uncinata. AB - Eight new bisdesmosidic triterpenoid saponins, clematiunicinosides A-H (1-8), along with eleven known ones (9-19), were isolated from the roots of Clematis uncinata. Their structures were elucidated on the basis of spectroscopic analysis and chemical evidence. All the isolated saponins were tested for their cytotoxic activities on human caski cervical cancer (Caski) cells, and compounds 13, 17 and 19 exhibited inhibitory effect on Caski cells. PMID- 24152569 TI - Mechanistic beliefs determine adherence to the Markov property in causal reasoning. AB - What kind of information do people use to make predictions? Causal Bayes nets theory implies that people should follow structural constraints like the Markov property in the form of the screening-off rule, but previous work shows little evidence that people do. We tested six hypotheses that attempt to explain violations of screening off, some by asserting that people use mechanistic knowledge to infer additional latent structure. In three experiments, we manipulated whether the causal relations among variables within a causal structure were supported by the same or different mechanisms. The experiments differed in the type of causal structures (common cause vs. chain), the way that causal structures were presented (verbal description vs. observational learning), how the mechanisms were presented (explicit description vs. implicit description vs. visual hint), and the number of predictions requested (2 vs. 24). The results revealed that the screening-off rule was violated more often when the mechanisms were the same than when they were different. The findings suggest that people use knowledge about underlying mechanisms to infer latent structure for prediction. PMID- 24152570 TI - Peer mentoring: evaluation of a novel programme in paediatrics. AB - BACKGROUND: Mentoring is important for personal and professional development of doctors. Peer mentoring is a core skill in the UK paediatric postgraduate curriculum. However, there is a paucity of peer mentoring programmes aimed at postgraduate doctors in training (postgraduate trainees), and there are no such schemes within paediatrics described in the literature. We developed a regional peer mentoring programme for postgraduate trainees in paediatrics to assess demand and need for peer mentoring and to explore the benefits for both peer mentees and mentors. PROGRAMME DESIGN: Junior postgraduate trainees, randomly selected from volunteers, received peer mentoring from more senior trainees for 1 year. Peer mentors were selected by competitive application and undertook tailored training followed by an experiential learning programme. The programme was evaluated using structured questionnaires. RESULTS: 90% (76/84) of first-year postgraduate trainees in paediatrics applied to participate, demonstrating high demand. 18 peer mentor-mentee pairs were matched. Peer mentors and mentees reported high satisfaction rates, acquisition of new and transferable skills and changed behaviours. All peer mentors intended to use the skills in their workplace and, later, as an educational supervisor. CONCLUSIONS: Our programme represents a novel approach to meeting the demonstrated demand and the curriculum requirement for peer mentoring, and enabled peer mentors and mentees to develop a valuable and versatile skill set. To our knowledge, it is the first such programme in paediatrics and provides a feasibility model that may be adapted locally to allow education providers to offer this important experience to postgraduate trainees. PMID- 24152571 TI - Vitamin D deficiency: are we preventing the preventable? PMID- 24152572 TI - Are school physical activity characteristics associated with weight status in primary school children? A multilevel cross-sectional analysis of routine surveillance data. AB - BACKGROUND: The school environment potentially influences the development of childhood obesity. Changes to schooling could be used as an intervention to reduce obesity but the features of the school environment that influence obesity are unknown. AIM: To estimate the interschool variation in body mass index (BMI) z-scores in primary school children and examine the individual and school physical activity characteristics contributing to this. METHODS: Cross-sectional analysis and multilevel modelling at individual and school level, with BMI SD scores (z-scores) as the outcome. Individual and school data were obtained for 11 118 reception year children (age 4-5) and 10 151 year 6 children (age 10-11) from 296 primary schools in Birmingham. Data sources were the UK National Child Measurement Programme and the annual National School Sport Survey in 2006/7. RESULTS: In reception year children, 4.2% of the variation in BMI z-scores is attributed to differences between schools. Individual characteristics explained 24% of this between-school variation and certain school physical activity characteristics (the time schools devote to physical education) explained a further 28%. In year 6 children, only 0.9% of the variation in BMI z-scores was between-school variation. BMI z-scores were significantly higher in year 6 than reception year children, with the largest increases between year groups in the South Asian and African-Caribbean ethnic groups. Deprivation was positively associated with BMI z-scores. CONCLUSIONS: In addition to the association between individual characteristics and BMI z-score, there is a small but significant association between school characteristics and BMI z-score, which is in part explained by the time schools devote to physical education. This modest school effect has the potential to have a substantial impact on children's weight status at a population level. PMID- 24152573 TI - In situ sonosynthesis of nano TiO2 on cotton fabric. AB - Here, titanium dioxide nanoparticles (NPs) were sonosynthesized and loaded simultaneously onto the cotton fabric. Titanium tetra isopropoxide (TTIP) was used as precursor and ultrasonic irradiation was utilized as a tool for synthesis of TiO2 in low temperature with anatase structure and loading nanoparticles onto the cotton fabric. TiO2 loaded cotton fabric was characterized by XRD, FE-SEM, EDS, and XRF. Moreover, several properties of the treated cotton fabrics such as self-cleaning, UV protection, washing durability, and tensile strength were studied. The effect of variables, including TTIP concentration and sonication time, was investigated based on central composite design (CCD) and response surface methodology (RSM). The results confirmed formation of anatase TiO2 nanoparticles with 3-6 nm crystalline size loaded onto the cotton fabric at low temperature (75 degrees C) that led to good self-cleaning and UV-protection properties. The excellent UV-protection rating of the treated fabric maintained even after 25 home launderings indicating an excellent washing durability. Interestingly, sonochemical method had no negative influence on the cotton fabric structure. The statistical analysis indicated significant effect of both TTIP concentration and sonication time on the content of the loaded TiO2 on the fiber and self-cleaning properties of the fabric. PMID- 24152574 TI - Molecular epidemiology of influenza A virus infection in Cyprus in four consecutive seasons (2009 pandemic-2013). AB - The aim of this study was to investigate the epidemiology of influenza A virus infection in Cyprus from the 2009 pandemic until 2013. Pandemic influenza A(H1N1)2009 virus infections outnumbered infections with other respiratory viruses until the end of 2009. The pandemic virus was also the prevalent influenza strain during influenza season 2010-2011; however, it was completely replaced by H3N2 subtype in the next season. During the most recent influenza season, 2012-2013, the pandemic strain was once again the only influenza A virus circulating in Cyprus. Full-length neuraminidase gene sequencing revealed mutations that had previously been identified as permissive. No significant difference in the expression of the IFN-inducible genes OAS and IFIT1 were observed. The phylogenetic analysis of the neuraminidase gene sequences revealed a picture of continuous importation of influenza strains in the island of Cyprus with local circulation playing only a minor role in determining the prevalent strain of the next influenza season. PMID- 24152575 TI - Relationships between trunk muscle strength, spinal mobility, and balance performance in older adults. AB - This study investigated associations between variables of trunk muscle strength (TMS), spinal mobility, and balance in seniors. Thirty-four seniors (sex: 18 female, 16 male; age: 70 +/- 4 years; activity level: 13 +/- 7 hr/week) were tested for maximal isometric strength (MIS) of the trunk extensors, flexors, lateral flexors, rotators, spinal mobility, and steady-state, reactive, and proactive balance. Significant correlations were detected between all measures of TMS and static steady-state balance (r = .43-.57, p < .05). Significant correlations were observed between specific measures of TMS and dynamic steady state balance (r = .42-.55, p < .05). No significant correlations were found between all variables of TMS and reactive/proactive balance and between all variables of spinal mobility and balance. Regression analyses revealed that TMS explains between 1-33% of total variance of the respective balance parameters. Findings indicate that TMS is related to measures of steady-state balance which may imply that TMS promoting exercises should be integrated in strength training for seniors. PMID- 24152576 TI - Effectiveness of olive oil for the prevention of pressure ulcers caused in immobilized patients within the scope of primary health care: study protocol for a randomized controlled trial. AB - BACKGROUND: Pressure ulcers are considered an important issue, mainly affecting immobilized older patients. These pressure ulcers increase the care burden for the professional health service staff as well as pharmaceutical expenditure. There are a number of studies on the effectiveness of different products used for the prevention of pressure ulcers; however, most of these studies were carried out at a hospital level, basically using hyperoxygenated fatty acids (HOFA). There are no studies focused specifically on the use of olive-oil-based products and therefore this research is intended to find the most cost-effective treatment and achieve an alternative treatment. METHODS/DESIGN: The main objective is to assess the effectiveness of olive oil, comparing it with HOFA, to treat immobilized patients at home who are at risk of pressure ulcers. As a secondary objective, the cost-effectiveness balance of this new application with regard to the HOFA will be assessed. The study is designed as a noninferiority, triple blinded, parallel, multi-center, randomized clinical trial. The scope of the study is the population attending primary health centers in Andalucia (Spain) in the regional areas of Malaga, Granada, Seville, and Cadiz. Immobilized patients at risk of pressure ulcers will be targeted. The target group will be treated by application of an olive-oil-based formula whereas the control group will be treated by application of HOFA to the control group. The follow-up period will be 16 weeks. The main variable will be the presence of pressure ulcers in the patient. Secondary variables include sociodemographic and clinical information, caregiver information, and whether technical support exists. Statistical analysis will include the Kolmogorov-Smirnov test, symmetry and kurtosis analysis, bivariate analysis using the Student's t and chi-squared tests as well as the Wilcoxon and the Man-Whitney U tests, ANOVA and multivariate logistic regression analysis. DISCUSSION: The regular use of olive-oil-based formulas should be effective in preventing pressure ulcers in immobilized patients, thus leading to a more cost-effective product and an alternative treatment. TRIAL REGISTRATION: Clinicaltrials.gov identifier: NCT01595347. PMID- 24152578 TI - Use of electronic health records in residential care communities. AB - KEY FINDINGS: In 2010, only 17% of residential care communities in the United States used electronic health records. Residential care communities that used electronic health records were more likely to be larger, not-for-profit, chain affiliated, colocated with another care setting, and in a nonmetropolitan statistical area. The types of information most commonly tracked electronically by residential care communities that used electronic health records were medical provider information, resident demographics, individual service plans, and lists of residents' medications and active medication allergies. Four in 10 residential care communities that used electronic health records also had support for electronic exchange of health information with service providers; nearly 25% could exchange with pharmacies, and 17% could exchange with physicians. PMID- 24152577 TI - Changes of neuregulin-1 (NRG-1) expression in a rat model of overactive bladder induced by partial urethral obstruction: is NRG-1 a new biomarker of overactive bladder? AB - BACKGROUND: To determine whether neuregulin-1(NRG-1) is a potential new biomarker of overactive bladder (OAB) induced by partial urethral obstruction in a rat model of OAB and to evaluate the urothelium as a therapeutic target of OAB. METHODS: Female Sprague-Dawley rats were separated into three 20-animal groups: normal, OAB, and 5-hydroxymethyl tolterodine (5-HMT)-treated OAB. In the OAB and OAB + 5-HMT groups, the urethra of each animal was partially obstructed; the OAB + 5-HMT group received intravenous 5-HMT for 3 weeks. At the conclusion of the 5 HMT dosing, the rats in each group underwent cystometrography, and the bladders were histologically evaluated. The expression of brain derived-neurotrophic factor (BDNF) and NRG-1 were evaluated in the urothelium. RESULTS: Compared with the control group, the OAB group showed a markedly increased bladder weight and a significant decrease in the micturition interval and volume; rats in the OAB + 5 HMT group showed decreased bladder weights and an improved micturition interval and volume. BDNF and NRG-1 were expressed at significantly higher levels in the OAB group, and were significantly reduced in the OAB + 5-HMT group compared with the control group. CONCLUSIONS: The study suggests that NRG-1 is a potential new biomarker of OAB; the urothelium might be a therapeutic target for OAB treatment. PMID- 24152579 TI - Pulmonary fungus ball caused by Penicillium capsulatum in a patient with type 2 diabetes: a case report. AB - BACKGROUND: Following the recent transfer of all accepted species of Penicillium subgenus Biverticillium to Talaromyces (including Talaromyces marneffei, formerly Penicillium marneffei), Penicillium species are becoming increasingly rare causal agents of invasive infections. Herein, we present a report of a type 2 diabetes patient with a fungus ball in the respiratory tract caused by Penicillium capsulatum. CASE PRESENTATION: A 56-year-old Chinese female gardener with a 5 year history of type 2 diabetes presented at the Shanghai Changzheng Hospital with fever, a cough producing yellow-white sputum, and fatigue. The therapeutic effect of cefoxitin was poor. An HIV test was negative, but the beta-D-glucan test was positive (459.3 pg/ml). Chest radiography revealed a cavitary lesion in the left upper lobe, and a CT scan showed globate cavities with a radiopaque, gravity-dependent ball. The histopathologic features of the tissue after haematoxylin-eosin staining showed septate hyphae. The fungus was isolated from the gravity-dependent ball and identified as Penicillium capsulatum based on the morphological analysis of microscopic and macroscopic features and on ribosomal internal transcribed spacer sequencing. After surgery, the patient was cured with a sequential treatment of fluconazole 400 mg per day for 90 days and caspofungin 70 mg per day for 14 days. CONCLUSIONS: Although the prognosis is often satisfactory, clinicians, mycologists and epidemiologists should be aware of the possibility of infection by this uncommon fungal pathogen in diabetes patients, since it may cause severe invasive infections in immunocompromised hosts such as diabetes and AIDS patients. PMID- 24152581 TI - MicroRNA-210 overexpression induces angiogenesis and neurogenesis in the normal adult mouse brain. AB - Angiogenesis and neurogenesis are crucial processes for brain tissue repair and remodeling after brain injury. Current study shows that microRNA-210 (miR-210) promotes vascular endothelial cell migration and tube formation under hypoxia in vitro. Whether miR-210 overexpression promotes focal angiogenesis and neurogenesis in the normal adult brain is unknown. Adult male C57BL/6 mice (n=54) underwent stereotactic injection of a lentiviral vector carrying miR-210 (LV-miR 210). Following 28 days of miR-210 gene transfer, endothelial cell and neural precursor cell proliferation, microvessel density and downstream angiogenic factor were genotyped. miR-210 was highly expressed in neurons, astrocytes and endothelial cells of the LV-miR-210-injected brain hemisphere. The endothelial cell proliferation and the number of newly formed microvessels were greatly increased in the LV-miR-210-treated mice compared with the controls (P<0.05). Neural progenitor cells in the subventricular zone were greatly increased compared with the controls (P<0.05). The data indicate that miR-210 is a key factor at the microRNA level in promoting angiogenesis and neurogenesis, which was associated with local increased vascular endothelial growth factor (VEGF) levels, suggesting that miR-210 may be a potential target for ischemic stroke therapy. PMID- 24152580 TI - Therapeutic expression of hairpins targeting apolipoprotein B100 induces phenotypic and transcriptome changes in murine liver. AB - Constitutive expression of short hairpin RNAs (shRNAs) may cause cellular toxicity in vivo and using microRNA (miRNA) scaffolds can circumvent this problem. Previously, we have shown that embedding small interfering RNA sequences targeting apolipoprotein B100 (ApoB) in shRNA (shApoB) or miRNA (miApoB) scaffolds resulted in differential processing and long-term efficacy in vivo. Here we show that adeno-associated virus (AAV)-shApoB- or AAV-miApoB-mediated ApoB knockdown induced differential liver morphology and transcriptome expression changes. Our analyses indicate that ApoB knockdown with both shApoB and miApoB resulted in alterations of genes involved in lipid metabolism. In addition, in AAV-shApoB-injected animals, genes involved in immune system activation or cell growth and death were affected, which was associated with increased hepatocyte proliferation. Subsequently, in AAV-miApoB-injected animals, changes of genes involved in oxidoreductase activity, oxidative phosphorylation and nucleic bases biosynthetic processes were observed. Our results demonstrate that long-term knockdown of ApoB in vivo by shApoB or miApoB induces several transcriptome changes in murine liver. The increased hepatocyte profileration by AAV-shRNA may have severe long-term effects indicating that AAV-mediated RNA interference therapy using artificial miRNA may be a safer approach for familial hypercholesterolemia therapy. PMID- 24152583 TI - Stereological estimation of orientation distribution of generalized cylinders from a unique 2D slice. AB - Though three-dimensional (3D) imaging gives deep insight into the inner structure of complex materials, the stereological analysis of 2D snapshots of material sections is still necessary for large-scale industrial applications for reasons related to time and cost constraints. In this paper, we propose an original framework to estimate the orientation distribution of generalized cylindrical structures from a single 2D section. Contrary to existing approaches, knowledge of the cylinder cross-section shape is not necessary. The only requirement is to know the area distribution of the cross-sections. The approach relies on minimization of a least squares criterion under linear equality and inequality constraints that can be solved with standard optimization solvers. It is evaluated on synthetic data, including simulated images, and is applied to experimental microscopy images of fibrous composite structures. The results show the relevance and capabilities of the approach though some limitations have been identified regarding sensitivity to deviations from the assumed model. PMID- 24152582 TI - Sustained relief of neuropathic pain by AAV-targeted expression of CBD3 peptide in rat dorsal root ganglion. AB - The Ca(2+) channel-binding domain 3 (CBD3) peptide, derived from the collapsin response mediator protein 2 (CRMP-2), is a recently discovered voltage-gated Ca(2+) channel (VGCC) blocker with a preference for CaV2.2. Rodent administration of CBD3 conjugated to cell penetrating motif TAT (TAT-CBD3) has been shown to reduce pain behavior in inflammatory and neuropathic pain models. However, TAT CBD3 analgesia has limitations, including short half-life, lack of cellular specificity and undesired potential off-site effects. We hypothesized that these issues could be addressed by expressing CBD3 encoded by high-expression vectors in primary sensory neurons. We constructed an adeno-associated viral (AAV) vector expressing recombinant fluorescent CBD3 peptide and injected it into lumbar dorsal root ganglia (DRGs) of rats before spared nerve injury (SNI). We show that selective expression of enhanced green fluorescent protein (EGFP)-CBD3 in lumbar 4 (L4) and L5 DRG neurons and their axonal projections results in effective attenuation of nerve injury-induced neuropathic pain in the SNI model. We conclude that AAV-encoded CBD3 delivered to peripheral sensory neurons through DRG injection may be a valuable approach for exploring the role of presynaptic VGCCs and long-term modulation of neurotransmission, and may also be considered for development as a gene therapy strategy to treat chronic neuropathic pain. PMID- 24152584 TI - International chemical identifier for reactions (RInChI). AB - The IUPAC International Chemical Identifier (InChI) provides a method to generate a unique text descriptor of molecular structures. Building on this work, we report a process to generate a unique text descriptor for reactions, RInChI. By carefully selecting the information that is included and by ordering the data carefully, different scientists studying the same reaction should produce the same RInChI. If differences arise, these are most likely the minor layers of the InChI, and so may be readily handled. RInChI provides a concise description of the key data in a chemical reaction, and will help enable the rapid searching and analysis of reaction databases. PMID- 24152586 TI - Small bowel feeding versus gastric feeding in critically ill adults: more attention should be paid to specific populations. PMID- 24152585 TI - Inhibition of cancer cell proliferation and apoptosis-inducing activity of fungal taxol and its precursor baccatin III purified from endophytic Fusarium solani. AB - BACKGROUND: Taxol (generic name paclitaxel), a plant-derived antineoplastic agent, used widely against breast, ovarian and lung cancer, was originally isolated from the bark of the Pacific yew, Taxus brevifolia. The limited supply of the drug has prompted efforts to find alternative sources, such as chemical synthesis, tissue and cell cultures of the Taxus species both of which are expensive and yield low levels. Fermentation processes with microorganisms would be the methods of choice to lower the costs and increase yields. Previously we have reported that F. solani isolated from T. celebica produced taxol and its precursor baccatin III in liquid grown cultures J Biosci 33:259-67, 2008. This study was performed to evaluate the inhibition of proliferation and induction of apoptosis of cancer cell lines by the fungal taxol and fungal baccatin III of F. solani isolated from T. celebica. METHODS: Cell lines such as HeLa, HepG2, Jurkat, Ovcar3 and T47D were cultured individually and treated with fungal taxol, baccatin III with or without caspase inhibitors according to experimental requirements. Their efficacy on apoptotic induction was examined. RESULTS: Both fungal taxol and baccatin III inhibited cell proliferation of a number of cancer cell lines with IC50 ranging from 0.005 to 0.2 MUM for fungal taxol and 2 to 5 MUM for fungal baccatin III. They also induced apoptosis in JR4-Jurkat cells with a possible involvement of anti-apoptotic Bcl2 and loss in mitochondrial membrane potential, and was unaffected by inhibitors of caspase-9,-2 or -3 but was prevented in presence of caspase-10 inhibitor. DNA fragmentation was also observed in cells treated with fungal taxol and baccatin III. CONCLUSIONS: The cytotoxic activity exhibited by fungal taxol and baccatin III involves the same mechanism, dependent on caspase-10 and membrane potential loss of mitochondria, with taxol having far greater cytotoxic potential. PMID- 24152587 TI - Childhood brain tumor survivors at risk for impaired health-related quality of life. AB - This study aimed to assess health-related quality of life (HRQOL)-mean scores and percentages at risk for impaired HRQOL in childhood brain tumor survivors (CBTS) and to explore differences between CBTS treated with surgery only (SO) versus CBTS treated with surgery and adjuvant therapy (SA). HRQOL was evaluated in 34 CBTS (mean age=14.7 y; mean time since the end of treatment=6.4 y) with the KIDSCREEN. Being at risk for impaired HRQOL was defined as a T-score >=1 SD below the norm population mean. The total and the SA group, but not the SO group, had significantly lower mean scores than the Dutch norm population in the domains of "physical well-being," "psychological well-being," and "peers and social support." High percentages (35% to 53%) of both the SO and the SA groups appeared to be at risk for impaired HRQOL in the domains of "physical well-being," "moods and emotions," "peers and social support," and "bullying," compared to 16% in the norm population. In conclusion, although HRQOL in some domains appeared similar to the norm population, a considerable number of CBTS-reported impaired HRQOL in several other domains. It is recommended to systematically monitor HRQOL in CBTS regardless of the therapy applied. PMID- 24152588 TI - Long-term outcome in pediatric renal tumor survivors: experience of a single center. AB - Medical records of 30 children with renal tumor diagnosed at Siriraj Hospital during 1996 to 2007 were reviewed. Mean age at diagnosis was 36 months; male to female ratio was 1.7:1. Clinical manifestations included abdominal mass (96.7%), hypertension (40.0%), abdominal pain (36.7%), hematuria (26.7%), postrenal obstruction (16.7%), and proteinuria (13.3%). Eight patients had Denys-Drash malformations, WAGR, Dandy-Walker malformation, or genitourinary anomalies. Twenty-seven patients (90%) had Wilms tumor. Sixteen patients were stage 3 or more at diagnosis. Rhabdoid tumor was found in 3 patients. All patients received chemotherapy, 13 patients also received radiation therapy. Acute complications included febrile neutropenia (44.4%), hypokalemia (37.0%), hyponatremia (29.6%), Fanconi syndrome (11.1%), urinary tract Infection (10.0%), and acute renal failure (7.4%). Mean follow-up time was 57.2 months. Ten patients died from progressive disease. Five-year patient survival was 69.7%. Two patients had chronic kidney disease. One of these had Denys-Drash malformations. Both patients received ifosfamide-carboplatin-etoposide protocol and abdominal radiation. Antihypertensive medications were needed in 9 patients for a mean duration of 164 days. None had persistent proteinuria or hematuria. No difference was found among mean estimated glomerular filtration rate at diagnosis, 1 year after treatment, and at last follow-up. Long-term follow-up, especially renal function, is recommended. PMID- 24152589 TI - Lung injury and its prognostic significance in acute liver failure. AB - OBJECTIVE: Hypoxemia is a feared complication of acute liver failure, and high oxygen requirements will frequently lead to removal of patients from the transplant list. As data regarding the prevalence and outcome of acute respiratory distress syndrome in acute liver failure are scant and hypoxemia being a commonly encountered systemic complication, we analyzed radiological, gas exchange, and ventilator data in consecutive patients admitted with acute liver failure. PATIENTS: Acute liver failure patients receiving mechanical ventilation admitted between January 2007 and February 2011 were included. INTERVENTIONS: Patients were categorized according to the Berlin definition as: no acute respiratory distress syndrome, acute respiratory distress syndrome (PaO2/FIO2 < 300 mm Hg), and subdivisions of mild, moderate, and severe acute respiratory distress syndrome (200-300 mm Hg, 100-200 mm Hg, and < 100 mm Hg, respectively). Chest radiographs were independently assessed by two observers for the presence or absence of acute respiratory distress syndrome. Absence of left atrial pressure elevation was based on combined hemodynamic and echocardiographic assessment. MEASUREMENTS AND MAIN RESULTS: Two hundred acute liver failure patients were admitted during the study period of whom 148, median age 39 years (16-74 yr), were included. Thirty-one (21%) had acute respiratory distress syndrome (17 mild acute respiratory distress syndrome [12%], 9 moderate acute respiratory distress syndrome [12%], and 5 severe acute respiratory distress syndrome) within the first 72 hours following admission. Acute respiratory distress syndrome patients required higher positive end-expiratory pressure (7 vs 6 vs 10 vs 15 cm H2O for no, mild, moderate, or severe acute respiratory distress syndrome, p = 0.014), had reduced respiratory system compliance (34 vs 29 vs 30 vs 23 L/cm H2O, p = 0.028), and an increased number of ventilator days (no acute respiratory distress syndrome, 10 d; mild acute respiratory distress syndrome acute lung injury, 12 d; moderate acute respiratory distress syndrome, 23 d; severe acute respiratory distress syndrome, 22 d; p = 0.097). Duration of liver intensive therapy unit stay (p = 0.175), survival (p = 0.877), inotrope requirements (p = 0.495), need for extracorporeal renal support (p = 0.565), and severity of organ failure scores were not affected. Extravascular lung water index had a moderate sensitivity of 65% and specificity of 77% for the prediction of acute respiratory distress syndrome. CONCLUSION: The prevalence of lung injury is relatively low in acute liver failure, where 21% fulfilled acute respiratory distress syndrome criteria. Overall presence of acute respiratory distress syndrome appeared to have a limited impact on outcome. PMID- 24152590 TI - The association of lacking insurance with outcomes of severe sepsis: retrospective analysis of an administrative database*. AB - OBJECTIVE: Patients with severe sepsis have high mortality that is improved by timely, often expensive, treatments. Patients without insurance are more likely to delay seeking care; they may also receive less intense care. DESIGN: We performed a retrospective analysis of administrative database-Healthcare Costs and Utilization Project's Nationwide Inpatient Sample-to test whether mortality is more likely among uninsured patients hospitalized for severe sepsis. PATIENTS: None. INTERVENTIONS: We used International Classification of Diseases-9th Revision, Clinical Modification, codes indicating sepsis and organ system failure to identify hospitalizations for severe sepsis among patients aged 18-64 between 2000 and 2008. We excluded patients with end-stage renal disease or solid organ transplants because very few are uninsured. We performed multivariate logistic regression modeling to examine the association of insurance status and in hospital mortality, adjusted for patient and hospital characteristics. We performed subgroup analysis to examine whether the impact of insurance status varied by geographical region; by patient age, sex, or race; or by hospital characteristics such as teaching status, size, or ownership. We used similar methods to examine the impact of insurance status on the use of certain procedures, length of stay, and discharge destination. MEASUREMENTS AND MAIN RESULTS: There were 1,600,269 discharges with severe sepsis from 2000 through 2008 in the age group 18-64 years. Uninsured people, who accounted for 7.5% of admissions with severe sepsis, had higher adjusted odds of mortality (odds ratio, 1.43; 95% CI, 1.37-1.47) than privately insured people. The higher mortality in uninsured was present in all subgroups and was similar in each year from 2000 to 2008. After adjustment, uninsured individuals had a slightly shorter length of stay than insured people and were less likely to receive five of the six interventions we examined. They were also less likely to be discharged to skilled nursing facilities or with home healthcare after discharge. CONCLUSIONS: Uninsured are more likely to die following admission for severe sepsis than patients with insurance, even after adjusting for potential confounders. This was not due to a hospital effect or demographic or clinical factors available in our administrative database. Further research should examine the mechanisms that lead to this association. PMID- 24152592 TI - RP-HPLC method development and validation for simultaneous estimation of atorvastatin calcium and pioglitazone hydrochloride in pharmaceutical dosage form. AB - A simple, selective, rapid, precise and economical reversed-phase high performance liquid chromatographic (RP-HPLC) method has been developed for simultaneous estimation of atorvastatin calcium (ATV) and pioglitazone hydrochloride (PIO) from pharmaceutical formulation. The method is carried out on a C8 (25 cm * 4.6 mm i.d., 5 MUm) column with a mobile phase consisting of acetonitrile (ACN):water (pH adjusted to 6.2 using o-phosphoric acid) in the ratio of 45:55 (v/v). The retention time of ATV and PIO is 4.1 and 8.1 min, respectively, with the flow rate of 1 mL/min with diode array detector detection at 232 nm. The linear regression analysis data from the linearity plot showed good linear relationship with a correlation coefficient (R(2)) value for ATV and PIO of 0.9998 and 0.9997 in the concentration range of 10-80 ug mL(-1), respectively. The relative standard deviation for intraday precision has been found to be <2.0%. The method is validated according to the ICH guidelines. The developed method is validated in terms of specificity, selectivity, accuracy, precision, linearity, limit of detection, limit of quantitation and solution stability. The proposed method can be used for simultaneous estimation of these drugs in marketed dosage forms. PMID- 24152591 TI - Executive functioning and the metabolic syndrome: a project FRONTIER study. AB - Decrements in cognitive functioning have been linked to the metabolic syndrome (MetS), a risk factor for cardiovascular disease defined by the presence of three of the following: elevated blood pressure, increased waist circumference, elevated blood glucose, elevated triglycerides, and low high-density lipoprotein cholesterol. We examined the relationship between four measures of executive functioning (EF) and MetS as diagnosed by National Heart, Lung, and Blood Institute-American Heart Association criteria. MetS was examined in a rural population of 395 persons with a mean age of 61.3 years, 71.4% women, 37.0% Hispanic, 53.7% White non-Hispanic. There was a 61.0% prevalence of MetS. We derived a factor score from the four executive function measures which was used to compare those with and without the syndrome, as well as any additive effects of components of the syndrome. Those with MetS exhibited significantly poorer performance than those without the syndrome. However, there was no additive effect, having more components of the syndrome was not related to lower performance. The presence of MetS was associated with poorer EF in this rural cohort of community dwelling volunteers. PMID- 24152596 TI - Comment on the paper "Synthesis, growth, structural, spectral, thermal, chemical etching, linear and nonlinear optical and mechanical studies of an organic single crystal 4-chloro 4-nitrostilbene (CONS): a potential NLO material" by P.M. Dinakaran, S. Kalainathan [Spectrochim. Acta A 111 (2013) 123-130]. AB - We argue that (trans)-4-chloro-4'-nitrostilbene is not a new organic nonlinear optical material as claimed by Dinakaran and Kalainathan [P.M. Dinakaran, S. Kalainathan, Synthesis, growth, structural, spectral, thermal, chemical etching, linear and nonlinear optical and mechanical studies of an organic single crystal 4-Chloro 4-Nitrostilbene (CONS): a potential NLO material, Spectrochim. Acta A 111 (2013) 123-130], but instead a well-known compound whose synthesis, spectral data, single crystal structure and second harmonic generation (SHG) efficiency are well documented in the literature. The title paper is completely erroneous. PMID- 24152597 TI - Non-classical transformation of benzendiazonium hydrogen sulfates. Access to 1,3 dimethylisochromeno[4,3-c]pyrazol-5(1H)-one, a potential benzodiazepine receptor ligand. AB - The compound 2-((1,3-dimethyl-1H-pyrazol-5-yl)(methyl)carbamoyl)benzene-diazonium hydrogen sulfate (10) was reacted with copper sulfate and sodium chloride, in the presence of ascorbic acid as reducing agent, to afford a mixture of the chlorinated epimers 4'-chloro-2,2',5'-trimethyl-2',4'-dihydrospiro[isoindoline 1,3'-pyrazol]-3-one (18) and (19), the epimers 4'-hydroxy-2,2',5'-trimethyl-2',4' dihydrospiro[isoindoline-1,3'-pyrazol]-3-one (20) and (21), and N-(1,3-dimethyl 1H-pyrazol-5-yl)benzamide (22). Under the foregoing conditions, diazonium salt 10 affords neither the 2-chloro-N-(1,3-dimethyl-1H-pyrazol-5-yl)-N-methylbenzamide (23) nor the tricyclic derivative 24, the classical products of the Sandmeyer and Pschorr reactions, respectively. Finally, by heating 20 at 210 degrees C the compound 1,3-dimethylisochromeno[4,3-c]pyrazol-5(1H)-one (24) was obtained. The transformation under the above conditions of 2-((4-chloro-3-methyl-1-phenyl- 1H pyrazol-5-yl)(methyl)carbamoyl)benzendiazonium hydrogen sulphate (11) afforded 4',4'-dichloro-2,5'-dimethyl-2'-phenyl-2',4'-dihydrospiro[isoindoline-1,3' pyrazol]-3-one (29) as the sole reaction product. PMID- 24152593 TI - BIGH3 modulates adhesion and migration of hematopoietic stem and progenitor cells. AB - Cell adhesion and migration are important determinants of homing and development of hematopoietic stem and progenitor cells (HSPCs) in bone marrow (BM) niches. The extracellular matrix protein transforming growth factor-beta (TGF-beta) inducible gene H3 (BIGH3) is involved in adhesion and migration, although the effect of BIGH3 is highly cell type-dependent. BIGH3 is abundantly expressed by mesenchymal stromal cells, while its expression in HSPCs is relatively low unless induced by certain BM stressors. Here, we set out to determine how BIGH3 modulates HSPC adhesion and migration. We show that primary HSPCs adhere to BIGH3 coated substrates, which is, in part, integrin-dependent. Overexpression of BIGH3 in HSPCs and HL60 cells reduced the adhesion to the substrate fibronectin in adhesion assays, which was even more profound in electrical cell-substrate impedance sensing (ECIS) assays. Accordingly, the CXCL12 induced migration over fibronectin-coated surface was reduced in BIGH3-expressing HSPCs. The integrin expression profile of HSPCs was not altered upon BIGH3 expression. Although expression of BIGH3 did not alter actin polymerization in response to CXCL12, it inhibited the PMA-induced activation of the small GTPase RAC1 as well as the phosphorylation and activation of extracellular-regulated kinases (ERKs). Reduced activation of ERK and RAC1 may be responsible for the inhibition of cell adhesion and migration by BIGH3 in HSPCs. Induced BIGH3 expression upon BM stress may contribute to the regulation of BM homeostasis. PMID- 24152598 TI - Synthesis and structural characterization of fluorinated thiosemicarbazones. AB - Six new fluorinated thiosemicarbazones R-C(R')=N-NH-C(S)NH(2) (R = 2,4 C(6)H(3)F(2), R' = H (1); R = 2,5-C(6)H(3)F(2), R' = H (2); R = 2,6-C(6)H(3)F(2), R' = H (3); R = 3,4-C(6)H(3)F(2), R' = H (4); R = 3,5-C(6)H(3)F(2), R' = H (5) and R = 4-C(6)H(4)F, R' = C(6)H(5), (6)) have been prepared. The molecular structures of compounds 1 to 6 have been determined. PMID- 24152599 TI - Geospatial analyses to identify clusters of adverse antenatal factors for targeted interventions. AB - BACKGROUND: Late antenatal care and smoking during pregnancy are two important factors that are amenable to intervention. Despite the adverse health impacts of smoking during pregnancy and the health benefits of early first antenatal visit on both the mother and the unborn child, substantial proportions of women still smoke during pregnancy or have their first antenatal visit after 10 weeks gestation. This study was undertaken to assess the usefulness of geospatial methods in identifying communities at high risk of smoking during pregnancy and timing of the first antenatal visit, for which targeted interventions may be warranted, and more importantly, feasible. METHODS: The Perinatal Data Collection, from 1999 to 2008 for south-western Sydney, were obtained from the New South Wales Ministry of Health. Maternal addresses at the time of delivery were georeferenced. A spatial scan statistic implemented in SaTScan was then used to identify statistically significant spatial clusters of women who smoked during pregnancy or women whose first antenatal care visit occurred at or after 10 weeks of pregnancy. RESULTS: Four spatial clusters of maternal smoking during pregnancy and four spatial clusters of first antenatal visit occurring at or after 10 weeks were identified in our analyses. In the maternal smoking during pregnancy clusters, higher proportions of mothers, were aged less than 35 years, had their first antenatal visit at or after 10 weeks and a lower proportion of mothers were primiparous. For the clusters of increased risk of late first antenatal visit at or after 10 weeks of gestation, a higher proportion of mothers lived in the most disadvantaged areas and a lower proportion of mothers were primiparous. CONCLUSION: The application of spatial analyses provides a means to identify spatial clusters of antenatal risk factors and to investigate the associated socio-demographic characteristics of the clusters. PMID- 24152600 TI - Does telecare prolong community living in dementia? A study protocol for a pragmatic, randomised controlled trial. AB - BACKGROUND: Assistive technology and telecare (ATT) are relatively new ways of delivering care and support to people with social care needs. It is claimed that ATT reduces the need for community care, prevents unnecessary hospital admission, and delays or prevents admission into residential or nursing care. The current economic situation in England has renewed interest in ATT instead of community care packages. However, at present, the evidence base to support claims about the impact and effectiveness of ATT is limited, despite its potential to mitigate the high financial cost of caring for people with dementia and the social and psychological cost to unpaid carers. METHOD/DESIGN: ATTILA (Assistive Technology and Telecare to maintain Independent Living At Home for People with Dementia) is a pragmatic, multi-centre, randomised controlled trial over 104 weeks that compares outcomes for people with dementia who receive ATT and those who receive equivalent community services but not ATT. The study hypothesis is that fewer people in the ATT group will go into institutional care over the 4-year period for which the study is funded. The study aims to recruit 500 participants, living in community settings, with dementia or significant cognitive impairment, who have recently been referred to social services.Primary outcome measures are time in days from randomisation to institutionalisation and cost effectiveness. Secondary outcomes are caregiver burden, health-related quality of life in carers, number and severity of serious adverse events, and data on acceptability, applicability and reliability of ATT intervention packages. Assessments will be undertaken in weeks 0 (baseline), 12, 24, 52 and 104 or until institutionalisation or withdrawal of the participant from the trial. DISCUSSION: In a time of financial austerity, CASSRs in England are increasingly turning to ATT in the belief that it will deliver good outcomes for less money. There is an absence of robust evidence for the cost-effectiveness and benefit of using assistive technology and telecare. The ATTILA trial meets a pressing need for robust, generalisable evidence to either justify continuing investment or reappraise the appropriate scale of ATT use. TRIAL REGISTRATION: Current Controlled Trials ISRCTN86537017. PMID- 24152602 TI - Mass population screening for celiac disease in children: the experience in Republic of San Marino from 1993 to 2009. AB - BACKGROUND: Prevalence of celiac disease in developed countries is assessed about 1:100-1:150. The real prevalence is unknown because mass screenings are expensive and difficult to organize. Moreover celiac disease can affect people at every age and studies on asymptomatic subjects at different ages are not comparable. In this study we wanted to know the real prevalence of celiac disease in children in the Republic of San Marino. We also analysed concordance of different tests used and costs of mass screening. METHODS: The study started in 1993. From 1993 to 1997 children aged 6, 10 and 14 were screened. Since 1997 only children aged 6 were monitored, in order to have a homogeneous population. In fact, every child born since 1980 was taken into account. Children were recruited by classroom lists of students for general paediatric examination. Until 2005 the screening test was based on dosage of antibodies anti-gliadin (AGA) IgA and IgG on venous blood. Since 2006 these tests were replaced by anti-transglutaminase IgA antibodies (ATTG). Anti-endomysial antibodies (EMA) were performed if result of any between either AGA or ATTG tests was positive or borderline; if EMA was positive, then an endoscopy with histological examination was performed to confirm the final diagnosis. RESULTS: Attendance to paediatric examination was 96%, submission to blood test was 87%. 42 on 5092 (0,8%; 1:125) children resulted affected by celiac disease. Histology always confirmed diagnosis by serology except for two cases. AGA test (until 2005) yielded 28 on 4304 (0,7% 1:143); ATTG test (since 2006) revealed 14 positive cases on 788 (1,8%; 1:55) leading to a larger percentage of diagnosis. EMA antibodies always confirmed positivity of ATTG. CONCLUSIONS: Prevalence of celiac disease in children of Republic of San Marino is comparable to other North-European Countries. Sensitivity of ATTG proved much higher than that of anti-gliadin antibodies. Concordance between ATTG and EMA was 100%. Concordance between serology and histology was approximately 100%. Cost of screening was yearly about 5000 euros (250 children screened every year). PMID- 24152601 TI - Development of a quantitative rapid diagnostic test for multibacillary leprosy using smart phone technology. AB - BACKGROUND: Despite efforts to eliminate leprosy as public health problem, delayed diagnosis and disabilities still occur in many countries. Leprosy diagnosis remains based on clinical manifestations and the number of clinicians with expertise in leprosy diagnosis is in decline. We have developed a new immunochromatographic test with the goal of producing a simple and rapid system that can be used, with a minimal amount of training, to provide an objective and consistent diagnosis of multibacillary leprosy. METHODS: The test immobilizes two antigens that have been recognized as excellent candidates for serologic diagnosis (the PGL-I mimetic, ND-O, and LID-1), on a nitrocellulose membrane. This allows the detection of specific IgM and IgG antibodies within 20 minutes of the addition of patient sera. Furthermore, we coupled the NDO-LID(r) rapid tests with a new cell phone-based test reader platform (Smart Reader(r)) to provide objective interpretation that was both quantifiable and consistent. RESULTS: Direct comparison of serologic responses indicated that the rapid test detected a greater proportion of leprosy patients than a lab-based PGL-I ELISA. While positive responses were detected by PGL-I ELISA in 83.3% of multibacillary patients and 15.4% of paucibacillary patients, these numbers were increased to 87% and 21.2%, respectively, when a combination of the NDO-LID(r) test and Smart Reader(r) was used. Among multibacillary leprosy the sensitivity of NDO-LID(r) test assessed by Smart Reader(r) was 87% (95% CI, 79.2-92.7%) and the specificity was 96.1% (95% CI, 91.7- 98.6%). The positive predictive value and the negative predictive value of NDO-LID(r) tests were 94% (95% CI, 87.4-97.8%) and 91.4% (95% CI, 85.9-95.2%), respectively. CONCLUSION: The widespread provision of rapid diagnostic tests to facilitate the diagnosis or prognosis of multibacillary leprosy could impact on leprosy control programs by aiding early detection, directing appropriate treatment and potentially interrupting Mycobacterium leprae transmission. PMID- 24152603 TI - Application of population pharmacokinetic modeling to explore the impact of alternative roflumilast dosing regimens on tolerability. AB - OBJECTIVE: Roflumilast is the first phosphodiesterase 4 (PDE4) inhibitor approved for the treatment of chronic obstructive pulmonary disease (COPD) associated with chronic bronchitis and history of exacerbations. In clinical practice, side effects such as diarrhea appear to be somewhat more frequent in patients than that observed in clinical trials. We hypothesize that if patients could take a reduced dose for the first few weeks of therapy, the incidence of adverse events (AEs) could be reduced. METHODS: We used previously reported population pharmacokinetic/ pharmacodynamic modeling to simulate three dosing scenarios of roflumilast: 500 MU once daily (OD) (approved dose), 250 MU OD and 500 MU every other day (EoD). RESULTS: These models predicted that the 250 MU and EoD regimens were associated with lower plasma concentrations, lower total PDE4 inhibition, and lower incidence of diarrhea, nausea, and headache, versus the 500 MU OD dose. CONCLUSIONS: Reduction of roflumilast dose in the first few weeks of therapy may be able to reduce the incidence of treatment-related AEs. Clearly, modeling provides only the basis for hypothesis generation, and must be supported with clinical evidence from carefully designed trials. PMID- 24152604 TI - Effect of food on the pharmacokinetics of empagliflozin, a sodium glucose cotransporter 2 (SGLT2) inhibitor, and assessment of dose proportionality in healthy volunteers. AB - OBJECTIVES: Empagliflozin is an orally available, potent and highly selective inhibitor of the sodium glucose cotransporter 2 (SGLT2). This study was undertaken to investigate the effect of food on the pharmacokinetics of 25 mg empagliflozin and to assess dose proportionality between 10 mg and 25 mg empagliflozin under fasted conditions. MATERIALS AND METHODS: In this open-label, 3-way, cross-over study, 18 healthy volunteers received 3 single doses of empagliflozin in a randomized sequence (25 mg empagliflozin under fasted conditions, 25 mg empagliflozin after a high-fat, high-calorie breakfast and 10 mg empagliflozin under fasted conditions), each separated by a washout period of at least 7 days. Serial plasma samples were collected at selected time points over a period of 72 hours. RESULTS: Administration with food had no clinically relevant effect on the area under the plasma concentration-time curve (AUC0 infinity) of empagliflozin (geometric mean ratio (GMR): 84.04, 90% confidence interval (CI): 80.86 - 87.34). The decrease observed in the maximum plasma concentrations (Cmax) of empagliflozin (GMR: 63.22, 90% CI: 56.74 - 70.44) when administered with food was not considered clinically meaningful. The increases in AUC0-infinity and Cmax for 10 mg vs. 25 mg empagliflozin administered under fasting conditions were roughly dose-proportional, as demonstrated by the slope beta of the regression lines being slightly less than 1 (slope beta for AUC0 infinity: 0.94, 95% CI: 0.90 - 0.97; slope beta for Cmax: 0.91, 95% CI: 0.80 - 1.01). Empagliflozin was well tolerated under fed and fasting conditions. CONCLUSIONS: The results support administration of empagliflozin tablets independently of food. Increases in empagliflozin exposure under fasting conditions were roughly dose-proportional between 10 mg and 25 mg empagliflozin. PMID- 24152605 TI - Minimally invasive treatment of urinary fistulas using N-butyl-2-cyanoacrylate: a valid first line option. AB - BACKGROUND: A few single case reports and only one clinical series have been published so far about the use of N-butyl-2-cyanoacrylate in the treatment of urinary fistulas persisting after conventional urinary drainage. CASE PRESENTATION: We treated five patients with a mean age of 59.2 years presenting iatrogenic urinary fistulas which persisted following conventional drainage manouvres. There were 3 calyceal fistulas following open, laparoscopic and robotic removal of renal lesions respectively, one pelvic fistula after orthotopic ileal neobladder and a bilateral dehiscence of uretero-sigmoidostomy. We used open-end catheters of different sizes adopting a retrograde endoscopic approach for cyanoacrylate injection in the renal calyces, while a descending percutaneous approach via the pelvic drain tract and bilateral nephrostomies respectively was used for the pelvic fistulas. Fluoroscopic control was always used during the occlusion procedures. The amount of adhesive injected ranged between 2 and 5 cc and in one case the procedure was repeated. With a median follow-up of 11 months we observed clinical and radiological resolution in 4 cases (80%), while a recurrent and infected calyceal fistula after laparoscopic thermal renal damage during tumor enucleoresection required nephrectomy. No significant complications were documented. CONCLUSIONS: In an attempt to spare further challenging surgery in patients that had been already operated on recently, minimally invasive occlusion of persistent urinary fistulas with N butyl-2-cyanoacrylate represents a valid first line treatment, justified in cases when the urinary output is not excessive and there is a favorable ratio between the length and diameter of the fistulous tract. PMID- 24152607 TI - Physician experience with electronic health record systems that meet meaningful use criteria: NAMCS physician workflow survey, 2011. AB - KEY FINDINGS: Data from the National Ambulatory Medical Care Survey's (NAMCS) Physician Workflow Survey, 2011. About three-quarters of physicians with electronic health record (EHR) systems have systems that meet meaningful use criteria. Physicians with EHR systems that meet meaningful use criteria were more likely to report that their system provides time savings than physicians with systems not meeting meaningful use criteria, but only in some areas. Physicians with EHR systems that meet meaningful use criteria were more likely to report enhanced confidentiality and less disruption in their interactions with patients than physicians with systems not meeting meaningful use criteria. Physicians with EHR systems that meet meaningful use criteria were no more likely to report financial benefits and selected clinical benefits than those with systems not meeting meaningful use criteria. PMID- 24152606 TI - Identification of PrP sequences essential for the interaction between the PrP polymers and Abeta peptide in a yeast-based assay. AB - Alzheimer disease is associated with the accumulation of oligomeric amyloid beta peptide (Abeta), accompanied by synaptic dysfunction and neuronal death. Polymeric form of prion protein (PrP), PrP(Sc), is implicated in transmissible spongiform encephalopathies (TSEs). Recently, it was shown that the monomeric cellular form of PrP (PrP(C)), located on the neuron surface, binds Abeta oligomers (and possibly other beta-rich conformers) via the PrP(23-27) and PrP(90 110) segments, acting as Abeta receptor. On the other hand, PrP(Sc) polymers efficiently bind to Abeta monomers and accelerate their oligomerization. To identify specific PrP sequences that are essential for the interaction between PrP polymers and Abeta peptide, we have co-expressed Abeta and PrP (or its shortened derivatives), fused to different fluorophores, in the yeast cell. Our data show that the 90-110 and 28-89 regions of PrP control the binding of proteinase-resistant PrP polymers to the Abeta peptide, whereas the 23-27 segment of PrP is dispensable for this interaction. This indicates that the set of PrP fragments involved in the interaction with Abeta depends on PrP conformational state. PMID- 24152608 TI - Cryogenic Transmission Electron Microscopy: Aqueous Suspensions of Nanoscale Objects-ERRATUM. PMID- 24152609 TI - Sigma-1 receptor antagonist, BD1047 reduces nociceptive responses and phosphorylation of p38 MAPK in mice orofacial formalin model. AB - Sigma-1 receptors (Sig-1Rs) play a role in different types of pain and in central sensitization mechanism in spinal cord. However, it is currently unexplored whether Sig-1Rs are involved in orofacial pain processing. Here we show whether a selective Sig-1R antagonist, BD1047 reduces nociceptive responses in the mouse orofacial formalin model and the number of Fos-immunoreactive (ir) cells in the trigeminal nucleus caudalis (TNC). In addition, it was examined whether the phosphorylation of extracellular signal-regulated kinase (pERK) or p38 (pp38) mitogen-activated protein kinases (MAPK), which are closely linked to pain signaling and sensitization, in TNC was modified by BD1047. The 5% formalin (10 uL) was subcutaneously injected into the right upper lip, and the rubbing responses with ipsilateral fore- or hind paw were counted for 45 min. BD1047 (1, 3 or 10 mg/kg) were intraperitoneally treated 30 min before formalin injection. High dose of BD1047 (10 mg/kg) produced significant anti-nociceptive effects in the first and the second phase. The number of Fos-ir cells in ipsilateral side of TNC was also reduced by BD1047 as compared to that in saline-treated animals. In addition, the number of pp38-ir cells in ipsilateral TNC was decreased in BD1047 treated animals, whereas the number of pERK-ir cells was not modified. Collectively, these results demonstrate that Sig-1Rs play a pivotal role in the orofacial pain processing, and the pp38 signaling pathway can be associated with Sig-1R's action in TNC. PMID- 24152610 TI - Ultrastructure of vitrified rabbit transgenic embryos. AB - The aim of the study was to determine the viability of rabbit transgenic (enhanced green fluorescent protein (EGFP)-positive) embryos cultured in vitro and compare with gene-microinjected (Mi) non-transgenic (EGFP-negative) embryos following vitrification. Non-microinjected and non-vitrified embryos were used as the control. Morphological signs of injury to embryo organelles were determined at the ultrastructural level using transmission electron microscopy (TEM). Morphometric evaluation was performed on cellular organelles using microphotographs obtained by TEM. Intact and Mi embryos recovered from in vivo fertilized eggs at 19-20 hours post coitum (hpc) were cultured for up to 72 hpc (morula stage), evaluated for the EGFP gene integration and then vitrified in 0.25 ml insemination straws in modified EFS (40% ethylene glycol + 18% Ficoll 70 + 0.3 M sucrose) vitrification solution. After 1-3 days the embryos were devitrified, a representative selection of embryos was analyzed by TEM and the remaining embryos were subjected to additional in vitro culture. Observations by TEM showed that the vitrified/warmed EGFP-positive and EGFP-negative embryos had a slight accumulation of cellular debris and lipid droplets compared with the control intact embryos. More severe changes were detected in the membrane structures of the treated embryos, mostly in the cytoplasmic envelope, trophoblastic microvilli, junctional contacts and mitochondria. We suggest that the higher proportion of deteriorated cell structures and organelles in the treated embryos may be due to the vitrification process rather than to mechanical violation (the gene-microinjection procedure), as a detailed inspection of ultrastructure revealed that most damage occurred in the cell membrane structures. PMID- 24152611 TI - Clinical effectiveness of electroacupuncture in meralgia paraesthetica: a case series. AB - BACKGROUND: Meralgia paraesthetica is a fairly common condition resulting from entrapment of the lateral femoral cutaneous nerve. I have found that acupuncture produces a rapid improvement, sometimes effecting a cure, after only one or two treatments. I therefore invited referrals in order to collect a case series. METHODS: A series of 10 patients, which included two who had refused surgery, but excluded those with significant lumbar spine problems, were treated. Visual Analogue Scale pain scores and analgesic intake were recorded weekly, starting before treatment. Four patients were receiving high doses of analgesics and the average period of symptoms was 3-4 years. Acupuncture points used were BL25, GB30, GB34, GB31, GB32, Huatuojiaji and ah shi points of the buttock and thigh, up to a depth of 7.5 cm. Electroacupuncture was normally given from the second treatment. RESULTS: Without exception, patients were specifically tender over GB31 before they started treatment. Most were also tender over the upper lumbar spine. An average of four to five sessions of acupuncture was given. The pain scores for all 10 patients improved by at least 50%, including that of a patient with a 20-year history. At follow-up (varying from 3 to 36 months), improvement was nearly 100%. Most patients were able to stop their analgesics. CONCLUSIONS: Meralgia paraesthetica appears to respond rapidly to electroacupuncture. A significant trigger point at GB31 was universally present, which may aid diagnosis, although the reason for this is unclear. Further controlled studies are justified. PMID- 24152612 TI - [Scientific statement] Report of the Salt Reduction Committee of the Japanese Society of Hypertension(2) Goal and strategies of dietary salt reduction in the management of hypertension. AB - In this section of the Report of the Salt Reduction Committee of the Japanese Society of Hypertension, the target level of dietary salt reduction and its scientific evidence, present status of salt consumption in Japan, salt-reducing measures/guidance methods in individuals and population strategies to reduce salt intake are introduced. In the Dietary Reference Intake for the general population in Japan (2010 version), the target levels of salt restriction in men and women were established as less than 9.0 per day and 7.5 g per day, respectively. The Japanese Society of Hypertension Guidelines for the Management of Hypertension 2009 recommended the target level of dietary salt restriction in patients with hypertension as less than 6 g per day. However, the National Health and Nutrition Survey of Japan in 2010 reported that the mean salt intake in adults was 10.6 g per day (men: 11.4 g per day and women: 9.8 g per day). To effectively decrease salt intake in Japan, it is necessary to reduce the consumption of high-salt foods (especially traditional foods) and replace high-salt seasonings (soy sauce and so on) with low-salt alternatives. Health-care professionals must effectively perform salt-reduction guidance for hypertensive patients in hospitals/administrative organizations. To promote population strategies for salt reduction in the whole society of Japan, social strategies, such as administrative policies, companies' cooperation and educational staff's cooperation, are necessary. PMID- 24152613 TI - [Scientific statement] Report of the Salt Reduction Committee of the Japanese Society of Hypertension(1) Role of salt in hypertension and cardiovascular diseases. AB - Dietary salt consumption is closely associated with the level of blood pressure (BP); stricter salt reduction more markedly decreased BP. Obesity/metabolic syndrome, Dietary Approach to Stop Hypertension (DASH) diet, exercise and mental stress influence the BP-elevating effect of high-salt diet. Observational and intervention studies suggested that salt restriction improved the risk of cardiovascular diseases. However, the effects may differ among the types of the hypertensive complications; salt reduction may decrease the risk of stroke more than that of ischemic heart disease. Small-scale studies demonstrated that excess salt increased the risk of the left ventricular hypertrophy, heart failure, the urinary protein/albumin levels and end-stage renal failure. These diverse beneficial effects of salt reduction are probably because low-salt diet is an effective strategy to decrease BP and body fluid volume but is less effective to ameliorate the other cardiovascular risk factors. A mean salt intake in Japan is markedly high. Considering the present condition, salt reduction is essential for the prevention and treatment of hypertension and for the prevention of cardiovascular diseases. PMID- 24152614 TI - [Scientific statement] Report of the Salt Reduction Committee of the Japanese Society of Hypertension (3) Assessment and application of salt intake in the management of hypertension. AB - Salt-reduction guidance to hypertensive patients should be performed by evaluating salt intake of the individuals. However, each method to assess salt intake has both merits and limitations. Therefore, evaluation methods must be selected in accordance with the subject and facility's environment. In special facilities for hypertension treatment, measurement of sodium (Na) excretion with 24-h pooled urine or a survey on dietary contents by dietitians is recommended. In medical facilities in general, measurement of the levels of Na and creatinine (Cr) using second urine samples after waking-up or spot urine samples is recommended. The reliability of this method improves by using formulae including a formula to estimate 24-h Cr excretion. A method to estimate salt intake based on the Na excretion per gram Cr using the Na/Cr ratio in spot urine is simple, but not reliable. The method to estimate the daily excretion of salt from nighttime urine using an electronic salt sensor installed with a formula is recommended to hypertensive patients. Although its reliability is not high, patients themselves can measure this parameter simply at home and thus useful for monitoring salt intake and may intensify consciousness regarding salt reduction. Using these methods, salt intake (excretion) should be evaluated, and salt reduction guidance targeting <6 g (Na: 100 mmol) per day should be conducted in the management of hypertension. PMID- 24152615 TI - Grover disease (transient acantholytic dermatosis) in acute myeloid leukemia on FDG PET/CT. AB - A 48-year-old man with a newly diagnosed acute myeloid leukemia developed purpuric rash on day 6 after chemotherapy. Skin biopsy on day 8 demonstrated Grover disease. Triamcinolone treatment started on day 10 with subjective improvement on day 15. Initial FDG PET/CT on day 12 demonstrated rarely seen diffuse skin uptake that was interpreted as technical artifact and repeated on day 16. Accurately reviewing both PET and CT imaging would prevent confusion between diffuse cutaneous hypermetabolic activity and a technical artifact. Grover disease usually affects the trunk and may be related to the elimination of chemotherapy agents by sweating. PMID- 24152616 TI - False-positive 123I-MIBG scintigraphy due to multiple focal nodular hyperplasia. AB - 123I-MIBG accumulation in focal nodular hyperplasia was demonstrated. A 16-year old girl who received radiotherapy for neuroblastoma at the age of 5 presented for abdominal pain. Three MIBG-avid tumors within the liver were proven to be focal nodular hyperplasias through biopsy. Previous neuroblastoma was transformed to non-MIBG-avid ganglioneuroma. MIBG accumulation does not necessarily indicate the presence of neuroendocrine tumor. PMID- 24152617 TI - SPECT and 18F-FDG PET/CT imaging of multiple paragangliomas and a growth hormone producing pituitary adenoma as phenotypes from a novel succinate dehydrogenase subunit D mutation. AB - Mutations in the subunits B, C, D, and recently in A of the succinate dehydrogenase have been associated with the development of paragangliomas. We report the case of a 37-year-old man presented with multiple paragangliomas and a growth hormone-producing pituitary adenoma, with a novel succinate dehydrogenase subunit D mutation as the genetic analysis revealed. We present the similarities and the differences of the findings in patient imaging with either methods of SPECT (I-MIBG and In-pentetreotide) or PET/CT with F-FDG. This case revealed that F-FDG PET/CT detected more lesions and was superior compared with the other methods. PMID- 24152618 TI - Natalizumab-induced progressive multifocal leukoencephalopathy. AB - A 55-year-old woman with known relapsing-remitting multiple sclerosis (RRMS) on natalizumab (Tysabri(r)) for 3 years was admitted to the hospital with worsening word-finding difficulties and gait instability. Neurologic examination revealed right hemianopia, right arm hemiplegia, right-sided sensory loss, and global aphasia. The patient underwent MRI and PET imaging with concurrent electroencephalogram. She was subsequently diagnosed with natalizumab-induced progressive multifocal leukoencephalopathy (PML) and treated with plasmapheresis, intravenous immunoglobulin, and high-dose intravenous steroids. Steroids were continued over a 3-month hospital course and tapered upon discharge. Speech, arm strength, and ambulation have since improved. PMID- 24152619 TI - FDG PET/CT showing erythema nodosum associated with tuberculous lymphadenitis. AB - Erythema nodosum (EN) is histopathologically an acute septal panniculitis of subcutaneous adipose lobule. It can be either idiopathic or secondary to various underlying conditions. A female patient with EN underwent FDG PET/CT to search underlying cause. The images showed enlarged lymph nodes in the mediastinum with moderately elevated FDG uptake and multifocal increased FDG uptake over her lower extremities. The patient's condition was subsequently diagnosed with EN associated with mediastinal tuberculous lymphadenitis based on skin biopsy, tuberculin skin test, and treatment response. PMID- 24152620 TI - 99mTcO4 visualization of septic pulmonary emboli during thyroid scintigraphy. AB - A case of 99mTcO4 accumulation within the thorax is reported, consistent with septic emboli and thyroiditis during routine thyroid scintigraphy for subclinical hyperthyroidism. After antibiotic treatment, repeated 99mTcO4 imaging revealed complete resolution of foci of septic emboli. PMID- 24152621 TI - Predictive value of 68Ga-DOTANOC PET/CT in patients with suspicion of neuroendocrine tumors: is its routine use justified? AB - OBJECTIVE: The objective of this study was to evaluate the predictive value of Ga DOTANOC PET/CT in patients with suspected neuroendocrine tumor (NET). METHODS: Data of 164 patients (mean age, 42.5 +/- 17.3 years; 54.8% male) who underwent Ga DOTANOC PET/CT for suspected NET were retrospectively analyzed. Neuroendocrine tumor was suspected based on clinical features (n = 94) and/or raised biochemical markers (n = 83, serum chromogranin A, gastrin, serum/urinary catecholamines, insulin/C-peptide, and 5-hydroxytrytophan/5-hydroxyindoleacetic acid) and/or imaging findings (n = 93). PET/CT images were reviewed by 2 experienced nuclear medicine physicians, and any nonphysiological Ga-DOTANOC uptake was taken as positive for NET. Histopathology (n = 55) and clinical/imaging follow-up (n = 109; median, 11 months) was used as reference standard. RESULTS: Based on the reference standard, 97 of 164 patients had NET. Ga-DOTANOC PET/CT was positive for NET in 101 and negative in 63 patients. Primary tumor was demonstrated in 90 patients (commonest site-pancreas) and metastasis in 30 (commonest site-liver). PET/CT was true positive in 92 patients, true negative in 58, false positive in 9, and false negative in 5. The overall sensitivity was 94.8%, specificity was 86.5%, positive predictive value was 91%, negative predictive value was 92%, and accuracy was 91.4%. The accuracy of PET-CT in patients with clinical features of NET was 90.4%, with raised biochemical markers was 86.7%, and with imaging findings suggestive of NET was 93.5%. No difference was seen in the accuracy in patients with or without clinical symptoms (P = 0.794), raised versus those with normal/unknown biochemical markers (P = 0.094), and suggestive imaging versus those with negative/unavailable imaging (P = 0.420). CONCLUSIONS: Ga-DOTANOC PET CT shows high positive and negative predictive values in patients with suspected NET and can be routinely used for this purpose. PMID- 24152622 TI - Lymph node to primary tumor SUV ratio by 18F-FDG PET/CT and the prediction of axillary lymph node metastases in breast cancer. AB - PURPOSE: The authors evaluated the usefulness of axillary lymph node (ALN) to primary breast tumor SUV ratio (determined by 18F-FDG PET/CT) for predicting the presence of ALN metastasis in breast cancer. METHODS: One hundred thirty-six consecutive female patients with breast cancer were enrolled in this retrospective study between January 2009 and November 2012. All patients underwent surgical resection without neoadjuvant chemotherapy, and ALN metastases were histologically confirmed by ALN dissection (n = 75) or sentinel lymph node (LN) biopsy (n = 61). The maximum SUVs of FDG-avid ALNs (SUVLN) and of primary breast tumors were measured on preoperative 18F-FDG PET/CT images, and ALN to primary breast tumor SUV ratios (LN/T ratios) were calculated. In a subgroup of patients with FDG-avid ALNs, optimal cutoff values for SUVLN and LN/T ratio were determined by receiver operating characteristic curve analysis for predicting the presence of ALN metastasis. Subsequently, the diagnostic performances of visual analysis (presence of FDG-avidity), SUVLN, and LN/T ratio for the prediction of ALN metastasis were determined. RESULTS: In a subgroup of patients with FDG-avid ALNs (n = 65), the area under the curve and the optimal criteria of SUVLN for detecting ALN metastasis were 0.655 and greater than 2.1, and those of LN/T ratio were 0.739 and greater than 0.2, respectively. For these criteria, the sensitivity, specificity, and diagnostic accuracy of detecting ALN metastasis were 71.4%, 77.3%, and 74.3%, respectively, for visual analysis; 47.1%, 93.9%, and 69.9%, respectively, for SUVLN; and 62.9%, 92.4%, and 77.2%, respectively, for LN/T ratio in all patients. The specificity of LN/T ratio was significantly higher than that of visual analysis (P = 0.0259). Although the sensitivity of LN/T ratio was higher than that of SUVLN, it did not reach a statistical significance (P = 0.0874). CONCLUSIONS: The LN/T ratio better predicts the presence of ALN metastasis than visual analysis or SUVLN in breast cancer. PMID- 24152623 TI - Anatomic and metabolic evaluation of peripheral nerve sheath tumors in patients with neurofibromatosis 1 using whole-body MRI and (18)F-FDG PET fusion. AB - PURPOSE: Malignant peripheral nerve sheath tumors (MPNSTs) are the leading cause of death for patients with neurofibromatosis type 1 (NF1). Identification of hypermetabolic lesions on PET may help identify patients at risk for MPNST. The objective of this study was to identify clinical and MRI-derived variables that predicted increased metabolic activity of neurofibromas in NF1 patients as determined by PET. METHODS: This prospective study included NF1 patients with neurofibromas of 5 cm in diameter or greater. All patients underwent whole-body MRI and F-FDG PET imaging. Tumor volume was calculated from the MR scans using a semiautomated 3-dimensional segmentation method. SUVmax's were calculated to quantify metabolic activity. Logistic regression analyses were performed to determine the relationship among SUVmax, tumor volume, location (extremity vs trunk), type (plexiform vs circumscribed), depth (superficial vs deep), patient age, and whole-body tumor burden. RESULTS: A total of 311 neurofibromas were identified in 19 NF1 patients (mean age, 38 years; range, 19-58 years). One extreme outlier was excluded from analysis. Whole-body tumor volumes ranged from 0.4 to 1182.4 mL. Fifty of 310 tumors were FDG-avid on PET (16%) with median SUVmax of 2.2 (range, 0.4-9.6). Metabolic activity (SUVmax >2.5) correlated with tumor location (deep > superficial, trunk > extremity) in tumors with PET avidity. CONCLUSIONS: In NF1 patients with neurofibromas of 5 cm or greater, the majority of internal tumors are not metabolically active on PET. Tumors with increased metabolic activity as defined by SUVmax greater than 2.5 (ie, suggestive of MPNST) are more likely to be deep and located within the trunk. PMID- 24152624 TI - Multiple organ metastases from ameloblastoma detected by FDG PET/CT imaging. AB - A 74-year-old patient was admitted to our hospital with recurrent ameloblastoma of the right mandible. Multiple lung nodules were noted during the presurgical evaluation. FDG PET/CT was subsequently performed to assess the nature of the nodules and search the possible primary tumors. The images showed abnormal FDG activity not only in the lung nodules but also in the lumbar vertebral body and the liver. Pathologic examination after hepatic biopsy demonstrated metastases from ameloblastoma. PMID- 24152625 TI - Solitary extramedullary plasmacytoma of the parotid gland imaged with 18F-FDG PET/CT. AB - A 75-year-old woman presented with a 1-year history of an enlarging mass in the left parotid gland. Biopsy revealed a parotid plasmacytoma, and the patient was referred for a staging F-FDG PET/CT to evaluate the presence of multiple myeloma bone involvement. The PET/CT scan showed intense FDG uptake in the neck mass but no FDG-avid lymphadenopathy or distant metastases. Plasmacytoma involving the parotid gland is extremely rare. We present the F-FDG PET/CT imaging of solitary parotid plasmacytoma. PMID- 24152627 TI - False-positive result in 18F-fluorocholine PET/CT due to incidental and ectopic parathyroid hyperplasia. AB - PET/CT with F-fluorocholine (a positron-labeled choline analog) is currently used as a diagnostic tool for restaging prostate cancer patients with increasing prostate-specific antigen. We present an unusual case of a false-positive result using F-fluorocholine PET/CT because of incidental and ectopic parathyroid hyperplasia. PMID- 24152626 TI - Enhanced CT and FDG PET/CT findings of splenic hamartoma. AB - Splenic hamartomas are very rare benign vascular tumors. A 67-year-old man was referred after an incidental detection of a splenic lesion. Abdominal-enhanced CT showed a splenic lesion with progressive enhancement. This lesion showed intense FDG uptake with an SUVmax of 9.2. The patient underwent splenectomy. Splenic hamartoma was confirmed by pathologic evaluation. In this tumor, the disorganized splenic sinus contained a large amount of lymphocytes and plasma cells, which may contribute to the intense FDG uptake. This case indicates that splenic hamartoma should be included in the differential diagnosis of focal FDG accumulation along with tumor and nontumor conditions. PMID- 24152628 TI - 68Ga DOTATATE PET/CT in a rare coexistence of pituitary macroadenoma and multiple paragangliomas. AB - The coexistence of a pituitary neoplasm and pheochromocytoma is a rare condition, which may be another undefined variant of Multiple endocrine neoplasia (MEN) syndrome. Moreover, the coexistence of pituitary macroadenoma and multiple paragangliomas is more uncommon and only few authors have reported these findings. We are reporting the use of Ga DOTATATE PET/CT in a rare case of coexisting pituitary macroadenoma and multiple paragangliomas. PMID- 24152629 TI - Carcinosarcoma of the uterine corpus on 18F-FDG PET/CT in a postmenopausal woman with elevated AFP. AB - Uterine carcinosarcoma (termed malignant mixed mullerian tumor) is a rare neoplasm of the uterus with a poor prognosis. There have been very few cases in the literature describing the PET/CT findings of uterine carcinosarcoma. We report a case of tissue-proven carcinosarcoma of the uterine corpus in a 65-year old woman with elevated serum alpha-fetoprotein (AFP), whose 18F-FDG PET/CT showed a 10.3-cm mass in the uterus with uneven high FDG uptake. The SUVmax was 12.8. After surgery, the patient received 6 courses of chemotherapy, and the serum levels of AFP decreased to reference range. PMID- 24152631 TI - Tips for a physician in getting the right job, part V: Some types of interviews for an executive position. AB - Some physicians interviewing for an executive job will encounter the same types of interviews that a physician looking for a clinical job will experience. Typically, at least some elements of the same types of interviews will be given. However, those who desire an administrative position may in addition encounter 1 or more different types of interviews, which are known as the stress, behavioral, and situational interviews. This article describes some characteristics of these interviews, to prepare physicians to do well in these situations. PMID- 24152630 TI - 18F-FDG PET/CT for staging and detection of extramedullary organ involvement in chronic myelomonocytic leukemia. AB - Chronic myelomonocytic leukemia (CMML) is a rare hematologic malignancy characterized by the accumulation of monocytes in the blood and bone marrow, dysplastic hematopoiesis, and potential leukemic involvement of organs. We report a case of leukemic involvement of cervical lymph nodes detected by 18F-FDG PET/CT. A 53-year-old woman with CMML and newly diagnosed cervical lymphadenopathy underwent whole-body PET/CT for evaluation of extramedullary disease. PET demonstrated marked tracer uptake in cervical lymph nodes. Histopathological evaluation revealed leukemic involvement. 18F-FDG PET/CT is a valuable tool enabling sensitive staging of CMML, particularly in case of extramedullary organ involvement. PMID- 24152632 TI - Hepatic tuberculosis mimics metastasis revealed by 18F-FDG PET/CT. AB - Extrapulmonary tuberculosis can affect almost any organ in the body. Here, we report a rare case of primary hepatic tuberculosis presented as multiple hepatic lesions and enlarged lymph nodes in the retroperitoneum and porta hepatis. PET/CT imaging showed avid FDG uptake by these lesions but did not find any definite primary malignancy. Finally, a diagnosis of primary hepatic tuberculosis was made with histopathologic examination. PMID- 24152633 TI - Comparison of renal transplant scintigraphy with renal resistance index for prediction of early graft dysfunction and evaluation of acute tubular necrosis and acute rejection. AB - PURPOSE: We discuss whether resistance index (RI) and renal scintigraphy obtained within 48 hours after operation could predict the early graft dysfunction. We also aimed to assess the uses of scintigraphy and RI in diagnosis of acute rejection (AR) and acute tubular necrosis (ATN). METHODS: A total of 153 studies were performed in 109 patients. T1/2 of perfusion peak, perfusion curve grades, and accumulation index (R20/3) were used as scintigraphic parameters. Baseline studies obtained within 48 hours after transplantation were evaluated for prediction of early graft dysfunction. All data were then assessed for specific diagnosis. RESULTS: Scintigraphic parameters were significantly higher in patients with delayed graft function (DGF) and slow graft function (SGF) than in patients with immediate graft function. These parameters in DGF were also considerably different from those in SGF. The mean RI was significantly high in DGF, but there was no difference between SGF and immediate graft function. In diagnostic groups, the mean values of all tests were significantly different between normal functioning grafts and pathological grafts (ATN + AR). There was no significant difference between AR and ATN. However, renal scintigraphy has higher sensitivity and specificity for AR as compared with RI of Doppler ultrasonography (US). CONCLUSIONS: In predicting graft dysfunction and separating normal functioning graft from pathological graft (ATN + AR), renal scintigraphy provides more accurate information than Doppler US. Even though it is superior to Doppler US, renal scintigraphy also cannot reliably separate ATN from AR. The major advantage of renal scintigraphy is the early detection of reduced renal function. PMID- 24152634 TI - Ollier disease with digital enchondromatosis: anatomic and functional imaging. AB - Ollier disease is a rare skeletal disorder characterized by multiple enchondromas at metaphyseal regions of the bones. The disease is nonhereditary and usually the result of postzygote mutations during development. We present the features of digital enchondromatosis on bone scintigraphy, PET/CT, radiographs, and MRI in a patient, with a childhood diagnosis of Ollier disease. PMID- 24152635 TI - Bone scintigraphy in children with cat scratch disease. AB - AIM: The objective of this study was to evaluate the degree and incidence of bone involvement in patients with cat scratch disease. METHODS: Patients admitted between 2004 and 2011 at the pediatric department for cat scratch disease and a positive serology for Bartonella henselae were identified. Only those having undergone a bone scintigraphy (BS) were included in this retrospective study. RESULTS: Sixteen girls and 8 boys with a mean age of 7 years were studied. Bone scintigraphy was positive in 6 (25%), but only 2 had bone pain. Axial involvement was present in all 6 patients, and appendicular lesions in 3 of them. Three patients had a BS control, with improvement or normalization after treatment with antibiotics. CONCLUSIONS: Bone involvement occurs infrequently in patients with cat scratch disease and is not always associated with specific signs. Cat scratch disease must be suspected in patients with fever of unknown origin presenting multifocal lesions on BS. PMID- 24152636 TI - 68Ga DOTATATE PET/CT imaging of a solitary fibrous tumor of the nasopharynx. AB - Solitary fibrous tumors (SFTs) are rare group of mesenchymal tumors that occurs predominantly in the pleura. The role of PET/CT imaging in characterizing the SFT is not well reported. Mesenchymal tumors may express somatostatin receptors. We hereby report a rare case of SFT of the nasopharynx showing Ga DOTATATE avidity. PMID- 24152637 TI - A hepatoid adenocarcinoma of the stomach evaluated with (18)F-FDG PET/CT: intense (18)F-FDG uptake contrary to the previous report. AB - The condition of a 55-year-old man was diagnosed with unresectable advanced gastric cancer, and initial biopsy revealed adenocarcinoma. On evaluation of treatment response after chemotherapy, F-FDG PET/CT showed large residual stomach cancer with increased FDG uptake (SUVmax, 13.6), lymph node metastasis with mild FDG uptake (SUVmax, 2.5), and no distant metastasis. Palliative subtotal gastrectomy was done, and the finding was hepatoid adenocarcinoma. Compared with the previous report of Pan et al (Clin Nucl Med. 2011;36:1137-1139), our patient had more increased FDG uptake of SUVmax (13.6 vs 1.9) in the gastric mass and lymph node metastases but no liver metastasis. PMID- 24152638 TI - Brain PET metabolic abnormalities in a case of varicella-zoster virus encephalitis. AB - The role of brain 18F-FDG PET in the diagnostic evaluation of encephalitis has been recently suggested, especially in limbic encephalitis, but descriptions are mainly limited to small case reports. However, the evaluation of cerebral metabolism by 18F-FDG PET has never been described for varicella-zoster virus encephalitis. We report the first case of varicella-zoster virus encephalitis in which 18F-FDG PET revealed brain metabolic abnormalities. Brain metabolic PET imaging was analyzed by comparing the patient's brain 18F-FDG PET scans to that of 12 healthy subjects. Compared with healthy subjects, significant hypometabolism and hypermetabolism were found and evolved over time with treatment. PMID- 24152639 TI - (68)Ga DOTATATE uptake in vertebral hemangioma. AB - Somatostatin receptor scintigraphy is an established modality for imaging well differentiated neuroendocrine tumors. It is known that inflammatory diseases (eg, tuberculosis) may also accumulate somatostatin receptor analogs. Here, we present the case of a 69-year-old patient with a neuroendocrine tumor of the rectum showing uptake of Ga DOTATATE in 2 vertebrae that was caused by vertebral hemangiomas. This could be clearly demonstrated on the CT scan. Although studies outlining the normal distribution of Ga DOTATATE exist, uptake in vertebral hemangiomas has not been described yet. As the case shows, vertebral hemangiomas should be kept in mind as a benign differential diagnosis. PMID- 24152640 TI - Bone marrow metastases from alveolar rhabdomyosarcoma with impressive FDG PET/CT finding but less-revealing bone scintigraphy. AB - An 18F-FDG PET/CT scan was performed in a 26-year-old man with a known alveolar rhabdomyosarcoma for staging. The PET/CT scan showed abnormally increased FDG activity involving almost all bones in the imaged regions. In contrast, 99mTc-MDP whole-body bone scan demonstrated only very limited bone metastases. PMID- 24152641 TI - Usefulness of FDG PET/CT in the diagnosis of eosinophilic fasciitis. AB - Eosinophilic fasciitis is a rare disorder with similar characteristics of scleroderma-like illness. We report a case of eosinophilic fasciitis in a 37-year old woman with a 3-month history of progressive stiffness involving her forearms and lower legs. Laboratory test disclosed elevated erythrocyte sedimentation ratio and hypereosinophilia. On PET/CT images, FDG uptake was increased along the fasciae of bilateral upper and lower extremities while sparing muscles and subcutaneous fat. Biopsy was performed and histologic examination confirmed diagnosis of eosinophilic fasciitis. FDG PET/CT may be helpful in the diagnosis of eosinophilic fasciitis as it could clearly illustrate anatomical involvement of the disease. PMID- 24152642 TI - Primary central nervous system lymphoma and meningioma in DOTATATE PET/CT. AB - Although meningiomas are among the most frequent intracranial tumors, primary central nervous system lymphoma represents a rare variant of extranodal non Hodgkin-type lymphoma. Here, we report on a 73-year-old man with 2 suspicious intracerebral lesions. Combined DOTATATE PET/CT identified 1 lesion as meningioma, whereas the second lesion could not be further specified although a different meningioma was felt very unlikely. Open biopsy of this lesion confirmed the diagnosis of primary central nervous system lymphoma. PMID- 24152643 TI - Huge primary soft tissue sarcoma of the breast on bone scan. AB - A 54-year-old woman had a primary breast sarcoma with rapid enlargement in 3 months. The mass became so huge that it was more than 20 cm in diameter and occupied the entire right breast on presentation. Extraosseous uptake was present in this mass and demonstrated a unique picture, mimicking the posture of a racing driver who holds a helmet under the armpit, on the bone scan. PMID- 24152644 TI - Multiple-gated acquisition scan with normal left ventricular ejection fraction and LBBB. AB - Multiple-gated blood pool angiography (MUGA) using 99mTc-UltraTag (Mallinckrodt Inc., Maryland Heights, MO) labeled RBCs was performed in a patient with B-cell lymphoma for evaluation of the left ventricular ejection fraction before starting chemotherapy. Quantitative measurements from MUGA demonstrated normal left ventricular ejection fraction. However, cine images revealed delayed contraction of the left ventricle compared with that of the right, and phase contrast images demonstrated offset of the ventricles' phases. Evaluation with ECG showed delayed depolarization of the left ventricle consistent with LBBB. Phase imaging abnormalities detected on MUGA may be overlooked. Specific patterns of phase abnormalities may direct the physicians' attention toward yet unrecognized diagnoses. PMID- 24152645 TI - 99mTc-sestamibi using a direct conversion molecular breast imaging system to assess tumor response to neoadjuvant chemotherapy in women with locally advanced breast cancer. AB - PURPOSE: The objective of this study was to determine the ability of breast imaging with 99mTc-sestamibi and a direct conversion-molecular breast imaging (MBI) system to predict early response to neoadjuvant chemotherapy (NAC). METHODS: Patients undergoing NAC for breast cancer were imaged with a direct conversion-MBI system before (baseline), at 3 to 5 weeks after onset, and after completion of NAC. Tumor size and tumor-to-background (T/B) uptake ratio measured from MBI images were compared with extent of residual disease at surgery using the residual cancer burden. RESULTS: Nineteen patients completed imaging and proceeded to surgical resection after NAC. Mean reduction in T/B ratio from baseline to 3 to 5 weeks for patients classified as RCB-0 (no residual disease), RCB-1 and RCB-2 combined, and RCB-3 (extensive residual disease) was 56% (SD, 0.20), 28% (SD, 0.20), and 4% (SD, 0.15), respectively. The reduction in the RCB 0 group was significantly greater than in RCB-1/2 (P = 0.036) and RCB-3 (P = 0.001) groups. The area under the receiver operator characteristic curve for determining the presence or absence of residual disease was 0.88. Using a threshold of 50% reduction in T/B ratio at 3 to 5 weeks, MBI predicted presence of residual disease at surgery with a diagnostic accuracy of 89.5% (95% confidence interval [CI], 0.64%-0.99%), sensitivity of 92.3% (95% CI, 0.74% 0.99%), and specificity of 83.3% (95% CI, 0.44%-0.99%). The reduction in tumor size at 3 to 5 weeks was not statistically different between RCB groups. CONCLUSIONS: Changes in T/B ratio on MBI images performed at 3 to 5 weeks following initiation of NAC were accurate at predicting the presence or absence of residual disease at NAC completion. PMID- 24152646 TI - Axillary reverse mapping using 99mTc-SC: a case illustration. AB - Lymphedema is a common complication in breast carcinoma patients undergoing axillary lymph node dissection. Although there is a significant reduction in the lymphedema rate with sentinel lymph node biopsy compared to axillary lymph node dissection, there is some risk after sentinel lymph node biopsy. Axillary reverse mapping, an emerging concept aims at identifying and preserving the draining lymph node of the arm that is invariably devoid of malignancy. This concept if validated may prevent lymphedema in breast carcinoma patients. Axillary reverse mapping node can be identified using a radiotracer or blue dye. We describe the procedure using filtered Tc-SC. PMID- 24152647 TI - Dual-isotope 99mTc-MIBI/123I parathyroid scintigraphy in primary hyperparathyroidism: comparison of subtraction SPECT/CT and pinhole planar scan. AB - PURPOSE: In patients with primary hyperparathyroidism, the preoperative imaging objective is to locate accurately and reliably uniglandular or multiglandular hyperfunctioning parathyroid, to guide surgery, particularly for minimally invasive method. Subtraction planar scintigraphy with dual-isotope (I/Tc-MIBI) is an efficient examination to specify abnormal parathyroid location, but without accurate anatomic reference. This lack should be avoided by a hybrid SPECT/CT image acquisition. METHODS: We compared planar scans (neck and mediastinum parallel-hole, associated with anterior neck pinhole) to neck and mediastinum SPECT/CT, all with subtraction (I/Tc-MIBI) method, in exact location of abnormal parathyroid in 50 patients with sporadic primary hyperparathyroidism. Surgical and histological findings were used as the standard of comparison. RESULTS: Sensitivity is equivalent for the 2 protocols (86% and 75% for SPECT/CT and planar protocol, respectively, P = 0.15), but SPECT/CT was highly specific (specificity 100% and 90% for SPECT/CT and planar protocol, respectively, P = 0.04). In patients with concomitant thyroid disease, subtraction SPECT/CT appeared to be more sensitive than planar protocol (88% and 62% for SPECT/CT and planar protocol, respectively, P = 0.04). CONCLUSIONS: In preoperative assessment of primary hyperparathyroidism and to guide surgery, we propose to perform first subtraction SPECT/CT and to complete it with neck pinhole, only if tomoscintigraphy is negative. PMID- 24152648 TI - Robin Hood caught in Wonderland: brain SPECT findings. AB - We present the case of a 53-year-old woman presenting several episodes of body image distortions, ground deformation illusions, and problems assessing distance in the orthostatic position corresponding to the Alice in Wonderland syndrome. No symptoms were reported when sitting or lying down. She had uncontrolled hypertension, hyperglycemia, hypercholesterolemia, and a history of head trauma. Her condition had been diagnosed with left internal carotid artery dissection 2 years earlier. Brain SPECT with 99mTc-ECD performed after i.v. injection of the radiotracer in supine and in standing positions showed hypoperfusion in the healthy contralateral frontoparietal operculum (Robin Hood syndrome), deteriorating when standing up. PMID- 24152649 TI - Potential false-positive meckel scan due to displaced kidney caused by recurrent retroperitoneal teratoma. AB - We report the findings of a Meckel scan in a 19-year-old patient treated for retroperitoneal teratoma with intermittent tarry stool for 1 month. Two focal stases of radioactivity in the right upper quadrant of the abdomen were noted. SPECT/CT for localization revealed that these 2 foci were within the displaced right kidney along with an adjacent bulky retroperitoneal mass. The patient subsequently underwent surgery, and histopathological studies confirmed recurrent teratoma. Two foci of increased radioactivity instead of 1 may have provided hints for the physiological characteristics of such lesions. PMID- 24152650 TI - PET/CT study performed after an oral administration of 18F-fluoride. AB - A 52-year-old woman with right breast cancer was referred for 18F-fluoride whole body PET/CT for the assessment of bone metastases. The peripheral i.v. access was not obtained after multiple attempts. The radiopharmaceutical was administered by oral route. PMID- 24152651 TI - Combined measurement of cerebral and cerebellar blood flow on preoperative brain perfusion SPECT imaging predicts development of new cerebral ischemic events after endarterectomy for symptomatic unilateral cervical carotid stenosis. AB - PURPOSE: The aim of this study was to determine whether the ratio of blood flow contralateral-to-affected asymmetry in the cerebellar hemisphere to blood flow affected-to-contralateral asymmetry in the middle cerebral artery (MCA) territory (AR(cbl)/AR(MCA)) on preoperative brain perfusion SPECT could identify patients at risk for new cerebral ischemic events after carotid endarterectomy (CEA) for symptomatic unilateral cervical carotid stenosis. For the purposes of this study, new cerebral ischemic events included neurological deficits and cerebral ischemic lesions on diffusion-weighted MRI. METHODS: Brain blood flow was assessed using 123I-IMP SPECT in 101 patients. A region of interest was automatically placed in the bilateral MCA territories and in the bilateral cerebellar hemispheres using a 3-dimensional stereotaxic region-of-interest template, and the AR(cbl)/AR(MCA) was calculated. Diffusion-weighted MRI was performed within 3 days before and 24 hours after surgery. Patients were neurologically tested before induction of general anesthesia and after recovery from general anesthesia. RESULTS: New cerebral ischemic events after CEA were observed in 12 patients (12%). Multivariate analysis revealed that only high AR(cbl)/AR(MCA) was significantly associated with the development of new postoperative cerebral ischemic events (95% confidence interval, 1.945-8.452; P = 0.0070). The AR(cbl)/AR(MCA) provided 75% sensitivity, 84% specificity, and 39% positive and 96% negative predictive values in predicting development of new postoperative cerebral ischemic events. CONCLUSIONS: The AR(cbl)/AR(MCA) on preoperative brain perfusion SPECT could identify patients at risk for new cerebral ischemic events after CEA for unilateral cervical carotid stenosis. PMID- 24152653 TI - An unusual case of diffuse large B-cell lymphoma involving the vulva evaluated by 18F-FDG PET/CT. AB - We describe an unusual case of diffuse large B-cell lymphoma involving the vulva detected and staged by F-FDG PET/CT. An 83-year-old female patient with history of endometrial carcinoma underwent F-FDG PET/CT for follow-up. PET/CT detected an area of increased F-FDG uptake corresponding to a vulvar nodule; moderate and diffuse F-FDG uptake in the bone marrow was also evident. Based on these PET/CT findings, the patient underwent biopsy of the vulvar nodule. Histology demonstrated the presence of a diffuse large B-cell lymphoma of the vulva. Bone marrow biopsy was positive for lymphoid infiltration. PMID- 24152654 TI - Tips for a physician in getting the right job, part VI: some possible interview questions for an executive position. AB - This article examines numerous general questions and possible responses that will be of special interest for those doctors interviewing for an administrative position. These queries will be presented under the topic headings of why do you want to change jobs, what are your strong and weak points, what are your credentials to do this job well, and what are your career objectives. However, some of these questions and answers will also be helpful to those physicians seeking a clinical job. Additional types of questions and answers, such as those found in behavioral, situational, and stress interviews, will be discussed in subsequent articles. PMID- 24152652 TI - FDG PET/CT imaging of oropharyngeal squamous cell carcinoma: characteristics of human papillomavirus-positive and -negative tumors. AB - OBJECTIVE: The objective of this study was to assess differences in morphological and glycolytic characteristics of primary tumors and locoregional nodal disease between human papillomavirus (HPV)-positive and HPV-negative oropharyngeal head and neck squamous cell carcinoma. METHODS: This was a retrospective analysis of 123 baseline FDG PET/CT scans from patients (aged 57.0 +/- 10.6 years) with newly diagnosed oropharyngeal SCC between January 2003 and June 2012. There were 98 HPV positive and 25 HPV-negative patients. SUVmax, SUVpeak, and SUVmean based on lean body mass, as well as RECIST (Response Evaluation Criteria In Solid Tumors) dimensions, metabolic tumor volume (gradient and threshold-segmentation methods) and total lesion glycolysis, were determined for primary and locoregional nodal disease. RESULTS: Human papillomavirus-negative primary tumors were significantly larger as measured by RECIST longest diameter (P = 0.002) and slightly more heterogeneous as measured by the heterogeneity index (P = 0.07), higher SUVmax (P < 0.01), SUVpeak (P = 0.01), SUVmean (P = 0.01), metabolic tumor volume (P = 0.002), and total lesion glycolysis (P = 0.001), for both segmentation methods. Index parameters of HPV-positive nodal disease tend to be larger, but some with no statistical significance (P > 0.05). There was no significant difference in the metabolic parameters of primary tumor or nodal metastases for HPV-positive patients with and without smoking history. CONCLUSIONS: Index morphologic and glycolytic parameters as measured in FDG PET/CT are significantly larger in HPV negative as compared with HPV-positive primary oropharyngeal carcinoma. In contrast, the same parameters trended to be larger in HPV-positive regional nodal disease. PMID- 24152655 TI - Port-site metastasis after laparoscopic removal of an isolated adrenal metastasis in a patient with breast cancer detected with FDG PET/CT. AB - Adrenal metastasis from breast cancer rarely occurs in the course of this disease. Laparoscopic surgery has increased in the therapy for malignant tumors because of its lower morbidity and mortality compared with conventional surgical methods. However, complications such as the appearance of a port-site metastasis may also occur. Clinical examination and conventional cross-sectional imaging usually reveal this only at advanced stage. The authors reported on a case with abdominal wall port-site metastasis detected with F-FDG PET/CT 33 months after the laparoscopic removal of a late-onset, PET/CT-verified adrenal metastasis from lobular breast cancer. PMID- 24152656 TI - FDG PET/CT findings in 3 cases of pulmonary peripheral T-cell lymphoma. AB - Pulmonary involvement of peripheral T-cell lymphoma is rare. It is difficult to make a clinical and radiologic diagnosis of pulmonary lymphomatous involvement, yet the diagnosis is often critical in determining treatment. We present 3 cases of pulmonary peripheral T-cell lymphoma with FDG PET/CT findings. In these 3 cases, FDG PET/CT images revealed multiple bilateral FDG-avid nodules, masses, or mass-like consolidations with or without air bronchogram. Familiarity with these imaging features may be helpful for the diagnosis and differential diagnosis. PMID- 24152657 TI - Enhanced CT and FDG PET/CT in malignant solitary fibrous tumor of the lung. AB - Although some histological features of solitary fibrous tumor are related to its aggressive behavior, tumors with benign features may also follow an aggressive behavior. An 18-year-old male patient was referred after the detection of multiple bilateral pulmonary lesions on a chest x-ray in a health examination 2 months ago. These lesions showed inhomogeneous enhancement on enhanced CT and intense FDG uptake (SUVmax, 21.8) on PET/CT. CT-guided biopsy revealed histologically benign solitary fibrous tumor. PMID- 24152658 TI - Integrated whole-body PET/MRI with 18F-FDG, 18F-FDOPA, and 18F-FDA in paragangliomas in comparison with PET/CT: NIH first clinical experience with a single-injection, dual-modality imaging protocol. AB - PURPOSE: Paragangliomas (PGLs) are tumors that can metastasize and recur; therefore, lifelong imaging follow-up is required. Hybrid PET/CT is an essential tool to image PGLs. Novel hybrid PET/MRI scanners are currently being studied in clinical oncology. We studied the feasibility of simultaneous whole-body PET/MRI to evaluate patients with PGLs. METHODS: Fifty-three PGLs or PGL-related lesions from 8 patients were evaluated. All patients underwent a single-injection, dual modality imaging protocol consisting of a PET/CT and a subsequent PET/MRI scan. Four patients were evaluated with F-FDG, 2 with F-fluorodihydroxyphenylalanine, and 2 with F-fluorodopamine. PET/MRI data were acquired using a hybrid whole-body 3-tesla integrated PET/MRI scanner. PET and MRI data (Dixon sequence for attenuation correction and T2-weighted sequences for anatomic allocation) were acquired simultaneously. Imaging workflow and imaging times were documented. PET/MRI and PET/CT data were visually assessed (blindly) in regards to image quality, lesion detection, and anatomic allocation and delineation of the PET findings. RESULTS: With hybrid PET/MRI, we obtained high-quality images in an acceptable acquisition time (median, 31 minutes; range, 25-40 minutes) with good patient compliance. A total of 53 lesions, located in the head and neck area (6 lesions), mediastinum (2 lesions), abdomen and pelvis (13 lesions), lungs (2 lesions), liver (4 lesions), and bones (26 lesions), were evaluated. Fifty-one lesions were detected with PET/MRI and confirmed by PET/CT. Two bone lesions (L4 body, 8 mm, and sacrum, 6 mm) were not detectable on an F-FDA scan PET/MRI, likely because F-FDA was washed out between PET/CT and PET/MRI acquisitions. Coregistered MRI tended to be superior to coregistered CT for head and neck, abdomen, pelvis, and liver lesions for anatomic allocation and delineation. CONCLUSIONS: Clinical PGL evaluation with hybrid PET/MRI is feasible with high quality image and can be obtained in a reasonable time. It could be particularly beneficial for the pediatric population and for precise lesion definition in the head and neck, abdomen, pelvis, and liver. PMID- 24152659 TI - MRI, enhanced CT, and FDG PET/CT in basal cell carcinoma of the prostate. AB - Primary basal cell carcinoma of the prostate is a very rare neoplasm with a good prognosis. A 55-year-old man presented with urinary frequency for 2 months. Serum prostate-specific antigen level was normal. T2-weighted MR images showed an inhomogeneously hyperintense tumor in the prostate. Enhanced CT showed heterogeneous enhancement of the tumor. FDG PET/CT showed strong FDG uptake of the tumor with SUVmax of 14.1. Prostate biopsy findings revealed basal cell carcinoma with high proliferation index. PMID- 24152660 TI - Rosai-Dorfman disease mimics lymphoma on FDG PET/CT in a pediatric patient. AB - A previously healthy 3-year-old girl developed rhinorrhea, painful right neck swelling, and fever. Contrast-enhanced CT of the neck revealed cervical lymphadenopathy, for which lymphoma was considered. FDG PET/CT images showed intense activity not only in the neck but also in the thorax, abdomen, and pelvis. Biopsy was performed, and the diagnosis of Rosai-Dorfman disease was made. PMID- 24152662 TI - Intense splenic 99mTc-MDP uptake in a patient with myelofibrosis. AB - 99mTc-MDP bone scan was performed in a 49-year-old woman with breast cancer. Whole-body bone scan showed multiple foci of increased MDP activity in the bone and intense splenic 99mTc-MDP uptake. Initial bone marrow aspiration in multiple locations yielded no blood cells. A subsequent bone marrow biopsy in the left anterior superior iliac spine showed myelofibrosis in addition to the known bone metastasis. PMID- 24152661 TI - Tube feeding increases the gastric-emptying rate determined by gastroesophageal scintigraphy. AB - OBJECTIVE: The aim of this study was to determine whether tube feeding affects the rate of gastric emptying determined by gastroesophageal reflux scintigraphy in pediatric patients. METHODS: Gastroesophageal reflux scintigraphy studies of 700 pediatric patients aged 1 week to 16 years were retrospectively analyzed. From these, 350 subjects received their study meal via a feeding tube, and 350 subjects received their meal as oral feeding. Gastric-emptying rate at 60 minutes was calculated, and the results compared. Stratification analysis for age, sex, and type and volume of administered meal was also performed. RESULTS: The average rate of the gastric emptying was higher in the tube feeding compared with oral feeding group (52.9% +/- 17.9% vs 44.2% +/- 15.1% gastric emptying at 1 hour, P < 0.01). The prevalence of fast gastric emptying, defined as greater than 50% emptying at 60 minutes, was also higher in the tube feeding group, being registered in 59.7% (209/350 cases) versus only 31.4% (110/350 cases) in the oral feeding group, P < 0.01. The difference persisted following stratification analysis for sex, age, and type and volume of ingested meal. CONCLUSIONS: Our findings show that tube feeding increases the rate of gastric emptying determined by gastroesophageal reflux scintigraphy in pediatric patients. The effect proved independent on such factors as sex, age, and type or volume of ingested meal. PMID- 24152663 TI - Head and neck tumor hypoxia imaging by 18F-fluoroazomycin-arabinoside (18F-FAZA) PET: a review. AB - Tumor hypoxia is known to be associated with poor clinical outcome; therefore, patients with hypoxic tumors might benefit from more intensive treatment approaches. This is particularly true for patients with head and neck cancer. Pretreatment assessment of hypoxia in tumors would be desirable, not only to predict prognosis but also to select patients for more aggressive treatment.As an alternative to the invasive polarographic needle electrode method, there is the possibility of using PET with radiopharmaceuticals visualizing hypoxia. Most hypoxia imaging studies on head and cancer have been performed using F-labeled fluoromisonidazole (F-FMISO). A chemically related molecule, F-fluoroazomycin arabinoside (F-FAZA), seems to have superior kinetic properties and may therefore be the radiopharmaceutical of choice.This minireview summarizes the published literature on animal and human F-FAZA PET studies. Furthermore, future perspectives on how individualized treatment could be applied in patients with hypoxic head and neck tumors are discussed, for instance, the use of hypoxia sensitizers or special intensity-modulated radiation therapy techniques achieving tumor subvolume dose escalation. PMID- 24152664 TI - Changing the intraoperative nodal status of a breast cancer patient using freehand SPECT for sentinel lymph node biopsy. AB - Radio-guided sentinel lymph node biopsy in early-stage breast cancer is standard of care. Freehand SPECT is a system for intraoperative visualization of radioactivity in the body. It generates a 3-dimensional image of the radioactivity distribution complementing the acoustic information of the gamma probe by providing depth and radioactive uptake information. In the reported case, freehand SPECT was used in a breast cancer patient as a control method after conventional sentinel lymph node biopsy. Freehand SPECT identified an additional lymph node, changing the original stage from pN1(mic) (micrometastasis) to pN1a (nodal positive), resulting in an axillary lymph node dissection. PMID- 24152665 TI - 131I therapy using rhTSH stimulation and dosimetry in metastatic malignant struma ovarii. AB - A 38-year-old woman with metastatic malignant struma ovarii, including massive liver metastases and retroperitoneal lymphadenopathy, underwent ovarian resection and retroperitoneal lymph nodes excision, partial hepatectomy, and radiofrequency ablation for liver metastases. She underwent thyroidectomy and received three I treatments using recombinant human thyrotropin stimulation and radioiodine dosimetry. posttherapy I imaging, anatomic images, and thyroglobulin levels showed significant diminution in the tumor burdens and remarkable decline in thyroglobulin levels. This case provided valuable information on recombinant human thyrotropin-assisted I ablation in conjunction with dosimetry in an unusual presentation of iodine-avid malignant struma ovarii with bulky metastases. PMID- 24152666 TI - Gene transcription in the zebrafish embryo: regulators and networks. AB - The precise spatial and temporal control of gene expression is a key process in the development, maintenance and regeneration of the vertebrate body. A substantial proportion of vertebrate genomes encode genes that control the transcription of the genetic information into mRNA. The zebrafish is particularly well suited to investigate gene regulatory networks underlying the control of gene expression during development due to the external development of its transparent embryos and the increasingly sophisticated tools for genetic manipulation available for this model system. We review here recent data on the analysis of cis-regulatory modules, transcriptional regulators and their integration into gene regulatory networks in the zebrafish, using the developing spinal cord as example. PMID- 24152667 TI - Effects of a one-year home-based case management intervention on falls in older people: a randomized controlled trial. AB - OBJECTIVES: To investigate the effects of a home-based one-year case management intervention in older people with functional dependency and repeated contact with the health care services on self-reported falls and self-reported injurious falls. METHODS: The study was a randomized controlled trial with repeated follow ups. The sample (n = 153) was consecutively and randomly assigned to the intervention group (n = 80, mean age = 81.4 [SD 5.9]) or control group (n = 73, mean age = 81.6 [SD 6.8]). The intervention group received a case management intervention which comprised monthly home visits during 12 months by nurses and physiotherapists employing a multifactorial preventive approach. RESULTS: In the intervention group, 96 falls occurred during the intervention period compared with 85 falls in the control group (p = .900). There were 40 and 38 injurious falls (p = .669) in the intervention and control groups, respectively. CONCLUSIONS: This home-based case management intervention was not able to prevent falls or injurious falls. PMID- 24152668 TI - Protein adsorption on various plasma-treated polyethylene terephthalate substrates. AB - Protein adhesion and cell response to plasma-treated polymer surfaces were studied. The polymer polyethylene terephthalate (PET) was treated in either an oxygen plasma to make the surface hydrophilic, or a tetrafluoromethane CF(4) plasma to make the surface hydrophobic. The plasma source was radiofrequency (RF) discharge. The adsorption of albumin and other proteins from a cell-culture medium onto these surfaces was studied using a quartz crystal microbalance (QCM), X-ray photoelectron spectroscopy (XPS) and atomic force microscopy (AFM). The cellular response to plasma-treated surfaces was studied as well using an MTT assay and scanning electron microscopy (SEM). The fastest adsorption rate was found on the hydrophilic oxygen plasma-treated sample, and the lowest was found on the pristine untreated sample. Additionally, the amount of adsorbed proteins was higher for the oxygen-plasma-treated surface, and the adsorbed layer was more viscoelastic. In addition, cell adhesion studies support this finding because the best cell adhesion was observed on oxygen-plasma-treated substrates. PMID- 24152669 TI - Four new glycosides from the fruit of Xanthium sibiricum Patr. AB - Four new glycosides, namely 3beta-norpinan-2-one 3-O-beta-d-apiofuranosyl-(1->6) beta-d-glucopyranoside (1), (6Z)-3-hydroxymethyl-7-methylocta-1,6-dien-3-ol 8-O beta-d-glucopyranoside (2), (6E)-3-hydroxymethyl-7-methylocta-1,6-dien-3-ol 8-O beta-d-gluco-pyranoside (3), and 7-[(beta-d-apiofuranosyl-(1->6)-beta-d glucopyranosyl)oxymethy]-8,8-dimethyl-4,8-dihydrobenzo[1,4]thiazine-3,5-dione (4), were isolated from the fruits of Xanthium sibiricum Patr together with three known compounds, xanthiside (5), adenosine (6), and 2,3-dihydroxy-1-(4-hydroxy-3 methoxyphenyl)-propan-1-one (7). The structures of the new compounds were determined on the basis of detailed spectroscopic analyses. PMID- 24152670 TI - Ultrasound-assisted extraction (UAE) and solvent extraction of papaya seed oil: yield, fatty acid composition and triacylglycerol profile. AB - The main objective of the current work was to evaluate the suitability of ultrasound-assisted extraction (UAE) for the recovery of oil from papaya seed as compared to conventional extraction techniques (i.e., Soxhlet extraction (SXE) and solvent extraction (SE)). In the present study, the recovery yield, fatty acid composition and triacylglycerol profile of papaya seed oil obtained from different extraction methods and conditions were compared. Results indicated that both solvent extraction (SE, 12 h/25 degrees C) and ultrasound-assisted extraction (UAE) methods recovered relatively high yields (79.1% and 76.1% of total oil content, respectively). Analysis of fatty acid composition revealed that the predominant fatty acids in papaya seed oil were oleic (18:1, 70.5% 74.7%), palmitic (16:0, 14.9%-17.9%), stearic (18:0, 4.50%-5.25%), and linoleic acid (18:2, 3.63%-4.6%). Moreover, the most abundant triacylglycerols of papaya seed oil were triolein (OOO), palmitoyl diolein (POO) and stearoyl oleoyl linolein (SOL). In this study, ultrasound-assisted extraction (UAE) significantly (p < 0.05) influenced the triacylglycerol profile of papaya seed oil, but no significant differences were observed in the fatty acid composition of papaya seed oil extracted by different extraction methods (SXE, SE and UAE) and conditions. PMID- 24152671 TI - Copper-catalyzed three- five- or seven-component coupling reactions: the selective synthesis of cyanomethylamines, N,N-bis(cyanomethyl)amines and N,N' bis(cyanomethyl)methylenediamines based on a Strecker-type synthesis. AB - We have demonstrated that a cooperative catalytic system comprised of CuCl and Cu(OTf)(2) could be used to effectively catalyse the three-, five- and seven component coupling reactions of aliphatic or aromatic amines, formaldehyde, and trimethylsilyl cyanide (TMSCN), and selectively produce in good yields the corresponding cyanomethylamines, N,N-bis(cyanomethyl)amines and N,N' bis(cyanomethyl)methylenediamines. PMID- 24152672 TI - G-quadruplexes as potential therapeutic targets for embryonal tumors. AB - Embryonal tumors include a heterogeneous group of highly malignant neoplasms that primarily affect infants and children and are characterized by a high rate of mortality and treatment-related morbidity, hence improved therapies are clearly needed. G-quadruplexes are special secondary structures adopted in guanine (G) rich DNA sequences that are often present in biologically important regions, e.g. at the end of telomeres and in the regulatory regions of oncogenes such as MYC. Owing to the significant roles that both telomeres and MYC play in cancer cell biology, G-quadruplexes have been viewed as emerging therapeutic targets in oncology and as tools for novel anticancer drug design. Several compounds that target these structures have shown promising anticancer activity in tumor xenograft models and some of them have entered Phase II clinical trials. In this review we examine approaches to DNA targeted cancer therapy, summarize the recent developments of G-quadruplex ligands as anticancer drugs and speculate on the future direction of such structures as a potential novel therapeutic strategy for embryonal tumors of the nervous system. PMID- 24152673 TI - Volatile compounds profile of sous-vide cooked pork cheeks as affected by cooking conditions (vacuum packaging, temperature and time). AB - The volatile organic compound (VOC) profile of pork cheeks as affected by the cooking conditions was investigated. Pork cheeks were cooked under different combinations of temperature (60 degrees C or 80 degrees C), time (5 or 12 h) and vacuum (vacuum or air-packaged). As a general rule, the VOCs originating from lipid degradation were positively affected by the cooking temperature and negatively by the cooking time, reaching the highest amounts in pork cheeks cooked at 80 degrees C during 5 h and the lowest in samples cooked at 80 degrees C during 12 h. On the contrary, VOCs originated from amino acids and Maillard reactions were positively affected by both factors. The proportion between lipid degradation and amino acids reactions was estimated by the hexanal/3-methylbutanal ratio, which reached its highest values in samples cooked at 60 degrees C during 5 h in the presence of air and the lowest values in samples cooked at 80 degrees C during 12 h, regardless of the vacuum status. PMID- 24152674 TI - Hypolipidemic and antioxidant properties of phenolic compound-rich extracts from white ginseng (Panax ginseng) in cholesterol-fed rabbits. AB - In this study, the effect of low-molecular weight white ginseng compounds on various biochemical indices, including blood lipid concentrations and antioxidant enzyme activities and morphological changes was investigated in rabbits with high cholesterol diet-induced hypercholesterolemia. The experimental animals were 16 week-old male New Zealand white rabbits divided into normal control diet, high cholesterol diet, and high cholesterol with 0.05% white ginseng low-molecule compound groups, treated for 4 weeks. Blood lipid concentrations were higher in the high cholesterol groups compared to the normal control group but were not improved by the white ginseng low-molecular weight compound. We note however that antioxidant enzyme activities and morphological changes of the aorta showed that white ginseng small compounds had a positive effect on hypercholesterolemia. Based on such results, low-molecular weight compounds rich in phenolic compounds in white ginseng can be said to be effective in part in improving hyperlipidemia and atherosclerosis induced by a high cholesterol diet among New Zealand white rabbits. PMID- 24152675 TI - Synthesis and structure-activity relationships of amino acid conjugates of cholanic acid as antagonists of the EphA2 receptor. AB - The Eph-ephrin system plays a critical role in tumor growth and vascular functions during carcinogenesis. We had previously identified cholanic acid as a competitive and reversible EphA2 antagonist able to disrupt EphA2-ephrinA1 interaction and to inhibit EphA2 activation in prostate cancer cells. Herein, we report the synthesis and biological evaluation of a set of cholanic acid derivatives obtained by conjugation of its carboxyl group with a panel of naturally occurring amino acids with the aim to improve EphA2 receptor inhibition. Structure-activity relationships indicate that conjugation of cholanic acid with linear amino acids of small size leads to effective EphA2 antagonists whereas the introduction of aromatic amino acids reduces the potency in displacement studies. The b-alanine derivative 4 was able to disrupt EphA2 ephrinA1 interaction in the micromolar range and to dose-dependently inhibit EphA2 activation on PC3 cells. These findings may help the design of novel EphA2 antagonists active on cancer cell lines. PMID- 24152676 TI - Sesquiterpene lactones and their derivatives inhibit high glucose-induced NF kappaB activation and MCP-1 and TGF-beta1 expression in rat mesangial cells. AB - Diabetic nephropathy (DN) is one of the most common and serious chronic complications of diabetes mellitus, however, no efficient clinical drugs exist for the treatment of DN. We selected and synthesized several sesquiterpene lactones (SLs), and then used the MTT assay to detect rat mesangial cells (MCs) proliferation, ELISA to measure the expression level of monocyte chemoattractant protein-1 (MCP-1), transforming growth factor beta (TGF-beta1) and fibronectin(FN), real-time fluorescent quantitative PCR analysis to measure the MCP-1 and TGF-beta1 gene expression, western blot to detect the level of IkappaBalpha protein and EMSA to measure the activation of nuclear factor kappa B (NF-kappaB). We discovered that SLs, including parthenolide (PTL), micheliolide (MCL), arglabin, and isoalantolactone (IAL), as well as several synthetic analogs of these molecules, could effectively attenuate the high glucose-stimulated activation of NF-kappaB, the degradation of IkappaBalpha, and the expression of MCP-1, TGF-beta1 and FN in rat mesangial cells (MCs). These findings suggest that SLs and their derivatives have potential as candidate drugs for the treatment of DN. PMID- 24152677 TI - Synthesis of laboratory Ultrasound Contrast Agents. AB - Ultrasound Contrast Agents (UCAs) were developed to maximize reflection contrast so that organs can be seen clearly in ultrasound imaging. UCAs increase the signal to noise ratio (SNR) by linear and non-linear mechanisms and thus help more accurately visualize the internal organs and blood vessels. However, the UCAs on the market are not only expensive, but are also not optimized for use in various therapeutic research applications such as ultrasound-aided drug delivery. The UCAs fabricated in this study utilize conventional lipid and albumin for shell formation and perfluorobutane as the internal gas. The shape and density of the UCA bubbles were verified by optical microscopy and Cryo SEM, and compared to those of the commercially available UCAs, Definity(r) and Sonovue(r). The size distribution and characteristics of the reflected signal were also analyzed using a particle size analyzer and ultrasound imaging equipment. Our experiments indicate that UCAs composed of spherical microbubbles, the majority of which were smaller than 1 um, were successfully synthesized. Microbubbles 10 um or larger were also identified when different shell characteristics and filters were used. These laboratory UCAs can be used for research in both diagnoses and therapies. PMID- 24152678 TI - Utility of warning signs in guiding admission and predicting severe disease in adult dengue. AB - BACKGROUND: The recommendation from the 2009 World Health Organization guidelines for managing dengue suggests that patients with any warning sign can be hospitalized for observation and management. We evaluated the utility of using warning signs to guide hospital admission and predict disease progression in adults. METHODS: We conducted a prospective cohort study from January 2010 to September 2012. Daily demographic, clinical and laboratory data were collected from adult dengue patients. Warning signs were recorded. The proportion of admitted patients using current admission criteria and warning signs was compared. The sensitivity, specificity, positive and negative predictive values of warning signs in predicting disease progression were also evaluated. RESULTS: Four hundred and ninety-nine patients with confirmed dengue were analyzed. Using warning signs instead of the current admission criteria will lead to a 44% and 31% increase in admission for DHF II-IV and SD cases respectively. The proportion of non-severe dengue cases which were admitted also increased by 32% for non DHF II-IV and 33% for non-SD cases. Absence of any warning signs had a NPV of 91%, 100% and 100% for DHF I-IV, DHF II-IV and SD. Of those who progressed to severe illness, 16.3% had warning signs on the same day while 51.3% had warning signs the day before developing severe illness, respectively. CONCLUSIONS: Our findings demonstrated that patients without any warning signs can be managed safely with ambulatory care to reduce hospital resource burden. No single warning sign can independently predict disease progression. The window from onset of warning sign to severe illness in most cases was within one day. PMID- 24152679 TI - Lemierre's syndrome. AB - Lemierre's syndrome is a condition characterized by thrombophlebitis of the internal jugular vein and bacteremia caused by primarily anaerobic organisms, following a recent oropharyngeal infection. This has been an uncommon illness in the era of antibiotic therapy, though it has been reported with increasing frequency in the past 15 years. Lemierre's syndrome should be suspected in young healthy patients with prolonged symptoms of pharyngitis followed by symptoms of septicemia or pneumonia, or an atypical lateral neck pain. Diagnosis is often confirmed by identification of thrombophlebitis of the internal jugular vein and growth of anaerobic bacteria on blood culture. Treatment involves prolonged antibiotic therapy occasionally combined with anticoagulation. We review the literature and a case of a child with Lemierre's syndrome. PMID- 24152680 TI - Transplantation of enteric neural stem/progenitor cells into the irradiated young mouse hippocampus. AB - Radiotherapy is an effective treatment for brain tumors but often results in cognitive deficits in survivors. Transplantation of embryonic or brain-derived neural stem/progenitor cells (BNSPCs) ameliorated cognitive impairment after irradiation (IR) in animal models. However, such an approach in patients requires a clinically relevant source of cells. We show for the first time the utilization of enteric neural stem/progenitor cells (ENSPCs) from the postnatal intestinal wall as a source of autologous cells for brain repair after injury caused by IR. Cells were isolated from the intestinal wall and propagated in vitro for 1 week. Differentiation assays showed that ENSPCs are multipotent and generated neurons, astrocytes, and myofibroblasts. To investigate whether ENSPCs can be used in vivo, postnatal day 9 mice were subjected to a single moderate irradiation dose (6 or 8 Gy). Twelve days later, mice received an intrahippocampal injection of syngeneic ENSPCs. Four weeks after transplantation, 0.5% and 1% of grafted ENSPCs were detected in the dentate gyrus of sham and irradiated animals, respectively, and only 0.1% was detected after 16 weeks. Grafted ENSPCs remained undifferentiated but failed to restore IR-induced loss of BNSPCs and the subsequent impaired growth of the dentate gyrus. We observed microglia activation, astrogliosis, and loss of granule neurons associated with grafted ENSPC clusters. Transplantation of ENSPCs did not ameliorate IR-induced impaired learning and memory. In summary, while autologous ENSPC grafting to the brain worked technically, even in the absence of immunosuppression, the protocols need to be modified to improve survival and integration. PMID- 24152681 TI - Metformin increases the novel adipokine cartonectin/CTRP3 in women with polycystic ovary syndrome. AB - CONTEXT: Recently cartonectin was reported as a novel adipokine, with lower levels in diet-induced obese mice, glucose-lowering effects, and antiinflammatory and cardioprotective properties. Polycystic ovary syndrome (PCOS) is a proinflammatory state associated with obesity, diabetes, dyslipidemia, and cardiovascular complications. OBJECTIVES: The objective of the study was to investigate cartonectin levels and regulation in sera and adipose tissue (AT) as well as the effects of metformin of women with PCOS and control subjects. DESIGN: This was a cross-sectional study [PCOS (n = 83) and control (n = 39) subjects]. Real-time PCR and Western blotting were used to assess mRNA and protein expression of cartonectin. Serum cartonectin was measured by an ELISA. RESULTS: Serum and omental adipose tissue cartonectin were significantly lower in women with PCOS compared with control subjects (P < .05 and P < .01, respectively). Furthermore, cartonectin showed a significant negative association with body mass index, waist to hip ratio, glucose, insulin, total cholesterol, low-density lipoprotein-cholesterol, triglycerides, High sensitivity C-reactive protein (hs CRP) and intima-media thickness (P < .05 and P < .01, respectively); in multiple regression analyses, triglycerides (P =.040) and hs-CRP (P = .031) were predictive of cartonectin levels (P < .05). After 6 months of metformin treatment, there was an associated increase in serum cartonectin (P < .05). Importantly, changes in hs-CRP were significantly negatively correlated with changes in serum cartonectin (P = .033). Finally, cartonectin protein production and secretion into conditioned media were significantly increased by metformin in control human omental AT explants (P < .05). CONCLUSIONS: Serum and omental AT cartonectin are lower in women with PCOS. Metformin treatment increases serum cartonectin levels in these women and in omental AT explants. PMID- 24152682 TI - Dandy-Walker malformation, papillary thyroid carcinoma, and SDHD-associated paraganglioma syndrome. PMID- 24152683 TI - Hibernoma: a clinical model for exploring the role of brown adipose tissue in the regulation of body weight? AB - CONTEXT: Hibernoma is a rare benign tumor histologically similar to brown adipose tissue. Some studies reported weight loss in patients with this tumor; however, the mechanisms have never been investigated. OBJECTIVE: The purpose of this study is to explore the impact of hibernoma resection on the whole-body metabolism. PATIENT AND METHODS: A 68-year-old woman was examined after a weight loss of 10 kg in 6 months. Body composition, food intake, physical activity, blood levels of thyroid hormones, and lipid profile were assessed before surgery and during 1 year after surgery. The patient's resting energy expenditure (REE) over time was compared to a control group of 18 matched healthy volunteers. RESULTS: Within 1 year after hibernoma resection, the patient gained 15 kg of body weight. This was associated with fat mass gain (+41%), mainly in the abdominal region (+48%). The patient also developed hepatic nonalcoholic steatosis, mild hypertriglyceridemia, and reduced levels of high-density lipoproteins. REE increased during the dynamic phase of weight gain, compared to the presurgery measurement, and returned to baseline after 1 year. Food intake was increased by 37.5% 6 weeks after resection of the hibernoma and returned to baseline values within 6 months. CONCLUSIONS: In our study conditions, hibernoma did not alter REE, but weight gain did. Specific physical activities and dietetic follow-ups are suggested for those patients to prevent excess fat mass gain and metabolic disorders after hibernoma resection. More studies should focus on hibernoma mechanisms inducing weight loss. PMID- 24152684 TI - Multicenter clinical experience with the Afirma gene expression classifier. AB - BACKGROUND: Increasingly, patients with thyroid nodule cytology labeled atypical (or follicular lesion) of undetermined significance (AUS/FLUS) or follicular neoplasm (FN) undergo diagnostic analysis with the Afirma gene expression classifier (GEC). No long-term, multisite analysis of Afirma GEC performance has yet been performed. METHODS: We analyzed all patients who had received Afirma GEC testing at five academic medical centers between 2010 and 2013. Nodule and patient characteristics, fine needle aspiration cytology, Afirma GEC results, and subsequent clinical or surgical follow-up were obtained for 339 patients. Results were analyzed for pooled test performance, impact on clinical care, and site-to site variation. RESULTS: Three hundred thirty-nine patients underwent Afirma GEC testing of cytologically indeterminate nodules (165 AUS/FLUS; 161 FN; 13 suspicious for malignancy) and 174 of 339 (51%) indeterminate nodules were GEC benign, whereas 148 GEC were suspicious (44%). GEC results significantly altered care recommendations, as 4 of 175 GEC benign were recommended for surgery in comparison to 141 of 149 GEC suspicious (P<.01). Of 121 Cyto Indeterminate/GEC Suspicious nodules surgically removed, 53 (44%) were malignant. Variability in site-to-site GEC performance was confirmed, as the proportion of GEC benign varied up to 29% (P=.58), whereas the malignancy rate in nodules cytologically indeterminate/GEC suspicious varied up to 47% (P=.11). Seventy-one of 174 GEC benign nodules had documented clinical follow-up for an average of 8.5 months, in which 1 of 71 nodules proved cancerous. CONCLUSIONS: These multicenter, clinical experience data confirm originally published Afirma GEC test performance and demonstrate its substantial impact on clinical care recommendations. Although nonsignificant site-to-site variation exists, such differences should be anticipated by the practicing clinician. Follow-up of GEC benign nodules thus far confirm the clinical utility of this diagnostic test. PMID- 24152685 TI - Prognostic nomograms to predict oncological outcome of thyroid cancers. AB - CONTEXT: Thyroid cancers represent a conglomerate of diverse histological types with equally variable prognosis. There is no reliable prognostic model to predict the risks of relapse and death for different types of thyroid cancers. OBJECTIVE: The purpose of this study was to build prognostic nomograms to predict individualized risks of relapse and death of thyroid cancer within 10 years of diagnosis based on patients' prognostic factors. DESIGN: Competing risk subhazard models were used to develop prognostic nomograms based on the information on individual patients in a population-based thyroid cancer cohort followed up for a median period of 126 months. Analyses were conducted using R version 2.13.2. The R packages cmprsk10, Design, and QHScrnomo were used for modeling, developing, and validating the nomograms for prediction of patients' individualized risks of relapse and death of thyroid cancer. SETTING: This study was performed at CancerCare Manitoba, the sole comprehensive cancer center for a population of 1.2 million. PATIENTS: Participants were a population-based cohort of 2306 consecutive thyroid cancers observed in 2296 patients in the province of Manitoba, Canada, during 1970 to 2010. MAIN OUTCOME MEASURES: Outcomes were discrimination (concordance index) and calibration curves of nomograms. RESULTS: Our cohort of 570 men and 1726 women included 2155 (93.4%) differentiated thyroid cancers. On multivariable analysis, patient's age, sex, tumor histology, T, N, and M stages, and clinically or radiologically detectable posttreatment gross residual disease were independent determinants of risk of relapse and/or death. The individualized 10-year risks of relapse and death of thyroid cancer in the nomogram were predicted by the total of the weighted scores of these determinants. The concordance indices for prediction of thyroid cancer-related deaths and relapses were 0.92 and 0.76, respectively. The calibration curves were very close to the diagonals. CONCLUSIONS: We have successfully developed prognostic nomograms for thyroid cancer with excellent discrimination (concordance indices) and calibration. PMID- 24152686 TI - A Leydig cell tumor of the ovary resulting in extreme hyperandrogenism, erythrocytosis, and recurrent pulmonary embolism. AB - CONTEXT: Secondary erythrocytosis due to androgens is most commonly seen in the context of T replacement therapy in men. Leydig cell ovarian tumors are a rare cause of virilization, erythrocytosis, and thromboembolism. PATIENT CASE: We describe the case of a 55-year-old postmenopausal woman who presented with a 3 year history of frontal balding and virilization and a 5-year history of obstructive sleep apnea. She had not experienced significant alteration in libido or mood. Menstruation had ceased at age 46. She had a history of recurrent pulmonary embolism and unexplained secondary erythrocytosis. Past hematological investigations had not revealed any evidence of malignancy or thrombophilia, and the JAK2 mutation was negative. The serum erythropoietin was mildly elevated at 20.3 mIU/mL (normal range, 3.6-16.6 mIU/mL). The serum T was initially reported (by immunoassays) as >1600 ng/dL (>55 nmol/L). Similarly, serum androstenedione (>1000 ng/dL; >35 nmol/L), estradiol (169 pg/mL; 621 pmol/L), and dehydroepiandrosterone sulfate (348 MUg/dL; 9.4 MUmol/L) were all elevated for a postmenopausal woman. Repeat analysis of the serum T by mass spectrometry showed an extremely elevated level of 4270 ng/dL (148 nmol/L). Computed tomography scan revealed a 5.0-cm right ovarian tumor. After surgical removal of an ovarian Leydig cell tumor, her virilization, erythrocytosis, and sleep apnea resolved. CONCLUSION: Hyperandrogenism in women should be considered as a rare but important cause of erythrocytosis, recurrent thromboembolism, and sleep apnea. The diagnosis of hyperandrogenism requires a careful history and physical examination because in postmenopausal women, menstrual disturbance does not occur and cosmetic measures may mask overt clinical features. PMID- 24152687 TI - Characterization of SNARE proteins in human pituitary adenomas: targeted secretion inhibitors as a new strategy for the treatment of acromegaly? AB - CONTEXT: Targeted secretion inhibitors (TSIs), a new class of recombinant biotherapeutic proteins engineered from botulinum toxin, represent a novel approach for treating diseases with excess secretion. They inhibit hormone secretion from targeted cell types through cleavage of SNARE (soluble N ethylmaleimide-sensitive factor-activating protein receptor) proteins. qGHRH LH(N)/D is a TSI targeting pituitary somatotroph through binding to the GHRH receptor and cleavage of the vesicle-associated membrane protein (VAMP) family of SNARE proteins. OBJECTIVE: Our objective was to study SNARE protein expression in pituitary adenomas and to inhibit GH secretion from somatotropinomas using qGHRH LH(N)/D. DESIGN: We analyzed human pituitary adenoma analysis for SNARE expression and response to qGHRH-LH(N)/D treatment. SETTING: The study was conducted in University Hospitals. PATIENTS: We used pituitary adenoma samples from 25 acromegaly and 47 nonfunctioning pituitary adenoma patients. OUTCOME: Vesicle-SNARE (VAMP1-3), target-SNARE (syntaxin1, SNAP-23, and SNAP-25), and GHRH receptor detection with RT-qPCR, immunocytochemistry, and immunoblotting. Assessment of TSI catalytic activity on VAMPs and release of GH from adenoma cells. RESULTS: SNARE proteins were variably expressed in pituitary samples. In vitro evidence using recombinant GFP-VAMP2&3 or pituitary adenoma lysates suggested sufficient catalytic activity of qGHRH-LH(N)/D to degrade VAMPs, but was unable to inhibit GH secretion in somatotropinoma cell cultures. CONCLUSIONS: SNARE proteins are present in human pituitary somatotroph adenomas that can be targeted by TSIs to inhibit GH secretion. qGHRH-LH(N)/D was unable to inhibit GH secretion from human somatotroph adenoma cells. Further studies are required to understand how the SNARE proteins drive GH secretion in human somatotrophs to allow the development of novel TSIs with a potential therapeutic benefit. PMID- 24152688 TI - Statin therapy worsens insulin sensitivity in women with polycystic ovary syndrome (PCOS): a prospective, randomized, double-blind, placebo-controlled study. AB - CONTEXT: Statins have been shown to improve hyperandrogenism in women with polycystic ovary syndrome (PCOS). However, their use has also been associated with impairment of glucose metabolism and an increased risk of type 2 diabetes mellitus. Because women with PCOS are prone to disturbances in glucose metabolism, statin therapy could also have negative effects. OBJECTIVE: Our objective was to explore the effects of atorvastatin therapy on hormonal and metabolic parameters in women with PCOS. DESIGN AND SETTING: We conducted a randomized, double-blind, placebo-controlled 6-month follow-up study conducted at Oulu University Hospital, Finland. PATIENTS: Women with PCOS (Rotterdam criteria) were treated with atorvastatin (20 mg/d, n = 15) or placebo (n = 13) for 6 months. INTERVENTIONS: Fasting serum samples were collected at baseline and at 3 and 6 months. Oral and iv glucose tolerance tests were performed at 0 and 6 months. MAIN OUTCOME MEASURES: Androgen secretion and glucose metabolism were measured. RESULTS: Fasting levels and area under the curve of insulin increased significantly and insulin sensitivity (insulinogenic and Matsuda indexes) decreased during 6 months of atorvastatin therapy. Serum levels of dehydroepiandrosterone sulfate decreased in the atorvastatin group, whereas no change was observed in serum testosterone levels. Levels of C-reactive protein, total and low-density lipoprotein-cholesterol, and triglycerides decreased significantly during statin therapy. CONCLUSIONS: Atorvastatin therapy improves chronic inflammation and lipid profile, but it impairs insulin sensitivity in women with PCOS. Because women with PCOS have an increased risk of developing type 2 diabetes mellitus, the results suggest that statin therapy should be initiated on the basis of generally accepted criteria and individual risk assessment of cardiovascular disease, and not only because of PCOS. PMID- 24152689 TI - Clinical review: Diabetes in the adolescent: transitional issues. AB - CONTENT: Orchestrating a seamless transition from pediatric to adult care can be a daunting task in caring for youth with diabetes mellitus. This clinical review focuses on physical and psychosocial aspects affecting the care of adolescents and young adults with diabetes, evaluates how these aspects can be barriers in the process of transitioning these patients to adult diabetes care, and provides clinical approaches to optimizing the transition process in order to improve diabetes care and outcomes. EVIDENCE ACQUISITION AND SYNTHESIS: A PubMed search identified articles related to transition to adult diabetes care and physical and psychosocial assessment of adolescents with diabetes. An Internet search for transition of diabetes care identified online transition resources. The synthesis relied on the cumulative experience of the authors. We identify barriers to successful transition and provide a checklist for streamlining the process. CONCLUSIONS: Key points in the transition to adult diabetes care include: 1) starting the process at least 1 year before the anticipated transition; 2) assessing individual patients' readiness and preparedness for adult care; 3) providing guidance and education to the patient and family; 4) utilizing transition guides and resources; and 5) maintaining open lines of communication between the pediatric and adult providers. No current single approach is effective for all patients. Challenges remain in successful transition to avoid short- and long-term complications of diabetes mellitus. PMID- 24152690 TI - Hyperthyroidism increases brown fat metabolism in humans. AB - CONTEXT: Thyroid hormones are important regulators of brown adipose tissue (BAT) development and function. In rodents, BAT metabolism is up-regulated by thyroid hormones. OBJECTIVE: The purpose of this article was to investigate the impact of hyperthyroidism on BAT metabolism in humans. DESIGN: This was a follow-up study using positron emission tomography imaging. MAIN OUTCOME MEASURES: Glucose uptake (GU) and perfusion of BAT, white adipose tissue, skeletal muscle, and thyroid gland were measured using [18F]2-fluoro-2-deoxy-D-glucose and [15O]H2O and positron emission tomography in 10 patients with overt hyperthyroidism and in 8 healthy participants. Five of the hyperthyroid patients were restudied after restoration of euthyroidism. Supraclavicular BAT was quantified with magnetic resonance imaging or computed tomography and energy expenditure (EE) with indirect calorimetry. RESULTS: Compared with healthy participants, hyperthyroid participants had 3-fold higher BAT GU (2.7+/-2.3 vs 0.9+/-0.1 MUmol/100 g/min, P=.0013), 90% higher skeletal muscle GU (P<.005), 45% higher EE (P<.005), and a 70% higher lipid oxidation rate (P=.001). These changes were reversible after restoration of euthyroidism. During hyperthyroidism, serum free T4 and free T3 were strongly associated with EE and lipid oxidation rates (P<.001). TSH correlated inversely with BAT and skeletal muscle glucose metabolism (P<.001). Hyperthyroidism had no effect on BAT perfusion, whereas it stimulated skeletal muscle perfusion (P=.04). Thyroid gland GU did not differ between hyperthyroid and euthyroid study subjects. CONCLUSIONS: Hyperthyroidism increases GU in BAT independently of BAT perfusion. Hyperthyroid patients are characterized by increased skeletal muscle metabolism and lipid oxidation rates. PMID- 24152692 TI - The drivers of woody species richness and density in a Neotropical savannah. AB - Environmental filtering prevents species without certain attributes from occurring in local communities. Traits respond differently to different abiotic factors, assembling communities with varying composition along environmental gradients. Here, we measured proxies of soil fertility, disturbance by fire, response and physiological traits to assess how these variables interact to determine woody species richness and density in a Neotropical savannah. We explicitly incorporated our assumptions about how different abiotic filters influence different subsets of traits into a statistical model using structural equation modelling, yielding a more accurate representation of the assembly process. Fire had an effect on resistance traits, whereas soil fertility influenced physiological traits. Resistance traits explained both the richness and density of plots, whereas physiological traits explained only the density. Fewer fire events led to richer and denser plots. Similarly, areas with lower cation exchange capacity assembled less dense communities. Furthermore, we showed that structural equation modelling yielded a realistic representation of the bivariate interactions of distinct environmental filters with different subsets of traits. PMID- 24152691 TI - Validation of an instrument to evaluate quality of life in the aging population: WHOQOL-AGE. AB - BACKGROUND: There is a need for short, specific instruments that assess quality of life (QOL) adequately in the older adult population. The aims of the present study were to obtain evidence on the validity of the inferences that could be drawn from an instrument to measure QOL in the aging population (people 50+ years old), and to test its psychometric properties. METHODS: The instrument, WHOQOL AGE, comprised 13 positive items, assessed on a five-point rating scale, and was administered to nationally representative samples (n = 9987) from Finland, Poland, and Spain. Cronbach's alpha was employed to assess internal consistency reliability, whereas the validity of the questionnaire was assessed by means of factor analysis, graded response model, Pearson's correlation coefficient and unpaired t-test. Normative values were calculated across countries and for different age groups. RESULTS: The satisfactory goodness-of-fit indices confirmed that the factorial structure of WHOQOL-AGE comprises two first-order factors. Cronbach's alpha was 0.88 for factor 1, and 0.84 for factor 2. Evidence supporting a global score was found with a second-order factor model, according to the goodness-of-fit indices: CFI = 0.93, TLI = 0.91, RMSEA = 0.073. Convergent validity was estimated at r = 0.75 and adequate discriminant validity was also found. Significant differences were found between healthy individuals (74.19 +/- 13.21) and individuals with at least one chronic condition (64.29 +/- 16.29), supporting adequate known-groups validity. CONCLUSIONS: WHOQOL-AGE has shown good psychometric properties in Finland, Poland, and Spain. Therefore, considerable support is provided to using the WHOQOL-AGE to measure QOL in older adults in these countries, and to compare the QOL of older and younger adults. PMID- 24152693 TI - Disruptive camouflage impairs object recognition. AB - Whether hiding from predators, or avoiding battlefield casualties, camouflage is widely employed to prevent detection. Disruptive coloration is a seemingly well known camouflage mechanism proposed to function by breaking up an object's salient features (for example their characteristic outline), rendering objects more difficult to recognize. However, while a wide range of animals are thought to evade detection using disruptive patterns, there is no direct experimental evidence that disruptive coloration impairs recognition. Using humans searching for computer-generated moth targets, we demonstrate that the number of edge intersecting patches on a target reduces the likelihood of it being detected, even at the expense of reduced background matching. Crucially, eye-tracking data show that targets with more edge-intersecting patches were looked at for longer periods prior to attack, and passed-over more frequently during search tasks. We therefore show directly that edge patches enhance survivorship by impairing recognition, confirming that disruptive coloration is a distinct camouflage strategy, not simply an artefact of background matching. PMID- 24152694 TI - Indian monsoons shape dispersal phenology of plants. AB - The Indian monsoons are a major seasonal climatic event over the Indian subcontinent, heralding the arrival of the wet season. Many features of life, biological and cultural, are intimately synchronized to this seasonality. In this paper, we show that the Indian monsoons might have played an important role in shaping the fruiting time and hence dispersal phenology of plant species in the subcontinent. PMID- 24152696 TI - Severe acute dystonia/akathisia after paliperidone palmitate application--a case study. PMID- 24152695 TI - Context-dependent expression of sperm quality in the fruitfly. AB - In most species, females mate multiply within a reproductive cycle, invoking post copulatory selection on ejaculatory components. Much research has focused on disentangling the key traits important in deciding the outcomes of sperm competition and investigating patterns of covariance among these traits. Less attention has focused on the degree to which such patterns might be context dependent. Here, we examine whether the expression of sperm viability-a widely used measure of sperm quality-and patterns of covariance between this trait and male reproductive morphologies, change across distinct age classes and across naturally occurring genotypes, when expressed in both heterozygotic (extreme outbred) and homozygotic (extreme inbred) states in the fruitfly Drosophila melanogaster. Older males, and heterozygous males, generally exhibited higher sperm viability. The male age effect seems at least partly explained by a positive association between sperm numbers and viability. First, old males possessed more stored sperm than young males, and second, sperm numbers and viability were also positively associated within each age class. Furthermore, we found a positive association between sperm viability and testis size, but only among heterozygous, old males. These results suggest that sperm quality is a labile trait, with expression levels that are context-dependent and shaped by multiple, potentially interacting, factors. PMID- 24152697 TI - Through the keyhole: expanding the scope of feline medicine. PMID- 24152698 TI - Introduction to endoscopy in the cat: where to start? What to buy? AB - PRACTICAL RELEVANCE: For many years, endoscopy and minimally invasive surgery have been considered 'standard' in human healthcare. With the expansion of the used medical equipment market, and the falling cost of new equipment, veterinary practitioners are now starting to appreciate first-hand the benefits of performing endoscopic procedures: for example, vastly improved visualisation of the surgical site, reduced tissue trauma, minimal postoperative pain and faster recovery times, especially in feline patients. In addition, clients almost always choose a less invasive procedure if the capabilities are present, and will often consent to these procedures sooner than they would to conventional surgery. AIM: This article aims to guide the general feline practitioner towards a basic understanding of endoscopic and ancillary equipment, and in the direction of appropriate training required to perform routine endoscopic procedures. EVIDENCE BASE: The authors draw on information provided in a combination of published texts, articles, reviews and their own clinical experience to provide a practical information guide for the clinician interested in feline endoscopy. PMID- 24152699 TI - Gastrointestinal endoscopy in the cat: equipment, techniques and normal findings. AB - PRACTICAL RELEVANCE: Feline gastrointestinal (GI) endoscopy is in high demand, particularly by cat owners already aware of the clinical benefits and availability of this procedure within the human healthcare system. This article will provide a basic introduction to GI flexible endoscopy, covering important aspects of endoscope selection, clinical indications, and basic techniques required to perform a thorough and diagnostically meaningful examination in the cat. CLINICAL CHALLENGES: Challenges associated with implementing endoscopy in GI tract investigations can include lack of appropriate/suitable-sized equipment to perform a thorough examination in the cat, insufficient operator training/understanding in how to 'drive the scope' through the GI tract, and/or lack of confidence in differentiating normal from abnormal. AUDIENCE: This article is intended to familiarize and motivate the feline practitioner to develop basic endoscopic skills. Clinical proficiency can only be obtained through use of appropriate equipment, formal training and hours of practice indistinguishing normal from abnormal. EVIDENCE BASE: The guidance contained in this article is based on a combination of the published literature, the authors' personal experience and the experience of colleagues. PMID- 24152700 TI - Gastrointestinal endoscopy in the cat: diagnostics and therapeutics. AB - PRACTICAL RELEVANCE: Endoscopic examination of the feline gastrointestinal (GI) tract is a minimally invasive method for obtaining biopsy samples of the GI mucosa, which is often necessary for a diagnosis of chronic GI diseases. In addition endoscopy has several therapeutic indications including foreign body retrieval, oesophageal stricture dilation and placement of a percutaneous gastrostomy tube. CLINICAL CHALLENGES: Initially, practitioners must learn the subtle manipulations necessary to efficiently guide the endoscope through the GI tract to obtain biopsy samples of high diagnostic quality, and develop skills for implementing interventional procedures (eg, foreign body removal). Another challenge in mastering GI endoscopy is the ability to recognise normal from abnormal, which requires many years of practice and experience. Endoscopy is a diagnostic and interventional procedure that should be performed only in conjunction with a thorough history, physical examination, appropriate laboratory evaluation, and radiographic and/or ultrasonographic imaging. AUDIENCE: This review is intended to familiarize both the general and referral practitioner with GI endoscopy as a minimally invasive diagnostic and therapeutic intervention for the feline patient. EVIDENCE BASE: The guidance contained within this article is based on a combination of the published literature, the authors' personal experience and the experience of colleagues. PMID- 24152701 TI - Upper respiratory tract endoscopy in the cat: a minimally invasive approach to diagnostics and therapeutics. AB - CLINICAL CHALLENGES: Endoscopy of the feline upper respiratory tract has always taken a bit of a back seat to exploration of the canine nose and paranasal sinuses, pharynx and trachea, due to some anatomic limitations and lack of availability of appropriate-sized equipment. PRACTICAL RELEVANCE: With proper training, however, even the inexperienced endoscopist can find that endoscopy and endoscopic surgery can be of tremendous utility in feline practice. What had previously been largely off-limits sites, in terms of direct visualization and surgical intervention, the feline rhinarium, paranasal sinuses, pharynx and trachea are now anatomic areas that can be effectively visualized in most clinical scenarios. Moreover, endoscopic surgery is now an area gaining significant appreciation for its diagnostic and therapeutic benefits. AUDIENCE: This article will not serve as a complete treatise on disease processes of the upper respiratory tract in cats, but rather is intended as a technical and instructional reference point on upper airway endoscopy for veterinary surgeons, both in first opinion as well as referral small animal practice. PMID- 24152703 TI - Your cat's environmental needs: practical tips for pet owners. PMID- 24152702 TI - Lower respiratory tract endoscopy in the cat: diagnostic approach to bronchial disease. AB - PRACTICAL RELEVANCE: Respiratory endoscopy is a useful diagnostic tool to evaluate the airways for the presence of mass lesions or foreign material while allowing for sample collection for cytologic and microbiologic assessment. While bronchial disease (eosinophilic or neutrophilic) is the most common lower respiratory disease identified in cats, infectious, anomalous and neoplastic conditions can clinically mimic inflammatory bronchial disease. Diagnostic imaging is unable to define the etiology for clinical signs of cough, tachypnea or respiratory difficulty, necessitating visual evaluation and collection of airway samples. Endoscopy allows intervention that can be life-saving and also confirmation of disease, which is important given that life-long medication is likely to be required for management of inflammatory airway disease. PATIENT GROUP: Cats with either airway or pulmonary disease benefit from laryngoscopy, tracheoscopy and bronchoscopy to determine an etiologic diagnosis. In the best situation, animals that require these procedures present early in the course of disease before clinical decompensation precludes anesthetic intervention. However, in some instances, these tests must be performed in unstable cats, which heightens the risk of the procedure. Cats that do not respond to empiric medical therapy can also benefit from bronchoscopic evaluation. CLINICAL CHALLENGES: Due to the small size of feline airways and the tendency for cats to develop laryngospasm, passage of endoscopic equipment can be difficult. Bronchoconstriction can lead to hemoglobin desaturation with oxygen and respiratory compromise. EVIDENCE BASE: This article reviews published studies and case reports pertaining to the diagnostic approach to feline respiratory disease, focusing specifically on endoscopic examination of the lower airways in cats. It also discusses appropriate case selection, equipment, endoscopic techniques and visual findings based primarily on the authors' experiences. PMID- 24152706 TI - The effect of creatine loading on neuromuscular fatigue in women. AB - PURPOSE: This study aimed to examine the effects of intermittent isometric fatigue on maximal voluntary contraction (MVC) strength, percent voluntary activation (%VA), peak twitch force (PTF), peak rate of force development (PRFD), half relaxation time (HRT), and maximal compound action potential (M-wave) amplitude of the soleus and medial gastrocnemius muscles before and after creatine (Cr) loading. METHODS: Using a double-blinded, placebo-controlled, randomized design, 12 women were assigned to a Cr (n = 6; mean age +/- SD = 23.3 +/- 3.0 yr) or placebo (PL; n = 6; mean age +/- SD = 21.3 +/- 1.6 yr) group. Participants supplemented four times daily for 5 d with 5 g of Cr + 10 g of fructose or 10 g of fructose. At baseline and after testing, an isometric MVC and the twitch interpolation procedure were used before and after a 4-min isometric fatigue protocol of the plantarflexor muscles, which consisted of six intermittent duty cycles per minute (7-s contraction, 3-s relaxation) at 70% MVC. RESULTS: There were no interactions between the Cr and PL groups (P > 0.05) for any dependent variable. The fatigue protocol reduced voluntary strength (-17.8%, P < 0.001) and %VA (-3.7%, P = 0.005). Baseline PTF (P < 0.005) and PRFD (P < 0.001) values were less than those of all respective time points, but PTF value decreased from 3 min to 4 min and after testing (P < 0.005). HRT increased from baseline to minutes 1 and 2 and then returned to baseline at minutes 3 and 4 and after testing. The M-wave did not change (P > 0.05). CONCLUSIONS: Five days of Cr loading did not influence isometric force, %VA, evoked twitch properties, or the central and peripheral aspects of fatigue measured in this study. PMID- 24152707 TI - Standing and mortality in a prospective cohort of Canadian adults. AB - PURPOSE: Several studies have documented significant associations between sedentary behaviors such as sitting or television viewing and premature mortality. However, the associations between mortality and other low-energy expenditure activities such as standing have not been explored. The purpose of this study was to examine the association between daily standing time and mortality among 16,586 Canadian adults 18-90 yr of age. METHODS: Information on self-reported time spent standing as well as several covariates including smoking, alcohol consumption, physical activity readiness, and moderate-to vigorous physical activity was collected at baseline in the 1981 Canada Fitness Survey. Participants were followed for an average of 12.0 yr for the ascertainment of mortality status. RESULTS: There were 1785 deaths (743 from cardiovascular disease [CVD], 530 from cancer, and 512 from other causes) in the cohort. After adjusting for age, sex, and additional covariates, time spent standing was negatively related to mortality rates from all causes, CVD, and other causes. Across successively higher categories of daily standing, the multivariable-adjusted hazard ratios were 1.00, 0.79, 0.79, 0.73, and 0.67 for all-cause mortality (P for trend <0.0001); 1.00, 0.82, 0.84, 0.68, and 0.75 for CVD mortality (P for trend 0.02); and 1.00, 0.76, 0.63, 0.67, and 0.65 for other mortality (P for trend <0.001). There was no association between standing and cancer mortality. There was a significant interaction between physical activity and standing (P < 0.05), and the association between standing and mortality was significant only among the physically inactive (<7.5 MET.h.wk). CONCLUSIONS: The results suggest that standing may not be a hazardous form of behavior. Given that mortality rates declined at higher levels of standing, standing may be a healthier alternative to excessive periods of sitting. PMID- 24152708 TI - S100A7 in the Fallopian tube: a comparative study. AB - The oviduct is a dynamic organ in which final gamete maturation, fertilization and early embryo development take place. It is considered to be a sterile site; however the mechanism for sterility maintenance is still unknown. S100A7 is an anti-microbial peptide that has been reported in human reproductive tissues such as prostate, testicle, ovary, normal cervical epithelium and sperm. The current work reports the presence of S100A7 in the Fallopian tube and its localization at the apical surface of epithelial cells. For comparison, porcine S100A7 was used for antibody development and search for peptide in reproductive tissues. Although present in boar seminal vesicles and seminal plasma, S100A7 was not detected on female porcine organs. Also, in contrast with the human protein, porcine S100A7 did not show anti-microbial activity under the conditions tested. Phylogenetic analyses showed high divergence of porcine S100A7 from human, primate, bovine, ovine and equine sequences, being the murine sequence at a most distant branch. The differences in sequence homology, Escherichia coli-cidal activity, detectable presence and localization of S100A7 from human and pig, suggest that there are possible different functions in each organism. PMID- 24152709 TI - Emergency department visits by persons aged 65 and over: United States, 2009 2010. AB - KEY FINDINGS: Data from the National Hospital Ambulatory Medical Care Survey, 2009-2010. In 2009-2010, a total of 19.6 million emergency department (ED) visits in the United States were made by persons aged 65 and over. The visit rate for this age group was 511 per 1,000 persons and increased with age. The percentage of ED visits made by nursing home residents, patients arriving by ambulance, and patients admitted to the hospital increased with age. Twenty-nine percent of ED visits by persons aged 65 and over were related to injury, and the percentage was higher among those aged 85 and over than among those aged 65-74 or 75-84. The percentage of ED visits caused by falls increased with age. PMID- 24152710 TI - Human T cell lymphotropic virus type 1- associated infective dermatitis in KwaZulu Natal, South Africa. AB - BACKGROUND: The Human T cell lymphotropic virus type 1 (HTLV-1)-associated infective dermatitis (IDH), is a chronic relapsing dermatitis which usually presents in children older than 2 years. A total of 300 cases have been reported worldwide (Latin America, the Caribbean and only 5 from Senegal). Neither IDH, nor its complications have been reported from the rest of Africa. We aimed to examine the clinical and aetiological characteristics of IDH in a cohort of South African children. METHODS: Attendees at the dermatology clinic at King Edward VIII Hospital, Durban underwent clinical examination. After obtaining consent those suspected of IDH had specimens taken for blood counts, immunoglobulins, serum protein electrophoresis, viral studies (including genotyping), skin swabs and stool examinations. RESULTS: Nineteen of 60 suspected cases recruited over 3 years met the diagnostic criteria for IDH. The male-to-female ratio was 1:2; mean age 8 years (range 0.7 to 15). Dermatitis mostly affected the scalp (78.9%) and axilla (73.7%); fewer children had nasal crusting (47.4%). Mean Ig A, IgG and IgM were raised, at 3.52 g/l, 22.6 g/l and 1.38 g/l, respectively. The median CD4 cell count was 1958 cells/mm3. Viral genotyping of all tested samples were positive for the Cosmopolitan, Subtype A (HTLV-1a). CONCLUSIONS: IDH is a distinct entity which also affects South Africans. Our patients were older at presentation and the majority did not present with nasal crusting as has been described in other countries. PMID- 24152711 TI - Positive epistasis between co-infecting plasmids promotes plasmid survival in bacterial populations. AB - Plasmids have a key role in the horizontal transfer of genes among bacteria. Although plasmids are catalysts for bacterial evolution, it is challenging to understand how they can persist in bacterial populations over the long term because of the burden they impose on their hosts (the 'plasmid paradox'). This paradox is especially perplexing in the case of 'small' plasmids, which are unable to self-transfer by conjugation. Here, for the first time, we investigate how interactions between co-infecting plasmids influence plasmid persistence. Using an experimental model system based on interactions between a diverse assemblage of 'large' plasmids and a single small plasmid, pNI105, in the pathogenic bacterium Pseudomonas aeruginosa, we demonstrate that positive epistasis minimizes the cost associated with carrying multiple plasmids over the short term and increases the stability of the small plasmid over a longer time scale. In support of these experimental data, bioinformatic analysis showed that associations between small and large plasmids are more common than would be expected owing to chance alone across a range of families of bacteria; more generally, we find that co-infection with multiple plasmids is more common than would be expected owing to chance across a wide range of bacterial phyla. Collectively, these results suggest that positive epistasis promotes plasmid stability in bacterial populations. These findings pave the way for future mechanistic studies aimed at elucidating the molecular mechanisms of plasmid plasmid interaction, and evolutionary studies aimed at understanding how the coevolution of plasmids drives the spread of plasmid-encoded traits. PMID- 24152712 TI - Modular community structure suggests metabolic plasticity during the transition to polar night in ice-covered Antarctic lakes. AB - High-latitude environments, such as the Antarctic McMurdo Dry Valley lakes, are subject to seasonally segregated light-dark cycles, which have important consequences for microbial diversity and function on an annual basis. Owing largely to the logistical difficulties of sampling polar environments during the darkness of winter, little is known about planktonic microbial community responses to the cessation of photosynthetic primary production during the austral sunset, which lingers from approximately February to April. Here, we hypothesized that changes in bacterial, archaeal and eukaryotic community structure, particularly shifts in favor of chemolithotrophs and mixotrophs, would manifest during the transition to polar night. Our work represents the first concurrent molecular characterization, using 454 pyrosequencing of hypervariable regions of the small-subunit ribosomal RNA gene, of bacterial, archaeal and eukaryotic communities in permanently ice-covered lakes Fryxell and Bonney, before and during the polar night transition. We found vertically stratified populations that varied at the community and/or operational taxonomic unit-level between lakes and seasons. Network analysis based on operational taxonomic unit level interactions revealed nonrandomly structured microbial communities organized into modules (groups of taxa) containing key metabolic potential capacities, including photoheterotrophy, mixotrophy and chemolithotrophy, which are likely to be differentially favored during the transition to polar night. PMID- 24152713 TI - Diverse capacity for 2-methylhopanoid production correlates with a specific ecological niche. AB - Molecular fossils of 2-methylhopanoids are prominent biomarkers in modern and ancient sediments that have been used as proxies for cyanobacteria and their main metabolism, oxygenic photosynthesis. However, substantial culture and genomic based evidence now indicates that organisms other than cyanobacteria can make 2 methylhopanoids. Because few data directly address which organisms produce 2 methylhopanoids in the environment, we used metagenomic and clone library methods to determine the environmental diversity of hpnP, the gene encoding the C-2 hopanoid methylase. Here we show that hpnP copies from alphaproteobacteria and as yet uncultured organisms are found in diverse modern environments, including some modern habitats representative of those preserved in the rock record. In contrast, cyanobacterial hpnP genes are rarer and tend to be localized to specific habitats. To move beyond understanding the taxonomic distribution of environmental 2-methylhopanoid producers, we asked whether hpnP presence might track with particular variables. We found hpnP to be significantly correlated with organisms, metabolisms and environments known to support plant-microbe interactions (P-value<10(-6)); in addition, we observed diverse hpnP types in closely packed microbial communities from other environments, including stromatolites, hot springs and hypersaline microbial mats. The common features of these niches indicate that 2-methylhopanoids are enriched in sessile microbial communities inhabiting environments low in oxygen and fixed nitrogen with high osmolarity. Our results support the earlier conclusion that 2-methylhopanoids are not reliable biomarkers for cyanobacteria or any other taxonomic group, and raise the new hypothesis that, instead, they are indicators of a specific environmental niche. PMID- 24152714 TI - Down under the tunic: bacterial biodiversity hotspots and widespread ammonia oxidizing archaea in coral reef ascidians. AB - Ascidians are ecologically important components of marine ecosystems yet the ascidian microbiota remains largely unexplored beyond a few model species. We used 16S rRNA gene tag pyrosequencing to provide a comprehensive characterization of microbial symbionts in the tunic of 42 Great Barrier Reef ascidian samples representing 25 species. Results revealed high bacterial biodiversity (3 217 unique operational taxonomic units (OTU0.03) from 19 described and 14 candidate phyla) and the widespread occurrence of ammonia-oxidizing Thaumarchaeota in coral reef ascidians (24 of 25 host species). The ascidian microbiota was clearly differentiated from seawater microbial communities and included symbiont lineages shared with other invertebrate hosts as well as unique, ascidian-specific phylotypes. Several rare seawater microbes were markedly enriched (200-700 fold) in the ascidian tunic, suggesting that the rare biosphere of seawater may act as a conduit for horizontal symbiont transfer. However, most OTUs (71%) were rare and specific to single hosts and a significant correlation between host relatedness and symbiont community similarity was detected, indicating a high degree of host-specificity and potential role of vertical transmission in structuring these communities. We hypothesize that the complex ascidian microbiota revealed herein is maintained by the dynamic microenvironments within the ascidian tunic, offering optimal conditions for different metabolic pathways such as ample chemical substrate (ammonia-rich host waste) and physical habitat (high oxygen, low irradiance) for nitrification. Thus, ascidian hosts provide unique and fertile niches for diverse microorganisms and may represent an important and previously unrecognized habitat for nitrite/nitrate regeneration in coral reef ecosystems. PMID- 24152715 TI - Single-cell genome and metatranscriptome sequencing reveal metabolic interactions of an alkane-degrading methanogenic community. AB - Microbial interactions have a key role in global geochemical cycles. Although we possess significant knowledge about the general biochemical processes occurring in microbial communities, we are often unable to decipher key functions of individual microorganisms within the environment in part owing to the inability to cultivate or study them in isolation. Here, we circumvent this shortcoming through the use of single-cell genome sequencing and a novel low-input metatranscriptomics protocol to reveal the intricate metabolic capabilities and microbial interactions of an alkane-degrading methanogenic community. This methanogenic consortium oxidizes saturated hydrocarbons under anoxic conditions through a thus-far-uncharacterized biochemical process. The genome sequence of a dominant bacterial member of this community, belonging to the genus Smithella, was sequenced and served as the basis for subsequent analysis through metabolic reconstruction. Metatranscriptomic data generated from less than 500 pg of mRNA highlighted metabolically active genes during anaerobic alkane oxidation in comparison with growth on fatty acids. These data sets suggest that Smithella is not activating hexadecane by fumarate addition. Differential expression assisted in the identification of hypothetical proteins with no known homology that may be involved in hexadecane activation. Additionally, the combination of 16S rDNA sequence and metatranscriptomic data enabled the study of other prevalent organisms within the consortium and their interactions with Smithella, thus yielding a comprehensive characterization of individual constituents at the genome scale during methanogenic alkane oxidation. PMID- 24152716 TI - Quantitative and qualitative impact of hospital effluent on dissemination of the integron pool. AB - There is increasing evidence that human activity, and especially the resulting effluent, has a major role in the dissemination of bacterial antibiotic resistance determinants in the environment. Hospitals are the major antibiotic consumers and thus facilitate the spread of antibiotic resistance. Questions are increasingly being raised about the management of hospital effluents, but their involvement in antibiotic-resistance dissemination has never been assessed. Integrons are a paradigm of genetic transfer between the environmental resistome and both commensal and pathogenic bacteria. In order to assess the impact of hospital activities on antibiotic-resistance dissemination in the environment, we monitored integrons and their gene cassettes in hospital effluents, and their release in the environment. We found that bacterial communities present in a hospital effluent contained a high proportion of integrons. In terms of both their gene cassette diversity and gene cassette arrays, the urban effluent and municipal wastewater treatment plant (WWTP) influent were most similar, whereas the hospital effluent and recirculation sludge exhibited very specific patterns. We found that anthropogenic activities led to the release of abundant integrons and antibiotic-resistance gene cassettes, but we observed no specific impact of hospital activities on the receiving environment. Furthermore, although the WWTP did not reduce the normalized integron copy number, it reduced the diversity of gene cassette arrays contained in the raw wastewater, underlining the effect of the biological treatment on the anthropogenic integron pool arriving at the WWTP. PMID- 24152717 TI - MIxS-BE: a MIxS extension defining a minimum information standard for sequence data from the built environment. PMID- 24152718 TI - Biofilm development and enhanced stress resistance of a model, mixed-species community biofilm. AB - Most studies of biofilm biology have taken a reductionist approach, where single species biofilms have been extensively investigated. However, biofilms in nature mostly comprise multiple species, where interspecies interactions can shape the development, structure and function of these communities differently from biofilm populations. Hence, a reproducible mixed-species biofilm comprising Pseudomonas aeruginosa, Pseudomonas protegens and Klebsiella pneumoniae was adapted to study how interspecies interactions affect biofilm development, structure and stress responses. Each species was fluorescently tagged to determine its abundance and spatial localization within the biofilm. The mixed-species biofilm exhibited distinct structures that were not observed in comparable single-species biofilms. In addition, development of the mixed-species biofilm was delayed 1-2 days compared with the single-species biofilms. Composition and spatial organization of the mixed-species biofilm also changed along the flow cell channel, where nutrient conditions and growth rate of each species could have a part in community assembly. Intriguingly, the mixed-species biofilm was more resistant to the antimicrobials sodium dodecyl sulfate and tobramycin than the single-species biofilms. Crucially, such community level resilience was found to be a protection offered by the resistant species to the whole community rather than selection for the resistant species. In contrast, community-level resilience was not observed for mixed-species planktonic cultures. These findings suggest that community level interactions, such as sharing of public goods, are unique to the structured biofilm community, where the members are closely associated with each other. PMID- 24152719 TI - Integrated transcriptomic and proteomic analysis of the global response of Wolbachia to doxycycline-induced stress. AB - The bacterium Wolbachia (order Rickettsiales), representing perhaps the most abundant vertically transmitted microbe worldwide, infects arthropods and filarial nematodes. In arthropods, Wolbachia can induce reproductive alterations and interfere with the transmission of several arthropod-borne pathogens. In addition, Wolbachia is an obligate mutualist of the filarial parasites that cause lymphatic filariasis and onchocerciasis in the tropics. Targeting Wolbachia with tetracycline antibiotics leads to sterilisation and ultimately death of adult filariae. However, several weeks of treatment are required, restricting the implementation of this control strategy. To date, the response of Wolbachia to stress has not been investigated, and almost nothing is known about global regulation of gene expression in this organism. We exposed an arthropod Wolbachia strain to doxycycline in vitro, and analysed differential expression by directional RNA-seq and label-free, quantitative proteomics. We found that Wolbachia responded not only by modulating expression of the translation machinery, but also by upregulating nucleotide synthesis and energy metabolism, while downregulating outer membrane proteins. Moreover, Wolbachia increased the expression of a key component of the twin-arginine translocase (tatA) and a phosphate ABC transporter ATPase (PstB); the latter is associated with decreased susceptibility to antimicrobials in free-living bacteria. Finally, the downregulation of 6S RNA during translational inhibition suggests that this small RNA is involved in growth rate control. Despite its highly reduced genome, Wolbachia shows a surprising ability to regulate gene expression during exposure to a potent stressor. Our findings have general relevance for the chemotherapy of obligate intracellular bacteria and the mechanistic basis of persistence in the Rickettsiales. PMID- 24152721 TI - Platelet activation dynamics evaluated using platelet-derived microparticles in Kawasaki disease. AB - BACKGROUND: Little is known about the platelet dynamics and the effect of antiplatelet therapy in Kawasaki disease (KD). The aim of this study was to clarify platelet activation dynamics in acute-phase KD patients by assaying platelet-derived microparticles (PDMPs). METHODS AND RESULTS: The PDMP level in 18 patients with acute KD was measured on ELISA. Of the 18 patients, 14 were receiving oral aspirin and i.v. immunoglobulin (IVIG) and 4, oral aspirin alone. Blood samples were drawn before, immediately after, and 10-14 days after IVIG infusion; thereafter, at 1, 2, and 3 months after the onset of disease. PDMP level before aspirin treatment was significantly higher in acute-phase KD patients than in the control subjects with common febrile diseases (P<0.01). In the acute-phase KD patients, IVIG significantly decreased PDMP level; the PDMP level was not lower on the similar day of KD in the patients who did not receive IVIG. Eight patients' PDMP level rebounded after aspirin was discontinued. CONCLUSIONS: Platelets are activated during acute-phase KD, which confirms the importance of antiplatelet therapy. In addition, platelet activation continues as long as 2 or 3 months after the acute phase, the time at which aspirin is commonly discontinued, and the timing of aspirin discontinuation should therefore be evaluated in each individual patient. PMID- 24152720 TI - Sympatric inhibition and niche differentiation suggest alternative coevolutionary trajectories among Streptomycetes. AB - Soil bacteria produce a diverse array of antibiotics, yet our understanding of the specific roles of antibiotics in the ecological and evolutionary dynamics of microbial interactions in natural habitats remains limited. Here, we show a significant role for antibiotics in mediating antagonistic interactions and nutrient competition among locally coexisting Streptomycete populations from soil. We found that antibiotic inhibition is significantly more intense among sympatric than allopatric Streptomycete populations, indicating local selection for inhibitory phenotypes. For sympatric but not allopatric populations, antibiotic inhibition is significantly positively correlated with niche overlap, indicating that inhibition is targeted toward bacteria that pose the greatest competitive threat. Our results support the hypothesis that antibiotics serve as weapons in mediating local microbial interactions in soil and suggest that coevolutionary niche displacement may reduce the likelihood of an antibiotic arms race. Further insight into the diverse roles of antibiotics in microbial ecology and evolution has significant implications for understanding the persistence of antibiotic inhibitory and resistance phenotypes in environmental microbes, optimizing antibiotic drug discovery and developing strategies for managing microbial coevolutionary dynamics to enhance inhibitory phenotypes. PMID- 24152722 TI - Assessing the cardiovascular risk between celecoxib and nonselective nonsteroidal antiinflammatory drugs in patients with rheumatoid arthritis and osteoarthritis. AB - BACKGROUND: A prospective, 3-year comparative observational study compared the risk of cardiovascular events in patients with osteoarthritis or rheumatoid arthritis prescribed celecoxib or a nonsteroidal antiinflammatory drug (NSAID). METHODS AND RESULTS: Patients prescribed celecoxib (n=5,470) or NSAIDs (n=5,059) between November 1, 2007, and July 31, 2008 in 1,084 hospitals and clinics in Japan were eligible for safety analysis. Mean (standard deviation) observation for the celecoxib group was 716 (420) days and 692 (426) days for the NSAID group (P=0.004). Composite I (adjudicated cardiovascular adverse events of myocardial infarction, angina pectoris, heart failure, cerebral infarction, cerebral hemorrhage) number of events (percentage) and rate/1,000 person years was 66 (1.2%) and 6.2 (10,745 person years), respectively, for the celecoxib and 65 (1.3%) and 6.8 (9,601 person years) for the NSAID (P=0.58) groups. Composite II (all cardiovascular events) number of events (percentage) and rate/1,000 person years was 79 (1.4%) and 7.4, respectively, for the celecoxib and 84 (1.7%) and 8.8 for the NSAID (P=0.26) group. Adjusted Cox hazards ratio (95% confidence interval) was 0.89 (0.63-1.27; P=0.52) for Composite I, 0.87 (0.63-1.19; P=0.39) for Composite II and 1.03 (0.75-1.41; P=0.87) for death from all causes. CONCLUSIONS: After adjustment for confounding variables, celecoxib was not associated with an increase of cardiovascular risk in comparison with nonselective NSAID in Japanese patients with rheumatoid arthritis or osteoarthritis in an observational setting. PMID- 24152723 TI - The adult with a fontan: a panacea without a cure? Review of long-term complications. AB - The univentricular heart includes a spectrum of complex cardiac defects that are managed by staged palliative surgical procedures, ultimately resulting in a Fontan procedure. Since 1971, when it was first developed, the procedure has undergone several variations. These patients require lifelong management, including a thorough knowledge of their anatomic substrate, hemodynamic status, management of rhythm and ventricular function, together with multi-organ evaluation. As these patients enter middle age, there is increasing awareness of long-term complications and mortality. This review highlights the concept behind the staged surgical palliations, the unique single ventricle physiology and the long-term complications in this complex cohort of patients. PMID- 24152724 TI - Asymmetry of the variability of heart rate and conduction time between atria and ventricles. AB - BACKGROUND: Heart rate asymmetry is caused by an unequal contribution of heart rate decelerations and accelerations to heart rate variability. This study evaluates the asymmetric properties of the variability of the AA, HH, VV, AH and HV intervals. METHODS AND RESULTS: We recorded 50 1-min intracardiac ECG tracings from 10 patients (18-66 years old; 8 females) during a routine electrophysiological study. Standard descriptors of variance asymmetry were calculated for all intervals. Nonparametric tests were used for statistical comparisons. The prolongations of VV (P=0.0297), AH (P=0.0133) and HV (P=0.0004) intervals contributed significantly more than their shortenings to their short term variance. The proportion of recordings with a larger contribution of prolongations than shortenings was significantly different from random for VV (0.66, P=0.0328), AH (0.68, P=0.0154) HV (0.74, P=0.0009). CONCLUSIONS: In addition to heart rate asymmetry (VV interval), the conduction from the atria, through the atrioventricular node, His-Purkinje system to ventricles shows asymmetric properties in 1-min tracings. PMID- 24152725 TI - Update on pediatric pulmonary arterial hypertension. Differences and similarities to adult disease. AB - Children and adults with pulmonary arterial hypertension (PAH) have similarities and differences in their background characteristics, hemodynamics, and clinical manifestations. Regarding genetic background, mutations in BMPR2-related pathways seem to be pivotal; however, it is likely that other modifier genes and bioactive mediators have roles in the various forms of PAH in children and adults. In pediatric PAH, there are no clear sex differences in incidence, age at onset, disease severity, or prognosis but, as compared with adults, syncope incidence, pulmonary vascular resistance, and mean pulmonary artery pressure are higher, and vasoreactivity to acute drug testing is more frequent, among children. Nevertheless, the pharmacokinetic effects of 3 major pulmonary vasodilators appear to be similar in children and adults with PAH. This review focuses on the specific pathophysiologic features of PAH in children. PMID- 24152726 TI - Ectopic pancreatic pseudocyst and cyst presenting as a cervical and mediastinal mass: case report and review of the literature. AB - Ectopic pancreas in the mediastinum is extremely rare. We are reporting on a case of a twenty two year old woman who presented to our clinic with a large cervical mass. The CT scan revealed a cystic lesion in the anterior mediastinum. The patient underwent surgical resection by cervical approach. A Cystic mass with pseudocysts, cysts and complete pancreatic tissue were found in pathology. There were no signs of pancreatitis or malignancy. No recurrence was observed after a follow up of four years. We reviewed the case reports describing this rare condition in the medical literature.We conclude that the possibility of ectopic pancreatic tissue should be included in the differential diagnosis of anterior mediastinal cystic mass, though as a remote possibility. Surgery is probably needed for the diagnosis and treatment. Posterior mediastinal pseudocyst is a different entity associated with acute pancreatitis. In those cases surgery is not recommended. Our third conclusion is that pancreatic tissue should be actively sought, if a structure resembling a pseudocyst is found in an unexpected location. VIRTUAL SLIDES: The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/1849369005957671. PMID- 24152727 TI - Enhanced cellular responses and distinct gene profiles in human fetoplacental artery endothelial cells under chronic low oxygen. AB - Fetoplacental endothelial cells are exposed to oxygen levels ranging from 2% to 8% in vivo. However, little is known regarding endothelial function within this range of oxygen because most laboratories use ambient air (21% O2) as a standard culture condition (SCN). We asked whether human umbilical artery endothelial cells (HUAECs) that were steadily exposed to the physiological chronic normoxia (PCN, 3% O2) for ~20-25 days differed in their proliferative and migratory responses to FGF2 and VEGFA as well as in their global gene expression compared with those in the SCN. We observed that PCN enhanced FGF2- and VEGFA-stimulated cell proliferation and migration. In oxygen reversal experiments (i.e., when PCN cells were exposed to SCN for 24 h and vice versa), we found that preexposure to 21% O2 decreased the migratory ability, but not the proliferative ability, of the PCN-HUAECs in response to FGF2 and VEGFA. These PCN-enhanced cellular responses were associated with increased protein levels of HIF1A and NOS3, but not FGFR1, VEGFR1, and VEGFR2. Microarray analysis demonstrated that PCN up-regulated 74 genes and down-regulated 86, 14 of which were directly regulated by hypoxia inducible factors as evaluated using in silico analysis. Gene function analysis further indicated that the PCN-regulated genes were highly related to cell proliferation and migration, consistent with the results from our functional assays. Given that PCN significantly alters cellular responses to FGF2 and VEGFA as well as transcription in HUAECs, it is likely that we may need to reexamine the current cellular and molecular mechanisms controlling fetoplacental endothelial functions, which were largely derived from endothelial models established under ambient O2. PMID- 24152728 TI - CCN2 modulates hair follicle cycling in mice. AB - It is critical to understand how stem cell activity is regulated during regeneration. Hair follicles constitute an important model for organ regeneration because, throughout adult life, they undergo cyclical regeneration. Hair follicle stem cells-epithelial cells located in the follicle bulge-are activated by periodic beta-catenin activity, which is regulated not only by epithelial-derived Wnt, but also, through as-yet-undefined mechanisms, the surrounding dermal microenvironment. The matricellular protein connective tissue growth factor (CCN2) is secreted into the microenvironment and acts as a multifunctional signaling modifier. In adult skin, CCN2 is largely absent but is unexpectedly restricted to the dermal papillae and outer root sheath. Deletion of CCN2 in dermal papillae and the outer root sheath results in a shortened telogen-phase length and elevated number of hair follicles. Recombinant CCN2 causes decreased beta-catenin stability in keratinocytes. In vivo, loss of CCN2 results in elevated numbers of K15-positive epidermal stem cells that possess elevated beta catenin levels and beta-catenin-dependent reporter gene expression. These results indicate that CCN2 expression by dermal papillae cells is a physiologically relevant suppressor of hair follicle formation by destabilization of beta-catenin and suggest that CCN2 normally acts to maintain stem cell quiescence. PMID- 24152729 TI - Stathmin and microtubules regulate mitotic entry in HeLa cells by controlling activation of both Aurora kinase A and Plk1. AB - Depletion of stathmin, a microtubule (MT) destabilizer, delays mitotic entry by ~4 h in HeLa cells. Stathmin depletion reduced the activity of CDC25 and its upstream activators, Aurora A and Plk1. Chemical inhibition of both Aurora A and Plk1 was sufficient to delay mitotic entry by 4 h, while inhibiting either kinase alone did not cause a delay. Aurora A and Plk1 are likely regulated downstream of stathmin, because the combination of stathmin knockdown and inhibition of Aurora A and Plk1 was not additive and again delayed mitotic entry by 4 h. Aurora A localization to the centrosome required MTs, while stathmin depletion spread its localization beyond that of gamma-tubulin, indicating an MT-dependent regulation of Aurora A activation. Plk1 was inhibited by excess stathmin, detected in in vitro assays and cells overexpressing stathmin-cyan fluorescent protein. Recruitment of Plk1 to the centrosome was delayed in stathmin-depleted cells, independent of MTs. It has been shown that depolymerizing MTs with nocodazole abrogates the stathmin-depletion induced cell cycle delay; in this study, depolymerization with nocodazole restored Plk1 activity to near normal levels, demonstrating that MTs also contribute to Plk1 activation. These data demonstrate that stathmin regulates mitotic entry, partially via MTs, to control localization and activation of both Aurora A and Plk1. PMID- 24152730 TI - Estrogen regulates histone deacetylases to prevent cardiac hypertrophy. AB - The development and progression of cardiac hypertrophy often leads to heart failure and death, and important modulators of hypertrophy include the histone deacetylase proteins (HDACs). Estrogen inhibits cardiac hypertrophy and progression in animal models and humans. We therefore investigated the influence of 17-beta-estradiol on the production, localization, and functions of prohypertrophic (class I) and antihypertrophic (class II) HDACs in cultured neonatal rat cardiomyocytes. 17-beta-Estradiol or estrogen receptor beta agonists dipropylnitrile and beta-LGND2 comparably suppressed angiotensin II-induced HDAC2 (class I) production, HDAC-activating phosphorylation, and the resulting prohypertrophic mRNA expression. In contrast, estrogenic compounds derepressed the opposite effects of angiotensin II on the same parameters for HDAC4 and 5 (class II), resulting in retention of these deacetylases in the nucleus to inhibit hypertrophic gene expression. Key aspects were confirmed in vivo from the hearts of wild-type but not estrogen receptor beta (ERbeta) gene-deleted mice administered angiotensin II and estrogenic compounds. Our results identify a novel dual regulation of cardiomyocyte HDACs, shown here for the antihypertrophic sex steroid acting at ERbeta. This mechanism potentially supports using ERbeta agonists as HDAC modulators to treat cardiac disease. PMID- 24152731 TI - Regulation of mitosis by the NIMA kinase involves TINA and its newly discovered partner, An-WDR8, at spindle pole bodies. AB - The NIMA kinase is required for mitotic nuclear pore complex disassembly and potentially controls other mitotic-specific events. To investigate this possibility, we imaged NIMA-green fluorescent protein (GFP) using four dimensional spinning disk confocal microscopy. At mitosis NIMA-GFP locates to spindle pole bodies (SPBs), which contain Cdk1/cyclin B, followed by Aurora, TINA, and the BimC kinesin. NIMA promotes NPC disassembly in a spatially regulated manner starting near SPBs. NIMA is also required for TINA, a NIMA interacting protein, to locate to SPBs during initiation of mitosis, and TINA is then necessary for locating NIMA back to SPBs during mitotic progression. To help expand the NIMA-TINA pathway, we affinity purified TINA and found it to uniquely copurify with An-WDR8, a WD40-domain protein conserved from humans to plants. Like TINA, An-WDR8 accumulates within nuclei during G2 but disperses from nuclei before locating to mitotic SPBs. Without An-WDR8, TINA levels are greatly reduced, whereas TINA is necessary for mitotic targeting of An-WDR8. Finally, we show that TINA is required to anchor mitotic microtubules to SPBs and, in combination with An-WDR8, for successful mitosis. The findings provide new insights into SPB targeting and indicate that the mitotic microtubule-anchoring system at SPBs involves WDR8 in complex with TINA. PMID- 24152732 TI - The nuclear basket proteins Mlp1p and Mlp2p are part of a dynamic interactome including Esc1p and the proteasome. AB - The basket of the nuclear pore complex (NPC) is generally depicted as a discrete structure of eight protein filaments that protrude into the nucleoplasm and converge in a ring distal to the NPC. We show that the yeast proteins Mlp1p and Mlp2p are necessary components of the nuclear basket and that they also embed the NPC within a dynamic protein network, whose extended interactome includes the spindle organizer, silencing factors, the proteasome, and key components of messenger ribonucleoproteins (mRNPs). Ultrastructural observations indicate that the basket reduces chromatin crowding around the central transporter of the NPC and might function as a docking site for mRNP during nuclear export. In addition, we show that the Mlps contribute to NPC positioning, nuclear stability, and nuclear envelope morphology. Our results suggest that the Mlps are multifunctional proteins linking the nuclear transport channel to multiple macromolecular complexes involved in the regulation of gene expression and chromatin maintenance. PMID- 24152733 TI - Ubiquitination-dependent quality control of hERG K+ channel with acquired and inherited conformational defect at the plasma membrane. AB - Membrane trafficking in concert with the peripheral quality control machinery plays a critical role in preserving plasma membrane (PM) protein homeostasis. Unfortunately, the peripheral quality control may also dispose of partially or transiently unfolded polypeptides and thereby contribute to the loss-of expression phenotype of conformational diseases. Defective functional PM expression of the human ether-a-go-go-related gene (hERG) K(+) channel leads to the prolongation of the ventricular action potential that causes long QT syndrome 2 (LQT2), with increased propensity for arrhythmia and sudden cardiac arrest. LQT2 syndrome is attributed to channel biosynthetic processing defects due to mutation, drug-induced misfolding, or direct channel blockade. Here we provide evidence that a peripheral quality control mechanism can contribute to development of the LQT2 syndrome. We show that PM hERG structural and metabolic stability is compromised by the reduction of extracellular or intracellular K(+) concentration. Cardiac glycoside-induced intracellular K(+) depletion conformationally impairs the complex-glycosylated channel, which provokes chaperone- and C-terminal Hsp70-interacting protein-dependent polyubiquitination, accelerated internalization, and endosomal sorting complex required for transport dependent lysosomal degradation. A similar mechanism contributes to the down regulation of PM hERG harboring LQT2 missense mutations, with incomplete secretion defect. These results suggest that PM quality control plays a determining role in the loss-of-expression phenotype of hERG in certain hereditary and acquired LTQ2 syndromes. PMID- 24152734 TI - Bidirectional coupling between integrin-mediated signaling and actomyosin mechanics explains matrix-dependent intermittency of leading-edge motility. AB - Animal cell migration is a complex process characterized by the coupling of adhesion, cytoskeletal, and signaling dynamics. Here we model local protrusion of the cell edge as a function of the load-bearing properties of integrin-based adhesions, actin polymerization fostered by adhesion-mediated signaling, and mechanosensitive activation of RhoA that promotes myosin II-generated stress on the lamellipodial F-actin network. Analysis of stochastic model simulations illustrates how these pleiotropic functions of nascent adhesions may be integrated to govern temporal persistence and frequency of protrusions. The simulations give mechanistic insight into the documented effects of extracellular matrix density and myosin abundance, and they show characteristic, nonnormal distributions of protrusion duration times that are similar to those extracted from live-cell imaging experiments. Analysis of the model further predicts relationships between measurable quantities that reflect the partitioning of stress between tension on F-actin-bound adhesions, which act as a molecular clutch, and dissipation by retrograde F-actin flow. PMID- 24152736 TI - ER-associated SNAREs and Sey1p mediate nuclear fusion at two distinct steps during yeast mating. AB - During yeast mating, two haploid nuclei fuse membranes to form a single diploid nucleus. However, the known proteins required for nuclear fusion are unlikely to function as direct fusogens (i.e., they are unlikely to directly catalyze lipid bilayer fusion) based on their predicted structure and localization. Therefore we screened known fusogens from vesicle trafficking (soluble N-ethylmaleimide sensitive factor attachment protein receptors [SNAREs]) and homotypic endoplasmic reticulum (ER) fusion (Sey1p) for additional roles in nuclear fusion. Here we demonstrate that the ER-localized SNAREs Sec20p, Ufe1p, Use1p, and Bos1p are required for efficient nuclear fusion. In contrast, Sey1p is required indirectly for nuclear fusion; sey1Delta zygotes accumulate ER at the zone of cell fusion, causing a block in nuclear congression. However, double mutants of Sey1p and Sec20p, Ufe1p, or Use1p, but not Bos1p, display extreme ER morphology defects, worse than either single mutant, suggesting that retrograde SNAREs fuse ER in the absence of Sey1p. Together these data demonstrate that SNAREs mediate nuclear fusion, ER fusion after cell fusion is necessary to complete nuclear congression, and there exists a SNARE-mediated, Sey1p-independent ER fusion pathway. PMID- 24152735 TI - The Rac-GAP Bcr is a novel regulator of the Par complex that controls cell polarity. AB - Cell polarization is essential for many biological processes, including directed cell migration, and loss of polarity contributes to pathological conditions such as cancer. The Par complex (Par3, Par6, and PKCzeta) controls cell polarity in part by recruiting the Rac-specific guanine nucleotide exchange factor T-lymphoma invasion and metastasis 1 (Tiam1) to specialized cellular sites, where Tiam1 promotes local Rac1 activation and cytoskeletal remodeling. However, the mechanisms that restrict Par-Tiam1 complex activity to the leading edge to maintain cell polarity during migration remain unclear. We identify the Rac specific GTPase-activating protein (GAP) breakpoint cluster region protein (Bcr) as a novel regulator of the Par-Tiam1 complex. We show that Bcr interacts with members of the Par complex and inhibits both Rac1 and PKCzeta signaling. Loss of Bcr results in faster, more random migration and striking polarity defects in astrocytes. These polarity defects are rescued by reducing PKCzeta activity or by expressing full-length Bcr, but not an N-terminal deletion mutant or the homologous Rac-GAP, Abr, both of which fail to associate with the Par complex. These results demonstrate that Bcr is an integral member of the Par-Tiam1 complex that controls polarized cell migration by locally restricting both Rac1 and PKCzeta function. PMID- 24152739 TI - Has the Standard of the Reporting of Rehabilitation Improved in Articular Cartilage Repair Studies Involving Third-Generation Autologous Chondrocyte Implantation in the Knee? A Systematic Review. AB - CONTEXT: Autologous chondrocyte implantation (ACI) is a tissue-engineered surgical technique initially developed for articular cartilage repair of isolated chondral lesions of the knee. Third generation techniques (ACI3) are now available that deliver autologous cultured chondrocytes into the defect using cell scaffolds. The successful outcomes of these techniques have some dependency on the pre and post-surgical patient rehabilitation. OBJECTIVES: To determine if the standard of reporting for rehabilitation has improved in ACI3 studies; previous reviews in this field recommended describing the detail of this rehabilitation and patient compliance as integral elements. EVIDENCE ACQUISITION: A computerized search was performed in March 2013. Criteria for inclusion were any studies that evaluated or described the process of ACI3 in the knee and subsequent rehabilitation. The modified Coleman Methodology Score (CMS) was used to rate the standard of reporting of rehabilitation and surgical procedures; review articles were also evaluated for quality using the Strength of Recommendation Taxonomy (SORT). Mean scores, odds ratios, 95% confidence intervals and Mann-Whitney U statistics were calculated. EVIDENCE SYNTHESIS: An improvement in mean CMS was seen compared to previous reviews but rehabilitation reporting scores were lower than their surgical equivalent; significant association was seen between those studies with rehabilitator involvement and high scores in the individual CMS rehabilitation element. Predominant SORT scores of 2A indicated medium strength of recommendation. CONCLUSIONS: The CMS provides a general overview of methodological quality but a more specialised tool to report on the quantitative and qualitative aspects of the rehabilitation process would assist in raising the standards. It is recommended that rehabilitation therapists are included as key members of research teams and are involved in the design, implementation and reporting of future studies. PMID- 24152738 TI - Emerin organizes actin flow for nuclear movement and centrosome orientation in migrating fibroblasts. AB - In migrating fibroblasts, rearward movement of the nucleus orients the centrosome toward the leading edge. Nuclear movement results from coupling rearward-moving, dorsal actin cables to the nucleus by linear arrays of nesprin-2G and SUN2, termed transmembrane actin-associated nuclear (TAN) lines. A-type lamins anchor TAN lines, prompting us to test whether emerin, a nuclear membrane protein that interacts with lamins and TAN line proteins, contributes to nuclear movement. In fibroblasts depleted of emerin, nuclei moved nondirectionally or completely failed to move. Consistent with these nuclear movement defects, dorsal actin cable flow was nondirectional in cells lacking emerin. TAN lines formed normally in cells lacking emerin and were coordinated with the erratic nuclear movements, although in 20% of the cases, TAN lines slipped over immobile nuclei. Myosin II drives actin flow, and depletion of myosin IIB, but not myosin IIA, showed similar nondirectional nuclear movement and actin flow as in emerin-depleted cells. Myosin IIB specifically coimmunoprecipitated with emerin, and emerin depletion prevented myosin IIB localization near nuclei. These results show that emerin functions with myosin IIB to polarize actin flow and nuclear movement in fibroblasts, suggesting a novel function for the nuclear envelope in organizing directional actin flow and cytoplasmic polarity. PMID- 24152737 TI - The spatial segregation of pericentric cohesin and condensin in the mitotic spindle. AB - In mitosis, the pericentromere is organized into a spring composed of cohesin, condensin, and a rosette of intramolecular chromatin loops. Cohesin and condensin are enriched in the pericentromere, with spatially distinct patterns of localization. Using model convolution of computer simulations, we deduce the mechanistic consequences of their spatial segregation. Condensin lies proximal to the spindle axis, whereas cohesin is radially displaced from condensin and the interpolar microtubules. The histone deacetylase Sir2 is responsible for the axial position of condensin, while the radial displacement of chromatin loops dictates the position of cohesin. The heterogeneity in distribution of condensin is most accurately modeled by clusters along the spindle axis. In contrast, cohesin is evenly distributed (barrel of 500-nm width * 550-nm length). Models of cohesin gradients that decay from the centromere or sister cohesin axis, as previously suggested, do not match experimental images. The fine structures of cohesin and condensin deduced with subpixel localization accuracy reveal critical features of how these complexes mold pericentric chromatin into a functional spring. PMID- 24152740 TI - Biologic therapy for atopic asthma and beyond. AB - PURPOSE OF REVIEW: Most asthma patients are easily managed with a standard combination of therapies consisting of inhaled controller and reliever drugs, but there remains a large unmet need at the severe end of the disease spectrum. For these patients, development of safer and more effective therapies for asthmatic patients with severe refractory disease remains a top priority. Here, drugs in development for the severe asthma sufferers and their specific mechanism-based pharmacological rationale will be reviewed with a focus on biologics. A systematic search of the literature was made using Medline, and publications were selected on the basis of their relevance to the topic. Here, the authors will review the existing efficacy and safety data from clinical trials of some of the new biologic therapies that are in development for severe asthma. RECENT FINDINGS: Despite strong preclinical data for many of the more recently identified asthma targets, especially those relating to the T-helper 2 allergic pathway, clinical trials with specific biologics have been largely disappointing. However, there is scope for their specific role in distinctively targeted subpopulations of severe asthmatic patients. SUMMARY: It is clear that more efforts should be devoted towards establishing new and more efficient key targets. A closer interaction between industry, academia and health workers will be required to achieve this goal effectively. PMID- 24152741 TI - Will the damage be done before we feel the heat? Infectious disease emergence and human response. AB - The global political economy is facing extreme challenges against a backdrop of large-scale expansion of human and domestic animal populations and related impacts on the biosphere. Significant global socio-ecological changes have occurred in the period of a single lifetime, driven by increased technology and access to physical and biological resources through open markets and globalization. Current resource consumption rates are not sustainable and ecological tipping points are being reached and one of the indicators of these may be a changing balance between hosts and pathogens. A period of extraordinary progress in reducing infection risk and disease impact on humans and domestic animals in the 20th Century is reversing in the 21st, but not always and not everywhere. Drivers for this shift are discussed in terms of demographics, agroecology, biodiversity decline and loss of resilience in ecosystems, climate change and increasing interconnectedness between species globally. Causality of disease emergence remains highly speculative, but patterns and data are emerging to commend a precautionary approach, while reassessing our global political, social and economic systems. PMID- 24152742 TI - Prevalence of obesity among adults: United States, 2011-2012. AB - KEY FINDINGS: Data from the National Health and Nutrition Examination Survey, 2011-2012. More than one-third (34.9%) of adults were obese in 2011-2012. In 2011 2012, the prevalence of obesity was higher among middle-aged adults (39.5%) than among younger (30.3%) or older (35.4%) adults. The overall prevalence of obesity did not differ between men and women in 2011-2012. Among non-Hispanic black adults, however, 56.6% of women were obese compared with 37.1% of men. In 2011 2012, the prevalence of obesity was higher among non-Hispanic black (47.8%), Hispanic (42.5%), and non-Hispanic white (32.6%) adults than among non-Hispanic Asian adults (10.8%). The prevalence of obesity among adults did not change between 2009-2010 and 2011-2012. PMID- 24152743 TI - Reply to "The significance of significance: overstating in the setting of many comparisons". PMID- 24152744 TI - Perceptions and use of the national kidney foundation KDOQI guidelines: a survey of U.S. renal healthcare providers. AB - BACKGROUND: The National Kidney Foundation (NKF) Kidney Disease Outcomes Quality Initiative (KDOQI) developed guidelines to care for patients with chronic kidney disease (CKD). While these are disseminated through the NKF's website and publications, the guidelines' usage remains suboptimal. The KDOQI Educational Committee was formed to identify barriers to guideline implementation, determine provider and patient educational needs and develop tools to improve care of patients with CKD. METHODS: An online survey was conducted from May to September 2010 to evaluate renal providers' familiarity, current use of and attitudes toward the guidelines and tools to implement the guidelines. RESULTS: Most responders reported using the guidelines often and felt that they could be easily implemented into clinical practice; however, approximately one-half identified at least one barrier. Physicians and physician extenders most commonly cited the lack of evidence supporting KDOQI guidelines while allied health professionals most commonly listed patient non-adherence, unrealistic guideline goals and provider time-constraints. Providers thought that the guidelines included too much detail and identified the lack of a quick resource as a barrier to clinical implementation. Most were unaware of the Clinical Action Plans. CONCLUSIONS: Perceived barriers differed between renal clinicians and allied health professionals; educational and implementation tools tailored for different providers are needed. PMID- 24152745 TI - Mobilization of stored iron in mammals: a review. AB - From the nutritional standpoint, several aspects of the biochemistry and physiology of iron are unique. In stark contrast to most other elements, most of the iron in mammals is in the blood attached to red blood cell hemoglobin and transporting oxygen to cells for oxidative phosphorylation and other purposes. Controlled and uncontrolled blood loss thus has a major impact on iron availability. Also, in contrast to most other nutrients, iron is poorly absorbed and poorly excreted. Moreover, amounts absorbed (~1 mg/day in adults) are much less than the total iron (~20 mg/day) cycling into and out of hemoglobin, involving bone marrow erythropoiesis and reticuloendothelial cell degradation of aged red cells. In the face of uncertainties in iron bioavailability, the mammalian organism has evolved a complex system to retain and store iron not immediately in use, and to make that iron available when and where it is needed. Iron is stored innocuously in the large hollow protein, ferritin, particularly in cells of the liver, spleen and bone marrow. Our current understanding of the molecular, cellular and physiological mechanisms by which this stored iron in ferritin is mobilized and distributed-within the cell or to other organs-is the subject of this review. PMID- 24152747 TI - The importance of dose, frequency and duration of vitamin D supplementation for plasma 25-hydroxyvitamin D. AB - The importance of dose, frequency and duration of vitamin D supplementation for plasma 25(OH)D levels is not well described and rarely reported for supplementation that exceeds 2000 IU per day. The objective is to examine dose, frequency and duration of supplementation in relation to plasma 25(OH)D in a large population-based sample. We accessed data on 2714 volunteers that contributed to 4224 visits and applied multilevel regression. Compared to not using supplements, a minimum regimen of 1000-2000 IU once or twice per week for one month was not effective in raising 25(OH)D. Compared to this minimum regimen, higher doses of 2000-3000, 3000-4000, and 5000 IU or more were associated with a 7.49, 13.19 and 30.22 nmol/L 25(OH)D increase, respectively; frequencies of three to four, five to six and seven times/week were associated with a 5.44, 16.52 and 30.69 nmol/L increase, respectively; and supplementation of five months or longer was associated with an increase of 6.68 nmol/L (p < 0.01 for all). Age, body weight, physical activity, smoking, and self-rated health were significantly associated with 25(OH)D. Whereas dose, frequency and duration of supplementation are important to healthy subjects committed to optimizing their nutritional status, to the design of clinical trials, individual characteristics and lifestyle contribute substantially to 25(OH)D. PMID- 24152746 TI - Food predictors of plasma carotenoids. AB - Empirical prediction models that weight food frequency questionnaire (FFQ) food items by their relation to nutrient biomarker concentrations may estimate nutrient exposure better than nutrient intakes derived from food composition databases. Carotenoids may especially benefit because contributing foods vary in bioavailability and assessment validity. Our objective was to develop empirical prediction models for the major plasma carotenoids and total carotenoids and evaluate their validity compared with dietary intakes calculated from standard food composition tables. 4180 nonsmoking women in the Nurses' Health Study (NHS) blood subcohort with previously measured plasma carotenoids were randomly divided into training (n = 2787) and testing (n = 1393) subsets. Empirical prediction models were developed in the training subset by stepwise selection from foods contributing >=0.5% to intake of the relevant carotenoid. Spearman correlations between predicted and measured plasma concentrations were compared to Spearman correlations between dietary intake and measured plasma concentrations for each carotenoid. Three to 12 foods were selected for the alpha-carotene, beta carotene, beta-cryptoxanthin, lutein/zeaxanthin, lycopene, and total carotenoids prediction models. In the testing subset, Spearman correlations with measured plasma concentrations for the calculated dietary intakes and predicted plasma concentrations, respectively, were 0.31 and 0.37 for alpha-carotene, 0.29 and 0.31 for beta-carotene, 0.36 and 0.41 for beta-cryptoxanthin, 0.28 and 0.31 for lutein/zeaxanthin, 0.22 and 0.23 for lycopene, and 0.22 and 0.27 for total carotenoids. Empirical prediction models may modestly improve assessment of some carotenoids, particularly alpha-carotene and beta-cryptoxanthin. PMID- 24152748 TI - Impact of multi-micronutrient supplementation on growth and morbidity of HIV infected South African children. AB - Poor growth, micronutrient deficiencies and episodes of diarrhea and respiratory infections occur frequently in HIV-infected children. We investigated whether multi-micronutrient supplementation would improve the growth performance and reduce the number of episodes of diarrhea and/or of respiratory symptoms in HIV infected children. In a double-blind randomized trial, HIV-infected South African children aged 4-24 months (n = 201) were assigned to receive multi-micronutrient supplements or placebo daily for six months. The children were assessed for respiratory symptoms or diarrhea bi-weekly; weights and heights were measured monthly. In total, 121 children completed the six month follow up study period (60%). A total of 43 children died; 27 of them had received supplements. This difference in mortality was not statistically significant (p = 0.12). Weight-for height Z-scores improved significantly (p < 0.05) among children given supplements compared with those given placebo (0.40 (0.09-0.71)) versus -0.04 ( 0.39-0.31) (mean (95% CI)). Height-for-age Z-scores did not improve in both treatment groups. The number of monthly episodes of diarrhea in the placebo group (0.36 (0.26-0.46)) was higher (p = 0.09) than in the supplement group (0.25 (0.17 0.33)) and the number of monthly episodes of respiratory symptoms was significantly higher (p < 0.05) among children on placebos (1.01 (0.83-1.79)) than those on supplements (0.66 (0.52-0.80)). Multi-micronutrient supplements significantly improved wasting and reduced the number of episodes of diarrhea and respiratory symptoms. PMID- 24152749 TI - Nutritional management of insulin resistance in nonalcoholic fatty liver disease (NAFLD). AB - Nonalcoholic fatty liver disease (NAFLD) is an emerging global health concern. It is the most common form of chronic liver disease in Western countries, affecting both adults and children. NAFLD encompasses a broad spectrum of fatty liver disease, ranging from simple steatosis (NAFL) to nonalcoholic steatohepatitis (NASH), and is strongly associated with obesity, insulin resistance, and dyslipidemia. First-line therapy for NAFLD includes weight loss achieved through diet and physical activity. However, there is a lack of evidenced-based dietary recommendations. The American Diabetes Association's (ADA) recommendations that aim to reduce the risk of diabetes and cardiovascular disease may also be applicable to the NAFLD population. The objectives of this review are to: (1) provide an overview of NAFLD in the context of insulin resistance, and (2) provide a rationale for applying relevant aspects of the ADA recommendations to the nutritional management of NAFLD. PMID- 24152750 TI - Maize prolamins could induce a gluten-like cellular immune response in some celiac disease patients. AB - Celiac disease (CD) is an autoimmune-mediated enteropathy triggered by dietary gluten in genetically prone individuals. The current treatment for CD is a strict lifelong gluten-free diet. However, in some CD patients following a strict gluten free diet, the symptoms do not remit. These cases may be refractory CD or due to gluten contamination; however, the lack of response could be related to other dietary ingredients, such as maize, which is one of the most common alternatives to wheat used in the gluten-free diet. In some CD patients, as a rare event, peptides from maize prolamins could induce a celiac-like immune response by similar or alternative pathogenic mechanisms to those used by wheat gluten peptides. This is supported by several shared features between wheat and maize prolamins and by some experimental results. Given that gluten peptides induce an immune response of the intestinal mucosa both in vivo and in vitro, peptides from maize prolamins could also be tested to determine whether they also induce a cellular immune response. Hypothetically, maize prolamins could be harmful for a very limited subgroup of CD patients, especially those that are non-responsive, and if it is confirmed, they should follow, in addition to a gluten-free, a maize free diet. PMID- 24152752 TI - Eating and obesity--the new world disorder. AB - Obesity is not a new phenomenon. Paleolithic artefacts, some almost 35,000 years old, depict obesity in its classical gynoid form, suggesting that early hunter gathers were not entirely safeguarded by the assumed Stone Age diet. Nevertheless it has been convincingly argued by Boyd Eaton and others that the 21st century epidemic of non-communicable diseases (NCDs), including obesity, is attributable to mankind no longer enjoying the diet of our ancestors for which we remain genetically and metabolically programmed. Even if our forebears seemed to revere obesity sufficiently to carve out stone "venuses", it is still unclear if they were documenting a commonplace feature, although the frequency with which these venuses appear across thousands of years and even thousands of miles apart might suggest that obesity, in women at least, was not a complete rarity. PMID- 24152751 TI - IGF-1, the cross road of the nutritional, inflammatory and hormonal pathways to frailty. AB - The decline in functional capacity is a heterogeneous phenomenon in the elderly. An accelerated ageing determines a frail status. It results in an increased vulnerability to stressors for decreased physiological reserves. The early identification of a frail status is essential for preventing loss of functional capacity, and its clinical consequences. Frailty and mobility limitation result from an interplay of different pathways including multiple anabolic deficiency, inflammation, oxidative stress, and a poor nutritional status. However, the age related decline in insulin-like growth factor 1 (IGF-1) bioactivity deserves special attention as it could represent the ideal crossroad of endocrine, inflammatory, and nutritional pathways to frailty. Several minerals, namely magnesium, selenium, and zinc, appear to be important determinants of IGF-1 bioactivity. This review aims to provide an overview of the potential usefulness of nutrients modulating IGF-1 as potential therapeutic targets in the prevention of mobility limitation occurring in frail older subjects. PMID- 24152753 TI - Manifestations of fasting-induced fatty liver and rapid recovery from steatosis in voles fed lard or flaxseed oil lipids. AB - Long-chain n-3 polyunsaturated fatty acids (PUFA) can have beneficial effects against fat deposition, cardiovascular diseases, and liver steatosis. We investigated how diets based on lard (predominantly saturated and monounsaturated fatty acids) or flaxseed oil (rich in 18:3n-3) affect liver fat-% and fatty acid profiles of tundra voles (Microtus oeconomus). We also studied potential participation of hyaluronan (HA) in the pathology of fatty liver and whether the development and recovery of fasting-induced steatosis are influenced by n-3 PUFA. The dietary fatty acid composition was manifested in the liver fatty acid signatures. Fasting for 18 h induced macrovesicular steatosis and the liver fat-% increased to 22% independent of the preceding diet. Fasting-induced steatosis did not involve inflammation or connective tissue activation indicated by the absence of both leukocyte accumulation and increased HA. Food deprivation modified the liver fatty acid signatures to resemble more closely the diets. Fasting reduced the proportions of long-chain n-3 PUFA in both dietary regimes and n-3/n-6 PUFA ratios in the lard-fed voles. Decreases in long-chain n-3 PUFA may promote lipid accumulation by modulating the expression of lipid-metabolizing genes. Dietary 18:3n-3 did not prevent the development or attenuate the manifestation of steatosis in the fasted voles or promote the recovery. PMID- 24152756 TI - How long should we check thyroid function after amiodarone withdrawal? PMID- 24152755 TI - The gluten-free diet: testing alternative cereals tolerated by celiac patients. AB - A strict gluten-free diet (GFD) is the only currently available therapeutic treatment for patients with celiac disease, an autoimmune disorder of the small intestine associated with a permanent intolerance to gluten proteins. The complete elimination of gluten proteins contained in cereals from the diet is the key to celiac disease management. However, this generates numerous social and economic repercussions due to the ubiquity of gluten in foods. The research presented in this review focuses on the current status of alternative cereals and pseudocereals and their derivatives obtained by natural selection, breeding programs and transgenic or enzymatic technology, potential tolerated by celiac people. Finally, we describe several strategies for detoxification of dietary gluten. These included enzymatic cleavage of gliadin fragment by Prolyl endopeptidases (PEPs) from different organisms, degradation of toxic peptides by germinating cereal enzymes and transamidation of cereal flours. This information can be used to search for and develop cereals with the baking and nutritional qualities of toxic cereals, but which do not exacerbate this condition. PMID- 24152754 TI - Iron, human growth, and the global epidemic of obesity. AB - Iron is an essential nutrient utilized in almost every aspect of cell function and its availability has previously limited life. Those same properties which allow iron to function as a catalyst in the reactions of life also present a threat via generation of oxygen-based free radicals. Accordingly; life exists at the interface of iron-deficiency and iron-sufficiency. We propose that: (1) human life is no longer positioned at the limits of iron availability following several decades of fortification and supplementation and there is now an overabundance of the metal among individuals of many societies; (2) this increased iron availability exerts a positive effect on growth by targeting molecules critical in regulating the progression of the cell cycle; there is increased growth in humans provided greater amounts of this metal; and indices of obesity can positively correlate with body stores of iron; and (3) diseases of obesity reflect this over-abundance of iron. Testing potential associations between iron availability and both obesity and obesity-related diseases in populations will be difficult since fortification and supplementation is so extensively practiced. PMID- 24152757 TI - Predictors of change in objectively measured and self-reported health behaviours among individuals with recently diagnosed type 2 diabetes: longitudinal results from the ADDITION-Plus trial cohort. AB - BACKGROUND: There is limited evidence about predictors of health behaviour change in people with type 2 diabetes. The aim of this study was to assess change in health behaviours over one year and to identify predictors of behaviour change among adults with screen-detected and recently clinically diagnosed diabetes. METHODS: ADDITION-Plus was a randomised controlled trial of a behaviour change intervention among 478 patients (40-69 years). Physical activity and diet were measured objectively (physical activity at 1 year) and by self-report at baseline and one year. Associations between baseline predictors and behaviour change were quantified using multivariable linear regression. RESULTS: Participants increased their plasma vitamin C and fruit intake, reduced energy and fat intake from baseline to follow-up. Younger age, male sex, a smaller waist circumference, and a lower systolic blood pressure at baseline were associated with higher levels of objectively measured physical activity at one year. Greater increases in plasma vitamin C were observed in women (beta-coefficient [95% CI]: beta = -5.52 [-9.81, -1.22]) and in those with screen-detected diabetes (beta = 6.09 [1.74, 10.43]). Younger age predicted a greater reduction in fat (beta = -0.43 [-0.72, -0.13]) and energy intake (beta = -6.62 [-13.2, -0.05]). Patients with screen-detected diabetes (beta = 74.2 [27.92, 120.41]) reported a greater increase in fruit intake. There were no significant predictors of change in self-reported physical activity. Beliefs about behaviour change and diabetes did not predict behaviour change. CONCLUSIONS: Older patients, men and those with a longer duration of diabetes may need more intensive support for dietary change. We recommend that future studies use objective measurement of health behaviours and that researchers add predictors beyond the individual level. Our results support a focus on establishing healthy lifestyle changes early in the diabetes disease trajectory. PMID- 24152758 TI - Depression and other behavioral and psychological symptoms of dementia--separate research worlds in need of a common understanding. PMID- 24152761 TI - Herpes simplex virus drug-resistance: new mutations and insights. AB - PURPOSE OF REVIEW: Acyclovir (ACV) is the first-line treatment for the management of herpes simplex virus 1 (HSV-1) and 2 (HSV-2) diseases. Long-term administration of the drug for the treatment of chronic infections in the immunocompromised host can lead to the development of ACV-resistance. This review provides an update of the mutations linked to drug-resistance and issues to be considered in the management of HSV infections refractory to antiviral therapy. RECENT FINDINGS: Recent data have shown that HSV drug-resistance should be taken into account not only in immunocompromised individuals but also in immunocompetent persons when HSV infections involve 'immune-privileged sites'. Thus, drug-resistance typing is recommended in cases of ACV unresponsive herpetic keratitis and herpes simplex encephalitis. Several issues regarding HSV drug resistance were highlighted by recent studies. Phenotypic and genotypic antiviral resistance may vary not only from different compartments but also over time, highlighting the importance of characterizing longitudinal HSV isolates from all sites. Combination therapy should be considered when viruses with distinct phenotype/genotype are identified at one or at distinct body sites. SUMMARY: Surveillance of HSV drug-resistance is highly recommended in immunocompromised patients and in immunocompetent individuals with infections implicating 'immune privileged sites' to rationally adapt antiviral treatment. PMID- 24152759 TI - Tumor hypoxia as a driving force in genetic instability. AB - Sub-regions of hypoxia exist within all tumors and the presence of intratumoral hypoxia has an adverse impact on patient prognosis. Tumor hypoxia can increase metastatic capacity and lead to resistance to chemotherapy and radiotherapy. Hypoxia also leads to altered transcription and translation of a number of DNA damage response and repair genes. This can lead to inhibition of recombination mediated repair of DNA double-strand breaks. Hypoxia can also increase the rate of mutation. Therefore, tumor cell adaptation to the hypoxic microenvironment can drive genetic instability and malignant progression. In this review, we focus on hypoxia-mediated genetic instability in the context of aberrant DNA damage signaling and DNA repair. Additionally, we discuss potential therapeutic approaches to specifically target repair-deficient hypoxic tumor cells. PMID- 24152760 TI - Entangled effects of allelic and clonal (genotypic) richness in the resistance and resilience of experimental populations of the seagrass Zostera noltii to diatom invasion. AB - BACKGROUND: The relationship between species diversity and components of ecosystem stability has been extensively studied, whilst the influence of the genetic component of biodiversity remains poorly understood. Here we manipulated both genotypic and allelic richness of the seagrass Zostera noltii, in order to explore their respective influences on the resistance of the experimental population to stress. Thus far intra-specific diversity was seldom taken into account in management plans, and restoration actions showed very low success. Information is therefore needed to understand the factors affecting resistance and resilience of populations. RESULTS: Our results show a positive influence of both allelic and genotypic richness on the resistance of meadows to environmental perturbations. They also show that at the low genotypic (i.e. clonal) richness levels used in prior experimental approaches, the effects of genotypic and allelic richness could not be disentangled and allelic richness was a likely hidden treatment explaining at least part of the effects hitherto attributed to genotypic richness. CONCLUSIONS: Altogether, these results emphasize the need to acknowledge and take into account the interdependency of both genotypic and allelic richness in experimental designs attempting to estimate their importance alone or in combination. A positive influence of allelic richness on resistance to perturbations, and of allelic richness combined with genotypic richness on the recovery (resilience) of the experimental populations is supported by differential mortality. These results, on the key species structuring of one of the most threatened coastal ecosystem worldwide, seagrass meadows, support the need to better take into account the distinct compartments of clonal and genetic diversity in management strategies, and in possible restoration plans in the future. PMID- 24152762 TI - Pharmacological considerations on the use of antiretrovirals in pregnancy. AB - PURPOSE OF REVIEW: Treatment with combination antiretroviral therapy during pregnancy reduces the chance of mother to child transmission of HIV. Physiological changes during pregnancy can lead to lower exposure to antiretrovirals, possibly resulting in virological failure. For most antiretrovirals, data on exposure during pregnancy and transplacental passage are limited. This review summarizes the most recent information on pharmacokinetics (including transplacental passage), efficacy, as well as the safety of antiretrovirals during pregnancy. RECENT FINDINGS: Intensive-sampling pharmacokinetic studies as well as observational studies using sparse sampling were performed to explore the exposure to antiretrovirals during pregnancy. Transplacental passage, efficacy (viral load at delivery and infection status of the newborn) and safety information were evaluated for several antiretrovirals. SUMMARY: For most nucleoside/nucleotide reverse transcriptase inhibitors and protease inhibitors, recent research shows a decreased exposure during pregnancy. However, the advantage of a general dose increase during pregnancy still remains unclear. For newer compounds and efavirenz, limited or no data on pharmacokinetics during pregnancy or transplacentally are available, while the mechanisms of transplacental passage also remain unknown. For safety reasons, it will be important to monitor pregnancy outcomes in resource-limited settings during the implementation of the WHO guidelines (including the use of efavirenz during pregnancy). PMID- 24152763 TI - Lessons learned in the multistate fungal infection outbreak in the United States. AB - PURPOSE OF REVIEW: The recent outbreak of fungal meningitis related to contaminated methylprednisolone acetate injections represents an important cause of morbidity and continues to be a significant public health problem in the United States. RECENT FINDINGS: As of August 2013, there have been 749 cases and 63 deaths in 20 states associated with epidemic fungal meningitis, most of these because of Exserohilum rostratum. Clinical experience in managing these cases has grown dramatically in the last several months; most patients require at least 6 months of antifungal therapy for complicated disease. Most patients are treated with voriconazole, with or without liposomal amphotericin B, for central nervous system and paraspinal complications of the disease. For disease involving the sacroiliac and peripheral joints, voriconazole alone has been preferred. MRI spine imaging has identified several cases of asymptomatic disease, suggesting an aggressive diagnostic approach to exposed asymptomatic patients. Mortality remains low (<10%), but morbidity relating to persistent symptoms and treatment associated toxicity is high. SUMMARY: The ongoing fungal meningitis epidemic demonstrates an important achievement for the public health community. Important questions remain relating to the diagnosis, management, and long-term outcomes of these patients. Important research questions pertaining to specific risks influencing disease manifestations remain unanswered. PMID- 24152764 TI - Macrophages: the neglected barrier to eradication. AB - PURPOSE OF REVIEW: There has been a shift towards HIV-1 eradication research in the last three years, yet much is still unknown about the precise role that macrophages will play in any such strategy. This review attempts to summarize the latest data on this subject. RECENT FINDINGS: A new generation of histone deacetylase inhibitors, ITF2357, belinostat, givinostat, panobinostat, and the cancer drug JQ1, have been shown to induce viral reactivation in a monocyte cell line. In macrophages chronically infected with HIV-1 in vitro, drugs blocking pre integration steps have demonstrated poor efficacy in controlling viral replication in comparison to protease inhibitors, thus questioning whether drugs can control this reservoir following histone deacetylase inhibition. Finally, non human primate data suggest that CD8+ T cells may not be able to clear infected macrophages. SUMMARY: Given these data highlighting the barriers to addressing the macrophage reservoir, functional rather than sterilizing cure may be a realistic goal. More research on macrophages is needed and animal models may prove useful in future HIV-1 eradication studies by offering a clinically relevant way to study macrophage infection in vivo. PMID- 24152765 TI - Restoration of synaptic plasticity in the host striatum: can transplants make it? AB - Intrastriatal transplantation of dopamine (DA) neurons can restore DA levels in the striatum and improve parkinsonian deficits in experimental studies. However, the mechanisms underlying these effects are poorly understood. Corticostriatal synaptic plasticity represents an important cellular mechanism for information storage and behavioural learning in the brain. This mechanism is defective in Parkinson's disease (PD). Indeed, the lack of endogenous DA innervation to the striatum causes morphological and functional rearrangements that are associated with altered synaptic plasticity in the corticostriatal pathway. In turn, malfunctioning synaptic plasticity is associated with motor deficits that resemble features of PD. It is yet unknown whether or not transplanted dopaminergic neurons can restore these striatal deficits in PD. Could this be the mechanism underlying the therapeutic effects of transplants? Recent studies have begun to shed light on this matter using different approaches. PMID- 24152766 TI - Enhanced recovery from chronic ischemic injury by bone marrow cells in a rat model of ischemic stroke. AB - Even after decades of intensive studies, therapeutic options for patients with stroke are rather limited. Thrombolytic drugs effectively treat the very acute stage of stroke, and several neuroprotectants that are designed to treat secondary injury following stroke are being tested in clinical trials. However, these pharmacological approaches primarily focus on acute stroke recovery, and few options are available for treating chronic stroke patients. In recent years, stem cell-mediated regenerative approaches have emerged as promising therapeutic strategies for treating the chronic stage of stroke. In this study, we examined whether systemically administered bone marrow cells (BMCs) could have beneficial effects in a rat model of chronic ischemia. Our transplantation experiments using BMCs obtained from ischemic donor rats showed functional and structural recovery during the chronic stage of stroke. BMC-mediated neural proliferation was prominent in the brains of rats with chronic stroke, and most of the new cells eventually became neurons instead of astrocytes. BMC-mediated enhanced neural proliferation coincided with a significant reduction (~50%) in the number of activated microglia, which is consistent with previous reports of enhanced neural proliferation being linked to microglial inactivation. Strikingly, approximately 57% of the BMCs that infiltrated the chronic ischemic brain were CD25(+) cells, suggesting that these cells may exert the beneficial effects associated with BMC transplantation. Based on the reported anti-inflammatory role of CD25(+) regulatory T-cells in acute experimental stroke, we propose a working model delineating the positive effects of BMC transplantation during the chronic phase of stroke; infiltrating BMCs (mostly CD25(+) cells) reduce activated microglia, which leads to enhanced neural proliferation and enhanced recovery from neuronal damage in this rat model of chronic stroke. This study provides valuable insights into the effect of BMC transplantation in the chronic ischemic brain, which may lead to the development of effective therapy for chronic stroke patients who currently lack satisfactory therapeutic options. PMID- 24152767 TI - Neospora caninum antibodies in dairy cows and domestic dogs from Vojvodina, Serbia. AB - Neospora caninum, the causative agent of neosporosis, is a protozoan parasite responsible for high rate of abortion in cattle worldwide. In dogs, consequences of infection vary from severe neuromuscular disorders to asymptomatic infection and shedding of environmentally resistant oocysts. In this study, we determined the occurrence of N. caninum antibodies in dairy cattle and dogs in Vojvodina (Northern Province of Serbia) and possible risk factors. N. caninum antibodies were found in 15.4% (55/356, CI 95%:12.0-19.6) of cows and 17.2% (17/99, CI 95%: 10.8-26.2) of dogs. Cows from smallholdings showed significantly greater odds (OR = 5.28, CI 95%: 2.0-13.6, p = 0.0006) of being seropositive in comparison to the farm cows. Epidemiological importance of results is discussed. PMID- 24152768 TI - Genetic risk transmission in a family affected by familial breast cancer. AB - Breast Cancer is the most common malignancy among women. Family history is the strongest single predictor of breast cancer risk, and thus great attention has been focused on BRCA1 and BRCA2 genes whose mutations lead to a high risk of developing this disease. Today, only 25% of high- and moderate-risk genes are known, suggesting the importance of the discovery of new risk modifiers. Therefore, the investigation of new polygenic alterations is of great importance, especially if considered high- and moderate-risk variants. In this study, the transmission of BRCA1-2 polymorphisms in association with the transmission of polymorphisms in the genes NUMA1, CCND1, COX11, FGFR2, TNRC9 and SLC4A7 were examined in all members of a family with the BRCA2 c.6447_6448dup mutation. This is the first study about the transmission of high-risk polygenic variants in all members of a family with a strong history of breast cancer. The results about the possible polygenic variant associations that could increase and modify the risk suggested the importance to search new variants to better manage patients and their family members. PMID- 24152772 TI - Speculating on a public figure's mental health. PMID- 24152770 TI - A general regression framework for a secondary outcome in case-control studies. AB - Modern case-control studies typically involve the collection of data on a large number of outcomes, often at considerable logistical and monetary expense. These data are of potentially great value to subsequent researchers, who, although not necessarily concerned with the disease that defined the case series in the original study, may want to use the available information for a regression analysis involving a secondary outcome. Because cases and controls are selected with unequal probability, regression analysis involving a secondary outcome generally must acknowledge the sampling design. In this paper, the author presents a new framework for the analysis of secondary outcomes in case-control studies. The approach is based on a careful re-parameterization of the conditional model for the secondary outcome given the case-control outcome and regression covariates, in terms of (a) the population regression of interest of the secondary outcome given covariates and (b) the population regression of the case-control outcome on covariates. The error distribution for the secondary outcome given covariates and case-control status is otherwise unrestricted. For a continuous outcome, the approach sometimes reduces to extending model (a) by including a residual of (b) as a covariate. However, the framework is general in the sense that models (a) and (b) can take any functional form, and the methodology allows for an identity, log or logit link function for model (a). PMID- 24152769 TI - Exploring the pathophysiology behind the more common genetic and acquired lipodystrophies. AB - Lipodystrophies are an immense group of genetic or acquired metabolic disorders that are characterized by varying degrees of body fat loss and in some instances localized accumulation of subcutaneous fat. Lipodystrophies are often tightly linked with profound metabolic complications; this strong bond emphasizes and reinforces the significance of adipose tissue as a dynamic endocrine organ. The extent of fat loss determines the severity of associated metabolic complications such as diabetes mellitus, hypertriglyceridemia and hepatic steatosis. The lipodystrophies can be divided into generalized, partial or local, depending on the degree and locality of the observable fat loss; moreover, the generalized and partial divisions can be partitioned further into inherited or acquired forms. The major genetic factors in the generalized forms of the lipodystrophies, particularly Congenital generalized lipodystrophy (CGL)-Berardinelli-Seip syndrome, are the AGPAT2, BSCL2, caveolin 1 (CAV1) and polymerase-I-and transcriptrelease factor (PTRF) genes. In the acquired forms, genes such as LMNA, PPARG, CIDEC (cell-death-inducing DNA fragmentation factor a-like effector c) and PLIN1 are heavily involved in familial partial lipodystrophy (FPLD) type 2 (also known as the Dunnigan-Variety) and WRN along with RECQL5 in Werner Syndrome (WS). Autoimmune causes are particularly noted in acquired partial lipodystrophy (APL) Barraquer-Simons syndrome and in AGL-Lawrence syndrome; panniculitis has been shown to have a substantial role in the former as well as in other forms of localized lipodystrophies. Patients with human immunodeficiency virus (HIV) exposed to protease inhibitors, nucleoside reverse transcriptase inhibitors (NRTIs) (for example, zidovudine and stavudine) or non-nucleoside reverse transcriptase inhibitors (NNRTIs) (for example, efavirenz) while undergoing Highly Active Antiretroviral Therapy (HAART) have led to the current most prevalent form of the lipodystrophies: lipodystrophy in HIV-infected patients (LD HIV) and HAART-associated lipodystrophy syndrome (HALS). PMID- 24152773 TI - Pedophilia: is there a duty to report? PMID- 24152774 TI - The treating psychiatrist and worker's compensation reporting. PMID- 24152775 TI - Civil commitment for substance abuse. PMID- 24152776 TI - The evolving definition of posttraumatic stress disorder: legal ramifications. PMID- 24152777 TI - Dynamic descriptions of personality disorder in the DSM-5. PMID- 24152778 TI - Juvenile forensic psychiatric evaluations. PMID- 24152779 TI - Court diversion for juveniles with mental health disorders. PMID- 24152780 TI - Civil commitment for sex offenders. PMID- 24152781 TI - Sanism and the law. PMID- 24152782 TI - Deinstitutionalization of people with mental illness: causes and consequences. PMID- 24152783 TI - Mental illness, inside and out. PMID- 24152784 TI - Registries, violence, and threats of harm. PMID- 24152785 TI - Detail and the devil of on-farm parasite control under climate change. AB - Levels and seasonal patterns of parasite challenge to livestock are likely to be affected by climate change, through direct effects on life cycle stages outside the definitive host and through alterations in management that affect exposure and susceptibility. Net effects and options for adapting to them will depend very strongly on details of the system under consideration. This short paper is not a comprehensive review of climate change effects on parasites, but rather seeks to identify key areas in which detail is important and arguably under-recognized in supporting farmer adaptation. I argue that useful predictions should take fuller account of system-specific properties that influence disease emergence, and not just the effects of climatic variables on parasite biology. At the same time, excessive complexity is ill-suited to useful farm-level decision support. Dealing effectively with the 'devil of detail' in this area will depend on finding the right balance, and will determine our success in applying science to climate change adaptation by farmers. PMID- 24152786 TI - Epithelial-mesenchymal transition and its regulators are major targets of triple negative breast cancer. AB - Triple negative breast cancers (TNBCs) represent a distinct subtype of breast cancers that are associated with early recurrence and an aggressive metastatic progression of the disease and consequently poor outcome. Recently, it was reported that c-Met growth factor receptor is overexpressed in around 52% of TNBCs. On the other hand, it is known that c-Met signaling pathways initiate the epithelial-mesenchymal transition (EMT) phenomenon, which is described as a crucial event during cancer metastasis. Herein, we discuss the association between c-Met and EMT in the TNBC group. PMID- 24152787 TI - Effect of substrate and cation requirement on anaerobic volatile fatty acid conversion rates at elevated biogas pressure. AB - This work studied the anaerobic conversion of neutralized volatile fatty acids (VFA) into biogas under Autogenerative High Pressure Digestion (AHPD) conditions. The effects of the operating conditions on the biogas quality, and the substrate utilisation rates were evaluated using 3 AHPD reactors (0.6 L); feeding a concentration of acetate and VFA (1-10 g COD/L) corresponding to an expected pressure increase of 1-20 bar. The biogas composition improved with pressure up to 4.5 bar (>93% CH4), and stabilized at 10 and 20 bar. Both, acetotrophic and hydrogenotrophic methanogenic activity was observed. Substrate utilisation rates of 0.2, 0.1 and 0.1 g CODCH4/g VSS/d for acetate, propionate and butyrate were found to decrease by up to 50% with increasing final pressure. Most likely increased Na(+)-requirement to achieve CO2 sequestration at higher pressure rather than end-product inhibition was responsible. PMID- 24152788 TI - Dynamic microstructures and fractal characterization of cell wall disruption for microwave irradiation-assisted lipid extraction from wet microalgae. AB - To extract lipids from wet microalgae through cell disruption, the effects of microwave treatment on the dynamic cell wall microstructures were investigated. The fractal dimension of raw, untreated microalgal cells was 1.46. The disruption level of microalgal cell walls was enhanced when microwave treatment temperature increased from 80 to 120 degrees C, resulting in an increase in microalgal cell fractal dimension from 1.61 to 1.91. The cell wall thickness and pore diameters in cell walls increased from 0.11 to 0.59 MUm and from 0.005 to 0.18 MUm, respectively, when microwave treatment time increased from 0 to 20 min. The outer pectin layers of cell walls gradually detached and the porosity of inner cellulose layers increased when microwave treatment time increased to 26 min. The initial point of disruption appeared at the maximum curvature (approximately 1.01*10(7) m(-1)) of cell walls. Numbers of short-chain and saturated lipids increased because of microwave electromagnetic effect. PMID- 24152789 TI - Enhancement of eucalypt chips' enzymolysis efficiency by a combination method of alkali impregnation and refining pretreatment. AB - A combination process of alkali impregnation and refining was used as a pretreatment to improve the production of fermentable sugar. The surface structures and crystallinities of wood samples were characterized to explain the relationships between the pretreatment action and enzymatic efficiency. After refining, the reducing sugar contents in hydrolyzates were analyzed by UV-Vis and HPLC. The results showed that the enzymatic efficiency could be improved by the combined pretreatment, due to the increment of specific surface area and the release of more free hydroxyls. Comparing to the sodium hydroxide and deionized water, the impregnation with magnesium hydroxide had low refining energy consumption and high yield of reducing sugar (glucose and xylose) in enzymolysis process, where about 560 kWh/t of the energy was saved in refining, and the yield of the reducing sugar was as high as 91.53%. And the enzymolysis could be improved by a certain amount of magnesium ions. PMID- 24152790 TI - Rubisco-based engineered Escherichia coli for in situ carbon dioxide recycling. AB - In this study, ribulose-1,5-bisphosphate carboxylase/oxygenase (Rubisco) and phosphoribulokinase (PrkA) were overexpressed individually and in combination in Escherichia coli under different fermentation conditions. While wild-type E. coli produced 0.731 mol of CO2 per consumption of one mole of arabinose, engineered E. coli JB, containing both heterologous Rubisco and PrkA, produced only 0.621 mol of CO2 per consumption of one mole of arabinose. This represents a 15% reduction in CO2 emission and achieves 38% of theoretical CO2 reduction. The CO2 fixation rate of Rubisco-based engineered E. coli JB is 67 mg-CO2.mole-arabinose(-1) L(-1) h(-1), which is comparable to the performance of microalgae and cyanobacteria. It has been found that overexpressing Rubisco dramatically elevates the bacteria growth and sugar consumptions in the presence of oxygen and L-arabinose. It has been also found that overexpressing PrkA could demolish the balance of ATP regeneration, yet can be recovered simply by controlling the pH at 7.0+/-0.1. PMID- 24152793 TI - USP9X expression correlates with tumor progression and poor prognosis in esophageal squamous cell carcinoma. AB - BACKGROUND: Ubiquitination is a reversible process of posttranslational protein modification through the action of the family of deubiquitylating enzymes which contain ubiquitin-specific protease 9x (USP9X). Recent evidence indicates that USP9X is involved in the progression of various human cancers. The aim was to detect the expression of USP9X in the progression from normal epithelium to invasive esophageal squamous cell cancer (ESCC) and evaluate the relevance of USP9X expression to the tumor progression and prognosis. METHODS: In this study, USP9X immunohistochemical analysis was performed on tissues constructed from ESCC combined with either normal epithelium or adjacent precursor tissues of 102 patients. All analyses were performed by SPSS 13.0 software. RESULTS: We observed that the level of high USP9X expression increased gradually in the transformation from normal epithelium (4.0%), to low grade intraepithelial neoplasia (10.5%), then to high grade intraepithelial neoplasia (28.6%), and finally to invasive ESCC (40.2%). The expression of USP9X was found to be significantly different between the normal mucosa and ESCC (P < 0.001), and between low grade intraepithelial neoplasia and high grade intraepithelial neoplasia (p = 0.012). However, no difference was observed between the high expression of USP9X in normal mucosa and low grade intraepithelial neoplasia (P = 0.369), nor between high grade intraepithelial neoplasia and ESCC (p = 0.115). Interestingly, the most intensive staining for USP9X was usually observed in the basal and lower spinous layers of the esophageal epithelium with precursor lesions which often resulted in the earliest malignant lesion. USP9X expression status was positively associated with both depth of invasion (p = 0.046) and lymph node metastasis (p = 0.032). Increased USP9X expression was significantly correlated to poorer survival rate in ESCC patients (p = 0.001). When adjusted by multivariate analysis, USP9X expression (HR 2.066, P = 0.005), together with TNM stage (HR 1.702, P = 0.042) was an independent predictor for overall survival. CONCLUSIONS: Up-regulation of USP9X plays an important role in formation and progression of precancerous lesions in ESCC and USP9X expression levels were significantly correlated with the survival of ESCC patients. Thus, USP9X could be considered as a potential biomarker and prognostic predictor for ESCC. VIRTUAL SLIDES: The virtual slides for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/1945302932102737. PMID- 24152794 TI - Meta-analysis of molecular response of kidney to ischemia reperfusion injury for the identification of new candidate genes. AB - BACKGROUND: Accumulated to-date microarray data on ischemia reperfusion injury (IRI) of kidney represent a powerful source for identifying new targets and mechanisms of kidney IRI. In this study, we conducted a meta-analysis of gene expression profiles of kidney IRI in human, pig, rat, and mouse models, using a new scoring method to correct for the bias of overrepresented species. The gene expression profiles were obtained from the public repositories for 24 different models. After filtering against inclusion criteria 21 experimental settings were selected for meta-analysis and were represented by 11 rat models, 6 mouse models, and 2 models each for pig and human, with a total of 150 samples. Meta-analysis was conducted using expression-based genome-wide association study (eGWAS). The eGWAS results were corrected for a rodent species bias using a new weighted scoring algorithm, which favors genes with unidirectional change in expression in all tested species. RESULTS: Our meta-analysis corrected for a species bias, identified 46 upregulated and 1 downregulated genes, of which 26 (55%) were known to be associated with kidney IRI or kidney transplantation, including LCN2, CCL2, CXCL1, HMOX1, ICAM1, ANXA1, and TIMP1, which justified our approach. Pathway analysis of our candidates identified "Acute renal failure panel" as the most implicated pathway, which further validates our new method. Among new IRI candidates were 10 novel (<5 published reports related to kidney IRI) and 11 new candidates (0 reports related to kidney IRI) including the most prominent candidates ANXA2, CLDN4, and TYROBP. The cross-species expression pattern of these genes allowed us to generate three workable hypotheses of kidney IRI, one of which was confirmed by an additional study. CONCLUSIONS: Our first in the field kidney IRI meta-analysis of 150 microarray samples, corrected for a species bias, identified 10 novel and 11 new candidate genes. Moreover, our new meta analysis correction method improved gene candidate selection by identifying genes that are model and species independent, as a result, function of these genes can be directly extrapolated to the disease state in human and facilitate translation of potential diagnostic or therapeutic properties of these candidates to the bedside. PMID- 24152792 TI - Hematopoietic expression of oncogenic BRAF promotes aberrant growth of monocyte lineage cells resistant to PLX4720. AB - Mutational activation of BRAF leading to expression of the BRAF(V600E) oncoprotein was recently identified in a high percentage of specific hematopoietic neoplasms in monocyte/histiocyte and mature B-cell lineages. Although BRAF(V600E) is a driver oncoprotein and pharmacologic target in solid tumors such as melanoma, lung, and thyroid cancer, it remains unknown whether BRAF(V600E) is an appropriate therapeutic target in hematopoietic neoplasms. To address this critical question, we generated a mouse model expressing inducible BRAF(V600E) in the hematopoietic system, and evaluated the efficacy of pathway targeted therapeutics against primary hematopoietic cells. In this model, BRAF(V600E) expression conferred cytokine-independent growth to monocyte/macrophage-lineage progenitors leading to aberrant in vivo and in vitro monocyte/macrophage expansion. Furthermore, transplantation of BRAF(V600E) expressing bone marrow cells promoted an in vivo pathology most notable for monocytosis in hematopoietic tissues and visceral organs. In vitro analysis revealed that MAP-ERK kinase inhibition, but not RAF inhibition, effectively suppressed cytokine-independent clonal growth of monocyte/macrophage-lineage progenitors. However, combined RAF and phosphoinositide 3-kinase (PI3K) inhibition effectively inhibited cytokine-independent colony formation, suggesting autocrine PI3K pathway activation. Taken together, these results provide evidence that constitutively activated BRAF(V600E) drives aberrant proliferation of monocyte-lineage cells. IMPLICATIONS: This study supports the development of pathway-targeted therapeutics in the treatment of BRAF(V600E) expressing hematopoietic neoplasms in the monocyte/histiocyte lineage. PMID- 24152795 TI - Autonomic complaints in patients with restless legs syndrome. AB - BACKGROUND: Data regarding autonomic function in restless legs syndrome (RLS) are limited to heart rate and blood pressure changes in cases with periodic limb movements (PLMS). METHODS: We compared autonomic symptoms of 49 subjects with RLS vs 291 control subjects using the Scales for Outcome in Parkinson disease Autonomic (SCOPA-AUT) questionnaire, consisting of 23 items in six domains scored from 0 to 3. The total score and domain scores were transformed to 0-100 points. Subjects with neurodegenerative disorders (i.e., dementia, Parkinsonism) were excluded. RESULTS: The RLS group was younger (mean+/-standard deviation, 77.9+/ 8.0 vs 80.5+/-7.9years; P=.03) and included more women (84% vs 69%; P=.04). The mean SCOPA-AUT total score was higher in the RLS group compared with the control group (20+/-11 vs 16+/-9; P=.005). Additionally the RLS group had abnormalities in gastrointestinal, cardiovascular, and pupillomotor domains. When comparing the percentage of subjects with any complaint on individual questions (score of ?1), the RLS group had a greater number of subjects with sialorrhea, constipation, early abdominal fullness, lightheadedness when standing, and heat intolerance. CONCLUSIONS: Autonomic complaints, especially gastrointestinal, cardiovascular, and oversensitivity to light, were significantly increased in subjects with RLS. Causes for autonomic dysfunction in RLS require further investigation. PMID- 24152796 TI - Serum urate levels are unchanged with continuous positive airway pressure therapy for obstructive sleep apnea: a randomized controlled trial. AB - OBJECTIVE: Hyperuricemia is associated with the presence and severity of obstructive sleep apnea (OSA). Previous work has shown that treatment of OSA with continuous positive airway pressure (CPAP) therapy reduces urinary uric acid excretion and serum urate, but there has been no previous randomized controlled investigation on the effects of CPAP therapy on serum urate; we aimed to assess this association. METHODS: Serum urate was measured in samples from participants of a previously published randomized controlled trial. Samples were taken at baseline and after 3months from men with known type 2 diabetes mellitus (T2DM) and newly diagnosed OSA, randomized to receive either therapeutic (n=19) or placebo (n=19) CPAP for 3months. RESULTS: Both groups were well matched at baseline, with no significant difference in age, body mass index (BMI), glycosylated hemoglobin (HbA1c), or oxygen desaturation index (ODI). There was no significant difference in therapeutic or placebo CPAP usage. There was no significant difference in urate levels between groups at baseline (362MUmol/L [standard deviation {SD}, 96] vs 413MUmol/L [SD, 91] [reference range, 110 428MUmol/L]) or at 3months. Baseline urate did not correlate with ODI, BMI, or HbA1c. The mean change in urate at 3months did not significantly differ between treatment groups (-7.6MUmol/L [SD, 35.9] vs -6.2MUmol/L [SD, 46.2]) (P=.9; [95% confidence interval, -28.7 to +25.9]). CONCLUSION: Our randomized controlled trial has shown no significant reduction in serum urate following 3months treatment with therapeutic or placebo CPAP. PMID- 24152797 TI - Predictors of uvulopalatopharyngoplasty success in the treatment of obstructive sleep apnea syndrome. AB - OBJECTIVE: Uvulopalatopharyngoplasty (UPPP) has been described as an option for treating obstructive sleep apnea syndrome (OSAS), with variable success rates. The main purpose of our study was to correlate UPPP success to craniofacial bony structure and orofacial muscles function. METHODS: Clinical variables, including body mass index (BMI), age, and preoperative apnea-hypopnea index (AHI); cephalometric measurements of the craniofacial region and hyoid bone position; and muscle function variables including clinical protocol and tongue strength measures were evaluated in 54 patients who underwent UPPP in the last 7years. The measurements were related to the success or failure of UPPP based on the results of preoperative and postoperative polysomnography (PSG). RESULTS: The variables BMI, preoperative AHI, and cephalometric measurements showed no influence on surgical success. The clinical muscle protocol also was similar between groups. However, the muscle strength of the anterior portion of the tongue was significantly greater in the group that showed surgical success compared to those with surgical failure. CONCLUSION: OSAS is a multifactorial disease and diagnostic symptom assessments should be individualized. In addition, special attention should be given to functional muscle alterations of the airways, as they might influence the evolution of the disease. PMID- 24152799 TI - The definition of sleep duration and the risk for hypertension: caution for meta analysis. PMID- 24152798 TI - Seasonal trends in restless legs symptomatology: evidence from Internet search query data. AB - OBJECTIVE: Patients with Willis-Ekbom disease (restless legs syndrome [RLS]) frequently report seasonal worsening of their symptoms; however, seasonal patterns in this disorder have not been systematically evaluated. The purpose of our investigation was to utilize Internet search query data to test the hypothesis that restless legs symptoms vary by season, with worsening in the summer months. METHODS: Internet search query data were obtained from Google Trends. Monthly normalized search volume was determined for the term restless legs between January 2004 and December 2012. Using cosinor analysis, seasonal effects were tested for data from the United States, Australia, Germany, the United Kingdom, and Canada. RESULTS: Cosinor analysis revealed statistically significant seasonal effects on search queries in the United States (P=.005), Australia (P=.00007), Germany (P=.00009), and the United Kingdom (P=.003), though a trend was present in the search data from Canada (P=.098). Search queries peaked in summer months in both northern (June and July) and southern (January) hemispheres. Search query volume increased by 24-40% during summer relative to winter months across all evaluated countries. CONCLUSIONS: Evidence from Internet search queries across a wide range of dates and geographic areas suggested a seasonality of restless legs symptomatology with a peak in summer months. Our novel finding in RLS epidemiology needs to be confirmed in additional samples, and underlying mechanisms must be elucidated. PMID- 24152800 TI - Central apnea at electroencephalographic seizure onset. PMID- 24152802 TI - What Are Athletes' Perceptions of Rehabilitation Outcome One Year Post Hip Arthroscopy? AB - BACKGROUND: Hip arthroscopy is a minimally invasive surgical procedure. Femoroacetabular impingement (FAI) is being increasingly recognized as a cause of hip pain in athletes and is a growing indication for arthroscopic surgery. Few studies have attempted to address patient views on outcome following arthroscopy and no qualitative studies have been carried out to date. OBJECTIVES: The aims of this study are to explore athletes' perceptions of rehabilitation outcome, the rehabilitative process and return to sport and to gain an insight into factors that affected this process. METHODOLOGY: A retrospective qualitative approach was adopted using semi-structured interviews. Eight eligible participants were interviewed. Each had been treated with hip arthroscopy for FAI between September November 2010. Data were audio-taped, transcribed verbatim and analyzed using thematic analysis. RESULTS: Three main themes emerged. 1. Ability to participate in sport; athletes were relatively satisfied with outcome despite some limitations in sporting ability. 2. Perceptions of hip problems; there was a lack of understanding and an association of hip problems with older people among the general public. 3. Athletes' perception of rehabilitation; athletes were dissatisfied with the rehabilitation and sought greater physiotherapy input. CONCLUSIONS: Overall, athletes were relatively satisfied with their outcome, one year post hip arthroscopy, despite some having to adapt their sporting activities. Key areas that need to be addressed in future research include factors affecting outcomes of hip arthroscopy, longer term outcomes, perception of FAI among the public and health practitioners and the development of standardized evidence-based rehabilitation protocol. PMID- 24152801 TI - Identification of serum insulin-like growth factor binding protein 1 as diagnostic biomarker for early-stage alcohol-induced liver disease. AB - BACKGROUND: Alcohol consumption is a major cause of liver disease in humans. The use and monitoring of biomarkers associated with early, pre-clinical stages of alcohol-induced liver disease (pre-ALD) could facilitate diagnosis and treatment, leading to improved outcomes. METHODS: We investigated the pathological, transcriptomic and protein changes in early stages of pre-ALD in mice fed the Lieber-Decarli liquid diet with or without alcohol for four months to identify biomarkers for the early stage of alcohol induced liver injury. Mice were sampled after 1, 2 and 4 months treatment. RESULTS: Pathological examination revealed a modest increase in fatty liver changes in alcohol-treated mice. Transcriptomics revealed gene alterations at all time points. Most notably, the Igfbp1 (Insulin Like Growth Factor Binding Protein 1) was selected as the best candidate gene for early detection of liver damage since it showed early and continuously enhanced induction during the treatment course. Consistent with the microarray data, both Igfbp1mRNA expression in the liver tissue and the IGFBP1 serum protein levels showed progressive and significant increases over the course of pre-ALD development. CONCLUSIONS: The results suggest that in conjunction with other tests, serum IGFBPI protein could provide an easily measured biomarker for early detection of alcohol-induced liver injury in humans. PMID- 24152803 TI - [Evaluation of the resident pharmacist program of Fukuoka University Hospital]. AB - Fukuoka University Hospital began to employ a resident pharmacist system in 2006. In the present study, to evaluate our resident program, we conducted a questionnaire survey of graduates who completed program as well as staff of the Pharmaceutical Department of this hospital. In addition, based on the results of this survey, we examined the current state and future of postgraduate training programs that can be offered to those who have completed a 6-year pharmacy course. The proportion of residents and staff who responded to the survey was 76.5% (13/17) and 100% (42/42), respectively. Of these two groups, the program was rated as beneficial by 92% and 72%, respectively. Regarding the contents of the training program, both residents and staff highly evaluated guidance on drug management on wards and the preparation of drugs (including anti-cancer agents) because these were useful for actual work. The necessity and usefulness of a resident program under the 6-year course system were also suggested. According to those graduating from a 6-year pharmacy course, a training program should include training instructions for students in a long-term internship during the 1st year, and specialty pharmacist education during the 2nd year. The results of our study suggest that it is advisable to begin to provide graduates on a 6-year course who participate in a resident program with specialized education focused on ward duties from the latter half of the 1st year based on their undergraduate education. PMID- 24152804 TI - Visualizing death and burial: past and present. PMID- 24152805 TI - A systematic analysis of a mi-RNA inter-pathway regulatory motif. AB - BACKGROUND: The continuing discovery of new types and functions of small non coding RNAs is suggesting the presence of regulatory mechanisms far more complex than the ones currently used to study and design Gene Regulatory Networks. Just focusing on the roles of micro RNAs (miRNAs), they have been found to be part of several intra-pathway regulatory motifs. However, inter-pathway regulatory mechanisms have been often neglected and require further investigation. RESULTS: In this paper we present the result of a systems biology study aimed at analyzing a high-level inter-pathway regulatory motif called Pathway Protection Loop, not previously described, in which miRNAs seem to play a crucial role in the successful behavior and activation of a pathway. Through the automatic analysis of a large set of public available databases, we found statistical evidence that this inter-pathway regulatory motif is very common in several classes of KEGG Homo Sapiens pathways and concurs in creating a complex regulatory network involving several pathways connected by this specific motif. The role of this motif seems also confirmed by a deeper review of other research activities on selected representative pathways. CONCLUSIONS: Although previous studies suggested transcriptional regulation mechanism at the pathway level such as the Pathway Protection Loop, a high-level analysis like the one proposed in this paper is still missing. The understanding of higher-level regulatory motifs could, as instance, lead to new approaches in the identification of therapeutic targets because it could unveil new and "indirect" paths to activate or silence a target pathway. However, a lot of work still needs to be done to better uncover this high-level inter-pathway regulation including enlarging the analysis to other small non-coding RNA molecules. PMID- 24152806 TI - Does orthodontic treatment provide a real functional improvement? a case control study. AB - BACKGROUND: Electromyographic analysis of the masticatory muscles provides useful data on the behavior of these muscles during stomatognathic system functioning and allows a functional assessment of orthodontic treatments. This study was undertaken to verify if achieving an Angle Class I bite through orthodontic treatment can lead to neuromuscular balance. METHODS: This study enrolled 30 patients (20 females, 10 males, mean age: 15.78 years) with an Angle Class II, division 1 malocclusion that was orthodontically treated. A group of 30 subjects (19 females, 11 males; mean age: 16.15 years), randomly selected among subjects with an Angle Class II, division 1 malocclusion that had not been orthodontically treated served as the Control group. Both groups were subjected to electromyography to study their neuromuscular characteristics. The Shapiro-Wilk's test revealed a non normal distribution, therefore we used a Friedman two way ANOVA by ranks test to compare differences of surface electromyography values between treated and untreated subjects at closed and open eyes condition. RESULTS: A statistically significant interaction between orthodontic treatment and open eyes conditions was detected for anterior temporal muscles. A significant imbalance of the anterior temporal muscles, which is indicative of an asymmetric electromyographic pattern, was also found. CONCLUSIONS: The present data indicate that achieving a correct occlusal target does not necessarily correspond to a neuromuscular balance. PMID- 24152807 TI - Painful knee prosthesis: can we help with bone SPECT/CT? AB - OBJECTIVES: The aim of the study was to evaluate the value of single-photon emission computerized tomography/computed tomography (SPECT/CT) in the clinical assessment of painful knee prostheses. MATERIALS AND METHODS: Between 2009 and 2011 we identified 105 patients who had undergone Tc-hydroxydiphosphonate SPECT/CT for painful knee prosthesis. Complete follow-up data were available for 69 patients (50 women and 19 men; mean age, 71 years) with painful knee prostheses (59 total, nine unicompartmental, one patellofemoral) and clinical suspicion of infection or loosening. The imaging test report in conjunction with the clinical data from the patient's notes was used to gauge how useful the test had been in terms of patient management. RESULTS: SPECT/CT confirmed the suspected clinical diagnosis of loosening in nine patients (13%) and of infection in two (2.9%) and identified other causes in 43 patients (62.3%). In 85.5% of patients, SPECT/CT was clinically useful (both positive and negative results), whereas in 14.5% it had no clinical impact on patient management. Revision surgery was performed in 24/69 (34.8%) patients and confirmed the SPECT/CT diagnosis in 21 patients (seven loosening, one infection, two subchondral fractures, two postoperative inflammation and nine patellofemoral osteoarthritis). CONCLUSION: SPECT/CT is a useful tool for the evaluation of painful knee prosthesis in 85.5% of cases and helps in confirming mechanical loosening and in excluding other causes such as infection and patellofemoral osteoarthritis. PMID- 24152811 TI - Selection methods regulate evolution of cooperation in digital evolution. AB - A key, yet often neglected, component of digital evolution and evolutionary models is the 'selection method' which assigns fitness (number of offspring) to individuals based on their performance scores (efficiency in performing tasks). Here, we study with formal analysis and numerical experiments the evolution of cooperation under the five most common selection methods (proportionate, rank, truncation-proportionate, truncation-uniform and tournament). We consider related individuals engaging in a Prisoner's Dilemma game where individuals can either cooperate or defect. A cooperator pays a cost, whereas its partner receives a benefit, which affect their performance scores. These performance scores are translated into fitness by one of the five selection methods. We show that cooperation is positively associated with the relatedness between individuals under all selection methods. By contrast, the change in the performance benefit of cooperation affects the populations' average level of cooperation only under the proportionate methods. We also demonstrate that the truncation and tournament methods may introduce negative frequency-dependence and lead to the evolution of polymorphic populations. Using the example of the evolution of cooperation, we show that the choice of selection method, though it is often marginalized, can considerably affect the evolutionary dynamics. PMID- 24152812 TI - A model comparison reveals dynamic social information drives the movements of humbug damselfish (Dascyllus aruanus). AB - Animals make use a range of social information to inform their movement decisions. One common movement rule, found across many different species, is that the probability that an individual moves to an area increases with the number of conspecifics there. However, in many cases, it remains unclear what social cues produce this and other similar movement rules. Here, we investigate what cues are used by damselfish (Dascyllus aruanus) when repeatedly crossing back and forth between two coral patches in an experimental arena. We find that an individual's decision to move is best predicted by the recent movements of conspecifics either to or from that individual's current habitat. Rather than actively seeking attachment to a larger group, individuals are instead prioritizing highly local and dynamic information with very limited spatial and temporal ranges. By reanalysing data in which the same species crossed for the first time to a new coral patch, we show that the individuals use static cues in this case. This suggests that these fish alter their information usage according to the structure and familiarity of their environment by using stable information when moving to a novel area and localized dynamic information when moving between familiar areas. PMID- 24152814 TI - Reorientation patterns in central-place foraging: internal clocks and klinokinesis. AB - We study central-place foraging patterns of Aphaenogaster senilis ants at a population level by video framing individual ant trajectories in a circular arena with a nest connected to its centre. The ants naturally leave and enter the nest and forage generating non-trivial movement patterns around the nest. Our data analysis indicated that the trajectories observed can be classified into two strategies: the risk-averse strategy, which involves wandering around the nest without departing far from it and the risk-prone strategy, which involves long exploration paths with periodic returns to the central region, nearby the nest. We found that both risk-prone and risk-averse strategies exhibit qualitatively the same reorientation patterns, with the time between consecutive reorientations covering a wide range of scales, and fitting a stretched exponential function. Nevertheless, differences in the temporal scales and the time variability of such reorientation events differ, together with other aspects of motion, such as average speed and turns. Our results give experimental evidence that the internal mechanisms driving reorientations in ants tend to favour frequently long relocations, as theory predicts for efficient exploration in patchy landscapes, but ants engaged in central-place foraging can modulate such behaviour to control distances from the nest. Previous works on the species support the idea that risk prone and risk-averse strategies may reflect actual differences between individuals age and experience; these factors (age and experience) should be then relevant in modulating the internal reorientation clocks. To support the validity of our findings, we develop a random-walk model combining stretched exponential reorientation clocks with klinokinesis that fits the time length and the travelled distance distributions of the observed trajectories. PMID- 24152816 TI - Molecular insights into brain tumors: ready for translation into novel treatment strategies? PMID- 24152813 TI - Biomechanical regulation of vascular smooth muscle cell functions: from in vitro to in vivo understanding. AB - Vascular smooth muscle cells (VSMCs) have critical functions in vascular diseases. Haemodynamic factors are important regulators of VSMC functions in vascular pathophysiology. VSMCs are physiologically active in the three dimensional matrix and interact with the shear stress sensor of endothelial cells (ECs). The purpose of this review is to illustrate how haemodynamic factors regulate VSMC functions under two-dimensional conditions in vitro or three dimensional co-culture conditions in vivo. Recent advances show that high shear stress induces VSMC apoptosis through endothelial-released nitric oxide and low shear stress upregulates VSMC proliferation and migration through platelet derived growth factor released by ECs. This differential regulation emphasizes the need to construct more actual environments for future research on vascular diseases (such as atherosclerosis and hypertension) and cardiovascular tissue engineering. PMID- 24152817 TI - Malignant astrocytoma in elderly patients: where do we stand? AB - PURPOSE OF REVIEW: Age is inversely correlated with clinical outcome and a strong prognostic factor for the course of most primary brain tumors including malignant astrocytoma, i.e. anaplastic astrocytoma and glioblastoma. We here review available clinical outcome data and discuss future directions of clinical research. RECENT FINDINGS: The standard of care in patients with malignant astrocytoma above the range of 65-70 years was considered radiotherapy, preferentially using a hypofractionated regimen (15 * 2.66 Gy). Two phase III clinical trials, the NOA-08 and Nordic trials, demonstrated that temozolomide (TMZ) therapy alone was not inferior to radiotherapy alone, and methylation of the O-methylguanine-DNA-methyltransferase (MGMT) gene promoter was predictive with a methylated MGMT promoter indicating a benefit from TMZ chemotherapy. Ongoing clinical trials in this patient population include the National Cancer Institute of Canada/European Organisation for Research and Treatment of Cancer intergroup trial, investigating the combination of hypofractionated radiotherapy and TMZ chemotherapy, and the Swiss ARTE trial, investigating the combination of bevacizumab and hypofractionated radiotherapy. Recent translational studies indicate that prognostically favorable factors in malignant astrocytoma from younger patients are virtually absent in the elderly. SUMMARY: Current standard of care for elderly patients with malignant astrocytoma involves a treatment strategy based on the MGMT gene promoter methylation status. The role of combined radiotherapy and TMZ chemotherapy and a potential role for the addition of anti VEGF therapy to radiotherapy are currently addressed in ongoing trials. The lack of favorable prognostic factors in tumor tissue might in part explain the poorer clinical outcome of elderly patients. PMID- 24152819 TI - Delirium and cognitive decline: more than a coincidence. AB - PURPOSE OF REVIEW: To review the recent findings on the relationships between delirium and cognitive decline in the elderly. RECENT FINDINGS: Current advances in the field include substantial new evidence that delirium increases the risk of dementia in patients without previous cognitive impairment and accelerates cognitive decline in patients with Alzheimer's disease. Findings on cognitive trajectories and domains affected contribute to better understanding of the clinical nature of cognitive impairment after delirium. Volume loss and disruption of white matter integrity may represent early MRI markers for long term cognitive impairment. Neurodegenerative and low-level chronic inflammatory processes predispose to exaggerated response to incident stimuli that may precipitate both acute brain dysfunction and persisting cerebral damage. SUMMARY: Still little is known about the relationship between delirium and cognitive trajectories in the elderly, and the underlying pathophysiological mechanisms. The association of neurodegenerative and inflammatory processes appears to play an important role in the pathogenesis and the clinical course of cognitive impairment after delirium. The hypothetical role of several other factors remains to be clarified. Further clinical studies are needed to evaluate whether prevention and treatment approaches that proved to be useful to reduce delirium incidence and severity may also improve long-term outcomes, and prevent cognitive decline. PMID- 24152818 TI - The evolving landscape of glioblastoma stem cells. AB - PURPOSE OF REVIEW: Recent advances in the role of cancer stem cells (CSCs) in glioblastoma will be reviewed. RECENT FINDINGS: In the decade since the description of brain tumor CSCs, the potential significance of these cells in tumor growth, therapeutic resistance, and spread has become evident. Most recently, the interplay between CSCs, tumor genetics, and the microenvironment has offered potential nodes of fragility under therapeutic development. The CSC phenotype is informed by specific receptor signaling, and study of the regulation of stem cell genes by transcription factors and microRNAs has identified a number of new targets amenable to treatment. Like normal stem cells, CSCs display specific epigenetic landscapes and metabolic profiles. SUMMARY: Brain cancers activate core stem cell regulatory pathways to empower self-renewal, maintenance of an organ system (albeit an aberrant one), and survival under stress that collectively permits tumor growth, therapeutic resistance, invasion, and angiogenesis. These properties have implicated CSCs as contributors in GBM progression and recurrence, spurring a search for anti-CSC therapies that do not disrupt normal stem cell maintenance. The last year has witnessed a rapid evolution in the understanding of CSC biology to inform preclinical targeting. PMID- 24152820 TI - Impact of beta-thalassemia trait carrier state on cardiovascular risk factors and metabolic profile in patients with newly diagnosed hypertension. AB - Thalassemia minor (Tm), the beta-thalassemia carrier state, is followed by favorable lipidemic profile and seems to protect against myocardial infarction mainly in men. However, the cardiovascular risk factor (CRF) and metabolic profile of these subjects has not been thoroughly addressed, although it is not known whether gender differences are involved. We evaluated CRFs, metabolic parameters and risk-prediction equations along with renal function and selected echocardiographic indices in 23,680 consecutive subjects, that is, 11,192 women and 12,488 men, with newly diagnosed hypertension according to the presence or absence of Tm. Of 23,680 patients, 548 (2.3%) had Tm. Compared with patients without Tm, Tm cases had similar gender distribution, age, body mass index and blood pressure. Besides having a better lipidemic profile, Tm patients were less frequently smokers (25% vs. 32%, P<0.001), had a lower prevalence of metabolic syndrome (26% vs. 39%, P<0.001) and lower HeartSCORE and INTERHEART scores (P<0.001). Tm patients also had lower levels of fibrinogen and plasminogen activator inhibitor-1 (P<0.001), lower serum creatinine and higher estimated glomerular filtration rate (P<0.001), lower prevalence of left ventricular hypertrophy (35% vs. 48%, P<0.001) and higher total and mid-wall fractional shortening (P=0.03 and <0.001, respectively). Most of these differences were consistent in both genders, whereas the HeartSCORE and the echo indices were significantly better in Tm only in women. Among patients with newly diagnosed hypertension, those with Tm have a better overall CRF and metabolic profile, beyond the well-known differences in serum lipids. Compared with men, women seem to be at least equally protected. PMID- 24152821 TI - Effect of supine versus sitting position on noninvasive assessment of aortic pressure waveform: a randomized cross-over study. AB - Biomarkers derived noninvasively from the aortic blood pressure (BP) waveform provide information regarding cardiovascular (CV) risk independently of brachial BP (bBP). Although body position has significant impact on the assessment of bBP, its effect on aortic hemodynamics remains unknown. This study investigated the changes in both brachial and aortic hemodynamics, between the supine and sitting position. In this randomized cross-over study, the bBP and the aortic pressure waveform were assessed after a 5 min rest (sitting and supine in randomized order); aortic BP, pulse pressure (PP) amplification, augmentation index (AIx) and subendocardial viability index (SEVR) were assessed. Sixty-one subjects were examined (36 males, mean age 50+/-12 years). Mean BP did not differ between the sitting and supine position (110.8+/-13.7 vs 110.9+/-14.9, respectively, P=0.945). However, significant difference between the sitting and supine position in brachial PP (45.9+/-16.0 vs 52.6+/-15.6, respectively, P<0.001), aortic PP (36.7+/-15.2 vs 43.1+/-13.9, P<0.001), PP amplification (1.28+/-0.1 vs 1.23+/ 0.1, P<0.001), AIx (26.9+/-11.9 vs 31.1+/-10.2, P<0.001) and SEVR (179.6+/-25.7 vs 161.2+/-25.8, P<0.001) were found. Review of the literature identified underestimation of the role of body position on aortic hemodynamics. In conclusion, increased PP in both the aorta and brachial artery were found in the supine compared to the sitting position. Reduced PP amplification and SEVR were further observed in the supine position, due to increased pressure wave reflections (AIx). PMID- 24152822 TI - Patients' preference for ambulatory versus home blood pressure monitoring. AB - Patient's preference might influence compliance with antihypertensive treatment and thereby long-term blood pressure (BP) control. This study compared patients' preference in using ambulatory (ABPM) versus home BP monitoring (HBPM). Subjects referred for hypertension were evaluated with 24-h ABPM and 7-day HBPM. Participants filled a questionnaire including demographics and Likert scale questions regarding their acceptance, preference, disturbance, activity restriction and feasibility of using ABPM and HBPM. A total of 119 patients were invited and 104 (87%) were included (mean age 51+/-11 years, 58% men, 38% time to work >8 h). A total of 82% reported a positive overall opinion for HBPM versus 63% for ABPM (P<0.05). 62% considered ABPM as more reliable than HBPM but 60% would choose HBPM for their next BP evaluation (P<0.05 for both comparisons). Moderate to severe discomfort from ABPM was reported by 55% and severe restriction of their daily activities by 30% compared with 13% and 7%, respectively, from HBPM (P<0.001 for both comparisons). The overall score for HBPM and ABPM (range 4-25; higher score indicating worse performance) was 6.6+/ 2.5 and 10+/-4.0 (mean difference 4.4+/-4.6, P<0.001), respectively. In binary logistic regression models, neither previous experience with BP monitoring nor demographic characteristics appeared to influence patients' preference. These data suggest that HBPM is superior to ABPM in terms of overall acceptance and preference by hypertensive patients. Patients' preference deserves further research and should be taken into account in decision making in clinical practice. PMID- 24152823 TI - Do level and variability of systolic blood pressure predict arterial properties or vice versa? AB - No longitudinal study addressed whether systolic blood pressure level (SBPL) or within-visit variability (SBPV) predict arterial properties or vice versa. In families randomly recruited from a Flemish population, we determined SBPL and SBPV from five consecutive blood pressure readings. The indexes of SBPV were variability independent of the mean, the difference between maximum and minimum SBPL, and average real variability. We measured carotid intima-media thickness and distensibility by ultrasound and carotid-femoral pulse wave velocity by tonometry (SphygmoCor, version 8.2). Effect sizes were computed for 1-s.d. increments in the predictors, while accounting for covariables and family clusters. Among 1087 participants (50.4% women; mean age, 41.8 years), followed up for 2.55 years (median), higher SBPL predicted (P < or = 0.019) higher carotid intima-media thickness (+15 MUm), lower carotid distensibility (-1.53 10(-3) kPa( 1)) and faster carotid-femoral pulse wave velocity (+0.285 m s(-1)) at follow-up, whereas none of the SBPV indexes predicted the arterial traits at follow-up (P> or = 0.11). In a subset of 713 participants, followed up for another 3.14 years, lower carotid distensibility predicted (P<0.01) higher SBPL (+2.57 mm Hg), variability independent of the mean (+0.531 units), difference between maximum and minimum SBPL (+1.75 mm Hg) and average real variability (+0.654 mm Hg). Higher carotid-femoral pulse wave velocity predicted a 1.11 mm Hg increase SBPL (P=0.031). In conclusion, temporality and effect size suggest that SBPL but not within-visit SBPV cause arterial stiffness and carotid intima-media thickness. Carotid stiffness, independent of SBPL, predicts within-visit SBPV, possibly because baroreflexes originating from a stiff carotid artery wall are impaired. Finally, stiffness of the aorta contributes to the age-related SBPL possibly, because faster returning reflected waves augments SBPL. PMID- 24152825 TI - Surveillance tools and strategies for animal diseases in a shifting climate context. AB - Animal disease surveillance is watching an animal population closely to determine if a specific disease or a group of diseases makes an incursion so that a prior plan of action can be implemented. The purpose of this paper is to review existing tools and techniques for an animal disease-surveillance system that can incorporate the monitoring of climate factors and related data to enhance understanding of disease epidemiology. In recent decades, there has been interest in building information systems by combining various data sources for different purposes. Within the field of animal health, there have only been limited attempts at the integration of surveillance data with relevant climate conditions. Statistical techniques for data integration, however, have been explored and used by several disciplines. Clearly the application of available techniques for linking climate data with surveillance systems should be explored with the aim of facilitating prevention, mitigation, and adaptation responses in the surveillance setting around climate change and animal disease risks. Drawing on this wider body of work, three of the available techniques that can be utilized in the analysis of surveillance data with the available climate data sets are reviewed. PMID- 24152824 TI - Renin-sensitive microRNAs correlate with atherosclerosis plaque progression. AB - Recent trials with inhibition of the renin-angiotensin-aldosterone system (RAAS) in patients with established atherosclerosis have been equivocal. MicroRNAs (miRs) are known to affect multiple pathways relevant to atherosclerosis, including RAAS. We postulated that the use of a direct renin antagonist would result in differential regulation of miRs. We examined monocyte miR expression before and after treatment with renin antagonist, Aliskiren, in patients with established cardiovascular disease as part of a prospective, single-center, randomized, double-blind and placebo-controlled clinical trial (NCT01417104). After screening, patients (mean age 62+/-3 years) were randomized to placebo or Aliskiren. Three-dimensional dark-blood magnetic resonance imaging assessment of atherosclerosis in the thoracic and abdominal aorta was conducted at baseline and at study completion (19-36 weeks). MiR expression arrays were performed on RNA from peripheral blood mononuclear cells collected at baseline and 12 weeks following randomization to placebo or Aliskiren and showed that hsa-miR-106b-5p, 27a-3p and 18b-5p were significantly downregulated with Aliskiren. Baseline expression of these miRs positively correlated with normalized total wall volume in subjects taking Aliskiren (miR-106b, R=0.62; miR-27a, R=0.63; miR-18b, R=0.77; P<0.05). Hsa-miR-106b-5p, 27a-3p and 18b-5p may represent pathway-specific adaptations to renin inhibition relevant to atherosclerosis. PMID- 24152826 TI - Psychoneuroimmunology and health psychology: inflammation and protective factors. AB - A common clinical observation is the adverse relationship between stress and human diseases. The attention of scientific research on health has been disproportionately focused on risk factors that predict the onset of certain health outcomes, in particular there has been an increasing interest in the role of inflammation as a common mechanism of disease in a number of medical and neuropsychiatric diseases. Despite the importance of such research being undisputed, it is necessary to emphasize what the protective factors are that promote psychosocial recovery processes and increased survival rates in a biopsychosocial perspective. This article aims to understand the relationship between psychosocial factors and immune system in the interests of health psychology, highlighting the protective factors that promote recovery, resiliency and resistance to disease. PMID- 24152827 TI - The dual Aurora kinase inhibitor ZM447439 prevents anaplastic thyroid cancer cell growth and tumorigenicity. AB - The anaplastic thyroid cancer (ATC) is among the most aggressive human tumors which fail to respond to all the currently available therapeutic approaches. As a consequence most patients die within a few months from diagnosis. In the present preclinical study, the effects of the ZM447439, a functional inhibitor of Aurora kinases, on the growth and tumorigenicity of a panel of ATC derived cell lines (CAL-62, 8305C, 8505C and BHT-101) were evaluated. The treatment of the different ATC cells with ZM447439 inhibited proliferation in a time- and dose-dependent manner, with IC50 comprised between 0.5 mM and 5 mM. Moreover, the drug remarkably impaired the formation of colonies in soft agar of all the cell lines. Consistently with Aurora inhibition, immunofluorescence and immunoblotting experiments demonstrated that Aurora auto-phosphorylation following drug treatment was completely abrogated, and treated cells were characterized by the presence of multiple spindles with short microtubules. In the same experiments we observed the loss of histone H3 phosphorylation on Ser10, specifically due to Aurora-B, after ZM447439 treatment. Time-lapse videomicroscopy and flow cytometric analysis demonstrated that in presence of ZM447439 the cells were able to enter mitosis but not to complete it, becoming polyploid. Almost all the ATC cell lines studied showed increased apoptosis after only 48 h of treatment. In conclusion, our data demonstrate that ZM447439 is effective in reducing cell growth and tumorigenicity of different ATC derived cell lines, and further investigations are needed to exploit its potential therapeutic value for ATC treatment. PMID- 24152828 TI - 7T mMR in the assessment of acute arterial mesenteric ischemia in a rat model. AB - To validate a rat model of acute arterial mesenteric ischemia correlating MRI patterns with macro and microscopic changes in the small bowel. Thirty Sprague Dawley rats were assigned to two experimental groups (Group I and Group II) of fifteen rats each. Group I underwent surgical procedure of superior mesenteric artery (SMA) ligation, followed by macroscopic observation. In Group II, a loop was tied loosely around the SMA without occluding the vessel. Three days after surgery, the loop was tied by external tips to completely occlude the artery. 7T microMR (7Tesla microMR) was performed before and 8 hours after SMA occlusion. At predetermined time-points the histopathological examinations were performed in both of groups. Macroscopic monitoring revealed thinning of mesenteric vessels, hypotonic reflex ileus and chromatic change of some loops. 7T microMR sequences evidenced loop dilation with gas-fluid mixed stasis, intraperitoneal free fluid and bowel wall hyperintensity. There were no significant differences in the histological analysis between the two groups. The gap of three days from surgery, adopted in the Group 2, allowed to avoid signs of peritoneal and mesenteric irritation which could bias imaging patterns. MR succeeded to identify the signs of arterial mesenteric ischemia. PMID- 24152829 TI - Effect of MN (III) tetrakis (4-benzoic acid) porphyrin by photodynamically generated free radicals on SODs keratinocytes. AB - Superoxide, a reactive form of oxygen, can be produced in vivo either in normal and under pathophysiologic conditions or by photosensitizing chemicals, as during photodynamic treatment. Photodynamic therapies (PDT), widely adopted in Dermatology and Oncology, are known to generate reactive oxygen species (ROS) and may contribute to structural alterations and oxidatively generated modifications of cellular antioxidants. We hypothesized that over-production of free radicals would decrease the enzymatic activities of endogenous cellular antioxidants. To test this hypothesis, keratinocytes were treated with the photosensitizer Photofrin plus visible light to produce free radicals and CuZnSOD and MnSOD activities were measured. Photodynamic treatment of keratinocytes increases malonylaldehyde production, nitrotyrosine staining and superoxide production. The enzymatic activities of CuZnSOD and MnSOD were significantly decreased after Photofrin plus visible light treatment. Our results suggest that the main cellular antioxidant system can be inactivated by photodynamically generated ROS. Pretreatment of keratinocytes with free radicals scavenger such as Mn (III) tetrakis (4-benzoic acid) porphyrin (MnTBAP) was able to restore the endogenous antioxidant system activities, inhibiting the MDA formation, nitrotyrosine staining and superoxide formation. Antioxidant therapy could therefore be a useful tool in protecting healthy epidermal cells against common side effects induced by antitumor targeted therapies. PMID- 24152831 TI - Stress hormones regulate periodontal inflammation. AB - Periodontal disease involves inflammation of the gingival tissues, caused by microbial pathogens. Recent papers suggest that emotional stress worsens periodontal disease. Here we review the literature and propose that corticotropin releasing hormone (CRH) secreted under stress stimulates gingival mast cells together with other neuropeptides and cytokines to secrete pro-inflammatory molecules that contribute to periodontal pathology. Stress reduction and/or mast cell inhibition may provide additional therapeutic approaches. PMID- 24152830 TI - The tumor necrosis factor-alpha-induced protein 8 family in immune homeostasis and inflammatory cancer diseases. AB - Within the immune system homeostasis is maintained by a myriad of mechanisms that include the regulation of immune cell activation and programmed cell death. The breakdown of immune homeostasis may lead to fatal inflammatory diseases. We set out to identify genes of tumor necrosis factor-alpha-induced protein 8 (TNFAIP8) family that has a functional role in the process of immune homeostasis. Tumor necrosis factor-alpha-induced protein 8 (TNFAIP8), which functions as an oncogenic molecule, is also associated with enhanced cell survival and inhibition of apoptosis. Tumor necrosis factor-alpha-induced protein 8-like 2 (TIPE2) governs immune homeostasis in both the innate and adaptive immune system and prevents hyper-responsiveness by negatively regulating signaling via T cell receptors and Toll-like receptors (TLRs). There also exist two highly homologous but uncharacterized proteins, TIPE1 and TIPE3. This review is an attempt to provide a summary of TNFAIP8 family associated with immune homeostasis and inflammatory cancer diseases. PMID- 24152832 TI - Immunostimulants and prevention of recurrent respiratory tract infections. AB - Recurrent respiratory tract infections (RRTIs) are very common in children and a major challenge for pediatricians. They affect the children's quality of life, cause absences from school and lost parental working days, and repeated medical examinations, hospital admissions as well as antibiotic therapies lead to high costs for society. Given their prevalence and clinical importance, various prevention strategies have been developed. One of the most widely used is the administration of immunostimulants: i.e. molecules of bacterial or synthetic origin that interact with immunological mechanisms in vitro and in vivo. A number of studies have investigated their effects on cellular and innate immunity, and their clinical efficacy, but there is no consensus as to their real usefulness. The main aim of this review is to analyse the available data concerning the activity and efficacy of immunostimulants in preventing pediatric RRTIs. The majority of studies have shown that the number of infections decreases after immunostimulant treatment, but they are affected by various methodological weaknesses. Further studies are urgently needed to confirm whether, when and which immunostimulants should be used. PMID- 24152833 TI - Resistin - from gene expression to development of diabetes. AB - Adipocyte-originated hormonal factors, playing a role of signaling particles, are widely engaged in energy control, feeding behavior and general glucose or lipid metabolism. One of them ? resistin ? has been suspected to initiate or develop insulin resistance and diabetes. From the moment of discovery of resistin, during last 13 years, numerous investigations put some light on a potential role of this hormone in mammals. In this review knowledge on resistin, including its structure, physiological role related to obesity and diabetes, as well as, gene sequence and phenotypic effects of the identified polymorphisms in human and domestic mammals is discussed. PMID- 24152834 TI - Mast cell involvement in rheumatoid arthritis. AB - Autoimmunity is a failure of self-tolerance resulting in immune reactions against autologous antigen. Rheumatoid arthritis is characterized by inflammation of synovium associated with destruction of the join cartilage and bone. A role of mast cell-mediated inflammation and antibodies are involved in this disease. Numerous cytokines such as IL-1, TNF, IL-8, IL-33 and IFN gamma have been implicated in rheumatoid arthritis and in particular in the synovial joint fluid. Since TNF is believed to activates resident synovial cells to produce collagenase that mediate destruction of cartilage, antagonists against the inflammatory cytokine TNF have a beneficial effects in this disease. Here we review the interrelationship between rheumatoid arthritis and mast cell activation. PMID- 24152835 TI - Zinc deficiency adversely influences interleukin-4 and interleukin-6 signaling. AB - Zinc deficiency is accompanied by a severe impairment of the immune system, causing a high risk for infections and autoimmune diseases due to altered functionality of B- and T- cells. The influence of zinc deficiency on T- and B- cells via alteration of cytokine expression is well established. The aim of this study was to examine potential direct effects of zinc deficiency on the reactivity of B- and T- cells. Zinc deficient B- and T- cells revealed divergent reaction patterns compared to zinc sufficienT-cells. This was manifested by a stronger proliferative response following IL-6 and IL-2 stimulation on the one hand, but less proliferation following IL-4 stimulation on the other hand. Moreover, these results were supported by the finding that the B- and T-cell signaling cascades activated by IL-4 or IL-6, respectively, were affected directly by zinc deficiency, resulting in reduced Stat6 phosphorylation and increased Stat3 phosphorylation. Whereas the transcription factor Stat6 is involved in IL-4 signaling, Stat3 is activated by IL-6 signaling. Consequently, these results show opposing effects of zinc deficiency on IL-4 and IL-6/IL-2 signaling pathways, thus underlying the importance of zinc for proper immune function. PMID- 24152836 TI - Guanosine promotes proliferation of neural stem cells through cAMP-CREB pathway. AB - In previous studies, we have found that extracellular guanosine can stimulate endogenous progenitor/stem cell proliferation in the spinal cord following chronic injury and in the subventricular zone of the brains of rats afflicted with Parkinson's Disease. In this study, using neural stem cells isolated from one-day old rats, we found that guanosine could stimulate neural stem cell proliferation, and that the proliferation was not due to the guanosine metabolism mechanism since guanine, which is interconverted by an ecto-purine nucleoside phosphorylase from guanosine, has no stimulating effect on the proliferation of neural stem cells. We determined that second messenger cAMP was involved in the pathway as results showed that 100 microM guanosine stimulated cAMP accumulation. Using western blot analysis, we found that 100 microM guanosine can activate the phosphorylation of CREB without changing the total amount of CREB. In conclusion, guanosine can stimulate neural stem cell proliferation, and the cAMP-CREB pathway is involved in this biological effect. PMID- 24152837 TI - The effects of interleukin-10 or TGF-beta on anti-CD3/CD28 induced activation of CD8+CD28- and CD8+CD28+ T cells in allergic asthma. AB - The CD8+CD28- and CD8+CD28+ T cells play a primordial role in peripheral tolerance, but little is known about their implication in allergic asthma. This study was designed to determine the changes in a proportion of human circulatory CD8+ subsets before and after short term culture in the presence of anti-CD3/CD28 and IL-10 or TGF-beta. Flow cytometry analysis revealed increased percentage of CD8+CD28- T cells but decreased percentage of CD8+CD28+ T cells enriched from peripheral blood of adult allergic asthma individuals compared to controls (baseline). In comparison to the baseline, co-stimulation with anti-CD3/CD28 and IL-10 decreased the proportion of CD8+CD28- T cells in severe allergic asthma subjects, whereas it increased this value in mild to moderate asthmatic subjects and controls. Adding TGF-beta decreased the proportion of CD8+CD28- T cells from allergic asthma subjects, whereas it has opposite effects on this subset from controls. IL-10 and TGF-beta had some plethoric effects on FoxP3 expression in anti-CD3/CD28 activated CD8+CD28- T cells. Thus, these findings indicate that a control mechanism involving IL-10 and TGF-beta might be defective in allergic asthma subjects. PMID- 24152838 TI - Involvement of renal cytochromes P450 and arachidonic acid metabolites in diabetic nephropathy. AB - Diabetic nephropathy (DN) is one of the most serious complications of type I and type II diabetes. DN is characterized by hyperfiltration, hypertrophy, extracellular matrix accumulation, and proteinuria. This advances into renal fibrosis and loss of renal function. Reactive oxygen species (ROS) and TGF-beta have been implicated in the pathogenesis of diabetic nephropathy. Early stages of diabetic nephropathy are also associated with alterations in renal sodium handling as well as hypertension; both are processes linked by involvement of the arachidonic acid (AA) metabolites, 20-hydroxyeicosatetraenoic acid (20-HETE, produced by cytochrome P450-4a, (CYP4A) and epoxyeicosatrienoic acids (EETs). Indeed, metabolism of AA is increased in a rat model of diabetes. In this study, we demonstrate that rats with streptozotocin-induced diabetes of 1 month duration develop renal hypertrophy and increased fibronectin and TGF-beta1 expression/cortical levels concomitant with an increase in CYP4A expression and 20 HETE production. These results were also paralleled by an increase in reactive oxygen species (ROS) production and NADPH oxidase activity. Treatment of diabetic rats with HET0016, selective inhibitor of CYP 4A, prevented all these changes. Our results suggest that diabetes-induced induction of CYP4A and 20-HETE production could be a major pathophysiological mechanism leading to activation of ROS through an NADPH dependent pathway and TGF-beta1 thus resulting in major renal pathology. Inhibitors of 20-HETE production could thus have an important therapeutic potential in the treatment of diabetic nephropathy. PMID- 24152839 TI - Effects of Berberis aristata/Silybum marianum association on metabolic parameters and adipocytokines in overweight dyslipidemic patients. AB - Nutraceuticals and functional foods have attracted considerable interest as potential alternative therapies for treatment of different cardiovascular disorders and insulin resistance. We evaluated the efficacy of a combination of Berberis Aristata/Silybum Marianum extract (Berberol(r)) in a sample of overweight, dyslipidemic patients at low cardiovascular risk. We enrolled 105 Caucasian, euglycemic, overweight, dyslipidemic patients, of either sex. At baseline all patients underwent a 6 months run-in period during which they followed an adequate diet and practiced physical activity. At the end of the run in period, patients were randomised to take placebo or a combination of Berberis aristata/Silybum marianum, 1 tablet during the lunch and 1 tablet during the dinner, for three months, in a double-blind, placebo-controlled design. Berberis aristata/Silybum marianum and placebo were then interrupted for 2 months (wash out period), and all patients continued with only diet and physical activity. At the end of the wash-out period, patients re-started Berberis aristata/Silybum marianum or placebo twice a day for further 3 months. We evaluated during the run in period, at randomisation, before and after the wash-out period these parameters: body weight and BMI, fasting plasma glucose, lipid profile, insulin resistance, retinol binding protein-4 (RBP-4), adiponectin (ADN), resistin. Total cholesterol, LDL-C, and Tg decreased, and HDL-C increase after 3 months of Berberis aristata/Silybum marianum, both compared to baseline and placebo. Berberis aristata/Silybum marianum decreased fasting plasma insulin, and HOMA-IR, both compared to baseline and to placebo. Moreover, there was a decrease of RBP 4, and resistin, and an increase of ADN after 3 months of Berberis aristata/Silybum marianum. All these positive effects disappeared after the wash out period, and re-appeared after the re-introduction of the drug. We observed a significant correlation between HOMA-index decrease and resistin, and RBP-4 decrease, and between HOMA-index decrease and ADN increase in Berberis aristata/Silybum marianum group, but not in placebo group. Berberis aristata/Silybum marianum fixed combination seems to be safe and effective in improving lipid profile, but also in improving insulin resistance and adipocytokines levels. PMID- 24152840 TI - Transcriptional profile characterization for the identification of peripheral blood biomarkers in patients with cerebral aneurysms. AB - We tried to identify molecular markers in peripheral blood to predict high risk of aneurysm rupture. Extraction of the total population of peripheral blood mononuclear cell (PBMC) from total blood volume, total RNA extraction from PBMC and Agilent One Color Gene-expression Oligo-Microarray were performed on peripheral venous blood samples from 45 patients with ruptured, unruptured cerebral aneurysms and control group (15). Mean foreground/ background signal intensities and A (log2(R*G)/2) values were calculated for each spot. Genes with absolute fold change (FC) greater than or equal to plus or minus 1.5 and p-value less than 0.05 were considered differentially expressed in the 3 groups (Student T-test). Genes coding for MMPs were strongly underexpressed in ruptured aneurysms group, suggesting a possible role in aneurysms development more than their rupture. Genes coding for adhesine proteins of the extracellular matrix (ICAM1) and cytoskeleton (WIPF1,TUBA4A) were underexpressed in ruptured aneurysms. Genes coding proteins involved in the regulation of apoptotic processes may be important in aneurysm development and rupture, resulting into an increased rate of remodeling processes in the arterial wall. Fas coding gene, SUMO1, ZFAT, BCL2, CCR5 genes were all over-represented in unruptured aneurysms. The coexisting over representation of pro-apoptotic genes and the underexpression of cytoskeleton and extracellular matrix genes confirms that aneurysms development and evolution are part of a degenerative process of the arterial wall not involved in aneurysms rupture. MMPs may be involved in repairing chronic damages to the arterial walls and preventing SAH. Unexpectedly, Heat Shock Proteins (HSP90AA1, HSPA1A, HSPB1), G and RAS proteins, generally activated by stress situations were under represented in aneurysmal walls. Further PCR and Western Blotting studies are needed to confirm such findings and to identify diagnostic and prognostic markers in order to define screening protocols for intracranial aneurysms. PMID- 24152841 TI - Negative feedback interaction of HO-1/INOS in PBMC of acute congestive heart failure patients. AB - Heart failure (HF) is a common clinical syndrome with frequent exacerbations requiring hospitalization. Among the various mechanisms that underlie the pathogenesis of HF, the activation of the immune system leads to a progressive and redundant release of proinflammatory cytokines responsible for a variety of deleterious effects in heart failure, such as endothelial dysfunction, apoptosis of myocytes, activation of MMPs (Matrix Metallo Proteinases) and oxidative stress, with the result of decreased inotropism and clinical syndrome such as pulmonary edema,. The condition of oxidative stress induces the expression of genes coding for the proteins inducible nitric oxide synthase (iNOS) and heme oxygenase-1 (HO-1). Twenty-five hospitalized cardiology patients with symptomatic acute congestive HF (NYHA Class III-IV) and impaired left ventricular (LV) function (ejection fraction less than 35 percent) were included in the study. The aim of this study was to evaluate the cytokines plasma concentrations and the expression and activity of iNOS and HO-1 proteins in peripheral blood mononuclear cell (PBMC) extracted from patients in comparison to control group. In ACHF; left ventricular ejection fraction (LVEF) percent was reduced. Furthermore; iNOS and HO-1 expression and cytokines plasma levels were significantly higher in patients with ACHF as compared to controls group. Moreover the enzyme activity presents an opposite trend compared to that obtained in the analysis of the transcript and proteins. Our studies suggest a negative feedback interaction between iNOS and HO 1 important in the physiopathology of heart failure that could be considered a good candidate as a future therapeutic target for the development of new drugs. PMID- 24152842 TI - Plasma myeloperoxidase in patients with erectile dysfunction of arteriogenic- and non-arteriogenic origin: association with markers of endothelial dysfunction. AB - Endothelial dysfunction and the disruption of the nitric oxide-cyclic guanosine monophosphate (cGMP) pathway have been considered the early mechanisms for the development of erectile dysfunction (ED). Myeloperoxidase (MPO), a heme containing enzyme mainly released by activated neutrophils and monocytes, may contribute to endothelial dysfunction by promoting oxidation of different substrates and thus may play a role in ED. MPO level and its correlation with different plasma biomarkers of endothelial dysfunction were studied in patient with ED of arteriogenic (A-ED) and non-arteriogenic (NA-ED) to assess potential differences between the two ED subgroups. Diagnosis of ED was based on the International Index of Erectile Function Score. Its etiology was classified with penile echo-color Doppler at baseline and after intracavernous injection of prostaglandin E1. MPO, soluble (s) cGMP, sICAM-1, sVCAM-1 and sP-Selectin were measured by enzyme-linked immunosorbent assay. MPO concentration in A-ED was significantly higher compared to control subjects and NA-ED patients. Plasmatic cGMP level resulted lower both in A-ED and in NA-ED patients, whereas no difference has been observed between the two ED groups. sICAM-1 concentration resulted higher in A-ED compared both to controls and NA-ED. sVCAM-1 level was the same in controls, A-ED and NA-ED patients. sP-Selectin concentration resulted higher both in A-ED and in NA-ED patients than in controls, whereas no difference has been observed between the two ED groups. Correlation analysis indicated a positive correlation between plasmatic MPO, sICAM-1 and sP-Selectin levels. MPO may represent an important link between oxidation, inflammation and cardiovascular diseases and may also represent a potential marker to distinguish between the two subgroups of ED patients. Moreover, in ED subjects circulating cGMP may reflect the local signaling dysfunction. The use cGMP as a potential marker for monitoring the disease needs further investigation. PMID- 24152843 TI - DHT and IGF-1 in peripheral blood lymphocytes: new markers for the biological passport of athletes. AB - We performed a pilot study using human peripheral blood lymphocytes (PBL) as a novel system to identify new biomarkers of dihydrotestosterone (DHT) and insulin like growth factor-1 (IGF-1) abuse in sport. First, to obtain a gene signature, we treated cultures of lymphocytes from sedentary males with three doses of 0.237 microg/ml DHT, each of which is 80-fold the physiological concentration in young adult male serum, at days 0, 2 and 4, or with a single dose of 1.25 microg/ml IGF 1, which is 5-fold the physiological concentration in young adult male serum. We then used the Human Genome U133 Plus 2.0 microarray to identify a gene signature related to DHT or IGF-1 administration. Gene expression was evaluated after 7 and 21 days of DHT treatment, and after 24 h, 72 h and 7 days of IGF-1 treatment. Microarray analysis yielded a list of genes whose expression was altered after DHT or IGF-1 treatment. Among these we selected the genes that are most representative of the pathways associated with skeletal and muscular disorders using the IPA bioinformatics tool. We identified six (IDO1, CXCL13, CCL1, GZMB, VDR and IL2RA) and two (FN1 and RAB31) genes that were up-regulated in lymphocytes from sedentary subjects after 7 days of DHT and IGF-1 treatment, respectively. The expression of these genes in lymphocytes from differently trained athletes was either down-regulated or similar to that in lymphocytes from sedentary subjects. This finding suggests that up-regulation was due to the drug and not to physical exercise. In conclusion, we demonstrate that PBL can be useful in anti-doping checks, and we describe new biomarkers of DHT and IGF-1 abuse which can be included in the Athlete's Biological Passport. PMID- 24152844 TI - Are HMGB1 protein expression and secretion markers of upper airways inflammatory diseases? AB - Taking into account the mechanisms at the origin of the airways inflammatory pathologies, our attention has been recently addressed to the study of HMGB1, a protein belonging to the group of alarmins. Alarmins are those molecules which in homeostatic conditions carry out specific metabolic and/or structural functions; furthermore, after a direct trauma or an infection, these molecules are released in the extracellular milieu becoming there activators of the innate immunity and powerful inflammatory factors. In a previous research we found in patients affected with chronic rhinosinusitis with/without nasal polyposis (CRSwNP) an increased expression of this protein in the nucleus of nasal mucosa epithelial cells. HMGB1 was overexpressed also as focal subepithelial infiltration and in the inflammatory cells of patients in comparison with controls. These results suggested a possible pathogenetic role of HMGB1 in CRSwNP. The aim of the present study was to investigate if the expression and localization (nuclear, cytoplasmic and extracellular) of the HMGB1 protein-cytokine is somehow related to the severity and complexity of the histological and clinical picture. We noticed values which have around statistical significance between nuclear HMGB1 and eosinophils infiltrate (p=0.0607) and between nuclear HMGB1 and inflammatory infiltrate (P=0.0524). Even more significant was the correlation between extra cellular HMGB1 expression and the presence of allergic-hyper reactive conditions such as asthma, allergic rhinitis, NSADs intolerance, antibiotic allergy. HMGB1 was significantly more expressed in the nucleus (p=0.0499) and in the intercellular space (p=0.0380) in allergic patients than in non-allergic subjects and as extra-cellular infiltrate in patients with NSADs intolerance (p=0.0022). These results confirm the role of HMGB1 in the pathogenesis of chronic rhinosinusitis with/without nasal polyposis; besides the higher extra-cellular expression in patients with a more severe clinical and inflammatory picture and the presence of associated co-morbidities suggests to seek for new compounds: these compounds, decreasing the extra-cellular release of this alarmin through a scavenger mechanism, could keep under control the inflammatory process without interfering with the nuclear transcriptional messengers. PMID- 24152845 TI - Toxicity of cadmium on Sertoli cell functional competence: an in vitro study. AB - Cadmium (Cd), an ubiquitous environmental metal, mainly used for industrial purposes, may be toxic at level of the reproductive system. Testis tubular-based Sertoli cells (SC), play a major role in constituting the blood-testis barrier and provide a unique microenvironment for the genesis and differentiation of germ cells. Hence SC strictly control sperm qualitative and quantitative parameters. We aimed to assess whether exposure to Cd would adversely affect superior mammal SC viability and function. We isolated and purified SC from pre-pubertal pig testes according to our method and incubated the retrieved cells with three different Cadmium chloride concentrations (5-10-15 microM). Parameters of SC function such as inhibin B and anti-Mullerian hormone (AMH) were depressed by Cd exposure, contrary to what observed in untreated controls. No impairment of the FSH receptor integrity on the SC, as assessed by 17-beta-estradiol production, upon stimulation with FSH, was observed in either 5 microM Cd-treated or untreated controls. Differences, on the contrary, were observed for higher Cd concentrations (10 and 15 mM), in terms of FSH receptor integrity, that was altered, as compared to untreated controls, in terms of lower production of 17 beta-estradiol. In addition, the apoptotic test showed a significant increase of early (ANNEXIN V-/Propidium Iodide+) (AV-/PI+) and late apoptotic cells (AV+/ PI+) in all Cd -treated SC conditions as compared to controls. In conclusion, the Cd -related toxicity on SC, clearly demonstrated by our study, even at low concentrations, is expected to damage spermatogenesis that directly is dependent upon retention of SC viability and function. PMID- 24152846 TI - Role of 3D MRI with proset technique in the evaluation of lumbar radiculopathy. AB - The aim of this study is to demonstrate the effectiveness of 3-Dimensional Magnetic Resonance Imaging (3D MRI) using the ProSet technique in the diagnosis of lumbar radiculopathy and to compare morphological findings with clinical and neurophysiological data. 40 patients suffering from L5 or S1 mono-radiculopathy caused by a disc herniation were evaluated through preliminary clinical assessment and electromyography (EMG) technique. Both conventional spin-echo sequences and 3D coronal FFE with selective water excitation (ProSet imaging) were acquired. Indentation, swelling and tilt angle of the nerve root were assessed by means of a 3D MR radiculography. 3D ProSet multiplanar reconstructions (MPR) were used for quantitative measurements of L5 and S1 nerve root widths. Widths of the symptomatic nerve root were compared with those of the contralateral nerve. Data were processed using Epi Info 3.3 software (CDC, Atlanta, GA, USA) and were compared through a paired t-Student test. We observed an abnormal tilt angle in 22 patients (57,2 percent, P less than 0.05). Morphologic alterations such as monolateral swelling or indentation of the involved roots were found in 36 patients (90 percent, P less than0.01) using 3D MR radiculography. In 10 patients, EMG revealed more nerve roots involved, while 3D FFE with ProSet technique shows a single root involved. In 2 patients, alterations were demonstrated only through EMG technique. We suggest that 3D MR radiculography can provide more information than other techniques about symptomatic disc herniation, supporting the detection of morphological changes of all nerve segments. 3D FFE with ProSet technique demonstrates high sensibility to exactly identify the level of the root involved and can provide an extremely useful tool to lead a surgical planning. PMID- 24152847 TI - Expression and function of Angiopoietins and their tie receptors in human basophils and mast cells. AB - The Angiopoietin/Tie system is a key regulator of vascular remodeling, maturation, angiogenesis and lymphangiogenesis. In humans there are three angiopoietins: Angiopoietin-1 (Ang1), Angiopoietin-2 (Ang2), and Angiopoietin-4 (Ang4). Ang1 and Ang2 are the best characterized angiopoietins. The angiopoietin receptor system consists of two type I tyrosine kinase receptors (Tie1 and Tie2). Tie2 binds all known angiopoietins. We sought to characterize Ang1, Ang2, Tie1 and Tie2 expression and functions in human basophils and mast cells. Basophils, LAD-2 cells and Human Lung Mast Cells (HLMCs) constitutively express Ang1 and Ang2 mRNA. Intracellular staining for Ang1 and Ang2 was stronger in basophils than in mast cells. Immunoelectron microscopy demonstrated Ang1 in cytoplasmic vesicles of basophils. The protein kinase C activators phorbol diester (PMA) and bryostatin 1 (Bryo1) stimulated basophils to rapidly release a large amount of Ang1. PMA-induced Ang1 release was inhibited by brefeldin A. Tie1 and Tie2 mRNAs were expressed in basophils, LAD-2 and HLMCs. Basophils, LAD-2 and HLMCs expressed Tie1 on the cell surface. HLMCs and LAD-2 expressed Tie2 on the cell surface, whereas basophils did not. Ang1, but not Ang2, induced migration of mast cells through the engagement of Tie2. Neither Ang1 nor Ang2 induced basophil chemotaxis. We have identified a novel mechanism of cross-talk between human basophils and mast cells mediated by the Ang1/Tie2 system that might be relevant in the orchestration of inflammatory and neoplastic angiogenesis. PMID- 24152848 TI - Novel path to IL-6 trans-signaling through thrombin-induced soluble IL-6 receptor release by platelets. AB - Interleukin (IL)-6 is a multifunctional cytokine with a critical role in inflammatory, immunoregulatory and haemopoietic responses. Its receptor consists of an ubiquitously expressed membrane transducing element (gp130) and of the specific element IL-6R-alpha (gp80), present only on hepatocytes and some leukocyte subsets. IL-6R-alpha also exists as soluble protein (sIL-6R) that, in the presence of IL-6, forms a complex able to bind gp130 and, thanks to the mechanism called trans-signaling, transduces IL-6 effect through tyrosine phosphorylation and activation of the signal transducer and transcription activator (STAT)-3. The aim of this study was to analyze the bidirectional relationships between platelet aggregation and IL-6-dependent effects. While platelets do not produce IL-6, we found that resting platelets express gp130, but not gp80, on their membranes. Upon activation by thrombin or calcium ionophore A23187, but not by ADP, the IL-6R-alpha is released in soluble form, while cangrelor, the specific inhibitor of P2Y12 receptor, can partially inhibit sIL-6R release. This sIL-6R is biologically active and, in the presence of IL-6, can trigger IL-6 trans-signaling, inducing an autocrine activation loop (as measured by an increase in gp80 and gp130 content) and STAT3 phosphorylation. On the other hand, IL-6 trans-signaling has no effect on platelet degranulation or aggregation by itself, nor on thrombin-induced platelet aggregation. Our data add an important piece to the puzzle of thrombosis and inflammation: in the presence of IL-6, which can be produced by stressed endothelial cells, the platelet-derived IL-6 trans-signaling could be crucial for the evolution of inflammation within a damaged vessel. PMID- 24152849 TI - Muscoloskeletal disorders and occupational stress of violinists. AB - Although musculoskeletal disorders are the most frequent cause of occupational diseases in musicians, very few studies have focused attention on a single category of instruments, in particular on the violin. This involves, in its practice, almost all the areas of the body, besides being in the category of strings which is the most numerous in an orchestra. A specific protocol, investigating postural and clinical profiles of the musculoskeletal apparatus as well as job stress, was utilized in a conservatory on graduates in the tenth year of violin study, who regularly participated in activities of orchestras or string quartets. The investigation revealed target segments of osteoarticular apparatus (jaw, vertebral spine, shoulders, elbows, hands and fingers, lower limbs) electively subjected to overuse, as well as muscle contracture of trapezoids and hyperkeratosis of fingers and clavicle. Although the work environment was comfortable, most violinists claimed to undergo intense rhythms and competitiveness. This study, highlighting subclinical occupational diseases in young musicians (violinists) suggests adequate prevention measures. PMID- 24152850 TI - Entero-colpo-defecography vs supine entero-MRI: which one is the best tool in the differentiation of enterocele, elytrocele and edrocele? AB - Pelvic floor disorders represent a significant cause of morbidity associated with a severe reduction of quality of life. It represents a very common clinical problem that afflicts women three to seven time more often than men. The purpose of this study was to assess the diagnostic tools available to define the imaging strategy in patients with pelvic floor dynamic dysfunctions and to investigate their abilities in the diagnosis of enterocele, elytrocele and edrocele. From January 2008 to May 2011, 614 patients with symptoms related to pelvic floor dynamic dysfunctions were enrolled in our retrospective study. After anamnesis and clinical examination, entero-colpo-defecography (ECD) and supine entero magnetic resonance (SE-MR) exams were performed in all patients. This study showed that the diagnostic efficacy of ECD is higher than that of SE-MR in the detection of enterocele and edrocele. Furthermore, elytrocele can be visualized only with ECD considering the position of patient during SE-MR examination. In addition, in patients planned for surgery, SE-MR is more useful to clarify the intra-pelvic interaction of multiple organ prolapse and to better define the pelvic anatomy and functioning. PMID- 24152851 TI - Comparison of effect of sex hormone manipulation during neonatal period, on mRNA expression of Slc9a4, Nr3c2, Htr5b and Mas1 in hippocampus and frontal cortex of male and female rats. AB - It has long been known that spatial memory and the ability to navigate through space are sexually dimorphic traits among mammals, and numerous studies have shown that these traits can be altered by means of sex hormone manipulation. Hippocampus, the main organ involved in this kind of memory, has specific signature genes with high expression level compared to other regions of the brain. Based on their expression levels and the role that products of these genes can play in processes like signal transduction, mediation of hormone effects and long term potentiation, these genes can be considered as genes necessary for routine tasks of hippocampus. Male and female rat pups were injected with estradiol and testosterone respectively. at early stage of their lives to examine the effect of sex hormone manipulation on mRNA expression of Slc9a4, Nr3c2, Htr5b and Mas1 using comparative quantitative real-time polymerase chain reaction. The results showed that expressions of these genes are strongly influenced by sex hormones in both the frontal cortex and hippocampus, especially in male hippocampus, in which expression of all genes were up-regulated. Htr5b was the only gene that was affected only in the males. Expression of Mas1 was contrary to expectations, showed stronger changes in its expression in cortex than in hippocampus. Nr3c2 was down regulated in all samples but up regulated in male hippocampus, and Slc9a4 also showed a huge up-regulation in male hippocampus compared to other samples. PMID- 24152852 TI - Prophylactic strategies in recurrent vulvovaginal candidiasis: a 2-year study testing a phytonutrient vs itraconazole. AB - The aim of the present study was to assess the clinical efficacy of a one week/month treatment with a phytocompound with antimycotic properties (K-712, with following 100 mg composition: 10 mg of oleoresin from Pseudowintera colorata at 30 percent concentration in Polygodial together with trace amounts of Olea europea) in recurrent vulvo-vaginal candidiasis (RVVC), as compared to once a week treatment with an azole drug for 24 months follow up. This prospective randomized study involving 122 women (19 to 63 years old) with a history of proven episodes of RVVC in the prior 12 months. Patients were allocated in two treatment groups of 61 patients each and given A) Itraconazole 200 mg orally once a week or B) 1 tab twice a day of K-712 for one week/month. Each treatment schedule was well tolerated with 19 patients in the azole group complaining of transient mild symptoms (nausea, abdominal discomfort, unpleasant taste), while only 3 patients on K-712 reported slight dyspepsia. The number of relapses was significantly lower in the K-712-treated group as compared to the itraconazole group (22 vs 39, p less than 0.05). Moreover, the former group showed a significantly decreased number of cases resistant or dose-dependent susceptible as compared to group A (p less than 0.05 vs itraconazole) and the same occurred for the occurrence of non-albicans species (group A 64.1 percent vs group B 31.8 percent, p less than 0.05). The overall mycological cure at the end of the 2-year study showed a comparable benefit between the two groups. From these data it appears that the present antifungal phytonutrient is equally effective as itraconazole in the overall treatment of RVVC over a 2-year follow-up, but yielding a significantly better prophylactic effect and also maintenance benefit with lower relapse rate, antifungal susceptibility and growth of azole-resistant species. PMID- 24152853 TI - Distribution of extended spectrum beta-lactamase resistance genes among nosocomial imipenem resistant A. Baumannii strains harboring BLAoxa-23 carbapenemases isolated from Ilam and Tehran. AB - Antimicrobial susceptibility and ESBLs genes of 42 imipenem resistant A. baumannii carried out by DDST and PCR. The most antimicrobial agents against A. baumannii strains, harboring blaOXA-23-like carbapenemases, were meropenem (33.4 percent), piperacillin-tazobactam (23.9 percent), ceftazidime (14.3 percent) and gatifoxacin (19.1 percent), respectively. All the 42 isolates harbored the blaTEM gene, but the bla SHV and VEB genes were not present among all the isolates. With the exception of seven isolates, all the A. baumannii strains harbor blaTEM showed ESBL positivity in DDST. The result of this study show that resistance against antimicrobial agents, especially carbapenems, has increased and that blaTEM harboring A. baumannii strains can be help the blaOXA-like carbapenemase genes to code for resistance against carbapenem antibiotics. PMID- 24152854 TI - Thermal water of Vetriolo, Trentino, inhibits the negative effect of interleukin 1β on nitric oxide production and apoptosis in human osteoarthritic chondrocyte. AB - The thermal water of Vetriolo in Trentino, Italy (VW) has been known over 150 years for its therapeutic properties in the treatment of osteoarthritis (OA). This is a highly mineralized water, strongly acidic sulfate, rich in calcium, magnesium and iron and used for balneotherapy after dilution. The aim of our study was to investigate the possible in vitro effects of the VW in human OA chondrocytes cultivated in the presence or in the absence of Interleukin-1 beta (IL-1beta). OA chondrocytes were cultivated in Deionized Water (DW) (DW-DMEM, controls), or in one of three different VW-DMEM media, in which DW had been totally (100 percent) or in part (25 or 50 percent) substituted with VW. All samples were analyzed before and after treatment with IL-1beta at a concentration of 5 ng/ml. After 48 h, we evaluated the cell viability, the release of nitric oxide (NO) in culture medium, the inducible nitric oxide synthase (iNOS) expression, and the percentage of apoptosis and necrosis. Finally, we carried out a morphological assessment using a transmission electron microscope (TEM). Our data showed that VW alone at 25 or 50 percent concentration did not affect the viability of cultured OA chondrocytes, and determined a significant survival recovery rate in cultures stimulated with IL-1beta. On the contrary, the VW alone at 100 percent of concentration reduced, in a significant (P less than 0.05) manner, the cells viability. NO levels were low both in DW-DMEM cultures and in those reconstituted with 25 or 50 percent of VW, and were significantly (P less than 0.05) increased in cultures with 100 percent of VW. VW at 25 or 50 percent concentration significantly (P less than 0.001) reduced the NO production induced by IL-1beta. The data of the NO levels were confirmed by the immunocytochemistry assay for iNOS. Our experiments confirmed the pro-apoptotic effect of IL-1beta and demonstrated a protective effect of VW at 25 or 50 percent concentration. These findings were confirmed by TEM. In conclusion, our study demonstrated that VW alone at 25 or 50 percent concentration modifies neither morphology nor NO production and neither iNOS expression nor apoptosis, but it inhibits the negative effects of IL-1beta in chondrocytes cultures. PMID- 24152855 TI - High density cholesterol level as predictor of clinical response to anti-TNF alpha therapy in psoriatic patients. AB - Psoriasis is a common, chronic, inflammatory, and debilitating disease of the skin. Infliximab is a human/mouse chimeric anti-TNF-alpha antibody effective in the management of psoriasis. Availability of biomarkers for prediction of response, could optimize the therapeutic approach. The aim of this study was to identify predictors of clinical response to infliximab in psoriatic patients in the long-term treatment. Patients affected with psoriasis and suitable for treatment with infliximab were prospectively enrolled. Patients treated for a period longer than 96 weeks were included in the study and divided into high responders and low responders according to infliximab efficacy (PASI 90). A logistic regression analysis was used to explore independent association between high clinical response and possible biomarkers of prediction. A total of 112 patients were included for the analysis. Multiple regression analysis showed that high levels of HDL cholesterol and the short duration of psoriasis [OR 1.11 (CI 1.05-1.18) and OR 0.94 (CI 0.89-0.99)] predicted the most effective clinical response to infliximab. Our findings, which highlight a possible role for HDL cholesterol as clinical predictor for psoriasis treatment, are particularly noteworthy in the context of clinical strategies, but also suggest a possible role for lipid metabolism in aspects of psoriasis that deserves further investigation. PMID- 24152856 TI - Besides the HLA loci: SNPs and non-HLA gene products as immunoregulatory factors in the onset of psoriatic arthritis subtypes. AB - Psoriatic arthritis (PsA) is described as a multifactorial autoimmune rheumatic disease although its development is surely linked to some specific HLA genes (especially the HLA-Cw*06:02 allele). To date, its complex immunopathogenetic mechanism is not well clarified. Actually, increasing evidence suggest that qualitative and quantitative interplays between some PsA-susceptibility HLA alleles and other genetic, regulatory and environmental factors, may develop distinct subphenotypes of PsA. We first provide a brief summary of current knowledge about the various PsA conditions. Then, we consider the reasons why further analysis of the clinical course of patients affected by distinct PsA subsets, and who receive different therapeutic treatments, should be carried out in conjunction with deeper investigations about the identification of key genes and immunoregulatory agents by applying the most recent advances in biotechnology. This approach could better explain the molecular mechanisms responsible for both the onset and progression of this multi-faceted pathology with the purpose of significantly improving the management of PsA patients. PMID- 24152857 TI - Karyometry and quantitative immunohistochemical analysis of the urothelium in tissue sections: a feasibility study based on chromatin remodeler DAXX immunostaining. AB - The aim of this study was to investigate the feasibility of applying a software traditionally used in the field of engineering to pathology, in particular to tissue sections from normal urothelium (NU) immuno-stained for the chromatin remodeler DAXX (death domain-associated protein). The study included 5 cases of NU. Images were recorded with a Nikon digital camera. The nuclear area and the intensity of nuclear staining were analyzed with a software package developed in LabVIEW environment. The nuclear size is 14.8 plus or minus 6.5 square microns. The nuclei in the cells adjacent to the stroma are slightly smaller than in the intermediate cells by a factor of 0.86. The mean nuclear area of the nuclei in the superficial cell layer in NU is identical to the nuclei in the intermediate cell layers. For each nucleus intensity of nuclear staining is calculated based on the gray value of the individual picture elements in the green color plane. The mean and standard deviation of nuclear gray value are 106 plus or minus 15. The mean value in the nuclei adjacent to the stroma is slightly greater by a factor 1.02 and 1.04 compared to the intermediate and superficial cell layers. In conclusion, this exploratory study shows that karyometry and quantitative immunohistochemical analysis can be done accurately by using a digital camera commonly available to pathologists and an image analysis software routinely used in the field of engineering. PMID- 24152858 TI - TUBB3: neuronal marker or melanocyte mimic? PMID- 24152859 TI - Mortality among high-risk patients with acute myocardial infarction admitted to U.S. teaching-intensive hospitals in July: a retrospective observational study. AB - BACKGROUND: Studies of whether inpatient mortality in US teaching hospitals rises in July as a result of organizational disruption and relative inexperience of new physicians (July effect) find small and mixed results, perhaps because study populations primarily include low-risk inpatients whose mortality outcomes are unlikely to exhibit a July effect. METHODS AND RESULTS: Using the US Nationwide Inpatient sample, we estimated difference-in-difference models of mortality, percutaneous coronary intervention rates, and bleeding complication rates, for high- and low-risk patients with acute myocardial infarction admitted to 98 teaching-intensive and 1353 non-teaching-intensive hospitals during May and July 2002 to 2008. Among patients in the top quartile of predicted acute myocardial infarction mortality (high risk), adjusted mortality was lower in May than July in teaching-intensive hospitals (18.8% in May, 22.7% in July, P<0.01), but similar in non-teaching-intensive hospitals (22.5% in May, 22.8% in July, P=0.70). Among patients in the lowest three quartiles of predicted acute myocardial infarction mortality (low risk), adjusted mortality was similar in May and July in both teaching-intensive hospitals (2.1% in May, 1.9% in July, P=0.45) and non-teaching-intensive hospitals (2.7% in May, 2.8% in July, P=0.21). Differences in percutaneous coronary intervention and bleeding complication rates could not explain the observed July mortality effect among high risk patients. CONCLUSIONS: High-risk acute myocardial infarction patients experience similar mortality in teaching- and non-teaching-intensive hospitals in July, but lower mortality in teaching-intensive hospitals in May. Low-risk patients experience no such July effect in teaching-intensive hospitals. PMID- 24152860 TI - The July phenomenon revisited: new insights on a lore of academic medicine. PMID- 24152861 TI - Impact of preoperative moderate/severe mitral regurgitation on 2-year outcome after transcatheter and surgical aortic valve replacement: insight from the Placement of Aortic Transcatheter Valve (PARTNER) Trial Cohort A. AB - BACKGROUND: The effect of preoperative mitral regurgitation (MR) on clinical outcomes of patients undergoing transcatheter aortic valve replacement (TAVR) is controversial. This study sought to examine the impact of moderate and severe MR on outcomes after TAVR and surgical aortic valve replacement (SAVR). METHODS AND RESULTS: Data were drawn from the randomized Placement of Aortic Transcatheter Valve (PARTNER) Trial cohort A patients with severe, symptomatic aortic stenosis undergoing either TAVR (n=331) or SAVR (n=299). Both TAVR and SAVR patients were dichotomized according to the degree of preoperative MR (moderate/severe versus none/mild). At baseline, moderate or severe MR was reported in 65 TAVR patients (19.6%) and 63 SAVR patients (21.2%). At 30 days, among survivors who had isolated SAVR/TAVR, moderate/severe MR had improved in 25 SAVR patients (69.4%) and 30 TAVR patients (57.7%), was unchanged in 10 SAVR patients (27.8%) and 19 TAVR patients (36.5%), and worsened in 1 SAVR patient (2.8%) and 4 TAVR patients (5.8%; all P=NS). Mortality at 2 years was higher in SAVR patients with moderate or severe MR than in those with mild or less MR (49.8% versus 28.1%; adjusted hazard ratio, 1.73; 95% confidence interval, 1.01-2.96; P=0.04). In contrast, MR severity at baseline did not affect mortality in TAVR patients (37.0% versus 32.7%, moderate/severe versus none/mild; hazard ratio, 1.14; 95% confidence interval, 0.72-1.78; P=0.58; P for interaction=0.05). CONCLUSIONS: Both TAVR and SAVR were associated with a significant early improvement in MR in survivors. However, moderate or severe MR at baseline was associated with increased 2-year mortality after SAVR but not after TAVR. TAVR may be a reasonable option in selected patients with combined aortic and mitral valve disease. CLINICAL TRIAL REGISTRATION URL: http://www.clinicaltrials.gov. Unique identifier: NCT00530894. PMID- 24152862 TI - Selenized milk casein in the diet of BALB/c nude mice reduces growth of intramammary MCF-7 tumors. AB - BACKGROUND: Dietary selenium has the potential to reduce growth of mammary tumors. Increasing the Se content of cows' milk proteins is a potentially effective means to increase Se intake in humans. We investigate the effects of selenized milk protein on human mammary tumor progression in immunodeficient BALB/c nude mice. METHODS: Four isonitrogenous diets with selenium levels of 0.16, 0.51, 0.85 and 1.15 ppm were formulated by mixing low- and high-selenium milk casein isolates with a rodent premix. MCF-7 cells were inoculated into the mammary fat pad of female BALB/c nude mice implanted with slow-release 17 beta estradiol pellets. Mice with palpable tumors were randomly assigned to one of the four diets for 10 weeks, during which time weekly tumor caliper measurements were conducted. Individual growth curves were fit with the Gompertz equation. Apoptotic cells and Bcl-2, Bax, and Cyclin D1 protein levels in tumors were determined. RESULTS: There was a linear decrease in mean tumor volume at 70 days with increasing Se intake (P < 0.05), where final tumor volume decreased 35% between 0.16 and 1.15 ppm Se. There was a linear decrease in mean predicted tumor volume at 56, 63 and 70 days, and the number of tumors with a final volume above 500 mm3, with increasing Se intake (P < 0.05). This tumor volume effect was associated with a decrease in the proportion of tumors with a maximum growth rate above 0.03 day-1. The predicted maximum volume of tumors (Vmax) and the number of tumors with a large Vmax, were not affected by Se-casein. Final tumor mass, Bcl 2, Bax, and Cyclin D1 protein levels in tumors were not significantly affected by Se-casein. There was a significantly higher number of apoptotic cells in high-Se tumors as compared to low-Se tumors. CONCLUSIONS: Taken together, these results suggest that turnover of cells in the tumor, but not its nutrient supply, were affected by dairy Se. We have shown that 1.1 ppm dietary Se from selenized casein can effectively reduce tumor progression in an MCF-7 xenograft breast cancer model. These results show promise for selenized milk protein as an effective supplement during chemotherapy. PMID- 24152863 TI - Effect of glutathione on peroxyoxalate chemiluminescence of hypericin as the fluorophore. AB - Herein, the effect of amino acid Glutathione (GSH) on Peroxyoxalate Chemiluminescence was studied for the first time. Hypericin (HYP) was employed as the efficient fluorophore. The investigated parameters included rise and fall rate constant for the chemiluminescence burst, theoretical and experimental maximum intensity, the time-needed to reach maximum intensity and the total light yield emission which theoretically was evaluated using the pooled intermediate model by a computerized non-linear least-squares curve fitting program (KINFIT). Furthermore, based on observed quenching effect of GSH, the Stern-Volmer plot in quencher concentration range of 2.8*10(-6) to 3.4*10(-5)M with KQ value of 1.59*10(4) was calculated. The bimolecular quenching rate constant (Kq) was also estimated about 2.8*10(12) and M(-1) S(-1). Moreover the system was applied successfully to determine glutathione in biological samples. PMID- 24152864 TI - Shape tailored green synthesis and catalytic properties of gold nanocrystals. AB - The use of environmentally benign procedures is highly desirable for the synthesis of nanoparticles. Here we report a simple, versatile, economic, ecofriendly and reproducible green method for the size-tunable synthesis of stable and crystalline gold nanoparticles of varied shape using aqueous extract of Garcinia Combogia fruit. The predominant anisotropic nature in the morphology of synthesized particles at lower quantities of extract gradually shifted to spherical particles with larger quantity of extract and increase of temperature. The onset of reduction, the time-evolution of the Surface Plasmon Resonance (SPR) and the catalytic activity are studied using UV-Visible spectroscopy. The Selected Area Diffraction (SAED) pattern, the lattice fringes in the High Resolution Transmission Electron Microscopic (HRTEM) image and the X-ray Diffraction (XRD) pattern clearly show the pure crystalline nature of the synthesized gold nanoparticles. The role of carboxyl group present in Garcinia Combogia fruit extract in the reduction of chloroaurate ions is established using Fourier Transform Infrared (FTIR) spectra. The size dependent catalytic activity of the green synthesized gold nanoparticles on the reduction of 4-Nitrophenol to 4-Aminophenol using sodium borohydride is studied and reported for the first time. The first order kinetics is fitted and rate constants are calculated. Catalytically active green synthesized gold nanoparticles with controllable size and shape presents an advanced step in future biomedical and chemical applications. PMID- 24152865 TI - Detection of DNA damage based on metal-mediated molecular beacon and DNA strands displacement reaction. AB - DNA hairpin structure probes are usually designed by forming intra-molecular duplex based on Watson-Crick hydrogen bonds. In this paper, a molecular beacon based on silver ions-mediated cytosine-Ag(+)-cytosine base pairs was used to detect DNA. The inherent characteristic of the metal ligation facilitated the design of functional probe and the adjustment of its binding strength compared to traditional DNA hairpin structure probes, which make it be used to detect DNA in a simple, rapid and easy way with the help of DNA strands displacement reaction. The method was sensitive and also possesses the good specificity to differentiate the single base mismatched DNA from the complementary DNA. It was also successfully applied to study the damage effect of classic genotoxicity chemicals such as styrene oxide and sodium arsenite on DNA, which was significant in food science, environmental science and pharmaceutical science. PMID- 24152866 TI - Synthesis, spectroscopic and theoretical studies of ethyl (2E)-3-amino-2-({[(4 benzoyl-1,5-diphenyl-1H-pyrazol-3-yl)carbonyl]amino}carbonothioyl)but-2-enoate butanol solvate. AB - We have synthesized ethyl (2E)-3-amino-2-({[(4-benzoyl-1,5-diphenyl-1H-pyrazol-3 yl)carbonyl]amino}carbonothioyl)but-2-enoate (2) by the reaction of 4-benzoyl-1,5 diphenyl-1H-pyrazole-3-carbonyl chloride (1), ammonium thiocyanate and ethyl 3 aminobut-2-enoate and then characterized by elemental analyses, IR, Raman, (1)H NMR, (13)C NMR and X-ray diffraction methods. The experimental and theoretical vibrational spectra of 2 were investigated. The experimental FT-IR (4000-400 cm( 1)) and Laser-Raman spectra (4000-100 cm(-1)) of the molecule in the solid phase were recorded. Theoretical vibrational frequencies and geometric parameters (bond lengths, bond angles) were calculated using Ab Initio Hartree Fock (HF), Density Functional Theory (B3LYP) methods with 6-311++G(d,p) basis set by Gaussian 09W program. The computed values of frequencies are scaled using a suitable scale factor to yield good coherence with the observed values. The assignments of the vibrational frequencies were performed by potential energy distribution (PED) analysis by using VEDA 4 program. The theoretical optimized geometric parameters and vibrational frequencies were compared with the corresponding experimental X ray diffraction data, and they were seen to be in a good agreement with each other. Also, the highest occupied molecular orbital (HOMO) and the lowest unoccupied molecular orbital (LUMO) energies were calculated. PMID- 24152867 TI - Structural features of the 2-amino-5-nitrobenzophenone by means of vibrational spectroscopy HF and DFT, first order hyperpolarizability, NBO, HOMO-LUMO and theromodynamic properties. AB - The FT-IR and Raman spectra of 2-amino-5-nitrobenzophenone (ANBP) molecule have been recorded using Brucker IFS 66 V spectrometer in the range of 4000-100 cm( 1). The molecular geometry and vibrational frequencies in the ground state are calculated using the Hartree-Fock (HF) and B3LYP with 6-311+G(d) basis set. The computed values of frequencies are scaled using a suitable scale factor to yield good coherence with the observed values. The isotropic HF and DFT analysis showed good agreement with experimental observations comparison of the fundamental vibrational frequencies with calculated results by HF and B3LYP methods indicates that B3LYP/6-311+G(d) is superior to HF/6-311+G(d) for molecular vibrational problems. The electric dipole moment (MU) and first hyper polarizability (beta) values of the investigated molecule were computed using density functional theory calculations. Stability of the molecule arising from hyperconjucative interactions leading to its bioactivity, charge delocalization have been analyzed using natural bond orbital (NBO) analysis. The calculated HOMO-LUMO energies shows that charge transfer occur within the molecule. The thermodynamic functions (heat capacity, internal heat energy, Gibbs energy and entropy) from spectroscopic data by statistical methods were obtained for the range of temperature 100-1000 K. The observed and calculated frequencies are found to be in good agreement. PMID- 24152868 TI - Synthesis, structural and luminescence studies of magnesium oxide nanopowder. AB - Nanoparticles of magnesium oxide (MgO) have been prepared by low temperature solution combustion and hydrothermal method respectively. Powder X-ray diffraction (PXRD) patterns of MgO samples prepared by both the methods show cubic phase. The Scanning Electron Microscopy (SEM) studies reveal, the combustion derived product show highly porous, foamy and fluffy in nature than hydrothermally derived sample. The optical absorption studies of MgO show surface defects in the range 250-300 nm. The absorption peak at ~290 nm might be due to F centre. Photoluminescence (PL) studies were carried upon exciting at 290 nm. The sample prepared via combustion method show broad emission peak centred at ~395 nm in the bluish-violet (3.14 eV) region. However, in hydrothermal prepared sample show the emission peaks at 395 and 475 nm. These emission peaks were due to surface defects present in the sample since nanoparticles exhibits large surface to volume ratio and quantum confinement effect. PMID- 24152869 TI - Study of self-defocusing, reverse saturable absorption and photoluminescence in anthraquinone PMMA nanocomposite film. AB - The nanocomposite film of 1,5-diamino-9,10-anthraquinone in poly methyl methacrylate has been fabricated by following guest-host method. Intense reverse saturable absorption and self-defocusing effect have been investigated by employing Z-scan technique with low power CW laser at 532 nm with different intensities for the dye-polymer composite film. The estimated values of nonlinear absorption coefficient beta, nonlinear refractive index n2 and third order susceptibility chi((3)) of the composite film are of the order of 10(-3) (m/W), 10(-11) (m(2)/W) and 10(-4) (esu), respectively. The dye molecules have been encapsulated uniformly between molecules of polymer as a nanocomposite with average roughness ~7.96 nm as characterized by AFM technique. The nanocomposite film also exhibited strong photoluminescence emission when excited with 532 nm. The second order hyperpolarizability of composite film has also been estimated. The evaluated figure of merit W having a value greater than 1, and the results obtained suggest that the composite film of 1,5-diamino-9,10-anthraquinone-PMMA has potential applications in nonlinear optical devices. PMID- 24152870 TI - Adsorption of lead over graphite oxide. AB - The adsorption efficiency and kinetics of removal of lead in presence of graphite oxide (GO) was determined using the Atomic Absorption Spectrophotometer (AAS). The GO was prepared by the chemical oxidation of graphite and characterized using FTIR, SEM, TGA and XRD. The adsorption efficiency of GO for the solution containing 50, 100 and 150 ppm of Pb(2+) was found to be 98%, 91% and 71% respectively. The adsorption ability of GO was found to be higher than graphite. Therefore, the oxidation of activated carbon in removal of heavy metals may be a viable option to reduce pollution in portable water. PMID- 24152871 TI - Influence of molecular structure on the photoluminescence of 2-methyl benzimidazolium picrate: a new fluorescent material. AB - This work reports the structural and photo luminescent characterization of the 2 methyl benzimidazolium picrate salt for the first time. This new material exhibits the pi-pi stacking of aromatic rings involving the benzimidazolium cation and picrate anion, which is additionally supported with a rare n->pi interaction as well as with the extended networks of intermolecular hydrogen bonds in the solid state. The FT-IR and UV characterizations further support the solid state structural features of the salt. However, the spectroscopic results reveal that the stacking of ion pairs, which is observed in the solid state, is not maintained in solution. The DSC result indicates that the material is stable under ambient temperature conditions. Interestingly, upon photo excitation at 325 nm in the solid state, the material shows an unusual red emission around 615 nm, which is probably attributed to the supramolecular stacked nature of the ion pairs, along with a usual picrate centered green emission at 530 nm. However, the fluorescence measurement in solution, wherein the stacking of ion pairs are not maintained, shows only a single peak at lower wavelength. These observations highlight the influencing role of the supramolecular stacking interactions on the photoluminescence of the material, due to which, a chemical sensing action may be envisaged. PMID- 24152872 TI - Dynamic forces on agglomerated particles caused by high-intensity ultrasound. AB - In this paper the acoustic forces on particles and agglomerates caused by high intensity ultrasound in gaseous atmosphere are derived by means of computational fluid dynamics (CFD). Sound induced forces cause an oscillating stress scenario where the primary particles of an agglomerate are alternatingly pressed together and torn apart with the frequency of the applied wave. A comparison of the calculated acoustic forces with respect to the inter particle adhesion forces from Van-der-Waals and liquid bridge interactions reveals that the separation forces may reach the same order of magnitude for 80 MUm sized SiO2-particles. Hence, with finite probability acoustically agitated gases may de agglomerate/disperse solid agglomerate structures. This effect is confirmed by dispersion experiments in an acoustic particle levitation setup. PMID- 24152873 TI - Dysthymic disorder in the elderly population. AB - The diagnosis of dysthymic disorder was created in DSM-III and maintained in DSM IV to describe a depressive syndrome of mild to moderate severity of at least two years' duration that did not meet criteria for major depressive disorder. The prevalence of dysthymic disorder is approximately 2% in the elderly population where subsyndromal depressions of lesser severity are more common. Dysthymic disorder was replaced in DSM-V by the diagnosis of "persistent depressive disorder" that includes chronic major depression and dysthymic disorder. In older adults, epidemiological and clinical evidence supports the use of the term "dysthymic disorder." In contrast to young adults with dysthymic disorder, older adults with dysthymic disorder commonly present with late age of onset, without major depression and other psychiatric disorders, and with a low rate of family history of mood disorders. They often have stressors such as loss of social support and bereavement, and some have cerebrovascular or neurodegenerative pathology. A minority has chronic depression dating from youth with psychiatric comorbidity similar to young adults with dysthymic disorder. In older adults, both dysthymic disorder and subsyndromal depression increase disability and lead to poor medical outcomes. Elderly patients with dysthymic disorder are seen mainly in primary care where identification and treatment are often inadequate. Treatment with antidepressant medication shows marginal superiority over placebo in controlled trials, and problem-solving therapy shows similar efficacy. Combined treatment and collaborative care models show slightly better results, but cost effectiveness is a concern. Further work is needed to clarify optimal approaches to the treatment of dysthymic disorder in elderly patients. PMID- 24152874 TI - Chemically linked phage idiotype vaccination in the murine B cell lymphoma 1 model. AB - BACKGROUND: B cell malignancies are characterized by clonal expansion of B cells expressing tumor-specific idiotypes on their surface. These idiotypes are ideal target antigens for an individualized immunotherapy. However, previous idiotype vaccines mostly lacked efficiency due to a low immunogenicity of the idiotype. The objective of the present study was the determination of the feasibility, safety and immunogenicity of a novel chemically linked phage idiotype vaccine. METHODS: In the murine B cell lymphoma 1 model, tumor idiotypes were chemically linked to phage particles used as immunological carriers. For comparison, the idiotype was genetically expressed on the major phage coat protein g8 or linked to keyhole limpet hemocynanin. After intradermal immunizations with idiotype vaccines, tolerability and humoral immune responses were assessed. RESULTS: Feasibility and tolerability of the chemically linked phage idiotype vaccine was demonstrated. Vaccination with B cell lymphoma 1 idiotype expressing phage resulted in a significant survival benefit in the murine B cell lymphoma 1 protection model (60.2+/-23.8 days vs. 41.8+/-1.6 days and 39.8+/-3.8 days after vaccination with wild type phage or phosphate buffered saline, respectively). Superior immunogenicity of the chemically linked phage idiotype vaccine compared to the genetically engineered phage idiotype and keyhole limpet hemocynanin coupled idiotype vaccine was demonstrated by significantly higher B cell lymphoma 1 idiotype-specific IgG levels after vaccination with chemically linked phage idiotype. CONCLUSION: We present a novel, simple, time- and cost-efficient phage idiotype vaccination strategy, which represents a safe and feasible therapy and may produce a superior immune response compared to previously employed idiotype vaccination strategies. PMID- 24152875 TI - Chimeras of sperm PLCzeta reveal disparate protein domain functions in the generation of intracellular Ca2+ oscillations in mammalian eggs at fertilization. AB - Phospholipase C-zeta (PLCzeta) is a sperm-specific protein believed to cause Ca(2+) oscillations and egg activation during mammalian fertilization. PLCzeta is very similar to the somatic PLCdelta1 isoform but is far more potent in mobilizing Ca(2+) in eggs. To investigate how discrete protein domains contribute to Ca(2+) release, we assessed the function of a series of PLCzeta/PLCdelta1 chimeras. We examined their ability to cause Ca(2+) oscillations in mouse eggs, enzymatic properties using in vitro phosphatidylinositol 4,5-bisphosphate (PIP2) hydrolysis and their binding to PIP2 and PI(3)P with a liposome interaction assay. Most chimeras hydrolyzed PIP2 with no major differences in Ca(2+) sensitivity and enzyme kinetics. Insertion of a PH domain or replacement of the PLCzeta EF hands domain had no deleterious effect on Ca(2+) oscillations. In contrast, replacement of either XY-linker or C2 domain of PLCzeta completely abolished Ca(2+) releasing activity. Notably, chimeras containing the PLCzeta XY linker bound to PIP2-containing liposomes, while chimeras containing the PLCzeta C2 domain exhibited PI(3)P binding. Our data suggest that the EF hands are not solely responsible for the nanomolar Ca(2+) sensitivity of PLCzeta and that membrane PIP2 binding involves the C2 domain and XY-linker of PLCzeta. To investigate the relationship between PLC enzymatic properties and Ca(2+) oscillations in eggs, we have developed a mathematical model that incorporates Ca(2+)-dependent InsP3 generation by the PLC chimeras and their levels of intracellular expression. These numerical simulations can for the first time predict the empirical variability in onset and frequency of Ca(2+) oscillatory activity associated with specific PLC variants. PMID- 24152876 TI - Collagen and glycosaminoglycan profiles in the canine cervix during different stages of the estrous cycle and in open- and closed-cervix pyometra. AB - The extracellular matrix of the cervix that comprises collagen, elastin, proteoglycans and glycosaminoglycans (GAGs) is thought to have an essential role in cervical relaxation. This study investigated the proportion of collagen and smooth muscle as well as the GAGs in cervices obtained from healthy bitches at different stages of the estrous cycle and bitches with open- and closed-cervix pyometra. Cervices were collected after ovariohysterectomy. The proportion of collagen to smooth muscle was determined using Masson's trichrome staining. Alcian blue staining was used to evaluate the relative distribution of cervical GAGs. The proportion of cervical collagen relative to smooth muscle was higher at estrus compared to anestrus (P<=0.05). It was also higher (P<=0.05) in bitches with open- compared to those with closed-cervix pyometra. Overall, hyaluronan (HA) was the predominant GAG in the canine cervix. In the luminal epithelium, the staining intensity for HA was stronger in estrus than in anestrus (P<=0.05), but not in diestrus (P>0.05). On the contrary, the intensity for the combined keratan sulfate (KS) and heparan sulfate (HS) was stronger in anestrus than in estrus and diestrus (P<=0.05). In bitches with pyometra, the staining intensity of the stroma for KS and HS was weaker in open- compared to closed-cervix pyometra (P<=0.05). Collectively, the different profiles of collagen and GAG suggest that the metabolism of both collagen and GAGs in the canine cervix is associated with hormonal statuses during the estrous cycle and cervical patency of bitches with pathological uterine conditions, such as pyometra. PMID- 24152877 TI - Quorum sensing activity of Enterobacter asburiae isolated from lettuce leaves. AB - Bacterial communication or quorum sensing (QS) is achieved via sensing of QS signaling molecules consisting of oligopeptides in Gram-positive bacteria and N acyl homoserine lactones (AHL) in most Gram-negative bacteria. In this study, Enterobacteriaceae isolates from Batavia lettuce were screened for AHL production. Enterobacter asburiae, identified by matrix-assisted laser desorption ionization time of flight mass spectrometry (MALDI-TOF-MS) was found to produce short chain AHLs. High resolution triple quadrupole liquid chromatography mass spectrometry (LC/MS) analysis of the E. asburiae spent supernatant confirmed the production of N-butanoyl homoserine lactone (C4-HSL) and N-hexanoyl homoserine lactone (C6-HSL). To the best of our knowledge, this is the first report of AHL production by E. asburiae. PMID- 24152878 TI - A highly sensitive fiber optic sensor based on two-core fiber for refractive index measurement. AB - A simple and compact fiber optic sensor based on a two-core fiber is demonstrated for high-performance measurements of refractive indices (RI) of liquids. In order to demonstrate the suitability of the proposed sensor to perform high-sensitivity sensing in a variety of applications, the sensor has been used to measure the RI of binary liquid mixtures. Such measurements can accurately determine the salinity of salt water solutions, and detect the water content of adulterated alcoholic beverages. The largest sensitivity of the RI sensor that has been experimentally demonstrated is 3,119 nm per Refractive Index Units (RIU) for the RI range from 1.3160 to 1.3943. On the other hand, our results suggest that the sensitivity can be enhanced up to 3485.67 nm/RIU approximately for the same RI range. PMID- 24152879 TI - Towards a chemiresistive sensor-integrated electronic nose: a review. AB - Electronic noses have potential applications in daily life, but are restricted by their bulky size and high price. This review focuses on the use of chemiresistive gas sensors, metal-oxide semiconductor gas sensors and conductive polymer gas sensors in an electronic nose for system integration to reduce size and cost. The review covers the system design considerations and the complementary metal-oxide semiconductor integrated technology for a chemiresistive gas sensor electronic nose, including the integrated sensor array, its readout interface, and pattern recognition hardware. In addition, the state-of-the-art technology integrated in the electronic nose is also presented, such as the sensing front-end chip, electronic nose signal processing chip, and the electronic nose system-on-chip. PMID- 24152880 TI - A randomised, multicentre clinical trial of specialised palliative care plus standard treatment versus standard treatment alone for cancer patients with palliative care needs: the Danish palliative care trial (DanPaCT) protocol. AB - BACKGROUND: Advanced cancer patients experience considerable symptoms, problems, and needs. Early referral of these patients to specialised palliative care (SPC) could improve their symptoms and problems.The Danish Palliative Care Trial (DanPaCT) investigates whether patients with metastatic cancer, who report palliative needs in a screening, will benefit from being referred to 'early SPC'. METHODS/DESIGN: DanPaCT is a clinical, multicentre, parallel-group superiority trial with balanced randomisation (1:1). The planned sample size is 300 patients. Patients are randomised to specialised palliative care (SPC) plus standard treatment versus standard treatment. Consecutive patients from oncology departments are screened for palliative needs with a questionnaire if they: a) have metastatic cancer; b) are 18 years or above; and c) have no prior contact with SPC. Patients with palliative needs (i.e. symptoms/problems exceeding a certain threshold) according to the questionnaire are eligible. The primary outcome is the change in the patients' primary need (the most severe symptom/problem measured with the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30)). Secondary outcomes are other symptoms/problems (EORTC QLQ-C30), satisfaction with health care (FAMCARE P-16), anxiety and depression (the Hospital Anxiety and Depression scale), survival, and health care costs. DISCUSSION: Only few trials have investigated the effects of SPC. To our knowledge DanPaCT is the first trial to investigate screening based 'early SPC' for patients with a broad spectrum of cancer diagnosis. TRIAL REGISTRATION: Current controlled Trials NCT01348048. PMID- 24152882 TI - Myopia research: far from shortsighted. PMID- 24152881 TI - Increased expression of alpha-methylacyl-coenzyme A racemase (AMACR; p504s) and p16 in distal hyperplastic polyps. AB - BACKGROUND: Hyperplastic polyps (HP) and sessile serrated adenomas (SSA) share morphological similarities. In this immunohistochemical study we chose a panel of potential relevant and promising biomarkers including alpha-methylacyl-coenzyme A racemase (AMACR; p504s), which is involved in the degradation of branched chained fatty acids derivates, and analysed a cohort of HPs and SSAs in order to identify different immunophenotypes in relation to lesion localisation. METHODS: 154 specimen were carefully selected and a micro tissue array (TMA) was constructed. Immunohistochemistry of p16Ink4a, Ki67, alpha-methylacyl-coenzyme A racemase (AMACR; p504s), BRAF, CK 20, MLH1 and beta-catenin was performed and and immunoexpression was compared among proximal and distal HPs as well as SSAs. RESULTS: None of the markers revealed a differential expression among HPs and SSAs. However, the study demonstrates a significant overexpression of AMACR (p = 0.004) and p16Ink4a (p = 0.028) in distal HPs compared to proximal HPs. In addition AMACR overexpression was associated with increased p16Ink4a immunoexpression (p < 0.001). CONCLUSIONS: In this study we describe differential AMACR and p16Ink4a in HPs in relation to their localisation. Distal HPs were characterized by AMACR and p16Ink4a overexpression in contrast to proximal HPs, although morphological identically. Thus AMACR overexpression points towards a pathobiological relevance of the protein in distal HPs. In context of recently published data this suggest distal HPs as potential precursor lesions of certain adenoma subtypes. However, at this point of time this finding remains speculative and needs to be confirmed by further studies. VIRTUAL SLIDES: The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/1836116001066768. PMID- 24152883 TI - Myopia--yesterday, today, and tomorrow. PMID- 24152886 TI - Reconstruction and correction of four historical biometry data sets. AB - PURPOSE: To reconstruct and correct four historical biometry data sets. METHODS: The data sets measured by Stenstrom (1946), Sorsby (1957), Zeeman (1911), and Awerbach (1900) are of great historical interest but have issues that need to be dealt with before they may be of practical use in comparative studies. These issues range from only publishing statistical descriptors instead of the numerical data (Stenstrom) to assuming an equivalent refractive index of the crystalline lens that was constant with age (Sorsby) and calculation errors (Awerbach and Zeeman). These issues were corrected by only considering subjects with ages ranging between 20 and 35 years and refraction within +/-8D. This left 86 eyes for Sorsby, 73 for Zeeman, and 54 for Awerbach that could be used for further study. For the Stenstrom data set, the statistical descriptors of 983 eyes were used to generate data that are statistically indistinguishable from the original data through multivariate Gaussian modeling. RESULTS: After verification that all biometric parameters, except refraction, could be well approximated by a Gaussian distribution, a statistical eye model was defined for the Stenstrom data set. By means of the "two-one-sided t test" procedure, it was demonstrated that the data generated by the model are statistically indistinguishable from the original data at a confidence level of 99%. CONCLUSIONS: These results provide the best possible correction and reconstruction of the historical data sets. Provided one acknowledges the limitations of the data acquisition at the time, these data may be of use in studies on how ocular biometry has changed in the past century. PMID- 24152888 TI - Initial clinical experience with a quadrupole butterfly coil for spinal injection interventions in an open MRI system at 1.0 tesla. AB - PURPOSE: To report our initial clinical experience with a new magnetic resonance imaging (MRI) quadrupole coil that allows interventions in prone position. MATERIALS AND METHODS: Fifteen patients (seven women, eight men; average age, 42.8 years) were treated in the same 1.0-Tesla Panorama High Field Open (HFO) MRI system (Panorama HFO) using a quadrupole butterfly coil (Bfly) and compared with 15 patients matched for sex, age, and MR intervention using the MultiPurposeL coil (MPL), performed in conventional lateral decubitus position (all, Philips Medical Systems, Best, The Netherlands). All interventions were performed with a near-real-time proton density turbo spin echo (PD TSE) sequence (time to repeat/time to echo/flip angle/acquisition time, 600 ms/10 ms/90 degrees /3 s/image). Qualitative and quantitative image analyses were performed, including signal intensity, signal-to-noise and contrast-to-noise ratio (SNR, CNR), contrast, and full width at half maximum (FWHM) measurements. RESULTS: Contrast differed significantly between the needle and muscles (Bfly 0.27/MPL 0.17), as well as the needle and periradicular fat (0.13/0.24) during the intervention (both, p=0.029), as well as the CNR between muscles and the needle (10.61/5.23; p=0.010), although the FWHM values did not (2.4/2.2; p=0.754). The signal intensity of the needle in interventional imaging (1152.9/793.2; p=0.006) and the postinterventional SNR values of subcutaneous fat (15.3/28.6; p=0.007), muscles (6.6/11.8; p=0.011), and the CNR between these tissues (8.7/17.5; p=0.004) yielded significant differences. CONCLUSION: The new coil is a valid alternative for MR-guided interventions in an open MRI system at 1.0 tesla, especially if patients cannot (or prefer not to) be in a lateral decubitus position or if prone positioning yields better access to the target zone. PMID- 24152885 TI - Retinal image quality during accommodation in adult myopic eyes. AB - PURPOSE: Reduced retinal image contrast produced by accommodative lag is implicated with myopia development. Here, we measure accommodative error and retinal image quality from wavefront aberrations in myopes and emmetropes when they perform visually demanding and naturalistic tasks. METHODS: Wavefront aberrations were measured in 10 emmetropic and 11 myopic adults at three distances (100, 40, and 20 cm) while performing four tasks (monocular acuity, binocular acuity, reading, and movie watching). For the acuity tasks, measurements of wavefront error were obtained near the end point of the acuity experiment. Refractive state was defined as the target vergence that optimizes image quality using a visual contrast metric (VSMTF) computed from wavefront errors. RESULTS: Accommodation was most accurate (and image quality best) during binocular acuity whereas accommodation was least accurate (and image quality worst) while watching a movie. When viewing distance was reduced, accommodative lag increased and image quality (as quantified by VSMTF) declined for all tasks in both refractive groups. For any given viewing distance, computed image quality was consistently worse in myopes than in emmetropes, more so for the acuity than for reading/movie watching. Although myopes showed greater lags and worse image quality for the acuity experiments compared to emmetropes, acuity was not measurably worse in myopes compared to emmetropes. CONCLUSIONS: Retinal image quality present when performing a visually demanding task (e.g., during clinical examination) is likely to be greater than for less demanding tasks (e.g., reading/movie watching). Although reductions in image quality lead to reductions in acuity, the image quality metric VSMTF is not necessarily an absolute indicator of visual performance because myopes achieved slightly better acuity than emmetropes despite showing greater lags and worse image quality. Reduced visual contrast in myopes compared to emmetropes is consistent with theories of myopia progression that point to image contrast as an inhibitory signal for ocular growth. PMID- 24152889 TI - Ferrous bisglycinate 25 mg iron is as effective as ferrous sulfate 50 mg iron in the prophylaxis of iron deficiency and anemia during pregnancy in a randomized trial. AB - OBJECTIVE: To compare the effects of oral ferrous bisglycinate 25 mg iron/day vs. ferrous sulfate 50 mg iron/day in the prevention of iron deficiency (ID) and iron deficiency anemia (IDA) in pregnant women. DESIGN: Randomized, double-blind, intention-to-treat study. SETTING: Antenatal care clinic. SAMPLE: 80 healthy ethnic Danish pregnant women. METHODS: Women were allocated to ferrous bisglycinate 25 mg elemental iron (Aminojern(r)) (n=40) or ferrous sulfate 50 mg elemental iron (n=40) from 15 to 19 weeks of gestation to delivery. Hematological status (hemoglobin, red blood cell indices) and iron status (plasma iron, plasma transferrin, plasma transferrin saturation, plasma ferritin) were measured at 15 19 weeks (baseline), 27-28 weeks and 36-37 weeks of gestation. MAIN OUTCOME MEASURES: Occurrence of ID (ferritin <15 MUg/L) and IDA (ferritin <12 MUg/L and hemoglobin <110 g/L). RESULTS: At inclusion, there were no significant differences between the bisglycinate and sulfate group concerning hematological status and iron status. The frequencies of ID and IDA were low and not significantly different in the two iron groups. The frequency of gastrointestinal complaints was lower in the bisglycinate than in the sulfate group (P=0.001). Newborns weight was slightly higher in the bisglycinate vs. the sulfate group (3601+/-517 g vs. 3395+/-426 g, P=0.09). CONCLUSIONS: In the prevention of ID and IDA, ferrous bisglycinate was not inferior to ferrous sulfate. Ferrous bisglycinate in a low dose of 25 mg iron/day appears to be adequate to prevent IDA in more than 95% of Danish women during pregnancy and postpartum. PMID- 24152890 TI - Insulin resistance in young adults born small for gestational age (SGA). AB - OBJECTIVE: This work aimed to assess glucose metabolism and insulin sensitivity in young adults born small for gestational age (SGA) as well as to measure the body composition and adipocytokines of these subjects. METHODS: A total of 108 out of 342 SGA-born participants were invited for reexamination from the former Bavarian Longitudinal Study (BLS), in which 7505 risk-newborns of the years 1985 to 1986 were prospectively followed. Of these, 76 (34 female/42 male) participants at the age of 19.7+/-0.5 years were enrolled. Clinical examination and oral glucose tolerance testing (oGTT) was performed with assessment of insulin resistance indices, HbA1c, body mass index (BMI), adipocytokines, and body composition by bioimpedance analysis (BIA). RESULTS: A total of 25 out of 76 (32.9%) patients had abnormal fasting and/or glucose-stimulated insulin levels. Glucose values measured during oGTT showed no abnormalities, except one participant who had impaired glucose tolerance. Homeostasis model assessment insulin resistance index (HOMA-IR) was 1.92+/-4.2, and insulin sensitivity index by Matsuda (ISI(Matsuda)) showed mean values of 7.85+/-4.49. HOMA-IR>2.5 was found in 8 patients (10.5%), and 20 patients (26.3%) had an ISI(Matsuda)<5, both interpreted as insulin resistant. No alterations of adipocytokines were found. Fat mass (FM) measured by BIA was within the normal range for both genders and correlated significantly with BMI (r=0.465, p<0.001) and leptin (r=0.668, p>0.001), but not with adiponectin. Insulin resistance correlated with change in weight-for-height Z-score during the first 3 months of age, indicating that weight gain during that early phase might be a risk factor for the development of insulin resistance in children born SGA. CONCLUSIONS: A high percentage of insulin-resistant subjects were reconfirmed in a large German cohort of young adults born SGA. Therefore, regular screening for disturbances in glucose metabolism is recommended in these subjects. PMID- 24152891 TI - Reversal of alcohol induced testicular hyperlipidemia by supplementation of ascorbic acid and its comparison with abstention in male guinea pigs. AB - BACKGROUND: Chronic ethanol exposure causes hyperlipidemia. The present study was designed to investigate the impact of ascorbic acid supplementation on ethanol induced hyperlipidemia in testis and to compare it with that of abstinence from taking alcohol. METHODS: Thirty-six male guinea pigs were divided into two groups and were maintained for 90 days as follows (1) control (C) (2) ethanol treated group (E) (4 g/kg body wt/day). Ethanol was administered for 90 days and on 90th day, alanine amino transaminase (ALT), aspartate amino transaminase (AST) and gamma-glutamyltransferase (GGT) in serum was assayed. The animals in the ethanol group were further divided into an ascorbic acid supplemented group (25 mg/100 g body wt/day) (E+AA) and an ethanol abstention group (EAG) and those in the control group were divided into a control group and a control+ascorbic acid group (C+AA). RESULTS: There was significant increase in levels of testicular cholesterol, free fatty acid, phospholipids and triglycerides in the ethanol group. There was also a significant increase in the activity of HMG CoA reductase and decrease in activity of testicular glucose-6-phosphate dehydrogenase (G6PDH) and malic enzyme in ethanol-ingested animals that further led to decreased levels of serum testosterone. Alcohol administration also enhanced the activity of testicular alcohol dehydrogenase (ADH). Ascorbic acid supplementation and abstention altered all these parameters induced by chronic alcohol administration. Histological studies were also in line with the above results. CONCLUSIONS: Ascorbic acid was able to reinstate the cholesterol homeostasis in testis which could have further restored the testicular steroidogenesis. The present study demonstrated that ascorbic acid is effective in reducing the hyperlipidemia induced by chronic alcohol administration and produced a better recovery than abstention. PMID- 24152892 TI - Drug interactions with statins. AB - The 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) are generally well tolerated as monotherapy. Statins are associated with two important adverse effects, asymptomatic elevation in liver enzymes and myopathy. Myopathy is most likely to occur when statins are administered with other drugs. Statins are substrates of multiple drug transporters (including OAT- -P1B1, BCRP and MDR1) and several cytochrome P450 (CYP) enzymes (including CYP3A4, CYP2C8, CYP2C19, and CYP2C9). Possible adverse effects of statins can occur due to interactions in concomitant use of drugs that substantially inhibit or induce their methabolic pathway. This review summarizes the most important interactions of statins. PMID- 24152893 TI - Nanofibers and their biomedical use. AB - The idea of creating replacement for damaged or diseased tissue, which will mimic the physiological conditions and simultaneously promote regeneration by patients' own cells, has been a major challenge in the biomedicine for more than a decade. Therefore, nanofibers are a promising solution to address these challenges. These are solid polymer fibers with nanosized diameter, which show improved properties compared to the materials of larger dimensions or forms and therefore cause different biological responses. On the nanometric level, nanofibers provide a biomimetic environment, on the micrometric scale three-dimensional architecture with the desired surface properties regarding the intended application within the body, while on the macrometric scale mechanical strength and physiological acceptability. In the review, the development of nanofibers as tissue scaffolds, modern wound dressings for chronic wound therapy and drug delivery systems is highlighted. Research substantiates the effectiveness of nanofibers for enhanced tissue regeneration, but ascertains that evidences from clinical studies are currently lacking. Nevertheless, due to the development of nano- and bio sciences, products on the market can be expected in the near future. PMID- 24152894 TI - Methods of amorphization and investigation of the amorphous state. AB - The amorphous form of pharmaceutical materials represents the most energetic solid state of a material. It provides advantages in terms of dissolution rate and bioavailability. This review presents the methods of solid- -state amorphization described in literature (supercooling of liquids, milling, lyophilization, spray drying, dehydration of crystalline hydrates), with the emphasis on milling. Furthermore, we describe how amorphous state of pharmaceuticals differ depending on the method of preparation and how these differences can be screened by a variety of spectroscopic (X-ray powder diffraction, solid state nuclear magnetic resonance, atomic pairwise distribution, infrared spectroscopy, terahertz spectroscopy) and calorimetry methods. PMID- 24152895 TI - Cyclodextrin based nanosponges for pharmaceutical use: a review. AB - Nanosponges are a novel class of hyper-crosslinked polymer based colloidal structures consisting of solid nanoparticles with colloidal sizes and nanosized cavities. These nano-sized colloidal carriers have been recently developed and proposed for drug delivery, since their use can solubilize poorly water-soluble drugs and provide prolonged release as well as improve a drug's bioavailability by modifying the pharmacokinetic parameters of actives. Development of nanosponges as drug delivery systems, with special reference to cyclodextrin based nanosponges, is presented in this article. In the current review, attempts have been made to illustrate the features of cyclodextrin based nanosponges and their applications in pharmaceutical formulations. Special emphasis has been placed on discussing the methods of preparation, characterization techniques and applications of these novel drug delivery carriers for therapeutic purposes. Nanosponges can be referred to as solid porous particles having a capacity to load drugs and other actives into their nanocavity; they can be formulated as oral, parenteral, topical or inhalation dosage forms. Nanosponges offer high drug loading compared to other nanocarriers and are thus suitable for solving issues related to stability, solubility and delayed release of actives. Controlled release of the loaded actives and solubility enhancement of poorly water-soluble drugs are major advantages of nanosponge drug delivery systems. PMID- 24152896 TI - Bioadhesive vaginal tablets containing spray dried microspheres loaded with clotrimazole for treatment of vaginal candidiasis. AB - The aim of the present investigation was to prepare and evaluate novel bioadhesive vaginal tablets containing clotrimazole loaded microspheres in order to provide long-term therapeutic activity at the site of infection. Tablets were prepared by incorporating drug loaded microspheres and using bioadhesive polymers hydroxypropylmethylcellulose, sodium carboxymethylcellulose and Carbopol. Microspheres were prepared by the spray drying technique using Eudragit RS-100 and Eudragit RL-100. Microspheres were characterized by SEM, DSC, FTIR, particle size analysis and evaluated for percentage yield, drug loading, encapsulation efficiency and in vitro drug release. To achieve bioadhesion to the mucosal tissue, optimized microspheres were incorporated into bioadhesive tablets and were evaluated for in vitro drug release, in vitro and in vivo mucoadhesion. FTIR and DSC studies showed that no chemical interaction occurred between the drug and polymers. The sphericity factor indicated that the prepared microspheres were spherical. Formulation Mt6 indicated a controlled in vitro drug release and good bioadhesive strength. The in vivo images confirmed the bioadhesion and retention property of tablets up to 24 h. The results indicated that this drug delivery system can be explored for controlled intravaginal drug release. PMID- 24152897 TI - Quantification of ascorbic acid and sodium ascorbate in powder blends for tableting and in vitamin C chewable tablets by NIR-chemometry. AB - The paper proposes a near infrared method able to directly and simultaneously quantify ascorbic acid and sodium ascorbate in powder blends for tableting and in vitamin C chewable tablets without any sample preparation. In the first step, calibration models for the quantification of ascorbic acid and sodium ascorbate in powder blends for tableting and subsequently in chewable vitamin C tablets (corresponding to 80-120 % active substance) were developed according to an experimental design with 2 variables and 5 levels. Then, using the best calibration models, the methods were fully validated in terms of recovery, precision and accuracy for both powder blends and vitamin C chewable tablets. The validated concentration range was 15.14-18.51 % for ascorbic acid and 12.06-14.49 % for sodium ascorbate in powder blends and 91.85-111.03 mg per tablet for ascorbic acid and 71.01-84.50 mg per tablet for sodium ascorbate in tablets. Validation results showed good precision and accuracy. PMID- 24152898 TI - Synthesis of the impurities during the manufacture of bulk drug midazolam and separation of these impurities by HPLC. AB - During the manufacture of bulk drug midazolam various impurities arised that can be the related products or degradation products. Structures of eight impurities that can arise during the manufacture of bulk drug midazolam were proposed. In the present work, synthesis of these impurities and their characterization by different spectroscopic techniques have been done. HPLC method was developed for the separation of impurities from the bulk drug. The developed method separates midazolam from its eight impurities/degradation products within a run time of 45 min. PMID- 24152899 TI - Synthesis, in vitro anticancer and antioxidant activity of thiadiazole substituted thiazolidin-4-ones. AB - A series of novel 5-alkyl/aryl thiadiazole substituted thiazolidin-4-ones were synthesized by a two-step process. In the first step, 5-alkyl/aryl substituted 2 aminothiadiazoles were synthesized, which on reaction with substituted aromatic aldehydes and thioglycolic acid in the presence of dicyclohexylcarbodiimide afforded thiazolidin- 4-ones. All the compounds were synthesized in fairly good yields and their structures were confirmed by spectral and physical data. The title compounds were screened for in vitro anti-proliferative activity on human breast adenocarcinoma cells (MCF-7) by MTT assay. Most of the derivatives showed an IC50 less than 150 MUmol L-1. Among the compounds tested, 2-(2-nitrophenyl)- 3 (5-methyl-1,3,4-thiadiazol-2-yl)-thiazolidin-4-one (3f), 2-(3-fluorophenyl)-3-(5 methyl-1,3,4-thiadiazol-2- -yl)-thiazolidin-4-one (3b), and 2-(4-chlorophenyl)-3- -(5-methyl-1,3,4-thiadiazol-2-yl)-thiazolidin-4-one (3c) were found to be the most active derivatives with IC50 values of 46.34, 66.84, and 60.71 MUmol L-1, respectively. Antioxidant studies of all the synthesized compounds were carried out by diphenylpicrylhydrazyl (DPPH) assay. Among the compounds tested, 2-phenyl 3-(5-styryl- -1,3,4-thiadiazol-2-yl)-thiazolidin-4-one (3s) elicited superior antioxidant activity with IC50 of 161.93 MUmol L-1. PMID- 24152900 TI - A convenient synthesis of new NSAID esters containing amino acid, urea and amide moieties. AB - Abstract A convenient synthetic method for the preparation of novel NSAID twin esters 6a-i containing amino acid residue, urea and amide moieties has been developed. The synthetic pathway applied for the preparation of target compounds and key intermediates 1-benzotriazolecarboxylic acid chloride (1), NSAID benzotriazolides 2a-c and N-(1-benzotriazolecarbonyl)-amino acids 3a-d involved benzotriazole as a synthetic auxiliary. The final preparation step of esters 6a-i included the solvent-free reaction of compounds 2a-c with amino acid derivatives 5a-g, bearing two hydroxyl groups, one at each terminal, beside urea and amide functionalities. PMID- 24152901 TI - Development and validation of RP HPLC method for determination of betamethasone dipropionate in gingival crevicular fluid. AB - Abstract A simple RP HPLC method for quantification of betamethasone dipropionate (BDP) in gingival crevicular fluid (GCF) has been developed and validated. GCF represents a valuable matrix for therapeutic monitoring of drugs used in the treatment of periodontal disease. The proposed method involves single step extraction for sample preparation. The calibration curve for BDP was linear over the concentration range of 0.10-2.00 MUg mL-1 (R2 = 0.9971). RSD values of intra- and inter-day precision ranged 2.2-4.5 and 1.6-5.7 %, while accuracy values were higher than 96.6 and 97.0 %, respectively. The described method can be successfully applied for determination of betamethasone concentrations in GCF obtained from patients with chronic periodontitis after local treatment with BDP cream 0.5 mg g-1. PMID- 24152902 TI - Crosstalk of lipid and protein homeostasis to maintain membrane function. AB - Biological membranes are a defining feature of cellular life. They serve as selective diffusion barriers, compartmentalize biochemical processes and protect the cellular milieu. We are only beginning to understand the principles underlying their homeostasis and the functional relevance of their complex compositions. Here, we summarize some recent evidences that suggest an intense crosstalk between the pathways of protein quality control and lipid homeostasis. We discuss paradigms of lipid regulation by protein degradation machineries and highlight the intricate connections between lipid droplet morphology, membrane biogenesis and ER-stress. PMID- 24152903 TI - Agreement of seven 25-hydroxy vitamin D3 immunoassays and three high performance liquid chromatography methods with liquid chromatography tandem mass spectrometry. AB - BACKGROUND: Several recent studies have shown some discrepancies between 25 hydroxyvitamin D [25(OH)D] assay methods, despite some improvement in the past few years. The accuracy of 25(OH)D assay methods is still a real challenge for clinical laboratories. The aim of this study was to assess the agreement between a large panel of routine assays and a two-dimensional liquid chromatography/tandem mass spectrometry (2D LC-MS/MS) method, selected as the reference method. METHODS: Forty-nine human plasma samples with only endogenous 25(OH)D3 were analyzed with 11 different methods, especially with three LC-UV methods that differed in the extraction step. Seven routine immunoassays were also tested: two manual (RIA and EIA from IDS) and five fully-automated methods. The results of the 25(OH)D3 assays were compared with those of the 2D LC-MS/MS method using weighted Deming regression analysis, Bland-Altman plots and concordance correlation coefficient (CCC). The ability of these methods to properly classify patients was evaluated by sorting results depending on vitamin D status. RESULTS: The CCC was >0.90 for the three LC-UV methods and for most of the automated IA, meaning substantial agreement with 2D LC-MS/MS results. The ability to properly classify patients according to their vitamin D status was overall satisfactory for most of the methods tested (concordance >90%). CONCLUSIONS: The immunoassays available on Liaison, Isys, Architect and Elecsys, together with our in-house LC-UV method preceded by an SLE step met the minimum requirements for the assessment of vitamin D status in clinical laboratories. PMID- 24152904 TI - D-dimer testing for suspected venous thromboembolism in the emergency department. Consensus document of AcEMC, CISMEL, SIBioC, and SIMeL. AB - D-dimer testing is currently considered a cornerstone in the diagnostic approach of patients with suspected venous thromboembolism (VTE) across different health care settings, including the emergency department (ED). Nevertheless, inappropriate or incorrect activities developing throughout the total testing process may substantially impair the clinical usefulness of this test and delay or even challenge the fast rule out or diagnosis of VTE. The leading problem of D dimer is represented by the poor specificity for diagnosing VTE, wherein a minority of patients with a positive D-dimer are finally diagnosed with VTE, and even more importantly, the specificity further decreases with ageing, thus contributing to increase the overcrowding in short stay units such as the ED. Due to the large heterogeneity that characterizes the use of D-dimer in the emergency room, three Italian societies of laboratory medicine (Italian Committee for Standardization of Hematology and Laboratory Methods, Italian Society of Clinical Biochemistry and Molecular Biology, and Italian Society of Laboratory Medicine), along with the Academy of Emergency Medicine and Care, have developed a consensus document about the use of D-dimer testing for diagnostics of patients with suspected VTE in this health-care setting. The evidence-based indications contained in this document will cover the leading preanalytical, analytical, and postanalytical issues that may impair the clinical efficacy of D-dimer testing in the ED. PMID- 24152906 TI - Looking through a cranial window: intravital microscopy for in vivo study of cerebral malaria. PMID- 24152907 TI - Long-term outcome and prospective validation of NIH response criteria in 39 patients receiving imatinib for steroid-refractory chronic GVHD. AB - Forty adults aged 28 to 73 years were entered into a prospective trial of imatinib for the treatment of steroid-refractory chronic graft-versus-host disease (SR-cGVHD). After 6 months, intention-to-treat (ITT) analysis of 39 patients who received the drug, regardless of the duration of treatment, revealed 14 partial responses (PR), 4 minor responses (MR) with relevant steroid sparing (46%) according to Couriel criteria, and 20 >= PR (51.3%), as per the National Institutes of Health (NIH) criteria and NIH severity score changes. The best responses were seen in the lungs, gut, and skin (35%, 50%, and 32%, respectively). After a median follow-up of 40 months, 28 patients were alive, with a 3-year overall survival (OS) and event-free survival of 72% and 46%, respectively. The 3-year OS was 94% for patients responding at 6 months and 58% for nonresponders according to NIH response, suggesting that these criteria represent a reliable tool for predicting OS after second-line treatment. Monitoring of anti-platelet-derived growth factor receptor (PDGF-R) antibodies showed a significant decrease in PDGF-R stimulatory activity in 7 responders, whereas it remained high in 4 nonresponders. This study confirms the efficacy of imatinib against SR-cGVHD and suggests that the response at 6 months significantly predicts long-term survival. PMID- 24152908 TI - Biogenesis of the demarcation membrane system (DMS) in megakaryocytes. AB - The demarcation membrane system (DMS) in megakaryocytes forms the plasma membrane (PM) of future platelets. Using confocal microscopy, electron tomography, and large volume focused ion beam/scanning electron microscopy (FIB/SEM), we determined the sequential steps of DMS formation. We identified a pre-DMS that initiated at the cell periphery and was precisely located between the nuclear lobes. At all developmental stages, the DMS remained continuous with the cell surface. The number of these connections correlated well with the nuclear lobulation, suggesting a relationship with cleavage furrow formation and abortive cytokinesis. On DMS expansion, Golgi complexes assembled around the pre-DMS, and fusion profiles between trans-golgi network-derived vesicles and the DMS were observed. Brefeldin-A reduced DMS expansion, indicating that the exocytic pathway is essential for DMS biogenesis. Close contacts between the endoplasmic reticulum (ER) and the DMS were detected, suggesting physical interaction between the 2 membrane systems. FIB/SEM revealed that the DMS forms an intertwined tubular membrane network resembling the platelet open canalicular system. We thus propose the following steps in DMS biogenesis: (1) focal membrane assembly at the cell periphery; (2) PM invagination and formation of a perinuclear pre-DMS; (3) expansion through membrane delivery from Golgi complexes; and (4) ER-mediated lipid transfer. PMID- 24152909 TI - Protein tyrosine phosphatase controls breast cancer invasion through the expression of matrix metalloproteinase-9. AB - The expression of matrix metalloproteinases (MMPs) produced by cancer cells has been associated with the high potential of metastasis in several human carcinomas, including breast cancer. Several pieces of evidence demonstrate that protein tyrosine phosphatases (PTP) have functions that promote cell migration and metastasis in breast cancer. We analyzed whether PTP inhibitor might control breast cancer invasion through MMP expression. Herein, we investigate the effect of 4-hydroxy-3,3-dimethyl-2H benzo[g]indole-2,5(3H)-dione (BVT948), a novel PTP inhibitor, on 12-O-tetradecanoyl phorbol-13-acetate (TPA)-induced MMP-9 expression and cell invasion in MCF-7 cells. The expression of MMP-9 and cell invasion increased after TPA treatment, whereas TPA-induced MMP-9 expression and cell invasion were decreased by BVT948 pretreatment. Also, BVT948 suppressed NF kappaB activation in TPA-treated MCF-7 cells. However, BVT948 didn't block TPA induced AP-1 activation in MCF-7 cells. Our results suggest that the PTP inhibitor blocks breast cancer invasion via suppression of the expression of MMP 9. PMID- 24152911 TI - miR-15b induced by platelet-derived growth factor signaling is required for vascular smooth muscle cell proliferation. AB - The platelet-derived growth factor (PDGF) signaling pathway is essential for inducing a dedifferentiated state of vascular smooth muscle cells (VSMCs). Activation of PDGF inhibits smooth muscle cell (SMC)-specific gene expression and increases the rate of proliferation and migration, leading to dedifferentiation of VSMCs. Recently, microRNAs have been shown to play a critical role in the modulation of the VSMC phenotype in response to extracellular signals. However, little is known about microRNAs regulated by PDGF in VSMCs. Herein, we identify microRNA-15b (miR-15b) as a mediator of VSMC phenotype regulation upon PDGF signaling. We demonstrate that miR-15b is induced by PDGF in pulmonary artery smooth muscle cells and is critical for PDGF-mediated repression of SMC-specific genes. In addition, we show that miR-15b promotes cell proliferation. These results indicate that PDGF signaling regulates SMC-specific gene expression and cell proliferation by modulating the expression of miR-15b to induce a dedifferentiated state in the VSMCs. PMID- 24152910 TI - Thrombin inhibits HMGB1-mediated proinflammatory signaling responses when endothelial protein C receptor is occupied by its natural ligand. AB - High mobility group box 1 (HMGB1) is involved in the pathogenesis of vascular diseases. Unlike activated protein C (APC), the activation of PAR-1 by thrombin is known to elicit proinflammatory responses. To determine whether the occupancy of EPCR by the Gla-domain of APC is responsible for the PAR-1-dependent antiinflammatory activity of the protease, we pretreated HUVECs with the PC zymogen and then activated PAR-1 with thrombin. It was found that thrombin down regulates the HMGB1-mediated induction of both TNF-alpha and IL-6 and inhibits the activation of both p38 MAPK and NF-kappaB in HUVECs pretreated with PC. Furthermore, thrombin inhibited HMGB1-mediated hyperpermeability and leukocyte adhesion/migration by inhibiting the expression of cell adhesion molecules in HUVECs if EPCR was occupied. Collectively, these results suggest the concept that thrombin can initiate proinflammatory responses in vascular endothelial cells through the activation of PAR-1 may not hold true for normal vessels expressing EPCR under in vivo conditions. PMID- 24152912 TI - Protein tyrosine phosphatase profiling studies during brown adipogenic differentiation of mouse primary brown preadipocytes. AB - There is a correlation between obesity and the amount of brown adipose tissue; however, the molecular mechanism of brown adipogenic differentiation has not been as extensively studied. In this study, we performed a protein tyrosine phosphatase (PTP) profiling analysis during the brown adipogenic differentiation of mouse primary brown preadipocytes. Several PTPs, including PTPRF, PTPRZ, and DUSP12 showing differential expression patterns were identified. In the case of DUSP12, the expression level is dramatically downregulated during brown adipogenesis. The ectopic expression of DUSP12 using a retroviral expression system induces the suppression of adipogenic differentiation, whereas a catalytic inactive DUSP12 mutant showed no effect on differentiation. These results suggest that DUSP12 is involved in brown adipogenic differentiation and may be used as a target protein for the treatment or prevention of obesity by the regulation of brown adipogenic differentiation. PMID- 24152913 TI - Fenobam promoted the neuroprotective effect of PEP-1-FK506BP following oxidative stress by increasing its transduction efficiency. AB - We examined the ways in which fenobam could promote not only the transduction of PEP-1-FK506BP into cells and tissues but also the neuroprotective effect of PEP-1 FK506BP against ischemic damage. Fenobam strongly enhanced the protective effect of PEP-1-FK506BP against H2O2-induced toxicity and DNA fragmentation in C6 cells. In addition, combinational treatment of fenobam with PEP-1-FK506BP significantly inhibited the activation of Akt and MAPK induced by H2O2, compared to treatment with PEP-1-FK506BP alone. Interestingly, our results showed that fenobam significantly increased the transduction of PEP-1-FK506BP into both C6 cells and the hippocampus of gerbil brains. Subsequently, a transient ischemic gerbil model study demonstrated that fenobam pretreatment led to the increased neuroprotection of PEP-1-FK506BP in the CA1 region of the hippocampus. Therefore, these results suggest that fenobam can be a useful agent to enhance the transduction of therapeutic PEP-1-fusion proteins into cells and tissues, thereby promoting their neuroprotective effects. PMID- 24152914 TI - Modification and inactivation of Cu,Zn-superoxide dismutase by the lipid peroxidation product, acrolein. AB - Acrolein is the most reactive aldehydic product of lipid peroxidation and is found to be elevated in the brain when oxidative stress is high. The effects of acrolein on the structure and function of human Cu,Zn-superoxide dismutase (SOD) were examined. When Cu,Zn-SOD was incubated with acrolein, the covalent crosslinking of the protein was increased, and the loss of enzymatic activity was increased in a dose-dependent manner. Reactive oxygen species (ROS) scavengers and copper chelators inhibited the acrolein-mediated Cu,Zn-SOD modification and the formation of carbonyl compound. The present study shows that ROS may play a critical role in acrolein-induced Cu,Zn-SOD modification and inactivation. When Cu,Zn-SOD that has been exposed to acrolein was subsequently analyzed by amino acid analysis, serine, histidine, arginine, threonine and lysine residues were particularly sensitive. It is suggested that the modification and inactivation of Cu,Zn-SOD by acrolein could be produced by more oxidative cell environments. PMID- 24152916 TI - Management of cervicofacial nontuberculous lymphadenitis in children. AB - PURPOSE OF REVIEW: To review the body of literature on the treatment options for nontuberculous cervicofacial lymphadenitis in children, focusing on the most recent reports describing outcomes utilizing either observation alone, medical therapy or various forms of surgical intervention. RECENT FINDINGS: Large studies have defined the time course of the disease and the safety and efficacy in treating nontuberculosis cervicofacial lymphadenitis with a wait-and-see approach. SUMMARY: Nontuberculosis cervicofacial lymphadenitis is a disease with several stages that provides for various treatment options. All treatment regimens--wait-and-see approach, medical therapy, and surgical excision--have their risks and benefits. The current body of literature allows the otolaryngologist an assortment of treatment choices that permits him to tailor the treatment with an individualized approach for each family's preferences. PMID- 24152915 TI - Role of gangliosides in the differentiation of human mesenchymal-derived stem cells into osteoblasts and neuronal cells. AB - Gangliosides are complex glycosphingolipids that are the major component of cytoplasmic cell membranes, and play a role in the control of biological processes. Human mesenchymal stem cells (hMSCs) have received considerable attention as alternative sources of adult stem cells because of their potential to differentiate into multiple cell lineages. In this study, we focus on various functional roles of gangliosides in the differentiation of hMSCs into osteoblasts or neuronal cells. A relationship between gangliosides and epidermal growth factor receptor (EGFR) activation during osteoblastic differentiation of hMSCs was observed, and the gangliosides may play a major role in the regulation of the differentiation. The roles of gangliosides in osteoblast differentiation are dependent on the origin of hMSCs. The reduction of ganglioside biosynthesis inhibited the neuronal differentiation of hMSCs during an early stage of the differentiation process, and the ganglioside expression can be used as a marker for the identification of neuronal differentiation from hMSCs. PMID- 24152917 TI - Community-based urgent care in Israel and worldwide. AB - BACKGROUND: Intermittent treatment of acute lower acuity situations has come to be defined as urgent rather than emergent care. The location of urgent care delivery has been shifting from exclusively hospital or office settings to other community locales. AIMS: To review the concept of urgent care and the new models of health care delivery in the niche between hospitals and primary care. To highlight the roles of urgent care in Israel and compare these roles with those in other countries. METHOD: Narrative review of the literature. MAIN FINDINGS: The new models of community based urgent care include 1) the urgent care center; 2) the retail or convenience clinic, 3) the free standing emergency center, and 4) the walk-in clinic. These models fall on a continuum of comprehensiveness. They offer care at a lower cost than hospital-based emergency departments and greater temporal convenience than primary care physicians. However, their impact on emergency department utilization and overcrowding or primary care physician overload is unclear.Israel has integrated its urgent care centers into its national health system by encouraging the use of urgent care centers and by requiring all health insurance funds to reimburse patients who use these centers. This integration is similar to the approach in England; however, the type of service is different in that the service in England is provided by nurses. It is different from most other countries where urgent care facilities are primarily private ventures. CONCLUSIONS: Community-based acute care facilities are becoming a part of the medical landscape in a number of countries. Still, they remain primarily on the fringe of organized medicine. Despite the important role of community-based acute care facilities in Israel, no nationwide study has been done in two decades. Health policy planning in Israel necessitates further study of urgent care use and its clinical outcomes. PMID- 24152918 TI - The climate change-infectious disease nexus: is it time for climate change syndemics? AB - Conceptualizing climate as a distinct variable limits our understanding of the synergies and interactions between climate change and the range of abiotic and biotic factors, which influence animal health. Frameworks such as eco epidemiology and the epi-systems approach, while more holistic, view climate and climate change as one of many discreet drivers of disease. Here, I argue for a new paradigmatic framework: climate-change syndemics. Climate-change syndemics begins from the assumption that climate change is one of many potential influences on infectious disease processes, but crucially is unlikely to act independently or in isolation; and as such, it is the inter-relationship between factors that take primacy in explorations of infectious disease and climate change. Equally importantly, as climate change will impact a wide range of diseases, the frame of analysis is at the collective rather than individual level (for both human and animal infectious disease) across populations. PMID- 24152919 TI - Sphenoderiidae (fam. nov.), a new clade of euglyphid testate amoebae characterized by small, round scales surrounding the aperture. AB - Euglyphid testate amoebae are a highly conspicuous group of Cercozoa whose systematics is based mainly on the shape and ultrastructure of the shell. However, only a couple of species have been studied with molecular methods. As a consequence, there are still some genera whose classification remains uncertain. Amongst those are Sphenoderia and Trachelocorythion, two genera with diverging ecological requirements that share a collar composed of small scales around the aperture. We demonstrate here with a molecular and morphological approach that they are closely related, and propose a new family, Sphenoderiidae fam. nov. to group these species. Some species share almost similar morphology in spite of being genetically distantly related (Sphenoderia minuta and S. pseudominuta sp. nov.), underlining the importance of combining ultrastructural and morphological data when describing new species of protists. In addition, we describe here Sphenoderia valdiviana sp. nov., a new species isolated from Southern Chile temperate rainforests. PMID- 24152920 TI - Adaptive multi-node multiple input and multiple output (MIMO) transmission for mobile wireless multimedia sensor networks. AB - Mobile wireless multimedia sensor networks (WMSNs), which consist of mobile sink or sensor nodes and use rich sensing information, require much faster and more reliable wireless links than static wireless sensor networks (WSNs). This paper proposes an adaptive multi-node (MN) multiple input and multiple output (MIMO) transmission to improve the transmission reliability and capacity of mobile sink nodes when they experience spatial correlation. Unlike conventional single-node (SN) MIMO transmission, the proposed scheme considers the use of transmission antennas from more than two sensor nodes. To find an optimal antenna set and a MIMO transmission scheme, a MN MIMO channel model is introduced first, followed by derivation of closed-form ergodic capacity expressions with different MIMO transmission schemes, such as space-time transmit diversity coding and spatial multiplexing. The capacity varies according to the antenna correlation and the path gain from multiple sensor nodes. Based on these statistical results, we propose an adaptive MIMO mode and antenna set switching algorithm that maximizes the ergodic capacity of mobile sink nodes. The ergodic capacity of the proposed scheme is compared with conventional SN MIMO schemes, where the gain increases as the antenna correlation and path gain ratio increase. PMID- 24152921 TI - GeoCENS: a geospatial cyberinfrastructure for the world-wide sensor web. AB - The world-wide sensor web has become a very useful technique for monitoring the physical world at spatial and temporal scales that were previously impossible. Yet we believe that the full potential of sensor web has thus far not been revealed. In order to harvest the world-wide sensor web's full potential, a geospatial cyberinfrastructure is needed to store, process, and deliver large amount of sensor data collected worldwide. In this paper, we first define the issue of the sensor web long tail followed by our view of the world-wide sensor web architecture. Then, we introduce the Geospatial Cyberinfrastructure for Environmental Sensing (GeoCENS) architecture and explain each of its components. Finally, with demonstration of three real-world powered-by-GeoCENS sensor web applications, we believe that the GeoCENS architecture can successfully address the sensor web long tail issue and consequently realize the world-wide sensor web vision. PMID- 24152922 TI - Design and development of a low-cost optical current sensor. AB - In this paper we demonstrate the design of a low-cost optical current sensor. The sensor principle is the Faraday rotation of a light beam through a magneto optical material, SF2, when a magnetic field is present. The prototype has a high sensitivity and a high linearity for currents ranging from 0 up to 800 A. The error of the optical fibre sensor is smaller than 1% for electric currents over 175 A. PMID- 24152923 TI - A thermoelectric generator using porous Si thermal isolation. AB - In this paper we report on a thermoelectric generator (TEG) using thermal isolation provided by a thick porous Si layer locally formed on the Si wafer and thermocouples composed of p-doped polycrystalline Si/Al. The "hot" contacts of the thermocouples lie on the porous Si layer, while the "cold" contacts lie on bulk crystalline Si. A housing was also designed and fabricated in order to transfer any external temperature change on the "hot" contacts of the thermocouples, the "cold" contacts being isolated from the "hot" contacts by a thick resist layer. The fabrication of the sensing element (Si die) is fully compatible with batch Si processing. The output power of the thermoelectric generator depends on the porous Si isolation layer thickness, porosity, structure and morphology. For a mesoporous Si layer of 60% porosity and a macroscopic temperature differential of 10 K, an output power of 0.39 MUW/cm2 was measured for a 50 MUm thick porous Si layer. PMID- 24152924 TI - On using maximum a posteriori probability based on a Bayesian model for oscillometric blood pressure estimation. AB - The maximum amplitude algorithm (MAA) is generally utilized in the estimation of the pressure values, and it uses heuristically obtained ratios of systolic and diastolic oscillometric amplitude to the mean arterial pressure (known as systolic and diastolic ratios) in order to estimate the systolic and diastolic pressures. This paper proposes a Bayesian model to estimate the systolic and diastolic ratios. These ratios are an improvement over the single fixed systolic and diastolic ratios used in the algorithms that are available in the literature. The proposed method shows lower mean difference (MD) with standard deviation (SD) compared to the MAA for both SBP and DBP consistently in all the five measurements. PMID- 24152926 TI - Eyeglasses lens contour extraction from facial images using an efficient shape description. AB - This paper presents a system that automatically extracts the position of the eyeglasses and the accurate shape and size of the frame lenses in facial images. The novelty brought by this paper consists in three key contributions. The first one is an original model for representing the shape of the eyeglasses lens, using Fourier descriptors. The second one is a method for generating the search space starting from a finite, relatively small number of representative lens shapes based on Fourier morphing. Finally, we propose an accurate lens contour extraction algorithm using a multi-stage Monte Carlo sampling technique. Multiple experiments demonstrate the effectiveness of our approach. PMID- 24152925 TI - Aptamers as theranostic agents: modifications, serum stability and functionalisation. AB - Aptamers, and the selection process known as Systematic Evolution of Ligands by Exponential Enrichment (SELEX) used to generate them, were first described more than twenty years ago. Since then, there have been numerous modifications to the selection procedures. This review discusses the use of modified bases as a means of enhancing serum stability and producing effective therapeutic tools, as well as functionalising these nucleic acids to be used as potential diagnostic agents. PMID- 24152927 TI - Microelectrode arrays with overlapped diffusion layers as electroanalytical detectors: theory and basic applications. AB - This contribution contains a survey of basic literature dealing with arrays of microelectrodes with overlapping diffusion layers as prospective tools in contemporary electrochemistry. Photolithographic thin layer technology allows the fabrication of sensors of micrometric dimensions separated with a very small gap. This fact allows the diffusion layers of single microelectrodes to overlap as members of the array. Various basic types of microelectrode arrays with interacting diffusion layers are described and their analytical abilities are accented. Theoretical approaches to diffusion layer overlapping and the consequences of close constitution effects such as collection efficiency and redox cycling are discussed. Examples of basis applications in electroanalytical chemistry such as amperometric detectors in HPLC and substitutional stripping voltammetry are also given. PMID- 24152928 TI - Video sensor-based complex scene analysis with Granger causality. AB - In this report, we propose a novel framework to explore the activity interactions and temporal dependencies between activities in complex video surveillance scenes. Under our framework, a low-level codebook is generated by an adaptive quantization with respect to the activeness criterion. The Hierarchical Dirichlet Processes (HDP) model is then applied to automatically cluster low-level features into atomic activities. Afterwards, the dynamic behaviors of the activities are represented as a multivariate point-process. The pair-wise relationships between activities are explicitly captured by the non-parametric Granger causality analysis, from which the activity interactions and temporal dependencies are discovered. Then, each video clip is labeled by one of the activity interactions. The results of the real-world traffic datasets show that the proposed method can achieve a high quality classification performance. Compared with traditional K means clustering, a maximum improvement of 19.19% is achieved by using the proposed causal grouping method. PMID- 24152929 TI - A silicon nanomembrane detector for matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) of large proteins. AB - We describe a MALDI-TOF ion detector based on freestanding silicon nanomembrane technology. The detector is tested in a commercial MALDI-TOF mass spectrometer with equimolar mixtures of proteins. The operating principle of the nanomembrane detector is based on phonon-assisted field emission from these silicon nanomembranes, in which impinging ion packets excite electrons in the nanomembrane to higher energy states. Thereby the electrons can overcome the vacuum barrier and escape from the surface of the nanomembrane via field emission. Ion detection is demonstrated of apomyoglobin (16,952 Da), aldolase (39,212 Da), bovine serum albumin (66,430 Da), and their equimolar mixtures. In addition to the three intact ions, a large number of fragment ions are also revealed by the silicon nanomembrane detector, which are not observable with conventional detectors. PMID- 24152931 TI - Sensing lanthanide metal content in biological tissues with magnetic resonance spectroscopy. AB - The development and validation of MRI contrast agents consisting of a lanthanide chelate often requires a determination of the concentration of the agent in ex vivo tissue. We have developed a protocol that uses 70% nitric acid to completely digest tissue samples that contain Gd(III), Dy(III), Tm(III), Eu(III), or Yb(III) ions, or the MRI contrast agent gadodiamide. NMR spectroscopy of coaxial tubes containing a digested sample and a separate control solution of nitric acid was used to rapidly and easily measure the bulk magnetic susceptibility (BMS) shift caused by each lanthanide ion and gadodiamide. Each BMS shift was shown to be linearly correlated with the concentration of each lanthanide ion and gadodiamide in the 70% nitric acid solution and in digested rat kidney and liver tissues. These concentration measurements had outstanding precision, and also had good accuracy for concentrations >=10 mM for Tm(III) Eu(III), and Yb(III), and >=3 mM for Gd(III), gadodiamide, and Dy(III). Improved sample handling methods are needed to improve measurement accuracy for samples with lower concentrations. PMID- 24152930 TI - Tissue discrimination by uncorrected autofluorescence spectra: a proof-of principle study for tissue-specific laser surgery. AB - Laser surgery provides a number of advantages over conventional surgery. However, it implies large risks for sensitive tissue structures due to its characteristic non-tissue-specific ablation. The present study investigates the discrimination of nine different ex vivo tissue types by using uncorrected (raw) autofluorescence spectra for the development of a remote feedback control system for tissue-selective laser surgery. Autofluorescence spectra (excitation wavelength 377 +/- 50 nm) were measured from nine different ex vivo tissue types, obtained from 15 domestic pig cadavers. For data analysis, a wavelength range between 450 nm and 650 nm was investigated. Principal Component Analysis (PCA) and Quadratic Discriminant Analysis (QDA) were used to discriminate the tissue types. ROC analysis showed that PCA, followed by QDA, could differentiate all investigated tissue types with AUC results between 1.00 and 0.97. Sensitivity reached values between 93% and 100% and specificity values between 94% and 100%. This ex vivo study shows a high differentiation potential for physiological tissue types when performing autofluorescence spectroscopy followed by PCA and QDA. The uncorrected autofluorescence spectra are suitable for reliable tissue discrimination and have a high potential to meet the challenges necessary for an optical feedback system for tissue-specific laser surgery. PMID- 24152932 TI - Development of an amorphous selenium-based photodetector driven by a diamond cold cathode. AB - Amorphous-selenium (a-Se) based photodetectors are promising candidates for imaging devices, due to their high spatial resolution and response speed, as well as extremely high sensitivity enhanced by an internal carrier multiplication. In addition, a-Se is reported to show sensitivity against wide variety of wavelengths, including visible, UV and X-ray, where a-Se based flat-panel X-ray detector was proposed. In order to develop an ultra high-sensitivity photodetector with a wide detectable wavelength range, a photodetector was fabricated using a-Se photoconductor and a nitrogen-doped diamond cold cathode. In the study, a prototype photodetector has been developed, and its response to visible and ultraviolet light are characterized. PMID- 24152933 TI - Multi sensor fusion framework for indoor-outdoor localization of limited resource mobile robots. AB - This paper presents a sensor fusion framework that improves the localization of mobile robots with limited computational resources. It employs an event based Kalman Filter to combine the measurements of a global sensor and an inertial measurement unit (IMU) on an event based schedule, using fewer resources (execution time and bandwidth) but with similar performance when compared to the traditional methods. The event is defined to reflect the necessity of the global information, when the estimation error covariance exceeds a predefined limit. The proposed experimental platforms are based on the LEGO Mindstorm NXT, and consist of a differential wheel mobile robot navigating indoors with a zenithal camera as global sensor, and an Ackermann steering mobile robot navigating outdoors with a SBG Systems GPS accessed through an IGEP board that also serves as datalogger. The IMU in both robots is built using the NXT motor encoders along with one gyroscope, one compass and two accelerometers from Hitecnic, placed according to a particle based dynamic model of the robots. The tests performed reflect the correct performance and low execution time of the proposed framework. The robustness and stability is observed during a long walk test in both indoors and outdoors environments. PMID- 24152934 TI - Development of anodic titania nanotubes for application in high sensitivity amperometric glucose and uric acid biosensors. AB - The purpose of this study was to develop novel nanoscale biosensors using titania nanotubes (TNTs) made by anodization. Titania nanotubes were produced on pure titanium sheets by anodization at room temperature. In this research, the electrolyte composition ethylene glycol 250 mL/NH4F 1.5 g/DI water 20 mL was found to produce the best titania nanotubes array films for application in amperometric biosensors. The amperometric results exhibit an excellent linearity for uric acid (UA) concentrations in the range between 2 and 14 mg/dL, with 23.3 (uA.cm-2).(mg/dL)-1 UA sensitivity, and a correlation coefficient of 0.993. The glucose biosensor presented a good linear relationship in the lower glucose concentration range between 50 and 125 mg/dL, and the corresponding sensitivity was approximately 249.6 (uA.cm-2).(100 mg/dL)-1 glucose, with a correlation coefficient of 0.973. PMID- 24152935 TI - Remote driven and read MEMS sensors for harsh environments. AB - The utilization of high accuracy sensors in harsh environments has been limited by the temperature constraints of the control electronics that must be co-located with the sensor. Several methods of remote interrogation for resonant sensors are presented in this paper which would allow these sensors to be extended to harsh environments. This work in particular demonstrates for the first time the ability to acoustically drive a silicon comb drive resonator into resonance and electromagnetically couple to the resonator to read its frequency. The performance of this system was studied as a function of standoff distance demonstrating the ability to excite and read the device from 22 cm when limited to drive powers of 30 mW. A feedback architecture was implemented that allowed the resonator to be driven into resonance from broadband noise and a standoff distance of 15 cm was demonstrated. It is emphasized that no junction-based electronic device was required to be co-located with the resonator, opening the door for the use of silicon-based, high accuracy MEMS devices in high temperature wireless applications. PMID- 24152936 TI - Tools for advancing research into social networks and cognitive function in older adults. PMID- 24152937 TI - Achieving an AIDS-free world: science and implementation. PMID- 24152938 TI - Antiretroviral treatment of HIV-1 prevents transmission of HIV-1: where do we go from here? AB - Antiretroviral drugs that inhibit viral replication were expected to reduce transmission of HIV by lowering the concentration of HIV in the genital tract. In 11 of 13 observational studies, antiretroviral therapy (ART) provided to an HIV infected index case led to greatly reduced transmission of HIV to a sexual partner. In the HPTN 052 randomised controlled trial, ART used in combination with condoms and counselling reduced HIV transmission by 96.4%. Evidence is growing that wider, earlier initiation of ART could reduce population-level incidence of HIV. However, the full benefits of this strategy will probably need universal access to very early ART and excellent adherence to treatment. Challenges to this approach are substantial. First, not all HIV-infected individuals can be located, especially people with acute and early infection who are most contagious. Second, the ability of ART to prevent HIV transmission in men who have sex with men (MSM) and people who use intravenous drugs has not been shown. Indeed, the stable or increased incidence of HIV in MSM in some communities where widespread use of ART has been established emphasises the concern that not enough is known about treatment as prevention for this crucial population. Third, although US guidelines call for immediate use of ART, such guidelines have not been embraced worldwide. Some experts do not believe that immediate or early ART is justified by present evidence, or that health-care infrastructure for this approach is sufficient. These concerns are very difficult to resolve. Ongoing community-based prospective trials of early ART are likely to help to establish the population-level benefit of ART, and-if successful-to galvanise treatment as prevention. PMID- 24152940 TI - Thoracic aorta vasoreactivity in rats under exhaustive exercise: effects of Lycium barbarum polysaccharides supplementation. AB - BACKGROUND: Reduced arterial compliance is associated with an increased rate of morbidity and mortality in cardiovascular disease. Exercise is beneficial for compromised arterial compliance. However, the beneficial effects of exercise are lost with exhaustion. Lycium barbarum L. has been used in China for centuries to maintain good health. In this regard, the primary purpose of this study was to characterize the effects of the polysaccharides from Lycium barbarum (LBPs) on arterial compliance during exhaustive exercise. METHODS: A four-week swimming exercise program was designed for rats, and the blood levels of malondialdehyde (MDA), super oxide dismutase (SOD), nitric oxide(NO) and heat shock protein 70(HSP70) were detected. The tension of aorta rings was measured to evaluate the response of rats on noradrenaline (NA)-induced contractions. RESULTS: The rats administered LBPs showed longer swimming time until exhaustion than the control group of rats. Exercise-induced MDA elevation was repressed by LBPs supplementation. The LBPs-supplemented rats displayed a significant increase of SOD, NO, HSP70 than the non-supplemented rats. Additionally, LBPs significantly up-regulated the expression of eNOS and improved the endothelium-dependent vasodilatation of the aorta ring. CONCLUSION: Our study proved that LBPs administration significantly inhibited the oxidative stress, and improved the arterial compliance. PMID- 24152939 TI - The end of AIDS: HIV infection as a chronic disease. AB - The success of antiretroviral therapy has led some people to now ask whether the end of AIDS is possible. For patients who are motivated to take therapy and who have access to lifelong treatment, AIDS-related illnesses are no longer the primary threat, but a new set of HIV-associated complications have emerged, resulting in a novel chronic disease that for many will span several decades of life. Treatment does not fully restore immune health; as a result, several inflammation-associated or immunodeficiency complications such as cardiovascular disease and cancer are increasing in importance. Cumulative toxic effects from exposure to antiretroviral drugs for decades can cause clinically-relevant metabolic disturbances and end-organ damage. Concerns are growing that the multimorbidity associated with HIV disease could affect healthy ageing and overwhelm some health-care systems, particularly those in resource-limited regions that have yet to develop a chronic care model fully. In view of the problems inherent in the treatment and care for patients with a chronic disease that might persist for several decades, a global effort to identify a cure is now underway. PMID- 24152943 TI - 2013 American Pancreatic Association presidential address: widening the reach of the APA. PMID- 24152941 TI - Astragalus saponins affect proliferation, invasion and apoptosis of gastric cancer BGC-823 cells. AB - BACKGROUND: Astragalus memebranaceus is a traditional Chinese herbal medicine used in treatment of common cold, diarrhea, fatigue, anorexia and cardiac diseases. Recently, there are growing evidences that Astragalus extract may be a potential anti-tumorigenic agent. Some research showed that the total saponins obtained from Astragalus membranaceus possess significant antitumorigenic activity. Gastric cancer is one of the most frequent cancers in the world, almost two-thirds of gastric cancer cases and deaths occur in less developed regions. But the effect of Astragalus membranaceus on proliferation, invasion and apoptosis of gastric cancer BGC-823 cells remains unclear. METHODS: Astragalus saponins were extracted. Cells proliferation was determined by CCK-8 assay. Cell cycle and apoptosis were detected by the flow cytometry. Boyden chamber was used to evaluate the invasion and metastasis capabilities of BGC-823 cells. Tumor growth was assessed by subcutaneous inoculation of cells into BALB/c nude mice. RESULTS: The results demonstrated that total Astragalus saponins could inhibit human gastric cancer cell growth both in vitro and in vivo, in additional, Astragalus saponins deceased the invasion ability and induced the apoptosis of gastric cancer BGC-823 cells. CONCLUSIONS: Total Astragalus saponins inhibited human gastric cancer cell growth, decreased the invasion ability and induced the apoptosis. This suggested the possibility of further developing Astragalus as an alternative treatment option, or perhaps using it as adjuvant chemotherapeutic agent in gastric cancer therapy. PMID- 24152942 TI - Recognition of physiotherapists' expertise in Parkinson's disease. AB - BACKGROUND: Publicly available information comparing performance across quality and costs has proliferated in recent years, both about individual healthcare professionals and hospitals. This type of information is now becoming increasingly available for physiotherapists with expertise in Parkinson's disease (PD). Our study aimed to explore the ability of people with Parkinson's disease to recognise expertise, and to what extent respondents selectively choose such expert physiotherapists. METHODS: We used claim data from the period 2009-2010 to select customers with PD who claimed physiotherapy. A random sample of 500 eligible respondents received a paper-based survey. We used descriptive statistics to compare the respondent characteristics, a qualitative programme to analyse the qualitative items, and univariate and multivariate regression. RESULTS: Most respondents (89%) took their referring physician's advice when selecting a physiotherapist, although this advice rarely was supported with arguments. The remaining respondents (11%) searched for comparative performance information about physiotherapists. Respondents who recognised the added value of PD expertise among physiotherapists were 3.28 times as likely to search for comparative performance information as those who did not understand. Respondents were willing to switch to an expert physiotherapist (68%), and this willingness increased if they recognised the value of PD expertise (p < .001). CONCLUSION: The participants were able to recognise certain aspects of expertise. Though they showed relatively few signs of selectively choice behaviour for expert physiotherapists. Both respondents and referring professionals need more understanding about the added value of an expert physiotherapist, to foster selective provider choice. PMID- 24152944 TI - American Pancreatic Association: 2013 Vay Liang and Frisca Go award for lifetime achievement and distinguished service award. PMID- 24152945 TI - Diabetes mellitus and pancreatic cancer: why the association matters? PMID- 24152946 TI - The impact of perioperative blood glucose levels on pancreatic cancer prognosis and surgical outcomes: an evidence-based review. AB - Although diabetes mellitus (DM) and pancreatic cancer (PC) are intricately linked, a comprehensive review addressing the impact of DM on PC prognosis and surgical outcomes is lacking. PubMed search was performed (1980-2012) using keywords "pancreatic cancer", "diabetes mellitus", "glucose intolerance", "pancreatic resection", "prognosis", and "post-operative outcomes". The search results were analyzed to determine the strength of association between DM and PC and to assess the impact of DM on PC prognosis and postoperative outcomes. Thirty one studies involving 38,777 patients were identified. Patients with non-insulin dependent DM have 1.5-2 fold increased relative risk of developing PC. Non insulin-dependent DM is identified in 25.7% of patients with PC compared to 10.4% age-matched controls (95% confidence interval, 1.5-4.7; P < 0.0001). Patients with PC are more likely to have a diagnosis of new-onset DM than age-matched controls (14.7% vs 2.7%; P < 0.0001). Patients with PC with DM have a significantly lower overall survival than those without DM (14.4 vs 21.7 months; P < 0.001). The presence of DM significantly increases overall postoperative complication rates (45.6% vs 35.6%; P < 0.008). Patients with new-onset non insulin-dependent DM are at a higher risk of developing PC and have a worse long term survival and a higher rate of postoperative complications. PMID- 24152947 TI - Pancreatic cancer: modulation of KRAS, MicroRNAs, and intercellular communication in the setting of tumor heterogeneity. AB - Mutations in KRAS-one of the ras family of oncogenes, encoding a GTPase critical to intracellular signal transduction--are more prevalent (80%-95%) in pancreatic cancer than in any other malignancy. There is increasing evidence that stromal cells--including pancreatic stellate cells--play a vital role in development and progression of pancreatic carcinomas. Advances in understanding the underlying biology of tumor-stroma interactions and tumor heterogeneity are critical to guiding rational approaches to designing treatments tailored to targeting KRAS in the stroma-rich microenvironment. Areas of interest in creating novel approaches to therapy include elucidating interactions of KRAS with microRNAs, the role of intratumoral hypoxia, and exploration of diverse modes of intercellular propagation of signals that stimulate malignant invasion and metastasis. This article provides an overview and state-of-the-art update of knowledge regarding pancreatic tumor biology, with a special focus on pancreatic tumor heterogeneity, the role of microRNA-mediated and hypoxic alterations in gene expression and interactions with KRAS, intercellular communication and trafficking, and progress in understanding KRAS as a potential target for pancreatic cancer therapy. PMID- 24152949 TI - Clinical evaluation of international consensus diagnostic criteria for type 1 autoimmune pancreatitis in comparison with Japanese diagnostic criteria 2011. AB - OBJECTIVES: The objective of this study was to evaluate the International Consensus Diagnostic Criteria (ICDC) for type 1 autoimmune pancreatitis (AIP) in comparison with the Japanese criteria 2011 (JPS2011). METHODS: We retrospectively investigated the usefulness of ICDC in comparison with JPS2011 in 64 patients with AIP and 90 patients with pancreatic cancer. RESULTS: The sensitivity and specificity of ICDC for AIP were 98.4% (63/64) and 100% (90/90), respectively. The sensitivities and specificities of ductal imaging, serology, other organ involvement, and pancreatic histology were 74.1%, 89.1%, 53.1%, and 26.1% and 94.7%, 94.5%, 100%, and 100%, respectively. On the other hand, the sensitivities and specificities of JPS2011 for AIP were 84.4% (54/64) and 100% (90/90), respectively. The condition of all the 10 patients who were deniable or possible under the JPS2011 could be diagnosed as definitive AIP under the ICDC. The sensitivities and specificities of Japanese criteria 2006, Asian Diagnostic Criteria, and HISORt criteria were 80.6%, 84.4%, and 92.2% and 95.8%, 87.8%, and 100%, respectively. CONCLUSIONS: The sensitivity and specificity of ICDC are higher than those of previous criteria. The JPS2011 is easy to handle for general practice, and specificity is very high. However, the sensitivity of JPS2011 is lower than that of ICDC, and improvement of sensitivity is to be hoped in the future. PMID- 24152948 TI - Pancreatitis-diabetes-pancreatic cancer: summary of an NIDDK-NCI workshop. AB - A workshop sponsored by the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) and the National Cancer Institute (NCI) on "Pancreatitis Diabetes-Pancreatic Cancer" focused on the risk factors of chronic pancreatitis (CP) and diabetes mellitus (DM) on the development of pancreatic ductal adenocarcinoma (PDAC). Sessions were held on (a) an overview of the problem of PDAC; (b) CP as a risk factor of PDAC; (c) DM as a risk factor of PDAC; (d) pancreatogenic, or type 3c, DM; (e) genomic associations of CP, DM, and PDAC; (f) surveillance of high-risk populations and early detection of PDAC; and (g) effects of DM treatment on PDAC. Recent data and current understandings of the mechanisms of CP- and DM-associated factors on PDAC development were discussed, and a detailed review of the possible risks of DM treatment on the development of PDAC was provided by representatives from academia, industry, and the Food and Drug Administration. The current status of possible biomarkers of PDAC and surveillance strategies for high-risk populations were discussed, and the gaps in knowledge and opportunities for further research were elucidated. A broad spectrum of expertise of the speakers and the discussants provided an unusually productive workshop, the highlights of which are summarized in the accompanying article. PMID- 24152950 TI - A population-based study of severity in patients with acute on chronic pancreatitis. AB - OBJECTIVES: The objectives of this study were to evaluate the severity of patients with acute pancreatitis (AP) on chronic pancreatitis (CP) and compare this to patients with AP without CP. METHODS: The Maryland Health Services database was queried for all adult inpatient discharges with a primary diagnosis of AP from 1994 to 2010. Acute pancreatitis on CP and AP without CP were defined by the presence of the associated diagnosis code for CP. Severity was defined as organ failure, intensive care unit stay, or mortality. RESULTS: Acute pancreatitis on CP accounted for 13.7% of all AP discharges (9747/70,944). The proportion of AP-on-CP discharges doubled during the study period (8.8% to 17.6%; P < 0.0001). When compared with patients with AP without CP, AP-on-CP patients were younger, were more likely to be male and black, had higher rates of alcohol and drug abuse, and had less severe disease with lower rates of mortality, organ failure, need for mechanical ventilation, and intensive care unit stay. Among AP on-CP patients, significant predictors of severity included advanced age, weight loss, and 2 or more comorbidities. CONCLUSIONS: Patients with AP on CP have less severe disease than do those with AP without CP. Weight loss, advanced age, and comorbidity increase the risk of severity in patients with AP on CP. PMID- 24152951 TI - Splanchnic vein thrombosis in acute pancreatitis: a single-center experience. AB - OBJECTIVES: This study aimed to estimate outcomes of splanchnic vein thrombosis (SVT) in hospitalized patients with acute pancreatitis (AP). METHODS: This was a retrospective study (January 1996 to December 2006) via chart review. RESULTS: Over 10 years, 1.8% (45/2454) of patients with AP with a mean (SD) age of 58 (15) years were diagnosed with SVT. Splenic vein thrombosis was the most common form of SVT (30/45 patients, 67%). Seventeen patients were anticoagulated with heparin, when the SVT was diagnosed in the acute stage followed by oral anticoagulation (AC). The thrombosis that was most commonly anticoagulated was portal vein thrombosis in 11 (65%) of 17 patients. Of 17 patients in the AC group, 2 (12%) showed recanalization as compared with 3 (11%) of 28 patients in the non-AC group (P > 0.05). The mortality was 3 (7%) of 45 (2 from the AC group versus 1 in the non-AC group, P > 0.05). Two of these died of multiorgan failure, and the other, from septic shock. None of the deaths were due to bleeding complications. CONCLUSIONS: Splanchnic vein thrombosis occurred in 1.8% patients of AP. The use of AC was reasonably safe with no fatal bleeding complications. However, there was no significant difference in the recanalization rates in those with and without AC. PMID- 24152952 TI - An evidence-based proposal for predicting organ failure in severe acute pancreatitis. AB - OBJECTIVES: Early, efficient, and accurate evaluation for organ failure is an important step for improving outcome in severe acute pancreatitis (SAP). We aim to develop a method that can early, efficiently, and accurately evaluate the in hospital organ failure in patients with SAP. METHODS: Using multivariate logistic regression analysis, the associative factors for in-hospital organ failure were evaluated retrospectively from conventional data obtained from 393 patients with SAP from 2000 to 2012. In classification and regression tree analysis, a new clinical scoring system was developed for the evaluation of in-hospital organ failure in SAP. We also compared the accuracy of our new scoring system with multiple organ dysfunction score and Acute Physiology and Chronic Health Examination II score by the receiver operating characteristic curve. RESULTS: Laboratory results revealed serum calcium level greater than or equal to 1.84 mmol/L, serum creatinine level greater than or equal to 110 umol/L, age greater than or equal to 72 years, activated partial thromboplastin time less than or equal to 30.95 seconds, and Balthazar computed tomography score greater than or equal to 7 (CCAAB) score system, each contributed 1 point for the prediction of organ failure. The area under the curve of the CCAAB score system was similar to multiple organ dysfunction scores and Acute Physiology and Chronic Health Examination II scores. CONCLUSIONS: The new scoring system CCAAB is an efficient and accurate method for the early evaluation of patients with SAP for in-hospital organ failure. PMID- 24152953 TI - Histological advantages of the tumor graft: a murine model involving transplantation of human pancreatic cancer tissue fragments. AB - OBJECTIVES: Experimental data based on cell line-derived xenograft models (cell xenograft) seldom reproduce the clinical situation, and therefore we demonstrated here the superiority of a murine model involving transplantation of human pancreatic cancer tissue fragments (tumor graft), focusing on the histological features and drug delivery characteristics. METHODS: Tumor pieces from 10 pancreatic cancer patients were transplanted into SCID (severe combined immunodeficient) mice. Histological characteristics of tumor grafts, including morphology, desmoplastic reaction, and vascularization, were compared with those of cell xenografts. Drug delivery was evaluated by quantifying the concentrations of injected drug, and the results were compared with its histological features. RESULTS: Eight of the 10 transplanted tumors successfully engrafted. Histological comparisons between tumor grafts and cell xenografts revealed the following: the amount of stroma was more (22.9% +/- 11.8% vs 10.8% +/- 5.4%; P < 0.05), vessel cancer cell distance was longer (35.3 +/- 39.0 vs 3.9 +/- 3.1 MUm; P < 0.001), and microvessel density was lower (6.8 +/- 1.9 vs 10.8 +/- 2.1 vessels/0.4 mm(2); P < 0.05) in tumor grafts. Drug concentrations in tumor grafts were lower than those in cell xenografts (3.3 +/- 1.2 vs 6.0+/-0.2 MUg/mL; P = 0.003), and the differences were correlated with the histological differences. CONCLUSIONS: Pancreatic tumor grafts better reproduce the histological nature of clinical cancer and thus provide a more realistic model that is applicable for pharmacokinetic studies. PMID- 24152954 TI - Reduction of fibrosis in dibutyltin dichloride-induced chronic pancreatitis using rat umbilical mesenchymal stem cells from Wharton's jelly. AB - OBJECTIVES: The objective of this study was to investigate the effects of rat umbilical cord mesenchymal stem cells (UCMSCs) from Wharton's jelly on dibutyltin dichloride (DBTC)-induced chronic pancreatitis (CP) and subsequent pancreatic fibrosis in rats. METHODS: A rat model of CP induced by DBTC was used. Male Sprague-Dawley rats were randomly divided into 4 groups: the control, DBTC, DBTC + UCMSCs, and control + UCMSC groups. Umbilical cord mesenchymal stem cells were administered intravenously on day 5 after the administration of DBTC. On days 14 and 28, the rats were evaluated morphologically and biochemically. The expression levels of inflammatory cytokines and chemokines in the pancreatic tissues of different groups were evaluated using quantitative real-time polymerase chain reaction. The activation of pancreatic stellate cells was estimated by immunochemistry and Western blot analysis of alpha-smooth muscle actin. RESULTS: Umbilical cord mesenchymal stem cells were detected in inflamed pancreatic tissues. Umbilical cord mesenchymal stem cell treatment improved the histological scores and alleviated the fibrosis of pancreas samples, The expression of cytokines in the DBTC + UCMSC group was significantly lower than that in the DBTC group. Also, pancreatic stellate cell activation was inhibited by UCMSC treatment. CONCLUSIONS: Xenogeneic transplantation of UCMSCs is a novel approach for the treatment of CP and subsequent fibrosis. Umbilical cord mesenchymal stem cells may be a promising therapeutic intervention for human CP in the future. PMID- 24152955 TI - A meta-analysis of gemcitabine biomarkers in patients with pancreaticobiliary cancers. AB - OBJECTIVES: The objective of this study was to summarize all clinical studies evaluating the prognostic role of gemcitabine (GEM) metabolic genes in pancreaticobiliary (PB) cancer patients receiving GEM therapy in the neoadjuvant, adjuvant, or palliative settings. METHODS: Meta-analyses were performed to calculate the pooled hazard ratios for each gene by each clinical outcome (overall survival [OS], disease-free survival [DFS], and progression-free survival) using a random-effects approach. RESULTS: The search strategy identified 16 eligible studies, composed of 632 PB patients total, with moderate quality. Compared with low expression, pooled hazard ratios for OS of hENT1, dCK, RRM1, RRM2, and DPD were 0.37 (95% confidence interval [CI], 0.28-0.47), 0.40 (95% CI, 0.20-0.80), 2.21 (95% CI, 1.12-4.36), 2.13 (95% CI, 1.00-4.52), and 1.91 (95% CI, 1.16-3.17), respectively. A similar trend was observed for each of these biomarkers in DFS and progression-free survival prognostication. Subgroup analyses for hENT1 showed a comparable survival correlation in the adjuvant and palliative settings. CONCLUSIONS: High expression of hENT1 in PB cancer patients receiving GEM-based adjuvant therapy is associated with improved OS and DFS and may be the best examined prognostic marker to date. Evidence for other biomarkers is limited by a small number of publications investigating these markers. PMID- 24152957 TI - Diagnostic performance of MDCT for predicting important prognostic factors in pancreatic cancer. AB - OBJECTIVES: Tumor stage, node metastasis, tumor size, vascular invasion, and perineural invasion are the most important prognostic factors that might be determined by preoperative multidetector computed tomography (MDCT) in pancreatic cancer. The purpose of our study is to investigate diagnostic accuracy of MDCT for determining these prognostic factors. METHODS: For 6 years, 111 patients with surgically resected pancreatic cancer underwent preoperative MDCT. Two radiologists retrospectively assessed tumor stage, node metastasis, tumor size, and vascular invasion. They also graded perineural invasion using a 3-point scale focused on 5 routes. Statistical analyses were performed using the receiver operating characteristic analysis, McNemar test, and paired t test. RESULTS: Statistically, tumor size on specimens (3.4 +/- 1.46 cm) is larger than tumor size on MDCT (3.2 +/- 1.41 cm; P = 0.001). The diagnostic accuracy rates for tumor stage were 82.9% and 77.5%, with moderate agreement (kappa = 0.732). The accuracy rates for node metastasis were 59.5% and 55.0%, with fair agreement (kappa = 0.597). The diagnostic accuracy rates for vascular invasion were 94% and 92%. The areas under the curve for perineural invasion were 0.733 and 0.66 (P = 0.069), with moderate agreement (kappa = 0.77). CONCLUSIONS: Multidetector computed tomography is very useful for the preoperative evaluation of tumor stage, perineural invasion, and vascular invasion of pancreatic cancer, but it has limited evaluation of node metastasis and tumor size. PMID- 24152956 TI - Modified FOLFIRINOX regimen with improved safety and maintained efficacy in pancreatic adenocarcinoma. AB - OBJECTIVES: FOLFIRINOX (5-fluorouracil [5-FU], oxaliplatin, and irinotecan) as compared with gemcitabine in pancreatic cancer (PC) has superior activity and increased toxicity. The bolus 5-FU contributes to the toxicity. We hypothesized that the elimination of bolus 5-FU and use of hematopoietic growth factor will improve the safety profile without compromising the activity of FOLFIRINOX. METHODS: Sixty patients with PC treated with modified FOLFIRINOX (no bolus 5-FU) were reviewed. Patients were divided into metastatic or nonmetastatic (locally advanced or borderline resectable) disease. Toxicity, response rate, progression free survival, and overall survival were evaluated. RESULTS: Nonmetastatic and metastatic disease were present in 24 (40%) and 36 (60%) patients, respectively. The incidence of grade 4 neutropenia, grade 3/4 diarrhea, and fatigue were 3%, 13%, and 13%, respectively. Response rate was 30%. The median progression-free survival for nonmetastatic disease was 13.7 months (95% confidence interval [CI], 9.6-24.6 months), and that for metastatic disease was 8.5 months (95% CI, 3.7 11.0 months), respectively. The median overall survival for nonmetastatic disease was 17.8 months (95% CI, 9.9 months to not estimable), and that for metastatic disease was and 9.0 months (95% CI, 7.1 months to not estimable), respectively. CONCLUSIONS: Modified FOLFIRINOX has an improved safety profile with maintained efficacy in metastatic PC. Modified FOLFIRINOX has promising activity in nonmetastatic disease. PMID- 24152958 TI - Giant insulinoma: a report of 3 cases and review of the literature. AB - Insulinoma is a rare pancreatic neuroendocrine tumor that is usually described as benign, sporadic, and very small (<2 cm). However, there have been rare case reports of insulinoma presenting as a giant tumor. We describe 3 cases of giant insulinomas, all of which developed liver metastases. The patients were aged 38, 63, and 67 years. Clinically, all patients presented with Whipple's triad associated with a large mass located in the pancreatic tail. The tumors ranged in size from 10 to 15 cm. On microscopic examination, the tumors were well differentiated with amyloid deposition ranging between 20% and 30%. Immunohistochemically, all 3 tumors showed strong diffuse expression of chromogranin and synaptophysin, whereas they were only focally positive for insulin. One patient developed liver recurrence 3 years after resection of the primary tumor yet remained asymptomatic without treatment. Another patient with liver recurrence underwent right hepatectomy and has been free of disease for 2 years. The third patient died of metastatic disease 13 years after initial surgery. Giant insulinomas are characterized by focal expression of insulin and high rates of liver metastases. Long-term follow-up is mandatory in these patients, as recurrence is expected after primary surgery. PMID- 24152959 TI - Minutes of the business meeting of the American Pancreatic Association, Friday, November 2, 2012, Miami, Florida. PMID- 24152960 TI - Pancreatic intraepithelial neoplasia in patients with intraductal papillary mucinous neoplasms: the interest of endoscopic ultrasonography. AB - OBJECTIVES: Intraductal papillary mucinous neoplasms (IPMNs) and pancreatic intraepithelial neoplasia (PanIN) are both precancerous lesions. Papillary mucinous neoplasms have been described in patients with IPMN, but their relationship is still poorly understood. The aims of this study were to look for PanIN lesions in patients operated on for IPMN and to search for correlations between endoscopic ultrasonography(EUS) features and pathologic findings. METHODS: Endoscopic ultrasonography was preoperatively performed in all patients with IPMN consecutively operated on in our center. Endoscopic ultrasonography features were prospectively compared with pathologic data from surgical specimen. RESULTS: Forty patients underwent resection for benign (52.5%) or malignant (47.5%) IPMN. Pancreatic intraepithelial neoplasia lesions were observed in 78% of cases (PanIN-3 in 19% of patients). PanIN-3 lesions were observed in 11% and 26% of patients with benign and malignant IPMN, respectively. Endoscopic ultrasonography changes(microcysts and/or hyperechoic foci) corresponded to PanIN lesions in 83% of cases. Endoscopic ultrasonography detected 69% of patients with PanIN lesions and 57% of those with panIN-3 lesions. CONCLUSIONS: Pancreatic intraepithelial neoplasia lesions are very frequently associated with IPMN, and 19% of patients with IPMN had PanIN-3 lesions. In two thirds of patients, EUS can detect minimal changes in the pancreas corresponding to PanIN lesions. PMID- 24152961 TI - Geographic remoteness, area-level socioeconomic disadvantage and inequalities in colorectal cancer survival in Queensland: a multilevel analysis. AB - BACKGROUND: To explore the impact of geographical remoteness and area-level socioeconomic disadvantage on colorectal cancer (CRC) survival. METHODS: Multilevel logistic regression and Markov chain Monte Carlo simulations were used to analyze geographical variations in five-year all-cause and CRC-specific survival across 478 regions in Queensland Australia for 22,727 CRC cases aged 20 84 years diagnosed from 1997-2007. RESULTS: Area-level disadvantage and geographic remoteness were independently associated with CRC survival. After full multivariate adjustment (both levels), patients from remote (odds Ratio [OR]: 1.24, 95%CrI: 1.07-1.42) and more disadvantaged quintiles (OR=1.12, 1.15, 1.20, 1.23 for Quintiles 4, 3, 2 and 1 respectively) had lower CRC-specific survival than major cities and least disadvantaged areas. Similar associations were found for all-cause survival. Area disadvantage accounted for a substantial amount of the all-cause variation between areas. CONCLUSIONS: We have demonstrated that the area-level inequalities in survival of colorectal cancer patients cannot be explained by the measured individual-level characteristics of the patients or their cancer and remain after adjusting for cancer stage. Further research is urgently needed to clarify the factors that underlie the survival differences, including the importance of geographical differences in clinical management of CRC. PMID- 24152962 TI - Effects of protein kinase a on the phosphorylation status and transverse stiffness of cardiac myofibrils. AB - Stimulation of beta-adrenergic receptors in cardiac myocytes activates cyclic AMP dependent protein kinase A (PKA). PKA-mediated phosphorylation of myofibrils decreases their longitudinal stiffness, but its effect on transverse stiffness is not fully understood. We thus examined the effects of PKA treatment on the transverse stiffness of cardiac myofibrils by atomic force microscopy and determined the phosphorylation levels of myofibril components by SDS-PAGE. Transverse stiffness was significantly decreased by PKA treatment concomitantly with increased phosphorylation of troponin I, myosin-binding protein C, and titin (also called connectin). Subsequent treatment with protein phosphatase 1 abrogated these PKA-mediated effects. PMID- 24152963 TI - Protective effects of a dietary carotenoid, astaxanthin, against light-induced retinal damage. AB - Dietary carotenoids exhibit various biological activities, including antioxidative activity. In particular, astaxanthin, a type of carotenoid, is well known as a powerful antioxidant. We investigated whether astaxanthin would protect against light-induced retinal damage. In an in vivo study, ddY male mice were exposed to white light at 8,000 lux for 3 h to induce retinal damage. Five days after light exposure, retinal damage was evaluated by measuring electroretinogram (ERG) amplitude and outer nuclear layer (ONL) thickness. Furthermore, expression of apoptotic cells, 8-hydroxy-deoxyguanosine (8-OHdG), was measured. In an in vitro study, retinal damage was induced by white light exposure at 2,500 lux for 24 h, and propidium iodide (PI)-positive cells was measured and intracellular reactive oxygen species (ROS) activity was examined. Astaxanthin at 100 mg/kg inhibited the retinal dysfunction in terms of ERG and ONL loss and reduced the expression of apoptotic and 8-OHdG-positive cells induced by light exposure. Furthermore, astaxanthin protected against increases of PI-positive cells and intracellular reactive oxygen species (ROS) activity in 661W cells. These findings suggest that astaxanthin has protective effects against light-induced retinal damage via the mechanism of its antioxidative effect. PMID- 24152964 TI - Evaluation of the therapeutic index of a novel phosphodiesterase 4B-selective inhibitor over phosphodiesterase 4D in mice. AB - Phosphodiesterase 4 (PDE4) inhibitors have been developed for the treatment of pulmonary inflammatory diseases, but their clinical use was dose-limited by mainly gastric adverse effects. Recent studies suggested PDE4B-selective inhibitors over PDE4D are supposed to display a wider therapeutic index than subtype non-selective PDE4 inhibitors such as roflumilast. Compound A was identified as an orally active PDE4B-selective inhibitor over PDE4D both in humans (80-fold selective) and mice (29-fold selective). In this study, the therapeutic effects of compound A and roflumilast were evaluated on lipopolysaccaride (LPS) injection-induced plasma TNF-alpha elevation and on LPS inhalation-induced pulmonary neutrophilia in mice. The inhibitory effect on gastric emptying in mice was evaluated as a gastric adverse effect. The therapeutic index for TNF-alpha production (TI(TNF) = ID50 in gastric emptying / ID50 in LPS injection-induced plasma TNF-alpha elevation) of compound A was larger than roflumilast (9.0 and 0.2, respectively), whereas the therapeutic index for pulmonary neutrophilia (TI(Neu) = ID50 in gastric emptying / ID50 in LPS inhalation-induced pulmonary neutrophilia) of compound A was comparable to roflumilast (1.0 and 0.5, respectively). In conclusion, the TI(Neu) of compound A was not superior compared to that of roflumilast in spite of its high selectivity for PDE4B over PDE4D in mice. PMID- 24152965 TI - Biosurveillance enterprise for operational awareness, a genomic-based approach for tracking pathogen virulence. AB - To protect our civilians and warfighters against both known and unknown pathogens, biodefense stakeholders must be able to foresee possible technological trends that could affect their threat risk assessment. However, significant flaws in how we prioritize our countermeasure-needs continue to limit their development. As recombinant biotechnology becomes increasingly simplified and inexpensive, small groups, and even individuals, can now achieve the design, synthesis, and production of pathogenic organisms for offensive purposes. Under these daunting circumstances, a reliable biosurveillance approach that supports a diversity of users could better provide early warnings about the emergence of new pathogens (both natural and manmade), reverse engineer pathogens carrying traits to avoid available countermeasures, and suggest the most appropriate detection, prophylactic, and therapeutic solutions. While impressive in data mining capabilities, real-time content analysis of social media data misses much of the complexity in the factual reality. Quality issues within freeform user-provided hashtags and biased referencing can significantly undermine our confidence in the information obtained to make critical decisions about the natural vs. intentional emergence of a pathogen. At the same time, errors in pathogen genomic records, the narrow scope of most databases, and the lack of standards and interoperability across different detection and diagnostic devices, continue to restrict the multidimensional biothreat assessment. The fragmentation of our biosurveillance efforts into different approaches has stultified attempts to implement any new foundational enterprise that is more reliable, more realistic and that avoids the scenario of the warning that comes too late. This discussion focus on the development of genomic-based decentralized medical intelligence and laboratory system to track emerging and novel microbial health threats in both military and civilian settings and the use of virulence factors for risk assessment. Examples of the use of motif fingerprints for pathogen discrimination are provided. PMID- 24152967 TI - Anoctamin 1 induces calcium-activated chloride secretion and proliferation of renal cyst-forming epithelial cells. AB - Polycystic kidney diseases are characterized by multiple bilateral renal cysts that gradually enlarge and lead to a decline in renal function. Cyst enlargement is driven by transepithelial chloride secretion, stimulated by enhanced levels of cyclic adenosine monophosphate, which activates apical cystic fibrosis transmembrane conductance regulator chloride channels. However, chloride secretion by calcium-dependent chloride channels, activated through stimulation of purinergic receptors, also has a major impact. To identify the molecular basis of calcium-dependent chloride secretion in cyst expansion, we determined the role of anoctamin 1 and 6, two recently discovered calcium-activated chloride channels both of which are expressed in epithelial cells. We found that anoctamin 1, which plays a role in epithelial fluid secretion and proliferation, is strongly expressed in principal-like MDCK cells (PLCs) forming cysts within a collagen matrix, in an embryonic kidney cyst model, and in human autosomal dominant polycystic kidney disease tissue. Knockdown of anoctamin 1 but not anoctamin 6 strongly diminished the calcium-dependent chloride secretion of PLCs. Moreover, two inhibitors of anoctamin ion channels, tannic acid and a more selective inhibitor of anoctamin 1, significantly inhibited PLC cyst growth and cyst enlargement in an embryonic kidney cyst model. Knockdown of ANO1 by morpholino analogs also attenuated embryonic cyst growth. Thus, calcium-activated chloride secretion by anoctamin 1 appears to be a crucial component of renal cyst growth. PMID- 24152966 TI - Whole-exome resequencing reveals recessive mutations in TRAP1 in individuals with CAKUT and VACTERL association. AB - Congenital abnormalities of the kidney and urinary tract (CAKUT) account for approximately half of children with chronic kidney disease and they are the most frequent cause of end-stage renal disease in children in the US. However, its genetic etiology remains mostly elusive. VACTERL association is a rare disorder that involves congenital abnormalities in multiple organs including the kidney and urinary tract in up to 60% of the cases. By homozygosity mapping and whole exome resequencing combined with high-throughput mutation analysis by array-based multiplex PCR and next-generation sequencing, we identified recessive mutations in the gene TNF receptor-associated protein 1 (TRAP1) in two families with isolated CAKUT and three families with VACTERL association. TRAP1 is a heat-shock protein 90-related mitochondrial chaperone possibly involved in antiapoptotic and endoplasmic reticulum stress signaling. Trap1 is expressed in renal epithelia of developing mouse kidney E13.5 and in the kidney of adult rats, most prominently in proximal tubules and in thick medullary ascending limbs of Henle's loop. Thus, we identified mutations in TRAP1 as highly likely causing CAKUT or VACTERL association with CAKUT. PMID- 24152968 TI - The protective roles of GLP-1R signaling in diabetic nephropathy: possible mechanism and therapeutic potential. AB - Glucagon-like peptide-1 (GLP-1) is a gut incretin hormone that has an antioxidative protective effect on various tissues. Here, we determined whether GLP-1 has a role in the pathogenesis of diabetic nephropathy using nephropathy resistant C57BL/6-Akita and nephropathy-prone KK/Ta-Akita mice. By in situ hybridization, we found the GLP-1 receptor (GLP-1R) expressed in glomerular capillary and vascular walls, but not in tubuli, in the mouse kidney. Next, we generated C57BL/6-Akita Glp1r knockout mice. These mice exhibited higher urinary albumin levels and more advanced mesangial expansion than wild-type C57BL/6-Akita mice, despite comparable levels of hyperglycemia. Increased glomerular superoxide, upregulated renal NAD(P)H oxidase, and reduced renal cAMP and protein kinase A (PKA) activity were noted in the Glp1r knockout C57BL/6-Akita mice. Treatment with the GLP-1R agonist liraglutide suppressed the progression of nephropathy in KK/Ta-Akita mice, as demonstrated by reduced albuminuria and mesangial expansion, decreased levels of glomerular superoxide and renal NAD(P)H oxidase, and elevated renal cAMP and PKA activity. These effects were abolished by an adenylate cyclase inhibitor SQ22536 and a selective PKA inhibitor H-89. Thus, GLP-1 has a crucial role in protection against increased renal oxidative stress under chronic hyperglycemia, by inhibition of NAD(P)H oxidase, a major source of superoxide, and by cAMP-PKA pathway activation. PMID- 24152969 TI - Triple infection with HIV-1, HTLV-1 and Strongyloides stercoralis, rendering CD4+ T-cell counts a misleading entity. AB - We report the case of a Gabonese HIV-patient who presented with haemoptysis, weight loss, fulminant diarrhoea and subsequent ileus and elevated CD4+ T-cell counts. He was diagnosed with Strongyloides stercoralis and human T-lymphotrophic virus type-1 infection. After treatment of the strongyloides hyperinfection syndrome, his CD4+ T-cell counts dropped greatly. The initially elevated CD4+ T cell counts were misleading to the clinicians with regard to decision-making on antiretroviral therapy initiation. PMID- 24152970 TI - Progress in cellular neurorestoratology: a brief introduction to the IANR supplement issue. PMID- 24152972 TI - Urgent Care: the evolution of a revolution. AB - The rapid and global growth of urgent care centers has had a revolutionary, though poorly understood, impact on the health care delivery system. The consumer driven care model inherent in urgent care and other so-called convenience care models is permeating into more conventional health care models. In addition, physician and hospital payment models are evolving, especially in the United States and are creating new market forces that will impact the organization and importance of integrated health care networks in the future. Together, these transformative changes are creating evolutionary pressures on traditional urgent care. Lessons learned from both the Israeli and American experience can be especially helpful for drafting a successful urgent care model for the future. This is a commentary on http://www.ijhpr.org/content/2/1/38/. PMID- 24152973 TI - Research gaps in understanding how climate change will affect arboviral diseases. AB - Climate change is widely expected to cause the emergence and spread of vector borne diseases, and predictive models are needed so that we can be prepared. We developed a climate-sensitive, predictive, model that describes the risk of bluetongue, an arboviral disease of ruminants, which has emerged dramatically in Europe. Developing the predictive bluetongue model led to the identification of numerous gaps in both the understanding and the availability of data. These mostly pertain to the vectors and their interaction with hosts. Closing these gaps will allow better models, with more precise predictions, to be produced. These research gaps apply to many other arboviral diseases as well. As a consequence, there needs to be an increase in research on the vectors that transmit arboviral diseases. Priorities are the training of a new generation of taxonomists, studies on the field biology of potential vectors, and increased coordination of vector surveillance and recording between countries facing similar threats. PMID- 24152971 TI - The angiogenic properties of mesenchymal stem/stromal cells and their therapeutic potential. AB - BACKGROUND: Blood vessel formation is fundamental to development, while its dysregulation can contribute to serious disease. Expectations are that hundreds of millions of individuals will benefit from therapeutic developments in vascular biology. MSCs are central to the three main vascular repair mechanisms. SOURCES OF DATA: Key recent published literature and ClinicalTrials.gov. AREAS OF AGREEMENT: MSCs are heterogeneous, containing multi-lineage stem and partly differentiated progenitor cells, and are easily expandable ex vivo. There is no single marker defining native MSCs in vivo. Their phenotype is strongly determined by their specific microenvironment. Bone marrow MSCs have skeletal stem cell properties. Having a perivascular/vascular location, they contribute to vascular formation and function and might be harnessed to regenerate a blood supply to injured tissues. AREAS OF CONTROVERSY: These include MSC origin, phenotype and location in vivo and their ability to differentiate into functional cardiomyocytes and endothelial cells or act as vascular stem cells. In addition their efficacy, safety and potency in clinical trials in relation to cell source, dose, delivery route, passage and timing of administration, but probably even more on the local preconditioning and the mechanisms by which they exert their effects. GROWING POINTS: Understanding the origin and the regenerative environment of MSCs, and manipulating their homing properties, proliferative ability and functionality through drug discovery and reprogramming strategies are important for their efficacy in vascular repair for regenerative medicine therapies and tissue engineering approaches. AREAS TIMELY FOR DEVELOPING RESEARCH: Characterization of MSCs' in vivo origins and biological properties in relation to their localization within tissue niches, reprogramming strategies and newer imaging/bioengineering approaches. PMID- 24152974 TI - Dementia care management: going new ways in ambulant dementia care within a GP based randomized controlled intervention trial. AB - BACKGROUND: Increasing prevalence of dementia is a major challenge for the German healthcare system. The study DelpHi-MV ("Dementia: life- and person-centered help in Mecklenburg-Western Pomerania") aims to implement and evaluate an innovative subsidiary support system for persons with dementia (PwDs) living at home and their caregivers. METHODS: DelpHi-MV is a GP-based cluster randomized controlled intervention trial. DelpHi-Intervention aims to provide "optimum care" by integrating multi-professional and multimodal strategies to individualize and optimize treatment of dementia within the framework of the established healthcare and social service system. The intervention is conducted by Dementia Care Managers (DCMs)--nurses with dementia-specific training--at the people's homes. Based on German guidelines for evidence-based diagnoses and treatment of dementia, a comprehensive set of 95 interventio--modules--the "DelpHi-Standard"- was defined. Each module consists of predefined trigger condition(s), a subsequent intervention task, as well as at least one criterion for its completion. The intervention begins with a comprehensive assessment of the care situation, needs, and resources. The DCM develops and implements an intervention plan tailored to the individual conditions in close cooperation with the GP. EXPECTED RESULTS AND CONCLUSIONS: We expect statistically significant differences between control and intervention group in primary outcomes (quality of life, behavioral and psychological symptoms of dementia, pharmacotherapy, caregiver burden). Results can provide evidence for the effectiveness and efficacy of dementia care management according to the "Delphi-Standard"--prerequisites for implementing this concept into routine healthcare. PMID- 24152975 TI - Dying of brain tumours: specific aspects of care. AB - PURPOSE OF REVIEW: Patients with brain tumours show a high symptom burden, and symptoms are difficult to treat and prone to be overlooked. This review of publications dealing with advanced stages of brain tumours tries to assess the knowledge gained in the past 2 years and to develop an outlook for further investigations. RECENT FINDINGS: We searched for publications on advanced brain tumours in a palliative medicine setting. Of 138 publications retrieved by search in PubMed, 22 publications met our criteria for inclusion. We predefined categories of interest: epidemiology and treatment of symptoms; quality of life; and impact on next of kin, caregivers, medico-social system and decision-making. SUMMARY: Data suggest that patients with primary or metastatic brain tumours often have a high symptom burden and unmet needs for palliative care, and symptoms are hard to diagnose; patients suffer often and early from cognitive impairment but are rarely appropriately prepared concerning end-of-life wishes. This reflects on their caregivers' burden as well. For symptomatic treatment of common symptoms such as fatigue, depression and cognitive impairment, methylphenidate has established an important role. For assessment of these symptoms, a shortened questionnaire Quality of Life Questionnaire-15-Palliative shows potential. Cancer-directed therapy in advanced stages of brain tumours has to be weighed critically. To assess adequate strategies to help patients and caregivers with the challenges of brain tumour-specific symptoms, randomized intervention studies are necessary. The same accounts for cancer-directed treatment in relation to quality of life in advanced stages of brain tumours. PMID- 24152976 TI - Artificial nutrition in old patients dying of dementia. AB - PURPOSE OF REVIEW: The aim of the review is to show main and recent evidence on and tendencies about artificial nutrition in advanced dementia. RECENT FINDINGS: Several studies in the last decade had been performed to provide evidence that supports lack of benefits or improvements in many aspects about caring of the elderly with advanced dementia. In spite of the evidence, we find an increased number of patients still submitted to artificial nutrition. There is high prevalence of misperceptions and misbeliefs about artificial nutrition among healthcare professionals in this scenario. Hand feeding for these patients is offered as an alternative arrangement, which may be characterized as dilemma. The decision-making process in artificial nutrition is considered as a difficult, complex and distressful issue, which addresses new strategies for improvement. SUMMARY: Despite the lack of evidence of benefits, the use of artificial nutrition remains commonplace in advanced dementia. Patient's wishes and family values should be taken into account in the decision-making process, as well as legal and ethical issues. Communication skills and acknowledgment of recent evidence are essential in decision-making in order to achieve the patient's best interests. Educational strategies and randomized prospective studies concerned about dying patients with advanced dementia are required. PMID- 24152977 TI - Advance directives in the context of end-of-life palliative care. AB - PURPOSE OF REVIEW: To review the definition of advanced directive, understand the implications for the patient, family and healthcare team, and address the obstacles involved in the implementation. RECENT FINDINGS: Advanced directives propose a model of healthcare based on patient preferences. Although there is sufficient evidence related to their usefulness, various factors are known to affect the use of advanced directives. Therefore, rules need to be established in order to optimize the implementation process. SUMMARY: An advanced directive is a legal document based on the principle of autonomy that expresses the desire of the patient in relation to different medical treatments when the patient is unable to make those decisions. The advanced directives are represented in three formats: Living Will, Appointment of a Healthcare Proxy and Legal Status of Preferences. The uses of advanced directives have an impact not only on the patients and their families, but also on the healthcare team. Despite their utility being well known, there are several general barriers that affect implementation, as well as factors related to characteristics of each study population. PMID- 24152978 TI - [Pathophysiology of bone metastases and new molecular targets involved in bone remodelling]. AB - Bone metastases are common complications of cancers. These skeletal lesions are usually osteolytic (excess of bone destruction), osteosclerostic (excess of bone formation) or mixed. Metastatic cancer cells residing in the bone marrow alter the functions of bone-resorbing (osteoclasts) and bone-forming (osteoblasts) cells and hijack signals coming from the bone matrix. In this review, we first described cellular and molecular mechanisms that drive cancer cells to colonize the bone marrow. We next show how cancer cells alter bone remodelling to promote the formation of osteolytic or osteosclerotic lesions. PMID- 24152979 TI - The impact on patient health and service outcomes of introducing nurse consultants: a historically matched controlled study. AB - BACKGROUND: The position of nurse consultant (NC) was introduced in Hong Kong by the Hospital Authority in January 2009. Seven NCs were appointed in five clinical specialties: diabetes, renal, wound and stoma care, psychiatrics, and continence. This was a pilot to explore the impact of the introduction of NCs on patient health and service outcomes. METHODS: The present paper describes a historically matched controlled study. A total of 280 patients, 140 in each cohort under NC or non-NC care, participated in the study. The patient health and service outcomes of both cohorts were evaluated and compared: accident and emergency visits, hospital admissions, length of hospital stays, number of acute complications, number of times of treatment or regimen altered by nurses according to patient's condition, glycated haemoglobin A1c (HbA1c) levels, urea and urea-to-creatinine ratios, and number of wound dressings for patients in corresponding specialty units. A patient satisfaction instrument was also used to assess the NC cohort. RESULTS: The study showed that patients under NC care had favourable patient health and service outcomes compared with those under non-NC care. The NC cohort also reported a high level of patient satisfaction. CONCLUSIONS: The study demonstrates that the introduction of NCs in specialty units may have a positive impact on patients' health and service outcomes. The high level of patient satisfaction scores indicates that patients appreciate the care they are receiving with the introduction of NCs. PMID- 24152980 TI - An updated review of target-specific oral anticoagulants used in stroke prevention in atrial fibrillation, venous thromboembolic disease, and acute coronary syndromes. PMID- 24152981 TI - Changes in lipoprotein-Associated phospholipase A2 activity predict coronary events and partly account for the treatment effect of pravastatin: results from the Long-Term Intervention with Pravastatin in Ischemic Disease study. AB - BACKGROUND: Lipoprotein-associated phospholipase A2 (Lp-PLA2) levels are associated with coronary heart disease (CHD) in healthy individuals and in patients who have had ischemic events. METHODS AND RESULTS: The Long-term Intervention with Pravastatin in Ischemic Disease (LIPID) study randomized 9014 patients with cholesterol levels of 4.0 to 7.0 mmol/L to placebo or pravastatin 3 to 36 months after myocardial infarction or unstable angina and showed a reduction in CHD and total mortality. We assessed the value of baseline and change in Lp-PLA2 activity to predict outcomes over a 6-year follow-up, the effect of pravastatin on Lp-PLA2 levels, and whether pravastatin treatment effect was related to Lp-PLA2 activity change. Lp-PLA2 was measured at randomization and 1 year, and levels were grouped as quartiles. The prespecified end point was CHD death or nonfatal myocardial infarction. Baseline Lp-PLA2 activity was positively associated with CHD events (P < 0.001) but not after adjustment for 23 baseline factors (P = 0.66). In 6518 patients who were event free at 1 year, change in Lp PLA2 was a significant independent predictor of subsequent CHD events after adjustment for these risk factors, including LDL cholesterol and LDL cholesterol changes (P < 0.001). Pravastatin reduced Lp-PLA2 by 16% compared with placebo (P < 0.001). After adjustment for Lp-PLA2 change, the pravastatin treatment effect was reduced from 23% to 10% (P = 0.26), with 59% of the treatment effect accounted for by changes in Lp-PLA2. Similar reductions in treatment effect were seen after adjustment for LDL cholesterol change. CONCLUSION: Reduction in Lp PLA2 activity during the first year was a highly significant predictor of CHD events, independent of change in LDL cholesterol, and may account for over half of the benefits of pravastatin in the LIPID study. PMID- 24152982 TI - Plasma free H2S levels are elevated in patients with cardiovascular disease. AB - BACKGROUND: Hydrogen sulfide (H2S) has been implicated in regulating cardiovascular pathophysiology in experimental models. However, there is a paucity of information regarding the levels of H2S in health and cardiovascular disease. In this study we examine the levels of H2S in patients with cardiovascular disease as well as bioavailability of nitric oxide and inflammatory indicators. METHODS AND RESULTS: Patients over the age of 40 undergoing coronary or peripheral angiography were enrolled in the study. Ankle brachial index (ABI) measurement, measurement of plasma-free H2S and total nitric oxide (NO), thrombospondin-1 (TSP-1), Interleukin-6 (IL-6), and soluble intercellular adhesion molecule-1 (sICAM-1) levels were performed. Patients with either coronary artery disease alone (n = 66), peripheral arterial disease (PAD) alone (n = 13), or any vascular disease (n = 140) had higher plasma-free H2S levels compared to patients without vascular disease (n = 53). Plasma-free H2S did not distinguish between disease in different vascular beds; however, total NO levels were significantly reduced in PAD patients and the ratio of plasma free H2S to NO was significantly greater in patients with PAD. Lastly, plasma IL-6, ICAM-1, and TSP-1 levels did not correlate with H2S or NO bioavailability in either vascular disease condition. CONCLUSIONS: Findings reported in this study reveal that plasma-free H2S levels are significantly elevated in vascular disease and identify a novel inverse relationship with NO bioavailability in patients with peripheral arterial disease. PMID- 24152984 TI - Pathogenesis of chagas cardiomyopathy: role of inflammation and oxidative stress. PMID- 24152983 TI - Prokineticin receptor-1 is a new regulator of endothelial insulin uptake and capillary formation to control insulin sensitivity and cardiovascular and kidney functions. AB - BACKGROUND: Reciprocal relationships between endothelial dysfunction and insulin resistance result in a vicious cycle of cardiovascular, renal, and metabolic disorders. The mechanisms underlying these impairments are unclear. The peptide hormones prokineticins exert their angiogenic function via prokineticin receptor 1 (PKR1). We explored the extent to which endothelial PKR1 contributes to expansion of capillary network and the transcapillary passage of insulin into the heart, kidney, and adipose tissues, regulating organ functions and metabolism in a specific mice model. METHODS AND RESULTS: By combining cellular studies and studies in endothelium-specific loss-of-function mouse model (ec-PKR1-/-), we showed that a genetically induced PKR1 loss in the endothelial cells causes the impaired capillary formation and transendothelial insulin delivery, leading to insulin resistance and cardiovascular and renal disorders. Impaired insulin delivery in endothelial cells accompanied with defective expression and activation of endothelial nitric oxide synthase in the ec-PKR1-/- aorta, consequently diminishing endothelium-dependent relaxation. Despite having a lean body phenotype, ec-PKR1-/- mice exhibited polyphagia, polydipsia, polyurinemia, and hyperinsulinemia, which are reminiscent of human lipodystrophy. High plasma free fatty acid levels and low leptin levels further contribute to the development of insulin resistance at the later age. Peripheral insulin resistance and ectopic lipid accumulation in mutant skeletal muscle, heart, and kidneys were accompanied by impaired insulin-mediated Akt signaling in these organs. The ec PKR1-/- mice displayed myocardial fibrosis, low levels of capillary formation, and high rates of apoptosis, leading to diastolic dysfunction. Compact fibrotic glomeruli and high levels of phosphate excretion were found in mutant kidneys. PKR1 restoration in ec-PKR1-/- mice reversed the decrease in capillary recruitment and insulin uptake and improved heart and kidney function and insulin resistance. CONCLUSIONS: We show a novel role for endothelial PKR1 signaling in cardiac, renal, and metabolic functions by regulating transendothelial insulin uptake and endothelial cell proliferation. Targeting endothelial PKR1 may serve as a therapeutic strategy for ameliorating these disorders. PMID- 24152985 TI - Searching for sudden death snps in calcium handling genes. PMID- 24152987 TI - Comparison of clean-up methods for ochratoxin A on wine, beer, roasted coffee and chili commercialized in Italy. AB - The most common technique used to detect ochratoxin A (OTA) in food matrices is based on extraction, clean-up, and chromatography detection. Different clean-up cartridges, such as immunoaffinity columns (IAC), molecular imprinting polymers (MIP), MycosepTM 229, MycospinTM, and Oasis(r) HLB (Hydrophilic Lipophilic balance) as solid phase extraction were tested to optimize the purification for red wine, beer, roasted coffee and chili. Recovery, reproducibility, reproducibility, limit of detection (LOD) and limit of quantification (LOQ) were calculated for each clean-up method. IAC demonstrated to be suitable for OTA analysis in wine and beer with recovery rate >90%, as well as MycosepTM for wine and chili. On the contrary, MIP columns were the most appropriate to clean up coffee. A total of 120 samples (30 wines, 30 beers, 30 roasted coffee, 30 chili) marketed in Italy were analyzed, by applying the developed clean-up methods. Twenty-seven out of 120 samples analyzed (22.7%: two wines, five beers, eight coffees, and 12 chili) resulted positive to OTA. A higher incidence of OTA was found in chili (40.0%) more than wine (6.6%), beers (16.6%) and coffee (26.6%). Moreover, OTA concentration in chili was the highest detected, reaching 47.8 ug/kg. Furthermore, three samples (2.5%), two wines and one chili, exceeded the European threshold. PMID- 24152986 TI - Toxicity of ochratoxin a and its modulation by antioxidants: a review. AB - Ochratoxin A (OTA) is a mycotoxin involved in the development of different types of cancers in rats, mice and humans. A growing number of in vitro and in vivo studies has been collected and has described evidence compatible with a role for oxidative stress in OTA toxicity and carcinogenicity. Because the contribution of the oxidative stress response in the development of cancers is well established, a role in OTA carcinogenicity is plausible. Several studies have been performed to try to counteract the adverse effects of oxygen radicals generated under OTA exposure. A number of molecules with various antioxidant properties were tested, using in vivo or in vitro models. Protection against OTA-induced DNA damage, lipid peroxidation, as well as cytotoxicity were observed, further confirming the link between OTA toxicity and oxidative damage. These studies demonstrated that antioxidants are able to counteract the deleterious effects of chronic consumption or exposure to OTA and confirmed the potential effectiveness of dietary strategies to counteract OTA toxicity. PMID- 24152988 TI - Mouse in vivo neutralization of Escherichia coli Shiga toxin 2 with monoclonal antibodies. AB - Shiga toxin-producing Escherichia coli (STEC) food contaminations pose serious health concerns, and have been the subject of massive food recalls. STEC has been identified as the major cause of the life-threatening complication of hemolytic uremic syndrome (HUS). Besides supportive care, there currently are no therapeutics available. The use of antibiotics for combating pathogenic E. coli is not recommended because they have been shown to stimulate toxin production. Clearing Stx2 from the circulation could potentially lessen disease severity. In this study, we tested the in vivo neutralization of Stx2 in mice using monoclonal antibodies (mAbs). We measured the biologic half-life of Stx2 in mice and determined the distribution phase or t(1/2) alpha to be 3 min and the clearance phase or t(1/2) beta to be 40 min. Neutralizing mAbs were capable of clearing Stx2 completely from intoxicated mouse blood within minutes. We also examined the persistence of these mAbs over time and showed that complete protection could be passively conferred to mice 4 weeks before exposure to Stx2. The advent of better diagnositic methods and the availability of a greater arsenal of therapeutic mAbs against Stx2 would greatly enhance treatment outcomes of life threatening E. coli infections. PMID- 24152989 TI - Assessment of the functional regions of the superantigen staphylococcal enterotoxin B. AB - The functional activity of superantigens is based on capacity of these microbial proteins to bind to both the beta-chain of the T cell receptor (TcR) and the major histocompatibility complex (MHC) class II dimer. We have previously shown that a subset of the bacterial superantigens also binds to a membrane protein, designated p85, which is expressed by renal epithelial cells. This binding activity is a property of SEB, SEC1, 2 and 3, but not SEA, SED, SEE or TSST. The crystal structure of the tri-molecular complex of the superantigen staphylococcal enterotoxin B (SEB) with both the TcR and class II has previously been reported. However, the relative contributions of regions of the superantigen to the overall functional activity of this superantigen remain undefined. In an effort to better define the molecular basis for the interaction of SEB with the TcR beta-chain, we report studies here which show the comparative contributions of amino- and carboxy-terminal regions in the superantigen activity of SEB. Recombinant fusion proteins composed of bacterial maltose-binding protein linked to either full length or truncated toxins in which the 81 N-terminal, or 19 or 34 C-terminal amino acids were deleted, were generated for these studies. This approach provides a determination of the relative strength of the functional activity of the various regions of the superantigen protein. PMID- 24152990 TI - Aflatoxin, fumonisin and Shiga toxin-producing Escherichia coli infections in calves and the effectiveness of Celmanax(r)/Dairyman's ChoiceTM applications to eliminate morbidity and mortality losses. AB - Mycotoxin mixtures are associated with Shiga toxin-producing Escherichia coli (STEC) infections in mature cattle. STEC are considered commensal bacteria in mature cattle suggesting that mycotoxins provide a mechanism that converts this bacterium to an opportunistic pathogen. In this study, we assessed the mycotoxin content of hemorrhaged mucosa in dairy calves during natural disease outbreaks, compared the virulence genes of the STECs, evaluated the effect of the mucosal mycotoxins on STEC toxin expression and evaluated a Celmanax(r)/Dairyman's ChoiceTM application to alleviate disease. As for human infections, the OI-122 encoded nleB gene was common to STEC genotypes eliciting serious disease. Low levels of aflatoxin (1-3 ppb) and fumonisin (50-350 ppb) were detected in the hemorrhaged mucosa. Growth of the STECs with the mycotoxins altered the secreted protein concentration with a corresponding increase in cytotoxicity. Changes in intracellular calcium indicated that the mycotoxins increased enterotoxin and pore-forming toxin activity. A prebiotic/probiotic application eliminated the morbidity and mortality losses associated with the STEC infections. Our study demonstrates: the same STEC disease complex exists for immature and mature cattle; the significance of the OI-122 pathogenicity island to virulence; the significance of mycotoxins to STEC toxin activity; and, finally, provides further evidence that prebiotic/probiotic applications alleviate STEC shedding and mycotoxin/STEC interactions that lead to disease. PMID- 24152991 TI - Cyanobacteria and cyanotoxins: from impacts on aquatic ecosystems and human health to anticarcinogenic effects. AB - Cyanobacteria or blue-green algae are among the pioneer organisms of planet Earth. They developed an efficient photosynthetic capacity and played a significant role in the evolution of the early atmosphere. Essential for the development and evolution of species, they proliferate easily in aquatic environments, primarily due to human activities. Eutrophic environments are conducive to the appearance of cyanobacterial blooms that not only affect water quality, but also produce highly toxic metabolites. Poisoning and serious chronic effects in humans, such as cancer, have been described. On the other hand, many cyanobacterial genera have been studied for their toxins with anticancer potential in human cell lines, generating promising results for future research toward controlling human adenocarcinomas. This review presents the knowledge that has evolved on the topic of toxins produced by cyanobacteria, ranging from their negative impacts to their benefits. PMID- 24152992 TI - Effect of thioridazine on erythrocytes. AB - BACKGROUND: Thioridazine, a neuroleptic phenothiazine with antimicrobial efficacy is known to trigger anemia. At least in theory, the anemia could result from stimulation of suicidal erythrocyte death or eryptosis, which is characterized by cell shrinkage and by phospholipid scrambling of the cell membrane with phosphatidylserine exposure at the erythrocyte surface. Triggers of eryptosis include increase of cytosolic Ca2+-concentration ([Ca2+](i)) and activation of p38 kinase. The present study explored, whether thioridazine elicits eryptosis. METHODS: [Ca2+](i) has been estimated from Fluo3-fluorescence, cell volume from forward scatter, phosphatidylserine exposure from annexin-V-binding, and hemolysis from hemoglobin release. RESULTS: A 48 hours exposure to thioridazine was followed by a significant increase of [Ca2+](i) (30 uM), decrease of forward scatter (30 uM), and increase of annexin-V-binding (>=12 uM). Nominal absence of extracellular Ca2+ and p38 kinase inhibitor SB203580 (2 uM) significantly blunted but did not abolish annexin-V-binding following thioridazine exposure. CONCLUSIONS: Thioridazine stimulates eryptosis, an effect in part due to entry of extracellular Ca2+ and activation of p38 kinase. PMID- 24152994 TI - A flexible mouse-on-mouse immunohistochemical staining technique adaptable to biotin-free reagents, immunofluorescence, and multiple antibody staining. AB - Immunohistochemistry on mouse tissue utilizing mouse monoclonal antibodies presents a challenge. Secondary antibodies directed against the mouse monoclonal primary antibody of interest will also detect endogenous mouse immunoglobulin in the tissue. This can lead to significant spurious staining. Therefore, a "mouse on-mouse" staining strategy is needed to yield credible data. This paper presents a method that is easy to use and highly flexible to accommodate both an avidin biotin detection system as well as a biotin-free polymer detection system. The mouse primary antibody is first combined with an Fab fragment of an anti-mouse antibody in a tube and allowed sufficient time to form an antibody complex. Any non-complexed secondary antibody is bound up with mouse serum. The mixture is then applied to the tissue. The flexibility of this method is confirmed with the use of different anti-mouse antibodies followed by a variety of detection reagents. These techniques can be used for immunohistochemistry (IHC), immunofluorescence (IF), as well as staining with multiple primary antibodies. This method has also been adapted to other models, such as using human antibodies on human tissue and using multiple rabbit antibodies in dual immunofluorescence. PMID- 24152993 TI - KSGal6ST is essential for the 6-sulfation of galactose within keratan sulfate in early postnatal brain. AB - Keratan sulfate (KS) comprises repeating disaccharides of galactose (Gal) and N acetylglucosamine (GlcNAc). Residues of Gal and GlcNAc in KS are potentially modified with sulfate at their C-6 positions. The 5D4 monoclonal antibody recognizes KS structures containing Gal and GlcNAc, both 6-sulfated, and has been used most extensively to evaluate KS expression in mammalian brains. We previously showed that GlcNAc6ST1 is an enzyme responsible for the synthesis of the 5D4 epitope in developing brain and in the adult brain, where it is induced after injury. It has been unclear which sulfotransferase is responsible for Gal-6 sulfation within the 5D4 KS epitope in developing brains. We produced mice deficient in KSGal6ST, a Gal-6-sulfotransferase. Western blotting and immunoprecipitation revealed that all 5D4-immunoreactivity to proteins, including phosphacan, were abolished in KSGal6ST-deficient postnatal brains. Likewise, the 5D4 epitope, expressed primarily in the cortical marginal zone and subplate and dorsal thalamus, was eliminated in KSGal6ST-deficient mice. Disaccharide analysis showed the loss of Gal-6-sulfate in KS of the KSGal6ST-deficient brains. Transfection studies revealed that GlcNAc6ST1 and KSGal6ST cooperated in the expression of the 5D4 KS epitope in HeLa cells. These results indicate that KSGal6ST is essential for C-6 sulfation of Gal within KS in early postnatal brains. PMID- 24152996 TI - Prevalence of Exclusive Breastfeeding Practices and associated factors among mothers in Bahir Dar city, Northwest Ethiopia: a community based cross-sectional study. AB - BACKGROUND: Breastfeeding is an unequalled way of providing ideal food for the healthy growth and development of infants. World Health Organization (WHO) recommend exclusive breastfeeding (EBF) for six months which has a great contribution in reducing under five mortality, which otherwise leads to death of 88/1000 live birth yearly in Ethiopia. Hence, this study aimed to assess prevalence of EBF and associated factors in mothers in the city of Bahir Dar, Northwest Ethiopia. METHODS: A community-based cross-sectional study was conducted from 10 to 25 June 2012 among mothers who delivered 12 months earlier in Bahir Dar city, Northwest Ethiopia. A cluster sampling technique was used to select a sample of 819 participants. Data were collected using a structured and pre-tested questionnaire by face-to-face interview technique. Bivariate and multivariate analyses were performed to check associations and control confounding. RESULTS: Of 819 mother-infant pairs sampled, the overall age appropriate rate of EBF practice was found to be 50.3%. Having a young infant aged 0-1 month (AOR = 3.77, 95% CI = 1.54, 9.24) and 2-3 months (AOR = 2.80, 95% CI = 1.71, 4.58), being a housewife (AOR = 2.16, 95% CI = 1.48, 3.16), having prenatal EBF plan (AOR = 3.75, 95% CI = 2.21, 6.37), delivering at a health facility (AOR = 3.02, 95% CI = 1.55, 5.89), giving birth vaginally (AOR = 2.33, 95% CI = 1.40, 3.87) and receiving infant feeding counseling/advice (AOR = 5.20, 95% CI = 2.13, 12.68) were found to be significantly associated with EBF practice. CONCLUSION: Prevalence of exclusive breastfeeding was low in Bahir Dar. Strengthening infant feeding advice/counseling both at the community and institutional levels, promoting institutional delivery, providing adequate pain relief and early assistance for mothers who gave birth by caesarean section, and enabling every mother a prenatal EBF plan during antenatal care were recommended in order to increase the proportion of women practicing EBF. PMID- 24152995 TI - Peroxiredoxin I and II in human eyes: cellular distribution and association with pterygium and DNA damage. AB - Peroxiredoxin I and II are both 2-Cys members of the peroxiredoxin family of antioxidant enzymes and inactivate hydrogen peroxide. On western blotting, both enzymes appeared as 22-kD proteins and were present in the sclera, retina and iris. Immunohistochemistry showed strong cytoplasmic labeling in the basal cells of the corneal epithelial layer and the corneoscleral limbus. The melanocytes within the stroma of the iris and the anterior epithelial cells of the lens also showed strong cytoplasmic labeling. The fibrous structure of the stroma and the posterior surface of the ciliary body were also labeled. There was also strong labeling for both enzymes in the photoreceptors and the inner and outer plexiform layers of the retina. There was increased labeling of peroxiredoxin I and II in pterygium. In normal conjunctiva and cornea, only the basal cell layer showed labeling for peroxiredoxin I and II, whereas, in pterygia, there was strong cytoplasmic labeling in most cells involving the full thickness of the epithelium. Co-localization of the DNA oxidation product 8-hydroxy-2' deoxyguanosine antibody with the nuclear dye 4',6'-diamidino-2-phenylindole dihydrochloride indicated that the majority of the oxidative damage was cytoplasmic; this suggested that the mitochondrial DNA was most affected by the UV radiation in this condition. PMID- 24152997 TI - Effects of deep cervical flexor training on pressure pain thresholds over myofascial trigger points in patients with chronic neck pain. AB - OBJECTIVE: The purpose of this study was to assess the effects of a low-load training program for the deep cervical flexors (DCFs) on pain, disability, and pressure pain threshold (PPT) over cervical myofascial trigger points (MTrPs) in patients with chronic neck pain. METHODS: Thirty patients with chronic idiopathic neck pain participated in a 6-week program of specific training for the DCF, which consisted of active craniocervical flexion performed twice per day (10-20 minutes) for the duration of the trial. Perceived pain and disability (Neck Disability Index, 0-50) and PPT over MTrPs of the upper trapezius, levator scapulae, and splenius capitis muscles were measured at the beginning and end of the training period. RESULTS: After completion of training, there was a significant reduction in Neck Disability Index values (before, 18.2 +/- 12.1; after, 13.5 +/- 10.6; P < .01). However, no significant changes in PPT were observed over the MTrPs. CONCLUSION: Patients performing DCF training for 6 weeks demonstrated reductions in pain and disability but did not show changes in pressure pain sensitivity over MTrPs in the splenius capitis, levator scapulae, or upper trapezius muscles. PMID- 24152998 TI - Lean mass inversely predicts plasma glucose levels after oral glucose load independent of insulin secretion or insulin sensitivity in glucose intolerance subjects. AB - Muscle mass inversely relates to 2 hours glucose levels after oral glucose load in non-diabetic subjects. A study in glucose intolerance subjects has never been performed. We conducted this study to determine the relationship between muscle mass and glucose level after oral glucose load in glucose intolerance subjects. Sixty Thai subjects, 44 drug-naive, newly diagnosed type 2 diabetes mellitus and 16 impaired glucose tolerance were studied. The 180 min 75 g oral glucose tolerance test was performed. Total body fat and lean mass were measured by dual energy x-ray absorptiometry. Insulin sensitivity was determined by insulin sensitivity index using model of Matsuda & DeFronzo. The 1st-phase and total insulin secretion were determined from glucose tolerance data. Pearson correlation and linear regression were used for the analysis. Lean mass was inversely correlated with area-under-curves of glucose 0-180 min (r =-0.320; p=0.013). The relationship was significant after adjustment with age and body mass-index (r =-0.350; p=0.007). Area-under-curves of glucose 0-180 min was correlated with height (r =-0.282; p=0.029), fasting glucose (r =0.742; p<0.0001), log area-under-curves of insulin 0-180 min (r =-0.258; p=0.047) and log 1st-phase insulin secretion (r =-0.518; p<0.0001). By multivariate analysis, fasting glucose (standardized beta=4.54; p<0.001), log 1st-phase insulin secretion (standardized beta=-43.09; p=0.005) and lean mass (standardized beta= 0.003; p=0.011) were the significant parameters predicting area-under-curves of glucose 0-180 min. In conclusion, lean mass inversely predicted glucose levels after oral glucose load independent of insulin secretion and insulin sensitivity in glucose intolerance subjects. PMID- 24152999 TI - A MEN2A family with two asymptomatic carriers affected by unilateral renal agenesis. AB - Accumulating evidences suggest RET gene's involvement in development of the kidney in mice and humans. Although it is well known that RET mutation causes multiple endocrine neoplasia type 2A (MEN2A), thus far only 3 individuals have been reported to have MEN2A and renal agenesis/dysgenesis. We report a MEN2A family with RET mutation in which two asymptomatic carriers presented with unilateral renal agenesis. A 48-year-old woman underwent total thyroidectomy with regional lymph node dissection in our department for medullary thyroid carcinoma. She had earlier surgical treatment for a left adrenal pheochromocytoma at the age of 45. In the screening for MEN type 2 for her three sons, a CT scan for adrenal pheochromocytoma incidentally found unilateral renal agenesis in two of the sons, one of whom had suffered from Hirschsprung's disease (HSCR). They had contralateral kidneys exhibiting compensatory hypertrophy and normal renal function. Genetic analysis detected C618R RET mutation in the proband and her 3 sons, and no other mutations were found in RET as well as glial cell line-derived neurotrophic factor (GDNF). Our data lend support to the hypothesis that constitutive active RET mutation in MEN type 2 might partially impair RET function and thereby cause loss of function phenotype such as renal agenesis or HSCR. PMID- 24153000 TI - The evolution of non-diabetic hyperglycemia: a longitudinal study. AB - The risk factors for impaired fasting glucose (IFG) and impaired glucose tolerance (IGT) have yet to be established. Our aim was to elucidate the predisposing factors for IFG and IGT in Japanese subjects with normal glucose tolerance (NGT). Using a 75 g oral glucose tolerance test (OGTT), we analyzed 604 adults with the ADA-defined NGT. Follow-up glucose tolerance status was determined by 75 g OGTT performed 3.7 yrs later. Glucose-stimulated insulin secretion (GSIS), whole body insulin sensitivity (SI) and beta cell function (BCF) were estimated by Stumvoll indices, ISI(Matsuda), and a product of Stumvoll 1(st) and ISI(Matsuda), respectively, and hepatic SI by quantitative insulin sensitivity check index. Logistic regression analysis revealed that attenuated BCF due to low GSIS was an independent risk factor for IFG. Low whole body SI was an additional risk for IGT. Male gender and high BMI were independently related to the progression to both IFG and IGT, whereas a positive diabetes family history was independently related to IGT. The worsening of glucose tolerance at large was predicted with 66% sensitivity by risk engine with GSIS, whole body SI, gender, BMI and glucose. This finding may help when implementing early intervention strategies for diabetes. PMID- 24153001 TI - Evaluation of a family intervention programme for the treatment of overweight and obese children (Nereu Programme): a randomized clinical trial study protocol. AB - BACKGROUND: Obesity is mainly attributed to environmental factors. In developed countries, the time spent on physical activity tasks is decreasing, whereas sedentary behaviour patterns are increasing.The purpose of the intervention is to evaluate the effectiveness of an intensive family-based behavioural multi component intervention (Nereu programme) and compared it to counselling intervention such as a health centre intervention programme for the management of children's obesity. METHODS/DESIGN: The study design is a randomized controlled multicenter clinical trial using two types of interventions: Nereu and Counselling. The Nereu programme is an 8-month intensive family-based multi component behavioural intervention. This programme is based on a multidisciplinary intervention consisting of 4 components: physical activity sessions for children, family theoretical and practical sessions for parents, behaviour strategy sessions involving both, parents and children, and lastly, weekend extra activities for all. Counselling is offered to the family in the form of a monthly physical health and eating habits session. Participants will be recruited according the following criteria: 6 to 12 year-old-children, referred from their paediatricians due to overweight or obesity according the International Obesity Task Force criteria and with a sedentary profile (less than 2 hours per week of physical activity), they must live in or near the municipality of Lleida (Spain) and their healthcare paediatric unit must have previously accepted to cooperate with this study. The following variables will be evaluated: a) cardiovascular risk factors (anthropometric parameters, blood test and blood pressure), b) sedentary and physical activity behaviour and dietary intake, c) psychological aspects d) health related quality of life (HRQOL), e) cost-effectiveness of the intervention in relation to HRQOL. These variables will be then be evaluated 4 times longitudinally: at baseline, at the end of the intervention (8 months later), 6 and 12 months after the intervention. We have considered necessary to recruit 100 children and divide them in 2 groups of 50 to detect the differences between the groups. DISCUSSION: This trial will provide new evidence for the long-term effects of childhood obesity management, as well as help to know the impact of the present intervention as a health intervention tool for healthcare centres. TRIAL REGISTRATION: ClinicalTrials.gov, NCT01878994. PMID- 24153002 TI - Microcephaly models in the developing zebrafish retinal neuroepithelium point to an underlying defect in metaphase progression. AB - Autosomal recessive primary microcephaly (MCPH) is a congenital disorder characterized by significantly reduced brain size and mental retardation. Nine genes are currently known to be associated with the condition, all of which encode centrosomal or spindle pole proteins. MCPH is associated with a reduction in proliferation of neural progenitors during fetal development. The cellular mechanisms underlying the proliferation defect, however, are not fully understood. The zebrafish retinal neuroepithelium provides an ideal system to investigate this question. Mutant or morpholino-mediated knockdown of three known MCPH genes (stil, aspm and wdr62) and a fourth centrosomal gene, odf2, which is linked to several MCPH proteins, results in a marked reduction in head and eye size. Imaging studies reveal a dramatic rise in the fraction of proliferating cells in mitosis in all cases, and time-lapse microscopy points to a failure of progression through prometaphase. There was also increased apoptosis in all the MCPH models but this appears to be secondary to the mitotic defect as we frequently saw mitotically arrested cells disappear, and knocking down p53 apoptosis did not rescue the mitotic phenotype, either in whole retinas or clones. PMID- 24153003 TI - A novel taxonomic marker that discriminates between morphologically complex actinomycetes. AB - In the era when large whole genome bacterial datasets are generated routinely, rapid and accurate molecular systematics is becoming increasingly important. However, 16S ribosomal RNA sequencing does not always offer sufficient resolution to discriminate between closely related genera. The SsgA-like proteins are developmental regulatory proteins in sporulating actinomycetes, whereby SsgB actively recruits FtsZ during sporulation-specific cell division. Here, we present a novel method to classify actinomycetes, based on the extraordinary way the SsgA and SsgB proteins are conserved. The almost complete conservation of the SsgB amino acid (aa) sequence between members of the same genus and its high divergence between even closely related genera provides high-quality data for the classification of morphologically complex actinomycetes. Our analysis validates Kitasatospora as a sister genus to Streptomyces in the family Streptomycetaceae and suggests that Micromonospora, Salinispora and Verrucosispora may represent different clades of the same genus. It is also apparent that the aa sequence of SsgA is an accurate determinant for the ability of streptomycetes to produce submerged spores, dividing the phylogenetic tree of streptomycetes into liquid culture sporulation and no liquid-culture sporulation branches. A new phylogenetic tree of industrially relevant actinomycetes is presented and compared with that based on 16S rRNA sequences. PMID- 24153004 TI - Pleiotropic regulatory genes bldA, adpA and absB are implicated in production of phosphoglycolipid antibiotic moenomycin. AB - Unlike the majority of actinomycete secondary metabolic pathways, the biosynthesis of peptidoglycan glycosyltransferase inhibitor moenomycin in Streptomyces ghanaensis does not involve any cluster-situated regulators (CSRs). This raises questions about the regulatory signals that initiate and sustain moenomycin production. We now show that three pleiotropic regulatory genes for Streptomyces morphogenesis and antibiotic production-bldA, adpA and absB-exert multi-layered control over moenomycin biosynthesis in native and heterologous producers. The bldA gene for tRNA(Leu)UAA is required for the translation of rare UUA codons within two key moenomycin biosynthetic genes (moe), moeO5 and moeE5. It also indirectly influences moenomycin production by controlling the translation of the UUA-containing adpA and, probably, other as-yet-unknown repressor gene(s). AdpA binds key moe promoters and activates them. Furthermore, AdpA interacts with the bldA promoter, thus impacting translation of bldA dependent mRNAs-that of adpA and several moe genes. Both adpA expression and moenomycin production are increased in an absB-deficient background, most probably because AbsB normally limits adpA mRNA abundance through ribonucleolytic cleavage. Our work highlights an underappreciated strategy for secondary metabolism regulation, in which the interaction between structural genes and pleiotropic regulators is not mediated by CSRs. This strategy might be relevant for a growing number of CSR-free gene clusters unearthed during actinomycete genome mining. PMID- 24153006 TI - Invasive Candidiasis in preterm neonates in China: a retrospective study from 11 NICUS during 2009-2011. AB - BACKGROUND: Candida species is an important cause of nosocomial infection in neonatal intensive care units (NICUs). However, most reports in China have been limited to single institutions. The aim of this study is to investigate the epidemiology of invasive candidiasis in multiple NICUs across China. METHODS: We retrospectively collected demographic data, clinical characteristics, microbiological results and outcome of preterm infants with invasive candidiasis discharged from 11 academic tertiary NICUs during January 2009 to December 2011. RESULTS: There were 30,045 preterm infants discharged from 11 NICUs during the study period. We detected 223 infants with invasive candidiasis, resulting in an incidence of 0.74 cases per 100 preterm discharges from NICUs. In very low birth weight infants, the incidence was 3.42 cases per 100 very low birth weight discharges. Mean gestational age of infected infants was 31.4 weeks and median birth weight was 1410 gram. Among the cohort of infants with invasive candidiasis, 214 (96.0%) infants had positive blood culture for fungus, 5 infants had positive urine culture, 3 from cerebrospinal fluid and 1 from articular effusion in the shoulder joint. Among the cohort of infants with candidemia, 48 (22.4%) infants had fungal meningitis. Candida albicans accounted for 57.4% of total positive cultures. Overall mortality attributable to invasive candidiasis was 19.3%. CONCLUSIONS: Invasive candidiasis is a common problem among preterm neonates in China, especially among very low birth weight infants and it is associated with a high mortality. The preponderance of infections was due to Candida albicans. PMID- 24153008 TI - Cerebellitis and acute obstructive hydrocephalus associated with Mycoplasma pneumoniae infection. AB - Mycoplasma pneumoniae is associated with a variety of extrapulmonary manifestations, including central nervous system inflammation. A 9-year-old boy presented with acute cerebellitis and M. pneumoniae infection, resulting in obstructive hydrocephalus requiring neurosurgical intervention. This case, along with 4 similar ones reported in the literature, suggests a distinct clinicopathologic sequence caused by mycoplasma infection. PMID- 24153005 TI - MicroRNA-independent roles of the RNase III enzymes Drosha and Dicer. AB - The ribonuclease III enzymes Drosha and Dicer are renowned for their central roles in the biogenesis of microRNAs (miRNAs). For many years, this has overshadowed the true versatility and importance of these enzymes in the processing of other RNA substrates. For example, Drosha also recognizes and cleaves messenger RNAs (mRNAs), and potentially ribosomal RNA. The cleavage of mRNAs occurs via recognition of secondary stem-loop structures similar to miRNA precursors, and is an important mechanism of repressing gene expression, particularly in progenitor/stem cell populations. On the other hand, Dicer also has critical roles in genome regulation and surveillance. These include the production of endogenous small interfering RNAs from many sources, and the degradation of potentially harmful short interspersed element and viral RNAs. These findings have sparked a renewed interest in these enzymes, and their diverse functions in biology. PMID- 24153009 TI - The population-based health effect of hand, foot and mouth disease in children in Shanghai. AB - BACKGROUND: An effective enterovirus 71 (EV71) vaccine is needed to control the annual outbreaks of hand, foot and mouth disease (HFMD) in China. Adequate epidemiologic data relating to HFMD are needed to make decisions about appropriate public health interventions and implementation of the new EV71 vaccine. METHODS: We analyzed the population-based epidemiologic characteristics, clinical outcome and laboratory investigation of the 2011 HFMD outbreak in children based on the citywide surveillance system in Shanghai. RESULTS: The incidence rate of HFMD was 25.8 per 1000 in children <10 years of age in Shanghai in 2011, ranging from 2.5 per 1000 in the age group 7 to 9.9 years to 48.4 per 1000 in the age group 3 to 3.9 years. Children 1 to 1.9 years were at the highest risk of developing severe complications and most susceptible to HFMD. Boys and migrant children had significantly increased risks of contracting HFMD and developing severe disease. More institutional clusters/outbreaks occurred in the winter peak months than in the summer peak months. Migrant young children played a central role in the spread of HFMD in the community. EV71 was identified in 39.7% of mild HFMD outpatients, 47.4% of hospitalized patients, 92.1% of severe inpatients with complications, 50% of outbreaks and 38.8% of clusters in institutions. CONCLUSION: HFMD and EV71 infections have a significant health effect on Shanghai children. PMID- 24153010 TI - Pediatric Chagas disease in Europe: 45 cases from Spain and Switzerland. AB - BACKGROUND: Chagas disease, a potentially fatal parasitic infection, is emerging in Europe in the context of international migration but there is little public health attention and frequent lack of clinicians' awareness. To date, there is no published information about clinical characteristics in children. METHODS: We reviewed the medical files of all children (<18 years) with Chagas disease managed in 2 hospitals in Barcelona, Spain and Geneva, Switzerland between January 2004 and July 2012. RESULTS: Forty-five cases were identified. Two children (4.4%) were diagnosed during the acute phase and the remaining 43 (95.6%) were in the chronic phase of the infection. All but 1 were asymptomatic. Of the 41 treated children, 40 (97.6%) completed 60 days of treatment. Thirty five (85.4%) received benznidazole, 5 (12.2%) nifurtimox and 1 (2.4%) both drugs consecutively. There were 2 (4.9%) treatment interruptions due to adverse events. The most frequent adverse events were rash (24.4%), anorexia or insufficient weight gain (14.6%) and anemia (2.4%). Twenty-nine (64.4%) children were followed up by serology after 2 years. Five (17.2%) were cured. CONCLUSIONS: Pediatric Chagas disease is an emerging health issue in Europe that requires enhanced attention. Greater emphasis should be put on screening pregnant women at risk and their newborns in case of infection along with older children and relatives. Pediatricians have a central role to play in providing families with information and offering testing in situations of risk. PMID- 24153011 TI - Spontaneously regressing leukoencephalopathy with bilateral temporal cysts in congenital rubella infection. AB - Very little is known regarding neuroimaging findings in patients with congenital rubella syndrome. We report a 1.9-year-old boy with congenital rubella syndrome who presented in the neonatal period with severe multisystem involvement and diffuse leukoencephalopathy with subcortical anterior temporal cysts, which showed spontaneous improvement during a period of 3 years. PMID- 24153012 TI - Coinhibitory molecule PD-1 as a potential target for the immunotherapy of multiple myeloma. AB - The adaptive immune system is clearly capable of recognizing and attacking malignant plasma cells in patients with multiple myeloma (MM). However, MM patients evidence severe defects of humoral and cellular immunity, and it is likely that the profound immune dysregulation typical for this malignancy contributes to its eventual escape from natural immune control. One of the factors responsible for the immune dysfunction in MM might be the programmed death 1 (PD-1) protein. The physiological role of PD-1 is to guarantee T-cell homeostasis by limiting T-cell activation and proliferation. Accordingly, binding of the ligand PD-L1 to PD-1 expressed on the surface of activated T cells delivers an inhibitory signal, reducing cytokine production and proliferation. Using the same mechanism, PD-L1/PD-1 interactions have been shown in a number of animal models to confer tumor escape from immune control. Recently, clinical trials have suggested a significant therapeutic impact of PD-1/PD-L inhibition on a variety of solid tumors-for example, by the application of monoclonal antibodies. We show here that based on (1) the broad expression of PD-1 and its ligands in the microenvironment of myeloma, (2) data indicating an important role of the PD-1 pathway in the immune evasion by MM cells and (3) preclinical results providing a strong rationale for therapeutic PD-1/PD-L inhibition in this malignancy, MM may be very well suited for immunotherapy, for example, a monoclonal antibody, targeting PD-1 and/or its ligands. PMID- 24153013 TI - Altered expression of miR-24, miR-126 and miR-365 does not affect viability of childhood TCF3-rearranged leukemia cells. AB - Among the microRNAs (miRNAs) that control different cellular processes, miR-24, miR-126 and miR-365 were shown to regulate cell cycle progression and apoptosis in various types of tumors. Interestingly, these three miRNAs were downregulated in pediatric TCF3-rearranged B-cell precursor acute lymphoblastic leukemia (BCP ALL). Here, we showed that individual or combined overexpression of miR-24, miR 126 and miR-365 can neither alter the cell cycle progression nor the amount of apoptosis in 697, KASUMI-2 or MHH-CALL-3 TCF3-rearranged leukemic cells. We further integrated the miRNA-mRNA expression data of 37 children with BCP-ALL to identify candidate target genes for these three miRNAs. However, the expression levels of selected candidate target genes (ELL, EBF3 and IRF4 for miR-24, PITPNC1 for miR-126 and ZAP-70 for miR-365) did not reduce upon miRNAs overexpression in MHH-CALL-3 TCF3-rearranged leukemic cells. Although the expression level of AURKB a validated target for miR-24-was reduced upon miR-24 overexpression in hepatocarcinoma HEP-G2 cells, overexpression of miR-24 cannot alter AURKB expression levels in MHH-CALL-3 TCF3-rearranged leukemic cells. Taken together, our data suggest that miRNAs' function is highly tissue-dependent and that a defined biological target gene or function of one miRNA in a specific tissue cannot be extended as a generalized target/function for that miRNA in all types of cells/tissues. PMID- 24153014 TI - Increasing genomic and epigenomic complexity in the clonal evolution from in situ to manifest t(14;18)-positive follicular lymphoma. AB - Follicular lymphoma (FL) is characterized besides the t(14;18)(q32;q21), by recurrent chromosomal alterations and somatic mutations. In this study, we analyzed cases of FL in situ (FLIS) without manifest FL (mFL), partial involvement by FL (PFL) and paired cases of FLIS and mFL to detect possible early chromosomal imbalances, mutations, as well as DNA-methylation patterns of genomic regions of selected genes. We demonstrate that all paired FLIS and mFL cases were clonally related, based on IGH rearrangement patterns and BCL2 breakpoint sequences. FLIS and PFL had no or few secondary chromosomal imbalances detectable by array comparative genomic hybridization (FLIS 0.8 copy number alterations (CNA)/case; PFL 2.0 CNA/case; mFL 6.3 CNA/case) and a lower level of DNA methylation of genes recurrently de novo methylated in lymphomas, as compared with mFL. EZH2 Tyr641 mutations were detected in a subset of both FLIS (2/9) and PFL (1/3) cases. In conclusion, these findings provide evidence that FLIS represents a FL precursor lesion of long-lived clonal B cells carrying the t(14;18) with no or few secondary genetic changes. Our data suggest that there may be more than one distinct lesion driving the progression from FLIS to manifest lymphoma. PMID- 24153015 TI - Inhibition of JAK3 with a novel, selective and orally active small molecule induces therapeutic response in T-cell malignancies. PMID- 24153016 TI - The current understanding of sepsis and research priorities for the future. PMID- 24153017 TI - Delivering palliative care to patients and caregivers in inner-city communities: challenges and opportunities. AB - OBJECTIVE: Social and economic barriers can hinder access to quality palliative and end-of-life care for patients living in inner-city communities. Using a community-based participatory research (CBPR) approach, we investigated the stresses associated with living with a chronic disease and barriers to access and utilization of palliative care resources experienced by low-income patients and caregivers in five inner-city communities. METHODS: Four focus groups (N = 33) were conducted with community stakeholders, including healthcare professionals (social workers and nurses), persons living with chronic illnesses (e.g., HIV/AIDS, cardiovascular disease, and cancer), and caregivers. Focus group responses were analyzed using thematic analyses. RESULTS: Patients' and caregivers' stresses centered around five themes: lack of family support, communication barriers with healthcare professionals, minority stress, caregiver burden, and lack of spiritual support. The community stakeholders identified resources and services to improve access to care and the quality of life of underserved, low-income populations living with chronic illnesses. SIGNIFICANCE OF RESULTS: A CBPR approach enabled us to develop an interdisciplinary and culturally sensitive intervention to begin addressing the palliative and end-of life needs of the patients and caregivers of the inner-city community. PMID- 24153018 TI - Measuring anxiety about aging across the adult lifespan. AB - BACKGROUND: The development of instruments to measure aging attitudes is an essential part of research into the role of individual differences in the aging process, giving clarification to the relationship between attitudes and behavior across the lifespan. Here we test the structural validity of Lasher and Faulkender's (1993) Anxiety about Aging Scale (AAS), and explore measurement invariance across age and gender. METHODS: A sample of 783 adults (42% females) age ranging from 20 to 97 years (M = 57.3, SD = 13.66) participated. RESULTS: The first-order four-factor AAS model reflecting the original Lasher and Faulkender (1993) structure showed a better fit to the data than the second-order model. Measurement invariance for both gender and age groups (young adults 20-44 years; mid-aged adults 45-64 years, older adults 65+ years old) was found for three of the factors, but not for all items in the Fear of Losses factor. Structural covariance inequality between the Fear of Losses and Physical Appearance factors was shown between males and females. CONCLUSIONS: Findings indicate that the original AAS measures four distinct dimensions of anxiety about aging. These dimensions were shown to be generally comparable across age and gender, indicating that the AAS is a suitable measure for providing meaningful comparison of anxiety about aging across the lifespan. The exception is the Fear of Losses factor, where items may have differential meanings across groups based on cultural and social attitudes regarding aging and gender. PMID- 24153019 TI - Radiology department, human factors and organizational perspectives: using action research to improve patient safety. AB - BACKGROUND: Action research is a participatory research method based on active cooperation between researchers and subjects. In clinical practice, action research enables active involvement of workers in developing and implementing actions promoting patient safety. This article describes a participatory action research project that was conducted in the radiology department of a tertiary care university hospital. The main objectives were: identifying potential adverse events in the department of radiology, and offering a proactive approach to improving patient safety. METHODS: Phase one of the study included observing 100 patients in three units of the department and identifying potential adverse events using an observation form. According to the data obtained from the observations, multidisciplinary research teams developed and initiated, together with front-line workers, four types of interventions: ergonomic interventions in work environment design, interventions in work procedure and task design, training and guidance, and managerial interventions. Phase two included evaluation of the interventions after six months of implementation. RESULTS: Results showed different weaknesses in each of the three radiology units tested, including incomplete medical information necessary for performing the radiological procedure, and discontinuity of care. Post-intervention observations showed a significant reduction in the prevalence of potential adverse events. At the Angiography unit, potential adverse events related to incomplete medical information dropped from 50% to 32%, and at the CT unit they dropped from 70% to 23%. At the MRI unit potential adverse events related to discontinuity of care dropped from 61% to 19%. CONCLUSIONS: The current study demonstrates the value of action research in non-hospitalizing health units and the benefits of cooperation between medical teams and human factor professionals in promoting patient safety. Methods similar to those described in the current paper are applicable to medical work teams in a broad range of practices. PMID- 24153020 TI - Undenatured type II collagen (UC-II(r)) for joint support: a randomized, double blind, placebo-controlled study in healthy volunteers. AB - BACKGROUND: UC-II contains a patented form of undenatured type II collagen derived from chicken sternum. Previous preclinical and clinical studies support the safety and efficacy of UC-II in modulating joint discomfort in osteoarthritis and rheumatoid arthritis. The purpose of this study was to assess the efficacy and tolerability of UC-II in moderating joint function and joint pain due to strenuous exercise in healthy subjects. METHODS: This randomized, double-blind, placebo-controlled study was conducted in healthy subjects who had no prior history of arthritic disease or joint pain at rest but experienced joint discomfort with physical activity. Fifty-five subjects who reported knee pain after participating in a standardized stepmill performance test were randomized to receive placebo (n = 28) or the UC-II (40 mg daily, n = 27) product for 120 days. Joint function was assessed by changes in degree of knee flexion and knee extension as well as measuring the time to experiencing and recovering from joint pain following strenuous stepmill exertion. RESULTS: After 120 days of supplementation, subjects in the UC-II group exhibited a statistically significant improvement in average knee extension compared to placebo (81.0 +/- 1.3o vs 74.0 +/- 2.2o; p = 0.011) and to baseline (81.0 +/- 1.3o vs 73.2 +/- 1.9o; p = 0.002). The UC-II cohort also demonstrated a statistically significant change in average knee extension at day 90 (78.8 +/- 1.9o vs 73.2 +/- 1.9o; p = 0.045) versus baseline. No significant change in knee extension was observed in the placebo group at any time. It was also noted that the UC-II group exercised longer before experiencing any initial joint discomfort at day 120 (2.8 +/- 0.5 min, p = 0.019), compared to baseline (1.4 +/- 0.2 min). By contrast, no significant changes were seen in the placebo group. No product related adverse events were observed during the study. At study conclusion, five individuals in the UC-II cohort reported no pain during or after the stepmill protocol (p = 0.031, within visit) as compared to one subject in the placebo group. CONCLUSIONS: Daily supplementation with 40 mg of UC-II was well tolerated and led to improved knee joint extension in healthy subjects. UC-II also demonstrated the potential to lengthen the period of pain free strenuous exertion and alleviate the joint pain that occasionally arises from such activities. PMID- 24153022 TI - Safety of cidofovir by intratympanic delivery technique. AB - BACKGROUND: Congenital cytomegalovirus (CMV) infection is one of the most common infectious causes of congenital sensorineural hearing loss. To date, a safe and effective therapy for CMV-induced hearing loss does not exist. We hypothesize that the antiviral cidofovir (CDV) can be delivered to the inner ear via intratympanic (IT) injections to safely and effectively mitigate CMV-induced hearing loss. METHODS: To evaluate the safety of CDV IT injections, weanling guinea pigs with normal hearing were injected intratympanically with 3 mg or 5 mg concentrations of CDV and compared to control animals injected with sterile saline. A separate group of weanling guinea pigs were inoculated with CMV and a subset of this group was treated with CDV following inoculation. RESULTS: The 3 mg/ml and 5 mg/ml CDV concentrations resulted in hearing loss following IT injection into uninfected animals. No signs of inflammation or toxicity were noted on histologic analysis and there was no evidence of systemic toxicity in serology. Hearing loss induced as a result of guinea pig CMV infection recovered by day 21 in animals treated with IT injections of 5 mg/ml CDV. CONCLUSIONS: We provide promising evidence demonstrating both the efficacy and safety of IT CDV in the guinea pig animal model. This research further establishes a sound framework upon which ongoing investigations into drug delivery mechanisms for CMV induced hearing loss will be based. PMID- 24153023 TI - Household income modifies the association of insurance and dental visiting. AB - BACKGROUND: Dental insurance and income are positively associated with regular dental visiting. Higher income earners face fewer financial barriers to dental care, while dental insurance provides partial reimbursement. The aim was to explore whether household income has an effect on the relationship between insurance and visiting. METHODS: A random sample of adults aged 30-61 years living in Australia was drawn from the Electoral Roll. Data were collected by mailed survey in 2009-10, including age, sex, dental insurance status and household income. RESULTS: Responses were collected from n = 1,096 persons (response rate = 39.1%). Dental insurance was positively associated with regular visiting (adjusted prevalence ratio (PR) = 1.18; 95% CI: 1.01-1.36). Individuals in the lowest income tertile had a lower prevalence of regular visiting than those in the highest income group (PR = 0.78; 95% CI: 0.65-0.93). Visiting for a check-up was less prevalent among lower income earners (PR = 0.65; 95% CI: 0.50 0.83). Significant interaction terms indicated that the associations between insurance and visiting varied across income tertiles showing that income modified the effect. CONCLUSIONS: Household income modified the relationships between insurance and regular visiting and visiting for a check-up, with dental insurance having a greater impact on visiting among lower income groups. PMID- 24153024 TI - Control of olfactory ensheathing cell behaviors by electrospun silk fibroin fibers. AB - Olfactory ensheathing cells (OECs), the only glial cell type that normally penetrates the transition zone between the peripheral and central nervous systems, are one of the most promising candidates for cell transplantation in repairing spinal cord injury (SCI). However, we must manipulate and regulate OECs' behavior to make these cells effective in cell transplantation. In the present study, we assessed the response of rat OECs to different variants of nanofibrous silk fibroin mats with regard to cell morphology, adhesion, proliferation, and migration and the related gene and protein expression. Results showed that OECs adhere and spread more easily on Tussah silk fibroin (TSF) fibers than Bombyx mori silk fibroin fibers, resulting in a higher rate of cell proliferation and gene and protein expression, examined by RT-PCR and ELISA. In addition, the morphology of OECs on microfibers is mainly polygonal with short protrusions, whereas the OECs on nanofibers exhibit a bipolar shape with long protrusions that align along the fibers, especially when aligned fibers are employed. Moreover, OECs on silk fibroin nanofibers migrate more efficiently than those on poly-L-lysine (PLL). Based on the experimental results, the morphology, adhesion, spread, gene and protein expression, and migration of OECs could be modulated and regulated by adjusting the contents and structure of silk fibroin nanofibers, shedding light on the control of OECs' behavior in nerve tissue engineering and thus the future therapeutic intervention for nerve repair after injury. This manuscript is published as part of the International Association of Neurorestoratology (IANR) supplement issue of Cell Transplantation. PMID- 24153025 TI - [Interventional radiology for bone metastases]. AB - The management of bone metastases requires a multidisciplinary staff to include systemic and local treatments like radiotherapy, surgery or interventional radiology (IR). Patients are often fragile. Imaging allows safe guidance to create "mini-invasive" procedures under adequate anesthesia. Patients' selection is important. If the goal is pain relief, cementoplasty provides a very effective bone consolidation and pain control. Simple and low-risk, vertebroplasty is the technique of choice in case of lytic bone metastases with spinal fracture risk or after failure of analgesic radiotherapy. If the medical project is curative, the tumor ablation procedures are realised through thermic or embolic techniques. After 60 degrees C, the heat induces a coagulative necrose. Under -20 degrees C, the cold leads to destroy the tissues. The major advantage of the cryotherapy is the predictibility of the ablation zone due to the well-visualized ice ball on perprocedural images. This technique is much more adapted to spare the nervous structures closed to the metastasis. The development of these new techniques of IR will treat bone metastases earlier, sometimes asymptomatic and thus improves the quality of life in patients with bone metastases. PMID- 24153026 TI - A cluster randomised controlled trial and economic evaluation of a structured training programme for caregivers of inpatients after stroke: the TRACS trial. AB - BACKGROUND: The majority of stroke patients are discharged home dependent on informal caregivers, usually family members, to provide assistance with activities of daily living (ADL), including bathing, dressing and toileting. Many caregivers feel unprepared for this role and this may have a detrimental effect on both the patient and caregiver. OBJECTIVE: To evaluate whether or not a structured, competency-based training programme for caregivers [the London Stroke Carer Training Course (LSCTC)] improved physical and psychological outcomes for patients and their caregivers after disabling stroke, and to determine if such a training programme is cost-effective. DESIGN: A pragmatic, multicentre, cluster randomised controlled trial. SETTING: Stratified randomisation of 36 stroke rehabilitation units (SRUs) to the intervention or control group by geographical region and quality of care. PARTICIPANTS: A total of 930 stroke patient and caregiver dyads were recruited. Patients were eligible if they had a confirmed diagnosis of stroke, were medically stable, were likely to return home with residual disability at the time of discharge and had a caregiver available, willing and able to provide support after discharge. The caregiver was defined as the main person--other than health, social or voluntary care provider--helping with ADL and/or advocating on behalf of the patient. INTERVENTION: The intervention (the LSCTC) comprised a number of caregiver training sessions and competency assessment delivered by SRU staff while the patient was in the SRU and one recommended follow-up session after discharge. The control group continued to provide usual care according to national guidelines. Recruitment was completed by independent researchers and participants were unaware of the SRUs' allocation. MAIN OUTCOME MEASURES: The primary outcomes were self-reported extended ADL for the patient and caregiver burden measured at 6 months after recruitment. Secondary outcomes included quality of life, mood and cost-effectiveness, with final follow-up at 12 months. RESULTS: No differences in primary outcomes were found between the groups at 6 months. Adjusted mean differences were -0.2 points [95% confidence interval (CI) -3.0 to 2.5 points; p = 0.866; intracluster correlation coefficient (ICC) = 0.027] for the patient Nottingham Extended Activities of Daily Living score and 0.5 points (95% CI -1.7 to 2.7 points; p = 0.660; ICC = 0.013) for the Caregiver Burden Scale. Furthermore, no differences were detected in any of the secondary outcomes. Intervention compliance varied across the units. Half of the participating centres had a compliance rating of > 60%. Analysis showed no evidence of higher levels of patient independence or lower levels of caregiver burden in the SRUs with better levels of intervention compliance. The economic evaluation suggests that from a patient and caregiver perspective, health and social care costs, societal costs and outcomes are similar for the intervention and control groups at 6 months, 12 months and over 1 year. CONCLUSIONS: We have conducted a robust multicentre, cluster randomised trial, demonstrating for the first time that this methodology is feasible in stroke rehabilitation research. There was no difference between the LSCTC and usual care with respect to improving stroke patients' recovery, reducing caregivers' burden, or improving other physical and psychological outcomes, nor was it cost-effective compared with usual care. Compliance with the intervention varied, but analysis indicated that a dose effect was unlikely. It is possible that the immediate post-stroke period may not be the ideal time for the delivery of structured training. The intervention approach might be more relevant if delivered after discharge by community-based teams. TRIAL REGISTRATION: Current Controlled Trials ISRCTN49208824. FUNDING: This project was funded by the MRC and is managed by the NIHR (project number 09/800/10) on behalf of the MRC-NIHR partnership, and will be published in full in Health Technology Assessment; Vol. 17, No. 46. See the NIHR Journals Library website for further project information. PMID- 24153027 TI - Effects of skilled nursing facility structure and process factors on medication errors during nursing home admission. AB - BACKGROUND: Older adults are at greatest risk of medication errors during the transition period of the first 7 days after admission and readmission to a skilled nursing facility (SNF). PURPOSE: The aim of this study was to evaluate structure- and process-related factors that contribute to medication errors and harm during transition periods at a SNF. METHODOLOGY/APPROACH: Data for medication errors and potential medication errors during the 7-day transition period for residents entering North Carolina SNFs were from the Medication Error Quality Initiative-Individual Error database from October 2006 to September 2007. The impact of SNF structure and process measures on the number of reported medication errors and harm from errors were examined using bivariate and multivariate model methods. FINDINGS: A total of 138 SNFs reported 581 transition period medication errors; 73 (12.6%) caused harm. Chain affiliation was associated with a reduction in the volume of errors during the transition period. One third of all reported transition errors occurred during the medication administration phase of the medication use process, where dose omissions were the most common type of error; however, dose omissions caused harm less often than wrong-dose errors did. Prescribing errors were much less common than administration errors but were much more likely to cause harm. PRACTICE IMPLICATIONS: Both structure and process measures of quality were related to the volume of medication errors.However, process quality measures may play a more important role in predicting harm from errors during the transition of a resident into an SNF. Medication errors during transition could be reduced by improving both prescribing processes and transcription and documentation of orders. PMID- 24153028 TI - The evolution of knowledge exchanges enabling successful practice change in two intensive care units. AB - BACKGROUND: Many hospitals are unable to consistently implement evidence-based practices. For example, implementation of the central line bundle (CLB), known to prevent catheter-related bloodstream infections (CRBSIs), is often challenging. This problem is broadly characterized as "change implementation failure." PURPOSE: The theoretical literature on organizational change has suggested that periodic top-down communications promoting tacit knowledge exchanges across professional subgroups may be effective for enabling learning and change in health care organizations. However, gaps remain in understanding the mechanisms by which top-down communications enable practice change at the unit level. Addressing these gaps could help identify evidence-based management strategies for successful practice change at the unit level. Our study sought to address this gap. METHODS: A prospective study was conducted in two intensive care units within an academic health center. Both units had low baseline adherence to CLB and higher-than-expected CRBSIs. Periodic top-down quality improvement communications were conducted over a 52-week period to promote CLB implementation in both units. Simultaneously, the study examined (a) the content and frequency of communication related to CLB through weekly "communication logs" completed by unit physicians, nurses, and managers and (b) unit outcomes, that is, CLB adherence rates through weekly chart reviews. FINDINGS: Both units experienced substantially improved outcomes, including increased adherence to CLB and statistically significant (sustained) declines in both CRBSIs and catheter days (i.e., central line use). Concurrently, both units indicated a statistically significant increase in "proactive" communications-that is, communications intended to reduce infection risk-between physicians and nurses over time. Further analysis revealed that, during the early phase of the study, "champions" emerged within each unit to initiate process improvements. PRACTICE IMPLICATIONS: The study helps identify evidence-based management strategies for successful practice change at the unit level. For example, it underscores the importance of (a) screening each unit for change champions and (b) enabling champions to emerge from within the unit to foster change implementation. PMID- 24153029 TI - Association of cognitive impairment with frailty in community-dwelling older adults. AB - BACKGROUND: Frailty is highly prevalent in older people, but its association with cognitive function is poorly understood. The aim of this study was to examine the association between cognitive function and frailty in community-dwelling older adults. METHODS: Data were from the 2008 Living Profiles of Older People Survey, comprising 10,388 nationally representative sample aged 65 years and older living in the community in South Korea. Frailty criteria included unintentional weight loss, exhaustion, weakness, low physical activity, and slow walking speed. Cognitive function was assessed using the Korean version of the Mini-Mental State Examination. Multinomial logistic regression models were constructed with frailty status regressed on cognitive impairment and subdomains of cognitive function, adjusting for covariates. RESULTS: Those who were frail showed a higher percentage of cognitive impairment (55.8% in men, 35.2% in women) than those who were not (22.1% in men, 15.6% in women). Cognitive impairment was associated with an increased risk of frailty in men (odds ratio (OR) = 1.81, 95% confidence interval (CI): 1.25-2.60) and women (OR = 1.69, 95% CI: 1.25-2.30) even after controlling for all covariates. Among the subdomains of cognitive function, time orientation, registration, attention, and judgment were associated with a lower likelihood of frailty in both men and women after adjusting for confounders. Among women higher scores on recall, language components, and visual construction were also significantly associated with lower odds of frailty. CONCLUSIONS: Cognitive impairment was associated with a higher likelihood of frailty in community-dwelling older men and women. Total scores and specific subdomains of cognitive function were inversely associated with frailty. PMID- 24153030 TI - Development and evaluation of an automated histology classification system for veterinary pathology. AB - A 2-stage algorithmic framework was developed to automatically classify digitized photomicrographs of tissues obtained from bovine liver, lung, spleen, and kidney into different histologic categories. The categories included normal tissue, acute necrosis, and inflammation (acute suppurative; chronic). In the current study, a total of 60 images per category (normal; acute necrosis; acute suppurative inflammation) were obtained from liver samples, 60 images per category (normal; acute suppurative inflammation) were obtained from spleen and lung samples, and 60 images per category (normal; chronic inflammation) were obtained from kidney samples. An automated support vector machine (SVM) classifier was trained to assign each test image to a specific category. Using 10 training images/category/organ, 40 test images/category/organ were examined. Employing confusion matrices to represent category-specific classification accuracy, the classifier-attained accuracies were found to be in the 74-90% range. The same set of test images was evaluated using a SVM classifier trained on 20 images/category/organ. The average classification accuracies were noted to be in the 84-95% range. The accuracy in correctly identifying normal tissue and specific tissue lesions was markedly improved by a small increase in the number of training images. The preliminary results from the study indicate the importance and potential use of automated image classification systems in the histologic identification of normal tissues and specific tissue lesions. PMID- 24153031 TI - Availability of a fetal goat tongue cell line ZZ-R 127 for isolation of Foot-and mouth disease virus (FMDV) from clinical samples collected from animals experimentally infected with FMDV. AB - The availability of the fetal goat tongue cell line ZZ-R 127 for the isolation of Foot-and-mouth disease virus (FMDV) has not been evaluated using clinical samples other than epithelial suspensions. Therefore, in the current study, the availability of ZZ-R 127 cells for the isolation of FMDV was evaluated using clinical samples (e.g., sera, nasal swabs, saliva, feces, and oropharyngeal fluids) collected from animals experimentally infected with an FMDV isolate. Virus isolation rates for the ZZ-R 127 cells were statistically higher than those for the porcine kidney cell line (IB-RS-2) in experimental infections using cattle, goats, and pigs (P < 0.01). Virus titers in the ZZ-R 127 cells were also statistically higher than those in the IB-RS-2 cells. The availability of ZZ-R 127 cells for the isolation of FMDV not only from epithelial suspensions but also from other clinical samples was confirmed in the current study. PMID- 24153032 TI - Molecular detection of Salmonella species in bovine fecal samples. AB - A study was performed to assess the validity of the BAX automated polymerase chain reaction system (DuPont Nutrition & Health, Wilmington, Delaware) to detect the shedding of Salmonella species in bovine fecal samples. A total of 133 bovine fecal samples that were submitted to the Cornell University Animal Health Diagnostic Laboratory for Salmonella culture were also tested in the BAX system with a modified version of the manufacturer's enrichment protocol. Using culture as the gold standard test, the BAX system was found to have a sensitivity of 85.7% and a specificity of 90.5%. There was excellent agreement (kappa = 0.71, standard error = 0.072) and no significant differences between the 2 methods (McNemar chi(2) = 0.180). PMID- 24153033 TI - Geotrichum candidum as a possible cause of bovine abortion. AB - Geotrichum spp. are ubiquitous, saprotrophic fungi found in soil, organic matter, and silage, as a contaminant in food products and in the digestive tracts of mammals. The current study reports a case of Geotrichum candidum infection with dermatitis in an aborted bovine fetus with skin and lung lesions. A 6-month-old aborted male Holstein Friesian fetus displayed unusual lesions on the skin of the abdomen, thorax, and head, which was excessively thickened and wrinkled. These changes corresponded to orthokeratotic hyperkeratosis, neutrophil accumulation in the stratum corneum, a pyogranulomatous inflammatory infiltrate, and superficial dermal necrosis. Moderate suppurative multifocal pneumonia was observed. Large numbers of mononuclear cells and occasional fibrin thrombi within blood vessels were found in the lungs, brain, and cerebellum. Gridley staining revealed fungal structures within the skin lesions. The mycological exam demonstrated the growth of G. candidum, and phase contrast microscopy conducted on the abomasal fluid revealed hyphae compatible with this agent. The skin lesions observed, in association with the fungus isolated, indicated that the abortion was due to G. candidum infection of the bovine fetus. PMID- 24153034 TI - An outbreak of caprine meningoencephalitis due to Escherichia coli O157:H7. AB - Five 1-month-old kid goats from a local herd in Kozani (northwest Greece) developed neurological disorders characterized by decreased appetite, ataxia, and head pressing. The animals received a 3-day course of treatment with intramuscular administration of enrofloxacin and ketoprofen. However, no significant clinical improvement was achieved, and 2 kids died. The remaining 3 animals were euthanized, and a necropsy was performed within 1 hr. Macroscopic lesions were confined to the central nervous system, with congestion and petechiae in the meninges. Microscopic lesions in all 3 animals revealed multifocal acute meningoencephalitis characterized by infiltrations composed of mononuclear inflammatory cells, lesser numbers of lymphocytes, and occasionally neutrophils and eosinophils. Additionally, in the kidney, there was multifocal expansion of the glomerular tufts by eosinophilic amorphous material, multifocal interstitial hemorrhages, and multifocal glomerular hypercellularity. The above noted lesions are consisted with an acute ongoing nephropathy indicative of a septicemic-toxemic procedure at its primary stages. Small, gray bacterial colonies, 3-4 mm in diameter, were obtained in pure culture from the brain of all 3 necropsied animals and were confirmed as Escherichia coli O157:H7 by use of phenotypic and genotypic methods. The isolates were sensitive to cefuroxime, ceftazidime, and gentamicin. In contrast, resistance to enrofloxacin, trimethoprim-sulfamethoxazole, and tetracycline was displayed. Additionally the bacterial isolates were found to carry a plasmid that harbored qnrS, sulII, and tetB genes that contribute to high-level resistance to fluoroquinolones, co trimoxazole, and tetracycline, respectively. PMID- 24153035 TI - Testicular yolk sac tumor of myxomatous, reticular, and polyvesicular vitelline type in a newborn calf. AB - Yolk sac tumors (YSTs) are rare neoplasms of germ cell origin. In humans, the tumors primarily occur in the testes or ovaries, but occasionally develop at other sites. The neoplastic cells of YSTs form many histological patterns resembling embryonal structures, and the World Health Organization classification lists 11 such patterns: reticular, macrocystic, endodermal sinus, papillary, solid, glandular-alveolar, myxomatous, sarcomatoid, polyvesicular vitelline, hepatoid, and parietal. Among domestic animals, only 2 cases of YST, which were of testicular and abdominal cavity origin, have been reported in calves. In both cases, neoplastic cells had epithelial properties and disseminated metastases in the abdomen. In the present study, the enlarged testis of a newborn calf, which was subsequently diagnosed as YST and exhibited myxomatous, reticular, and polyvesicular vitelline histological patterns, is described. There was no metastasis in this case, and histological and immunohistochemical features varied from previous cases of YST. PMID- 24153036 TI - Opportunities for bead-based multiplex assays in veterinary diagnostic laboratories. AB - Bead-based multiplex assays (BBMAs) are applicable for high throughput, simultaneous detection of multiple analytes in solution (from several to 50-500 analytes within a single, small sample volume). Currently, few assays are commercially available for veterinary applications, but they are available to identify and measure various cytokines, growth factors and their receptors, inflammatory proteins, kinases and inhibitors, neurobiology proteins, and pathogens and antibodies in human beings, nonhuman primates, and rodent species. In veterinary medicine, various nucleic acid and protein-coupled beads can be used in, or for the development of, antigen and antibody BBMAs, with the advantage that more data can be collected using approximately the same amount of labor as used for other antigen and antibody assays. Veterinary-related BBMAs could be used for detection of pathogens, genotyping, measurement of hormone levels, and in disease surveillance and vaccine assessment. It will be important to evaluate whether BBMAs are "fit for purpose," how costs and efficiencies compare between assays, which assays are published or commercially available for specific veterinary applications, and what procedures are involved in the development of the assays. It is expected that many veterinary-related BBMAs will be published and/or become commercially available in the next few years. The current review summarizes the BBMA technology and some of the currently available BBMAs developed for veterinary settings. Some of the human diagnostic BBMAs are also described, providing an example of possible templates for future development of new veterinary-related BBMAs. PMID- 24153037 TI - Public health economics: a systematic review of guidance for the economic evaluation of public health interventions and discussion of key methodological issues. AB - BACKGROUND: If Public Health is the science and art of how society collectively aims to improve health, and reduce inequalities in health, then Public Health Economics is the science and art of supporting decision making as to how society can use its available resources to best meet these objectives and minimise opportunity cost. A systematic review of published guidance for the economic evaluation of public health interventions within this broad public policy paradigm was conducted. METHODS: Electronic databases and organisation websites were searched using a 22 year time horizon (1990-2012). References of papers were hand searched for additional papers for inclusion. Government reports or peer reviewed published papers were included if they; referred to the methods of economic evaluation of public health interventions, identified key challenges of conducting economic evaluations of public health interventions or made recommendations for conducting economic evaluations of public health interventions. Guidance was divided into three categories UK guidance, international guidance and observations or guidance provided by individual commentators in the field of public health economics. An assessment of the theoretical frameworks underpinning the guidance was made and served as a rationale for categorising the papers. RESULTS: We identified 5 international guidance documents, 7 UK guidance documents and 4 documents by individual commentators. The papers reviewed identify the main methodological challenges that face analysts when conducting such evaluations. There is a consensus within the guidance that wider social and environmental costs and benefits should be looked at due to the complex nature of public health. This was reflected in the theoretical underpinning as the majority of guidance was categorised as extra welfarist. CONCLUSIONS: In this novel review we argue that health economics may have come full circle from its roots in broad public policy economics. We may find it useful to think in this broader paradigm with respect to public health economics. We offer a 12 point checklist to support government, NHS commissioners and individual health economists in their consideration of economic evaluation methodology with respect to the additional challenges of applying health economics to public health. PMID- 24153038 TI - The antiproliferative effects of ouabain and everolimus on adrenocortical tumor cells. AB - Ouabain is a cardiotonic steroid obtained from Strophanthus. Recently its role as antiproliferative agent has been investigated in tumor cells. Everolimus is a derivative of rapamycin and acts as a signal transduction inhibitor. Adrenocortical carcinoma is a rare cancer, with poor prognosis. This research focuses on antineoplastic properties of ouabain and its association with everolimus. We analyzed the effects of drugs on cells by MTT assay, by [(3)H] thymidine assay, by Wright's staining, by homogeneous caspases assay, by flow cytometry analysis and by Western blot analysis on H295R and SW13 cells and on primary adrenocortical tumor cells. Ouabain induced cell viability reduction in SW13, H295R and 5 primary adrenocortical tumor cells. Combination of ouabain with everolimus produced a stronger cytotoxic effect on cell proliferation and viability. Marked morphological changes were observed in both SW13 and H295R cell lines after ouabain treatment, with an increase in necrosis. Cell cycle distribution was altered by ouabain in SW13. Analysis of apoptosis demonstrated an increase in caspase activity, clearly evident for SW13 at 72h. FACS analysis by Annexin V-FITC kit and propidium iodide confirmed an increased level of necrosis at higher concentrations. Western blot analysis showed that PI3k/Akt signaling pathway was modified after ouabain treatments in SW13. Ouabain exerts antiproliferative effects on SW13 and H295R cell lines and on primary adrenocortical tumor cells. These data suggest that ouabain or ouabain derivatives may be potential anticancer agents. PMID- 24153039 TI - [State of the art in nuclear imaging for the diagnosis of bone metastases]. AB - Cancers prone to spread to bone include prostate, lung, kidney, breast and thyroid cancers. While bone scanner has been widely used in the past decades, PET based imaging modalities are increasingly used. Current modalities of PET imaging of bone metastases include tumor and inflammatory targeting with FDG-PET, bone imaging with NaF-PET, and direct cancer-specific markers such as FDOPA-PET or PET using choline. The cancer-specific metastatic patterns and the relative prognosis conferred by osseous metastases (versus visceral metastases) may determine the need for bone scan, FDG-PET for the detection of bone metastases. Because some cancers have a mixed skeletal and visceral, cocktails PET radiopharmaceuticals may also be discussed in the future. The cancer-specific context and performances of bone scan and PET imaging are discussed. PMID- 24153040 TI - Head and neck cancer patients want us to support them psychologically in the posttreatment period: Survey results. AB - OBJECTIVES: No study systematically has investigated the supportive care needs of general head and neck cancer patients using validated measures. These needs include physical and daily living needs, health system and information needs, patient care and support needs, psychological needs, and sexuality needs. Identifying the unmet needs of head and neck cancer patients is a necessary first step to improving the care we provide to patients seen in our head and neck oncology clinics. It is recommended as the first step in intervention development in the Pan-Canadian Clinical Practice Guideline of the Canadian Partnership Against Cancer (see Howell, 2009). This study aimed to identify: (1) met and unmet supportive care needs of head and neck cancer patients, and (2) variability in needs according to demographics, disease variables, level of distress, and quality-of-life domains. METHODS: Participants were recruited from the otolaryngology-head and neck surgery clinics of two university teaching hospitals. Self-administered questionnaires included sociodemographic and medical questions, as well as validated measures such as the Supportive Care Needs Survey Short Form (SCNS-SF34), the Hospital Anxiety and Depression Scale (HADS), and the Functional Assessment of Cancer Therapy-General (FACT-G) and Head and Neck Module (FACT-H&N) (quality of life measures). RESULTS: One hundred and twenty-seven patients participated in the survey. 68% of them experienced unmet needs, and 25% revealed a clinically significant distress level on the HADS. The highest unmet needs were psychological (7 of top 10 needs). A multiple linear regression indicated a higher level of overall unmet needs when patients were divorced, had a high level of anxiety (HADS subscale), were in poor physical condition, or had a diminished emotional quality of life (FACT-G subscales). SIGNIFICANCE OF RESULTS: The results of this study highlight the overwhelming presence of unmet psychological needs in head and neck cancer patients and underline the importance of implementing interventions to address these areas perceived by patients as important. In line with hospital resource allocation and cost-effectiveness, one may also contemplate screening patients for high levels of anxiety, as well as target patients who are divorced and present low levels of physical well-being, as these patients may have more overall needs to be met. PMID- 24153041 TI - Daring discourse: a new section for readers. PMID- 24153042 TI - Persistent phrenic nerve paresis after interscalene block: a "triple crush" hypothesis of nerve injury. PMID- 24153043 TI - Block success rate: a question of target and definition. PMID- 24153044 TI - Reply to Drs Bloc, Rontes, Mercadal, and Delbos. PMID- 24153045 TI - Toward a better understanding of brachial plexus anatomy for shoulder, forearm, and hand anesthesia. PMID- 24153046 TI - Reply to Dr Price. PMID- 24153047 TI - Distal injection site may explain lack of analgesia from fascia iliaca block for total hip. PMID- 24153048 TI - Reply to Dr Vaughan et al. PMID- 24153049 TI - Recruiting clinical personnel as research participants: a framework for assessing feasibility. AB - Increasing numbers of research studies test interventions for clinicians in addition to or instead of interventions for patients. Although previous studies have enumerated barriers to patient enrolment in clinical trials, corresponding barriers have not been identified for enrolling clinicians as subjects. We propose a framework of metrics for evidence-based estimation of time and resources required for recruiting clinicians as research participants, and present an example from a federally funded study. Our framework proposes metrics for tracking five steps in the recruitment process: gaining entry into facilities, obtaining accurate eligibility and contact information, reaching busy clinicians, assessing willingness to participate, and scheduling participants for data collection. We analyzed recruitment records from a qualitative study exploring performance feedback at US Department of Veterans Affairs Medical Centers (VAMCs); five recruiters sought to reach two clinicians at 16 facilities for a one-hour interview. Objective metrics were calculable for all five steps; metric values varied considerably across facilities. Obtaining accurate contact information slowed down recruiting the most. We conclude that successfully recruiting even small numbers of employees requires considerable resourcefulness and more calendar time than anticipated. Our proposed framework provides an empirical basis for estimating research-recruitment timelines, planning subject recruitment strategies, and assessing the research accessibility of clinical sites. PMID- 24153050 TI - The time is now for action research. AB - Despite highly systematic methods for identifying priority problems and assessing intervention effects, the recent study by Tourgeman-Bashkin and colleagues would not be considered rigorous by conventional standards of validity, nor would its sample size of three units impress policymakers eager to promote large-scale change through improvement programs. Yet, study findings suggest that no single intervention would have accomplished as much as the action research approach the authors' employed. This perspective argues that although action research may lend itself to neither clean comparisons of intervention and control units over time nor far-reaching improvement campaigns, its advantages, including responsiveness to context, emphasis on implementation and sustainability, and insight about underlying mechanisms of change, make rigorous action research a highly attractive alternative for engendering real world improvement. PMID- 24153051 TI - The pattern of LH secretion and the ovarian response to the 'ram effect' in the anoestrous ewe is influenced by body condition but not by short-term nutritional supplementation. AB - In sheep, the 'ram effect' induces out-of-season fertility and good nutrition increases prolificacy. This experiment determined if fatness or short-term nutritional supplementation modified the response to the 'ram effect'. A group of 48 Ile-de-France ewes were fed diets that produced groups with body-condition scores (BCS) of >3.0 and <2.0. Within each BCS group animals were supplemented daily with 500g of lupins from Day -5 to Day 0 (ram introduction) resulting in four groups: low BCS, supplemented (n=7) and non-supplemented (n=8) and high BCS, supplemented (n=12) and non-supplemented (n=11). The blood concentrations of glucose and insulin and the LH response to gonadotrophin-releasing hormone (GnRH) were determined. After the 'ram effect' the pattern of LH pulsatility, the LH surge and ovarian responses were analysed. Low BCS ewes had lower glucose and insulin (P<0.001) and supplementation increased both (P<=0.001). The increase in LH induced by GnRH was reduced in low BCS ewes (P=0.015) but it was not affected by supplementation. Similarly, LH pulsatility was reduced in low BCS ewes (P<0.05). The LH surge and ovarian cyclicity were not affected but the follow-up cycle was delayed (P=0.034) and progesterone was reduced (P=0.029) in low BCS ewes. There was an effect of BCS on ovulation rate (P<0.05). These results show that the BCS can modify the response to the 'ram effect' and that supplementation has little effect on this response. PMID- 24153052 TI - Fabrication of graphene films with high transparent conducting characteristics. AB - We present a study on the transparent conducting characteristics of graphene based films prepared by means of rapid chemical vapor deposition. The graphene films were grown on quartz slides with a CH4/Ar mixed gas under a constant flow at 950 degrees C and then annealed at 1,000 degrees C. It was found that the graphene films present excellent electrical conductivity with high transparency. The conductivity is up to 1,240 S/cm, the sheet resistance is lower than 1 kOmega/sq, and the transparency is well over 85% in the visible wavelength range of 400 to 800 nm, showing that the graphene films have very low resistivity and superior transparency and completely satisfy the need for transparent conductors. These properties can be used in many applications, such as transparent conductor films for touch panels. PACS: 61.48.+c, 78.67.Pt, 68.37.Hk, 68.65.Ac. PMID- 24153054 TI - Social feedback activates the endogenous opioid system. PMID- 24153053 TI - Effectiveness of two interventions based on improving patient-practitioner communication on diabetes self-management in patients with low educational level: study protocol of a clustered randomized trial in primary care. AB - BACKGROUND: In the last decades the presence of social inequalities in diabetes care has been observed in multiple countries, including Spain. These inequalities have been at least partially attributed to differences in diabetes self management behaviours. Communication problems during medical consultations occur more frequently to patients with a lower educational level. The purpose of this cluster randomized trial is to determine whether an intervention implemented in a General Surgery, based in improving patient-provider communication, results in a better diabetes self-management in patients with lower educational level. A secondary objective is to assess whether telephone reinforcement enhances the effect of such intervention. We report the design and implementation of this on going study. METHODS/DESIGN: The study is being conducted in a General Practice located in a deprived neighbourhood of Granada, Spain. Diabetic patients 18 years old or older with a low educational level and inadequate glycaemic control (HbA1c > 7%) were recruited. General Practitioners (GPs) were randomised to three groups: intervention A, intervention B and control group. GPs allocated to intervention groups A and B received training in communication skills and are providing graphic feedback about glycosylated haemoglobin levels. Patients whose GPs were allocated to group B are additionally receiving telephone reinforcement whereas patients from the control group are receiving usual care. The described interventions are being conducted during 7 consecutive medical visits which are scheduled every three months. The main outcome measure will be HbA1c; blood pressure, lipidemia, body mass index and waist circumference will be considered as secondary outcome measures. Statistical analysis to evaluate the effectiveness of the interventions will include multilevel regression analysis with three hierarchical levels: medical visit level, patient level and GP level. DISCUSSION: The results of this study will provide new knowledge about possible strategies to promote a better diabetes self-management in a particularly vulnerable group. If effective, this low cost intervention will have the potential to be easily incorporated into routine clinical practice, contributing to decrease health inequalities in diabetic patients. TRIAL REGISTRATION: Clinical Trials U.S. National Institutes of Health, NCT01849731. PMID- 24153056 TI - Raising a child with disability and dealing with life events: a mother's journey. AB - Intellectual disability services recognise people with intellectual disability as a family member and aim to provide effective support that facilitates family cohesion. However, the needs of families and individuals within the family should be addressed in a holistic manner to ensure a seamless service. This article outlines a mother's reflections on her experience of raising a child with autism spectrum disorder and its impact on her life. The article focuses on one mother's feelings, coping or lack of coping and growth during a time of sadness. This article written by a mother, nurse and academic through their shared interest in supporting families of children with a disability all came together to tell this story. It is hoped that this article will assist professionals understand a mother's perspective when raising a child with intellectual disability and support professionals to recognise the importance of listening, coordinated support and working in partnership. PMID- 24153055 TI - Genetic and antigenic characterization of complete genomes of Type 1 Porcine Reproductive and Respiratory Syndrome viruses (PRRSV) isolated in Denmark over a period of 10 years. AB - Porcine Reproductive and Respiratory Syndrome (PRRS) caused by the PRRS virus (PRRSV) is considered one of the most devastating swine diseases worldwide. PRRS viruses are divided into two major genotypes, Type 1 and Type 2, with pronounced diversity between and within the genotypes. In Denmark more than 50% of the herds are infected with Type 1 and/or Type 2 PRRSV. The main objective of this study was to examine the genetic diversity and drift of Type 1 viruses in a population with limited introduction of new animals and semen. A total of 43 ORF5 and 42 ORF7 nucleotide sequences were obtained from viruses collected from 2003 to February 2013. Phylogenetic analysis of ORF5 nucleotide sequences showed that the Danish isolates formed two major clusters within the subtype 1. The nucleotide identity to the subtype 1 protogenotype Lelystad virus (LV) spanned 84.9-98.8% for ORF5 and 90.7-100% for ORF7. Among the Danish viruses the pairwise nucleotide identities in ORF5 and ORF7 were 81.2-100% and 88.9-100%, respectively. Sequencing of the complete genomes, including the 5'- and 3'-end nucleotides, of 8 Danish PRRSV Type 1 showed that the genome lengths differed from 14,876 to 15,098 nucleotides and the pairwise nucleotide identity among the Danish viruses was 86.5-97.3% and the identity to LV was 88.7-97.9%. The study strongly indicated that there have been at least two independent introductions of Type 1 PRRSV in Denmark and analysis of the full genomes revealed a significant drift in several regions of the virus. PMID- 24153057 TI - How do people with intellectual disabilities view abuse and abusers? AB - People with intellectual disabilities have a higher risk of being abused than other people, but to date research has not explored their views regarding abuse. This article reports the findings relating to one question within a participatory research study concerning the abuse of people with intellectual disabilities. This question asked what people with intellectual disabilities' views are concerning abuse. Data were gathered via individual interviews (n = 14) and focus groups (7 groups involving 47 people in total), which were then analysed via a process of sorting statements into themes followed by group discussion and analysis of these themes. Participants expressed a range of views regarding abuse, some of which revealed strong emotions: a number of participants indicated that abuse could make people feel as though their lives are not worth living. People with intellectual disabilities can discuss their feelings around abuse and recognise the impact this has on their lives. There is, however, a need for improved responses to disclosures of abuse and the provision of ongoing support to address psychological issues. PMID- 24153058 TI - The DeISGylase USP18 limits TRAIL-induced apoptosis through the regulation of TRAIL levels: Cellular levels of TRAIL influences responsiveness to TRAIL-induced apoptosis. AB - Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) is a promising molecule for anti-cancer therapies. Unfortunately, cancer cells frequently acquire resistance to rhTRAIL. Various co-treatments have been proposed to overcome apoptosis resistance to TRAIL. Here we show that downregulation of the deISGylase USP18 sensitizes cancer cells to rhTRAIL, whereas, elevate levels of USP18 inhibit TRAIL-induced apoptosis, in a deISGylase independent manner. USP18 influences TRAIL signaling through the control of the IFN autocrine loop. In fact, cells with downregulated USP18 expression augment the expression of cellular TRAIL. Downregulation of cellular TRAIL abrogates the synergism between TRAIL and USP18 siRNA and also limits cell death induced by rhTRAIL. By comparing the apoptotic responsiveness to TRAIL in a panel of cancer cell lines, we have discovered a correlation between TRAIL levels and the apoptotic susceptibility to rhTRAIL, In cells expressing high levels of TRAIL-R2 susceptibility to rhTRAIL correlates with TRAIL expression. In conclusion, we propose that cellular TRAIL is an additional factor that can influence the apoptotic response to rhTRAIL. PMID- 24153059 TI - Inhibition of histone deacetylation and DNA methylation improves gene expression mediated by the adeno-associated virus/phage in cancer cells. AB - Bacteriophage (phage), viruses that infect bacteria only, have become promising vectors for targeted systemic delivery of genes to cancer, although, with poor efficiency. We previously designed an improved phage vector by incorporating cis genetic elements of adeno-associated virus (AAV). This novel AAV/phage hybrid (AAVP) specifically targeted systemic delivery of therapeutic genes into tumors. To advance the AAVP vector, we recently introduced the stress-inducible Grp78 tumor specific promoter and found that this dual tumor-targeted AAVP provides persistent gene expression, over time, in cancer cells compared to silenced gene expression from the CMV promoter in the parental AAVP. Herein, we investigated the effect of histone deacetylation and DNA methylation on AAVP-mediated gene expression in cancer cells and explored the effect of cell confluence state on AAVP gene expression efficacy. Using a combination of AAVP expressing the GFP reporter gene, flow cytometry, inhibitors of histone deacetylation, and DNA methylation, we have demonstrated that histone deacetylation and DNA methylation are associated with silencing of gene expression from the CMV promoter in the parental AAVP. Importantly, inhibitors of histone deacetylases boost gene expression in cancer cells from the Grp78 promoter in the dual tumor-targeted AAVP. However, cell confluence had no effect on AAVP-guided gene expression. Our findings prove that combination of histone deacetylase inhibitor drugs with the Grp78 promoter is an effective approach to improve AAVP-mediated gene expression in cancer cells and should be considered for AAVP-based clinical cancer gene therapy. PMID- 24153060 TI - CD8 and CD4 T cells in west nile virus immunity and pathogenesis. AB - CD4 and CD8 T lymphocytes are adaptive immune cells that play a key role in the immune response to pathogens. They have been extensively studied in a variety of model systems and the mechanisms by which they function are well described. However, the responses by these cell types vary widely from pathogen to pathogen. In this review, we will discuss the role of CD8 and CD4 T cells in the immune response to West Nile virus infection. PMID- 24153061 TI - Foamy virus vectors for HIV gene therapy. AB - Highly active antiretroviral therapy (HAART) has vastly improved outcomes for patients infected with HIV, yet it is a lifelong regimen that is expensive and has significant side effects. Retroviral gene therapy is a promising alternative treatment for HIV/AIDS; however, inefficient gene delivery to hematopoietic stem cells (HSCs) has so far limited the efficacy of this approach. Foamy virus (FV) vectors are derived from non-pathogenic viruses that are not endemic to the human population. FV vectors have been used to deliver HIV-inhibiting transgenes to human HSCs, and they have several advantages relative to other retroviral vectors. These include an attractive safety profile, broad tropism, a large transgene capacity, and the ability to persist in quiescent cells. In addition, the titers of FV vectors are not reduced by anti-HIV transgenes that affect the production of lentivirus (LV) vectors. Thus FV vectors are very promising for anti-HIV gene therapy. This review covers the advantages of FV vectors and describes their preclinical development for anti-HIV gene therapy. PMID- 24153085 TI - First, do no (more) harm. PMID- 24153062 TI - Detection and molecular diversity of spike gene of porcine epidemic diarrhea virus in China. AB - Since late 2010, porcine epidemic diarrhea virus (PEDV) has rapidly disseminated all over the China and caused considerable morbidity and high mortality (up to 100%) in neonatal piglets. 79.66% (141 of 177) pig farms in 29 provinces (excluding Tibet and Hainan, China) and 72.27% (417 of 577) samples were positive for PEDV confirmed by reverse transcription-polymerase chain reaction (RT-PCR). The full-length S genes of representative field strains were sequenced. 33 field strains share 93.5%-99.9% homologies with each other at the nucleotide sequence level and 92.3%-99.8% homologies with each other at the amino acids sequence level. Most field strains have nucleotide deletion and insertion regions, and show lower homologies (93.5%-94.2%) with Chinese classical strain CH/S, however higher homologies (97.1%-99.3%) with recent strain CHGD-1. The phylogenetic analysis showed there are classical strains and variants prevailing in pig herd in China. PEDV has a high detection rate in pig herds in China. Sequence analysis indicated the S genes of recent field strains have heterogeneity and the variants are predominant. PMID- 24153063 TI - Evolution of specific antibodies and proviral DNA in milk of small ruminants infected by small ruminant lentivirus. AB - The diagnosis of Small Ruminant Lentivirus (SRLV) is based on clinical signs, pathological lesions and laboratory testing. No standard reference test for the diagnosis of maedi visna has been validated up to the present, and it is puzzling that tests which detect antibodies against the virus and tests which detect the proviral genome may render opposite results. The aim of this study was to evaluate the presence in milk throughout a lactation period of specific antibodies by ELISA and of SRLV proviral DNA by a PCR of the highly conserved pol region. A six-month study was conducted with the milk of 28 ewes and 31 goats intensively reared. The percentage of animals with antibodies against SRLV increased throughout the study period. Seroprevalence in sheep was 28% at the beginning of the study and by the end it had increased up to 52.4%. In goats, initial seroprevalence of 5.6% increased to 16%. The percentage of PCR positive ewes was stable throughout the study period. Of the positive sheep, 21.4% were PCR-positive before antibodies could be detected and most of them became PCR negative shortly after the first detection of antibodies. This might suggest that antibodies have a neutralizing effect. In addition, an equal percentage of sheep were always PCR-negative but either became ELISA-positive or was always ELISA positive, which might support this hypothesis. On the other hand, the PCR results in goats did not follow any pattern and oscillated between 35.3% and 55.6% depending on the month. Most goats positive by PCR failed to develop antibodies in the 6 months tested. We may conclude that the infection and the antibody response to it follow a different trend in sheep and goats. PMID- 24153086 TI - Which analgesics are appropriate in patients with liver dysfunction? AB - Dose and frequency adjustments to analgesics may be needed for patients with liver dysfunction to avoid toxicity and minimize adverse reactions. PMID- 24153087 TI - A collection of red macules on a forearm. PMID- 24153089 TI - Understanding facial nerve paralysis. AB - Facial nerve paralysis has many causes and can be acute or chronic. Understanding the signs and symptoms, performing a careful patient evaluation, and obtaining appropriate diagnostic testing can help guide clinicians and improve outcomes. PMID- 24153090 TI - Saddle pulmonary tumor embolus secondary to renal cell carcinoma. AB - Most pulmonary tumor emboli are microscopic and occlude small arteries and arterioles with subsequent insidious clinical presentation. These emboli usually need conservative treatment. Emboli that spread to large proximal pulmonary arteries, although rare, can be life-threatening. This article focuses on the importance of prompt recognition, diagnosis, and appropriate management of pulmonary tumor emboli. PMID- 24153091 TI - Access to care: beyond health insurance. AB - Access to healthcare is derived from a complex mix of personal beliefs, cultural norms, and social structure, combined with available individual and community resources. This article reviews the concept of access to care and its evolution since the 1960s. The difference between potential and realized access and the question of social justice as it relates to access to care also are explored. PMID- 24153092 TI - Aortic stenosis. PMID- 24153093 TI - A puzzling urinary tract infection in a newborn. PMID- 24153094 TI - Recognizing and treating ADHD in adults. AB - Patients with attention deficit hyperactivity disorder (ADHD) commonly present in primary care settings. Because untreated adult ADHD can impair patients' quality of life, clinicians need to know how to recognize and treat this potentially lifelong disorder. PMID- 24153095 TI - Considering an aortic arch anomaly in patients with dysphagia. AB - In patients presenting with a chief complaint of dysphagia, physician assistants should consider anomalous vascularity as a possible cause of esophageal obstruction. PMID- 24153096 TI - An unusual and painful plantar eruption. PMID- 24153098 TI - Post radiation skin tumors: basal cell carcinomas, squamous cell carcinomas and angiosarcomas. A review of this late effect of radiotherapy. AB - This review gives an overview of radiotherapy-induced malignant skin tumors as described in the present medical literature. Basal cell carcinomas are the most frequent post-radiation malignant skin tumors; however, specific incidence ratios are few and show ratios of 2%. Squamous cell carcinomas are briefly discussed, followed by post-radiation sarcomas. Most cases of post-radiation cutaneous sarcomas are angiosarcoma, malignant fibrous histiocytoma, leiomyosarcoma and fibrosarcoma. In cases of radiotherapy for breast cancer, angiosarcomas are the most frequently found malignant sarcomas worldwide (incidence 0.5%) in the irradiated area. We present 192 cases of angiosarcomas after radiotherapy for breast cancer. Also, the atypical vascular lesion, a benign vascular skin lesion occurring after radiotherapy, and the important differential diagnosis of angiosarcoma will be presented and discussed. Other skin tumors supposedly related to radiotherapy are occasionally published and summarized in this review. Because most radiation-induced malignant tumors occur many years after the initiation of radiotherapy and incidences are low, we suggest good instruction of patients regarding self control of the skin rather than a yearly follow-up. PMID- 24153099 TI - Physical activity in adults with and without diabetes: from the 'high-risk' approach to the 'population-based' approach of prevention. AB - BACKGROUND: The prevalence rates of physical inactivity and diabetes in the MENA region are among the highest in the world. However, studies that focus on factors that influence the pattern of physical activity in the region remain very scarce. This study aimed to determine the prevalence and correlates of physical activity in the general population and among subjects with and without diabetes in Lebanon, a small middle-income country in the MENA region. METHODS: We conducted a cross-sectional nation-wide study of 2,195 randomly selected adults aged 25 years and older. Participants completed a comprehensive questionnaire based on the WHO-STEPwise guidelines. Physical activity was assessed using the International Physical Activity Questionnaire. Type 2 diabetes risk factors examined were age >= 45 years, BMI >= 25 kg/m2, hypertension, hyperlipidemia, cardiovascular disease and family history of diabetes. RESULTS: Close to 10% of adults with diabetes were physically active versus 23.4% without diabetes. Prevalence rates of physical activity declined consistently as the number of diabetes risk factors increased. Odds ratios for physical activity were lower among the educated (0.75, 95% CI= 0.57-0.98), those who owned at least one car (0.71, 95% CI= 0.57-0.88) and those who resided in the capital city (0.62, 95% CI 0.47-0.83). Health professionals gave 'advice to exercise' most to patients with or at highest risk for diabetes, and these were more likely to engage in physical activity than those without diabetes receiving the same advice, net of the effect of other covariates (OR=3.68 and 1.17, respectively). CONCLUSIONS: The inverse associations between physical activity and SES indicators suggest a negative influence of urbanization on activity levels of Lebanese adults. The missed opportunity for clinical primary preventive services for the majority non diabetic population calls for population-based public health approaches that promote physical activity as a routine lifestyle in the general population. PMID- 24153100 TI - The use of oral recombinant feline interferon omega in two cats with type II diabetes mellitus and concurrent feline chronic gingivostomatitis syndrome. AB - Feline Chronic Gingivostomatitis Syndrome (FCGS) is a common disease in clinical practice. Among the therapeutic options available, long-acting corticosteroids are frequently used due to their anti-inflammatory and immunosuppressive properties. Although they may improve the clinical symptoms, they can lead to a progressive form of the disease that becomes refractory to treatment. Furthermore, their direct relationship with type II diabetes mellitus (DM) is well known. Consequently, these drugs are controversial and not recommended for routine management of FCGS. Recombinant feline interferon-omega (rFeIFN-omega) is an immunomodulatory compound. Recently, its daily oral administration has been shown to be successful in treating refractory cases of FCGS. This case study describes two clinical cases of type II DM complicated by FCGS. Both animals were calicivirus positive and they had been previously treated with long-acting corticosteroids, which may have been the major cause of DM. The two cats were treated with glargine insulin (Lantus, starting dose 1 IU/cat twice daily (BID)), achieving remission 10 and 18 weeks later respectively. Considering the difficulty with control of FCGS in these animals, an oral daily dose of rFeIFN omega was started as an alternative to long-acting corticosteroids. In both cats oral clinical signs gradually improved and 60 days after the start of therapy the owners reported a significant relief of pain during mastication. According to the authors' knowledge, this is the first case report that describes the successful use of rFeIFN-omega in the management of FCGS in type II diabetic cats, in which long-acting corticosteroids are contraindicated. PMID- 24153101 TI - Profile and genetic parameters of dairy cattle locomotion score and lameness across lactation. AB - This study investigated the profile of locomotion score and lameness before the first calving and throughout the first (n=237) and second (n=66) lactation of 303 Holstein cows raised on a commercial farm. Weekly heritability estimates of locomotion score and lameness, and their genetic and phenotypic correlations with milk yield, body condition score, BW and reproduction traits were derived. Daughter future locomotion score and lameness predictions from their sires??? breeding values for conformation traits were also calculated. First-lactation cows were monitored weekly from 6 weeks before calving to the end of lactation. Second-lactation cows were monitored weekly throughout lactation. Cows were locomotion scored on a scale from one (sound) to five (severely lame); a score greater than or equal to two defined presence of lameness. Cows??? weekly body condition score and BW was also recorded. These records were matched to corresponding milk yield records, where the latter were 7-day averages on the week of inspection. The total number of repeated records amounted to 12 221. Data were also matched to the farm???s reproduction database, from which five traits were derived. Statistical analyses were based on uni- and bivariate random regression models. The profile analysis showed that locomotion and lameness problems in first lactation were fewer before and immediately after calving, and increased as lactation progressed. The profile of the two traits remained relatively constant across the second lactation. Highest heritability estimates were observed in the weeks before first calving (0.66 for locomotion score and 0.54 for lameness). Statistically significant genetic correlations were found for first lactation weekly locomotion score and lameness with body condition score, ranging from ???0.31 to ???0.65 and from ???0.44 to ???0.76, respectively, suggesting that cows genetically pre-disposed for high body condition score have fewer locomotion and lameness issues. Negative (favourable) phenotypic correlations between first lactation weekly locomotion score/lameness and milk yield averaged ???0.27 and ???0.17, respectively, and were attributed to management factors. Also a phenotypic correlation between lameness and conception rate of ???0.19 indicated that lame cows were associated with lower success at conceiving. First-lactation daughter locomotion score and/or lameness predictions from sires??? estimated breeding values for conformation traits revealed a significant linear effect of rear leg side view, rear leg rear view, overall conformation, body condition score and locomotion, and a quadratic effect of foot angle. PMID- 24153102 TI - In vitro study of combined cilengitide and radiation treatment in breast cancer cell lines. AB - BACKGROUND: Brain metastasis from breast cancer poses a major clinical challenge. Integrins play a role in regulating adhesion, growth, motility, and survival, and have been shown to be critical for metastatic growth in the brain in preclinical models. Cilengitide, an alphavbeta3/alphavbeta5 integrin inhibitor, has previously been studied as an anti-cancer drug in various tumor types. Previous studies have shown additive effects of cilengitide and radiation in lung cancer and glioblastoma cell lines. The ability of cilengitide to enhance the effects of radiation was examined preclinically in the setting of breast cancer to assess its possible efficacy in the setting of brain metastasis from breast cancer. METHODS: Our panel of breast cells was composed of four cell lines: T-47D (ER/PR+, Her2-, luminal A), MCF-7 (ER/PR+, Her2-, luminal A), MDA-MB-231 (TNBC, basal B), MDA-MB-468 (TNBC, basal A). The presence of cilengitide targets, beta3 and beta5 integrin, was first determined. Cell detachment was determined by cell counting, cell proliferation was determined by MTS proliferation assay, and apoptosis was measured by Annexin V staining and flow cytometry. The efficacy of cilengitide treatment alone was analyzed, followed by assessment of combined cilengitide and radiation treatment. Integrin beta3 knockdown was performed, followed by cilengitide and radiation treatment to test for incomplete target inhibition by cilengitide, in high beta3 expressing cells. RESULTS: We observed that all cell lines examined expressed both beta3 and beta5 integrin and that cilengitide was able to induce cell detachment and reduced proliferation in our panel. Annexin V assays revealed that a portion of these effects was due to cilengitide-induced apoptosis. Combined treatment with cilengitide and radiation served to further reduce proliferation compared to either treatment alone. Following beta3 integrin knockdown, radiosensitization in combination with cilengitide was observed in a previously non-responsive cell line (MDA-MB-231). Clonogenic assays suggested little radiosensitization effects of cilengitide. CONCLUSIONS: Cilengitide appears to enhance radiation response in preclinical models of breast cancer. These data suggest that the combination of radiation therapy and cilengitide may prove to be effective where radiation is utilized for the treatment of gross disease in breast cancer, such as in the setting of brain metastasis. PMID- 24153103 TI - Echocardiography in sickle cell anaemia patients under 20 years of age: a descriptive study in the Brazilian Western Amazon. AB - INTRODUCTION: Cardiac abnormalities in sickle cell anaemia are frequent and early, despite being more evident in adulthood. The study on cardiac abnormalities is essential in the current context, as, owing to improved health, children are increasingly able to reach adulthood and suffering the consequences of chronic cardiac injury. OBJECTIVE: The aim of this study was to determine the prevalence of echocardiographic changes in patients under 20, suffering from sickle cell disease in Rio Branco, Brazilian Western Amazon. METHODS: The descriptive epidemiological study compare two sets of children and adolescents, one including sickle cell anaemia patients (n=45), and other one (n=109) without sickle cell anaemia or heart disease. The echocardiographic measurements were indexed according to body surface using z-scores, and the prevalence of echocardiographic changes in both groups, with their respective 95% confidence intervals, ascertained and compared. RESULTS: Compared with the non-sickle cell anaemia series, the sickle cell anaemia group showed z-scores 13.1-fold higher for the diastolic diameter of the left ventricle, 5.2 times higher for the thickness of the posterior wall, 4.9 higher for the left atrium, 2.5 times higher for the right ventricle and 2.0 times higher for the septum thickness. Also the rate of left ventricular mass, systolic pressure of the right ventricle and the relative wall thickness were significantly higher in sickle cell anaemia set. CONCLUSIONS: Cardiac abnormalities were observed in 93.5% of patients. Early detection of cardiac abnormalities and quantifying them using the indexation of echocardiographic measurements according to body surface will allow proper identification and attendance of these children. PMID- 24153104 TI - Renal vasodilatory action of arginine vasopressin in extremely low birth weight infants. AB - In extremely low birth weight (ELBW) infants, systemic hypotension is associated with poor neurological outcomes as a result of cerebral hypoperfusion. Treatment with arginine vasopressin (AVP) has been shown to increase blood pressure (BP) and urine output in ELBW infants suffering from refractory hypotension. The purpose of this study was to clarify whether low doses of AVP increased renal blood flow (RBF) in ELBW infants. We retrospectively analyzed data from the medical charts describing nine AVP infusions at 0.3-0.8 mU/kg/min in four ELBW infants. The median gestational age was 23 (22.5-23.5, interquartile range) weeks, and the median birth weight was 466 (414-563) g. Changes in the heart rate, BP, urine output, and RBF velocity patterns in response to the AVP infusions were compared using statistical analyses. The AVP infusion caused significant increases in systolic BP from 44 (41.0-47.0) to 50 (42.5-55.5) mmHg, diastolic BP from 17 (15.0-26.5) to 31 (28.5-33.0) mmHg, mean BP from 26 (24.5 30.5) to 36 (34.5-40.5) mmHg, and urine output from 1.4 (0.2-2.5) to 2.8 (1.0 8.6) mL/kg/hr. We also observed significant decreases in the resistance index from 1.0 (0.96-1.0) to 0.8 (0.71-0.91) and peak systolic flow velocity in the renal artery from 40 (27.2-50.6) to 28 (16.0-28.9) cm/s after AVP infusions. AVP infusions at 0.3-0.8 mU/kg/min in ELBW infants appeared to significantly increase the RBF by inducing renal vascular dilation and increasing the BP. Increasing the RBF most likely induces an increase in the glomerular filtration rate, resulting in the diuretic effect of AVP. PMID- 24153105 TI - EZH2 is essential for development of mouse preimplantation embryos. AB - Enhancer of zeste homologue 2 (Ezh2) is essential for the development of the early mouse preimplantation embryo. Loss of Ezh2 results in embryonic lethality in mice. Ezh2-deficient embryos display impaired outgrowth potential, defective establishment of Ezh2-null embryonic stem (ES) cells and adherence and differentiation of the trophoblast layer into giant cells. We investigated if Ezh2 controls the fate of embryos at an earlier stage by treating with cycloheximide (CHX) or microinjecting short interfering RNA (siRNA) to restrict embryonic Ezh2 expression during preimplantation. CHX inhibited de novo EZH2 protein synthesis in zygotes, suggesting that EZH2 requires de novo synthesis during post-fertilisation stages. We found that loss of Ezh2 at the pronuclear stage caused severe growth retardation and reduced blastocyst formation. Expression of the pluripotency-associated markers Oct4, Sox2 and Nanog were significantly decreased in embryos that had been injected with Ezh2 siRNA. In addition, Ezh2 loss induced upregulated expression of genes related to the differentiation of germ layers, including Gata6, Hoxb1 and Hand1. Finally, apoptosis was increased in the blastocyst embryos with Ezh2 knockdown. Modification of histone H3-Lysine 27 de-methylation and tri-methylation (H3K27me2/3) was strongly reduced in Ezh2 siRNA embryos. We conclude that Ezh2 is essential for early preimplantation embryo development through the regulation of epigenetic modification and apoptosis. PMID- 24153106 TI - Cracked titanium film on an elastomeric substrate for highly flexible, transparent, and low-power strain sensors. AB - Strain-dependent cracking behaviors in thin titanium (Ti) films on polydimethylsiloxane (PDMS) substrates were systematically investigated for their application to sensitive, flexible, transparent, and portable strain sensors. When uniaxially elongated, vertical cracks were developed in the low-strain range, and beyond a critical strain, tilted cracks appeared to intersect the vertical cracks. The cracking behaviors were also dependent on Ti film thickness. The varying strain-dependent crack patterns produced a significant resistance change in response to the applied strain, particularly, in the high- and broad strain range. For a 180-nm-thick Ti film on PDMS substrate, a gauge factor of 2 was achieved in the range of 30% to 50% strain. The operation power was extremely low. All the Ti films on PDMS substrates were transparent, highly flexible, and very easy to fabricate. These results suggest that cracked Ti films on PDMS substrates could be a viable candidate for realizing a low-cost, flexible, transparent, and portable strain sensor. PMID- 24153107 TI - Lung cancer stem cells and low-intensity laser irradiation: a potential future therapy? AB - Lung cancer is notably a significant threat when considering worldwide cancer related deaths. Despite significant advances in treatment modalities, death rates as a result of cancer relapse remain high. Relapse can occur as a result of metastasis. Cancer stem cells (CSCs) have been implicated as an important contributory factor in the development of metastasis. CSCs have the same characteristics as normal stem cells; that is, they can proliferate indefinitely and are capable of both self-renewal and differentiating into specialized cells. The molecular and cellular characteristics of stem cells and CSCs are coded for by cell-specific genes, which can be analyzed by using molecular assays setting the standard to work from. Low-intensity laser irradiation (LILI) has been applied in the treatment of numerous diseases and pathological conditions. LILI has been shown to stimulate proliferation of cells, capillary growth, and cellular metabolism as observed by adenosine triphosphate activation. It has been shown, by using different dosing levels of LILI, to either stimulate or inhibit cellular functions. One treatment strategy used on cancer cells is photodynamic therapy (PDT), in which cancer cells are treated with a photosensitizer (PS) in combination with laser irradiation. PSs are non-toxic by themselves but, with light activation, cause reactive oxygen species generation, which causes cancer cell death. Cell-specific PSs are being developed for future cancer treatment. In this review, we look at the potential effects of LILI and PDT on lung CSCs. PMID- 24153109 TI - PDBsum additions. AB - PDBsum, http://www.ebi.ac.uk/pdbsum, is a website providing numerous pictorial analyses of each entry in the Protein Data Bank. It portrays the structural features of all proteins, DNA and ligands in the entry, as well as depicting the interactions between them. The latest features, described here, include annotation of human protein sequences with their naturally occurring amino acid variants, dynamic graphs showing the relationships between related protein domain architectures, analyses of ligand binding clusters across different experimental determinations of the same protein, analyses of tunnels in proteins and new search options. PMID- 24153108 TI - Association between the seven-repeat allele of the dopamine-4 receptor gene (DRD4) and spontaneous food intake in pre-school children. AB - BACKGROUND: Studies in adults show associations between the hypofunctional seven repeat allele (7R) of the dopamine-4 receptor gene (DRD4), increased eating behaviour and/or obesity, particularly in females. We examined whether 7R is associated with total caloric intake and/or food choices in pre-schoolers. METHODS: 150 four-year-old children taking part in a birth cohort study in Canada were administered a snack test meal in a laboratory setting. Mothers also filled out a food frequency questionnaire to address childrens' habitual food consumption. Total caloric and individual macronutrient intakes during the snack meal and specific types of foods as reported in the food diaries were compared across 7R allele carriers vs. non-carriers, using current BMI as a co-variate. RESULTS: We found significant sex by genotype interactions for fat and protein intake during the snack test. Post hoc testing revealed that in girls, but not boys, 7R carriers ate more fat and protein than did non-carriers. Based on the food diaries, across both sexes, 7R carriers consumed more portions of ice cream and less vegetables, eggs, nuts and whole bread, suggesting a less healthy pattern of habitual food consumption. CONCLUSION: The 7R allele of DRD4 influences macronutrient intakes and specific food choices as early as four years of age. The specific pattern of results further suggests that prior associations between the 7R allele and adult overeating/obesity may originate in food choices observable in the preschool years. Longitudinal follow-up of these children will help establish the relevance of these findings for obesity risk and prevention. PMID- 24153110 TI - One-pot DNA construction for synthetic biology: the Modular Overlap-Directed Assembly with Linkers (MODAL) strategy. AB - Overlap-directed DNA assembly methods allow multiple DNA parts to be assembled together in one reaction. These methods, which rely on sequence homology between the ends of DNA parts, have become widely adopted in synthetic biology, despite being incompatible with a key principle of engineering: modularity. To answer this, we present MODAL: a Modular Overlap-Directed Assembly with Linkers strategy that brings modularity to overlap-directed methods, allowing assembly of an initial set of DNA parts into a variety of arrangements in one-pot reactions. MODAL is accompanied by a custom software tool that designs overlap linkers to guide assembly, allowing parts to be assembled in any specified order and orientation. The in silico design of synthetic orthogonal overlapping junctions allows for much greater efficiency in DNA assembly for a variety of different methods compared with using non-designed sequence. In tests with three different assembly technologies, the MODAL strategy gives assembly of both yeast and bacterial plasmids, composed of up to five DNA parts in the kilobase range with efficiencies of between 75 and 100%. It also seamlessly allows mutagenesis to be performed on any specified DNA parts during the process, allowing the one-step creation of construct libraries valuable for synthetic biology applications. PMID- 24153112 TI - Associations between intronic non-B DNA structures and exon skipping. AB - Non-B DNA structures are abundant in the genome and are often associated with critical biological processes, including gene regulation, chromosome rearrangement and genome stabilization. In particular, G-quadruplex (G4) may affect alternative splicing based on its ability to impede the activity of RNA polymerase II. However, the specific role of non-B DNA structures in splicing regulation still awaits investigation. Here, we provide a genome-wide and cross species investigation of the associations between five non-B DNA structures and exon skipping. Our results indicate a statistically significant correlation of each examined non-B DNA structures with exon skipping in both human and mouse. We further show that the contributions of non-B DNA structures to exon skipping are influenced by the occurring region. These correlations and contributions are also significantly different in human and mouse. Finally, we detailed the effects of G4 by showing that occurring on the template strand and the length of G-run, which is highly related to the stability of a G4 structure, are significantly correlated with exon skipping activity. We thus show that, in addition to the well-known effects of RNA and protein structure, the relative positional arrangement of intronic non-B DNA structures may also impact exon skipping. PMID- 24153111 TI - Dynamic interactions of the HIV-1 Tat with nucleic acids are critical for Tat activity in reverse transcription. AB - The HIV-1 transactivator of transcription (Tat) protein is thought to stimulate reverse transcription (RTion). The Tat protein and, more specifically, its (44 61) domain were recently shown to promote the annealing of complementary DNA sequences representing the HIV-1 transactivation response element TAR, named dTAR and cTAR, that plays a key role in RTion. Moreover, the kinetic mechanism of the basic Tat(44-61) peptide in this annealing further revealed that this peptide constitutes a representative nucleic acid annealer. To further understand the structure-activity relationships of this highly conserved domain, we investigated by electrophoresis and fluorescence approaches the binding and annealing properties of various Tat(44-61) mutants. Our data showed that the Tyr47 and basic residues of the Tat(44-61) domain were instrumental for binding to cTAR through stacking and electrostatic interactions, respectively, and promoting its annealing with dTAR. Furthermore, the annealing efficiency of the mutants clearly correlates with their ability to rapidly associate and dissociate the complementary oligonucleotides and to promote RTion. Thus, transient and dynamic nucleic acid interactions likely constitute a key mechanistic component of annealers and the role of Tat in the late steps of RTion. Finally, our data suggest that Lys50 and Lys51 acetylation regulates Tat activity in RTion. PMID- 24153113 TI - Rotational positioning of nucleosomes facilitates selective binding of p53 to response elements associated with cell cycle arrest. AB - The tumor suppressor protein p53 exhibits high affinity to the response elements regulating cell cycle arrest genes (CCA-sites), but relatively low affinity to the sites associated with apoptosis (Apo-sites). This in vivo tendency cannot be explained solely by the p53-DNA binding constants measured in vitro. Since p53 can bind nucleosomal DNA, we sought to understand if the two groups of p53 sites differ in their accessibility when embedded in nucleosomes. To this aim, we analyzed the sequence-dependent bending anisotropy of human genomic DNA containing p53 sites. For the 20 CCA-sites, we calculated rotational positioning patterns predicting that most of the sites are exposed on the nucleosomal surface. This is consistent with experimentally observed positioning of human nucleosomes. Remarkably, the sequence-dependent DNA anisotropy of both the p53 sites and flanking DNA work in concert producing strong positioning signals. By contrast, both the predicted and observed rotational settings of the 38 Apo-sites in nucleosomes suggest that many of these sites are buried inside, thus preventing immediate p53 recognition and delaying gene induction. The distinct chromatin organization of the CCA response elements appears to be one of the key factors facilitating p53-DNA binding and subsequent activation of genes associated with cell cycle arrest. PMID- 24153114 TI - Do knowledge brokers facilitate implementation of the stroke guideline in clinical practice? AB - BACKGROUND: The implementation of clinical practice guidelines in rehabilitation practice is often troublesome and incomplete. An intervention to enhance the implementation of guidelines is the knowledge transfer program built around the activities of a knowledge broker (KB).This study investigates the use of KBs to implement guideline recommendations for intensive therapy and physical activity for patients post-stroke in 22 stroke units in hospitals and rehabilitation centers in The Netherlands. METHODS/DESIGN: This study includes a quantitative evaluation with a non controlled pre-post intervention design and a mixed methods process evaluation. From each stroke unit, enterprising nurses and therapists will be recruited and trained as KB. The KB will work for one year on the implementation of the guideline recommendations in their team. To evaluate the effectiveness of the KB, a questionnaire will be administered to patients, health professionals and KBs at baseline (T0) and after one year (T1). Furthermore, semi structured interviews with 5 KBs will be performed at T1.The primary outcome of this implementation project will be the support health professionals give patients to exercise and be physically active, as reported by patients and health professionals themselves. The support immediately after the intervention is compared with the support at the start of the intervention.Additionally we will explore the influence of socio-demographic characteristics of health professionals and determinants identified in the Theory of Planned Behavior (intention, attitude, subjective norm and perceived behavioral control) on the change of supportive behavior of health professionals. Finally, KBs will complete a questionnaire on their own psychological and social demographic characteristics and on organizational conditions needed for health-care improvement such as time, workforce, sponsoring and support from management. DISCUSSION: With this study we will gain insight in when and why knowledge brokers seem to be effective. Also we will identify determinants that predict which health professionals are susceptible to change their behavior. This study will provide guidance how to implement guidelines and will help to improve stroke rehabilitation services. PMID- 24153115 TI - TRIM5alpha variations influence transduction efficiency with lentiviral vectors in both human and rhesus CD34(+) cells in vitro and in vivo. AB - Human immunodeficiency virus type 1 (HIV-1) vectors can transduce human hematopoietic stem cells (HSC), but transduction efficiency varies among individuals. The innate immune factor tripartite motif-containing protein 5alpha (TRIM5alpha) plays an important role for restriction of retroviral infection. In this study, we examined whether TRIM5alpha could account for variations in transduction efficiency using both an established rhesus gene therapy model and human CD34(+) cell culture. Evaluation of TRIM5alpha genotypes (Mamu-1, -2, -3, 4, -5, and TrimCyp) in 16 rhesus macaques that were transplanted with transduced CD34(+) cells showed a significant correlation between TRIM5alpha Mamu-4 and high gene marking in both lymphocytes and granulocytes 6 months after transplantation. Since significant human TRIM5alpha coding polymorphisms were not known, we evaluated TRIM5alpha expression levels in human CD34(+) cells from 14 donors. Three days after HIV-1 vector transduction, measured transduction efficiency varied significantly among donors and was negatively correlated with TRIM5alpha expression levels. In summary, transduction efficiency in both rhesus and human CD34(+) cells was influenced by TRIM5alpha variations (genotypes and expression levels). Our findings are important for both understanding and mitigating the variability of transduction efficiency for rhesus and human CD34(+) cells. PMID- 24153116 TI - The tumor suppressing effects of QKI-5 in prostate cancer: a novel diagnostic and prognostic protein. AB - In recent years, the RNA-binding protein quaking 5 (QKI-5) has been recognized as a novel tumor suppressor in many cancers. To date, no studies have examined the role of QKI-5 in prostate cancer. The present study was designed to elucidate the correlation of QKI-5 expression with the clinical pathological features and prognosis of prostate cancer. In an overwhelming majority of the 184 cases of prostate cancer samples analyzed, the QKI-5 expression was significantly decreased, which was largely due to the high promoter methylation levels. Using lentiviral vectors, we established two stable prostate cancer cell lines with altered QKI-5 expression, including a QKI-5 overexpressing PC3 cell line and a DU145 cell line with knocked-down QKI-5 expression. The effects of the lentiviral mediated QKI-5 knockdown on the PC3 cells and DU145 cells were assessed by cell growth curves, flow cytometry (FCM), and an invasion assay. The PC3 cells were transplanted into nude mice, and then, the tumor growth curves and TUNEL staining were determined. These results demonstrated that QKI-5 was highly expressed in benign prostatic hyperplasia (BPH) tissues but not in carcinomatous tissues and that QKI-5 effectively inhibited prostate cancer cell proliferation in vitro and in vivo. In addition, the decrease in QKI-5 expression was closely correlated with the prostate cancer Gleason score, poor differentiation, degree of invasion, lymph node metastasis, distant metastasis, TNM grading, and poor survival. These results indicate that the QKI-5 expression may be a novel, independent factor in the prognosis of prostate cancer patients. PMID- 24153117 TI - Optimal culture incubation time in orthopedic device-associated infections: a retrospective analysis of prolonged 14-day incubation. AB - Accurate diagnosis of orthopedic device-associated infections can be challenging. Culture of tissue biopsy specimens is often considered the gold standard; however, there is currently no consensus on the ideal incubation time for specimens. The aim of our study was to assess the yield of a 14-day incubation protocol for tissue biopsy specimens from revision surgery (joint replacements and internal fixation devices) in a general orthopedic and trauma surgery setting. Medical records were reviewed retrospectively in order to identify cases of infection according to predefined diagnostic criteria. From August 2009 to March 2012, 499 tissue biopsy specimens were sampled from 117 cases. In 70 cases (59.8%), at least one sample showed microbiological growth. Among them, 58 cases (82.9%) were considered infections and 12 cases (17.1%) were classified as contaminations. The median time to positivity in the cases of infection was 1 day (range, 1 to 10 days), compared to 6 days (range, 1 to 11 days) in the cases of contamination (P < 0.001). Fifty-six (96.6%) of the infection cases were diagnosed within 7 days of incubation. In conclusion, the results of our study show that the incubation of tissue biopsy specimens beyond 7 days is not productive in a general orthopedic and trauma surgery setting. Prolonged 14-day incubation might be of interest in particular situations, however, in which the prevalence of slow-growing microorganisms and anaerobes is higher. PMID- 24153118 TI - Real-time reverse transcription-PCR assay panel for Middle East respiratory syndrome coronavirus. AB - A new human coronavirus (CoV), subsequently named Middle East respiratory syndrome (MERS)-CoV, was first reported in Saudi Arabia in September 2012. In response, we developed two real-time reverse transcription-PCR (rRT-PCR) assays targeting the MERS-CoV nucleocapsid (N) gene and evaluated these assays as a panel with a previously published assay targeting the region upstream of the MERS CoV envelope gene (upE) for the detection and confirmation of MERS-CoV infection. All assays detected <=10 copies/reaction of quantified RNA transcripts, with a linear dynamic range of 8 log units and 1.3 * 10(-3) 50% tissue culture infective doses (TCID50)/ml of cultured MERS-CoV per reaction. All assays performed comparably with respiratory, serum, and stool specimens spiked with cultured virus. No false-positive amplifications were obtained with other human coronaviruses or common respiratory viral pathogens or with 336 diverse clinical specimens from non-MERS-CoV cases; specimens from two confirmed MERS-CoV cases were positive with all assay signatures. In June 2012, the U.S. Food and Drug Administration authorized emergency use of the rRT-PCR assay panel as an in vitro diagnostic test for MERS-CoV. A kit consisting of the three assay signatures and a positive control was assembled and distributed to public health laboratories in the United States and internationally to support MERS-CoV surveillance and public health responses. PMID- 24153119 TI - Pre-multidrug-resistant Mycobacterium tuberculosis Beijing strain associated with disseminated tuberculosis in a pet dog. AB - Resistance to isoniazid, ethambutol, and streptomycin was detected in a Mycobacterium tuberculosis strain, belonging to the Beijing family lineage, isolated from two nodule exudates of a Yorkshire terrier with generalized tuberculosis. This report alerts medical practitioners to the risk of dissemination of pre-multidrug-resistant tuberculosis (preMDR-TB) through exposure to M. tuberculosis-shedding pets. PMID- 24153120 TI - Newly emerging mutations in the matrix genes of the human influenza A(H1N1)pdm09 and A(H3N2) viruses reduce the detection sensitivity of real-time reverse transcription-PCR. AB - New variants of the influenza A(H1N1)pdm09 and A(H3N2) viruses were detected in Taiwan between 2012 and 2013. Some of these variants were not detected in clinical specimens using a common real-time reverse transcription-PCR (RT-PCR) assay that targeted the conserved regions of the viral matrix (M) genes. An analysis of the M gene sequences of the new variants revealed that several newly emerging mutations were located in the regions where the primers or probes of the real-time RT-PCR assay bind; these included three mutations (G225A, T228C, and G238A) in the A(H1N1)pdm09 virus, as well as one mutation (C163T) in the A(H3N2) virus. These accumulated mismatch mutations, together with the previously identified C154T mutation of the A(H1N1)pdm09 virus and the C153T and G189T mutations of the A(H3N2) virus, result in a reduced detection sensitivity for the real-time RT-PCR assay. To overcome the loss of assay sensitivity due to mismatch mutations, we established a real-time RT-PCR assay using degenerate nucleotide bases in both the primers and probe and successfully increased the sensitivity of the assay to detect circulating variants of the human influenza A viruses. Our observations highlight the importance of the simultaneous use of different gene targeting real-time RT-PCR assays for the clinical diagnosis of influenza. PMID- 24153121 TI - Comparison of sputum and nasopharyngeal aspirate samples and of the PCR gene targets lytA and Spn9802 for quantitative PCR for rapid detection of pneumococcal pneumonia. AB - We aimed to compare sputum and nasopharyngeal aspirate (NpA) samples and the PCR gene targets lytA and Spn9802 in quantitative PCR (qPCR) assays for rapid detection of pneumococcal etiology in community-acquired pneumonia (CAP). Seventy eight adult patients hospitalized for radiologically confirmed CAP had both good quality sputum and NpA specimens collected at admission. These samples were subjected to lytA qPCR and Spn9802 qPCR assays with analytical times of <3 h. Thirty-two patients had CAP with a pneumococcal etiology, according to conventional diagnostic criteria. The following qPCR positivity rates were noted in CAP cases with and without pneumococcal etiology: 96% and 15% (sputum lytA assay), 96% and 17% (sputum Spn9802 assay), 81% and 11% (NpA lytA assay), and 81% and 20% (NpA Spn9802 assay), respectively. The mean lytA and Spn9802 DNA levels were significantly higher in qPCR-positive sputum samples from cases with pneumococcal etiology than in qPCR-positive sputum samples from CAP cases without pneumococcal etiology or qPCR-positive NpA samples from cases with pneumococcal etiology (P < 0.02 for all comparisons). For detection of pneumococcal etiology, receiver operating characteristic curve analysis showed that sputum specimens were superior to NpA specimens as the sample type (P < 0.02 for both gene targets) and lytA tended to be superior to Spn9802 as the gene target. The best performing test, the sputum lytA qPCR assay, showed high sensitivity (94%) and specificity (96%) with a cutoff value of 10(5) DNA copies/ml. In CAP patients with good sputum production, this test has great potential to be used for the rapid detection of pneumococcal etiology and to target penicillin therapy. PMID- 24153122 TI - Significant reduction in rate of indeterminate results of the QuantiFERON-TB Gold In-Tube test by shortening incubation delay. AB - The QuantiFERON-TB Gold In-Tube (QFT-G IT) test (Cellestis Inc., Valencia, CA) is one of the gamma interferon release assays (IGRAs) that are promising tools for diagnosing active or latent Mycobacterium tuberculosis infections. We investigated the clinical and laboratory factors that affect the rate of indeterminate QFT-G IT test results. We also suggest a workflow strategy for achieving optimized test results using the QFT-G IT test for the diagnosis of active tuberculosis (TB) or latent TB infection. We performed statistical analysis using data from a retrospective review of medical records. The first phase included 683 QFT-G IT test results from 676 patients tested between January 2008 and May 2008, and the second phase included an additional 663 QFT-G IT test results from 653 patients tested between January 2008 and December 2008 at Samsung Medical Center, a tertiary care hospital in South Korea. Immunosuppressive drug therapy, underlying diseases, bedridden status, and hypoalbuminemia were significantly associated with indeterminate QFT-G IT test results. With reduction of the incubation delay during the test procedure from an average of 9.82 h to an average of 2.70 h with changes in the workflow, the frequency of indeterminate QFT-G IT test results was significantly reduced from 11.4% to 2.7%. With >6 h of incubation delay, however, the frequency of indeterminate QFT-G IT test results was increased in a statistically significant manner. This study demonstrates that not only clinicopathological factors but also laboratory factors, such as incubation delay, significantly affect the rate of indeterminate QFT-G IT test results; therefore, optimization of the test procedure may contribute to reductions in the rate of indeterminate QFT-G IT test results, which delay the diagnosis of TB. PMID- 24153123 TI - An unusual case of acute cystitis associated with mixed flora in voided urine in an adult male. AB - This report describes two episodes of acute cystitis associated with "mixed flora" in an elderly male following a cystoscopy. The initial episode was accompanied by pyuria and a positive nitrite test. Both episodes responded to treatment with nitrofurantoin. Urine cultures were negative prior to the episodes and at a 1-year follow-up. PMID- 24153125 TI - Frequency of susceptibility testing for patients with persistent methicillin resistant Staphylococcus aureus bacteremia. AB - Currently, no standards exist for determining the optimal frequency of repeat antimicrobial susceptibility testing (AST) when an organism is recurrently isolated from the same specimen source. Although testing every 2 to 5 days is thought sufficient, we present three cases of methicillin-resistant Staphylococcus aureus (MRSA) bacteremia where current laboratory protocol for repeating AST every 5 days was inadequate to identify resistant organisms. PMID- 24153126 TI - High nasal burden of methicillin-resistant Staphylococcus aureus increases risk of invasive disease. AB - In a retrospective cohort study of 1,140 patients harboring methicillin-resistant Staphylococcus aureus, the nasal burden was low in 31%, category 1+ to 2+ in 54%, and category 3+ to 4+ in 15%. There was a significant trend in infection risk with increasing nasal burden (P = 0.007). In multivariate models, high nasal burden remained significantly associated with invasive infection. PMID- 24153127 TI - Monitoring of patients supported by extracorporeal membrane oxygenation for systemic infections by broad-range rRNA gene PCR amplification and sequence analysis. AB - The rRNA gene PCR and sequencing test, SepsiTest, was compared with blood culture (BC) regarding the diagnosis of pathogens in 160 blood samples drawn from 28 patients during extracorporeal membrane oxygenation. With 45% of positive samples, SepsiTest was 13 to 75 h faster than BC. SepsiTest indicated bacteremias in 25% of patients who were BC negative. PMID- 24153128 TI - Rapid identification and subtyping of Helicobacter cinaedi strains by intact-cell mass spectrometry profiling with the use of matrix-assisted laser desorption ionization-time of flight mass spectrometry. AB - Helicobacter cinaedi infection is recognized as an increasingly important emerging disease in humans. Although H. cinaedi-like strains have been isolated from a variety of animals, it is difficult to identify particular isolates due to their unusual phenotypic profiles and the limited number of biochemical tests for detecting helicobacters. Moreover, analyses of the 16S rRNA gene sequences are also limited due to the high levels of similarity among closely related helicobacters. This study was conducted to evaluate intact-cell mass spectrometry (ICMS) profiling using matrix-assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOF MS) as a tool for the identification of H. cinaedi. A total of 68 strains of H. cinaedi isolated from humans, dogs, a cat, and hamsters were examined in addition to other Helicobacter species. The major ICMS profiles of H. cinaedi were identical and differed from those of Helicobacter bilis, which show >98% sequence similarity at the 16S rRNA sequence level. A phyloproteomic analysis of the H. cinaedi strains examined in this work revealed that human isolates formed a single cluster that was distinct from that of the animal isolates, with the exception of two strains from dogs. These phyloproteomic results agreed with those of the phylogenetic analysis based on the nucleotide sequences of the hsp60 gene. Because they formed a distinct cluster in both analyses, our data suggest that animal strains may not be a major source of infection in humans. In conclusion, the ICMS profiles obtained using a MALDI-TOF MS approach may be useful for the identification and subtyping of H. cinaedi. PMID- 24153129 TI - Use of micafungin as a surrogate marker to predict susceptibility and resistance to caspofungin among 3,764 clinical isolates of Candida by use of CLSI methods and interpretive criteria. AB - Due to unacceptably high interlaboratory variation in caspofungin MIC values, we evaluated the use of micafungin as a surrogate marker to predict the susceptibility of Candida spp. to caspofungin using reference methods and species specific interpretive criteria. The MIC results for 3,764 strains of Candida (eight species), including 73 strains with fks mutations, were used. Caspofungin MIC values and species-specific interpretive criteria were compared with those of micafungin to determine the percent categorical agreement (%CA) and very major error (VME), major error (ME), and minor error rates as well as their ability to detect fks mutant strains of Candida albicans (11 mutants), Candida tropicalis (4 mutants), Candida krusei (3 mutants), and Candida glabrata (55 mutants). Overall, the %CA was 98.8% (0.2% VMEs and MEs, 0.8% minor errors) using micafungin as the surrogate marker. Among the 60 isolates of C. albicans (9 isolates), C. tropicalis (5 isolates), C. krusei (2 isolates), and C. glabrata (44 isolates) that were nonsusceptible (either intermediate or resistant) to both caspofungin and micafungin, 54 (90.0%) contained a mutation in fks1 or fks2. An additional 10 C. glabrata mutants, two C. albicans mutants, and one mutant each of C. tropicalis and C. krusei were classified as susceptible to both antifungal agents. Using the epidemiological cutoff values (ECVs) of 0.12 MUg/ml for caspofungin and 0.03 MUg/ml for micafungin to differentiate wild-type (WT) from non-WT strains of C. glabrata, 80% of the C. glabrata mutants were non-WT for both agents (96% concordance). Micafungin may serve as an acceptable surrogate marker for the prediction of susceptibility and resistance of Candida to caspofungin. PMID- 24153130 TI - Clinical evaluation of BioPlex 2200 HIV Ag-Ab, an automated screening method providing discrete detection of HIV-1 p24 antigen, HIV-1 antibody, and HIV-2 antibody. AB - Early and accurate diagnosis is essential for optimal therapeutic outcomes in patients infected with HIV. Currently, none of the commercially available fourth generation assays differentiate HIV-1 and HIV-2 antibodies (Ab) or the HIV-1 p24 antigen (Ag). The aim of this study was to evaluate the performance of a novel assay, the BioPlex 2200 HIV Ag-Ab. This assay uses a multiplex flow immunoassay design allowing the simultaneous detection and identification of antibodies to HIV-1 (groups M and O), HIV-2, and the HIV-1 p24 antigen, in addition to providing a traditional composite result. A total of 1,505 routine serum samples were prospectively tested. Results were compared with those from the Architect HIV Combo assay. The sensitivity of the BioPlex 2200 was 100%. The specificity assessed on repeated false-positive samples was 99.5%. In addition, 524 frozen specimens from patients known to be infected with HIV-1 or HIV-2 were tested. Of these specimens, 420 were infected with HIV-1, including 156 of known genotypes, 86 were infected with HIV-2, 7 were infected with HIV-1 and HIV-2, and 11 were from patients with acute HIV infection. Sensitivity was 100% for the HIV genotypes tested. The differentiation capabilities of the BioPlex 2200 HIV Ag-Ab assay for HIV-1, HIV-2, dual HIV-1/HIV-2, and early infections were 100%, 90.7%, 100%, and 90.9%, respectively. The BioPlex 2200 is a sensitive and specific assay that offers advantages over conventional HIV combo assays, also referred to as fourth-generation assays, to accurately differentiate and report HIV-1 p24 antigen and HIV-1 and HIV-2 antibodies. PMID- 24153131 TI - Sepsis with an Atopobium-like species in a patient with Fournier's gangrene. AB - Atopobium species are Gram-positive, anaerobic, catalase-negative, fastidious bacteria belonging to the family Coriobacteriaceae. We report the isolation of an Atopobium-like species in a patient with Fournier's gangrene and highlight the role of 16S rRNA gene sequencing in the identification of fastidious organisms in the clinical laboratory. PMID- 24153132 TI - Utility of a commercial PCR assay and a clinical prediction rule for detection of toxigenic Clostridium difficile in asymptomatic carriers. AB - A commercial PCR assay of perirectal swab specimens detected 17 (68%) of 25 asymptomatic carriers of toxigenic Clostridium difficile, including 93% with skin and/or environmental contamination. A clinical prediction rule, followed by PCR screening, could be used to identify carriers at high risk of C. difficile shedding. PMID- 24153133 TI - Detection of resistance to beta-lactamase inhibitors in strains with CTX-M beta lactamases: a multicenter external proficiency study using a well-defined collection of Escherichia coli strains. AB - Under the auspices of the Spanish Society for Infectious Diseases and Clinical Microbiology Quality Control program, 14 Escherichia coli strains masked as blood culture isolates were sent to 68 clinical microbiology laboratories for antimicrobial susceptibility testing to beta-lactam antibiotics. This collection included three control strains (E. coli ATCC 25922, an IRT-2 producer, and a CMY 2 producer), six isogenic strains with or without the OmpF porin and expressing CTX-M beta-lactamases (CTX-M-1, CTX-M-15, and CTX-M-14), one strain carrying a double mechanism for beta-lactam resistance (i.e., carrying CTX-M-15 and OXA-1 enzymes), and four strains carrying CTX-M variants with different levels of resistance to beta-lactams and beta-lactam-beta-lactamase inhibitor (BLBLI) combinations. The main objective of the study was to ascertain how these variants with reduced susceptibilities to BLBLIs are identified in clinical microbiology laboratories. CTX-M variants with high resistance to BLBLIs were mainly identified as inhibitor-resistant TEM (IRT) enzymes (68.0%); however, isogenic CTX-M mutant strains with reduced susceptibilities to BLBLIs and cephalosporins were mainly associated with extended-spectrum beta-lactamase production alone (51 to 80%) or in combination with other mechanisms (14 to 31%). Concerning all beta lactams tested, the overall interpretative discrepancy rate was 11.5%, of which 38.1% were the consequence of postreading changes in the clinical categories when a resistance mechanism was inferred. Therefore, failure to recognize these complex phenotypes might contribute to an explanation of their apparent absence in the clinical setting and might lead to inadequate drug treatment selection. A proposal for improving recognition is to adhere strictly to the current CLSI or EUCAST guidelines for detecting reduced susceptibility to BLBLI combinations, without any interpretative modification. PMID- 24153136 TI - The relationship between obesity and psoriasis in the pediatric population: implications and future directions. PMID- 24153135 TI - Rapid identification of Staphylococcus aureus directly from Bactec blood culture broth by the BinaxNOW S. aureus test. AB - The BinaxNOW Staphylococcus aureus testing showed sensitivity, specificity, and positive and negative predicative values of 97.6%, 100%, 100%, and 98.4%, respectively, for identification of S. aureus from Bactec blood culture broth. Importantly, the test performed equally well on aerobic and anaerobic culture broth. PMID- 24153137 TI - Health care reform and the sustainable growth rate: what's happening now? PMID- 24153134 TI - HIV diversity as a biomarker for HIV incidence estimation: including a high resolution melting diversity assay in a multiassay algorithm. AB - Multiassay algorithms (MAAs) can be used to estimate cross-sectional HIV incidence. We previously identified a robust MAA that includes the BED capture enzyme immunoassay (BED-CEIA), the Bio-Rad Avidity assay, viral load, and CD4 cell count. In this report, we evaluated MAAs that include a high-resolution melting (HRM) diversity assay that does not require sequencing. HRM scores were determined for eight regions of the HIV genome (2 in gag, 1 in pol, and 5 in env). The MAAs that were evaluated included the BED-CEIA, the Bio-Rad Avidity assay, viral load, and the HRM diversity assay, using HRM scores from different regions and a range of region-specific HRM diversity assay cutoffs. The performance characteristics based on the proportion of samples that were classified as MAA positive by duration of infection were determined for each MAA, including the mean window period. The cross-sectional incidence estimates obtained using optimized MAAs were compared to longitudinal incidence estimates for three cohorts in the United States. The performance of the HRM-based MAA was nearly identical to that of the MAA that included CD4 cell count. The HRM-based MAA had a mean window period of 154 days and provided cross-sectional incidence estimates that were similar to those based on cohort follow-up. HIV diversity is a useful biomarker for estimating HIV incidence. MAAs that include the HRM diversity assay can provide accurate HIV incidence estimates using stored blood plasma or serum samples without a requirement for CD4 cell count data. PMID- 24153138 TI - Eczematous-type multiple drug allergy from isoniazid and ethambutol with positive patch test results. AB - Multiple drug allergy (MDA) is characterized by hypersensitivity to 2 or more chemically unrelated drugs. Multiple drug allergy from simultaneous use of antituberculosis drugs is a rare phenomenon that mainly presents as an urticarial or maculopapular eruption. This case report describes a 58-year-old man who developed a generalized eczematous eruption during the sixth week of oral therapy with 4 antituberculosis drugs-isoniazid, ethambutol, rifampicin, and morphazinamide-for treatment of suspected pleural tuberculosis. The eruption resolved after treatment with systemic corticosteroids and cessation of isoniazid and ethambutol. During a lesion-free period 6 months after cessation of the corticosteroids, patch testing with serial dilutions of isoniazid and ethambutol revealed positive reactions; irritant patch test reactions were excluded by testing with graded concentrations of each drug. The patient avoided the causative drugs and reported no new eruptions at 1-year follow-up. It is important for dermatologists to consider the value of patch testing in determining the causative drugs in suspected cases of eczematous-type MDA. PMID- 24153139 TI - Subungual abscess caused by Staphylococcus lugdunensis. AB - Although Staphylococcus lugdunensis is a constituent of the normal human skin flora, it does have pathogenic potential. Infections can range from severe (eg, endocarditis, osteomyelitis) to less invasive skin and soft-tissue infections. We report a case of a subungual abscess in a patient with S lugdunensis infection. PMID- 24153140 TI - Partial reversal of androgenetic alopecia with methotrexate therapy for psoriasis. AB - We report the case of a 64-year-old man with androgenetic alopecia who was started on methotrexate therapy for treatment of psoriasis after traditional modalities failed. Following treatment with methotrexate, he noted hair regrowth on the scalp. We propose that methotrexate may inhibit gonadal steroidogenesis, therefore leading to lower testosterone levels, or may increase testosterone aromatization at the hair follicles. These mechanisms may account for the hair growth observed in our patient, which indicates that partial reversal of androgenetic alopecia may be a side effect of methotrexate therapy. PMID- 24153141 TI - Pulsed dye laser for the treatment of nail psoriasis. AB - Psoriasis can involve the skin, joints, and nails, either alone or in combination. Psoriasis of the nails can involve both the nail bed and nail matrix. The treatment of nail psoriasis largely depends on the severity of symptoms. The pulsed dye laser (PDL) recently has demonstrated efficacy in treating resistant plaque-type psoriasis and has been suggested as an alternative to conventional therapies. We review 4 studies of PDL for nail psoriasis and discuss the findings in relation to treatment recommendations. Ultimately, a standardized regimen for the treatment of nail psoriasis remains elusive. PMID- 24153142 TI - Lichen planus mimicking recalcitrant ulcerative psoriasis: when is it time to biopsy? AB - Hypertrophic lichen planus (LP), also known as LP verrucosus, is a rare disorder that presents as verrucous plaques, typically on the lower extremities and ankles. This variant differs from the common presentation of LP, which appears as flat, polygonal, pink-purple papules spread diffusely on the flexor wrists, trunk, shins, and dorsal aspects of the feet, frequently involving the oral mucosa. Clinically, hypertrophic LP can be confused with psoriasis and usually does not respond to therapy with biologics. We present a case of hypertrophic LP in a 42-year-old woman who had been treated extensively for psoriasis. Although the morphology and location of the hyperkeratotic plaques mimicked psoriasis, biopsy results exhibited characteristic features of hypertrophic LP, and the lesions responded to treatment with acitretin, clobetasol propionate ointment, hydroxychloroquine, and simple wound care. The hypertrophic variant of LP can be extremely challenging to differentiate from psoriasis. Physicians who treat patients with scaly plaques should think beyond psoriasis and consider the hypertrophic variant of LP as a potential diagnosis. PMID- 24153143 TI - Combination therapy with tumor necrosis factor inhibitors in psoriasis treatment. AB - Psoriasis is a systemic disease that affects approximately 2% of the US population. Traditional treatment modalities include phototherapy, topical therapy, methotrexate, cyclosporine, and retinoids. Three tumor necrosis factor (TNF) inhibitors have been approved by the US Food and Drug Administration for the treatment of plaque psoriasis: etanercept, infliximab, and adalimumab. The combination of TNF inhibitors with phototherapy and topical and systemic agents may be effective in treating patients who are recalcitrant to monotherapy. We examine clinical trials that evaluated the efficacy and safety of combination treatments with TNF inhibitors. This review elucidates that combination therapy is both effective and well tolerated among patients with refractory psoriasis. Furthermore, combination therapy may allow for reduction of required treatment doses, thereby decreasing the potential for toxicity. It is important to note, however, that the studies reviewed here are limited in the long-term follow-up of patients. We conclude that dermatologists can safely and effectively incorporate combination therapy with TNF inhibitors in the treatment of patients with recalcitrant psoriasis. PMID- 24153144 TI - Methotrexate toxicity induced by ciprofloxacin leading to psoriatic plaque ulceration: a case report. AB - We present the case of a 90-year-old woman with psoriasis vulgaris who had been treated with methotrexate for many years. The patient presented with psoriatic plaque ulcerations uniquely limited to the active border as well as acute oral ulcerations and severe gastrointestinal upset after undergoing a course of ciprofloxacin for treatment of a bacterial infection. PMID- 24153145 TI - Psoriasiform eruption associated with graft-versus-host disease. AB - Graft-versus-host disease (GVHD) is a frequent complication of bone marrow transplantation (BMT) that can be classified as acute or chronic. Characteristic cutaneous manifestations of acute GVHD, which generally occurs within 3 months following BMT, include maculopapular exanthema and perifollicular papular lesions. Psoriasiform skin eruption as a manifestation of acute GVHD is rare. We report the case of a 4-year-old boy who developed a generalized psoriasiform eruption shortly after undergoing an allogeneic BMT. Histologic features of both psoriasis and acute GVHD were present. PMID- 24153146 TI - Comment on "Dermatopathology in clinical practice: avoiding abuse of self referral and client billing" (Cutis. 2013;92:12-14). PMID- 24153147 TI - Angiolymphoid hyperplasia with eosinophilia. PMID- 24153148 TI - What is your diagnosis? PHACE syndrome. PMID- 24153149 TI - Multiple cysts in a renal transplant recipient. PMID- 24153150 TI - Board review study guides: a general overview. PMID- 24153151 TI - Psoriasis and leprosy: a mystifying coexistence. PMID- 24153152 TI - A case of localized scleroderma mimicking tinea cruris. PMID- 24153153 TI - Incapacitating pseudoverrucous papules and nodules: cure by shave excision. PMID- 24153154 TI - Circulating tumor cells are associated with diffuse spread in stage IV colorectal cancer patients. AB - BACKGROUND: Colorectal cancer (CRC) is the second leading cause of cancer-related deaths in the United States when combining both genders. Circulating tumor cells (CTCs) are a prognostic marker for stage IV CRC patients. We hypothesized that CTC quantity varies among stage IV CRC populations. METHODS: Blood (7.5 ml) was prospectively collected from 90 stage IV CRC patients. EpCAM(+) CTCs were analyzed with the FDA-approved CellSearch((r)) system. CRC tumors were immunohistochemically stained for EpCAM expression. Imaging and clinicopathological data were collected. Statistical analysis was performed using correlation analysis, Kruskal-Wallis, Fisher exact, and log-rank test. RESULTS: CTCs were detectable in 36/90 (40%) patients. Diffuse CRC metastases were associated with the highest CTC prevalence (24/40 [60%]), in contrast to limited lung (2/19 [11%]) or liver (10/31 [32%]) metastases (P = 0.027). The overall mean CTC number was 2.0 (range 0-56.3). The mean CTC number in patients with diffuse metastases was significantly higher (3.7 [SEM +/- 1.7, range 0-56.3]) than with limited lung metastases (0.1 [+/- 0.1; range 0-1]) or liver metastases (0.9 [+/- 0.3, range 0-7.0]) (P = 0.001). CRC tumors were consistently expressing EpCAM. CTC numbers did not correlate with serum CEA levels or other routine clinical parameters (P = N.S.). Patients with diffuse metastases had the poorest overall survival (P = 0.0042). CONCLUSIONS: CRC patients with diffuse metastases have the highest number of CTCs, in contrast to limited metastases to the liver or lungs. Future studies should correlate CTCs with recurrence patterns in patients with resected CRC lung or liver metastases to investigate whether CTCs represent micrometastatic disease causing early relapses. PMID- 24153155 TI - Three novel mutations in the SLCO2A1 gene in two Chinese families with primary hypertrophic osteoarthropathy. AB - BACKGROUND: Primary hypertrophic osteoarthropathy (PHO (MIM 167100)) is a rare genetic disease characterized by pachyderma, periostosis and digital clubbing. Mutations in the 15-hydroxy-prostaglandin dehydrogenase (HPGD) gene and solute carrier organic anion transporter family member 2A1 (SLCO2A1) gene have been demonstrated to be pathogenic causes. OBJECTIVE: We aimed to identify the genetic cause of 2 unrelated patients with PHO. METHOD: Urinary levels of prostaglandin E2 and prostaglandin E metabolite were measured in Proband 1 and his sister by competitive ELISAs. Mutation analysis of the HPGD and SLCO2A1 genes were conducted on both probands with PHO. Genomic DNAs of 100 healthy controls were isolated and subjected to polymerase chain reaction and direct DNA sequencing. The identified mutations were further confirmed in the parents of Proband 1. Protein modeling and data from PolyPhen-2 were used to evaluate the effects of novel missense mutations on protein SLCO2A1. RESULTS: The urinary levels of prostaglandin E2 and prostaglandin E metabolite in Proband 1 were much higher than those in unaffected individuals. Molecular genetic analysis revealed four SLCO2A1 mutations, including 3 novel ones (p.Arg603X, p.Gly183Arg and p.Asn534Lys) and a founder mutation, c.940+1G>A, in two probands with PHO. Missense mutations p.Gly183Arg and p.Asn534Lys, at highly conserved positions, were both predicted to be damaging. Protein modeling indicated that the mutation p.Gly183Arg altered the 3-dimensional structure of SLCO2A1. CONCLUSIONS: Three novel mutations within the SLCO2A1 gene have been demonstrated to be associated with Chinese PHO patients. PMID- 24153157 TI - Evaluation of hypertension and proteinuria as markers of efficacy in antiangiogenic therapy for metastatic colorectal cancer. AB - BACKGROUND: The vascular endothelial growth factor pathway is strongly implicated in cancer-related angiogenesis. Antiangiogenic agents such as bevacizumab commonly cause hypertension (HTN) and proteinuria (PTN), which may be biomarkers of response and clinical outcome. STUDY: We conducted a retrospective analysis of patients with histologically proven metastatic colorectal cancer (mCRC) treated with either bevacizumab or a tyrosine kinase inhibitor in combination with chemotherapy at The Christie Hospital from January 2006 to September 2009. RESULTS: Of 90 patients evaluated, 50 were eligible. Seventeen (34%), 4 (8%), and 3 (6%) patients developed Common Toxicity Criteria (v 3.0) grades 1, 2, and 3 HTN, respectively. Response rates were 42% for patients with grades 0 to 1 HTN compared with 86% for patients with >=grade 2 HTN (P=0.043). Median overall survival was 21.6 months for patients with grades 0 to 1 HTN and 25.2 months for patients with >=grade 2 HTN (P=0.270). Twelve patients (24%) developed grade 1 PTN and 4 patients (8%) developed >=grade 2 PTN. Median overall survival was 23.9 months for patients with grades 0 to 1 PTN and 4.2 months for those with >=grade 2 PTN (P=0.028). CONCLUSIONS: To our knowledge, this is the first study to demonstrate the utility of PTN as a surrogate marker of outcome in antiangiogenic therapy for metastatic colorectal cancer. Although HTN is predictive of a significantly higher response rate, the development of PTN during treatment with bevacizumab or tyrosine kinase inhibitor portends poorer survival and should be evaluated prospectively. PMID- 24153156 TI - Lamin A Deltaexon9 mutation leads to telomere and chromatin defects but not genomic instability. AB - Over 300 mutations in the LMNA gene, encoding A-type lamins, are associated with 15 human degenerative disorders and premature aging syndromes. Although genomic instability seems to contribute to the pathophysiology of some laminopathies, there is limited information about what mutations cause genomic instability and by which molecular mechanisms. Mouse embryonic fibroblasts depleted of A-type lamins or expressing mutants lacking exons 8-11 (Lmna(Delta8-11/Delta8-11)) exhibit alterations in telomere biology and DNA repair caused by cathepsin L mediated degradation of 53BP1 and reduced expression of BRCA1 and RAD51. Thus, a region encompassing exons 8-11 seems essential for genome integrity. Given that deletion of lamin A exon 9 in the mouse (Lmna(Delta9/Delta9)) results in a progeria phenotype, we tested if this domain is important for genome integrity. Lmna(Delta9/Delta9) MEFs exhibit telomere shortening and heterochromatin alterations but do not activate cathepsin L-mediated degradation of 53BP1 and maintain expression of BRCA1 and RAD51. Accordingly, Lmna(Delta9/Delta9) MEFs do not present genomic instability, and expression of mutant lamin A Deltaexon9 in lamin-depleted cells restores DNA repair factors levels and partially rescues nuclear abnormalities. These data reveal that the domain encoded by exon 9 is important to maintain telomere homeostasis and heterochromatin structure but does not play a role in DNA repair, thus pointing to other exons in the lamin A tail as responsible for the genomic instability phenotype in Lmna(Delta8-11/Delta8-11) mice. Our study also suggests that the levels of DNA repair factors 53BP1, BRCA1 and RAD51 could potentially serve as biomarkers to identify laminopathies that present with genomic instability. PMID- 24153158 TI - Pancreatitis before pancreatic cancer: clinical features and influence on outcome. AB - OBJECTIVES: Pancreatitis is considered a possible risk factor for and a presentation of pancreatic adenocarcinoma (PA). We aimed to evaluate a large PA patient registry to determine whether prior history of pancreatitis influenced survival. METHODS: We retrospectively analyzed the Mayo Clinic Biospecimen Resource for Pancreas Research database from January 1992 to September 2011. Data collected included demographic characteristics, history of tobacco or alcohol use, diabetes mellitus (DM), cholelithiasis, pseudocyst, and details regarding PA. Clinical characteristics and outcomes of PA patients with pancreatitis were compared with PA patients without pancreatitis history. RESULTS: We analyzed 2573 patients with PA diagnosis. Among these patients, 195 (8%) were identified who had pancreatitis diagnosis >= 10 days before PA diagnosis. The cohort with pancreatitis history included more patients with DM (30% vs. 18%; P<0.001) and more smokers (68% vs. 58%; P=0.02). Compared with patients without pancreatitis history, these patients received diagnoses of PA at a younger age (63 vs. 65 y; P=0.005) and earlier stage (stages I and II; 52% vs. 37%; P<0.001). A greater percentage had history of surgery with curative intent (50% vs. 43%; P=0.001) and significantly better survival [median (range), 387 d (314 to 460 d) vs. 325 d (306 to 344 d); P=0.003]. CONCLUSIONS: Patients with PA and pancreatitis had more weight loss and DM, but had PA diagnosis at an earlier stage, were more likely to have pancreatic surgery, and therefore better survival than PA patients without pancreatitis, likely due to the earlier diagnosis. Further studies are needed to evaluate whether screening for PA in patients with pancreatitis history would provide survival benefit. PMID- 24153159 TI - Association of the CYP2B6 c.516G>T polymorphism with high blood propofol concentrations in women from northern Greece. AB - Cytochrome P450 2B6 (CYP2B6) is responsible for the initial biotransformation of profol, an extensively metabolized intravenous anesthetic. In this study we examined the effect of the apparently functional CYP2B6 c.516G>T polymorphism on the distribution of propofol concentrations, quantified by GC/MS analysis following a single bolus dose, in the blood of 44 Greek women undergoing oocyte retrieval. Univariate analysis using age, height, weight and smoking status as covariates, as well as the Mann-Whitney non-parametric test, revealed a strong trend of association of the T allele with high propofol concentrations determined in whole blood, shortly after a single bolus dose. Propofol concentrations which were higher than one standard deviation of the mean were almost invariably associated with carriage of the T allele. PMID- 24153161 TI - Patent ductus arteriosus: an analysis of management. AB - To compare differences in the management of the neonatal patent ductus arteriosus between neonatologists and paediatric cardiologists, physicians throughout the South-West were contacted. In treatment-refractory cases, neonatologists considered ligation less frequently than paediatric cardiologists (0% versus 40%; p<0.05) and held haemodynamic effects more important for ligation decisions [median: 5 (range 2-5) versus median: 4 (range 2-5); p<0.05]. Furthermore, 81% felt the current guidelines were insufficient. PMID- 24153160 TI - Enantioselective monofluoromethylation of aldehydes with 2-fluoro-1,3 benzodithiole-1,1,3,3-tetraoxide catalyzed by a bifunctional cinchona alkaloid derived thiourea-titanium complex. AB - A catalytic enantioselective monofluoromethylation of aldehydes using 2-fluoro 1,3-benzodithiole-1,1,3,3-tetraoxide (FBDT) was realized. With a bifunctional thiourea-titanium catalytic system, the monofluoromethylated-adducts were obtained in good yields and high enantioselectivities, up to 96% ee. PMID- 24153162 TI - Compressive preload reduces segmental flexion instability after progressive destabilization of the lumbar spine. AB - STUDY DESIGN: Biomechanical human cadaveric study. OBJECTIVE: We hypothesized that increasing compressive preload will reduce the segmental instability after nucleotomy, posterior ligament resection, and decompressive surgery. SUMMARY OF BACKGROUND DATA: The human spine experiences significant compressive preloads in vivo due to spinal musculature and gravity. Although the effect of destabilization procedures on spinal motion has been studied, the effect of compressive preload on the motion response of destabilized, multisegment lumbar spines has not been reported. METHODS: Eight human cadaveric spines (L1-sacrum, 51.4 +/- 14.1 yr) were tested intact, after L4-L5 nucleotomy, after interspinous and supraspinous ligaments transection, and after midline decompression (bilateral laminotomy, partial medial facetectomy, and foraminotomy). Specimens were loaded in flexion (8 Nm) and extension (6 Nm) under 0-N, 200-N, and 400-N compressive follower preload. L4-L5 range of motion (ROM) and flexion stiffness in the high-flexibility zone were analyzed using repeated-measures analysis of variance and multiple comparisons with the Bonferroni correction. RESULTS: With a fixed set of loading conditions, a progressive increase in segmental ROM along with expansion of the high-flexibility zone (decrease of flexion stiffness) was noted with serial destabilizations. Application of increasing compressive preload did not substantially change segmental ROM, but did significantly increase the segmental stiffness in the high-flexibility zone. In the most destabilized condition, 400-N preload did not return the segmental stiffness to intact levels. CONCLUSION: Anatomical alterations representing degenerative and iatrogenic instabilities are associated with significant increases in segmental ROM and decreased segmental stiffness. Although application of compressive preload, mimicking the effect of increased axial muscular activity, significantly increased the segmental stiffness, it was not restored to intact levels; thereby suggesting that core strengthening alone may not compensate for the loss of structural stability associated with midline surgical decompression. This suggests that there may be a role for surgical implants or interventions that specifically increase flexion stiffness and limit flexion ROM to counteract the iatrogenic instability resulting from surgical decompression. LEVEL OF EVIDENCE: N/A. PMID- 24153163 TI - Efficacy of biphasic transcranial electric stimulation in intraoperative motor evoked potential monitoring for cervical compression myelopathy. AB - STUDY DESIGN: Retrospective analysis of prospectively collected data from consecutive patients undergoing 2 methods of transcranial electrical motor evoked potential (TCE-MEP) monitoring during cervical spine surgery. OBJECTIVE: To investigate the efficacy of biphasic transcranial electric stimulation, the deviation rate, amplitude of TCE-MEPs, complications, and sensitivity and specificity of TCE-MEP monitoring were compared between the biphasic and conventional monophasic stimulation methods. SUMMARY OF BACKGROUND DATA: With biphasic stimulation, unlike monophasic stimulation, measurement time can be reduced considerably because a single stimulation elicits bilateral responses almost simultaneously. However, no study has yet reported a detailed comparison of the 2 methods. METHODS: Examination 1: Amplitude and derivation rate of TCE MEPs was compared for monophasic and biphasic stimulation in the same 31 patients with cervical compression myelopathy. Examination 2: Sensitivity, specificity, and complications of TCE-MEP monitoring were compared in 200 patients with cervical compression myelopathy who received monophasic or biphasic stimulation (100 patients each) during intraoperative monitoring. RESULTS: Examination 1: Derivation rates of biphasic stimulation in the deltoid, biceps brachii, abductor digiti minimi, and flexor hallucis brevis muscles were the same or higher than for monophasic stimulation. TCE-MEP amplitudes elicited by biphasic stimulation compared with monophasic stimulation were significantly larger in the biceps (paired t, P < 0.0001), but similar in the other 3 muscles. Examination 2: In the biphasic and monophasic stimulation groups, warnings were issued to surgeons in 10 and 11 cases, for a sensitivity of 100% for both groups and specificity of 97.8% and 96.7%, respectively. No complications related to stimulation were observed in any of the 200 patients. CONCLUSION: Biphasic stimulation had similar or higher derivation rates and equivalent sensitivity and specificity than monophasic stimulation. No complications were observed for either stimulation method. Biphasic stimulation is an effective TCE-MEP monitoring method for cervical spine surgery that may also reduce measurement time. LEVEL OF EVIDENCE: 4. PMID- 24153165 TI - Rare true-positive isolated SSEP loss with preservation of MEPs response during scoliosis correction. AB - STUDY DESIGN: Case report. OBJECTIVE: To report a case of a true-positive isolated somatosensory evoked potential (SSEP) loss with preservation of motor evoked potential (MEP) response during scoliosis correction. SUMMARY OF BACKGROUND DATA: Combined intraoperative monitoring uses SSEPs and MEPs to decrease the probability of observing false-negative events. In combination, SSEPs and MEPs have become a standard of care for spinal deformity surgery. However, literature review reveals several cases of false-negative response with combined SSEPs and MEPs, raising the contention that intraoperative monitoring does not reliably identify all isolated selective spinal cord dysfunction. METHODS: A 15-year-old female patient with a 65 degrees right thoracic adolescent idiopathic scoliosis underwent correction and posterior spinal fusion with segmental pedicle screw instrumentation. After capture and derotation of the left concave rod, left-sided irreversible SSEP loss occurred whereas MEPs remained unchanged. After excluding systemic factors, anesthetic causes, or technical fault, deformity correction was released and instrumentation removed. No cortical breach was reported during pedicle screw removal. RESULTS: Postoperatively, no clinical sensory or motor deficit was present; computed tomography demonstrated a burst left pedicle at T10 with the medial pedicle wall fragment in direct contact with the dorsal spinal cord. Magnetic resonance imaging excluded cord edema or other evidence of injury. Three days after surgery, intraoperative monitoring showed delayed latencies and amplitudes of the left SSEP. An uneventful reinsertion of instrumentation and correction excluding the left T10 pedicle screw was performed 7 days after the initial surgery. CONCLUSION: This case report provides evidence of selective posterior spinal cord dysfunction with sparing of the anterior columns immediately after a correction maneuver and emphasizes the importance of simultaneous SSEP and MEP monitoring. To the authors' knowledge, there is no previous report of a true-positive isolated SSEP loss with preservation of MEP response during scoliosis correction. LEVEL OF EVIDENCE: N/A. PMID- 24153166 TI - Effect of recurrent low back pain history on volitional pre-emptive abdominal activation during a loaded functional reach activity. AB - STUDY DESIGN: A 2 (group) * 2 (abdominal contraction) * 2 (reach activity) crossover mixed design with repeated measures for contraction and activity examined the effects of a loaded (4.6 kg) forward-reach activity and abdominal drawing-in maneuver (ADIM) on transversus abdominis (TrA) contraction in subjects with nonspecific low back pain (NSLBP) history versus controls. OBJECTIVE: We measured TrA contraction during a loaded forward-reach activity while using the ADIM and examined if a NSLBP history affects TrA activity. SUMMARY OF BACKGROUND DATA: The ADIM supports trunk stability during function. Clinicians incorporate ADIM during patients' functional tasks. Pain-free individuals can sustain ADIM during function, such as forward-reach. However, this has not been tested in those with a NSLBP history. METHODS: Eighteen normal subjects and 18 subjects with a history of NSLBP participated. A blinded investigator recorded M-mode ultrasound imaging measurements of TrA thickness (mm) during 4 conditions as follows: (1) quiet standing without ADIM; (2) quiet standing with ADIM; (3) loaded forward-reach without ADIM; and (4) loaded forward-reach with ADIM. RESULTS: A mixed analysis of variance demonstrated a significant main effect for group (F [1, 34] = 5.404, P = 0.026; ), where TrA thickness was greater for NSLBP history (7.41 + 2.34 mm) versus controls (5.9 + 2.46 mm). A significant main effect was observed for abdominal contraction (F [1, 34] = 49.57, P < 0.0001; ), where TrA thickness was greater during ADIM (7.47 + 2.7 mm) versus without ADIM (5.84, 1.92 m). A significant main effect was observed for forward-reach activity (F [1, 34] = 12.79, P = 0.001; ), where TrA thickness was greater during a loaded forward-reach (7.04 + 2.6 mm) versus quiet standing (6.2 + 2.4 mm). There were no significant interactions. CONCLUSION: Individuals can use a volitional pre emptive ADIM for trunk protection during loaded forward-reach, potentially reducing injury risk. A NSLBP history increases TrA activation during ADIM, suggesting an enhanced protective role. LEVEL OF EVIDENCE: 2. PMID- 24153167 TI - A rare cause of postoperative paraplegia in minimally invasive spine surgery. AB - STUDY DESIGN: A case report. OBJECTIVE: To present a patient who underwent a minimally invasive transforaminal lumbar interbody fusion who postoperatively developed paraplegia as a rare complication of a Kirschner wire (K-wire). SUMMARY OF BACKGROUND DATA: The few complications of K-wires that have been reported include, dural tears and damage to intra-abdominal structures. METHODS: A case report of a rare complication of a K-wire is reported and the relevant literature was then reviewed. RESULTS: An 85-year-old female with an anterolisthesis at L4 L5 underwent a minimally invasive transforaminal lumbar interbody fusion. Postoperatively she developed paraplegia. A subdural hematoma from T12 to the sacrum was found and evacuated. It is proposed that this rare complication is a result of a K-wire. CONCLUSION: Care must be taken with the use of K-wires and additional measures should be carried out such as the marking of its position and radiological confirmation of depth. LEVEL OF EVIDENCE: 5. PMID- 24153168 TI - Lumbar clinical adjacent segment pathology: predilection for proximal levels. AB - STUDY DESIGN: Retrospective case series. OBJECTIVE: To evaluate reoperations for lumbar adjacent segment pathology (ASP) during a 10-year period. SUMMARY OF BACKGROUND DATA: ASP after lumbar arthrodesis is an important clinical problem. There remains controversy, however, on the distribution of the most commonly affected levels. METHODS: Thirty-one patients undergoing revision operation for ASP in the lumbar spine were included in this study. Patients' charts were evaluated for demographic data including age at index and revision operations, time to revision operation, and index and revision levels fused. RESULTS: L4-L5 was the most commonly instrumented level in both single-level (n = 12), and multilevel (n = 13) index fusions. The mean length of time from the index operation to revision surgery was 81 months (range, 11-570 mo). Kaplan-Meier analysis predicted a disease-free survival rate of 32.3% at 5 years and of 12.9% at 10 years after the index operation. L3-L4 was the most commonly affected level by ASP with 75% (16/20) requiring reoperation. L2-L3 was the next most commonly affected level at 52% (14/27). The L5-S1 disk was relatively protected from ASP, with only 4/17 (24%) disks at risk developing ASP. A subgroup analysis of patients undergoing revision after a single-level L4-L5 arthrodesis revealed ASP at L3-L4 in 83% (10/12) of patients, compared with only 3/12 (25%) at L5-S1 (P < 0.05). Of all cases of ASP, the proximal segments were involved 90% of the time. CONCLUSION: ASP most commonly affects proximal levels in the lumbar spine. In this cohort of patients undergoing revision fusion for ASP, 90% of affected levels were rostral to the index level(s). In patients undergoing L4-L5 single level arthrodesis, L3-L4 is at high risk, whereas L5-S1 is somewhat protected. Surgeons should pay particular attention to proximal levels when planning a lumbar arthrodesis, however, motion segments distal to fusion may not be as protected as previously thought. LEVEL OF EVIDENCE: 4. PMID- 24153169 TI - Low body mass index in adolescent idiopathic scoliosis: relationship with pre- and postsurgical factors. AB - STUDY DESIGN: Retrospective cohort study. OBJECTIVE: To determine the association between low preoperative body mass index (BMI) and outcome of spinal fusion in adolescent idiopathic scoliosis (AIS). SUMMARY OF BACKGROUND DATA: Several studies report a lower weight and BMI in untreated subjects with AIS than nonscoliotic age-matched controls. However, very little is known about the clinical impact of low BMI on pre- or postsurgical parameters in this patient group. METHODS: Seventy-seven eligible patients with AIS who underwent 1-stage posterior spinal fusion and correction at 2 tertiary centers (January 2010-April 2012) were included. Preoperative weight, corrected height, and BMI values were converted to z scores using the British 1990 growth reference data. Relationships between anthropometric indices and comorbidities, laboratory blood data, radiographical outcomes, length of hospital stay, and perioperative complications were examined, and the independent factors associated with low BMI (z score < -1) evaluated using binary logistic regression analysis. RESULTS: In this AIS cohort (mean age, 15.04 yr; n = 72 females), 21 subjects (27.3%) had a low preoperative BMI; of these, 5 cases (6.5%) were considered severely thin. Lower BMI and weight z scores correlated with a greater percent correction of thoracic curves (rs = 0.287 and rs = -0.257, respectively, P < 0.05). In both the univariate and multivariate regression analysis, low BMI was significantly associated with preoperative asthma incidence (adjusted odds ratio 5.33, P = 0.023) and prolonged prothrombin time (adjusted odds ratio 4.53, P = 0.027), in addition to postoperative ileus development (adjusted odds ratio 11.96, P = 0.019). Preoperative Cobb angle, estimated intraoperative blood loss and length of hospital stay did not significantly differ between the BMI groups. CONCLUSION: Significantly increased preoperative coagulation abnormality and asthma incidence as well as a greater percent correction of thoracic curves were associated with low BMI in this series. It was also found that postoperative ileus was independently associated with low BMI. LEVEL OF EVIDENCE: 3. PMID- 24153170 TI - Thoracic scoliosis prevalence in patients 50 years or older and its relationship with age, sex, and thoracic kyphosis. AB - STUDY DESIGN: Cross-sectional study. OBJECTIVE: To determine the prevalence of thoracic scoliosis in patients aged 50 years or older and to investigate the association of adult thoracic scoliosis with age, sex, and thoracic sagittal curve. SUMMARY OF BACKGROUND DATA: The prevalence of adult thoracic scoliosis has not been clearly determined. In addition, limited data are available on the correlation of adult thoracic scoliosis to age, sex, and thoracic kyphosis. METHODS: We studied 760 patients aged 50 years or older (380 males and 380 females) who were evaluated using standing chest plain radiographs. The thoracic curvatures in the coronal and sagittal planes were measured using the Cobb method. Scoliosis was defined by the presence of a coronal curvature 10 degrees or more. We performed a correlation analysis of the coronal curve with age and sagittal curve; in addition, a linear regression analysis was carried out to evaluate age, sex, and sagittal curve as independent predictors of the coronal Cobb angle of the thoracic spine. RESULTS: The prevalence of thoracic scoliosis was 24.2% (184 cases); 160 patients (21.1%) had curves 10 degrees or more but less than 20 degrees ; 20 patients (2.6%) had curves 20 degrees or more but less than 30 degrees ; and 4 patients (0.5%) had curves 30 degrees or more. Females exhibited a higher prevalence of scoliosis (28.9%) than did males (19.4%), P < 0.01. The older patients exhibited increased scoliosis, but no differences were observed in thoracic kyphosis with increasing scoliosis. Age and sex were independent predictors of the coronal Cobb angle; however, the sagittal angle was not. CONCLUSION: We found a 24.2% prevalence of thoracic scoliosis in patients 50 years or older; most curves were less than 20 degrees . Thoracic scoliosis was more common in females and in older patients. LEVEL OF EVIDENCE: 3. PMID- 24153171 TI - Surgical versus nonoperative treatment for lumbar disc herniation: eight-year results for the spine patient outcomes research trial. AB - STUDY DESIGN: Concurrent prospective randomized and observational cohort studies. OBJECTIVE: To assess the 8-year outcomes of surgery versus nonoperative care. SUMMARY OF BACKGROUND DATA: Although randomized trials have demonstrated small short-term differences in favor of surgery, long-term outcomes comparing surgical with nonoperative treatment remain controversial. METHODS: Surgical candidates with imaging-confirmed lumbar intervertebral disc herniation meeting Spine Patient Outcomes Research Trial eligibility criteria enrolled into prospective randomized (501 participants) and observational cohorts (743 participants) at 13 spine clinics in 11 US states. Interventions were standard open discectomy versus usual nonoperative care. Main outcome measures were changes from baseline in the SF-36 Bodily Pain and Physical Function scales and the modified Oswestry Disability Index-AAOS/Modems version assessed at 6 weeks, 3 months, and 6 months, and annually thereafter. RESULTS: Advantages were seen for surgery in intent-to treat analyses for the randomized cohort for all primary and secondary outcomes other than work status; however, with extensive nonadherence to treatment assignment (49% patients assigned to nonoperative therapy receiving surgery versus 60% of patients assigned to surgery) these observed effects were relatively small and not statistically significant for primary outcomes (bodily pain, physical function, Oswestry Disability Index). Importantly, the overall comparison of secondary outcomes was significantly greater with surgery in the intent-to-treat analysis (sciatica bothersomeness [P > 0.005], satisfaction with symptoms [P > 0.013], and self-rated improvement [P > 0.013]) in long-term follow up. An as-treated analysis showed significant surgical treatment effects for primary outcome measures (mean change, surgery vs. nonoperative care; treatment effect; 95% confidence interval): bodily pain (45.3 vs. 34.4; 10.9; 7.7 to 14); PF (42.2 vs. 31.5; 10.6; 7.7 to 13.5); and Oswestry Disability Index (-36.2 vs. 24.8; -11.3; -13.6 to -9.1). CONCLUSION: Carefully selected patients who underwent surgery for a lumbar disc herniation achieved greater improvement than nonoperatively treated patients; there was little to no degradation of outcomes in either group (operative and nonoperative) from 4 to 8 years. LEVEL OF EVIDENCE: 2. PMID- 24153172 TI - Dynamic changes in spinal cord compression by cervical ossification of the posterior longitudinal ligament evaluated by kinematic computed tomography myelography. AB - STUDY DESIGN: A prospective clinical study. OBJECTIVE: To investigate the dynamic causative factor in the pathogenesis of myelopathy in patients with cervical ossification of the posterior longitudinal ligament (OPLL) using kinematic computed tomography (CT) myelography. SUMMARY OF BACKGROUND DATA: Kinematic CT myelography is useful for dynamically evaluating the cervical spine with high resolution images, particularly in bony compressive lesions. However, no studies have evaluated the dynamic factors in patients with OPLL using kinematic CT myelography. METHODS: From 2008 to 2013, 51 consecutive patients with OPLL who presented with myelopathy were prospectively enrolled in this study. The patients were examined with kinematic (flexion-extension) CT myelography using a multidetector CT scanner. The range of motion at C2-C7 from flexion to extension was measured in the sagittal view. The segmental range of motion, anterior posterior diameter and cross-sectional area (CSA) of the spinal cord were measured at the level where the spinal cord was most compressed by OPLL. RESULTS: The neurological condition of the patients evaluated by Japanese Orthopaedic Association scores were 10.8 +/- 2.4 points. The mean range of motion at C2-C7 and at the most compressed segment were 23.1 +/- 11.7 and 7.0 +/- 4.4 degrees , respectively. Both the anterior-posterior diameter and the CSA at the most compressed levels were significantly decreased during neck extension compared with flexion. Interestingly, the anterior-posterior diameter and the CSA were decreased during neck flexion in 13.7% (7/51) of the patients. All 7 of these patients had massive OPLL with an occupying rate 60% or more. The dynamic change rate of CSA (flexion/extension) was significantly smaller in patients with an OPLL occupying rate 60% or more compared with patients with an occupying rate less than 60%. CONCLUSION: Although spinal cord compression was increased during neck extension in most of the patients, greater levels of compression could be placed on the spinal cord during neck flexion when the patients had OPLL with a high occupying rate. LEVEL OF EVIDENCE: 4. PMID- 24153173 TI - Effectiveness and safety of recombinant human bone morphogenetic protein-2 versus local bone graft in primary lumbar interbody fusions. AB - STUDY DESIGN: Retrospective cohort study. OBJECTIVE: To compare clinical outcomes, fusion rates, and rates of complications in posterior lumbar interbody fusions (PLIFs) and transforaminal lumbar interbody fusion procedures with either recombinant human bone morphogenetic protein-2 (rhBMP-2) and local bone graft (LBG) or LBG alone used as graft material. SUMMARY OF BACKGROUND DATA: rhBMP-2 is often used in PLIF and transforaminal lumbar interbody fusion procedures, but is associated with complications. Furthermore, recent evidence suggests that using LBG may be sufficient to induce fusion. METHODS: All patients who underwent primary interbody fusions under a single surgeon were identified from the surgeon's records. In November 2008, the surgeon changed from routinely using LBG to using LBG and rhBMP-2 routinely, limiting selection bias. A retrospective review of prospectively collected data preoperatively and up to 12 months postoperatively was performed. Data collected included visual analogue scale, pain scores for back and leg, Oswestry Disability Index scores, Short-Form 36 (SF 36), standing lumbar radiographs, and clinical notes. RESULTS: Seventy-seven patients met the study criteria and 70 consented to be part of the study. Fifty one were treated with rhBMP-2 and 19 with LBG. At 12-month follow-up, no significant differences were seen in visual analogue scale score, Oswestry Disability Index score, or SF-36 scores. A total of 89.5% of the LBG group and 94.1% of the rhBMP-2 group went on to show radiographical evidence of fusion by 12-month follow-up (P = 0.61). The rhMBP-2 group had a higher complication rate (41.2% vs. 10.5%, incidence rate ratio = 3.91, P = 0.05). CONCLUSION: In comparison we found no difference in clinical outcomes, comparable rates of fusion and a significant increase in complication rates with rhBMP-2. Using rhBMP 2 may unnecessarily increase the risk of complication in routine PLIF and transforaminal lumbar interbody fusion procedures. LEVEL OF EVIDENCE: 3. PMID- 24153174 TI - Evidence-based recommendations for spine surgery. PMID- 24153175 TI - High-impact literature: what it requires beyond evidence-based medicine. PMID- 24153176 TI - Facile one-pot synthesis of flower-like AgCl microstructures and enhancing of visible light photocatalysis. AB - Flower-like AgCl microstructures with enhanced visible light-driven photocatalysis are synthesized by a facile one-pot hydrothermal process for the first time. The evolution process of AgCl from dendritic structures to flower like octagonal microstructures is investigated quantitatively. Furthermore, the flower-like AgCl microstructures exhibit enhanced ability of visible light assisted photocatalytic degradation of methyl orange. The enhanced photocatalytic activity of the flower-like AgCl microstructure is attributed to its three dimensional hierarchical structure exposing with [100] facets. This work provides a fresh view into the insight of electrochemical process and the application area of visible light photocatalysts. PMID- 24153177 TI - SHANK3 overexpression causes manic-like behaviour with unique pharmacogenetic properties. AB - Mutations in SHANK3 and large duplications of the region spanning SHANK3 both cause a spectrum of neuropsychiatric disorders, indicating that proper SHANK3 dosage is critical for normal brain function. However, SHANK3 overexpression per se has not been established as a cause of human disorders because 22q13 duplications involve several genes. Here we report that Shank3 transgenic mice modelling a human SHANK3 duplication exhibit manic-like behaviour and seizures consistent with synaptic excitatory/inhibitory imbalance. We also identified two patients with hyperkinetic disorders carrying the smallest SHANK3-spanning duplications reported so far. These findings indicate that SHANK3 overexpression causes a hyperkinetic neuropsychiatric disorder. To probe the mechanism underlying the phenotype, we generated a Shank3 in vivo interactome and found that Shank3 directly interacts with the Arp2/3 complex to increase F-actin levels in Shank3 transgenic mice. The mood-stabilizing drug valproate, but not lithium, rescues the manic-like behaviour of Shank3 transgenic mice raising the possibility that this hyperkinetic disorder has a unique pharmacogenetic profile. PMID- 24153178 TI - Minimal-excitation states for electron quantum optics using levitons. AB - The on-demand generation of pure quantum excitations is important for the operation of quantum systems, but it is particularly difficult for a system of fermions. This is because any perturbation affects all states below the Fermi energy, resulting in a complex superposition of particle and hole excitations. However, it was predicted nearly 20 years ago that a Lorentzian time-dependent potential with quantized flux generates a minimal excitation with only one particle and no hole. Here we report that such quasiparticles (hereafter termed levitons) can be generated on demand in a conductor by applying voltage pulses to a contact. Partitioning the excitations with an electronic beam splitter generates a current noise that we use to measure their number. Minimal-excitation states are observed for Lorentzian pulses, whereas for other pulse shapes there are significant contributions from holes. Further identification of levitons is provided in the energy domain with shot-noise spectroscopy, and in the time domain with electronic Hong-Ou-Mandel noise correlations. The latter, obtained by colliding synchronized levitons on a beam splitter, exemplifies the potential use of levitons for quantum information: using linear electron quantum optics in ballistic conductors, it is possible to imagine flying-qubit operation in which the Fermi statistics are exploited to entangle synchronized electrons emitted by distinct sources. Compared with electron sources based on quantum dots, the generation of levitons does not require delicate nanolithography, considerably simplifying the circuitry for scalability. Levitons are not limited to carrying a single charge, and so in a broader context n-particle levitons could find application in the study of full electron counting statistics. But they can also carry a fraction of charge if they are implemented in Luttinger liquids or in fractional quantum Hall edge channels; this allows the study of Abelian and non Abelian quasiparticles in the time domain. Finally, the generation technique could be applied to cold atomic gases, leading to the possibility of atomic levitons. PMID- 24153180 TI - Structural biology: Pivotal findings for a transcription machine. PMID- 24153179 TI - Differential L1 regulation in pluripotent stem cells of humans and apes. AB - Identifying cellular and molecular differences between human and non-human primates (NHPs) is essential to the basic understanding of the evolution and diversity of our own species. Until now, preserved tissues have been the main source for most comparative studies between humans, chimpanzees (Pan troglodytes) and bonobos (Pan paniscus). However, these tissue samples do not fairly represent the distinctive traits of live cell behaviour and are not amenable to genetic manipulation. We propose that induced pluripotent stem (iPS) cells could be a unique biological resource to determine relevant phenotypical differences between human and NHPs, and that those differences could have potential adaptation and speciation value. Here we describe the generation and initial characterization of iPS cells from chimpanzees and bonobos as new tools to explore factors that may have contributed to great ape evolution. Comparative gene expression analysis of human and NHP iPS cells revealed differences in the regulation of long interspersed element-1 (L1, also known as LINE-1) transposons. A force of change in mammalian evolution, L1 elements are retrotransposons that have remained active during primate evolution. Decreased levels of L1-restricting factors APOBEC3B (also known as A3B) and PIWIL2 (ref. 7) in NHP iPS cells correlated with increased L1 mobility and endogenous L1 messenger RNA levels. Moreover, results from the manipulation of A3B and PIWIL2 levels in iPS cells supported a causal inverse relationship between levels of these proteins and L1 retrotransposition. Finally, we found increased copy numbers of species-specific L1 elements in the genome of chimpanzees compared to humans, supporting the idea that increased L1 mobility in NHPs is not limited to iPS cells in culture and may have also occurred in the germ line or embryonic cells developmentally upstream to germline specification during primate evolution. We propose that differences in L1 mobility may have differentially shaped the genomes of humans and NHPs and could have continuing adaptive significance. PMID- 24153181 TI - Biophysics: Rough passage across a barrier. PMID- 24153183 TI - Marine biology: Coral animals combat stress with sulphur. PMID- 24153182 TI - RNA polymerase I structure and transcription regulation. AB - Transcription of ribosomal RNA by RNA polymerase (Pol) I initiates ribosome biogenesis and regulates eukaryotic cell growth. The crystal structure of Pol I from the yeast Saccharomyces cerevisiae at 2.8 A resolution reveals all 14 subunits of the 590-kilodalton enzyme, and shows differences to Pol II. An 'expander' element occupies the DNA template site and stabilizes an expanded active centre cleft with an unwound bridge helix. A 'connector' element invades the cleft of an adjacent polymerase and stabilizes an inactive polymerase dimer. The connector and expander must detach during Pol I activation to enable transcription initiation and cleft contraction by convergent movement of the polymerase 'core' and 'shelf' modules. Conversion between an inactive expanded and an active contracted polymerase state may generally underlie transcription. Regulatory factors can modulate the core-shelf interface that includes a 'composite' active site for RNA chain initiation, elongation, proofreading and termination. PMID- 24153185 TI - Single-molecule fluorescence probes dynamics of barrier crossing. AB - Kramers developed the theory on how chemical reaction rates are influenced by the viscosity of the medium. At the viscosity of water, the kinetics of unimolecular reactions are described by diffusion of a Brownian particle over a free-energy barrier separating reactants and products. For reactions in solution this famous theory extended Eyring's transition state theory, and is widely applied in physics, chemistry and biology, including to reactions as complex as protein folding. Because the diffusion coefficient of Kramers' theory is determined by the dynamics in the sparsely populated region of the barrier top, its properties have not been directly measured for any molecular system. Here we show that the Kramers diffusion coefficient and free-energy barrier can be characterized by measuring the temperature- and viscosity-dependence of the transition path time for protein folding. The transition path is the small fraction of an equilibrium trajectory for a single molecule when the free-energy barrier separating two states is actually crossed. Its duration, the transition path time, can now be determined from photon trajectories for single protein molecules undergoing folding/unfolding transitions. Our finding of a long transition path time with an unusually small solvent viscosity dependence suggests that internal friction as well as solvent friction determine the Kramers diffusion coefficient for alpha helical proteins, as opposed to a breakdown of his theory, which occurs for many small-molecule reactions. It is noteworthy that the new and fundamental information concerning Kramers' theory and the dynamics of barrier crossings obtained here come from experiments on a protein rather than a much simpler chemical or physical system. PMID- 24153184 TI - Crystal structure of the 14-subunit RNA polymerase I. AB - Protein biosynthesis depends on the availability of ribosomes, which in turn relies on ribosomal RNA production. In eukaryotes, this process is carried out by RNA polymerase I (Pol I), a 14-subunit enzyme, the activity of which is a major determinant of cell growth. Here we present the crystal structure of Pol I from Saccharomyces cerevisiae at 3.0 A resolution. The Pol I structure shows a compact core with a wide DNA-binding cleft and a tightly anchored stalk. An extended loop mimics the DNA backbone in the cleft and may be involved in regulating Pol I transcription. Subunit A12.2 extends from the A190 jaw to the active site and inserts a transcription elongation factor TFIIS-like zinc ribbon into the nucleotide triphosphate entry pore, providing insight into the role of A12.2 in RNA cleavage and Pol I insensitivity to alpha-amanitin. The A49-A34.5 heterodimer embraces subunit A135 through extended arms, thereby contacting and potentially regulating subunit A12.2. PMID- 24153186 TI - Photosynthetic entrainment of the Arabidopsis thaliana circadian clock. AB - Circadian clocks provide a competitive advantage in an environment that is heavily influenced by the rotation of the Earth, by driving daily rhythms in behaviour, physiology and metabolism in bacteria, fungi, plants and animals. Circadian clocks comprise transcription-translation feedback loops, which are entrained by environmental signals such as light and temperature to adjust the phase of rhythms to match the local environment. The production of sugars by photosynthesis is a key metabolic output of the circadian clock in plants. Here we show that these rhythmic, endogenous sugar signals can entrain circadian rhythms in Arabidopsis thaliana by regulating the gene expression of circadian clock components early in the photoperiod, thus defining a 'metabolic dawn'. By inhibiting photosynthesis, we demonstrate that endogenous oscillations in sugar levels provide metabolic feedback to the circadian oscillator through the morning expressed gene PSEUDO-RESPONSE REGULATOR 7 (PRR7), and we identify that prr7 mutants are insensitive to the effects of sucrose on the circadian period. Thus, photosynthesis has a marked effect on the entrainment and maintenance of robust circadian rhythms in A. thaliana, demonstrating that metabolism has a crucial role in regulation of the circadian clock. PMID- 24153187 TI - Quantum physics: Single electrons pop out of the Fermi sea. PMID- 24153189 TI - DMSP biosynthesis by an animal and its role in coral thermal stress response. AB - Globally, reef-building corals are the most prolific producers of dimethylsulphoniopropionate (DMSP), a central molecule in the marine sulphur cycle and precursor of the climate-active gas dimethylsulphide. At present, DMSP production by corals is attributed entirely to their algal endosymbiont, Symbiodinium. Combining chemical, genomic and molecular approaches, we show that coral juveniles produce DMSP in the absence of algal symbionts. DMSP levels increased up to 54% over time in newly settled coral juveniles lacking algal endosymbionts, and further increases, up to 76%, were recorded when juveniles were subjected to thermal stress. We uncovered coral orthologues of two algal genes recently identified in DMSP biosynthesis, strongly indicating that corals possess the enzymatic machinery necessary for DMSP production. Our results overturn the paradigm that photosynthetic organisms are the sole biological source of DMSP, and highlight the double jeopardy represented by worldwide declining coral cover, as the potential to alleviate thermal stress through coral produced DMSP declines correspondingly. PMID- 24153190 TI - Adenosine capped QDs based fluorescent sensor for detection of dopamine with high selectivity and sensitivity. AB - Facile detection of dopamine (DA) in biological samples for diagnostics remains a challenge. This paper reported an effective fluorescent sensor based on adenosine capped CdSe/ZnS quantum dots (A-QDs) for highly sensitive detection of DA in human urine samples. In this assay, adenosine serves as a capping ligand or stabilizer for QDs to render high-quality QDs dispersed in water, and as a receptor for DA to attach DA onto the surface of A-QDs. DA molecules can bind to A-QDs via non-covalent bonding, leading to the fluorescence quenching of A-QDs due to electron transfer. The A-QDs based fluorescence probe showed a limit of detection (LOD) of ca. 29.3 nM for DA detection. This facile method exhibited high selectivity and anti-interference in the presence of amino acid, ascorbic acid (AA), uric acid (UA) and glucide with 100-fold higher concentration in PBS solution. Furthermore, it was also successfully used in the detection of DA in the human urine samples with quantitative recoveries (94.80-103.40%). PMID- 24153188 TI - Structure of the SecY channel during initiation of protein translocation. AB - Many secretory proteins are targeted by signal sequences to a protein-conducting channel, formed by prokaryotic SecY or eukaryotic Sec61 complexes, and are translocated across the membrane during their synthesis. Crystal structures of the inactive channel show that the SecY subunit of the heterotrimeric complex consists of two halves that form an hourglass-shaped pore with a constriction in the middle of the membrane and a lateral gate that faces the lipid phase. The closed channel has an empty cytoplasmic funnel and an extracellular funnel that is filled with a small helical domain, called the plug. During initiation of translocation, a ribosome-nascent chain complex binds to the SecY (or Sec61) complex, resulting in insertion of the nascent chain. However, the mechanism of channel opening during translocation is unclear. Here we have addressed this question by determining structures of inactive and active ribosome-channel complexes with cryo-electron microscopy. Non-translating ribosome-SecY channel complexes derived from Methanocaldococcus jannaschii or Escherichia coli show the channel in its closed state, and indicate that ribosome binding per se causes only minor changes. The structure of an active E. coli ribosome-channel complex demonstrates that the nascent chain opens the channel, causing mostly rigid body movements of the amino- and carboxy-terminal halves of SecY. In this early translocation intermediate, the polypeptide inserts as a loop into the SecY channel with the hydrophobic signal sequence intercalated into the open lateral gate. The nascent chain also forms a loop on the cytoplasmic surface of SecY rather than entering the channel directly. PMID- 24153191 TI - Expression of hypoxia-inducible factor-1alpha and vascular density in mammary adenomas and adenocarcinomas in bitches. AB - BACKGROUND: The study aimed at examining hypoxia-inducible factor (HIF)1alpha expression in adenocarcinomas and adenomas in bitches in regard to tumour malignancy grade, proliferation, apoptosis and vascularisation. Therefore, paraffin sections of 15 adenomas and 64 adenocarcinomas sampled from 79 dogs aged 6 to 16 years were analysed. RESULTS: A significantly higher HIF-1alpha expression was noted in adenocarcinomas in comparison to adenomas (P < 0.0004). Moreover, HIF-1alpha expression in adenocarcinomas correlated positively with tumour malignancy grade (r = 0.59, P < 0.05), Ki-67 antigen expression (r = 0.43; P < 0.0005), TUNEL-positive cells (r = 0.62, P < 0001) and tumour vascularity measured by quantification of vessels characterized by the expression of von Willebrand Factor (r = 0.57, P < 0.05). CONCLUSION: Results of this study indicate a similar biological role of HIF-1alpha in dogs and in humans, which may confirm suitability of the animal model in investigations on progression of tumours in humans. PMID- 24153192 TI - Efficacy and safety of cutting balloons for the treatment of obstructive lesions in the internal jugular veins. AB - BACKGROUND: In this technical note we present the results of endovascular treatment for chronic cerebrospinal venous insufficiency with the use of cutting balloons, with focus on feasibility and safety of these endovascular devices. METHODS: We used cutting balloons during 70 procedures in 65 multiple sclerosis patients presenting with strictures of the internal jugular veins, primarily at the level of jugular valves. These devices were used only in selected cases, following unsuccessful standard balloon angioplasty, and on condition that commercially available devices could be applied (currently they are maximally 8 mm in diameter). RESULTS: In all cases the perioperative course was uneventful, with no serious adverse events. Immediate technical success rate was 94.3%. In four cases (5.7%) cutting-balloon angioplasty alone was unsuccessful and stents were implanted. Primary, assisted primary and secondary patency rates after 6 months were: 94%, 98.5%, and 98.5%, respectively. Follow-up has revealed that out of the remaining 66 angioplasties four procedures failed (failure rate: 6.1%): in two patients stents were implanted, in one patient successful redo cutting balloon angioplasty was performed, while in another case the treated segment of jugular vein totally occluded and was not feasible to reopen endovascularly. CONCLUSIONS: Cutting balloons can be safely used for the management of stenosed internal jugular veins. These devices can replace stents in the majority of cases, especially if standard balloon angioplasty is insufficient to restore proper outflow. However, the use of cutting balloons in this particular venous territory is limited by the fact that currently only small diameter devices are available. PMID- 24153193 TI - Role of neutrophil/lymphocyte ratio in assessing the risk of postoperative atrial fibrillation. AB - AIM: Atrial fibrillation is the most common arrhythmia and complication following coronary bypass surgery. Besides well-known risk factors, inflammatory parameters have gained popularity assessing the risk of postoperative atrial fibrillation. In this study, we aimed to document the relation between neutrophil/lymphocyte ratio and postoperative atrial fibrillation. METHODS: Between January 2011 and June 2012, 523 patients on normal sinus rhythm, undergoing elective on-pump coronary bypass operations were prospectively followed up for occurrence of postoperative atrial fibrillation. Total and differential white blood cell counts were made immediately before the operation and on postoperative day 2. Neutrophil/lymphocyte ratio was calculated from these measured values. RESULTS: Ninety-one (17.4%) patients developed postoperative atrial fibrillation The mean age of the patients maintaining normal sinus rhythm was lower compared to ones with atrial fibrillation (60.76+/-9.59 vs. 65.44+/-8.63, P<0.001). Preoperative and postoperative total and differential white blood cell counts did not have any effect on occurrence of atrial fibrillation. There were not statistically significant differences between normal sinus rhythm and atrial fibrillation groups when preoperative and postoperative neutrophil/lymphocyte ratios were considered (2.90+/-2.11 vs. 3.02+/-2.30, P=0.619; 10.07+/-21.97 vs. 9.34+/-6.73, P=0.752, respectively). CONCLUSION: Neutrophil/lymphocyte ratio was not found to be a predictor for new onset atrial fibrillation following coronary bypass surgery. PMID- 24153194 TI - The global quest for nursing excellence. AB - In this month's column, Stephanie Ferguson, PhD, RN, FAAN, Director, International Council of Nurses' (ICN) Leadership for Change Programme; Facilitator, ICN Global Nursing Leadership Institute; ICN Consultant for Nursing and Health Policy; and World Health Organization Consultant, provides a perspective on the importance of global nursing excellence and highlights the American Nurses Credentialing Center's strategic global quest for nursing excellence. PMID- 24153195 TI - Ward warriors: the complex nature of nurse mobility. AB - As systems evolve over time, their natural tendency is to become increasingly more complex. Studies in the field of complex systems have generated new perspectives on the application of management strategies in health systems. Much of this research appears as a natural extension of the cross-disciplinary field of systems theory. In this article, the authors discuss the impact of complex system behavior on nurse workflow and its broader implications. PMID- 24153196 TI - Leaning in: lessons for leadership career development. AB - This department highlights change management strategies that may be successful in strategically planning and executing organizational change initiatives. With the goal of presenting practical approaches helpful to nurse leaders advancing organizational change, content includes evidence-based projects, tools, and resources that mobilize and sustain organizational change initiatives. In this article, the author introduces the book Lean In and presents applicable lessons for nursing leadership career development. PMID- 24153197 TI - Structural empowerment and the nursing practice environment in Magnet(r) organizations. AB - OBJECTIVE: The aim of this study was to describe the characteristics of shared governance and its relationship with nursing practice environments in Magnet(r) organizations. BACKGROUND: Structural empowerment is a core Magnet model component illustrated through shared governance. A paucity of literature exists describing it and its relationship to the nursing practice environment in Magnet organizations. METHODS: E-mail surveys of Magnet chief nursing officers and leaders of their organization's nursing practice council were conducted using the Index of Professional Nursing Governance (IPNG) and the nursing Work Index Revised (NWI-R). RESULTS: In Magnet organizations, the primary governance distribution is shared governance, with most subscales in the IPNG within the shared governance range. Total and subscale scores on the NWI-R ranged from 1.35 to 1.48, with significant, positive correlation between total IPNG score and total NWI-R score (r = 0.416, P < .001), as well as the NWI-R and IPNG subscales. CONCLUSIONS: This study provides new evidence that demonstrates the positive relationship between shared governance and the nursing practice environment in Magnet organizations. PMID- 24153198 TI - Retirement financial planning and the RN: an integrative literature review. AB - This integrative literature review examined the current research on RN retirement. The review identified 3 critical gaps in knowledge: (a) minimal knowledge regarding the economic impact on RN retirement, (b) incomplete information regarding the demographics of RN retirement, and (c) a scarcity of prospective longitudinal RN workforce studies. Future research must address these gaps to better address RN workforce sustainability. PMID- 24153199 TI - California's nurse-to-patient ratios, part 3: eight years later, what do we know about patient level outcomes? AB - OBJECTIVE: The objective of this study was to describe the impact of California's nurse-to-patient ratios on patient-level outcomes from a comprehensive literature review. BACKGROUND: While implemented in 2004, questions remain about the effects the ratios have had on patients. METHODS: A comprehensive literature review was conducted. RESULTS: Patient outcome results are mixed in the 8 identified studies, with 3 studies finding both positive and negative outcomes and 5 studies reporting no significant changes in patient outcomes. CONCLUSIONS: Findings from this review suggest some improvements have resulted from the implementation of staffing ratios, but the positives have not been as significant and widespread as predicted. Further studies are needed to explore the relationship between patient outcomes and mandated staffing levels in this state and other settings. PMID- 24153200 TI - RN workgroup job satisfaction and patient falls in acute care hospital units. AB - OBJECTIVE: The aim of this study was to examine the relationship between registered nurse (RN) workgroup job satisfaction and patient falls on 4 types of acute care hospital units. BACKGROUND: Although a link has been found between nurse job satisfaction and quality of patient care, little research has been conducted to examine the effect of RN job satisfaction on patient clinical outcomes in acute care hospitals. METHODS: Random-intercept negative binomial regression analyses were performed using 2009 unit-level data from 2,763 units in 576 National Database of Nursing Quality Indicators hospitals. RESULTS: Controlling for unit (nurse staffing, RN education, and RN unit tenure) and hospital (Magnet(r) status, hospital size, and teaching status) characteristics, RN workgroup job satisfaction was inversely associated with patient falls (incident rate ratio, 0.941, 95% confidence interval, 0.911-0.972). CONCLUSIONS: Higher RN workgroup job satisfaction is significantly related to fewer patient falls on acute care hospital units. PMID- 24153201 TI - The presence and roles of nurse navigators in acute care hospitals. AB - OBJECTIVE: A survey of hospital-based nurse executives was conducted to determine the extent, approaches, and outcomes of nurse navigator (NN) programs. BACKGROUND: Nurse navigators are distinct from other recognized healthcare roles. Navigators most commonly focus on a single health condition with the goal of improving the provision of specified health services for an individual patient. METHODS: An 11-question Internet-based survey was e-mailed to 580 nurse executives in Texas. RESULTS: Of the respondents, only 24% implemented any type of NN program. Most of the respondents with navigators rated these programs as successful. Most of the NN programs served cancer patients. Sixty percent implemented noncancer NN programs, with most reporting quality improvement as the main outcome measure for patients with conditions such as diabetes, cardiovascular disease, and high-risk obstetrics. CONCLUSIONS: Opportunities exist in demonstrating the value of NN roles. To increase support for the role, nurse executives should develop the programs to meet the clinical, marketing, and financial objectives of the organization and targeted patient populations. PMID- 24153202 TI - Residency programs for new nurse graduates: how widespread are they and what are the primary obstacles to further adoption? AB - OBJECTIVE: The objective of this study was to determine the prevalence of hospital RN residencies and the associated factors. BACKGROUND: The 2010 Institute of Medicine/Robert Wood Johnson Foundation report, The Future of Nursing: Leading Change, Advancing Health, recommends the adoption of nurse residency programs. METHODS: Members of the American Organization of Nurse Executives were surveyed, and covariates were identified. RESULTS: We found approximately 36.9% of all hospitals in our study offered a nurse residency in 2011. Associated covariates included not-for-profit status, midsize, and location in the South. Hospitals that offer residency programs were more likely to have other training programs. CONCLUSIONS: Findings suggest that residencies have been widely supported even in times of economic recession. It is important to track the expansion of these programs and to initiate research to examine the long-term impacts of residencies on nurse retention and clinical outcomes. PMID- 24153203 TI - Meeting the needs of new-graduate nurse practitioners: a model to support transition. AB - The transition of newly graduated nurse practitioners (NPs) into practice can be challenging for the employer and the NPs. A new-graduate residency model for NPs along with evaluative criteria is presented from a primary care setting. Residency models are of benefit for new-graduate NPs to ease the transition to practice and promote patient care quality, and nurse retention, and satisfaction. PMID- 24153204 TI - Evaluation of the use of bar-code medication administration in nursing practice using an evidence-based checklist. AB - The goal of this project was to determine whether the use of bar-code medication administration complied with current evidence as to how it should be used. Using an evidence-based checklist, we performed a gap analysis on bar-code medication administration (BCMA) in an acute care setting. Compliance with current evidence was identified through observation and unstructured nurse interviews. Based on findings from the initial gap analysis, quality improvement initiatives were implemented followed by a reassessment to identify possible improvement of the identified gaps. Initially, there was 72% compliance with current evidence-based practices using BCMA. After implementation of initial quality improvement initiatives targeting 3 of 9 areas with deficits in compliance, compliance was found to be 81%. The evidence-based checklist was helpful in identifying gaps in current performance and opportunities for improvement with BCMA. PMID- 24153205 TI - 4-Bicyclic heteroaryl-piperidine derivatives as potent, orally bioavailable Stearoyl-CoA desaturase-1 (SCD1) inhibitors. Part 1: urea-based analogs. AB - A new series of urea-based, 4-bicyclic heteroaryl-piperidine derivatives as potent SCD1 inhibitors is described. The structure-activity relationships focused on bicyclic heteroarenes and aminothiazole-urea portions are discussed. A trend of dose-dependent decrease in body weight gain in diet-induced obese (DIO) mice is also demonstrated. PMID- 24153206 TI - Design, synthesis and in vitro anticancer evaluation of 4,6-diamino-1,3,5 triazine-2-carbohydrazides and -carboxamides. AB - Series of substituted 4,6-diamino-1,3,5-triazine-2-carbohydrazides and carboxamides have been synthesised, based on molecular modelling of candidate structures related to the previously reported Rad6B-inhibitory diamino triazinylmethyl benzoate anticancer agents TZ8 and TZ9. Synthesis of the target compounds was readily accomplished in two steps from aryl biguanides via reaction of phenylhydrazine or benzylamines with key 4-amino-6-(arylamino)-1,3,5-triazine 2-carboxylate intermediates. These new triazine derivatives were tested for in vitro anticancer activity against the Rad6B expressing human breast cancer cell lines MDA-MB-231 and MCF-7. Active compounds, such as the triazinyl carbohydrazides 3a-e, were found to exhibit low micromolar IC50 values particularly in the Rad6B-overexpressing MDA-MB-231 cell line. PMID- 24153207 TI - Postoperative transplant immunosuppression in the critical care unit. PMID- 24153209 TI - Highlights from the creating healthy work environments conference. PMID- 24153210 TI - Assent and dissent in pediatric progressive and critical care. PMID- 24153211 TI - The Cochrane Collaboration: 20th anniversary celebrations. PMID- 24153212 TI - Effects of education on nurse confidence and cardiac surgical glycemic control. AB - This research was conducted to (1) determine the relationship between nurses' confidence levels using an endocrine order set after educational interventions and experience and (2) measure glycemic control after cardiac surgery with the use of order sets. Findings showed that nurses' confidence increased with ongoing education and experience. Furthermore, tighter glycemic control was achieved on postoperative days 1 and 2, as the protocol was refined, and as the nurses became more comfortable with its use. PMID- 24153213 TI - Publishing in professional journals, part II: writing the manuscript. AB - A great deal of work goes into the planning phase of a manuscript. These important planning steps are necessary to complete before you start the writing process. Often, inexperienced writers do not spend enough time on these vital planning steps, and that oversight can be a major factor in having a manuscript rejected for publication. The purpose of this article is to guide you in the process of writing your manuscript on the basis of your well-designed plan. Topics that are covered include avoiding writer's block, making time to write, developing the first draft using appropriate writing style, creating and submitting the final draft, and receiving feedback from the editor. PMID- 24153215 TI - Alarm fatigue: a patient safety concern. AB - Research has demonstrated that 72% to 99% of clinical alarms are false. The high number of false alarms has led to alarm fatigue. Alarm fatigue is sensory overload when clinicians are exposed to an excessive number of alarms, which can result in desensitization to alarms and missed alarms. Patient deaths have been attributed to alarm fatigue. Patient safety and regulatory agencies have focused on the issue of alarm fatigue, and it is a 2014 Joint Commission National Patient Safety Goal. Quality improvement projects have demonstrated that strategies such as daily electrocardiogram electrode changes, proper skin preparation, education, and customization of alarm parameters have been able to decrease the number of false alarms. These and other strategies need to be tested in rigorous clinical trials to determine whether they reduce alarm burden without compromising patient safety. PMID- 24153214 TI - Patient safety issues in critical care. PMID- 24153217 TI - Medication errors in the intensive care unit: literature review using the SEIPS model. AB - Medication errors in intensive care units put patients at risk for injury or death every day. Safety requires an organized and systematic approach to improving the tasks, technology, environment, and organizational culture associated with medication systems. The Systems Engineering Initiative for Patient Safety model can help leaders and health care providers understand the complicated and high-risk work associated with critical care. Using this model, the author combines a human factors approach with the well-known structure process-outcome model of quality improvement to examine research literature. The literature review reveals that human factors, including stress, high workloads, knowledge deficits, and performance deficits, are associated with medication errors. Factors contributing to medication errors are frequent interruptions, communication problems, and poor fit of health information technology to the workflow of providers. Multifaceted medication safety interventions are needed so that human factors and system problems can be addressed simultaneously. PMID- 24153218 TI - Human factors issues in the intensive care unit. AB - In the context of an aging population, more critically ill patients, and a change in intensive care unit (ICU) services stemming from advances in technology, prevalent medical errors and staff burnout in the ICU are not surprising. The ICU provides ample opportunity for human factors experts to apply their knowledge about the strengths and weaknesses of human capabilities to design more effective care delivery. Human factors experts design work processes, technology, and environmental factors to effectively and constructively channel the attention and behavior of those providing care; a few areas of focus can have marked impacts on care delivery and patient outcomes. In this review, we focus on these 3 areas and investigate the solutions and problems addressed by previous research. PMID- 24153220 TI - How to find and evaluate pertinent research. PMID- 24153221 TI - Molecular actuators driven by cooperative spin-state switching. AB - Molecular switches have great potential to convert different forms of energy into mechanical motion; however, their use is often limited by the narrow range of operating conditions. Here we report on the development of bilayer actuator devices using molecular spin crossover materials. Motion of the bilayer cantilever architecture results from the huge spontaneous strain accompanying the spin-state switching. The advantages of using spin crossover complexes here are substantial. The operating conditions used to switch the device can be manipulated through chemical modification, and there are many existing compounds to choose from. Spin crossover materials may be switched by diverse stimuli including light, temperature, pressure, guest molecules and magnetic field, allowing complex input combinations or highly specific operation. We demonstrate the versatility of this approach by fabricating actuators from four different spin crossover materials and by using both thermal variation and light to induce motion in a controlled direction. PMID- 24153222 TI - Serotonin syndrome: is it a reason to avoid the use of tramadol with antidepressants? AB - BACKGROUND: There is a warning associated with all serotonergic antidepressants and its concomitant use with tramadol due to the concern for a drug-drug interaction resulting in serotonin syndrome (SS). The prescribing of antidepressants with tramadol may be unnecessarily restricted due to fear of causing this syndrome. OBJECTIVES: There are 3 objectives of this review. To (1) review case reports of SS associated with the combination of tramadol and antidepressant drugs in recommended doses, (2) describe the mechanisms of the drug interaction, and (3) identify the potential risk factors for SS. METHODS: Case reports of SS associated with tramadol and antidepressants were identified via Cochrane Library, PubMed, and Ovid (through October 2012) using search terms SS, tramadol, antidepressants, fluoxetine, sertraline, paroxetine, fluvoxamine, citalopram, escitalopram, venlafaxine, desvenlafaxine, duloxetine, mirtazapine, milnacipran, trazodone, vilazodone, and bupropion. Cases involving monoamine oxidase inhibitors (MAOIs) and tricyclic antidepressants were excluded. RESULTS: Nine articles were identified describing 10 cases of suspected SS associated with therapeutic doses of tramadol combined with an antidepressant. Mechanisms of the drug-drug interactions involve pharmacodynamic, pharmacokinetic, and possible pharmacogenetic factors. CONCLUSIONS: Review of the available case reports of tramadol combined with antidepressant drugs in therapeutic doses indicates caution in regard to the potential for SS but does not constitute a contraindication to their use. Tramadol is only contraindicated in combination with MAOIs but not other antidepressants in common use today. These case reports do suggest several factors associated with a greater risk of SS, including increased age, higher dosages, and use of concomitant potent cytochrome P450 2D6 inhibitors. Tramadol can be safely combined with antidepressants; however, monitoring and counseling patients are prudent when starting a new serotonergic agent or when doses are increased. PMID- 24153223 TI - Single-step formation of micron long (OH)3Al2O3Ge(OH) imogolite-like nanotubes. AB - Micron-long germanium-based double-walled imogolite nanotubes were synthesized at high concentrations, as evidenced by cryo-TEM, AFM, SAXS and IR characterization methods. In addition, the spontaneous formation of a liquid-crystalline phase was observed. The novel synthesis route made it possible for the first time to obtain both long and concentrated germanium-based imogolite-like nanotubes in a single step. PMID- 24153224 TI - Anomalous diffusion and response in branched systems: a simple analysis. AB - We revisit the diffusion properties and the mean drift induced by an external field of a random walk process in a class of branched structures, as the comb lattice and the linear chains of plaquettes. A simple treatment based on scaling arguments is able to predict the correct anomalous regime for different topologies. In addition, we show that even in the presence of anomalous diffusion, Einstein's relation still holds, implying a proportionality between the mean square displacement of the unperturbed systems and the drift induced by an external forcing. PMID- 24153225 TI - [Plant potyvirus evolution: the survey of the genetic structure of populations]. AB - The Potyvirus is the largest genus of the largest family of plant RNA viruses, the Potyviridae. The potyviruses infect not only dicotyledonous but also monocotyledonous plants. The potyvirus phylogeny shows that the genus probably originated from a virus of monocotyledonous plants and that it first diverged approximately 7250 years ago in Southwest Eurasia or North Africa. Turnip mosaic virus (TuMV) belongs to the genus Potyvirus and infects a wide range of plant species, most from the family Brassicaceae. TuMV is most studied a potyvirus species for molecular evolution and the genetic structure of populations. The use of computer programs for better understanding of the evolution and the genetic structures of populations of potyviruses and TuMV are illustrated. PMID- 24153226 TI - [Role of Follicular helper CD4 T cells in HIV/SIV infection]. AB - Follicular CD4 T helper (TFH) cells promote the survival, isotype switching and generation of high affinity memory B cells and plasma cells. There are numerous reports regarding the dysfunction of B cell mediated immune responses, the lack of memory CD4 T cells and the dysfunction of HIV specific CD4 T cells in SIV/HIV infection. During chronic SIV/HIV infection, TFH cell accumulation may drive B cell dysfunction and become a major HIV reservoir. In this review, we discuss the relationship between TFH cells and B cells in SIV/HIV infection. PMID- 24153227 TI - [Protective immune responses against HIV/SIV by live attenuated vaccine in non human primate models]. AB - Live attenuated simian immunodeficiency virus (SIV) vaccines (LAVs) are currently the most effective vaccines in nonhuman primate models for AIDS, yet the basis of their robust protection remains poorly understood. Our recent immune correlate study revealed that degree of protection against pathogenic SIV challenge strongly correlated with the SIV-specific CD4+ and CD8+ T cell responses in the lymph node but neither with the responses of such T cells in the peripheral blood and mucosal tissues nor with humoral immune responses. Interestingly, the maintenance of protective T cell responses in the lymph node was associated with the amount of persistent LAV replication in the lymph node, which localized almost exclusively in follicular helper T cells. The protected monkeys manifested greater magnitude of functional effector CD8+ T cells in the lymph node, suggesting that the induction and maintenance of antiviral effector memory T cells derived by persistent antigen production have a vital role in establishment of protection. This article reviews the mechanisms of the protection in monkeys vaccinated with LAV and their implication for development of successful AIDS vaccine. PMID- 24153228 TI - [Morbilliviruses]. AB - The genus Morbillivirus in the family Paramyxoviridae contains many pathogens, which are important for medicine or veterinary medicine. Because each morbillivirus has restricted host range and serologically monotypic, the virus infection and transmission is effectively controlled by vaccinations and surveillance. Rinderpest virus has been eradicated in 2011, and elimination of measles virus progresses worldwide. Recently, a new cell receptor for measles virus, nectin4 was identified. Both SLAM, a molecule expressing on immune cells, and nectin4, a molecule expressing on epithelial cells, are important to infectivity and pathogenicity of the virus. PMID- 24153229 TI - [Rhabdoviruses]. AB - The family Rhabdoviridae has a non-segmented single stranded negative-sense RNA and its genome ranges in size from approximately 11 kb to almost 16 kb. It is one of the most ecologically diverse families of RNA viruses with members infecting a wide range of organisms. The five structural protein genes are arranged in the same linear order (3'-N-P-M-G-L-5') and may be interspersed with one more additional accessory gene. For many years, a full of knowledge of the rhabdoviridae has been established on extensive studies of two kinds of prototype viruses; vesicular stomatitis virus (VSV) and rabies virus (RABV). Among them, the genus Lyssavirus includes RABV and rabies-related viruses naturally infect mammals and chiropterans via bite-exposure by rabid animals and finally cause fatal encephalitis. In this review, we describe the sketch of the various virological features of the Rhabdoviridae, especially focusing on VSV and RABV. PMID- 24153230 TI - [Filoviruses]. AB - Filoviruses (Ebola and Marburg viruses) cause severe hemorrhagic fever in humans and nonhuman primates. No effective prophylaxis or treatment for filovirus diseases is yet commercially available. Recent studies have advanced our knowledge of filovirus protein functions and interaction between viral and host factors in the replication cycle. Current findings on the ecology of filoviruses (i.e., natural infection of nonprimate animals and discovery of a new member of filoviruses in Europe) have also provided new insights into the epidemiology of Ebola and Marburg hemorrhagic fever. This article reviews the fundamental aspects of filovirus biology and the latest topics on filovirus research. PMID- 24153231 TI - [Bornaviruses]. AB - Bornaviridae is an enveloped animal virus carrying an 8.9 kb non-segmented, negative-strand RNA genome. The genus bornavirus contains two members infecting vertebrates, Borna disease virus (BDV) and avian bornavirus (ABV), which could preferably infect the nervous systems. BDV causes classical Borna disease, a progressive meningoencephalomyelitis, in horses and sheep, and ABV is known to induce proventricular dilatation disease, a fatal disease characterized by a lymphocytic, plasmacytic inflammation of central and peripheral nervous tissues, in multiple avian species. Recent evidences have demonstrated that bornavirus is unique among RNA viruses as they not only establish a long-lasting, persistent infection in the nucleus, but also integrate their own DNA genome copy into the host chromosome. In this review, I outline the recent knowledge about the unique virological characteristics of bornaviruses, as well as the diseases caused by the infection of BDV and ABV. PMID- 24153232 TI - [Orthomyxoviruses]. AB - The Orthomyxoviridae is a family of viruses that possess segmented, single stranded, and negative-sense RNA genome. It contains influenza A virus, which is one of the most important pathogens to our public health. Here, I review general properties of Orthomyxoviruses with a focus on influenza viruses. PMID- 24153233 TI - [Arenavirus infections]. AB - Arenaviruses are the collective name for viruses, which belong to the family Arenaviridae. They replicate in the cytoplasm of cells, and were named after the sandy (Latin, arenosus) appearance of the ribosomes often seen in thin sections of virions under electron microscope. Several arenaviruses, such as Lassa virus in West Africa, and Junin, Guanarito, Sabia, Machupo, and Chapare viruses in South America, cause sever viral hemorrhagic fevers (VHF) in humans and represent a serious public health problem. These viruses are categorized as category 1 pathogens thus should be handles in a BSL4 laboratory. Recently, Lujo virus was isolated as a newly discovered novel arenavirus associated with a VHF outbreak in southern Africa in 2008. Although, we have no VHF patients caused by arenaviruses in Japan, except for a single imported Lassa fever case in 1987, it is possible that VHF patients occur as imported cases as for other VHF in the future. Therefore, it is necessary to develop the diagnostics and therapeutics in consideration of patient's severe symptoms and high mortality even in the disease free countries. In this review, we will broadly discuss the current knowledge from the basic researches to diagnostics and vaccine developments for arenavirus diseases. PMID- 24153234 TI - [Bunyavirus and its ecology]. AB - The family Bunyaviridae consists of over 300 virus species and strains that are divided into 5 genera: orthobunyavirus, hantavirus, nairovirus, phlebovirus, and tospovirus. All members of family Bunyaviridae possess a negative-sense, single stranded tripartite RNA genome, consisting of large (L), medium (M) and small (S) segments, which encode an RNA-dependent RNA polymerase, two envelope glyoproteins (Gn and Gc) and nucleocapsid (N) protein, respectively. Insects and arthropods serve as vectors of viruses in the Bunyaviridae, except for hantviruses, which instead are harbored by rodents. However, phylogenetically distinct soricomorph associated hantaviruses have been discovered in widely separated geographical regions spanning four continents. This new finding strongly suggests that evolutionary record of hantaviruses is far more complex and ancient than originally expected. Severe fever with thrombocytopenia syndrome (SFTS) is an emerging infectious disease recently described in northeast and central China. The causative agent of SFTS is phylogenetically classified to genus phlebivirus, but unlike to other member in genus phlebovirus, SFTV transmit by ticks. This review provides a brief overview of hantavirus and hantavirus infection and describes about two newly appeared viruses in the family Bunyaviridae. PMID- 24153235 TI - Pituitary gonadotropins and autoimmunity. AB - Autoimmune disease occurs when the body produces an inappropriate immune response against its own tissues producing antibodies, called autoantibodies, reacting to specific antigens. Studies regarding the presence of an autoimmune process specifically involving gonadotropins date from over than 20 years ago, when antibodies to gonadotropic-secreting cells were found by immunofluorescence in sera from a group of patients affected by cryptorchidism. Later on, antibodies detected by the same technique, and directed to the same cells were also found at high titer in sera from patients affected by hypogonadotropic hypogonadism, Kallmann's syndrome, lymphocytic hypophysitis with isolated gonadotropin deficiency, as well as autoimmune polyendocrine syndrome. Concerning the autoimmune target/s within the gonadotropic cells, rarely autoantibodies were found labeling gonadotropins while in a large number of cases, auto-antigens remained to be identified. Since pituitary gonadotropins are fundamental for the sexual maturity and reproductive mechanisms, patients with infertility were largely investigated by enzyme-linked immunosorbent assay for the presence of circulating antibodies likely interfering with gonadotropin activity. In infertile women, autoantibodies to gonadotropins were found related to ovarian autoimmunity, ovarian disorders that cause infertility and also associated with in vitro fertilization treatments. In infertile men, autoantibodies to gonadotropins may alter the testicular spermatogenesis and cause apoptosis of the spermatogenic cells. In conclusion, circulating antibodies were found labeling gonadotropic cells and/or gonadotropins, and in both cases they could create dysfunctions in gonadotropin related mechanism. The intriguing question of what can cause the production of such autoantibodies is not clear yet. PMID- 24153236 TI - High levels of molecular orientation of surface azo chromophores can be optically induced even in a wet biological environment. AB - We have developed polyelectrolyte multilayer bio-films containing azobenzene chromophores that enhance reversible photo-orientation upon irradiation with linearly polarized light, to effect surface photo-switching of adjacent biological systems. When conditions of film preparation and irradiation were optimized, we could observe the highest measured birefringence to date in amorphous systems (Deltan > 0.2). This birefringence change to probe orientation was also for the first time measured and determined to be stable completely underwater, permitting optimization for in situ applications immersed in biological conditions. PMID- 24153237 TI - A BODIPY dye as a reactive chromophoric/fluorogenic probe for selective and quick detection of vapors of secondary amines. AB - A new reaction based fluorescence turn-off strategy for detection of secondary amines was developed. The probe shows fast response and high selectivity to secondary amines in solution/film at sub-ppm levels through chromogenic and fluorescent dual-mode signal changes. PMID- 24153238 TI - Eosinophilic granulomatosis with polyangiitis (Churg-Strauss Syndrome) with microscopic eosinophilic thromboembolism and cardiac involvement: report of two cases. AB - Eosinophilic granulomatosis with polyangiitis (EGPA) is a multisystem vasculitis of small- and medium-sized vessels and approximately 40% of patients with EGPA have circulating anti-neutrophil cytoplasmic antibodies (ANCAs). Recent studies have demonstrated that ANCA-negative EGPA patients have cardiac involvement and tissue eosinophilic infiltration more frequently than ANCA-positive patients. However, a causative relationship between cardiac involvement and tissue eosinophilic infiltration remains to be elucidated. Here we report two cases of ANCA-negative EGPA with microscopic eosinophilic thromboembolism as well as cardiac impairment. Although the cutaneous manifestations of the two cases were quite different, skin specimens from both patients demonstrated that the vessels in the mid- to deep dermis were occluded with fibrin materials and surrounded by marked eosinophilic infiltration without overt leukocytoclastic vasculitis or extravascular necrotizing granuloma. The thrombogenic potential of the eosinophil was revealed by the strong expression of major basic protein, which is thought to be involved in the inhibition of natural anti-coagulation activity and activation of platelets, in the walls of the occluded vessels. The implication of microscopic eosinophilic thromboembolism in EGPA without vasculitic or granulomatous lesions is discussed. PMID- 24153239 TI - Barriers to study enrollment in patients with advanced cancer referred to a phase I clinical trials unit. AB - We conducted this retrospective study to identify reasons that patients referred to a phase I clinical trial failed to enroll or delayed enrollment onto the trial. MATERIALS AND METHODS: Outcome analyses were conducted independently on data collected from electronic medical records of two sets of consecutive patients referred to a phase I clinical trial facility at MD Anderson Cancer Center. Data from the first set of 300 patients were used to determine relevant variables affecting enrollment; data from the second set of 957 patients were then analyzed for these variables. RESULTS: Results from the two sets of patients were similar. Approximately 55% of patients were enrolled in a phase I trial. Patients referred from within MD Anderson were more likely to be enrolled than patients seen originally outside the institution (p = .006); black patients were more likely than white patients to enroll (69% vs. 43%; p = .04). The median interval from the initial visit to initiation of treatments was 19 days. Major reasons for failure to enroll included failure to return to the clinic (36%), opting for treatment in another clinic (17%), hospice referral (11%), early death (10%), and lack of financial clearance (5%). Treatment was delayed for three weeks or more in 250 patients; in 85 patients (34%), the delay was caused by financial and insurance issues. CONCLUSION: Failure to return to the clinic, pursuit of other therapy, and rapid deterioration were the major reasons for failure to enroll; lengthy financial clearance was the most common reason for delayed enrollment onto a phase I trial. PMID- 24153241 TI - Michael Rawlins: pet hate is the daily mail. PMID- 24153240 TI - Clinical efficacy of targeted biologic agents as second-line therapy of advanced thyroid cancer. AB - Targeted biologic agents showed clinically meaningful efficacy as front-line therapy for advanced radioiodine-refractory and medullary thyroid cancer. The clinical benefit of these agents beyond the front line has yet to be established. METHODS: We assessed the clinical benefit of targeted agents in patients with advanced differentiated and medullary thyroid cancer treated at a single academic cancer center. We determined efficacy and compared front-line and second-line benefit using biochemical and anatomic response, time to treatment failure, and progression-free survival (PFS). Statistical differences were assessed by t test and chi-square test. Survival curves were generated by the Kaplan-Meier method. Differences in survival were assessed using the log-rank test, and a p value <.05 was considered significant. RESULTS: We identified 39 patients with advanced differentiated and medullary thyroid cancer treated with targeted biologic agents. Median age was 56.3 years. Overall, 25 men and 14 women participated. Histology showed 23% medullary and 77% differentiated cancer. Nineteen patients progressed on front-line therapy and subsequently received second-line therapy. Targeted agents conferred clinically meaningful benefit in the second-line setting in terms of biochemical response (13.3%), clinical benefit (83.3%), median time to treatment failure (4.0 months; 95% confidence interval: 2.6-8.2), and median PFS (4.6 months; 95% confidence interval: 3.2-8.2). Second-line benefit (median PFS) was more modest in comparison to the front-line setting in both genders (women: 3 months vs. 12.2 months; men: 6 months vs. 19.7 months), in differentiated cancers (4.1 months vs. 15.7 months), and with vascular targeting agents (4.4 months vs. 20.1 months). CONCLUSION: Patients with advanced thyroid cancer derived meaningful clinical benefit from additional therapy with a biologic agent following disease progression on front-line targeted therapy. PMID- 24153242 TI - Universal health coverage: a policy whose time has come. PMID- 24153243 TI - Five year results show success of first tissue engineered trachea transplant. PMID- 24153244 TI - More patients are getting rapid access to carotid endarterectomy, but variation remains. PMID- 24153245 TI - Young black UK women are less likely than young white women to survive breast cancer. PMID- 24153246 TI - Has health in Spain been declining since the economic crisis? AB - BACKGROUND: The economic recession starting in 2008 may be having negative effects on health. PURPOSE: We aimed to identify and characterise changes in trends in 15 health indicators in Spain during the recession. METHODS: Joinpoint regression and average annual percent change (AAPC) were used to compare trends. RESULTS: Premature mortality rates from several causes of death, except from cancer, showed statistically significant downward trends during the recession, as did poor self-reported health. HIV incidence was stable. No indicator declined significantly more slowly during the recession than in the preceding 4-year period, and two declined significantly faster. CONCLUSION: Health in Spain has continued to improve during the first four years of the economic recession at a rate equal to or higher than in previous years. PMID- 24153247 TI - Employment predicts decreased mortality among HIV-seropositive illicit drug users in a setting of universal HIV care. AB - OBJECTIVE: Given the link between employment and mortality in the general population, we sought to assess this relationship among HIV-positive people who use illicit drugs in Vancouver, Canada. METHODS: Data were derived from a prospective cohort study of HIV seropositive people who use illicit drugs (n=666) during the period of May 1996-June 2010 linked to comprehensive clinical data in Vancouver, Canada, a setting where HIV care is delivered without charge. We estimated the relationship between employment and mortality using proportional hazards survival analysis, adjusting for relevant behavioural, clinical, social and socioeconomic factors. RESULTS: In a multivariate survival model, a time updated measure of full time, temporary or self-employment compared with no employment was significantly associated with a lower risk of death (adjusted HR=0.44, 95% CI 0.22 to 0.91). Results were robust to adjustment for relevant confounders, including age, injection and non-injection drug use, plasma viral load and baseline CD4 T-cell count. CONCLUSIONS: These findings suggest that employment may be an important dimension of mortality risk of HIV-seropositive illicit drug users. The potentially health-promoting impacts of labour market involvement warrant further exploration given the widespread barriers to employment and persistently elevated levels of preventable mortality among this highly marginalised population. PMID- 24153248 TI - The burden of stomach cancer in indigenous populations: a systematic review and global assessment. AB - OBJECTIVE: Stomach cancer is a leading cause of cancer death, especially in developing countries. Incidence has been associated with poverty and is also reported to disproportionately affect indigenous peoples, many of whom live in poor socioeconomic circumstances and experience lower standards of health. In this comprehensive assessment, we explore the burden of stomach cancer among indigenous peoples globally. DESIGN: The literature was searched systematically for studies on stomach cancer incidence, mortality and survival in indigenous populations, including Indigenous Australians, Maori in New Zealand, indigenous peoples from the circumpolar region, native Americans and Alaska natives in the USA, and the Mapuche peoples in Chile. Data from the New Zealand Health Information Service and the Surveillance Epidemiology and End Results (SEER) Program were used to estimate trends in incidence. RESULTS: Elevated rates of stomach cancer incidence and mortality were found in almost all indigenous peoples relative to corresponding non-indigenous populations in the same regions or countries. This was particularly evident among Inuit residing in the circumpolar region (standardised incidence ratios (SIR) males: 3.9, females: 3.6) and in Maori (SIR males: 2.2, females: 3.2). Increasing trends in incidence were found for some groups. CONCLUSIONS: We found a higher burden of stomach cancer in indigenous populations globally, and rising incidence in some indigenous groups, in stark contrast to the decreasing global trends. This is of major public health concern requiring close surveillance and further research of potential risk factors. Given evidence that improving nutrition and housing sanitation, and Helicobacter pylori eradication programmes could reduce stomach cancer rates, policies which address these initiatives could reduce inequalities in stomach cancer burden for indigenous peoples. PMID- 24153249 TI - In vitro infection of primary human hepatocytes by HCV-positive sera: insights on a highly relevant model. AB - OBJECTIVE: Adult primary human hepatocytes (PHHs) support the complete infection cycle of natural HCV from patients' sera. The molecular details underlying sera infectivity towards these cells remain largely unknown. Therefore, we sought to gain a deeper comprehension of these features in the most physiologically relevant culture system. DESIGN: Using kinetic experiments, we defined the optimal conditions to infect PHH and explored the link between cell organisation and permissivity. Based on their infectivity, about 120 sera were classified in three groups. Concentration of 52 analytes was measured in 79 selected sera using multiplexed immunobead-based analyte profiling. RESULTS: PHH permissivity towards HCV infection negatively correlated with cell polarisation and formation of functional bile canaliculi. PHH supported HCV replication for at least 2 weeks with de novo virus production. Depending on their reactivity, sera could be classified in three groups of high, intermediate or low infectivity toward PHH. Infectivity could not be predicted based on the donors' clinical characteristics, viral load or genotype. Interestingly, highly infectious sera displayed a specific cytokine profile with low levels of most of the 52 tested analytes. Among them, 24 cytokines/growth factors could impact hepatocyte biology and infection efficiency. CONCLUSIONS: We identified critical factors leading to efficient PHH infection by HCV sera in vitro. Overall, we showed that this cellular model provides a useful tool for studying the mechanism of HCV infection in its natural host cell, selecting highly infectious isolates, and determining the potency of drugs towards various HCV strains. PMID- 24153250 TI - Psychological stress and corticotropin-releasing hormone increase intestinal permeability in humans by a mast cell-dependent mechanism. AB - OBJECTIVE: Intestinal permeability and psychological stress have been implicated in the pathophysiology of IBD and IBS. Studies in animals suggest that stress increases permeability via corticotropin-releasing hormone (CRH)-mediated mast cell activation. Our aim was to investigate the effect of stress on intestinal permeability in humans and its underlying mechanisms. DESIGN: Small intestinal permeability was quantified by a 2 h lactulose-mannitol urinary excretion test. In a first study, 23 healthy volunteers were subjected to four different conditions: control; indomethacin; public speech and anticipation of electroshocks. In a second study, five test conditions were investigated in 13 volunteers: control; after pretreatment with disodium cromoglycate (DSCG); administration of CRH; DSCG+CRH and DSCG+public speech. RESULTS: Indomethacin, as a positive comparator (0.071+/-0.040 vs 0.030+/-0.022; p<0.0001), and public speech (0.059+/-0.040; p<0.01), but not the shock protocol increased intestinal permeability. Similarly, salivary cortisol was only increased after public speech. Subgroup analysis demonstrated that the effect of public speech on permeability was only present in subjects with a significant elevation of cortisol. CRH increased the lactulose-mannitol ratio (0.042+/-0.021 vs 0.028+/ 0.009; p=0.02), which was inhibited by the mast cell stabiliser DSCG. Finally, intestinal permeability was unaltered by public speech with DSCG pretreatment. CONCLUSIONS: Acute psychological stress increases small intestinal permeability in humans. Peripheral CRH reproduces the effect of stress and DSCG blocks the effect of both stress and CRH, suggesting the involvement of mast cells. These findings provide new insight into the complex interplay between the central nervous system and GI function in man. PMID- 24153251 TI - An apPEAling new therapeutic for ulcerative colitis? PMID- 24153252 TI - Human miRNome profiling identifies microRNAs differentially present in the urine after kidney injury. AB - BACKGROUND: Extracellular microRNAs (miRNAs) have been proposed as potentially robust and stable biomarkers of various disease conditions. The primary objective of this study was to identify miRNAs differentially occurring in the urine that could serve as potential biomarkers of acute kidney injury (AKI), because traditional AKI markers have limitations with respect to sensitivity, specificity, and timeliness of diagnosis. METHODS: We profiled 1809 miRNAs in pooled urine samples from 6 patients with AKI and from 6 healthy controls. We measured the 378 stably detectable miRNAs in the 12 samples individually and selected the top 7 miRNAs that were most different in the urine of patients with AKI compared with the non-AKI control individuals. These miRNAs were assessed in a larger cohort of patients with AKI (n = 98: 71 AKI patients in the intensive care unit (ICU) and 27 kidney transplantation patients with biopsy-proven tubular injury) and patients without AKI (n = 97: 74 healthy volunteers and 23 ICU patients without AKI). RESULTS: We identified 4 miRNAs capable of significantly differentiating patients with AKI from individuals without AKI: miR-21 (P = 0.0005), miR-200c (P < 0.0001), miR-423 (P = 0.001), and miR-4640 (P = 0.0355). The combined cross-validated area under the ROC curve for these 4 miRNAs was 0.91. The imprecision with respect to miRNA isolation and reverse transcription efficiency was <9% across 224 samples. CONCLUSIONS: In this study we determined the entire miRNome of human urine and identified a panel of miRNAs that are both detectable noninvasively and diagnostically sensitive indicators of kidney damage. PMID- 24153253 TI - The potential role of oral fluid in antidoping testing. AB - BACKGROUND: Currently, urine and blood are the only matrices authorized for antidoping testing by the World Anti-Doping Agency (WADA). Although the usefulness of urine and blood is proven, issues remain for monitoring some drug classes and for drugs prohibited only in competition. The alternative matrix oral fluid (OF) may offer solutions to some of these issues. OF collection is easy, noninvasive, and sex neutral and is directly observed, limiting potential adulteration, a major problem for urine testing. OF is used to monitor drug intake in workplace, clinical toxicology, criminal justice, and driving under the influence of drugs programs and potentially could complement urine and blood for antidoping testing in sports. CONTENT: This review outlines the present state of knowledge and the advantages and limitations of OF testing for each of the WADA drug classes and the research needed to advance OF testing as a viable alternative for antidoping testing. SUMMARY: Doping agents are either prohibited at all times or prohibited in competition only. Few OF data from controlled drug administration studies are available for substances banned at all times, whereas for some agents prohibited only in competition, sufficient data may be available to suggest appropriate analytes and cutoffs (analytical threshold concentrations) to identify recent drug use. Additional research is needed to characterize the disposition of many banned substances into OF; OF collection methods and doping agent stability in OF also require investigation to allow the accurate interpretation of OF tests for antidoping monitoring. PMID- 24153256 TI - Universities must inspire students as well as teach. PMID- 24153255 TI - A novel untargeted metabolomics correlation-based network analysis incorporating human metabolic reconstructions. AB - BACKGROUND: Metabolomics has become increasingly popular in the study of disease phenotypes and molecular pathophysiology. One branch of metabolomics that encompasses the high-throughput screening of cellular metabolism is metabolic profiling. In the present study, the metabolic profiles of different tumour cells from colorectal carcinoma and breast adenocarcinoma were exposed to hypoxic and normoxic conditions and these have been compared to reveal the potential metabolic effects of hypoxia on the biochemistry of the tumour cells; this may contribute to their survival in oxygen compromised environments. In an attempt to analyse the complex interactions between metabolites beyond routine univariate and multivariate data analysis methods, correlation analysis has been integrated with a human metabolic reconstruction to reveal connections between pathways that are associated with normoxic or hypoxic oxygen environments. RESULTS: Correlation analysis has revealed statistically significant connections between metabolites, where differences in correlations between cells exposed to different oxygen levels have been highlighted as markers of hypoxic metabolism in cancer. Network mapping onto reconstructed human metabolic models is a novel addition to correlation analysis. Correlated metabolites have been mapped onto the Edinburgh human metabolic network (EHMN) with the aim of interlinking metabolites found to be regulated in a similar fashion in response to oxygen. This revealed novel pathways within the metabolic network that may be key to tumour cell survival at low oxygen. Results show that the metabolic responses to lowering oxygen availability can be conserved or specific to a particular cell line. Network based correlation analysis identified conserved metabolites including malate, pyruvate, 2-oxoglutarate, glutamate and fructose-6-phosphate. In this way, this method has revealed metabolites not previously linked, or less well recognised, with respect to hypoxia before. Lactate fermentation is one of the key themes discussed in the field of hypoxia; however, malate, pyruvate, 2-oxoglutarate, glutamate and fructose-6-phosphate, which are connected by a single pathway, may provide a more significant marker of hypoxia in cancer. CONCLUSIONS: Metabolic networks generated for each cell line were compared to identify conserved metabolite pathway responses to low oxygen environments. Furthermore, we believe this methodology will have general application within metabolomics. PMID- 24153254 TI - Sox17 is indispensable for acquisition and maintenance of arterial identity. AB - The functional diversity of the arterial and venous endothelia is regulated through a complex system of signalling pathways and downstream transcription factors. Here we report that the transcription factor Sox17, which is known as a regulator of endoderm and hemopoietic differentiation, is selectively expressed in arteries, and not in veins, in the mouse embryo and in mouse postnatal retina and adult. Endothelial cell-specific inactivation of Sox17 in the mouse embryo is accompanied by a lack of arterial differentiation and vascular remodelling that results in embryo death in utero. In mouse postnatal retina, abrogation of Sox17 expression in endothelial cells leads to strong vascular hypersprouting, loss of arterial identity and large arteriovenous malformations. Mechanistically, Sox17 acts upstream of the Notch system and downstream of the canonical Wnt system. These data introduce Sox17 as a component of the complex signalling network that orchestrates arterial/venous specification. PMID- 24153269 TI - Death row incurs drug penalty. PMID- 24153270 TI - Brazil fetes open-access site. PMID- 24153271 TI - Pain of US shutdown lingers. PMID- 24153272 TI - Europe debates fisheries funding. PMID- 24153273 TI - Final word is near on dark-matter signal. PMID- 24153274 TI - Volcanic-ash sensor to take flight. PMID- 24153276 TI - Palaeontology: The truth about T. rex. PMID- 24153277 TI - Brain decoding: Reading minds. PMID- 24153287 TI - Genetics: Cattle, cheese and conservation. PMID- 24153288 TI - Patents: Universities profit from products. PMID- 24153289 TI - Computing: Scientific software needs quality control. PMID- 24153291 TI - Ronald Harry Coase (1910-2013). PMID- 24153290 TI - Patents: Universities are right to partner. PMID- 24153292 TI - Palaeoanthropology: Small-brained and big-mouthed. PMID- 24153293 TI - Astrophysics: Recipe for regularity. PMID- 24153294 TI - Physiology: A metabolic minuet. PMID- 24153296 TI - Inorganic chemistry: A reducing role for boron. PMID- 24153297 TI - Astronomy: New distance record for galaxies. PMID- 24153298 TI - Transcription and epigenetics. PMID- 24153299 TI - Chromatin dynamics during cellular reprogramming. AB - Induced pluripotency is a powerful tool to derive patient-specific stem cells. In addition, it provides a unique assay to study the interplay between transcription factors and chromatin structure. Here, we review the latest insights into chromatin dynamics that are inherent to induced pluripotency. Moreover, we compare and contrast these events with other physiological and pathological processes that involve changes in chromatin and cell state, including germ cell maturation and tumorigenesis. We propose that an integrated view of these seemingly diverse processes could provide mechanistic insights into cell fate transitions in general and might lead to new approaches in regenerative medicine and cancer treatment. PMID- 24153300 TI - TET enzymes, TDG and the dynamics of DNA demethylation. AB - DNA methylation has a profound impact on genome stability, transcription and development. Although enzymes that catalyse DNA methylation have been well characterized, those that are involved in methyl group removal have remained elusive, until recently. The transformative discovery that ten-eleven translocation (TET) family enzymes can oxidize 5-methylcytosine has greatly advanced our understanding of DNA demethylation. 5-Hydroxymethylcytosine is a key nexus in demethylation that can either be passively depleted through DNA replication or actively reverted to cytosine through iterative oxidation and thymine DNA glycosylase (TDG)-mediated base excision repair. Methylation, oxidation and repair now offer a model for a complete cycle of dynamic cytosine modification, with mounting evidence for its significance in the biological processes known to involve active demethylation. PMID- 24153301 TI - Chromatin proteins and modifications as drug targets. AB - A plethora of groundbreaking studies have demonstrated the importance of chromatin-associated proteins and post-translational modifications of histones, proteins and DNA (so-called epigenetic modifications) for transcriptional control and normal development. Disruption of epigenetic control is a frequent event in disease, and the first epigenetic-based therapies for cancer treatment have been approved. A generation of new classes of potent and specific inhibitors for several chromatin-associated proteins have shown promise in preclinical trials. Although the biology of epigenetic regulation is complex, new inhibitors such as these will hopefully be of clinical use in the coming years. PMID- 24153303 TI - Topology of mammalian developmental enhancers and their regulatory landscapes. AB - How a complex animal can arise from a fertilized egg is one of the oldest and most fascinating questions of biology, the answer to which is encoded in the genome. Body shape and organ development, and their integration into a functional organism all depend on the precise expression of genes in space and time. The orchestration of transcription relies mostly on surrounding control sequences such as enhancers, millions of which form complex regulatory landscapes in the non-coding genome. Recent research shows that high-order chromosome structures make an important contribution to enhancer functionality by triggering their physical interactions with target genes. PMID- 24153302 TI - The nexus of chromatin regulation and intermediary metabolism. AB - Living organisms and individual cells continuously adapt to changes in their environment. Those changes are particularly sensitive to fluctuations in the availability of energy substrates. The cellular transcriptional machinery and its chromatin-associated proteins integrate environmental inputs to mediate homeostatic responses through gene regulation. Numerous connections between products of intermediary metabolism and chromatin proteins have recently been identified. Chromatin modifications that occur in response to metabolic signals are dynamic or stable and might even be inherited transgenerationally. These emerging concepts have biological relevance to tissue homeostasis, disease and ageing. PMID- 24153304 TI - A galaxy rapidly forming stars 700 million years after the Big Bang at redshift 7.51. AB - Of several dozen galaxies observed spectroscopically that are candidates for having a redshift (z) in excess of seven, only five have had their redshifts confirmed via Lyman alpha emission, at z = 7.008, 7.045, 7.109, 7.213 and 7.215 (refs 1-4). The small fraction of confirmed galaxies may indicate that the neutral fraction in the intergalactic medium rises quickly at z > 6.5, given that Lyman alpha is resonantly scattered by neutral gas. The small samples and limited depth of previous observations, however, makes these conclusions tentative. Here we report a deep near-infrared spectroscopic survey of 43 photometrically selected galaxies with z > 6.5. We detect a near-infrared emission line from only a single galaxy, confirming that some process is making Lyman alpha difficult to detect. The detected emission line at a wavelength of 1.0343 micrometres is likely to be Lyman alpha emission, placing this galaxy at a redshift z = 7.51, an epoch 700 million years after the Big Bang. This galaxy's colours are consistent with significant metal content, implying that galaxies become enriched rapidly. We calculate a surprisingly high star-formation rate of about 330 solar masses per year, which is more than a factor of 100 greater than that seen in the Milky Way. Such a galaxy is unexpected in a survey of our size, suggesting that the early Universe may harbour a larger number of intense sites of star formation than expected. PMID- 24153305 TI - Thermal maps of gases in heterogeneous reactions. AB - More than 85 per cent of all chemical industry products are made using catalysts, the overwhelming majority of which are heterogeneous catalysts that function at the gas-solid interface. Consequently, much effort is invested in optimizing the design of catalytic reactors, usually by modelling the coupling between heat transfer, fluid dynamics and surface reaction kinetics. The complexity involved requires a calibration of model approximations against experimental observations, with temperature maps being particularly valuable because temperature control is often essential for optimal operation and because temperature gradients contain information about the energetics of a reaction. However, it is challenging to probe the behaviour of a gas inside a reactor without disturbing its flow, particularly when trying also to map the physical parameters and gradients that dictate heat and mass flow and catalytic efficiency. Although optical techniques and sensors have been used for that purpose, the former perform poorly in opaque media and the latter perturb the flow. NMR thermometry can measure temperature non-invasively, but traditional approaches applied to gases produce signals that depend only weakly on temperature are rapidly attenuated by diffusion or require contrast agents that may interfere with reactions. Here we present a new NMR thermometry technique that circumvents these problems by exploiting the inverse relationship between NMR linewidths and temperature caused by motional averaging in a weak magnetic field gradient. We demonstrate the concept by non-invasively mapping gas temperatures during the hydrogenation of propylene in reactors packed with metal nanoparticles and metal-organic framework catalysts, with measurement errors of less than four per cent of the absolute temperature. These results establish our technique as a non-invasive tool for locating hot and cold spots in catalyst-packed gas-solid reactors, with unprecedented capabilities for testing the approximations used in reactor modelling. PMID- 24153311 TI - Controversy about ultrahard nanotwinned cBN. PMID- 24153306 TI - A diurnal serum lipid integrates hepatic lipogenesis and peripheral fatty acid use. AB - Food intake increases the activity of hepatic de novo lipogenesis, which mediates the conversion of glucose to fats for storage or use. In mice, this program follows a circadian rhythm that peaks with nocturnal feeding and is repressed by Rev-erbalpha/beta and an HDAC3-containing complex during the day. The transcriptional activators controlling rhythmic lipid synthesis in the dark cycle remain poorly defined. Disturbances in hepatic lipogenesis are also associated with systemic metabolic phenotypes, suggesting that lipogenesis in the liver communicates with peripheral tissues to control energy substrate homeostasis. Here we identify a PPARdelta-dependent de novo lipogenic pathway in the liver that modulates fat use by muscle via a circulating lipid. The nuclear receptor PPARdelta controls diurnal expression of lipogenic genes in the dark/feeding cycle. Liver-specific PPARdelta activation increases, whereas hepatocyte-Ppard deletion reduces, muscle fatty acid uptake. Unbiased metabolite profiling identifies phosphatidylcholine 18:0/18:1 (PC(18:0/18:1) as a serum lipid regulated by diurnal hepatic PPARdelta activity. PC(18:0/18:1) reduces postprandial lipid levels and increases fatty acid use through muscle PPARalpha. High-fat feeding diminishes rhythmic production of PC(18:0/18:1), whereas PC(18:0/18:1) administration in db/db mice (also known as Lepr(-/-)) improves metabolic homeostasis. These findings reveal an integrated regulatory circuit coupling lipid synthesis in the liver to energy use in muscle by coordinating the activity of two closely related nuclear receptors. These data implicate alterations in diurnal hepatic PPARdelta-PC(18:0/18:1) signalling in metabolic disorders, including obesity. PMID- 24153312 TI - Tian et al. reply. PMID- 24153313 TI - Progress toward global eradication of dracunculiasis--January 2012-June 2013. AB - Dracunculiasis (Guinea worm disease) is caused by Dracunculus medinensis, a parasitic worm. Approximately 1 year after infection from contaminated drinking water, the worm emerges through the skin of the infected person, usually on the lower limb. Pain and secondary bacterial infection can cause temporary or permanent disability that disrupts work and schooling. In 1986, the World Health Assembly (WHA) called for dracunculiasis elimination, and the global Guinea Worm Eradication Program, supported by The Carter Center, World Health Organization (WHO), United Nations Children's Fund (UNICEF), CDC, and other partners, began assisting ministries of health of dracunculiasis-endemic countries in meeting this goal. At that time, an estimated 3.5 million cases occurred each year in 20 countries in Africa and Asia. This report updates published and unpublished surveillance data reported by ministries of health and describes progress toward dracunculiasis eradication. A total of 542 cases were reported in 2012, compared with 1,058 in 2011. The disease remains endemic in four countries in 2013, but the overall rate of reduction in cases has accelerated compared with the first 6 months of 2012. In the month of January 2013, no cases were reported worldwide for the first time since the eradication program began in 1986. Failures in surveillance and containment, lack of clean drinking water, insecurity in Mali and parts of South Sudan, and an unusual epidemiologic pattern in Chad are the main remaining challenges to dracunculiasis eradication. PMID- 24153314 TI - Histoplasmosis in a state where it is not known to be endemic--Montana, 2012 2013. AB - Histoplasmosis is caused by infection with the dimorphic fungus, Histoplasma capsulatum, following inhalation of contaminated soil. Among symptomatic patients, the most common clinical presentation is acute pneumonia. Persons with compromised immune systems are at risk for disseminated histoplasmosis, a severe illness requiring antifungal therapy that is often characterized by fever, malaise, anorexia, and weight loss. H. capsulatum is endemic in the Ohio River and Mississippi River valleys, where it is found in soil enriched with bird droppings and bat guano. During November 2012-February 2013, histoplasmosis was diagnosed in four Montana residents by four different physicians. No epidemiologic links among the cases were identified. Each patient's medical records were reviewed, and their exposure and travel histories were obtained. Three patients reported no recent travel outside of Montana and likely were exposed in Montana, which is west of areas where H. capsulatum is recognized as endemic. One patient reported recent travel to California, where she was exposed to potting soil containing bat guano. Low clinical suspicion, probably related to lack of history of exposure to areas where H. capsulatum is known to be endemic, likely delayed diagnosis and appropriate therapy for three patients. Health-care providers should be aware of the possibility of histoplasmosis in Montana and consider the diagnosis in patients with clinically compatible illnesses. PMID- 24153315 TI - Update: influenza activity--United States and worldwide, May 19-September 28, 2013. AB - During May 19-September 28, 2013,* the United States experienced low levels of seasonal influenza activity overall. Influenza A (H1N1) pdm09 (pH1N1), influenza A (H3N2), and influenza B viruses were detected worldwide and were identified sporadically in the United States. In June, influenza A (H3N2) variant(?) viruses (H3N2)v were first detected in Indiana, and between June 18 and September 28, a total of 20 cases of influenza A variant viruses ([H3N2]v and influenza A (H1N1) variant [H1N1]v) were reported from five states. This report summarizes influenza activity in the United States and worldwide from May 19 through September 28, 2013. PMID- 24153316 TI - Notes from the field: Strongyloidiasis in a rural setting--Southeastern Kentucky, 2013. AB - Strongyloidiasis is caused by Strongyloides stercoralis, a parasitic nematode (worm). Initial symptoms can include abdominal pain, diarrhea, or rash. Infection is often asymptomatic in the chronic phase but can be life-threatening in immunosuppressed persons. Transmission typically occurs when larvae from stool contaminated soil penetrate skin; intraintestinal autoinfection is also possible, sometimes allowing infection to persist for decades. Serologic studies are often used in prevalence estimates because intermittent shedding can make stool-based testing insensitive. Strongyloidiasis is most common in tropical and subtropical environments with poor sanitation. In the United States, it is commonly reported among refugees and immigrants; in the 1980s, studies in the rural southeastern United States also reported prevalence estimates ranging from 1.2%-6.1%. Prevalence might have since decreased because of investments in sanitation; however, no recent studies have been done, and strongyloidiasis is not a reportable disease in any state. PMID- 24153317 TI - Notes from the field: strongyloides infection among patients at a long-term care facility--Florida, 2010-2012. AB - During a 2-week period in August 2011, two patients in a long-term care facility in Miami-Dade County, Florida, had gastrointestinal symptoms; microscopic examination of stool specimens showed that both harbored Strongyloides stercoralis, an intestinal nematode. A subsequent chart review revealed an additional case within the facility 1 year earlier. Concerned about the possibility of an outbreak, the associate director of patient care services at the facility contacted the Florida Department of Health in Miami-Dade County and the Florida State Department of Health, which contacted CDC. This report describes the subsequent investigation. PMID- 24153318 TI - Raman database of amino acids solutions: a critical study of extended multiplicative signal correction. AB - The Raman spectra of biological materials always exhibit complex profiles, constituting several peaks and/or bands which arise due to the large variety of biomolecules. The extraction of quantitative information from these spectra is not a trivial task. While qualitative information can be retrieved from the changes in peaks frequencies or from the appearance/disappearance of some peaks, quantitative analysis requires an examination of peak intensities. Unfortunately in biological samples it is not easy to identify a reference peak for normalizing intensities, and this makes it very difficult to study the peak intensities. In the last decades a more refined mathematical tool, the extended multiplicative signal correction (EMSC), has been proposed for treating infrared spectra, which is also capable of providing quantitative information. From the mathematical and physical point of view, EMSC can also be applied to Raman spectra, as recently proposed. In this work the reliability of the EMSC procedure is tested by application to a well defined biological system: the 20 standard amino acids and their combination in peptides. The first step is the collection of a Raman database of these 20 amino acids, and subsequently EMSC processing is applied to retrieve quantitative information from amino acids mixtures and peptides. A critical review of the results is presented, showing that EMSC has to be carefully handled for complex biological systems. PMID- 24153319 TI - An NBD-armed tetraaza macrocyclic lysosomal-targeted fluorescent probe for imaging copper(II) ions. AB - An NBD-armed tetraaza macrocyclic lysosomal-targeted fluorescent probe for detecting Cu(2+) was synthesized and used for fluorescence imaging in HeLa cells. The probe was specifically localized in lysosomes and successfully applied to visualize Cu(2+) as well as to monitor Cu(2+) level changes in the lysosomes of living cells. PMID- 24153323 TI - Long-term results of selective dorsal rhizotomy for hereditary spastic paraparesis. AB - Pure hereditary spastic paraparesis usually presents with progressive weakness and spasticity of the legs, which is similar to spastic cerebral palsy. In this study selective dorsal rhizotomy (SDR) was performed to improve the spasticity of pure hereditary spastic paraparesis and the long-term results were followed. A series of four patients with pure hereditary spastic paraparesis diagnosed by a multidisciplinary team received SDR. The dorsal rootlets from the L2 to S1 levels were selectively resected under electrophysiological monitoring. The patients were followed up for more than 2 years to evaluate the outcome of surgery. There was a significant reduction in muscular spasm after SDR. Standing and walking stability were improved in all patients which led to improvement in walking posture and longer walking distance without assistance. No urinary retention, cerebrospinal fluid leak, surgical infection or kyphosis occurred. For severe pure hereditary spastic paraparesis, SDR can reduce muscle spasm and improve standing and walking stability. These results were stable throughout follow-up. SDR performed at the level of the conus medullaris through a laminectomy from T12 to L1 or L1 to L2 requires a shorter incision, laminectomy of fewer segments, and has a shorter operation time than the usual method (laminectomy from L2 to S1). Intraoperative electrophysiological monitoring is helpful to discriminate abnormal rootlets and protect sphincter function. PMID- 24153324 TI - Minimally invasive thoracic decompression for multi-level thoracic pathologies. AB - We describe our experience using a minimal access approach for multi-level dorsal decompression of the thoracic spine that may limit approach-related soft-tissue injury and spinal destabilization. Additionally, three patients, each with unique compressive thoracic pathology, are discussed. A single minimal access technique, using multi-level hemilaminotomies, was used to address these unique pathologies via a similar approach. The three patients in this study had a mean age of 49.3 years (range: 45-55 years), mean estimated blood loss of 750 cc (range: 350-1000 cc), mean operative time of 3.8 hours (range: 3-5 hours), and a mean post operative hospital stay of 2.3 days (range: 2-3 days). Complete decompression was achieved with resolution of symptoms in all patients. Long-term follow-up averaged 26.7 months (range: 15-36 months). Radiographic decompression was demonstrated in all patients. Minimal access techniques using muscle-splitting tubular retractor systems can effectively treat multi-level dorsal compression of the thoracic cord, while potentially limiting morbidity and long-term spinal instability. PMID- 24153325 TI - Density of states features in some anomalous melting elements. AB - Valence band photoemission measurements have been made on crystalline and supercooled liquid gallium, and across the liquid and solid phases of bismuth and indium. Measurements are angle integrated and made using photon excitations of 21.21 and 40.81 eV. In all cases the Bloch states are destroyed upon melting and the free electron gas is constrained by a charge-neutral liquid. The spectra of indium show little change upon solidification, indicating a common electronic structure for crystalline and liquid phases. In contrast, the energy distribution curves for supercooled gallium and bismuth show large changes in the electronic structure from solid to liquid phases, giving rise to the formation of pseudogaps in the density of states at the Fermi energy, EF. Observations of this kind enable us to distinguish normal or anomalous melting from photoemission measurements. PMID- 24153326 TI - Synergistic Lewis base and anion-binding catalysis for the enantioselective vinylogous addition of deconjugated butenolides to allenoates. AB - An enantioselective vinylogous umpolung addition of deconjugated butenolides to allenoates has been developed for the first time with the help of synergistic combination of an achiral phosphine and a chiral squaramide, and represents the first example of a catalytic enantioselective Cgamma-Cgamma bond formation between two different carbonyl partners. PMID- 24153327 TI - A novel test of planning ability: great apes can plan step-by-step but not in advance of action. AB - The ability to identify an appropriate sequence of actions or to consider alternative possible action sequences might be particularly useful during problem solving in the physical domain. We developed a new 'paddle-box' task to test the ability of different ape species to plan an appropriate sequence of physical actions (rotating paddles) to retrieve a reward from a goal location. The task had an adjustable difficulty level and was not dependent on species-specific behaviours (e.g. complex tool use). We investigated the planning abilities of captive orangutans (Pongo pygmaeus) and bonobos (Pan paniscus) using the paddle box. In experiment 1, subjects had to rotate one or two paddles before rotating the paddle with the reward on. Subjects of both species performed poorly, though orangutans rotated more non-food paddles, which may be related to their greater exploratory tendencies and bolder temperament compared with bonobos. In experiment 2 subjects could always rotate the paddle with the reward on first and still succeed, and most subjects of both species performed appropriate sequences of up to three paddle rotations to retrieve the reward. Poor performance in experiment 1 may have been related to subjects' difficulty in inhibiting the prepotent response to act on the reward immediately. PMID- 24153328 TI - Distribution of magnesium, calcium, sodium and potassium in tissues of the hip joint. AB - The aim of this study was to determine the distribution of magnesium, calcium, sodium and potassium in tissues of the hip joint and to look for any correlations between these minerals. The study was performed using hip joint samples taken from people living in the Upper Silesian Industrial Region in Poland. Ninety one subjects, 66 women and 25 men, were included in this study. The samples were obtained intra-operatively during hip joint replacement procedures. The concentrations of magnesium, calcium, sodium and potassium were measured by atomic absorption spectrophotometry (AAS). Our results showed that these minerals are most abundant in the cancellous bone of the hip joint. They were found next more abundantly in the cortical bone and the cancellous bone from the intertrochanteric area. Levels of magnesium, potassium and calcium were lower in articular cartilage compared with other parts of the hip joint; however, sodium levels were at their highest in this tissue. The lowest levels of these minerals were found in the articular capsule. Those patients with fractures of the femoral neck had lower levels of magnesium, potassium, and calcium, but higher levels of sodium compared with the group with degenerative changes. We can also confirm that in the population studied, calcium levels in cancellous bone of the head of the femur decreased with age. PMID- 24153329 TI - Therapeutic evaluation of outpatient submucosal inferior turbinate surgery for patients with severe allergic rhinitis. AB - BACKGROUND: Surgical treatment for inferior turbinate (IT) is selected to treat severe allergic rhinitis (AR) that is unresponsive to conservative treatment. This study aimed to determine the clinical effects of outpatient submucosal IT surgery (OSITS) on patients with severe AR. METHODS: Between January 2008 and August 2012, 95 patients with severe AR who underwent OSITS at the Department of Otolaryngology, Hyogo College of Medicine, were retrospectively analyzed. There were 53 men and 42 women. Their mean age was 27 years (11-75 years). OSITS was bilaterally performed using a bipolar radiofrequency electrocautery under local anesthesia. Symptoms, QOL, and physical findings were evaluated using scores from both pre- and postoperative periods (average: 12.4 months), according to Practical Guideline for the Management of AR in Japan 2009. RESULTS: In perennial AR, all mean scores of nasal symptoms, QOL, and physical findings significantly improved after OSITS (p < 0.05, n = 83). Nasal obstruction, sleep problems, and IT congestion were the most strongly affected. Eye symptoms were not influenced by OSITS. OSITS also showed significant effects on nasal obstruction and IT congestion in seasonal AR (p < 0.05, n = 12), but not sneezing, nasal discharge, and QOL. In terms of the efficacy, OSITS was beneficial in 90% of perennial AR cases and 75% of seasonal AR cases. Epistaxis (1%), vestibulitis (1%), and IT atrophy (4%) were observed after OSITS. CONCLUSIONS: These data indicate that OSITS using radiofrequency electrocautery could be a beneficial therapeutic option in patients with severe AR. PMID- 24153330 TI - Aspirin augments IgE-mediated histamine release from human peripheral basophils via Syk kinase activation. AB - BACKGROUND: Non-steroidal anti-inflammatory drugs (NSAIDs), especially aspirin, and food additives (FAs) may exacerbate allergic symptoms in patients with chronic idiopathic urticaria and food-dependent exercise-induced anaphylaxis (FDEIA). Augmentation of histamine release from human mast cells and basophils by those substances is speculated to be the cause of exacerbated allergic symptoms. We sought to investigate the mechanism of action of aspirin on IgE-mediated histamine release. METHODS: The effects of NSAIDs, FAs or cyclooxygenase (COX) inhibitors on histamine release from human basophils concentrated by gravity separation were evaluated. RESULTS: Benzoate and tartrazine, which have no COX inhibitory activity, augmented histamine release from basophils similar to aspirin. In contrast, ibuprofen, meloxicam, FR122047 and NS-398, which have COX inhibitory activity, did not affect histamine release. These results indicate that the augmentation of histamine release by aspirin is not due to COX inhibition. It was observed that aspirin augmented histamine release from human basophils only when specifically activated by anti-IgE antibodies, but not by A23187 or formyl-methionyl-leucyl-phenylalanine. When the IgE receptor signaling pathway was activated, aspirin increased the phosphorylation of Syk. Moreover, patients with chronic urticaria and FDEIA tended to be more sensitive to aspirin as regards the augmentation of histamine release, compared with healthy controls. CONCLUSIONS: Aspirin enhanced histamine release from basophils via increased Syk kinase activation, and that the augmentation of histamine release by NSAIDs or FAs may be one possible cause of worsening symptoms in patients with chronic urticaria and FDEIA. PMID- 24153331 TI - Determining minimal clinically important differences in Japanese cedar/cypress pollinosis patients. AB - BACKGROUND: Statistically significant results of medical intervention trials are not always clinically meaningful. We sought to estimate the minimal clinically important difference (MCID) (the smallest change in a given endpoint that is meaningful to a patient) during seasonal alteration of Japanese cedar/cypress pollinosis (JCCP). METHODS: Results of a double-blinded, placebo-controlled trial of JCCP patients conducted between 2008 and 2010 were analyzed using an anchor based method in which a face scale for Japanese rhinoconjunctivitis quality-of life questionnaire (JRQLQ) was set as an anchor. MICDs were calculated as changes of average scores, including those for naso-ocular symptoms with 5 items in diary cards (T5SS), naso-ocular symptoms with 6 items (T6SS) and QOL with 17 items on the JRQLQ when face scale scores either improved or deteriorated by one point. RESULTS: In 2009 and 2010, 3,698 and 374, respectively, grains/cm(2) of pollens were dispersed. The MCIDs for T5SS in 2009 and 2010 were 1.426 (0.285 per item) and 1.441 (0.288), respectively. The MCIDs for T6SS were 4.115 (0.686) and 3.183 (0.531) in 2009 and 2010, respectively. The MCIDs for QOL were 10.469 (0.616) and 6.026 (0.354) in 2009 and 2010, respectively. CONCLUSIONS: For T5SS in the diary, T6SS and QOL in JRQLQ, unit differences of 1.5 (0.3 per item), 3.6 (0.6) and 8.2 (0.5), respectively, were considered clinically meaningful by JCCP patients. The MCID for symptoms recorded in the diary was stable irrespective of the dispersed pollen level. PMID- 24153332 TI - Increased CXCL10 expression in nasal fibroblasts from patients with refractory chronic rhinosinusitis and asthma. AB - BACKGROUND: Chronic rhinosinusitis (CRS) is characterized by local inflammation of the sinonasal tissues. CRS patients with nasal polyps and asthma often develop acute exacerbation of sinonasal symptoms after upper respiratory tract infections. However, the influence of concomitant asthma on the nasal immune response to viral infection remains unclear. METHODS: Specimens of nasal polyp and mucosal tissues were obtained from 3 groups of CRS patients (n = 14 per group): 1) patients without asthma (CRS group), 2) patients with aspirin-tolerant asthma (ATA group), and 3) patients with aspirin-intolerant asthma (AIA group). Nasal fibroblasts isolated from the specimens were stimulated with poly I:C. CXCL10 expression was analyzed by the quantitative real-time polymerase chain reaction and enzyme-linked immunoadsorbent assay. Biopsy specimens from CRS patients without asthma were subjected to immunohistochemistry for detection of T bet and GATA-3 expression in CD3+ T cells by double labeling. RESULTS: Nasal fibroblasts from the ATA and AIA groups showed significantly enhanced expression of CXCL10 mRNA and protein after poly I:C stimulation compared with cells from the CRS group and the control group (normal nasal mucosa). In addition to T helper (Th)2 cells, there was more abundant infiltration of Th1 cells into tissues from the AIA and ATA groups. CONCLUSIONS: Our findings suggest that CRS associated with asthma may become intractable through the over-production of CXCL10 in response to viral infection. PMID- 24153333 TI - Mechanisms of allergen-specific immunotherapy and novel ways for vaccine development. AB - Allergen-specific immunotherapy (SIT) is the only available curative treatment of allergic diseases. Recent evidence provided a plausible explanation to its multiple mechanisms inducing both rapid desensitization and long-term allergen specific immune tolerance, and suppression of allergic inflammation in the affected tissues. During SIT, peripheral tolerance is induced by the generation of allergen-specific regulatory T cells, which suppress proliferative and cytokine responses against the allergen of interest. Regulatory T cells are characterized by IL-10 and TGF-beta secretion and expression of important cell surface suppressive molecules such as cytotoxic T lymphocyte antigen-4 and programmed death-1 that directly or indirectly influence effector cells of allergic inflammation, such as mast cells, basophils and eosinophils. Regulatory T cells and particularly IL-10 also have an influence on B cells, suppressing IgE production and inducing the production of blocking type IgG4 antibodies. In addition, development of allergen-specific B regulatory cells that produce IL-10 and develop into IgG4 producing plasma cells represent essential players in peripheral tolerance. These findings together with the new biotechnological approaches create a platform for development of the advanced vaccines. Moreover, reliable biomarkers could be selected and validated with the intention to select the patients who will benefit most from this immune-modifying treatment. Thus, allergen-SIT could provide a complete cure for a larger number of allergic patients and novel preventive approaches need to be elaborated. PMID- 24153334 TI - Cysteinyl leukotriene levels correlate with 8-isoprostane levels in exhaled breath condensates of atopic and healthy children. AB - BACKGROUND: Cysteinyl leukotrienes are important mediators of airway inflammation, whereas 8-isoprostane is a biomarker of oxidative stress. This study evaluated the distributions of cysteinyl leukotriene and 8-isoprostane concentrations in exhaled breath condensates (EBCs) of children. The relationship between cysteinyl leukotriene and 8-isoprostane concentrations in the EBCs was also evaluated. METHODS: The EBCs were collected from 34 children with allergic respiratory diseases and 24 healthy children. All recruited children underwent pulmonary function testing every season. The severity of allergic respiratory diseases and medication status were assessed every month in children with allergic respiratory diseases. RESULTS: The EBC cysteinyl leukotriene and 8 isoprostane levels were higher in children with asthma and allergic rhinitis than in those with asthma only and healthy children. In asthmatic children, cysteinyl leukotriene and 8-isoprostane levels peaked in the summer. All children showed a clear association between EBC cysteinyl leukotriene and EBC 8-isoprostane levels. CONCLUSION: The cysteinyl leukotriene and 8-isoprostane concentrations in the EBCs of children significantly varied by season. Oxidative stress correlated with airway inflammation in children. PMID- 24153335 TI - Model-based identification of drug targets that revert disrupted metabolism and its application to ageing. AB - The growing availability of 'omics' data and high-quality in silico genome-scale metabolic models (GSMMs) provide a golden opportunity for the systematic identification of new metabolic drug targets. Extant GSMM-based methods aim at identifying drug targets that would kill the target cell, focusing on antibiotics or cancer treatments. However, normal human metabolism is altered in many diseases and the therapeutic goal is fundamentally different--to retrieve the healthy state. Here we present a generic metabolic transformation algorithm (MTA) addressing this issue. First, the prediction accuracy of MTA is comprehensively validated using data sets of known perturbations. Second, two predicted yeast lifespan-extending genes, GRE3 and ADH2, are experimentally validated, together with their associated hormetic effect. Third, we show that MTA predicts new drug targets for human ageing that are enriched with orthologs of known lifespan extending genes and with genes downregulated following caloric restriction mimetic treatments. MTA offers a promising new approach for the identification of drug targets in metabolically related disorders. PMID- 24153336 TI - Percutaneous sclerotherapy with ethanolamine oleate for lymphatic malformations of the head and neck. AB - INTRODUCTION: Lymphatic malformations are low flow congenital lesions that frequently occur in the head and neck, and often require treatment. Multiple therapeutic modalities exist, including percutaneous sclerotherapy, which has been performed successfully with numerous sclerosants. Few data exist on use of ethanolamine oleate to treat lymphatic malformations. This study reports single center results using this agent to treat lymphatic malformations of the head and neck. MATERIALS AND METHODS: Prospectively maintained procedural records were retrospectively reviewed to identify all patients with lymphatic malformations who underwent percutaneous sclerotherapy. The Mulliken and Glowacki classification was used to diagnose lymphatic malformations. Medical records and images were reviewed to record demographic information, lesion characteristics, treatment sessions, and clinical and imaging response. Lesions and outcomes were evaluated with both qualitative and quantitative volumetric analysis. Response was assessed after each session and after all sessions in those patients undergoing more than one intervention, and chi(2) analysis was performed to evaluate the effects of lesion and demographic characteristics on outcomes. RESULTS: 12 interventions were performed for lesions in 10 patients. No procedural complications occurred following any procedures. Four (40.0%) patients had an excellent result after treatment, which was accomplished in one session for each of these lesions. Four (40.0%) had good results. One (10.0%) had a fair result after three sessions. One (10.0%) patient with an indeterminate syndrome with multiple congenital anomalies had a poor response following treatment. The family decided to withdraw care, and the airway was compromised. Average lesion volume reduction was 28% for all lesions and 42% when excluding the lesion for which future treatments were declined. Purely macrocystic lesions were more likely to have an excellent response to treatment than lesions with both macrocystic and microcystic components. CONCLUSIONS: Percutaneous sclerotherapy using ethanolamine oleate to treat lymphatic malformations of the head and neck appears safe and efficacious. This agent should be considered when treating these complex lesions, particularly those that are exclusively macrocystic. Further investigation of such treatments should evaluate this agent alongside the many others currently utilized. PMID- 24153337 TI - Percutaneous trigeminal rhizotomy in a biplane angiosuite: technical assessment. AB - BACKGROUND: Percutaneous trigeminal rhizotomy (PTR) uses fluoroscopic guidance to cannulate the foramen ovale for the treatment of trigeminal neuralgia. OBJECTIVE: To describe the use of a high-resolution biplane neuroangiosuite for PTR and retrospectively to assess the performance of this technique. METHODS: From 1990 through 2010, 67 PTRs were performed in 51 patients at our institution; 47 used the c-arm in the operating room (OR) and 20 used the biplane angiosuite. Hospital charts were reviewed for demographics, symptomatology, operative time, number of cannulation attempts, fluoroscopy time and pain outcome. Two-tailed univariate analyses were performed to compare the OR and angiosuite groups. RESULTS: In 20 of 67 PTRs, biplane fluoroscopic guidance in the angiosuite was used. Variations in type of PTR, fluoroscopy technique and follow-up time barred meaningful comparison of these variables between OR and biplane groups. However, the biplane group had significantly fewer mean cannulation attempts (1 vs 2.2, p<0.001). CONCLUSIONS: High-resolution biplane neuroangiosuites offer a readily available alternative to ORs for PTR in the treatment of trigeminal neuralgia. Use of the biplane fluoroscopy machine was practical, safe and at least as effective as the use of the c-arm. It may also offer the advantages of a reduced number of cannulation attempts. PMID- 24153338 TI - Is aneurysm repair justified for the patients aged 80 or older after aneurysmal subarachnoid hemorrhage? AB - BACKGROUND: With the advancement of an aging society in the world, an increasing number of elderly patients have been hospitalized due to aneurysmal subarachnoid hemorrhage (aSAH). There is no study that compares the elderly cases of aSAH who receive the definitive treatment with those who treated conservatively. The aim of this study was to investigate the feasibility of the definitive surgery for the acute subarachnoid cases aged 80 or older. METHODS: We reviewed 500 consecutive cases with acute aSAH with surgical indication for aneurysm repair. Inoperable cases such as dead-on-arrival and the cases with both pupils dilated were excluded. We compared the cases aged 80 or older that received clipping or coil embolization with the controls that the family selected conservative treatment. RESULTS: 69 cases were included in this study (ranged 80-98, male:female=9:60). 56 cases (81.2%) had an aneurysm in the anterior circulation. 23 cases received clipping, 20 cases coil embolization and 26 cases treated conservatively. The cases with aneurysm repair showed significantly better clinical outcome than the controls, while World Federation of Neurological Surgeons (WFNS) grade on admission and premorbid modified Rankin Scale showed no difference between them. CONCLUSIONS: Better prognosis was obtained when ruptured aneurysm was repaired in the elderly than it was treated conservatively. From the results of this study, we should not hesitate to offer the definitive surgery for the elderly with aSAH. PMID- 24153339 TI - Modified balloon assisted coil embolization for the treatment of intracranial and cervical arterial aneurysms using coaxial dual lumen balloon microcatheters: initial experience. AB - INTRODUCTION: Traditional balloon assisted coil embolization techniques for intracranial aneurysms require a single lumen balloon to remodel the aneurysm neck and a separate microcatheter to place coils. Here we report utilization of a single coaxial dual balloon microcatheter to achieve both coil placement and neck remodeling in a series of intracranial and cervical arterial aneurysms. MATERIALS AND METHODS: A series of five patients, including two with subarachnoid hemorrhage, presented to our institution with wide necked oblong aneurysms (8-30 mm maximum diameter). Coil embolization in four of these aneurysms was performed by advancing the tip of either a 4*10 mm Scepter C or a 4*11 mm Scepter XC balloon microcatheter (Microvention, Tustin, USA) into the aneurysm, inflating the balloon at the aneurysm neck, and placing the coils through the same microcatheter. In the fifth patient, who had a giant aneurysm at the top of the basilar artery, two Scepter XC balloon microcatheters were placed side by side and inflated simultaneously at the neck of the aneurysm; coil embolization was then successfully performed through both Scepter XC microcatheters. RESULTS: Coil embolization was successfully performed with this technique in all five aneurysms. There was no instance of aneurysm rupture, thromboembolic complications, occlusion of branch vessels near the aneurysm neck, or prolapse of coil loops into the parent vessel. CONCLUSIONS: Aneurysmal neck remodeling and coil embolization can both be achieved using a single coaxial dual lumen balloon microcatheter in selected oblong intracranial and cervical arterial aneurysms. PMID- 24153340 TI - Association of erythrocyte membrane fatty acids with changes in glycemia and risk of type 2 diabetes. AB - BACKGROUND: The significance of erythrocyte membrane fatty acids (EMFAs) and their ratios to predict hyperglycemia and incident type 2 diabetes is unclear. OBJECTIVE: We investigated EMFAs as predictors of the worsening of hyperglycemia and incident type 2 diabetes in a 5-y follow-up of a population-based study. DESIGN: We measured EMFAs in 1346 Finnish men aged 45-73 y at baseline [mean +/- SD age: 55 +/- 6 y; body mass index (in kg/m(2)): 26.5 +/- 3.5]. Our prospective follow-up study included only men who were nondiabetic at baseline and who had data available at the 5-y follow-up visit (n = 735). RESULTS: Our study showed that, after adjustment for confounding factors, palmitoleic acid (16:1n-7; P = 2.8 * 10(-7)), dihomo-gamma-linolenic acid (20:3n-6; P = 2.3 * 10(-4)), the ratio of 16:1n-7 to 16:0 (P = 1.6 * 10(-8)) as a marker of stearoyl coenzyme A desaturase 1 activity, and the ratio of 20:3n-6 to 18:2n-6 (P = 9.4 * 10(-7)) as a marker of Delta(6)-desaturase activity significantly predicted the worsening of hyperglycemia (glucose area under the curve in an oral-glucose-tolerance test). In contrast, linoleic acid (18:2n-6; P = 0.0015) and the ratio of 18:1n-7 to 16:1n-7 (P = 1.5 * 10(-9)) as a marker of elongase activity had opposite associations. Statistical significance persisted even after adjustment for baseline insulin sensitivity, insulin secretion, and glycemia. Palmitoleic acid (P = 0.010) and the ratio of 16:1n-7 to 16:0 (P = 0.004) nominally predicted incident type 2 diabetes, whereas linoleic acid had an opposite association (P = 0.004), and n-3 polyunsaturated fatty acids did not show any associations. CONCLUSION: EMFAs and their ratios are associated longitudinally with changes in glycemia and the risk type 2 diabetes. PMID- 24153341 TI - The use of linear programming to determine whether a formulated complementary food product can ensure adequate nutrients for 6- to 11-month-old Cambodian infants. AB - BACKGROUND: A new software tool, Optifood, developed by the WHO and based on linear programming (LP) analysis, has been developed to formulate food-based recommendations. OBJECTIVE: This study discusses the use of Optifood for predicting whether formulated complementary food (CF) products can ensure dietary adequacy for target populations in Cambodia. DESIGN: Dietary data were collected by 24-h recall in a cross-sectional survey of 6- to 11-mo-old infants (n = 78). LP model parameters were derived from these data, including a list of foods, median serving sizes, and dietary patterns. Five series of LP analyses were carried out to model the target population's baseline diet and 4 formulated CF products [WinFood (WF), WinFood-Lite (WF-L), Corn-Soy-Blend Plus (CSB+), and Corn Soy-Blend Plus Plus (CSB++)], which were added to the diet in portions of 33 g/d dry weight (DW) for infants aged 6-8 mo and 40 g/d DW for infants aged 9-11 mo. In each series of analyses, the nutritionally optimal diet and theoretical range, in diet nutrient contents, were determined. RESULTS: The LP analysis showed that baseline diets could not achieve the Recommended Nutrient Intake (RNI) for thiamin, riboflavin, niacin, folate, vitamin B-12, calcium, iron, and zinc (range: 14-91% of RNI in the optimal diets) and that none of the formulated CF products could cover the nutrient gaps for thiamin, niacin, iron, and folate (range: 22-86% of the RNI). Iron was the key limiting nutrient, for all modeled diets, achieving a maximum of only 48% of the RNI when CSB++ was included in the diet. Only WF and WF-L filled the nutrient gap for calcium. WF-L, CSB+, and CSB++ filled the nutrient gap for zinc (9- to 11-mo-olds). CONCLUSIONS: The formulated CF products improved the nutrient adequacy of complementary feeding diets but could not entirely cover the nutrient gaps. These results emphasize the value of using LP to evaluate special CF products during the intervention planning phase. The WF study was registered at controlled-trials.com as ISRCTN19918531. PMID- 24153342 TI - Adapted dietary inflammatory index and its association with a summary score for low-grade inflammation and markers of glucose metabolism: the Cohort study on Diabetes and Atherosclerosis Maastricht (CODAM) and the Hoorn study. AB - BACKGROUND: Diet may be associated with the development of type 2 diabetes through its effects on low-grade inflammation. OBJECTIVES: We investigated whether an adapted dietary inflammatory index (ADII) is associated with a summary score for low-grade inflammation and markers of glucose metabolism. In addition, we investigated the mediating role of inflammation in the association between ADII and markers of glucose metabolism. DESIGN: We performed cross-sectional analyses of 2 Dutch cohort studies (n= 1024). An ADII was obtained by multiplying standardized energy-adjusted intakes of dietary components by literature-based dietary inflammatory weights that reflected the inflammatory potential of components. Subsequently, these multiplications were summed. Six biomarkers of inflammation were compiled in a summary score. Associations of the ADII (expressed per SD) with the summary score for inflammation and markers of glucose metabolism were investigated by using multiple linear regression models. Inflammation was considered a potential mediator in the analysis with markers of glucose metabolism. RESULTS: A higher ADII was associated with a higher summary score for inflammation [beta-adjusted = 0.04 per SD (95% CI: 0.01, 0.07 per SD)]. The ADII was also adversely associated with insulin resistance [homeostatic model assessment of insulin resistance (HOMA-IR): beta-adjusted = 3.5% per SD (95% CI: 0.6%, 6.3% per SD)]. This association was attenuated after the inclusion of the summary score for inflammation [beta-adjusted+inflammation = 2.2% (95% CI: -0.6%, 5.0%)]. The ADII was also adversely associated with fasting glucose and postload glucose but not with glycated hemoglobin. CONCLUSION: The significant mediating role of low-grade inflammation in the association between the ADII and HOMA-IR suggests that inflammation might be one of the pathways through which diet affects insulin resistance. PMID- 24153343 TI - Dietary intake and breast cancer among carriers and noncarriers of BRCA mutations in the Korean Hereditary Breast Cancer Study. AB - BACKGROUND: Soy intake is associated with a lower risk of breast cancer. However, it is unclear whether the same reduction in risk associated with high soy intake is also applicable to familial or genetic breast cancer. OBJECTIVE: The aim of this study was to assess the dietary factors among carriers and noncarriers of BRCA mutations in the Korean Hereditary Breast Cancer Study (KOHBRA). DESIGN: The KOHBRA Study is an ongoing project composed of affected breast cancer patients and familial members of breast cancer cases with BRCA mutations. To assess the association between dietary diversity and breast cancer risk, an HR was estimated by comparing affected subjects with their familial nonaffected members. To assess the interaction between the combination of BRCA mutation and diet diversity, the case-only OR (COR) was estimated by comparing BRCA mutation carriers and noncarriers only in affected subjects. RESULTS: Soy product intake was associated with a lower risk of breast cancer in carriers (HR: 0.39; 95% CI: 0.19, 0.79 for the highest quartile). The highest quartile of meat intake was associated with a higher risk of breast cancer regardless of BRCA mutation in carriers (HR: 1.97; 95% CI: 1.13, 3.44) and noncarriers (95% CI: 1.41; 1.12, 1.78). The associations of meat intake and soybean intake for breast cancer were more prominent in BRCA2 mutation carriers. In the analysis with only cases, the highest quartile of soy intake, but not meat intake, was associated with BRCA-related breast cancer (COR: 0.57; 95% CI: 0.36, 0.91). CONCLUSION: Our study suggests that soy product consumption is associated with lower breast cancer risk and it had an interaction with BRCA mutation. PMID- 24153344 TI - A comparison of the Slaughter skinfold-thickness equations and BMI in predicting body fatness and cardiovascular disease risk factor levels in children. AB - BACKGROUND: Although estimation of percentage body fat with the Slaughter skinfold-thickness equations (PBF(Slaughter)) is widely used, the accuracy of this method has not been well studied. OBJECTIVE: The objective was to determine the accuracy of the Slaughter skinfold-thickness equations. DESIGN: We compared agreement between PBF(Slaughter) and estimations derived from dual-energy X-ray absorptiometry (PBF(DXA)) in 1169 children in the Pediatric Rosetta Body Composition Project and the relation to cardiovascular disease risk factors, as compared with body mass index (BMI), in 6725 children in the Bogalusa Heart Study. RESULTS: PBF(Slaughter) was highly correlated (r = 0.90) with PBF(DXA), but it markedly overestimated levels of PBF(DXA) in children with large skinfold thicknesses. In the 65 boys with a sum of skinfold thicknesses (subscapular- plus triceps-skinfold thicknesses) >= 50 mm, PBF(Slaughter) overestimated PBF(DXA) by 12 percentage points. The comparable overestimation in girls with a high skinfold sum was 6 percentage points. We also found that, after adjustment for sex and age, BMI showed slightly stronger associations with lipid, lipoprotein, insulin, and blood pressure values than did PBF(Slaughter). CONCLUSIONS: These results indicate that PBF(Slaughter), which was developed among a group of much thinner children and adolescents, is fairly accurate among nonobese children, but markedly overestimates the body fatness of children who have thick skinfold thicknesses. Furthermore, PBF(Slaughter) has no advantage over sex- and age adjusted BMIs at identifying children who are at increased risk of cardiovascular disease based on lipid, lipoprotein, insulin, and blood pressure values. PMID- 24153345 TI - Energy intake and diet selection during buffet consumption in women classified by the 6-n-propylthiouracil bitter taste phenotype. AB - BACKGROUND: Exposure to a variety of energy-dense foods promotes increased energy intake and adiposity. Taste blindness to the bitterness of 6-n-propylthiouracil (PROP) has been associated with increased adiposity in women and might be linked to an increased energy intake and greater selection of dietary fat. OBJECTIVE: We investigated whether PROP nontaster (NT) women would consume more fat and energy in a buffet setting than medium taster (MT) or supertaster (ST) women. DESIGN: Seventy-five non-diet-restrained, lean, young women [mean +/- SEM BMI (in kg/m2): 21.5 +/- 0.6; age: 26.1 +/- 1.3 y) ate lunch and dinner in the laboratory for 3 consecutive days under the following 2 conditions: ad libitum control meals (CONTs) or high-variety buffet meals (BUFFs). A standard breakfast was consumed each day of the study (4 - d washout between conditions). RESULTS: NTs and MTs consumed more energy and fat (as the percentage of energy) from BUFFs than did STs (P < 0.01), which contributed to higher daily energy intakes in these 2 groups of women during BUFFs (2149 +/- 49 kcal/d for NTs and 2209 +/- 48 kcal/d for MTs compared with 1933 +/- 50 kcal/d for STs; P < 0.01). Together, NTs and MTs consumed an extra 246 kcal/d during BUFFs than during CONTs. In addition, compared with STs, NTs and MTs consumed more added fats and sweets (servings/d; P < 0.003) and more energy from snacks (P < 0.01) across all study days. CONCLUSIONS: NT and MT women consume more daily energy than do ST women when eating in a buffet setting, which is a common type of dietary exposure. This increase in energy intake over time could contribute to a positive energy balance and increased adiposity previously reported in these women. PMID- 24153346 TI - Specific plasma lipid classes and phospholipid fatty acids indicative of dairy food consumption associate with insulin sensitivity. AB - BACKGROUND: Reports have suggested that the consumption of dairy foods may reduce risk of type 2 diabetes on the basis of evidence of raised circulating ruminant fatty acids. OBJECTIVE: We determined whether certain phospholipid species and fatty acids that are associated with full-fat dairy consumption may also be linked to diminished insulin resistance. DESIGN: Four variables of insulin resistance and sensitivity were defined from oral-glucose-tolerance tests in 86 overweight and obese subjects with metabolic syndrome. Plasma phospholipids, sphingolipids, and fatty acids were determined by using a lipidomic analysis and gas chromatography-mass spectrometry to provide objective markers of dairy consumption. Food records provided information on dairy products. Associations were determined by using linear regression analyses adjusted for potential confounders age, sex, systolic blood pressure, waist:hip ratio, or body mass index (BMI) and corrected for multiple comparisons. RESULTS: Lysophosphatidylcholine, lyso-platelet-activating factor, and several phospholipid fatty acids correlated directly with the number of servings of full fat dairy foods. Lysophosphatidylcholine and lyso-platelet-activating factor were also associated directly with insulin sensitivity when accounting for the waist:hip ratio (Matsuda index unadjusted, P < 0.001 for both; adjusted for multiple comparisons, P < 0.02 for both) and inversely with insulin resistance (fasting insulin unadjusted, P < 0.001 for both; adjusted, P = 0.04 and P < 0.05, respectively; homeostasis model assessment of insulin resistance adjusted, P = 0.04 for both; post-glucose insulin area under the plasma insulin curve during the 120 min of the test adjusted, P < 0.01 for both). The substitution of BMI for the waist:hip ratio attenuated associations modestly. Phospholipid fatty acid 17:0 also tended to be associated directly with insulin sensitivity and inversely with resistance. CONCLUSION: Variables of insulin resistance were lower at higher concentrations of specific plasma phospholipids that were also indicators of full fat dairy consumption. This trial was registered at clinicaltrials.gov as NCT00163943. PMID- 24153347 TI - Clinical use of cyclooxygenase inhibitors impairs vitamin B-6 metabolism. AB - BACKGROUND: A low circulating vitamin B-6 concentration, which is an independent risk factor for cardiovascular disease, is commonly seen in human inflammation. OBJECTIVE: We investigated whether cyclooxygenase inhibitors alter vitamin B-6 metabolism. DESIGN: To investigate whether subjects taking a cyclooxygenase inhibitor had an altered vitamin B-6 profile, we conducted a cross-sectional study that involved 150 rheumatoid arthritis patients, with and without cyclooxygenase inhibitor treatments. C57BL/6J mice and hyperlipidemic Syrian hamsters received drug regimens that reflected clinical nonsteroidal antiinflammatory drug (NSAID) uses in treating human inflammation. The impact of long-term physiologic use of selective and nonselective cyclooxygenase inhibitors on vitamin B-6 metabolism was systematically investigated in these independent in vivo models. RESULTS: Patients who were taking cyclooxygenase inhibitors had lower circulating pyridoxal-5'-phosphate, especially those taking NSAIDs >6 mo. Long-term celecoxib and naproxen use reduced hepatic pyridoxal-5'-phosphate in mice. Nonselective cyclooxygenase inhibitor naproxen significantly decreased vitamin B-6 vitamers in the kidney. CONCLUSIONS: To our knowledge, we show novel findings that long-term physiologic doses of cyclooxygenase inhibitor may impede the synthesis of the coenzymatically active form of vitamin B-6. Because the cause of vitamin B-6 depletion in inflammation remains unknown, this study provides a potential mechanism that could account for the poor vitamin B-6 status in human inflammation. Moreover, this study further raises concerns about the long-term clinical use of antiinflammatory NSAIDs in humans. Vitamin B-6 status should be carefully monitored in long-term NSAID users. Future randomized placebo controlled studies are needed to determine the impacts of antiinflammatory cyclooxygenase inhibitor use on vitamin B-6 metabolism in humans. PMID- 24153348 TI - The association of fast food consumption with poor dietary outcomes and obesity among children: is it the fast food or the remainder of the diet? AB - BACKGROUND: Although fast food consumption has been linked to adverse health outcomes, the relative contribution of fast food itself compared with the rest of the diet to these associations remains unclear. OBJECTIVE: Our objective was to compare the independent associations with overweight/obesity or dietary outcomes for fast food consumption compared with dietary pattern for the remainder of intake. DESIGN: This cross-sectional analysis studied 4466 US children aged 2-18 y from NHANES 2007-2010. Cluster analysis identified 2 dietary patterns for the non-fast food remainder of intake: Western (50.3%) and Prudent. Multivariable adjusted linear and logistic regression models examined the association between fast food consumption and dietary pattern for the remainder of intake and estimated their independent associations with overweight/obesity and dietary outcomes. RESULTS: Half of US children consumed fast food: 39.5% low-consumers (<=30% of energy from fast food) and 10.5% high-consumers (>30% of energy). Consuming a Western dietary pattern for the remainder of intake was more likely among fast food low-consumers (OR: 1.51; 95% CI: 1.24, 1.85) and high-consumers (OR: 2.21; 95% CI: 1.60, 3.05) than among nonconsumers. The remainder of diet was independently associated with overweight/obesity (beta: 5.9; 95% CI: 1.3, 10.5), whereas fast food consumption was not, and the remainder of diet had stronger associations with poor total intake than did fast food consumption. CONCLUSIONS: Outside the fast food restaurant, fast food consumers ate Western diets, which might have stronger associations with overweight/obesity and poor dietary outcomes than fast food consumption itself. Our findings support the need for prospective studies and randomized trials to confirm these hypotheses. PMID- 24153349 TI - Association between prenatal polychlorinated biphenyl exposure and obesity development at ages 5 and 7 y: a prospective cohort study of 656 children from the Faroe Islands. AB - BACKGROUND: Chemicals with endocrine-disrupting abilities may act as obesogens and interfere with the body's natural weight-control mechanisms, especially if exposure occurs during prenatal life. OBJECTIVE: We examined the association between prenatal exposure to polychlorinated biphenyls (PCBs) and p,p' dichlorodiphenyldichloroethylene (DDE) and subsequent obesity at 5 and 7 y of age. DESIGN: From 1997 to 2000, 656 pregnant Faroese women were recruited. PCB and DDE were measured in maternal serum and breast milk, and children's weight, height, and waist circumference (WC) were measured at clinical examinations at 5 and 7 y of age. The change in body mass index (BMI) from 5 to 7 y of age was calculated. Analyses were performed by using multiple linear regression models for girls and boys separately, taking into account maternal prepregnancy BMI. RESULTS: For 7-y-old girls who had overweight mothers, PCB was associated with increased BMI (beta = 2.07, P = 0.007), and PCB and DDE were associated with an increased change in BMI from 5 to 7 y of age (PCB: beta = 1.23, P = 0.003; DDE: beta = 1.11, P = 0.008). No association was observed with BMI in girls with normal-weight mothers. PCB was associated with increased WC in girls with overweight mothers (beta = 2.48, P = 0.001) and normal-weight mothers (beta = 1.25, P = 0.04); DDE was associated with increased WC only in girls with overweight mothers (beta = 2.21, P = 0.002). No associations were observed between PCB or DDE and BMI in 5-y-old girls. For boys, no associations were observed. CONCLUSIONS: Results suggest that prenatal exposure to PCB and DDE may play a role for subsequent obesity development. Girls whose mothers have a high prepregnancy BMI seem most affected. PMID- 24153350 TI - Absence of somatic MYD88 L265P mutations in patients with primary Sjogren's syndrome. AB - Sjogren's syndrome (SS) is a chronic autoimmune disorder with the highest risk for lymphoma development among all autoimmune diseases. In order to evaluate whether the presence of the recently described MYD88 L265P mutation in patients with Waldenstrom's macroglobulinemia (WM) is contributory to SS-associated lymphomagenesis, a quantitative allele-specific PCR method was performed in peripheral blood derived from 90 SS patients as well as in minor salivary gland tissues derived from 12 primary SS patients with or without lymphoma. MYD88 L265P was not detected in either of the samples tested. Although the absence of the MyD88 L265P somatic mutation in our SS cohort does not exclude a common germline susceptibility gene in SS, it might suggest a distinct operating pathogenetic mechanism in SS-related lymphoma compared with WM and other hematological malignancies. PMID- 24153351 TI - Reversible addition of the OH radical to p-cymene in the gas phase: kinetic analysis assuming formation of a single adduct. Part 1. AB - A flash photolysis-resonance fluorescence (FP-RF) technique was employed to study the kinetics and mechanism of the reaction of OH radicals with p-cymene at temperatures between 297 and 413 K in helium buffer gas. FP-RF experiments involved time-resolved detection of OH radicals by RF following vacuum-UV flash photolysis of H2O-p-cymene-He and H2O-He mixtures. Biexponential functions were fitted to decays of OH radicals according to reversible addition of OH radicals to p-cymene to form a single adduct. A rate constant of (15.7 +/- 1.1) * 10(-12) is obtained (in units of cm(3) s(-1)) at room temperature (298 K) for the sum of the addition and abstraction channels (k1a + k1b) according to this simplified model. The Arrhenius plot reveals the step function typical of other aromatics and can be described using the expressions: 2 * 10(-13) exp(+1300 K/T) at temperatures between 297 K and 324 K and 10(-11) exp(-250 K/T) at temperatures between 345 K and 413 K. After consideration of the abstraction channel an equilibrium constant of k1a/k-1a = 6 * 10(-26) exp(+9700 K/T) cm(3) is obtained at temperatures between 297 and 325 K and 2 * 10(-36) exp(+17,000 K/T) cm(3) at temperatures between 325 and 380 K. PMID- 24153352 TI - NHS regulator plans to make it easier for doctors to raise concerns and break "mafia" code of silence. PMID- 24153353 TI - Obama promises to fix troubled health insurance exchange website. PMID- 24153354 TI - Human rhino- and enteroviruses in children with respiratory symptoms in Luanda, Angola. AB - OBJECTIVES: The role of human rhinoviruses (HRV) and human enteroviruses (HEV) in common colds, as well as their seasonality, remains largely unknown in tropical environments. The study aimed to define the frequency and clinical features of HRV and HEV in children with respiratory symptoms in tropical Africa during autumn and winter. METHODS: Clinical data and PCR assays of nasopharyngeal swabs (NPS) were collected from 67 (66%) children with and 35 (34%) children without chronic illnesses who were attending different outpatient clinics at a paediatric tertiary-care hospital in Luanda, Angola. RESULTS: Thirty-six (35%) children had HIV infection, and 27 (26%) were malnourished. Thirty-seven (36%) out of 102 NPS specimens were virus-positive: 34 (33%) for HRV and 10 (10%) for HEV. Seven (7%) had co-infection. The highest HRV-positivity rate (47%) occurred in July (P = 0.02), a mid-winter month with high relative humidity but no precipitation. Virus positivity was associated with younger age (median 36 vs 52 months, P = 0.02) but not with specific symptoms or findings. CONCLUSIONS: HRVs play a major role in young children's respiratory infections in urban tropical Angola during autumn and winter. A better understanding is required of the seasonality and clinical outcomes of these viruses in children living in resource-poor tropical countries. PMID- 24153356 TI - Alkynyl monosaccharide analogues as a tool for evaluating Golgi glycosylation efficiency: application to Congenital Disorders of Glycosylation (CDG). AB - The visualization of Golgi glycosylation defects in patients' cells with Congenital Disorders of Glycosylation (CDG) is challenging and necessitates the use of cumbersome glycan analysis methods that are barely adapted to clinical research. We show here that metabolic labelling of patient cells with alkyne tagged sialic-acid (SiaNAl) enables an easy and reliable readout assay for the detection of CDG occurrence. It also provides valuable clues regarding the pathological processes by assessing the distribution of sialic acid analogues within the cells. PMID- 24153363 TI - Processive catalysis: Thread and cut. PMID- 24153364 TI - Prebiotic chemistry: Ribozyme takes its vitamins. PMID- 24153365 TI - Chemical reactivity: Inverse solvent design. PMID- 24153366 TI - Conjugated macrocycles: Excitations get random. PMID- 24153367 TI - The past, present and potential for microfluidic reactor technology in chemical synthesis. AB - The past two decades have seen far-reaching progress in the development of microfluidic systems for use in the chemical and biological sciences. Here we assess the utility of microfluidic reactor technology as a tool in chemical synthesis in both academic research and industrial applications. We highlight the successes and failures of past research in the field and provide a catalogue of chemistries performed in a microfluidic reactor. We then assess the current roadblocks hindering the widespread use of microfluidic reactors from the perspectives of both synthetic chemistry and industrial application. Finally, we set out seven challenges that we hope will inspire future research in this field. PMID- 24153368 TI - In situ growth of nanoparticles through control of non-stoichiometry. AB - Surfaces decorated with uniformly dispersed catalytically active nanoparticles play a key role in many fields, including renewable energy and catalysis. Typically, these structures are prepared by deposition techniques, but alternatively they could be made by growing the nanoparticles in situ directly from the (porous) backbone support. Here we demonstrate that growing nano-size phases from perovskites can be controlled through judicious choice of composition, particularly by tuning deviations from the ideal ABO3 stoichiometry. This non-stoichiometry facilitates a change in equilibrium position to make particle exsolution much more dynamic, enabling the preparation of compositionally diverse nanoparticles (that is, metallic, oxides or mixtures) and seems to afford unprecedented control over particle size, distribution and surface anchorage. The phenomenon is also shown to be influenced strongly by surface reorganization characteristics. The concept exemplified here may serve in the design and development of more sophisticated oxide materials with advanced functionality across a range of possible domains of application. PMID- 24153369 TI - Optical control of antibacterial activity. AB - Bacterial resistance is a major problem in the modern world, stemming in part from the build-up of antibiotics in the environment. Novel molecular approaches that enable an externally triggered increase in antibiotic activity with high spatiotemporal resolution and auto-inactivation are highly desirable. Here we report a responsive, broad-spectrum, antibacterial agent that can be temporally activated with light, whereupon it auto-inactivates on the scale of hours. The use of such a 'smart' antibiotic might prevent the build-up of active antimicrobial material in the environment. Reversible optical control over active drug concentration enables us to obtain pharmacodynamic information. Precisely localized control of activity is achieved, allowing the growth of bacteria to be confined to defined patterns, which has potential for the development of treatments that avoid interference with the endogenous microbial population in other parts of the organism. PMID- 24153370 TI - Water lubricates hydrogen-bonded molecular machines. AB - The mechanical behaviour of molecular machines differs greatly from that of their macroscopic counterparts. This applies particularly when considering concepts such as friction and lubrication, which are key to optimizing the operation of macroscopic machinery. Here, using time-resolved vibrational spectroscopy and NMR lineshape analysis, we show that for molecular machinery consisting of hydrogen bonded components the relative motion of the components is accelerated strongly by adding small amounts of water. The translation of a macrocycle along a thread and the rotation of a molecular wheel around an axle both accelerate significantly on the addition of water, whereas other protic liquids have much weaker or opposite effects. We tentatively assign the superior accelerating effect of water to its ability to form a three-dimensional hydrogen-bond network between the moving parts of the molecular machine. These results may indicate a more general phenomenon that helps explain the function of water as the 'lubricant of life'. PMID- 24153371 TI - Water vibrations have strongly mixed intra- and intermolecular character. AB - The ability of liquid water to dissipate energy efficiently through ultrafast vibrational relaxation plays a key role in the stabilization of reactive intermediates and the outcome of aqueous chemical reactions. The vibrational couplings that govern energy relaxation in H2O remain difficult to characterize because of the limitations of current methods to visualize inter- and intramolecular motions simultaneously. Using a new sub-70 fs broadband mid infrared source, we performed two-dimensional infrared, transient absorption and polarization anisotropy spectroscopy of H2O by exciting the OH stretching transition and characterizing the response from 1,350 cm(-1) to 4,000 cm(-1). These spectra reveal vibrational transitions at all frequencies simultaneous to the excitation, including pronounced cross-peaks to the bend vibration and a continuum of induced absorptions to combination bands that are not present in linear spectra. These observations provide evidence for strong mixing of inter- and intramolecular vibrations in liquid H2O, and illustrate the shortcomings of traditional relaxation models. PMID- 24153372 TI - A broadly applicable [18F]trifluoromethylation of aryl and heteroaryl iodides for PET imaging. AB - Molecules labelled with the unnatural isotope fluorine-18 are used for positron emission tomography. Currently, this molecular imaging technology is not exploited at its full potential because many (18)F-labelled probes are inaccessible or notoriously difficult to produce. Typical challenges associated with (18)F radiochemistry are the short half-life of (18)F (<2 h), the use of sub stoichiometric amounts of (18)F, relative to the precursor and other reagents, as well as the limited availability of parent (18)F sources of suitable reactivity ([(18)F]F(-) and [(18)F]F2). There is a high-priority demand for general methods allowing access to [(18)F]CF3-substituted molecules for application in pharmaceutical discovery programmes. We report the development of a process for the late-stage [(18)F]trifluoromethylation of (hetero)arenes from [(18)F]fluoride using commercially available reagents and (hetero)aryl iodides. This [(18)F]CuCF3 based protocol benefits from a large substrate scope and is characterized by its operational simplicity. PMID- 24153373 TI - A clamp-like biohybrid catalyst for DNA oxidation. AB - In processive catalysis, a catalyst binds to a substrate and remains bound as it performs several consecutive reactions, as exemplified by DNA polymerases. Processivity is essential in nature and is often mediated by a clamp-like structure that physically tethers the catalyst to its (polymeric) template. In the case of the bacteriophage T4 replisome, a dedicated clamp protein acts as a processivity mediator by encircling DNA and subsequently recruiting its polymerase. Here we use this DNA-binding protein to construct a biohybrid catalyst. Conjugation of the clamp protein to a chemical catalyst with sequence specific oxidation behaviour formed a catalytic clamp that can be loaded onto a DNA plasmid. The catalytic activity of the biohybrid catalyst was visualized using a procedure based on an atomic force microscopy method that detects and spatially locates oxidized sites in DNA. Varying the experimental conditions enabled switching between processive and distributive catalysis and influencing the sliding direction of this rotaxane-like catalyst. PMID- 24153374 TI - Computer-aided molecular design of solvents for accelerated reaction kinetics. AB - Solvents can significantly alter the rates and selectivity of liquid-phase organic reactions, often hindering the development of new synthetic routes or, if chosen wisely, facilitating routes by improving rates and selectivities. To address this challenge, a systematic methodology is proposed that quickly identifies improved reaction solvents by combining quantum mechanical computations of the reaction rate constant in a few solvents with a computer aided molecular design (CAMD) procedure. The approach allows the identification of a high-performance solvent within a very large set of possible molecules. The validity of our CAMD approach is demonstrated through application to a classical nucleophilic substitution reaction for the study of solvent effects, the Menschutkin reaction. The results were validated successfully by in situ kinetic experiments. A space of 1,341 solvents was explored in silico, but required quantum-mechanical calculations of the rate constant in only nine solvents, and uncovered a solvent that increases the rate constant by 40%. PMID- 24153375 TI - Layer-by-layer cell membrane assembly. AB - Eukaryotic subcellular membrane systems, such as the nuclear envelope or endoplasmic reticulum, present a rich array of architecturally and compositionally complex supramolecular targets that are as yet inaccessible. Here we describe layer-by-layer phospholipid membrane assembly on microfluidic droplets, a route to structures with defined compositional asymmetry and lamellarity. Starting with phospholipid-stabilized water-in-oil droplets trapped in a static droplet array, lipid monolayer deposition proceeds as oil/water-phase boundaries pass over the droplets. Unilamellar vesicles assembled layer-by-layer support functional insertion both of purified and of in situ expressed membrane proteins. Synthesis and chemical probing of asymmetric unilamellar and double bilayer vesicles demonstrate the programmability of both membrane lamellarity and lipid-leaflet composition during assembly. The immobilized vesicle arrays are a pragmatic experimental platform for biophysical studies of membranes and their associated proteins, particularly complexes that assemble and function in multilamellar contexts in vivo. PMID- 24153376 TI - Fluctuating exciton localization in giant pi-conjugated spoked-wheel macrocycles. AB - Conjugated polymers offer potential for many diverse applications, but we still lack a fundamental microscopic understanding of their electronic structure. Elementary photoexcitations (excitons) span only a few nanometres of a molecule, which itself can extend over microns, and how their behaviour is affected by molecular dimensions is not immediately obvious. For example, where is the exciton formed within a conjugated segment and is it always situated on the same repeat units? Here, we introduce structurally rigid molecular spoked wheels, 6 nm in diameter, as a model of extended pi conjugation. Single-molecule fluorescence reveals random exciton localization, which leads to temporally varying emission polarization. Initially, this random localization arises after every photon absorption event because of temperature-independent spontaneous symmetry breaking. These fast fluctuations are slowed to millisecond timescales after prolonged illumination. Intramolecular heterogeneity is revealed in cryogenic spectroscopy by jumps in transition energy, but emission polarization can also switch without a spectral jump occurring, which implies long-range homogeneity in the local dielectric environment. PMID- 24153377 TI - A thiamin-utilizing ribozyme decarboxylates a pyruvate-like substrate. AB - Vitamins are hypothesized to be relics of an RNA world, and were probably participants in RNA-mediated primordial metabolism. If catalytic RNAs, or ribozymes, could harness vitamin cofactors to aid their function in a manner similar to protein enzymes, it would enable them to catalyse a much larger set of chemical reactions. The cofactor thiamin diphosphate, a derivative of vitamin B1 (thiamin), is used by enzymes to catalyse difficult metabolic reactions, including decarboxylation of stable alpha-keto acids such as pyruvate. Here, we report a ribozyme that uses free thiamin to decarboxylate a pyruvate-based suicide substrate (LnkPB). Thiamin conjugated to biotin was used to isolate catalytic individuals from a pool of random-sequence RNAs attached to LnkPB. Analysis of a stable guanosine adduct obtained via digestion of an RNA sequence (clone dc4) showed the expected decarboxylation product. The discovery of a prototypic thiamin-utilizing ribozyme has implications for the role of RNA in orchestrating early metabolic cycles. PMID- 24153378 TI - Manganese the protector. PMID- 24153379 TI - Asymmetries in altruistic behavior during violent intergroup conflict. AB - Recent theoretical and experimental investigations of altruistic behavior in intergroup conflict in humans frequently make use of the assumption that warfare can be modeled as a symmetrical n-person prisoner's dilemma, abstracting away the strategic differences between attack and defense. In contrast, some empirical studies on intergroup conflict in hunter-gatherer societies and chimpanzees indicate that fitness relevant risks and potential benefits of attacks and defenses might have differed substantially under ancestral conditions. Drawing on these studies, it is hypothesized that the success of defenses was much more important for individual and kin survival and that a disposition to act altruistically during intergroup conflict is thus more likely to evolve for the strategic situation of defense. It is then investigated empirically if such asymmetries in the occurrence of altruistic behavior during intergroup conflict can be found. Analyzing detailed historical case data from 20th century wars, this study finds that altruistic behavior towards members of the in-group indeed seems to occur more frequently when soldiers are defending themselves and their comrades against enemy attacks. It is proposed that this asymmetry reflects adaptive behavioral responses to the materially different strategic character of attacks and defenses under ancestral conditions. If true, this would call for a refinement of theories of the evolutionary interaction of intergroup conflict and altruism. PMID- 24153380 TI - Uxoricide in pregnancy: ancient Greek domestic violence in evolutionary perspective. AB - Previous studies of ancient Greek examples of uxoricide in pregnancy have concluded that the theme is used to suggest tyrannical abuse of power and that the violence is a product of the patriarchal nature of ancient society. This article uses evolutionary analyses of violence during pregnancy to argue that the themes of sexual jealousy and uncertainty over paternity are as crucial as the theme of power to an understanding of these examples and that the examples can be seen as typical instances of spousal abuse as it occurs in all types of society. PMID- 24153381 TI - Coulomb repulsion versus cycloaddition: formation of anionic four-membered rings from sodium phosphaethynolate, Na(OCP). AB - Carbon dioxide and two equivalents of Na(OCP) form, in an equilibrium reaction, a CO2 adduct of the composition Na2(P2C3O4). The anion of this salt, [O2C P(CO)2P](2-), is built up by a four-membered 1,3-diphosphetane-2,4-dione ring and a carboxylate unit attached to one of the phosphorus atoms. A remarkable pi delocalization was observed within the OCPCO moiety. The stepwise reaction mechanism leading to Na2(P2C3O4) was investigated with quantum chemical calculations. Accompanied by the release of CO2, Na2(P2C3O4) reacts with both 2 iodopropane and 4,4',4''-trimethoxytriphenylmethyl chloride to form four-membered cyclic anions. For comparison the analogous reactions were performed with Na(OCP) instead of Na2(P2C3O4) and the results are discussed in detail. PMID- 24153382 TI - Monitoring the mineralisation of bone nodules in vitro by space- and time resolved Raman micro-spectroscopy. AB - Raman microscopy was used as a label-free method to study the mineralisation of bone nodules formed by mesenchymal stem cells cultured in osteogenic medium in vitro. Monitoring individual bone nodules over 28 days revealed temporal and spatial changes in the crystalline phase of the hydroxyapatite components of the nodules. PMID- 24153393 TI - In-chip fabrication of free-form 3D constructs for directed cell migration analysis. AB - Free-form constructs with three-dimensional (3D) microporosity were fabricated by two-photon polymerization inside the closed microchannel of an injection-molded, commercially available polymer chip for analysis of directed cell migration. Acrylate constructs were produced as woodpile topologies with a range of pore sizes from 5 * 5 MUm to 15 * 15 MUm and prefilled with fibrillar collagen. Dendritic cells seeded into the polymer chip in a concentration gradient of the chemoattractant CCL21 efficiently negotiated the microporous maze structure for pore sizes of 8 * 8 MUm or larger. The cells migrating through smaller pore sizes made significantly more turns than those through larger pores. The introduction of additional defined barriers in the microporous structure resulted in dendritic cells making more turns while still being able to follow the chemoattractant concentration gradient. PMID- 24153394 TI - Ultrafast charge localization in a stripe-phase nickelate. AB - Self-organized electronically ordered phases are a recurring feature in correlated materials, resulting in, for example, fluctuating charge stripes whose role in high-TC superconductivity is under debate. However, the relevant cause effect relations between real-space charge correlations and low-energy excitations remain hidden in time-averaged studies. Here we reveal ultrafast charge localization and lattice vibrational coupling as dynamic precursors of stripe formation in the model compound La(1.75)Sr(0.25)NiO4, using ultrafast and equilibrium mid-infrared spectroscopy. The opening of a pseudogap at a crossover temperature T* far above long-range stripe formation establishes the onset of electronic localization, which is accompanied by an enhanced Fano asymmetry of Ni O stretch vibrations. Ultrafast excitation triggers a sub-picosecond dynamics exposing the synchronous modulation of electron-phonon coupling and charge localization. These results illuminate the role of localization in forming the pseudogap in nickelates, opening a path to understanding this mysterious phase in a broad class of complex oxides. PMID- 24153395 TI - Improving cabazitaxel chemical stability in parenteral lipid emulsions using cholesterol. AB - Intravenous lipid emulsions of cabazitaxel (CLEs) with a high stability were prepared by adding cholesterol (CH) to provide a new and more suitable delivery system for its administration. The factors affecting CLEs, such as the solubility of cabazitaxel in various oils, different kinds of lecithin, pH, different types of oil phases, and different concentrations of lipoid E80(r), CH and poloxamer 188 were investigated systematically. The degradation of cabazitaxel in aqueous solution and lipid emulsion both followed pseudo first-order kinetics. A degradation mechanism was suggested by the U-shaped pH-rate profile of cabazitaxel. A formulation containing 0.5% (w/v) CH and another formulation without CH were made to investigate the protective influence of CH on the chemical stability of CLEs. The activation energy of the two formulations was calculated to be 65.74+/-6.88 and 54.24+/-1.43 kJ/mol (n=3), respectively. Compared with the untreated CH, the shelf-life of cabazitaxel with added CH was longer, namely 134.0+/-23.4 days versus 831.4+/-204.4 days (n=3) at 4 degrees C. This indicates that the addition of CH significantly improved the lifetime of cabazitaxel in intravenous lipid emulsions. The hydrogen bonding that takes place between cabazitaxel and CH accounts for the protective effect of CH on the chemical stability of CLEs in two ways: preventing cabazitaxel from leaking and hydrolyzing in aqueous solution and hindering hydrolysis in the oil phase. Finally, the hypothesis was confirmed by LC/TOFMS and Fourier-transform infrared spectroscopy. As a result, CLEs were obtained successfully by the addition of CH and were stable enough to allow further research. PMID- 24153396 TI - Synthesis and biological evaluation of pyrrolidine-2-carbonitrile and 4 fluoropyrrolidine-2-carbonitrile derivatives as dipeptidyl peptidase-4 inhibitors for the treatment of type 2 diabetes. AB - A novel series of pyrrolidine-2-carbonitrile and 4-fluoropyrrolidine-2 carbonitrile derivatives was designed, synthesized, and found to act as dipeptidyl peptidase-4 (DPP-4) inhibitors. From this series of compounds, compound 17a was identified as an efficacious, safe, and selective inhibitor of DPP-4. In vivo studies in ICR and KKAy mice showed that administration of this compound resulted in decreased blood glucose in these mice after an oral glucose challenge. Compound 17a showed high DPP-4 inhibitory activity (IC(50)=0.017 MUM), moderate selectivity against DPP-4 (selective ratio: DPP-8/DPP-4=1324; DPP-9/DPP 4=1164), and good efficacy in oral glucose tolerance tests in ICR and KKAy mice. These in vivo anti-diabetic properties and its desirable pharmacokinetic profile in Sprague-Dawley rats demonstrate that compound 17a is a promising candidate for development as an anti-diabetic agent. PMID- 24153397 TI - Comparison between theory and simulations for the magnetization and the susceptibility of polydisperse ferrofluids. AB - The influence of polydispersity on the magnetization of ferrofluids is studied based on a previously published magnetization equation of state (Szalai and Dietrich, 2011 J. Phys.: Condens. Matter 23 326004) and computer simulations. The polydispersity of the particle diameter is described by the gamma distribution function. Canonical ensemble Monte Carlo simulations have been performed in order to test these theoretical results for the initial susceptibility and the magnetization. The results for the magnetic properties of the polydisperse systems turn out to be in quantitative agreement with our present simulation data. In addition, we find good agreement between our theory and experimental data for magnetite-based ferrofluids. PMID- 24153398 TI - Dehydrogenative coupling of aromatic thiols with Et3SiH catalysed by N heterocyclic carbene nickel complexes. AB - A series of new tetramethylcyclopentadienyl-functionalised N-heterocyclic carbene ligands with different wingtip substituents have been prepared and characterised. These ligands have been successfully coordinated to nickel affording complexes of the general type (Cp*-NHC(R))NiX (X = Cl, I). These well-defined nickel complexes selectively catalysed the coupling of aromatic thiols with Et3SiH to give the corresponding silylthioethers (RSSiEt3). The nickel complexes bearing ethyl, iso butyl, and n-butyl wingtips displayed comparable catalytic efficiency, while the nickel complex bearing a methyl substituent on the wingtip was the worst performing catalyst. PMID- 24153399 TI - Stem cell factor improves lung recovery in rats following neonatal hyperoxia induced lung injury. AB - BACKGROUND: Stem cell factor (SCF) and its receptor, c-kit, are modulators of angiogenesis. Neonatal hyperoxia-induced lung injury (HILI) is characterized by disordered angiogenesis. The objective of this study was to determine whether exogenous SCF improves recovery from neonatal HILI by improving angiogenesis. METHODS: Newborn rats assigned to normoxia (RA: 20.9% O2) or hyperoxia (90% O2) from postnatal day (P) 2 to 15, received daily injections of SCF 100 MUg/kg or placebo (PL) from P15 to P21. Lung morphometry was performed at P28. Capillary tube formation in SCF-treated hyperoxia-exposed pulmonary microvascular endothelial cells (HPMECs) was determined by Matrigel assay. RESULTS: As compared with RA, hyperoxic-PL pups had decrease in alveolarization and in lung vascular density, and this was associated with increased right ventricular systolic pressure (RVSP), right ventricular hypertrophy, and vascular remodeling. In contrast, SCF-treated hyperoxic pups had increased angiogenesis, improved alveolarization, and attenuation of pulmonary hypertension as evidenced by decreased RVSP, right ventricular hypertrophy, and vascular remodeling. Moreover, in an in vitro model, SCF increased capillary tube formation in hyperoxia-exposed HPMECs. CONCLUSION: Exogenous SCF restores alveolar and vascular structure in neonatal rats with HILI by promoting neoangiogenesis. These findings suggest a new strategy to treat lung diseases characterized by dysangiogenesis. PMID- 24153400 TI - Deficits in serum amyloid A contribute to increased neonatal mortality during murine listeriosis. AB - BACKGROUND: To understand the increased susceptibility of preterm neonates to infection. METHODS: A murine listeriosis model using immunohistochemistry, microarray technology, and real-time polymerase chain reaction (PCR). RESULTS: We report that recombinant serum amyloid A (SAA) administered prophylactically 18 h before intraperitoneal (i.p.) inoculation with Listeria monocytogenes conferred a dramatic survival benefit compared with administration of only vehicle in neonatal mice. Neonates that received the recombinant SAA protein had significantly fewer Listeria colony counts on plating of infected liver and showed significantly more activated macrophages, but SAA did not affect postnatal growth. Real-time PCR was used to confirm the microarray findings that gene expression levels for the SAA proteins 1 (Saa1) and 2 (Saa2), in addition to that for orosomucoid-2 (Orm2), were strikingly elevated in the adult compared with those in the neonate. Real-time PCR analysis showed that of the acute phase cytokines, tumor necrosis factor (TNF) gene expression increased exponentially with time in the infected adult, whereas neonates did not show similar increases. CONCLUSION: The increased susceptibility of neonatal mice to listeriosis is in part mediated by a deficiency in the acute phase response, specifically expression of SAA, and that prophylactic SAA protein before neonatal murine listeriosis results in more macrophage activation, lower Listeria counts, and greater survival. PMID- 24153401 TI - Performance of Children With Developmental Dyslexia on Two Skill Learning Tasks Serial Reaction Time and Tower of Hanoi Puzzle: A Test of the Specific Procedural Learning Difficulties Theory. AB - Among the various theories proposed to explain developmental dyslexia (DD), the theory of specific procedural learning difficulties has gained certain support and is the framework for the current research. This theory claims that an inability to achieve skill automaticity explains the difficulties experienced by individuals with DD. Previous research on automaticity and DD has exhibited methodological issues such as a failure to test a range of skills. The current study broadens previous findings by delineating various reading skills correlated with several aspects of skill acquisition. Furthermore, the study utilizes two nonverbal tasks that reflect distinct types of skills: Serial Reaction Time (SRT) and the Tower of Hanoi Puzzle (TOHP). A total of 53 children aged 11 to 13 participated in the study, of whom 23 were children with DD and 30 were controls. Participants completed a test battery that consisted of reading tests, the SRT, and the TOHP. Results show no differences in learning rate between individuals with or without DD, although individuals with DD performed both tasks at a slower rate. Correlations were identified between a number of reading measures and measures of skill acquisition, expressed primarily in individuals with DD. Implications are examined in the discussion. PMID- 24153402 TI - Test Anxiety Among College Students With Specific Reading Disability (Dyslexia): Nonverbal Ability and Working Memory as Predictors. AB - Test anxiety and its correlates were examined with college students with and without specific reading disability (RD; n = 50 in each group). Results indicated that college students with RD reported higher test anxiety than did those without RD, and the magnitude of these differences was in the medium range on two test anxiety scales. Relative to college students without RD, up to 5 times as many college students with RD reported clinically significant test anxiety. College students with RD reported significantly higher cognitively based test anxiety than physically based test anxiety. Reading skills, verbal ability, and processing speed were not correlated with test anxiety. General intelligence, nonverbal ability, and working memory were negatively correlated with test anxiety, and the magnitude of these correlations was medium to large. When these three cognitive constructs were considered together in multiple regression analyses, only working memory and nonverbal ability emerged as significant predictors and varied based on the test anxiety measure. Implications for assessment and intervention are discussed. PMID- 24153403 TI - Gender Differences in Reading Impairment and in the Identification of Impaired Readers: Results From a Large-Scale Study of At-Risk Readers. AB - Reading impairment is more common in males, but the magnitude and origin of this gender difference are debated. In a large-scale study of reading impairment among 491,103 beginning second-graders, gender differences increased with greater severity of reading impairment, peaking at a ratio of 2.4:1 for a broad measure of fluency and a ratio of 1.6:1 for a narrow measure of decoding. Results from three tests indicate that gender differences in reading impairment are attributable primarily to male vulnerability rather than ascertainment bias. Correspondence between identification as an impaired reader by our study criteria and school identification as learning disabled was poor overall and worse for girls: Only 1 out of 4 boys and 1 out of 7 girls identified as reading impaired in our study was school identified as learning disabled. PMID- 24153404 TI - A synthesis of mathematical and cognitive performances of students with mathematics learning disabilities. AB - The purpose of this study was to synthesize the findings from 23 articles that compared the mathematical and cognitive performances of students with mathematics learning disabilities (LD) to (a) students with LD in mathematics and reading, (b) age- or grade-matched students with no LD, and (c) mathematical-ability matched younger students with no LD. Overall results revealed that students with mathematics LD exhibited higher word problem-solving abilities and no significant group differences on working memory, long-term memory, and metacognition measures compared to students with LD in mathematics and reading. Findings also revealed students with mathematics LD demonstrated significantly lower performance compared to age- or grade-matched students with no LD on both mathematical and cognitive measures. Comparison between students with mathematics LD and younger students with no LD revealed mixed outcomes on mathematical measures and generally no significant group differences on cognitive measures. PMID- 24153405 TI - Mitochondrial AtPAM16 is required for plant survival and the negative regulation of plant immunity. AB - Proteins containing nucleotide-binding and leucine-rich repeat domains (NB-LRRs) serve as immune receptors in plants and animals. Negative regulation of immunity mediated by NB-LRR proteins is crucial, as their overactivation often leads to autoimmunity. Here we describe a new mutant, snc1-enhancing (muse) forward genetic screen, targeting unknown negative regulators of NB-LRR-mediated resistance in Arabidopsis. From the screen, we identify MUSE5, which is renamed as AtPAM16 because it encodes the ortholog of yeast PAM16, part of the mitochondrial inner membrane protein import motor. Consistently, AtPAM16-GFP localizes to the mitochondrial inner membrane. AtPAM16L is a paralog of AtPAM16. Double mutant Atpam16-1 Atpam16l is lethal, indicating that AtPAM16 function is essential. Single mutant Atpam16 plants exhibit a smaller size and enhanced resistance against virulent pathogens. They also display elevated reactive oxygen species (ROS) accumulation. Therefore, AtPAM16 seems to be involved in importing a negative regulator of plant immunity into mitochondria, thus protecting plants from over-accumulation of ROS and preventing autoimmunity. PMID- 24153406 TI - Cell culture process operations for recombinant protein production. AB - The market for protein therapeutics has grown significantly over the past two decades and the pace of development continues to increase. It is a challenge to the industry to maintain the desired quality attributes while accelerating delivery to patients, reducing the cost of goods, and providing production flexibility. Efficient manufacturing scale production of protein therapeutics is required to continue to meet the needs of the patients and stockholders. This chapter describes batch, fed-batch, and perfusion processes and their utilization in the production of monoclonal antibodies and other therapeutic proteins. In addition, we have provided detailed discussions of the ongoing challenges of lactate metabolism and the future prospects of process monitoring and control. PMID- 24153408 TI - Improving the understanding of DNA-propanediyl-1,3-bis(dodecyldimethylammonium) dibromide interaction using thermodynamic, structural and kinetic approaches. AB - A kinetic, thermodynamic and structural study of the interaction of the gemini surfactant propanediyl-1,3-bis(dimethyldodecylammonium dibromide) (12-3-12.2Br) with calf thymus DNA was carried out at several ionic strengths (NaCl) in aqueous solutions. A new 12-3-12(2+)-selective membrane was prepared in order to gain insight into the factors that control the binding of 12-3-12.2Br to DNA. We used ethidium bromide (EB) as a fluorescence probe to follow the kinetics of the interaction by using the stopped-flow fluorescence technique. The results can be explained in terms of a reaction mechanism involving two consecutive reversible (fast and slow) steps. The fast step was attributed to the union/separation of the surfactant with/from the DNA polynucleotide. Changes in the kinetic constants in the forward and backward directions were discussed in terms of the Bronsted Pitzer equation and of the increase in hydrophobic interactions of the surfactant tails as a consequence of salting-out effects, respectively. The slow step corresponds to a conformational change of the surfactant-DNA complex to a more compacted form. The equilibrium constant, calculated from the forward and reverse rate constants of these steps, agrees with the results obtained from potentiometric titration using a 12-3-12-(2+) selective electrode. PMID- 24153409 TI - Iodotyrosine deiodinase: a unique flavoprotein present in organisms of diverse phyla. AB - Iodide is required for thyroid hormone synthesis in mammals and other vertebrates. The role of both iodide and iodinated tyrosine derivatives is currently unknown in lower organisms, yet the presence of a key enzyme in iodide conservation, iodotyrosine deiodinase (IYD), is suggested by genomic data from a wide range of multicellular organisms as well as some bacteria. A representative set of these genes has now been expressed, and the resulting enzymes all catalyze reductive deiodination of diiodotyrosine with kcat/Km values within a single order of magnitude. This implies a physiological presence of iodotyrosines (or related halotyrosines) and a physiological role for their turnover. At least for Metazoa, IYD should provide a new marker for tracing the evolutionary development of iodinated amino acids as regulatory signals through the tree of life. PMID- 24153410 TI - Ray-optics cloaking devices for large objects in incoherent natural light. AB - A cloak that can hide living creatures from sight is a common feature of mythology but still remains unrealized as a practical device. To preserve the wave phase, the previous cloaking solution proposed by Pendry and colleagues required transformation of the electromagnetic space around the hidden object in such a way that the rays bending around the object inside the cloak region have to travel faster than those passing it by. This difficult phase preservation requirement is the main obstacle for building a broadband polarization insensitive cloak for large objects. Here we propose a simplified version of Pendry's cloak by abolishing the requirement for phase preservation, as it is irrelevant for observation using incoherent natural light with human eyes, which are phase and polarization insensitive. This allows for a cloak design on large scales using commonly available materials. We successfully demonstrate the cloaking of living creatures, a cat and a fish, from the eye. PMID- 24153412 TI - Use of proton pump inhibitors and the risk of coronary events in new users of low dose acetylsalicylic acid in UK primary care. AB - This study evaluated the risk of cardiovascular events associated with the use of proton pump inhibitors (PPIs) in new users of acetylsalicylic acid (ASA) for the secondary prevention of cardiovascular events. Two cohorts of patients aged 50-84 years were identified from UK primary care databases: individuals with a first prescription for ASA (75-300 mg/day) for secondary prevention of cardiovascular events (n = 39,513; CVD cohort) or with a record of hospitalisation for an acute coronary event (n = 42,542; ACS cohort) in 2000-2007. Cases of non-fatal myocardial infarction (MI) and coronary death were identified: 1,222 in the CVD cohort and 604 among new users of ASA in the ACS cohort. A nested case-control analysis estimated the relative risk (RR) of non-fatal MI or coronary death associated with use vs non-use of PPI therapy. Current continuous use of PPI therapy was not associated with a significant increase in RR overall: in the CVD cohort (RR = 1.14 [95% confidence interval = 0.91-1.43]); in the ACS cohort (0.88 [0.66-1.18]); or among current continuous users of ASA as antiplatelet monotherapy (CVD cohort: 1.15 [0.80-1.66]; ACS cohort: 0.73 [0.43-1.23]; pooled analysis of both cohorts: 0.96 [0.62-1.48]). In conclusion, among first-time users of ASA for the secondary prevention of cardiovascular events, PPI use was not shown to be associated with an increased risk of non-fatal MI or coronary death. PMID- 24153411 TI - A randomized, double-blind evaluation of buprenorphine taper duration in primary prescription opioid abusers. AB - IMPORTANCE: Although abuse of prescription opioids (POs) is a significant public health problem, few experimental studies have investigated the treatment needs of this growing population. OBJECTIVE: To evaluate, following brief stabilization with a combination of buprenorphine hydrochloride and naloxone hydrochloride dihydrate, the relative efficacy of 1-, 2-, and 4-week buprenorphine tapering regimens and subsequent naltrexone hydrochloride therapy in PO-dependent outpatients. DESIGN, SETTING, AND PARTICIPANTS: A double-blind, 12-week randomized clinical trial was conducted in an outpatient research clinic. Following a brief period of buprenorphine stabilization, 70 PO-dependent adults were randomized to receive 1-, 2-, or 4-week tapers followed by naltrexone therapy. INTERVENTION: During phase 1 (weeks 1-5 after randomization), participants visited the clinic daily; during phase 2 (weeks 6-12), visits were reduced to thrice weekly. Participants received behavioral therapy and urine toxicology testing throughout the trial. MAIN OUTCOMES AND MEASURES: The percentage of participants negative for illicit opioid use, retention, naltrexone ingestion, and favorable treatment response (ie, retained in treatment, opioid abstinent, and receiving naltrexone at the end of the study). RESULTS: Opioid abstinence at the end of phase 1 was greater in the 4-week compared with the 2- and 1-week taper conditions (P = .02), with 63% (n = 14), 29% (n = 7), and 29% (n = 7) of participants abstinent in the 4-, 2-, and 1-week conditions, respectively. Abstinence at the end of phase 2 was also greater in the 4-week compared with the 2- and 1-week conditions (P = .03), with 50% (n = 11), 16% (n = 4), and 20% (n = 5) of participants abstinent in the 4-, 2-, and 1-week conditions, respectively. There were more treatment responders in the 4-week condition (P = .03), with 50% (n = 11), 17% (n = 4), and 21% (n = 5) of participants in the 4-, 2-, and 1-week groups considered responders at the end of treatment, respectively. Retention and naltrexone ingestion also were superior in the 4-week vs briefer tapers (both P = .04). Experimental condition (ie, taper duration) was the strongest predictor of treatment response, followed by buprenorphine stabilization dose. CONCLUSIONS AND RELEVANCE: This study represents a rigorous experimental evaluation of outpatient buprenorphine stabilization, brief taper, and naltrexone maintenance for treatment of PO dependence. Results suggest that a meaningful subset of PO-dependent outpatients may respond positively to a 4-week taper plus naltrexone maintenance intervention. PMID- 24153413 TI - Identifying non-elliptical entity mentions in a coordinated NP with ellipses. AB - Named entities in the biomedical domain are often written using a Noun Phrase (NP) along with a coordinating conjunction such as 'and' and 'or'. In addition, repeated words among named entity mentions are frequently omitted. It is often difficult to identify named entities. Although various Named Entity Recognition (NER) methods have tried to solve this problem, these methods can only deal with relatively simple elliptical patterns in coordinated NPs. We propose a new NER method for identifying non-elliptical entity mentions with simple or complex ellipses using linguistic rules and an entity mention dictionary. The GENIA and CRAFT corpora were used to evaluate the performance of the proposed system. The GENIA corpus was used to evaluate the performance of the system according to the quality of the dictionary. The GENIA corpus comprises 3434 non-elliptical entity mentions in 1585 coordinated NPs with ellipses. The system achieves 92.11% precision, 95.20% recall, and 93.63% F-score in identification of non-elliptical entity mentions in coordinated NPs. The accuracy of the system in resolving simple and complex ellipses is 94.54% and 91.95%, respectively. The CRAFT corpus was used to evaluate the performance of the system under realistic conditions. The system achieved 78.47% precision, 67.10% recall, and 72.34% F-score in coordinated NPs. The performance evaluations of the system show that it efficiently solves the problem caused by ellipses, and improves NER performance. The algorithm is implemented in PHP and the code can be downloaded from https://code.google.com/p/medtextmining/. PMID- 24153414 TI - The fate of pulmonary conduits after the Ross procedure: longitudinal analysis of the German-Dutch Ross registry experience. AB - OBJECTIVE: To assess allograft function over time after the Ross procedure. DESIGN: Prospective multicentre registry. SETTING: 10 cardiac surgery departments in Germany and the Netherlands. PATIENTS: Among 1775 consecutive adult patients (mean age 43.7+/-12.0) who underwent the Ross procedure, 1645 (93%) received an allograft (pulmonary=1612, aortic=12, unknown=21), 120 (6%) a bioprosthesis, and 5 (0.3%) a bovine jugular vein for right ventricular outflow tract reconstruction. INTERVENTION: Ross procedure. MAIN OUTCOME MEASURES: Using non linear longitudinal models, serial echocardiographic records (N=6950) were studied to assess pulmonary conduit function over time in patients who had undergone the Ross procedure, with a maximum echocardiographic follow-up of 22.4 years (5.5+/-4.3 years). RESULTS: A slight increase in pulmonary conduit regurgitation grade was observed during follow-up. Freedom from regurgitation grade >=2+ was 95% after 14 years. Female patient gender, allograft use (compared to bioprosthesis), male donor gender, antibiotic treatment of the allograft, and specific surgical adjustments were associated with a significantly higher regurgitation grade. Mean conduit gradient increased from 4.7 mm Hg at 1 month to 10 mm Hg by 14 years, while peak gradient increased from 8.4 to 18.5 mm Hg. Smaller conduit diameter, male patient gender, younger patient age, younger donor age, and use of a bioprosthesis were associated with a significantly higher mean and peak gradient. During follow-up, 76 reinterventions were required on the pulmonary conduit in 67 patients. Freedom from pulmonary conduit reintervention or dysfunction was 90.6% (95% CI 87.7% to 93.6%) and 79.5% (95% CI 75.2% to 84.0%) at 15 years, respectively. CONCLUSIONS: Echocardiographic follow-up of pulmonary conduits shows good conduit durability. Clinically important conduit regurgitation and stenosis are rare in adult patients after the Ross operation. PMID- 24153415 TI - Lipoprotein(a): the underestimated cardiovascular risk factor. PMID- 24153416 TI - Diagnosis of neurally mediated syncope at initial evaluation and with tilt table testing compared with that revealed by prolonged ECG monitoring. An analysis from the Third International Study on Syncope of Uncertain Etiology (ISSUE-3). AB - OBJECTIVE: According to the guidelines of the European Society of Cardiology, a presumed diagnosis of neurally mediated syncope (NMS) can be made when patients have a consistent history and competing diagnoses are excluded. In the present study, we compared the initial diagnosis of NMS by means of implantable loop recorder (ILR) documentation. METHODS: In this prospective multicentre observational study which involved 51 hospitals in nine countries in Europe and Canada, 504 NMS patients >=40 years, who had suffered >=3 syncopal episodes in the previous 2 years received an ILR and were followed up for a mean of 15+/-11 months. RESULTS: ILR recorded a spontaneous syncope in 187 cases, with an estimated diagnostic yield of 47% at 3 years. ILR findings were consistent with the initial diagnosis of presumed NMS in 162 (87%) patients whereas did not confirm NMS in another 25 (13%), who had an intrinsic cardiac arrhythmic cause (atrial tachyarrhythmias (#6), long pause on termination of tachyarrhythmia (#8), persistent bradycardia (#3), ventricular tachycardia (#4)) or a non-arrhythmic loss of consciousness (non-syncopal (#3), orthostatic hypotension (#1)). No clinical baseline feature was able to predict an intrinsic cardiac cause with the exception of more frequent non-syncopal atrial tachyarrhythmias on clinical history, which were present in 38% of cardiac versus 5% of NMS patients (p=0.001). Tilt table testing (TT) was positive in 76/136 (56%) presumed NMS and in 9/21 (43%) non-NMS patients (p=0.35); an asystolic response was present in 28/136 (21%) NMS and in 0/21 (0%) non-NMS patients (p=0.03). CONCLUSIONS: ILR findings showed results other than NMS in a small, although non-negligible, number of patients older than 40 years. TT was unable to discriminate between presumed NMS and non-NMS with the exception of an asystolic response which was highly specific. PMID- 24153417 TI - Relationship between flow-mediated vasodilation and cardiovascular risk factors in a large community-based study. AB - OBJECTIVE: To determine the relationships between flow-mediated vasodilation (FMD) and cardiovascular risk factors, and to evaluate confounding factors for measurement of FMD in a large general population in Japan. METHODS: This was a cross-sectional study. A total of 5314 Japanese adults recruited from people who underwent health screening from 1 April 2010 to 31 August 2012 at 3 general hospitals in Japan. Patients' risk factors (age, Body Mass Index, blood pressure, cholesterol parameters, glucose level and HbA1c level) and prevalence of cardiovascular disease (coronary heart disease and cerebrovascular disease) were investigated. RESULTS: Univariate regression analysis revealed that FMD correlated with age (r=-0.27, p<0.001), Body Mass Index (r=-0.14, p<0.001), systolic blood pressure (r=-0.18, p<0.001), diastolic blood pressure (r=-0.13, p<0.001), total cholesterol (r=-0.07, p<0.001), triglycerides (r=-0.10, p<0.001), high-density lipoprotein cholesterol (r=0.06, p<0.001), low-density lipoprotein cholesterol (r=-0.04, p=0.01), glucose level (r=-0.14, p<0.001), HbA1c (r=-0.14, p<0.001), and baseline brachial artery diameter (r=-0.43, p<0.001) as well as Framingham Risk score (r=-0.29, p<0.001). Multivariate analysis revealed that age (t value=-9.17, p<0.001), sex (t value=9.29, p<0.001), Body Mass Index (t value=4.27, p<0.001), systolic blood pressure (t value=-2.86, p=0.004), diabetes mellitus (t value=-4.19, p<0.001), smoking (t value=-2.56, p=0.01), and baseline brachial artery diameter (t value=-29.4, p<0.001) were independent predictors of FMD. CONCLUSIONS: FMD may be a marker of the grade of atherosclerosis and may be used as a surrogate marker of cardiovascular outcomes. Age, sex, Body Mass Index, systolic blood pressure, diabetes mellitus, smoking and, particularly, baseline brachial artery diameter are potential confounding factors in the measurement of FMD. PMID- 24153418 TI - Analysis of rice ER-resident J-proteins reveals diversity and functional differentiation of the ER-resident Hsp70 system in plants. AB - The heat shock protein 70 (Hsp70) chaperone system participates in protein folding and quality control of unfolded proteins. To examine the roles of co chaperones in the rice Hsp70 chaperone system in the endoplasmic reticulum (ER), the functions of six ER-resident J-proteins (OsP58A, OsP58B, OsERdj2, OsERdj3A, OsERdj3B, and OsERdj7) in rice were investigated. The expression of OsP58B, OsERdj3A, and OsERdj3B was predominantly up-regulated in roots subjected to ER stress. This response was mediated by signalling through ATF6 orthologues such as OsbZIP39 and OsbZIP60, but not through the IRE1/OsbZIP50 pathway. A co immunoprecipitation assay demonstrated that OsP58A, OsP58B, and OsERdj3B preferentially interact with the major OsBiP, OsBiP1, while OsERdj3A interacts preferentially with OsBiP5, suggesting that there are different affinities between OsBiPs and J-proteins. In the endosperm tissue, OsP58A, OsP58B, and OsERdj2 were mainly localized in the ER, whereas OsERdj2 was localized around the outer surfaces of ER-derived protein bodies (PB-Is). Furthermore, OsERdj3A was not expressed in wild-type seeds but was up-regulated in transgenic seeds accumulating human interleukin-7 (hIL-7). Since ERdj3A-green fluorescent protein (GFP) was also detected in vacuoles of callus cells under ER stress conditions, OsERdj3A is a bona fide vacuole-localized protein. OsP58A, OsP58B and OsERdj3A were differentially accumulated in transgenic plants expressing various recombinant proteins. These results reveal the functional diversity of the rice ER-resident Hsp70 system. PMID- 24153419 TI - Elevated [CO2] magnifies isoprene emissions under heat and improves thermal resistance in hybrid aspen. AB - Isoprene emissions importantly protect plants from heat stress, but the emissions become inhibited by instantaneous increase of [CO2], and it is currently unclear how isoprene-emitting plants cope with future more frequent and severe heat episodes under high [CO2]. Hybrid aspen (Populus tremula x Populus tremuloides) saplings grown under ambient [CO2] of 380 MUmol mol(-1) and elevated [CO2] of 780 MUmol mol(-1) were used to test the hypothesis that acclimation to elevated [CO2] reduces the inhibitory effect of high [CO2] on emissions. Elevated-[CO2]-grown plants had greater isoprene emission capacity and a stronger increase of isoprene emissions with increasing temperature. High temperatures abolished the instantaneous [CO2] sensitivity of isoprene emission, possibly due to removing the substrate limitation resulting from curbed cycling of inorganic phosphate. As a result, isoprene emissions were highest in elevated-[CO2]-grown plants under high measurement [CO2]. Overall, elevated growth [CO2] improved heat resistance of photosynthesis, in particular, when assessed under high ambient [CO2] and the improved heat resistance was associated with greater cellular sugar and isoprene concentrations. Thus, contrary to expectations, these results suggest that isoprene emissions might increase in the future. PMID- 24153420 TI - A correlative microscopy approach relates microtubule behaviour, local organ geometry, and cell growth at the Arabidopsis shoot apical meristem. AB - Cortical microtubules (CMTs) are often aligned in a particular direction in individual cells or even in groups of cells and play a central role in the definition of growth anisotropy. How the CMTs themselves are aligned is not well known, but two hypotheses have been proposed. According to the first hypothesis, CMTs align perpendicular to the maximal growth direction, and, according to the second, CMTs align parallel to the maximal stress direction. Since both hypotheses were formulated on the basis of mainly qualitative assessments, the link between CMT organization, organ geometry, and cell growth is revisited using a quantitative approach. For this purpose, CMT orientation, local curvature, and growth parameters for each cell were measured in the growing shoot apical meristem (SAM) of Arabidopsis thaliana. Using this approach, it has been shown that stable CMTs tend to be perpendicular to the direction of maximal growth in cells at the SAM periphery, but parallel in the cells at the boundary domain. When examining the local curvature of the SAM surface, no strict correlation between curvature and CMT arrangement was found, which implies that SAM geometry, and presumed geometry-derived stress distribution, is not sufficient to prescribe the CMT orientation. However, a better match between stress and CMTs was found when mechanical stress derived from differential growth was also considered. PMID- 24153421 TI - Radon concentration in drinking water and supplementary exposure in Baita-Stei mining area, Bihor county (Romania). AB - The radon concentration was measured in the drinking water of public water supply and private wells located in the mining area of BaiTa-Stei, Bihor County, Romania. The measurements were performed using the LUK-VR system based on radon gas measurement with Lucas cell. The results show that the radon concentrations are within the range of 1.9-134.3 kBq m(-3) with an average value of 35.5 kBq m( 3) for well water, 18.5 kBq m(-3) for spring water and 6.9 kBq m(-3) for tap water. Comparing with previous data from the whole of Transylvania, the average value is two times higher, proving this zone to be a radon-prone area. From the results of this study the effective dose to the population is between 4.78 and 338.43 uSv y(-1). These doses are within the recommended limits of the world organisations. PMID- 24153422 TI - High-energy quasi-monoenergetic neutron fields: existing facilities and future needs. AB - The argument that well-characterised quasi-monoenergetic neutron (QMN) sources reaching into the energy domain >20 MeV are needed is presented. A brief overview of the existing facilities is given, and a list of key factors that an ideal QMN source for dosimetry and spectrometry should offer is presented. The authors conclude that all of the six QMN facilities currently in existence worldwide operate in sub-optimal conditions for dosimetry. The only currently available QMN facility in Europe capable of operating at energies >40 MeV, TSL in Uppsala, Sweden, is threatened with shutdown in the immediate future. One facility, NFS at GANIL, France, is currently under construction. NFS could deliver QMN beams up to about 30 MeV. It is, however, so far not clear if and when NFS will be able to offer QMN beams or operate with only so-called white neutron beams. It is likely that by 2016, QMN beams with energies >40 MeV will be available only in South Africa and Japan, with none in Europe. PMID- 24153423 TI - Broken discrete and continuous symmetries in two-dimensional spiral antiferromagnets. AB - We study the occurrence of symmetry breaking, at zero and finite temperatures, in the J1-J3 antiferromagnetic Heisenberg model on the square lattice using Schwinger boson mean field theory. For spin-1/2 the ground state always breaks the SU(2) symmetry with a continuous quasi-critical transition at J3/J1 ~ 0.38, from Neel to spiral long range order, although local spin fluctuation considerations suggest an intermediate disordered regime around 0.35 ? J3/J1 ? 0.5, in qualitative agreement with recent numerical results. At low temperatures we find a Z2 broken symmetry region with short range spiral order characterized by an Ising-like nematic order parameter that compares qualitatively well with classical Monte Carlo results. At intermediate temperatures the phase diagram shows regions with collinear short range orders: for J3/J1 < 1 Neel (pi,pi) correlations and for J3/J1 > 1 a novel phase consisting of four decoupled third neighbour sublattices with Neel (pi,pi) correlations in each one. We conclude that the effect of quantum and thermal fluctuations is to favour collinear correlations even in the strongly frustrated regime. PMID- 24153424 TI - Cardiovascular disease: the other face of diabetes. AB - Despite glycemic control, evidence suggests that mortality and morbidity remain high in diabetes. Regulatory agencies deem, therefore, additional safety trials necessary for the approval of new antidiabetic drugs. Nevertheless, markers of cardiovascular risk, which can be used as response predictors, are not available. In contrast with current efforts on further understanding of glucose-insulin homeostasis, a model-based approach is required to assess the correlation between hyperglycemia and cardiometabolic phenotypes, enabling prediction of the underlying cardiovascular risk.CPT: Pharmacometrics & Systems Pharmacology (2013) 2, e81; doi:10.1038/psp.2013.57; advance online publication 23 October 2013. PMID- 24153425 TI - A cyano-terminated dithienyldiketopyrrolopyrrole dimer as a solution processable ambipolar semiconductor under ambient conditions. AB - A cyano-terminated dimer of dithienyldiketopyrrolopyrrole (TDPP), DPP2-CN, is a solution processable ambipolar semiconductor with field-effect hole and electron mobilities of 0.066 and 0.033 cm(2) V(-1) s(-1), respectively, under ambient conditions. PMID- 24153426 TI - Heterozygous mutations in PALB2 cause DNA replication and damage response defects. AB - Besides mutations in BRCA1/BRCA2, heterozygous defects in PALB2 are important in breast cancer predisposition. PALB2 heterozygosity increases the risk of malignancy about sixfold. PALB2 interacts with BRCA1 and BRCA2 to regulate homologous recombination and mediate DNA damage response. Here we show, by analysing lymphoblastoid cell lines from heterozygous female PALB2 mutation carriers, that PALB2 haploinsufficiency causes aberrant DNA replication/damage response. Mutation carrier cells show increased origin firing and shorter distance between consecutive replication forks. Carrier cell lines also show elevated ATR protein, but not phosphorylation levels, and a majority of them display aberrant Chk1-/Chk2-mediated DNA damage response. Elevated chromosome instability is observed in primary blood lymphocytes of PALB2 mutation carriers, indicating that the described mechanisms of genome destabilization operate also at the organism level. These findings provide a new mechanism for early stages of breast cancer development that may also apply to other heterozygous homologous recombination signalling pathway gene mutations in hereditary cancer predisposition. PMID- 24153429 TI - Ethanol-mediated relaxation of guinea pig urinary bladder smooth muscle: involvement of BK and L-type Ca2+ channels. AB - Mechanisms underlying ethanol (EtOH)-induced detrusor smooth muscle (DSM) relaxation and increased urinary bladder capacity remain unknown. We investigated whether the large conductance Ca(2+)-activated K(+) (BK) channels or L-type voltage-dependent Ca(2+) channels (VDCCs), major regulators of DSM excitability and contractility, are targets for EtOH by patch-clamp electrophysiology (conventional and perforated whole cell and excised patch single channel) and isometric tension recordings using guinea pig DSM cells and isolated tissue strips, respectively. EtOH at 0.3% vol/vol (~50 mM) enhanced whole cell BK currents at +30 mV and above, determined by the selective BK channel blocker paxilline. In excised patches recorded at +40 mV and ~300 nM intracellular Ca(2+) concentration ([Ca(2+)]), EtOH (0.1-0.3%) affected single BK channels (mean conductance ~210 pS and blocked by paxilline) by increasing the open channel probability, number of open channel events, and open dwell-time constants. The amplitude of single BK channel currents and unitary conductance were not altered by EtOH. Conversely, at ~10 MUM but not ~2 MUM intracellular [Ca(2+)], EtOH (0.3%) decreased the single BK channel activity. EtOH (0.3%) affected transient BK currents (TBKCs) by either increasing frequency or decreasing amplitude, depending on the basal level of TBKC frequency. In isolated DSM strips, EtOH (0.1 1%) reduced the amplitude and muscle force of spontaneous phasic contractions. The EtOH-induced DSM relaxation, except at 1%, was attenuated by paxilline. EtOH (1%) inhibited L-type VDCC currents in DSM cells. In summary, we reveal the involvement of BK channels and L-type VDCCs in mediating EtOH-induced urinary bladder relaxation accommodating alcohol-induced diuresis. PMID- 24153428 TI - Rab11a-positive compartments in proximal tubule cells sort fluid-phase and membrane cargo. AB - The proximal tubule (PT) reabsorbs the majority of sodium, bicarbonate, and chloride ions, phosphate, glucose, water, and plasma proteins from the glomerular filtrate. Despite the critical importance of endocytosis for PT cell (PTC) function, the organization of the endocytic pathway in these cells remains poorly understood. We have used immunofluorescence and live-cell imaging to dissect the itinerary of apically internalized fluid and membrane cargo in polarized primary cultures of PTCs isolated from mouse kidney cortex. Cells from the S1 segment could be distinguished from those from more distal PT segments by their robust uptake of albumin and comparatively low expression of gamma glutamyltranspeptidase. Rab11a in these cells is localized to variously sized spherical compartments that resemble the apical vacuoles observed by electron microscopy analysis of PTCs in vivo. These Rab11a-positive structures are highly dynamic and receive membrane and fluid-phase cargo. In contrast, fluid-phase cargoes are largely excluded from Rab11a-positive compartments in immortalized kidney cell lines. The unusual morphology and sorting capacity of Rab11a compartments in primary PTCs may reflect a unique specialization of these cells to accommodate the functional demands of handling a high endocytic load. PMID- 24153430 TI - Changes in translation rate modulate stress-induced damage of diverse proteins. AB - Proteostasis is the maintenance of the proper function of cellular proteins. Hypertonic stress disrupts proteostasis and causes rapid and widespread protein aggregation and misfolding in the nematode Caenorhabditis elegans. Optimal survival in hypertonic environments requires degradation of damaged proteins. Inhibition of protein synthesis occurs in response to diverse environmental stressors and may function in part to minimize stress-induced protein damage. We recently tested this idea directly and demonstrated that translation inhibition by acute exposure to cycloheximide suppresses hypertonicity-induced aggregation of polyglutamine::YFP (Q35::YFP) in body wall muscle cells. In this article, we further characterized the relationship between protein synthesis and hypertonic stress-induced protein damage. We demonstrate that inhibition of translation reduces hypertonic stress-induced formation and growth of Q35::YFP, Q44::YFP, and alpha-synuclein aggregates; misfolding of paramyosin and ras GTPase; and aggregation of multiple endogenous proteins expressed in diverse cell types. Activation of general control nonderepressible-2 (GCN-2) kinase signaling during hypertonic stress inhibits protein synthesis via phosphorylation of eukaryotic initiation factor-2alpha (eIF-2alpha). Inhibition of GCN-2 activation prevents the reduction in translation rate and greatly exacerbates the formation and growth of Q35::YFP aggregates and the aggregation of endogenous proteins. The current studies together with our previous work provide the first direct demonstration that hypertonic stress-induced reduction in protein synthesis minimizes protein aggregation and misfolding. Reduction in translation rate also serves as a signal that activates osmoprotective gene expression. The cellular proteostasis network thus plays a critical role in minimizing hypertonic stress induced protein damage, in degrading stress-damaged proteins, and in cellular osmosensing and signaling. PMID- 24153431 TI - Physical biology in cancer. 1. Cellular physics of cancer metastasis. AB - One of the major challenges in cancer research today is developing new therapeutic strategies to control metastatic disease, the spread of cancer cells from a primary tumor to seed in a distant site. Advances in diagnosis and treatment options have increased the survival rate for most patients with local tumors; however, less progress has been made in treatment of disseminated disease. According to the SEER Cancer Statistics Review, 1975-2010, in the case of breast and prostate cancers, only one in four patients diagnosed with distant metastatic disease will survive more than five years. Current research efforts largely focus on identifying biological targets, such as specific genes and signaling pathways that drive two key steps of metastasis, invasion from the primary tumor and growth in the secondary site. On the other hand, there are phenotypic traits and dynamics in the metastatic process that are not encoded by single genes or signaling pathways but, rather, a larger system of events and biophysical characteristics. Connecting genomic and pathway investigations with quantitative physical phenotypic characteristics of cells, the physical microenvironment, and the physical spatiotemporal interactions of the metastatic process provides a stronger complementary understanding of the disease. PMID- 24153432 TI - Tanshinone IIA inhibits lipopolysaccharide-induced MUC1 overexpression in alveolar epithelial cells. AB - The anti-inflammatory function of tanshinone IIA (TIIA), an active natural compound from Chinese herbal medicine Danshen, has been well recognized, and therefore TIIA has been widely used to treat various inflammatory conditions associated with cardiac and lung diseases. Mucin 1 (Muc1) plays important anti inflammatory roles in resolution of acute lung inflammation. In this study, we investigated the effects of TIIA on LPS-induced acute lung inflammation, as well as its relationship to Muc1 expression in mouse lung and MUC1 in human alveolar epithelial cells. TIIA pretreatment significantly inhibited LPS-induced pulmonary inflammation in both Muc1 wild-type (Muc1(+/+)) and knockout (Muc1(-/-)) mice, as manifested by reduced neutrophil infiltration and reduced TNF-alpha and keratinocyte chemoattractant levels in bronchoalveolar lavage fluid. The inhibitory effects of TIIA on airway inflammation were associated with reduced expression of Muc1 in Muc1(+/+) mouse lung. Moreover, pretreatment with TIIA significantly inhibited LPS-induced MUC1 expression and TNF-alpha release in A549 alveolar epithelial cells. TNF-alpha upregulated MUC1 mRNA and protein expression in A549 cells, which was inhibited by pretreatment with TIIA. The LPS-induced MUC1 expression was blocked when A549 cells were transfected with siRNA targeting for TNF-alpha receptor 1. Furthermore, TIIA inhibited LPS-induced nuclear translocation of NF-kappaB and upregulation of Toll-like receptor 4 in A549 cells. Taken together, these results demonstrate that TIIA suppressed LPS-induced acute lung inflammation regardless of the presence of Muc1, and TIIA inhibited LPS- and TNF-alpha-induced MUC1/Muc1 expression in airway epithelial cells, suggesting that MUC1/Muc1 does not account for the mechanisms of the anti inflammatory effects of TIIA in the airway. PMID- 24153434 TI - Comment on "tissue factor expressed by microparticles is associated with mortality but not with thrombosis in cancer patients". PMID- 24153433 TI - Polycystin-1 binds Par3/aPKC and controls convergent extension during renal tubular morphogenesis. AB - Several organs, including the lungs and kidneys, are formed by epithelial tubes whose proper morphogenesis ensures correct function. This is best exemplified by the kidney, where defective establishment or maintenance of tubular diameter results in polycystic kidney disease, a common genetic disorder. Most polycystic kidney disease cases result from loss-of-function mutations in the PKD1 gene, encoding Polycystin-1, a large receptor of unknown function. Here we demonstrate that PC-1 has an essential role in the establishment of correct tubular diameter during nephron development. Polycystin-1 associates with Par3 favouring the assembly of a pro-polarizing Par3/aPKC complex and it regulates a programme of cell polarity important for oriented cell migration and for a convergent extension-like process during tubular morphogenesis. Par3 inactivation in the developing kidney results in defective convergent extension and tubular morphogenesis, and in renal cyst formation. Our data define Polycystin-1 as central to cell polarization and to epithelial tube morphogenesis and homeostasis. PMID- 24153435 TI - Excited state dynamics of beta-carotene studied by means of transient absorption spectroscopy and multivariate curve resolution alternating least-squares analysis. AB - Determination of the excited-state dynamics of carotenoids has attracted considerable interest, engendering a number of controversial hypotheses because of the strongly overlapping spectral peaks and complicated dynamics of transient species. In the present work, aiming for better understanding the complexity of excited-state processes in carotenoids, excited-state dynamics of all-trans-beta carotene in ethanol was investigated by femtosecond pump-probe spectroscopy. Following the excitation of the strongly allowed S2 state of the beta-carotene, transient absorption spectra were recorded in the visible spectral range. For comparison, the time-resolved transient absorption spectra are analyzed in a conventional way, fitting kinetic traces with a multi-exponential function at chosen wavelengths from obtained spectra, and then again by means of the soft modeling multivariate curve resolution alternating least-squares analysis (MCR ALS) method for modeling pure profiles and the generalized two-dimensional (2D) correlation spectroscopy data analysis for providing additional information on the dynamics of spectral features. MCR-ALS analysis shows that both the dynamics of the S* state, identified using the 2D correlation spectra, and the S1 state develop on a different timescale than the relaxation of the vibrationally hot S1v' state. Hot S1v' and S* states are shown to have different species associated difference spectra. Results of our analysis indicate that the S* state observed in this work is not the hot S1v' state but instead a separate singlet state. PMID- 24153436 TI - Fac and mer isomers of Ru(II) tris(pyrazolyl-pyridine) complexes as models for the vertices of coordination cages: structural characterisation and hydrogen bonding characteristics. AB - We have prepared a series of mononuclear fac and mer isomers of Ru(II) complexes containing chelating pyrazolyl-pyridine ligands, to examine their differing ability to act as hydrogen-bond donors in MeCN. This was prompted by our earlier observation that octanuclear cube-like coordination cages that contain these types of metal vertex can bind guests such as isoquinoline-N-oxide (K = 2100 M( 1) in MeCN), with a significant contribution to binding being a hydrogen-bonding interaction between the electron-rich atom of the guest and a hydrogen-bond donor site on the internal surface of the cage formed by a convergent set of CH2 protons close to a 2+ metal centre. Starting with [Ru(L(H))3](2+) [L(H) = 3-(2 pyridyl)-1H-pyrazole] the geometric isomers were separated by virtue of the fact that the fac isomer forms a Cu(I) adduct which the mer isomer does not. Alkylation of the pyrazolyl NH group with methyl iodide or benzyl bromide afforded [Ru(L(Me))3](2+) and [Ru(L(bz))3](2+) respectively, each as their fac and mer isomers; all were structurally characterised. In the fac isomers the convergent group of pendant -CH2R or -CH3 protons defines a hydrogen-bond donor pocket; in the mer isomer these protons do not converge and any hydrogen-bonding involving these protons is expected to be weaker. For both [Ru(L(Me))3](2+) and [Ru(L(bz))3](2+), NMR titrations with isoquinoline-N-oxide in MeCN revealed weak 1 : 1 binding (K ~ 1 M(-1)) between the guest and the fac isomer of the complex that was absent with the mer isomer, confirming a difference in the hydrogen-bond donor capabilities of these complexes associated with their differing geometries. The weak binding compared to the cage however occurs because of competition from the anions, which are free to form ion-pairs with the mononuclear complex cations in a way that does not happen in the cage complexes. We conclude that (i) the presence of fac tris-chelate sites in the cage to act as hydrogen-bond donors, and (ii) exclusion of counter-ions from the central cavity leaving these hydrogen bonding sites free to interact with guests, are both important design criteria for future coordination cage hosts. PMID- 24153437 TI - 2-Iodoxybenzoic acid organosulfonates: preparation, X-ray structure and reactivity of new, powerful hypervalent iodine(V) oxidants. AB - New powerful hypervalent iodine(V) oxidants, tosylate and mesylate derivatives of 2-iodoxybenzoic acid (IBX), were prepared by the reaction of IBX with the corresponding sulfonic acids. Single crystal X-ray crystallography of the diacetate derivative of IBX-tosylate revealed an unusual heptacoordinated iodine geometry without any significant intermolecular secondary interactions. PMID- 24153438 TI - The birth of protein electrochemistry. AB - The results from a final-year undergraduate project led to an $876M sale of a spin-out company 19 years later: the 1977 communication from Mark Eddowes and Allen Hill seeded the rich field of protein electrochemistry, the technology that underpins commercial glucose biosensors. PMID- 24153439 TI - Do breast cancer risk factors differ among those who do and do not undertake mammography screening? AB - OBJECTIVES: There is considerable interest in whether mammography screening leads to over-diagnosis of breast cancer. However self-selection into screening programmes may lead to risk differences that affect estimates of over-diagnosis. This study compares the breast cancer risk profiles of participants and non participants of population-based mammography screening. Risk profiles are also compared between those who have and have not used private screening services. SETTING: This study involved 1162 women aged 40-84 who participated in the 2012 Health Omnibus, an annual face-to-face interview-based survey of a representative sample of the population in the state of South Australia. METHODS: Data were collected on participation in mammography screening, demographic characteristics and breast cancer risk factors (including reproductive, familial and lifestyle factors). Missing data were multiply imputed. Factors independently associated with ever having been screened were identified using multivariable logistic regression, for population-based and ad hoc, private mammography screening separately. RESULTS: Compared with non-participants, participants of population based screening were more likely to have used hormone replacement therapy (odds ratio [OR] = 3.72), experienced breast biopsy or surgery (OR = 2.22), and be overweight or obese (OR = 1.57). They were less likely to be sufficiently active (OR = 0.57) or be born in a non-English speaking country (OR = 0.50) or aged under 50 (OR = 0.09). Women who were screened privately were more likely to have a family history of breast cancer (OR = 1.66) and have experienced breast biopsy or surgery (OR = 3.17) than those who had not. CONCLUSIONS: South Australian women who participated in the population-based mammography screening have a slightly higher prevalence of breast cancer risk factors. This also applies to those who undertook private screening. PMID- 24153440 TI - Spinal cord injury and type 2 diabetes: results from a population health survey. AB - OBJECTIVE: The objective of this study was to evaluate the association between spinal cord injury (SCI) and type 2 diabetes in a large representative sample and to determine whether an association exists irrespective of known risk factors for type 2 diabetes. METHODS: Data were obtained on 60,678 respondents to the Statistics Canada 2010 Cycle of the cross-sectional Canadian Community Health Survey. Multivariable logistic regression, incorporating adjustment for confounders and probability weights to account for the Canadian Community Health Survey sampling method, was conducted to quantify this association. RESULTS: After adjustment for both sex and age, SCI was associated with a significant increased odds of type 2 diabetes (adjusted odds ratio = 1.66, 95% confidence interval 1.16-2.36). These heightened odds persisted after additional adjustment for smoking status, hypertension status, body mass index, daily physical activity, alcohol intake, and daily consumption of fruits and vegetables (fully adjusted odds ratio = 2.45, 95% confidence interval 1.34-4.47). CONCLUSIONS: There is a strong association between SCI and type 2 diabetes, which is not explained by known risk factors for type 2 diabetes. PMID- 24153441 TI - Comment: Increased risk for type 2 diabetes in spinal cord injury. AB - The prevalence of diabetes is increasing globally, with an estimated 371 million individuals affected globally and 4.8 million people who died due to diabetes in 2012.(1) Type 2 diabetes accounts for at least 90% of all cases of diabetes, and the number of people with type 2 diabetes is increasing in every country.(1) Abnormalities of carbohydrate and lipid metabolism are more common among people in the spinal cord injury (SCI) population than in the able-bodied population.(2) There is increased morbidity and mortality due to type 2 diabetes in SCI. PMID- 24153442 TI - New territory opened by periodic paralysis associated with mitochondrial DNA mutation. PMID- 24153443 TI - Episodic weakness due to mitochondrial DNA MT-ATP6/8 mutations. AB - OBJECTIVE: To report that homoplasmic deleterious mutations in the mitochondrial DNA MT-ATP6/8 genes may be responsible for acute episodes of limb weakness mimicking periodic paralysis due to channelopathies and dramatically responding to acetazolamide. METHODS: Mitochondrial DNA sequencing and restriction PCR, oxidative phosphorylation functional assays, reactive oxygen species metabolism, and patch-clamp technique in cultured skin fibroblasts. RESULTS: Occurrence of a typical MELAS (mitochondrial encephalopathy with lactic acidosis and stroke-like episodes) syndrome in a single member of a large pedigree with episodic weakness associated with a later-onset distal motor neuropathy led to the disclosure of 2 deleterious mitochondrial DNA mutations. The MT-ATP6 m.9185T>C p.Leu220Pro mutation, previously associated with Leigh syndrome, was present in all family members, while the MT-TL1 m.3271T>C mutation, a known cause of MELAS syndrome, was observed in the sole patient with MELAS presentation. Significant defect of complexes V and I as well as oxidative stress were observed in both primary fibroblasts and cybrid cells with 100% m.9185T>C mutation. Permanent plasma membrane depolarization and altered permeability to K(+) in fibroblasts provided a link with the paralysis episodes. Screening of 9 patients, based on their clinical phenotype, identified 4 patients with similar deleterious MT-ATP6 mutations (twice m.9185T>C and once m.9176T>C or m.8893T>C). A fifth patient presented with an original potentially deleterious MT-ATP8 mutation (m.8403T>C). All mutations were associated with almost-normal complex V activity but significant oxidative stress and permanent plasma membrane depolarization. CONCLUSION: Homoplasmic mutations in the MT-ATP6/8 genes may cause episodic weakness responding to acetazolamide treatment. PMID- 24153444 TI - Higher glucose levels associated with lower memory and reduced hippocampal microstructure. AB - OBJECTIVES: For this cross-sectional study, we aimed to elucidate whether higher glycosylated hemoglobin (HbA1c) and glucose levels exert a negative impact on memory performance and hippocampal volume and microstructure in a cohort of healthy, older, nondiabetic individuals without dementia. METHODS: In 141 individuals (72 women, mean age 63.1 years +/- 6.9 SD), memory was tested using the Rey Auditory Verbal Learning Test. Peripheral levels of fasting HbA1c, glucose, and insulin and 3-tesla MRI scans were acquired to assess hippocampal volume and microstructure, as indicated by gray matter barrier density. Linear regression and simple mediation models were calculated to examine associations among memory, glucose metabolism, and hippocampal parameters. RESULTS: Lower HbA1c and glucose levels were significantly associated with better scores in delayed recall, learning ability, and memory consolidation. In multiple regression models, HbA1c remained strongly associated with memory performance. Moreover, mediation analyses indicated that beneficial effects of lower HbA1c on memory are in part mediated by hippocampal volume and microstructure. CONCLUSIONS: Our results indicate that even in the absence of manifest type 2 diabetes mellitus or impaired glucose tolerance, chronically higher blood glucose levels exert a negative influence on cognition, possibly mediated by structural changes in learning-relevant brain areas. Therefore, strategies aimed at lowering glucose levels even in the normal range may beneficially influence cognition in the older population, a hypothesis to be examined in future interventional trials. PMID- 24153445 TI - Synthesis and antiproliferative activity of hydroxyferrocifen hybrids against triple-negative breast cancer cells. AB - We have recently shown that the combination of chemical motifs of vorinostat () and ferrocifen () in the single hybrid produced beneficial effects in terms of antiproliferative activity of both agents against cancer cells. Since hydroxylation of to form hydroxyferrocifen () improves the biological response, we explore in this work the anticancer effects of a new family of hybrid phenolic compounds bearing some molecular features of , and . Results concerning their cytotoxicity on both triple-negative MDA-MB-231 and hormone-dependent MCF-7 breast cancer cells are reported here. Organometallic compounds showed better antiproliferative activities than organic analogs. For instance, (IC50 = 1.5 MUM) was around seven times more active than (IC50 = 10.9 MUM) against MCF-7 cells. In the case of triple-negative MDA-MB-231 cells, the IC50 values for ferrocene compounds are in the range of 1.3-4.5 MUM and those for organic derivatives are 5.2-34.5 MUM. Studies concerning the isomerization and redox behaviors of these compounds are also presented. Despite the potential of to exhibit ex cellulo redox activation, it seems that this feature is not completely expressed in cellulo. This surprising behavior is related to the driving effect of the side chain to direct the new constructs to different targets. PMID- 24153446 TI - Role of CT perfusion imaging in evaluating the effects of multiple burr hole surgery on adult ischemic Moyamoya disease. AB - INTRODUCTION: To evaluate the effects of the multiple burr hole (MBH) revascularization on ischemic type adult Moyamoya disease (MMD) by computed tomography perfusion (CTP). METHODS: Eighty-six ischemic MMD patients received CTP 1 week before and 3 weeks after MBH operation. Fifty-seven patients received it again at 6 month and underwent digital subtraction angiography (DSA) and mRS follow-up. Cerebral blood flow (CBF), cerebral blood volume (CBV), mean transit time (MTT), time to peak (TTP), and relative values of ischemic symptomatic hemispheres were measured. Differences in pre- and post-surgery perfusion CT values were assessed. RESULTS: There were significant differences of CBF, TTP, and relative time to peak (rTTP) in ischemic hemisphere between 1 week before and 3 weeks after surgery, and no significant difference in relative cerebral blood flow (rCBF), CBV, relative cerebral blood volume (rCBV), MTT, relative mean transit time (rMTT). According to whether there was symptom improvement or not on 3 weeks after MBH, the rTTP value was not statistically significant in the patients whose symptoms were not improved at all on 3 weeks after operation. Six month follow-up showed that CBF, rCBF, and rCBV values were significantly higher than those before operation. Postoperative MTT, TTP, rMTT, and rTTP values were significantly lower than those before operation. CONCLUSION: CTP is a sensitive method to obtain functional imaging of cerebral microcirculation, which can be a noninvasive assessment of the abnormalities of intracranial arteries and cerebral perfusion changes in MMD before and after surgery. CBF and TTP map, especially the relative values of TTP, seems to have the capability of being quite sensitive to the presence of altered brain perfusion at early time after indirect revascularization. PMID- 24153447 TI - Sporadic meningioangiomatosis: imaging findings with histopathologic correlations in seven patients. AB - INTRODUCTION: Meningioangiomatosis (MA) is a rare benign cerebral lesion. We aimed to evaluate the CT and MR features of sporadic MA, with a focus on the correlation between imaging and histopathologic findings. METHODS: CT (n = 7) and MR (n = 8) images of eight patients (6 men and 2 women; mean age, 12.8 years; range, 4-22 years) with pathologically proven MA were retrospectively reviewed. After dividing the MA lesions according to their distribution into cortical and subcortical white matter components, the morphologic characteristics were analyzed and correlated with histopathologic findings in seven patients. RESULTS: CT and MR images showed cortical (n = 4, 50%) and subcortical white matter (n = 7, 88%) components of MA. All four cortical components revealed hyperattenuation on CT scan and T1 isointensity/T2 hypointensity on MR images, whereas subcortical white matter components showed hypoattenuation on CT scan and T1 hypointensity/T2 hyperintensity on MR images. Two cortical components (25%) demonstrated enhancement and one subcortical white matter component demonstrated cystic change. Seven cases were available for imaging-histopathologic correlation. In all seven cases, the cortex was involved by MA and six patients (86%) showed subcortical white matter involvement by MA. There were excellent correlations between the imaging and histopathologic findings in subcortical white matter components, and the accuracy was 100% (seven of seven); whereas there were poor correlations in cortical components, and the accuracy was 43% (three of seven). CONCLUSIONS: The cerebral cortex and subcortical white matter were concomitantly involved by MA. Subcortical white matter components of MA were more apparent than cortical components on CT and MR imaging. PMID- 24153448 TI - Impact of Joule heating, roughness, and contaminants on the relative hardness of polycrystalline gold. AB - Asperities play a central role in the mechanical and electrical properties of contacting surfaces. Changes in trends of uniaxial compression of an asperity tip in contact with a polycrystalline substrate as a function of substrate geometry, compressive stress and applied voltage are investigated here by implementation of a coupled continuum and atomistic approach. Surprisingly, an unmodified Au polycrystalline substrate is found to be softer than one containing a void for conditions of high stress and an applied voltage of 0.2 V. This is explained in terms of the temperature distribution and weakening of Au as a function of temperature. The findings in this communication are important to the design of materials for electrical contacts because applied conditions may play a role in reversing relative hardness of the materials for conditions experienced during operation. PMID- 24153449 TI - Deep eutectic solvents based on N-methylacetamide and a lithium salt as suitable electrolytes for lithium-ion batteries. AB - In this work, we present a study on the physical and electrochemical properties of three new Deep Eutectic Solvents (DESs) based on N-methylacetamide (MAc) and a lithium salt (LiX, with X = bis[(trifluoromethyl)sulfonyl]imide, TFSI; hexafluorophosphate, PF6; or nitrate, NO3). Based on DSC measurements, it appears that these systems are liquid at room temperature for a lithium salt mole fraction ranging from 0.10 to 0.35. The temperature dependences of the ionic conductivity and the viscosity of these DESs are correctly described by using the Vogel-Tammann-Fulcher (VTF) type fitting equation, due to the strong interactions between Li(+), X(-) and MAc in solution. Furthermore, these electrolytes possess quite large electrochemical stability windows up to 4.7-5 V on Pt, and demonstrate also a passivating behavior toward the aluminum collector at room temperature. Based on these interesting electrochemical properties, these selected DESs can be classified as potential and promising electrolytes for lithium-ion batteries (LIBs). For this purpose, a test cell was then constructed and tested at 25 degrees C, 60 degrees C and 80 degrees C by using each selected DES as an electrolyte and LiFePO4 (LFP) material as a cathode. The results show a good compatibility between each DES and LFP electrode material. A capacity of up to 160 mA h g(-1) with a good efficiency (99%) is observed in the DES based on the LiNO3 salt at 60 degrees C despite the presence of residual water in the electrolyte. Finally preliminary tests using a LFP/DES/LTO (lithium titanate) full cell at room temperature clearly show that LiTFSI-based DES can be successfully introduced into LIBs. Considering the beneficial properties, especially, the cost of these electrolytes, such introduction could represent an important contribution for the realization of safer and environmentally friendly LIBs. PMID- 24153451 TI - Transforming growth factor-beta1 and tumor necrosis factor-alpha are associated with clinical severity and airflow limitation of COPD in an additive manner. AB - BACKGROUND: The role of tumor necrosis factor-alpha (TNF-alpha) and transforming growth factor-beta1 (TGF-beta1) in chronic obstructive pulmonary disease (COPD) is controversial. The purpose of this study was to assess the relationships among polymorphisms, clinical phenotypes, and the serum levels of TNF-alpha and TGF beta1. METHODS: Polymorphisms of promoters of TNF-alpha (rs 361525 and rs 1800629) and TGF-beta1 (rs 1800469) in 110 COPD patients, 110 nonsmoker health controls without COPD, and 34 smokers were evaluated. Pulmonary functions, chest computed tomography, TGF-beta1, and TNF-alpha were assessed. RESULTS: The genetic polymorphism of TNF-alpha (rs 361525) was associated with COPD. More severe COPD patients had higher serum levels of TNF-alpha and TGF-beta1; moreover, serum levels of TGF-beta1of mild COPD patients were higher than normal controls. All of the studied subjects were divided into four groups by the 95th percentile value of control as cutoff serum value of TGF-beta1 (224.35 rhog/ml) or TNF-alpha (17.56 rhog/ml) to define the high value of TGF-beta1 or TNF-alpha, which are higher than those cutoff of values (>224.35 or 17.56 rhog/ml). The FEV1 of the group with high TGF-beta1 + low TNF-alpha or low TGF-beta1 + high TNF-alpha or high TNF-alpha + high TGF-beta1 was lower than the group with low TGF-beta1 + low TNF-alpha group. Moreover, the lowest value of FEV1 was in the group with high TNF-alpha + high TGF-beta1. CONCLUSIONS: The genetic polymorphism of the TNF alpha is associated with COPD. Both TGF-beta1 and TNF-alpha modulate clinical severity and airflow limitation in an additive manner. PMID- 24153450 TI - Lung cancer screening: review and performance comparison under different risk scenarios. AB - Lung cancer is currently one of the most common malignant diseases and is responsible for substantial mortality worldwide. Compared with never smokers, former smokers remain at relatively high risk for lung cancer, accounting for approximately half of all newly diagnosed cases in the US. Screening offers former smokers the best opportunity to reduce their risk of advanced stage lung cancer and there is now evidence that annual screening using low-dose computed tomography (LDCT) is effective in preventing mortality. Studies are being conducted to evaluate whether the benefits of LDCT screening outweigh its costs and potential harms and to determine the most appropriate workup for patients with screen-detected lung nodules. Program efficiency would be optimized by targeting high-risk current smokers, but low uptake among this group is a concern. Former smokers may be invited for screening; however, if fewer long-term current smokers and more former smokers with long quit duration elect to attend, this could have very adverse effects on cost and screening test parameters. To illustrate this point, we present three possible screening scenarios with lung cancer prevalence ranging from between 0.62 and 5.0 %. In summary, cost effectiveness of lung cancer screening may be improved if linked to successful smoking cessation programs and if better approaches are developed to reach very high-risk patients, e.g., long-term current smokers or others based on more accurate risk prediction models. PMID- 24153452 TI - Cardiovascular safety of long acting beta agonist-inhaled corticosteroid combination products in adult patients with asthma: a systematic review. AB - INTRODUCTION: Long-acting beta agonists and inhaled corticosteroids combination products (LABA-ICS) are widely used in the treatment of asthma. However, there appears to be little data on their cardiovascular safety. The purpose of this study was to conduct a systematic review of the available studies and trials on the cardiovascular safety of LABA-ICS in adults with asthma. METHODS: Two independent reviewers screened citations from PubMed and National Clinical Trials registry to identify studies and trials on the cardiovascular effects of LABA-ICS in patients with asthma. RESULTS: A total of 15 studies (with 17 cohorts on LABA ICS to compare with a comparator or placebo) with 5,440 total study participants met the inclusion criteria. Two studies on budesonide-formoterol and one on fluticasone-salmeterol reported treatment emergent cardiovascular adverse events, all of which were dysrhythmias. For comparison, the pooled estimate of the Peto odds ratio (0.72; 95 % confidence interval [CI] 0.17-3; p = 0.65) and the summary risk ratio (0.77; 95 % CI 0.26-2.3; p = 0.64) indicated a nonsignificant difference between LABA-ICS and comparator/placebo groups. CONCLUSIONS: Our systematic review found that few studies and trials reported treatment emergent cardiovascular adverse events with LABA-ICS. However, the Peto odds ratio and risk ratio for these outcomes was statistically nonsignificant. This suggests that LABA-ICS products may have a safe cardiovascular profile in asthma patients. PMID- 24153593 TI - Abstracts of CHEST 2013. October 26-31, 2013. Chicago, Illinois, USA. PMID- 24154485 TI - Solvent-controlled synthesis of tetranuclear cage-like copper(II) silsesquioxanes. Remarkable features of the cage structures and their high catalytic activity in oxidation with peroxides. AB - Two principally different in their molecular architecture isomeric tetranuclear copper(ii) silsesquioxanes, "Globule"-like compound [(PhSiO1.5)12(CuO)4(NaO0.5)4] (1) and "Sandwich"-like derivative [(PhSiO1.5)6(CuO)4(NaO0.5)4(PhSiO1.5)6] (2), were synthesized by the partial cleavage of polymeric copper(ii) silsesquioxane [(PhSiO1.5)2(CuO)]n by tetraphenylcyclotetrasiloxanolate. The route leading to the formation of either 1 or 2 entirely depends on the nature and composition of the solvent used for this reaction. Thus, the process in an ethanol-1-butanol solution gives compound 1. When a 1,4-dioxane-methanol mixture was used, compound 2 was prepared. The structures and unusual crystal packing of the cages were confirmed by the X-ray studies. It has been found that the reaction of benzene with H2O2 in acetonitrile solution at 50 degrees C catalyzed by 1 requires addition of trifluoroacetic acid (TFA) in low concentration and gives phenol with a turnover number (TON) of 250 after 3 h. The initial reaction rate W0 linearly depends on the concentration of catalyst 2. The oxidation of 1-phenylethanol to acetophenone with hydrogen peroxide catalyzed by complex 1 in the presence of TFA is not efficient. In contrast, 1 exhibited excellent activity in the oxidation with tert-butyl hydroperoxide (TBHP) in the absence of any acid (the yield of acetophenone was close to the quantitative, TON attained 475 after 2 h). A kinetic study of this reaction led to the conclusion that the process occurs with the participation of radicals tert-BuO produced in the Cu-promoted decomposition of TBHP. The mode of dependence of W0 on the initial concentration of TBHP indicates the formation of an intermediate adduct between the catalyst 1 and TBHP (characterized by the equilibrium constant K1~ 2 M(-1) for the conditions of conducted experiments) followed by subsequent decomposition of the adduct (k2~ 0.2 s(-1)) to generate an intermediate species tert-BuO which induces the alcohol oxidation. PMID- 24154486 TI - Aberrant methylation of hypermethylated-in-cancer-1 and exocyclic DNA adducts in tobacco smokers. AB - Tobacco smoke has been shown to produce both DNA damage and epigenetic alterations. However, the potential role of DNA damage in generating epigenetic changes is largely underinvestigated in human studies. We examined the effects of smoking on the levels of DNA methylation in genes for tumor protein p53, cyclin dependent kinase inhibitor2A, hypermethylated-in-cancer-1 (HIC1), interleukin-6, Long Interspersed Nuclear Element type1, and Alu retrotransposons in blood of 177 residents in Thailand using bisulfite-PCR andpyrosequencing. Then, we analyzed the relationship of this methylation with the oxidative DNA adduct, M1dG (a malondialdehyde adduct), measured by 32P-postlabeling. Multivariate statistical analyses showed that HIC1 methylation levels were significantly increased in smokers compared with nonsmokers (p <= .05). A dose response was observed, with the highest HIC1 methylation levels in smokers of >= 10 cigarettes/day relative to nonsmokers and intermediate values in smokers of 1-9 cigarettes/day (p for trend <= .001). No additional relationships were observed. We also evaluated correlations between M1dG and the methylation changes at each HIC1 CpG site individually. The levels of this adduct in smokers showed a significant linear correlation with methylation at one of the 3 CpGs evaluated in HIC1: hypermethylation at position 1904864340 was significantly correlated with the adduct M1dG (covariate-adjusted regression coefficient (beta) = .224 +/- .101 [SE], p <= .05). No other correlations were detected. Our study extends prior work by others associating hypermethylation of HIC1 with smoking; shows that a very specific hypermethylation event can arise from smoking; and encourages future studies that explore a possible role for M1dG in connecting smoking to this latter hypermethylation. PMID- 24154487 TI - Cumulative risk: toxicity and interactions of physical and chemical stressors. AB - Recent efforts to update cumulative risk assessment procedures to incorporate nonchemical stressors ranging from physical to psychosocial reflect increased interest in consideration of the totality of variables affecting human health and the growing desire to develop community-based risk assessment methods. A key roadblock is the uncertainty as to how nonchemical stressors behave in relationship to chemical stressors. Physical stressors offer a reasonable starting place for measuring the effects of nonchemical stressors and their modulation of chemical effects (and vice versa), as they clearly differ from chemical stressors; and "doses" of many physical stressors are more easily quantifiable than those of psychosocial stressors. There is a commonly held belief that virtually nothing is known about the impact of nonchemical stressors on chemically mediated toxicity or the joint impact of coexposure to chemical and nonchemical stressors. Although this is generally true, there are several instances where a substantial body of evidence exists. A workshop titled "Cumulative Risk: Toxicity and Interactions of Physical and Chemical Stressors" held at the 2013 Society of Toxicology Annual Meeting provided a forum for discussion of research addressing the toxicity of physical stressors and what is known about their interactions with chemical stressors, both in terms of exposure and effects. Physical stressors including sunlight, heat, radiation, infectious disease, and noise were discussed in reference to identifying pathways of interaction with chemical stressors, data gaps, and suggestions for future incorporation into cumulative risk assessments. PMID- 24154488 TI - Aryl hydrocarbon receptor-dependent induction of liver fibrosis by dioxin. AB - The contribution of environmental pollutants to liver fibrosis is an important and poorly explored issue. In vitro studies suggest that the environmental pollutant 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and other aryl hydrocarbon receptor (AhR) ligands induce several genes that are known to be upregulated during liver fibrosis. Our aim was to determine whether exposure to such pollutants can lead to liver fibrosis and to characterize the mechanisms of action. Mice were treated for 2, 14, or 42 days, once a week with 25 ug/kg of TCDD. Gene and protein expression, in vitro and in vivo, as well as liver histology were investigated for each treatment. Treatment of mice with TCDD for 2 weeks modified the hepatic expression of markers of fibrosis such as collagen 1A1 and alpha-smooth muscle actin. This is not observed in AhR knockout mice. Following 6 weeks of treatment, histological features of murine hepatic fibrosis became apparent. In parallel, the levels of inflammatory cytokines (interleukin-1 beta, tumor necrosis factor alpha) and of markers of activated fibroblasts(fibroblast-specific protein 1) were found to be upregulated. Interestingly, we also found increased expression of genes of the TGF-beta pathway and a concomitant decrease of miR-200a levels. Because the transcription factors of the Snail family were shown to be involved in liver fibrosis, we studied their regulation by TCDD. Two members of the Snail family were increased, whereas their negative targets, the epithelial marker E-cadherin and Claudin 1, were decreased. Further, the expression of mesenchymal markers was increased. Finally, we confirmed that Snai2 is a direct transcriptional target of TCDD in the human hepatocarcinoma cell line, HepG2. The AhR ligand, TCDD, induces hepatic fibrosis by directly regulating profibrotic pathways. PMID- 24154489 TI - Characterization of vemurafenib phototoxicity in a mouse model. AB - Vemurafenib is a first-in-class, small molecule B-Raf kinase inhibitor for the treatment of patients with unresectable or metastatic melanoma carrying the BRAFV600E mutation, commercially available since 2011. A general phototoxic potential was identified early during development; however, based on results of an animal study in hairless rats, it was concluded that there would exist no relevant risk for humans. Surprisingly, signs of clinical photosensitivity were reported in many patients during clinical development. Therefore, it became a fundamental question to understand this discrepancy. An established mouse model (oral UV-Local Lymph Node Assay, UV-LLNA) for the assessment of in vivo photosafety was used to investigate the impact of formulations, dose levels, duration of treatment, and timing of irradiation. Moreover, a basic pharmacokinetic profile was established within the same mouse strain. We were able to demonstrate dose- and time-dependent phototoxicity of vemurafenib using commercially available tablets (stabilized amorphous material). The lowest phototoxic dose was 350 mg/kg administrated for 3 consecutive days followed by exposure to UV-visible irradiation at a UVA-normalized dose of 10 J/cm2. In comparison, pure vemurafenib, which easily forms crystalline variants and is known to have poor bioavailability, was tested at 350 mg/kg, and no signs of phototoxicity could be seen. The most apparent difference between the early study in hairless rats and this study in mice was the spectral range of the irradiation light source (350-400 nm vs 320-700 nm). Because vemurafenib does not absorb sufficiently light above 350 nm, this difference can easily explain the negative earlier study result in hairless rats. PMID- 24154490 TI - A high-throughput screen for teratogens using human pluripotent stem cells. AB - There is need in the pharmaceutical and chemical industries for high-throughput human cell-based assays for identifying hazardous chemicals, thereby reducing the overall reliance on animal studies for predicting the risk of toxic responses in humans. Despite instances of human-specific teratogens such as thalidomide, the use of human cell-teratogenicity assays has just started to be explored. Herein, a human pluripotent stem cell test (hPST) for identifying teratogens is described, benchmarking the in vitro findings to traditional preclinical toxicology teratogenicity studies and when available to teratogenic outcomes in humans. The hPST method employs a 3-day monolayer directed differentiation of human embryonic stem cells. The teratogenic risk of a compound is gauged by measuring the reduction in nuclear translocation of the transcription factor SOX17 in mesendodermal cells. Decreased nuclear SOX17 in the hPST model was strongly correlated with in vivo teratogenicity. Specifically, 71 drug-like compounds with known in vivo effects, including thalidomide, were examined in the hPST. A threshold of 5 MUM demonstrated 94% accuracy (97% sensitivity and 92% specificity). Furthermore, 15 environmental toxicants with physicochemical properties distinct from small molecule pharmaceutical agents were examined and a similarly strong concordance with teratogenicity outcomes from in vivo studies was observed. Finally, to assess the suitability of the hPST for high-throughput screens, a small library of 300 kinase inhibitors was tested, demonstrating the hPST platform's utility for interrogating teratogenic mechanisms and drug safety prediction. Thus, the hPST assay is a robust predictor of teratogenicity and appears to be an improvement over existing in vitro models. PMID- 24154491 TI - A combination of pterostilbene with autophagy inhibitors exerts efficient apoptotic characteristics in both chemosensitive and chemoresistant lung cancer cells. AB - The emergence of multidrug resistance (MDR), meaning that cancer cells develop simultaneous resistance to different drugs, has limited the clinical efficacy and application of chemotherapy. Pterostilbene, a naturally occurring phytoalexin exerts a variety of pharmacologic activities, including cancer prevention, cytotoxicity, and antioxidant activity. In this study, results proved the capability of pterostilbene to effectively inhibit the cell viability of docetaxel-induced MDR human lung cancer cell lines through cell cycle arrest and apoptosis. Meanwhile, the observation of LC3-II production and formation of acidic vesicular organelles revealed an induction of autophagy at an early stage by pterostilbene, which was triggered by an inhibition of the AKT and JNK pathways and activation of ERK1/2. Furthermore, pretreatment with the autophagy inhibitors 3-methyladenine and bafilomycin A1 or with beclin-1 small interfering RNA was able to enhance pterostilbene-triggered apoptosis. In conclusion, this study demonstrated that pterostilbene causes autophagy and apoptosis in lung cancer cells. Furthermore, pterostilbene in combination with autophagy inhibitors may strengthen the efficiency of chemotherapeutic strategies in both chemosensitive and chemoresistant lung cancer cells, which may be of immense value for the clinical management of lung cancer patients with MDR. PMID- 24154492 TI - Visualization and targeted disruption of protein interactions in living cells. AB - Protein-protein interactions are the basis of all processes in living cells, but most studies of these interactions rely on biochemical in vitro assays. Here we present a simple and versatile fluorescent-three-hybrid (F3H) strategy to visualize and target protein-protein interactions. A high-affinity nanobody anchors a GFP-fusion protein of interest at a defined cellular structure and the enrichment of red-labelled interacting proteins is measured at these sites. With this approach, we visualize the p53-HDM2 interaction in living cells and directly monitor the disruption of this interaction by Nutlin 3, a drug developed to boost p53 activity in cancer therapy. We further use this approach to develop a cell permeable vector that releases a highly specific peptide disrupting the p53 and HDM2 interaction. The availability of multiple anchor sites and the simple optical readout of this nanobody-based capture assay enable systematic and versatile analyses of protein-protein interactions in practically any cell type and species. PMID- 24154493 TI - Ultrabright and multicolorful fluorescence of amphiphilic polyethyleneimine polymer dots for efficiently combined imaging and therapy. AB - Multifunctional nanoparticles as theranostic tools hold great potential for its unique and efficient way to visualize the process of disease treatment. However, the toxicity of conventional fluorescent labels and difficulty of functionalization limit their widespread use. Recently, a number of amino-rich polymers have demonstrated high luminescent fluorescence but rarely showed potential for in vivo imaging due to their blue fluorescence. Here, a general route has been found to construct polymer-based multifunctional nanoparticles for combined imaging and drug delivering. The weak fluorescent polyethyleneimine (PEI) has been conjugated with hydrophobic polylactide as the amphiphilic PEI for construction of nanoparticles which showed bright and multicolor fluorescence with high drug loading capacity. The paclitaxel-loaded nanoparticles showed significant therapy effect in contrast to the free paclitaxel. Meanwhile, fluorescence imaging of the nanoparticles showed accumulation around tumor. These results demonstrate a new type of polymer-based multifunctional nanoparticles for imaging-guided drug delivery. PMID- 24154495 TI - Agrobacterium tumefaciens-mediated transgenic plant and somaclone production through direct and indirect regeneration from leaves in Stevia rebaudiana with their glycoside profile. AB - Agrobacterium tumefaciens (EHA-105 harboring pCAMBIA 1304)-mediated transgenic plant production via direct regeneration from leaf and elite somaclones generation through indirect regeneration in Stevia rebaudiana is reported. Optimum direct regeneration frequency along with highest transformation frequency was found on MS + 1 mg/l BAP + 1 mg/l NAA, while indirect regeneration from callus was obtained on MS + 1 mg/l BAP + 2 mg/l NAA. Successful transfer of GUS positive (GUS assay and PCR-based confirmation) transgenic as well as four somaclones up to glasshouse acclimatization has been achieved. Inter-simple sequence repeat (ISSR) profiling of transgenic and somaclonal plants showed a total of 113 bands, out of which 49 were monomorphic (43.36 %) and 64 were polymorphic (56.64 %). Transgenic plant was found to be closer to mother plant, while on the basis of steviol, stevioside, and rebaudioside A profile, somaclone S2 was found to be the best and showed maximum variability in ISSR profiling. PMID- 24154494 TI - Mentha arvensis exhibit better adaptive characters in contrast to Mentha piperita when subjugated to sustained waterlogging stress. AB - Waterlogging is becoming a critical threat to plants growing in areas prone to flooding. Some plants adapt various morphological and biochemical alterations which are regulated transcriptionally to cope with the situation. A comparative study of waterlogging response in two different varieties of Mentha namely Mentha piperita and Mentha arvensis was performed. M. arvensis showed better response towards waterlogging in comparison to M. piperita. M. arvensis maintained a healthy posture by utilizing its carbohydrate content; also, it showed a flourished vegetative growth under waterlogged condition. Soluble protein, chlorophyll content, relative water content, and nitric oxide scavenging activity were comparatively more salient in M. arvensis during this hypoxia treatment. Lipid peroxidation was less in M. arvensis. M. arvensis also showed vigorous outgrowth of adventitious roots to assist waterlogging tolerance. To further investigate the possible gene transcripts involved in this response, we did cDNA subtraction of waterlogging treated M. piperita and M. arvensis seedlings. cDNA subtraction has identified thirty seven novel putative Expressed Sequence Tags which were further classified functionally. Functional classification revealed that maximum percentage of proteins belonged to hypothetical proteins followed by proteins involved in biosynthesis. Some of the identified ESTs were further quantified for their induced expression in M. arvensis in comparison to M. piperita through quantitative real-time PCR. PMID- 24154496 TI - A chiral open-framework fluoroaluminophosphate with enantiomeric excess in the bulk product. AB - A novel chiral open-framework fluoroaluminophosphate [C4N3H16][Al6P3O12F6(OH)6] was hydrothermally synthesized using diethylenetriamine as a structure-directing agent. The significant enantiomeric excess of the bulk product was confirmed by the solid state vibrational circular dichroism (VCD) spectrum. PMID- 24154497 TI - [Combined modality treatment of oesophageal cancer]. AB - Oesophageal carcinoma reflects a tumor entity which can be optimally treated with multimodal therapy. Early lymphatic spread and late symptoms lead to mostly advanced tumors at primary diagnosis, which means that they can not be cured by surgery alone. On the other hand these tumors show high sensitivity towards chemo and radiotherapy. Chemoradiotherapy followed by surgery (trimodal therapy) is considered an international standard of care for operable patients. Definitive chemoradiotherapy or the flexible concept of chemoradiotherapy with optional salvage surgery can be curative options for patients with increased operative risk. PMID- 24154498 TI - [Treatment of gastric cancer]. AB - From a global perspective, gastric cancer including adenocarcinoma of the esophagogastric junction is the fourth most common malignant tumor and the second most common cause of cancer-related death. Due to the lack of specific symptoms of early cancer, most gastric cancers are diagnosed in advanced stages. Staging should include high-resolution computed tomography of the thorax, abdomen, and pelvis and documented video-endoscopy and endoscopic ultrasound. In mucosal gastric cancer, endoscopic resection can replace surgical resection. In more advanced stages, perioperative chemotherapy has been established as a standard of care. In the metastatic setting, treatment goals are palliative. Chemotherapy can prolong survival, improve symptoms, and enhance the quality of life. Combination chemotherapy including a platinum salt plus fluoropyrimidine is the standard of care. About 16 % of gastric cancers exhibit overexpression of the growth factor receptor HER2. Trastuzumab has shown to prolong survival when combined with chemotherapy in HER2-positive gastric cancer. PMID- 24154499 TI - [Functional gastrointestinal diseases]. AB - Functional dyspepsia (FD) and irritable bowel syndrome (IBS) are the most important functional gastrointestinal diseases (FGID), and both affect about 5-15 % of the German population. The patients' symptoms are caused by disturbances of gastrointestinal (GI) motility, secretion and sensitivity. Central processing of visceral afferences is disturbed, and the course of the disease and individual symptom perception are influenced by psychosocial factors. Diagnosis of FD and IBS is based on a compatible symptom pattern, absence of alarm symptoms and exclusion of relevant differential diagnoses. The diagnosis of FD requires a normal upper GI endoscopy. Current German guidelines also demand a normal colonoscopy for diagnosis of IBS. Basic therapeutic measures include explanation of the nature of the disease and its harmlessness quo ad vitam . Individual trigger factors should be identified and eliminated if possible. Drug therapy of persisting complaints is guided by the dominant symptom. PMID- 24154501 TI - Benefit-to-harm ratio of thromboprophylaxis for patients undergoing major orthopaedic surgery. A systematic review. AB - Surgeons consider the benefit-to-harm ratio when making decisions regarding the use of anticoagulant venous thromboembolism (VTE) prophylaxis. We evaluated the benefit-to-harm ratio of the use of newer anticoagulants as thromboprophylaxis in patients undergoing major orthopaedic surgery using the likelihood of being helped or harmed (LHH), and assessed the effects of variation in the definition of major bleeding on the results. A systematic literature search was performed to identify phase II and phase III studies that compared regulatory authority approved newer anticoagulants to the low-molecular-weight heparin enoxaparin in patients undergoing major orthopaedic surgery. Analysis of outcomes data estimated the clinical benefit (number-needed-to-treat [NNT] to prevent one symptomatic VTE) and clinical harm (number-needed-to-harm [NNH] or the NNT to cause one major bleeding event) of therapies. We estimated each trial's benefit to-harm ratio from NNT and NNH values, and expressed this as LHH = (1/NNT)/(1/NNH) = NNH/NNT. Based on reporting of efficacy and safety outcomes, most studies favoured enoxaparin over fondaparinux, and rivaroxaban over enoxaparin. However, when using the LHH metric, most trials favoured enoxaparin over both fondaparinux and rivaroxaban when they included surgical-site bleeding that did not require reoperation in the definition of major bleeding. The exclusion of bleeding at surgical site which did not require reoperation shifted the benefit-to-harm ratio in favour of the newer agents. Variations in the definitions of major bleeding may change the benefit-to-harm ratio and subsequently affect its interpretation. Clinical trials should attempt to improve the consistency of major bleeding reporting. PMID- 24154502 TI - Surface-charge distribution on a dielectric sphere due to an external point charge: examples of C60 and C240 fullerenes. AB - An analytical solution for the distribution of surface charge on a dielectric sphere due to the presence of an external point charge is presented. This solution describes how charge on the surface of the sphere is polarised in the electric field into regions of negative and positive charge. The polarisation effect (distribution of surface charge) generally varies with the separation between the sphere and the charge, and it is particularly significant at very short separations. Results obtained from the classical electrostatic model are in qualitative agreement with density functional theory calculations of charge separation in C60 and C240 fullerenes in the presence of an external point charge. This suggests that, from an electrostatic point of view, in the static electric field of external charges these molecules exhibit dielectric behaviour. PMID- 24154503 TI - Association between anemia and packed cell transfusion and outcomes of ventricular septal defect and atrioventricular canal repair in children. AB - Data on the prevalence and impact of anemia and packed red blood cell (PRBC) transfusions in children with congenital heart disease are limited. Our objectives were to determine the prevalence of anemia and its impact and the impact of PRBC transfusion in the initial 5 days after surgical repair on postoperative outcomes in infants with ventricular septal defect (VSD) and atrioventricular (AV) canal. Retrospective chart review of infants (1 year old) (n = 195) with AV canal or VSD who underwent surgical repair at Children's Hospital of Michigan during a 10-year period. Statistical analyses (SPSS 17.0) included Chi square and Student t test as well as regression analysis with significance set at p = 0.05. Preoperative anemia was diagnosed in 45 of 195 (23%) children. Anemic infants had VSD more frequently (80%), significantly shorter bypass and cross-clamp durations, and higher red cell distribution widths. Postoperative outcomes and PRBC transfusions were similar in the groups. On regression analysis, AV canal was associated with a significantly lower (odds ratio 0.21; 95% confidence interval 0.07-0.68, p = 0.009) risk of anemia. Infants who received a PRBC transfusion (n = 42) had significantly lower birth weights as well as weights at surgery and longer postoperative durations of pressor use, ventilation, oxygen supplementation, and length of stay than those who did not (n = 153) receive transfusions. PRBC transfusion was independently associated with longer postoperative length of stay, oxygen, pressor use, and ventilator duration. Approximately 23% of infants with AV canal or VSD are anemic. PRBC transfusions in the initial 5 postoperative days, but not anemia, are independently associated with adverse postoperative outcomes. Further studies to evaluate conservative transfusion strategies in this population are needed. PMID- 24154505 TI - On the OCTET and supervised community treatment orders. PMID- 24154504 TI - Abnormal abdominal aorta hemodynamics are associated with necrotizing enterocolitis in infants with hypoplastic left heart syndrome. AB - The risk of necrotizing enterocolitis (NEC) in association with congenital heart disease is highest in patients with hypoplastic left heart syndrome (HLHS). Within the HLHS population, however, risk factors for NEC remain debated. We hypothesized that some infants with HLHS have vascular changes that contribute to gut hypoperfusion independent of diastolic runoff and low cardiac output. We analyzed the abdominal aorta pulsatility index and right-ventricular function on routine preoperative and postoperative echocardiograms for all infants who underwent stage I palliation for HLHS from January 2007 to January 2012. The echocardiography findings and clinical course were compared between those with and those without an episode of NEC. Of the 61 cases reviewed, 11 (18 %) developed NEC during a mean follow-up of 3.8 +/- 1.3 years. Those with NEC had a lower abdominal aorta pulsatility index compared with those without NEC both on stage I preoperative (3.38 +/- 0.15 vs. 3.89 +/- 0.09, p < 0.05) and postoperative echocardiograms (2.21 +/- 0.28 vs. 3.05 +/- 0.78, p = 0.01) despite similar ventricular function and operative risk. Abdominal aorta Doppler pulsations are lower in patients with HLHS whose clinical course is complicated by NEC. This finding suggests that the systemic vasculature in a subset of neonates with HLHS may be inherently abnormal. Further investigation is warranted to determine if this is secondary to structural changes in the mesenteric and/or systemic vasculature. PMID- 24154506 TI - Graphene mediated domain formation in exchange coupled graphene/Co3O4(111)/Co(0001) trilayers. AB - Graphene grown directly on Co3O4(111)/Co(0001) by molecular beam epitaxy exhibits extrinsic p-type doping, as demonstrated by photoemission and conductivity measurements. Trilayer heterostructures of graphene/Co3O4(111)/Co(0001) reveal an unconventional magneto-optical Kerr hysteresis with vanishing remanence for temperatures up to 400 K. Magnetic force microscopy measurements demonstrate that the vanishing remanence is due to a complex domain state, indicating substrate induced graphene spin polarization. The domain formation of the Co magnetization is in strong contrast to the magnetic behavior of Co in Co/Co3O4 bilayers. This suggests that the Co3O4 interlayer mediates the variable Co magnetization and induced graphene spin polarization, with possible retroaction of graphene on the Co film. PMID- 24154507 TI - Trastuzumab-related cardiac events in the treatment of early breast cancer. AB - Trastuzumab is considered a cornerstone in the treatment of human epidermal growth factor receptor-2 (HER2)-positive breast cancer. Cardiac toxicity is an important side effect of treatment and can limit the use of this drug known to act synergistically with cardiotoxicity from anthracyclines. A retrospective study was performed on breast cancer patients with early breast cancer, and HER2 overexpression treated with adjuvant/neoadjuvant chemotherapy and trastuzumab between 2005 and 2010. Cardiac events (CE) were recorded if left ventricular ejection fraction (LVEF) reduction was more than 10 % from baseline echocardiography. Treatment-related potential risk and protective factors were recorded. Median age of the 124 patients included in this analysis was 51 years (range 29-70 years). Treatment regimens were anthracycline-cyclophosphamide (AC) Taxol (105 patients), TCH (12 patients), and CAF/Taxol combination (7 patients). CE were observed in 26 (21 %) patients. Trastuzumab was stopped in 9 (7 %) patients and rechallenged in five after periods ranging from 19 to 120 days. There was a significant decrease in LVEF between baseline/post-AC and during trastuzumab treatment (mean LVEF 64.29 vs. 61.97 %, p < 0.001). Treatment-related risk factors were age and interval since last AC. Trastuzumab loading dose (8 vs. 4 mg) did not influence CE rate. 56 (45 %) patients received left chest wall irradiation with significantly increased CE rates, 16 (31.4 %) versus 10 (15.4 %), in patients without radiotherapy (p < 0.05). The presence of any cardiac risk factor caused a trend toward increased risk, not statistically significant. No connection was found between possible cardioprotective drugs and reduced rates of toxicity. The incidence of cardiac toxicity with trastuzumab adjuvant treatment in our study is similar to other reports. Only radiotherapy to the left chest wall increased the risk for CE. Further prospective studies are needed, including echocardiographic measurement and biochemical data (troponin I), for early recognition and monitoring of high-risk patients. PMID- 24154508 TI - Progress in peripheral nerve disease research in the last two years. AB - Peripheral nerve disorders have been a Cinderella subspecialty for neurologists because of the limited treatment options and difficulties in obtaining a genetic diagnosis. In the last decade, there has been great progress in the management of patients with peripheral nerve disease. In this paper, we review a selection of diagnostic and therapeutic papers in this area published in the Journal of Neurology over the last 24 months. PMID- 24154509 TI - Preference for linoleic acid in obesity-prone and obesity-resistant rats is attenuated by the reduction of CD36 on the tongue. AB - Differential sensing of dietary fat and fatty acids by the oral cavity is proposed to regulate the susceptibility to obesity. In the current experiments, animals that differ in their susceptibility to obesity were used to investigate the influence of the oral cavity on the preference for the polyunsaturated fatty acid, linoleic acid. In experiment 1, the preference for differing concentrations of linoleic acid was determined in obesity-prone Osborne-Mendel (OM) and obesity resistant S5B/Pl (S5B) rats. The preference threshold for linoleic acid was lower in S5B rats, compared with OM rats. To determine whether differences in linoleic acid preference threshold were related to innate strain differences in the fatty acid receptors on the tongue, the expression of GPR120, GPR40, and CD36 on the circumvallate papillae were assessed in OM and S5B rats. Results indicated that the expression of CD36, GPR40, and GPR120 did not differ between these two strains. Numerous studies have examined the role of CD36 on fat intake; therefore, in experiment 3, RNA interference was used to decrease the expression of CD36 on the tongues of OM and S5B rats, and the effect of decreased CD36 expression on linoleic acid preference was determined. CD36 siRNA attenuated linoleic acid preference for the most preferred concentration in both OM and S5B rats. Overall, these data indicate that there are innate differences in the preference threshold for linoleic acid in obesity-prone and obesity-resistant rats. Experimentally reducing the expression of CD36 on the circumvallate papillae attenuated the preference for linoleic acid in both strains. PMID- 24154510 TI - GPR40 and GPR120 fatty acid sensors are critical for postoral but not oral mediation of fat preferences in the mouse. AB - In addition to orosensory signals, postoral actions of fat stimulate appetite and condition flavor preferences, but the gut sensors mediating these responses are unknown. Here, we investigated the role of the fatty acid sensors GPR40 and GPR120 in postoral and oral preferences for a soybean oil emulsion (Intralipid). Mice were trained to drink a flavored solution (CS+) paired with intragastric (IG) oil infusions and another flavored solution (CS-) paired with water infusions. Knockout (KO) mice missing GPR40 or GPR120 sensors increased their CS+ intake in one-bottle tests (1 h/day) but less so than wild-type (WT) mice. The KO mice also preferred the CS+ to CS- in a two-bottle test, but the preference was attenuated in GPR40 KO mice. Double-knockout (DoKO) mice missing both GPR40 and GPR120 displayed attenuated stimulation of CS+ intake and only a marginal CS+ preference. The DoKO mice developed a more substantial CS+ preference when tested 24 h/day, although weaker than that of WT mice. The DoKO mice also consumed less of the CS+ paired with IG Intralipid, as well as less Intralipid in oral tests. However, DoKO mice, like GPR40 KO and GPR120 KO mice did not differ from WT mice in their preference for Intralipid over water at 0.001%-20% concentrations. In contrast to prior results obtained with mice missing the CD36 fatty acid sensor, these findings indicate that, together, GPR40 and GPR120 play a critical role in the postoral stimulation of appetite by fat but are not essential for oral fat preferences. PMID- 24154511 TI - Pilot investigation of changes in readiness and confidence to quit smoking after E-cigarette experimentation and 1 week of use. AB - INTRODUCTION: This study examined changes in smokers' readiness and confidence to quit smoking, smoking behavior, nicotine withdrawal symptoms, and tobacco product preference following electronic cigarette (EC) experimentation and 1 week of ad libitum use. METHODS: Current cigarette smokers, with no prior use of ECs and uninterested in quitting, completed 3 study phases: baseline assessment (N = 20), experimentation (N = 19), and ad libitum use (N = 16). Baseline assessment consisted of completion of assessment measures and exhaled carbon monoxide measurements. Experimentation phases consisted of four, 75-min sessions in which participants completed assessment measures and sampled 3 EC brands and their own brand of cigarette (OBC). Ad libitum use included participants selecting and being provided their preferred EC brand from the experimentation phase to be used "as you want" for 1 week. Outcome measures included readiness and confidence to quit smoking, nicotine withdrawal symptoms, product preference/satisfaction, and smoking behavior items. RESULTS: Readiness and confidence to quit increased significantly during the experimentation period and continued to increase during ad libitum use. There were no significant differences in reported effectiveness in reducing smoking urges and cravings between OBC and EC though OBC were rated as more enjoyable and satisfying. During ad libitum use, regular cigarette smoking decreased by approximately 44% from baseline levels with overall tobacco use (EC + OBC) remaining the same. CONCLUSIONS: Among a small convenience sample of unmotivated cigarette smokers, EC experimentation and 1 week of ad libitum use increased readiness and confidence to quit regular cigarettes and reduced regular cigarette smoking. PMID- 24154512 TI - Hookah use among adolescents in the United States: results of a national survey. AB - INTRODUCTION: U.S. adolescents increasingly use alternative tobacco products (ATPs), including hookah. No study has previously assessed correlates of adolescent hookah use in a nationally representative sample. METHODS: Cross sectional, nationally representative data of adolescents from the 2011 National Youth Tobacco Survey (NYTS) were used. Student demographics and their use of, exposure to, and beliefs about tobacco were examined as correlates of hookah use. RESULTS: Of adolescents nationwide, 7.3% reported ever trying hookah and 2.6% reported using hookah within the past month. Increasing age was associated with trying hookah, but not current hookah use. Sex was unassociated with hookah use. Asians were most likely to have tried hookah; Hispanics and those of another race reported greater current hookah use. Hookah use increased with perceived ease of access to and willingness to try tobacco. Students with a hookah user at home were more likely to have tried hookah and to currently use hookah. Current cigarette use was not associated with current hookah use (odds ratio [OR] = 1.3, 95% CI = 0.8-2.1), but was associated with trying hookah (OR = 1.5, 95% CI = 1.1 2.2). Non-cigarette tobacco use was associated with trying hookah (OR = 2.7, 95% CI = 2.1-3.5) and current hookah use (OR = 4.8, 95% CI = 2.7-8.7). CONCLUSIONS: A sizeable minority of U.S. adolescents use hookah, particularly those living with hookah users, those who use other ATPs, and those who perceive tobacco as easily accessible. Current cigarette use was not associated with current hookah use. Future studies assessing the dangers of hookah use and interventions to curb this emerging problem appear warranted. PMID- 24154513 TI - Shortness of Breath with Daily Activities questionnaire: validation and responder thresholds in patients with chronic obstructive pulmonary disease. AB - OBJECTIVES: To test the reliability, validity and responsiveness of the 13-item Shortness of Breath with Daily Activities (SOBDA) questionnaire, and determine the threshold for response and minimal important difference (MID). DESIGN: 6 week, randomised, double-blind, placebo-controlled study. SETTING: 40 centres in the USA between 29 October 2009 and 1 July 2010. PRIMARY AND SECONDARY OUTCOME MEASURES: 547 patients with chronic obstructive pulmonary disease (COPD) were enrolled and 418 entered the 2-week run-in period. Data from the run-in period were collected to test internal consistency, test-retest reliability, convergent validity and known-groups validity of the SOBDA. Three hundred and sixty six patients were randomised 2:2:1 to fluticasone propionate/salmeterol 250/50 ug, salmeterol 50 ug or placebo, twice daily. Results from the SOBDA questionnaire, Patient Global Assessment of Change Question, modified Medical Research Council Dyspnoea Scale (mMRC), Clinician Global Impression of Dysponea Severity (CGI-S), Clinician Global Impression of Change Question and Chronic Respiratory Disease Questionnaire self-administered standardised version (CRQ-SAS) were evaluated; spirometry and safety parameters were measured. Study endpoints were selected to investigate the cross-sectional and longitudinal validity of the SOBDA questionnaire in relation to the clinical criteria. RESULTS: Internal consistency of the SOBDA questionnaire (Cronbach alpha) was 0.89. Test-retest reliability (intraclass correlation) was 0.94. The SOBDA weekly scores correlated with the patient-reported and clinician-reported mMRC, CGI-S and CRQ-SAS dyspnoea domain scores (0.29, 0.24, 0.24 and -0.68, respectively). The SOBDA weekly scores differentiated between the responders and the non-responders as rated by the patients and the clinicians. Anchor-based and supportive distribution-based analyses produced a range of the potential values for the threshold for the responders and MID. CONCLUSIONS: The 13-item SOBDA questionnaire is reliable, valid and responsive to change in patients with COPD. On using anchor-based methods, the proposed responder threshold shows a -0.1 to -0.2 score change. A specific threshold value will be identified as more data are generated from future clinical trials. TRIAL REGISTRATION: NCT00984659; GlaxoSmithKline study number: ASQ112989. PMID- 24154514 TI - Women's experiences in relation to stillbirth and risk factors for long-term post traumatic stress symptoms: a retrospective study. AB - OBJECTIVES: (1) To investigate the experiences of women with a previous stillbirth and their appraisal of the care they received at the hospital. (2) To assess the long-term level of post-traumatic stress symptoms (PTSS) in this group and identify risk factors for this outcome. DESIGN: A retrospective study. SETTING: Two university hospitals. PARTICIPANTS: The study population comprised 379 women with a verified diagnosis of stillbirth (>=23 gestational weeks or birth weight >=500 g) in a singleton or twin pregnancy 5-18 years previously. 101 women completed a comprehensive questionnaire in two parts. PRIMARY AND SECONDARY OUTCOME MEASURES: The women's experiences and appraisal of the care provided by healthcare professionals before, during and after stillbirth. PTSS at follow-up was assessed using the Impact of Event Scale (IES). RESULTS: The great majority saw (98%) and held (82%) their baby. Most women felt that healthcare professionals were supportive during the delivery (85.6%) and showed respect towards their baby (94.9%). The majority (91.1%) had received some form of short term follow-up. One-third showed clinically significant long-term PTSS (IES >= 20). Independent risk factors were younger age (OR 6.60, 95% CI 1.99 to 21.83), induced abortion prior to stillbirth (OR 5.78, 95% CI 1.56 to 21.38) and higher parity (OR 3.46, 95% CI 1.19 to 10.07) at the time of stillbirth. Having held the baby (OR 0.17, 95% CI 0.05 to 0.56) was associated with less PTSS. CONCLUSIONS: The great majority saw and held their baby and were satisfied with the support from healthcare professionals. One in three women presented with a clinically significant level of PTSS 5-18 years after stillbirth. Having held the baby was protective, whereas prior induced abortion was a risk factor for a high level of PTSS. TRIAL REGISTRATION: The study was registered at http://www.clinicaltrials.gov, with registration number NCT 00856076. PMID- 24154515 TI - The impact of an intervention programme employing a hands-on technique to reduce the incidence of anal sphincter tears: interrupted time-series reanalysis. AB - OBJECTIVE: To re-evaluate previously published findings from an uncontrolled before-after evaluation of an intervention programme to reduce the incidence of anal sphincter tears. A key component of the programme was the use of a hands-on technique where the birth attendant presses the neonate's head during the final stage of delivery while simultaneously supporting the woman's perineum with the other hand. DESIGN: Interrupted time-series analysis using segmented regression modelling. SETTING: Obstetric departments of five Norwegian hospitals. PARTICIPANTS: All women giving births vaginally in the study hospitals, 2002 2008. METHODS: The main data source was the Medical Birth Registry of Norway. We estimated the change in incidence of anal sphincter tears before and after implementation of the intervention in the five intervention hospitals, taking into account the trends in incidence before and after implementation. MAIN OUTCOME MEASURES: Incidence of anal sphincter tears and episiotomies. RESULTS: There were 75 543 registered births at the five included hospitals. We found a 2% absolute reduction in incidence of anal sphincter tears associated with the hospital intervention programme, representing almost a halving in the number of women experiencing serious anal sphincter tears. This is a substantially smaller estimate than previously reported. However, it does represent a highly significant decrease in anal sphincter injuries. The programme was also associated with a significant increase in episiotomies. CONCLUSIONS: The intervention programme was associated with a significant reduction in the incidence of obstetric anal sphincter tears. Still, the findings should be interpreted with caution as they seem to contradict the findings from randomised controlled studies of similar interventions. PMID- 24154516 TI - Modelling factors in primary care quality improvement: a cross-sectional study of premature CHD mortality. AB - OBJECTIVES: To identify features of primary care quality improvement associated with improved health outcomes using premature coronary heart disease (CHD) mortality as an example, and to determine impacts of different modelling approaches. DESIGN: Cross-sectional study of mortality rates in 229 general practices. SETTING: General practices from three East Midlands primary care trusts. PARTICIPANTS: Patients registered to the practices above between April 2006 and March 2009. MAIN OUTCOME MEASURES: Numbers of CHD deaths in those aged under 75 (premature mortality) and at all ages in each practice. RESULTS: Population characteristics and markers of quality of primary care were associated with variations in premature CHD mortality. Increasing levels of deprivation, percentages of practice populations on practice diabetes registers, white, over 65 and male were all associated with increasing levels of premature CHD mortality. Control of serum cholesterol levels in those with CHD and the percentage of patients recalling access to their preferred general practitioner were both associated with decreased levels of premature CHD mortality. Similar results were found for all-age mortality. A combined measure of quality of primary care for CHD comprising 12 quality outcomes framework indicators was associated with decreases in both all-age and premature CHD mortality. The selected models suggest that practices in less deprived areas may have up to 20% lower premature CHD mortality than those with median deprivation and that improvement in the CHD care quality from 83% (lower quartile) to 86% (median) could reduce premature CHD mortality by 3.6%. Different modelling approaches yielded qualitatively similar results. CONCLUSIONS: High-quality primary care, including aspects of access to and continuity of care, detection and management, appears to be associated with reducing CHD mortality. The impact on premature CHD mortality is greater than on all-age CHD mortality. Determining the most useful measures of quality of primary care needs further consideration. PMID- 24154517 TI - Assessing the impact on chronic disease of incorporating the societal cost of greenhouse gases into the price of food: an econometric and comparative risk assessment modelling study. AB - OBJECTIVES: To model the impact on chronic disease of a tax on UK food and drink that internalises the wider costs to society of greenhouse gas (GHG) emissions and to estimate the potential revenue. DESIGN: An econometric and comparative risk assessment modelling study. SETTING: The UK. PARTICIPANTS: The UK adult population. INTERVENTIONS: Two tax scenarios are modelled: (A) a tax of L2.72/tonne carbon dioxide equivalents (tCO2e)/100 g product applied to all food and drink groups with above average GHG emissions. (B) As with scenario (A) but food groups with emissions below average are subsidised to create a tax neutral scenario. OUTCOME MEASURES: Primary outcomes are change in UK population mortality from chronic diseases following the implementation of each taxation strategy, the change in the UK GHG emissions and the predicted revenue. Secondary outcomes are the changes to the micronutrient composition of the UK diet. RESULTS: Scenario (A) results in 7770 (95% credible intervals 7150 to 8390) deaths averted and a reduction in GHG emissions of 18 683 (14 665to 22 889) ktCO2e/year. Estimated annual revenue is L2.02 (L1.98 to L2.06) billion. Scenario (B) results in 2685 (1966 to 3402) extra deaths and a reduction in GHG emissions of 15 228 (11 245to 19 492) ktCO2e/year. CONCLUSIONS: Incorporating the societal cost of GHG into the price of foods could save 7770 lives in the UK each year, reduce food-related GHG emissions and generate substantial tax revenue. The revenue neutral scenario (B) demonstrates that sustainability and health goals are not always aligned. Future work should focus on investigating the health impact by population subgroup and on designing fiscal strategies to promote both sustainable and healthy diets. PMID- 24154518 TI - Use of autologous fat grafting for reconstruction postmastectomy and breast conserving surgery: a systematic review protocol. AB - INTRODUCTION: There is growing interest in the potential use of autologous fat grafting (AFG) for the purposes of breast reconstruction. However, concerns have been raised regarding the technique's clinical effectiveness, safety and interference with screening mammography. The objective of this systematic review was to determine the oncological, clinical, aesthetic and functional, patient reported, process and radiological outcomes for AFG. METHODS AND ANALYSIS: All original studies, including randomised controlled trials, cohorts studies, case control studies, case series and case reports involving women undergoing breast reconstruction. All AFG techniques performed for the purposes of reconstruction in the postmastectomy or breast conserving surgery setting will be considered. Outcomes are defined within this protocol along; oncological, clinical, aesthetic and functional, patient reported, process and radiological domains. The search strategy has been devised to find papers about 'fat grafting and breast reconstruction' and is outlined within the body of this protocol. The full search strategy is outlined within the body of the protocol. The following electronic databases will be searched from 1 January 1986 to 6 June 2013: PubMed, MEDLINE, EMBASE, SCOPUS, CINAHL, PsycINFO, SciELO, The Cochrane Library, including the Cochrane Database of Systematic Reviews (CDSR), Cochrane Central Register of Controlled Trials (CENTRAL), Database of Abstracts of Reviews of Effect (DARE), the Cochrane Methodology Register, Health Technology Assessment Database, the NHS Economic Evaluation Databases and Cochrane Groups, ClinicalTrials.gov, Current Controlled Trials Database, the World Health Organisation (WHO) International Clinical Trials Registry Platform, UpToDate.com, NHS Evidence and the York Centre for Reviews and Dissemination. Grey literature searches will also be conducted as detailed in our review protocol. Eligibility assessment occurred in two stages, title and abstract screening and then full text assessment. Data were extracted and stored in a database with standardised extraction fields to facilitate easy and consistent data entry. ETHICS AND DISSEMINATION: This systematic review will be published in a peer-reviewed journal. It will also be presented at national and international conferences in the fields of plastic, reconstructive and aesthetic surgery and at more general surgical and methodological conferences. It will be disseminated electronically and in print. Brief reports of the review findings will be disseminated directly to the appropriate audiences of surgeons and societies through email and other modes of communication. Updates of the review will be conducted to inform and guide healthcare practice and policy. PROTOCOL REGISTRATION: PROSPERO-National Institute of Health Research (NIHR) Prospective Register of Systematic Reviews (CRD42013005254). PMID- 24154519 TI - Investigation of alcohol-related social norms among youth aged 14-17 years in Perth, Western Australia: protocol for a respondent-driven sampling study. AB - INTRODUCTION: Alcohol use among young people is a major public health concern in Australia and internationally. Research elucidating social norms influencing alcohol use supports the desire to conform to peers. However, there is a lack of evidence on how social norms are transmitted from the community to young people and between family members and peers, as previous studies are limited to mainly school and university environments. This article describes the proposed process to investigate common alcohol-related norms held by 14-year-olds to 17-year-olds in Perth, Western Australia, and to clarify the process and pathways through which proalcohol norms are transmitted to adolescents. METHODS AND ANALYSIS: This cross-sectional quantitative study will use respondent-driven sampling (RDS) to recruit a sample of 672 adolescents from sporting groups, youth programmes and the community in Perth. Data will be collected with a previously developed and validated multidimensional online survey instrument. A variety of strategies will be explored to aid participation including face-to-face recruitment and survey administration, web-based RDS and a 'mature minor' consent assessment protocol. Data analysis will include descriptive statistics of demographic characteristics, as well as social network and dyadic analyses, to explore the connections between shared understanding of norms and behaviours among individuals and how these translate into reported practices. ETHICS AND DISSEMINATION: This research is expected to extend our understanding of normative development pathways to inform future interventions, and will be widely disseminated through conference presentations, peer-reviewed papers, media channels and community seminars. A study reference group of key health industry stakeholders will be established to encourage integration of study findings into policy and practice, and results will guide the development of community interventions. The Curtin University Human Research Ethics Committee has granted approval for this research. PMID- 24154520 TI - Publishing priorities of biomedical research funders. AB - OBJECTIVES: To understand the publishing priorities, especially in relation to open access, of 10 UK biomedical research funders. DESIGN: Semistructured interviews. SETTING: 10 UK biomedical research funders. PARTICIPANTS: 12 employees with responsibility for research management at 10 UK biomedical research funders; a purposive sample to represent a range of backgrounds and organisation types. CONCLUSIONS: Publicly funded and large biomedical research funders are committed to open access publishing and are pleased with recent developments which have stimulated growth in this area. Smaller charitable funders are supportive of the aims of open access, but are concerned about the practical implications for their budgets and their funded researchers. Across the board, biomedical research funders are turning their attention to other priorities for sharing research outputs, including data, protocols and negative results. Further work is required to understand how smaller funders, including charitable funders, can support open access. PMID- 24154521 TI - A self-renewing division of zebrafish Muller glial cells generates neuronal progenitors that require N-cadherin to regenerate retinal neurons. AB - Muller glia function as retinal stem cells in adult zebrafish. In response to loss of retinal neurons, Muller glia partially dedifferentiate, re-express neuroepithelial markers and re-enter the cell cycle. We show that the immunoglobulin superfamily adhesion molecule Alcama is a novel marker of multipotent retinal stem cells, including injury-induced Muller glia, and that each Muller glial cell divides asymmetrically only once to produce an Alcama negative, proliferating retinal progenitor. The initial mitotic division of Muller glia involves interkinetic nuclear migration, but mitosis of retinal progenitors occurs in situ. Rapidly dividing retinal progenitors form neurogenic clusters tightly associated with Alcama/N-cadherin-labeled Muller glial radial processes. Genetic suppression of N-cadherin function interferes with basal migration of retinal progenitors and subsequent regeneration of HuC/D(+) inner retinal neurons. PMID- 24154522 TI - Cxcl12/Cxcr4 signaling controls the migration and process orientation of A9-A10 dopaminergic neurons. AB - CXCL12/CXCR4 signaling has been reported to regulate three essential processes for the establishment of neural networks in different neuronal systems: neuronal migration, cell positioning and axon wiring. However, it is not known whether it regulates the development of A9-A10 tyrosine hydroxylase positive (TH(+)) midbrain dopaminergic (mDA) neurons. We report here that Cxcl12 is expressed in the meninges surrounding the ventral midbrain (VM), whereas CXCR4 is present in NURR1(+) mDA precursors and mDA neurons from E10.5 to E14.5. CXCR4 is activated in NURR1(+) cells as they migrate towards the meninges. Accordingly, VM meninges and CXCL12 promoted migration and neuritogenesis of TH(+) cells in VM explants in a CXCR4-dependent manner. Moreover, in vivo electroporation of Cxcl12 at E12.5 in the basal plate resulted in lateral migration, whereas expression in the midline resulted in retention of TH(+) cells in the IZ close to the midline. Analysis of Cxcr4(-/-) mice revealed the presence of VM TH(+) cells with disoriented processes in the intermediate zone (IZ) at E11.5 and marginal zone (MZ) at E14. Consistently, pharmacological blockade of CXCR4 or genetic deletion of Cxcr4 resulted in an accumulation of TH(+) cells in the lateral aspect of the IZ at E14, indicating that CXCR4 is required for the radial migration of mDA neurons in vivo. Altogether, our findings demonstrate that CXCL12/CXCR4 regulates the migration and orientation of processes in A9-A10 mDA neurons. PMID- 24154523 TI - The imprinted polycomb group gene Sfmbt2 is required for trophoblast maintenance and placenta development. AB - Imprinted genes play important roles in placenta development and function. Parthenogenetic embryos, deficient in paternally expressed imprinted genes, lack extra-embryonic tissues of the trophoblast lineage. Parthenogenetic trophoblast stem cells (TSCs) are extremely difficult to derive, suggesting that an imprinted gene(s) is necessary for TSC establishment or maintenance. In a candidate study, we were able to narrow the list to one known paternally expressed gene, Sfmbt2. We show that mouse embryos inheriting a paternal Sfmbt2 gene trap null allele have severely reduced placentae and die before E12.5 due to reduction of all trophoblast cell types. We infected early embryos with lentivirus vectors expressing anti-Sfmbt2 shRNAs and found that TSC derivation was significantly reduced. Together, these observations support the hypothesis that loss of SFMBT2 results in defects in maintenance of trophoblast cell types necessary for development of the extra-embryonic tissues, the placenta in particular. PMID- 24154524 TI - Visualizing developmentally programmed endoreplication in mammals using ubiquitin oscillators. AB - The majority of mammalian somatic cells maintain a diploid genome. However, some mammalian cell types undergo multiple rounds of genome replication (endoreplication) as part of normal development and differentiation. For example, trophoblast giant cells (TGCs) in the placenta become polyploid through endoreduplication (bypassed mitosis), and megakaryocytes (MKCs) in the bone marrow become polyploid through endomitosis (abortive mitosis). During the normal mitotic cell cycle, geminin and Cdt1 are involved in 'licensing' of replication origins, which ensures that replication occurs only once in a cell cycle. Their protein accumulation is directly regulated by two E3 ubiquitin ligase activities, APC(Cdh1) and SCF(Skp2), which oscillate reciprocally during the cell cycle. Although proteolysis-mediated, oscillatory accumulation of proteins has been documented in endoreplicating Drosophila cells, it is not known whether the ubiquitin oscillators that control normal cell cycle transitions also function during mammalian endoreplication. In this study, we used transgenic mice expressing Fucci fluorescent cell-cycle probes that report the activity of APC(Cdh1) and SCF(Skp2). By performing long-term, high temporal-resolution Fucci imaging, we were able to visualize reciprocal activation of APC(Cdh1) and SCF(Skp2) in differentiating TGCs and MKCs grown in our custom-designed culture wells. We found that TGCs and MKCs both skip cytokinesis, but in different ways, and that the reciprocal activation of the ubiquitin oscillators in MKCs varies with the polyploidy level. We also obtained three-dimensional reconstructions of highly polyploid TGCs in whole, fixed mouse placentas. Thus, the Fucci technique is able to reveal the spatiotemporal regulation of the endoreplicative cell cycle during differentiation. PMID- 24154525 TI - Conserved molecular signatures of neurogenesis in the hippocampal subgranular zone of rodents and primates. AB - The neurogenic potential of the subgranular zone (SGZ) of the hippocampal dentate gyrus is likely to be regulated by molecular cues arising from its complex heterogeneous cellular environment. Through transcriptome analysis using laser microdissection coupled with DNA microarrays, in combination with analysis of genome-wide in situ hybridization data, we identified 363 genes selectively enriched in adult mouse SGZ. These genes reflect expression in the different constituent cell types, including progenitor and dividing cells, immature granule cells, astrocytes, oligodendrocytes and GABAergic interneurons. Similar transcriptional profiling in the rhesus monkey dentate gyrus across postnatal development identified a highly overlapping set of SGZ-enriched genes, which can be divided based on temporal profiles to reflect maturation of glia versus granule neurons. Furthermore, we identified a neurogenesis-related gene network with decreasing postnatal expression that is highly correlated with the declining number of proliferating cells in dentate gyrus over postnatal development. Many of the genes in this network showed similar postnatal downregulation in mouse, suggesting a conservation of molecular mechanisms underlying developmental and adult neurogenesis in rodents and primates. Conditional deletion of Sox4 and Sox11, encoding two neurogenesis-related transcription factors central in this network, produces a mouse with no hippocampus, confirming the crucial role for these genes in regulating hippocampal neurogenesis. PMID- 24154526 TI - Accelerated homologous recombination and subsequent genome modification in Drosophila. AB - Gene targeting by 'ends-out' homologous recombination enables the deletion of genomic sequences and concurrent introduction of exogenous DNA with base-pair precision without sequence constraint. In Drosophila, this powerful technique has remained laborious and hence seldom implemented. We describe a targeting vector and protocols that achieve this at high frequency and with very few false positives in Drosophila, either with a two-generation crossing scheme or by direct injection in embryos. The frequency of injection-mediated gene targeting can be further increased with CRISPR-induced double-strand breaks within the region to be deleted, thus making homologous recombination almost as easy as conventional transgenesis. Our targeting vector replaces genomic sequences with a multifunctional fragment comprising an easy-to-select genetic marker, a fluorescent reporter, as well as an attP site, which acts as a landing platform for reintegration vectors. These vectors allow the insertion of a variety of transcription reporters or cDNAs to express tagged or mutant isoforms at endogenous levels. In addition, they pave the way for difficult experiments such as tissue-specific allele switching and functional analysis in post-mitotic or polyploid cells. Therefore, our method retains the advantages of homologous recombination while capitalising on the mutagenic power of CRISPR. PMID- 24154527 TI - Generation of the podocyte and tubular components of an amniote kidney: timing of specification and a role for Wnt signaling. AB - Kidneys remove unwanted substances from the body and regulate the internal body environment. These functions are carried out by specialized cells (podocytes) that act as a filtration barrier between the internal milieu and the outside world, and by a series of tubules and ducts that process the filtrate and convey it to the outside. In the kidneys of amniote vertebrates, the filtration (podocyte) and tubular functions are tightly integrated into functional units called nephrons. The specification of the podocyte and tubular components of amniote nephrons is currently not well understood. The present study investigates podocyte and tubule differentiation in the avian mesonephric kidney, and presents several findings that refine our understanding of the initial events of nephron formation. First, well before the first morphological or molecular signs of nephron formation, mesonephric mesenchyme can be separated on the basis of morphology and the expression of the transcription factor Pod1 into dorsal and ventral components, which can independently differentiate in culture along tubule and podocyte pathways, respectively. Second, canonical Wnt signals, which are found in the nephric duct adjacent to the dorsal mesonephric mesenchyme and later in portions of the differentiating nephron, strongly inhibit podocyte but not tubule differentiation, suggesting that Wnt signaling plays an important role in the segmentation of the mesonephric mesenchyme into tubular and glomerular segments. The results are discussed in terms of their broader implications for models of nephron segmentation. PMID- 24154529 TI - Catalyst design for iron-promoted reductions: an iron disilyl-dicarbonyl complex bearing weakly coordinating eta2-(H-Si) moieties. AB - Iron disilyl dicarbonyl complex 1, in which two H-Si moieties of the 1,2 bis(dimethylsilyl)benzene ligand were coordinated to the iron center in an eta(2) (H-Si) fashion, was synthesized by the reaction of (eta(4)-C6H8)Fe(CO)3 with 2 equiv. of 1,2-bis(dimethylsilyl)benzene under photo-irradiation. Complex 1 demonstrated high catalytic activity toward the hydrogenation of alkenes, the hydrosilylation of alkenes and the reduction of carbonyl compounds. PMID- 24154534 TI - Impact of population expansion on genetic diversity and structure of river otters (Lontra canadensis) in Central North America. AB - Populations of North American river otters (Lontra canadensis) declined throughout large portions of the continent during the early 1900s due to habitat degradation and unregulated trapping. River otters had been extirpated in North Dakota (ND), but the Red River Valley has since been recolonized, with potential source populations including the neighboring states of Minnesota or South Dakota, or the Canadian province of Manitoba (MB). We genotyped 9 microsatellite loci in 121 samples to determine the source population of river otters in the Red River Valley of ND, as well as to assess population structure and diversity of river otters in central North America. Overall, genetic diversity was high, with an average observed heterozygosity of 0.58. Genetic differentiation was low (F ST < 0.05) between river otters in ND and those of Minnesota, suggesting that eastern ND was recolonized by river otters from Minnesota. River otters from MB were genetically distinct from all other sampled populations. Low genetic differentiation (F ST = 0.044) between South Dakota and Louisiana (LA) suggested that reintroductions using LA stock were successful. The genetic distinctiveness of river otters from different geographic regions should be considered when deciding on source populations for future translocations. PMID- 24154535 TI - Genetic variation and population structure in the endangered Hermann's tortoise: the roles of geography and human-mediated processes. AB - The Hermann's tortoise (Testudo hermanni) is an endangered land tortoise distributed in disjoint populations across Mediterranean Europe. We investigated its genetic variation by typing 1 mitochondrial locus and 9 nuclear microsatellites in approximately 300 individuals from 22 localities. Our goal was to understand the relative impact of natural and human-mediated processes in shaping the genetic structure and to identify the genetic priorities for the conservation of this species. We found that 1) all geographic areas are highly differentiated, mainly as a function of their distance but with a clear genetic discontinuity (F st values larger than 0.4) between the Eastern and the Western subspecies; 2) the contact zone between subspecies is located farthest to the west than previously believed, and it probably coincides with the delta of the largest Italian river; 3) extinction events due to climatic conditions in the Upper Palaeolithic and subsequent human-mediated translocations in the Neolithic possibly explain the unexpected similarity among Spain, Sicily, and Corsica. For conservation purposes, the large majority of genetic pools appears native although hybridization among subspecies, related to extensive 20th century trade of tortoises across Europe, is observed in Spain and some Italian samples. Most populations do not seem at immediate risk of low genetic variation, except the French population, which has very low nuclear genetic diversity (heterozygosity = 0.25) and where 50 out of 51 sampled animals shared the same mitochondrial sequence. In general, restocking and reintroduction plans should carefully consider the genetic background of the individuals. PMID- 24154528 TI - Hox11 genes are required for regional patterning and integration of muscle, tendon and bone. AB - Development of the musculoskeletal system requires precise integration of muscles, tendons and bones. The molecular mechanisms involved in the differentiation of each of these tissues have been the focus of significant research; however, much less is known about how these tissues are integrated into a functional unit appropriate for each body position and role. Previous reports have demonstrated crucial roles for Hox genes in patterning the axial and limb skeleton. Loss of Hox11 paralogous gene function results in dramatic malformation of limb zeugopod skeletal elements, the radius/ulna and tibia/fibula, as well as transformation of the sacral region to a lumbar phenotype. Utilizing a Hoxa11eGFP knock-in allele, we show that Hox11 genes are expressed in the connective tissue fibroblasts of the outer perichondrium, tendons and muscle connective tissue of the zeugopod region throughout all stages of development. Hox11 genes are not expressed in differentiated cartilage or bone, or in vascular or muscle cells in these regions. Loss of Hox11 genes disrupts regional muscle and tendon patterning of the limb in addition to affecting skeletal patterning. The tendon and muscle defects in Hox11 mutants are independent of skeletal patterning events as disruption of tendon and muscle patterning is observed in Hox11 compound mutants that do not have a skeletal phenotype. Thus, Hox genes are not simply regulators of skeletal morphology as previously thought, but are key factors that regulate regional patterning and integration of the musculoskeletal system. PMID- 24154536 TI - Large modulation of zero-dimensional electronic states in quantum dots by electric-double-layer gating. AB - Electrical manipulation and read-out of quantum states in zero-dimensional nanostructures by nano-gap metal electrodes is expected to bring about innovation in quantum information processing. However, electrical tunability of the quantum states in zero-dimensional nanostructures is limited by the screening of gate electric fields. Here we demonstrate a new way to realize wide-range electrical modulation of quantum states of single self-assembled InAs quantum dots (QDs) with a liquid-gated electric-double-layer (EDL) transistor geometry. The efficiency of EDL gating is 6-90 times higher than that of the conventional solid gating. The quantized energy level spacing is modulated from ~15 to ~25 meV, and the electron g-factor is electrically tuned over a wide range. Such a field effect tuning can be explained by the modulation in the confinement potential of electrons in the QDs. The EDL gating on the QDs also provides potential compatibility with optical manipulation of single-electron charge/spin states. PMID- 24154537 TI - Enantioselective Pd(II)-Pd(IV) catalysis utilizing a SPRIX ligand: efficient construction of chiral 3-oxy-tetrahydrofurans. AB - Novel enantioselective catalysis involving a Pd(II)-Pd(IV) cycle was developed by utilizing a SPRIX ligand. Treatment of alkenyl alcohols with a catalytic amount of Pd-SPRIX and TfOH in the presence of PhI(OAc)2 gave optically active 3-oxy tetrahydrofuran derivatives in good yields. PMID- 24154539 TI - A facile method for the large-scale continuous synthesis of graphene sheets using a novel catalyst. AB - This study reports on a facile and economical method for the scalable continuous synthesis of graphene sheets by the thermocatalytic decomposition of methane using a unique and novel unsupported catalyst of iron particles. Single-layered and few-layered graphene sheets were continuously synthesized by the isothermal decomposition reaction of methane over a catalyst of iron particles under atmospheric pressure without the need for a cooling precipitation process. In contrast with the methods currently reported in the published literature, this method exhibits remarkably high capacity and efficiency in terms of graphene throughput and yield, respectively. A maximum graphene yield rate of 20 mg/min per g of catalyst and a graphene output of 6 g per g of catalyst were achieved in this study; this graphene output has far surpassed the best graphene yield of 50 mg per 500 mg of catalyst, thus reported so far, by 60 times. PMID- 24154540 TI - Partial complex I deficiency due to the CNS conditional ablation of Ndufa5 results in a mild chronic encephalopathy but no increase in oxidative damage. AB - Deficiencies in the complex I (CI; NADH-ubiquinone oxidoreductase) of the respiratory chain are frequent causes of mitochondrial diseases and have been associated with other neurodegenerative disorders, such as Parkinson's disease. The NADH-ubiquinone oxidoreductase 1 alpha subcomplex subunit 5 (NDUFA5) is a nuclear-encoded structural subunit of CI, located in the peripheral arm. We inactivated Ndufa5 in mice by the gene-trap methodology and found that this protein is required for embryonic survival. Therefore, we have created a conditional Ndufa5 knockout (KO) allele by introducing a rescuing Ndufa5 cDNA transgene flanked by loxP sites, which was selectively ablated in neurons by the CaMKIIalpha-Cre. At the age of 11 months, mice with a central nervous system knockout of Ndufa5 (Ndufa5 CNS-KO) showed lethargy and loss of motor skills. In these mice cortices, the levels of NDUFA5 protein were reduced to 25% of controls. Fully assembled CI levels were also greatly reduced in cortex and CI activity in homogenates was reduced to 60% of controls. Despite the biochemical phenotype, no oxidative damage, neuronal death or gliosis were detected in the Ndufa5 CNS-KO brain at this age. These results showed that a partial defect in CI in neurons can lead to late-onset motor phenotypes without neuronal loss or oxidative damage. PMID- 24154541 TI - Human APOE genotype affects intraneuronal Abeta1-42 accumulation in a lentiviral gene transfer model. AB - Intraneuronal accumulation of beta-amyloid (Abeta)42 is one of the earliest pathological events in humans and in animal models of Alzheimer's disease (AD). Apolipoprotein E 4 (APOE4) is the major identified genetic risk factor for late onset AD, with Abeta deposition beginning earlier in apoE4-positive subjects. To directly determine the effects of APOE genotype on intraneuronal accumulation of Abeta1-42 at the onset of AD pathogenesis, we introduced lentiviral Abeta1-42 into the cortex of APOE targeted replacement (TR) mice at the age of 8-9 months. We demonstrated a significant isoform-dependent effect of human APOE, with dramatically enhanced intracellular Abeta1-42 deposits in the cerebral cortex of APOE4-TR mice 2 weeks after injection. Double-immunofluorescent staining showed that intracellular accumulation of lentiviral Abeta1-42 was mainly present in neurons, localized to late endosomes/lysosomes. This intraneuronal accumulation of Abeta1-42 correlated with increased tau phosphorylation and cell death in the ipsilateral cortex around the injection site. Abeta1-42 was also observed in microglia, but not in astrocytes. Quantitative analysis revealed more neurons with Abeta1-42 while less microglia with Abeta1-42 nearest to the injection site of Abeta1-42 lentivirus in APOE4-TR mice. Finally, apoE was present in neurons of the ipsilateral cortex of APOE-TR mice at 2 weeks after lentivirus injection, in addition to astrocytes and microglia in both the ipsilateral and contralateral cerebral cortex. Taken together, these results demonstrate that apoE4 tips the balance of the glial and neuronal Abeta toward the intraneuronal accumulation of Abeta. PMID- 24154543 TI - Differential autumn migration of the aquatic warbler Acrocephalus paludicola. AB - Relatively little attention has been paid to sex differences in the migration of birds in autumn. We studied the autumn migration strategy of molecularly sexed males and females in the globally threatened aquatic warbler Acrocephalus paludicola. We captured 176 birds at a stopover site in the Loire estuary at Donges, France. The median date for the passage of adults was 8 days earlier in males than females, although the timing of migration in first-year males and females was similar. This indicates that males, who are without parental duties, can start their migration earlier than females and first-year birds. Adults were significantly heavier than immature birds but did not have higher fat scores. In both age categories, more males (two to three times more) were captured. However, various factors (including tape-luring) can affect observed sex ratio. PMID- 24154542 TI - Abnormal mitochondrial transport and morphology are common pathological denominators in SOD1 and TDP43 ALS mouse models. AB - Neuronal mitochondrial morphology abnormalities occur in models of familial amyotrophic lateral sclerosis (ALS) associated with SOD1 and TDP43 mutations. These abnormalities have been linked to mitochondrial axonal transport defects, but the temporal and spatial relationship between mitochondrial morphology and transport alterations in these two distinct genetic forms of ALS has not been investigated in vivo. To address this question, we crossed SOD1 (wild-type SOD1(WT) and mutant SOD1(G93A)) or TDP43 (mutant TDP43(A315T)) transgenic mice with mice expressing the fluorescent protein Dendra targeted to mitochondria in neurons (mitoDendra). At different time points during the disease course, we studied mitochondrial transport in the intact sciatic nerve of living mice and analyzed axonal mitochondrial morphology at multiple sites, spanning from the spinal cord to the motor terminals. Defects of retrograde mitochondrial transport were detected at 45 days of age, before the onset of symptoms, in SOD1(G93A) and TDP43(A315T) mice, but not in SOD1(WT). At later disease stages, also anterograde mitochondrial transport was affected in both mutant mouse lines. In SOD1(G93A) mice, mitochondrial morphological abnormalities were apparent at 15 days of age, thus preceding transport abnormalities. Conversely, in TDP43(A315T) mice, morphological abnormalities appeared after the onset of transport defects. Taken together, these findings demonstrate that neuronal mitochondrial transport and morphology abnormalities occur in vivo and that they are common denominators of different genetic forms of the ALS. At the same time, differences in the temporal and spatial manifestation of mitochondrial abnormalities between the two mouse models of familial ALS imply that different molecular mechanisms may be involved. PMID- 24154544 TI - Tuning the iridescence of chiral nematic cellulose nanocrystals and mesoporous silica films by substrate variation. AB - We have discovered that the self-assembly of cellulose nanocrystals (CNCs) into chiral nematic phases varies significantly with the substrate and evaporation rate. These variables allow the reflectance peak of iridescent chiral nematic films of CNCs and mesoporous silica templated from CNCs to be tuned over a wide range of wavelengths. PMID- 24154545 TI - Letter regarding article by Ni et al.: Press-fit cementless acetabular fixation with and without screws. PMID- 24154547 TI - Impact of copper-catalyzed cross-coupling reactions in natural product synthesis: the emergence of new retrosynthetic paradigms. AB - Copper-catalyzed Ullmann-Goldberg-type cross-coupling reactions have undergone nothing short of a renaissance over the last decade and an impressive number of procedures are now available for the formation of C-N, C-O and C-S bonds with remarkable efficiencies and surgical precision. These reactions have been recently integrated into natural product synthesis, which clearly resulted in the emergence of new retrosynthetic paradigms and bond disconnections. The impact of copper-catalyzed cross-coupling reactions in natural product synthesis will be overviewed in this article with an emphasis on the evolution of strategies due to copper catalysis, mostly by comparison with alternative tactics and their relative efficiencies. PMID- 24154548 TI - Investigating the efficacy of pamidronate, a chemical inhibitor of farnesyl pyrophosphate synthase, in the inhibition of influenza virus infection in vitro and in vivo. AB - Influenza A virus has caused significant pandemics in the past decades, including the H1N1-2009 pandemic. Viperin is an interferon-inducible protein that acts as a broad-spectrum antiviral protein via the inhibition of farnesyl pyrophosphate synthase (FPPS). To mimic this activity of viperin, the present study investigated the effectiveness of a commercially available FPPS inhibitor (pamidronate) as an inhibitor of influenza virus infection in vitro and in vivo. HeLaM cells were treated with pamidronate to determine its effect on the replication of influenza virus A/H1N1/WSN/1933. C57BL/6 mice were also subjected to intratracheal pamidronate treatment regimes prior to and following lethal influenza challenge. Treatment with the FPPS inhibitor in vitro resulted in a considerable reduction in the viral titer of ~1 log and diminished lipid raft formation without cellular toxicity, thus mimicking the antiviral effect of viperin. However, pamidronate lacked efficacy in vivo and was associated with increased pulmonary damage, most likely due to the complexity of drug-host interactions in the infected mice. Further studies are warranted on pamidronate treatment in other infectious diseases that are more susceptible to FPPS inhibition. PMID- 24154546 TI - Insulin and IGFs in obesity-related breast cancer. AB - Obesity and the Metabolic Syndrome are associated with multiple factors that may cause an increased risk for cancer and cancer-related mortality. Factors involved include hyperinsulinemia, hyperglycemia, hyperlipidemia and IGFs. Insulin resistance is also associated with alterations in the levels of proinflammatory cytokines, chemokines, adipokines (leptin, adiponectin) that may also be contributing factors. The insulin family of proteins is ubiquitously expressed and has pleiotropic effects on metabolism and growth. However insulin, IGF-1 and particularly IGF-2 have been identified as tumor promoters in multiple studies. Mouse models have focused on insulin and IGF-1 and their receptors as being involved in tumor progression and metastases. The role of the insulin receptor as either mediating the effects on tumors or as compensating for the insulin-like growth factor receptor has arisen. Its role has been supported by preclinical studies and the importance of insulin resistance and hyperinsulinemia in obesity and early diabetes. Since the focus of this review is the insulin-family we will focus on insulin, IGF-1 and IGF-2. PMID- 24154549 TI - A non-interventional comparison of rivaroxaban with standard of care for thromboprophylaxis after major orthopaedic surgery in 17,701 patients with propensity score adjustment. AB - Rivaroxaban demonstrated superior efficacy and a similar safety profile to enoxaparin for the prevention of venous thromboembolism in the phase III RECORD programme in patients undergoing elective hip or knee replacement surgery. The XAMOS study investigated adverse events, including bleeding and thromboembolic events, in patients receiving rivaroxaban for thromboprophylaxis in routine clinical practice. XAMOS was a non-interventional, open-label cohort study in patients undergoing major orthopaedic surgery of the hip or knee (predominantly elective arthroplasty), in which rivaroxaban was compared with other pharmacological thromboprophylaxis. All adverse events were documented, including symptomatic thromboembolic and bleeding events. Crude and adjusted incidences based on propensity score subclasses were calculated and compared between the rivaroxaban and standard-of-care groups. A total of 17,701 patients were enrolled from 252 centres in 37 countries. Crude incidences of symptomatic thromboembolic events three months after surgery in the safety population were 0.89% in the rivaroxaban group (n=8,778) and 1.35% in the standard-of-care group (n=8,635; odds ratio [OR] 0.65; 95% confidence interval [CI] 0.49-0.87), and 0.91% and 1.31% (weighted) in the propensity score-adjusted analysis (OR 0.69; 95% CI 0.56 0.85), respectively. Treatment-emergent major bleeding events (as defined in the RECORD studies) occurred in 0.40% and 0.34% of patients in the rivaroxaban and standard-of-care groups in the safety population (OR 1.19; 95% CI 0.73-1.95), and in 0.44% versus 0.33% (weighted) in the propensity score-adjusted analysis (OR 1.35; 95% CI 0.94-1.93), respectively.This study in unselected patients confirmed the favourable benefit-risk profile of rivaroxaban seen in the RECORD programme. PMID- 24154550 TI - The doping mechanism of Cr into TiO2 and its influence on the photocatalytic performance. AB - The chromium doped titanium dioxide (Cr-TiO2) has been synthesized using a hydrothermal method. The as-prepared samples have been characterized by X-ray photoelectron spectroscopy (XPS), X-ray diffraction (XRD), transmission electron microscopy (TEM), high resolution TEM (HR-TEM), XPS valence band spectroscopy, UV vis diffuse reflectance spectroscopy (UV-vis DR), photoluminescence (PL) spectroscopy and time resolved PL (TR-PL) spectroscopy. The doping mechanism and related influence on the photocatalytic performance of TiO2 are thus proposed. The doped Cr(3+) ions can replace the Ti atoms in the lattice with oxygen vacancy compensation, distribute homogeneously in the framework of TiO2 crystals, and may make the n-type TiO2 less n-type or more p-type due to the resultant formation of oxygen vacancies, resulting in absorption of visible light, decrease of the intensity of PL emission and prolonged lifetime of photogenerated charge carriers. Compared with TiO2, the doped samples exhibit an improved visible-light photocatalytic activity. The influence of nitrogen modification has also been studied. We envision that these results would afford a better understanding of the doping mechanism of TiO2 using metal ions and, therefore, may provide a feasible way to prepare the TiO2-based photocatalysts for real applications. PMID- 24154551 TI - C-terminal region of teneurin-1 co-localizes with the dystroglycan complex in adult mouse testes and regulates testicular size and testosterone production. AB - Testicular size is directly proportional to fertility potential and is dependent on the integration of developmental proteins, trophic factors, and sex steroids. The teneurins are transmembrane glycoproteins that function as signaling and cell adhesion molecules in the establishment and maintenance of the somatic gonad, gametogenesis, and basement membrane. Moreover, teneurins are thought to function redundantly to the extracellular matrix protein, dystroglycan. Encoded on the last exon of the teneurin genes is a family of bioactive peptides termed the teneurin C-terminal-associated peptides (TCAPs). One of these peptides, TCAP-1, functionally interacts with beta-dystroglycan to act as a neuromodulatory peptide with trophic characteristics independent from the teneurins. However, little is known about the localization and relationship between the teneurin-TCAP-1 system and the dystroglycans in the gonad. In the adult mouse testis, immunoreactive TCAP-1 was localized to spermatogonia and spermatocytes and co-localized with beta-dystroglycan. However, teneurin-1 was localized to the peritubular myoid cell layer of seminiferous tubules and tubules within the epididymis, and co localized with alpha-dystroglycan and alpha-smooth muscle actin. TCAP-1-binding sites were identified in the germ cell layers and adluminal compartment of the seminiferous tubules, and epithelial cells of the epididymis. In vivo, TCAP-1 administration to adult mice for 9 days increased testicular size, seminiferous and epididymal tubule short-diameter and elevated testosterone levels. TCAP-1 treated mice also showed increased TCAP-1 immunoreactivity in the caput and corpa epididymis. Our data provide novel evidence of TCAP-1 localization in the testes that is distinct from teneurin-1, but is integrated through an association with the dystroglycan complex. PMID- 24154552 TI - Massive mediastinal teratoma mimicking a pleural effusion on computed tomography. AB - Mediastinal teratomas have been reported to mimic pleural effusions on chest radiography. Further evaluation of such tumours using computed tomography usually yields diagnostic characteristics that distinguish them from pleural collections. We report a patient with a mediastinal teratoma that mimicked a massive left pleural effusion on chest radiography and computed tomography. PMID- 24154554 TI - Recurrent extended-spectrum beta-lactamase-producing Escherichia coli urinary tract infection due to an infected intrauterine device. AB - The use of intrauterine devices (IUDs) have been widespread since the 1960s. In 2002, the World Health Organization estimated that approximately 160 million women worldwide use IUDs. However, IUDs are associated with short-term complications such as vaginal bleeding, pelvic discomfort, dyspareunia and pelvic infection. Herein, we report the case of a woman who had recurrent urinary tract infection (UTI) due to the use of an IUD, even after treatment. The patient developed four episodes of UTI within a seven-month period after IUD insertion. During each episode of UTI, extended-spectrum beta-lactamase (ESBL)-producing Escherichia coli (E. coli) was cultured from the patient's midstream urine. The IUD was finally removed, and culture of the removed IUD was positive for ESBL producing E. coli. An infected IUD as a source of recurrent UTI should be considered in women with IUD in situ who develop recurrent UTI even after treatment. PMID- 24154555 TI - An unusual case of dysphonia and dysphagia. AB - A 68-year-old man presented with a six-month history of painless dysphagia, malnutrition, anorexia and vocal hoarseness. Signs of severe mitral regurgitation and preserved left atrial dimensions were discovered on transthoracic echocardiography. However, electrocardiography and chest radiography were strongly suggestive of left atrial enlargement. Further investigations confirmed extrinsic compression of the oesophagus, which caused the dysphagia. Computed tomography of the throrax revealed a giant left atrium that was not appreciated on echocardiography. Hoarseness was found to be caused by right recurrent laryngeal nerve palsy. Ortner's syndrome, which describes the occurrence of vocal hoarseness due to a cardiopulmonary disease that results in the compression of the left recurrent laryngeal nerve, is usually associated with severe mitral stenosis. Herein, we report an unusual case of Ortner's syndrome caused by a giant left atrium, which resulted from severe mitral regurgitation, causing extrinsic oesophageal compression and right recurrent laryngeal nerve palsy. Physicians should remain cognisant of cardiovascular disorders as uncommon causes of painless dysphagia or vocal hoarseness. PMID- 24154556 TI - Unusual presentation of adult xanthogranuloma: a case report. AB - Xanthogranulomas are the most common form of non-Langerhans cell histiocytosis. Both adult and childhood forms have been described. Adult cutaneous forms can present as solitary or multiple yellowish, orange-red or tan-hued papules. Herein, we present the case of a 28-year-old Chinese man with a skin-coloured nodule on his left nasal ala that persisted for several months. While initial impression was that of a fibrous papule of the nose, the results of an excision biopsy showed histological features corresponding to xanthogranuloma. This case demonstrates the condition's myriad of dermatological presentations, and adds to the differential diagnoses of a cutaneous lesion found in the head and neck region. PMID- 24154557 TI - New organo- and amidozinc derivatives of primary amines. AB - Five new zinc derivatives of primary amines [R'ZnN(H)R]2 [R = SiPh3, R' = Me (1), N(SiMe3)2 (4); R = Si(NMe2)3, R' = Me (2), Et (3), N(SiMe3)2 (5)] have been synthesised by reaction of R'2Zn and H2NR. All five species are dimers in which the N-H groups are disposed in a trans manner about a central Zn2N2 ring. In 1 and 4 the coordination at zinc is trigonal planar, while in 2, 3, 5 the zinc is in a distorted tetrahedral environment due to additional Me2N: -> Zn coordination from one SiNMe2 group. 5 was found to be generally resistant to NH deprotonation by bases such as MN(SiMe3)2 (M = Li, K) or Zn[N(SiMe3)2]2, but reacts with Sn[N(SiMe3)2]2 to give the tin-free, tetrameric mixed zinc-imido/amido species, [{(Me3Si)2N}{(Me2N)3SiN(H)}{(Me2N)3SiN}Zn2]2 (6) which can be viewed as part of a hexameric Zn6N6 drum which has lost a Zn2N2 ring. PMID- 24154558 TI - Deterministic quasi-random nanostructures for photon control. AB - Controlling the flux of photons is crucial in many areas of science and technology. Artificial materials with nano-scale modulation of the refractive index, such as photonic crystals, are able to exercise such control and have opened exciting new possibilities for light manipulation. An interesting alternative to such periodic structures is the class of materials known as quasi crystals, which offer unique advantages such as richer Fourier spectra. Here we introduce a novel approach for designing such richer Fourier spectra, by using a periodic structure that allows us to control its Fourier components almost at will. Our approach is based on binary gratings, which makes the structures easy to replicate and to tailor towards specific applications. As an example, we show how these structures can be employed to achieve highly efficient broad-band light trapping in thin films that approach the theoretical (Lambertian) limit, a problem of crucial importance for photovoltaics. PMID- 24154559 TI - Epigenetic mechanisms linking diabetes and synaptic impairments. AB - Diabetes is one of the major risk factors for dementia. However, the molecular mechanism underlying the risk of diabetes for dementia is largely unknown. Recent studies revealed that epigenetic modifications may play a role in the pathogenesis of diabetes. We hypothesized that diabetes may cause epigenetic changes in the brain that may adversely affect synaptic function. We found significant elevation in the expression of histone deacetylases (HDACs) class IIa in the brains of diabetic subjects compared with control subjects, and these changes coincide with altered expression of synaptic proteins. In a mouse model of diet-induced type 2 diabetes (T2D), we found that, similar to humans, T2D mice also showed increased expression of HDAC IIa in the brain, and these alterations were associated with increased susceptibility to oligomeric Abeta-induced synaptic impairments in the hippocampal formation and eventually led to synaptic dysfunction. Pharmacological inhibition of HDAC IIa restored synaptic plasticity. Our study demonstrates that diabetes may induce epigenetic modifications affecting neuropathological mechanisms in the brain leading to increased susceptibility to insults associated with neurodegenerative or vascular impairments. Our study provides, for the first time, an epigenetic explanation for the increased risk of diabetic patients developing dementia. PMID- 24154561 TI - Binary switching in a 'symmetric' potential landscape. AB - A binary switch is the basic building block for information processing. The potential energy profile of a bistable binary switch is a 'symmetric' double well. The traditional method of switching it from one state (one well) to the other is to tilt the profile towards the desired state. Here, we present a case, where no such tilting is necessary to switch successfully, even in the presence of thermal noise. This happens because of the built-in dynamics inside the switch itself. It differs from the general perception on binary switching that in a 'symmetric' potential landscape, the switching probability is 50% in the presence of thermal noise. Our results, considering the complete three-dimensional potential landscape, demonstrate intriguing phenomena on binary switching mechanism. With experimentally feasible parameters, we theoretically demonstrate such intriguing possibility in electric field induced magnetization switching of a shape-anisotropic single-domain magnetostrictive nanomagnet with two stable states at room-temperature. PMID- 24154560 TI - High-load resistance exercise with superimposed vibration and vascular occlusion increases critical power, capillaries and lean mass in endurance-trained men. AB - PURPOSE: It is a widely accepted premise in the scientific community and by athletes alike, that adding resistance exercise to a regular regimen of endurance training increases endurance performance in endurance-trained men. However, critical power (CP), capillarization, and myofiber size remain unaffected by this addition. Therefore, we tested whether the superimposition of resistance exercise with whole-body vibration and vascular occlusion (vibroX) would improve these variables in endurance-trained males relative to resistance exercise alone. METHODS: Twenty-one young, endurance-trained males were randomly assigned either to a vibroX (n = 11) or resistance (n = 10) training group. Both groups trained in a progressive mode twice a week for 8 weeks. Pre and post training, histochemical muscle characteristics, thigh muscle size, endurance and strength parameters were determined. RESULTS: vibroX increased CP (P = 0.001), overall capillary-to-fiber ratio (P = 0.001) and thigh lean mass (P < 0.001), while these parameters were unaffected by resistance training. The gain in CP by vibroX was positively correlated with the gain in capillarization (R(2) = 0.605, P = 0.008), and the gain in thigh lean mass was paralleled by increases in MyHC-1 and MyHC-2 fiber cross-sectional areas and strength. Maximum voluntary torque and the finite work capacity above CP (W') increased significantly only following resistance training. CONCLUSIONS: We achieved a proof of concept by demonstrating that modification of resistance exercise by superimposing side-alternating whole-body vibration and sustained vascular occlusion induced further improvements in CP, capillarization and hypertrophy, all of which were not observed with resistance training alone. PMID- 24154562 TI - Photophysical studies and submicron ring formation of morpholino U-nucleoside monomers. AB - Synthesis, photophysical properties and submicron ring formation of functionalized uracil morpholino monomers have been reported. A series of characterization techniques indicated that the rings are formed by the inter molecular hydrogen bonding of the uracil nucleus having a trityl-protected morpholino moiety. This is the smallest nucleoside unit known to date for submicron size ring formation. PMID- 24154564 TI - Optimized multimodal nanoplatforms for targeting alpha(v)beta3 integrins. AB - Magnetic Resonance Imaging (MRI) using contrast agents is a very powerful technique for diagnosis in clinical medicine and biomedical research. The synthesis of ultrasmall superparamagnetic iron oxide (USPIO) nanoparticles targeting alphavbeta3 integrins and acting as new MRI contrast agents seems to be a promising way for cancer diagnosis. Indeed, it is well established that alphavbeta3 integrin plays a key role in tumor angiogenesis acting like a receptor for the extracellular matrix proteins like vitronectin, fibronectin through the arginine-glycine-aspartic acid (RGD) sequence. Up-regulation of alphavbeta3 has been found to be associated with a wide range of cancers, making it a broad-spectrum tumor-marker. In this study, USPIO nanocrystals were synthesized and surface passivated with caffeic acid. The large number of the carboxylic acid functions at the outer surface of the nanoplatforms was used for the covalent coupling of Rhodamine123, polyethylene glycol (PEG) and cyclic RGD. Soluble carbodiimide (EDC) and N-hydroxysuccinimide (NHS) were used to crosslink carboxylic acid with the amino group of the ligands. We examined the design of the nanoplatforms with each individual entity and then the combination of two and three of them. Several methods were used to characterize the nanoparticle surface functionalization and the magnetic properties of these contrast agents were studied using a 1.5 T clinical MRI scanner. The affinity towards integrins was evidenced by surface plasmon resonance and solid-phase receptor-binding assay. PMID- 24154566 TI - A model-based analysis of the clinical and economic impact of personalising P2Y12 receptor inhibition with platelet function testing in acute coronary syndrome patients. AB - Although some observational studies reported that the measured level of P2Y12 inhibition is predictive for thrombotic events, the clinical and economic benefit of incorporating PFT to personalize P2Y12-receptor directed antiplatelet treatment is unknown. Here, we assessed the clinical impact and cost effectiveness of selecting P2Y12-inhibitors based on platelet function testing (PFT) in acute coronary syndrome (ACS) patients undergoing PCI. A decision model was developed to analyse the health economic effects of different strategies. PFT guided treatment was compared with the three options of general clopidogrel, prasugrel or ticagrelor treatment. In the PFT arm, low responders to clopidogrel received prasugrel, while normal responders carried on with clopidogrel. The associated endpoints in the model were cardiovascular death, stent thrombosis and major bleeding. With a simulated cohort of 10,000 patients treated for one year, there were 93 less events in the PFT arm compared to general clopidogrel. In prasugrel and ticagrelor arms, 110 and 86 events were prevented compared to clopidogrel treatment, respectively. The total expected costs (including event costs, drug costs and PFT costs) for generic clopidogrel therapy were US$ 1,059/patient. In the PFT arm, total costs were US$ 1,494, while in the prasugrel and ticagrelor branches they were US$ 3,102 and US$ 3,771, respectively. The incremental-cost-effectiveness-ratio (ICER) was US$ 46,770 for PFT-guided therapy, US$ 185,783 for prasugrel and US$ 315,360 for ticagrelor. In this model based analysis, a PFT-guided therapy may have fewer adverse outcomes than general treatment with clopidogrel and may be more cost-effective than prasugrel or ticagrelor treatment in ACS patients undergoing PCI. PMID- 24154567 TI - Do longer formula feeding and later introduction of solids increase risk for pediatric acute lymphoblastic leukemia? AB - Milk formula feeding can elevate insulin-like growth factor-1 levels, possibly impacting leukemogenesis. The intent of the current study is to examine the associations between infant feeding practices and age at introduction of solids on risk of childhood acute lymphoblastic leukemia (ALL). Incident cases of infant and childhood (aged <=14 years) ALL (n = 142) were enrolled in a case-control study. Cases were frequency matched on age, sex, race, and ethnicity to two sets of controls (n = 284 total). Multivariable logistic regression was used to determine the association between infant feeding practices and age at the introduction of solids and the odds ratio of ALL. In adjusted multivariable analyses, each additional month of formula feeding was associated with a 1.17 (1.09-1.25) odds ratio; each additional month of age at introduction of solids was associated with a 1.18 (1.07-1.30) odds ratio. In this study, longer duration of formula feeding and later age at the introduction of solid foods were independently associated with increased risk of ALL. Additional studies are needed to address the factors influencing duration of formula feeding and delayed introduction of solids. The results support the potential role of energy balance in early life as a contributor to risk for pediatric acute lymphoblastic leukemia. PMID- 24154568 TI - Anhedonia and depressed mood in adolescence: course, stability, and reciprocal relation in the TRAILS study. AB - Adolescence is marked by increases in the incidence of major depression (MDD), a disorder recognized as one of the leading causes of disability. Anhedonia and depressed mood predict both onset and chronicity of major depression (MDD), but have never been studied together longitudinally in the general adolescent population. The present study examined (1) the course and the stability of anhedonia and depressed mood and (2) their cross-sectional and longitudinal relations during adolescence. The study cohort consisted of 2,230 adolescents. Anhedonia and depressed mood were assessed with items of the YSR and ASR self report forms at four measurement waves between ages 11 and 19. The proportion of adolescents reporting anhedonia decreased between ages 11 and 19, while the proportion of female adolescents reporting depressed mood increased. The stability of anhedonia and the cross-sectional association between anhedonia and depressed mood was larger at age 19 than at age 11. We found a mutual association between anhedonia and depressed mood without a clear temporal sequence. The presence of anhedonia at the end of adolescence might put adolescents at increased risk for MDD given the increasingly stronger stability and association with depressed mood. This suggests that it becomes more difficult to prevent MDD during late adolescence compared with early and middle adolescence. PMID- 24154569 TI - HL7 engine module for healthcare information systems. AB - The integration of applications is always the most important issue for a development team especially in the healthcare industry. In this paper, a Health Level 7 (HL7) engine system is proposed to solve HL7 challenges, which are associated with applying HL7 in healthcare organizations. This new HL7 engine has been implemented in a hospital as a solution for challenges we have faced. The engine shows great success overcoming known HL7 limitations. PMID- 24154570 TI - Mutations in the PTEN tumor gene and risk of endometriosis: a case-control study. AB - STUDY QUESTION: Are mutations in the phosphatase and tensin homolog deleted on chromosome 10 (PTEN) gene associated with endometriosis? SUMMARY ANSWER: Loss of heterozygosity (LOH) at the 10q23.3 locus, PTEN somatic mutations and changes in the levels and distribution of proteins in the PTEN-PI3K/Akt signal transduction pathway are associated with endometriosis. WHAT IS KNOWN ALREADY: Endometriosis has a strong genetic basis. Recent genome-wide association and linkage studies have reported a significant association of endometriosis with 7p15.2, 9p21 and 10q23-26 loci. PTEN, which maps to 10q23.3, acts as a tumor suppressor gene through the action of its phosphatase protein product, phosphatase and tensin homolog (PTEN). This phosphatase is involved in the regulation of the cell cycle, and mutations of PTEN are a step in the development of many cancers. STUDY DESIGN, SIZE, DURATION: A total of 1252 subjects of Indian origin (endometriosis patients = 752; controls = 500) were recruited to participate in this case control study. Recruitment took place from 2001 to 2009 at Institute of Reproductive Medicine (IRM), Kolkata, India; Infertility Institute and Research Centre (IIRC), Secundrabad, India and Vasavi Medical and Research Centre, Hyderabad, India. PARTICIPANTS/MATERIALS, SETTING, METHODS: LOH on 10q, 9p and 7p was analyzed in analogous ectopic-eutopic endometria along with blood samples from 32 advanced stage endometriosis patients by PCR-GeneScan analysis. Genotyping of PTEN was carried out on genomic DNA of analogous ectopic-eutopic endometria (n = 32) as well as blood samples from 720 patients and 500 controls by PCR-sequencing analysis to explore somatic and germ-line mutations, respectively. The levels and distribution of PTEN, p-Akt, p-Bad and p27 were analyzed in the eutopic endometria of patients (n = 5) and controls (n = 5) using western-blot and immunohistochemistry. MAIN RESULTS AND THE ROLE OF CHANCE: PCR GeneScan analysis revealed a higher LOH frequency at 10q23.3 (84.4%) compared with other loci analyzed, hence we focused our attention on PTEN. PCR-sequencing analysis revealed seven novel somatic mutations and 23 germ-line polymorphisms in patients. Among somatic mutations, a frame-shift insertion at 10:89692992 89692993 (in the functionally important N-terminal phosphatase domain of PTEN) occurred in 11 of the 32 ectopic endometria. Western-blot and immunohistochemical analysis revealed decreased PTEN and increased p-Akt and p-Bad levels in eutopic endometria of patients compared with controls (all comparisons, P < 0.0001). Furthermore, PTEN loss was more frequent in the nucleus than in the cytoplasm. Expression of p27 did not differ between patients and controls. LIMITATIONS, REASONS FOR CAUTION: Protein analysis was performed in eutopic endometrial samples from only a small number of patients and controls. In future investigations, a larger sample size should be used and the role of the other genes involved in the PTEN-PI3K/Akt signal transduction pathway should be analyzed. WIDER IMPLICATIONS OF THE FINDINGS: Our findings revealed a possible involvement of the PTEN-PI3K/Akt-Bad axis in the pathogenesis of endometriosis, which may facilitate the discovery of suitable pathway inhibitors for disease treatment. STUDY FUNDING/COMPETING INTEREST(S): This study was supported by grants from the Science & Engineering Research Board (SERB), India (Lr No: SR/FT/LS-188/2009) to BM. The authors have no competing interests to declare. PMID- 24154571 TI - Relaxation dynamics of photoexcited resorcinol: internal conversion versus H atom tunnelling. AB - The excited state dynamics of resorcinol (1,3-dihydroxybenzene) following UV excitation at a range of pump wavelengths, 278 >= lambda >= 255 nm, have been investigated using a combination of time-resolved velocity map ion imaging and ultrafast time-resolved ion yield measurements coupled with complementary ab initio calculations. After excitation to the 1(1)pipi* state we extract a timescale, tau1, for excited state relaxation that decreases as a function of excitation energy from 2.70 ns to ~120 ps. This is assigned to competing relaxation mechanisms. Tunnelling beneath the 1(1)pipi*/(1)pisigma* conical intersection, followed by coupling onto the dissociative (1)pisigma* state, yields H atoms born with high kinetic energy (~5000 cm(-1)). This mechanism is in competition with an internal conversion process that is able to transfer population from the photoexcited 1(1)pipi* state back to a vibrationally excited ground state, S0*. When exciting between 264-260 nm a second decay component, tau2, is observed and we put forth several possible explanations as to the origins of tau2, including conformer specific dynamics. Excitation with 237 nm light (above the 1(1)pipi*/(1)pisigma* conical intersection) yields high kinetic energy H atoms (~11,000 cm(-1)) produced in ~260 fs, in line with a mechanism involving ultrafast coupling between the 1(1)pipi* (or 2(1)pipi*) and (1)pisigma* state followed by dissociation. The results presented highlight the profound effect the presence of additional functional groups, and more specifically the precise location of the functional groups, can have on the excited state dynamics of model heteroaromatic systems following UV excitation. PMID- 24154572 TI - Demarcation of the ethics of care as a discipline: discussion article. AB - This article aims to initiate a discussion on the demarcation of the ethics of care. This discussion is necessary because the ethics of care evolves by making use of insights from varying disciplines. As this involves the risk of contamination of the care ethical discipline, the challenge for care ethical scholars is to ensure to retain a distinct care ethical perspective. This may be supported by an open and critical debate on the criteria and boundaries of the ethics of care. As a contribution, this article proposes a tentative outline of the care ethical discipline. What is characteristic of this outline is the emphasis on relational programming, situation-specific and context-bound judgments, a political-ethical perspective, and empirical groundedness. It is argued that the ethics of care is best developed further by means of an intradisciplinary approach. Two intradisciplinary examples show how within the frame of one discipline, other disciplines are absorbed, both with their body of knowledge and their research methodology. PMID- 24154573 TI - Adrenomedullin and adrenotensin increase the transcription of regulator of G protein signaling 2 in vascular smooth muscle cells via the cAMP-dependent and PKC pathways. AB - The regulator of G-protein signaling 2 (RGS2) has been shown to be crucial in the regulation of vascular tone and blood pressure. The vascular activities of adrenomedullin (ADM) and adrenotension (ADT), two natural peptides, are dependent upon the modulation of RGS2 expression. However, the effects and pathways involved in their modulation remain unknown. This study aimed to observe the changes of RGS2 expression in response to ADM and ADT in cultured vascular smooth muscle cells and to clarify the potential signaling pathways in vitro. In the present study, vascular smooth muscle cells (VSMCs) were cultured with ADM and ADT of various concentrations for different time periods, and the gene expression of RGS2 was analyzed by PCR. ADM significantly increased the gene expression at 0.5 h to ~35-fold of that at baseline, whereas ADT marginally increased the expression after 1-2 h. SQ22,536 and chelerythrine were used to block the protein kinase A (PKA) and PKC pathways activated by incubation with ADM. The gene expression of RGS2 was reduced by SQ22,536 only. Furthermore, when SQ22,536 and chelerythrine were added to the cells incubated with ADT, the gene expression was markedly reduced by both SQ22,536 and chelerythrine. In conclusion, ADM immediately showed a marked increase in the gene expression of RGS2 in cultured VSMCs via a cAMP-dependent pathway and ADT gradually showed a marginal increase in the gene expression via a cAMP-dependent pathway and a PKC pathway. PMID- 24154574 TI - State of the art of robotic thymectomy. AB - BACKGROUND: Thymectomy is a widely accepted treatment for most cases of myasthenia gravis and essential for the treatment of thymoma. The development of a minimally invasive procedure for thymectomy resulted in a variety of approaches for surgery on the thymic gland. The use of thoracoscopy-based techniques has continued to increase, including the latest advance in this field, robotic thymectomy. METHODS: We review the rapid development and actual use of this approach by examining published reports, worldwide registries, and personal communications and by analyzing our database, which is the largest single-center experience and contains 317 thymectomies until 12/2012. The technical modifications of robotic thymectomy are also described. RESULTS: Since 2001, approximately 3,500 robotic thymectomies have been registered worldwide. Meanwhile, the results of approximately 500 thymectomy cases have been published. Robotic thymectomy is performed most frequently through a standardized unilateral three-trocar approach. All reports describe promising and satisfactory results for myasthenia gravis. For early-stage thymoma, robotic thymectomy is a technically sound and safe procedure with a very low complication rate and short hospital stay. Oncological outcome without recurrences is promising, but a longer follow-up is needed. CONCLUSION: The unilateral robotic technique can be considered an adequate approach for thymectomy, even with demanding anatomical configurations. Robotic thymectomy has spread worldwide over the last decade because of the promising results in myasthenia gravis and thymoma patients. PMID- 24154575 TI - Re-validating the Observational Teamwork Assessment for Surgery tool (OTAS-D): cultural adaptation, refinement, and psychometric evaluation. AB - BACKGROUND: The nontechnical and team skills of surgical teams are critical for safety and efficiency in the operating room. Assessment of nontechnical and team skills can facilitate improvement by encouraging both self-reflection and team reflection, identifying training needs, and informing operating room (OR) team training approaches. The observational teamwork assessment for surgery (OTAS) tool is a well-validated and robust tool for capturing teamwork in the operating room. The aims of the present study were to systematically adapt and refine the OTAS for German-speaking OR staff and to test the adapted assessment tool (OTAS D) for psychometric properties and metric equivalence. METHODS: The study was carried out in three stages: at stage 1, OTAS was translated into German. At stage 2, experienced German OR experts (surgeons, OR nurses, anesthetists) were interviewed. At stage 3, two blinded assessors observed 11 general surgical operations (general surgical and vascular procedures) and interrater reliability was tested for refined OTAS-D behavioral exemplars and scorings. RESULTS: The German OR experts confirmed the applicability and content validity of the vast majority of translated behavioral exemplars. After their evaluation, 32 items were changed slightly, six were changed substantially, and one item was added. During observations, perfect and substantial interobserver agreement was found for 77 behavioral exemplars (67.1 % of the items, kappa coefficient >0.60). Rating at all OTAS behaviors showed acceptable levels of reliability (intraclass correlation coefficients >0.72). CONCLUSIONS: The OTAS-D is a tool for valid and reliable assessment of nontechnical skills that contribute to safe and effective surgical performance in ORs staffed by German-speaking professionals. Furthermore, our study serves as an example for systematically adapting and customizing well-established observational tools across different healthcare environments. PMID- 24154576 TI - PILL series. Management of child abuse. AB - Children deserve a childhood free from abuse, where their basic physical, intellectual, emotional and social needs are met. Child abuse is defined as any act of omission or commission by a parent or guardian that would endanger or impair the child's physical or emotional well-being, or that is judged by a mixture of community values and professionals to be inappropriate. A total of 247 cases of suspected child abuse in Singapore was investigated in 2012. Physical abuse, sexual abuse, and physical neglect or emotional abuse accounted for 60%, 30% and 10% of these cases, respectively. Primary care providers play an important role in the early detection and referral of child abuse cases, which enable timely intervention to ensure the well-being of the child and prevent further abuse. Hospitals and other medical centres form the largest source of referrals of suspected child abuse. PMID- 24154577 TI - Advances in rehabilitation medicine. AB - Rehabilitation medicine is the medical specialty that integrates rehabilitation as its core therapeutic modality in disability management. More than a billion people worldwide are disabled, and the World Health Organization has developed the International Classification of Functioning, Disability and Health as a framework through which disability is addressed. Herein, we explore paradigm shifts in neurorehabilitation, with a focus on restoration, and provide overviews on developments in neuropharmacology, rehabilitation robotics, virtual reality, constraint-induced therapy and brain stimulation. We also discuss important issues in rehabilitation systems of care, including integrated care pathways, very early rehabilitation, early supported discharge and telerehabilitation. Finally, we highlight major new fields of rehabilitation such as spasticity management, frailty and geriatric rehabilitation, intensive care and cancer rehabilitation. PMID- 24154578 TI - The evolution of sports medicine in Singapore. AB - Sports medicine is a relatively new subspecialty in Singapore. This commentary chronicles its evolution in Singapore from 1969, through various milestones, to the present day. The first sports medicine clinic in Singapore was established in 1971 at Farrer Park. Notable institutions that followed include the Sports Medicine and Research Centre (1973), Soldier Performance Centre, Changi Sports Medicine Centre (2003), Singapore Sports Medicine Centre (2006), and other multidisciplinary centres of restructured hospitals. Formal groundwork to establish sports medicine as a subspecialty began in 2005, with its first trainee commencing traineeship at the Changi Sports Medicine Centre in 2007, and culminated in the subspecialty register at the beginning of 2011. Also captured in this discussion are the broader scopes of sports medicine, including military sports medicine, the sports sciences, exercise medicine, and event medical coverage. PMID- 24154579 TI - Arthroscopic Bankart repair augmented by plication of the inferior glenohumeral ligament via horizontal mattress suturing for traumatic shoulder instability. AB - INTRODUCTION: This study aimed to evaluate the two-year clinical outcomes of arthroscopic Bankart repair augmented by plication of the inferior glenohumeral ligament (IGHL) via horizontal mattress suturing. METHODS: This study was a retrospective analysis of 76 arthroscopic Bankart repairs by a single surgeon from 2004 to 2008. Bioabsorbable suture anchors were used, with anchors placed at the 5:30, 4 and 3 o'clock positions of the right shoulder (correspondingly at the 6:30, 8 and 9 o'clock positions for the left shoulder). The lower most anchor was tied via horizontal mattress suture with plication of the IGHL, while the remaining two anchors were tied using simple sutures. The patients were postoperatively assessed, clinically and using the University of California Los Angeles (UCLA) shoulder rating scale. RESULTS: The mean age of the patients at the time of presentation was 24.09 +/- 7.98 years, and the mean duration of follow-up was 28.7 months. The postoperative recurrence rate of dislocation was 7.89% (six shoulders), of which five shoulders required revision surgeries. Excluding the revision cases, clinical assessment of the strength of the supraspinatus and the range of motion of the operated shoulders at two years post operation were either maintained or full in all patients. Analysis of the UCLA results showed pre- and postoperative mean scores of 25.94 +/- 3.43 and 33.77 +/- 3.07, respectively (p < 0.05). CONCLUSION: Arthroscopic Bankart repair augmented by plication of the IGHL and anchored via horizontal mattress suturing is a safe and reliable treatment for shoulder instability, with good clinical outcomes and low recurrence rates. PMID- 24154580 TI - A Singapore perspective on the use of a short course of chemothromboprophylaxis in patients who underwent total knee arthroplasty. AB - INTRODUCTION: There is considerable controversy regarding the best method to prevent venous thromboembolism. In 2008, the American College of Chest Physicians (ACCP) published specific guidelines recommending the use of ow-molecular-weight heparin or warfarin, and a target international normalised ratio of 2.0-3.0 for a duration of at least 7-10 days, after elective knee arthroplasties. Many orthopaedic surgeons believe that these recommendations are biased toward reducing deep venous thrombosis (DVT), but neglect the implicated possibility of a higher incidence of wound complications. In order to enable an objective evaluation of the fit of the ACCP recommendations to the needs of our local cohort of patients, we aimed to look at the incidence of DVT in our local population. METHODS: This study was a prospective observational study involving existing local patients in Singapore General Hospital, Singapore, who underwent total knee arthroplasty (TKA) and were on a short course of chemothromboprophylaxis (< 7 days) after the operation. The incidence of DVT in patients was evaluated using DVT imaging 4-6 days after the operation and at one month after the operation. RESULTS: In our study cohort, the prevalence of DVT during the period between postoperative Days 4 and 6 was 12% (11% were distal DVT and 1% was proximal DVT). Only 9% of the patients had DVT one month after the operation. Using chi-square analysis, we found that there was no significant increase in the number of DVT and pulmonary embolism cases 4-6 days and 1 month after the operation (p > 0.05). CONCLUSION: Contrary to the ACCP guidelines, a short course of chemothromboprophylaxis post TKA, lasting no more than 7 days, is safe and adequate in the low-risk Asian population. PMID- 24154581 TI - Level and predictors of participation in patients with stroke undergoing inpatient rehabilitation. AB - INTRODUCTION: The level of participation is an important factor influencing rehabilitation outcome. However, few studies have evaluated rehabilitation participation and its clinical predictors in patients with stroke. This study aimed to establish the level of participation in patients with stroke undergoing inpatient rehabilitation, and define the clinical predictors for participation. METHODS: This was a prospective observational study of first-time patients with stroke admitted to a rehabilitation centre over a 12-month period. The primary outcome measure was the level of rehabilitation participation as measured on the Pittsburgh Rehabilitation Participation Scale (PRPS). PRPS measurements were made one week after admission and one week before planned discharge from inpatient rehabilitation. Other outcome measures evaluated were the National Institute of Health Stroke Scale, Functional Independence Measure (FIM), Elderly Cognitive Assessment Questionnaire (ECAQ), Centre for Epidemiologic Studies-Depression Scale, Fatigue Severity Scale (FSS), Lubben Social Network Scale-Revised, and Multidimensional Health Questionnaire. RESULTS: A total of 122 patients with stroke were studied. The mean PRPS score on admission was relatively high at 4.30 +/- 0.90, and this improved to 4.65 +/- 0.79 before planned discharge (p < 0.001). On multivariate analysis, the mean PRPS score on admission was predicted by FIM, EACQ and FSS scores on admission, but not by variables such as age, gender, depression, social support, or health attitudes and beliefs. CONCLUSION: Patients with lower levels of participation were more likely to be functionally dependent, cognitively impaired and have more fatigue. We suggest that in addition to cognition, fatigue should be routinely screened in patients with stroke undergoing rehabilitation. PMID- 24154582 TI - Factors affecting falls in community-dwelling individuals with stroke in Singapore after hospital discharge. AB - INTRODUCTION: This study aimed to investigate the factors affecting the incidence of falls among individuals with stroke living in the community one year after discharge from a rehabilitation hospital in Singapore. METHODS: A cross-sectional telephone survey of individuals with stroke living in the community was carried out one year after discharge. The interview covered aspects such as incidence and circumstances of fall, use of walking aids, and presence of environmental obstacles. Each participant's case record was retrospectively reviewed using discharge Fugl-Meyer (FM) assessment of the upper and lower limbs, functional independence measure (FIM) and Berg Balance Scale (BBS). RESULTS: A total of 126 individuals with stroke were interviewed. Overall, 24% fell in the year following their discharge. Factors associated with falls were longer length of hospital stay, lower BBS and lower-limb FM scores, and lower discharge FIM scores for the Bladder and Bowel Management, Transfer, Mobility, Communication, and Social Cognition domains (p < 0.05). The fallers were more likely to use walking aids, and required help with basic activities of daily living after discharge (p < 0.05). Multivariate logistic regression analysis revealed that only the Transfer domain was an independent factor for falls. CONCLUSION: Discharge FIM outcomes, especially for the Transfer domain, can be used to identify communitydwelling individuals with stroke who have a high fall risk after discharge. Identification of such individuals will enable early fall prevention management, which will in turn minimise fall events in the community. PMID- 24154583 TI - Cross-validation of a non-exercise measure for cardiorespiratory fitness in Singaporean adults. AB - INTRODUCTION: Cardiorespiratory fitness (CRF) is an independent predictor of voluminous health outcomes and can be measured using non-exercise fitness assessment (NEFA) equations. However, the accuracy of such equations in Asian populations is unknown. The objective of this study was to cross-validate the NEFA equation, developed by Jurca et al in 2005, in the adult Singaporean population. METHODS: A total of 100 participants (57 men, 43 women; aged 18-65 years) were recruited, and their maximal oxygen consumption (VO2 max) was measured in the laboratory by indirect calorimetry. The participants also completed the NEFA questionnaire, which helps to predict VO2 max with the NEFA equation. The relationship between NEFA-predicted and laboratory-measured VO2 max values was analysed. RESULTS: Overall, our study demonstrated a high correlation between the NEFA-predicted and laboratory-measured VO2 max values (r = 0.83). The Pearson's correlation coefficient values for the men and women in the study were 0.61 and 0.77, respectively. To improve the accuracy of the predictive equation, we transformed the original equation developed by Jurca et al into new equations that would allow estimation of VO2 max with and without resting heart rate as a variable. CONCLUSION: The modified NEFA equations accurately estimated CRF and may be applied to the majority of adult Singaporeans. With this, health practitioners and researchers are now able to assess CRF levels at both the individual and population levels in either the primary care, fitness or research setting. PMID- 24154584 TI - Barriers to participation in physical activity and exercise among middle-aged and elderly individuals. AB - INTRODUCTION Although the benefits of physical activity and exercise are widely acknowledged, many middle-aged and elderly individuals remain sedentary. This cross-sectional study aimed to identify the external and internal barriers to physical activity and exercise participation among middle-aged and elderly individuals, as well as identify any differences in these barriers between the two groups. METHODS Recruited individuals were categorised into either the middle aged (age 45-59 years, n = 60) or elderly (age >= 60 years, n = 60) group. Data on demographics, anthropometry, as well as external and internal barriers to participation in physical activity and exercise were collected. RESULTS Analysis showed no significant differences in the total scores of all internal barriers between the two groups (p > 0.05). The total scores for most external barriers between the two groups also showed no significant differences (p > 0.05); only 'cost' (p = 0.045) and 'exercise interferes with social/family activities' (p = 0.011) showed significant differences. The most common external barriers among the middle-aged and elderly respondents were 'not enough time' (46.7% vs. 48.4%), 'no one to exercise with' (40.0% vs. 28.3%) and 'lack of facilities' (33.4% vs. 35.0%). The most common internal barriers for middle-aged respondents were 'too tired' (48.3%), 'already active enough' (38.3%), 'do not know how to do it' (36.7%) and 'too lazy' (36.7%), while those for elderly respondents were 'too tired' (51.7%), 'lack of motivation' (38.4%) and 'already active enough' (38.4%). CONCLUSION Middle-aged and elderly respondents presented with similar external and internal barriers to physical activity and exercise participation. These factors should be taken into account when healthcare policies are being designed and when interventions such as the provision of facilities to promote physical activity and exercise among older people are being considered. PMID- 24154585 TI - Pattern of muscle injuries and predictors of return-to-play duration among Malaysian athletes. AB - INTRODUCTION: The purpose of this study was to investigate the pattern of muscle injuries and the factors that predict the return-to-play duration among Malaysian athletes. METHODS: This is a retrospective review of the case notes of athletes who attended the National Sports Institute Clinic in Malaysia. The medical records of athletes with muscle injury, diagnosed on clinical assessment and confirmed by diagnostic ultrasonography, were included for final analysis. RESULTS: From June 2006 to December 2009, 397 cases of muscle injury were diagnosed among 360 athletes. The median age of the athletes with muscle injuries was 20.0 years. Muscle injuries were mostly diagnosed among national-level athletes and frequently involved the lower limb, specifically the hamstring muscle group. Nearly all of the athletes (99.2%) were treated conservatively. The median return-to-play duration was 7.4 weeks. Athletes who waited more than one week before seeking medical attention, those with recurrent muscle injuries and female athletes were significantly more likely (p < 0.05) to take more than six weeks before returning to the sport. CONCLUSION: Grade 2 lower limb muscle injury was commonly diagnosed among national-level athletes in this study. The frequency of weekly physiotherapy sessions did not affect the return-to-play duration. Factors such as initial consultation at more than one week post injury, recurrent muscle injuries and female gender were significant predictors of return-to-play duration among Malaysian athletes. These predictive factors should be kept in mind during clinical assessment so as to aid in prognosticating recovery after muscle injury. PMID- 24154586 TI - Causes and assessment of subacute and chronic wrist pain. AB - Wrist pain is a common presentation to the general practitioner and emergency department. Most cases are simple to treat, and pain frequently resolves with conservative treatment. However, there are certain conditions, such as scaphoid nonunion and Kienbock's disease, where delayed diagnosis and treatment can result in long-term deformity or disability. This article covers the various causes of wrist pain, recommendations on how wrist pain should be assessed, as well as details some of the common conditions that warrant specialist referral. PMID- 24154587 TI - Pulmonary embolism as a cause of unexplained sinus tachycardia after right ventricular myocardial infarction. AB - We present the case of a patient who developed new-onset asymptomatic sinus tachycardia after undergoing treatment for a right ventricular myocardial infarction. Even after excluding heart failure, infection and bleeding, the sinus tachycardia persisted. Computed tomography pulmonary angiography showed multiple bilateral pulmonary emboli. The vital sign abnormality resolved after treatment with an anticoagulant. We postulate that the pulmonary emboli originated from thrombi that were formed in the infarcted and dysfunctional right ventricle. Pulmonary embolism is a very rare complication of right ventricular myocardial infarction, and patients usually present with pleuritic chest pain. Our case highlights that asymptomatic sinus tachycardia could be a presenting feature of pulmonary embolism after the occurrence of a right ventricular myocardial infarction. A high index of suspicion is warranted in order to detect this potentially lethal complication. PMID- 24154588 TI - Abdominal neuroblastoma in a child with inferior vena cava anomaly. AB - Congenital anomalies of the inferior vena cava are rare. Such anomalies pose great challenges to the surgeon in neuroblastoma surgery, especially when unrecognised preoperatively. We report the first case of an abdominal neuroblastoma detected in a child with a developmental anomaly of the left-sided inferior vena cava. The patient underwent surgical resection after good response to preoperative chemotherapy. PMID- 24154589 TI - Radical abdominal trachelectomy for stage IB1 cervical cancer in Singapore. AB - We report the first case of radical abdominal trachelectomy (RAT) and bilateral pelvic lymphadenectomy performed in Singapore, which was performed for a 35-year old woman with stage IB1 cervical cancer, and review the current literature on this novel fertility-sparing surgery. Radical hysterectomy and pelvic lymphadenectomy are the conventional treatment for stage IB1 cervical cancer, but this results in the loss of fertility. However, the last 20 years have seen the development of fertility-sparing surgeries for young women with early-stage cervical cancer. Among these, laparoscopy-assisted radical vaginal trachelectomy (i.e. Dargent's procedure) is the most established technique, with good, documented long-term oncological and pregnancy outcomes. RAT, an alternative technique, was developed in the last decade. Although less than 200 reported cases worldwide have reported on the use of RAT, early data suggests good oncological outcome. PMID- 24154590 TI - Laryngeal histoplasmosis: an occupational hazard. AB - Isolated laryngeal histoplasmosis is a very rare entity. It has variable clinical presentations that might mimic both benign and malignant lesions, and is usually associated with pulmonary and other disseminated forms of histoplasmosis. Herein, we report a case of primary laryngeal histoplasmosis without the involvement of other systems in a 70-year-old Chinese man, who previously worked as a miner. He presented with a history of hoarseness for two months, with no other associated symptoms. Direct laryngoscopy revealed irregularity of the posterior one-third of both vocal folds. Histopathological examination revealed the presence of Histoplasma capsulatumon periodic acidSchiff and Grocott's methenamine silver staining. The lesion resolved after one month of oral itraconazole treatment. However, the patient had to complete six months of antifungal treatment to prevent recurrence. PMID- 24154591 TI - Painful pretibial pseudocyst at bioabsorbable interference screw aperture two years after anterior cruciate ligament reconstruction. AB - We report the case of a patient with a painful subcutaneous nodule, measuring 13 mm * 17 mm, at the pretibial graft aperture site, which presented two years after a successful anterior cruciate ligament reconstruction with an autologous hamstring graft. A bioabsorbable poly-L-lactide interference screw was used for graft fixation at the tibial aperture. The patient underwent surgical excision of the lesion and curettage at the tunnel aperture. Grossly, extruded fragments of the screw and a thick pseudocapsule of surrounding tissue were excised. There was no communication between the tunnel aperture and the knee joint. The graft was also intact. Histological analysis revealed fragments of the bioabsorbable material in association with fibrous and granulomatous chronic inflammatory cells. This was consistent with a foreign body reaction. The patient subsequently recovered and resumed preinjury level of activity. To the best of our knowledge, this is the first report describing a nodular granulomatous type reaction to foreign bioabsorbable poly-L-lactide screw material subsequent to an anterior cruciate reconstruction surgery. PMID- 24154592 TI - Cryoablation and cementoplasty of a pathologic fracture in the sternum. AB - A 49-year-old man with metastatic melanoma and pathologic fracture of the sternum was deemed to be a poor candidate for general anaesthesia. He suffered severe pain and range of motion limitation that did not respond to narcotic therapy. Ultimately, the lesion was managed with computed tomography-guided cryoablation and subsequent cementoplasty, and saw good initial clinical results. PMID- 24154593 TI - Cellular network entropy as the energy potential in Waddington's differentiation landscape. AB - Differentiation is a key cellular process in normal tissue development that is significantly altered in cancer. Although molecular signatures characterising pluripotency and multipotency exist, there is, as yet, no single quantitative mark of a cellular sample's position in the global differentiation hierarchy. Here we adopt a systems view and consider the sample's network entropy, a measure of signaling pathway promiscuity, computable from a sample's genome-wide expression profile. We demonstrate that network entropy provides a quantitative, in-silico, readout of the average undifferentiated state of the profiled cells, recapitulating the known hierarchy of pluripotent, multipotent and differentiated cell types. Network entropy further exhibits dynamic changes in time course differentiation data, and in line with a sample's differentiation stage. In disease, network entropy predicts a higher level of cellular plasticity in cancer stem cell populations compared to ordinary cancer cells. Importantly, network entropy also allows identification of key differentiation pathways. Our results are consistent with the view that pluripotency is a statistical property defined at the cellular population level, correlating with intra-sample heterogeneity, and driven by the degree of signaling promiscuity in cells. In summary, network entropy provides a quantitative measure of a cell's undifferentiated state, defining its elevation in Waddington's landscape. PMID- 24154595 TI - Tailoring the chirality of magnetic domain walls by interface engineering. AB - Contacting ferromagnetic films with normal metals changes how magnetic textures respond to electric currents, enabling surprisingly fast domain wall motions and spin texture-dependent propagation direction. These effects are attributed to domain wall chirality induced by the Dzyaloshinskii-Moriya interaction at interfaces, which suggests rich possibilities to influence domain wall dynamics if the Dzyaloshinskii-Moriya interaction can be adjusted. Chiral magnetism was seen in several film structures on appropriately chosen substrates where interfacial spin-orbit-coupling effects are strong. Here we use real-space imaging to visualize chiral domain walls in cobalt/nickel multilayers in contact with platinum and iridium. We show that the Dzyaloshinskii-Moriya interaction can be adjusted to stabilize either left-handed or right-handed Neel walls, or non chiral Bloch walls by adjusting an interfacial spacer layer between the multilayers and the substrate. Our findings introduce domain wall chirality as a new degree of freedom, which may open up new opportunities for spintronics device designs. PMID- 24154594 TI - Application of recombinant Cryptosporidium parvum P23 for isolation and prevention. AB - Cryptosporidium parvum is a coccidian protozoan that causes diarrhea in immunocompromised humans and newborn animals. Billions of oocysts of C. parvum can be released from the infected calves and can contaminate the environment. The severity of the disease depends on the immunological status of the individual. Oocysts of Cryptosporidium are extremely resistant to many environmental stresses, and no effective disinfectant and curative agent against this organism is available. In our study, recombinant C. parvum P23 was prepared for application in the isolation and prevention of cryptosporidiosis. P23 is a glycoprotein that belongs to a family of protein of 23-27 kDa and is believed to be expressed in the different life stages of the parasite. Immunostaining analysis using the indirect fluorescent antibody test showed that P23 could be recognized on the surface of the oocysts. The antibody prepared in rabbit against P23 was bound to Sepharose 4B and used for the isolation of oocysts. The results showed that the prepared column was able to bind specifically only the oocysts. The effect of specific recombinant C. parvum IgY antibody against infection with C. parvum was examined in a mouse model. For this aim, purified egg yolk antibody prepared from immunized hens was used to analyze the protective effect of recombinant P23 specific antibody in immunosuppressed adult mice. The results showed more than 70% reduction in oocyst shedding after challenge with 1 * 10(4) oocysts. These results support previous studies of other investigators regarding the protective effect of P23 as an antigen against C. parvum infection and showed that it could be possible to design a passive immunization strategy against C. parvum based on the anti-P23 yolk antibody in animals and immunosuppressed humans. PMID- 24154596 TI - "tissue factor expressed by microparticles is associated with mortality but not with thrombosis in cancer patients." reply to a comment by Geddings and Mackman. PMID- 24154598 TI - A new hope for precision medicine. AB - The SS1P immunotoxin is combined with immunomodulatory therapy in order to improve its efficacy in human mesothelioma (Hassan et al., this issue). PMID- 24154600 TI - Deep brain stimulation of the midbrain locomotor region improves paretic hindlimb function after spinal cord injury in rats. AB - In severe spinal cord injuries, the tracts conveying motor commands to the spinal cord are disrupted, resulting in paralysis, but many patients still have small numbers of spared fibers. We have found that excitatory deep brain stimulation (DBS) of the mesencephalic locomotor region (MLR), an important control center for locomotion in the brain, markedly improved hindlimb function in rats with chronic, severe, but incomplete spinal cord injury. The medial medullary reticular formation was essential for this effect. Functional deficits of rats with 20 to 30% spared reticulospinal fibers were comparable to patients able to walk but with strong deficits in strength and speed [for example, individuals with American Spinal Injury Association Impairment Scale (AIS)-D scores]. MLR DBS enabled close to normal locomotion in these rats. In more extensively injured animals, with less than 10% spared reticulospinal fibers, hindlimbs were almost fully paralyzed, comparable to wheelchair-bound patients (for example, AIS-A, B, and C). With MLR DBS, hindlimb function reappeared under gravity-released conditions during swimming. We propose that therapeutic MLR DBS using the brain's own motor command circuits may offer a potential new approach to treat persistent gait disturbances in patients suffering from chronic incomplete spinal cord injury. PMID- 24154599 TI - Genetic and environmental determinants of human NK cell diversity revealed by mass cytometry. AB - Natural killer (NK) cells play critical roles in immune defense and reproduction, yet remain the most poorly understood major lymphocyte population. Because their activation is controlled by a variety of combinatorially expressed activating and inhibitory receptors, NK cell diversity and function are closely linked. To provide an unprecedented understanding of NK cell repertoire diversity, we used mass cytometry to simultaneously analyze 37 parameters, including 28 NK cell receptors, on peripheral blood NK cells from 5 sets of monozygotic twins and 12 unrelated donors of defined human leukocyte antigen (HLA) and killer cell immunoglobulin-like receptor (KIR) genotype. This analysis revealed a remarkable degree of NK cell diversity, with an estimated 6000 to 30,000 phenotypic populations within an individual and >100,000 phenotypes in the donor panel. Genetics largely determined inhibitory receptor expression, whereas activation receptor expression was heavily environmentally influenced. Therefore, NK cells may maintain self-tolerance through strictly regulated expression of inhibitory receptors while using adaptable expression patterns of activating and costimulatory receptors to respond to pathogens and tumors. These findings further suggest the possibility that discrete NK cell subpopulations could be harnessed for immunotherapeutic strategies in the settings of infection, reproduction, and transplantation. PMID- 24154601 TI - Major cancer regressions in mesothelioma after treatment with an anti-mesothelin immunotoxin and immune suppression. AB - Immunotoxins are potent anticancer agents with an unusual mechanism of action: inhibition of protein synthesis resulting in apoptotic cell death. Immunotoxins have produced many durable complete responses in refractory hairy cell leukemia, where patients rarely form antibodies to the bacterial toxin component of the immunotoxin. Patients with mesothelioma, however, have normal immune systems and form antibodies after one cycle, and tumor responses to the immunotoxin have not been observed in this disease. We describe the results of a trial in which major antitumor responses were seen in patients with advanced mesothelioma who received the anti-mesothelin immunotoxin SS1P, together with pentostatin and cyclophosphamide, to deplete T and B cells. Of 10 patients with chemotherapy refractory mesothelioma, 3 have had major tumor regressions with 2 ongoing at 15 months, and 2 others responded to chemotherapy after discontinuing immunotoxin therapy. Antibody formation was markedly delayed, allowing more SS1P cycles to be given, but this alone does not appear to account for the marked antitumor activity observed. PMID- 24154602 TI - Slow-wave activity saturation and thalamocortical isolation during propofol anesthesia in humans. AB - The altered state of consciousness produced by general anesthetics is associated with a variety of changes in the brain's electrical activity. Under hyperpolarizing influences such as anesthetic drugs, cortical neurons oscillate at ~1 Hz, which is measurable as slow waves in the electroencephalogram (EEG). We have administered propofol anesthesia to 16 subjects and found that, after they had lost behavioral responsiveness (response to standard sensory stimuli), each individual's EEG slow-wave activity (SWA) rose to saturation and then remained constant despite increasing drug concentrations. We then simultaneously collected functional magnetic resonance imaging and EEG data in 12 of these subjects during propofol administration and sensory stimulation. During the transition to SWA saturation, the thalamocortical system became isolated from sensory stimuli, whereas internal thalamocortical exchange persisted. Rather, an alternative and more fundamental cortical network (which includes the precuneus) responded to all sensory stimulation. We conclude that SWA saturation is a potential individualized indicator of perception loss that could prove useful for monitoring depth of anesthesia and studying altered states of consciousness. PMID- 24154604 TI - Pulmonary arterial hypertension: challenges in translational research and a vision for change. AB - Pulmonary arterial hypertension (PAH) is a vascular remodeling disease with a relentless course toward heart failure and early death. Existing PAH therapies, all of which were developed originally to treat systemic vascular diseases, cannot reverse the disease or markedly improve survival and are expensive. Although there has been a recent increase in the number of potential new therapies emerging from animal studies, less than 3% of the active PAH clinical trials are examining such therapies. There are many potential explanations for the translational gap in this complex multifactorial disease. We discuss these challenges and propose solutions that range from including clinical endpoints in animal studies and improving the rigor of human trials to conducting mechanistic early-phase trials and randomized trials with innovative designs based on personalized medicine principles. Global, independent patient and tissue registries and enhanced communication among academics, industry, and regulatory authorities are needed. The diversity of the mechanisms and pathology of PAH calls for broad comprehensive theories that encompass emerging evidence for contributions of metabolism and inflammation to PAH to support more effective therapeutic target identification. PMID- 24154603 TI - Targeting RNA foci in iPSC-derived motor neurons from ALS patients with a C9ORF72 repeat expansion. AB - Amyotrophic lateral sclerosis (ALS) is a severe neurodegenerative condition characterized by loss of motor neurons in the brain and spinal cord. Expansions of a hexanucleotide repeat (GGGGCC) in the noncoding region of the C9ORF72 gene are the most common cause of the familial form of ALS (C9-ALS), as well as frontotemporal lobar degeneration and other neurological diseases. How the repeat expansion causes disease remains unclear, with both loss of function (haploinsufficiency) and gain of function (either toxic RNA or protein products) proposed. We report a cellular model of C9-ALS with motor neurons differentiated from induced pluripotent stem cells (iPSCs) derived from ALS patients carrying the C9ORF72 repeat expansion. No significant loss of C9ORF72 expression was observed, and knockdown of the transcript was not toxic to cultured human motor neurons. Transcription of the repeat was increased, leading to accumulation of GGGGCC repeat-containing RNA foci selectively in C9-ALS iPSC-derived motor neurons. Repeat-containing RNA foci colocalized with hnRNPA1 and Pur-alpha, suggesting that they may be able to alter RNA metabolism. C9-ALS motor neurons showed altered expression of genes involved in membrane excitability including DPP6, and demonstrated a diminished capacity to fire continuous spikes upon depolarization compared to control motor neurons. Antisense oligonucleotides targeting the C9ORF72 transcript suppressed RNA foci formation and reversed gene expression alterations in C9-ALS motor neurons. These data show that patient derived motor neurons can be used to delineate pathogenic events in ALS. PMID- 24154605 TI - Protamine sulfate-nanodiamond hybrid nanoparticles as a vector for MiR-203 restoration in esophageal carcinoma cells. AB - We report an innovative approach for miRNA-203 delivery in esophageal cancer cells using protamine sulphate (PS)-nanodiamond (ND) nanoparticles. The efficient delivery of miR-203 significantly suppressed the proliferation and migration of cancer cells through targeting Ran and DeltaNp63, exhibiting a great potential for PS@ND nanoparticles in miRNA-based cancer therapy. PMID- 24154608 TI - alpha-MnO2 nanowire catalysts with ultra-high capacity and extremely low overpotential in lithium-air batteries through tailored surface arrangement. AB - We here report on very high capacity (11,000 mA h g(-1)), superb rate capability (4500 mA h g(-1) at 5000 mA g(-1)) and high reversibility of Li-air batteries using alpha-MnO2 NW catalysts mainly associated with their relatively large amount of Mn(3+) exposed on the NW surface and a unique mechanism for deposition of discharge products. Our findings of the unprecedentedly fast Li ion transport and reversible formation-decomposition of discharge products attributed to the modified surface arrangement of alpha-MnO2 NWs suggest a strategy for achieving high-power Li-air batteries in combination with nano-architecture tailoring. PMID- 24154606 TI - Risk factors for development of cholestatic drug-induced liver injury: inhibition of hepatic basolateral bile acid transporters multidrug resistance-associated proteins 3 and 4. AB - Impaired hepatic bile acid export may contribute to development of cholestatic drug-induced liver injury (DILI). The multidrug resistance-associated proteins (MRP) 3 and 4 are postulated to be compensatory hepatic basolateral bile acid efflux transporters when biliary excretion by the bile salt export pump (BSEP) is impaired. BSEP inhibition is a risk factor for cholestatic DILI. This study aimed to characterize the relationship between MRP3, MRP4, and BSEP inhibition and cholestatic potential of drugs. The inhibitory effect of 88 drugs (100 MUM) on MRP3- and MRP4-mediated substrate transport was measured in membrane vesicles. Drugs selected for investigation included 50 BSEP non-inhibitors (24 non cholestatic; 26 cholestatic) and 38 BSEP inhibitors (16 non-cholestatic; 22 cholestatic). MRP4 inhibition was associated with an increased risk of cholestatic potential among BSEP non-inhibitors. In this group, for each 1% increase in MRP4 inhibition, the odds of the drug being cholestatic increased by 3.1%. Using an inhibition cutoff of 21%, which predicted a 50% chance of cholestasis, 62% of cholestatic drugs inhibited MRP4 (P < 0.05); in contrast, only 17% of non-cholestatic drugs were MRP4 inhibitors. Among BSEP inhibitors, MRP4 inhibition did not provide additional predictive value of cholestatic potential; almost all BSEP inhibitors were also MRP4 inhibitors. Inclusion of pharmacokinetic predictor variables (e.g., maximal unbound concentration in plasma) in addition to percent MRP4 inhibition in logistic regression models did not improve cholestasis prediction. Association of cholestasis with percent MRP3 inhibition was not statistically significant, regardless of BSEP-inhibition status. Inhibition of MRP4, in addition to BSEP, may be a risk factor for the development of cholestatic DILI. PMID- 24154607 TI - Exploring telicity and transitivity in primordial thought language and body boundary imagery. AB - Linguistics research on 'unconscious knowledge' related to the right brain hemisphere represents a shift from the prevalent scientific investigation of the linguistic processes of grammatical structures associated with the dominant 'verbal' left brain-hemisphere. This study explores the relationship among primordial thought language, body boundary awareness and syntactic features- i.e., telicity, perfectivity and transitivity-in autobiographical narratives of everyday and dream memories. The results showed that event descriptions with atelic predicates and intransitive structures were more frequent in dream recall than in narratives of everyday memories. Primordial thought language and body boundary awareness, however, decreased with atelic predicates and transitive structures, which might indicate both the tendency of events to describe result states, such as achievements and accomplishments, as a means to bring about an unconscious wish fulfilment and the emphasis on event arguments to be realised without the inclusion of an external object. In narratives of everyday memories, penetration imagery increased with imperfective verb forms and decreased with perfective verb forms, and emotion lexis increased with atelic predicates and transitive structures, but not in dream memories. PMID- 24154609 TI - Molecular tectonics: from crystals to crystals of crystals. AB - The in situ combination of M(II) cations (Co, Ni, Cu or Zn) with 2,4,6 pyridinetricarboxylic acid as a ligand, a bisamidinium dication as a H-bond donor tecton and NaOH leads to the formation of anionic metal complexes ML2(2-) and their interconnection into isomorphous 3D H-bonded networks displaying different colours which were used as preformed seed crystals for the formation of crystals of crystals by 3D epitaxial growth. PMID- 24154610 TI - Structural analysis and molecular dynamics simulations of novel delta-endotoxin Cry1Id from Bacillus thuringiensis to pave the way for development of novel fusion proteins against insect pests of crops. AB - The theoretical three-dimensional structure of a novel delta-endotoxin Cry1Id (81 kDa) belonging to Cry1I class, toxic to many of the lepidopteran pests has been investigated through comparative modeling. Molecular dynamics (MD) simulations was carried out to characterize its structural and dynamical features at 10 ns in explicit solvent using the GROMACS version 4.5.4. Finally the simulated model was validated by the SAVES, WHAT IF, MetaMQAP, ProQ, ModFOLD and MolProbity servers. Despite low sequence identity with its structural homologs, Cry1Id not only resembles the previously reported Cry structures but also shares the common five conserved blocks of amino acid residues. Although the domain II of Cry1Id superpose well with its closest structural homolog Cry8Ea1, variation of amino acids and length in the apical loop2 of domain II was observed. In this work, we have hypothesized that the variations in apical loop2 might be the sole factor for providing variable surface accessibility to Cry1Id protein that could be important in receptor recognition. MD simulation showed the proposed endotoxin retains its stable conformation in aqueous solution. The result from this study is expected to aid in the development hybrid Cry proteins and new potent fusion proteins with novel specificities against different insect pests for improved pest management of crop plants. PMID- 24154611 TI - Structure-property relationships for three indoline dyes used in dye-sensitized solar cells: TDDFT study of visible absorption and photoinduced charge-transfer processes. AB - The electronic structures of three D-A-pi-A indoline dyes (WS-2, WS-6, and WS-11) used in dye-sensitized solar cells (DSSCs) were studied by performing quantum chemistry calculations. The coplanarity of the A-pi-A segment and distinct noncoplanarity of the indoline donor part of each dye were confirmed by checking the calculated geometric parameters. The relationships between molecular modifications and the optical properties of the dyes were derived in terms of the partial density of states, absorption spectrum, frontier molecular orbital, and excited-state charge transfer. 3D real-space analysis of the transition density (TD) and charge difference density (CDD) was also performed to further investigate the excited-state features of the molecular systems, as they provide visualized physical pictures of the charge separation and transfer. It was found that modifying the alkyl chain of the bridge unit near the acceptor unit is an efficient way to decrease dye aggregation and improve DSSC efficiency. Inserting a hexylthiophene group next to the donor unit leads to a complicated molecular structure and a decrease in the charge-transfer ability of the system, which has an unfavorable impact on DSSC performance. PMID- 24154613 TI - Seasonal trends in organochlorine pesticide residues in raw bovine milk from rural areas of Haryana, India. AB - Seasonal trends in organochlorine pesticides residues namely, 1,2,3,4,5,6 hexachlorocyclohexane (HCH) isomers, 1,1,1-trichloro-2,2-bis (p-chlorophenyl) ethane (DDT) and its metabolites and endosulfan stereo isomers were investigated in raw bovine milk samples from rural areas of Ambala, Gurgaon and Hisar districts of the state of Haryana for winter, summer, and post-monsoon seasons. Highest concentration of HCH and DDT was found in 43 % and 53 % milk samples, respectively in post-monsoon season whereas highest values of endosulfan was reported in 36 % samples during winter season. During the study period only 2 % milk samples exceeded the maximum residue limit recommended by WHO for SigmaHCH, 1 % samples each for alpha-HCH and gamma-HCH, 9 % samples for beta-HCH as recommended by PFAA and 30 % samples for SigmaDDT as prescribed by FAO. No statistical difference in the mean concentration of ?HCH and ?Endosulfan could be observed in any of the three districts. However, ?DDT concentration showed marked difference [F(2, 25) = 12.42, p = 0.00018)] among the three districts. PMID- 24154612 TI - Stacking and hydrogen bond interactions between adenine and gallic acid. AB - We have performed DFT and DFT-SAPT calculations on dimers of gallic acid, the model system for plant polyphenols, and the DNA base adenine. These dimers were selected for this study as they exhibit simultaneously hydrogen bonds and stacking interactions and it allows to quantify the relative values of these interactions. We calculate the relationships between the stability of the complexes, the charge transfer between monomers and the properties of the intermolecular bonds including hydrogen bonds and other bonds that do not involve hydrogen atoms. DFT-SAPT calculations were also performed to obtain the participation of the different types of energy and so the resulting physical effects. The results show that the presence of hydrogen bonds is the main stabilizing factor for dimers: the higher number and strength, the lower the dimer energy. The contribution of stacking to the stabilization is related to the strength and number of bonds between non-hydrogen atoms and quantified by the contribution of the dispersion terms to the interaction energy. Dimers I and II are mainly stabilized due to hydrogen bonds whereas dimer III is mainly stabilized by stacking interactions. PMID- 24154614 TI - Cytotoxic effects of polystyrene-titanium-arsenate composite in cultured H9c2 cardiomyoblasts. AB - In the present report, we explored the toxicological behaviour of engineered polystyrene-titanium-arsenate (PS-Ti-As) composite using cultured H9c2 cardiomyoblasts in vitro. From in vitro cytotoxicity studies, it appears that the composite can be toxic to the cardiac cells and the value of IC50 investigated to be the highest concentration of 500 MUg mL(-1), during 16-24 h of incubation period. The cell morphological studies based on dual staining with acridine orange and ethidium bromide indicates that apoptosis is the dominating pathway of cell death. Furthermore, an enhanced DNA fragmentation, increased reactive oxygen species production and caspase release demonstrates the potential risks associated with the exposure of PS-Ti-As composite to the cardiac cells. PMID- 24154615 TI - Radial artery complications occurring after transradial coronary procedures using long hydrophilic-coated introducer sheath: a frequency domain-optical coherence tomography study. AB - This study was performed to analyze the impact of transradial intervention (TRI), performed by long (25-cm) hydrophilic-coated radial introducer sheath (HRS), on radial artery (RA). Both acute damages and chronic intimal modifications, occurring in RA, were assessed using frequency domain-optical coherence tomography (FD-OCT). FD-OCT evaluation of RA was performed in 51 consecutive patients, undergoing TRI by long (25-cm) HRS. FD-OCT was performed from RA ostium to the puncture site. Acute damages such as intimal tears and medial dissections together with chronic intimal modifications, assessed as intimal hyperplasia indexes, were observed and compared between proximal and distal RA segments. Intimal tears were detected in 37% of patients, especially located in proximal RA segment (p = 0.09). Medial dissections were imaged in 9.8% of patients with no significant difference between proximal and distal RA segments. Intimal hyperplasia indexes were higher in distal RA segment, with no significant association with a previous history of TRI. In the setting of TRI, performed by long HRS, intimal tears represented the main RA injury occurring in about one third of patients, while medial dissections only occurred in a small proportion of patients. Distal RA segment was more prone to intimal thickening, although this phenomenon was not associated with repeated transradial procedures. PMID- 24154617 TI - Proliferation of parenchymal microglia is the main source of microgliosis after ischaemic stroke. AB - Stroke induces rapid activation and expansion of microglia, but the main source of microgliosis is controversial. Here we investigated the formation of microgliosis and infiltration of circulating cells in a photothrombosis stroke model by taking advantage of parabiosis and two-photon microscopy. We found that a small population of blood-derived CX3CR1(GFP/+) cells infiltrated the cerebral parenchyma, but these cells did not proliferate and were phenotypically distinguishable from resident microglia. CX3CR1(GFP/+) infiltrating cells also displayed different kinetics from reactive microglia. The number of CX3CR1(GFP/+) infiltrating cells peaked on Day 5 after stroke and then decreased. The decline of these infiltrating cells was associated with an active apoptotic process. In contrast, reactive microglia were recruited to the ischaemic area continuously during the first week after stroke induction. Immunohistology and in vivo two photon imaging revealed that cells involved in the process of microgliosis were mainly derived from proliferating resident microglia. Expansion of microglia exhibited a consistent pattern and our in vivo data demonstrated for the first time that microglia underwent active division in regions surrounding the ischaemic core. Together, these results indicated that CX3CR1(GFP/+) infiltrating cells and reactive microglia represented two distinct populations of cells with different functions and therapeutic potentials for the treatment of stroke. PMID- 24154618 TI - A direct relationship between oscillatory subthalamic nucleus-cortex coupling and rest tremor in Parkinson's disease. AB - Electrophysiological studies suggest that rest tremor in Parkinson's disease is associated with an alteration of oscillatory activity. Although it is well known that tremor depends on cortico-muscular coupling, it is unclear whether synchronization within and between brain areas is specifically related to the presence and severity of tremor. To tackle this longstanding issue, we took advantage of naturally occurring spontaneous tremor fluctuations and investigated cerebral synchronization in the presence and absence of rest tremor. We simultaneously recorded local field potentials from the subthalamic nucleus, the magnetoencephalogram and the electromyogram of forearm muscles in 11 patients with Parkinson's disease (all male, age: 52-74 years). Recordings took place the day after surgery for deep brain stimulation, after withdrawal of anti parkinsonian medication. We selected epochs containing spontaneous rest tremor and tremor-free epochs, respectively, and compared power and coherence between subthalamic nucleus, cortex and muscle across conditions. Tremor-associated changes in cerebro-muscular coherence were localized by Dynamic Imaging of Coherent Sources. Subsequently, cortico-cortical coupling was analysed by computation of the imaginary part of coherency, a coupling measure insensitive to volume conduction. After tremor onset, local field potential power increased at individual tremor frequency and cortical power decreased in the beta band (13-30 Hz). Sensor level subthalamic nucleus-cortex, cortico-muscular and subthalamic nucleus-muscle coherence increased during tremor specifically at tremor frequency. The increase in subthalamic nucleus-cortex coherence correlated with the increase in electromyogram power. On the source level, we observed tremor associated increases in cortico-muscular coherence in primary motor cortex, premotor cortex and posterior parietal cortex contralateral to the tremulous limb. Analysis of the imaginary part of coherency revealed tremor-dependent coupling between these cortical areas at tremor frequency and double tremor frequency. Our findings demonstrate a direct relationship between the synchronization of cerebral oscillations and tremor manifestation. Furthermore, they suggest the feasibility of tremor detection based on local field potentials and might thus become relevant for the design of closed-loop stimulation systems. PMID- 24154619 TI - The antioxidant activity of daidzein metabolites, O-desmethylangolensin and equol, in HepG2 cells. AB - Daidzein and its glycoside form daidzin, are known to have potential health benefits and are metabolized to O-desmethylangolensin (O-DMA) and equol following consumption. In the current study, the antioxidant activity and cytotoxicity of O DMA, equol, daidzein and daidzin was investigated and their effects on HepG2 human hepatocelluar carcinoma cells were compared. For cytotoxicity assays, lactose dehydrogenase (LDH) release and 3-(4,5-dimethylthiazol-2-yl)-2,5 diphenyltetrazolium bromide-based cell viability, cells were exposed to various concentrations of each compound (5-200 uM) for 24, 48 or 72 h. O-DMA and equol did not affect LDH release, but higher concentrations (<75 uM) showed inhibition of cell growth. By contrast, daidzein and daidzin (200 uM) increased LDH release and cell growth. All compounds stimulated catalase and total superoxide dismutase (SOD) (CuZn- and Mn-SOD) activity, and mRNA and protein expression. This phenomenon was most pronounced for O-DMA and equol, as their effects were similar. These data suggested that O-DMA and equol possess greater antioxidant properties compared with daidzein and may, thus, be beneficial for human health. PMID- 24154620 TI - Chloroplast phosphoglycerate kinase is involved in the targeting of Bamboo mosaic virus to chloroplasts in Nicotiana benthamiana plants. AB - The Bamboo mosaic virus (BaMV) is a positive-sense, single-stranded RNA virus. Previously, we identified that the chloroplast phosphoglycerate kinase (chl-PGK) from Nicotiana benthamiana is one of the viral RNA binding proteins involved in the BaMV infection cycle. Because chl-PGK is transported to the chloroplast, we hypothesized that chl-PGK might be involved in viral RNA localization in the chloroplasts. To test this hypothesis, we constructed two green fluorescent protein (GFP)-fused mislocalized PGK mutants, the transit peptide deletion mutant (NO TRANSIT PEPTIDE [NOTP]-PGK-GFP) and the nucleus location mutant (nuclear location signal [NLS]-PGK-GFP). Using confocal microscopy, we demonstrated that NOTP-PGK-GFP and NLS-PGK-GFP are localized in the cytoplasm and nucleus, respectively, in N. benthamiana plants. When NOTP-PGK-GFP and NLS-PGK-GFP are transiently expressed, we observed a reduction in BaMV coat protein accumulation to 47% and 27% that of the wild-type PGK-GFP, respectively. To localize viral RNA in infected cells, we employed the interaction of NLS-GFP-MS2 (phage MS2 coat protein) with the modified BaMV RNA containing the MS2 coat protein binding sequence. Using confocal microscopy, we observed that BaMV viral RNA localizes to chloroplasts. Furthermore, elongation factor1a fused with the transit peptide derived from chl-PGK or with a Rubisco small subunit can partially restore BaMV accumulation in NbPGK1-knockdown plants by helping BaMV target chloroplasts. PMID- 24154621 TI - Wide-angle x-ray scattering and solid-state nuclear magnetic resonance data combined to test models for cellulose microfibrils in mung bean cell walls. AB - A synchrotron wide-angle x-ray scattering study of mung bean (Vigna radiata) primary cell walls was combined with published solid-state nuclear magnetic resonance data to test models for packing of (1->4)-beta-glucan chains in cellulose microfibrils. Computer-simulated peak shapes, calculated for 36-chain microfibrils with perfect order or uncorrelated disorder, were sharper than those in the experimental diffractogram. Introducing correlated disorder into the models broaden the simulated peaks but only when the disorder was increased to unrealistic magnitudes. Computer-simulated diffractograms, calculated for 24- and 18-chain models, showed good fits to experimental data. Particularly good fits to both x-ray and nuclear magnetic resonance data were obtained for collections of 18-chain models with mixed cross-sectional shapes and occasional twinning. Synthesis of 18-chain microfibrils is consistent with a model for cellulose synthesizing complexes in which three cellulose synthase polypeptides form a particle and six particles form a rosette. PMID- 24154622 TI - Economic evaluation of smoke alarm distribution methods in Baltimore, Maryland. AB - OBJECTIVE: This paper analyses costs and potential lives saved from a door-to door smoke alarm distribution programme using data from a programme run by the Baltimore City Fire Department in 2010-2011. DESIGN: We evaluate the impact of a standard home visit programme and an enhanced home visit programme that includes having community health workers provide advance notice, promote the programme, and accompany fire department personnel on the day of the home visit, compared with each other and with an option of not having a home visit programme (control). RESULTS: Study data show that the home visit programme increased by 10% the number of homes that went from having no working alarm to having any working alarm, and the enhanced programme added an additional 1% to the number of homes protected. We use published reports on the relative risk of death in homes with and without a working smoke alarm to show that the standard programme would save an additional 0.24 lives per 10,000 homes over 10 years, compared with control areas and the enhanced home visit programme saved an additional 0.07 lives compared with the standard programme. The incremental cost of each life saved for the standard programme compared with control was $28,252 per death averted and $284,501per additional death averted for the enhanced compared with the standard. CONCLUSIONS: Following the US guidelines for the value of a life, both programmes are cost effective, however, the standard programme may offer a better value in terms of dollars per death averted. The study also highlights the need for better data on the benefits of current smoke alarm recommendations and their impact on injury, death and property damage. PMID- 24154623 TI - A major QTL controlling deep rooting on rice chromosome 4. AB - Drought is the most serious abiotic stress that hinders rice production under rainfed conditions. Breeding for deep rooting is a promising strategy to improve the root system architecture in shallow-rooting rice cultivars to avoid drought stress. We analysed the quantitative trait loci (QTLs) for the ratio of deep rooting (RDR) in three F2 mapping populations derived from crosses between each of three shallow-rooting varieties ('ARC5955', 'Pinulupot1', and 'Tupa729') and a deep-rooting variety, 'Kinandang Patong'. In total, we detected five RDR QTLs on chromosomes 2, 4, and 6. In all three populations, QTLs on chromosome 4 were found to be located at similar positions; they explained from 32.0% to 56.6% of the total RDR phenotypic variance. This suggests that one or more key genetic factors controlling the root growth angle in rice is located in this region of chromosome 4. PMID- 24154624 TI - Optimized tetramer analysis reveals Ly49 promiscuity for MHC ligands. AB - Murine Ly49 receptors, which are expressed mainly on NK and NKT cells, interact with MHC class I (MHC-I) molecules with varying specificity. Differing reports of Ly49/MHC binding affinities may be affected by multiple factors, including cis versus trans competition and species origin of the MHC-I L chain (beta2 microglobulin). To determine the contribution of each of these factors, Ly49G, Ly49I, Ly49O, Ly49V, and Ly49Q receptors from the 129 mouse strain were expressed individually on human 293T cells or the mouse cell lines MHC-I-deficient C1498, H 2(b)-expressing MC57G, and H-2(k)-expressing L929. The capacity to bind to H 2D(b)- and H-2K(b)-soluble MHC-I tetramers containing either human or murine beta2-microglobulin L chains was tested for all five Ly49 receptors in all four cell lines. We found that most of these five inhibitory Ly49 receptors show binding for one or both self-MHC-I molecules in soluble tetramer binding assays when three conditions are fulfilled: 1) lack of competing cis interactions, 2) tetramer L chain is of mouse origin, and 3) Ly49 is expressed in mouse and not human cell lines. Furthermore, Ly49Q, the single known MHC-I receptor on plasmacytoid dendritic cells, was shown to bind H-2D(b) in addition to H-2K(b) when the above conditions were met, suggesting that Ly49Q functions as a pan-MHC Ia receptor on plasmacytoid dendritic cells. In this study, we have optimized the parameters for soluble tetramer binding analyses to enhance future Ly49 ligand identification and to better evaluate specific contributions by different Ly49/MHC-I pairs to NK cell education and function. PMID- 24154625 TI - Acute-phase protein hemopexin is a negative regulator of Th17 response and experimental autoimmune encephalomyelitis development. AB - Hemopexin (Hx) is an acute-phase protein synthesized by hepatocytes in response to the proinflammatory cytokines IL-6, IL-1beta, and TNF-alpha. Hx is the plasma protein with the highest binding affinity to heme and controls heme-iron availability in tissues and also in T lymphocytes, where it modulates their responsiveness to IFN-gamma. Recent data have questioned regarding an anti inflammatory role of Hx, a role that may be both heme-binding dependent and independent. The aim of this study was to investigate the role of Hx in the development of a T cell-mediated inflammatory autoimmune response. During experimental autoimmune encephalomyelitis (EAE), the mouse model of multiple sclerosis, Hx content in serum increased and remained high. When EAE was induced in Hx knockout (Hx(-/-)) mice, they developed a clinically earlier and exacerbated EAE compared with wild-type mice, associated to a higher amount of CD4(+)-infiltrating T cells. The severe EAE developed by Hx(-/-) mice could be ascribed to an enhanced expansion of Th17 cells accounting for both a higher disposition of naive T cells to differentiate toward the Th17 lineage and a higher production of Th17 differentiating cytokines IL-6 and IL-23 by APCs. When purified human Hx was injected in Hx(-/-) mice before EAE induction, Th17 expansion, as well as disease severity, were comparable with those of wild-type mice. Taken together, these data indicate that Hx has a negative regulatory role in Th17-mediated inflammation and prospect its pharmacological use to limit the expansion of this cell subset in inflammatory and autoimmune disease. PMID- 24154626 TI - Programmed death 1-mediated T cell exhaustion during visceral leishmaniasis impairs phagocyte function. AB - Control of Leishmania infantum infection is dependent upon Th1 CD4(+) T cells to promote macrophage intracellular clearance of parasites. Deficient CD4(+) T cell effector responses during clinical visceral leishmaniasis (VL) are associated with elevated production of IL-10. In the primary domestic reservoir of VL, dogs, we define occurrence of both CD4(+) and CD8(+) T cell exhaustion as a significant stepwise loss of Ag-specific proliferation and IFN-gamma production, corresponding to increasing VL symptoms. Exhaustion was associated with a 4-fold increase in the population of T cells with surface expression of programmed death 1 (PD-1) between control and symptomatic populations. Importantly, exhausted populations of CD8(+) T cells and to a lesser extent CD4(+) T cells were present prior to onset of clinical VL. VL-exhausted T cells did not undergo significant apoptosis ex vivo after Ag stimulation. Ab block of PD-1 ligand, B7.H1, promoted return of CD4(+) and CD8(+) T cell function and dramatically increased reactive oxygen species production in cocultured monocyte-derived phagocytes. As a result, these phagocytes had decreased parasite load. To our knowledge, we demonstrate for the first time that pan-T cell, PD-1-mediated, exhaustion during VL influenced macrophage-reactive oxygen intermediate production. Blockade of the PD 1 pathway improved the ability of phagocytes isolated from dogs presenting with clinical VL to clear intracellular parasites. T cell exhaustion during symptomatic canine leishmaniasis has implications for the response to vaccination and therapeutic strategies for control of Leishmania infantum in this important reservoir species. PMID- 24154630 TI - Three-dimensional SiO2@Fe3O4 core/shell nanorod array/graphene architecture: synthesis and electromagnetic absorption properties. AB - We developed a new strategy, i.e., a seed-assisted method, to fabricate a three dimensional (3D) SiO2@Fe3O4 core/shell nanorod array/graphene architecture. The fabrication processes involved deposition of beta-FeOOH seeds on the graphene surfaces in the ferric nitrate aqueous solution, subsequent growth of beta-FeOOH nanorod arrays on the graphene surfaces in the ferric chloride aqueous solution under hydrothermal conditions, deposition of SiO2 coating on the surfaces of beta FeOOH nanorods, and final formation of the 3D architecture by a thermal treatment process. Scanning electron microscopy and transmission electron microscopy measurements showed that the SiO2@Fe3O4 core/shell nanorods with a length and diameter of about 60 and 25 nm, respectively, were almost grown perpendicularly on both side surfaces of graphene sheets. The measured electromagnetic parameters showed that the 3D architecture exhibited excellent electromagnetic wave absorption properties, i.e., more than 99% of electromagnetic wave energy could be attenuated by the 3D architecture with an addition amount of only 20 wt% in the paraffin matrix. In addition, the growth mechanism of the 3D architecture was proposed, and thus, the strategy presented here could be used as a typical method to synthesize other 3D magnetic graphene nanostructures for extending their application areas. PMID- 24154629 TI - Construction of a supF-based system for detection of mutations in the chromosomal DNA of Arabidopsis. AB - The factors maintaining genomic integrity, which have been studied in detail in other species, have yet to be investigated in plants. Recent progress in gene silencing technology has made it possible to produce transgenic plants with loss of-function phenotypes for the effective analysis of these factors, even with the high redundancy of genes in plants. Therefore, a mutation-detection system for plants is necessary to estimate the biological function of a target gene for mutation frequencies and spectra. Here, we reported the development of a novel system to analyze mutations in the chromosomal DNA of plants. The supF gene of E. coli was used as a target for the mutation because it was possible to detect all mutational base changes. Based on the plasmid pTN30, which carries supF, we constructed a binary Ti vector for its introduction to Arabidopsis genomes. The system was validated by measuring mutations in both non-treated and mutagen treated transgenic plants. DNA fragments including pTN30 were rescued from the plants, and introduced into E. coli KS40/pOF105 to isolate the supF mutant clones conferring both nalidixic acid and streptomycin resistance on transformants. We found that the mutation frequency was approximately three times higher with the ethyl methanesulfonate (EMS) treatment than without it and G:C to A:T transitions dominated, which was the most reasonable mutation induced by EMS. These results show that this system allowed for the rapid analysis of mutations in plants, and may be useful for analyzing plant genes related to the functions of genomic stability and monitoring environmental genotoxic substances. PMID- 24154631 TI - Nanocrystals from solutions: catalysts. AB - The ultimate goal of nanoscale science and technology is to manipulate single atoms, assemble atoms in a controllable way and design nanostructured materials with the desired physical and chemical properties (e.g. catalytic properties). In order to achieve this goal, the nucleation and growth mechanism of nanocrystals (NCs) as well as the relationship between the macroscopic properties and microscopic structures of nanocrystals should be fully understood. In this tutorial review, we firstly summarize the latest research developments and experimental methods to exploit the nucleation and growth process of nanocrystals, then discuss the essence of nanocrystal catalysis, and finally present our personal perspectives on the opportunities and challenges of this promising field. PMID- 24154627 TI - Complement factor B is the downstream effector of TLRs and plays an important role in a mouse model of severe sepsis. AB - Severe sepsis involves massive activation of the innate immune system and leads to high mortality. Previous studies have demonstrated that various types of TLRs mediate a systemic inflammatory response and contribute to organ injury and mortality in animal models of severe sepsis. However, the downstream mechanisms responsible for TLR-mediated septic injury are poorly understood. In this article, we show that activation of TLR2, TLR3, and TLR4 markedly enhanced complement factor B (cfB) synthesis and release by macrophages and cardiac cells. Polymicrobial sepsis, created by cecal ligation and puncture in a mouse model, augmented cfB levels in the serum, peritoneal cavity, and major organs including the kidney and heart. Cecal ligation and puncture also led to the alternative pathway activation, C3 fragment deposition in the kidney and heart, and cfB dependent C3dg elevation. Bacteria isolated from septic mice activated the serum alternative pathway via a factor D-dependent manner. MyD88 deletion attenuated cfB/C3 upregulation as well as cleavage induced by polymicrobial infection. Importantly, during sepsis, absence of cfB conferred a protective effect with improved survival and cardiac function and markedly attenuated acute kidney injury. cfB deletion also led to increased neutrophil migratory function during the early phase of sepsis, decreased local and systemic bacterial load, attenuated cytokine production, and reduced neutrophil reactive oxygen species production. Together, our data indicate that cfB acts as a downstream effector of TLR signaling and plays a critical role in the pathogenesis of severe bacterial sepsis. PMID- 24154628 TI - Base excision repair AP endonucleases and mismatch repair act together to induce checkpoint-mediated autophagy. AB - Cellular responses to DNA damage involve distinct DNA repair pathways, such as mismatch repair (MMR) and base excision repair (BER). Using Caenorhabditis elegans as a model system, we present genetic and molecular evidence of a mechanistic link between processing of DNA damage and activation of autophagy. Here we show that the BER AP endonucleases APN-1 and EXO-3 function in the same pathway as MMR, to elicit DNA-directed toxicity in response to 5-fluorouracil, a mainstay of systemic adjuvant treatment of solid cancers. Immunohistochemical analyses suggest that EXO-3 generates the DNA nicks required for MMR activation. Processing of DNA damage via this pathway, in which both BER and MMR enzymes are required, leads to induction of autophagy in C. elegans and human cells. Hence, our data show that MMR- and AP endonuclease-dependent processing of 5 fluorouracil-induced DNA damage leads to checkpoint activation and induction of autophagy, whose hyperactivation contributes to cell death. PMID- 24154632 TI - Validation of the Portuguese version of the Functional Assessment of Chronic Illness Therapy-Spiritual Well-Being scale (FACIT-Sp 12) among Brazilian psychiatric inpatients. AB - Functional Assessment of Chronic Illness Therapy-Spiritual Well-Being scale (FACIT-Sp 12) is one of the most used and most validated instruments for assessing spiritual well-being in the world. Some Brazilian studies have used this instrument without, however, assessing its psychometric properties. The present study aims to validate the Portuguese version of the FACIT-Sp 12 among Brazilian psychiatric inpatients. A self-administered questionnaire, covering spiritual well-being (FACIT-Sp 12), depression, anxiety, religiosity, quality of life, and optimism, was administered. Of those who met the inclusion criteria, 579 patients were invited to participate and 493 (85.1 %) were able to fill out the FACIT-Sp 12 twice (test and retest). Subsequently, the validation analysis was carried out. Estimation of test-retest reliability, discriminant, and convergent validity was determined by the Spearman's correlation test, and the internal consistency was examined by the Cronbach's alpha. The sample was predominantly male (63.9 %) with a mean age of 35.9 years, and the most common psychiatric condition was bipolar disorder (25.7 %) followed by schizophrenia (20.4 %), drug use (20.0 %), and depression (17.6 %) according to ICD-10. The total FACIT-Sp 12 scale as well as the subscales demonstrated high internal consistency (coefficient alphas ranging from 0.893 for the total scale to 0.655 for the Meaning subscale), good convergent and divergent validity, and satisfactory test-retest reliability (rho = 0.699). The Portuguese version of FACIT-Sp 12 is a valid and reliable measure to use in Brazilian psychiatric inpatients. The availability of a brief and broad measure of spiritual well-being can help the study of spirituality and its influence on health by researchers from countries that speak the Portuguese language. PMID- 24154633 TI - How to use...the paediatric ECG. PMID- 24154634 TI - Relationship between the ansa cervicalis and the omohyoid muscle: clinical consequences in parathyroid surgery. AB - PURPOSE: To determine the position of the lower loop of the ansa cervicalis (AC) compared to the inferior edge of the omohyoid muscle to guide minimally invasive surgery for the lateral oblique approach of parathyroid glands. METHODS: Authors performed 36 anatomical dissections in the laboratory of anatomy (Laboratoire d'Anatomie Des Alpes Francaises) of the Grenoble medical school in 2012 on human cadavers. They independently measured the distance between the caudal extremity of the AC and the lower edge of the superior belly of the omohyoid muscle. Then, they controlled this measure on pictures. RESULTS: The study shows a majority of long AC (under the omohyoid muscle) in 66.7 % of cases. In addition, the AC was located on an average value of 0.1 cm below the lower edge of the omohyoid muscle (median -0.5 cm). Thus, two-thirds of AC are between 0 and -2 cm under the omohyoid muscle. Furthermore, the AC is generally non-symmetrical: there is a mean difference of 1.3 cm between the left and right AC. In this series, there are as many long AC on the right side as on the left side. CONCLUSIONS: These results are in contradiction with literature data. To preserve the ansa cervicalis and its phonatory functions, it is necessary for the surgeon to perform a systematic per operative identification of the AC because the position of the AC is mainly under the omohyoid muscle and because of an asymmetry. Per operative neurostimulation and/or magnified lenses might be helpful during the surgical approach. PMID- 24154635 TI - Torcular Herophili classification and evaluation of dural venous sinus variations using digital subtraction angiography and magnetic resonance venographies. AB - PURPOSE: The configurations of cerebral veins and dural venous sinuses differ not only between individuals, but also between the two brain hemispheres of an individual, making the anatomical classification of the cerebral veins difficult. We evaluated the superior dural venous sinuses and classified their types and variations using magnetic resonance venography (MRV) and digital substraction angiography (DSA). METHODS: A total of 394 patients were studied retrospectively. Superior dural venous sinuses were evaluated and the confluence of the sinuses was classified on 2-dimensional time-of-flight MRV, contrast-enhanced 3 dimensional spoiled gradient recalled echo magnetic resonance imaging, and/or cerebral DSA. Confluens sinuum was divided into three types: true confluence, partial confluence, and non-confluence. RESULTS: Of the three types, partial confluence (type II) was most frequently seen. Co-dominance of the transverse sinuses was most frequently observed. An occipital sinus was observed in 15 % of the patients. There were statistically significant differences between the left transverse sinus agenesis and the presence of the occipital sinus (p < 0.001), between the co-presence of the partial confluence type torcular and the occipital sinus (p = 0.040), and between the co-presence of the fenestrated straight sinus and the occipital sinus (p = 0.010). CONCLUSIONS: Although anatomical variations of dural venous sinuses are seen frequently, classification of venous sinuses helps surgeons in preoperative evaluation and management, and prevention of possible complications. In this study, we think that a comprehensive evaluation and classification of dural venous sinuses is a significant contribution to the literature. PMID- 24154638 TI - Epidemiology of Clostridium difficile-associated disease (CDAD): a shift from hospital-acquired infection to long-term care facility-based infection. AB - BACKGROUND: Previous epidemiological studies on Clostridium-difficile-Associated Diarrhea (CDAD) have focused on hospitalized patients with nosocomial transmission. However, increasing numbers of patients with CDAD are being admitted to acute-care hospitals from long-term care facilities (LTCFs) and the local community. The purpose of our study was to study the changing epidemiological trends of CDAD patients admitted to an acute-care hospital and examine factors contributing to this shift in epidemiology. MATERIALS AND METHODS: This IRB-approved retrospective study included 400 randomly selected patients with a diagnosis of CDAD, admitted to an acute-care hospital between January, 2005 and December, 2010. CDAD was defined as >=3 episodes of loose stools in <24 h with a positive Clostridium difficile stool toxin assay. The patients were divided into three groups: hospital-acquired CDAD, long-term care facility (LTCF)-acquired CDAD, and community-acquired CDAD. The groups were compared in terms of demographics, ICU admissions, hospital length of stay, co morbidities, presenting complaint, and medication use. Patients who were hospitalized in the preceding 12 weeks or who had history of antibiotic use in the prior 8 weeks were excluded. RESULTS: Final analysis included 258 toxin positive CDAD patients. Only 53 (20.6%) patients had hospital-acquired CDAD. Patients from LTCFs (n=119, 46.1%) and the community (86 patients, 33.3%) comprised 79.4% of patients. The mean age for LTCF population was significantly higher than the hospital-acquired and community-acquired CDAD groups (p<0.0001). The presenting complaint was categorized as diarrhea or non-diarrheal symptom. Other non-diarrheal symptoms included fever, abdominal pain and altered mental status. Only 15.2% of LTCF patients had diarrhea as their presenting complaint (n=18) as compared to 29.1% of patients from the community (n=25; p<0.05). Most LTCF patients (n=101, 84.8%) had non-diarrheal symptoms as their presenting complaint as compared to only 61 patients from the community (70.9%) (p<0.05). Use of proton pump inhibitor (PPI) was more frequent in LTCF patients (73%) and patients with hospital-acquired CDAD (69.8%) as compared to patients with community-acquired CDAD (43%) (p<0.05). No valid indication was found for PPI use in 24.13% of LTCF patients and 32.1% of patients with community-acquired CDAD as compared to only 12.9% of patients with hospital-acquired CDAD. CONCLUSION: These observations suggest that CDAD originated predominantly in patients from LTCFs (46.1%) and community (33.3%) rather than from hospitalized patients (20.6%). Diarrhea was the presenting complaint in LTCF patients in only 15.2% of cases. Hence, CDAD should be suspected if LTCF patients present with symptoms such as abdominal pain, fever, or altered mental status along with loose stools. Majority of the LTCF patients were found to be on PPIs, a risk factor for CDAD, with as many as 24% of these patients with no valid indication for their use. PMID- 24154637 TI - Clinical outcomes of hepatitis C treated with pegylated interferon and ribavirin via telemedicine consultation in Northern California. AB - BACKGROUND: Patients in rural communities are less likely to receive treatment for their hepatitis C (HCV) infection. Telemedicine (TM) consultation can close the gap of access to specialists in remote and under-served areas. AIM: To determine treatment response and side-effect profiles among HCV patients treated with pegylated interferon and ribavirin via TM consultation in different rural locations in Northern California compared with patients treated in traditional hepatology office visits. METHODS: We performed a retrospective analysis of 80 HCV patients treated at different TM sites (TM, n=40) and at the University of California Davis Hepatology Clinic (HC, n=40) between 2006 and 2010, comparing baseline characteristics and clinical outcomes. RESULTS: At baseline, response to therapy was similar for patients in both groups. Sustained virological response (SVR) was similar in both groups (TM: 55 vs. HC: 43%; p=0.36), and a higher proportion of patients treated via telemedicine completed treatment (TM: 78 vs. HC: 53%; p=0.03). TM patients had many more visits per week of therapy (TM: 0.61 vs. HC: 0.07; p<0.001). Neutropenia, GI side effects, fatigue, depression, weight loss, insomnia, and skin rash were similar in both groups. For HC patients incidence of anemia was significantly higher (53%) than for the TM group (25%; p=0.02). CONCLUSIONS: The two groups had equivalent SVR. For the TM group therapy completion was superior and incidence of anemia was lower. This initial study suggests that, as a group, patients with HCV, can be safely and effectively treated via telemedicine. PMID- 24154639 TI - Exome sequencing revealed novel germline mutations in Chinese Peutz-Jeghers syndrome patients. AB - BACKGROUND AND AIMS: Peutz-Jeghers Syndrome (PJS) is an autosomal dominant disorder which predisposes to the development of various cancers. Germline mutation in the serine/threonine kinase 11 gene (STK11) is known as one of the major causes of PJS. However, a notable proportion of PJS samples do not carry any mutation in STK11, suggesting possible genetic heterogeneity in the disease and the existence of other causative variants. METHODS AND RESULTS: In order to identify other germline variants in the coding regions of the genome that are associated with PJS, we performed exome sequencing in three Chinese individuals with PJS and identified 16 common germline variants (12 protein-coding including STK11, 4 in pre-microRNAs). We further validated protein-coding variants in six PJS individuals (three with wild-type STK11) and predicted the functional impact. As result, we found that 7 coding variants are likely to have functional impacts. Especially, we identified 2 new germline variants which are represented in all six PJS samples and are independent of STK11 mutation. CONCLUSIONS: Our study provided an exomic view of PJS. The germline variants identified in our analysis may help to resolve the complex genetic background of the disease and thus lead to the discovery of novel causative variants of PJS. PMID- 24154640 TI - Serum levels of CXCR3 ligands predict T cell-mediated acute rejection after kidney transplantation. AB - The early diagnosis of acute rejection is crucial for graft survival after kidney transplantation. The interferon-gamma (IFNgamma)-CXCR3-chemokine-dependent inflammatory loop plays a pivotal role in the recruitment of T lymphocytes during acute rejection. Previously published studies have typically focused on the CXCR3 receptor rather than on its ligands. In the present study, we used Luminex assays to detect the levels of CXCR3 ligands, monokine induced by IFNgamma (MIG), IFN induced protein 10 (IP-10) and IFN-induced T-cell chemoattractant (I-TAC), in the serum of renal allograft recipients. According to a renal biopsy performed one month after kidney transplantation, 32 recipients were diagnosed with T cell mediated acute rejection and 38 patients were evaluated as stable. Serum was collected after the diagnosis of acute rejection or one month after transplantation. The concentrations of MIG (median, 4,271 pg/ml), IP-10 (median, 686.7 pg/ml) and I-TAC (median, 44.32 pg/ml) in the serum during an acute rejection episode were significantly higher compared with those of the stable patients (MIG, P=0.0002; IP-10, P=0.0001; I-TAC, P=0.0103; vs. the stable function group, P<0.05). Based on the receiver-operating characteristic (ROC) curve, the joint detection of MIG, IP-10 and I-TAC in the serum using Luminex analysis may constitute a non-invasive and efficient method for the early prediction of T cell-mediated acute rejection following kidney transplantation. PMID- 24154641 TI - Frailty and cognition: linking two common syndromes in older persons. PMID- 24154643 TI - The cognitive impairment of frail older persons. PMID- 24154644 TI - Cognitive frailty. PMID- 24154642 TI - Cognitive frailty: rational and definition from an (I.A.N.A./I.A.G.G.) international consensus group. AB - The frailty syndrome has recently attracted attention of the scientific community and public health organizations as precursor and contributor of age-related conditions (particularly disability) in older persons. In parallel, dementia and cognitive disorders also represent major healthcare and social priorities. Although physical frailty and cognitive impairment have shown to be related in epidemiological studies, their pathophysiological mechanisms have been usually studied separately. An International Consensus Group on "Cognitive Frailty" was organized by the International Academy on Nutrition and Aging (I.A.N.A) and the International Association of Gerontology and Geriatrics (I.A.G.G) on April 16th, 2013 in Toulouse (France). The present report describes the results of the Consensus Group and provides the first definition of a "Cognitive Frailty" condition in older adults. Specific aim of this approach was to facilitate the design of future personalized preventive interventions in older persons. Finally, the Group discussed the use of multidomain interventions focused on the physical, nutritional, cognitive and psychological domains for improving the well-being and quality of life in the elderly. The consensus panel proposed the identification of the so-called "cognitive frailty" as an heterogeneous clinical manifestation characterized by the simultaneous presence of both physical frailty and cognitive impairment. In particular, the key factors defining such a condition include: 1) presence of physical frailty and cognitive impairment (CDR=0.5); and 2) exclusion of concurrent AD dementia or other dementias. Under different circumstances, cognitive frailty may represent a precursor of neurodegenerative processes. A potential for reversibility may also characterize this entity. A psychological component of the condition is evident and concurs at increasing the vulnerability of the individual to stressors. PMID- 24154645 TI - Cognitive frailty: frontiers and challenges. PMID- 24154646 TI - Association between illness progression measures and total cost in Alzheimer's disease. AB - OBJECTIVE: To compare the associations between dependence and clinical measures of cognition, function and behaviour and total care cost using data from a longitudinal study in Alzheimer's disease (AD). DESIGN: Longitudinal, observational study. SETTING: Community-dwelling subjects. PARTICIPANTS: Male and female subjects between 50 and 85 years of age with mild to moderate AD. INTERVENTION: None. MEASUREMENTS: Subject dependence was assessed using the Dependence Scale (DS), cognition (ADAS-Cog, MMSE), function (DAD), behaviour (NPI) and resource utilization with the Resource Utilization in Dementia Questionnaire. RESULTS: The repeated measures models confirmed a significant association between the DS and total care cost indicating an increase in cost with increasing dependence. A 1-unit increase in DS score was associated with a 28.60% increase in total care cost. Model 2 indicated that a one point change in MMSE, DAD and NPI is associated with 5.29%, 2.32% and 1.71% increase in total cost, respectively. Model 3 indicated that a one point change in ADAS-Cog, DAD and NPI is associated with a 1.74%, 2.42%and 1.62% increase in total cost, respectively. CONCLUSION: Strategies which prevent deterioration in clinical measures or delay dependence should result in total cost savings. The quantitative relationships observed should assist in the economic assessment of interventions which effect cognition, function, behaviour and dependence. PMID- 24154647 TI - The influence of nutritional supplement drinks on providing adequate calorie and protein intake in older adults with dementia. AB - OBJECTIVES: Investigate the impact of the provision of ONS on protein and energy intake from food and ability to meet protein and calorie requirements in people with dementia. DESIGN: After consent by proxy was obtained, participants took part in a cross over study comparing oral intake on an intervention day to an adjacent control day. SETTING: The study occurred in Nursing homes and hospitalised settings. PARTICIPANTS: Older adults with dementia over the age of 65 were recruited. 26 participants (aged 83.9+/-8.4years, MMSE 13.08+/-8.13) took part. Intervention (if any): On the intervention day nutritional supplement drinks were provided three times. Each drink provided 283.3+/-41.8 Kcal of energy and 13.8+/-4.7g of protein. Supplements were removed approximately 1 hour before meals were served and weighed waste (g) was obtained. MEASUREMENTS: Intake of food consumed was determined on intervention and control days using the quartile method (none, quarter, half, three quarters, all) for each meal component. RESULTS: More people achieved their energy and protein requirements with the supplement drink intervention with no sufficient impact on habitual food consumption. CONCLUSION: Findings from these 26 participants with dementia indicate that supplement drinks may be beneficial in reducing the prevalence of malnutrition within the group as more people meet their nutritional requirements. As the provision of supplement drinks is also demonstrated to have an additive effect to consumption of habitual foods these can be used alongside other measures to also improve oral intake. PMID- 24154648 TI - A cross sectional study to examine the association between dietary patterns and cognitive impairment in older Chinese people in Hong Kong. AB - BACKGROUND: Dietary patterns can be identified using a priori and a posterior approaches. Few studies have related dietary patterns with cognitive impairment in Chinese population. This study examined the risk of cognitive impairment associated with dietary patterns identified by both approaches. METHODS: Baseline data on 1,926 Chinese men and 1,744 Chinese women aged > 65 years participating in a cohort study examining the risk factors for osteoporosis in Hong Kong were analyzed. Dietary data were collected using a validated food frequency questionnaire. Adherence to a priori dietary patterns, namely the Mediterranean Diet Score (MDS) was assessed. Factor analysis (FA) identified three a posterior dietary patterns: "vegetables-fruits" pattern which was rich in vegetables, fruits, soy products and legumes, "snacks-drinks-milk products" pattern which was a mixture of healthy and unhealthy food groups including fast food, sweets and desserts, nuts, milk products and whole grains, and "meat-fish" pattern which included frequent intake of meat, fish and seafood. Cognitive function was assessed by the Community Screening Instrument for Dementia (CSI-D). Multivariate logistic regression examined the risk of cognitive impairment with adjustment for potential confounders. RESULTS: A total of 221 men and 656 women was classified as cognitive impaired. Neither the MDS nor the dietary patterns identified by FA were associated with risk of cognitive impairment in men. In women, higher "vegetables-fruits" pattern score was associated with reduced risk of cognitive impairment [Adjusted OR=0.73 (95% CI: 0.54-1.00) of the highest quartile of "vegetables-fruits" pattern score compared with the lowest quartile, ptrend=0.018]. Similar inverse trend was observed for "snacks-drinks-milk products" pattern score [Adjusted OR=0.65 (95% CI: 0.47-0.90) of the highest quartile of "snacks-drinks-milk products" pattern score compared with the lowest quartile, ptrend=0.003]. There was no association of "meat-fish" pattern or the MDS with risk of cognitive impairment in women. CONCLUSION: Higher "vegetables fruits" and "snacks-drinks-milk products" pattern scores were associated with reduced risk of cognitive impairment in Chinese older women in Hong Kong. PMID- 24154649 TI - Relationship between anticholinergic drug use and one-year outcome among elderly people hospitalised in medical wards via emergency department: the SAFES cohort study. AB - AIM: To investigate the relationship between anticholinergic drug use and one year outcome of elderly patients hospitalised via the emergency department. METHODS: Prospective, multicentre, cohort study of patients aged 75 years and older. Comprehensive geriatric evaluation was performed. We included in this analysis all patients for whom data on drug use was available. Anticholinergic drugs were coded using the online database "Thesorimed". One-year mortality and nursing home admission were analysed using a Cox model, with matching on the propensity to use anticholinergic drugs. RESULTS: In total, 1176 subjects were included in this analysis, average age 85+/-6 years, 65% women. Overall, 144 (12%) were taking at least one anticholinergic drug. Mortality and nursing home admission at one year were respectively 29% and 30% in the anticholinergic group, and 34% and 33% respectively in subjects not taking anticholinergic drugs. No significant relationship was observed between anticholinergic drug use and the main endpoints. CONCLUSION: Although we did not observed any statistically significant relationship between use of anticholinergic drugs and one-year outcome in elderly patients, the long-term use of anticholinergic drugs can have deleterious effects on memory and functional capacity, and therefore requires prescriptions to be reviewed regularly. PMID- 24154651 TI - Reversible slurred speech related to capecitabine and lapatinib combination in patients with breast cancer. AB - Capecitabine plus lapatinib combination is an effective chemotherapy regimen in patients with advanced breast cancer. Neurological adverse effects secondary to this regimen were reported rarely in literature. A woman with breast cancer presented with complaints of slurred speech while using the capecitabine and lapatinib combination. Her major complaint was slurred speech. No other radiologic or laboratory disorders were detected in the patient. Slurred speech improved one week after the capecitabine and lapatinib combination was discontinued without any further intervention. PMID- 24154652 TI - Authorising bortezomib treatment prior to reviewing haematology results: a step toward home administration. AB - Bortezomib treatment requires four visits to a chemotherapy unit in each 21-day cycle. Analysis of the Day 1 full blood count could allow clinicians to predict the risk of Grade 4 thrombocytopenia, thus negating the need to review the full blood count prior to each dose. The freedom to administer bortezomib without reviewing full blood count results on each treatment day could minimise appointment times and be a step toward home administration. A prospective study of treatment authorisation following a full toxicity assessment and full blood count results from the previous treatment day was undertaken. The full blood count results from 27 patients, receiving 381 doses revealed 12 treatment episodes where bortezomib was administered in the presence of Grade 4 thrombocytopenia. One instance of bleeding and two episodes of neutropenic sepsis were detected during toxicity assessments and treatment was not administered. Only one instance of Grade 4 thrombocytopenia was reported on any other treatment day when the Day 1 platelet count was greater than 75 * 10(9) units/l. From this data, Day 1 full blood count parameters were derived, which minimise the risk of Grade 4 haematological toxicity on subsequent treatment days, allowing clinicians to identify suitable patients for administration of bortezomib prior to reviewing full blood count results. When platelet counts on Day 1 are greater than 75 * 10(9) units/l and neutrophil counts are greater than 1.0 * 10(9) units/l, the administration of bortezomib can be authorised without the need for review of the full blood count on subsequent days of that cycle. PMID- 24154653 TI - The virulence of Streptococcus mutans and the ability to form biofilms. AB - In some diseases, a very important role is played by the ability of bacteria to form multi-dimensional complex structure known as biofilm. The most common disease of the oral cavity, known as dental caries, is a top leader. Streptococcus mutans, one of the many etiological factors of dental caries, is a microorganism which is able to acquire new properties allowing for the expression of pathogenicity determinants determining its virulence in specific environmental conditions. Through the mechanism of adhesion to a solid surface, S. mutans is capable of colonizing the oral cavity and also of forming bacterial biofilm. Additional properties enabling S. mutans to colonize the oral cavity include the ability to survive in an acidic environment and specific interaction with other microorganisms colonizing this ecosystem. This review is an attempt to establish which characteristics associated with biofilm formation--virulence determinants of S. mutans--are responsible for the development of dental caries. In order to extend the knowledge of the nature of Streptococcus infections, an attempt to face the following problems will be made: Biofilm formation as a complex process of protein-bacterium interaction. To what extent do microorganisms of the cariogenic flora exemplified by S. mutans differ in virulence determinants "expression" from microorganisms of physiological flora? How does the environment of the oral cavity and its microorganisms affect the biofilm formation of dominant species? How do selected inhibitors affect the biofilm formation of cariogenic microorganisms? PMID- 24154656 TI - [Current pediatric orthopedics]. PMID- 24154655 TI - A cross-sectional survey of prevalence and correlates of couple sexual concurrency among married couples in fishing communities along Lake Victoria in Kisumu, Kenya. AB - OBJECTIVE: Sexual concurrency has been associated with HIV infection. Since HIV in sub-Saharan Africa is mostly spread within the context of heterosexual couples, it is necessary that intervention is focused on such couples. We sought to establish the correlates of couple sexual concurrency in Kisumu, Kenya. METHODS: We conducted 1090 gender-matched interviews in 545 couples in a cross sectional survey. A random sample of fishermen and their spouses from 33 fish landing beaches along the shores of Lake Victoria in Kisumu were asked to enrol in the study. Couples were separated into different private rooms for simultaneous interviews that documented socioeconomic and behavioural characteristics, and information on number of sexual partnerships in the preceding 6 months and their status. Based on reported concurrency status of the spouses, a couple was categorised as either concurrent when at least one spouse reported a concurrent sexual relationship or non-concurrent. RESULTS: Overall, 32.1% of the men and 6.2% of the women had concurrent sexual relationships in the 6 months preceding the study, resulting in 37.6% of the couples being sexually concurrent. Unmet sexual desire, intra-spousal suspicions of infidelity, male dominance scripts, domestic violence, couples' children and women's age were the correlates of couple sexual concurrency. CONCLUSIONS: Unmet sexual desires, inter spousal infidelity suspicions, male dominance scripts and domestic violence were the main correlates of couple sexual concurrency in these fishing communities. PMID- 24154654 TI - Characteristics of Haemophilus influenzae invasive isolates from Portugal following routine childhood vaccination against H. influenzae serotype b (2002 2010). AB - We aimed to characterize Haemophilus influenzae invasive isolates recovered in Portugal over a 9-year period (2002-2010) following the inclusion of H. influenzae serotype b (Hib) conjugate vaccination in the National Immunization Program (NIP) in the year 2000 and compare the results with those obtained in a similar study from the pre-vaccination era (1989-2001) previously described by us. As part of a laboratory-based passive surveillance system, 144 invasive isolates obtained in 28 Portuguese hospitals were received at the National Reference Laboratory for Bacterial Respiratory Infections and were characterized. Capsular types and antibiotic susceptibility patterns were determined. The ftsI gene encoding PBP3 was sequenced for beta-lactamase-negative ampicillin-resistant (BLNAR) isolates. Genetic relatedness among isolates was examined by multilocus sequencing typing (MLST). Most isolates (77.1%) were non-capsulated, a significant increase compared to the pre-vaccination era (19.0%, p < 0.001). Serotype b strains decreased significantly (from 81.0 to 13.2%, p < 0.001) and serotype f increased significantly (from 0.8 to 6.9%, p = 0.03). Ten percent of the isolates were beta-lactamase producers, a value lower than that previously observed (26.9%, p = 0.005). Eight percent of all isolates were BLNAR. A high genetic diversity among non-capsulated isolates was found. By contrast, capsulated isolates were clonal. The implementation of Hib vaccination has resulted in a significant decline in the proportion of serotype b H. influenzae invasive disease isolates. Most episodes of invasive disease occurring in Portugal are now due to fully susceptible, highly diverse, non-capsulated strains. Given the evolving dynamics of this pathogen and the increase in non type b capsulated isolates, continuous surveillance is needed. PMID- 24154657 TI - [Minimally invasive treatment of congenital foot deformities in infants: new findings and midterm-results]. AB - In the last decade treatment of foot deformities has changed from extensive surgery to casting and minimally invasive surgery. The Ponseti method has become the most preferred treatment for clubfoot deformities and early evaluations showed promising results. Mid-term results for idiopathic clubfoot revealed the need for additional surgery by anterior tibial tendon transfer in 11-32% of cases depending on the duration of bracing. Anterior tibial tendon transfer is the most important surgical procedure for relapses in the Ponseti concept. Casting, recasting in cases of relapses, bracing and anterior tibial tendon transfer altogether represent the Ponseti method and cannot be considered as single entities.The Dobbs method is a new concept for the treatment of vertical talus. Treatment of vertical talus should start with the Dobbs method but in comparison to clubfoot treatment there has not been a complete change to minimally invasive treatment. Especially in non-idiopathic vertical talus cases open reduction of the talonavicular and calcaneocuboid joint are often necessary. PMID- 24154658 TI - [Significance of sonographically guided percutaneous needle biopsy in the diagnostics of soft tissue tumors]. AB - BACKGROUND: The role of percutaneous needle biopsy in the diagnostics of soft tissue tumors is controversially discussed. The specificity of this method has been examined in this study based on the collective of patients treated in our university hospital. Secondly, the influence of the specialization of the treating surgeon has been evaluated. PATIENTS AND METHODS: This study included 96 patients who underwent percutaneous needle biopsy and, if necessary, surgical resection. The specificity, logistic requirements and possible complications of percutaneous biopsy were evaluated. Special attention was paid to the influence of specialization of the treating surgical team on the specificity of the method. RESULTS: The results of the biopsy were able to define the entity of the lesion correctly in 69.7 %, the dignity in 75.0 % and the grading in 72.0 % of the cases. In the group treated by a specialized team, the specificity of the method was 84.6 % concerning the entity of the lesion, 84.6 % concerning the dignity and 80 % concerning the grading. With regard to the entity the specificity was significantly increased (p < 0.05). CONCLUSION: The findings show that percutaneous needle biopsy represents a logistically simple and efficient diagnostic method for soft tissue tumors which is rarely associated with complications. Subsequent treatment should be performed in a specialized centre. PMID- 24154659 TI - [Spin out - an avoidable complication in total knee replacement]. AB - Spin out of a rotating polyethylene (PE) platform after total knee replacement leads to rotation of the bearing compared to the fixed metal components of the prosthesis at the femur and tibia of approximately 90 degrees . This complication occurs only in prosthesis designs which do not have a rotation limitation. Identification of this complication and its management are described exemplified by two cases. Strategies to avoid spin out are discussed. The most promising way is to avoid using prosthesis designs in which spin out can occur. PMID- 24154660 TI - [Publication activity at a high level]. PMID- 24154661 TI - High frequency of copy number variations (CNVs) in the chromosome 11p15 region in patients with Beckwith-Wiedemann syndrome. AB - Beckwith-Wiedemann syndrome (BWS), an overgrowth and tumor predisposition syndrome is clinically heterogeneous. Its variable presentation makes molecular diagnosis particularly important for appropriate counseling of patients with respect to embyronal tumor risk and recurrence risk. BWS is characterized by macrosomia, omphalocele, and macroglossia. Additional clinical features can include hemihyperplasia, embryonal tumors, umbilical hernia, and ear anomalies. BWS is etiologically heterogeneous arising from dysregulation of one or both of the chromosome 11p15.5 imprinting centers (IC) and/or imprinted growth regulatory genes on chromosome 11p15.5. Most BWS cases are sporadic and result from loss of maternal methylation at imprinting center 2 (IC2), gain of maternal methylation at imprinting center 1 (IC1) or paternal uniparental disomy (UPD). Heritable forms of BWS (15 %) have been attributed mainly to mutations in the growth suppressor gene CDKN1C, but have also infrequently been identified in patients with copy number variations (CNVs) in the chromosome 11p15.5 region. Four hundred and thirty-four unrelated BWS patients referred to the molecular diagnostic laboratory were tested by methylation-specific multiplex ligation-dependent probe amplification. Molecular alterations were detected in 167 patients, where 103 (62 %) showed loss of methylation at IC2, 23 (14 %) had gain of methylation at IC1, and 41 (25 %) showed changes at both ICs usually associated with paternal UPD. In each of the three groups, we identified patients in whom the abnormalities in the chromosome 11p15.5 region were due to CNVs. Surprisingly, 14 patients (9 %) demonstrated either deletions or duplications of the BWS critical region that were confirmed using comparative genomic hybridization array analysis. The majority of these CNVs were associated with a methylation change at IC1. Our results suggest that CNVs in the 11p15.5 region contribute significantly to the etiology of BWS. We highlight the importance of performing deletion/duplication testing in addition to methylation analysis in the molecular investigation of BWS to improve our understanding of the molecular basis of this disorder, and to provide accurate genetic counseling. PMID- 24154662 TI - Next generation sequencing-based molecular diagnosis of retinitis pigmentosa: identification of a novel genotype-phenotype correlation and clinical refinements. AB - Retinitis pigmentosa (RP) is a devastating form of retinal degeneration, with significant social and professional consequences. Molecular genetic information is invaluable for an accurate clinical diagnosis of RP due to its high genetic and clinical heterogeneity. Using a gene capture panel that covers 163 of the currently known retinal disease genes, including 48 RP genes, we performed a comprehensive molecular screening in a collection of 123 RP unsettled probands from a wide variety of ethnic backgrounds, including 113 unrelated simplex and 10 autosomal recessive RP (arRP) cases. As a result, 61 mutations were identified in 45 probands, including 38 novel pathogenic alleles. Interestingly, we observed that phenotype and genotype were not in full agreement in 21 probands. Among them, eight probands were clinically reassessed, resulting in refinement of clinical diagnoses for six of these patients. Finally, recessive mutations in CLN3 were identified in five retinal degeneration patients, including four RP probands and one cone-rod dystrophy patient, suggesting that CLN3 is a novel non syndromic retinal disease gene. Collectively, our results underscore that, due to the high molecular and clinical heterogeneity of RP, comprehensive screening of all retinal disease genes is effective in identifying novel pathogenic mutations and provides an opportunity to discover new genotype-phenotype correlations. Information gained from this genetic screening will directly aid in patient diagnosis, prognosis, and treatment, as well as allowing appropriate family planning and counseling. PMID- 24154663 TI - Beneficial effects of Chrysin against Methotrexate-induced hepatotoxicity via attenuation of oxidative stress and apoptosis. AB - Methotrexate (MTX), a folic acid antagonist, an effective chemotherapeutic agent is used in the treatment of a wide range of tumors and autoimmune diseases. Moreover, hepatotoxicity limits its clinical use. Several studies have already confirmed that the oxidative stress plays a major role in the pathogenesis of MTX induced damage in the various organs especially in liver. The aim of this study was to determine the protective effect of Chrysin against MTX-induced hepatic oxidative stress and apoptosis in rats. In the present study, efficacy of Chrysin was investigated against hepatotoxicity caused by MTX in terms of biochemical investigations of antioxidant enzymes, apoptosis, and histopathological alteration in rat liver. In the MTX-treated group there was a significant increase in alanine transaminase, aspartate aminotransferase, lactate dehydrogenase activity and malondialdehyde content as well as decreased glutathione peroxidase, glutathione reductase, superoxide dismutase, catalase activities and reduced glutathione content were also observed compared to the control group as a marker of oxidative stress. Histopathological alterations and apoptosis through the immunopositive staining of p53, cleaved caspases-3 and Bcl 2-associated X protein in rat liver were observed. Pretreatment of Chrysin at both doses prevents the hepatotoxicity by ameliorating oxidative stress, histopathological alterations, and apoptosis and thus our results suggest that Chrysin has a protective effect against hepatotoxicity induced by MTX and it may, therefore, improve the therapeutic index of MTX if co-administration is done. PMID- 24154664 TI - CaMKII activity in the ventral tegmental area gates cocaine-induced synaptic plasticity in the nucleus accumbens. AB - Addictive drugs such as cocaine induce synaptic plasticity in discrete regions of the reward circuit. The aim of the present study is to investigate whether cocaine-evoked synaptic plasticity in the ventral tegmental area (VTA) and nucleus accumbens (NAc) is causally linked. Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) is a central regulator of long-term synaptic plasticity, learning, and drug addiction. We examined whether blocking CaMKII activity in the VTA affected cocaine conditioned place preference (CPP) and cocaine-evoked synaptic plasticity in its target brain region, the NAc. TatCN21 is a CaMKII inhibitory peptide that blocks both stimulated and autonomous CaMKII activity with high selectivity. We report that intra-VTA microinjections of tatCN21 before cocaine conditioning blocked the acquisition of cocaine CPP, whereas intra-VTA microinjections of tatCN21 before saline conditioning did not significantly affect cocaine CPP, suggesting that the CaMKII inhibitor blocks cocaine CPP through selective disruption of cocaine-cue-associated learning. Intra-VTA tatCN21 before cocaine conditioning blocked cocaine-evoked depression of excitatory synaptic transmission in the shell of the NAc slices ex vivo. In contrast, intra-VTA microinjection of tatCN21 just before the CPP test did not affect the expression of cocaine CPP and cocaine-induced synaptic plasticity in the NAc shell. These results suggest that CaMKII activity in the VTA governs cocaine-evoked synaptic plasticity in the NAc during the time window of cocaine conditioning. PMID- 24154666 TI - Influence of RGS2 on sertraline treatment for social anxiety disorder. AB - Only a minority of patients with social anxiety disorder (SAD) has a robust therapeutic response to evidence-based serotonin reuptake inhibitor (SSRI) treatment. To help improve the personalized medicine approach to psychiatric care, we evaluated several candidate genetic predictors of SSRI response in SAD. At the start of a randomized controlled trial (NCT00282828), 346 patients with SAD at three sites received protocol-driven, open-label treatment with sertraline, up to 200. mg/d over 10 weeks. Efficacy was determined using a continuous measure of outcome (Liebowitz Social Anxiety Scale (LSAS)) and dichotomous indicators of response (LSAS <= 50) and remission (LSAS <= 30). Predictors of efficacy were examined in multivariate regression models that included eight polymorphic variants in four candidate genes (four in RGS2, two in HTR2A, one in SLC6A2, and one in SLC6A4). Adjusting for genetic ancestral cluster and non-genetic predictors of response, all four single-nucleotide polymorphisms (SNPs) in RGS2 predicted change in LSAS over time, at study-wise significance (p=0.00833), with the minor allele associated with less improvement over time. After adjusting for genetic ancestral cluster and non-genetic predictors of remission, two of the four RGS2 SNPs predicted likelihood of remission at or just below study-wise significance (p=0.025): rs4606 (AOR=0.49 (95% CI=0.27-0.90), p=0.022) and rs1819741 (AOR=0.50 (95% CI=0.28-0.92), p=0.027). Variation in RGS2, a gene previously shown to be associated with social anxiety phenotypes and serotonergic neurotransmission, may be a biomarker of the likelihood of substantially benefiting from sertraline among patients with SAD. PMID- 24154665 TI - Elevated monoamine oxidase a binding during major depressive episodes is associated with greater severity and reversed neurovegetative symptoms. AB - Inadequate treatment response occurs in approximately 40% of major depressive episodes (MDEs), and one approach to solve this is careful matching of treatment to the specific pathologies of MDE. One such biological abnormality is elevated monoamine oxidase A (MAO-A) levels, which occurs in the prefrontal and anterior cingulate cortex (PFC and ACC) during MDE; however, the subtypes for which this abnormality is most prominent are unknown. We hypothesized that MAO-A levels in the PFC and ACC are most elevated in MDE with greater severity and reversed neurovegetative symptoms (hypersomnia and either hyperphagia or weight gain). MAO A VT (an index of MAO-A density) was measured using [(11)C]harmine positron emission tomography (PET) in 42 subjects with MDEs secondary to major depressive disorder and 37 healthy controls. The effect of severity and reversed neurovegetative symptoms on MAO-A VT in the PFC and ACC was analyzed using a multivariate analysis of variance (MANOVA). Greater severity and reversed neurovegetative symptoms were associated with elevated MAO-A VT in the PFC and ACC (MANOVA, severity: F(2,38)=5.44, p=0.008; reversed neurovegetative symptoms: F(2,38)=5.13, p=0.01). Increased MAO-A level, when greater severity and reversed neurovegetative symptoms are present, may explain the association of these clinical features with a preferential response to MAO inhibitors, which is especially well-evidenced for reversed neurovegetative symptoms in MDE. As MAO-A creates oxidative stress, facilitates apoptosis, and metabolizes monoamines, therapeutics opposing these processes are predicted to best treat MDE with greater severity and reversed neurovegetative symptoms. PMID- 24154667 TI - Abnormal GABAergic function and negative affect in schizophrenia. AB - Deficits in the gamma-aminobutyric acid (GABA) system have been reported in postmortem studies of schizophrenia, and therapeutic interventions in schizophrenia often involve potentiation of GABA receptors (GABAR) to augment antipsychotic therapy and treat negative affect such as anxiety. To map GABAergic mechanisms associated with processing affect, we used a benzodiazepine challenge while subjects viewed salient visual stimuli. Fourteen stable, medicated schizophrenia/schizoaffective patients and 13 healthy comparison subjects underwent functional magnetic resonance imaging using the blood oxygenation level dependent (BOLD) technique while they viewed salient emotional images. Subjects received intravenous lorazepam (LRZ; 0.01 mg/kg) or saline in a single-blinded, cross-over design (two sessions separated by 1-3 weeks). A predicted group by drug interaction was noted in the dorsal medial prefrontal cortex (dmPFC) as well as right superior frontal gyrus and left and right occipital regions, such that psychosis patients showed an increased BOLD signal to LRZ challenge, rather than the decreased signal exhibited by the comparison group. A main effect of reduced BOLD signal in bilateral occipital areas was noted across groups. Consistent with the role of the dmPFC in processing emotion, state negative affect positively correlated with the response to the LRZ challenge in the dmPFC for the patients and comparison subjects. The altered response to LRZ challenge is consistent with altered inhibition predicted by postmortem findings of altered GABAR in schizophrenia. These results also suggest that negative affect in schizophrenia/schizoaffective disorder is associated-directly or indirectly-with GABAergic function on a continuum with normal behavior. PMID- 24154668 TI - Repeated transcranial direct current stimulation prevents abnormal behaviors associated with abstinence from chronic nicotine consumption. AB - Successful available treatments to quit smoking remain scarce. Recently, the potential of transcranial direct current stimulation (tDCS) as a tool to reduce craving for nicotine has gained interest. However, there is no documented animal model to assess the neurobiological mechanisms of tDCS on addiction-related behaviors. To address this topic, we have developed a model of repeated tDCS in mice and used it to validate its effectiveness in relieving nicotine addiction. Anodal repeated tDCS was applied over the frontal cortex of Swiss female mice. The stimulation electrode (anode) was fixed directly onto the cranium, and the reference electrode was placed onto the ventral thorax. A 2 * 20 min/day stimulation paradigm for five consecutive days was used (0.2 mA). In the first study, we screened for behaviors altered by the stimulation. Second, we tested whether tDCS could alleviate abnormal behaviors associated with abstinence from nicotine consumption. In naive animals, repeated tDCS had antidepressant-like properties 3 weeks after the last stimulation, improved working memory, and decreased conditioned place preference for nicotine without affecting locomotor activity and anxiety-related behavior. Importantly, abnormal behaviors associated with chronic nicotine exposure (ie, depression-like behavior, increase in nicotine-induced place preference) were normalized by repeated tDCS. Our data show for the first time in an animal model that repeated tDCS is a promising, non expensive clinical tool that could be used to reduce smoking craving and facilitate smoking cessation. Our animal model will be useful to investigate the mechanisms underlying the effects of tDCS on addiction and other psychiatric disorders. PMID- 24154669 TI - Size dependent structural and magnetic properties of FeO-Fe3O4 nanoparticles. AB - The magnetic properties of monodisperse FeO-Fe3O4 nanoparticles with different mean sizes and volume fractions of FeO synthesized via decomposition of iron oleate were correlated to their crystallographic and phase compositional features by exploiting high resolution transmission electron microscopy, X-ray diffraction, Mossbauer spectroscopy and field and zero field cooled magnetization measurements. A model describing the phase transformation from a pure Fe3O4 phase to a mixture of Fe3O4, FeO and interfacial FeO-Fe3O4 phases as the particle size increases was established. The reduced magnetic moment in FeO-Fe3O4 nanoparticles was attributed to the presence of differently oriented Fe3O4 crystalline domains in the outer layers and paramagnetic FeO phase. The exchange bias energy, dominating magnetization reversal mechanism and superparamagnetic blocking temperature in FeO-Fe3O4 nanoparticles depend strongly on the relative volume fractions of FeO and the interfacial phase. PMID- 24154670 TI - Metabolic and protein interaction sub-networks controlling the proliferation rate of cancer cells and their impact on patient survival. AB - Cancer cells can have a broad scope of proliferation rates. Here we aim to identify the molecular mechanisms that allow some cancer cell lines to grow up to 4 times faster than other cell lines. The correlation of gene expression profiles with the growth rate in 60 different cell lines has been analyzed using several genome-scale biological networks and new algorithms. New possible regulatory feedback loops have been suggested and the known roles of several cell cycle related transcription factors have been confirmed. Over 100 growth-correlated metabolic sub-networks have been identified, suggesting a key role of simultaneous lipid synthesis and degradation in the energy supply of the cancer cells growth. Many metabolic sub-networks involved in cell line proliferation appeared also to correlate negatively with the survival expectancy of colon cancer patients. PMID- 24154672 TI - Self-assembly of a heteroleptic one-dimensional chain comprising different dinuclear meso-helicates in the solid-state. AB - We describe two mesocate assemblies that contain either an ethylene glycol or ammonium group which form a heteroleptic one-dimensional infinite chain in the solid state. PMID- 24154674 TI - Aprotinin revisited. PMID- 24154671 TI - Tissue-specific gene expression and functional regulation of uncoupling protein 2 (UCP2) by hypoxia and nutrient availability in gilthead sea bream (Sparus aurata): implications on the physiological significance of UCP1-3 variants. AB - The aim of this study was to assess in an integrative manner the physiological regulation of uncoupling protein 2 (UCP2) in gilthead sea bream. A contig of 1,325 nucleotides in length with an open reading frame of 307 amino acids was recognized as UCP2 after searches in our transcriptome reference database ( http://www.nutrigroup-iats.org/seabreamdb ). Gene expression mapping by quantitative real-time PCR revealed a ubiquitous profile that clearly differs from that of UCP1 and UCP3 variants with the greatest abundance in liver and white skeletal muscle, respectively. The greatest abundance of UCP2 transcripts was found in the heart, with a relatively high expression level in blood cells, where UCP1 and UCP3 transcripts were practically undetectable. Functional studies revealed that UCP2 mRNA expression remains either unaltered or up-regulated upon feed restriction in glycolytic (white skeletal muscle) and highly oxidative muscle tissues (heart and red skeletal muscle), respectively. In contrast, exposure to hypoxic conditions (18-19% oxygen saturation) markedly down-regulated the UCP2 mRNA expression in blood cells in a cellular environment with increased haematocrit, blood haemoglobin content, and circulating levels of glucose and lactate, and total plasma antioxidant activity. These findings demonstrated that UCP2 expression is highly regulated at the transcriptional level, arising this UCP variant as an important piece of the complex trade-off between metabolic and redox sensors. This feature would avoid the activation of futile cycles of energy wastage if changes in tissue oxidative and antioxidant metabolic capabilities are able to maintain the production of reactive oxygen species at a low regulated level. PMID- 24154675 TI - What is new in prevention of muscle weakness in critically ill patients? PMID- 24154676 TI - Intra-abdominal candidiasis: the guidelines-forgotten non-candidemic invasive candidiasis. PMID- 24154677 TI - Dermatologic findings in 16 patients with Cockayne syndrome and cerebro-oculo facial-skeletal syndrome. AB - IMPORTANCE: Cockayne syndrome (CS) and cerebro-oculo-facial-skeletal (COFS) syndrome are autosomal recessive diseases that belong to the family of nucleotide excision repair disorders. Our aim was to describe the cutaneous phenotype of patients with these rare diseases. OBSERVATIONS: A systematic dermatologic examination of 16 patients included in a European study of CS was performed. The patients were aged 1 to 28 years. Six patients (38%) had mutations in the Cockayne syndrome A (CSA) gene, and the remaining had Cockayne syndrome B (CSB) gene mutations. Fourteen patients were classified clinically as having CS and 2 as having COFS syndrome. Photosensitivity was present in 75% of the patients and was characterized by sunburn after brief sun exposure. Six patients developed symptoms after short sun exposure through a windshield. Six patients had pigmented macules on sun-exposed skin, but none developed a skin neoplasm. Twelve patients (75%) displayed cyanotic acral edema of the extremities. Eight patients had nail dystrophies and 7 had hair anomalies. CONCLUSIONS AND RELEVANCE: The dermatologic findings of 16 cases of CS and COFS syndrome highlight the high prevalence of photosensitivity and hair and nail disorders. Cyanotic acral edema was present in 75% of our patients, a finding not previously reported in CS. PMID- 24154680 TI - Syntheses, structures and properties of two 2-D layered hybrid organic-inorganic materials based on different V4O12 building units. AB - Two new layered hybrid organic-inorganic compounds [Zn(pyim)]2V4O12 () (pyim = 2 (2-pyridyl)imidazole) and [Cu(bim)2]2V4O12(H2O).CH3CH2OH () (bim = bis(1 imidazolyl)methane) based on polyoxovanadates (POVs) and organic ligands decorated transition metal units have been synthesized by hydrothermal and solvothermal methods respectively. Single crystal XRD, fluorescence spectrum, magnetic measurement, IR spectra, powder XRD and thermogravimetric (TG) measurements were performed to analyze the structures and properties of and . The structural analysis reveals that compound features a two-dimensional {[Zn(pyim)]2V4O12}n layered structure, constructed by sine wave-like {V4O12}n(4n ) chains, Zn(2+) ions and pyim ligands. In the layered structure of , {V4O12}(4-) circles are connected by Cu(2+) ions to form {Cu(V4O12)}n(2n-) chains, which are further linked by {Cu(bim)4}(2+) subunits to generate a hybrid layer of . The magnetic susceptibility measurement indicates strong antiferromagnetic interactions between Cu(2+) ions in . PMID- 24154679 TI - Targeting connective tissue growth factor (CTGF) in acute lymphoblastic leukemia preclinical models: anti-CTGF monoclonal antibody attenuates leukemia growth. AB - Connective tissue growth factor (CTGF/CCN2) is involved in extracellular matrix production, tumor cell proliferation, adhesion, migration, and metastasis. Recent studies have shown that CTGF expression is elevated in precursor B-acute lymphoblastic leukemia (ALL) and that increased expression of CTGF is associated with inferior outcome in B-ALL. In this study, we characterized the functional role and downstream signaling pathways of CTGF in ALL cells. First, we utilized lentiviral shRNA to knockdown CTGF in RS4;11 and REH ALL cells expressing high levels of CTGF mRNA. Silencing of CTGF resulted in significant suppression of leukemia cell growth compared to control vector, which was associated with AKT/mTOR inactivation and increased levels of cyclin-dependent kinase inhibitor p27. CTGF knockdown sensitized ALL cells to vincristine and methotrexate. Treatment with an anti-CTGF monoclonal antibody, FG-3019, significantly prolonged survival of mice injected with primary xenograft B-ALL cells when co-treated with conventional chemotherapy (vincristine, L-asparaginase and dexamethasone). Data suggest that CTGF represents a targetable molecular aberration in B-ALL, and blocking CTGF signaling in conjunction with administration of chemotherapy may represent a novel therapeutic approach for ALL patients. PMID- 24154681 TI - The C-H bond activation in 1-ethyl-3-methylimidazolium acetate-copper(II) acetate water-air (dioxygen) systems. AB - Ionic liquid (1-ethyl-3-methylimidazolium acetate, [C2C1im][AcO])-copper(ii) diacetate monohydrate-water-air (O2) systems have been investigated by (13)C NMR, EPR, spectrophotometry, HPLC, and synthetic chemistry methods at different temperatures. The C-H bond activation of [C2C1im](+) with the formation of the unusual dication 1,1'-diethyl-3,3'-dimethyl-2,2'-biimidazolium ([(C2C1im)2](2+)) at 50 degrees C and 1-ethyl-3-methyl-1H-imidazol-2(3H)-one (C2C1imO) at 50-85 degrees C was revealed. Two new complexes with the above compounds, [(C2C1im)2][Cu(AcO)4] and Cu2(AcO)4(C2C1imO)2, were isolated from the systems and characterized by X-ray structural analysis. Catalytic cycles with the participation of copper(ii) acetate and dioxygen and the production of [(C2C1im)2](2+) and C2C1imO have been proposed. The catalysis presumably includes the formation of the Cu(II)(O2)Cu(II) active centre with MU-eta(2):eta(2) peroxide bridging in analogy with tyrosinase and catechol oxidase activity. PMID- 24154682 TI - Phamacokinetics of rivaroxaban in adolescents. AB - BACKGROUND: The direct factor Xa inhibitor rivaroxaban is approved for venous thromboembolism (VTE) treatment in adults. However, in all phase-III trials children or adolescents have not been included. For under-aged VTE patients, current standard treatment consists of low molecular weight heparin or Vitamin K antagonists. Rivaroxaban could be an attractive alternative, however, no data on the pharmacokinetics (PK) of rivaroxaban in adolescents are currently available. PATIENT, METHODS: We report PK data for rivaroxaban derived from a girl (age:15 years), who presented three month after acute deep vein thrombosis, already receiving rivaroxaban therapy. In the steady state of rivaroxaban therapy (20 mg once daily), plasma levels at baseline, 3 and 6 hours after intake of rivaroxaban were measured to evaluate the pharmacokinetics and changes of global coagulation tests. RESULTS: At baseline, a very low trough level of only 9.9 ng/ml rivaroxaban was found. At 3 hours, a peak concentration of 137.76 ng/ml rivaroxaban was observed with a rapid decrease within 6 hours after drug intake, when plasma levels of 34.45 ng/ml were measured. The patients INR and aPTT values reacted correspondingly. CONCLUSION: Our data indicate that adolescents may exhibit lower peak and trough levels after rivaroxaban intake compared to adult patients, but seem to have similar PK curves during the elimination phase. While our case is the first published case of a successful VTE treatment in an under aged patient, we strongly discourage the routine use of rivaroxaban in non-adult patients, until data from phase II and III trials are available. PMID- 24154683 TI - 'Me and my bump': an interpretative phenomenological analysis of the experiences of pregnancy for vulnerable women. AB - Eight pregnant women, considered to be 'vulnerable' due to exposure to a number of underlying risk factors, participated in semi-structured interviews regarding their experiences of pregnancy and of Mellow Bumps, a 6-week targeted antenatal intervention. Interview transcripts were explored using interpretative phenomenological analysis. The analysis revealed five superordinate themes: pregnancy as a time of reflection; the body being taken over; pregnancy as an emotional rollercoaster; relationships as important; separating identities. Pre- and post-natal attachment theories were found to be useful in interpreting the data. Findings suggest that pregnancy may be 'normalising' and provide an important opportunity for building more positive representations of the self. Findings also provide clinical support for the assertion that the attachment relationship begins before birth. The Mellow Bumps intervention was uniformly seen as helpful. It appeared to nurture prenatal attachment relationships, playing a potentially protective role, by helping to establish the foundations for secure mother-infant relationships in the future. Meeting similar women and engaging in ordinary, supportive conversation during Mellow Bumps seemed to reduce feelings of isolation and stigma. Implications for clinical practice are considered. PMID- 24154684 TI - Endocrine side effects of anti-cancer drugs: effects of anti-cancer targeted therapies on lipid and glucose metabolism. AB - During the past years, targeted therapies for cancer have been developed using drugs that have significant metabolic consequences. Among them, the mammalian target of rapamycin (mTOR) inhibitors and, to a much lesser extent, the tyrosine kinase inhibitors (TKIs) are involved. mTOR plays a key role in the regulation of cell growth as well as lipid and glucose metabolism. Treatment with mTOR inhibitors is associated with a significant increase in plasma triglycerides and LDL cholesterol. mTOR inhibitors seem to increase plasma triglycerides by reducing the activity of the lipoprotein lipase which is in charge of the catabolism of triglyceride-rich lipoproteins. The increase in LDL cholesterol observed with mTOR inhibitors seems to be due to a decrease in LDL catabolism secondary to a reduction of LDL receptor expression. In addition, treatment with mTOR inhibitors is associated with a high incidence of hyperglycemia, ranging from 13 to 50% in the clinical trials. The mechanisms responsible for hyperglycemia with new onset diabetes are not clear, but are likely due to the combination of impaired insulin secretion and insulin resistance. TKIs do not induce hyperlipidemia but alter glucose homeostasis. Treatment with TKIs may be associated either with hyperglycemia or hypoglycemia. The molecular mechanism by which TKIs control glucose homeostasis remains unknown. Owing to the metabolic consequences of these agents used as targeted anti-cancer therapies, a specific and personalized follow-up of blood glucose and lipids is recommended when using mTOR inhibitors and of blood glucose when using TKIs. PMID- 24154685 TI - Acute and sub-chronic effects of purified cathinone from khat (Catha edulis) on behavioural profiles in vervet monkeys (Chlorocebus aethiops). AB - We investigated the cumulative effects of cathinone on behavioural alterations in single-caged vervet monkeys. Fourteen adult vervets were divided into tests (12 animals) and controls (2 animals), and exposed to escalating doses of cathinone at alternate days of each week for 4 months in presence and absence of cage enrichment. One month of pre-treatment phase served to establish baseline values. Composite behavioural scores of aggression, anxiety, abnormal responses, withdrawal and appetite loss were done. A series of repeated measures analysis of variances were conducted to examine the extent to which cathinone administration was associated with patterns of changes in behavioural data. Results indicate a dose-dependent effect of cathinone on increases of aggression, anxiety, abnormal responses, withdrawal, and appetite loss. The findings demonstrate that at high doses and long-term exposure, cathinone causes behavioural alterations probably via changes in presynaptic striatal dopamine system. PMID- 24154687 TI - A radical pathway in catecholase activity with nickel(II) complexes of phenol based "end-off" compartmental ligands. AB - Seven dinuclear and one dinuclear based dicyanamide bridged polymeric Ni(II) complexes of phenol based compartmental ligands (HL(1)-HL(4)) have been synthesized with the aim to investigate their catecholase-like activity and to evaluate the most probable mechanistic pathway involved in this process. The complexes have been characterized by routine physicochemical studies as well as by X-ray single crystal structure analyses namely [Ni2(L(2))(SCN)3(H2O)(CH3OH)] (), [Ni2(L(4))(SCN)3(CH3OH)2] (), [Ni2(L(2))(SCN)2(AcO)(H2O)] (), [Ni2(L(4))(SCN)(AcO)2] (), [Ni2(L(2))(N3)3(H2O)2] (), [Ni2(L(4))(N3)3(H2O)2] (), [Ni2(L(1))(AcO)2(N(CN)2)]n () and [Ni2(L(3))(AcO)2(N(CN)2)] (), [SCN = isothiocyanate, AcO = acetate, N3 = azide, and N(CN)2 = dicyanamide anion; L(1-4) = 2,6-bis(R2-iminomethyl)-4-R1-phenolato, where R1 = methyl and tert-butyl, R2 = N,N-dimethyl ethylene for L(1-2) and R1 = methyl and tert-butyl, R2 = 2-(N-ethyl) pyridine for L(3-4)]. A UV-vis spectrophotometric study using 3,5-di-tert butylcatechol (3,5-DTBC) reveals that all the complexes are highly active in catalyzing the aerobic oxidation of (3,5-DTBC) to 3,5-di-tert-butylbenzoquinone (3,5-DTBQ) in methanol medium with the formation of hydrogen peroxide. An EPR study confirms the generation of radicals during the catalysis. Cyclic voltammetric studies of the complexes in the presence and absence of 3,5-DTBC have been performed. Reduction of Ni(II) to Ni(I) and that of the imine bond of the ligand system have been detected at ~-1.0 V and ~-1.5 V, respectively. Coulometric separation of the species at -1.5 V followed by the EPR study at 77 K confirms the species as an organic radical and thus most probably reduced imine species. Spectroelectrochemical analysis at -1.5 V clearly indicates the oxidation of 3,5-DTBC and thus suggests that the radical pathway is supposed to be responsible for the catecholase-like activity exhibited by the nickel complexes. The ligand centred radical generation has further been verified by density functional theory calculation. PMID- 24154686 TI - Reduced clearance of proteins labeled with diisopropylfluorophosphate in portacaval-shunted rats. AB - Portacaval shunting is a model for hepatic encephalopathy that causes chronic hyperammonemia, disruption of metabolic, signaling, and neurotransmitter systems, and progressive morphological changes. Exposure of cultured cells to ammonia raises intralysosomal pH and inhibits proteolysis, and the present study tested the hypothesis that proteolytic capacity is diminished in portacaval-shunted rats. Proteins were labeled in vivo with tracer doses of diisopropylfluorophosphate (DFP) and clearance of label was assayed. This approach labeled proteins independent of protein synthesis, which is reported to be altered in shunted rats, and avoided complications arising from re-utilization of labeled amino acids that causes underestimation of degradation rate. Characterization of DFP labeling showed that protein labeling was fast, about 50% of the label was released during a 24 h interval, labeling by DFP metabolites was negligible, inhibition of brain acetylcholinesterase was not detectable, and labeling by [(3)H]- and [(14)C]DFP was equivalent. To assay degradative capacity, proteins were first labeled with [(3)H]DFP, followed by labeling with [(14)C]DFP that was given 24 or 72 h later. The (3)H/(14)C ratio in each animal was used as a relative measure of removal of (3)H-labeled proteins. (3)H/(14)C ratios were generally significantly higher in portacaval-shunted rats than in controls, consistent with reduced proteolytic capacity. Assays of amino acid incorporation into brain protein generally replicated literature reports, supporting the conclusion that protein synthesis unlikely to be markedly inhibited and amino acid recycling influences calculated protein synthesis rates in shunted rats. Therapeutic strategies to reduce ammonia level would help normalize lysosomal functions and protein and lipid turnover. PMID- 24154688 TI - JAK1 truncating mutations in gynecologic cancer define new role of cancer associated protein tyrosine kinase aberrations. AB - Cancer-associated protein tyrosine kinase (PTK) mutations usually are gain-of function (GOF) mutations that drive tumor growth and metastasis. We have found 50 JAK1 truncating mutations in 36 of 635 gynecologic tumors in the Total Cancer Care(r) (TCC(r)) tumor bank. Among cancer cell lines containing JAK1 truncating mutations in the Cancer Cell Line Encyclopedia databank, 68% are gynecologic cancer cells. Within JAK1 the K142, P430, and K860 frame-shift mutations were identified as hot spot mutation sites. Sanger sequencing of cancer cell lines, primary tumors, and matched normal tissues confirmed the JAK1 mutations and showed that these mutations are somatic. JAK1 mediates interferon (IFN)-gamma regulated tumor immune surveillance. Functional assays show that JAK1 deficient cancer cells are defective in IFN-gamma-induced LMP2 and TAP1 expression, loss of which inhibits presentation of tumor antigens. These findings identify recurrent JAK1 truncating mutations that could contribute to tumor immune evasion in gynecologic cancers, especially in endometrial cancer. PMID- 24154690 TI - Metabolism: Nuclear or cytoplasmic? PMID- 24154689 TI - Stem cells: As directed. PMID- 24154692 TI - Significant water absorption goes paracellular in kidney proximal tubules. PMID- 24154691 TI - The direction and role of phenotypic transition between podocytes and parietal epithelial cells in focal segmental glomerulosclerosis. AB - Focal segmental glomerulosclerosis (FSGS) is a podocyte disease. Among the various histologies of FSGS, active epithelial changes, hyperplasia, as typically seen in the collapsing variant, indicates disease progression. Using a podocyte specific injury model of FSGS carrying a genetic podocyte tag combined with double immunostaining by different sets of podocytes and parietal epithelial cell (PEC) markers [nestin/Pax8, Wilms' tumor-1 (WT1)/claudin1, and podocalyxin/Pax2], we investigated the direction of epithelial phenotypic transition and its role in FSGS. FSGS mice showed progressive proteinuria and renal dysfunction often accompanied by epithelial hyperplasia, wherein 5-bromo-4-chloro-3-indoyl beta-d galactoside (X-gal)-positive podocyte-tagged cells were markedly decreased. The average numbers of double-positive cells in all sets of markers were significantly increased in the FSGS mice compared with the controls. In addition, the average numbers of double-positive cells for X-gal/Pax8, nestin/Pax8 and podocalyxin/Pax2 staining in the FSGS mice were comparable, whereas those of WT1/claudin1 were significantly increased. When we divided glomeruli from FSGS mice into those with FSGS lesions and those without, double-positive cells tended to be more closely associated with glomeruli without FSGS lesions compared with those with FSGS lesions. Moreover, the majority of double-positive cells appeared to be isolated and very rarely associated with FSGS lesions (1/1,997 glomeruli). This study is the first to show the incidence and localization of epithelial cells with phenotypical changes in FSGS using a genetic tag. The results suggest that the major direction of epithelial phenotypic transition in cellular FSGS is from podocytes to PECs and that these cells were less represented in the active lesions of FSGS. PMID- 24154693 TI - Role of epoxyeicosatrienoic acids (EETs) in mediation of dopamine's effects in the kidney. AB - We have recently demonstrated that intrarenal dopamine plays an important role in preventing the development of systemic hypertension. Similarly, renal cytochrome P-450 (CYP)-epoxygenase-derived arachidonic acid metabolites, epoxyeicosatrienoic acids (EETs), also are antihypertensive through inhibiting sodium reabsorption and vasodilation. The potential interaction between renal dopamine and epoxygenase systems was investigated. Catechol-O-methyl-transferase (COMT)(-/-) mice with increased intrarenal dopamine levels and proximal tubule deletion of aromatic amino acid decarboxylase (ptAADC(-/-)) mice with renal dopamine deficiency were treated with a low-salt diet or high-salt diet for 2 wk. Wild type or Cyp2c44(-/-) mice were treated with gludopa, which selectively increased renal dopamine levels. In low salt-treated mice, urinary EET levels were related to renal dopamine levels, being highest in COMT(-/-) mice and lowest in ptAADC(-/ ) mice. In high salt-treated mice, total EET and individual EET levels in both the kidney and urine were also highest in COMT(-/-) mice and lowest in ptAADC(-/ ) mice. Selective increases in renal dopamine in response to gludopa administration led to marked increases in both total and all individual EET levels in the kidney without any changes in blood levels. qRT-PCR and immunoblotting indicated that gludopa increased renal Cyp2c44 mRNA and protein levels. Gludopa induced marked increases in urine volume and urinary sodium excretion in wild-type mice. In contrast, gludopa did not induce significant increases in urine volume or urinary sodium excretion in Cyp2c44(-/-) mice. These studies demonstrate that renal EET levels are maintained by intrarenal dopamine, and Cyp2c44-derived EETs play an important role in intrarenal dopamine-induced natriuresis and diuresis. PMID- 24154694 TI - Cinacalcet attenuates the renal endothelial-to-mesenchymal transition in rats with adenine-induced renal failure. AB - Elevated serum parathyroid hormone (PTH) is an important complicated phenomenon in patients with chronic kidney disease (CKD). Emerging evidence indicates the involvement of PTH in organ fibrosis, and suppression of PTH by cinacalcet (CINA) ameliorates the progression of fibrotic disorders. However, the underlying mechanisms are largely unknown. The endothelial-to-mesenchymal transition (EndMT) has been shown to be an important mechanism involved in renal fibrosis. The present study aimed to investigate whether CINA treatment attenuated renal EndMT in rats with adenine-induced chronic renal failure (CRF). Compared with the control group, serum PTH was significantly higher in the CRF group and was suppressed after CINA treatment. Serum calcium, phosphorus, and calcium * phosphorus product levels were similar in the CRF group and CINA-treated CRF group. Renal collagen accumulation was significantly increased in the CRF group, which was markedly ameliorated by CINA treatment. Expression of the endothelial marker CD31 was significantly downregulated in rats with CRF, whereas expression of the mesenchymal markers fibroblast specific-protein 1 and alpha-smooth muscle actin was markedly upregulated. These changes were inhibited by CINA treatment. The protein levels of these EndMT-related markers were strongly correlated with serum PTH concentrations. Furthermore, the in vitro study showed that PTH could significantly increase the expression of fibroblast specific-protein 1 and alpha smooth muscle actin and decrease CD31 in mRNA and protein levels in a concentration- and time-dependent manner. In conclusion, our study suggests that reducing serum PTH by CINA treatment could attenuate renal fibrosis via suppression of EndMT in the adenine-induced CRF rat model. PMID- 24154695 TI - Metallothionein deficiency exacerbates diabetic nephropathy in streptozotocin induced diabetic mice. AB - Oxidative stress and inflammation play important roles in diabetic complications, including diabetic nephropathy. Metallothionein (MT) is induced in proximal tubular epithelial cells as an antioxidant in the diabetic kidney; however, the role of MT in renal function remains unclear. We therefore investigated whether MT deficiency accelerates diabetic nephropathy through oxidative stress and inflammation. Diabetes was induced by streptozotocin injection in MT-deficient (MT(-/-)) and MT(+/+) mice. Urinary albumin excretion, histological changes, markers for reactive oxygen species (ROS), and kidney inflammation were measured. Murine proximal tubular epithelial (mProx24) cells were used to further elucidate the role of MT under high-glucose conditions. Parameters of diabetic nephropathy and markers of ROS and inflammation were accelerated in diabetic MT(-/-) mice compared with diabetic MT(+/+) mice, despite equivalent levels of hyperglycemia. MT deficiency accelerated interstitial fibrosis and macrophage infiltration into the interstitium in the diabetic kidney. Electron microscopy revealed abnormal mitochondrial morphology in proximal tubular epithelial cells in diabetic MT(-/-) mice. In vitro studies demonstrated that knockdown of MT by small interfering RNA enhanced mitochondrial ROS generation and inflammation-related gene expression in mProx24 cells cultured under high-glucose conditions. The results of this study suggest that MT may play a key role in protecting the kidney against high glucose induced ROS and subsequent inflammation in diabetic nephropathy. PMID- 24154696 TI - Demeclocycline attenuates hyponatremia by reducing aquaporin-2 expression in the renal inner medulla. AB - Binding of vasopressin to its type 2 receptor in renal collecting ducts induces cAMP signaling, transcription and translocation of aquaporin (AQP)2 water channels to the plasma membrane, and water reabsorption from the prourine. Demeclocycline is currently used to treat hyponatremia in patients with the syndrome of inappropriate antidiuretic hormone secretion (SIADH). Demeclocycline's mechanism of action, which is poorly understood, is studied here. In mouse cortical collecting duct (mpkCCD) cells, which exhibit deamino-8-D arginine vasopressin (dDAVP)-dependent expression of endogenous AQP2, demeclocycline decreased AQP2 abundance and gene transcription but not its protein stability. Demeclocycline did not affect vasopressin type 2 receptor localization but decreased dDAVP-induced cAMP generation and the abundance of adenylate cyclase 3 and 5/6. The addition of exogenous cAMP partially corrected the demeclocycline effect. As in patients, demeclocycline increased urine volume, decreased urine osmolality, and reverted hyponatremia in an SIADH rat model. AQP2 and adenylate cyclase 5/6 abundances were reduced in the inner medulla but increased in the cortex and outer medulla, in the absence of any sign of toxicity. In conclusion, our in vitro and in vivo data indicate that demeclocycline mainly attenuates hyponatremia in SIADH by reducing adenylate cyclase 5/6 expression and, consequently, cAMP generation, AQP2 gene transcription, and AQP2 abundance in the renal inner medulla, coinciding with a reduced vasopressin escape response in other collecting duct segments. PMID- 24154697 TI - Effects of PGE2 EP3/EP4 receptors on bladder dysfunction in mice with experimental autoimmune encephalomyelitis. AB - To investigate the expression of four subtypes of PGE2 E-prostanoid (EP) receptors (EP1-EP4) and the effects of EP3/EP4 on bladder dysfunction in a new neurogenic bladder model induced by experimental autoimmune encephalomyelitis (EAE), the mouse model of EAE was induced using a previously established method, and bladder function in mice with different defined levels of neurological impairment was then examined, including micturition frequencies and voiding weight. Bladders were then harvested for analysis of EP receptor expression by Western blot. Activities of agonists/antagonists of EP3 and EP4 receptors as well as PGE2 were also evaluated at different stages of EAE. The results showed that EAE mice developed profound bladder dysfunction characterized by significantly increased micturition and significantly decreased urine output per micturition. EAE-induced upregulation of EP3 and EP4 receptors in the bladder was accompanied by bladder dysfunction. However, EAE had no significant effect on EP1 and EP2 receptors. Moreover, PGE2 and agonists/antagonists of EP3 and EP4 receptors significantly affected bladder dysfunction in EAE mice. Thus, we believe that EAE mice are useful for investigations of the neurogenic bladder. In addition, EP3 and EP4 receptors play a role in EAE-induced bladder dysfunction, providing us with a new target for the treatment of neurogenic bladders. PMID- 24154698 TI - A role for the circadian clock protein Per1 in the regulation of aldosterone levels and renal Na+ retention. AB - The circadian clock plays an important role in the regulation of physiological processes, including renal function and blood pressure. We have previously shown that the circadian protein period (Per)1 regulates the expression of multiple Na(+) transport genes in the collecting duct, including the alpha-subunit of the renal epithelial Na(+) channel. Consistent with this finding, Per1 knockout mice exhibit dramatically lower blood pressure than wild-type mice. We have also recently demonstrated the potential opposing actions of cryptochrome (Cry)2 on Per1 target genes. Recent work by others has demonstrated that Cry1/2 regulates aldosterone production through increased expression of the adrenal gland-specific rate-limiting enzyme 3beta-dehydrogenase isomerase (3beta-HSD). Therefore, we tested the hypothesis that Per1 plays a role in the regulation of aldosterone levels and renal Na(+) retention. Using RNA silencing and pharmacological blockade of Per1 nuclear entry in the NCI-H295R human adrenal cell line, we showed that Per1 regulates 3beta-HSD expression in vitro. These results were confirmed in vivo: mice with reduced levels of Per1 had decreased levels of plasma aldosterone and decreased mRNA expression of 3beta-HSD. We postulated that mice with reduced Per1 would have a renal Na(+)-retaining defect. Indeed, metabolic cage experiments demonstrated that Per1 heterozygotes excreted more urinary Na(+) compared with wild-type mice. Taken together, these data support the hypothesis that Per1 regulates aldosterone levels and that Per1 plays an integral role in the regulation of Na(+) retention. PMID- 24154699 TI - Inhibition of bladder overactivity by duloxetine in combination with foot stimulation or WAY-100635 treatment in cats. AB - The purpose of this study was to determine whether duloxetine [a serotonin (5-HT) norepinephrine reuptake inhibitor] combined with transcutaneous foot stimulation or WAY-100635 (a 5-HT1A antagonist) can enhance inhibition of bladder overactivity in cats. Cystometrograms were performed on eight cats under alpha chloralose anesthesia by infusing saline and then 0.25% acetic acid (AA) to induce bladder overactivity. To inhibit bladder overactivity, foot stimulation (5 Hz) was applied via transcutaneous pad electrodes to the right hindfoot at two and four times the threshold intensity for inducing a toe twitch. Duloxetine (0.003-3 mg/kg) was administered intravenously to determine the effect of combination treatment. After the 3 mg/kg dose of duloxetine, WAY-100635 (0.5 mg/kg) was given intravenously. AA irritation significantly (P < 0.0001) reduced bladder capacity to 42.7 +/- 7.4% of the saline control capacity. Foot stimulation alone at both two and four times the threshold intensity significantly (P < 0.0001) inhibited bladder overactivity and increased bladder capacity to 66.7 +/- 6.3% and 85.7 +/- 6.5% of the saline control, respectively. Duloxetine alone dose dependently inhibited bladder overactivity and completely restored bladder capacity to the saline control (109 +/- 15.5%) at 3 mg/kg. Although duloxetine combined with foot stimulation did not further enhance inhibition, WAY-100635 (0.5 mg/kg) given after 3 mg/kg duloxetine further increased (P = 0.008) bladder capacity to 162.2 +/- 22.5% of the saline control. Although duloxetine and foot stimulation independently inhibited bladder overactivity, combined treatment did not enhance inhibition. Duloxetine combined with WAY-100635, however, synergistically enhanced bladder inhibition, indicating a potential novel treatment for overactive bladder if duloxetine is combined with a 5-HT1A receptor antagonist drug. PMID- 24154700 TI - Efficacy of palonosetron for the prevention of postoperative nausea and vomiting: a randomized, double-blinded, placebo-controlled trial. AB - BACKGROUND: The aim of this study was to evaluate the efficacy of palonosetron, the latest 5-HT3 receptor antagonist, for the prevention of postoperative nausea and vomiting (PONV) during the first 72 h after operation. METHODS: In this randomized, double-blinded, placebo-controlled study, 204 healthy inpatients who were undergoing elective surgery with general anaesthesia were enrolled. Patients were divided into two groups: the palonosetron group (palonosetron 0.075 mg i.v.; n=102) and the placebo group (normal saline i.v.; n=102). The treatments were given after the induction of anaesthesia. The incidence of nausea, vomiting, severity of nausea, and the use of rescue anti-emetics during the first 72 h after surgery were evaluated. RESULTS: The incidence of PONV was lower in the palonosetron group compared with the placebo group during the 0-24 h (33% vs 47%) and 0-72 h period (33% vs 52%) (P<0.05), but not during the 24-72 h postoperative period (6% vs 11%). The incidence of nausea was also significantly lower in the palonosetron group than in the placebo group during the 0-24 and 0-72 h period (P<0.05), but not during the 24-72 h postoperative period. However, there were no significant differences in the incidence of vomiting, and the use of rescue anti emetics between the groups. CONCLUSIONS: Palonosetron 0.075 mg i.v. effectively reduced the incidence of PONV during the first 72 h after operation, with most of the reduction occurring in the first 24 h. PMID- 24154701 TI - Activation of K(2)P channel-TREK1 mediates the neuroprotection induced by sevoflurane preconditioning. AB - BACKGROUND: Preconditioning with volatile anaesthetic agents induces tolerance to focal cerebral ischaemia, although the underlying mechanisms have not been clearly defined. The present study analyses whether TREK-1, a two-pore domain K(+) channel and target for volatile anaesthetics, plays a role in mediating neuroprotection by sevoflurane. METHODS: Differentiated SH-SY5Y cells were preconditioning with sevoflurane and challenged by oxygen-glucose deprivation (OGD). Cell viability and expression of caspase-3 and TREK-1 were evaluated. Rats that were preconditioned with sevoflurane were subjected to middle cerebral artery occlusion (MCAO), and the expression of TREK-1 protein and mRNA was analysed. Neurological scores were evaluated and infarction volume was examined. RESULTS: Sevoflurane preconditioning reduced cell death in differentiated SH-SY5Y cells challenged by OGD. Sevoflurane preconditioning reduced infarct volume and improved neurological outcome in rats subjected to MCAO. Sevoflurane preconditioning increased levels of TREK-1 mRNA and protein. Knockdown of TREK-1 significantly attenuated sevoflurane preconditioning-induced neuroprotective effects in vitro and in vivo. CONCLUSIONS: Sevoflurane preconditioning-induced neuroprotective effects against transient cerebral ischaemic injuries involve TREK-1 channels. These results suggest a novel mechanism for sevoflurane preconditioning-induced tolerance to focal cerebral ischaemia. PMID- 24154702 TI - Anti-laminin gamma1 pemphigoid accompanied by autoantibodies to laminin alpha3 and gamma2 subunits of laminin-332. PMID- 24154703 TI - Genetic analysis of population differentiation and adaptation in Leuciscus waleckii. AB - Demographic events and natural selection both influence animal phenotypic and genetic variation; exploring the effects of demography and selection on population divergence is of great significance in evolutionary biology. To uncover the causes behind the patterns of genetic differentiation and adaptation among six populations of Leuciscus waleckii from Dali Basin (two populations, alkaline vs. freshwater) and Amur Basin (four populations, freshwater rivers vs. alkaline lake), a set of 21 unlinked polymorphic microsatellite markers and two mitochondrial DNA sequences (Cytb and D-loop) were applied to examine whether populations from different environments or habitats have distinct genetic differentiation and whether alkalinity is the major factor that caused population divergence. Bayesian analysis and principal component analysis as well as haplotype network analysis showed that these populations are primarily divided into two groups, which are congruent with geographic separation but not inconsistent with the habitat environment (alkalinity). Using three different approaches, outlier detection indicated that one locus, HLJYL017, may be under directional selection and involved in local adaptation processes. Overall, this study suggested that demographic events and selection of local environmental conditions including of alkalinity are jointly responsible for population divergence. These findings constitute an important step towards the understanding of the genetic basis of differentiation and adaptation, as well as towards the conservation of L. waleckii. PMID- 24154704 TI - Benchmark calculations of metal carbonyl cations: relativistic vs. electron correlation effects. AB - In this paper we present benchmark results for isoelectronic metal carbonyl complexes of the groups 11 and 12 of the periodic table. The focus is on the geometry, vibrational frequencies, bond dissociation energy and chemical bonding. The description of these complexes requires a good balance between electron correlation and relativistic effects. Our results demonstrate that the combination of the effective core potential and the MP2 method gives quantitative results for the first- and the second-row transition metal complexes and only qualitative agreement for the third-row complexes. In order to obtain quantitative results for the whole series the use of four-component or X2C methods is mandatory. The fourth-row transition metal carbonyl complexes from groups 11 and 12 have been studied for the first time. The metal-carbon bond strength pattern along the group is shown to be highly dependent on the correct description of the relativistic effects. Finally, the relativistic effects on the bonding are studied by means of electron density difference maps, the analysis of the bond critical points of the electron density and the mechanism for sigma donation and pi-backdonation. Our analysis indicates that the fourth-row complexes exhibit a strong covalent character induced by relativistic effects. PMID- 24154705 TI - A thermo-driven DNA zipper. AB - A DNA nano-zipper built from double crossover structures is demonstrated in this work. The open and close states of the zipper are reversibly controlled by the temperature switch. PMID- 24154706 TI - Increased levels of lysosomal cysteinyl cathepsins in human varicose veins: a histology study. AB - Varicose veins are a major chronic venous disease characterised by extensive remodelling of the extracellular matrix architecture in the vascular wall. Although matrix metalloproteinases have been implicated in these pathologic events, little is known about the functional relevance of other protease family members. Here, we studied the distribution of lysosomal cysteine proteases, cathepsins B, L, K, and S, and their endogenous inhibitor, cystatin C, in long saphenous vein specimens from nine normal donors and 18 patients with varicose veins (VVs). Immunohistochemical analysis demonstrated increased levels of cathepsins L, K, B, and S and reduced levels of cystatin C in VVs. This imbalance between cysteinyl cathepsins and cystatin C may favour VV remodelling. To investigate the inflammatory mechanism of their expression, we examined a detailed inflammatory cell profile in VVs, including macrophages, T lymphocytes, and mast cells. Increased numbers of CD3-positive T cells and tryptase-positive mast cells were found in VVs, and enhanced levels of cysteinyl cathepsins were detected from lesion CD3-positive T cells, chymase-positive mast cells, endothelial cells, and smooth-muscle cells. Elevated cathepsins, and their co localisation to infiltrated inflammatory cells and to vascular cells, suggest that these proteases participate in extracellular matrix degradation in response to inflammation during VV pathogenesis. PMID- 24154711 TI - Anatomic medial patellofemoral ligament reconstruction using patellar suture anchor fixation for recurrent patellar instability. AB - PURPOSE: The purpose of this study was to prospectively evaluate clinical and radiographic outcomes following anatomic medial patellofemoral ligament (MPFL) reconstruction using patellar suture anchor fixation for recurrent patellar instability. METHODS: Twenty patients (20 knees) were enrolled in this study. The median age was 21 years, and the median follow-up was 34.5 months. Reconstruction was performed using a hamstring autograft fixed with two suture anchors at native patellar site of the MPFL. No patient had undergone additional medial tibial tuberosity transfer. Clinical scores (Kujala, Lysholm, and Tegner score) and apprehension test were completed preoperatively and at the follow-up. Preoperative and follow-up radiographic assessments included modified Insall Salvati ratio, congruence angle, and lateral patellofemoral angle. RESULTS: The preoperative Kujala and Lysholm scores were 52.6+/-12.4 and 49.2+/-10.7, and at follow-up visits, corresponding values were 90.9+/-4.5 (p<0.001) and 90.9+/-5.2 (p<0.001). Tegner score increased from 3.0 (range 1-4) to 5.0 (range 4-7) (p<0.001). The apprehension test was positive in all patients preoperatively, but only positive in one patient at follow-up. All radiographic assessments were significantly improved; modified Insall-Salvati index (from 1.75 to 1.65) (p=0.002), congruence angle (from 6.3 degrees to -7.0 degrees ) (p<0.001), and lateral patellofemoral angle (from 2.1 degrees to 4.9 degrees ) (p=0.008). No patient experienced a patellar fracture or redislocation. CONCLUSION: These results are comparable to those of bone tunnel techniques reported in the literature. This study shows that anatomic MPFL reconstruction using two suture anchors is a reliable treatment option. LEVEL OF EVIDENCE: Case series with no comparison group, Level IV. PMID- 24154707 TI - Renin inhibition ameliorates renal damage through prominent suppression of both angiotensin I and II in human renin angiotensinogen transgenic mice with high salt loading. AB - BACKGROUND: The renin-angiotensin-aldosterone system (RAAS) plays pivotal roles in the pathogenesis of chronic kidney disease (CKD) progression. Aliskiren, a direct renin inhibitor, inhibits the rate-limiting step of the RAAS without any alternative pathway. It is proven to reduce albuminuria in CKD patients treated with angiotensin blockade. However, there are few reports which evaluate the advantage of aliskiren as the first-line drug against CKD progression in RAAS activated hypertensive patients. METHODS: Tsukuba hypertensive mice (THM), double transgenic mice carrying both the human renin and human angiotensinogen genes, were fed a high-salt diet and treated with hydraladine, ramipril and aliskiren for 10 weeks. Blood pressure and urinary albumin excretion were measured every 2 weeks during the experimental period. We evaluated renal histological changes and gene expression. Plasma angiotensin concentration was measured to evaluate the RAAS inhibitory effect. RESULTS: High-salt-loaded THM showed severe hypertension and renal injury. All antihypertensive drugs suppressed blood pressure and prevented renal disease progression. RAAS blockade showed a higher renoprotective effect than hydraladine despite an equivalent blood pressure lowering effect. Aliskiren exhibited even stronger renoprotection than ramipril. Plasma angiotensin concentration was increased in THM fed both normal salt and high salt. Hydraladine did not alter the plasma angiotensin concentration. Ramipril significantly decreased angiotensin II concentration. Aliskiren treatment almost completely suppressed angiotensin I and resulted in lower angiotensin II concentration than ramipril treatment. CONCLUSION: Aliskiren prevents renal disease progression by suppressing both angiotensin I and II in RAAS-activated pathology. Our data suggest the application of a renin inhibitor for preventing kidney disease progression in CKD patients. PMID- 24154712 TI - Can hip impingement be mistaken for tendon pain in the groin? A long-term follow up of tenotomy for groin pain in athletes. AB - PURPOSE: There are several reports on the association between pubalgia and intra articular hip disorders. The purpose of this study was to evaluate the long-term outcome in athletes who underwent tenotomy due to long-standing groin pain. A secondary purpose was evaluating the frequency of femoro-acetabular impingement (FAI) and its impact on the long-term outcome. METHODS: Thirty-two high-level male athletes treated with adductor tenotomy, rectus abdominis tenotomy or both were included. At a median follow-up time of 6 years after the tenotomy, the subjects underwent standardised clinical examination, plain radiographs, completed web-based health-related patient-reported outcomes, including iHOT12, HAGOS (six subscales), EQ-5D (two subscales), HSAS for physical activity level and a VAS for overall hip function. Furthermore, patient satisfaction and return to sports were documented. RESULTS: Twenty-four of the 32 (75 %) athletes were satisfied with the outcome of the tenotomy, and 22 of the athletes (69 %) were able to return to their pre-injury sport. Before the long-term follow-up, two of these satisfied athletes had undergone repeat surgery (one hip arthroscopy due to FAI and one repeat tenotomy). Of the 24 satisfied athletes, eight (33 %) had a positive hip impingement test at the follow-up. Of the remaining eight athletes not satisfied with the outcome, only one returned to their pre-injury sport and three had undergone hip arthroscopy prior to follow-up. Five had positive hip impingement tests which was significantly more frequently than in the satisfied group (p = 0.008). The group with a positive hip impingement test reported significantly more pain and symptoms, more hip problems during sports and physical activity, as well as lower hip-related quality of life according to the HAGOS scores (p < 0.05), at follow-up. CONCLUSION: Tenotomy for pubalgia yielded a satisfactory long-term outcome, with three of four athletes being able to return to their pre-injury sport. The athletes that did not return to their pre injury sport had higher frequency of positive hip impingement test and inferior functional outcome compared with the athletes that did return to their pre-injury sport. It is therefore recommended that the hip should be carefully evaluated for hip impingement before tenotomy is considered as treatment for athletes with pubalgia. PMID- 24154713 TI - Maternal criticism and adolescent depressive and generalized anxiety disorder symptoms: a 6-year longitudinal community study. AB - This 6-year longitudinal study examined the direction of effects (i.e., parent effects, child effects, or reciprocal effects) between maternal criticism and adolescent depressive and Generalized Anxiety Disorder (GAD) symptoms, including adolescents' perceptions of criticism as a potential mediator. Consistent with recent empirical findings on associations between parenting and adolescent internalizing symptoms, we hypothesized stronger child effects than parent effects. A community sample of 497 adolescents (M age = 13.03 at T1, 57 % boys) reported annually on their depressive and GAD symptoms as well as their perceptions of parental criticism. Their mothers (M age = 44.41 at T1) also reported annually on their own critical behavior toward their adolescent. As expected, cross-lagged panel models demonstrated stronger child effects (i.e., adolescent psychopathology predicting maternal criticism) than parent effects (i.e., maternal criticism predicting adolescent psychopathology) for both adolescent depressive and GAD symptoms, including adolescent perceived criticism as a significant mediator. Our results emphasize the importance of considering (1) potential bidirectional influences over time, contrary to a focus on parent effects on adolescent mental health, as well as (2) adolescent perceptions of parenting as an important potential mediator in associations between aspects of the parent-adolescent relationship and adolescent internalizing psychopathological symptoms. PMID- 24154714 TI - Multiple verrucous asymptomatic lesions in an elderly patient. PMID- 24154715 TI - Cancer genomics: A panoramic view of cancer. PMID- 24154717 TI - Codon optimisation improves the expression of Trichoderma viride sp. endochitinase in Pichia pastoris. AB - The mature cDNA of endochitinase from Trichoderma viride sp. was optimised based on the codon bias of Pichia pastoris GS115 and synthesised by successive PCR; the sequence was then transformed into P. pastoris GS115 via electroporation. The transformant with the fastest growth rate on YPD plates containing 4 mg/mL G418 was screened and identified. This transformant produced 23.09 U/mL of the recombinant endochitinase, a 35% increase compared to the original strain bearing the wild-type endochitinase cDNA. The recombinant endochitinase was sequentially purified by ammonia sulphate precipitation, DE-52 anion-exchange chromatography and Sephadex G-100 size-exclusion chromatography. Thin-layer chromatography indicated that the purified endochitinase could hydrolyse chito-oligomers or colloidal chitin to generate diacetyl-chitobiose (GlcNAc)2 as the main product. This study demonstrates (1) a means for high expression of Trichoderma viride sp. endochitinase in P. pastoris using codon optimisation and (2) the preparation of chito-oligomers using endochitinase. PMID- 24154718 TI - Photosynthetic microbial desalination cells (PMDCs) for clean energy, water and biomass production. AB - Current microbial desalination cell (MDC) performances are evaluated with chemical catalysts such as ferricyanide, platinum catalyzed air-cathodes or aerated cathodes. All of these methods improve power generation potential in MDCs, however, they are not preferable for large scale applications due to cost, energy and environmental toxicity issues. In this study, performance of microbial desalination cells with an air cathode and an algae biocathode (Photosynthetic MDC - PMDC) were evaluated, both under passive conditions (no mechanical aeration or mixing). The results indicate that passive algae biocathodes perform better than air cathodes and enhance COD removal and utilize treated wastewater as the growth medium to obtain valuable biomass for high value bioproducts. Maximum power densities of 84 mW m(-3) (anode volume) or 151 mW m(-3) (biocathode volume) and a desalination rate of 40% were measured with 0.9 : 1 : 0.5 volumetric ratios of anode, desalination and algae biocathode chambers respectively. This first proof-of-concept study proves that the passive mechanisms can be beneficial in enhancing the sustainability of microbial desalination cells. PMID- 24154716 TI - Inflammation-induced cancer: crosstalk between tumours, immune cells and microorganisms. AB - Inflammation is a fundamental innate immune response to perturbed tissue homeostasis. Chronic inflammatory processes affect all stages of tumour development as well as therapy. In this Review, we outline the principal cellular and molecular pathways that coordinate the tumour-promoting and tumour antagonizing effects of inflammation and we discuss the crosstalk between cancer development and inflammatory processes. In addition, we discuss the recently suggested role of commensal microorganisms in inflammation-induced cancer and we propose that understanding this microbial influence will be crucial for targeted therapy in modern cancer treatment. PMID- 24154719 TI - A multiantigen vaccine targeting neu, IGFBP-2, and IGF-IR prevents tumor progression in mice with preinvasive breast disease. AB - A multiantigen multipeptide vaccine, targeting proteins expressed in preinvasive breast lesions, can stimulate type I CD4(+) T cells which have been shown to be deficient in both patients with breast cancer and mice that develop mammary tumors. Transgenic mice (TgMMTV-neu) were immunized with a multiantigen peptide vaccine specific for neu, insulin-like growth factor-binding protein 2 and insulin-like growth factor receptor-I at a time when some of the animals already had preinvasive lesions (18 weeks of age). Although immunization with each individual antigen was partially effective in inhibiting tumor growth, immunization with the multiantigen vaccine was highly effective, blocking development of palpable lesions in 65% of mice and slowing tumor growth in the infrequent palpable tumors, which did arise. Protection was mediated by CD4(+) T cells, and the few slow-growing tumors that did develop demonstrated a significant increase in intratumoral CD8(+) T cells as compared with controls (P = 0.0007). We also combined the vaccine with agents that were, by themselves, partially effective inhibitors of tumor progression in this model; lapatinib and the RXR agonist bexarotene. Although the combination of lapatinib and vaccination performed similarly to vaccination alone (P = 0.735), bexarotene and vaccination significantly enhanced disease-free survival (P < 0.0001), and approximately 90% of the mice showed no pathologic evidence of carcinomas at one year. The vaccine also demonstrated significant clinical efficacy in an additional transgenic model of breast cancer (TgC3(I)-Tag). Chemoimmunoprevention combinations may be an effective approach to breast cancer prevention even when the vaccine is administered in the presence of subclinical disease. PMID- 24154720 TI - Numerical simulation of bubble dynamics in an elastic vessel. AB - The nonlinear evolution of a gas bubble in the middle of an elastic vessel is investigated numerically. The fluids inside and outside the vessel are assumed to be incompressible and potential. A boundary element method (BEM) is adopted to solve the Laplace equation for the velocity potential. The gas inside the bubble is described by the Boyle Law. The fluid outside the vessel is assumed to contain the elasticity. The dynamic boundary condition on the vessel interface i is obtained from the derived Bernoulli Equation. This numerical model is validated through the comparisons with both the analytic solution of Rayleigh-Plesset equation and spark bubble experiment. The bubble dynamic behavior with different elastic parameters and vessel inner radius is further discussed. PMID- 24154721 TI - Optimal control of particle separation in inertial microfluidics. AB - Recently, inertial mircofluidics has emerged as a promising tool to manipulate complex liquids with possible biomedical applications, for example, to particle separation. Indeed, in experiments different particle types were separated based on their sizes (A.J. Mach, D. Di Carlo, Biotechnol. Bioeng. 107, 302 (2010)). In this article we use a theoretical study to demonstrate how concepts from optimal control theory help to design optimized profiles of control forces that allow to steer particles to almost any position at the outlet of a microfluidic channel. We also show that one specific control force profile is sufficient to guide two types of particles to different locations at the channel outlet, where they can be separated from each other. The particles just differ by their size which determines the strength of the inertial lift forces they experience. Our approach greatly enhances the efficiency of particle separation in the inertial regime. PMID- 24154722 TI - Low-frequency collective exchange mode in the dielectric spectrum of salt-free dilute polyelectrolyte solutions. AB - We study the frequency-dependent dielectric response of flexible polyelectrolyte chains in aqueous salt-free dilute solution as a function of polymer concentration and length by means of Brownian dynamics simulations including hydrodynamic interactions. We show that condensed and uncondensed counter ions are characterized by different dielectric response spectra and thus confirm long held scaling assumptions used for the interpretation of experimental data. In addition to the well-known relaxation modes of condensed and uncondensed counter ions we observe for a single polyelectrolyte chain, we find in many-chain simulations a novel spectral feature at low frequencies that essentially corresponds to an exchange of counter ions between neighboring polyelectrolytes. Our results suggest that the experimental low-frequency dielectric mode might not be due to condensed counter ions, as is commonly assumed, but rather due to a collective many-chain process. This could resolve a long-standing puzzle in the comparison of experimental results and scaling predictions. PMID- 24154723 TI - Biasing the lipoxin A4/formyl peptide receptor 2 pushes inflammatory resolution. PMID- 24154724 TI - Regulation of the immune system by biodiversity from the natural environment: an ecosystem service essential to health. AB - Epidemiological studies suggest that living close to the natural environment is associated with long-term health benefits including reduced death rates, reduced cardiovascular disease, and reduced psychiatric problems. This is often attributed to psychological mechanisms, boosted by exercise, social interactions, and sunlight. Compared with urban environments, exposure to green spaces does indeed trigger rapid psychological, physiological, and endocrinological effects. However, there is little evidence that these rapid transient effects cause long term health benefits or even that they are a specific property of natural environments. Meanwhile, the illnesses that are increasing in high-income countries are associated with failing immunoregulation and poorly regulated inflammatory responses, manifested as chronically raised C-reactive protein and proinflammatory cytokines. This failure of immunoregulation is partly attributable to a lack of exposure to organisms ("Old Friends") from mankind's evolutionary past that needed to be tolerated and therefore evolved roles in driving immunoregulatory mechanisms. Some Old Friends (such as helminths and infections picked up at birth that established carrier states) are almost eliminated from the urban environment. This increases our dependence on Old Friends derived from our mothers, other people, animals, and the environment. It is suggested that the requirement for microbial input from the environment to drive immunoregulation is a major component of the beneficial effect of green space, and a neglected ecosystem service that is essential for our well-being. This insight will allow green spaces to be designed to optimize health benefits and will provide impetus from health systems for the preservation of ecosystem biodiversity. PMID- 24154725 TI - MicroRNA-based regulation of epithelial-hybrid-mesenchymal fate determination. AB - Forward and backward transitions between epithelial and mesenchymal phenotypes play crucial roles in embryonic development and tissue repair. Aberrantly regulated transitions are also a hallmark of cancer metastasis. The genetic network that regulates these transitions appears to allow for the existence of a hybrid phenotype (epithelial/mesenchymal). Hybrid cells are endowed with mixed epithelial and mesenchymal characteristics, enabling specialized capabilities such as collective cell migration. Cell-fate determination between the three phenotypes is in fact regulated by a circuit composed of two highly interconnected chimeric modules--the miR-34/SNAIL and the miR-200/ZEB mutual inhibition feedback circuits. Here, we used detailed modeling of microRNA-based regulation to study this core unit. More specifically, we investigated the functions of the two isolated modules and subsequently of the combined unit when the two modules are integrated into the full regulatory circuit. We found that miR-200/ZEB forms a tristable circuit that acts as a ternary switch, driven by miR-34/SNAIL, that is a monostable module that acts as a noise-buffering integrator of internal and external signals. We propose to associate the three stable states--(1,0), (high miR-200)/(low ZEB); (0,1), (low miR-200)/(high ZEB); and (1/2,1/2), (medium miR-200)/(medium ZEB)--with the epithelial, mesenchymal, and hybrid phenotypes, respectively. Our (1/2,1/2) state hypothesis is consistent with recent experimental studies (e.g., ZEB expression measurements in collectively migrating cells) and explains the lack of observed mesenchymal-to hybrid transitions in metastatic cells and in induced pluripotent stem cells. Testable predictions of dynamic gene expression during complete and partial transitions are presented. PMID- 24154727 TI - IFI16 senses DNA forms of the lentiviral replication cycle and controls HIV-1 replication. AB - Replication of lentiviruses generates different DNA forms, including RNA:DNA hybrids, ssDNA, and dsDNA. Nucleic acids stimulate innate immune responses, and pattern recognition receptors detecting dsDNA have been identified. However, sensors for ssDNA have not been reported, and the ability of RNA:DNA hybrids to stimulate innate immune responses is controversial. Using ssDNAs derived from HIV 1 proviral DNA, we report that this DNA form potently induces the expression of IFNs in primary human macrophages. This response was stimulated by stem regions in the DNA structure and was dependent on IFN-inducible protein 16 (IFI16), which bound immunostimulatory DNA directly and activated the stimulator of IFN genes TANK-binding kinase 1 - IFN regulatory factors 3/7 (STING-TBK1-IRF3/7) pathway. Importantly, IFI16 colocalized and associated with lentiviral DNA in the cytoplasm in macrophages, and IFI16 knockdown in this cell type augmented lentiviral transduction and also HIV-1 replication. Thus, IFI16 is a sensor for DNA forms produced during the lentiviral replication cycle and regulates HIV-1 replication in macrophages. PMID- 24154728 TI - Mouse model of intrahepatic cholangiocarcinoma validates FIG-ROS as a potent fusion oncogene and therapeutic target. AB - Cholangiocarcinoma is the second most common primary liver cancer and responds poorly to existing therapies. Intrahepatic cholangiocarcinoma (ICC) likely originates from the biliary tree and develops within the hepatic parenchyma. We have generated a flexible orthotopic allograft mouse model of ICC that incorporates common genetic alterations identified in human ICC and histologically resembles the human disease. We examined the utility of this model to validate driver alterations in ICC and tested their suitability as therapeutic targets. Specifically, we showed that the fused-in-glioblastoma-c-ros-oncogene1 (FIG-ROS1(S); FIG-ROS) fusion gene dramatically accelerates ICC development and that its inactivation in established tumors has a potent antitumor effect. Our studies establish a versatile model of ICC that will be a useful preclinical tool and validate ROS1 fusions as potent oncoproteins and therapeutic targets in ICC and potentially other tumor types. PMID- 24154729 TI - Prognostic significance of residual venous obstruction in patients with treated unprovoked deep vein thrombosis: a patient-level meta-analysis. AB - Residual venous obstruction (RVO) could improve the stratification of the risk of recurrence after unprovoked deep vein thrombosis (DVT), but results from clinical studies and study-level meta-analyses are conflicting. It was the objective of this analysis to determine if RVO is a valid predictor of recurrent venous thromboembolism (VTE) in patients with a first unprovoked DVT who had received at least three months of anticoagulant therapy. Individual patient data were obtained from the datasets of original studies, after a systematic search of electronic databases (Medline, Embase, Cochrane Library), supplemented by manual reviewing of the reference lists and contacting content experts. A multivariate, shared-frailty Cox model was used to calculate hazard ratios (HRs) for recurrent VTE, including, as covariates: RVO; age; sex; anticoagulation duration before RVO assessment; and anticoagulation continuation after RVO assessment. A total of 2,527 patients from 10 prospective studies were included. RVO was found in 1,380 patients (55.1%) after a median of six months from a first unprovoked DVT. Recurrent VTE occurred in 399 patients (15.8%) during a median follow-up of 23.3 months. After multivariate Cox analysis, RVO was independently associated with recurrent VTE (HR = 1.32, 95% confidence interval [CI]: 1.06-1.65). The association was stronger if RVO was detected early, i.e. at three months after DVT (HR = 2.17; 95% CI: 1.11-4.25), but non-significant if detected later, i.e. >6 months (HR = 1.19; 95% CI: 0.87-1.61). In conclusion, after a first unprovoked DVT, RVO is a weak overall predictor of recurrent VTE. The association is stronger if RVO is detected at an earlier time (3 months) after thrombosis. PMID- 24154730 TI - Comparison of ethyl glucuronide and carbohydrate-deficient transferrin in different body fluids for post-mortem identification of alcohol use. AB - AIMS: Alcohol abuse is a major risk factor for premature death. Confirming the role of alcohol consumption in cause-of-death investigations has, however, remained difficult, due to lack of reliable biomarkers. METHODS: We compared ethyl glucuronide (EtG) and carbohydrate-deficient transferrin (CDT) assays from serum, urine, cerebrospinal fluid and vitreous humor in a forensic autopsy population with either a positive (n = 38) or negative (n = 22) history of alcohol abuse based on detailed medical and police records and forensic toxicological investigations. RESULTS: A positive blood alcohol concentration (median 1.150/00, range 0-3.30/00) was found in 26/38 (68%) of the cases with a documented history of alcohol abuse. EtG concentrations (mean +/- SD) in urine (339 +/- 389 mg/l, P < 0.001), vitreous humor (4.2 +/- 4.8 mg/l, P < 0.001), serum (6.9 +/- 8.9 mg/l, P < 0.01) and cerebrospinal fluid (1.7 +/- 2.7 mg/l, P < 0.01) were significantly higher among the cases with a positive history of alcohol use than those in the alcohol-history negative group, whereas in corresponding comparisons CDT was significantly different only in cerebrospinal fluid (4.3 +/- 2.1 vs. 2.3 +/- 0.6%, P < 0.05). The highest sensitivities (92%) in detecting ante-mortem alcohol use were obtained for urine and vitreous humor EtG assays. CONCLUSION: Our data indicate that measurements of EtG in urine or vitreous humor show the highest diagnostic accuracies in post-mortem investigations of excessive alcohol consumption and can be recommended for routine applications. PMID- 24154731 TI - Pyrid-2-yl and 2-CyanoPhenyl fused heterocyclic compounds as human P2X3 inhibitors: a combined approach based on homology modelling, docking and QSAR analysis. AB - P2X receptors are hetero-oligomeric proteins that function as membrane ion channels and are gated by extracellular ATP. The hP2X[Formula: see text] subunit is a constituent of the channels on a subset of sensory neurons involved in pain signaling, where ATP released by damaged and inflamed tissue can initiate action potentials. Hence, the inhibition of ATP-activated P2X3 receptor is an exciting approach for the treatment of inflammatory and neuropathic pain. Recently, the crystal structures of zebrafish P2X4 (zP2X4) were obtained in closed, apo state (PDB ID: 3I5D) and ATP-bound, open state (PDB ID: 4DW1). These structures were used to develop a homology model of human P2X3 (hP2X3 in order to identify through docking studies, the binding modes of known P2X3 inhibitors and their key active site interactions, along with a pharmacophore-based 3D-QSAR model for a series of 136 Pyrid-2-yl and 2-CyanoPhenyl fused heterocyclic compounds. These 3D QSAR models have been developed with different combinations of training and test set divisions obtained by random separation, Jarvis-Patrick clustering, K-means clustering and sphere exclusion methods. The best predictive 3D-QSAR model resulted in training set R2 of 0.75, internal test set Q2 of 0.74, Pearson-R value of 0.87 and root mean square error of 0.37. The information generated by the pharmacophore model and docking analyses using the homology model provides valuable clues to design novel potent hP2X3 inhibitors. PMID- 24154732 TI - Expanding the substrate scope of Ugi five-center, four-component reaction U-5C 4CR): ketones as coupling partners for secondary amino acids. AB - Various symmetrical and unsymmetrical ketones were successfully coupled with secondary amino acids in the course of Ugi five-center, four-component reaction (U-5C-4CR), thus expanding the molecular diversity possible to be achieved by the reaction. The chemical yields depended on the degree of hindrance of the components employed and were satisfactory in view of possible steric interactions in the U-5C-4CR zwitterionic intermediate. The sense of diastereoinduction for reactions employing unsymmetrical ketones was examined by converting the resulting Ugi adducts into the corresponding rigid 2,6-diketopiperazine derivatives. PMID- 24154733 TI - Pd-catalyzed synthesis of symmetrical and unsymmetrical siloxanes. AB - A palladium-catalyzed arylation of hydrosiloxanes was developed for the synthesis of symmetrical and unsymmetrical siloxanes. Reactive functional moieties such as hydroxy or cyano groups were able to tolerate the reaction conditions and several novel unsymmetrical siloxanes were synthesized in moderate to high yield. PMID- 24154734 TI - Polio outbreak among nomads in Chad: outbreak response and lessons learned. AB - BACKGROUND: In response to the 2011 and 2012 polio epidemic in Chad, Chad's Ministry of Public Health, with support from Global Polio Eradication Initiative partners, took steps to increase vaccination coverage of nomadic children with targeted polio campaigns. This article describes the strategies we used to vaccinate nomads in 3 districts of Chad. METHODS: Our targeted interventions involved using mobile vaccination teams, recruiting local nomads to identify settlements, using social mobilization, and offering vaccinations to children, women, and animals. RESULTS: Vaccination coverage of nomadic children 0-59 months of age increased, particularly among those never before vaccinated against polio. These increases occurred mostly in the intervention districts of Dourbali, from 2956 to 8164 vaccinated children, and Kyabe, from 7319 to 15 868. The number of first-time vaccinated nomadic children also increased the most in these districts, from 60 to 131 in Dourbali and from 1302 to 2973 in Kyabe. Coverage in the Massaguet district was only 37.7%. CONCLUSIONS: Our success was probably due to (1) appointment of staff to oversee implementation, (2) engagement of the national government and its partners, (3) participation of nomadic community leaders, (4) intersectoral collaboration between human and animal health services, and (5) flexibility and capacity of vaccinators to vaccinate when and where nomads were available. PMID- 24154735 TI - HTLV-1 and HTLV-2 prevalence in the United States. PMID- 24154736 TI - Multifaceted effects of human milk oligosaccharides. PMID- 24154737 TI - Compromised function of natural killer cells in acute and chronic viral hepatitis. AB - BACKGROUND: Natural killer (NK) cells are an integral part of the innate immune system. They have been suggested to play an important role in both defense against viral hepatitis and the pathogenesis of other liver diseases. METHODS: NK cells from 134 individuals including patients with acute hepatitis B and C as well as chronic hepatitis B, C, and delta (D) patients were studied. RESULTS: Infection with viral hepatitis was associated with increased frequencies of NK cells in the peripheral blood; that NK cells showed a less activated phenotype and were compromised in cytolotytic function and cytokine production in all viral hepatitis infections: Hepatitis virus infections did not alter NK cell differentiation, and the activity and severity of liver disease were reflected by alterations of NK cell surface receptors as demonstrated by principal component analysis. CONCLUSION: NK cell phenotypic and functional alterations can equally be observed in HBV, HCV, and HDV infections. Instead, patterns of NK cell alterations differ in acute and chronic infections. Thus, our data suggest a common mechanism in the alteration of NK cell phenotype and function with unique variations that depend on disease activity rather than virus-specific factors. PMID- 24154738 TI - In vivo emergence of a novel mutant L159F/L320F in the NS5B polymerase confers low-level resistance to the HCV polymerase inhibitors mericitabine and sofosbuvir. AB - BACKGROUND: Resistance to mericitabine (prodrug of HCV NS5B polymerase inhibitor PSI-6130) is rare and conferred by the NS5B S282T mutation. METHODS: Serum HCV RNA from patients who experienced viral breakthrough, partial response, or nonresponse in 2 clinical trials in which patients received mericitabine plus peginterferon alfa-2a (40KD)/ribavirin were analyzed by population and clonal sequence analysis as well as phenotypic assay for assessment of in vivo mericitabine resistance. RESULTS: Among 405 patients treated with mericitabine plus peginterferon alfa-2a/ribavirin in PROPEL and JUMP-C, virologic breakthrough or nonresponse were not observed; 12 patients experienced a partial response. The NS5B S282T resistance mutation was not observed in any patient. A number of treatment-associated NS5B changes were observed and characterized. A novel double mutant (L159F/L320F) with impaired replication capacity was detected in one HCV genotype 1b-infected patient. Introduction of double mutant L159F/L320F into genotype 1a (H77) and 1b (Con-1) replicons, respectively, increased the EC50 for mericitabine by 3.1- and 5.5-fold and the EC90 by 3.1- and 8.9-fold. The double mutant also decreased susceptibility to sofosbuvir (GS-7977) and GS-938 but not setrobuvir, relative to wild-type. CONCLUSIONS: A novel and replication-deficient double mutation (L159F/L320F) confers low-level resistance to mericitabine and cross-resistance to both sofosbuvir and GS-938. CLINICAL TRIALS REGISTRATION: NCT00869661, NCT01057667. PMID- 24154739 TI - Atomistic nature of the DPT tautomerisation of the biologically important C.C* DNA base mispair containing amino and imino tautomers of cytosine: a QM and QTAIM approach. AB - A theoretical study of tautomerisation of the biologically important cytosine.cytosine* (C.C*) DNA mismatch with a propeller-like structure (|C4N3N3C4| = 32.4 degrees ; C1 symmetry) and cis-oriented N1H glycosidic bonds, formed by the amino and imino tautomers of the C nucleobase, via the asynchronous concerted double proton transfer (DPT) along two H-bonds through the transition state (TSC.C*<->C*.C) (|C4N3N3C4| = 48.5 degrees ; C1 symmetry) into the C*.C mispair was carried out for the first time. It was established that the C.C*/C*.C DNA base mispair is associated by the antiparallel N4H...N4 (6.66 kcal mol(-1)), N3H...N3 (6.47 kcal mol(-1)) H-bonds and the O2...O2 van der Waals (vdW) contact (0.33 kcal mol(-1)), while the zwitterionic TSC.C*<->C*.C is stabilized by the parallel N4(+)H...N4(-) (13.55 kcal mol(-1)), N3(+)H...N3(-) (13.20 kcal mol(-1)) H-bonds and the O2(+)...O2(-) vdW contact (0.60 kcal mol(-1)). It was shown that the C.C* <-> C*.C tautomerisation via the DPT is assisted by the O2...O2 vdW contact, that in contrast to the two others N4H...N4 and N3H...N3 H-bonds exists along the entire intrinsic reaction coordinate (IRC) range. The positive values of the Grunenberg's compliance constants (30.919 and 21.384 A mdyn(-1) for C.C*/C*.C and TSC.C*<->C*.C, respectively) indicate that the O2...O2 vdW contact is a stabilizing closed-shell interaction. It was found that the middle N3H...N3 H-bond is anti-cooperative with the upper N4H...N4 H-bond and cooperative with the lower O2...O2 vdW contact. The 9 key points, which can be considered as electron-topological "fingerprints" of the asynchronous concerted C.C* <-> C*.C tautomerisation process via the DPT were revealed along the IRC and examined in detail. It was shown that the C.C*/C*.C base mispair is a thermodynamically and dynamically stable structure. Its lifetime is equal to 1.53 * 10(-7) s at the MP2/cc-pVQZ//B3LYP/6-311++G(d,p) level of theory in vacuum. All 6 low-frequency intermolecular vibrations are able to develop during this time span. PMID- 24154741 TI - Me-too drugs and me-too people. PMID- 24154740 TI - Neutropenia management and granulocyte colony-stimulating factor use in patients with solid tumours receiving myelotoxic chemotherapy--findings from clinical practice. AB - PURPOSE: Clinical practice adherence to current guidelines that recommend primary prophylaxis (PP) with granulocyte colony-stimulating factors (G-CSFs) for patients at high (>=20 %) overall risk of febrile neutropenia (FN) was evaluated. METHODS: Adult patients with breast cancer, non-small cell lung cancer (NSCLC), small-cell lung cancer (SCLC), or ovarian cancer were enrolled if myelotoxic chemotherapy was planned, and they had an investigator-assessed overall FN risk >=20 %. The primary outcome was FN incidence. RESULTS: In total, 1,347 patients were analysed (breast cancer, n = 829; NSCLC, n = 224; SCLC, n = 137; ovarian cancer, n = 157). Patients with breast cancer exhibited fewer individual FN risk factors than patients with other cancers and were far more likely to have received a high-FN-risk chemotherapy regimen. However, a substantial proportion of all patients (45-80 % across tumour types) did not receive G-CSF PP in alignment with investigator risk assessment and guideline recommendations. FN occurred in 127 patients overall (9 %, 95% confidence interval (CI) 8-11 %), and incidence was higher in SCLC (15 %) than other tumour types (8 % in ovarian and NSCLC, 9 % in breast cancer). A post hoc analysis of G-CSF use indicated that G CSF prophylaxis was not given within the recommended timeframe after chemotherapy (within 1-3 days) or was not continued across all cycles in 39 % of patients. CONCLUSIONS: FN risk assessment was predominantly based on clinical judgement and individual risk factors, and guidelines regarding G-CSF PP for patients at high FN risk were not consistently followed. Improved education of physicians may enable more fully informed neutropenia management in patients with solid tumours. PMID- 24154742 TI - Simple sling incision for the treatment of iatrogenic bladder outlet obstruction. AB - INTRODUCTION AND HYPOTHESIS: Bladder outlet obstruction (BOO) is reported to occur in 15 % of women after anti-incontinence surgery. In the past, iatrogenic BOO from slings was treated with urethrolysis. However, urethrolysis is not without morbidity, including significant bleeding, urethral injury, and recurrent stress urinary incontinence (SUI). Several studies have shown simple sling incision to be as effective as urethrolysis with less morbidity and lower rates of recurrent SUI. [1-3] METHODS: We demonstrate the technique of transvaginal simple sling incision in two patients, one with a synthetic midurethral sling, and one with a biologic bladder-neck sling. RESULTS: Simple sling incision is an effective and less morbid treatment than urethrolysis for iatrogenic urethral obstruction; 70-90 % of women will have significant improvement in obstructive voiding symptoms. Recurrent SUI is seen in approximately 20 % of women after sling incision. CONCLUSIONS: This video shows that simple sling incision is an effective, simple, and safe treatment for women with iatrogenic BOO after sling surgery and should be used as a first-line treatment. PMID- 24154743 TI - Dorsal onlay buccal mucosal graft urethroplasty in female urethral stricture disease: a single-center experience. AB - INTRODUCTION AND HYPOTHESIS: The aim of this report is to present our initial, short-term experience with dorsal onlay buccal mucosal graft urethroplasty (DBMGU) in women with urethral stricture. METHODS: Between May 2011 and April 2013, eight women with moderate to severe bothersome lower urinary tract symptoms due to mid- or distal urethral stricture underwent DBMGU. All women were evaluated preoperatively with the American Urological Association (AUA) symptom score, uroflowmetry with post-void residual volume (PVR) estimation, urodynamic study, calibration with 14 F catheter, and voiding cystourethrography. Postoperatively, the women were followed at regular intervals with AUA symptom score, uroflowmetry, and PVR estimation. Increase in AUA symptom score, maximum flow rate (Q(max)) < 12 ml/s, and failure to calibrate with 18 F catheter were considered as recurrence of the disease. RESULTS: The mean age of the patients was 40.6 years. The mean follow-up period was 14.8 months. All women voided successfully after catheter removal. One patient was lost to follow-up after 3 months. There was significant improvement in AUA symptom score and Q(max) and reduction in PVR (p < 0.0001) at 3, 6, and 9 months. Two women had recurrence of stricture at 12 months, while another had recurrence at 18 months which was treated by urethral dilatation followed by a self-dilatation protocol. The limitations of the study include the small number of cases with short follow-up. CONCLUSIONS: DBMGU is a simple and safe method of urethroplasty in women with unsatisfactory results. Large size studies with long-term follow-up are desirable to document the success rates. PMID- 24154745 TI - Endoscopic anatomy of the pediatric middle ear. AB - Traditionally, otologists have aimed to produce a clean, dry, safe ear with the best possible hearing result. More recently, "less invasively" has been added to this list of goals. The development of small-diameter, high-quality rigid endoscopes and high-definition video systems has made totally endoscopic, transcanal surgery a reality in adult otology and a possibility in pediatric otology. This article reviews the anatomy of the pediatric middle ear and its surrounding airspaces and structures based on the work of dozens of researchers over the past 50 years. It will focus on the developmental changes in ear anatomy from birth through the first decade, when structure and function change most rapidly. Understanding the limits and possibilities afforded by new endoscopic technologies, the pediatric otologist can strive for results matching or exceeding those achieved by more invasive surgical approaches. PMID- 24154744 TI - Impact of perineural invasion in the pathologically N0 neck in oral cavity squamous cell carcinoma. AB - OBJECTIVE: Patients with oral cavity squamous cell carcinoma (OCSCC) undergo adjuvant radiation for pathologically high-risk features including positive nodal disease and extracapsular spread (ECS). In the absence of these high-risk features, our objective was to determine if perineural invasion (PNI) is an independent risk factor and if adjuvant radiation (XRT) improves disease control rates. STUDY DESIGN: Historical cohort analysis. SETTING: Tertiary university hospital. METHODS: Eighty-eight OCSCC patients (46 males, 42 females; mean age = 56.7 years; median follow-up = 4.6 years) treated surgically with pathologically N0 (pN0) necks were studied. Overall, 23% (20/88) were pN0/PNI+ and of those with PNI, 70% (14/20) underwent XRT. Survival analysis using Kaplan-Meier followed by multivariable Cox models was performed. RESULTS: Multivariate analysis verified PNI to be associated with worse disease-free interval (DFI) (P = .012) and local regional control (LRC) (P = .005) and perivascular invasion (PVI) associated with worse DFI (P = .05). Among pN0/PNI+ patients, those who received XRT demonstrated significantly improved DFI (mean = 6.5 years vs 1.7 years; P = .014) and LRC (mean 6.7 years vs 1.9 years; P = .047). There was no improvement in overall survival (P = .68) or disease-specific survival (P = .8) in those receiving XRT. CONCLUSIONS: PNI is an independent adverse risk factor in the absence of nodal metastasis and extracapsular spread. We observed a statistically significantly longer DFI and LRC when patients were treated with adjuvant radiation. PMID- 24154746 TI - Otolaryngological progression of granulomatosis with polyangiitis after systemic treatment with rituximab. AB - OBJECTIVE: Rituximab is used for the treatment of granulomatosis with polyangiitis (GPA), historically known as Wegener's granulomatosis. However, the otolaryngological progression of GPA after systemic treatment with rituximab (Rituxan) is unclear. We therefore examined the disease sequelae of patients with GPA who were treated with rituximab. STUDY DESIGN: Case series with chart review. SETTING: Tertiary care medical center. SUBJECTS AND METHODS: Patients with a diagnosis of GPA who were treated with rituximab between 2006 and 2012 were included in this study. Systemic and otolaryngological symptomatology, prednisone usage, and procedural interventions following B-cell depletion were analyzed. RESULTS: We identified 11 patients who met our inclusion criteria. The average length of follow-up after treatment with rituximab was 23.5 months. After treatment with rituximab, there was a significant decrease in daily prednisone dose at 3, 12, and 18 months postinfusion (P < .05). However, there was no observed improvement in patients' otolaryngological complaints as measured by the Birmingham Vasculitis Activity Score. Furthermore, patients treated with rituximab underwent numerous otolaryngological interventions during follow-up. Patients with a history of subglottic stenosis (n = 6) underwent an average of 3.40 laryngoscopies and 0.58 dilations per year during rituximab remission, and patients with sinusitis also underwent multiple nasal endoscopies (4.54 per year, n = 9) and nasal debridements (1.34, n = 9). CONCLUSIONS: While rituximab has been shown to be noninferior to cyclophosphamide with respect to remission from systemic GPA, these patients continue to have chronic otolaryngological manifestations of their disease. Otolaryngologists must continue to play a supportive role throughout their maintenance period. PMID- 24154747 TI - Multiportal robotic access to the anterior cranial fossa: a surgical and engineering feasibility study. AB - OBJECTIVE: Integration of robotic surgical technology into skull base surgery is limited due to minimum angle requirements between robotic tools (narrow funnel effect), steep angle of approach, and instrumentation size. The objectives of this study were to systematically analyze surgical approach portals using a computer model, determine optimal approaches, and assess feasibility of the derived approaches on robotic surgical systems. STUDY DESIGN: Computer analysis on 10 computed tomography scans was performed to determine approach trajectories, angles between robotic tools, and distances to specified skull base target locations for transorbital and transnasal surgical approach portals. SETTING: Dry laboratory and cadaver laboratory. SUBJECTS AND METHODS: The optimal combinations were tested on the da Vinci and Raven robotic systems. RESULTS: Multiportal analyses showed the angles between 2 robotic tools were 14.7, 28.3, and 52.0 degrees in the cases of 2 transnasal portals, combined transnasal and medial orbit portals, and bilateral superior orbit portals, respectively, approaching a prechiasmatic target. The addition of medial and superior transorbital portals improved the skull base trajectory angles 21 and 27 degrees, respectively. Two robotic tools required an angle of at least 20 degrees between them to function effectively at skull base targets. CONCLUSION: Technical feasibility of robotic transorbital and transnasal approaches to access sella and parasellar target locations was demonstrated. This technique addresses the 2 major drawbacks of (1) the narrow funnel effect generated from portals in close proximity and (2) the steep angle of approach to the skull base, as observed in previous studies analyzing transoral, transcervical, transmaxillary, and transhyoid portals. PMID- 24154748 TI - Reviewing the systematic reviews in OSA surgery. AB - OBJECTIVE: There is an extensive amount of literature on surgeries as treatment for obstructive sleep apnea syndrome on adults. Previous systematic reviews have been performed to summarize the outcomes for sleep surgeries, with conflicting results. The objective of this study was to critically evaluate these systematic reviews to provide an overview of their quality, strengths, and conclusions. DATA SOURCES: MEDLINE, Scopus, and the Cochrane Collaboration databases were searched from inception to April 2013. REVIEW METHODS: An overview of systematic reviews was undertaken. Studies included in this review are the systematic reviews whose primary objective was to evaluate the outcomes of sleep apnea surgery on adults. The methodological quality of the studies was analyzed with AMSTAR checklist, and the quality of evidence was evaluated using the GRADE assessment tool. Primary outcome measures assessed the effect of surgery on snoring, sleepiness, and the apnea-hypopnea index. RESULTS: A total of 11 studies were included in this study, and the pooled overview includes 378 studies. The systematic reviews were mostly graded as low quality using the GRADE tool and low to moderate according to the AMSTAR checklist. Outcome for apnea-hypopnea index demonstrated substantial variation leading to conflicting results. Despite a high amount of heterogeneity, outcomes for sleepiness and snoring demonstrated significant improvement across included reviews. CONCLUSIONS: Although obstructive sleep apnea surgery is associated with improved outcomes in most studies, the level and quality of evidence reviews requires improvement. PMID- 24154750 TI - [Diagnostics of fungal infections - how far does identification of the pathogen need to go?]. PMID- 24154749 TI - Perception of better nasal patency correlates with increased mucosal cooling after surgery for nasal obstruction. AB - OBJECTIVES: To (1) quantify mucosal cooling (ie, heat loss) spatially in the nasal passages of nasal airway obstruction (NAO) patients before and after surgery using computational fluid dynamics (CFD) and (2) correlate mucosal cooling with patient-reported symptoms, as measured by the Nasal Obstruction Symptom Evaluation (NOSE) and a visual analog scale (VAS) for sensation of nasal airflow. STUDY DESIGN: Prospective. SETTING: Academic tertiary medical center. SUBJECTS AND METHODS: Computed tomography (CT) scans and NOSE and VAS surveys were obtained from 10 patients before and after surgery to relieve NAO. Three dimensional models of each patient's nasal anatomy were used to run steady-state CFD simulations of airflow and heat transfer during inspiration. Heat loss across the nasal vestibule and the entire nasal cavity, as well as the surface area of mucosa exposed to heat fluxes >50 W/m(2), were compared pre- and postoperatively. RESULTS: After surgery, heat loss increased significantly on the preoperative most obstructed side (P < .0002). A larger surface area of nasal mucosa was exposed to heat fluxes >50 W/m(2) after surgery. The best correlation between patient-reported and CFD measures of nasal patency was obtained for NOSE against surface area in which heat fluxes were >50 W/m(2) (Pearson r = -0.76). CONCLUSION: A significant postoperative increase in mucosal cooling correlates well with patients' perception of better nasal patency after NAO surgery. Computational fluid dynamics-derived heat fluxes may prove to be a valuable predictor of success in NAO surgery. PMID- 24154751 TI - [Differential diagnosis for detection of hyphae in tissue]. AB - Usually the detection of hyphae in tissue is unmistakable evidence of a deep mycosis requiring antimycotic treatment. Micromorphology alone rarely allows a specific diagnosis, thus confusion is possible between Candida, Aspergillus, Alternaria and Fusarium species or several other fungal agents. If broad, nearly non-septated hyphae are detected histologically mucormycosis can be suspected. Detection of hyphae in tissue is always a cause for concern because therapeutic consequences must follow. Because therapeutic strategies may differ depending on the specific fungal agent, a suspected diagnosis should be supplemented by other methods, e.g. culture of unfixed specimens, by immunohistology or molecular biological methods. PMID- 24154753 TI - [Differential diagnoses for detection of yeasts and yeast-like organisms]. AB - The differential diagnosis of yeasts or yeast-like organisms includes a series of imported and domestic fungal pathogens. The spectrum of fungal pathogens involves dimorphic fungi which may cause deep mycoses in healthy people as well as opportunistic fungi, which require predisposing factors for infection, e.g. immunosuppression or a trauma. The histology is sometimes unambiguous; however, frequently there is a great similarity between diverse fungal infections in tissues and the diagnostically decisive criteria are only obvious in a few pathogens. In addition to a classical culture technique in doubtful cases molecular biological or serological methods are necessary to confirm any suspected pathogen diagnosis. PMID- 24154754 TI - [Fungal infections of the central nervous system in the immunocompetent host]. AB - The majority of mycoses which lead to mycotic tumors in patients without any predisposing underlying disease are either caused by Cryptococcus gattii and C. neoformans or by dematiaceous fungi which include Cladophialophora bantiana, Ramichloridium mackenziei, Exophiala and Fonsecaea species. The detection of hyphae in granuloma in the brain should lead to screening for pigmented fungi, which are recognized best in hematoxylin eosin (HE) or sometimes also in periodic acid-Schiff (PAS) stained sections. In patients who survive a near drowning accident and those who develop brain abscesses, scedosporiosis should always be considered as a possible infection. PMID- 24154755 TI - [Atypical tumor regression]. AB - A 67-year-old man presented with a poorly differentiated squamous cell carcinoma of the esophagus diagnosed by biopsy. After neoadjuvant radiochemotherapy the gastroesophagectomy specimen showed diffuse polymorphic and anuclear cell residues ranging from 35 um to 46 um in size. Immunohistochemically, PanCK and AE1-3 revealed a positive staining while CD68 and MIB1 showed a negative staining. The retrospective anamnesis revealed that the patient had chronic polyarthritis as underlying illness, for which reason he had been taking humira and methotrexate, a cytostatic drug, for many years. Therefore, the development of the tumor might have been enhanced by these drugs. Electron microscopic analysis confirmed that the avital akaryote cell residues represented a special type of tumor regression. Complete tumor regression level IV without vital rest tumor tissue based on Baldus et al. was diagnosed. PMID- 24154756 TI - [Vasculitis. New nomenclature of the Chapel Hill consensus conference 2012]. AB - In recent years, many advances have been made in our understanding of vasculitis etiopathology as well as of different disease courses. The revised Chapel Hill Consensus Conference (CHCC) 2012 nomenclature reflects current knowledge about etiopathology, in addition to the descriptive principles of vessel size and type of inflammation. Anti-neutrophil cyptoplasmic antibody (ANCA)-associated vasculitides have been classified as a separate group, as opposed to immune complex small vessel vasculitis. In cases where consensus was achieved, eponyms have been replaced by systematic names, such as granulomatosis with polyangiitis (Wegener's) or eosinophilic granulomatosis with polyangiitis (Churg-Strauss syndrome). Moreover, clinically important but less well-known types of vasculitis have now been included in the CHCC nomenclature. This article presents the changes, focussing on those types that are relevant to the histopathologist, and summarizes the results of important new articles on morphology and clinical picture of vasculitis. PMID- 24154759 TI - Nutritional strategies for dealing with depression. AB - Depression is a highly recurrent and debilitating psychiatric disorder associated with multicausal origins. Impairments in the monoaminergic transmission, increased glutamatergic excitotoxicity, neuroinflammation, oxidative stress and deficits in neurotrophic factors are the main hypothesis raised in order to explain the etiological basis of depression. Although the current antidepressant therapy usually alleviates symptoms and prevents recurrence of episodes, the delay in the onset of the therapeutic effect and the refractory or intolerant responses exhibited by a large number of patients are the main drawbacks of the current therapy. For these reasons, several studies have dealt with the investigation of alternative therapeutic approaches or adjunctive strategies which could improve clinical outcomes. One potential adjunctive treatment with conventional antidepressants involves the use of nutraceuticals (a food, a part of a food, a vitamin, a mineral, or a herb that provides health benefits). In this review, we will focus on the main nutrients, phytochemicals and food that have been shown to have beneficial effects against depression. PMID- 24154760 TI - Beyond modularisation: the need of a socio-neuro-constructionist model of autism. AB - Autism is a developmental disorder defined by social and communication impairments. Current theoretical approaches and research studies however conceptualise autism as both static and independent from the social context in which it develops. Two lines of research stand out from this general trend. First, research from the neuroconstructivist approach of Karmiloff-Smith (Hum Brain Mapp 31:934-941, 2010) aims to establish developmental trajectories of cognitive impairments in autism over time. Second, studies from intersubjective approaches such as that of Hobson (The cradle of thought, Macmillan, London, 2002) focus on the influence of emotional engagement in cognitive impairments. Although these two lines of research have made an invaluable contribution towards our understanding of autism, both offer only partial explanations: Intersubjective approaches fail to provide a developmental perspective and the neuroconstructivist model neglects the role of the social context. This paper argues that the nature of autism demands the theoretical and methodological integration of these two approaches so that developmental and social aspects are investigated in tandem. PMID- 24154761 TI - A review of cardiac autonomic measures: considerations for examination of physiological response in children with autism spectrum disorder. AB - The autonomic nervous system (ANS) is responsible for multiple physiological responses, and dysfunction of this system is often hypothesized as contributing to cognitive, affective, and behavioral responses in children. Research suggests that examination of ANS activity may provide insight into behavioral dysregulation in children with autism spectrum disorders (ASD), however, there is wide variability in samples, methods, and measures reported. The purpose of this review is to describe frequently reported cardiac ANS measures; discuss theoretical models linking ANS measures with neurological structures; and synthesize pediatric literature using ANS measures on typical and ASD samples. Such a synthesis will provide researchers with a foundation for the use of ANS cardiac methods and measures in ASD research. PMID- 24154762 TI - The expression and regulation of DFNA5 in human hepatocellular carcinoma DFNA5 in hepatocellular carcinoma. AB - Hepatocellular carcinoma is a primary malignancy of hepatocytes which accounts for 80 % of all primary liver cancers. DFNA5 has been identified as a tumor suppressor gene with an important role in several frequent forms of cancers, while little is known about its role in hepatocellular carcinoma. Through comparison of the DFNA5 protein expression in hepatocellular carcinoma cells (HepG2) with human fetal lung fibroblast cells (MRC5), we found that the DFNA5 protein expression in hepatocellular carcinoma cells was significantly lower than that in normal cells. The transfection of DFNA5 gene into HepG2 cells could increase DFNA5 protein expression, which subsequently led to inhibition of cell proliferation. Underlying mechanism study revealed that decreased proliferation was due to increased apoptosis and cell cycle arrest. In view of the important role of DFNA5 gene in carcinogenesis, these findings are expected to provide new understanding on development and treatment of human hepatocellular carcinoma. PMID- 24154763 TI - Polymorphic variant at the IL2 region is associated with type 1 diabetes and may affect serum levels of interleukin-2. AB - Polymorphic variants at the interleukin-2 (IL2) locus affect the risk of several autoimmune disorders. Our aim was to evaluate the association of the four IL2 polymorphisms (rs6822844, rs6534349, rs2069762 and rs3136534) with type 1 diabetes (T1D) in the Polish population, and to correlate them with the serum interleukin-2 levels. 543 unrelated T1D patients and 706 healthy control subjects were enrolled. The minor T allele at rs6822844 was significantly less frequent in T1D compared to controls (p = 0.002; OR 0.71; 95 % CI 0.571-0.880). Likewise, the frequency of the TT genotype was decreased among the affected individuals (p = 0.007). In healthy subjects, stratification according to the rs6822844 genotype revealed significant differences in circulating interleukin-2 (p = 0.037) with the highest levels in TT protective genotypes. Three other IL2 polymorphisms did not display significant differences in allele and genotype distribution. In conclusion, the rs6822844 variant is associated with T1D and may play a functional role, or reflect the influence of another causative genetic variant in linkage disequilibrium. PMID- 24154764 TI - Effects of mulberry ethanol extracts on hydrogen peroxide-induced oxidative stress in pancreatic beta-cells. AB - Reactive oxygen species (ROS) are key mediators of mammalian cellular damage and are associated with diseases such as aging, arteriosclerosis, inflammation, rheumatoid arthritis and diabetes. Type 1 diabetes develops upon the destruction of pancreatic beta-cells, which is partly due to ROS activity. In this study, we investigated the cytoprotective and anti-oxidative effects of fractionated mulberry extracts in mouse insulin-producing pancreatic beta-cells (MIN6N cells). Treatment with hydrogen peroxide (H2O2) induced significant cell death and increased intracellular ROS levels, lipid peroxidation and DNA fragmentation in the MIN6N cells. Fractionated mulberry extracts significantly reduced the H2O2 dependent production of intracellular ROS, 2,2-diphenyl-1-picrylhydrazyl (DPPH) radicals and lipid peroxidation. In addition, mulberry extracts inhibited DNA fragmentation induced by H2O2. Thus, the antioxidant properties of mulberry extracts in pancreatic beta-cells may be exploited for the prevention or treatment of type 1 diabetes. PMID- 24154765 TI - Dealing with colorectal cancer in New Zealand. PMID- 24154766 TI - Continued progress with stage III colorectal cancer--a triple cohort study. AB - INTRODUCTION: Colorectal cancer is a common cause of death in New Zealand and its burden is projected to increase in the future. Oncological outcomes from modern treatment have improved, but evidence from the published literature is conflicting. We studied survival outcomes from a series of patients at our local health board. METHODS: A retrospective analysis of disease patterns, surgical procedures, adjuvant therapy and oncological outcomes was performed in three patient cohorts; January 1993-December 1994, January 1998-June 1999, and January 2004-December 2005 at Christchurch Hospital. Univariate, multivariate and Kaplan Meier survival analysis was performed to identify differences between the three cohorts. RESULTS: There were 1091 patients [(355, 317, 419 per cohort, 808 colon (281,227,300) and 283 rectal (74,90,119)] with cancer over the 3 cohorts. Median age was 76 (IQR 67-84) years. Median follow-up was 44 (IQR 13-81) months. For both colon and rectal cancer, patients in later cohorts had early disease, were more likely to have the operation performed by a consultant, were more likely to be referred for an oncological opinion and were more likely to receive adjuvant treatment (p<0.05 respectively). Differences in survival were particularly marked in the later cohort of patients with Stage III colonic cancer. DISCUSSION: There have been significant improvements in oncological outcome with stage three colon and rectal cancer over the study period. Greater specialisation of surgeons, more operations by consultants and use of chemotherapy are all likely contributing factors. PMID- 24154767 TI - Colonoscopy audit over 10 years--what can be learnt? AB - INTRODUCTION: The goals of colonoscopy are changing over time and it is important to regularly determine if endoscopists are achieving key performance indicators. METHODS: Data on key performance indicators were recorded independently by nursing staff for all colonoscopies performed during a 10-year period. The results were discussed at regular meetings and feedback given to endoscopists. RESULTS: Audit data was recorded for 67,570 procedures. The key performance indicators (time to caecum, withdrawal time, adjusted caecal intubation rate and polyp detection rate) all improved over the audit period (p<0.0001 for trend). For each endoscopist the mean withdrawal time was highly variable ranging from 3.1 mins (95%CI 3.0; 3.1) to 11.2 mins (11.0; 11.3). For each endoscopist mean polyp detection rate varied from 29% (CI 26, 31%) to 69% (CI 68, 70%). There was a significant correlation between mean withdrawal time and mean polyp detection rate for each endoscopist (r=0.42; p=0.03). The polyp detection rate improved from 29% in 1999 to 49% in 2010. The proportion of procedures with more than 2 polyps increased from 22% in 2001 to 33% in 2010. There was a significant association of patient discomfort with time to caecum and also to level of consciousness, p<0.0001. There was a significant decrease in the proportion with significant discomfort over the audit period, p<0.0001. CONCLUSIONS: Colonoscopy audit as a routine process with data collection by endoscopy nurses over several years may be able to improve key performance indicators by the process of regular feedback to endoscopists. Audit should be encouraged as a routine process rather than simply as a research tool for a limited period. PMID- 24154768 TI - The diagnostic yield of colonoscopy in patients with isolated abdominal pain. AB - AIM: Colonoscopy is an overstretched resource and there is no consensus on whether isolated abdominal pain is an appropriate indication for colonoscopy. We evaluated the proportion of patients referred for colonoscopy with isolated abdominal pain and determined the diagnostic yield for this indication. METHODS: All patients registered as having a colonoscopy at Waitemata District Health Board on Endoscribe reporting database between March 2005 and February 2010 were included. Patients were recruited based on the indication for colonoscopy of: abdominal pain, iron deficiency anaemia or overt rectal bleeding. All investigations and electronic clinical documents for patients with abdominal pain were retrieved and patients with concurrent anaemia, rectal bleeding, weight loss, altered bowel habit, abdominal mass, previous abnormal investigations and history of inflammatory bowel disease or bowel malignancy were excluded. The diagnostic yield between the 3 study groups were compared using Chi-squared test, Wilcoxon rank sum test and multiple logistic regression models. RESULTS: Total of 10,052 colonoscopies were performed of which only 2,633 fulfilled our inclusion criteria. The abdominal pain group accounted for 1.2% of colonoscopies performed and had the lowest diagnostic yield of 48.8% (P<0.001). Among those with abdominal pain, significant neoplasia was found in 3.3% and was significantly lower than those with iron deficiency anaemia or overt rectal bleeding groups (P<0.001). When segregated by age, the abdominal pain group continued to have significant less neoplasia (3.8%, P=0.001) among those 50 and older but no difference was found among younger patients. CONCLUSIONS: A small proportion of colonoscopy resources are being used to investigate isolated abdominal pain, which is appropriate given the low diagnostic yield of significant pathology, particularly amongst those less than 50 years old. PMID- 24154769 TI - A novel pathway for investigation of colorectal symptoms with colonoscopy or computed tomography colonography. AB - BACKGROUND: Colorectal cancer (CRC) is a common problem in New Zealand and there is significant pressure on colonoscopy resources. Lower gastrointestinal symptoms are common in the community hence the appropriate selection of patients for colonoscopy is problematic. The Canterbury District Health Board recently developed the Canterbury Colorectal Symptom Pathway (CCrSP) to attempt to improve prioritisation using a combination of presenting clinical features integrated into a scoring tool. This study describes that pathway and its outcomes over a 6 month period. METHOD: Following implementation of the CCrSP, all outpatient referrals receiving colonoscopy or Computerised Tomography Colonography (CTC) over a 6-month period were audited. The clinical features included in the referral, waiting time and outcome of investigation were recorded. Using the scoring tool, a score was calculated for all referrals and compared with outcome. RESULTS: Some 1,369 procedures were performed during the study period. Of the symptomatic patients, 38 CRCs were diagnosed from 633 colonoscopies and 253 CTCs. Individual factors predictive for CRC were rectal bleeding (OR 2.1, 95%CI 1.1 4.2), iron deficiency anaemia (OR 3.2, 95%CI 1.6-6.3) and positive faecal occult blood test (OR 6.1, 95%CI 2.1-16.3). No CRCs were diagnosed in the group scoring below the pre-set threshold for investigation. Multiple logistic regression analysis demonstrated a 1 unit increase in score increased the likelihood of CRC by 7.2% (95%CI 4.4%-10.1%, p<0.001). Of the 11 CRCs suggested by CTC, there was one false positive. The follow up colonoscopy rate after CTC was 11.5% and further radiology was recommended in 7.9%. CONCLUSION: The CCrSP pathway was accurate for predicting CRC and offers a reliable triage tool. The scoring tool was both sensitive for CRC and predictive of the risk of CRC in patients who received colonoscopy or CTC. PMID- 24154770 TI - Perceived risks and benefits of surveillance colonoscopy in people undergoing surveillance for family history of colorectal cancer. AB - AIM: To determine perceived risks and benefits of colonoscopy surveillance among patients undergoing surveillance colonoscopy due to family history of colorectal cancer (CRC). METHOD: We conducted a standardised phone interview of 250 randomly selected people who had undergone surveillance colonoscopy at Dunedin Hospital. We assessed perceptions of colonoscopy effectiveness, complication rates, and CRC risk. RESULTS: We included 148 (69%) participants. Most felt well informed about surveillance (66.7%), but many wanted further information (63.2%). Most accurately estimated complication rates (discomfort: Common/Uncommon 70.3%; pain: Rare/Uncommon 58.8%; bleeding: Rare/Uncommon 72.3%; perforation: Very rare 62.8%), and benefits (mean reduction in risk of CRC 72.6% and death 76.2%). Most (55.1%) over-estimated their CRC risk. 13.5% thought perforation never occurred, and 12.8% thought colonoscopy either completely prevented, or had no effect on risk of developing or dying from CRC. Patients giving unrealistic estimates had similar demographics and clinical variables to the wider cohort. CONCLUSION: Our results suggest current surveillance education adequately communicates risks and benefits to most patients. A minority have unrealistic views and further education may be indicated. PMID- 24154772 TI - Pathological reporting of malignant colorectal polyps. AB - AIM: The pathological reporting of malignant colorectal polyps plays an important role in determining whether definitive surgical resection is required following endoscopic polypectomy. This study aims to assess the adequacy of reporting on malignant polyp specimens at Auckland Hospital and whether synoptic reporting results in an improvement. METHOD: The pathology database at Auckland Hospital was accessed using a search strategy to identify all malignant polyps diagnosed between 1999 and 2011. Pathology reports were reviewed retrospectively. RESULTS: In total 121 malignant polyps were found. Of these, 73 were colonoscopic polypectomies, 41 were colectomy specimens, and seven transanal resections. Of the 41 colectomy specimens, 19 (46%) were reported in synoptic format compared with none of the colonoscopic polypectomies or transanal resections. The status of the margin of excision, differentiation, and presence of lymphovascular invasion were given in 100% of synoptic reports compared with 51% of non-synoptic reports. CONCLUSION: Synoptic reporting does improve the completeness of pathological reporting in malignant colorectal polyps. Currently none of the colonoscopically excised malignant polyps are reported in this format at Auckland Hospital. The development and routine use of a synoptic system for reporting on malignant polyps would give clinicians more information on which to base decisions. PMID- 24154771 TI - Immunochemistry screening for Lynch syndrome in colorectal adenocarcinoma using an initial two antibody panel can replace a four antibody panel. AB - AIM: The current practice in immunochemistry staining for Lynch syndrome (LS) is to use a four-antibody panel, (MLH1, MSH2, MSH6, PMS2) to screen for the four Mismatch Repair (MMR) gene expressions involved. We hypothesised that testing two antibodies (MSH6 and PMS2), followed by the other two only when there is loss of expression of the first two antibodies, would be equally effective as a four antibody panel in detecting LS. This hypothesis is based on the biochemical binding properties of the MMR proteins. METHODS: We tested this hypothesis on a patient cohort consisting of all cases of colorectal cancer that were stained for MMR gene expression at Auckland City Hospital (Auckland, New Zealand) from the years 2000 to 2010 (inclusive), providing a series of 410 cases for this study. Exclusions were made based on heterogeneous staining pattern and unsatisfactory staining results on MSH6 and PMS2, which left n=400 included in the study. RESULTS: The MMR gene protein stains were regarded as demonstrating loss of expression (LOE) when there was no uptake in the nucleus of the tumour cells, with a positive internal control. The results from our analysis supported our hypothesis. Seventy-four cases showed LOE of MSH6 or PMS2. One of them showed LOE of all four MMR proteins. For the remaining 326 cases, there was no LOE of all four MMR proteins. CONCLUSION: Our study gives further evidence that an initial two-antibody panel consisting of PMS2 and MSH6 would be as effective as a four antibody panel in detecting DNA MMR gene protein LOE. This study has implications for significant cost cutting and improved efficiency in detection of DNA MMR gene protein LOE in LS. PMID- 24154773 TI - Carbon dioxide insufflation during colonoscopy: a randomised controlled trial. AB - AIM: To determine if carbon dioxide (CO2), insufflated during colonoscopy reduces pain experienced by patients post colonoscopy compared to air. METHOD: A randomised, double-blinded, controlled trial with 205 consecutive consented patients referred for elective colonoscopy was undertaken at MidCentral Health Gastroenterology Department. Patients were randomised to colonic insufflation with either air or CO2. A comparison of reported pain was undertaken using a 0-10 point numeric rating scale at several time periods; intra procedure, 10, 30, and 60 minutes post procedure. In addition groups were compared on the proportion of participants reporting 0 pain levels at each of the same time periods. RESULTS: CO2 insufflation was provided to 108 patients and air to 97 patients. No differences in mean pain scores or the proportion of those who report zero pain were found between the groups intra procedure. However, those who received CO2 insufflation were found to have significantly lower mean pain scores (p<0.001) and to have a significantly greater proportion of persons reporting 0 pain scores (p<0.001) at all three observation times post procedure than those who received air. CONCLUSION: Those receiving CO2 during colonoscopy experienced less post colonoscopy pain than those who received air insufflation. Carbon dioxide should be considered as the insufflating gas during colonoscopy. PMID- 24154774 TI - Symptom presentations and other characteristics of colorectal cancer patients and the diagnostic performance of the Auckland Regional Grading Criteria for Suspected Colorectal Cancer in the South Auckland population. AB - AIM: This study reviews the presenting symptoms of colorectal cancer in the ethnically diverse Middlemore Hospital referral population of South Auckland, New Zealand. The performance of the newly introduced Auckland Regional Grading Criteria as prediction tool for selecting colorectal cancer cases referred from primary care was evaluated in this group. METHOD: Retrospective review of all colorectal cancer (CRC) cases diagnosed between January 2006 and January 2011. Information extracted from case note review was used to grade patients using the Auckland Regional Grading Criteria. RESULTS: A total of 799 patients were included. The commonest symptoms were: rectal bleeding (25.5-42.3%) and change in bowel habit (20.6-26.8%). Low-risk symptoms including abdominal pain (16.3-46.8%) and weight loss (18.4-26.1%) were not uncommon. 64.4% of Maori and 64.9% of Pacific patients had stage III or IV cancers. Pacific patients had more stage IV disease, 37.7% (p<0.001) and were less likely to undergo tumour resection, 26.0% (p<0.001). The Auckland Regional Grading Criteria would miss 24.7% of the patients with CRC in the referral population. CONCLUSION: While rectal bleeding and change in bowel habit are frequent presenting symptoms, low-risk atypical symptoms including constipation, weight loss and abdominal pain were not uncommon. Significant proportion of Pacific patients present with late-stage disease. The current Auckland Regional grading criteria would miss significant proportion of our study population with colorectal cancer. PMID- 24154775 TI - Medical image. The histological diagnosis was rectal schistosomiasis granulomata. PMID- 24154776 TI - Medical image. Frontotemporal dementia (FTD). PMID- 24154777 TI - A New Zealand doctor visits a Syrian refugee camp in Iraqi Kurdistan. PMID- 24154778 TI - Gout--is adequate attention devoted to preventing haemorrhagic risk when benzbromarone is administered with warfarin? PMID- 24154779 TI - Gout--is Lee's 2008 risk:benefit conclusion for benzbromarone hepatotoxicity still relevant today? PMID- 24154781 TI - Benzbromarone: availability for general prescribing in New Zealand (a response to letters by Dr Lance Gravatt onbenzbromarone). PMID- 24154780 TI - New urate-lowering therapies in Aotearoa New Zealand: a response to Dr Lance Gravatt's letter on benzbromarone hepatotoxicity. PMID- 24154782 TI - A house call. PMID- 24154783 TI - Recognition of burns as a marker of child abuse in the paediatric emergency department. PMID- 24154784 TI - Response to NZMJ editorial by Dr Elana Curtis entitled Deserving of more: framing of Maori inequities in cardiovascular care remain a challenge. PMID- 24154785 TI - HIV screening in New Zealand: time for a change. PMID- 24154786 TI - Performing a secondary executive task with affective stimuli interferes with decision making under risk conditions. AB - Previous studies demonstrated that executive functions are crucial for advantageous decision making under risk and that therefore decision making is disrupted when working memory capacity is demanded while working on a decision task. While some studies also showed that emotions can affect decision making under risk, it is unclear how affective processing and executive functions predict decision-making performance in interaction. The current experimental study used a between-subjects design to examine whether affective pictures (positive and negative pictures compared to neutral pictures), included in a parallel executive task (working memory 2-back task), have an impact on decision making under risk as assessed by the Game of Dice Task (GDT). Moreover, the performance GDT plus 2-back task was compared to the performance in the GDT without any additional task (GDT solely). The results show that the performance in the GDT differed between groups (positive, negative, neutral, and GDT solely). The groups with affective pictures, especially those with positive pictures in the 2-back task, showed more disadvantageous decisions in the GDT than the groups with neutral pictures and the group performing the GDT without any additional task. However, executive functions moderated the effect of the affective pictures. Regardless of affective influence, subjects with good executive functions performed advantageously in the GDT. These findings support the assumption that executive functions and emotional processing interact in predicting decision making under risk. PMID- 24154788 TI - Bone and the kidney: it's complex. PMID- 24154787 TI - Ticagrelor versus prasugrel in diabetic patients with an acute coronary syndrome. A pharmacodynamic randomised study. AB - Optimal P2Y12 receptor blockade is critical to prevent ischaemic recurrence in patients undergoing percutaneous coronary intervention (PCI). We aimed to compare the level of platelet reactivity (PR) inhibition achieved by prasugrel and ticagrelor loading dose (LD) in diabetic acute coronary syndrome (ACS) patients undergoing PCI. We performed a single-center prospective open-label randomised trial. Patients with diabetes mellitus undergoing PCI for an ACS were randomised to receive prasugrel 60 mg or ticagrelor 180 mg. The primary endpoint of the study was the level of platelet reactivity (PR) assessed between 6 and 18 hours post-LD using the VASP index. We randomised 100 diabetic patients undergoing PCI for an ACS. No difference was observed in baseline characteristics between the two groups. In particular, the rate of patient receiving insulin therapy was identical (25 vs 28.6%; p =0.7). Ticagrelor achieved a significantly lower PR compared to prasugrel loading dose (17.3 +/- 14.2 vs 27.7 +/- 23.3%; p=0.009). In addition the rate of high on-treatment platelet reactivity, defined by a VASP >=50%, tend to be lower in the ticagrelor group although the difference did not reach statistical significance (6 vs 16%; p=0.2). The rate of low on treatment PR was identical (60 vs 54%; p=0.8). The present study demonstrates that ticagrelor LD is superior to prasugrel LD to reduce PR in ACS patients with diabetes mellitus. Whether the higher potency of ticagrelor could translate into a clinical benefit should be investigated. PMID- 24154789 TI - Novel analytical approaches for the study of mobility and relaxation phenomena in positional isomers of GABA. AB - gamma-Aminobutyric acid (GABA), and its positional isomers DL-alpha-aminobutyric acid (AABA) and DL-beta-aminobutyric acid (BABA) have been analysed, in the solid state, using thermally stimulated current (TSC) spectroscopy. Secondary relaxations in these molecules have been detected for the first time. GABA displays two secondary relaxations at 77 +/- 2 degrees C and 114 +/- 2 degrees C, whilst AABA and BABA each display a single secondary relaxation at 109 +/- 1 degrees C and 104 +/- 1 degrees C, respectively. Analysis (decoupling of molecular mobilities) of secondary relaxations using thermal windowing (TW) and relaxation map analysis (RMA) show that the dipole relaxation associated with secondary transitions observed for the aminobutyric acids requires activation energies of 189.9 +/- 3.2 kJ mol(-1) (GABA), 142.4 +/- 1.4 kJ mol(-1) (AABA) and 195.7 +/- 0.8 kJ mol(-1) (BABA). However, the DeltaH(?) values observed were found to exhibit negligible deviations from the zero entropy line. This indicates that the relaxation processes are localised, non-cooperative rotational motions that have a negligible influence on entropy changes of detected molecular mobilities. Furthermore, RMA analysis revealed that AABA and BABA display compensation behaviour i.e., entropy and enthalpy are linearly related to each other, whereas GABA did not demonstrate such behaviour. The coordinates of the compensation point (compensation temperature (Tc) and the compensation relaxation time (tauc)) were found to be 214 +/- 6 degrees C and 0.051 +/- 0.024 s, respectively for AABA and 153 +/- 3 degrees C and 0.025 +/- 0.011 s for BABA. For the molecules investigated the compensation points coincide with the starting temperature of the higher temperature thermal events i.e. sublimation, melt/decomposition, and indicate a correlation between secondary relaxation processes and the main thermal transitions, found via TGA and DSC studies. PMID- 24154790 TI - Recent developments in surgery: minimally invasive approaches for patients requiring pancreaticoduodenectomy. AB - Over the past decade, minimally invasive surgery has been introduced as a means to allow manipulation of delicate tissues with outstanding visualization of the surgical field. The purpose of this article is to review the available literature regarding early postoperative outcomes and the technical challenges of minimally invasive pancreaticoduodenectomy, including robotic techniques. Herein, we provide a retrospective review of all published studies in the English literature in which a minimally invasive pancreaticoduodenectomy was performed. The reported advantages of minimally invasive pancreaticoduodenectomy include better visualization, faster recovery time, and decreased length of hospital stay. In cases of robotic approaches, some of the proposed advantages include increased dexterity and a superior ergonomic position for the operating surgeon. To our knowledge, few studies have reported results comparable to open techniques in oncologic outcomes with regard to the number of lymph nodes resected and clear margins obtained. An increasing number of pancreatic resections are being performed using minimally invasive approaches. It remains to be determined if the benefits of this technique outweigh its longer operative times and higher costs. PMID- 24154791 TI - Temporal variation of the leak pressure of uncuffed endotracheal tubes following pediatric intubation: an observational study. AB - PURPOSE: Uncuffed endotracheal tubes are still preferred over cuffed tubes in certain situations in pediatric anesthesia. Inaccurately sized uncuffed endotracheal tubes may lead to inadequate ventilation or tracheal mucosal damage during anesthesia. Endotracheal tube size in children is usually assessed by measuring the audible leak pressure; if the fit of the tube and the leak pressure decrease significantly with time, reintubation during surgery as a result of inability to ventilate effectively may be challenging, and could lead to patient morbidity. There is no evidence to indicate whether leak pressure increases or decreases with time following endotracheal intubation with uncuffed tubes in children. METHODS: We measured leak pressure for 30 min following tracheal intubation in 46 ASA I children age 0-7 years after excluding factors known to modify leak pressure. RESULTS: The largest mean change in leak pressure occurred between time points 0 and 15 min, an increase of 3.5 cmH2O. Endotracheal tube size and type of procedure were associated with the leak pressure. In the final linear mixed model, there were no statistically significant variations in leak pressure over time (P = 0.129) in this group of children. CONCLUSIONS: We did not identify a consistent change in leak pressure within 30 min following tracheal intubation with uncuffed endotracheal tubes in this group of children. PMID- 24154792 TI - Combining automated attenuation-based tube voltage selection and iterative reconstruction: a liver phantom study. AB - OBJECTIVES: To determine the value of combined automated attenuation-based tube potential selection and iterative reconstructions (IRs) for optimising computed tomography (CT) imaging of hypodense liver lesions. METHODS: A liver phantom containing hypodense lesions was imaged by CT with and without automated attenuation-based tube-potential selection (80, 100 and 120 kVp). Acquisitions were reconstructed with filtered back projection (FBP) and sinogram-affirmed IR. Image noise and contrast-to-noise ratio (CNR) were measured. Two readers marked lesion localisation and rated confidence, sharpness, noise and image quality on a five-point scale (1 = worst, 5 = best). RESULTS: Image noise was lower (31-52%) and CNR higher (43-102%) on IR than on FBP images at all tube voltages. On 100 kVp and 80-kVp IR images, confidence and sharpness were higher than on 120-kVp FBP images. Scores for image quality score and noise as well as sensitivity for 100-kVp IR were similar or higher than for 120-kVp FBP and lower for 80-kVp IR. Radiation dose was reduced by 26% at 100 kVp and 56% at 80 kVp. CONCLUSIONS: Compared with 120-kVp FBP images, the combination of automated attenuation-based tube-potential selection at 100 kVp and IR provides higher image quality and improved sensitivity for detecting hypodense liver lesions in vitro at a dose reduced by 26%. KEY POINTS: * Combining automated tube voltage selection/iterative CT reconstruction improves image quality. * Attenuation values remain stable on IR compared with FBP images. * Lesion detection was highest on 100-kVp IR images. PMID- 24154793 TI - Clinical impact of hyperattenuation of adrenal glands on contrast-enhanced computed tomography of polytraumatised patients. AB - OBJECTIVE: To evaluate the prognostic value of hyperattenuating adrenal glands on contrast-enhanced CT of polytraumatised patients. METHODS: Two hundred ninety-two patients (195 men and 97 women, mean age 45.3 +/- 23.3 years) were included in this retrospective study. CT examinations were performed 60 s after intravenous injection of contrast material. Image analysis was performed by two radiologists. Patients were assigned to one of two groups according to the attenuation of the adrenal gland [group 1: adrenal glands >= inferior vena cava (IVC); group 2: adrenal glands < IVC]. RESULTS: Eighteen patients (42.2 years +/- 24.2) were assigned to group 1 and 274 patients (48.4 years +/- 22.4) to group 2. The average adrenal density was 150.8 +/- 36.1 HU in group 1 and 83.7 +/- 23.6 HU in group 2 (P < 0.0001). Eight of the 18 patients in group 1 (44.4%) and 33 of the 274 patients in group 2 (12.4%) died during hospitalisation (P < 0.05). Mean adrenal enhancement was significantly higher in patients who died (101.9 +/- 40.6 HU) compared with survivors (86.1 +/- 27.0 HU; P < 0.001). CONCLUSION: Hyperattenuation of adrenal glands is associated with a higher mortality rate in polytraumatised patients and may serve as a predictor of poor clinical outcome. KEY POINTS: * Hyperattenuating adrenal glands can be observed in 6.2% of polytraumatised patients. * Hyperattenuating adrenal glands indicate poor clinical outcome in polytraumatised patients. * In polytraumatised patients, hyperattenuating adrenal glands are associated with a high mortality rate. * Adrenal enhancement is higher amongst patients who died than amongst survivors. PMID- 24154794 TI - Frequent T cell responses against immunogenic targets in lung cancer patients for targeted immunotherapy. AB - To date, lung cancer is one of the leading causes of cancer mortality with short overall survival despite adequate therapy. New immunotherapeutic strategies using peptides derived from tumor-associated antigens (TAAs) can induce a specific cytotoxic T cell (CTL) response leading to a targeted tumor cell death. In the present study, we addressed whether there are further significant immunogenic candidate targets that may induce strong immune reactions with a high frequency in lung cancer patients eligible for cellular immunotherapeutic approaches, such as in a polyvalent vaccination approach. In this study, we investigated specific CTL responses of 14 HLA-A*0201-positive patients (of 33 screened patients) with non-small cell lung cancer (NSCLC; n=12) or small cell lung cancer (SCLC; n=2) against several known and novel TAA-derived peptides from lung cancer and/or other tumor entities, by measuring granzyme B (GrB) and/or interferon gamma (IFNgamma) secretion using enzyme-linked immunospot (ELISpot) analysis. Specific T cell responses could be detected for hTERT (4/13), two MAGE-A3-derived peptides (4/13 and 3/13, respectively), RHAMM (4/14), PRAME (8/14), G250 (7/12), survivin (3/13), HER2 (5/10) and WT1 (2/14), but also novel epitopes derived from Aurora kinase A (4/13) and B (5/13). Additionally, simultaneous CTL responses against the different peptides were examined and specific T cell responses against at least one of these TAAs could be detected in 13/14 (93%) patients. It could be shown that all patients with immune reactions against RHAMM and hTERT showed also immune responses against PRAME. Furthermore, patients with CTL responses against the Aurora kinase A peptide (Aura A1) also demonstrated a response against the Aurora kinase B peptide (Aura B1). Taken together, we showed that these TAA derived peptides induce frequent specific T cell responses in patients with metastatic lung cancer and are, therefore, novel candidates for targeted immunotherapies and polyvalent approaches. PMID- 24154795 TI - An under-recognised cause of spastic paraparesis in middle-aged women. AB - Having excluded common structural, inflammatory and vascular causes of a spastic paraparesis, the diagnostic yield of further clinical investigations is low. Here, we show that testing for rare metabolic and genetic causes can have important implications for both the patient and their family. PMID- 24154796 TI - The pathophysiological mechanisms underlying mucus hypersecretion induced by cold temperatures in cigarette smoke-exposed rats. AB - In a recent study, we demonstrated that transient receptor potential melastatin 8 (TRPM8), a calcium-permeable cation channel that is activated by cold temperatures, is localized in the bronchial epithelium and is upregulated in subjects with chronic obstructive pulmonary disease, which causes them to be more sensitive to cold air. In the present study, we found that exposure to cold temperatures induced ciliary ultrastructural anomalies and mucus accumulation on the epithelial surface. Male Sprague-Dawley rats were exposed to cold temperatures to determine the effects of cold air on ultrastructural changes in cilia and the airway epithelial surface. The rats were also exposed to cigarette smoke and/or cold temperatures to determine the effects of smoke and cold air on TRPM8 expression and the role of cold air in cigarette smoke-induced mucus hypersecretion. Following real-time RT-PCR and western blot analysis, we observed a high expression of TRPM8 mRNA and protein in the bronchial tissue following cigarette smoke inhalation. As shown by ELISA, concurrent cold air enhanced the levels of mucin 5AC (MUC5AC) protein, as well as those of inflammatory factors [tumor necrosis factor (TNF)-alpha and interleukin (IL)-8] that were induced by cigarette smoke inhalation to a greater extent than stimulation with separate stimuli (cold air and cigarette smoke separately). The results suggest that cold air stimuli are responsible for the ultrastructural abnormalities of bronchial cilia, which contribute to abnormal mucus clearance. In addition, cold air synergistically amplifies cigarette smoke-induced mucus hypersecretion and the production of inflammatory factors through the elevated expression of the TRPM8 channel that is initiated by cigarette smoke inhalation. PMID- 24154797 TI - The outcome of different post-thawed culture period in frozen-thawed embryo transfer cycle. AB - PURPOSE: To study the influence of post-thawed culture (2-4 h and 20-24 h) on the outcome of frozen-thawed embryo transfer (FET) cycle. METHODS: In this retrospective study, a total of 1,353 patients were undergoing the FET treatment at the reproductive medical center between June 2010 and July 2012. 3,398 frozen thawed embryos were divided in two study groups, depending on their post-thawed culture period: short culture (2-4 h) group and long culture (20-24 h) group. Groups were compared including clinical pregnancy rate, implantation rate, spontaneous abortion rate, ectopic pregnancy rate, multiple pregnancy rate, live birth rate and birth weight. RESULTS: When embryos including at least one grade I embryo after thawed transferred, the clinical pregnancy rate, implantation rate, multiple pregnancy rate, abortion rate, ectopic pregnancy rate, live birth rate and birth weight were similar in the short culture group compared with these in the long culture group. CONCLUSIONS: The outcomes of the two approaches (short culture and long culture) are no different in FET cycles. PMID- 24154798 TI - Networking necessities in the world of big science. PMID- 24154799 TI - Mosaicism for an unbalanced Y;21 translocation in an infertile man: a case report. PMID- 24154800 TI - Rehabilitation after hip fracture. AB - Low-trauma hip fracture in old age leads to impairment, increased need of care and mortality. Rehabilitation should start in the department for traumatology and accompany the patient through different settings until the pretraumatic status is reached. Besides the surgical procedure and the medical management of an aged person with complex disease and polypharmacy, the multidisciplinary rehabilitation process is an important factor for regaining ability for self-care and autonomous decisions. Pain management supports the process. The ideal setting is not clear yet. Besides established rehabilitation facilities for elderly people, including the departments for 'Akutgeriatrie/Remobilisation', the 'Outreach Geriatric Remobilisation' project offers new perspectives. It was designed to remobilise patients with multimorbidity in their own homes. PMID- 24154801 TI - Unclassified cardiomyopathies in neuromuscular disorders. AB - OBJECTIVES: Unclassified cardiomyopathies (CMPs) include left ventricular hypertrabeculation or noncompaction (LVHT) and Takotsubo syndrome (TTS). Unclassified CMPs are frequently associated with noncardiac disease, including neuromuscular disorders (NMDs). This review aims at summarizing and discussing recent findings concerning the association of NMDs with unclassified CMPs. METHODS: Literature search using the database PubMed from 1966 to June 2013 was performed. RESULTS: LVHT has been described in association with dystrophinopathies, myotonic dystrophies, zaspopathies, laminopathies, dystrobrevinopathies, oculopharyngeal muscular dystrophy, tropomyosin-1 mutations, multiminicore disease, Danon disease, mitochondrial disorders, myoadenylate deaminase deficiency, Pompe's disease, glycogen storage disease-IV, fatty acid oxidation disorder, Barth syndrome, ryanodine receptor mutation, inclusion body myopathy, dystrophic epidermolysis bullosa, Charcot-Marie-Tooth neuropathy, hereditary cobolamine deficiency, beta-thalassemia, poliomyelitis, and Friedreich ataxia. Takotsubo syndrome has been described in association with myasthenia gravis, amyotrophic lateral sclerosis, Guillain-Barre syndrome, rhabdomyolysis, mitochondrial disorder, hypokalemia-related myopathy, syndrome malin, hereditary sensorimotor neuropathy, Beals syndrome, polymyalgia rheumatica, and unclassified myopathy. It is important for treating physicians to know about these associations because treatment and outcome of LVHT, including artificial ventilation, are determined by the presence or absence of an NMD. There are also indications that LVHT in NMDs favors the development of TTS. CONCLUSIONS: LVHT and TTS may be associated with NMDs. The pathogenetic link between unclassified CMPs and NMDs remains elusive. Outcome of LVHT and treatment of TTS are additionally determined by the presence or absence of an NMD. PMID- 24154802 TI - Multifunctional tumor-targeting nanocarriers based on hyaluronic acid-mediated and pH-sensitive properties for efficient delivery of docetaxel. AB - PURPOSE: The objective of this work was to develop a multifunctional tumor targeting nanocarrier based on the mechanism of CD44-mediated endocytosis and pH induced drug release to improve the therapeutic efficacy of docetaxel (DTX). METHODS: Hyaluronic acid-coated docetaxel-loaded cholesteryl hemisuccinate vesicles (HA-CHEMS vesicles) were prepared. The physiochemical properties and pH dependent drug release of HA-CHEMS vesicles were evaluated. The HA-CHEMS vesicles were investigated for CD44-mediated internalization and in vitro cell viability using MCF-7,A549 and L929 cells.In addition,tissue distribution as well as antitumor efficacy was also evaluated in MCF-7 tumor-bearing mouse model. RESULTS: The particle size and zeta potential of HA-CHEMS vesicles were 131.4 +/- 6.2 nm and -13.3 +/- 0.04 mV,respectively. The in vitro drug release results demonstrated a pH-responsive drug release under different pH conditions. In vitro cell viability tests suggested that the encapsulation of DTX in HA-CHEMS vesicles led to more than 51.6-fold and 46.3-fold improved growth inhibition in MCF-7 and A549 cell lines,respectively compared to Taxotere(r). From the cell uptake studies,the coumarin 6-loaded HA-CHEMS vesicles enhanced intracellular fluorescent intensity in the CD44-overexpressing cell line (MCF-7). Biodistribution studies revealed selective accumulation of HA-CHEMS vesicles in the MCF-7 bearing BalB/c nude mice as a result of passive accumulation and active targeting (CD44-mediated endocytosis). Compared to Taxotere(r),HA-CHEMS vesicles exhibited higher antitumor activity by reducing tumor volume (P < 0.05) and drug toxicity,demonstrating the success of the multifunctional targeting delivery. CONCLUSIONS: This work corresponds to the preparation of a multifunctional tumor targeted delivery system. Our investigation shows that hyaluronan-bearing docetaxel-loaded cholesteryl hemisuccinate vesicles (HA-CHEMS vesicles) is a highly promising therapeutic system,leading to tumor regression after intravenous administration without visible toxicity. PMID- 24154803 TI - A systematic review of models used in cost-effectiveness analyses of preventing osteoporotic fractures. AB - This review was aimed at the evolution of health economic models used in evaluations of clinical approaches aimed at preventing osteoporotic fractures. Models have improved, with medical continuance becoming increasingly recognized as a contributor to health and economic outcomes, as well as advancements in epidemiological data. Model-based health economic evaluation studies are increasingly used to investigate the cost-effectiveness of osteoporotic fracture preventions and treatments. The objective of this study was to carry out a systematic review of the evolution of health economic models used in the evaluation of osteoporotic fracture preventions. Electronic searches within MEDLINE and EMBASE were carried out using a predefined search strategy. Inclusion and exclusion criteria were used to select relevant studies. References listed of included studies were searched to identify any potential study that was not captured in our electronic search. Data on country, interventions, type of fracture prevention, evaluation perspective, type of model, time horizon, fracture sites, expressed costs, types of costs included, and effectiveness measurement were extracted. Seventy-four models were described in 104 publications, of which 69% were European. Earlier models focused mainly on hip, vertebral, and wrist fracture, but later models included multiple fracture sites (humerus, pelvis, tibia, and other fractures). Modeling techniques have evolved from simple decision trees, through deterministic Markov processes to individual patient simulation models accounting for uncertainty in multiple parameters. Treatment continuance has been increasingly taken into account in the models in the last decade. Models have evolved in their complexity and emphasis, with medical continuance becoming increasingly recognized as a contributor to health and economic outcomes. This evolution may be driven in part by the desire to capture all the important differentiating characteristics of medications under scrutiny, as well as the advancement in epidemiological data relevant to osteoporosis fractures. PMID- 24154804 TI - Monacolin K and monascin attenuated pancreas impairment and hyperglycemia induced by advanced glycation endproducts in BALB/c mice. AB - Several lines of evidence have implicated high levels of advanced glycation endproducts (AGEs) in diabetes. Pancreas impairment caused by AGEs has been found in recent studies. Monascin (MS) and monacolin K (MK) are active compounds identified from Monascus-fermented products, which have been reported to inhibit inflammation and improve insulin resistance. In order to confirm the protective effects of MS and MK on pancreatic function, BALB/c mice were treated with AGEs via intraperitoneal injection for 22 weeks to induce hyperglycemia, and the pancreas-protecting mechanism of MS and MK from AGE-induced damage was investigated. We found that the expression of pancreatic and duodenal homeobox-1 (PDX-1) and glucose transporter 2 (GLUT2) was recovered by MS or MK administration to AGE-treated mice. In addition, MS strongly improved performance in the oral glucose tolerance test (OGTT) and the insulin tolerance test (ITT), suggesting that MS sensitized to insulin in AGE-treated mice. Both MS and MK elevated pancreatic insulin expression when compared to the AGE-treated group, suggesting that MS and MK attenuated AGE-induced pancreatic dysfunction. Histopathology studies showed that intraperitoneal injection of AGEs did not result in pancreas damage. These findings confirm that the potential mechanism of AGEs on pancreatic dysfunction involves the induction of inflammation and the suppression of PDX-1 and GLUT2 expression. Taken together, MS and MK may be developed as an anti-diabetic agent in the future. PMID- 24154806 TI - DNA crosslinks, DNA damage and repair in peripheral blood lymphocytes of non small cell lung cancer patients treated with platinum derivatives. AB - Lung cancer is the leading cause of cancer-related mortality in the world. Chemotherapy has been the mainstay of treatment for advanced non-small cell lung cancer (NSCLC) and platinum-based derivatives have been shown to improve overall survival. The aim of the present study was to investigate the DNA damage [single strand breaks (SSBs) and DNA crosslinks] and DNA repair in peripheral blood lymphocytes in patients with NSCLC treated with platinum derivatives using modified comet assay. Twenty patients in the final (4th) stage of NSCLC and 10 age-corresponding healthy controls participated in the study. Alkaline comet assay was performed according to the appropriate protocol. The DNA base excision repair (BER) activity of the controls was significantly higher compared to that of cancer patients, and the activity of DNA nucleotide excision repair (NER) was almost at the same level both in controls and patients. We observed changes in the amount of SSBs and DNA crosslinks during the course of chemotherapy. We found a significantly higher level of SSBs immediately after administration of chemotherapy. Similarly, we found the highest incidence of DNA crosslinks immediately or 1 day after chemotherapy (compared to measurement before chemotherapy). Moreover, we compared the levels of DNA repair in patients who survived chemotherapy with those in patients who died in the course of chemotherapy: the activity of BER was higher in the case of surviving patients, while the levels of NER were essentially the same. The data arising from the present study confirm the findings of other studies dealing with DNA damage and repair in cancer patients treated with chemotherapy. Moreover, our results indicated that despite the fact that cisplatin-DNA adducts are removed by the NER pathway, BER may also play a role in the clinical status of patients and their survival. PMID- 24154805 TI - Prefusion structure of trimeric HIV-1 envelope glycoprotein determined by cryo electron microscopy. AB - The activation of trimeric HIV-1 envelope glycoprotein (Env) by its binding to the cell-surface receptor CD4 and co-receptors (CCR5 or CXCR4) represents the first of a series of events that lead to fusion between viral and target-cell membranes. Here, we present the cryo-EM structure, at subnanometer resolution (~6 A at 0.143 FSC), of the 'closed', prefusion state of trimeric HIV-1 Env complexed to the broadly neutralizing antibody VRC03. We show that three gp41 helices at the core of the trimer serve as an anchor around which the rest of Env is reorganized upon activation to the 'open' quaternary conformation. The architecture of trimeric HIV-1 Env in the prefusion state and in the activated intermediate state resembles the corresponding states of influenza hemagglutinin trimers, thus providing direct evidence for the similarity in entry mechanisms used by HIV-1, influenza and related enveloped viruses. PMID- 24154807 TI - Clopidogrel results in favourable changes in nitric oxide metabolism in patients undergoing percutaneous coronary intervention. PMID- 24154808 TI - Two-Point Correlation as a Feature for Histology Images: Feature Space Structure and Correlation Updating. AB - The segmentation of tissues in whole-slide histology images is a necessary step for the morphological analyses of tissues and cellular structures. Previous works have demonstrated the potential of two-point correlation functions (TPCF) as features for tissue segmentation, however the feature space is not yet well understood and computational methods are lacking. This paper illustrates several fundamental aspects of TPCF feature space and contributes a fast algorithm for deterministic feature computation. Despite the high-dimensionality of TPCF feature space, the features corresponding to different tissues are shown to be characterized by low-dimensional manifolds. The relationship between TPCF and the familiar co-occurrence matrix is highlighted, and it is shown that costly cross correlations are not necessary to achieve an accurate segmentation. For computation, the method of correlation updating, based on the linearity of the correlation operator, is proposed and shown to achieve up to a 67X speedup over frequency domain computation methods. Segmentation results are demonstrated on multiple tissues and natural texture images. PMID- 24154809 TI - Abdominal pain and a biliary abnormality. PMID- 24154810 TI - Optical absorption in donor-acceptor polymers--alternating vs. random. AB - We investigate in a combined theoretical and experimental study the influence that the specific arrangement, e.g., alternating or random, of donor and acceptor units has on the optical absorption of extended molecules. Because of its important role in low gap polymers we discuss in particular the energetic position of the first electronic transition. We theoretically determine the excitations in extended oligomers with thiophene as the donor and 2,1,3 benzothiadiazole as the acceptor component by using time-dependent density functional theory based on non-empirically tuned range separated hybrid functionals. Corresponding systems are synthesized and theoretical and experimental data are critically compared to each other. We conclude that the influence of the specific arrangement of donor and acceptor monomers on the optical gap is limited and that effects beyond the single molecule level effectively limit the size of the experimentally observed optical gap. PMID- 24154811 TI - Vitamin D and Crohn's disease in the adult patient: a review. AB - Crohn's disease (CD) is characterized as a chronic immune-mediated inflammatory disorder of the gastrointestinal tract. Current consensus surrounding the cause of the disease suggests a complex interplay between genetic susceptibility, the intestinal microbiome and environmental factors, leading to the aberrant Th1 and Th17 immune cell mediated response. Vitamin D deficiency is common in CD patients, and long-standing deficiency has been associated with reduced bone mineral density (BMD). Accumulating evidence now suggests that in addition to maintaining skeletal integrity, vitamin D also plays an integral role in regulating the general immune response, a function employed via its genomic actions on the vitamin D receptor (VDR). The VDR is expressed in all immune cells and both directly and indirectly targeted by the bioactive form of vitamin D, 1,25-Dihydroxyvitamin D (1,25[OH]2D). Impaired regulation or deficiency of the vitamin has been linked to the promotion of self-reactive T cell development, loss of immune tolerance to self-structures, and experimental colitis in animal models, whereas the subsequent administration of the vitamin in these models resulted in the improvement of immune-mediated symptoms. In addition, low vitamin D has been associated with disease activity in CD patients, and supplementation appears to be beneficial in improving clinical scores and reducing inflammation. Therefore, the primary aims of this article were to review the molecular evidence supporting the immunoregulatory roles of vitamin D and its supplementation in the CD patient, based on existing literature. The physiological processes, accepted serum concentration values, and its well-recognized role in bone health were also summarized. PMID- 24154812 TI - Redo-urethroplasty: comparison of early functional results and quality of life in penile and bulbar strictures. AB - PURPOSE: To assess bothersome results of surgery and changes in quality of life (QoL) in patients with redo-urethroplasty, comparing the functional results of penile and bulbar cases. As after previous urethroplasty scar tissue formation is likely to occur, less favorable functional results than at primary repair could be expected. Yet data on these items for techniques currently used are limited. METHODS: Retrospective analysis with standardized questionnaire including 33 consecutive patients treated with redo-urethroplasty for bulbar or penile strictures. Previous surgeries, recurrence rate, complications, incontinence, erectile function, satisfaction with the surgery and QoL were assessed. RESULTS: Overall success rate was 78.8 %, number of previous open urethroplasty once in 24 patients (72.7 %), and more than once in 9 (27.3 %). Urinary stress incontinence Grade I occurred in 5 patients (15.2 %) and Grade II in 2 patients (6.1 %). In 24 patients (72.7 %), no penile shortening occurred and in 28 (84.8 %), no deviation was observed. Eight patients (24.2 %) reported their glans sensitivity to be altered, in 3 (9.1 %) a disturbing alteration occurred. Overall satisfaction with the surgery was high (70 %), and an improvement in QoL was seen in 72.7 % (24 patients). CONCLUSIONS: Urethroplasty after failed open repair gives good functional results and shows a high patient satisfaction rate. However, results are not quite as good as for primary repair, emphasizing the importance of a successful primary repair. PMID- 24154814 TI - Delineating the membrane-disrupting and seeding properties of the TDP-43 amyloidogenic core. AB - The amyloidogenic core in the TAR DNA-binding protein (TDP-43) C-terminal fragment has been characterized with its chemical, biochemical, and structural properties delineated. Various properties of the core sequence, including membrane impairment ability and the seeding effect, have also been studied. PMID- 24154816 TI - T cells in atherosclerosis. AB - Atherosclerosis is a chronic inflammatory disease of the artery wall. Atherosclerotic lesions contain monocytes, macrophages, smooth muscle cells and T lymphocytes. Here, we review the role of T-lymphocyte subsets in atherosclerosis. Among CD4+T cells, T(h)1 cells are pro-atherogenic, T(reg) cells are athero protective and the role of T(h)2 and T(h)17 cells remains unclear. The role of follicular helper T cells in atherosclerosis remains unknown, as is the role of CD8+T cells. NKT cells bind glycolipid antigens and exert a pro-atherogenic role. The antigen specificity of T-cell responses in atherosclerosis is poorly understood. In order to enable antigen-specific prevention or therapy, a better understanding of these mechanisms is needed. PMID- 24154820 TI - Effect of a specific supplement enriched with n-3 polyunsaturated fatty acids on markers of inflammation, oxidative stress and metabolic status of ear, nose and throat cancer patients. AB - Malnutrition affects 40-50% of patients with ear, nose and throat (ENT) cancer. The aim of this study was to assess changes induced by a specific nutritional supplement enriched with n-3 polyunsaturated fatty acids, fiber and greater amounts of proteins and electrolytes, as compared with a standard nutritional supplement, on markers of inflammation, oxidative stress and metabolic status of ENT cancer patients undergoing radiotherapy (RT). Fourteen days after starting RT, 26 patients were randomly allocated to one of two groups, 13 supplemented with Prosure, an oncologic formula enriched with n-3 polyunsaturated fatty acids, fiber and greater amounts of proteins and electrolytes (specific supplement), and 13 supplemented with Standard-Isosource (standard supplement). Patients were evaluated before RT, and 14, 28 and 90 days after starting RT. The results showed that there were no significant differences between the groups, but greater changes were observed in the standard supplement group, such as a decline in body mass index (BMI), reductions in hematocrit, erythrocyte, eosinophil and albumin levels, and a rise in creatinine and urea levels. We concluded that metabolic, inflammatory and oxidative stress parameters were altered during RT, and began to normalize at the end of the study. Patients supplemented with Prosure showed an earlier normalization of these parameters, with more favorable changes in oxidative stress markers and a more balanced evolution, although the difference was not significant. PMID- 24154821 TI - Differential methylation of the arsenic (III) methyltransferase promoter according to arsenic exposure. AB - Inorganic arsenic is methylated in the body by arsenic (III) methyltransferase (AS3MT). Arsenic methylation is thought to play a role in arsenic-related epigenetic phenomena, including aberrant DNA and histone methylation. However, it is unclear whether the promoter of the AS3MT gene, which codes for AS3MT, is differentially methylated as a function of arsenic exposure. In this study, we evaluated AS3MT promoter methylation according to exposure, assessed by urinary arsenic excretion in a stratified random sample of 48 participants from the Strong Heart Study who had urine arsenic measured at baseline and DNA available from 1989 to 1991 and 1998-1999. For this study, all data are from the 1989-1991 visit. We measured AS3MT promoter methylation at its 48 CpG loci by bisulphite sequencing. We compared mean % methylation at each CpG locus by arsenic exposure group using linear regression adjusted for study centre, age and sex. A hypomethylated region in the AS3MT promoter was associated with higher arsenic exposure. In vitro, arsenic induced AS3MT promoter hypomethylation, and it increased AS3MT expression in human peripheral blood mononuclear cells. These findings may suggest that arsenic exposure influences the epigenetic regulation of a major arsenic metabolism gene. PMID- 24154823 TI - Metal sensing and signal transduction by CnrX from Cupriavidus metallidurans CH34: role of the only methionine assessed by a functional, spectroscopic, and theoretical study. AB - When CnrX, the periplasmic sensor protein in the CnrYXH transmembrane signal transduction complex of Cupriavidus metallidurans CH34, binds the cognate metal ions Ni(II) or Co(II), the ECF-type sigma factor CnrH is made available in the cytoplasm for the RNA-polymerase to initiate transcription at the cnrYp and cnrCp promoters. Ni(II) or Co(II) are sensed by a metal-binding site with a N3O2S coordination sphere with octahedral geometry, where S stands for the thioether sulfur of the only methionine (Met123) residue of CnrX. The M123A-CnrX derivative has dramatically reduced signal propagation in response to metal sensing while the X-ray structure of Ni-bound M123A-CnrXs showed that the metal-binding site was not affected by the mutation. Ni(II) remained six-coordinate in M123A-CnrXs, with a water molecule replacing the sulfur as the sixth ligand. H32A-CnrXs, the soluble model of the wild-type membrane-anchored CnrX, was compared to the double mutants H32A-M123A-CnrXs and H32A-M123C-CnrXs to spectroscopically evaluate the role of this unique ligand in the binding site of Ni or Co. The Co- and Ni-bound forms of the protein display unusually blue-shifted visible spectra. TD-DFT calculations using structure-based models allowed identification and assignment of the electronic transitions of Co-bound form of the protein and its M123A derivative. Among them, the signature of the S-Co transition is distinguishable in the shoulder at 530 nm. In vitro affinity measurements point out the crucial role of Met123 in the selectivity for Ni or Co, and in vivo data support the conclusion that Met123 is a trigger of the signal transduction. PMID- 24154822 TI - A secondary metabolite of Brassicales, 1-methoxy-3-indolylmethyl glucosinolate, as well as its degradation product, 1-methoxy-3-indolylmethyl alcohol, forms DNA adducts in the mouse, but in varying tissues and cells. AB - 1-Methoxy-3-indolylmethyl (1-MIM) glucosinolate, a secondary metabolite of Brassicales species, and its breakdown product 1-MIM alcohol are mutagenic in cells in culture after activation by plant beta-thioglucosidase and human sulphotransferase, respectively. In the present study, we administered these compounds orally to mice to study time course, dose dependence, tissue distribution and cellular localization of the 1-MIM DNA adducts formed. We used isotope-dilution ultra-performance liquid chromatography-tandem mass spectrometry to quantify the adducts and raised an antiserum for their immunohistochemical localization. Both compounds formed the same adducts, N(2)-(1-MIM)-2' deoxyguanosine and N(6)-(1-MIM)-2'-deoxyadenosine, approximately in a 3.3:1 ratio. 1-MIM glucosinolate primarily formed these adducts in the large intestine, with a luminal-basal gradient, probably due to activation by thioglucosidase from intestinal bacteria. 1-MIM alcohol formed higher levels of adduct than the glucosinolate. Unlike after treatment with the glucosinolate, luminal and basal enterocytes were similarly affected in caecum, and liver and stomach were additional important target tissues. Maximal adduct levels were reached 8 h after the administration of both compounds. The hepatic DNA adducts persisted for the entire observation period (48 h), whereas those in large intestine rapidly declined due to cell turnover, as verified by immunohistochemistry. Hepatic adduct formation was focused on the periportal hepatocytes with concomitant depletion of glycogen, p53 activation and p21 induction. Adduct formation in caecum was associated with massive apoptosis, p53 activation and p21 induction, in particular after treatment with 1-MIM alcohol. It remains to be studied whether similar effects occur in humans after the consumption of Brassicales species. PMID- 24154824 TI - Spectral decompositions of multiple time series: a Bayesian non-parametric approach. AB - We consider spectral decompositions of multiple time series that arise in studies where the interest lies in assessing the influence of two or more factors. We write the spectral density of each time series as a sum of the spectral densities associated to the different levels of the factors. We then use Whittle's approximation to the likelihood function and follow a Bayesian non-parametric approach to obtain posterior inference on the spectral densities based on Bernstein-Dirichlet prior distributions. The prior is strategically important as it carries identifiability conditions for the models and allows us to quantify our degree of confidence in such conditions. A Markov chain Monte Carlo (MCMC) algorithm for posterior inference within this class of frequency-domain models is presented.We illustrate the approach by analyzing simulated and real data via spectral one-way and two-way models. In particular, we present an analysis of functional magnetic resonance imaging (fMRI) brain responses measured in individuals who participated in a designed experiment to study pain perception in humans. PMID- 24154825 TI - Disease acceptance and adherence to imatinib in Taiwanese chronic myeloid leukaemia outpatients. AB - BACKGROUND: The launch of imatinib has turned chronic myeloid leukaemia (CML) into a chronic illness due to the dramatic improvement in survival. Several recent studies have demonstrated that poor adherence to imatinib may hamper the therapeutic outcomes and result in increased medical expenditures, whilst research on exploring the reasons for non-adherence to imatinib is still limited. OBJECTIVE: This study aimed to explore the experience of patients as they journey through their CML treatments and associated imatinib utilisation in order to understand the perceptions, attitudes and concerns that may influence adherence to imatinib treatment. SETTING: This study was conducted at oncology outpatient clinics in a medical centre in southern Taiwan. METHODS: CML patients who regularly attended the oncology outpatient clinics to receive imatinib treatment from October 2011 to March 2012 were invited to participate in the study. Semi structured face-to-face interviews were used to explore patients' experiences and views of their treatment, their current CML status and CML-related health conditions, their concerns about imatinib treatment and imatinib-taking behaviours. Patient interviews were recorded, transcribed verbatim and thematically analysed using the constant comparison approach. MAIN OUTCOME MEASURE: Themes related to patients' views of the disease and health conditions, worries and concerns influencing imatinib utilisation behaviours are reported. RESULTS: Forty-two CML patients participated in the interviews. The emerging themes included: acceptance of current disease and health status, misconceptions about disease progression, factors associated with adherence to imatinib, concerns and management of adverse drug effects. Participants regarded CML as a chronic disease but had misconceptions about disease progression, therapeutic monitoring, resistance to imatinib and symptoms of side effects. Participants were generally adherent to imatinib and favoured long-term prescriptions to avoid regular outpatient visits for medication refills. Experiencing adverse effect was the main reason influencing adherence and led to polypharmacy. Most participants altered medicine-taking behaviours to maintain long-term use of imatinib. CONCLUSION: Taiwanese CML patients are adherent to imatinib but report changing their medication-taking behaviour due to adverse drug effects and associated polypharmacy. Patients' misconceptions of the disease and medication suggests that it is necessary to improve communication between patients and healthcare professionals. Routinely providing updated information as part of the patient counselling process should be considered as a means of improving this communication. PMID- 24154826 TI - Structural functionality, catalytic mechanism modeling and molecular allergenicity of phenylcoumaran benzylic ether reductase, an olive pollen (Ole e 12) allergen. AB - Isoflavone reductase-like proteins (IRLs) are enzymes with key roles in the metabolism of diverse flavonoids. Last identified olive pollen allergen (Ole e 12) is an IRL relevant for allergy amelioration, since it exhibits high prevalence among atopic patients. The goals of this study are the characterization of (A) the structural-functionality of Ole e 12 with a focus in its catalytic mechanism, and (B) its molecular allergenicity by extensive analysis using different molecular computer-aided approaches covering (1) physicochemical properties and functional-regulatory motifs, (2) sequence analysis, 2-D and 3D structural homology modeling comparative study and molecular docking, (3) conservational and evolutionary analysis, (4) catalytic mechanism modeling, and (5) sequence, structure-docking based B-cell epitopes prediction, while T-cell epitopes were predicted by inhibitory concentration and binding score methods. Structural-based detailed features, phylogenetic and sequences analysis have identified Ole e 12 as phenylcoumaran benzylic ether reductase. A catalytic mechanism has been proposed for Ole e 12 which display Lys133 as one of the conserved residues of the IRLs catalytic tetrad (Asn-Ser-Tyr-Lys). Structure characterization revealed a conserved protein folding among plants IRLs. However, sequence polymorphism significantly affected residues involved in the catalytic pocket structure and environment (cofactor and substrate interaction recognition). It might also be responsible for IRLs isoforms functionality and regulation, since micro-heterogeneities affected physicochemical and posttranslational motifs. This polymorphism might have large implications for molecular differences in B- and T-cells epitopes of Ole e 12, and its identification may help designing strategies to improve the component-resolving diagnosis and immunotherapy of pollen and food allergy through development of molecular tools. PMID- 24154827 TI - Individual factors associated with neck disability in patients with cervical radiculopathy scheduled for surgery: a study on physical impairments, psychosocial factors, and life style habits. AB - PURPOSE: The influence of individual factors on patient-reported outcomes is important in the interpretation of disability and treatment effectiveness. The purpose of this study was to assess how physical impairments, psychosocial factors, and life style habits were associated with neck disability based on the Neck Disability Index (NDI), in patients with cervical radiculopathy scheduled for surgery. METHODS: This cross-sectional study included 201 patients (105 men, 96 women; mean age 50 years). Data included self-reported measures and a clinical examination. Multiple linear regressions were performed to identify significant influencing factors. RESULTS: Pain, physical impairments in the cervical active range of motion, low self-efficacy, depression, and sickness-related absences explained 73% of the variance in NDI scores (p < 0.001). CONCLUSION: Assessments of physical impairments and psychosocial factors in patients with cervical radiculopathy could improve the description of neck disability and the interpretation of treatment outcomes in longitudinal studies. PMID- 24154829 TI - Carotid intervention in the elderly: who is old and who benefits? PMID- 24154828 TI - Biomechanical effects of cervical arthroplasty with U-shaped disc implant on segmental range of motion and loading of surrounding soft tissue. AB - PURPOSE: Various design concepts have been adopted in cervical disc prostheses, including sliding articulation and standalone configuration. This study aimed to evaluate the biomechanical effects of the standalone U-shaped configuration on the cervical spine. METHODS: Based on an intact finite element model of C3-C7, a standalone U-shaped implant (DCI) was installed at C5-C6 and compared with a sliding articulation design (Prodisc-C) and an anterior fusion system. The range of motion (ROM), adjacent intradiscal pressure (IDP) and capsular ligament strain were calculated under different spinal motions. RESULTS: Compared to the intact configuration, the ROM at C5-C6 was reduced by 90% after fusion, but increased by 70% in the Prodisc-C model, while the maximum percentage change in the DCI model was 30% decrease. At the adjacent segments, up to 32% increase in ROM happened after fusion, while up to 34% decrease occurred in Prodisc-C model and 17% decrease in DCI model. The IDP increased by 11.6% after fusion, but decreased by 5.6 and 6.3% in the DCI and Prodisc-C model, respectively. The capsular ligament strain increased by 147% in Prodisc-C and by 13% in the DCI model. The DCI implant exhibited a high stress distribution. CONCLUSIONS: Spinal fusion resulted in compensatory increase of ROM at the adjacent sites, thereby elevating the IDP. Prodisc-C resulted in hyper-mobility at the operative site that led to an increase of ligament force and strain. The U-shaped implant could maintain the spinal kinematics and impose minimum influence on the adjacent soft tissues, despite the standalone configuration encountering the disadvantages of high stress distribution. PMID- 24154830 TI - Anti-oxidised-phospholipid antibodies do not correlate with specific anti phospholipid syndrome classes, but with disease duration. PMID- 24154831 TI - Ion channel recordings on an injection-molded polymer chip. AB - In this paper, we demonstrate recordings of the ion channel activity across the cell membrane in a biological cell by employing the so-called patch clamping technique on an injection-molded polymer microfluidic device. The findings will allow direct recordings of ion channel activity to be made using the cheapest materials and production platform to date and with the potential for very high throughput. The employment of cornered apertures for cell capture allowed the fabrication of devices without through holes and via a scheme comprising master origination by dry etching in a silicon substrate, electroplating in nickel and injection molding of the final part. The most critical device parameters were identified as the length of the patching capillary and the very low surface roughness on the inside of the capillary. The cross-sectional shape of the orifice was found to be less critical, as both rectangular and semicircular profiles seemed to have almost the same ability to form tight seals with cells with negligible leak currents. The devices were functionally tested using human embryonic kidney cells expressing voltage-gated sodium channels (Nav1.7) and benchmarked against a commercial state-of-the-art system for automated ion channel recordings. These experiments considered current-voltage (IV) relationships for activation and inactivation of the Nav1.7 channels and their sensitivity to a local anesthetic, lidocaine. Both IVs and lidocaine dose response curves obtained from the injection-molded polymer device were in good agreement with data obtained from the commercial system. PMID- 24154832 TI - Expression, purification, and characterization of a recombinant methionine adenosyltransferase pDS16 in Pichia pastoris. AB - Methionine adenosyltransferase (MAT, EC2.5.1.6) catalyzes the synthesis of S adenosylmethionine (SAM) using L-methionine and adenosine triphosphate (ATP) as substrates. The mutant MAT pDS16 was obtained through DNA shuffling previously in our lab. Overexpression of pDS16 in Pichia pastoris led to about 65 % increase of MAT activity and SAM accumulation, compared with the strain overexpressing Saccharomyces cerevisiae MAT gene SAM2. Different strategies were tested to facilitate the expression and purification of pDS16. However, addition of the hexahistidine tag to pDS16 was shown to decrease the enzyme activity, and the yeast alpha-factor signal sequence could not effectivley direct the secretion of pDS16. The intracellular pDS16 was purified by a simple two-step procedure combining an ion exchange and hydrophobic interaction chromatography. Protein purity was verified by sodium dodecyl sulfate polyacrylamide gel electrophoresis to be 93%, with the specific activity of 1.828 U/mg. Two-dimensional electrophoresis revealed pI of ~5.5. The purified enzyme followed Michaelis kinetics with a Km of 1.72 and 0.85 mM, and Vmax of 1.54 and 1.15 MUmol/min/mg for ATP and L-methionine, respectively. pDS16 exhibited optimal activity at pH 8.5 and 45 degrees C with the requirement of divalent cation Mg(2+) and was slightly stimulated by the monovalent cation K(+). It showed an improved thermostability, about 50% of the enzyme activity was retained even after preincubation at 50 degrees C for 2 h. PMID- 24154833 TI - Lessons in media advocacy: a look back at Saskatchewan's nursing education debate. AB - Nurses are encouraged to exert their influence in the realm of public policy, particularly policies related to the nursing profession, the health care system and the health of their clients. Media advocacy can be used by nursing organizations to mobilize public support on policy issues in order to influence policy makers. This article retrospectively examined the media advocacy efforts of nursing stakeholders in Saskatchewan, Canada in response to a new government policy that would have impacted educational requirements for licensure as a registered nurse (RN) in that province. Print media sources from the period January to March, 2000 were examined to determine the specific media advocacy techniques used by nursing organizations within the framework of the policy cycle. The success of nursing stakeholders in reversing the government position highlights the effectiveness of media advocacy as a tool to disseminate messages from the nursing profession in order to impact policy. PMID- 24154834 TI - Impact of an automated email notification system for results of tests pending at discharge: a cluster-randomized controlled trial. AB - BACKGROUND AND OBJECTIVE: Physician awareness of the results of tests pending at discharge (TPADs) is poor. We developed an automated system that notifies responsible physicians of TPAD results via secure, network email. We sought to evaluate the impact of this system on self-reported awareness of TPAD results by responsible physicians, a necessary intermediary step to improve management of TPAD results. METHODS: We conducted a cluster-randomized controlled trial at a major hospital affiliated with an integrated healthcare delivery network in Boston, Massachusetts. Adult patients with TPADs who were discharged from inpatient general medicine and cardiology services were assigned to the intervention or usual care arm if their inpatient attending physician and primary care physician (PCP) were both randomized to the same study arm. Patients of physicians randomized to discordant study arms were excluded. We surveyed these physicians 72 h after all TPAD results were finalized. The primary outcome was awareness of TPAD results by attending physicians. Secondary outcomes included awareness of TPAD results by PCPs, awareness of actionable TPAD results, and provider satisfaction. RESULTS: We analyzed data on 441 patients. We sent 441 surveys to attending physicians and 353 surveys to PCPs and received 275 and 152 responses from 83 different attending physicians and 112 different PCPs, respectively (attending physician survey response rate of 63%). Intervention attending physicians and PCPs were significantly more aware of TPAD results (76% vs 38%, adjusted/clustered OR 6.30 (95% CI 3.02 to 13.16), p<0.001; 57% vs 33%, adjusted/clustered OR 3.08 (95% CI 1.43 to 6.66), p=0.004, respectively). Intervention attending physicians tended to be more aware of actionable TPAD results (59% vs 29%, adjusted/clustered OR 4.25 (0.65, 27.85), p=0.13). One hundred and eighteen (85%) and 43 (63%) intervention attending physician and PCP survey respondents, respectively, were satisfied with this intervention. CONCLUSIONS: Automated email notification represents a promising strategy for managing TPAD results, potentially mitigating an unresolved patient safety concern. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov (NCT01153451). PMID- 24154835 TI - Patient access to medical records and healthcare outcomes: a systematic review. AB - OBJECTIVES: We conducted a systematic review to determine the effect of providing patients access to their medical records (electronic or paper-based) on healthcare quality, as defined by measures of safety, effectiveness, patient centeredness, timeliness, efficiency, and equity. METHODS: Articles indexed in PubMed from January 1970 to January 2012 were reviewed. Twenty-seven English language controlled studies were included. Outcomes were categorized as measures of effectiveness (n=19), patient-centeredness (n=16), and efficiency (n=2); no study addressed safety, timeliness, or equity. RESULTS: Outcomes were equivocal with respect to several aspects of effectiveness and patient-centeredness. Efficiency outcomes in terms of frequency of in-person and telephone encounters were mixed. Access to health records appeared to enhance patients' perceptions of control and reduced or had no effect on patient anxiety. CONCLUSION: Although few positive findings generally favored patient access, the literature is unclear on whether providing patients access to their medical records improves quality. PMID- 24154836 TI - Unrealized potential and residual consequences of electronic prescribing on pharmacy workflow in the outpatient pharmacy. AB - INTRODUCTION: Electronic prescribing systems have often been promoted as a tool for reducing medication errors and adverse drug events. Recent evidence has revealed that adoption of electronic prescribing systems can lead to unintended consequences such as the introduction of new errors. The purpose of this study is to identify and characterize the unrealized potential and residual consequences of electronic prescribing on pharmacy workflow in an outpatient pharmacy. METHODS: A multidisciplinary team conducted direct observations of workflow in an independent pharmacy and semi-structured interviews with pharmacy staff members about their perceptions of the unrealized potential and residual consequences of electronic prescribing systems. We used qualitative methods to iteratively analyze text data using a grounded theory approach, and derive a list of major themes and subthemes related to the unrealized potential and residual consequences of electronic prescribing. RESULTS: We identified the following five themes: Communication, workflow disruption, cost, technology, and opportunity for new errors. These contained 26 unique subthemes representing different facets of our observations and the pharmacy staff's perceptions of the unrealized potential and residual consequences of electronic prescribing. DISCUSSION: We offer targeted solutions to improve electronic prescribing systems by addressing the unrealized potential and residual consequences that we identified. These recommendations may be applied not only to improve staff perceptions of electronic prescribing systems but also to improve the design and/or selection of these systems in order to optimize communication and workflow within pharmacies while minimizing both cost and the potential for the introduction of new errors. PMID- 24154837 TI - Efficient sequential and parallel algorithms for record linkage. AB - BACKGROUND AND OBJECTIVE: Integrating data from multiple sources is a crucial and challenging problem. Even though there exist numerous algorithms for record linkage or deduplication, they suffer from either large time needs or restrictions on the number of datasets that they can integrate. In this paper we report efficient sequential and parallel algorithms for record linkage which handle any number of datasets and outperform previous algorithms. METHODS: Our algorithms employ hierarchical clustering algorithms as the basis. A key idea that we use is radix sorting on certain attributes to eliminate identical records before any further processing. Another novel idea is to form a graph that links similar records and find the connected components. RESULTS: Our sequential and parallel algorithms have been tested on a real dataset of 1,083,878 records and synthetic datasets ranging in size from 50,000 to 9,000,000 records. Our sequential algorithm runs at least two times faster, for any dataset, than the previous best-known algorithm, the two-phase algorithm using faster computation of the edit distance (TPA (FCED)). The speedups obtained by our parallel algorithm are almost linear. For example, we get a speedup of 7.5 with 8 cores (residing in a single node), 14.1 with 16 cores (residing in two nodes), and 26.4 with 32 cores (residing in four nodes). CONCLUSIONS: We have compared the performance of our sequential algorithm with TPA (FCED) and found that our algorithm outperforms the previous one. The accuracy is the same as that of this previous best-known algorithm. PMID- 24154838 TI - Roles of carbohydrate reserves for local adaptation to low temperatures in the freeze tolerant oligochaete Enchytraeus albidus. AB - Geographic variation in cold tolerance and associated physiological adaptations were investigated in the freeze tolerant enchytraeid Enchytraeus albidus (Oligochaeta). Specimens from Svalbard, Greenland (Nuuk), Iceland (Holar and Mossfellsbaer) and continental Europe [Norway (Bergen), Sweden (Kullen) and Germany] were reared in the laboratory in a common-garden experiment. The aim was to test for variations in minimum lethal temperature, freeze duration tolerance, carbohydrate reserves and metabolic rate among the populations. Cold tolerance was related to environmental temperature of the respective location. Populations from the coldest climatic regions were able to tolerate freezing down to at least -15 degrees C and endured being frozen at -5 degrees C for 27-48 days, respectively. Populations from milder climates had a lower freeze duration tolerance (about -9 degrees C) and endured -5 degrees C for a shorter period (between 9 and 16 days). Glucose accumulation and glycogen reserves varied significantly between populations, but was not related directly to cold tolerance. Metabolic rate varied significantly between populations, but was not significantly related to cold tolerance. The metabolic rates at -2 degrees C of frozen and unfrozen worms from Germany and Svalbard were tested. The metabolic depression due to freezing of these populations was relatively small (<50 %), suggesting that the large carbohydrate accumulations may also be important as fuel during long-term freezing at moderately low temperatures. Differences in metabolic depression may partly explain the difference in cold tolerance of these two populations, however, the mechanisms behind local adaptation to low winter temperatures in these enchytraeid populations seem more complex than earlier studies have indicated. PMID- 24154839 TI - Floxuridine hepatic arterial infusion associated biliary toxicity is increased by concurrent administration of systemic bevacizumab. AB - PURPOSE: Systemic bevacizumab (Bev) was added to hepatic arterial infusion (HAI) floxuridine (FUDR)-based chemotherapy in three studies in an attempt to improve outcomes. A specific review of biliary toxicity was carried out. METHODS: This analysis included 203 patients from three prospective studies. The first (study A) was an adjuvant study after liver resection of colorectal metastases in which patients received HAI and systemic chemotherapy (Sys) with or without Bev. Study B comprised unresectable colorectal patients who received HAI and Sys plus Bev. Study C included patients with unresectable cholangiocarcinoma or hepatocellular carcinoma who received HAI plus systematic Bev. The outcome and toxicity of patients in studies B and C were compared with historical controls. RESULTS: In all three studies, the incidence of hyperbilirubinemia and biliary stent placement within 1 year of treatment was increased with the addition of Bev. In the no-Bev versus Bev groups, the placement of biliary stents was as follows: study A, 0 of 38 versus 4 of 35 patients (p = 0.05); study B, 0 of 49 versus 3 of 24 (p = 0.06); and study C, 0 of 34 versus 3 of 22 (p = 0.15). Elevation in bilirubin was noted in the no-Bev versus Bev groups: study A, 0 of 38 versus 5 of 35 patients (p = 0.02); study B, 1 of 49 versus 7 of 24 (p = 0.005); and study C, 2 of 34 versus 5 of 22 (p = 0.10). The addition of Bev did not seem to be associated with improved progression-free or overall survival. CONCLUSIONS: The addition of Bev to HAI FUDR resulted in increased biliary toxicity in three separate studies. Although the sample sizes were small, there was no evidence of improved PFS or OS with the addition of Bev. Bev should not be combined with HAI FUDR. PMID- 24154840 TI - The microRNA-21/PTEN pathway regulates the sensitivity of HER2-positive gastric cancer cells to trastuzumab. AB - BACKGROUND: The ToGA trial demonstrated the significant efficacy of trastuzumab in addition to chemotherapy in patients with HER2-positive gastric cancer (GC). Although trastuzumab has become a key drug in breast cancer treatment, resistance to trastuzumab is a major problem in clinical practice. The aim of the current study was to identify the micro-RNA (miR)/gene pathway regulating the sensitivity of HER2-positive GC cells to trastuzumab. METHODS: Correlations between the expression levels of miR-21, PTEN, and p-AKT were analyzed by real-time PCR and Western blot test in HER2-positive GC cell lines. The effects of overexpression or suppression of miR-21 on the sensitivity of GC cells to trastuzumab were also analyzed in vitro. RESULTS: Overexpression of miR-21 down-regulated PTEN expression, increased AKT phosphorylation, and did not affect HER2 expression. Inversely, suppression of miR-21 increased PTEN expression and down-regulated AKT phosphorylation, but still did not affect HER2 expression. Overexpression of miR 21 decreased the sensitivity of GC cells to trastuzumab, while suppression of miR 21 expression restored the resistance of GC cells to trastuzumab. Overexpression of miR-21 significantly suppressed trastuzumab-induced apoptosis. CONCLUSIONS: To our knowledge, this study was the first reveal the miR-21/PTEN pathway regulated the sensitivity of HER2-positive GC cell lines to trastuzumab through modulation apoptosis. These findings suggest that this pathway may be crucial to the mechanism of resistance to trastuzumab in GC, which may lead to the development of individualized treatment in clinical practice. PMID- 24154841 TI - Psychometric properties of the self-report Malay version of the Pediatric Quality of Life (PedsQLTM) 4.0 Generic Core Scales among multiethnic Malaysian adolescents. AB - Adolescence is the potential period for growth and optimal functioning, but developmental issues like time of transition from childhood to adulthood will create stress and affect the adolescent's quality of life (QOL). However, there is a lack of research tool for measuring adolescent's QOL in Malaysia. The aim of the study was to determine the validity and reliability of the self-report Malay version of the pediatric QOL (PedsQLTM) 4.0 Generic Core Scales in assessing the QOL of Malaysian adolescents. A cross-sectional study design using the 23-item self-report Malay version of the PedsQL 4.0 Generic Core Scales was administered on a convenient cluster sampling (n = 297 adolescent) from a secondary school. The internal consistency reliability had Cronbach's alpha values ranging from .70 to .89. Factor analysis reported a six-factor structure via principal axis factor analysis. In conclusion, the self-report Malay version of the pediatric QOL 4.0 Generic Core Scales is a reliable and valid tool to measure the QOL of multiethnic Malaysian adolescents. PMID- 24154842 TI - Cross-cultural adaptation and validation of the Malay language version of the TZO AZL Preschool Children Quality of Life questionnaire: A health-related quality of life instrument for preschool children. AB - The aim of this study is to evaluate the psychometric properties of the translated Malay language version of TZO-AZL Preschool Children Quality of Life (TAPQOL) questionnaire in preschool children. Preterm children and term children aged between two and five years were enrolled into the study. The Malay language version of TAPQOL and a set of questions regarding the child's health status were answered by the caregivers. The internal consistency, Spearman's correlation coefficients and principal component analysis (PCA) with Varimax rotation and Mann-Whitney U test for group comparison were employed to evaluate the psychometric properties of this instrument. A total of 258 children (120 preterm children and 138 term children) were recruited to this study with a response rate of 94%. All (sub)domains except one had Cronbach's alpha coefficients of more than .7. The Spearman's correlation coefficients between 12 subdomains were generally low. PCA supported the structural unidimensionality of the items in the instrument. Preterm children had lower quality of life scores than that of term children. Malay version of TAPQOL has multidimensional construct. It is a reliable and valid instrument for preschool children, with almost similar psychometric properties to the original version. PMID- 24154843 TI - The experiences of parents and nurses of hospitalised infants requiring oxygen therapy for severe bronchiolitis: A phenomenological study. AB - Bronchiolitis is a major cause of children's admission to hospital. The study aim was to describe the experiences of parents who had, or nurses who cared for, a child admitted to hospital for severe bronchiolitis requiring oxygen therapy. A descriptive phenomenological approach was used to interview 12 mothers and 12 nurses. The findings were clustered into three domains: fear, parent-child interaction and technical caring. The mothers found the experience to be extremely frightening, based on their fear that their child could die. This was compounded by their lack of knowledge and understanding about what was happening and their inability to fulfil their mothering role. Although nurses recognised that parents were anxious, they did not seem to appreciate fully the depth of fear and emotion that mothers were experiencing and tended to describe procedural aspects of their role. The mothers' relationship with their child was focused upon physical contact and the desire to comfort their child. Their ability to do so was significantly impacted upon by the method of oxygen delivery to their child. For nurses, although they recognised the psychosocial dimension, their emphasis was on health and safety aspects of oxygen therapy, both for the child and themselves. PMID- 24154844 TI - Belgian siblings of children with a chronic illness: Is their quality of life different from their peers? AB - To assess Belgian siblings' self-reported quality of life (QoL) and the impact of illness on four different paediatric illnesses. Healthy siblings (n = 131) of children with type 1 diabetes, cancer, congenital heart disease (CHD) and cystic fibrosis (CF) completed the Child Health Questionnaire and the Sibling Perception Questionnaire. Results were compared to those of a matched group of siblings of healthy children. Siblings reported a good QoL, similar to controls, with the exception that siblings reported better on the QoL domain pain (p < .01). QoL was not related to time since diagnosis but the impact of illness was higher nearer to the time of diagnosis (r = -.39, p < .001). QoL of siblings of children with CHD or cancer was lower than QoL in the CF or type 1 diabetes group whilst impact of illness was highest for the CHD group. QoL of siblings of a child with a chronic illness is similar to the QoL of peers. Studies investigating siblings' QoL or the impact of illness on siblings should include the day-to-day demands of the illness as well as less obvious illness-related issues like 'hidden stress' and 'sense of control'. PMID- 24154845 TI - Experiences of expressing and storing colostrum antenatally: A qualitative study of mothers in regional Western Australia. AB - This qualitative study explored the experiences and breastfeeding outcomes of a group of mothers who expressed colostrum in the antenatal period. In-depth interviews were conducted over the telephone with 12 women who had attended a unique antenatal lactation clinic appointment at 37 weeks' gestation. Seven main response themes were identified. Most women reflected positively upon their attendance and reported that the experience of expressing colostrum allowed them to become familiar with their breasts and gave them a sense of security by having a supply of colostrum stored for possible use after birth. The main negative emotions reported were a sense of embarrassment at expressing the colostrum, particularly in front of another person, the difficulties with expressing colostrum and in one instance, the physical pain associated with the process. Antenatal expression of colostrum may improve maternal breastfeeding confidence. Further research using long-term records will determine whether this practice improves breastfeeding outcomes. PMID- 24154846 TI - ICD-11 for quality and safety: overview of the WHO Quality and Safety Topic Advisory Group. AB - This paper outlines the approach that the WHO's Family of International Classifications (WHO-FIC) network is undertaking to create ICD-11. We also outline the more focused work of the Quality and Safety Topic Advisory Group, whose activities include the following: (i) cataloguing existing ICD-9 and ICD-10 quality and safety indicators; (ii) reviewing ICD morbidity coding rules for main condition, diagnosis timing, numbers of diagnosis fields and diagnosis clustering; (iii) substantial restructuring of the health-care related injury concepts coded in the ICD-10 chapters 19/20, (iv) mapping of ICD-11 quality and safety concepts to the information model of the WHO's International Classification for Patient Safety and the AHRQ Common Formats; (v) the review of vertical chapter content in all chapters of the ICD-11 beta version and (vi) downstream field testing of ICD-11 prior to its official 2015 release. The transition from ICD-10 to ICD-11 promises to produce an enhanced classification that will have better potential to capture important concepts relevant to measuring health system safety and quality-an important use case for the classification. PMID- 24154847 TI - [Informations and recommendations of the German Respiratory Society and the Paul Ehrlich-Society for chemotherapy concerning the outbreak of influenza A(H7N9) virus infections in humans]. AB - In March 2013, the first cases of avian influenza virus infections in humans were reported by the authorities of the PR of China to the World Health Organization. This influenza A(H7N9) virus comprises genes of at least four different avian influenza viruses, some segments mimicking human-like influenza-signatures. Until 11 August, 2013 135 humans were infected, 44 (33%) died. The clinical course is characterized by fever, cough, gastrointestinal symptoms, lympho- and thrombopenia as well by the rapid onset of an acute respiratory distress syndrome in nearly 25% of the cases. Although human to human transmission may have occurred only in the context of three clusters, strict hygiene measures should be instituted and any suspect case should be reported to the local health authorities immediately. The detection of influenza A(H7N9) is based on real-time polymerase chain reaction (PCR). Antiviral treatment should be initiated as early as possible for suspect, probable or confirmed cases, even when 48 hours have passed after symptom onset. At present the future development of this epidemic cannot be predicted. PMID- 24154848 TI - microRNA-27a functions as a tumor suppressor in esophageal squamous cell carcinoma by targeting KRAS. AB - microRNAs (miRNAs) have been suggested to play a vital role in regulating tumor progression and invasion. However, the expression of miR-27a in esophageal squamous cell carcinoma (ESCC) and its effect on the tumorigenesis of ESCC are unclear. In the present study, we found that miR-27a was downregulated in esophageal carcinoma cell lines and ESCC specimens with lymph node metastasis. Furthermore, we demonstrated that miR-27a binds to the 3'-untranslated region (UTR) of KRAS and inhibits the expression of the KRAS protein. miR-27a levels were inversely correlated with levels of KRAS mRNA and protein in ESCC specimens. Both in vitro and in vivo assays revealed that miR-27a attenuated ESCC proliferation, invasion and tumor growth in nude mice. miR-27a exerts its tumor suppressor function through inhibition of the KRAS-related ERK pathways. Our findings suggest, for the first time, that miR-27a suppresses tumorigenesis of ESCC by targeting KRAS. PMID- 24154849 TI - Appropriateness of use criteria for transthoracic echocardiography: are they relevant outside the USA? AB - BACKGROUND: Appropriateness of use criteria (AUC) for transthoracic echocardiography (TTE) have been developed by American cardiology associations to help avoid unnecessary scans by formalizing indications for imaging. There are 98 indications classified as either appropriate (A), inappropriate (I), or uncertain (U). AUC may allow better targeting of limited resources, but they have not been tested systematically outside the USA. AIM OF THE STUDY: To test AUC in Wales, one of the four countries of the UK. METHODS: We collected requests for TTE and the corresponding TTE reports from all Welsh hospitals during 1 week in June 2012 and analysed them according to appropriateness, specialty, and location (secondary vs. tertiary services) of the referring physician. RESULTS: We analysed 1070 pairs of echocardiography requests and TTE reports from 14 hospitals [mean age 66.5 (16.1) years; 579 (51%) M]: A-922 (86%); I-115 (11%), and U-33 (3%); 287 (25%) studies were from two tertiary centres and 338 (29.5%) were of inpatients. Main indications were the evaluation of: cardiac structure and function (489, 45.7%), valvular function (267, 25%), and hypertension, heart failure, or cardiomyopathy (149, 13.9%). In-patient requests (main indication- 'initial evaluation of left ventricle ejection fraction post acute coronary syndrome'--44 studies, 13.7%) were more often appropriate than outpatients (main indication--'symptoms/conditions potentially related to suspected cardiac aetiology'--142 studies, 19.8%): 94.4 vs. 83.5%, P < 0.05. The most common inappropriate indication was 'initial evaluation for a murmur/click without symptoms/signs of structural heart disease' (29 studies, 2.7%). The proportion of appropriate requests by specialty was 89% for medical, 87% for GPs, 85.3% for cardiologists, 80.8% for surgical, and 60% for cardiac surgeons (P < 0.05 for cardiac surgeons); 47.8% of requests were generated by cardiologists, and abnormalities were detected in 82% of all scans (37% minor findings and 45% major findings), least often in those requested by general practitioners. CONCLUSION: Application of AUC yields results similar to those reported from the USA; ~1 in 10 scans could be avoided. PMID- 24154850 TI - Climate change and agricultural development: adapting Polish agriculture to reduce future nutrient loads in a coastal watershed. AB - Currently, there is a major concern about the future of nutrient loads discharged into the Baltic Sea from Polish rivers because they are main contributors to its eutrophication. To date, no watershed-scale studies have properly addressed this issue. This paper fills this gap by using a scenario-modeling framework applied in the Reda watershed, a small (482 km2) agricultural coastal area in northern Poland. We used the SWAT model to quantify the effects of future climate, land cover, and management changes under multiple scenarios up to the 2050s. The combined effect of climate and land use change on N-NO3 and P-PO4 loads is an increase by 20-60 and 24-31 %, respectively, depending on the intensity of future agricultural usage. Using a scenario that assumes a major shift toward a more intensive agriculture following the Danish model would bring significantly higher crop yields but cause a great deterioration of water quality. Using vegetative cover in winter and spring (VC) would be a very efficient way to reduce future P PO4 loads so that they are lower than levels observed at present. However, even the best combination of measures (VC, buffer zones, reduced fertilization, and constructed wetlands) would not help to remediate heavily increased N-NO3 loads due to climate change and agricultural intensification. PMID- 24154851 TI - Role of GABAergic activity of sodium valproate against ischemia-reperfusion induced acute kidney injury in rats. AB - Gamma amino butyric acid (GABA) has been reported to be renoprotective in various preclinical studies. Sodium valproate (SVP) is documented to protect against renal injury through its histone deacetylase-inhibiting activity. The present study investigated the involvement of GABAA receptors and the role of GABAergic activity of SVP against ischemia-reperfusion-induced acute kidney injury (AKI) in rats. The rats were subjected to bilateral renal ischemia for 40 min followed by reperfusion for 24 h to induce AKI. The creatinine clearance, serum urea, uric acid, lactate dehydrogenase, potassium, fractional excretion of sodium, and microproteinuria were measured to assess kidney injury. The thiobarbituric acid reactive substances, reduced glutathione level, myeloperoxidase, and catalase activity were assayed to assess oxidative stress in renal tissues along with hematoxylin-eosin staining to observe histopathological changes. The ischemia reperfusion-induced AKI witnessed an increase in serum parameters, microproteinuria, oxidative stress, and histopathological changes in renal tissues. Picrotoxin aggravated ischemia-reperfusion injury-induced AKI confirming the role of GABAA receptors in AKI. The SVP treatment afforded protection against AKI that was blocked by concurrent treatment with picrotoxin. Hence, it is concluded that regulation of GABAA receptors is important for management of AKI. Moreover, the GABAergic activity of SVP is important for its renoprotective effect. PMID- 24154853 TI - Sources of polycyclic hydrocarbons and pesticides in soluble fraction of deposition samples in Kocaeli, Turkey. AB - A wet-dry deposition sampler was located at The Scientific and Technological Research Council of Turkey-National Metrology Institute (TUBITAK-UME) station, and a bulk deposition sampler was placed at the Kadilli village to determine the atmospheric deposition flux of polycyclic aromatic hydrocarbons (PAHs) and pesticides (organochlorine and organophosphorus) in soluble fraction of samples in Kocaeli, Turkey. The 28 samples for each wet, dry, and total deposition were collected weekly from March 2006 to March 2007. Gas chromatography-tandem mass spectrometry was used to analyze the samples which were prepared by using solid phase extraction (SPE) method. The sum of volume weighted mean of deposition fluxes was obtained as 7.43 MUg m(-2) day(-1) for wet deposition, 0.28 MUg m(-2) day(-1) for dry deposition and 0.54 MUg m(-2) day(-1) for bulk deposition samples for PAHs and 9.88 MUg m(-2) day(-1) for wet deposition, 4.49 MUg m(-2) day(-1) for dry deposition, and 3.29 MUg m(-2) day(-1) for bulk deposition samples for pesticides. While benzo(a)anthracene had the highest fluxes among PAH compounds for all types of depositions, guthion and phosphamidon had the highest deposition flux compared with the other pesticides. Benzo(ghi)perylene, dibenz(a,h)anthracene, indeno(1,2,3-c,d)pyrene, benzo(a)pyrene, and acenaphthene were not detected in any of the samples. Beta-HCH, gamma-HCH, and endrin aldehyde were the only compounds among 18 organochlorine pesticides to be detected in all deposition samples. The main sources of pesticides were the high number of greenhouses around the sampling stations. However, all of the organophosphorus pesticides were detected in all deposition samples. The pollution sources were identified as coal and natural gas combustion, petrogenic sources, and traffic for TUBITAK-UME station whereas coal and natural gas combustion and traffic were the main sources for Kadilli station by considering the results of factor analysis, ratios, and wind sector analysis. PMID- 24154852 TI - The function of EHD2 in endocytosis and defense signaling is affected by SUMO. AB - Post-translational modification of target proteins by the small ubiquitin-like modifier protein (SUMO) regulates many cellular processes. SUMOylation has been shown to regulate cellular localization and function of a variety of proteins, in some cases affecting nuclear import or export. We have previously characterized two EHDs (EH domain containing proteins) in Arabidospis and showed their involvement in plant endocytosis. AtEHD2 has an inhibitory effect on endocytosis of transferrin, FM-4-64, and the leucine rich repeat receptor like protein LeEix2, an effect that requires and intact coiled-coil domain. Inhibition of endocytosis of LeEix2 by EHD2 is effective in inhibiting defense responses mediated by the LeEix2 receptor in response to its ligand EIX. In the present work we demonstrate that SUMOylation of EHD2 appears to be required for EHD2 induced inhibition of LeEix2 endocytosis. Indeed, we found that a mutant form of EHD2, possessing a defective SUMOylation site, has an increased nuclear abundance, can no longer be SUMOylated and is no longer effective in inhibiting LeEix2 endocytosis or defense signaling in response to EIX. PMID- 24154855 TI - Characteristics and significance of colorectal cancer associated lymphoid reaction. AB - A subset of colorectal cancers (CRCs) exhibits so-called Crohn's like lymphoid reaction (CLR), an inflammatory reaction pattern that consists of numerous transmural lymphoid aggregates. However, the composition of these aggregates, their biological mechanisms and their prognostic significance are not well defined. We analyzed two CRC cohorts (418 and 149 patients) and determined clinicopathological features including survival. A new method for evaluating CLR based on counting the areal density of the lymphoid follicles (CLR density) was adopted. Immune cell densities at intratumoral and peritumoral regions, as well as the composition of the lymphoid follicles, were studied by immunohistochemistry. We found that CLR comprised of lymphoid aggregates with no evidence of granuloma formation. High CLR density associated with lower tumor stage, lack of preoperative radiotherapy or chemoradiotherapy and deficient mismatch repair enzyme expression. CLR density had positive correlations with peritumoral and intratumoral densities of CD83(+) mature dendritic cells and T cells. High CLR density associated with better survival and had prognostic value that was independent of stage, Klintrup-Makinen score for peritumoral inflammation and the numbers of tumor infiltrating T cells. CLR density evaluation had excellent intraobserver and interobserver agreement. In conclusion, the results suggest that CLR contributes to the adaptive antitumor immunity. Quantitative evaluation of CLR density is a relevant prognostic indicator in CRC. PMID- 24154854 TI - Monitoring of non-destructive sampling strategies to assess the exposure of avian species in Jiangsu Province, China to heavy metals. AB - To assess the exposure of avian species in Jiangsu Province, China to eight heavy metals (As, Cd, Cr, Cu, Hg, Ni, Pb and Zn), the flight feathers, eggshells and feces of total ten avian species (including four herons, four cranes, one stork and one gull) were collected during March to May in 2012. The total concentrations of As, Cd and Hg were measured by Atomic Fluorescence Spectrometer; Cr, Cu, Ni, Pb and Zn were measured by inductively coupled plasma optical emission spectrometer. The determined concentrations of Cr (3.94, 1.33 8.30 mg kg(-1)), Cu (15.02, 7.34-35.53 mg kg(-1)) and Zn (134.66, 77.26-242.25 mg kg(-1)) in fresh feathers and Cd (7.93, 7.44-9.12 mg kg(-1)), Ni (22.74, 19.38 24.71 mg kg(-1)), Pb (85.06, 78.72-91.95 mg kg(-1)) and Zn (63.54, 55.82-72.14 mg kg(-1)) in eggshells were higher than the mean values of other reported data, indicating a considerable heavy metal pollution status in local area. Comparing to the heavy metal levels in early historic feathers (1992-2000), a significant elevation of concentrations has been observed in recent bird feathers. For feathers of Grus japonensis, the heavy metal concentrations increased by 19-267%. This increased tendency was consistent with local GDP (Gross Domestic Products) development. The anthropogenic economic activity especially industrial development may be a critical reason that caused the increase of heavy metal levels in local avian species. PMID- 24154856 TI - Impact of tissue characteristics on luminal narrowing of mild angiographic coronary stenosis: assessment of integrated backscatter intravascular ultrasound. AB - Integrated backscatter intravascular ultrasound (IB-IVUS) is a useful method for analyzing coronary plaque tissue. We evaluated whether tissue composition determined using IB-IVUS is associated with the progression of stenosis in coronary angiography. Sixty-three nontarget coronary lesions in 63 patients with stable angina were evaluated using conventional IVUS and IB-IVUS. IB-IVUS images were analyzed at 1-mm intervals for a length of 10 mm. After calculating the relative areas of the tissue components using the IB-IVUS system, fibrous volume (FV) and lipid volume (LV) were calculated through integration of the slices, after which percentages of per-plaque volume (%FV/PV, %LV/PV) and per-vessel volume (%FV/VV, %LV/VV) were calculated. Progression of coronary stenosis was interpreted from the increase in percent diameter stenosis (%DS) from baseline to the follow-up period (6-9 months) using quantitative coronary angiography. %DS was 24.1 +/- 12.8 % at baseline and 23.2 +/- 13.7 % at follow-up. Using IB-IVUS, LV was 31.7 +/- 10.5 mm(3), and %LV/PV and %LV/VV were 45.6 +/- 10.3 % and 20.2 +/- 6.0 %, respectively. FV, %FV/PV, and %FV/VV were 35.5 +/- 12.1 mm(3), 52.1 +/ 9.5 %, and 23.4 +/- 7.1 %, respectively. The change in %DS was -0.88 +/- 7.25 % and correlated closely with %LV/VV (r = 0.27, P = 0.03) on simple regression. Multivariate regression after adjustment for potentially confounding risk factors showed %LV/VV to be correlated independently with changes in %DS (r = 0.42, P = 0.02). Logistic regression analysis after adjusting for confounding coronary risk factors showed LV (odds ratio 1.08; 95 % confidence interval 1.01-1.16; P = 0.03) and %LV/VV (odds ratio 1.13; 95 % confidence interval 1.01-1.28; P = 0.03) to be independent predictors of the progression of angiographic coronary stenosis. Our findings suggest that angiographic luminal narrowing of the coronary artery is likely associated with tissue characteristics. IB-IVUS may provide information about the natural progression of luminal narrowing in coronary stenosis. PMID- 24154858 TI - Meta-analysis and meta-regression analysis of outcomes of carotid endarterectomy and stenting in the elderly. AB - IMPORTANCE: Uncertainty exists about the influence of advanced age on the outcomes of carotid revascularization. OBJECTIVE: To undertake a comprehensive review of the literature and conduct an analysis of the outcomes of carotid interventions in the elderly. DESIGN AND SETTING: A systematic literature review was conducted to identify articles comparing early outcomes of carotid endarterectomy (CEA) or carotid stenting (CAS) in elderly and young patients. MAIN OUTCOMES AND MEASURES: Combined overall effect sizes were calculated using fixed or random effects models. Meta-regression models were formed to explore potential heterogeneity as a result of changes in practice over time. RESULTS Our analysis comprised 44 studies reporting data on 512,685 CEA and 75,201 CAS procedures. Carotid stenting was associated with increased incidence of stroke in elderly patients compared with their young counterparts (odds ratio [OR], 1.56; 95% CI, 1.40-1.75), whereas CEA had equivalent cerebrovascular outcomes in old and young age groups (OR, 0.94; 95% CI, 0.88-0.99). Carotid stenting had similar peri-interventional mortality risks in old and young patients (OR, 0.86; 95% CI, 0.72-1.03), whereas CEA was associated with heightened mortality in elderly patients (OR, 1.62; 95% CI, 1.47-1.77). The incidence of myocardial infarction was increased in patients of advanced age in both CEA and CAS (OR, 1.64; 95% CI, 1.57-1.72 and OR, 1.30; 95% CI, 1.16-1.45, respectively). Meta-regression analyses revealed a significant effect of publication date on peri-interventional stroke (P = .003) and mortality (P < .001) in CAS. CONCLUSIONS AND RELEVANCE: Age should be considered when planning a carotid intervention. Carotid stenting has an increased risk of adverse cerebrovascular events in elderly patients but mortality equivalent to younger patients. Carotid endarterectomy is associated with similar neurologic outcomes in elderly and young patients, at the expense of increased mortality. PMID- 24154859 TI - A programmable and reconfigurable microfluidic chip. AB - This article reports an original concept enabling the rapid fabrication of continuous-flow microfluidic chips with a programmable and reconfigurable geometry. The concept is based on a digital microfluidic platform featuring an array of individually addressable electrodes. A selection of electrodes is switched on sequentially to create a de-ionized (DI) water finger specific pattern, while the surrounding medium consists of liquid-phase paraffin. The water displacement is induced by both electrowetting on dielectric and liquid dielectrophoresis phenomena. Once the targeted DI water pattern is obtained, the chip temperature is lowered by turning on an integrated thermoelectric cooler, forming channel structures made of solidified paraffin with edges delimitated by the DI water pattern. As a result, the chip can be used afterwards to conduct in flow continuous microfluidic experiments. This process is resettable and reversible by heating up the chip to melt the paraffin and reconfigure the microchannel design on demand, offering the advantages of cost, adaptability, and robustness. This paper reports experimental results describing the overall concept, which is illustrated with typical and basic fluidic geometries. PMID- 24154860 TI - Chemical compounds related to nutraceutical and industrial qualities of non transgenic soybean genotypes. AB - BACKGROUND: Information about the chemical profile of soybean seed is valuable for breeding programs aimed at obtaining value-added products to meet the demands of niche markets. The objective of this study was to determine seed composition of non-transgenic soybean genotypes with specialty characters in different environments of Argentina. RESULTS: Protein and oil contents ranged from 396 to 424 g kg-1 and from 210 to 226 g kg-1, respectively. Oleic and linolenic acid ratio, the general indicator of oil quality, varied from 2.7 to 3.8. The oil contained high levels of total tocopherols (1429-1558 mg kg-1) and the meal exhibited high levels of total isoflavones (2.91-4.62 mg g-1). The biplot showed that oleic, linoleic and linolenic acids, gamma-, delta- and total tocopherols, genistin, malonyl daidzin and genistin, acetyl daidzin and glycitin and total isoflavones allowed the greatest discrimination among the genotypes studied. CONCLUSION: Different chemical profiles of each non-transgenic genotype analyzed were established and, therefore, their identity was defined. These results are important for breeders who intend to obtain new genotypes with improved meal and oil quality, as well as for processors and exporters, who could use them directly as raw material for soyfood processing for nutraceutical purposes. PMID- 24154862 TI - The inflammatory response of lymphatic endothelium. AB - Lymphatic vessels have traditionally been regarded as a rather inert drainage system, which just passively transports fluids, leukocytes and antigen. However, it is becoming increasingly clear that the lymphatic vasculature is highly dynamic and plays a much more active role in inflammatory and immune processes. Tissue inflammation induces a rapid, stimulus-specific upregulation of chemokines and adhesion molecules in lymphatic endothelial cells and a proliferative expansion of the lymphatic network in the inflamed tissue and in draining lymph nodes. Moreover, increasing evidence suggests that inflammation-induced changes in the lymphatic vasculature have a profound impact on the course of inflammatory and immune responses, by modulating fluid drainage, leukocyte migration or the removal of inflammatory mediators from tissues. In this review we will summarize and discuss current knowledge of the inflammatory response of lymphatic endothelium and of inflammation-induced lymphangiogenesis and the current perspective on the overall functional significance of these processes. PMID- 24154861 TI - Antagonism of PDGF-BB suppresses subretinal neovascularization and enhances the effects of blocking VEGF-A. AB - Hypoxia-inducible factor-1 (HIF-1) plays an important role in retinal and subretinal neovascularization (NV). Increased levels of HIF-1 cause increased expression of vascular endothelial growth factor (VEGF-A) and current therapies for ocular NV focus on neutralizing VEGF-A, but there is mounting evidence that other HIF-1-responsive gene products may also participate. In this study, we tested the effect of a designed ankyrin repeat protein (DARPin) that selectively binds and antagonizes the hypoxia-regulated gene product PDGF-BB in three models of subretinal NV (relevant to neovascular age-related macular degeneration) and compared its effects to a DARPin that selectively antagonizes VEGF-A. Daily intraperitoneal injections of 10 mg/kg of the anti-PDGF-BB DARPin or 1 mg/kg of the anti-VEGF DARPin significantly suppressed subretinal NV from laser-induced rupture of Bruch's membrane. Injections of 1 mg/kg/day of the anti-PDGF-BB DARPin had no significant effect, but when combined with 1 mg/kg/day of the anti-VEGF-A DARPin there was greater suppression than injection of the anti-VEGF-A DARPin alone. In Vldlr (-/-) mice which spontaneously develop subretinal NV, intraocular injection of 1.85 MUg of anti-PDGF-BB or anti-VEGF-A DARPin caused significant suppression of NV and when combined there was greater suppression than with either alone. The two DARPins also showed an additive effect in Tet/opsin/VEGF double transgenic mice, a particularly severe model of subretinal NV and exudative retinal detachment. In addition, intraocular injection of 1.85 MUg of anti-PDGF-BB DARPin strongly suppressed ischemia-induced retinal NV, which is relevant to proliferative diabetic retinopathy and retinopathy of prematurity. These data demonstrate that PDGF-BB is another hypoxia-regulated gene product that along with VEGF-A contributes to ocular NV and suppression of both provides an additive effect. PMID- 24154863 TI - Pharmacodynamic effects of standard dose prasugrel versus high dose clopidogrel in non-diabetic obese patients with coronary artery disease. AB - Increased body weight is independently associated with impaired clopidogrel pharmacodynamic (PD) response. Prasugrel has more potent PD effects compared with clopidogrel, although its PD effects in obese patients are unknown. The aim of this prospective, randomised, study was to compare the PD effects of standard dose prasugrel [60 mg loading dose (LD)/10 mg daily maintenance dose (MD)] with high-dose clopidogrel (900 mg LD/150 mg daily MD) in non-diabetic obese [body mass index (BMI) >=30 kg/m2] patients, with coronary artery disease (CAD) on aspirin therapy. PD assessments (baseline, 2 hours post-LD and 6 +/- 2 days after MD) were conducted using four platelet function assays, and the platelet reactivity index (PRI) assessed by VASP was used for sample size estimation. A total of 42 patients with a BMI of 36.42 +/- 5.6 kg/m2 completed the study. There were no differences in baseline PD measures between groups. At 2 hours post-LD, prasugrel was associated with lower PRI compared with clopidogrel (24.3 +/- 5.5 vs 58.7 +/- 5.7, p<=0.001), with consistent findings for all assays. At one-week, PRI values on prasugrel MD were lower than clopidogrel MD without reaching statistical significance (34.7 +/- 5.8 vs 42.9 +/- 5.8, p=0.32), with consistent findings for all assays. Accordingly, rates of high on-treatment platelet reactivity were markedly reduced after prasugrel LD, but not after MD. In conclusion, in non-diabetic obese patients with CAD, standard prasugrel dosing achieved more potent PD effects than high-dose clopidogrel in the acute phase of treatment, but this was not sustained during maintenance phase treatment. Whether an intensified prasugrel regimen is required in obese patients warrants investigation. PMID- 24154864 TI - Reading aids for adults with low vision. AB - BACKGROUND: The purpose of low-vision rehabilitation is to allow people to resume or to continue to perform daily living tasks, with reading being one of the most important. This is achieved by providing appropriate optical devices and special training in the use of residual-vision and low-vision aids, which range from simple optical magnifiers to high-magnification video magnifiers. OBJECTIVES: To assess the effects of reading aids for adults with low vision. SEARCH METHODS: We searched CENTRAL (which contains the Cochrane Eyes and Vision Group Trials Register) (The Cochrane Library 2013, Issue 1), Ovid MEDLINE, Ovid MEDLINE In Process and Other Non-Indexed Citations, Ovid MEDLINE Daily, Ovid OLDMEDLINE, (January 1950 to January 2013), EMBASE (January 1980 to January 2013), Latin American and Caribbean Literature on Health Sciences (LILACS) (January 1982 to January 2013), OpenGrey (System for Information on Grey Literature in Europe) (www.opengrey.eu/), the metaRegister of Controlled Trials (mRCT) (www.controlled trials.com), ClinicalTrials.gov (www.clinicaltrials.gov/) and the WHO International Clinical Trials Registry Platform (ICTRP) (www.who.int/ictrp/search/en). We did not use any date or language restrictions in the electronic searches for trials. We last searched the electronic databases on 31 January 2013. We searched the reference lists of relevant articles and used the Science Citation Index to find articles that cited the included studies and contacted investigators and manufacturers of low-vision aids. We handsearched the British Journal of Visual Impairment from 1983 to 1999 and the Journal of Visual Impairment and Blindness from 1976 to 1991. SELECTION CRITERIA: This review includes randomised and quasi-randomised trials in which any device or aid used for reading had been compared to another device or aid in people aged 16 or over with low vision as defined by the study investigators. DATA COLLECTION AND ANALYSIS: At least two authors independently assessed trial quality and extracted data. MAIN RESULTS: We included nine small studies with a cross-over-like design (181 people overall) and one study with three parallel arms (243 participants) in the review. All studies reported the primary outcome, results for reading speed.Two studies including 92 participants found moderate- or low-quality evidence suggesting that reading speed is higher with stand-mounted electronic devices or electronic devices with the camera mounted in a 'mouse' than with optical magnifiers, which in these trials were generally stand-mounted or, less frequently, hand-held magnifiers or microscopic lenses. In another study of 20 participants there was moderate-quality evidence that optical devices are better than head-mounted electronic devices (four types).There was low-quality evidence from three studies (93 participants) that reading using head-mounted electronic devices is slower than with stand-based electronic devices. The technology of electronic devices may have changed and improved since these studies were conducted.One study suggested no difference between a diffractive spectacle mounted magnifier and either refractive (15 participants) or aplanatic (15 participants) magnifiers.One study of 10 people suggested that several overlay coloured filters were no better and possibly worse than a clear filter.A parallel arm study including 243 participants with age-related macular degeneration found that custom or standard prism spectacles were no different from conventional reading spectacles, although the data did not allow precise estimates of performance to be made. AUTHORS' CONCLUSIONS: There is insufficient evidence on the effect of different types of low-vision aids on reading performance. It would be necessary to investigate which patient characteristics predict performance with different devices, including costly electronic devices. Better-quality research should also focus on assessing sustained long-term use of each device. Authors of studies testing several devices on the same person should consider design and reporting issues related to their sequential presentation and to the cross-over-like study design. PMID- 24154865 TI - Equity-focused knowledge translation: a framework for "reasonable action" on health inequities. AB - OBJECTIVES: To identify gaps in procedural approaches to knowledge translation and outline a more relational approach that addresses health inequities based on creating collaborative environments for reasonable action. METHODS: A literature review encompassing approaches to critical inquiry of the institutional conditions in which knowledge is created combined with a process for encouraging reflexive professional practice provide the conceptual foundation for our approach, called equity-focused knowledge translation (EqKT). RESULTS: The EqKT approach creates a matrix through which teams of knowledge stakeholders (researchers, practitioners, and policymakers) can set common ground for taking collaborative action on health inequities. CONCLUSIONS: Our approach can contribute to the call by the WHO Commission on the Social Determinants of Healths for more reasonable action on health inequities by being incorporated into numerous public health settings and processes. Further steps include empirical applications and evaluations of EqKT in real world applications. PMID- 24154866 TI - Heme oxygenase 1-mediated neurogenesis is enhanced by Ginkgo biloba (EGb 761(r)) after permanent ischemic stroke in mice. AB - Stroke is the fourth leading cause of death and a major cause of disability in stroke survivors. Studies have underlined the importance of repair mechanisms in the recovery phase of stroke. Neurogenesis in response to brain injury is one of the regeneration processes that, if enhanced, may offer better stroke treatment alternatives. Previously, we have demonstrated antioxidant, neuritogenic, and angiogenic properties of Ginkgo biloba/EGb 761(r) (EGb 761) in different mouse models of stroke. In the present study, we were interested to study whether EGb 761 could protect mice from permanent middle cerebral artery occlusion (pMCAO) and enhance neurogenesis. EGb 761 pre- and posttreated mice had lower infarct volume and improved motor skills with enhanced proliferation of neuronal stem/progenitor cells (NSPCs) at 24 h and 7 days posttreatment. Netrin-1 and its receptors (DCC and UNC5B) that mediate axonal attraction and repulsion were observed to be overexpressed in NSPCs only, implying that netrin-1 and its receptors might have partly played a role in enhanced neurogenesis. Interestingly, in heme oxygenase 1 knockout mice (HO1(-/-)), neurogenesis was significantly lower than in vehicle-treated mice at day 8. Furthermore, EGb 761 posttreated mice also demonstrated heme oxygenase 1 (HO1)-activated pathway of phosphorylated glycogen synthase kinase 3 alpha/beta (p-GSK-3 alpha/beta), collapsin response mediator protein 2 (CRMP-2), semaphorin3A (SEMA3A), and Wnt, suggesting probable signaling pathways involved in proliferation, differentiation, and migration of NSPCs. Together, these results propose that EGb 761 not only has antioxidant, neuritogenic, and angiogenic properties, but can also augment the repair and regeneration mechanisms following stroke. PMID- 24154867 TI - Clinical implication of sagittal translation in lengthening over nail of tibia. AB - PURPOSE: During the surgery of lengthening over nail (LON), we sometimes observe sagittal translation of proximal tibia (STPT) when the nail is inserted into the canal. We investigated the factors that lead to STPT and its clinical significance. METHODS: We reviewed 35 consecutive patients who underwent bilateral tibial lengthening with LON. The following parameters were assessed to evaluate the factors that can lead to STPT; the level of tibia osteotomy (OT) in sagittal plane, the type of the nail, the nail entry point in sagittal/coronal planes, and the type of the OT. Then, the followings are analyzed to find any possible clinical significance of this phenomenon: the change of posterior proximal tibial angle (PPTA), the cortical healing index, and the translation of the sagittal mechanical axis (SMA) of the lower extremity. RESULTS: The postoperative STPT was 3.04 +/- 2.73 mm, and proximal location of the OT in relation to the nail bending point was found to increase STPT. The nail entry point in sagittal/coronal planes and the type of tibia OT had no significant correlations with STPT. It had no significant relations with the PPTA or cortical healing index. It pushed the SMA posteriorly, but the SMA was always anterior to the center of rotation of the knee joint. CONCLUSIONS: Proximal location of the OT in relation to the nail bending point is related to STPT. However, it does not negatively influence cortical healing, posterior tibial slope, or SMA of the lower extremity. PMID- 24154868 TI - Iron-molybdenum-oxo complexes as initiators for olefin autoxidation with O2. AB - The reaction between [(TPA)Fe(MeCN)2](OTf)2 and [nBu4N](Cp*MoO3) yields the novel tetranuclear complex [(TPA)Fe(MU-Cp*MoO3)]2(OTf)2, 1, with a rectangular [Mo-O-Fe O-]2 core containing high-spin iron(ii) centres. 1 proved to be an efficient initiator/(pre)catalyst for the autoxidation of cis-cyclooctene with O2 to give cyclooctene epoxide. To test, which features of 1 are essential in this regard, analogues with zinc(ii) and cobalt(ii) central atoms, namely [(TPA)Zn(Cp*MoO3)](OTf), 3, and [(TPA)Co(Cp*MoO3)](OTf), 4, were prepared, which proved to be inactive. The precursor compounds of 1, [(TPA)Fe(MeCN)2](OTf)2 and [nBu4N](Cp*MoO3) as well as Cp2*Mo2O5, were found to be inactive, too. Reactivity studies in the absence of cyclooctene revealed that 1 reacts both with O2 and PhIO via loss of the Cp* ligands to give the triflate salt 2 of the known cation [((TPA)Fe)2(MU-O)(MU-MoO4)](2+). The cobalt analogue 4 reacts with O2 in a different way yielding [((TPA)Co)2(MU-Mo2O8)](OTf)2, 5, featuring a Mo2O8(4-) structural unit which is novel in coordination chemistry. The compound [(TPA)Fe(MU-MoO4)]2, 6, being related to 1, but lacking Cp* ligands failed to trigger autoxidation of cyclooctene. However, initiation of autoxidation by Cp* radicals was excluded via experiments including thermal dissociation of Cp2*. PMID- 24154869 TI - Characteristics and well-being of informal caregivers: Results from a nationally representative US survey. AB - OBJECTIVES: Given ongoing concerns about high levels of burden reported among some informal caregivers, the goal of this study was to characterize their sociodemographics, health, and well-being. METHODS: Using cross-sectional data from a large nationally representative survey in the United States (N = 438,712) we identified adults who provided informal care to friends or family members with a health problem, long-term illness, or disability. Descriptive statistics and propensity matching were used to characterize caregivers and compare their health and social support to sociodemographically-similar adults who were not caregivers. Logistic regression models examined associations between caregiving and respondents' mental health, general health, perceived social support, and sleep problems. RESULTS: A total of 111,156 (25.3%) participants reported being caregivers, most of whom reported good mental health (90%) good general health (83%), and adequate social support (77%). After adjusting for respondents' gender, caregivers reported worse mental health than non-caregivers (odds ratio (OR) = 1.35, 95% confidence interval (CI) = 1.31-1.39 for >15 days poor mental health in the past month) but better general health (OR = 0.96, 95%CI = 0.94-0.98 for fair or poor health). Men caregivers reported somewhat worse overall health than non-caregivers (OR = 1.09, 95%CI = 1.05-1.13) whereas women reported better overall health. DISCUSSION: Although reporting good overall well-being, caregivers remain vulnerable for worse outcomes than non-caregivers. Caregiving is associated with poor mental health, and may have additional impacts on the physical health of caregiving men. PMID- 24154870 TI - TLR9 signaling in the tumor microenvironment initiates cancer recurrence after radiotherapy. AB - Cancer radiotherapy may be immunogenic, but it is unclear why its immunogenic effects are rarely sufficient to prevent tumor recurrence. Here, we report a novel Toll-like receptor 9 (TLR9)-dependent mechanism that initiates tumor regrowth after local radiotherapy. Systemic inhibition of TLR9, but not TLR4, delayed tumor recurrence in mouse models of B16 melanoma, MB49 bladder cancer, and CT26 colon cancer after localized high-dose tumor irradiation. Soluble factors in the microenvironment of regressing tumors triggered TLR9 signaling in freshly recruited myeloid cells appearing within four days of radiotherapy. The tumorigenic effects of TLR9 depended on MyD88/NF-kappaB-mediated upregulation of interleukin (IL)-6 expression, which in turn resulted in downstream activation of Jak/STAT3 signaling in myeloid cells. In comparing global gene expression in wild type, TLR9-, or STAT3-deficient myeloid cells derived from irradiated tumors, we identified a unique set of TLR9/STAT3-regulated genes involved in tumor-promoting inflammation and revascularization. Blocking STAT3 function by two myeloid specific genetic strategies corrected TLR9-mediated cancer recurrence after radiotherapy. Our results suggest that combining localized tumor irradiation with myeloid cell-specific inhibition of TLR9/STAT3 signaling may help eliminate radioresistant cancers. PMID- 24154871 TI - PTEN loss mitigates the response of medulloblastoma to Hedgehog pathway inhibition. AB - Medulloblastoma is a cancer of the cerebellum, for which there is currently no approved targeted therapy. Recent transcriptomics approaches have demonstrated that medulloblastoma is composed of molecularly distinct subgroups, one of which is characterized by activation of the Hedgehog pathway, which in mouse models is sufficient to drive medulloblastoma development. There is thus considerable interest in targeting the Hedgehog pathway for therapeutic benefit in medulloblastoma, particularly given the recent approval of the Hedgehog pathway inhibitor vismodegib for metastatic and locally advanced basal cell carcinoma. Like other molecularly targeted therapies, however, there have been reports of acquired resistance to vismodegib, driven by secondary Hedgehog pathway mutations and potentially by activation of the phosphatidylinositol 3-kinase (PI3K) pathway. Given that acquired resistance to vismodegib may occur as a result of inappropriate PI3K pathway activation, we asked if loss of the PI3K pathway regulator, phosphatase and tensin homologue (Pten), which has been reported to occur in patients within the Hedgehog subgroup, would constitute a mechanism of innate resistance to vismodegib in Hedgehog-driven medulloblastoma. We find that Hedgehog pathway inhibition successfully restrains growth of Pten-deficient medulloblastoma in this mouse model, but does not drive tumor regression, as it does in Pten-wild-type medulloblastoma. Combined inhibition of the Hedgehog and PI3K pathways may lead to superior antitumor activity in PTEN-deficient medulloblastoma in the clinic. PMID- 24154872 TI - Functional TLR5 genetic variants affect human colorectal cancer survival. AB - Toll-like receptors (TLR) are overexpressed on many types of cancer cells, including colorectal cancer cells, but little is known about the functional relevance of these immune regulatory molecules in malignant settings. Here, we report frequent single-nucleotide polymorphisms (SNP) in the flagellin receptor TLR5 and the TLR downstream effector molecules MyD88 and TIRAP that are associated with altered survival in a large cohort of Caucasian patients with colorectal cancer (n = 613). MYD88 rs4988453, a SNP that maps to a promoter region shared with the acetyl coenzyme-A acyl-transferase-1 (ACAA1), was associated with decreased survival of patients with colorectal cancer and altered transcriptional activity of the proximal genes. In the TLR5 gene, rs5744174/F616L was associated with increased survival, whereas rs2072493/N592S was associated with decreased survival. Both rs2072493/N592S and rs5744174/F616L modulated TLR5 signaling in response to flagellin or to different commensal and pathogenic intestinal bacteria. Notably, we observed a reduction in flagellin-induced p38 phosphorylation, CD62L shedding, and elevated expression of interleukin (IL)-6 and IL-1beta mRNA in human primary immune cells from TLR5 616LL homozygote carriers, as compared with 616FF carriers. This finding suggested that the well documented effect of cytokines like IL-6 on colorectal cancer progression might be mediated by TLR5 genotype-dependent flagellin sensing. Our results establish an important link between TLR signaling and human colorectal cancer with relevance for biomarker and therapy development. PMID- 24154873 TI - DeltaNp63 promotes pediatric neuroblastoma and osteosarcoma by regulating tumor angiogenesis. AB - The tumor suppressor gene p53 and its family members p63/p73 are critical determinants of tumorigenesis. DeltaNp63 is a splice variant of p63, which lacks the N-terminal transactivation domain. It is thought to antagonize p53-, p63-, and p73-dependent translation, thus blocking their tumor suppressor activity. In our studies of the pediatric solid tumors neuroblastoma and osteosarcoma, we find overexpression of DeltaNp63; however, there is no correlation of DeltaNp63 expression with p53 mutation status. Our data suggest that DeltaNp63 itself endows cells with a gain-of-function that leads to malignant transformation, a function independent of any p53 antagonism. Here, we demonstrate that DeltaNp63 overexpression, independent of p53, increases secretion of interleukin (IL)-6 and IL-8, leading to elevated phosphorylation of STAT3 (Tyr-705). We show that elevated phosphorylation of STAT3 leads to stabilization of hypoxia-inducible factor 1alpha (HIF-1alpha) protein, resulting in VEGF secretion. We also show human clinical data, which suggest a mechanistic role for DeltaNp63 in osteosarcoma metastasis. In summary, our studies reveal the mechanism by which DeltaNp63, as a master transcription factor, modulates tumor angiogenesis. PMID- 24154874 TI - APOBEC3B upregulation and genomic mutation patterns in serous ovarian carcinoma. AB - Ovarian cancer is a clinically and molecularly heterogeneous disease. The driving forces behind this variability are unknown. Here, we report wide variation in the expression of the DNA cytosine deaminase APOBEC3B, with elevated expression in the majority of ovarian cancer cell lines (three SDs above the mean of normal ovarian surface epithelial cells) and high-grade primary ovarian cancers. APOBEC3B is active in the nucleus of several ovarian cancer cell lines and elicits a biochemical preference for deamination of cytosines in 5'-TC dinucleotides. Importantly, examination of whole-genome sequence from 16 ovarian cancers reveals that APOBEC3B expression correlates with total mutation load as well as elevated levels of transversion mutations. In particular, high APOBEC3B expression correlates with C-to-A and C-to-G transversion mutations within 5'-TC dinucleotide motifs in early-stage high-grade serous ovarian cancer genomes, suggesting that APOBEC3B-catalyzed genomic uracil lesions are further processed by downstream DNA "repair" enzymes including error-prone translesion polymerases. These data identify a potential role for APOBEC3B in serous ovarian cancer genomic instability. PMID- 24154875 TI - A circadian clock transcription model for the personalization of cancer chronotherapy. AB - Circadian timing of anticancer medications has improved treatment tolerability and efficacy several fold, yet with intersubject variability. Using three C57BL/6 based mouse strains of both sexes, we identified three chronotoxicity classes with distinct circadian toxicity patterns of irinotecan, a topoisomerase I inhibitor active against colorectal cancer. Liver and colon circadian 24-hour expression patterns of clock genes Rev-erbalpha and Bmal1 best discriminated these chronotoxicity classes, among 27 transcriptional 24-hour time series, according to sparse linear discriminant analysis. An 8-hour phase advance was found both for Rev-erbalpha and Bmal1 mRNA expressions and for irinotecan chronotoxicity in clock-altered Per2(m/m) mice. The application of a maximum-a posteriori Bayesian inference method identified a linear model based on Rev erbalpha and Bmal1 circadian expressions that accurately predicted for optimal irinotecan timing. The assessment of the Rev-erbalpha and Bmal1 regulatory transcription loop in the molecular clock could critically improve the tolerability of chemotherapy through a mathematical model-based determination of host-specific optimal timing. PMID- 24154877 TI - Immunomodulatory effects of 1-(6-hydroxy-2-isopropenyl-1-benzofuran-5-yl)-1 ethanone from Petasites hybridus and its synthesized benzoxazepine derivatives. AB - 1-(6-Hydroxy-2-isopropenyl-1-benzofuran-5-yl)-1-ethanone (1), isolated from the roots of Petasites hybridus L., and a series of synthetic benzoxazepine derivatives of compound 1 (2-6) were evaluated for their immunomodulatory effects. The compounds were evaluated for their effects on the respiratory burst of human whole blood and isolated human polymorphonuclear leukocytes (PMNs) using luminol- and lucigenin-based chemiluminescence (CL) assays, and their effect on chemotactic migration of PMNs was assessed using the Boyden chamber technique. Compound 1 exhibited stronger inhibition than acetylsalicylic acid (ASA) on luminol-enhanced CL of PMNs. It also inhibited PMN chemotaxis with an IC50 value comparable to that of ibuprofen. Of the compounds tested, 5 was the most effective in inhibiting luminol-enhanced CL and also strongly inhibited lucigenin enhanced CL with IC50 values lower than that of ASA. Compound 2 was the most active in inhibiting migration of PMNs and was five times stronger than ibuprofen. The results suggest that compound 1 and its synthesized benzoxazepine derivatives, especially compounds 2 and 5, were able to modulate the innate immune response of phagocytes at different steps, emphasizing their potential as leads for the development of new immunomodulatory agents. PMID- 24154876 TI - TRAF4 is a critical molecule for Akt activation in lung cancer. AB - TRAF4 is an adapter protein overexpressed in certain cancers, but its contributions to tumorigenesis are unclear. In lung cancer cells and primary lung tumors, we found that TRAF4 is overexpressed. RNA interference-mediated attenuation of TRAF4 expression blunted the malignant phenotype in this setting, exerting inhibitory effects on cell proliferation, anchorage-independent growth, and tumor development in a xenograft mouse model. Unexpectedly, we discovered that TRAF4, but not Skp2, was required for activation of the pivotal cell survival kinase Akt through ubiquitination. Furthermore, TRAF4 attenuation impaired glucose metabolism by inhibiting expression of Glut1 and HK2 mediated by the Akt pathway. Overall, our work suggests that TRAF4 offers a candidate molecular target for lung cancer prevention and therapy. PMID- 24154878 TI - Comprehensive gene expression analysis reveals multiple signal pathways associated with prostate cancer. AB - Prostate cancer (PC) depends on androgenic signaling for growth and survival. To data, the exact molecular mechanism of hormone controlling proliferation and tumorigenesis in the PC remains unclear. Therefore, in this study, we explored the differentially expressed genes (DEGs) and identified featured genes related to hormone stimulus from PC. Two sets of gene expression data, including PC and normal control sample, were downloaded from Gene Expression Omnibus (GEO) database. The t-test was used to identify DEGs between PC and controls. Gene ontology (GO) functional annotation was applied to analyze the function of DEGs and screen hormone-related DEGs. Then these hormone-related DEGs were further analyzed in constructed cancer network and Human Protein Reference Database to screen important signaling pathways they participated in. A total of 912 DEGs were obtained which included 326 up-regulated genes and 586 down-regulated genes. GO functional enrichment analysis identified 50 hormone-related DEGs associated with PC. After pathway and PPI network analysis, we found these hormone-related DEGs participated in several important signaling pathways including TGF-beta (TGFB2, TGFB3 and TGFBR2), MAPK (TGFB2, TGFB3 and TGFBR2), insulin (PIK3R3, SHC1 and EIF4EBP1), and p53 signaling pathways (CCND2 and CDKN1A). In addition, a total of five hormone-related DEGs (SHC1, CAV1, RXRA, CDKN1A and SRF) were located in the center of PPI network and 12 hormone-related DEGs formed six protein modules. These important signal pathways and hormone-related DEGs may provide potential therapeutic targets for PC. PMID- 24154879 TI - Determining the etiology of cardiac arrest. A challenging part of diagnosis. PMID- 24154880 TI - Are we aware of stent fracture? AB - Drug-eluting stents (DESs) have dramatically reduced the rates of in-stent restenosis compared with those of bare-metal stents. DES placement is frequently followed by high-pressure postdilatation to prevent incomplete stent apposition that may cause a further stent fracture (SF). SF may remain asymptomatic but it is an important cause of stent thrombosis, can be difficult to diagnose, and may be life-threatening. PMID- 24154881 TI - Coexistence of cardiomyopathy and pericardial effusion: A challenging diagnosis. PMID- 24154882 TI - Lipoma in the right atrium. PMID- 24154883 TI - Postexercise recovery phase T-wave notching in concealed long QT syndrome. PMID- 24154884 TI - Decreased left ventricular torsion in patients with isolated mitral stenosis. AB - BACKGROUND: Left ventricular (LV) torsion is a sensitive indicator of myocardial contractility and cardiac structure, and has recently been recognized as a sensitive indicator of cardiac performance. The aim of our study was to assess the effect of isolated mitral stenosis on LV torsion. PATIENTS AND METHODS: We enrolled 19 patients with isolated mitral stenosis and 19 age- and gender-matched healthy subjects in the study. All patients had a normal sinus rhythm. All study subjects underwent two-dimensional echocardiography. Basal and apical LV rotations and LV torsion were evaluated using speckle-tracking echocardiography. RESULTS: Demographic characteristics, basic echocardiographic measures of LV ejection fraction, LV wall thickness, and LV mass index were similar between the two groups. The degrees of LV torsion (11.3 +/- 4.7, 15.4 +/- 4.9 degrees , p=0.014) and LV basal rotation (- 3.7 +/- 1.9, - 6.5 +/- 2.1 degrees , p< 0.001) were significantly decreased in the mitral stenosis group. There was a moderate positive correlation between mitral valve area and LV torsion (r=0.531, p=0.019). CONCLUSION: We showed significant reductions in LV torsion and LV basal rotation in patients with mitral valve stenosis. Structural and anatomical changes occurring during the progression of mitral stenosis may be responsible for these impaired movements. PMID- 24154885 TI - Pneumomediastinum, pneumopericardium, and subcutaneous emphysema after transesophageal echocardiography. PMID- 24154887 TI - Type-1 Brugada-like ECG pattern induced by adrenal crisis. PMID- 24154886 TI - Early coronary vein stenosis after cardiac resynchronization therapy. PMID- 24154888 TI - Anomalous origin of the right pulmonary artery from the ascending aorta: successful correction in an adult patient. PMID- 24154889 TI - Paradoxical embolism causing acute embolic events in a patient with hereditary thrombophilia. AB - Paradoxical embolism (PDE) is an uncommon but clinically important entity. In clinical practice, PDE involving multiple organs is a rarely reported occurrence. Herein, we present a case of acute pulmonary embolism complicated by PDE through an atrial septal defect (ASD) causing a series of embolic events. Subsequent laboratory screening confirmed the patient to be a heterozygous carrier of the factor V Leiden mutation that increases the risk for deep venous thrombosis (DVT). The patient was treated with warfarin indefinitely and underwent transcatheter ASD closure and implantation of an inferior vena cava filter. PMID- 24154890 TI - Left atrial myxoma in a patient with paroxysmal atrial fibrillation. PMID- 24154891 TI - Mortality in vitamin K antagonist-related intracerebral bleeding treated with plasma or 4-factor prothrombin complex concentrate. AB - Prothrombin complex concentrates (PCC) can rapidly normalise prolonged prothrombin time, induced by vitamin K antagonists (VKA). We conducted a multicentre retrospective study to investigate whether reversal of VKA coagulopathy with 4-factor PCC improves the survival of patients with VKA-related intracerebral haemorrhage as compared to plasma.We included 135 consecutive patients with VKA-related intracerebral haemorrhage treated either with plasma (mainly in Canada) or 4-factor PCC (The Netherlands and Sweden) for the reversal of VKA. Data on characteristics of the patients and the haemorrhage were collected. The volume of intracerebral haematoma was calculated from the first computed tomography (CT) scan. The unadjusted and adjusted odds ratio (OR) for 30 day all-cause mortality in both treatment groups was compared using logistic regression. Patients who received plasma (n=35, median 4 units) more often had diabetes, antiplatelet therapy, and intraventricular haemorrhage on the initial CT scans than patients who received PCC (n=100, median 22.5 IU/kg [interquartile range 20-26 IU], median of total dose 1,700 IU). The volume of intracerebral haematoma was larger in the plasma-treated group compared to the PCC-treated group (haematoma, mean 64.5 vs 36.0 cm3; p=0.021). The unadjusted OR for all cause 30-day mortality in the PCC group was 0.40 (95% confidence interval, 0.18 0.87; p=0.021) compared to the plasma group. After adjusting for the haematoma volume, bleeding localisation and age, the effect of PCC on mortality became non significant. In conclusion, treatment with 4-factor PCC for VKA reversal in patients with intracerebral haemorrhage does not seem to reduce the 30-day all cause mortality compared to plasma. PMID- 24154892 TI - Sonographically guided cervical facet nerve and joint injections: why sonography? PMID- 24154893 TI - Challenges and regulatory considerations in the acoustic measurement of high frequency (>20 MHz) ultrasound. AB - This article examines the challenges associated with making acoustic output measurements at high ultrasound frequencies (>20 MHz) in the context of regulatory considerations contained in the US Food and Drug Administration industry guidance document for diagnostic ultrasound devices. Error sources in the acoustic measurement, including hydrophone calibration and spatial averaging, nonlinear distortion, and mechanical alignment, are evaluated, and the limitations of currently available acoustic measurement instruments are discussed. An uncertainty analysis of acoustic intensity and power measurements is presented, and an example uncertainty calculation is done on a hypothetical 30 MHz high-frequency ultrasound system. This analysis concludes that the estimated measurement uncertainty of the acoustic intensity is +73%/-86%, and the uncertainty in the mechanical index is +37%/-43%. These values exceed the respective levels in the Food and Drug Administration guidance document of 30% and 15%, respectively, which are more representative of the measurement uncertainty associated with characterizing lower-frequency ultrasound systems. Recommendations made for minimizing the measurement uncertainty include implementing a mechanical positioning system that has sufficient repeatability and precision, reconstructing the time-pressure waveform via deconvolution using the hydrophone frequency response, and correcting for hydrophone spatial averaging. PMID- 24154894 TI - A double-gaussian, percentile-based method for estimating maximum blood flow velocity. AB - OBJECTIVES: Transcranial Doppler sonography allows for the estimation of blood flow velocity, whose maximum value, especially at systole, is often of clinical interest. Given that observed values of flow velocity are subject to noise, a useful notion of "maximum" requires a criterion for separating the signal from the noise. All commonly used criteria produce a point estimate (ie, a single value) of maximum flow velocity at any time and therefore convey no information on the distribution or uncertainty of flow velocity. This limitation has clinical consequences especially for patients in vasospasm, whose largest flow velocities can be difficult to measure. Therefore, a method for estimating flow velocity and its uncertainty is desirable. METHODS: A gaussian mixture model is used to separate the noise from the signal distribution. The time series of a given percentile of the latter, then, provides a flow velocity envelope. This means of estimating the flow velocity envelope naturally allows for displaying several percentiles (e.g., 95th and 99th), thereby conveying uncertainty in the highest flow velocity. RESULTS: Such envelopes were computed for 59 patients and were shown to provide reasonable and useful estimates of the largest flow velocities compared to a standard algorithm. Moreover, we found that the commonly used envelope was generally consistent with the 90th percentile of the signal distribution derived via the gaussian mixture model. CONCLUSIONS: Separating the observed distribution of flow velocity into a noise component and a signal component, using a double-gaussian mixture model, allows for the percentiles of the latter to provide meaningful measures of the largest flow velocities and their uncertainty. PMID- 24154895 TI - Trends in diagnostic ultrasound acoustic output from data reported to the US Food and Drug Administration for device indications that include fetal applications. AB - OBJECTIVES: A survey was conducted of acoustic output data received by the US Food and Drug Administration for diagnostic ultrasound devices whose indications for use include fetal applications to assess trends in maximum available acoustic output over time. METHODS: Data were collected from 124 regulatory submissions received between 1984 and 2010. Data collection excluded transducers not indicated for diagnostic fetal imaging. The output parameters of ultrasonic power, mean center frequency, and bone thermal index (TIB) were extracted or computed from the submissions for 3 periods: 1984-1989, 1992-1997, and 2005-2010. The data were stratified according to the following imaging modes: M-mode, B/M mode, pulsed wave Doppler, color flow Doppler, and continuous wave Doppler. RESULTS: Ultrasonic power and maximum TIB values have increased roughly an order of magnitude from pre-1991 to post-1991 periods; the center frequency has decreased somewhat (4.2 to 3.4 MHz). The percentage of Doppler-mode transducers has increased substantially over time, with the majority of the diagnostic fetal imaging transducers currently designed to operate in Doppler modes; this increase is particularly important, since Doppler modes generate much higher TIB levels than B/M-modes. Color flow Doppler ultrasound currently operates at the highest mean ultrasonic power level (with a 14-fold increase over time). CONCLUSIONS: The observed trends in increased acoustic output for both Doppler and non-Doppler modes underscore the widely recognized importance of adherence to the ALARA (as low as reasonably achievable) principle and prudent use in fetal ultrasound imaging. PMID- 24154896 TI - Clinical outcomes of mild isolated cerebral ventriculomegaly in the presence of other neurodevelopmental risk factors. AB - OBJECTIVES: The purpose of this study was to evaluate neuropsychological test data in school-aged children whose fetal sonograms revealed mild isolated cerebral ventriculomegaly without asymmetry of the lateral ventricles. METHODS: Nine of 52 children 6 years and older with sonographic evidence of mild isolated cerebral ventriculomegaly without asymmetry of the lateral ventricles were able to be recruited for follow-up school-aged neuropsychological testing. The children received a half-day battery of neuropsychological tests, including the Wechsler Abbreviated Scales of Intelligence; Beery-Buktenica Developmental Test of Visual Motor Integration, Fifth Edition; Wide Range Achievement Test, Fourth Edition; and Integrated Visual and Auditory Continuous Performance Test. Parents completed the Conners 3 Parent Short Form and the Personality Inventory for Children, Second Edition. RESULTS: In this small group, other risk factors for neurodevelopmental disorders were often present, including preterm birth, perinatal hypoxia, and a family history of psychiatric disease or substance abuse. Within this sample, the proportion of children with a pattern of test results showing poorer nonverbal intelligence than verbal intelligence scores and poorer math than reading performance, as well as meeting criteria for a diagnosis of attention deficit/hyperactivity disorder, was higher than the basal rates of these problems among children in general. CONCLUSIONS: Particularly given the complexity of various factors affecting neurodevelopment, follow-up neuropsychological evaluation is warranted in children with sonographic evidence of mild isolated cerebral ventriculomegaly without asymmetry of the lateral ventricle (eg, in the context of poor school performance). PMID- 24154897 TI - New formulas for calculating the lung-to-head ratio in healthy fetuses between 20 and 40 weeks' gestation. AB - OBJECTIVES: The purpose of this study was to develop new formulas for the expected fetal lung area-to-head circumference ratio in normal singleton pregnancies between 20 and 40 weeks' gestation. METHODS: The lung-to-head ratio and complete fetal biometric parameters of 126 fetuses between 20 and 40 weeks' gestation were prospectively measured. The lung-to-head ratio was measured by 3 different methods (longest diameter, anteroposterior diameter, and tracing). Formulas for predicting right and left lung-to-head ratios with regard to gestational age and biometric parameters were derived by stepwise regression analysis. RESULTS: New formulas for calculating right and left lung-to-head ratios by each measurement method were derived. The formulas included gestational age only and no biometric parameters. CONCLUSIONS: The new formulas for estimating the expected lung-to-head ratio by the 3 different methods in normal singleton pregnancies up to 40 weeks' gestation may help improve the prognostic power of observed-to-expected lung-to-head ratio assessment in fetuses with congenital diaphragmatic hernias. PMID- 24154898 TI - Bidirectional flow in the vertebral artery is not always indicative of the subclavian steal phenomenon. AB - OBJECTIVE: To evaluate the causes of bidirectional flow in the vertebral artery detected by Doppler sonography and its differential diagnosis. METHODS: Twenty nine patients with bidirectional flow in the vertebral artery were retrospectively studied. The vertebral artery parameters, including peak antegrade velocity (PAV), peak reversed velocity (PRV), maximum peak velocity (MPV), peak systolic velocity, resistive index (RI), and diameter, were measured. The MPV was defined as the MPV of bidirectional flow regardless of the velocity of antegrade or retrograde flow. To better predict the cause of bidirectional flow, receiver operating characteristic curves were constructed for these parameters, and the best cutoff values were obtained. The cause of bidirectional flow was determined by angiography. RESULTS: The causes of bidirectional flow were classified as the subclavian steal phenomenon (n = 21) and factors unrelated to the steal phenomenon (n = 8, including a hypoplastic vertebral artery [n = 4] and proximal vertebral artery stenosis and occlusion [n = 4]). Significant differences were observed between the steal phenomenon and non-steal phenomenon groups (P< .05) for MPV, PRV, PAV, target vertebral artery diameter, and contralateral RI. To determine the cause of bidirectional flow, areas under the receiver operating characteristic curves for the different parameters were obtained: 0.929 for MPV, 0.881 for PRV, 0.824 for PAV, 0.753 for target vertebral artery diameter, and 0.845 for contralateral RI. The cutoff value for MPV was 26.1 cm/s, and the accuracy was 93% (27 of 29). CONCLUSIONS: Bidirectional flow in the vertebral artery is not always indicative of the subclavian steal phenomenon. Measurement of hemodynamic parameters in the vertebral artery, such as MPV, can facilitate determination of the cause of bidirectional flow. PMID- 24154899 TI - Speckle-tracking imaging to monitor myocardial function after coronary artery bypass graft surgery. AB - OBJECTIVES: The purpose of this study was to investigate the changes in myocardial function in patients after coronary artery bypass graft (CABG) surgery using longitudinal and circumferential strain on speckle-tracking imaging. METHODS: A total of 145 patients who successfully underwent CABG surgery with a left ventricular ejection fraction (LVEF) of 50% or greater were enrolled in this study. Patients were classified into 4 groups based on age: group 1 (33-59 years), group 2 (60-64 years), group 3 (65-69 years), and group 4 (70-79 years). Routine echocardiography and longitudinal and circumferential strain measurements on speckle-tracking imaging were performed 1 week before and 1, 3, and 6 months after the CABG. RESULTS: In all groups, longitudinal strain increased significantly at 3 and 6 months after CABG therapy compared to baseline (P < .05). A significant increase in circumferential strain was found 1 month after the CABG in groups 1, 2, and 3, and a continuous increase in the parameter was observed in all groups 3 months after therapy (P < .05). However, the LVEF, left ventricular end-diastolic dimension, and stroke volume measured by routine echocardiography were not significantly changed after successful CABG treatment in all groups during 6 months of follow-up. CONCLUSIONS: Based on the results of our study in all age groups, speckle-tracking imaging parameters are more effective than the LVEF, left ventricular end-diastolic dimension, and stroke volume for monitoring improvement in myocardial function after CABG surgery. PMID- 24154900 TI - Abdominal fat sonographic measurement compared to anthropometric indices for predicting the presence of coronary artery disease. AB - OBJECTIVES: Sonography for measuring intra-abdominal fat is more accurate than anthropometric measurements. Computed tomographic (CT) angiography has become an accurate noninvasive method for detection of coronary artery disease (CAD). We examined the associations between both sonographic and anthropometric measurements of abdominal adiposity and the presence of CAD on CT angiography. METHODS: We evaluated 83 consecutive patients (70% men; mean age +/- SD, 56 +/- 10.8 years) who were referred for CT angiography. Clinical and laboratory variables were determined, and CT angiography was performed using a 64-slice scanner. The severity of CAD was defined by visual assessment of any plaque, either calcified or noncalcified. Preperitoneal fat, subcutaneous fat, and visceral fat thicknesses were determined on sonography, and the abdominal fat index was calculated as the preperitoneal fat thickness-to-subcutaneous fat thickness ratio. RESULTS: Coronary artery disease was detected in 56 patients (67%). Patients with CAD had higher visceral fat thickness (9.3 +/- 2.0 versus 8.2 +/- 2.2 cm; P = .035) and a higher waist-to-hip ratio (0.97 +/- 0.07 versus 0.92 +/- 0.07; P = .018) than those without CAD. The preperitoneal fat thickness, subcutaneous fat thickness, and abdominal fat index were not correlated with the CAD status. After adjusting for traditional cardiovascular risk factors, however, only a waist-to-hip ratio higher than 0.95 remained significantly associated with the presence of CAD (odds ratio, 4.03; 95% confidence interval, 1.2-13.4). CONCLUSIONS: This study shows that sonographically based obesity measurements are not superior to anthropometric indices in predicting the presence of CAD. PMID- 24154901 TI - Value of the left inferior thyroid artery peak systolic velocity in diagnosing autoimmune thyroid disease. AB - OBJECTIVES: The purpose of this study was to calculate a number of thyroid grayscale and Doppler sonographic parameters in healthy individuals and patients with Hashimoto thyroiditis or Graves disease and assess their sensitivity and specificity for the diagnosis of autoimmune thyroid disease using receiver operating characteristic curves. METHODS: A consecutive series of 153 patients (70 euthyroid and 54 hypothyroid patients with Hashimoto thyroiditis and 29 patients with Graves disease), all selected from an outpatient endocrine clinic, and 48 age- and sex-matched healthy control participants were evaluated with grayscale and power Doppler sonography. RESULTS: An irregular echo pattern in the thyroid parenchyma had 92.8% sensitivity for the diagnosis of autoimmune thyroid disease, and a left inferior thyroid artery peak systolic velocity (PSV) greater than 26.11 cm/s had 91.7% specificity. Of 8 patients with Hashimoto thyroiditis and normal grayscale sonographic characteristics, 6 had a left inferior thyroid artery PSV greater than 26.11 cm/s. A left inferior thyroid artery PSV greater than 61.65 cm/s had 82.8% sensitivity and 86.9% specificity for differentiating Hashimoto thyroiditis from Graves disease. CONCLUSIONS: The left inferior thyroid artery PSV was the most accurate sonographic parameter for the diagnosis of autoimmune thyroid disease. Measurement of the inferior thyroid artery PSV could be used in patients with a normal grayscale sonographic appearance and inconclusive clinical and biochemical parameters to substantiate the diagnosis of autoimmune thyroid disease. Further studies are needed to evaluate and expand the use of this index. PMID- 24154902 TI - Correlation between sonography and antibody activity in patients with Hashimoto thyroiditis. AB - OBJECTIVES: Patients with Hashimoto thyroiditis show structural changes of the thyroid that can be identified by a variety of sonographic criteria. We conducted this study to investigate whether there is a correlation between sonography and antibody activity and to assess the role of sonography in the diagnosis and follow-up of Hashimoto thyroiditis. In addition, we present a new classification system (termed the VESINC system [volume, echogenicity, sonographic texture, pseudonodular hypoechoic infiltration, nodules, and cysts]), which helps improve the clarity of sonographic findings. METHODS: The study included 223 consecutive patients with previously diagnosed Hashimoto autoimmune thyroiditis who attended the thyroid clinic of the German Armed Forces Central Hospital in Koblenz for follow-up examinations between 2006 and 2008. Laboratory tests were performed to measure the levels of free triiodothyronine, free thyroxine, thyrotropin, anti thyroglobulin antibodies (TgAbs), and antithyroid peroxidase antibodies (TPOAbs). Sonography was performed according to a strict protocol. We then assessed whether a correlation existed between antibody activity and the 6 sonographic variables of the VESINC system. RESULTS: Hypoechogenicity, heterogeneity, and pseudonodular hypoechoic infiltration were associated with significantly higher TPOAb activity (P < .001). There were no significant correlations between the other sonographic variables examined (cysts, nodules, and volume) or the biometric data with the TPOAb and TgAb levels. In addition, an assessment of TgAb levels did not show significant differences in correlations with any of the sonographic variables. CONCLUSIONS: Sonography is a noninvasive diagnostic imaging modality that provides information about the level of inflammatory activity. Markedly decreased echogenicity, heterogeneity, and multifocal pseudoinodular hypoechoic infiltration are indicative of a high level of inflammatory activity. The sonographic classification system presented here (VESINC system) can be a useful tool for comparing sonographic findings in a rapid and objective manner during follow-up of Hashimoto thyroiditis. PMID- 24154903 TI - Diagnostic utility of sonography and correlation between sonographic and clinical findings in patients with carpal tunnel syndrome. AB - OBJECTIVES: First, we investigated the accuracy of carpal tunnel syndrome diagnosis by comparing the cross-sectional area of the median nerve measured at the level of proximal inlet of the carpal tunnel with that measured at the level of the distal radioulnar joint on sonography. Second, we evaluated the correlation between sonographic and neurophysiologic findings and clinical findings assessed by the Carpal Tunnel Syndrome Instrument of the Japanese Society for Surgery of the Hand (JSSH). METHODS: Fifty wrists in 34 patients and 81 wrists in 45 healthy volunteers were examined. The proximal cross-sectional area and the difference (Delta) between the proximal and distal cross-sectional areas were calculated for each wrist. Nerve conduction velocity tests were performed for all patients with carpal tunnel syndrome. The proximal, distal, and Delta cross-sectional areas were compared for the two groups. We examined the correlation between the proximal, distal, and Delta areas, nerve conduction velocity findings, and JSSH scores in the patients. RESULTS: The diagnosis of carpal tunnel syndrome determined by the Delta cross-sectional area was more accurate than the diagnosis determined by the proximal area on receiver operating characteristic curve analysis (P = .006). Statistically significant correlations were found between proximal area, Delta area, and nerve conduction velocity findings (proximal, r = 0.45; P = .0013; Delta, r = 0.44; P = .001). The proximal and distal areas were positively correlated with the JSSH symptom severity score (proximal, r= 0.39; P= .005; distal, r = 0.35; P = .014). CONCLUSIONS: The cross sectional area method using sonography has excellent performance for diagnosing carpal tunnel syndrome. It was useful for measuring the proximal and distal cross sectional areas to evaluated the symptom severity and for calculating the Delta cross-sectional area to assess motor nerve damage in patients with carpal tunnel syndrome. PMID- 24154904 TI - Sex-related changes in tissue Doppler imaging parameters among patients with acute pulmonary thromboembolism. AB - OBJECTIVES: There are few studies evaluating serial changes in tissue Doppler imaging parameters in acute pulmonary thromboembolism. We aimed to compare these changes in male and female patients separately. METHODS: Between September 2010 and September 2011, 41 of 64 hemodynamically stable acute patients with pulmonary thromboembolism were included in the study. Twenty-two healthy individuals served as a control group. RESULTS: Compared to the control group, the acute pulmonary thromboembolism group had a lower tricuspid annular plane systolic excursion, basal peak systolic velocity of the tricuspid valvular annulus, right ventricular (RV) peak systolic strain, and RV peak systolic strain rate and a higher RV diameter, peak systolic pulmonary artery pressure, and RV myocardial performance index (P < .05). Values for these parameters were not different between men and women in the patient group. In men, compared to admission, predischarge echocardiography showed significant improvement in the tricuspid annular plane systolic excursion (mean +/- SD, 16.08 +/- 4.33 versus 19.29 +/- 3.74 mm; P = .002), basal tricuspid annular peak systolic velocity (10.11 +/- 3.66 versus 11.66 +/- 3.38 cm/s; P = .007), and peak systolic strain (-13.00% +/- 14.99% versus -23.20% +/- 10.23%; P = .001), whereas in women, predischarge and 3-month follow-up echocardiography showed marked improvement in the tricuspid annular plane systolic excursion (17.50 +/- 4.88 versus 19.79 +/- 5.58 mm; P = .021) and peak systolic strain (-15.70% +/- 13.52% versus -21.01% +/- 10.57%, respectively; P= .045). Female patients did not show improvement in these parameters during hospitalization. CONCLUSIONS: Patterns of changes in the RV function over time during a 3-month follow-up might differ between male and female patients with acute pulmonary thromboembolism, and the recovery process could be slower in women. Moreover, the midventricular peak systolic strain might be useful for serial evaluation of the recovery process. PMID- 24154905 TI - Focused renal sonography performed and interpreted by internal medicine residents. AB - OBJECTIVES: Intensivist-performed focused sonography, including renal sonography, is becoming accepted practice. Whether internal medicine residents can be trained to accurately rule out renal obstruction and identify sonographic findings of chronic kidney disease is unknown. The purpose of this study was to test the ability of residents to evaluate for this specific constellation of findings. METHODS: Internal medicine residents were trained in a 5-hour module on focused renal sonography evaluating renal length, echogenicity, hydronephrosis, and cysts on a convenience sample of medical ward, intermediate care, and medical intensive care unit patients. All patients underwent comprehensive sonography within 24 hours. The primary outcome was represented by the Fleiss kappa statistic, which indicated the degree of interobserver agreement between residents and radiologists. Sensitivity, specificity, and positive and negative predictive values were calculated using the comprehensive radiologist-read examination as the reference. RESULTS: Seventeen internal medicine residents imaged 125 kidneys on 66 patients. The average number of studies performed was 7.3 (SD, 6.6). Residents demonstrated excellent agreement with radiologists for hydronephrosis (kappa = 0.73; P < .001; SE, 0.15; sensitivity, 94%; specificity, 93%), moderate agreement for echogenic kidneys (kappa = 0.43; P < .001; SE, 0.13; sensitivity, 40%; specificity, 98%), and substantial agreement for renal cysts (kappa = 0.61; P < .001; SE, 0.12; sensitivity, 60%; specificity, 96%). Residents showed sensitivity of 100% and specificity of 88% for identification of atrophic kidneys, defined as length less than 8 cm. CONCLUSIONS: After a 5-hour training course, medical residents accurately identified hydronephrosis and key sonographic findings of chronic kidney disease in a cohort of medical patients. Screening for hydronephrosis and renal atrophy can be performed by medical residents after adequate training. PMID- 24154906 TI - Sonographically guided transhepatic core biopsies of right renal and adrenal masses: safety and short-term follow-up. AB - OBJECTIVES: The purpose of this study was to retrospectively evaluate the accuracy and safety of sonographically guided transhepatic biopsies of right upper renal and adrenal masses. METHODS: Ten sonographically guided transhepatic biopsies were performed in 10 patients with 6 right upper renal masses and 4 right adrenal masses that were invisible or inaccessible via an extrahepatic route. The control population comprised 19 sonographically guided extrahepatic biopsies that were performed in 19 patients with 18 right upper renal masses and 1 right adrenal mass. Transhepatic and extrahepatic biopsies were compared with respect to the diagnostic and complication rates. The mass sizes, biopsy distances, numbers and lengths of cores, and biopsy durations were also compared. RESULTS: The diagnostic rates of transhepatic and extrahepatic biopsies were 90% (9 of 10) and 89% (17 of 19), respectively (P > .999). The complication rates of transhepatic and extrahepatic biopsies were 10% (1 of 10) and 21% (4 of 19; P > .999). None of these biopsies resulted in major complications. The mean mass sizes, biopsy distances, and numbers of cores +/- SD for transhepatic and extrahepatic biopsies were 33.0 +/- 14.3 and 46.9 +/- 18.5 mm, 100.5 +/- 17.9 and 76.5 +/- 9.9 mm, and 2.7 +/- 0.9 and 4.0 +/- 0.7, respectively (P = .046, .038, and .001). However, the core lengths and biopsy durations were not significantly different between these biopsies (P = .91 and .077). CONCLUSIONS: Sonographically guided transhepatic core biopsies appear to be feasible and safe procedures for the histologic diagnosis of right upper renal and adrenal masses that are either invisible or inaccessible via an extrahepatic route. PMID- 24154908 TI - Mimickers of breast malignancy on breast sonography. AB - The aim of this article is to review benign breast lesions that can mimic carcinoma on sonography. Cases of benign lesions mimicking carcinoma on sonography were collected among lesions that were initially assessed as suspicious on sonography according to the American College of Radiology Breast Imaging Reporting and Data System category. Sonographically guided core needle biopsy was performed, and the pathologic types were confirmed to be benign. Cases of benign lesions mimicking carcinoma on sonography were shown to include fat necrosis, diabetic mastopathy, fibrocystic changes, sclerosing adenosis, ruptured inflammatory cysts, inflammatory abscesses, granulomatous mastitis, fibroadenomas, fibroadenomatous mastopathy, and apocrine metaplasia. Benign breast lesions may present with malignant features on imaging. A clear understanding of the range of appearances of benign breast lesions that mimic malignancy is important in radiologic-pathologic correlation to ensure that benign results are accepted when concordant with imaging and clinical features but, when discordant, there is no delay in further evaluation up to and including excisional biopsy. PMID- 24154907 TI - Sonographically guided core biopsy: a minimally invasive procedure for managing adnexal masses. AB - OBJECTIVES: We hypothesized that sonographically guided core biopsy is an effective method for the differential diagnosis of adnexal masses and evaluated patients who underwent core biopsies in our gynecologic oncology department. METHODS: We reviewed the medical records of 55 patients who underwent sonographically guided core biopsies in our gynecologic oncology department between 2010 and 2013. Patients with suspected ovarian malignancies who were unsuitable for optimal debulking surgery and patients at risk for higher morbidity and mortality because of a poor performance status, suspected nongynecologic tumors, and peritoneal tuberculosis were indicated for sonographically guided biopsy. RESULTS: The indications for sonographically guided core biopsy were candidacy for suboptimal cytoreduction (n = 32 [58.2%]), a poor performance status (n = 11 [20.0%]), and suspected nongynecologic tumors (n = 12 [21.8%]). Histopathologic evaluations revealed primary ovarian tumors in 36 patients (65.5%). Tuberculosis was found to be the second most common disease (n = 8 [14.5%]) among the patients who underwent core biopsies. In 2 patients (3.6%), histologic examination revealed metastatic colorectal cancer. CONCLUSIONS: Sonographically guided core biopsy may be preferred as a minimally invasive procedure for managing adnexal masses, particularly in patients with advanced ovarian cancer and high comorbidities who might benefit from neoadjuvant chemotherapy and in cases of suspected nongynecologic tumors, including pelvic tuberculosis. PMID- 24154909 TI - Transoral sonographic diagnosis of tonsilloliths: report of 3 cases. AB - Tonsilloliths are calcified concretions that develop in tonsillar crypts. They are usually asymptomatic; however, they may cause problems such as halitosis, dysphagia, a globus sensation, and otalgia. Tonsilloliths may be diagnosed by a simple inspection or palpation of tonsillar crypts, which can be confirmed by panoramic radiography, computed tomography, or magnetic resonance imaging. We report 3 cases of tonsilloliths diagnosed by transoral sonography that was performed easily and comfortably in an office-based setting. PMID- 24154910 TI - Skin-covered bladder exstrophy diagnosed antenatally. PMID- 24154911 TI - Congenital atresia of the left main coronary artery: preliminary diagnosis by echocardiography. PMID- 24154912 TI - Concentric and eccentric: muscle contraction or exercise? PMID- 24154913 TI - Reply: To PMID 23525391. PMID- 24154915 TI - Statins, aspirin and risk of venous thromboembolic events in breast cancer patients. AB - Venous thromboembolic events (VTE's) are associated with decreased survival in breast cancer patients. Studies suggested that statins reduce the risk of VTE's in the general population. Low dose Aspirin reduces risk of VTE's in high risk populations. The Breast Cancer in Northern Israel Study is a case-control study of consecutive breast cancer cases diagnosed in northern Israel and matched controls. The present analysis was limited to cases with breast cancer enrolled in the study. Data was extracted from Clalit Health Services (CHS) database and from computerized pharmacy records. Out of 3,585 patients enrolled, 261 (7.3%) had a VTE during median follow up of 4.2 years. The 1 and 2 year cumulative incidence was 2.64 and 3.65%. 55.7% of patients used statins, predominantly simvastatin (75.8%). 44.5% used aspirin. In multivariate analysis neither statins nor aspirin use was associated with a reduced risk for a VTE. Unadjusted HR for statin and aspirin was 1.461 (1.018-2.096) and 1.293 (0.846-1.976), respectively, and the adjusted HR were 0.86 (0.648-1.14) and 1.013 (0.737-1.392). Results were similar when only simvastatin use was assessed. Metastatic disease, chemotherapy, age, BMI and presence of comorbidities were significantly associated with risk of VTE's. Our study is the first to look at the effect of statins and aspirin on the incidence of VTE's in patients with breast cancer. In our cohort, statin and aspirin use did not decrease the risk for a VTE. Our results might be explained by use of low potency statins (simvastatin and pravastatin) and by alternate mechanisms for VTE formation in patients with cancer. PMID- 24154916 TI - Shear-wave elastography in carotid plaques: comparison with grayscale median and histological assessment in an interesting case. PMID- 24154917 TI - Social influence and perceptual decision making: a diffusion model analysis. AB - Classic studies on social influence used simple perceptual decision-making tasks to examine how the opinions of others change individuals' judgments. Since then, one of the most fundamental questions in social psychology has been whether social influence can alter basic perceptual processes. To address this issue, we used a diffusion model analysis. Diffusion models provide a stochastic approach for separating the cognitive processes underlying speeded binary decisions. Following this approach, our study is the first to disentangle whether social influence on decision making is due to altering the uptake of available sensory information or due to shifting the decision criteria. In two experiments, we found consistent evidence for the idea that social influence alters the uptake of available sensory evidence. By contrast, participants did not adjust their decision criteria. PMID- 24154918 TI - Value judgments and the true self. AB - The belief that individuals have a "true self" plays an important role in many areas of psychology as well as everyday life. The present studies demonstrate that people have a general tendency to conclude that the true self is fundamentally good--that is, that deep inside every individual, there is something motivating him or her to behave in ways that are virtuous. Study 1 finds that observers are more likely to see a person's true self reflected in behaviors they deem to be morally good than in behaviors they deem to be bad. Study 2 replicates this effect and demonstrates observers' own moral values influence what they judge to be another person's true self. Finally, Study 3 finds that this normative view of the true self is independent of the particular type of mental state (beliefs vs. feelings) that is seen as responsible for an agent's behavior. PMID- 24154919 TI - Fluid movement and fluid social cognition: bodily movement influences essentialist thought. AB - Rigid social categorization can lead to negative social consequences such as stereotyping and prejudice. The authors hypothesized that bodily experiences of fluidity would promote fluidity in social-categorical thinking. Across a series of experiments, fluid movements compared with nonfluid movements led to more fluid lay theories of social categories, more fluidity in social categorization, and consequences of fluid social-categorical thinking, decreased stereotype endorsement, and increased concern for social inequalities. The role of sensorimotor states in fluid social cognition, with consequences for social judgment and behavior, is discussed. PMID- 24154920 TI - NiTi superelastic orthodontic archwires with polyamide coating. AB - Twenty orthodontic archwires with 55.2% Ni and 44.8% Ti (% weight) were subjected to a dipping treatment to coat the NiTi surface by a polyamide polymer. It has been selected a Polyamide 11 due to its remarkable long lasting performance. The transformation temperatures as well as the transformation stresses of the NiTi alloy were determined in order to know whether the coating process can alter its properties. The adhesive wear tests have been demonstrated that the wear rates as well as the dynamic friction coefficients MU of polymer coated wires are much lower than metallic wires. The corrosion studies have shown that the use of this polymer, as coating, seals the NiTi surface to prevent corrosion and the release of nickel ions. The average decrease of Ni ions release due to this coating is around 85%. PMID- 24154921 TI - HIV and stigma in Liuzhou, China. AB - This paper describes emergent stigma-related themes from individual descriptions of living with HIV in Liuzhou, China. Qualitative interviews were conducted with 23 people living with HIV (PLHIV). To provide contextual information, 14 public health personnel and 4 community workers in Liuzhou were also interviewed. PLHIV experienced enacted, anticipated, and internalized HIV-related stigma, which resulted in negative affective, behavioral, and physical health outcomes, including barriers to health care, preemptive self-isolation, suicidal ideation, and poverty. To lessen stigma, future programs should aim to increase HIV knowledge and empathy for PLHIV among family members, community workers, and health professionals. HIV programs should also include suicide risk assessment for PLHIV, especially immediately after diagnosis and at the onset of HIV-related symptoms. PMID- 24154922 TI - Surgical techniques for implanting implantable cardioverter defibrillators in children and infants. AB - Implantable cardioverter defibrillators (ICDs) are now being used in children. ICDs can be used to prevent sudden cardiac death caused by not only congenital heart defects, but also various non-structural diseases, such as long QT syndrome. However, a standard implantation technique for children, especially infants, has not yet been established. As the surgical implantation in infants is not amenable to transvenous lead placement, it was necessary to choose from epicardial, subcutaneous and pericardial ICD systems. However, many of these systems are associated with high rates of late complications. Lead fracture, insulation breakage, migration, buckling or crinkling of the patch lead and constrictive pericarditis have been reported as the most common lead-related complications. An increase in the defibrillation threshold is another issue that must be considered when using an ICD in a child or infant. Further studies on the outcomes, psychosomatic impact and other specific complications in the pediatric population need to be considered. The clinical use of ICDs in infants is still limited. Therefore, it is important to have many surgical options available so that the treatment can be custom-tailored to suit individual patients. PMID- 24154923 TI - Long-term survival after excision of a giant esophageal gastrointestinal stromal tumor with imatinib mesylate resistance: report of a case. AB - A 69-year-old woman underwent 4 months of imatinib mesylate chemotherapy for a diagnosed gastrointestinal stromal tumor of the esophagus. This treatment was suspended because of its side effects and because radiological examinations showed that the tumor had not changed or had even increased slightly in size. Thus, we performed esophagectomy via left thoracotomy and removed a tumor that measured 18 * 17 * 10 cm. Immunohistochemical examination revealed positive reactions for c-kit and CD34, suggestive of a high-risk malignancy. The patient was discharged from hospital on postoperative day 30, and has remained well with no sign of tumor recurrence for more than 5 years, without adjuvant chemotherapy. PMID- 24154924 TI - A micro-liter viscosity and density sensor for the rheological characterization of DNA solutions in the kilo-hertz range. AB - When measuring the properties of fluids from biological sources, sample volumes in the micro-liter range are often desired as higher volumes may not be available or are very expensive. Miniaturized viscosity and density sensors based on a vibrating cantilever fulfill this requirement. In this paper, the possibility of measuring viscosity and density of DNA solutions at the same time using such a sensor is shown. The sensor requires a sample volume of 10 MUl. By doing a titration of a solution containing 110 bp long strands of DNA in the diluted, Newtonian regime, the intrinsic viscosity can be determined to be 0.047 ml mg(-1) using the cantilever sensor. The cantilever is also tested with solutions of 10 kbp long strands with concentrations in the semi-dilute, non-Newtonian regime. The comparably small change in resonance frequency and damping observed using these solutions at 12.5 kHz is attributed to shear thinning, which is expected when extrapolating results from other groups. PMID- 24154925 TI - Novel nanomaterials used for sample preparation for protein analysis. AB - Sample preparation is of vital importance for proteomic analysis because of the high complexity of biological samples. The rapid development of novel nanomaterials with various compositions, morphologies, and proper surface modifications provides a category of powerful tools for the sample preparation for protein analysis. In this paper, we have summarized recent progresses for the applications of novel nanomaterials in sample preparation for the analysis of proteomes, especially for phosphoproteomes, glycoproteomes, and peptidoms. Several kinds of novel nanomaterials were also discussed for their use in other kinds of proteomics analysis. PMID- 24154926 TI - Surface-enhanced Raman scattering for quantitative detection of ethyl carbamate in alcoholic beverages. AB - Ethyl carbamate, a by-product of fermentation and storage with widespread occurrence in fermented food and alcoholic beverages, is a compound potentially toxic to humans. In this work, a new approach for quantitative detection of ethyl carbamate in alcoholic beverages, based on surface-enhanced Raman scattering (SERS), is reported. Individual silver-coated gold nanoparticle colloids are used as SERS amplifiers, yielding high Raman enhancement of ethyl carbamate in three kinds of alcoholic beverages (vodka, Obstler, and white rum). The characteristic band at 1,003 cm(-1), which is the strongest and best reproducible peak in the SERS spectra, was used for quantitative evaluation of ethyl carbamate. The limit of detection, which corresponds to a signal-to-noise ratio of 3, was 9.0 * 10(-9) M (0.8 MUg . L(-1)), 1.3 * 10(-7) M (11.6 MUg . L(-1)), and 7.8 * 10(-8) M (6.9 MUg . L(-1)), respectively. Surface-enhanced Raman spectroscopy offers great practical potential for the in situ assessment and identification of ethyl carbamate in the alcoholic beverage industry. PMID- 24154927 TI - Use of alkaline or enzymatic sample pretreatment prior to characterization of gold nanoparticles in animal tissue by single-particle ICPMS. AB - Inductively coupled plasma mass spectrometry in single-particle mode (spICPMS) is a promising method for the detection of metal-containing nanoparticles (NPs) and the quantification of their size and number concentration. Whereas existing studies mainly focus on NPs suspended in aqueous matrices, not much is known about the applicability of spICPMS for determination of NPs in complex matrices such as biological tissues. In the present study, alkaline and enzymatic treatments were applied to solubilize spleen samples from rats, which had been administered 60-nm gold nanoparticles (AuNPs) intravenously. The results showed that similar size distributions of AuNPs were obtained independent of the sample preparation method used. Furthermore, the quantitative results for AuNP mass concentration obtained with spICPMS following alkaline sample pretreatment coincided with results for total gold concentration obtained by conventional ICPMS analysis of acid-digested tissue. The recovery of AuNPs from enzymatically digested tissue, however, was approximately four times lower. Spiking experiments of blank spleen samples with AuNPs showed that the lower recovery was caused by an inferior transport efficiency of AuNPs in the presence of enzymatically digested tissue residues. PMID- 24154928 TI - Remote monitoring of a high-risk patient with Brugada syndrome: association of different arrhythmic manifestations. AB - We report on the remote arrhythmia monitoring of a 34-year-old man with highly symptomatic Brugada syndrome, who initially presented with syncope, paroxysmal atrial fibrillation, and spontaneous coved-type electrocardiogram. The patient received a dual-chamber implantable cardioverter-defibrillator (ICD) with Home MonitoringTM facilities and experienced recurrent ICD shocks for spontaneous ventricular fibrillation (VF) episodes during the first year after ICD implantation. Remote monitoring revealed an increased burden of premature ventricular complexes and atrial arrhythmias each time VF spontaneously occurred. Atrial and ventricular arrhythmias were effectively suppressed by low-dose quinidine without severe side effects. PMID- 24154929 TI - Identification of the methylation of p14ARF promoter as a novel non-invasive biomarker for early detection of lung cancer. AB - BACKGROUND: Recent diagnostic procedure advances have greatly improved early lung cancer detection. However, the invasive, unpleasant and inconvenient nature of current diagnostic procedures limits their application. There is a great need of novel non-invasive biomarkers for early lung cancer diagnosis. In the present study, we intend to determine whether the blood signatures of p14ARF promoter methylation are suitable for early detection of lung cancer. METHODS: The study aimed to assess the probability of p14ARF promoter methylation in plasma samples to detect early lung cancer using nested methylation-specific PCR in the training set consisted of tumor tissues and paired blood. Besides, we were further to discuss the difference in time to progression between methylation and unmethylation of p14ARF promoter using univariate and multivariate analysis. RESULTS: The methylation of p14ARF promoter was detected in 33.6 % of tumor tissues, and 12.1 and 25.2 % in distant-cancer mucosa and matched plasma, respectively, and our study has also demonstrated the positive correlation between them by Pearson's test (r = 0.300). The tumor-free survival time of the unmethylation of p14ARF promoter is significantly longer than that of the methylation of p14ARF promoter in tumor tissues (chi (2) = 7.149, P = 0.008). CONCLUSION: The methylation of p14ARF promoter in plasma samples has strong potential as a novel non-invasive biomarker for early detection of lung cancer, and the methylation of p14ARF promoter was considered as prognostic factor in our study. PMID- 24154930 TI - Distribution of human papillomavirus genotypes, assessment of HPV 16 and 18 viral load and anal related lesions in HIV positive patients: a cross-sectional analysis. AB - Natural history of anal intraepithelial neoplasia and anal cancer is not fully understood. Factors associated with cytological abnormalities and predictors of progression to high-grade anal intraepithelial neoplasia still deserve investigation. The aim of this cross-sectional study was to assess the prevalence of HPV types, the relationship between HPV genotypes, HPV 16/18 viral load and cytological abnormalities in male and female HIV-infected patients. One hundred and twenty-two (72.6%) patients were infected with HPV, 75 (61%) had multiple HPV infection, and 94 (77%) had high-risk HPV infection. The most frequently identified HPV types were HPV 16 (64%), HPV 6 (39%), HPV 18 (31%), HPV 53 (14.7%), HPV 33 (10.6%), HPV 11 (8.2%), HPV 70 (5.7%), and HPV 61 (4.9%). The HPV types which were most frequently found in combination were HPV 6 + 16 (9.8%), 6 + 16 + 18 (8.2%), 16 + 18 (6.6%), 6 + 18 (4.9%), 16 + 33 (3.3%), 16 + 53 (3.3%). Median HPV16 and 18 viral loads were 6.1 log10 copies/10(6) cells [IQR 5.0-7.3] and 6.1 log10 copies/10(6) cells [IQR 5.7-6.0], respectively. Male gender (P = 0.03, OR: 1.2 [1.0-1.4]) and homo/bisexual transmission routes (P = 0.044, OR: 1.4 [1.0-1.9]) were associated with HPV 16 infection. An HPV 16 viral load cut off >=5.3 log10 copies/10(6) cells and a CD4+ cell count <=200/ul were independent factors associated with abnormal cytology. In the absence of national consensus guidelines, a strict regular follow-up at shorter intervals is recommended for HIV-infected patients with abnormal cytology, especially low grade squamous intraepithelial lesions, an HPV 16 viral load >=5.3 log/10(6) cells and a CD4+ cell count <=200/ul. PMID- 24154931 TI - State parity laws and access to treatment for substance use disorder in the United States: implications for federal parity legislation. AB - IMPORTANCE: The passage of the 2008 Mental Health Parity and Addiction Equity Act and the 2010 Affordable Care Act incorporated parity for substance use disorder (SUD) treatment into federal legislation. However, prior research provides us with scant evidence as to whether federal parity legislation will hold the potential for improving access to SUD treatment. OBJECTIVE: To examine the effect of state-level SUD parity laws on state-aggregate SUD treatment rates and to shed light on the impact of the recent federal SUD parity legislation. DESIGN, SETTING, AND PARTICIPANTS: We conducted a quasi-experimental study using a 2-way (state and year) fixed-effect method. We included all known specialty SUD treatment facilities in the United States and examined treatment rates from October 1, 2000, through March 31, 2008. Our main source of data was the National Survey of Substance Abuse Treatment Services, which provides facility-level information on specialty SUD treatment. INTERVENTIONS: State-level SUD parity laws during the study period. MAIN OUTCOMES AND MEASURES: State-aggregate SUD treatment rates in (1) all specialty SUD treatment facilities and (2) specialty SUD treatment facilities accepting private insurance. RESULTS: The implementation of any SUD parity law increased the treatment rate by 9% (P < .001) in all specialty SUD treatment facilities and by 15% (P = .02) in facilities accepting private insurance. Full parity and parity only if SUD coverage is offered increased the SUD treatment rate by 13% (P = .02) and 8% (P = .04), respectively, in all facilities and by 21% (P = .03) and 10% (P = .04), respectively, in facilities accepting private insurance. CONCLUSIONS AND RELEVANCE: We found a positive effect of the implementation of state SUD parity legislation on access to specialty SUD treatment. Furthermore, the positive association is more pronounced in states with more comprehensive parity laws. Our findings suggest that federal parity legislation holds the potential to improve access to SUD treatment. PMID- 24154932 TI - Effect of atorvastatin on baroreflex sensitivity in subjects with type 2 diabetes and dyslipidaemia. AB - In this prospective study, we examined the effect of atorvastatin treatment on baroreflex sensitivity (BRS) in subjects with type 2 diabetes. A total of 79 patients with type 2 diabetes with dyslipidaemia were recruited. A total of 46 subjects were enrolled to atorvastatin 10 mg daily and low-fat diet and 33 patients to low-fat diet only. BRS was assessed non-invasively using the sequence method at baseline, 3, 6 and 12 months. Treatment with atorvastatin increased BRS after 12 months (from 6.46 +/- 2.79 ms/mmHg to 8.05 +/- 4.28 ms/mmHg, p = 0.03), while no effect was seen with low-fat diet. Further sub-analysis according to obesity status showed that BRS increased significantly only in the non-obese group (p = 0.036). A low dose of atorvastatin increased BRS in non-obese subjects with type 2 diabetes and dyslipidaemia after 1-year treatment. This finding emphasizes the beneficial effect of atorvastatin on cardiovascular system, beyond the lipid-lowering effects. PMID- 24154933 TI - Metropolitan racial residential segregation and cardiovascular mortality: exploring pathways. AB - Racial residential segregation has been associated with an increased risk for heart disease and stroke deaths. However, there has been little research into the role that candidate mediating pathways may play in the relationship between segregation and heart disease or stroke deaths. In this study, we examined the relationship between metropolitan statistical area (MSA)-level segregation and heart disease and stroke mortality rates, by age and race, and also estimated the effects of various educational, economic, social, and health-care indicators (which we refer to as pathways) on this relationship. We used Poisson mixed models to assess the relationship between the isolation index in 265 U.S. MSAs and county-level (heart disease, stroke) mortality rates. All models were stratified by race (non-Hispanic black, non-Hispanic white), age group (35-64 years, >= 65 years), and cause of death (heart disease, stroke). We included each potential pathway in the model separately to evaluate its effect on the segregation-mortality association. Among blacks, segregation was positively associated with heart disease mortality rates in both age groups but only with stroke mortality rates in the older age group. Among whites, segregation was marginally associated with heart disease mortality rates in the younger age group and was positively associated with heart disease mortality rates in the older age group. Three of the potential pathways we explored attenuated relationships between segregation and mortality rates among both blacks and whites: percentage of female-headed households, percentage of residents living in poverty, and median household income. Because the percentage of female-headed households can be seen as a proxy for the extent of social disorganization, our finding that it has the greatest attenuating effect on the relationship between racial segregation and heart disease and stroke mortality rates suggests that social disorganization may play a strong role in the elevated rates of heart disease and stroke found in racially segregated metropolitan areas. PMID- 24154934 TI - Atorvastatin reduces the myocardial content of coenzyme Q10 in isoproterenol induced heart failure in rats. AB - The present study was aimed to study the effects of different doses of atorvastatin on Co Q10 content in the myocardium tissue in rats. A subcutaneous injection of isoproterenol (5 mg/kg/day) for 10 days was used for the induction of heart failure. Rats were randomly assigned to control, treatment with atorvastatin (5, 10, 20 mg/kg/day) and treatment with atorvastatin plus coenzyme Q10 (10 mg/kg/day). Coenzyme Q10 content of myocardium was measured using HPLC method with UV detector after hemodynamic parameters measurements. The malondialdehyde (MDA) content of the myocardium was evaluated in order to determine coenzyme Q10 antioxidative effect. A high dose of atorvastatin (20 mg/kg/day) was significantly reduced the myocardium content of coenzyme Q10 as compared with isoproterenol treated group (p<0.001). Compared with atorvastatin alone treated animals, co-administration of coenzyme Q10 with atorvastatin was improved the level of coenzyme Q10 in the myocardium (p<0.05, p<0.001). Increasing the dose of atorvastatin also led to increase in MDA content of the myocardium (p<0.01). Serum lipid profile showed no changes in atorvastatin treated groups. The results of this study demonstrate that high doses of atorvastatin reduce coenzyme Q10 content of the myocardium and increase lipid peroxidation in myocardium which is reversed by coenzyme Q10 co-administration. PMID- 24154935 TI - Bioequivalence of Linagliptin 5 mg once daily and 2.5 mg twice daily: pharmacokinetics and pharmacodynamics in an open-label crossover trial. AB - Linagliptin is an oral antihyperglycemic drug that acts by inhibiting the dipeptidyl peptidase-4 enzyme. A 5-mg once-daily regimen is available, but an alternative regimen was needed for twice-daily fixed-dose combinations. Although linagliptin has non-linear pharmacokinetics, simulation suggested 2.5 mg twice daily would provide bioequivalent exposure and comparable plasma dipeptidyl peptidase-4 inhibition to 5 mg once-daily.This crossover study compared steady state pharmacokinetics and pharmacodynamics of linagliptin 5 mg once-daily and 2.5 mg twice-daily, both administered for 7 days.In total, 16 healthy volunteers entered the study, and 15 completed both treatment periods. Exposure over 24-h at steady state (AUC0-24,ss) was similar for linagliptin 5 mg once-daily and 2.5 mg twice-daily (132 vs. 124 nmol . h/L), and the 90% confidence interval of the adjusted geometric mean ratio of AUC0-24,ss was well within the acceptance range for bioequivalence (ratio 93.9%; 90% confidence interval 89.5, 98.5). Median dipeptidyl peptidase-4 inhibition over a 24-h interval at steady state was 85.9% with linagliptin 5 mg once-daily and 86.5% with 2.5 mg twice-daily, and median dipeptidyl peptidase-4 inhibition values were approximately 80.0% at trough. Most subjects had no adverse events and there were no serious adverse events.Linagliptin 5 mg once-daily and 2.5 mg twice-daily provided bioequivalent exposure and similar inhibition of dipeptidyl peptidase-4 over the whole dosing interval. PMID- 24154936 TI - Pharmacokinetics of niacin, simvastatin and their metabolites in healthy Chinese subjects after single and multiple doses of a fixed dose combination tablet of niacin extended release/simvastatin. AB - OBJECTIVE: A fixed dose combination tablet of niacin extended release (ER)/simvastatin was recently developed in China. This study was designed to assess and compare the pharmacokinetics of niacin, simvastatin and their metabolites in healthy Chinese subjects after single and multiple doses administration. METHODS: From day 1 to day 7, 12 Chinese subjects were given a tablet every day at approximately 10 p.m. Serial blood samples were collected. Niacin and nicotinuric acid (NUA) in plasma, niacin, NUA, N-methylnicotinamide (MNA) and N-methyl-2-pyridone-5-carboxamide (2PY) in urine, simvastatin and simvastatin acid in plasma were determined by LC/MS/MS methods. Pharmacokinetic parameters on days 1 and 7 were compared. RESULTS: The main pharmacokinetic parameters for the single and multiple doses were as -follows: Niacin: Tmax were 3.8+/-1.5 h and 3.9+/-2.0 h; Cmax were 2 091+/-1 315 ng/ml and 2 323+/-1 542 ng/ml; AUC0-t were 4 123.88+/-3 138.48 ng ? h/ml and 4 385.98+/-3 127.05 ng ? h/ml. NUA: Tmax were 4.7+/-1.7 h and 3.8+/-1.5 h; Cmax were 1 057+/-549 ng/ml and 1 087+/-470 ng/ml; AUC0-t were 4 012.49+/-2 168.68 ng ? h/ml and 4 040.45+/-1 886.57 ng ? h/ml. Simvastatin: Tmax were 1.8+/-1.0 h and 2.5+/-2.5 h; Cmax were 3.15+/-1.67 ng/ml and 4.87+/-4.11 ng/ml; AUC0-t were 9.03+/-5.10 ng ? h/ml and 17.63+/-13.93 ng ? h/ml. Simvastatin acid: Tmax were 5.8+/-1.7 h and 6.5+/-1.4 h; Cmax were 4.22+/-2.10 ng/ml and 9.30+/-8.09 ng/ml; AUC0-t were 34.65+/-16.89 ng ? h/ml and 61.62+/-46.41 ng ? h/ml. Urine Recovery rate of total niacin: (40.55+/ 7.38)% and (62.87+/-12.04)%. CONCLUSION: Compared with those after a single dose, pharmacokinetics of niacin and NUA was similar; total urine recovery of niacin was higher; exposure to simvastatin and simvastatin acid were higher following multiple doses. PMID- 24154937 TI - Augmenting the expression of NKp44 molecule and the natural killer activity in peripheral blood mononuclear cells from patients with malignant colorectal carcinoma. AB - OBJECTIVE: NKp44 and NKG2D are of the main NK activating receptors involved in recognition and killing of tumors. Here we studied the stimulatory effects of PHA and/or K562 cell line on induction of NKp44 and NKG2D expression and the NK activity of PBMCs from patients with colorectal carcinoma (CRC). MATERIALS AND METHODS: Peripheral blood samples were collected from 10 patients with CRC. The peripheral blood mononuclear cells (PBMCs) from each patient received a single stimulation with PHA or double stimulation with PHA and irradiated K562 cell line (iK562). The expression of CD56, NKG2D and NKp44 were detected by flowcytometry. The NK activity of PBMCs against a colorectal carcinoma cell line named as SW742 was determined with 51Cr-release assay. RESULTS: Double stimulation of PBMCs with PHA+iK562 significantly augmented the number CD56(+) cells compared to PHA alone and non-stimulated PBMCs (P<0.000, P<0.0000; respectively). A single stimulation of PBMCs with PHA resulted in an enhancement in NKG2D and NKp44 expression from 16.6+/-3.3% (for non-stimulated PBMCs) to 42+/-5.6% and 48.1+/-3.8% respectively (p<0.05). Double stimulation of PBMCs augmented the NKp44 expression significantly in comparison with single stimulation with PHA (73.6+/-12%, p<0.05). Double stimulation of PBMCs significantly enhanced the NK activity against SW742 target cells compared to single stimulation with PHA (p<0.05). DISCUSSION AND CONCLUSION: Our results demonstrated that the mitogen and iK562 exposure to PBMCs can significantly improve NK activity which is co-related to the higher expression of NKp44 and NKG2D. These data may help to improve cancer immunotherapy protocols. PMID- 24154938 TI - The anti-tumoral efficacy of a docetaxel-loaded liposomal drug delivery system modified with transferrin for ovarian cancer. AB - To reduce the toxic effect on normal cells and improve the treatment effects of docetaxel, a novel transferrin modified docetaxel-loaded long circulating liposome for ovarian tumor was established for the first time. The transferrin modified long-circulating liposomes loaded with docetaxel (TF-LP-DOC) were prepared by the post-insertion method and exhibited excellent characteristics in terms of particle size, encapsulation efficiency and stability. We investigated the targeting efficiencies of liposomes by the cellular uptake in vitro and biodistribution in vivo, and identified the therapeutic effects using cytotoxicity experiment (in vitro)and tumor growth inhibition (in vivo) on ovarian cancer. The in vitro and in vivo results showed that TF-LP-DOC were successfully established and presented an enhanced targeting ability. With decreased side effect and improved anti-tumor efficacy of chemotherapeutic drugs, TF-LP-DOC proved itself to be a very promising tumor targeted drug delivery system. PMID- 24154939 TI - Determinants of climate change adaptation strategies used by fish farmers in Epe Local Government Area of Lagos State, Nigeria. AB - BACKGROUND: Undesirable impacts of climate change have been a common occurrence that has made fish farmers in developing countries adopt some climate-change adaptation strategies. However, little is known about determinants of climate change adaptation strategies used by these fish farmers. This study, therefore, articulates novelties on adaptation to climate change, as well ascertains determinants of adaptation strategies used by fish farmers in Epe, Lagos State, Nigeria. RESULTS: Climate change adaptation strategies mostly used by fish farmers include frequent seeking for early warning information about climate change (76.7%) and avoidance of areas susceptible to flooding (60.0%). Climate change adaptation strategies used by fish farmers were significantly influenced by access to early warning information (beta = 7.21), knowledge of farmers about climate change adaptation strategies (beta = 8.86), access to capital (beta = 28.25), and participation in workshop and conferences (beta = 37.19) but were reduced by number of fish stocking (beta = -2.06). CONCLUSION: The adaptation strategies used by fish farmers were autonomous and mostly determined by the access to credit facilities and information. Development policy should focus on carbon capture and storage technology in order to reduce adverse impacts of climate change, as well as making early warning information on climate change available to fish farmers. These will enhance adaptation to climate change. PMID- 24154940 TI - Sensitivity and specificity of bedside ultrasonography in the diagnosis of fractures of the fifth metacarpal. AB - OBJECTIVES: Ultrasonography is becoming increasingly common in the diagnosis of fracture in emergency medicine. The aim of our study was to investigate the diagnostic accuracy of sonographic examinations for diagnosing fifth metacarpal fractures. METHODS: A prospective study was performed of consecutive patients aged >14 years admitted to the emergency department with hand trauma and tenderness over the fifth metacarpal. Anteroposterior and oblique plain x-rays were taken on all patients. Emergency physicians performed bedside sonographic examination. The x-rays were reported by an orthopaedic surgeon who was blinded to the sonographic examination findings. The orthopaedic surgeon's report was considered the gold standard unless a CT scan was performed. In the single case where this occurred, the CT scan report was considered the gold standard. RESULTS: Eighty one patients were included in the study, 39 of whom had fractures. Sonographic examination identified the fractures in 38 patients. One occult fracture undetected by plain radiography, later shown on CT scan, was identified by sonographic examination. There were three cases with false positive ultrasound findings. The sensitivity of the diagnosis of fifth metacarpal fractures by ultrasonography was 97.4% (95% CI 84.9% to 99.9%), specificity was 92.9% (95% CI 79.4% to 98.1%), positive likelihood ratio (LR) was 14 (95% CI 4.58 to 41), negative LR was 0.03 (95% CI 0.00 to 0.19), negative predictive value was 97.5% (95% CI 85.3% to 99.9%) and positive predictive value was 92.6% (95% CI 79% to 98.1%). CONCLUSIONS: Sonographic examination can be used as an effective diagnostic tool in patients with fifth metacarpal trauma. PMID- 24154941 TI - An observational study of extracorporeal CPR for in-hospital cardiac arrest secondary to myocardial infarction. PMID- 24154942 TI - An application of the learning curve-cumulative summation test to evaluate training for endotracheal intubation in emergency medicine. AB - OBJECTIVE: The learning curve-cumulative summation (LC-CUSUM) test allows for quantitative and individual assessments of the learning process. In this study, we evaluated the process of skill acquisition for performing endotracheal intubation (ETI) in three emergency medicine (EM) residents over a 2 year period in their first 2 years of their EM residency. METHODS: We evaluated 342 ETI cases performed by three EM residents using the LC-CUSUM test according to their rate of success or failure of ETI. A 90% success rate (SR) was chosen to define adequate performance and an SR of 80% was considered inadequate. After the learning phase, the standard CUSUM test was applied to ensure that performance was maintained. RESULTS: The mean number of ETI cases required to reach the predefined level of performance was 74.7 (95% CI 62.0 to 87.3). CUSUM tests confirmed that performance was maintained after the learning phase. CONCLUSIONS: By using the LC-CUSUM test, we were able to quantitatively monitor the acquisition of the skill of ETI by EM residents. The LC-CUSUM could be useful for monitoring the learning process for the training of airway management in the practice of EM. PMID- 24154943 TI - Near-infrared spectroscopy in the assessment of suspected sepsis in the emergency department. AB - BACKGROUND AND AIMS: The conventional approach to sepsis resuscitation involves early interventions targeting global oxygenation and macro-haemodynamic variables such as central venous and systemic arterial pressures. There is increasing recognition of the importance of microcirculatory changes in shock states, including sepsis, and the relationship of these to outcome. Near-infrared spectroscopy (NIRS) is a recently developed non-invasive technology that measures tissue oxygen saturations (StO2), which may be an indirect measure of the adequacy of the microcirculation. StO2 measurements, therefore, have the potential to identify patients who are at risk of progressing to organ dysfunction and could be used to guide resuscitation. This article reviews the current state of knowledge of NIRS in the setting of sepsis, examining its application, validity and prognostic value. METHODS: A search of the relevant literature was performed using Medline, Embase and Cochrane databases, and a qualitative analysis was undertaken. RESULTS: A limited number of observational studies, mostly conducted among patients with severe sepsis, have shown that NIRS may correlate with severity of illness but demonstrate a variable relationship between StO2 and outcome. CONCLUSIONS: Outstanding questions still remain as to whether NIRS can help to risk-stratify patients with suspected sepsis in the emergency department and the utility of StO2 as a resuscitation target. PMID- 24154944 TI - CXCR2-mediated tumor-associated neutrophil recruitment is regulated by IFN-beta. AB - The chemokine receptor CXCR2 and its ligands CXCL1, CXCL2 and CXCL5 play an important role in homing of tumor-associated neutrophils (TANs) into developing tumors. TANs are known to support the development of blood vessels in growing solid tumors, hence contributing to tumor growth. Here, we show that the migration of neutrophils is influenced by endogenous interferon-beta (IFN-beta) via regulation of such chemokines and their receptor. We could demonstrate that CXCL1 and CXCL2 gradients are formed in tumor-bearing mice, i.e., low chemokine level in bone marrow (BM) and high level in the tumor. This supports migration of neutrophils into the tumor. Moreover, expression of CXCR2 was highest on neutrophils from BM and lowest in TANs. Importantly, although IFN-beta appears to have only a minor influence on the expression of CXCR2, it strongly regulates the CXCR2 ligands. In the absence of endogenous IFN-beta, they were expressed significantly higher in tumor-infiltrating neutrophils. Treatment of such neutrophils from tumor-bearing Ifnb1(-/-) mice with recombinant IFN-beta downregulated CXCR2 ligand expression to wild-type levels. This explains the reduced migration of neutrophils into tumors and the diminished tumor angiogenesis in IFN-beta-sufficient mice. Our results add a novel functional aspect of the type I IFN system as effector molecules of natural cancer surveillance and open interesting possibilities for antineutrophil therapies against cancer. PMID- 24154945 TI - Amide proton transfer imaging of high intensity focused ultrasound-treated tumor tissue. AB - PURPOSE: In this study, the suitability of amide proton transfer (APT) imaging as a biomarker for the characterization of high intensity focused ultrasound (HIFU) treated tumor tissue was assessed. METHODS: APT imaging was performed on tumor bearing mice before (n = 15), directly after (n = 15) and at 3 days (n = 8) after HIFU treatment. A control group (n = 7) of nontreated animals was scanned at the same time points. Histogram analysis of the tumor APT-weighted signal distributions was performed to assess HIFU-induced changes in the tumor APT contrast. RESULTS: Distinct regions of decreased APT-weighted signal were observed at both time points after HIFU treatment. Analysis of the tumor APT weighted signal distribution showed a pronounced shift toward lower APT-weighted signal values after HIFU treatment. A significantly increased fraction of pixels with an APT-weighted signal value between -10 and -2% was observed both directly (0.37 +/- 0.16) and at 3 days (0.49 +/- 0.16) after HIFU treatment as compared to baseline (0.22 +/- 0.16). CONCLUSION: The presented results show that APT imaging is sensitive to HIFU-induced changes in tumor tissue and may thus serve as a new biomarker for monitoring the response of tumor tissue to HIFU treatment. PMID- 24154946 TI - Amino and acetamide functional group effects on the ionization and fragmentation of sugar chains in positive-ion mass spectrometry. AB - To elucidate the influence of amino (-NH2) and acetamide (-NHCOCH3, -NAc) groups in sugar chains on their ionization and fragmentation, cycloamyloses (cyclodextrins, CyDs) and lacto-oligosaccharide are analyzed by MALDI TOF/TOF and ESI Q-TOF mass spectrometry. CyD derivatives substituted by amino or acetamide groups are ideal analytes to extract the function group effects, which are amino CyD with one hexosamine (HexNH2) and acetamide-CyD with one N-acetyl hexosamine (HexNAc). Interestingly, the relative ion intensities and isotope-like patterns in their product ion spectra depend on the functional groups and ion forms of sugar chains. Consequently, the results indicate that a proton (H(+)) localizes on the amino group of the amino sugar, and that the proton (H(+)) induces their fragmentation. Sodium cation (Na(+)) attachment is independent from amino group and exerts no influence on their fragmentation patterns in amino group except for mono- and disaccharide fragment ions because there is the possibility of the reducing end effect. In contrast, a sodium cation localizes much more frequently on the acetamide group in acetamide-CyDs because the chemical species with HexNAc are stable. Thus, their ions with HexNAc are abundant. These results are consistent with the fragmentation of lacto-neo-N-tetraose and maltotetraose, suggesting that a sodium cation generally localizes much more frequently on the acetamide group in sugar chains. PMID- 24154947 TI - Artificial and factitious foods support the development and reproduction of the predatory mite Amblyseius swirskii. AB - The generalist predatory mite Amblyseius swirskii Athias-Henriot (Acari: Phytoseiidae) was reared on Ephestia kuehniella Zeller eggs (Lepidoptera: Pyralidae), decapsulated dry cysts of the brine shrimp Artemia franciscana Kellogg (Anostraca: Artemiidae), and on meridic artificial diets (composed of honey, sucrose, tryptone, yeast extract, and egg yolk) supplemented with pupal hemolymph of the Chinese oak silkworm Antheraea pernyi (Guerin-Meneville) (Lepidoptera: Saturniidae) (AD1), with E. kuehniella eggs (AD2) or with A. franciscana cysts (AD3). Development, reproduction and predation capacity of the predatory mites were assessed in the first (G1) and sixth generation (G6) of rearing on the different diets. Immature survival rates in G1 were similar on all diets (96.8-100 %). After six generations, however, survival of A. swirskii was significantly reduced on all diets except on A. franciscana cysts. Oviposition rates did not differ between generations when females were fed on E. kuehniella, AD2 or AD3. The total number of deposited eggs was similar among diets except in G6 where the females fed on A. franciscana cysts produced more eggs than those maintained on E. kuehniella eggs. On most diets the intrinsic rates of increase in G1 were superior to those in G6, except for predators supplied with A. franciscana cysts where no differences were observed among generations. Female mites did not lose their capacity to kill first instar Frankliniella occidentalis (Pergande) (Thysanoptera: Thripidae) after six generations on the different diets, but predation rates in G6 on E. kuehniella were lower than in G1. In conclusion, the different factitious and artificial diets tested in the present study supported the development and reproduction of A. swirskii for a single generation but fitness losses occurred to a varying degree after several generations on E. kuehniella eggs or the artificial diets. Artificial diet enriched with A. franciscana cysts yielded better results than the other artificial diets. Amblyseius swirskii performed best on decapsulated Artemia cysts indicating their potential for use in the mass production of the predator or to sustain its populations in the crop after release. PMID- 24154949 TI - Efficient foreign gene expression in planta using a plantago asiatica mosaic virus-based vector achieved by the strong RNA-silencing suppressor activity of TGBp1. AB - Plant virus expression vectors provide a powerful tool for basic research as well as for practical applications. Here, we report the construction of an expression vector based on plantago asiatica mosaic virus (PlAMV), a member of the genus Potexvirus. Modification of a vector to enhance the expression of a foreign gene, combined with the use of the foot-and-mouth disease virus 2A peptide, allowed efficient expression of the foreign gene in two model plant species, Arabidopsis thaliana and Nicotiana benthamiana. Comparison with the widely used potato virus X (PVX) vector demonstrated that the PlAMV vector retains an inserted foreign gene for a longer period than PVX. Moreover, our results showed that the GFP expression construct PlAMV-GFP exhibits stronger RNA silencing suppression activity than PVX-GFP, which is likely to contribute to the stability of the PlAMV vector. PMID- 24154948 TI - Discovery of a new sesquiterpenoid from Phellinus ignarius with antiviral activity against influenza virus. AB - Seven natural products, including one new sesquiterpenoid (eudesm-1beta, 6alpha, 11-triol, compound 1), one ergosta -4, 6, 8(14), 22-tetraen-3-one (compound 2), four polyphenols (compounds 3, 4, 5, 6), and one pyrone (3-hydroxy-2-methyl-4 pyrone, compound 7) were isolated from cultures of Phellinus ignarius by column chromatography. The detailed structure of compound 1 was determined using a combination of one- and two-dimensional nuclear magnetic resonance, mass spectrometry and infrared spectroscopy. The antiviral activity of these compounds against H5N1 influenza A virus was investigated using an MTT colorimetric assay system in Madin-Darby canine kidney cells. The results indicate that compound 1 possesses significant ability to inhibit influenza virus. The 50 % effective concentration was 0.14 +/- 0.04 MUM. Molecular modeling further suggested that the anti-influenza virus activity of this compound was partially attributed to the interactions of hydroxyl groups with an amino acid residue (Asn 170) of neuraminidase (NA) at the binding site. Moreover, the results of enzyme inhibition assays indicated that 50 % inhibition of NA was achieved by compound 1 at a concentration of 0.657 +/- 0.325 mg/mL, which suggested that compound 1 is likely to interact with the NA enzyme. PMID- 24154950 TI - Epidemiological and genetic analysis of human group C rotaviruses isolated from outbreaks of acute gastroenteritis in Yokohama, Japan, between 2006 and 2012. AB - Group C rotavirus (GCRV) infection has been described in several parts of the world, predominantly as sporadic cases of acute gastroenteritis. Little is known about the yearly changes in the GCRV strains from diarrheal outbreaks. Stool samples collected from outbreaks of acute gastroenteritis in Yokohama, Japan, between 2006 and 2012 that were negative for norovirus, sapovirus, and group A rotavirus, were screened for GCRV using a reverse passive hemagglutination method. The GCRV strains were characterized by nucleotide sequence and phylogenetic analysis of their VP6, VP7, VP4, and NSP4 genes. Samples from nine of 735 outbreaks in Yokohama (1 %) contained GCRV, and eight of these outbreaks occurred in primary schools. The nucleotide sequences of the strains detected in this study were more closely related to Asian strains than to those from other regions of the world. The nucleotide sequences of the VP7 gene in these nine strains differed, and yearly changes were observed in the amino acid sequences of the VP4 genes. Phylogenetic trees constructed using the nucleotide sequences of the VP6, VP7, VP4, and NSP4 genes showed that sublineage S1 has divided into S1-1 and S1-2 in the VP4 gene only. Our results confirm that the prevalent strains of GCRV change yearly in Yokohama. This is the first study to demonstrate GCRV associated gastroenteritis outbreaks in Yokohama, Japan. PMID- 24154951 TI - Biological and genomic analysis of a PBSX-like defective phage induced from Bacillus pumilus AB94180. AB - Defective prophages, which are found in the genomes of many bacteria, are unable to complete a viral replication cycle and propagate in their hosts as healthy prophages. They package random DNA fragments derived from various sites of the host chromosome instead of their own genomes. In this study, we characterized a defective phage, PBP180, which was induced from Bacillus pumilus AB94180 by treatment with mitomycin C. Electron microscopy showed that the PBP180 particle has a head with a hexagonal outline of ~40 nm in diameter and a long tail. The DNA packaged in the PBP180 head consists of 8-kb DNA fragments from random portions of the host chromosome. The head and tail proteins of the PBP180 particle consist of four major proteins of approximately 49, 33, 16 and 14 kDa. The protein profile of PBP180 is different from that of PBSX, a well-known defective phage induced from Bacillus subtilis 168. A killing activity test against two susceptible strains each of B. subtilis and B. pumilus showed that the defective particles of PBP180 killed three strains other than its own host, B. pumilus AB94180, differing from the host-killing ranges of the defective phages PBSX, PBSZ (induced from B. subtilis W23), and PBSX4 (induced from B. pumilus AB94044). The genome of the PBP180 prophage, which is integrated in the B. pumilus AB94180 chromosome, is 28,205 bp in length, with 40 predicted open reading frames (ORFs). Further genomic comparison of prophages PBP180, PBSX, PBSZ and other PBSX-like prophage elements in B. pumilus strains revealed that their overall architectures are similar, but significant low homology exists in ORF29 ORF38, which presumably encode tail fiber proteins involved in recognition and killing of susceptible strains. PMID- 24154952 TI - Quantitative susceptibility mapping of kidney inflammation and fibrosis in type 1 angiotensin receptor-deficient mice. AB - Disruption of the regulatory role of the kidneys leads to diverse renal pathologies; one major hallmark is inflammation and fibrosis. Conventional magnitude MRI has been used to study renal pathologies; however, the quantification or even detection of focal lesions caused by inflammation and fibrosis is challenging. We propose that quantitative susceptibility mapping (QSM) may be particularly sensitive for the identification of inflammation and fibrosis. In this study, we applied QSM in a mouse model deficient for angiotensin receptor type 1 (AT1). This model is known for graded pathologies, including focal interstitial fibrosis, cortical inflammation, glomerulocysts and inner medullary hypoplasia. We acquired high-resolution MRI on kidneys from AT1 deficient mice that were perfusion fixed with contrast agent. Two MR sequences were used (three-dimensional spin echo and gradient echo) to produce three image contrasts: T1, T2* (magnitude) and QSM. T1 and T2* (magnitude) images were acquired to segment major renal structures and to provide landmarks for the focal lesions of inflammation and fibrosis in the three-dimensional space. The volumes of major renal structures were measured to determine the relationship of the volumes to the degree of renal abnormalities and magnetic susceptibility values. Focal lesions were segmented from QSM images and were found to be closely associated with the major vessels. Susceptibilities were relatively more paramagnetic in wild-type mice: 1.46 +/- 0.36 in the cortex, 2.14 +/- 0.94 in the outer medulla and 2.10 +/- 2.80 in the inner medulla (10(-2) ppm). Susceptibilities were more diamagnetic in knockout mice: -7.68 +/- 4.22 in the cortex, -11.46 +/- 2.13 in the outer medulla and -7.57 +/- 5.58 in the inner medulla (10(-2) ppm). This result was consistent with the increase in diamagnetic content, e.g. proteins and lipids, associated with inflammation and fibrosis. Focal lesions were validated with conventional histology. QSM was very sensitive in detecting pathology caused by small focal inflammation and fibrosis. QSM offers a new MR contrast mechanism to study this common disease marker in the kidney. PMID- 24154954 TI - Protection goals in environmental risk assessment: a practical approach. AB - Policy protection goals are set up in most countries to minimise harm to the environment, humans and animals caused by human activities. Decisions on whether to approve new agricultural products, like pesticides or genetically modified (GM) crops, take into account these policy protection goals. To support decision making, applications for approval of commercial uses of GM crops usually comprise an environmental risk assessment (ERA). These risk assessments are analytical tools, based on science, that follow a conceptual model that includes a problem formulation step where policy protection goals are considered. However, in most countries, risk assessors face major problems in that policy protection goals set in the legislation are stated in very broad terms and are too ambiguous to be directly applicable in ERAs. This means that risk assessors often have to interpret policy protection goals without clear guidance on what effects would be considered harmful. In this paper we propose a practical approach that may help risk assessors to translate policy protection goals into unambiguous (i.e., operational) protection goals and to establish relevant assessment endpoints and risk hypotheses that can be used in ERAs. Examples are provided to show how this approach can be applied to two areas of environmental concern relevant to the ERAs of GM crops. PMID- 24154955 TI - Gypsy moth caterpillar feeding has only a marginal impact on phenolic compounds in old-growth black poplar. AB - Species of the Salicaceae produce phenolic compounds that may function as anti herbivore defenses. Levels of these compounds have been reported to increase upon herbivory, but only rarely have these changes in phenolics been studied under natural conditions. We profiled the phenolics of old-growth black poplar (Populus nigra L.) and studied the response to gypsy moth (Lymantria dispar L.) herbivory in two separate field experiments. In a first experiment, foliar phenolics of 20 trees were monitored over 4 weeks after caterpillar infestation, and in a second experiment the bark and foliar phenolics of a single tree were measured over a week. Of the major groups of phenolics, salicinoids (phenolic glycosides) showed no short term response to caterpillar feeding, but after 4 weeks they declined up to 40 % in herbivore damaged and adjacent undamaged leaves on the same branch when compared to leaves of control branches. Flavonol glycosides, low molecular weight flavan-3-ols, and condensed tannins were not affected by herbivory in the first experiment. However, in the single-tree experiment, foliar condensed tannins increased by 10-20 % after herbivory, and low molecular weight flavan-3 ols decreased by 10 % in the leaves but increased by 10 % in the bark. Despite 15 % experimental leaf area loss followed by a 5-fold increase in foliar jasmonate defense hormones, we found no evidence for substantial induction of phenolic defense compounds in old growth black poplar trees growing in a native stand. Thus, if phenolics in these trees function as defenses against herbivory, our results suggest that they act mainly as constitutive defenses. PMID- 24154956 TI - F-waves in diabetes mellitus: Answers and questions. PMID- 24154957 TI - Sensory hyperinnervation and increase in NGF, TRPV1 and P2X3 expression in the epidermis following cast immobilization in rats. AB - BACKGROUND: Cast immobilization is known to induce pain in humans and experimental animal models; however, the detailed mechanisms underlying this pain have yet to be elucidated. Recently, several lines of evidence have indicated that morphological changes in sensory innervation and changes in the expression of pain-related molecules in the epidermis are related to certain painful conditions. The aim of the present study was to temporally investigate the histological changes in the glabrous skin of the rat hind paw after 1, 2 and 4 weeks of ankle joint immobilization by casting. METHODS: The von Frey test and the plantar test were performed to examine noxious sensitivity of the skin. Immunohistochemical methods were used to assess sensory nerve fibre profiles and to examine the expression of the nerve growth factor (NGF), transient receptor potential vanilloid 1 (TRPV1) and P2X3 in the epidermis. RESULTS: Cast immobilization produced a time-dependent increase in mechanical and thermal sensitivity. In the plantar skin of immobilized rats, both myelinated A fibres and unmyelinated C fibres were increased. NGF, TRPV1 and P2X3 expression levels in the epidermis were also increased. Although the level of NGF expression did not display a meaningful change throughout the immobilization period, other changes became remarkable, depending on the period of immobilization. CONCLUSIONS: The time course of the increase in peripheral nerve fibres and in the expression of TRPV1 and P2X3 paralleled the development of hypersensitivity, which suggests that histological changes of the skin following cast immobilization may have some relation to the resulting hypersensitivity. PMID- 24154959 TI - Departure from Network Equilibrium (DNE): an efficient and scalable measure of instantaneous network dynamics, with an application to magnetoencephalography. AB - The assessment of the dynamic status of a network is currently unavailable. It is important to know how far a network is away from its equilibrium (as an indicator of instability) at a moment, and over periods of time. Here, we introduce the Departure from Network Equilibrium (DNE), a new measure of instantaneous network dynamics. DNE is simple, fast to compute, and scalable with network size. We present the results of its application on white noise networks (as a basis) and on networks derived from magnetoencephalographic recordings from the human brain. PMID- 24154958 TI - Enrichment of human prostate cancer cells with tumor initiating properties in mouse and zebrafish xenografts by differential adhesion. AB - BACKGROUND: Prostate tumor-initiating cells (TICs) have intrinsic resistance to current therapies. TICs are commonly isolated by cell sorting or dye exclusion, however, isolating TICs from limited primary prostate cancer (PCa) tissues is inherently inefficient. We adapted the collagen adherence feature to develop a combined immunophenotypic and time-of-adherence assay to identify human prostate TICs. METHODS: PCa cells from multiple cell lines and primary tissues were allowed to adhere to several matrix molecules, and fractions of adherent cells were examined for their TIC properties. RESULTS: Collagen I rapidly-adherent PCa cells have significantly higher clonogenic, migration, and invasion abilities, and initiated more tumor xenografts in mice when compared to slowly-adherent and no-adherent cells. To determine the relative frequency of TICs among PCa cell lines and primary PCa cells, we utilized zebrafish xenografts to define the tumor initiation potential of serial dilutions of rapidly-adherent alpha2beta1(hi) /CD44(hi) cells compared to non-adherent cells with alpha2beta1(low) /CD44(low) phenotype. Tumor initiation from rapidly-adherent alpha2beta1(hi) /CD44(hi) TICs harboring the TMPRSS2:ERG fusion generated xenografts comprising of PCa cells expressing Erg, AMACR, and PSA. Moreover, PCa-cell dissemination was consistently observed in the immune-permissive zebrafish microenvironment from as-few-as 3 rapidly-adherent alpha2beta1(hi) /CD44(hi) cells. In zebrafish xenografts, self renewing prostate TICs comprise 0.02-0.9% of PC3 cells, 0.3-1.3% of DU145 cells, and 0.22-14.3% of primary prostate adenocarcinomas. CONCLUSION: Zebrafish PCa xenografts were used to determine that the frequency of prostate TICs varies among PCa cell lines and primary PCa tissues. These data support a paradigm of utilizing zebrafish xenografts to evaluate novel therapies targeting TICs in prostate cancer. PMID- 24154960 TI - Phytochemicals in fruits of Hawaiian wild cranberry relatives. AB - BACKGROUND: Cranberries (Vaccinium macrocarpon Ait.) contain high levels of phytochemicals such as proanthocyanidins (PACs). These polymeric condensations of flavan-3-ol monomers are associated with health benefits. Our objective was to evaluate phytochemicals in fruit from Hawaiian cranberry relatives, V. reticulatum Sm. and V. calycinum Sm. Normal-phase HPLC coupled with fluorescence and ESI-MS detected PACs; the colorimetric 4-dimethylaminocinnamaldehyde (DMAC) assay was used to determine total PACs. Spectrophotometric tests and reverse phase HPLC coupled to photodiode array and refractive index detectors evaluated phenolics, sugars, and organic acids. Antioxidant capacity was determined by the ORAC and FRAP assays. RESULTS: Antioxidant capacities of Hawaiian berries were high. The FRAP measurement for V. calycinum was 454.7 +/- 90.2 umol L(-1) Trolox equivalents kg(-1) for pressed fruit. Hawaiian berries had lower peonidin, quinic and citric acids amounts and invert (~1) glucose/fructose ratio compared with cranberry. Both Hawaiian Vaccinium species were good sources of PACs; they contained phenolics and PAC monomers, A and B-type trimers, tetramers and larger polymers. Vaccinium reticulatum and V. calycinum showed comparable or higher PAC levels than in cranberry. Cranberries had higher percentage of A-type dimers than did V. reticulatum. A and B-type dimers were not differentiated in V. calycinum. The total PACs (as measured by DMAC) for V. calycinum (24.3 +/- 0.10 mg catechin equivalents kg(-1) ) were about twice that in cranberry. CONCLUSION: Berries of V. reticulatum and V. calycinum could serve as a rich dietary source of PACs, comparable to or greater than cranberries. These finding suggest that Hawaiian Vaccinium berries could be a functional food. Additional examination of the phytochemicals in other wild Vaccinium species is warranted. PMID- 24154961 TI - Distribution of TERT promoter mutations in pediatric and adult tumors of the nervous system. AB - Hot spot mutations in the promoter region of telomerase reverse transcriptase (TERT) have recently been described in several human tumor entities. These mutations result in an upregulation of the telomerase complex activity and thus constitute a relevant mechanism for immortalization of tumor cells. Knowledge of the TERT promoter status in tumors is likely to be of interest for molecular classification and as a potential target for therapy. We, therefore, performed a systematic analysis of TERT promoter mutations in 1,515 tumors of the human nervous system and its coverings including 373 pediatric and 1,142 adult patients. We detected a total of 327 mutations. TERT promoter mutations were exceedingly rare in tumors typically encountered in pediatric patients. In entities typically encountered in adult patients TERT promoter mutations were strongly associated with older age (p < 0.0001). Highest mutation frequencies were detected in gliosarcomas (81 %), oligodendrogliomas (78 %), oligoastrocytomas (58 %), primary glioblastomas (54 %), and solitary fibrous tumors (50 %). Related to other molecular alterations, TERT promoter mutations were strongly associated with 1p/19q loss (p < 0.0001), but inversely associated with loss of ATRX expression (p < 0.0001) and IDH1/IDH2 mutations (p < 0.0001). TERT promoter mutations are typically found in adult patients and occur in a highly tumor type-associated distribution. PMID- 24154963 TI - Alzheimer's disease biomarkers: walk with deliberate haste, don't run blithely on? PMID- 24154964 TI - Cyclic loading of growing tissue in a bioreactor: mathematical model and asymptotic analysis. AB - A simplified 2D mathematical model for tissue growth within a cyclically-loaded tissue engineering scaffold is presented and analyzed. Such cyclic loading has the potential to improve yield and functionality of tissue such as bone and cartilage when grown on a scaffold within a perfusion bioreactor. The cyclic compression affects the flow of the perfused nutrient, leading to flow properties that are inherently unsteady, though periodic, on a timescale short compared with that of tissue proliferation. A two-timescale analysis based on these well separated timescales is exploited to derive a closed model for the tissue growth on the long timescale of proliferation. Some sample numerical results are given for the final model, and discussed. PMID- 24154962 TI - Glioblastomas are composed of genetically divergent clones with distinct tumourigenic potential and variable stem cell-associated phenotypes. AB - Glioblastoma (GBM) is known to be a heterogeneous disease; however, the genetic composition of the cells within a given tumour is only poorly explored. In the advent of personalised medicine the understanding of intra-tumoural heterogeneity at the cellular and the genetic level is mandatory to improve treatment and clinical outcome. By combining ploidy-based flow sorting with array-comparative genomic hybridization we show that primary GBMs present as either mono- or polygenomic tumours (64 versus 36%, respectively). Monogenomic tumours were limited to a pseudodiploid tumour clone admixed with normal stromal cells, whereas polygenomic tumours contained multiple tumour clones, yet always including a pseudodiploid population. Interestingly, pseudodiploid and aneuploid fractions carried the same aberrations as defined by identical chromosomal breakpoints, suggesting that evolution towards aneuploidy is a late event in GBM development. Interestingly, while clonal heterogeneity could be recapitulated in spheroid-based xenografts, we find that genetically distinct clones displayed different tumourigenic potential. Moreover, we show that putative cancer stem cell markers including CD133, CD15, A2B5 and CD44 were present on genetically distinct tumour cell populations. These data reveal the clonal heterogeneity of GBMs at the level of DNA content, tumourigenic potential and stem cell marker expression, which is likely to impact glioma progression and treatment response. The combined knowledge of intra-tumour heterogeneity at the genetic, cellular and functional level is crucial to assess treatment responses and to design personalized treatment strategies for primary GBM. PMID- 24154965 TI - Prevalence and spectrum of sexual abuse among adolescents in Kerala, South India. AB - OBJECTIVE: To study the prevalence and spectrum of sexual abuse among adolescents in Kerala, South India. METHODS: A self- report survey was conducted among adolescents in the 15-19 y age group, studying in the plus one and plus two classes in selected schools. RESULTS: Of the 1614 respondents (688 boys and 926 girls), 36 % of boys and 35 % of girls had experienced sexual abuse at some point during their lifetime. Most instances were sexual advances while using public transport. Feelings of insecurity and isolation at home, of being disliked by parents and of being depressed were significantly more in adolescents who had experienced sexual abuse, compared to those who had not. CONCLUSIONS: Sexual abuse is widely prevalent and both boys and girls are equally susceptible. There is a need to evolve strategies to protect children from sexual abuse and the programmes should address both boys and girls. PMID- 24154953 TI - Psychosocial interventions for supporting women to stop smoking in pregnancy. AB - BACKGROUND: Tobacco smoking in pregnancy remains one of the few preventable factors associated with complications in pregnancy, stillbirth, low birthweight and preterm birth and has serious long-term implications for women and babies. Smoking in pregnancy is decreasing in high-income countries, but is strongly associated with poverty and increasing in low- to middle-income countries. OBJECTIVES: To assess the effects of smoking cessation interventions during pregnancy on smoking behaviour and perinatal health outcomes. SEARCH METHODS: In this fifth update, we searched the Cochrane Pregnancy and Childbirth Group's Trials Register (1 March 2013), checked reference lists of retrieved studies and contacted trial authors to locate additional unpublished data. SELECTION CRITERIA: Randomised controlled trials, cluster-randomised trials, randomised cross-over trials, and quasi-randomised controlled trials (with allocation by maternal birth date or hospital record number) of psychosocial smoking cessation interventions during pregnancy. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed trials for inclusion and trial quality, and extracted data. Direct comparisons were conducted in RevMan, and subgroup analyses and sensitivity analysis were conducted in SPSS. MAIN RESULTS: Eighty-six trials were included in this updated review, with 77 trials (involving over 29,000 women) providing data on smoking abstinence in late pregnancy.In separate comparisons, counselling interventions demonstrated a significant effect compared with usual care (27 studies; average risk ratio (RR) 1.44, 95% confidence interval (CI) 1.19 to 1.75), and a borderline effect compared with less intensive interventions (16 studies; average RR 1.35, 95% CI 1.00 to 1.82). However, a significant effect was only seen in subsets where counselling was provided in conjunction with other strategies. It was unclear whether any type of counselling strategy is more effective than others (one study; RR 1.15, 95% CI 0.86 to 1.53). In studies comparing counselling and usual care (the largest comparison), it was unclear whether interventions prevented smoking relapse among women who had stopped smoking spontaneously in early pregnancy (eight studies; average RR 1.06, 95% CI 0.93 to 1.21). However, a clear effect was seen in smoking abstinence at zero to five months postpartum (10 studies; average RR 1.76, 95% CI 1.05 to 2.95), a borderline effect at six to 11 months (six studies; average RR 1.33, 95% CI 1.00 to 1.77), and a significant effect at 12 to 17 months (two studies, average RR 2.20, 95% CI 1.23 to 3.96), but not in the longer term. In other comparisons, the effect was not significantly different from the null effect for most secondary outcomes, but sample sizes were small.Incentive-based interventions had the largest effect size compared with a less intensive intervention (one study; RR 3.64, 95% CI 1.84 to 7.23) and an alternative intervention (one study; RR 4.05, 95% CI 1.48 to 11.11).Feedback interventions demonstrated a significant effect only when compared with usual care and provided in conjunction with other strategies, such as counselling (two studies; average RR 4.39, 95% CI 1.89 to 10.21), but the effect was unclear when compared with a less intensive intervention (two studies; average RR 1.19, 95% CI 0.45 to 3.12).The effect of health education was unclear when compared with usual care (three studies; average RR 1.51, 95% CI 0.64 to 3.59) or less intensive interventions (two studies; average RR 1.50, 95% CI 0.97 to 2.31).Social support interventions appeared effective when provided by peers (five studies; average RR 1.49, 95% CI 1.01 to 2.19), but the effect was unclear in a single trial of support provided by partners.The effects were mixed where the smoking interventions were provided as part of broader interventions to improve maternal health, rather than targeted smoking cessation interventions.Subgroup analyses on primary outcome for all studies showed the intensity of interventions and comparisons has increased over time, with higher intensity interventions more likely to have higher intensity comparisons. While there was no significant difference, trials where the comparison group received usual care had the largest pooled effect size (37 studies; average RR 1.34, 95% CI 1.25 to 1.44), with lower effect sizes when the comparison group received less intensive interventions (30 studies; average RR 1.20, 95% CI 1.08 to 1.31), or alternative interventions (two studies; average RR 1.26, 95% CI 0.98 to 1.53). More recent studies included in this update had a lower effect size (20 studies; average RR 1.26, 95% CI 1.00 to 1.59), I(2)= 3%, compared to those in the previous version of the review (50 studies; average RR 1.50, 95% CI 1.30 to 1.73). There were similar effect sizes in trials with biochemically validated smoking abstinence (49 studies; average RR 1.43, 95% CI 1.22 to 1.67) and those with self-reported abstinence (20 studies; average RR 1.48, 95% CI 1.17 to 1.87). There was no significant difference between trials implemented by researchers (efficacy studies), and those implemented by routine pregnancy staff (effectiveness studies), however the effect was unclear in three dissemination trials of counselling interventions where the focus on the intervention was at an organisational level (average RR 0.96, 95% CI 0.37 to 2.50). The pooled effects were similar in interventions provided for women with predominantly low socio-economic status (44 studies; average RR 1.41, 95% CI 1.19 to 1.66), compared to other women (26 studies; average RR 1.47, 95% CI 1.21 to 1.79); though the effect was unclear in interventions among women from ethnic minority groups (five studies; average RR 1.08, 95% CI 0.83 to 1.40) and aboriginal women (two studies; average RR 0.40, 95% CI 0.06 to 2.67). Importantly, pooled results demonstrated that women who received psychosocial interventions had an 18% reduction in preterm births (14 studies; average RR 0.82, 95% CI 0.70 to 0.96), and infants born with low birthweight (14 studies; average RR 0.82, 95% CI 0.71 to 0.94). There did not appear to be any adverse effects from the psychosocial interventions, and three studies measured an improvement in women's psychological wellbeing. AUTHORS' CONCLUSIONS: Psychosocial interventions to support women to stop smoking in pregnancy can increase the proportion of women who stop smoking in late pregnancy, and reduce low birthweight and preterm births. PMID- 24154966 TI - Influence of manganese on apoptosis and glutathione content of cumulus cells during in vitro maturation in bovine oocytes. AB - We have investigated the effect of different Mn concentrations on (1) DNA integrity of cumulus cells by olive tail moment (OTM); (2) cumulus cells apoptosis by Annexin V staining assay; (3) intracellular total glutathione (GSH GSSG) content; and (4) oocyte nuclear maturation and embryo cleavage after in vitro fertilisation (IVF). For this purpose, 0 (control), 2 (Mn1), 5 (Mn2) and 6 ng/mL (Mn3) Mn concentrations were added to IVM medium. Comet assay analysed by OTM was significantly higher in cumulus cells arising from COCs matured without Mn (control, P < 0.01) respect to cumulus cells obtained from COCs matured with Mn (control: 5.18 +/- 2.3; Mn1: 2.93 +/- 2.2; Mn2: 2.63 +/- 2.4; Mn3: 2.92 +/- 2.4). The frequency of apoptotic cells was higher in the control group (control: 6.63 +/- 0.59; Mn1: 5.05 +/- 0.5; Mn2: 4.61 +/- 0.49; Mn3: 3.33 +/- 0.42). Intracellular concentration of GSH-GSSG increased in oocytes and cumulus cells matured in the presence of Mn (P < 0.01). There were no differences in percentages of nuclear maturation when Mn was added to IVM medium at any concentration, but at 6 ng/mL Mn a higher cleavage rate was observed respect to the control group (P < 0.05). In conclusion, deficiency in Mn concentration during in vitro maturation increased the damage in the DNA molecule and the frequency of apoptotic cumulus cells. However, the addition of an adequate Mn concentration (6 ng/mL Mn) to IVM medium improved the health of cumulus-oocyte complexes and produced more cleaved embryos 48 h after IVF. PMID- 24154967 TI - A conserved C-terminal sequence of high-risk cutaneous beta-human papillomavirus E6 proteins alters localization and signalling of beta1-integrin to promote cell migration. AB - Beta-human papillomaviruses (beta-HPV) infect cutaneous epithelia, and accumulating evidence suggests that the virus may act as a co-factor with UV induced DNA damage in the development and progression of non-melanoma skin cancer, although the molecular mechanisms involved are poorly understood. The E6 protein of cutaneous beta-HPV types encodes functions consistent with a role in tumorigenesis, and E6 expression can result in papilloma formation in transgenic animals. The E6 proteins of high-risk alpha-HPV types, which are associated with the development of anogenital cancers, have a conserved 4 aa motif at their extreme C terminus that binds to specific PDZ domain-containing proteins to promote cell invasion. Likewise, the high-risk beta-HPVs HPV5 and HPV8 E6 proteins also share a conserved C-terminal motif, but this is markedly different from that of alpha-HPV types, implying functional differences. Using binding and functional studies, we have shown that beta-HPV E6 proteins target beta1-integrin using this C-terminal motif. E6 expression reduced membrane localization of beta1 integrin, but increased overall levels of beta1-integrin protein and its downstream effector focal adhesion kinase in human keratinocytes. Altered beta1 integrin localization due to E6 expression was associated with actin cytoskeleton rearrangement and increased cell migration that was abolished by point mutations in the C-terminal motif of E6. We concluded that modulation of beta1-integrin signalling by E6 proteins may contribute towards the pathogenicity of these beta HPV types. PMID- 24154972 TI - A dissociation of performance and awareness during binocular rivalry. AB - When conflicting stimuli are presented to equivalent locations in each eye, people experience binocular rivalry, a phenomenon characterized by alternations in conscious awareness of each eye's image. Attempts at objective measurement using monocular probe-detection methods show that sensitivity to probe stimuli is reduced during periods when those stimuli are reportedly suppressed. But are observers really able to detect stimuli that are perceptually invisible, or does the probe presentation itself reverse rivalry dominance between the two eyes? Here, we measured both judgment accuracy and confidence in those judgments across multiple probe contrast levels, and we found evidence for high accuracy with reduced awareness during suppression that was not due to probe-induced switches in rivalry dominance. This dissociation points to the existence of blindsight like behavior in normal observers. PMID- 24154974 TI - On some problems of inorganic supramolecular chemistry. AB - In this study, some features that distinguish inorganic supramolecular host-guest objects from traditional architectures are considered. Crystalline inorganic supramolecular structures are the basis for the development of new functional materials. Here, the possible changes in the mechanism of crystalline inorganic supramolecular structure self-organization at high interaction potentials are discussed. The cases of changes in the host structures and corresponding changes in the charge states under guest intercalation, as well as their impact on phase stability and stoichiometry are considered. It was demonstrated that the deviation from the geometrical and topological complementarity conditions may be due to the additional energy gain from forming inorganic supramolecular structures. It has been assumed that molecular recognition principles can be employed for the development of physicochemical analysis and interpretation of metastable states in inorganic crystalline alloys. PMID- 24154973 TI - Identification of genes expressed by immune cells of the colon that are regulated by colorectal cancer-associated variants. AB - A locus on human chromosome 11q23 tagged by marker rs3802842 was associated with colorectal cancer (CRC) in a genome-wide association study; this finding has been replicated in case-control studies worldwide. In order to identify biologic factors at this locus that are related to the etiopathology of CRC, we used microarray-based target selection methods, coupled to next-generation sequencing, to study 103 kb at the 11q23 locus. We genotyped 369 putative variants from 1,030 patients with CRC (cases) and 1,061 individuals without CRC (controls) from the Ontario Familial Colorectal Cancer Registry. Two previously uncharacterized genes, COLCA1 and COLCA2, were found to be co-regulated genes that are transcribed from opposite strands. Expression levels of COLCA1 and COLCA2 transcripts correlate with rs3802842 genotypes. In colon tissues, COLCA1 co localizes with crystalloid granules of eosinophils and granular organelles of mast cells, neutrophils, macrophages, dendritic cells and differentiated myeloid derived cell lines. COLCA2 is present in the cytoplasm of normal epithelial, immune and other cell lineages, as well as tumor cells. Tissue microarray analysis demonstrates the association of rs3802842 with lymphocyte density in the lamina propria (p = 0.014) and levels of COLCA1 in the lamina propria (p = 0.00016) and COLCA2 (tumor cells, p = 0.0041 and lamina propria, p = 6 * 10(-5)). In conclusion, genetic, expression and immunohistochemical data implicate COLCA1 and COLCA2 in the pathogenesis of colon cancer. Histologic analyses indicate the involvement of immune pathways. PMID- 24154975 TI - Detection of Cancer Cell Death Mediated by a Synthetic Granzyme B-like Peptide Fluorescent Conjugate and the same Peptide Binding in Bacteria. AB - Granzyme-mediated apoptosis, supported by pore-forming perforin, plays an important role in CD8+ T lymphocytes (CTL)-dependent cellular immunity protection against both cancer and viral infection. Quantitative and qualitative problems with CTL are potential contributing factors to disease progression. The feasibility of developing CTL-independent cellular immunity is desired but must first overcome the barrier of CTL-independent target cell recognition. Granzyme B with its strong pro-apoptotic activity in many different target cells is investigated for use in the CTL-independent cellular immunity approach, and granzyme B or its bioactive peptides without the enzymatic activity are more desirable for use. Native granzyme B with enzymatic activity is usually investigated in cancer cells for its mediation of apoptosis by detection of DNA fragmentation. Detection of cell death mediated by such peptides in cancer cells is needed to demonstrate the potential therapeutic purposes. We show with never before-seen microscopic images using fluorescence microscopy that a synthetic granzyme B-like peptide fluorescent conjugate (GP1R) can: 1) mediate cell death of different cancer cells via membrane extrusion, 2) bind to constitutively expressed binding targets in different cancer cells and bacteria, and 3) promote bacterial phagocytosis. The putative binding targets may serve as a universal pathologic biomarker detectable by GP1R. Our data taken together demonstrate the potential applications of GP1R for use in CTL-independent target cell recognition and target cell death induction. It may lead to development of rapid targeted detection and new treatment of cancer, viral and bacterial infections. The new treatment may show mutual benefits for two or more diseases. PMID- 24154976 TI - Effect of salt-tolerant yeast of Candida versatilis and Zygosaccharomyces rouxii on the production of biogenic amines during soy sauce fermentation. AB - BACKGROUND: This study aimed to enhance and improve the quality and safety of soy sauce. In the present work, the change of biogenic amines, such as histamine, tyramine, cadaverine, spermidine, was examined by the treatment of Candida versatilis and Zygosaccharomyces rouxii, and the influence of salt-tolerant yeast on biogenic amines was analysed during the whole fermentation process. RESULTS: The results showed that the content of biogenic amines was elevated after yeast treatment and the content of biogenic amines was influenced by using yeast. The dominating biogenic amine in soy sauce was tyramine. At the end of fermentation, the concentrations of biogenic amines produced by Zygosaccharomyces rouxii and Candida versatilis in the soy mash were 122.71 mg kg(-1) and 69.96 mg kg(-1) . CONCLUSIONS: The changes of biogenic amines in high-salt liquid soy mash during fermentation process indicated that a variety of biogenic amines were increased in the fermentation ageing period, which may be due to amino acid decarboxylation to form biogenic amines by yeast decarboxylase. The fermentation period of soy sauce should be longer than 5 months because biogenic amines began to decline after this time period. PMID- 24154977 TI - Vitamin C for asthma and exercise-induced bronchoconstriction. AB - BACKGROUND: Dietary antioxidants, such as vitamin C, in the epithelial lining and lining fluids of the lung may be beneficial in the reduction of oxidative damage (Arab 2002). They may therefore be of benefit in reducing symptoms of inflammatory airway conditions such as asthma, and may also be beneficial in reducing exercise-induced bronchoconstriction, which is a well-recognised feature of asthma and is considered a marker of airways inflammation. However, the association between dietary antioxidants and asthma severity or exercise-induced bronchoconstriction is not fully understood. OBJECTIVES: To examine the effects of vitamin C supplementation on exacerbations and health-related quality of life (HRQL) in adults and children with asthma or exercise-induced bronchoconstriction compared to placebo or no vitamin C. SEARCH METHODS: We identified trials from the Cochrane Airways Group's Specialised Register (CAGR). The Register contains trial reports identified through systematic searches of a number of bibliographic databases, and handsearching of journals and meeting abstracts. We also searched trial registry websites. The searches were conducted in December 2012. SELECTION CRITERIA: We included randomised controlled trials (RCTs). We included both adults and children with a diagnosis of asthma. In separate analyses we considered trials with a diagnosis of exercise-induced bronchoconstriction (or exercise-induced asthma). We included trials comparing vitamin C supplementation with placebo, or vitamin C supplementation with no supplementation. We included trials where the asthma management of both treatment and control groups provided similar background therapy. The primary focus of the review is on daily vitamin C supplementation to prevent exacerbations and improve HRQL. The short-term use of vitamin C at the time of exacerbations or for cold symptoms in people with asthma are outside the scope of this review. DATA COLLECTION AND ANALYSIS: Two review authors independently screened the titles and abstracts of potential studies, and subsequently screened full text study reports for inclusion. We used standard methods expected by The Cochrane Collaboration. MAIN RESULTS: A total of 11 trials with 419 participants met our inclusion criteria. In 10 studies the participants were adults and only one was in children. Reporting of study design was inadequate to determine risk of bias for most of the studies and poor availability of data for our key outcomes may indicate some selective outcome reporting. Four studies were parallel-group and the remainder were cross-over studies. Eight studies included people with asthma and three studies included 40 participants with exercise-induced asthma. Five studies reported results using single-dose regimes prior to bronchial challenges or exercise tests. There was marked heterogeneity in vitamin C dosage regimes used in the selected studies, compounding the difficulties in carrying out meaningful analyses.One study on 201 adults with asthma reported no significant difference in our primary outcome, health-related quality of life (HRQL), and overall the quality of this evidence was low. There were no data available to evaluate the effects of vitamin C supplementation on our other primary outcome, exacerbations in adults. One small study reported data on asthma exacerbations in children and there were no exacerbations in either the vitamin C or placebo groups (very low quality evidence). In another study conducted in 41 adults, exacerbations were not defined according to our criteria and the data were not available in a format suitable for evaluation by our methods. Lung function and symptoms data were contributed by single studies. We rated the quality of this evidence as moderate, but further research is required to assess any clinical implications that may be related to the changes in these parameters. In each of these outcomes there was no significant difference between vitamin C and placebo. No adverse events at all were reported; again this is very low quality evidence.Studies in exercise induced bronchoconstriction suggested some improvement in lung function measures with vitamin C supplementation, but theses studies were few and very small, with limited data and we judged the quality of the evidence to be low. AUTHORS' CONCLUSIONS: Currently, evidence is not available to provide a robust assessment on the use of vitamin C in the management of asthma or exercise-induced bronchoconstriction. Further research is very likely to have an important impact on our confidence in the estimates of effect and is likely to change the estimates. There is no indication currently that vitamin C can be recommended as a therapeutic agent in asthma. There was some indication that vitamin C was helpful in exercise-induced breathlessness in terms of lung function and symptoms; however, as these findings were provided only by small studies they are inconclusive. Most published studies to date are too small and inconsistent to provide guidance. Well-designed trials with good quality clinical endpoints, such as exacerbation rates and health-related quality of life scores, are required. PMID- 24154978 TI - Reply: To PMID 24155028. PMID- 24154979 TI - Fusarial wilt control and growth promotion of pigeon pea through bioactive metabolites produced by two plant growth promoting rhizobacteria. AB - The bioactive metabolites produced by two plant growth promoting rhizobacteria strains, a Pseudomonas aeruginosa strain RRLJ 04 and a Bacillus cereus strain BS 03, which showed growth promotion and disease control in pigeon pea against Fusarium udum, were isolated and screened for their efficacy to control fusarial wilt of pigeon pea under gnotobiotic and nursery condition. Bioactive metabolites viz., BM 1 and BM 2 from RRLJ 04 and BM 3 from BS 03 also showed in vitro antibiosis against F. udum. Seeds treated with 50 MUl seed-1 of BM 1, 30 MUl seed 1 of BM 2 and 70 MUl seed-1 of BM 3 and grown in pathogen infested soil showed suppression of wilt disease besides growth enhancement. Per cent disease control was 90 % with BM 2 application as compared to 87 and 83 %, respectively in BM 1 and BM 3 after 90 days of growth. BM 2 treated plants were more resistant to the pathogen as compared to the other fractions tested. Mycelial dry weight was found to be reduced on treatment with the bioactive metabolites. Formation of chlamydospore-like structures was observed in the pathogen mycelium treated with BM 3. The analytical studies confirmed that two of these metabolites are phenazine derivatives. PMID- 24154980 TI - The epigenetic basis of behavioral phenotypes: is there reason for continued optimism? PMID- 24154981 TI - Screening for cardiac HERG potassium channel interacting proteins using the yeast two-hybrid technique. AB - The human ERG protein (HERG or Kv 11.1) encoded by the human ether-a-go-go related gene (herg) is the pore-forming subunit of the cardiac delayed rectifier potassium current (IKr) responsible for action potential (AP) repolarization. Mutations in HERG lead to long-QT syndrome, a major cause of arrhythmias. Protein protein interactions are fundamental for ion channel trafficking, membrane localization, and functional modulation. To identify proteins involved in the regulation of the HERG channel, we conducted a yeast two-hybrid screen of a human heart cDNA library using the C-terminus or N-terminus of HERG as bait. Fifteen proteins were identified as HERG amino terminal (HERG-NT)-interacting proteins, including Caveolin-1 (a membrane scaffold protein with multiple interacting partners, including G-proteins, kinases and NOS), the zinc finger protein, FHL2 and PTPN12 (a non-receptor tyrosine phosphatase). Eight HERG carboxylic terminal (HERG-CT)-interacting proteins were also identified, including the NF-kappaB interacting protein myotrophin, We have identified multiple potential interacting proteins that may regulate cardiac IKr through cytoskeletal interactions, G protein modulation, phosphorylation and downstream second messenger and transcription cascades. These findings provide further insight into dynamic modulation of HERG under physiological conditions and arrhythmogenesis. PMID- 24154982 TI - The production effect in paired-associate learning: benefits for item and associative information. AB - In five experiments, we extended the production effect-better memory for items said aloud than for items read silently-to paired-associate learning, the goal being to explore whether production enhances associative information in addition to enhancing item information. In Experiments 1 and 2, we used a semantic relatedness task in addition to the production manipulation and found no evidence of a production effect, whether the measure was cued recall or item recognition. Experiment 3 showed that the semantic-relatedness task had overshadowed the production effect; the effect was present when the semantic-relatedness task was removed, again whether cued recall or item recognition was the measure. Experiments 4 and 5 provided further evidence that production can enhance recall for word pairs and, using an associate recognition test with intact versus rearranged pairs, indicated that production may also enhance associative information. That production boosts memory for both types of information is considered in terms of distinctive encoding. PMID- 24154984 TI - Valproyl-CoA inhibits the activity of ATP- and GTP-dependent succinate:CoA ligases. AB - BACKGROUND: Valproic acid (VPA) is an effective antiepileptic drug that may induce progressive microvesicular steatosis. The impairment of mitochondrial function may be an important metabolic effect of VPA treatment with potential adverse consequences. OBJECTIVE: To investigate the influence of VPA on the activity of GTP- and ATP-specific succinate:CoA ligases (G-SUCL and A-SUCL). METHODS: The GTP- and ATP-specific SUCL activities were measured in human fibroblasts in the reverse direction, i.e. the formation of succinyl-CoA. These were assessed at different concentrations of succinate in the presence of VPA, valproyl-CoA and zinc chloride, an established inhibitor of the enzymes. Activities were measured using an optimized HPLC procedure. RESULTS: Valproyl-CoA (1 mM) inhibited the activity of A-SUCL and G-SUCL by 45-55% and 25-50%, respectively. VPA (1 mM) had no influence on the activity of the two enzymes. DISCUSSION: Valproyl-CoA appears to affect the activity of SUCL, especially with the ATP-specific enzyme. Considering the key role of SUCL in the Krebs cycle, interference with its activity might impair the cellular energy status. Moreover, A-SUCL is bound to the nucleoside diphosphate kinase (NDPK), which is responsible for the mitochondrial (deoxy)nucleotide synthesis. An inhibition of A-SUCL might influence the activity of NDPK inducing an imbalance of nucleotides in the mitochondria and eventually mitochondrial DNA depletion. This may account for the potential liver failure associated with valproate therapy, reported in patients with deficiencies within the mitochondrial DNA replicase system such as polymerase gamma 1. PMID- 24154985 TI - Camurati-Engelmann disease (progressive diaphyseal dysplasia): reports of an Indian kindred. AB - Camurati-Engelmann disease (CED, OMIM 131300), or progressive diaphyseal dysplasia, is a rare autosomal dominant skeletal dysplasia, caused by mutations in the transforming growth factor-beta1 (TGFbeta1) gene. We describe the first Indian CED family with genetic confirmation and presenting manifestations. The proband is a 17-year-old woman who presented with lower limb pain and proximal muscle weakness. Skeletal radiographs of the long bones revealed cortical, periosteal, and endosteal thickenings, predominantly affecting the diaphyses of the long bones. On detailed evaluation, there was a strong family history of bone disorder with similar symptoms of pain and radiological findings in several family members. Exon sequencing of the TGFbeta1 gene was performed in available family members. Based on clinical and radiographic studies and its familial nature, a diagnosis of CED was made and confirmed by mutation analysis. A heterozygous G to A transition in exon 4 of the TGFbeta1 gene (R218H) was detected in 5 out of 10 available family members, including 4 affecteds and 1 asymptomatic individual. Many of our affected individuals responded to glucocorticoids and cortical windowing. CED is a rare genetic disease with variable clinical manifestations and incomplete penetrance. CED needs to be considered in the differential diagnosis of nonspecific limb pain and waddling gait in all young individuals. PMID- 24154986 TI - CRAFT (complete reduction to amplitude frequency table)--robust and time efficient Bayesian approach for quantitative mixture analysis by NMR. AB - The intrinsic quantitative nature of NMR is increasingly exploited in areas ranging from complex mixture analysis (as in metabolomics and reaction monitoring) to quality assurance/control. Complex NMR spectra are more common than not, and therefore, extraction of quantitative information generally involves significant prior knowledge and/or operator interaction to characterize resonances of interest. Moreover, in most NMR-based metabolomic experiments, the signals from metabolites are normally present as a mixture of overlapping resonances, making quantification difficult. Time-domain Bayesian approaches have been reported to be better than conventional frequency-domain analysis at identifying subtle changes in signal amplitude. We discuss an approach that exploits Bayesian analysis to achieve a complete reduction to amplitude frequency table (CRAFT) in an automated and time-efficient fashion - thus converting the time-domain FID to a frequency-amplitude table. CRAFT uses a two-step approach to FID analysis. First, the FID is digitally filtered and downsampled to several sub FIDs, and secondly, these sub FIDs are then modeled as sums of decaying sinusoids using the Bayesian approach. CRAFT tables can be used for further data mining of quantitative information using fingerprint chemical shifts of compounds of interest and/or statistical analysis of modulation of chemical quantity in a biological study (metabolomics) or process study (reaction monitoring) or quality assurance/control. The basic principles behind this approach as well as results to evaluate the effectiveness of this approach in mixture analysis are presented. PMID- 24154987 TI - Combining self-affirmation and implementation intentions: evidence of detrimental effects on behavioral outcomes. AB - BACKGROUND: There is limited evidence that self-affirmation manipulations can promote health behavior change. PURPOSE: The purpose of this study was to explore whether the efficacy of a self-affirmation manipulation at promoting exercise could be enhanced by an implementation intention intervention. METHODS: Participants (Study 1 N = 120, Study 2 N = 116) were allocated to one of four conditions resulting from the two (self-affirmation manipulation: no affirmation, affirmation) by two (implementation intention manipulation: no implementation intention, implementation intention) experimental design. Exercise behavior was assessed 1 week post-intervention. RESULTS: Contrary to prediction, those participants receiving both manipulations were significantly less likely to increase the amount they exercised compared to those receiving only the self affirmation manipulation. CONCLUSION: Incorporating an implementation intention manipulation alongside a self-affirmation manipulation had a detrimental effect on exercise behavior; participants receiving both manipulations exercised significantly less in the week following the intervention. PMID- 24154988 TI - Structural stigma and hypothalamic-pituitary-adrenocortical axis reactivity in lesbian, gay, and bisexual young adults. AB - BACKGROUND: Youth exposed to extreme adverse life conditions have blunted cortisol responses to stress. PURPOSE: This study aims to examine whether growing up in highly stigmatizing environments similarly shapes stigmatized individuals' physiological responses to identity-related stress. METHODS: We recruited 74 lesbian, gay, and bisexual young adults (mean age = 23.68) from 24 states with varying levels of structural stigma surrounding homosexuality. State-level structural stigma was coded based on several dimensions, including policies that exclude sexual minorities from social institutions (e.g., same-sex marriage). Participants were exposed to a laboratory stressor, the Trier Social Stress Test (TSST), and neuroendocrine measures were collected. RESULTS: Lesbian, gay, and bisexual young adults who were raised in highly stigmatizing environments as adolescents evidenced a blunted cortisol response following the TSST compared to those from low-stigma environments. CONCLUSIONS: The stress of growing up in environments that target gays and lesbians for social exclusion may exert biological effects that are similar to traumatic life experiences. PMID- 24154989 TI - Performance of maximum number of repetitions with cluster-set configuration. AB - PURPOSE: To analyze performance during the execution of a maximum number of repetitions (MNR) in a cluster-set configuration. METHOD: Nine judokas performed 2 sessions of parallel squats with a load corresponding to 4-repetition maximum (4RM) with a traditional-training (TT) and cluster-training (CT) set configuration. The TT consisted of 3 sets of repetitions leading to failure and 3 min of rest between sets. In the CT the MNR was performed with a rest interval between repetitions (45.44 +/- 11.89 s). The work-to-rest ratio was similar for CT and TT. RESULTS: MNR in CT was 45.5 +/- 32 repetitions and was 9.33 +/- 1.87 times the volume in TT. There was a tendency for the average mean propulsive velocity (MPV) to be higher in CT (0.39 +/- 0.04 vs 0.36 +/- 0.04 m/s for CT and TT, respectively, P = .054, standardized mean difference [d] = 0.57). The average MPV was higher in CT for a similar number of repetitions (0.44 +/- 0.08 vs 0.36 +/- 0.04 m/s for CT and TT, respectively, P = .006, d = 1.33). The number of repetitions in TT was correlated with absolute 4RM load (r = -.719, P = .031) but not in CT (r = -.273, P = .477). CONCLUSIONS: A cluster-set configuration allows for a higher number of repetitions and improved sustainability of mechanical performance. CT, unlike TT, was not affected by absolute load, suggesting an improvement of training volume with high absolute loads. PMID- 24154990 TI - Radio-responsive tumors exhibit greater intratumoral immune activity than nonresponsive tumors. AB - Radiation therapy (RT) continues to be a cornerstone in the treatment for many cancers. Unfortunately, not all individuals respond effectively to RT resulting clinically in two groups consisting of nonresponders (progressive disease) and responders (tumor control/cure). The mechanisms that govern the outcome of radiotherapy are poorly understood. Interestingly, a new paradigm has emerged demonstrating that the immune system mediates many of the antitumor effects of RT. Therefore, we hypothesized that the immune response following RT may dictate the efficacy of treatment. To examine this, we developed a tumor model that mirrors this clinically relevant phenomenon in which mice bearing Colon38, a colon adenocarcinoma, were treated locally with 15Gy RT resulting in both nonresponders and responders. More importantly, we were able to distinguish responders from nonresponders as early as 4 days post-RT allowing for the unique opportunity to identify critical events that ultimately determined the effectiveness of therapy. Intratumoral immune cells and interferon-gamma were increased in responsive tumors and licensed CD8 T cells to exhibit lytic activity against tumor cells, a response that was diminished in tumors refractory to RT. Combinatorial treatment with RT and the immunomodulatory cytokine IL-12 resulted in complete remission of cancer in 100% of cases compared to a cure rate of only 12% with RT alone. Similar data were obtained when IL-12 was delivered by microspheres. Therefore, the efficacy of RT may depend on the strength of the immune response induced after radiotherapy. Additionally, immunotherapy that further stimulates the immune cells may enhance the effectiveness of RT. PMID- 24154992 TI - Utilization of silver hydrogel sheet dressing on postsurgical incisions: a pilot study in foot and ankle surgery. AB - Silver hydrogel dressings are antimicrobial, nonadherent, and have an absorptive capacity many times their weight. Fifty-nine (49.44 +/- 16.85 years) foot and ankle patients with incisions >1 cm were prospectively enrolled to compare infection, scarring, and complication rates between the postoperative use of a silver hydrogel sheet (SHS) dressing and a standard petroleum-based (P) dressing. Overall, there were 5 (8.47%) infections; 4 (6.78%) superficial and 1 (1.69%) deep. The SHS group had 1 (3.45%) superficial infection, whereas the P group had 3 (10.00%) superficial infections and 1 (3.33%) deep infection. Infection incidence was similar for both groups (P = .37). However, in the P group, 3 (10.00%) patients developed wound dehiscence and 1 (1.69%) patient developed a fibrinous scab. Compared with SHS patients, the P patients had a greater incidence of incisional complications (1 [3.45%] vs 8 [26.67%], respectively; P = .03). The percent change in scar length was greater in the SHS group (18.04 +/- 41.10%) when compared with the P group (2.00 +/- 9.93%; P < .001) while the percent change in scar width was similar in the 2 groups (P = .19). The lower incidence of incisional complications and the greater reduction in scar length suggest that the inherent properties of the silver hydrogel dressing aid in postsurgical healing. PMID- 24154991 TI - A Chinese risk score model for identifying postprandial hyperglycemia without oral glucose tolerance test. AB - BACKGROUND: The aim of the study is to develop a risk score model for identifying postprandial hyperglycemia without oral glucose tolerance tests (OGTT) in Chinese population, and minimize the number of subjects needing further OGTT. METHODS: Multivariable stepwise logistic regression was used to develop risk score models in a derivation cohort (7953 participants without known diabetes). The developed models were verified in a validation cohort (another 1455 subjects without known diabetes). All subjects had completed questionnaires, physical examination and OGTT. Performances of the risk score models were estimated using receiver operating characteristic curves. RESULTS: Two risk score models for screening postprandial hyperglycemia were developed. The simple model used non-invasive risk factors (age, height, weight, waist, systolic blood pressure, pulse, hypertension, dyslipidemia and family history of diabetes mellitus), and the full model contained additional variables [fasting blood glucose (FBG), triglyceride/high density lipoprotein cholesterol] obtainable by invasive laboratory tests. The area under receiver operating characteristic curve (AUC) of simple model was similar to FBG and glycated haemoglobin. The full model has the largest AUC [0.799 (0.789-0.809) and 0.730 (0.702-0.758)] in both derivation and validation cohorts (p < 0.001 compared with simple model, FBG, and glycated haemoglobin). At a cutoff point of 80, the sensitivity, specificity and percentage that needed subsequent OGTT were 75.97, 67.56 and 48.38%, respectively. CONCLUSIONS: We developed a risk score model for screening postprandial hyperglycemia based on routine clinical information. It could effectively identify patients at high-risk for postprandial hyperglycemia and remarkably reduce the number of subjects requiring OGTT. PMID- 24154993 TI - Comparative study of scarf and extended chevron osteotomies for correction of hallux valgus. AB - BACKGROUND: Scarf and chevron osteotomies are two described treatments for the correction of hallux valgus deformity, but they have traditionally been employed for different levels of severity. We hypothesized that there would be no statistically significant difference between the results of these two treatments. METHODS: This study is a retrospective review of 70 consecutive patients treated operatively for moderate and severe hallux valgus malalignment. The two groups based on their operative treatment: scarf osteotomy (Group A) and extended chevron osteotomy (Group B). Preoperative and postoperative hallux valgus angle (HVA), intermetatarsal angle and distal metatarsal articular angle (DMAA) were measured at final follow-up. Charts were also assessed to determine the postoperative rate of satisfaction, stiffness, and pain. RESULTS: There were no statistically significant differences between Groups A and B with regard to the HVA preoperatively and postoperatively. The DMAA was statistically significantly higher for Group B both preoperatively (p=0.0403) and postoperatively (p<0.0001). The differences in HVA correction and IMA correction were not statistically significant. There were no statistically significant differences with regard to post-operative stiffness, pain, and satisfaction. DISCUSSION: The scarf and extended chevron osteotomies are capable of adequately reducing the HVA and IMA in patients with moderate to severe hallux valgus. These two techniques yielded similar patient outcomes in terms of stiffness, pain and satisfaction. Based on these results, we recommend both the scarf and extended chevron osteotomy as acceptable forms of correction for moderate to severe hallux valgus. PMID- 24154994 TI - Identification and characterisation of phenolics in Polygonum capitatum by ultrahigh-performance liquid chromatography with photodiode array detection and tandem mass spectrometry. AB - INTRODUCTION: Polygonum capitatum is a well-known Chinese medicinal plant widely used by the Miao people for the treatment of various urologic disorders. Previous investigations have shown the presence of various types of phenolics. Our ultrahigh-performance liquid chromatography with photodiode array detection and mass spectrometry (UPLC-PDA-MS) analysis indicated that flavonoid glycosides and polyphenolic glycosides were its major constituents and quite a number of phenolic compounds have not yet been identified. Identification or characterisation of the major compounds of this plant will contribute to the scientific understanding of the medicinal plant and the authentication of the plant material and its pharmaceutical preparations. OBJECTIVE: To develop an efficient method for the identification and structural characterisation of the major compounds present in P. capitatum. METHODS: Elution of the 70% ethanol extract of P. capitatum by 80% ethanol on a D101 macroporous resin column afforded a phenolics-enriched fraction, separation of which by Sephadex LH-20 column chromatography eluted with absolute ethanol gave a tannin-free phenolic fraction (TFPF). Compounds present in TFPF were identified and structurally characterised by UPLC-PDA-ESI-MS/MS. RESULTS: An amino acid and 40 phenolics including a number of flavonoid glycosides and polyphenolic glycosides were identified or structurally characterised in TFPF. Among these compounds, four were new and 19 were described in the plant for the first time. CONCLUSION: The study showed that TFPF of P. capitatum contained flavonoid glycosides and polyphenolic glycosides as its major principles. Polyphenolic glycosides were perhaps the most typical chemical markers of P. capitatum. PMID- 24154995 TI - Using care ethics to enhance qualitative research on rural aging and care. AB - Qualitative research offers important insights into the subjectivity, complexity, and relationality of care. In this article, we examine the particular processes and relationships involved in doing qualitative research about care with older people in rural places. We draw on our experience completing two related qualitative studies of rural care in Canada to extend discussions about responsible research practice in relation to participant recruitment, interviews, and focus groups. By applying Hankivsky's principles of care ethics in our reflection on research practices, we make explicit the role of emotions in connecting with research participants, collecting and participating in narrative based research, and negotiating identity. We conclude with a discussion of the distinct ways in which applying care ethics throughout the research process can augment reflexive practice and enhance the integrity and theoretical contributions of qualitative health research while developing more inclusive understandings of vulnerability in older rural populations. PMID- 24154996 TI - Exploiting mTOR signaling: a novel translatable treatment strategy for traumatic optic neuropathy? AB - Retinal ganglion cell (RGC) death and a failure of axon regeneration contribute to the profound visual loss experienced by patients after traumatic optic neuropathy (TON), for which there are no effective treatments. Experimental manipulations of cellular signaling pathways in animal models have demonstrated that neuronal survival and axon regeneration in the mature central nervous system (CNS) are possible, and increased understanding of the molecular basis of prosurvival and regenerative signals has led to the identification of candidate targets for novel therapeutic strategies. The axogenic pathway is activated sequentially, after growth factor/receptor binding, through phosphoinositide-3 kinase (PI3K) and the downstream serine/threonine kinase Akt. Akt is a nodal point for the regulation of growth cone dynamics by glycogen synthase kinase (GSK3beta) and axon protein synthesis/RGC survival by the mammalian target of rapamycin (mTOR). The mTOR signaling pathway has a pivotal role in numerous cellular processes. It is active during development, but downregulated in the mature CNS and further suppressed by axonal injury, and experimental upregulation of mTOR signaling promotes RGC survival and axon regeneration after optic nerve crush injury. However, several translational challenges remain, including understanding the regulatory mechanisms of axotomy-induced mTOR and GSK3beta signaling, and the disparity between the RGC survival and axon regenerative effects. In this review, we explore the molecular basis of RGC regenerative failure and assess the potential for manipulations of mTOR signaling as a novel translatable treatment for TON. PMID- 24154997 TI - Insulinoma presenting with cardiac arrest and cardiomyopathy. AB - A 33-year-old woman presented with ventricular fibrillation cardiac arrest and was found to have a blood glucose of 1.83 mmol/L. Cardiac catheterisation revealed a dilated left ventricle with an ejection fraction (EF) of 26% and angiographically normal coronary arteries. Continuous dextrose infusion was required to treat hypoglycaemia, which prompted consideration of insulinoma as a possible cause for her cardiomyopathy. Whipple's triad was demonstrated; a 72 h fast provided biochemical evidence of insulinoma, and imaging localised a tumour in her pancreas. The tumour was resected and pathology confirmed insulinoma; pancreaticoduodenectomy cured her hypoglycaemia. No alternate cause of cardiomyopathy was found and 4 months after surgery her EF improved to 41%. High insulin levels can close cardiac K(ATP) channels associated with dilated cardiomyopathy; the catecholamine surge from hypoglycaemia may also contribute to ventricular remodelling. Hypoglycaemia can cause QT segment prolongation, and may have precipitated fibrillation in this patient's arrhythmia-prone myocardium. PMID- 24154998 TI - A rare nidus for pulmonary thromboembolism after vertebroplasty. AB - Percutaneous vertebroplasty is used to treat osteoporotic compression fractures and bone loss due to malignancy. The cement used can serve as a potential nidus for pulmonary thromboembolism (PTE). An 87-year-old woman with recent L2 vertebroplasty presented with abdominal pain and shortness of breath. Thoracoabdominal CT scan revealed extensive bilateral pulmonary emboli associated with a 9 cm cement fragment in the inferior vena cava (IVC) extending proximally from the level of the right superior renal vein, likely secondary to cement leak from the vertebral plexus into the IVC. She refused catheter extraction was managed conservatively. There are 51 reported cases of cement pulmonary embolism. IVC foreign bodies serving as a nidus for PTE have been reported with IVC filters with an incidence of 6.2%. This is the second reported case of vertebroplasty cement serving as a nidus for PTE. Treatment depends on time interval between the procedure and the symptom onset. PMID- 24154999 TI - Refractory postsurgical pyoderma gangrenosum in a patient with Beckwith Wiedemann syndrome: response to multimodal therapy. AB - Pyoderma gangrenosum (PG) is a rare neutrophilic dermatosis that may be difficult to diagnose and treat. We presented a 41-year-old woman who required skin grafting following third-degree burns to her left breast. She suffered recurrent graft dehiscence and infections over many years, prompting elective bilateral reduction mammoplasty. She subsequently developed suture margin ulcerations unresponsive to topical therapies and antibiotics. Skin biopsies were non specific, and a clinical diagnosis of PG was established. Although initially responsive to corticosteroids, wounds promptly recurred following steroid taper. She was treated unsuccessfully with various immunomodulatory agents and underwent elective bilateral mastectomy. Following a mastectomy, she developed progressive deep chest wall ulcerations. She failed numerous immunomodulatory treatments, surgical wound closure and negative pressure wound therapy. Ultimately, treatment with adalimumab, mycophenolate mofetil and prednisone, in addition to hyperbaric oxygen therapy facilitated progressive healing. Our case highlights the role of collaborative multimodal therapy for the treatment of refractory PG. PMID- 24155000 TI - Pyogenic ventriculitis following urosepsis caused by Escherichia coli. PMID- 24155001 TI - Alcoholic cardiomyopathy. PMID- 24155002 TI - The CARE guidelines: consensus-based clinical case reporting guideline development. AB - A case report is a narrative that describes, for medical, scientific or educational purposes, a medical problem experienced by one or more patients. Case reports written without guidance from reporting standards are insufficiently rigorous to guide clinical practice or to inform clinical study design. Develop, disseminate and implement systematic reporting guidelines for case reports. We used a three-phase consensus process consisting of (1) premeeting literature review and interviews to generate items for the reporting guidelines, (2) a face to-face consensus meeting to draft the reporting guidelines and (3) postmeeting feedback, review and pilot testing, followed by finalisation of the case report guidelines. This consensus process involved 27 participants and resulted in a 13 item checklist-a reporting guideline for case reports. The primary items of the checklist are title, key words, abstract, introduction, patient information, clinical findings, timeline, diagnostic assessment, therapeutic interventions, follow-up and outcomes, discussion, patient perspective and informed consent. We believe the implementation of the CARE (CAse REport) guidelines by medical journals will improve the completeness and transparency of published case reports and that the systematic aggregation of information from case reports will inform clinical study design, provide early signals of effectiveness and harms, and improve healthcare delivery. PMID- 24155004 TI - The cerebral representation of scratching-induced pleasantness. AB - Itch is an unpleasant sensation with the desire to scratch. Although it is well known that scratching itchy skin is pleasurable, the cerebral mechanisms underlying this phenomenon are poorly understood. We hypothesized that the reward system is associated with scratching-induced pleasantness. To investigate this hypothesis, a functional magnetic resonance imaging study was performed in 16 healthy subjects. Pleasantness was evoked by scratching the wrists where itch stimuli were applied, while scratching the dorsal forearms, far from itch stimuli, did not evoke pleasantness. Interestingly, pleasantness evoked by scratching activated not only the reward system (i.e., the striatum and midbrain) but also key regions of perception (i.e., the primary somatosensory cortex) and awareness of subjective feelings (i.e., the insular cortex), indicating that a broad network is involved in scratching-induced pleasantness. Moreover, although itch was suppressed by scratching, motor-related regions such as the supplementary motor area, premotor cortex, and cerebellum showed significant activation when pleasantness was evoked. This activation could explain why scratching-induced pleasantness potentially reinforces scratching behaviors. This study is the first to identify networks activated by scratching-induced pleasantness. The results of the present study provide important information on the cerebral mechanisms underlying why scratching itchy skin evokes pleasurable feelings that reinforce scratching behaviors. PMID- 24155003 TI - Is GABA neurotransmission enhanced in auditory thalamus relative to inferior colliculus? AB - Gamma-aminobutyric acid (GABA) is the major inhibitory neurotransmitter in the central auditory system. Sensory thalamic structures show high levels of non desensitizing extrasynaptic GABAA receptors (GABAARs) and a reduction in the redundancy of coded information. The present study compared the inhibitory potency of GABA acting at GABAARs between the inferior colliculus (IC) and the medial geniculate body (MGB) using quantitative in vivo, in vitro, and ex vivo experimental approaches. In vivo single unit studies compared the ability of half maximal inhibitory concentrations of GABA to inhibit sound-evoked temporal responses, and found that GABA was two to three times (P < 0.01) more potent at suppressing MGB single unit responses than IC unit responses. In vitro whole cell patch-clamp slice recordings were used to demonstrate that gaboxadol, a delta subunit selective GABAAR agonist, was significantly more potent at evoking tonic inhibitory currents from MGB neurons than IC neurons (P < 0.01). These electrophysiological findings were supported by an in vitro receptor binding assay which used the picrotoxin analog [(3)H]TBOB to assess binding in the GABAAR chloride channel. MGB GABAARs had significantly greater total open chloride channel capacity relative to GABAARs in IC (P < 0.05) as shown by increased total [(3)H]TBOB binding. Finally, a comparative ex vivo measurement compared endogenous GABA levels and suggested a trend towards higher GABA concentrations in MGB than in IC. Collectively, these studies suggest that, per unit GABA, high affinity extrasynaptic and synaptic GABAARs confer a significant inhibitory GABAAR advantage to MGB neurons relative to IC neurons. This increased GABA sensitivity likely underpins the vital filtering role of auditory thalamus. PMID- 24155005 TI - A mixed Ca2+ channel blocker, A-1264087, utilizes peripheral and spinal mechanisms to inhibit spinal nociceptive transmission in a rat model of neuropathic pain. AB - N-, T- and P/Q-type voltage-gated Ca(2+) channels are critical for regulating neurotransmitter release and cellular excitability and have been implicated in mediating pathological nociception. A-1264087 is a novel state-dependent blocker of N-, T- and P/Q-type channels. In the present studies, A-1264087 blocked (IC50 = 1.6 MUM) rat dorsal root ganglia N-type Ca(2+) in a state-dependent fashion. A 1264087 (1, 3 and 10 mg/kg po) dose-dependently reduced mechanical allodynia in rats with a spinal nerve ligation (SNL) injury. A-1264087 (4 mg/kg iv) inhibited both spontaneous and mechanically evoked activity of spinal wide dynamic range (WDR) neurons in SNL rats but had no effect in uninjured rats. The inhibitory effect on WDR neurons remained in spinally transected SNL rats. Injection of A 1264087 (10 nmol/0.5 MUl) into the spinal cord reduced both spontaneous and evoked WDR activity in SNL rats. Application of A-1264087 (300 nmol/20 MUl) into the receptive field on the hindpaw attenuated evoked but not spontaneous firing of WDR neurons. Using electrical stimulation, A-1264087 (4 mg/kg iv) inhibited Adelta- and C-fiber evoked responses and after-discharge of WDR neurons in SNL rats. These effects by A-1264087 were not present in uninjured rats. A-1264087 moderately attenuated WDR neuron windup in both uninjured and SNL rats. In summary, these results indicate that A-1264087 selectively inhibited spinal nociceptive transmission in sensitized states through both peripheral and central mechanisms. PMID- 24155007 TI - Integration and segregation of multiple motion signals by neurons in area MT of primate. AB - We used multielectrode arrays to measure the response of populations of neurons in primate middle temporal area to the transparent motion of two superimposed dot fields moving in different directions. The shape of the population response was well predicted by the sum of the responses to the constituent fields. However, the population response profile for transparent dot fields was similar to that for coherent plaid motion and hence an unreliable cue to transparency. We then used single-unit recording to characterize component and pattern cells from their response to drifting plaids. Unlike for plaids, component cells responded to the average direction of superimposed dot fields, whereas pattern cells could signal the constituent motions. This observation provides support for a strong prediction of the Simoncelli and Heeger (1998) model of motion analysis in area middle temporal, and suggests that pattern cells have a special status in the processing of superimposed dot fields. PMID- 24155006 TI - Habenula functional resting-state connectivity in pediatric CRPS. AB - The habenula (Hb) is a small brain structure located in the posterior end of the medial dorsal thalamus and through medial (MHb) and lateral (LHb) Hb connections, it acts as a conduit of information between forebrain and brainstem structures. The role of the Hb in pain processing is well documented in animals and recently also in acute experimental pain in humans. However, its function remains unknown in chronic pain disorders. Here, we investigated Hb resting-state functional connectivity (rsFC) in patients with complex regional pain syndrome (CRPS) compared with healthy controls. Twelve pediatric patients with unilateral lower extremity CRPS (9 females; 10-17 yr) and 12 age- and sex-matched healthy controls provided informed consent to participate in the study. In healthy controls, Hb functional connections largely overlapped with previously described anatomical connections in cortical, subcortical, and brainstem structures. Compared with controls, patients exhibited an overall Hb rsFC reduction with the rest of the brain and, specifically, with the anterior midcingulate cortex, dorsolateral prefrontal cortex, supplementary motor cortex, primary motor cortex, and premotor cortex. Our results suggest that Hb rsFC parallels anatomical Hb connections in the healthy state and that overall Hb rsFC is reduced in patients, particularly connections with forebrain areas. Patients' decreased Hb rsFC to brain regions implicated in motor, affective, cognitive, and pain inhibitory/modulatory processes may contribute to their symptomatology. PMID- 24155008 TI - Modulation of transcallosal inhibition by bilateral activation of agonist and antagonist proximal arm muscles. AB - Transcallosal inhibitory interactions between proximal representations in the primary motor cortex remain poorly understood. In this study, we used transcranial magnetic stimulation to examine the ipsilateral silent period (iSP; a measure of transcallosal inhibition) in the biceps and triceps brachii during unilateral and bilateral isometric voluntary contractions. Healthy volunteers performed 10% of maximal isometric voluntary elbow flexion or extension with one arm while the contralateral arm remained at rest or performed 30% of maximal isometric voluntary elbow flexion or extension. The iSP was measured in the arm performing 10% contractions, and electromyographic (EMG) recordings were comparable across conditions. The iSP onset and duration in the biceps and triceps brachii were comparable. In both muscles, the iSP depth and area were increased during bilateral contractions of homologous agonist muscles (extension extension and flexion-flexion) compared with a unilateral contraction, whereas during bilateral contractions of nonhomologous antagonist muscles (extension flexion and flexion-extension), the iSP depth and area were decreased compared with a unilateral contraction, and sometimes facilitation of EMG was seen. This effect was never observed during bilateral activation of homologous muscles. The size of responses evoked by cervicomedullary electrical stimulation in the arm that made 10% contractions remained unchanged across conditions. Thus transcallosal inhibition targeting triceps and biceps brachii is upregulated by voluntary contraction of the contralateral agonist muscle and downregulated by voluntary contraction of the contralateral antagonist muscle. We speculate that these reciprocal task-dependent interactions between bilateral flexor and extensor arm regions of the motor cortex may contribute to coupling between the arms during motor behavior. PMID- 24155010 TI - Bilateral saccadic deficits following large and reversible inactivation of unilateral frontal eye field. AB - Inactivation permits direct assessment of the functional contribution of a given brain area to behavior. Previous inactivation studies of the frontal eye field (FEF) have either used large permanent ablations or reversible pharmacological techniques that only inactivate a small volume of tissue. Here we evaluated the impact of large, yet reversible, FEF inactivation on visually guided, delayed, and memory-guided saccades, using cryoloops implanted in the arcuate sulcus. While FEF inactivation produced the expected triad of contralateral saccadic deficits (increased reaction time, decreased accuracy and peak velocity) and performance errors (neglect or misdirected saccades), we also found consistent increases in reaction times of ipsiversive saccades in all three tasks. In addition, FEF inactivation did not increase the proportion of premature saccades to ipsilateral targets, as was predicted on the basis of pharmacological studies. Consistent with previous studies, greater deficits accompanied saccades toward extinguished visual cues. Our results attest to the functional contribution of the FEF to saccades in both directions. We speculate that the comparative effects of different inactivation techniques relate to the volume of inactivated tissue within the FEF. Larger inactivation volumes may reveal the functional contribution of more sparsely distributed neurons within the FEF, such as those related to ipsiversive saccades. Furthermore, while focal FEF inactivation may disinhibit the mirroring site in the other FEF, larger inactivation volumes may induce broad disinhibition in the other FEF that paradoxically prolongs oculomotor processing via increased competitive interactions. PMID- 24155009 TI - Modulation of high- and low-frequency components of the cortical local field potential via nicotinic and muscarinic acetylcholine receptors in anesthetized mice. AB - Release of acetylcholine (ACh) in neocortex is important for learning, memory and attention tasks. The primary source of ACh in neocortex is axons ascending from the basal forebrain. Release of ACh from these axons evokes changes in the cortical local field potential (LFP), including a decline in low-frequency spectral power that is often referred to as desynchronization of the LFP and is thought to result from the activation of muscarinic ACh receptors. Using channelrhodopsin-2, we selectively stimulated the axons of only cholinergic basal forebrain neurons in primary somatosensory cortex of the urethane-anesthetized mouse while monitoring the LFP. Cholinergic stimulation caused desynchronization and two brief increases in higher-frequency power at stimulus onset and offset. Desynchronization (1-6 Hz) was localized, extending <= 1 mm from the edge of stimulation, and consisted of both nicotinic and muscarinic receptor-mediated components that were inhibited by mecamylamine and atropine, respectively. Hence we have identified a nicotinic receptor-mediated component to desynchronization. The increase in higher-frequency power (>10 Hz) at stimulus onset was also mediated by activation of nicotinic and muscarinic receptors. However, the increase in higher-frequency power (10-20 Hz) at stimulus offset was evoked by activation of muscarinic receptors and inhibited by activation of nicotinic receptors. We conclude that the activation of nicotinic and muscarinic ACh receptors in neocortex exerts several effects that are reflected in distinct frequency bands of the cortical LFP in urethane-anesthetized mice. PMID- 24155011 TI - Modification of cutaneous reflexes during visually guided walking. AB - Although it has become apparent that cutaneous reflexes can be adjusted based on the phase and context of the locomotor task, it is not clear to what extent these reflexes are regulated when locomotion is modified under visual guidance. To address this, we compared the amplitude of cutaneous reflexes while subjects performed walking tasks that required precise foot placement. In one experiment, subjects walked overground and across a horizontal ladder with narrow raised rungs. In another experiment, subjects walked and stepped onto a series of flat targets, which required different levels of precision (large vs. narrow targets). The superficial peroneal or tibial nerve was electrically stimulated in multiple phases of the gait cycle in each condition and experiment. Reflexes between 50 and 120 ms poststimulation were sorted into 10 equal phase bins, and the amplitudes were then averaged. In each experiment, differences in cutaneous reflexes between conditions occurred predominantly during swing phase when preparation for precise foot placement was necessary. For instance, large excitatory cutaneous reflexes in ipsilateral tibialis anterior were present in the ladder condition and when stepping on narrow targets compared with inhibitory responses in the other conditions, regardless of the nerve stimulated. In the ladder experiments, additional effects of walking condition were evident during stance phase when subjects had to balance on the narrow ladder rungs and may be related to threat and/or the unstable foot-surface interaction. Taken together, these results suggest that cutaneous reflexes are modified when visual feedback regarding the terrain is critical for successful walking. PMID- 24155013 TI - Dual sensitivity of inferior colliculus neurons to ITD in the envelopes of high frequency sounds: experimental and modeling study. AB - Human listeners are sensitive to interaural time differences (ITDs) in the envelopes of sounds, which can serve as a cue for sound localization. Many high frequency neurons in the mammalian inferior colliculus (IC) are sensitive to envelope-ITDs of sinusoidally amplitude-modulated (SAM) sounds. Typically, envelope-ITD-sensitive IC neurons exhibit either peak-type sensitivity, discharging maximally at the same delay across frequencies, or trough-type sensitivity, discharging minimally at the same delay across frequencies, consistent with responses observed at the primary site of binaural interaction in the medial and lateral superior olives (MSO and LSO), respectively. However, some high-frequency IC neurons exhibit dual types of envelope-ITD sensitivity in their responses to SAM tones, that is, they exhibit peak-type sensitivity at some modulation frequencies and trough-type sensitivity at other frequencies. Here we show that high-frequency IC neurons in the unanesthetized rabbit can also exhibit dual types of envelope-ITD sensitivity in their responses to SAM noise. Such complex responses to SAM stimuli could be achieved by convergent inputs from MSO and LSO onto single IC neurons. We test this hypothesis by implementing a physiologically explicit, computational model of the binaural pathway. Specifically, we examined envelope-ITD sensitivity of a simple model IC neuron that receives convergent inputs from MSO and LSO model neurons. We show that dual envelope-ITD sensitivity emerges in the IC when convergent MSO and LSO inputs are differentially tuned for modulation frequency. PMID- 24155014 TI - Paclitaxel resistance by random mutagenesis of alpha-tubulin. AB - Many mammalian beta-tubulin mutations that confer paclitaxel resistance have been characterized, but little is currently known about the role of alpha-tubulin mutations in drug resistance. Previous studies using two-dimensional gel electrophoresis showed that alpha-tubulin mutations occur with a frequency equal to beta-tubulin mutations among CHO cells selected for resistance to paclitaxel but the identities of those mutations are largely unknown. We have now sequenced the major alpha-tubulin gene in several paclitaxel resistant CHO cell lines with lesions in genomic DNA and identified five mutations that predominately affect the amino terminal part of the protein. We also used random mutagenesis and transfection of alpha-tubulin cDNA to select further paclitaxel resistant mutants in an effort to remove genomic constraints that may limit the diversity of mutations. This approach led to the identification of 16 additional mutations that were distributed throughout the alpha-tubulin sequence. The mutations were confirmed as sufficient to confer resistance by site-directed mutagenesis, and they acted by a mechanism that involved reductions in microtubule assembly. One mutation prevented the acetylation of alpha-tubulin but otherwise produced a phenotype similar to the other mutations. A scan of the literature revealed that a significant number of drug resistance mutations overlap or lie close to lesions that have been reported in patients with brain disorders suggesting that alterations in microtubule assembly underlie both cellular resistance and developmental defects. PMID- 24155012 TI - Targeted disruption of layer 4 during development increases GABAA receptor neurotransmission in the neocortex. AB - Cortical dysplasia (CD) associates with clinical pathologies, including epilepsy and mental retardation. CD results from impaired migration of immature neurons to their cortical targets, leading to clustering of neural cells and changes in cortical properties. We developed a CD model by administering methylazoxymethanol (MAM), an anti-mitotic, to pregnant ferrets on embryonic day 33; this leads to reduction in cortical thickness in addition to redistribution and increased expression of GABAA receptors (GABAAR). We evaluated the impact of MAM treatment on GABAAR-mediated synaptic transmission in postnatal day 0-1 neurons, leaving the ganglionic eminence (GE) and in layer 2/3 pyramidal cells of postnatal day 28 38 ferrets. Embryonic day 33 MAM treatment significantly increases the amplitude and frequency of spontaneous GABAAR-mediated inhibitory postsynaptic currents (IPSCs) in the cells leaving the GE. In older MAM-treated animals, the amplitude and frequency of GABAAR-mediated spontaneous IPSCs in layer 2/3 pyramidal cells is increased, as are the amplitude and frequency of miniature IPSCs. The kinetics of GABAAR opening also altered following treatment with MAM. Western blot analysis shows that the expression of the GABAAalpha3R and GABAAgamma2R subunits amplified in our model animals. We did not observe any significant change in the passive properties of either the layer 2/3 pyramidal cells or cells leaving the GE after MAM treatment. These observations reinforce the idea that synaptic neurotransmission through GABAAR enhances following treatment with MAM and coincides with our finding of increased GABAAalphaR expression within the upper cortical layers. Overall, we demonstrate that small amounts of toxins delivered during corticogenesis can result in long-lasting changes in ambient expression of GABAAR that influence intrinsic neuronal properties. PMID- 24155015 TI - The value of a genetic counselor: improving identification of cancer genetic counseling patients with chart review. AB - Advances in genetics are changing cancer care and requiring institutions to maximize the unique skills of genetics professionals. The identification of genetic syndromes is vital for prevention and management of families with high cancer risks. Despite this, high risk individuals who qualify are often not referred. Genetic counselors could review oncology charts to improve identification. A genetics assessment tool developed by NCI Community Cancer Centers Program was used to perform self-assessment of the genetics program. A weekly report of all new oncology patients was provided to a genetic counselor for chart review. In 2010, 58 % of all eligible patients (n = 152) were offered a genetics evaluation. In 2011 this improved to 70 % (n = 167), which was a statistically significant difference, X (2)(1) = 5.13, p = 0.02. By cancer site, ovarian cancer referrals also showed statistically significant improvement, X (2)(1) = 6.36, p = 0.01. Breast and colon referrals were improved but not significant. Over 10 months, 129 patients were identified through the chart review program. Three were confirmed to have a genetic mutation for a hereditary cancer syndrome. An average week included review of 73 charts for 10 medical oncologists, 4 radiation oncologists, and 4 pediatric oncologists which generated 60-80 min of work for the genetic counselor. This program improved patient identification and quality, and allowed physicians to become more aware of opportunities for genetic counseling and more patients to receive genetic counseling and testing. PMID- 24155016 TI - Chiral 38-gold-atom nanoclusters: synthesis and chiroptical properties. AB - Enantioselective synthesis of chiral Au38 nanoclusters is achieved with chiral 2 phenylpropane-1-thiol (abbreviated as R/S-PET, organic soluble), captopril and glutathione (water soluble) as the respective ligand. The circular dichroism (CD) spectra of Au38 (R-PET)24 and Au38 (S-PET)24 show multiple bands which are precisely mirror-imaged, while their normal optical absorption spectra are identical with each other and also superimposable with that of the racemic Au38 (SCH2 CH2 Ph)24 nanoclusters. The observed CD signals are not from the chiral ligands themselves (which only give rise to CD signals in the UV (<250 nm), rather than in the visible wavelength region). Chiral Au38 nanoclusters with different types of ligands are further compared. Although the Au38 core is intrinsically chiral, different chiral ligands are found to largely influence the chiroptical response of the overall nanocluster. Thus, the chiral response of ligand-protected nanoclusters has both contributions from the metal core and the ligand shell around it. These optically active nanoclusters hold promise in future applications such as chiral sensing and catalysis. PMID- 24155017 TI - Effective therapies or effective mechanisms in treatment guidelines for depression? PMID- 24155019 TI - Synthesis, analgesic, anti-inflammatory and in vitro antimicrobial activities of some novel isoxazole coupled quinazolin-4(3H)-one derivatives. AB - A series of novel isoxazole coupled quinazolin-4(3H)-one derivatives were synthesized and characterized by FT-IR, 1H NMR, mass spectroscopy and bases of elemental analysis with the aim of developing potent analgesic, anti-inflammatory and antimicrobial agents. Tail-flick technique, carrageenan-induced foot paw edema test and agar streak dilution test were performed for screening analgesic, anti-inflammatory and in vitro antimicrobial activity respectively. Moreover all compounds were examined for its ulcerogenicity. Results revealed that entire series of compounds exhibited mild to good analgesic, anti-inflammatory and antimicrobial activity with low to moderate ulcer index. The relationship between the functional group variation and the biological activity of the evaluated compounds was discussed. Out of various synthesized compounds, 2-methyl-3-(4-(5 (4-(trifluoromethyl)phenyl) isoxazol-3-yl)phenyl)quinazolin-4(3H)-one 5e was found to be the most active compound. PMID- 24155018 TI - Orthodontic treatment for distalising upper first molars in children and adolescents. AB - BACKGROUND: When orthodontic treatment is provided with fixed appliances, it is sometimes necessary to move the upper molar teeth backwards (distalise) to create space or help to overcome anchorage requirements. This can be achieved with the use of extraoral or intraoral appliances. The most common appliance is extraoral headgear, which requires considerable patient co-operation. Further, reports of serious injuries have been published. Intraoral appliances have been developed to overcome such shortcomings. The comparative effects of extraoral and intraoral appliances have not been fully evaluated. OBJECTIVES: To assess the effects of orthodontic treatment for distalising upper first molars in children and adolescents. SEARCH METHODS: We searched the following electronic databases: the Cochrane Oral Health Group's Trials Register (to 10 December 2012), the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2012, Issue 11), MEDLINE via OVID (1946 to 10 December 2012) and EMBASE via OVID (1980 to 10 December 2012). No restrictions were placed on the language or date of publication when searching the electronic databases. SELECTION CRITERIA: Randomised clinical trials involving the use of removable or fixed orthodontic appliances intended to distalise upper first molars in children and adolescents. DATA COLLECTION AND ANALYSIS: We used the standard methodological procedures expected by The Cochrane Collaboration. We performed data extraction and assessment of the risk of bias independently and in duplicate. We contacted authors to clarify the inclusion criteria of the studies. MAIN RESULTS: Ten studies, reporting data from 354 participants, were included in this review, the majority of which were carried out in a university dental hospital setting. The studies were published between 2005 and 2011 and were conducted in Europe and in Brazil. The age range of participants was from nine to 15 years, with an even distribution of males and females in seven of the studies, and a slight predominance of female patients in three of the studies. The quality of the studies was generally poor; seven studies were at an overall high risk of bias, three studies were at an unclear risk of bias, and we judged no study to be at low risk of bias.We carried out random-effects meta-analyses as appropriate for the primary clinical outcomes of movement of upper first molars (mm), and loss of anterior anchorage, where there were sufficient data reported in the primary studies. Four studies, involving 159 participants, compared a distalising appliance to an untreated control. Meta-analyses were not undertaken for all primary outcomes due to incomplete reporting of all summary statistics, expected outcomes, and differences between the types of appliances. The degree and direction of molar movement and loss of anterior anchorage varied with the type of appliance. Four studies, involving 150 participants, compared a distalising appliance versus headgear. The mean molar movement for intraoral distalising appliances was -2.20 mm and -1.04 mm for headgear. There was a statistically significant difference in mean distal molar movement (mean difference (MD) -1.45 mm; 95% confidence interval (CI) -2.74 to -0.15) favouring intraoral appliances compared to headgear (four studies, high or unclear risk of bias, 150 participants analysed). However, a statistically significant difference in mean mesial upper incisor movement (MD 1.82 mm; 95% CI 1.39 to 2.24) and overjet (fixed-effect: MD 1.64 mm; 95% CI 1.26 to 2.02; two studies, unclear risk of bias, 70 participants analysed) favoured headgear, i.e. there was less loss of anterior anchorage with headgear. We reported direct comparisons of intraoral appliances narratively due to the variation in interventions (three studies, high or unclear risk of bias, 93 participants randomised). All appliances were reported to provide some degree of distal movement, and loss of anterior anchorage varied with the type of appliance.No included studies reported on the incidence of adverse effects (harm, injury), number of attendances or rate of non compliance. AUTHORS' CONCLUSIONS: It is suggested that intraoral appliances are more effective than headgear in distalising upper first molars. However, this effect is counteracted by loss of anterior anchorage, which was not found to occur with headgear when compared with intraoral distalising appliance in a small number of studies. The number of trials assessing the effects of orthodontic treatment for distilisation is low, and the current evidence is of low or very low quality. PMID- 24155020 TI - Apotransferrin has a second mechanism for anticandidal activity through binding of Candida albicans. AB - It has been reported that transferrin has antibacterial and antifungal activities via iron chelation in the environment surrounding the microbes. In the present study, we investigated whether the binding of transferrin to Candida albicans mediates growth inhibition. By using cultures that contained iron-free (apo)transferrin glycoprotein either in contact with candidal cells or separated from candidal cells by a dialysis membrane, we distinguished the growth inhibition by transferrin-cell interaction from that of simple iron chelation. Maximal growth inhibition always occurred when the apotransferrin interacted directly with the cells. Additionally, there was partial inhibition even when candidal cells were in contact with iron-saturated transferrin. Binding studies with (59)Fe(3+) radiolabeled-transferrin indicated that the apo-protein can bind to the candidal cell surface. The binding sites were saturable and it was dose dependent. Chemicals (hydrogen peroxide, dithiothreitol, sodium dodecyl sulfate) blocked transferrin binding to C. albicans, and among the three, hydrogen peroxide (HP) was the most effective for the blocking. When HP-treated yeast cells were added to the culture that was pretreated with apotransferrin, candidal cell growth increased by 5-fold as compared to the growth of HP-untreated candidal cells under apotransferrin-regulation (P < 0.05). Combined all data together, it was concluded that transferrin has a second mechanism of anticandidal activity that is mediated by binding to the surface of C. albicans yeast cells. PMID- 24155021 TI - (--)-Catechin glycosides from Ulmus davidiana. AB - Extensive chromatographic separation of the n-BuOH soluble fraction obtained from the stem and root barks of U. davidiana resulted in five hitherto unknown compounds together with a known one (-)-catechin 1. Structures of the five compounds were elucidated by chemical and spectroscopic analyses, to be (-) catechin-7-O-gallate-5-O-(5""-trans-caffeoyl)-beta-D-apiofuranoside-3-O-beta-D apiofuranosyl-(1 -> 2)-beta-D-glucopyranoside 2, (-)-catechin-7-O-gallate-5-O (5""-trans-caffeoyl)-beta-D-apiofuranoside-3-O-beta-D-glucopyranoside 3, (-) catechin-7-O-gallate-5-O-beta-D-apiofuranoside-3-O-(2"-O-galloyl)-beta-D glucopyranoside 4, (-)-catechin-7-O-gallate-5-O-(5""-trans-caffeoyl)-beta-D apiofuranoside 5, and (-)-catechin-7-O-gallate-5-O-(5""-trans-feruloyl)-beta-D apiofuranoside 6. PMID- 24155022 TI - A study of analytical methods for the determination of propofol in blood. AB - Propofol (2,6-diisopropylphenol) is a commonly used short-acting intravenous anesthetic agent. However, because of the risk of drug abuse and propofol related death, in Korea propofol is a controlled drug. In this review, the analytical methods using liquid chromatography (LC), gas chromatography/mass spectrometry, or LC coupled with tandem mass spectrometry to detect and quantify propofol or its metabolites in blood were described. The validation data for the analytical methods and propofol concentrations in the blood were reviewed. PMID- 24155023 TI - Anti-Helicobacter pylori xanthones of Garcinia fusca. AB - A new geranylated xanthone derivative, fuscaxanthone I (1), along with nine xanthones (2-9 and 11), a biphenyl (10) and three biflavonoids (12-14) were isolated from the roots of Garcinia fusca Pierre. Compounds 8, 10 and 11-14 were reported from this plant species for the first time. Their structures were elucidated by spectroscopic analyses, including 1D- and 2D-NMR and MS. The isolated compounds were evaluated for antibacterial activity against Helicobacter pylori. Cowaxanthone (5) and fukugiside (14) exhibited stronger inhibitory activity against H. pylori DMST reference strain at MICs 4.6 and 10.8 MUM, respectively, than that of the control metronidazole. Isojacareubin (8) displayed the most potent activity against H. pylori HP40 clinical isolate with MIC 23.9 MUM, which was approximately two times greater than that of the standard drug amoxicillin. PMID- 24155024 TI - Physiological differences between sprint- and distance-specialized cross-country skiers. AB - PURPOSE: Sprint- (<=1.8 km) and distance-skiing (>=15 km) performance rely heavily on aerobic capacity. However, in sprint skiing, due to the ~20% higher speed, anaerobic capacity contributes significantly. This study aimed to identify the possible anthropometric and physiological differences between elite male sprint and distance skiers. METHODS: Six sprint and 7 distance international level cross-country skiers completed testing using the V2 skating technique on a roller-ski treadmill. Measurements included submaximal O2 cost (5 degrees , 3 m/s) and a 1000-m time trial (6 degrees , >3.25 m/s) to assess VO2peak and accumulated oxygen (sigmaO2) deficit. RESULTS: The groups displayed similar O2 cost during the submaximal load. The sprint skiers had a higher sigmaO2 deficit (79.0 +/- 11.3 vs 65.7 +/- 7.5.mL/kg, P = .03, ES = 1.27) and VO2peak in absolute values (6.6 +/- 0.5 vs 6.0 +/- 0.5 L/ min, P = .04, ES =1.23), while VO2peak relative to body mass was lower than in the distance skiers (76.4 +/- 4.4 vs 83.0 +/- 3.2 mL . kg-1 . min-1, P = .009, ES = 1.59). The sprint skiers were heavier than the distance skiers (86.6 +/- 6.1 vs 71.8 +/- 7.2 kg, P = .002, ES = 2.07), taller (186 +/- 5 vs 178 +/- 7 cm, P = .04, ES = 1.25), and had a higher body mass index (24.9 +/- 0.8 vs 22.5 +/- 1.3 kg/m2, P = .003, ES = 2.05). CONCLUSION: The elite male sprint skiers showed different anthropometric and physiological qualities than the distance skiers, with these differences being directly related to body mass. PMID- 24155026 TI - Coronary involvement in Churg-Strauss syndrome: a case report with CT findings. AB - We report a case of Churg-Strauss syndrome (CSS) associated with coronary artery involvement, as demonstrated on coronary CT angiography (CCTA), without specific cardiac symptoms. A 69-year-old male had an 8-year history of bronchial asthma and chronic sinusitis with hypereosinophilia (35 %), polyneuropathy, and a positive antineutrophil cytoplasmic antibody titer, so he was diagnosed with CSS. The patient had no specific cardiac symptoms, but CCTA showed vasculitis and a saccular aneurysm involving the proximal coronary arteries. The 3-year follow-up CCTA demonstrated an increase in the extent of soft-tissue wall thickening and infiltration involving the coronary arteries. Although vasculitis of the major coronary arteries is not a prominent feature of CSS, our case suggests that the coronary arteries may also be targeted in this syndrome. PMID- 24155025 TI - NADPH oxidase enzymes in skin fibrosis: molecular targets and therapeutic agents. AB - Fibrosis is characterized by the excessive deposition of extracellular matrix components eventually resulting in organ dysfunction and failure. In dermatology, fibrosis is the hallmark component of many skin diseases, including systemic sclerosis, graft-versus-host disease, hypertrophic scars, keloids, nephrogenic systemic fibrosis, porphyria cutanea tarda, restrictive dermopathy and other conditions. Fibrotic skin disorders may be debilitating and impair quality of life. There are few FDA-approved anti-fibrotic drugs; thus, research in this area is crucial in addressing this deficiency. Recent investigations elucidating the pathogenesis of skin fibrosis have implicated endogenous reactive oxygen species produced by the multicomponent nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (Nox) enzyme complex. In this review, we discuss Nox enzymes and their role in skin fibrosis. An overview of the Nox enzyme family is presented and their role in the pathogenesis of skin fibrosis is discussed. The mechanisms by which Nox enzymes influence specific fibrotic skin disorders are also reviewed. Finally, we describe the therapeutic approaches to ameliorate skin fibrosis by directly targeting Nox enzymes with the use of statins, p47phox subunit modulators, or GKT137831, a competitive inhibitor of Nox enzymes. Nox enzymes can also be targeted indirectly via scavenging ROS with antioxidants. We believe that Nox modulators are worthy of further investigation and have the potential to transform the management of skin fibrosis by dermatologists. PMID- 24155027 TI - Real-time virtual sonography (RVS)-guided vacuum-assisted breast biopsy for lesions initially detected with breast MRI. AB - PURPOSE: To report on our initial experiences with a new method of real-time virtual sonography (RVS)-guided 11-gauge vacuum-assisted breast biopsy for lesions that were initially detected with breast MRI. MATERIALS AND METHODS: RVS guided 11-gauge vacuum-assisted biopsy is performed when a lesion with suspicious characteristics is initially detected with breast MRI and is occult on mammography, sonography, and physical examination. Live sonographic images were co-registered to the previously loaded second-look spine contrast-enhanced breast MRI volume data to correlate the sonography and MR images. RESULTS: Six lesions were examined in six consecutive patients scheduled to undergo RVS-guided 11 gauge vacuum-assisted biopsy. One patient was removed from the study because of non-visualization of the lesion in the second-look spine contrast-enhanced breast MRI. Five patients with non-mass enhancement lesions were biopsied. The lesions ranged in size from 9 to 13 mm (mean 11 mm). The average procedural time, including the sonography and MR image co-registration time, was 25 min. All biopsies resulted in tissue retrieval. One was fibroadenomatous nodules, and those of four were fibrocystic changes. There were no complications during or after the procedures. CONCLUSION: RVS-guided 11-gauge vacuum-assisted breast biopsies provide a safe and effective method for the examination of suspicious lesions initially detected with MRI. PMID- 24155028 TI - Muscle fiber conduction velocity estimation by the multi-dip method: how deep can you dip? PMID- 24155029 TI - Acetazolamide triggers death inducing autophagy in T-47D breast cancer cells. AB - The inhibitory effects of acetazolamide on the growth and proliferation of epithelial breast cancer cells (T-47D) were investigated. Analysis of morphological changes indicated little apoptosis in T-47D cells incubated with acetazolamide, according to data from flow cytometry, DNA laddering, and expression of AIF. However, an increase in caspase-3 activity was detected in cells. This was concomitant with an increase in DFF45/DFF40 ratio leading to inhibition of caspase-3 activity, DNA fragmentation and progression of apoptosis. Flow cytometry also confirmed that acetazolamide had no significant effect on cell cycle progression. These results are consistent with lack of change in the expression of cell cycle regulatory proteins p21, p27, cdc2 and cyclinD1. Increased expression of ATG5, p53 and DRAM, along with an increase in BCLN1/Bcl-2 ratio, indicated that acetazolamide inhibited the proliferation of T-47D cells by inducing autophagy. Increased expression of PTEN, along with decreased expression of Akt1, also showed that acetazolamide treatment resulted in death inducing autophagy. Collectively the results indicate that autophagy is an adequate mechanism mediating the anti-cancer effects of acetazolamide in T-47D cells through engagement of p53/DRAM pathway and attenuation of Akt survival signalling. PMID- 24155030 TI - HER2-positive patients receiving trastuzumab treatment have a comparable prognosis with HER2-negative advanced gastric cancer patients: a prospective cohort observation. AB - The monoclonal antibody trastuzumab has brought survival benefit to patients with advanced gastric cancer (AGC) that have human epidermal growth factor receptor 2 (HER2) over expression or amplification. This study was designed to compare the clinical outcomes of HER2-negative and HER2-positive AGC patients with or without trastuzumab treatment. There were three groups of patients enrolled for analysis. Group A was 51 HER2-positive AGC patients treated with trastuzumab and chemotherapy; group B was a matched control group of 47 HER2-positive patients who received chemotherapy only; group C was a matched group of 251 HER2-negative patients who received chemotherapy. All the patients were enrolled at Sun Yat-sen University Cancer Center or Zhongshan Hospital, Fudan University between January 2010 and December 2012. The primary endpoint was overall survival (OS). The Kaplan-Meier method and log-rank test were used for survival analysis. The median duration of follow-up was 13.5 months (range 5-18.6 months). The median OS of these three groups of patients was 14.8 months, 11.3 months and 14.4 months respectively (p < 0.001). The survival difference between group A and B was significant, p < 0.001. Similarly, there was significant difference between group B and C, p < 0.001. Moreover the survival between group A and C was comparable, p = 0.281. The median progression-free survival for these three groups was 7.4, 6.0 and 7.2 months. Multivariate analysis confirmed that trastuzumab treatment was an independent prognostic factor in group A and B patients (p = 0.017). HER2 positive was an independent adverse prognostic factor in group B and C patients (p = 0.013). PMID- 24155032 TI - Efficacy of raltegravir switching strategies in HIV-infected patients with suppressed viraemia according to the genotypic sensitivity score. AB - BACKGROUND AND PURPOSE: The lack of antiretroviral (ARV) backbone activity associated with raltegravir has been proposed as the main explanation for virological relapse observed in patients with undetectable viraemia who are switched from a ritonavir-boosted protease inhibitor (PI) to raltegravir. However ARV activity remains difficult to assess in this context. The aim of our study was to precisely assess the ARV backbone activity in patients with undetectable viraemia who underwent raltegravir switching strategies and to evaluate the efficacy of such switching strategies based on the genotypic sensitivity score (GSS). METHODS: Patients with a plasma human immunodeficiency virus type 1 (HIV 1) RNA level of <50 copies/mL on a stable two ARV-class regimen were enrolled if they switched one of their ARV drugs to raltegravir 400 mg twice daily. The GSS was calculated using a genotyping test performed on the HIV-1 RNA of the last plasma measurement with a HIV-1 RNA level of >50 copies/mL before the switch and on the results of all previous genotyping tests. The primary endpoint was the proportion of patients with a plasma HIV-1 RNA level of <50 copies/mL at week 24. RESULTS: Fifty-six patients were enrolled in this study. The proportion of patients with a plasma HIV-1 RNA level of <50 copies/mL at week 24 was 92.9 % (range 83.0-97.2 %) in the intent-to-treat analysis and 98.1 % (90.0-99.7 %) in per-protocol analysis. When the backbone was fully active, the proportion was 100.0 % (86.7-100.0 %) at week 24 and week 48 in the per-protocol analysis. We observed a decrease in plasma total cholesterol and triglycerides of -12.7 % (p = 0.005) and -26.5 % (p = 0.001), respectively. CONCLUSIONS: Raltegravir switching strategies are effective when the associated backbone is fully active according to the GSS. In the context of undetectable viraemia, where ARV activity remains difficult to assess, the determination of the GSS requires the entire ARV history of the patient and all previous HIV-RNA genotyping test results. PMID- 24155033 TI - Evaluation of Rho-kinase activity in mice brain using N-[11C]methyl hydroxyfasudil with positron emission tomography. AB - PURPOSE: Rho is a small molecular weight GTP-binding protein and works as a molecular shuttling switch between an active (GTP-bound) and inactive (GDP-bound) state. Rho is known to be involved in cell motility, cell adhesion, and cytokinesis through actin cytoskeleton reorganization. The GTP-bound form of Rho interacts with its specific downstream target, triggering intracellular signaling cascades. Rho effectors such as Rho-kinases have been isolated on the basis of their selective binding to the GTP-bound form of Rho. Rho-kinase is thought to have an important role in the pathogenesis of a variety of neurological diseases because activation of the Rho/Rho-kinase pathway has been observed in various central nervous system disorders. Previous histochemical studies have shown multiple molecular mechanisms for the regulation of Rho-kinase. Neuroimaging of Rho/Rho-kinase has rarely been studied because of a lack of appropriate radiotracers. Recently, N-[(11)C]methyl-hydroxyfasudil, a new radiotracer for positron emission tomography (PET), has been introduced to measure Rho-kinase activity. In this study, the regional distribution and kinetics of N [(11)C]methyl-hydroxyfasudil were investigated in the brains of mice. PROCEDURES: A 90-min dynamic scan was performed following intravenous infusion of N [(11)C]methyl-hydroxyfasudil. RESULTS: The uptake of N-[(11)C]methyl hydroxyfasudil reached a maximum within 5 min and gradually decreased in all organs. The standard uptake values (SUVs) in the brain, liver, and kidney on average between 30 to 60 min were 0.17 +/- 0.03, 0.76 +/- 0.18, and 0.62 +/- 0.18 and from 60 to 90 min were 0.15 +/- 0.01, 0.69 +/- 0.33, and 0.64 +/- 0.17, respectively. N-[(11)C]Methyl-hydroxyfasudil showed a widespread distribution throughout the brain, with low levels of radioactivity. Radioactivity concentration in plasma at 90 min after injection of N-[(11)C]methyl hydroxyfasudil resulted in SUVs in the control and fasudil pretreatment of 0.0013 and 0.0023 +/- 0.0008, respectively. Compared to normal control mice, about twofold higher radioactivity concentration was observed in fasudil-pretreated mice. In a cold brain injury mouse model, accumulation of N-[(11)C]methyl hydroxyfasudil was slightly higher at the injury site than that at the control site, and the difference was statistically significant in the "24 h after injury" group (P < 0.05). CONCLUSIONS: These results suggest that following brain injury, N-[(11)C]methyl-hydroxyfasudil binds to the active form of Rho-kinase. PET imaging using N-[(11)C]methyl-hydroxyfasudil could provide new insights into the pathophysiology of a variety of neurological disorders including stroke, inflammatory diseases, demyelinating diseases, Alzheimer's disease, and neuropathic pain. PMID- 24155031 TI - Cholesterol as a co-solvent and a ligand for membrane proteins. AB - As of mid 2013 a Medline search on "cholesterol" yielded over 200,000 hits, reflecting the prominence of this lipid in numerous aspects of animal cell biology and physiology under conditions of health and disease. Aberrations in cholesterol homeostasis underlie both a number of rare genetic disorders and contribute to common sporadic and complex disorders including heart disease, stroke, type II diabetes, and Alzheimer's disease. The corresponding author of this review and his lab stumbled only recently into the sprawling area of cholesterol research when they discovered that the amyloid precursor protein (APP) binds cholesterol, a topic covered by the Hans Neurath Award lecture at the 2013 Protein Society Meeting. Here, we first provide a brief overview of cholesterol-protein interactions and then offer our perspective on how and why binding of cholesterol to APP and its C99 domain (beta-CTF) promotes the amyloidogenic pathway, which is closely related to the etiology of Alzheimer's disease. PMID- 24155034 TI - A case for the standardized letter of recommendation in otolaryngology residency selection. PMID- 24155036 TI - Are first-generation adolescents less likely to be overweight? Results from a survey of Boston youth. AB - The effect of years of residence in the US on the weight of adolescents is unclear. We examined the association between generation (i.e. 1st, 1.5, 2nd, and 3rd) and weight indicators among Boston adolescents. Data are from a sample of 1,420 9-12th grade public school students in Boston, Massachusetts. We used self reported information to calculate generation and weight characteristics (i.e., body mass index (BMI), BMI z-score, overweight status), and ran multivariate analyses to estimate the association between generation and weight characteristics, adjusting for race/ethnicity, gender, age and school. In pooled multivariate models, 1.5 generation, second generation, and third generation youth had significantly higher mean BMI scores and mean BMI z-scores than first generation youth. Second (RR 1.87, 95% CI 1.13-3.12) and third generation youth (RR 2.06, 95% CI 1.21-3.50) were also significantly more likely to be overweight than first generation youth. In multivariate models stratified by sex, this pattern persisted for females only. There is a positive, linear trend in BMI by generation that differs by gender. Mechanisms underlying this association should be addressed. PMID- 24155035 TI - Two birds with one stone: doing metabolomics with your proteomics kit. AB - Proteomic research facilities and laboratories are facing increasing demands for the integration of biological data from multiple '-OMICS' approaches. The aim to fully understand biological processes requires the integrated study of genomes, proteomes and metabolomes. While genomic and proteomic workflows are different, the study of the metabolome overlaps significantly with the latter, both in instrumentation and methodology. However, chemical diversity complicates an easy and direct access to the metabolome by mass spectrometry (MS). The present review provides an introduction into metabolomics workflows from the viewpoint of proteomic researchers. We compare the physicochemical properties of proteins and peptides with metabolites/small molecules to establish principle differences between these analyte classes based on human data. We highlight the implications this may have on sample preparation, separation, ionisation, detection and data analysis. We argue that a typical proteomic workflow (nLC-MS) can be exploited for the detection of a number of aliphatic and aromatic metabolites, including fatty acids, lipids, prostaglandins, di/tripeptides, steroids and vitamins, thereby providing a straightforward entry point for metabolomics-based studies. Limitations and requirements are discussed as well as extensions to the LC-MS workflow to expand the range of detectable molecular classes without investing in dedicated instrumentation such as GC-MS, CE-MS or NMR. PMID- 24155038 TI - The impact of Girdin expression on recurrence-free survival in patients with luminal-type breast cancer. AB - BACKGROUND: In patients with luminal-type breast cancer (positive for ER and/or PgR), a complete consensus on the threshold indication for a combination of chemotherapy and endocrine therapy has not been achieved, especially for patients with HER2-negative luminal type (HNLT). Girdin, an actin-binding Akt substrate, plays a crucial role in the migration of cancer cells. This study examined the expression of Girdin in relation to clinicopathological features and other immunohistochemical markers (HER2, Ki-67), especially in patients with HNLT breast cancer. METHODS: One hundred one breast cancer patients who underwent surgery were evaluated. Immunohistochemical staining was performed for Girdin and other biomarkers, such as ER, PgR, HER2, and Ki-67. RESULTS: Positive expression of Girdin was observed in 26 patients. The expression of Girdin was significantly associated with the incidence of lymph node metastases (p = 0.001). Among the other examined biomarkers, positive expression of Ki-67 also showed a significant association with the incidence of lymph node metastases (p = 0.04). In the HNLT breast cancer patients (n = 73), the 5-year recurrence-free survival rate was significantly lower (57 %) in patients with positive expression of both Girdin and Ki-67 than the rate in other patients (92 %) (p = 0.002). CONCLUSION: This study demonstrated that the expression of Girdin in invasive breast cancer is strongly associated with lymph node metastasis. The expression status of Girdin and Ki-67 can be a useful biomarker in stratifying patients with HNLT breast cancer into those with high risk of recurrence and the need for additional chemotherapy. PMID- 24155037 TI - Care and survival of Mexican American women with node negative breast cancer: historical cohort evidence of health insurance and barrio advantages. AB - We hypothesized 3-way ethnicity by barrio by health insurance interactions such that the advantages of having adequate health insurance were greatest among Mexican American (MA) women who lived in barrios. Barrios were neighborhoods with relatively high concentrations of MAs (60% or more). Data were analyzed for 194 MA and 2,846 non-Hispanic white women diagnosed with, very treatable, node negative breast cancer in California between 1996 and 2000 and followed until 2011. Significant interactions were observed such that the protective effects of Medicare or private health insurance on radiation therapy access and long term survival were largest for MA women who resided in MA barrios, neighborhoods that also tended to be extremely poor. These paradoxical findings are consistent with the theory that more facilitative social and economic capital available to MA women in barrios enables them to better absorb the indirect and direct, but uncovered, costs of breast cancer care. PMID- 24155041 TI - Carprofen analogues as sirtuin inhibitors: enzyme and cellular studies. AB - The best of both: SIRT1/2 inhibitors were developed by combining chemical features of selisistat (SIRT1-selective inhibitor; blue) and carprofen (anti inflammatory drug; red). The most potent compound (shown) increased acetyl-p53 and acetyl-alpha-tubulin levels, and induced slight apoptosis at 50 MUM in U937 cells, differently from selisistat and carprofen. PMID- 24155042 TI - Characterization of telmisartan-derived PPARgamma agonists: importance of moiety shift from position 6 to 5 on potency, efficacy and cofactor recruitment. AB - Selective modulation of the peroxisome proliferator-activated receptor gamma (PPARgamma) by direct binding of small molecules demonstrates a promising tool for treatment of insulin resistance and type 2 diabetes mellitus. Besides its blood pressure-lowering properties, the AT1-receptor blocker telmisartan has been shown to be a partial agonist of PPARgamma with beneficial metabolic effects in vitro and in mice. In our previous work, comprehensive structure-activity relationship (SAR) studies discussed the different parts of the telmisartan structure and various moieties. Based on these findings, we designed and synthesized new PPARgamma ligands with a benzimidazole (agonists 4-5 and 4-6), benzothiophene (agonists 5-5 and 5-6) or benzofuran (agonists 6-5 and 6-6) moiety either at position 5 or 6 of the benzimidazole core structure. Lipophilicity and EC50 values were improved for all new compounds compared with telmisartan. Regarding PPARgamma activation, the compounds were characterized by a differentiation assay using 3T3-L1 cells and a luciferase assay with COS-7 cells transiently transfected with pGal4-hPPARgDEF, pGal5-TK-pGL3 and pRL-CMV. A decrease in both potency and efficacy was observed after the shift of either the benzothiophene or the benzofuran moiety from position 6 to position 5. Selective recruitment of the coactivators TRAP220, SRC-1 and PGC-1alpha, and release of corepressor NCoR1 determined by time-resolved fluorescence resonance energy transfer (TR-FRET) was detected depending on residues in position 5 or 6. PMID- 24155044 TI - Neoplastic causes of abnormal puberty. AB - BACKGROUND: Neoplasm-related precocious puberty (PP) is a rare presenting feature of childhood cancer. Moreover, evaluation of suspected PP in a child is complex, and cancer is often not considered. We characterized the clinicopathologic features of patients presenting with PP at a large pediatric cancer center, reviewed the relevant literature, and developed an algorithm for the diagnostic work-up of these patients. METHODS: We examined the records of all patients with a neoplasm and concomitant PP treated at St. Jude Children's Research Hospital from January 1975 through October 2011, reviewed the available literature, and analyzed the demographic, clinical, endocrine, and neoplasm-related features. RESULTS: Twenty-four of 13,615 children and adolescents (0.18%) were diagnosed with PP within 60 days of presentation. Primary diagnoses included brain tumor (12), adrenocortical carcinoma (5), hepatoblastoma (4), and others (3). PP was observed 0-48 months before diagnosis of neoplasm; 17 patients had peripheral PP and 7 had central PP. CONCLUSIONS: Neoplasm-related PP is rare and takes the form of a paraneoplastic syndrome caused by tumor production of hormones or by alteration of physiologic gonadotropin production. PP can precede diagnosis of malignancy by months or years, and neoplastic causes should be considered early to avoid delayed cancer diagnosis. Treatment of the primary malignancy resolved or diminished PP in surviving patients with an intact hypothalamic-pituitary gonadal axis. PMID- 24155045 TI - Muscle shear modulus measured with ultrasound shear-wave elastography across a wide range of contraction intensity. AB - INTRODUCTION: In this study we examine the repeatability of measuring muscle shear modulus using ultrasound shear-wave elastography between trials and between days, and the association between shear modulus and contraction intensity over a wide range of intensities. METHODS: Shear modulus of the biceps brachii was determined using ultrasound shear-wave elastography during static elbow flexion (up to 60% of maximal contraction) in healthy young adults. RESULTS: The correspondence of shear modulus was confirmed in phantoms between the manufacturer-calibrated values and the shear-wave elastography values. The intraclass correlation coefficient of muscle shear modulus was high: 0.978 between trials and 0.948 between days. Shear modulus increased linearly with elbow flexion torque across contraction intensity, and its slope was associated negatively with muscle strength. CONCLUSIONS: Muscle shear modulus measured with ultrasound shear-wave elastography may be useful for inferring muscle stiffness across a wide range of contraction intensity. In addition, it has high repeatability between trials and between days. PMID- 24155046 TI - Characteristics of human adipose mesenchymal stem cells isolated from healthy and cancer affected people and their interactions with human breast cancer cell line MCF-7 in vitro. AB - Adipose tissue is an attractive source of mesenchymal stem/stromal cells (MSCs) with potential applications in reconstructive plastic surgery and regenerative medicine. The aim of this study was to characterise human adipose tissue MSCs (ASCs) derived from healthy individuals and cancer patients and to compare their interactions with tumour cells. ASCs were isolated from adipose tissue of healthy donors, breast cancer-adjacent adipose tissue of breast cancer patients and tumour-adjacent adipose tissue of non-breast cancer patients. Their proliferation, differentiation, immunophenotype and gene expression were assessed and effects on the proliferation of human breast cancer cell line MCF-7 compared. ASCs from all sources exhibited similar morphology, proliferative and differentiation potential, showing the characteristic pattern of mesenchymal surface markers expression (CD90, CD105, CD44H, CD73) and the lack of HLA-DR and hematopoietic markers (CD11a, CD33, CD45, Glycophorin-CD235a), but uneven expression of CD34. ASCs also shared a common positive gene expression of HLA-DR, HLA-A, IL-6, TGF-beta and HIF-1, but were negative for HLA-G, while the expression levels of Cox-2 and IDO-1 varied. All ASCs significantly stimulated the proliferation of MCF-7 tumour cells in direct mixed co-cultures and transwell system, although their conditioned media displayed antiproliferative activity. Data obtained showed that ASCs with similar characteristics are easily isolated from various donors and sites of origin, although ASCs could both suppress and favour tumour cells growth, emphasising the importance of cellular context within the microenvironment and pointing to the significance of safety studies to exclude any potential clinical risk of their application in regenerative medicine. PMID- 24155047 TI - WITHDRAWN: Vitamin C supplementation for asthma. PMID- 24155048 TI - Helicobacter pylori antibody responses and evolution of precancerous gastric lesions in a Chinese population. AB - Helicobacter pylori-specific proteins are involved in gastric carcinogenesis. To investigate the seroprevalence of six H. pylori-specific antibodies in patients with different gastric histology, and the impact of seropositivities on the evolution of precancerous gastric lesions, a follow-up study was conducted in Linqu County, China. The seropositivities for CagA, VacA, GroEL, UreA, HcpC and gGT were assessed by recomLine analysis in 573 H. pylori-positive subjects and correlated with evolution of precancerous gastric lesions. We found that the score of H. pylori recomLine test was significantly increased in subjects with chronic atrophic gastritis (CAG, p < 0.0001) or intestinal metaplasia (IM, p = 0.0125), and CagA was an independent predictor of advanced gastric lesions, adjusted odds ratios (ORs) were 2.54 (95% CI = 1.42-4.55) for IM and 2.38 (95% CI = 1.05-5.37) for dysplasia (DYS). Moreover, seropositivities for CagA and GroEL were identified as independent predictors for progression of gastric lesions in a longitudinal study, and ORs were 2.89 (95% CI = 1.27-6.59) and 2.20 (95% CI = 1.33-3.64), respectively. Furthermore, the risk of progression was more pronounced in subjects with more than three positive antigens (p(for) trend = 0.0003). This population-based study revealed that seropositivities for CagA and GroEL might be potential markers to identify patients infected with high-risk H. pylori strains, which are related to the development of GC in a Chinese high-risk population, and recomLine test might serve as a tool for risk stratification. PMID- 24155049 TI - Analysis of jump performance of world-class mogul skiers over an Olympic quadrennial cycle: a case study. AB - This case study examines the longitudinal jump data of 1 male and 1 female world class mogul skier over the course of a quadrennial leading to the 2010 Winter Olympics. Between-subjects standard deviation, smallest worthwhile enhancement, % coefficient of variance, and effect size (ES) were calculated from team jump testing taking place immediately preceding the 2010 Winter Olympics, as this was deemed the point in the quadrennial that the athlete group would be most likely near their best performance. These data were then used to characterize the progression of explosive power of elite mogul skiers over an Olympic quadrennial. Jump data for both the male and the female athlete showed trivial to large improvements in jump performance from Q1 (quadrennial year 1) to Q2, variable changes in performance from Q2 to Q4, and an overall improvement (small to large ES) from Q1 to Q4. Explosive power is a critical component of performance for moguls, and an analysis of the group data (Canadian athletes 2006-2010) shows that of all performance markers, jump testing is the variable that clearly delineates between World Cup and developmental athletes. PMID- 24155050 TI - Drug-induced sleep endoscopy in sleep-disordered breathing: report on 1,249 cases. AB - OBJECTIVES/HYPOTHESIS: To describe upper airway (UA) collapse patterns during drug-induced sleep endoscopy (DISE) in a large cohort of patients with sleep disordered breathing (SDB) and to assess associations with anthropometric and polysomnographic parameters. STUDY DESIGN: Observational study. METHODS: A total of 1,249 patients [age 47 +/- 10 y; apnea-hypopnea index (AHI) 18.9 +/- 15.3/h; body mass index (BMI) 27.2 +/- 3.7 kg/m(2)] underwent polysomnography and DISE. DISE findings were categorized to the following UA levels: palate, oropharynx, tongue base, and hypopharynx. The degree of collapse was reported as complete, partial, or none. The pattern of the obstruction was described as anteroposterior, lateral, or concentric. Associations between DISE findings and anthropometric and polysomnographic parameters were analyzed. RESULTS: Palatal collapse was seen most frequently (81%). Multilevel collapse was noted in 68.2% of all patients. The most frequently observed multilevel collapse pattern was a combination of palatal and tongue base collapse (25.5%). Palatal collapse was seen most frequently (81%). The prevalence of complete collapse, multilevel collapse, and hypopharyngeal collapse increased with increasing severity of obstructive sleep apnea (OSA). Multilevel and complete collapse were more prevalent in obese patients and in those with more severe OSA. Both higher BMI and AHI values were associated with a higher probability of complete concentric palatal collapse. CONCLUSION: The current study provides an overview of UA collapse patterns in a large cohort of SDB patients who underwent DISE. The associations found in this study may indicate that UA collapse patterns observed during DISE cannot be fully explained by selected baseline polysomnographic and anthropometric characteristics. PMID- 24155051 TI - alpha-(1,4)-Amylase, but not alpha- and beta-(1,3)-glucanases, may be responsible for the impaired growth and morphogenesis of Paracoccidioides brasiliensis induced by N-glycosylation inhibition. AB - The cell wall of Paracoccidioides brasiliensis, which consists of a network of polysaccharides and glycoproteins, is essential for fungal pathogenesis. We have previously reported that N-glycosylation of proteins such as N-acetyl-beta-D glucosaminidase is required for the growth and morphogenesis of P. brasiliensis. In the present study, we investigated the influence of tunycamicin (TM)-mediated inhibition of N-linked glycosylation on alpha- and beta-(1,3)-glucanases and on alpha-(1,4)-amylase in P. brasiliensis yeast and mycelium cells. The addition of 15 ug/ml TM to the fungal cultures did not interfere with either alpha- or beta (1,3)-glucanase production and secretion. Moreover, incubation with TM did not alter alpha- and beta-(1,3)-glucanase activity in yeast and mycelium cell extracts. In contrast, alpha-(1,4)-amylase activity was significantly reduced in underglycosylated yeast and mycelium extracts after exposure to TM. In spite of its importance for fungal growth and morphogenesis, N-glycosylation was not required for glucanase activities. This is surprising because these activities are directed to wall components that are crucial for fungal morphogenesis. On the other hand, N-glycans were essential for alpha-(1,4)-amylase activity involved in the production of malto-oligosaccharides that act as primer molecules for the biosynthesis of alpha-(1,3)-glucan. Our results suggest that reduced fungal alpha (1,4)-amylase activity affects cell wall composition and may account for the impaired growth of underglycosylated yeast and mycelium cells. PMID- 24155052 TI - [How sustainable is supported employment? A follow-up investigation]. AB - SUBJECT: The largest European multicenter randomized controlled trial to date on the effectiveness of supported employment (EQOLISE) was conducted in six European centres until 2005. It revealed that the intervention "individual placement and support" was more effective than conventional prevocational training services. The aim of this investigation was to assess the Zurich sample (individuals with schizophrenic, schizoaffective or bipolar disorders) 24 months after termination of the EQOLISE trial in terms of working situation, income, and hospital admissions. More favorable outcomes concerning these parameters were assumed for the intervention group. METHODS: Assessment of the working situation and psychiatric hospitalizations since the end as well as the development of salaries since the start of EQOLISE. Comparisons between groups and illustration of incomes using a random coefficient model were conducted. RESULTS: 50% of the original sample could be assessed. All subjects who worked in competitive workplaces at the end of EQOLISE were met in a different situation. No differences were found concerning hospital admissions. The mean monthly income considerably increased during EQOLISE and decreased during the third year. At the time of follow-up it was approximately at the same level as the slightly increased control group. CONCLUSIONS: This investigation points at limited sustainability of supported employment among individuals with severe mental disorders in terms of maintenance of employment and income if the job coaching is not continued. PMID- 24155053 TI - Refined structures of mouse P-glycoprotein. AB - The recently determined C. elegans P-glycoprotein (Pgp) structure revealed significant deviations compared to the original mouse Pgp structure, which suggested possible misinterpretations in the latter model. To address this concern, we generated an experimental electron density map from single-wavelength anomalous dispersion phasing of an original mouse Pgp dataset to 3.8 A resolution. The map exhibited significantly more detail compared to the original MAD map and revealed several regions of the structure that required de novo model building. The improved drug-free structure was refined to 3.8 A resolution with a 9.4 and 8.1% decrease in R(work) and R(free), respectively, (R(work) = 21.2%, R(free) = 26.6%) and a significant improvement in protein geometry. The improved mouse Pgp model contains ~95% of residues in the favorable Ramachandran region compared to only 57% for the original model. The registry of six transmembrane helices was corrected, revealing amino acid residues involved in drug binding that were previously unrecognized. Registry shifts (rotations and translations) for three transmembrane (TM)4 and TM5 and the addition of three N-terminal residues were necessary, and were validated with new mercury labeling and anomalous Fourier density. The corrected position of TM4, which forms the frame of a portal for drug entry, had backbone atoms shifted >6 A from their original positions. The drug translocation pathway of mouse Pgp is 96% identical to human Pgp and is enriched in aromatic residues that likely play a collective role in allowing a high degree of polyspecific substrate recognition. PMID- 24155054 TI - Ezrin expression is an independent prognostic factor in gastro-intestinal cancers. AB - BACKGROUND: Ezrin, a member of the ezrin-radixin-moesin (ERM) family of plasma membrane-cytoskeleton linker proteins, has been associated with metastatic behavior. METHODOLOGY: Microarrayed pathological tissues of surgically resected colorectal cancer liver metastasis (CRLM) and whole tissue sections of cancer of the ampulla of Vater (CAV) were analyzed to determine ezrin expression levels and correlation with survival. The requirement of ezrin in invasive capability was assessed using in vitro assays. RESULTS: Surgically resected CAV showing a low ezrin score have a better 5-year disease-specific survival than those showing a high ezrin score (P < 0.0001). Similarly, high ezrin expression at the invasive front of CRLM resulted in poor disease-free survival (P = 0.05). Multivariate analysis demonstrated high ezrin expression to be an independent adverse prognostic factor for CAV (hazard ratio (HR) 15.22 (95 % confidence interval (CI) 1.98-117.03), P < 0.01) and CRLM (HR 6.42 (95 % CI 1.01-52.43), P = 0.05), among other clinically relevant variables such as lymph node metastasis (for CAV) and the presence of extrahepatic disease, large hepatic metastases (>5 cm), and close surgical resection margins (<5 mm) (all for CRLM). In vitro experiments indicated that ezrin expression was vital for cellular processes such as adhesive and invasive activity. SIGNIFICANCE: High ezrin expression indicates an adverse prognosis in primary CAV and CRLM. PMID- 24155055 TI - Cross-sectional assessment of exertional dyspnea in otherwise healthy children. AB - OBJECTIVES: Exertional dyspnea during sport at school in children with asthma or in otherwise healthy children is commonly attributed to exercise-induced asthma (EIA), but when a short-acting beta agonist (SABA) trial fails to improve symptoms the physician is often at a loose end. DESIGN: The aims were to prospectively assess the causes of exertional dyspnea in children/adolescents with or without asthma using a cardiopulmonary exercise test while receiving a SABA and to assess the effects of standardized breathing/reassurance therapy. RESULTS: Seventy-nine patients (12.2 +/- 2.3 years, 41 girls, 49 with previously diagnosed asthma) with dyspnea unresponsive to SABA were prospectively included. Exercise test outcomes depicted normal or subnormal performance with normal ventilatory demand and capacity in 53/79 children (67%) defining a physiological response. The remaining 26 children had altered capacity (resistant EIA [n = 17, 9 with previous asthma diagnosis], vocal cord dysfunction [n = 2]) and/or increased demand (alveolar hyperventilation [n = 3], poor conditioning [n = 7]). Forty-two children who had similar characteristics than the remaining 37 children underwent the two sessions of standardized reassurance therapy. They all demonstrated an improvement that was rated "large." The degree of improvement correlated with % predicted peak V'O2 (r = -0.37, P = 0.015) and peak oxygen pulse (r = -0.45, P = 0.003), whatever the underlying dyspnea cause. It suggested a higher benefit in those with poorer conditioning condition. CONCLUSIONS: The most frequent finding in children/adolescents with mild exertional dyspnea unresponsive to preventive SABA is a physiological response to exercise, and standardized reassurance afforded early clinical improvement, irrespective of the dyspnea cause. PMID- 24155056 TI - Age distribution for partial and radical nephrectomy: whose nephrons are being spared? AB - INTRODUCTION: Nephron sparing surgery (NSS) is recommended for patients with T1 renal cell carcinoma (RCC) whenever surgically feasible. By analyzing data from all urological clinics in the whole state of Lower Saxony, Germany, regardless of clinic size or level of expertise, we investigated whether current practice reflects the need for NSS in older patients on a broader scale. METHODS: From 2005 to 2010, more than 100 medical facilities and urological clinics in Lower Saxony, Germany were evaluated for their individual rates of partial nephrectomy (PN) and radical nephrectomy (RN) based on patient's age in 5-year intervals. RESULTS: Sufficient data on age were available for 3,332 out of 3,693 patients with RCC undergoing surgery. PN rates for all patients and for those with T1 RCC were 19.9% and 29.5%, respectively. For all patients with RCC, the rates for PN and RN below the median age (<66.8 years) were 365 (21.9%) and 1,302 (78.1%) and above the median age were 297 (17.8%) and 1,368 (82.2%), respectively (P = 0.003). For patients with T1 RCC, the rates for PN and RN below the median age (<66.5 years) were 341 (32.6%) and 704 (67.4%) and above the median age were 277 (26.4%) and 774 (73.6%), respectively (P = 0.002). The highest rate for each type of surgery was seen in those aged 65-70 years, except for patients with T1 RCC receiving RN who were mostly operated on when aged 70-75 years. CONCLUSION: The rate of PN for all patients with RCC in this series and especially for patients with T1 RCC is significantly lower in older patients, thereby not reflecting the need and understanding for NSS in the higher age segment. Broader education and teaching of NSS might improve treatment of RCC in the future. PMID- 24155057 TI - Prevalence and properties of mecC methicillin-resistant Staphylococcus aureus (MRSA) in bovine bulk tank milk in Great Britain. AB - OBJECTIVES: mecC methicillin-resistant Staphylococcus aureus (MRSA) represent a newly recognized form of MRSA, distinguished by the possession of a divergent mecA homologue, mecC. The first isolate to be identified came from bovine milk, but there are few data on the prevalence of mecC MRSA among dairy cattle. The aim of this study was to conduct a prevalence study of mecC MRSA among dairy farms in Great Britain. METHODS: Test farms were randomly selected by random order generation and bulk tank samples were tested for the presence of mecC MRSA by broth enrichment and plating onto chromogenic agar. All MRSA isolated were screened by PCR for mecA and mecC, and mecC MRSA were further characterized by multilocus sequence typing, spa typing and antimicrobial susceptibility testing. RESULTS: mecC MRSA were detected on 10 of 465 dairy farms sampled in England and Wales (prevalence 2.15%, 95% CI 1.17%-3.91%), but not from 625 farms sampled in Scotland (95% CI of prevalence 0%-0.61%). Seven isolates belonged to sequence type (ST) 425, while the other three belonged to clonal complex 130. Resistance to non-beta-lactam antibiotics was uncommon. All 10 isolates produced a negative result by slide agglutination for penicillin-binding protein 2a. mecA MRSA ST398 was detected on one farm in England. CONCLUSIONS: mecC MRSA is widely distributed among dairy farms in Great Britain, but this distribution is not uniform across the whole country. These results provide an important baseline dataset to monitor the epidemiology of this emerging form of MRSA. PMID- 24155058 TI - Pharmacokinetic evaluation of the interaction between etravirine and rifabutin or clarithromycin in HIV-negative, healthy volunteers: results from two Phase 1 studies. AB - OBJECTIVES: Drug-drug interactions between etravirine and rifabutin or clarithromycin were examined in two separate open-label, randomized, two-period, crossover trials in HIV-negative, healthy volunteers. METHODS: Rifabutin study: 16 participants received 300 mg of rifabutin once daily (14 days) and then 800 mg of etravirine twice daily (Phase 2 formulation; 21 days) plus 300 mg of rifabutin once daily (days 8-21). Clarithromycin study: 16 participants received 200 mg of etravirine twice daily (commercial formulation; 8 days) and then 500 mg of clarithromycin twice daily (13 days) plus 200 mg of etravirine twice daily (days 6-13). A 14 day washout period between treatments was mandatory in both studies. Full pharmacokinetic profiles of each drug and safety/tolerability were assessed. RESULTS: Rifabutin decreased etravirine exposure by 37%; etravirine decreased rifabutin and 25-O-desacetyl rifabutin exposure by 17%. Clarithromycin increased etravirine exposure by 42%, whereas etravirine decreased clarithromycin exposure by 39% and increased 14-OH clarithromycin exposure by 21%. No serious adverse events were reported in either trial. CONCLUSIONS: Short-term etravirine coadministration with rifabutin or clarithromycin was well tolerated. Etravirine can be coadministered with 300 mg of rifabutin once daily in the absence of an additional potent cytochrome P450 inducer. No dose adjustments are required upon etravirine/clarithromycin coadministration, but alternatives to clarithromycin are recommended when used for Mycobacterium avium complex prophylaxis or treatment. PMID- 24155060 TI - Genomic analysis of the emergence and evolution of multidrug resistance during a Klebsiella pneumoniae outbreak including carbapenem and colistin resistance. AB - OBJECTIVES: To characterize at the genomic level the evolution of multiresistance during an outbreak of Klebsiella pneumoniae in a burns intensive care unit. The outbreak involved a DHA-1 beta-lactamase-producing strain that later acquired carbapenem and fosfomycin resistance, and in one case colistin resistance. METHODS: The genomes of two isolates were sequenced and compared with a previously sequenced genome. The role of hypermutability was investigated by measuring the mutation frequencies of the isolates and comparison with a collection of control strains. RESULTS: Sequence comparison identified four single-nucleotide variants and two transposon insertions. Analysis of the variants in the whole collection related carbapenem and fosfomycin resistance to a nonsense mutation in the ompK36 porin gene and colistin resistance to an IS1 insertion in the mgrB gene. The plasmid carrying the blaDHA-1 gene was unstable in the absence of antibiotics, and analysis of isolates that had lost the plasmid showed that the porin mutation alone was not sufficient to generate carbapenem resistance. The mutation frequencies were similar among all the strains analysed. CONCLUSIONS: Carbapenem resistance required production of the DHA-1 beta lactamase and decreased permeability, but fosfomycin resistance depended only on permeability. Resistance to colistin might be related to an alteration in the regulation of the phoPQ system. Hypermutation is not related to the selection of porin mutants. Plasmid instability might be due to the high number of mobile elements and suggests a major role for antibiotic selection pressure in the emergence and evolution of this outbreak. PMID- 24155061 TI - Combretastatin A-4 induces p53 mitochondrial-relocalisation independent-apoptosis in non-small lung cancer cells. AB - Combretastatin A-4 (CA-4) is one of the most effective agents used in chemotherapy. Nevertheless, the contribution of p53 and Bim proteins in the CA-4 induced apoptosis in non-small lung cancer cells (NSCLC) remains unresolved, specifically on involving of p53 in the mitochondrial pathway activation by a transcription-independent mechanism. In this context, the p53-null H1299 and wt p53 H460 NSCLC cells, in the absence and presence of pifithrin-u (PFTu), an inhibitor of p53 mitochondrial-translocation, were treated with CA-4 and different cellular endpoints were analysed. In contrast to previous observations in H460 cells, CA-4 failed in the activation of an apoptotic response in H1299 cells, thus indicating an involvement of p53 in the cell death induced by the drug. We found that CA-4 led to p53 cellular re-localisation in H460 cells; in particular, p53 was released from the microtubular network and accumulated at mitochondria where it interacts with Bim protein and other proteins of the Bcl-2 (B-cell leukaemia-2) family, leading to cytochrome c release, alteration in the mitochondrial membrane polarisation, cell cycle arrest at the G2/M-phase, and cell death. Interestingly, the cytosolic and the mitochondrial accumulation of protein Bim was strictly dependent on p53 status. The extent of cell death was not reduced in H460 after combined treatment of PFTu with CA-4. Overall, the data support a model of CA-4-induced apoptosis in NSCLC, for which the expression of p53 protein is essential, but its mitochondrial function, linked to p53 transcription independent apoptosis pathway, is negligible. PMID- 24155062 TI - Effects of 1 versus 2 games a week on physical and subjective scores of subelite soccer players. AB - The physical-performance profiles of subelite male footballers were monitored during 6 wk of a competitive season. The same squad of players played either 1 (1G, n = 15) or 2 (2G, n = 15) competitive matches per week. On weeks 0, 3, and 6, 48 h postmatch, players completed countermovement jump (CMJ), 10- and 20-m sprints, the Yo-Yo Intermittent Recovery Test (YYIRT), and the Recovery-Stress Questionnaire. Both groups undertook 2 weekly training sessions. The 2G showed after 6 wk lower YYIRT (-11% to 3%, 90% CI -15.8% to -6.8%; P < .001) and CMJ performances (-18.7%, -21.6 to -15.9%; P = .007) and higher 10-m (4.4%, 1.8-6.9%; P = .007) and 20-m sprints values (4.7%, 2.9% to 6.4%; P < .001). No differences were found at 3 wk (.06 < P < .99). No changes over time (.169 < P < .611) and no differences time * group interactions (.370 < P < .550) were found for stress, recovery, and the Stress Recovery Index. In conclusion players' ability to sprint, jump, and perform repeated intense exercise was impaired when playing 2 competitive matches a week over 6 wk. PMID- 24155059 TI - Longitudinal analysis of HIV-1 coreceptor tropism by single and triplicate HIV-1 RNA and DNA sequencing in patients undergoing successful first-line antiretroviral therapy. AB - OBJECTIVES: Maraviroc has been shown to be effective in patients harbouring CCR5 tropic HIV-1. While this CCR5 antagonist has initially been used in salvage therapy, its excellent safety profile makes it ideal for antiretroviral treatment simplification strategies in patients with suppressed plasma viraemia. The aim of this study was to compare HIV-1 tropism as detected in baseline plasma RNA and peripheral blood mononuclear cell (PBMC) DNA prior to first-line therapy and to analyse tropism evolution while on successful treatment. METHODS: HIV-1 tropism was determined using triplicate genotypic testing combined with geno2pheno[coreceptor] analysis at a 10% false positive rate in 42 patients. Paired pre-treatment plasma RNA and PBMC DNA and two subsequent PBMC DNA samples (the first obtained after reaching undetectable plasma HIV-1 RNA and the second after at least 2 years of suppression of plasma viraemia) were evaluated. RESULTS: Coreceptor tropism was completely concordant in paired pre-treatment RNA and DNA, with 26.2% of HIV-1 sequences predicted to be non-CCR5-tropic. During follow-up, coreceptor tropism switches were detected in 4 (9.5%) patients without any preferential direction. Although false positive rate discrepancies within triplicates were common, the rate of discordance of coreceptor tropism assignment among triplicate results in this mostly CCR5-tropic dataset was only 2.1%, questioning the added value of triplicate testing compared with single testing. CONCLUSIONS: HIV-1 coreceptor tropism changes during virologically successful first-line treatment are infrequent. HIV-1 DNA analysis may thus support the choice of a CCR5 antagonist in treatment switch strategies; however, maraviroc treatment outcome data are required to confirm this option. PMID- 24155063 TI - Efficient chemical and visible-light-driven water oxidation using nickel complexes and salts as precatalysts. AB - Chemical and visible-light-driven water oxidation catalyzed by a number of Ni complexes and salts have been investigated at pH 7-9 in borate buffer. For chemical oxidation, [Ru(bpy)3](3+) (bpy = 2,2'-bipyridine) was used as the oxidant, with turnover numbers (TONs) >65 and a maximum turnover frequency (TOFmax) >0.9 s(-1). Notably, simple Ni salts such as Ni(NO3 )2 are more active than Ni complexes that bear multidentate N-donor ligands. The Ni complexes and salts are also active catalysts for visible-light-driven water oxidation that uses [Ru(bpy)3](2+) as the photosensitizer and S2 O8 (2-) as the sacrificial oxidant; a TON>1200 was obtained at pH 8.5 by using Ni(NO3)2 as the catalyst. Dynamic light scattering measurements revealed the formation of nanoparticles in chemical and visible-light-driven water oxidation by the Ni catalysts. These nanoparticles aggregated during water oxidation to form submicron particles that were isolated and shown to be partially reduced beta-NiOOH by various techniques, which include SEM, energy-dispersive X-ray spectroscopy, X-ray photoelectron spectroscopy, XRD, and IR spectroscopy. These results suggest that the Ni complexes and salts act as precatalysts that decompose under oxidative conditions to form an active nickel oxide catalyst. The nature of this active oxide catalyst is discussed. PMID- 24155064 TI - Voice in female-to-male transsexual persons after long-term androgen therapy. AB - OBJECTIVES/HYPOTHESIS: The aim of the present study was to 1) document voice in a large sample of female-to-male transsexual persons (FMT), 2) compare their vocal characteristics with those of heterosexual biological males, and 3) determine hormonal factors with impact on their fundamental frequency. STUDY DESIGN: This was a controlled cross-sectional study. It is the largest study to date on voice and voice change in FMT, and the first to include a control group and FMT who were under long-term androgen administration. METHODS: Thirty-eight FMT, ranging in age between 22 and 54 years, and 38 controls, frequency matched by age and smoking behavior, underwent a voice assessment that comprised the determination of pitch, intonation, and perturbation parameters measured during sustained vowel production, counting, and reading. Hormonal factors explored were hematocrit, total testosterone level, luteinizing hormone level, and biallelic mean length of the cytosine-adenine-guanine (CAG) trinucleotide repeat sequence in the androgen receptor gene. RESULTS: It was found that the FMT as a group did not differ significantly from controls for any of the acoustic voice variables studied. However, in about 10% pitch lowering was not totally unproblematic. The lowest pitched (i.e., more male) voices were observed in FMT with higher hematocrit and longer CAG repeats. CONCLUSION: After long-term androgen therapy, FMT generally demonstrate an acceptable male voice. Pitch-lowering difficulties can be expected in about 10% of cases and appear, at least in part, to be associated with diminished androgen sensitivity. LEVEL OF EVIDENCE: 3b. PMID- 24155065 TI - Ovarian reserve test: an impartial means to resolve the mismatch between chronological and biological age in the assessment of female reproductive chances. AB - Nowadays, the ovarian reserve (OR) is considered more important than chronological age to estimate female reproductive capability. We conducted a retrospective, observational, and cohort study in order to detect the best predictor marker of OR, ovarian response, chances to obtain high-quality embryos, and pregnancy after in vitro fertilization (IVF) cycle in elderly women. For all eligible patients (aged between 40 and 50 and admitted to their first IVF cycle for primary infertility), we investigated the biochemical parameters and ultrasound aspects of ovaries and how they affected IVF outcomes. Age, basal follicle-stimulating hormone, basal luteinizing hormone, and basal-17beta estradiol are better related to the dose of gonadotropin used during a controlled ovarian stimulation cycle. Basal anti-Mullerian hormone (AMH), antral follicular count (AFC), and maximum serum level of 17beta-estradiol before pickup resulted the best predictors of chances to retrieve at least 6 oocytes (at least 3 in metaphase II) and to have at least 1 to 3 embryos. The basal AMH, AFC and maximum serum level of 17beta-estradiol before pickup continue to show higher correlation to pregnancy rate. The maximum endometrial thickness at pickup resulted important to predict the pregnancy rate and the chances to detect ongoing pregnancy. It seems mandatory to well define the ovarian biological age rather than the chronological one in women older than 40 years of age in order to give the best counseling and to choose the most appropriate IVF protocols. PMID- 24155066 TI - Excess maternal glucocorticoids in response to in utero undernutrition inhibit offspring angiogenesis. AB - To test the hypothesis that inhibition of offspring angiogenesis by maternal undernutrition (MUN) is mediated by maternal glucocorticoids, 3 groups of dams were studied: controls received ad libitum food; MUN dams were food restricted by 50% from day 10 of gestation; and metyrapone (MET) dams were food restricted and treated with 0.5 mg/mL of MET, a glucocorticoid synthesis inhibitor. The MUN reduced birth weights, reduced vascular endothelial growth factor (VEGF) abundance in P1 aortas, reduced VEGF and VEGF-R2 abundances in P1 mesenteric arterioles, reduced arteriolar endothelial nitric oxide synthase abundance, reduced microvessel density in the anterior tibialis, reduced endothelial cell branching in culture, reduced arteriolar immunoreactivity for proliferating cell nuclear antigen (PCNA), increased active caspase 3 in P1 mesenteric arterioles, and decreased matrix metalloproteinase (MMP)-2 and MMP-9 abundances in lysates of P1 aortas. All of these effects were prevented by treatment with metyrapone. Collectively, these findings suggest that reduced angiogenesis in MUN offspring involves direct inhibitory effects of maternal glucorticoid on fetal VEGF and its receptors. PMID- 24155068 TI - Signs of early sub-clinical atherosclerosis in childhood cancer survivors. AB - BACKGROUND: Cancer is the leading cause of death by disease among U.S. children ages 1-14 years; however, over the last few decades there has been a dramatic increase in survival in these individuals. Although free of cancer, survivors are faced with a variety of chronic health problems including an increased risk of cardiovascular and metabolic abnormalities. The effect of cancer treatments on vascular structure and function in childhood cancer survivors (CCS) has not been examined. PROCEDURE: Measures of carotid artery stiffness (compliance and distensibility) and thickness (IMT), brachial artery endothelial-dependent dilation (EDD), and endothelial-independent dilation (EID) were obtained from ultrasound imaging in 319 CCS (age: 14.6 +/- 0.1 years; male/female: 112/96) who were >5 years from diagnosis and 208 (age: 13.6 +/- 0.2 years; male/female: 171/148) siblings who had never been diagnosed with cancer. Participants were 9 18 years of age at examination. RESULTS: Survivors of leukemia had lower carotid distensibility and compliance, indicating increased arterial stiffness, when compared to controls. There were no significant differences in measures of carotid stiffness or EDD in survivors of solid tumors and central nervous system (CNS) tumors compared to controls. EDD was lower in leukemia survivors than in controls, and EID was greater in survivors of CNS tumors than in controls. CONCLUSION: These results demonstrate that early in life, CCS have arterial changes indicating increased risk for premature atherosclerosis and cardiovascular disease. Therefore, it is reasonable to advocate that efforts should be directed at monitoring and managing cardiovascular risk factors in CCS. PMID- 24155067 TI - Trophoblast invasion and blood vessel remodeling are altered in a rat model of lifelong maternal obesity. AB - Maternal obesity is associated with an increased risk of a number of pregnancy complications, including fetal demise, which may be linked to impaired placental development as a result of altered trophoblast invasion and vessel remodeling. Therefore, we examined these parameters in pregnant rats fed a control (normal weight) or high fat (HF) diet (obese) at 2 critical times of rat placental development. Early trophoblast invasion was increased by approximately 2-fold in HF-fed dams with a concomitant increase in the expression of matrix metalloproteinase 9 protein, a mediator of tissue remodeling and invasion. Furthermore, we observed significantly higher levels of smooth muscle actin surrounding the placental spiral arteries of HF-fed dams, suggesting impaired spiral artery remodeling. Taken together, the results of this study suggest that altered placental development is an important contributor to the poor pregnancy outcomes and increased fetal demise in our model of lifelong maternal obesity. PMID- 24155069 TI - Effects of acupuncture on Chinese medicine syndromes of vascular dementia. AB - OBJECTIVE: To study the effects of acupuncture on Chinese medicine syndromes of vascular dementia (VaD). METHODS: Sixty-three VaD patients were divided into three groups. Those willing to be randomized were randomly assigned to receive either acupuncture (random acupuncture group, 24 cases) or rehabilitation training (guided rehabilitation group, 24 cases) for 6 weeks. Those unwilling to be randomized also received acupuncture for 6 weeks (non-random acupuncture group, 19 cases). Patient syndromes and their severity were evaluated before treatment (baseline), at the end of treatment, and at 4-week follow-up after the completion of treatment using a CM scoring system (scale of differentiation of syndromes of vascular dementia, SDSVD). The SDSVD scores of the random and non random acupuncture groups, and of all patients who received acupuncture (combined acupuncture group, 43 cases), were compared with those in the guided rehabilitation group. RESULTS: In the random, non-random, and combined acupuncture groups, SDSVD scores were significantly reduced at the end of treatment and at follow-up than at baseline. In the guided rehabilitation group, SDSVD scores were similar to baseline scores at the end of treatment and at follow-up. However, there were no significant differences in SDSVD scores among the three groups or between the combined acupuncture group and the guided rehabilitation group at any time points. In the non-random and combined acupuncture groups, SDSVD scores were significantly reduced at the end of treatment than at baseline in patients with hyperactivity of Liver (Gan)-yang or phlegm obstruction of the orifices. CONCLUSIONS: Acupuncture reduced the severity of VaD. The improvement was the greatest in patients undergoing their treatment of choice. Treatments in this study were more effective for excess syndromes, such as Liver-yang hyperactivity or phlegm obstruction of the orifices than deficiency syndromes, such as Kidney (Shen)-essence deficiency. PMID- 24155070 TI - Effect of curcumin on aged Drosophila melanogaster: a pathway prediction analysis. AB - OBJECTIVE: To re-analyze the data published in order to explore plausible biological pathways that can be used to explain the anti-aging effect of curcumin. METHODS: Microarray data generated from other study aiming to investigate effect of curcumin on extending lifespan of Drosophila melanogaster were further used for pathway prediction analysis. The differentially expressed genes were identified by using GeneSpring GX with a criterion of 3.0-fold change. Two Cytoscape plugins including BisoGenet and molecular complex detection (MCODE) were used to establish the protein-protein interaction (PPI) network based upon differential genes in order to detect highly connected regions. The function annotation clustering tool of Database for Annotation, Visualization and Integrated Discovery (DAVID) was used for pathway analysis. RESULTS: A total of 87 genes expressed differentially in D. melanogaster melanogaster treated with curcumin were identified, among which 50 were up-regulated significantly and 37 were remarkably down-regulated in D. melanogaster melanogaster treated with curcumin. Based upon these differential genes, PPI network was constructed with 1,082 nodes and 2,412 edges. Five highly connected regions in PPI networks were detected by MCODE algorithm, suggesting anti-aging effect of curcumin may be underlined through five different pathways including Notch signaling pathway, basal transcription factors, cell cycle regulation, ribosome, Wnt signaling pathway, and p53 pathway. CONCLUSION: Genes and their associated pathways in D. melanogaster melanogaster treated with anti-aging agent curcumin were identified using PPI network and MCODE algorithm, suggesting that curcumin may be developed as an alternative therapeutic medicine for treating aging-associated diseases. PMID- 24155071 TI - Delisheng Injection (), a Chinese medicinal compound, enhanced the effect of cis platinum on lung carcinoma cell line PGCL3. AB - OBJECTIVE: To investigate the effect of Delisheng Injection (, DLS), a Chinese medicinal compound, DLS combined with cis-platinum (DDP), an active agent used in lung cancer chemotherapy, on a human highly metastatic giant lung carcinoma cell line PGCL3. METHODS: The suspended PGCL3 cells at 10(5) /mL cultured in 96-well tissue culture plates were divided into 4 groups: DLS treatment group (2 MUL/mL, 5 MUL/mL, 10 MUL/mL, 25 MUL/mL), DDP treatment group (1 MUg/mL, 2 MUg/mL, 5 MUg/mL, 15 MUg/mL), combined DLS with DDP treatment group (DLS:DDP 2 MUL/mL:1 MUg/mL, 5 MUL/mL:2 MUg/mL, 10 MUL/mL:5 MUg/mL, 25 MUL/mL:15 MUg/mL) and a control group. The cytotoxicity of DLS with different concentrations (2 MUL/mL, 5 MUL/mL, 10 MUL/mL, 25 MUL/mL) on PGCL3 cells was determined by 3-(4,5)-dimethylthiahiazo( z-y1)-3,5-di-phenytetrazoliumromide (MTT) assay. Effect of DLS on adhesion of PGCL-3 cells was tested by cell-matrigel adhesion assay. Chemotactic movement model of transwell camerula was used to determine the effect of DLS on invasion and migration of PGCL-3 cells. RESULTS: Compared with the control group, DLS (2 MUL/mL, 5 MUL/mL, 10 MUL/mL, 25 MUL/mL) could significantly decrease cell proliferation, adhesion, invasion and migration abilities (P <0.05). Cell adhesion, invasion and migration abilities were significantly decreased after combination treatment of DLS:DDP (2 MUL/mL:1 MUg/mL, 5 MUL/mL:2 MUg/mL, 10 MUL/mL:5 MUg/mL, 25 MUL/mL:15 MUg/mL) compared with DDP single-agent treatment (1 MUg/mL, 2 MUg/mL, 5 MUg/mL, 15 MUg/mL, P<0.05), respectively. CONCLUSIONS: DLS single-agent has a satisfying inhibition effect in PGCL3 cell line and DLS might enhance the inhibition effect of DDP on cancer metastasis. Our research provided a experimental basis about the treatment on highly metastatic lung caner. PMID- 24155075 TI - The prevalence of asthma in Canadian children of South Asian descent. AB - BACKGROUND: Asthma is the most common disease in childhood. The prevalence of asthma is known to vary greatly between and within countries and among different ethnic groups. In this study, we aimed to determine the prevalence of asthma and wheezing symptoms in South Asian children living in Canada. METHODS: In a cross sectional study, data from the Phase III International Study on Asthma and Allergies in Childhood (ISAAC) were analyzed. A surname algorithm to determine South Asian ethnic descent was used. Prevalence was calculated and compared to non-South Asian children from the same survey and to the reported prevalence from the Indian subcontinent ISAAC III survey for children ages 6-9 and 13-16. RESULTS: The prevalence of asthma and wheezing did not differ between children of South Asian descent and non-South Asians living Canada. When compared to the children living in India, the prevalence of asthma, wheeze, and exercise induced wheeze was significantly higher in the South Asian children living in Canada. Higher body mass index of the child, parental smoking, and pet ownership were strongly associated with asthma and wheeze. CONCLUSIONS: In contrast to other studies these data suggest that South Asian children living in Canada have a similar asthma prevalence to non-South Asian children; both of whom had higher asthma prevalence compared with children residing in South Asia. This suggests that environmental and social factors play a role in asthma prevalence. Risk factors for asthma in children of South Asian descent living in Canada are similar to those of the overall population. PMID- 24155076 TI - An overview of the health economic implications of elective caesarean section. AB - The caesarean section rate has continued to increase in most industrialised countries, which raises a number of economic concerns. This review provides an overview of the health economic implications of elective caesarean section. It provides a succinct summary of the health consequences associated with elective caesarean section for both the infant and the mother over the perinatal period and beyond. It highlights factors that complicate our understanding of the health consequences of elective caesarean section, including inconsistencies in definitions and coding of the procedure, failure to adopt an intention-to-treat principle when drawing comparisons, and the widespread reliance on observational data. The paper then summarises the economic costs associated with elective caesarean section. Evidence is presented to suggest that planned caesarean section may be less costly than planned vaginal birth in some clinical contexts, for example where the singleton fetus lies in a breech position at term. In contrast, elective caesarean section (or caesarean section as a whole) appears to be more costly than vaginal delivery (either spontaneous or instrumented) in low risk or unselected populations. The paper proceeds with an overview of economic evaluations associated with elective caesarean section. All are currently based on decision-analytic models. Evidence is presented to suggest that planned trial of labour (attempted vaginal birth) following a previous caesarean section appears to be a more cost-effective option than elective caesarean section, although its cost effectiveness is dependent upon the probability of successful vaginal delivery. There is conflicting evidence on the cost effectiveness of maternal request caesareans when compared with trial of labour. The paucity of evidence on the value pregnant women, clinicians and other groups in society place on the option of elective caesarean section is highlighted. Techniques that might be used to elicit preferences for elective caesarean section and its attributes are outlined. The review concludes with directions for future research in this area. PMID- 24155083 TI - Doped nanocrystals as plasmonic probes of redox chemistry. AB - A (nano)crystal-clear view: With doped semiconductor nanocrystals, local chemical events can be probed through their perturbation of the carrier density of the nanocrystal. Examples demonstrate that redox processes and ligand chemistry can induce changes in the vacancy density within copper(I) sulfide nanorods, allowing such events to be detected by strong shifts in localized surface plasmon resonance. PMID- 24155084 TI - Cholesterol pericarditis without active inflammatory change: evaluation by positron emission tomography and computed tomography. PMID- 24155085 TI - Guidelines in review: 2013 ACCF/AHA Guideline for the Management of ST-Elevation Myocardial Infarction. PMID- 24155086 TI - Past residence outside of the United States is associated with diet quality in adults currently residing in the United States. AB - OBJECTIVE: To evaluate healthy dietary factors in relation to prior residence outside the United States (US) among university-affiliated individuals currently residing in the US. METHODS: Current diet information was collected via a 4-day food record and residential history data were collected by in-person interview for 114 individuals. RESULTS: Residence outside of the US at any point during the interviewee's life was associated with higher diet quality (Healthy Eating Index 2005: 50.0 vs. 46.8) and lower added sugar intake (25.8 vs. 34.9 g/d). Concordance of residence as a child (<=12 years of age) and within the prior 5 years was more strongly associated with higher HEI-2005 score (52.7) than if childhood was outside of the US and recent within the US (47.1), compared with individuals who have only resided within the US (46.9). Results were similar when also accounting for self-reported current residence as permanent residence. Current diet quality, food groups, and nutrient intakes differed depending on where in the world region individuals resided as a child. Restricting the analyzes to a subgroup of individuals of younger age and similar education attenuated associations. CONCLUSIONS: Lower added sugar intake and higher overall diet quality were most consistently associated with residence outside of the US, and recent residence outside of the US may be more strongly associated than childhood residence. Some of these differences may be explained by demographic or socioeconomic factors. Future studies could evaluate explanatory factors for these observations, including detailed socioeconomic factors, exposure to diverse foods, and accessibility of processed foods. PMID- 24155087 TI - Compressive force-produced CCN2 induces osteocyte apoptosis through ERK1/2 pathway. AB - Osteocytes produce various factors that mediate the onset of bone formation and resorption and play roles in maintaining bone homeostasis and remodeling in response to mechanical stimuli. One such factor, CCN2, is thought to play a significant role in osteocyte responses to mechanical stimuli, but its function in osteocytes is not well understood. Here, we showed that CCN2 induces apoptosis in osteocytes under compressive force loading. Compressive force increased CCN2 gene expression and production, and induced apoptosis in osteocytes. Application of exogenous CCN2 protein induced apoptosis, and a neutralizing CCN2 antibody blocked loading-induced apoptosis. We further examined how CCN2 induces loaded osteocyte apoptosis. In loaded osteocytes, extracellular signal-regulated kinase 1/2 (ERK1/2) was activated, and an ERK1/2 inhibitor blocked loading-induced apoptosis. Furthermore, application of exogenous CCN2 protein caused ERK1/2 activation, and the neutralizing CCN2 antibody inhibited loading-induced ERK1/2 activation. Therefore, this study demonstrated for the first time to our knowledge that enhanced production of CCN2 in osteocytes under compressive force loading induces apoptosis through activation of ERK1/2 pathway. PMID- 24155088 TI - Cobalt-based particles formed upon electrocatalytic hydrogen production by a cobalt pyridine oxime complex. AB - An open-coordination-sphere cobalt(III) oximato-based complex was designed as a putative catalyst for the hydrogen evolution reaction (HER). Electrochemical alteration in the presence of acid occurs, leading to the formation of cobalt based particles that act as an efficient catalyst for HER at pH 7. The exact chemical nature of these particles is yet to be determined. This study thus raises interesting issues regarding the fate of molecular-based complexes designed for the HER, and points to the challenging task of identifying the real catalytic species. Moreover, understanding and rationalizing the alteration pathways can be seen as a new route to reach catalytic particulates. PMID- 24155089 TI - Atmospheric pressure plasma jet treatment evokes transient oxidative stress in HaCaT keratinocytes and influences cell physiology. AB - Modern non-thermal atmospheric pressure plasma sources enable controllable interaction with biological systems. Their future applications - e.g. wound management - are based on their unique mixture of reactive components sparking both stimulatory as well as inhibitory processes. To gain detailed understanding of plasma-cell interaction and with respect to risk awareness, key mechanisms need to be identified. This study focuses on the impact of an argon non-thermal atmospheric pressure plasma jet (kINPen 09) on human HaCaT keratinocytes. With increasing duration, cell viability decreased. In accordance, cells accumulated in G2/M phase within the following 24 h. DNA single-strand breaks were detected immediately after treatment and receded in the aftermath, returning to control levels after 24 h. No directly plasma-related DNA double-strand breaks were detected over the same time. Concurrently, DNA synthesis decreased. Coincident with treatment time, an increase in intracellular 2',7' dichlorodihydrofluorescein diacetate (H(2)DCFDA) conversion increased reactive oxygen species (ROS) levels. The radical scavenging activity of culture medium crucially influenced these effects. Thus, ROS changed DNA integrity, and the effectiveness of cellular defence mechanisms characterises the interaction of non thermal plasma and eukaryotic cells. Effects were time-dependent, indicating an active response of the eukaryotic cells. Hence, a stimulation of eukaryotic cells using short-term non-thermal plasma treatment seems possible, eg in the context of chronic wound care. Long-term plasma treatments stopped in cell proliferation and apoptosis, which might be relevant in controlling neoplastic conditions. PMID- 24155090 TI - miRNA-199a-5p regulates VEGFA in endometrial mesenchymal stem cells and contributes to the pathogenesis of endometriosis. AB - It is believed that endometrial miRNAs contribute to the aetiology of endometriosis in stem cells; however, the mechanisms remain unclear. Here we collected serum samples from patients with or without endometriosis and characterized the miRNA expression profiles of these two groups. MicroRNA-199a-5p (miR-199a-5p) was dramatically down-regulated in patients with endometriosis compared with control patients. In addition, we found that the tumour suppressor gene, SMAD4, could elevate miR-199a-5p expression in ectopic endometrial mesenchymal stem cells. Up-regulation of miR-199a-5p suppressed cell proliferation, motility and angiogenesis of these ectopic stem cells by targeting the 3' untranslated region of VEGFA. Furthermore, we established an animal model of endometriosis and found that miR-199a-5p could decrease the size of endometriotic lesions in vivo. Taken together, this newly identified miR-199a-5p module provides a new avenue to the understanding of the processes of endometriosis development, especially proliferation, motility and angiogenesis, and may facilitate the development of potential therapeutics against endometriosis. PMID- 24155091 TI - Idiopathic portal hypertension: natural history and long-term outcome. AB - Idiopathic portal hypertension (IPH) is a rare cause of intrahepatic portal hypertension. Data on natural history and prognosis of IPH are limited. We sought to describe the complications and long-tem outcome of IPH by retrospectively studying 69 biopsy-proven cases of IPH. Mean duration of follow-up was 6.7 +/- 4.6 years. All patients had evidence of portal hypertension (PH) at diagnosis, and 42% were symptomatic. Variceal bleeding (VB) was the most common manifestation. In those without bleeding at diagnosis, 74% had varices at first endoscopy. In those with large varices, the 1-year probability of first bleeding despite primary prophylaxis was 9%. The 1-year probability of rebleeding was 22%. Ascites and hepatic encephalopathy was documented in 26% and 7% of patients, respectively, at least once during the clinical course. The 1-year probability of developing portal vein thrombosis (PVT) was 9%, and 53% of patients receiving anticoagulation achieved recanalization. Human immunodeficiency virus (HIV) infection and VB at diagnosis were the independent predictors of PVT. Seven patients died (6 as a result of an IPH-related cause) and 2 were transplanted. Probability of liver transplantation-free survival was 82% at 10 years. Presence of a severe associated disorder and ascites as a presenting symptom were associated with poor survival. CONCLUSION: Variceal bleeding is a major complication of IPH. Using, in IPH patients, the same management approach for PH as in cirrhosis is safe and maintains a low incidence of first bleeding and rebleeding in IPH patients. PVT is a frequent complication, particularly in those with HIV infection. Despite several complications, overall survival of patients with IPH is considerably good. PMID- 24155092 TI - Impact of direct stenting on outcome of patients with ST-elevation myocardial infarction transferred for primary percutaneous coronary intervention (from the EUROTRANSFER registry). AB - OBJECTIVES: We sought to evaluate the impact of direct stenting technique on angiographic and clinical outcomes of patients with ST-segment elevation myocardial infarction (STEMI) undergoing primary angioplasty (PCI). METHODS: Data on 1,419 patients who underwent immediate PCI for STEMI with implantation of >=1 stent within native coronary artery were retrieved from the EUROTRANSFER Registry database. Patients were stratified based on the stent implantation technique: direct (without predilatation) vs. conventional stenting. Propensity score adjustment was used to control possible selection bias. RESULTS: Direct stenting technique was used in 276 (19.5%) patients. Remaining 1,143 patients were treated with stent implantation after balloon predilatation. Direct compared with conventional stenting resulted in significantly greater rates of postprocedural TIMI grade 3 flow (conventional vs. direct stenting: 91.5% vs. 94.9%, adjusted OR 2.09 (1.13-3.89), P = 0.020), and lower risk of no-reflow (3.4% vs. 1.4%, adjusted OR 0.31 (0.10-0.92), P = 0.035). The rates for ST-segment resolution >50% after PCI were higher in patients treated with direct stenting technique (76.3% vs. 86.2%, adjusted OR 1.64 (1.10-2.46), P = 0.016). A significant reduction in 1-year mortality in patients from the direct stenting group compared with the conventional stenting group, even after adjustment for propensity score was observed (6.5% vs. 2.9%, adjusted OR 0.45 (0.21-0.99), P = 0.047). CONCLUSIONS: When anatomically and technically feasible, the use of direct stenting technique may result in improved long-term survival in patients with STEMI undergoing primary PCI. PMID- 24155093 TI - Sodium bicarbonate and high-intensity-cycling capacity: variability in responses. AB - PURPOSE: To determine whether gastrointestinal (GI) distress affects the ergogenicity of sodium bicarbonate and whether the degree of alkalemia or other metabolic responses is different between individuals who improve exercise capacity and those who do not. METHODS: Twenty-one men completed 2 cycling capacity tests at 110% of maximum power output. Participants were supplemented with 0.3 g/kg body mass of either placebo (maltodextrin) or sodium bicarbonate (SB). Blood pH, bicarbonate, base excess, and lactate were determined at baseline, preexercise, immediately postexercise, and 5 min postexercise. RESULTS: SB supplementation did not significantly increase total work done (TWD; P = .16, 46.8 +/- 9.1 vs 45.6 +/- 8.4 kJ, d = 0.14), although magnitude-based inferences suggested a 63% likelihood of a positive effect. When data were analyzed without 4 participants who experienced GI discomfort, TWD (P = .01) was significantly improved with SB. Immediately postexercise blood lactate was higher in SB for the individuals who improved but not for those who did not. There were also differences in the preexercise-to-postexercise change in blood pH, bicarbonate, and base excess between individuals who improved and those who did not. CONCLUSIONS: SB improved high-intensity-cycling capacity but only with the exclusion of participants experiencing GI discomfort. Differences in blood responses suggest that SB may not be beneficial to all individuals. Magnitude based inferences suggested that the exercise effects are unlikely to be negative; therefore, individuals should determine whether they respond well to SB supplementation before competition. PMID- 24155094 TI - Assessment of aspiration risk from dynamic modulation of endotracheal tube cuff pressure. AB - OBJECTIVES/HYPOTHESIS: To assess the risk of aspiration using a novel valve circuit that dynamically modulates endotracheal tube cuff pressure during the ventilatory cycle using bench and live animal models. STUDY DESIGN: Animal model. METHODS: The bench model consisted of a cuffed endotracheal tube inserted into an artificial trachea. Leakage of liquid around the cuff was measured after 4 hours of constant or dynamic modulation of cuff pressure at variable peak end expiratory pressures. In the porcine model, eight animals were ventilated with the modulating valve circuit and compared to eight controls ventilated with a constant cuff pressure (25 cm of water). Aspiration was monitored quantitatively using a pH probe (measured as voltage) and visually using fluoroscopy. RESULTS: There was no difference in the amount of fluid leakage around the endotracheal tube cuff in the constant or dynamically modulated pressure-cuff groups in the bench or animal models. CONCLUSION: Dynamically modulating endotracheal tube-cuff pressures to minimize tracheal mucosal damage does not increase the tendency to leak around the cuff compared to endotracheal tube cuffs inflated to a constant pressure. LEVEL OF EVIDENCE: N/A. PMID- 24155097 TI - Low level of tracheal cellular fibronectin in extremely premature infants with funisitis: relationship with respiratory distress 1 month after birth. AB - BACKGROUND: Funisitis reflects the fetal systemic inflammatory response in premature infants. Macrophages and neutrophils have been identified as key elements in the inflammatory process of the lungs, and secrete proteases that cause the destruction of the extracellular matrix (ECM). Fibronectin (FN) is the major constituent of the pulmonary ECM and exists in multiple isoforms arising from alternative RNA splicing. Extra domain A (EDA) is the major alternatively spliced segment, and the expression of EDA containing FN (EDA + FN) in the lungs is associated with distal pulmonary cell proliferation during alveolar formation. OBJECTIVE: To study the relationship between the presence of funisitis and EDA + FN levels in the tracheal aspirate fluid (TAF) of infants of less than 28 weeks' gestation. METHODS: The subjects included in this study were 26 extremely premature infants of <28 weeks' gestation at <24 hr of age, from whom the TAF was collected. These preterm infants were divided into two groups according to placental histology. The funisitis (+) group (n = 9) was compared with the funisitis (-) group (n = 17). The TAF supernatants were analyzed for IL-1beta, IL 6, IL-8, neutrophil elastase, and EDA + FN using enzyme-linked immunosorbent assay (ELISA). RESULTS: There were no significant differences in gestational age or birthweight between these groups. The funisitis (+) group had a significantly higher ventilator setting (inspired O(2) * mean airway pressure) at Day 28 than the funisitis (-) group. In the TAF, the concentrations of IL-1beta were significantly higher in the funisitis (+) group than in the funisitis (-) group, as were the concentrations of neutrophil elastase. The concentrations of EDA + FN were significantly lower in the funisitis (+) group than in the funisitis (-) group. CONCLUSIONS: Decreased EDA + FN in TAF might be one of the risk factors leading to respiratory distress in extremely premature infants with funisitis. PMID- 24155096 TI - Postelectrospinning modifications for alginate nanofiber-based wound dressings. AB - Alginate nanofibers have been attractive for potential tissue regeneration applications due to a combination of their moisture retention ability and large surface area available in a nonwoven nanofiber form. This study aims to address several challenges in alginate nanofiber application, including the lack of structural stability in aqueous environment and limited cell attachment as compared to commercial wound dressings, via examining crosslinking techniques. In addition to the commonly performed divalent ion crosslinking, a glutaraldehyde double-crosslinking step and polylysine addition were applied to an electrospun alginate nanofiber nonwoven mat. With optimization of the electrospinning solution, nanofiber morphology was maintained after the two-stage crosslinking process. Extensibility of the nanofiber mat reduced after the crosslinking process. However, both aqueous stability and cell attachment improved after the postspinning modifications, as shown through degradation tests in phosphate buffered saline solutions and fibroblast cell culture studies, respectively. PMID- 24155095 TI - Telomeric impact of conventional chemotherapy. AB - The increased level of chromosome instability in cancer cells, leading to aneuploidy and gross chromosomal rearrangements, is not only a driving force for oncogenesis but also can be the Achille's heel of the disease since many chemotherapies (CT) kill cells by inducing a non-tolerable rate of DNA damage. A wealth of published evidence showed that telomere stability can be more affected than the bulk of the genome by several conventional antineoplasic drugs. These results raise the interesting possibility that CT with genotoxic drugs preferentially target telomeres. In agreement with this view, accelerated shortening of telomere length has been described in blood lineage cells following high-dose CT (stem cell transplantation) or non-myeloablative CT. However, almost nothing is known on the consequences of this shortening in terms of telomere stability, senescence and on the development of second cancers or post-treatment aging-like syndromes in cancer survivors (cognitive defect, fertility impairment, etc.). In this article, we propose: (1) telomeres of cancer cells are preferential genomic targets of chemotherapies altering chromosome maintenance; (2) telomere functional parameters can be a surrogate marker of chemotherapy sensitivity and toxicity; (3) the use of anti-telomere molecule could greatly enhance the sensitivity to standards chemotherapies. PMID- 24155098 TI - An A-site-deficient perovskite offers high activity and stability for low temperature solid-oxide fuel cells. AB - Solid oxide fuel cells (SOFCs) directly convert fossil and/or renewable fuels into electricity and/or high-quality heat in an environmentally friendly way. However, high operating temperatures result in high cost and material issues, which have limited the commercialization of SOFCs. To lower their operating temperatures, highly active and stable cathodes are required to maintain a reasonable power output. Here, we report a layer-structured A-site deficient perovskite Sr0.95 Nb0.1 Co0.9 O3-delta (SNC0.95) prepared by solid-state reactions that shows not only high activity towards the oxygen reduction reaction (ORR) at operating temperatures below 600 degrees C, but also offers excellent structural stability and compatibility, and improved CO2 resistivity. An anode supported fuel cell with SNC0.95 cathode delivers a peak power density as high as 1016 mW cm(-2) with an electrode-area-specific resistance of 0.052 Omega cm(2) at 500 degrees C. PMID- 24155099 TI - Targeting DUSPs in glioblastomas - wielding a double-edged sword? AB - Several dual-specificity phosphatases (DUSPs) that play key roles in the direct or indirect inactivation of different MAP kinases (MAPKs) have been implicated in human cancers over the past decade. This has led to a growing interest in identifying DUSPs and their specific inhibitors for further testing and validation as therapeutic targets in human cancers. However, the lack of understanding of the complex regulatory mechanisms and cross-talks between MAPK signaling pathways, combined with the fact that DUSPs can act as a double-edged sword in cancer progression, calls for a more careful and thorough investigation. Among the various types of brain cancer, glioblastoma multiforme (GBM) is notorious for its aggressiveness and resistance to current treatment modalities. This has led to the search for new molecular targets, particularly those involving various signaling pathways. DUSPs appear to be a promising target, but much more information on DUSP targets and their effects on GBM is needed before potential therapies can be developed, tested, and validated. This review identifies and summarize the specific roles of DUSP1, DUSP4, DUSP6 and DUSP26 that have been implicated in GBM. PMID- 24155100 TI - A defined co-culture of Geobacter sulfurreducens and Escherichia coli in a membrane-less microbial fuel cell. AB - Wastewater-fed microbial fuel cells (MFCs) are a promising technology to treat low-organic carbon wastewater and recover part of the chemical energy in wastewater as electrical power. However, the interactions between electrochemically active and fermentative microorganisms cannot be easily studied in wastewater-fed MFCs because of their complex microbial communities. Defined co culture MFCs provide a detailed understanding of such interactions. In this study, we characterize the extracellular metabolites in laboratory-scale membrane less MFCs inoculated with Geobacter sulfurreducens and Escherichia coli co culture and compare them with pure culture MFCs. G. sulfurreducens MFCs are sparged to maintain anaerobic conditions, while co-culture MFCs rely on E. coli for oxygen removal. G. sulfurreducens MFCs have a power output of 128 mW m(-2) , compared to 63 mW m(-2) from the co-culture MFCs. Analysis of metabolites shows that succinate production in co-culture MFCs decreases current production by G. sulfurreducens and that the removal of succinate is responsible for the increased current density in the late co-culture MFCs. Interestingly, pH adjustment is not required for co-culture MFCs but a base addition is necessary for E. coli MFCs and cultures in vials. Our results show that defined co-culture MFCs provide clear insights into metabolic interactions among bacteria while maintaining a low operational complexity. PMID- 24155101 TI - A review of the positive and negative effects of cardiovascular drugs on sexual function: a proposed table for use in clinical practice. AB - Several antihypertensive drugs, such as diuretics and beta-blockers, can negatively affect sexual function, leading to diminished quality of life and often to noncompliance with the therapy. Other drug classes, however, such as angiotensin II receptor blockers (ARBs) are able to improve patients' sexual function. Sufficient knowledge about the effects of these widely used antihypertensive drugs will make it possible for cardiologists and general practitioners to spare and even improve patients' sexual health by switching to different classes of cardiac medication. Nevertheless, previous data (part I) indicate that most cardiologists lack knowledge about the effects cardiovascular agents can have on sexual function and will thus not be able to provide the necessary holistic patient care with regard to prescribing these drugs. To be able to improve healthcare on this point, we aimed to provide a practical overview, for use by cardiologists as well as other healthcare professionals, dealing with sexual dysfunction in their clinical practices. Therefore, a systematic review of the literature was performed. The eight most widely used classes of antihypertensive drugs have been categorised in a clear table, marking whether they have a positive, negative or no effect on sexual function. PMID- 24155102 TI - Clinical outcome of ablation for long-standing persistent atrial fibrillation with or without defragmentation. AB - OBJECTIVE: To assess the outcome and associated risks of atrial defragmentation for the treatment of long-standing persistent atrial fibrillation (LSP-AF). METHODS: Thirty-seven consecutive patients (60.4 +/- 7.3 years; 28 male) suffering from LSP-AF who underwent pulmonary vein isolation (PVI) and linear ablation were compared. All patients were treated with the Stereotaxis magnetic navigation system (MNS). Two groups were distinguished: patients with (n = 20) and without (n = 17) defragmentation. The primary endpoint of the study was freedom of AF after 12 months. Secondary endpoints were AF termination, procedure time, fluoroscopy time and procedural complications. Complications were divided into two groups: major (infarction, stroke, major bleeding and tamponade) and minor (fever, pericarditis and inguinal haematoma). RESULTS: No difference was seen in freedom of AF between the defragmentation and the non-defragmentation group (56.2 % vs. 40.0 %, P = 0.344). Procedure times in the defragmentation group were longer; no differences in fluoroscopy times were observed. No major complications occurred. A higher number of minor complications occurred in the defragmentation group (45.0 % vs. 5.9 %, P = 0.009). Mean hospital stay was comparable (4.7 +/- 2.2 vs. 3.4 +/- 0.8 days, P = 0.06). CONCLUSION: Our study suggests that complete defragmentation using MNS is associated with a higher number of minor complications and longer procedure times and thus compromises efficiency without improving efficacy. PMID- 24155103 TI - Current discharge management of acute coronary syndromes: data from the Rijnmond Collective Cardiology Research (CCR) study. AB - BACKGROUND: Medical discharge management of acute coronary syndromes (ACS) remains suboptimal outside randomised trials and constitutes an essential quality benchmark for ACS. We sought to evaluate the rates of key guideline-recommended pharmacological agents after ACS and characteristics associated with optimal treatment at discharge. METHODS: The Rijnmond Collective Cardiology Research (CCR) registry is an ongoing prospective, observational study in the Netherlands that aims to enrol 4000 patients with ACS. We examined discharge and 1-month follow-up medication use among the first 1000 patients enrolled in the CCR registry. Logistic regression was performed to identify patient and hospital characteristics associated with collective guideline-recommended pharmacotherapy at hospital discharge. RESULTS: At discharge, 94 % of patients received aspirin, 100 % thienopyridines, 80 % angiotensin-converting enzyme inhibitors/angiotensin II receptor blockers, 87 % beta-blockers, 96 % statins, and 65 % the combination of all 5 agents. ST-segment elevation myocardial infarction, hypertension, hypercholesterolaemia, and enrolment in an interventional centre were positive independent predictors of 5-drug combination therapy at discharge. Negative independent predictors were unstable angina and advanced age. CONCLUSION: Current data from the CCR registry reflect a high quality of care for ACS discharge management in the Rotterdam-Rijnmond region. However, potential still remains for further optimisation. PMID- 24155104 TI - Internal cardioversion of persistent atrial fibrillation in implantable cardioverter defibrillator patients: the juice is not worth the squeeze. PMID- 24155105 TI - Toward force fields for atomistic simulations of iridium-containing complexes. AB - The structural and energetic characterization of metal complexes is important in catalysis and photochemical applications. Unraveling their modes-of-action can be greatly assisted by computation, which typically is restricted to computationally demanding methods including electronic structure calculations with density functional theory. Here, we present an empirical force field based on valence bond theory applicable to a range of octahedral Ir(III) complexes with different coordinating ligands, including iridium complexes with a chiral P,N ligand. Using an approach applicable to metal-containing complexes in general, it is shown that with one common parametrization 85% of the 116 diastereomers--all within 21 kcal/mol of the lowest energy conformation of each series--can be correctly ranked. For neutral complexes, all diastereomers are ranked correctly. This helps to identify the most relevant diastereomers which, if necessary, can be further investigated by more demanding computational methods. Furthermore, if one specific complex is considered, the root mean square deviation between reference data from electronic structure calculations and the force field is ~1 kcal/mol. This, together with the possibility to carry out explicit simulations in solution paves the way for an atomistic understanding of iridium-containing complexes in catalysis. PMID- 24155106 TI - The effects of 3 years of calcium supplementation on common carotid artery intimal medial thickness and carotid atherosclerosis in older women: an ancillary study of the CAIFOS randomized controlled trial. AB - Calcium is an essential nutrient for skeletal health; however, it has been suggested that supplemental calcium may be associated with adverse cardiovascular effects, raising widespread concern about their use. One suggested mechanism is via increasing carotid atherosclerosis, however few randomized controlled trials (RCT) of calcium supplements have assessed these mechanisms. The calcium intake fracture outcome study (CAIFOS) was a 5-year RCT (1998 to 2003) of 1.2 g of elemental calcium in the form of calcium carbonate in 1460 elderly women. An ancillary study of 1103 women assessed common carotid artery intimal medial thickness (CCA-IMT) and carotid atherosclerosis at year 3 (2001). The effects of supplementation were studied in intention-to-treat (ITT) and per-protocol (PP) analyses before and after adjustment for baseline cardiovascular risk factors. The mean age of participants at baseline was 75.2 +/- 2.7 years. In ITT analyses, women randomized to calcium supplementation had no difference in multivariable adjusted mean CCA-IMT (calcium 0.778 +/- 0.006 mm, placebo 0.783 +/- 0.006 mm, p = 0.491) and maximum CCA-IMT (calcium 0.921 +/- 0.007 mm, placebo 0.929 +/- 0.006 mm, p = 0.404). Women randomized to calcium did not have increased carotid atherosclerosis (calcium 47.2%, placebo 52.7%, p = 0.066). However, in women taking at least 80% of the supplements, a significant reduction in carotid atherosclerosis was observed in unadjusted but not in multivariate-adjusted models (p = 0.033 and p = 0.064, respectively). Participants in the highest tertile of total calcium (diet and supplements) had reduced carotid atherosclerosis in unadjusted and multivariable-adjusted analyses compared with participants in the lowest tertile (odds ratio [OR] = 0.67 [95% confidence interval (CI) 0.50-0.90], p = 0.008, and OR = 0.70 [95% CI 0.51-0.96], p = 0.028, respectively). In conclusion, these findings do not support the hypothesis that calcium supplementation increases carotid artery intimal medial thickness or carotid atherosclerosis, and high calcium intake may reduce this surrogate cardiovascular risk factor. PMID- 24155107 TI - Is genotype 3 of the hepatitis C virus the new villain? AB - Genotype 3 of the hepatitis C virus (HCV) has been long considered an easy-to treat infection, with higher cure rates (~70%) than other viral genotypes with the standard combination of pegylated interferon-alpha and ribavirin. However, the relative insensitivity of this genotype to most protease inhibitors and the recent unexpected data on decreased effectiveness of sofosbuvir have raised questions on how to achieve universal cure, a goal that seems reasonable for other genotypes. In addition, increasing clinical and experimental data show that HCV genotype 3 may be associated not only with severe steatosis, but also with accelerated fibrosis progression rate and increased oncogenesis. CONCLUSION: Currently available data suggest that we should increase our efforts to understand the virology and pathogenesis of HCV genotype 3, aiming at better and more potent, genotype-targeted treatments. PMID- 24155108 TI - Single-molecule chemical reactions tracked at the atomic-bond level. AB - On the right track: Recent advances in noncontact atomic force microscopy (nc AFM) have enabled the bond-resolved imaging of reaction pathways. In particular, unprecedented insights into complex enediyne cyclization cascades on silver surfaces were gained by single-molecule imaging. PMID- 24155109 TI - The impact of intranasal corticosteroids on lung function in children with allergic rhinitis. AB - BACKGROUND: Subjects with allergic rhinitis (AR) suffer from impaired lung function, especially decreased FEF(25-75%). The purpose of this study was to examine lung function and the long-term response to INCS in AR patients with impaired lung function, and to characterize the phenotype of these children. METHODS: Two hundred two children with AR underwent an allergy evaluation including a skin prick test and spirometry. Children with impaired lung function were treated with daily nasal corticosteroids spray (INCS) and antihistamine as needed. RESULTS: Fifty-three children out of 202 (26.3%) had impaired lung function: 34 of them (64.2%) had FEF(25-75%) values under 80% of predicted and normal FEV(1) values, and 19 individuals (35.8%), had both FEF(25-75%) and FEV(1) values below 80% of predicted. A positive correlation between FEV(1) and FEF(25 75%) values (r = 0.369, P = 0.007) and a reverse correlation between duration of nasal symptoms and FEF(25-75%) values (r = -0.364, P = 0.012) were found. Post ronchodilation FEV(1) levels increased from 81.9 +/- 8.0 to 87.7 +/- 10.4 (P < 0.0001). Thirty-five of the 53 children complied with a continuous INCS treatment regimen over a period of 3-12 months, demonstrated increased FEF(25-75%) (84.4 +/ 13.6 vs. 70.1 +/- 7.1, P < 0.001) and FEV(1) (92.3 +/- 10.9 vs. 84.4 +/- 7.8, P < 0.0001) after INCS treatment. However, FEF(25-75%) values were still significantly lower compared to the group of AR children with normal lung function (84.4 +/- 13.6 vs. 95.7 +/- 8.8, P < 0.0001). CONCLUSIONS: INCS improve FEF(25-75%) above 80% of predicted values in 2/3 of children with abnormal lung function. However, this improvement does not reach levels of AR children with normal lung function. Pediatr PMID- 24155110 TI - Metabolic surgery for type 2 diabetes in BMI <35: a surgeon's view. PMID- 24155111 TI - Correspondence: Response to letter to the editor by K Scharf and J Morton. PMID- 24155112 TI - The impact of Helicobacter pylori on the complications of laparoscopic sleeve gastrectomy. AB - Helicobacter pylori (H. pylori) is a very common bacterium present in the gastric tissue of up to 50 % of people, and the mucosal damage it causes can predispose to multiple comorbid conditions. This study aims to observe the prevalence of H. pylori infection in patients undergoing laparoscopic sleeve gastrectomy (LSG) and its correlation with postoperative complications. A retrospective study was done on the gastric pathology specimen results of 682 patients who underwent LSG at Amiri Hospital from 2008 to 2012. Symptomatic patients had preoperative upper gastrointestinal endoscopies (UGIEs) based on the decision of the treating surgeon, along with campylobacter-like organism test (CLO test) for H. pylori detection. The intraoperatively excised gastric specimen was sent for histopathological assessment of H. pylori, and the patients were followed up for complications. Of the 682 patients, 629 (92.2 %) were found to be H. pylori negative intraoperatively, while 53 (7.8 %) were positive. A total of 32 (4.7 %) patients were found to have postoperative complications, of which 2 (6.3 %) had H. pylori intraoperatively. No statistical significance (p = 0.71), however, was seen between the overall complication rate and H. pylori. Specifically, there were five (0.7 %) cases of leak and eight (1.2 %) cases of neuropathy, both of which were not significantly associated with H. pylori (p = 0.33 and p = 0.12, respectively). All the other complications had no evidence of H. pylori. There appears to be no association between H. pylori infection and post-LSG complications. PMID- 24155113 TI - Identification of microRNAs involved in the radioresistance of esophageal cancer cells. AB - Radioresistance is considered as the most important reason for local tumour recurrence. This study investigates the role of miRNAs in radioresistant human esophageal cancer cells. Human miRNA microarray has been used to detect the differential expressed microRNAs between radioresistant esophageal cell line KYSE 150R and the parental cell line KYSE-150. The relative expression of some candidate miRNAs was measured by quantitative real-time PCR (qRT-PCR). Potential mRNA targets were analysed bioinformatically. Significant upregulation of 10 microRNAs and downregulation of 25 microRNAs were detected. The statistical significance of downregulation in hsa-miR-301a, hsa-miR-141 and hsa-miR-18b expression (P < 0.05) were confirmed by qRT-PCR. The correlation of the predicted microRNA target genes to apoptosis (63 genes), cell cycle (67 genes), DNA damage and repair (18 genes) were confirmed by functional annotation. The downregulation of hsa-miR-301a promoted radioresistance in KYSE-150R through the upregulation of wnt1, indicating that wnt/beta-catenin signal pathway might be important in radioresistance. In conclusion, a unique set of miRNAs and their expression profiles in radiation resistance have been identified, providing a solid basis for future studies to investigate the target genes of these miRNAs and their function. PMID- 24155114 TI - Critical analysis of cyanoacrylate in intestinal and colorectal anastomosis. AB - BACKGROUND: Although cyanoacrylate glue (CA) has been widely used in various kinds of medical applications, its application in gastrointestinal anastomosis remains limited, and outcomes of experimental studies have not been satisfactory. This systematic review summarizes research regarding CA application in intestinal and colorectal anastomosis, and correlates methodological aspects to experimental outcomes. METHODS: A systematic literature search was performed using Medline, Embase, Cochrane, and Web-of-Science libraries. Articles were selected if CA was applied to intestinal or colorectal anastomoses. Included articles were categorized according to CA molecular structure; the method details in each study were extracted and analyzed. RESULTS: Twenty-two articles were included. More than half of the inclusions reported positive outcomes (seven articles) or neutral outcomes (eight articles). Analysis of the methods revealed that methodological details such as CA dosage, time of polymerization were not consistently reported. Porcine studies, inverted anastomosis, and n-butyl cyanoacrylate studies showed more positive outcomes; everted anastomosis, and oversized sutures might negatively influence the outcomes. CONCLUSIONS: Owing to the positive outcome from the porcine studies, application of CA in gastrointestinal (GI) anastomosis still seems promising. To achieve a better consistency, more methodological details need to be provided in future studies. Optimizing the dosage of CA, choice of animal model, inverted anastomosis construction, and other method details may improve intestinal and colorectal anastomoses with CA application in future studies. PMID- 24155115 TI - Optical coherence tomography derived differences of plaque characteristics in coronary culprit lesions between type 2 diabetic patients with and without acute coronary syndrome. AB - OBJECTIVE: To compare optical coherence tomography (OCT)-derived plaque characteristics of coronary target lesions between diabetic patients with acute coronary syndrome (ACS) versus stable angina pectoris (SAP). BACKGROUND: In vivo assessment of plaque composition of coronary culprit lesions in a cardiovascular high-risk population with diabetes mellitus is incompletely elucidated. METHODS: 102 diabetic patients with coronary de novo lesions were enrolled and categorized into an ACS-group (40 patients) and a SAP-group (62 patients) according to their clinical presentation. Assessment of clinical data, angiographic, and OCT imaging including the analysis of plaque composition and lipid content of the target lesions were performed prior to percutaneous coronary intervention and compared between the two groups. RESULTS: Plaque characteristics of patients in the ACS group compared with the SAP-group showed a higher incidence of lipid-rich plaque [33 (82.5%) vs. 25 (40.3%)], thin-capped fibroatheroma [29 (72.5%) vs. 10 (16.1%)], macrophage infiltration [32 (80.0%) vs. 21 (33.9%)], thrombus [23 (57.5%) vs. 2 (3.2%)], and plaque rupture [27 (67.5%) vs. 2 (3.2%)] (all P < 0.001). Moreover, there was a wider lipid arc (174.5 +/- 33.8 degrees vs. 122.9 +/- 43.9 degrees ), a longer lipid plaque length (6.52 +/- 2.04 mm vs. 3.73 +/- 2.16 mm), a greater lipid volume index (1117.2 +/- 349.9 vs. 504.8 +/- 379.3), and a smaller minimal fibrous cap thickness (51.52 +/- 9.14 um vs. 80.33 +/- 26.71 um) within lipid-rich lesions of ACS patients (all P < 0.001). CONCLUSION: Diabetic patients with ACS exhibit more vulnerable plaque features in coronary culprit lesions compared with diabetic patients with SAP. This may provide rationale for a specific therapeutic strategy either by pharmacological plaque stabilization or coronary intervention in any lesion with vulnerable plaque morphology in patients with diabetes. PMID- 24155116 TI - Round window membrane vibration may increase the effect of intratympanic dexamethasone injection. AB - OBJECTIVES/HYPOTHESIS: We investigated whether the round window membrane (RWM) vibration can facilitate dexamethasone perfusion via the RWM in patients with sudden hearing loss. STUDY DESIGN: Prospective study. METHODS: We first performed an in vitro study using a semipermeable membrane. In the subsequent in vivo study, 20 mice were randomized into two groups: an intratympanic dexamethasone injection (ITDI)-only group, and an ITDI with RWM vibration group. Concentration of dexamethasone was investigated using high performance liquid chromatography. Third, we performed a prospective clinical study. Fifty-five refractory sudden hearing loss patients were divided into two groups: those who received ITDI only (n = 36) and those who received ITDI with RWM vibration (n = 19). Final hearing assessments were conducted 2 months after salvage treatment. RESULTS: In the in vitro study, the concentration of dexamethasone increased with vibration time with the peak concentration observed at 3 minutes of vibration. In the in vivo study, ITDI with RWM vibration resulted in a significantly higher perilymph concentration of dexamethasone (7.68 +/- 3.13 ug/ml) than that in the ITDI-only group (2.66 +/- 1.73 ug/ml). In a clinical setting, the overall improvement in hearing was similar between the two groups. However, when we compared the speech discrimination score between the two groups, we found that the relative discrimination gain in the ITDI with RWM vibration group (18.11 +/- 23.54%) was higher than that in the ITDI-only group (7.00 +/- 15.54%) (P = 0.042). CONCLUSION: RWM vibration can enhance the effect of intratympanic dexamethasone injection and is a viable treatment option for sudden hearing loss. LEVELS OF EVIDENCE: N/A. PMID- 24155118 TI - The back squat and the power clean: elicitation of different degrees of potentiation. AB - PURPOSE: To compare the acute effects of back squats and power cleans on sprint performance. METHODS: Thirteen elite junior rugby league players performed 20-m linear sprints before and 7 min after 2 different conditioning activities or 1 control condition. The conditioning activities included 1 set of 3 back squats or power cleans at 90% 1-repetition maximum. A 2 * 2 repeated-measures ANOVA was used to compare preconditioning and postconditioning changes in sprint performance. RESULTS: Both the back-squat and power-clean conditioning activities demonstrated a potentiation effect as indicated by improved sprint time (back squat: P = .001, ES = -0.66; power cleans: P = .001, ES = -0.92), velocity (back squat: P = .001, ES = 0.63; power cleans: P = .001, ES = 0.84), and average acceleration over 20 m (back squat: P = .001, ES = 0.70; power cleans: P = .001, ES = 1.00). No potentiation effect was observed after the control condition. Overall, the power clean induced a greater improvement in sprint time (P = .042, ES = 0.83), velocity (P = .047, ES = 1.17), and average acceleration (P = .05, ES = 0.87) than the back squat. CONCLUSIONS: Back-squat and power-clean conditioning activities both induced improvements in sprint performance when included as part of a potentiation protocol. However, the magnitude of improvement was greater after the power cleans. From a practical perspective, strength and conditioning coaches should consider using power cleans rather than back squats to maximize the performance effects of potentiation complexes targeting the development of sprint performance. PMID- 24155117 TI - Gender differences in cardiovascular therapy: focus on antithrombotic therapy and percutaneous coronary intervention. AB - The epidemiology of coronary artery disease (CAD) differs between women and men: female cardiac patients are older and have poorer risk profiles than their male counterparts. This results in a preferential exclusion of women from participation in clinical trials, reducing their power to detect differences in performance of cardiovascular therapies in women. In general, all the antiplatelet and anticoagulant medications used in cardiac patients are equally effective in men and women, although women tend to experience a higher relative benefit due to their poorer risk profile. In particular, women with CAD benefit the most from interventional treatment combined with modern antithrombotic drugs. No gender-related differences in the reduction of thromboembolic risk with more potent antithrombotic drugs have been reported. On the other hand, a clear trend to a higher incidence of bleeding complications has been consistently reported in women, which might be related to a more frequent over-dosage of antithrombotic treatment in women than in men. Women are therefore one of the subgroups that might benefit the most from careful dose adjustment of available antithrombotic drugs. However, the development of a gender-based dosage guideline remains an unmet need in cardiology. PMID- 24155119 TI - Genetic score of multiple risk-associated single nucleotide polymorphisms is a marker for genetic susceptibility to bladder cancer. AB - Genome-wide association studies have identified 13 single nucleotide polymorphisms (SNPs) that are associated with bladder cancer; three of these SNPs were validated in the Chinese population. This study assessed the performance of these three SNPs, in combination, to predict genetic susceptibility to bladder cancer in Chinese. Three previously established bladder cancer risk-associated SNPs (rs798766 in TACC3, rs9642880 in MYC, and rs2294008 in PSCA) were genotyped in 1,210 bladder cancer patients and 1,008 control subjects in Shanghai, China. A genetic score was calculated for each subject based on these three SNPs. Each of these three SNPs was significantly associated with bladder cancer risk in this independent study population, P < 0.05. The genetic score based on these three SNPs was significantly higher in cases than controls, with a mean of 1.05 and 0.99, respectively, P = 1.03E-05. Compared with subjects with a genetic score <= 1.00, subjects with an elevated genetic score (>1.00) had a significantly increased risk for bladder cancer after adjusting for age, gender, and smoking status, OR = 1.58, 95% Confidence Interval (CI) = 1.21 - 2.06, P = 0.0007. When tested separately for lower (Ta) or higher (Tis, T1-T4) tumor stage, the association was significantly stronger for lower (OR = 2.24, 95% CI = 1.66 - 3.01, P = 1.02E-07) than higher tumor stage (OR = 1.33, 95% CI = 1.00 - 1.78, P = 0.05), P = 0.001. In conclusion, A combination of three previously implicated bladder cancer risk-associated SNPs is a significant predictor of genetic susceptibility to bladder cancer in Chinese. PMID- 24155120 TI - Effect of indigenous mycobiota on ochratoxin A production by Aspergillus carbonarius isolated from soil: ochratoxin in mixed cultures. AB - This study determined the biotic interaction between 30 non-toxigenic indigenous strains of Aspergillus niger aggregate, Aspergillus flavus, Trichoderma spp., Mucor spp., Cladosporium spp., Ulocladium spp., Curvularia spp., Absidia spp., Geotrichum spp. and Acremonium spp., isolated from soil destined for maize crops, with respect to their ability to prevent ochratoxin A (OTA) production by A. carbonarius on "in vitro" assay, on liquid and solid medium. OTA production was completely inhibited when A. carbonarius was inoculated in a interactive mixed culture with all A. niger aggregate strains assayed, a 80 % of Trichoderma spp. strains, a 40 % of Cladosporium spp. strains, Acremonium spp and Geotrichum spp; only one strain of A. flavus tested was able to completely inhibit the mycotoxin accumulation. OTA production increased when A. carbonarius ACS 8 was growing on liquid interactive mixed culture with Mucor spp strains. These results demonstrated that OTA production by Aspergillua carbonarius strain was significantly influenced by the presence of different non-toxigenic fungal strains when growing together on paired cultures. PMID- 24155121 TI - Hierarchical sulfur-based cathode materials with long cycle life for rechargeable lithium batteries. AB - Composite materials of porous pyrolyzed polyacrylonitrile-sulfur@graphene nanosheet (pPAN-S@GNS) are fabricated through a bottom-up strategy. Microspherical particles are formed by spray drying of a mixed aqueous colloid of PAN nanoparticles and graphene nanosheets, followed by a simple heat treatment with elemental sulfur. The pPAN-S primary nanoparticles are wrapped homogeneously and loosely within a three-dimensional network of graphene nanosheets (GNS). The hierarchical pPAN-S@GNS composite shows a high reversible capacity of 1449.3 mAh g(-1) sulfur or 681.2 mAh g(-1) composite in the second cycle; after 300 cycles at a 0.2 C charge/discharge rate the capacity retention is 88.8 % of its initial reversible value. Additionally, the coulombic efficiency (CE) during cycling is near 100 %, apart from in the first cycle, in which CE is 81.1 %. A remarkable capacity of near 700 mAh g(-1) sulfur is obtained, even at a high discharge rate of 10 C. The superior performance of pPAN-S@GNS is ascribed to the spherical secondary GNS structure that creates an electronically conductive 3D framework and also reinforces structural stability. PMID- 24155122 TI - Targeted next-generation sequencing and non-coding RNA expression analysis of clear cell papillary renal cell carcinoma suggests distinct pathological mechanisms from other renal tumour subtypes. AB - Clear cell tubulopapillary renal cell carcinoma (CCPRCC) is a recently described rare renal malignancy that displays characteristic gross, microscopic and immunohistochemical differences from other renal tumour types. However, CCPRCC remains a very poorly understood entity. We therefore sought to elucidate some of the molecular mechanisms involved in this neoplasm by carrying out targeted next generation sequencing (NGS) to identify associated mutations, and in addition examined the expression of non-coding (nc) RNAs. We identified multiple somatic mutations in CCPRCC cases, including a recurrent [3/14 cases (21%)] non synonymous T992I mutation in the MET proto-oncogene, a gene associated with epithelial-to-mesenchymal transition (EMT). Using a microarray approach, we found that the expression of mature (n = 1105) and pre-miRNAs (n = 1105), as well as snoRNA and scaRNAs (n = 2214), in CCPRCC cases differed from that of clear cell renal cell carcinoma (CCRCC) or papillary renal cell carcinoma (PRCC) tumours. Surprisingly, and unlike other renal tumour subtypes, we found that all five members of the miR-200 family were over-expressed in CCPRCC cases. As these miRNAs are intimately involved with EMT, we stained CCPRCC cases for E-cadherin, vimentin and beta-catenin and found that the tumour cells of all cases were positive for all three markers, a combination rarely reported in other renal tumours that could have diagnostic implications. Taken together with the mutational analysis, these data suggest that EMT in CCPRCC tumour cells is incomplete or blocked, consistent with the indolent clinical course typical of this malignancy. In summary, as well as describing a novel pathological mechanism in renal carcinomas, this study adds to the mounting evidence that CCPRCC should be formally considered a distinct entity. Microarray data have been deposited in the GEO database [GEO accession number (GSE51554)]. PMID- 24155123 TI - Quantitative three-dimensional assessment of port-wine stain clearance after laser treatments. AB - BACKGROUND AND OBJECTIVE: Outcomes analysis of laser treatment for port-wine stains has been hampered by the lack of an objective measure of surface area and volume; moreover, treatment success is often gauged by clinician subjective assessment. Three-dimensional (3D) surface imaging has been applied in several medical disciplines to quantify surface changes, with promising results. We hypothesized that 3D surface imaging could be used to objectively measure changes in area and volume of port-wine stains following laser treatment. STUDY DESIGN/MATERIALS AND METHODS: We performed a retrospective review of consecutive patients with port-wine stains treated over a 20-month time period. Area and volume of the lesions were measured using 3dMD photogrammetric software (3dMD, Atlanta, GA) before and after a series of sequential pulsed dye laser and/or alexandrite laser treatments. RESULTS: Fifty-five patients with 59 port-wine stains were included in the study. The initial average measured area was 44.3 cm(2) ; final average measured area decreased to 36.9 cm(2) (P < 0.001). The average volume change was 1.20 cc for all PWS included in the study and 1.90 cc for lesions that received at least 5 laser treatments within the study period. CONCLUSION: Three-dimensional photography demonstrated area and volume changes in patients with port-wine stains after laser treatments. Future studies to determine if statistically significant changes correlate with clinically appreciable changes are warranted. PMID- 24155124 TI - Fabrication of three-dimensional porous scaffolds with controlled filament orientation and large pore size via an improved E-jetting technique. AB - Biodegradable polymeric scaffolds have been widely used in tissue engineering as a platform for cell proliferation and subsequent tissue regeneration. Conventional microextrusion methods for three-dimensional (3D) scaffold fabrication were limited by their low resolution. Electrospinning, a form of electrohydrodynamic (EHD) printing, is an attractive method due to its capability of fabricating high-resolution scaffolds at the nanometer/micrometer scale level. However, the scaffold was composed of randomly orientated filaments which could not guide the cells in a specific direction. Furthermore, the pores of the electrospun scaffold were small, thus preventing cell infiltration. In this study, an alternative EHD jet printing (E-jetting) technique has been developed and employed to fabricate 3D polycaprolactone (PCL) scaffolds with desired filament orientation and pore size. The effect of PCL solution concentration was evaluated. Results showed that solidified filaments were achieved at concentration >70% (w/v). Uniform filaments of diameter 20 MUm were produced via the E-jetting technique, and X-ray diffraction and attenuated total reflectance Fourier transform infrared spectroscopic analyses revealed that there was no physicochemical changes toward PCL. Scaffold with a pore size of 450 MUm and porosity level of 92%, was achieved. A preliminary in vitro study illustrated that live chondrocytes were attaching on the outer and inner surfaces of collagen coated E-jetted PCL scaffolds. E-jetted scaffolds increased chondrocytes extracellular matrix secretion, and newly formed matrices from chondrocytes contributed significantly to the mechanical strength of the scaffolds. All these results suggested that E-jetting is an alternative scaffold fabrication technique, which has the capability to construct 3D scaffolds with aligned filaments and large pore sizes for tissue engineering applications. PMID- 24155125 TI - Conjugation of peptide nucleic acid with a pyrrole/imidazole polyamide to specifically recognize and cleave DNA. AB - Cut loose: A pseudocomplementary peptide nucleic acid was tethered to a pyrrole/imidazole hairpin polyamide, and was used to selectively target a specific DNA sequence. Binding even occurs under high salt conditions. Furthermore, the conjugate facilitated sequence-specific scission of long dsDNA. This simple approach promises to resolve the technical difficulties in targeting DNA sequences with PNA. PMID- 24155126 TI - Contemporary risk of hip fracture in type 1 and type 2 diabetes: a national registry study from Scotland. AB - The purpose of this study was to compare contemporary risk of hip fracture in type 1 and type 2 diabetes with the nondiabetic population. Using a national diabetes database, we identified those with type 1 and type 2 diabetes who were aged 20 to 84 years and alive anytime from January 1, 2005 to December 31, 2007. All hospitalized events for hip fracture in 2005 to 2007 for diabetes patients were linked and compared with general population counts. Age- and calendar-year adjusted incidence rate ratios were calculated by diabetes type and sex. One hundred five hip fractures occurred in 21,033 people (59,585 person-years) with type 1 diabetes; 1421 in 180,841 people (462,120 person-years) with type 2 diabetes; and 11,733 hip fractures over 10,980,599 person-years in the nondiabetic population (3.66 million people). Those with type 1 diabetes had substantially elevated risks of hip fracture compared with the general population incidence risk ratio (IRR) of 3.28 (95% confidence interval [CI] 2.52-4.26) in men and 3.54 (CI 2.75-4.57) in women. The IRR was greater at younger ages, but absolute risk difference was greatest at older ages. In type 2 diabetes, there was no elevation in risk among men (IRR 0.97 [CI 0.92-1.02]) and the increase in risk in women was small (IRR 1.05 [CI 1.01-1.10]). There remains a substantial elevation relative risk of hip fracture in people with type 1 diabetes, but the relative risk is much lower than in earlier studies. In contrast, there is currently little elevation in overall hip fracture risk with type 2 diabetes, but this may mask elevations in risk in particular subgroups of type 2 diabetes patients with different body mass indexes, diabetes duration, or drug exposure. PMID- 24155127 TI - The diagnostic accuracy of estimated continuous cardiac output compared with transthoracic echocardiography. AB - PURPOSE: Estimated continuous cardiac output (esCCO) is a new and noninvasive cardiac output (CO) monitoring device using pulse wave transit time. The aim of this study was to assess rapid changes in CO using esCCO (DeltaCOesCCO) without invasive calibration and to compare the results with those using transthoracic Doppler echocardiography (DeltaCOTTE). METHODS: Fifty-four consecutive patients were enrolled in this study following elective cardiac surgery. The COesCCO and COTTE were collected during four consecutive steps: 1) at baseline, 2) during passive leg raising (PLR), 3) at return to baseline, and 4) after a fluid challenge. The relationship between DeltaCOesCCO and DeltaCOTTE induced by PLR and a fluid challenge was assessed and a polar plot analysis was performed. Relationship, Bland-Altman analysis, and percentage error for absolute values of COesCCO and COTTE were also performed. RESULTS: Twenty-four patients were excluded from the analysis. No correlation was found between DeltaCOesCCO and DeltaCOTTE during PLR (r = 0.07; P = 0.732; n = 30) and after a fluid challenge (r = 0.24; P = 0.394; n = 14). The polar plot analysis showed that 21 data points (87%) of significant changes in CO were above the 30 degrees radial sector lines and confirmed that esCCO was unable to track changes in CO. A weak positive relationship was found between absolute values of COesCCO and COTTE (r = 0.28; P = 0.004). Bias, precision, and limits of agreement were 0.25 L.min(-1), 2.4 L.min(-1), and -4.4 to 4.9 L.min(-1), respectively. The percentage error was 80%. CONCLUSIONS: Estimated continuous cardiac output without external calibration seems unable to assess rapid changes in CO following cardiac surgery and was not interchangeable with transthoracic Doppler echocardiography. PMID- 24155128 TI - Incidence of underlying laryngeal pathology in patients initially diagnosed with laryngopharyngeal reflux. AB - OBJECTIVES/HYPOTHESIS: To characterize the videoendoscopic laryngeal findings in patients with a prior established diagnosis of laryngopharyngeal reflux disease (LPR) as the sole etiology for their chief complaint of hoarseness. We hypothesized that many, if not all, of these patients would present with discrete laryngeal pathology, divergent from LPR. STUDY DESIGN: Prospective, nonintervention. METHODS: Patients presenting to a tertiary laryngology practice with an established diagnosis of LPR as the sole etiology of their hoarseness were included. All subjects completed the Voice Handicap Index and Reflux Symptom Index, in addition to a questionnaire regarding their reflux diagnosis and prior treatment. Laryngoscopic examinations were reviewed by the laryngologist caring for the patients. Reliability of findings was assessed by interpretation of videoendoscopic findings by three outside laryngologists not involved in the care of the patients. RESULTS: Laryngeal pathology distinct from LPR was identified in all 21 patients felt to be causative of the chief complaint of dysphonia. Specifically, the most common findings were benign mucosal lesions and vocal fold paresis (29% each), followed by muscle tension dysphonia (14%). Two patients were found to have vocal fold leukoplakia, of which one was confirmed to be a microinvasive carcinoma upon removal. CONCLUSION: LPR may be overdiagnosed; other etiologies must be considered for patients with hoarseness who fail empiric LPR treatment. LEVEL OF EVIDENCE: 4. PMID- 24155129 TI - Effects of Achilles tendon immersion in saline and perfluorochemicals on T2 and T2*. AB - PURPOSE: To determine if immersion of Achilles tendon segments into various solutions improved qualitative delineation of tendon and affected quantitative MR values of T2 and T2*. MATERIALS AND METHODS: Six Achilles tendons were dissected, sectioned (proximal, midportion, and distal tensile pieces) and imaged at 3T both at baseline in air and after immersion into saline, Fomblin, and perfluorooctyl bromide (PFOB), respectively, for 24 h. Blinded readers qualitatively assessed the delineation of tendon boundaries and quantitatively Carr-Purcell-Meiboom-Gill (CPMG) T2 and ultrashort echo time (UTE) T2* was calculated. Comparison between images obtained in air and in solution was made. RESULTS: On qualitative evaluation, all images obtained in air had larger air-tissue susceptibility effects. Mean T2 values of saline, Fomblin, and PFOB groups were 16.1 +/- 3.7, 16.6 +/- 2.9, and 18.8 +/- 2.6 ms at baseline in air, and 14.8 +/- 4.6, 15.9 +/- 3.0, and 17.7 +/- 3.0 ms after immersion in the fluid, respectively. Mean T2* values of saline, Fomblin, and PFOB groups were 2.0 +/- 0.8, 1.6 +/- 0.5, and 1.5 +/- 0.5 ms at baseline in air, and 2.1 +/- 0.5, 1.6 +/- 0.5, and 1.4 +/- 0.5 ms after immersion in the fluid, respectively. There was no significant effect of immersion or fluid type on measured T2 or T2* (P > 0.1). CONCLUSION: These results validate the continued use of these solutions to prevent tendon specimen dehydration and to minimize susceptibility effects. PMID- 24155130 TI - Phosphoserine promotes osteogenic differentiation of human adipose stromal cells through bone morphogenetic protein signalling. AB - Phosphoserine has potential effectiveness as a simple substrate in preparing bone replacement materials, which could enhance bone forming ability. However, there is a need to investigate the independent effect of phosphoserine on osteogenic differentiation of human adipose stem cells (hADSCs). hADSCs were cultured in an osteogenic medium with phosphoserine. Cell proliferation was analysed by CCK8 and osteogenic differentiation was measured by alkaline phosphatase (ALP) activity, von Kossa staining and real time-polymerase chain reaction (RT-PCR). No stimulatory effect of phosphoserine on cell proliferation was noted at Days 1, 4 and 7. Deposition of calcium increased after the addition of phosphoserine. mRNA expression of type I collagen (COL-I), alkaline phosphatase (ALP), osteocalcin (OCN), Osterix, bone morphogenetic protein-2 (BMP-2) and RUNX2 increased markedly with phosphoserine treatment. The BMP-2 antagonist, noggin, and its receptor kinase inhibitors, dorsomorphin and LDN-193189, attenuated phosphoserine-promoted ALP activity. BMP-responsive and Runx2-responsive reporters were activated by phosphoserine treatment. Thus phosphoserine can promote osteogenic differentiation of hADSCs, probably by activating BMP and Runx2 pathways, which could be a promising approach for enhancing osteogenic capacity of cell-based construction in bone tissue engineering. PMID- 24155131 TI - Endovascular management of splenic artery aneurysms: case series using telescoping guide and cage/coil technique. AB - Splenic artery aneurysms are rare, but still the third most common abdominal aneurysm. Rupture is associated with significant morbidity and mortality. Traditionally, cardiologists have rarely been involved in the management of this entity. We present a series of four patients managed percutaneously by interventional cardiology using a combined telescoping guide and cage/coil technique. PMID- 24155132 TI - Prognostic role of internal jugular vein preservation in neck dissection for head and neck cancer. AB - BACKGROUND AND OBJECTIVES: Sparing internal jugular vein (IJV) in neck dissection for head and neck cancer is controversial. We aimed at evaluating the prognostic impact of IJV preservation. METHODS: We examined 206 files of head and neck cancer patients who underwent radical or modified radical neck dissection at the Otolaryngology University of Florence. The site of primary tumor was larynx and hypopharynx in 44.66%, oropharynx in 25.24%, oral cavity in 23.3%, unknown in 4.85%, salivary glands and rhinopharynx in 0.97%. In 60.19% the IJV was resected, in 39.81% preserved. Prognostic impact of IJV preservation was assessed by Kaplan Meier and multivariate analysis. RESULTS: Neck recurrence occurred in 25.2%: the IJV was resected in 42.31%, in 57.69% preserved (P = 0.02). At multivariate analysis, neck recurrence resulted significantly associated to extracapsular spread (ECS) (P = 0.009), IJV preservation (P = 0.01), positive margins (P = 0.02). In ECS positive patients, a higher risk of neck recurrence was documented for IJV preservation (P = 0.012). A worse prognosis was observed for patients with IJV spared (P = 0.06). CONCLUSIONS: IJV preservation is associated with an increased risk of neck failure and a worse outcome, mainly in patients with ECS of nodes. PMID- 24155133 TI - Associations of bread and pasta with the risk of cancer of the breast and colorectum. AB - BACKGROUND: Carbohydrate foods with high glycemic and insulinemic potential may influence cancer risk possibly through the insulin/growth-factor axis. Two staple carbohydrate foods of the Mediterranean diet, bread and pasta, have different glycemic and insulinemic responses and hence may affect cancer risk differently. MATERIALS AND METHODS: We studied the association of bread and pasta with breast and colorectal cancer risk using data from two Italian case-control studies. These studies included 2569 women with histologically confirmed breast cancer and 1953 men and women with colorectal cancer. Controls were 2588 and 4154, respectively, admitted to the same hospitals as cases for acute, non-neoplastic conditions. Multivariate odds ratios (ORs) were obtained after allowance for relevant confounding factors. RESULTS: The ORs of breast cancer for the highest versus the lowest quintile were 1.28 (95% confidence interval, CI: 1.03-1.58, P trend = 0.0342) for bread and 1.07 (95% CI: 0.88-1.31, P-trend = 0.7072) for pasta. The association with bread remained virtually unchanged with postmenopause and overweight. The ORs of colorectal cancer in women for the highest versus the lowest quintile were 2.02 (95% CI: 1.46-2.80, P-trend = 0.0002) for bread and 1.37 (95% CI: 1.00-1.88, P-trend = 0.0164) for pasta. The associations remained significant only for bread in strata of menopausal status and in women with overweight. No significant associations were seen in men for either bread or pasta. CONCLUSIONS: Overall, these two cancer case-control studies showed stronger positive associations with bread than pasta in women, particularly if overweight, suggesting possible hormonal-related mechanisms. PMID- 24155134 TI - Monitoring the effect of race-analysis parameters on performance in elite swimmers. AB - Time trials are commonly used in the lead-up to competition. A method that evaluates the relationship between time trial and competition performance in swimming would be useful for developing performance-enhancement strategies. PURPOSE: To use linear mixed modeling to identify key parameters that can be used to relate time-trial and competition performance. METHODS: Ten swimmers participated in the study. Each swimmer was analyzed during 3 time trials and 1 competition. Race video footage was analyzed to determine several key parameters. Pooling of strokes and distances was achieved by modeling changes in parameters between time trials and competition within each subject as linear predictors of percent change in performance using mixed modeling of log-transformed race times. RESULTS: When parameters were evaluated as the effect of 2 SD on performance time, there were very large effects of start time (2.6%, 90% confidence interval 1.8-3.3%) and average velocity (-2.3%, -2.8% to -1.8%). There was also a small effect for stroke rate (-0.6%, -1.3% to 0.2%). Further analysis revealed an improvement in performance time of 2.4% between time trials and competition, of which 1.8% (large; 1.4-2.1%) was due to a change in average velocity and 0.9% (moderate; 0.6-1.1%) was due to a change in start time; changes in remaining parameters had trivial effects on performance. CONCLUSION: This study illustrates effective analytical strategies for identifying key parameters that can be the focus of training to improve performance in small squads of elite swimmers and other athletes. PMID- 24155135 TI - Preface to topic "Robotic surgery for hepato-biliary-pancreatic (HBP) surgery". PMID- 24155136 TI - Size and composition of synthetic calcium sulfate beads influence dissolution and elution rates in vitro. AB - Treatments of osteomyelitis lag behind bacterial resistance to antibiotics. We tested different-sized calcium sulfate beads and their ability to elute multiple antibiotics in vitro as a possible method to improve the therapeutic delivery in patients. Two sizes of calcium sulfate beads (4.8 and 3.0 mm diameter) that contained vancomycin, tobramycin, or both were dissolved in phosphate-buffered saline, and the rate of dissolution by weight and antibiotic elution by the disc diffusion assay and high-pressure liquid chromatography were measured. The 4.8 mm beads showed significantly higher dissolution rates relative to the 3.0 mm beads (2.3 mg/day vs. 1.3 mg/day). While the vancomycin-loaded 4.8 mm beads eluted for a longer time relative to the 3.0 mm beads (20 days vs. 10 days), the smaller beads had threefold higher elution for the first 2 days, before dropping to near zero elution by day 4. The presence of tobramycin extended the elution of the vancomycin to day 40, which closely matches the recommended 6 weeks to treat orthopedic staphylococcus infections. These data suggest that size and content of the bead are variables that could affect their clinical success, and both could be exploited to tailor treatments of specific infections and injuries. PMID- 24155137 TI - Ultrafast energy transfer to liquid water by sub-picosecond high-intensity terahertz pulses: an ab initio molecular dynamics study. AB - Sub-picosecond heating of bulk water is accomplished by ultrashort and intense THz pulses which are able to transfer a large amount of energy to the liquid. The energy transferred corresponds to a temperature jump of about 600 K. Liquid water becomes a structureless and hot gas-like system still at the density of the liquid, in which the hydrogen-bonding structure has been washed out. PMID- 24155138 TI - Quality of life in children and adolescents with autism spectrum disorders: what is known about the effects of pharmacotherapy? AB - A diagnosis of autistic spectrum disorder (ASD), now estimated to affect one in 88 children, requires deficits in social communication and interactions, and restricted interests and/or repetitive behaviors. Almost all children with ASD have deficits in adaptive skills, many have intellectual disability, and others have co-occurring psychiatric disorders or symptoms. Thus, this complex disorder has shown to have a substantial impact on patients' quality of life (QoL) and that of their families. Medication treatment is considered by clinicians and families to address problems with functioning due to psychiatric problems, and, as such, one-third of children and adolescents with ASD take at least one psychotropic medication and many use complementary and alternative medicine. This paper reviews what is known about the benefits and risks of psychotropic medications on the QoL of children with ASD. Although scarce, there are studies of psychiatric medications in autistic patients that include QoL measures, such as the pediatric studies of aripiprazole for irritability and one adult study of oxytocin. The aripiprazole study showed a positive effect on QoL in treated patients, as did the oxytocin study. Several other psychotropic medications are used in the treatment of children with ASD, and although information is available on the risks and benefits of each, we do not have specific data on the QoL impact of these medications. The aripiprazole and oxytocin studies exemplify how researchers can include QoL measures and use this information to guide clinicians. Additionally, we will recommend areas of further study in pharmacotherapy and QoL research in the context of treating children with ASD. PMID- 24155139 TI - Tocilizumab: a review of its use in the treatment of juvenile idiopathic arthritis. AB - Tocilizumab (RoActemra((r)); Actemra((r))) is a recombinant humanized monoclonal antibody that acts as an interleukin-6 receptor antagonist. Both in the US and EU, tocilizumab has been approved for the treatment of two subtypes of juvenile idiopathic arthritis (JIA), namely systemic JIA (sJIA) and polyarticular JIA (pJIA), in patients aged >=2 years. These approvals are based on favorable results from two randomized, double-blind, placebo-controlled, multinational, phase III trials in which patients aged 2-17 years with active sJIA (TENDER) or pJIA (CHERISH) received an intravenous dose of tocilizumab based on bodyweight every 2 or 4 weeks, respectively. Tocilizumab met the primary endpoint in both of these ongoing, multi-part studies. That is, in TENDER, significantly more tocilizumab recipients than placebo recipients achieved a JIA American College of Rheumatology (ACR) 30 response plus absence of fever, as assessed at the end of a 12-week double-blind treatment period, while in CHERISH, significantly fewer tocilizumab recipients than placebo recipients experienced a JIA ACR 30 flare during a 24-week double-blind withdrawal period (all patients had previously received open-label tocilizumab in a 16-week lead-in phase). Tocilizumab was generally well tolerated in the TENDER trial. Infections (e.g. upper respiratory tract infection and pharyngitis or nasopharyngitis) accounted for just over one third of all reported adverse events in this trial; tocilizumab-treated patients appeared to have an approximately 11 % risk of a serious infection per year of treatment. Clinical laboratory abnormalities included neutropenia and elevated aminotransferase levels. The tolerability profile of tocilizumab in CHERISH was generally consistent with that of the drug in TENDER. PMID- 24155140 TI - In vivo, high-resolution, three-dimensional imaging of port wine stain microvasculature in human skin. AB - BACKGROUND AND OBJECTIVES: Port-wine stain (PWS) is a congenital, progressive vascular malformation of the dermis. The use of optical coherence tomography (OCT) for the characterization of blood vessels in PWS skin has been demonstrated by several groups. In the past few years, advances in OCT technology have greatly increased imaging speed. Sophisticated numerical algorithms have improved the sensitivity of Doppler OCT dramatically. These improvements have enabled the noninvasive, high-resolution, three-dimensional functional imaging of PWS skin. Here, we demonstrate high-resolution, three-dimensional, microvasculature imaging of PWS and normal skin using Doppler OCT technique. STUDY DESIGN/MATERIALS AND METHODS: The OCT system uses a swept source laser which has a central wavelength of 1,310 nm, an A-line rate of 50 kHz and a total average power of 16 mW. The system uses a handheld imaging probe and has an axial resolution of 9.3 um in air and a lateral resolution of approximately 15 um. Images were acquired from PWS subjects at the Beckman Laser Institute and Medical Clinic. Microvasculature of the PWS skin and normal skin were obtained from the PWS subject. RESULTS: High resolution, three-dimensional microvasculature of PWS and normal skin were obtained. Many enlarged PWS vessels are detected in the dermis down to 1.0 mm below the PWS skin surface. In one subject, the blood vessel diameters range from 40 to 90 um at the epidermal-dermal junction and increase up to 300-500 um at deeper regions 700-1,000 um below skin surface. The blood vessels close to the epidermal-dermal junction are more uniform, in terms of diameter. The more tortuous and dilated PWS blood vessels are located at deeper regions 600-1,000 um below the skin surface. In another subject example, the PWS skin blood vessels are dilated at very superficial layers at a depth less than 500 um below the skin surface. The PWS skin vessel diameters range from 60 to 650 um, with most vessels having a diameter of around 200 um. CONCLUSIONS: OCT can be used to quantitatively image in vivo skin micro-vasculature. Analysis of the PWS and normal skin blood vessels were performed and the results can provide quantitative information to optimize laser treatment on an individual patient basis. PMID- 24155141 TI - A tribute to Philip Quanjer. PMID- 24155142 TI - Triggers for driving treatment of at-risk patients with invasive fungal disease. AB - Timing of treatment for invasive fungal disease (IFD) is critical for making appropriate clinical decisions. Historically, many centres have treated at-risk patients prior to disease detection to try to prevent fungal colonization or in response to antibiotic-resistant fever. Many studies have indicated that a diagnostic-driven approach, using radiological tests and biomarkers to guide treatment decisions, may be a more clinically relevant and cost-effective approach. The Invasive Fungal Infections Cooperative Group of the European Organization for Research and Treatment of Cancer/Mycoses Study Group (EORTC/MSG) defined host clinical and mycological criteria for proven, probable and possible classes of IFD, to aid diagnosis. However, some patients at risk of IFD do not meet EORTC/MSG criteria and have been termed Groups B (patients with persistent unexplained febrile neutropenia) and C (patients with non-definitive signs of IFD) in a study by Maertens et al. (Haematologica 2012; 97: 325-7). Consequently, we considered the most appropriate triggers (clinical or radiological signs or biomarkers) for treatment of all patient groups, especially the unclassified B and C groups, based on our clinical experience. For Group C patients, additional diagnostic testing is recommended before a decision to treat, including repeat galactomannan tests, radiological scans and analysis of bronchoalveolar lavage fluid. Triggers for stopping antifungal treatment were considered to include resolution of all clinical signs and symptoms. For Group B patients, it was concluded that better definition of risk factors predisposing patients to fungal infection and the use of more sensitive diagnostic tests are required to aid treatment decisions and improve clinical outcomes. PMID- 24155143 TI - A multidisciplinary team approach to the management of patients with suspected or diagnosed invasive fungal disease. AB - Implementation of evidence-based guidelines for the treatment of invasive fungal disease (IFD) requires collaboration among numerous clinical and laboratory services, as partners in patient care. The multidisciplinary team (MDT) approach has emerged as a way of providing comprehensive medical care by bringing together professionals from a wide range of disciplines in a coordinated and effective manner. Here, we propose an MDT model for IFD management aimed at facilitating communication among consultants, adherence to clinical pathways and optimized use of resources available at each centre. PMID- 24155144 TI - Preventing invasive fungal disease in patients with haematological malignancies and the recipients of haematopoietic stem cell transplantation: practical aspects. AB - Invasive fungal disease (IFD), predominantly aspergillosis, is associated with significant morbidity and mortality in immunocompromised patients, especially those with haematological malignancies and recipients of allogeneic haematopoietic stem cell transplantation. There has been a great deal of scientific debate as to the effectiveness of antifungal prophylaxis in preventing infection in different patient groups and in which patients it is an appropriate management option. Deciding on an appropriate prophylaxis regimen for IFD is challenging as the incidence varies among different patient groups, due to the varied nature of their underlying haematological disease, and in different regions and centres. Attempts have been made to define risk factors and include them in treatment protocols. Impaired immune status of the patient, especially neutropenia, is a key risk factor for IFD and can sometimes be related to specific polymorphisms of genes controlling innate immunity. Risk factors also vary according to the type of fungal pathogen. Consequently, prophylaxis needs to be tailored to individual patient groups. Furthermore, the choice of antifungal agent for prophylaxis depends on the potential for drug-drug interactions with the patients' concomitant medications. Additional challenges are optimal timing of antifungal prophylaxis, when to change from prophylaxis to antifungal treatment and how to prevent recurrence of IFD. This article considers the use of antifungal prophylaxis for patients at risk of IFD in daily clinical practice, with clinical profiles that may be distinct from those covered by guidelines, and aims to provide practical advice for treatment of these patient groups. PMID- 24155145 TI - Interleukin 1 beta gene and risk of schizophrenia: detailed case-control and family-based studies and an updated meta-analysis. AB - OBJECTIVE: Interleukin-1 beta (IL-1beta) has been implicated in the pathophysiology of schizophrenia. To assess whether the IL1B gene confers increased susceptibility to schizophrenia, we conducted case-control and family based studies and an updated meta-analysis. METHODS: We tested the association between IL1B and schizophrenia in 1229 case-control and 112 trio samples using 12 markers, including common tagging single nucleotide variations (SNVs) and a rare non-synonymous variation detected by resequencing the coding regions. We also performed a meta-analysis of rs16944 using a total of 8724 case-control and 201 trio samples from 16 independent populations. RESULTS: We found no significant associations between any of the 12 SNVs examined and schizophrenia in either case control or trio samples. Moreover, our meta-analysis results showed no significant association between the common SNV, rs16944, and schizophrenia. CONCLUSIONS: The present study does not support a role for IL1B in schizophrenia susceptibility. PMID- 24155146 TI - Comorbid insomnia and sleep disordered breathing. AB - OPINION STATEMENT: Sufficient evidence has accumulated to warrant conceptualization of comorbid insomnia and sleep disordered breathing (SDB) as a distinct clinical syndrome. As such, diagnostic and treatment approaches should be founded on an integrated and multidisciplinary approach with equivalent clinical attention and priority given to both insomnia and respiratory aspects of patients' presenting complaints. Several well established and effective treatments exist for both insomnia and SDB. Although questions of optimal treatment combination and sequence remain to be examined, current evidence provides preliminary guidance regarding the sequential or concurrent management of insomnia and sleep disordered breathing when comorbid. Unsatisfactory response to pharmacotherapy or cognitive-behavioral therapy for chronic insomnia should trigger evaluation for comorbid sleep-related breathing disturbance prior to more aggressive or off label pharmacotherapy. Presence and course of insomnia symptoms should be monitored closely in SDB patients with persistence of insomnia symptoms following SDB treatment prompting targeted treatment of insomnia. Aggressive treatment of insomnia prior to or in combination with SDB treatment may be particularly indicated in situations where insomnia is suspected to interfere with diagnosis or treatment of SDB. Insomnia and sleep disordered breathing appear to uniquely contribute to the morbidity of patients with this comorbidity. With this in mind, active engagement and monitoring of SDB and insomnia will often be necessary to achieve optimal outcomes. PMID- 24155147 TI - Going Pro to enhance T-cell immunogenicity: easy as pi? AB - MHC class I molecules bind intracellular oligopeptides and present them on the cell surface for CD8(+) T-cell activation and recognition. Strong peptide/MHC class I (pMHC) interactions typically induce the best CD8(+) T-cell responses; however, many immunotherapeutic tumor-specific peptides bind MHC with low affinity. To overcome this, immunologists can carefully alter peptides for enhanced MHC affinity but often at the cost of decreased T-cell recognition. A new report published in this issue of the European Journal of Immunology [Eur. J. Immunol. 2013. 43:3051-3060] shows that the substitution of proline at the third residue (p3P) of a common tumor peptide increases pMHC affinity and complex stability while enhancing T-cell receptor recognition. X-ray crystallography indicates that stability is generated through newly introduced CH-pi bonding between p3P and a conserved residue (Y159) in the MHC heavy chain. This finding highlights a previously unappreciated role for CH-pi bonding in MHC peptide binding, and importantly, arms immunologists with a novel and possibly general approach for increasing pMHC stability without compromising T-cell recognition. PMID- 24155149 TI - FGF2 and insulin signaling converge to regulate cyclin D expression in multipotent neural stem cells. AB - The ex vivo expansion of stem cells is making major contribution to biomedical research. The multipotent nature of neural precursors acutely isolated from the developing central nervous system has been established in a series of studies. Understanding the mechanisms regulating cell expansion in tissue culture would support their expanded use either in cell therapies or to define disease mechanisms. Basic fibroblast growth factor (FGF2) and insulin, ligands for tyrosine kinase receptors, are sufficient to sustain neural stem cells (NSCs) in culture. Interestingly, real-time imaging shows that these cells become multipotent every time they are passaged. Here, we analyze the role of FGF2 and insulin in the brief period when multipotent cells are present. FGF2 signaling results in the phosphorylation of Erk1/2, and activation of c-Fos and c-Jun that lead to elevated cyclin D mRNA levels. Insulin signals through the PI3k/Akt pathway to regulate cyclins at the post-transcriptional level. This precise Boolean regulation extends our understanding of the proliferation of multipotent NSCs and provides a basis for further analysis of proliferation control in the cell states defined by real-time mapping of the cell lineages that form the central nervous system. PMID- 24155150 TI - Short- and long-term results of lateral pancreaticojejunostomy for chronic pancreatitis: a retrospective Japanese single-center study. AB - BACKGROUND: The study aim was to determine the short- and long-term results of lateral pancreaticojejunostomy for chronic pancreatitis at a single center in Japan. METHODS: The records of 64 consecutive patients were retrospectively reviewed. All patients underwent surgery at Hiroshima University Hospital between December 1996 and April 2013. Long-term follow-up was performed in 58 patients (91%) for a median period of 34 months. RESULTS: The 53 men (83%) and 11 women (17%) had a mean age of 55 years. The etiology of pancreatitis was chronic alcohol abuse in 44 patients (69%). The major indication for surgery was acute pancreatitis exacerbation (80%). There was no postoperative mortality. Postoperative morbidity occurred in 21 patients (33%), with severe complications requiring non-surgical intervention in four (6%). The percentage of pain-free patients after surgery was 91%, and further acute exacerbation was prevented in 95%. Four patients (7%) required subsequent surgery for pancreatitis-related complications. Of the patients that completed follow-up, 33 (57%) had diabetes mellitus, including 11 patients (19%) with new-onset diabetes; 30 patients (56%) developed pancreatic exocrine insufficiency. CONCLUSIONS: Full-length lateral pancreaticojejunostomy is safe, feasible, and effective for managing chronic pancreatitis. The technique prevents further exacerbations and maintains appropriate pancreatic endocrine and exocrine function. PMID- 24155151 TI - Metal release and speciation of released chromium from a biomedical CoCrMo alloy into simulated physiologically relevant solutions. AB - The objective of this study was to investigate the extent of released Co, Cr(III), Cr(VI), and Mo from a biomedical high-carbon CoCrMo alloy exposed in phosphate-buffered saline (PBS), without and with the addition of 10 uM H2 O2 (PBS + H2 O2 ), and 10 g L(-1) bovine serum albumin (PBS + BSA) for time periods up to 28 days. Comparative studies were made on AISI 316L for the longest time period. No Cr(VI) release was observed for any of the alloys in either PBS or PBS + H2 O2 at open-circuit potential (no applied potential). However, at applied potentials (0.7 V vs. Ag/AgCl), Cr was primarily released as Cr(VI). Co was preferentially released from the CoCrMo alloy at no applied potential. As a consequence, Cr was enriched in the utmost surface oxide reducing the extent of metal release over time. This passivation effect was accelerated in PBS + H2 O2 . As previously reported for 316L, BSA may also enhance metal release from CoCrMo. However, this was not possible to verify due to the precipitation of metal protein complexes with reduced metal concentrations in solution as a consequence. This was particularly important for Co-BSA complexes after sufficient time and resulted in an underestimation of metals in solution. PMID- 24155152 TI - In vivo assessment of the biomechanical properties of the uterine cervix in pregnancy. AB - Measuring the stiffness of the cervix might be useful in the prediction of preterm delivery or successful induction of labor. For that purpose, a variety of methods for quantitative determination of physical properties of the pregnant cervix have been developed. Herein, we review studies on the clinical application of these new techniques. They are based on the quantification of mechanical, optical, or electrical properties associated with increased hydration and loss of organization in collagen structure. Quasi-static elastography determines relative values of stiffness; hence, it can identify differences in deformability. Quasi static elastography unfortunately cannot quantify in absolute terms the stiffness of the cervix. Also, the current clinical studies did not demonstrate the ability to predict the time point of delivery. In contrast, measurement of maximum deformability of the cervix (e.g. quantified with the cervical consistency index) provided meaningful results, showing an increase in compliance with gestational age. These findings are consistent with aspiration measurements on the pregnant ectocervix, indicating a progressive decrease of stiffness along gestation. Cervical consistency index and aspiration measurements therefore represent promising techniques for quantitative assessment of the biomechanical properties of the cervix. PMID- 24155153 TI - Metastasectomy for gastrointestinal stromal tumors. AB - Gastrointestinal stromal tumor (GIST) is the most common sarcoma of the intestinal tract. Improvements in understanding the molecular pathogenesis of GIST have resulted in novel treatment strategies combining surgery with tyrosine kinase inhibitors (TKIs). Metastasectomy in carefully selected patients who have stable or responsive disease on imatinib should be considered in the multidisciplinary setting. We review existing data on surgical cytoreduction in metastatic GIST while on targeted therapy and compare outcomes with either treatment alone. PMID- 24155154 TI - Renal artery duplex ultrasound criteria for the detection of significant in-stent restenosis. AB - OBJECTIVES: To define velocity criteria by ultrasonography for the detection of hemodynamically significant (>60%) renal artery in-stent restenosis (ISR). BACKGROUND: The restenosis rate after renal artery stenting ranges between 10% and 20%. While duplex ultrasound criteria have been validated for native renal artery stenosis, there are no uniformly accepted validated criteria for stented renal arteries. METHODS: Vascular laboratory databases from two academic medical centers were retrospectively reviewed for patients who underwent renal artery stenting followed by duplex ultrasound evaluation and angiography (CT angiography or catheter angiography) as the gold standard. RESULTS: A cohort of 132 stented renal arteries that had angiographic comparisons was analyzed. Eighty-eight renal arteries demonstrated 0-59% stenosis while 44 renal arteries revealed 60-99% stenosis by angiography. Both the mean peak systolic velocity (PSV) and the renal artery-to-aortic ratio (RAR) were significantly higher in renal arteries with 60 99% restenosis compared with those with 0-59% restenosis (PSV: 382 cm/sec +/- 128 vs. 129 cm/sec +/- 62, P<0.001; RAR: 5.3 +/- 2.4 vs. 2.1 +/- 1.0, P <0.001). The optimal PSV and RAR cutoffs for detecting 60-99% ISR were calculated by receiver operator characteristics curve analysis. The velocity criteria that are associated with these results will be discussed. CONCLUSION: Duplex ultrasonography is an accurate technique to identify significant restenosis in stented renal arteries. The PSV and RAR cutoffs for detecting renal artery ISR are higher than those in native, unstented renal arteries. A normal duplex ultrasound after renal artery stenting virtually excludes significant restenosis. PMID- 24155155 TI - Examination of calcium-binding protein expression in the inner ear of wild-type, heterozygous and homozygous pituitary adenylate cyclase-activating polypeptide (PACAP)-knockout mice in kanamycin-induced ototoxicity. AB - Pituitary adenylate cyclase-activating polypeptide (PACAP) is a neuropeptide with diverse biological effects. It also occurs and exerts protective effects in sensory organs; however, little is known about its effects in the auditory system. Recently, we have shown that PACAP protects cochlear cells against oxidative-stress-induced apoptosis and homozygous PACAP-deficient animals show stronger expression of Ca(2+)-binding proteins in the hair cells of the inner ear, but there are no data about the consequences of the lack of endogenous PACAP in different ototoxic insults such as aminoglycoside-induced toxicity. In this study, we examined the effect of kanamycin treatment on Ca(2+)-binding protein expression in hair cells of wild-type, heterozygous and homozygous PACAP deficient mice. We treated 5-day-old mice with kanamycin, and 2 days later, we examined the Ca(2+)-binding protein expression of the hair cells with immunohistochemistry. We found stronger expression of Ca(2+)-binding proteins in the hair cells of control heterozygous and homozygous PACAP-deficient mice compared with wild-type animals. Kanamycin induced a significant increase in Ca(2+)-binding protein expression in wild-type and heterozygous PACAP-deficient mice, but the baseline higher expression in homozygous PACAP-deficient mice did not show further changes after the treatment. Elevated endolymphatic Ca(2+) is deleterious for the cochlear function, against which the high concentration of Ca(2+)-buffers in hair cells may protect. Meanwhile, the increased immunoreactivity of Ca(2+)-binding proteins in the absence of PACAP provide further evidence for the important protective role of PACAP in ototoxicity, but further investigations are necessary to examine the exact role of endogenous PACAP in ototoxic insults. PMID- 24155157 TI - Reassessment of tigecycline bone concentrations in volunteers undergoing elective orthopedic procedures. AB - The goal of the this study was to re-evaluate tigecycline bone concentrations in subjects undergoing elective orthopedic surgery, using multiple doses and a more robust bone assay than was used in a previous study. Each subject received three intravenous doses of tigecycline (one 100-mg infusion followed by two 50-mg infusions, each administered over 30 minutes). A single bone sample was collected from each subject at one of the following times: 1, 2, 4, 6, 8, or 12 hours after the third dose. Four blood samples were collected from each subject: before the first dose, before and after the third dose, and within 15 minutes of the collection time of the bone sample. Noncompartmental pharmacokinetic analysis serum and bone area under the curve for the given dose interval (AUCtau ) values were 2,402 ng h/mL and 11,465 ng h/g, and maximum concentration (Cmax ) values were 974 ng/mL and 2,262 ng/g, respectively. The bone to serum ratio calculated using the AUCtau values was 4.77, confirming tigecycline penetration into bone. PMID- 24155156 TI - Neuromelanin of the human substantia nigra: an update. AB - Dopaminergic neurons of the substantia nigra selectively degenerate over the course of Parkinson's disease. These neurons are also the most heavily pigmented cells of the brain, accumulating the dark pigment neuromelanin over a lifetime. The massive presence of neuromelanin in these brain areas has long been suspected as a key factor involved in the selective vulnerability of neurons. The high concentration of neuromelanin in substantia nigra neurons seems to be linked to the presence of considerable amounts of cytosolic dopamine that have not been sequestered into synaptic vesicles. Over the past few years, studies have uncovered a dual nature of neuromelanin. Intraneuronal neuromelanin can be a protective factor, shielding the cells from toxic effects of redox active metals, toxins, and excess of cytosolic catecholamines. In contrast, neuromelanin released by dying neurons can contribute to the activation of neuroglia triggering the neuroinflammation that characterizes Parkinson's disease. This article reviews recent studies on the molecular aspects of neuromelanin of the human substantia nigra. PMID- 24155159 TI - "Broader impacts" or "responsible research and innovation"? A comparison of two criteria for funding research in science and engineering. AB - Our subject is how the experience of Americans with a certain funding criterion, "broader impacts" (and some similar criteria) may help in efforts to turn the European concept of Responsible Research and Innovation (RRI) into a useful guide to funding Europe's scientific and technical research. We believe this comparison may also be as enlightening for Americans concerned with revising research policy. We have organized our report around Rene Von Schomberg's definition of RRI, since it seems both to cover what the European research group to which we belong is interested in and to be the only widely accepted definition of RRI. According to Von Schomberg, RRI: "... is a transparent, interactive process by which societal actors and innovators become mutually responsive to each other with a view to the (ethical) acceptability, sustainability and societal desirability of the innovation process and its marketable products (in order to allow a proper embedding of scientific and technological advances in our society)." While RRI seeks fundamental changes in the way research is conducted, Broader Impacts is more concerned with more peripheral aspects of research: widening participation of disadvantaged groups, recruiting the next generation of scientists, increasing the speed with which results are used, and so on. Nevertheless, an examination of the broadening of funding criteria over the last four decades suggests that National Science Foundation has been moving in the direction of RRI. PMID- 24155160 TI - One-pot zinc-promoted asymmetric alkynylation/brook-type rearrangement/ene-allene cyclization: highly selective formation of three new bonds and two stereocenters in acyclic systems. AB - It's as easy as 1, 2, 3: In a one-pot sequence, two stereocenters and three new bonds were created with high selectivity through an asymmetric alkynylation of acyl silanes, a tandem Brook-type rearrangement and Zn-ene-allene cyclization, the addition of an electrophile, and finally oxidation. The straightforward nature of the synthetic procedure contrasts strongly with the complexity of the densely functionalized products obtained. PMID- 24155158 TI - Blind prediction of interfacial water positions in CAPRI. AB - We report the first assessment of blind predictions of water positions at protein protein interfaces, performed as part of the critical assessment of predicted interactions (CAPRI) community-wide experiment. Groups submitting docking predictions for the complex of the DNase domain of colicin E2 and Im2 immunity protein (CAPRI Target 47), were invited to predict the positions of interfacial water molecules using the method of their choice. The predictions-20 groups submitted a total of 195 models-were assessed by measuring the recall fraction of water-mediated protein contacts. Of the 176 high- or medium-quality docking models-a very good docking performance per se-only 44% had a recall fraction above 0.3, and a mere 6% above 0.5. The actual water positions were in general predicted to an accuracy level no better than 1.5 A, and even in good models about half of the contacts represented false positives. This notwithstanding, three hotspot interface water positions were quite well predicted, and so was one of the water positions that is believed to stabilize the loop that confers specificity in these complexes. Overall the best interface water predictions was achieved by groups that also produced high-quality docking models, indicating that accurate modelling of the protein portion is a determinant factor. The use of established molecular mechanics force fields, coupled to sampling and optimization procedures also seemed to confer an advantage. Insights gained from this analysis should help improve the prediction of protein-water interactions and their role in stabilizing protein complexes. PMID- 24155161 TI - Expansion of activated regulatory T cells by myeloid-specific chemokines via an alternative pathway in CSF of bacterial meningitis patients. AB - Previous studies have demonstrated that activation/expansion by certain cytokines as well as recruitment by specific chemokines is involved in enrichment of regulatory T (Treg) cells in local tissues or organs under pathological conditions. Recent evidence indicates that human Treg cells are a heterogeneous population that comprises three distinct subpopulations: CD25+CD45RA+ resting Treg (rTreg) cells, CD25(hi)CD45RA- activated Treg (aTreg) cells, which are both suppressive, and CD25+CD45RA- cytokine-secreting T cells with proinflammatory capacity. Moreover, rTreg cells can proliferate and convert to aTreg cells. Here, we found an increase in aTreg-cell frequency in the cerebrospinal fluid (CSF) of patients with postneurosurgery bacterial meningitis. We revealed that such an increased aTreg-cell frequency in the CSF was not due to enhanced chemotaxis. Instead of a classic conversion pathway from rTreg to aTreg cells, we identified an alternative route of Treg-cell conversion from cytokine-secreting cells to aTreg cells induced by myeloid-specific chemokine CXC chemokine receptor (CXCR) ligand 5 via CXCR1 and CXCR2 receptors, or by CSF myeloid cells in a cell-cell contact manner. Our results reveal a different view of how the immune system controls overwhelming local immune responses during infection, and provide evidence of how innate immunity negatively regulates adaptive immunity. PMID- 24155162 TI - Answer to the letter of Caudri, van der Valk, de Jongste and Smit. PMID- 24155163 TI - Management of recurrent retroperitoneal sarcoma. AB - Approximately 15% of soft tissue sarcomas are retroperitoneal. The occult location and anatomic complexity results in local recurrences in the majority of patients. Predictors of recurrence include histological subtype, completeness of resection, and the hospital case volume. The most significant predictor of outcome following local recurrence is the resectability of the recurrent disease. An understanding of the implication of tumor biology on outcomes is essential in determining optimal management for patients with recurrent retroperitoneal sarcoma. PMID- 24155164 TI - Concise review: harmonies played by microRNAs in cell fate reprogramming. AB - It is now well-established that somatic cells can be reprogrammed to alternative cell fates by ectopic coexpression of defined factors. Reprogramming technology has uncovered a huge plasticity besides gene regulatory networks (GRNs) of differentiated cell states. MicroRNAs (miRNAs), which are an integral part of GRNs, have recently emerged as a powerful reprogramming toolbox. They regulate numerous genes, thereby modulating virtually all cellular processes, including somatic cell reprogramming. Not only can miRNAs provide novel opportunities for interrogating mechanisms of induced pluripotency and direct lineage reprogramming but they also offer hope for the efficient creation of safe cell sources for regenerative medicine. In reviewing landmark roles of miRNAs in cell reprogramming, we offer suggestions for evolution of the reprogramming field. PMID- 24155167 TI - Conditioned medium as a strategy for human stem cells chondrogenic differentiation. AB - Paracrine signalling from chondrocytes has been reported to increase the synthesis and expression of cartilage extracellular matrix (ECM) by stem cells. The use of conditioned medium obtained from chondrocytes for stimulating stem cells chondrogenic differentiation may be a very interesting alternative for moving into the clinical application of these cells, as chondrocytes could be partially replaced by stem cells for this type of application. In the present study we aimed to achieve chondrogenic differentiation of two different sources of stem cells using conditioned medium, without adding growth factors. We tested both human bone marrow-derived mesenchymal stem cells (hBSMCs) and human Wharton's jelly-derived stem cells (hWJSCs). Conditioned medium obtained from a culture of human articular chondrocytes was used to feed the cells during the experiment. Cultures were performed in previously produced three-dimensional (3D) scaffolds, composed of a blend of 50:50 chitosan:poly(butylene succinate). Both types of stem cells were able to undergo chondrogenic differentiation without the addition of growth factors. Cultures using hWJSCs showed significantly higher GAGs accumulation and expression of cartilage-related genes (aggrecan, Sox9 and collagen type II) when compared to hBMSCs cultures. Conditioned medium obtained from articular chondrocytes induced the chondrogenic differentiation of MSCs and ECM formation. Obtained results showed that this new strategy is very interesting and should be further explored for clinical applications. PMID- 24155168 TI - High macrosomia rate in healthy fetuses after enlarged nuchal translucency. AB - OBJECTIVE: The aim of this study was to investigate the association of the first trimester screening variables nuchal translucency (NT), pregnancy associated plasma protein (PAPP-A), and free beta-human chorionic gonadotrophin (betahCG) and birth weight, with a focus on the prediction of macrosomia. METHODS: The database of our Fetal Medicine Unit was searched for all singleton pregnancies, who underwent first trimester Down syndrome screening. Live born infants born at term without chromosomal or structural defects from non-diabetic mothers constituted the study population. Birth weight percentiles were corrected for gestational age at delivery, parity, and gender. Macrosomia was defined as birth weight >=95th centile. RESULTS: We included 6503 fetuses. Multivariate analysis demonstrated that birth weight centile was positively correlated with NT multiples of the median (MoM), PAPP-A MoM, and maternal body mass index, and it was negatively correlated with smoking. An NT >=95th centile was present in 315 fetuses (4.8%). Although median birth weight centile was not significantly different between cases with NT >=95th centile and those <95th (P54 vs P52), a birth weight >95th centile was more common (11% vs 7%) in the presence of NT >=95th centile. Pregnancy associated plasma protein was elevated (>=95th centile) in 303 cases (7.9%). Median birth weight was higher (P56 vs P51, P = 0.03) in case of elevated PAPP-A compared with PAPP-A <95th centile. There was a trend toward higher macrosomia rate in case of PAPP-A >=95th centile (7.4% vs 6.3%, P = 0.07). Area under the receiver operating characteristics (ROC) curve for the prediction of macrosomia (birth weight >=95th centile) by NT MoM, PAPP-A MoM, maternal body mass index, and maternal smoking was 0.64 (P < 0.001). CONCLUSIONS: First trimester PAPP-A MoM and NT MoM are significantly related to birth weight centiles. Enlarged NT is associated with macrosomia. PMID- 24155170 TI - Selective synthesis of a [32]octaphyrin(1.0.1.0.1.0.1.0) bis(palladium) complex by a metal-templated strategy. AB - A shapely figure: A [32]octaphyrin(1.0.1.0.1.0.1.0) bis[palladium(II)] complex was selectively obtained through a metal-templated intermolecular homocoupling of a alpha,alpha'-dibromodipyrrin palladium(II) complex without formation the norcorrole. The weak antiaromatic character of the figure-eight [32]octaphyrin(1.0.1.0.1.0.1.0) system has been elucidated by spectroscopic measurements and DFT calculations. PMID- 24155171 TI - Laser in infra-popliteal and popliteal stenosis (LIPS): retrospective review of laser-assisted balloon angioplasty versus balloon angioplasty alone for below knee peripheral arterial disease. AB - Despite the use of laser technology over the last decade, there are limited data to show its procedural and clinical success in infra-popliteal disease. We hypothesized that laser-assisted balloon angioplasty (LABA) is at least similar or better in procedural and peri-procedural outcomes compared to balloon angioplasty (BA) alone, despite adverse lesion characteristics prior to intervention. Retrospective chart and angiogram review of consecutive critical limb ischemia (CLI) patients who underwent endovascular revascularization in the popliteal or infra-popliteal vessels between 2007 and 2012 with LABA or BA alone. Data from 731 patients revealed that baseline demographics were similar in the LABA (n = 398) and BA group (n = 333) with minor exceptions. More patients in the LABA group had TASC-D lesions (92.5 vs. 66.7 %; P < 0.0001) and chronic total occlusions (CTOs) in both vessel 1 (86.4 vs. 49.5 %; P < 0.0001) and vessel 2 (78.6 vs. 47.8 %; P < 0.0001). Multivariate analysis performed using logistic regression after adjusting for confounding factors showed use of LABA was associated with a 7 times greater likelihood of achieving <50 % residual disease compared to BA alone (OR 7.59, P < 0.0001), and a 5 times greater likelihood of improvement in the infra-popliteal lesion severity score than balloon angioplasty alone (OR 4.77, p < 0.0001). LABA is significantly better at achieving angiographic success and improving lesion severity score in spite of adverse lesion characteristics (more TASC-D lesions and CTOs) compared with BA alone. Our findings suggest that the use of LABA is an endovascular approach that is at least as effective and safe or better compared to BA for the treatment of CLI from complex popliteal and infra-popliteal vascular disease. PMID- 24155172 TI - Diversity of HPV types in cancerous and pre-cancerous penile lesions of South African men: implications for future HPV vaccination strategies. AB - This study reports the detection of HPV types from cancerous and pre-cancerous penile lesions that were diagnosed histologically. Sixty-six (22 pre-cancerous and 44 cancerous lesions) tissue biopsies, received between 2004 and 2011 by the Anatomical Pathology Department at Dr. George Mukhari Hospital were selected for this study. Total DNA was extracted and genotyped using type specific real-time quantitative polymerase chain reaction (qPCR) for 18 HPV types. Of 66 samples, only 51 were included in the analysis. Overall, HPV 11 (50.9%) and HPV 16 (49.1%) showed almost similar incidence in the study patients. In pre-cancerous lesions, HPV 11 was more frequent (80.0%), followed by HPV 31 and HPV 16 at 25.0% each and other HPV types included 35 (15.0%), 59 (15.0%), 53 (10.0%), 33 (10.0%), 18 (5.0%), 51 (5.0%), 52 (5.0%), 56 (5.0%), and 67 (5.0%). For cancerous lesions, HPV 16 was the most detected (62.9%), followed by HPV 11 (34.3%), and other HPV types included 18 (11.4%), 33 (5.7%), 39 (5.7%), 45 (5.7%), 66 (5.7%), 52 (2.9%), 58 (2.9%), 6 (2.9%), and 67 (2.9%). Several lesions demonstrated multiple HPV infections, ranging from two to six different types in one lesion. The study showed high diversity of HPV types in cancerous and pre-cancerous lesions of South African males with the most frequent being HPV types 11 and 16. The data suggest that boys could directly benefit from vaccination as they are exposed to variety of HPV types as early as 10 years of age in Africa. PMID- 24155173 TI - The in vivo evaluation of tissue-based biomaterials in a rat full-thickness abdominal wall defect model. AB - Hernias are defects in which an anatomical fascia is breached resulting in ectopic positioning of an organ into an orifice which routinely does not contain it. Intervention often involves repositioning translocated organs and repair of damaged fascia using exogenous grafts. Despite hernia prevalence, repairs can still fail due to postoperative complications, such as chronic pain and decreased mobility. This study compared repair capacities and characterized the foreign body response elicited by a number of hernia repair grafts to deduce their bulk inflammatory properties while also concluding the point in their fabrication when these are inferred. Materials derived from human dermis (Alloderm((r)) ), porcine dermis (PermacolTM, patch A, patch D and Strattice((r)) ), porcine small intestinal submucosa (SurgisisTM) and a synthetic (multifilament SurgiproTM) were implanted into a rat full-thickness abdominal wall excision model, incubated for up to 2 years and characterized histopathologically. SurgisisTM resorbed the fastest of the materials tested (1-3 months) resulting in a mechanically stable parietal peritoneum. Decellularization using sodium dodecyl sulfate (patch A) stimulated a large early inflammatory response which ultimately may have contributed to increased resorption of porcine dermal matrix however the remaining materials typically persisted throughout the 2-year incubation. Cross linking porcine dermis using 1,6-hexamethylene disocyanate (vs. an identical noncross-linked counterpart) showed no difference in cell recruitment or material integration over 2 years. Typically Strattice((r)) and Alloderm((r)) recruited larger early populations of cells than PermacolTM; however, over extended periods of time in vivo this response normalized. PMID- 24155174 TI - Risk of biochemical recurrence and positive surgical margins in patients with pT2 prostate cancer undergoing radical prostatectomy. AB - BACKGROUND AND OBJECTIVE: To investigate risk factors associated with positive surgical margins (PSM) and biochemical recurrence (BR) in organ confined tumors (pT2) after radical prostatectomy (RP) for localized prostate cancer (PCa). METHODS: Between 1995 and 2011, 1,649 patients underwent RP at our institution. The study includes the 1,133 consecutive patients with pT2 tumors at final histopathology. Logistic regression analysis was used for risk of PSM. Risk of BR, defined as the first PSA >= 0.2 ng/ml, was analyzed with Kaplan-Meier and Cox regression analysis. RESULTS: Median follow-up was 3.6 years (range: 0.5-15.5 years). In logistic regression, NS surgery was independently associated with an increased risk of pT2 PSM (OR = 1.68, 95% CI: 1.3-2.0, P = 0.01) relative to non NS surgery. NS surgery was not independently associated with BR but the interaction of PSM and NS surgery trended (P = 0.08) to increase the risk of BR compared to PSM and non-NS surgery. CONCLUSION: Several factors influence the risk of pT2 PSMs in radical prostatectomy. In our cohort pT2 PSM is associated with NS surgery and trend to increase risk of BR compared to non-NS surgery. The optimal selection of candidates for NS surgery is still not clear. PMID- 24155175 TI - Comparison of two aspiration techniques of bronchoalveolar lavage in children. AB - BACKGROUND: Although bronchoalveolar lavage (BAL) via flexible bronchoscopy is an essential diagnostic tool, its technique is not standardized in children. Our objective was to compare two different aspiration techniques of BAL in children (continuous wall suction vs. handheld syringe suction) in regards to the percentage of fluid recovered and the odds of performing a technically acceptable procedure (i.e., >40% of volume return). METHODS: We conducted a review of all pediatric flexible bronchoscopies with BAL conducted at our institution over a 2 year period. To minimize the differences between groups at baseline and reduce the possibility of bias, we used one-to-one propensity score (PS) caliper matching with no replacement for statistical analyses. RESULTS: We identified 539 procedures that met pre-specified criteria. There were considerable covariate imbalances between procedures in the handheld syringe group (n = 147) and those in the continuous wall group (n = 392); however, these imbalances were substantially reduced after the PS matching. In the matched sample (n = 236), children in the handheld syringe group had ~7% higher volume return (95% CI = 3.4 11.0, P < 0.001) from BAL and threefold higher odds (95% CI = 1.5-8.6, P = 0.002) of performing a technically acceptable procedure. CONCLUSIONS: Our results suggest that handheld syringe suction offers a higher percentage of volume return from BAL and increases the odds of performing a technically acceptable procedure in children when compared to continuous wall suction. PMID- 24155176 TI - Characterization of primary cilia distribution and morphology during lactation, stasis, and involution in the bovine mammary gland. AB - Primary cilia are small, sensory organelles projecting from virtually all cells and are vital for cellular and tissue function. Their distribution in bovine mammary tissue has not previously been assessed, despite the potential for these organelles to provide specialized perceptive and regulatory functions to this acutely responsive and adaptive gland. The research objectives were to assess ciliary distribution and morphology during active lactation, milk stasis, and early involution using tissue samples obtained following the abrupt cessation of milk removal in nonpregnant, Friesian dairy cows at mid-lactation. Routinely processed tissue sections were obtained at intervals from 6 to 192 hr after the last milking (N = 3 animals per group) and assigned to active lactation (6-12 hr), milk stasis (18-36 hr), and early involution (72-192 hr). Primary cilia were observed in luminal secretory epithelial cells (SECs), myoepithelial cells, and stromal cells following fluorescent immunohistochemistry and confocal microscopy. In SECs, some primary cilia appeared deflected against the apical cell membrane. The proportion of those deflected was greater during milk stasis than active lactation. Data show that primary cilia were suitably placed in three important cell types to potentially coordinate various forms of signal transduction relying on both mechanosensation and chemosensation, according to the physical and physiological state of the gland. Their cell-type distribution and morphology provide new directions in the study of mammary regulation to enhance the understanding of how various mammary-specific cellular responses may be initiated by biochemical or local biophysical factors. PMID- 24155177 TI - Inhibition of plasminogen activator inhibitor type-1 activity enhances rapid and sustainable hematopoietic regeneration. AB - The prognosis of patients undergoing hematopoietic stem cell transplantation (HSCT) depends on the rapid recovery and sustained life-long hematopoiesis. The activation of the fibrinolytic pathway promotes hematopoietic regeneration; however, the role of plasminogen activator inhibitor-1 (PAI-1), a negative regulator of the fibrinolytic pathway, has not yet been elucidated. We herein demonstrate that bone marrow (BM) stromal cells, especially osteoblasts, produce PAI-1 in response to myeloablation, which negatively regulates the hematopoietic regeneration in the BM microenvironment. Total body irradiation in mice dramatically increased the local expression levels of fibrinolytic factors, including tissue-type plasminogen activator (tPA), plasmin, and PAI-1. Genetic disruption of the PAI-1 gene, or pharmacological inhibition of PAI-1 activity, significantly improved the myeloablation-related mortality and promoted rapid hematopoietic recovery after HSCT through the induction of hematopoiesis promoting factors. The ability of a PAI-1 inhibitor to enhance hematopoietic regeneration was abolished when tPA-deficient mice were used as recipients, thus indicating that PAI-1 represses tPA-dependent hematopoietic regeneration. The PAI 1 inhibitor not only accelerated the expansion of the donor HSCs during the early stage of regeneration, but also supported long-term hematopoiesis. Our results indicate that the inhibition of PAI-1 activity could be a therapeutic approach to facilitate the rapid recovery and sustained hematopoiesis after HSCT. PMID- 24155178 TI - International consensus on periprosthetic joint infection: description of the consensus process. PMID- 24155179 TI - Guest editorial: A redefined life: Safak Pavey speaks at the 2013 ABJS (r) Meeting in Istanbul, Turkey. PMID- 24155180 TI - Determination of chromium(III) in aqueous solution using CePO4 :Tb(3+) nanocrystals in a fluorescence resonance energy transfer system. AB - Trivalent chromium is an essential element required for normal carbohydrate, lipid and protein metabolism in humans and animals. This article describes an efficient fluorescence resonance energy transfer (FRET) system between CePO4 :Tb(3+) nanocrystals as the donor and chromium(III) as the acceptor. CePO4 :Tb(3+) nanocrystals were synthesized in aqueous solution, and characterized by transmission electron microscopy. Under optimum conditions, a linear calibration graph was obtained (R(2) = 0.996). The linear range and detection limit of chromium(III) were 0.01-2.2 MUM, and 9.1 nM, respectively. The proposed method had a wide linear range and proved to be very sensitive, rapid and simple. Moreover, the method was applied successfully to the determination of chromium(III) in synthetic samples and tap water. PMID- 24155181 TI - Genotoxicity of doxorubicin in F344 rats by combining the comet assay, flow cytometric peripheral blood micronucleus test, and pathway-focused gene expression profiling. AB - Doxorubicin (DOX) is an antineoplastic drug effective against many human malignancies. DOX's clinical efficacy is greatly limited because of severe cardiotoxicity. To evaluate if DOX is genotoxic in the heart, ~7-week-old, male F344 rats were administered intravenously 1, 2, and 3 mg/kg bw DOX at 0, 24, 48, and 69 hr and the Comet assays in heart, liver, kidney, and testis and micronucleus (MN) assay in the peripheral blood (PB) erythrocytes using flow cytometry were conducted. Rats were euthanized at 72 hr and PB was removed for the MN assay and single cells were isolated from multiple tissues for the Comet assays. None of the doses of DOX induced a significant DNA damage in any of the tissues examined by the alkaline Comet assay. Contrastingly, the glycosylase enzymes-modified Comet assay showed a significant dose dependent increase in the oxidative DNA damage in the cardiac tissue (P <= 0.05). In the liver, only the top dose induced significant increase in the oxidative DNA damage (P <= 0.05). The histopathology showed no severe cardiotoxicity but non-neoplastic lesions were present in both untreated and treated samples. A severe toxicity likely occurred in the bone marrow because no viable reticulocytes could be screened for the MN assay. Gene expression profiling of the heart tissues showed a significant alteration in the expression of 11 DNA damage and repair genes. These results suggest that DOX is genotoxic in the heart and the DNA damage may be induced primarily via the production of reactive oxygen species. PMID- 24155182 TI - Borrelidin has limited anti-cancer effects in bcl-2 overexpressing breast cancer and leukemia cells and reveals toxicity in non-malignant breast epithelial cells. AB - Clinically effective anti-cancer drugs have to tread a narrow line between selective cytotoxicity on tumor cells and tolerable adverse effects against healthy tissues. This causes the failure of many potential cancer drugs in advanced clinical trials, hence signifying the importance of a comprehensive initial estimate of the cytotoxicity of prospective anti-cancer drugs in preclinical studies. In this study, the cytotoxicity of borrelidin, a macrolide antibiotic with a high cytotoxic selectivity for proliferating endothelial cells and leukemia cells, was tested on malignant and non-malignant breast cells. Highly metastatic breast cancer cell lines (MDA-MB-231 and MDA-MB-435) showed promising results and exhibited good sensitivity to borrelidin at low nanomolar concentrations, but borrelidin was cytotoxic to a non-malignant breast epithelial cell line (MCF10A) as well. Furthermore, although a high sensitivity of endothelial cells (human umbilical vein endothelial cells; HUVEC) and individual leukemia cell lines (Jurkat and IM9) to borrelidin was confirmed in this study, another leukemia cell line (HL60) and an immortalized endothelial cell line (EA.hy926) displayed a significantly decreased sensitivity. Reduced sensitivity to borrelidin was associated with elevated bcl-2 expression in these cell lines. In conclusion, the results presented show that borrelidin displays high and selective cytotoxicity against subgroups of cancer cells and endothelial cells, but, owing to its non-specific toxicity to non-malignant cells, its clinical application might be restricted because of likely adverse effects and limited efficacy in bcl2-overexpressing cancer cells. PMID- 24155183 TI - How to define a refractory idiopathic overactive bladder? AB - AIMS: To present the different definitions of "refractory" IOAB. MATERIALS AND METHODS: A review of the literature based on PubMed and Cochrane library databases has been conducted. The criteria for defining the success or failure of antimuscarinic treatment and the different definitions of refractory IOAB used in studies evaluating the effects of posterior tibial nerve stimulation, sacral neuromodulation and intradetrusor botulinum toxin-A injections, have been presented. The primary endpoints of these studies were compared. Additionally, different definitions of refractory IOAB were retrieved. RESULTS: There are discrepancies in the definition of "refractory" IOAB in the literature. The definitions of antimuscarinic success in clinical trials are not always transposable into daily practice. Moreover, these clinical trial endpoints do not explore the entirety of a meaningful patient-centered outcome. The failure of antimuscarinic treatments may be defined by different factors, including lack and loss of efficacy, intolerance to side effects, contraindications, willingness of patients to go further with treatment and inadequacy of patient's expectations. Ideally, the best functional outcomes would assess patient's expectations and the physician's objectives and objective measurements. Finally, assessing quality of life might be the most reliable outcome to measure, by considering of all the discussed data. CONCLUSIONS: An appropriate definition is complex and needs to consider subjective tools. The "refractory" IOAB needs to be more specifically defined so that alternative treatments can be used at the appropriate time. PMID- 24155185 TI - Topology and mental distress: self-care in the life spaces of home. AB - This article develops a topological approach derived from Kurt Lewin to analyse the psychological life space/s produced in a mental health service user's home. Drawing on arguments that space plays an important part in the organisation and management of mental distress, photographs of a service user's home are analysed as topological spaces. The article argues that topological theory can contribute to community health psychology through framing psychological distress as spatially distributed, meaning individual bodies, environments and action are conceptualised as equally contributing to the organisation and management of health-related experience and activity. PMID- 24155184 TI - Adlerian parental counseling in eating disorders: preliminary data of a controlled clinical trial. AB - OBJECTIVE: Counseling interventions for parents with a daughter affected by an eating disorder (ED) may represent a useful and cost-effective tool to improve patients' compliance to treatment and overall outcome. The present study evaluates the outcome of Adlerian Parental Counseling (APC) on individuals affected by ED and their parents. METHODS: We assessed 114 patients whose parents underwent APC and 44 individuals whose parents did not receive this intervention. All patients received multimodal treatment and were assessed at intake and at a 6 month follow-up. Patients were assessed using: the first scale and the improvement scale (GI) of the Clinical Global Impression (CGI) and the Family Assessment Device (FAD). Parents underwent APC and completed several psychometric tests: Attachment Style Questionnaire, State-Trait Anger Expression Inventory, Symptom Questionnaire, and Family Assessment Device. RESULTS: The GI of the ED group whose parents received APC significantly improved when compared with baseline. Moreover, the improvement was significantly greater for the APC group with respect to the non-APC group if the initial CGI score was considered. After counseling, mothers displayed poorer FAD scores, but their sense of inadequacy, their anxiety symptoms and their preoccupation with relationships improved. Fathers improved their social trust and reduced introverted anger. APC reduced the differences as regards family functioning perception among family members. CONCLUSION: Parents reported a subjective improvement in psychopathology scales and a better fine-tuning of their perception of family dynamics with those of their daughters and husband. The improvement in family dynamics along with the motivational effect of parents' participation in counseling may have positively influenced the outcome of the multimodal treatment. Moreover, this intervention could also have been helpful for those with a severe ED. PMID- 24155186 TI - Association between anxiety and pain in the latent phase of labour upon admission to the maternity hospital: a prospective, descriptive study. AB - This study investigated the association between anxiety experienced by the mother, a request for analgesia, and the level of pain at maternity hospital admission in early labour. Anxiety levels were measured by the State-Trait Anxiety Inventory and pain was assessed using a Visual Analogue Scale. Anxiety and Visual Analogue Scale scores were compared using a linear regression model and indicated a statistically significant association between the anxiety state and degree of pain (p < 0.016; Y = 0.895 x score + 32.656). There was no significant association between anxiety and a request for epidural analgesia. During labour, an evaluation of anxiety should be associated with an assessment of the perceived degree of pain. PMID- 24155187 TI - Towards a new theory of practice for community health psychology. AB - The article sets out the value of theorizing collective action from a social science perspective that engages with the messy actuality of practice. It argues that community health psychology relies on an abstract version of Paulo Freire's earlier writing, the Pedagogy of the Oppressed, which provides scholar-activists with a 'map' approach to collective action. The article revisits Freire's later work, the Pedagogy of Hope, and argues for the importance of developing a 'journey' approach to collective action. Theories of practice are discussed for their value in theorizing such journeys, and in bringing maps (intentions) and journeys (actuality) closer together. PMID- 24155188 TI - Metonymic objects, cultural practices and narrative repair: Sri Lankan responses to the Indian Ocean tsunami. AB - The 2004 Indian Ocean tsunami resulted in a tragic loss of life and immense suffering. This article explores the ways in which a group of people from Sri Lanka worked to address the disruption to their life narratives caused by the loss of loved ones. We go beyond a focus on 'talk' in narrative research in health psychology to explore the importance of material objects in sustaining continued bonds with the deceased. This article provides an alternative to the tendency in mainstream psychology to pathologise grief and highlights the importance of culturally patterned responses to disaster. PMID- 24155189 TI - Lay theories of smoking and young adult nonsmokers' and smokers' smoking expectations. AB - This study investigated the relationship between lay theories of cigarette smoking and expectations to smoke. An incremental lay theory of smoking entails the belief that smoking behavior can change; an entity theory entails the belief that smoking behavior cannot change. Undergraduate nonsmokers and smokers completed a survey that assessed lay theories of smoking and smoking expectations. Results demonstrated that lay theories of smoking were differentially associated with smoking expectations for nonsmokers and smokers: stronger incremental beliefs were associated with greater expectations of trying smoking for nonsmokers but lower expectations of becoming a regular smoker for smokers. Implications for interventions are discussed. PMID- 24155190 TI - Human papillomavirus vaccine intentions among males: a test of the Parallel Processing Model. AB - We investigated the cognitive and emotional reactions resulting from a human papillomavirus-related illness threat (i.e. testing positive for human papillomavirus) and the potential behavioral implications resulting from these psychosocial processes among men (N = 536). Structural equation modeling was used to explore a theoretical model explaining human papillomavirus vaccine intentions. The model fit the data well and explained 16 percent of the variance in vaccine intentions. Negative emotional response mediated the path between illness threat and vaccine intentions. Threat of genital warts was a salient concern and was positively associated with negative emotional response and subsequent vaccine intentions. Implications for vaccine promotion are discussed. PMID- 24155191 TI - Are child anxiety and somatization associated with pain in pain-related functional gastrointestinal disorders? AB - This study investigated individual and incremental contributions of somatization and trait anxiety to pain report in children with pain-related functional gastrointestinal disorders. Eighty children (7-10 years) with pain-related functional gastrointestinal disorders completed the State-Trait Anxiety Inventory for Children, the Children's Somatization Inventory, and 2-week pain diaries (assessing pain frequency and maximum pain). Hierarchical regressions indicated that both trait anxiety and somatization were significantly related to maximum pain and pain frequency, with somatization explaining more variance. Trait anxiety did not significantly add to prediction above somatization. Assessment of somatization may assist with treatment planning for children with functional abdominal pain. PMID- 24155193 TI - The association of personality, appraisal, catastrophising and vigilance with gastrointestinal symptom-specific anxiety. AB - This study investigates the relationship between psychosocial factors and functional gastrointestinal disorder symptomatology by testing a more comprehensive and integrated model than found in prior research. A total of 233 respondents completed an online battery to assess factors such as personality, dysfunctional cognitions and gastrointestinal anxiety. Results based on path modelling provided support for the majority of the hypothesised pathways. This study implicates a number of personality factors and dysfunctional cognitive processes as relevant to functional gastrointestinal disorder symptom burden. These findings have implications for future research, including which dysfunctional cognitive processes should be targeted therapeutically. PMID- 24155192 TI - Weight- and race-based bullying: health associations among urban adolescents. AB - Stigma-based bullying is associated with negative mental and physical health outcomes. In a longitudinal study, surveys and physical assessments were conducted with mostly Black and Latino, socioeconomically disadvantaged, urban students. As hypothesized, greater weight- and race-based bullying each was significantly indirectly associated with increased blood pressure and body mass index, as well as decreased overall self-rated health across 2 years, through the mechanism of more negative emotional symptoms. Results support important avenues for future research on mechanisms and longitudinal associations of stigma-based bullying with health. Interventions are needed to reduce stigma-based bullying and buffer adolescents from adverse health effects. PMID- 24155195 TI - New, normative, English-sample data for the Short Form Perceived Stress Scale (PSS-4). AB - This article provides population norms for the Short Form Perceived Stress Scale (PSS-4) and investigates the relationship between PSS-4 scores and sociodemographic variables. The PSS-4 was administered to an English sample (n = 1568) and was found to have acceptable psychometric properties. Sociodemographic variables explained 19.5% of variance in PSS-4 scores, and mean PSS-4 scores were significantly different from the mean scores reported in Cohen and Williamson's original study. Greater levels of perceived health status, greater levels of social support, being male and being older were predictive of lower PSS-4 scores. Norm values for interpreting PSS-4 scores are presented. PMID- 24155194 TI - Measuring kidney patients' motivation to pursue living donor kidney transplant: development of stage of change, decisional balance and self-efficacy measures. AB - While educational interventions to increase patient motivation to pursue living donor kidney transplant have shown success in increasing living donor kidney transplant rates, there are no validated, theoretically consistent measures of Stage of Change, a measure of readiness to pursue living donor kidney transplant; Decisional Balance, a weighted assessment of living donor kidney transplant's advantages/disadvantages; and Self-Efficacy, a measure of belief that patients can pursue living donor kidney transplant in difficult circumstances. This study developed and validated measures of these three constructs. In two independent samples of kidney patients (N 1 = 279 and N 2 = 204), results showed good psychometric properties and support for their use in the assessment of living donor kidney transplant interventions. PMID- 24155196 TI - The experience of hepatitis C treatment for people with a history of mental health problems: An interpretative phenomenological analysis. AB - This qualitative study explores the experience of hepatitis C virus treatment for people with pre-existing mental health problems within a large city hospital. Four men and four women with pre-existing mental health problems who had received hepatitis C virus treatment took part in semi-structured interviews which were analysed using interpretative phenomenological analysis. A central theme of 'Self, stigma and change' was identified which interlinked with three other main themes of 'Coping and responding to treatment', 'Connectedness to others' and 'The impact of information'. These themes and their sub-themes are discussed in relation to existing literature and clinical practice guidelines. PMID- 24155197 TI - Psychometric assessment of the Health Care Alliance Questionnaire with women in prenatal care. AB - The current study assessed the reliability and validity of the Health Care Alliance Questionnaire, which was developed using a Delphi process and embedded in an ongoing perinatal outcomes study. The Health Care Alliance Questionnaire exhibited content and face validity and high reliability. Results indicated concurrent validity in relation to satisfaction with practitioner and discriminant validity in relation to interpersonal sensitivity and posttraumatic stress disorder. The Health Care Alliance Questionnaire demonstrated predictive validity in relation to perceptions of practitioner's care during labor and postpartum depression. Overall, results suggest that alliance may be an important factor in maternity care processes and outcomes. Further psychometric work is warranted. PMID- 24155198 TI - The cigarette box as an advertising vehicle in the United Kingdom: A case for plain packaging. AB - This research aimed to study tobacco advertising between 1950-2003 and to evaluate the role of the cigarette box in advertising. Tobacco company advertisements (n = 204) were coded for content and meanings used to promote their product. There was a significant shift from cigarettes being displayed to the cigarette box only. Changes in advertising and the meanings evoked were unrelated to changes in smoking behaviour. It is argued that the cigarette box has absorbed the meanings associated with smoking and has become an effective vehicle for advertising. It is also argued that this can only be minimised with plain packaging. PMID- 24155199 TI - Impact of virus clearance for the development of hemorrhagic stroke in chronic hepatitis C. AB - The aim of this retrospective cohort study was to assess the cumulative incidence and predictive factors for intracerebral hemorrhagic stroke after the termination of interferon (IFN) therapy in Japanese patients with hepatitis C virus (HCV). A total of 4,649 HCV-positive patients treated with IFN were enrolled. The primary goal is the first onset of intracerebral hemorrhagic stroke. The mean observation period was 8.0 years. Evaluation was performed using the Kaplan-Meier method and the Cox proportional hazard model. A P-value of less than 0.05 was considered statistically significant. A total of 28 developed intracerebral hemorrhagic stroke. The cumulative incidence of intracerebral hemorrhagic stroke was 0.3% at 5 years, 0.8% at 10 years, and 1.7% at 15 years. Intracerebral hemorrhagic stroke occurred when patients had age increments of 10 years (hazard ratio: 2.77; 95% confidence interval (CI) 1.48-5.18; P = 0.001), hypertension (hazard ratio: 2.30; 95% CI 1.09-4.83; P = 0.021), liver cirrhosis (hazard ratio: 4.50; 95% CI 2.07 9.78; P < 0.001), and HCV non-clearance (hazard ratio: 3.22; 95% CI 1.22-8.53; P = 0.018). On the intracerebral hemorrhagic stroke based on the difference of liver fibrosis and efficacy of IFN therapy, HCV clearance reduced to 24.3% (1/4.11) compared to HCV non-clearance in cirrhotic patients (P = 0.040). In conclusion, HCV clearance reduced the development of intracerebral hemorrhagic stroke. In particular, HCV clearance reduced intracerebral hemorrhagic stroke to about one-fourth in cirrhotic patients. PMID- 24155204 TI - Subgroups of patients with very large gastrointestinal stromal tumors with distinct prognoses: a multicenter study. AB - BACKGROUND AND OBJECTIVES: Any gastrointestinal stromal tumors (GISTs) larger than 10 cm are classified as "high risk" according to the modified National Institutes of Health consensus criteria. We conducted a multicenter study to identify a subgroup with moderate prognosis even within the "high-risk" group. METHODS: We retrospectively collected data on 107 patients with tumors >=10 cm from a multicenter database of GIST patients. Patients with macroscopic residual lesions or tumor rupture were excluded. The relationship between recurrence-free survival (RFS) and clinicopathological factors was analyzed. RESULTS: The median tumor size and mitotic count were 12.5 cm and 8/50 HPF. The RFS rate was 58.5% at 3 years, 52.1% at 5 years. Only mitotic count was an independent prognostic factor of RFS in the multivariate analysis (P = 0.001). The hazard ratio for recurrence in the subgroup with mitotic count >5/50 HPF was 2.91 (95% confidence interval, 1.53 to 5.56). The subgroup with mitotic count <=5/50 HPF showed significantly better RFS than the mitotic count >5/50 HPF subgroup (P < 0.001). CONCLUSIONS: Mitotic count is closely associated with outcome in patients with large GISTs. This suggests that the subset of large GISTs with low mitotic counts may be considered as "intermediate-risk" lesions. PMID- 24155203 TI - Separate and joint effects of tranplacental and postnatal inhalatory exposure to polycyclic aromatic hydrocarbons: prospective birth cohort study on wheezing events. AB - The goal of this epidemiologic investigation was to analyze the associations between prenatal and postnatal exposure to airborne polycyclic aromatic hydrocarbons (PAH) and severity of wheeze and recurrent wheeze. The 257 children included in this analysis had a complete set of prenatal and postnatal PAH measurements and attended regular health checkups over a 4-year follow-up period since birth. Transplacental PAH exposure was measured by personal air monitoring of the mothers during the second trimester of pregnancy; postnatal exposure was estimated using the same instruments indoors at the children's residences at age 3. Chemical analysis tests were performed to determine airborne concentrations of nine PAH compounds. The results show that both prenatal and postnatal exposure were associated positively with the severity of wheezing days and recurrent wheezing reported in the follow-up. While the incidence rate ratio (IRR) for severity of wheeze and prenatal PAH exposure was 1.53 (95%CI: 1.43-1.64) that for postnatal PAH exposure was 1.13 (95%CI: 1.08-1.19). However, recurrent wheezing was more strongly associated with airborne PAH levels measured at age 3 (OR = 2.31, 95%CI: 1.26-4.22) than transplacental PAH exposure (OR = 1.40, 95% CI: 0.85 2.09), but the difference was statistically insignificant. In conclusion, it appears that prenatal PAH exposure may precipitate and intensify early onset of wheezing symptoms in childhood, resulting from the postnatal exposure and suggest that success in reducing the incidence of respiratory diseases in children would depend on reducing both fetal and childhood exposure to air pollution. PMID- 24155205 TI - MicroRNA-127 is downregulated by Tudor-SN protein and contributes to metastasis and proliferation in breast cancer cell line MDA-MB-231. AB - Tudor-SN is a multifunctional protein that is highly expressed in multiple cancers including breast cancer. Tudor-SN, as a component in RNA-induced splicing complex, was recently reported to regulate gene expression in a microRNA (miRNA) dependent manner, such as let-7, miR-34a and miR-221. However, how Tudor-SN is associated with cancer development still remains largely elusive. In the present study, we explored the role of Tudor-SN in breast cancer. Stable knockdown of endogenous Tudor-SN, performed on the breast cancer cell line MDA-MB-231 by small hairpin RNA expression vectors, suppressed the in vitro migration and invasion ability of the metastatic breast cancer cell line. Interestingly, we found Tudor SN as a miRNA regulator according to microarray analysis, and further identified that Tudor-SN negatively regulated the expression of miR-127, and consequently increased the expression of the proto-oncogene BCL6 which was a convincing target of miR-127. Moreover, overexpression of miR-127 reduced the in vitro migration and proliferation ability of breast cancer cell MDA-MB-231. Collectively, our results suggested a novel mechanism that Tudor-SN promoted metastasis and proliferation of breast cancer cells via downregulating the miR-127 expression. PMID- 24155206 TI - Organoytterbium ate complexes extend the value of cyclobutenediones as isoprene equivalents. AB - Changing course: While organolithium and Grignard reagents favor addition to C1 of A (R=Me), the corresponding organoytterbium reagents add to C2 (R=tBu). Computational studies provide insights into the nature of organoytterbium species and their reactivity, and a total synthesis of (-)-mansonone B illustrates the utility of the method in terpenoid synthesis. Tf=trifluoromethanesulfonyl. PMID- 24155207 TI - Screening study on hemolysis suppression effect of an alternative plasticizer for the development of a novel blood container made of polyvinyl chloride. AB - The aim of this study is to identify a plasticizer that is effective in the suppression of the autohemolysis of the stored blood and can be used to replace di(2-ethylhexyl) phthalate (DEHP) in blood containers. The results of hemolysis test using mannitol-adenine-phosphate/red cell concentrates (MAP/RCC) spiked with plasticizers included phthalate, phthalate-like, trimeliate, citrate, and adipate derivatives revealed that di-isononyl-cyclohexane-1,2-dicarboxylate (Hexamoll((r)) DINCH), di(2-ethylhexyl)-1,2,3,6-tetrahydro-phthalate (DOTP), and diisodecyl phthalate (DIDP) exhibited a hemolysis suppression effect almost equal to that of DEHP, but not other plasticizers. This finding suggested that the presence of 2 carboxy-ester groups at the ortho position on a 6-membered ring of carbon atoms may be required to exhibit such an effect. The hemolytic ratios of MAP/RCC-soaked polyvinyl chloride (PVC) sheets containing DEHP or different amounts of DINCH or DOTP were reduced to 10.9%, 9.2-12.4%, and 5.2-7.8%, respectively (MAP/RCC alone, 28.2%) after 10 weeks of incubation. The amount of plasticizer eluted from the PVC sheet was 53.1, 26.1-36.5, and 78.4-150 ug/mL for DEHP, DINCH, and DOTP, respectively. PVC sheets spiked with DIDP did not suppress the hemolysis induced by MAP/RCC because of low leachability (4.8-6.0 ug/mL). These results suggested that a specific structure of the plasticizer and the concentrations of least more than ~10 ug/mL were required to suppress hemolysis due to MAP/RCC. PMID- 24155208 TI - WKYMVm-induced activation of formyl peptide receptor 2 stimulates ischemic neovasculogenesis by promoting homing of endothelial colony-forming cells. AB - Endothelial colony-forming cells (ECFCs) are recruited to the sites of ischemic injury in order to contribute to neovascularization and repair of injured tissues. However, therapeutic potential of ECFCs is limited due to low homing and engraftment efficiency of transplanted ECFCs. The G-protein-coupled formyl peptide receptor (FPR) 2 has been implicated in regulation of inflammation and angiogenesis, while the role of FPR2 in homing and engraftment of ECFCs and neovascularization in ischemic tissues has not been fully defined. This study was undertaken to investigate the effects of WKYMVm, a selective FPR2 agonist isolated by screening synthetic peptide libraries, on homing ability of ECFCs and vascular regeneration of ischemic tissues. WKYMVm stimulated chemotactic migration, angiogenesis, and proliferation ability of human ECFCs in vitro. Small interfering RNA-mediated silencing of FPR2, but not FPR3, abrogated WKYMVm induced migration and angiogenesis of ECFCs. Intramuscular injection of WKYMVm resulted in attenuation of severe hind limb ischemia and promoted neovascularization in ischemic limb. ECFCs transplanted via tail vein into nude mice were incorporated into capillary vessels in the ischemic hind limb, resulting in augmented neovascularization and improved ischemic limb salvage. Intramuscular injection of WKYMVm promoted homing of exogenously administered ECFCs to the ischemic limb and ECFC-mediated vascular regeneration. Silencing of FPR2 expression in ECFCs resulted in abrogation of WKYMVm-induced in vivo homing of exogenously transplanted ECFCs to the ischemic limb, neovascularization, and ischemic limb salvage. These results suggest that WKYMVm promotes repair of ischemic tissues by stimulating homing of ECFCs and neovascularization via a FPR2 dependent mechanism. PMID- 24155209 TI - Protective effects of schizandrin and schizandrin B towards cisplatin nephrotoxicity in vitro. AB - Renal proximal tubular epithelial cells are the main targets of toxic drugs such as cisplatin (CisPt), an alkylating agent indicated for the treatment of solid organ tumors. Current techniques aiming at reducing nephrotoxicity in patients receiving CisPt are still not satisfactory as they can only partially prevent acute kidney injury. New nephroprotective strategies remain to be developed. In the present in vitro study, schizandrin (Schi) and schizandrin B (Schi B), major phytochemicals from Schisandra chinensis (Turcz.) Baill. fruits, were tested on HK-2 cells along four processes that could help alleviate CisPt toxicity. Results indicated that: (i) both Schi and Schi B enhanced cell survival via reducing apoptosis rate; (ii) only Schi showed moderate effects towards modulation of regeneration capacities of healthy cells; (iii) both Schi and Schi B limited extracellular matrix deposition; and (iv) both compounds could help preventing dedifferentiation processes via the beta-catenin pathway. Schi and Schi B present promising activities for future development of protective agents against CisPt nephrotoxicity. PMID- 24155210 TI - Introduction. PMID- 24155211 TI - Associations between MTHFR Ala222Val polymorphism and risks of hepatitis and hepatitis-related liver cancer: a meta-analysis. AB - Chronic infection of viral hepatitis is the main cause of liver cancer. There were many studies assessing the associations of methylenetetrahydrofolate reductase (MTHFR) Ala222Val polymorphism with risks of hepatitis and hepatitis related liver cancer, but no consistent results were reported. To investigate the associations of MTHFR Ala222Val polymorphism with risks of hepatitis and hepatitis-related liver cancer, we performed a meta-analysis of published case control studies. Eligible studies were searched from PubMed and Chinese National Knowledge Infrastructure (CNKI) databases. The odds ratio (OR) and corresponding 95 % confidence interval (95 %CI) were used to assess the associations. Twenty one individual studies with a total of 8,187 subjects were included. Overall, MTHFR Ala222Val polymorphism was not significantly associated with risks of liver cancer, hepatitis-related liver cancer, and non-hepatitis-related liver cancer. However, MTHFR Ala222Val polymorphism was significantly associated with risk of hepatitis infection (Val vs. Ala: OR = 1.15, 95 %CI 1.01-1.32, P = 0.03; ValVal/AlaVal vs. AlaAla: OR = 1.37, 95 %CI 1.11-1.68, P = 0.003). Therefore, MTHFR Ala222Val polymorphism is significantly associated with risk of hepatitis infection but not liver cancer. More studies are needed to further assess the association between MTHFR Ala222Val polymorphism and hepatitis-related liver cancer. PMID- 24155212 TI - Expression of RRM1 and RRM2 as a novel prognostic marker in advanced non-small cell lung cancer receiving chemotherapy. AB - The aim of this study was to examine the prognostic value of BRCA1, RRM1, and RRM2 in patients with non-small cell lung cancer (NSCLC) who received adjuvant chemotherapy. A total of 418 patients who underwent curative pulmonary resection were obtained between January 2007 and November 2009. The relative cDNA quantification for BRCA1, RRM1, and RRM2 was conducted using a fluorescence based, real-time detection method, and beta-actin was used as a reference gene. The low expression of RRM1 and RRM2 significantly increased the platinum-based chemotherapy response (For RRM1: odds ratio (OR) = 2.09, 95% confidence interval (CI) = 1.38-3.18; For RRM2: OR = 1.64, 95% CI = 1.09-2.48). The univariate analysis indicated that low expression of RRM1 attained a longer time to progression and overall survival time, with HR (95% CI) of 0.50 (0.33-0.77) and 0.60 (0.39-0.92), respectively. Similarly, low expression of RRM2 had a longer time to progression and overall survival, with HR (95% CI) of 0.57 (0.38-0.86) and 0.47 (0.31-0.71), respectively. In conclusion, low expression of RRM1 and RRM2 could be used to predict the treatment response to platinum-based chemotherapy and survival in NSCLC. The RRM1 and RRM2 could substantially contribute to the future design of individualized cancer treatment in NSCLC patients. PMID- 24155213 TI - Prognostic information derived from RT-PCR analysis of peritoneal fluid in gastric cancer patients: results from a prospective multicenter clinical trial. AB - OBJECTIVE: The purpose of this study is to define the clinical significance of the molecular analysis of peritoneal lavage fluid in patients with gastric cancer in a multicenter prospective trial. METHODS: Quantitative RT-PCR with CEA and CK 20 mRNA as target markers was introduced for peritoneal lavage diagnosis in 141 patients with clinically advanced gastric cancer from 9 different institutes. We then evaluated the prognostic factors in patients and also evaluated predictive markers for peritoneal recurrence in 124 patients without peritoneal metastasis at surgery RESULTS: Out of the 141 cases, 140 patients were successfully analyzed by RT-PCR of peritoneal lavage fluids. According to multivariate analysis, the combined results of RT-PCR (CEA and CK-20) and CK-20 alone in addition to pathological N (pN)-stage were significantly correlated with overall survival. Multivariate analysis showed that the RT-PCR (CEA and CK-20) and CEA alone in addition to pathological T-stage, pN-stage, and histological grade were significantly correlated with peritoneal recurrence after surgery. CONCLUSION: This is the first multicenter prospective study to show that RT-PCR analysis of peritoneal lavage fluid with the combination of CEA and CK-20 markers was useful for predicting overall survival and peritoneal recurrence in patients with clinically advanced gastric cancer. PMID- 24155214 TI - Motor function is associated with 1,25(OH)(2)D and indices of insulin-glucose dynamics in non-diabetic older adults. AB - BACKGROUND: Advancing age is accompanied by changes in metabolic characteristics, such as reduced insulin sensitivity and low levels of vitamin D, which may exacerbate age-related declines in physical function. AIMS: The aim of the present study was to determine the associations between insulin-glucose dynamics, vitamin D metabolites, and performance on a battery of motor tasks in healthy, non-diabetic older adults. METHODS: Sixty-nine community-dwelling men and women (65-90 years) were recruited. Insulin-glucose dynamics were determined by an intravenous glucose tolerance test, and vitamin D metabolites were measured. Motor function was characterized by the time to walk 500 m, chair-rise time, lower body strength, dorsiflexor steadiness and endurance time, and muscle coactivation. RESULTS: Significant unadjusted correlations were found between insulin-glucose dynamics and 1,25-dihydroxyvitamin D [1,25(OH)2D] with walk time, strength, steadiness, endurance time, and muscle activation (p < 0.05). A significant amount of the variance in walking endurance was explained by the sex of the individual, 1,25(OH)2D, and fasting blood insulin (R (2) = 0.36, p < 0.001). Strength could be partially explained by age, body fatness, and fasting glucose (R (2) = 0.55, p < 0.001). DISCUSSION: Poor motor function in non diabetic older men and women was associated with indices of insulin-glucose dynamics and the bio-active vitamin D metabolite 1,25(OH)2D. Walking endurance and strength were explained by 1,25(OH)2D and fasting blood glucose and insulin, even after adjusting for age, sex, and body fat. CONCLUSION: Motor function in a relatively small sample of non-diabetic older men and women was associated with metabolic factors that increase in prevalence with aging. PMID- 24155215 TI - Hydrogen evolution by tungsten carbonitride nanoelectrocatalysts synthesized by the formation of a tungsten acid/polymer hybrid in situ. AB - A step forward for tungsten: Nitrogen-rich tungsten carbonitride (WCN) nanomaterials can act as stable and efficient hydrogen evolution electrocatalysts with a much higher activity than conventional WCN materials. The use of a polymerization process provides a unique synthetic route to H2 WO4 nanoparticles, which can then be used to synthesize the WCN-derived catalysts. PMID- 24155216 TI - Polymerase chain reaction in respiratory samples alone is not a reliable marker of bocavirus infection. PMID- 24155217 TI - Rare single nucleotide polymorphisms in the regulatory regions of the superoxide dismutase genes in autism spectrum disorder. AB - Oxidative stress is suspected to be one of the several contributing factors in the etiology of autism spectrum disorder (ASD). We analyzed genes of the superoxide dismutase family (SOD1, SOD2, and SOD3) that are part of a major antioxidative stress system in human in order to detect the genetic variants contributing to the development of ASD. Using the optimized high-resolution melting (HRM) analysis, we identified two rare single nucleotide polymorphisms (SNPs) associated with the etiology of ASD. Both are located in the superoxide dismutase 1 (SOD1) gene and have a minor allele frequency in healthy population ~5%. The SNP c.239 + 34A>C (rs2234694) and SNP g.3341C>G (rs36233090) were detected with an odds ratio of 2.65 and P < 0.01. Both are located in the noncoding potentially regulatory regions of the SOD1 gene. This adds to the importance of rare SNPs in the etiology of complex diseases as well as to the importance of noncoding genetic variants analysis with a potential influence on the regulation of gene expression. PMID- 24155218 TI - Distinct genetic requirements for BX-C-mediated specification of abdominal denticles. AB - BACKGROUND: Hox genes encode transcription factors playing important role in segment specific morphogenesis along the anterior posterior axis. Most work in the Hox field aimed at understanding the basis for specialised Hox functions, while little attention was given to Hox common function. In Drosophila, genes of the Bithorax complex [Ultrabithorax (Ubx), abdominalA (abdA), and AbdominalB (AbdB)] all promote abdominal identity. While Ubx and AbdA share extensive sequence conservation, AbdB is highly divergent, questioning how it can perform similar functions as Ubx and AbdA. RESULTS: In this study, we investigate the genetic requirement for the specification of abdominal-type denticles by Ubx, AbdA, and AbdB. The impact of ectopic expression of Hox proteins in embryos mutant for Exd as well as of Wingless or Hedgehog signaling involved in intrasegmental patterning was analyzed. Results indicated that Ubx and AbdA do not require Exd, Wg, and Hh activity for specifying abdominal-type denticles, while AbdB does. CONCLUSIONS: Our results support that distinct regulatory mechanisms underlie Ubx/AbdA- and AbdB-mediated specification of abdominal-type denticles, highlighting distinct strategies for achieving a similar biological output. This suggests that common function performed by distinct paralogue Hox proteins may also rely on newly acquired property, instead of conserved/ancestral properties. PMID- 24155219 TI - Cancer-associated fibroblasts might sustain the stemness of scirrhous gastric cancer cells via transforming growth factor-beta signaling. AB - Cancer-associated fibroblasts (CAFs) have recently been implicated in tumor growth and metastasis in gastric cancer. Cancer stem cells (CSCs) have been proposed to have an important role in cancer progression. The aim of this study was to clarify the effect of CAFs on CSCs characteristics in gastric carcinoma. Scirrhous gastric cancer cell lines, OCUM-12 and OCUM-2MD3, and non-scirrhous gastric cancer cell lines, MKN-45 and MKN-74, were used. OCUM-12/side population (SP) cells and OCUM-2MD3/SP cells were sorted by flow cytometry as CSC-rich cells from the parent cells. CaF-37 was established from the tumoral gastric specimens as CAFs. Flow cytometric analysis of SP fraction, spheroid colony assay, and RT PCR analysis of CSC markers were performed to identify CSCs properties. Effect of CAFs on the tumorigenicity by OCUM-12/SP cells was examined using nude mice. CAF CM significantly increased the percentages of the SP fraction of OCUM-12/SP and OCUM-2MD3/SP cells, but not that of MKN-45/SP and MKN-74/SP cells. Taken together, CM from CaF-37 significantly increased the number of spheroid colonies and the expression level of CSC markers of OCUM-12/SP and OCUM-2MD3/SP cells. These stimulating-activities by CM were significantly decreased by TGFbeta inhibitors, but not FGFR and cMet inhibitor. Tumorigenicity by subcutaneous coinoculation of OCUM-12/SP cells with CAFs was significantly high in comparison with that by OCUM-12/SP cells alone. Phospho-Smad2 expression level was significantly increased by co-inoculation with CAFs. These findings suggested that CAFs might regulate the stemness of CSCs in scirrhous gastric cancer by TGFbeta signaling. PMID- 24155220 TI - Phylogenetic characterization of enterovirus 68 strains in patients with respiratory syndromes in Italy. AB - Enterovirus 68 (EV-D68) was associated with mild to severe respiratory infections. In the last 4 years, circulation of different EV-D68 strains has been documented worldwide. In this study, the phylogenetic characterization of nine EV D68 strains identified in patients in the 2010-2012 period and 12 additional EV D68 Italian strains previously identified in 2008 in Italy was described. From January 2010 to December 2012, a total of 889 respiratory specimens from 588 patients stayed or visited at the Fondazione IRCCS Policlinico San Matteo were positive for HRV or HEV. Extracted nucleic acids were amplified by one-step RT PCR with primer specific for VP1 region of EV-D68 and purified positive PCR products were directly sequenced. Overall, 9/3736 (0.24%) patients were EV-D68 positive. Of these, 7/9 (77.8%) were pediatric and two (22.2%) were adults. Five out of seven (71.4%) pediatric patients had lower respiratory tract infection with oxygen saturation <94%. Four cases were detected from August through October 2010, while five other cases from September through December 2012. The Italian EV D68 strains in 2008 belonged to clade A (n = 5) and clade C (n = 7). In 2010 all the Italian strains belonged to clade A (n = 4) and in 2012, four Italian strains belonged to clade B and one to clade A. In conclusion, we provide additional evidence supporting a role of EV-D68 in severe respiratory infection in pediatric patients. In addition, all the three EV-D68 clades circulating worldwide were identified in Italy in a 5-year period of time. PMID- 24155221 TI - Increased risk of ischemic stroke among women with bladder pain syndrome/interstitial cystitis: a cohort study from Taiwan. AB - AIM: Vascular factors are proposed in the etiology of bladder pain syndrome/interstitial cystitis (BPS/IC). In this study, we investigated the risk of stroke among women following a diagnosis of BPS/IC over 3 years of follow-up, compared to controls without a BPS/IC diagnosis. METHODS: This retrospective cohort study used data retrieved from the Taiwan "Longitudinal Health Insurance Database 2000." We identified 847 women who received a diagnosis of BPS/IC between January 1, 2001 and December 31, 2008 (study group) and 4,235 comparison women (women without a BPS/IC diagnosis matched on age and other selected demographic variables. All subjects were tracked for 3 years following the index date to identify those who received a diagnosis of stroke during follow-up. RESULTS: The stroke incidence rate was 20.86 (95% confidence interval (CI): 15.78 27.07) and 11.65 (95% CI: 9.88-13.64) per 1,000 person-years among the study and comparison cohorts, respectively. Cox regression analysis showed a stroke hazard ratio (HR) of 1.52 (95% CI: 1.09-2.14) in the BPS/IC group relative to the comparison group over 3-year follow-up, after adjusting for hypertension, diabetes, coronary heart disease, atrial fibrillation, hyperlipidemia, and chronic kidney disease. The adjusted HR of ischemic stroke was 1.52 (95% CI: 1.02 2.27). However, there was no significant difference between the two groups in hemorrhagic stroke risk. CONCLUSIONS: Our study demonstrates an association between BPS/IC and a subsequent ischemic stroke diagnosis among women in Taiwan. PMID- 24155222 TI - Development of a rotational cell-seeding system for tubularized extracellular matrix (ECM) scaffolds in vascular surgery. AB - Tubularized porcine extracellular matrices (ECMs) are under investigation as adjuvant scaffolds for endovascular aneurismal repair (EVAR). Limitations with tubularized ECMs in this setting include difficulties in achieving a confluent endothelium on the scaffold's luminal surface prior to in vivo implantation. In this in vitro study a rotational "cell-seeding rig" (RCR) was constructed to assess the potential for endothelialization of tubular ECM constructs. Human aortic endothelial cells (HAECs) were cultured onto the luminal surfaces of tubular porcine urinary bladder matrix (UBM) scaffolds and rotated in the RCR at experimental rotational speeds. Results showed that endothelial attachment occurred at a rotation speed of six revolutions per hour. HAECs continued to proliferate after the initial attachment period of 24 h and formed a confluent endothelial monolayer after 14 days of growth. Our results demonstrate that RCRs facilitate attachment of HAECs in vitro at a speed of six revolutions per hour. The endothelialization technique presented in the current study may be important for advancing tissue-engineering approaches to address some of the current limitations in endovascular treatments of abdominal aortic aneurysms. PMID- 24155223 TI - Malignant potential of endometrial stromal tumor with limited infiltration: a case report. AB - Endometrial stromal tumors (ESTs) with limited infiltration were first proposed by Dionigi et al.(1) However, the prognostic significance of these tumors is unclear. We report a case of a 60-year-old woman who presented with a prolapsed uterine corpus and then underwent laparoscopic-assisted vaginal hysterectomy. A very small EST was incidentally found. The tumor manifested focal irregularity and finger-like permeation into the adjacent myometrium not exceeding 3 mm but exceeding 3 in number, features intermediate between a low-grade endometrial stromal sarcoma and an endometrial stromal nodule. By definition, we rendered a descriptive diagnosis of "endometrial stromal tumor with limited infiltration." A subsequent staging operation confirmed metastasis and, hence, a malignant potential. PMID- 24155224 TI - Concise review: Spinal cord injuries: how could adult mesenchymal and neural crest stem cells take up the challenge? AB - Since several years, adult/perinatal mesenchymal and neural crest stem cells have been widely used to help experimental animal to recover from spinal cord injury. More interestingly, recent clinical trials confirmed the beneficial effect of those stem cells, which improve functional score of patients suffering from such lesions. However, a complete understanding of the mechanisms of stem cell-induced recovery is seriously lacking. Indeed, spinal cord injuries gathered a wide range of biochemical and physiopathological events (such as inflammation, oxidative stress, axonal damage, demyelination, etc.) and the genuine healing process after cell transplantation is not sufficiently defined. This review aims to sum up recent data about cell therapy in spinal cord lesions using mesenchymal or recently identified neural crest stem cells, by describing precisely which physiopathological parameter is affected and the exact processes underlying the observed changes. Overall, although significant advances are acknowledged, it seems that further deep mechanistic investigation is needed for the development of optimized and efficient cell-based therapy protocols. PMID- 24155225 TI - Cytotoxicity of silica nanoparticles on HaCaT cells. AB - Despite the widespread use of silica nanoparticles (SiO2 NPs) in biological and medical fields, their adverse effects have not been clearly elucidated. In this study, spherical SiO2 NPs with a 50 nm diameter were used to study their interaction with HaCaT cells. SiO2 NPs were found to be readily internalized into HaCaT cells and localized in the cytoplasm, lysosomes and autophagosomes. Decreased cell viability and damaged cell membrane integrity showed the cytotoxicity of SiO2 NPs. Significant glutathione depletion and reactive oxygen species generation, which reduced the cellular antioxidant level, could be the major factor of cytotoxicity induced by SiO2 NPs. PMID- 24155226 TI - A novel coumarin-quinone derivative SV37 inhibits CDC25 phosphatases, impairs proliferation, and induces cell death. AB - Cell division cycle (CDC) 25 proteins are key phosphatases regulating cell cycle transition and proliferation by regulating CDK/cyclin complexes. Overexpression of these enzymes is frequently observed in cancer and is related to aggressiveness, high-grade tumors and poor prognosis. Thus, targeting CDC25 by compounds, able to inhibit their activity, appears a good therapeutic approach. Here, we describe the synthesis of a new inhibitor (SV37) whose structure is based on both coumarin and quinone moieties. An analytical in vitro approach shows that this compound efficiently inhibits all three purified human CDC25 isoforms (IC50 1-9 uM) in a mixed-type mode. Moreover, SV37 inhibits growth of breast cancer cell lines. In MDA-MB-231 cells, reactive oxygen species generation is followed by pCDK accumulation, a mark of CDC25 dysfunction. Eventually, SV37 treatment leads to activation of apoptosis and DNA cleavage, underlining the potential of this new type of coumarin-quinone structure. PMID- 24155227 TI - Insecticide-induced hormesis and arthropod pest management. AB - Ecological backlashes such as insecticide resistance, resurgence and secondary pest outbreaks are frequent problems associated with insecticide use against arthropod pest species. The last two have been particularly important in sparking interest in the phenomenon of insecticide-induced hormesis within entomology and acarology. Hormesis describes a biphasic dose-response relationship that is characterized by a reversal of response between low and high doses of a stressor (e.g. insecticides). Although the concept of insecticide-induced hormesis often does not receive sufficient attention, or has been subject to semantic confusion, it has been reported in many arthropod pest species and natural enemies, and has been linked to pest outbreaks and potential problems with insecticide resistance. The study of hormesis remains largely neglected in entomology and acarology. Here, we examined the concept of insecticide-induced hormesis in arthropods, its functional basis and potential fitness consequences, and its importance in arthropod pest management and other areas. PMID- 24155228 TI - The delivery and evaluation of RNAi therapeutics for heterotopic ossification pathologies. AB - RNA interference (RNAi) is a powerful tool being used to develop therapies for pathologies caused by gene overexpression. Heterotopic ossification pathologies such as trauma-induced heterotopic ossification and fibrodysplasia ossificans progressiva may be treatable with an RNAi approach. However, there is a lack of consensus in literature regarding the delivery conditions and evaluation of RNAi therapeutics in these disease models. Here, we describe in vitro protocols for the delivery of polymer-based RNAi therapeutics as well as a streamlined strategy for the assessment of osteoblast lineage progression due to dysregulated bone morphogenetic protein signaling. This strategy focuses on the quantification of early-stage osteoblast transcription factors RUNX2 and OSX, followed by the measurement of alkaline phosphatase activity and late-stage matrix deposition. PMID- 24155229 TI - Microfluidic device to culture 3D in vitro human capillary networks. AB - Models that aim to recapitulate the dynamic in vivo features of the microcirculation are crucial for studying vascularization. Cells in vivo respond not only to biochemical cues (e.g., growth factor gradients) but also sense mechanical cues (e.g., interstitial flow, vessel perfusion). Integrating the response of cells, the stroma, and the circulation in a dynamic 3D setting will create an environment suitable for the exploration of many fundamental vascularization processes. Here in this chapter, we describe an in vivo-inspired microenvironment that is conducive to the development of perfused human capillaries. PMID- 24155230 TI - An assay to quantify chemotactic properties of degradation products from extracellular matrix. AB - The endogenous chemotaxis of cells toward sites of tissue injury and/or biomaterial implantation is an important component of the host response. Implanted biomaterials capable of recruiting host stem/progenitor cells to a site of interest may obviate challenges associated with cell transplantation. An assay for the identification and quantification of chemotaxis induced by surgically placed biologic scaffolds composed of extracellular matrix is described herein. PMID- 24155231 TI - Mimicking bone microenvironment for directing adipose tissue-derived mesenchymal stem cells into osteogenic differentiation. AB - Adipose tissue-derived mesenchymal stem cells (ASCs) have become an increasingly interested cell source for the scientists in the fields of stem cell biology and regenerative medicine. ASCs have already been used in a number of clinical trials, and some successful outcomes have been reported in bone tissue regeneration. Here we describe the protocols which mimic the factors in bone healing microenvironment, including inflammation burst, osteoblasts, and bone biomimetic scaffolds to direct ASCs into osteogenic differentiation. PMID- 24155232 TI - Derivation and network formation of vascular cells from human pluripotent stem cells. AB - As the lifeline of almost all living tissues, blood vessels are a major focus of tissue-regenerative therapies. Rebuilding blood vessels has vast implications for the study of vascular growth and treatment of diseases in which vascular function is compromised. Toward this end, human pluripotent stem cells have been widely studied for their differentiation capacity toward vascular lineages. We demonstrate methods to derive a bicellular population of early specialized vascular cells from human pluripotent stem cells, to differentiate these toward mature endothelial cells and pericytes, and to utilize a collagen scaffold to facilitate organization into vascular networks. PMID- 24155233 TI - Reconstruction of normal and pathological human epidermis on polycarbonate filter. AB - This chapter provides methods suitable for the culture of primary human keratinocytes in serum-free culture conditions, starting from very small skin biopsies. It also explains procedures required for reconstruction of a stratified epidermis on polycarbonate filter, starting from keratinocytes cultured in serum free conditions. Tissues reconstructed according to this method have been proven suitable for characterization of epidermal morphogenesis and for in vitro studies of the epidermal barrier. Utilization of the same method for successful isolation of keratinocytes from a patient suffering from Darier's disease and the reconstruction of a pathological epidermis which displays the same histological features as in vivo are also presented. PMID- 24155234 TI - Growth and differentiation of HaCaT keratinocytes. AB - HaCaT cells are a spontaneously immortalized, human keratinocyte line that has been widely used for studies of skin biology and differentiation. Under typical culture conditions HaCaT cells have a partially to fully differentiated phenotype due to the high calcium content of both standard media and fetal bovine serum. This chapter describes low-calcium culture conditions for reverting HaCaT cells to the fully basal state followed by subsequent controlled differentiation using calcium induction. PMID- 24155235 TI - Transcription activator-like effector nuclease (TALEN)-mediated gene correction in integration-free beta-thalassemia induced pluripotent stem cells. AB - beta-Thalassemia (beta-Thal) is a group of life-threatening blood disorders caused by either point mutations or deletions of nucleotides in beta-globin gene (HBB). It is estimated that 4.5% of the population in the world carry beta-Thal mutants (1), posing a persistent threat to public health. The generation of patient-specific induced pluripotent stem cells (iPSCs) and subsequent correction of the disease-causing mutations offer an ideal therapeutic solution to this problem. However, homologous recombination-based gene correction in human iPSCs remains largely inefficient. Here, we describe a robust process combining efficient generation of integration-free beta-Thal iPSCs from the cells of patients and transcription activator-like effector nuclease (TALEN)-based universal correction of HBB mutations in situ. We generated integration-free and gene-corrected iPSC lines from two patients carrying different types of homozygous mutations and showed that these iPSCs are pluripotent and have normal karyotype. We showed that the correction process did not generate TALEN-induced off targeting mutations by sequencing. More importantly, the gene-corrected beta Thal iPS cell lines from each patient can be induced to differentiate into hematopoietic progenitor cells and then further to erythroblasts expressing normal beta-globin. Our studies provide an efficient and universal strategy to correct different types of beta-globin mutations in beta-Thal iPSCs for disease modeling and applications. PMID- 24155236 TI - Functional consequences of complementarity-determining region deactivation in a multifunctional anti-nucleic acid antibody. AB - Many murine monoclonal anti-DNA antibodies (Abs) derived from mice models for systemic lupus erythematosus have additional cell-penetration and/or nucleic acid hydrolysis properties. Here, we examined the influence of deactivating each complementarity-determining region (CDR) within a multifunctional anti-nucleic acid antibody (Ab) that possesses these activities, the catalytic 3D8 single chain variable fragment (scFv). CDR-deactivated 3D8 scFv variants were generated by replacing all of the amino acids within each CDR with Gly/Ser residues. The structure of 3D8 scFv accommodated single complete CDR deactivations. Different functional activities of 3D8 scFv were affected differently depending on which CDR was deactivated. The only exception was CDR1, located within the light chain (LCDR1); deactivation of LCDR1 abolished all of the functional activities of 3D8 scFv. A hybrid Ab, HW6/3D8L1, in which the LCDR1 from an unrelated Ab (HW6) was replaced with the LCDR1 from 3D8, acquired all activities associated with the 3D8 scFv. These results suggest that the activity of a multifunctional 3D8 scFv Ab can be modulated by single complete CDR deactivation and that the LCDR1 plays a crucial role in maintaining Ab properties. This study presents a new approach for determining the role of individual CDRs in multifunctional Abs with important implications for the future of Ab engineering. PMID- 24155237 TI - Enzymatic basis for N-glycan sialylation: structure of rat alpha2,6 sialyltransferase (ST6GAL1) reveals conserved and unique features for glycan sialylation. AB - Glycan structures on glycoproteins and glycolipids play critical roles in biological recognition, targeting, and modulation of functions in animal systems. Many classes of glycan structures are capped with terminal sialic acid residues, which contribute to biological functions by either forming or masking glycan recognition sites on the cell surface or secreted glycoconjugates. Sialylated glycans are synthesized in mammals by a single conserved family of sialyltransferases that have diverse linkage and acceptor specificities. We examined the enzymatic basis for glycan sialylation in animal systems by determining the crystal structures of rat ST6GAL1, an enzyme that creates terminal alpha2,6-sialic acid linkages on complex-type N-glycans, at 2.4 A resolution. Crystals were obtained from enzyme preparations generated in mammalian cells. The resulting structure revealed an overall protein fold broadly resembling the previously determined structure of pig ST3GAL1, including a CMP sialic acid-binding site assembled from conserved sialylmotif sequence elements. Significant differences in structure and disulfide bonding patterns were found outside the sialylmotif sequences, including differences in residues predicted to interact with the glycan acceptor. Computational substrate docking and molecular dynamics simulations were performed to predict and evaluate the CMP-sialic acid donor and glycan acceptor interactions, and the results were compared with kinetic analysis of active site mutants. Comparisons of the structure with pig ST3GAL1 and a bacterial sialyltransferase revealed a similar positioning of donor, acceptor, and catalytic residues that provide a common structural framework for catalysis by the mammalian and bacterial sialyltransferases. PMID- 24155238 TI - Mechanism of transport modulation by an extracellular loop in an archaeal excitatory amino acid transporter (EAAT) homolog. AB - Secondary transporters in the excitatory amino acid transporter family terminate glutamatergic synaptic transmission by catalyzing Na(+)-dependent removal of glutamate from the synaptic cleft. Recent structural studies of the aspartate specific archaeal homolog, Glt(Ph), suggest that transport is achieved by a rigid body, piston-like movement of the transport domain, which houses the substrate binding site, between the extracellular and cytoplasmic sides of the membrane. This transport domain is connected to an immobile scaffold by three loops, one of which, the 3-4 loop (3L4), undergoes substrate-sensitive conformational change. Proteolytic cleavage of the 3L4 was found to abolish transport activity indicating an essential function for this loop in the transport mechanism. Here, we demonstrate that despite the presence of fully cleaved 3L4, Glt(Ph) is still able to sample conformations relevant for transport. Optimized reconstitution conditions reveal that fully cleaved Glt(Ph) retains some transport activity. Analysis of the kinetics and temperature dependence of transport accompanied by direct measurements of substrate binding reveal that this decreased transport activity is not due to alteration of the substrate binding characteristics but is caused by the significantly reduced turnover rate. By measuring solute counterflow activity and cross-link formation rates, we demonstrate that cleaving 3L4 severely and specifically compromises one or more steps contributing to the movement of the substrate-loaded transport domain between the outward- and inward facing conformational states, sparing the equivalent step(s) during the movement of the empty transport domain. These results reveal a hitherto unknown role for the 3L4 in modulating an essential step in the transport process. PMID- 24155239 TI - E6-AP/UBE3A protein acts as a ubiquitin ligase toward SOX9 protein. AB - SOX9 is a transcription factor that acts as a key regulator at various stages of cartilage differentiation. There is ample evidence that intracellular SOX9 protein levels are tightly regulated both by sumoylation and by degradation through the ubiquitin-proteasome pathway. Using a proteomics approach, here we report the identification of a SOX9-binding protein, E6-AP/UBE3A, that may act as a ubiquitin ligase toward Sox9. E6-AP bound SOX9 through the region consisting mostly of its high mobility group domain in vitro. In nuclear lysates, FLAG tagged E6-AP coprecipitated with Sox9 and its high mobility group domain. This finding was estimated using nuclear lysates from a chondrocytic cell line that endogenously expresses E6-AP and SOX9. Accordingly, ectopically expressed E6-AP and SOX9 colocalized in the nucleus. We show that E6-AP ubiquitinates SOX9 in vitro and in vivo and that SOX9 levels are enhanced after addition of the proteasome inhibitor bortezomib. Similar, siRNA knockdown of E6-AP and the E2 ligase Ubc9 increased cellular SOX9 amounts, supporting the notion that SOX9 may be ubiquitinated in hypertrophic chondrocytes by E6-AP and degraded by proteasomes. This is in accordance with the distribution of SOX9 levels, which are high in proliferating and prehypertrophic chondrocytes but low in hypertrophic chondrocytes, whereas E6-AP levels are high in hypertrophic chondrocytes and low in prehypertrophic chondrocytes. Furthermore, E6-AP deficient mice showed SOX9 accumulation in chondrocytes and the brain. These findings support the concept that E6-AP regulates SOX9 levels in developing cartilage by acting as a ubiquitin ligase. PMID- 24155240 TI - NAT8L (N-acetyltransferase 8-like) accelerates lipid turnover and increases energy expenditure in brown adipocytes. AB - NAT8L (N-acetyltransferase 8-like) catalyzes the formation of N-acetylaspartate (NAA) from acetyl-CoA and aspartate. In the brain, NAA delivers the acetate moiety for synthesis of acetyl-CoA that is further used for fatty acid generation. However, its function in other tissues remained elusive. Here, we show for the first time that Nat8l is highly expressed in adipose tissues and murine and human adipogenic cell lines and is localized in the mitochondria of brown adipocytes. Stable overexpression of Nat8l in immortalized brown adipogenic cells strongly increases glucose incorporation into neutral lipids, accompanied by increased lipolysis, indicating an accelerated lipid turnover. Additionally, mitochondrial mass and number as well as oxygen consumption are elevated upon Nat8l overexpression. Concordantly, expression levels of brown marker genes, such as Prdm16, Cidea, Pgc1alpha, Pparalpha, and particularly UCP1, are markedly elevated in these cells. Treatment with a PPARalpha antagonist indicates that the increase in UCP1 expression and oxygen consumption is PPARalpha-dependent. Nat8l knockdown in brown adipocytes has no impact on cellular triglyceride content, lipogenesis, or oxygen consumption, but lipolysis and brown marker gene expression are increased; the latter is also observed in BAT of Nat8l-KO mice. Interestingly, the expression of ATP-citrate lyase is increased in Nat8l-silenced adipocytes and BAT of Nat8l-KO mice, indicating a compensatory mechanism to sustain the acetyl-CoA pool once Nat8l levels are reduced. Taken together, our data show that Nat8l impacts on the brown adipogenic phenotype and suggests the existence of the NAT8L-driven NAA metabolism as a novel pathway to provide cytosolic acetyl-CoA for lipid synthesis in adipocytes. PMID- 24155241 TI - Dendrimers as high relaxivity MR contrast agents. AB - Dendrimers are versatile macromolecules with tremendous potential as magnetic resonance imaging (MRI) contrast agents. Dendrimer-based agents provide distinct advantages over low-molecular-weight gadolinium chelates, including enhanced r1 relaxivity due to slow rotational dynamics, tunable pharmacokinetics that can be adapted for blood pool, liver, kidney, and lymphatic imaging, the ability to be a drug carrier, and flexibility for labeling due to their inherent multivalency. Clinical applications are increasingly being developed, particularly in lymphatic imaging. Herein we present a broad overview of dendrimer-based MRI contrast agents with attention to the unique chemistry and physical properties as well as emerging clinical applications. PMID- 24155242 TI - Novel animal pole-enriched maternal mRNAs are preferentially expressed in neural ectoderm. AB - BACKGROUND: Many animals utilize maternal mRNAs to pre-pattern the embryo before the onset of zygotic transcription. In Xenopus laevis, vegetal factors specify the germ line, endoderm, and dorsal axis, but there are few studies demonstrating roles for animal-enriched maternal mRNAs. Therefore, we carried out a microarray analysis to identify novel maternal transcripts enriched in 8-cell-stage animal blastomeres. RESULTS: We identified 39 mRNAs isolated from 8-cell animal blastomeres that are >4-fold enriched compared to vegetal pole mRNAs. We characterized 14 of these that are of unknown function. We validated the microarray results for 8/14 genes by qRT-PCR and for 14/14 genes by in situ hybridization assays. Because no developmental functions are reported yet, we provide the expression patterns for each of the 14 genes. Each is expressed in the animal hemisphere of unfertilized eggs, 8-cell animal blastomeres, and diffusely in blastula animal cap ectoderm, gastrula ectoderm and neural ectoderm, neural crest (and derivatives) and cranial placodes (and derivatives). They have varying later expression in some mesodermal and endodermal tissues in tail bud through larval stages. CONCLUSIONS: Novel animal-enriched maternal mRNAs are preferentially expressed in ectodermal derivatives, particularly neural ectoderm. However, they are later expressed in derivatives of other germ layers. PMID- 24155243 TI - Acetylcholinesterase-catalyzed hydrolysis allows ultrasensitive detection of pathogens with the naked eye. PMID- 24155244 TI - Distribution of molecules locally delivered from bone cement. AB - Revision of infected orthopedic implants is successful in most cases when antimicrobials are delivered locally (mixed with bone cement or bone graft which is placed in the site from which the infected tissue was removed); however, there is still a substantial rate of recurrence most likely due to the antimicrobials not achieving a therapeutic dose at all locations in the tissue. To study transport within this environment, gadolinium chelated in diethylene triamine pentaacetic acid (Gd-DTPA), a MRI contrast agent with size and solubility similar to two common antimicrobials (gentamicin and vancomycin), was mixed with bone cement, implanted in vivo into two models of orthopedic surgical wounds, and imaged using MRI 5.5 h after implantation. Image thresholding was used to create two-dimensional and three-dimensional representations of areas/volumes containing detectable concentrations of Gd-DTPA. Distribution is found to be anisotropic with Gd-DTPA transporting preferentially anterior of the implant toward the skin. When fascia is not closed over the implant site, Gd-DTPA transports to the skin and along the subcutaneous plane. The distance transported indicates that transport is likely driven by convection. Finally, the tissue concentration of Gd DTPA is much less than the concentration loaded into the bone cement. PMID- 24155245 TI - Genomic diversity of low-risk human papillomavirus genotypes HPV 40, HPV 42, HPV 43, and HPV 44. AB - In order to investigate the genomic diversity of low-risk human papillomavirus (HPV) genotypes, a total of 108 isolates of HPV 40, HPV 42, HPV 43, or HPV 44, obtained from anal swabs or tissue specimens of patients with anogenital warts, and cervical swabs of women with cervical intraepithelial neoplasia of different grades, were analyzed. The characterization of genomic variants was established by sequencing one third of the viral genome and analysis of three different genomic regions: L1, LCR, and E6. Maximum variant divergence accounted for 0.4 1.1% of the investigated genomic segments. Several novel, potentially important nucleotide substitutions, deletions, and insertions are described. Altogether, among 14 HPV 40 isolates, a total of nine different genomic variants were identified, composed of eight L1, five LCR, and four E6 genomic variants. Among 49 HPV 42 isolates, a total of 30 genomic variants were identified, composed of 20 L1, 18 LCR, and four E6 genomic variants. Among 10 HPV 43 isolates, distributed into two major genomic variant lineages with clearly defined nucleotide signatures, three genomic variants were identified, composed of three L1, two LCR, and two E6 genomic variants. Among 35 HPV 44 isolates, a total of eight HPV 44 and 11 subtype HPV 44 genomic variants were identified, composed of 13 L1, 14 LCR, and 6 E6 genomic variants. A similar level of genomic diversity of HPV 44 and its subtype was identified in our geographic region as has been reported previously on isolates collected worldwide. PMID- 24155246 TI - A systematic review of the effects of neuromodulation on eating and body weight: evidence from human and animal studies. AB - BACKGROUND: Eating disorders (ED) are chronic and sometimes deadly illnesses. Existing treatments have limited proven efficacy, especially in the case of adults with anorexia nervosa (AN). Emerging neural models of ED provide a rationale for more targeted, brain-directed interventions. AIMS: This systematic review has examined the effects of neuromodulation techniques on eating behaviours and body weight and assessed their potential for therapeutic use in ED. METHOD: All articles in PubMed, PsychInfo and Web of Knowledge were considered and screened against a priori inclusion/exclusion criteria. The effects of repetitive transcranial magnetic stimulation (rTMS), transcranial direct current stimulation, vagus nerve stimulation (VNS) and deep brain stimulation (DBS) were examined across studies in ED samples, other psychiatric and neurological disorders, and animal models. RESULTS: Sixty studies were identified. There is evidence for ED symptom reduction following rTMS and DBS in both AN and bulimia nervosa. Findings from studies of other psychiatric and neurological disorders and from animal studies demonstrate that increases in food intake and body weight can be achieved following DBS and that VNS has potential value as a means of controlling eating and inducing weight loss. CONCLUSIONS: Neuromodulation tools have potential for reducing ED symptomatology and related behaviours, and for altering food intake and body weight. In response to such findings, and emerging neural models of ED, treatment approaches are highly unlikely to remain 'brainless'. More research is required to evaluate the potential of neuromodulation procedures for improving long-term outcomes in ED. PMID- 24155247 TI - Improvements in symptoms following neuronavigated repetitive transcranial magnetic stimulation (rTMS) in severe and enduring anorexia nervosa: findings from two case studies. AB - BACKGROUND: Advances in the treatment of anorexia nervosa (AN) are most likely to arise from targeted, brain-directed treatments, such as repetitive transcranial magnetic stimulation (rTMS). We describe findings from two individuals with treatment-resistant AN who received 19-20 sessions of neuronavigated, high frequency rTMS, applied to the left dorsolateral prefrontal cortex. METHOD: Within-session measures assessed changes pre-rTMS, post-rTMS in subjective eating disorder (ED) experiences. Weight, ED symptoms and mood were assessed pre treatment, post-treatment and at 1 month follow-up. RESULTS: In both cases, there was improvement in ED symptomatology and mood after 19-20 sessions of neuronavigated rTMS, and these changes persisted or continued to improve at follow-up. Within sessions, Patient A demonstrated a consistent reduction in subjective ED experiences, and Patient B a reduction in some ED related experiences. CONCLUSIONS: These findings suggest that rTMS has potential as an adjunct to the treatment of AN and deserves further study. PMID- 24155248 TI - Premenopausal serum sex hormone levels in relation to breast cancer risk, overall and by hormone receptor status - results from the EPIC cohort. AB - Results from prospective studies on premenopausal serum hormone levels in relation to breast cancer risk have been inconclusive, especially with regard to tumor subtypes. Using a case-control study nested within the prospective European Prospective Investigation into Cancer and Nutrition (EPIC) cohort (801 breast cancer cases and 1,132 matched control subjects), we analyzed the relationships of prediagnostic serum estradiol, free estradiol, progesterone, testosterone, free testosterone and sex hormone-binding globulin (SHBG) levels with the risk of breast cancer by estrogen and progesterone receptor-positive and -negative breast tumors and by age at diagnoses. Higher prediagnostic serum levels of testosterone and free testosterone were associated with an increased overall risk of breast cancer [ORQ4-Q1 = 1.56 (95% CI 1.15-2.13), ptrend = 0.02 for testosterone and ORQ4-Q1 = 1.33 (95% CI 0.99-1.79), ptrend = 0.04 for free testosterone], but no significant risk association was observed for estradiol, free estradiol, progesterone and SHBG. Tests for heterogeneity between receptor-positive and negative tumors were not significant. When analysis were stratified by age at tumor diagnosis, the odds ratios observed for estradiol were stronger and borderline significant for breast cancer diagnosed at age less than 50 [ORQ4-Q1 = 1.32 (95% CI 0.87-2.01), ptrend = 0.05] compared to breast cancer diagnosed at age 50 or above [ORQ4-Q1 = 0.94 (95% CI 0.60-1.47), ptrend = 0.34, phet = 0.04]. In conclusion, our data indicate that higher premenopausal circulating testosterone levels are associated with an increased risk of developing breast cancer, but do not show a significant association of estradiol or progesterone with breast cancer risk, overall, by menstrual cycle phase or by tumor receptor status, although a possible risk increase with higher estradiol levels for tumors diagnosed before age 50 was seen. PMID- 24155249 TI - PTEN regulates matrix synthesis in adult human chondrocytes under oxidative stress. AB - Phosphatase and tensin homologue deleted on chromosome 10 (PTEN) was identified as an important tumor suppressor gene. PTEN functions as a negative regulator of phosphoinositol-3-kinase (PI3K)-Akt and MEK/ERK signaling. The PI3K-Akt pathway is critical for cell survival, differentiation, and matrix synthesis. Oxidative stress is considered a critical factor in the onset and progression of osteoarthritis (OA). Therefore, we investigated the function of PTEN in OA chondrocytes under oxidative stress. Chondrocytes were treated with insulin-like growth factor-1 (IGF-1) and/or tert-butyl hydroperoxide (tBHP), which causes oxidative stress. The expression levels of type2 collagen (Col2a1) and aggrecan were analyzed by real-time PCR, and phosphorylation of Akt and ERK1/2 was analyzed by Western blotting. Chondrocytes were treated with PTEN-specific small interfering RNA (siRNA), as well as IGF-1 and/or tBHP. PTEN and IGF-1 expressions in OA chondrocytes were increased. The downregulation of PTEN expression increased the expression levels of Col2a1 and aggrecan, and increased proteoglycan synthesis under oxidative stress. Oxidative stress decreased the phosphorylation of Akt and increased that of ERK1/2. The downregulation of PTEN expression increased Akt phosphorylation, but did not increase that of ERK 1/2. Our results suggest that PTEN regulates matrix synthesis via the PI3K-Akt pathway under oxidative stress. PMID- 24155250 TI - Glucose metabolism, insulin sensitivity and beta-cell function in type A insulin resistance syndrome around puberty: a 9-year follow-up. AB - Diabetes mellitus is thought to be progressive. Insufficient insulin secretion in compensation for insulin resistance leads to glucose intolerance. A previously reported proband with type A insulin resistance syndrome and her younger twin brothers with and without the R1174W missense mutation in the insulin receptor gene were followed for 9 years to study the progression of glucose metabolism, insulin sensitivity, and beta-cell function around puberty. Five-hour OGTT was performed in them at each visit. Areas under the curves of glucose, insulin and C peptides, insulinogenic index, AIR, and Homa indices were assessed. Intramyocellular lipids (IMCLs) were quantified in the proband and compared to those of 12 nondiabetic subjects, 118 newly diagnosed type 2 diabetic patients. The proband maintained normal HbA1c (27-37 mmol/mol) and fasting plasma glucose (3.7-4.5 mmol/l), and her glucose tolerance ameliorated over years. The proband's Homa-IR decreased into adulthood, while her Homa-B, insulinogenic index, AIR, AUCs of insulin, and C-peptide decreased accordingly. Homa-B to Homa-IR ratios stayed significantly higher than normal. Homa-B, AUCs of insulin, and C-peptide of the twin brothers increased in response to the increment of Homa-IR as they entered middle and late puberty. The changes were more dramatic in the twin brothers carrying the mutation. IMCLs of the proband were lower than those of the nondiabetic counterparts and were disproportional for the degree of insulin resistance. Our longitudinal data of type A insulin resistance syndrome around puberty provide significant information for the study of insulin secretion in compensation for insulin resistance. PMID- 24155251 TI - The thermic effect of food is reduced in older adults. AB - The thermic effect of food accounts for ~10% of daily energy expenditure. A reduction in the thermic effect of food, which has been variably observed in the older adults, could predispose to fat gain. We tested whether the thermic effect of food is reduced in older adults compared with young adults by analyzing our database of standardized studies conducted at the Mayo Clinic between 1999 and 2009. Data were available from 136 older adult volunteers aged 60-88 (56 females) and 141 young adults aged 18-35 years (67 females). Basal energy expenditure was measured by indirect calorimetry to assess basal metabolic rate. Body fat, fat free mass, and visceral fat were measured using a combination of dual energy X ray absorptiometry and an abdominal CT scan. The thermic effect of food and postprandial insulinemia were measured in 123 older adults (52 females) and 86 young adults (38 females) of these volunteers. Basal metabolic rate adjusted for fat-free mass was less in older adults (p=0.01) and the thermic effect of food was ~1% (p=0.02) less in the older adults. After controlling for meal size and fat-free mass, body fat and fat distribution did not predict the thermic effect of food. Both basal metabolic rate and the thermic effect of food are less in older adults than young adults, even when they have similar amounts of lean tissue and consume a similar size meal. These factors contribute to lower daily energy expenditure in the older adults. PMID- 24155252 TI - Interaction between energy homeostasis and reproduction: central effects of leptin and ghrelin on the reproductive axis. AB - Reproductive maturation and function are sensitive to the metabolic state of the organism and the magnitude of body fuel reserves; hence, conditions ranging from energy insufficiency to morbid obesity impact the timing of puberty and are frequently linked to fertility problems. This phenomenon is the result of the close interplay between a diversity of nutritional cues and metabolic signals (including hormones) with different elements of the so-called hypothalamic pituitary-gonadal (HPG) axis. In this review, we will focus our attention on the 'reproductive' roles of 2 key metabolic hormones, namely, the adipose signal, leptin, and the gut hormone, ghrelin. These 2 factors, which have been proposed to operate as functional antagonists in the control of metabolism and energy homeostasis, are also provided with important, and in many cases opposite, roles in the regulation of puberty onset and gonadal function. We will provide herein an update view of the reproductive effects of leptin and ghrelin, with a major emphasis on the actions of these 2 key hormones upon the central elements of the HPG axis, including their putative effects on Kiss1 and other reproductive neuronal networks. This will help to understand the mechanisms whereby reproductive function is gated and dynamically regulated by metabolic signals at different key developmental stages, such as puberty and adulthood. PMID- 24155253 TI - Layer selective control of the lattice structure in oxide superlattices. AB - A combined synchrotron X-ray diffraction and transmission electron microscopy study reveals a structural phase transition controlled by the overall thickness of epitaxial nickelate-aluminate superlattices. The transition between uniform and twin-domain states is confined to the nickelate layers and leaves the aluminate layers unaffected. PMID- 24155254 TI - From integrated pest management to integrated pest eradication: technologies and future needs. AB - BACKGROUND: With growing globalization and trade, insect incursions are increasing worldwide. A proportion of incursions involve pests of major economic crops (e.g.Mediterranean fruit fly), conservation value (e.g. tramp ants) or health significance(e.g.mosquitoes), and maybe the targets of eradication programmes. Historically, such responses have included the use of broad spectrum insecticides. However, with increasing public awareness of the negative aspects of pesticides, new environmentally friendly and effective techniques are needed. Here, we review and evaluate a range of selective to broad-spectrum tactical options for suppression which either have, or show potential for, integration within arthropod eradication programmes. RESULTS: Most of the available technologies have their roots in pest management, but higher efficacy is required. Further refinement may be needed for use in eradication. Integration of several tactics is usually needed, as compatible tools can be used simultaneously to target different parts of the pest life cycle. However, not all technologies are fully compatible; for example, the simultaneous use of mass trapping and the sterile insect technique (SIT) may be suboptimal, although sequential application may still be effective. CONCLUSIONS: Broad-spectrum insecticides are generally incompatible with some biologically based technologies such as the SIT, but may be used to reduce the population so that density-dependent tactics can be used. Several novel technologies with fewer nontarget impacts have been proposed in recent years, and need to be properly evaluated for their applicability to insecteradication. Overall, there are still major gaps in surveillance and selective eradication technologies for most insects. PMID- 24155255 TI - Absorption, metabolism and effect of compatibility on absorption of qishenyiqi dropping pill. AB - Qishenyiqi dropping pill (QSYQ), is a traditional Chinese medicine (TCM) prescription for treating heart diseases in China. Knowledge concerning the systemic identification of active compounds and metabolic components of QSYQ is generally lacking. Therefore, it is essential to develop a valid method for the analysis of active compounds of the combined prescription and determination of interactions among the herbs. The absorbable compounds and metabolites of QSYQ were profiled using computational chemistry prediction, an improved everted gut sac in vitro experiment, the Caco-2 cell monolayer in vitro test, a rat in vivo experiment and ultra-performance liquid chromatography/diode array detection/quadrupole-time of flight mass spectrum (UPLC/DAD/Q-TOF MS). In total, 42 prototype compounds were recognized as absorbable compounds, and eight metabolites were identified by UPLC/DAD/Q-TOF MS. The absorption rates of phenolic acids and saponins were significantly improved and the absorption of isoflavone was inhibited after compatibility. The volatile oil component had an improved effect on the absorption of other compounds, while its own absorption was inhibited. In conclusion, the present study established a rapid and effective strategy for demonstrating the absorption and metabolism of QSYQ and revealing the compatible relationship among herbs. This investigation can provide a reference for the compatibility of prescriptions and the modernization of TCM. PMID- 24155256 TI - The expanding superfamily of gelsolin homology domain proteins. AB - The gelsolin homology (GH) domain has been found to date exclusively in actin binding proteins. In humans, three copies of the domain are present in CapG, five copies in supervillin, and six copies each in adseverin, gelsolin, flightless I and the villins: villin, advillin and villin-like protein. Caenorhabditis elegans contains a four-GH-domain protein, GSNL-1. These architectures are predicted to have arisen from gene triplication followed by gene duplication to result in the six-domain protein. The subsequent loss of one, two or three domains produced the five-, four-, and three-domain proteins, respectively. Here we conducted BLAST and hidden Markov based searches of UniProt and NCBI databases to identify novel gelsolin domain containing proteins. The variety in architectures suggests that the GH domain has been tested in many molecular constructions during evolution. Of particular note is flightless-like I protein (FLIIL1) from Entamoeba histolytica, which combines a leucine rich repeats (LRR) domain, seven GH domains, and a headpiece domain, thus combining many of the features of flightless I with those of villin or supervillin. As such, the GH domain superfamily appears to have developed along complex routes. The distribution of these proteins was analyzed in the 343 completely sequenced genomes, mapped onto the tree of life, and phylogenetic trees of the proteins were constructed to gain insight into their evolution. (c) 2013 Wiley Periodicals, Inc. PMID- 24155257 TI - Origin and specification of the brain leucokinergic neurons of Drosophila: similarities to and differences from abdominal leucokinergic neurons. AB - BACKGROUND: The Drosophila central nervous system contains many types of neurons that are derived from a limited number of progenitors as evidenced in the ventral ganglion. The situation is much more complex in the developing brain. The main neuronal structures in the adult brain are generated in the larval neurogenesis, although the basic neuropil structures are already laid down during embryogenesis. The embryonic factors involved in adult neuron origin are largely unknown. To shed light on how brain cell diversity is achieved, we studied the early temporal and spatial cues involved in the specification of lateral horn leucokinin peptidergic neurons (LHLKs). RESULTS: Our analysis revealed that these neurons have an embryonic origin. We identified their progenitor neuroblast as Pcd6 in the Technau and Urbach terminology. Evidence was obtained that a temporal series involving the transcription factors Kr, Pdm, and Cas participates in the genesis of the LHLK lineage, the Castor window being the one in which the LHLKs neurons are generated. It was also shown that Notch signalling and Dimmed are involved in the specification of the LHLKs. CONCLUSIONS: Serial homologies with the origin and factors involved in specification of the abdominal leucokinergic neurons (ABLKs) have been detected. PMID- 24155259 TI - Intermolecular interactions and conformation of antibody dimers present in IgG1 biopharmaceuticals. AB - Intermolecular interactions and conformation in dimer species of Palivizumab, a monoclonal antibody (IgG1), were investigated to elucidate the physical and chemical properties of the dimerized antibody. Palivizumab solution contains ~1% dimer and 99% monomer. The dimer species was isolated by size-exclusion chromatography and analysed by a number of methods including analytical ultracentrifugation-sedimantetion velocity (AUC-SV). AUC-SV in the presence of sodium dodecyl sulphate indicated that approximately half of the dimer fraction was non-covalently associated, whereas the other half was dimerized by covalent bond. Disulphide bond and dityrosine formation were likely to be involved in the covalent dimerization. Limited proteolysis of the isolated dimer by Lys-C and mass spectrometry for the resultant products indicated that the dimer species were formed by Fab-Fc or Fab-Fab interactions, whereas Fc-Fc interactions were not found. It is thus likely that the dimerization occurs mainly via the Fab region. With regard to the conformation of the dimer species, the secondary and tertiary structures were shown to be almost identical to those of the monomer. Furthermore, the thermal stability turned out also to be very similar between the dimer and monomer. PMID- 24155260 TI - Smart nanovehicles based on pH-triggered disassembly of supramolecular peptide amphiphiles for efficient intracellular drug delivery. AB - A novel type of nanovehicle (NV) based on stimuli-responsive supramolecular peptide-amphiphiles (SPAs, dendritic poly (L-lysine) non-covalently linked poly (L-leucine)) is developed for intracellular drug delivery. To determine the pH dependent mechanism, the supramolecular peptide-amphiphile system (SPAS) is investigated at different pH conditions using a variety of physical and chemical approaches. The pH-triggered disassembly of SPAS can be attributed to the disappearance of non-covalent interactions within SPAs around the isoelectric point of poly (L-leucine). SPAS is found to encapsulate guest molecules at pH 7.4 but release them at pH 6.2. In this way, SPAS is able to act as a smart NV to deliver its target to tumor cells using intracellular pH as a trigger. The DOX loaded NVs are approximately 150 nm in size. In vitro release profiles and confocal laser scanning microscopy (CLSM) images of HepG2 cells confirm that lower pH conditions can trigger the disassembly of NVs and so achieve pH dependent intracellular DOX delivery. In vitro cytotoxicity of the DOX-loaded NVs to HepG2 cells demonstrate that the smart NVs enhance the efficacy of hydrophobic DOX. Fluorescence-activated cell sorting (FACS) and CLSM results show that the NVs can enhance the endocytosis of DOX into HepG2 cells considerably and deliver DOX to the nuclei. PMID- 24155261 TI - Pharmacological properties of shikonin - a review of literature since 2002. AB - The naphthoquinone shikonin is the main active principle of Zicao, a traditional Chinese herbal medicine made from the dried root of Lithospermum erythrorhizon. Studies carried out over the past 30 years have provided a scientific basis for the use of Zicao which has been long employed in folk medicine to treat a variety of inflammatory and infectious diseases. In particular, shikonin has been shown to possess many diverse properties, including antioxidant, anti-inflammatory, antithrombotic, antimicrobial, and wound healing effects. The fact that shikonin shows so many beneficial properties has increased the interest in this molecule dramatically, especially in the past few years. The aim of this review is to provide an update of the new data published on shikonin, whose wide spectrum of pharmacological effects as well as pharmacokinetic properties and toxicity make it a highly interesting target molecule. PMID- 24155262 TI - Suppression of adrenal gland-derived epinephrine enhances the corticosterone induced antinociceptive effect in the mouse formalin test. AB - BACKGROUND: There is both clinical and experimental evidence to support the application of corticosterone in the management of inflammation and pain. Corticosterone has been used to treat painful inflammatory diseases and can produce antinociceptive effects. Epinephrine is synthesized from norepinephrine by the enzyme phenylethanolamine N-methyltransferase (PNMT) and works as an endogenous adrenoceptor ligand secreted peripherally by the adrenal medulla. It is currently unclear whether corticosterone's antinociceptive effect is associated with the modulation of peripheral epinephrine. METHODS: We first determined whether exogenous corticosterone treatment actually produced an antinociceptive effect in a formalin-induced pain model, and then examined whether this corticosterone-induced antinociceptive effect was altered by suppression of adrenal-derived epinephrine, using the following three suppression methods: (1) inhibition of the PNMT enzyme; (2) blocking peripheral epinephrine receptors; and (3) adrenalectomy. RESULTS: Exogenous treatment with corticosterone at a high dose (50 mg/kg), but not at lower doses (5, 25 mg/kg), significantly reduced pain responses in the late phase. Moreover, injection of 2,3-dichloro-a-methylbenzylamine, a PNMT enzyme inhibitor, (10 mg/kg) before corticosterone treatment caused a leftward shift in the dose-response curve for corticosterone and injection of propranolol (5 mg/kg), but not phentolamine, also shifted the dose-response curve to the left during the late phase. Chemical sympathectomy with 6-hydroxydopamine had no effect on corticosterone-induced antinociceptive effect, but injection of a low dose of corticosterone produced an antinociceptive effect in adrenalectomized animals. CONCLUSIONS: These results demonstrate that suppression of epinephrine, derived from adrenal gland, enhances the antinociceptive effect of exogenous corticosterone treatment in an inflammatory pain model. PMID- 24155263 TI - Interactions of the tooth and bone during development. AB - The tooth works as a functional unit with its surrounding bony socket, the alveolar bone. The growth of the tooth and alveolar bone is co-ordinated so that a studied distance always separates the 2, known as the tooth-bone interface (TBI). Lack of mineralization, a crucial feature of the TBI, creates the space for the developing tooth to grow and the soft tissues of the periodontium to develop. We have investigated the interactions between the tooth and its surrounding bone during development, focusing on the impact of the developing alveolar bone on the development of the mouse first molar (M1). During development, TRAP-positive osteoclasts are found to line the TBI as bone starts to be deposited around the tooth, removing the bone as the tooth expands. An enhancement of osteoclastogenesis through RANK-RANKL signaling results in an expansion of the TBI, showing that osteoclasts are essential for defining the size of this region. Isolation of the M1 from the surrounding mesenchyme and alveolar bone leads to an expansion of the tooth germ, driven by increased proliferation, indicating that, during normal development, the growth of the tooth germ is constrained by the surrounding tissues. PMID- 24155264 TI - Randomized control trial of composite cuspal restorations: five-year results. AB - The objective of this randomized control trial was to compare the five-year clinical performance of direct and indirect resin composite restorations replacing cusps. In 157 patients, 176 restorations were made to restore maxillary premolars with Class II cavities and one missing cusp. Ninety-two direct and 84 indirect resin composite restorations were placed by two operators, following a strict protocol. Treatment technique and operator were assigned randomly. Follow up period was at least 4.5 yrs. Survival rates were determined with time to reparable failure and complete failure as endpoints. Kaplan-Meier five-year survival rates were 86.6% (SE 0.27%) for reparable failure and 87.2% (SE 0.27%) for complete failure. Differences between survival rates of direct and indirect restorations [89.9% (SE 0.34%) vs. 83.2% (SE 0.42%) for reparable failure and 91.2% (SE 0.32%) vs. 83.2% (SE 0.42%) for complete failure] were not statistically significant (p = .23 for reparable failure; p = .15 for complete failure). Mode of failure was predominantly adhesive. The results suggest that direct and indirect techniques provide comparable results over the long term (trial registration number: ISRCTN29200848). PMID- 24155266 TI - Radiofrequency pulse design in parallel transmission under strict temperature constraints. AB - PURPOSE: To gain radiofrequency (RF) pulse performance by directly addressing the temperature constraints, as opposed to the specific absorption rate (SAR) constraints, in parallel transmission at ultra-high field. METHODS: The magnitude least-squares RF pulse design problem under hard SAR constraints was solved repeatedly by using the virtual observation points and an active-set algorithm. The SAR constraints were updated at each iteration based on the result of a thermal simulation. The numerical study was performed for an SAR-demanding and simplified time of flight sequence using B1 and DeltaB0 maps obtained in vivo on a human brain at 7T. RESULTS: The proposed adjustment of the SAR constraints combined with an active-set algorithm provided higher flexibility in RF pulse design within a reasonable time. The modifications of those constraints acted directly upon the thermal response as desired. CONCLUSION: Although further confidence in the thermal models is needed, this study shows that RF pulse design under strict temperature constraints is within reach, allowing better RF pulse performance and faster acquisitions at ultra-high fields at the cost of higher sequence complexity. PMID- 24155265 TI - Contribution of mesenchymal proliferation in tooth root morphogenesis. AB - In mouse tooth development, the roots of the first lower molar develop after crown formation to form 2 cylindrical roots by post-natal day 5. This study compared the morphogenesis and cellular events of the mesial-root-forming (MRF) and bifurcation-forming (BF) regions, located in the mesial and center of the first lower molar, to better define the developmental mechanisms involved in multi-rooted tooth formation. We found that the mesenchyme in the MRF showed relatively higher proliferation than the bifurcation region. This suggested that spatially regulated mesenchymal proliferation is required for creating cylindrical root structure. The mechanism may involve the mesenchyme forming a physical barrier to epithelial invagination of Hertwig's epithelial root sheath. To test these ideas, we cultured roots in the presence of pharmacological inhibitors of microtubule and actin polymerization, nocodazole and cytochalasin D. Cytochalasin D also inhibits proliferation in epithelium and mesenchyme. Both drugs resulted in altered morphological changes in the tooth root structures. In particular, the nocodazole- and cytochalasin-D-treated specimens showed a loss of root diameter and formation of a single-root, respectively. Immunolocalization and three-dimensional reconstruction results confirmed these mesenchymal cellular events, with higher proliferation in MRF in multi-rooted tooth formation. PMID- 24155267 TI - Simultaneous presence of both open metal sites and free functional organic sites in a noncentrosymmetric dynamic metal-organic framework with bimodal catalytic and sensing activities. AB - Assimilation of open metal sites (OMSs) and free functional organic sites (FOSs) with a framework strut has opened up a new route for the fabrication of novel metal-organic materials, thereby providing a unique opportunity to explore their multiple functionalities. A new metal-organic framework (MOF), {[Cu(ina)2(H2O)][Cu(ina)2(bipy)].2H2O}n (1) (ina=isonicotinate, bipy=4,4' bipyridine), has been synthesized and characterized. Complex 1 is crystallized in the orthorhombic noncentrosymmetric space group Aba2 and consists of two different 2D coordination polymers, [Cu(ina)2(H2O)]n and [Cu(ina)2(bipy)]n, with entrapped solvent water molecules. Hydrogen-bonding interactions assemble these two different 2D coordination layers in a single-crystal structure with interdigitation of pendant 4,4'-bipy from one layer into the groove of another. Upon removal of guest molecules, 1 undergoes a structural transformation in single-crystal-to-single-crystal fashion with expansion of the effective void space. Each metal center is five-coordinated and thus can potentially behave as an OMS, and the free pyridyl groups of pendant 4,4'-bipy moieties and free -C=O groups can act as free FOSs. Thus, owing to presence of both OMSs and free FOSs, the framework exhibits multifunctional properties. Owing to the presence of OMSs, the framework can act as a Lewis acid catalyst as well as a small-molecule sensor material, and in a similar way, owing to the presence of free FOSs, it performs as a Lewis base catalyst and a cation sensor material. Furthermore, owing to noncentrosymmetry with large polarity along a particular direction, it shows strong second-harmonic generation/nonlinear optical (SHG-NLO) activity. PMID- 24155269 TI - Flexible polyester cellulose paper supercapacitor with a gel electrolyte. AB - A low-cost polyester cellulose paper has been used as a substrate for a flexible supercapacitor device that contains aqueous carbon nanotube ink as the electrodes and a polyvinyl alcohol (PVA)-based gel as the electrolyte. Gel electrolytes have attracted much interest due to their solvent-holding capacity and good film forming capability. The electrodes are characterized for their conductivity and morphology. Because of its high conductivity, the conductive paper is studied in supercapacitor applications as active electrodes and as separators after coating with polyvinylidene fluoride. Carbon nanotubes deposited on porous paper are more accessible to ions in the electrolyte than those on flat substrates, which results in higher power density. A simple fabrication process is achieved and paper supercapacitors are tested for their performance in both aqueous and PVA gel electrolytes by using galvanostatic and cyclic voltammetry methods. A high specific capacitance of 270 F g(-1) and an energy density value of 37 W h kg(-1) are achieved for devices with PVA gel electrolytes. Furthermore, this device can maintain excellent specific capacitance even under high currents. This is also confirmed by another counter experiment with aqueous sulfuric acid as the electrolyte. The cycle life, one of the most critical parameters in supercapacitor operations, is found to be excellent (6000 cycles) and less than 0.5 % capacitance loss is observed. Moreover, the supercapacitor device is flexible and even after twisting does not show any cracks or evidence of breakage, and shows almost the same specific capacitance of 267 F g(-1) and energy density of 37 W h kg(-1) . This work suggests that a paper substrate can be a highly scalable and low-cost solution for high-performance supercapacitors. PMID- 24155270 TI - Immunolocalization of substance P and NK-1 receptor in Hofbauer cells in human normal placenta. AB - Substance P (SP) after binding to the neurokinin-1 (NK-1) receptor regulates many biological functions. Both SP and the NK-1 receptor are expressed in human normal placenta cells, monocytes, and macrophages. However, to our knowledge, the presence of both SP and the NK-1 receptor in macrophages of the placenta, the Hofbauer cells, is unknown. We demonstrate by immunohistochemistry in human normal placenta samples the presence of both SP and NK-1 receptors in the cytoplasm and in the nucleus of Hofbauer cells. The findings suggest a functional role of the SP/NK-1 receptor system in the physiology and pathophysiology of Hofbauer cells in the human placenta. PMID- 24155271 TI - Mechanisms of inhibition of endothelial cell migration by taxanes. AB - Several antiangiogenic mechanisms have been proposed for the widely-used cancer chemotherapeutic drugs taxotere (docetaxel) and taxol (paclitaxel), but none has been definitively identified. We analyzed their effects at a range of concentrations on migration and mitosis of human umbilical vein endothelial cells (HUVECs) on microtubule and focal adhesion morphology and microtubule dynamic instability during migration. Both taxanes inhibited migration by inhibiting both maintenance of the forward direction of the cell and by slowing migration over the entire contorted path length. At low (but not all) taxane concentrations that inhibit HUVEC migration, the shortening rates and shortening lengths of microtubules at the leading edge were strongly inhibited; peripheral microtubules were reduced in number and fewer targeted focal adhesions; focal adhesions doubled in length and became ring-shaped, elongate, and reduced in number; and an increase in stabilized microtubules occurred centrally. HUVEC migration was 13-19 fold more sensitive to taxanes than was mitosis confirming that taxanes exhibit significant effects in addition to mitotic arrest that may contribute to their overall antitumor effects. No relationship was detected between centrosome position and migration characteristics. The data suggest that taxanes inhibit migration, at least in part, by inhibiting the dynamic instability of microtubules that possibly interact with guanine nucleotide exchange factors and thus with the focal adhesion-associated G-proteins that then lead to disruption of the regulated formation and turnover of focal adhesions. A mechanism is presented by which subcytotoxic concentrations of taxanes might stabilize dynamic instability of a few microtubules and thereby inhibit migration and angiogenesis. PMID- 24155272 TI - Molecular self-assembly on graphene. AB - The formation of ordered arrays of molecules via self-assembly is a rapid, scalable route towards the realization of nanoscale architectures with tailored properties. In recent years, graphene has emerged as an appealing substrate for molecular self-assembly in two dimensions. Here, the first five years of progress in supramolecular organization on graphene are reviewed. The self-assembly process can vary depending on the type of graphene employed: epitaxial graphene, grown in situ on a metal surface, and non-epitaxial graphene, transferred onto an arbitrary substrate, can have different effects on the final structure. On epitaxial graphene, the process is sensitive to the interaction between the graphene and the substrate on which it is grown. In the case of graphene that strongly interacts with its substrate, such as graphene/Ru(0001), the inhomogeneous adsorption landscape of the graphene moire superlattice provides a unique opportunity for guiding molecular organization, since molecules experience spatially constrained diffusion and adsorption. On weaker-interacting epitaxial graphene films, and on non-epitaxial graphene transferred onto a host substrate, self-assembly leads to films similar to those obtained on graphite surfaces. The efficacy of a graphene layer for facilitating planar adsorption of aromatic molecules has been repeatedly demonstrated, indicating that it can be used to direct molecular adsorption, and therefore carrier transport, in a certain orientation, and suggesting that the use of transferred graphene may allow for predictible molecular self-assembly on a wide range of surfaces. PMID- 24155273 TI - Substance P as a neuronal factor in the enteric nervous system of the porcine descending colon in physiological conditions and during selected pathogenic processes. AB - The present investigation pertains to changes in substance P-like immunoreactive (SP-LI) nerve structures of the enteric nervous system (ENS) in the porcine descending colon, caused by chemically-induced inflammation and nerve injury (axotomy). The distribution pattern of SP-LI structures was studied using the double immunofluorescence technique in the myenteric (MP), outer submucous (OSP) and inner submucous (ISP) plexuses, as well as in the circular muscle and mucosal layers. Under physiological conditions, SP-LI neurons have been shown to constitute 4.13 +/- 0.24%, 3.36 +/- 0.26%, and 7.92 +/- 0.16% in the MP, OSP, and ISP, respectively. Changes in SP-immunoreactivity depended on the pathological factor studied. The numbers of the SP-LI perikarya amounted to 7.89 +/- 0.34, 5.56 +/- 0.30, and 19.96 +/- 0.57 in chemically-induced colitis, and 4.28 +/- 0.13%, 7.18 +/- 20%, and 11.62 +/- 0.48% after axotomy in MP, OSP, and ISP, respectively. The both studied processes generally resulted in an increase in the number of SP-LI nerve fibers in the circular muscle and mucosal layers. The obtained results suggest that SP-LI nerve structures of the ENS may participate in various pathological processes in the porcine descending colon and exact functions of SP probably depend on the type of the pathological factor. PMID- 24155275 TI - Rapid ex vivo imaging of PAIII prostate to bone tumor with SWIFT-MRI. AB - PURPOSE: The limiting factor for MRI of skeletal/mineralized tissue is fast transverse relaxation. A recent advancement in MRI technology, SWIFT (Sweep Imaging with Fourier Transform), is emerging as a new approach to overcome this difficulty. Among other techniques like UTE, ZTE, and WASPI, the application of SWIFT technology has the strong potential to impact preclinical and clinical imaging, particularly in the context of primary or metastatic bone cancers because it has the added advantage of imaging water in mineralized tissues of bone allowing MRI images to be obtained of tissues previously visible only with modalities such as computed tomography (CT). The goal of the current study is to examine the feasibility of SWIFT for the assessment of the prostate cancer induced changes in bone formation (osteogenesis) and destruction (osteolysis) in ex vivo specimens. METHODS: A luciferase expressing prostate cancer cell line (PAIII) or saline control was inoculated directly into the tibia of 6-week-old immunocompromised male mice. Tumor growth was assessed weekly for 3 weeks before euthanasia and dissection of the tumor bearing and sham tibias. The ex vivo mouse tibia specimens were imaged with a 9.4 Tesla (T) and 7T MRI systems. SWIFT images are compared with traditional gradient-echo and spin-echo MRI images as well as CT and histological sections. RESULTS: SWIFT images with nominal resolution of 78 MUm are obtained with the tumor and different bone structures identified. Prostate cancer induced changes in the bone microstructure are visible in SWIFT images, which is supported by spin-echo, high resolution CT and histological analysis. CONCLUSION: SWIFT MRI is capable of high-quality high-resolution ex vivo imaging of bone tumor and surrounding bone and soft tissues. Furthermore, SWIFT MRI shows promise for in vivo bone tumor imaging, with the added benefits of nonexposure to ionizing radiation, quietness, and speed. PMID- 24155276 TI - Invasion and genome reproduction of the trophoblast cells of placenta junctional zone in the field vole, Microtus rossiaemeridionalis. AB - In the field vole Microtus rossiaemeridionalis, like in other rodents, invasive secondary giant trophoblast cells (SGTC) form a continuous layer at the foeto maternal interface in the beginning of placentation. However, in the field vole, at midgestation, clusters of junctional zone (JZ) trophoblast non-giant cells interrupt SGTC layer and progressively replace SGTC at the border of decidua basalis. As a result, 'border' cells form a continuous stratum of cytokeratin positive glycogen-rich cells at the foeto-maternal interface. SGTC plunge into JZ and line the lacunae with maternal blood. SGTC are bound by their highly cytokeratin-positive sprouts forming a framework that holds other trophoblast cell populations. According to DNA cytophotometry, the 'border' cells show the highest ploidy among the JZ cells (up to 46% of 8c cells). Thus, in M. rossiaemeridionalis the role of barrier between semiallogenic foetal and maternal tissues is shifted from the highly endopolyploid (32c-1024c) SGTC to the specific subpopulation of glycogen-rich non-giant (2c-16c) 'border' trophoblast cells that, however, exceed the ploidy of the deeply located and/or proliferative JZ trophoblast cells. PMID- 24155277 TI - Quantification of human lung structure and physiology using hyperpolarized 129Xe. AB - PURPOSE: To present in vivo, human validation of a previously proposed method to measure key pulmonary parameters related to lung microstructure and physiology. Some parameters, such as blood-air barrier thickness, cannot be measured readily by any other noninvasive modality. METHODS: Healthy volunteers (n = 12) were studied in 1.5T and 3T whole body human scanners using hyperpolarized xenon. Xenon uptake by lung parenchyma and blood was measured using a chemical shift saturation recovery sequence. Both dissolved-xenon peaks at 197 ppm and 217-218 ppm were fitted against a model of xenon exchange (MOXE) as functions of exchange time. Parameters related to lung function and structure can be obtained by fitting to this model. RESULTS: The following results were obtained from xenon uptake (averaged over all healthy volunteers): surface-area-to-volume ratio = 210 +/- 50 cm(-1) ; total septal wall thickness = 9.2 +/- 6.5 MUm; blood-air barrier thickness = 1.0 +/- 0.3 MUm; hematocrit = 27 +/- 4%; pulmonary capillary blood transit time = 1.3 +/- 0.3 s, in good agreement with literature values from invasive experiments. More detailed fitting results are listed in the text. CONCLUSION: The initial in vivo human results demonstrate that our proposed methods can be used to noninvasively determine lung physiology by simultaneous quantification of a few important pulmonary parameters. This method is highly promising to become a versatile screening method for lung diseases. PMID- 24155281 TI - Informative reporting of systematic reviews in radiology. PMID- 24155282 TI - Empathy's vital role in putting patients first. PMID- 24155283 TI - Imaging in anterior glenohumeral instability. AB - In the shoulder, the advantages of range of motion are traded for the disadvantages of vulnerability to injury and the development of instability. Glenohumeral instability encompasses a broad spectrum of clinical complaints and presentations. The diagnosis can be obvious or entirely unsuspected. Imaging findings depend on numerous factors and range from gross osseous defects to equivocal labral abnormalities and undetectable capsular lesions. This review focuses on the imaging findings in three distinct clinical scenarios: acute first time shoulder dislocation, chronic instability with repeated dislocation, and chronic instability without repeated dislocation. The biomechanics of dislocation and the pathophysiology of labral-ligamentous injury are discussed. The authors distinguish the findings that occur in the acutely traumatized shoulder from those that typify the chronic unstable joint. The roles of different imaging modalities are also distinguished, including magnetic resonance arthrography and the value of specialized imaging positions. The goal of imaging depends on the clinical scenario. Image interpretation and reporting may need to emphasize diagnosis and the identification of lesions that are associated with instability or the characterization of lesions for treatment planning. PMID- 24155285 TI - Case 199: Aggressive angiomyolipoma with renal vein thrombosis and pulmonary fat embolus. PMID- 24155286 TI - Optimal timing of the delayed phase in dynamic contrast-enhanced imaging of the liver. PMID- 24155287 TI - Reproducibility of dynamic contrast-enhanced MR imaging. PMID- 24155288 TI - Adenocarcinoma of the esophagogastric junction: how to measure the tumor volume? PMID- 24155289 TI - Anxiety and depression in patients with liver cirrhosis. PMID- 24155290 TI - Increase in creatinine for the prediction of contrast-induced nephropathy. PMID- 24155291 TI - Follicle development, endocrine profiles and ovulation rate in adult Merino ewes: effects of early nutrition (pre- and post-natal) and supplementation with lupin grain. AB - In adult ewes, we tested whether ovarian function, including the response to short-term supplementation, was affected by the nutrition of their mothers during the pre-/post-natal period. A 2*2 factorial design was used with nutrition in early life (low or high) and a 6-day supplement (with or without) as factors. All ewes received three prostaglandin (PG) injections 7 days apart, and the supplement (lupin grain) was fed for 6 days from 2 days after the second until the third PG injection. We measured reproductive and metabolic hormones, studied follicle dynamics (ultrasonography), and evaluated granulosa cell numbers, aromatase activity and oestradiol (E2) concentrations in follicular fluid in healthy follicles at days 3 and 7 of supplementation. Ovulation rate was increased by 25% by exposure to high pre-/post-natal nutrition (1.5 vs 1.2; P<0.05), in association with a small decrease in FSH concentrations (P=0.06) and a small increase in insulin concentrations (P=0.07). The number of healthy antral follicles was not affected. Acute supplementation increased the number of granulosa cells (3.7+/-0.2 vs 3.0+/-0.2 million; P<0.05) in the largest follicle, and the circulating concentrations of E2 (4.6+/-0.3 vs 3.9+/-0.3 pmol/l; P<0.05) and glucose (3.4+/-0.03 vs 3.3+/-0.03 mmol/l; P<0.01). Both early life nutrition and acute supplementation appear to affect ovulation rate through changes in glucose-insulin homoeostasis that alter follicular responsiveness to FSH and therefore E2-FSH balance. PMID- 24155292 TI - Dopamine D4 receptor excitation of lateral habenula neurons via multiple cellular mechanisms. AB - Glutamatergic lateral habenula (LHb) output communicates negative motivational valence to ventral tegmental area (VTA) dopamine (DA) neurons via activation of the rostromedial tegmental nucleus (RMTg). However, the LHb also receives a poorly understood DA input from the VTA, which we hypothesized constitutes an important feedback loop regulating DA responses to stimuli. Using whole-cell electrophysiology in rat brain slices, we find that DA initiates a depolarizing inward current (I(DAi)) and increases spontaneous firing in 32% of LHb neurons. I(DAi) was also observed upon application of amphetamine or the DA uptake blockers cocaine or GBR12935, indicating involvement of endogenous DA. I(DAi) was blocked by D4 receptor (D4R) antagonists (L745,870 or L741,742), and mimicked by a selective D4R agonist (A412997). I(DAi) was associated with increased whole cell conductance and was blocked by Cs+ or a selective blocker of hyperpolarization-activated cyclic nucleotide-gated (HCN) ion channel, ZD7288. I(DAi) was also associated with a depolarizing shift in half-activation voltage for the hyperpolarization-activated cation current (Ih) mediated by HCN channels. Recordings from LHb neurons containing fluorescent retrograde tracers revealed that I(DAi) was observed only in cells projecting to the RMTg and not the VTA. In parallel with direct depolarization, DA also strongly increased synaptic glutamate release and reduced synaptic GABA release onto LHb cells. These results demonstrate that DA can excite glutamatergic LHb output to RMTg via multiple cellular mechanisms. Since the RMTg strongly inhibits midbrain DA neurons, activation of LHb output to RMTg by DA represents a negative feedback loop that may dampen DA neuron output following activation. PMID- 24155293 TI - The infralimbic cortex bidirectionally modulates mesolimbic dopamine neuron activity via distinct neural pathways. AB - The ventral tegmental area (VTA) has been implicated in a number of psychiatric disorders, including schizophrenia, depression, and bipolar disorder. One major regulator of the mesolimbic dopaminergic system is the medial prefrontal cortex (mPFC), which makes direct and indirect connections to the hippocampus and amygdala, as well as directly to the VTA. The mPFC is comprised of two subregions: the infralimbic and prelimbic cortices (ilPFC and plPFC). However, the specific roles of these subregions in regulating VTA dopamine activity have remained unclear. In this study, we aim to clarify this role and to examine the divergent neuranatomical circuits by which the mPFC regulates VTA activity. Using in vivo extracellular recordings in rats, we tested the effects of pharmacological activation (with NMDA) and inactivation (with TTX) of the ilPFC and plPFC on dopamine neuron activity, and tested the roles of the ventral subiculum (vSub) and basolateral amygdala in this process. We found that the ilPFC exerts a bidirectional control of VTA dopamine neurons, which are differentially modulated through the vSub and the basolateral amygdala. Specifically, activation or inactivation of the ilPFC attenuated or activated dopamine neuron population activity, respectively. Furthermore, dopamine activation depended on the ventral hippocampus and inactivation on the amygdala. In contrast, only inactivation of the plPFC altered dopamine neuron activity. These data indicate that the mPFC has the ability to uniquely fine-tune dopaminergic activity in the VTA. Furthermore, the data presented here suggest that the ilPFC may have a role in the pathophysiology of psychiatric disorders. PMID- 24155294 TI - Stereotypical alterations in cortical patterning are associated with maternal illness-induced placental dysfunction. AB - We have previously shown in mice that cytokine-mediated damage to the placenta can temporarily limit the flow of nutrients and oxygen to the fetus. The placental vulnerability is pronounced before embryonic day 11, when even mild immune challenge results in fetal loss. As gestation progresses, the placenta becomes increasingly resilient to maternal inflammation, but there is a narrow window in gestation when the placenta is still vulnerable to immune challenge yet resistant enough to allow for fetal survival. This gestational window correlates with early cortical neurogenesis in the fetal brain. Here, we show that maternal illness during this period selectively alters the abundance and laminar positioning of neuronal subtypes influenced by the Tbr1, Satb2, and Ctip2/Fezf2 patterning axis. The disturbances also lead to a laminar imbalance in the proportions of projection neurons and interneurons in the adult and are sufficient to cause changes in social behavior and cognition. These data illustrate how the timing of an illness-related placental vulnerability causes developmental alterations in neuroanatomical systems and behaviors that are relevant to autism spectrum disorders. PMID- 24155295 TI - The impact of dopamine on aggression: an [18F]-FDOPA PET Study in healthy males. AB - Cerebral dopamine (DA) transmission is thought to be an important modulator for the development and occurrence of aggressive behavior. However, the link between aggression and DA transmission in humans has not been investigated using molecular imaging and standardized behavioral tasks. We investigated aggression as a function of DA transmission in a group of (N = 21) healthy male volunteers undergoing 6-[18F]-fluoro-L-DOPA (FDOPA)-positron emission tomography (PET) and a modified version of the Point Subtraction Aggression Paradigm (PSAP). This task measures aggressive behavior during a monetary reward-related paradigm, where a putative adversary habitually tries to cheat. The participant can react in three ways (i.e., money substraction of the putative opponent [aggressive punishment], pressing a defense button, or continuing his money-making behavior). FDOPA-PET was analyzed using a steady-state model yielding estimates of the DA-synthesis capacity (K), the turnover of tracer DA formed in living brain (kloss), and the tracer distribution volume (Vd), which is an index of DA storage capacity. Significant negative correlations between PSAP aggressive responses and the DA synthesis capacity were present in several regions, most prominently in the midbrain (r = -0.640; p = 0.002). Lower degrees of aggressive responses were associated with higher DA storage capacity in the striatum and midbrain. Additionally, there was a significant positive correlation between the investment into monetary incentive responses on the PSAP and DA-synthesis capacity, notably in the midbrain (r = +0.618, p = 0.003). The results suggest that individuals with low DA transmission capacity are more vulnerable to reactive/impulsive aggression in response to provocation. PMID- 24155297 TI - Perceived size change induced by nonvisual signals in darkness: the relative contribution of vergence and proprioception. AB - Most of the time, the human visual system computes perceived size by scaling the size of an object on the retina with its perceived distance. There are instances, however, in which size-distance scaling is not based on visual inputs but on extraretinal cues. In the Taylor illusion, the perceived afterimage that is projected on an observer's hand will change in size depending on how far the limb is positioned from the eyes-even in complete darkness. In the dark, distance cues might derive from hand position signals either by an efference copy of the motor command to the moving hand or by proprioceptive input. Alternatively, there have been reports that vergence signals from the eyes might also be important. We performed a series of behavioral and eye-tracking experiments to tease apart how these different sources of distance information contribute to the Taylor illusion. We demonstrate that, with no visual information, perceived size changes mainly as a function of the vergence angle of the eyes, underscoring its importance in size-distance scaling. Interestingly, the strength of this relationship decreased when a mismatch between vergence and proprioception was introduced, indicating that proprioceptive feedback from the arm also affected size perception. By using afterimages, we provide strong evidence that the human visual system can benefit from sensory signals that originate from the hand when visual information about distance is unavailable. PMID- 24155296 TI - Soluble guanylate cyclase generation of cGMP regulates migration of MGE neurons. AB - Here we have provided evidence that nitric oxide-cyclic GMP (NO-cGMP) signaling regulates neurite length and migration of immature neurons derived from the medial ganglionic eminence (MGE). Dlx1/2(-/-) and Lhx6(-/-) mouse mutants, which exhibit MGE interneuron migration defects, have reduced expression of the gene encoding the alpha subunit of a soluble guanylate cyclase (Gucy1A3). Furthermore, Dlx1/2(-/-) mouse mutants have reduced expression of NO synthase 1 (NOS1). Gucy1A3(-/-) mice have a transient reduction in cortical interneuron number. Pharmacological inhibition of soluble guanylate cyclase and NOS activity rapidly induces neurite retraction of MGE cells in vitro and in slice culture and robustly inhibits cell migration from the MGE and caudal ganglionic eminence. We provide evidence that these cellular phenotypes are mediated by activation of the Rho signaling pathway and inhibition of myosin light chain phosphatase activity. PMID- 24155298 TI - Activation of axonal receptors by GABA spillover increases somatic firing. AB - Axons can be depolarized by ionotropic receptors and transmit subthreshold depolarizations to the soma by passive electrical spread. This raises the possibility that axons and axonal receptors can participate in integration and firing in neurons. Previously, we have shown that exogenous GABA depolarizes cerebellar granule cell axons through local activation of GABA(A) receptors (GABA(A)Rs) and the soma through electrotonic spread of the axonal potential resulting in increased firing. We show here that excitability of granule cells is also increased by release of endogenous GABA from molecular layer interneurons (MLIs) and spillover activation of parallel fiber GABA(A)Rs in mice and rats. Changes in granule cell excitability were assessed by excitability testing after activation of MLIs with channelrhodopsin or electrical stimulation in the molecular layer. In granule cells lacking an axon, excitability was not changed, suggesting that axonal receptors are required. To determine the distance over which subthreshold potentials may spread, we estimated the effective axonal electrical length constant (520 MUm) by excitability testing and focal uncaging of RuBi-GABA on the axon at varying distances from the soma. These data suggest that GABA(A)R-mediated axonal potentials can participate in integration and firing of cerebellar granule cells. PMID- 24155299 TI - Regulator of calcineurin 1 modulates expression of innate anxiety and anxiogenic responses to selective serotonin reuptake inhibitor treatment. AB - Regulator of calcineurin 1 (RCAN1) controls the activity of calcium/calmodulin dependent phosphatase calcineurin (CaN), which has been implicated in human anxiety disorders. Previously, we reported that RCAN1 functioned as an inhibitor of CaN activity in the brain. However, we now find enhanced phosphorylation of a CaN substrate, cAMP response element-binding protein (CREB), in the brains of Rcan1 knock-out (KO) mice. Consistent with enhanced CREB activation, we also observe enhanced expression of a CREB transcriptional target, brain-derived neurotrophic factor (BDNF) in Rcan1 KO mice. We also discovered that RCAN1 deletion or blockade of RCAN1-CaN interaction reduced CaN and protein phosphatase 1 localization to nuclear-enriched protein fractions and promoted CREB activation. Because of the potential links between CREB, BDNF, and anxiety, we examined the role of RCAN1 in the expression of innate anxiety. Rcan1 KO mice displayed reduced anxiety in several tests of unconditioned anxiety. Acute pharmacological inhibition of CaN rescued these deficits while transgenic overexpression of human RCAN1 increased anxiety. Finally, we found that Rcan1 KO mice lacked the early anxiogenic response to the selective serotonin reuptake inhibitor (SSRI) fluoxetine and had improved latency for its therapeutic anxiolytic effects. Together, our study suggests that RCAN1 plays an important role in the expression of anxiety-related and SSRI-related behaviors through CaN dependent signaling pathways. These results identify RCAN1 as a mediator of innate emotional states and possible therapeutic target for anxiety. PMID- 24155301 TI - Affective modulation of cognitive control is determined by performance contingency and mediated by ventromedial prefrontal and cingulate cortex. AB - Cognitive control requires a fine balance between stability, the protection of an on-going task-set, and flexibility, the ability to update a task-set in line with changing contingencies. It is thought that emotional processing modulates this balance, but results have been equivocal regarding the direction of this modulation. Here, we tested the hypothesis that a crucial determinant of this modulation is whether affective stimuli represent performance-contingent or task irrelevant signals. Combining functional magnetic resonance imaging with a conflict task-switching paradigm, we contrasted the effects of presenting negative- and positive-valence pictures on the stability/flexibility trade-off in humans, depending on whether picture presentation was contingent on behavioral performance. Both the behavioral and neural expressions of cognitive control were modulated by stimulus valence and performance contingency: in the performance contingent condition, cognitive flexibility was enhanced following positive pictures, whereas in the nonperformance-contingent condition, positive stimuli promoted cognitive stability. The imaging data showed that, as anticipated, the stability/flexibility trade-off per se was reflected in differential recruitment of dorsolateral frontoparietal and striatal regions. In contrast, the affective modulation of stability/flexibility shifts was mirrored, unexpectedly, by neural responses in ventromedial prefrontal and posterior cingulate cortices, core nodes of the "default mode" network. Our results demonstrate that the affective modulation of cognitive control depends on the performance contingency of the affect-inducing stimuli, and they document medial default mode regions to mediate the flexibility-promoting effects of performance-contingent positive affect, thus extending recent work that recasts these regions as serving a key role in on-task control processes. PMID- 24155300 TI - NMDA receptor activation and calpain contribute to disruption of dendritic spines by the stress neuropeptide CRH. AB - The complex effects of stress on learning and memory are mediated, in part, by stress-induced changes in the composition and structure of excitatory synapses. In the hippocampus, the effects of stress involve several factors including glucocorticoids and the stress-released neuropeptide corticotropin-releasing hormone (CRH), which influence the integrity of dendritic spines and the structure and function of the excitatory synapses they carry. CRH, at nanomolar, presumed-stress levels, rapidly abolishes short-term synaptic plasticity and destroys dendritic spines, yet the mechanisms for these effects are not fully understood. Here we tested the hypothesis that glutamate receptor-mediated processes, which shape synaptic structure and function, are engaged by CRH and contribute to spine destabilization. In cultured rat hippocampal neurons, CRH application reduced dendritic spine density in a time- and dose-dependent manner, and this action depended on the CRH receptor type 1. CRH-mediated spine loss required network activity and the activation of NMDA, but not of AMPA receptors; indeed GluR1-containing dendritic spines were resistant to CRH. Downstream of NMDA receptors, the calcium-dependent enzyme, calpain, was recruited, resulting in the breakdown of spine actin-interacting proteins including spectrin. Pharmacological approaches demonstrated that calpain recruitment contributed critically to CRH-induced spine loss. In conclusion, the stress hormone CRH co opts mechanisms that contribute to the plasticity and integrity of excitatory synapses, leading to selective loss of dendritic spines. This spine loss might function as an adaptive mechanism preventing the consequences of adverse memories associated with severe stress. PMID- 24155302 TI - Nonlinear dynamics support a linear population code in a retinal target-tracking circuit. AB - A basic task faced by the visual system of many organisms is to accurately track the position of moving prey. The retina is the first stage in the processing of such stimuli; the nature of the transformation here, from photons to spike trains, constrains not only the ultimate fidelity of the tracking signal but also the ease with which it can be extracted by other brain regions. Here we demonstrate that a population of fast-OFF ganglion cells in the salamander retina, whose dynamics are governed by a nonlinear circuit, serve to compute the future position of the target over hundreds of milliseconds. The extrapolated position of the target is not found by stimulus reconstruction but is instead computed by a weighted sum of ganglion cell outputs, the population vector average (PVA). The magnitude of PVA extrapolation varies systematically with target size, speed, and acceleration, such that large targets are tracked most accurately at high speeds, and small targets at low speeds, just as is seen in the motion of real prey. Tracking precision reaches the resolution of single photoreceptors, and the PVA algorithm performs more robustly than several alternative algorithms. If the salamander brain uses the fast-OFF cell circuit for target extrapolation as we suggest, the circuit dynamics should leave a microstructure on the behavior that may be measured in future experiments. Our analysis highlights the utility of simple computations that, while not globally optimal, are efficiently implemented and have close to optimal performance over a limited but ethologically relevant range of stimuli. PMID- 24155303 TI - Slower rate of binocular rivalry in autism. AB - An imbalance between cortical excitation and inhibition is a central component of many models of autistic neurobiology. We tested a potential behavioral footprint of this proposed imbalance using binocular rivalry, a visual phenomenon in which perceptual experience is thought to mirror the push and pull of excitatory and inhibitory cortical dynamics. In binocular rivalry, two monocularly presented images compete, leading to a percept that alternates between them. In a series of trials, we presented separate images of objects (e.g., a baseball and a broccoli) to each eye using a mirror stereoscope and asked human participants with autism and matched control subjects to continuously report which object they perceived, or whether they perceived a mixed percept. Individuals with autism demonstrated a slower rate of binocular rivalry alternations than matched control subjects, with longer durations of mixed percepts and an increased likelihood to revert to the previously perceived object when exiting a mixed percept. Critically, each of these findings was highly predictive of clinical measures of autistic symptomatology. Control "playback" experiments demonstrated that differences in neither response latencies nor response criteria could account for the atypical dynamics of binocular rivalry we observed in autistic spectrum conditions. Overall, these results may provide an index of atypical cortical dynamics that may underlie both the social and nonsocial symptoms of autism. PMID- 24155304 TI - Topographic representation of an occluded object and the effects of spatiotemporal context in human early visual areas. AB - Occlusion is a primary challenge facing the visual system in perceiving object shapes in intricate natural scenes. Although behavior, neurophysiological, and modeling studies have shown that occluded portions of objects may be completed at the early stage of visual processing, we have little knowledge on how and where in the human brain the completion is realized. Here, we provide functional magnetic resonance imaging (fMRI) evidence that the occluded portion of an object is indeed represented topographically in human V1 and V2. Specifically, we find the topographic cortical responses corresponding to the invisible object rotation in V1 and V2. Furthermore, by investigating neural responses for the occluded target rotation within precisely defined cortical subregions, we could dissociate the topographic neural representation of the occluded portion from other types of neural processing such as object edge processing. We further demonstrate that the early topographic representation in V1 can be modulated by prior knowledge of a whole appearance of an object obtained before partial occlusion. These findings suggest that primary "visual" area V1 has the ability to process not only visible or virtually (illusorily) perceived objects but also "invisible" portions of objects without concurrent visual sensation such as luminance enhancement to these portions. The results also suggest that low-level image features and higher preceding cognitive context are integrated into a unified topographic representation of occluded portion in early areas. PMID- 24155305 TI - Deletion of CPEB3 enhances hippocampus-dependent memory via increasing expressions of PSD95 and NMDA receptors. AB - Long-term memory requires activity-dependent synthesis of plasticity-related proteins (PRPs) to strengthen synaptic efficacy and consequently consolidate memory. Cytoplasmic polyadenylation element binding protein (CPEB)3 is a sequence specific RNA-binding protein that regulates translation of several PRP RNAs in neurons. To understand whether CPEB3 plays a part in learning and memory, we generated CPEB3 knock-out (KO) mice and found that the null mice exhibited enhanced hippocampus-dependent, short-term fear memory in the contextual fear conditioning test and long-term spatial memory in the Morris water maze. The basal synaptic transmission of Schaffer collateral-CA1 neurons was normal but long-term depression evoked by paired-pulse low-frequency stimulation was modestly facilitated in the juvenile KO mice. Molecular and cellular characterizations revealed several molecules in regulating plasticity of glutamatergic synapses are translationally elevated in the CPEB3 KO neurons, including the scaffolding protein PSD95 and the NMDA receptors along with the known CPEB3 target, GluA1. Together, CPEB3 functions as a negative regulator to confine the strength of glutamatergic synapses by downregulating the expression of multiple PRPs and plays a role underlying certain forms of hippocampus dependent memories. PMID- 24155306 TI - Alpha 2B adrenoceptor genotype moderates effect of reboxetine on negative emotional memory bias in healthy volunteers. AB - Evidence suggests that emotional memory plays a role in the pathophysiology of depression/anxiety disorders. Noradrenaline crucially modulates emotional memory. Genetic variants involved in noradrenergic signaling contribute to individual differences in emotional memory and vulnerability to psychopathology. A functional deletion polymorphism in the alpha-2B adrenoceptor gene (ADRA2B) has been linked to emotional memory and post-traumatic stress disorder. The noradrenaline reuptake inhibitor reboxetine attenuates enhanced memory for negative stimuli in healthy and depressed individuals. We examined whether the effect of reboxetine on emotional memory in healthy individuals would be moderated by ADRA2B genotype. ADRA2B deletion carriers demonstrated enhanced emotional memory for negative stimuli compared with deletion noncarriers, consistent with prior studies. Reboxetine attenuated enhanced memory for negative stimuli in deletion noncarriers but had no significant effect in deletion carriers. This is the first demonstration of genetic variation influencing antidepressant drug effects on emotional processing in healthy humans. PMID- 24155307 TI - Local generation and propagation of ripples along the septotemporal axis of the hippocampus. AB - A topographical relationship exists between the septotemporal segments of the hippocampus and their entorhinal-neocortical targets, but the physiological organization of activity along the septotemporal axis is poorly understood. We recorded sharp-wave ripple patterns in rats during sleep from the entire septotemporal axis of the CA1 pyramidal layer. Qualitatively similar ripples emerged at all levels. From the local seed, ripples traveled septally or temporally at a speed of ~0.35 m/s, and the spatial spread depended on ripple magnitude. Ripples propagated smoothly across the septal and intermediate segments of the hippocampus, but ripples in the temporal segment often remained isolated. These findings show that ripples can combine information from the septal and intermediate hippocampus and transfer integrated signals downstream. In contrast, ripples that emerged in the temporal pole broadcast largely independent information to their cortical and subcortical targets. PMID- 24155308 TI - Mitochondrial alterations near amyloid plaques in an Alzheimer's disease mouse model. AB - While accumulation of amyloid-beta (Abeta) deposited as senile plaques is a hallmark feature of Alzheimer's disease (AD), the neurotoxicity of these deposits remains controversial. Recent in vitro studies suggested a link between elevated Abeta and mitochondrial dysfunction that might contribute to the pathogenesis of AD. However, the in vivo evidence for mitochondria dysfunction caused by Abeta is still missing. Using intravital multiphoton imaging with a range of fluorescent markers, we systematically surveyed mitochondrial structural and functional changes in AD mouse models. We observed severe impairments to be limited to the vicinity of Abeta plaques, which included reduction of both numbers and membrane potential of mitochondria and the emergence of dystrophic and fragmented mitochondria. Both neuronal soma and neurites with oxidative stress show severe alterations in mitochondrial membrane potential in amyloid precursor protein mice. These results provide in vivo evidence revealing Abeta plaques as focal sources of toxicity that lead to severe structural and functional abnormalities in mitochondria. These alterations may contribute to neuronal network dysfunction and warrant further investigation as possible targets for therapeutic intervention in AD. PMID- 24155309 TI - Ordinality and the nature of symbolic numbers. AB - The view that representations of symbolic and nonsymbolic numbers are closely tied to one another is widespread. However, the link between symbolic and nonsymbolic numbers is almost always inferred from cardinal processing tasks. In the current work, we show that considering ordinality instead points to striking differences between symbolic and nonsymbolic numbers. Human behavioral and neural data show that ordinal processing of symbolic numbers (Are three Indo-Arabic numerals in numerical order?) is distinct from symbolic cardinal processing (Which of two numerals represents the greater quantity?) and nonsymbolic number processing (ordinal and cardinal judgments of dot-arrays). Behaviorally, distance effects were reversed when assessing ordinality in symbolic numbers, but canonical distance-effects were observed for cardinal judgments of symbolic numbers and all nonsymbolic judgments. At the neural level, symbolic number ordering was the only numerical task that did not show number-specific activity (greater than control) in the intraparietal sulcus. Only activity in left premotor cortex was specifically associated with symbolic number-ordering. For nonsymbolic numbers, activation in cognitive-control areas during ordinal processing and a high degree of overlap between ordinal and cardinal processing networks indicate that nonsymbolic ordinality is assessed via iterative cardinality judgments. This contrasts with a striking lack of neural overlap between ordinal and cardinal judgments anywhere in the brain for symbolic numbers, suggesting that symbolic number processing varies substantially with computational context. Ordinal processing sheds light on key differences between symbolic and nonsymbolic number processing both behaviorally and in the brain. Ordinality may prove important for understanding the power of representing numbers symbolically. PMID- 24155311 TI - Altered intrinsic neuronal interactions in the visual cortex of the blind. AB - In congenital blindness, the brain develops under severe sensory deprivation and undergoes remarkable plastic changes in both structure and function. Visually deprived occipital cortical regions are histologically and morphologically altered and exhibit a strikingly remodeled functional state: absolute levels of neural activity are heightened and are modulated by nonvisual sensory stimulation as well as higher cognitive processes. However, the neuronal mechanisms that underlie this altered functional state remain largely unknown. Here, we show that the visual cortex of the congenitally blind exhibits a characteristic gain in frequency-specific intrinsic neuronal interactions. We studied oscillatory activity in 11 congenitally blind humans and matched sighted control subjects with magnetoencephalography at rest. We found increased spontaneous correlations of delta band (1-3 Hz) and gamma band (76-128 Hz) oscillations across the visual cortex of the blind that were functionally coupled. Local delta phase modulated gamma amplitude. Furthermore, classical resting rhythms (8-20 Hz) were reduced in amplitude but showed no altered correlation pattern. Our results suggest that both decreased inhibition and circuit mechanisms that support active processing are intrinsic features underlying the altered functional state of the visual cortex in congenitally blind individuals. PMID- 24155310 TI - Lateral mobility of presynaptic alpha7-containing nicotinic receptors and its relevance for glutamate release. AB - Surface diffusion of postsynaptic receptors shapes synaptic transmission. Presynaptic receptors also influence transmission, but the relevance of their mobility for synaptic function is unknown. Using single-particle tracking with quantum dots, we show that calcium-permeable alpha7-containing nicotinic acetylcholine receptors (alpha7-nAChRs), capable of promoting transmitter release, are mobile on presynaptic terminals but constrained in synaptic space on rat hippocampal neurons in culture. Additional immobilization of presynaptic alpha7-nAChRs by antibody crosslinking increases glutamate release capacity as seen in the frequency of spontaneous miniature postsynaptic currents and the size of the readily releasable pool of transmitter. Conversely, blocking glutamate release by targeting tetanus toxin to individual synapses increases alpha7-nAChR dwell time at presynaptic sites. The effects on release require functional alpha7 nAChRs and may to depend on CAST/ELKS (calpastatin/glutamine, leucine, lysine, and serine-rich protein), which an unbiased proteomic screen yielded. The results support a new homeostatic regulatory mechanism in which alpha7-nAChR restrain may be adjusted as needed at presynaptic sites via active zone proteins to maintain transmitter release capability. PMID- 24155312 TI - Visuomotor adaptation changes stereoscopic depth perception and tactile discrimination. AB - Perceptual judgments of relative depth from binocular disparity are systematically distorted in humans, despite in principle having access to reliable 3D information. Interestingly, these distortions vanish at a natural grasping distance, as if perceived stereo depth is contingent on a specific reference distance for depth-disparity scaling that corresponds to the length of our arm. Here we show that the brain's representation of the arm indeed powerfully modulates depth perception, and that this internal calibration can be quickly updated. We used a classic visuomotor adaptation task in which subjects execute reaching movements with the visual feedback of their reaching finger displaced farther in depth, as if they had a longer arm. After adaptation, 3D perception changed dramatically, and became accurate at the "new" natural grasping distance, the updated disparity scaling reference distance. We further tested whether the rapid adaptive changes were restricted to the visual modality or were characteristic of sensory systems in general. Remarkably, we found an improvement in tactile discrimination consistent with a magnified internal image of the arm. This suggests that the brain integrates sensory signals with information about arm length, and quickly adapts to an artificially updated body structure. These adaptive processes are most likely a relic of the mechanisms needed to optimally correct for changes in size and shape of the body during ontogenesis. PMID- 24155313 TI - piezo2b regulates vertebrate light touch response. AB - The sense of touch allows an organism to detect and respond to physical environmental stimuli. Mechanosensitive proteins play a crucial role in this process by converting the mechanical cue into a biological response. Recently, the Piezo family of stretch-activated ion channels has been identified as genuine mechanosensitive proteins. We set out to determine whether any of these genes are involved in touch response during zebrafish development. In situ hybridization indicates that piezo2b is specifically expressed in a subset of neurons (Rohon Beard cells) responsible for detecting light touch. Using morpholino-mediated knockdown, we specifically targeted piezo2b and determined that it is involved in mediating touch-evoked response. PMID- 24155314 TI - Dopamine-dependent compensation maintains motor behavior in mice with developmental ablation of dopaminergic neurons. AB - The loss of dopaminergic neurons in the substantia nigra pars compacta (SNc) and consequent depletion of striatal dopamine are known to underlie the motor deficits observed in Parkinson's disease (PD). Adaptive changes in dopaminergic terminals and in postsynaptic striatal neurons can compensate for significant losses of striatal dopamine, resulting in preservation of motor behavior. In addition, compensatory changes independent of striatal dopamine have been proposed based on PD therapies that modulate nondopaminergic circuits within the basal ganglia. We used a genetic strategy to selectively destroy dopaminergic neurons in mice during development to determine the necessity of these neurons for the maintenance of normal motor behavior in adult and aged mice. We find that loss of 90% of SNc dopaminergic neurons and consequent depletion of >95% of striatal dopamine does not result in changes in motor behavior in young-adult or aged mice as evaluated by an extensive array of motor behavior tests. Treatment of aged mutant mice with the dopamine receptor antagonist haloperidol precipitated motor behavior deficits in aged mutant mice, indicating that <5% of striatal dopamine is sufficient to maintain motor function in these mice. We also found that mutant mice exhibit an exaggerated response to l-DOPA compared with control mice, suggesting that preservation of motor function involves sensitization of striatal dopamine receptors. Our results indicate that congenital loss of dopaminergic neurons induces remarkable adaptions in the nigrostriatal system where limited amounts of dopamine in the dorsal striatum can maintain normal motor function. PMID- 24155316 TI - Deciphering dead-end docking of large dense core vesicles in bovine chromaffin cells. AB - Large dense core vesicle (LDCV) exocytosis in chromaffin cells follows a well characterized process consisting of docking, priming, and fusion. Total internal reflection fluorescence microscopy (TIRFM) studies suggest that some LDCVs, although being able to dock, are resistant to calcium-triggered release. This phenomenon termed dead-end docking has not been investigated until now. We characterized dead-end vesicles using a combination of membrane capacitance measurement and visualization of LDCVs with TIRFM. Stimulation of bovine chromaffin cells for 5 min with 6 MUm free intracellular Ca2+ induced strong secretion and a large reduction of the LDCV density at the plasma membrane. Approximately 15% of the LDCVs were visible at the plasma membrane throughout experiments, indicating they were permanently docked dead-end vesicles. Overexpression of Munc18-2 or SNAP-25 reduced the fraction of dead-end vesicles. Conversely, expressing open-syntaxin increased the fraction of dead-end vesicles. These results indicate the existence of the unproductive target soluble N ethylmaleimide-sensitive factor attachment protein receptor acceptor complex composed of 2:1 syntaxin-SNAP-25 in vivo. More importantly, they define a novel function for this acceptor complex in mediating dead-end docking. PMID- 24155315 TI - Strabismus disrupts binocular synaptic integration in primary visual cortex. AB - Visual disruption early in development dramatically changes how primary visual cortex neurons integrate binocular inputs. The disruption is paradigmatic for investigating the synaptic basis of long-term changes in cortical function, because the primary visual cortex is the site of binocular convergence. The underlying alterations in circuitry by visual disruption remain poorly understood. Here we compare membrane potential responses, observed via whole-cell recordings in vivo, of primary visual cortex neurons in normal adult cats with those of cats in which strabismus was induced before the developmental critical period. In strabismic cats, we observed a dramatic shift in the ocular dominance distribution of simple cells, the first stage of visual cortical processing, toward responding to one eye instead of both, but not in complex cells, which receive inputs from simple cells. Both simple and complex cells no longer conveyed the binocular information needed for depth perception based on binocular cues. There was concomitant binocular suppression such that responses were weaker with binocular than with monocular stimulation. Our estimates of the excitatory and inhibitory input to single neurons indicate binocular suppression that was not evident in synaptic excitation, but arose de novo because of synaptic inhibition. Further constraints on circuit models of plasticity result from indications that the ratio of excitation to inhibition evoked by monocular stimulation decreased mainly for nonpreferred eye stimulation. Although we documented changes in synaptic input throughout primary visual cortex, a circuit model with plasticity at only thalamocortical synapses is sufficient to account for our observations. PMID- 24155318 TI - A scaffold for efficiency in the human brain. AB - The comprehensive relations between healthy adult human brain white matter (WM) microstructure and gray matter (GM) function, and their joint relations to cognitive performance, remain poorly understood. We investigated these associations in 27 younger and 28 older healthy adults by linking diffusion tensor imaging (DTI) with functional magnetic resonance imaging (fMRI) data collected during an n-back working memory task. We present a novel application of multivariate Partial Least Squares (PLS) analysis that permitted the simultaneous modeling of relations between WM integrity values from all major WM tracts and patterns of condition-related BOLD signal across all GM regions. Our results indicate that greater microstructural integrity of the major WM tracts was negatively related to condition-related blood oxygenation level-dependent (BOLD) signal in task-positive GM regions. This negative relationship suggests that better quality of structural connections allows for more efficient use of task related GM processing resources. Individuals with more intact WM further showed greater BOLD signal increases in typical "task-negative" regions during fixation, and notably exhibited a balanced magnitude of BOLD response across task-positive and -negative states. Structure-function relations also predicted task performance, including accuracy and speed of responding. Finally, structure function-behavior relations reflected individual differences over and above chronological age. Our findings provide evidence for the role of WM microstructure as a scaffold for the context-relevant utilization of GM regions. PMID- 24155317 TI - Partial restoration of cardiovascular function by embryonic neural stem cell grafts after complete spinal cord transection. AB - High-level spinal cord injury can lead to cardiovascular dysfunction, including disordered hemodynamics at rest and autonomic dysreflexia during noxious stimulation. To restore supraspinal control of sympathetic preganglionic neurons (SPNs), we grafted embryonic brainstem-derived neural stem cells (BS-NSCs) or spinal cord-derived neural stem cells (SC-NSCs) expressing green fluorescent protein into the T4 complete transection site of adult rats. Animals with injury alone served as controls. Implanting of BS-NSCs but not SC-NSCs resulted in recovery of basal cardiovascular parameters, whereas both cell grafts alleviated autonomic dysreflexia. Subsequent spinal cord retransection above the graft abolished the recovery of basal hemodynamics and reflexic response. BS-NSC graft derived catecholaminergic and serotonergic neurons showed remarkable long distance axon growth and topographical innervation of caudal SPNs. Anterograde tracing indicated growth of medullar axons into stem cell grafts and formation of synapses. Thus, grafted embryonic brainstem-derived neurons can act as functional relays to restore supraspinal regulation of denervated SPNs, thereby contributing to cardiovascular functional improvement. PMID- 24155319 TI - Dynamic and permissive roles of TRPV1 and TRPV4 channels for thermosensation in mouse supraoptic magnocellular neurosecretory neurons. AB - The transient receptor potential vanilloid 1 and 4 genes (trpv1, trpv4) encode temperature-sensitive cation channels hypothesized to mediate thermoresponses in mammalian cells. Although such channels were shown to participate in the peripheral detection of ambient temperature, the specific roles of these channels in central thermosensory neurons remain unclear. Here we report that the membrane potential and excitability of mouse magnocellular neurosecretory cells (MNCs) maintained at physiological temperature were lowered in an additive manner upon pharmacological blockade, or genetic deletion, of trpv1 and trpv4. However extracellular recordings from spontaneously active MNCs in situ showed that blockade or genetic deletion of trpv4 does not interfere with thermally induced changes in action potential firing, whereas loss of trpv1 abolished this phenotype. These findings indicate that channels encoded by trpv4 play a permissive role that contributes to basal electrical activity, but that trpv1 plays a dynamic role that is required for physiological thermosensation by MNCs. PMID- 24155320 TI - GABA type B receptor signaling in proopiomelanocortin neurons protects against obesity, insulin resistance, and hypothalamic inflammation in male mice on a high fat diet. AB - There is evidence suggesting that the GABA system in the arcuate nucleus, where orexigenic neuropeptide Y and agouti-related peptide as well as anorexigenic proopiomelanocortin (POMC) are expressed, plays an important role in energy balance. In this study, we generated POMC-specific GABAB receptor-deficient [knock-out (KO)] mice. Male KO mice on a high-fat diet (HFD) showed mild increases in body weight (BW) at the age of 9 weeks compared to wild-type (WT) mice, and the differences remained significant until 16 weeks old. However, there was no difference in BW in females between genotypes. While food intake was similar between genotypes, oxygen consumption was significantly decreased in the male KO mice. The insulin tolerance test revealed that the male KO mice were less insulin sensitive compared to WT mice at the age of 8 weeks, when there was no significant difference in BW between genotypes. Despite increased BW, POMC mRNA expression in the arcuate nucleus was significantly decreased in the KO mice compared to WT mice at the age of 16 weeks. Furthermore, the expression of TNFalpha as well as IL-6, proinflammatory markers in the hypothalamus, was significantly increased in the KO mice on a HFD compared to WT mice. This demonstrates that the deletion of GABAB receptors in POMC neurons in the male mice on a HFD results in obesity, insulin resistance, and hypothalamic inflammation. Furthermore, the decreased POMC expression in the obese KO mice suggests that the regulation of POMC expression through GABAB receptors is essential for proper energy balance. PMID- 24155322 TI - Spinal mitogen-activated protein kinase phosphatase-3 (MKP-3) is necessary for the normal resolution of mechanical allodynia in a mouse model of acute postoperative pain. AB - The mechanisms that drive the normal resolution of acute postoperative pain are not completely understood. We hypothesize a pivotal role of a major spinal mitogen-activated protein kinase (MAPKs) regulator, MAPK phosphatase (MKP)-3, in the resolution of postoperative pain. We used wild-type and MKP-3 knock-out (KO) mice, a paw incision model of acute postoperative pain, and behavioral and molecular biology experiments. We observed persistent mechanical allodynia in mice lacking MKP-3 (postoperative day 21), concurrently with persistent phosphorylation of spinal p38 and extracellular signal-regulated kinases (ERK) 1/2 on postoperative day 12, while both MAPK phosphorylation and allodynia resolved on postoperative day 7 in wild-type mice. Spinal p-ERK was expressed mainly in neurons and microglia, while spinal p-p38 was expressed mostly in microglia in MKP-3 KO mice, and their selective pharmacological inhibition reduced the persistent allodynia observed in these mice. Our findings strongly suggest that dysregulation of MKP-3 prevents spontaneous resolution of acute postoperative pain and drives its transition to persistent pain via persistent neuronal and microglial MAPK phosphorylation in the spinal cord. PMID- 24155321 TI - Automatic semantic facilitation in anterior temporal cortex revealed through multimodal neuroimaging. AB - A core property of human semantic processing is the rapid, facilitatory influence of prior input on extracting the meaning of what comes next, even under conditions of minimal awareness. Previous work has shown a number of neurophysiological indices of this facilitation, but the mapping between time course and localization-critical for separating automatic semantic facilitation from other mechanisms-has thus far been unclear. In the current study, we used a multimodal imaging approach to isolate early, bottom-up effects of context on semantic memory, acquiring a combination of electroencephalography (EEG), magnetoencephalography (MEG), and functional magnetic resonance imaging (fMRI) measurements in the same individuals with a masked semantic priming paradigm. Across techniques, the results provide a strikingly convergent picture of early automatic semantic facilitation. Event-related potentials demonstrated early sensitivity to semantic association between 300 and 500 ms; MEG localized the differential neural response within this time window to the left anterior temporal cortex, and fMRI localized the effect more precisely to the left anterior superior temporal gyrus, a region previously implicated in semantic associative processing. However, fMRI diverged from early EEG/MEG measures in revealing semantic enhancement effects within frontal and parietal regions, perhaps reflecting downstream attempts to consciously access the semantic features of the masked prime. Together, these results provide strong evidence that automatic associative semantic facilitation is realized as reduced activity within the left anterior superior temporal cortex between 300 and 500 ms after a word is presented, and emphasize the importance of multimodal neuroimaging approaches in distinguishing the contributions of multiple regions to semantic processing. PMID- 24155323 TI - Neural underpinnings of the identifiable victim effect: affect shifts preferences for giving. AB - The "identifiable victim effect" refers to peoples' tendency to preferentially give to identified versus anonymous victims of misfortune, and has been proposed to partly depend on affect. By soliciting charitable donations from human subjects during behavioral and neural (i.e., functional magnetic resonance imaging) experiments, we sought to determine whether and how affect might promote the identifiable victim effect. Behaviorally, subjects gave more to orphans depicted by photographs versus silhouettes, and their shift in preferences was mediated by photograph-induced feelings of positive arousal, but not negative arousal. Neurally, while photographs versus silhouettes elicited activity in widespread circuits associated with facial and affective processing, only nucleus accumbens activity predicted and could statistically account for increased donations. Together, these findings suggest that presenting evaluable identifiable information can recruit positive arousal, which then promotes giving. We propose that affect elicited by identifiable stimuli can compel people to give more to strangers, even despite costs to the self. PMID- 24155324 TI - Mechanisms underlying the rules for associative plasticity at adult human neocortical synapses. AB - The neocortex in our brain stores long-term memories by changing the strength of connections between neurons. To date, the rules and mechanisms that govern activity-induced synaptic changes at human cortical synapses are poorly understood and have not been studied directly at a cellular level. Here, we made whole-cell recordings of human pyramidal neurons in slices of brain tissue resected during neurosurgery to investigate spike timing-dependent synaptic plasticity in the adult human neocortex. We find that human cortical synapses can undergo bidirectional modifications in strength throughout adulthood. Both long term potentiation and long-term depression of synapses was dependent on postsynaptic NMDA receptors. Interestingly, we find that human cortical synapses can associate presynaptic and postsynaptic events in a wide temporal window, and that rules for synaptic plasticity in human neocortex are reversed compared with what is generally found in the rodent brain. We show this is caused by dendritic L-type voltage-gated Ca2+ channels that are prominently activated during action potential firing. Activation of these channels determines whether human synapses strengthen or weaken. These findings provide a synaptic basis for the timing rules observed in human sensory and motor plasticity in vivo, and offer insights into the physiological role of L-type voltage-gated Ca2+ channels in the human brain. PMID- 24155325 TI - Long-term potentiation of inhibitory synaptic transmission onto cerebellar Purkinje neurons contributes to adaptation of vestibulo-ocular reflex. AB - Synaptic plasticity in the cerebellum is thought to contribute to motor learning. In particular, long-term depression (LTD) at parallel fiber (PF) to Purkinje neuron (PN) excitatory synapses has attracted much attention of neuroscientists as a primary cellular mechanism for motor learning. In contrast, roles of plasticity at cerebellar inhibitory synapses in vivo remain unknown. Here, we have investigated the roles of long-lasting enhancement of transmission at GABAergic synapses on a PN that is known as rebound potentiation (RP). Previous studies demonstrated that binding of GABAA receptor with GABAA receptor associated protein (GABARAP) is required for RP, and that a peptide that blocks this binding suppresses RP induction. To address the functional roles of RP, we generated transgenic mice that express this peptide fused to a fluorescent protein selectively in PNs using the PN-specific L7 promoter. These mice failed to show RP, although they showed no changes in the basal amplitude or frequency of miniature IPSCs. The transgenic mice also showed no abnormality in gross cerebellar morphology, LTD, or other excitatory synaptic properties, or intrinsic excitability of PNs. Next, we attempted to evaluate their motor control and learning ability by examining reflex eye movements. The basal dynamic properties of the vestibulo-ocular reflex and optokinetic response, and adaptation of the latter, were normal in the transgenic mice. In contrast, the transgenic mice showed defects in the adaptation of vestibulo-ocular reflex, a model paradigm of cerebellum-dependent motor learning. These results together suggest that RP contributes to a certain type of motor learning. PMID- 24155329 TI - Lamins are rapamycin targets that impact human longevity: a study in centenarians. AB - The dynamic organisation of the cell nucleus is profoundly modified during growth, development and senescence as a result of changes in chromatin arrangement and gene transcription. A plethora of data suggests that the nuclear lamina is a key player in chromatin dynamics and argues in favour of a major involvement of prelamin A in fundamental mechanisms regulating cellular senescence and organism ageing. As the best model to analyse the role of prelamin A in normal ageing, we used cells from centenarian subjects. We show that prelamin A is accumulated in fibroblasts from centenarians owing to downregulation of its specific endoprotease ZMPSTE24, whereas other nuclear envelope constituents are mostly unaffected and cells do not enter senescence. Accumulation of prelamin A in nuclei of cells from centenarians elicits loss of heterochromatin, as well as recruitment of the inactive form of 53BP1, associated with rapid response to oxidative stress. These effects, including the prelamin-A mediated increase of nuclear 53BP1, can be reproduced by rapamycin treatment of cells from younger individuals. These data identify prelamin A and 53BP1 as new targets of rapamycin that are associated with human longevity. We propose that the reported mechanisms safeguard healthy ageing in humans through adaptation of the nuclear environment to stress stimuli. PMID- 24155330 TI - The Ski-Zeb2-Meox2 pathway provides a novel mechanism for regulation of the cardiac myofibroblast phenotype. AB - Cardiac fibrosis is linked to fibroblast-to-myofibroblast phenoconversion and proliferation but the mechanisms underlying this are poorly understood. Ski is a negative regulator of TGF-beta-Smad signaling in myofibroblasts, and might redirect the myofibroblast phenotype back to fibroblasts. Meox2 could alter TGF beta-mediated cellular processes and is repressed by Zeb2. Here, we investigated whether Ski diminishes the myofibroblast phenotype by de-repressing Meox2 expression and function through repression of Zeb2 expression. We show that expression of Meox1 and Meox2 mRNA and Meox2 protein is reduced during phenoconversion of fibroblasts to myofibroblasts. Overexpression of Meox2 shifts the myofibroblasts into fibroblasts, whereas the Meox2 DNA-binding mutant has no effect on myofibroblast phenotype. Overexpression of Ski partially restores Meox2 mRNA expression levels to those in cardiac fibroblasts. Expression of Zeb2 increased during phenoconversion and Ski overexpression reduces Zeb2 expression in first-passage myofibroblasts. Furthermore, expression of Meox2 is decreased in scar following myocardial infarction, whereas Zeb2 protein expression increases in the infarct scar. Thus Ski modulates the cardiac myofibroblast phenotype and function through suppression of Zeb2 by upregulating the expression of Meox2. This cascade might regulate cardiac myofibroblast phenotype and presents therapeutic options for treatment of cardiac fibrosis. PMID- 24155331 TI - Actin network disassembly powers dissemination of Listeria monocytogenes. AB - Several bacterial pathogens hijack the actin assembly machinery and display intracellular motility in the cytosol of infected cells. At the cell cortex, intracellular motility leads to bacterial dissemination through formation of plasma membrane protrusions that resolve into vacuoles in adjacent cells. Here, we uncover a crucial role for actin network disassembly in dissemination of Listeria monocytogenes. We found that defects in the disassembly machinery decreased the rate of actin tail turnover but did not affect the velocity of the bacteria in the cytosol. By contrast, defects in the disassembly machinery had a dramatic impact on bacterial dissemination. Our results suggest a model of L. monocytogenes dissemination in which the disassembly machinery, through local recycling of the actin network in protrusions, fuels continuous actin assembly at the bacterial pole and concurrently exhausts cytoskeleton components from the network distal to the bacterium, which enables membrane apposition and resolution of protrusions into vacuoles. PMID- 24155332 TI - S-adenosylmethionine limitation induces p38 mitogen-activated protein kinase and triggers cell cycle arrest in G1. AB - The primary methyl group donor S-adenosylmethionine (SAM) is important for a plethora of cellular pathways including methylation of nucleic acids, proteins, and the 5' cap structure of mRNAs, as well as biosynthesis of phospholipids and polyamines. In addition, because it is the cofactor for chromatin methylation, SAM is an important metabolite for the establishment and maintenance of epigenetic marks. Here, we demonstrate that cells halt proliferation when SAM levels become low. Cell cycle arrest occurs primarily in the G1 phase of the cell cycle and is accompanied by activation of the mitogen-activated protein kinase p38 (MAPK14) and subsequent phosphorylation of MAPK-activated protein kinase-2 (MK2). Surprisingly, Cdk4 activity remains high during cell cycle arrest, whereas Cdk2 activity decreases concomitantly with cyclin E levels. Cell cycle arrest was induced by both pharmacological and genetic manipulation of SAM synthesis through inhibition or downregulation of methionine adenosyltransferase, respectively. Depletion of methionine, the precursor of SAM, from the growth medium induced a similar cell cycle arrest. Unexpectedly, neither methionine depletion nor inhibition of methionine adenosyltransferase significantly affected mTORC1 activity, suggesting that the cellular response to SAM limitation is independent from this major nutrient-sensing pathway. These results demonstrate a G1 cell cycle checkpoint that responds to limiting levels of the principal cellular methyl group donor S-adenosylmethionine. This metabolic checkpoint might play important roles in maintenance of epigenetic stability and general cellular integrity. PMID- 24155345 TI - Assessment of OLED displays for vision research. AB - Vision researchers rely on visual display technology for the presentation of stimuli to human and nonhuman observers. Verifying that the desired and displayed visual patterns match along dimensions such as luminance, spectrum, and spatial and temporal frequency is an essential part of developing controlled experiments. With cathode-ray tubes (CRTs) becoming virtually unavailable on the commercial market, it is useful to determine the characteristics of newly available displays based on organic light emitting diode (OLED) panels to determine how well they may serve to produce visual stimuli. This report describes a series of measurements summarizing the properties of images displayed on two commercially available OLED displays: the Sony Trimaster EL BVM-F250 and PVM-2541. The results show that the OLED displays have large contrast ratios, wide color gamuts, and precise, well-behaved temporal responses. Correct adjustment of the settings on both models produced luminance nonlinearities that were well predicted by a power function ("gamma correction"). Both displays have adjustable pixel independence and can be set to have little to no spatial pixel interactions. OLED displays appear to be a suitable, or even preferable, option for many vision research applications. PMID- 24155346 TI - Modulation of peripheral MU-opioid analgesia by sigma1 receptors. AB - We evaluated the effects of sigma1-receptor inhibition on MU-opioid-induced mechanical antinociception and constipation. sigma1-Knockout mice exhibited marked mechanical antinociception in response to several MU-opioid analgesics (fentanyl, oxycodone, morphine, buprenorphine, and tramadol) at systemic (subcutaneous) doses that were inactive in wild-type mice and even unmasked the antinociceptive effects of the peripheral MU-opioid agonist loperamide. Likewise, systemic (subcutaneous) or local (intraplantar) treatment of wild-type mice with the selective sigma1 antagonists BD-1063 [1-[2-(3,4-dichlorophenyl)ethyl]-4 methylpiperazine dihydrochloride] or S1RA [4-[2-[[5-methyl-1-(2-naphthalenyl)1H pyrazol-3-yl]oxy]ethyl] morpholine hydrochloride] potentiated MU-opioid antinociception; these effects were fully reversed by the sigma1 agonist PRE-084 [2-(4-morpholinethyl)1-phenylcyclohexanecarboxylate) hydrochloride], showing the selectivity of the pharmacological approach. The MU-opioid antinociception potentiated by sigma1 inhibition (by sigma1-receptor knockout or sigma1 pharmacological antagonism) was more sensitive to the peripherally restricted opioid antagonist naloxone methiodide than opioid antinociception under normal conditions, indicating a key role for peripheral opioid receptors in the enhanced antinociception. Direct interaction between the opioid drugs and sigma1 receptor cannot account for our results, since the former lacked affinity for sigma1 receptors (labeled with [(3)H](+)-pentazocine). A peripheral role for sigma1 receptors was also supported by their higher density (Western blot results) in peripheral nervous tissue (dorsal root ganglia) than in several central areas involved in opioid antinociception (dorsal spinal cord, basolateral amygdala, periaqueductal gray, and rostroventral medulla). In contrast to its effects on nociception, sigma1-receptor inhibition did not alter fentanyl- or loperamide induced constipation, a peripherally mediated nonanalgesic opioid effect. Therefore, sigma1-receptor inhibition may be used as a systemic or local adjuvant to enhance peripheral MU-opioid analgesia without affecting opioid-induced constipation. PMID- 24155347 TI - Battlefield administration of tranexamic acid by combat troops: a feasibility analysis. AB - This paper suggests that 1 g tranexamic acid should be incorporated as an intramuscular auto-injector and issued to combat troops for self- or buddy administration in the event of suffering severe injury. Early administration of tranexamic acid has shown to be beneficial in preventing death from bleeding in trauma patients in both the military and the civilian settings. Tranexamic acid is cheap, safe, easy to administer and saves lives. Future conflicts may be characterised by prolonged pre-hospital times and delayed access to advanced medical care. The use of this drug is the next logical step in reducing combat trauma deaths. PMID- 24155354 TI - Editor's Commentary. PMID- 24155355 TI - The science guiding selection of an aerosol delivery device. AB - Aerosol therapy continues to be considered as one of the cornerstones of the profession of respiratory care, even after 60 years. Aerosol therapy serves as a critical intervention for both exacerbations and chronic maintenance for a variety of respiratory care conditions. Aerosol therapy uniquely blends both the art and science of medicine together to produce the practical and necessary clinical outcomes for patients with respiratory diseases. This review was presented as part of the New Horizons Symposium on how to guide the scientific selection of an appropriate aerosol device. PMID- 24155356 TI - The scientific basis for postoperative respiratory care. AB - Postoperative pulmonary complications (PPCs) are common and expensive. Costs, morbidity, and mortality are higher with PPCs than with cardiac or thromboembolic complications. Preventing and treating PPCs is a major focus of respiratory therapists, using a wide variety of techniques and devices, including incentive spirometry, CPAP, positive expiratory pressure, intrapulmonary percussive ventilation, and chest physical therapy. The scientific evidence for these techniques is lacking. CPAP has some evidence of benefit in high risk patients with hypoxemia. Incentive spirometry is used frequently, but the evidence suggests that incentive spirometry alone has no impact on PPC. Chest physical therapy, which includes mechanical clapping and postural drainage, appears to worsen atelectasis secondary to pain and splinting. As with many past respiratory therapy techniques, the profession needs to take a hard look at these techniques and work to provide only practices based on good evidence. The idea of a PPC bundle has merit and should be studied in larger, multicenter trials. Additionally, intraoperative ventilation may play a key role in the development of PPCs and should receive greater attention. PMID- 24155358 TI - Bubble CPAP: not all bubbling is good bubbling. PMID- 24155359 TI - Synchronized intermittent mandatory ventilation: time to send this workhorse out to pasture. PMID- 24155360 TI - Early tracheostomy or prolonged translaryngeal intubation in the ICU: a long running story. PMID- 24155361 TI - Neurally adjusted ventilatory assist: insufficient evidence of broad clinical outcomes. PMID- 24155362 TI - Neurally adjusted ventilatory assist: insufficient evidence of broad clinical outcomes--reply. PMID- 24155363 TI - The whisper game. PMID- 24155364 TI - The whisper game--reply. PMID- 24155365 TI - Iron deficiency in systemic sclerosis patients with and without pulmonary hypertension. AB - OBJECTIVES: SSc-associated pulmonary hypertension (SSc-PH) has a worse prognosis compared with SSc without PH (SSc-nonPH). Iron deficiency (ID) was previously associated with worse clinical outcome and survival in other types of PH, but ID effects in SSc-PH are unknown. Therefore we investigated the prevalence and clinical significance of ID in systemic sclerosis patients with and without PH. METHODS: Body iron status was determined in SSc-PH (n = 47) and SSc-nonPH patients (n = 122). ID was defined by circulating soluble transferrin receptor (sTfR) levels >28.1 nmol/l. Clinical and exercise parameters were compared between the groups. Four-year survival after iron measurements was determined. RESULTS: ID prevalence was 46.1% in SSc-PH compared with 16.4% in SSc-nonPH patients (P < 0.001). Overall hepcidin levels were high compared with reference values and related to sTfR, but not with IL-6 (P = 0.82). Six-minute walking distance and maximal achieved work at ergometry was lower in SSc-PH compared with SSc-nonPH patients (P < 0.001 and P < 0.01, respectively) and was even further reduced in case of ID (P(interaction) < 0.05). In addition, ID SSc-PH patients had a poorer survival compared with non-ID patients [hazard ratio (HR) 0.34, 95% CI 0.14, 0.82, P < 0.05) and a similar trend was observed in SSc-nonPH patients (HR 0.16, 95% CI 0.02, 1.11, P = 0.06). CONCLUSION: ID is more prevalent in SSc PH than in SSc-nonPH patients and is associated with exercise impairment in both SSc-PH and SSc-nonPH. In addition, ID SSc-PH patients have a significantly worse survival compared with non-ID patients. PMID- 24155369 TI - Powerful sequence similarity search methods and in-depth manual analyses can identify remote homologs in many apparently "orphan" viral proteins. AB - The genome sequences of new viruses often contain many "orphan" or "taxon specific" proteins apparently lacking homologs. However, because viral proteins evolve very fast, commonly used sequence similarity detection methods such as BLAST may overlook homologs. We analyzed a data set of proteins from RNA viruses characterized as "genus specific" by BLAST. More powerful methods developed recently, such as HHblits or HHpred (available through web-based, user-friendly interfaces), could detect distant homologs of a quarter of these proteins, suggesting that these methods should be used to annotate viral genomes. In-depth manual analyses of a subset of the remaining sequences, guided by contextual information such as taxonomy, gene order, or domain cooccurrence, identified distant homologs of another third. Thus, a combination of powerful automated methods and manual analyses can uncover distant homologs of many proteins thought to be orphans. We expect these methodological results to be also applicable to cellular organisms, since they generally evolve much more slowly than RNA viruses. As an application, we reanalyzed the genome of a bee pathogen, Chronic bee paralysis virus (CBPV). We could identify homologs of most of its proteins thought to be orphans; in each case, identifying homologs provided functional clues. We discovered that CBPV encodes a domain homologous to the Alphavirus methyltransferase-guanylyltransferase; a putative membrane protein, SP24, with homologs in unrelated insect viruses and insect-transmitted plant viruses having different morphologies (cileviruses, higreviruses, blunerviruses, negeviruses); and a putative virion glycoprotein, ORF2, also found in negeviruses. SP24 and ORF2 are probably major structural components of the virions. PMID- 24155370 TI - Human cytomegalovirus UL50 and UL53 recruit viral protein kinase UL97, not protein kinase C, for disruption of nuclear lamina and nuclear egress in infected cells. AB - Herpesvirus nucleocapsids traverse the nuclear envelope into the cytoplasm in a process called nuclear egress that includes disruption of the nuclear lamina. In several herpesviruses, a key player in nuclear egress is a complex of two proteins, whose homologs in human cytomegalovirus (HCMV) are UL50 and UL53. However, their roles in nuclear egress during HCMV infection have not been shown. Based largely on transfection studies, UL50 and UL53 have been proposed to facilitate disruption of the nuclear lamina by recruiting cellular protein kinase C (PKC), as occurs with certain other herpesviruses, and/or the viral protein kinase UL97 to phosphorylate lamins. To investigate these issues during HCMV infection, we generated viral mutants null for UL50 or UL53. Correlative light electron microscopic analysis of null mutant-infected cells showed the presence of intranuclear nucleocapsids and the absence of cytoplasmic nucleocapsids. Confocal immunofluorescence microscopy revealed that UL50 and UL53 are required for disruption of the nuclear lamina. A subpopulation of UL97 colocalized with the nuclear rim, and this was dependent on UL50 and, to a lesser extent, UL53. However, PKC was not recruited to the nuclear rim, and its localization was not affected by the absence of UL50 or UL53. Immunoprecipitation from cells infected with HCMV expressing tagged UL53 detected UL97 but not PKC. In summary, HCMV UL50 and UL53 are required for nuclear egress and disruption of nuclear lamina during HCMV infection, and they recruit UL97, not PKC, for these processes. Thus, despite the strong conservation of herpesvirus nuclear egress complexes, a key function can differ among them. PMID- 24155371 TI - Crystal structure of pb9, the distal tail protein of bacteriophage T5: a conserved structural motif among all siphophages. AB - The tail of Caudovirales bacteriophages serves as an adsorption device, a host cell wall-perforating machine, and a genome delivery pathway. In Siphoviridae, the assembly of the long and flexible tail is a highly cooperative and regulated process that is initiated from the proteins forming the distal tail tip complex. In Gram-positive-bacterium-infecting siphophages, the distal tail (Dit) protein has been structurally characterized and is proposed to represent a baseplate hub docking structure. It is organized as a hexameric ring that connects the tail tube and the adsorption device. In this study, we report the characterization of pb9, a tail tip protein of Escherichia coli bacteriophage T5. By immunolocalization, we show that pb9 is located in the upper part of the cone of the T5 tail tip, at the end of the tail tube. The crystal structure of pb9 reveals a two-domain protein. Domain A exhibits remarkable structural similarity with the N-terminal domain of known Dit proteins, while domain B adopts an oligosaccharide/oligonucleotide-binding fold (OB-fold) that is not shared by these proteins. We thus propose that pb9 is the Dit protein of T5, making it the first Dit protein described for a Gram-negative-bacterium-infecting siphophage. Multiple sequence alignments suggest that pb9 is a paradigm for a large family of Dit proteins of siphophages infecting mostly Gram-negative hosts. The modular structure of the Dit protein maintains the basic building block that would be conserved among all siphophages, combining it with a more divergent domain that might serve specific host adhesion properties. PMID- 24155372 TI - Minimal features of efficient incorporation of the hemagglutinin-neuraminidase protein into sendai virus particles. AB - Two transmembrane glycoproteins form spikes on the surface of Sendai virus, a member of the Respirovirus genus of the Paramyxovirinae subfamily of the Paramyxoviridae family: the hemagglutinin-neuraminidase (HN) and the fusion (F) proteins. HN, in contrast to F, is dispensable for viral particle production, as normal amounts of particles can be produced with highly reduced levels of HN. This HN reduction can result from mutation of an SYWST motif in its cytoplasmic tail to AFYKD. HNAFYKD accumulates at the infected cell surface but does not get incorporated into particles. In this work, we derived experimental tools to rescue HNAFYKD incorporation. We found that coexpression of a truncated HN harboring the wild-type cytoplasmic tail, the transmembrane domain, and at most 80 amino acids of the ectodomain was sufficient to complement defective HNAFYKD incorporation into particles. This relied on formation of disulfide-bound heterodimers carried out by the two cysteines present in the HN 80-amino-acid (aa) ectodomain. Finally, the replacement of the measles virus H cytoplasmic and transmembrane domains with the corresponding HN domains promoted measles virus H incorporation in Sendai virus particles. PMID- 24155373 TI - The D10 decapping enzyme of vaccinia virus contributes to decay of cellular and viral mRNAs and to virulence in mice. AB - Posttranscriptional mechanisms are important for regulation of cellular and viral gene expression. The presence of the 5' cap structure m(7)G(5')ppp(5')Nm is a general feature of mRNAs that provides protection from exoribonuclease digestion and enhances translation. Vaccinia virus and other poxviruses encode enzymes for both cap synthesis and decapping. Decapping is mediated by two related enzymes, D9 and D10, which are synthesized before and after viral DNA replication, respectively. The timing of D10 synthesis correlates better with the shutdown of host gene expression, and deletion of this gene has been shown to cause persistence of host and viral mRNAs in infected cells. Here, we constructed specific mutant viruses in which translation of D10 was prevented by stop codons or activity of D10 was abrogated by catalytic site mutations, without other genomic alterations. Both mutants formed plaques of normal size and replicated to similar extents as the parental virus in monkey epithelial cells and mouse embryonic fibroblasts. The synthesis of viral proteins was slightly delayed, and cellular and viral mRNAs persisted longer in cells infected with the mutants compared to either the parental virus or clonal revertant. Despite the mild effects in vitro, both mutants were more attenuated than the revertants in intranasal and intraperitoneal mouse models, and less infectious virus was recovered from organs. In addition, there was less lung histopathology following intranasal infection with mutant viruses. These data suggest that the D10 decapping enzyme may help restrict antiviral responses by accelerating host mRNA degradation during poxvirus infection. PMID- 24155374 TI - Isolation and characterization of the herpes simplex virus 1 terminase complex. AB - During herpes simplex virus 1 (HSV-1) infection, empty procapsids are assembled and subsequently filled with the viral genome by means of a protein complex called the terminase, which is comprised of the HSV-1 UL15, UL28, and UL33 proteins. Biochemical studies of the terminase proteins have been hampered by the inability to purify the intact terminase complex. In this study, terminase complexes were isolated by tandem-affinity purification (TAP) using recombinant viruses expressing either a full-length NTAP-UL28 fusion protein (vFH476) or a C terminally truncated NTAP-UL28 fusion protein (vFH499). TAP of the UL28 protein from vFH476-infected cells, followed by silver staining, Western blotting, and mass spectrometry, identified the UL15, UL28, and UL33 subunits, while TAP of vFH499-infected cells confirmed previous findings that the C terminus of UL28 is required for UL28 interaction with UL33 and UL15. Analysis of the oligomeric state of the purified complexes by sucrose density gradient ultracentrifugation revealed that the three proteins formed a complex with a molecular mass that is consistent with the formation of a UL15-UL28-UL33 heterotrimer. In order to assess the importance of conserved regions of the UL15 and UL28 proteins, recombinant NTAP-UL28 viruses with mutations of the putative UL28 metal-binding domain or within the UL15 nuclease domain were generated. TAP of UL28 complexes from cells infected with each domain mutant demonstrated that the conserved cysteine residues of the putative UL28 metal-binding domain and conserved amino acids within the UL15 nuclease domain are required for the cleavage and packaging functions of the viral terminase, but not for terminase complex assembly. PMID- 24155375 TI - Varicella-zoster virus ORF49 functions in the efficient production of progeny virus through its interaction with essential tegument protein ORF44. AB - The ORF49 tegument protein of varicella-zoster virus (VZV) is one of the core gene products that is conserved among herpesvirus family members. Although ORF49 is known to be a cell-tropic factor, its detailed functions remain elusive. ORF44 is another core gene product reported to be essential, although its characterization and detailed functional analysis have not been reported. These two core gene products form a complex in other herpesviruses beyond the host species and herpesvirus subfamilies. Here, we show that complex formation between ORF44 and ORF49 is conserved in VZV. We serendipitously found that binding is eliminated by an amino acid substitution at position 129 (phenylalanine 129), and four amino acids in the carboxyl-terminal half of the acidic cluster in ORF49 (i.e., aspartate-phenylalanine-aspartate-glutamate from positions 41 to 44 [41DFDE44]) were identified as its binding motif. Alanine substitutions in each domain rendered the ORF44F129A mutation lethal for VZV, similar to deletion of the entire ORF44. The phenotype of the ORF49-41AAAA44 mutation was comparable to that of the ORF49-defective virus, including small-plaque formation, impaired growth, and low infectious virus production. These results suggest that the interaction between ORF44 and ORF49 is essential for their role in VZV infection and that ORF49 is required for the efficient production of infectious progeny virus mediated by the conserved interaction between the two proteins. PMID- 24155376 TI - Resistance to infection, early and persistent suppression of simian immunodeficiency virus SIVmac251 viremia, and significant reduction of tissue viral burden after mucosal vaccination in female rhesus macaques. AB - The efficacy of oral, intestinal, nasal, and vaginal vaccinations with DNA simian immunodeficiency virus (SIV)/interleukin-2 (IL-2)/IL-15, SIV Gag/Pol/Env recombinant modified vaccinia virus Ankara (rMVA), and AT-2 SIVmac239 inactivated particles was compared in rhesus macaques after low-dose vaginal challenge with SIVmac251. Intestinal immunization provided better protection from infection, as a significantly greater median number of challenges was necessary in this group than in the others. Oral and nasal vaccinations provided the most significant control of disease progression. Fifty percent of the orally and nasally vaccinated animals suppressed viremia to undetectable levels, while this occurred to a significantly lower degree in intestinally and vaginally vaccinated animals and in controls. Viremia remained undetectable after CD8(+) T-cell depletion in seven vaccinated animals that had suppressed viremia after infection, and tissue analysis for SIV DNA and RNA was negative, a result consistent with a significant reduction of viral activity. Regardless of the route of vaccination, mucosal vaccinations prevented loss of CD4(+) central memory and CD4(+)/alpha4beta7(+) T cell populations and reduced immune activation to different degrees. None of the orally vaccinated animals and only one of the nasally vaccinated animals developed AIDS after 72 to 84 weeks of infection, when the trial was closed. The levels of anti-SIV gamma interferon-positive, CD4(+), and CD8(+) T cells at the time of first challenge inversely correlated with viremia and directly correlated with protection from infection and longer survival. PMID- 24155377 TI - Mutations in the amino terminus of herpes simplex virus type 1 gL can reduce cell cell fusion without affecting gH/gL trafficking. AB - The gH/gL heterodimer represents two of the four herpes simplex virus glycoproteins necessary and sufficient for membrane fusion. We generated deletions and point mutations covering gL residues 24 to 43 to investigate that region's role in gH/gL intracellular trafficking and in membrane fusion. Multiple mutants displayed a 40 to 60% reduction in cell fusion with no effect on gH/gL trafficking. The amino terminus of gL plays an important role in the gH/gL contribution to membrane fusion. PMID- 24155378 TI - A first-in-class NAE inhibitor, MLN4924, blocks lentiviral infection in myeloid cells by disrupting neddylation-dependent Vpx-mediated SAMHD1 degradation. AB - MLN4924 is a first-in-class cancer drug that inhibits the Nedd8-activating enzyme (NAE). Herein, we report that MLN4924 inhibits Vpx/Vpr-induced SAMHD1 degradation by inhibiting the neddylation of E3 ubiquitin ligase and blocks macaque simian immunodeficiency virus (SIVmac) replication in myeloid cells. SAMHD1 is required for MLN4924-mediated SIVmac inhibition. Our findings indicate the potential efficacy of inhibiting neddylation as an antiretroviral strategy and identify the readily available anticancer drug MLN4924 as a candidate agent for that purpose. PMID- 24155379 TI - CD4 T cell help is limiting and selective during the primary B cell response to influenza virus infection. AB - Influenza virus vaccination strategies are focused upon the elicitation of protective antibody responses through administration of viral protein through either inactivated virions or live attenuated virus. Often overlooked in this strategy is the CD4 T cell response: how it develops into memory, and how it may support future primary B cell responses to heterologous infection. Through the utilization of a peptide-priming regimen, this study describes a strategy for developing CD4 T cell memory with the capacity to robustly expand in the lung draining lymph node after live influenza virus infection. Not only were frequencies of antigen-specific CD4 T cells enhanced, but these cells also supported an accelerated primary B cell response to influenza virus-derived protein, evidenced by high anti-nucleoprotein (NP) serum antibody titers early, while there is still active viral replication ongoing in the lung. NP-specific antibody-secreting cells and heightened frequencies of germinal center B cells and follicular T helper cells were also readily detectable in the draining lymph node. Surprisingly, a boosted memory CD4 T cell response was not sufficient to provide intermolecular help for antibody responses. Our study demonstrates that CD4 T cell help is selective and limiting to the primary antibody response to influenza virus infection and that preemptive priming of CD4 T cell help can promote effective and rapid conversion of naive B cells to mature antibody secreting cells. PMID- 24155380 TI - Guiding the immune response against influenza virus hemagglutinin toward the conserved stalk domain by hyperglycosylation of the globular head domain. AB - Influenza virus hemagglutinin consists of a highly variable and immunodominant head domain and a more conserved but immunosubdominant stalk domain. We introduced seven N-linked glycosylation sites in the hemagglutinin head domain to shield the immunodominant antigenic sites. The hyperglycosylated hemagglutinin enhanced stalk-directed seroreactivity while dampening the head response in immunized mice. Upon influenza virus challenge, mice vaccinated with the hyperglycosylated hemagglutinin were better protected against morbidity and mortality than mice receiving the wild-type hemagglutinin. PMID- 24155381 TI - An avian retrovirus uses canonical expression and processing mechanisms to generate viral microRNA. AB - To date, the vast majority of known virus-encoded microRNAs (miRNAs) are derived from polymerase II transcripts encoded by DNA viruses. A recent demonstration that the bovine leukemia virus, a retrovirus, uses RNA polymerase III to directly transcribe the pre-miRNA hairpins to generate viral miRNAs further supports the common notion that the canonical pathway of miRNA biogenesis does not exist commonly among RNA viruses. Here, we show that an exogenous virus-specific region, termed the E element or XSR, of avian leukosis virus subgroup J (ALV-J), a member of avian retrovirus, encodes a novel miRNA, designated E (XSR) miRNA, using the canonical miRNA biogenesis pathway. Detection of novel microRNA species derived from the E (XSR) element, a 148-nucleotide noncoding RNA with hairpin structure, showed that the E (XSR) element has the potential to function as a microRNA primary transcript, demonstrating a hitherto unknown function with possible roles in myeloid leukosis associated with ALV-J. PMID- 24155382 TI - Nonmuscle myosin heavy chain IIA is a critical factor contributing to the efficiency of early infection of severe fever with thrombocytopenia syndrome virus. AB - Severe fever with thrombocytopenia syndrome virus (SFTSV) is a novel phlebovirus in the Bunyaviridae family. Most patients infected by SFTSV present with fever and thrombocytopenia, and up to 30% die due to multiple-organ dysfunction. The mechanisms by which SFTSV enters multiple cell types are unknown. SFTSV contains two species of envelope glycoproteins, Gn (44.2 kDa) and Gc (56 kDa), both of which are encoded by the M segment and are cleaved from a precursor polypeptide (about 116 kDa) in the endoplasmic reticulum (ER). Gn fused with an immunoglobulin Fc tag at its C terminus (Gn-Fc) bound to multiple cells susceptible to the infection of SFTSV and blocked viral infection of human umbilical vein endothelial cells (HUVECs). Immunoprecipitation assays following mass spectrometry analysis showed that Gn binds to nonmuscle myosin heavy chain IIA (NMMHC-IIA), a cellular protein with surface expression in multiple cell types. Small interfering RNA (siRNA) knockdown of NMMHC-IIA, but not the closely related NMMHC-IIB or NMMHC-IIC, reduced SFTSV infection, and NMMHC-IIA specific antibody blocked infection by SFTSV but not other control viruses. Overexpression of NMMHC-IIA in HeLa cells, which show limited susceptivity to SFTSV, markedly enhanced SFTSV infection of the cells. These results show that NMMHC-IIA is critical for the cellular entry of SFTSV. As NMMHC-IIA is essential for the normal functions of platelets and human vascular endothelial cells, it is conceivable that NMMHC-IIA directly contributes to the pathogenesis of SFTSV and may be a useful target for antiviral interventions against the viral infection. PMID- 24155383 TI - Cytomegalovirus expresses the chemokine homologue vXCL1 capable of attracting XCR1+ CD4- dendritic cells. AB - Cytomegaloviruses (CMV) have developed various strategies to escape the immune system of the host. One strategy involves the expression of virus-encoded chemokines to modulate the host chemokine network. We have identified in the English isolate of rat CMV (murid herpesvirus 8 [MuHV8]) an open reading frame encoding a protein homologous to the chemokine XCL1, the only known C chemokine. Viral XCL1 (vXCL1), a glycosylated protein of 96 amino acids, can be detected 13 h postinfection in the supernatant of MuHV8-infected rat embryo fibroblasts. vXCL1 exclusively binds to CD4(-) rat dendritic cells (DC), a subset of DC that express the corresponding chemokine receptor XCR1. Like endogenous rat XCL1, vXCL1 selectively chemoattracts XCR1(+) CD4(-) DC. Since XCR1(+) DC in mice and humans have been shown to excel in antigen cross-presentation and thus in the induction of cytotoxic CD8(+) T lymphocytes, the virus has apparently hijacked this gene to subvert cytotoxic immune responses. The biology of vXCL1 offers an interesting opportunity to study the role of XCL1 and XCR1(+) DC in the cross presentation of viral antigens. PMID- 24155384 TI - Activation of influenza A viruses by host proteases from swine airway epithelium. AB - Pigs are important natural hosts of influenza A viruses, and due to their susceptibility to swine, avian, and human viruses, they may serve as intermediate hosts supporting adaptation and genetic reassortment. Cleavage of the influenza virus surface glycoprotein hemagglutinin (HA) by host cell proteases is essential for viral infectivity. Most influenza viruses, including human and swine viruses, are activated at a monobasic HA cleavage site, and we previously identified TMPRSS2 and HAT to be relevant proteases present in human airways. We investigated the proteolytic activation of influenza viruses in primary porcine tracheal and bronchial epithelial cells (PTEC and PBEC, respectively). Human H1N1 and H3N2 viruses replicated efficiently in PTECs and PBECs, and viruses containing cleaved HA were released from infected cells. Moreover, the cells supported the proteolytic activation of HA at the stage of entry. We found that swine proteases homologous to TMPRSS2 and HAT, designated swTMPRSS2 and swAT, respectively, were expressed in several parts of the porcine respiratory tract. Both proteases cloned from primary PBECs were shown to activate HA with a monobasic cleavage site upon coexpression and support multicycle replication of influenza viruses. swAT was predominantly localized at the plasma membrane, where it was present as an active protease that mediated activation of incoming virus. In contrast, swTMPRSS2 accumulated in the trans-Golgi network, suggesting that it cleaves HA in this compartment. In conclusion, our data show that HA activation in porcine airways may occur by similar proteases and at similar stages of the viral life cycle as in human airways. PMID- 24155386 TI - Switching a replication-defective adenoviral vector into a replication-competent, oncolytic adenovirus. AB - The adenovirus immediate early gene E1A initiates the program of viral gene transcription and reprograms multiple aspects of cell function and behavior. For adenoviral (Ad) vector-mediated gene transfer and therapy approaches, where replication-defective (RD) gene transfer is required, E1A has thus been the primary target for deletions. For oncolytic gene therapy for cancer, where replication-competent (RC) Ad viral gene expression is needed, E1A has been either mutated or placed under tumor-specific transcriptional control. A novel Ad vector that initially infected target tumor cells in an RD manner for transgene expression but that could be "switched" into an RC, oncolytic state when needed might represent an advance in vector technology. Here, we report that we designed such an Ad vector (proAdDelta24.GFP), where initial Ad replication is silenced by a green fluorescent protein (GFP) transgene that blocks cytomegalovirus (CMV) mediated transcription of E1A. This vector functions as a bona fide E1A-deleted RD vector in infected tumor cells. However, because the silencing GFP transgene is flanked by FLP recombination target (FRT) sites, we show that it can be efficiently excised by Flp recombinase site-specific recombination, either when Flp is expressed constitutively in cells or when it is provided in trans by coinfection with a second RD herpes simplex virus (HSV) amplicon vector. This switches the RD Ad, proAdDelta24.GFP, into a fully RC, oncolytic Ad (rAdDelta24) that lyses tumor cells in culture and generates oncolytic progeny virions. In vivo, coinfection of established flank tumors with the RD proAdDelta24.GFP and the RD Flp-bearing HSV1 amplicon leads to generation of RC, oncolytic rAdDelta24. In an orthotopic human glioma xenograft tumor model, coinjection of the RD proAdDelta24.GFP and the RD Flp-bearing HSV1 amplicon also led to a significant increase in animal survival, compared to controls. Therefore, Flp-FRT site specific recombination can be applied to switch RD Ad into fully oncolytic RC Ad for tumor therapy and is potentially applicable to a variety of gene therapy approaches. PMID- 24155385 TI - Host restriction of influenza virus polymerase activity by PB2 627E is diminished on short viral templates in a nucleoprotein-independent manner. AB - Most avian influenza viruses do not replicate efficiently in human cells. This is partly due to the low activity of the RNA polymerase of avian influenza viruses in mammalian cells. Nevertheless, this impediment can be overcome through an E->K adaptive mutation at residue 627 of the PB2 subunit of the polymerase. Accordingly, viral ribonucleoprotein (RNP) reconstitution assays show that a viral polymerase containing PB2 627E has impaired activity in mammalian cells compared to a viral polymerase that contains PB2 627K, characteristic of mammalian-adapted influenza viruses. In contrast, purified viral polymerases containing either PB2 627E or PB2 627K show comparable levels of activity in transcription assays that require no RNP assembly. We sought to reconcile these conflicting observations by using an NP-independent cell-based transcription/replication assay to assess viral polymerase activity. We found that PB2 627E polymerase restriction in mammalian cells is independent of NP expression but is dependent on the length of the viral RNA template. In addition, restriction of PB2 627E polymerase was overcome by mutations specific to the viral RNA template promoter sequence. Consequently, we propose that PB2 627E affects recruitment of the viral RNA promoter by the viral polymerase in mammalian cells. PMID- 24155387 TI - Crystal structure of the nipah virus phosphoprotein tetramerization domain. AB - The Nipah virus phosphoprotein (P) is multimeric and tethers the viral polymerase to the nucleocapsid. We present the crystal structure of the multimerization domain of Nipah virus P: a long, parallel, tetrameric, coiled coil with a small, alpha-helical cap structure. Across the paramyxoviruses, these domains share little sequence identity yet are similar in length and structural organization, suggesting a common requirement for scaffolding or spatial organization of the functions of P in the virus life cycle. PMID- 24155388 TI - A novel subnucleocapsid nanoplatform for mucosal vaccination against influenza virus that targets the ectodomain of matrix protein 2. AB - In this study, subnucleocapsid nanorings formed by the recombinant nucleoprotein (N) of the respiratory syncytial virus were evaluated as a platform to anchor heterologous antigens. The ectodomain of the influenza virus A matrix protein 2 (M2e) is highly conserved and elicits protective antibodies when it is linked to an immunogenic carrier, making it a promising target to develop universal influenza vaccines. In this context, one or three M2e copies were genetically linked to the C terminus of N to produce N-M2e and N-3M2e chimeric recombinant nanorings. Mice were immunized intranasally with N-M2e or N-3M2e or with M2e or 3M2e control peptides. N-3M2e-vaccinated mice showed the strongest mucosal and systemic antibody responses. These mice presented a reduced viral load and minor weight loss, and all survived upon challenge with influenza virus A/PR8/34 (H1N1) (PR8). We compared the intranasal route to the subcutaneous route of N-3M2e immunization. Only the intranasal route induced a strong local IgA response and led to the protection of mice upon challenge. Finally, we demonstrated that the induction of anti-M2e antibodies by N-3M2e is not impaired by preexisting anti-N immunity. Overall, these results show that the N nanoring is a potent carrier for mucosal delivery of vaccinal antigens. PMID- 24155389 TI - Adaptive mutations in the nuclear export protein of human-derived H5N1 strains facilitate a polymerase activity-enhancing conformation. AB - The nuclear export protein (NEP) (NS2) of the highly pathogenic human-derived H5N1 strain A/Thailand/1(KAN-1)/2004 with the adaptive mutation M16I greatly enhances the polymerase activity in human cells in a concentration-dependent manner. While low NEP levels enhance the polymerase activity, high levels are inhibitory. To gain insights into the underlying mechanism, we analyzed the effect of NEP deletion mutants on polymerase activity after reconstitution in human cells. This revealed that the polymerase-enhancing function of NEP resides in the C-terminal moiety and that removal of the last three amino acids completely abrogates this activity. Moreover, compared to full-length NEP, the C terminal moiety alone exhibited significantly higher activity and seemed to be deregulated, since even the highest concentration did not result in an inhibition of polymerase activity. To determine transient interactions between the N- and C terminal domains in cis, we fused both ends of NEP to a split click beetle luciferase and performed fragment complementation assays. With decreasing temperature, increased luciferase activity was observed, suggesting that intramolecular binding between the C- and N-terminal domains is preferentially stabilized at low temperatures. This stabilizing effect was significantly reduced with the adaptive mutation M16I or a combination of adaptive mutations (M16I, Y41C, and E75G), which further increased polymerase activity also at 34 degrees C. We therefore propose a model in which the N-terminal moiety of NEP exerts an inhibitory function by back-folding to the C-terminal domain. In this model, adaptive mutations in NEP decrease binding between the C- and N-terminal domains, thereby allowing the protein to "open up" and become active already at a low temperature. PMID- 24155390 TI - Human plasmacytoid dendritic cells sense lymphocytic choriomeningitis virus infected cells in vitro. AB - We previously reported that exosomal transfer of hepatitis C virus (HCV) positive strand RNA from human Huh-7 hepatoma cells to human plasmacytoid dendritic cells (pDCs) triggers pDC alpha/beta interferon (IFN-alpha/beta) production in a Toll like receptor 7 (TLR7)-dependent, virus-independent manner. Here we show that human pDCs are also activated by a TLR7-dependent, virus-independent, exosomal RNA transfer mechanism by human and mouse hepatoma and nonhepatoma cells that replicate the negative-strand lymphocytic choriomeningitis virus (LCMV). PMID- 24155391 TI - Discovery of novel ribonucleoside analogs with activity against human immunodeficiency virus type 1. AB - Reverse transcription is an important early step in retrovirus replication and is a key point targeted by evolutionarily conserved host restriction factors (e.g., APOBEC3G, SamHD1). Human immunodeficiency virus type 1 (HIV-1) reverse transcriptase (RT) is a major target of antiretroviral drugs, and concerns regarding drug resistance and off-target effects have led to continued efforts for identifying novel approaches to targeting HIV-1 RT. Several observations, including those obtained from monocyte-derived macrophages, have argued that ribonucleotides and their analogs can, intriguingly, impact reverse transcription. For example, we have previously demonstrated that 5-azacytidine has its greatest antiviral potency during reverse transcription by enhancement of G-to-C transversion mutations. In the study described here, we investigated a panel of ribonucleoside analogs for their ability to affect HIV-1 replication during the reverse transcription process. We discovered five ribonucleosides-8 azaadenosine, formycin A, 3-deazauridine, 5-fluorocytidine, and 2'-C methylcytidine-that possess anti-HIV-1 activity, and one of these (i.e., 3 deazauridine) has a primary antiviral mechanism that involves increased HIV-1 mutational loads, while quantitative PCR analysis determined that the others resulted in premature chain termination. Taken together, our findings provide the first demonstration of a series of ribonucleoside analogs that can target HIV-1 reverse transcription with primary antiretroviral mechanisms that include premature termination of viral DNA synthesis or enhanced viral mutagenesis. PMID- 24155392 TI - Evolution of the influenza A virus genome during development of oseltamivir resistance in vitro. AB - Influenza A virus (IAV) is a major cause of morbidity and mortality throughout the world. Current antiviral therapies include oseltamivir, a neuraminidase inhibitor that prevents the release of nascent viral particles from infected cells. However, the IAV genome can evolve rapidly, and oseltamivir resistance mutations have been detected in numerous clinical samples. Using an in vitro evolution platform and whole-genome population sequencing, we investigated the population genomics of IAV during the development of oseltamivir resistance. Strain A/Brisbane/59/2007 (H1N1) was grown in Madin-Darby canine kidney cells with or without escalating concentrations of oseltamivir over serial passages. Following drug treatment, the H274Y resistance mutation fixed reproducibly within the population. The presence of the H274Y mutation in the viral population, at either a low or a high frequency, led to measurable changes in the neuraminidase inhibition assay. Surprisingly, fixation of the resistance mutation was not accompanied by alterations of viral population diversity or differentiation, and oseltamivir did not alter the selective environment. While the neighboring K248E mutation was also a target of positive selection prior to H274Y fixation, H274Y was the primary beneficial mutation in the population. In addition, once evolved, the H274Y mutation persisted after the withdrawal of the drug, even when not fixed in viral populations. We conclude that only selection of H274Y is required for oseltamivir resistance and that H274Y is not deleterious in the absence of the drug. These collective results could offer an explanation for the recent reproducible rise in oseltamivir resistance in seasonal H1N1 IAV strains in humans. PMID- 24155393 TI - Kinase control of latent HIV-1 infection: PIM-1 kinase as a major contributor to HIV-1 reactivation. AB - Despite the clinical relevance of latent HIV-1 infection as a block to HIV-1 eradication, the molecular biology of HIV-1 latency remains incompletely understood. We recently demonstrated the presence of a gatekeeper kinase function that controls latent HIV-1 infection. Using kinase array analysis, we here expand on this finding and demonstrate that the kinase activity profile of latently HIV 1-infected T cells is altered relative to that of uninfected T cells. A ranking of altered kinases generated from these kinome profile data predicted PIM-1 kinase as a key switch involved in HIV-1 latency control. Using genetic and pharmacologic perturbation strategies, we demonstrate that PIM-1 activity is indeed required for HIV-1 reactivation in T cell lines and primary CD4 T cells. The presented results thus confirm that kinases are key contributors to HIV-1 latency control. In addition, through mutational studies we link the inhibitory effect of PIM-1 inhibitor IV (PIMi IV) on HIV-1 reactivation to an AP-1 motif in the CD28-responsive element of the HIV-1 long terminal repeat (LTR). The results expand our conceptual understanding of the dynamic interactions of the host cell and the latent HIV-1 integration event and position kinome profiling as a research tool to reveal novel molecular mechanisms that can eventually be targeted to therapeutically trigger HIV-1 reactivation. PMID- 24155394 TI - Latent gammaherpesvirus 68 infection induces distinct transcriptional changes in different organs. AB - Previous studies identified a role for latent herpesvirus infection in cross protection against infection and exacerbation of chronic inflammatory diseases. Here, we identified more than 500 genes differentially expressed in spleens, livers, or brains of mice latently infected with gammaherpesvirus 68 and found that distinct sets of genes linked to different pathways were altered in the spleen compared to those in the liver. Several of the most differentially expressed latency-specific genes (e.g., the gamma interferon [IFN-gamma], Cxcl9, and Ccl5 genes) are associated with known latency-specific phenotypes. Chronic herpesvirus infection, therefore, significantly alters the transcriptional status of host organs. We speculate that such changes may influence host physiology, the status of the immune system, and disease susceptibility. PMID- 24155395 TI - Human cytomegalovirus infection of langerhans-type dendritic cells does not require the presence of the gH/gL/UL128-131A complex and is blocked after nuclear deposition of viral genomes in immature cells. AB - Human cytomegalovirus (CMV) enters its host via the oral and genital mucosae. Langerhans-type dendritic cells (LC) are the most abundant innate immune cells at these sites, where they constitute a first line of defense against a variety of pathogens. We previously showed that immature LC (iLC) are remarkably resistant to CMV infection, while mature LC (mLC) are more permissive, particularly when exposed to clinical-strain-like strains of CMV, which display a pentameric complex consisting of the viral glycoproteins gH, gL, UL128, UL130, and UL131A on their envelope. This complex was recently shown to be required for the infection of immature monocyte-derived dendritic cells. We thus sought to establish if the presence of this complex is also necessary for virion penetration of LC and if defects in entry might be the source of iLC resistance to CMV. Here we report that the efficiency of LC infection is reduced, but not completely abolished, in the absence of the pentameric complex. While virion penetration and nuclear deposition of viral genomes are not impaired in iLC, the transcription of the viral immediate early genes UL122 and UL123 and of the delayed early gene UL50 is substantially lower than that in mLC. Together, these data show that the UL128, UL130, and UL131A proteins are dispensable for CMV entry into LC and that progression of the viral cycle in iLC is restricted at the step of viral gene expression. PMID- 24155396 TI - PLC-gamma1 signaling plays a subtype-specific role in postbinding cell entry of influenza A virus. AB - Host signaling pathways and cellular proteins play important roles in the influenza viral life cycle and can serve as antiviral targets. In this study, we report the engagement of host phosphoinositide-specific phospholipase gamma1 (PLC gamma1) in mediating cell entry of influenza virus H1N1 but not H3N2 subtype. Both PLC-gamma1-specific inhibitor and short hairpin RNA (shRNA) strongly suppress the replication of H1N1 but not H3N2 viruses in cell culture, suggesting that PLC-gamma1 plays an important subtype-specific role in the influenza viral life cycle. Further analyses demonstrate that PLC-gamma1 activation is required for viral postbinding cell entry. In addition, H1N1, but not H3N2, infection leads to the phosphorylation of PLC-gamma1 at Ser 1248 immediately after infection and independent of viral replication. We have further shown that H1N1 induced PLC-gamma1 activation is downstream of epidermal growth factor receptor (EGFR) signaling. Interestingly, both H1N1 and H3N2 infections activate EGFR, but only H1N1 infection leads to PLC-gamma1 activation. Taking our findings together, we have identified for the first time the subtype-specific interplay of host PLC gamma1 signaling and H1N1 virus that is critical for viral uptake early in the infection. Our study provides novel insights into how virus interacts with the cellular signaling network by demonstrating that viral determinants can regulate how the host signaling pathways function in virally infected cells. PMID- 24155397 TI - Human T-cell leukemia/lymphoma virus type 1 p30, but not p12/p8, counteracts toll like receptor 3 (TLR3) and TLR4 signaling in human monocytes and dendritic cells. AB - The human T-cell leukemia/lymphoma virus type 1 (HTLV-1) p30 protein, essential for virus infectivity in vivo, is required for efficient infection of human dendritic cells (DCs) but not B and T cells in vitro. We used a human monocytic cell line, THP-1, and dendritic cells to study the mechanism of p30 and p12/p8 requirements in these cell types. p30 inhibited the expression of interferon (IFN)-responsive genes (ISG) following stimulation by lipopolysaccharide (LPS) of Toll-like receptor 4 (TLR4) and by poly(I.C) of TLR3 but not of TLR7/8 with imiquimod. Results with THP-1 mirrored those for ex vivo human primary monocytes and monocyte-derived dendritic cells (Mo-mDC). The effect of p30 on TLR signaling was also demonstrated by ablating its expression within a molecular clone of HTLV 1. HTLV-1 infection of monocytes inhibited TLR3- and TLR4-induced ISG expression by 50 to 90% depending on the genes, whereas the isogenic clone p30 knockout virus was less effective at inhibiting TLR3 and TRL4 signaling and displayed lower infectivity. Viral expression and inhibition of ISG transcription was, however, rescued by restoration of p30 expression. A chromatin immunoprecipitation assay demonstrated that p30 inhibits initiation and elongation of PU.1-dependent transcription of IFN-alpha1, IFN-beta, and TLR4 genes upon TLR stimulation. In contrast, experiments conducted with p12/p8 did not demonstrate an effect on ISG expression. These results provide a mechanistic explanation of the requirement of p30 for HTLV-1 infectivity in vivo, suggest that dampening interferon responses in monocytes and DCs is specific for p30, and represent an essential early step for permissive HTLV-1 infection and persistence. PMID- 24155398 TI - Control of simian immunodeficiency virus replication by vaccine-induced Gag- and Vif-specific CD8+ T cells. AB - For development of an effective T cell-based AIDS vaccine, it is critical to define the antigens that elicit the most potent responses. Recent studies have suggested that Gag-specific and possibly Vif/Nef-specific CD8(+) T cells can be important in control of the AIDS virus. Here, we tested whether induction of these CD8(+) T cells by prophylactic vaccination can result in control of simian immunodeficiency virus (SIV) replication in Burmese rhesus macaques sharing the major histocompatibility complex class I (MHC-I) haplotype 90-010-Ie associated with dominant Nef-specific CD8(+) T-cell responses. In the first group vaccinated with Gag-expressing vectors (n = 5 animals), three animals that showed efficient Gag-specific CD8(+) T-cell responses in the acute phase postchallenge controlled SIV replication. In the second group vaccinated with Vif- and Nef-expressing vectors (n = 6 animals), three animals that elicited Vif-specific CD8(+) T-cell responses in the acute phase showed SIV control, whereas the remaining three with Nef-specific but not Vif-specific CD8(+) T-cell responses failed to control SIV replication. Analysis of 18 animals, consisting of seven unvaccinated noncontrollers and the 11 vaccinees described above, revealed that the sum of Gag and Vif-specific CD8(+) T-cell frequencies in the acute phase was inversely correlated with plasma viral loads in the chronic phase. Our results suggest that replication of the AIDS virus can be controlled by vaccine-induced subdominant Gag/Vif epitope-specific CD8(+) T cells, providing a rationale for the induction of Gag- and/or Vif-specific CD8(+) T-cell responses by prophylactic AIDS vaccines. PMID- 24155399 TI - Effects of alpha interferon treatment on intrinsic anti-HIV-1 immunity in vivo. AB - Alpha interferon (IFN-alpha) suppresses human immunodeficiency virus type 1 (HIV 1) replication in vitro by inducing cell-intrinsic retroviral restriction mechanisms. We investigated the effects of IFN-alpha/ribavirin (IFN-alpha/riba) treatment on 34 anti-HIV-1 restriction factors in vivo. Expression of several anti-HIV-1 restriction factors was significantly induced by IFN-alpha/riba in HIV/hepatitis C virus (HCV)-coinfected individuals. Fold induction of cumulative restriction factor expression in CD4(+) T cells was significantly correlated with viral load reduction during IFN-alpha/riba treatment (r(2) = 0.649; P < 0.016). Exogenous IFN-alpha induces supraphysiologic restriction factor expression associated with a pronounced decrease in HIV-1 viremia. PMID- 24155400 TI - Generation of a complete single-gene knockout bacterial artificial chromosome library of cowpox virus and identification of its essential genes. AB - Cowpox virus (CPXV) belongs to the genus Orthopoxvirus in the Poxviridae family. It infects a broad range of vertebrates and can cause zoonotic infections. CPXV has the largest genome among the orthopoxviruses and is therefore considered to have the most complete set of genes of all members of the genus. Since CPXV has also become a model for studying poxvirus genetics and pathogenesis, we created and characterized a complete set of single gene knockout bacterial artificial chromosome (BAC) clones of the CPXV strain Brighton Red. These mutants allow a systematic assessment of the contribution of single CPXV genes to the outcome of virus infection and replication, as well as to the virus host range. A full length BAC clone of CPXV strain Brighton Red (pBRF) harboring the gene expressing the enhanced green fluorescent protein under the control of a viral late promoter was modified by introducing the mrfp1 gene encoding the monomeric red fluorescent protein driven by a synthetic early vaccinia virus promoter. Based on the modified BAC (pBRFseR), a library of targeted knockout mutants for each single viral open reading frame (ORF) was generated. Reconstitution of infectious virus was successful for 109 of the 183 mutant BAC clones, indicating that the deleted genes are not essential for virus replication. In contrast, 74 ORFs were identified as essential because no virus progeny was obtained upon transfection of the mutant BAC clones and in the presence of a helper virus. More than 70% of all late CPXV genes belonged to this latter group of essential genes. PMID- 24155401 TI - Mobilization of circulating endothelial progenitor cells correlates with the clinical course of hantavirus disease. AB - Infections with hemorrhagic fever viruses are characterized by increased permeability leading to capillary leakage. Hantavirus infection is associated with endothelial dysfunction, and the clinical course is related to the degree of vascular injury. Circulating endothelial progenitor cells (cEPCs) play a pivotal role in the repair of the damaged endothelium. Therefore, we analyzed the number of cEPCs and their mobilizing growth factors in patients suffering from hantavirus disease induced by infection with Puumala virus. The numbers of EPCs of 36 hantavirus-infected patients and age- and gender-matched healthy controls were analyzed by flow cytometry. Concentrations of cEPC-mobilizing growth factors in plasma were determined by enzyme-linked immunosorbent assay. Laboratory parameters were correlated with the number of cEPCs. In patients infected with hantavirus, the number of cEPCs was significantly higher than that in healthy controls. Levels of mobilizing cytokines were upregulated in patients, and the mobilization of cEPCs is paralleled with the normalization of clinical parameters. Moreover, higher levels of cEPCs correlated with higher serum albumin levels and platelet concentrations. Our data indicate that cEPCs may play a role in the repair of hantavirus-induced endothelial damage, thereby influencing the clinical course and the severity of symptoms. PMID- 24155402 TI - Echovirus 7 entry into polarized caco-2 intestinal epithelial cells involves core components of the autophagy machinery. AB - Echovirus 7 enters polarized Caco-2 intestinal epithelial cells by a clathrin mediated endocytic process and then moves through the endosomal system before releasing its genome into the cytoplasm. We examined the possible role in virus entry of core components of the autophagy machinery. We found that depletion of Beclin-1, Atg12, Atg14, Atg16, or LC3 with specific small interfering RNAs inhibited echovirus 7 infection upstream of uncoating but had little or no effect on virus attachment to the cell surface. These data indicate that multiple autophagy-related proteins are important for one or more events that occur after the virus has bound its receptor on the cell surface but before RNA is released from the virus capsid. Although we have not determined the mechanism by which each protein contributes to virus entry, we found that stable depletion of Atg16L1 interfered with virus internalization from the cell surface rather than with intracellular trafficking. Autophagy gene products may thus participate in the endocytic process that moves virus into polarized Caco-2 cells. PMID- 24155403 TI - NF-kappaB activation coordinated by IKKbeta and IKKepsilon enables latent infection of Kaposi's sarcoma-associated herpesvirus. AB - All herpesviruses share a remarkable propensity to establish latent infection. Human Kaposi's sarcoma-associated herpesvirus (KSHV) effectively enters latency after de novo infection, suggesting that KSHV has evolved with strategies to facilitate latent infection. NF-kappaB activation is imperative for latent infection of gammaherpesviruses. However, how NF-kappaB is activated during de novo herpesvirus infection is not fully understood. Here, we report that KSHV infection activates the inhibitor of kappaB kinase beta (IKKbeta) and the IKK related kinase epsilon (IKKepsilon) to enable host NF-kappaB activation and KSHV latent infection. Specifically, KSHV infection activated IKKbeta and IKKepsilon that were crucial for latent infection. Knockdown of IKKbeta and IKKepsilon caused aberrant lytic gene expression and impaired KSHV latent infection. Biochemical and genetic experiments identified RelA as a key player downstream of IKKbeta and IKKepsilon. Remarkably, IKKbeta and IKKepsilon were essential for phosphorylation of S(536) and S(468) of RelA, respectively. Phosphorylation of RelA S(536) was required for phosphorylation of S(468), which activated NF-kappaB and promoted KSHV latent infection. Expression of the phosphorylation-resistant RelA S(536)A increased KSHV lytic gene expression and impaired latent infection. Our findings uncover a scheme wherein NF-kappaB activation is coordinated by IKKbeta and IKKepsilon, which sequentially phosphorylate RelA in a site-specific manner to enable latent infection after KSHV de novo infection. PMID- 24155404 TI - Measles virus C protein impairs production of defective copyback double-stranded viral RNA and activation of protein kinase R. AB - Measles virus (MV) lacking expression of C protein (C(KO)) is a potent activator of the double-stranded RNA (dsRNA)-dependent protein kinase (PKR), whereas the isogenic parental virus expressing C protein is not. Here, we demonstrate that significant amounts of dsRNA accumulate during C(KO) mutant infection but not following parental virus infection. dsRNA accumulated during late stages of infection and localized with virus replication sites containing N and P proteins. PKR autophosphorylation and stress granule formation correlated with the timing of dsRNA appearance. Phospho-PKR localized to dsRNA-containing structures as revealed by immunofluorescence. Production of dsRNA was sensitive to cycloheximide but resistant to actinomycin D, suggesting that dsRNA is a viral product. Quantitative PCR (qPCR) analyses revealed reduced viral RNA synthesis and a steepened transcription gradient in C(KO) virus-infected cells compared to those in parental virus-infected cells. The observed alterations were further reflected in lower viral protein expression levels and reduced C(KO) virus infectious yield. RNA deep sequencing confirmed the viral RNA expression profile differences seen by qPCR between C(KO) mutant and parental viruses. After one subsequent passage of the C(KO) virus, defective interfering RNA (DI-RNA) with a duplex structure was obtained that was not seen with the parental virus. We conclude that in the absence of C protein, the amount of PKR activator RNA, including DI-RNA, is increased, thereby triggering innate immune responses leading to impaired MV growth. PMID- 24155405 TI - Near-atomic resolution cryo-electron microscopic structure of dengue serotype 4 virus. AB - Dengue virus (DENV), a mosquito-borne virus, is responsible for millions of cases of infections worldwide. There are four DENV serotypes (DENV1 to -4). After a primary DENV infection, the antibodies elicited confer lifetime protection against that DENV serotype. However, in a secondary infection with another serotype, the preexisting antibodies may cause antibody-dependent enhancement (ADE) of infection of macrophage cells, leading to the development of the more severe form of disease, dengue hemorrhagic fever. Thus, a safe vaccine should stimulate protection against all dengue serotypes simultaneously. To facilitate the development of a vaccine, good knowledge of different DENV serotype structures is crucial. Structures of DENV1 and DENV2 had been solved previously. Here we present a near-atomic resolution cryo-electron microscopy (cryo-EM) structure of mature DENV4. Comparison of the DENV4 structure with similar resolution cryo-EM structures of DENV1 and DENV2 showed differences in surface charge distribution, which may explain their differences in binding to cellular receptors, such as heparin. Also, observed variations in amino acid residues involved in interactions between envelope and membrane proteins on the virus surface correlate with their ability to undergo structural changes at higher temperatures. PMID- 24155406 TI - Differential accessibility of a rotavirus VP6 epitope in trimers comprising type I, II, or III channels as revealed by binding of a human rotavirus VP6-specific antibody. AB - Previous human antibody studies have shown that the human VH1-46 antibody variable gene segment encodes much of the naturally occurring human B cell response to rotavirus and is directed to virus protein 6 (VP6). It is currently unknown why some of the VH1-46-encoded human VP6 monoclonal antibodies inhibit viral transcription while others do not. In part, there are affinity differences between antibodies that likely affect inhibitory activity, but we also hypothesize that there are differing modes of binding to VP6 that affect the ability to block the transcriptional pore on double-layered particles. Here, we used a hybrid method approach for antibody epitope mapping, including single particle cryo-electron microscopy (cryo-EM) and enhanced amide hydrogen-deuterium exchange mass spectrometry (DXMS) to determine the location and mode of binding of a VH1-46-encoded antibody, RV6-25. The structure of the RV6-25 antibody-double layered particle (DLP) complex indicated a very complex binding pattern that revealed subtle differences in accessibility of the VP6 epitope depending on its position in the type I, II, or III channels. These subtle variations in the presentation or accessibility of the RV VP6 capsid layer led to position-specific differences in occupancy for binding of the RV6-25 antibody. The studies also showed that the location of binding of the noninhibitory antibody RV6-25 on the apical surface of RV VP6 head domain does not obstruct the transcription pore upon antibody binding, in contrast to binding of an inhibitory antibody, RV6-26, deeper in the transcriptional pore. PMID- 24155408 TI - The legal aspects of cosmetic surgery - a comment. PMID- 24155409 TI - Use of undercover cameras - a comment. PMID- 24155407 TI - Genomewide mapping and screening of Kaposi's sarcoma-associated herpesvirus (KSHV) 3' untranslated regions identify bicistronic and polycistronic viral transcripts as frequent targets of KSHV microRNAs. AB - Kaposi's sarcoma-associated herpesvirus (KSHV) encodes over 90 genes and 25 microRNAs (miRNAs). The KSHV life cycle is tightly regulated to ensure persistent infection in the host. In particular, miRNAs, which primarily exert their effects by binding to the 3' untranslated regions (3'UTRs) of target transcripts, have recently emerged as key regulators of KSHV life cycle. Although studies with RNA cross-linking immunoprecipitation approach have identified numerous targets of KSHV miRNAs, few of these targets are of viral origin because most KSHV 3'UTRs have not been characterized. Thus, the extents of viral genes targeted by KSHV miRNAs remain elusive. Here, we report the mapping of the 3'UTRs of 74 KSHV genes and the effects of KSHV miRNAs on the control of these 3'UTR-mediated gene expressions. This analysis reveals new bicistronic and polycistronic transcripts of KSHV genes. Due to the 5'-distal open reading frames (ORFs), KSHV bicistronic or polycistronic transcripts have significantly longer 3'UTRs than do KSHV monocistronic transcripts. Furthermore, screening of the 3'UTR reporters has identified 28 potential new targets of KSHV miRNAs, of which 11 (39%) are bicistronic or polycistronic transcripts. Reporter mutagenesis demonstrates that miR-K3 specifically targets ORF31-33 transcripts at the lytic locus via two binding sites in the ORF33 coding region, whereas miR-K10a-3p and miR-K10b-3p and their variants target ORF71-73 transcripts at the latent locus through distinct binding sites in both 5'-distal ORFs and intergenic regions. Our results indicate that KSHV miRNAs frequently target the 5'-distal coding regions of bicistronic or polycistronic transcripts and highlight the unique features of KSHV miRNAs in regulating gene expression and life cycle. PMID- 24155410 TI - Use of undercover cameras - a reply. PMID- 24155411 TI - More North American veterinary schools. PMID- 24155412 TI - An ethicist's commentary on horse with possible equine herpes virus. PMID- 24155413 TI - Emergence of influenza: expecting the unexpected: 2013 Reginald Thomson Lecture. PMID- 24155414 TI - Spinal meningiomas in dogs: description of 8 cases including a novel radiological and histopathological presentation. AB - Clinical, imaging, and histological features of 8 canine spinal meningiomas, including a cervical cystic meningioma with imaging and intraoperative features of an arachnoid cyst, are described. All meningiomas were histologically classified and graded following the international World Health Organization human classification for tumors. Six meningiomas were located in the cervical spinal cord. Myelography showed intradural/ extramedullary lesions in 3/4 cases. Magnetic resonance imaging revealed hyperintense intradural/extramedullary masses on pre-contrast T1-weighted and T2-weighted images with homogeneous contrast enhancement in 7/8 cases. One dog had a cerebrospinal fluid-filled subarachnoid cavity dorsal to the cervical spinal cord. A spinal arachnoid cyst was diagnosed on imaging, but the histopathological study of the resected tissue revealed a grade I meningothelial cystic meningioma. There were no differences in outcome associated with tumor grade and surgical treatment (6/8). Cystic meningioma should be considered in the differential diagnosis of intraspinal cystic lesions, and biopsy is necessary for definitive diagnosis. PMID- 24155416 TI - Computed tomography findings in a 5-year-old Australian Cashmere goat (Capra hircus) suffering leukoencephalomyelitis due to caprine arthritis encephalitis virus. AB - Computed tomography was used to aid in the antemortem diagnosis of leukoencephalomyelitis in a goat infected by caprine arthritis encephalitis virus (CAEV). Imaging results were corroborated by histologic examination. This report discusses various methods of imaging the nervous system and their potential for use in the antemortem diagnosis of CAEV neurologic changes. PMID- 24155415 TI - Cervical lung lobe herniation in dogs identified by fluoroscopy. AB - This study aimed to determine the frequency of cervical lung lobe herniation (CLLH) in dogs evaluated fluoroscopically and to identify associated characteristics. Reports of diagnostic procedures and patient summaries from 2008 to 2010 were reviewed retrospectively. Signalment, body weight, duration of cough, presence of heart murmur and airway collapse, and radiographic findings were compared between dogs with and without CLLH. Of the 121 dogs that were examined, CLLH occurred in 85 (70%). The extra-thoracic trachea kinked during herniation in 33 (39%) dogs with CLLH. Collapse of the intra-thoracic trachea (assessed fluoroscopically or bronchoscopically) and collapse of major bronchi (assessed fluoroscopically) were strongly associated with CLLH. Although redundant dorsal tracheal membrane on radiographs was associated with CLLH, extra thoracic tracheal collapse, assessed fluoroscopically or bronchoscopically, was not. No other associations were found. Cervical lung lobe herniation was present in most dogs evaluated during cough and was associated with intra-thoracic large airway collapse, but not duration of cough. PMID- 24155417 TI - Portomesenteric venous gas in a 2-week-old Holstein calf. AB - A 2-week-old Holstein Friesian female calf was presented with profuse diarrhea and abdominal distension. Clinicopathological findings included marked hypoproteinemia, hypoglycemia and leucopenia, mild hyperlactatemia, and hyperfibrinogenemia. On abdominal ultrasonography, features were consistent with portomesenteric venous gas (PVG), a rare condition reported in the medical literature. The PVG in this calf was associated with severe gastrointestinal illness and sepsis. PMID- 24155418 TI - Thoracolumbar spinal arachnoid diverticula in 5 pug dogs. AB - Clinical features, myelography, and computed tomography imaging findings as well as neurological outcome with and without surgery in 5 pug dogs with thoracolumbar arachnoid diverticula are described. Short-term prognosis after surgical therapy may not be as good as reported for other canine breeds, since immediate postsurgical deterioration is possible. Improvement of neurological deficits beyond the presurgical status may take several months. PMID- 24155420 TI - Severe gastric impaction secondary to a gastric polyp in a horse. AB - A 13-year-old Percheron gelding was presented for refractory gastric impaction. At necropsy a pedunculated 10 cm * 11 cm * 14 cm mass, histologically identified as an inflammatory polyp, was suspected to have been partly obstructing the pylorus. This is the first report of a polyp resulting in gastric outflow obstruction in a horse. PMID- 24155419 TI - Cutaneous lymphoid hyperplasia mimicking cutaneous lymphoma in a hyperthyroid cat. AB - A 12-year-old neutered male domestic shorthair cat presented for chronic, localized, swelling and crusting of the left upper lip, weight loss, sporadic vomiting, and focal alopecia between the scapulae was diagnosed with hyperthyroidism and regional eosinophilic lymphadenitis. Treatment with methimazole exacerbated an underlying hypersensitivity disorder leading to marked generalized lymphadenopathy that histologically mimicked lymphoma. PMID- 24155421 TI - Nasal-skin-fold transposition flap for upper lip reconstruction in a French bulldog. AB - Upper-lip reconstruction after mast-cell tumor-resection in a French bulldog was achieved by using a transposition flap from the nasal-skin-fold and an oral mucosal flap. The new technique is an alternative for reconstruction of extensive upper-lip defects in brachycephalic dogs and achieves satisfactory functional and cosmetic results. PMID- 24155422 TI - Thyrotoxicosis in a dog induced by the consumption of feces from a levothyroxine supplemented housemate. AB - A 9-year-old golden retriever dog was evaluated for polyuria, polydipsia, weight loss, and elevated serum thyroxine. Targeted questioning revealed that the dog was coprophagic and routinely ingested the feces of a dog that was treated with twice-daily levothyroxine. Clinical signs resolved and serum thyroxine decreased to normal levels in the affected dog with prevention of coprophagy. PMID- 24155423 TI - Gait analysis in a cat with scapular luxation and contralateral forelimb amputation. AB - This report describes the use of a pressure-sensitive walkway to evaluate an uncommon case of a cat with dorsal luxation of the left scapula and an amputated right forelimb. The findings suggest that limb amputation induced load redistribution mostly to the contralateral forelimb despite the scapular luxation. PMID- 24155424 TI - Memory, emotion, and compliance. PMID- 24155425 TI - Why get involved? PMID- 24155426 TI - An ethicist's commentary on the appeal to standard practice. PMID- 24155427 TI - Cantharidin toxicosis in 2 alpacas. AB - Two adult alpacas were presented for recumbency and reluctance to rise. Cantharidin toxicosis was suspected based on clinical and ancillary diagnostic findings. The diagnosis was confirmed by gas chromatography-mass spectrometry of gastric contents and urine. Despite medical treatment, neither alpaca survived. Blister beetle toxicosis has not been previously described in camelids. Challenges in treatment of affected ruminants or pseudoruminants are noted. PMID- 24155428 TI - Acute hind limb paralysis secondary to an extradural spinal cord Cryptococcus gattii lesion in a dog. AB - A 2-year-old, spayed female, German short-haired pointer was presented with a 1 day history of non-ambulatory paraplegia with absent deep pain perception. A computed tomography scan revealed an irregular eighth thoracic vertebral body and an extradural compressive lesion. Decompression was performed and abnormal tissues were submitted for analysis. Findings were consistent with a Cryptococcus gattii infection. PMID- 24155429 TI - Sialolipoma of a minor salivary gland in a dog. AB - A 10-year-old golden retriever dog was presented for evaluation of progressive panting, inspiratory stridor, and gagging. Oropharyngeal examination revealed a soft, nonulcerated, pedunculated mass arising from the right tonsillar fossa. The mass was completely excised and histopathology was consistent with a sialolipoma. No regrowth of the mass was evident 6 months after surgery. PMID- 24155430 TI - Severe propofol-associated dystonia in a dog. AB - A 2-year-old castrated dog was presented for chronic coughing that was evaluated with bronchoscopy following intravenous boluses of propofol. During recovery the dog developed severe rigidity of muscles of the neck and thoracic limbs, which was unresponsive to treatment but subsided over 25 minutes. A presumptive diagnosis of propofol-associated dystonia was made. The clinical characteristics and theorized pathophysiology of propofol-associated dystonia are discussed. PMID- 24155431 TI - Type II atresia ani associated with rectovaginal fistula in a male pseudohermaphrodite kitten. AB - A combination of gastrointestinal and urogenital congenital abnormalities was diagnosed and surgically treated in a kitten. Physical examination, exploratory laparotomy, castration, histological examination, and cytogenetic karyotyping were utilized to determine the true gender of the kitten. The kitten was confirmed to be a male (38 XY) pseudohermaphrodite with Type II atresia ani and rectovaginal fistula. PMID- 24155432 TI - Efficacy of a botanical preparation for the intramammary treatment of clinical mastitis on an organic dairy farm. AB - The objective was to evaluate the efficacy of a botanical product (PHYTO MAST((r))) for the intra-mammary treatment of clinical mastitis (CM) in dairy cows managed in an organic system. The study involved 194 naturally occurring cases of clinical mastitis. Treatment was applied every 12 hours for 3 days and cows were evaluated for clinical cure starting on day 4. Outcomes of interest consisted of mastitis resolution at day 4, time to resolution, somatic cell score (SCS) after recovery, and bacteriological cure at 14 and 28 d after treatment. There was no significant effect on clinical mastitis resolution at day 4 for treatment compared with the control group. However, there was a faster recovery for the treatment group compared to the control group with median intervals from end of treatment to recovery of 4.6 d and 6.5 d, respectively. There was no effect on the probability of a SCS < 4 (200 000 SC/mL) after treatment. No significant effects were found for treatment on bacteriological cure at days 14 and 28. PMID- 24155433 TI - Increase in average testis size of Canadian beef bulls. AB - Selection for adequate testis size in beef bulls is an important part of bull breeding soundness evaluation. Scrotal circumference (SC) is highly correlated with paired testis weight and is a practical method for estimating testis weight in the live animal. Most bulls presented for sale in Canada have SC included in the presale information. Scrotal circumference varies by age and breed, and may change over time due to selection for larger testis size. Therefore, it is important to periodically review the mean SC of various cattle breeds to provide valid bull selection criteria. Scrotal circumference data were obtained from bulls sold in western Canada from 2008 to 2011 and in Quebec from 2006 to 2010. Average scrotal circumferences for the most common beef breeds in Canada have increased significantly in the last 25 years. Differences between breeds have remained unchanged and Simmental bulls still have the largest SC at 1 year of age. Data provided here could aid in the establishment of new suggested minimum SC measurements for beef bulls. PMID- 24155434 TI - An investigation of ear necrosis in pigs. AB - Porcine ear necrosis was investigated in 23 conveniently chosen farms, consisting of 14 case farms and 9 control farms. Biopsies of lesions and oral swabs from pigs on 11 case farms were examined by histology and bacterial culture. All farms were visited for observations and a survey on management, housing, and the presence of other clinical signs or behavioral vices. Histological examination revealed that the lesions began on the surface and progressed to deeper layers, and that vascular damage did not appear to be the initiating cause. Spirochetes were only rarely observed in histological examination and were not cultured from biopsies and oral swabs. Staphylococcus aureus and Staphylococcus hyicus were cultured from 91% and 66% of samples, respectively. Ear biting and a humid environment were associated with ear necrosis. On some farms large numbers of pigs were affected and lesions were sometimes extensive. The condition appears to be an infectious disease beginning on the surface of the skin; contributing environmental and management factors are likely. PMID- 24155435 TI - Feline leptospirosis serosurvey from a Quebec referral hospital. AB - Epidemiologic studies have linked interactions with cats as a risk factor for human leptospirosis, but serosurveys of feline Leptospira spp. infection are scarce in the veterinary literature. The objective of this study was to conduct a serosurvey of Leptospira spp. infection in cats presenting to an eastern Canadian veterinary teaching hospital (VTH). All serum samples collected from cats presented to the VTH were tested by the microscopic agglutination test (MAT) for the Leptospira serovars Canicola, Grippotyphosa, Icterohaemorrhagiae, Bratislava, Pomona, and Autumnalis. Ten of 40 cats [25%; 95% confidence interval (CI): 12.7% to 41.2%] tested had positive antibody titers (>= 1:100). All 10 cats with positive titers were positive for Bratislava and 2 were also positive for Autumnalis. This high incidence of seropositivity for Leptospira spp. may suggest that the disease could be of more clinical importance than previously recognized. PMID- 24155436 TI - Swine influenza test results from animal health laboratories in Canada. AB - Due to its infrastructure and partnerships the Canadian Animal Health Surveillance Network was able to rapidly collect test results from 9 Canadian laboratories that were conducting primary testing for influenza on swine-origin samples, in response to the threat posed by the pandemic H1N1 influenza virus in 2009. PMID- 24155437 TI - How do swine practitioners and veterinary pathologists arrive at a diagnosis of Clostridium perfringens type A enteritis in neonatal piglets? AB - A questionnaire was administered to 22 veterinary practitioners and 17 veterinary pathologists to investigate the methods used for diagnosis of Clostridium perfringens type A enteritis in neonatal pigs. Practitioners generally diagnosed C. perfringens type A associated enteritis by age of onset of diarrhea (between 1 to 7 days of age). Most practitioners (95%) were moderately to very confident in their diagnosis. Pathologists generally diagnosed C. perfringens type A associated enteritis by combinations of isolation of the organism, genotyping or detecting the toxins of the organism, and ruling out other pathogens through histopathology. Almost half (41%) of the pathologists were not confident of their diagnosis. This study reports that the current diagnostic method for C. perfringens type A enteritis is not specific, and although many pathologists expressed reservations about making a diagnosis of C. perfringens type A enteritis, most practitioners were confident in their diagnosis, even though reported clinical signs of clostridial diarrhea are similar to those of a number of other enteric diseases. PMID- 24155438 TI - Traumatic diaphragmatic hernia in a 5-month-old boxer dog. AB - A 5-month-old intact male boxer dog was presented to the Metro Animal Emergency Clinic, Dartmouth, Nova Scotia after being hit by a car. Radiography identified a diaphragmatic hernia with the stomach herniated into the thoracic cavity. Diaphragmatic herniorrhaphy and splenectomy were performed without complication. The patient returned to his regular active lifestyle. PMID- 24155439 TI - 2012 wage report for non-DVMs. PMID- 24155440 TI - Diagnostic ophthalmology. PMID- 24155441 TI - Letters to the editor. PMID- 24155442 TI - An ethicist's commentary on balancing business and veterinary care. PMID- 24155443 TI - Meaningful communication with children. PMID- 24155444 TI - Aggressive dogs: What questions do we need to ask? PMID- 24155445 TI - Advisory: Bromethalin rodenticide - No known antidote. PMID- 24155446 TI - Survey of western Canadian beef producers regarding calf-hood diseases, management practices, and veterinary service usage. AB - Cow-calf producers in western Canada were surveyed in June 2010 regarding calf hood diseases and veterinary service usage; 310 producers responded. Use of veterinary services, particularly herd-health related services, increased with herd size as did neonatal diarrhea and clostridial vaccine usage. Administration of clostridial vaccines to pregnant dams before calving was associated with a reduction in neonatal diarrhea treatments; however, there was no association between neonatal diarrhea vaccine usage and a reduction in diarrhea treatments. Producers with > 220 breeding females were more likely than those with < 85 breeding females to seek veterinary advice regarding treating sick calves, have a veterinarian necropsy dead calves, have a veterinarian pregnancy check their bred females, and evaluate their herd bulls for breeding soundness. PMID- 24155447 TI - Historical aspects of Potomac horse fever in Ontario (1924-2010). AB - In the summer of 1924 Dr. Frank W. Schofield conducted investigations into an endemic disease of horses in the Kent and Essex counties of Ontario. According to farmers in these counties the disease had existed in this region for at least 50 years previously. The clinical, pathological, histopathological, and epidemiological findings outlined in Schofield's detailed report strongly suggest that this endemic disease was what was designated in 1979 as "Potomac horse fever" (PHF). This assumption is further substantiated by transmission experiments involving horses and laboratory animals that were conducted by Schofield utilizing horse feces, whole blood, and mayflies. The aim of this paper is to present Schofield's detailed investigations and findings and to compare these with PHF research conducted from 1979 to 2010 that ultimately led to the discovery of Neorickettsia risticii as the etiological agent and to elucidation of the organism's complex life cycle. PMID- 24155449 TI - Proportional mortality: A study of 152 goats submitted for necropsy from 13 goat herds in Quebec, with a special focus on caseous lymphadenitis. AB - The objectives of this study were to determine the main causes of mortality, with a special focus on caseous lymphadenits as a cause of death or wasting in caprine herds from Quebec. Goats (n = 152) from 13 herds were submitted for necropsy; the cause of mortality, and the presence, location, and cause of abscesses (if present) were recorded. Proportional mortalities were distributed as: Clostridium perfringens type D enterotoxemia (17.1%), pneumonia (13.8%), paratuberculosis (10.5%), listeriosis (6.6%), pregnancy toxemia (5.3%), caprine arthritis encephalitis (4.6%), and caseous lymphadenitis (3.9%). Caseous lymphadenitis was diagnosed in 24.3% of the submitted goats, but was not a major cause of wasting or mortality. Abscesses were localized internally in 54.1% of the cases. Paratuberculosis was diagnosed in 29 goats (16 as cause of death) and was considered a major cause of wasting and/or mortality. PMID- 24155448 TI - The effect of a gelatin beta-tricalcium phosphate sponge loaded with mesenchymal stem cells (MSC), bone morphogenic protein-2, and platelet-rich plasma (PRP) on equine articular cartilage defect. AB - We evaluated the curative efficacy of a gelatin beta-tricalcium phosphate (beta TCP) sponge loaded with mesenchymal stem cells (MSC), bone morphogenic protein-2 (BMP-2), and platelet-rich plasma (PRP) by insertion into an experimentally induced osteochondral defect. A hole of 10 mm diameter and depth was drilled in the bilateral medial femoral condyles of 7 thoroughbred horses, and into each either a loaded sponge (treatment) or a saline-infused beta-TCP sponge (control) was inserted. After 16 weeks, defects were examined by computed tomography, macroscopic analyses, and histological analyses. The median subchondral bone density and macroscopic subscores for joint healing were significantly higher in the treatment legs (P < 0.05). Although there was no significant difference in total histological scores between groups, hyaline cartilaginous tissue was observed across a wider area in the treatment group. Equine joint healing can be enhanced by inserting a BMP-2-, MSC-, and PRP-impregnated beta-TCP sponge at the lesion site. PMID- 24155450 TI - The effects of an oral distraction on cattle during a painful procedure. AB - An oral distraction was investigated as a way to reduce struggle and heart rate of beef cattle undergoing freeze branding. Oral distraction reduced the struggle of steers, regardless of branding treatment. No effect on heart rate was found. Distractions may provide a way to reduce struggle by animals during restraint. PMID- 24155451 TI - Tongue rotation for reconstruction after rostral hemiglossectomy for excision of a liposarcoma of the rostral quadrant of the tongue in a dog. AB - A 15-year-old female beagle dog was presented for a lingual liposarcoma. Full staging of the disease did not show any evidence of metastasis. A tongue rotation for reconstruction after rostral hemiglossectomy was performed after removal of the mass. This surgical technique may be useful in tongue reconstruction after trauma or tumor excision. PMID- 24155452 TI - A case of canine discospondylitis and epidural empyema due to Salmonella species. AB - A case of canine discospondylitis and epidural empyema due to Salmonella species is reported. The history, clinical signs, and magnetic resonance imaging were suggestive of discospondylitis and empyema, which was subsequently confirmed by blood cultures. To the authors' knowledge, this is the first reported case of canine discospondylitis due to Salmonella species. PMID- 24155453 TI - Mandibular degloving injury in an Arabian filly. AB - A 6-month-old Arabian filly escaped its handler while being led and slipped on pavement. The referring veterinarian recognized severe, soft tissue damage to the filly's lower jaw and referred the filly to the Veterinary Teaching Hospital for surgical management. PMID- 24155454 TI - Primary central nervous system T-cell lymphoma mimicking meningoencephalomyelitis in a cat. AB - A cat was presented with right head tilt and circling. The lack of expression of virus antigens did not support the postmortem diagnosis of encephalomyelitis pointing to a diffuse primary central nervous system T-cell lymphoma on the basis of CD3 and CD45R co-expression with absence of CD79alpha staining. PMID- 24155455 TI - Electrochemotherapy for the treatment of recurring aponeurotic fibromatosis in a dog. AB - This paper reports the clinical findings, histopathology, and clinical outcome of a rare case of aponeurotic fibromatosis in a dog. The dog was treated with 4 courses of electrochemotherapy using the drugs cisplatin and bleomycin. There was complete remission and the dog was still disease-free after 18 months. PMID- 24155456 TI - Volunteerism - the lifeblood of the CVMA. PMID- 24155457 TI - Comment re: Accepting that veterinary medicine is a profession and business, how does one balance the business with professional and medically appropriate veterinary care? (Can Vet J 2013;54:213). PMID- 24155458 TI - An ethicist's commentary on the use of undercover cameras. PMID- 24155459 TI - 2012 annual report of the Canadian Veterinary Medical Association. PMID- 24155460 TI - Primary cardiac spindle cell tumor in a dog. AB - An adult Labrador retriever dog was presented with respiratory signs and heart murmur. Echocardiography and thoracic radiographs revealed a heart base mass infiltrating the left atrial wall. Microscopically, neoplastic tissues consisted of spindle cells and abundant extracellular matrix. Based on histochemical stain and immunohistochemistry, a diagnosis of primary cardiac sarcoma was made. PMID- 24155461 TI - Anuria due to inadvertent prostatectomy during cryptorchidectomy. AB - This report describes an 8-month-old male Labrador retriever dog that was evaluated for a 2-day history of anuria and vomiting following a suspected inadvertent prostatectomy during a cryptorchidectomy. A positive contrast urethrogram was performed to definitively diagnose the absence of a patent prostatic urethra and necropsy confirmed inadvertent prostatectomy. PMID- 24155462 TI - Dural tear and myelomalacia caused by an airgun pellet in a cat. AB - An 8-year-old cat was presented with severe neurological deficits secondary to a traumatic cervical spinal cord injury caused by an airgun pellet. This report describes, for the first time, the myelographic findings of a dural rupture in a cat and also describes a bilateral Horner's syndrome in a cat. PMID- 24155463 TI - Renal nephroblastoma in a 3-month-old golden retriever. AB - Nephrectomy was performed in a 3-month-old intact female golden retriever dog for a renal nephroblastoma. The dog has remained disease-free for 19 months with nephrectomy alone. The adoption of human Wilms' tumor grading criteria may be useful in determining clinical stage, adjuvant treatment options, and prognosis in this rare disease. PMID- 24155464 TI - A fatal case of complicated congenital peritoneopericardial diaphragmatic hernia in a Holstein calf. AB - Congenital peritoneopericardial diaphragmatic hernia is a rare condition most commonly reported in cats and dogs. A 6-week-old Holstein heifer calf with a congenital peritoneopericardial diaphragmatic hernia complicated by a perforated abomasal ulcer is described. The clinical signs and pathological findings are compared with those reported in other species. PMID- 24155465 TI - An unusual case of urinary retention and ulcerative cystitis in a horse, sequelae of pelvic abscessation, and adhesions. AB - A 21-year-old Quarter horse gelding was presented with stranguria and incontinence of 10 days duration. Despite catheterization and antibiotic therapy, the horse was euthanized. Necropsy revealed posterior abdominal and pelvic abscessation with adhesions of the urinary bladder and severe ulcerative cystitis. PMID- 24155466 TI - Herd-level risk factors associated with fecal shedding of Shiga toxin-encoding bacteria on dairy farms in Minnesota, USA. AB - This study aimed to identify herd-level risk factors associated with fecal shedding of Shiga toxin-encoding bacteria (STB) on dairy cattle farms in Minnesota, USA. After adjustment for farm size, risk factors included: use of total mixed ration (TMR) for lactating dairy cows [odds ratio (OR) = 3.0; 95% confidence interval (CI): 1.8 to 5.1], no use of monensin for weaned calves (OR = 4.8, 95% CI: 2.5, 9.3), and no use of decoquinate for preweaned calves (OR = 2.2, 95% CI: 1.4, 3.6). Fecal shedding of STB was more common in small herds (< 100 cows, OR = 3.6, 95% CI: 2.1, 6.2) than in large herds (>= 100 cows). Herd management factors related to cattle feeding practices were associated with fecal shedding of STB. PMID- 24155467 TI - Spontaneous capital femoral physeal fracture in a cat. AB - A young neutered male cat was presented with a 1-week history of left hind limb lameness. Pain and crepitus were identified on manipulation of the left coxofemoral joint. Radiographic evaluation led to the diagnosis of physeal dysplasia with slipped capital femoral epiphysis of the left femur, which did not respond to conservative management. PMID- 24155468 TI - Managing expenses with budgeting. PMID- 24155469 TI - Diagnostic ophthalmology. PMID- 24155470 TI - Is there a MOOC in your future? PMID- 24155471 TI - An ethicist's commentary on mildly anemic dogs. PMID- 24155472 TI - Diagnosis and successful surgical treatment of an unusual inguinal liposarcoma in a pet ferret (Mustela putorius furo). AB - A 4 1/2-year-old female spayed ferret (Mustela putorius furo) was presented for a rapidly growing mass in the inguinal region. Following a complete clinical evaluation, the unusual mass was surgically removed and the histopathological diagnosis was an inguinal liposarcoma. No post-operative complications were observed over a 14-month follow-up period. PMID- 24155473 TI - Hookworm dermatitis due to Uncinaria stenocephala in a dog from Saskatchewan. AB - Uncinaria stenocephala hookworm dermatitis (uncinariosis) was diagnosed on fecal examination and macerated skin biopsy in a 1.5-year-old greyhound dog from Saskatchewan. This is the first reported case in Canada. Treatment with moxidectin cleared gastrointestinal and dermal infections. PMID- 24155474 TI - Oronasal blastomycosis in a golden retriever. AB - Blastomycosis is one of the most common systemic fungal infections in dogs in North America Pulmonary manifestations are most common; localized disease is rare. A case of localized oronasal blastomycosis mimicking oral neoplasia is described. Long-term therapy with itraconazole resulted in clinical cure. PMID- 24155475 TI - Prevalence and geographic distribution of canine and feline blastomycosis in the Canadian prairies. AB - This retrospective study reports patient signalment, method of diagnosis and geographic distribution, and examines trends in prevalence and seasonal distribution of blastomycosis cases submitted to a veterinary diagnostic laboratory in Saskatchewan over a 21-year period. Of the 143 cases that originated from Saskatchewan and Manitoba 137 were from canine and 6 from feline patients. Signalment was similar to that previously reported. All cases originated in southern Saskatchewan and Manitoba, primarily from Regina, Moose Jaw, Swift Current, and Winnipeg. Case numbers showed a significant increase in the period 2001 to 2010 compared to 1990 to 2000. Seasonally, there was an increasing trend in the number of diagnoses from February to November. There was no correlation between average seasonal temperature or average seasonal total precipitation and the number of cases of blastomycosis. The persistence of blastomycosis in southern Saskatchewan indicates that Blastomyces dermatitidis is now endemic in this region. PMID- 24155476 TI - Management of bilateral idiopathic renal hematuria in a dog with silver nitrate. AB - Renal hematuria has limited treatment options. This report describes management of bilateral idiopathic renal hematuria in a dog with surgically assisted installation of 0.5% silver nitrate solution. Initial treatment resulted in freedom from clinical signs or recurrent anemia for 10 months; however, recurrence of bleeding following a nephrectomy resulted in euthanasia. PMID- 24155477 TI - Aseptic tenosynovitis of the carpal flexor sheath caused by rupture of the accessory ligament of the deep digital flexor tendon. AB - A mare was evaluated for acute left forelimb lameness with effusion of the carpal flexor sheath. No osseous abnormalities were noted during radiographic examination. Significant disruption of the accessory ligament of the deep digital flexor tendon was seen during ultrasonographic examination. Carpal sheath effusion and lameness resolved after medical treatment. PMID- 24155478 TI - Transport versus on-farm slaughter of bison: physiological stress, animal welfare, and avoidable trim losses. AB - Ranched bison are typically less acclimated to handling than are domesticated livestock, suggesting that they might be more vulnerable to handling and transportation stressors. Grain-finished bison were slaughtered on-farm (n = 11), or held for 48 h, transported to a research abattoir, held in lairage for 18 h, and then slaughtered (n = 11). An additional group (n = 10) was sampled at a conventional fixed location abattoir. Measures included serum cortisol and corticosterone concentrations during on-farm handling and exsanguination, serum glucose, creatinine phosphokinase (CPK), aspartate aminotransferase (AST), and trim losses. Transport was associated with an increase in trim loss. On-farm, glucose was elevated, CPK was positively associated with handling order over 12 h, and corticosterone concentration, although lower than cortisol concentration, showed a greater response to prolonged disturbance. With appropriate on-farm handling facilities, the use of on-farm slaughter and mobile abattoir could avoid muscle damage and trim losses, and mitigate injuries sustained during handling and transport of bison. PMID- 24155479 TI - Comparison of disease trends in the Ontario swine population using active practitioner-based surveillance and passive laboratory-based surveillance (2007 2009). AB - A concern about emerging swine diseases led to a pilot study to determine the feasibility of an active surveillance system referred to as the Ontario Swine Veterinary-based Surveillance System (OSVS). The OSVS recorded the incidence of various syndromes and investigated potential outbreaks. However, validation of the disease patterns observed was needed. The objective of this study was to compare the disease patterns observed in the OSVS system with submission data obtained from a regional diagnostic laboratory - the Animal Health Laboratory (AHL). Higher rates of submission were reported to the OSVS compared with AHL records. However, OSVS and AHL data captured similar trends of disease. The OSVS data captured potential outbreaks that were not reflected in the laboratory data. Validation of active and passive syndromic surveillance data is necessary, and efforts should be made to integrate these types of data sources. PMID- 24155480 TI - Concurrent gall bladder, liver lobe torsion, and bile peritonitis in a German shepherd dog 2 months after gastric dilatation/volvulus gastropexy and splenectomy. AB - Postmortem examination of a 7-year-old German shepherd dog which had gastric dilatation/volvulus and splenectomy 2 months earlier revealed that the right middle and quadrate liver lobes were diffusely congested and torsed. The gall bladder was grossly distended and torsed along its long axis and there was evidence of bile peritonitis. PMID- 24155481 TI - High-throughput sequencing revealed the presence of an unforeseen parvovirus species in Canadian swine: the porcine partetravirus. PMID- 24155482 TI - Burnout and health promotion in veterinary medicine. PMID- 24155483 TI - When "the sky's the limit" isn't enough. PMID- 24155484 TI - The end of associations as we know them? PMID- 24155485 TI - Veterinary medical ethics. PMID- 24155486 TI - Inguinal herniation with hydrometra/mucometra in a poodle bitch. AB - A 5-year-old, sexually intact poodle bitch was presented with a 2-year history of inguinal mass. A tentative diagnosis of hydrometra/mucometra with inguinal herniation was made and ovariohysterectomy with hernia repair was performed. Both fluid-filled uterine horns, both broad ligaments, and the uterine body were observed to be herniated through the inguinal ring. On histopathology, marked edema and diffuse hemorrhage were diagnosed in the uterus. PMID- 24155488 TI - Laminar epidermal hyperplasia and hyperkeratosis in an equine hoof. AB - A 6-year-old Canadian Warmblood gelding was presented for suspicion of keratoma growth, based on a history of recurring abscesses in the right front foot. Radiographic examination and computed tomography identified 2 bilaterally symmetrical, laminar epidermal ingrowths adhered to the hoof wall at the level of the lateral and medial heels. PMID- 24155487 TI - Hepatocellular carcinoma in a young dog. AB - A 25-month-old Chihuahua dog with no clinical signs was evaluated for high serum liver enzymes. Ultrasonography and computed tomography revealed a mass in the left hepatic medial lobe. The histological diagnosis reached using resected tissues was hepatocellular carcinoma (HCC). To the authors' knowledge, this is the youngest dog diagnosed with HCC. PMID- 24155489 TI - Lawsonia intracellularis-associated ulcerative and necro-hemorrhagic enteritis in 5 weanling foals. AB - This report describes 5 cases of fatal Lawsonia intracellularis-associated ulcerative and necro-hemorrhagic enteritis in weanling Thoroughbred and Standardbred foals. The lesions are similar to those of the L. intracellularis associated ulcerative and necro-hemorrhagic enteritis syndrome in pigs. Two foals had concurrent severe typhlo-colitis as a result of a large burden of encysted cyathostomes. The clinical, diagnostic, and therapeutic challenges, and the potential complications encountered during the management of such cases are discussed. PMID- 24155490 TI - Bacterial diskospondylitis in juvenile mink from 2 Ontario mink farms. AB - Nine juvenile mink with hind-limb paresis/paralysis from 2 Ontario farms were submitted for necropsy. Diagnostic tests revealed spinal compression and severe thoracic diskospondylitis with intralesional Gram-positive coccoid bacterial colonies. Streptococcus canis, Streptococcus dysgalactiae subsp. equisimilis, and hemolytic Staphylococcus spp. were isolated from vertebral lesions. PMID- 24155491 TI - Clinical use of a low-dose medetomidine infusion in healthy dogs undergoing ovariohysterectomy. AB - Eight healthy dogs undergoing elective ovariohysterectomy were anesthetized with a standard protocol and received a low-dose medetomidine constant rate infusion during surgery. Cardiorespiratory parameters, including non-invasive cardiac output, were measured at various times. This protocol resulted in acceptable and stable cardiovascular performance, allowed low isoflurane concentrations, and provided smooth recoveries. PMID- 24155492 TI - Home-care treatment of swimmer syndrome in a miniature schnauzer dog. AB - A 50-day-old, female miniature schnauzer dog was presented for astasia, dorsoventral flattening of the thorax, hypoplasia of hind-limb muscles, stiffness of hind-limb joints, paddling leg motion, and panting. The dog was diagnosed with swimmers syndrome. The dog recovered completely following 40 days of home-care treatment that involved environmental and nutritional management along with intensive physiotherapy. PMID- 24155493 TI - A case of necrolytic migratory erythema managed for 24 months with intravenous amino acid and lipid infusions. AB - A 9-year-old castrated male Shetland sheepdog was diagnosed with necrolytic migratory erythema and hepatocutaneous syndrome. Necrolytic migratory erythema was treated with intermittent intravenous amino acids as needed to control cutaneous lesions. The addition of lipid infusions extended the treatment interval. The patient had a favorable response for 24 months. PMID- 24155494 TI - Tyzzer's disease in foals: retrospective studies from 1969 to 2010. AB - Reports of 148 cases of Tyzzer's disease in foals in central Kentucky were analyzed to identify features of the disease and factors associated with it. The records indicate that Tyzzer's disease is a rapidly progressive, highly fatal hepatitis caused by Clostridium piliforme. Common clinical findings are lethargy, fever, anorexia, and icterus. Seizures, coma, and death may rapidly ensue. Laboratory findings are leukopenia, metabolic acidosis, hypoglycemia, and increased activity of hepatic enzymes. Diagnosis is primarily based on clinical signs and postmortem findings but a polymerase chain reaction (PCR) is now available to detect C. piliforme DNA in organs and feces. Disease occurred most frequently in foals between 9 and 30 days of age that were born in April to May and was associated with heavy rainfall in the spring and high protein and nitrogenous diets fed to nursing mares. The findings are consistent with the ingestion of C. piliforme in the feces of adult horses and overgrowth in the intestine of foals with a high level of nutrients in their intestine. PMID- 24155495 TI - Prospective trial of autologous conditioned plasma versus hyaluronan plus corticosteroid for elbow osteoarthritis in dogs. AB - This prospective, randomized, double-blinded trial compared outcomes in dogs with bilateral elbow osteoarthritis (OA) treated with hyaluronan plus methylprednisolone (HA + S) or autologous conditioned plasma (ACP((r)); Arthrex). An investigator blinded to the treatments graded lameness (0-4) before and 6 months after a single injection with either HA + S or ACP. Clients were blinded to treatment and completed a validated survey before and 1, 6, 12, and 24 weeks after injection. Ten dogs (5 per group) completed all parts of the study. Pre treatment lameness grades were 1.2 +/- 0.97 for HA + S and 1.8 +/- 1.1 for ACP and were not different between groups. Post-treatment lameness grades were 0.4 +/ 0.55 for HA + S and 0.8 +/- 0.64 for ACP with significant (P < 0.05) improvement with either treatment but without differences between groups. Client-based assessments demonstrated improvements in activity, lameness, and pain with HA + S and ACP. These data suggest that both treatments have beneficial effects for dogs with bilateral elbow OA. PMID- 24155497 TI - Why should you do whole-mouth intra-oral dental radiographs? PMID- 24155496 TI - Clinical, hematological, and biochemical findings in puppies with coronavirus and parvovirus enteritis. AB - The clinical and laboratory findings in puppies naturally infected with canine coronavirus (CCoV) and/or canine parvovirus (CPV) were compared with findings in uninfected puppies. Lymphopenia was the only parameter related to CCoV infection that was statistically significant; vomiting, anorexia, lethargy, hemorrhagic fluid diarrhea, leukopenia, lymphopenia, thrombocytopenia, hypoglycemia, and hypoproteinemia were correlated with CPV infection. PMID- 24155498 TI - John Mills' research notes on nutrition and metabolic diseases of domestic animals. PMID- 24155499 TI - Comparing fee guides. PMID- 24155500 TI - Diagnostic ophthalmology. Anterior uveitis of the right eye. PMID- 24155501 TI - Desiccation kinetics of biopreservation solutions in microchannels. AB - A microfluidic device was utilized to measure the viscosity gradients formed in carbohydrate solutions of biological significance during desiccation and skin formation. A complementary numerical model employed the free volume theory to predict the concentration-dependent diffusion coefficients and viscosity gradients in concentrated solutions. It was established that the glassy skin formation at the gas-liquid interface played a key role in water entrapment and the formation and persistence of very steep concentration and viscosity gradients in the desiccating solutions. The results of this study highlighted an important phenomenon that should be accounted for during isothermal drying of glass-forming solutions: solutions with high glass transition temperatures, inevitably, dry heterogeneously. In the final product, there are significant spatial variations in water and solute content affecting the storage stability. PMID- 24155502 TI - Synthesis of 13C2-Benzo[a]pyrene and its 7,8-Dihydrodiol and 7,8-Dione Implicated as Carcinogenic Metabolites. AB - Synthesis of the 13C2-labelled analogues of the carcinogenic polycyclic aromatic hydrocarbon benzo[a]pyrene and its active metabolites are described. The method entails Pd-catalyzed Suzuki-Miyaura coupling of a naphthalene boronic acid with 2 bromobenzene-1,3-dialdehyde followed by Wittig reaction of the product with 13CH2=PPh3. PMID- 24155504 TI - Warmth and Competence: Stereotype Content Issues for Clinicians and Researchers. AB - Stereotypes are often accidents of history, based on passing configurations of groups' societal interdependence and status. This article overviews our framework for understanding all this: the Stereotype Content Model, focused on two fundamental dimension of intergroup and interpersonal cognition, perceived warmth (from interdependence) and perceived competence (from relative status); then it discusses immigrant images as a case study; next, the article focuses on the toxic and potentially curative effects of each dimension. PMID- 24155505 TI - Focus on Israel: in the beginning .... PMID- 24155506 TI - Kaplan's Corner. PMID- 24155503 TI - Zinc Finger Nucleases: Tailor-made for Gene Therapy. AB - Genome editing with the use of zinc finger nucleases has been successfully applied to variety of a eukaryotic cells. Furthermore, the proof of concept for this approach has been extended to diverse animal models from Drosophila to mice. Engineered zinc finger nucleases are able to target specifically and manipulate disease-causing genes through site-specific double strand DNA breaks followed by non-homologous end joining or homologous recombination mechanisms. Consequently, this technology has considerable flexibility that can result in either a gain or loss of function of the targeted gene. In addition to this flexibility, gene therapy by zinc finger nucleases may enable persistent long term gene modification without continuous transfection- a potential advantage over RNA interference or direct gene inhibitors. With systemic viral delivery systems, this gene-editing approach corrected the mutant factor IX in models of mouse hemophilia. Moreover, phase I clinical trials have been initiated with zinc finger nucleases in patients with glioblastoma and HIV. Thus, this emerging field has significant promise as a therapeutic strategy for human genetic diseases, infectious diseases and oncology. In this article, we will review recent advances and potential risks in zinc finger nuclease gene therapy. PMID- 24155507 TI - New classification for single-system light treatment. AB - BACKGROUND AND AIMS: Although the use of the laser in medical applications has increased dramatically during the last three decades, it is significant that during the last few years non-laser light sources have gained prominence in photomedicine and photosurgery, particularly the use of light-emitting diodes (LEDs) and intense pulsed light (IPL). The author therefore believed it was important to devise a new classification of light/tissue interactions, and that the well-accepted acronym LLLT and HLLT should now stand for low level light therapy and for high level light treatment, since the 'L' in 'laser', LED and IPL stands for 'light'. RATIONALE: The author herein presents a classification, which is based on the level of reaction induced by the light incident on tissue, rather than being based on the system used to deliver the light energy. When the level of tissue reactivity to light of very low incident power and energy densities is well below the cells' damage threshold, so that instead of being damaged the cells are directly activated by the low incident photon density, the changes in the irradiated tissue are photoactivative and reversible: the author hereafter refers to this group of reactions as low level light therapy (LLLT). When the level of tissue reactivity to light of very high incident power and energy densities is over the cells' damage threshold, so that the cells are directly destroyed, the changes in the irradiated tissue are photodestructive and irreversible: the author hereafter refers to this group of reactions as high level light treatment (HLLT). For levels of tissue reaction intermediate to HLLT and LLLT, the author suggests the new term, medium level light treatment (MLLT), as described in detail herein. CONCLUSIONS: When the new classification system of light treatment (LT) is understood and used, the author feels this offers an accurate and simple method of classifying light/tissue reactions by the therapeutic reaction itself, rather than by the light source, laser, LED, IPL system or other, used to produce the reaction. PMID- 24155508 TI - A possible mechanism for the bactericidal effect of visible light. AB - Visible light at high intensity was found to kill bacteria while low-power light in the visible and near infrared region enhances bacterial proliferation. The present review summarizes evidence demonstrating that the mechanism of visible light- bacteria interaction involves reactive oxygen species (ROS) generation. The ROS are photo induced by bacterial endogenous photosensitizers. Phototoxic effects were found to involve induction of high amounts of reactive oxygen species (ROS) by the bacteria while low amounts of ROS may promote their proliferation. Intense blue light, preferably at 415nm, is better than red light for bacteria killing. PMID- 24155510 TI - Diamond shaped optical fiber delivery system. AB - BACKGROUND: Optical fibers are generally used with a flat cut end. The adaptation of a coaxial exit of a refrigerated gas near the distal tip of the optical fiber cools the tissue where the laser beam is applied and reduces the injury of thermal effects on biological tissue. MATERIALS AND METHODS: We have changed the flat end geometry of the fiber's end to a pyramidal end shape (named: Diamond tip). In this project we have evaluated the new shape of the fiber's end using laboratory tests and in real conditions. We have examined the emission pattern in the air and in water as well as its performance in surgery. RESULTS: With the new shape better results were obtained: higher power density, more utilizations of the same fiber (after sterilization) resulting in economical savings. The diamond tip is characterized by greater mechanical resistance then conical tip delivery systems. The greater resistance of the Diamond tip prevents optical fiber breakage during surgery. The delivered system can be reshaped by a trained hospital physician and reused. Our experience shows that delivery systems intended by the producer to one use only can be converted, by reshaping their tips, to highly performing delivery systems, which can be reused many times. In addition less power was needed, with less tissue penetration. The thermal effect was minimized and higher mechanical resistance was achieved, which allowed reusing the fiber more than six times. The special structure of the faces of the optical fiber diamond tip eased its sliding. CONCLUSION: The Diamond tip is superior to other fiber end tips by having minimal thermal effects, higher mechanical resistance and by being reused many times. PMID- 24155509 TI - The aesthetic applications of intense pulsed light using the Lumenis M-22 device. AB - BACKGROUND: Fifteen years have passed since the first Intense Pulsed Light (IPL) devices were introduced into the market. A variety of devices that use light energy for aesthetic puposes are currently manufactured by several companies, and newer devices offering improved performance and features are periodically being introduced. Herein we present our experience with the MP-22 device (Lumenis Ltd., Yokneam, Israel) for cosmetic treatment of benign skin lesions. PATIENTS AND METHODS: We collected patient data from all patients who received IPL and Nd:Yag laser treatments with the MP-22 over a one year period (Jan 2009-Jan 2010). The study group included 92 patients who were treated on the face, neck, trunk and hands. The main indications for treatment were lentigo and superficial vascular lesions. Patient age ranged from 16 to 72 years old, and 89 patients were female. Exclusion criteria for treatment were suspicion of skin cancer, isotretinoin treatment during the previous 6 months, and pregnancy. Satisfaction after treatment was evaluated by the patients on a scale ranging from 0 to 5, with 5 = excellent, 4 = very good, 3= good, 2= moderate improvement, 1= mild improvement and 0= no improvement. RESULTS: Ninety-three percent of the patients were satisfied (rating 3, 4 or 5 on the above scale). Ninety-five percent of the patients had one or two treatment sessions. Of the treatments, 82 were on the face, two on the neck, four on the trunk and 13 on the dorsal aspect of the hands. Minor side effects such as erythema for longer than 24 hours and facial edema for more than one day were reported by 9 patients. Major complications such as scars, hyperpigmentation or hypopigmentation were not recorded. The fluence delivered varied from 14-18 J/cm(2). CONCLUSION: IPL is an effective and safe method for skin treatments, namely removal of vascular and pigmented lesions. PMID- 24155511 TI - A new lightening approach to acne treatment-combining therapy modalities for maximizing acne treatment: Phototherapy (LHETM), drugs, skin rejuvenation and skin tightening. AB - BACKGROUND: Combination therapies are increasingly being used for the treatment of acne. OBJECTIVE: 2 years of clinical experience using a combination of drugs with LHETM phototherapy on moderate to severe acne patients. METHODS: Patients first underwent a series of 8-10 bi-weekly LHE treatments to reduce their dermal inflammatory process. These treatments were combined with keratolytic agents which are not contraindicated with phototherapy. The combined LHE/drug treatment regimen was followed by a series of LHE skin rejuvenation procedures to treat post acne symptoms of localized erythema, post inflammatory hyperpigmentation and scars. CONCLUSIONS: This double phototherapy protocol appears to offer excellent clinical and aesthetic results with no side effects or complications and may be repeated if relapse occurs. PMID- 24155512 TI - Preliminary experience in facial and body contouring with 1444 nm micropulsed Nd:YAG laser-assisted lipolysis: A review of 24 cases. AB - BACKGROUND AND AIMS: Near-infrared laser-assisted lipolysis has claimed attention recently as a fast, safe and effective way to remove unwanted fat from various areas of the body. Removal of fat from the face has however proved more difficult. A novel 1444 nm line of the micropulsed Nd:YAG has recently been developed, offering superior duality of absorption in both fat and water. The present preliminary study was designed to assess the efficacy of the 1444 nm wavelength in facial and body contouring. SUBJECTS AND METHODS: Twenty-four informed and consenting female patients (ages ranging from 23 yr to 59 yr, mean age 32.38 +/- 7.26 yrs) were recruited into the study. The laser used was a micropulsed 1444 nm Nd:YAG system. Following tumescent anesthesia, the tip of the optical fiber was placed in the subcutaneous fat via a cannula inserted through a small puncture wound, and lasing was commenced while the tissue over the end of the optical fiber was continuously palpated to check for excessive heat formation. Cold compresses were applied post-lasing. Patients were followed for at least 2 months with clinical photography at baseline, immediately post treatment and at subsequent assessment points. RESULTS: All patients successfully completed the study. Patient subjective satisfaction was high, and an objective clinician assessment from the clinical photography showed good efficacy. There were no major adverse side effects. Minor side effects were transitory, all resolved spontaneously and good results were maintained during a 2-3-month follow up. CONCLUSIONS: The present study showed high efficacy for the 100 MUs micropulsed Nd:YAG laser at 1444 nm for laser-assisted lipolysis of both body and facial areas, with no adverse side effects and virtually no downtime. The high absorption rate of 1444 nm in both fat and water, coupled with the 100 MUs pulse, was believed to contribute highly to the success of the study and the satisfaction of the patients. Further larger studies are warranted. PMID- 24155513 TI - Enhancement of microtubule-associated protein-1 Alpha gene expression in osteoblasts by low level laser irradiation. AB - BACKGROUND: Low level laser irradiation (LLLI) stimulates bone regeneration. However, the molecular mechanisms leading to this is not yet understood. The stepwise subtractive cDNA cloning technology has been developed, coupled with DNA homology searched in DNA database is useful to identify the certain gene. AIM: In order to understand the mechanism, we attempted to identify genes whose expressions are enhanced by LLLI. MC3T3-E1 osteoblastic cells were irradiated with an 830 nm Ga-Al-As diode laser, and a cDNA library was constructed using subtractive gene cloning. MATERIAL AND METHODS: The cDNA library of osteoblasts which was treated by LLLI was constructed. Nucleotide sequences were analyzed and homology searched in a DNA database using BLASTN program to identify the gene with altered expression. Altered mRNA levels by LLLI were confirmed by reverse transcription polymerase chain reaction (RT-PCR) and real-time PCR. RESULTS: The DNA sequence of a subtracted gene clone MCL129 indicated high homology (99%) with the microtubule-associated protein 1A (MAP1A) gene. Increase in MAP-1A mRNA level by LLLI was successfully confirmed by RT-PCR and real-time PCR. DISCUSSION: MAP1A has been shown to promote microtubule assembly and its functional expression. Microtubules play an important role in cell division, cell shape and polarity, cell movement, intracellular transport, signal transduction, and synthesis and secretion of collagen. Thus, enhancement of MAP1A gene expression by LLLI may be one of the molecular mechanisms involved in accelerating bone formation by LLLI. CONCLUSION: LLLI irradiation enhances MAP1A gene expression and modulates microtubule assembly and the functional structure of microtubules, in turn, stimulates osteoblastic proliferation and differentiation. PMID- 24155515 TI - Erratum. PMID- 24155514 TI - Reduction of CXCR4 expression in Rheumatoid Arthritis Rat Joints by low level diode laser irradiation. AB - BACKGROUND: Rheumatoid arthritis (RA) is an inflammatory joint disorder, whose progression leads to the destruction of cartilage and bone. Chemokines and their receptors are potential therapeutic targets in RA. Among these, it has been suggested that CXC chemokine 4 (CXCR4) and its ligand CXC ligand 12 (CXCL12) are involved in RA pathogenesis. Low-level laser irradiation (LLLI) is currently being evaluated for the treatment of RA; however, the molecular mechanisms underlying its effectiveness remain unclear. AIM: To understand the anti inflammatory effect of LLLI, we used the collagen-induced arthritis (CIA) rat as RA model and analyzed the gene expression profile in synovial membrane in the hindpaw joints of control, CIA and CIA + LLLI. Expression of CXCR4 and CXCL12 genes were also studied. MATERIALS AND METHODS: Total RNA was isolated from the synovial membrane tissue of CIA rat joints or CIA joints treated with LLLI (830 nm Ga-Al-As diode), and gene expression profiles were analyzed by DNA microarray (41,000 rat genes). The mRNA levels were confirmed by reverse transcription polymerase chain reaction (RT-PCR) and real-time PCR. Immunohistochemical examination to examine CXCR4 protein expression was also carried out. RESULTS: DNA microarray analysis showed that CXCR4 gene expression was increased in CIA tissue and LLLI treatment significantly decreased CIA-induced CXCR4 mRNA levels. In contrast, CXCL12 did not show any significant changes. The microarray data of CXCR4 mRNA levels were further validated using RT-PCR and real-time PCR. Increased CXCR4 mRNA levels by CIA and its reduction following LLLI was successfully confirmed. CXCR4 production was increased in CIA joints and its production was decreased by LLLI. CONCLUSION: Decreased CXCR4 expression may be one of the mechanisms in LLLI-mediated reduction of RA inflammation. PMID- 24155517 TI - Kaplan's Corner. PMID- 24155516 TI - Shaken but not defeated. AB - SINCERE CONDOLENCES FROM ALL LASER THERAPY EDITORIAL STAFF TO THE VICTIMS OF THE GREAT TOHOKU-KANTO EARTHQUAKE AND TSUNAMI, MARCH 11(th) 2011, THEIR FAMILIES AND FRIENDS: OUR THOUGHTS AND PRAYERS ARE WITH BOTH THOSE WHO WERE LOST, AND THE SURVIVORS. PMID- 24155518 TI - Laser safety: Risks, hazards, and control measures. AB - Now that laser technology has emerged from hospital operating rooms, and has become available to office practices, clinics, and private enterprises, the burden of responsibility for safety has shifted from hospital staff to the individual user, often without benefit of appropriate or adequate resources. What remains, regardless of the practice site, application, or system in use, is the constant goal of establishing and maintaining a laser safe environment for the patient, the staff, and the user, at all times. This should be the goal of all who are involved with the sale, purchase, application, and management of all medical laser systems-under all circumstances. Laser safety is EVERYONE'S concern! A laser is as safe or as hazardous as the user-and that user's knowledge and skill, defines how well laser safety is managed. Of all hazards, complacency is the most dangerous, and it is imperative to develop a risk management perspective on laser safety. Proper safety management requires a fourfold approach including: knowledge of standards, identification of hazards and risks, implementation of appropriate control measures, and consistent program audit to demonstrate quality assurance. PMID- 24155519 TI - Photodynamic therapy as an adjunct to surgery or other treatments for squamous cell lung cancers. AB - OBJECTIVES: Photodynamic therapy (PDT) was performed on 14 cases of tracheobronchial malignancies with variable tumor stages as an adjunct to surgery. We retrospectively reviewed these PDT cases to evaluate safety and oncologic outcome. METHODS: From June 2004 to August 2010, PDT was performed in 14 cases for lung cancer. Medical records were reviewed, including demographic data, indication of the PDT, and oncologic outcomes, during the follow-up period. RESULTS: There were 5 deaths, 1 loss of follow-up, and 5 patients that are still alive. There were 8 cases of complete response (CR), 4 cases of no response (NR), and 2 cases of partial response (PR). Among the recurrent tracheoendobronchial lesions in 5 patients, CR was accomplished in 4 patients and NR was observed in 1 patient. The mean survival of all patients was 23.9 months after PDT with a range of 6 - 66 months. CONCLUSION: PDT demonstrates a safe and effective role as an adjunct to surgery in treating recurrent mucosal carcinoma in surgically high risk patients. It is also effective for palliation of bronchial obstruction by cancer mass. PMID- 24155520 TI - Low level laser therapy (LLLT) for patients with sacroiliac joint pain. AB - BACKGROUND AND AIMS: Sacroiliac joint pain not associated with a major etiological factor is a common problem seen in the orthopedic clinical setting, but diagnosis is difficult because of the anatomical area and thus it is sometimes difficult to effect a complete cure. Low level laser therapy (LLLT) has been well-reported as having efficacy in difficult pain types, so the following preliminary study was designed to assess the efficacy of LLLT for sacroiliac pain. MATERIALS AND METHODS: Nine patients participated, 4 males and 5 females, average age of 50.4 yrs, who attended the outpatient department with sacroiliac pain. The usual major disorders were ruled out. Pain was assessed subjectively pre-and post-LLLT on a visual analog scale, and trunk range of motion was examined with the flexion test to obtain the pre- and post-treatment finger to floor distance (FFD). The LLLT system used was an 830 nm CW diode laser, 1000 mW, 30 sec/point (20 J/cm(2)) applied on the bilateral tender points twice/week for 5 weeks. Baseline and final assessment values (after the final treatment session) were compared with the Wilcoxon signed rank test (nonparametric score). RESULTS: All patients completed the study. Eight of the 9 patients showed significant pain improvement and 6 demonstrated significantly increased trunk mobility (P <0.05 for both). CONCLUSIONS: LLLT was effective for sacroiliac pain, and this may be due to improvement of the blood circulation of the strong ligaments which support the sacroiliac joint, activation of the descending inhibitory pathway, and the additional removal of irregularities of the sacroiliac joint articular surfaces. Further larger-scale studies are warranted. PMID- 24155521 TI - Effect of low-level monochromatic radiations on some morphological and physiological parameters of plants. AB - BACKGROUND: Studying the behavior of living organisms under the action of some physical or chemical factors (corpuscular or electromagnetic radiation, magnetic or electric field, sound waves, salinity, stimulants etc.) is enjoying major interest nowadays.(1,2)) The main goal is to understand the mechanisms of action of these factors on biological tissues, and use this knowledge for applications in biology and medicine. A special place in modern medicine is occupied by the therapeutic applications of laser radiation. AIMS: In the current study we are attempting to determine whether the therapeutic lasers used in medicine have the potential to produce changes of some morphological and physiological parameters of plants. If these changes actually occur, the next task is to determine whether they are due to laser action on water used for watering by changing its properties, or by the direct action of laser radiation on the plants cells. Matcrials and Mcthods: We used as samples two groups of wheat seeds, planted in cotton. In the first group we only irradiated irrigation water, while in the second group only plants. We used as sources of radiation lasers and LEDs, with wavelengths between 455 nm and 850 nm. Power density was P = 50 mW/cm(2) for all samples, the exposure time ranged between 1s and 80s, and energy density (or fluence) between 0 and 4J/cm(2). We measured modifications of some morphological and physiological parameters (the biomass quantity, germination rate of seeds, number and height of the seedlings etc.) as a function of fluence. RESULTS: When only irrigation water was irradiated, we have found for all wavelength used a strong inhibitory effect on germination (between 30% and 50% for samples grown in the ground and between 13% and 40% for those grown in cotton). Regarding the other parameters determined, a stimulating effect, but less pronounced than if the plant was only irradiated, was noticed. When only plant was irradiated, the effects are altered depending on the wavelength and fluence. DISCUSSION AND CONCLUSION: Although apparently different, plant and animal cells have some similar characteristics, the differences between them not being essential, involving mainly the quantitative aspect. In these circumstances the study of the monochromatic radiation effects on plants is useful to characterize the action of those radiations on the animal and human tissues. Studies on plants exhibit a series of advantages: they are cheap, easily reproduced and suitable for producing good statistics etc. It can also be verified as to which extent the laws of classic photobiology show modifications when low level lasers are utilized. PMID- 24155522 TI - Effect of 630-NM pulsed laser irradiation on the proliferation of HeLa cells in Photofrin((r))-mediated photodynamic therapy. AB - BACKGROUND AND AIMS: Red laser light of wavelength 630 nm is usually used for Photofrin((r))-mediated photodynamic therapy (PDT). The 630-nm light employed in PDT corresponds to the region of the wavelength used in low-level laser therapy (LLLT) may influence on the photodynamic effect required for killing cancer cells. The aim of this in vitro study was to investigate the changes in cell viability and degree of cell proliferation after Photofrin((r))-mediated PDT using 630-nm pulsed laser irradiation (10 Hz repetition rate and 7-9 ns pulse width), which was clinically found to induce no remarkable cell injury. MATERIALS AND METHODS: A study has been conducted in which HeLa cells are incubated with Photofrin((r)) for 15 min (10 ug/ml). Irradiation was carried out at an average fluence rate of 50 mW/cm(2) with light doses of 1, 3, and 5 J/cm(2). The cytotoxic effects on the cells are evaluated by the XTT (2,3-bis[2-methoxy-4 nitro-5-sulfophenyl]-5-[(phenylamino)carbonyl]-2H-tetrazolium hydroxide) assay. RESULTS: The results showed that the laser irradiated cells exhibited a greater clonogenic activity than normal and PDT treated cells for a short period after the laser irradiation. CONCLUSION: If the level of 630-nm pulsed laser irradiation employed in a PDT is comparatively lowered, it would have a biostimulatory effect like that of in LLLT. PMID- 24155524 TI - Through turbulence to stability. PMID- 24155523 TI - Novel multi-source phase-controlled radiofrequency technology for non-ablative and micro-ablative treatment of wrinkles, lax skin and acne scars. AB - The basic properties of lasers and pulsed light sources limit their ability to deliver high energy to the dermis and subcutaneous tissues without excessive damage to the epidermis. Radiofrequency was shown to penetrate deeper than optical light sources independent of skin color. The early RF-based devices used single source bipolar RF, which is safe but limited in use due to the superficial flow of energy between the two bipolar electrodes. Another type of single source RF employs a single electrode (monopolar) in which the RF energy flows from one electrode on the surface of the skin through the entire body to a plate under the body. Although more effective than bipolar, this devices require intense active cooling of the skin and may be associated with considerable pain and other systemic and local safety concerns. Latest generation of RF technology developed by EndyMed Medical Ltd. (Caesarea, Israel) utilizes simultaneously six or more phase controlled RF generators (3DEEP technology). The multiple electrical fields created by the multiple sources "repel" or "attract" each other, leading to the precise 3 dimensional delivery of RF energy to the dermal and sub-dermal targets minimizing the energy flow through the epidermis without the need for active cooling. Confocal microscopy of the skin has shown that 6 treatment sessions of Multisource RF technology improve skin structure features. The skin after treatment had longer and narrower dermal papilla and denser and finer collagen fiber typical to younger skin as compared to pre treatment skin. Ultrasound of the skin showed after 6 treatment sessions reduction of 10 percent in the thickness of the subcutaneous fat layer. Non ablative facial clinical studies showed a significant reduction of wrinkles after treatment further reduced at 3 months follow-up. Body treatment studies showed a circumference reduction of 2.9 cm immediately after 6 treatments, and 2 cm at 12 months after the end of treatment, proving long term collagen remodeling effect. Clinical studies of the multisource fractional RF application have shown significant effects on wrinkles reduction and deep atrophic acne scars after 1-3 treatment sessions. PMID- 24155525 TI - Kaplan's Corner. PMID- 24155526 TI - Treatment of enlarged pores with the quasi long-pulsed versus Q-switched 1064 nm Nd:YAG lasers: A split-face, comparative, controlled study. AB - BACKGROUND AND AIMS: A variety of treatment modalities have been used to reduce the size of en-larged pores. The 1064 nm Nd:YAG laser, in addition to its role in removal of tattoos and age-related dyschromia, depilation and skin rejuvenation, may also play a role in reducing the size of enlarged pores. The present split face controlled study assessed and compared the efficacy between the quasi long pulsed (micropulsed) and the Q-switched modes of the Nd:YAG laser in the treatment of enlarged pores. SUBJECTS AND METHODS: Twenty subjects with enlarged pores were recruited for the micropulsed vs Q-switched study, all treated with the same 1064 nm Nd:YAG laser system. Ten subjects were treated with the 300 us micropulsed mode and the other ten subjects were treated with the 5 ns Q-switched mode. All subjects were treated on the right half of the face, the left half serving as an untreated control. Five laser sessions were performed. The pore sizes were measured using an image analysis program and the sebum level was measured with a Sebumeter((r)) before and after the treatments. RESULTS: The pore size and sebum level significantly decreased with treatment on the treated side (right cheek and right half of nose) in both the micropulsed and Q-switched modes compared to the control side (p<0.05), but without any statistically significant difference between the modes. CONCLUSIONS: The micropulsed and Q-switched Nd:YAG laser treatments reduced pore size and sebum levels with more or less equal efficacy and with no adverse side effects. PMID- 24155527 TI - Enlarged pores treated with a combination of Q-switched and micropulsed 1064 nm Nd:YAG laser with and without topical carbon suspension: A simultaneous split face trial. AB - BACKGROUND AND AIMS: Enlarged facial pores remain one of the major cosmetic concerns among Asian females. This study attempted to assess and compare the efficacy of a combination of the Q-switched and quasi long-pulsed (micropulsed) Nd:YAG laser to reduce the size of the enlarged pores with and without an exogenous photoenhancer. METHODS: In twenty five female subjects mean age 34.04 yr and skin type II-IV, a carbon lotion as a photoenhancer was applied on one side of the face (Method 1) and the other side was used as the control (Method 2). The entire face was then treated with a single pass of the 1064 nm Nd:YAG laser in the micropulsed mode, pulse fluence and width of 2.3 J/cm(2) and 300 usec, respectively. Multiple passes were then delivered in the Q-switched mode (2.5 J/cm(2) and 5 nsec). RESULTS: Three weeks after the final treatment, 75% of the subjects showed improvement with method 1 whereas 67% showed improvement with method 2. No adverse side effects were reported with either method. CONCLUSIONS: Although histological confirmation was not performed, we were able to prove both subjectively and objectively that the use of the combination of the micropulsed and Q-switched modes of the Nd:YAG laser was useful in reducing pore size, and that the photoenhancer improved the efficacy. PMID- 24155528 TI - The dual toning technique for melasma treatment with the 1064 nm Nd: YAG laser: A preliminary study. AB - BACKGROUND AND AIMS: Melasma is a treatment-resistant and acquired pigmentary facial skin condition of uncertain etiology particularly prevalent in the older Asian female. Traditional bleaching agents have offered some success. Intense pulsed light (IPL), fractionated nonablative and more recently ablative laser technology have also been used, but were associated with postoperative hyperpigmentation in the Asian skin. The present study examined the consecutive application of 2 modes of the 1064 nm Nd:YAG laser in the 'dual toning' process. SUBJECTS AND METHODS: Thirty females, mean age 41.4 +/- 11.96 yr, Fitzpatrick skin type IV, participated in the prospective uncontrolled study. All subjects were treated with the 1064 nm Nd:YAG laser, first with the 5 ns Q-switched mode, 1.2 J/cm(2), 8 mm collimated handpiece with multiple passes and then immediately after with the micropulsed mode, 300 us, 7.0 J/cm(2), 5 mm handpiece, multiple passes. Mild and even erythema was the endpoint. Treatments were given every other week until maximum improvement was obtained. Improvement was rated at a final assessment 6 weeks after the final treatment on a 5 point scale where 1 was little or no improvement and 5 was maximum improvement. RESULTS: At the final treatment session and at the 6-week assessment, 20 of the 30 patients (67%) saw a fair to excellent degree of improvement, 7 (23%) had visible improvement and little or no improvement was seen in 3 (10%) patients. There were no unexpected side effects in any patients. CONCLUSIONS: The dual toning technique using the 1064 nm Nd:YAG laser was safe and effective, and well-tolerated by all patents without anesthesia. Larger controlled studies are merited with more objective measurement techniques to confirm the results of this preliminary study. PMID- 24155529 TI - Development and optimization of a diode laser for photodynamic therapy. AB - BACKGROUND AND AIMS: This study demonstrated the development of a laser system for cancer treatment with photodynamic therapy (PDT) based on a 635 nm laser diode. In order to optimize efficacy in PDT, the ideal laser system should deliver a homogeneous nondivergent light energy with a variable spot size and specific wavelength at a stable output power. MATERIALS AND METHODS: We developed a digital laser beam controller using the constant current method to protect the laser diode resonator from the current spikes and other fluctuations, and electrical faults. To improve the PDT effects, the laser system should deliver stable laser energy in continuous wave (CW), burst mode and super burst mode, with variable irradiation times depending on the tumor type and condition. RESULTS AND COMMENTS: The experimental results showed the diode laser system described herein was eminently suitable for PDT. The laser beam was homogeneous without diverging and the output power increased stably and in a linear manner from 10 mW to 1500 mW according to the increasing input current. Variation between the set and delivered output was less than 7%. CONCLUSIONS: The diode laser system developed by the author for use in PDT was compact, user-friendly, and delivered a stable and easily adjustable output power at a specific wavelength and user-set emission modes. PMID- 24155530 TI - Is light-emitting diode phototherapy (LED-LLLT) really effective? AB - BACKGROUND: Low level light therapy (LLLT) has attracted attention in many clinical fields with a new generation of light-emitting diodes (LEDs) which can irradiate large targets. To pain control, the first main application of LLLT, have been added LED-LLLT in the accelerated healing of wounds, both traumatic and iatrogenic, inflammatory acne and the patient-driven application of skin rejuvenation. Rationale and Applications: The rationale behind LED-LLLT is underpinned by the reported efficacy of LED-LLLT at a cellular and subcellular level, particularly for the 633 nm and 830 nm wavelengths, and evidence for this is presented. Improved blood flow and neovascularization are associated with 830 nm. A large variety of cytokines, chemokines and macromolecules can be induced by LED phototherapy. Among the clinical applications, non-healing wounds can be healed through restoring the collagenesis/collagenase imbalance in such examples, and 'normal' wounds heal faster and better. Pain, including postoperative pain, postoperative edema and many types of inflammation can be significantly reduced. Experimental and clinical evidence: Some personal examples of evidence are offered by the first author, including controlled animal models demonstrating the systemic effect of 830 nm LED-LLLT on wound healing and on induced inflammation. Human patients are presented to illustrate the efficacy of LED phototherapy on treatment-resistant inflammatory disorders. CONCLUSIONS: Provided an LED phototherapy system has the correct wavelength for the target cells, delivers an appropriate power density and an adequate energy density, then it will be at least partly, if not significantly, effective. The use of LED-LLLT as an adjunct to conventional surgical or nonsurgical indications is an even more exciting prospect. LED-LLLT is here to stay. PMID- 24155531 TI - Clinical application of laser treatment for cardiovascular surgery. AB - BACKGROUND: Recently, several kinds of lasers have been widely employed in the field of medicine and surgery. However, laser applications are very rare in the field of cardiovascular surgery throughout the world. So, we have experimentally tried to use lasers in the field of cardiovascular surgery. There were three categories: 1) Transmyocardial laser revascularization (TMLR), 2) Laser vascular anastomosis, and 3) Laser angioplasty in the peripheral arterial diseases. By the way, surgery for ischemic heart disease has been widely performed in Japan. Especially coronary artery bypass grafting (CABG) for these patients has been done as a popular surgical method. Among these patients there are a few cases for whom CABG and percutaneous coronary intervention (PCI) could not be carried out, because of diffuse stenosis and small caliber of coronary arteries. Materials and methods of TMLR: A new method of tranasmyocardial revascularization by CO2 laser (output 100 W, irradiation time 0.2 sec) was experimentally performed to save severely ill patients. In this study, a feasibility of transmyocardial laser revascularization from left ventricular cavity through artificially created channels by laser was precisely evaluated. RESULTS: In trials on dogs laser holes 0.2mm in diameter have been shown microscopically to be patent even 3 years after their creation, thus this procedure could be used as a new method of transmyocardial laser revascularization. Clinical application of TMLR: Subsequently, transmyocardial laser revascularization was employed in a 55-year old male patient with severe angina pectoris who had undergone pericardiectomy 7 years before. He was completely recovered from severe chest pain. Conclusions of TMLR: This patient was the first successful case in the world with TMLR alone. This method might be done for the patients who percutaneous coronary intervention and coronary artery bypass grafting could be carried out. Laser vascular anastomosis: At present time, in vascular surgery there are some problems to keep long-term patency after anastomosis of the conventional suture method, especially for small-caliber vessels. Materials and methods of Laser vascular anastomosis: From these standpoints, a low energy CO2 laser was employed experimentally in vascular anastomosis for small-caliber vessels. Resullts of Laser vascular anastomosis: From preliminary experiments it could be concluded that the optimal laser output was 20-40 mW and irradiation time was 6-12 sec/mm for vascular anastomosis of small-caliber vessels in the extremities. And then, histologic findings and intensity of the laser anastomotic sites were investigated thereafter. Subseqently, good enough intensity and good healing of laser anastomotic sites as well as the conventional suture method could be observed. There were no statistic differences between laser and suture methods. A feasibility of laser anastomosis could be considered and clinical application could be recognized. Clinical applications of Laser vascular anastomosis: On February 21, 1985, arterio-venous laser anastomosis for the patient with renal failure was smoothly done and she could accept hemodialysis. Conclusions of Laser vascular anastomosis: This patient was the first clinical successful case in the world. Thereafter, Laser vascular anastomosis were in 111 patients with intermittent claudication, refractory crural ulcer, and coronary disorders. Thereafter, they are going well. Laser angioplasty: Laser angioplasty for peripheral arterial diseases. There are many methods to treat peripheral arterial diseases such as balloon method, atherectomy, laser technique and stenting graft in the field of endovascular treatment. Recent years, minimal invasive treatment should be employed even in the surgical treatment. However, there are different images between these methods. Materials and methods of Laser angioplasty: We have chosen to use laser for endovascular treatment for peripheral arterial diseases. We have tried to check between laser energy and vessel wall. Results of Laser angioplasty: Subsequently, it could be concluded that optimal conditions for laser angioplasty were 6 W in output and irradiation time was 5 sec. And with another method of feedback control system, temperature of metal tip probe was 200 degrees C and irradiation time was 5 sec for each shot. And histological study and feasibility of angioscopic guidance could be done and clinical application was started. Until now, 115 patients were successfully treated with their life longevity. Conclusions of Laser angioplasty: Thus, laser applications were useful methods to treat a lot of patients with some ischemic problems. PMID- 24155533 TI - Focus on taiwan. PMID- 24155532 TI - LLLT and PDT. PMID- 24155534 TI - Kaplan's Corner. PMID- 24155535 TI - Long term follow-up of intralesional laser photocoagulation (ILP) for hemangioma patients. AB - BACKGROUND AND OBJECTIVES: Hemangiomas remain a challenge for patients and plastic surgeons. Promising results have been reported using intralesional photocoagulation (ILP) for treatment. The objective of our study is to review the long term results of a large series of hemangiomas in patients treated by ILP. Materials (Subjects) and Methods: A retrospective review of 684 hemangiomas in patients were treated by ILP with an Nd:YAG (neodymium-yttrium-aluminium-garnet) (1064 nm) laser over a period of 10 years (January 1996-January 2005). Patients' ages ranged from one month to 11 years 5 months (mean, 1 year 10 months). The patient group consisted of 474 females and 210 males. RESULTS: Patients were treated with an Nd:YAG laser delivered through a 600 m optical fiber. Laser power was set at 7 to 15 watts (W) and delivered with pulse duration of 7 to 15 seconds (s). The results showed 603 (88.6%) patients had more than 50% reduction of the volume in hemangiomas at 3 months after one treatment; and 663 (96.9%) patients had more than 50% reduction of the volume at 3 months after two treatments. Patients who had continuous ILP achieved excellent results. CONCLUSIONS: Postoperative complications have been related to photocoagulation that has been delivered too extensively or superficially, with resultant ulceration, infection, bleeding, and scarring. These complications can be avoided if this potential for harm is kept in mind. PMID- 24155536 TI - Update on flashlamp pumped pulsed dye laser treatment for port wine stains (capillary malformation) patients. AB - BACKGROUND AND AIMS: Currently, the method of choice for the treatment of port wine stains is laser photocoagulation. Because of evolving treatment options, it is no longer enough for port-wine stains merely to be lightened through laser treatment. The best course of management consists of the most appropriate laser that will produce the most complete clearing of a lesion in the fewest treatment sessions with the least morbidity. The goal is generally accomplished with the use of yellow-light lasers. Materials (Subjects) and Methods: Absorption of laser energy by melanin causes localized heating in the epidermis, which may, if not controlled, produce permanent complications such as hypertrophic scarring or dyspigmentation. Refinements of the results can be achieved by using the flashlamp-pumped pulsed dye laser (FLPDL) in conjunction with the cryogen spray cooling (CSC) system. In our related studies, the infrared thermal image instrument is used for doctors in determining the optimum laser light dosage and preventing the side effects caused by FLPDL. Topic application of angiogenesis inhibitor (Imiquimod) in conjunction with pulsed dye laser treatment for the PWS patients has been assessed for improvement of FLPDL treatment. RESULTS: We present the clinical effect of FLPDL, and the efficacy and safety of cooled laser treatment of PWS birthmarks. Our clinical outcome in the laser treatment of patients with PWS has been achieved to maximize thermal impact on targeted vessels, while minimizing adverse complications. CONCLUSIONS: CSC in conjunction with FLPDL can improve the treatment of PWS. The infrared image instrument is helpful for doctors in determining the optimum laser light dosage. Topic application of angiogenesis inhibitor (Imiquimod) in conjunction with laser treatment for the PWS patients is promising in the near future. PMID- 24155537 TI - Laser assisted tooth replantation case report. AB - BACKGROUND AND AIM: Although intentional replantation for extraoral treatment is a solution for complicated endodontic cases, it is accompanied with risk of root resorption which is most likely due to extraction trauma and infected remnants. Laser therapies have long been proved for bactericidal and biostimulation effects. In the present case, a pulpitis combined severe periodontal destruction molar was extracted with an Er:YAG laser for thorough degranulation and disinfection. Before the extraction and right after the treatment, low level laser therapy (LLLT) with 810nm diode was applied for biostimulation. RESULT: Patient reported no post operative pain after laser treatment. Clinical follow-up showed uneventful healing, and excellent bone regeneration. CONCLUSION: The Er:YAG laser coupled with low level laser therapy (810 nm diode) has shown to assist and improve intentional replantation in disinfection procedure, and it may preserve more vital cells and enhance bioregeneration for less operative pain and better healing. PMID- 24155538 TI - Treatment of refractory keloids with pulsed dye laser alone and with rotational pulsed dye laser and intralesional corticosteroids: A retrospective case series. AB - BACKGROUND AND AIMS: The limited available effective treatments make the management of keloids challenging. Intralesional triamcinolone and pulsed dye laser have been used for the treatment of keloids. We sought to assess the efficacy of a treatment regime using rotational intralesional triamcinolone and pulsed dye laser in the management of keloids. Materials (Subjects) and Methods: Case notes and photographic records of 99 patients with keloids treated with pulsed dye laser (PDL) alone or rotational PDL and intralesional triamcinolone (ILT) at our centre between 2005 and 2010 were reviewed. Patients with raised, erythematous and/or symptomatic keloids unresponsive to ILT alone (usually 6 treatments) are referred for consideration of PDL. Patients are offered repeated rotational treatments of three PDL (4-15 J/cm(2), 7 mm spot, 1.5 msec pulse duration, 595 nm wavelength, DCD, 30 msec spray: 20 msec delay; spaced at 6-8 weeks intervals) followed by one ILT (10 mg or 40 mg/dl). ILT-treated flat but erythematous and/or symptomatic keloids are treated with PDL alone at 6-8 week intervals. Response after each laser treatment is documented as a percentage improvement from baseline. Based on the improvement in redness, thickness and pruritus the operator classified the response to treatment as mild (0-49%), moderate (50-75%) or excellent (>75%). Patients are reviewed at 6 months following last treatment. A patient satisfaction questionnaire was also sent out to all patients who received treatments between 2005 and 2010 and this was compared with the information gathered from the notes. RESULTS: Of the 99 patients, 58 were women and 41 were men and most were Caucasian (n=84). A total of 755 keloids were treated. The average number of PDL treatments to achieve a moderate-excellent result was 14 in male and 12 in females. Moderate-excellent improvement was seen in 76% patients. The average number of ILT required to achieve a moderate-excellent result was 5 in males and 4 in females. All patients were sent a satisfaction questionnaire and 33 responses were received wherein patients reported an average of 70% improvement in the redness and thickness of the keloids. Localised cutaneous atrophy, self-limiting erythema and injection site discomfort were noted in 3 female patients whilst no side-effects noted in the male cohort. CONCLUSIONS: Pulsed dye laser with or without intralesional triamcinolone is a moderately effective treatment of keloid scars with a very good side-effect profile and high patient satisfaction. PMID- 24155539 TI - Low level laser therapy on experimental myopathy. AB - PURPOSE: The aim of the present work was to study the effect of Helium-Neon (HeNe) and Gallium Arsenide (GaAs) laser upon nitric oxide (NO) plasma levels, an inflammatory biomarker associated with oxidative stress, in rats with experimental myopathy. These were evaluated through histological assessment. MATERIALS AND METHODS: The groups studied were: (A) control (intact rats that received LLLT sham exposures), (B) rats with myopathy and sacrificed at 24 h later, (C) rats with myopathy and sacrificed 8 days later, (D) rats with myopathy and treated with HeNe laser, (E) rats with myopathy and treated with GaAs laser, (F) intact rats treated with HeNe laser and (G) intact rats treated with GaAs laser. Myopathy was induced by injecting 50MUl of 1% carrageenan lambda (type IV) in the left gastrocnemius muscle. Low Level Laser Therapy (LLLT) was applied with 9.5 J.cm(-2) daily for 10 consecutive days with each laser. The determination of the NO was made by spectrophotometry. The muscles were stained with Hematoxylin Eosin and examined by optic microscopy. Quantitative variables were statistically analyzed by the Fisher test, and categorical by applying Pearson's Chi Squared test at p <0.05 for all cases. RESULTS: In groups B and C, NO was significantly increased compared to groups A, D, E, F and G (p<0.05). In group C, the percentage of area with inflammatory infiltration was significantly increased compared to the other groups (p<0.001). CONCLUSIONS: LLLT decreased plasma levels of NO in rats with experimental myopathies and significant muscle recovery. PMID- 24155540 TI - Reduction of interleukin-6 expression in human synoviocytes and rheumatoid arthritis rat joints by linear polarized near infrared light (Superlizer) irradiation. AB - BACKGROUND: Rheumatoid arthritis (RA) is a systemic autoimmune disorder that involves inflammation and pain of joints. Low-level laser irradiation is being evaluated for treating RA, however, the effectiveness of linear polarized near infrared light (SuperLizer; SL) irradiation is unclear. AIM: It has been reported that interleukin 6 (IL-6) plays a key role in the progression of RA. In our previous study, using DNA microarray analysis, we examined the gene expression profiling of human rheumatoid fibroblast-like synoviocyte MH7A in response to IL 1beta administration and SL irradiation. As a result, IL-6 was listed in altered gene as increased by IL-1beta and decreased by SL irradiation. MATERIAL AND METHODS: The reduction of IL-6 gene expression in MH7A by SL irradiation was confirmed by reverse transcription polymerase chain reaction (RT-PCR) and real time PCR. Effect of SL irradiation on the RA inflammation in the collagen induced arthritis (CIA) rats was also studied by measuring temperature. IL-6 production in knee joint of rats was analyzed by immunohisto-chemistry. RESULTS: Scatter plot analysis demonstrated that an increase in IL-6 gene expression by IL-1beta was reduced by SL irradiation. The reduction of IL-6 mRNA level by SL irradiation was successfully confirmed by RT-PCR and real-time PCR. SL irradiation treated CIA rat decreased the temperature of knee joints. The immunohistochemical analysis demonstrated a strong IL-6 staining in synovial membrane tissue of CIA rat joint, and SL irradiation significantly reduced the staining. DISCUSSION: Since IL-6 has been identified to be an important proinflarnmatory cytokine in the pathogenesis of RA, the reduction of IL-6 expression is one of mechanisms in reduction of inflammation in RA joints by SL irradiation suggesting that SL irradiation may be useful for RA therapy. CONCLUSION: SL irradiation reduced IL-6 gene expression in MH7A, and reduced inflammation and IL-6 protein expression in knee joint of CIA rats. PMID- 24155541 TI - New combined laser therapy for small mass of melanocytic nevi on the face. AB - BACKGROUND AND AIMS: A small mass of melanocytic nevi on the face is commonly treated by surgical resection. This method is associated with cosmetic complications, such as scarring and scar contracture. The use of CO2 Laser treatment to avoid these complications is increasing. However, scarring or recurrence may still occur after CO2 Laser treatment. To resolve these problems, we developed a new Combined Laser Therapy (CLT) protocol using three laser instruments. SUBJECTS AND METHODS: We used CO2 Laser, Nd:YAG Laser and Q-Switched Ruby Laser. The first treatment was a minimal mass reduction using CO2 Laser. The surface is covered with carbonized tissue. The second treatment with Nd:YAG Laser which removes the carbonized tissue, because the laser specifically absorbs black chromatophores. Finally, any surviving nevus cells containing melanin are destroyed with Q-Switched Ruby Laser. RESULTS: This method was used for 12 cases presenting with small masses of melanocytic nevi on the face. The maximum size of the mass was 20 mm. All cases resulted in a cosmetic improvement and there was no scarring or recurrence. Either satisfactory or greatly improved cosmetic results were obtained in all cases. CONCLUSIONS: We think that the wound healing without scarring observed in all of our cases is related to the administration of both CLT and auto-simultaneous Low reactive Level Laser Therapy (LLLT) in these cases. Therefore, this method may provide the better treatment than surgical resection in the future. PMID- 24155542 TI - It's official! LASER THERAPY has been awarded PubMed Central listing!! PMID- 24155543 TI - Kaplan's Corner. PMID- 24155544 TI - CO2 laser oral soft tissue welding: an in vitro study. AB - BACKGROUND AND AIM: Although there are some studies reporting the benefits of using laser to improve wound closure, there were a few studies in a model of oral mucosa. The aim of this in vitro study was to compare immediate tensile strength of the wound closure between suture alone and suture combined with CO2 laser welding. MATERIALS AND METHODS: The study was conducted in 40 samples of the tissue blocks from ventral sides of pig tongues. A 20 mm-length and 5 mm-depth incision was made in each sample. The samples were randomly allocated into 2 groups namely: the control group and the experimental group. The samples of the control group were sutured with 3- stitch of 4-0 black silk. The samples of the experimental group were irradiated with CO2 laser (ultrapulse mode, 800 Watt peak power, 10 Hz, 0.2 ms pulse duration and 2,262.62 J/cm(2) energy density) before sutured. The immediate tensile strength of the wound was measured by using customized tensiometer under stereomicroscope. RESULTS: The median of tensile strength of the control group and the experimental group were 30.40 g/cm(2) and 40.50 g/cm(2), respectively. There was no statistically significant difference between the groups (P value = 0.58). The proportions of the samples without wound dehiscence at the maximum limit of the tensiometer (120 g/cm(2)) were 0.15 (3/20) in the control group and 0.35 (7/20) in the experimental group. CONCLUSION: The CO2 laser welding used in this study failed to show a greater immediate tensile strength but had a higher proportion of the wound without dehiscence at the 120 g/cm(2) tensile strength by comparison with the suture alone. PMID- 24155545 TI - Low level laser therapy for sports injuries. AB - BACKGROUND AND AIMS: Our hospital has used LLLT in the treatment of athletes since 1990. We had a good result about LLLT for sports injuries. However, few articles have attempted to evaluate the efficacy of LLLT for sports injuries. The aims of this study was to evaluate the efficacy of LLLT for sports injuries. Materials (Subjects) and Methods: Forty one patients underwent LLLT in our hospital. These patients included 22 men and 19 women with an average age of 38.9 years old. Patients were irradiated by diode laser at points of pain and/or acupuncture points. Patients underwent LLLT a maximum treatment of 10 times (mean 4.1 times). We evaluated the efficacy of LLLT using a Pain relief score (PRS). A score of 2 to 5 after treatment was regarded as very good, 6 to 8 as good, and 9 to 10 as poor. A PRS score of less than 5 was regarded as effective. RESULTS: The rate of effectiveness (PRS of 5 or less) after LLLT was 65.9% (27/41 patients). DISCUSSION: In this study, the resulting rate of effectiveness was 65.9% for all sports injuries. However, we have a high rate of effectiveness for Jumper's knee, tennis elbow and Achilles tendinitis and cases that were irradiated laser by a physician. CONCLUSIONS: LLLT is an effective treatment for sports injuries, particularly jumper's knee, tennis elbow and Achilles tendinitis. PMID- 24155546 TI - Effect of low-level laser therapy on blood flow and oxygen- hemoglobin saturation of the foot skin in healthy subjects: a pilot study. AB - BACKGROUND AND AIMS: This study on healthy test subjects intends to show whether one-off Low-Level Laser Therapy (LLLT) has an instant effect on the perfusion or the oxygenation of the skin tissue. These possible instant effects may have an influence on the accelerated wound healing which is often observed after application of LLLT, in addition to the usual postulated effects of LLLT which occur with a time delay normally. STUDY DESIGN/MATERIALS AND METHODS: The study was carried out double-blind and placebo-controlled in two batches of testing. The test subjects received one-off LLLT on a defined area of the arch of the foot. Simultaneously a placebo treatment was carried out on the corresponding contralateral area. In the first batch of tests, the blood flow was measured immediately before and after treatment using thermography and LDI. In the second batch of tests, the blood flow and the oxygen saturation were determined immediately before and after the treatment using an O2C device. RESULTS: No evidence that the LLLT has a significant instant effect on the circulation or the oxygen saturation could be found. CONCLUSION: No immediate effect of an LLLT on the perfusion or oxygenation situation is to be expected with physiologically normal starting conditions. An additional investigation should be carried out in which either the radiation dose is varied or the starting conditions are pathological (e.g. chronic wounds) in order to rule out immediate effects on circulation or oxygen saturation as the cause of the improved wound healing which is often observed. PMID- 24155547 TI - Er:YAG and adhesion in conservative dentistry : clinical overview. AB - The notion of utilizing laser technology in conservative dentistry was proposed in 1990 by Hibst and Keller, who introduced the possibility of using an Er:YAG laser as alternative to conventional instruments such as the turbine and micro motor. In subsequent years a continuing effort has been made by clinicians, researchers and commercial companies to improve the technology. The aim of this clinical study is to demonstrate, by the description of different clinical cases, the possibilities and the advantages of using Er:YAG lasers in conservative dentistry and to show that better results may be achieved in terms of stronger adhesion, less invasiveness, reduced pain as well as greater comfort and satisfaction of patients. PMID- 24155548 TI - Surface enhanced Raman spectroscopy in breast cancer cells. AB - BACKGROUND AND AIMS: Raman spectroscopy is a vibrational technique which provides information about the chemical structure. Nevertheless, since many chemicals are present in a cell at very low concentration, the Raman signal observed from a single cell is extremely weak. In surface enhanced Raman scattering (SERS), Raman signals can be enhanced by many orders of magnitude when nanoparticles are incorporated into the cell. Materials (subjects) and methods: The tumor biopsies were obtained from 5 patients who were clinically diagnosed with breast cancer. Breast cancer cells isolated from the biopsy were washed, centrifuged and seeded out. Cultivation took place in DMEM at 37 degrees C in a humidified of 5% CO2 in air with addition of colloidal silver nanoparticles of 40 nm into the cell by sonication. Immediately, the washed cells were analyzed in phosphate buffered saline (PBS) at pH 7. Raman analysis was carried out on the Jobin-Yvon LabRAM HR800 microscope system, with a NIR 830 nm laser excitation source. RESULTS: The strongly enhanced Raman signals allow Raman measurements of a single cell in the 200-1800 cm(-1) range in relatively short collection times (5 second) using 17 mW near-infrared excitation. Observed spectral features differed across the cell, but chemical constituents in the cell nucleus and cytoplasm, such as DNA, RNA, and amino acids tyrosine and phenylalanine can be identified. CONCLUSIONS: Particularly strong field enhancement can be observed when nanoparticles form colloidal clusters. The results suggest that SERS could be a new technique for the identification of breast cancer cell. PMID- 24155549 TI - 830 nm light-emitting diode low level light therapy (LED-LLLT) enhances wound healing: a preliminary study. AB - BACKGROUND AND AIMS: The application of light-emitting diodes in a number of clinical fields is expanding rapidly since the development in the late 1990s of the NASA LED. Wound healing is one field where low level light therapy with LEDs (LED-LLLT) has attracted attention for both accelerating wound healing and controlling sequelae. The present study evaluated LED-LLLT in 5 wounds of various etiologies. SUBJECTS AND METHODS: There were 5 patients with ages ranging from 7 to 54 years, comprising 2 males and 3 females. The study followed 5 wounds, namely 2 acute excoriation wounds; 1 acute/subacute dog bite with infection; 1 subacute post-filler ulcerated wound with necrotic ischemic tissue and secondary infection; and 1 subacute case of edema and infection of the lips with herpes simplex involvement after an illegal cosmetic tattoo operation. All patients were in varying degrees of pain. All wounds were treated with multiple sessions (daily, every other day or twice weekly) using an LED-LLLT system (830 nm, CW, irradiance of 100 mW/cm(2) and fluence of 60 J/cm(2)) till improvement was achieved. RESULTS: Full wound healing and control of infection and discomfort were achieved in all patients, with wound condition-mediated treatment periods ranging from 1 to 8 weeks. No recurrence of the herpes simplex case was seen in a 4-month follow-up. CONCLUSIONS: 830 nm LED-LLLT successfully brought about accelerated healing in wounds of different etiologies and at different stages, and successfully controlled secondary infection. LED-LLLT was easy and pain-free to apply, and was well-tolerated by all patients. The good results warrant the design of controlled studies with a larger patient population. PMID- 24155551 TI - Laser dentistry establishing a strong connection with laser therapy. PMID- 24155550 TI - Recalcitrant molluscum contagiosum successfully treated with the pulsed dye laser. AB - BACKGROUND AND AIMS: Molluscum contagiosum is caused by the molluscum contagiosum virus (MCV) and is a very common skin disorder mainly involving young children Cryotherapy, curettage or some topical therapies have been applied for MC, but all of these treatments need several sessions, can be somewhat ineffective, and very painful. The present study assessed the impact of a single session of pulsed dye laser treatment of MC lesions which had proved resistant to other approaches Subjects and methods: Fifteen children comprised the study subjects, 11 boys and 4 girls, 3-5 years of age (mean 4.2 yr) with recalcitrant MC. Lesions were counted at baseline, and a single shot from a 585 nm pulsed dye laser was applied to each lesion (3 mm, 300 ms, 8.0 J/cm(2)). Lesions were counted again at 1 week post-treatment and followed for up to 3 months thereafter. RESULTS: All patients completed the study and no patient dropped out through pain or discomfort. Purpura was seen at each treated lesion immediately after irradiation, but at 1 week after treatment, lesion clearance was virtually complete which was maintained for 1 month, and no recurrence was seen at 3 months in 8 of the 15 patients who remained available for followup. CONCLUSIONS: A single treatment of MC lesions with the pulsed dye laser successfully cured even recalcitrant lesions with no recurrence on follow up, and was well tolerated by the young subjects. PMID- 24155552 TI - Surgery in infection. PMID- 24155553 TI - Stem cells in regenerative medicine. AB - BACKGROUND: A number of cardiovascular, neurological, musculoskeletal and other diseases have a limited capacity for repair and only a modest progress has been made in treatment of brain diseases. The discovery of stem cells has opened new possibilities for the treatment of these maladies, and cell therapy now stands at the cutting-edge of modern regenerative medicine and tissue engineering. Experimental data and the first clinical trials employing stem cells have shown their broad therapeutic potential and have brought hope to patients suffering from devastating pathologies of different organs and systems. AIMS: Here, we briefly review the main achievements and trends in cell-based therapy, with an emphasis on the main types of stem cells: embryonic, mesenchymal stromal and induced pluripotent cells. DISCUSSION: Many questions regarding the application of stem cells remain unanswered, particularly tumorigenicity, immune rejection and danger of gene manipulation. Currently, only MSC seems to be safe and might be considered to be a leading candidate for human application to treat pathologies that affect the cardiovascular, neurological and musculoskeletal systems. PMID- 24155554 TI - Effect of pinpoint plantar long-wavelength infrared light irradiation on subcutaneous temperature and stress markers. AB - BACKGROUND AND AIMS: The current investigation was aimed at the development of a novel non-invasive treatment system, "pinpoint plantar long-wavelength infrared light irradiation (PP-LILI)", which may be able to relieve mental stress and reduce stress-related hormones. Materials (Subjects) and methods: We compared the subcutaneous temperature, blood pressure, the degree of secretion of stress hormones before and after pinpoint irradiations (wavelength: 8-11 MUm; output: 30mW). The study enrolled 15 subjects (Japanese healthy adults; 8 males, 7 females; average age 47.8 +/- 14.6 years). Two parts of the planter region were irradiated for 15 min respectively. The stress markers such as ACTH, salivary amylase and cortisol were measured. As well, core body temperature and blood pressure were analyzed before and after the irradiation. RESULTS: A series of experiments revealed increased body temperature, decreased levels of blood pressure and stress markers described above after the irradiation. CONCLUSIONS: These results clearly suggest that the PP-LILI system will be quite useful for relieving stress and improvement of homeostatic functions in the body. PMID- 24155555 TI - Laser ion acceleration toward future ion beam cancer therapy - Numerical simulation study -. AB - BACKGROUND: Ion beam has been used in cancer treatment, and has a unique preferable feature to deposit its main energy inside a human body so that cancer cell could be killed by the ion beam. However, conventional ion accelerator tends to be huge in its size and its cost. In this paper a future intense-laser ion accelerator is proposed to make the ion accelerator compact. SUBJECTS AND METHODS: An intense femtosecond pulsed laser was employed to accelerate ions. The issues in the laser ion accelerator include the energy efficiency from the laser to the ions, the ion beam collimation, the ion energy spectrum control, the ion beam bunching and the ion particle energy control. In the study particle computer simulations were performed to solve the issues, and each component was designed to control the ion beam quality. RESULTS: When an intense laser illuminates a target, electrons in the target are accelerated and leave from the target; temporarily a strong electric field is formed between the high-energy electrons and the target ions, and the target ions are accelerated. The energy efficiency from the laser to ions was improved by using a solid target with a fine sub wavelength structure or by a near-critical density gas plasma. The ion beam collimation was realized by holes behind the solid target. The control of the ion energy spectrum and the ion particle energy, and the ion beam bunching were successfully realized by a multi-stage laser-target interaction. CONCLUSIONS: The present study proposed a novel concept for a future compact laser ion accelerator, based on each component study required to control the ion beam quality and parameters. PMID- 24155556 TI - Use of laser in orthodontics: applications and perspectives. AB - Laser technology got in these years a more and more important role in modern dentistry and, recently, also in orthodontics was proposed the utilization of laser devices. The aim of this work is to describe the utilization of this technology both in soft and hard oral tissues to improve orthodontic treatment. Several cases, with different wavelengths (532, 810, 980, 1064, 2940 and 10600 nm) and in different times of the treatment (before, during and after) are presented. All the cases reported showed, according to the literature, that the use of the laser related to orthodontic treatment offers several advantages when compared with conventional methods. In the soft tissues surgery it allows to reduce or eliminate the use of anesthetic injection, to avoid use of sutures and to bond bracket in dry enamel; associated with orthophosphoric acid, it gives a stronger adhesion of the brackets to the enamel and, in the case of porcelain brackets, it detaches them without damages; at low power (LLLT) it permits to control the pain of the first period after bonding and, by increasing the speed of teeth movement in the bone, reduces the time of the treatment. PMID- 24155557 TI - Effects of Tooth Coating Material and Finishing Agent on Bleached Enamel Surfaces by KTP Laser. AB - OBJECTIVE: The purpose of this study was to evaluate the effect of tooth coating material and finishing agent on bleached enamel surfaces after using KTP laser with 27% hydrogen peroxide. BACKGROUND DATA: There have been few reports on the effects of tooth coating materials and finishing agents after bleaching. METHODS: After 40 crowns of human extracted maxillary incisors were bleached by KTP laser, bleached enamels were finished with fluoride only or both of fluoride and nano hydroxyapatite as a finishing agent. After application(s) of fluoride and/or finishing agent, the enamel surfaces were divided into 2 groups, which were covered with the coating material or without coating material. After application of coating materials, all specimens were kept for 2 weeks at 37 degrees C of 100% humidity. After removing the coating material, color changing was measured and enamel surfaces were examined by scanning electron microscopy (SEM). RESULTS: SEM observation of enamel surfaces treated the fluoride gel, finishing agent and coating material showed the most flattered surface compared to other groups. By measuring the color changing, few color changing was observed on the enamel surfaces treated the fluoride gel, finishing agents and coating material. CONCLUSION: These results suggested that applications of fluoride gel, finishing agent and coating material made the enamel-surfaces flattered and kept effects of bleaching, could prevent the re-coloration. After applications of fluoride gel and finishing agent, covering the bleached-enamel surfaces with the coating material enhanced the keeping whiteness. It would give the patients satisfaction of whiteness. PMID- 24155558 TI - Ultrastructural assessment of cellulite morphology: clues to a therapeutic strategy? AB - INTRODUCTION AND AIMS: Cellulite is a problematic condition affecting mostly women, characterized by a bumpy or nodular skin surface. Recent approaches with laser treatment have offered some promise. The present study sought to identify possible targets for laser treatment or light therapy through an ultrastructural investigation of the condition. SUBJECTS AND METHODS: Study subjects comprised 7 healthy Japanese female volunteers (Age range 37-46 yr, average 38.4) with cellulite, graded on the 4-point Nurnberger-Muller cellulite severity scale. Four patients were at grade 2 and 3 at grade 3. Three millimeter punch biopsies were obtained and routinely processed for light and transmission electron microscopy. RESULTS: Microphotography of specimens from cellulite patients demonstrated the presence of fibrotic septa which divided up larger clusters of adipose tissue into smaller packets, with the septa acting as a tethering system, thus producing the typical dimpling pattern. Ultrastructural findings showed proliferation of collagen and elastic fibers down into the cellulite tissue with compression of capillaries and congestion of arterioles, resulting in poor blood flow. CONCLUSIONS: The histological and ultrastructural findings of cellulite clearly distinguish the condition from simple fat deposition. The remodeling of the fat layer into lobulated packets of lipocytes sequestered by fibrotic septa with a high proportion of elastic fibers would suggest the use of a fiber-based interstitial laser-assisted lipolysis system at an appropriate wavelength which might offer benefits through disruption of the septae through a photomechanical effect and lipolysis of the sequestered lipocytes. This could be followed by a course of near-infrared phototherapy to accelerate clearance of freed lipid and debris and reestablish the vascular system. PMID- 24155559 TI - Occurrence of Spontaneous Tumors in the Central Nervous System (CNS) of F344 and SD Rats. AB - In order to accurately assess the carcinogenicity of chemicals with regard to rare tumors such as rat CNS tumors, sufficient information about spontaneous tumors are very important. This paper presents the data on the type, incidence and detected age of CNS tumors in F344/DuCrlCrlj (a total of 1363 males and 1363 females) and Crl:CD(SD) rats (a total of 1650 males and 1705 females) collected from in-house background data-collection studies and control groups of carcinogenicity studies at our laboratory, together with those previously reported in F344 and SD rats. The present data on F344/DuCrlCrlj rats (F344 rats) and Crl:CD(SD) rats (SD rats) clarified the following. (1) The incidences of all CNS tumors observed in F344 rats were less than 1%. (2) The incidences of malignant astrocytoma and granular cell tumor were higher in male SD rats than in female SD rats. (3) The incidences of astrocytoma and granular cell tumor were higher in SD rats than in F344 rats. (4) Among astrocytoma, oligodendroglioma and granular cell tumor, oligodendroglioma was detected at the youngest age, followed by astrocytoma, and ultimately, granular cell tumor developed in both strains. The incidences observed in our study were almost consistent with those previously reported in F344 and SD rats. PMID- 24155560 TI - Corneal mineralization in wistar hannover rats. AB - We have recently started using Wistar Hannover rats in Japan and are now collecting background data. We have been frequently observing corneal mineralization in Wistar Hannover rats of both the RccHan(TM):WIST and Crl:WI (Han) strains. In this study, details of corneal mineralization in Wistar Hannover rats were histopathologically and ultrastructurally investigated. According to the results, Wistar Hannover rats had a much higher incidence of corneal mineralization compared with Sprague-Dawley rats. The incidence of corneal mineralization was higher in males than females. According to the histological examination, mineral deposits were positive for calcium by von Kossa's method. Furthermore, in response to mineralization, keratocytes probably become active to play an important role against the mineralized substance. PMID- 24155561 TI - Pulmonary edema due to oral gavage in a toxicological study related to aquaporin 1, -4 and -5 expression. AB - A one-time oral gavage can be enough to cause of alveologenic edema with higher expression of AQP-1 and -4 than that with repeated-dose oral gavage, which caused both profound perivascular edema and hydrostatic pressure edema, while AQP-5 was similarly expressed. The alteration of AQPs expression was probably related to alveolar fluid clearance across the alveolar and bronchiolar epithelium in different stages of lung injury. The results clarified the type of lung edema in acute and sub-chronic toxicity studies without treatment related effect of tested material. The pathogenesis of pulmonary edema due to oral gavage toxicological study is associated with the cellular immune response to the reflux materials. Mast cell and leukocyte accumulation may contribute to increase vascular permeability leading to permeability edema. The increase in alveolar septum epithelium, perivascular and peribronchial cuffing, accumulation alveolar lipid containing macrophage and medial hyperplasia of the pulmonary artery might have been caused to increase airway resistance, which resulted in hydrostatic pressure edema. PMID- 24155562 TI - Biochemical and histological study of rat liver and kidney injury induced by Cisplatin. AB - Cisplatin is a chemotherapeutic agent widely used in treatment of several cancers. It is documented as a major cause of clinical nephrotoxicity and hepatotoxicity. The purpose of this study was to investigate the involvement of oxidative stress in the pathogenesis of cisplatin-induced liver and kidney injury. Wistar rats were divided into four groups. Group 1 (control) was intraperitoneally (IP) injected with a single dose of 0.85% normal saline. Groups 2, 3 and 4 were IP injected with single doses of cisplatin at 10, 25 and 50 mg/kg body weight (BW), respectively. At 24, 48, 72, 96 and 120 h after injection, BW, levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), blood urea nitrogen (BUN), creatinine, malondialdehyde (MDA), and activity of superoxide dismutase (SOD) and histology of the liver and kidney were evaluated. Cisplatin caused a reduction in BW of rats in groups 2, 3 and 4 at all post injection intervals. The levels of serum ALT, AST, BUN and creatinine and MDA of the kidney and liver were markedly increased especially at 48 and 72 h, whereas the activity of SOD was decreased after cisplatin injection. Liver sections revealed moderate to severe congestion with dilation of the hepatic artery, portal vein and bile duct and disorganization of hepatic cords at 50 mg/kg of cisplatin. Kidney sections illustrated mild to moderate tubular necrosis at 25 and 50 mg/kg of cisplatin. Therefore, oxidative stress was implicated in the pathogenesis of liver and kidney injury causing biochemical and histological alterations. PMID- 24155563 TI - Spontaneous Malignant T Cell Lymphoma in a Young Male Common Marmoset (Callithrix jacchus). AB - We histopathologically and immunohistochemically investigated a case of malignant lymphoma that spontaneously developed in a male common marmoset at two years of age. Beginning at two years four months of age, the animal had an enlargement of the submandibular and inguinal lymph nodes, small subcutaneous nodules near the right breast and an approximately fivefold increase in peripheral lymphocyte count compared with the previous examination value. The postmortem findings at two years eight months of age showed lymphadenopathy with enlargement of the thymus and spleen. Small- to intermediate-sized neoplastic lymphocytes had diffusely proliferated in the enlarged nodes. The neoplastic cells were pleomorphic and had irregularly shaped nuclei. The nuclear chromatin staining revealed hyperchromatism in the small-sized cells, and the intermediate-sized cells exhibited vesicular staining. An immunohistochemical examination indicated that the neoplastic lymphocytes were positive for CD3 and negative for CD20, thus suggesting that they had originated from T cells. In addition, the proliferation of high endothelial venules and reactive epithelioid histiocytes was observed. Scattered tingible body-laden macrophages were infrequently detected. Neoplastic lymphocytes were also observed in the thymus, spleen, heart, lungs, liver, kidneys, adrenal glands and femoral and sternal bone marrow. This malignant lymphoma in a young male common marmoset was considered to fit the category of "peripheral T-cell lymphoma, not otherwise specified (PTCL-NOS)" according to the new WHO system of classification. PMID- 24155564 TI - Spontaneous Extraskeletal Osteosarcoma in a Rabbit (Oryctolagus cuniculus): Histopathological and Immunohistochemical Findings. AB - A spontaneously occurring subcutaneous mass in the left forelimb of a nine-year old rabbit (Oryctolagus cuniculus) was examined histopathologically and immunohistochemically. Clinically, edema and hemorrhage were seen around the mass. No connection of the tumor mass to the appendicular skeleton was found. The tumor was arranged in a solid growth pattern and irregular bundles, and neoplastic cells were polygonal to spindle-shape. Osteoid (positive for osteocalcin) and multinucleated giant cells were diffusely or focally seen. Neoplastic cells were positive for vimentin, osterix and Ki-67, indicating the nature of osteoblasts with proliferating activity, but negative for alpha-smooth muscle actin, desmin or CD204. Based on these findings, a diagnosis of extraskeletal osteosarcoma was made, a very rare tumor both in laboratory and pet rabbits. PMID- 24155565 TI - Bacterial pleuritis with thickened mesothelial hyperplasia in a young beagle dog. AB - A five-month-old male beagle dog suddenly became moribund. Bloody fluid accumulated in the thoracic and abdominal cavities, and soft yellow flecks were floating in the thoracic fluid. The mediastinum and pericardium became dark reddish with villous thickening. Other parietal and pulmonary pleurae were rough, and the organs adhered to each other. Histologically, most mediastinal pleura formed papillary projections covered by a single layer of mesothelial cells. Many macrophages and neutrophils infiltrated the submesothelial connective tissue. At the mediastinum adjacent to the pericardium, cuboidal mesothelial cells proliferated solidly and formed a thick surface stratum. The flecks consisted of gram-negative filamentous or small bacillary (coccoid) bacteria. In the right posterior lobe of the lung, neutrophilic infiltration and a large encapsulated abscess including a bacterial colony were present. We diagnosed this case as "bacterial pleuritis with thickened mesothelial hyperplasia". The cause of the pleuritis might be a chronic pleural infection spread via the lung abscess. PMID- 24155566 TI - A case of metastatic adrenocortical carcinoma diagnosed with steroidogenic factor 1 in a sprague-dawley rat. AB - This report describes the morphological and immunohistochemical characteristics of an adrenocortical carcinoma with distant metastasis in a Sprague-Dawley rat. Macroscopically, a single large mass was observed in the adrenal gland, and multiple nodules were noted in the lung, liver and thyroid. Histologically, the adrenal tumor consisted of a solid growth of eosinophilic round cells with nuclear atypia. Vascular invasion was present, and multiple metastatic lesions were also observed in the lungs, liver, and mediastinal lymph nodes. Immunohistochemically, the nuclei of these tumor cells were positive for Steroidogenic Factor-1 (SF-1). In the thyroid, tumor cells histologically resembling adrenal cells were immunohistochemically negative for SF-1 but positive for calcitonin; thus the lesion was diagnosed as thyroid C-cell carcinoma. From these results, the present case was diagnosed as adrenocortical carcinoma with distant metastases. SF-1 could be a valuable marker for the differential diagnosis of adrenocortical tumors versus other endocrine tumors such as C-cell carcinoma. PMID- 24155567 TI - Spontaneous ameloblastic fibroma in a young Guinea pig. AB - A spontaneous ameloblastic fibroma was found in a 9-week-old guinea pig. Histopathologically, neoplastic cells consisted of two components: an odontogenic epithelium and odontogenic mesenchyme. The odontogenic epithelium formed strands, nests and islands that were interspersed within the odontogenic mesenchyme. In the marginal region, odontoblasts and scant dysplastic eosinophilic material were seen between these two components. Immunohistochemically, the odontogenic epithelium was positive for cytokeratin AE1/AE3, and the odontogenic mesenchyme and odontoblast were positive for vimentin, in the same manner as in the normal tooth germ (control). We could not obtain conclusive data suggesting that the eosinophilic material was dental hard tissue because the eosinophilic material was not stained specifically by any methods. Based on these histological characteristics, the tumor in the present case was diagnosed as an ameloblastic fibroma. This is the first report of ameloblastic fibroma in guinea pigs. PMID- 24155568 TI - Testicular Mineralization in KK-A(y) Mice Treated with an Oxovanadium Complex. AB - Vanadium has potential for use in diabetes therapy. Many investigators have reported toxic effects of inorganic vanadium salts; however, there are few reports on toxic effects of oxovanadium(VO(2+)) complexes. Therefore, we studied VO(2+) toxicity by examining histological changes and measuring the vanadium concentration in the testis after repeated oral administration of bis(1-oxy-2 pyridine-thiolato)oxovanadium(VO(2+)) (VO(opt)2) for 2 or 4 weeks in KK-A(y) mice. Severe mineralization and degeneration/necrosis of the seminiferous tubules were detected after either 2 or 4 weeks of administration. Vacuolar changes in Sertoli cells and the seminiferous epithelia, and hyperplasia of Leydig cells were observed in the testes of some animals. Vanadium concentrations in the mineralized testis were much higher than those in the testis of untreated KK-A(y) mice. These results represent the first report of the possibility for seminiferous tubules mineralization induced by VO(opt)2 administration. Therefore, our research provides important information about the potentially toxic effects of VO(2+) complexes. PMID- 24155569 TI - Theory of effective drug release from medical implants based on the Higuchi model and physico-chemical hydrodynamics. AB - Combining the approach of colloid transport with the generalized Higuchi theory of drug release and with the concept of minimum inhibitory concentration (MIC) known in microbiology, the theory of effective drug release from implants has been developed. Effective release of an antibiotic at a concentration above MIC is a necessary condition to achieve protection against infection from implants such as central catheters. The Higuchi theory in its present form is not predictive of the therapeutic effect from medical implants. The theory of effective release presented in this paper specifies two release modes, namely: one with therapeutic usefulness (effective release) and another without therapeutic effect. Therapeutic usefulness may be achieved when the antibiotic concentration, Cti , on the implant surface kills the organisms of interest and prevents the formation and propagation of biofilm when Cti exceeds the corresponding MIC of the released antibiotic compound. Currently, neither the Higuchi theory nor any other theory can provide such prediction. The present approach requires quantification of the antibiotic transport from the drug polymer blend implant surface into the tissue and accounts for its coupling with drug diffusion inside the blend, a task that has not been developed in existing theories. Our solution to this task resulted in the derivation of an equation for the time of duration of effective release, Te , which depends on MIC, the Higuchi invariant and the characteristics of convective diffusion within the tissue. The latter characteristics include: diffusivity Dti and diffusion layer thickness delta which is controlled by the velocity of the interstitial fluid in tissue. A smaller Dti is favorable because transport from the catheter surface is weaker, while a thinner diffusion layer is harmful because this transport is stronger. The influence of the tangential component of interstitial velocity in the tissue is especially harmful because the diffusion within the incision exit site (IES) will be extremely enhanced such that it may decrease Cti to zero. The incorporation of convective diffusion into the theory of antibacterial protection by means of antibiotic release has revealed that physicochemical mechanisms predict the effectiveness of antibiotic-loaded catheters and defines the conditions necessary to achieve better protection by means of combining the level of catheter loading with antibiotics and the use of wound (IES) dressing. PMID- 24155570 TI - A simple and scalable route to wafer-size patterned graphene. AB - Producing large-scale graphene films with controllable patterns is an essential component of graphene-based nanodevice fabrication. Current methods of graphene pattern preparation involve either high cost, low throughput patterning processes or sophisticated instruments, hindering their large-scale fabrication and practical applications. We report a simple, effective, and reproducible approach for patterning graphene films with controllable feature sizes and shapes. The patterns were generated using a versatile photocoupling chemistry. Features from micrometres to centimetres were fabricated using a conventional photolithography process. This method is simple, general, and applicable to a wide range of substrates including silicon wafers, glass slides, and metal films. PMID- 24155571 TI - Reliability of mandibular canines as indicators for sexual dichotomy. AB - INTRODUCTION: Amongst the various calcified structures in the human body, teeth have gained lot of popularity in estimating the sex of an individual as they are highly resistant to destruction and decomposition. Using permanent mandibular canines many researchers have predicted a high level of accuracy in identifying the sex correctly. The purpose of our study was to gauge the effectiveness of mandibular canines in discerning sex. MATERIALS & METHODS: Fifty dental casts each of males and females were utilized for the study. Mesio-distal dimension and inter-canine distance of mandibular right and left canine was recorded using digital vernier caliper and mandibular canine index was calculated. RESULTS: The mean value of mesio-distal dimensions of right and left mandibular canine was slightly greater in males compared to females. The mandibular canine index was equal in both sexes. Inter-canine distance was marginally higher in males compared to females. Despite of higher values in males none of the parameters were statistically significant. CONCLUSION: The results herein bolster contemporary studies that mesio-distal dimensions of mandibular canines and mandibular canine index do not reflect sexual dimorphism and that its application should be discontinued in sex prediction among Indian populations. How to cite this article: Hosmani J V, Nayak R S, Kotrashetti V S, Pradeep S, Babji D. Reliability of Mandibular Canines as Indicators for Sexual Dichotomy. J Int Oral Health 2013; 5(1):1-7. PMID- 24155572 TI - Oral Health Coalition: Knowledge, Attitude, Practice Behaviours among Gynaecologists and Dental Practitioners. AB - OBJECTIVES: Every expectant mother should receive a comprehensive oral health education & risk assessment. Numerous reports have shown association between oral diseases and preterm, low birth weight and gestational diabetes. The purpose of this study is to understand the attitude, knowledge regarding prenatal and perinatal oral health care among obstetricians and knowledge, attitude & practice skills of dental professionals. MATERIALS AND METHODS: The study involved a survey of 36 each gynaecologists and general dental practitioners. The pre tested questionnaire on oral health for expectant mothers was used to collect data related. The data collected was subjected to statistical analysis using frequency of responses and standard deviation. RESULTS: Analysis of data demonstrated that 98% of general dental practitioners felt that delay in dental treatment effect both the mother and the child. 85.7% (p>0.05) of gynaecologist never examined the oral cavity of the patient during routine checkup. CONCLUSION: The findings of this survey with dentists and gynaecologist showed that dental management during pregnancy still presents some deviations from scientific literature recommendations, indicating the need to update these health care professionals in order to establish guidelines for prenatal dental care. How to cite this article: Patil S, Thakur R, Madhu K, Paul S T, Gadicherla P. Oral Health Coalition: Knowledge, Attitude, Practice Behaviours among Gynaecologists and Dental Practitioners. J Int Oral Health 2013; 5(1):8-15. PMID- 24155573 TI - Correlation between Chronological Age, Dental Age and Skeletal Age among Monozygoyic and Dizygotic Twins. AB - INTRODUCTION: Chronological age, dental development, height and weight measurements, sexual maturation characteristics and skeletal age are some biological indicators that have been used to identify time of growth. Many researchers have agreed that skeletal maturity is closely related to the craniofacial growth, and bones of hand and wrist are reliable parameters in assessing it. The complete hand and wrist radiograph involves 30 bones and assessment of these bones is one elaborate task. The present study is therefore, undertaken to assess the correlation between the chronological age, dental age and skeletal ages among different types of twins. MATERIALS AND METHODS: The study consisted of 60 subjects (30 twins) aged 8 to 16 years, divided into group of 10 monozygotic, 10 dizygotic and 10 mixed sex twins. The sample was selected from Twin Survey- 2008 conducted by Department of Orthodontics and Dentofacial Orthopaedics, Sree Balaji Dental College and Hospital, Chennai. Their zygosity was determined by sex, blood groups and by the parent. The chronological age was measured by the date of birth given by the parents. Panoramic and hand wrist x rays were taken. Dental age was assessed by Demerjian et al method and skeletal age by Greulich and Pyle method. The correlation among twins in dental and skeletal ages with the chronological age was assessed using Correlation Coefficient and Student's't' Test. RESULTS: The obtained data was fed into the computer and statistical analysis was done for the same using the SPSS version 10.0. Statistical significance was tested at P<0.05 level. Mean and Standard Deviation, Correlation Coefficient, Student's't' Test statistical methods were employed. The result showed highly significant 'p' value as <0.001 in all the correlations except for mixed pairs. Descriptive statistics in most of the areas demonstrated a non-significant result between zygosity groups. CONCLUSION: There is a correlation existing between the individual's chronological age, dental age and skeletal age and correlation also exists in the twin pairs of the same zygosity and among each pair but no correlation exists between different zygotic twins. How to cite this article: Gupta M, Divyashree R, Abhilash P R, Bijle M N A, Murali K V. Correlation between Chronological Age, Dental Age and Skeletal Age among Monozygoyic and Dizygotic Twins. J Int Oral Health 2013; 3(1):16-22. PMID- 24155574 TI - Light intensity decay in quartz-tungsten-halogen polymerization units. AB - OBJECTIVES: The aim of this study was to determine the effect of ageing on the light intensity of quartz-tungsten-halogen (QTH) polymerization units in dental schools and dental clinics. MATERIALS & METHODS: Two dental schools and multiple public health dental clinics were visited and the light intensity of curing units was assessed. The age, make, model and service history were recorded. A calibrated radiometer (range 0-1000 nm) was used to measure the light intensity of 171 QTH units. At the end of each visit, the team members provided each dental clinic with a verbal report of the test results and recommendations on maintenance of light polymerization units. RESULTS: The 171 units tested were from seven different manufacturers. The mean light intensity was 373.1 mW/cm(2), the lowest intensity being 95.3 and the highest 526.60 mW/cm(2). Only 29 QTH units recorded more than 500 mW/cm(2); 102 units showed readings that ranged between 300 and 500 mW/cm(2) and 39 units recorded readings below 300 mW/cm(2). It was not able that one unit had light intensity reading of less than 100 mW/cm(2). The age distribution was as follows: 35 units were more than 10 years old, 79 were from 5 to 10 years old and 57 were less than 5 years old. There was a high statistical significant relation between the mean light intensity and age (P = 0.001). CONCLUSION: Light intensity values used in some dental clinics were to be found lower than what is recommended for optimum polymerization of resin based composite restorations. Awareness among dentists of the value of QTH light curing units and their commitment to care and maintenance are crucial to achieving optimum restoration properties. How to cite this article: Al-Samadani KH, Al-Dharrab A, Wahbi MA , Algizani L. Light Intensity Decay in Quartz-Tungsten Halogen Polymerization Units. J Int Oral Health 2013; 5(1):23-30. PMID- 24155575 TI - Revelation in the field of tissue preservation - a preliminary study on natural formalin substitutes. AB - INTRODUCTION: The quest for formalin substitutes has long been going on due to its health hazards. Honey has been proven as a safe alternative to formalin. However, we explored more economical, eco-friendly & readily available substances like sugar & jaggery as natural substitutes for formalin. The aim of this study was to compare the tissue fixation abilities of honey, sugar syrup & jaggery syrup with that of formalin using H & E stain and to determine the best fixative among the three. MATERIALS AND METHODS: Commercially available fresh goat meat (buccal mucosa) was cut into five bits & each bit was placed in five different containers containing 10% buffered formalin, distilled water, 20% honey, 20% sugar syrup & 30% jaggery syrup with formalin as positive control & distilled water as negative control. 24 hours tissue fixation was attained at room temperature followed by conventional processing and staining. The tissue sections were assessed for cytoplasmic, nuclear details & staining quality under light microscopy. Each criteria was rated on a scale of 1- 4 (1 for poor & 4 for excellent) & the whole procedure was blinded. RESULTS were analysed by Kruskal Wallis ANOVA test. Inter-observer variability was determined by Kappa statistics. RESULTS: The preservation of tissue by honey, sugar & jaggery syrup was comparable to that of formalin. Among the three natural fixatives, jaggery syrup excelled. CONCLUSION: Our effort of using sugar and jaggery for tissue fixation is first of its kind and yielded good results. Hence they can be successfully adopted in routine histopathology laboratories in place of formalin. CLINICAL RELEVANCE: Natural fixatives can be used in place of the hazardous formalin with equal efficiency. Also, jaggery being highly economical and universally available can be employed in large scale as in screening camps. How to cite this article: Patil S, Premalatha B R, Rao R S, Ganavi B S. Revelation in the Field of Tissue Preservation - A Preliminary Study on Natural Formalin Substitutes. J Int Oral Health 2013; 5(1):31-38. PMID- 24155576 TI - Changes in Cranial Base Morphology in Class I and Class II Division 1 Malocclusions. AB - INTRODUCTION: The cranial base plays a key role in craniofacial growth; it helps to integrate spatially and functionally different patterns of growth in various adjoining regions of the skull such as components of the brain, the nasal and oral cavity and the pharynx. The aim of this study was to evaluate the difference in cranial base flexure between skeletal and dental Class I and Class II division 1. MATERIALS & METHODS: Lateral cephalometric radiograph, of Class I and Class II with an average growth pattern were analyzed and compared. A total of 103 patients having class I (n=52) and class II (n=51) malocclusion, were taken from Department of Orthodontics, Rajasthan Dental College & Hospital, Jaipur. Cranial base angle (N-S-Ar) and ANB were measured on pre treatment lateral cephalograms. RESULTS: In this study cranial base angle did not show statistically significant difference between the two groups studied. CONCLUSION: In the assessment of orthodontic problems involving anteroposterior malrelationships of the jaws, the problem is usually the result of size, form and position of the jaw. The present study failed to find any differences in cranial base angle between sagittal malocclusions. How to cite this article: Agarwal A, Pandey H, Bajaj K, Pandey L. Changes in Cranial Base Morphology in Class I and Class II Division 1 Malocclusion. J Int Oral Health 2013; 5(1):39-42. PMID- 24155577 TI - Prevalence of Impacted Molar Teeth among Saudi Population in Asir Region, Saudi Arabia - A Retrospective Study of 3 Years. AB - AIM: To report the prevalence of impacted third molars according to the age, gender and type among Saudi population. MATERIALS AND METHODS: This retrospective study involved 3800 panoramic radiographs of subjects aged 18 to 45 years who presented to the College of Dentistry, King Khalid University, Abha, Kingdom of Saudi Arabia for oral care during the period from February 2009 to February 2011. Data collected was entered into a spreadsheet (Excel 2000; Microsoft, US) and analyzed using Statistical Package for Social Sciences (SPSS) version 16.0. RESULTS: A total of 713 impacted teeth were identified (18.76%) (p=0.003). The male to female ratio with impacted third molars was 604:109 (5.54:1) and the ratio of patients with impacted teeth was (5:1). Age group 1 (i.e., 20 to 25 years)had the highest prevalence of third molar tooth impaction (64.5%) and this decreased with increasing age. CONCLUSION: Incidence of tooth impaction is higher in the mandible than in maxilla. Males had a higher incidence of third molar impaction as compared to the females. Highest incidence is found in the age group of 20-25 years. Mesio-angular impaction was the most predominant type. How to cite this article: Syed KB, Kota Z, Ibrahim M, Bagi MA, Assiri MA. "Prevalence of Impacted Molar Teeth among Saudi Population in Asir Region, Saudi Arabia - A Retrospective Study of 3 Years". J Int Oral Health 2013; 5(1):43-47. PMID- 24155578 TI - Articaine for surgical removal of impacted third molar; a comparison with lignocaine. AB - AIM: Articaine is an amide local anesthetic that differs from other agents of its group due to the presence of thiophene ring instead of a benzene ring. Some researchers claim that articaine is superior to lidocaine in its biologic profile. The aim of the study is to compare the efficacy of articaine with that of lidocaine which has proven efficacy. MATERIALS AND METHOD: This study was done on 50 subjects; 25 of them received 4 % articaine HCl with 1:100000 epinephrine and the next 25 received 2% lignocaine HCl with 1:100000 epinephrine. Time of injection, onset of anesthesia, amount of anesthetic injected were recorded. Efficacy was determined using visual analog scale. The values were statistically analyzed. RESULTS: The mean onset time of anesthesia in study group was 2.07 +/- 0.22 and 2.18 +/- 0.26 minutes in comparison group. A mean duration of 4.28 +0.78 hours was seen with articaine group and 3.51 + 0.45 hours with the lignocaine group. No statistical difference between the two groups with regard to pain experience. CONCLUSION: Articaine has similar efficacy as that of lignocaine with slightly longer duration and can be used as an alternative to lignocaine in third molar surgeries. CLINICAL SIGNIFICANCE: Increased availability of local anesthetics has improved interest in research about dental pain control. a quest for new methods of pain reduction is always justified. How to cite this article: R Shruthi, S N Kedarnath, S Mamatha N, Rajaram P, Dinesh B. Articaine For Surgical Removal of Impacted Third Molar; A Comparison With Lignocaine. J Int Oral Health 2013; 5(1):48-53. PMID- 24155579 TI - Comparative evaluation of sealing ability of three newer root canal obturating materials guttaflow, resilon and thermafil: an in vitro study. AB - INTRODUCTION: Microleakage continues to be a main reason for failure of root canal treatment where the challenge has been to achieve an adequate seal between the internal structure and the main obturating material. The objective of this study is to compare the sealing ability of 3 newer obturating materials GuttaFlow, Resilon/Epiphany system (RES) and Thermafil, using silver nitrate dye and observing under stereomicroscope. METHODOLOGY: Thirty single rooted teeth were divided into following groups. Group I : GuttaFlow ;Group II : Resilon /Epiphany sealer Group III : Thermafil with AH-Plus sealer. Teeth were decoronated and instrumented with profile rotary system and obturated with specified materials. Apical seal was determined by dye penetration method using silver nitrate. Then the specimens were transversely sectioned at each mm till 3 mm from the apex. Dye leakage was determined using stereomicroscope. Statistical analysis of the results was performed using Kruskall-Wallis test. RESULTS: The results showed that Group II i.e., Resilon with Epiphany sealer showed the least amount of microleakage when compared to Group I i.e., GuttaFlow and Group III i.e., Thermafil with AH-plus sealer. CONCLUSION: Based on the results of this study it can be concluded that RES had higher sealing ability followed by Thermafil and GuttaFlow in vitro but further studies have to be carried out to make a direct correlation between these results and invivo situation. How to cite this article: Bhandi S H, Subhash T S. Comparative Evaluation of Sealing Ability of Three Newer Root Canal Obturating Materials Guttaflow, Resilon and Thermafil: An In Vitro Study. J Int Oral Health 2013; 5(1):54-65. PMID- 24155580 TI - Smear Layer Evaluation on Root Canal Preparation with Manual and Rotary Techniques using EDTA as an Irrigant: A Scanning Electron Microscopy Study. AB - INTRODUCTION: The aim of any root canal treatment is to achieve a canal free of micro organisms, residual pulp remnants, debris and smear layer for the long term success of the procedure. Manual and automated instrumentation techniques along with proper irrigation regime is used to arrive at the aforementioned goal. Many authors focused on the preparation capabilities of various manual and rotary instruments but very few investigators stressed on the actual cleaning abilities of these instruments. AIMS AND OBJECTIVES: This study was undertaken to evaluate the cleaning efficiency of manual K flex files and rotary Pro File systems in the root canals using a scanning electron microscope. MATERIAL AND METHODS: Thirty single rooted mandibular first premolars were divided into two groups and randomized (the manual group-M and the ProFile group-P) with respect to the preparation technique. The Manual group was hand instrumented with stainless steel K- Flexofiles by means of a conventional filing technique. The Pro File group was instrumented according to the manufacturer's instructions using a rotary handpiece. All canals were shaped and cleaned under frequent irrigation with EDTA. Final irrigation was carried out with 3 mL of normal saline solution to neutralize the action of the irrigant. The roots were split, one half of each tooth was selected for further SEM technique analysis and examined under the scanning electron microscope. The canal walls were quantitatively evaluated for the amount of debris and smear layer. The apical, middle and coronal regions of the canal surface, were graded (1-5) for debris and smear layer. A statistical analysis was performed using a Mann-Whitney Rank Sum test. ProFile performed least effective cleaning. Manual K-Flexofiles led to a grooved pattern. RESULTS AND CONCLUSION: A statistically significant difference was observed (p<0.05) between the two instrumentation techniques concerning the amount of debris and smear layer at the apical level. The manually filed canals had less debris and smear layer than those using a rotary technique. It was concluded from this study that none of the instrumentation techniques employed, produced the canal walls which were free of surface debris and smear layer. The manual instrumentation technique was better in cleaning the canals compared to the ProFile rotary Ni-Ti instruments despite the step-back technique used for manual instrumentation. How to cite this article: Manjunatha M, Kini A, Sudhakar V, Sunil K V C, Hiremath V K, Shah A. Smear Layer Evaluation on Root Canal Preparation with Manual and Rotary Techniques using EDTA as an Irrigant: A Scanning Electron Microscopy Study. J Int Oral Health 2013; 5(1):66-78. PMID- 24155581 TI - Multidisciplinary Approach in Management of Fractured Central Incisor through Composite Plug Stabilization - A Case Report. AB - Crown fracture is the most frequent type of traumatic injury in permanent dentition. Traumatized anterior teeth requires quick functional and esthetic repair. Traditionally such injuries have been restored with conventional post core and crown techniques after endodontic treatment. This article presents an innovative technique of managing a complicate crown fracture of anterior tooth where plain orthodontic band was used for stabilization and post endodontic restoration was done with adhesively luted fiber reinforced composite post through fragment and composite plug stabilization. How to cite this article: Sushil K C, Rao A, Sheila K, Hanumanth R G. Multidisciplinary Approach in Management of Fractured Central Incisor through Composite Plug Stabilization - A Case Report. J Int Oral Health 2013; 5(1):79-82. PMID- 24155582 TI - Chronic inflammatory gingival overgrowths: laser gingivectomy & gingivoplasty. AB - It is quite common to note chronic inflammatory Gingival overgrowths during and/or post orthodontic treatment. Sometimes the overgrowths may even potentially complicate and/or interrupt orthodontic treatment. With the introduction of soft tissue lasers these problems can now be addressed more easily. Amongst many LASERS now available in Dentistry DIODE LASERS seem to be most ideal for orthodontic soft tissue applications. As newer treatments herald into minimally invasive techniques, DIODE LASERS are becoming more promising both in patient satisfaction and dentist satisfaction. How to cite this article: Shankar BS, Ramadevi T, Neetha M S, Reddy P S K, Saritha G, Reddy J M. Chronic Inflammatory Gingival Overgrowths: Laser Gingivectomy & Gingivoplasty. J Int Oral Health 2013; 5(1):83-87. PMID- 24155583 TI - Management of pregnant patient in dentistry. AB - The purpose of this article is to update general dentists and maxillofacial surgeons in the perioperative management of the pregnant patient. Pregnancy results in physiologic changes in almost all organ systems in the body mediated mainly by hormones; which influences the treatment schedule. Understanding these normal changes is essential for providing quality care for pregnant women. The general principles that apply in this situation are discussed, followed by the relevant physiologic changes and their treatment implications, the risks of various medications to the mother and fetus, the management of concomitant medical problems in the pregnant patient, appropriate timing of oral and maxillofacial surgery during pregnancy, and management of emergencies during pregnancy. Information about the compatibility, complications, and excretion of the common drugs during pregnancy is provided. Guidelines for the management of a pregnant patient in the dental office are summarized. How to cite this article: Kurien S, Kattimani V S, Sriram R, Sriram S K, Prabhakar Rao V K, Bhupathi A, Bodduru R, Patil N N. Management of Pregnant Patient in Dentistry. J Int Oral Health 2013; 5(1):88-97. PMID- 24155584 TI - Effect of vitality on translucent dentine - a study. AB - BACKGROUND: Sclerosis of dentinal tubules may be a response to pathological or physiological insult in the crown & root. The mechanism by which apical translucency is produced is still uncertain. The increase in size of the apical zone of sclerotic dentin in human teeth has been used often in forensic science as a method of age estimation. However, only few studies have been done to compare percentage of translucency between vital and non-vital teeth. Conflicting concepts exist regarding the amount of translucent dentin in the vital & non vital teeth and correlation of this variation with age of the subject. AIMS: To investigate the amount and distribution of apical translucent dentin in group matched vital and non-vital teeth. MATERIALS AND METHODS: Study was conducted on 70 extracted teeth, which were subjected for vitality test before extraction, and divided into two groups (vital & non-vital teeth) with a minimum of 35 teeth in each group. Ground sections of 150u thickness were observed under Stereomicroscope and photographed. The distribution of area and length was measured on the images captured, using PROPLUS IMAGE ANALYSIS SOFTWARE version 4.1.0.0 software. RESULTS AND CONCLUSIONS: The present study revealed significant differences (p < 0.05) in apical translucency of dentin, when both vital and non vital teeth types were compared. There was more apical translucency present in non-vital when compared with vital teeth at any given age. Key words: Apical translucency; vital teeth; non-vital teeth. How to cite this article: Selvamani M, Madhushankari G S, Basandi P S, Donoghue M, Nayak V, Diwakar G. Effect of Vitality on Translucent Dentine - A Study. J Int Oral Health 2013; 5(2):1-7. PMID- 24155585 TI - Anti cariogenic efficacy of herbal and conventional tooth pastes - a comparative in-vitro study. AB - BACKGROUND: An upsurge of herbal products in various catalogues of fast moving consumer goods is evident. Dental creams or pastes which have numerous brands since years, have addition of many more herbal tooth pastes. Main claim of these herbal tooth pastes being effective reduction in cavities and plaque control. Proven fact is that proper brushing with a tooth brush and tooth paste brings down the caries incidence, and there is a substantial amount of contribution made by indispensable ingredient i.e, tooth pastes and their antibacterial component. AIM: To evaluate the antibacterial efficacy of various herbal tooth pastes available in the market and compare it with a conventional tooth paste with known antibacterial effect. MATERIALS & METHODS: The antibacterial efficacy of five herbal tooth pastes and two conventional tooth pastes with different ingredients was evaluated by the zone of inhibition created around the disc on the culture plates against streptococcus mutans and lactobacillus acidophilus. RESULTS: The herbal tooth pastes showed similar efficacy as that of the conventional tooth pastes. One herbal tooth paste with multiple herbal ingredients had greater zone of inhibition compared to the conventional tooth pastes and other herbal tooth pastes. CONCLUSION: Herbal tooth pastes have similar antibacterial effect as conventional tooth pastes. Tooth paste with multiple herbal ingredients is more efficient than the tooth pastes with fewer herbal ingredients in an anticariogenic property. Key words: Anti-carcinogenicity, Herbal tooth pastes, Plaque Control. How to cite this article: Mohan Kumar K P, Priya N K, Madhushankari G S. Anti Cariogenic Efficacy of Herbal and Conventional Tooth Pastes - A Comparative In-Vitro Study. J Int Oral Health 2013; 5(2):8-13. PMID- 24155586 TI - Evaluation of the Antibacterial efficacy of Omeprazole with Sodium Hypochlorite as an Endodontic Irrigating Solution- An Invivo Study. AB - BACKGROUND: Proton pump inhibitors are used in endodontic disinfection of root canals for elimination of enterococcus faecalis. This invivo study on Wistner Rats is carried out to determine antimicrobial efficacy of proton pump inhibitor in combination with sodium hypochlorite & Mixture of Isomer of tetracycline, acid and detergent (MTAD) against E. Faecalis Materials & Methods: Periapical lesions were induced on the 30 Incisor teeth of 30 male Wistner rats (10per group). After 28 days, root canals of each tooth were instrumented to 35# k file, during the process of instrumentation canals were irrigated with their respective irrigation solutions. Group-1: 2% CHX + 5.2% NaOCL, Group-2: MTAD(Dentsply Tulsa Dental, Tulsa, OK) + 5.2% NaOCL, Group-3: 8.5% Omeprazole (Dr Reddy's labs private limited - Hyderabad) + 5.2% NaOCL. Microbiological samples were collected by using #35 sterilized paper points after 28 days of inducing periapical lesions, Sample (S1) was collected before instrumentation and Sample (S2) was collected after instrumentation and Irrigation data were subjected to analysis of variance, followed by Newman Keuls Post Hoc test. RESULTS: Microbiological Analysis revealed significant decrease of colony forming units from S1 to S2 Samples in all the 3 groups. CONCLUSION: Our data showed that association of Omeprazole with NaOCL showed a superior antibacterial efficacy against Enterococcus faecalis in comparision with other irrigants. Key words: Sodium Hypochlorite, Chlorhexidine, Gluconate, MTAD, Omeprazole. PMID- 24155587 TI - Coronally Positioned Flap for Root Coverage: Comparison between Smokers and Nonsmokers. AB - BACKGROUND: Gingival recession is significantly more common among smokers, while cigarette smoking has been shown to negatively influence healing following periodontal therapeutic procedures as compared to non-smokers. The objective of this study was to evaluate the influence of cigarette smoking on the outcome of coronally positioned flap (CPF) in the treatment of Miller Class I gingival recession defects. MATERIALS AND METHODS: Ten current smokers (>=10 cigarettes daily for at least 5 years) and 10 non-smokers (never smokers), each with one 3 to 4-mm Miller Class I recession defect in an upper canine or bicuspid, were treated with CPF. At baseline and 6 months, clinical parameters, probing depth (PD), clinical attachment level (CAL), recession depth (RD), recession width (RW) and apico-coronal width of keratinized tissue (KT) were determined. RESULTS: Intra-group analysis showed that CPF was able to reduce RD and improve CAL in both groups (P < 0.001). Intergroup analysis demonstrated that smokers presented greater residual RD at 6 months and lower percentage of root coverage (60.09% versus 76.05%; P < 0.05). No smokers obtained complete root coverage compared to 30% of non-smokers (P < 0.05). CONCLUSION: Within the limits of present study, it can be concluded that cigarette smoking may present negative impact on root coverage outcome by CPF as compared to non-smokers and therefore represent one more challenge to periodontal plastic therapy. Key words: Gingival recession/therapy; flap; smoking/adverse effects. How to cite this article:Nanavati B, Bhavsar N V, Mali J. Coronally Positioned Flap for Root Coverage: Comparison between Smokers and Nonsmokers. J Int Oral Health 2013; 5(2):21-27. PMID- 24155588 TI - Correlation of masseter muscle thickness and intermolar width - an ultrasonography study. AB - BACKGROUND: To determine the association between the thickness of masseter muscle and the maxillary dental arch width. To explore the influence of gender on masseter muscle thickness. MATERIALS & METHODS: Seventy subjects (35 females and 35 males) of age 18 to 25 years were selected for the study based on class I molar relationship. The masseter muscle thickness of the right and left sides in every subject were found out through ultrasound scanning of the muscle, in both relaxed and clenched states. The maxillary dental arch width was measured on the study model with an electronic caliper. Student t test, Pearson's Correlation Coefficient was performed to assess the sample. RESULTS: Masseter Muscle Thickness showed a positive correlation with Maxillary Dental Arch Width r <=0.74. The masseter muscle thickness is greater in male subjects in both relaxed (0.001

5 cm, 3 lesions with 1 or more > 3 cm) or at the upper limit of Milan criteria (single lesions between 4.1 cm and 5.0 cm), with a predicted waiting time of more than 3 months, received carboplatin-based tace treatments. Exclusion criteria for tace included Child-Pugh C cirrhosis or the presence of portal vein invasion or extrahepatic disease on imaging. Only patients without tumour progression after tace underwent lt. RESULTS: Of 160 hcc patients who received liver grafts between 1997 and 2010, 35 were treated with tace preoperatively. The median of the sum of tumour diameters was 6.7 cm (range: 4.8-8.5 cm), which decreased with tace to 5.0 cm (range: 3.3-7.0 cm) at transplantation (p < 0.0004). The percentage drop in alpha-fetoprotein (alphafp) was a positive predictor (p = 0.0051) and the time from last tace treatment to transplantation was a negative predictor (p < 0.0001) for overall survival. CONCLUSIONS: The percentage drop in alphafp and a shorter time from the final tace treatment to transplantation significantly predicted improved overall survival after lt for hcc downsized with tace. As a serum marker, alphafp should be followed when tace is used as a strategy to stabilize or downsize hcc lesions before lt. PMID- 24155633 TI - Provincial rates and time trends in pancreatic cancer outcomes. PMID- 24155632 TI - Hereditary colorectal cancer registries in Canada: report from the Colorectal Cancer Association of Canada consensus meeting; Montreal, Quebec; October 28, 2011. AB - At a consensus meeting held in Montreal, October 28, 2011, a multidisciplinary group of Canadian experts in the fields of genetics, gastroenterology, surgery, oncology, pathology, and health care services participated in presentation and discussion sessions for the purpose of developing consensus statements pertaining to the development and maintenance of hereditary colorectal cancer registries in Canada. Five statements were approved by all participants. PMID- 24155634 TI - Predicting the risk of cardiovascular comorbidities in adult cancer survivors. AB - OBJECTIVES: Data on how to identify cancer survivors (css) at the greatest risk for cardiovascular conditions are limited. We aimed to characterize the clinical factors associated with ischemic heart disease (ihd) and congestive heart failure (chf) in css and to develop a stratification schema for predicting the risk of cardiovascular comorbidities in css. METHODS: Cancer survivors and non-cancer controls (nccs) were identified from the U.S. National Health and Nutrition Examination Survey. Independent factors associated with increased relative risk (rr) for cardiovascular conditions were determined. A risk stratification schema was devised that correlated risk score with the prevalence of cardiovascular comorbidities in cs. RESULTS: Baseline characteristics were similar for the 1869 css and 24,337 nccs included in the study. Compared with nccs, css were more likely to report ihd (13.7% vs. 5.2%), chf (7.9% vs. 2.1%), or both (4.2% vs. 1.2%; all p < 0.01). Based on multivariate analyses, risk factors for cardiovascular problems included ages 40-60 years (rr: 3.66; 95% ci: 1.87 to 7.17), 60-80 years (rr: 14.18; 95% ci: 7.65 to 26.30), and 80 years or older (rr: 25.34; 95% ci: 13.16 to 48.78); male sex (rr: 2.25; 95% ci: 1.72 to 2.94); U.S. citizenship (rr: 2.10; 95% ci: 1.08 to 4.08); annual incomes of $20,000-$45,000 (rr: 1.81; 95% ci: 1.21 to 2.70) and less than $20,000 (rr: 3.05; 95% ci: 1.81 to 5.14); comorbid diabetes mellitus (rr: 2.97; 95% ci: 2.05 to 4.32); and physical inactivity (rr: 1.98; 95% ci: 1.41 to 2.79). CONCLUSIONS: Independent risk factors for ihd and chf in css were identified. The risk stratification schema presented here may be helpful in developing a risk-based approach to preventive cardiovascular strategies for css. PMID- 24155635 TI - Cost-effectiveness of lapatinib plus letrozole in her2-positive, hormone receptor positive metastatic breast cancer in Canada. AB - BACKGROUND: The cost-effectiveness of first-line treatment with lapatinib plus letrozole for postmenopausal women with hormone receptor-positive (hr+), human epidermal growth factor receptor 2-positive (her2+) metastatic breast cancer (mbc) has not been assessed from the Canadian health care system and societal perspectives. METHODS: A partitioned survival analysis model with 3 health states (alive, pre-progression; alive, post-progression; dead) was developed to estimate direct and indirect costs and quality-adjusted life years (qalys) with lapatinib letrozole, letrozole, anastrozole, or trastuzumab-anastrozole as first-line treatment. Clinical inputs for lapatinib-letrozole and letrozole were taken from the EGF30008 trial (NCT00073528). Clinical inputs for anastrozole and trastuzumab anastrozole were taken from a network meta-analysis of published studies. Drug costs were obtained from the manufacturer's price list, the Quebec list of medications, and imsBrogan. Other costs were taken from the Ontario Health Insurance Plan's Schedule of Benefits and Fees and published studies. A 10-year time horizon was used. Costs and qalys were discounted at 5% annually. Deterministic and probabilistic sensitivity analyses were performed to assess the effects of changes in model parameters. RESULTS: Quality-adjusted life years gained with lapatinib-letrozole were 0.236 compared with trastuzumab-anastrozole, 0.440 compared with letrozole, and 0.568 compared with anastrozole. Assuming a health care system perspective, incremental costs were $5,805, $67,029, and $67,472 respectively. Given a cost per qaly threshold of $100,000, the probability that lapatinib-letrozole is preferred was 21% compared with letrozole, 36% compared with anastrozole, and 68% compared with trastuzumab anastrozole. Results from the societal perspective were similar. CONCLUSIONS: In postmenopausal women with hr+/her2+ mbc receiving first-line treatment, lapatinib letrozole may not be cost-effective compared with letrozole or anastrozole, but may be cost-effective compared with trastuzumab-anastrozole. PMID- 24155636 TI - Helicobacter pylori infection predicts favorable outcome in patients with gastric cancer. AB - BACKGROUND: Recent studies have suggested a controversial role of Helicobacter pylori infection in gastric cancer prognosis. The aim of the present study was to investigate the potential impact of H. pylori status on the prognosis of patients with gastric cancer in a Chinese prospective cohort. METHODS: Between 2007 and 2009, 261 patients with curatively resected gastric cancer were enrolled in the study. H. pylori status was defined by means of immunohistochemical staining in tumour and non-neoplastic tissues. Treatment prognosis was measured in terms of cancer-specific survival and disease-free survival (dfs). Univariate and multivariate Cox regression models were used to assess the association between H. pylori status and patient prognosis. RESULTS: Positivity for H. pylori infection was observed in 188 of the 261 patients (72.0%). In patients positive for H. pylori, mean cancer-specific survival was 55.2 months [95% confidence interval (ci): 53.4 to 56.9 months] and mean dfs was 53.9 months (95% ci: 51.8 to 56.0 months); the same survivals were, respectively, 45.1 months (95% ci: 42.2 to 47.9 months) and 43.7 months (95% ci: 40.4 to 47.0 months) in patients negative for H. pylori. In univariate analysis, positive H. pylori status was associated with better cancer-specific survival [hazard ratio (hr): 0.486; 95% ci: 0.271 to 0.870; p = 0.015] and dfs (hr: 0.540; 95% ci: 0.307 to 0.950; p = 0.033). In multivariate analysis, H. pylori was an independent prognostic factor for cancer specific survival (hr: 0.485; 95% ci: 0.265 to 0.889; p = 0.019). CONCLUSIONS: Our study demonstrates that positive H. pylori status is a beneficial prognostic indicator in patients with gastric cancer and might suggest possible therapeutic approaches for gastric cancer. Further research is required to better understand inflammation mechanisms and cancer progression. PMID- 24155637 TI - Patterns of practice in the prescription of palliative radiotherapy for the treatment of bone metastases at the Rapid Response Radiotherapy Program between 2005 and 2012. AB - OBJECTIVE: We examined whether patterns of practice in the prescription of palliative radiation therapy for bone metastases had changed over time in the Rapid Response Radiotherapy Program (rrrp). METHODS: After reviewing data from August 1, 2005, to April 30, 2012, we analyzed patient demographics, diseases, organizational factors, and possible reasons for the prescription of various radiotherapy fractionation schedules. The chi-square test was used to detect differences in proportions between unordered categorical variables. Univariate logistic regression analysis and the simple Fisher exact test were also used to determine the factors most significant to choice of dose-fractionation schedule. RESULTS: During the study period, 2549 courses of radiation therapy were prescribed. In 65% of cases, a single fraction of radiation therapy was prescribed, and in 35% of cases, multiple fractions were prescribed. A single fraction of radiation therapy was more frequently prescribed when patients were older, had a prior history of radiation, or had a prostate primary, and when the radiation oncologist had qualified before 1990. CONCLUSIONS: For patients with bone metastasis, a single fraction of radiation therapy was prescribed with significantly greater frequency. PMID- 24155638 TI - Recurrent nasopharyngeal carcinoma: a clinical dilemma and challenge. AB - Recurrent nasopharyngeal carcinoma, which represents a small proportion of head and-neck cancers, has a unique set of patho-clinical characteristics. The management of recurrent nasopharyngeal carcinoma remains a challenging clinical problem. Traditional treatments offer limited local control and survival benefits; more seriously, they frequently induce severe late complications. Recently, novel treatment techniques and strategies-including precision radiotherapy, endoscopic surgery or transoral robotic resection, third-generation chemotherapy regimens, and targeted therapies and immunotherapy-have provided new hope for patients with recurrent nasopharyngeal carcinoma. Some of these patients can potentially be cured with modern treatments. However, a lack of adequate evidence makes it difficult for clinicians to apply these powerful techniques and strategies. Individualized management guidelines, full evaluation of quality of life in these patients, and a further understanding of the mechanisms underlying recurrence are future directions for research into recurrent nasopharyngeal carcinoma. PMID- 24155639 TI - Should noncurative resection of the primary tumour be performed in patients with stage iv colorectal cancer? A systematic review and meta-analysis. AB - PURPOSE: Surgical resection of the primary tumour in patients with advanced colorectal cancer (crc) remains controversial. This review compares survival in patients with advanced crc who underwent surgical resection of the primary tumour with that in patients not undergoing resection, and determines rates of post operative mortality and nonfatal complications, the primary tumour complication rate, the non-resection surgical procedures rate, and quality of life (qol). METHODS: Reports in the central, medline, and embase databases were searched for relevant studies, which were selected using pre-specified eligibility criteria. The search was also restricted to publication dates from 1980 onward, the English language, and studies involving human subjects. Screening, evaluation of relevant articles, and data abstraction were performed in duplicate, and agreement between the abstractors was assessed. Articles that met the inclusion criteria were assessed for quality using the Newcastle-Ottawa Scale. Data were collected and synthesized per protocol. RESULTS: From among the 3379 reports located, fifteen retrospective observational studies were selected. Of the 12,416 patients in the selected studies, 8620 (69%) underwent surgery. Median survival was 15.2 months (range: 10-30.7 months) in the resection group and 11.4 months (range: 3-22 months) in the non-resection group. Hazard ratio for survival was 0.69 [95% confidence interval (ci): 0.61 to 0.79] favouring surgical resection. Mean rates of postoperative mortality and nonfatal complications were 4.9% (95% ci: 0% to 9.7%) and 25.9% (95%ci: 20.1% to 31.6%) respectively. The mean primary tumour complication rate was 29.7% (95% ci: 18.5% to 41.0%), and the non-resection surgical procedures rate in the non-resection group was 27.6% (95 ci: 15.4% to 39.9%). No study provided qol data. CONCLUSIONS: Although this review supports primary tumour resection in advanced crc, the results have significant biases. Randomized trials are warranted to confirm the findings. PMID- 24155640 TI - Denosumab and giant cell tumour of bone-a review and future management considerations. AB - Giant cell tumour of bone (gctb) is one type of giant-cell-rich bone lesion characterized by the presence of numerous multinucleated osteoclast-type giant cells. Giant cells are known to express rankl (receptor activator of nuclear factor kappaB ligand) and are responsible for the aggressive osteolytic nature of the tumour. No available treatment option is definitively effective in curing this disease, especially in surgically unsalvageable cases. In recent years, several studies of denosumab in patients with advanced or unresectable gctb have shown objective changes in tumour composition, reduced bony destruction, and clinical benefit. Denosumab is a fully human monoclonal antibody that targets and binds with high affinity and specificity to rankl. Several large phase iii studies have shown that denosumab is more effective than bisphosphonates in reducing skeletal morbidity arising from a wide range of tumours and that it can delay bone metastasis. The relevant articles are reviewed here. The controversies related to the future use of denosumab in the treatment of gctb are discussed. PMID- 24155641 TI - Chemotherapy (gemcitabine, docetaxel plus gemcitabine, doxorubicin, or trabectedin) in inoperable, locally advanced, recurrent, or metastatic uterine leiomyosarcoma: a clinical practice guideline. AB - QUESTIONS: Does chemotherapy-that is, gemcitabine, gemcitabine plus docetaxel, doxorubicin, or trabectedin-improve clinical outcomes in women with inoperable, locally advanced, recurrent, or metastatic uterine leiomyosarcoma (lms)? Is there a difference in the tumour response rate to chemotherapy between recurrent pelvic disease and extrapelvic metastases in the target patients? METHODS: This guideline was developed by Cancer Care Ontario's Program in Evidence-Based Care, the Sarcoma Disease Site Group (dsg), and the Gynecologic Cancer dsg. The core methodology was the systematic review. The medline and embase databases (2004 to June 2011), the Cochrane Library, main guideline Web sites, and relevant annual meeting abstracts (2005-2010) were searched. Internal and external reviews were conducted, with final approval by the dsgs and the Program in Evidence-Based Care. CLINICAL PRACTICE GUIDELINE: Based on currently available evidence from the medical literature (four single-arm phase ii studies, one arm of a randomized controlled trial, and one abstract), doxorubicin alone, gemcitabine alone, or gemcitabine plus docetaxel may be treatment options in first- or second-line therapy (or both) for women with inoperable, locally advanced, recurrent, or metastatic uterine lms. Hematologic toxicity is common and should be monitored, and granulocyte colony-stimulating factor should be considered when gemcitabine plus docetaxel is used. Other toxicities, such as neurotoxicity, pulmonary toxicity, and cardiovascular toxicity should be monitored. No recommendation is made for or against the use of trabectedin in the targeted patients. No data were available concerning differences in response in recurrent pelvic disease or extrapelvic metastases, or concerning quality of life. PMID- 24155642 TI - Eastern Canadian Colorectal Cancer Consensus Conference: standards of care for the treatment of patients with rectal, pancreatic, and gastrointestinal stromal tumours and pancreatic neuroendocrine tumours. AB - The annual Eastern Canadian Colorectal Cancer Consensus Conference was held in Halifax, Nova Scotia, October 20-22, 2011. Health care professionals involved in the care of patients with colorectal cancer participated in presentation and discussion sessions for the purposes of developing the recommendations presented here. This consensus statement addresses current issues in the management of rectal cancer, including pathology reporting, neoadjuvant systemic and radiation therapy, surgical techniques, and palliative care of rectal cancer patients. Other topics discussed include multidisciplinary cancer conferences, treatment of gastrointestinal stromal tumours and pancreatic neuroendocrine tumours, the use of folfirinox in pancreatic cancer, and treatment of stage ii colon cancer. PMID- 24155643 TI - Oncofertility in Canada: an overview of Canadian practice and suggested action plan. AB - BACKGROUND: Cancer can be a devastating diagnosis. In particular, malignancy and its indicated treatments have profoundly negative effects on the fertility of young cancer patients. Oncofertility has emerged as a new interdisciplinary field to address the issue of gonadotoxicity associated with cancer therapies and to facilitate fertility preservation. In Canada, these fertility issues are often inadequately addressed despite the availability of resources. The goal of this four-part series is to facilitate systemic improvements in fertility preservation for adolescent and young adult Canadians with a new diagnosis of cancer. METHODS: Here, we describe the services currently available in Canada and the challenges associated with their utilization. Finally, we outline strategies to help maximize and facilitate fertility preservation in the young cancer patient. RESULTS: Despite an existing infrastructure to the oncofertility system in Canada, the ability of that system's components to function together and to coordinate patient care is a challenge. Areas of weakness include poor access and referral to fertility services, a lack of readily available education for patients and health care providers, and inconsistent interdisciplinary coordination in patient care. CONCLUSIONS: The implementation of a framework for multidisciplinary resource allocation, education, patient referral, and established lines of communication may facilitate a functional oncofertility system in Canada. PMID- 24155644 TI - Benefits, issues, and recommendations for personalized medicine in oncology in Canada. AB - The burden of cancer for Canadian citizens and society is large. New technologies have the potential to increase the use of genetic information in clinical decision-making, furthering prevention, surveillance, and safer, more effective drug therapies for cancer patients. Personalized medicine can have different meanings to different people. The context for personalized medicine in the present paper is genetic testing, which offers the promise of refining treatment decisions for those diagnosed with chronic and life-threatening illnesses. Personalized medicine and genetic characterization of tumours can also give direction to the development of novel drugs. Genetic testing will increasingly become an essential part of clinical decision-making. In Canada, provinces are responsible for health care, and most have unique policies and programs in place to address cancer control. The result is inconsistency in access to and delivery of therapies and other interventions, beyond the differences expected because of demographic factors and clinical education. Inconsistencies arising from differences in resources, policy, and application of evidence-informed personalized cancer medicine exacerbate patient access to appropriate testing and quality care. Geographic variations in cancer incidence and mortality rates in Canada-with the Atlantic provinces and Quebec having higher rates, and British Columbia having the lowest rates-are well documented. Our purpose here is to provide an understanding of current and future applications of personalized medicine in oncology, to highlight the benefits of personalized medicine for patients, and to describe issues and opportunities for improvement in the coordination of personalized medicine in Canada. Efficient and more rapid adoption of personalized medicine in oncology in Canada could help overcome those issues and improve cancer prevention and care. That task might benefit from the creation of a National Genetics Advisory Panel that would review research and provide recommendations on tests for funding or reimbursement, guidelines, service delivery models, laboratory quality assurance, education, and communication. More has to be known about the current state of personalized cancer medicine in Canada, and strategies have to be developed to inform and improve understanding and appropriate coordination and delivery. Our hope is that the perspectives emphasized in this paper will stimulate discussion and further research to create a more informed response. PMID- 24155645 TI - Drug-induced subacute cutaneous lupus erythematosus associated with nab paclitaxel therapy. AB - Drug-induced lupus erythematosus (dile) syndromes are documented complications of chemotherapeutic agents, including paclitaxel. Subacute cutaneous lupus erythematosus (scle) is a distinct dile syndrome presenting with characteristic annular or papulosquamous skin lesions in a photosensitive distribution with associated high anti-ssa titres. Previously, dile syndromes complicating paclitaxel therapy have been attributed to polyethoxylated castor oil (Kolliphor EL: BASF, Ludwigshafen, Germany), the biologic solvent included in the drug's original formulation (Taxol: Bristol-Myers Squibb, Montreal, QC), rather than the parent chemotherapy molecule. Here, we report a characteristic case of drug induced scle complicating treatment with nanoparticle albumin bound (nab) paclitaxel (Abraxane: Celgene, Summit, NJ, U.S.A.), a solvent-free taxane formulation. The pertinent English-language literature is also discussed. This case report is the first to link solvent-free paclitaxel with scle, and it suggests that the parent molecule is responsible for the reaction. PMID- 24155647 TI - "His turn". PMID- 24155646 TI - Breast cancer and the environment: why research and preventive action are needed. PMID- 24155649 TI - Leishmaniasis recidiva cutis and its topical treatment in ecuador. PMID- 24155650 TI - Contamination by Vibrio parahaemolyticus and Its Virulent Strains in Seafood Marketed in Thailand, Vietnam, Malaysia, and Indonesia. AB - Infections by virulent strains of Vibrio parahaemolyticus are frequently reported in Southeast Asia. This is due to the frequent seafood contamination by virulent strains. In this study conducted from 2008 to 2011, seafood like fish, shrimp, squid, crab, and molluscan shellfish were purchased from provinces in Thailand and three Southeast Asian countries and examined for the prevalence of three genetic markers of V. parahaemolyticus (species-specific gene: toxR gene, virulence genes: tdh and trh genes). An enrichment culture of seafood was examined for these markers using PCR methods. Molluscan shellfish showed a high frequency of contamination in Thailand. The shellfish harvested from the Gulf of Thailand were significantly more contaminated with virulence genes than those from the Andaman Sea. The seafood purchased from three Southeast Asian countries was positive for the three markers of V. parahaemolytcus at differing frequencies. The virulence markers (tdh and trh markers) were frequently detected in molluscan shellfish from Vietnam (17.9 and 8.0%, respectively), Malaysia (11.1 and 16.7%), and Indonesia (9.1 and 13.6%). These data suggest that the molluscan shellfish sold in Southeast Asian markets are highly contaminated with virulent strains of V. parahaemolyticus. PMID- 24155651 TI - First isolation of dengue virus from the 2010 epidemic in Nepal. AB - Dengue is an emerging disease in Nepal and was first observed as an outbreak in nine lowland districts in 2006. In 2010, however, a large epidemic of dengue occurred with 4,529 suspected and 917 serologically-confirmed cases and five deaths reported in government hospitals in Nepal. The collection of demographic information was performed along with an entomological survey and clinical evaluation of the patients. A total of 280 serum samples were collected from suspected dengue patients. These samples were subjected to routine laboratory investigations and IgM-capture ELISA for dengue serological identification, and 160 acute serum samples were used for virus isolation, RT-PCR, sequencing and phylogenetic analysis. The results showed that affected patients were predominately adults, and that 10% of the cases were classified as dengue haemorrhagic fever/ dengue shock syndrome. The genetic characterization of dengue viruses isolated from patients in four major outbreak areas of Nepal suggests that the DENV-1 strain was responsible for the 2010 epidemic. Entomological studies identified Aedes aegypti in all epidemic areas. All viruses belonged to a monophyletic single clade which is phylogenetically close to Indian viruses. The dengue epidemic started in the lowlands and expanded to the highland areas. To our knowledge, this is the first dengue isolation and genetic characterization reported from Nepal. PMID- 24155652 TI - Fact-finding Survey of Nosocomial Infection Control in Hospitals in Kathmandu, Nepal-A Basis for Improvement. AB - The purpose of this study was to investigate the actual conditions of nosocomial infection control in Kathmandu City, Nepal as a basis for the possible contribution to its improvement. The survey was conducted at 17 hospitals and the methods included a questionnaire, site visits and interviews. Nine hospitals had manuals on nosocomial infection control, and seven had an infection control committee (ICC). The number of hospitals that met the required amount of personal protective equipment preparation was as follows: gowns (13), gloves (13), surgical masks (12). Six hospitals had carried out in-service training over the past one year, but seven hospitals responded that no staff had been trained. Eight hospitals were conducting surveillance based on the results of bacteriological testing. The major problems included inadequate management of ICC, insufficient training opportunities for hospital staff, and lack of essential equipment. Moreover, increasing bacterial resistance to antibiotics was recognized as a growing issue. In comparison with the results conducted in 2003 targeting five governmental hospitals, a steady improvement was observed, but further improvements are needed in terms of the provision of high quality medical care. Particularly, dissemination of appropriate manuals, enhancement of basic techniques, and strengthening of the infection control system should be given priority. PMID- 24155653 TI - A High Incidence of Intussusception Revealed by a Retrospective Hospital-Based Study in Nha Trang, Vietnam between 2009 and 2011. AB - Rotavirus is a leading cause of severe diarrhea among children worldwide. Thus, the World Health Organization recommended including rotavirus vaccines in national immunization programs. One concern about rotavirus vaccine, however, is a possible association with intussusception. Thus, it is crucial to know the baseline incidence of intussusception in the first year of life. A study conducted in Hanoi, Vietnam showed that the incidence of intussusception was the highest in the world. This retrospective cross-sectional study was undertaken to determine the incidence of intussusception among children <5 years of age in Nha Trang, Vietnam. Hospital charts between 2009 and 2011 were reviewed in Khanh Hoa Provincial General Hospital where virtually all cases of intussusception occurring in the city were assumed to have been encountered. The incidence of intussusception among children <1 year of age was 296 per 100,000 person-years (95% confidence interval [CI]: 225-382), and that among children <5 years of age was 196 per 100,000 person-years (95% CI: 169-226), confirming the high incidence of intussusception in Vietnam. Nevertheless, there was no intussusception in the first three months of life. We therefore recommend that the first dose of any rotavirus vaccine be administered to infants between 6 and 12 weeks of age. PMID- 24155654 TI - The first identification of rotavirus B from children and adults with acute diarrhoea in kathmandu, Nepal. AB - Rotavirus B (RVB) in the genus Rotavirus of the family Reoviridae is known to be a cause of acute gastroenteritis among children and adults in parts of Asia including China, India, Bangladesh and Myanmar. In a 15-month surveillance programme between March 2007 and May 2008, 3,080 stool specimens were collected from children and adults with acute gastroenteritis in an infectious disease hospital in Kathmandu, Nepal. In 25 (0.8%) specimens RVB was detected, for the first time in Nepal, by the use of polyacrylamide gel electrophoresis followed by confirmation with reverse-transcription PCR and sequencing. The strains detected in this study had very similar electropherotypes, and their VP7 sequences were almost identical and phylogenetically belonged to the Indo-Bangladeshi lineage which was distinct from the Chinese lineage. Thus, this study showed the circulation of RVB strains belonging to the Indo-Bangladeshi lineage in a broader region than previously documented, suggesting that this phylogenetic divide corresponded to the geographic divide created by the Himalayan Mountains. Further studies may be warranted to identify and characterize the RVB strains in northern Vietnam which is adjacent to southern China with a long and less mountainous border. PMID- 24155655 TI - Can Japan Contribute to the Post Millennium Development Goals? Making Human Security Mainstream through the TICAD Process. AB - In 2013, the fifth Tokyo International Conference on African Development (TICAD V) will be hosted by the Japanese government. TICAD, which has been held every five years, has played a catalytic role in African policy dialogue and a leading role in promoting the human security approach (HSA). We review the development of the HSA in the TICAD dialogue on health agendas and recommend TICAD's role in the integration of the HSA beyond the 2015 agenda. While health was not the main agenda in TICAD I and II, the importance of primary health care, and the development of regional health systems was noted in TICAD III. In 2008, when Japan hosted both the G8 summit and TICAD IV, the Takemi Working Group developed strong momentum for health in Africa. Their policy dialogues on global health in Sub-Saharan Africa incubated several recommendations highlighting HSA and health system strengthening (HSS). HSA is relevant to HSS because it focuses on individuals and communities. It has two mutually reinforcing strategies, a top down approach by central or local governments (protection) and a bottom-up approach by individuals and communities (empowerment). The "Yokohama Action Plan," which promotes HSA was welcomed by the TICAD IV member countries. Universal health coverage (UHC) is a major candidate for the post-2015 agenda recommended by the World Health Organization. We expect UHC to provide a more balanced approach between specific disease focus and system-based solutions. Japan's global health policy is coherent with HSA because human security can be the basis of UHC-compatible HSS. PMID- 24155656 TI - Salmonella typhimurium mediated delivery of Apoptin in human laryngeal cancer. AB - An effective cancer therapeutic should target tumours specifically with limited systemic toxicity. Here, we transformed an attenuated Salmonella typhimurium (S. typhimurium) with an Apoptin expressing plasmid into a human laryngeal carcinoma cell line. The expression of the inserted gene was measured using fluorescence and immunoblotting assays. The attenuated S. typhimurium-mediated Apoptin significantly decreased cytotoxicity and strongly increased cell apoptosis through the activation of caspase-3. The process was mediated by Bax, cytochrome c and caspase-9. A syngeneic nude murine tumour model was used to determine the anti-tumour effects of the recombinant bacteria in vivo. Systemic injection of the recombinant bacteria with and without re-dosing caused significant tumour growth delay and reduced tumour microvessel density, thereby extending host survival. Our findings indicated that the use of recombinant Salmonella typhimurium as an Apoptin expression vector has potential cancer therapeutic benefits. PMID- 24155657 TI - High-expression of DJ-1 and loss of PTEN associated with tumor metastasis and correlated with poor prognosis of gastric carcinoma. AB - BACKGROUND AND AIMS: DJ-1 and PTEN have been shown to involve in multiple cell processes and play an important role in cancer development and progression. However, their relationship with gastric carcinoma (GC) has not been identified yet. The purpose of this study is to clarify the relationship of DJ-1 and phosphatase and tensin homolog (PTEN) with clinicopathological parameters and prognosis in GC. METHODS: 114 specimens were collected from GC patients and expression of DJ-1 and PTEN in tissue microarray was evaluated by immunohistochemical staining. Correlation between immunostainings and clinicopathological parameters, follow-up data of patients, was analyzed statistically. RESULTS: High expression of DJ-1 was found in 66.7% (76/114) and associated with tumor depth (P=0.003), lymph node metastasis (P=0.011), distant metastasis (P=0.001) and advanced clinical stage (P=0.001). Loss or downregulation of PTEN was found in 58.7% (67/114) and associated with advanced clinical stage (P=0.018) and high expression of DJ-1 in tumor cells (P=0.006). In univariate survival analysis, high-expression of DJ-1 or loss of PTEN was significantly associated with poor prognosis of GC patients. However, only tumor depth (P=0.011) and coexistence of DJ-1 and PTEN abnormal expression (P=0.009) emerged as strong independent prognostic factors for overall survival of GC patients. CONCLUSIONS: the present study indicates that DJ-1 and PTEN may play their roles in progression of GC in a cooperating pattern. Co-existence of abnormal DJ-1 and PTEN expression is likely to serve as an independent predictive factor for prognosis of GC patients. PMID- 24155658 TI - Airway administration of vascular endothelial growth factor siRNAs induces transient airspace enlargement in mice. AB - PURPOSE: Reduction in the level of vascular endothelial growth factor (VEGF) has been implicated in the pathogenesis of pulmonary emphysema. To this end, pharmacological VEGF receptor blockade, and the Cre-lox system models have been utilized to study the effects of VEGF depletion in the lung. These models generally reproduce air space enlargement resembling clinical emphysema. Here we report a potentially more readily available model of lung targeted VEGF depletion by airway administration of VEGF small inhibitory RNA oligonucleotides (siRNAs) in mice. METHODS: Airway administration of VEGF siRNAs were done in C57BL/6 mice. The lungs were removed for histology and protein analysis 2, and 4 days later. Airspace enlargement was evaluated by lung volume measurement, and histological analyses. VEGF levels were analyzed by western blot and immunohistochemistry. RESULTS: Airway administration of VEGF siRNAs induced transient air space enlargement in the mouse lung morphologically resembling the previously reported models of pulmonary emphysema. VEGF expression was significantly reduced in the lung, particularly in the alveolar septal cells. We also found that in this particular model, sequential airway administration of recombinant VEGF protein attenuated this air space enlargement. Additionally, we found that airway administration of DCI, a combination of dexamethasone, 3'-5'-cyclic adenosine monophosphate, and isobutylmethylxanthine attenuated the air space enlargement in this particular model, at least in part through the recovery of lung VEGF expression. CONCLUSIONS: The pathogenesis of pulmonary emphysema is likely to be multifaceted, but the present mouse model may be useful in dissecting the involvement of VEGF in pulmonary emphysema. PMID- 24155659 TI - DNA methylation profiling revealed promoter hypermethylation-induced silencing of p16, DDAH2 and DUSP1 in primary oral squamous cell carcinoma. AB - BACKGROUND: Hypermethylation in promoter regions of genes might lead to altered gene functions and result in malignant cellular transformation. Thus, biomarker identification for hypermethylated genes would be very useful for early diagnosis, prognosis, and therapeutic treatment of oral squamous cell carcinoma (OSCC). The objectives of this study were to screen and validate differentially hypermethylated genes in OSCC and correlate the hypermethylation-induced genes with demographic, clinocopathological characteristics and survival rate of OSCC. METHODS: DNA methylation profiling was utilized to screen the differentially hypermethylated genes in OSCC. Three selected differentially-hypermethylated genes of p16, DDAH2 and DUSP1 were further validated for methylation status and protein expression. The correlation between demographic, clinicopathological characteristics, and survival rate of OSCC patients with hypermethylation of p16, DDAH2 and DUSP1 genes were analysed in the study. RESULTS: Methylation profiling demonstrated 33 promoter hypermethylated genes in OSCC. The differentially hypermethylated genes of p16, DDAH2 and DUSP1 revealed positivity of 78%, 80% and 88% in methylation-specific polymerase chain reaction and 24% and 22% of immunoreactivity in DDAH2 and DUSP1 genes, respectively. Promoter hypermethylation of p16 gene was found significantly associated with tumour site of buccal, gum, tongue and lip (P=0.001). In addition, DDAH2 methylation level was correlated significantly with patients' age (P=0.050). In this study, overall five-year survival rate was 38.1% for OSCC patients and was influenced by sex difference. CONCLUSIONS: The study has identified 33 promoter hypermethylated genes that were significantly silenced in OSCC, which might be involved in an important mechanism in oral carcinogenesis. Our approaches revealed signature candidates of differentially hypermethylated genes of DDAH2 and DUSP1 which can be further developed as potential biomarkers for OSCC as diagnostic, prognostic and therapeutic targets in the future. PMID- 24155660 TI - Circulating progenitor and mature endothelial cells in deep vein thrombosis. AB - INTRODUCTION: Mature circulating endothelial cells (CEC) and circulating endothelial progenitor cells (EPC) have been described in several conditions associated with endothelial injury. Their role in deep vein thrombosis (DVT) has not been previously evaluated. PATIENTS AND METHODS: In this pilot study we evaluated the time course of CEC and EPC release after vena cava experimental DVT in mice, using the FeCl3 model. We also evaluated their presence in patients with DVT at different phases of the disease (acute and chronic phase). CEC and EPC were evaluated by Flow Cytometry. RESULTS: In mice, both CEC and EPC were increased 24 hours after DVT induction, peaking 48 hours thereafter. After 72 hours, CEC counts decreased sharply, whereas EPC counts decreased less substantially. In DVT patients we observed a significant increase in CEC counts immediately after DVT compared to healthy individuals. Patients with chronic disease also presented a significant elevation of these cell count. In a subgroup of patients for whom serial samples were available, CEC counts decreased significantly after 9-15 months of the acute event. CONCLUSIONS: Our results suggest the participation of these cells in the reparative processes that follows DVT, both at immediate and late time-points. The different kinetics of CEC and EPC release in experimental DVT suggests a heterogeneous role for these cells in the reparative events after DVT. PMID- 24155661 TI - Silencing of atp6v1c1 prevents breast cancer growth and bone metastasis. AB - Previous studies have shown that Atp6v1c1, a regulator of the assembly of the V0 and V1 domains of the V-ATPase complex, is up-regulated in metastatic oral tumors. Despite these studies, the function of Atp6v1c1 in tumor growth and metastasis is still unknown. Atp6v1c1's expression in metastatic oral squamous cell carcinoma indicates that Atp6v1c1 has an important function in cancer growth and metastasis. We hypothesized that elevated expression of Atp6v1c1 is essential to cancer growth and metastasis and that Atp6v1c1 promotes cancer growth and metastasis through activation of V-ATPase activity. To test this hypothesis, a Lentivirus-mediated RNAi knockdown approach was used to study the function of Atp6v1c1 in mouse 4T1 mammary tumor cell proliferation and migration in vitro and cancer growth and metastasis in vivo. Our data revealed that silencing of Atp6v1c1 in 4T1 cancer cells inhibited lysosomal acidification and severely impaired 4T1 cell growth, migration, and invasion through Matrigel in vitro. We also show that Atp6v1c1 knockdown with Lenti-c1s3, a lentivirus targeting Atp6v1c1 for shRNA mediated knockdown, can significantly inhibit 4T1 xenograft tumor growth, metastasis, and osteolytic lesions in vivo. Our study demonstrates that Atp6v1c1 may promote breast cancer growth and bone metastasis through regulation of lysosomal V-ATPase activity, indicating that Atp6v1c1 may be a viable target for breast cancer therapy and silencing of Atp6v1c1 may be an innovative therapeutic approach for the treatment and prevention of breast cancer growth and metastasis. PMID- 24155662 TI - Permethrin induction of multiple cytochrome P450 genes in insecticide resistant mosquitoes, Culex quinquefasciatus. AB - The expression of some insect P450 genes can be induced by both exogenous and endogenous compounds and there is evidence to suggest that multiple constitutively overexpressed P450 genes are co-responsible for the development of resistance to permethrin in resistant mosquitoes. This study characterized the permethrin induction profiles of P450 genes known to be constitutively overexpressed in resistant mosquitoes, Culex quinquefasciatus. The gene expression in 7 of the 19 P450 genes CYP325K3v1, CYP4D42v2, CYP9J45, (CYP) CPIJ000926, CYP325G4, CYP4C38, CYP4H40 in the HAmCqG8 strain, increased more than 2-fold after exposure to permethrin at an LC50 concentration (10 ppm) compared to their acetone treated counterpart; no significant differences in the expression of these P450 genes in susceptible S-Lab mosquitoes were observed after permethrin treatment. Eleven of the fourteen P450 genes overexpressed in the MAmCqG6 strain, CYP9M10, CYP6Z12, CYP9J33, CYP9J43, CYP9J34, CYP306A1, CYP6Z15, CYP9J45, CYPPAL1, CYP4C52v1, CYP9J39, were also induced more than doubled after exposure to an LC50 (0.7 ppm) dose of permethrin. No significant induction in P450 gene expression was observed in the susceptible S-Lab mosquitoes after permethrin treatment except for CYP6Z15 and CYP9J39, suggesting that permethrin induction of these two P450 genes are common to both susceptible and resistant mosquitoes while the induction of the others are specific to insecticide resistant mosquitoes. These results demonstrate that multiple P450 genes are co up-regulated in insecticide resistant mosquitoes through both constitutive overexpression and induction mechanisms, providing additional support for their involvement in the detoxification of insecticides and the development of insecticide resistance. PMID- 24155663 TI - A novel zinc finger protein 219-like (ZNF219L) is involved in the regulation of collagen type 2 alpha 1a (col2a1a) gene expression in zebrafish notochord. AB - The notochord is required for body plan patterning in vertebrates, and defects in notochord development during embryogenesis can lead to diseases affecting the adult. It is therefore important to elucidate the gene regulatory mechanism underlying notochord formation. In this study, we cloned the zebrafish zinc finger 219-like (ZNF219L) based on mammalian ZNF219, which contains nine C2H2 type zinc finger domains. Through whole-mount in situ hybridization, we found that znf219L mRNA is mainly expressed in the zebrafish midbrain-hindbrain boundary, hindbrain, and notochord during development. The znf219L morpholino knockdown caused partial abnormal notochord phenotype and reduced expression of endogenous col2a1a in the notochord specifically. In addition, ZNF219L could recognize binding sites with GGGGG motifs and trigger augmented activity of the col2a1a promoter in a luciferase assay. Furthermore, in vitro binding experiments revealed that ZNF219L recognizes the GGGGG motifs in the promoter region of the zebrafish col2a1a gene through its sixth and ninth zinc finger domains. Taken together, our results reveal that ZNF219L is involved in regulating the expression of col2a1a in zebrafish notochord specifically. PMID- 24155664 TI - Hydrogen as a new class of radioprotective agent. AB - It is well known that most of the ionizing radiation-induced damage is caused by hydroxyl radicals (.OH) follows radiolysis of H2O. Molecular hydrogen (H2) has antioxidant activities by selectively reducing .OH and peroxynitrite(ONOO-). We firstly hypothesized and demonstrated the radioprotective effect of H2 in vitro and in vivo, which was also repeated on different experimental animal models by different departments. A randomized, placebo-controlled study showed that consumption of hydrogen-rich water reduces the biological reaction to radiation induced oxidative stress without compromising anti-tumor effects. These encouraging results suggested that H2 represents a potentially novel preventative strategy for radiation-induced oxidative injuries. H2 is explosive. Therefore, administration of hydrogen-rich solution (physiological saline/pure water/other solutions saturated with H2) may be more practical in daily life and more suitable for daily consumption. This review focuses on major scientific and clinical advances of hydrogen-rich solution/H2 as a new class of radioprotective agent. PMID- 24155665 TI - PBMC transcription profiles of pigs with divergent humoral immune responses and lean growth performance. AB - BACKGROUND: The identification of key genes and regulatory networks in the transcriptomic responses of blood cells to antigen stimulation could facilitate the understanding of host defence and disease resistance. Moreover, genetic relationships between immunocompetence and the expression of other phenotypes, such as those of metabolic interest, are debated but incompletely understood in farm animals. Both positive and negative associations between immune responsiveness and performance traits such as weight gain or lean growth have been reported. We designed an in vivo microarray study of transcriptional changes in porcine peripheral blood mononuclear cells (PBMCs) during the immune response to tetanus toxoid (TT) as a model antigen for combined cellular (Th1) and humoral (Th2) responses. The aim of the study was to investigate the responsiveness of PBMCs against the background of divergent lean growth (LG) performance and anti TT antibody (AB) titers and to compare lean growth and humoral immune performance phenotypes. RESULTS: In general, high LG phenotypes had increased cellular immune response transcripts, while low AB phenotypes had increased transcripts for canonical pathways that represented processes of intracellular and second messenger signaling and immune responses. Comparison of lean growth phenotypes in the context of high AB titers revealed higher cellular immune response transcripts in high LG phenotypes. Similar comparisons in the context of low AB titers failed to identify any corresponding pathways. When high and low AB titer phenotypes were differentially compared, low AB phenotypes had higher cellular immune response transcripts on a low LG background and higher cell signaling, growth, and proliferation transcripts on a high LG background. CONCLUSIONS: Divergent phenotypes of both lean growth performance and humoral immune response are affected by significant and functional transcript abundance changes throughout the immune response. The selected high-performance phenotypes demonstrated both high AB titers and increased transcript abundance of cellular immune response genes, which were possibly offset by lower expression of other cellular functions. Further, indications of compensatory effects were observed between cellular and humoral immune responses that became visible only in low performance phenotypes. PMID- 24155669 TI - Hoxc gene collinear expression and epigenetic modifications established during embryogenesis are maintained until after birth. AB - The Hox genes, which are organized into clusters on different chromosomes, are key regulators of embryonic anterior-posterior (A-P) body pattern formation and are expressed at specific times and in specific positions in developing vertebrate embryos. Previously, we have shown that histone methylation patterns are closely correlated with collinear Hox gene expression patterns along the A-P axis of E14.5 mouse embryos. Since histone modification is thought to play a crucial mechanistic role in the highly coordinated pattern of collinear Hox gene expression, we examined the maintenance of the spatial collinear expression pattern of Hoxc genes and the corresponding histone modifications during embryogenesis and in early postnatal mice. Hox expression patterns and histone modifications were analyzed by semi-quantitative RT-PCR and chromatin immunoprecipitation (ChIP)-PCR analyses, respectively. The spatiotemporal expression patterns of Hoxc genes in a cluster were maintained until the early postnatal stage (from E8.5 through P5). Examination of histone modifications in E14.5 and P5 tissues revealed that level of H3K27me3 is only a weak correlation with collinear Hoxc gene expression in the trunk regions although diminished in general, however the enrichment of H3K4me3 is strongly correlated with the gene expression in both stages. In summary, the initial spatiotemporal collinear expression pattern of Hoxc genes and epigenetic modifications are maintained after birth, likely contributing to the establishment of the gene expression code for position in the anatomic body axis throughout the entire life of the organism. PMID- 24155666 TI - The many faces of C/EBPdelta and their relevance for inflammation and cancer. AB - The CCAAT/enhancer binding protein delta (CEBPD, C/EBPdelta) is a transcription factor that modulates many biological processes including cell differentiation, motility, growth arrest, proliferation, and cell death. The diversity of C/EBPdelta's functions depends in part on the cell type and cellular context and can have opposing outcomes. For example, C/EBPdelta promotes inflammatory signaling, but it can also inhibit pro-inflammatory pathways, and in a mouse model of mammary tumorigenesis, C/EBPdelta reduces tumor incidence but promotes tumor metastasis. This review highlights the multifaceted nature of C/EBPdelta's functions, with an emphasis on pathways that are relevant for cancer and inflammation, and illustrates how C/EBPdelta emerged from the shadow of its family members as a fascinating "jack of all trades." Our current knowledge on C/EBPdelta indicates that, rather than being essential for a specific cellular process, C/EBPdelta helps to interpret a variety of cues in a cell-type and context-dependent manner, to adjust cellular functions to specific situations. Therefore, insights into the roles and mechanisms of C/EBPdelta signaling can lead to a better understanding of how the integration of different signaling pathways dictates normal and pathological cell functions and physiology. PMID- 24155668 TI - Glutamate, glutamate receptors, and downstream signaling pathways. AB - Glutamate is a nonessential amino acid, a major bioenergetic substrate for proliferating normal and neoplastic cells, and an excitatory neurotransmitter that is actively involved in biosynthetic, bioenergetic, metabolic, and oncogenic signaling pathways. Glutamate signaling activates a family of receptors consisting of metabotropic glutamate receptors (mGluRs) and ionotropic glutamate receptors (iGluRs), both of which have been implicated in chronic disabling brain disorders such as Schizophrenia and neurodegenerative diseases like Alzheimer's, Parkinson's, and multiple sclerosis. In this review, we discuss the structural and functional relationship of mGluRs and iGluRs and their downstream signaling pathways. The three groups of mGluRs, the associated second messenger systems, and subsequent activation of PI3K/Akt, MAPK, NFkB, PLC, and Ca/CaM signaling systems will be discussed in detail. The current state of human mGluR1a as one of the most important isoforms of Group I-mGluRs will be highlighted. The lack of studies on the human orthologues of mGluRs family will be outlined. We conclude that upon further study, human glutamate-initiated signaling pathways may provide novel therapeutic opportunities for a variety of non-malignant and malignant human diseases. PMID- 24155670 TI - Interleukin-8 regulates endothelial permeability by down-regulation of tight junction but not dependent on integrins induced focal adhesions. AB - Interleukin-8 (IL-8) is a common inflammatory factor, which involves in various non-specific pathological processes of inflammation. It has been found that increased endothelial permeability accompanied with high expression of IL-8 at site of injured endothelium and atherosclerotic plaque at early stages, suggesting that IL-8 participated in regulating endothelial permeability in the developing processes of vascular disease. The purpose of this study is to investigate the regulation effects of IL-8 on the vascular endothelial permeability, and the mRNA and protein expression of tight junction components (i.e., ZO-1, Claudin-5 and Occludin). Endothelial cells were stimulated by IL-8 with the dose of 50, 100 and 200 ng/mL, and duration of 2, 4, 6, 8h, respectively. The mRNA and protein expression level of tight junction components with IL-8 under different concentration and duration was examined by RT-PCR and Western blot, respectively. Meanwhile, the integrins induced focal adhesions event with IL-8 stimulation was also investigated. The results showed that IL-8 regulated the permeability of endothelium by down-regulation of tight junction in a dose- and time-dependence manner, but was not by integrins induced focal adhesions. This finding reveals the molecular mechanism in the increase of endothelial cell permeability induced by IL-8, which is expected to provide a new idea as a therapeutic target in vascular diseases. PMID- 24155671 TI - Molecular characterization and alternative splicing of a sodium channel and DSC1 ortholog genes in Liposcelis bostrychophila Badonnel (Psocoptera: Liposcelididae). AB - Alternative splicing greatly contributes to the structural and functional diversity of voltage-gated sodium channels (VGSCs) by generating various isoforms with unique functional and pharmacological properties. Here, we identified a new optional exon 23 located in the linker between domains II and III, and four mutually exclusive exons (exons 27A, 27B, 27C, and 27D) in domains IIIS3 and IIIS4 of the sodium channel of Liposcelis bostrychophila (termed as LbVGSC). This suggested that more alternative splicing phenomena remained to be discovered in VGSCs. Inclusion of exon 27C might lead to generation of non-functional isoforms. Meanwhile, identification of three alternative exons (exons 11, 13A, and 13B), which were located in the linker between domains II and III, indicated that abundant splicing events occurred in the DSC1 ortholog channel of L. bostrychophila (termed as LbSC1). Exons 13A and 13B were generated by intron retention, and the presence of exon 13B relied on the inclusion of exon 13A. Exon 13B was specifically expressed in the embryonic stage and contained an in-frame stop codon, inclusion of which led to generation of truncated proteins with only the first two domains. Additionally, several co-occurring RNA editing events were identified in LbSC1. Furthermore, remarkable similarity between the structure and expression patterns of LbVGSC and LbSC1 were discovered, and a closer evolutionary relationship between VGSCs and DSC1 orthologs was verified. Taken together, the data provided abundant molecular information on VGSC and DSC1 orthologs in L. bostrychophila, a representative Psocoptera storage pest, and insights into the alternative splicing of these two channels. PMID- 24155672 TI - Identification and expression profile analysis of antimicrobial peptide/protein in Asian corn borer, Ostrinia furnacalis (Guenee). AB - Antimicrobial peptides/proteins (AMPs) are a group of immune proteins that exhibit strong antibiotic properties against numerous infectious bacterial strains. They are evolutionarily conserved and present in every kingdom and phylum, ranging from prokaryotes to humans. We analyzed the transciptome from the larvae of Asian corn borer, Ostrinia furnacalis (Guenee), and identified several putative AMP transcripts, OfgLys5, OfgLys6, OfgLys10, OfgAtt, and OfgIID. OfgLys5, OfgLys6, and OfgLys10 are all highly homologous with c-type lysozymes, and OfgAtt shows significant identities with Lepidoptera attacin. The amino acid sequence of OfgLys5 and OfgLys6 possessed all conserved features critical for fundamental structure and function of c-type lysozyme, including the two catalytic sites, Glu(32) and Asp(50). OfgAtt is a typical glycine-rich protein. The antimicrobial activity of O. furnacalis hemolymph increased significantly after injection with Escherichia coli, Micrococcus luteus, or Beauveria bassiana. OfgAtt, IDD, and Lys6 are expressed at low level prior to the challenge, but strongly induced against Gram-positive and negative bacteria, and fungi. Under the same inducement conditions, the transcripts of these three genes elevated most when fifth instar larvae were injected. Therefore, O. furnacalis larvae are induced to produce antimicrobial materials in the hemolymph after the infection, and increase of lysozyme and attacin may contribute to the antimicrobial activity. PMID- 24155673 TI - Stereotactic body radiotherapy for early stage lung cancer. AB - Stereotactic body radiation therapy (SBRT) is a newly developed technique currently in clinical use. SBRT originated from stereotactic radiosurgery for intracranial tumors. SBRT has been widely used clinically for lung cancer. The practice of SBRT demands different kinds of patient fixation, breathing control, target determination, treatment planning, and verifications. The history and current standard technique are reviewed. Clinical studies of lung cancer showed high local control rates with acceptable toxicities. Past and on-going clinical trials are reviewed. PMID- 24155674 TI - Survival of korean adult cancer patients by stage at diagnosis, 2006-2010: national cancer registry study. AB - PURPOSE: Although the cancer stage at diagnosis is the most important prognostic factor for patients' survival, there are few population-based estimates of stage specific survival outcome, especially in Asian countries. Our study aims to estimate stage-specific survival for Korean patients. MATERIALS AND METHODS: We analyzed the Korea National Cancer Incidence Database data on 626,506 adult patients aged >= 20 years, who were diagnosed between 2006 and 2010 with stomach, colorectal, liver, lung, breast, cervix, prostate, and thyroid cancers. Patients were followed up to December 2011, and the 5-year relative survival rates (RSRs) were calculated for gender and age group by Surveillance, Epidemiology, and End Results (SEER) stage at diagnosis. RESULTS: The 5-year RSRs for all localized stage cancers, except for lung and liver, exceeded 90% with that for thyroid cancer being the highest at 100.4%. These values for distant stage liver, lung, and stomach cancers were very dismal at 2.5%, 4.8%, and 5.5%, respectively, while it was 69.1% for thyroid cancer, and was in the range of 18.3-36.4% for colorectal, cervix, breast and prostate cancers. Overall, the 5-year RSRs for all cancer types decreased with aging across all the disease stages with exception of prostate cancer, which suggests biologic difference in these cancer types in a young age group. When compared with US SEER data, Korean patients had better stage-specific survival rates for stomach, colorectal, liver, and cervical cancers. CONCLUSION: Korean cancer patients showed relatively favorable stage distribution and 5-year RSRs, which suggests potential contribution of the national cancer screening program. PMID- 24155675 TI - A Phase II Study to Evaluate the Efficacy of Ramosetron, Aprepitant, and Dexamethasone in Preventing Cisplatin-Induced Nausea and Vomiting in Chemotherapy Naive Cancer Patients. AB - PURPOSE: Combination therapy with aprepitant, serotonin receptor antagonist, and steroids improves the complete response rate of both acute and delayed chemotherapy-induced nausea and vomiting (CINV). However, it is not known whether ramosetron is suitable for administration in combination with aprepitant. Therefore, we conducted a multicenter, open-label, prospective, phase II study in order to assess the efficacy and tolerability of combination therapy with ramosetron, aprepitant, and dexamethasone (RAD) for prevention of cisplatin-based CINV in chemotherapy-naive patients with solid cancers. MATERIALS AND METHODS: Forty-one patients with various solid cancers (31 male and 10 female; median age, 59 years) who received treatment with highly emetogenic chemotherapy (median cisplatin dose, 70 mg/m(2); range 50 to 75 mg/m(2)) were enrolled in this study. Oral aprepitant (125 mg on day 1; 80 mg on days 2 and 3), intravenous ramosetron (0.6 mg on day 1), and oral dexamethasone (12 mg on day 1; 8 mg on days 2-4) were administered for prevention of CINV. RESULTS: The complete response (no emesisand retching and no rescue medication) rate was 94.9% in the acute period (24 hours post-chemotherapy), 92.3% in the delayed period (24-120 hours post-chemotherapy), and 92.3% in the overall period (0-120 hours). The absolute complete response (complete response plus no nausea) rate was 74.4% in the acute period, 51.3% in the delayed period, and 46.2% in the overall period. There were no grade 3 or 4 toxicities related to these antiemetic combinations. CONCLUSION: RAD regimen is a safe and effective antiemetic treatment for prevention of CINV in patients receiving highly emetogenic chemotherapy. PMID- 24155676 TI - How Molecular Understanding Affects to Prescribing Patterns and Clinical Outcome of Gefitinib in Non-small Cell Lung Cancer? 10 Year Experience of Single Institution. AB - PURPOSE: Gefitinib was introduced in 2002 for treatment of non-small cell lung cancer (NSCLC); however, it is not clear whether its use in daily practice has changed the outcome of patients. The purpose of this study is to evaluate the question of how molecular understanding regarding gefitinib and epidermal growth factor receptor (EGFR) mutation affect the prescribing patterns and clinical outcomes of treatment with gefitinib in NSCLC, in a real practical field. MATERIALS AND METHODS: We conducted a retrospective analysis of the consecutive database of NSCLC patients who were treated with gefitinib at Seoul National University Hospital between January 2002 and December 2011. Prescribing patterns and clinical outcomes were analyzed by year. RESULTS: A total of 1,115 NSCLC patients, who received gefitinib at recurred or metastatic setting, were included in this study. Proportion of patients receiving gefitinib, for the first line, showed a gradual increase, from 5.2% in 2002-2003 to 30.6% in 2010-2011. Proportion of patients who underwent EGFR mutation testing showed a rapid increase, from 0.6% in 2004-2005 to 73.5% in 2010-2011. The response rate also showed a gradual increase, from 17.2% in 2002-2003 to 57.1% in 2010-2011 (p<0.001). The median progression-free survival of gefitinib was increased with statistical significance from 2.8 months in 2002-2003 to 9.1 months in 2010-2011 (p<0.001). CONCLUSION: We demonstrated that molecular understanding and practical use of EGFR mutation testing have resulted in a change in the prescription patterns of gefitinib. Use of an enrichment strategy can lead to improvement in the efficacy of gefitinib in real practice. PMID- 24155677 TI - Prognostic significance of serum carcinoembryonic antigen normalization on survival in rectal cancer treated with preoperative chemoradiation. AB - PURPOSE: The purpose of this retrospective study was to identify factors predictive of survival in rectal cancer patients who received surgery with curative intent after preoperative chemoradiotherapy (CRT). MATERIALS AND METHODS: Between July 1996 and June 2010, 104 patients underwent surgery for rectal cancer after preoperative CRT. The median dose of radiotherapy was 50.4 Gy (range, 43.2 to 54.4 Gy) for 6 weeks. Chemotherapy was a bolus injection of 5 fluorouracil and leucovorin for the first and last week of radiotherapy (n=84, 77.1%) or capecitabine administered daily during radiotherapy (n=17, 16.3%). Low anterior resection (n=86, 82.7%) or abdominoperineal resection (n=18, 17.3%) was performed at a median 47 days from the end of radiotherapy, and four cycles of adjuvant chemotherapy was administered. The serum carcinoembryonic antigen (CEA) level was checked at initial diagnosis and just before surgery. RESULTS: After a median follow-up of 48 months (range, 9 to 174 months), 5-year disease free survival (DFS) was 74.5% and 5-year overall survival (OS) was 86.4%. Down staging of T diagnoses occurred in 32 patients (30.8%) and of N diagnoses in 40 patients (38.5%). The CEA change from initial diagnosis to pre-surgery (high-high vs. high normal vs. normal-normal) was a statistically significant prognostic factor for DFS (p=0.012), OS (p=0.002), and distant metastasis free survival (p=0.018) in a multivariate analysis. CONCLUSION: Patients who achieve normal CEA level by the time of surgery have a more favorable outcome than those who retain a high CEA level after preoperative CRT. The normalization of CEA levels can provide important information about the prognosis in rectal cancer treatment. PMID- 24155678 TI - Impact of Chemoradiation on Prognosis in Stage IVB Cervical Cancer with Distant Lymphatic Metastasis. AB - PURPOSE: The purpose of this study was to determine whether chemoradiation (CCR) is efficient for improving prognosis, compared with systemic chemotherapy (SC), in patients with stage IVB cervical cancer who have distant lymphatic metastasis. MATERIALS AND METHODS: Among 2,322 patients with cervical cancer between January 2000 and March 2010, 43 patients (1.9%) had stage IVB disease. After exclusion of 19 patients due to insufficient data and hematogenous metastasis, 24 patients (1%) who received CCR (n=10) or SC (n=14) were enrolled. We compared tumor response, progression-free survival (PFS) and overall survival (OS), and disease recurrence between CCR and SC. RESULTS: Complete response rates were 60% and 0% after CCR and SC (p<0.01). Grade 3 or 4 leukopenia was more common in patients treated with CCR (24.4% vs. 9.1%, p=0.03), whereas grade 3 or 4 neuropenia was more frequent in those treated with SC (28.4% vs. 11.1%, p=0.03). Development of grade 3 proctitis occurred as a late radiotherapy (RT)-related toxicity in only one patient (10%) treated with CCR. In addition, squamous cell carcinoma and CCR were favorable prognostic factors for improvement of PFS (adjusted hazard ratios [HRs], 0.17 and 0.12; 95% confidence intervals [CIs], 0.04 to 0.80 and 0.03 to 0.61), and only CCR was significant for improvement of OS (adjusted HR, 0.15; 95% CI, 0.02 to 0.90). However, no differences in the rate and pattern of disease recurrence were observed between CCR and SC. CONCLUSION: CCR may be more effective than SC for improving survival, and can be regarded as a feasible method with some caution regarding late RT-related toxicity for treatment of stage IVB cervical cancer with distant lymphatic metastasis. PMID- 24155679 TI - Role of postoperative radiotherapy for microscopic margin involvement in the squamous cell carcinoma of esophagus. AB - PURPOSE: The objective of this study was to assess the effect of postoperative radiotherapy on the outcome of esophageal cancer with microscopically positive resection margin by comparing the results with those of patients with negative resection margin. MATERIALS AND METHODS: Medical records of 88 patients treated with macroscopic resection followed by postoperative radiotherapy for stage II or III squamous cell carcinoma of the esophagus from June 1984 to March 2008 were reviewed. Twelve patients had received chemotherapy. Patients were classified into two groups based on resection margin status: negative resection margin (group A, n=66) and microscopically positive resection margin (group B, n=22). Median follow-up duration of living patients was 68 months (range, 18 to 115 months). Median total radiation dose of group A and group B was 51.5 Gy (range, 45 to 69 Gy) and 52.1 Gy (range, 45 to 64 Gy), respectively. RESULTS: Median overall survival and disease-free survival were 15 and 10 months, respectively. The five-year overall survival, disease-free survival, and local control rates for group A and group B were 15.9% and 16.4%, 13.5% and 9.1%, and 76.3% and 69.6%, respectively. No statistically significant difference in terms of overall survival, disease-free survival, and local control (p=0.295, p=0.209, and p=0.731, respectively) was observed between group A and group B. Seven patients experienced toxicity of grade 3 or higher. CONCLUSION: A significant portion of patients with margin involvement reached long term survival after addition of postoperative radiotherapy. These results suggest a potential role of postoperative radiotherapy, especially for patients with margin involvement. PMID- 24155680 TI - Prognostic role of interleukin-6, interleukin-8, and leptin levels according to breast cancer subtype. AB - PURPOSE: Inflammation within the tumor microenvironment has been reported to show an association with poor prognosis in breast cancer. However, the associations may differ according to breast cancer subtype. In this study, we investigated the association between inflammation-related markers and breast cancer recurrence according to patients' tumor subtypes. MATERIALS AND METHODS: This prospective study included 240 patients who underwent surgery for management of newly diagnosed breast cancer. Levels of inflammation-related markers (interleukin [IL] 1beta, IL-6, IL-8, monocyte chemoattractant protein-1 [MCP-1], leptin, and adiponectin) were measured at diagnosis, and the associations between these markers and breast cancer recurrence during a six-year follow-up period were examined using the Kaplan-Meier statistical method. RESULTS: Overall, inflammation-related markers showed no association with breast cancer recurrence. However, when data were stratified by tumor subtype, higher levels of some mediators showed an association with poor prognosis among patients with particular subtypes. Compared to patients without recurrence, patients with recurrence had higher levels of circulating IL-6 (p=0.024) and IL-8 (p=0.016) only among those with HER2(-) tumors and had higher levels of leptin (p=0.034) only among those with estrogen receptor (ER)(+)/progesterone receptor (PR)(+) tumors. Results of survival analyses revealed an association of high levels of IL 6 (p=0.016) and IL-8 (p=0.022) with poor recurrence-free survival in patients with HER2(-) tumors. In addition, higher leptin levels indicated shorter recurrence-free survival time only among patients with ER(+)/PR(+) tumors (p=0.022). CONCLUSION: We found that certain cytokines could have a differential prognostic impact on breast cancer recurrence according to breast cancer subtype. Conduct of additional large studies will be required in order to elucidate the precise roles of these cytokines in breast cancer progression. PMID- 24155681 TI - Evaluation of Prescribing Medications for Terminal Cancer Patients near Death: Essential or Futile. AB - PURPOSE: The purpose of this study is to evaluate the prescription of essential or futile medications for terminal cancer patients during their final admission. MATERIALS AND METHODS: We conducted a retrospective review of the medical charts of terminally ill cancer patients admitted to the Hemato-oncology Department of two teaching hospitals from March 1, 2007 to December 31, 2009. Essential medications were based on the drugs listed by the International Association for Hospice and Palliative Care, while futile medications were defined when short term benefit to patients with respect to survival, quality of life, or symptom control was not anticipated. RESULTS: A total of 196 patients were included. Among essential medications, strong opioids were the most frequently prescribed drugs during the last admission (62.2% fentanyl, 44.3% morphine), followed by megestrol (46.0%), and metoclopramide (37.2%); 51% of gastric protectors were prescribed with potential futility. Anti-hypertensive and antiglycemic agents were administered to those who experienced arterial blood pressure below 90 mm Hg (47.3%) or presented with a single measurement of fasting glucose below 50 mg/dL (10.7%), respectively. Statins were prescribed to 6.1% (12/196) of patients, and 75% of those prescriptions were regarded as futile. CONCLUSION: Our data suggest that effective prescription of essential medications and withdrawal from futile medications should be actively reconciled for improvement of a patient's end-of life care. PMID- 24155682 TI - Psychosocial impact of cancer patients on their family members. AB - PURPOSE: A population-based study was conducted in order to examine the characteristics of family members of cancer patients in comparison with the general population and also to evaluate the psychosocial impact of cancer patients on their family members. MATERIALS AND METHODS: From the Fourth Korea National Health and Nutrition Examination Surveys (KNHANES IV) (2007-2009) dataset, we identified 460 cancer patients and then selected family members of these patients who were aged 20 years or older (n=565). The control group was sampled from members of families without a cancer patient with matching for sex and age (n=2,260). Serial conditional logistic regression models were used for comparison of characteristics between family members of cancer patients and subjects in the control group. RESULTS: Family members of cancer patients were less employed (57.9% vs. 63.0%, p<0.001), more functionally limited (20.2% vs. 16.5%, p=0.032), and had lower self-rated health (p=0.023) compared with sex and age-matched control subjects. They also had a significantly higher level of stress (79.7% vs. 76.1%, p=0.008), history of depression (12.9% vs. 10.2%, p=0.035), and current depressive symptoms (5.5% vs. 3.5%, p=0.038). However, higher physical activity was reported in family members of cancer patients (13.6% vs. 9.6%, p=0.003) than in control subjects. The presence of a cancer patient in the family showed an association with current depressive symptoms (odds ratio, 1.62; 95% confidence interval, 1.05 to 2.48; p=0.028), however, the association was no longer significant after adjustment for household income, education level, and employment status (p=0.304). CONCLUSION: Family members of cancer patients are more susceptible to depression, probably due to adverse change in socioeconomic status. Use of multidisciplinary approaches for promotion of psychological health and well-being is essential. PMID- 24155683 TI - A rare presentation of follicular lymphoma: cerebellar involvement, successfully treated with a combination of radiotherapy and chemotherapy. AB - The central nervous system (CNS) is an important area of involvement for both high-grade, aggressive primary and secondary lymphomas. Although follicular lymphoma represents a low-grade histology, it may rarely present with CNS involvement. Here, we describe a patient diagnosed with follicular lymphoma who was presented with cerebellar involvement. PMID- 24155684 TI - Angiomatoid fibrous histiocytoma as a second tumor in a young adult with testicular cancer. AB - Angiomatoid fibrous histiocytoma (AFH) is a rare soft tissue tumor, with a low grade malignant potential, occurring predominantly in children and young adults. Association between AFH and other malignancies has been rarely reported. A 27 year-old man who presented with a palpable abdominal mass was diagnosed as having testicular cancer with multiple liver and lung metastases. At 16 months after chemotherapy, a follow-up computed tomographic scan revealed a supraclavicular mass measuring 3 cm in size, which was suspected to be a recurrence. The patient underwent surgical excision, and the mass was pathologically diagnosed as a AFH. The patient has had no local recurrence and no distant metastasis for 12 months after resection. To the best of our knowledge, this is the first case report of AFH as a second tumor in a patient with testicular cancer. PMID- 24155685 TI - Successful treatment by chemotherapy of pineal parenchymal tumor with intermediate differentiation: a case report. AB - A 37-year-old male presented with a mass measuring 2.5 cm in size in the midbrain and obstructive hydrocephalus, which had manifested as a headache and dizziness. Magnetic resonance (MR) imaging of the brain showed intermediate enhancement on T1-weighted MR imaging and a high intensity of enhancement on T2-weighted MR. Neurosurgeons performed an occipital craniotomy with partial removal of the tumor and the postoperative diagnosis was a pineal parenchymal tumor with intermediate differentiation. He had undergone irradiation with 54 Gy of radiation on 27 fractions for removal of the remaining tumor approximately one month after surgery. However, in follow-up imaging performed four months after radiotherapy, a remnant mass in the superoposterior aspect of the midbrain was found to have extended to the hypothalamus and the third ventricle. He was treated with six cycles of procarbazine, lomustine, vincristine chemotherapy. At five months since the completion of chemotherapy, the brain MR imaging showed no evidence of any remaining tumor and he no longer displayed any of his initial symptoms. PMID- 24155686 TI - A nutrition intervention with a main focus on vegetables and bread consumption among young men in the Norwegian National Guard. AB - BACKGROUND: Young men are difficult to reach with conventional nutrition information and they have a low intake of vegetables and whole grain cereals. Few intervention studies have focused on improving young men's consumption of vegetables and whole grains. OBJECTIVE: A 5-month intervention focusing on a combination of increased availability of healthy foods and nutritional information was developed to stimulate the intake of vegetables and semi-whole grain bread among a group of young men in the Norwegian military. SUBJECTS: A total of 376 recruits in the intervention group and 105 recruits in the control group participated in the entire study. RESULTS: The average daily increase in consumption of vegetables was 82 g (p<0.001), and semi-whole grain bread 47 g (p<0.001) between baseline and follow-up in the intervention group. No significant changes were observed in the control group. Differences between intervention and control group at follow-up were significant (p<0.001) for vegetables and semi-whole grain bread, when controlling for baseline values, and seasonal variation for vegetables. The recruits in the intervention group received higher scores on the questions concerning nutritional knowledge after the intervention, compared to baseline (p<0.001). There was a significantly higher increase in the intake of vegetables among the recruits who increased the number of correct answers to the knowledge questions (beta-value: 0.14, p<0.05) than among the others. There was no significant change in scores of food satisfaction after the intervention. CONCLUSION: The combination of increased availability of healthy food items and nutrition information was an effective way to increase the intake of vegetables and semi-whole grain bread, without a reduction in food satisfaction, among young men in the military. PMID- 24155687 TI - The role of orphanin FQ/nociceptin in neuroplasticity: relationship to stress, anxiety and neuroinflammation. AB - The neuropeptide, orphanin FQ/nociceptin (OFQ/N or simply, nociceptin), is expressed in both neuronal and non-neuronal tissue, including the immune system. In the brain, OFQ/N has been investigated in relation to stress, anxiety, learning and memory, and addiction. More recently, it has also been found that OFQ/N influences glial cell functions, including oligodendrocytes, astrocytes, and microglial cells. However, this latter research is relatively small, but potentially important, when observations regarding the relationship of OFQ/N to stress and emotional functions is taken into consideration and integrated with the growing evidence for its involvement in cells that mediate inflammatory events. This review will first provide an overview and understanding of how OFQ/N has been implicated in the HPA axis response to stress, followed by an understanding of its influence on natural and learned anxiety-like behavior. What emerges from an examination of the literature is a neuropeptide that appears to counteract anxiogenic influences, but paradoxically, without attenuating HPA axis responses generated in response to stress. Studies utilized both central administration of OFQ/N, which was shown to activate the HPA axis, as well as antagonism of NOP-R, the OFQ/N receptor. In contrast, antagonist or transgenic OFQ/N or NOP-R knockout studies, showed augmentation of HPA axis responses to stress, suggesting that OFQ/N may be needed to control the magnitude of the HPA axis response to stress. Investigations of behavior in standard exploratory tests of anxiogenic behavior (eg., elevated plus maze) or learned fear responses have suggested that OFQ/N is needed to attenuate fear or anxiety-like behavior. However, some discrepant observations, in particular, those that involve appetitive behaviors, suggest a failure of NOP-R deletion to increase anxiety. However, it is also suggested that OFQ/N may operate in an anxiolytic manner when initial anxiogenic triggers (eg., the neuropeptide CRH) are initiated. Finally, the regulatory functions of OFQ/N in relation to emotion-related behaviors may serve to counteract potential neuroinflammatory events in the brain. This appears to be evident within the glial cell environment of the brain, since OFQ/N has been shown to reduce the production of proinflammatory cellular and cytokine events. Given that both OFQ/N and glial cells are activated in response to stress, it is possible that there is a possible convergence of these two systems that has important repercussions for behavior and neuroplasticity. PMID- 24155688 TI - Cellular and molecular mechanisms involved in the neuroprotective effects of VEGF on motoneurons. AB - Vascular endothelial growth factor (VEGF), originally described as a factor with a regulatory role in vascular growth and development, it is also known for its direct effects on neuronal cells. The discovery in the past decade that transgenic mice expressing reduced levels of VEGF developed late-onset motoneuron pathology, reminiscent of amyotrophic lateral sclerosis (ALS), opened a new field of research on this disease. VEGF has been shown to protect motoneurons from excitotoxic death, which is a relevant mechanism involved in motoneuron degeneration in ALS. Thus, VEGF delays motoneuron degeneration and increases survival in animal models of ALS. VEGF exerts its anti-excitotoxic effects on motoneurons through molecular mechanisms involving the VEGF receptor-2 resulting in the activation of the PI3-K/Akt signaling pathway, upregulation of GluR2 subunit of AMPA receptors, inhibition of p38MAPK, and induction of the anti apoptotic molecule Bcl-2. In addition, VEGF acts on astrocytes to reduce astroglial activation and to induce the release of growth factors. The potential use of VEGF as a therapeutic tool in ALS is counteracted by its vascular effects and by its short effective time frame. More studies are needed to assess the optimal isoform, route of administration, and time frame for using VEGF in the treatment of ALS. PMID- 24155689 TI - Imaging neuron-glia interactions in the enteric nervous system. AB - The enteric nervous system (ENS) is a network of neurons and glia within the wall of the gastrointestinal tract that is able to control many aspects of digestive function independently from the central nervous system. Enteric glial cells share several features with astrocytes and are closely associated with enteric neurons and their processes both within enteric ganglia, and along interconnecting fiber bundles. Similar to other parts of the nervous system, there is communication between enteric neurons and glia; enteric glial cells can detect neuronal activity and have the machinery to intermediate neurotransmission. However, due to the close contact between these two cell types and the particular characteristics of the gut wall, the recording of enteric glial cell activity in live imaging experiments, especially in the context of their interaction with neurons, is not straightforward. Most studies have used calcium imaging approaches to examine enteric glial cell activity but in many cases, it is difficult to distinguish whether observed transients arise from glial cells, or neuronal processes or varicosities in their vicinity. In this technical report, we describe a number of approaches to unravel the complex neuron-glia crosstalk in the ENS, focusing on the challenges and possibilities of live microscopic imaging in both animal models and human tissue samples. PMID- 24155691 TI - Niche derived oligodendrocyte progenitors: a source of rejuvenation or complementation for local oligodendrogenesis? PMID- 24155690 TI - Glycine receptors and brain development. AB - Glycine receptors (GlyRs) are ligand-gated chloride ion channels that mediate fast inhibitory neurotransmission in the spinal cord and the brainstem. There, they are mainly involved in motor control and pain perception in the adult. However, these receptors are also expressed in upper regions of the central nervous system, where they participate in different processes including synaptic neurotransmission. Moreover, GlyRs are present since early stages of brain development and might influence this process. Here, we discuss the current state of the art regarding GlyRs during embryonic and postnatal brain development in light of recent findings about the cellular and molecular mechanisms that control brain development. PMID- 24155693 TI - Toward a self-wired active reconstruction of the hippocampal trisynaptic loop: DG CA3. AB - The mammalian hippocampus functions to encode and retrieve memories by transiently changing synaptic strengths, yet encoding in individual subregions for transmission between regions remains poorly understood. Toward the goal of better understanding the coding in the trisynaptic pathway from the dentate gyrus (DG) to the CA3 and CA1, we report a novel microfabricated device that divides a micro-electrode array into two compartments of separate hippocampal network subregions connected by axons that grow through 3 * 10 * 400 MUm tunnels. Gene expression by qPCR demonstrated selective enrichment of separate DG, CA3, and CA1 subregions. Reconnection of DG to CA3 altered burst dynamics associated with marked enrichment of GAD67 in DG and GFAP in CA3. Surprisingly, DG axon spike propagation was preferentially unidirectional to the CA3 region at 0.5 m/s with little reverse transmission. Therefore, select hippocampal subregions intrinsically self-wire in anatomically appropriate patterns and maintain their distinct subregion phenotype without external inputs. PMID- 24155692 TI - Cortico-basal ganglia networks subserving goal-directed behavior mediated by conditional visuo-goal association. AB - Action is often executed according to information provided by a visual signal. As this type of behavior integrates two distinct neural representations, perception and action, it has been thought that identification of the neural mechanisms underlying this process will yield deeper insights into the principles underpinning goal-directed behavior. Based on a framework derived from conditional visuomotor association, prior studies have identified neural mechanisms in the dorsal premotor cortex (PMd), dorsolateral prefrontal cortex (dlPFC), ventrolateral prefrontal cortex (vlPFC), and basal ganglia (BG). However, applications resting solely on this conceptualization encounter problems related to generalization and flexibility, essential processes in executive function, because the association mode involves a direct one-to-one mapping of each visual signal onto a particular action. To overcome this problem, we extend this conceptualization and postulate a more general framework, conditional visuo goal association. According to this new framework, the visual signal identifies an abstract behavioral goal, and an action is subsequently selected and executed to meet this goal. Neuronal activity recorded from the four key areas of the brains of monkeys performing a task involving conditional visuo-goal association revealed three major mechanisms underlying this process. First, visual-object signals are represented primarily in the vlPFC and BG. Second, all four areas are involved in initially determining the goals based on the visual signals, with the PMd and dlPFC playing major roles in maintaining the salience of the goals. Third, the cortical areas play major roles in specifying action, whereas the role of the BG in this process is restrictive. These new lines of evidence reveal that the four areas involved in conditional visuomotor association contribute to goal directed behavior mediated by conditional visuo-goal association in an area dependent manner. PMID- 24155694 TI - Neural representation in the auditory midbrain of the envelope of vocalizations based on a peripheral ear model. AB - The auditory midbrain implant (AMI) consists of a single shank array (20 sites) for stimulation along the tonotopic axis of the central nucleus of the inferior colliculus (ICC) and has been safely implanted in deaf patients who cannot benefit from a cochlear implant (CI). The AMI improves lip-reading abilities and environmental awareness in the implanted patients. However, the AMI cannot achieve the high levels of speech perception possible with the CI. It appears the AMI can transmit sufficient spectral cues but with limited temporal cues required for speech understanding. Currently, the AMI uses a CI-based strategy, which was originally designed to stimulate each frequency region along the cochlea with amplitude-modulated pulse trains matching the envelope of the bandpass-filtered sound components. However, it is unclear if this type of stimulation with only a single site within each frequency lamina of the ICC can elicit sufficient temporal cues for speech perception. At least speech understanding in quiet is still possible with envelope cues as low as 50 Hz. Therefore, we investigated how ICC neurons follow the bandpass-filtered envelope structure of natural stimuli in ketamine-anesthetized guinea pigs. We identified a subset of ICC neurons that could closely follow the envelope structure (up to ~100 Hz) of a diverse set of species-specific calls, which was revealed by using a peripheral ear model to estimate the true bandpass-filtered envelopes observed by the brain. Although previous studies have suggested a complex neural transformation from the auditory nerve to the ICC, our data suggest that the brain maintains a robust temporal code in a subset of ICC neurons matching the envelope structure of natural stimuli. Clinically, these findings suggest that a CI-based strategy may still be effective for the AMI if the appropriate neurons are entrained to the envelope of the acoustic stimulus and can transmit sufficient temporal cues to higher centers. PMID- 24155695 TI - Optogenetic stimulation effectively enhances intrinsically generated network synchrony. AB - Synchronized bursting is found in many brain areas and has also been implicated in the pathophysiology of neuropsychiatric disorders such as epilepsy, Parkinson's disease, and schizophrenia. Despite extensive studies of network burst synchronization, it is insufficiently understood how this type of network wide synchronization can be strengthened, reduced, or even abolished. We combined electrical recording using multi-electrode array with optical stimulation of cultured channelrhodopsin-2 transducted hippocampal neurons to study and manipulate network burst synchronization. We found low frequency photo stimulation protocols that are sufficient to induce potentiation of network bursting, modifying bursting dynamics, and increasing interneuronal synchronization. Surprisingly, slowly fading-in light stimulation, which substantially delayed and reduced light-driven spiking, was at least as effective in reorganizing network dynamics as much stronger pulsed light stimulation. Our study shows that mild stimulation protocols that do not enforce particular activity patterns onto the network can be highly effective inducers of network level plasticity. PMID- 24155697 TI - Distribution of neurons in functional areas of the mouse cerebral cortex reveals quantitatively different cortical zones. AB - How are neurons distributed along the cortical surface and across functional areas? Here we use the isotropic fractionator (Herculano-Houzel and Lent, 2005) to analyze the distribution of neurons across the entire isocortex of the mouse, divided into 18 functional areas defined anatomically. We find that the number of neurons underneath a surface area (the N/A ratio) varies 4.5-fold across functional areas and neuronal density varies 3.2-fold. The face area of S1 contains the most neurons, followed by motor cortex and the primary visual cortex. Remarkably, while the distribution of neurons across functional areas does not accompany the distribution of surface area, it mirrors closely the distribution of cortical volumes-with the exception of the visual areas, which hold more neurons than expected for their volume. Across the non-visual cortex, the volume of individual functional areas is a shared linear function of their number of neurons, while in the visual areas, neuronal densities are much higher than in all other areas. In contrast, the 18 functional areas cluster into three different zones according to the relationship between the N/A ratio and cortical thickness and neuronal density: these three clusters can be called visual, sensory, and, possibly, associative. These findings are remarkably similar to those in the human cerebral cortex (Ribeiro et al., 2013) and suggest that, like the human cerebral cortex, the mouse cerebral cortex comprises two zones that differ in how neurons form the cortical volume, and three zones that differ in how neurons are distributed underneath the cortical surface, possibly in relation to local differences in connectivity through the white matter. Our results suggest that beyond the developmental divide into visual and non-visual cortex, functional areas initially share a common distribution of neurons along the parenchyma that become delimited into functional areas according to the pattern of connectivity established later. PMID- 24155696 TI - Activation of high and low affinity dopamine receptors generates a closed loop that maintains a conductance ratio and its activity correlate. AB - Neuromodulators alter network output and have the potential to destabilize a circuit. The mechanisms maintaining stability in the face of neuromodulation are not well described. Using the pyloric network in the crustacean stomatogastric nervous system, we show that dopamine (DA) does not simply alter circuit output, but activates a closed loop in which DA-induced alterations in circuit output consequently drive a change in an ionic conductance to preserve a conductance ratio and its activity correlate. DA acted at low affinity type 1 receptors (D1Rs) to induce an immediate modulatory decrease in the transient potassium current (IA) of a pyloric neuron. This, in turn, advanced the activity phase of that component neuron, which disrupted its network function and thereby destabilized the circuit. DA simultaneously acted at high affinity D1Rs on the same neuron to confer activity-dependence upon the hyperpolarization activated current (Ih) such that the DA-induced changes in activity subsequently reduced Ih. This DA-enabled, activity-dependent, intrinsic plasticity exactly compensated for the modulatory decrease in IA to restore the IA:Ih ratio and neuronal activity phase, thereby closing an open loop created by the modulator. Activation of closed loops to preserve conductance ratios may represent a fundamental operating principle neuromodulatory systems use to ensure stability in their target networks. PMID- 24155698 TI - 3-D neurohistology of transparent tongue in health and injury with optical clearing. AB - Tongue receives extensive innervation to perform taste, sensory, and motor functions. Details of the tongue neuroanatomy and its plasticity in response to injury offer insights to investigate tongue neurophysiology and pathophysiology. However, due to the dispersed nature of the neural network, standard histology cannot provide a global view of the innervation. We prepared transparent mouse tongue by optical clearing to reveal the spatial features of the tongue innervation and its remodeling in injury. Immunostaining of neuronal markers, including PGP9.5 (pan-neuronal marker), calcitonin gene-related peptide (sensory nerves), tyrosine hydroxylase (sympathetic nerves), and vesicular acetylcholine transporter (cholinergic parasympathetic nerves and neuromuscular junctions), was combined with vessel painting and nuclear staining to label the tissue network and architecture. The tongue specimens were immersed in the optical-clearing solution to facilitate photon penetration for 3-dimensiontal (3-D) confocal microscopy. Taking advantage of the transparent tissue, we simultaneously revealed the tongue microstructure and innervation with subcellular-level resolution. 3-D projection of the papillary neurovascular complex and taste bud innervation was used to demonstrate the spatial features of tongue mucosa and the panoramic imaging approach. In the tongue injury induced by 4-nitroquinoline 1 oxide administration in the drinking water, we observed neural tissue remodeling in response to the changes of mucosal and muscular structures. Neural networks and the neuromuscular junctions were both found rearranged at the peri-lesional region, suggesting the nerve-lesion interactions in response to injury. Overall, this new tongue histological approach provides a useful tool for 3-D imaging of neural tissues to better characterize their roles with the mucosal and muscular components in health and disease. PMID- 24155700 TI - Electrophysiological and neuropsychological predictors of conversion to schizophrenia in at-risk subjects. AB - Patients with schizophrenia show neurophysiological and psychological disturbances before the onset of the illness. Mismatch negativity (MMN), an event related potential, has been shown to be associated with cognitive function. Specifically, duration MMN (dMMN) amplitudes have been indicated to predict progression to overt schizophrenia in subjects with at-risk mental state. The aim of this article is to provide a hypothesis that a combined assessment of dMMN and neuropsychological performance would enhance accuracy for predicting conversion to schizophrenia in at-risk subjects. Data from these neurocognitive modalities in subjects with first-episode schizophrenia (FES) are also presented. There is accumulated evidence that converters to schizophrenia among at-risk subjects show significantly smaller dMMN amplitudes than those in healthy control (HC) subjects at the frontal lead before the onset. In fact, the amplitudes in these converters have been reported to be similar to those in FES to begin with. dMMN current source density, by means of low-resolution brain electromagnetic tomography, was significantly lower in FES than HC subjects, especially in some medial temporal regions which are implicated in the pathophysiology of schizophrenia. Importantly, dMMN current density in the frontal lobe was positively correlated with working memory performance in FES subjects. These findings indicate the utility of the combination of electrophysiological/neuropsychological assessments for early intervention into patients with schizophrenia and high-risk people. PMID- 24155699 TI - Early neural disruption and auditory processing outcomes in rodent models: implications for developmental language disability. AB - Most researchers in the field of neural plasticity are familiar with the "Kennard Principle," which purports a positive relationship between age at brain injury and severity of subsequent deficits (plateauing in adulthood). As an example, a child with left hemispherectomy can recover seemingly normal language, while an adult with focal injury to sub-regions of left temporal and/or frontal cortex can suffer dramatic and permanent language loss. Here we present data regarding the impact of early brain injury in rat models as a function of type and timing, measuring long-term behavioral outcomes via auditory discrimination tasks varying in temporal demand. These tasks were created to model (in rodents) aspects of human sensory processing that may correlate-both developmentally and functionally with typical and atypical language. We found that bilateral focal lesions to the cortical plate in rats during active neuronal migration led to worse auditory outcomes than comparable lesions induced after cortical migration was complete. Conversely, unilateral hypoxic-ischemic (HI) injuries (similar to those seen in premature infants and term infants with birth complications) led to permanent auditory processing deficits when induced at a neurodevelopmental point comparable to human "term," but only transient deficits (undetectable in adulthood) when induced in a "preterm" window. Convergent evidence suggests that regardless of when or how disruption of early neural development occurs, the consequences may be particularly deleterious to rapid auditory processing (RAP) outcomes when they trigger developmental alterations that extend into subcortical structures (i.e., lower sensory processing stations). Collective findings hold implications for the study of behavioral outcomes following early brain injury as well as genetic/environmental disruption, and are relevant to our understanding of the neurologic risk factors underlying developmental language disability in human populations. PMID- 24155701 TI - An investigation into "two hit" effects of BDNF deficiency and young-adult cannabinoid receptor stimulation on prepulse inhibition regulation and memory in mice. AB - Reduced brain-derived neurotrophic factor (BDNF) signaling has been shown in the frontal cortex and hippocampus in schizophrenia. The aim of the present study was to investigate whether a BDNF deficit would modulate effects of chronic cannabis intake, a well-described risk factor for schizophrenia development. BDNF heterozygous mice (HET) and wild-type controls were chronically treated during weeks 6, 7, and 8 of life with the cannabinoid receptor agonist, CP55,940 (CP). After a 2-week delay, there were no CP-induced deficits in any of the groups in short-term spatial memory in a Y-maze task or novel object recognition memory. Baseline prepulse inhibition (PPI) was lower but average startle was increased in BDNF HET compared to wild-type controls. Acute CP administration before the PPI session caused a marked increase in PPI in male HET mice pre-treated with CP but not in any of the other male groups. In females, there were small increases of PPI in all groups upon acute CP administration. Acute CP administration furthermore reduced startle and this effect was greater in HET mice irrespective of chronic CP pre-treatment. Analysis of the levels of [(3)H]CP55,940 binding by autoradiography revealed a significant increase in the nucleus accumbens of male BDNF HET mice previously treated with CP but not in any of the other groups or in the caudate nucleus. These results show that BDNF deficiency and chronic young adult cannabinoid receptor stimulation do not interact in this model on learning and memory later in life. In contrast, male "two hit" mice, but not females, were hypersensitive to the effect of acute CP on sensorimotor gating. These effects may be related to a selective increase of [(3)H]CP55,940 binding in the nucleus accumbens, reflecting up-regulation of CB1 receptor density in this region. These data could be of relevance to our understanding of differential "two hit" neurodevelopmental mechanisms in schizophrenia. PMID- 24155702 TI - Approaches to local connectivity in autism using resting state functional connectivity MRI. AB - While the literature on aberrant long-distance connectivity in autism spectrum disorder (ASD) has grown fast over the past decade, little is known about local connectivity. We used regional homogeneity and local density approaches at different spatial scales to examine local connectivity in 29 children and adolescents with ASD and 29 matched typically developing participants, using resting state functional magnetic resonance imaging data. Across a total of 12 analysis pipelines, the gross pattern of between-group findings was overall stable, with local overconnectivity in the ASD group in occipital and posterior temporal regions and underconnectivity in middle/posterior cingulate, and medial prefrontal regions. This general pattern was confirmed in secondary analyses for low-motion subsamples (n = 20 per group), in which time series segments with >0.25 mm head motion were censored, as well as in an analysis including global signal regression. Local overconnectivity in visual regions appears consistent with preference for local over global visual processing previously reported in ASD, whereas cingulate and medial frontal underconnectivity may relate to aberrant function within the default mode network. PMID- 24155704 TI - A neural disconnection hypothesis on impaired numerical processing. PMID- 24155703 TI - Serotonergic hyperactivity as a potential factor in developmental, acquired and drug-induced synesthesia. AB - Though synesthesia research has seen a huge growth in recent decades, and tremendous progress has been made in terms of understanding the mechanism and cause of synesthesia, we are still left mostly in the dark when it comes to the mechanistic commonalities (if any) among developmental, acquired and drug-induced synesthesia. We know that many forms of synesthesia involve aberrant structural or functional brain connectivity. Proposed mechanisms include direct projection and disinhibited feedback mechanisms, in which information from two otherwise structurally or functionally separate brain regions mix. We also know that synesthesia sometimes runs in families. However, it is unclear what causes its onset. Studies of psychedelic drugs, such as psilocybin, LSD and mescaline, reveal that exposure to these drugs can induce synesthesia. One neurotransmitter suspected to be central to the perceptual changes is serotonin. Excessive serotonin in the brain may cause many of the characteristics of psychedelic intoxication. Excessive serotonin levels may also play a role in synesthesia acquired after brain injury. In brain injury sudden cell death floods local brain regions with serotonin and glutamate. This neurotransmitter flooding could perhaps result in unusual feature binding. Finally, developmental synesthesia that occurs in individuals with autism may be a result of alterations in the serotonergic system, leading to a blockage of regular gating mechanisms. I conclude on these grounds that one commonality among at least some cases of acquired, developmental and drug-induced synesthesia may be the presence of excessive levels of serotonin, which increases the excitability and connectedness of sensory brain regions. PMID- 24155705 TI - Evidence for dysregulation of axonal growth and guidance in the etiology of ASD. AB - Current theories concerning the cause of autism spectrum disorders (ASDs) have converged on the concept of abnormal development of brain connectivity. This concept is supported by accumulating evidence from functional imaging, diffusion tensor imaging, and high definition fiber tracking studies which suggest altered microstructure in the axonal tracts connecting cortical areas may underly many of the cognitive manifestations of ASD. Additionally, large-scale genomic studies implicate numerous gene candidates known or suspected to mediate neuritic outgrowth and axonal guidance in fetal and perinatal life. Neuropathological observations in postmortem ASD brain samples further support this model and include subtle disturbances of cortical lamination and subcortical axonal morphology. Of note is the relatively common finding of poor differentiation of the gray-white junction associated with an excess superficial white matter or "interstitial" neurons (INs). INs are thought to be remnants of the fetal subplate, a transient structure which plays a key role in the guidance and morphogenesis of thalamocortical and cortico-cortical connections and the organization of cortical columnar architecture. While not discounting the importance of synaptic dysfunction in the etiology of ASD, this paper will briefly review the cortical abnormalities and genetic evidence supporting a model of dysregulated axonal growth and guidance as key developmental processes underlying the clinical manifestations of ASD. PMID- 24155706 TI - Functional and anatomical correlates of word-, sentence-, and discourse-level integration in sign language. AB - In both vocal and sign languages, we can distinguish word-, sentence-, and discourse-level integration in terms of hierarchical processes, which integrate various elements into another higher level of constructs. In the present study, we used magnetic resonance imaging and voxel-based morphometry (VBM) to test three language tasks in Japanese Sign Language (JSL): word-level (Word), sentence level (Sent), and discourse-level (Disc) decision tasks. We analyzed cortical activity and gray matter (GM) volumes of Deaf signers, and clarified three major points. First, we found that the activated regions in the frontal language areas gradually expanded in the dorso-ventral axis, corresponding to a difference in linguistic units for the three tasks. Moreover, the activations in each region of the frontal language areas were incrementally modulated with the level of linguistic integration. These dual mechanisms of the frontal language areas may reflect a basic organization principle of hierarchically integrating linguistic information. Secondly, activations in the lateral premotor cortex and inferior frontal gyrus were left-lateralized. Direct comparisons among the language tasks exhibited more focal activation in these regions, suggesting their functional localization. Thirdly, we found significantly positive correlations between individual task performances and GM volumes in localized regions, even when the ages of acquisition (AOAs) of JSL and Japanese were factored out. More specifically, correlations with the performances of the Word and Sent tasks were found in the left precentral/postcentral gyrus and insula, respectively, while correlations with those of the Disc task were found in the left ventral inferior frontal gyrus and precuneus. The unification of functional and anatomical studies would thus be fruitful for understanding human language systems from the aspects of both universality and individuality. PMID- 24155707 TI - Attention and predictions: control of spatial attention beyond the endogenous exogenous dichotomy. AB - The mechanisms of attention control have been extensively studied with a variety of methodologies in animals and in humans. Human studies using non-invasive imaging techniques highlighted a remarkable difference between the pattern of responses in dorsal fronto-parietal regions vs. ventral fronto-parietal (vFP) regions, primarily lateralized to the right hemisphere. Initially, this distinction at the neuro-physiological level has been related to the distinction between cognitive processes associated with strategic/endogenous vs. stimulus driven/exogenous of attention control. Nonetheless, quite soon it has become evident that, in almost any situation, attention control entails a complex combination of factors related to both the current sensory input and endogenous aspects associated with the experimental context. Here, we review several of these aspects first discussing the joint contribution of endogenous and stimulus driven factors during spatial orienting in complex environments and, then, turning to the role of expectations and predictions in spatial re-orienting. We emphasize that strategic factors play a pivotal role for the activation of the ventral system during stimulus-driven control, and that the dorsal system makes use of stimulus-driven signals for top-down control. We conclude that both the dorsal and the vFP networks integrate endogenous and exogenous signals during spatial attention control and that future investigations should manipulate both these factors concurrently, so as to reveal to full extent of these interactions. PMID- 24155708 TI - Origins of specificity during tDCS: anatomical, activity-selective, and input bias mechanisms. AB - Transcranial Direct Current Stimulation (tDCS) is investigated for a broad range of neuropsychiatric indications, various rehabilitation applications, and to modulate cognitive performance in diverse tasks. Specificity of tDCS refers broadly to the ability of tDCS to produce precise, as opposed to diffuse, changes in brain function. Practically, specificity of tDCS implies application-specific customization of protocols to maximize desired outcomes and minimize undesired effects. Especially given the simplicity of tDCS and the complexity of brain function, understanding the mechanisms leading to specificity is fundamental to the rational advancement of tDCS. We define the origins of specificity based on anatomical and functional factors. Anatomical specificity derives from guiding current to targeted brain structures. Functional specificity may derive from either activity-selectivity, where active neuronal networks are preferentially modulated by tDCS, or input-selectivity, where bias is applied to different synaptic inputs. Rational advancement of tDCS may require leveraging all forms of specificity. PMID- 24155710 TI - Performance improvements from imagery: evidence that internal visual imagery is superior to external visual imagery for slalom performance. AB - We report three experiments investigating the hypothesis that use of internal visual imagery (IVI) would be superior to external visual imagery (EVI) for the performance of different slalom-based motor tasks. In Experiment 1, three groups of participants (IVI, EVI, and a control group) performed a driving-simulation slalom task. The IVI group achieved significantly quicker lap times than EVI and the control group. In Experiment 2, participants performed a downhill running slalom task under both IVI and EVI conditions. Performance was again quickest in the IVI compared to EVI condition, with no differences in accuracy. Experiment 3 used the same group design as Experiment 1, but with participants performing a downhill ski-slalom task. Results revealed the IVI group to be significantly more accurate than the control group, with no significant differences in time taken to complete the task. These results support the beneficial effects of IVI for slalom based tasks, and significantly advances our knowledge related to the differential effects of visual imagery perspectives on motor performance. PMID- 24155709 TI - Neural implementation of musical expertise and cognitive transfers: could they be promising in the framework of normal cognitive aging? AB - Brain plasticity allows the central nervous system of a given organism to cope with environmental demands. Therefore, the quality of mental processes relies partly on the interaction between the brain's physiological maturation and individual daily experiences. In this review, we focus on the neural implementation of musical expertise at both an anatomical and a functional level. We then discuss how this neural implementation can explain transfers from musical learning to a broad range of non-musical cognitive functions, including language, especially during child development. Finally, given that brain plasticity is still present in aging, we gather arguments to propose that musical practice could be a good environmental enrichment to promote cerebral and cognitive reserves, thereby reducing the deleterious effect of aging on cognitive functions. PMID- 24155711 TI - Klein and Loftus's model of trait self-knowledge: the importance of familiarizing oneself with the foundational research prior to reading about its neuropsychological applications. PMID- 24155712 TI - Erratum: Effects of pro-cholinergic treatment in patients suffering from spatial neglect. AB - [This corrects the article on p. 574 in vol. 7, PMID: 24062674.]. PMID- 24155713 TI - Discriminative analysis of non-linear brain connectivity in schizophrenia: an fMRI Study. AB - BACKGROUND: Dysfunctional integration of distributed brain networks is believed to be the cause of schizophrenia, and resting-state functional connectivity analyses of schizophrenia have attracted considerable attention in recent years. Unfortunately, existing functional connectivity analyses of schizophrenia have been mostly limited to linear associations. OBJECTIVE: The objective of the present study is to evaluate the discriminative power of non-linear functional connectivity and identify its changes in schizophrenia. METHOD: A novel measure utilizing the extended maximal information coefficient was introduced to construct non-linear functional connectivity. In conjunction with multivariate pattern analysis, the new functional connectivity successfully discriminated schizophrenic patients from healthy controls with relative higher accuracy rate than the linear measure. RESULT: We found that the strength of the identified non linear functional connections involved in the classification increased in patients with schizophrenia, which was opposed to its linear counterpart. Further functional network analysis revealed that the changes of the non-linear and linear connectivity have similar but not completely the same spatial distribution in human brain. CONCLUSION: The classification results suggest that the non linear functional connectivity provided useful discriminative power in diagnosis of schizophrenia, and the inverse but similar spatial distributed changes between the non-linear and linear measure may indicate the underlying compensatory mechanism and the complex neuronal synchronization underlying the symptom of schizophrenia. PMID- 24155714 TI - Correlations in background activity control persistent state stability and allow execution of working memory tasks. AB - Working memory (WM) requires selective information gating, active information maintenance, and rapid active updating. Hence performing a WM task needs rapid and controlled transitions between neural persistent activity and the resting state. We propose that changes in correlations in neural activity provides a mechanism for the required WM operations. As a proof of principle, we implement sustained activity and WM in recurrently coupled spiking networks with neurons receiving excitatory random background activity where background correlations are induced by a common noise source. We first characterize how the level of background correlations controls the stability of the persistent state. With sufficiently high correlations, the sustained state becomes practically unstable, so it cannot be initiated by a transient stimulus. We exploit this in WM models implementing the delay match to sample task by modulating flexibly in time the correlation level at different phases of the task. The modulation sets the network in different working regimes: more prompt to gate in a signal or clear the memory. We examine how the correlations affect the ability of the network to perform the task when distractors are present. We show that in a winner-take-all version of the model, where two populations cross-inhibit, correlations make the distractor blocking robust. In a version of the mode where no cross inhibition is present, we show that appropriate modulation of correlation levels is sufficient to also block the distractor access while leaving the relevant memory trace in tact. The findings presented in this manuscript can form the basis for a new paradigm about how correlations are flexibly controlled by the cortical circuits to execute WM operations. PMID- 24155715 TI - Experimentally constrained CA1 fast-firing parvalbumin-positive interneuron network models exhibit sharp transitions into coherent high frequency rhythms. AB - The coupling of high frequency oscillations (HFOs; >100 Hz) and theta oscillations (3-12 Hz) in the CA1 region of rats increases during REM sleep, indicating that it may play a role in memory processing. However, it is unclear whether the CA1 region itself is capable of providing major contributions to the generation of HFOs, or if they are strictly driven through input projections. Parvalbumin-positive (PV+) interneurons may play an essential role in these oscillations due to their extensive connections with neighboring pyramidal cells, and their characteristic fast-spiking. Thus, we created mathematical network models to investigate the conditions under which networks of CA1 fast-spiking PV+ interneurons are capable of producing high frequency population rhythms. We used whole-cell patch clamp recordings of fast-spiking, PV+ cells in the CA1 region of an intact hippocampal preparation in vitro to derive cellular properties, from which we constrained an Izhikevich-type model. Novel, biologically constrained network models were constructed with these individual cell models, and we investigated networks across a range of experimentally determined excitatory inputs and inhibitory synaptic strengths. For each network, we determined network frequency and coherence. Network simulations produce coherent firing at high frequencies (>90 Hz) for parameter ranges in which PV-PV inhibitory synaptic conductances are necessarily small and external excitatory inputs are relatively large. Interestingly, our networks produce sharp transitions between random and coherent firing, and this sharpness is lost when connectivity is increased beyond biological estimates. Our work suggests that CA1 networks may be designed with mechanisms for quickly gating in and out of high frequency coherent population rhythms, which may be essential in the generation of nested theta/high frequency rhythms. PMID- 24155716 TI - The role of the harmonic vector average in motion integration. AB - The local speeds of object contours vary systematically with the cosine of the angle between the normal component of the local velocity and the global object motion direction. An array of Gabor elements whose speed changes with local spatial orientation in accordance with this pattern can appear to move as a single surface. The apparent direction of motion of plaids and Gabor arrays has variously been proposed to result from feature tracking, vector addition and vector averaging in addition to the geometrically correct global velocity as indicated by the intersection of constraints (IOC) solution. Here a new combination rule, the harmonic vector average (HVA), is introduced, as well as a new algorithm for computing the IOC solution. The vector sum can be discounted as an integration strategy as it increases with the number of elements. The vector average over local vectors that vary in direction always provides an underestimate of the true global speed. The HVA, however, provides the correct global speed and direction for an unbiased sample of local velocities with respect to the global motion direction, as is the case for a simple closed contour. The HVA over biased samples provides an aggregate velocity estimate that can still be combined through an IOC computation to give an accurate estimate of the global velocity, which is not true of the vector average. Psychophysical results for type II Gabor arrays show perceived direction and speed falls close to the IOC direction for Gabor arrays having a wide range of orientations but the IOC prediction fails as the mean orientation shifts away from the global motion direction and the orientation range narrows. In this case perceived velocity generally defaults to the HVA. PMID- 24155717 TI - Age-dependent and coordinated shift in performance between implicit and explicit skill learning. AB - It has been reported recently that while general sequence learning across ages conforms to the typical inverted-U shape pattern, with best performance in early adulthood, surprisingly, the basic ability of picking up in an implicit manner triplets that occur with high vs. low probability in the sequence is best before 12 years of age and it significantly weakens afterwards. Based on these findings, it has been hypothesized that the cognitively controlled processes coming online at around 12 are useful for more targeted explicit learning at the cost of becoming relatively less sensitive to raw probabilities of events. To test this hypothesis, we collected data in a sequence learning task using probabilistic sequences in five age groups from 11 to 39 years of age (N = 288), replicating the original implicit learning paradigm in an explicit task setting where subjects were guided to find repeating sequences. We found that in contrast to the implicit results, performance with the high- vs. low-probability triplets was at the same level in all age groups when subjects sought patterns in the sequence explicitly. Importantly, measurements of explicit knowledge about the identity of the sequences revealed a significant increase in ability to explicitly access the true sequences exactly around the age where the earlier study found the significant drop in ability to learn implicitly raw probabilities. These findings support the conjecture that the gradually increasing involvement of more complex internal models optimizes our skill learning abilities by compensating for the performance loss due to down-weighting the raw probabilities of the sensory input, while expanding our ability to acquire more sophisticated skills. PMID- 24155718 TI - Automated parcellation of the brain surface generated from magnetic resonance images. AB - We have developed a fast and reliable pipeline to automatically parcellate the cortical surface into sub-regions. The pipeline can be used to study brain changes associated with psychiatric and neurological disorders. First, a genus zero cortical surface for one hemisphere is generated from the magnetic resonance images at the parametric boundary of the white matter and the gray matter. Second, a hemisphere-specific surface atlas is registered to the cortical surface using geometry features mapped in the spherical domain. The deformation field is used to warp statistic labels from the atlas to the subject surface. The Dice index of the labeled surface area is used to evaluate the similarity between the automated labels with the manual labels on the subject. The average Dice across 24 regions on 14 testing subjects is 0.86. Alternative evaluations have also chosen to show the accuracy and flexibility of the present method. The point-wise accuracy of 14 testing subjects is above 86% in average. The experiment shows that the present method is highly consistent with FreeSurfer (>99% of the surface area), using the same set of labels. PMID- 24155719 TI - A realistic implementation of ultrasound imaging as a human-machine interface for upper-limb amputees. AB - In the past years, especially with the advent of multi-fingered hand prostheses, the rehabilitation robotics community has tried to improve the use of human machine interfaces to reliably control mechanical artifacts with many degrees of freedom. Ideally, the control schema should be intuitive and reliable, and the calibration (training) short and flexible. This work focuses on medical ultrasound imaging as such an interface. Medical ultrasound imaging is rich in information, fast, widespread, relatively cheap and provides high temporal/spatial resolution; moreover, it is harmless. We already showed that a linear relationship exists between ultrasound image features of the human forearm and the hand kinematic configuration; here we demonstrate that such a relationship also exists between similar features and fingertip forces. An experiment with 10 participants shows that a very fast data collection, namely of zero and maximum forces only and using no force sensors, suffices to train a system that predicts intermediate force values spanning a range of about 20 N per finger with average errors in the range 10-15%. This training approach, in which the ground truth is limited to an "on-off" visual stimulus, constitutes a realistic scenario and we claim that it could be equally used by intact subjects and amputees. The linearity of the relationship between images and forces is furthermore exploited to build an incremental learning system that works online and can be retrained on demand by the human subject. We expect this system to be able in principle to reconstruct an amputee's imaginary limb, and act as a sensible improvement of, e.g., mirror therapy, in the treatment of phantom-limb pain. PMID- 24155721 TI - A new paradigm shift in antithrombotic therapy. AB - Decades after the introduction of oral anti-coagulants namely the vitamin K antagonist (VKA) Warfarin and antiplatelet agents such as Aspirin and Plavix, new classes of direct, small molecule, novel oral anti-coagulant medications and antiplatelet P2Y12 receptor inhibitors have recently become available. For the novel oral anticoagulants (NOAC), these agents can be separated by direct thrombin inhibitors such as Dabigatran and direct Factor Xa inhibitors such as Rivaroxaban and Apixaban. For next generation antiplatelet agents such as Ticagrelor and Prasugrel, these new P2Y12 receptor inhibitors form the cornerstone of therapy for patients with acute coronary syndrome (ACS) or undergoing percutaneous interventions. These novel oral antithrombotics are revolutionizing the field of stroke prevention, atrial fibrillation (AF), the management of venous thromboembolism (VTE) and treatment of ACS. This article reviews the current research developed in order to identify therapeutic effects and establish net clinical benefits of these new oral antithrombotics. PMID- 24155722 TI - The role of incline, performance level, and gender on the gross mechanical efficiency of roller ski skating. AB - The ability to efficiently utilize metabolic energy to produce work is a key factor for endurance performance. The present study investigated the effects of incline, performance level, and gender on the gross mechanical efficiency during roller ski skating. Thirty-one male and nineteen female elite cross-country skiers performed a 5-min submaximal session at approximately 75% of VO2peak on a 5% inclined treadmill using the G3 skating technique. Thereafter, a 5-min session on a 12% incline using the G2 skating technique was performed at a similar work rate. Gross efficiency was calculated as the external work rate against rolling friction and gravity divided by the metabolic rate using gas exchange. Performance level was determined by the amount of skating FIS points [the Federation of International Skiing (FIS) approved scoring system for ski racing] where fewer points indicate a higher performance level. Strong significant correlations between work rate and metabolic rate within both inclines and gender were revealed (r = -0.89 to 0.98 and P < 0.05 in all cases). Gross efficiency was higher at the steeper incline, both for men (17.1 +/- 0.4 vs. 15.8 +/- 0.5%, P < 0.05) and women (16.9 +/- 0.5 vs. 15.7 +/- 0.4%, P < 0.05), but without any gender differences being apparent. Significant correlations between gross efficiency and performance level were found for both inclines and genders (r = 0.65 to 0.81 and P < 0.05 in all cases). The current study demonstrated that cross-country skiers of both genders used less metabolic energy to perform the same amount of work at steeper inclines, and that the better ranked elite male and female skiers skied more efficiently. PMID- 24155720 TI - Managing the complexity of communication: regulation of gap junctions by post translational modification. AB - Gap junctions are comprised of connexins that form cell-to-cell channels which couple neighboring cells to accommodate the exchange of information. The need for communication does, however, change over time and therefore must be tightly controlled. Although the regulation of connexin protein expression by transcription and translation is of great importance, the trafficking, channel activity and degradation are also under tight control. The function of connexins can be regulated by several post translational modifications, which affect numerous parameters; including number of channels, open probability, single channel conductance or selectivity. The most extensively investigated post translational modifications are phosphorylations, which have been documented in all mammalian connexins. Besides phosphorylations, some connexins are known to be ubiquitinated, SUMOylated, nitrosylated, hydroxylated, acetylated, methylated, and gamma-carboxyglutamated. The aim of the present review is to summarize our current knowledge of post translational regulation of the connexin family of proteins. PMID- 24155724 TI - Why should one normalize heart rate variability with respect to average heart rate. PMID- 24155723 TI - Na(+) dependent acid-base transporters in the choroid plexus; insights from slc4 and slc9 gene deletion studies. AB - The choroid plexus epithelium (CPE) is located in the ventricular system of the brain, where it secretes the majority of the cerebrospinal fluid (CSF) that fills the ventricular system and surrounds the central nervous system. The CPE is a highly vascularized single layer of cuboidal cells with an unsurpassed transepithelial water and solute transport rate. Several members of the slc4a family of bicarbonate transporters are expressed in the CPE. In the basolateral membrane the electroneutral Na(+) dependent Cl(-)/HCO3 (-) exchanger, NCBE (slc4a10) is expressed. In the luminal membrane, the electrogenic Na(+):HCO3 (-) cotransporter, NBCe2 (slc4a5) is expressed. The electroneutral Na(+):HCO3 (-) cotransporter, NBCn1 (slc4a7), has been located in both membranes. In addition to the bicarbonate transporters, the Na(+)/H(+) exchanger, NHE1 (slc9a1), is located in the luminal membrane of the CPE. Genetically modified mice targeting slc4a2, slc4a5, slc4a7, slc4a10, and slc9a1 have been generated. Deletion of slc4a5, 7 or 10, or slc9a1 has numerous impacts on CP function and structure in these mice. Removal of the transporters affects brain ventricle size (slc4a5 and slc4a10) and intracellular pH regulation (slc4a7 and slc4a10). In some instances, removal of the proteins from the CPE (slc4a5, 7, and 10) causes changes in abundance and localization of non-target transporters known to be involved in pH regulation and CSF secretion. The focus of this review is to combine the insights gathered from these knockout mice to highlight the impact of slc4 gene deletion on the CSF production and intracellular pH regulation resulting from the deletion of slc4a5, 7 and 10, and slc9a1. Furthermore, the review contains a comparison of the described human mutations of these genes to the findings in the knockout studies. Finally, the future perspective of utilizing these proteins as potential targets for the treatment of CSF disorders will be discussed. PMID- 24155725 TI - Executive cognitive dysfunction and ADHD in cocaine dependence: searching for a common cognitive endophenotype for addictive disorders. AB - BACKGROUND: Cocaine-dependent individuals (CDI) present executive cognitive function (ECF) deficits, but the impact of psychiatric comorbidities such as Attention-Deficit Hyperactivity Disorder (ADHD) on neuropsychological functioning is still poorly understood. The aim of this study was to investigate if CDI with ADHD (CDI + ADHD) would have a distinct pattern of executive functioning when compared with CDI without ADHD (CDI). METHODS: We evaluated 101 adults, including 69 cocaine-dependent subjects (divided in CDI and CDI + ADHD) and 32 controls. ECF domains were assessed with Digits Forward (DF), Digits Backward (DB), Stroop Color Word Test (SCWT), the Wisconsin Card Sorting Test (WCST), and the Frontal Assessment Battery (FAB). DSM-IV criteria for ADHD were used for diagnosis and previous ADHD symptoms (in the childhood) were retrospectively assessed by the Wender-Utah Rating Scale (WURS). RESULTS: There were no significant differences between CDI + ADHD, CDI, and controls in estimated intellectual quotient (IQ), socioeconomic background, education (in years), and pre-morbid IQ (p > 0.05). SCWT and WCST scores did not differ across groups (p > 0.05). Nevertheless, CDI and CDI + ADHD performed more poorly than controls in total score of the FAB (p < 0.05). Also, CDI + ADHD did worse than CDI on DF (F = 4.756, p = 0.011), DB (F = 8.037, p = 0.001), Conceptualization/FAB (F = 4.635, p = 0.012), and Mental flexibility/FAB (F = 3.678, p = 0.029). We did not find correlations between cocaine-use variables and neuropsychological functioning, but previous ADHD symptoms assessed by WURS were negatively associated with DF (p = 0.016) and with the total score of the FAB (p = 0.017). CONCLUSION: CDI + ADHD presented more pronounced executive alterations than CDI and CDI exhibited poorer cognitive functioning than controls. Pre-existing ADHD symptoms may have a significant negative impact on executive dysfunction in CDI. It remains to be investigated by future studies if symptoms such as impulsivity or a pre-existing ECF dysfunction could represent underlying cognitive endophenotypes that would substantially increase the risk for acquiring addictive disorders. PMID- 24155726 TI - Association of the Nicotinic Receptor alpha7 Subunit Gene (CHRNA7) with Schizophrenia and Visual Backward Masking. AB - The nicotinic system is involved in the pathophysiology of schizophrenia. However, very little is known about its genetic basis and how it relates to clinical symptoms and potentially pharmacological intervention. Here, we investigated five single nucleotide polymorphisms (SNPs) [rs3826029] [rs2337506] [rs982574] [rs904952] [rs2337980] of the cholinergic nicotinic receptor gene, alpha 7 subunit (CHRNA7) and their association to schizophrenia. We found an association with rs904952 (p = 0.009) in a German sample of 224 schizophrenic patients and 224 healthy control subjects. The same trend was shown in an independent Georgian sample of 50 schizophrenic patients, 57 first order unaffected relatives, and 51 healthy controls. In addition, visual backward masking (VBM), a sensitive test for early visual information processing, was assessed in the Georgian sample. In line with prior studies, VBM performance deficits were much more pronounced in schizophrenic patients and their unaffected relatives compared to healthy controls (schizophrenic patients: 156 ms; unaffected relatives: 60 ms; healthy controls: 33 ms). VBM was strongly correlated with SNP rs904952 (H[2] = 7.3, p = 0.026). Our results further support the notion that changes in the nicotinic system are involved in schizophrenia and open the avenue for pharmacological intervention. PMID- 24155727 TI - Neuron-glia interaction as a possible glue to translate the mind-brain gap: a novel multi-dimensional approach toward psychology and psychiatry. AB - Neurons and synapses have long been the dominant focus of neuroscience, thus the pathophysiology of psychiatric disorders has come to be understood within the neuronal doctrine. However, the majority of cells in the brain are not neurons but glial cells including astrocytes, oligodendrocytes, and microglia. Traditionally, neuroscientists regarded glial functions as simply providing physical support and maintenance for neurons. Thus, in this limited role glia had been long ignored. Recently, glial functions have been gradually investigated, and increasing evidence has suggested that glial cells perform important roles in various brain functions. Digging up the glial functions and further understanding of these crucial cells, and the interaction between neurons and glia may shed new light on clarifying many unknown aspects including the mind-brain gap, and conscious-unconscious relationships. We briefly review the current situation of glial research in the field, and propose a novel translational research with a multi-dimensional model, combining various experimental approaches such as animal studies, in vitro & in vivo neuron-glia studies, a variety of human brain imaging investigations, and psychometric assessments. PMID- 24155729 TI - My brain knows numbers! - an ERP study of preschoolers' numerical knowledge. AB - This study investigated brain activity in numerical processing at early stages of development. Brain activity of preschoolers was measured while they performed a numerical Stroop task. Participants were asked to decide which of two digits was numerically or physically larger. Behavioral distance and size congruity effects (SiCEs) were found. However, a reverse facilitation was observed, where responses to neutral trials were faster than to congruent ones. The event-related potentials data showed the expected distance effect at occipitoparietal scalp areas. Moreover, conflict was related to effects both at frontal and parietal scalp areas. In addition, there was a difference between the timing of the interference compared to the facilitation components in the SiCE. In parietal scalp areas, facilitation was significant in an early time window and interference was significant at a later time window. This is consistent with the idea that facilitation and interference are separate processes. Our findings indicate that children as young as 5-6 years old can automatically process the numerical meaning of numerals. In addition, our findings are consistent with the idea that, children might use both frontal and parietal areas in order to process irrelevant numerical information. PMID- 24155728 TI - Fluctuating disinhibition: implications for the understanding and treatment of alcohol and other substance use disorders. AB - Disinhibition is present in various maladaptive behaviors, including substance use disorders. Most previous research has assumed that disinhibition is a psychological construct that is relatively stable within individuals. However, recent evidence suggests that the ability to inhibit behavior fluctuates in response to environmental and psychological triggers. In this review we discuss some of the factors that cause (dis)inhibition to fluctuate, we examine whether these fluctuations contribute to subjective craving and substance consumption, and we ask if they might increase the risk of relapse in those who are attempting to abstain. The research that we discuss has furthered our understanding of the causal relationships between disinhibition and substance use disorders, and it also highlights opportunities to develop novel treatment interventions. We conclude that substance misusers and their therapists should be made aware of the triggers that can cause disinhibition to fluctuate, and we highlight the need for more research to investigate the effectiveness of inhibitory control training in clinical settings. PMID- 24155730 TI - Processing of complex distracting sounds in school-aged children and adults: evidence from EEG and MEG data. AB - When a perceiver performs a task, rarely occurring sounds often have a distracting effect on task performance. The neural mismatch responses in event related potentials to such distracting stimuli depend on age. Adults commonly show a negative response, whereas in children a positive as well as a negative mismatch response has been reported. Using electro- and magnetoencephalography (EEG/MEG), here we investigated the developmental changes of distraction processing in school-aged children (9-10 years) and adults. Participants took part in an auditory-visual distraction paradigm comprising a visuo-spatial primary task and task-irrelevant environmental sounds distracting from this task. Behaviorally, distractors delayed reaction times (RTs) in the primary task in both age groups, and this delay was of similar magnitude in both groups. The neurophysiological data revealed an early as well as a late mismatch response elicited by distracting stimuli in both age groups. Together with previous research, this indicates that deviance detection is accomplished in a hierarchical manner in the auditory system. Both mismatch responses were localized to auditory cortex areas. All mismatch responses were generally delayed in children, suggesting that not all neurophysiological aspects of deviance processing are mature in school-aged children. Furthermore, the P3a, reflecting involuntary attention capture, was present in both age groups in the EEG with comparable amplitudes and at similar latencies, but with a different topographical distribution. This suggests that involuntary attention shifts toward complex distractors operate comparably in school-aged children and adults, yet undergoing generator maturation. PMID- 24155731 TI - View dependencies in the visual recognition of social interactions. AB - Recognizing social interactions, e.g., two people shaking hands, is important for obtaining information about other people and the surrounding social environment. Despite the visual complexity of social interactions, humans have often little difficulties to visually recognize social interactions. What is the visual representation of social interactions and the bodily visual cues that promote this remarkable human ability? Viewpoint dependent representations are considered to be at the heart of the visual recognition of many visual stimuli including objects (Bulthoff and Edelman, 1992), and biological motion patterns (Verfaillie, 1993). Here we addressed the question whether complex social actions acted out between pairs of people, e.g., hugging, are also represented in a similar manner. To this end, we created 3-D models from motion captured actions acted out by two people, e.g., hugging. These 3-D models allowed to present the same action from different viewpoints. Participants' task was to discriminate a target action from distractor actions using a one-interval-forced-choice (1IFC) task. We measured participants' recognition performance in terms of reaction times (RT) and d-prime (d'). For each tested action we found one view that led to superior recognition performance compared to other views. This finding demonstrates view-dependent effects of visual recognition, which are in line with the idea of a view dependent representation of social interactions. Subsequently, we examined the degree to which velocities of joints are able to predict the recognition performance of social interactions in order to determine candidate visual cues underlying the recognition of social interactions. We found that the velocities of the arms, both feet, and hips correlated with recognition performance. PMID- 24155732 TI - Examination of food reward and energy intake under laboratory and free-living conditions in a trait binge eating subtype of obesity. AB - BACKGROUND/AIMS: Trait binge eating has been proposed as a "hedonic subtype" of obesity characterized by enhanced food liking and wanting, and a preference for high-fat sweet foods in the laboratory. The current study examined the influence of trait binge eating in overweight or obese women on eating behavior under laboratory and free-living conditions over a 48-h period. METHODS: In a matched pairs design, 24 overweight or obese females (BMI: 30.30 +/- 2.60 kg/m(2); Age: 25.42 +/- 3.65 years) with high or low scores on the Binge Eating Scale (BSE) were divided into one of two groups; Obese Binge (O-B) and Obese Non-binge (O NB). Energy intake was assessed using combined laboratory energy intake measures and 24-h dietary recall procedures. Liking and wanting were assessed using the Leeds Food Preference Questionnaire (LFPQ). RESULTS: There was a significant association between overall energy consumed, and energy consumed from snack foods under laboratory and free-living conditions. O-B exhibited a greater preference for sweet snack foods in their laboratory and free-living eating behavior. These findings were supported by greater laboratory-based measures of wanting and craving for this food type in O-B. In addition, O-B consumed significantly more energy than their estimated daily energy requirements in the laboratory suggesting that they over-consumed compared to O-NB. CONCLUSIONS: The measurement concordance between laboratory and free-living based energy intake supports the validity of laboratory-based test meal methodologies Variation in trait binge eating was associated with increased craving and wanting for high-fat sweet foods and overconsumption in the laboratory. These findings support the use of trait binge eating as a common hedonic subtype of obesity and extend the relevance of this subtype to habitual patterns of energy intake. PMID- 24155734 TI - Learning autonomy in two or three steps: linking open-ended development, authority, and agency to motivation. AB - In this paper we connect open-ended development, authority, agency, and motivation through (1) an analysis of the demands of existing in a complex world and (2) environmental appraisal in terms of affordance content and the complexity to select appropriate behavior. We do this by identifying a coherent core from a wide range of contributing fields. Open-ended development is a structured three step process in which the agent first learns to master the body and then aims to make the mind into a reliable tool. Preconditioned on success in step two, step three aims to effectively co-create an optimal living environment. We argue that these steps correspond to right-left-right hemispheric dominance, where the left hemisphere specializes in control and the right hemisphere in exploration. Control (e.g., problem solving) requires a closed and stable world that must be maintained by external authorities or, in step three, by the right hemisphere acting as internal authority. The three-step progression therefore corresponds to increasing autonomy and agency. Depending on how we appraise the environment, we formulate four qualitatively different motivational states: submission, control, exploration, and consolidation. Each of these four motivational states has associated reward signals of which the last three-successful control, discovery of novelty, and establishing new relations-form an open-ended development loop that, the more it is executed, helps the agent to become progressively more agentic and more able to co-create a pleasant-to-live-in world. We conclude that for autonomy to arise, the agent must exist in a (broad) transition region between order and disorder in which both danger and opportunity (and with that open-ended development and motivation) are defined. We conclude that a research agenda for artificial cognitive system research should include open-ended development through intrinsic motivations and ascribing more prominence to right hemispheric strengths. PMID- 24155733 TI - Synesthesia: a colorful word with a touching sound? AB - Synesthesia is a fairly common condition in which individuals experience atypical responses (such as color experiences) in association with certain types of stimuli (such as non-colored letters). Although synesthesia has been described for centuries, only very recently has there been an explosive growth of systematic scientific examinations of this condition. In this article, we review and critically evaluate current methods for both assessing synesthesia and examining its psychological basis, including the "test-retest" procedure, online battery assessments, and behavioral experiments. We highlight the limitations of these methods for understanding the nature of this complex condition and propose potential solutions to address some of these limitations. We also provide a set of markers that aid in distinguishing synesthesia from other closely related psychological phenomena. PMID- 24155735 TI - Experience and generalization in a connectionist model of Mandarin Chinese relative clause processing. AB - Sentences containing relative clauses are well known to be difficult to comprehend, and they have long been an arena in which to investigate the role of working memory in language comprehension. However, recent work has suggested that relative clause processing is better described by ambiguity resolution processes than by limits on extrinsic working memory. We investigated these alternative views with a Simple Recurrent Network (SRN) model of relative clause processing in Mandarin Chinese, which has a unique pattern of word order across main and relative clauses and which has yielded mixed results in human comprehension studies. To assess the model's ability to generalize from similar sentence structures, and to observe effects of ambiguity through the sentence, we trained the model on several different sentence types, based on a detailed corpus analysis of Mandarin relative clauses and simple sentences, coded to include patterns of noun animacy in the various structures. The model was evaluated on 16 different relative clause subtypes. Its performance corresponded well to human reading times, including effects previously attributed to working memory overflow. The model's performance across a wide variety of sentence types suggested that the seemingly inconsistent results in some prior empirical studies stemmed from failures to consider the full range of sentence types in empirical studies. Crucially, sentence difficulty for the model was not simply a reflection of sentence frequency in the training set; the model generalized from similar sentences and showed high error rates at points of ambiguity. The results suggest that SRNs are a powerful tool to examine the complicated constraint-satisfaction process of sentence comprehension, and that understanding comprehension of specific structures must include consideration of experiences with other similar structures in the language. PMID- 24155736 TI - Neural model for learning-to-learn of novel task sets in the motor domain. AB - During development, infants learn to differentiate their motor behaviors relative to various contexts by exploring and identifying the correct structures of causes and effects that they can perform; these structures of actions are called task sets or internal models. The ability to detect the structure of new actions, to learn them and to select on the fly the proper one given the current task set is one great leap in infants cognition. This behavior is an important component of the child's ability of learning-to-learn, a mechanism akin to the one of intrinsic motivation that is argued to drive cognitive development. Accordingly, we propose to model a dual system based on (1) the learning of new task sets and on (2) their evaluation relative to their uncertainty and prediction error. The architecture is designed as a two-level-based neural system for context-dependent behavior (the first system) and task exploration and exploitation (the second system). In our model, the task sets are learned separately by reinforcement learning in the first network after their evaluation and selection in the second one. We perform two different experimental setups to show the sensorimotor mapping and switching between tasks, a first one in a neural simulation for modeling cognitive tasks and a second one with an arm-robot for motor task learning and switching. We show that the interplay of several intrinsic mechanisms drive the rapid formation of the neural populations with respect to novel task sets. PMID- 24155737 TI - Promoting psychology to students: embracing the multiplicity of research foci and method. AB - In order for the discipline of psychology to continue to thrive it is imperative that future students are effectively recruited into the field. Research is an important part of the discipline and it is argued that the nature of psychological research is naturally one of multiplicity in topic and methodology and that promoting and highlighting this should be considered as a potentially effective recruitment strategy. In this study, a snap-shot of current research topics and methodologies was collected based on published papers from one typical academic psychology department in Australia. Fifty articles published in the period 2010-2013 were randomly selected and then grouped using content analysis to form topic clusters. Five main clusters were identified and included: Grief and Loss; Psychopathology; Sociocultural Studies; Attachment and Parenting; and Developmental Disorders. The studies spanned the full spectrum of research methodologies from quantitative to qualitative and had implications for assessment practices, diagnosis, prevention and treatment, education, and policy. The findings are discussed in terms of the unique characteristics of psychology as a discipline and how this diversity ought to be utilized as the main selling point of the discipline to future students. PMID- 24155738 TI - Iconic gestures prime words: comparison of priming effects when gestures are presented alone and when they are accompanying speech. AB - Previous studies have shown that iconic gestures presented in an isolated manner prime visually presented semantically related words. Since gestures and speech are almost always produced together, this study examined whether iconic gestures accompanying speech would prime words and compared the priming effect of iconic gestures with speech to that of iconic gestures presented alone. Adult participants (N = 180) were randomly assigned to one of three conditions in a lexical decision task: Gestures-Only (the primes were iconic gestures presented alone); Speech-Only (the primes were auditory tokens conveying the same meaning as the iconic gestures); Gestures-Accompanying-Speech (the primes were the simultaneous coupling of iconic gestures and their corresponding auditory tokens). Our findings revealed significant priming effects in all three conditions. However, the priming effect in the Gestures-Accompanying-Speech condition was comparable to that in the Speech-Only condition and was significantly weaker than that in the Gestures-Only condition, suggesting that the facilitatory effect of iconic gestures accompanying speech may be constrained by the level of language processing required in the lexical decision task where linguistic processing of words forms is more dominant than semantic processing. Hence, the priming effect afforded by the co-speech iconic gestures was weakened. PMID- 24155739 TI - Are you a good mimic? Neuro-acoustic signatures for speech imitation ability. AB - We investigated individual differences in speech imitation ability in late bilinguals using a neuro-acoustic approach. One hundred and thirty-eight German English bilinguals matched on various behavioral measures were tested for "speech imitation ability" in a foreign language, Hindi, and categorized into "high" and "low ability" groups. Brain activations and speech recordings were obtained from 26 participants from the two extreme groups as they performed a functional neuroimaging experiment which required them to "imitate" sentences in three conditions: (A) German, (B) English, and (C) German with fake English accent. We used recently developed novel acoustic analysis, namely the "articulation space" as a metric to compare speech imitation abilities of the two groups. Across all three conditions, direct comparisons between the two groups, revealed brain activations (FWE corrected, p < 0.05) that were more widespread with significantly higher peak activity in the left supramarginal gyrus and postcentral areas for the low ability group. The high ability group, on the other hand showed significantly larger articulation space in all three conditions. In addition, articulation space also correlated positively with imitation ability (Pearson's r = 0.7, p < 0.01). Our results suggest that an expanded articulation space for high ability individuals allows access to a larger repertoire of sounds, thereby providing skilled imitators greater flexibility in pronunciation and language learning. PMID- 24155740 TI - The goldilocks dilemma in acute ischemic stroke. AB - Despite the advent of and exciting advances in novel endovascular therapies, t-PA remains the only proven treatment for acute ischemic stroke to date. Although a variety of reasons likely underlie why past trials of endovascular strategies have been unsuccessful, we address in this perspective piece one critical unknown for which a solution is undoubtedly necessary if future ones are to meet with success: determination and selection of patients that are "just right" for endovascular treatments, or the Goldilocks dilemma. Key clinical criteria highlighted in past trials may help provide a solution to this critical problem. However, for them to do so, we propose that they must be applied in service of a model that accounts for the nuanced, dynamic nature of acute ischemic stroke better than the prevailing "time is brain" model. We provide and examine three clinical cases to illustrate this proposal towards solving the Goldilocks dilemma and advancing treatment in acute ischemic stroke. Further, we address our field's ongoing challenge and mission in the meantime to best care for the "not-so-right" patients, by far the majority of the affected stroke population. PMID- 24155742 TI - Regulated Control of Melanin-Concentrating Hormone Receptor 1 through Posttranslational Modifications. AB - Melanin-concentrating hormone (MCH) is a hypothalamic neuropeptide that plays an important role in feeding behavior. It activates two G-protein-coupled receptors, MCHR1 and MCHR2, of which MCHR1 is the primary regulator of food intake and energy homeostasis in rodents. In mammalian cells transfected with MCHR1, MCH is able to activate multiple signaling pathways including calcium mobilization, extracellular signal-regulated kinase activation, and inhibition of cyclic AMP generation through Gi/o- and Gq-coupled pathways. Further evidence suggests that MCHR1 is regulated through posttranslational modifications, which control its intracellular localization and provide appropriate cellular responses involving G protein signaling. This review summarizes the current data on the control of MCHR1 function through glycosylation and phosphorylation, as related to cell function. Especially, a series of mutagenesis study highlights the importance of complete glycosylation of MCHR1 for efficient trafficking to the plasma membrane. PMID- 24155741 TI - The cortical acto-Myosin network: from diffusion barrier to functional gateway in the transport of neurosecretory vesicles to the plasma membrane. AB - Dysregulation of regulated exocytosis is linked to an array of pathological conditions, including neurodegenerative disorders, asthma, and diabetes. Understanding the molecular mechanisms underpinning neuroexocytosis including the processes that allow neurosecretory vesicles to access and fuse with the plasma membrane and to recycle post-fusion, is therefore critical to the design of future therapeutic drugs that will efficiently tackle these diseases. Despite considerable efforts to determine the principles of vesicular fusion, the mechanisms controlling the approach of vesicles to the plasma membrane in order to undergo tethering, docking, priming, and fusion remain poorly understood. All these steps involve the cortical actin network, a dense mesh of actin filaments localized beneath the plasma membrane. Recent work overturned the long-held belief that the cortical actin network only plays a passive constraining role in neuroexocytosis functioning as a physical barrier that partly breaks down upon entry of Ca(2+) to allow secretory vesicles to reach the plasma membrane. A multitude of new roles for the cortical actin network in regulated exocytosis have now emerged and point to highly dynamic novel functions of key myosin molecular motors. Myosins are not only believed to help bring about dynamic changes in the actin cytoskeleton, tethering and guiding vesicles to their fusion sites, but they also regulate the size and duration of the fusion pore, thereby directly contributing to the release of neurotransmitters and hormones. Here we discuss the functions of the cortical actin network, myosins, and their effectors in controlling the processes that lead to tethering, directed transport, docking, and fusion of exocytotic vesicles in regulated exocytosis. PMID- 24155743 TI - Autophagy and the (Pro)renin Receptor. AB - The (pro)renin receptor (PRR) is a newly reported member of the renin-angiotensin system (RAS); a hormonal cascade responsible for regulating blood pressure. Originally, identification of PRR was heralded as the next drug target of the RAS, of which such therapies would have increased benefits against target-organ damage and hypertension. However, in the years since its discovery, several conditional knockout mouse models of PRR have demonstrated an essential role for this receptor unrelated to the RAS and blood pressure. Specific deletion of PRR in podocytes or cardiomyocytes resulted in the rapid onset of organ failure and subsequently animal mortality after only a matter of weeks. In both cell types, loss of PRR resulted in the intracellular accumulation of autophagosomes and misfolded proteins, indicating a disturbance in autophagy. In light of the fact that the majority of PRR is located intracellularly, this molecular function appears to be more relevant than its ability to bind to high, non-physiological concentrations of (pro)renin. This review will focus on the role of PRR in autophagy and its importance in maintaining cellular homeostasis. Understanding the link between PRR, autophagy and how its loss results in cell death will be essential for deciphering its role in physiology and pathology. PMID- 24155746 TI - Phenotypic characterization of human intermediate monocytes. PMID- 24155744 TI - A Nod to disease vectors: mitigation of pathogen sensing by arthropod saliva. AB - Arthropod saliva possesses anti-hemostatic, anesthetic, and anti-inflammatory properties that facilitate feeding and, inadvertently, dissemination of pathogens. Vector-borne diseases caused by these pathogens affect millions of people each year. Many studies address the impact of arthropod salivary proteins on various immunological components. However, whether and how arthropod saliva counters Nod-like (NLR) sensing remains elusive. NLRs are innate immune pattern recognition molecules involved in detecting microbial molecules and danger signals. Nod1/2 signaling results in activation of the nuclear factor-kappaB and the mitogen-activated protein kinase pathways. Caspase-1 NLRs regulate the inflammasome~- a protein scaffold that governs the maturation of interleukin (IL) 1beta and IL-18. Recently, several vector-borne pathogens have been shown to induce NLR activation in immune cells. Here, we provide a brief overview of NLR signaling and discuss clinically relevant vector-borne pathogens recognized by NLR pathways. We also elaborate on possible anti-inflammatory effects of arthropod saliva on NLR signaling and microbial pathogenesis for the purpose of exchanging research perspectives. PMID- 24155745 TI - Modulation of Signal Strength Switches Notch from an Inducer of T Cells to an Inducer of ILC2. AB - Innate lymphoid cells (ILCs) are emerging key players of the immune system with close lineage relationship to T cells. ILC2 play an important role in protective immunity against multicellular parasites, but are also involved in the pathogenesis of type 2 immune diseases. Here, we have studied the developmental requirements for human ILC2. We report that ILC2 are present in the thymus of young human donors, possibly reflecting local differentiation. Furthermore, we show that uncommitted lineage(-)CD34(+)CD1a(-)human thymic progenitors have the capacity to develop into ILC2 in vitro under the influence of Notch signaling, either by stimulation with the Notch ligand Delta like 1 (Dll1) or by expression of the active intracellular domain of NOTCH1 (NICD1). The capacity of NICD1 to mobilize the ILC2 differentiation program was sufficiently potent to override commitment to the T cell lineage in CD34(+)CD1a(+) progenitors and force them into the ILC2 lineage. As Notch is an important factor also for T cell development, these results raise the question how one and the same signaling pathway can elicit such distinct developmental outcomes from the same precursors. We provide evidence that Notch signal strength is a critical determinant in this decision: by tuning signal amplitude, Notch can be converted from a T cell inducer (low signal strength) to an ILC2 inducer (high signal strength). Thus, this study enhances our understanding of human ILC2 development and identifies a mechanism determining specificity of Notch signal output during T cell and ILC2 differentiation. PMID- 24155747 TI - Recognition of Extracellular Bacteria by NLRs and Its Role in the Development of Adaptive Immunity. AB - Innate immune recognition of bacteria is the first requirement for mounting an effective immune response able to control infection. Over the previous decade, the general paradigm was that extracellular bacteria were only sensed by cell surface-expressed Toll-like receptors (TLRs), whereas cytoplasmic sensors, including members of the Nod-like receptor (NLR) family, were specific to pathogens capable of breaching the host cell membrane. It has become apparent, however, that intracellular innate immune molecules, such as the NLRs, play key roles in the sensing of not only intracellular, but also extracellular bacterial pathogens or their components. In this review, we will discuss the various mechanisms used by bacteria to activate NLR signaling in host cells. These mechanisms include bacterial secretion systems, pore-forming toxins, and outer membrane vesicles. We will then focus on the influence of NLR activation on the development of adaptive immune responses in different cell types. PMID- 24155748 TI - Recent Advances in Plant NLR Structure, Function, Localization, and Signaling. AB - Nucleotide-binding domain leucine-rich repeat (NLR) proteins play a central role in the innate immune systems of plants and vertebrates. In plants, NLR proteins function as intracellular receptors that detect pathogen effector proteins directly, or indirectly by recognizing effector-induced modifications to other host proteins. NLR activation triggers a suite of defense responses associated with programed cell death (PCD). The molecular mechanisms underlying NLR activation, and how activation is translated into defense responses, have been particularly challenging to elucidate in plants. Recent reports, however, are beginning to shed some light. It is becoming clear that plant NLR proteins are targeted to diverse sub-cellular locations, likely depending on the locations where the effectors are detected. These reports also indicate that some NLRs re localize following effector detection, while others do not, and such relocalization may reflect differences in signaling pathways. There have also been recent advances in understanding the structure of plant NLR proteins, with crystal structures now available for the N-terminal domains of two well-studied NLRs, a coiled-coil (CC) domain and a Toll-interleukin Receptor (TIR). Significant improvements in molecular modeling have enabled more informed structure-function studies, illuminating roles of intra- and inter-molecular interactions in NLR activation regulation. Several independent studies also suggest that intracellular trafficking is involved in NLR-mediated resistance. Lastly, progress is being made on identifying transcriptional regulatory complexes activated by NLRs. Current models for how plant NLR proteins are activated and how they induce defenses are discussed, with an emphasis on what remains to be determined. PMID- 24155750 TI - Global climate change and above- belowground insect herbivore interactions. AB - Predicted changes to the Earth's climate are likely to affect above-belowground interactions. Our understanding is limited, however, by past focus on two-species aboveground interactions mostly ignoring belowground influences. Despite their importance to ecosystem processes, there remains a dearth of empirical evidence showing how climate change will affect above-belowground interactions. The responses of above- and belowground organisms to climate change are likely to differ given the fundamentally different niches they inhabit. Yet there are few studies that address the biological and ecological reactions of belowground herbivores to environmental conditions in current and future climates. Even fewer studies investigate the consequences of climate change for above-belowground interactions between herbivores and other organisms; those that do provide no evidence of a directed response. This paper highlights the importance of considering the belowground fauna when making predictions on the effects of climate change on plant-mediated interspecific interactions. PMID- 24155749 TI - Characterization of cell death inducing Phytophthora capsici CRN effectors suggests diverse activities in the host nucleus. AB - Plant-Microbe interactions are complex associations that feature recognition of Pathogen Associated Molecular Patterns by the plant immune system and dampening of subsequent responses by pathogen encoded secreted effectors. With large effector repertoires now identified in a range of sequenced microbial genomes, much attention centers on understanding their roles in immunity or disease. These studies not only allow identification of pathogen virulence factors and strategies, they also provide an important molecular toolset suited for studying immunity in plants. The Phytophthora intracellular effector repertoire encodes a large class of proteins that translocate into host cells and exclusively target the host nucleus. Recent functional studies have implicated the CRN protein family as an important class of diverse effectors that target distinct subnuclear compartments and modify host cell signaling. Here, we characterized three necrosis inducing CRNs and show that there are differences in the levels of cell death. We show that only expression of CRN20_624 has an additive effect on PAMP induced cell death but not AVR3a induced ETI. Given their distinctive phenotypes, we assessed localization of each CRN with a set of nuclear markers and found clear differences in CRN subnuclear distribution patterns. These assays also revealed that expression of CRN83_152 leads to a distinct change in nuclear chromatin organization, suggesting a distinct series of events that leads to cell death upon over-expression. Taken together, our results suggest diverse functions carried by CRN C-termini, which can be exploited to identify novel processes that take place in the host nucleus and are required for immunity or susceptibility. PMID- 24155751 TI - Intraspecific variation in root and leaf traits and leaf-root trait linkages in eight aspen demes (Populus tremula and P. tremuloides). AB - Leaf and fine root morphology and physiology have been found to vary considerably among tree species, but not much is known about intraspecific variation in root traits and their relatedness to leaf traits. Various aspen progenies (Populus tremula and P. tremuloides) with different growth performance are used in short rotation forestry. Hence, a better understanding of the link between root trait syndromes and the adaptation of a deme to a particular environment is essential in order to improve the match between planted varieties and their growth conditions. We examined the between-deme (genetic) and within-deme (mostly environmental) variation in important fine root traits [mean root diameter, specific root area (SRA) and specific root length (SRL), root tissue density (RTD), root tip abundance, root N concentration] and their co-variation with leaf traits [specific leaf area (SLA), leaf size, leaf N concentration] in eight genetically distinct P. tremula and P. tremuloides demes. Five of the six root traits varied significantly between the demes with largest genotypic variation in root tip abundance and lowest in mean root diameter and RTD (no significant difference). Within-deme variation in root morphology was as large as between deme variation suggesting a relatively low genetic control. Significant relationships existed neither between SLA and SRA nor between leaf N and root N concentration in a plant. Contrary to expectation, high aboveground relative growth rates (RGR) were associated with large, and not small, fine root diameters with low SRA and SRL. Compared to leaf traits, the influence of root traits on RGR was generally low. We conclude that aspen exhibits large intraspecific variation in leaf and also in root morphological traits which is only partly explained by genetic distances. A root order-related analysis might give deeper insights into intraspecific root trait variation. PMID- 24155752 TI - DDM1 and ROS1 have a role in UV-B induced- and oxidative DNA damage in A. thaliana. AB - Absorption of UV-B by DNA induces the formation of covalent bonds between adjacent pyrimidines. In maize and arabidopsis, plants deficient in chromatin remodeling show increased DNA damage compared to WT plants after a UV-B treatment. However, the role of enzymes that participate in DNA methylation in DNA repair after UV-B damage was not previously investigated. In this work, we analyzed how chromatin remodeling activities that have an effect on DNA methylation affects the repair of UV-B damaged DNA using plants deficient in the expression of DDM1 and ROS1. First, we analyzed their regulation by UV-B radiation in arabidopsis plants. Then, we demonstrated that ddm1 mutants accumulated more DNA damage after UV-B exposure compared to Col0 plants. Surprisingly, ros1 mutants show less CPDs and 6-4PPs than WT plants after the treatment under light conditions, while the repair under dark conditions is impaired. Transcripts for two photolyases are highly induced by UV-B in ros1 mutants, suggesting that the lower accumulation of photoproducts by UV-B is due to increased photorepair in these mutants. Finally, we demonstrate that oxidative DNA damage does not occur after UV-B exposure in arabidopsis plants; however, ros1 plants accumulate high levels of oxoproducts, while ddm1 mutants have less oxoproducts than Col0 plants, suggesting that both ROS1 and DDM1 have a role in the repair of oxidative DNA damage. Together, our data provide evidence that both DDM1 and ROS1, directly or indirectly, participate in UV-B induced- and oxidative DNA damage repair. PMID- 24155753 TI - The korean hereditary breast cancer study: review and future perspectives. AB - Most studies related to BRCA mutations have been performed in Western populations, and only a few small studies have been conducted in Korean populations. In 2007, the Korean Hereditary Breast Cancer (KOHBRA) Study was established to obtain evidence for the accurate risk assessment and management of hereditary breast and ovarian cancer (HBOC) in Korea. Between May 2007 and May 2010, the first phase of the KOHBRA Study was performed to estimate the prevalence of BRCA1/2 mutations among patients and their families at risk for HBOC. Between June 2010 and May 2013, the second phase of the KOHBRA Study was performed to identify the clinical characteristics and prognostic indicators of BRCA-related breast cancer and environmental and genetic modifiers of BRCA mutations and to develop a Korean BRCA risk calculator and nationwide genetic counseling network for HBOC. Herein, we review the results of the KOHBRA Study and describe the future perspectives of the study. PMID- 24155754 TI - Lymphoma affecting the breast: a pictorial review of multimodal imaging findings. AB - Hematological malignancies rarely affect the breast, and the majority of those that do are lymphomas. In this review, we describe the clinical aspects and multimodal imaging findings of breast lymphoma. We also illustrate the key clinical and radiological findings that allow it to be distinguished from various other malignant and benign diseases of the breast. Breast lymphoma manifests as a breast mass, a change in the subcutaneous tissue or the skin, or enlargement of the associated lymph node on radiological examination. Radiological findings associated with other breast malignancies, such as calcifications, spiculations, or architectural distortions are extremely rare. Skin and subcutaneous changes frequently accompany T-cell lymphoma. Multimodal breast imaging characteristics may aid in the diagnosis of breast lymphoma. PMID- 24155755 TI - Association of Human Epidermal Growth Factor Receptor 2 with Radiotherapy Resistance in Patients with T1N0M0 Breast Cancer. AB - PURPOSE: Preclinical studies have shown that human epidermal growth factor receptor 2 (HER2) status is associated with resistance to radiotherapy (RT). In this study, we evaluated the overall survival of a T1N0M0 breast cancer cohort in Korea according to the use of RT and the HER2 status. METHODS: We analyzed data collected from 11,552 patients with invasive breast cancer who were enrolled in the Korean Breast Cancer Society Registration Program between 1999 and 2007. Data on the TNM stage, estrogen receptor status, progesterone receptor status, HER2 status, operation method, and the use of RT were analyzed. RESULTS: The median follow-up period was 51 months. A significant improvement in overall survival after RT was observed only in the HER2(-) group. In this group, the 10-year overall survival rate was 95.5% for patients who did not receive RT and 96.3% for patients who received RT (p=0.037). In contrast, in the HER2(+) group, RT was not associated with a survival benefit (p=0.887). Multivariate analysis showed that RT was significantly associated with a reduction in mortality in the HER2(-) group (hazard ratio, 0.738; 95% confidence interval, 0.549-0.993; p=0.045). CONCLUSION: We found that postoperative RT was not associated with a survival benefit in HER2(+) breast cancer patients, suggesting that HER2(+) breast cancers could be RT resistant. PMID- 24155756 TI - Prognostic value of the nodal ratio and ki-67 expression in breast cancer patients treated with postmastectomy radiotherapy. AB - PURPOSE: This pilot study aimed to evaluate prognostic factors of postmastectomy radiotherapy (PMRT) for breast cancer patients undergoing systemic therapy in either preoperative or postoperative setting. METHODS: Between 2003 and 2009, 113 patients received PMRT: 61 underwent preoperative systemic therapy (PST subgroup) and 52 received postoperative systemic therapy (non-PST subgroup). RESULTS: The median follow-up time was 72.3 months (range, 34.0-109.4 months) for surviving patients. In univariate analysis of all patients, disease-free survival (DFS) was associated with age, nodal ratio (NR), and Ki-67 expression; overall survival (OS) was associated with NR and Ki-67 expression. Pathologic N stage and HER2 expression were marginally associated with DFS and OS. In the non-PST subgroup, DFS was associated with age, NR, venous invasion, and Ki-67 expression; OS was associated with age. In the PST subgroup, DFS was associated with ypN stage and NR; OS was associated with ypN, histologic grade, HER2 expression, and p53 expression. In multivariate analysis of all patients, DFS and OS were significantly associated with NR (p=0.003 and p=0.019, respectively) and Ki-67 expression (p=0.002 and p=0.015, respectively). Patients were classified into low risk (NR <=0.2 and Ki-67 <=20%; n=34), intermediate-risk (NR >0.2 or Ki-67 >20%; n=63), and high-risk (NR >0.2 and Ki-67 >20%; n=16) subgroups. All low-risk patients were alive at the time of analysis. High-risk (p<0.001 and p=0.001, respectively) and intermediate-risk (p=0.022 and p=0.008, respectively) patients had significantly shorter DFS and OS than low-risk patients. This prognostic model was statistically significant for DFS when applied to the PST (p=0.001) and non-PST (p=0.016) subgroups separately. CONCLUSION: For breast cancer patients undergoing PMRT, NR and Ki-67 are potential prognostic factors. A model using these factors might help predict a poor prognosis. Whether NR and Ki-67 are also prognostic for different setting of systemic therapy, preoperative or postoperative, warrants further study. PMID- 24155757 TI - Cytogenetic finding of breast cancer cases and in their first-degree relatives. AB - PURPOSE: The aim of this study was to evaluate and compare the rate of sister chromatid exchange (SCE), the occurrence of micronuclei, and the lymphocyte proliferation rate index (PRI) in patients with breast cancer, their first-degree relatives, and healthy volunteers. METHODS: We analyzed the frequency of SCE and micronuclei, and the PRI in the peripheral blood lymphocytes of 30 women with breast cancer, 22 of their female family members, and 20 age-matched healthy female volunteers. RESULTS: SCE occurred significantly more often in the lymphocytes of breast cancer patients (10.84+/-0.4 per metaphase), compared with their first-degree relatives (7.45+/-0.54) and controls (5.94+/-0.2) (p<0.001 for both). The mean SCE frequency was not statistically different between first degree relatives and controls (p=0.071). Similarly, micronuclei occurred at a significantly higher rate in breast cancer patients (9.6+/-0.72), and in their first-degree relatives (7+/-0.64), compared to controls (3.85+/-0.4) (p<0.001 and p=0.001, respectively). There was also a significant difference between the occurrence of micronuclei in patients compared to their family members (p=0.021). The PRI was significantly lower in patients (1.61+/-0.1), compared with both their first-degree relatives (1.75+/-0.1), and controls (1.74+/-0.1) (p=0.001 and p=0.002, respectively). CONCLUSION: Increased SCE and the occurrence of micronuclei, as well as a reduced PRI are associated with breast cancer. Furthermore, increased SCE and the frequency of micronuclei in a first-degree relative suggest that they exhibit greater genetic instability than women of the same age. PMID- 24155758 TI - Silencing of fanconi anemia complementation group f exhibits potent chemosensitization of mitomycin C activity in breast cancer cells. AB - PURPOSE: Fanconi anemia complementation group F (FANCF) is a key factor to maintaining the function of Fanconi anaemia/BRCA (FA/BRCA) pathway, a DNA-damage response pathway. However, the functional role of FANCF in breast cancer has not been elucidated. In the present study, we evaluated the chemosensitization effect of FANCF in breast cancer cells. METHODS: We performed specific knockdown of the endogenous FANCF in breast cancer cells by transfecting the cells with an FANCF short hairpin RNA (shRNA) vector. Cell viability was measured with a Cell Counting Kit-8, and DNA damage was assessed with the alkaline comet assay. The apoptosis, cell cycle, and drug accumulation were measured by flow cytometric analysis. Protein expression levels were determined by Western blot analysis, using specific antibodies. RESULTS: The analyses of two breast cancer cell lines (MCF-7 and MDA-MB-435S) demonstrated that the FANCF shRNA could effectively block the FA/BRCA pathway through the inhibition of Fanconi anemia complementation group D2 ubiquitination. Moreover, FANCF silencing potentiated the sensitivity of cells to mitomycin C (MMC), where combined FANCF shRNA/MMC treatment inhibited cell proliferation, induced S-phase arrest, apoptosis, and DNA fragmentation, and reduced the mitochondrial membrane potential, compared with MMC treatment alone. CONCLUSION: Taken together, this study demonstrates that the inhibition of FANCF by its shRNA leads to a synergistic enhancement of MMC cytotoxicity in breast cancer cells. These results suggest that the inhibition of the FA/BRCA pathway is a useful adjunct to cytotoxic chemotherapy for the treatment of breast cancer. PMID- 24155759 TI - Comparison of electron and x-ray beams for tumor bed boost irradiation in breast conserving treatment. AB - PURPOSE: This study aimed to compare the dosimetric profiles of electron beams (EB) and X-ray beams (XB) for boosting irradiation in breast cancer patients who underwent breast-conserving surgery and postoperative radiotherapy. METHODS: For 131 breast cancer patients who underwent breast-conserving surgery, we compared plans for EB and XB boost irradiation after whole-breast irradiation. The organs at risk (OAR) included the cardiac chambers, coronary arteries, ipsilateral lung, and skin. The conformity index (CI), inhomogeneity index (IHI), and dose-volume parameters for the planning target volume (PTV), and OAR were calculated. Postradiotherapy chest computed tomography scans were performed to detect radiation pneumonitis. RESULTS: XB plans showed a significantly better CI and IHI for the PTVs, compared to the EB plans. Regarding OAR sparing, the XB reduced the high-dose volume at the expense of an increased low-dose volume. In 33 patients whose radiation fields included nipples, IHI was higher in the EB plans, whereas the presence of a nipple in the radiation field did not interfere with the XB. EB treated patients developed more subclinical radiation pneumonitis. CONCLUSION: XB plans were superior to EB plans in terms of PTV coverage (homogeneity and conformity) and high-dose volume sparing in OAR when used as boost irradiation after breast-conserving surgery. A disadvantage of the XB plan was an increased low-dose volume in the OAR, but this was offset by the increased electron energy. Consequently, tailored plans with either XB or EB are necessary to adapt to patient anatomic variance and tumor bed geometric properties. PMID- 24155760 TI - Association between BRCA Mutation Status, Pathological Findings, and Magnetic Resonance Imaging Features in Patients with Breast Cancer at Risk for the Mutation. AB - PURPOSE: We investigated the relationship between BRCA mutations, pathological findings, and magnetic resonance imaging (MRI) features in patients with breast cancer at risk for the mutation. METHODS: Genetic testing for BRCA mutations was performed in 275 breast cancer patients with at least one risk factor for the mutation. Using the breast imaging reporting and data system MR lexicon, morphological and kinetic features were reviewed on MRI scans of 230 tumors in 209 patients. The relationship between BRCA mutations, pathologic findings, and MRI data was examined, and disease recurrence was estimated. RESULTS: BRCA mutations were detected in 48 patients (23.0%), of which 21 (10.0%) were in BRCA1, and 25 (12.0%) in BRCA2. Additionally, two patients (1.0%) had mutations in both genes. Cancers in patients with BRCA1 mutations more frequently showed a higher nuclear grade (p=0.0041), and triple-negative (TN) phenotype (p<0.0001). On MRI scans, the cancers were seen as mass-type in 182 out of 230 lesions (79.1%), and nonmass type in 48 cases (20.9%). Among the features indentified by MRI, rim enhancement was significantly associated with molecular subtypes based on immunohistochemistry (p<0.0001), and nuclear grade (p=0.0387) in multiple logistic regression analysis. Rim enhancement on MRI, along with advanced pathologic N stage, was associated with increased disease recurrence (p=0.0023) based on multivariate analysis. However, the proportion of mass and nonmass tumors, and the distribution of morphological shape, margin, internal enhancement, and kinetic features assessed by MRI were not different according to BRCA mutation status. CONCLUSION: BRCA1 mutations were associated with aggressive pathological characteristics, and the TN phenotype. Rim enhancement was frequently seen on MRI scans of high-grade cancers and in the TN phenotype. And it was a significant predictor of disease recurrence. However, a direct association with BRCA mutations was not observed. PMID- 24155761 TI - The Comparative Study of Ultrasonography, Contrast-Enhanced MRI, and (18)F-FDG PET/CT for Detecting Axillary Lymph Node Metastasis in T1 Breast Cancer. AB - PURPOSE: A more noninvasive evaluation of axillary lymph node in breast cancer is one of the principal challenges of breast cancer treatment. To detect axillary lymph node metastasis (ALNM) in T1 breast cancer, we have compared the axillary ultrasonography (AUS), contrast-enhanced magnetic resonance imaging (cMRI), and (18)F-fluorodeoxyglucose positron emission tomography/computed tomography (PET/CT) to determine the most adequate test or a combination of tests. METHODS: Retrospectively, 349 T1 breast cancer patients who were preoperatively examined using AUS, cMRI, and PET/CT between 2008 and 2011 and whom underwent pathological evaluations of axillary lymph nodes were reviewed and analyzed. RESULTS: In total, 26.4% (92/349) of patients exhibited ALNM. The sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and accuracy of AUS for determining ALNM were 44.6%, 88.7%, 58.6%, 81.7%, and 77.1%, respectively. cMRI was similar to AUS. The sensitivity, specificity, PPV, NPV, and accuracy of PET/CT were 44.5%, 94.2%, 73.2%, 82.6%, and 81.1%, respectively. The combination including cMRI and PET/CT was the most accurate with sensitivity, specificity, PPV, NPV, and accuracy values of 39.1%, 98.8%, 92.3%, 81.9%, and 83.1%, respectively. The mean number (3.5+/-4.2) of ALNMs in the patients who were positive based on cMRI and PET/CT and also pathologically proven to exhibit ALNM was significantly larger than the number (2.16+/-2.26) in other patients who exhibited ALNM (p=0.035). CONCLUSION: There are no definitive modalities for detecting ALNM in T1 breast cancers to replace sentinel lymph node biopsy (SLNB). If ALNM is suspected based on cMRI and PET/CT, the axillary dissection without SLNB might be a better option because it is related to high possibilities of ALNM and large axillary metastatic volumes. PMID- 24155762 TI - Detection of breast cancer in asymptomatic and symptomatic groups using computer aided detection with full-field digital mammography. AB - PURPOSE: We aimed to determine the sensitivity of computer-aided detection (CAD) applied to digital mammography in asymptomatic and symptomatic breast cancer patients. METHODS: We retrospectively analyzed digital mammography and CAD images from 210 patients diagnosed with breast cancer. The patients were divided into symptomatic and asymptomatic groups. The sensitivity of CAD in both groups was assessed in relation to breast tissue density, histopathological type of breast cancer, and tumor size. RESULTS: The detection rate of the CAD system was 87.8% in the asymptomatic group. The sensitivity in different tissue densities was 100% in fatty breasts (P1), 88.9% with scattered fibroglandular densities (P2), 94.4% in heterogeneously dense breasts (P3), and 66.7% in extremely dense breasts (P4). The detection rate of the CAD system in the symptomatic group was 87.2%, and the sensitivity was 90.5%, 90%, 86.6%, and 75% in P1-P4 breasts, respectively. In the asymptomatic group, the CAD system detected 90.3% of invasive ductal carcinomas, not otherwise specified (IDC-NOS) and 88.9% of ductal carcinomas in situ (DCIS), but did not detect other types of malignancy. In the symptomatic group, the CAD system detected 88.2% of IDC-NOS, 88.9% of DCIS and 75% of other types of malignancy. When analyzed according to tumor size, the sensitivity of CAD in the asymptomatic and symptomatic groups was 82.6% and 83.3% for tumors <1 cm, 76.5% and 82.4% for tumors between 1 and 2 cm, and 91.7% and 89% in tumors >2 cm. CONCLUSION: The sensitivity of CAD was low in P4 breasts and high for tumors larger than 2 cm, with no statistically significant differences between the asymptomatic and symptomatic groups for IDC-NOS and DCIS. CAD showed greater sensitivity for other neoplasms in symptomatic patients. PMID- 24155763 TI - The clinical utility of automated breast volume scanner: a pilot study of 139 cases. AB - PURPOSE: The aim of this study is to evaluate the clinical utility of automated breast volume scanner (ABVS) for detecting and diagnosing the breast lesions. METHODS: From December 2010 to January 2012, bilateral whole breast examinations were performed with ABVS for 139 women. Based on the Breast Imaging Reporting and Data System (BI-RADS) categories, the breast lesions were evaluated on coronal multiplanar reconstruction images using the ABVS workstation. Then, the imaging results were compared with those on conventional handheld ultrasound (HHUS) images. Histological diagnoses were performed on BI-RADS category 4 and 5 lesions. RESULTS: A total of 453 lesions were detected by ABVS. On the HHUS, 33 new lesions were detected but 69 lesions were not detected. BI-RADS category 2 and 3 matched to those on ABVS at 73.5% (61/83) and 85.4% (276/323). In 47 lesions of BI-RADS category 4 or 5, there was an exact match to those on ABVS. In addition, 47 lesions were classified as BI-RADS category 4 and 5, for which an ultrasound-guided core needle biopsy was performed. The malignant lesions of BI RADS category 4 and 5 showed the following: 2/27 (7.4%) in 4A, 4/5 (80%) in 4B, 2/2 (100%) in 4C, and 13/13 (100%) in 5. The ABVS showed 21 true positives and a positive predictive value of 44.7% (21/47). CONCLUSION: There was considerable agreement in the assessment of the breast lesions by ABVS and HHUS. The ABVS had advantages of high diagnostic accuracy, examiner-independence, multislice visualization of the whole breast and less time-consuming. Our results indicate that ABVS might be a useful modality in diagnosing breast lesions. PMID- 24155764 TI - The effects of a genetic counseling educational program on hereditary breast cancer for korean healthcare providers. AB - PURPOSE: Systematic educational programs and genetic counseling certification courses for hereditary breast/ovarian cancer (HBOC) have not yet been introduced in Korea. We provided and evaluated the effects of genetic counseling education on Korean healthcare providers' knowledge, awareness, and counseling skills for patients at high risk of HBOC. METHODS: A 3-day educational program was conducted for healthcare providers who were interested in genetic counseling for patients at high risk of HBOC. Participants who completed a knowledge test and satisfaction questionnaire were included in the present sample. Pre-post comparisons were conducted to determine the effects of the intervention. RESULTS: Significant differences between preprogram and postprogram knowledge scores were observed (p=0.002). Awareness (p<0.001) and confidence (p<0.001) regarding genetic counseling significantly increased after the training. Doctors and participants with fewer years of work experience performed well on the knowledge test. Previous educational experience was correlated with increased confidence in knowledge and counseling skills. CONCLUSION: Genetic counseling education regarding HBOC improved knowledge and awareness of HBOC and enhanced confidence in the counseling process. The effects varied according to occupation and participants' previous education. The implementation of systematic educational programs that consider participant characteristics may improve the effects of such interventions. PMID- 24155765 TI - Genomic profiling shows increased glucose metabolism in luminal B breast cancer. AB - We had previously reported a close association between pathological response and the maximum tumor standardized uptake value (SUVmax) measured by (18)F fluorodeoxyglucose positron emission tomography prior to chemotherapy in estrogen receptor (ER)-positive breast cancer. We hypothesized that glucose hypermetabolism by luminal B tumors may result in chemotherapy responsiveness. Using a single-gene expression assay, TargetPrint(r) (Agendia) and a 70-gene expression classifier, MammaPrint(r) (Agendia), we divided 20 patients with ER positive primary breast cancer into luminal A and luminal B subtypes and compared the tumor SUVmax value between the two groups. A significantly higher SUVmax was measured for luminal B tumors (n=10; mean+/-SD, 7.6+/-5.6) than for luminal A tumors (n=10; mean+/-SD, 2.6+/-1.2; p=0.01). Glucose hypermetabolism could help predict intrinsic subtyping and chemotherapy responsiveness as a supplement to ER, progesterone receptor, HER2, and Ki-67 histochemical scores. PMID- 24155766 TI - Breast metastasis from rhabdomyosarcoma of the anus in an adolescent female. AB - Rhabdomyosarcoma (RMS) of the breast is rare and there is scant information about the clinical behavior and treatment strategies. We report an adolescent female patient with metastatic RMS of the breast from the anus. An 18-year-old female patient was referred to our clinic due to palpable mass in the left breast. At age seven, she was diagnosed with acute lymphoblastic leukemia and treated with chemoradiation therapy. After 10 years of complete remission state, she presented with anal mass which was diagnosed as RMS and she received chemoradiation therapy. After 1 year of complete remission state, she noticed a palpable mass in her left breast. The breast mass was diagnosed as metastatic RMS based on core needle biopsy specimen. The RMS in breast was excised for the decreasing tumor burden despite of another metastatic lesion. Although rarely reported, metastasis of RMS should be considered as a cause of breast mass. Tissue biopsy is recommended when clinically suspected lesion is detected. PMID- 24155767 TI - Breast carcinoma with choriocarcinomatous features: a case report. AB - Nongestational choriocarcinoma differentiation is extremely rare in breast neoplasms. It is characterized by tumor cells similar to chorionic trophoblastic cells, which react with human placental lactogen and human chorionic gonadotropin (hCG). A 56-year-old woman presented with a palpable right breast mass without past history of trophoblastic tumors. An F-18 fluorodeoxyglucose (FDG) positron emission tomography/computed tomography (PET/CT) scan revealed one focus with low accumulation of FDG in the right breast (maximum standardized uptake value, 1.98). The patient underwent a right mastectomy and biopsy of sentinel nodes. Microscopically, the tumor was a typical invasive ductal carcinoma with multiple foci of choriocarcinoma features. Immunohistochemistry showed that the tumor cells resembling choriocarcinoma were positive for hCG antibody, but negative for HER2/neu, estrogen receptor, and progesterone receptor. A pathologic diagnosis of breast carcinoma with choriocarcinomatous features was made. To our knowledge, this is the first report of invasive carcinoma with choriocarcinomatous features and an unusual finding of low accumulation in an F-18 FDG PET/CT scan in Korea. PMID- 24155768 TI - Neutrophil to lymphocyte ratio may predict mortality in breast cancer patients. PMID- 24155769 TI - The prevalence of four types of childhood maltreatment in denmark. AB - OBJECTIVES: To estimate the prevalence of four types of childhood maltreatment in Denmark while taking into considerations how each of the types of maltreatment vary as a function of gender or child-protection status. METHODS: Data were collected from a Danish national study conducted by The Danish National Centre for Social Research in 2008 and 2009. The study used a stratified random probability sample of young people aged 24 years. A sample of 4718 young adults were randomly selected by Statistics Denmark using the total birth cohort of all children born in 1984. The response rate was 63% leaving a total effective sample size of 2980. A structured residential or telephone interview enquired about a range of respondents maltreatment experiences. RESULTS: Maltreatment is experienced by a significant proportion of Danish children. The reported prevalence rates were; physical neglect (3.0%), emotional abuse (5.2%), physical abuse (5.4%) and sexual abuse (3.4%). All trauma types were experienced by a greater percentage of females compared to males with the exception of physical abuse and all trauma types were experienced by a greater percentage of children given child-protection status. CONCLUSIONS: Female children and children who are given child protection status are those most at risk for experiencing maltreatment in Denmark. However, variability in prevalence rates of maltreatment across studies is problematic. Methodological variations and variation in abuse definitions may be partly attributable. PMID- 24155770 TI - Attachment and parenting in adult patients with anxiety disorders. AB - BACKGROUND: The literature suggests that dysfunctional parenting and insecure attachment may increase risk of anxiety-related psychopathology. This study aimed at testing the association between anxiety disorders, attachment insecurity and dysfunctional parenting while controlling for factors usually not controlled for in previous studies, such as gender, age, and being ill. METHODS: A sample of 32 non-psychotic inpatients with SCID-I diagnosis of an anxiety disorder, either alone or in comorbidity, was compared with two age- and sex-matched control groups consisting of 32 non-clinical participants and 32 in-patients with drug resistant epilepsy. Study measures included the Experience in Close Relationships questionnaire (ECR) and the Parental Bonding Instrument (PBI). RESULTS: The patients with anxiety disorders scored significantly higher on attachment-related anxiety and avoidance than patients with drug-resistant epilepsy and non-clinical participants. These findings were independent of comorbidity for mood disorders. ECR scores did not differ among diagnostic subgroups (generalized anxiety disorder, panic disorder, other anxiety disorders). Patients with anxiety disorders scored significantly lower on PBI mother's care and borderline significantly lower on PBI father's care than patients with drug-resistant epilepsy. CONCLUSIONS: Although limitations such as the relatively small sample size and the cross-sectional nature suggest caution in interpreting these findings, they are consistent with the few previous adult studies performed on this topic and corroborate Bowlby's seminal hypothesis of a link between negative attachment-related experiences, attachment insecurity, and clinical anxiety. Attachment theory provides a useful theoretical framework for integrating research findings from several fields concerning the development of anxiety disorders and for planning therapeutic interventions. PMID- 24155771 TI - Diagnostic Accuracy of the Primary Care Screener for Affective Disorder (PC-SAD) in Primary Care. AB - BACKGROUND: Depression goes often unrecognised and untreated in non-psychiatric medical settings. Screening has recently gained acceptance as a first step towards improving depression recognition and management. The Primary Care Screener for Affective Disorders (PC-SAD) is a self-administered questionnaire to screen for Major Depressive Disorder (MDD) and Dysthymic Disorder (Dys) which has a sophisticated scoring algorithm that confers several advantages. This study tested its performance against a 'gold standard' diagnostic interview in primary care. METHODS: A total of 416 adults attending 13 urban general internal medicine primary care practices completed the PC-SAD. Of 409 who returned a valid PC-SAD, all those scoring positive (N=151) and a random sample (N=106) of those scoring negative were selected for a 3-month telephone follow-up assessment including the administration of the Structured Clinical Interview for DSM-IV-TR Axis I Disorders (SCID-I) by a psychiatrist who was masked to PC-SAD results. RESULTS: Most selected patients (N=212) took part in the follow-up assessment. After adjustment for partial verification bias the sensitivity, specificity, positive and negative predictive value for MDD were 90%, 83%, 51%, and 98%. For Dys, the corresponding figures were 78%, 79%, 8%, and 88%. CONCLUSIONS: While some study limitations suggest caution in interpreting our results, this study corroborated the diagnostic validity of the PC-SAD, although the low PPV may limit its usefulness with regard to Dys. Given its good psychometric properties and the short average administration time, the PC-SAD might be the screening instrument of choice in settings where the technology for computer automated scoring is available. PMID- 24155772 TI - Normal Sequence and Activity but Reduced Levels of DNA-Pkcs in Human Lymphoblastic Cells Implicate Impaired Protein Stability with Radiosensitive Phenotype. AB - BACKGROUND: Non-homologous end joining (NHEJ) is the main repair pathway for DNA double strand breaks (DSBs) induced by ionizing radiation in mammalian cells. Subsets of cancer patients are hypersensitive to radiotherapy after standard doses. We sought to determine the radiosensitivity of human lymphoblastic cells (LB0005) for the abnormality in NHEJ components. METHODS: Lymphoblastic (LB0005) cells are derived from an adult cancer patient with late radionecrosis. A low magnesium in vitro DNA-end joining assay was performed to examine for any defect in NHEJ activity. Single-nucleotide polymorphism (SNP) and sequence analysis were performed to examine for abnormality if any, in the genetic sequence of known NHEJ components. RESULTS: LB0005 cells showed a gain of functional abnormality in the NHEJ pathway. While genetic sequence analysis showed no apparent mutational variations in the known classical NHEJ components, DNA-PKcs (DNA-dependent protein kinase catalytic subunit) protein is reduced in quantity compared to normal control, in spite of higher transcript levels. CONCLUSIONS: Taken together cells derived from a radiosensitive patient showed an abnormality in NHEJ activity. Proteins other than the classical NHEJ factors may regulate the NHEJ activity. Furthermore, the defect in theses regulatory proteins may have an impact on the stability of DNA-PKcs. PMID- 24155773 TI - CRM1 Inhibition Sensitizes Drug Resistant Human Myeloma Cells to Topoisomerase II and Proteasome Inhibitors both In Vitro and Ex Vivo. AB - Multiple myeloma (MM) remains an incurable disease despite improved treatments, including lenalidomide/pomalidomide and bortezomib/carfilzomib based therapies and high-dose chemotherapy with autologous stem cell rescue. New drug targets are needed to further improve treatment outcomes. Nuclear export of macromolecules is misregulated in many cancers, including in hematological malignancies such as MM. CRM1 (chromosome maintenance protein-1) is a ubiquitous protein that exports large proteins (>40 kDa) from the nucleus to the cytoplasm. We found that small molecule Selective Inhibitors of Nuclear Export (SINE) prevent CRM1-mediated export of p53 and topoisomerase IIalpha (topo IIalpha). SINE's CRM1-inhibiting activity was verified by nuclear-cytoplasmic fractionation and immunocytochemical staining of the CRM1 cargoes p53 and topo IIalpha in MM cells. We found that SINE molecules reduced cell viability and induced apoptosis when used as both single agents in the sub-micromolar range and when combined with doxorubicin, bortezomib, or carfilzomib but not lenalidomide, melphalan, or dexamethasone. In addition, CRM1 inhibition sensitized MM cell lines and patient myeloma cells to doxorubicin, bortezomib, and carfilzomib but did not affect peripheral blood mononuclear or non-myeloma bone marrow mononuclear cells as shown by cell viability and apoptosis assay. Drug resistance induced by co-culture of myeloma cells with bone marrow stroma cells was circumvented by the addition of SINE molecules. These results support the continued development of SINE for patients with MM. PMID- 24155774 TI - Nuclear Nano-architecture Markers of Gastric Cardia and Upper Squamous Esophagus Detect Esophageal Cancer "Field Effect". AB - BACKGROUND: Barrett's esophagus (BE) affects up to 12 million Americans and confers an increased risk for development of esophageal adenocarcinoma (EAC). EAC is often fatal unless detected early. Given the high prevalence, high cost of surveillance and relatively low risk of most affected individuals, identification of high-risk patients for additional scrutiny, regular surveillance, or ablative therapy is crucial. The exploration of "field effect" by probing uninvolved esophageal mucosa to predict the risk of EAC has the potential as an improved surveillance and prevention strategy. In this study, we evaluate the ability of nuclear nano-architecture markers from normal squamous esophagus and gastric cardia to detect the "field effect" of esophageal dysplasia and EAC, and their response to endoscopic therapy. METHODS: Patients with normal esophagus, gastroesophageal reflux, BE and EAC were eligible for enrollment. We performed endoscopic cytology brushings of the gastric cardia, ~1-2 cm below the gastroesophageal junction, and of the normal squamous esophageal mucosa at ~20 cm from the incisors and standard cytology slides were made using Thinprep method. Optical analysis was performed on the cell nuclei of cytologically normal appearing epithelial cells. RESULTS: The study cohort consisted of 128 patients. The nuclear nano-architecture markers detected the presence of esophageal dysplasia and EAC with statistical significance. The field effect does not exhibit a spatial dependence. These markers reverted toward normal in response to endoscopic therapy. CONCLUSIONS: Optical analysis of gastric cardia and upper squamous esophagus represents a potentially viable method to improve risk stratification and ease of surveillance of patients with Barrett's esophagus and to monitor the efficacy of ablative therapy. PMID- 24155775 TI - Treatment for hepatocellular carcinoma in elderly patients: a literature review. AB - An aging society means that the number of elderly patients with cancer is predicted to rise in the future. Hepatocellular carcinoma (HCC) usually develops in patients with hepatitis B virus infection, hepatitis C virus infection, or alcoholic liver disease. The risk of developing HCC is also known to be age dependent and elderly patients sometimes present with HCC. The increased longevity of the population thus means that more elderly HCC patients are to be expected in the coming years. In general, many elderly patients are not receiving optimal therapy for malignancies, because it is often withheld from them because of perceived minimal survival advantage and the fear of potential toxicity. Comprehensive data with regard to treatment of elderly patients with HCC are currently limited. Furthermore, current guidelines for the management of HCC do not satisfy strategies according to age. Thus, there is urgent need for investigation of safety and clinical outcomes in elderly patients who receive therapy for HCC. In this review, we primarily refer to current knowledge of clinical characteristics and outcome in elderly patients with HCC who underwent different treatment approaches (i.e., surgical resection, liver transplantation, locoregional therapies, and molecular-targeting therapy). PMID- 24155776 TI - A target-specific oral formulation of Doxorubicin-protein nanoparticles: efficacy and safety in hepatocellular cancer. AB - BACKGROUND/AIMS: Hepatocellular carcinoma (HCC) also known as malignant hepatoma is a most common liver cancer. Doxorubicin (Doxo) is an anti-cancer drug having activity against a wide spectrum of cancer types. Clinical Utility of doxo has been limited due to its poor bioavailability and toxicity to heart and spleen. Furthermore, cancer chemotherapeutics have limited oral absorption. Transferrin family proteins are highly abundant and plays important role in transport and storage of iron in cells and tissues. Since apotransferrin and lactoferrin receptors are highly expressed on the surface of metabolically active cancer cells, the principal objective of present study is to evaluate efficacy of doxorubicin loaded apotransferrin and lactoferrin nanoparticles (apodoxonano or lactodoxonano) in oral treatment of HCC in rats. STUDY DESIGN: HCC was induced in rats by supplementing 100 mg/L of diethylnitrosamine (DENA) in drinking water for 8 weeks. A week after the last day of DENA administration, rats were divided into four groups, each group comprising of five animals. Each group was administered with one of the drug viz., saline, doxorubicin (doxo), apodoxonano and lactodoxonano (4 mg/ kg equivalent of drug). In each case, they received 8 doses of the drug orally with six day interval. One week after the last dose, anticancer activity was evaluated by counting the liver nodules, H & E analysis of tissue sections and expression levels of angiogenic and antitumor markers. RESULTS: In rats treated with apodoxonano and lactodoxonano, the number of neoplastic nodules was significantly lower than that of rats administered with saline or with doxo. Apodoxonano and lactodoxonano did not exhibit decrease in mean body weight, which was markedly reduced by 22% in the case of doxo administered rats. In rats treated with nanoformulations, the number of liver nodules was found reduced by >93%. Both nanoformulations showed significantly high localization in liver compared to doxo. CONCLUSIONS: Apodoxonano and lactodoxonano showed improved efficacy, bioavailability and safety compared to doxo for treatment of HCC in rats when administered orally. PMID- 24155777 TI - Kisspeptin/KISS1R System in Breast Cancer. AB - Kisspeptins (KP), peptide products of the kisspeptin-1 (KISS1) gene are the endogenous ligands for a G protein-coupled receptor (GPCR) - KP receptor (KISS1R). KISS1R couples to the Galphaq/11 signaling pathway. KISS1 is a metastasis suppressor gene and the KP/KISS1R signaling has anti-metastatic and tumor-suppressant effects in numerous human cancers. On the other hand, recent studies indicate that KP/KISS1R pathway plays detrimental roles in breast cancer. In this review, we summarize recent developments in the understanding of the mechanisms regulating KP/KISS1R signaling in breast cancer metastasis. PMID- 24155778 TI - UCHL1 Is a Putative Tumor Suppressor in Ovarian Cancer Cells and Contributes to Cisplatin Resistance. AB - Ubiquitin carboxyl terminal hydrolase 1 (UCHL1) catalyzes the hydrolysis of COOH terminal ubiquityl esters and amides. It has been reported as either an oncogene or a tumor suppressor in cancers. However, UCHL1's role in ovarian cancer is still unclear. Therefore, we conducted an analysis to understand the role of UCHL1 in ovarian cancer. Firstly, we detected UCHL1 promoter methylation status in 7 ovarian cancer cell lines. 4 of them with UCHL1 silencing showed heavy promoter methylation while the other 3 with relative high UCHL1 expression showed little promoter methylation. Then we reduced UCHL1 expression in ovarian cancer cell line A2780 and IGROV1 and found that inhibition of UCHL1 promoted cell proliferation by increasing cells in S phases of cell cycle. Knockdown of UCHL1 also reduced cell apoptosis and contributed to cisplatin resistance. Furthermore, the expression level of UCHL1 in several ovarian cancer cell lines correlated negatively with their cisplatin resistance levels. Microarray data revealed that UCHL1 related genes are enriched in apoptosis and cell death gene ontology (GO) terms. Several apoptosis related genes were increased after UCHL1 knockdown, including apoptosis regulator BCL2, BCL11A, AEN and XIAP. Furthermore, we identified up-regulation of Bcl-2 and pAKT as well as down-regulation of Bax in UCHL1 knockdown cells, while no significant alteration of p53 and AKT1 was found. This study provides a new and promising strategy to overcome cisplatin resistance in ovarian cancer via UCHL1 mediated pathways. PMID- 24155779 TI - Aspirin Blocks EGF-stimulated Cell Viability in a COX-1 Dependent Manner in Ovarian Cancer Cells. AB - OBJECTIVE: Although aspirin has been associated with a reduction of the risk of cancer when used as a nonsteroidal anti-inflammatory drug, its use to reduce the risk of ovarian cancer is controversial. Ovarian cancer cells usually express high levels of cyclooxygenase-1 (COX)-1. Because aspirin is a rather selective inhibitor of COX-1, the ability of aspirin to reduce the risk of ovarian cancer may be dependent on the level of COX-1 expression in those cells. Furthermore, epidermal growth factor receptor (EGFR) is frequently overexpressed in the malignant phenotype of ovarian cancer leading to increased cell proliferation and survival. Here we investigated if aspirin attenuates EGFR-activated ovarian cancer cell growth in a COX-1 dependent manner. METHODS: Cell viability assays and Western blot analyses were used to determine the effect of aspirin on EGF stimulated cell proliferation. Gene silencing and gene expression techniques were employed to knockdown or to express COX-1, respectively. RESULTS: Aspirin inhibited cell viability induced by EGF in a dose dependent manner in COX-1 positive ovarian cancer cells. On the other hand, aspirin had no effect on cell viability in COX-1 negative ovarian cancer cells. In particular, aspirin decreased phosphorylated Akt and Erk activated by EGF. COX-1 silencing in COX-1 positive cells attenuated the inhibitory effect of aspirin on EGF-stimulated cell viability. Furthermore, we developed a COX-1 expressing cell line (SKCOX-1) by stably transfecting COX-1 expression vector into COX-1 negative SKOV-3 cells. SKCOX-1 cells were more responsive to aspirin when compared to cells transfected with empty vector, and decreased EGF-activated Akt and Erk as well as cell viability. CONCLUSIONS: Taken together, aspirin inhibits viability of ovarian cancer cells by blocking phosphorylation of Akt and Erk activated by EGF. Thus it may potentiate the therapeutic efficacy of drugs used to treat COX-1 positive ovarian cancer subsets. PMID- 24155780 TI - Paclitaxel and Trastuzumab as Maintenance Therapy in Patients with HER2-Positive Metastatic Breast Cancer Who Underwent High-Dose Chemotherapy and Autologous Hematopoietic Stem Cell Transplantation. AB - We examined the feasibility and safety of using paclitaxel and trastuzumab as maintenance therapy after high-dose chemotherapy (HDC) with autologous hematopoietic stem cell transplantation (AHST) for patients with HER2-positive metastatic breast cancer. Ten patients (9 women and 1 man) were enrolled in the study. The median age was 46.5 years (range, 27-65 years). The median follow-up time was 1003 days (range, 216-2526 days). All patients had metastatic disease, but 2 had only bone metastasis. One patient had complete response, 6 had partial response and 3 had stable disease to the standard-dose chemotherapy prior to transplantation. The conditioning regimen consisted of cyclophosphamide, carmustine, and thiotepa. After AHST, patients received weekly paclitaxel for 12 doses and trastuzumab every 3 weeks for 1 year as maintenance therapy. All patients experienced successful engraftment. The only grade 4 toxic effects observed were leukopenia and thrombocytopenia. The most common grade 3 toxic effect was neutropenic fever. No treatment-related deaths were observed. The median progression-free survival time was 441 days, and the median overall survival time was 955 days. Two patients died in accidents while their disease remained in remission. Five patients died with disease progression. At the time of this report, 3 patients are alive with stable disease, 1 of whom has remained free of disease progression for 2526 days since transplantation. Our findings indicate that paclitaxel plus trastuzumab as maintenance therapy after HDC with AHST for patients with HER2-positive metastatic breast cancer not only is feasible and safe but also results in survival outcomes similar to historical results. PMID- 24155781 TI - The efficacy of adjuvant chemotherapy for locally advanced upper tract urothelial cell carcinoma. AB - OBJECTIVE: To evaluate the efficacy of adjuvant cisplatin-based chemotherapy for locally advanced upper tract urothelial cell carcinoma (UTUC) following radical nephroureterectomy with bladder cuff resection (RNU) in terms of survival and recurrence. MATERIALS AND METHODS: Between January 2000 and January 2013, among 145 patients with upper tract urothelial cell carcinoma, a total of 65 patients with locally advanced UTUC (a diagnosis of pT3 or pT4 or pT1-2N1-3) underwent RNU. Of these 65 patients, 36 patients received at least three cycles of adjuvant gemcitabine plus cisplatin chemotherapy and the remaining 29 patient did not receive adjuvant chemotherapy. Clinical characteristics, bladder recurrence, distant metastasis, and cancer-specific survival were retrospectively reviewed. RESULTS: The mean age of the 65 patients was 60.4 (range, 37-87) years and the median follow-up period was 34 (range, 12-114) months. Patent demographics were not statistically different between the two groups. During the follow-up period, 14 patients (21.5%) experienced distant metastasis; 8 (8/36, 22.2%) patients who had undergone adjuvant chemotherapy and 6 (6/29, 20.7%) patients who did not. Bladder recurrence was noted in 17 patients (26.2%), 5 (5/36, 13.9%) of whom received adjuvant chemotherapy while the remaining 12 (12/29, 41.4%) did not. Kaplan-Meire and multivariate analysis showed that the incidence of bladder recurrence was significantly higher in patients who did not undergo adjuvant chemotherapy, and cancer specific survival was not significantly associated with adjuvant chemotherapy. CONCLUSIONS: Adjuvant chemotherapy for locally advanced UTUC can prevent bladder recurrence, but has a minimal effect on cancer-specific survival. PMID- 24155782 TI - Potential role of periodontal infection in respiratory diseases - a review. AB - Respiratory diseases are responsible for a significant number of deaths and considerable suffering in humans. Accumulating evidence suggests that oral disorders, particularly periodontal disease, may influence the course of respiratory infections like bacterial pneumonia and chronic obstructive pulmonary disease (COPD). Oral periodontopathic bacteria can be aspirated into the lung causing aspiration pneumonia. The teeth may also serve as a reservoir for respiratory pathogen colonization and subsequent nosocomial pneumonia. The overreaction of the inflammatory process that leads to the destruction of the connective tissue is present in both periodontal disease and emphysema. This overreaction may explain the association between periodontal disease and chronic obstructive pulmonary disease. The mechanisms of infection could be the aspiration into the lung of oral pathogens capable of causing pneumonia, colonization of dental plaque by respiratory pathogens followed by aspiration, or facilitation of colonization of the upper airway by pulmonary pathogens by periodontal pathogens. The present article briefly reviews the epidemiologic evidence & role of periodontopathogens in causing respiratory infections. PMID- 24155783 TI - Prognosis elements in surgical treatment of complicated umbilical hernia in patients with liver cirrhosis. AB - INTRODUCTION: The surgical treatment of umbilical hernia in cirrhosis patients raises special management challenges. The attitude upon the repair of these hernias varies from expectancy or elective treatment in early stages of the disease to the surgical treatment only if complications occur. MATERIAL AND METHOD: We have assessed 22 consecutive cases of cirrhosis patients treated for complicated umbilical hernia in the Surgical Department of "Sf. Pantelimon" Emergency Hospital in Bucharest between January 2008 and December 2012. The patients' stratification was done in stages of liver disease based upon Child Pugh classification. Complications that required emergency repair were the following: strangulation, incarceration and hernia rupture. The postoperative complications were ordered in five grades of severity based upon Clavien classification. RESULTS: The severity of the complications was higher in advanced stages of liver cirrhosis, Child B and C. There were 5 deaths representing 22,7%, four of them in patients with Child C disease stage. CONCLUSION: The incidence of morbidity and mortality after umbilical hernia repair in emergencies increases in advanced stages of liver cirrhosis. It is advisable to prevent complications occurrence and perform surgical repair of umbilical hernia in elective condition. PMID- 24155784 TI - The implications and consequences of maternal obesity on fetal intrauterine growth restriction. AB - CONTEXT: The prevalence of maternal obesity has been increasing dramatically in the recent years (body mass index >= 30 kg/m2). Maternal obesity is associated with an unequivocal increase in maternal and fetal complications of pregnancy and more than that, these complications also extend beyond fetal life in childhood and adulthood. Objective. The aim of this study was to evaluate maternal and neonatal complications at birth associated with maternal obesity. MATERIALS AND METHODS: The study included all women who gave birth between January 1, 2012 and December 31, 2012 at Bucharest University Emergency Hospital. Collected data included information about maternal health (the degree of obesity, associated complications of birth, anemia, and type of birth) and neonatal status (birth weight, gestational age, associated diseases and Apgar score). RESULTS: A higher incidence of IUGR, as well as an increased frequency of infants who needed intensive care after birth, a higher rate of cesarean surgery and a higher frequency of thromboembolic complications were observed in patients with associated obesity. CONCLUSIONS: Complications grow both in number and severity with increasing obesity. Diagnosis of the fetuses with IUGR is important for the monitoring and management of the pregnancy associated with obesity and it involves a close collaboration between obstetrician, family physician and neonatologist. PMID- 24155785 TI - Antithyroid drugs induced agranulocytosis and multiple myeloma: case report and general considerations. AB - Antithyroid drugs as thionamides are largely used in the treatment of the thyrotoxicosis. Side effects were reported in less than 10% of the cases, especially hematological, hepatic or skin allergies. One of the most severe manifestations is agranulocytosis, probably based on an immune mechanism that is exacerbated by the presence of the thyroid autoimmune disease itself. If the presence of the severe leucopenia is actually an epiphenomenon of a preexisting hematological disturbance as multiple myeloma is debated. The myeloma may also be correlated with an autoimmune predisposition. We present the case of a 56 years old female patient diagnosed with Graves' disease, who developed agranulocytosis after 8 months of therapy with thiamazole. Two months after antithyroid drug's withdrawal, the granulocytes number increased and she received therapy with radioiodine. Two years later she came back for diffuse bone pain that turned out to be caused by a multiple myeloma, confirmed by bone marrow biopsy. It might be a connection between the severe form of leucopenia that the patient developed and the medullar malignancy. PMID- 24155786 TI - Electrophysiological changes in optic neuropathy of streptozotocin induced diabetic rats. AB - The visually evoked potentials are electrical signals generated by the occipital cortex due to electrical stimulus. The clinical importance of VEP is to diagnose the functional changes of the optic nerve in different diseases such as diabetic mellitus. Our study sought latency of VEP changes depending on glycemic value and duration of diabetes in Wistar rats. METHODS: this study evaluated the VEP of 25 rats in three groups: control group, diabetic group 1 with glycemic values between 200-400mg/dl and diabetic group 2 with glycemic values between 400 and 600mg/dl. These rats from diabetic group 2 were followed for 4 months and the ones in control group and diabetic group 1 for 5 months. RESULTS: the latency of VEP shows slight changes without any statistical significance in the control group. In diabetic group 1 and 2 similar changes occurred, with statistical significance and the amplitude of the changes was proportional with the glycemic value. The rats had a rapid increase of VEP latency after the induction of diabetes and returned to a normal range in the first month. After a time, when the latencies of VEP were in normal range, a new growth appeared faster and larger as the glycemic values were higher. CONCLUSION: diabetes brings changes to the visual signal transmission and to the central processing, this being revealed by the examination of the visually evoked potential. Increased VEP latency is statistically correlated with the changes that occur at the level of the values of glucose in blood. A rapid growth in blood sugar lowers the visual signal transmission. This change is temporary despite the persistence of elevated blood glucose values, probably by adjusting to the new condition. However, maintaining high glycemic values remotely produces a progressive increase of the delay of the visual signal. This progressive increase is faster as blood glucose levels are higher. PMID- 24155787 TI - The impact of domain knowledge on structured data collection and templated note design. AB - OBJECTIVE: The objective of this case report is to evaluate the importance of specialized domain knowledge when designing and using structured templated notes in a clinical environment. METHODS: To analyze the impact of specialization on structured note generation we compared notes generated for three scenarios: 1) We compared the templated history of present illness (HPI) for patients presenting with a dermatology concern to the dermatologist versus the emergency department. 2) We compared the evaluation of chest pain by ED physicians versus cardiologists. 3) Finally, we compared the data elements asked for in the evaluation of the gastrointestinal system between cardiologists and the liver transplant service (LTS). We used the SNOMED CT representation via BioPortal to evaluate specificity and grouping between data elements and specialized physician groups. RESULTS: We found few similarities in structured data elements designed by and for the specific physician groups. The distinctness represented both differences in granularity as well as fundamental differences in data elements requested. When compared to ED physicians, dermatologists had different and more granular elements while cardiologists requested much more granular data. Comparing cardiologists and LTS, there were differences in the data elements requested. CONCLUSION: This case study supports the importance of domain knowledge in EHR design and implementation. That different specialities should want and use different information is well supported by cognitive science literature. Despite this, it is rare for domain knowledge to be considered in EHR implementation. Physicians with correct domain knowledge should be involved in the design process of templated notes. PMID- 24155788 TI - STARE-HI - Statement on Reporting of Evaluation Studies in Health Informatics: explanation and elaboration. AB - BACKGROUND: Improving the quality of reporting of evaluation studies in health informatics is an important requirement towards the vision of evidence-based health informatics. The STARE-HI - Statement on Reporting of Evaluation Studies in health informatics, published in 2009, provides guidelines on the elements to be contained in an evaluation study report. OBJECTIVES: To elaborate on and provide a rationale for the principles of STARE-HI and to guide authors and readers of evaluation studies in health informatics by providing explanatory examples of reporting. METHODS: A group of methodologists, researchers and editors prepared the present elaboration of the STARE-HI statement and selected examples from the literature. RESULTS: The 35 STARE-HI items to be addressed in evaluation papers describing health informatics interventions are discussed one by one and each is extended with examples and elaborations. CONCLUSION: The STARE HI statement and this elaboration document should be helpful resources to improve reporting of both quantitative and qualitative evaluation studies. Evaluation manuscripts adhering to the principles will enable readers of such papers to better place the studies in a proper context and judge their validity and generalizability, and thus in turn optimize the exploitation of the evidence contained therein. LIMITATIONS: This paper is based on experiences of a group of editors, reviewers, authors of systematic reviews and readers of the scientific literature. The applicability of the details of these principles has to evolve as a function of their use in practice. PMID- 24155789 TI - Developing software to "track and catch" missed follow-up of abnormal test results in a complex sociotechnical environment. AB - BACKGROUND: Abnormal test results do not always receive timely follow-up, even when providers are notified through electronic health record (EHR)-based alerts. High workload, alert fatigue, and other demands on attention disrupt a provider's prospective memory for tasks required to initiate follow-up. Thus, EHR-based tracking and reminding functionalities are needed to improve follow-up. OBJECTIVES: The purpose of this study was to develop a decision-support software prototype enabling individual and system-wide tracking of abnormal test result alerts lacking follow-up, and to conduct formative evaluations, including usability testing. METHODS: We developed a working prototype software system, the Alert Watch And Response Engine (AWARE), to detect abnormal test result alerts lacking documented follow-up, and to present context-specific reminders to providers. Development and testing took place within the VA's EHR and focused on four cancer-related abnormal test results. Design concepts emphasized mitigating the effects of high workload and alert fatigue while being minimally intrusive. We conducted a multifaceted formative evaluation of the software, addressing fit within the larger socio-technical system. Evaluations included usability testing with the prototype and interview questions about organizational and workflow factors. Participants included 23 physicians, 9 clinical information technology specialists, and 8 quality/safety managers. RESULTS: Evaluation results indicated that our software prototype fit within the technical environment and clinical workflow, and physicians were able to use it successfully. Quality/safety managers reported that the tool would be useful in future quality assurance activities to detect patients who lack documented follow-up. Additionally, we successfully installed the software on the local facility's "test" EHR system, thus demonstrating technical compatibility. CONCLUSION: To address the factors involved in missed test results, we developed a software prototype to account for technical, usability, organizational, and workflow needs. Our evaluation has shown the feasibility of the prototype as a means of facilitating better follow up for cancer-related abnormal test results. PMID- 24155790 TI - Comparing predictions made by a prediction model, clinical score, and physicians: pediatric asthma exacerbations in the emergency department. AB - BACKGROUND: Asthma exacerbations are one of the most common medical reasons for children to be brought to the hospital emergency department (ED). Various prediction models have been proposed to support diagnosis of exacerbations and evaluation of their severity. OBJECTIVES: First, to evaluate prediction models constructed from data using machine learning techniques and to select the best performing model. Second, to compare predictions from the selected model with predictions from the Pediatric Respiratory Assessment Measure (PRAM) score, and predictions made by ED physicians. DESIGN: A two-phase study conducted in the ED of an academic pediatric hospital. In phase 1 data collected prospectively using paper forms was used to construct and evaluate five prediction models, and the best performing model was selected. In phase 2 data collected prospectively using a mobile system was used to compare the predictions of the selected prediction model with those from PRAM and ED physicians. MEASUREMENTS: Area under the receiver operating characteristic curve and accuracy in phase 1; accuracy, sensitivity, specificity, positive and negative predictive values in phase 2. RESULTS: In phase 1 prediction models were derived from a data set of 240 patients and evaluated using 10-fold cross validation. A naive Bayes (NB) model demonstrated the best performance and it was selected for phase 2. Evaluation in phase 2 was conducted on data from 82 patients. Predictions made by the NB model were less accurate than the PRAM score and physicians (accuracy of 70.7%, 73.2% and 78.0% respectively), however, according to McNemar's test it is not possible to conclude that the differences between predictions are statistically significant. CONCLUSION: Both the PRAM score and the NB model were less accurate than physicians. The NB model can handle incomplete patient data and as such may complement the PRAM score. However, it requires further research to improve its accuracy. PMID- 24155791 TI - Development and validation of a portable platform for deploying decision-support algorithms in prehospital settings. AB - BACKGROUND: Advanced decision-support capabilities for prehospital trauma care may prove effective at improving patient care. Such functionality would be possible if an analysis platform were connected to a transport vital-signs monitor. In practice, there are technical challenges to implementing such a system. Not only must each individual component be reliable, but, in addition, the connectivity between components must be reliable. OBJECTIVE: We describe the development, validation, and deployment of the Automated Processing of Physiologic Registry for Assessment of Injury Severity (APPRAISE) platform, intended to serve as a test bed to help evaluate the performance of decision support algorithms in a prehospital environment. METHODS: We describe the hardware selected and the software implemented, and the procedures used for laboratory and field testing. RESULTS: The APPRAISE platform met performance goals in both laboratory testing (using a vital-sign data simulator) and initial field testing. After its field testing, the platform has been in use on Boston MedFlight air ambulances since February of 2010. CONCLUSION: These experiences may prove informative to other technology developers and to healthcare stakeholders seeking to invest in connected electronic systems for prehospital as well as in-hospital use. Our experiences illustrate two sets of important questions: are the individual components reliable (e.g., physical integrity, power, core functionality, and end-user interaction) and is the connectivity between components reliable (e.g., communication protocols and the metadata necessary for data interpretation)? While all potential operational issues cannot be fully anticipated and eliminated during development, thoughtful design and phased testing steps can reduce, if not eliminate, technical surprises. PMID- 24155792 TI - Medical student appraisal: electronic resources for inpatient pre-rounding. AB - BACKGROUND: Pre-rounding is essential to preparing for morning rounds. Despite its importance, pre-rounding is rarely formally taught within the medical school curriculum and more often informally learned by modeling residents. The evolution of mobile applications provides opportunities to optimize this process. OBJECTIVES: To evaluate three options available to medical students while pre rounding and promote adoption of mobile resources in clinical care. METHODS: Six medical students formed the evaluation cohort. Students were surveyed to assess pre-rounding practices. Participants utilized paper-based pre-rounding templates for two weeks followed by two weeks of the electronic note-taking service Evernote. A review of mobile applications on the iTunes and Google Play stores was performed, with each application informally reviewed by a single student. The application Scutsheet was selected for formal review by all students. Data was collected from narrative responses supplied by students throughout the evaluation periods and aggregated to assess strengths and limitations of each application. RESULTS: Pre-study responses demonstrated two consistent processes: verbal sign out of overnight events and template use to organize patient information. The paper-based template was praised for its organization and familiarity amongst residents, but perceived as limited by the requirement of re-copying data into the hospital's electronic medical record (EMR). Evernote excelled due to compatibility across multiple operating systems, including accessibility from clinical workstations and ability to copy notes into the hospital's EMR. Scutsheet allowed for retention of data across multiple hospital days, but was limited by inability to export data or modify the electronic template. Aggregated user feedback identified the abilities to customize templates and copy information into the EMR as two prevailing characteristics that enhanced the efficiency of pre-rounding. DISCUSSION: Mobile devices offer the potential to enhance pre-rounding efficiency for medical students and residents. A customizable Evernote-based system is described in sufficient detail for reproduction by interested students. PMID- 24155793 TI - Retrospective derivation and validation of a search algorithm to identify emergent endotracheal intubations in the intensive care unit. AB - BACKGROUND: The development and validation of automated electronic medical record (EMR) search strategies are important in identifying emergent endotracheal intubations in the intensive care unit (ICU). OBJECTIVE: To develop and validate an automated search algorithm (strategy) for emergent endotracheal intubation in the critically ill patient. METHODS: The EMR search algorithm was created through sequential steps with keywords applied to an institutional EMR database. The search strategy was derived retrospectively through a secondary analysis of a 450 patient subset from the 2,684 patients admitted to either a medical or surgical ICU from January 1, 2010, through December 31, 2011. This search algorithm was validated against an additional 450 randomly selected patients. Sensitivity, specificity, and negative and positive predictive values of the automated search algorithm were compared with a manual medical record review (the reference standard) for data extraction of emergent endotracheal intubations. RESULTS: In the derivation subset, the automated electronic note search strategy achieved a sensitivity of 74% (95% CI, 69%-79%) and a specificity of 98% (95% CI, 92%-100%). With refinements in the search algorithm, sensitivity increased to 95% (95% CI, 91%-97%) and specificity decreased to 96% (95% CI, 92%-98%) in this subset. After validation of the algorithm through a separate patient subset, the final reported sensitivity and specificity were 95% (95% CI, 86%-99%) and 100% (95% CI, 98% 100%). CONCLUSIONS: Use of electronic search algorithms allows for correct extraction of emergent endotracheal intubations in the ICU, with high degrees of sensitivity and specificity. Such search algorithms are a reliable alternative to manual chart review for identification of emergent endotracheal intubations. PMID- 24155794 TI - The challenges of publishing on health informatics in developing countries. AB - The Journal of Health Informatics in Developing Countries was established to meet a perceived need for Health Informaticians in developing countries to be able to share the results of their research in an affordable and easy-to-access online publication. The journal was developed using the open source platform "Open Journal System," and has now published 67 articles across 13 issues. A collaborative editorial approach has been established to address the problems of limited research budgets, difficulties with translating to English and other problems specific to authors from developing countries. The journal faces many challenges including ensuring future financial sustainability and inclusion in journal indexing systems. However, the continuing support of an international body of Associate Editors and Editorial Board Members has enabled a wide range of useful and informative health informatics research to be disseminated across the developing world. PMID- 24155795 TI - What big size you have! Using effect sizes to determine the impact of public health nursing interventions. AB - BACKGROUND: The Omaha System is a standardized interface terminology that is used extensively by public health nurses in community settings to document interventions and client outcomes. Researchers using Omaha System data to analyze the effectiveness of interventions have typically calculated p-values to determine whether significant client changes occurred between admission and discharge. However, p-values are highly dependent on sample size, making it difficult to distinguish statistically significant changes from clinically meaningful changes. Effect sizes can help identify practical differences but have not yet been applied to Omaha System data. METHODS: We compared p-values and effect sizes (Cohen's d) for mean differences between admission and discharge for 13 client problems documented in the electronic health records of 1,016 young low income parents. Client problems were documented anywhere from 6 (Health Care Supervision) to 906 (Caretaking/parenting) times. RESULTS: On a scale from 1 to 5, the mean change needed to yield a large effect size (Cohen's d >= 0.80) was approximately 0.60 (range = 0.50 - 1.03) regardless of p-value or sample size (i.e., the number of times a client problem was documented in the electronic health record). CONCLUSIONS: Researchers using the Omaha System should report effect sizes to help readers determine which differences are practical and meaningful. Such disclosures will allow for increased recognition of effective interventions. PMID- 24155796 TI - Matching clinicians to operative cases: a novel application of a patient acuity score. AB - BACKGROUND: Patient and surgical case complexity are important considerations in creating appropriate clinical assignments for trainees in the operating room (OR). The American Society of Anesthesiologists (ASA) Physical Status Classification System is the most commonly used tool to classify patient illness severity, but it requires manual evaluation by a clinician and is highly variable. A Risk Stratification System for surgical patients was recently published which uses administrative billing codes to calculate four Risk Stratification Indices (RSIs) and provides an objective surrogate for patient complexity that does not require clinical evaluation. This risk score could be helpful when assigning operating room cases. OBJECTIVES: This is a technical feasibility study to evaluate the process and potential utility of incorporating an automatic risk score calculation into a web-based tool for assigning OR cases. METHODS: We created a web service implementation of the RSI model for one-year mortality and automatically calculated the RSI values for patients scheduled to undergo an operation the following day. An analysis was conducted on data availability for the RSI model and the correlation between RSI values and ASA physical status. RESULTS: In a retrospective analysis of 46,740 patients who received surgery in the year preceding the web tool implementation, RSI values were generated for 20,638 patients (44%). The Spearman's rank correlation coefficient between ASA physical status classification and one-year mortality RSI values was 0.404. CONCLUSION: We have shown that it is possible to create a web based tool that uses existing billing data to automatically calculate risk scores for patients scheduled to undergo surgery. Such a risk scoring system could be used to match patient acuity to physician experience, and to provide improved patient and clinician experiences. The web tool could be improved by expanding the input database or utilizing procedure booking codes rather than billing data. PMID- 24155798 TI - Myocardial Perfusion SPECT Utility in Predicting Cardiovascular Events Among Indonesian Diabetic Patients. AB - BACKGROUND: Indonesia has the fourth largest number of diabetes patients after India, China and the USA. Coronary artery disease (CAD) is the most common cause of death in diabetic patients. Early detection and risk stratification is important for optimal management. Abnormal myocardial perfusion imaging (MPI) is an early manifestation in the ischemic cascade. Previous studies have demonstrated the use of MPI to accurately diagnose obstructive CAD and predict adverse cardiac events. This study evaluated whether MPI predicts adverse cardiac event in an Indonesian diabetic population. METHOD: The study was undertaken in a consecutive cohort of patients with suspected or known CAD fulfilling entry criteria. All had adenosine stress MPI. The end point was a major adverse cardiac event (MACE) defined as cardiac death or nonfatal myocardial infarction (MI). RESULTS: Inclusion and exclusion criteria were satisfied by 300 patients with a mean follow-up of 26.7 +/- 8.8 months. The incidence of MACEs was 18.3% among diabetic patients, versus 9% in the non-diabetic population (p < 0.001). A multivariable Cox proportional hazard model demonstratedin dependent predictors for a MACE as abnormal MPI [HR: 9.30 (3.01 - 28.72), p < 0.001], post stress left ventricular ejection fraction (LVEF) <=30% [HR:2.72 (1.21 - 6.15), p = 0.016] and the patients diabetic status [HR:2.28 (1.04 - 5.01), p = 0.04]. The Kaplan Meier event free survival curve constructed for the different subgroups based on the patients' diabetic status and MPI findings demonstrated that diabetic patients with an abnormal MPI had the worst event free survival (log rank p value < 0.001). CONCLUSIONS: In an Indonesian population with suspected or known CAD abnormal adenosine stress MPI is an independent and potent predictor for adverse cardiovascular events and provides incremental prognostic value in cardiovascular risk stratification of patients with diabetes. PMID- 24155799 TI - Niacin Modulates Pro-inflammatory Cytokine Secretion. A Potential Mechanism Involved in its Anti-atherosclerotic Effect. AB - The pathogenesis of atherosclerosis includes the assignment of a critical role to cells of the monocyte/macrophage lineage and to pro-inflammatory cytokines. Niacin is known to improve lipid metabolism and to produce beneficial modification of cardiovascular risk factors. The aim of this work was to investigate if Niacin is able to modulate pro-inflammatory cytokine production in macrophages in a murine model of atherosclerosis. For this purpose C57Bl/6J mice fed with atherogenic diet (AGD) or with conventional chow diet were used. The AGD group showed an increase in body weight and in total plasma cholesterol, with no differences in triglyceride or HDL levels. Lesions in arterial walls were observed. The characterization of Niacin receptor showed an increase in the receptor number of macrophages from the AGD group. Macrophages from control and AGD animals treated in vitro with an inflammatory stimulus showed elevated levels of IL-6, IL-1 and TNF-alpha, that were even higher in macrophages from AGD mice. Niacin was able to decrease the production of pro-inflammatory cytokines in stimulated macrophages. Similar effect of Niacin was observed in an in vivo model of inflammation. These results show an attenuating inflammatory mechanism for this therapeutic agent and would point out its potential action in plaque stabilization and in the prevention of atherosclerosis progression. Furthermore, the present results provide the basis for future studies on the potential contribution of Niacin to anti-inflammatory therapies. PMID- 24155800 TI - Treatment of a Class II Division 2 Patient with Severe Skeletal Discrepancy by Using a Custom Made TPA Proclination Spring. AB - This case report describes the orthodontic treatment of a boy, aged 15.3 years, with permanent dentition, mesofacial typology, affected with a severe sagittal skeletal Class II division 2 malocclusion, due to a mandibular retrusion. His chief compliant was the position of the maxillary incisors, displaced too palatally, and an impaired facial profile. Herbst and multi-bracket straightwire fixed appliances, together with a custom made modified transpalatal arch (i.e. TPA proclination spring), were used to correct the sagittal discrepancy and to improve the attractiveness of the impaired facial profile. PMID- 24155801 TI - Fractures of the clavicle: an overview. AB - Fractures of the clavicle are a common injury and most often occur in younger individuals. For the most part, they have been historically treated conservatively with acceptable results. However, over recent years, more and more research is showing that operative treatment may decrease the rates of fracture complications and increase functional outcomes. This article first describes the classification of clavicle fractures and then reviews the literature over the past decades to form a conclusion regarding the appropriate management. A thorough literature review was performed on assessment of fractures of the clavicle, their classification and the outcomes following conservative treatment. Further literature was gathered regarding the surgical treatment of these fractures, including the methods of fixation and the surgical approaches used. Both conservative and surgical treatments were then compared and contrasted. The majority of recent data suggests that operative treatment may be more appropriate as it improves functional outcome and reduces the risk of complications such as non-union. This is particularly evident in mid shaft fractures, although more high grade evidence is needed to fully recommend this, especially regarding certain fractures of the medial and lateral clavicle. PMID- 24155802 TI - Low Level Laser Therapy (LLLT) for Neck Pain: A Systematic Review and Meta Regression. AB - PURPOSE: This systematic review update evaluated low level laser therapy (LLLT) for adults with neck pain. METHODS: Computerized searches (root up to Feb 2012) included pain, function/disability, quality of life (QoL) and global perceived effect (GPE). GRADE, effect-sizes, heterogeneity and meta-regression were assessed. RESULTS: Of 17 trials, 10 demonstrated high risk of bias. For chronic neck pain, there was moderate quality evidence (2 trials, 109 participants) supporting LLLT over placebo to improve pain/disability/QoL/GPE up to intermediate-term (IT). For acute radiculopathy, cervical osteoarthritis or acute neck pain, low quality evidence suggested LLLT improves ST pain/function/QoL over a placebo. For chronic myofascial neck pain (5 trials, 188 participants), evidence was conflicting; a meta-regression of heterogeneous trials suggests super-pulsed LLLT increases the chance of a successful pain outcome. CONCLUSIONS: We found diverse evidence using LLLT for neck pain. LLLT may be beneficial for chronic neck pain/function/QoL. Larger long-term dosage trials are needed. PMID- 24155803 TI - What is the Experience of Receiving Health Care for Neck Pain? AB - This study used a descriptive phenomenological approach to describe the experience of finding and receiving health services for neck pain. Nineteen participants (18 females, 1 male) with neck pain (>3 months) were interviewed using a semi-structured questionnaire guide. Interviews were recorded, transcribed and coded. Two overarching themes described the experience: complexity in finding effective health care; and the need for informative, personalized, respectful communication. Complexity in finding effective health care was attributed to the variable approach and effectiveness of different health professionals, the need to experiment with care to find what works, the need to differentiate temporary versus permanent treatment effects, concerns about treatment side effects and the sense that financial factors influence personal treatment choices and provider behaviours. The need for informative, personalized, respectful communications was broken down into the following subthemes: the importance of being listened to, seen and believed; the need for useful information; and a desire to have outcomes formally tracked as a means of individualizing treatment. Overall, patients struggled to navigate the variable health services and providers that were available and that provided variable outcomes. They often did so through a trial and error approach. As such, patients remain open to unproven, even controversial treatment options. Research evidence was not a key ingredient in patient decision-making about accessing health services. The environmental, personal, health behavior factors interacted to contribute to health service utilization and would increase the burden of these for both the individual and society at large. The effectiveness of neck pain interventions is dependent on complex interactions between the context, individual, and health care provider, therefore, physiological responses cannot be considered as being distinct from these determinants. PMID- 24155804 TI - An ICON Overview on Physical Modalities for Neck Pain and Associated Disorders. AB - INTRODUCTION: Neck pain is common, can be disabling and is costly to society. Physical modalities are often included in neck rehabilitation programs. Interventions may include thermal, electrotherapy, ultrasound, mechanical traction, laser and acupuncture. Definitive knowledge regarding optimal modalities and dosage for neck pain management is limited. PURPOSE: To systematically review existing literature to establish the evidence-base for recommendations on physical modalities for acute to chronic neck pain. METHODS: A comprehensive computerized and manual search strategy from January 2000 to July 2012, systematic review methodological quality assessment using AMSTAR, qualitative assessment using a GRADE approach and recommendation presentation was included. Systematic or meta-analyses of studies evaluating physical modalities were eligible. Independent assessment by at least two review team members was conducted. Data extraction was performed by one reviewer and checked by a second. Disagreements were resolved by consensus. RESULTS: Of 103 reviews eligible, 20 were included and 83 were excluded. Short term pain relief - Moderate evidence of benefit: acupuncture, intermittent traction and laser were shown to be better than placebo for chronic neck pain. Moderate evidence of no benefit: pulsed ultrasound, infrared light or continuous traction was no better than placebo for acute whiplash associated disorder, chronic myofascial neck pain or subacute to chronic neck pain. There was no added benefit when hot packs were combined with mobilization, manipulation or electrical muscle stimulation for chronic neck pain, function or patient satisfaction at six month follow-up. CONCLUSIONS: The current state of the evidence favours acupuncture, laser and intermittent traction for chronic neck pain. Some electrotherapies show little benefit for chronic neck pain. Consistent dosage, improved design and long term follow-up continue to be the recommendations for future research. PMID- 24155805 TI - Pharmacological Interventions Including Medical Injections for Neck Pain: An Overview as Part of the ICON Project. AB - OBJECTIVES: To conduct an overview (review-of-reviews) on pharmacological interventions for neck pain. SEARCH STRATEGY: Computerized databases and grey literature were searched from 2006 to 2012. SELECTION CRITERIA: Systematic reviews of randomized controlled trials (RCT) in adults with acute to chronic neck pain reporting effects of pharmacological interventions including injections on pain, function/disability, global perceived effect, quality of life and patient satisfaction. DATA COLLECTION & ANALYSIS: Two independent authors selected articles, assessed risk of bias and extracted data The GRADE tool was used to evaluate the body of evidence and an external panel provided critical review. MAIN RESULTS: We found 26 reviews reporting on 47 RCTs. Most pharmacological interventions had low to very low quality methodologic evidence with three exceptions. For chronic neck pain, there was evidence of: a small immediate benefit for eperison hydrochloride (moderate GRADE, 1 trial, 157 participants);no short-term pain relieving benefit for botulinum toxin-A compared to saline (strong GRADE; 5 trial meta-analysis, 258 participants) nor for subacute/chronic whiplash (moderate GRADE; 4 trial meta-analysis, 183 participants) including reduced pain, disability or global perceived effect; andno long-term benefit for medial branch block of facet joints with steroids (moderate GRADE; 1 trial, 120 participants) over placebo to reduce pain or disability; REVIEWERS' CONCLUSIONS: While in general there is a lack of evidence for most pharmacological interventions, current evidence is against botulinum toxin-A for chronic neck pain or subacute/chronic whiplash; against medial branch block with steroids for chronic facet joint pain; but in favour of the muscle relaxant eperison hydrochloride for chronic neck pain. PMID- 24155806 TI - Physician-delivered injection therapies for mechanical neck disorders: a systematic review update (non-oral, non-intravenous pharmacological interventions for neck pain). AB - BACKGROUND: Controversy persists regarding medicinal injections for mechanical neck disorders (MNDs). OBJECTIVES: To determine the effectiveness of physician delivered injections on pain, function/disability, quality of life, global perceived effect and patient satisfaction for adults with MNDs. SEARCH METHODS: We updated our previous searches of CENTRAL, MEDLINE and EMBASE from December 2006 through to March 2012. SELECTION CRITERIA: We included randomized controlled trials of adults with neck disorders treated by physician-delivered injection therapies. DATA COLLECTION AND ANALYSIS: Two authors independently selected articles, abstracted data and assessed methodological quality. When clinical heterogeneity was absent, we combined studies using random-effects models. RESULTS: We included 12 trials (667 participants). No high or moderate quality studies were found with evidence of benefit over control. Moderate quality evidence suggests little or no difference in pain or function/disability between nerve block injection of steroid and bupivacaine vs bupivacaine alone at short, intermediate and long-term for chronic neck pain. We found limited very low quality evidence of an effect on pain with intramuscular lidocaine vs control for chronic myofascial neck pain. Two low quality studies showed an effect on pain with anaesthetic nerve block vs saline immediately post treatment and in the short-term. All other studies were of low or very low quality with no evidence of benefit over controls. AUTHORS' CONCLUSIONS: Current evidence does not confirm the effectiveness of IM-lidocaine injection for chronic mechanical neck pain nor anaesthetic nerve block for cervicogenic headache. There is moderate evidence of no benefit for steroid blocks vs controls for mechanical neck pain. PMID- 24155807 TI - Knowledge Translation Tools are Emerging to Move Neck Pain Research into Practice. AB - Development or synthesis of the best clinical research is in itself insufficient to change practice. Knowledge translation (KT) is an emerging field focused on moving knowledge into practice, which is a non-linear, dynamic process that involves knowledge synthesis, transfer, adoption, implementation, and sustained use. Successful implementation requires using KT strategies based on theory, evidence, and best practice, including tools and processes that engage knowledge developers and knowledge users. Tools can provide instrumental help in implementing evidence. A variety of theoretical frameworks underlie KT and provide guidance on how tools should be developed or implemented. A taxonomy that outlines different purposes for engaging in KT and target audiences can also be useful in developing or implementing tools. Theoretical frameworks that underlie KT typically take different perspectives on KT with differential focus on the characteristics of the knowledge, knowledge users, context/environment, or the cognitive and social processes that are involved in change. Knowledge users include consumers, clinicians, and policymakers. A variety of KT tools have supporting evidence, including: clinical practice guidelines, patient decision aids, and evidence summaries or toolkits. Exemplars are provided of two KT tools to implement best practice in management of neck pain-a clinician implementation guide (toolkit) and a patient decision aid. KT frameworks, taxonomies, clinical expertise, and evidence must be integrated to develop clinical tools that implement best evidence in the management of neck pain. PMID- 24155808 TI - Should a Patients BMI Status be Used to Restrict Access to Total Hip and Knee Arthroplasty? Functional Outcomes of Arthroplasty Relative to BMI - Single Centre Retrospective Review. AB - We reviewed the experience of a dedicated orthopaedic elective service to determine whether we could establish a BMI group where arthroplasty was no longer effective as assessed by the patient's functional outcome. This was a prospective observational study with retrospective analysis of data collected on 1439 total hip arthroplasty, 934 total knee arthroplasty and 326 unicompartment knee arthroplasty patients. Functional scores (WOMAC, Oxford hip and knee scores and HAAS) were obtained preoperatively and at 12 months post op. Patients had their BMI recorded at the preoperative assessment and were divided into BMI groups (BMI<25, BMI 25-30, BMI 30-35 and BMI > 35). Patients with a BMI of <= 30 had significantly better functional scores at 12 months post op compared to those with a BMI of > 35. The absolute gain in functional scores from pre op to 12 months post op did not differ significantly between BMI groups, the only significant difference we found for absolute gain showed patients with a BMI of > 35 have a greater increase in HAAS scores following total hip arthroplasty compared to patients with a BMI of 30 or less (p = 0.0435). Our patients with higher BMI's had worse preoperative and post operative functional scores but their benefit from surgery measured by the change in functional scores showed no difference compared to patients with lower BMI. We could find no reason on the basis of the 12-month results to limit surgery to obese patients because of an expected poorer functional outcome. PMID- 24155809 TI - Pharmacy Practice suffered a plagiarism case. PMID- 24155810 TI - How can pharmacist remuneration systems in Europe contribute to generic medicine dispensing? AB - Generic medicines can generate larger savings to health care budgets when their use is supported by incentives on both the supply-side and the demand-side. Pharmacists''remuneration is one factor influencing the dispensing of generic medicines. OBJECTIVE: The aim of this article is to provide an overview of different pharmacist remuneration systems for generic medicines in Europe, with a view to exploring how pharmacist remuneration systems can contribute to generic medicine dispensing. METHODS: Data were obtained from a literature review, a Master thesis in Pharmaceutical Care at the Catholic University of Leuven and a mailing sent to all members of the Pharmaceutical Group of the European Union with a request for information about the local remuneration systems of community pharmacists and the possible existence of reports on discounting practices. RESULTS: Pharmacists remuneration in most European countries consists of the combination of a fixed fee per item and a certain percentage of the acquisition cost or the delivery price of the medicines. This percentage component can be fixed, regressive or capped for very high-cost medicines and acts as a disincentive for dispensing generic medicines. Discounting for generic medicines is common practice in several European countries but information on this practice tends to be confidential. Nevertheless, data for Belgium, France, the Netherlands and United Kingdom indicated that discounting percentages varied from 10% to 70% of the wholesale selling price. CONCLUSIONS: Pharmacists can play an important role in the development of a generic medicines market. Pharmacists should not be financially penalized for dispensing generic medicines. Therefore, their remuneration should move towards a fee-for-performance remuneration instead of a price-dependent reimbursement which is currently used in many European countries. Such a fee-for-performance remuneration system provides a stimulus for generic medicines dispensing as pharmacists are not penalized for dispensing them but also needs to account for the loss of income to pharmacists from prohibiting discounting practices. PMID- 24155811 TI - Analysis of potential interactions between warfarin and prescriptions in Estonian outpatients aged 50 years or more. AB - In Estonia, warfarin is widely prescribed by general practitioners to prevent and treat thromboembolic diseases. To date, there has been no systematic analysis of the potential risk of warfarin interactions with other drugs in the outpatient population. OBJECTIVE: The aim of the study was to analyze the incidence of potential interactions in prescription schemes in Estonia in a cohort of outpatients receiving warfarin treatment. METHODS: The retrospective study population included 203,646 outpatients aged 50 years or older of whom 7,175 received warfarin therapy. Patients who had used at least one prescription drug for a minimum period of 7 days concomitantly with warfarin were analyzed. Potential drug interactions were analyzed using Epocrates online, Stockley's Drug Interactions and domestic drug interaction databases. RESULTS: The average number of drugs used concomitantly with warfarin was 4.8 (SD=1.9) (males: 4.7 SD=2.0, females: 4.9 SD=2.0). No potential interactions in treatment regimens were found in 38% of patients, one potential interaction was observed in 29% and two or more potential interactions were observed in 33% of patients. The mean number of all potential interactions was 1.2 per patient and about the same in men and women. Potential interactions were associated with the number of drugs. Warfarin-related interactions were detected in 57% of patients, and the number of interactions related to warfarin per patient varied from 1 to 5. Most frequent were use of warfarin with NSAIDs (14%), followed by simvastatin (9%) and amiodarone (7%). CONCLUSIONS: This study shows that 57% of outpatients in Estonia receiving warfarin have drugs potentially interacting with warfarin in their treatment schemes. Most interactions (14%) with warfarin are associated with the prescription of NSAIDs. PMID- 24155812 TI - Societal perspectives on community pharmacy services in West Bank - Palestine. AB - BACKGROUND: Understanding the public's view of professional competency is extremely important; however little has been reported on the public's perception of community pharmacists in Palestine. OBJECTIVE: To determine the perception of Palestinian consumers of the community pharmacist and the services they offer. METHODS: This project used the survey methodology administered by structured interviews to consumers who attended the 39 randomly selected pharmacies, in six main cities in Palestine. The questionnaire had range of structured questions covering: Consumers' patronage patterns, consumers' interaction with community pharmacists, consumers' views on how the pharmacist dealt with personal health issues, procedure with regard to handling private consultations. RESULTS: Of 1,017 consumers approached, 790 consumers completed the questionnaire (77.7 %). Proximity to home and presence of knowledgeable pharmacist were the main reasons for patients to visit the same pharmacy. Physicians were identified as the preferred source of advice by 57.2% and pharmacists by 23.8%. Only 17% of respondents considered pharmacists as health professionals who know a lot about drugs and are concerned about and committed to caring for the public. In addition, 49% indicated that pharmacists spoke more quietly cross the counter during counseling and almost one third reported that the pharmacist used a private area within the pharmacy. The majority of respondents would be happy to receive different extended services in the community pharmacy like blood pressure monitoring. CONCLUSIONS: Palestinian consumers have a positive overall perception of community pharmacists and the services they offer. Awareness should be created amongst the public about the role of pharmacist and the added value they can provide as health care professional. There is a need to consider privacy when giving patient counseling to increase user satisfaction. PMID- 24155813 TI - A collaborative cardiologist-pharmacist care model to improve hypertension management in patients with or at high risk for cardiovascular disease. AB - Physician led collaborative drug therapy management utilizing clinical pharmacists to aid in the medication management of patients with hypertension has been shown to improve blood pressure control. With recommendations for lower blood pressures in patients with coronary artery disease, a cardiologist pharmacist collaborative care model may be a novel way to achieve these more rigorous goals of therapy. OBJECTIVE: The purpose of this project was to evaluate this type of care model in a high cardiac risk patient population. METHODS: A retrospective cohort study determined the ability of a cardiologist-pharmacist care model (n=59) to lower blood pressure and achieve blood pressure goals (< 130/80 mmHg) in patients with or at high risk for coronary artery disease compared to usual cardiologist care (n=58) in the same clinical setting. RESULTS: The cardiologist-pharmacist care model showed a higher percentage of patients obtaining their goal blood pressure compared to cardiologist care alone, 49.2% versus 31.0% respectively, p=0.0456. Greater reductions in systolic blood pressure (-22 mmHg versus -12 mmHg, p=0.0077) and pulse pressure (-15 mmHg versus -7 mmHg, p=0.0153) were noted in the cardiologist-pharmacist care model. No differences in diastolic blood pressure were found. There was a shorter duration of clinic follow-up (7.0 versus 13.2 months, p=0.0013) but a higher frequency of clinic visits (10.7 versus 3.45, p<0.0001) in the cardiologist-pharmacist care model compared to usual care. The number of antihypertensive agents used did not change over the time period evaluated. CONCLUSIONS: This study suggests a team based approach to hypertensive care using a collaborative cardiologist-pharmacist care model improves blood pressure from baseline in a high cardiac risk patient population and was more likely to obtain more stringent blood pressure goals than usual care. PMID- 24155814 TI - The conflicts between professional and non professional work of community pharmacists in Indonesia. AB - OBJECTIVE: The study aimed to determine the type of professional and non professional work of community pharmacists in Surabaya Indonesia and find the difference between time spent for performing both works in actual (current) situation and ideal (expected) situation. METHODS: A cross sectional study was conducted by combining purposive sampling for selecting the community pharmacists. Afterwards, the data was analyzed using SPSS v16 to provide the descriptive results and completed with Wilcoxon signed rank test to find the difference between time spent in actual and ideal situation. The sample size was 100 respondents of 300 pharmacists who have been practicing in Surabaya. RESULTS: From 100 participants just 30 participants gave response to the questionnaire, 67% was female who 20-30 years old at most (53%) with working experience as pharmacist less than 3 years (60%) and working 30 hours per week (60%) in pharmacy. Significant difference between time spent in actual and ideal situation was found. DISCUSSION: The time spent for performing professional and non professional work in ideal situation was significantly higher than in actual situation except for preparing medicines activity. This finding illustrated that the respondents did not have adequate time to provide ideal services in their daily practice. Therefore, they expected to improve their time and level of work in more professional manner. Surprisingly, they were also willing to provide more time and higher level of work in some non professional work. CONCLUSIONS: The Indonesian community pharmacists spent little time on both professional work and non-professional work in their daily activities. This indicated that the pharmacists did not focus on delivering quality professional work. PMID- 24155815 TI - Days lost due to disability of diclofenac-induced adverse drug reactions. AB - Disability Adjusted Life Years (DALY) is a widely used measure to quantify the burden of diseases or illness. DALYs for a disease is calculated as the sum of the Years of Life Lost (YLL) due to premature mortality in the population and the equivalent healthy Years Lost due to Disability (YLD). The only difference from the YLD and Days Lost due to Disability (DLD) calculation is that instead of considering the duration of Adverse Drug Reaction (ADR) in years, it is calculated in days. OBJECTIVE: DLD was measured for diclofenac tablets to prepare the ADR profile. METHODS: The study was done on the patients (18-65 years old) attending the community pharmacy at Kasaragod district, South India, with prescription of diclofenac tablets. Patients reported ADRs on their next visit to the pharmacy or they had called to the provided phone number and reported it. Disability Weight (DW) was calculated in an analogue scale from 0-1. Zero represent complete health and 1 represent death or equivalent condition. DW was multiplied with occurrence and duration of ADRs in days. RESULTS: About 943 patients received diclofenac tablets in 1000 prescriptions were successfully followed up for possible, probable and definite ADRs. A total of 561 reactions reported in 2010 for diclofenac tablet in the study population. There were 34 different types of ADRs under 12 physiological systems/organs. Most common reactions were on gastrointestinal (GI) system (48%), followed by skin (14%), Central Nervous System (10%), renal (7%), and cardiovascular (7%). Abdominal pain, cramps or flatulence was the highest occurring GI ADR (107), followed by 43 rashes, 42 nausea/vomiting, 37 indigestion, 34 peptic ulcers, 31 edema etc. DLD for peptic ulcer was considerably high (0.078) per 1000 of the study population on diclofenac. The most damaging ADR were peptic ulcer with or without perforation, followed by rash 0.036 DLD and edema 0.027 DLD. There was considerable DLD by acute renal failure (0.012) Steven-Johnson syndrome (0.013) even though few cases were reported. CONCLUSIONS: Diclofenac has a complex adverse drug profile. Around 34 types of reactions were reported. Diclofenac was widely prescribed because of the experiential belief of comparative safety with other NSAIDs. The study shows the importance of pharmacovigilance even on the most prescribed medicine. Most disabling ADR for the study population was peptic ulcer with or without perforation. YLD or DLD are useful measures of calculating disability caused by ADRs. Future studies could focus on improving the usefulness & precision of DLD. PMID- 24155816 TI - Evaluation of an intensive insulin transition protocol in the intensive care unit setting: a before and after study. AB - The benefits of controlling blood glucose levels in intensive care units (ICUs) are well documented. OBJECTIVE: This study determined the effectiveness and safety of a standardized transition order set for converting a continuous insulin infusion to a subcutaneous insulin regimen in non-cardiovascular surgery ICUs patient population. METHODS: A retrospective study was conducted. Patients presenting with diabetic ketoacidosis or hyperosmolar hyperglycemic syndrome were excluded. One hundred patients were included prior to and 100 patients were included after initiating the transition order set. Blood glucose control was reviewed for up to 72 hours following the transition. RESULTS: A total of 115 patients were included in data analysis: 85 prior to and 30 after transition protocol. All patients transitioned using the protocol were transitioned to basal insulin, compared to only 40% of the prior to protocol group. Patients transitioned correctly per the transition order set, "per protocol," had 54% of blood sugars within the desired range, no increase in hypoglycemic events, and on average 5.56 hyperglycemic events (blood glucose >180 mg/dL) per person during the 72 hours compared to 6.68 and 9.00 for the prior to protocol group and the "off protocol" group (transitioned different than the protocol recommended), respectively (p= 0.05). There were significant differences in blood sugar control at 48 and 72 hours between the "per protocol" and "off protocol" groups (p= 0.01) and a 40% reduction in sliding scale or correctional insulin coverage. CONCLUSIONS: The addition of basal insulin to transition regimens resulted in fewer hyperglycemic events with no increase in hypoglycemic events. Patients transitioned "per protocol" had better glucose control demonstrated by: less hyperglycemic events, lower mean blood glucose levels at 48 and 72 hours, and lower need for correctional insulin. These findings showed benefits of glycemic control in the ICU by following a standardized transition protocol. PMID- 24155817 TI - Qualitative interviews of pharmacy interns: determining curricular preparedness for work life. AB - One of the key features affecting the transition from university to paid employment is the graduate's perception of their capability to satisfactorily perform the work of a graduate. In some professions such as in nursing, the concept of "transition shock" is referred to. There is a need to understand how pharmacy students perceive the transition to their first job as intern pharmacists and identify potential curriculum gaps in their pharmacy studies. To date, little evidence around whether university programs are effective in equipping pharmacy graduates in transitioning to the world of work has been published. OBJECTIVE: To explore from the perspective of new pharmacy professionals, graduated from one Australian university areas that need to be addressed in pharmacy programs to prepare graduates for the transition to full time work as interns in pharmacy. METHODS: Thematic analysis of interviews with interns. RESULTS: Subthemes were identified within the responses- relationships within the workplace and graduates needing to interest themselves in other people, adjusting to work hours and the differences between university assessments and performing in a workplace. Suggestions were made by graduates that the placement period within the pharmacy program be increased. CONCLUSIONS: Pharmacy graduates appear prepared for the world of pharmacy work. The concept of "transition shock" or "transition stress" described for graduates of other health professions commencing work was not apparent. PMID- 24155818 TI - Attitudes of consumers and healthcare professionals towards the patient package inserts - a study in Palestine. AB - Reading the patient package inserts (PPIs) is a key source of information about medications for patients. They should be clear and understandable to the general population. OBJECTIVE: The aims of this study were to obtain base-line data on the extent of reading PPIs by consumers and possible factors that might affect this; to explore the attitude of the Palestinian public and healthcare professionals towards the patient package inserts (PPIs); and to review a random sample of PPIs for the availability of different information. METHODS: The first part of the study was a cross-sectional self-administered questionnaire. The questionnaire for consumers included 15 items. The questionnaire for healthcare professionals included 10 items and it was very similar to that of consumers with some modifications. In the second part, a random sample of PPIs was reviewed. In our community pharmacies, where medications are arranged according to their producing company, a researcher was asked to choose randomly 10-15 medications for every company to check for the availability of pharmacological, pharmaceutical and clinical information. RESULTS: A total of 304 healthcare professionals out of 320 (95.0%) and 223 consumers out of 240 (92.9%) accepted to answer the survey. Forty five percent consumers reported that they always read the PPIs, and 29.3% said that they read the PPIs most of the times. Increased rate of reading the leaflet was found among females (P = 0.047). The preferred language for the PPIs was Arabic for most of the consumers (89.6%) while it was English for most of the healthcare professionals (80.8%). 35.9% of the consumers and 43.6% of the healthcare professionals found the font size suitable. 42.3% of the consumers and 25.5% of the healthcare professionals said that they found the information in the PPIs useful and enough. The PPIs of 135 randomly sampled medications were reviewed. Many important sections were not found in the PPIs' sample. CONCLUSIONS: A high percentage of consumers read the PPIs, but still this needs to be improved. People would appreciate a more detailed and clear PPI. Pharmacists should advocate reading the PPIs but they need to provide consumers with detailed counseling to compensate for the missing information in some of the PPIs. Authorities and manufacturers should implement appropriate measures to regulate the quality and quantity of information in the PPIs. PMID- 24155819 TI - Efficacy of class III antiarrhythmics and magnesium combination therapy for atrial fibrillation. AB - Atrial fibrillation is a common cardiac arrhythmia, and has been a significant financial burden. Class III antiarrhythmics such as dofetilide, ibutilide, and amiodarone are indicated for rhythm control. Magnesium may possess intrinsic antiarrhythmic properties, and may potentially increase the efficacy of class III antiarrhythmics when used concomitantly. OBJECTIVE: The purpose of this article is to review the literature on the efficacy of magnesium in addition to Class III antiarrhythmics, specifically amidarone, ibutilide, and dofetilide for the cardioversion of atrial fibrillation. METHODS: Databases Pubmed and CINAHL are utilized along with the search terms amiodarone, dofetilide, ibutlide, magnesium, atrial fibrillation, conversion, rhythm control, and cardioversion. RESULTS: One study on dofetilide and 5 studies on ibutilide were identified. No studies were found on amiodarone. Patients with atrial fibrillation who received dofetilide and magnesium had higher rates of successful cardioversion as compared to those who only received dofetilide. Conversion rates were similar between the 2 treatment groups for patients with atrial flutter. As for ibutilide, 4 studies have shown that the addition of magnesium significantly increases conversion rates for patients with atrial fibrillation or typical atrial flutter. Conversion rates were similar for patients with atypical atrial flutter. One study showed that addition of magnesium did not improve efficacy of ibutilide. Higher doses of magnesium (4 g) were associated with improved outcomes. Adverse effects of magnesium were mild and included flushing, tingling, and dizziness. Patients who received magnesium had shorter corrected QT intervals and smaller increase in corrected QT interval from baseline. Compare to previous studies, studies included in this review had higher conversion rates for dofetilide and ibutilide as well as dofetilide and magnesium or ibutilide and magnesium combination therapies. However, only 2 ibutilide studies and 1 dofetilide study reported baseline characteristics such as left atrial size, history of heart failure, and duration of atrial fibrillation, which are significant predictors of successful cardioversion. Therefore, differences in baseline demographics may have influenced the results. CONCLUSIONS: Magnesium may be used as adjunct for dofetilide and ibutilide due to potential improved efficacy and minimal toxicity. Dose ranging studies should be conducted in the future to establish the optimal dose and duration of therapy as well as the optimal serum magnesium concentration in order for the clinician to manage and monitor patients appropriately. PMID- 24155820 TI - Use of a generic protocol in documentation of prescription errors in Estonia, Norway and Sweden. AB - Pharmacists have an important role in detecting, preventing, and solving prescription problems, which if left unresolved, may pose a risk of harming the patient. OBJECTIVE: The objectives of this study were to evaluate the feasibility of a generic study instrument for documentation of prescription problems requiring contact with prescriber before dispensing. The study was organized: 1) by countries: Estonia, Norway and Sweden; 2) by type of prescriptions: handwritten prescriptions, printouts of prescriptions in the electronic medical record and electronically transmitted prescriptions to pharmacies; and 3) by recording method - self-completion by pharmacists and independent observers. METHODS: Observational study with independent observers at community pharmacies in Estonia (n=4) and Sweden (n=7) and self-completed protocols in Norway (n=9). RESULTS: Pharmacists''in Estonia contacted the prescriber for 1.47% of the prescriptions, about 3 times as often as in Norway (0.45%) and Sweden (0.38%). Handwritten prescriptions dominated among the problem prescriptions in Estonia (73.2%), printouts of prescriptions in the electronic medical record (89.1%) in Norway and electronically transmitted prescriptions to pharmacies (55.9%) in Sweden. More administrative errors were identified on handwritten prescriptions and printouts of prescriptions in the electronic medical record in Estonia and in Norway compared with electronically transmitted prescriptions to pharmacies in Sweden (p<0.05 for prescription types and p<0.01 for countries). However, clinically important errors and delivery problems appeared equally often on the different types of prescriptions. In all three countries, only few cases of drug interactions and adverse drug reactions were identified. CONCLUSIONS: Despite the different patterns of prescription problems in three countries, the instrument was feasible and can be regarded appropriate to document and classify prescription problems necessitating contact with prescriber before dispensing, irrespective of the type of prescription or recording method. PMID- 24155821 TI - Student pharmacist initiated medication reconciliation in the outpatient setting. AB - The Joint Commission continues to emphasize the importance of medication reconciliation in all practice settings. Pharmacists and student pharmacists are uniquely trained in this aspect of patient care, and can assist with keeping accurate and complete medication records through patient interview in the outpatient setting. OBJECTIVE: The objective of this study was to quantify and describe medication reconciliation efforts by student pharmacists in an outpatient family medicine center. METHODS: A retrospective review was conducted of all standard medication reconciliation forms completed by student pharmacists during patient interviews from April 2010 to July 2010. The number of reviews conducted was recorded, along with the frequency of each type of discrepancy. A discrepancy was defined as any lack of agreement between the medication list in the electronic health record (EHR) and the patient-reported regimen and included any differences in dose or frequency of a medication, duplication of the same medication, medication no longer taken or omission of any medication. RESULTS: A total of 213 standard medication forms from the 4 month period were reviewed. A total of 555 discrepancies were found, including medications no longer taken, prescription medications that needed to be added to the EHR, over-the counter(OTC) and herbal medications that needed to be added to the EHR, medications taken differently than recorded in the EHR, and medication allergies which needed to be updated. An average of 2.6 discrepancies was found per patient interviewed. CONCLUSIONS: Student pharmacist-initiated medication reconciliation in an outpatient family medicine center resulted in the resolution of numerous discrepancies in the medication lists of individual patients. Pharmacists and student pharmacists are uniquely trained in medication history taking and play a vital role in medication reconciliation in the outpatient setting. PMID- 24155822 TI - Potentially inappropriate prescribing in institutionalised older patients in Spain: the STOPP-START criteria compared with the Beers criteria. AB - OBJECTIVE: The aims of this study were to identify potentially inappropriate prescribing using the Beers and STOPP criteria. The START criteria were applied to detect prescription omission in the geriatric population. We compared the utility of these criteria in institutionalised older people. METHODS: Descriptive study reviewing the medication and clinical records of 81 residents (aged 65 years and more) by pharmacists in a nursing home in the Lleida region (Spain). RESULTS: The mean patients''age was 84 (SD=8) years, with an average of 5 drugs per resident (total prescriptions: 416 medicines). The Beers criteria identified potentially inappropriate medication use in 25% of patients and 48% of patients used at least 1 inappropriate medication according to STOPP criteria. The most frequent potentially inappropriate medications for both criteria were long-acting benzodiazepines and NSAIDs. START detected 58 potential prescribing omissions in 44% of patients. Calcium-vitamin D supplementation in osteoporosis was the most frequent rule (15%), but omissions corresponding to the cardiovascular system implied 23% of patients. CONCLUSIONS: The STOPP-START criteria reveal that potentially inappropriate prescribing (PIP) is a highly prevalent problem among Spanish nursing home residents, and a statistically significant positive correlation was found between the number of medicines prescribed and the number of PIP detected in this study. The STOPP criteria detect a larger number of PI medications in this geriatric population than the Beers criteria. The prescribing omissions detected by the START criteria are relevant and require intervention. Pharmacists' review of medications may help identify potentially inappropriate prescribing and, through an interdisciplinary approach, working with physicians may improve prescribing practices among geriatric residents of nursing homes. PMID- 24155823 TI - Pharmacy residents and students as an adjunct to current smoking cessation education. AB - OBJECTIVE: The purpose of this study was to evaluate the impact of individualized tobacco cessation counseling provided by pharmacy residents and students to patients in the inpatient setting at an academic medical center. METHODS: Documented tobacco users were evaluated for study inclusion. The intervention group received counseling specific to their readiness to quit. After discharge, patients in the intervention group received weekly phone calls for additional counseling and data collection. One month after discharge, the standard therapy group received one phone call for data collection. RESULTS: No significant differences were found between groups for demographic variables or number of years smoking. At baseline, the intervention group reported significantly fewer quit attempts and more packs per day than the control group. The odds ratio (OR) for the primary outcome, abstinence, was 1.68 [95%CI=0.29:9.748] favoring the intervention group. The OR for patients using outpatient pharmacotherapy was 3.20 [95%CI=0.484:21.167] for the intervention group compared to the control group. The percentage of patients using outpatient treatment programs was 5.26% in the control group vs. 0% in the intervention group. CONCLUSIONS: Results showed a trend toward significance for abstinence and increased use of outpatient pharmacotherapy; however, our sample size and study period limit conclusions that may be drawn. Further study is warranted for definitive results. PMID- 24155824 TI - Educating patients about warfarin therapy using information technology: A survey on healthcare professionals' perspectives. AB - OBJECTIVE: To explore healthcare professionals' views about the benefits and challenges of using information technology (IT) resources for educating patients about their warfarin therapy. METHODS: A cross-sectional survey of both community and hospital-based healthcare professionals (e.g., doctors, pharmacists and nurses) involved using a purpose-designed questionnaire. The questionnaires were distributed using a multi-modal approach to maximise response rates. RESULTS: Of the total 300 questionnaires distributed, 109 completed surveys were received (43.3% response rate). Over half (53.2%) of the healthcare participants were aged between 40-59 years, the majority (59.5%) of whom were female. Fifty nine (54.1%) participants reported having had no access to warfarin-specific IT-based patient education resources, and a further 19 (38.0%) of the participants who had IT access reported that they never used such resources. According to the healthcare participants, the main challenges associated with educating their patients about warfarin therapy included: patient-related factors, such as older age, language barriers, cognitive impairments and/or ethnic backgrounds or healthcare professional factors, such as time constraints. The healthcare professionals reported that there were several aspects about warfarin therapy which they found difficult to educate their patients about which is why they identified computers and interactive touch screen kiosks as preferred IT devices to deliver warfarin education resources in general practices, hospital-based clinics and community pharmacies. At the same time, the healthcare professionals also identified a number of facilitators (e.g., to reinforce warfarin education, to offer reliable and easily comprehensible information) and barriers (e.g., time and costs of using IT resources, difficulty in operating the resources) that could impact on the effective implementation of these devices in educating patients about their warfarin therapy. CONCLUSIONS: The findings of the study suggest that there is a need for improving healthcare professionals' use of, and access to IT-based warfarin education resources for patients. The study findings also suggest addressing the concerns raised by the healthcare professionals when implementing such IT resources successfully to help educate patients about their warfarin therapy. PMID- 24155825 TI - Impact of a pharmacist-directed educational program on the long-term knowledge and use of folic acid among college women: a 12-month follow-up study. AB - Few studies have examined the impact of educational interventions on participants' long-term knowledge and use of folic acid for prevention of neural tube defects (NTD). OBJECTIVE: The objective of this pilot study was to evaluate changes in knowledge and behaviors in a sample of college women one year after such a program. METHODS: Female students of a residential college campus voluntarily attended the event, which was advertised to the campus community as a women's health seminar. Participants completed a multiple-choice test assessing knowledge of folic acid and NTD and frequency of multivitamin use before and immediately after a 30-minute oral presentation. Following 3 reminder messages sent via email or mail, knowledge and multivitamin use were re-assessed 1-month and 12-months post-intervention. RESULTS: Thirty-two college women participated in the educational intervention; 27 (84%) completed the 12-month post-test. At 12 months, statistically significant increases in knowledge from baseline remained for questions pertaining to food high in folic acid (p=0.023); completion of spinal column (p=0.011); and 2 questions on NTD prevention (p=0.044). Increases in knowledge regarding recommended daily allowance of folic acid (p=0.817) and difficulty in receiving adequate folic acid from diet alone (p=0.617) were not statistically significant from baseline. Regular multivitamin use (>=4 times per week) was not statistically significantly increased from baseline (p=0.592). CONCLUSIONS: Although it was encouraging that the women retained much of the information learned during the program, it appears that the changes in multivitamin use seen at 1-month were not sustained at 12-months. Further study with larger groups of college women is recommended. PMID- 24155826 TI - Are Sudanese community pharmacists capable to prescribe and demonstrate asthma inhaler devices to patrons? A mystery patient study. AB - Although community pharmacists have become more involved in the care of asthma patients, several studies have assessed pharmacists''ability to illustrate appropriately inhalation technique of different asthma devices. Many studies addressed inappropriate use of asthma devices by patients and pharmacists, in addition to its clinical, humanistic and economic burden. OBJECTIVE: To evaluate community pharmacists' practical knowledge and skills of demonstrating proper inhalation technique of asthma inhaler devices available in Sudan. METHODS: THREE HUNDRED COMMUNITY PHARMACIES LOCATED AROUND THE THREE MAJOR HOSPITALS IN THE CAPITAL CITY (KHARTOUM) AND FOUR OTHER PROVINCES WERE APPROACHED, AND FOUR ASTHMA DEVICES WERE ASSESSED: Metered-dose inhaler (MDI) (n=105), MDI with Spacer (n=83), Turbuhaler (n=61), and Diskus (n=51). Investigator (a pharmacist) acted as a mystery patient. He selected one device and asked the serving pharmacist to demonstrate how to use the device. Investigator completed a checklist of 9 steps of inhaler device use immediately after leaving the pharmacy. Essential steps derived from published literature were pre-specified for each device. Five evaluation categories were accordingly formulated as follows: optimal technique, adequate technique, poor technique, totally unfamiliar with the device, and does not know. RESULTS: More than half of the pharmacists approached with metered dose inhaler did not know how to use optimal technique (ie all steps correct) all through. A third poorly demonstrated the technique, and only one pharmacist was categorized as being able to demonstrate an "optimal technique". The majority of pharmacists approached with spacing chamber and dry powder inhalers (Turbuhaler and Diskus) either did not know proper technique or were totally unfamiliar with the devices. CONCLUSIONS: The majority of community pharmacists, who were expected to educate asthma patients on their dispensed inhalers, lack the basic knowledge of proper use of commonly dispensed asthma inhaler devices. PMID- 24155827 TI - Community pharmacy-based medication therapy management services: financial impact for patients. AB - OBJECTIVE: To determine the direct financial impact for patients resulting from Medication Therapy Management (MTM) interventions made by community pharmacists. Secondary objectives include evaluating the patient and physician acceptance rates of the community pharmacists' recommended MTM interventions. METHODS: This was a retrospective observational study conducted at 20 Price Chopper and Hen House grocery store chain pharmacies in the Kansas City metro area from January 1, 2010 to December 31, 2010. Study patients were Medicare Part D beneficiaries eligible for MTM services. The primary outcome was the change in patient out-of pocket prescription medication expense as a result of MTM services. RESULTS: Of 128 patients included in this study, 68% experienced no out-of-pocket financial impact on their medication expenses as a result of MTM services. A total of 27% of the patients realized a cost-savings (USD440.50 per year, (SD=289.69)) while another 5% of patients saw a cost increase in out-of-pocket expense (USD255.66 per year, (SD=324.48)). The net financial impact for all 128 patients who participated in MTM services was an average savings of USD102.83 per patient per year (SD=269.18, p<0.0001). Pharmacists attempted a total of 732 recommendations; 391 (53%) were accepted by both the patient and their prescriber. A total of 341 (47%) recommendations were not accepted because of patient refusal (290, 85%) or prescriber refusal (51, 15%). CONCLUSIONS: Patient participation in MTM services reduces patient out-of-pocket medication expense. However, this savings is driven by only 32% of subjects who are experiencing a financial impact on out-of-pocket medication expense. Additionally, the majority of the pharmacists' recommended interventions (53%) were accepted by patients and prescribers. PMID- 24155828 TI - Disclosure and adverse effects of complementary and alternative medicine used by hospitalized patients in the North East of England. AB - OBJECTIVE: This study aimed to investigate the prevalence, disclosure and adverse effects of complementary and alternative medicine (CAM) use in hospitalised patients, and to explore the associations between patients' perceived side effects and relevant factors. METHODS: Patients who were admitted to a district general hospital and met the eligibility criteria were interviewed using a semi structured questionnaire. Their medications and pertinent details were verified from the medical notes. All quantitative and qualitative data were collated and analysed. A chi-squared test was performed to test the associations of the perceived CAM side-effects with the significance level determined at alpha=0.05. RESULTS: A total of 240 in-patients completed the study. They were mostly white British (98.8%). The prevalence of CAM use within two years was 74.6% and one month 37.9%. Only 19 of 91 patients (20.9%) using CAM within one month disclosed their current CAM applications. Nearly half of patients (45.8%) who used CAM within two years experienced various CAM side-effects that tended to resolve after discontinuation. Slightly more than half (57.6%) perceived CAM side-effects and their perceptions were significantly associated with gender (P=0.048) and consideration for future CAM use (P=0.033). Potential interactions between herbal remedies/dietary supplements and prescribed drugs, such as garlic with lisinopril or aspirin, were assessed in 82 patients (45.8%). CONCLUSIONS: Most in-patients used CAM and experienced some adverse effects. The disclosure of CAM use and its adverse outcomes should be encouraged by healthcare professionals. PMID- 24155829 TI - Evaluation of angiotensin II receptor blockers for drug formulary using objective scoring analytical tool. AB - Drug selection methods with scores have been developed and used worldwide for formulary purposes. These tools focus on the way in which the products are differentiated from each other within the same therapeutic class. Scoring Analytical Tool (SAT) is designed based on the same principle with score and is able to assist formulary committee members in evaluating drugs either to add or delete in a more structured, consistent and reproducible manner. OBJECTIVE: To develop an objective SAT to facilitate evaluation of drug selection for formulary listing purposes. METHODS: A cross-sectional survey was carried out. The proposed SAT was developed to evaluate the drugs according to pre-set criteria and sub criteria that were matched to the diseases concerned and scores were then assigned based on their relative importance. The main criteria under consideration were safety, quality, cost and efficacy. All these were converted to questionnaires format. Data and information were collected through self administered questionnaires that were distributed to medical doctors and specialists from the established public hospitals. A convenient sample of 167 doctors (specialists and non-specialists) were taken from various disciplines in the outpatient clinics such as Medical, Nephrology and Cardiology units who prescribed ARBs hypertensive drugs to patients. They were given a duration of 4 weeks to answer the questionnaires at their convenience. One way ANOVA, Kruskal Wallis and post hoc comparison tests were carried out at alpha level 0.05. RESULTS: Statistical analysis showed that the descending order of ARBs preference was Telmisartan or Irbesartan or Losartan, Valsartan or Candesartan, Olmesartan and lastly Eprosartan. The most cost saving ARBs for hypertension in public hospitals was Irbesartan. CONCLUSIONS: SAT is a tool which can be used to reduce the number of drugs and retained the most therapeutically appropriate drugs in the formulary, to determine most cost saving drugs and has the potential to complement the conventional method of drug selection as it is effective in aiding decision making process through the pre-established criteria and increasing scientific ground of decisions and transparency. PMID- 24155830 TI - The importance of health literacy in the development of 'Self Care'' cards for community pharmacies in Ireland. AB - OBJECTIVE: 'Self Care''cards play a significant role in delivering health education via community pharmacies in Australia and New Zealand. The primary objective of this study was to evaluate whether such an initiative could have a similar impact in an Irish context. The secondary objective was to understand the importance of health literacy to this initiative. METHODS: Ten cards were developed for the Irish healthcare setting and trialed as a proof of concept study. The pilot study ran in ten community pharmacies in the greater Cork area for a six-month period. Using a mixed methods approach (Questionnaires & focus group) staff and patient reactions to the initiative were obtained. Concurrent to the pilot study, readability scores of cards (Flesch-Kincaid, Fry, SMOG methods) and the Rapid Estimate of Adult Literacy in Medicine (REALM) health literacy screening tool was administered to a sample of patients. RESULTS: 88.7% of patient respondents (n=53) liked the concept of the 'Self Care'' cards and 83% of respondents agreed that the use of the card was beneficial to their understanding of their ailment. Focus groups with Pharmacy staff highlighted the importance of appropriate training for the future development of this initiative. An emerging theme from designing the cards was health literacy. The pilot 'Self Care''cards were pitched at too high a literacy level for the general Irish public to understand as determined by readability score methods. It was found that 19.1% of a sample population (n=199) was deemed to have low health literacy skills. CONCLUSIONS: The 'Self Care''initiative has the potential to be Pharmacy's contribution to health education in Ireland. The initiative needs to be cognizant of the health literacy framework that equates the skills of individuals to the demands placed upon them. PMID- 24155831 TI - Exploring long term implementation of cognitive services in community pharmacies a qualitative study. AB - Implementing cognitive services in community pharmacies faces certain obstacles. One approach aimed at improving long-term implementation is to consider the implementation process as consisting of different stages, all of which require tailored initiatives. Taking this approach into account, there is a marked need for increased knowledge regarding the initiatives necessary to support especially the later phases of the implementation process. OBJECTIVE: The aim of this project was to develop insight into factors pertaining to the later phases of implementing cognitive services in community pharmacies. METHODS: A qualitative study was conducted, consisting of semi-structured interviews with 12 Danish pharmacy staff members, who were all in charge of improving the implementation of the Inhaler Technique Assessment Service (ITAS) in the 5 years following its introduction. The interviews were used to explore which implementation barriers had been identified by the staff and how they had sought to overcome them. The interviews were analyzed by combining content and critical common sense analysis with theoretical interpretations based on Rogers "Diffusion of innovation" theory. RESULTS: The most predominant long-term barrier was the staff members' adoption of the ITAS at very different rates. The problem of laggards was not lack of competencies, but a lack of self-efficacy in believing that their actual competencies were sufficient to provide the service. Lack of time and attention to the service and obtaining support from the more senior members of the pharmacy were also problematic. Both individual and group activities were launched to overcome the identified challenges belonging to different phases of the implementation process. CONCLUSIONS: Those in charge of ensuring long term implementation of cognitive services in community pharmacies should consider the necessity to handle several simultaneous actions of both an individual and collective kind at the same time. Hence, the implementation process should be perceived as a series of interrelated stages rather than a linear process where one stage succeeds the other. PMID- 24155832 TI - Bioidentical hormone therapy: Nova Scotia pharmacists' knowledge and beliefs. AB - OBJECTIVE: To investigate Nova Scotia (NS) pharmacists' knowledge and beliefs regarding the use of bioidentical hormones (BHs) for the management of menopause related symptoms. METHODS: Using Dillman's tailored design methodology, an invitation to complete the web-based questionnaire was emailed to pharmacists in NS as part of the Dalhousie College of Pharmacy Continuing Pharmacy Education Department's (CPE) weekly email update. Data was analyzed using descriptive statistics. RESULTS: Of approximately 1300 e-mails sent, 113 pharmacists completed the questionnaire (response rate 8.7%). The majority of respondents (94%) knew that BHs were not free from adverse drug reactions. More than 50% were aware that conjugated equine estrogens and medroxyprogesterone acetate were not examples of BHs. For seven of eleven knowledge questions, 33-45% indicated that they did not know the answer. When asked about their beliefs regarding BHs, many believed that BHs were similar in efficacy (49%) or more effective (21%) than conventional hormone therapy (CHT) for vasomotor symptoms. Most respondents also believed that both BHs and CHT had similar safety profiles. Additionally, responding pharmacists indicated that more education would be helpful, especially in the area of safety and efficacy of BHTs compared to CHT. CONCLUSIONS: NS pharmacists knew BHs were not free of adverse effects, however knowledge was lacking in other areas. This may reflect the level of coverage of this topic in pharmacy school curriculums and in the pharmacy literature. Results indicate a need for additional education of NS pharmacists with respect to BHs, which could be accomplished through modification of undergraduate pharmacy programs and supplementary CPE. PMID- 24155833 TI - Knowledge of folic acid and counseling practices among Ohio community pharmacists. AB - OBJECTIVE: To determine knowledge of folic acid use for neural tube defect (NTD) prevention and counseling practices among community pharmacists registered in Ohio. METHODS: A cross-sectional study was performed on a random sample (n=500) of community pharmacists registered with the Ohio Board of Pharmacy and practicing in Ohio. A survey previously used by researchers to assess folic acid knowledge and practices among samples of other healthcare provider groups in the United States was adapted with permission for this study. The final tool consisted of 28 questions evaluating the knowledge, counseling practices, and demographics of respondents. The cover letter did not reveal the emphasis on folic acid, and surveys were completed anonymously. The university institutional review board deemed the study exempt. RESULTS: Of the 122 pharmacists who completed the survey, 116 (95.1%) knew that folic acid prevents some birth defects. Twenty-eight (22.9%) responded that they "always" or "usually" discuss multivitamins with women of childbearing potential, and 19 (15.6%) responded that they "always" or "usually" discuss folic acid supplements. Some gaps in knowledge specific to folic acid were revealed. While 63.1% of pharmacists selected the recommended dose of folic acid intake for most women of childbearing potential, 13.1% could identify the dose recommended for women who have had a previous NTD affected pregnancy. Respondents identified continuing education programs, pharmacy journals/magazines, and the Internet as preferred avenues to obtain additional information about folic acid and NTD. CONCLUSIONS: This study represents the first systematic evaluation of folic acid knowledge and counseling practices among a sample of pharmacists in the United States. As highly accessible healthcare professionals, community pharmacists can fulfill a vital public health role by counseling women of childbearing potential about folic acid intake. Educational materials may be beneficial in augmenting knowledge of folic acid and facilitating patient education. PMID- 24155834 TI - Impact of a clinical pharmacist on a cardiovascular surrogate endpoint: a pilot study. AB - Utilizing a multidisciplinary approach to management of patients with certain chronic cardiovascular diseases (CVD) has been shown to improve treatment outcomes. The role of clinical pharmacists in comprehensive outpatient CVD management has not been evaluated. OBJECTIVE: The objective of this pilot study was to evaluate the impact of a clinical pharmacist added to cardiologist care on blood pressure (BP), a key surrogate marker of CVD, in outpatients with CVD compared to cardiologist care alone. METHODS: A retrospective, matched-control study was conducted in patients established in a cardiovascular clinic. The intervention was referral to a pharmacist clinic; control was usual care from the cardiologist. The surrogate marker evaluated was the change in BP. RESULTS: Patients in the pharmacist-intervention (n=57) experienced significant reductions in diastolic BP (-2.6 mmHg, p=0.05) and non-significant reductions in systolic BP (-4.3 mmHg, p=0.16) compared to baseline, whereas patients in the control group experienced non-significant increases in both systolic and diastolic BP (+1.6/+0.7 mmHg, p=NS). Similarly, there were significant reductions in diastolic BP and non-significant reductions in systolic BP for the intervention group when compared to controls (difference 3.3 mmHg, p=0.04 and 5.9 mmHg, p=0.1, respectively). Lastly, the proportion of patients categorized as having Stage 2 BP was significantly reduced in the intervention group (p=0.02), but not in the controls (p=0.5). CONCLUSIONS: The multidisciplinary model of care that included a clinical pharmacist reduced BP more than usual care by a cardiologist alone. This benefit was demonstrated in complex patients with CVD who were already receiving specialized care. The impact of this model on clinical outcomes requires further evaluation and should be a high priority given the burden of CVD in the population. PMID- 24155835 TI - Clinical pharmacist evaluation of medication inappropriateness in the emergency department of a teaching hospital in Malta. AB - Appropriate prescribing remains an important priority in all medical areas of practice. OBJECTIVE: The objective of this study was to apply a Medication Appropriateness Index (MAI) to identify issues of inappropriate prescribing amongst patients admitted from the Emergency Department (ED). METHODS: This study was carried out at Malta's general hospital on 125 patients following a two-week pilot period on 10 patients. Patients aged 18 years and over and on medication therapy were included. Medication treatment for inappropriateness was assessed by using the MAI. Under-prescribing was also screened for. RESULTS: Treatment charts of 125 patients, including 697 medications, were assessed using a MAI. Overall, 115 (92%) patients had one or more medications with one or more MAI criteria rated as inappropriate, giving a total of 384 (55.1%) medications prescribed inappropriately. The mean SD MAI score per drug was 1.78 (SD=2.19). The most common medication classes with appropriateness problems were biguanides (100%), anti-arrhythmics (100%) and anti-platelets (96.8%). The most common problems involved incorrect directions (26%) and incorrect dosages (18.5%). There were 36 omitted medications with untreated indications. CONCLUSIONS: There is considerable inappropriate prescribing which could have significant negative effects regarding patient care. PMID- 24155836 TI - Assessing pharmacists' perspectives of HIV and the care of HIV-infected patients in Alabama. AB - OBJECTIVE: The purpose was to assess factors potentially affecting care pharmacists provide to HIV/AIDS patients including comfort level, confidence, education, experience, professional competence, continuity of care and patient provider relationship between pharmacists and HIV-infected patients. METHODS: A 24-item questionnaire assessed the constructs of this study. Surveys were distributed from October 2009 to April 2010 to pharmacists in Alabama with varying levels of experience treating HIV-infected patients. Chi-square tests determined whether relationships existed between responses, consisting of how often respondents reported treating HIV-infected patients, amount of HIV education respondents had, participants' confidence with HIV/AIDS knowledge and comfort level counseling HIV-infected patients about their medications. RESULTS: Thirty-three percent of the pharmacists cared for HIV-infected patients on a monthly basis, yet 86% do not feel very confident with their HIV/AIDS knowledge. Forty-four percent were not comfortable counseling patients on antiretroviral medications, and 77% would feel more comfortable with more education. Significant, positive relationships were revealed concerning how often respondents treat HIV-infected patients and their comfort level counseling them (r=0.208, p<0.05). Similar relationships pertaining to the amount of education respondents had regarding HIV, how confident they are in their HIV/AIDS knowledge (r=0.205, p< 0.05), and their comfort level counseling HIV-infected patients on their medications (r=0.312, p<0.01) were found. The time spent treating HIV infected patients and the education respondents had pertaining to HIV/AIDS related to increased comfort levels concerning counseling patients on their medications. CONCLUSIONS: This research uncovered areas where pharmacists can improve care and treatment for HIV-infected patients. Increasing education on HIV/AIDS and treatment options may lead to increased comfort and confidence in therapeutic management. Through changes in pharmacists' perspectives and abilities to care for their patients, the patient-provider relationship could strengthen, potentially leading to improved medication compliance, enhanced overall health, and a better quality of life for HIV-infected patients. PMID- 24155837 TI - An analysis of the warning letters issued by the FDA to pharmaceutical manufacturers regarding misleading health outcomes claims. AB - OBJECTIVE: To evaluate the number and type of warning letters issued by the US Food and Drug Administration (FDA) to pharmaceutical manufacturers for promotional violations. METHODS: Two reviewers downloaded, printed and independently evaluated warning letters issued by the FDA to pharmaceutical manufacturers from years 2003-2008. Misleading claims were broadly classified as clinical, Quality-of-Life (QoL), and economic claims. Clinical claims included claims regarding unsubstantiated efficacy, safety and tolerability, superiority, broadening of indication and/or omission of risk information. QoL claims included unsubstantiated quality of life and/or health-related quality of life claims. Economic claims included any form of claim made on behalf of the pharmaceutical companies related to cost superiority of or cost savings from the drug compared to other drugs in the market. RESULTS: In the 6-year study period, 65 warning letters were issued by FDA, which contained 144 clinical, three QoL, and one economic claim. On an average, 11 warning letters were issued per year. Omission of risk information was the most frequently violated claim (30.6%) followed by unsubstantiated efficacy claims (18.6%). Warning letters were primarily directed to manufacturers of cardiovascular (14.6%), anti-microbial (14.6%), and CNS (12.5%) drugs. Majority of the claims referenced in warning letters contained promotional materials directed to physicians (57%). CONCLUSIONS: The study found that misleading clinical outcome claims formed the majority of the promotional violations, and majority of the claims were directed to physicians. Since inadequate promotion of medications may lead to irrational prescribing, the study emphasizes the importance of disseminating reliable, credible, and scientific information to patients, and more importantly, physicians to protect public health. PMID- 24155838 TI - Knowledge and attitudes of the pharmacists, prescribers and patients towards generic drug use in Istanbul - Turkey. AB - The use of generic drugs has increased significantly in recent years. Since generic drugs are available at a lower cost, they provide an opportunity for savings in drug expenditure. Thus, use of generic drugs is encouraged especially in developing countries. There are only a few studies concerning the perceptions and attitudes of the healthcare providers and patients towards generic drug use. METHODS: The present study was conducted by a face to face questionnaire in the Kadikoy district of Istanbul in April 2010. From randomly chosen respondents, 68 pharmacists, 56 prescribers and 101 patients consented to participate in the study. RESULTS: Thirty one and 32 % of the pharmacists and prescribers, respectively, expressed that they believed that the generics did not differ from the original drugs, whereas only 24% of the patients believed so. Forty percent of the pharmacists and 82% of the prescribers told that they were unsure about the bioequivalence of the generics. Ten percent of the patients claimed that they immediately accept generic substitution by the pharmacist, while 26% accepted it if it was substituted by the prescriber. Cost was the most important factor taken into consideration about generic substitution (92% for prescribers; 83% for patients and 82% for pharmacists). CONCLUSIONS: Our findings demonstrated that healthcare providers as well as the drug consumers have insufficient knowledge about generic drugs. Therefore, they should be better educated with respect to generic substitution. PMID- 24155839 TI - Women and men report different behaviours in, and reasons for medication non adherence: a nationwide Swedish survey. AB - OBJECTIVE: The aim of the present study was to analyse gender differences in self reported non-adherence (NA) to prescribed medication in the Swedish general population. We aimed to study unintentional and intentional NA as well as the reasons given for NA. METHODS: A questionnaire was mailed to a cross-sectional, random, national sample of people aged 18-84 years in Sweden (n=7985). The response rate was 61.1% (n=4875). The questionnaire covered use of prescription drugs, NA behaviour and reasons for NA. RESULTS: Use of prescription drugs was reported by 59.5% (n=2802) of the participants, and 66.4% (n=1860) of these participants did not adhere to the prescribed regimen. No overall gender differences in reporting NA were found. However, when analysing the various types of NA behaviour and the reasons for NA, different gender patterns emerged. Men were more likely to report forgetting [OR=0.77 (95%CI 0.65:0.92)], changing the dosage [OR=0.64 (95%CI 0.52:0.79)] and that they had recovered [14.3%, (OR=0.71 (95%CI 0.56:0.90)] as a reason. In contrast, more women than men reported filling the prescription but not taking the drug [OR=1.25 (95%CI 1.02:1.54)] and reported the development of adverse drug reactions (ADRs) [OR=1.89 (95%CI 1.37:2.59)] as a reason more commonly. The gender differences remained, in most cases, after controlling for confounders such as age, socioeconomic factors, medical problems and attitudes toward drugs. CONCLUSIONS: Women and men have different patterns of NA behaviour and different reasons for NA. Therefore, if adherence is to be improved, a wide knowledge of all the reasons for NA is required, along with an understanding of the impact of gender on the outcomes. PMID- 24155840 TI - Knowledge, perception and practice of pharmacovigilance among community pharmacists in South India. AB - Pharmacovigilance has not progressed well in India and the concept is still in its infancy. India rates below 1% in pharmacovigilance as against the world rate of 5%. OBJECTIVE: The aim of our study was to evaluate the knowledge, perception and practice of pharmacovigilance among registered community pharmacists in Hyderabad, India. METHODS: This was a prospective study to find out the knowledge, perception and practice of adverse drug reaction reporting among community pharmacists. It was conducted by a face to face questionnaire and the convenience factor of the pharmacist was taken into consideration. RESULTS: From the 650 questionnaire administered to community pharmacists, 347 (53.3%) were returned completely filled questionnaires. A number of 120 (34.6%) pharmacists could define the term 'pharmacovigilance' to an acceptable extent and 119 (34.3%) knew about the National Pharmacovigilance Programme in India. 96 (27.7%) had good knowledge, 36(10.4%) had fair knowledge and 215(61.9%) had poor knowledge about pharmacovigilance. We have found that 196 (56.5%) had good perception, 94(27.1%) had fair perception and 57(16.4%) had poor perception. Only 41(11.8%) pharmacists ever reported an ADR and the other never reported ADR. The majority of pharmacists 223(64.3%) felt that the AE is very simple and non-serious and hence did not report. Pharmacists have poor knowledge, good perception and negligibly low reporting rates. CONCLUSIONS: Incorporation of ADR reporting concepts in education curriculum, training of pharmacists and voluntary participation of pharmacists in ADR reporting is very crucial in achieving the safety goals and safeguarding public health. PMID- 24155841 TI - Job satisfaction among chain community pharmacists: results from a pilot study. AB - OBJECTIVE: The objectives of this study were to obtain pilot data concerning the job satisfaction of Tucson area retail chain setting and to identify the facets of community practice that have the greatest contribution to job satisfaction. METHODS: This was a cross-sectional study of chain pharmacists in the Tucson area. The Warr-Cook-Wall questionnaire of job satisfaction was used to evaluate community pharmacists' satisfaction with their current position. This study used Rasch analysis to assess the validity and reliability of the questionnaire. The Rasch scores obtained for each respondent were used as a dependent variable in univariate and bivariate analyses to evaluate differences in job satisfaction. RESULTS: A total of 32 pharmacists responded from 129 chain community pharmacies in the cities of Tucson, Marana and Oro Valley, Arizona. The mean (SD) Rasch score for job satisfaction was 0.93 (2.1). Results from bivariate analysis indicate that pharmacists in the Tucson area with practice experience outside community pharmacy were less satisfied with their job compared to those without experience outside community pharmacy (p<0.01). CONCLUSIONS: This pilot evaluation suggests that having pharmacy experience outside community practice affects pharmacist job satisfaction. Additionally, findings from this study indicate that there is reliability and validity evidence to support the use of the modified Warr-Cook-Wall questionnaire for assessing overall job satisfaction in chain community pharmacy practice. PMID- 24155842 TI - What is 'pharmaceutical care' in 2013? PMID- 24155843 TI - Assessment of community pharmacists' counselling skills on headache management by using the simulated patient approach: a pilot study. AB - BACKGROUND: Headache, or cephalalgia, is one of the 20 most disabling diseases in the world and affects a large portion of the world's population. People generally use over-the-counter medications to treat headaches and other minor symptoms. A pharmacist should help patients choose the most effective, safe, and convenient pharmacotherapeutic option. OBJECTIVE: To assess the counselling skills of community pharmacists for headache management by using the simulated patient approach. METHODS: A cross-sectional study was conducted from March 2010 to July 2010. Data were obtained from a convenience sample consisting of one pharmacist from each of the 24 participating community pharmacies. In order to evaluate the pharmacists' counselling skills, a simulated patient role played a standardized headache case requesting self-medication. The interactions of the simulated patient with the pharmacists were audiovisually recorded using a hidden micro camera, and these recordings were analysed using a validated questionnaire. RESULTS: Of the 24 evaluated pharmacists, 19 (79.1%) were women. Information was spontaneously provided by 15 (62.5%) pharmacists. At least one question was asked by the pharmacist to assess the signs and symptoms. Most pharmacists (n=17, 70.8%) recommended sodium dipyrone, either alone or in combination with other drugs. The most discussed items in the simulation visits were contraindications (n=17, 70.8%), indications (n=10, 41.6%), and drug administration times (n=8, 33.3%). None of the pharmacists recommended any non-pharmacological therapeutic alternatives. The overall impressions of the pharmacists' professional counselling skills ranged from poor to fair. CONCLUSIONS: This study showed that the pharmacists' counselling skills and the guidance provided by the pharmacists to the simulated patient were insufficient for the satisfactory management of headache. PMID- 24155844 TI - Case management of malaria fever at community pharmacies in Pakistan: a threat to rational drug use. AB - OBJECTIVE: To document the case management of uncomplicated malaria fever at community pharmacies located in the two major cities of Pakistan; Islamabad (national capital) and Rawalpindi (twin city). METHODS: A comparative, cross sectional study was designed to document the management of uncomplicated malaria fever at community pharmacies in twin cities of Pakistan through simulated patient visits. Visits were conducted in 238 randomly selected pharmacies to request advice for a simulated patient case of malaria. The pharmacy's management was scored on a checklist including history taking and provision of advice and information. Kruskal-Wallis test and Mann-Whitney U test were used to compare management of uncomplicated malaria fever by different types of dispensers working at community pharmacies situated at different locations in the twin cities. RESULTS: The simulated patients were handled by salesmen (74.8%, n=178), pharmacist (5.4%, n=13) and diploma holders (19.8 %, n=47). Medication was dispensed in 83.1 % (n=198) of the visits, but only few of the treated cases were in accordance to standard treatment guidelines for malaria. However, in 14.8% (n=35) of the cases the simulated patients were directly referred to a physician. There was a significant difference observed in the process of history taking performed by different dispensers (e.g. pharmacist, pharmacy assistant, pharmacy diploma holders and salesman) while no significant differences in the provision of advice by these dispensers was observed. Pharmacists were seen more frequently involved in the process of history taking if available at the community pharmacies. On the other hand, no significant differences were observed in the case management (history taking and provision of advice) for the treatment of malaria fever among community pharmacies situated at different locations (e.g. near hospital/super market/small market) in the twin cities. CONCLUSIONS: The results of the study revealed that the overall process of disease management of uncomplicated malaria fever at community pharmacies was not in accordance with the national standard treatment guidelines for malaria. Patients were being treated by untrained personnel's at community pharmacies without any understanding of referral. However, pharmacists were more frequently involved in history taking, though their availability was low at community pharmacies. PMID- 24155845 TI - Use of non-formulary drugs in children at a Brazilian teaching hospital: a descriptive study. AB - OBJECTIVE: To characterise the prescription of non-formulary drugs to children and neonates at a Brazilian teaching hospital and identify adverse drug reactions (ADRs), drug interactions, and prescription of potentially hazardous medicines. METHODS: A prospective exploratory study was carried out between January and May 2011 at the general paediatric wards and paediatric oncology, paediatric intensive care, and neonatal care units of the study hospital. Non-formulary drugs were categorised as approved, off-label, or not approved for use in children according to Brazilian compendia. Electronic health records were actively searched for ADRs and the possibility of moderate to severe interactions between non-formulary drugs and other medicines was determined with the Micromedex(r) database. RESULTS: Overall, 109 children or neonates received non formulary drugs. Of these drugs, 54% were approved for use in children, 12.2% were used off-label, and 33.8% were not approved for use in children. Non formulary drugs accounted for 13.4% of total prescriptions; 5.3% of drugs had a potential for interactions and five were possibly associated with ADRs. CONCLUSIONS: Prescription of non-formulary drugs not approved for use in children was common at the study hospital. Studies such as this provide information on the use of medicines for special indications and permit assessment of the relevance of hospital formularies for the paediatric population. PMID- 24155846 TI - Prevalence and control of hypertension in a Niger Delta semi urban community, Nigeria. AB - BACKGROUND: Hypertension is a public health problem worldwide, but the prevalence in Amassoma, Southern Ijaw Local Government Area is not known. OBJECTIVE: To investigate the prevalence of hypertension in the locality and the extent of control in diagnosed cases. METHODS: It is a prospective study involving interviewing. Four hundred adults aged 20 years and above selected through stratified random sampling across the various compounds called "AMA"; a unit of settlement comprising extended families of common ancestors. A self-developed, validated and pretested interviewer-administered questionnaire on demographics, predisposing factors, and medication history was used. In addition, measurement of respondents' blood pressure, weight and height was carried out. The Body Mass Index calculated and the data were appropriately analysed. RESULTS: The response rate of questionnaire distribution was 100.0% being interviewer administered alongside weight, height and blood pressure measurement. Majority of respondents were female. Almost half of respondents (46.5%) had their BMI above normal, 15.3% (61) of which falls within the obese region (>30.0kg/m2). The mean (SD) systolic blood pressure among males was 133.3 (3.2) mmHg and that of females was 127.4 (3.0) while the mean (SD) diastolic blood pressures were 86.2 (1.7) and 83.9 (2.4) for males and females respectively. Crude prevalence rate of hypertension in the community was 15.0% (60) out of which 13.8 % (55) were previously diagnosed. The hypertension was that of Stage I in 11.5% (46) and Stage II in 3.5% (14). Hypertension prevalence was slightly higher in males (18.8%) than that of the females (12.5%) (p= 0.0889), Relative Risk (RR)=1.500 [95%CI 0.9422:2.388]. The prevalence rate among 40 years and above was 41.6% (42/101) who also constituted 70.0% (42/60) of participants with hypertension in the survey and 10.5% (42/400) of the total. Of the previously diagnosed cases of hypertension, only 31% (17/55) were taking their drugs during the survey and only 12.7% (07/55) had regular adherence to medication and adequate BP control was achieved in 7.3% (04/55). Majority of the patients on drugs (21.8%) (12/55) were either taking methydopa as monotherapy or in combination with amiloride and hydrochlorothiazide. Other drugs being taken by patients include lisinopril, propranolol, amlodipine, atenolol, nifedipine and low dose aspirin. CONCLUSIONS: The prevalence of hypertension in the semi urban community is 15.0% with a pre hypertension in another 23.5%. There was poor control of blood pressure among previously hypertensive patients. PMID- 24155847 TI - Demonstration of anticoagulation patient self-testing feasibility at an Indian Health Service facility: A case series analysis. AB - BACKGROUND: Anticoagulation patient self-testing (PST) represents an alternative approach to warfarin monitoring by enabling patients to use coagulometers to test their international normalized ratio (INR) values. PST offers several advantages that potentially improve warfarin management. OBJECTIVE: To describe implementation and associated performance of a PST demonstration program at an Indian Health Service (IHS) facility. METHODS: A non-consecutive case series analysis of patients from a pharmacy-managed PST demonstration program was performed at an IHS facility in Oklahoma between July 2008 and February 2009. RESULTS: Mean time in therapeutic range (TTR) for the seven patients showed a small, absolute increase during the twelve weeks of PST compared to the twelve weeks prior to PST. Four of the seven patients had an increase in TTR during the twelve week course of PST compared to their baseline TTR. Three of four patients with increased TTR in the final eight week period of PST achieved a TTR of 100%. Of the three patients who experienced a decrease in TTR after initiating self testing, two initially presented with a TTR of 100% prior to PST and one patient had a TTR of 100% for the final eight weeks of PST. The two patients not achieving a TTR of 100% during the twelve week PST period demonstrated an increase in TTR following the first four weeks of PST. CONCLUSIONS: Although anticoagulation guidelines now emphasize patient self-management (PSM) only, optimal PST remains an integral process in PSM delivery. In the patients studied, the results of this analysis suggest that PST at the IHS facility provided a convenient, alternative method for management of chronic warfarin therapy for qualified patients. More than half of the patients demonstrated improvement in TTR. Although there is a learning curve immediately following PST initiation, the mean TTR for the entire PST period increased modestly when compared to the time period prior to PST. PMID- 24155848 TI - A bibliometric study of publication patterns in rational use of medicines in Iran. AB - BACKGROUND: Inappropriate use of drugs is commonly observed in health care system throughout the world especially in developing countries. The consequences of irrational use of drugs are enormous for patients and communities. Proper interventions would have important financial and public health benefits. Several studies have been performed about rational use of drugs in Iran. OBJECTIVE: The objective of this study was to assess scientific output on rational use of drugs in Iran using a bibliometric analysis of publications. METHODS: A systematic search was conducted for finding all papers (English and Persian) using Pubmed, Web of Science, Google Scholar, CINAHL, Proquest, International Pharmaceutical Abstract and Persian databases including SID, Iran Medex and MagIran. Retrieved articles were categorized by research topics and year of publication. Impact Factor of the journals, citation analysis of first authors, most cited topics and average citations per item were analyzed. RESULTS: A total of 668 articles were retrieved from all search engines after excluding irrelevant, 466 articles were included in the review. Number of publications increased dramatically after 2001(more than 10 times). Evaluation of prescribing pattern (15%), self medication (11.3%) and adverse drug reaction (9.1%) were among the most studied topics. From the total of 165 journals, 60 of them had Impact factors and 125 articles were published in these journals. Antimicrobial resistance and adverse drug reaction were the most cited topic. CONCLUSIONS: Publication of articles on rational use of drugs research in Iran has undergone an important increase during last decade. Further analysis of research outputs is necessary to achieve rational use of medicines goal. PMID- 24155849 TI - A retrospective evaluation of the efficacy of intravenous bumetanide and comparison of potency with furosemide. AB - BACKGROUND: The potency of intravenous bumetanide to furosemide using a ratio of 1:40 has been suggested; however, there are little data supporting this ratio. Recent drug shortages required the use of bumetanide in a large patient population, enabling further characterization of the efficacy of IV bumetanide. OBJECTIVE: The primary objective of this study was to estimate a dose-response effect of IV bumetanide on urine output (UOP) in all patients that received 48 hours of therapy as well as in a subgroup of patients with heart failure (HF). This subgroup was used to compare the potency of bumetanide with furosemide. A secondary safety objective described electrolyte replacement required during therapy. METHODS: This was a single-center retrospective study examining the dose response effect of IV bumetanide in patients receiving at least 48 hours of intermittent (iIV) or continuous (cIV) dosing, measured by UOP per mg of drug received (mL/mg). The potency of IV bumetanide was compared with furosemide in a subset of patients with HF using pre-existing data. The safety of IV bumetanide was analyzed by quantifying electrolyte replacement received during the study period. RESULTS: The primary outcome was higher in the iIV group (n=93) at 1273 +/- 844 mL/mg compared with the cIV group (n=16) at 749 +/- 370 mL/mg (P=0.002). Among patients with HF who received furosemide (iIV n=30, cIV n=26) or bumetanide (iIV n=30, cIV n=3), a potency ratio of 41:1 was found for the iIV group and 34:1 for all patients with HF. There was no significant difference in electrolyte replacement between groups. CONCLUSIONS: A greater response was seen with intermittent bumetanide compared with continuous infusion bumetanide. This study supports the 40:1 dose equivalence ratio (furosemide:bumetanide) in patients with HF receiving at least 48 hours of intravenous intermittent bumetanide. PMID- 24155850 TI - Implementing ward based clinical pharmacy services in an Ethiopian University Hospital. AB - BACKGROUND: Clinical pharmacy practice has developed internationally to expand the role of a pharmacist well beyond the traditional roles of compounding, dispensing and supplying drugs to roles more directly in caring for patients. Studies on the activities of the clinical pharmacist in an inpatient ward in resource constrained settings are scarce, however. OBJECTIVE: To assess ward based clinical pharmacy services in an internal medicine ward of Jimma University Specialized Hospital. METHODS: The study was carried out in the internal medicine ward from March to April, 2011 at Jimma University Specialized Hospital. The study design was a prospective observational study where pharmaceutical care services provided by clinical pharmacists for inpatients were documented over a period of two months. Interventions like optimization of rational drug use and physician acceptance of these recommendations were documented. Clinical significance of interventions was evaluated by an independent team (1 internist, 1 clinical pharmacologist) using a standardized method for categorizing drug related problems (DRPs). RESULTS: A total of 149 drug related interventions conducted for 48 patients were documented; among which 133(89.3%) were clinical pharmacists initiated interventions and 16(10.7%) interventions were initiated by other health care professionals. The most frequent DRPs underlying interventions were unnecessary drug therapy, 36(24.2%); needs additional drug therapy, 34(22.8%) and noncompliance, 29(19.5%). The most frequent intervention type was change of dosage/instruction for use, 23(15.4%). Acceptance rate by physicians was 68.4%. Among the interventions that were rated as clinically significant, 46(48.9%) and 25(26.6%) had major and moderate clinical importance respectively. CONCLUSIONS: Involving trained clinical pharmacists in the healthcare team leads to clinically relevant and well accepted optimization of medicine use in a resource limited settings. This approach can likely be generalized to other health care settings in the country to improve medication outcomes. PMID- 24155851 TI - Advancing interprofessional education through the use of high fidelity human patient simulators. AB - BACKGROUND: Modern medical care increasingly requires coordinated teamwork and communication between healthcare professionals of different disciplines. Unfortunately, healthcare professional students are rarely afforded the opportunity to learn effective methods of interprofessional (IP) communication and teamwork strategies during their education. The question of how to best incorporate IP interactions in the curricula of the schools of health professions remains unanswered. OBJECTIVE: We aim to solve the lack of IP education in the pharmacy curricula through the use of high fidelity simulation (HFS) to allow teams of medical, pharmacy, nursing, physician assistant, and social work students to work together in a controlled environment to solve cases of complex medical and social issues. METHODS: Once weekly for a 4-week time period, students worked together to complete complex simulation scenarios in small IP teams consisting of pharmacy, medical, nursing, social work, and physician assistant students. Student perception of the use of HFS was evaluated by a survey given at the conclusion of the HFS sessions. Team communication was evaluated through the use of Communication and Teamwork Skills (CATS) Assessment by 2 independent evaluators external to the project. RESULTS: The CATS scores improved from the HFS sessions 1 to 2 (p = 0.01), 2 to 3 (p = 0.035), and overall from 1 to 4 (p = 0.001). The inter-rater reliability between evaluators was high (0.85, 95% CI 0.71, 0.99). Students perceived the HFS improved: their ability to communicate with other professionals (median =4); confidence in patient care in an IP team (median=4). It also stimulated student interest in IP work (median=4.5), and was an efficient use of student time (median=4.5). CONCLUSIONS: The use of HFS improved student teamwork and communication and was an accepted teaching modality. This method of exposing students of the health sciences to IP care should be incorporated throughout the curricula. PMID- 24155852 TI - Patient knowledge of medicines dispensed from Ghanaian community pharmacies. AB - BACKGROUND: One vital requirement for patient adherence to medicines is good patient knowledge of the medicines dispensed and this will invariably be linked to good labelling and counselling. OBJECTIVE: The aim of this study was to evaluate the quality of labelling of medicines and determine patient knowledge of the administration of medicines dispensed from a community pharmacy in Ghana. METHODS: From 6th to 29th January, 2010, dispensed prescriptions of 280 clients were purposely sampled to evaluate the quality of labelling. These clients were also interviewed about their knowledge of the last medicine received immediately after dispensing. A scoring system was employed by awarding a point for each attribute written on the package and each attribute stated by the patient. The dispensing attributes noted were name, dosage, frequency, duration, quantity and route of administration. RESULTS: Of the 280 patients interviewed, 157 (56%) were males. Thirty one (11%) had no education and 99(35%) were secondary school graduates. Antimalarials comprised 17.9% and analgesics, 15.4% of medicines dispensed. The name, quantity, dosage, frequency, duration of therapy and route of administration were written on the label in 98%, 99%, 55%, 54%, 6% and 2% respectively of the dispensed medicines. The mean labelling score was 3.096 (SD=1.05) out of 6. The corresponding patient knowledge values were 63%, 80%, 80%, 75%, 57% and 86%. The mean knowledge score was 4.375 (SD; 1.38) out of 6. The chi square test p-value for the effect of demographic characteristics (sex, educational background, location) on patient knowledge of medicines dispensed were p=0.454; p=0.000, and p=0.138 respectively. CONCLUSIONS: Patient knowledge of the administration of dispensed medicines was rated good; and this largely corresponded with the quality of labelling, except that the duration of therapy and route of administration was not frequently written and so labelling was rated just above average. PMID- 24155853 TI - Associations of gender and age groups on the knowledge and use of drug information resources by American pharmacists. AB - OBJECTIVE: To explore knowledge and use of drug information resources by pharmacists and identify patterns influenced by gender and age-group classification. METHODS: A survey questionnaire was mailed nationwide to 1,000 practitioners working in community (n = 500) and hospital (n = 500) settings who answer drug information questions as part of their expected job responsibilities. Responses pertaining to drug information resource use and knowledge of different types of drug-related queries, resource media preferences, and perceived adequacy of resources maintained in the pharmacy were analyzed by gender and age group. The t statistic was used to test for significant differences of means and percentages between genders and between age groups. Descriptive statistics were used to characterize other findings. RESULTS: Gender and age group classification influenced patterns of knowledge and use of drug information resources by pharmacists. They also affected pharmacists' perceptions of the most common types of questions prompting them to consult a drug information reference, as well as the resources consulted. Micromedex, exclusively available in electronic format, was the most commonly consulted resource overall by pharmacists. Lexi-Comp Online was the leading choice by women, preferred over Micromedex, but was not one of the top two resources selected by men. CONCLUSIONS: This study successfully identified the influence of gender and age-group classification in assessing drug information resource knowledge and use of general and specific types of drug related queries. PMID- 24155854 TI - Information on antidepressants for psychiatric inpatients: the divide between patient needs and professional practice. AB - BACKGROUND: Medicine information is an integral part of patient care and a patient right. In particular, patients with a mental health diagnosis have a need for information on medicines. OBJECTIVE: This study aims to describe the current practice on information provision on antidepressants to inpatients in psychiatric hospitals. METHODS: A qualitative study was conducted consisting of semi structured interviews with health care professionals (n=46) and patients (n=17) in 11 Flemish psychiatric hospitals. Two topic guides were designed for conducting the interviews with these respective stakeholders. The issues addressed in the topic guides related to: organization of information provision in the hospital, information on demand of the patient, information provision by health care professionals, information for relatives, evaluation of provided information, interdisciplinary contacts on information provision and satisfaction on current practice of information provision. The interviews were analysed according to the five stages of the framework analysis. RESULTS: Psychiatrists and nurses are the key players to provide information on antidepressants. Their approach depends on patient characteristics and mental state. Information is provided mainly orally. Health care professionals consider non-verbal cues of patients to verify if information has been understood. Health care professionals reported lack of time and lack of interdisciplinary contacts as negative aspects. Patients indicated that health care professionals take too little initiative to provide medicine information. CONCLUSIONS: Patients are informed about their antidepressants through various pathways. Although the awareness is present of the importance of the individual approach and efforts are done to tailor information to the individual patient, improvement is still possible. Tailoring communication; assessing patient needs and preferences; matching of health care professional style and patient needs; and achieving concordance, is a complex and challenging task for health care professionals in mental health care. PMID- 24155855 TI - Adverse events in patients initiated on dabigatran etexilate therapy in a pharmacist-managed anticoagulation clinic. AB - BACKGROUND: Vitamin K antagonists have been the treatment of choice in preventing thromboembolic events, but problems such as frequent dose adjustment and monitoring of coagulation status, including multiple drug and food interactions, make their use difficult. Dabigatran etexilate is a new oral direct thrombin inhibitor not requiring routine monitoring and since its approval in the United States, many clinicians have been interested in utilizing this new therapy. OBJECTIVE: This study documented adverse drug events (ADEs) recorded in patients started on dabigatran therapy, including those who were previously controlled on warfarin and those who were anticoagulant naive. METHODS: In an outpatient pharmacist-managed anticoagulation clinic, a total of 221 patients were initiated on dabigatran therapy over an 18-month period. 43.0% of these patients were previously controlled on warfarin. RESULTS: 54 of the 221 patients (24.4%) developed an ADE while on dabigatran. The average time to event was 48.4 days. Nine of the fifty-four patients experienced a major bleeding ADE; six patients developed a serious non-bleeding ADE. Five of these fifteen patients died; one death was directly related to dabigatran therapy. The remaining thirty-nine of the fifty-four patients experienced a clinically relevant non-major ADE. Of the fifty-four patients who experienced an ADE, thirty were male. The average age was 73.8 years and the average weight was 92.8kg. Fifty-four percent of those who experienced an ADE were previously anticoagulant naive. CONCLUSIONS: While many clinicians have been interested in utilizing the new direct thrombin inhibitor dabigatran etexilate, this new therapy is not without risks. This study documented adverse drug events in 24.4% of patients who were initiated on dabigatran etexilate therapy over an eighteen month period. ADEs were more common in patients who were anticoagulant naive prior to dabigatran etexilate therapy and not those who were previously controlled on warfarin therapy. PMID- 24155856 TI - Prevalence and risk factor analysis of resistant Escherichia coli urinary tract infections in the emergency department. AB - BACKGROUND: Escherichia coli (E. coli) is a frequent uropathogen in urinary tract infections (UTI). Widespread resistance to sulfamethoxazole-trimethoprim (SMX TMP) and increasing resistance to fluoroquinolones amongst these isolates has been recognized. There are limited data demonstrating risk factors for resistance to both SMX-TMP and fluoroquinolones. OBJECTIVE: This study was conducted to assess for the prevalence of community resistance amongst E. coli isolates to SMX TMP and levofloxacin in ambulatory patients discharged from the emergency department (ED). METHODS: Adults presenting for evaluation and discharged from the ED with a diagnosis of an E. coli UTI were retrospectively reviewed. Utilizing demographic and clinical data the prevalence of E. coli resistance and risk factors associated with SMX-TMP- and fluoroquinolone-resistant infection were determined. RESULTS: Among the 222 patients, the mean rates of E. coli susceptibility to levofloxacin and SMX-TMP were 82.4% and 72.5%, respectively. Significant risk factors for resistance to SMX-TMP included prior antibiotic use (p=0.04) and prior diagnosis of UTI (p= 0.01). Significant risk factors for resistance to levofloxacin included: male gender, age, presence of hypertension, diabetes, chronic respiratory disease, nursing home resident, previous antibiotic use, previous diagnosis of UTI, existence of renal or genitourinary abnormalities, and prior surgical procedures (p <0.05 for all comparisons). The number of hospital days prior to initial ED evaluation (p<0.001) was determined to be a predictive factor in hospital and ED readmission. CONCLUSIONS: These results suggest that conventional approaches to monitoring for patterns of susceptibility may be inadequate. It is imperative that practitioners develop novel approaches to identifying patients with risk factors for resistance. Identification of risk factors from this evaluation should prompt providers to scrutinize the use of these agents in the setting of patients presenting with an uncomplicated UTI in the ED. PMID- 24155857 TI - Statins decrease mortality in Lebanese patients with sepsis: A multicenter study. AB - BACKGROUND: Sepsis is a significant public health concern. The clinical response to statins is variable among sepsis patients. OBJECTIVE: The aim of the study was to determinate the effect of statin-treatment on mortality in Lebanese patients with sepsis. METHODS: A retrospective multicenter study on Lebanese patients with sepsis between January 2008 and March 2012 was conducted. Patients with a primary diagnosis of sepsis admitted to the intensive care unit of two tertiary care hospitals in Beirut were included. Patients who continued to receive statin therapy for dyslipidemia during the hospital course were included in the statin treatment group. The control group consisted of patients not taking statin. Demographic characteristics, clinical signs, standard laboratory test and treatment received were compared between these two groups using univariate analysis. Logistic regression and survival analysis were performed by SPSS. RESULTS: THREE HUNDRED FIFTY ONE LEBANESE PATIENTS WERE INCLUDED (AGE: 71.33 SD=14.97 years; Male: 56%). Among them, 30% took a statin at the doses recommended for dyslipidemia. The comparison of the two groups showed that in the statin treatment group: The mean serum level of C-reactive protein at the time of sepsis was significantly decreased (P=0.050), the length-stay at ICU significantly increased (P=0.047) and mortality significantly reduced (P<0.001). Results were confirmed by logistic regression, particularly for mortality. In the Cox regression analysis, hypothermia and shock were significantly associated with high mortality while statin treatment decreased mortality (hazard ratio = 0.540; 95% CI: 0.302-0.964; P=0.037). CONCLUSIONS: At usual doses for dyslipidemia, statin treatment decreased incidence of mortality related to sepsis and improved the survival in this Lebanese septic population. Large randomized controlled clinical trials must be realized to give conclusive results about the potential beneficial effect of statins in sepsis. PMID- 24155858 TI - The inclusion of a business management module within the master of pharmacy degree: a route to asset enrichment? AB - BACKGROUND: Over the past decade the profession of pharmacy has steadily evolved. The New Pharmacy Contract exposed pharmacists to a fundamental change in traditional pharmacy business models. OBJECTIVE: This study will consider whether community pharmacists, pharmacy undergraduates and academic staff within the United Kingdom believe it would be beneficial to incorporate a business management module within the Master of Pharmacy (MPharm) undergraduate degree along with potential mechanisms of delivery. METHODS: Further to ethical approval, the questionnaire was distributed to UK registered pharmacists (n=600), MPharm undergraduates (n=441) and academic staff at Liverpool John Moores University (n=44). The questions were formatted as multiple choice questions, Likert scales or the open answer type. On questionnaire completion and return, data were analysed using simple frequencies, cross tabulations and non-parametric techniques in the SPSS (v18). RESULTS: The majority of pharmacists (84.9%) confirmed that business skills affect their everyday responsibilities to a considerable extent. A high proportion of undergraduate students (92.8%) believed that business management skills will impact on their future role. In total, 64.3% of this cohort declared that if a module were introduced they would study it. The majority of staff (79%) agreed that business skills are gaining increased importance within the field of pharmacy. CONCLUSIONS: Data suggest that business skills are of relevance to the practice of pharmacy. Appropriate staff to deliver the taught material would include business owners / lecturers and teaching practitioners covering topics including management, leadership, interpersonal skills and regulation. We suggest the inclusion of a business module with the MPharm degree would be of great value in preparing individuals for practice within a modern day healthcare setting. PMID- 24155859 TI - A qualitative study exploring the impact and consequence of the medicines use review service on pharmacy support-staff. AB - BACKGROUND: Pharmacy support-staff (pharmacy technicians, dispensers and Medicines Counter Assistants) support the delivery of pharmaceutical and retail functions of the pharmacy. Workflow is supervised and at times dependent upon the pharmacist's presence. Policy makers and pharmacy's representative bodies are seeking to extend the community pharmacist's role including requiring the pharmacist to undertake private consultations away from the dispensary and shop floor areas. However, support-staff voices are seldom heard and little is known about the impact such policies have on them. OBJECTIVE: The objective of this study is to explore the impact and consequences of the English Medicine Use Review (MUR) service on pharmacy support-staff. METHODS: Ten weeks of ethnographic-oriented observations in two English community pharmacies and interviews with 5 pharmacists and 12 support-staff. A thematic approach was used to analyse the data. RESULTS: Despite viewing MURs as a worthwhile activity, interviews with support-staff revealed that some felt frustrated when they were left to explain to patients why the pharmacist was not available when carrying out an MUR. Dependency on the pharmacist to complete professional and accuracy checks on prescriptions grieved dispensing staff because dispensing workflow was disrupted and they could not get their work done. Medicines Counter Assistants were observed to have less dependency when selling medicines but some still reported concerns over of customers and patients waiting for the pharmacist. A range of tacit and ad hoc strategies were consequently found to be deployed to handle situations when the pharmacist was absent performing an MUR. CONCLUSIONS: Consideration should be given to support-staff and pharmacists' existing work obligations when developing new pharmacy extended roles that require private consultations with patients. Understanding organisational culture and providing adequate resourcing for new services are needed to avoid improvisations or enactments by pharmacy support-staff and to allow successful innovation and policy implementation. PMID- 24155860 TI - Attitudes and cognitive distances: On the non-unitary and flexible nature of cognitive maps. AB - Spatial relations of our environment are represented in cognitive maps. These cognitive maps are prone to various distortions (e.g., alignment and hierarchical effects) caused by basic cognitive factors (such as perceptual and conceptual reorganization) but also by affectively loaded and attitudinal influences. Here we show that even differences in attitude towards a single person representing a foreign country (here Barack Obama and the USA) can be related to drastic differences in the cognitive representation of distances concerning that country. Europeans who had a positive attitude towards Obama's first presidential program estimated distances between US and European cities as being much smaller than did people who were skeptical or negative towards Obama's ideas. On the basis of this result and existing literature, arguments on the non-unitary and flexible nature of cognitive maps are discussed. PMID- 24155861 TI - Simultaneous and preceding sounds enhance rapid visual targets: Evidence from the attentional blink. AB - Presenting two targets in a rapid visual stream will frequently result in the second target (T2) being missed when presented shortly after the first target (T1). This so-called attentional blink (AB) phenomenon can be reduced by various experimental manipulations. This study investigated the effect of combining T2 with a non-specific sound, played either simultaneously with T2 or preceding T2 by a fixed latency. The reliability of the observed effects and their correlation with potential predictors were studied. The tone significantly improved T2 identification rates regardless of tone condition and of the delay between targets, suggesting that the crossmodal facilitation of T2 identification is not limited to visual-perceptual enhancement. For the simultaneous condition, an additional time-on-task effect was observed in form of a reduction of the AB that occurred within an experimental session. Thus, audition-driven enhancement of visual perception may need some time for its full potential to evolve. Split-half and test-retest reliability were found consistently only for a condition without additional sound. AB magnitude obtained in this condition was related to AB magnitudes obtained in both sound conditions. Self-reported distractibility and performance in tests of divided attention and of cognitive flexibility correlated with the AB magnitudes of a subset but never all conditions under study. Reliability and correlation results suggest that not only dispositional abilities but also state factors exert an influence on AB magnitude. These findings extend earlier work on audition-driven enhancement of target identification in the AB and on the reliability and behavioural correlates of the AB. PMID- 24155862 TI - More than meets the eye: The attentional blink in multisensory environments. Commentary on Kranczioch and Thorne. AB - Temporal fluctuations of attention can influence performance of cognitive tasks substantially. A common paradigm to investigate temporal fluctuations of attention is the attentional blink paradigm. Kranczioch and Thorne (2013) report new evidence for the impact of auditory stimuli on the visual attentional blink in the current issue of Advances in Cognitive Psychology. PMID- 24155863 TI - An orienting response is not enough: Bivalency not infrequency causes the bivalency effect. AB - When switching tasks, occasionally responding to bivalent stimuli (i.e., stimuli with relevant features for two different tasks) slows performance on subsequent univalent stimuli, even when they do not share relevant features with bivalent stimuli. This performance slowing is labelled the bivalency effect. Here, we investigated whether the bivalency effect results from an orienting response to the infrequent stimuli (i.e., the bivalent stimuli). To this end, we compared the impact of responding to infrequent univalent stimuli to the impact of responding to infrequent bivalent stimuli. For the latter, the results showed a performance slowing for all trials following bivalent stimuli. This indicates a long-lasting bivalency effect, replicating previous findings. For infrequent univalent stimuli, however, the results showed a smaller and shorter-lived performance slowing. These results demonstrate that the bivalency effect does not simply reflect an orienting response to infrequent stimuli. Rather it results from the conflict induced by bivalent stimuli, probably by episodic binding with the more demanding context created by them. PMID- 24155864 TI - Regulation of DNA conformations and dynamics in flows with hybrid field microfluidics. AB - Visualizing single DNA dynamics in flow provides a wealth of physical insights in biophysics and complex flow study. However, large signal fluctuations, generated from diversified conformations, deformation history dependent dynamics and flow induced stochastic tumbling, often frustrate its wide adoption in single molecule and polymer flow study. We use a hybrid field microfluidic (HFM) approach, in which an electric field is imposed at desired locations and appropriate moments to balance the flow stress on charged molecules, to effectively regulate the initial conformations and the deformation dynamics of macromolecules in flow. With lambda-DNA and a steady laminar shear flow as the model system, we herein studied the performance of HFM on regulating DNA trapping, relaxation, coil stretch transition, and accumulation. DNA molecules were found to get captured in the focused planes when motions caused by flow, and the electric field were balanced. The trapped macromolecules relaxed in two different routes while eventually became more uniform in size and globule conformations. When removing the electric field, the sudden stretching dynamics of DNA molecules exhibited a more pronounced extension overshoot in their transient response under a true step function of flow stress while similar behaviors to what other pioneering work in steady shear flow. Such regulation strategies could be useful to control the conformations of other important macromolecules (e.g., proteins) and help better reveal their molecular dynamics. PMID- 24155865 TI - Surface tension effects on submerged electrosprays. AB - Electrosprays are a powerful technique to generate charged micro/nanodroplets. In the last century, the technique has been extensively studied, developed, and recognized with a shared Nobel price in Chemistry in 2002 for its wide spread application in mass spectrometry. However, nowadays techniques based on microfluidic devices are competing to be the next generation in atomization techniques. Therefore, an interesting development would be to integrate the electrospray technique into a microfluidic liquid-liquid device. Several works in the literature have attempted to build a microfluidic electrospray with disputable results. The main problem for its integration is the lack of knowledge of the working parameters of the liquid-liquid electrospray. The "submerged electrosprays" share similar properties as their counterparts in air. However, in the microfluidic generation of micro/nanodroplets, the liquid-liquid interfaces are normally stabilized with surface active agents, which might have critical effects on the electrospray behavior. In this work, we review the main properties of the submerged electrosprays in liquid baths with no surfactant, and we methodically study the behavior of the system for increasing surfactant concentrations. The different regimes found are then analyzed and compared with both classical and more recent experimental, theoretical and numerical studies. A very rich phenomenology is found when the surface tension is allowed to vary in the system. More concretely, the lower states of electrification achieved with the reduced surface tension regimes might be of interest in biological or biomedical applications in which excessive electrification can be hazardous for the encapsulated entities. PMID- 24155866 TI - Simulation guided design of a microfluidic device for electrophoretic stretching of DNA. AB - We have used Brownian dynamics-finite element method (BD-FEM) to guide the optimization of a microfluidic device designed to stretch DNA for gene mapping. The original design was proposed in our previous study [C. C. Hsieh and T. H. Lin, Biomicrofluidics 5(4), 044106 (2011)] for demonstrating a new pre conditioning strategy to facilitate DNA stretching through a microcontraction using electrophoresis. In this study, we examine the efficiency of the original device for stretching DNA with different sizes ranging from 48.5 kbp (lambda-DNA) to 166 kbp (T4-DNA). The efficiency of the device is found to deteriorate with increasing DNA molecular weight. The cause of the efficiency loss is determined by BD-FEM, and a modified design is proposed by drawing an analogy between an electric field and a potential flow. The modified device does not only regain the efficiency for stretching large DNA but also outperforms the original device for stretching small DNA. PMID- 24155867 TI - Determinants of the pace of global innovation in energy technologies. AB - Understanding the factors driving innovation in energy technologies is of critical importance to mitigating climate change and addressing other energy related global challenges. Low levels of innovation, measured in terms of energy patent filings, were noted in the 1980s and 90s as an issue of concern and were attributed to limited investment in public and private research and development (R&D). Here we build a comprehensive global database of energy patents covering the period 1970-2009, which is unique in its temporal and geographical scope. Analysis of the data reveals a recent, marked departure from historical trends. A sharp increase in rates of patenting has occurred over the last decade, particularly in renewable technologies, despite continued low levels of R&D funding. To solve the puzzle of fast innovation despite modest R&D increases, we develop a model that explains the nonlinear response observed in the empirical data of technological innovation to various types of investment. The model reveals a regular relationship between patents, R&D funding, and growing markets across technologies, and accurately predicts patenting rates at different stages of technological maturity and market development. We show quantitatively how growing markets have formed a vital complement to public R&D in driving innovative activity. These two forms of investment have each leveraged the effect of the other in driving patenting trends over long periods of time. PMID- 24155868 TI - Prevention of neuromusculoskeletal frailty in slow-aging ames dwarf mice: longitudinal investigation of interaction of longevity genes and caloric restriction. AB - Ames dwarf (Prop1 (df/df) ) mice are remarkably long-lived and exhibit many characteristics of delayed aging and extended healthspan. Caloric restriction (CR) has similar effects on healthspan and lifespan, and causes an extension of longevity in Ames dwarf mice. Our study objective was to determine whether Ames dwarfism or CR influence neuromusculoskeletal function in middle-aged (82 +/- 12 weeks old) or old (128 +/- 14 w.o.) mice. At the examined ages, strength was improved by dwarfism, CR, and dwarfism plus CR in male mice; balance/ motor coordination was improved by CR in old animals and in middle-aged females; and agility/ motor coordination was improved by a combination of dwarfism and CR in both genders of middle-aged mice and in old females. Therefore, extension of longevity by congenital hypopituitarism is associated with improved maintenance of the examined measures of strength, agility, and motor coordination, key elements of frailty during human aging, into advanced age. This study serves as a particularly important example of knowledge related to addressing aging associated diseases and disorders that results from studies in long-lived mammals. PMID- 24155869 TI - Learning to recognize phenotype candidates in the auto-immune literature using SVM re-ranking. AB - The identification of phenotype descriptions in the scientific literature, case reports and patient records is a rewarding task for bio-medical text mining. Any progress will support knowledge discovery and linkage to other resources. However because of their wide variation a number of challenges still remain in terms of their identification and semantic normalisation before they can be fully exploited for research purposes. This paper presents novel techniques for identifying potential complex phenotype mentions by exploiting a hybrid model based on machine learning, rules and dictionary matching. A systematic study is made of how to combine sequence labels from these modules as well as the merits of various ontological resources. We evaluated our approach on a subset of Medline abstracts cited by the Online Mendelian Inheritance of Man database related to auto-immune diseases. Using partial matching the best micro-averaged F score for phenotypes and five other entity classes was 79.9%. A best performance of 75.3% was achieved for phenotype candidates using all semantics resources. We observed the advantage of using SVM-based learn-to-rank for sequence label combination over maximum entropy and a priority list approach. The results indicate that the identification of simple entity types such as chemicals and genes are robustly supported by single semantic resources, whereas phenotypes require combinations. Altogether we conclude that our approach coped well with the compositional structure of phenotypes in the auto-immune domain. PMID- 24155870 TI - Conflicts of interest among authors of clinical practice guidelines for glycemic control in type 2 diabetes mellitus. AB - BACKGROUND: Conflict of interest (COI) is an important potential source of bias in the development of clinical practice guidelines (CPGs). OBJECTIVES: To examine rates of disclosure of COI, including financial interests in companies that manufacture drugs that are recommended in CPGs on glycemic control in type 2 diabetes mellitus, and to explore the relationship between recommendations for specific drugs in a guideline and author COI. METHODS: We identified a cohort of relevant guidelines from the National Guideline Clearinghouse (NGC) and abstracted COI disclosures from all guideline authors for this observational, cross-sectional study. We determined which hypoglycemic drugs were recommended in each guideline, and explored the relationship between specific disclosures and whether a drug was recommended. RESULTS: Among 13 included guidelines, the percentage of authors with one or more financial disclosures varied from 0 to 94% (mean 44.2%), and was particularly high for two US-based guidelines (91% and 94%). Three guidelines disclosed no author financial COI. The percentage of authors with disclosures of financial interests in manufacturers of recommended drugs was also high (mean 30%). On average, 56% of manufacturers of patented drugs recommended in each guideline had one or more authors with a financial interest in their company. We did not find a significant relationship between financial interests and whether a drug was recommended in our sample; US-based guidelines were more likely to make recommendations for a specific drug compared to non-US based guidelines. DISCUSSION: Authors of this cohort of guidelines have financial interests directly related to the drugs that they are recommending. Although we did not find an association between author COI and drugs recommended in these guidelines and we cannot draw conclusions about the validity of the recommendations, the credibility of many of these guidelines is in doubt. PMID- 24155871 TI - Essential roles of GABA transporter-1 in controlling rapid eye movement sleep and in increased slow wave activity after sleep deprivation. AB - GABA is the major inhibitory neurotransmitter in the mammalian central nervous system that has been strongly implicated in the regulation of sleep. GABA transporter subtype 1 (GAT1) constructs high affinity reuptake sites for GABA and regulates GABAergic transmission in the brain. However, the role of GAT1 in sleep wake regulation remains elusive. In the current study, we characterized the spontaneous sleep-wake cycle and responses to sleep deprivation in GAT1 knock-out (KO) mice. GAT1 KO mice exhibited dominant theta-activity and a remarkable reduction of EEG power in low frequencies across all vigilance stages. Under baseline conditions, spontaneous rapid eye movement (REM) sleep of KO mice was elevated both during the light and dark periods, and non-REM (NREM) sleep was reduced during the light period only. KO mice also showed more state transitions from NREM to REM sleep and from REM sleep to wakefulness, as well as more number of REM and NREM sleep bouts than WT mice. During the dark period, KO mice exhibited more REM sleep bouts only. Six hours of sleep deprivation induced rebound increases in NREM and REM sleep in both genotypes. However, slow wave activity, the intensity component of NREM sleep was briefly elevated in WT mice but remained completely unchanged in KO mice, compared with their respective baselines. These results indicate that GAT1 plays a critical role in the regulation of REM sleep and homeostasis of NREM sleep. PMID- 24155872 TI - Evidence supporting a role for mammalian chitinases in efficacy of caspofungin against experimental aspergillosis in immunocompromised rats. AB - OBJECTIVES: Caspofungin, currently used as salvage therapy for invasive pulmonary aspergillosis (IPA), strangely only causes morphological changes in fungal growth in vitro but does not inhibit the growth. In vivo it has good efficacy. Therefore the question arises how this in vivo activity is reached. Caspofungin is known to increase the amount of chitin in the fungal cell wall. Mammals produce two chitinases, chitotriosidase and AMCase, which can hydrolyse chitin. We hypothesized that the mammalian chitinases play a role in the in vivo efficacy of caspofungin. METHODS: In order to determine the role of chitotriosidase and AMCase in IPA, both chitinases were measured in rats which did or did not receive caspofungin treatment. In order to understand the role of each chitinase in the breakdown of the caspofungin-exposed cells, we also exposed caspofungin treated fungi to recombinant enzymes in vitro. RESULTS: IPA in immunocompromised rats caused a dramatic increase in chitinase activity. This increase in chitinase activity was still noted when rats were treated with caspofungin. In vitro, it was demonstrated that the action of both chitinases were needed to lyse the fungal cell wall upon caspofungin exposure. CONCLUSION: Caspofungin seemed to alter the cell wall in such a way that the two chitinases, when combined, could lyse the fungal cell wall and assisted in clearing the fungal pathogen. We also found that both chitinases combined had a direct effect on the fungus in vitro. PMID- 24155873 TI - PET-scan shows peripherally increased neurokinin 1 receptor availability in chronic tennis elbow: visualizing neurogenic inflammation? AB - In response to pain, neurokinin 1 (NK1) receptor availability is altered in the central nervous system. The NK1 receptor and its primary agonist, substance P, also play a crucial role in peripheral tissue in response to pain, as part of neurogenic inflammation. However, little is known about alterations in NK1 receptor availability in peripheral tissue in chronic pain conditions and very few studies have been performed on human beings. Ten subjects with chronic tennis elbow were therefore examined by positron emission tomography (PET) with the NK1 specific radioligand [(11)C]GR205171 before and after treatment with graded exercise. The radioligand signal intensity was higher in the affected arm as compared with the unaffected arm, measured as differences between the arms in volume of voxels and signal intensity of this volume above a reference threshold set as 2.5 SD above mean signal intensity of the unaffected arm before treatment. In the eight subjects examined after treatment, pain ratings decreased in all subjects but signal intensity decreased in five and increased in three. In conclusion, NK1 receptors may be activated, or up-regulated in the peripheral, painful tissue of a chronic pain condition. This up-regulation does, however, have moderate correlation to pain ratings. The increased NK1 receptor availability is interpreted as part of ongoing neurogenic inflammation and may have correlation to the pathogenesis of chronic tennis elbow. TRIAL REGISTRATION: ClinicalTrials.gov NCT00888225 http://clinicaltrials.gov/ PMID- 24155874 TI - Altered intracellular localization of SOD1 in leukocytes from patients with sporadic amyotrophic lateral sclerosis. AB - Several lines of evidence support the hypothesis of a toxic role played by wild type SOD1 (WT-SOD1) in the pathogenesis of sporadic amyotrophic lateral sclerosis (SALS). In this study we investigated both distribution and expression profile of WT-SOD1 in leukocytes from 19 SALS patients and 17 healthy individuals. Immunofluorescence experiments by confocal microscopy showed that SOD1 accumulates in the nuclear compartment in a group of SALS subjects. These results were also confirmed by western blot carried out on soluble nuclear and cytoplasmic fractions, with increased nuclear SOD1 level (p<0.05). In addition, we observed the presence of cytoplasmic SOD1 aggregates in agreement with an increased amount of the protein recovered by the insoluble fraction. A further confirmation of the overall increased level of SOD1 has been obtained from single cells analysis using flow cytometry as cells from SALS patients showed an higher SOD1 protein content (p<0.05). These findings add further evidence to the hypothesis of an altered WT-SOD1 expression profile in peripheral blood mononuclear cells (PBMCs) from patients with ALS suggesting that WT-SOD1 species with different degrees of solubility could be involved in the pathogenesis of the disease. PMID- 24155876 TI - Capturing ecosystem services, stakeholders' preferences and trade-offs in coastal aquaculture decisions: a Bayesian belief network application. AB - Aquaculture activities are embedded in complex social-ecological systems. However, aquaculture development decisions have tended to be driven by revenue generation, failing to account for interactions with the environment and the full value of the benefits derived from services provided by local ecosystems. Trade offs resulting from changes in ecosystem services provision and associated impacts on livelihoods are also often overlooked. This paper proposes an innovative application of Bayesian belief networks - influence diagrams - as a decision support system for mediating trade-offs arising from the development of shrimp aquaculture in Thailand. Senior experts were consulted (n = 12) and primary farm data on the economics of shrimp farming (n = 20) were collected alongside secondary information on ecosystem services, in order to construct and populate the network. Trade-offs were quantitatively assessed through the generation of a probabilistic impact matrix. This matrix captures nonlinearity and uncertainty and describes the relative performance and impacts of shrimp farming management scenarios on local livelihoods. It also incorporates export revenues and provision and value of ecosystem services such as coastal protection and biodiversity. This research shows that Bayesian belief modeling can support complex decision-making on pathways for sustainable coastal aquaculture development and thus contributes to the debate on the role of aquaculture in social-ecological resilience and economic development. PMID- 24155875 TI - Using bosentan to treat paraquat poisoning-induced acute lung injury in rats. AB - BACKGROUND: Paraquat poisoning is well known for causing multiple organ function failure (MODS) and high mortality. Acute lung injury and advanced pulmonary fibrosis are the most serious complications. Bosentan is a dual endothelin receptor antagonist. It plays an important role in treating PF. There is no related literature on the use of bosentan therapy for paraquat poisoning. OBJECTIVE: To study the use of bosentan to treat acute lung injury and pulmonary fibrosis as induced by paraquat. METHOD: A total of 120 adult Wister male rats were randomly assigned to three groups: the paraquat poisoning group (rats were intragastrically administered with paraquat at 50 mg/kg body weight once at the beginning); the bosentan therapy group (rats were administered bosentan at 100 mg/kg body weight by intragastric administration half an hour after paraquat was administered, then the same dose was administered once a day); and a control group (rats were administered intragastric physiological saline). On the 3rd, 7th, 14th, and 21st days following paraquat exposure, rats were sacrificed, and samples of lung tissue and venous blood were collected. The levels of transforming growth factor-beta1 (TGF-beta1), endothelin-1 (ET-1), and hydroxyproline (HYP) in the plasma and lung homogenate were determined. Optical and electronic microscopes were used to examine pathological changes. RESULT: The TGF-beta1, ET-1, and HYP of the paraquat poisoning group were significantly higher than in the control group, and they were significantly lower in the 21st day therapy group than in the paraquat poisoning group on the same day. Under the optical and electronic microscopes, lung tissue damage was observed to be more severe but was then reduced after bosentan was administered. CONCLUSION: Bosentan can reduce inflammation factor release. It has a therapeutic effect on acute lung injury as induced by paraquat. PMID- 24155877 TI - Methamphetamine increases locomotion and dopamine transporter activity in dopamine d5 receptor-deficient mice. AB - Dopamine regulates the psychomotor stimulant activities of amphetamine-like substances in the brain. The effects of dopamine are mediated through five known dopamine receptor subtypes in mammals. The functional relevance of D5 dopamine receptors in the central nervous system is not well understood. To determine the functional relevance of D5 dopamine receptors, we created D5 dopamine receptor deficient mice and then used these mice to assess the roles of D5 dopamine receptors in the behavioral response to methamphetamine. Interestingly, D5 dopamine receptor-deficient mice displayed increased ambulation in response to methamphetamine. Furthermore, dopamine transporter threonine phosphorylation levels, which regulate amphetamine-induced dopamine release, were elevated in D5 dopamine receptor-deficient mice. The increase in methamphetamine-induced locomotor activity was eliminated by pretreatment with the dopamine transporter blocker GBR12909. Taken together, these results suggest that dopamine transporter activity and threonine phosphorylation levels are regulated by D5 dopamine receptors. PMID- 24155878 TI - PNPLA3 I148M polymorphism, clinical presentation, and survival in patients with hepatocellular carcinoma. AB - BACKGROUND & AIMS: Aim of this study was to evaluate whether the PNPLA3 I148M polymorphism, previously associated with hepatocellular carcinoma (HCC) risk, influences the clinical presentation of HCC and survival. METHODS: we considered 460 consecutive HCC patients referred to tertiary care centers in Northern Italy, 353 with follow-up data. RESULTS: Homozygosity for PNPLA3 148M at risk allele was enriched in HCC patients with alcoholic liver disease or nonalcoholic fatty liver disease (ALD&NAFLD: relative risk 5.9, 95% c.i. 3.5-9.9; other liver diseases: relative risk 1.9, 95% c.i. 1.1-3.4). In ALD&NAFLD patients, the PNPLA3 148M allele was associated with younger age, shorter history of cirrhosis, less advanced (Child A) cirrhosis at HCC diagnosis, and lower HCC differentiation grade (p<0.05). Homozygosity for PNPLA3 148M was associated with reduced survival in the overall series (p = 0.009), and with a higher number of HCC lesions at presentation (p = 0.007) and reduced survival in ALD&NAFLD patients (p = 0.003; median survival 30, 95% c.i. 20-39 vs. 45, 95% c.i. 38-52 months), but not in those with HCC related to other etiologies (p = 0.86; 48, 95% c.i. 32-64 vs. 55, 95% c.i. 43-67 months). At multivariate Cox regression analysis, homozygosity for PNPLA3 148M was the only negative predictor of survival in ALD&NAFLD patients (HR of death 1.57, 95% c.i. 1.12-2.78). CONCLUSIONS: PNPLA3 148M is over-represented in ALD&NAFLD HCC patients, and is associated with occurrence at a less advanced stage of liver disease in ALD&NAFLD. In ALD&NAFLD, PNPLA3 148M is associated with more diffuse HCC at presentation, and with reduced survival. PMID- 24155879 TI - Putative DHHC-cysteine-rich domain S-acyltransferase in plants. AB - Protein S-acyltransferases (PATs) containing Asp-His-His-Cys within a Cys-rich domain (DHHC-CRD) are polytopic transmembrane proteins that are found in eukaryotic cells and mediate the S-acylation of target proteins. S-acylation is an important secondary and reversible modification that regulates the membrane association, trafficking and function of target proteins. However, little is known about the characteristics of PATs in plants. Here, we identified 804 PATs from 31 species with complete genomes. The analysis of the phylogenetic relationships suggested that all of the PATs fell into 8 groups. In addition, we analysed the phylogeny, genomic organization, chromosome localisation and expression pattern of PATs in Arabidopsis, Oryza sative, Zea mays and Glycine max. The microarray data revealed that PATs genes were expressed in different tissues and during different life stages. The preferential expression of the ZmPATs in specific tissues and the response of Zea mays to treatments with phytohormones and abiotic stress demonstrated that the PATs play roles in plant growth and development as well as in stress responses. Our data provide a useful reference for the identification and functional analysis of the members of this protein family. PMID- 24155880 TI - Spatial wavelet analysis of calcium oscillations in developing neurons. AB - Calcium signals play a major role in the control of all key stages of neuronal development, and in particular in the growth and orientation of neuritic processes. These signals are characterized by high spatial compartmentalization, a property which has a strong relevance in the different roles of specific neuronal regions in information coding. In this context it is therefore important to understand the structural and functional basis of this spatial compartmentalization, and in particular whether the behavior at each compartment is merely a consequence of its specific geometry or the result of the spatial segregation of specific calcium influx/efflux mechanisms. Here we have developed a novel approach to separate geometrical from functional differences, regardless on the assumptions on the actual mechanisms involved in the generation of calcium signals. First, spatial indices are derived with a wavelet-theoretic approach which define a measure of the oscillations of cytosolic calcium concentration in specific regions of interests (ROIs) along a cell, in our case developing chick ciliary ganglion neurons. The resulting spatial profile demonstrates clearly that different ROIs along the neuron are characterized by specific patterns of calcium oscillations. Next we have investigated whether this inhomogeneity is due just to geometrical factors, namely the surface to volume ratio in the different subcompartments (e.g. soma vs. growth cone) or it depends on their specific biophysical properties. To this aim correlation functions are computed between the activity indices and the surface/volume ratio along the cell: the data thus obtained are validated by a statistical analysis on a dataset of [Formula: see text] different cells. This analysis shows that whereas in the soma calcium dynamics is highly correlated to the surface/volume ratio, correlations drop in the growth cone-neurite region, suggesting that in this latter case the key factor is the expression of specific mechanisms controlling calcium influx/efflux. PMID- 24155881 TI - Small-aperture monovision and the Pulfrich experience: absence of neural adaptation effects. AB - PURPOSE: To explore whether adaptation reduces the interocular visual latency differences and the induced Pulfrich effect caused by the anisocoria implicit in small-aperture monovision. METHODS: Anisocoric vision was simulated in two adults by wearing in the non-dominant eye for 7 successive days, while awake, an opaque soft contact lens (CL) with a small, central, circular aperture. This was repeated with aperture diameters of 1.5 and 2.5 mm. Each day, monocular and binocular pattern-reversal Visual Evoked Potentials (VEP) were recorded. Additionally, the Pulfrich effect was measured: the task of the subject was to state whether a a 2-deg spot appeared in front or behind the plane of a central cross when moved left-to-right or right-to-left on a display screen. The retinal illuminance of the dominant eye was varied using neutral density (ND) filters to establish the ND value which eliminated the Pulfrich effect for each lens. All experiments were performed at luminance levels of 5 and 30 cd/m(2). RESULTS: Interocular differences in monocular VEP latency (at 30 cd/m(2)) rose to about 12 15 ms and 20-25 ms when the CL aperture was 2.5 and 1.5 mm, respectively. The effect was more pronounced at 5 cd/m(2) (i.e. with larger natural pupils). A strong Pulfrich effect was observed under all conditions, with the effect being less striking for the 2.5 mm aperture. No neural adaptation appeared to occur: neither the interocular differences in VEP latency nor the ND value required to null the Pulfrich effect reduced over each 7-day period of anisocoric vision. CONCLUSIONS: Small-aperture monovision produced marked interocular differences in visual latency and a Pulfrich experience. These were not reduced by adaptation, perhaps because the natural pupil diameter of the dominant eye was continually changing throughout the day due to varying illumination and other factors, making adaptation difficult. PMID- 24155882 TI - High variation of fluorescence protein maturation times in closely related Escherichia coli strains. AB - Fluorescent proteins (FPs) are widely used in biochemistry, biology and biophysics. For quantitative analysis of gene expression FPs are often used as marking molecules. Therefore, sufficient knowledge of maturation times and their affecting factors is of high interest. Here, we investigate the maturation process of the FPs GFP and mCherry expressed by the three closely related Escherichia coli strains of the Colicin E2 system, a model system for colicinogenic interaction. One strain, the C strain produces Colicin, a toxin to which the S strain is sensitive, and against which the R strain is resistant. Under the growth conditions used in this study, the S and R strain have similar growth rates, as opposed to the C strain whose growth rate is significantly reduced due to the toxin production. In combination with theoretical modelling we studied the maturation kinetics of the two FPs in these strains and could confirm an exponential and sigmoidal maturation kinetic for GFP and mCherry, respectively. Our subsequent quantitative experimental analysis revealed a high variance in maturation times independent of the strain studied. In addition, we determined strain dependent maturation times and maturation behaviour. Firstly, FPs expressed by the S and R strain mature on similar average time-scales as opposed to FPs expressed by the C strain. Secondly, dependencies of maturation time with growth conditions are most pronounced in the GFP expressing C strain: Doubling the growth rate of this C strain results in an increased maturation time by a factor of 1.4. As maturation times can vary even between closely related strains, our data emphasize the importance of profound knowledge of individual strains' maturation times for accurate interpretation of gene expression data. PMID- 24155883 TI - Compound eye adaptations for diurnal and nocturnal lifestyle in the intertidal ant, Polyrhachis sokolova. AB - The Australian intertidal ant, Polyrhachis sokolova lives in mudflat habitats and nests at the base of mangroves. They are solitary foraging ants that rely on visual cues. The ants are active during low tides at both day and night and thus experience a wide range of light intensities. We here ask the extent to which the compound eyes of P. sokolova reflect the fact that they operate during both day and night. The ants have typical apposition compound eyes with 596 ommatidia per eye and an interommatidial angle of 6.0 degrees . We find the ants have developed large lenses (33 um in diameter) and wide rhabdoms (5 um in diameter) to make their eyes highly sensitive to low light conditions. To be active at bright light conditions, the ants have developed an extreme pupillary mechanism during which the primary pigment cells constrict the crystalline cone to form a narrow tract of 0.5 um wide and 16 um long. This pupillary mechanism protects the photoreceptors from bright light, making the eyes less sensitive during the day. The dorsal rim area of their compound eye has specialised photoreceptors that could aid in detecting the orientation of the pattern of polarised skylight, which would assist the animals to determine compass directions required while navigating between nest and food sources. PMID- 24155884 TI - Substitution of glutamate residue by lysine in the dimerization domain affects DNA binding ability of HapR by inducing structural deformity in the DNA binding domain. AB - HapR has been given the status of a high cell density master regulatory protein in Vibrio cholerae. Though many facts are known regarding its structural and functional aspects, much still can be learnt from natural variants of the wild type protein. This work aims at investigating the nature of functional inertness of a HapR natural variant harboring a substitution of a conserved glutamate residue at position 117 which participates in forming a salt bridge by lysine (HapRV2G-E(117)K). Experimental evidence presented here reveals the inability of this variant to interact with various cognate promoters by in vitro gel shift assay. Furthermore, the elution profiles of HapRV2G-E(117)K protein along with the wild type functional HapRV2G in size-exclusion chromatography as well as circular dichroism spectra did not reflect any significant differences in its structure, thereby indicating the intactness of dimer in the variant protein. To gain further insight into the global shape of the proteins, small angle X-ray scattering analysis (SAXS) was performed. Intriguingly, increased radius of gyration of HapRV2G-E(117)K of 27.5 A in comparison to the wild type protein from SAXS data analyses implied a significant alteration in the global shape of the dimeric HapRV2G-E(117)K protein. Structure reconstruction brought forth that the DNA binding domains were substantially "parted away" in this variant. Taken together, our data illustrates that substitution of the conserved glutamate residue by lysine in the dimerization domain induces separation of the two DNA binding domains from their native-like positioning without altering the dimeric status of HapR variant. PMID- 24155885 TI - Lineage-specific responses of tooth shape in murine rodents (murinae, rodentia) to late Miocene dietary change in the Siwaliks of Pakistan. AB - Past ecological responses of mammals to climate change are recognized in the fossil record by adaptive significance of morphological variations. To understand the role of dietary behavior on functional adaptations of dental morphology in rodent evolution, we examine evolutionary change of tooth shape in late Miocene Siwalik murine rodents, which experienced a dietary shift toward C4 diets during late Miocene ecological change indicated by carbon isotopic evidence. Geometric morphometric analysis in the outline of upper first molars captures dichotomous lineages of Siwalik murines, in agreement with phylogenetic hypotheses of previous studies (two distinct clades: the Karnimata and Progonomys clades), and indicates lineage-specific functional responses to mechanical properties of their diets. Tooth shapes of the two clades are similar at their sympatric origin but deviate from each other with decreasing overlap through time. Shape change in the Karnimata clade is associated with greater efficiency of propalinal chewing for tough diets than in the Progonomys clade. Larger body mass in Karnimata may be related to exploitation of lower-quality food items, such as grasses, than in smaller-bodied Progonomys. The functional and ecophysiological aspects of Karnimata exploiting C4 grasses are concordant with their isotopic dietary preference relative to Progonomys. Lineage-specific selection was differentially greater in Karnimata, and a faster rate of shape change toward derived Karnimata facilitated inclusion of C4 grasses in the diet. Sympatric speciation in these clades is most plausibly explained by interspecific competition on resource utilization between the two, based on comparisons of our results with the carbon isotope data. Interspecific competition with Karnimata may have suppressed morphological innovation of the Progonomys clade. Pairwise analyses of morphological and carbon isotope data can uncover ecological causes of sympatric speciation and define functional adaptations of teeth to resources. PMID- 24155886 TI - A preference based measure of complementary feeding quality: application to the Avon longitudinal study of parents and children. AB - This paper presents the development of the Complementary Feeding Utility Index (CFUI), a composite index aimed to measure adherence to infant feeding guidelines. Through an axiomatic characterization this paper shows the advantages in using the CFUI are the following: it avoids the use of arbitrary cut-offs, and by converting observed diet preferences into utilities, summing the score is meaningful. In addition, as the CFUI is designed to be scored continuously, it allows the transition from intake of beneficial foods (in low quantities) and intake of detrimental foods (in high quantities) to be more subtle. The paper first describes the rationale being the development of the CFUI and then elaborates on the methodology used to develop the CFUI, including the process of selecting the components. The methodology is applied to data collected from the Avon Longitudinal Study of Parents and Children to show the advantages of the CFUI over traditional diet index approaches. Unlike traditional approaches, the distribution of the CFUI does not peak towards mean value but distributes evenly towards the tails of the distribution. PMID- 24155887 TI - Serum tryptase monitoring in indolent systemic mastocytosis: association with disease features and patient outcome. AB - BACKGROUND: Serum baseline tryptase (sBT) is a minor diagnostic criterion for systemic mastocytosis (SM) of undetermined prognostic impact. We monitored sBT levels in indolent SM (ISM) patients and investigated its utility for predicting disease behaviour and outcome. METHODS: In total 74 adult ISM patients who were followed for >=48 months and received no cytoreductive therapy were retrospectively studied. Patients were classified according to the pattern of evolution of sBT observed. RESULTS: Overall 16/74 (22%) cases had decreasing sBT levels, 48 (65%) patients showed increasing sBT levels and 10 (13%) patients showed a fluctuating pattern. Patients with significantly increasing sBT (sBT slope >=0.15) after 48 months of follow-up showed a slightly greater rate of development of diffuse bone sclerosis (13% vs. 2%) and hepatomegaly plus splenomegaly (16% vs. 5%), as well as a significantly greater frequency of multilineage vs. mast cells (MC)-restricted KIT mutation (p = 0.01) together with a greater frequency of cases with progression of ISM to smouldering and aggressive SM (p = 0.03), and a shorter progression-free survival (p = 0.03). CONCLUSIONS: Monitoring of sBT in ISM patients is closely associated with poor prognosis disease features as well as with disease progression, pointing out the need for a closer follow-up in ISM patients with progressively increasing sBT values. PMID- 24155888 TI - Isolation of novel Afipia septicemium and identification of previously unknown bacteria Bradyrhizobium sp. OHSU_III from blood of patients with poorly defined illnesses. AB - Cultures previously set up for isolation of mycoplasmal agents from blood of patients with poorly-defined illnesses, although not yielding positive results, were cryopreserved because of suspicion of having low numbers of unknown microbes living in an inactive state in the broth. We re-initiated a set of 3 cultures for analysis of the "uncultivable" or poorly-grown microbes using NGS technology. Broth of cultures from 3 blood samples, submitted from OHSU between 2000 and 2004, were inoculated into culture flasks containing fresh modified SP4 medium and kept at room temperature (RT), 30 degrees C and 35 degrees C. The cultures showing evidence of microbial growth were expanded and subjected to DNA analysis by genomic sequencing using Illumina MiSeq. Two of the 3 re-initiated blood cultures kept at RT after 7-8 weeks showed evidence of microbial growth that gradually reached into a cell density with detectable turbidity. The microbes in the broth when streaked on SP4 agar plates produced microscopic colonies in ~ 2 weeks. Genomic studies revealed that the microbes isolated from the 2 blood cultures were a novel Afipia species, tentatively named Afipia septicemium. Microbes in the 3(rd) culture (OHSU_III) kept at RT had a limited level of growth and could not reach a plateau with high cell density. Genomic sequencing identified the microbe in the culture as a previously unknown species of Bradyrhizobium bacteria. This study reports on the isolation of novel Afipia and Bradyrhizobium species. Isolation of Bradyrhizobium species bacteria has never been reported in humans. The study also reveals a previously unrecognized nature of hematogenous infections by the 2 unique groups of Bradyrhizobiaceae. Our studies show that improvement of culture system plus effective use of NGS technology can facilitate findings of infections by unusual microbes in patients having poorly-defined, sometimes mysterious illnesses. PMID- 24155889 TI - Loss of DAP12 and FcRgamma drives exaggerated IL-12 production and CD8(+) T cell response by CCR2(+) Mo-DCs. AB - Dap12 and FcRgamma, the two transmembrane ITAM-containing signaling adaptors expressed in dendritic cells (DC), are implicated in the regulation of DC function. Several activating and adhesion receptors including integrins require these chains for their function in triggering downstream signaling and effector pathways, however the exact role(s) for Dap12 and FcRgamma remains elusive as their loss can lead to both attenuating and enhancing effects. Here, we report that mice congenitally lacking both Dap12 and FcRgamma chains (DF) show a massively enhanced effector CD8(+) T cell response to protein antigen immunization or West Nile Virus (WNV) infection. Thus, immunization of DF mice with MHCI-restricted OVA peptide leads to accumulation of IL-12-producing monocyte-derived dendritic cells (Mo-DC) in draining lymph nodes, followed by vastly enhanced generation of antigen-specific IFNgamma-producing CD8(+) T cells. Moreover, DF mice show increased viral clearance in the WNV infection model. Depletion of CCR2+ monocytes/macrophages in vivo by administration anti-CCR2 antibodies or clodronate liposomes completely prevents the exaggerated CD8+ T cell response in DF mice. Mechanistically, we show that the loss of Dap12 and FcRgamma-mediated signals in Mo-DC leads to a disruption of GM-CSF receptor induced STAT5 activation resulting in upregulation of expression of IRF8, a transcription factor. Consequently, Dap12- and FcRgamma-deficiency exacerbates GM CSF-driven monocyte differentiation and production of inflammatory Mo-DC. Our data suggest a novel cross-talk between DC-ITAM and GM-CSF signaling pathways, which controls Mo-DC differentiation, IL-12 production, and CD8(+) T cell responses. PMID- 24155890 TI - Identification of a STAT5 target gene, Dpf3, provides novel insights in chronic lymphocytic leukemia. AB - STAT5 controls essential cellular functions and is encoded by two genes, Stat5a and Stat5b. To provide insight to the mechanisms linking hematologic malignancy to STAT5 activation/regulation of target genes, we identified STAT5 target genes and focused on Dpf3 gene, which encodes for an epigenetic factor. Dpf3 expression was induced upon IL-3 stimulation in Ba/F3 cells, while strong binding of both STAT5a and STAT5b was detected in its promoter. Reduced expression of Dpf3 was detected in Ba/F3 cells with Stat5a and Stat5b knock-down, suggesting that this gene is positively regulated by STAT5, upon IL-3 stimulation. Furthermore, this gene was significantly up-regulated in CLL patients, where DPF3 gene/protein up regulation and strong STAT5 binding to the DPF3 promoter, correlated with increased STAT5 activation, mainly in non-malignant myeloid cells (granulocytes). Our findings provide insights in the STAT5 dependent transcriptional regulation of Dpf3, and demonstrate for the first time increased STAT5 activation in granulocytes of CLL patients. Novel routes of investigation are opened to facilitate the understanding of the role of STAT5 activation in the communication between non-malignant myeloid and malignant B-cells, and the functions of STAT5 target genes networks in CLL biology. PMID- 24155891 TI - IL-27 enhances the expression of TRAIL and TLR3 in human melanomas and inhibits their tumor growth in cooperation with a TLR3 agonist poly(I:C) partly in a TRAIL dependent manner. AB - Interleukin (IL)-27 is a member of the IL-6/IL-12 cytokine family and possesses potent antitumor activity, which is mediated by multiple mechanisms. Toll-like receptor (TLR)3 is the critical sensor of the innate immune system that serves to identify viral double-stranded RNA. TLR3 is frequently expressed by various types of malignant cells, and recent studies reported that a synthetic TLR3 agonist, polyinosinic-polycytidylic acid [poly(I:C)], induces antitumor effects on malignant cells. In the present study, we have explored the effect of IL-27 on human melanomas and uncovered a previously unknown mechanism. We found that IL-27 inhibits in vitro tumor growth of human melanomas and greatly enhances the expression of TNF-related apoptosis inducing ligand (TRAIL) in a dose-dependent manner. Neutralizing antibody against TRAIL partly but significantly blocked the IL-27-mediated inhibition of tumor growth. In addition, IL-27 and poly(I:C) cooperatively augmented TRAIL expression and inhibited tumor growth. The cooperative effect could be ascribed to the augmented expression of TLR3, but not retinoic acid-inducible gene-I or anti-melanoma differentiation-associated gene 5, by IL-27. The inhibition of tumor growth by the combination was also significantly abrogated by anti-TRAIL neutralizing antibody. Moreover, IL-27 and poly(I:C) cooperatively suppressed in vivo tumor growth of human melanoma in immunodeficient mice. Taken together, these results suggest that IL-27 enhances the expression of TRAIL and TLR3 in human melanomas and inhibits their tumor growth in cooperation with poly(I:C), partly in a TRAIL-dependent manner. Thus, IL-27 and the combination of IL-27 and poly(I:C) may be attractive candidates for cancer immunotherapy. PMID- 24155892 TI - Combined inhibition of epidermal growth factor receptor and cyclooxygenase-2 leads to greater anti-tumor activity of docetaxel in advanced prostate cancer. AB - The epidermal growth factor receptor (EGFR) and cyclooxygenase-2(COX-2) play a critical role in disease progression, relapse and therapeutic resistance of advanced prostate cancer (PCa). In this paper, we evaluated, for the first time, the therapeutic benefit of blocking EGRF and/or COX-2 (using gefitinib and NS 398, respectively) in terms of improving the efficacy of the conventional clinical chemotherapeutic drug docetaxel in vitro and vivo. We showed that EGFR and COX-2 expression was higher in metastatic than non-metastatic PCa tissues and cells. Docetaxel, alone or in combination with gefitinib or NS-398, resulted in a small decrease in cell viability. The three drug combination decreased cell viability to a greater extent than docetaxel alone or in combination with gefitinib or NS-398. Docetaxel resulted in a modest increase in apoptotic cell in metastatic and non-metastatic cell lines. NS-398 markedly enhanced docetaxel induced cell apoptosis. The combination of the three drugs caused even more marked apoptosis and resulted in greater suppression of invasive potential than docetaxel alone or in association with gefitinib or NS-398. The combination of all three drugs also resulted in a more marked decrease in NF-KappaB, MMP-9 and VEGF levels in PC-3M cells. These in vitro findings were supported by in vivo studies showing that docetaxel in combination with gefitinib and NS-398 was significantly more effective than any individual agent. Based on previous preclinical research, we conclude that simultaneously blocking EGFR and COX-2 by gefitinib and NS-398 sensitizes advanced PCa cells to docetaxel-induced cytotoxicity. PMID- 24155893 TI - Expression of the agmatine deiminase pathway in Enterococcus faecalis is activated by the AguR regulator and repressed by CcpA and PTS(Man) systems. AB - Although the agmatine deiminase system (AgDI) has been investigated in Enterococcus faecalis, little information is available with respect to its gene regulation. In this study we demonstrate that the presence of exogenous agmatine induces the expression of agu genes in this bacterium. In contrast to the homologous and extensively characterized AgDI system of S. mutants, the aguBDAC operon in E. faecalis is not induced in response to low pH. In spite of this, agmatine catabolism in this bacterium contributes by neutralizing the external medium while enhancing bacterial growth. Our results indicate that carbon catabolic repression (CCR) operates on the AgDI system via a mechanism that involves interaction of CcpA and P-Ser-HPr with a cre site found in an unusual position considering the aguB promoter (55 nt upstream the +1 position). In addition, we found that components of the mannose phosphotransferase (PTS(Man)) system also contributed to CCR in E. faecalis since a complete relief of the PTS sugars repressive effect was observed only in a PTS(Man) and CcpA double defective strain. Our gene context analysis revealed that aguR is present in oral and gastrointestinal microorganisms. Thus, regulation of the aguBDAC operon in E. faecalis seems to have evolved to obtain energy and resist low pH conditions in order to persist and colonize gastrointestinal niches. PMID- 24155895 TI - Identification of novel predictor classifiers for inflammatory bowel disease by gene expression profiling. AB - BACKGROUND: Improvement of patient quality of life is the ultimate goal of biomedical research, particularly when dealing with complex, chronic and debilitating conditions such as inflammatory bowel disease (IBD). This is largely dependent on receiving an accurate and rapid diagnose, an effective treatment and in the prediction and prevention of side effects and complications. The low sensitivity and specificity of current markers burden their general use in the clinical practice. New biomarkers with accurate predictive ability are needed to achieve a personalized approach that take the inter-individual differences into consideration. METHODS: We performed a high throughput approach using microarray gene expression profiling of colon pinch biopsies from IBD patients to identify predictive transcriptional signatures associated with intestinal inflammation, differential diagnosis (Crohn's disease or ulcerative colitis), response to glucocorticoids (resistance and dependence) or prognosis (need for surgery). Class prediction was performed with self-validating Prophet software package. RESULTS: Transcriptional profiling divided patients in two subgroups that associated with degree of inflammation. Class predictors were identified with predictive accuracy ranging from 67 to 100%. The expression accuracy was confirmed by real time-PCR quantification. Functional analysis of the predictor genes showed that they play a role in immune responses to bacteria (PTN, OLFM4 and LILRA2), autophagy and endocytocis processes (ATG16L1, DNAJC6, VPS26B, RABGEF1, ITSN1 and TMEM127) and glucocorticoid receptor degradation (STS and MMD2). CONCLUSIONS: We conclude that using analytical algorithms for class prediction discovery can be useful to uncover gene expression profiles and identify classifier genes with potential stratification utility of IBD patients, a major step towards personalized therapy. PMID- 24155894 TI - Natriuretic peptide receptor-C agonist attenuates the expression of cell cycle proteins and proliferation of vascular smooth muscle cells from spontaneously hypertensive rats: role of Gi proteins and MAPkinase/PI3kinase signaling. AB - Vascular smooth muscle cells (VSMC) from spontaneously hypertensive rats (SHR) exhibit hyperproliferation and overexpression of cell cycle proteins. We earlier showed that small peptide fragments of cytoplasmic domain of natriuretic receptor C (NPR-C) attenuate vasoactive peptide-induced hyperproliferation of VSMC. The present study investigated if C-ANP4-23, a specific agonist of NPR-C, could attanuate the hyperproliferation of VSMC from SHR by inhibiting the overexpression of cell cycle proteins and examine the underlying signaling pathways contributing to this inhibition. The proliferation of VSMC was determined by [(3)H] thymidine incorporation and the expression of proteins was determined by Western blotting. The hyperproliferation of VSMC from SHR and overexpression of cyclin D1,cyclin A, cyclin E, cyclin-dependent kinase 2 (cdk2), phosphorylated retinoblastoma protein (pRb), Gialpha proteins and enhanced phosphorylation of ERK1/2 and AKT exhibited by VSMC from SHR were attenuated by C ANP4-23 to control levels. In addition, in vivo treatment of SHR with C-ANP4-23 also attenuated the enhanced proliferation of VSMC. Furthemore, PD98059, wortmannin and pertussis toxin, the inhibitors of MAP kinase, PI3kinase and Gialpha proteins respectively, also attenuated the hyperproliferation of VSMC from SHR and overexpression of cell cycle proteins to control levels. These results indicate that NPR-C activation by C-ANP4-23 attenuates the enhanced levels of cell cycle proteins through the inhibition of enhanced expression of Gialpha proteins and enhanced activation of MAPkinase/PI3kinase and results in the attenuation of hyperproliferation of VSMC from SHR. It may be suggested that C-ANP4-23 could be used as a therapeutic agent in the treatment of vascular complications associated with hypertension, atherosclerosis and restenosis. PMID- 24155896 TI - Calmodulin binding to Dfi1p promotes invasiveness of Candida albicans. AB - Candida albicans, a dimorphic fungus, undergoes hyphal development in response to many different environmental cues, including growth in contact with a semi-solid matrix. C. albicans forms hyphae that invade agar when cells are embedded in or grown on the surface of agar, and the integral membrane protein Dfi1p is required for this activity. In addition, Dfi1p is required for full activation of mitogen activated protein kinase Cek1p during growth on agar. In this study, we identified a putative calmodulin binding motif in the C-terminal tail of Dfi1p. This region of Dfi1p bound to calmodulin in vitro, and mutations that affected this region affected both calmodulin binding in vitro and invasive filamentation when incorporated into the full length Dfi1p protein. Moreover, increasing intracellular calcium levels led to calcium-dependent, Dfi1p-dependent Cek1p activation. We propose that conformational changes in Dfi1p in response to environmental conditions encountered during growth allow the protein to bind calmodulin and initiate a signaling cascade that activates Cek1p. PMID- 24155897 TI - Outcome of tuberculosis treatment in patients with diabetes mellitus treated in the revised national tuberculosis control programme in Malappuram District, Kerala, India. AB - SETTINGS: Kerala State, India has reported the greatest dual burden of Tuberculosis (TB) and Diabetes Mellitus (DM). Malappuram district in Kerala has monitored and recorded DM status and its control from 2010 under Revised National Tuberculosis Control Program (RNTCP). OBJECTIVES: To assess, under programme conditions, comprehensiveness of recording DM status among TB cases and the TB treatment outcomes among DM patients (disaggregated by glycemic control) and compare with-non DM patients. DESIGN: This retrospective record review included 3,116TB patients from April 2010 to September 2011.DM was defined as per international guidelines and TB treatment outcomes were categorized as favourable(cured and treatment completed) and unfavourable(death, default, failure and transfer out). Relative Risk (RR) and 95% confidence intervals(CI) were calculated to assess the risk of unfavourable outcomes. RESULTS: DM status was recorded in 90% of TB cases and 667 (24%) had DM. 17% of DM patients and 23% of patients with unknown DM status had unfavourable outcomes but this difference was not statistically significant. Unadjusted RR for poor glycemic control or unknown control status for unfavourable outcome were (2.00; 95% CI 0.97-4.13) and (2.14; 95% CI 1.11-4.13). CONCLUSION: This study could not confirm an adverse association between DM or its control during treatment and the course of response to TB treatment.DM screening in TB cases and recording of DM care needs to be improved to enable more conclusive evidence. PMID- 24155898 TI - Angiotensin II facilitates fibrogenic effect of TGF-beta1 through enhancing the down-regulation of BAMBI caused by LPS: a new pro-fibrotic mechanism of angiotensin II. AB - Angiotensin II has progressively been considered to play an important role in the development of liver fibrosis, although the mechanism isn't fully understood. The aim of this study was to investigate a possible pro-fibrotic mechanism, by which angiotensin II would enhance the pro-fibrotic effect of transforming growth factor beta 1 (TGF-beta1) through up-regulation of toll-like receptor 4 (TLR4) and enhancing down-regulation of TGF-beta1 inhibitory pseudo-receptor-BAMBI caused by LPS in hepatic stellate cells (HSCs). Firstly, the synergistic effects of angiotensin II, TGF-beta1 and LPS on collagen 1alpha production were confirmed in vitro by ELISA, in which angiotensin II, LPS and TGF-beta1 were treated sequentially, and in vivo by immunofluorescence, in the experiments single or multiple intra-peritoneally implanted osmotic mini-pumps administrating angiotensin II or LPS combined with intra-peritoneal injections of TGF-beta1 were used. We also found that only LPS and TGF-beta1 weren't enough to induce obvious fibrogenesis without angiotensin II. Secondly, to identify the reason of why angiotensin II is so important, the minute level of TLR4 in activated HSCs - T6 and primary quiescent HSCs of rat, up-regulation of TLR4 by angiotensin II and blockage by different angiotensin II receptor type 1 (AT1) blockers in HSCs were assayed by western blotting in vitro and immunofluorescence in vivo. Finally, BAMBI expression level, which is regulated by LPS-TLR4 pathway, was detected by qRT-PCR and results showed angiotensin II enhanced the down-regulation of BAMBI mRNA caused by LPS in vitro and in vivo, and TLR4 neutralization antibody blocked this interactive effect. These data demonstrated that angiotensin II enhances LPS TLR4 pathway signaling and further down-regulates expression of BAMBI through up regulation of TLR4, which results in facilitation of pro-fibrotic activity of TGF beta1. Angiotensin II, LPS and TGF-beta1 act synergistically during hepatic fibrogenesis, showing crosstalks between angiotensin II-AT1, LPS-TLR4 and TGF beta1-BAMBI signal pathways in rat HSCs. PMID- 24155899 TI - Species distribution models for crop pollination: a modelling framework applied to Great Britain. AB - Insect pollination benefits over three quarters of the world's major crops. There is growing concern that observed declines in pollinators may impact on production and revenues from animal pollinated crops. Knowing the distribution of pollinators is therefore crucial for estimating their availability to pollinate crops; however, in general, we have an incomplete knowledge of where these pollinators occur. We propose a method to predict geographical patterns of pollination service to crops, novel in two elements: the use of pollinator records rather than expert knowledge to predict pollinator occurrence, and the inclusion of the managed pollinator supply. We integrated a maximum entropy species distribution model (SDM) with an existing pollination service model (PSM) to derive the availability of pollinators for crop pollination. We used nation wide records of wild and managed pollinators (honey bees) as well as agricultural data from Great Britain. We first calibrated the SDM on a representative sample of bee and hoverfly crop pollinator species, evaluating the effects of different settings on model performance and on its capacity to identify the most important predictors. The importance of the different predictors was better resolved by SDM derived from simpler functions, with consistent results for bees and hoverflies. We then used the species distributions from the calibrated model to predict pollination service of wild and managed pollinators, using field beans as a test case. The PSM allowed us to spatially characterize the contribution of wild and managed pollinators and also identify areas potentially vulnerable to low pollination service provision, which can help direct local scale interventions. This approach can be extended to investigate geographical mismatches between crop pollination demand and the availability of pollinators, resulting from environmental change or policy scenarios. PMID- 24155900 TI - Physical and genetic associations of the Irc20 ubiquitin ligase with Cdc48 and SUMO. AB - A considerable percentage of the genome is dedicated to the ubiquitin-proteasome system, with the yeast genome predicted to encode approximately 100 ubiquitin ligases (or E3s), and the human genome predicted to encode more than 600 E3s. The most abundant class of E3s consists of RING finger-containing proteins. Although many insights have been obtained regarding the structure and catalytic mechanism of the E3s, much remains to be learned about the function of the individual E3s. Here we characterize IRC20, which encodes a dual RING- and Snf/Swi family ATPase domain-containing protein in yeast that has been implicated in DNA repair. We found that overexpression of IRC20 causes two transcription-associated phenotypes and demonstrate that the Irc20 RING domain possesses ubiquitin E3 activity in vitro. Two mass spectrometry approaches were undertaken to identify Irc20 associated proteins. Wild-type Irc20 associated with Cdc48, a AAA-ATPase that serves as an intermediary in the ubiquitin-proteasome system. A second approach using a RING mutant derivative of Irc20 detected increased association of the Irc20 mutant with SUMO. These findings provide a foundation for understanding the roles of Irc20 in transcription and DNA repair. PMID- 24155901 TI - Ecoregion-based conservation planning in the Mediterranean: dealing with large scale heterogeneity. AB - Spatial priorities for the conservation of three key Mediterranean habitats, i.e. seagrass Posidonia oceanica meadows, coralligenous formations, and marine caves, were determined through a systematic planning approach. Available information on the distribution of these habitats across the entire Mediterranean Sea was compiled to produce basin-scale distribution maps. Conservation targets for each habitat type were set according to European Union guidelines. Surrogates were used to estimate the spatial variation of opportunity cost for commercial, non commercial fishing, and aquaculture. Marxan conservation planning software was used to evaluate the comparative utility of two planning scenarios: (a) a whole basin scenario, referring to selection of priority areas across the whole Mediterranean Sea, and (b) an ecoregional scenario, in which priority areas were selected within eight predefined ecoregions. Although both scenarios required approximately the same total area to be protected in order to achieve conservation targets, the opportunity cost differed between them. The whole-basin scenario yielded a lower opportunity cost, but the Alboran Sea ecoregion was not represented and priority areas were predominantly located in the Ionian, Aegean, and Adriatic Seas. In comparison, the ecoregional scenario resulted in a higher representation of ecoregions and a more even distribution of priority areas, albeit with a higher opportunity cost. We suggest that planning at the ecoregional level ensures better representativeness of the selected conservation features and adequate protection of species, functional, and genetic diversity across the basin. While there are several initiatives that identify priority areas in the Mediterranean Sea, our approach is novel as it combines three issues: (a) it is based on the distribution of habitats and not species, which was rarely the case in previous efforts, (b) it considers spatial variability of cost throughout this socioeconomically heterogeneous basin, and (c) it adopts ecoregions as the most appropriate level for large-scale planning. PMID- 24155902 TI - Protein-protein interactions as a strategy towards protein-specific drug design: the example of ataxin-1. AB - A main challenge for structural biologists is to understand the mechanisms that discriminate between molecular interactions and determine function. Here, we show how partner recognition of the AXH domain of the transcriptional co-regulator ataxin-1 is fine-tuned by a subtle balance between self- and hetero-associations. Ataxin-1 is the protein responsible for the hereditary spinocerebellar ataxia type 1, a disease linked to protein aggregation and transcriptional dysregulation. Expansion of a polyglutamine tract is essential for ataxin-1 aggregation, but the sequence-wise distant AXH domain plays an important aggravating role in the process. The AXH domain is also a key element for non aberrant function as it intervenes in interactions with multiple protein partners. Previous data have shown that AXH is dimeric in solution and forms a dimer of dimers when crystallized. By solving the structure of a complex of AXH with a peptide from the interacting transcriptional repressor CIC, we show that the dimer interface of AXH is displaced by the new interaction and that, when blocked by the CIC peptide AXH aggregation and misfolding are impaired. This is a unique example in which palindromic self- and hetero-interactions within a sequence with chameleon properties discriminate the partner. We propose a drug design strategy for the treatment of SCA1 that is based on the information gained from the AXH/CIC complex. PMID- 24155904 TI - Revealing sources and distribution changes of dissolved organic matter (DOM) in pore water of sediment from the Yangtze estuary. AB - Dissolved organic matter (DOM) in sediment pore waters from Yangtze estuary of China based on abundance, UV absorbance, molecular weight distribution and fluorescence were investigated using a combination of various parameters of DOM as well as 3D fluorescence excitation emission matrix spectra (F-EEMS) with the parallel factor and principal component analysis (PARAFAC-PCA). The results indicated that DOM in pore water of Yangtze estuary was very variable which mainly composed of low aromaticity and molecular weight materials. Three humic like substances (C1, C2, C4) and one protein-like substance (C3) were identified by PARAFAC model. C1, C2 and C4 exhibited same trends and were very similar. The separation of samples on both axes of the PCA showed the difference in DOM properties. C1, C2 and C4 concurrently showed higher positive factor 1 loadings, while C3 showed highly positive factor 2 loadings. The PCA analysis showed a combination contribution of microbial DOM signal and terrestrial DOM signal in the Yangtze estuary. Higher and more variable DOM abundance, aromaticity and molecular weight of surface sediment pore water DOM can be found in the southern nearshore than the other regions primarily due to the influence of frequent and intensive human activities and tributaries inflow in this area. The DOM abundance, aromaticity, molecular weight and fluorescence intensity in core of different depth were relative constant and increased gradually with depth. DOM in core was mainly composed of humic-like material, which was due to higher release of the sedimentary organic material into the porewater during early diagenesis. PMID- 24155903 TI - Dietary zinc deficiency exaggerates ethanol-induced liver injury in mice: involvement of intrahepatic and extrahepatic factors. AB - Clinical studies have demonstrated that alcoholics have a lower dietary zinc intake compared to health controls. The present study was undertaken to determine the interaction between dietary zinc deficiency and ethanol consumption in the pathogenesis of alcoholic liver disease. C57BL/6N mice were subjected to 8-week feeding of 4 experimental liquid diets: (1) zinc adequate diet, (2) zinc adequate diet plus ethanol, (3) zinc deficient diet, and (4) zinc deficient diet plus ethanol. Ethanol exposure with adequate dietary zinc resulted in liver damage as indicated by elevated plasma alanine aminotransferase level and increased hepatic lipid accumulation and inflammatory cell infiltration. Dietary zinc deficiency alone increased hepatic lipid contents, but did not induce hepatic inflammation. Dietary zinc deficiency showed synergistic effects on ethanol-induced liver damage. Dietary zinc deficiency exaggerated ethanol effects on hepatic genes related to lipid metabolism and inflammatory response. Dietary zinc deficiency worsened ethanol-induced imbalance between hepatic pro-oxidant and antioxidant enzymes and hepatic expression of cell death receptors. Dietary zinc deficiency exaggerated ethanol-induced reduction of plasma leptin, although it did not affect ethanol-induced reduction of white adipose tissue mass. Dietary zinc deficiency also deteriorated ethanol-induced gut permeability increase and plasma endotoxin elevation. These results demonstrate, for the first time, that dietary zinc deficiency is a risk factor in alcoholic liver disease, and multiple intrahepatic and extrahepatic factors may mediate the detrimental effects of zinc deficiency. PMID- 24155905 TI - Expression of plant sweet protein brazzein in the milk of transgenic mice. AB - Sugar, the most popular sweetener, is essential in daily food. However, excessive sugar intake has been associated with several lifestyle-related diseases. Finding healthier and more economical alternatives to sugars and artificial sweeteners has received increasing attention to fulfill the growing demand. Brazzein, which comes from the pulp of the edible fruit of the African plant Pentadiplandra brazzeana Baill, is a protein that is 2,000 times sweeter than sucrose by weight. Here we report the production of transgenic mice that carry the optimized brazzein gene driven by the goat Beta-casein promoter, which specifically directs gene expression in the mammary glands. Using western blot analysis and immunohistochemistry, we confirmed that brazzein could be efficiently expressed in mammalian milk, while retaining its sweetness. This study presents the possibility of producing plant protein-sweetened milk from large animals such as cattle and goats. PMID- 24155906 TI - XbaI and PvuII polymorphisms of estrogen receptor 1 gene in females with idiopathic scoliosis: no association with occurrence or clinical form. AB - INTRODUCTION: XbaI single nucleotide polymorphism (SNP) (A/G rs934099) in estrogen receptor 1 gene (ESR1) was described to be associated with curve severity in Japanese idiopathic scoliosis (IS) patients and in Chinese patients with both curve severity and predisposition to IS. PvuII SNP (C/T rs2234693) of ESR1 was described to be associated with the occurrence of IS in the Chinese population; however, two replication studies did not confirm the findings. The ESR1 SNPs have never been studied in Caucasian IS patients. METHODS: Case-control study. 287 females with IS underwent clinical, radiological and genetic examinations. The patients were divided into three groups according to curve progression velocity: non-progressive IS, slowly progressive IS (progression <1 degrees per month), and rapidly progressive IS (progression >=1 degrees per month). The radiological maximum Cobb angle was measured and surgery rate established. A control group consisted of 182 healthy females. RESULTS: All results followed Hardy-Weinberg equilibrium. In the case-control study, genotype frequency in the patients did not differ for the XbaI (AA = 33.5%, AG = 49.1%, GG = 17.4%), nor for the PvuII (TT = 26.8%, TC = 50.2%, CC = 23.0%) comparing to controls (AA = 33.5%, AG = 50.5%, GG = 15.9%) and (TT = 23.1%, TC = 51.1%, CC = 25.8%), respectively, p = 0.3685, p = 0.6046. The haplotype frequency for the patients (AT = 47.1%, GC = 39.2%, AC = 8.9%, GT = 2.8%) did not differ from the controls (AT = 44.8%, GC = 37.4%, AC = 14.0%, GT = 3.8%), p = 0.0645. No difference was found either in XbaI (p = 0.8671) or PvuII (p = 0.3601) allele distribution between the patients and the controls. In the case study, there was no significant difference in genotype frequency for the non-progressive, slowly progressive, and rapidly progressive scoliosis. No difference was found in genotype or haplotype distribution for the mean maximum Cobb angle or the surgery rate. CONCLUSIONS: No association was found between ESR1 XbaI or ESR1 PvuII SNP and idiopathic scoliosis in Caucasian females. None of the previously reported associations could be confirmed, regarding curve severity, progression or operation rate. PMID- 24155907 TI - Potential use of school absenteeism record for disease surveillance in developing countries, case study in rural Cambodia. AB - BACKGROUND: Disease surveillance allows prospective monitoring of patterns in disease incidence in the general community, specific institutions (e.g. hospitals, elderly care homes), and other important population subgroups. Surveillance activities are now routinely conducted in many developed countries and in certain easy-to-reach areas of the developing ones. However due to limited health resources, population in rural area that consisted of the most the vulnerable groups are not under surveillance. Cheaper alternative ways for disease surveillance were needed in resource-limited settings. METHODS AND FINDINGS: In this study, a syndromic surveillance system using disease specific absenteeism rates was established in 47 pre-schools with 1,417 students 3-6 y of age in a rural area of Kampot province, Cambodia. School absenteeism data were collected via short message service. Data collected between 1st January and 31st December 2012 was used for system evaluation for future potential use in larger scale. The system appeared to be feasible and acceptable in the rural study setting. Moderate correlation was found between rates of school absenteeism due to illness and the reference data on rates of attendance at health centers in persons <16 y (maximum cross-correlation coefficient = 0.231 at lag = -1 week). CONCLUSIONS: School absenteeism data is pre-existing, easily accessible and requires minimum time and resources after initial development, and our results suggest that this system may be able to provide complementary data for disease surveillance, especially in resource limited settings where there is very little information on illnesses in the community and traditional surveillance systems are difficult to implement. An important next step is to validate the syndromic data with other forms of surveillance including laboratory data. PMID- 24155908 TI - UVB-induced cell death signaling is associated with G1-S progression and transcription inhibition in primary human fibroblasts. AB - DNA damage induced by ultraviolet (UV) radiation can be removed by nucleotide excision repair through two sub-pathways, one general (GGR) and the other specific for transcribed DNA (TCR), and the processing of unrepaired lesions trigger signals that may lead to cell death. These signals involve the tumor suppressor p53 protein, a central regulator of cell responses to DNA damage, and the E3 ubiquitin ligase Mdm2, that forms a feedback regulatory loop with p53. The involvement of cell cycle and transcription on the signaling to apoptosis was investigated in UVB-irradiated synchronized, DNA repair proficient, CS-B (TCR deficient) and XP-C (GGR-deficient) primary human fibroblasts. Cells were irradiated in the G1 phase of the cell cycle, with two doses with equivalent levels of apoptosis (low and high), defined for each cell line. In the three cell lines, the low doses of UVB caused only a transient delay in progression to the S phase, whereas the high doses induced permanent cell cycle arrest. However, while accumulation of Mdm2 correlated well with the recovery from transcription inhibition at the low doses for normal and CS-B fibroblasts, for XP-C cells this protein was shown to be accumulated even at UVB doses that induced high levels of apoptosis. Thus, UVB-induced accumulation of Mdm2 is critical for counteracting p53 activation and apoptosis avoidance, but its effect is limited due to transcription inhibition. However, in the case of XP-C cells, an excess of unrepaired DNA damage would be sufficient to block S phase progression, which would signal to apoptosis, independent of Mdm2 accumulation. The data clearly discriminate DNA damage signals that lead to cell death, depending on the presence of UVB-induced DNA damage in replicating or transcribing regions. PMID- 24155909 TI - Manure refinement affects apple rhizosphere bacterial community structure: a study in sandy soil. AB - We used DNA-based pyrosequencing to characterize the bacterial community structure of the sandy soil of an apple orchard with different manure ratios. Five manure percentages (5%, 10%, 15%, 20% and 25%) were examined. More than 10,000 valid reads were obtained for each replicate. The communities were composed of five dominant groups (Proteobacteria, Actinobacteria, Chloroflexi, Acidobacteria and Bacteroidetes), of which Proteobacteria content gradually decreased from 41.38% to 37.29% as manure ratio increased from 0% to 25%, respectively. Redundancy analysis showed that 37 classes were highly correlated with manure ratio, 18 of which were positively correlated. Clustering revealed that the rhizosphere samples were grouped into three components: low manure (control, 5%) treatment, medium manure (10%, 15%) treatment and high manure (20%, 25%) treatment. Venn analysis of species types of these three groups revealed that the bacteria community difference was primarily reflected by quantity ratio rather than species variety. Although greater manure content led to higher soil organic matter content, the medium manure improved soil showed the highest urease activity and saccharase activity, while 5% to 20% manure ratio improvement also resulted in higher bacteria diversity than control and 25% manure ratio treatment. Our experimental results suggest that the use of a proper manure ratio results in significantly higher soil enzyme activity and different bacteria community patterns, whereas the use of excessive manure amounts has negative effect on soil quality. PMID- 24155911 TI - Deagrarianisation and forest revegetation in a biodiversity hotspot on the Wild Coast, South Africa. AB - Deagraianisation is a worldwide phenomenon with widespread social, ecological and economic effects yet with little consensus on the local or higher level causes. There have been contested views on the causes and consequences of deagrarianisation on South Africa's Wild Coast, which is an international biodiversity hotspot. Using GIS, household interviews and ecological sampling, we compared the perspectives of current and former cultivators as to why some have abandoned farming, whilst also tracking the uses and woody plant cover and composition of fields abandoned at different periods. The GIS analysis showed that field abandonment had been ongoing over several decades, with a decline from 12.5 % field cover in 1961 to 2.7 % in 2009. The area of forests and woodlands almost doubled in the corresponding period. There was a distinct peak in field abandonment during the time of political transition at the national level in the early 1990s. This political change led to a decrease in government support for livestock farming, which in turn resulted in reduced animal draught power at the household and community level, and hence reduced cropping. The study showed it is largely the wealthier households that have remained in arable agriculture and that the poorer households have abandoned farming. The abandoned fields show a distinct trend of increasing woody biomass and species richness with length of time since abandonment, with approximately three woody plant species added per decade. Most local respondents dislike the increases in forest and woodland extent and density because of anxiety about wild animals causing harm to crops and even humans, and the loss of an agricultural identity to livelihoods and the landscape. PMID- 24155910 TI - Insight into molecular and functional properties of NMNAT3 reveals new hints of NAD homeostasis within human mitochondria. AB - Among the enzymes involved in NAD homeostasis, nicotinamide mononucleotide adenylyltransferases (NMNAT1-3) are central to intracellular NAD formation. Although NMNAT3 is postulated to be a mitochondrial enzyme contributing to NAD dependent organelle functioning, information on endogenous proteins is lacking. We report that in human cells a single gene nmnat3 localized on chromosome 3 codes for two mRNA splice variants NMNATv1 and FKSG76, whereas the previously reported NMNAT3v2 transcript is not present. However, NMNAT3v1 and FKSG76 proteins are not detectable, consistent with the finding that an upstream ORF in their mRNAs negatively regulates translation. NMNAT3v1 transfection demonstrates that the protein is cytosolic and inactive, whereas FKSG76 is mitochondrial but operates NAD cleavage rather than synthesis. In keeping with the lack of NMNAT3, we show that extracellular NAD, but not its metabolic precursors, sustains mitochondrial NAD pool in an ATP-independent manner. Data of the present study modify the scenario of the origin of mitochondrial NAD by showing that, in human cells, NMNAT3 is absent in mitochondria, and, akin to plants and yeast, cytosolic NAD maintains the mitochondrial NAD pool. PMID- 24155912 TI - Understanding U.S. healthcare providers' practices and experiences with molluscum contagiosum. AB - INTRODUCTION: Molluscum contagiosum is a common superficial skin infection caused by the poxvirus, Molluscum Contagiosum virus. The study objective is to obtain a better understanding of physician practices and experiences with molluscum contagiosum in order to focus informational and guidance material. METHODS: A cross-sectional survey to assess medical practitioners' knowledge and practices with molluscum contagiosum was conducted using the 2009 DocStyles survey. Questions regarding category and number of molluscum contagiosum patients seen, treatments used and advice given to patients were included in the survey. RESULTS: Dermatologists saw the most cases, with the majority seeing 51-100 molluscum contagiosum cases/year. The most common cases seen were children with multiple lesions and adults with genital lesions. Respondents were most likely to recommend treatment to immunocompromised individuals, HIV patients, adults with genital lesions and children with multiple lesions. Cryotherapy was the top choice for all specialties with the exception of OB/GYNs, whose top choice was curettage. "Avoid intimate contact until lesions resolve", "Avoid touching lesions to reduce further spread", and "Don't be concerned, this will go away" were the top advice choices. DISCUSSION: Most survey respondents have dealt with molluscum contagiosum in their practice during the previous year. Overall, respondents picked appropriate choices for treatment and advice given; however some ineffective or unnecessary treatments were chosen and recommendations to prevent spread were chosen infrequently. Knowledge gaps for appropriate transmission precaution advice might cause unnecessary spread or autoinoculation. This survey has demonstrated that molluscum contagiosum is a common infection seen by many types of practitioners and therefore guidance on treatment considerations and infection control is valuable. PMID- 24155913 TI - An interactive association of advanced glycation end-product receptor gene four common polymorphisms with coronary artery disease in northeastern Han Chinese. AB - BACKGROUND: Growing evidence indicates that advanced glycation end-product receptor (RAGE) might play a contributory role in the pathogenesis of coronary artery disease (CAD). To shed some light from a genetic perspective, we sought to investigate the interactive association of RAGE gene four common polymorphisms (rs1800625 or T-429C, rs1800624 or T-374A, rs2070600 or Gly82Ser, and rs184003 or G1704A) with the risk of developing CAD in a large northeastern Han Chinese population. METHODOLOGY/PRINCIPAL FINDINGS: This was a hospital-based case control study incorporating 1142 patients diagnosed with CAD and 1106 age- and gender-matched controls. All individuals were angiographically confirmed. Risk estimates were expressed as odds ratio (OR) and 95% confidence interval (CI). Overall there were significant differences in the genotype and allele distributions of rs1800625 and rs184003, even after the Bonferroni correction. Logistic regression analyses indicated that rs1800625 and rs184003 were associated with significant risk of CAD under both additive (OR = 1.20 and 1.23; 95% CI: 1.06-1.37 and 1.06-1.42; P = 0.006 and 0.008) and recessive (OR = 1.75 and 2.39; 95% CI: 1.28-2.40 and 1.47-3.87; P<0.001 and <0.001) models after adjusting for confounders. In haplotype analyses, haplotypes C-T-G-G and T-A-G-T (alleles in order of rs1800625, rs1800624, rs2070600 and rs184003), overrepresented in patients, were associated with 52% (95% CI: 1.19-1.87; P = 0.0052) and 63% (95% CI: 1.14-2.34; P = 0.0075) significant increases in adjusted risk for CAD. Further interactive analyses identified an overall best multifactor dimensionality reduction (MDR) model including rs1800625 and rs184003. This model had a maximal testing accuracy of 0.6856 and a cross-validation consistency of 10 out of 10 (P = 0.0016). The validity of this model was substantiated by classical Logistic regression analysis. CONCLUSIONS: Our findings provided strong evidence for the potentially contributory roles of RAGE multiple genetic polymorphisms, especially in the context of locus-to-locus interaction, in the pathogenesis of CAD among northeastern Han Chinese. PMID- 24155915 TI - A voting-based sequential pattern recognition method. AB - We propose a novel method for recognizing sequential patterns such as motion trajectory of biological objects (i.e., cells, organelle, protein molecules, etc.), human behavior motion, and meteorological data. In the proposed method, a local classifier is prepared for every point (or timing or frame) and then the whole pattern is recognized by majority voting of the recognition results of the local classifiers. The voting strategy has a strong benefit that even if an input pattern has a very large deviation from a prototype locally at several points, they do not severely influence the recognition result; they are treated just as several incorrect votes and thus will be neglected successfully through the majority voting. For regularizing the recognition result, we introduce partial dependency to local classifiers. An important point is that this dependency is introduced to not only local classifiers at neighboring point pairs but also to those at distant point pairs. Although, the dependency makes the problem non Markovian (i.e., higher-order Markovian), it can still be solved efficiently by using a graph cut algorithm with polynomial-order computations. The experimental results revealed that the proposed method can achieve better recognition accuracy while utilizing the above characteristics of the proposed method. PMID- 24155914 TI - Differential effects of human L1CAM mutations on complementing guidance and synaptic defects in Drosophila melanogaster. AB - A large number of different pathological L1CAM mutations have been identified that result in a broad spectrum of neurological and non-neurological phenotypes. While many of these mutations have been characterized for their effects on homophilic and heterophilic interactions, as well as expression levels in vitro, there are only few studies on their biological consequences in vivo. The single L1-type CAM gene in Drosophila, neuroglian (nrg), has distinct functions during axon guidance and synapse formation and the phenotypes of nrg mutants can be rescued by the expression of human L1CAM. We previously showed that the highly conserved intracellular FIGQY Ankyrin-binding motif is required for L1CAM mediated synapse formation, but not for neurite outgrowth or axon guidance of the Drosophila giant fiber (GF) neuron. Here, we use the GF as a model neuron to characterize the pathogenic L120V, Y1070C, C264Y, H210Q, E309K and R184Q extracellular L1CAM missense mutations and a L1CAM protein with a disrupted ezrin moesin-radixin (ERM) binding site to investigate the signaling requirements for neuronal development. We report that different L1CAM mutations have distinct effects on axon guidance and synapse formation. Furthermore, L1CAM homophilic binding and signaling via the ERM motif is essential for axon guidance in Drosophila. In addition, the human pathological H210Q, R184Q and Y1070C, but not the E309K and L120V L1CAM mutations affect outside-in signaling via the FIGQY Ankyrin binding domain which is required for synapse formation. Thus, the pathological phenotypes observed in humans are likely to be caused by the disruption of signaling required for both, guidance and synaptogenesis. PMID- 24155916 TI - Glucose transporter expression in an avian nectarivore: the ruby-throated hummingbird (Archilochus colubris). AB - Glucose transporter (GLUT) proteins play a key role in the transport of monosaccharides across cellular membranes, and thus, blood sugar regulation and tissue metabolism. Patterns of GLUT expression, including the insulin-responsive GLUT4, have been well characterized in mammals. However, relatively little is known about patterns of GLUT expression in birds with existing data limited to the granivorous or herbivorous chicken, duck and sparrow. The smallest avian taxa, hummingbirds, exhibit some of the highest fasted and fed blood glucose levels and display an unusual ability to switch rapidly and completely between endogenous fat and exogenous sugar to fuel energetically expensive hovering flight. Despite this, nothing is known about the GLUT transporters that enable observed rapid rates of carbohydrate flux. We examined GLUT (GLUT1, 2, 3, & 4) expression in pectoralis, leg muscle, heart, liver, kidney, intestine and brain from both zebra finches (Taeniopygia guttata) and ruby-throated hummingbirds (Archilochus colubris). mRNA expression of all four transporters was probed using reverse-transcription PCR (RT-PCR). In addition, GLUT1 and 4 protein expression were assayed by western blot and immunostaining. Patterns of RNA and protein expression of GLUT1-3 in both species agree closely with published reports from other birds and mammals. As in other birds, and unlike in mammals, we did not detect GLUT4. A lack of GLUT4 correlates with hyperglycemia and an uncoupling of exercise intensity and relative oxidation of carbohydrates in hummingbirds. The function of GLUTs present in hummingbird muscle tissue (e.g. GLUT1 and 3) remain undescribed. Thus, further work is necessary to determine if high capillary density, and thus surface area across which cellular-mediated transport of sugars into active tissues (e.g. muscle) occurs, rather than taxon-specific differences in GLUT density or kinetics, can account for observed rapid rates of sugar flux into these tissues. PMID- 24155917 TI - Identification of Pyrus single nucleotide polymorphisms (SNPs) and evaluation for genetic mapping in European pear and interspecific Pyrus hybrids. AB - We have used new generation sequencing (NGS) technologies to identify single nucleotide polymorphism (SNP) markers from three European pear (Pyrus communis L.) cultivars and subsequently developed a subset of 1096 pear SNPs into high throughput markers by combining them with the set of 7692 apple SNPs on the IRSC apple Infinium(r) II 8K array. We then evaluated this apple and pear Infinium(r) II 9K SNP array for large-scale genotyping in pear across several species, using both pear and apple SNPs. The segregating populations employed for array validation included a segregating population of European pear ('Old Home'*'Louise Bon Jersey') and four interspecific breeding families derived from Asian (P. pyrifolia Nakai and P. bretschneideri Rehd.) and European pear pedigrees. In total, we mapped 857 polymorphic pear markers to construct the first SNP-based genetic maps for pear, comprising 78% of the total pear SNPs included in the array. In addition, 1031 SNP markers derived from apple (13% of the total apple SNPs included in the array) were polymorphic and were mapped in one or more of the pear populations. These results are the first to demonstrate SNP transferability across the genera Malus and Pyrus. Our construction of high density SNP-based and gene-based genetic maps in pear represents an important step towards the identification of chromosomal regions associated with a range of horticultural characters, such as pest and disease resistance, orchard yield and fruit quality. PMID- 24155918 TI - Long chain fatty Acyl-CoA synthetase 4 is a biomarker for and mediator of hormone resistance in human breast cancer. AB - The purpose of this study was to determine the role of long-chain fatty acyl-CoA synthetase 4 (ACSL4) in breast cancer. Public databases were utilized to analyze the relationship between ACSL4 mRNA expression and the presence of steroid hormone and human epidermal growth factor receptor 2 (HER2) in both breast cancer cell lines and tissue samples. In addition, cell lines were utilized to assess the consequences of either increased or decreased levels of ACSL4 expression. Proliferation, migration, anchorage-independent growth and apoptosis were used as biological end points. Effects on mRNA expression and signal transduction pathways were also monitored. A meta-analysis of public gene expression databases indicated that ACSL4 expression is positively correlated with a unique subtype of triple negative breast cancer (TNBC), characterized by the absence of androgen receptor (AR) and therefore referred to as quadruple negative breast cancer (QNBC). Results of experiments in breast cancer cell lines suggest that simultaneous expression of ACSL4 and a receptor is associated with hormone resistance. Forced expression of ACSL4 in ACSL4-negative, estrogen receptor alpha (ER)-positive MCF-7 cells resulted in increased growth, invasion and anchorage independent growth, as well as a loss of dependence on estrogen that was accompanied by a reduction in the levels of steroid hormone receptors. Sensitivity to tamoxifen, triacsin C and etoposide was also attenuated. Similarly, when HER2-positive, ACSL4-negative, SKBr3 breast cancer cells were induced to express ACSL4, the proliferation rate increased and the apoptotic effect of lapatinib was reduced. The growth stimulatory effect of ACSL4 expression was also observed in vivo in nude mice when MCF-7 control and ACSL4 expressing cells were utilized to induce tumors. Our data strongly suggest that ACSL4 can serve as both a biomarker for, and mediator of, an aggressive breast cancer phenotype. PMID- 24155919 TI - Discovery of Mycobacterium tuberculosis protein tyrosine phosphatase B (PtpB) inhibitors from natural products. AB - Protein tyrosine phosphatase B (PtpB) is one of the virulence factors secreted into the host cell by Mycobacterium tuberculosis. PtpB attenuates host immune defenses by interfering with signal transduction pathways in macrophages and, therefore, it is considered a promising target for the development of novel anti tuberculosis drugs. Here we report the discovery of natural compound inhibitors of PtpB among an in house library of more than 800 natural substances by means of a multidisciplinary approach, mixing in silico screening with enzymatic and kinetics studies and MS assays. Six natural compounds proved to inhibit PtpB at low micromolar concentrations (< 30 uM) with Kuwanol E being the most potent with K i = 1.6 +/- 0.1 uM. To the best of our knowledge, Kuwanol E is the most potent natural compound PtpB inhibitor reported so far, as well as it is the first non peptidic PtpB inhibitor discovered from natural sources. Compounds herein identified may inspire the design of novel specific PtpB inhibitors. PMID- 24155920 TI - Involvement of miRNAs in the differentiation of human glioblastoma multiforme stem-like cells. AB - Glioblastoma multiforme (GBM)-initiating cells (GICs) represent a tumor subpopulation with neural stem cell-like properties that is responsible for the development, progression and therapeutic resistance of human GBM. We have recently shown that blockade of NFkappaB pathway promotes terminal differentiation and senescence of GICs both in vitro and in vivo, indicating that induction of differentiation may be a potential therapeutic strategy for GBM. MicroRNAs have been implicated in the pathogenesis of GBM, but a high-throughput analysis of their role in GIC differentiation has not been reported. We have established human GIC cell lines that can be efficiently differentiated into cells expressing astrocytic and neuronal lineage markers. Using this in vitro system, a microarray-based high-throughput analysis to determine global expression changes of microRNAs during differentiation of GICs was performed. A number of changes in the levels of microRNAs were detected in differentiating GICs, including over-expression of hsa-miR-21, hsa-miR-29a, hsa-miR-29b, hsa-miR 221 and hsa-miR-222, and down-regulation of hsa-miR-93 and hsa-miR-106a. Functional studies showed that miR-21 over-expression in GICs induced comparable cell differentiation features and targeted SPRY1 mRNA, which encodes for a negative regulator of neural stem-cell differentiation. In addition, miR-221 and miR-222 inhibition in differentiated cells restored the expression of stem cell markers while reducing differentiation markers. Finally, miR-29a and miR-29b targeted MCL1 mRNA in GICs and increased apoptosis. Our study uncovers the microRNA dynamic expression changes occurring during differentiation of GICs, and identifies miR-21 and miR-221/222 as key regulators of this process. PMID- 24155921 TI - Phosphorylation of FOXP3 by LCK downregulates MMP9 expression and represses cell invasion. AB - Forkhead Box P3 (FOXP3) is a member of the forkhead/winged helix family of the transcription factors and plays an important role not only as a master gene in T regulatory cells, but also as a tumor suppressor. In this study, we identified lymphocyte-specific protein tyrosine kinase (LCK), which correlates with cancer malignancy, as a binding partner of FOXP3. FOXP3 downregulated LCK-induced MMP9, SKP2, and VEGF-A expression. We observed that LCK phosphorylated Tyr-342 of FOXP3 by immunoprecipitation and in vitro kinase assay, and the replacement of Tyr-342 with phenylalanine (Y342F) abolished the ability to suppress MMP9 expression. Although FOXP3 decreased the invasive ability induced by LCK in MCF-7 cells, Y342F mutation in FOXP3 diminished this suppressive effect. Thus we demonstrate for the first time that LCK upregulates FOXP3 by tyrosine phosphorylation, resulting in decreased MMP9, SKP2, and VEGF-A expression, and suppressed cellular invasion. We consider that further clarification of transcriptional mechanism of FOXP3 may facilitate the development of novel therapeutic approaches to suppress cancer malignancy. PMID- 24155922 TI - Identification and characterization of eleven novel human gamma-papillomavirus isolates from healthy skin, found at low frequency in a normal population. AB - Eleven novel human papillomavirus (HPV) types were isolated and characterized from healthy individuals in China. HPV163 belongs to the gamma-1 species, HPV 164 and HPV 168 fit in the gamma-8 species, HPV 165 and KC5 belongs to the gamma-12 species, HPV 168 is closely allied with the gamma-4 species, HPV 169 is closely related to the gamma-11 species, and HPV 170 is related to the gamma-12 species. In addition, HPV 161, HPV 162, and HPV 166 may form a new HPV species of the gamma-PV genus. The prevalence of these HPV types in the normal population is low. PMID- 24155924 TI - Aspergillus fumigatus invasion increases with progressive airway ischemia. AB - Despite the prevalence of Aspergillus-related disease in immune suppressed lung transplant patients, little is known of the host-pathogen interaction. Because of the mould's angiotropic nature and because of its capacity to thrive in hypoxic conditions, we hypothesized that the degree of Aspergillus invasion would increase with progressive rejection-mediated ischemia of the allograft. To study this relationship, we utilized a novel orthotopic tracheal transplant model of Aspergillus infection, in which it was possible to assess the effects of tissue hypoxia and ischemia on airway infectivity. Laser Doppler flowmetry and FITC lectin were used to determine blood perfusion, and a fiber optic microsensor was used to measure airway tissue oxygen tension. Fungal burden and depth of invasion were graded using histopathology. We demonstrated a high efficacy (80%) for producing a localized fungal tracheal infection with the majority of infection occurring at the donor-recipient anastomosis; Aspergillus was more invasive in allogeneic compared to syngeneic groups. During the study period, the overall kinetics of both non-infected and infected allografts was similar, demonstrating a progressive loss of perfusion and oxygenation, which reached a nadir by days 10 12 post-transplantation. The extent of Aspergillus invasion directly correlated with the degree of graft hypoxia and ischemia. Compared to the midtrachea, the donor-recipient anastomotic site exhibited lower perfusion and more invasive disease; a finding consistent with clinical experience. For the first time, we identify ischemia as a putative risk factor for Aspergillus invasion. Therapeutic approaches focused on preserving vascular health may play an important role in limiting Aspergillus infections. PMID- 24155923 TI - Occupational and environmental exposures associated with testicular germ cell tumours: systematic review of prenatal and life-long exposures. AB - BACKGROUND: Testicular germ cell tumours (TGCT) are the most common cancers in men aged between 15 and 44 years and the incidence has increased steeply over the past 30 years. The rapid increase in the incidence, the spatial variation and the evolution of incidence in migrants suggest that environmental risk factors play a role in TGCT aetiology. The purpose of our review is to summarise the current state of knowledge on occupational and environmental factors thought to be associated with TGCT. METHODS: A systematic literature search of PubMed. All selected articles were quality appraised by two independent researchers using the 'Newcastle-Ottawa Quality Assessment Scale'. RESULTS: After exclusion of duplicate reports, 72 relevant articles were selected; 65 assessed exposure in adulthood, 7 assessed parental exposures and 2 assessed both. Associations with occupation was reported for agricultural workers, construction workers, firemen, policemen, military personnel, as well as workers in paper, plastic or metal industries. Electromagnetic fields, PCBs and pesticides were also suggested. However, results were inconsistent and studies showing positive associations tended to had lower quality ranking using the assessment scale (p=0.02). DISCUSSION: Current evidence does not allow concluding on existence of any clear association between TGCT and adulthood occupational or environmental exposure. The limitations of the studies may partly explain the inconsistencies observed. The lack of association with adulthood exposure is in line with current hypotheses supporting the prenatal origin of TGCT. Future research should focus on prenatal or early life exposure, as well as combined effect of prenatal and later life exposure. National and international collaborative studies should allow for more adequately powered epidemiological studies. More sophisticated methods for assessing exposure as well as evaluating gene-environment interactions will be necessary to establish clear conclusion. PMID- 24155925 TI - Application of a novel functional gene microarray to probe the functional ecology of ammonia oxidation in nitrifying activated sludge. AB - We report on the first study trialling a newly-developed, functional gene microarray (FGA) for characterising bacterial and archaeal ammonia oxidisers in activated sludge. Mixed liquor (ML) and media biofilm samples from a full-scale integrated fixed-film activated sludge (IFAS) plant were analysed with the FGA to profile the diversity and relative abundance of ammonia-oxidising archaea and bacteria (AOA and AOB respectively). FGA analyses of AOA and AOB communities revealed ubiquitous distribution of AOA across all samples - an important finding for these newly-discovered and poorly characterised organisms. Results also revealed striking differences in the functional ecology of attached versus suspended communities within the IFAS reactor. Quantitative assessment of AOB and AOA functional gene abundance revealed a dominance of AOB in the ML and approximately equal distribution of AOA and AOB in the media-attached biofilm. Subsequent correlations of functional gene abundance data with key water quality parameters suggested an important functional role for media-attached AOB in particular for IFAS reactor nitrification performance and indicate possible functional redundancy in some IFAS ammonia oxidiser communities. Results from this investigation demonstrate the capacity of the FGA to resolve subtle ecological shifts in key microbial communities in nitrifying activated sludge and indicate its value as a tool for better understanding the linkages between the ecology and performance of these engineered systems. PMID- 24155926 TI - HIV gp120 induces mucus formation in human bronchial epithelial cells through CXCR4/alpha7-nicotinic acetylcholine receptors. AB - Lung diseases such as chronic obstructive pulmonary disease (COPD), asthma, and lung infections are major causes of morbidity and mortality among HIV-infected patients even in the era of antiretroviral therapy (ART). Many of these diseases are strongly associated with smoking and smoking is more common among HIV infected than uninfected people; however, HIV is an independent risk factor for chronic bronchitis, COPD, and asthma. The mechanism by which HIV promotes these diseases is unclear. Excessive airway mucus formation is a characteristic of these diseases and contributes to airway obstruction and lung infections. HIV gp120 plays a critical role in several HIV-related pathologies and we investigated whether HIV gp120 promoted airway mucus formation in normal human bronchial epithelial (NHBE) cells. We found that NHBE cells expressed the HIV coreceptor CXCR4 but not CCR5 and produced mucus in response to CXCR4-tropic gp120. The gp120-induced mucus formation was blocked by the inhibitors of CXCR4, alpha7-nicotinic acetylcholine receptor (alpha7-nAChR), and gamma-aminobutyric acid (GABA)AR but not the antagonists of CCR5 and epithelial growth factor receptor (EGFR). These results identify two distinct pathways (alpha7-nAChR GABAAR and EGFR) for airway mucus formation and demonstrate for the first time that HIV-gp120 induces and regulates mucus formation in the airway epithelial cells through the CXCR4-alpha7-nAChR-GABAAR pathway. Interestingly, lung sections from HIV +/- ART and simian immunodeficiency virus (SIV) +/- ART have significantly more mucus and gp120-immunoreactivity than control lung sections from humans and macaques, respectively. Thus, even after ART, lungs from HIV infected patients contain significant amounts of gp120 and mucus that may contribute to the higher incidence of obstructive pulmonary diseases in this population. PMID- 24155928 TI - High frequency ultrasound for in vivo pregnancy diagnosis and staging of placental and fetal development in mice. AB - BACKGROUND: Ultrasound is a valuable non-invasive tool used in obstetrics and gynecology to monitor the growth and well being of the human fetus. The laboratory mouse has recently emerged as an appropriate model for fetal and perinatal studies because morphogenetic processes in mice exhibit adequate homology to those in humans, and genetic manipulations are relatively simple to perform in mice. High-frequency ultrasound (HFUS) has recently become available for small animal preclinical imaging and can be used to study pregnancy and development in the mouse. The objective of the current study was to assess the main applications of HFUS in the evaluation of fetal growth and placental function and to better understand human congenital diseases. METHODOLOGY/PRINCIPAL FINDINGS: On each gestational day, at least 5 dams were monitored with HFUS; a total of ~200 embryos were examined. Because it is not possible to measure each variable for the entire duration of the pregnancy, the parameters were divided into three groups as a function of the time at which they were measured. Univariate analysis of the relationship between each measurement and the embryonic day was performed using Spearman's rank correlation (Rs). Continuous linear regression was adopted for multivariate analysis of significant parameters. All statistical tests were two-sided, and a p value of 0.05 was considered statistically significant. CONCLUSIONS/SIGNIFICANCE: The study describes the main applications of HFUS to assess changes in phenotypic parameters in the developing CD1 mouse embryo and fetus during pregnancy and to evaluating physiological fetal and placental growth and the development of principal organs such as the heart, kidney, liver, brain and eyes in the embryonic mouse. A database of normal structural and functional parameters of mouse development will provide a useful tool for the better understanding of morphogenetic and cardiovascular anomalies in transgenic and mutant mouse models. PMID- 24155927 TI - Vaccine-induced boosting of influenza virus-specific CD4 T cells in younger and aged humans. AB - Current yearly influenza virus vaccines induce strain-specific neutralizing antibody (NAb) responses providing protective immunity to closely matched viruses. However, these vaccines are often poorly effective in high-risk groups such as the elderly and challenges exist in predicting yearly or emerging pandemic influenza virus strains to include in the vaccines. Thus, there has been considerable emphasis on understanding broadly protective immunological mechanisms for influenza virus. Recent studies have implicated memory CD4 T cells in heterotypic immunity in animal models and in human challenge studies. Here we examined how influenza virus vaccination boosted CD4 T cell responses in younger versus aged humans. Our results demonstrate that while the magnitude of the vaccine-induced CD4 T cell response and number of subjects responding on day 7 did not differ between younger and aged subjects, fewer aged subjects had peak responses on day 14. While CD4 T cell responses were inefficiently boosted against NA, both HA and especially nucleocaspid protein- and matrix-(NP+M) specific responses were robustly boosted. Pre-existing CD4 T cell responses were associated with more robust responses to influenza virus NP+M, but not H1 or H3. Finally pre-existing strain-specific NAb decreased the boosting of CD4 T cell responses. Thus, accumulation of pre-existing influenza virus-specific immunity in the form of NAb and cross-reactive T cells to conserved virus proteins (e.g. NP and M) over a lifetime of exposure to infection and vaccination may influence vaccine-induced CD4 T cell responses in the aged. PMID- 24155929 TI - New tools to study DNA double-strand break repair pathway choice. AB - A broken DNA molecule is difficult to repair, highly mutagenic, and extremely cytotoxic. Such breaks can be repaired by homology-independent or homology directed mechanisms. Little is known about the network that controls the repair pathway choice except that a licensing step for homology-mediated repair exists, called DNA-end resection. The choice between these two repair pathways is a key event for genomic stability maintenance, and an imbalance of the ratio is directly linked with human diseases, including cancer. Here we present novel reporters to study the balance between both repair options in human cells. In these systems, a double-strand break can be alternatively repaired by homology independent or -dependent mechanisms, leading to the accumulation of distinct fluorescent proteins. These reporters thus allow the balance between both repair pathways to be analyzed in different experimental setups. We validated the reporters by analyzing the effect of protein downregulation of the DNA end resection and non-homologous end-joining pathways. Finally, we analyzed the role of the DNA damage response on double-strand break (DSB) repair mechanism selection. Our reporters could be used in the future to understand the roles of specific factors, whole pathways, or drugs in DSB repair pathway choice, or for genome-wide screening. Moreover, our findings can be applied to increase gene targeting efficiency, making it a beneficial tool for a broad audience in the biological sciences. PMID- 24155930 TI - Intron retention in the alternatively spliced region of RON results from weak 3' splice site recognition. AB - The RON gene encodes a tyrosine kinase receptor for macrophage-stimulating protein. A constitutively active isoform that arises by skipping of exon 11 is expressed in carcinomas and contributes to an invasive phenotype. However, a high proportion of the mRNA expressed from the endogenous gene, or from transfected minigenes, appears to retain introns 10 and 11. It is not known whether this represents specific repression or the presence of weak splicing signals. We have used chimeric pre-mRNAs spliced in vitro to investigate the reason for intron retention. A systematic test showed that, surprisingly, the exon sequences known to modulate exon 11 skipping were not limiting, but the 3' splice site regions adjacent to exons 11 and 12 were too weak to support splicing when inserted into a globin intron. UV-crosslinking experiments showed binding of hnRNP F/H just 5' of these regions, but the hnRNP F/H target sequences did not mediate inhibition. Instead, the failure of splicing is linked to weak binding of U2AF65, and spliceosome assembly stalls prior to formation of any of the ATP-dependent complexes. We discuss mechanisms by which U2AF65 binding is facilitated in vivo. PMID- 24155931 TI - Apolipoprotein a-I is a potential mediator of remote ischemic preconditioning. AB - BACKGROUND: Remote ischemic preconditioning (RIPC) has emerged as an attractive strategy in clinical settings. Despite convincing evidence of the critical role played by circulating humoral mediators, their actual identities remain unknown. In this study, we aimed to identify RIPC-induced humoral mediators using a proteomic approach. METHODS: and Results Rats were exposed to 10-min limb ischemia followed by 5- (RIPC 5') or 10-min (RIPC 10') reperfusion prior to blood sampling. The control group only underwent blood sampling. Plasma samples were analyzed using surface-enhanced laser desorption and ionization - time of flight mass spectrometry (SELDI-TOF-MS). Three protein peaks were selected for their significant increase in RIPC 10'. They were identified and confirmed as apolipoprotein A-I (ApoA-I). Additional rats were exposed to myocardial ischemia reperfusion (I/R) and assigned to one of the following groups RIPC+myocardial infarction (MI) (10-min limb ischemia followed by 10-min reperfusion initiated 20 minutes prior to myocardial I/R), ApoA-I+MI (10 mg/kg ApoA-I injection 10 minutes before myocardial I/R), and MI (no further intervention). In comparison with untreated MI rats, RIPC reduced infarct size (52.2+/-3.7% in RIPC+MI vs. 64.9+/ 2.6% in MI; p<0.05). Similarly, ApoA-I injection decreased infarct size (50.9+/ 3.8%; p<0.05 vs. MI). CONCLUSIONS: RIPC was associated with a plasmatic increase in ApoA-I. Furthermore, ApoA-I injection before myocardial I/R recapitulated the cardioprotection offered by RIPC in rats. This data suggests that ApoA-I may be a protective blood-borne factor involved in the RIPC mechanism. PMID- 24155932 TI - Efficacy of sorafenib monotherapy versus sorafenib-based loco-regional treatments in advanced hepatocellular carcinoma. AB - BACKGROUND: Although sorafenib is accepted as the standard of care in advanced hepatocellular carcinoma (HCC), its therapeutic benefit is marginal. Here, we aimed to compare the efficacy and safety of sorafenib monotherapy (S-M) and sorafenib-based loco-regional treatments (S-LRTs) in advanced HCC. METHODS: From 2007 to 2012, 290 patients with advanced HCC (Barcelona Clinic Liver Cancer stage C) with S-M (n = 226) or S-LRTs (n = 64) were reviewed retrospectively. Survival outcomes and treatment-related toxicities between two groups were analyzed. RESULTS: Variables related to tumor burden and liver function were similar between the groups (all P > 0.05). Within the entire population, the S-LRTs group had both longer median overall survival (OS) (8.5 vs 5.5 months, P = 0.001) and progression-free survival (PFS) (5.3 vs 3.0 months, P = 0.002) than the S-M group. Furthermore, the S-LRTs group had longer Os than the S-M group in a subgroup with neither extrahepatic spread (EHS) nor regional nodal involvement (RNI) (18.0 vs 7.8 months, P = 0.019) and in a subgroup with EHS and/or RNI (8.3 vs 4.8 months, P = 0.028). In addition, the S-LRTs group had longer PFS than the S-M group in the subgroup with neither EHS nor RNI (9.6 vs 3.2 months, P = 0.027). TREATMENT: Related toxicity was similar between two groups. CONCLUSION: Combined use of sorafenib and LRTs may provide better treatment outcomes without significantly increasing treatment-related toxicities, even in patients with EHS and/or RNI. Therefore, addition of active LRTs might be considered, if feasible. PMID- 24155934 TI - In situ proximity ligation assays indicate that hemochromatosis proteins Hfe and transferrin receptor 2 (Tfr2) do not interact. AB - The hemochromatosis associated proteins HFE and Transferrin Receptor 2 (TFR2) have been shown to be important for the proper regulation of hepcidin. A number of in vitro studies using transient overexpression systems have suggested that an interaction between HFE and TFR2 is required for the regulation of hepcidin. This model of iron sensing which centers upon the requirement for an interaction between HFE and TFR2 has recently been questioned with in vivo studies in mice from our laboratory and others which suggest that Hfe and Tfr2 can regulate hepcidin independently of each other. To re-examine the postulated interaction between Hfe and Tfr2 we developed a novel expression system in which both proteins are stably co-expressed and used the proximity ligation assay to examine the interactions between Hfe, Tfr1 and Tfr2 at a cellular level. We were able to detect the previously described interaction between Hfe and Tfr1, and heterodimers between Tfr1 and Tfr2; however no interaction between Hfe and Tfr2 was observed in our system. The results from this study indicate that Hfe and Tfr2 do not interact with each other when they are stably expressed at similar levels. Furthermore, these results support in vivo studies which suggest that Hfe and Tfr2 can independently regulate hepcidin. PMID- 24155933 TI - Zhangfei/CREB-ZF - a potential regulator of the unfolded protein response. AB - Cells respond to perturbations in the microenvironment of the endoplasmic reticulum (ER), and to the overloading of its capacity to process secretory and membrane-associate proteins, by activating the Unfolded Protein Response (UPR). Genes that mediate the UPR are regulated by three basic leucine-zipper (bLZip) motif-containing transcription factors - Xbp1s, ATF4 and ATF6. A failure of the UPR to achieve homeostasis and its continued stimulation leads to apoptosis. Mechanisms must therefore exist to turn off the UPR if it successfully restores normalcy. The bLZip protein Zhangfei/CREBZF/SMILE is known to suppress the ability of several, seemingly structurally unrelated, transcription factors. These targets include Luman/CREB3 and CREBH, ER-resident bLZip proteins known to activate the UPR in some cell types. Here we show that Zhangfei had a suppressive effect on most UPR genes activated by the calcium ionophore thapsigargin. This effect was at least partially due to the interaction of Zhangfei with Xbp1s. The leucine zipper of Zhangfei was required for this interaction, which led to the subsequent proteasomal degradation of Xbp1s. Zhangfei suppressed the ability of Xbp1s to activate transcription from a promoter containing unfolded protein response elements and significantly reduced the ability to Xbp1s to activate the UPR as measured by RNA and protein levels of UPR-related genes. Finally, specific suppression of endogenous Zhangfei in thapsigargin-treated primary rat sensory neurons with siRNA directed to Zhangfei transcripts, led to a significant increase in transcripts and proteins of UPR genes, suggesting a potential role for Zhangfei in modulating the UPR. PMID- 24155935 TI - Orthotopic kidney transplantation in mice: technique using cuff for renal vein anastomosis. AB - Mouse renal transplantation is a technically challenging procedure. Although the first kidney transplants in mice were performed over 34 years ago and refined some years later, the classical techniques of mouse renal transplantation required clamping both vena cava and aorta simultaneously and carry out suture anastomoses of the renal artery and vein in a heterotopic position. In our laboratory, we have successfully developed mouse orthotopic kidney transplantation for the first time, using a rapid "cuffed" renal vein technique for vessel anastomosis, wherein the donor's renal vein was inserted through an intravenous catheter, folded back and tied. During grafting, the cuffed renal vein was directly inserted into the recipient's renal vein without the need for the clamping vena cava and suturing of renal vein. This technique allowed for the exact transplantation of the kidney into the original position, compared to the classical technique, and has significantly shortened the clamping time due to a quicker and precise anastomosis of renal vein as described. This also allowed for a quicker recovery of the lower extremity activity, reduction in myoglobinuria with resultant kidney graft survival of 88.9%. Thus we believe that the cuffed renal vein technique simplifies microvascular anastomoses and affords important additional benefits. PMID- 24155936 TI - The long noncoding RNA HOTAIR contributes to cisplatin resistance of human lung adenocarcinoma cells via downregualtion of p21(WAF1/CIP1) expression. AB - HOTAIR, a long intervening non-coding RNA (lincRNA), associates with the Polycomb Repressive Complex 2 (PRC2) and is reported to reprogram chromatin organization and promote tumor progression. However, little is known about the roles of this gene in the development of chemoresistance phenotype of lung adenocarcinoma (LAD). Thus, we investigated the involvement of HOTAIR in the resistance of LAD cells to cisplatin. In this study, we show that HOTAIR expression was significantly upregulated in cisplatin-resistant A549/DDP cells compared with in parental A549 cells. Knockdown of HOTAIR by RNA interference could resensitize the responses of A549/DDP cells to cisplatin both in vitro and in vivo. In contrast, overexpression of HOTAIR could decrease the sensitivity of A549 and SPC A1 cells to cisplatin. We also found that the siRNA/HOTAIR1-mediated chemosensivity enhancement was associated with inhibition of cell proliferation, induction of G0/G1 cell-cycle arrest and apoptosis enhancement through regulation of p21(WAF1/CIP1) (p21) expression. Also, pcDNA/p21or siRNA/p21 could mimic the effects of siRNA/HOTAIR1 or pcDNA/HOTAIR on the sensitivity of LAD cells to cisplatin. Importantly, siRNA/p21 or pcDNA/p21 could partially rescue the effects of siRNA/HOTAIR1 or pcDNA/HOTAIR on both p21 expression and cisplatin sensitivity in LAD cells. Further, HOTAIR was observed to be significantly downregulated in cisplatin-responding LAD tissues, and its expression was inversely correlated with p21 mRNA expression. Taken together, our findings suggest that upregulation of HOTAIR contributes to the cisplatin resistance of LAD cells, at least in part, through the regulation of p21 expression. PMID- 24155937 TI - BdorCSP2 is important for antifeed and oviposition-deterring activities induced by Rhodojaponin-III against Bactrocera dorsalis. AB - Rhodojaponin-III is a nonvolatile botanical grayanoid diterpene compound, which has antifeedant and oviposition deterrence effects against many kinds of insects. However, the molecular mechanism of the chemoreception process remains unknown. In this study, the important role of BdorCSP2 in the recognition of Rhodojaponin III was identified. The full length cDNA encoding BdorCSP2 was cloned from legs of Bactrocera dorsalis. The results of expression pattern revealed that BdorCSP2 was abundantly expressed in the legs of adult B. dorsalis. Moreover, the expression of BdorCSP2 could be up-regulated by Rhodojaponin-III. In order to gain comprehensive understanding of the recognition process, the binding affinity between BdorCSP2 and Rhodojaponin-III was measured by fluorescence binding assay. Silencing the expression of BdorCSP2 through the ingestion of dsRNA could weaken the effect of oviposition deterrence and antifeedant of Rhodojaponin-III. These results suggested that BdorCSP2 of B. dorsalis could be involved in chemoreception of Rhodojaponin-III and played a critical role in antifeedant and oviposition behaviors induced by Rhodojaponin-III. PMID- 24155938 TI - Interaction of central and peripheral factors during repeated sprints at different levels of arterial O2 saturation. AB - PURPOSE: To investigate the interaction between the development of peripheral locomotor muscle fatigue, muscle recruitment and performance during repeated sprint exercise (RSE). METHOD: In a single-blind, randomised and cross-over design, ten male team-sport athletes performed two RSE (fifteen 5-s cycling sprints interspersed with 25 s of rest; power self-selected) in normoxia and in acute moderate hypoxia (FIO2 0.138). Mechanical work, total electromyographic intensity (summed quadriceps electromyograms, RMSsum) and muscle (vastus lateralis) and pre-fontal cortex near-infrared spectroscopy (NIRS) parameters were calculated for every sprint. Blood lactate concentration ([Lac(-)]) was measured throughout the protocol. Peripheral quadriceps fatigue was assessed via changes in potentiated quadriceps twitch force (DeltaQtw,pot) pre- versus post exercise in response to supra-maximal magnetic femoral nerve stimulation. The central activation ratio (QCAR) was used to quantify completeness of quadriceps activation. RESULTS: Compared with normoxia, hypoxia reduced arterial oxygen saturation (-13.7%, P=0.001), quadriceps RMSsum (-13.7%, P=0.022), QCAR (-3.3%, P=0.041) and total mechanical work (-8.3%, P=0.019). However, the magnitude of quadriceps fatigue induced by RSE was similar in the two conditions (DeltaQtw,pot: -53.5% and -55.1%, P=0.71). The lower cycling performance in hypoxia occurred despite similar metabolic (muscle NIRS parameters and blood [Lac(-)]) and functional (twitch and M-wave) muscle states. CONCLUSION: Results suggest that the central nervous system regulates quadriceps muscle recruitment and, thereby, performance to limit the development of muscle fatigue during intermittent, short sprints. This finding highlights the complex interaction between muscular perturbations and neural adjustments during sprint exercise, and further supports the presence of pacing during intermittent sprint exercise. PMID- 24155939 TI - Chimeric mouse model for the infection of hepatitis B and C viruses. AB - While the chimpanzee remains the only animal that closely models human hepatitis C virus (HCV) infection, transgenic and immunodeficient mice in which human liver can be engrafted serve as a partial solution to the need for a small animal model for HCV infection. The established system that was based on mice carrying a transgene for urokinase-type plasminogen activator (uPA) gene under the control of the human albumin promoter has proved to be useful for studies of virus infectivity and for testing antiviral drug agents. However, the current Alb-uPA transgenic model with a humanized liver has practical limitations due to the inability to maintain non-engrafted mice as dizygotes for the transgene, poor engraftment of hemizygotes, high neonatal and experimental death rates of dizygous mice and a very short time window for hepatocyte engraftment. To improve the model, we crossed transgenic mice carrying the uPA gene driven by the major urinary protein promoter onto a SCID/Beige background (MUP-uPA SCID/Bg). These transgenic mice are healthy relative to Alb-uPA mice and provide a long window from about age 4 to 12 months for engraftment with human hepatocytes and infection with hepatitis C or hepatitis B (HBV) viruses. We have demonstrated engraftment of human hepatocytes by immunohistochemistry staining for human albumin (30-80% engraftment) and observed a correlation between the number of human hepatocytes inoculated and the level of the concentration of human albumin in the serum. We have shown that these mice support the replication of both HBV and all six major HCV genotypes. Using HBV and HCV inocula that had been previously tittered in chimpanzees, we showed that the mice had approximately the same sensitivity for infection as chimpanzees. These mice should be useful for isolating non-cell culture adapted viruses as well as testing of antiviral drugs, antibody neutralization studies and examination of phenotypic changes in viral mutants. PMID- 24155940 TI - Call transmission efficiency in native and invasive anurans: competing hypotheses of divergence in acoustic signals. AB - Invasive species are a leading cause of the current biodiversity decline, and hence examining the major traits favouring invasion is a key and long-standing goal of invasion biology. Despite the prominent role of the advertisement calls in sexual selection and reproduction, very little attention has been paid to the features of acoustic communication of invasive species in nonindigenous habitats and their potential impacts on native species. Here we compare for the first time the transmission efficiency of the advertisement calls of native and invasive species, searching for competitive advantages for acoustic communication and reproduction of introduced taxa, and providing insights into competing hypotheses in evolutionary divergence of acoustic signals: acoustic adaptation vs. morphological constraints. Using sound propagation experiments, we measured the attenuation rates of pure tones (0.2-5 kHz) and playback calls (Lithobates catesbeianus and Pelophylax perezi) across four distances (1, 2, 4, and 8 m) and over two substrates (water and soil) in seven Iberian localities. All factors considered (signal type, distance, substrate, and locality) affected transmission efficiency of acoustic signals, which was maximized with lower frequency sounds, shorter distances, and over water surface. Despite being broadcast in nonindigenous habitats, the advertisement calls of invasive L. catesbeianus were propagated more efficiently than those of the native species, in both aquatic and terrestrial substrates, and in most of the study sites. This implies absence of optimal relationship between native environments and propagation of acoustic signals in anurans, in contrast to what predicted by the acoustic adaptation hypothesis, and it might render these vertebrates particularly vulnerable to intrusion of invasive species producing low frequency signals, such as L. catesbeianus. Our findings suggest that mechanisms optimizing sound transmission in native habitat can play a less significant role than other selective forces or biological constraints in evolutionary design of anuran acoustic signals. PMID- 24155941 TI - Effect of statin use on outcomes of adults with candidemia. AB - BACKGROUND: Statins have immunomodulatory properties and hinder Candida growth. However, it is unknown whether they may improve prognosis in patients with candidemia. We sought to determine the effect of prior statin use on the clinical outcomes of patients suffering candidemia. METHODS AND FINDINGS: Multicenter cohort study of hospitalized adults with candidemia between 2005 and 2011 in six hospitals in Spain, Brazil and Argentina. Of 326 candidemias, 44 (13.5%) occurred in statin users and 282 (86.5%) in statin non-users. The median value of APACHE II at candidemia diagnosis was similar between groups (18 vs. 16; p=.36). Candida albicans was the most commonly isolated species, followed by C. parapsilosis, C. tropicalis, C. glabrata, and C. krusei. There were no differences regarding appropriate empirical antifungal treatment. Statin users had a lower early (5 d) case-fatality rate than non-users (4.5 vs. 17%; p=.031). This effect was not observed with other cardiovascular drugs (aspirin, beta blockers and ACE inhibitors). Independent factor related to early case-fatality rate was APACHE II score (AOR, 1.08; 95% CI, 1.03-1.14; p=.002). An appropriate empirical antifungal therapy (AOR, 0.11; 95% CI, 0.04-0.26; p=<.001) and prior statin use were independently associated with lower early case-fatality (AOR, 0.17; 95% CI, 0.03 0.93; p=.041). Fourteen days (14d) and overall (30d) case-fatality rates were similar between groups (27% vs. 29%; p=0.77 and 40% vs. 44%; p=.66). CONCLUSIONS: The use of statins might have a beneficial effect on outcomes of patients with candidemia. This hypothesis deserves further evaluation in randomized trials. PMID- 24155942 TI - CD4(+)CD62L(+) central memory T cells can be converted to Foxp3(+) T cells. AB - The peripheral Foxp3(+) Treg pool consists of naturally arising Treg (nTreg) and adaptive Treg cells (iTreg). It is well known that naive CD4(+) T cells can be readily converted to Foxp3(+) iTreg in vitro, and memory CD4(+) T cells are resistant to conversion. In this study, we investigated the induction of Foxp3(+) T cells from various CD4(+) T-cell subsets in human peripheral blood. Though naive CD4(+) T cells were readily converted to Foxp3(+) T cells with TGF-beta and IL-2 treatment in vitro, such Foxp3(+) T cells did not express the memory marker CD45RO as do Foxp3(+) T cells induced in the peripheral blood of Hepatitis B Virus (HBV) patients. Interestingly, a subset of human memory CD4(+) T cells, defined as CD62L(+) central memory T cells, could be induced by TGF-beta to differentiate into Foxp3(+) T cells. It is well known that Foxp3(+) T cells derived from human CD4(+)CD25(-) T cells in vitro are lack suppressive functions. Our data about the suppressive functions of CD4(+)CD62L(+) central memory T cell derived Foxp3(+) T cells support this conception, and an epigenetic analysis of these cells showed a similar methylation pattern in the FOXP3 Treg-specific demethylated region as the naive CD4(+) T cell-derived Foxp3(+) T cells. But further research showed that mouse CD4(+) central memory T cells also could be induced to differentiate into Foxp3(+) T cells, such Foxp3(+) T cells could suppress the proliferation of effector T cells. Thus, our study identified CD4(+)CD62L(+) central memory T cells as a novel potential source of iTreg. PMID- 24155943 TI - Chitosan oligosaccharides attenuates oxidative-stress related retinal degeneration in rats. AB - This study investigated the therapeutic potential and mechanisms of chitosan oligosaccharides (COS) for oxidative stress-induced retinal diseases. Retinal oxidative damage was induced in Sprague-Dawley rats by intravitreal injection of paraquat (PQ). Low-dose (5 mg/kg) or high-dose (10 mg/kg) COS or PBS was intragastrically given for 14 days after PQ injection. Electroretinograms were performed to determine the functionality of the retinas. The surviving neurons in the retinal ganglion cell layer and retinal apoptosis were determined by counting Neu N-positive cells in whole-mounted retinas and TUNEL staining, respectively. The generation of reactive oxygen species (ROS) was determined by lucigenin- and luminol-enhanced chemiluminescence. Retinal oxidative damages were assessed by staining with nitrotyrosine, acrolein, and 8-hydroxy-2'-deoxyguanosine (8-OHdG). Immunohistochemical studies were used to demonstrate the expression of nuclear factor-kappa B (NF-kappaB) p65 in retinas. An in vitro study using RGC-5 cells was performed to verify the results. We demonstrated COS significantly enhanced the recovery of retinal function, preserved inner retinal thickness, and decreased retinal neurons loss in a dose-dependent manner. COS administration demonstrated anti-oxidative effects by reducing luminol- and lucigenin-dependent chemiluminenscense levels and activating superoxide dismutase and catalase, leading to decreased retinal apoptosis. COS markedly reduced retinal NF-kappaB p65. An in vitro study demonstrated COS increased IkappaB expression, attenuated the increase of p65 and thus decreased NF-kappaB/DNA binding activity in PQ stimulated RGC-5 cells. In conclusion, COS attenuates oxidative stress-induced retinal damages, probably by decreasing free radicals, maintaining the activities of anti-oxidative enzymes, and inhibiting the activation of NF-kappaB. PMID- 24155944 TI - Molecular cloning and characterization of a newly isolated pyrethroid-degrading esterase gene from a genomic library of Ochrobactrum anthropi YZ-1. AB - A novel pyrethroid-degrading esterase gene pytY was isolated from the genomic library of Ochrobactrum anthropi YZ-1. It possesses an open reading frame (ORF) of 897 bp. Blast search showed that its deduced amino acid sequence shares moderate identities (30% to 46%) with most homologous esterases. Phylogenetic analysis revealed that PytY is a member of the esterase VI family. pytY showed very low sequence similarity compared with reported pyrethroid-degrading genes. PytY was expressed, purified, and characterized. Enzyme assay revealed that PytY is a broad-spectrum degrading enzyme that can degrade various pyrethroids. It is a new pyrethroid-degrading gene and enriches genetic resource. Kinetic constants of Km and Vmax were 2.34 mmol.L(-1) and 56.33 nmol min(-1), respectively, with lambda-cyhalothrin as substrate. PytY displayed good degrading ability and stability over a broad range of temperature and pH. The optimal temperature and pH were of 35 degrees C and 7.5. No cofactors were required for enzyme activity. The results highlighted the potential use of PytY in the elimination of pyrethroid residuals from contaminated environments. PMID- 24155945 TI - PROX1: a lineage tracer for cortical interneurons originating in the lateral/caudal ganglionic eminence and preoptic area. AB - The homeobox-encoding gene Prox1 and its Drosophila homologue prospero are key regulators of cell fate-specification. In the developing rodent cortex a sparse population of cells thought to correspond to late-generated cortical pyramidal neuron precursors expresses PROX1. Using a series of transgenic mice that mark cell lineages in the subcortical telencephalon and, more specifically, different populations of cortical interneurons, we demonstrate that neurons expressing PROX1 do not represent pyramidal neurons or their precursors but are instead subsets of cortical interneurons. These correspond to interneurons originating in the lateral/caudal ganglionic eminence (LGE/CGE) and a small number of preoptic area (POA)-derived neurons. Expression within the cortex can be detected from late embryonic stages onwards when cortical interneurons are still migrating. There is persistent expression in postmitotic cells in the mature brain mainly in the outer cortical layers. PROX1(+ve) interneurons express neurochemical markers such as calretinin, neuropeptide Y, reelin and vasoactive intestinal peptide, all of which are enriched in LGE/CGE- and some POA-derived cells. Unlike in the cortex, in the striatum PROX1 marks nearly all interneurons regardless of their origin. Weak expression of PROX1 can also be detected in oligodendrocyte lineage cells throughout the forebrain. Our data show that PROX1 can be used as a genetic lineage tracer of nearly all LGE/CGE- and subsets POA-derived cortical interneurons at all developmental and postnatal stages in vivo. PMID- 24155946 TI - Genome-wide identification of KANADI1 target genes. AB - Plant organ development and polarity establishment is mediated by the action of several transcription factors. Among these, the KANADI (KAN) subclade of the GARP protein family plays important roles in polarity-associated processes during embryo, shoot and root patterning. In this study, we have identified a set of potential direct target genes of KAN1 through a combination of chromatin immunoprecipitation/DNA sequencing (ChIP-Seq) and genome-wide transcriptional profiling using tiling arrays. Target genes are over-represented for genes involved in the regulation of organ development as well as in the response to auxin. KAN1 affects directly the expression of several genes previously shown to be important in the establishment of polarity during lateral organ and vascular tissue development. We also show that KAN1 controls through its target genes auxin effects on organ development at different levels: transport and its regulation, and signaling. In addition, KAN1 regulates genes involved in the response to abscisic acid, jasmonic acid, brassinosteroids, ethylene, cytokinins and gibberellins. The role of KAN1 in organ polarity is antagonized by HD-ZIPIII transcription factors, including REVOLUTA (REV). A comparison of their target genes reveals that the REV/KAN1 module acts in organ patterning through opposite regulation of shared targets. Evidence of mutual repression between closely related family members is also shown. PMID- 24155947 TI - Antigen presenting B cells facilitate CD4 T cell cooperation resulting in enhanced generation of effector and memory CD4 T cells. AB - We show that the in vivo generation of cytokine-producing CD4 T cells specific for a given major histocompatibility class-II (MHCII)-binding peptide of hen egg lysozyme (HEL) is facilitated when mice are immunized with splenic antigen presenting cells (APC) pulsed with this HEL peptide and another peptide that binds a different MHCII molecule. This enhanced generation of peptide-specific effector CD4 T cells requires that the same splenic APC be pulsed with both peptides. Pulsed B cells, but not pulsed dendritic cells (DCs), can mediate CD4 T cell cooperation, which can be blocked by disrupting OX40-OX40L (CD134-CD252) interactions. In addition, the generation of HEL peptide-specific CD4 T cell memory is greater when mice are primed with B cells pulsed with the two peptides than with B cells pulsed with the HEL- peptide alone. Based on our findings, we suggest CD4 T cell cooperation is important for vaccine design, underlies the phenomenon of "epitope-spreading" seen in autoimmunity, and that the efficacy of B cell-depletion in the treatment of human cell-mediated autoimmune disease is due to the abrogation of the interactions between autoimmune CD4 T cells that facilitates their activation. PMID- 24155948 TI - No evidence for heritability of male mating latency or copulation duration across social environments in Drosophila melanogaster. AB - A key assumption underpinning major models of sexual selection is the expectation that male sexual attractiveness is heritable. Surprisingly, however, empirical tests of this assumption are relatively scarce. Here we use a paternal full sib/half-sib breeding design to examine genetic and environmental variation in male mating latency (a proxy for sexual attractiveness) and copulation duration in a natural population of Drosophila melanogaster. As our experimental design also involved the manipulation of the social environment within each full-sibling family, we were able to further test for the presence of genotype-by-environment interactions (GEIs) in these traits, which have the potential to compromise mate choice for genetic benefits. Our experimental manipulation of the social environment revealed plastic expression of both traits; males exposed to a rival male during the sensitive period of adult sexual maturation exhibited shorter mating latencies and longer copulation durations than those who matured in isolation. However, we found no evidence for GEIs, and no significant additive genetic variation underlying these traits in either environment. These results undermine the notion that the evolution of female choice rests on covariance between female preference and male displays, an expectation that underpins indirect benefit models such as the good genes and sexy sons hypotheses. However, our results may also indicate depletion of genetic variance in these traits in the natural population studied, thus supporting the expectation that traits closely aligned with reproductive fitness can exhibit low levels of additive genetic variance. PMID- 24155949 TI - Natural blood feeding and temperature shift modulate the global transcriptional profile of Rickettsia rickettsii infecting its tick vector. AB - Rickettsia rickettsii is an obligate intracellular tick-borne bacterium that causes Rocky Mountain Spotted Fever (RMSF), the most lethal spotted fever rickettsiosis. When an infected starving tick begins blood feeding from a vertebrate host, R. rickettsii is exposed to a temperature elevation and to components in the blood meal. These two environmental stimuli have been previously associated with the reactivation of rickettsial virulence in ticks, but the factors responsible for this phenotype conversion have not been completely elucidated. Using customized oligonucleotide microarrays and high throughput microfluidic qRT-PCR, we analyzed the effects of a 10 degrees C temperature elevation and of a blood meal on the transcriptional profile of R. rickettsii infecting the tick Amblyomma aureolatum. This is the first study of the transcriptome of a bacterium in the genus Rickettsia infecting a natural tick vector. Although both stimuli significantly increased bacterial load, blood feeding had a greater effect, modulating five-fold more genes than the temperature upshift. Certain components of the Type IV Secretion System (T4SS) were up-regulated by blood feeding. This suggests that this important bacterial transport system may be utilized to secrete effectors during the tick vector's blood meal. Blood feeding also up-regulated the expression of antioxidant enzymes, which might correspond to an attempt by R. rickettsii to protect itself against the deleterious effects of free radicals produced by fed ticks. The modulated genes identified in this study, including those encoding hypothetical proteins, require further functional analysis and may have potential as future targets for vaccine development. PMID- 24155950 TI - Combination of bortezomib and mitotic inhibitors down-modulate Bcr-Abl and efficiently eliminates tyrosine-kinase inhibitor sensitive and resistant Bcr-Abl positive leukemic cells. AB - Emergence of resistance to Tyrosine-Kinase Inhibitors (TKIs), such as imatinib, dasatinib and nilotinib, in Chronic Myelogenous Leukemia (CML) demands new therapeutic strategies. We and others have previously established bortezomib, a selective proteasome inhibitor, as an important potential treatment in CML. Here we show that the combined regimens of bortezomib with mitotic inhibitors, such as the microtubule-stabilizing agent Paclitaxel and the PLK1 inhibitor BI2536, efficiently kill TKIs-resistant and -sensitive Bcr-Abl-positive leukemic cells. Combined treatment activates caspases 8, 9 and 3, which correlate with caspase induced PARP cleavage. These effects are associated with a marked increase in activation of the stress-related MAP kinases p38MAPK and JNK. Interestingly, combined treatment induces a marked decrease in the total and phosphorylated Bcr Abl protein levels, and inhibits signaling pathways downstream of Bcr-Abl: downregulation of STAT3 and STAT5 phosphorylation and/or total levels and a decrease in phosphorylation of the Bcr-Abl-associated proteins CrkL and Lyn. Moreover, we found that other mitotic inhibitors (Vincristine and Docetaxel), in combination with bortezomib, also suppress the Bcr-Abl-induced pro-survival signals and result in caspase 3 activation. These results open novel possibilities for the treatment of Bcr-Abl-positive leukemias, especially in the imatinib, dasatinib and nilotinib-resistant CML cases. PMID- 24155951 TI - Disease interactions in a shared host plant: effects of pre-existing viral infection on cucurbit plant defense responses and resistance to bacterial wilt disease. AB - Both biotic and abiotic stressors can elicit broad-spectrum plant resistance against subsequent pathogen challenges. However, we currently have little understanding of how such effects influence broader aspects of disease ecology and epidemiology in natural environments where plants interact with multiple antagonists simultaneously. In previous work, we have shown that healthy wild gourd plants (Cucurbita pepo ssp. texana) contract a fatal bacterial wilt infection (caused by Erwinia tracheiphila) at significantly higher rates than plants infected with Zucchini yellow mosaic virus (ZYMV). We recently reported evidence that this pattern is explained, at least in part, by reduced visitation of ZYMV-infected plants by the cucumber beetle vectors of E. tracheiphila. Here we examine whether ZYMV-infection may also directly elicit plant resistance to subsequent E. tracheiphila infection. In laboratory studies, we assayed the induction of key phytohormones (SA and JA) in single and mixed infections of these pathogens, as well as in response to the feeding of A. vittatum cucumber beetles on healthy and infected plants. We also tracked the incidence and progression of wilt disease symptoms in plants with prior ZYMV infections. Our results indicate that ZYMV-infection slightly delays the progression of wilt symptoms, but does not significantly reduce E. tracheiphila infection success. This observation supports the hypothesis that reduced rates of wilt disease in ZYMV-infected plants reflect reduced visitation by beetle vectors. We also documented consistently strong SA responses to ZYMV infection, but limited responses to E. tracheiphila in the absence of ZYMV, suggesting that the latter pathogen may effectively evade or suppress plant defenses, although we observed no evidence of antagonistic cross-talk between SA and JA signaling pathways. We did, however, document effects of E. tracheiphila on induced responses to herbivory that may influence host-plant quality for (and hence pathogen acquisition by) cucumber beetles. PMID- 24155952 TI - Brain deactivation in the outperformance in bimodal tasks: an FMRI study. AB - While it is known that some individuals can effectively perform two tasks simultaneously, other individuals cannot. How the brain deals with performing simultaneous tasks remains unclear. In the present study, we aimed to assess which brain areas corresponded to various phenomena in task performance. Nineteen subjects were requested to sequentially perform three blocks of tasks, including two unimodal tasks and one bimodal task. The unimodal tasks measured either visual feature binding or auditory pitch comparison, while the bimodal task required performance of the two tasks simultaneously. The functional magnetic resonance imaging (fMRI) results are compatible with previous studies showing that distinct brain areas, such as the visual cortices, frontal eye field (FEF), lateral parietal lobe (BA7), and medial and inferior frontal lobe, are involved in processing of visual unimodal tasks. In addition, the temporal lobes and Brodmann area 43 (BA43) were involved in processing of auditory unimodal tasks. These results lend support to concepts of modality-specific attention. Compared to the unimodal tasks, bimodal tasks required activation of additional brain areas. Furthermore, while deactivated brain areas were related to good performance in the bimodal task, these areas were not deactivated where the subject performed well in only one of the two simultaneous tasks. These results indicate that efficient information processing does not require some brain areas to be overly active; rather, the specific brain areas need to be relatively deactivated to remain alert and perform well on two tasks simultaneously. Meanwhile, it can also offer a neural basis for biofeedback in training courses, such as courses in how to perform multiple tasks simultaneously. PMID- 24155953 TI - Smelling danger - alarm cue responses in the polychaete Nereis (Hediste) diversicolor (Muller, 1776) to potential fish predation. AB - The harbour ragworm, Nereis (Hediste) diversicolor is a common intertidal marine polychaete that lives in burrows from which it has to partially emerge in order to forage. In doing so, it is exposed to a variety of predators. One way in which predation risk can be minimised is through chemical detection from within the relative safety of the burrows. Using CCTV and motion capture software, we show that H. diversicolor is able to detect chemical cues associated with the presence of juvenile flounder (Platichthys flesus). Number of emergences, emergence duration and distance from burrow entrance are all significantly reduced during exposure to flounder conditioned seawater and flounder mucous spiked seawater above a threshold with no evidence of behavioural habituation. Mucous from bottom dwelling juvenile plaice (Pleuronectes platessa) and pelagic adult herring (Clupea harengus) elicit similar responses, suggesting that the behavioural reactions are species independent. The data implies that H. diversicolor must have well developed chemosensory mechanisms for predator detection and is consequently able to effectively minimize risk. PMID- 24155954 TI - PKCdelta localization at the membrane increases matrix traction force dependent on PLCgamma1/EGFR signaling. AB - INTRODUCTION: During wound healing, fibroblasts initially migrate into the wound bed and later contract the matrix. Relevant mediators of transcellular contractility revealed by systems analyses are protein kinase c delta/myosin light chain-2 (PKCdelta/MLC-2). PKCdelta is activated by growth factor-driven PLCgamma1 hydrolysis of phosphoinositide bisphosphate (PIP2) hydrolysis when it becomes tranlocated to the membrane. This leads to MLC-2 phosphorylation that regulates myosin for contractility. Furthermore, PKCdelta n-terminus mediates PKCdelta localization to the membrane in relative proximity to PLCgamma1 activity. However, the role this localization and the relationship to its activation and signaling of force is not well understood. Therefore, we investigated whether the membrane localization of PKCdelta mediates the transcellular contractility of fibroblasts. METHODS: To determine PKCdelta activation in targeted membrane locations in mouse fibroblast cells (NR6-WT), two PKCdelta constructs were generated; PKCdelta-CaaX with farnesylation moiety targeting PKCdelta to the membrane and PKCdelta-SaaX a non-targeting control. RESULTS: Increased mean cell force was observed before and during EGF stimulation in fibroblasts expressing membrane-targeted PKCdelta (PKCdelta-CaaX) when analyzed with 2D cell traction force and 3D compaction of collagen matrix. This effect was reduced in cells deficient in EGFR/PLCy1 signaling. In cells expressing non-membrane targeted PKCdelta (PKCdelta-SaaX), the cell force exerted outside the ECM (extracellular matrix) was less, but cell motility/speed/persistence was increased after EGF stimulation. Change in cell motility and increased force exertion was also preceded by change in cell morphology. Organization of actin stress fibers was also decreased as a result of increasing membrane targeting of PKCdelta. CONCLUSION: From these results membrane tethering of PKCdelta leads to increased force exertion on ECM. Furthermore, our data show PLCgamma1 regulation of PKCdelta, at least in part, drives transcellular contractility in fibroblasts. PMID- 24155955 TI - Adjuvant chemotherapy for brain tumors delivered via a novel intra-cavity moldable polymer matrix. AB - INTRODUCTION: Polymer-based delivery systems offer innovative intra-cavity administration of drugs, with the potential to better target micro-deposits of cancer cells in brain parenchyma beyond the resected cavity. Here we evaluate clinical utility, toxicity and sustained drug release capability of a novel formulation of poly(lactic-co-glycolic acid) (PLGA)/poly(ethylene glycol) (PEG) microparticles. METHODS: PLGA/PEG microparticle-based matrices were molded around an ex vivo brain pseudo-resection cavity and analyzed using magnetic resonance imaging and computerized tomography. In vitro toxicity of the polymer was assessed using tumor and endothelial cells and drug release from trichostatin A-, etoposide- and methotrexate-loaded matrices was determined. To verify activity of released agents, tumor cells were seeded onto drug-loaded matrices and viability assessed. RESULTS: PLGA/PEG matrices can be molded around a pseudo-resection cavity wall with no polymer-related artifact on clinical scans. The polymer withstands fractionated radiotherapy, with no disruption of microparticle structure. No toxicity was evident when tumor or endothelial cells were grown on control matrices in vitro. Trichostatin A, etoposide and methotrexate were released from the matrices over a 3-4 week period in vitro and etoposide released over 3 days in vivo, with released agents retaining cytotoxic capabilities. PLGA/PEG microparticle-based matrices molded around a resection cavity wall are distinguishable in clinical scanning modalities. Matrices are non-toxic in vitro suggesting good biocompatibility in vivo. Active trichostatin A, etoposide and methotrexate can be incorporated and released gradually from matrices, with radiotherapy unlikely to interfere with release. CONCLUSION: The PLGA/PEG delivery system offers an innovative intra-cavity approach to administer chemotherapeutics for improved local control of malignant brain tumors. PMID- 24155956 TI - The influence of anti-infective periodontal treatment on C-reactive protein: a systematic review and meta-analysis of randomized controlled trials. AB - BACKGROUND: Periodontal infections are hypothesized to increase the risk of adverse systemic outcomes through inflammatory mechanisms. The magnitude of effect, if any, of anti-infective periodontal treatment on systemic inflammation is unknown, as are the patient populations most likely to benefit. We conducted a systematic review and meta-analysis of randomized controlled trials (RCTs) to test the hypothesis that anti-infective periodontal treatment reduces systemic c reactive protein (CRP). METHODS AND FINDINGS: MEDLINE, EMBASE, CENTRAL and CINAHL databases were searched using sensitivity-enhancing search terms. Eligible RCTs enrolled patients with periodontal infection, compared a clearly defined anti infective periodontal intervention (experimental group) to an "inactive control" (no periodontal intervention) or to an "active control" (lower treatment intensity than the experimental group). Mean differences in final CRP values at the earliest post-treatment time point (typically 1-3 months) between experimental and control groups were analyzed using random-effects regression. Among 2,753 possible studies 20 were selected, which included 2,561 randomized patients(median=57). Baseline CRP values were >3.0 mg/L in 40% of trials. Among studies with a control group receiving no treatment, the mean difference in CRP final values among experimental treatment vs. control groups was -0.37 mg/L [95%CI=-0.64, -0.11], (P=0.005), favoring experimental treatment. Trials for which the experimental group received antibiotics had stronger effects (P for interaction=0.03) and the mean difference in CRP final values among experimental treatment vs. control was -0.75 mg/L [95%CI=-1.17,-0.33]. No treatment effect was observed among studies using an active treatment comparator. Treatment effects were stronger for studies that included patients with co-morbidities vs. studies that included "systemically healthy" patients, although the interaction was not significant (P=0.48). CONCLUSIONS: Anti-infective periodontal treatment results in short-term modest reductions in systemic CRP. PMID- 24155957 TI - Targeted delivery of an antigenic peptide to the endoplasmic reticulum: application for development of a peptide therapy for ankylosing spondylitis. AB - The development of suitable methods to deliver peptides specifically to the endoplasmic reticulum (ER) can provide some potential therapeutic applications of such peptides. Ankylosing spondylitis (AS) is strongly associated with the expression of human leukocytic antigen-B27 (HLA-B27). HLA-B27 heavy chain (HC) has a propensity to fold slowly resulting in the accumulation of misfolded HLA B27 HC in the ER, triggering the unfolded protein response, and forming a homodimer, (B27-HC)2. Natural killer cells and T-helper 17 cells are then activated, contributing to the major pathogenic potentials of AS. The HLA-B27 HC is thus an important target, and delivery of an HLA-B27-binding peptide to the ER capable of promoting HLA-B27 HC folding is a potential mechanism for AS therapy. Here, we demonstrate that a His6-ubiquitin-tagged Tat-derived peptide (THU) can deliver an HLA-B27-binding peptide to the ER promoting HLA-B27 HC folding. The THU-HLA-B27-binding peptide fusion protein crossed the cell membrane to the cytosol through the Tat-derived peptide. The HLA-B27-binding peptide was specifically cleaved from THU by cytosolic ubiquitin C-terminal hydrolases and subsequently transported into the ER by the transporter associated with antigen processing. This approach has potential application in the development of peptide therapy for AS. PMID- 24155958 TI - Erythropoietin receptor expression is a potential prognostic factor in human lung adenocarcinoma. AB - Recombinant human erythropoietins (rHuEPOs) are used to treat cancer-related anemia. Recent preclinical studies and clinical trials, however, have raised concerns about the potential tumor-promoting effects of these drugs. Because the clinical significance of erythropoietin receptor (EPOR) signaling in human non small cell lung cancer (NSCLC) also remains controversial, our aim was to study whether EPO treatment modifies tumor growth and if EPOR expression has an impact on the clinical behavior of this malignancy. A total of 43 patients with stage III-IV adenocarcinoma (ADC) and complete clinicopathological data were included. EPOR expression in human ADC samples and cell lines was measured by quantitative real-time polymerase chain reaction. Effects of exogenous rHuEPOalpha were studied on human lung ADC cell lines in vitro. In vivo growth of human ADC xenografts treated with rHuEPOalpha with or without chemotherapy was also assessed. In vivo tumor and endothelial cell (EC) proliferation was determined by 5-bromo-2'-deoxy-uridine (BrdU) incorporation and immunofluorescent labeling. Although EPOR mRNA was expressed in all of the three investigated ADC cell lines, rHuEPOalpha treatment (either alone or in combination with gemcitabine) did not alter ADC cell proliferation in vitro. However, rHuEPOalpha significantly decreased tumor cell proliferation and growth of human H1975 lung ADC xenografts. At the same time, rHuEPOalpha treatment of H1975 tumors resulted in accelerated tumor endothelial cell proliferation. Moreover, in patients with advanced stage lung ADC, high intratumoral EPOR mRNA levels were associated with significantly increased overall survival. This study reveals high EPOR level as a potential novel positive prognostic marker in human lung ADC. PMID- 24155959 TI - Language, reading, and math learning profiles in an epidemiological sample of school age children. AB - Dyscalculia, dyslexia, and specific language impairment (SLI) are relatively specific developmental learning disabilities in math, reading, and oral language, respectively, that occur in the context of average intellectual capacity and adequate environmental opportunities. Past research has been dominated by studies focused on single impairments despite the widespread recognition that overlapping and comorbid deficits are common. The present study took an epidemiological approach to study the learning profiles of a large school age sample in language, reading, and math. Both general learning profiles reflecting good or poor performance across measures and specific learning profiles involving either weak language, weak reading, weak math, or weak math and reading were observed. These latter four profiles characterized 70% of children with some evidence of a learning disability. Low scores in phonological short-term memory characterized clusters with a language-based weakness whereas low or variable phonological awareness was associated with the reading (but not language-based) weaknesses. The low math only group did not show these phonological deficits. These findings may suggest different etiologies for language-based deficits in language, reading, and math, reading-related impairments in reading and math, and isolated math disabilities. PMID- 24155960 TI - Early transcriptome analyses of Z-3-Hexenol-treated zea mays revealed distinct transcriptional networks and anti-herbivore defense potential of green leaf volatiles. AB - Green leaf volatiles (GLV), which are rapidly emitted by plants in response to insect herbivore damage, are now established as volatile defense signals. Receiving plants utilize these molecules to prime their defenses and respond faster and stronger when actually attacked. To further characterize the biological activity of these compounds we performed a microarray analysis of global gene expression. The focus of this project was to identify early transcriptional events elicited by Z-3-hexenol (Z-3-HOL) as our model GLV in maize (Zea mays) seedlings. The microarray results confirmed previous studies on Z-3-HOL -induced gene expression but also provided novel information about the complexity of Z-3-HOL -induced transcriptional networks. Besides identifying a distinct set of genes involved in direct and indirect defenses we also found significant expression of genes involved in transcriptional regulation, Ca(2+) and lipid-related signaling, and cell wall reinforcement. By comparing these results with those obtained by treatment of maize seedlings with insect elicitors we found a high degree of correlation between the two expression profiles at this early time point, in particular for those genes related to defense. We further analyzed defense gene expression induced by other volatile defense signals and found Z-3-HOL to be significantly more active than methyl jasmonate, methyl salicylate, and ethylene. The data presented herein provides important information on early genetic networks that are activated by Z-3-HOL and demonstrates the effectiveness of this compound in the regulation of typical plant defenses against insect herbivores in maize. PMID- 24155961 TI - Proteomic analyses reveal a role of cytoplasmic droplets as an energy source during epididymal sperm maturation. AB - A small portion of cytoplasm is generally retained as the cytoplasmic droplet (CD) on the flagellum of spermatozoa after spermiation in mice. CDs are believed to play a role in osmoadaptation by allowing water entrance or exit. However, many lines of evidence suggest that CDs may have roles beyond osmoregulation. To gain more insights, we purified CDs from murine epididymal spermatozoa and conducted proteomic analyses on proteins highly enriched in CDs. Among 105 proteins identified, 71 (68%) were enzymes involved in energy metabolism. We also found that sperm mitochondria underwent a reactivation process and glycolytic enzymes were further distributed and incorporated into different regions of the flagellum during epididymal sperm maturation. Both processes appeared to require CDs. Our data suggest that the CD represents a transient organelle that serves as an energy source essential for epididymal sperm maturation. PMID- 24155962 TI - GmFT2a polymorphism and maturity diversity in soybeans. AB - BACKGROUND: Soybean is a short-day crop of agricultural, ecological, and economic importance. The sensitive photoperiod responses significantly limit its breeding and adaptation. GmFT2a, a putative florigen gene with different transcription profiles in two cultivars (late-maturing Zigongdongdou and early-maturing Heihe 27) with different maturity profiles, is key to flowering and maturation. However, up to now, its role in the diverse patterns of maturation in soybeans has been poorly understood. METHODS: Eighty varieties, including 19 wild accessions, covering 11 of all 13 maturity groups, were collected. They were planted in pots and maintained under different photoperiodicity conditions (SD, short day; LD, long day; and ND, natural day). The day to first flowering was recorded and the sensitivity to photoperiod was investigated. Polymorphisms in the GmFT2a coding sequence were explored by searching the known SNP database (NCBI dbSNP). The GmFT2a promoter regions were then cloned from these varieties and sequenced. Further polymorphism and association analyses were conducted. RESULTS: These varieties varied greatly in time to first flowering under ND and exhibited a consecutive distribution of photoperiod sensitivity, which suggested that there is rich diversity in flowering time. Furthermore, although GmFT2a had only one known synonymous SNP in the coding sequence, there were 17 haplotypes of the GmFT2a promoter region, HT06 of which was extremely abundant. Further association analysis found some SNPs that might be associated with day to first flowering and photoperiod sensitivity. CONCLUSION: Although GmFT2a is a key flowering gene, GmFT2a polymorphism does not appear to be responsible for maturity diversity in soybean. PMID- 24155963 TI - Evaluation of a screening system for obesogenic compounds: screening of endocrine disrupting compounds and evaluation of the PPAR dependency of the effect. AB - Recently the environmental obesogen hypothesis has been formulated, proposing a role for endocrine disrupting compounds (EDCs) in the development of obesity. To evaluate this hypothesis, a screening system for obesogenic compounds is urgently needed. In this study, we suggest a standardised protocol for obesogen screening based on the 3T3-L1 cell line, a well-characterised adipogenesis model, and direct fluorescent measurement using Nile red lipid staining technique. In a first phase, we characterised the assay using the acknowledged obesogens rosiglitazone and tributyltin. Based on the obtained dose-response curves for these model compounds, a lipid accumulation threshold value was calculated to ensure the biological relevance and reliability of statistically significant effects. This threshold based method was combined with the well described strictly standardized mean difference (SSMD) method for classification of non-, weak- or strong obesogenic compounds. In the next step, a range of EDCs, used in personal and household care products (parabens, musks, phthalates and alkylphenol compounds), were tested to further evaluate the obesogenicity screening assay for its discriminative power and sensitivity. Additionally, the peroxisome proliferator activated receptor gamma (PPARgamma) dependency of the positive compounds was evaluated using PPARgamma activation and antagonist experiments. Our results showed the adipogenic potential of all tested parabens, several musks and phthalate compounds and bisphenol A (BPA). PPARgamma activation was associated with adipogenesis for parabens, phthalates and BPA, however not required for obesogenic effects induced by Tonalide, indicating the role of other obesogenic mechanisms for this compound. PMID- 24155964 TI - Choosing between an apple and a chocolate bar: the impact of health and taste labels. AB - Increasing the consumption of fruit and vegetables is a central component of improving population health. Reasons people give for choosing one food over another suggest health is of lower importance than taste. This study assesses the impact of using a simple descriptive label to highlight the taste as opposed to the health value of fruit on the likelihood of its selection. Participants (N=439) were randomly allocated to one of five groups that varied in the label added to an apple: apple; healthy apple; succulent apple; healthy and succulent apple; succulent and healthy apple. The primary outcome measure was selection of either an apple or a chocolate bar as a dessert. Measures of the perceived qualities of the apple (taste, health, value, quality, satiety) and of participant characteristics (restraint, belief that tasty foods are unhealthy, BMI) were also taken. When compared with apple selection without any descriptor (50%), the labels combining both health and taste descriptors significantly increased selection of the apple ('healthy & succulent' 65.9% and 'succulent & healthy' 62.4%), while the use of a single descriptor had no impact on the rate of apple selection ('healthy' 50.5% and 'succulent' 52%). The strongest predictors of individual dessert choice were the taste score given to the apple, and the lack of belief that healthy foods are not tasty. Interventions that emphasize the taste attributes of healthier foods are likely to be more effective at achieving healthier diets than those emphasizing health alone. PMID- 24155965 TI - Prevalence, hemodynamics, and cytokine profile of effusive-constrictive pericarditis in patients with tuberculous pericardial effusion. AB - BACKGROUND: Effusive constrictive pericarditis (ECP) is visceral constriction in conjunction with compressive pericardial effusion. The prevalence of proven tuberculous ECP is unknown. Whilst ECP is distinguished from effusive disease on hemodynamic grounds, it is unknown whether effusive-constrictive physiology has a distinct cytokine profile. We conducted a prospective study of prevalence and cytokine profile of effusive-constrictive disease in patients with tuberculous pericardial effusion. METHODS: From July 2006 through July 2009, the prevalence of ECP and serum and pericardial levels of inflammatory cytokines were determined in adults with tuberculous pericardial effusion. The diagnosis of ECP was made by combined pericardiocentesis and cardiac catheterization. RESULTS: Of 91 patients evaluated, 68 had tuberculous pericarditis. The 36/68 patients (52.9%; 95% confidence interval [CI]: 41.2-65.4) with ECP were younger (29 versus 37 years, P=0.02), had a higher pre-pericardiocentesis right atrial pressure (17.0 versus 10.0 mmHg, P<0.0001), serum concentration of interleukin-10 (IL-10) (38.5 versus 0.2 pg/ml, P<0.001) and transforming growth factor-beta (121.5 versus 29.1 pg/ml, P=0.02), pericardial concentration of IL-10 (84.7 versus 20.4 pg/ml, P=0.006) and interferon-gamma (2,568.0 versus 906.6 pg/ml, P=0.03) than effusive non constrictive cases. In multivariable regression analysis, right atrial pressure > 15 mmHg (odds ratio [OR] = 48, 95%CI: 8.7-265; P<0.0001) and IL-10 > 200 pg/ml (OR=10, 95%CI: 1.1, 93; P=0.04) were independently associated with ECP. CONCLUSION: Effusive-constrictive disease occurs in half of cases of tuberculous pericardial effusion, and is characterized by greater elevation in the pre pericardiocentesis right atrial pressure and pericardial and serum IL-10 levels compared to patients with effusive non-constrictive tuberculous pericarditis. PMID- 24155966 TI - The impact of KLF2 modulation on the transcriptional program and function of CD8 T cells. AB - Kruppel-like factor 2 (KLF2) is a transcription factor that is highly expressed in quiescent T lymphocytes and downregulated in effector T cells. We now show that antigen receptor engagement downregulates KLF2 expression in a graded response determined by the affinity of T cell antigen receptor (TCR) ligand and the integrated activation of protein kinase B and the MAP kinases ERK1/2. The present study explores the importance of KLF2 downregulation and reveals that the loss of KLF2 controls a select portion of the CD8 effector T cell transcriptional program. In particular, KLF2 loss is required for CD8 T cells to express the inflammatory chemokine receptor CXCR3 and for maximum clonal expansion of T cells. KLF2 thus negatively controls the ability of CD8 T cells to respond to the CXCR3 ligand CXCL10. Strikingly, the KLF2 threshold for restraining expression of CXCR3 is very low and quite distinct to the KLF2 threshold for restraining T cell proliferation. KLF2 is thus an analogue (tunable) not a digital (on/off) cellular switch where the magnitude of KLF2 expression differentially modifies the T cell responses. PMID- 24155967 TI - BMP12 induces tenogenic differentiation of adipose-derived stromal cells. AB - Adipose-derived stromal cells (ASCs) are pluripotent cells that have the capacity to differentiate into tendon fibroblasts (TFs). They are abundant in adults, easy to access, and are therefore an ideal cell source for tendon tissue engineering. Despite this potential, the molecular cues necessary for tenogenic differentiation of ASCs are unknown. Unlike other bone morphogenetic proteins (BMPs), BMP12, BMP13, and BMP14 have been reported to be less osteo-chondrogenic and to induce tendon rather than bone formation in vivo. This study investigated the effects of BMP12 and BMP14 on ASC differentiation in vitro. In canine ASCs, BMP12 effectively increased the expression of the tendon markers scleraxis and tenomodulin at both mRNA and protein levels. Consistent with these results, BMP12 induced scleraxis promoter driven-GFP and tenomodulin protein expression in mouse ASCs. Although BMP12 also enhanced the expression of the cartilage matrix gene aggrecan in ASCs, the resulting levels remained considerably lower than those detected in tendon fibroblasts. In addition, BMP12 reduced expression of the bone marker osteocalcin, but not the osteogenic transcription factor runx-2. BMP14 exhibited similar, but marginally less potent and selective effects, compared to BMP12. BMPs are known to signal through the canonical Smad pathway and the non canonical mitogen-activated protein kinase (MAPK) pathway. BMP12 triggered robust phosphorylation of Smad1/5/8 but not Smad2/3 or p38 MAPK in ASCs. The effect was likely conveyed by type I receptors ALK2/3/6, as phosphorylation of Smad1/5/8 was blocked by the ALK2/3/6 inhibitor LDN-193189 but not by the ALK4/5/7 inhibitor SB 505124. Moreover, ALK6 was found to be the most abundant type I receptor in ASCs, with mRNA expression 100 to 10,000 times that of any other type I receptor. Collectively, results support the conclusion that BMP12 induces tenogenic differentiation of ASCs via the Smad1/5/8 pathway. PMID- 24155968 TI - Kinetics of IL-6 production defines T effector cell responsiveness to regulatory T cells in multiple sclerosis. AB - In multiple sclerosis (MS) autoaggressive T effector cells (Teff) are not efficiently controlled by regulatory T cells (Treg) but the underlying mechanisms are incompletely understood. Proinflammatory cytokines are key factors facilitating Teff activity in chronic inflammation. Here we investigated the influence of IL-6 on Treg sensitivity of Teff from therapy-naive MS patients with or without active disease. Compared to healthy volunteers and independent of disease course CD4(+) and especially CD8(+) MS-Teff were insensitive against functional active Treg from healthy controls. This unresponsiveness was caused by accelerated production of IL-6, elevated IL-6 receptor expression and phosphorylation of protein kinase B (PKB)/c-Akt in MS-Teff. In a positive feedback loop, IL-6 itself induced its accelerated synthesis and enhanced phosphorylation of PKB/c-Akt that finally mediated Treg resistance. Furthermore, accelerated IL-6 release especially by CD8(+) Teff prevented control of surrounding Teff, described here as "bystander resistance". Blockade of IL-6 receptor signaling or direct inhibition of PKB/c-Akt phosphorylation restored Treg responsiveness of Teff and prevented bystander resistance. In Teff of healthy controls (HC) exogenous IL-6 also changed the kinetics of IL-6 production and induced Treg unresponsiveness. This modulation was only transient in Teff from healthy volunteers, whereas accelerated IL-6 production in MS-Teff maintained also in absence of IL-6. Hence, we showed that the kinetics of IL-6 production instead of elevated IL-6 levels defines the Teff responsiveness in early Treg-T cell communication in MS independent of their disease course and propose IL-6 and associated PKB/c-Akt activation as effective therapeutic targets for modulation of Teff activity in MS. PMID- 24155969 TI - Phyletic distribution of fatty acid-binding protein genes. AB - Fatty acid-binding proteins (FABPs) are a family of fatty acid-binding small proteins essential for lipid trafficking, energy storage and gene regulation. Although they have 20 to 70% amino acid sequence identity, these proteins share a conserved tertiary structure comprised of ten beta sheets and two alpha helixes. Availability of the complete genomes of 34 invertebrates, together with transcriptomes and ESTs, allowed us to systematically investigate the gene structure and alternative splicing of FABP genes over a wide range of phyla. Only in genomes of two cnidarian species could FABP genes not be identified. The genomic loci for FABP genes were diverse and their genomic structure varied. In particular, the intronless FABP genes, in most of which the key residues involved in fatty acid binding varied, were common in five phyla. Interestingly, several species including one trematode, one nematode and four arthropods generated FABP mRNA variants via alternative splicing. These results demonstrate that both gene duplication and post-transcriptional modifications are used to generate diverse FABPs in species studied. PMID- 24155970 TI - Complete nucleotide sequences of virulence-resistance plasmids carried by emerging multidrug-resistant Salmonella enterica Serovar Typhimurium isolated from cattle in Hokkaido, Japan. AB - In the present study, we have shown that virulence-resistance plasmids from emerging multidrug-resistant isolates of Salmonella enterica serovar Typhimurium were derived from a virulence-associated plasmid, essential for systematic invasiveness of S. Typhimurium in mice (pSLT), through acquisition of a large insert containing a resistance island flanked by IS1294 elements. A bla CMY-2 carrying plasmid from a cefotaxime-resistant isolate comprised a segment of Escherichia coli plasmid pAR060302 and the replication region (IncFIB) of a virulence-resistance plasmid. These results provide insights into the evolution of drug resistance in emerging clones of S. Typhimurium. PMID- 24155971 TI - Utility of a histone deacetylase inhibitor (PXD101) for thyroid cancer treatment. AB - BACKGROUND: We evaluated the therapeutic effects of the histone deacetylase inhibitor PXD101 alone and in combination with conventional chemotherapy in treating thyroid cancer. METHODOLOGY/PRINCIPAL FINDINGS: We studied eight cell lines from four types of thyroid cancer (papillary, follicular, anaplastic and medullary). The cytotoxicity of PXD101 alone and in combination with three conventional chemotherapeutic agents (doxorubicin, paclitaxel and docetaxel) was measured using LDH assay. Western blot assessed expression of acetylation of histone H3, histone H4 and tubulin, proteins associated with apoptosis, RAS/RAF/ERK and PI3K/AKT/mTOR signaling pathways, DNA damage and repair. Apoptosis and intracellular reactive oxygen species (ROS) were measured by flow cytometry. Mice bearing flank anaplastic thyroid cancers (ATC) were daily treated with intraperitoneal injection of PXD101 for 5 days per week. PXD101 effectively inhibited thyroid cancer cell proliferation in a dose-dependent manner. PXD101 induced ROS accumulation and inhibited RAS/RAF/ERK and PI3K/mTOR pathways in sensitive cells. Double-stranded DNA damage and apoptosis were induced by PXD101 in both sensitive and resistant cell lines. PXD101 retarded growth of 8505C ATC xenograft tumors with promising safety. Combination therapy of PXD101with doxorubicin and paclitaxel demonstrated synergistic effects against four ATC lines in vitro. CONCLUSIONS: PXD101 represses thyroid cancer proliferation and has synergistic effects in combination with doxorubicin and paclitaxel in treating ATC. These findings support clinical trials using PXD101 for patients with this dismal disease. PMID- 24155972 TI - A neuron-based screening platform for optimizing genetically-encoded calcium indicators. AB - Fluorescent protein-based sensors for detecting neuronal activity have been developed largely based on non-neuronal screening systems. However, the dynamics of neuronal state variables (e.g., voltage, calcium, etc.) are typically very rapid compared to those of non-excitable cells. We developed an electrical stimulation and fluorescence imaging platform based on dissociated rat primary neuronal cultures. We describe its use in testing genetically-encoded calcium indicators (GECIs). Efficient neuronal GECI expression was achieved using lentiviruses containing a neuronal-selective gene promoter. Action potentials (APs) and thus neuronal calcium levels were quantitatively controlled by electrical field stimulation, and fluorescence images were recorded. Images were segmented to extract fluorescence signals corresponding to individual GECI expressing neurons, which improved sensitivity over full-field measurements. We demonstrate the superiority of screening GECIs in neurons compared with solution measurements. Neuronal screening was useful for efficient identification of variants with both improved response kinetics and high signal amplitudes. This platform can be used to screen many types of sensors with cellular resolution under realistic conditions where neuronal state variables are in relevant ranges with respect to timing and amplitude. PMID- 24155973 TI - Improved PCR performance using template DNA from formalin-fixed and paraffin embedded tissues by overcoming PCR inhibition. AB - Formalin-fixed and paraffin-embedded (FFPE) tissues represent a valuable source for biomarker studies and clinical routine diagnostics. However, they suffer from degradation of nucleic acids due to the fixation process. Since genetic and epigenetic studies usually require PCR amplification, this degradation hampers its use significantly, impairing PCR robustness or necessitating short amplicons. In routine laboratory medicine a highly robust PCR performance is mandatory for the clinical utility of genetic and epigenetic biomarkers. Therefore, methods to improve PCR performance using DNA from FFPE tissue are highly desired and of wider interest. The effect of template DNA derived from FFPE tissues on PCR performance was investigated by means of qPCR and conventional PCR using PCR fragments of different sizes. DNA fragmentation was analyzed via agarose gel electrophoresis. This study showed that poor PCR amplification was partly caused by inhibition of the DNA polymerase by fragmented DNA from FFPE tissue and not only due to the absence of intact template molecules of sufficient integrity. This PCR inhibition was successfully minimized by increasing the polymerase concentration, dNTP concentration and PCR elongation time thereby allowing for the robust amplification of larger amplicons. This was shown for genomic template DNA as well as for bisulfite-converted template DNA required for DNA methylation analyses. In conclusion, PCR using DNA from FFPE tissue suffers from inhibition which can be alleviated by adaptation of the PCR conditions, therefore allowing for a significant improvement of PCR performance with regard to variability and the generation of larger amplicons. The presented solutions to overcome this PCR inhibition are of tremendous value for clinical chemistry and laboratory medicine. PMID- 24155974 TI - Habitual consumption of soy products and risk of nasopharyngeal carcinoma in Chinese adults: a case-control study. AB - BACKGROUND AND OBJECTIVES: Many studies have shown a negative association between the consumption of soy products and the risk of some cancers, but little is known about the effect of soy consumption on nasopharyngeal carcinoma. We assessed the association between the consumption of soy products on nasopharyngeal carcinoma risk in Chinese individuals. METHODS: This case-control study included 600 (448 males and 152 females) incident cases of nasopharyngeal carcinoma, and an equal number of controls, matched according to gender, age (+/- 3 y) and household type to the nasopharyngeal carcinoma cases. All subjects were recruited from hospitals in Guangzhou, China. A face-to-face interview was conducted with each study individual to collect general information and habitual dietary intake using a 78 item quantitative food-frequency questionnaire. Odds ratios and their 95% confidence intervals were estimated using conditional logistic regression analyses. RESULTS: The median intakes of soy foods (in protein) were 0.5/0.5, 1.4/1.7, 2.7/3.3 and 6.1/7.7 (male/female) g/d in the quartiles 1 to 4. Both univariate and multivariate analyses showed no significant association between the consumption of soy proteins or soy isoflavones and the risk of nasopharyngeal carcinoma. The adjusted odds ratios (95% confidence intervals) between extreme quartiles were 0.97 (0.66-1.45) for soy proteins and 0.97 (0.66-1.42) for total isoflavones. Null associations were also observed between intake of the individual isoflavones daidzein, genistein and glycitein and NPC risk, with adjusted odds ratios for the extreme quartiles ranging between 0.73 and 1.23. CONCLUSION: Habitual consumption of soy products had no significant effect on the risk of nasopharyngeal carcinoma in Chinese adults with a relatively low intake. PMID- 24155975 TI - Use of a capture-based pathogen transcript enrichment strategy for RNA-Seq analysis of the Francisella tularensis LVS transcriptome during infection of murine macrophages. AB - Francisella tularensis is a zoonotic intracellular pathogen that is capable of causing potentially fatal human infections. Like all successful bacterial pathogens, F. tularensis rapidly responds to changes in its environment during infection of host cells, and upon encountering different microenvironments within those cells. This ability to appropriately respond to the challenges of infection requires rapid and global shifts in gene expression patterns. In this study, we use a novel pathogen transcript enrichment strategy and whole transcriptome sequencing (RNA-Seq) to perform a detailed characterization of the rapid and global shifts in F. tularensis LVS gene expression during infection of murine macrophages. We performed differential gene expression analysis on all bacterial genes at two key stages of infection: phagosomal escape, and cytosolic replication. By comparing the F. tularensis transcriptome at these two stages of infection to that of the bacteria grown in culture, we were able to identify sets of genes that are differentially expressed over the course of infection. This analysis revealed the temporally dynamic expression of a number of known and putative transcriptional regulators and virulence factors, providing insight into their role during infection. In addition, we identified several F. tularensis genes that are significantly up-regulated during infection but had not been previously identified as virulence factors. These unknown genes may make attractive therapeutic or vaccine targets. PMID- 24155977 TI - Decreased proportion of cytomegalovirus specific CD8 T-cells but no signs of general immunosenescence in Alzheimer's disease. AB - Cytomegalovirus (CMV) has been suggested as a contributing force behind the impaired immune responsiveness in the elderly, with decreased numbers of naive T cells and an increased proportion of effector T-cells. Immunological impairment is also implicated as a part of the pathogenesis in Alzheimer's disease (AD). The aim of this study was to investigate whether AD patients present with a different CMV-specific CD8 immune profile compared to non-demented controls. Blood samples from 50 AD patients and 50 age-matched controls were analysed for HLA-type, CMV serostatus and systemic inflammatory biomarkers. Using multi-colour flow cytometry, lymphocytes from peripheral blood mononuclear cells were analysed for CMV-specific CD8 immunity with MHC-I tetramers A01, A02, A24, B07, B08 and B35 and further classified using CD27, CD28, CD45RA and CCR7 antibodies. Among CMV seropositive subjects, patients with AD had significantly lower proportions of CMV-specific CD8 T-cells compared to controls, 1.16 % vs. 4.13 % (p=0.0057). Regardless of dementia status, CMV seropositive subjects presented with a lower proportion of naive CD8 cells and a higher proportion of effector CD8 cells compared to seronegative subjects. Interestingly, patients with AD showed a decreased proportion of CMV-specific CD8 cells but no difference in general CD8 differentiation. PMID- 24155976 TI - Altered cardiac electrophysiology and SUDEP in a model of Dravet syndrome. AB - OBJECTIVE: Dravet syndrome is a severe form of intractable pediatric epilepsy with a high incidence of SUDEP: Sudden Unexpected Death in epilepsy. Cardiac arrhythmias are a proposed cause for some cases of SUDEP, yet the susceptibility and potential mechanism of arrhythmogenesis in Dravet syndrome remain unknown. The majority of Dravet syndrome patients have de novo mutations in SCN1A, resulting in haploinsufficiency. We propose that, in addition to neuronal hyperexcitability, SCN1A haploinsufficiency alters cardiac electrical function and produces arrhythmias, providing a potential mechanism for SUDEP. METHODS: Postnatal day 15-21 heterozygous SCN1A-R1407X knock-in mice, expressing a human Dravet syndrome mutation, were used to investigate a possible cardiac phenotype. A combination of single cell electrophysiology and in vivo electrocardiogram (ECG) recordings were performed. RESULTS: We observed a 2-fold increase in both transient and persistent Na(+) current density in isolated Dravet syndrome ventricular myocytes that resulted from increased activity of a tetrodotoxin resistant Na(+) current, likely Nav1.5. Dravet syndrome myocytes exhibited increased excitability, action potential duration prolongation, and triggered activity. Continuous radiotelemetric ECG recordings showed QT prolongation, ventricular ectopic foci, idioventricular rhythms, beat-to-beat variability, ventricular fibrillation, and focal bradycardia. Spontaneous deaths were recorded in 2 DS mice, and a third became moribund and required euthanasia. INTERPRETATION: These data from single cell and whole animal experiments suggest that altered cardiac electrical function in Dravet syndrome may contribute to the susceptibility for arrhythmogenesis and SUDEP. These mechanistic insights may lead to critical risk assessment and intervention in human patients. PMID- 24155978 TI - Possible involvement of nitric oxide and reactive oxygen species in glucose deprivation-induced activation of transcription factor rst2. AB - Glucose is one of the most important sources of cellular nutrition and glucose deprivation induces various cellular responses. In Schizosaccharomyces pombe, zinc finger protein Rst2 is activated upon glucose deprivation, and regulates gene expression via the STREP (stress response element of Schizosaccharomyces pombe) motif. However, the activation mechanism of Rst2 is not fully understood. We monitored Rst2 transcriptional activity in living cells using a Renilla luciferase reporter system. Hydrogen peroxide (H2O2) enhanced Rst2 transcriptional activity upon glucose deprivation and free radical scavenger inhibited Rst2 transcriptional activity upon glucose deprivation. In addition, deletion of the trx2 (+) gene encoding mitochondrial thioredoxin enhanced Rst2 transcriptional activity. Notably, nitric oxide (NO) generators enhanced Rst2 transcriptional activity upon glucose deprivation as well as under glucose-rich conditions. Furthermore, NO specific scavenger inhibited Rst2 transcriptional activity upon glucose deprivation. Altogether, our data suggest that NO and reactive oxygen species may be involved in the activation of transcription factor Rst2. PMID- 24155979 TI - Human bladder uroepithelial cells synergize with monocytes to promote IL-10 synthesis and other cytokine responses to uropathogenic Escherichia coli. AB - Urinary tract infections are a major source of morbidity for women and the elderly, with Uropathogenic Escherichia coli (UPEC) being the most prevalent causative pathogen. Studies in recent years have defined a key anti-inflammatory role for Interleukin-10 (IL-10) in urinary tract infection mediated by UPEC and other uropathogens. We investigated the nature of the IL-10-producing interactions between UPEC and host cells by utilising a novel co-culture model that incorporated lymphocytes, mononuclear and uroepithelial cells in histotypic proportions. This co-culture model demonstrated synergistic IL-10 production effects between monocytes and uroepithelial cells following infection with UPEC. Membrane inserts were used to separate the monocyte and uroepithelial cell types during infection and revealed two synergistic IL-10 production effects based on contact-dependent and soluble interactions. Analysis of a comprehensive set of immunologically relevant biomarkers in monocyte-uroepithelial cell co-cultures highlighted that multiple cytokine, chemokine and signalling factors were also produced in a synergistic or antagonistic fashion. These results demonstrate that IL-10 responses to UPEC occur via multiple interactions between several cells types, implying a complex role for infection-related IL-10 during UTI. Development and application of the co-culture model described in this study is thus useful to define the degree of contact dependency of biomarker production to UPEC, and highlights the relevance of histotypic co-cultures in studying complex host-pathogen interactions. PMID- 24155980 TI - Inflexible minds: impaired attention switching in recent-onset schizophrenia. AB - Impairment of sustained attention is assumed to be a core cognitive abnormality in schizophrenia. However, this seems inconsistent with a recent hypothesis that in schizophrenia the implementation of selection (i.e., sustained attention) is intact but the control of selection (i.e., switching the focus of attention) is impaired. Mounting evidence supports this hypothesis, indicating that switching of attention is a bigger problem in schizophrenia than maintaining the focus of attention. To shed more light on this hypothesis, we tested whether schizophrenia patients are impaired relative to controls in sustaining attention, switching attention, or both. Fifteen patients with recent-onset schizophrenia and fifteen healthy volunteers, matched on age and intelligence, performed sustained attention and attention switching tasks, while performance and brain potential measures of selective attention were recorded. In the sustained attention task, patients did not differ from the controls on these measures. In the attention switching task, however, patients showed worse performance than the controls, and early selective attention related brain potentials were absent in the patients while clearly present in the controls. These findings support the hypothesis that schizophrenia is associated with an impairment of the mechanisms that control the direction of attention (attention switching), while the mechanisms that implement a direction of attention (sustained attention) are intact. PMID- 24155981 TI - Specifically expressed genes of the nematode Bursaphelenchus xylophilus involved with early interactions with pine trees. AB - As the causal agent of pine wilt disease (PWD), the pine wood nematode (PWN), Bursaphelenchus xylophilus, causes huge economic losses by devastating pine forests worldwide. However, the pathogenesis-related genes of B. xylophilus are not well characterized. Thus, DNA microarrays were used to investigate differential gene expression in PWN where Pinus thunbergii was inoculated with nematodes, compared with those cultured on Botrytis cinerea. The microarrays comprised 31121 probes, 1310 (4.2%) of which were differentially regulated (changes of >2-fold, P < 0.01) in the two growth conditions. Of these 1310 genes, 633 genes were upregulated, whereas 677 genes were downregulated. Gene Ontology (GO) categories were assigned to the classes Cellular Component, Molecular Function, and Biological Process. The comparative gene expression analysis showed that a large number of the pathogenesis-related genes of B. xylophilus, such as pectate lyase genes, cytochrome P450s, UGTs, and ABC transporter genes, were highly expressed when B. xylophilus infected P. thunbergii. Annotation analysis indicated that these genes contributed to cell wall degradation, detoxification, and the reproduction process. The microarray results were validated using quantitative RT-PCR (qRT-PCR). The microarray data confirmed the specific expression of B. xylophilus genes during infection of P. thunbergii, which provides basic information that facilitates a better understanding of the molecular mechanism of PWD. PMID- 24155982 TI - Ankyrin-G participates in INa remodeling in myocytes from the border zones of infarcted canine heart. AB - Cardiac Na channel remodeling provides a critical substrate for generation of reentrant arrhythmias in border zones of the infarcted canine heart. Recent studies show that Nav1.5 assembly and function are linked to ankyrin-G, gap, and mechanical junction proteins. In this study our objective is to expound the status of the cardiac Na channel, its interacting protein ankyrinG and the mechanical and gap junction proteins at two different times post infarction when arrhythmias are known to occur; that is, 48 hr and 5 day post coronary occlusion. Previous studies have shown the origins of arrhythmic events come from the subendocardial Purkinje and epicardial border zone. Our Purkinje cell (Pcell) voltage clamp study shows that INa and its kinetic parameters do not differ between Pcells from the subendocardium of the 48hr infarcted heart (IZPCs) and control non-infarcted Pcells (NZPCs). Immunostaining studies revealed that disturbances of Nav1.5 protein location with ankyrin-G are modest in 48 hr IZPCs. Therefore, Na current remodeling does not contribute to the abnormal conduction in the subendocardial border zone 48 hr post myocardial infarction as previously defined. In addition, immunohistochemical data show that Cx40/Cx43 co-localize at the intercalated disc (IDs) of control NZPCs but separate in IZPCs. At the same time, Purkinje cell desmoplakin and desmoglein2 immunostaining become diffuse while plakophilin2 and plakoglobin increase in abundance at IDs. In the epicardial border zone 5 days post myocardial infarction, immunoblot and immunocytochemical analyses showed that ankyrin-G protein expression is increased and re-localized to submembrane cell regions at a time when Nav1.5 function is decreased. Thus, Nav1.5 and ankyrin-G remodeling occur later after myocardial infarction compared to that of gap and mechanical junctional proteins. Gap and mechanical junctional proteins remodel in IZPCs early, perhaps to help maintain Nav1.5 subcellular location position and preserve its function soon after myocardial infarction. PMID- 24155983 TI - Vitamin B12 and progression of white matter lesions. A 2-year follow-up study in first-ever lacunar stroke patients. AB - In cross-sectional studies periventricular white matter lesions (WML) were related to low plasma levels of vitamin B12. Whether low vitamin B12 levels are also related to progression of WML is still unknown. We studied baseline vitamin B12 levels and its association with progression of WML over 2 years of follow-up in first-ever lacunar stroke patients. In 107 first-ever lacunar stroke patients in whom baseline brain MRI and vitamin B12 status were available, we obtained a follow-up brain MRI after 2 years. We assessed progression of periventricular WML (pWML) and deep WML (dWML) using a visual WML change scale. We studied the relationship between baseline levels of plasma vitamin B12 and progression of WML after 2 years of follow-up by binary logistic regression analyses. Vitamin B12 deficiency was more frequent in patients with progression of pWML compared to those without progression (41.9% and 19.7% respectively, p = 0.02). Corrected for sex and age, progression of pWML was associated with lower baseline levels of vitamin B12 (OR 1.42 per 50 unit decrease, 95% CI 1.00-1.92). Vitamin B12 levels were not associated with progression of dWML. In conclusion progression of pWML after 2 years of follow-up relates to low levels of vitamin B12 at baseline in first-ever lacunar stroke patients. Whether this population could benefit from vitamin B12 supplementation is unknown and requires further investigation. PMID- 24155984 TI - Efficacy of biodegradable curcumin nanoparticles in delaying cataract in diabetic rat model. AB - Curcumin, the active principle present in the yellow spice turmeric, has been shown to exhibit various pharmacological actions such as antioxidant, anti inflammatory, antimicrobial, and anti-carcinogenic activities. Previously we have reported that dietary curcumin delays diabetes-induced cataract in rats. However, low peroral bioavailability is a major limiting factor for the success of clinical utilization of curcumin. In this study, we have administered curcumin encapsulated nanoparticles in streptozotocin (STZ) induced diabetic cataract model. Oral administration of 2 mg/day nanocurcumin was significantly more effective than curcumin in delaying diabetic cataracts in rats. The significant delay in progression of diabetic cataract by nanocurcumin is attributed to its ability to intervene the biochemical pathways of disease progression such as protein insolubilization, polyol pathway, protein glycation, crystallin distribution and oxidative stress. The enhanced performance of nanocurcumin can be attributed probably to its improved oral bioavailability. Together, the results of the present study demonstrate the potential of nanocurcumin in managing diabetic cataract. PMID- 24155986 TI - Measurement of microbial DNA polymerase activity enables detection and growth monitoring of microbes from clinical blood cultures. AB - Surveillance of bloodstream infections (BSI) is a high priority within the hospital setting. Broth-based blood cultures are the current gold standard for detecting BSI, however they can require lengthy incubation periods prior to detection of positive samples. We set out to demonstrate the feasibility of using enzymatic template generation and amplification (ETGA)-mediated measurement of DNA polymerase activity to detect microbes from clinical blood cultures. In addition to routine-collected hospital blood cultures, one parallel aerobic blood culture was collected and immediately refrigerated until being transported for ETGA analysis. After refrigeration holding and transport, parallel-collected cultures were placed into a BACTEC incubator and ETGA time-course analysis was performed. Of the 308 clinical blood cultures received, 22 were BACTEC positive, and thus were initially selected for ETGA time course analysis. The ETGA assay detected microbial growth in all 22 parallel-positive blood cultures in less time than a BACTEC incubator and also yielded genomic DNA for qPCR-based organism identification. In summary, feasibility of detecting microbes from clinical blood culture samples using the ETGA blood culture assay was demonstrated. Additional studies are being considered towards development of clinically beneficial versions of this methodology. PMID- 24155985 TI - The ESX-3 secretion system is necessary for iron and zinc homeostasis in Mycobacterium tuberculosis. AB - ESX-3 is one of the five type VII secretion systems encoded by the Mycobacterium tuberculosis genome. We recently showed the essentiality of ESX-3 for M. tuberculosis viability and proposed its involvement in iron and zinc metabolism. In this study we confirmed the role of ESX-3 in iron uptake and its involvement in the adaptation to low zinc environment in M. tuberculosis. Moreover, we unveiled functional differences between the ESX-3 roles in M. tuberculosis and M. smegmatis showing that in the latter ESX-3 is only involved in the adaptation to iron and not to zinc restriction. Finally, we also showed that in M. tuberculosis this secretion system is essential for iron and zinc homeostasis not only in conditions in which the concentrations of these metals are limiting but also in metal sufficient conditions. PMID- 24155987 TI - Citation classics in systematic reviews and meta-analyses: who wrote the top 100 most cited articles? AB - BACKGROUND: Systematic reviews of the literature occupy the highest position in currently proposed hierarchies of evidence. The aims of this study were to assess whether citation classics exist in published systematic review and meta-analysis (SRM), examine the characteristics of the most frequently cited SRM articles, and evaluate the contribution of different world regions. METHODS: The 100 most cited SRM were identified in October 2012 using the Science Citation Index database of the Institute for Scientific Information. Data were extracted by one author. Spearman's correlation was used to assess the association between years since publication, numbers of authors, article length, journal impact factor, and average citations per year. RESULTS: Among the 100 citation classics, published between 1977 and 2008, the most cited article received 7308 citations and the least-cited 675 citations. The average citations per year ranged from 27.8 to 401.6. First authors from the USA produced the highest number of citation classics (n=46), followed by the UK (n=28) and Canada (n=15). The 100 articles were published in 42 journals led by the Journal of the American Medical Association (n=18), followed by the British Medical Journal (n=14) and The Lancet (n=13). There was a statistically significant positive correlation between number of authors (Spearman's rho=0.320, p=0.001), journal impact factor (rho=0.240, p=0.016) and average citations per year. There was a statistically significant negative correlation between average citations per year and year since publication (rho = -0.636, p=0.0001). The most cited papers identified seminal contributions and originators of landmark methodological aspects of SRM and reflect major advances in the management of and predisposing factors for chronic diseases. CONCLUSIONS: Since the late 1970s, the USA, UK, and Canada have taken leadership in the production of citation classic papers. No first author from low or middle-income countries (LMIC) led one of the most cited 100 SRM. PMID- 24155988 TI - Atopic dermatitis and the stratum corneum: part 1: the role of filaggrin in the stratum corneum barrier and atopic skin. AB - This three-part review presents what is currently known about the involvement and interdependency of the barrier properties of the epidermis, especially the stratum corneum and various specific immunological responses in the etiopathogenesis of atopic dermatitis. Part 1 of this review depicts the role of filaggrin in atopic dermatitis while Part 2 (which will be published in an upcoming issue of The Journal of Clinical and Aesthetic Dermatology) evaluates the role of serine proteases and specific lipids in the structural and functional integrity of the stratum corneum and related barrier functions in atopic dermatitis. Filaggrin is a key component of the stratum corneum that is derived from a larger precursor protein and contributes to its physical strength, hydration status, skin pH, and buffering capacity among other physiochemical properties. Filaggrin gene loss of function mutations appear to play a pathophysiological role; however, they are not the sole pathogenic factor in atopic dermatitis. Adverse structural changes of the stratum corneum are caused by upregulation of serine proteases activity, which causes degradation of certain stratum corneum proteins that are integral to barrier functions; interference with the formation of the stratum corneum intercellular lipid membrane, which normally regulates epidermal water flux and gradient; and induction of a TH2 pattern of inflammation, which is characteristic of atopic skin. Alteration in lipid ratios and changes in lipid-directed enzymes may play a role in the impairment of epidermal barrier functions that are associated with atopic dermatitis. Part 3 of this review (which will be published in an upcoming issue of The Journal of Clinical and Aesthetic Dermatology) discusses how immune dysregulation, including upregulation of a TH2 inflammation pattern, augmented allergic sensitization, sustained wound healing inflammation, and impaired innate immunity all play a role in the development of atopic dermatitis. An increased understanding of the interdependence, polymorphisms, and dysregulations of epidermal barrier functions, including the stratum corneum permeability barrier, immune response barrier, and antimicrobial barrier, should provide further knowledge about the pathophysiological mechanisms that are related to the development of atopic dermatitis, are clinically relevant, and can better direct researchers to develop therapies that are targeted at important pathogenic components of the disease state. PMID- 24155989 TI - Psoriasis Improvement in Patients Using Glutathione-enhancing, Nondenatured Whey Protein Isolate: A Pilot Study. AB - BACKGROUND: Psoriasis is a common autoimmune disease with enhanced systemic inflammation and heightened levels of oxidative stress. Glutathione is the major antioxidant in human cells. OBJECTIVES: To determine if a nondenatured bioactive whey protein isolate previously demonstrated to increase glutathione levels can clinically improve patients with psoriasis vulgaris. METHODS: A single site, prospective, non-blinded trial. Seven patients with psoriasis were recruited to take a nondenatured bioactive whey protein isolate, 20g orally per day, in addition to their current treatments, if any. Psoriasis Area and Severity Index scores and photographs were taken at baseline and monthly for three months. RESULTS: Patients with psoriasis were found to have a beneficial clinical improvement, whether they were on existing topical therapy, narrowband ultraviolet B, or no other treatment. CONCLUSION: The positive preliminary outcomes from this pilot study suggest a randomized, double-blind, clinical trial would be worthwhile in evaluating whether this protein isolate would result in statistically significant improvement for patients with psoriasis. PMID- 24155990 TI - Safety and Cosmetic Effects of Photodynamic Therapy using Hexyl Aminolevulinate and Intense Pulsed Light: A Pilot Study Conducted in Subjects with Mild-to moderate Facial Photodamage. AB - OBJECTIVE: To assess the cosmetic effects of photodynamic therapy with hexyl aminolevulinate cream and intense pulsed light in subjects with mild-to-moderate facial photodamage. DESIGN: Six-month, open-label, single-center, pilot study comprising three study treatments, each separated by 30 days, and two follow-up visits (one and four months following third treatment). SETTING: Tennessee Clinical Research Center, Nashville, Tennessee. PARTICIPANTS: Ten women (ages 36 to 64 years) with skin color classified as Fitzpatrick I to III. MEASUREMENTS: The investigator evaluated erythema, dryness, bruising, crusts and erosions, and stinging/burning immediately before and after each treatment and at each follow up visit. In addition, the investigator rated cosmetic appearance at each follow up visit. Subjects rated stinging, tingling, itching, and burning 15 minutes after each treatment and cosmetic effects (radiance, smoothness, pore appearance, evenness of skin tone, and overall effect) at each follow-up visit. RESULTS: Mean (standard error of the mean) objective cosmetic appearance scores were 0.900 (0.233) and 1.400 (0.267) (0=very much improved; l=much improved; 2=improved) one and four months following treatment, respectively. Mean subjective assessments of radiance, smoothness, pore appearance, evenness of skin tone, and overall effect ranged from 2.200 to 2.800 (2=much improved; 3=improved) one and four months following treatment. Mean objective erythema, dryness, bruising, and stinging/burning scores were <1 (minimal/slight) at all time points. Mean subjective post-treatment stinging, tingling, itching, and burning scores were <1 (mild) at all time points. CONCLUSION: Photodynamic therapy with hexyl aminolevulinate and intense pulsed light improved cosmetic appearance and was generally well tolerated. Further investigation in larger patient populations is warranted. PMID- 24155991 TI - Adapalene 0.3% for the treatment of acne in women. AB - SETTING: Acne vulgaris is characterized by comedones, papules, pustules, and secondary lesions. Historically, it has been considered a disease primarily affecting adolescents, but recent reports over the past three decades suggest an increasing prevalence in adults, particularly women. Adapalene was developed for the topical treatment of acne. Adapalene (6-[3-(l-adamantyl)-4-methoxyphenyl]-2 naphthoic acid) is a synthetic naphthoic acid derivative with potent retinoid activity including the reversal of the abnormal follicular keratinization and microcomedo formation and decreasing inflammatory lesions. Design/objective: In this analysis, data from two studies comparing adapalene gel 0.3% to vehicle gel were combined and evaluated for change in lesion counts and Investigator's Global Assessment of success rates in adult female subjects ages 18 to 41 years with acne vulgaris. RESULTS: The results showed a statistically significant difference favoring adapalene gel 0.3% for reduction in total lesion count at Week 12 (P=0.045). Additionally, median reduction for inflammatory lesions (-61%) and noninflammatory lesions (-51%) also favored adapalene. In addition, adapalene gel, 0.3% was well tolerated with similar tolerability compared to adapalene gel 0.1%; the most common treatment-related adverse events were skin discomfort and dry skin. There were no reported serious adverse events in any group. CONCLUSION: In this subgroup analysis, adapalene gel 0.3% proved effective and well tolerated in adult women with acne vulgaris. PMID- 24155992 TI - Elastosis perforans serpiginosa in association with scabies mite. AB - Elastosis perforans serpiginosa is a form of perforating dermatoses, which has a characteristic clinical presentation of grouped keratotic papules coalescing into serpiginous or annular configurations. The majority of elastosis perforans serpiginosa cases are idiopathic; however, various etiologies have been postulated for the pathogenesis of this syndrome. The authors present a unique case of elastosis perforans serpiginosa that developed focally secondary to a scabies mite. PMID- 24155993 TI - Cutaneous Co-infected Cytomegalovirus and Herpes Simplex Virus Perigenital Ulcers in Human Immunodeficiency Virus Patients. AB - There is uncertainty regarding the pathogenic nature of cytomegalovirus in cutaneous lesions co-infected with herpes simplex virus. It is widely believed that herpes simplex virus is the main pathogenic factor in such lesions and that cytomegalovirus plays little if any role. There are, however, isolated case reports that describe cytomegalovirus as an important driving pathogen in such lesions. The authors present two human immunodeficiency virus patients who have cytomegalovirus and herpes simplex virus co-infected perigenital ulcers, one of whom improved on valacyclovir, while the other, who was already on valacyclovir for chronic herpes simplex virus suppression, showed no improvement with a single dose of cidofovir. He only showed rapid improvement when treated with valganciclovir. The latter patient underscores the viewpoint that at least in some cases, cytomegalovirus may be an important driving force behind the formation of such lesions. The authors therefore recommend that clinicians be aware of the possible pathogenic role of cytomegalovirus in these ulcers, and, in nonhealing ulcers, use anti-cytomegalovirus agents to prevent the onset of systemic disease. These results warrant further study of the pathogenesis of cytomegalovirus in co-infected herpes simplex virus ulcers. PMID- 24155994 TI - Acquired hemochromatosis with pronounced pigment deposition of the upper eyelids. AB - HEMOCHROMATOSIS MAY BE CLASSIFIED INTO TWO GROUPS: primary (hereditary) or secondary (acquired). The acquired type most commonly occurs after massive intake of iron supplements or blood transfusions and is also known as transfusional iron overload. In the past, hemochromatosis was usually recognized at an advanced stage by the classic triad of hyperpigmentation, diabetes mellitus ("bronze diabetes"), and hepatic cirrhosis. Cutaneous hyperpigmentation is present in 70 percent of patients due to two different mechanisms: (1) hemosiderin deposition resulting in diffuse, slate-gray darkening and (2) increased production of melanin in the epidermis. A 47-year-old woman who receives regular transfusions due to low iron and chronic, unresolving anemia and who subsequently developed pronounced hyperpigmentation of the upper eyelids is described. The presentation, diagnosis, pathogenesis, and treatment options of hyperpigmentation due to secondary hemochromatosis are discussed. PMID- 24155996 TI - A developing world experience with distal foot amputations for diabetic limb salvage. AB - OBJECTIVES: To evaluate the functional outcome, morbidity, and viability of foot salvage in diabetic patients. MATERIALS AND METHODS: This prospective case series was conducted from March 2007 to December 2012 at the department of surgery Pakistan Ordnance Factories Hospital, Wah Cantt, Pakistan. 123 males and 26 female patients were included in the study. All the patients were treated after getting admitted in the hospital and wounds were managed with daily dressings, nursing care and debridement of necrotic tissue with adequate antibiotic coverage. RESULTS: In total, 149 patients (mean age: 56+/-7.52 years) with 171 amputations were included in the study. The mean duration of diabetes mellitus (DM) was 9+/-4.43 years. Ninety-seven percent of the patients were diagnosed with type 2 DM. Wound debridement was performed under general anesthesia in 48 (33.2%) patients, whereas local anesthesia was used for the rest of the patients after having good glycemic control and improvement in general health. The most common pathogen isolated from the infected wounds was Staphylococcus aureus in approximately 46% cases. Regarding the types of amputation, partial toe amputation was performed in 21 (12.2%) cases, second-toe amputation in 60 (35%) cases, hallux amputation in 41 (24%) cases, multiple toe amputations in 29 (17%) cases, bilateral feet involvement was observed in 16 (9.3%) cases, and transmetatarsal amputation was performed in 4 (2.3%) cases. The wounds healed well except in 19 cases where amputation had to be revised to a more proximal level. Thirty-nine patients died during the study period: 3 died of wound-related complications and 36 died of systemic complications. CONCLUSION: With the ever increasing epidemic of DM, the number of patients with diabetic foot ulcers has also significantly risen. Early surgical management with good glycemic control and foot care with close monitoring can decrease amputations and thus foot salvage can be successfully achieved. PMID- 24155995 TI - Interactions of Candida albicans with host epithelial surfaces. AB - Candida albicans is an opportunistic, fungal pathogen of humans that frequently causes superficial infections of oral and vaginal mucosal surfaces of debilitated and susceptible individuals. The organism is however, commonly encountered as a commensal in healthy individuals where it is a component of the normal microflora. The key determinant in the type of relationship that Candida has with its host is how it interacts with the epithelial surface it colonises. A delicate balance clearly exists between the potentially damaging effects of Candida virulence factors and the nature of the immune response elicited by the host. Frequently, it is changes in host factors that lead to Candida seemingly changing from a commensal to pathogenic existence. However, given the often reported heterogeneity in morphological and biochemical factors that exist between Candida species and indeed strains of C. albicans, it may also be the fact that colonising strains differ in the way they exploit resources to allow persistence at mucosal surfaces and as a consequence this too may affect the way Candida interacts with epithelial cells. The aim of this review is to provide an overview of some of the possible interactions that may occur between C. albicans and host epithelial surfaces that may in turn dictate whether Candida removal, its commensal persistence or infection follows. PMID- 24155997 TI - A new approach to neuroplasty. PMID- 24155998 TI - Should we start treating chronic low back pain with antibiotics rather than with pain medications? AB - For those of us who have read the 2 recently published articles by a Danish - British research group, it might appear that we are observing an impending paradigm shift on the origins of chronic low back pain. The results of this research indicate, that chronic low back pain associated with bone marrow edema in vertebral endplates that are adjacent to herniated intervertebral discs may be caused by infections with anaerobic bacteria of low virulence. According to these articles, treatment with certain antibiotics is significantly more effective than placebo against this low back pain. If these findings are to hold true in repeat studies by other researchers, they stand to fundamentally change our concepts of low back pain, degenerative disc disease and in consequence the suitable therapies for these entities. It may in fact require pain specialists to become familiarized with the details of antibiotic treatments and their specific risks in order to be able to properly counsel their patients. While this seems hard to believe at first glance, bacteria have been implicated in the pathogenesis of other conditions that do not primarily impose as infectious diseases such as gastric ulcers. While the authors refer to a few previous studies pointing into the same direction, the relevant research is really only from one group of collaborating scientists. Therefore, before we start prescribing antibiotics for chronic low back pain, it is imperative that other researchers in different institutions confirm these results. PMID- 24155999 TI - Role of Catheter's Position for Final Results in Intrathecal Drug Delivery. Analysis Based on CSF Dynamics and Specific Drugs Profiles. AB - Intrathecal drug delivery is an effective and safe option for the treatment of chronic pathology refractory to conventional pain therapies. Typical intrathecal administered drugs are opioids, baclofen, local anesthetics and adjuvant medications. Although knowledge about mechanisms of action of intrathecal drugs are every day more clear many doubt remain respect the correct location of intrathecal catheter in order to achieve the best therapeutic result. We analyze the factors that can affect drug distribution within the cerebrospinal fluid. Three categories of variables were identified: drug features, cerebrospinal fluid (CSF) dynamics and patients features. First category includes physicochemical properties and pharmacological features of intrathecal administered drugs with special attention to drug lipophilicity. In the second category, the variables in CSF flow, are considered that can modify the drug distribution within the CSF with special attention to the new theories of liquoral circulation. Last category try to explain inter-individual difference in baclofen response with difference that are specific for each patients such as the anatomical area to treat, patient posture or reaction to inflammatory stimulus. We conclude that a comprehensive evaluation of the patients, including imaging techniques to study the anatomy and physiology of intrathecal environment and CSF dynamics, could become essential in the future to the purpose of optimize the clinical outcome of intrathecal therapy. PMID- 24156000 TI - An insight into neurophysiology of pulpal pain: facts and hypotheses. AB - Pain and pain control are important to the dental profession because the general perception of the public is that dental treatment and pain go hand in hand. Successful dental treatment requires that the source of pain be detected. If the origin of pain is not found, inappropriate dental care and, ultimately, extraction may result. Pain experienced before, during, or after endodontic therapy is a serious concern to both patients and endodontists, and the variability of discomfort presents a challenge in terms of diagnostic methods, endodontic therapy, and endodontic knowledge. This review will help clinicians understand the basic neurophysiology of pulpal pain and other painful conditions of the dental pulp that are not well understood. PMID- 24156001 TI - The effect of urinary trypsin inhibitor against neuropathic pain in rat models. AB - BACKGROUND: Nerve injury sometimes leads to chronic neuropathic pain associated with neuroinflammation in the nervous system. In the case of chronic neuropathic pain, the inflammatory and algesic mediators become predominant and result in pain hypersensitivity following nervous system damage. It is well known that urinary trypsin inhibitor (ulinastatin, UTI) has an anti-inflammatory activity. Recently, the neuroprotective action of UTI on the nervous system after ischemic injury has been reported. Thus, we evaluated the neuroprotective effect of ulinastatin in a rat model of neuropathic pain. METHODS: Neuropathic pain was induced with L5 spinal nerve ligation (SNL) in male Sprague-Dawley rats weighing 100-120 g. The rats were divided into 3 groups, with n = 8 in each group. The rats in the control group (group 1) were administered normal saline and those in group 2 were administered UTI (50,000 U/kg) intravenously through the tail vein for 3 days from the day of SNL. Rats in group 3 were administered UTI (50,000 U/kg) intravenously from the 5(th) day after SNL. The paw withdrawal threshold was measured using the von Frey test for 3 days starting from the 5(th) day after SNL. RESULTS: The paw withdrawal thresholds were significantly increased in the rats of group 2 compared to the other groups (P < 0.05). CONCLUSIONS: Ulinastatin, which was administered for 3 days after SNL, increased the paw withdrawal threshold and it could have a neuroprotective effect in the rat model of neuropathic pain. PMID- 24156002 TI - The analgesic effect of nefopam with fentanyl at the end of laparoscopic cholecystectomy. AB - BACKGROUND: Nefopam is a centrally acting analgesic that is used to control pain. The aim of this study was to find an appropriate dose of nefopam that demonstrates an analgesic effect when administered in continuous infusion with fentanyl at the end of laparoscopic cholecystectomy. METHODS: Ninety patients scheduled for laparoscopic cholecystectomy were randomly assigned to receive analgesia with fentanyl alone (50 ug, Group 1, n = 30), or with fentanyl in combination with nefopam 20 mg (Group 2, n = 30) or in combination with nefopam 40 mg (Group 3, n = 30) at the end of surgery. Pain and side effects were evaluated at 10 minutes, 30 minutes, 1 hour, 2 hours, 6 hours, and 12 hours after arrival in the post-anesthesia care unit (PACU). RESULTS: Pain was statistically significantly lower in Groups 2 and 3 than in Group 1 at 10 minutes, 2 hours, and 6 hours after arrival in the PACU. Nausea was statistically significantly lower in Group 2 than in Groups 1 and 3 at 10 minutes after arrival in the PACU. Shivering was statistically significantly lower in Groups 2 and 3 than in Group 1 at 10 minutes after arrival in the PACU. CONCLUSIONS: Nefopam is a drug that can be safely used as an analgesic after surgery, and its side effects can be reduced when fentanyl 50 ug is injected with nefopam 20 mg. PMID- 24156003 TI - Bertolotti syndrome: a diagnostic and management dilemma for pain physicians. AB - BACKGROUND: Bertolotti's syndrome (BS), a form of lumbago in lumbosacral transitional vertebrae, is an important cause of low back pain in young patients. The purpose of this study was to assess the etiology of low back pain and the efficacy of treatment offered to patients with BS. METHODS: All patients of BS Castellvi type1a during a period of 6 months were enrolled in the study. The patients underwent interventional pain procedures for diagnosis and pain relief. Response to the therapy was assessed based on VAS and ODI scores. A 50% decrease in VAS score or a VAS score less than 3 would be considered adequate pain relief. RESULTS: All 20 patients diagnosed with BS during the 6-month observation period had scoliosis. Common causes of back pain were the ipsilateral L5-S1 facet joint, neoarticulation, the SI joint, and disc degeneration. Responses to various interventions for pain relief were different and inconsistent from patient to patient. In particular, responses to interventions for neoarticular pain were generally poor. CONCLUSIONS: Pain in patients with BS does not usually respond to interventional pain treatment. A very dynamic treatment approach must be pursued while managing BS patients, and the treatment plan must be individualized at various stages in order to obtain satisfactory pain relief. PMID- 24156004 TI - The Effect of Ultrasound-guided TAPB on Pain Management after Total Abdominal Hysterectomy. AB - BACKGROUND: Incisional pain is particularly troublesome after hysterectomy. A method called transversus abdominis plane block (TAPB) has shown promise in managing postoperative pain. In this study, we evaluated the analgesic efficacy of ultrasound-guided TAPB after hysterectomy at different time points and at each time point separately for 48 hours. METHODS: Forty-two patients (ASA I, II) who were electively chosen to undergo total abdominal hysterectomy were divided into 2 groups, control (group C) and intervention (group I). Twenty-one patients underwent TAPB (group I) and 21 patients received only the standard treatment with a fentanyl pump (group C). Both groups received standard general anesthesia. For patients in group I, following the surgery and before emergence from anesthesia, 0.5 mg/kg of ropivacaine 0.2% (about 20 cc) was injected bilaterally between the internal oblique and transverse abdominis muscles using sonography. Pain scores using the Visual Analogue Scale (VAS) and drug consumption were measured at 2, 6, 12, 24, and 48 hours after TAPB. RESULTS: There were no significant differences in demographics between the two groups. VAS scores appeared to be lower in group I, although there was no interaction with time when we compared mean VAS measurements at different time points between group I and group C (P > 0.05). The amount of fentanyl flow was consistently higher in group C, but when we compared the two groups at each time point separately, the observed difference was not statistically significant (P < 0.053). The incidence of vomiting was 10% in group I and 28% in group C. There were no complaints of itching, and sedation score was 0 to 3. There were no complications. CONCLUSIONS: This study showed that TAPB did not result in a statistically significant decrease in VAS scores at different time points. TAPB did lead to decreased fentanyl flow, but when we compared the two groups at each time point separately, the observed difference was not statistically significant. PMID- 24156005 TI - Intrathecal Meperidine Plus Lidocaine for Prevention of Shivering during Cesarean Section. AB - BACKGROUND: Shivering related to spinal anesthesia may interfere with monitoring and is uncomfortable. The aim of the present study was to investigate low-dose intrathecal meperidine for the prevention of shivering after induction of spinal anesthesia in parturients with cesarean section. METHODS: This was a prospective randomized, double-blind, placebo-controlled trial including 100 parturients, of American Society of Anesthesiologists (ASA) physical status I or II, scheduled for elective cesarean section under spinal anesthesia who were randomly assigned to a meperidine (0.2 mg/kg) plus hyperbaric lidocaine (5%, 75 mg, n = 50; group M) group or a placebo plus hyperbaric lidocaine (5%, 75 mg, n = 50; group L) group. Demographic and surgical data, adverse events, and the mean intensity for each parturient were assessed during the entire study period by a blinded observer. RESULTS: There were no significant differences between the two study groups regarding the demographic and surgical data (P > 0.05). The incidence of shivering during the entire study period significantly decreased in the group of parturients who received intrathecal meperidine (P = 0.04). There were no significant differences in nausea and vomiting between the two groups. CONCLUSIONS: Low-dose intrathecal meperidine (10 mg) is safe and effective in reducing the incidence and severity of shivering associated with spinal anesthesia in parturients with cesarean section. PMID- 24156006 TI - Diagnosis of iliotibial band friction syndrome and ultrasound guided steroid injection. AB - A 64-year-old woman visited our pain clinic with the pain of right lateral side of thigh for one year. Her pain always started from knee and was radiated to buttock area when symptom was severe. She showed significant tenderness at knee lateral side and local tightness at lateral thigh. Magnetic resonance image of the knee was performed and we could identify high signal intensity of iliotibial band through coronal and axial view. In spite of medication and physical stretching exercise of iliotibial band for one month, she did not show any improvement of pain. To alleviate her symptom, ultrasound guided local corticosteroid injection targeting beneath the iliotibial band was performed. After the procedure, the reduction of pain was significant and there was no need for further management. PMID- 24156007 TI - Approach for epiduroscopic laser neural decompression in case of the sacral canal stenosis. AB - Epiduroscopy is very useful in the treatment of not only low back pain caused by failed back surgery syndrome, epidural scar or herniated disc but also by chronic refractory low back pain which does not respond to interventional conservative treatment including fluoroscopically-directed epidural steroid injections and percutaneous adhesiolysis. Because cauterization using a laser fiber has become recently available, a wider opening is required to enter into the sacral canal in the case of epiduroscopic laser neural decompression (ELND). However, in a few patients, it is difficult to insert a device into the epidural space due to stenosis around the opening, and there is no alternative method. Herein, we report a case where a hiatus rasp specially designed for such patients was used to perform the operation. PMID- 24156008 TI - Computed Tomography (CT) Simulated Fluoroscopy-Guided Transdiscal Approach in Transcrural Celiac Plexus Block. AB - Conventional transcrural CPB via the "walking off" the vertebra technique may injure vital organs while attempting to proximally spread injectate around the celiac plexus. Therefore, we attempted the CT-simulated fluoroscopy-guided transdiscal approach to carry out transcrural CPB in a safer manner, spreading the injectate more completely and closely within the celiac plexus area. A 54 year-old male patient with pancreatic cancer suffered from severe epigastric pain. The conventional transcrural approach was simulated, but the needle pathway was impeded by the kidney on the right side and by the aorta on the left side. After simulating the transdiscal pathway through the T11-12 intervertebral disc, we predetermined the optimal insertion point (3.6 cm from the midline), insertion angle (18 degrees), and advancement plane, as well as the proper depth. With the transdiscal approach, we successfully performed transcrural CPB within a narrow angle, and the bilateral approach was not necessary as we were able to achieve the bilateral spread of the injectate with the single approach. PMID- 24156009 TI - Percutaneous t2 and t3 radiofrequency sympathectomy for complex regional pain syndrome secondary to brachial plexus injury: a case series. AB - Complex regional pain syndrome secondary to brachial plexus injury is often severe, debilitating and difficult to manage. Percuteneous radiofrequency sympathectomy is a relatively new technique, which has shown promising results in various chronic pain disorders. We present four consecutive patients with complex regional pain syndrome secondary to brachial plexus injury for more than 6 months duration, who had undergone percutaneous T2 and T3 radiofrequency sympathectomy after a diagnostic block. All four patients experienced minimal pain relief with conservative treatment and stellate ganglion blockade. An acceptable 6 month pain relief was achieved in all 4 patients where pain score remained less than 50% than that of initial score and all oral analgesics were able to be tapered down. There were no complications attributed to this procedure were reported. From this case series, percutaneous T2 and T3 radiofrequency sympathectomy might play a significant role in multi-modal approach of CRPS management. PMID- 24156010 TI - Postoperative orthostatic intolerance and gender differences. PMID- 24156011 TI - A Simple Working Classification Proposed for Orofacial Pain (OFP) Commonly Encountered in Dental Practice. PMID- 24156012 TI - Synthesis and in vitro pharmacological evaluation of indolyl carboxylic amide analogues as D3 dopamine receptor selective ligands. AB - A series of substituted 1H-indolyl carboxylic acid amides that contain a N-(2 methoxyphenyl)piperazine or N-(2-fluoroethoxy)piperazine group were synthesized and their affinities for human dopamine D2, D3, and D4 receptors were determined. Two of these compounds, 14a and 14b, displayed high binding affinity at D3 (Ki = 0.18 and 0.4 nM, respectively), and selectivity for D3vs. D2 receptors (87-fold and 60-fold, respectively). These two compounds had low binding affinity at D4 receptors and sigma receptor sites. The intrinsic activity of these compounds at D2 and D3 receptors was determined using a forskolin-dependent adenylyl cyclase inhibition assay; both 14a and 14b were found to be partial agonists. Furthermore, for compound 14a, the log D value of 2.85 suggested it has suitable lipophilicity for crossing the blood-brain-barrier. PMID- 24156013 TI - Functional, metal-based crosslinkers for alpha-helix induction in short peptides. AB - Many protein-protein interactions that play a central role in cellular processes involve alpha-helical domains. Consequently, there has been great interest in developing strategies for stabilizing short peptides in alpha-helical conformations toward the inhibition and interrogation of protein-protein interactions. Here, we show that tridentate Hybrid Coordination Motifs (HCMs), which consist of a natural (histidine, His) and an unnatural (8-hydroxyquinoline, Quin) metal binding functionality, can bind divalent metal ions with high affinity and thereby induce/stabilize an alpha-helical configuration in short peptide sequences. The Quin functionality is readily introduced onto peptide platforms both during or after solid-state peptide synthesis, demonstrating the preparative versatility of HCMs. A systematic study involving a series of HCM bearing peptides has revealed the critical importance of the length of the linkage between the Quin moiety and the peptide backbone as well as the metal coordination geometry in determining the extent of alpha-helix induction. Through ZnII coordination or modification with ReI(Quin)(CO)3, the HCM-bearing peptides can be rendered luminescent in the visible region, thus showing that HCMs can be exploited to simultaneously introduce structure and functionality into short peptides. PMID- 24156014 TI - Toward a universal treatment for cancer: cell inflation assisted chemotherapy. AB - Cancers show considerable genetic and functional heterogeneity, preventing the development of a universal anticancer drug. Here, I argue that it is nevertheless possible to elaborate a therapeutic strategy that can be used in almost every cancer, exploiting the negative feedback effect of normal cells on the proliferation of their precursors. This method, termed cell inflation assisted chemotherapy, is aimed at blocking normal cell division prior to high-dose antimitotic chemotherapy. Evidence for a negative feedback effect on granulocyte production suggests that it is possible to prevent neutropenia by transfusion of autologous granulocytes. In a first step, this protocol will be devised to protect neutrophils and to prevent granulopenia in patients treated with intensive chemotherapy. In its simplest form, it will consist of a leukapheresis storage-reinjection sequence just prior to drug administration. Then, if the proof of concept is established, a more systematic use of intensive cell cycle specific chemotherapy, together with protection of other lineages through temporary mitotic blockade might be a treatment applicable for most cancers. PMID- 24156015 TI - Vessel co-option in primary human tumors and metastases: an obstacle to effective anti-angiogenic treatment? AB - Angiogenesis has been regarded as essential for tumor growth and progression. Studies of many human tumors, however, suggest that their microcirculation may be provided by nonsprouting vessels and that a variety of tumors can grow and metastasize without angiogenesis. Vessel co-option, where tumor cells migrate along the preexisting vessels of the host organ, is regarded as an alternative tumor blood supply. Vessel co-option may occur in many malignancies, but so far mostly reported in highly vascularized tissues such as brain, lung, and liver. In primary and metastatic lung cancer and liver metastasis from different primary origins, as much as 10-30% of the tumors are reported to use this alternative blood supply. In addition, vessel co-option is introduced as a potential explanation of antiangiogenic drug resistance, although the impact of vessel co option in this clinical setting is still to be further explored. In this review we discuss tumor vessel co-option with specific examples of vessel co-option in primary and secondary tumors and a consideration of the clinical implications of this alternative tumor blood supply. PMID- 24156016 TI - High expression of ZNF703 independent of amplification indicates worse prognosis in patients with luminal B breast cancer. AB - Amplification of 8p12-p11 is relatively common in breast cancer and several genes within the region have been suggested to affect breast tumor progression. The aim of the study was to map the amplified 8p12-p11 region in a large set of breast tumors in an effort to identify the genetic driver and to explore its impact on tumor progression and prognosis. Copy number alterations (CNAs) were mapped in 359 tumors, and gene expression data from 577 tumors (359 tumors included) were correlated with CNA, clinical-pathological factors, and protein expression (39 tumors). 8p12-p11 was amplified in 11.4% of tumors. The smallest region of amplification harbored one full-length gene, ZNF703. ZNF703 mRNA expression was significantly higher in estrogen receptor (ER)-positive than ER-negative tumors (P = 2 * 10(-16)), a reflection of high expression in luminal tumors. Forty-eight percent of tumors with ZNF703 amplification were luminal B tumors in which the best correlation between DNA copy number and mRNA was seen (P = 1.2 * 10(-7)) as well as correlation between mRNA and protein expression (P = 0.02). High ZNF703 mRNA correlated with poor survival in patients with ER-positive luminal B tumors (log rank P = 0.04). Furthermore, high ZNF703 mRNA expression correlated with poor outcome in patients with ZNF703 copy number neutral, ER-positive, luminal B tumors (log rank P = 0.004). The results support ZNF703 as the driver gene of the 8p12 amplification and suggest that independent of amplification, high expression of the gene affects prognosis in luminal B tumors. PMID- 24156017 TI - Contribution of BubR1 to oxidative stress-induced aneuploidy in p53-deficient cells. AB - DNA aneuploidy is observed in various human tumors and is associated with the abnormal expression of spindle assembly checkpoint (SAC) proteins. Oxidative stress (OS) causes DNA damage and chromosome instability that may lead to carcinogenesis. OS is also suggested to contribute to an increase in aneuploid cells. However, it is not clear how OS is involved in the regulation of SAC and contributes to carcinogenesis associated with aneuploidy. Here we show that an oxidant (KBrO3) activated the p53 signaling pathway and suppressed the expression of SAC factors, BubR1, and Mad2, in human diploid fibroblast MRC5 cells. This suppression was dependent on functional p53 and reactive oxygen species. In p53 knockdown cells, KBrO3 did not suppress BubR1 and Mad2 expression and increased both binucleated cells and cells with >4N DNA content. BubR1 and not Mad2 downregulation suppressed KBrO3-induced binucleated cells and cells with >4N DNA content in p53 knockdown cells, suggesting that BubR1 contributes to enhanced polyploidization by a mechanism other than its SAC function. In analysis of 182 gastric cancer specimens, we found that BubR1 expression was significantly high when p53 was positively stained, which indicates loss of p53 function (P = 0.0019). Moreover, positive staining of p53 and high expression of BubR1 in tumors were significantly correlated with DNA aneuploidy (P = 0.0065). These observations suggest that p53 deficiency may lead to the failure of BubR1 downregulation by OS and that p53 deficiency and BubR1 accumulation could contribute to gastric carcinogenesis associated with aneuploidy. PMID- 24156018 TI - Inhibition of MMP14 potentiates the therapeutic effect of temozolomide and radiation in gliomas. AB - Metalloproteinases are membrane-bound proteins that play a role in the cellular responses to antiglioma therapy. Previously, it has been shown that treatment of glioma cells with temozolomide (TMZ) and radiation (XRT) induces the expression of metalloproteinase 14 (MMP14). To investigate the role of MMP14 in gliomagenesis, we used several chemical inhibitors which affect MMP14 expression. Of all the inhibitors tested, we found that Marimastat not only inhibits the expression of MMP14 in U87 and U251 glioma cells, but also induces cell cycle arrest. To determine the relationship between MMP14 inhibition and alteration of the cell cycle, we used an RNAi technique. Genetic knockdown of MMP14 in U87 and U251 glioma cells induced G2/M arrest and decreased proliferation. Mechanistically, we show that TMZ and XRT regulated expression of MMP14 in clinical samples and in vitro models through downregulation of microRNA374. In vivo genetic knockdown of MMP14 significantly decreased tumor growth of glioma xenografts and improved survival of glioma-bearing mice. Moreover, the combination of MMP14 silencing with TMZ and XRT significantly improved the survival of glioma-bearing mice compared to a single modality treatment group. Therefore, we show that the inhibition of MMP14 sensitizes tumor cells to TMZ and XRT and could be used as a future strategy for antiglioma therapy. PMID- 24156019 TI - Reduction in serum clusterin is a potential therapeutic biomarker in patients with castration-resistant prostate cancer treated with custirsen. AB - Elevated levels of clusterin (CLU), a stress-induced and secreted cytoprotective chaperone, are associated with advanced tumor stage, metastasis, treatment resistance, and adverse outcome in several cancers. Custirsen, a second generation antisense oligonucleotide, inhibits CLU production in tumor cells and reduces serum CLU levels. A Phase 2 study evaluated custirsen in combination with second-line chemotherapy in men with metastatic castration-resistant prostate cancer (mCRPC) who had progressed while on or within 6 months of first-line docetaxel-based chemotherapy. Exploratory analyses evaluated serum CLU levels during custirsen treatment and correlative clinical effects on prostate-specific antigen (PSA) response, overall survival, and any relationship between serum CLU and PSA. Men with mCRPC were treated with mitoxantrone/prednisone/custirsen (MPC, n = 22) or docetaxel retreatment/prednisone/custirsen (DPC plus DPC-Assigned, n = 45) in an open-label, multicenter study. Subject-specific profiles of PSA and serum CLU levels during treatment were characterized using statistical modeling to compute subject-specific summary measures; these measures were analyzed for relationship to survival using proportional hazard regression. Estimated individual serum CLU response profiles were scored as below or at/above the median level for the population through 100 days postrandomization. Median survival was longer for subjects scoring below the median serum CLU level compared with subjects at/above the median level, respectively (MPC: 15.1 months vs. 6.2 months; DPC-Pooled: 17.0 months vs. 12.1 months). Lowered serum CLU levels during custirsen treatment when in combination with either chemotherapy regimen were predictive of longer survival in mCRPC. These results support further evaluation of serum CLU as a therapeutic biomarker. PMID- 24156020 TI - Schedule-dependent therapeutic efficacy of L19mTNF-alpha and melphalan combined with gemcitabine. AB - L19-tumor necrosis factor alpha (L19mTNF-alpha; L), a fusion protein consisting of mouse TNFalpha and the human antibody fragment L19 directed to the extra domain-B (ED-B) of fibronectin, is able to selectively target tumor vasculature and to exert a long-lasting therapeutic activity in combination with melphalan (M) in syngeneic mouse tumor models. We have studied the antitumor activity of single L19mTNF-alpha treatment in combination with melphalan and gemcitabine (G) using different administration protocols in two histologically different murine tumor models: WEHI-164 fibrosarcoma and K7M2 osteosarcoma. All responding mice showed significant reduction in myeloid-derived suppressor cells (MDSCs) and an increase in CD4(+) and CD8(+) T cells in the tumor infiltrates, as well as significant reduction in regulatory T cells (Treg) at the level of draining lymph nodes. What is important is that all cured mice rejected tumor challenge up to 1 year after therapy. Targeted delivery of L19mTNF-alpha synergistically increases the antitumor activity of melphalan and gemcitabine, but optimal administration schedules are required. This study provides information for designing clinical studies using L19mTNF-alpha in combination with chemotherapeutic drugs. PMID- 24156021 TI - Therapeutic enhancement of S-1 with CPT-11 through down-regulation of thymidylate synthase in bladder cancer. AB - Thymidylate synthase (TS), a target enzyme of 5-fluorouracil (5-FU), is significantly associated with prognosis in various cancers. Recently, it has been reported that S-1, a novel 5-FU-based agent has an effect on bladder cancer. However, in cells with high TS level, S-1 did not have significant effects. Therefore, we examined whether down-regulation of TS enhanced effects of S-1 in them. First, we measured TS level in an aggressive bladder cancer cell line, KU 19-19 by enzyme-linked immunosorbent assay (ELISA) and evaluated its sensitivity to 5-FU using a small interfering RNA (siRNA) for TS. Next, we measured TS mRNA after exposure to various agents. Finally, we evaluated enhancement of cytotoxicity of S-1 by CPT-11 (7-ethyl-10-[4-(1-piperidino)-1 piperidino]carbonyloxycamptothecin) which down-regulated TS in in vivo study. The median TS and dihydropyrimidine dehydrogenase (DPD) level was 53.3 ng/mg and 80.3 ng/mg in KU-19-19 cells, respectively. The 5-FU treatment in KU-19-19 cells transfected with siRNA for TS gene (TYMS) inhibited cell growth more significantly than that for nontargeting control. Down-regulation of TS was observed after exposure to SN-38 (7-ethyl-10-hydroxycamptothecin) in a dose dependent manner. The combination treatment of 5-FU and SN-38 significantly inhibited cell growth, as compared to the single treatment. Meanwhile, in cells transfected with siRNA for TYMS, neither an additive nor a synergistic effect was observed. Also, combined S-1 and CPT-11 dramatically inhibited tumor growth, compared to S-1 or CPT-11 alone in in vivo study. In conclusion, CPT-11 down regulated TS level and enhanced the effect of S-1. Thus, the combination therapy with S-1 and CPT-11 might be a novel modality for bladder cancer, even with high TS level. PMID- 24156022 TI - PTEN expression is consistent in colorectal cancer primaries and metastases and associates with patient survival. AB - Phosphatase and tensin homologue deleted on chromosome 10 (PTEN) negatively regulates the phosphoinositide-3-kinase (PI3K) signaling pathway. In colorectal cancer (CRC), observed frequencies of loss of PTEN expression, concordant expression in primary tumors and metastases, and the association of PTEN status with outcome vary markedly by detection method. We determined the degree to which PTEN expression is consistent in 70 matched human CRC primaries and liver metastases using a validated immunohistochemistry assay. We found loss of PTEN expression in 12.3% of assessable CRC primaries and 10.3% of assessable liver metastases. PTEN expression (positive or negative) was concordant in 98% of matched colorectal primaries and liver metastases. Next we related PTEN status to mutations in RAS and PI3K pathway genes (KRAS, NRAS, BRAF , and PIK3CA) and to overall survival (OS). PTEN expression was not significantly associated with the presence or absence of mutations in RAS or PI3K pathway genes. The median OS of patients whose tumors did not express PTEN was 9 months, compared to 49 months for patients whose tumors did express PTEN (HR = 6.25, 95% confidence intervals (CI) (1.98, 15.42), P = 0.0017). The association of absent PTEN expression with increased risk of death remained significant in multivariate analysis (HR = 6.31, 95% CI (2.03, 17.93), P = 0.0023). In summary, PTEN expression was consistent in matched CRC primaries and in liver metastases. Therefore, future investigations of PTEN in metastatic CRC can use primary tumor tissue. In patients with liver only metastases, loss of PTEN expression predicted poor OS. PMID- 24156023 TI - Absent/weak CD44 intensity and positive human papillomavirus (HPV) status in oropharyngeal squamous cell carcinoma indicates a very high survival. AB - Patients with human papillomavirus DNA positive (HPV(DNA+)) oropharyngeal squamous cell carcinoma (OSCC) have better clinical outcome than those with HPV DNA negative (HPV(DNA-)) OSCC upon intensive oncological treatment. All HPV(DNA+) OSCC patients may not require intensive treatment, however, but before potentially deintensifying treatment, additional predictive markers are needed. Here, we examined HPV, p16(INK4a), and CD44 in OSCC in correlation to clinical outcome. Pretreatment tumors from 290 OSCC patients, the majority not receiving chemotherapy, were analyzed for HPV DNA by Luminex and for p16(INK4a) and CD44 by immunohistochemistry. 225/290 (78%) tumors were HPV(DNA+) and 211/290 (73%) overexpressed p16(INK4a), which correlated to presence of HPV (P < 0.0001). Presence of HPV DNA, absent/weak CD44 intensity staining correlated to favorable 3-year disease-free survival (DFS) and overall survival (OS) by univariate and multivariate analysis, and likewise for p16(INK4a) by univariate analysis. Upon stratification for HPV, HPV(DNA+) OSCC with absent/weak CD44 intensity presented the significantly best 3-year DFS and OS, with >95% 3-year DFS and OS. Furthermore, in HPV(DNA+) OSCC, p16(INK4a)+ overexpression correlated to a favorable 3-year OS. In conclusion, patients with HPV(DNA+) and absent/weak CD44 intensity OSCC presented the best survival and this marker combination could possibly be used for selecting patients for tailored deintensified treatment in prospective clinical trials. PMID- 24156024 TI - The posttreatment mean apparent diffusion coefficient of primary tumor is superior to pretreatment ADCmean of primary tumor as a predictor of prognosis with cervical cancer. AB - The objective of this study was to investigate the correlation of pretreatment and posttreatment measurements as the mean apparent diffusion coefficient (ADCmean) by diffusion-weighted magnetic resonance imaging (DWI) findings with prognostic factors in patients with squamous cell carcinoma (SCC) of primary cervical cancer. The pretreatment and posttreatment ADCmean of the primary tumor were examined for their correlations with the prognosis in 69 patients with SCC of primary cervical cancer by radiotherapy (RT) with or without concurrent chemotherapy (CCRT). The median disease-free survival (DFS) and overall survival (OS) times of patients were 20.97 and 23.47 months (follow-up periods for DFS and OS: 1-72 and 1-72 months). The DFS and OS rates of patients with low pretreatment and posttreatment ADCmean of the primary tumor were also significantly worse than those of patients exhibiting high pretreatment and posttreatment ADCmean of the primary tumor (DFS; P = 0.0130 and P < 0.0001, OS; P = 0.0010 and P < 0.0001). Multivariate analyses showed that low posttreatment ADCmean of the primary tumor was an independent prognostic factor for DFS and OS (P < 0.0001 and P < 0.0001). The low posttreatment ADCmean of the primary tumor is a useful clinical prognostic biomarker for recurrence and survival in patients with cervical cancer. PMID- 24156025 TI - Severity of comorbid conditions and early-stage breast cancer therapy: linked SEER-Medicare data from 1993 to 2005. AB - Comorbidity burden has been suggested as influencing early-stage breast cancer therapy but previous studies have not considered the severity of these comorbidities. Therefore, we examined the influence of comorbidity severity by age and race/ethnicity on early-stage breast cancer treatment over time. We used linked Surveillance, Epidemiology, and End Results (SEER)-Medicare data to determine whether comorbidity severity influences receipt of definitive and preferred early-stage breast cancer treatment and explains racial/ethnic and age disparities in receiving such therapy. Definitive surgical therapy was defined as any primary surgery other than breast conserving surgery (BCS) without radiation therapy (RT). Preferred surgical therapy was defined as BCS plus RT. Comorbidities were defined as either "unstable" (life threatening or difficult to control) or "stable" (less serious but with potential to influence daily activity). Surgical treatment trends from 1993 to 2005 were analyzed in regression models adjusting for comorbidity burden, age, and race/ethnicity in 93,596 elderly female Medicare beneficiaries with stage 1-2 invasive breast cancer. Receipt of BCS alone (compared with any definitive surgical therapy) was independently associated with neighborhood socioeconomic status, unmarried status (OR [odds ratio] 1.18, 95% CI: 1.12-1.23), tumor size (OR 0.78, 95% CI: 0.69-0.87 for tumors >=4 cm vs. <2 cm), tumor grade (OR = 0.89, 0.88, and 0.81 for grades 2 4 vs. 1, respectively), stable comorbidities (OR = 0.76, 0.71, and 0.72 for 1, 2, and 3 vs. 0 stable comorbidities, respectively), and unstable comorbidities (OR 1.20, 95% CI: 1.14-1.28). Black women were 4-5% more likely to receive suboptimal therapy (BCS alone), even after adjusting for all available patient, tumor, and regional characteristics. Black race/ethnicity was associated with higher probability of receiving suboptimal treatment, independent of comorbidities, although we do not know whether this effect was due to clinicians' failure to offer RT or patients' failure to accept it. PMID- 24156026 TI - The changing face of thyroid cancer in a population-based cohort. AB - In North America, the incidence of thyroid cancer is increasing by over 6% per year. We studied the trends and factors influencing thyroid cancer incidence, its clinical presentation, and treatment outcome during 1970-2010 in a population based cohort of 2306 consecutive thyroid cancers in Canada, that was followed up for a median period of 10.5 years. Disease-specific survival (DSS) and disease free survival were estimated by the Kaplan-Meier method and the independent influence of various prognostic factors was evaluated by Cox proportional hazard models. Cumulative incidence of deaths resulting from thyroid cancer was calculated by competing risk analysis. A P-value <0.05 was considered to indicate statistical significance. The age standardized incidence of thyroid cancer by direct method increased from 2.52/100,000 (1970) to 9.37/100,000 (2010). Age at diagnosis, gender distribution, tumor size, and initial tumor stage did not change significantly during this period. The proportion of papillary thyroid cancers increased significantly (P < 0.001) from 58% (1970-1980) to 85.9% (2000 2010) while that of anaplastic cancer fell from 5.7% to 2.1% (P < 0.001). Ten year DSS improved from 85.4% to 95.6%, and was adversely influenced by anaplastic histology (hazard ratio [HR] = 8.7; P < 0.001), male gender (HR = 1.8; P = 0.001), TNM stage IV (HR = 8.4; P = 0.001), incomplete surgical resection (HR = 2.4; P = 0.002), and age at diagnosis (HR = 1.05 per year; P < 0.001). There was a 373% increase in the incidence of thyroid cancer in Manitoba with a marked improvement in the thyroid cancer-specific survival that was independent of changes in patient demographics, tumor stage, or treatment practices, and is largely attributed to the declining proportion of anaplastic thyroid cancers. PMID- 24156027 TI - FDG-PET as a predictive biomarker for therapy with everolimus in metastatic renal cell cancer. AB - The mTOR (mammalian target of rapamycin) inhibitor, everolimus, affects tumor growth by targeting cellular metabolic proliferation pathways and delays renal cell carcinoma (RCC) progression. Preclinical evidence suggests that baseline elevated tumor glucose metabolism as quantified by FDG-PET ([(18)F] fluorodeoxy glucose positron emission tomography) may predict antitumor activity. Metastatic RCC (mRCC) patients refractory to vascular endothelial growth factor (VEGF) pathway inhibition were treated with standard dose everolimus. FDG-PET scans were obtained at baseline and 2 weeks; serial computed tomography (CT) scans were obtained at baseline and every 8 weeks. Maximum standardized uptake value (SUVmax) of the most FDG avid lesion, average SUVmax of all measured lesions and their corresponding 2-week relative changes were examined for association with 8 week change in tumor size. A total of 63 patients were enrolled; 50 were evaluable for the primary endpoint of which 48 had both PET scans. Patient characteristics included the following: 36 (72%) clear cell histology and median age 59 (range: 37-80). Median pre- and 2-week treatment average SUVmax were 6.6 (1-17.9) and 4.2 (1-13.9), respectively. Response evaluation criteria in solid tumors (RECIST)-based measurements demonstrated an average change in tumor burden of 0.2% (-32.7% to 35.9%) at 8 weeks. Relative change in average SUVmax was the best predictor of change in tumor burden (all evaluable P = 0.01; clear cell subtype P = 0.02), with modest correlation. Baseline average SUVmax was correlated with overall survival and progression-free survival (PFS) (P = 0.023; 0.020), but not with change in tumor burden. Everolimus therapy decreased SUVs on follow-up PET scans in mRCC patients, but changes were only modestly correlated with changes in tumor size. Thus, clinical use of FDG-PET-based biomarkers is challenged by high variability. PMID- 24156028 TI - Management and outcome of 239 adolescent and adult rhabdomyosarcoma patients. AB - Adult rhabdomyosarcoma (RMS) is a rare tumor that has inferior outcome compared to younger patient population. The present work aims to study the age-related differences in management of adolescents and adults with RMS. Under an institutional review board-approved protocol, we retrospectively analyzed 239 patients, 10 years of age and greater, diagnosed with RMS at MD Anderson Cancer Center from 1957 through 2003. Of the 239 patients, 163 patients were nonmetastatic with a median overall survival (OS) of 3.8 years (95% CI 2.8-7.6). In the multivariate analysis, age >50 was significantly associated with shorter OS and recurrence-free survival (RFS) for primary patients. Metastases were present in 76 patients, the median OS was 1.4 years. Approximately 13% of metastatic patients <50 years old had a long-term survival exceeding 15 years. Multimodality therapy, including surgery, radiotherapy, and chemotherapy was significantly associated with longer OS in primary and metastatic patients. Use of bi- and triple modality treatment decreased in metastatic patients over 50 years of age compared to younger patients. RMS in adolescents and adults has a poor outcome compared with younger individuals. Increased use of multidisciplinary therapy may improve older patient clinical outcome. PMID- 24156029 TI - Increased platelet reactivity in patients with late-stage metastatic cancer. AB - Platelet hyperreactivity is associated with an increased risk of thrombosis. Cancer patients are at an increased risk of thrombosis, a risk that increases with disease progression. While cancer patients show evidence of platelet activation in vivo, few studies have extensively assessed whether these patients display platelet hyperreactivity. We hypothesized that patients with metastatic cancer would display platelet hyperreactivity, reflecting their associated high risk of thrombosis. In a cohort of patients with metastatic cancer (n = 13), we assessed platelet function using well-established assays of platelet reactivity (agonist-induced platelet aggregation, spontaneous platelet aggregation, and agonist-induced P-selectin expression). In comparison with healthy controls (n = 10), patients with metastatic cancer displayed global platelet hyperreactivity. Agonist-induced platelet aggregation responses to ADP (adenosine diphosphate), epinephrine, collagen, arachidonic acid, and PAR-1 (protease-activated receptor 1) activating peptide, as well as spontaneous platelet aggregation, were significantly increased in patients with metastatic cancer. Furthermore, agonist induced platelet P-selectin expression was also significantly increased within the patient cohort. We demonstrate that patients with metastatic cancer are characterized by global platelet hyperreactivity, a factor that may contribute to their increased risk of thrombosis. PMID- 24156031 TI - eLife and early career researchers. AB - There are many reasons for submitting your best work to eLife, especially if you are an early career researcher. PMID- 24156030 TI - Curcumin improves the therapeutic efficacy of Listeria(at)-Mage-b vaccine in correlation with improved T-cell responses in blood of a triple-negative breast cancer model 4T1. AB - Success of cancer vaccination is strongly hampered by immune suppression in the tumor microenvironment (TME). Interleukin (IL)-6 is particularly and highly produced by triple-negative breast cancer (TNBC) cells, and has been considered as an important contributor to immune suppression in the TME. Therefore, we hypothesized that IL-6 reduction may improve efficacy of vaccination against TNBC cancer through improved T-cell responses. To prove this hypothesis, we investigated the effect of curcumin, an inhibitor of IL-6 production, on vaccination of a highly attenuated Listeria monocytogenes (Listeria(at)), encoding tumor-associated antigens (TAA) Mage-b in a TNBC model 4T1. Two therapeutic vaccination strategies with Listeria(at)-Mage-b and curcumin were tested. The first immunization strategy involved all Listeria(at)-Mage-b vaccinations and curcumin after tumor development. As curcumin has been consumed all over the world, the second immunization strategy involved curcumin before and all therapeutic vaccinations with Listeria(at)-Mage-b after tumor development. Here, we demonstrate that curcumin significantly improves therapeutic efficacy of Listeria(at)-Mage-b with both immunization strategies particularly against metastases in a TNBC model (4T1). The combination therapy was slightly but significantly more effective against the metastases when curcumin was administered before compared to after tumor development. With curcumin before tumor development in the combination therapy, the production of IL-6 was significantly decreased and IL-12 increased by myeloid-derived suppressor cells (MDSC), in correlation with improved CD4 and CD8 T-cell responses in blood. Our study suggests that curcumin improves the efficacy of Listeria(at)-Mage-b vaccine against metastases in TNBC model 4T1 through reversal of tumor-induced immune suppression. PMID- 24156032 TI - Molecular diagnosis for personalized target therapy in gastric cancer. AB - Gastric cancer is the second leading cause of cancer-related deaths worldwide. In advanced and metastatic gastric cancer, the conventional chemotherapy with limited efficacy shows an overall survival period of about 10 months. Patient specific and effective treatments known as personalized cancer therapy is of significant importance. Advances in high-throughput technologies such as microarray and next generation sequencing for genes, protein expression profiles and oncogenic signaling pathways have reinforced the discovery of treatment targets and personalized treatments. However, there are numerous challenges from cancer target discoveries to practical clinical benefits. Although there is a flood of biomarkers and target agents, only a minority of patients are tested and treated accordingly. Numerous molecular target agents have been under investigation for gastric cancer. Currently, targets for gastric cancer include the epidermal growth factor receptor family, mesenchymal-epithelial transition factor axis, and the phosphatidylinositol 3-kinase-AKT-mammalian target of rapamycin pathways. Deeper insights of molecular characteristics for gastric cancer has enabled the molecular classification of gastric cancer, the diagnosis of gastric cancer, the prediction of prognosis, the recognition of gastric cancer driver genes, and the discovery of potential therapeutic targets. Not only have we deeper insights for the molecular diversity of gastric cancer, but we have also prospected both affirmative potentials and hurdles to molecular diagnostics. New paradigm of transdisciplinary team science, which is composed of innovative explorations and clinical investigations of oncologists, geneticists, pathologists, biologists, and bio-informaticians, is mandatory to recognize personalized target therapy. PMID- 24156033 TI - Robotic versus Laparoscopic versus Open Gastrectomy: A Meta-Analysis. AB - PURPOSE: To define the role of robotic gastrectomy for the treatment of gastric cancer, the present systematic review with meta-analysis was performed. MATERIALS AND METHODS: A comprehensive search up to July 2012 was conducted on PubMed, EMBASE, and the Cochrane Library. All eligible studies comparing robotic gastrectomy versus laparoscopic gastrectomy or open gastrectomy were included. RESULTS: Included in our meta-analysis were seven studies of 1,967 patients that compared robotic (n=404) with open (n=718) or laparoscopic (n=845) gastrectomy. In the complete analysis, a shorter hospital stay was noted with robotic gastrectomy than with open gastrectomy (weighted mean difference: -2.92, 95% confidence interval: -4.94 to -0.89, P=0.005). Additionally, there was a significant reduction in intraoperative blood loss with robotic gastrectomy compared with laparoscopic gastrectomy (weighted mean difference: -35.53, 95% confidence interval: -66.98 to -4.09, P=0.03). These advantages were at the price of a significantly prolonged operative time for both robotic gastrectomy versus laparoscopic gastrectomy (weighted mean difference: 63.70, 95% confidence interval: 44.22 to 83.17, P<0.00001) and robotic gastrectomy versus open gastrectomy (weighted mean difference: 95.83, 95% confidence interval: 54.48 to 137.18, P<0.00001). Analysis of the number of lymph nodes retrieved and overall complication rates revealed that these outcomes did not differ significantly between the groups. CONCLUSIONS: Robotic gastrectomy for gastric cancer reduces intraoperative blood loss and the postoperative hospital length of stay compared with laparoscopic gastrectomy and open gastrectomy at a cost of a longer operating time. Robotic gastrectomy also provides an oncologically adequate lymphadenectomy. Additional high-quality prospective studies are recommended to better evaluate both short and long-term outcomes. PMID- 24156034 TI - Preoperative N staging of gastric cancer by stomach protocol computed tomography. AB - PURPOSE: Clinical stage of gastric cancer is currently assessed by computed tomography. Accurate clinical staging is important for the tailoring of therapy. This study evaluated the accuracy of clinical N staging using stomach protocol computed tomography. MATERIALS AND METHODS: Between March 2004 and November 2012, 171 patients with gastric cancer underwent preoperative stomach protocol computed tomography (Jeju National University Hospital; Jeju, Korea). Their demographic and clinical characteristics were reviewed retrospectively. Two radiologists evaluated cN staging using axial and coronal computed tomography images, and cN stage was matched with pathologic results. The diagnostic accuracy of stomach protocol computed tomography for clinical N staging and clinical characteristics associated with diagnostic accuracy were evaluated. RESULTS: The overall accuracy of stomach protocol computed tomography for cN staging was 63.2%. Computed tomography images of slice thickness 3.0 mm had a sensitivity of 60.0%; a specificity of 89.6%; an accuracy of 78.4%; and a positive predictive value of 78.0% in detecting lymph node metastases. Underestimation of cN stage was associated with larger tumor size (P<0.001), undifferentiated type (P=0.003), diffuse type (P=0.020), more advanced pathologic stage (P<0.001), and larger numbers of harvested and metastatic lymph nodes (P<0.001 each). Tumor differentiation was an independent factor affecting underestimation by computed tomography (P=0.045). CONCLUSIONS: Computed tomography with a size criterion of 8 mm is highly specific but relatively insensitive in detecting nodal metastases. Physicians should keep in mind that computed tomography may not be an appropriate tool to detect nodal metastases for choosing appropriate treatment. PMID- 24156035 TI - Disappearance of Serum Methylated p16 Indicates Longer Survival in Patients with Gastric Cancer. AB - PURPOSE: The aim of this study was to assess clinical correlations with postoperative alteration of p16 DNA methylation, and to clarify whether postoperative changes in the serum DNA methylation status of p16 could be used as a reliable prognostic factor for gastric cancer. MATERIALS AND METHODS: Fifty three consecutive gastric adenocarcinoma patients who underwent gastric resection (Chung-Ang University Hospital, Seoul, Korea) were included. DNA methylation of p16 was evaluated by methylation-specific polymerase chain reaction using serum DNA preoperatively and at the 10th postoperative day. The correlation between changes in methylation status and patients' prognosis was analyzed. RESULTS: p16 was methylated in 79.2% of preoperative serum DNA and in 54.7% of postoperative serum DNA, respectively. Methylation in p16 disappeared more frequently in patients who underwent standard D2 lymphadenectomy compared to those who underwent modified D1+ lymphadenectomy (P=0.016). Whereas methylation of preoperative serum DNA was not correlated with survival, patients with postoperative disappearance of p16 methylation showed longer survival than those without postoperative disappearance of p16 methylation in the patients who had gastric cancer with lymph node metastasis (P=0.042). CONCLUSIONS: Postoperative disappearance of p16 methylation could be an available prognostic factor for node positive gastric cancer. PMID- 24156036 TI - Laparoscopy Assisted versus Open Distal Gastrectomy with D2 Lymph Node Dissection for Advanced Gastric Cancer: Design and Rationale of a Phase II Randomized Controlled Multicenter Trial (COACT 1001). AB - PURPOSE: Laparoscopy-assisted distal gastrectomy for early gastric cancer has gained acceptance and popularity worldwide. However, laparoscopy-assisted distal gastrectomy for advanced gastric cancer is still controversial. Therefore, we propose this prospective randomized controlled multi-center trial in order to evaluate the safety and feasibility of laparoscopy assisted D2-gastrectomy for advanced stage gastric cancer. MATERIALS AND METHODS: Patients undergoing distal gastrectomy for advanced gastric cancer staged cT2/3/4 cN0/1/2/3a cM0 by endoscopy and computed tomography are eligible for enrollment after giving their informed consent. Patients will be randomized either to laparoscopy-assisted distal gastrectomy or open distal gastrectomy. Sample size calculation revealed that 102 patients are to be included per treatment arm. The primary endpoint is the non-compliance rate of D2 dissection; relevant secondary endpoints are three year disease free survival, surgical and postoperative complications, hospital stay and unanimity rate of D2 dissection evaluated by reviewing the intraoperative video documentation. DISCUSSION: Oncologic safety is the major concern regarding laparoscopy-assisted distal gastrectomy for advanced gastric cancer. Therefore, the non-compliance rate of clearing the N2 area was chosen as the most important parameter for the technical feasibility of the laparoscopic procedure. Furthermore, surgical quality will be carefully reviewed, that is, three independent experts will review the video records and score with a check list. For a long-term result, disease free survival is considered a secondary endpoint for this trial. This study will offer promising evidence of the feasibility and safety of Laparoscopy-assisted distal gastrectomy for advanced gastric cancer. TRIAL REGISTRATION: NCT01088204 (international), NCCCTS-09-448 (Korea). PMID- 24156037 TI - Effects of 17beta-estradiol and estrogen receptor antagonists on the proliferation of gastric cancer cell lines. AB - PURPOSE: THE AIMS OF THIS STUDY WERE AS FOLLOW: 1) to de scribe the expression status of estrogen receptor-alpha and -beta mRNAs in five gastric carcinoma cell lines; 2) to evaluate in vitro the effects of 17beta-estradiol and estrogen receptor antagonists on the proliferation of the cell lines. MATERIALS AND METHODS: Detection of estrogen receptor-alpha and estrogen receptor-beta mRNA in five human gastric cancer cell lines (AGS, KATO III, MKN28, MKN45 and MKN74) was made by the reverse transcription-polymerase chain reaction system. To evaluate the effect of 17beta-estradiol and estrogen receptor antagonists on the proliferation of gastric cancer cell line, the cell lines which expressed both es trogen receptors were chosen and treated with 17beta-estradiol and estrogen receptor antagonists (methyl-piperidino-pyrazole and pyrazolo [1,5-a] pyrimidine). Cell proliferation was assessed with the methylthiazol tetrazolium test. RESULTS: Estrogen receptor-alpha and estrogen receptor-beta mRNAs were expressed in three (KATO III, MKN28 and MKN45) and all of the five gastric cancer cell lines, respectively. At higher concentrations, 17beta-estradiol inhibited cell growth of MKN28, MKN45 and KATO III cell lines. Neither estrogen receptor alpha nor estrogen receptor-beta antagonist blocked the anti-proliferative effect of 17beta-estradiol. CONCLUSIONS: Our results indicate that estrogen receptor beta mRNAs are preferentially expressed in gastric cancers and also imply that hormone therapy rather than estrogen receptor blockers may be a useful strategy for the treatment of estrogen receptor-beta positive gastric cancer. Its therapeutic significance in gastric cancer are, however, limited until more evidence of the roles of estrogen receptors in the gastric cancer are accumulated. PMID- 24156038 TI - Risk factors of postoperative pancreatic fistula in curative gastric cancer surgery. AB - PURPOSE: Postoperative pancreatic fistula is a dreadful complication after gastric cancer surgery. The purpose of this study is to evaluate the actual incidence and risk factors of postoperative pancreatic fistula after curative gastrectomy for gastric cancer. MATERIALS AND METHODS: A total of 900 patients who underwent gastrectomy for gastric cancer (laparoscopic gastrectomy, 594 patients; open gastrectomy 306 patients) were enrolled between January 2009 and December 2010. Clinical outcomes, including postoperative pancreatic fistula grade based on the International Study Group on Pancreatic Fistula, were investigated. RESULTS: Overall, the postoperative pancreatic fistula rate was 3.3% (30/900) (1.5% in laparoscopic gastrectomy versus 6.9% in open gastrectomy, P<0.001). Patients who underwent D2 lymphadenectomy, total gastrectomy, splenectomy or distal pancreatectomy showed higher postoperative pancreatic fistula rates (4.7%, 13.8%, 13.6%, or 57.1%, respectively, P<0.001). Patients with postoperative pancreatic fistula had higher morbidity (46.7% versus 13.1%, P<0.001), delayed gas out (4.9 days versus 3.8 days, P<0.001), belated diet start (5.8 days versus 3.5 days, P<0.001) and longer postoperative hospital stay (13.7 days versus 6.8 days, P<0.001). On the multivariate analysis, total gastrectomy (odds ratio 9.751, 95% confidence interval: 3.348 to 28.397, P<0.001), distal pancreatectomy (odds ratio 7.637, 95% confidence interval: 1.668 to 34.961, P=0.009) and open gastrectomy (odds ratio 2.934, 95% confidence interval: 1.100 to 7.826, P=0.032) were the independent risk factors of postoperative pancreatic fistula. CONCLUSIONS: Laparoscopic gastrectomy had an advantage over open gastrectomy in terms of the lower postoperative pancreatic fistula rate. Total gastrectomy and combined resection, such as distal pancreatectomy, should be performed carefully to minimize postoperative pancreatic fistula in gastric cancer surgery. PMID- 24156039 TI - Early gastric cancer with neurofibroma mimicking a metastatic node: a case report. AB - Neurofibromas are benign tumors that originate from the peripheral nerves, including neurites and fibroblasts. Generally, a solitary neurofibroma is located in the skin and rarely in other places. A 72-year-old female suffered from epigastric discomfort for 2 months. Endoscopic findings showed an early gastric cancer type IIc at the antrum. Abdominal computed tomography revealed early gastric cancer with a 1.6 cm-sized metastatic node posterior to the duodenum. Laparoscopic assisted distal gastrectomy and retro-pancreatic dissection were performed uneventfully. Histological examination revealed gastric adenocarcinoma, invading the mucosa without nodal metastasis, and a neurofibroma. Herein, we present a case of a gastric cancer patient with a solitary retroperitoneal neurofibroma which mimicked a distant metastatic node. PMID- 24156040 TI - Laparoscopic total gastrectomy in a gastric cancer patient with intestinal malrotation. AB - As the incidence of early gastric cancer increases, laparoscopic surgery has become one of the treatments of choice for gastric cancer. With the increase of laparoscopic surgery, the chance of discovering aberrant anatomy during the operation also increases. We present a case of laparoscopic total gastrectomy in gastric cancer patients with intestinal malrotation. Intestinal malrotation occurs in one in every 500 births. We found that laparoscopic total gastrectomy in such patients can be performed successfully when it is performed with a proper Roux limb orientation through an alternative minilaparotomy. PMID- 24156041 TI - Gastrointestinal stromal tumor with extensive lymphatic metastasis: a case report. AB - Gastrointestinal stromal tumor is a rare tumor which arises from the whole gastrointestinal tracts and most of it is detected in the stomach. It is uncommon with small intestine originated gastrointestinal stromal tumor and more uncommon with lymphatic metastasis. We experienced an unusual case of the small bowel gastrointestinal stromal tumor during experimental autopsy. Two primary tumors with central necrosis were detected in the ileum. The sizes of each tumor were 6.1*3.4*4.0 cm and 3.7*4.2*3.2 cm. There was extensive lymphatic metastasis on the greater omentum and mesenteric, iliac lymph nodes were also involved. With histologic findings, the eosinophilic spindle cells were densely distributed. Immunohistochemical findings were CD117 (-), CD34 (+), desmin (-), and S-100 protein (-). Therefore, we diagnosed the tumors as small bowel gastrointestinal stromal tumors with broad lymph node mestasis. PMID- 24156042 TI - Neutrophil-to-Lymphocyte Ratio in Prognosis of Gastric Cancer. PMID- 24156043 TI - Hyper-numerical aperture (NA = 2.8) microscope using lambda = 1.56 um femtosecond source for multi-photon imaging. AB - A new microscope is discussed, where the scanning illumination has a numerical aperture of 2.8 with lambda = 1.56 um femtosecond fiber laser. Samples are placed or grown on a silicon substrate. Multi-photon emission is imaged in transmission on a cooled CCD. Two-photon and three-photon effects are observed from the silicon/water interface and gold nanoparticles. Images of cells, reference spheres and gold nanoparticles illustrate imaging properties of the microscope. Spectral characteristics of individual particles are achieved with a blazed transmission grating. Emission properties of differently sized gold nanoparticles are studied in detail, which indicate that their emission is a two-photon effect due continuum generation. Interestingly, spectral shape and emission power are similar for 20nm, 40nm and 60nm diameter gold nanoparticles for the cases studied. PMID- 24156044 TI - Structured illumination quantitative phase microscopy for enhanced resolution amplitude and phase imaging. AB - Structured illumination microscopy (SIM) is an established microscopy technique typically used to image samples at resolutions beyond the diffraction limit. Until now, however, achieving sub-diffraction resolution has predominantly been limited to intensity-based imaging modalities. Here, we introduce an analogue to conventional SIM that allows sub-diffraction resolution, quantitative phase contrast imaging of optically transparent objects. We demonstrate sub-diffraction resolution amplitude and quantitative-phase imaging of phantom targets and enhanced resolution quantitative-phase imaging of cells. We report a phase accuracy to within 5% and phase noise of 0.06 rad. PMID- 24156045 TI - Maximum-likelihood estimation in Optical Coherence Tomography in the context of the tear film dynamics. AB - Understanding tear film dynamics is a prerequisite for advancing the management of Dry Eye Disease (DED). In this paper, we discuss the use of optical coherence tomography (OCT) and statistical decision theory to analyze the tear film dynamics of a digital phantom. We implement a maximum-likelihood (ML) estimator to interpret OCT data based on mathematical models of Fourier-Domain OCT and the tear film. With the methodology of task-based assessment, we quantify the tradeoffs among key imaging system parameters. We find, on the assumption that the broadband light source is characterized by circular Gaussian statistics, ML estimates of 40 nm +/- 4 nm for an axial resolution of 1 MUm and an integration time of 5 MUs. Finally, the estimator is validated with a digital phantom of tear film dynamics, which reveals estimates of nanometer precision. PMID- 24156046 TI - In vivo imaging of immune cell dynamics in skin in response to zinc-oxide nanoparticle exposure. AB - Zinc oxide (ZnO) nanoparticles (NPs) are widely used in cosmetic and sunscreen products which are applied topically to the skin. Despite their widespread use, the safety and biological response of these particles remains an active area of investigation. In this paper we present methods based on in vivo multiphoton microscopy (MPM) in skin to address relevant questions about the potential toxicity and immunological response of ZnO NPs. Registration of time-lapse volumetric MPM images allows the same skin site to be tracked across multiple days for visualizing and quantifying cellular and structural changes in response to NP exposure. Making use of the unique optical properties of ZnO enables high contrast detection of the NPs in the presence of strong autofluorescence and second harmonic generation (SHG) background from the skin. A green fluorescent protein (GFP) bone marrow (BM) transplanted mouse model is used to visualize and assess the dynamic response of BM-derived immune cells. These cells are visualized to assess the potential for ZnO NPs to interact with immune cells and elicit an immune reaction in skin. We investigate both topical and dermal exposure of the ZnO NPs. The methods and findings presented in this paper demonstrate a novel approach for tracking ZnO NPs in vivo and for visualizing the cellular response of the exposed tissue to assess the immunological response and potential toxicity of these particles. PMID- 24156047 TI - Separating structures of different fluorophore concentrations by principal component analysis on multispectral excitation-resolved fluorescence tomography images. AB - Multispectral excitation-resolved fluorescence tomography (MEFT) uses excitation light of different wavelengths to illuminate the fluorophores and obtains the reconstruction image frame which is fluorescence yield at each corresponding wavelength. For structures containing fluorophores of different concentrations, fluorescence yields show different variation trends with the excitation spectrum. In this study, principal component analysis (PCA) is used to analyze the MEFT reconstructed image frames. By taking advantage of the different variation trends of fluorescence yields, PCA can provide a set of principal components (PCs) in which structures containing different concentrations of fluorophores are shown separately. Simulations and experiments are both performed to test the performance of the proposed algorithm. The results suggest that the location and structure of fluorophores with different concentrations can be obtained and the contrast of fluorophores can be improved further by using this algorithm. PMID- 24156048 TI - In vivo three dimensional dual wavelength photoacoustic tomography imaging of the far red fluorescent protein E2-Crimson expressed in adult zebrafish. AB - For the first time the far red fluorescent protein (FP) E2-Crimson genetically expressed in the exocrine pancreas of adult zebrafish has been non-invasively mapped in 3D in vivo using photoacoustic tomography (PAT). The distribution of E2 Crimson in the exocrine pancreas acquired by PAT was confirmed using epifluorescence imaging and histology, with optical coherence tomography (OCT) providing complementary structural information. This work demonstrates the depth advantage of PAT to resolve FP in an animal model and establishes the value of E2 Crimson for PAT studies of transgenic models, laying the foundation for future longitudinal studies of the zebrafish as a model of diseases affecting inner organs. PMID- 24156050 TI - Intravascular optical coherence tomography measurement of size and apposition of metallic stents. AB - Effect of beam size and catheter position on the apparent size and apposition of metallic stent struts in IVOCT images were examined. Micro-CT data was employed to determine light - stent strut interactions. Simulated results suggest that location of the reflecting regions depend on relative orientation and position of stent struts to the IVOCT beam. Erroneous stent apposition measurements can occur when the IVOCT catheter is at an eccentric position. A method that mitigates stent strut apposition measurement errors is proposed. PMID- 24156049 TI - Evaluation of laser speckle contrast imaging as an intrinsic method to monitor blood brain barrier integrity. AB - The integrity of the blood brain barrier (BBB) can contribute to the development of many brain disorders. We evaluate laser speckle contrast imaging (LSCI) as an intrinsic modality for monitoring BBB disruptions through simultaneous fluorescence and LSCI with vertical cavity surface emitting lasers (VCSELs). We demonstrated that drug-induced BBB opening was associated with a relative change of the arterial and venous blood velocities. Cross-sectional flow velocity ratio (veins/arteries) decreased significantly in rats treated with BBB-opening drugs, <=0.81 of initial values. PMID- 24156051 TI - Effects of speckle/pixel size ratio on temporal and spatial speckle-contrast analysis of dynamic scattering systems: Implications for measurements of blood flow dynamics. AB - Laser Speckle Contrast Imaging (LSCI) is an optical technique used to generate blood flow maps with high spatial and temporal resolution. It is well known that in LSCI, the speckle size must exceed the Nyquist criterion to maximize the speckle's pattern contrast. In this work, we study experimentally the effect of speckle-pixel size ratio not only in dynamic speckle contrast, but also on the calculation of the relative flow speed for temporal and spatial analysis. Our data suggest that the temporal LSCI algorithm is more accurate at assessing the relative changes in flow speed than the spatial algorithm. PMID- 24156052 TI - Multi-MHz retinal OCT. AB - We analyze the benefits and problems of in vivo optical coherence tomography (OCT) imaging of the human retina at A-scan rates in excess of 1 MHz, using a 1050 nm Fourier-domain mode-locked (FDML) laser. Different scanning strategies enabled by MHz OCT line rates are investigated, and a simple multi-volume data processing approach is presented. In-vivo OCT of the human ocular fundus is performed at different axial scan rates of up to 6.7 MHz. High quality non mydriatic retinal imaging over an ultra-wide field is achieved by a combination of several key improvements compared to previous setups. For the FDML laser, long coherence lengths and 72 nm wavelength tuning range are achieved using a chirped fiber Bragg grating in a laser cavity at 419.1 kHz fundamental tuning rate. Very large data sets can be acquired with sustained data transfer from the data acquisition card to host computer memory, enabling high-quality averaging of many frames and of multiple aligned data sets. Three imaging modes are investigated: Alignment and averaging of 24 data sets at 1.68 MHz axial line rate, ultra-dense transverse sampling at 3.35 MHz line rate, and dual-beam imaging with two laser spots on the retina at an effective line rate of 6.7 MHz. PMID- 24156053 TI - Blood flow velocity quantification using split-spectrum amplitude-decorrelation angiography with optical coherence tomography. AB - The split-spectrum amplitude-decorrelation angiography (SSADA) algorithm was recently developed as a method for imaging blood flow in the human retina without the use of phase information. In order to enable absolute blood velocity quantification, in vitro phantom experiments are performed to correlate the SSADA signal at multiple time scales with various preset velocities. A linear model relating SSADA measurements to absolute flow velocities is derived using the phantom data. The operating range for the linear model is discussed along with its implication for velocity quantification with SSADA in a clinical setting. PMID- 24156054 TI - Endoscopic probe optics for spectrally encoded confocal microscopy. AB - Spectrally encoded confocal microscopy (SECM) is a form of reflectance confocal microscopy that can achieve high imaging speeds using relatively simple probe optics. Previously, the feasibility of conducting large-area SECM imaging of the esophagus in bench top setups has been demonstrated. Challenges remain, however, in translating SECM into a clinically-useable device; the tissue imaging performance should be improved, and the probe size needs to be significantly reduced so that it can fit into luminal organs of interest. In this paper, we report the development of new SECM endoscopic probe optics that addresses these challenges. A custom water-immersion aspheric singlet (NA = 0.5) was developed and used as the objective lens. The water-immersion condition was used to reduce the spherical aberrations and specular reflection from the tissue surface, which enables cellular imaging of the tissue deep below the surface. A custom collimation lens and a small-size grating were used along with the custom aspheric singlet to reduce the probe size. A dual-clad fiber was used to provide both the single- and multi- mode detection modes. The SECM probe optics was made to be 5.85 mm in diameter and 30 mm in length, which is small enough for safe and comfortable endoscopic imaging of the gastrointestinal tract. The lateral resolution was 1.8 and 2.3 um for the single- and multi- mode detection modes, respectively, and the axial resolution 11 and 17 um. SECM images of the swine esophageal tissue demonstrated the capability of this device to enable the visualization of characteristic cellular structural features, including basal cell nuclei and papillae, down to the imaging depth of 260 um. These results suggest that the new SECM endoscopic probe optics will be useful for imaging large areas of the esophagus at the cellular scale in vivo. PMID- 24156055 TI - Implementation of spatial overlap modulation nonlinear optical microscopy using an electro-optic deflector. AB - A spatial overlap modulation (SPOM) technique is a nonlinear optical microscopy technique which enhances the three-dimensional spatial resolution and rejects the out-of-focus background limiting the imaging depth inside a highly scattering sample. Here, we report on the implementation of SPOM in which beam pointing modulation is achieved by an electro-optic deflector. The modulation and demodulation frequencies are enhanced to 200 kHz and 400 kHz, respectively, resulting in a 200-fold enhancement compared with the previously reported system. The resolution enhancement and suppression of the out-of-focus background are demonstrated by sum-frequency-generation imaging of pounded granulated sugar and deep imaging of fluorescent beads in a tissue-like phantom, respectively. PMID- 24156056 TI - Perturbation Monte Carlo methods for tissue structure alterations. AB - This paper describes an extension of the perturbation Monte Carlo method to model light transport when the phase function is arbitrarily perturbed. Current perturbation Monte Carlo methods allow perturbation of both the scattering and absorption coefficients, however, the phase function can not be varied. The more complex method we develop and test here is not limited in this way. We derive a rigorous perturbation Monte Carlo extension that can be applied to a large family of important biomedical light transport problems and demonstrate its greater computational efficiency compared with using conventional Monte Carlo simulations to produce forward transport problem solutions. The gains of the perturbation method occur because only a single baseline Monte Carlo simulation is needed to obtain forward solutions to other closely related problems whose input is described by perturbing one or more parameters from the input of the baseline problem. The new perturbation Monte Carlo methods are tested using tissue light scattering parameters relevant to epithelia where many tumors originate. The tissue model has parameters for the number density and average size of three classes of scatterers; whole nuclei, organelles such as lysosomes and mitochondria, and small particles such as ribosomes or large protein complexes. When these parameters or the wavelength is varied the scattering coefficient and the phase function vary. Perturbation calculations give accurate results over variations of ~15-25% of the scattering parameters. PMID- 24156057 TI - Short-lag spatial coherence beamforming of photoacoustic images for enhanced visualization of prostate brachytherapy seeds. AB - Prostate brachytherapy, administered by implanting tiny radioactive seeds to treat prostate cancer, currently relies on transrectal ultrasound imaging for intraoperative visualization of the metallic seeds. Photoacoustic (PA) imaging has been suggested as a feasible alternative to ultrasound imaging due to its superior sensitivity to metal surrounded by tissue. However, PA images suffer from poor contrast when seeds are distant from the light source. We propose a transperineal light delivery method and investigate the application of a short lag spatial coherence (SLSC) beamformer to enhance low-contrast photoacoustic signals that are distant from this type of light source. Performance is compared to a conventional delay-and-sum beamformer. A pure gelatin phantom was implanted with black ink-coated brachytherapy seeds and the mean contrast was improved by 3 25 dB with the SLSC beamformer for fiber-seed distances ranging 0.6-6.3 cm, when approximately 10% of the receive aperture elements were included in the short-lag sum. For fiber-seed distances greater than 3-4 cm, the mean contrast-to-noise ratio (CNR) was approximately doubled with the SLSC beamformer, while mean signal to-noise ratios (SNR) were mostly similar with both beamformers. Lateral resolution was decreased by 2 mm, but improved with larger short-lag values at the expense of poorer CNR and SNR. Similar contrast and CNR improvements were achieved with an uncoated brachytherapy seed implanted in ex vivo tissue. Results indicate that the SLSC beamformer has potential to enhance the visualization of prostate brachytherapy seeds that are distant from the light source. PMID- 24156058 TI - Volumetric imaging and quantification of cytoarchitecture and myeloarchitecture with intrinsic scattering contrast. AB - We present volumetric imaging and computational techniques to quantify neuronal and myelin architecture with intrinsic scattering contrast. Using spectral / Fourier domain Optical Coherence Microscopy (OCM) and software focus-tracking we validate imaging of neuronal cytoarchitecture and demonstrate quantification in the rodent cortex in vivo. Additionally, by ex vivo imaging in conjunction with optical clearing techniques, we demonstrate that intrinsic scattering contrast is preserved in the brain, even after sacrifice and fixation. We volumetrically image cytoarchitecture and myeloarchitecture ex vivo across the entire depth of the rodent cortex. Cellular-level imaging up to the working distance of our objective (~3 mm) is demonstrated ex vivo. Architectonic features show the expected laminar characteristics; moreover, changes in contrast after the application of acetic acid suggest that entire neuronal cell bodies are responsible for the "negative contrast" present in the images. Clearing and imaging techniques that preserve tissue architectural integrity have the potential to enable non-invasive studies of the brain during development, disease, and remodeling, even in samples where exogenous labeling is impractical. PMID- 24156059 TI - Precise, motion-free polarization control in Second Harmonic Generation microscopy using a liquid crystal modulator in the infinity space. AB - Second Harmonic Generation (SHG) microscopy coupled with polarization analysis has great potential for use in tissue characterization, as molecular and supramolecular structural details can be extracted. Such measurements are difficult to perform quickly and accurately. Here we present a new method that uses a liquid crystal modulator (LCM) located in the infinity space of a SHG laser scanning microscope that allows the generation of any desired linear or circular polarization state. As the device contains no moving parts, polarization can be rotated accurately and faster than by manual or motorized control. The performance in terms of polarization purity was validated using Stokes vector polarimetry, and found to have minimal residual polarization ellipticity. SHG polarization imaging characteristics were validated against well-characterized specimens having cylindrical and/or linear symmetries. The LCM has a small footprint and can be implemented easily in any standard microscope and is cost effective relative to other technologies. PMID- 24156060 TI - Local assessment of myelin health in a multiple sclerosis mouse model using a 2D Fourier transform approach. AB - We present an automated two-dimensional Fourier transform (2D-FT) approach to analyze the local organization of myelinated axons in the spinal cord. Coherent anti-Stokes Raman scattering (CARS) microscopy was used to observe lesions in a commonly used animal model of multiple sclerosis (MS), experimental autoimmune encephalomyelitis (EAE). A 2D-FT was applied on the CARS images to find the average orientation and directional anisotropy of the fibers within contiguous image domains. We introduce the corrected correlation parameter (CCP), a measure of the correlation between orientations of adjacent domains. We show that in the EAE animal model of MS, the CCP can be used to quantify the degree of organization/disorganization in the myelin structure. This analysis was applied to a large image dataset from animals at different clinical scores and we show that some descriptors of the CCP probability density function are strongly correlated with the clinical scores. This procedure, compatible with live animal imaging, has been developed to perform local in situ evaluation of myelinated axons afflicted by EAE. PMID- 24156061 TI - Compensation of optode sensitivity and position errors in diffuse optical tomography using the approximation error approach. AB - Diffuse optical tomography is highly sensitive to measurement and modeling errors. Errors in the source and detector coupling and positions can cause significant artifacts in the reconstructed images. Recently the approximation error theory has been proposed to handle modeling errors. In this article, we investigate the feasibility of the approximation error approach to compensate for modeling errors due to inaccurately known optode locations and coupling coefficients. The approach is evaluated with simulations. The results show that the approximation error method can be used to recover from artifacts in reconstructed images due to optode coupling and position errors. PMID- 24156062 TI - Multi-penalty conditional random field approach to super-resolved reconstruction of optical coherence tomography images. AB - Improving the spatial resolution of Optical Coherence Tomography (OCT) images is important for the visualization and analysis of small morphological features in biological tissue such as blood vessels, membranes, cellular layers, etc. In this paper, we propose a novel reconstruction approach to obtaining super-resolved OCT tomograms from multiple lower resolution images. The proposed Multi-Penalty Conditional Random Field (MPCRF) method combines four different penalty factors (spatial proximity, first and second order intensity variations, as well as a spline-based smoothness of fit) into the prior model within a Maximum A Posteriori (MAP) estimation framework. Test carried out in retinal OCT images illustrate the effectiveness of the proposed MPCRF reconstruction approach in terms of spatial resolution enhancement, as compared to previously published super resolved image reconstruction methods. Visual assessment of the MPCRF results demonstrate the potential of this method in better preservation of fine details and structures of the imaged sample, as well as retaining the sharpness of biological tissue boundaries while reducing the effects of speckle noise inherent to OCT. Quantitative evaluation using imaging metrics such as Signal-to Noise Ratio (SNR), Contrast to Noise Ratio (CNR), Equivalent Number of Looks (ENL), and Edge Preservation Parameter show significant visual quality improvement with the MPCRF approach. Therefore, the proposed MPCRF reconstruction approach is an effective tool for enhancing the spatial resolution of OCT images without the necessity for significant imaging hardware modifications. PMID- 24156063 TI - Pulsatile motion of the trabecular meshwork in healthy human subjects quantified by phase-sensitive optical coherence tomography. AB - Aqueous leaves the anterior chamber of eye by passing through the trabecular meshwork (TM), a tissue thought to be responsible for increased outflow resistance in glaucoma. Motion assessment could permit characterization of TM biomechanical properties necessary to maintain intra-ocular pressure (IOP) within a narrow homeostatic range. In this paper, we report the first in vivo identification of TM motion in humans. We use a phase-sensitive optical coherence tomography (PhS-OCT) system with sub-nanometer sensitivity to detect and image dynamic pulse-induced TM motion. To permit quantification of TM motion and relationships we develop and apply a phase compensation algorithm permitting removal of the otherwise evitable confounding effects of bulk motion. Twenty healthy human eyes from 10 subjects are imaged. The results permit visualization of pulsatile TM motion visualization by PhS-OCT; correlation with the digital/cardiac pulse is highly significant. The correlation permits assessment of the phase lag and time delay between TM motion and the cardiac pulse. In this study, we find that the digital pulse leads the pulsatile TM motion by a mean phase of 3.53 +/- 0.48 rad and a mean time of 0.5 +/- 0.14 s in the fundamental frequency. A significant linear relationship is present between the TM phase lag and the heart rate (p value < 0.05). The TM phase lag is also affected by age, the relationship not quite reaching significance in the current study. PhS-OCT reveals pulse-induced motion of the TM that may provide insights into the biomechanics of the tissues involved in the regulation of IOP. PMID- 24156064 TI - Correction of image distortions in endoscopic optical coherence tomography based on two-axis scanning MEMS mirrors. AB - A two-axis scanning microelectromechanical (MEMS) mirror enables an optical coherence tomography (OCT) system to perform three-dimensional endoscopic imaging due to its fast scan speed and small size. However, the radial scan from the MEMS mirror causes various distortions in OCT images, namely spherical, fan-shaped and keystone distortions. In this paper, a new method is proposed to correct all of three distortions presented in OCT systems based on two-axis MEMS scanning mirrors. The spherical distortion is corrected first by directly manipulating the original spectral interferograms in the phase domain, followed by Fourier transform and three-dimensional geometrical transformation for correcting the other two types of distortions. OCT imaging experiments on a paper with square ink printed arrays and a glass tube filled with milk have been used to validate the proposed method. Distortions in OCT images of flat or curved surfaces can all be effectively removed. PMID- 24156065 TI - Imaging the bipolarity of myosin filaments with Interferometric Second Harmonic Generation microscopy. AB - We report that combining interferometry with Second Harmonic Generation (SHG) microscopy provides valuable information about the relative orientation of noncentrosymmetric structures composing tissues. This is confirmed through the imaging of rat medial gastrocnemius muscle. The inteferometric Second Harmonic Generation (ISHG) images reveal that each side of the myosin filaments composing the A band of the sarcomere generates pi phase shifted SHG signal which implies that the myosin proteins at each end of the filaments are oriented in opposite directions. This highlights the bipolar structural organization of the myosin filaments and shows that muscles can be considered as a periodically poled biological structure. PMID- 24156066 TI - Independent and simultaneous three-dimensional optical trapping and imaging. AB - Combining imaging and control of multiple micron-scaled objects in three dimensions opens up new experimental possibilities such as the fabrication of colloidal-based photonic devices, as well as high-throughput studies of single cell dynamics. Here we utilize the dual-objectives approach to combine 3D holographic optical tweezers with a spinning-disk confocal microscope. Our setup is capable of trapping multiple different objects in three dimensions with lateral and axial accuracy of 8 nm and 20 nm, and precision of 20 nm and 200 nm respectively, while imaging them in four different fluorescence channels. We demonstrate fabrication of ordered two-component and three dimensional colloidal arrays, as well as trapping of yeast cell arrays. We study the kinetics of the division of yeast cells within optical traps, and find that the timescale for division is not affected by trapping. PMID- 24156067 TI - Sequential average segmented microscopy for high signal-to-noise ratio motion artifact-free in vivo heart imaging. AB - In vivo imaging is often severely compromised by cardiovascular and respiratory motion. Highly successful motion compensation techniques have been developed for clinical imaging (e.g. magnetic resonance imaging) but the use of more advanced techniques for intravital microscopy is largely unexplored. Here, we implement a sequential cardiorespiratory gating scheme (SCG) for averaged microscopy. We show that SCG is very efficient in eliminating motion artifacts, is highly practical, enables high signal-to-noise ratio (SNR) in vivo imaging, and yields large field of views. The technique is particularly useful for high-speed data acquisition or for imaging scenarios where the fluorescence signal is not significantly above noise or background levels. PMID- 24156068 TI - An ideal-observer framework to investigate signal detectability in diffuse optical imaging. AB - With the emergence of diffuse optical tomography (DOT) as a non-invasive imaging modality, there is a requirement to evaluate the performance of the developed DOT systems on clinically relevant tasks. One such important task is the detection of high-absorption signals in the tissue. To investigate signal detectability in DOT systems for system optimization, an appropriate approach is to use the Bayesian ideal observer, but this observer is computationally very intensive. It has been shown that the Fisher information can be used as a surrogate figure of merit (SFoM) that approximates the ideal observer performance. In this paper, we present a theoretical framework to use the Fisher information for investigating signal detectability in DOT systems. The usage of Fisher information requires evaluating the gradient of the photon distribution function with respect to the absorption coefficients. We derive the expressions to compute the gradient of the photon distribution function with respect to the scattering and absorption coefficients. We find that computing these gradients simply requires executing the radiative transport equation with a different source term. We then demonstrate the application of the SFoM to investigate signal detectability in DOT by performing various simulation studies, which help to validate the proposed framework and also present some insights on signal detectability in DOT. PMID- 24156069 TI - Accelerated measurement of perikymata by an optical instrument. AB - The proposed device considerably reduces the measuring time of important microscopic features of tooth crown surfaces. The instrumentation is accompanied by a computer program to analyse the results. Tooth enamel is formed by ameloblasts, which demonstrate daily secretory rhythms developing tissue-specific structures known as cross striations, and longer period markings that are referred as striae of Retzius. These striae correspond to linear structures on the enamel surface. This newly developed optical measuring instrument can automatically, precisely and accurately record the number and periodicity of perikymata on the dental crown. Furthermore it can characterize the variability in periodicity of perikymata in hominids. The depth of field can be extended as desired by taking several images with different focus positions and combining them into a single composite image that contains all regions fully focused. PMID- 24156070 TI - 3D static elastography at the micrometer scale using Full Field OCT. AB - Full-Field OCT (FF-OCT) is able to image biological tissues in 3D with micrometer resolution. In this study we add elastographic contrast to the FF-OCT modality. By combining FF-OCT with elastography, we create a virtual palpation map at the micrometer scale. We present here a proof of concept on multi-layer phantoms and preliminary results on ex vivo biological samples such as porcine cornea, human breast tissues and rat heart. The 3D digital volume correlation that is used in connection with the 3D stack of images allows to access to the full 3D strain tensor and to reveal stiffness anisotropy. PMID- 24156071 TI - Extracting three-dimensional orientation and tractography of myofibers using optical coherence tomography. AB - Abnormal changes in orientation of myofibers are associated with various cardiac diseases such as arrhythmia, irregular contraction, and cardiomyopathy. To extract fiber information, we present a method of quantifying fiber orientation and reconstructing three-dimensional tractography of myofibers using optical coherence tomography (OCT). A gradient based algorithm was developed to quantify fiber orientation in three dimensions and particle filtering technique was employed to track myofibers. Prior to image processing, three-dimensional image data set were acquired from all cardiac chambers and ventricular septum of swine hearts using OCT system without optical clearing. The algorithm was validated through rotation test and comparison with manual measurements. The experimental results demonstrate that we are able to visualize three-dimensional fiber tractography in myocardium tissues. PMID- 24156072 TI - Comparative review of interferometric detection of plasmonic nanoparticles. AB - Noble metal nanoparticles exhibit enhanced scattering and absorption at specific wavelengths due to a localized surface plamson resonance. This unique property can be exploited to enable the use of plasmonic nanoparticles as contrast agents in optical imaging. A range of optical techniques have been developed to detect nanoparticles in order to implement imaging schemes. Here we review several different approaches for using optical interferometry to detect the presence and concentration of nanoparticles. The strengths and weaknesses of the various approaches are discussed and quantitative comparisons of the achievable signal to noise ratios are presented. The benefits of each approach are outlined as they relate to specific application goals. PMID- 24156073 TI - Multi-modal approach using Raman spectroscopy and optical coherence tomography for the discrimination of colonic adenocarcinoma from normal colon. AB - We report a multimodal optical approach using both Raman spectroscopy and optical coherence tomography (OCT) in tandem to discriminate between colonic adenocarcinoma and normal colon. Although both of these non-invasive techniques are capable of discriminating between normal and tumour tissues, they are unable individually to provide both the high specificity and high sensitivity required for disease diagnosis. We combine the chemical information derived from Raman spectroscopy with the texture parameters extracted from OCT images. The sensitivity obtained using Raman spectroscopy and OCT individually was 89% and 78% respectively and the specificity was 77% and 74% respectively. Combining the information derived using the two techniques increased both sensitivity and specificity to 94% demonstrating that combining complementary optical information enhances diagnostic accuracy. These data demonstrate that multimodal optical analysis has the potential to achieve accurate non-invasive cancer diagnosis. PMID- 24156074 TI - Label-free multi-photon imaging using a compact femtosecond fiber laser mode locked by carbon nanotube saturable absorber. AB - We demonstrate label-free multi-photon imaging of biological samples using a compact Er(3+)-doped femtosecond fiber laser mode-locked by a single-walled carbon nanotube (CNT). These compact and low cost lasers have been developed by various groups but they have not been exploited for multiphoton microscopy. Here, it is shown that various multiphoton imaging modalities (e.g. second harmonic generation (SHG), third harmonic generation (THG), two-photon excitation fluorescence (TPEF), and three-photon excitation fluorescence (3PEF)) can be effectively performed on various biological samples using a compact handheld CNT mode-locked femtosecond fiber laser operating in the telecommunication window near 1560nm. We also show for the first time that chlorophyll fluorescence in plant leaves and diatoms can be observed using 1560nm laser excitation via three photon absorption. PMID- 24156075 TI - Achromatic miniature lens system for coherent Raman scattering microscopy. AB - We discuss the design and performance of a miniature objective lens optimized for coherent Raman scattering microscopy. The packaged lens assembly has a numerical aperture of 0.51 in water and an outer diameter of 8 mm. The lens system exhibits minimum chromatic aberrations, and produces coherent Raman scattering images with sub-micrometer lateral resolution (0.648 MUm) using near-infrared excitation pulses. We demonstrate that despite the small dimensions of the miniature objective, the performance of this lens system is comparable to standard microscope objective lenses, offering opportunities for miniaturizing coherent Raman scattering imaging probes without sacrificing the image quality. PMID- 24156076 TI - Introduction to the Novel Techniques in Microscopy feature issue. AB - The editors introduce the feature issue on "Novel Techniques in Microscopy", which was the topic of a symposium held on April 14-18, 2013, in Waikoloa Beach, HI. This symposium was part of the Optics in the Life Sciences Congress. PMID- 24156077 TI - Light transport in turbid media with non-scattering, low-scattering and high absorption heterogeneities based on hybrid simplified spherical harmonics with radiosity model. AB - Modeling light propagation in the whole body is essential and necessary for optical imaging. However, non-scattering, low-scattering and high absorption regions commonly exist in biological tissues, which lead to inaccuracy of the existing light transport models. In this paper, a novel hybrid light transport model that couples the simplified spherical harmonics approximation (SPN) with the radiosity theory (HSRM) was presented, to accurately describe light transport in turbid media with non-scattering, low-scattering and high absorption heterogeneities. In the model, the radiosity theory was used to characterize the light transport in non-scattering regions and the SPN was employed to handle the scattering problems, including subsets of low-scattering and high absorption. A Neumann source constructed by the light transport in the non-scattering region and formed at the interface between the non-scattering and scattering regions was superposed into the original light source, to couple the SPN with the radiosity theory. The accuracy and effectiveness of the HSRM was first verified with both regular and digital mouse model based simulations and a physical phantom based experiment. The feasibility and applicability of the HSRM was then investigated by a broad range of optical properties. Lastly, the influence of depth of the light source on the model was also discussed. Primary results showed that the proposed model provided high performance for light transport in turbid media with non-scattering, low-scattering and high absorption heterogeneities. PMID- 24156078 TI - A least-squares fixed-point iterative algorithm for multiple illumination photoacoustic tomography. AB - The optical absorption of tissues provides important information for clinical and pre-clinical studies. The challenge in recovering optical absorption from photoacoustic images is that the measured pressure depends on absorption and local fluence. One reconstruction approach uses a fixed-point iterative technique based on minimizing the mean-squared error combined with modeling of the light source to determine optical absorption. With this technique, convergence is not guaranteed even with an accurate measure of optical scattering. In this work we demonstrate using simulations that a new multiple illumination least squares fixed-point iteration algorithm improves convergence - even with poor estimates of optical scattering. PMID- 24156079 TI - Multi-channel medical device for time domain functional near infrared spectroscopy based on wavelength space multiplexing. AB - We have designed a compact dual wavelength (687 nm, 826 nm) multi-channel (16 sources, 8 detectors) medical device for muscle and brain imaging based on time domain functional near infrared spectroscopy. The system employs the wavelength space multiplexing approach to reduce wavelength cross-talk and increase signal to-noise ratio. System performances have been tested on homogeneous and heterogeneous tissue phantoms following specifically designed protocols for photon migration instruments. Preliminary in vivo measurements have been performed to validate the instrument capability to monitor hemodynamic parameters changes in the arm muscle during arterial occlusion and in the adult head during a motor task experiment. PMID- 24156080 TI - Axial response of high-resolution microendoscopy in scattering media. AB - High-resolution microendoscopy (HRME) uses epi-fluorescence imaging with a coherent fiber-optic bundle to enable in vivo examination of cellular morphology. While the HRME platform has recently gained popularity as a simple alternative to confocal endomicroscopy, the axial response of HRME in thick, scattering tissue has yet to be described quantitatively. These details are important because when analyzing images collected by HRME, out-of-focus light may affect the accuracy of quantitative parameters such as nuclear-to-cytoplasm ratio, which has been proposed as a diagnostic indicator of dysplasia or cancer. In this study we investigated the imaging properties of the HRME system by using phantoms simulating scattering tissue with fluorescently labeled nuclei. We directly compared HRME imaging with confocal endomicroscopy in phantoms and in vivo human tissue. HRME images defocused (deep) objects with apparent diameters and intensity levels that are in agreement with a simple geometric model. Out-of focus nuclei contribute a relatively low, uniform background level to images which neither leads to the erroneous appearance of large nuclei from deep layers, nor prevents accurate imaging of superficial nuclei with high contrast. PMID- 24156081 TI - Non-contact in vivo diffuse optical imaging using a time-gated scanning system. AB - We report on the design and first in vivo tests of a novel non-contact scanning imaging system for time-domain near-infrared spectroscopy. Our system is based on a null source-detector separation approach and utilizes polarization-selective detection and a fast-gated single-photon avalanche diode to record late photons only. The in-vivo tests included the recording of hemodynamics during arm occlusion and two brain activation tasks. Localized and non-localized changes in oxy- and deoxyhemoglobin concentration were detected for motor and cognitive tasks, respectively. The tests demonstrate the feasibility of non-contact imaging of absorption changes in deeper tissues. PMID- 24156082 TI - Low-cost laser speckle contrast imaging of blood flow using a webcam. AB - Laser speckle contrast imaging has become a widely used tool for dynamic imaging of blood flow, both in animal models and in the clinic. Typically, laser speckle contrast imaging is performed using scientific-grade instrumentation. However, due to recent advances in camera technology, these expensive components may not be necessary to produce accurate images. In this paper, we demonstrate that a consumer-grade webcam can be used to visualize changes in flow, both in a microfluidic flow phantom and in vivo in a mouse model. A two-camera setup was used to simultaneously image with a high performance monochrome CCD camera and the webcam for direct comparison. The webcam was also tested with inexpensive aspheric lenses and a laser pointer for a complete low-cost, compact setup ($90, 5.6 cm length, 25 g). The CCD and webcam showed excellent agreement with the two camera setup, and the inexpensive setup was used to image dynamic blood flow changes before and after a targeted cerebral occlusion. PMID- 24156083 TI - Wage Slavery or Creative Work? AB - Western philosophical and scientific traditions often view human work as inherently onerous, wearisome, and degrading. Adam Smith, writing in the eighteenth century, saw work as the toil and trouble that is the real price humans pay for everything they need or want. Karl Marx, writing in the nineteenth century, considered wage labor alienating, but saw the possibility of self expressive work. Dupre and Gagnier, a philosopher and a critic writing near the end of the twentieth century, agreed that work could be self-fulfilling, but only for an elite minority. This article summarizes the Western philosophical views of work from ancient to modern times. It reframes the philosophical positions as empirical questions and addresses them with statistics and models drawn from a 1995 U.S. survey. Observations suggest that work, in modern America, is not usually alienated. The great majority of Americans rate their paid work or other main daily activities (mostly unpaid work) as more autonomous and creative than not. Emotional well-being and the sense of control over one's own life increase with the degree of autonomy and creativity. The employed report less autonomous but more creative activity than do the nonemployed. Emotional well-being and perceived control correlate more strongly with creativity than with autonomy. The overall association thus favors employment, especially for the poorly educated, even though they give up more autonomy when employed. On the whole, work in modern America seems more self-fulfilling than onerous, alienating, or degrading. PMID- 24156084 TI - Hereditary Coproporphyria Associated with the Q306X Mutation in the Coproporphyrin Oxidase Gene Presenting with Acute Ataxia. AB - BACKGROUND: Hereditary coproporphyria (HCPO) is a low-penetrance, autosomal dominant, acute hepatic porphyria characterized by the overproduction and excretion of coproporphyrin. The most common neurological manifestations of this entity include peripheral, predominantly motor dysfunction, and central nervous system dysfunction. Ataxia associated with HCPO has not been reported previously. The aim of this article is to report a patient with HCPO presenting with acute ataxia. CASE REPORT: We describe a 44-year-old patient presenting clinically with acute ataxia who was diagnosed with HCPO; mutations were analyzed in the coproporphyrin-oxidase III (CPOX) gene in the patient and in six asymptomatic first-degree relatives. DISCUSSION: The patient was heterozygous for a mutation causing the amino acid exchange Q306X in the CPOX gene. No relatives carried the same or another mutation in the CPOX gene. HCPO should be considered in the differential diagnosis for patients presenting with ataxia. PMID- 24156085 TI - "Club-cutting" dystonic tremor: a case report. AB - BACKGROUND: Focal task-specific dystonic postures are well recognized. Often a tremor may be the main feature with little or no dystonia. These have been well reported in writers, musicians, and sportspeople. CASE REPORT: Herein we report a novel task-specific dystonic tremor in a 44-year-old Irish hairdresser due to club-cutting, a standard haircutting technique. DISCUSSION: Hairdresser's dystonia is a novel task-specific dystonia. PMID- 24156086 TI - Status of the anaplastic lymphoma kinase (ALK) gene in inflammatory breast carcinoma. AB - BACKGROUND: Although preliminary reports suggest that ALK gene amplification may occur in inflammatory breast cancer (IBC), data are limited. We performed a comprehensive investigation of the status of ALK gene in IBC. METHODS: We used core biopsy (CB) samples from 30 IBC patients for immunohistochemistry (IHC), 25 of these samples for fluorescence in situ hybridization (FISH) of ALK gene rearrangement, 8 for chromosome 2 aneusomy, and 20 microdissected frozen CBs for array comparative genomic hybridization (CGH) and mRNA analysis. RESULTS: All 30 samples were negative for ALK protein expression by IHC. FISH analysis showed no EML4-ALK gene rearrangement in any samples, although 16 of the 25 samples (64%) contained 3 to 4 extra copies of the ALK gene, and chromosome 2 aneusomy was found in 7 of 8 samples that had extra copies of the ALK gene. Only 3 of the 20 samples showed evidence of mild ALK gene amplification by array CGH. mRNA analysis revealed that mRNA expression of ALK was not significantly higher in these samples compared with samples that showed no evidence of ALK gene amplification in CGH analysis, nor was mRNA expression of ALK significantly different in tumor compared with 5 normal breast samples (P > 0.05, t test). CONCLUSION: Our comprehensive evaluation suggests that ALK gene rearrangement did not occur in the IBC patients studied. The significance of our finding of mildly increased copy numbers of the ALK gene resulting from chromosome 2 aneusomy rather than mild amplification of the ALK gene requires further investigation. PMID- 24156087 TI - Clinical significance of the sub-classification of 71 cases mucinous breast carcinoma. AB - OBJECTIVE: Mucinous breast carcinoma (MBC) is classified into mixed mucinous breast carcinoma (MMBC) and pure mucinous breast carcinoma (PMBC) based on whether the tumor is with or without a component of invasive ductal carcinoma, respectively. PMBC is subtyped into hypocellular PMBC (PMBC-A) and hypercellular PMBC (PMBC-B). METHODS: Of 1,760 primary breast carcinomas, 71 were diagnosed as MBC, and were subtyped for comparison purposes. RESULTS: Seventy-one of all breast cancers (4.0%) were MBC, and consisted of 23 MMBC, 32 PMBC-A and 16 PMBC B. The MBC tumors were more often hormone receptor-positive and HER2-negative than non-MBC tumors. Patients with MMBC, PMBC-B or PMBC-A, in this order, had significantly higher recurrence rates than non-MBC cases (p=0.006, log-rank). CONCLUSIONS: In the NCCN guidelines, MBC is also regarded as "a histological type with a favorable prognosis" in a uniform manner, and "treatment for a histological type with a favorable prognosis" is recommended. However, the results of this study suggest that sub-classification-based, individualized therapeutic strategies should be considered. PMID- 24156088 TI - The importance of rapid aneuploidy screening and prenatal diagnosis in the detection of numerical chromosomal abnormalities. AB - OBJECTIVES: Evaluation of Fluorescent in situ hybridization (FISH) as a tool for rapid aneuploidy screening (RAS) of high risk pregnancies, before its approval in the national antenatal screening and genetic diagnosis program in Egypt. METHODS: The cytogenetic data of prenatal specimens, and results of FISH of 100 patients performed between, January 2009 and December 2009, at the Medical Genetics Center (MGC) laboratory were retrieved and reviewed. AneuVysion Assay kit was used for detection of 13, 21, X, Y, 18 aneuploidies. RESULTS: Maternal age varied from 21 to 44 years (mean was 35.6 year). Ninety percent of pregnancies had normal chromosomes and 10% of the cases had numerical chromosomal abnormalities. Trisomy 21 was the most frequent chromosomal disorder across all indications (5%), followed by Turner syndrome (2%), trisomy 18 (2%), and trisomy 13 (1%). When comparing the FISH data with karyotype results for chromosomes 13, 18, 21, X, and Y in the 83 individual tested, no false positive or negative results were detected by the FISH assay. The result obtained by FISH and the banding cytogenetic were in complete accordance. CONCLUSION: This study supports the integration of amniotic fluid (AF) FISH as a RAS test, in to routine antenatal practice for identification of chromosome aneuploidies. There are trends towards delayed childbearing and most cases of Down Syndrome (DS) are currently detected post-nataly in the Egyptian population. Consequently, the live birth prevalence of DS has increased, which might lead to a serious negative public health effects. PMID- 24156089 TI - Hybrid poplar plantations are suitable habitat for reintroduced forest herbs with conservation status. AB - Plantations of fast-growing tree species may be of use in conservation by accelerating the restoration of forest habitat on abandoned farmland and increasing connectivity in fragmented landscapes. The objective of this study was to determine if hybrid poplar plantations can be suitable habitats for the reintroduction of native forest plant species and, if so, which abiotic factors predict successful reintroduction. Four species of forest herb species (Trillium grandiflorum, Sanguinaria canadensis, Maianthemum racemosum, Asarum canadense), of which three have legal conservation status, were transplanted into experimental plantations of two hybrid poplar clones and nearby second-growth woodlots at six sites in southern Quebec, Canada. The transplanted individuals were protected from deer browsing with exclusion cages. After two years, the plant responses of all four species were stable or increased over two years in both types of hybrid poplar plantations. Sanguinaria showed a better response in the plantations than in the woodlots, preferring the rich post-agricultural soils of the plantations with low C:N ratios. Asarum and Maianthemum showed no significant difference between stand types, while Trillium grew better in the woodlots than in the plantations. Much of the variability in the response of the latter three species was unexplained by the measured environmental variables. These results suggest that certain forest herb species can be reintroduced as juvenile plants into plantations, knowing that their spontaneous recolonization is often limited by dispersal and/or seedling establishment. Plantations could also contribute to the conservation of biodiversity by providing an environment for the cultivation of forest herb species as an alternative to their destructive harvest from natural populations. PMID- 24156090 TI - Treatment of, and Candida utilis biomass production from shochu wastewater; the effects of maintaining a low pH on DOC removal and feeding cultivation on biomass production. AB - Shochu wastewater (SW; alcoholic distillery wastewater) contains large amounts of organic compounds (25,000 - 60,000 COD mg/L), nitrogen (1,000 - 6,000 T-N mg/L), and phosphorus (500 - 1,000 T-P mg/L). Despite its high nutrient content, SW is highly perishable, which limits its utilization for animal feed and fertilizer. Therefore, SW is mainly treated by methane fermentation. On the other hand, a feed yeast, Candida utilis, can utilize various organic compounds and be utilized as a yeast extract source and animal feed. We previously bred a mutant, C. utilis UNA1, that accumulates a large amount of nitrogen. Here, we investigated the use of C. utilis UNA1 to treat highly concentrated SW. With fed-batch cultivation using a 5-L jar fermenter, controlling pH at 5.0 with H2SO4, 62.9% of DOC, 38.4% of DTN, and 44.5% of DTP were stably removed from non-diluted barley shochu wastewater (BSW), and about 16.7 kg of freeze-dried yeast biomass was obtained. The yeast sludge biomass generated from BSW contains about 60% crude protein. Furthermore, using H2SO4 to control pH increased the sulfur content of wastewater, which increased the methionine composition of yeast sludge biomass. PMID- 24156091 TI - Nutritional outcomes from a randomised investigation of intradialytic oral nutritional supplements in patients receiving haemodialysis, (NOURISH): a protocol for a pilot randomised controlled trial. AB - Haemodialysis is a form of renal replacement therapy but is a catabolic process that not only filters toxins but is also known to lead to amino acid losses. Patients with chronic kidney disease often have a poor appetite and this in combination with limited dietary intake and the detrimental effects of haemodialysis can lead to the development of malnutrition. Between 20% and 50% of haemodialysis patients are thought to be malnourished. Malnutrition can worsen clinical outcomes and increase the risk of hospitalisation. We hypothesise that a nutritional supplement taken during haemodialysis may help to improve nutritional status. The aim of this study is to conduct a pilot randomised controlled trial to assess the use of an intradialytic nutritional supplement on nutritional status. The objectives are to assess the feasibility of the trial including: recruitment and retention of participants; preference of nutritional supplements; compliance with the intervention; ease of completion of the questionnaires and appropriateness of the tools used. Secondary outcomes include clinical outcomes to obtain variance in the patient population and estimates of effect size to inform the sample size for a future definitive trial. The trial is a single centre, randomised, parallel-group, two armed external pilot with an intervention and control group. The intervention group will take a nutritional supplement each dialysis session from a choice of prescribable drink or pudding style supplements. The control group will receive standard care. Recruitment and feasibility elements are the primary outcomes. Recruitment will be to time (t = 6 weeks). In order to collect sufficient data to inform a future sample size calculation, we will aim to recruit 30 participants to obtain 12 evaluable per arm anticipating some drop out. Secondary outcome measures include clinical variables; hand grip strength, quality of life, weight and biochemistry completed at baseline, 1 and 2 months. Descriptive statistics will be used to analyse the baseline characteristics of the recruited participants. Means, confidence intervals and standard deviations will be reported for the outcome measures of handgrip strength, dietary intake, quality of life and weight. TRIAL REGISTRATION: ISRCTN37431579. PMID- 24156092 TI - Initial serum sodium concentration determines the decrease in sodium level after terlipressin administration in patients with liver cirrhosis. AB - BACKGROUND: Terlipressin, as a prodrug of vasopressin, has agonistic effects on the V1 receptor and partial agonistic effects on renal vasopressin V2 receptors. However, its effects on serum sodium concentration are controversial. METHODS: This study retrospectively investigated 127 patients with liver cirrhosis to examine the incidence and risk factors for the decrease in serum sodium level following terlipressin administration. RESULTS: Terlipressin was prescribed for bleeding control (99) and management of hepatorenal syndrome (28). Serum sodium level decreased from 134.0 +/- 6.5 mmol/L to 130.4 +/- 6.2 mmol/L during or after terlipressin treatment (P < 0.001) in all patients. In 45 patients (35.4%), the serum sodium concentration decreased by > 5 mmol/L, in 29 patients (22.8%); by 5 10 mmol/L; and in 16 patients (12.6%), by > 10 mmol/L. Five patients in the latter group showed neurological manifestations. In the univariate analysis, several factors including age, purpose of use, serum creatinine, and Model for End-Stage Liver Disease score, representing liver function, were significantly associated with the decrease in serum sodium after terlipressin administration. However, a multivariate analysis revealed that only initial sodium level was the most powerful predictor of terlipressin-induced reduction in serum sodium. CONCLUSION: An acute reduction in serum sodium concentration was not uncommon during terlipressin treatment, and the baseline serum sodium level was closely related to the reduction in serum sodium concentration. PMID- 24156093 TI - EMG amplitude of the biceps femoris during jumping compared to landing movements. AB - Hamstrings injury is a common occurrence in athletic performance. These injuries tend to occur during a deceleration or landing task suggesting the negative work may be a key component in hamstrings injury. The purpose of this study was to investigate the muscular activity (EMG) of the biceps femoris (BF) in different phases (concentric vs. eccentric) of a Counter Movement Jump (CMJ), Squat Jump (SJ) and the Braking Phase (BP) of a landing task. Twelve female volleyball players performed 5 CMJs, SJs and BPs while surface EMG was recorded using a MuscleLab (BoscoSystem(TM), Norway). EMG values were normalized to an maximal voluntary contraction. A repeated measures analysis of variance (ANOVA) was used to compare mean normalized EMG values of the concentric and eccentric portions of the CMJ with the BP and SJ. The ANOVA revealed significantly lower BF activation in the concentric and eccentric portions of the CMJ compared to the BP (64%, p < 0.001) and SJ (7%, p = 0.02), respectively. These findings suggest that the CMJ relies on a greater contribution of elastic tissues during the concentric and eccentric portions of the movement and thus requires less muscle activation of the BF. PMID- 24156094 TI - MicroRNA-135b and Its Circuitry Networks as Potential Therapeutic Targets in Colon Cancer. PMID- 24156095 TI - Author's reply: To PMID 23579752. PMID- 24156096 TI - The semiochemistry of aphids. AB - Chemical signalling between aphids (small insects that suck plant sap) formating and avoidance of antagonistic organisms, and between aphids and plants for location of hosts or avoidance of unsuitable plants, employs minute levels of small lipophilic molecules (SLMs), termed "semiochemicals". These semiochemicals, which include sex and alarm pheromones, although often involving relatively simple volatile compounds to allow aerial transmission, convey highly accurate information, either through the uniqueness of their chemical structure or by acting together in characteristic mixtures. In addition, by chemical instability, they do not remain in the environment after their essential signalling role has occurred. Aphids, as a consequence of direct feeding or virus transmission, are major pests of agriculture and horticulture. Aphid semiochemicals present novel opportunities for management of pest populations, but problems of synthesis costs and delivery need to be overcome. Genes for associated enzymes in aphids and plants offer solutions, either for production and subsequent deployment in agriculture, or for direct biosynthesis by crop plants as a new generation of genetically modified organisms (GMOs). These approaches are currently under active investigation. Semiochemicals released from plants during aphid feeding can also "switch on" defence chemistry-related genes in intact plants under field conditions, and the gene promoter sequences involved could be used to produce novel types of sentinel plants. The molecular recognition mechanisms employed in aphid olfactory systems are being investigated to provide potential tools for recognition of SLMs, and the acceptance of substrate analogues is explored with enzymes synthesising aphid semiochemicals in an attempt to provide more active or stable structural analogues. PMID- 24156097 TI - Mosquito larval source management: evaluating evidence in the context of practice and policy. PMID- 24156098 TI - Oxygen therapy in acute myocardial infarction - good or bad? PMID- 24156099 TI - Factor Xa inhibitors: a step forward in the treatment of atrial fibrillation? PMID- 24156100 TI - Response to Effectiveness of adrenalectomy and aldosterone antagonists for long term treatment of primary aldosteronism. PMID- 24156101 TI - Response to Endothelial nitric oxide synthase, cyclooxygenase-2, and essential hypertension: is there an interaction? PMID- 24156102 TI - Response to Call for a re-evaluation of the American Heart Association's standpoint concerning device-guided slow breathing using the RESPeRATE device. PMID- 24156103 TI - Response to Lowered magnesium in hypertension. PMID- 24156104 TI - Response to Masked hypertension in untreated and treated patients with diabetes mellitus: attractive but questionable interpretations and response to Is masked hypertension related to diabetes mellitus? PMID- 24156106 TI - Memorable outliers. PMID- 24156105 TI - Paul W. Sternberg. PMID- 24156107 TI - Are memories just ripples in time? PMID- 24156108 TI - Killers on the road: Klebsiella and Pseudomonas bacteremia detected on peripheral blood smear. PMID- 24156109 TI - CNS involvement in DLBCL. PMID- 24156124 TI - [Thorax/lung and mediastinum, pleura cancer]. PMID- 24156125 TI - Author reply: To PMID 23793316. PMID- 24156126 TI - [Upper G.I. Cancer]. PMID- 24156127 TI - A New Year. PMID- 24156128 TI - [I. Current opinion for marker of metastases and recurrence- esophagus cancer and gastric cancer]. PMID- 24156129 TI - [II. Salvage surgery after chemoradiotherapy for esophagus cancer- treatment for esophagus cancer at the hospital]. PMID- 24156130 TI - [III. Robotic surgery for gastric cancer]. PMID- 24156131 TI - [IV. Current status and future for diagnosis and treatment of GIST]. PMID- 24156132 TI - TRICARE; removal of the prohibition to use addictive drugs in the maintenance treatment of substance dependence in TRICARE beneficiaries. Final rule. AB - The Department of Defense (DoD) is publishing this final rule to remove the exclusion of drug maintenance programs and allow TRICARE coverage of the substitution of a therapeutic drug, with addictive potential, for a drug of addiction when medically necessary and appropriate as part of a comprehensive treatment plan for an individual with substance use dependence. The current regulation prohibits coverage of drug maintenance programs where one addictive substance is substituted for another. The final rule allows TRICARE to cover, as part of otherwise authorized treatment of substance use disorder, utilization of a specific category of psychoactive agent when medically necessary and appropriate. Removal of the exclusion is based on recognition of the accumulated medical evidence supporting the use of certain pharmacotherapies as one component in the continuum of opioid treatment services. Medication assisted treatment, to include drug maintenance involving substitution of a therapeutic drug with addiction potential, for a drug of addiction, is now generally accepted by qualified professionals to be reasonable and adequate as a component in the safe and effective treatment of substance use disorders treatment services, and thus appropriate for inclusion as a component in the TRICARE authorized substance use disorder treatment for beneficiaries. PMID- 24156133 TI - VA Dental Insurance Program--federalism. Direct final rule. AB - The Department of Veterans Affairs (VA) is taking direct final action to amend its regulations related to the VA Dental Insurance Program (VADIP), a pilot program to offer premium-based dental insurance to enrolled veterans and certain survivors and dependents of veterans. Specifically, this rule will add language to clarify the limited preemptive effect of certain criteria in the VADIP regulations. PMID- 24156134 TI - International Conference on Harmonisation; Guidance on Q4B Evaluation and Recommendation of Pharmacopoeial Texts for Use in the International Conference on Harmonisation Regions; Annex 14 on Bacterial Endotoxins Test General Chapter; availability. Notice. AB - The Food and Drug Administration (FDA) is announcing the availability of a guidance entitled "Q4B Evaluation and Recommendation of Pharmacopoeial Texts for Use in the International Conference on Harmonisation Regions; Annex 14: Bacterial Endotoxins Test General Chapter.'' The guidance was prepared under the auspices of the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH). The guidance provides the results of the ICH Q4B evaluation of the Bacterial Endotoxins Test General Chapter harmonized text from each of the three pharmacopoeias (United States, European, and Japanese) represented by the Pharmacopoeial Discussion Group (PDG). The guidance conveys recognition of the three pharmacopoeial methods by the three ICH regulatory regions and provides specific information regarding the recognition. The guidance is intended to recognize the interchangeability between the local regional pharmacopoeias, thus avoiding redundant testing in favor of a common testing strategy in each regulatory region. The guidance is in the form of an annex to the core guidance on the Q4B process entitled "Q4B Evaluation and Recommendation of Pharmacopoeial Texts for Use in the ICH Regions (core ICH Q4B guidance). PMID- 24156135 TI - Dental caries: a disease which remains a public health concern in the 21st century--the exploration of a breakthrough technology for caries prevention. AB - This paper provides an overview of modern concepts of dental caries, including its etiology, prevalence, and risk factors. The multifactorial nature of the disease is reviewed, and the concept of reducing caries initiation and progression by reducing pathological factors and restoring caries balance is discussed. In addition, the role and efficacy of fluoride in reducing and preventing caries is highlighted, demonstrating its successes and limitations. A novel technology, based upon arginine and an insoluble calcium compound, has been identified which targets dental plaque to prevent initiation and progression of the caries process by reducing pathological factors. As the mechanisms of action of arginine and fluoride are highly complementary, a next-generation dentifrice has been developed, which combines arginine, an insoluble calcium compound, and fluoride, and has been clinically proven to provide superior caries prevention. PMID- 24156136 TI - A clinical investigation using quantitative light-induced fluorescence (QLF) of the anticaries efficacy of a dentifrice containing 1.5% arginine and 1450 ppm fluoride as sodium monofluorophosphate. AB - OBJECTIVE: The purpose of this study was to assess the ability of a new dentifrice containing arginine, an insoluble calcium compound, and fluoride to arrest or reverse naturally occurring buccal caries lesions measured using Quantitative Light-induced Fluorescence (QLF). METHODS: Three study groups used dentifrices which contained 1) 1.5% arginine and 1450 ppm fluoride as sodium monofluorophosphate (experimental), 2) 1450 ppm fluoride as sodium monofluorophosphate (positive control), and 3) no fluoride (negative control). All three dentifrices were formulated in the same calcium base. The study participants were from three schools in the city of Chengdu, Sichuan Province, China. A total of 446 of 450 recruited subjects completed the study. Of these, 147 were in the experimental, 148 in the positive control, and 151 in the negative control groups. The initial age of the children was 10-12 years (mean 11.4 +/- 0.54); 47.5% were female. RESULTS: Using QLF, assessments of buccal caries lesions were made at baseline and after three and six months of product use. For AQ, representing lesion volume, the baseline mean value for the three groups was 27.30, and at the three-month examination the mean values were 16.76, 19.25, and 25.89 for the experimental, positive, and negative control dentifrices, respectively. This represents improvements from baseline of 38.6%, 29.5%, and 5.2%. At six months, the deltaQ values for the three groups were 13.46, 18.47, and 24.18, representing improvements from baseline of 50.7%, 32.3%, and 11.4%. For all QLF metrics, deltaF (loss of fluorescence), area, and deltaQ, the differences between the negative control and both the experimental and positive control groups were statistically significant (p < or = 0.01). The differences between the experimental and positive control groups attained statistical significance for deltaQ (p < or = 0.003) at the six-month examination. CONCLUSION: It is concluded that both of the fluoride-containing toothpastes are significantly better at arresting and reversing buccal caries lesions than the non-fluoride toothpaste. Furthermore, it is concluded that the new dentifrice containing arginine, an insoluble calcium compound, and fluoride provides significantly greater anticaries benefit than a dentifrice containing fluoride alone. PMID- 24156137 TI - A clinical investigation of the efficacy of a dentifrice containing 1.5% arginine and 1450 ppm fluoride, as sodium monofluorophosphate in a calcium base, on primary root caries. AB - OBJECTIVE: The purpose of this six-month study was to assess the ability of a new dentifrice containing 1.5% arginine, an insoluble calcium compound, and 1450 ppm fluoride, as sodium monofluorophosphate, to arrest and reverse primary root caries lesions in adults. METHODS: Three test groups used dentifrices which contained either: 1) 1.5% arginine and 1450 ppm fluoride as sodium monofluorophosphate in a calcium base (experimental); 2) 1450 ppm fluoride as sodium fluoride in a silica base (positive control); or 3) no fluoride in a calcium base (negative control). The study participants were residents of the city of Chengdu, Sichuan Province, China. In order to take part, subjects had to have at least one non-cavitated primary root caries lesion. A total of 412 subjects completed the study. They were aged from 50 to 70 years (mean age 64 +/- 4.1 years) and 53.6% were female. Efficacy for arresting and reversal of primary root caries was assessed by clinical hardness measures and through the use of the Electrical Caries Monitor. RESULTS: After three months of product use, clinical hardness measures showed that 27.7%, 24.6%, and 13.1% of lesions had improved in the experimental, positive, and negative control groups, respectively, and 0.7%, 4.5%, and 16.8% had become worse, respectively. The differences in the distribution of lesion change between the negative control group and both the experimental (p < 0.001) and positive control (p = 0.001) were statistically significant. The Electrical Caries Monitor was also used as an objective measure of lesion severity. The end values increased from baseline to the three-month examinations, but none of the differences between the groups attained statistical significance. After six months, clinical hardness measures showed that only one lesion (0.7%) was worse than at the baseline examination-in the experimental group compared to 9.0% and 18.2% in the positive and negative control groups, respectively. In addition, 61.7%, 56.0%, and 27.0%, respectively, showed improvement for the three groups. The differences in the distribution of lesion change scores between the negative control group and both the experimental (p < 0.001) and positive control (p < 0.001) were statistically significant, as was the difference between the experimental group and the positive control (p = 0.006). The Electrical Caries Monitor end values for the experimental, positive, and negative control groups at the six-month examination were 7.9, 1.9 mega omega(s), and 387 kilo omegas(s), respectively. The differences between the negative control group and both the experimental (p < 0.001) and positive control (p < 0.001) were statistically significant. The difference between the experimental and positive control groups was also statistically significant (p = 0.03). CONCLUSION: It is concluded that the new toothpaste containing 1.5% arginine and 1450 ppm fluoride, as sodium monofluorophosphate in a calcium base, provided greater anticaries benefits than a conventional toothpaste containing 1450 ppm fluoride. Both fluoride toothpastes demonstrated greater benefits than non-fluoride toothpaste. PMID- 24156138 TI - In situ clinical effects of new dentifrices containing 1.5% arginine and fluoride on enamel de- and remineralization and plaque metabolism. AB - OBJECTIVE: The primary objective of the three studies reported in this paper was to evaluate the effects of new dentifrices containing 1.5% arginine, an insoluble calcium compound, and fluoride for their ability to promote remineralization of demineralized enamel, and to prevent mineral loss from sound enamel specimens. A secondary objective was to determine the effects on plaque metabolism with respect to the conversion of arginine to ammonia and sucrose to lactic acid. METHODS: In Study 1, an intraoral remineralization/demineralization clinical model was used to assess the ability to promote remineralization of enamel of two dentifrices containing 1.5% arginine and 1450 ppm fluoride, as sodium monofluorophosphate (MFP), relative to a positive control with dicalcium phosphate dihydrate (Dical) and 1450 ppm fluoride, and a negative control with Dical and 250 ppm fluoride. One of the arginine-containing dentifrices contained Dical, and the other contained calcium carbonate as the source of insoluble calcium. Microradiography and image analysis were used to measure mineral changes. The study used a double-blind crossover design with a two-week treatment period. Each treatment period was preceded by a one-week washout period. Each product was used twice a day for two weeks. In the two other studies, the ability of dentifrices containing 1.5% arginine and fluoride to prevent demineralization of sound enamel blocks was assessed using an intraoral demineralization/remineralization clinical model and a double-blind crossover design with a five-day treatment period. A one-week minimum washout period preceded each treatment phase. Microhardness was used to assess mineral changes. Cariogenic challenges were administered by dipping each intraoral retainer into a 10% sucrose solution four times per day. Each product was used twice per day during the treatment period. Plaque was harvested from the specimens to measure the ability of the plaque to convert arginine to ammonia (Studies 2 and 3) and sucrose to lactic acid (Study 3) at the end of each treatment period. In Study 2, a dentifrice containing 1.5% arginine, Dical, and 1450 ppm fluoride as MFP was compared to a matched positive control containing 1450 ppm fluoride and to a matched negative control containing 250 ppm fluoride. In Study 3, a dentifrice containing 1.5% arginine, calcium carbonate, and 1000 ppm fluoride as MFP was compared to a matched positive control containing 1000 ppm fluoride and to a matched negative control containing 0 ppm fluoride. RESULTS: In Study 1, the percent mineral changes were +18.64, +16.77, +4.08, and -24.95 for the 1.5% arginine/Dical/1450 ppm fluoride, the 1.5% arginine/calcium carbonate/1450 ppm fluoride, the positive control, and negative control dentifrices, respectively. Study validation was successfully achieved by showing that the positive control was statistically significantly better that the negative control in promoting remineralization (p = 0.0001). The two arginine-containing test products were statistically significantly better than the positive control (p < 0.05). No significant difference was observed in efficacy between the two arginine containing products, indicating that efficacy in promoting remineralization was independent of the choice of Dical or calcium carbonate as the source of insoluble calcium. In Study 2, the percent demineralization values were -8.50, +1.67, and +12.64 for the 1.5% arginine/Dical/1450 ppm fluoride, the positive control, and negative control dentifrices, respectively. Study validation was successfully achieved by showing that the positive control was statistically significantly better at preventing demineralization than the negative control (p < 0.0001). The arginine-containing dentifrice was shown to be statistically significantly better at preventing enamel demineralization than the positive control (p < 0.0001). Plaque metabolism measures for plaque exposed to the three treatments gave the following values for ammonia production after an arginine sucrose challenge, expressed in nanomoles per milligram plaque: 162.7; 105.4; and 115.9 for the 1.5% arginine/Dical/1450 ppm fluoride, positive control, and negative control dentifrices, respectively. No statistically significant differences were observed between the three treatments, but the arginine-based dentifrice showed directionally higher ammonia production than both the positive and negative controls In Study 3, the percent demineralization values were +1.16, +4.96, and +15.34, for the 1.5% arginine/calcium carbonate/1 000 ppm fluoride, the positive control, and negative control dentifrices, respectively. Study validation was successfully achieved by showing that the positive control was statistically significantly better at preventing demineralization than the negative control (p < 0.0001). The arginine-containing dentifrice was shown to be statistically significantly better at preventing enamel demineralization than the positive control (p < 0.05). Plaque metabolism measures for plaque exposed to the three treatments gave the following values for ammonia production after an arginine-sucrose challenge, expressed in nanomoles per milligram plaque: 99.6; 56.2; and 42.2 for the 1.5% arginine/calcium carbonate/1000 ppm fluoride, the positive control, and negative control dentifrices, respectively. Plaque treated with the arginine- containing dentifrice produced significantly more ammonia than the positive and negative control dentifrices (p < 0.05). No significant difference in ammonia production was observed between the two controls. Lactic acid production after a sucrose challenge gave the following values, expressed as nanomoles per milligram plaque: 4.06; 5.12; and 4.64 for the 1.5% arginine/calcium carbonate/1000 ppm fluoride, the positive control, and negative control dentifrices, respectively. No significant difference was observed between the three treatments, but the arginine-based treatment showed directionally lower lactic acid production. RESULTS: The results of these three studies show that dentifrices containing 1.5% arginine, an insoluble calcium compound, and fluoride have a significantly improved ability to promote remineralization and prevent demineralization of enamel relative to dentifrices containing the same level of fluoride alone. Two different sources of insoluble calcium were evaluated, Dical and calcium carbonate. Dentifrices with Dical and with calcium carbonate, each in combination with 1.5% arginine and fluoride, provided superior efficacy as compared to matched dentifrices with fluoride alone, and the two products demonstrated comparable efficacy in promoting remineralization. The results of these studies demonstrate that the addition of 1.5% arginine to Dical-and calcium carbonate-based fluoride dentifrices provides superior efficacy in preventing demineralization and promoting remineralization, and, further, indicate that he arginine-containing dentifrices enhance the ability of plaque to metabolize arginine to ammonia. PMID- 24156139 TI - In vivo effects of a new dentifrice containing 1.5% arginine and 1450 ppm fluoride on plaque metabolism. AB - OBJECTIVE: This paper presents the results of a clinical study assessing the in vivo effects on plaque metabolism of a new dentifrice containing 1.5% arginine, an insoluble calcium compound, and 1450 ppm fluoride compared to a commercially available dentifrice containing 1450 ppm fluoride alone. METHODS: A four-week, parallel, randomized, double-blind clinical study using 54 subjects was conducted at the New York University College of Dentistry Bluestone Center for Clinical Research. Two study groups used the following products for two weeks: 1) a dentifrice containing 1.5% arginine, an insoluble calcium compound, and 1450 ppm fluoride as sodium monofluorophosphate (MFP; test); and 2) a commercial silica dentifrice with 1450 ppm fluoride as sodium fluoride (NaF; control). In the following two-week period, all subjects used the control product. The effects of product use on plaque metabolism in vivo were assessed by conducting ex vivo analyses at baseline, after two weeks of assigned product use, and after two weeks of control product use. These plaque analyses comprised pH measurements before and after an in vivo sucrose rinse, and measurements of ammonia production and lactate production. RESULTS: The study showed that subjects using the test dentifrice, containing 1.5% arginine, an insoluble calcium compound, and 1450 ppm fluoride, had significantly higher plaque pH values before the sucrose challenge than those using the commercially available control dentifrice (p < or = 0.01). Plaque samples from subjects using the arginine-containing dentifrice also produced significantly higher levels of ammonia (p < or = 0.01). Subjects using the arginine-containing dentifrice also had a directionally higher plaque pH after the sucrose challenge, and their plaque samples produced a directionally lower level of lactate during the two-week treatment period compared to subjects using the control dentifrice. Following two weeks of subsequent use of the control product, there were no significant differences in plaque metabolism measures between groups. CONCLUSION: A new dentifrice containing 1.5% arginine, an insoluble calcium compound, and 1450 ppm fluoride has been shown in this study to modulate plaque metabolism, increasing ammonia production and decreasing lactate production, thereby increasing plaque pH to help restore a pH-neutral environment. PMID- 24156140 TI - Truth in advertising. PMID- 24156141 TI - Brain drain. Spotting a stroke fast can prevent damage. PMID- 24156142 TI - The letter. PMID- 24156143 TI - Flying forward. Parents of college students can help them leave the nest. PMID- 24156144 TI - Insulin's sidekicks. Developing alternative medications for type 1 diabetes. PMID- 24156145 TI - Safe at school. The American Diabetes Association goes to court on behalf of kids in California. PMID- 24156146 TI - Family ties. How one woman is working to end diabetes for future generations. PMID- 24156147 TI - Life without limits. Race car driver Ryan Reed takes a pit stop to speak about diabetes. PMID- 24156148 TI - Food deserts. Across America, there's food everywhere--and yet there's nothing to eat. Why? PMID- 24156149 TI - Preventing brain strain. A researcher probes the ill effects of prediabetes on cerebral blood vessels. PMID- 24156150 TI - Bernhard Gottlieb: his life, his work, and his lasting impact. PMID- 24156151 TI - Bernhard Gottlieb's impact on contemporary endodontology. AB - Bernhard Gottlieb, physician and dentist, was born in 1885 in Kuty, Galacia (later Czechoslovakia). He received his doctor of medicine degree from the University of Vienna and a doctorate in medical dentistry from the University of Bonn. He belonged to a group of Viennese scientists who originated periodontics, orthodontics, pedodontics, endodontics, and oral surgery. In the 1930s he began to address in the European sector, root canal treatment in teeth with a vital pulp; following his immigration to the United States, he settled in Texas, in the position of professor and head of the Department of Pathology and Research at Baylor College of Dentistry. Gottlieb wrote many scientific articles and textbooks and is responsible for the beginnings of oral histology as a distinct scientific discipline within dentistry. His initial investigations focused on the periodontium and resorptive activity identified during orthodontic treatment. However, his continued research interests, which are rarely highlighted, focused on teeth and pulps that had undergone trauma and teeth that presented with necrotic pulps. Moreover, his most important legacy may lie in his establishment of the foundation for tissue engineering within dentistry, through his research on the impact of hard tissue elements such as bone, dentin and cementum on the formation of new tissues (regeneration). As stated by Dr. Gottlieb, "This seems to be the goal for which science should strive in endodontia". PMID- 24156152 TI - Routine skin care as prophylaxis and treatment. PMID- 24156153 TI - Understanding skin barrier differences: a demographic, cultural, and medical diversity viewpoint. AB - Important differences exist in the physiology of the stratum corneum barrier according to demographic, cultural, and medical factors. Understanding these differences is crucial to choosing strategies for optimum clinical management. PMID- 24156154 TI - Update on the structure and function of the skin barrier: atopic dermatitis as an exemplar of clinical implications. AB - The healthy stratum corneum allows optimum permeability of water and provides the first line of defense against pathogenic and environmental assaults. The barrier functions of the stratum corneum are interrelated, coregulated, and interdependent. Research has demonstrated that three lipid species, which usually comprise 10% of the stratum corneum, are crucial to both its structure and its function; these must be present in sufficient quantities and in the correct proportions to provide optimum barrier function. The clinical implications of how the skin barrier works--and is supported and restored--can be seen in the current and emerging understanding of atopic dermatitis management. PMID- 24156155 TI - The chemistry of skin cleansers: an overview for clinicians. AB - Cleansers and other skin care products can be agents either of stratum corneum damage and skin barrier dysfunction or of maintaining or restoring healthy stratum corneum barrier structure and function. To guide patients toward beneficial choices most suitable for their individual skin conditions and needs, clinicians must be aware of and understand the ingredients in such skin care products and their potential effects on the stratum corneum barrier. In cleansers specifically, clinicians should be aware particularly of the benefits and potential problems associated with chemical components of surfactants, preservatives, and fragrances. PMID- 24156156 TI - A lifetime of well skin care: practical recommendations for clinicians and patients. AB - The skin is an indicator of overall health throughout life, and the skin's lifelong care and environment are reflected with aging. The goal of skin care education by clinicians is to teach and reinforce habits that will support and maintain optimum stratum corneum barrier function throughout life and, when dermatologic conditions or injuries arise, that will aid in recovery of barrier function. PMID- 24156157 TI - Skin-cleansing and care principles for special pediatric populations. AB - Good skin care has two overall goals: to support and maintain healthy stratum corneum function and to help restore barrier function perturbed by disease processes or injuries. In this article, we discuss the special attention that is required in the initial skin care of newborns, and we address what measures, beyond the basic skin care principles, are required for patients with conditions such as atopic dermatitis, acne, contact and allergic dermatitis, and diaper rash. PMID- 24156158 TI - The basics of skin care: cleanse, moisturize, protect. PMID- 24156159 TI - The rationale for renewed attention to onychomycosis. PMID- 24156160 TI - The epidemiology, etiology, and pathophysiology of onychomycosis. AB - The prevalence of onychomycosis in the United States is estimated to be at least 12%; prevalence increases with increasing age and is highest in individuals more than 65 years of age. Trichophyton rubrum, which also causes tinea pedis, is responsible for approximately 90% of cases of toenail onychomycosis. Risk factors include a family history of onychomycosis and previous injury to the nails, as well as advanced age and compromised peripheral circulation. Patients with compromised immune function may have an increased risk for onychomycosis and are susceptible to infection with less common dermatophytes and nondermatophyte organisms. PMID- 24156161 TI - Diagnosis, clinical implications, and complications of onychomycosis. AB - The diagnosis of onychomycosis is suggested by the clinical presentation as well as the family history and patient age. The definitive diagnosis of onychomycosis is based on (1) establishing the presence or absence of fungal elements using laboratory methods and/or (2) identifying the fungus using fungal culture or, in the future, by polymerase chain reaction as new developments emerge in this technology, making more widespread application of this technique possible. PMID- 24156162 TI - Current and emerging options in the treatment of onychomycosis. AB - Currently approved options for the treatment of onychomycosis include systemic therapy (the antifungal agents fluconazole, itraconazole, and terbinafine), topical agents (ciclopirox, which has been available since 1996, efinaconazole, currently pending approval), and laser systems. Phase III studies on another topical, tavaborole, have been completed and this medication also shows promise. Mechanical modalities are sometimes used but are seldom necessary. Recurrence of infection is common; the risk for recurrence may be reduced by adherence to preventive measures, especially avoiding (if possible) or promptly treating tinea pedis infections. PMID- 24156163 TI - Promoting and maintaining or restoring healthy nails: practical recommendations for clinicians and patients. AB - The American Academy of Dermatology guidelines for managing patients with onychomycosis, published almost 2 decades ago, provide sound, basic recommendations for clinicians. This article provides a quick reference for clinicians and includes a handout for patients to support the health care provider's educational efforts. PMID- 24156164 TI - Onychomycosis information for patients. PMID- 24156165 TI - Record keeping in practice. PMID- 24156166 TI - Venous leg ulcer management: single use negative pressure wound therapy. AB - A number of leg ulcer specialist/tissue viability specialists from across the UK were invited to evaluate PICO (Smith and Nephew, Hull) as a treatment for venous leg ulcers also in conjunction with a variety of compression bandages and garments. Patients across 5 sites had PICO applied in conjunction with compression therapy. This group of treating clinicians were then asked to give feedback on the outcome of the patients on whom they had used the new device. All feedback was recorded at a meeting and this was used to create a guideline for use. PMID- 24156167 TI - The Lindsay Leg Club: supporting the NHS to provide leg ulcer care. AB - Public health services will need to cope with additional demands due to an ageing society and the increasing prevalence of chronic conditions. Lower-limb ulceration is a long-term, life-changing condition and leg ulcer management can be challenging for nursing staff. The Lindsay Leg Club model is a unique partnership between community nurses, members and the local community, which provides quality of care and empowerment for patients with leg ulcers, while also supporting and educating nursing staff. The Leg Club model works in accord with core themes of Government and NHS policy. Patient feedback on the Leg Club model is positive and the Leg Clubs provide a service to members which is well accepted by patients, yet is more economically efficient than the traditional district nursing practice of home visits. Lindsay Leg Clubs provide a valuable support service to the NHS in delivering improved quality of care while improving efficiency. PMID- 24156168 TI - Use of the ostomy baseplate in negative pressure wound therapy. AB - The advent of the negative pressure wound therapy (NPWT) has been a significant advancement in wound-healing practices. However, as the therapy has gained popularity and increased usage in all areas of the body, obstacles have arisen. In certain areas of the body, namely those with crevices and folds, or an abundance of apocrine glands, the application of NPWT can be problematic. This study presents a novel technique for the application of the NPWT in the treatment of wounds in areas difficult to achieve an appropriate vacuum seal. This method eliminates the traditional problems encountered when applying the NPWT to areas with clefts and folds by utilising an ostomy baseplate to provide a more secure and accessible surface area. The patient is an 84-year-old male with a category IV sacral decubitus ulcer. Traditional methods of NPWT application initially proved inadequate due to difficulty sustaining negative pressure; however, subsequent use of an ostomy baseplate with NPWT successfully secured a seal and allowed for wound healing. Our technique allows for the preservation of a proper seal near clefted areas, provides ease of application, reduces the burden of dressing changes and reduces cost, benefiting both the patient and health care providers. PMID- 24156169 TI - Implications of patient shared decision-making on wound care. AB - This article discusses the Government's drive to promote health professional and patient partnership working within healthcare, with a focus on enhancing wellbeing and how this relates to tissue viability. The literature has demonstrated how wounds impact negatively on a patient's sense of wellbeing. Assessing the impact of a wound on patient wellbeing is an essential as part of an holistic assessment process, but is even more important when the wound is chronic or recalcitrant to treatment. Scenarios are presented that illustrate how working in partnership with patients with chronic wounds can result in a therapeutic and concordant relationship when the patient's priorities of care are established, even if they differ from those of the health professionals caring for them. The article also discusses objective and subjective methods of measuring wellbeing as a means of demonstrating alternative clinical outcomes of nursing interventions within a healthcare culture where the need to meet wound healing targets still remains the norm. PMID- 24156170 TI - A fresh way to treat venous leg ulcers with measured compression. AB - The majority of lower leg ulceration has a venous component. Compression therapy is the "Gold Standard" to reverse venous hypertension and heal venous ulceration. Over recent years, new compression systems have evolved which means greater choice for patients. This describes venous disease and assessment and treatment choices. Case studies are also presented. PMID- 24156171 TI - UrgoClean: a new dressing for desloughing exuding wounds. AB - Wound debridement plays a key role in wound bed preparation and the healing of chronic wounds. A variety of techniques can be used to achieve debridement and autolytic debridement is frequently the clinician's first choice. This is aided by dressings including hydrogels and hydrocolloids, which provide the moist environment required for white blood cells to function. This product focus uses 12 case studies to examine the effectiveness of UrgoClean in wound debridement. PMID- 24156172 TI - Hartford's gun buy-back program: are we on target? AB - Gunbuy-backprograms have been proposed as away to remove unwanted firearms from circulation, but remain controversial because their ability to prevent firearm injuries remains unproven. The purpose of this study is to describe the demographics of individuals participating in Connecticut's gun buy-backprogram in the context of annual gun sales and the epidemiology of firearm violence in the state. Over four years the buy-back program collected 464 firearms, including 232 handguns. In contrast, 91,602 firearms were sold in Connecticut during 2009 alone. The incidence of gun-related deaths was unchanged in the two years following the inception of the buy-back program. Suicide was associated with older age (mean = 51 +/- 18years) and Caucasian race (n = 539, 90%). Homicide was associated with younger age (mean = 30 +/- 12 years) and minority race (n = 425, 81%). A gun buy-back program alone is not likely to produce a measurable decrease in firearm injuries and deaths. PMID- 24156173 TI - Documentation proficiency of patients who leave the emergency department against medical advice. AB - STUDY OBJECTIVE: This study describes the current documentation practices of health-care providers in the emergency department (ED) during the discharge against medical advice (AMA) process. METHODS: This retrospective cohort study reviewed health care provider documentation of adult patients who left an ED AMA in one year. Each encounter documentation was reviewed for eight medicolegal standards including the documentation of 1) the patient's capacity; 2) the signs and symptoms; 3) the extent and limitation of the evaluation; 4) the current treatment plan, risks, and benefits; 5) the risks and benefits of forgoing treatment; 6) the alternatives to suggested treatment; 7) the explicit statement made by the patient who left AMA, as well as the explicit documentation of what the patient was refusing; and 8) the follow-up care including discharge instructions. RESULTS: There were 81,038 eligible ED encounters with a total of 418 patients identified as having left AMA resulting in an AMA discharge rate of 0.52%. No single chart fulfilled all eight medicolegal standards. Minimal standards established by the Emergency Medical Treatment and Active Labor Act (EMTALA) were fulfilled in only 17 charts (4.1%). Despite general acceptance in the legal and policy literature on the need to ensure capacity to make decisions, only 22.0% of the charts documented that the patient had such capacity. CONCLUSIONS: This study revealed suboptimal documentation in AMA cases by clinicians at a single ED and confirms disparities between federal and academic quality (safety documentation requirements and actual provider documentation). PMID- 24156174 TI - Feasibility of an electronic stethoscope system for monitoring neonatal bowel sounds. AB - OBJECTIVE: Bowel dysfunction remains a major problem in neonates. Traditional auscultation of bowel sounds as a diagnostic aid in neonatal gastrointestinal complications is limited by skill and inability to document and reassess. Consequently, we built a unique prototype to investigate the feasibility of an electronic monitoring system for continuous assessment of bowel sounds. METHOD: We attained approval by the Institutional Review Boards for the investigational study to test our system. The system incorporated a prototype stethoscope head with a built-in microphone connected to a digital recorder. Recordings made over extended periods were evaluated for quality. We also considered the acoustic environment of the hospital, where the stethoscope was used. The stethoscope head was attached to the abdomen with a hydrogel patch designed especially for this purpose. We used the system to obtain recordings from eight healthy, full-term babies. A scoring system was used to determine loudness, clarity, and ease of recognition comparing it to the traditional stethoscope. The recording duration was initially two hours and was increased to a maximum of eight hours. RESULTS: Median duration of attachment was three hours (3.75, 2.68). Based on the scoring, the bowel sound recording was perceived to be as loud and clear in sound reproduction as a traditional stethoscope. We determined that room noise and other noises were significant forms of interference in the recordings, which at times prevented analysis. However, no sound quality drift was noted in the recordings and no patient discomfort was noted. Minimal erythema was observed over the fixation site which subsided within one hour. CONCLUSION: We demonstrated the long-term recording of infant bowel sounds. Our contributions included a prototype stethoscope head, which was affixed using a specially designed hydrogel adhesive patch. Such a recording can be reviewed and reassessed, which is new technology and an improvement over current practice. The use of this system should also, theoretically, reduce risk of infection. Based on our research we concluded that while automatic assessment of bowel sounds is feasible over an extended period, there will be times when analysis is not possible. One limitation is noise interference. Our larger goals include producing a meaningful vital sign to characterize bowel sounds that can be produced in real-time, as well as providing automatic control for patient feeding pumps. PMID- 24156175 TI - Mediastinal choriocarcinoma presenting with syncope. AB - Mediastinal choriocarcinomas are rare germ-cell tumors that occur almost exclusively in young males. These tumors grow rapidly, causing compression of mediastinal structures, and are usually associated with a poor prognosis. We report herein a unique case documenting syncope as initial clinical presentation of a mediastinal choriocarcinoma causing a superior vena cava (SVC) syndrome. The patient was treated with a standard chemotherapy triplet, with normalization of the tumor markers after the first chemotherapy cycle. He remains with no evidence of disease relapse 18 months later. Clinicians should consider the diagnosis of a mediastinal germ-cell tumor in a younger male patient presenting with a syncopal episode. PMID- 24156176 TI - The elusive diagnosis: recurrent benign lymphocytic meningitis. AB - BACKGROUND: Recurrent benign lymphocytic meningitis (RBLM) or Mollaretmeningitis is a rare disease with a prevalence of 1-2.2/100,000 population. It is characterized by recurrent episodes of aseptic meningitis. The diagnosis is made via history fitting Bruyn's criteria, and confirmatory detection of HSV-2 in cerebrospinal fluid (CSF) via polymerase chain reaction (PCR). CASE: A 59-year old female with a past medical history (PMH) of rheumatoid arthritis in remission and 11 prior episodes of aseptic meningitis presented with sudden and severe headache, photophobia, nausea, vomiting, and meningismus without focal findings. CSF analysis revealed aseptic meningitis with Herpes simplex 2 virus (HSV-2) present by PCR. CONCLUSION: RBLM remains a rare and elusive diagnosis but PCR technology has made it easier to diagnose. We present a 59-year-old female with classic features of RBLM, now suffering a 12th episode of aseptic meningitis. Heightened awareness of RBLM among clinicians may allow for an earlier diagnosis, reduced use of unnecessary antibiotics, shortened hospitalizations, and lower costs. PMID- 24156177 TI - Hemophagocytic lymphohistiocytosis associated with dermatomyositis: a case report. AB - INTRODUCTION: Hemophagocytic lymphohistiocytosis (HLH) is an uncommon life threatening disorder of pathologic immune activation. HLH associated with autoimmune disease is recognized although the mechanism remains uncertain. HLH associated with dermatomyositis is very rare and just as rarely reported in medical literature. A high index of suspicion is warranted in the setting of fever, cytopenias, abnormal liver function, and markedly elevated ferritin. CASE PRESENTATION: A 61-year-old male presented with proximal weakness, rash, periorbital edema, and elevated creatine kinase (CK). He also had pancytopenia, abnormal liver functions, and elevated ferritin. His bone marrow biopsy confirmed HLH. He was treated with high-dose dexamethasone and etoposide and seemed to have been recovering. Soon after his second infusion, he died of a complication from an unrelated endoscopic procedure. CONCLUSION: Early recognition of HLH is critical to the establishment of appropriate management and the prevention of fatal outcomes. We should be aware of the cardinal signs and symptoms of HLH and it should be considered in patients presenting with inflammatory myopathies associated with cytopenias, abnormal liver functions, and markedly elevated ferritin level. PMID- 24156178 TI - Thyrotoxic hypokalemic periodic paralysis: two case reports and a brief review of literature. AB - Thyrotoxic Hypokalemic Periodic Paralysis (THPP) is a rare complication of thyrotoxicosis and can sometimes be fatal. It needs early recognition for proper management and prevention of recurrences. Here we describe two cases presenting with acute onset of paresis, low potassium levels, low levels of thyroid stimulating hormones (TSH), and elevated thyroid hormone levels. PMID- 24156179 TI - Life-threatening hyperkalemia: a potentially lethal drug combination. AB - Hyperkalemia is commonly seen in the elderly and is occasionally fatal. Inadvertently combining potassium sparing medications can result in profound hyperkalemia which may result in cardiac dysrhythmias, especially in the setting of chronic kidney disease. An 85 year-old woman on a drug regimen of sotalol, valsartan, spironolactone, and trimethoprim-sulfamethoxazole presented to the emergency department with hypotension and bradycardia. Presumptive treatment for hyperkalemia was started based on her initial electrocardiogram. This diagnosis was later confirmed with a serum potassium value of 10.1 mmol/L. Following pharmacologic treatment, emergency hemodialysis was performed and the patient subsequently recovered. It is known that several drug classes can cause hyperkalemia, with elderly patients at a higher risk of developing this side effect. It is believed that this was a major contributor to the degree of hyperkalemia seen in this patient. PMID- 24156180 TI - Combating the increase in opioid misuse. PMID- 24156181 TI - The big shakeout. PMID- 24156182 TI - New hearts for old. 1963. PMID- 24156183 TI - I didn't go to provider school. PMID- 24156184 TI - Membership: it is not just analog anymore. PMID- 24156185 TI - Changes. PMID- 24156186 TI - Forum on health insurance exchanges. PMID- 24156187 TI - Hot issue. PMID- 24156188 TI - Psychometric validation of a music-based attention assessment: revised for patients with traumatic brain injury. AB - BACKGROUND: An estimated 1.5 to 2 million people sustain a traumatic brain injury (TBI) each year in the United States. Impairments in attention following TBI severely limit everyday functioning in a multifaceted manner. A precise assessment is critical in identifying the types of attention impairments and in recommending appropriate tasks to aid in attention rehabilitation. A Music-based Attention Assessment (MAA) was developed to fill this need and revised to reflect variations of attention ability that exist in the general population. OBJECTIVE: The purpose of the study was to investigate the theoretically-based constructs of the Music-based Attention Assessment-Revised (MAA-R) using a factorial approach and to examine item properties and test reliability in relation to the exploratively-derived factor constructs. METHODS: The MAA-R is a 54-item multiple choice, melodic contour identification test, designed to assess three different types of auditory attention including sustained, selective, and divided attention. The psychometric validation of the MAA-R was conducted with healthy adults (n = 165) and patients diagnosed with a moderate to severe TBI (n = 22). RESULTS: Exploratory factor analysis identified five factor constructs, including Sustained-Short, Sustained-Med to Long, Selective-Noise, Selective & Divided, and Divided-Long. After item elimination, the final 45-item MAA-R provided evidence of high internal consistency as computed by split-half reliability coefficients (r = .836) and Cronbach's alpha (alpha = .940). CONCLUSION: The aggregate findings suggest that the MAA-R is a valid and reliable measure that provides assessment information in regards to the different types of auditory attention deficits frequently observed in patients with TBI. Development and revision issues as well as the use of melodic contours in auditory attention assessment are discussed along with suggestions for future research. PMID- 24156189 TI - Effect of music therapy with emotional-approach coping on preprocedural anxiety in cardiac catheterization: a randomized controlled trial. AB - BACKGROUND: Individuals undergoing cardiac catheterization are likely to experience elevated anxiety periprocedurally, with highest anxiety levels occurring immediately prior to the procedure. Elevated anxiety has the potential to negatively impact these individuals psychologically and physiologically in ways that may influence the subsequent procedure. OBJECTIVE: This study evaluated the use of music therapy, with a specific emphasis on emotional-approach coping, immediately prior to cardiac catheterization to impact periprocedural outcomes. METHODS: The randomized, pretest/posttest control group design consisted of two experimental groups--the Music Therapy with Emotional-Approach Coping group [MT/EAC] (n = 13), and a talk-based Emotional-Approach Coping group (n = 14), compared with a standard care Control group (n = 10). RESULTS: MT/EAC led to improved positive affective states in adults awaiting elective cardiac catheterization, whereas a talk-based emphasis on emotional-approach coping or standard care did not. All groups demonstrated a significant overall decrease in negative affect. The MT/EAC group demonstrated a statistically significant, but not clinically significant, increase in systolic blood pressure most likely due to active engagement in music making. The MT/EAC group trended toward shortest procedure length and least amount of anxiolytic required during the procedure, while the EAC group trended toward least amount of analgesic required during the procedure, but these differences were not statistically significant. CONCLUSIONS: Actively engaging in a session of music therapy with an emphasis on emotional approach coping can improve the well-being of adults awaiting cardiac catheterization procedures. PMID- 24156190 TI - Mixed methods research in music therapy research. AB - BACKGROUND: Music therapists have an ethical and professional responsibility to provide the highest quality care possible to their patients. Much of the time, high quality care is guided by evidence-based practice standards that integrate the most current, available research in making decisions. Accordingly, music therapists need research that integrates multiple ways of knowing and forms of evidence. Mixed methods research holds great promise for facilitating such integration. At this time, there have not been any methodological articles published on mixed methods research in music therapy. OBJECTIVE: The purpose of this article is to introduce mixed methods research as an approach to address research questions relevant to music therapy practice. METHODS: This article describes the core characteristics of mixed methods research, considers paradigmatic issues related to this research approach, articulates major challenges in conducting mixed methods research, illustrates four basic designs, and provides criteria for evaluating the quality of mixed methods articles using examples of mixed methods research from the music therapy literature. CONCLUSIONS: Mixed methods research offers unique opportunities for strengthening the evidence base in music therapy. Recommendations are provided to ensure rigorous implementation of this research approach. PMID- 24156191 TI - Revitalising district nursing. PMID- 24156192 TI - Improving patient outcomes following a cancer diagnosis. AB - Cancer survival is improving, incidence is increasing and, for many, cancer is now being regarded as a long-term condition. Traditional followup services are no longer meeting the needs of patients, nor are they sustainable. Based on a long term conditions model, NHS Improvement is working with test sites to develop new pathways of cancer aftercare. This article describes the new self-managed pathways and how they support recovery and health and wellbeing. With half of people with a cancer diagnosis having at least one other chronic condition (Elliott et al, 2011) and cancer more commonly being a disease affecting the elderly, community nurses have a role to play in sustaining self-management and supporting the seamless and coordinated delivery of these pathways. They are well placed to reinforce messages given in secondary care, to sell the benefits of a healthy lifestyle, to be aware of the local amenities to signpost patients to, and to encourage their uptake and embed self-management. PMID- 24156193 TI - Intermittent self-catheterisation and catheter fixation. PMID- 24156194 TI - Community nurses' participation in palliative care research: the Dignity Care Pathway. AB - Evidence-based practice is a cornerstone of modern health care. Ongoing challenges have been identified in the strength of the evidence base in community palliative care nursing (Walshe and Luker, 2010). This paper discusses the participation of community nurses in a palliative care research project. The Dignity Care Pathway (DCP) is an evidence-based framework developed using a collaborative research approach with community nurses in Scotland. Collaborative research has been advocated as one way to facilitate integrated knowledge transfer and to address the research-practice gap. The aim of this paper is to discuss the participation of community nurses in a collaborative research project to implement a palliative care intervention in practice. The discussion will draw on findings from the third phase of the DCP multiphase research project. PMID- 24156195 TI - Measuring the clinical effectiveness of district nurses. AB - This paper helps district nurses to understand how and why existing quality measurement tools can be used as part of everyday practice to demonstrate clinical effectiveness. We consider how productivity has historically been used to crudely indicate district nurses' clinical effectiveness and why this is now being balanced alongside a range of more robust clinical effectiveness measurement tools. Evaluating clinical effectiveness and improving future care involves examining a number of indicators alongside each other. These include patient safety indicators, patient satisfaction, productivity measurement tools, and how effective clinicians are in supporting people to achieve their best clinical outcomes. PMID- 24156196 TI - Physical activity among the elderly in China: a qualitative study. AB - The benefits of physical activity are well known, but little is known about the views of elderly Chinese people regarding physical activity, and what factors affect this. This qualitative study aims to explore the experiences and perceptions of the elderly community regarding physical activity and to gain a better understanding of these. A qualitative study of 12 elderly Chinese people was undertaken using the Colaizzi phenomenological approach and using semi structured interviews to gather data. Three key themes emerged relating to current physical activity status, beliefs about physical activity and factors influencing physical activity. This study provides new knowledge about the elderly community's experiences and perceptions of physical activity. By understanding these, were may show that promoting active lifestyles and building physical activity into and around day-to-day activities are important strategies in increasing levels of activity. Furthermore, the need for appropriate activity facilities, available space, peer motivation and general social support could promote activity beliefs and subsequent adherence among the elderly community. PMID- 24156197 TI - National District Nurses Network. PMID- 24156198 TI - Good handwriting: a vital element of a district nurse's duty of care. AB - Written records and prescriptions continue to be common in district nursing and will continue to be until the Government achieves its goal of a fully digital NHS by 2018. The main issue with written records and prescriptions is the risk to patient safety caused by poor handwriting, resulting in illegible instructions and prescriptions. In this article the author considers the duty of district nurses to write clearly and highlights the financial and human cost of poor handwriting. PMID- 24156199 TI - Empathy in palliative care: a biological inheritance. PMID- 24156200 TI - Minimising hazards as a community nurse. PMID- 24156201 TI - The Jay Sensitivity Sensor Probe to evaluate tactile sensitivity. PMID- 24156202 TI - A diagnostic device to record dentin hypersensitivity. PMID- 24156203 TI - Clinical evaluation of the Jay Sensitivity Sensor Probe: a new microprocessor controlled instrument to evaluate dentin hypersensitivity. AB - PURPOSE: To compare the Jay Sensitivity Sensor Probe (Jay Probe), a new microprocessor-based, pre-calibrated instrument, with well accepted methods used to evaluate sensitivity, i.e. tactile response to the Yeaple Probe, air blast (Schiff scale), and patient responses by Visual Analog Score (VAS). METHODS: Jay Probe assessments were accomplished using several approaches. With a cohort of 12 subjects, two clinical examiners compared the repeatability of the Jay and Yeaple Probes. A second evaluation of both probes was conducted during two independent parallel design clinical studies each enrolling 100 adults with dentin hypersensitivity (DH). In each study, subjects were evaluated for DH responses after twice daily oral hygiene with a negative control fluoride dentifrice or a positive control dentifrice formulated with ingredients proven to reduce sensitivity, i.e. potassium nitrate or 8.0% arginine with calcium carbonate. Tactile evaluations by the Jay and Yeaple Probes were conducted at baseline and recall visits over the 8-week duration of each study. Also evaluated at each visit were responses to air blast and to patient reported DH assessment by VAS. RESULTS: Low inter-examiner variability with no significant differences between replicate measurements (P > 0.05) was observed with the Jay Probe. Consistent with results from previous studies, subjects assigned dentifrices formulated with potassium nitrate or 8% arginine/calcium carbonate demonstrated improvements in Yeaple, air blast and VAS responses in comparison to those assigned the fluoride dentifrice (P < 0.05). Jay Probe responses correlated significantly with all other sensitivity measures (P < 0.05). Differences between these treatments were observed at all post-treatment evaluations using these methods. PMID- 24156204 TI - Clinical assessment of a new dentifrice with 8% arginine and calcium carbonate on dentin hypersensitivity in an Indian population using a new measuring device: the Jay Sensitivity Sensor Probe. AB - PURPOSE: To compare a new tactile hypersensitivity testing device [Jay Sensitivity Sensor (Jay) Probe] to three currently available methods of hypersensitivity testing: tactile hypersensitivity by the Yeaple probe, air blast (Schiff's Scale), and their overall hypersensitivity in the absence of any stimuli using the visual analog scores (VAS) during a clinical trial comparing the desensitizing potential of a dentifrice containing 8% arginine, calcium carbonate, and 1,000 ppm MFP (Colgate Sensitive Pro-Relief; Test) against a commercially available fluoride dentifrice (Colgate Cibaca; Negative control). METHODS: This 8-week clinical study enrolled 100 adults with dentin hypersensitivity (DH) to evaluate the desensitizing potential of a dentifrice with 8% arginine, calcium carbonate, and 1000 ppm MFP against a commercially available fluoride dentifrice, on an Indian population. This study included a new DH testing device (Jay Probe) in addition to the current three methods of dentin hypersensitivity testing. Subjects were randomly assigned a dentifrice and were evaluated for DH after 2-week, 4-week and 8-week use of assigned dentifrice. RESULTS: At the end of the 8-week period, the results showed a significant improvement in dentin hypersensitivity in the Test group as compared to the Negative control group. The mean tactile hypersensitivity scores at the 8-week examinations were 39.67 and 38.33 by the Yeaple and Jay Probes, respectively, for the Test group and 15.72 and 15.00 for the Negative control group. These observations were consistent with the other hypersensitivity examinations by air blast and VAS. PMID- 24156205 TI - Measurement of dentin hypersensitivity with the Jay Sensitivity Sensor Probe and the Yeaple probe to compare relief from dentin hypersensitivity by dentifrices. AB - PURPOSE: To compare relief from dentin hypersensitivity (DH) after use of dentifrices formulated with potassium nitrate or fluoride. For the study, DH evaluations were conducted with the Jay Sensitivity Sensor Probe (Jay Probe), a novel tactile hypersensitivity instrument, in conjunction with three other DH methods, i.e. Yeaple probe (tactile), air blast, and the Visual Analog Scale (VAS). METHODS: Adults (n = 100) who presented two teeth with DH and met study criteria were enrolled for this double-blind, randomized, parallel, controlled clinical trial conducted in an outpatient setting. DH evaluations at baseline were conducted by the tactile, air blast, and VAS methods. Subjects were randomly assigned a dentifrice formulated with 5% potassium nitrate and 1,000 ppm fluoride (as sodium monofluorophosphate) (Colgate Sensitive toothpaste; Test) or a commercially available fluoride dentifrice with 1,000 ppm fluoride as sodium monofluorophosphate (Colgate Cibaca toothpaste; Negative control). Subjects were recalled for DH evaluations after 4 and 8 weeks of product use. RESULTS: 85 subjects completed the entire study with evaluable results. Both treatments resulted in significant reductions in DH from baseline to all recall visits. In comparison to the Negative control, subjects in the Test group demonstrated significantly greater reductions for all DH evaluations at both 4 and 8 weeks (P < 0.05). Average tactile DH scores at week 8 for the Test and Negative control groups were 36.25 and 15.24 with the Yeaple probe and 35 and 12.43 with the Jay probe. Correspondingly, subjects in the Test group demonstrated significantly greater reductions in air blast and VAS responses for DH than those in the Negative control group (P < 0.05). PMID- 24156206 TI - A comparison of dentifrices for clinical relief from dentin hypersensitivity using the Jay Sensitivity Sensor Probe. AB - PURPOSE: To evaluate the clinical relief from dentin hypersensitivity among subjects provided with a dentifrice formulated with 8% arginine, calcium carbonate and 1,000 ppm fluoride [sodium monofluorophosphate (MFP)] in comparison to those issued a commercially available dentifrice containing 1,000 ppm fluoride [as sodium monofluorophosphate (MFP)]. Clinical evaluations for hypersensitivity were performed with a novel tactile hypersensitivity measuring instrument--the Jay Sensitivity Sensor (Jay) Probe--in conjunction with evaporative triggers by air blast (Schiff scale) and Visual Analog Scores (VAS). METHODS: Qualified adults from the Mangalore, India area who presented two teeth with dentin hypersensitivity were enrolled for this double-blind, randomized, parallel, controlled clinical trial conducted in an outpatient clinical setting. At baseline, dentin hypersensitivity was evaluated by the Jay Probe (tactile), air blast and VAS methods. Subjects were randomly issued a study dentifrice and instructed to brush their teeth for 1 minute twice daily with the provided dentifrice. Clinical evaluations for hypersensitivity were repeated after 2, 4 and 8 weeks of product use. RESULTS: 86 subjects (35 males and 51 females) complied with the study protocol and completed the entire study. At each recall visit, both treatment groups demonstrated significant reductions in dentin hypersensitivity from their corresponding baselines (P < 0.05). Subjects assigned the 8% arginine, calcium carbonate and 1,000 ppm fluoride dentifrice demonstrated statistically significant reductions in responses to tactile stimuli, air blast, and VAS responses in comparison to those using the dentifrice containing 1,000 ppm fluoride after 2, 4, and 8 weeks, respectively. PMID- 24156207 TI - Improving regulation. PMID- 24156208 TI - Reasons for pride. Interview by Paul O'Grady. PMID- 24156209 TI - An analysis of the attitudes of dental patients attending general dental practice in Galway. AB - AIM: To describe the patterns of dental attendance and attitudes towards tooth loss of general dental practice patients in Galway. OBJECTIVES: 1. To determine the pattern of adult dental attendance in general practices in Galway; and, 2. To examine the oral health attitudes of these patients. METHOD: Questionnaires were distributed to 311 consecutive adult patients in the waiting rooms of ten general dental practices in Galway, which were randomly selected from the telephone directory. RESULTS: A total of 254 of the 311 questionnaires distributed were fully completed, returned and included in the results, giving a response rate of 81.7%. A total of 59% of dentate participants attended their dentist for annual or biannual examinations compared to 23% of edentate patients. Some 10.5% of medical card holders and 0.5% of non-medical card holders were edentulous. CONCLUSIONS: The data from the survey indicated that medical card holders in Galway were more likely to be edentulous than nonmedical card holders. Edentate patients were less likely to be regular dental attenders than dentate patients. PMID- 24156210 TI - Effect of phase I periodontal therapy on pro-coagulant state in chronic periodontitis patients--a clinical and haematological study. AB - STATEMENT OF THE PROBLEM: The increase in white blood cell count (WBC) and platelet count due to systemic inflammation and infection is considered a risk factor for cardiovascular diseases. These parameters increase in periodontal disease. A decrease in WBC and platelet counts by periodontal therapy may decrease the risk for cardiovascular disease. PURPOSE OF THE STUDY: The present study is a treatment intervention model to investigate the effect of non-surgical periodontal therapy on total leucocyte count (TLC), differential leucocyte count (DLC) and platelet count in patients with chronic periodontitis. MATERIALS AND METHODS: Thirty systemically healthy patients were included in the study. Probing pocket depth (PPD), clinical attachment loss (CAL), bleeding on probing (BOP), TLC, DLC, platelet count, bleeding time (BT) and clotting time (CT) were evaluated at baseline and at two weeks after phase I therapy. RESULTS: A statistically highly significant decrease in the percentage of sites exhibiting BOP was observed, i.e., from 78.1% at baseline to 18.1% two weeks postoperatively (p = 0.000). There was also a statistically significant decrease in TLC from 7595/mm3 at baseline to 6690/mm3 two weeks following phase I therapy (p = 0.02). There was also a statistically highly significant decrease in platelet count from 2.1 lac/mm3 preoperatively to 1.9 lac/mm3 at two weeks postoperatively (p = 0.003). CONCLUSION: The present study depicts the importance of periodontal therapy to reduce the TLC and platelet count, thereby possibly decreasing the risk for the development of cardiovascular disease by lowering the established risk factors for periodontal atherosclerosis. PMID- 24156211 TI - Commonly used topical oral wound dressing materials in dental and surgical practice--a literature review. AB - A small number of medicaments are used in oral and maxillofacial surgery to dress wounds, relieve pain, prevent infection and promote healing. While these materials are routinely used, their constituents, uses and effects on oral tissues are rarely discussed. This literature review provides an overview of the constituents, uses and effects of the common materials--oxidised regenerated cellulose, Whitehead's varnish, Carnoy's solution, bismuth iodoform paraffin paste (BIPP), zinc oxide eugenol (ZOE) and Alvogyl. PMID- 24156212 TI - Practice made perfect. PMID- 24156213 TI - Safety and sample adequacy of renal transplant surveillance biopsies. AB - PURPOSE: To report on the safety and adequacy of surveillance biopsy for detecting subclinical lesions in clinically stable renal grafts. MATERIALS AND METHODS: We established an in-patient surveillance biopsy program with the elective performance of a renal transplant biopsy during the first year after renal transplantation. All biopsies in our centre were performed or supervised by the same operator. Patients were admitted to the hospital the day of biopsy and were discharged after 24h of observation. All patients were biopsied in supine position, using a 16-gauge needle with a spring-loaded gun (Bard) under real-time ultrasound guidance. Complication rates were retrospectively scored using the patients' charts and blood counts before and after biopsy. Major complications were defined as those requiring an intervention for resolution, a transfusion of blood products or an invasive procedure (angiography or surgery), and those that led to acute renal obstruction or failure, septicaemia, graft loss or death. In all other cases complications were considered minor. An adequate biopsy was defined as the presence of 7 or more glomeruli and at least one artery in the biopsy specimen. RESULTS: We performed 282 surveillance biopsies in 248 patients between January 2006 and December 2011. None of the complications were major. We observed 6% minor complications (n = 17). 5.6% (n = 16) of the complications were related to bleeding, with macroscopic haematuria as the most common condition (n = 10; 3.5%), followed by pain (n = 6; 2.1%) eighter due to a perinephric hematoma (n = 5) or a subcutaneous hematoma (n = 1). The biopsies contained a median number of 9 glomeruli (range 0-39) with 70% of biopsies containing at least 7 glomeruli and one artery. CONCLUSION: The procedure for taking surveillance biopsies was proven to be safe. There were no major complications and only rare minor complications. The majority of the samples were adequate for histological examination. PMID- 24156214 TI - Low yield by molecular detection of Chlamydophila pneumoniae in respiratory samples in Belgium questioning its etiological role in respiratory tract infections. AB - The actual burden of respiratory infections due to Chlamydophila pneumoniae is difficult to assess due to the major differences in positivity rates between PCR- and serology-based methods. The aim of the current study was to objectively analyse the yield of PCRs for the detection of C. pneumoniae in respiratory samples and to evaluate the additional value of performing laboratory diagnosis for C. pneumoniae in a setting of respiratory infection. The data based on routine analysis of respiratory samples with request for C. pneumoniae detection were collected from 4 large Belgian hospitals during 2 consecutive years. In total 3560 respiratory samples have been analysed and overall only 7 samples (0.2%) were found positive. Based on these observations, the critical evaluation of the actual role of C. pneumoniae in the etiology of lower respiratory infections and consequently of the extensive use of diagnostic tools for the detection of C. pneumoniae is needed. PMID- 24156215 TI - Cardiovascular mechanisms and consequences of obstructive sleep apnoea. AB - Obstructive sleep apnoea (OSA) is considered as a risk factor for the development of arterial hypertension, coronary artery disease (CAD), myocardial infarction and stroke. These clinical manifestations are the consequences of elevated sympathetic activity, cardiovascular variability, intrathoracic pressure changes, inflammation, oxidative stress, endothelial dysfunction, insulin resistance and thrombosis provoked by OSA. As a result, OSA is often present in patients with cardiovascular disease (CVD) and the increased prevalence of CVD in OSA population raises both cardiovascular morbidity and mortality and the demand of healthcare resources. Observational cohort studies indicate that untreated patients with OSA have an increased risk of fatal and non-fatal cardiovascular events, an increased risk of sudden cardiac death during the sleeping hours and a higher risk of stroke or death from any cause. Continuous positive airway pressure (CPAP) and oral appliance therapy are the two treatments for OSA whose effects on cardiovascular endpoints have been assessed in randomised trials. There is increasing evidence that adequate CPAP therapy leads to a significant reduction in cardiovascular morbidity. PMID- 24156216 TI - Stimulation of the i.v. to oral switch of bioavailable drugs by phone calls in a Belgian tertiary care hospital. AB - INTRODUCTION: Early switch from intravenous to oral administration of drugs with an almost complete oral bioavailability, can have important benefits. Drugs with almost complete bioavailability, like clindamycin (Dalacin), levofloxacin (Tavanic) and paracetamol (Perfusalgan/Dafalgan), are very suitable for an early intravenous to oral switch in patients whose gastrointestinal absorption is intact. The aim of this study was to investigate the impact of direct phone contact between pharmacist and clinician on the intravenous to oral switch and to evaluate the reasons, mentioned by clinicians, that prevented an early switch. MATERIALS & METHODS: The project was initiated in a Belgian 1900-bed tertiary care hospital with a poster, communicated through the hospital's intranet and spread to every hospital ward. During one month, all prescriptions for intravenous clindamycin, levofloxacin and paracetamol were evaluated. The treating clinician was contacted by phone to evaluate if an intravenous to oral switch was possible. RESULTS: Clinicians were contacted concerning 377 patients. For 58.7% of patients, the switch from intravenous to oral administration was made. In case of refusal, several reasons were mentioned by the clinician, some more appropriate than others. CONCLUSION: Despite several appropriate reasons preventing an early intravenous to oral switch, there are still some aberrant opinions circulating in the hospital environment. Active interventions of pharmacists to stimulate intravenous to oral switch, using phone contact with the treating clinicians, can possibly be an adequate technique to stimulate intravenous to oral switch, but this needs to be further optimized. PMID- 24156217 TI - Primary antimicrobial resistance of Helicobacter pylori in Belgium. AB - The increasing antimicrobial resistance of Helicobacter pylori jeopardizes the efficiency of the classical eradication triple therapy. In this article we assessed the primary resistance rates of Helicobacter pylori to the commonly used antibiotics for eradication in the area of Brussels and determined prospectively, through a questionnaire, the possible risk factors for resistance. Gastric biopsies were taken for histology and culture in all adult patients in whom Helicobacter pylori was searched from February 2009 to April 2010 at the UZBrussel hospital. Clinical and demographic data were collected through a questionnaire. Histology was positive in 222 out of 507 patients tested (43.7%). Culture was successful in 189 patients with a positive histology (85.1%), 4 patients had a positive culture with a negative histology. Resistance to clarithromycin, metronidazole, ciprofloxacin, and amoxicillin was tested. Primary resistance rates were 13.3% for clarithromycin, 26.1% for metronidazole, 23.9% for ciprofloxacin, 0.8% for amoxicillin. Dual resistance to claritromycin and metronidazole was seen in 3.9%, triple resistance (claritromycin, metronidazole and ciprofloxacin) in 1.7% and resistance to the 4 antibiotics in 0.6% of patients. We conclude that there is a decreasing resistance for clarithromycin, metronidazole resistance is stable and rapidly increasing ciprofloxacin resistance. Resistance to any of the tested antibiotics was not associated with origin, age, gender, number of siblings, level of education or status (p > 0.05). PMID- 24156218 TI - Detection of Giardia lamblia, Cryptosporidium spp. and Entamoeba histolytica in clinical stool samples by using multiplex real-time PCR after automated DNA isolation. AB - Diagnosis of intestinal parasites in stool samples is generally still carried out by microscopy; however, this technique is known to suffer from a low sensitivity and is unable to discriminate between certain protozoa. In order to overcome these limitations, a real-time multiplex PCR was evaluated as an alternative approach for diagnosing Giardia lamblia, Cryptosporidium spp. and Entamoeba histolytica in stool samples.Therefore, a total of 631 faecal samples were analysed both by microscopy as well as by real-time PCR following automated DNA extraction. Results showed that real-time PCR exhibited sensitivity and specificity of both 100%, whereas traditional microscopy exhibited sensitivity and specificity of 37.5% and 99.8% respectively. As real-time PCR provides simple, sensitive and specific detection of these three important pathogenic protozoan parasites, this technique, rather than microscopy, has become our diagnostic method of choice for the detection of enteric protozoan parasites for the majority of patients. PMID- 24156219 TI - Mycotic thoracic aortic aneurysm: review of the diagnostic and therapeutic options. AB - Along with greater life-expectancy, the prevalence of aortic aneurysm and its infected complicated variant increases. We present the case of a mycotic aortic aneurysm. Mycotic aneurysms represent only between 0.7% and 2.6% of all aortic aneurysms. It is a highly lethal variant of the classical aortic aneurysm in which death supervenes in all cases that are left untreated. Up to 60% of mycotic aortic aneurysms may present as ruptured. Time from admission to diagnosis of mycotic thoracic aortic aneurysm ranges from 1 to 4 days and the time from diagnosis to the necessity of surgery 1 to 11 days. Adequate knowledge about the diagnostic and therapeutic options is mandatory improve survival and will be reviewed in this article. PMID- 24156220 TI - Hospital-acquired infections in Belgian acute-care hospitals: financial burden of disease and potential cost savings. AB - INTRODUCTION: Hospital Acquired Infections (HAIs) are considered to be one of the most serious patient safety issues in healthcare today. It has been shown that HAIs contribute significantly not only to morbidity and mortality, but also to excessive costs for the health care system and for hospitalized patients. Since possibilities of prevention and control exist, hospital quality can be improved while simultaneously the cost of care is reduced. The objectives of this study were to examine the prevalence and the excess costs associated with HAIs. METHODS: A retrospective observational study was performed to estimate costs associated with hospital-acquired infections in Belgian hospitals, both in procedural admissions and in medical admissions. Hospital, diagnosis-related group, age and gender were used as matching factors to compare stays associated with HAIs and stays without HAIs. Data were obtained from the Minimum Basic Data Set 2008 used by Belgian hospitals to register case-mix data for each admission to obtain reimbursement from the authorities. Data included information from 45 hospitals representing 16,141 beds and 2,467,698 patient stays. Using the 2008 national feedback programme of the Belgian government, cost data were collected (prolonged length of stay, additional pharmaceuticals and procedures) and subsequently linked to the data set. By means of a sensitivity analysis we estimated potential monetary savings when a reduction in the incidence of HAIs in hospitals having a higher rate of hospital-acquired infections in comparison to other hospitals would be realized. RESULTS: In our sample 5.9% of the hospital stays were associated with a hospital-acquired infection. In the procedural admission subset this was the case for 4.7% of the hospital stays. The additional mean cost of the hospital-acquired infection was Euro 2,576 for all stays (P < 0.001) and Euro 3,776 for procedural stays (P < 0.001). The total burden of disease in Belgium is estimated at Euro 533,076,110 for all admissions and Euro 235,667,880 for the subset of procedural admissions. The excess length of stay varied between hospitals from 2.52 up to 8.06 days (Md 4.58, SD 1.01), representing an associated cost of Euro 355,060,174 (66.61% of the total cost). The cost of additional medical procedures and additional pharmaceutical products was estimated at Euro 62,864,544 (11.97%) and Euro 115,151,939 (21.60%) respectively. Overall, our results showed that considerable variability between hospitals regarding the incidence of HAIs (3.77-9.78%) for all hospital stays is present, indicating a potential for improvement. We provide a full overview of the potential monetary savings when reductions in HAIs are realized by applying different thresholds. For instance, if all Belgian hospitals having a higher rate of hospital-acquired infections improve their rate to the level of the hospital corresponding to percentile 75 (= 7.5% HAL) savings would be Euro 17,799,326. CONCLUSION: HALs are associated with important additional healthcare costs. Although not all hospital-acquired infections can be prevented, an opportunity to increase cost-effectiveness of hospital care delivery presents itself. This study is the first to estimate the annual economic burden of HALs for Belgium at a national level, incorporating all associated hospital costs. Apart from the fact that the cost of prolonged length of stay is of major importance, we have also shown that the cost of additional procedures and pharmaceutical products cannot be neglected when estimating the financial burden of HAIs. PMID- 24156221 TI - Sensitization to the mammalian oligosaccharide galactose-alpha-1,3-galactose (alpha-gal): experience in a Flemish case series. AB - BACKGROUND: Recent observations have disclosed that the galactose-alpha (1,3) galactose (alpha-gal) moiety of non-primate glycoproteins can constitute a target for meat allergy. OBJECTIVE: To describe adults with allergic reactions to mammalian meat, dairy products and gelatin. To investigate whether patients could demonstrate sensitization to activated recombinant human coagulation factor VII ectapog alpha that is produced in baby hamster kidney cells. METHODS: Ten adults with mammalian meat, dairy products and gelatin allergies were examined using quantification of specific IgE and/or skin prick test for red meat, milk, milk components, gelatin, cetuximab and eptacog alpha. RESULTS: Most patients demonstrate quite typical clinical histories and serological profiles, with anti alpha-gal titers varying from less than 1% to over 25% of total serum IgE. All patients demonstrate negative sIgE for gelatin, except the patient with a genuine gelatin allergy. All patients also demonstrated a negative sIgE to recombinant milk components casein, lactalbumin and lactoglobulin. Specific IgE to eptacog was positive in 5 out of the 9 patients sensitized to alpha-gal and none of the 10 control individuals. CONCLUSION: This series confirms the importance of the alpha-gal carbohydrate moiety as a potential target for allergy to mammalian meat, dairy products and gelatin (oral, topical or parenteral) in a Flemish population of meat allergic adults. It also confirms in vitro tests to mammalian meat generally to be more reliable than mammalian meat skin tests, but that diagnosis can benefit from skin testing with cetuximab. Specific IgE to gelatin is far too insensitive to diagnose alphaa-gal related gelatin allergy. IgE binding studies indicate a potential risk of alpha-gal-containing human recombinant proteins produced in mammalians. PMID- 24156222 TI - Identification of coryneform Actinomyces neuii by MALDI-TOF MS: 5 case reports and review of literature. AB - OBJECTIVES: We describe five cases of Actinomyces neuii, isolated from different clinical specimens over a period of five months (from June to October 2011), followed by a review of literature on infections with this micro-organism. METHODS: All Actinomyces neuii strains were cultured or subcultured on horse blood agar. Identification took place using matrix-assisted laser desorption ionisation time-of-flight mass spectrometry (MALDI-TOF MS). Identification was confirmed by conventional biochemical tests and API Coryne test strips (BioMerieux SA). Susceptibility testing was performed on Mueller-Hinton agar supplemented with horse blood, using E-tests (BioMerieux SA). The minimal inhibitory concentrations were determined after 24 and 48 hours of incubation in a 5% CO2 environment. RESULTS: Isolation of this micro-organism was associated with abscesses in two patients and chronic osteomyelitis in one patient. The remaining two patients had positive blood cultures which grew Actinomyces neuii, either as contamination or as catheter-related infection. All Actinomyces neuii identifications were obtained by MALDI-TOF MS and were confirmed by conventional biochemical and API Coryne tests. Identification of one isolate was also confirmed by 16S rRNA sequencing. All strains were susceptible to penicillin. One strain showed heteroresistance for macrolides and lincosamides. Minimal inhibitory concentrations were more reliable and easier to read after 48 hours of incubation, as compared to 24 hours. CONCLUSION: MALDI-TOF MS analysis allows rapid and reliable identification of Actinomyces neuii, even at subspecies level. PMID- 24156223 TI - Post-streptococcal glomerulonephritis: not an extinct disease! AB - We present the case of a 29-year-old type 1 diabetic patient with the diagnosis of acute post-streptococcal glomerulonephritis. The incidence of this textbook example of acute glomerulonephritis has dropped dramatically in the developed world during the past decades due to the more widespread use of antibiotics. However, the present case illustrates that it is not an extinct disease and that clinicians should be aware of this entity. Particular attention is needed for the fact that the clinical context in which the disease occurs may be different from the classical "post-angina" presentation. PMID- 24156224 TI - Relapse of asthma after surgical treatment of Cushing's syndrome. AB - Endogenous overproduction of glucocorticoids may mask the clinical course of some inflammatory/ autoimmune disorders. In the present paper, we report a man with a history of asthma, which spontaneously remitted after 20 years of duration. Several years later, he was diagnosed with Cushing's syndrome of pituitary origin and underwent transsphenoidal microsurgery of an ACTH-producing pituitary adenoma. Shortly after tumour removal, he developed a severe asthmatic attack requiring hospitalisation and intensive treatment. We conclude that patients with Cushing's syndrome and coexisting inflammatory/autoimmune disorders should be closely supervised after normalisation of cortisol production for exacerbation of the associated disease and would eventually benefit from glucocorticoid treatment. PMID- 24156225 TI - Meningitis and splenic infarction due to disseminated Mycobacterium genavense infection in an HIV patient. Case report and review of the literature. AB - We report a case of disseminated infection with Mycobacterium genavense in a 58 year old HIV positive woman presenting with fever, diarrhea, abdominal pain and weight loss. She had a striking hepatosplenomegaly, abdominal lymphadenopathy, anaemia and thrombopenia. Direct smears and cultures of blood, stool, sputum, urine and bone marrow were negative for common and opportunistic microorganisms. Splenectomy revealed numerous acid fast bacill. Lumbar puncture also showed acid fast bacilli at direct examination. Specific PCR and 16s rRNA gene sequencing identified M. genavense. The outcome was fatal despite antimycobacterial therapy. M. genavense must be included in the differential diagnosis of fever, weight loss, lymphadenopathy and splenomegaly in immunocompromised patients. Prompt diagnosis is based on molecular biology methods. Empirical therapy, using at least three antimycobacterial agents, including clarithromycin should be introduced in case of high clinical suspicion. PMID- 24156226 TI - Azathioprine hypersensitivity syndrome: a case report. AB - We report here the case of a 51-year-old man presenting to the Emergency Department with a febrile cutaneous eruption with diffuse arthralgia 10 days after the onset of azathioprine therapy. The clinical examination did not reveal any inflammatory syndrome and the results of all bacteriological tests were negative. A skin biopsy was performed, which revealed a granulocytary pustula with superficial dermal oedema and a neutrophil infiltration without sign of vasculitis. A side effect of azathioprine was suspected, and treatment was discontinued. Fortunately, the patient recovered within a few days. Azathioprine hypersensitivity syndrome is a rare side effect of azathioprine. Hypersensitivity syndrome is an idiosyncratic, non-IgE-mediated reaction that appears to be unrelated to thiopurine methyltransferase levels. Diagnosis is mainly clinical and requires an exclusion of other processes. The only treatment option available is to stop azathioprine intake. PMID- 24156227 TI - A 75-year-old missionary with fever, splenomegaly and pancytopenia. AB - We present a case of hyperreactive malarial splenomegaly, a disease which is exceptional in Caucasian people, but which is expected to become more important since the increasing number of travelling to tropical areas. It is the chronic stage of an abnormal long-term stimulation of the immune system secondary to plasmodial infection. Diagnostic criteria include long-term stay in an endemic zone, large splenomegaly and overproduction of both IgM and IgG antibodies. The disease can be treated by a short-term antimalarial therapy as long as the patient resides out of a malarial endemic country. PMID- 24156228 TI - D-lactic acidosis: an unusual cause of encephalopathy in a patient with short bowel syndrome. AB - A 24-year-old woman with a short bowel syndrome following post-ischemic small bowel resection, developed several episodes of lethargy, echolalia and ataxia. D lactic acidosis was identified as the cause of neurological disturbances. This infrequent disorder can be precipitated by intake of a large amount of sugars, in patients with short bowel syndrome. It should be suspected in the presence of metabolic acidosis with increased anion gap and a normal level of L-lactic acid. The diagnosis relies on the specific dosage of D-lactic stereoisomer. Proper management involves rehydration, diet adaptation and oral administration of poorly absorbed antibiotics in order to modify the colonic flora responsible for D-lactic production. PMID- 24156229 TI - Anticonvulsant hypersensitivity syndrome mimicking a viral illness with skin rash: a case report. AB - Anticonvulsant hypersensitivity syndrome (ACHSS) is rare and defined by a group of systemic symptoms: a typical clinical triad with skin rash, high fever and lymphadenopathy, with or without multiple organ dysfunctions. Its variable presentation renders diagnosis particularly difficult yet important, as delayed diagnosis can lead to serious complications. We describe a 31-year-old woman sent to the emergency department with symptoms of high fever, peripheral lymphadenopathy, arthralgia, nausea, vomiting and a vesiculobullous eruption resembling measles. First diagnostic hypothesis was that of a viral illness. However, thorough second anamnesis pointed towards a possible drug aetiology, as the patient had been prescribed lamotrigine 8 days prior to admission. Blood analysis showed an inflammatory syndrome, thrombocytopenia and moderate lymphopenia. A few days later, results indicated old immunisation for measles. Skin biopsy revealed dermal inflammation with presence of hypereosinophilia, thereby confirming ACHSS. It is important to recognise and treat this rare reaction to anticonvulsants as early as possible in order to prevent its potentially life-threatening complications. PMID- 24156230 TI - Unexpected urinary Schistosoma infection in a Belgian travel group returning from Malawi. AB - Urinary schistosomiasis, caused by Schistosoma haematobium, is a prevalent parasitic infection in certain areas of Africa and the Middle East. Humans can be infected by cercariae when they are in contact with contaminated freshwater. The adult worms reside in the veins of the vesical and pelvis plexuses. The urinary bladder, the seminal vesicles and the lower ends of the ureters are the most commonly affected organs. In this case report, we describe an unrecognised case of urinary schistosomiasis in a woman who was part of a Belgian travel group; two other patients out of eight were also infected. In Belgium, the number of reported cases of S. haematobium infection is limited. The aim of this report is to emphasize this parasitic infection should be suspected in patients who travel to endemic areas. PMID- 24156231 TI - Are anti-vitamin K drugs contraindicated with cetuximab during head-and-neck cancer concomitant radiotherapy? AB - Two cases of severe skin reactions to cetuximab and concomitant radiation therapy are reported in patients treated for locally advanced head-and-neck squamous cell carcinoma and concurrently treated with an antivitamin K drug for cardiovascular diseases. The role of vitamin K in the epidermal growth factor/epidermal growth factor receptor pathway is discussed. A plea for a specific registry is entered. PMID- 24156232 TI - A patient with interstitial lung disease secondary to dermatomyositis: a case report and review of the literature. AB - We describe the case of a man with known dermatomyositis who presented with a dry cough and who early after admission rapidly evolved to respiratory insufficiency. Based on pathological and radiological findings, the diagnosis of diffuse alveolar damage was made. Postmortem examination also revealed infection with yeast, Torulopsis glabrata. Polymyositis (PM) and dermatomyositis (DM) are both auto-immune diseases, which are characterised by the presence of auto-antibodies and tissue-inflammation, mainly involving the muscles. Patients with PM/DM may have pulmonary complications, often responsible for higher morbidity and mortality. Interstitial lung disease can present itself in different shapes and forms (bronchiolitis obliterans organising pneumonia, non-specific organising pneumonia, usual interstitial pneumonia, acute interstitial pneumonia) and the diagnosis is made based on the combination of pathological examination and radiological findings. PMID- 24156233 TI - A newly diagnosed Wegener's disease as the underlying cause for a disseminated coccidioidomycosis. AB - In most cases coccidioidomycosis presents as a benign mildly severe respiratory disease with a benign course and spontaneous resolution. Rarely dissemination can lead to complications. We believe this is the first published case of a patient with a disseminated coccidioidomycosis, as shown on a urinary sample, in association with Wegener's disease. It was a challenge to diagnose and consecutively treat the patient as therapies seem to be conflictual. This case illustrates how migration, changing habits and attitudes, travelling, changing geo-ecological circumstances can lead to a change in medical environment. It is therefore essential that the microbiologist becomes a clinical microbiologist who communicates intensively with his fellow clinicians. PMID- 24156234 TI - 'Pneumatosis' of the bladder in an elderly patient. PMID- 24156235 TI - Acute coronary syndrome after methadone overdose in an opiate-naive patient. PMID- 24156236 TI - Effect of charged amino acid side chain length at non-hydrogen bonded strand positions on beta-hairpin stability. AB - beta-Sheets have been implicated in various neurological disorders, and ~20% of protein residues adopt a sheet conformation. Therefore, studies on the structural origin of sheet stability can provide fundamental knowledge with potential biomedical applications. Oppositely charged amino acids are frequently observed across one another in antiparallel beta-sheets. Interestingly, the side chains of natural charged amino acids Asp, Glu, Arg, Lys have different numbers of hydrophobic methylenes linking the backbone to the hydrophilic charged functionalities. To explore the inherent effect of charged amino acid side chain length on antiparallel sheets, the stability of a designed hairpin motif containing charged amino acids with varying side chain lengths at non-hydrogen bonded positions was studied. Peptides with the guest position on the N-terminal strand and the C-terminal strand were investigated by NMR methods. The charged amino acids (Xaa) included negatively charged residues with a carboxylate group (Asp, Glu, Aad in increasing length), positively charged residues with an ammonium group (Dap, Dab, Orn, Lys in increasing length), and positively charged residues with a guanidinium group (Agp, Agb, Arg, Agh in increasing length). The fraction folded and folding free energy for each peptide were derived from the chemical shift deviation data. The stability of the peptides with the charged residues at the N-terminal guest position followed the trends: Asp > Glu > Aad, Dap < Dab < Orn ~ Lys, and Agb < Arg < Agh < Agp. The stability of the peptides with the charged residues at the C-terminal guest position followed the trends: Asp < Glu < Aad, Dap ~ Dab < Orn ~ Lys, and Agb < Arg ~ Agp < Agh. These trends were rationalized by thermodynamic sheet propensity and cross-strand interactions. PMID- 24156237 TI - Sleep apnea is associated with subclinical myocardial injury in the community. The ARIC-SHHS study. AB - RATIONALE: Obstructive sleep apnea (OSA) is associated with cardiovascular morbidity and mortality, although the underlying mechanisms are not well understood. OBJECTIVES: We aimed to determine whether more severe OSA, measured by the Respiratory Disturbance Index (RDI), is associated with subclinical myocardial injury and increased myocardial wall stress. METHODS: A total of 1,645 participants (62.5 +/- 5.5 yr and 54% women) free of coronary heart disease and heart failure and participating in both the Atherosclerosis Risk in the Communities and the Sleep Heart Health Studies underwent overnight polysomnography and measurement of high-sensitivity troponin T (hs-TnT) and N terminal pro B-type natriuretic peptide (NT-proBNP). MEASUREMENTS AND MAIN RESULTS: OSA severity was defined using conventional clinical categories: none (RDI <= 5), mild (RDI 5-15), moderate (RDI 15-30), and severe (RDI > 30). Hs-TnT, but not NT-proBNP, was associated with OSA after adjusting for 17 potential confounders (P = 0.02). Over a median of 12.4 (interquartile range, 11.6-13.1) years follow-up, hs-TnT was related to risk of death or incident heart failure in all OSA categories (P <= 0.05 in each category). CONCLUSIONS: In middle-aged to older individuals, OSA severity is independently associated with higher levels of hs-TnT, suggesting that subclinical myocardial injury may play a role in the association between OSA and risk of heart failure. OSA was not associated with NT proBNP levels after adjusting for multiple possible confounders. PMID- 24156238 TI - Anti-inflammatory effects of fish oil in ovaries of laying hens target prostaglandin pathways. AB - BACKGROUND: An effective way to control cancer is by prevention. Ovarian cancer is the most lethal gynecological malignancy. Progress in the treatment and prevention of ovarian cancer has been hampered due to the lack of an appropriate animal model and absence of effective chemo-prevention strategies. The domestic hens spontaneously develop ovarian adenocarcinomas that share similar histological appearance and symptoms such as ascites and metastasis with humans. There is a link between chronic inflammation and cancer. Prostaglandin E2 (PGE2) is the most pro-inflammatory ecoisanoid and one of the downstream products of two isoforms of cyclooxygenase (COX) enzymes: COX-1 and COX-2. PGE2 exerts its effects on target cells by coupling to four subtypes of receptors which have been classified as EP1-4. Fish oil is a source of omega-3 fatty acids (OM-3FAs) which may be effective in prevention of ovarian cancer. Our objective was to assess the potential impact of fish oil on expression of COX enzymes, PGE2 concentration, apoptosis and proliferation in ovaries of laying hens. METHODS: 48 white Leghorn hens were fed 50, 100, 175, 375 and 700 mg/kg fish oil for 21 days. The OM3-FAs and omega-6 fatty acids contents of egg yolks were determined by Gas Chromatography. Proliferation, apoptosis, COX-1, COX-2 and prostaglandin receptor subtype 4 (EP4) protein and mRNA expression and PGE2 concentration in ovaries were measured by PCNA, TUNEL, Western blot, quantitative real-time qPCR and ELISA, respectively. RESULTS: Consumption of fish oil increased the incorporation of OM-3FAs into yolks and decreased both COX-1 and COX-2 protein and mRNA expression. In correlation with COXs down-regulation, fish oil significantly reduced the concentrations of PGE2 in ovaries. EP4 protein and mRNA expression in ovaries of hens was not affected by fish oil treatment. A lower dose of fish oil increased the egg laying frequency. 175 and 700 mg/kg fish oil reduced proliferation and 700 mg/kg increased apoptosis in hen ovaries. CONCLUSIONS: Our findings suggest that the lower doses of fish oil reduce inflammatory PG and may be an effective approach in preventing ovarian carcinogenesis. These findings may provide the basis for clinical trials utilizing fish oil as a dietary intervention targeting prostaglandin biosynthesis for the prevention and treatment of ovarian cancer. PMID- 24156239 TI - Prenatal and perinatal anesthesia and the long-term cognitive sequelae: a review. AB - Many children have cognitive weaknesses or impairments of uncertain etiology. A variety of gestational and early-life variables contribute to normative neurocognitive development with countless events potentially hindering successful neural development. Recent research suggests that anesthesia has the potential to negatively affect fetal brain development both prenatally and perinatally. Some of the anesthesiology research suggests that under certain circumstances, children may have a heightened risk for attention-deficit hyperactivity disorder, learning disorders, and perhaps other issues. Though there are no prospective studies evaluating neurocognitive function in children after neonatal exposure to anesthetics, there are several retrospective reviews that demonstrate temporary neurological sequelae after prolonged anesthetic exposure in young children and larger studies identifying long-term neurodevelopmental impairment after neonatal surgery and anesthesia. Studies also suggest a heightened vulnerability likely during the first trimester, particularly when neurons are undergoing rapid development. Specifically, heightened vulnerability to cerebral dysfunction tends to be associated with exposure to multiple anesthetic agents, longer duration of exposure, and multiple episodes of exposure to anesthetic agents. PMID- 24156240 TI - Reactivation of latent HIV-1 in central memory CD4+ T cells through TLR-1/2 stimulation. AB - BACKGROUND: Toll-like receptors (TLRs) are crucial for recognition of pathogen associated molecular patterns by cells of the innate immune system. TLRs are present and functional in CD4+ T cells. Memory CD4+ T cells, predominantly central memory cells (TCM), constitute the main reservoir of latent HIV-1. However, how TLR ligands affect the quiescence of latent HIV within central memory CD4+ T cells has not been studied. RESULTS: We evaluated the ability of a broad panel of TLR agonists to reactivate latent HIV-1. The TLR-1/2 agonist Pam3CSK4 leads to viral reactivation of quiescent HIV in a model of latency based on cultured TCM and in resting CD4+ T cells isolated from aviremic patients. In addition, we investigated the signaling pathway associated with Pam3CSK4 involved in HIV-1 reactivation. We show that the transcription factors NFkappaB, NFAT and AP-1 cooperate to induce viral reactivation downstream of TLR-1/2 stimulation. Furthermore, increasing levels of cyclin T1 is not required for TLR-mediated viral reactivation, but induction of viral expression requires activated pTEFb. Finally, Pam3CSK4 reactivates latent HIV-1 in the absence of T cell activation or proliferation, in contrast to antigen stimulation. CONCLUSIONS: Our findings suggest that the signaling through TLR-1/2 pathway via Pam3CSK4 or other reagents should be explored as an anti-latency strategy either alone or in combination with other anti-latency drugs. PMID- 24156241 TI - The impact of inappropriate antibiotics on bacteremia patients in a community hospital in Taiwan: an emphasis on the impact of referral information for cases from a hospital affiliated nursing home. AB - BACKGROUND: Evidence for the impact of inappropriate antimicrobial therapy on bacteremia is mainly from studies in medical centers. We investigated the impact of inappropriate antimicrobial therapy on bacteremia in a community hospital. In particular, patients from the hospital's affiliated nursing home were sent to the hospital with adequate referral information. METHODS: We performed a retrospective study to collect data of patients with bacteremia in a community hospital in Taiwan from 2005 to 2007. RESULTS: A total of 222 patients with blood stream infection were diagnosed, of whom 104 patients (46.8%) died. The rate of initial inappropriate antibiotic prescriptions was high (59%). Multivariate analysis revealed that patients with initial inappropriate antibiotics, patients with ventilator support and patients requiring ICU care were the independent predictors for inhospital mortality. Patients referred from the hospital affiliated nursing home and patients with normal WBC counts had better survival outcome. More than 80% cases infected with methicillin-resistant Staphylococcus aureus (MRSA) and Enterococcus faecalis received initial inappropriate antimicrobial therapy. With the longer delay to administer appropriate antibiotic, a trend of higher mortality rates was observed. CONCLUSIONS: Bacteremia patients from a hospital-affiliated nursing home had a better prognosis, which may have been due to the adequate referral information. Clinicians should be aware of the commonly ignored drug resistant pathogens, and efforts should be made to avoid delaying the administration of appropriate antibiotic therapy. PMID- 24156242 TI - VAN: an R package for identifying biologically perturbed networks via differential variability analysis. AB - BACKGROUND: Large-scale molecular interaction networks are dynamic in nature and are of special interest in the analysis of complex diseases, which are characterized by network-level perturbations rather than changes in individual genes/proteins. The methods developed for the identification of differentially expressed genes or gene sets are not suitable for network-level analyses. Consequently, bioinformatics approaches that enable a joint analysis of high throughput transcriptomics datasets and large-scale molecular interaction networks for identifying perturbed networks are gaining popularity. Typically, these approaches require the sequential application of multiple bioinformatics techniques - ID mapping, network analysis, and network visualization. Here, we present the Variability Analysis in Networks (VAN) software package: a collection of R functions to streamline this bioinformatics analysis. FINDINGS: VAN determines whether there are network-level perturbations across biological states of interest. It first identifies hubs (densely connected proteins/microRNAs) in a network and then uses them to extract network modules (comprising of a hub and all its interaction partners). The function identifySignificantHubs identifies dysregulated modules (i.e. modules with changes in expression correlation between a hub and its interaction partners) using a single expression and network dataset. The function summarizeHubData identifies dysregulated modules based on a meta-analysis of multiple expression and/or network datasets. VAN also converts protein identifiers present in a MITAB-formatted interaction network to gene identifiers (UniProt identifier to Entrez identifier or gene symbol using the function generatePpiMap) and generates microRNA-gene interaction networks using TargetScan and Microcosm databases (generateMicroRnaMap). The function obtainCancerInfo is used to identify hubs (corresponding to significantly perturbed modules) that are already causally associated with cancer(s) in the Cancer Gene Census database. Additionally, VAN supports the visualization of changes to network modules in R and Cytoscape (visualizeNetwork and obtainPairSubset, respectively). We demonstrate the utility of VAN using a gene expression data from metastatic melanoma and a protein-protein interaction network from the Human Protein Reference Database. CONCLUSIONS: Our package provides a comprehensive and user-friendly platform for the integrative analysis of -omics data to identify disease-associated network modules. This bioinformatics approach, which is essentially focused on the question of explaining phenotype with a 'network type' and in particular, how regulation is changing among different states of interest, is relevant to many questions including those related to network perturbations across developmental timelines. PMID- 24156243 TI - Cost-effectiveness of rivaroxaban compared with enoxaparin plus a vitamin K antagonist for the treatment of venous thromboembolism. AB - BACKGROUND: Venous thromboembolism (VTE), comprised of deep vein thrombosis (DVT) and pulmonary embolism (PE), is commonly treated with a low-molecular-weight heparin such as enoxaparin plus a vitamin K antagonist (VKA) to prevent recurrence. Administration of enoxaparin + VKA is hampered by complexities of laboratory monitoring and frequent dose adjustments. Rivaroxaban, an orally administered anticoagulant, has been compared with enoxaparin + VKA in the EINSTEIN trials. The objective was to evaluate the cost-effectiveness of rivaroxaban compared with enoxaparin + VKA as anticoagulation treatment for acute, symptomatic, objectively-confirmed DVT or PE. METHODS: A Markov model was built to evaluate the costs, quality-adjusted life-years (QALYs), and incremental cost-effectiveness ratios associated with rivaroxaban compared to enoxaparin + VKA in adult patients treated for acute DVT or PE. All patients entered the model in the 'on-treatment' state upon commencement of oral rivaroxaban or enoxaparin + VKA for 3, 6, or 12 months. Transition probabilities were obtained from the EINSTEIN trials during treatment and published literature after treatment. A 3 month cycle length, US payer perspective ($2012), 5-year time horizon and a 3% annual discount rate were used. RESULTS: Treatment with rivaroxaban cost $2,448 per-patient less and was associated with 0.0058 more QALYs compared with enoxaparin + VKA, making it a dominant economic strategy. Upon one-way sensitivity analysis, the model's results were sensitive to the reduction in index VTE hospitalization length-of-stay associated with rivaroxaban compared with enoxaparin + VKA. At a willingness-to-pay threshold of $50,000/QALY, probabilistic sensitivity analysis showed rivaroxaban to be cost-effective compared with enoxaparin + VKA approximately 76% of the time. LIMITATIONS: The model did not account for the benefits associated with an oral and minimally invasive administration of rivaroxaban. 'Real-world' applicability is limited because data from the EINSTEIN trials were used in the model. Also, resource utilization and costs were based on the US healthcare system. CONCLUSION: Rivaroxaban is a cost-effective option for anticoagulation treatment of acute VTE patients. PMID- 24156245 TI - Spatial patterns of methylmercury risks to common loons and piscivorous fish in Canada. AB - Deposition of inorganic mercury (Hg) from the atmosphere remains the principle source of Hg contamination for most aquatic ecosystems. Inorganic Hg is readily converted to toxic methylmercury (MeHg) that bioaccumulates in aquatic food webs and may pose a risk to piscivorous fish and wildlife. We conducted a screening level risk assessment to evaluate the extent of risk to top aquatic piscivores: the common loon (Gavia immer), walleye (Sander vitreus), and northern pike (Esox lucius). Risk quotients (RQs) were calculated on the basis of a dietary Hg exposure indicator (HgPREY) modeled from over 230,000 observations of fish Hg concentrations at over 1900 locations across Canada and dietary Hg exposure screening benchmarks derived specifically for this assessment. HgPREY exceeded benchmark thresholds related to impaired productivity and behavior in adult loons at 10% and 36% of sites, respectively, and exceeded benchmark thresholds for impaired reproduction and health in fishes at 82% and 73% of sites, respectively. The ecozones of southeastern Canada characterized by extensive forest cover, elevated Hg deposition, and poorly buffered soils had the greatest proportion of RQs > 1.0. Results of this assessment suggest that common loons and piscivorous fishes would likely benefit from reductions in Hg deposition, especially in southeastern Canada. PMID- 24156244 TI - Urban versus rural differences in the occurrence of hip fractures in Japan's Kyoto prefecture during 2008-2010: a comparison of femoral neck and trochanteric fractures. AB - BACKGROUND: To investigate the differences in the characteristics of femoral neck and trochanteric fractures between urban and rural areas of Kyoto Prefecture in Japan. METHODS: Fracture type (neck vs. trochanteric), age, sex, place where fracture occurred (indoors vs. outdoors), and cause of injury were surveyed among patients aged >=65 years who sustained hip fractures between 2008 and 2010 and who were treated at 1 of 13 participating hospitals (5 urban, 8 rural). The ratio of sick beds to total number of beds at the participating hospitals was 19.6% (2,188/11,158) in the urban area and 34.9% (1,963/5,623) in the rural area. We also investigated the incidence of hip fracture in Tango medical district as a representative rural area. RESULTS: There were 1,346 neck (mean age, 82.4 years) and 1,606 trochanteric fractures (mean age, 85.0 years). The ratio of neck to trochanteric fractures was higher in the urban area than in the rural area in all age groups (65-74, 75-84, and >= 85 years). There were no apparent differences in place or cause of injury. The incidence of hip fracture in the women of Tango medical district was lower than the national average. CONCLUSIONS: There was a difference in the ratio of neck to trochanteric fractures between urban and rural areas. This difference is estimated to be caused by the high and low incidence of neck fracture in urban and rural areas, respectively. PMID- 24156247 TI - Attitudes, beliefs and norms relating to contraceptive use among young migrant and non-migrant adults in urban Dar es Salaam, Tanzania. AB - The young urban population of Tanzania is growing rapidly, primarily due to rural urban migration. More information is needed on the challenges facing young adult urban women and men in using family planning (FP). The purpose of this study is to identify perceptions, interpersonal and familial attitudes, and sociocultural norms regarding FP among young adults (18-25 years) in Dar es Salaam, Tanzania, comparing responses by sex, marital status and migration status. We conducted 12 focus groups with young adult men and women (n=74) in Dar es Salaam in December 2009. Participants knew of modern contraceptive methods, but had serious concerns about side effects. Single men and women preferred condoms. Female migrants stated that traditional methods were ineffective, yet commonly used in rural areas. Men's desires for more children frequently led female migrants not to use FP, while many married long-term residents used FP discreetly. Single women sometimes received the support of their parents/boyfriends to access and use contraception. Findings highlight differences in experiences among young adult men and women based on their migrant and marital status at the individual, interpersonal and normative levels. Future efforts to promote FP should engage existing social support systems and cultivate new ones in response to barriers. PMID- 24156246 TI - Soybean concentrated extract counteracts oxidative stress in the uterus of rats. AB - OBJECTIVE: To evaluate the effects of soy isoflavone extract in the pro oxidant/antioxidant balance in the uterus of ovariectomized rats. METHODS: Twenty 3-month-old adult female Wistar rats were divided into four equal groups: GI: sham-operated (estrous phase); GII: control ovariectomized rats; GIII: ovariectomized rats treated with genistein (50 MUg/kg/day) by gavage; GIV: ovariectomized rats subcutaneously treated with estrogen (10 MUg/kg/day). After 30 consecutive days of treatment, the rats were euthanized and the uterus removed. The distal thirds of the uterine horns were processed for histomorphometric analyses of endometrial and myometrial thicknesses and glandular area. Other regions of the uteri were kept in liquid nitrogen and subsequently processed for analysis of reactive species quantification (DCF), total antioxidant capacity (TAC) and lipid oxidation status (TBARS). Data were statistically analyzed by one-way ANOVA, complemented by the Tukey-Kramer test (p < 0.05). RESULTS: GII and GIII exhibited lower endometrial thickness, glandular area and myometrial thickness than GI and GIV, while a higher myometrial thickness was observed in GIV compared with the other groups. Moreover, the isoflavone-treated group showed lower DCF and TBARS compared to GII, and also an improvement of TAC compared to GI and GIV. Despite the significant decrease in TBARS, no significant difference in DCF nor a decrease in TAC were observed in GIV when compared to GII. CONCLUSION: Our data show that isoflavones improve antioxidant status and counteract oxidative stress, without promoting a trophic effect in the uterus of rats. PMID- 24156248 TI - Do medical educationalists like to teach? PMID- 24156249 TI - Odanacatib for the treatment of postmenopausal osteoporosis. AB - INTRODUCTION: The market of antiosteoporosis drugs has been declining in recent years, possibly in part due to the publicity around adverse events observed with bisphosphonates. Also, the proportion of patients with clinical fracture who receive adequate treatment remains low. Hence, there are still unmet needs in this field. Odanacatib is a cathepsin K inhibitor currently being developed for the treatment of postmenopausal osteoporosis that could be an advance in this context. AREA COVERED: Odanacatib is a bone resorption inhibitor, but it preserves some degree of bone formation, which differentiates this new family of drugs from existing therapies. Odanacatib increases bone mineral density (BMD) at the spine and hip, improves bone strength estimated using finite element analysis (FEA) at the spine and hip as well as at the distal tibia and radius. The safety profile has been satisfactory so far. A robust antifracture efficacy has been announced when the Phase III pivotal trial had been terminated after interim analysis, but we do not yet have access to the complete results. EXPERT OPINION: Odanacatib may have an important role in future guidelines if it provides a substantial advantage compared to the effective and inexpensive current generic drugs, in terms of antifracture efficacy or safety. PMID- 24156250 TI - Reactions of neutral platinum clusters with N2O and CO. AB - The reduction of N2O in the gas phase by isolated, neutral platinum clusters, Pt(n) (n = 4-12), was investigated using mass spectrometry. The associated oxygen transfer reactions had the general formula Pt(n)O(m-1) + N2O -> Pt(n)O(m) + N2 (m = 1 or 2). The rate constants k1 and k2 for the reactions in which m = 1 and 2, respectively, were ascertained and were found to be similar to one another. Unexpectedly, Pt6O was discovered to be completely unreactive with N2O under the applied experimental conditions. The reaction mechanism was elucidated on the basis of density functional theory (DFT) calculations, which indicated a reaction barrier between Pt6O + N2O and Pt6O2 + N2. The possibility of catalyzing either the reduction of N2O or the oxidation of CO using neutral Pt(n) species was also examined and the results showed that Pt(n) does not exhibit significant catalytic properties and that O and CO instead coadsorb to Pt(n). Desorption of CO2 from the coadsorbed clusters was not clearly identifiable from mass spectra. The reactivities of the platinum clusters were discussed and compared with the properties of the highly catalytically active rhodium clusters. PMID- 24156251 TI - Association of COL4A1 genetic polymorphisms with coronary artery disease in Uygur population in Xinjiang, China. AB - BACKGROUND: Type IV collagen is important for the structural integrity and function of basement membranes. Basement membranes surround vascular smooth muscle cells in the media, COL4A1 is the most abundant component of type IV collagen in all Basement membranes. However, the relationship between COL4A1 genetic polymorphisms and coronary artery disease (CAD) remains unclear. We performed a case-control study to explore the association of COL4A1 genetic polymorphisms with CAD in Uygur population of China. METHODS: 1095 Uygur people (727 men, 368 women) including 471 CAD patients and 624 controls were selected for the present study. Two SNPs (rs605143 and rs565470) were genotyped by using the polymerase chain reaction-restriction fragment length (PCR-RFLP) method. RESULTS: For total and men, the rs605143 was found to be associated with CAD by in a dominate model (p = 0.014, p = 0.013, respectively). The difference remained statistically significant after multivariate adjustment (p = 0.036, p = 0.014, respectively). The rs565470 was also found to be associated with CAD in a recessive model for total and men (both p < 0.001), and the difference remained statistically significant after multivariate adjustment (P = 0.002, P = 0.001, respectively). CONCLUSION: Both rs605143 and rs565470 of COL4A1gene are associated with CAD in Uygur population of China. PMID- 24156252 TI - Temporal dynamics and transcriptional control using single-cell gene expression analysis. AB - BACKGROUND: Changes in environmental conditions lead to expression variation that manifest at the level of gene regulatory networks. Despite a strong understanding of the role noise plays in synthetic biological systems, it remains unclear how propagation of expression heterogeneity in an endogenous regulatory network is distributed and utilized by cells transitioning through a key developmental event. RESULTS: Here we investigate the temporal dynamics of a single-cell transcriptional network of 45 transcription factors in THP-1 human myeloid monocytic leukemia cells undergoing differentiation to macrophages. We systematically measure temporal regulation of expression and variation by profiling 120 single cells at eight distinct time points, and infer highly controlled regulatory modules through which signaling operates with stochastic effects. This reveals dynamic and specific rewiring as a cellular strategy for differentiation. The integration of both positive and negative co-expression networks further identifies the proto-oncogene MYB as a network hinge to modulate both the pro- and anti-differentiation pathways. CONCLUSIONS: Compared to averaged cell populations, temporal single-cell expression profiling provides a much more powerful technique to probe for mechanistic insights underlying cellular differentiation. We believe that our approach will form the basis of novel strategies to study the regulation of transcription at a single-cell level. PMID- 24156253 TI - Intrapartum fetal heart rate monitoring: evaluation of a standardized system of interpretation for prediction of metabolic acidosis at delivery and neonatal neurological morbidity. AB - OBJECTIVE: To assess the ability of the intrapartum fetal heart rate interpretation system developed in 2008 by the National Institute of Child Health and Human Development (NICHD) to predict fetal metabolic acidosis at delivery and neonatal neurological morbidity. METHODS: We analyzed the intrapartum fetal heart rate tracings of 314 singleton fetuses at >= 37 weeks using the NICHD three-tier system of interpretation: Category I (normal), Category II (indeterminate) and Category III (abnormal). Category II was further divided into Category IIA, with moderate fetal heart rate variability or accelerations, and Category IIB, with minimal/absent fetal heart rate variability and no accelerations. The presence and duration of the different patterns were compared with several clinical neonatal outcomes and with umbilical artery acid-base balance at birth. RESULTS: The mean values of pH and base excess decreased proportionally as tracings worsened (p < 0.001). The duration of at least 30 min for Category III tracings was highly predictive of a pH <7.00 and a base excess <=-12 mmol/L. The same was true for the duration of Category IIB tracings that lasted for at least 50 min. CONCLUSIONS: Our study demonstrates that the interpretation of fetal heart rate tracings based on a strictly standardized system is closely associated with umbilical artery acid-base status at delivery. PMID- 24156254 TI - Bladder cancer--the neglected tumor: a descriptive analysis of publications referenced in MEDLINE and data from the register ClinicalTrials.gov. AB - BACKGROUND: Uro-oncological neoplasms have both a high incidence and mortality rate and are therefore a major public health problem. The aim of this study was to evaluate research activity in uro-oncology over the last decade. METHODS: We searched MEDLINE and ClinicalTrials.gov systematically for studies on prostatic, urinary bladder, kidney, and testicular neoplasms. The increase in newly published reports per year was analyzed using linear regression. The results are presented with 95% confidence intervals, and a p value <0.05 was considered statistically significant. RESULTS: The number of new publications per year increased significantly for prostatic, kidney and urinary bladder neoplasms (all <0.0001). We identified 1,885 randomized controlled trials (RCTs); also for RCTs, the number of newly published reports increased significantly for prostatic (p = 0.001) and kidney cancer (p = 0.005), but not for bladder (p = 0.09) or testicular (p = 0.44) neoplasms. We identified 3,114 registered uro-oncological studies in ClinicalTrials.gov. However, 85% of these studies are focusing on prostatic (45%) and kidney neoplasms (40%), whereas only 11% were registered for bladder cancers. CONCLUSIONS: While the number of publications on uro-oncologic research rises yearly for prostatic and kidney neoplasms, urothelial carcinomas of the bladder seem to be neglected despite their important clinical role. Clinical research on neoplasms of the urothelial bladder must be explicitly addressed and supported. PMID- 24156256 TI - Neuron-specific mitochondrial DNA deletion levels in sporadic Alzheimer's disease. AB - Oxidative stress is implicated in the pathogenesis of neurodegenerative diseases, including sporadic Alzheimer's disease (AD). Mitochondrial DNA (mtDNA) deletions are markers of oxidative damage and increase with age. To unravel the impact of mtDNA damage on AD development, we analyzed mtDNA deletion levels in diverse neuronal cell types of four brain regions (hippocampal CA1 and CA2 regions, nucleus tractus spinalis nervi trigemini, and the cerebellum) that exhibit differing levels of vulnerability to AD related changes at progressive Braak stages compared with age-matched controls. Neurons from these four brain regions were collected using laser microdissection, and analyzed using quantitative polymerase chain reaction (qPCR). Although, no correlation between mtDNA deletion levels and AD progression were found, the data revealed regional and cell type specific selective vulnerability towards mtDNA deletion levels. In conclusion, unexpected results were obtained as granule cells from the cerebellum and neurons from the nucleus tractus spinalis nervi trigemini of the brain stem displayed significant higher mtDNA deletion levels than pyramidal cells from hippocampal CA1 and CA2 region in age and AD. PMID- 24156255 TI - Detailed investigations of proximal tubular function in Imerslund-Grasbeck syndrome. AB - BACKGROUND: Imerslund-Grasbeck Syndrome (IGS) is a rare genetic disorder characterised by juvenile megaloblastic anaemia. IGS is caused by mutations in either of the genes encoding the intestinal intrinsic factor-vitamin B12 receptor complex, cubam. The cubam receptor proteins cubilin and amnionless are both expressed in the small intestine as well as the proximal tubules of the kidney and exhibit an interdependent relationship for post-translational processing and trafficking. In the proximal tubules cubilin is involved in the reabsorption of several filtered plasma proteins including vitamin carriers and lipoproteins. Consistent with this, low-molecular-weight proteinuria has been observed in most patients with IGS. The aim of this study was to characterise novel disease causing mutations and correlate novel and previously reported mutations with the presence of low-molecular-weight proteinuria. METHODS: Genetic screening was performed by direct sequencing of the CUBN and AMN genes and novel identified mutations were characterised by in silico and/or in vitro investigations. Urinary protein excretion was analysed by immunoblotting and high-resolution gel electrophoresis of collected urines from patients and healthy controls to determine renal phenotype. RESULTS: Genetic characterisation of nine IGS patients identified two novel AMN frameshift mutations alongside a frequently reported AMN splice site mutation and two CUBN missense mutations; one novel and one previously reported in Finnish patients. The novel AMN mutations were predicted to result in functionally null AMN alleles with no cell-surface expression of cubilin. Also, the novel CUBN missense mutation was predicted to affect structural integrity of the IF-B12 binding site of cubilin and hereby most likely cubilin cell-surface expression. Analysis of urinary protein excretion in the patients and 20 healthy controls revealed increased urinary excretion of cubilin ligands including apolipoprotein A-I, transferrin, vitamin D-binding protein, and albumin. This was, however, only observed in patients where plasma membrane expression of cubilin was predicted to be perturbed. CONCLUSIONS: In the present study, mutational characterisation of nine IGS patients coupled with analyses of urinary protein excretion provide additional evidence for a correlation between mutation type and presence of the characteristic low-molecular-weight proteinuria. PMID- 24156257 TI - The effects of different antioxidants on the activity of cerebrocortical MnSOD and Na,K-ATPase from post mortem Alzheimer's disease and age-matched normal brains. AB - Among the markers and targets of the early phase of Alzheimer's disease (AD) pathogenesis MnSOD (mitochondrial dysfunction) and Na-pump (disturbances in function/regulation) are often highlighted. This paper focused on comparison of the effects of three antioxidants on the activity of cerebrocortical MnSOD and Na,K-ATPase from post mortem Alzheimer's disease and age-matched normal brains. Antioxidant compounds with different origins: natural glutathione, synthetic UPF peptides (glutathione analogues) and phytoestrogen genistein were investigated. Firstly, MnSOD and Na,K-ATPase activities were found to be decreased in the post mortem AD brains compared with age-matched controls. Secondly, GSH had no effect on MnSOD activity, but decreased Na,K-ATPase activity both in the control and AD brains. Thirdly, UPF1 and UPF17 increased MnSOD activity, and UPF17 suppressed Na,K-ATPase activity. Further studies are needed to clarify, if the inhibitory effect of UPF17 on Na,K-ATPase could abolish the beneficial effect gained from MnSOD activation. Both the antioxidative potential of genistein and its potency to up-regulate Na,K-ATPase activity make it an attractive candidate substance to suppress the early phase of the pathogenesis of AD. PMID- 24156258 TI - Memory impairment is associated with serum methylarginines in older adults. AB - BACKGROUND: This study measured serum concentrations of vascular risk factors, asymmetric dimethylarginine (ADMA) and symmetric dimethylarginine (SDMA) in a representative sample of older community-dwelling adults and determined their associations with objective and subjective memory impairment. METHODS: Data on clinical, lifestyle, and demographic characteristics, serum ADMA, SDMA, and L arginine (measured using LC-MS/MS) were collected from a population-based sample of older Australian adults from the Hunter Community Study. Objective memory was measured with the Audio Recorded Cognitive Screen (ARCS) neuropsychological battery and subjective memory impairment was measured using the Memory Complaint Questionnaire (MAC-Q). RESULTS: Multivariate analysis revealed that SDMA and diabetes were significantly associated with objective memory impairment (Adjusted Odd ratio (AOR) = 3.90; 95% CI. 1.21 - 12.52 for fourth quartile (Q4) of SDMA. ADMA, SDMA, education, number of general practitioner visits and atrial fibrillation were all significantly associated with subjective memory impairment. (AOR = 1.82; 95% CI. 1.04 - 3.18 for Q4 ADMA. CONCLUSIONS: Higher serum SDMA was associated with objective and subjective memory impairment while higher serum ADMA was associated with subjective memory impairment. PMID- 24156259 TI - Relationships between white matter hyperintensities, cerebral amyloid angiopathy and dementia in a population-based sample of the oldest old. AB - Previous reports suggest that brain white matter changes, a surrogate for small vessel disease, are related to cerebral amyloid angiopathy (CAA). However, this relationship has not been explored in population-based studies or in the oldest old (>85 years of age). We studied the relationships between white matter hyperintensities (WMH) determined by post-mortem magnetic resonance imaging (MRI) and neuropathologically assessed CAA in demented and nondemented subjects enrolled in the prospective community-based Finnish Vantaa 85+ Study. In this analysis, we evaluated scans and brain samples from 123 subjects (86% women) with a mean age of 90.6 years. We found CAA to be present in 63 % of the 123 subjects, whereas WMH was present in 74%, and dementia in 59 %. The presence of WMH of any severity did not relate to the presence or the degree of CAA severity, irrespective of the dementia status of the subjects. Furthermore, multivariate regression analysis showed a clear association between CAA and dementia but WMH was not related to dementia in this very old sample. We conclude that severe WMH may not be determined by CAA in this very elderly population. PMID- 24156260 TI - Pan-amyloid oligomer specific scFv antibody attenuates memory deficits and brain amyloid burden in mice with Alzheimer's disease. AB - Amyloid oligomers have a critical function in the pathologic processes of various amyloidoses, such as Alzheimer's disease (AD), Parkinson disease (PD), Huntington's disease, prion-related diseases, type 2 diabetes, and hereditary renal amyloidosis. Our previous reports demonstrated that a conformation dependent oligomer-specific single-chain variable fragment (scFv) antibody, W20, isolated from a naive human scFv library, can recognize oligomers assembled from alpha-synuclein, amylin, insulin, Abeta40/42, prion peptide 106-126, and lysozyme, inhibit the aggregation of various amyloid, and attenuate amyloid oligomer-induced cytotoxicity In vitro. Furthermore, W20 recognized the amyloid oligomers in all types of plaques, Lewy bodies, and amylin deposits in the brain tissues of AD and PD patients and in the pancreas of type 2 diabetes patients. In the current study, we showed that W20 blocked the binding of Abeta oligomers to SH-SY5Y cells, did not bind to heat shock protein, rescued cognitive impairments in APP/PS1 transgenic mice, and interfered with Abeta levels and deposits in mouse brain. These results suggest that W20 may be a promising therapeutic for the treatment of AD. PMID- 24156261 TI - The self-reference effect on episodic memory recollection in young and older adults and Alzheimer's disease. AB - The Self-reference effect (SRE) on long-term episodic memory and autonoetic consciousness has been investigated in young adults, scarcely in older adults, but never in Alzheimer's patients. Is the functional influence of Selfreference still present when the individual's memory and identity are impaired? We investigated this issue in 60 young subjects, 41 elderly subjects, and 28 patients with Alzheimer's disease, by using 1) an incidental learning task of personality traits in three encoding conditions, inducing variable degrees of depth of processing and personal involvement, 2) a 2- minute retention interval free recall task, and 3) a 20-minute delayed recognition task, combined with a remember-know paradigm. Each recorded score was corrected for errors (intrusions in free recall, false alarms in recognition, and false source memory in remember responses). Compared with alternative encodings, the Self-reference significantly enhanced performance on the free recall task in the young group, and on the recognition task both in the young and older groups but not in the Alzheimer group. The most important finding in the Alzheimer group is that the Self reference led the most often to a subjective sense of remembering (especially for the positive words) with the retrieval of the correct encoding source. This Self reference recollection effect in patients was related to independent subjective measures of a positive and definite sense of Self (measured by the Tennessee Self Concept Scale), and to memory complaints in daily life. In conclusion, these results demonstrated the power and robustness of the Self-reference effect on recollection in long-term episodic memory in Alzheimer's disease, albeit the retrieval is considerably reduced. These results should open new perspectives for the development of rehabilitation programs for memory deficits. PMID- 24156262 TI - Amyloid-beta peptides, Alzheimer's disease and the blood-brain barrier. AB - Ever since amyloid-beta (Abeta) peptides were first identified in cerebral plaques in patients with Alzheimer's disease (AD), much research work has focused on the complex mechanisms through which these peptides are synthesized, transported and degraded. Although new information emerges on a regular basis, we consider that the importance of the blood-brain barrier (BBB) in the pathogenesis of AD has been underestimated. In fact, there are a number of obstacles that make it difficult to convince specialists in AD that the BBB indeed plays a key role in this disease: these include the complex physiology of the BBB and the technical difficulty of studying the barrier in vivo and reproducing its main properties in vitro. With these considerations in mind, the present review sets out summarize our current knowledge about the physiology of the BBB and describe recent research findings on the barrier's role in Abeta peptide proteostasis and thus in the mechanism of AD. PMID- 24156263 TI - Choline alphoscerate (alpha-glyceryl-phosphoryl-choline) an old choline- containing phospholipid with a still interesting profile as cognition enhancing agent. AB - Cholinergic precursors have represented the first approach to counter cognitive impairment occurring in adultonset dementia disorders. These compounds were early leaved because their clinical efficacy was not clearly demonstrated. This is probably not true for some choline-containing phospholipids including choline alphoscerate. Choline alphoscerate increases the release of acetylcholine in rat hippocampus, facilitates learning and memory in experimental animals, improves brain transduction mechanisms and decreases age-dependent structural changes occurring in rat brain areas involved in learning and memory. The compound exerts neuroprotective effects in models of altered cholinergic neurotransmission and of brain vascular injury. In clinical studies choline alphoscerate improved memory and attention impairment, as well as affective and somatic symptoms in dementia disorders. An ongoing trial indicates that association between the acetylcholinesterase inhibitor donepezil and choline alphoscerate is accompanied by an improvement in several cognitive tests superior to that induced by donepezil alone. It is suggested that this association may represent a therapeutic option to prolong beneficial effects of cholinergic therapies in Alzheimer's disease patients with concomitant ischemic cerebrovascular disorders. In summary, choline alphoscerate has significant effects on cognitive function with a good safety profile and tolerability. Although limited both in terms of size of the samples investigated and of the length of treatment, preclinical and clinical results presented suggest that cognitive enhancing capabilities of choline alphoscerate merit of being further investigated in appropriate trials. PMID- 24156264 TI - Differences in functional brain activation and hippocampal volume among amnestic mild cognitive impairment subtypes. AB - Patients with amnestic mild cognitive impairment (aMCI) often display deficits in episodic memory. Amnestic MCI is now recognized as a prodromal form of Alzheimer's disease. Various aMCI clinical subtypes have been identified as ingle domain (SD) or multi-domain (MD). The various subtypes represent heterogeneous syndrome indicating the probability of progression to AD, impaired cognitive domains and so on. To examine the characteristics of brain regions of aMCI subtypes is likely to be important for early diagnosis and prediction to AD. This study investigated brain functional activation and hippocampal atrophy during a visually complex scene encoding in 20 individuals with aMCI-SD, 14 individuals with aMCI-MD and 25 healthy controls. During the encoding task, aMCI-MD patients had reduced activation in right superior medial frontal, right inferior and middle temporal, right middle occipital and left inferior frontal regions compared to controls. The different active brain regions between aMCI-MD and aMCI SD patients are the right middle occipital and left middle cingulum regions. The aMCI-MD group had significantly lower left hippocampus volumes compared to the aMCI-SD group and controls, but there was no difference between aMCI-SD patients and the control group in terms of left hippocampus atrophy. The findings provide evidence that aMCI may represent a heterogeneous group. The aMCI-MD patients displayed more severe hippocampcal atrophy and fMRI activation changes than aMCI SD. The aMCIMD may represent a more advanced prodromal stage of AD. PMID- 24156265 TI - Reduced Alzheimer's disease pathology by St. John's Wort treatment is independent of hyperforin and facilitated by ABCC1 and microglia activation in mice. AB - Soluble beta-amyloid peptides (Abeta) and small Abeta oligomers represent the most toxic peptide moieties recognized in brains affected by Alzheimer's disease (AD). Here we provide the first evidence that specific St. John's wort (SJW) extracts both attenuate Abeta-induced histopathology and alleviate memory impairments in APP-transgenic mice. Importantly, these effects are attained independently of hyperforin. Specifically, two extracts characterized by low hyperforin content (i) significantly decrease intracerebral Abeta42 levels, (ii) decrease the number and size of amyloid plaques, (iii) rescue neocortical neurons, (iv) restore cognition to normal levels, and (iv) activate microglia in vitro and in vivo. Mechanistically, we reveal that the reduction of soluble Abeta42 species is the consequence of a highly increased export activity in the bloodbrain barrier ABCC1transporter, which was found to play a fundamental role in Abeta excretion into the bloodstream. These data (i) support the significant beneficial potential of SJW extracts on AD proteopathy, and (ii) demonstrate for the first time that hyperforin concentration does not necessarily correlate with their therapeutic effects. Hence, by activating ABC transporters, specific extracts of SJW may be used to treat AD and other diseases involving peptide accumulation and cognition impairment. We propose that the anti-depressant and anti-dementia effects of these hyperforin-reduced phytoextracts could be combined for treatment of the elderly, with a concomitant reduction in deleterious hyperforin-related side effects. PMID- 24156266 TI - Pathological reorganization of NMDA receptors subunits and postsynaptic protein PSD-95 distribution in Alzheimer's disease. AB - In Alzheimer's disease (AD), synaptic alterations play a major role and are often correlated with cognitive changes. In order to better understand synaptic modifications, we compared alterations in NMDA receptors and postsynaptic protein PSD-95 expression in the entorhinal cortex (EC) and frontal cortex (FC; area 9) of AD and control brains. We combined immunohistochemical and image analysis methods to quantify on consecutive sections the distribution of PSD-95 and NMDA receptors GluN1, GluN2A and GluN2B in EC and FC from 25 AD and control cases. The density of stained receptors was analyzed using multivariate statistical methods to assess the effect of neurodegeneration. In both regions, the number of neuronal profiles immunostained for GluN1 receptors subunit and PSD-95 protein was significantly increased in AD compared to controls (3-6 fold), while the number of neuronal profiles stained for GluN2A and GluN2B receptors subunits was on the contrary decreased (3-4 fold). The increase in marked neuronal profiles was more prominent in a cortical band corresponding to layers 3 to 5 with large pyramidal cells. Neurons positive for GluN1 or PSD-95 staining were often found in the same localization on consecutive sections and they were also reactive for the anti-tau antibody AD2, indicating a neurodegenerative process. Differences in the density of immunoreactive puncta representing neuropile were not statistically significant. Altogether these data indicate that GluN1 and PSD-95 accumulate in the neuronal perikarya, but this is not the case for GluN2A and GluN2B, while the neuropile compartment is less subject to modifications. Thus, important variations in the pattern of distribution of the NMDA receptors subunits and PSD-95 represent a marker in AD and by impairing the neuronal network, contribute to functional deterioration. PMID- 24156268 TI - The diagnostic value of CSF amyloid-beta(43) in differentiation of dementia syndromes. AB - Amyloid-beta (Abeta) is known as the most prominent core protein in Alzheimer's Disease (AD) senile plaques. Although research has focused mainly on Abeta40 and Abeta42 as potential cerebrospinal fluid (CSF) biomarkers, a range of Abeta peptides with variable lengths has been demonstrated in the brains and CSF of AD patients. Recently, it has been found that the Abeta43 peptide may be more abundant than previously assumed, could therefore play an important role in AD pathophysiology, and hence also function as putative biomarker. In this study the value of CSF Abeta43 in AD diagnosis was investigated. Abeta43 levels in CSF were highly correlated with Abeta42 levels. Furthermore, in differentiation of AD from nondemented controls and from patients with Lewy body dementia and frontotemporal dementia, Abeta43 had an equal diagnostic value as Abeta42, both as a single biomarker and in combination with total and phosphorylated tau. In conclusion, quantification of Abeta43 in CSF does not add novel diagnostic information to the differential diagnosis of AD compared to existing biomarkers. PMID- 24156267 TI - The human leukocyte antigen class III haplotype approach: new insight in Alzheimer's disease inflammation hypothesis. AB - The Alzheimer's disease "inflammation hypothesis" has emerged only recently, suggesting the risk of developing AD might be influenced by variants of genes encoding for inflammatory mediators. In order to investigate in this direction, genomic DNA from 194 Italian AD cases and 454 healthy controls matched by gender and ethnicity was analyzed for the Receptor for Advanced Glycation End products (RAGE, HLA class III-centromere portion) -374 and - 429 SNPs and for the Tumor Necrosis Factor-alpha (TNF-alpha, HLA class III-telomere portion) -857, -308 and 238 SNPs by RFLP and Real Time PCR. Our data show statistically significant deviations between AD patients and healthy controls concerning RAGE -374 SNP genotype (TT: p=0.0084) and allele (T, A: p=0.0081) frequencies; TNF-alpha -308 SNP AA genotype (p=0.0433) and TNF-alpha -238 SNP genotype (GG: p=0.0138) and allele (G, A: p=0.0151) frequencies. Furthermore, significant differences between the study groups and regarding RAGE TC (p=0.05) and AC (p=0.009) haplotypes are present, while TNF-alpha haplotype reconstruction point out a statistically significant difference between patients and controls regarding AGG haplotype (p=0.002). Finally, from the combination of the individually significant SNPs of the two genes (RAGE -374, TNF-alpha -238 and -308) we performed an HLA class III haplotype reconstruction finding significant differences between AD subjects and controls regarding the TAG (p=0.019) and TGA (p=0.008) haplotypes. The implication of these haplotypes with the disease points to a possible involvement of entire HLA class III region in AD susceptibility. PMID- 24156269 TI - The prediction of response to galantamine treatment in patients with mild to moderate Alzheimer's disease. AB - The prediction of efficacy in long-term treatment of acetylcholinesterase inhibitors (AChEIs) is a major clinical issue, although no consistently strong predictive factors have emerged thus far. The present analyses aimed to identify factors for predicting long-term outcome of galantamine treatment. Analyses were conducted with data from a 24 weeks randomized, double-blind, placebo controlled trial to evaluate the efficacy and the safety of galantamine in the treatment of 303 patients with mild to moderate AD. Patients were divided into responders (4 or more point improvement of ADAScog scores at 24 weeks of treatment) and non responders. We explored whether patients' background (e.g. sex, age, and duration of disease) and scores of cognitive scales at early stage, are relevant to the long-term response to AChEIs. Predictive values were estimated by the logistic regression model. The responder rate was 31.7%. We found that changes in scores of ADAS-J cog subscales between week 4 and baseline, especially word recognition, can be a good variable to predict subsequent response to galantamine, with approximately 75% of predictive performance. Characteristics of patients, including demographic characteristics, severity of disease and neuropsychological features before treatment were poorly predictive. The present study indicate that initial response to galantamine administration in patients with mild to moderate AD seems to be a reliable predictor of response of consequent galantamine treatment. Patients who show improvement of episodic memory function during the first 4 weeks of galantamine administration may be likely to particularly benefit from galantamine treatment. PMID- 24156270 TI - Proteasome inhibitors act as bifunctional antagonists of human immunodeficiency virus type 1 latency and replication. AB - BACKGROUND: Existing highly active antiretroviral therapy (HAART) effectively controls viral replication in human immunodeficiency virus type 1 (HIV-1) infected individuals but cannot completely eradicate the infection, at least in part due to the persistence of latently infected cells. One strategy that is being actively pursued to eliminate the latent aspect of HIV-1 infection involves therapies combining latency antagonists with HAART. However, discordant pharmacokinetics between these types of drugs can potentially create sites of active viral replication within certain tissues that might be impervious to HAART. RESULTS: A preliminary reverse genetic screen indicated that the proteasome might be involved in the maintenance of the latent state. This prompted testing to determine the effects of proteasome inhibitors (PIs) on latently infected cells. Experiments demonstrated that PIs effectively activated latent HIV-1 in several model systems, including primary T cell models, thereby defining PIs as a new class of HIV-1 latency antagonists. Expanding upon experiments from previous reports, it was also confirmed that PIs inhibit viral replication. Moreover, it was possible to show that PIs act as bifunctional antagonists of HIV-1. The data indicate that PIs activate latent provirus and subsequently decrease viral titers and promote the production of defective virions from activated cells. CONCLUSIONS: These results represent a proof-of concept that bifunctional antagonists of HIV-1 can be developed and have the capacity to ensure precise tissue overlap of anti-latency and anti-replication functions, which is of significant importance in the consideration of future drug therapies aimed at viral clearance. PMID- 24156271 TI - Influence of negative affectivity and self-esteem on the oral health related quality of life in patients receiving oral rehabilitation. AB - BACKGROUND: The aim of this study was to investigate if and how the personality traits Negative Affectivity (NA) and self-esteem influenced the Oral Health Related Quality of Life (OHRQoL) in patients receiving oral rehabilitation. METHODS: OHRQoL was measured by the Oral Health Impact Profile 49 (OHIP-49), NA with a short form of the Eysenck Personality Inventory Questionnaire (EPI-Q), and self-esteem with Rosenbergs Self-Esteem Scale (RSES) in 66 patients treated with removable dental prosthesis (RDP). The minimally important difference (MID), effect size (ES), and standard error of the measurement (SEM) were used to clinically interpret the patient-reported effect. RESULTS: The OHIP-49 score was significantly higher and exceeded the MID pre- and post-treatment in participants with high EPI-Q and low RSES score compared to participants with low EPI-Q and high RSES score. The improvement in OHIP-49 score was significant and not limited by high EPI-Q and low RSES score. High EPI-Q score was associated high improvement in OHIP-49 score and the ES of the improvement in participants with high EPI-Q was large and exceeded the MID and SEM. CONCLUSION: Treatment with RDP improves the OHRQoL regardless of level of NA and self-esteem. High NA is associated with a large effect, but both high NA and low self-esteem is associated with poorer OHRQoL both before and after treatment. PMID- 24156272 TI - Optimization of simultaneous screening of the main mutations involved in non syndromic deafness using the TaqMan(r) OpenArrayTM Genotyping platform. AB - BACKGROUND: Hearing loss is the most common sensory deficit in humans, affecting approximately 10% of the global population. In developed countries, one in every 500 individuals suffers from severe to profound bilateral sensorineural hearing loss. For those up to 5 years old, the proportion is higher, at 2.7 in 1000 individuals, and for adolescents the average is 3.5 in 1000. Among the causes of hearing loss, more than 50% are related to genetic factors. To date, nearly 150 loci and 64 genes have been associated with hearing loss. Mutations in the GJB2 gene, which encodes connexin 26, constitute the main genetic cause. So far, more than 300 variations have been described in this gene.As a response to the clinical and genetic heterogeneity of hearing loss and the importance of correct molecular diagnosis of individuals with hereditary hearing loss, this study worked in the optimization for a diagnostic protocol employing a high-throughput genotyping technology. METHODS: For this work, was used the TaqMan(r) OpenArrayTM Genotyping platform. This is a high performance, high-throughput technology based on real-time PCR, which enables the evaluation of up to 3072 SNPs (Single Nucleotide Polymorphisms), point mutations, small deletions, and insertions, using a single genotyping plate. For the study, were selected the layout allowing to analyze 32 alterations in 96 individuals simultaneously. In the end, the generated results were validated by conventional techniques, as direct sequencing, Multiplex PCR and RFLP-PCR. RESULTS: A total of 376 individuals were analyzed, of which 94 were healthy controls, totaling 4 plates in duplicate. All 31 of the changes analyzed were present in the nuclear genes GJB2, GJB6, CRYL1, TMC1, SLC26A4, miR-96, and OTOF, and in the mitochondrial genes MT-RNR1 and MT TS1. The reactions were subsequently validated by established techniques (direct sequencing, multiplex PCR, and RFLP-PCR) that had previously been used to perform molecular screening of hearing loss at the Human Genetics Laboratory of the Center for Molecular Biology and Genetic Engineering (CBMEG), at the State University of Campinas (UNICAMP). In total, 11,656 genotyping reactions were performed. Of these, only 351 reactions failed, representing approximately 3.01% of the total. The average accuracy of genotyping using the OpenArrayTM plates was 96.99%. CONCLUSIONS: The results demonstrated the accuracy, low cost, and good reproducibility of the technique, indicating that the TaqMan(r) OpenArrayTM Genotyping Platform is a useful and reliable tool for application in molecular diagnostic testing of hearing loss. PMID- 24156273 TI - Endothelial Kruppel-like factor 4 modulates pulmonary arterial hypertension. AB - Kruppel-like factor 4 (KLF4) is a transcription factor expressed in the vascular endothelium, where it promotes anti-inflammatory and anticoagulant states, and increases endothelial nitric oxide synthase expression. We examined the role of endothelial KLF4 in pulmonary arterial (PA) hypertension (PAH). Mice with endothelial KLF4 knockdown were exposed to hypoxia for 3 weeks, followed by measurement of right ventricular and PA pressures, pulmonary vascular muscularization, and right ventricular hypertrophy. The effect of KLF4 on target gene expression was assessed in lungs from these mice, verified in vitro by small interfering RNA (siRNA) knockdown of KLF4, and further studied at the promoter level with cotransfection experiments. KLF4 expression was measured in lung tissue from patients with PAH and normal control subjects. We found that, after hypoxia, right ventricular and PA pressures were significantly higher in KLF4 knockdown animals than controls. Knockdown animals also had more severe pulmonary vascular muscularization and right ventricular hypertrophy. KLF4 knockdown resulted in increased pulmonary expression of endothelin-1 and decreased expression of endothelial nitric oxide synthase, endothelin receptor subtype B, and prostacyclin synthase. Concordant findings were observed in vitro, both with siRNA knockdown of KLF4 and promoter activity assays. Finally, KLF4 expression was reduced in lungs from patients with PAH. In conclusion, endothelial KLF4 regulates the transcription of genes involved in key pathways implicated in PAH, and its loss exacerbates pulmonary hypertension in response to chronic hypoxia in mice. These results introduce a novel transcriptional modulator of PAH, with the potential of becoming a new therapeutic target. PMID- 24156275 TI - The use of jigsaw learning technique in teaching medical students prescribing skills. PMID- 24156276 TI - Vitamin D receptor gene and risk of fracture in postmenopausal women: a meta analysis. AB - OBJECTIVE: Fracture is the major clinical outcome of osteoporosis. The vitamin D receptor (VDR) gene is thought to be a candidate gene for osteoporosis. Many genetic studies have suggested an association of VDR polymorphisms and fracture risk, but evidence remains conflicting. The aim of this study was to evaluate the genetic effect of the BsmI, TaqI, ApaI and FokI polymorphisms in the VDR gene on fracture risk in postmenopausal women. METHODS: Relevant studies were identified from the following electronic databases: PubMed, Embase, and Web of Science before September 2013. Statistical analysis was performed by using the software STATA 12.0. A total 1975 fracture cases and 4565 controls in 14 studies with a total of 16 eligible comparisons were identified for data analysis. RESULTS: No evidence of relationship between the VDR BsmI, TaqI, ApaI or FokI polymorphisms and fracture risk was observed with any genetic model in postmenopausal women (BsmI: b vs. B: odds ratio (OR) 1.07, 95% confidence interval (CI) 0.90-1.29; TaqI: T vs. t: OR 0.89, 95% CI 0.68-1.15; ApaI: A vs. a: OR 0.91, 95% CI 0.76 1.08; FokI: F vs. f: OR 1.20, 95% CI 0.76-1.90). CONCLUSION: This meta-analysis suggests that ApaI, BsmI, TaqI and FokI polymorphisms may be not associated with the risk of fracture in postmenopausal women. Further studies in a larger sample population are required to confirm this finding. PMID- 24156274 TI - The pattern of mucocutaneous disorders in HIV infected children attending care and treatment in Tikur Anbesa specialized hospital, Addis Ababa, Ethiopia. AB - BACKGROUND: Children with HIV infection may develop a wide variety of infectious and inflammatory diseases of the skin. These disorders are often more severe and more difficult to treat than in the immunocompetent child. In some cases, disorders of the skin or mucous membranes may provide an early clue to the presence of pediatric HIV infection. METHODS: It is a descriptive cross-sectional study which was conducted at the pediatric infectious disease unit, department of pediatrics and child health, Tikur Anbesa specialized Hospital. Clinical information was collected using a questionnaire. The data was analyzed using SSPS 16.0 version. Chi-squared was utilized where appropriate and a p-value of less than 0.05 was considered statistically significant. RESULTS: Two hundred seventy HIV infected children were recruited in this study. Out of these females were 51.5% and males were 48.5%. Most of the children 196/270 (72.6%) were suffering from one or more mucocutanous disorders. The most prevalent mucocutanous disorders were infectious dermatosis. Overall, mucocutaneous disorders were more prevalent in advanced stages of HIV disease P < 0.001. Two or more mucocutanous disorders were found in moderate and sever immunosuppression. Seventy three percent of the HIV-infected children with mucocutaneous disorders were already on HAART. CONCLUSIONS: The prevalence of mucocutanous disorders is high in HIV infected children. Advanced immunosuppression is highly associated with a wide spectrum of mucocutanous disorders. PMID- 24156279 TI - The signaling pathway of NADPH oxidase and its role in glomerular diseases. AB - Nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (Nox), a major source of reactive oxygen species, is a critical mediator of redox signaling. It is well documented that oxidative stress is associated with the development of glomerular diseases (GN). Hence, the Nox was also thought to be involved in the pathogenesis of GN. However, the expression of Nox in various GN was not consistent, the mechanisms by which the activity of the Nox enzymes in regulating renal cells remains unclear. Signaling pathways might be very important in the pathogenesis of GN. We performed this review to provide a relatively complete signaling pathways flowchart for Nox to the investigators who were interested in the role of Nox in the pathogenesis of GN. Here, we reviewed the signal transduction pathway of Nox and its role in the pathogenesis of GN. PMID- 24156278 TI - A screen for hydroxymethylcytosine and formylcytosine binding proteins suggests functions in transcription and chromatin regulation. AB - BACKGROUND: DNA methylation (5mC) plays important roles in epigenetic regulation of genome function. Recently, TET hydroxylases have been found to oxidise 5mC to hydroxymethylcytosine (5hmC), formylcytosine (5fC) and carboxylcytosine (5caC) in DNA. These derivatives have a role in demethylation of DNA but in addition may have epigenetic signaling functions in their own right. A recent study identified proteins which showed preferential binding to 5-methylcytosine (5mC) and its oxidised forms, where readers for 5mC and 5hmC showed little overlap, and proteins bound to further oxidation forms were enriched for repair proteins and transcription regulators. We extend this study by using promoter sequences as baits and compare protein binding patterns to unmodified or modified cytosine using DNA from mouse embryonic stem cell extracts. RESULTS: We compared protein enrichments from two DNA probes with different CpG composition and show that, whereas some of the enriched proteins show specificity to cytosine modifications, others are selective for both modification and target sequences. Only a few proteins were identified with a preference for 5hmC (such as RPL26, PRP8 and the DNA mismatch repair protein MHS6), but proteins with a strong preference for 5fC were more numerous, including transcriptional regulators (FOXK1, FOXK2, FOXP1, FOXP4 and FOXI3), DNA repair factors (TDG and MPG) and chromatin regulators (EHMT1, L3MBTL2 and all components of the NuRD complex). CONCLUSIONS: Our screen has identified novel proteins that bind to 5fC in genomic sequences with different CpG composition and suggests they regulate transcription and chromatin, hence opening up functional investigations of 5fC readers. PMID- 24156277 TI - HIV-1 infection, response to treatment and establishment of viral latency in a novel humanized T cell-only mouse (TOM) model. AB - BACKGROUND: The major targets of HIV infection in humans are CD4+ T cells. CD4+ T cell depletion is a hallmark of AIDS. Previously, the SCID-hu thy/liv model was used to study the effect of HIV on thymopoeisis in vivo. However, these mice did not develop high levels of peripheral T cell reconstitution and required invasive surgery for infection and analysis. Here, we describe a novel variant of this model in which thy/liv implantation results in systemic reconstitution with human T cells in the absence of any other human hematopoietic lineages. RESULTS: NOD/SCID-hu thy/liv and NSG-hu thy/liv mice were created by implanting human fetal thymus and liver tissues under the kidney capsule of either NOD/SCID or NSG mice. In contrast to NOD/SCID-hu thy/liv mice that show little or no human cells in peripheral blood or tissues, substantial systemic human reconstitution occurs in NSG-hu thy/liv. These mice are exclusively reconstituted with human T cells (i.e. T-cell only mice or TOM). Despite substantial levels of human T cells no signs of graft-versus-host disease (GVHD) were noted in these mice over a period of 14 months. TOM are readily infected after parenteral exposure to HIV-1. HIV replication is sustained in peripheral blood at high levels and results in modest reduction of CD4+ T cells. HIV-1 replication in TOM responds to daily administration of combination antiretroviral therapy (ART) resulting in strong suppression of virus replication as determined by undetectable viral load in plasma. Latently HIV infected resting CD4+ T cells can be isolated from suppressed mice that can be induced to express HIV ex-vivo upon activation demonstrating the establishment of latency in vivo. CONCLUSIONS: NSG-hu thy/liv mice are systemically reconstituted with human T cells. No other human lymphoid lineages are present in these mice (i.e. monocytes/macrophages, B cells and DC are all absent). These T cell only mice do not develop GVHD, are susceptible to HIV-1 infection and can efficiently maintain virus replication. HIV infected TOM undergoing ART harbor latently infected, resting CD4+ T cells. PMID- 24156283 TI - Factors influencing HPV vaccination choices in different populations identified. PMID- 24156282 TI - Bright cathodoluminescent thin films for scanning nano-optical excitation and imaging. AB - Demand for visualizing nanoscale dynamics in biological and advanced materials continues to drive the development of subdiffraction optical probes. While many strategies employ scanning tips for this purpose, we instead exploit a focused electron beam to create scannable nanoscale optical excitations in an epitaxially grown thin-film of cerium-doped yttrium aluminum perovskite, whose cathodoluminescence response is bright, robust, and spatially resolved to 18 nm. We also demonstrate lithographic patterning of the film's luminescence at the nanoscale. We anticipate that converting these films into free-standing membranes will yield a powerful near-field optical microscopy without the complication of mechanical scanning. PMID- 24156281 TI - Positive affect and sleep in spousal Alzheimer caregivers: a longitudinal study. AB - This article examines the longitudinal relation between positive affect (PA) and sleep in 126 spousal Alzheimer's disease caregivers. Caregivers underwent 4 yearly assessments for the Positive and Negative Affect Schedule, the self-rated Pittsburgh Sleep Quality Index, and actigraphy to objectify nighttime total sleep time, wake after sleep onset, and percentage of sleep. Increased levels of PA and a greater positivity (i.e., positive-to-negative affect) ratio were significantly associated with better subjective sleep over the entire study period. Yearly increases in PA-even when controlling for negative affect (NA)-and in the positivity ratio were also associated with better subjective sleep. PA and actigraphy measures showed no significant relations. Increased PA is longitudinally associated with better sleep in dementia caregivers largely independent of NA. PMID- 24156284 TI - Cryptococcus antigens and immune responses: implications for a vaccine. AB - Cryptococcosis is a fungal disease primarily occurring in immunocompromised individuals, such as AIDS patients, and is associated with high morbidity and mortality. However, cryptococcosis can occur within immunocompetent populations as observed during an outbreak in Vancouver Island, British Columbia, Canada, the Pacific Northwest and other regions of the USA and in Mediterranean Europe. Mortality rates due to cryptococcosis have significantly declined in economically developed countries since the widespread implementation of highly active antiretroviral therapy. However, the incidence and mortality of this disease remains high in economically undeveloped areas in Africa and Asia where HIV infections are high and availability of HAART is limited. The continuing AIDS epidemic coupled with the increased usage of immunosuppressive drugs to prevent organ transplant rejection or to treat autoimmune diseases has resulted in an increase in individuals at risk for developing cryptococcosis. The purpose of this review is to discuss the need, challenges and potential for developing vaccines against cryptococcosis. PMID- 24156285 TI - Development of Vi conjugate - a new generation of typhoid vaccine. AB - Typhoid fever remains to be a serious disease burden worldwide with an estimated annual incidence about 20 million. The licensed vaccines showed moderate protections and have multiple deficiencies. Most important of all, none of the licensed typhoid vaccines demonstrated protection for children under 5 years old. These limitations impeded successful implementation of typhoid vaccination programs. To improve immunogenicity Vi was conjugated to rEPA, a recombinant exoprotein A from Pseudomonas aeruginosa. Vi-rEPA showed higher and longer lasting anti-Vi IgG in adults and children than Vi alone in high endemic areas. In school-age children and adults, the immunity persisted more than 8 years. In a double-blind, placebo-controlled and randomized efficacy trial in 2- to 5-year old children, Vi-rEPA conferred 89% protective efficacy against typhoid fever and the protection lasted at least 4 years. When given concomitantly with infant routine vaccines, Vi-rEPA was safe, immunogenic and showed no interference with the routine vaccines. Vi conjugate vaccine was also attempted and successfully demonstrated by several other laboratories and manufactures. Using either rEPA or different carrier proteins, such as diphtheria or tetanus toxoid, recombinant diphtheria toxin (CRM197), the Vi conjugates synthesized was significantly more immunogenic than Vi alone. Recently, two Vi-tetanus toxoid conjugates were licensed in India for all ages, starts as young as 3 month old. This new generation of typhoid vaccine opens up a new era for typhoid prevention and elimination. PMID- 24156286 TI - Structure and dynamics of nonionic surfactants adsorbed at vacuum/ionic liquid interfaces. AB - Structural and dynamical properties related to the adsorption of nonionic surfactants at vacuum/ionic liquid interfaces were studied using molecular dynamics simulations. Specifically, the surface activity of pentaethylene glycol monododecyl ether (C12E5) was investigated at the free interface of an imidazolium-based room temperature ionic liquid (RTIL), at different surface densities. At low surface coverages, the incorporation of C12E5 does not produce meaningful changes in the vacuum/RTIL interface: the C12E5 hydrophobic tails remain entangled with those of the RTIL cation groups in the outer shell, whereas the C12E5 hydrophilic heads reside at an inner layer. At high surface coverages, the structure in the substrate-in terms of the features exhibited by the local density profiles-practically vanishes; the interface becomes wider and the surfactant molecules shift toward more external positions. Information about the local structure of the interface at high surface densities can be recovered by performing a tessellation procedure. For the sake of comparison, the surface behavior of two commonly used ionic surfactants, sodium dodecyl sulfate and dodecyl trimethyl ammonium chloride, were also studied. The modifications in the width and structure of the bare vacuum/RTIL interface due to the presence of the ionic surfactants are markedly milder than those observed for the nonionic surfactant. Moreover, the RTIL seemed to behave as a better solvent for the chloride counterions than for sodium ones; which were found to remain bound to the surfactant head groups. An analysis of the dynamics at the surface was also performed. Our results indicate that the presence of increasing amounts of nonionic surfactants leads to a gradual reduction of the mobility of the RTIL species. When ionic surfactants are adsorbed, these retardations are even more severe for the surfactant head groups, where the corresponding diffusion coefficients show reductions of practically 1 order of magnitude. PMID- 24156287 TI - Effect of clinical context on simulator-based assessment of blood pressure taking - a pilot randomized study. AB - BACKGROUND: Blood pressure measurement is an essential clinical skill that can readily be assessed in objective structured clinical examination (OSCE). While the use of simulators can enhance test validity and reliability, the given clinical context may also affect student performance. AIMS: To investigate the impact of variations in clinical context on blood pressure measurement in a simulator-based OSCE. METHOD: We randomized 162 first-year medical students into four groups that received different lead-in statements before measuring blood pressure on a manikin simulator. These statements described hypothetical patients with different likelihoods of having systemic hypertension. RESULTS: The lead-in that described the highest likelihood of hypertension was associated with significantly higher reported readings and lower accuracy. The lead-in that suggested normality yielded the best performance. CONCLUSION: Student performance in simulator-based OSCE may be affected by the clinical context provided. However, we argue that construct validity should be viewed in light of the application of a test, in that patients may also present with different cues and likelihoods of having hypertension. Variations in construct design should be further explored to enhance the training and assessment of clinical competence that reflects the unpredictability encountered in daily clinical practice. PMID- 24156288 TI - Reactive pathways in the chlorobenzene-ammonia dimer cation radical: new insights from experiment and theory. AB - Building upon our recent studies of noncovalent interactions in chlorobenzene and bromobenzene clusters, in this work we focus on interactions of chlorobenzene (PhCl) with a prototypical N atom donor, ammonia (NH3). Thus, we have obtained electronic spectra of PhCl...(NH3)n (n = 1-3) complexes in the region of the PhCl monomer S0 -S1 (pipi*) transition using resonant 2-photon ionization (R2PI) methods combined with time-of-flight mass analysis. Consistent with previous studies, we find that upon ionization the PhCl...NH3 dimer cation radical reacts primarily via Cl atom loss. A second channel, HCl loss, is identified for the first time in R2PI studies of the 1:1 complex, and a third channel, H atom loss, is identified for the first time. While prior studies have assumed the dominance of a pi-type complex, we find that the reactive complex corresponds instead to an in-plane sigma-type complex. This is supported by electronic structure calculations using density functional theory and post-Hartree-Fock methods and Franck-Condon analysis. The reactive pathways in this system were extensively characterized computationally, and consistent with results from previous calculations, we find two nearly isoenergetic arenium ions (Wheland intermediates; denoted WH1, WH2), which lie energetically below the initially formed dimer cation radical complex. At the energy of our experiment, intermediate WH1, produced from ipso-addition, is not stable with respect to Cl or HCl loss, and the relative branching between these channels observed in our experiment is well reproduced by microcanonical transition state theory calculations based upon the calculated parameters. Intermediate WH2, where NH3 adds ortho to the halogen, decomposes over a large barrier via H atom loss to form protonated o-chloroaniline. This channel is not open at the (2-photon) energy of our experiments, and it is suggested that photodissociation of a long lived (i.e., several ns) WH2 intermediate leads to the observed products. PMID- 24156289 TI - Muscarinic M3 receptors contribute to allergen-induced airway remodeling in mice. AB - Asthma is a chronic obstructive airway disease, characterized by inflammation and remodeling. Acetylcholine contributes to symptoms by inducing bronchoconstriction via the muscarinic M3 receptor. Recent evidence suggests that bronchoconstriction can regulate airway remodeling, and therefore implies a role for the muscarinic M3 receptor. The objective of this work was to study the contribution of the muscarinic M3 receptor to allergen-induced remodeling using muscarinic M3 receptor subtype-deficient (M3R(-/-)) mice. Wild-type (WT), M1R(-/-), and M2R(-/ ) mice were used as controls. C57Bl/6 mice were sensitized and challenged with ovalbumin (twice weekly for 4 wk). Control animals were challenged with saline. Allergen exposure induced goblet cell metaplasia, airway smooth muscle thickening (1.7-fold), pulmonary vascular smooth muscle remodeling (1.5-fold), and deposition of collagen I (1.7-fold) and fibronectin (1.6-fold) in the airway wall of WT mice. These effects were absent or markedly lower in M3R(-/-) mice (30 100%), whereas M1R(-/-) and M2R(-/-) mice responded similarly to WT mice. In addition, airway smooth muscle and pulmonary vascular smooth muscle mass were 35 40% lower in saline-challenged M3R(-/-) mice compared with WT mice. Interestingly, allergen-induced airway inflammation, assessed as infiltrated eosinophils and T helper type 2 cytokine expression, was similar or even enhanced in M3R(-/-) mice. Our data indicate that acetylcholine contributes to allergen induced remodeling and smooth muscle mass via the muscarinic M3 receptor, and not via M1 or M2 receptors. No stimulatory role for muscarinic M3 receptors in allergic inflammation was observed, suggesting that the role of acetylcholine in remodeling is independent of the allergic inflammatory response, and may involve bronchoconstriction. PMID- 24156290 TI - Effect of a prescriptive dietary intervention on psychological dimensions of eating behavior in obese adolescents. AB - BACKGROUND: Overweight adolescents are more likely to have dysfunctional eating behaviours compared to normal weight adolescents. Little is known about the effects of obesity treatment on the psychological dimensions of eating behavior in this population. OBJECTIVE: To examine the effects of a prescriptive dietary intervention on external eating (eating in response to food cues, regardless of hunger and satiety), emotional eating and dietary restraint and their relation to weight loss. Parental acceptability was also examined. METHOD: This is a secondary study of a 12-month randomized trial, the RESIST study, which examined the effects of two diets on insulin sensitivity. Participants were 109 obese 10- to 17-year-olds with clinical features of insulin resistance. The program commenced with a 3-month dietary intervention using a structured meal plan, with the addition of an exercise intervention in the next 3 months and followed by a 6 month maintenance period.This paper presents changes in eating behaviors measured by the Eating Pattern Inventory for Children and parent rated diet acceptability during the first 6 months of the trial. As there was no difference between the diets on outcome of interest, both diet groups were combined for analyses. RESULTS: After 6 months, the proportion of participants who reported consuming more in response to external eating cues decreased from 17% to 5% (P = 0.003), whereas non- emotional eating increased from 48% to 65% (p = 0.014). Dietary restraint and parental pressure to eat remained unchanged. A reduction in external eating (rho = 0.36, P < 0.001) and a reduction in dietary restraint (r = 0.26, P = 0.013) were associated with greater weight loss at 3 and 6 months, respectively. Overall this approach was well accepted by parents with 72% of parents considered that their child would be able to follow the meal plan for the longer term. CONCLUSIONS: In the short to medium term, a prescriptive dietary intervention approach is a well-accepted and suitable option for obese adolescents with clinical features of insulin resistance. It may reduce external and emotional eating, led to modest weight loss and did not cause any adverse effect on dietary restraint. TRIAL REGISTRATION: Australian New Zealand Clinical Trial Registration Number (ACTRN) 12608000416392 https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=83071. PMID- 24156291 TI - Bilirubin and related tetrapyrroles inhibit food-borne mutagenesis: a mechanism for antigenotoxic action against a model epoxide. AB - Bilirubin exhibits antioxidant and antimutagenic effects in vitro. Additional tetrapyrroles that are naturally abundant were tested for antigenotoxicity in Salmonella. Un-/conjugated bilirubin (1 and 2), biliverdin (4), bilirubin and biliverdin dimethyl esters (3 and 5), stercobilin (6), urobilin (7), and protoporphyrin (8) were evaluated at physiological concentrations (0.01-2 MUmol/plate; 3.5-714 MUM) against the metabolically activated food-borne mutagens aflatoxin B1 (9) and 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (10). Compound 8 most effectively inhibited the mutagenic effects of 9 in strain TA102 and 10 in TA98. Compound 7 inhibited 9-induced mutagenesis in strain TA98 most effectively, while 1 and 4 were promutagenic in this strain. This is likely due to their competition with mutagens for phase-II detoxification. Mechanistic investigations into antimutagenesis demonstrate that tetrapyrroles react efficiently with a model epoxide of 9, styrene epoxide (11), to form covalent adducts. This reaction is significantly faster than that of 11 with guanine. Hence, the evaluated tetrapyrroles inhibited genotoxicity induced by poly /heterocyclic amines found in foods, and novel evidence obtained in the present investigation suggests this may occur via chemical scavenging of genotoxic metabolites of the mutagens investigated. This may have important ramifications for maintaining health, especially with regard to cancer prevention. PMID- 24156292 TI - Gas sorption, second-order nonlinear optics, and luminescence properties of a series of lanthanide-organic frameworks based on nanosized tris((4 carboxyl)phenylduryl)amine ligand. AB - By controlling the pH value of the reaction system, two sets of lanthanide (Ln) tris((4-carboxyl)phenylduryl)amine (Ln = Ce, Pr, Nd, Sm) frameworks have been generated. Four isostructural noninterpenetrating frameworks (FIR-8 to FIR-11) are constructed from rod-shaped secondary building units and four other isostructural frameworks (FIR-12 to FIR-15) based on single Ln nodes are described as 8-fold interpenetrating dia-type nets. Gas sorption measurements for FIR-8 give a Langmuir surface area of 633.8 m(2).g(-1) and a H2 uptake of 165.2 cm(3).g(-1) at 77 K and 1 atm. However, FIR-12 with smaller pores can hardly adsorb any N2 and H2. Because both FIR-8 and FIR-12 crystallize in acentric space group, the second-harmonic generation (SHG) measurements indicate that both of them display strong powder SHG efficiencies, which are approximately 8 and 3 times as strong as that of a potassium dihydrogen phosphate powder. In addition, the fluorescent emissions of all compounds in the solid state are also investigated in detail. PMID- 24156294 TI - The association between use of electronic media in bed before going to sleep and insomnia symptoms, daytime sleepiness, morningness, and chronotype. AB - This study investigated whether the use of a television, computer, gaming console, tablet, mobile phone, or audio player in bed before going to sleep was associated with insomnia, daytime sleepiness, morningness, or chronotype. 532 students aged 18-39 were recruited from lectures or via e-mail. Respondents reported the frequency and average duration of their in-bed media use, as well as insomnia symptoms, daytime sleepiness, morningness-eveningness preference and bedtime/rise time on days off. Mean time of media use per night was 46.6 minutes. The results showed that computer usage for playing/surfing/reading was positively associated with insomnia, and negatively associated with morningness. Mobile phone usage for playing/surfing/texting was positively associated with insomnia and chronotype, and negatively associated with morningness. None of the other media devices were related to either of these variables, and no type of media use was related to daytime sleepiness. PMID- 24156295 TI - Studies of association of AGPAT6 variants with type 2 diabetes and related metabolic phenotypes in 12,068 Danes. AB - BACKGROUND: Type 2 diabetes, obesity and insulin resistance are characterized by hypertriglyceridemia and ectopic accumulation of lipids in liver and skeletal muscle. AGPAT6 encodes a novel glycerol-3 phosphate acyltransferase, GPAT4, which catalyzes the first step in the de novo triglyceride synthesis. AGPAT6-deficient mice show lower weight and resistance to diet- and genetically induced obesity. Here, we examined whether common or low-frequency variants in AGPAT6 associate with type 2 diabetes or related metabolic traits in a Danish population. METHODS: Eleven variants selected by a candidate gene approach capturing the common and low-frequency variation of AGPAT6 were genotyped in 12,068 Danes from four study populations of middle-aged individuals. The case-control study involved 4,638 type 2 diabetic and 5,934 glucose-tolerant individuals, while studies of quantitative metabolic traits were performed in 5,645 non-diabetic participants of the Inter99 Study. RESULTS: None of the eleven AGPAT6 variants were robustly associated with type 2 diabetes in the Danish case-control study. Moreover, none of the AGPAT6 variants showed association with measures of obesity (waist circumference and BMI), serum lipid concentrations, fasting or 2-h post-glucose load levels of plasma glucose and serum insulin, or estimated indices of insulin secretion or insulin sensitivity. CONCLUSIONS: Common and low-frequency variants in AGPAT6 do not significantly associate with type 2 diabetes susceptibility, or influence related phenotypic traits such as obesity, dyslipidemia or indices of insulin sensitivity or insulin secretion in the population studied. PMID- 24156299 TI - Dimeric and tetrameric supramolecular aggregates of single-molecule magnets via carboxylate substitution. AB - [Mn3]2 and [Mn3]4 supramolecular aggregates of weakly exchange-coupled Mn(III)3 single-molecule magnets (SMMs) with S = 6 have been prepared by carboxylate substitution on [Mn3O(O2CMe)3(mpko)3](+) [mpkoH = methyl(pyridine-2-yl) ketone oxime)] with the dicarboxylic acids alpha-truxillic acid and fumaric acid, respectively. The method opens up a new approach to Mn3 SMM aggregates of various size and topology. PMID- 24156297 TI - On the self-assembly of brush block copolymers in thin films. AB - We describe a simple route to fabricate two dimensionally well-ordered, periodic nanopatterns using the self-assembly of brush block copolymers (brush BCPs). Well developed lamellar microdomains oriented perpendicular to the substrate are achieved, without modification of the underlying substrates, and structures with feature sizes greater than 200 nm are generated due to the reduced degree of chain entanglements of brush BCPs. A near-perfect linear scaling law was found for the period, L, as a function of backbone degree of polymerization (DP) for two series of brush BCPs. The exponent increases slightly from 0.99 to 1.03 as the side chain molecular weight increases from ~2.4 to ~4.5 kg/mol(-1) and saturated with further increase in the side chain molecular weight due to the entropic penalty associated with the packing of the side chains. Porous templates and scaffolds from brush BCP thin films are also obtained by selective etching of one component. PMID- 24156298 TI - Emergency department crowding in The Netherlands: managers' experiences. AB - BACKGROUND: In The Netherlands, the state of emergency department (ED) crowding is unknown. Anecdotal evidence suggests that current ED patients experience a longer length of stay (LOS) compared to some years ago, which is indicative of ED crowding. However, no multicenter studies have been performed to quantify LOS and assess crowding at Dutch EDs. We performed this study to describe the current state of emergency departments in The Netherlands regarding patients' length of stay and ED nurse managers' experiences of crowding. METHODS: A survey was sent to all 94 ED nurse managers in The Netherlands with questions regarding the type of facility, annual ED census, and patients' LOS. Additional questions included whether crowding was ever a problem at the particular ED, how often it occurred, which time periods had the worst episodes of crowding, and what measures the particular ED had undertaken to improve patient flow. RESULTS: Surveys were collected from 63 EDs (67%). Mean annual ED visits were 24,936 (SD +/- 9,840); mean LOS for discharged patients was 119 (SD +/- 40) min and mean LOS for admitted patients 146 (SD +/- 49) min. Consultation delays, laboratory and radiology delays, and hospital bed shortages for patients needing admission were the most cited reasons for crowding. Admitted patients had a longer LOS because of delays in obtaining inpatient beds. Thirty-nine of 57 respondents (68%) reported that crowding occurred several times a week or even daily, mostly between 12:00 and 20:00. Measures taken by hospitals to manage crowding included placing patients in hallways and using fasttrack with treatment of patients by trained nurse practitioners. CONCLUSIONS: Despite a relatively short LOS, frequent crowding appears to be a nationwide problem according to Dutch ED nurse managers, with 68% of them reporting that crowding occurred several times a week or even daily. Consultations delays, laboratory and radiology delays, and hospital bed shortage for patients needing admission were believed to be the most important factors contributing to ED crowding. PMID- 24156300 TI - IL-5 induces suspended eosinophils to undergo unique global reorganization associated with priming. AB - The experiments described herein define a unique program of polarization of suspended human eosinophils stimulated with IL-5 family cytokines. We found that eosinophil granules and the nucleus move in opposite directions to form, respectively, a granular compartment and the nucleopod, a specialized uropod occupied by the nucleus and covered with adhesion receptors, including P-selectin glycoprotein ligand-1, CD44, and activated alphaMbeta2 integrin. Ligated IL-5 family receptors localize specifically at the tip of the nucleopod in proximity to downstream signaling partners Janus tyrosine kinase 2, signal transducer and activator of transcription-1 and -5, and extracellular signal-regulated kinase. Microscopy and effects of cytochalasin B and nocodazole indicate that remodeling of filamentous actin and reorientation of the microtubule network are required for eosinophil polarization and nucleopod formation. IL-5 induces persistent polarization and extracellular signal-regulated kinase redistribution that are associated with eosinophil priming, a robust response on subsequent stimulation with N-formyl-methionyl-leucyl-phenylalanine. Global reorganization of cytoskeleton, organelles, adhesion receptors, and signaling molecules likely facilitates vascular arrest, extravasation, migration, granule release, and survival of eosinophils entering inflamed tissues from the bloodstream. PMID- 24156301 TI - Catalytic polyelectrolyte multilayers at the bipolar membrane interface. AB - Bipolar membranes are laminated anion and cation exchange membranes that split water at their interface very efficiently upon application of an electric field. This paper investigates the layer-by-layer (LbL) deposition of polyelectrolyte multilayers, as a tool to introduce molecularly thin catalyst groups at this interface of bipolar membranes. The bipolar membranes were prepared by first modifying an anion exchange membrane by consecutive dipping LbL assembly, then casting a thin highly charged intermediate layer followed by casting a cation exchange layer. The results reveal that polyelectrolytes of higher charge density coated on the anion exchange layer yield better performance. Several parameters of the LbL interface deposition were varied. Out of the investigated LbL assembly parameters, ionic strength and number of layers have shown the largest influence on catalytic activity as well as ionic selectivity. The membrane with two bilayers of poly(3,4-ethylenedioxythiophene) poly(styrenesulfonate) (PEDOT:PSS) and poly(ethyleneimine) (PEI), where the PEI was prepared in 0.5 M NaCl, gave rise to the best performance. Surprisingly, detailed data analysis at low electrical potential suggests that the interface layers of a bipolar membrane play a major role in its permselectivity. Previously, only the bulk thickness of the anion and cation exchange membrane was assumed to influence the bipolar membrane selectivity. PMID- 24156303 TI - Medical student electives and learning outcomes for global health: a commentary on behalf of the UK Medical Schools Elective Council. AB - BACKGROUND: Electives have the potential to have a very positive impact on the professional development of medical students. Education about issues in global health is widely regarded as a neglected area in the undergraduate curricula of many medical schools. Linking learning outcomes for global health to the elective offers a possible solution that avoids adding additional teaching to crowded courses. CONCLUSION: This commentary advocates caution as many potential learning outcomes are better addressed elsewhere and setting detailed outcomes erodes the essence of the elective - student choice. PMID- 24156304 TI - Clinical trial evaluating Viscoat and Visthesia ophthalmic viscosurgical devices in corneal endothelial loss after cataract extraction and intraocular lens implantation. AB - PURPOSE: To assess and compare the safety and the efficacy of VisThesiaTM and Viscoat(r) in cataract surgery. METHODS: This prospective randomized clinical trial included 44 eyes of 44 patients that were assigned randomly to undergo phacoemulsification either with VisThesiaTM or with Viscoat(r). Preoperative data included age, gender, visual acuity, IOP and mean endothelial cell density. Postoperative, best corrected visual acuity (BCVA), IOP, mean endothelial cell density and painful sensation during surgery were recorded. RESULTS: BCVA, evaluated with Snellen chart in decimal fraction, was statistically improved in both groups. Specifically, mean BCVA in VisThesia group was increased from 0.28 +/- 1.8 SD preoperatively to 0.83 +/- 1.4 SD postoperatively, whereas, in the Viscoat group, BCVA was increased from 0.31 +/- 2.1 SD preoperatively, to 0.85 +/ 1.2 SD after surgery (p > 0.1). The mean postoperative IOP was lower in the VisThesia group, but the difference was not statistically significant (p > 0.1). Preoperatively, the mean endothelial cell count was 2322.3 +/- 161.1 SD cells/mm(2) in Viscoat group and 2304.8 +/- 142.8 SD cells/mm(2) in the VisThesia group, similar between groups (p > 0.1). At day 15 after cataract surgery the postoperative endothelial cell count was 2102.9 +/- 182.8 SD cells/mm(2) in Viscoat group and 2032.6 +/- 160.4 SD cells/mm(2) in the VisThesia group (p > 0.1). The mean endothelial cell decrease was 212 cells/mm(2) (9.1%) in the Viscoat group and 272 cells/mm(2) (11.8%) in the VisThesia group. The difference was not statistically significant between the two groups (t-test = 0.18, p > 0.1). This value is within standard normal endothelial cell decrease after a cataract surgery. Painful sensation was not reported during any stage of the procedure. CONCLUSIONS: Topical-intracameral anesthesia with VisThesiaTM allows cataract surgery without any painful sensation in the majority of patients. Both Viscoat(r) and VisThesiaTM have similar safety profile during intra- and post operative period and identical endothelial protection, as endothelial cell loss is within normal limits. PMID- 24156302 TI - S100A9 protein is a novel ligand for the CD85j receptor and its interaction is implicated in the control of HIV-1 replication by NK cells. AB - BACKGROUND: The reportedly broad expression of CD85j across different immune cell types suggests an importance for this molecule in the human immune system. Previous reports have shown that this receptor interacts with several HLA class-I molecules, as well as with some viral proteins. We have demonstrated that the subset of CD85j + Natural Killer (NK) cells efficiently controls human immunodeficiency virus type 1 (HIV-1) replication in monocyte-derived dendritic cells (MDDC) in vitro and this led us to hypothesize that the CD85j + NK cell mediated anti-HIV activity in MDDC is specifically dependent on the interaction between the CD85j receptor and unknown non-HLA class-I ligand(s). RESULTS: In this study, we focused our efforts on the identification of these non-described ligands for CD85j. We found that the CD85j receptor interacts with a calcium binding proteins of the S100 family; namely, S100A9. We further demonstrated that HIV-1 infection of MDDC induces a modulation of S100A9 expression on surface of the MDDC, which potentially influences the anti-HIV-1 activity of human NK cells through a mechanism involving CD85j ligation. Additionally, we showed that stimulation of NK cells with exogenous S100A9 enhances the control of HIV-1 infection in CD4+ T cells. CONCLUSIONS: Our data show that S100A9 protein, through ligation with CD85j, can stimulate the anti-HIV-1 activity of NK cells. PMID- 24156306 TI - Continuous venovenous hemodiafiltration with a low citrate dose regional anticoagulation protocol and a phosphate-containing solution: effects on acid base status and phosphate supplementation needs. AB - BACKGROUND: Recent guidelines suggest the adoption of regional citrate anticoagulation (RCA) as first choice CRRT anticoagulation modality in patients without contraindications for citrate. Regardless of the anticoagulation protocol, hypophosphatemia represents a potential drawback of CRRT which could be prevented by the adoption of phosphate-containing CRRT solutions. The aim was to evaluate the effects on acid-base status and phosphate supplementation needs of a new RCA protocol for Continuous Venovenous Hemodiafiltration (CVVHDF) combining the use of citrate with a phosphate-containing CRRT solution. METHODS: To refine our routine RCA-CVVH protocol (12 mmol/l citrate, HCO3- 32 mmol/l replacement fluid) (protocol A) and to prevent CRRT-related hypophosphatemia, we introduced a new RCA-CVVHDF protocol (protocol B) combining an 18 mmol/l citrate solution with a phosphate-containing dialysate/replacement fluid (HCO3- 30 mmol/l, Phosphate 1.2). A low citrate dose (2.5-3 mmol/l) and a higher than usual target circuit Ca(2+) (<= 0.5 mmol/l) have been adopted. RESULTS: Two historical groups of heart surgery patients (n = 40) underwent RCA-CRRT with protocol A (n = 20, 102 circuits, total running time 5283 hours) or protocol B (n = 20, 138 circuits, total running time 7308 hours). Despite higher circuit-Ca(2+) in protocol B (0.37 vs 0.42 mmol/l, p < 0.001), circuit life was comparable (51.8 +/- 36.5 vs 53 +/- 32.6 hours). Protocol A required additional bicarbonate supplementation (6 +/- 6.4 mmol/h) in 90% of patients while protocol B ensured appropriate acid-base balance without additional interventions: pH 7.43 (7.40-7.46), Bicarbonate 25.3 (23.8-26.6) mmol/l, BE 0.9 (-0.8 to +2.4); median (IQR). No episodes of clinically relevant metabolic alkalosis, requiring modifications of RCA-CRRT settings, were observed. Phosphate supplementation was needed in all group A patients (3.4 +/- 2.4 g/day) and in only 30% of group B patients (0.5 +/- 1.5 g/day). Hypophosphatemia developed in 75% and 30% of group A and group B patients, respectively. Serum phosphate was significantly higher in protocol B patients (P < 0.001) and, differently to protocol A, appeared to be steadily maintained in near normal range (0.97-1.45 mmol/l, IQR). CONCLUSIONS: The proposed RCA-CVVHDF protocol ensured appropriate acid-base balance without additional interventions, providing prolonged filter life despite adoption of a higher target circuit-Ca(2+). The introduction of a phosphate-containing solution, in the setting of RCA, significantly reduced CRRT-related phosphate depletion. PMID- 24156307 TI - Absolute rate coefficient of the gas-phase reaction between hydroxyl radical (OH) and hydroxyacetone: investigating the effects of temperature and pressure. AB - The rate coefficient (k1) of the reaction between hydroxyl radical and hydroxyacetone, which remained so far controversial, was determined over the temperature range 290-500 K using pulsed-laser photolysis coupled to pulsed-laser induced fluorescence (PLP-PLIF). Hydroxyl radical was generated by pulsed photolysis of H2O2 at 248 nm. The results show that at a pressure of 50 Torr He, the rate coefficient obeys a negative temperature dependence k1(T) = (1.77 +/- 0.19) * 10(-12) exp((353 +/- 36)/T) cm(3) molecule(-1) s(-1) for temperatures between 290 and 380 K, in good agreement with the results of Dillon et al. (Phys. Chem. Chem. Phys. 2006, 8, 236) at 60 Torr He. However, always at 50 Torr He but for the higher temperature range 410-500 K, a positive temperature dependence was found: k1(T) = (1.14 +/- 0.25) * 10(-11) exp(-(378 +/- 102)/T) cm(3) molecule(-1) s(-1), close to the expression obtained by Baasandorj et al. (J. Phys. Chem. A 2009, 113, 10495) for pressures of 2 and 5 Torr He but at lower temperatures, 280 360 K, where their k1(T) values are well below these of Dillon et al. and of this work. Moreover, the rate coefficient k1(301 K) determined as a function of pressure, from 10 to 70 Torr He, shows a pronounced decrease once the pressure is below ~40 Torr He, thus explaining the disparity between the higher-pressure data of Dillon et al. and the lower-pressure results of Baasandorj et al. The pressure dependence of k1 and of its temperature-dependence below ~400 K is rationalized by the reaction proceeding via a hydrogen-bonded prereactive complex (PRC) and a submerged transition state, such that at high pressures collisionally thermalized PRCs contribute additional reactive flux over and through the submerged barrier. The high-pressure rate coefficient data both of Dillon et al. and of this work over the combined range 230-500 K can be represented by the theory-based expression k1(T) = 5.3 * 10(-20) * T(2.6) exp(1100/T) cm(3) molecule(-1) s(-1). PMID- 24156309 TI - Identifying accelerometer nonwear and wear time in older adults. AB - BACKGROUND: Five accelerometer-derived methods of identifying nonwear and wear time were compared with a self-report criterion in adults >= 56 years of age. METHODS: Two hundred participants who reported wearing an ActicalTM activity monitor for four to seven consecutive days and provided complete daily log sheet data (i.e., the criterion) were included. Four variables were obtained from log sheets: 1) dates the device was worn; 2) time(s) the participant put the device on each day; 3) time(s) the participant removed the device each day; and 4) duration of self-reported nonwear each day. Estimates of wear and nonwear time using 60, 90, 120, 150 and 180 minutes of consecutive zeroes were compared to estimates derived from log sheets. RESULTS: Compared with the log sheet, mean daily wear time varied from -84, -43, -24, -14 and -8 min/day for the 60-min, 90 min, 120-min, 150-min and 180-min algorithms, respectively. Daily log sheets indicated 8.5 nonwear bouts per week with 120-min, 150-min and 180-min algorithms estimating 8.2-8.9 nonwear bouts per week. The 60-min and 90-min methods substantially overestimated number of nonwear bouts per week and underestimated time spent in sedentary behavior. Sensitivity (number of compliant days correctly identified as compliant) improved with increasing minutes of consecutive zero counts and stabilized at the 120-min algorithm. The proportion of wear time being sedentary and absolute and proportion of time spent in physical activity of varying intensities were nearly identical for each method. CONCLUSIONS: Utilization of at least 120 minutes of consecutive zero counts will provide dependable population-based estimates of wear and nonwear time, and time spent being sedentary and active in older adults wearing the ActicalTM activity monitor. PMID- 24156308 TI - Si-Wu-tang extract stimulates bone formation through PI3K/Akt/NF-kappaB signaling pathways in osteoblasts. AB - BACKGROUND: Si-Wu-Tang (SWT), a Traditional Chinese Medicine (TCM) formula, is widely used for the treatment of gynopathies diseases such as menstrual discomfort, climacteric syndrome, dysmenorrhea, and other estrogen-related diseases. Recent studies have shown that SWT can treat primary dysmenorrhea, have anti-pruritic anti-inflammatory effects, and protect against radiation-induced bone marrow damage in an animal model. It has been reported that anti inflammatory and anti-oxidant agents have the potential to treat osteoporosis by increasing bone formation and/or suppressing bone resorption. However, the effect of SWT on bone cell function has not yet been reported. METHODS: Alkaline phosphatase (ALP), bone morphogenetic proteins (BMP)-2, and osteopontin (OPN) mRNA expression was analyzed by qPCR. The mechanism of action of SWT extract was investigated using western blotting. The in vivo anti-osteoporotic effect of SWT extract was assessed in ovariectomized mice. RESULTS: Here, we report that SWT increases ALP, BMP-2, and OPN expression as well as bone mineralization. In addition, we show that the PI3K, Akt, and NF-kappaB signaling pathways may be involved in the SWT-mediated increase in gene expression and bone mineralization. Notably, treatment of mice with SWT extract prevented bone loss induced by ovariectomy in vivo. CONCLUSION: SWT may be used to stimulate bone formation for the treatment of osteoporosis. PMID- 24156310 TI - Relational aggression in middle childhood predicting adolescent social psychological adjustment: the role of friendship quality. AB - The present longitudinal study examined the indirect effect of 6th-grade negative friendship quality on the associations between 5th-grade relational aggression and age 15 social-psychological adjustment (i.e., depressive symptoms and risky behavior). The study consisted of a secondary analysis of the National Institute of Child Health and Human Development Study of Early Child Care and Youth Development using 776 children (M = 10.42 years in 5th grade; 50.4% boys) from the original sample. Using teacher and self-report ratings, relational and physical aggression, friendship quality, depressive symptoms, and risky behavior were measured. Bootstrapping mediation analyses were conducted. Negative friendship quality was found to mediate the association between relational aggression and depressive symptoms as well as between relational aggression and risky behavior, when controlling for physical aggression, gender and age. This longitudinal study identifies possible developmental pathways by which relational aggression and future social psychological adjustment may be linked. PMID- 24156311 TI - Novel gelatin/alginate soft tissue adhesives loaded with drugs for pain management: structure and properties. AB - Interest in tissue adhesives as alternatives for conventional wound closing applications, such as sutures and staples, has increased in the last few decades due to numerous possible advantages, including less discomfort and lower cost. Novel tissue adhesives based on gelatin, with alginate as a polymeric additive and crosslinked by carbodiimide were developed and loaded with two types of drugs for pain relief, bupivacaine and ibuprofen, in order to improve the therapeutic effect. The release of the drugs from the adhesive matrix was found to be controlled mainly by the adhesive's characteristics, i.e. swelling and hydrophilic group concentration. The drug characteristics, i.e. hydrophilicity and electrical interactions between the drug and the polymeric components, were also found to have some effect. Incorporation of bupivacaine was found to improve the bonding strength of the adhesive due to its inert nature and the reinforcing effect of its fibrous crystals, whereas incorporation of ibuprofen was found to have an adverse effect on the bonding strength, probably due to its reaction with the other adhesive components which increased the crosslinking density. Overall, the novel drug-eluting gelatin-based bioadhesives investigated in this research, especially those loaded with bupivacaine, demonstrated a promising potential for use in wound closing applications. PMID- 24156314 TI - Semicarbazone analogs as anticonvulsant agents: a review. AB - Semicarbazones are synthesized by the condensation of semicarbazide and aldehyde/ketone. The literature survey revealed that semicarbazones had been emerged as compounds with diverse biological activities including anticonvulsant, antitubercular, anticancer, and antimicrobial activities. The anticonvulsant activity of semicarbazones is mainly attributed due to the presence of an aryl binding site with aryl/alkyl hydrophobic group, a hydrogen bonding domain and an electron donor group and they are suggested to act by inhibiting sodium ion (Na(+)) channel. Dimmock et al., reported an extensive series of semicarbazones and reported 4-(4-fluorophenoxy) benzaldehyde semicarbazone (C0102862, V102862) as lead molecule. In MES (oral) screening C0102862 showed protective index (PI > 315) more than carbamazepine (PI 101), phenytoin (PI > 21.6) and valproate (PI > 2.17). This review briefly describes the information available about semicarbazone analogs and their anticonvulsant activity. PMID- 24156315 TI - Synthesis and structural characterization of a series of Mn(III)OR complexes, including a water-soluble Mn(III)OH that promotes aerobic hydrogen-atom transfer. AB - Hydrogen-atom-transfer (HAT) reactions are a class of proton-coupled electron transfer (PCET) reactions used in biology to promote substrate oxidation. The driving force for such reactions depends on both the oxidation potential of the catalyst and the pKa value of the proton-acceptor site. Both high-valent transition-metal oxo M(IV)?O (M = Fe, Mn) and lower-valent transition-metal hydroxo compounds M(III)OH (M = Fe, Mn) have been shown to promote these reactions. Herein we describe the synthesis, structure, and reactivity properties of a series of Mn(III)OR compounds [R = (p)NO2Ph (5), Ph (6), Me (7), H (8)], some of which abstract H atoms. The Mn(III)OH complex 8 is water-soluble and represents a rare example of a stable mononuclear Mn(III)OH. In water, the redox potential of 8 was found to be pH-dependent and the Pourbaix (E(p,c) vs pH) diagram has a slope (52 mV pH(-1)) that is indicative of the transfer a single proton with each electron (i.e., PCET). The two compounds with the lowest oxidation potential, hydroxide- and methoxide-bound 7 and 8, are found to oxidize 2,2',6,6'-tetramethylpiperidin-1-ol (TEMPOH), whereas the compounds with the highest oxidation potential, phenol-ligated 5 and 6, are shown to be unreactive. Hydroxide-bound 8 reacts with TEMPOH an order of magnitude faster than methoxide bound 7. Kinetic data [kH/kD = 3.1 (8); kH/kD = 2.1 (7)] are consistent with concerted H-atom abstraction. The reactive species 8 can be aerobically regenerated in H2O, and at least 10 turnovers can be achieved without significant degradation of the "catalyst". The linear correlation between the redox potential and pH, obtained from the Pourbaix diagram, was used to calculate the bond dissociation free energy (BDFE) = 74.0 +/- 0.5 kcal mol(-1) for Mn(II)OH2 in water, and in MeCN, its BDFE was estimated to be 70.1 kcal mol(-1). The reduced protonated derivative of 8, [Mn(II)(S(Me2)N4(tren))(H2O)](+) (9), was estimated to have a pKa of 21.2 in MeCN. The ability (7) and inability (5 and 6) of the other members of the series to abstract a H atom from TEMPOH was used to estimate either an upper or lower limit to the Mn(II)O(H)R pKa based on their experimentally determined redox potentials. The trend in pKa [21.2 (R = H) > 16.2 (R = Me) > 13.5 (R = Ph) > 12.2 (R = (p)NO2Ph)] is shown to oppose that of the oxidation potential E(p,c) [-220 (R = (p)NO2Ph) > -300 (R = Ph) > -410 (R = Me) > -600 (R = H) mV vs Fc(+/0)] for this particular series. PMID- 24156317 TI - Color imaging via nearest neighbor hole coupling in plasmonic color filters integrated onto a complementary metal-oxide semiconductor image sensor. AB - State-of-the-art CMOS imagers are composed of very small pixels, so it is critical for plasmonic imaging to understand the optical response of finite-size hole arrays and their coupling efficiency to CMOS image sensor pixels. Here, we demonstrate that the transmission spectra of finite-size hole arrays can be accurately described by only accounting for up to the second nearest-neighbor scattering-absorption interactions of hole pairs, thus making hole arrays appealing for close-packed color filters for imaging applications. Using this model, we find that the peak transmission efficiency of a square-shaped hole array with a triangular lattice reaches ~90% that of an infinite array at an extent of ~6 * 6 MUm(2), the smallest size array showing near-infinite array transmission properties. Finally, we experimentally validate our findings by investigating the transmission and imaging characteristics of a 360 * 320 pixel plasmonic color filter array composed of 5.6 * 5.6 MUm(2) RGB color filters integrated onto a commercial black and white 1/2.8 in. CMOS image sensor, demonstrating full-color high resolution plasmonic imaging. Our results show good color fidelity with a 6-color-averaged color difference metric (DeltaE) in the range of 16.6-19.3, after white balancing and color-matrix correcting raw images taken with f-numbers ranging from 1.8 to 16. The integrated peak filter transmission efficiencies are measured to be in the 50% range, with a FWHM of 200 nm for all three RGB filters, in good agreement with the spectral response of isolated unmounted color filters. PMID- 24156316 TI - Experiment research on inhibition of glioma with sTRAIL in vitro. AB - We report that adenovirus mediated TNF-related apoptosis-inducing ligand (TRAIL) influenced the cell growth and cell cycle in the glioma cells in vitro. After being infected with the Ad-sTRAIL, U251 cell growth was inhibited. The expression of sTRAIL was detected using immunofluorescence. The higher rate of apoptosis was demonstrated using short-term microculture tetrazoliun (MTT) assay and flow cytometry. The rate of Ad-sTRAIL-inducing U251 cell apoptosis was increased depending on the dosage and the time. The apoptosis of G0/G1 and S phase cells was more significant than that of the control groups. The growth and proliferation of U251 cell line was inhibited after the infection of Ad-sTRAIL. It is dose- and time dependent. PMID- 24156318 TI - Coupling of NV centers to photonic crystal nanobeams in diamond. AB - The realization of efficient optical interfaces for solid-state atom-like systems is an important problem in quantum science with potential applications in quantum communications and quantum information processing. We describe and demonstrate a technique for coupling single nitrogen vacancy (NV) centers to suspended diamond photonic crystal cavities with quality factors up to 6000. Specifically, we present an enhancement of the NV center's zero-phonon line fluorescence by a factor of ~ 7 in low-temperature measurements. PMID- 24156320 TI - Metastatic process: the seed and the soil from bench to bedside. PMID- 24156321 TI - Patient approach in advanced/metastatic renal cell carcinoma: focus on the elderly population and treatment-related toxicity. AB - Recent therapeutic advances have changed the treatment landscape of metastatic renal cell carcinoma. Unfortunately, the seven agents now available are not based on biomarkers that would indicate which one could provide the best benefit for every patient. We have reviewed the avaliable information concerning the impact of each treatment on comorbidities or status that are frequently seen before commencing treatment for the advanced disease: elderly and patients with cardiovascular complications, metabolic and endocrinology disorders, and infections, as well as impaired organ function (kidney, liver and heart). Additional new drugs will be launched, but no predictive biomarkers are available. Head-to-head studies to evaluate the safety of the different drugs are rare. In this quite complex scenario, we believe that a decision-making approach focused on the patient may represent a suitable strategy. PMID- 24156322 TI - Multifunctional properties of RANKL/RANK in cell differentiation, proliferation and metastasis. AB - It is known that there are close relationships between bone destruction and tumor growth in bone metastasis. RANKL is a central factor in bone metastasis, inducing osteoclastogenesis mediated by its receptor RANK. Recent reports demonstrate that RANKL has important roles in organogenesis stimulating proliferation and differentiation of epithelial and stroma cells. RANKL is induced not only by cytokines and hormones but also by UV-irradiation, inflammation and carcinogens. Expression of RANK and RANKL is found in several human cancer cell lines, and RANK signaling stimulates proliferation, migration and epithelial-mesenchymal transition of cancer cells, which may be involved in metastasis via an autocrine/paracrine mechanism. RANKL regulates the number of Tregs that produce RANKL, which may affect cancer metastasis. In this review we discuss the multifunctional roles of RANKL/RANK in osteoclastogenesis, organogenesis, and the metastasis and tumorigenesis of cancer cells. PMID- 24156319 TI - Emerging pharmacotherapy for cancer patients with cognitive dysfunction. AB - Advances in the diagnosis and multi-modality treatment of cancer have increased survival rates for many cancer types leading to an increasing load of long-term sequelae of therapy, including that of cognitive dysfunction. The cytotoxic nature of chemotherapeutic agents may also reduce neurogenesis, a key component of the physiology of memory and cognition, with ramifications for the patient's mood and other cognition disorders. Similarly radiotherapy employed as a therapeutic or prophylactic tool in the treatment of primary or metastatic disease may significantly affect cognition. A number of emerging pharmacotherapies are under investigation for the treatment of cognitive dysfunction experienced by cancer patients. Recent data from clinical trials is reviewed involving the stimulants modafinil and methylphenidate, mood stabiliser lithium, anti-Alzheimer's drugs memantine and donepezil, as well as other agents which are currently being explored within dementia, animal, and cell culture models to evaluate their use in treating cognitive dysfunction. PMID- 24156323 TI - Role of hypoxia-inducible factors in breast cancer metastasis. AB - Human breast tumors contain regions of hypoxia in which cells that are located far from a functional blood vessel have significantly reduced oxygen concentrations when compared with normal mammary tissue. Breast cancer cells adapt to hypoxic conditions by increasing levels of hypoxia-inducible factors (HIFs), which induce the expression of multiple genes involved in angiogenesis, glucose utilization, resistance to oxidative stress, cell proliferation, resistance to apoptosis, invasion and metastasis. Breast cancer patients with increased HIF expression levels in primary tumor biopsies are at increased risk of metastasis. This is an important finding since 90% of breast cancer deaths are the result of metastasis, primarily to the bone, lungs, liver, brain and regional lymph nodes. Although the prognostic significance of reduced oxygen levels in primary breast tumors of cancer patients is well recognized, the mechanisms underlying hypoxia-induced, HIF-dependent breast cancer metastasis are just beginning to be uncovered. Recent studies have implicated HIF target genes in every step of the metastatic process. Drugs, such as digoxin, show the potential therapeutic effects of blocking HIF activity by decreasing primary tumor growth, vascularization, invasion and metastasis in animal models of breast cancer. PMID- 24156324 TI - Second-line systemic therapy for metastatic urothelial carcinoma of the bladder. AB - While platinum-based combination chemotherapy leads to high response rates in patients with advanced urothelial cancer of the bladder, most patients will ultimately progress and optimal treatment in the second-line setting still needs to be determined. Advanced age, poor performance status, comorbidities and rapidly progressive disease have rendered accrual into trials difficult. Vinflunine is the only cytotoxic agent to demonstrate survival benefit in a randomized Phase III setting, but its response rate is disappointing and it has not been compared with other currently used agents such as taxanes. Recent years have seen a better definition of prognostic and predictive factors in patients with relapsed urothelial cancer. In addition, several trials have investigated novel biological agents to target chemoresistant disease. This review provides an update on the current systemic management of advanced urothelial cancer on progression following first-line chemotherapy, and discusses emerging data from recent Phase II/III trials. PMID- 24156328 TI - Lessons from two domestic wars: cancer and poverty. PMID- 24156325 TI - Treatment of brain metastases from HER-2-positive breast cancer: current status and new concepts. AB - Breast cancer is the second most common source of brain metastases (BM). The incidence of BM in breast cancer patients has increased over the past decade, especially among patients with HER-2-positive breast cancer. This is probably due to how aggressive the HER-2-positive disease is but also to the prolongation of survival obtained with current treatments, which allow good control of extracranial disease but are unable to cross the blood-brain barrier. At present, whole-brain radiotherapy, surgery and radiosurgery/stereotactic radiotherapy represent the cornerstone of treatment for BM, while the role of pharmacological therapy remains uncertain. Lapatinib demonstrated activity against BM from HER-2 positive breast cancer in small Phase II and retrospective studies, mainly in combination with capecitabine, and cases of dramatic responses to such treatment are present in literature. In this review we focus on the available clinical data regarding the treatment of BM from HER-2-positive breast cancer and on new concepts about the treatment and evaluation of the CNS response. PMID- 24156327 TI - A perspective on the current management of advanced colorectal cancer. AB - Although the median survival of patients with advanced disease has progressively increased, colorectal cancer remains a major worldwide health problem, with approximately 1 million new cases and 500,000 deaths every year. At the 2013 World Congress on Gastrointestinal Cancers, investigators have recently dealt with many clinically relevant questions, such as the preferred biologic drug to be used upfront in patients with KRAS wild-type colorectal tumors, the optimal treatment intensity, the most suitable maintenance strategy, the need for deeper molecular information when using EGFR inhibitors and the use of antiangiogenic drugs in the elderly. Briefly summarizing all the news coming from this moving landscape, this article focuses on the results of the major randomized Phase III trials presented at the meeting. PMID- 24156329 TI - Tumor shrinkage and improved quality of life in a heavily pretreated metastatic breast cancer patient treated with eribulin. AB - Eribulin mesylate is approved for the treatment of metastatic breast cancer after progression with anthracyclines and taxanes. Here we report the case of a woman with triple-negative breast cancer who, after nine lines of chemotherapy, showed striking primary tumor shrinkage and regression of metastatic lesions with eribulin treatment. This response allowed the patient to undergo debulking surgery. Even though the patient was heavily pretreated, eribulin was well tolerated and improved her quality of life. Biological analysis of tumor specimens was performed to investigate the underlying mechanism of action of the drug. PMID- 24156330 TI - Gallbladder cancer-associated thrombotic microangiopathy. AB - Cancer-associated thrombotic microangiopathy (TMA) is a rare but serious condition seen in patients diagnosed with malignancy. Certain tumor characteristics highlight this entity, such as large tumor burden, adenocarcinoma histology with mucinous features and bone marrow infiltration. Although these tumors may originate from any site, the majority are of stomach, breast or prostate origin. The optimal therapy is unknown but there is evidence that immediate initiation of an effective antineoplastic regimen is important. However, it is difficult to differentiate cancer-associated TMA from primary thrombotic thrombocytopenic purpura in a timely manner. We present the first case of cancer-associated TMA in a patient secondary to a locally advanced gallbladder adenocarcinoma that lacked mucinous features and bone marrow involvement. The clinical presentation closely mimicked primary thrombocytopenic purpura and led to the ineffective use of plasma exchange. Nonetheless, the patient eventually received systemic chemotherapy and had a remarkable response by the resolution of her TMA. PMID- 24156331 TI - SAMITAL(r): a new botanical drug for the treatment of mucositis induced by oncological therapies. AB - SAMITAL((r)) (Indena SpA, Milan, Italy) is a new multicomponent and multiacting botanical formulation rationally designed for the relief of oral mucositis induced by chemotherapy and/or radiotherapy in oncological patients. Each of the individual botanical constituents of SAMITAL-standardized extracts of Vaccinium myrtillus, Macleaya cordata and Echinacea angustifolia have a long history of clinical use that corroborates their safety and activity in SAMITAL. A number of pilot trials in oncological patients demonstrated that SAMITAL has good clinical efficacy and tolerability as evidenced by its significant effects in terms of reduction of mucositis, pain and a general improvement in patient quality of life. Importantly, the use of this botanical formulation had the added benefit that patients were able to complete their chemotherapy/radiotherapy regimen. Phase II trials with SAMITAL as part of an overall clinical development program are currently ongoing in Italy and are planned in the USA. PMID- 24156332 TI - Effect of SAMITAL(r) in the treatment of chemotherapy-induced mucositis in adult oncohematological patients. AB - AIM: We sought to evaluate the efficacy and safety of SAMITAL((r)) (Indena SpA, Milan, Italy), a highly standardized botanical formulation, in reducing mucositis in patients undergoing treatment for hematological malignancies. PATIENTS & METHODS: In this observational, uncontrolled study, a total of 25 consecutively enrolled patients (19 males, aged 18-74 years) with chemotherapy-induced mucositis were compassionately treated orally with SAMITAL (three to four times per day) for 4-22 days per cycle. RESULTS: Patients demonstrated clinically relevant reductions in WHO mucositis grade with a reduction in pain, mucosal erosions, bleeding, dysphagia/feeding impairment and improvements in quality of life. SAMITAL was well tolerated and no local or systemic pharmacological, allergic, toxic or synergistic/antagonistic side effects were reported. Of note, SAMITAL also showed efficacy when administered prophylactically. CONCLUSION: These results add weight to previous experiences with SAMITAL. However, randomized, placebo-controlled clinical trials will need to confirm the suitability of SAMITAL for use in the treatment of mucositis. PMID- 24156334 TI - Optical techniques for the intraoperative assessment of nodal status. AB - The lymphatic system is an important pathway in the metastatic spread of many malignancies and a key prognostic indicator. Nondestructive assessment of the nodal status during surgery could limit the amount of lymph nodes that need to be resected and allow for immediate regional lymphadenectomy during sentinel lymph node biopsy procedures. This review looks into the possibilities of conventional medical imaging methods that are capable of intraoperative nodal assessment and discusses multiple newly developed optical techniques. The physical background behind these techniques is reviewed and a concise overview of their main advantages and disadvantages is provided. These recent innovations show that while the application of optical modalities for intraoperative nodal staging is not yet applied routinely, there is reason enough to expect their introduction in the near future. PMID- 24156335 TI - Wnt signaling in leukemias and myeloma: T-cell factors are in control. AB - Aberrant activation of the Wnt pathway has been implicated in the pathogenesis of many malignancies, especially solid tumors. During the past decade it also became clear that in hematological malignancies abnormal regulation of the Wnt pathway can either be causative or enhance disease progression, which will be discussed in detail in this review. PMID- 24156333 TI - IGF signaling pathway analysis of osteosarcomas reveals the prognostic value of pAKT localization. AB - AIM: The aim of this study was to examine the expression of the IGF signaling pathway components in osteosarcoma samples before and after chemotherapy with special emphasis on their prognostic value. MATERIALS & METHODS: Tumor material and follow-up data of 58 osteosarcoma patients were analyzed. Immunohistochemical staining was carried out to identify proteins related to the IGF pathway. Changes in protein expression during treatment, correlations between proteins and subsequent influence on survival were tested. RESULTS: Proteins of the IGF signaling system are widely expressed in osteosarcoma samples. We demonstrate a change in expression of intracellular pathway proteins after chemotherapy. Remarkably, cytoplasmic pAKT, but not nuclear pAKT, is associated with poor survival. CONCLUSION: IGF pathway proteins seem to be widely activated in osteosarcoma, but their expression changes after chemotherapy. This has implications for the timing of both measuring target expression and pathway interference. Our observations on the prognostic value of cytoplasmic pAKT warrant further investigation while considering the introduction of AKT inhibitors for osteosarcoma treatment. PMID- 24156336 TI - Potential role of Anxa1 in cancer. AB - The annexins are a well-known, closely related, multigene superfamily of Ca(2+) regulated, phospholipid-dependent, membrane-binding proteins. As a member of the annexins, Anxa1 participates in a variety of important biological processes, such as cellular transduction, membrane aggregation, inflammation, phagocytosis, proliferation, differentiation and apoptosis. Accumulated evidence has indicated that Anxa1 deregulations are associated with the development, invasion, metastasis, occurrence and drug resistance of cancers. The research evidence in recent years indicates that Anxa1 might specifically function either as a tumor suppressor or a tumor promoter candidate for certain cancers depending on the particular type of tumor cells/tissues. This article summarizes the associations between Anxa1 and malignant tumors, as well as potential action mechanisms. Anxa1 has the potential to be used in the future as a biomarker for the diagnosis, treatment and prognosis of certain tumors. PMID- 24156342 TI - Providing haptic feedback in robot-assisted minimally invasive surgery: a direct optical force-sensing solution for haptic rendering of deformable bodies. AB - This paper presents an enhanced haptic-enabled master-slave teleoperation system which can be used to provide force feedback to surgeons in minimally invasive surgery (MIS). One of the research goals was to develop a combined-control architecture framework that included both direct force reflection (DFR) and position-error-based (PEB) control strategies. To achieve this goal, it was essential to measure accurately the direct contact forces between deformable bodies and a robotic tool tip. To measure the forces at a surgical tool tip and enhance the performance of the teleoperation system, an optical force sensor was designed, prototyped, and added to a robot manipulator. The enhanced teleoperation architecture was formulated by developing mathematical models for the optical force sensor, the extended slave robot manipulator, and the combined control strategy. Human factor studies were also conducted to (a) examine experimentally the performance of the enhanced teleoperation system with the optical force sensor, and (b) study human haptic perception during the identification of remote object deformability. The first experiment was carried out to discriminate deformability of objects when human subjects were in direct contact with deformable objects by means of a laparoscopic tool. The control parameters were then tuned based on the results of this experiment using a gain scheduling method. The second experiment was conducted to study the effectiveness of the force feedback provided through the enhanced teleoperation system. The results show that the force feedback increased the ability of subjects to correctly identify materials of different deformable types. In addition, the virtual force feedback provided by the teleoperation system comes close to the real force feedback experienced in direct MIS. The experimental results provide design guidelines for choosing and validating the control architecture and the optical force sensor. PMID- 24156343 TI - Accuracy of computer-assisted total knee arthroplasty related to extra-articular tibial deformities. AB - OBJECTIVE: To compare the accuracy of postoperative mechanical alignment in computer-assisted total knee arthroplasties (CAS-TKA) related to various degrees of extra-articular tibial deformity. METHODS: We performed CAS-TKA on 30 knee models in which extra-articular proximal tibial deformities were preset to have malalignments ranging from 30 degrees of varus to 30 degrees of valgus. The knees were assigned to two groups, designated Group A (knees with <= 15 degrees preoperative malalignment) and Group B (knees with > 15 degrees preoperative malalignment), and the postoperative mechanical alignment in the two groups was compared using a computer-assisted surgery (CAS) system. Resected bone pieces from the distal femurs and proximal tibias were measured with a digital Vernier caliper and the results compared with the CAS calculations to evaluate the execution accuracy of the bone resection. RESULTS: There was no outlier in either group when a +/- 3 degrees deviation from neutral mechanical alignment was set as the acceptance criterion. Interestingly, Group B showed significantly more outliers when the acceptance criterion was a deviation of +/- 2 degrees (26.67%, p = 0.0317) or +/- 1 degrees (6.67%, p = 0.0007) from neutral alignment. There was no statistical difference between the groups in terms of the execution accuracy of the bone resection. DISCUSSION: The CAS-TKA approach provided significantly less alignment accuracy in tibia with greater preoperative frontal deformity, despite there being no outliers beyond +/- 3 degrees . PMID- 24156340 TI - Sub-threshold spinal cord stimulation facilitates spontaneous motor activity in spinal rats. AB - BACKGROUND: Epidural stimulation of the spinal cord can be used to enable stepping on a treadmill (electrical enabling motor control, eEmc) after a complete mid-thoracic spinal cord transection in adult rats. Herein we have studied the effects of eEmc using a sub-threshold intensity of stimulation combined with spontaneous load-bearing proprioception to facilitate hindlimb stepping and standing during daily cage activity in paralyzed rats. METHODS: We hypothesized that eEmc combined with spontaneous cage activity would greatly increase the frequency and level of activation of the locomotor circuits in paralyzed rats. Spontaneous cage activity was recorded using a specially designed swivel connector to record EMG signals and an IR based camcorder to record video. RESULTS AND CONCLUSION: The spinal rats initially were very lethargic in their cages showing little movement. Without eEmc, the rats remained rather inactive with the torso rarely being elevated from the cage floor. When the rats used their forelimbs to move, the hindlimbs were extended and dragged behind with little or no flexion. In contrast, with eEmc the rats were highly active and the hindlimbs showed robust alternating flexion and extension resulting in step-like movements during forelimb-facilitated locomotion and often would stand using the sides of the cages as support. The mean and summed integrated EMG levels in both a hindlimb flexor and extensor muscle were higher with than without eEmc. These data suggest that eEmc, in combination with the associated proprioceptive input, can modulate the spinal networks to significantly amplify the amount and robustness of spontaneous motor activity in paralyzed rats. PMID- 24156344 TI - Psychophysiological responses to emotional stimuli in children and adolescents with autism and fragile X syndrome. AB - Individuals with autism demonstrate atypical and variable responses to social and emotional stimuli, perhaps reflecting heterogeneity of the disorder. The goal of this study was to determine whether unique profiles of psychophysiological responses to such stimuli could be identified in individuals diagnosed with autism spectrum disorder (ASD), with fragile X syndrome (FXS), and with comorbid autism and fragile X syndrome (ASD + FXS), and in typically developing (TYP) individuals. This study included 52 boys (ages 10-17): idiopathic ASD (n = 12), FXS (n = 12), comorbid ASD + FXS (n = 17), and TYP (n = 11). Physiological responses, including potentiated startle, electrodermal response, heart rate variability, and vagal tone, were collected concurrently while participants viewed emotionally evocative pictures of human faces or nonsocial images. Although some of these measures have been utilized separately for investigations on these diagnostic groups, they have not been considered together. Results using Kruskal-Wallis one-way analysis of variance by ranks indicate statistically significant differences in distributions of autonomic regulation responses between groups. The most notable differences were between the ASD group and both the FXS groups on measures of sympathetic activity, with FXS groups evincing increased activity. Also, both the ASD and ASD + FXS groups showed significantly decreased parasympathetic activity compared with FXS and TYP groups. In addition, the ASD + FXS group demonstrated a unique distribution of startle potentiation and arousal modulation. This study provides evidence that autonomic arousal and regulation profiles could be useful for distinguishing subgroups of autism and shed light on the variability underlying emotional responsivity. PMID- 24156345 TI - Ependymal cells of the mouse brain express urate transporter 1 (URAT1). AB - BACKGROUND: Elevated uric acid (UA) is commonly associated with gout and it is also a known cardiovascular disease risk factor. In contrast to such deleterious effects, UA possesses neuroprotective properties in the brain and elucidating the molecular mechanisms involved may have significant value regarding the therapeutic treatment of neurodegenerative disease. However, it is not yet fully established how UA levels are regulated in the brain. In this study, we investigated the distribution of mouse urate transporter 1 (URAT1) in the brain. URAT1 is a major reabsorptive urate transporter predominantly found in the kidney. METHODS: Immunohistochemistry of wild type and URAT1 knockout mouse brain using paraffin or frozen sections and a rabbit polyclonal anti-mouse URAT1 antibody were employed. RESULTS: Antibody specificity was confirmed by the lack of immunostaining in brain tissue from URAT1 knockout mice. URAT1 was distributed throughout the ventricular walls of the lateral ventricle, dorsal third ventricle, ventral third ventricle, aqueduct, and fourth ventricle, but not in the non-ciliated tanycytes in the lower part of the ventral third ventricle. URAT1 was localized to the apical membrane, including the cilia, of ependymal cells lining the wall of the ventricles that separates cerebrospinal fluid (CSF) and brain tissue. CONCLUSION: In this study, we report that URAT1 is expressed on cilia and the apical surface of ventricular ependymal cells. This is the first report to demonstrate expression of the urate transporter in ventricular ependymal cells and thus raises the possibility of a novel urate transport system involving CSF. PMID- 24156350 TI - Chemically engineered graphene-based 2D organic molecular magnet. AB - Carbon-based magnetic materials and structures of mesoscopic dimensions may offer unique opportunities for future nanomagnetoelectronic/spintronic devices. To achieve their potential, carbon nanosystems must have controllable magnetic properties. We demonstrate that nitrophenyl functionalized graphene can act as a room-temperature 2D magnet. We report a comprehensive study of low-temperature magnetotransport, vibrating sample magnetometry (VSM), and superconducting quantum interference (SQUID) measurements before and after radical functionalization. Following nitrophenyl (NP) functionalization, epitaxially grown graphene systems can become organic molecular magnets with ferromagnetic and antiferromagnetic ordering that persists at temperatures above 400 K. The field-dependent, surface magnetoelectric properties were studied using scanning probe microscopy (SPM) techniques. The results indicate that the NP functionalization orientation and degree of coverage directly affect the magnetic properties of the graphene surface. In addition, graphene-based organic magnetic nanostructures were found to demonstrate a pronounced magneto-optical Kerr effect (MOKE). The results were consistent across different characterization techniques and indicate room-temperature magnetic ordering along preferred graphene orientations in the NP-functionalized samples. Chemically isolated graphene nanoribbons (CINs) were observed along the preferred functionality directions. These results pave the way for future magnetoelectronic/spintronic applications based on promising concepts such as current-induced magnetization switching, magnetoelectricity, half-metallicity, and quantum tunneling of magnetization. PMID- 24156347 TI - Solid state complex chemistry: formation, structure, and properties of homoleptic tetracyanamidogermanates RbRE[Ge(CN2)4] (RE = La, Pr, Nd, Gd). AB - Tetracyanamidometallates with the general formula RbRE[T(CN2)4] (RE = La, Pr, Nd, Gd; T = Si, Ge) were prepared by solid state metathesis reactions starting from stoichiometric mixtures of RECl3, A2[TF6], and Li2(CN2). Reactions were studied by differential thermal analysis that showed ignition temperatures between 360 and 390 degrees C for the formation of RbGd[T(CN2)4] with T = Si and Ge. The powder diffraction patterns of RbRE[Ge(CN2)4] were indexed isotypically to the already known RbRE[Si(CN2)4] compound. IR spectra of RbLa[Ge(CN2)4] were measured and compared with those of RbLa[Si(CN2)4]. (73)Ge, (87)Rb, and (139)La solid state NMR measurements and density functional theory calculations were used to verify the novel homoleptic [Ge(CN2)4](4-) ion. Luminescence properties of Eu(3+), Ce(3+), and Tb(3+) doped samples are reported. PMID- 24156357 TI - Raman fingerprint of aligned graphene/h-BN superlattices. AB - Graphene placed on hexagonal-boron nitride (h-BN) experiences a superlattice (Moire) potential, which leads to a strong reconstruction of graphene's electronic spectrum with new Dirac points emerging at sub-eV energies. Here we study the effect of such superlattices on graphene's Raman spectrum. In particular, the 2D Raman peak is found to be exquisitely sensitive to the misalignment between graphene and h-BN lattices, probably due to the presence of a strain distribution with the same periodicity of the Moire potential. This feature can be used to identify graphene superlattices with a misalignment angle smaller than 2 degrees . PMID- 24156356 TI - Antioxidant activity of essential oils. AB - Essential oils (EOs) are liquid mixtures of volatile compounds obtained from aromatic plants. Many EOs have antioxidant properties, and the use of EOs as natural antioxidants is a field of growing interest because some synthetic antioxidants such as BHA and BHT are now suspected to be potentially harmful to human health. Addition of EOs to edible products, either by direct mixing or in active packaging and edible coatings, may therefore represent a valid alternative to prevent autoxidation and prolong shelf life. The evaluation of the antioxidant performance of EOs is, however, a crucial issue, because many commonly used "tests" are inappropriate and give contradictory results that may mislead future research. The chemistry explaining EO antioxidant activity is discussed along with an analysis of the potential in food protection. Literature methods to assess EOs' antioxidant performance are critically reviewed. PMID- 24156346 TI - In vitro perfusion of engineered heart tissue through endothelialized channels. AB - In engineered heart tissues (EHT), oxygen and nutrient supply via mere diffusion is a likely factor limiting the thickness of cardiac muscle strands. Here, we report on a novel method to in vitro perfuse EHT through tubular channels. Adapting our previously published protocols, we expanded a miniaturized fibrin based EHT-format to a larger six-well format with six flexible silicone posts holding each EHT (15*25*3 mm3). Thin dry alginate fibers (17*0.04*0.04 mm) were embedded into the cell-fibrin-thrombin mix and, after fibrin polymerization, dissolved by incubation in alginate lyase or sodium citrate. Oxygen concentrations were measured with a microsensor in 14-day-old EHTs (37 degrees C, 21% oxygen) and ranged between 9% at the edges and 2% in the center of the tissue. Perfusion rapidly increased it to 10%-12% in the immediate vicinity of the microchannel. Continuous perfusion (20 MUL/h, for 3 weeks) of the tubular lumina (100-500 MUm) via hollow posts of the silicone rack increased mean dystrophin-positive cardiomyocyte density (36%+/-6% vs. 10%+/-3% of total cell number) and cross sectional area (73+/-2 vs. 48+/-1 MUm2) in the central part of the tissue compared to nonperfused EHTs. The channels were populated by endothelial cells present in the reconstitution cell mix. In conclusion, we developed a novel approach to generate small tubular structures suitable for perfusion of spontaneously contracting and force-generating EHTs and showed that prolonged perfusion improved cardiac tissue structure. PMID- 24156351 TI - Effect of protons on CdSe and CdSe-ZnS nanocrystals in organic solution. AB - Core and core-shell quantum dots are covered with a layer of organic ligands which prevents aggregation and eliminates surface defects, thus enhancing the photophysical properties and stability of the material. These ligands are usually Lewis bases and can therefore be affected by the presence of acid in the surrounding environment. We synthesized core CdSe and core-shell CdSe-ZnS quantum dots with various shell thicknesses and different organic ligands, and we investigated the effect of acid and base on their photophysical properties. In dilute CHCl3 solution, the organic ligands can be protonated upon addition of acid and detached from the surface of the nanoparticles. As a consequence, the nanoparticles aggregate and their luminescence is quenched. Aggregated particles can be partly disgregated and the luminescence restored by deprotonation of the free ligands with a base. Since the presence of organic ligands on the surface is an essential characteristic of quantum dots, these effects should be taken into consideration when designing quantum dot-based sensors. PMID- 24156359 TI - Mesenchymal stem cells to augment therapeutic angiogenesis in hind-limb ischemia models: how important is their source? AB - Murine models of hind-limb ischemia are frequently used to assess interventions aimed at improving therapeutic angiogenesis in critical limb ischemia. Much of the current focus of angiogenesis lies with mesenchymal stem cells (MSCs). Important considerations when using these models include the strain of mouse, because some strains recover from ischemia more rapidly than others, and the MSC source. MSCs derived from certain strains generate increased levels of growth factors such as vascular endothelial growth factor. This may significantly affect the limb?s ability to generate collateral vessels. PMID- 24156348 TI - Dosage strength is associated with medication persistence with Ginkgo biloba drug products: a cohort study of ambulatory drug claims data in Germany. AB - BACKGROUND: Ginkgo biloba drugs (Gb) are reimbursed within the German statutory health insurance (SHI) scheme for treatment of dementia. In 2008, a novel Gb product containing 240 mg Ginkgo extract EGb761(r) per tablet was introduced aiming to facilitate medication use by incorporating the recommended daily dose in one single tablet. The aim of this study was to evaluate the relationship between dosage strength and persistence in a representative population of patients treated with Gb. METHODS: Retrospective cohort study in ambulatory drug claims database within the German SHI system. Persistence was defined as continuous treatment with an allowable gap of 20% between refills. Multivariate regression models were conducted to identify variables associated with persistence. RESULTS: Among 13,810 patients initiating treatment with Gb in 2008, 430 (3.1%) received a dosage strength of 240 mg, 7,070 (51.2%) a dosage strength of 120 mg and 6,310 (45.7%) dosage strengths containing less than 120 mg Gb per tablet. After 6 months, persistence was highest for patients treated with the 240 mg dosage form (22.8% of patients), although persistence was low in general (5.7% and 0% of patients treated with 120 mg and less than 120 mg, respectively). Risk for non-persistence was reduced in patients receiving 240 mg products compared to 120 mg (HR = 0.63; 95%CI 0.57 - 0.70). CONCLUSIONS: Patients initially treated with Gb 240 mg were more persistent compared to those receiving lower dosage strengths. Nevertheless, persistence with Gb therapy is generally low and should be improved in order to better realize therapeutic effects. PMID- 24156352 TI - Electrodynamic pressure modulation of protein stability in cosolvents. AB - Cosolvents affect structural stability of proteins in aqueous solutions. A clear understanding of the mechanism by which cosolvents impact protein stability is critical to understanding protein folding in a biological milieu. In this study, we investigated the Lifshitz-van der Waals dispersion interaction of seven different solutes with nine globular proteins and report that in an aqueous medium the structure-stabilizing solutes exert a positive electrodynamic pressure, whereas the structure-destabilizing solutes exert a negative electrodynamic pressure on the proteins. The net increase in the thermal denaturation temperature (DeltaTd) of a protein in 1 M solution of various solutes was linearly related to the electrodynamic pressure (PvdW) between the solutes and the protein. The slope of the PvdW versus DeltaTd plots was protein dependent. However, we find a positive linear relationship (r(2) = 0.79) between the slope (i.e., d(DeltaTd)/dPvdW) and the adiabatic compressibility (betas) of the proteins. Together, these results clearly indicate that the Lifshitz's dispersion forces are inextricably involved in solute-induced stabilization/destabilization of globular proteins. The positive and/or negative electrodynamic pressure generated by the solute-protein interaction across the water medium seems to be the fundamental mechanism by which solutes affect protein stability. This is at variance with the existing preferential hydration concept. The implication of these results is significant in the sense that, in addition to the hydrophobic effect that drives protein folding, the electrodynamic forces between the proteins and solutes in the biological milieu also might play a role in the folding process as well as in the stability of the folded state. PMID- 24156360 TI - Etiologic subtype predicts outcome in mild stroke: prospective data from a hospital stroke registry. AB - BACKGROUND: Few studies on whether etiologic subtype can predict outcome in mild stroke are available. The study aim to explore the effect of different etiologic subtype on prognosis of these patients. METHODS: We prospectively registered consecutive cases of acute ischemic stroke from September. 01, 2009 to August. 31, 2011. Patients with National Institute of Health Stroke Scale (NIHSS) ?3 and within 30 days of symptom onset were included. All cause death or disability (defined as modified Rankin Scale >2) were followed up at 3 months. The multivariate logistical regression model was used to analyse relationship between etiologic subtype and clinical outcomes. RESULTS: We included 680 cases, which accounted for 41.1% (680/1655) of the total registered cases. Mean age were 62.54 +/- 13.51 years, and males were 65.4%. The median time of symptoms onset to admission was 72 hours. 3.8% (26/680) of cases admitted within 3 hours and 4.7% (32/680) admitted within 4.5 hours. However, no patient received intravenous thrombolysis. Of included patients, 21.5% large-artery atherosclerosis, 40.6% small-vessel disease, 7.5% cardioembolisms, 2.2% other causes and 28.2% undetermined causes. The rate of case fatality and death/disability was 2.2% and 10.1% respectively at 3 months. After adjustment of potential confounders, such as age, sex, NIHSS on admission and vascular risk factors et al., cardioembolism (RR = 3.395;95%CI 1.257 ~ 9.170) was the predictor of death or disability at 3 months and small vessel occlusion (RR = 0.412;95%CI 0.202 ~ 0.842) was the protective factor of death or disability at 3 months. CONCLUSION: Different etiologic subtype can predict the outcome in patients with mild stroke and it can help to stratify these patients for individual decision-making. PMID- 24156362 TI - Modelling hollow organs for impact conditions: a simplified case study. AB - This study compares the performances of three numerical approaches [Lagrangian (LAG), arbitrary Lagrangian-Eulerian (ALE) and control volume (CV)] for modelling the response of a short cylindrical pipe representing a portion of the intestines subjected to large and rapid compressions. While not being able to simulate sustained fluid flow, the LAG approach provided similar results as the ALE for moderate levels of compression. However, it was the stiffest approach for larger levels and had numerical issues for extreme compressions. While the ALE did not have these issues, its computing cost was very high, which would be problematic for large models. The CV approach had the lowest computing cost and seemed promising for larger compressions. However, its response was the softest and further investigations are needed to define its dependency to modelling parameters. PMID- 24156361 TI - A clinimetric study of outpatient diabetes consultations: the potential for telemedicine substitution. AB - BACKGROUND: The purpose of this study was to identify the clinimetric characteristics of specialist outpatient consultations for people with diabetes and to evaluate the possibility of providing such consultations remotely using telemedicine. MATERIALS AND METHODS: The process of care was analyzed during the specialist consultations provided by five endocrinologists in a tertiary hospital diabetes outpatient clinic. The specialists' opinion of the possibility of providing each consultation remotely was also sought. RESULTS: In total, 50 consultations were analyzed. The patients had type 1 and type 2 diabetes in 28% and 64% of the cases, respectively; 68% had at least one diabetes complication. Diabetic neuropathy was the most prevalent (42%) complication. Physical examination was not performed by the specialists in 34% of cases. General foot inspection, the most frequent examination, was performed in 54% of the consultations. After "general advice," ordering laboratory tests was the most frequent recommendation (80%), followed by adjustment of an insulin regimen (52%). In 86% of consultations, the specialists believed that it would have been possible to provide that consultation remotely via videoconferencing to a patient with the general practitioner present. In their opinion, communicating with the patients through e-mail was the least possible alternative means of providing the consultations. CONCLUSIONS: Endocrinologists with little telemedicine experience believe that a considerable proportion of outpatient specialty consultations for people with diabetes can be provided remotely via videoconferencing. The clinimetric analysis of 50 consultations supports this opinion. PMID- 24156349 TI - Proton pump inhibitor chemosensitization in human osteosarcoma: from the bench to the patients' bed. AB - BACKGROUND: Major goals in translational oncology are to reduce systemic toxicity of current anticancer strategies and improve effectiveness. An extremely efficient cancer cell mechanism to avoid and/or reduce the effects of highly cytotoxic drugs is the establishment of an acidic microenvironment, an hallmark of all malignant tumors. The H +-rich milieu that anticancer drugs meet once they get inside the tumor leads to their protonation and neutralization, therefore hindering their access into tumor cells. We have previously shown that proton pump inhibitors (PPI) may efficiently counterattack this tumor advantage leading to a consistent chemosensitization of tumors. In this study, we investigated the effects of PPI in chemosensitizing osteosarcoma. METHOD: MG-63 and Saos-2 cell lines were used as human osteosarcoma models. Cell proliferation after pretreatment with PPI and subsequent treatment with cisplatin was evaluated by using erythrosin B dye vital staining. Tumour growth was evaluated in xenograft treated with cisplatin after PPI pretreatment. Subsequently, a multi-centre historically controlled trial, was performed to evaluate the activity of a pre treatment administration of PPIs as chemosensitizers during neoadjuvant chemotherapy based on methotrexate, cisplatin, and adriamycin. RESULTS: Preclinical experiments showed that PPI sensitize both human osteosarcoma cell lines and xenografts to cisplatin. A clinical study subsequently showed that pretreatment with PPI drug esomeprazole leads to an increase in the local effect of chemotherapy, as expressed by percentage of tumor necrosis. This was particularly evident in chondroblastic osteosarcoma, an histological subtype that normally shows a poor histological response. Notably, no significant increase in toxicity was recorded in PPI treated patients. CONCLUSION: This study provides the first evidence that PPI may be beneficially added to standard regimens in combination to conventional chemotherapy. PMID- 24156358 TI - Future directions in the developmental science of addictions. AB - This article addresses important future directions for the study of addictions, emphasizing the incorporation of developmental perspectives into how we think about substance use and disorder as unfolding processes over time and context for a heterogeneous group of individuals. These perspectives articulate complexities in the developmental processes that underlie change and continuity in human behavior over time. We consider two key developmental concepts, namely, "time" and "heterogeneity." We argue that a lack of attention to time sampling creates ambiguity in the meaning of time-linked assessments, challenges in discerning which of multiple clocks may govern behavior, and the inability in some instances to distinguish which of multiple etiological processes may be driving behavior within our samples. Moreover, artificial divisions among disorders that commonly co-occur with substance use are a barrier to the further integration of the study and treatment of addictions with that of psychopathology. Similar to recent changes in the study of psychiatric disorders more broadly, we argue that identifying common deficits among commonly comorbid disorders, rather than patterns of comorbidity per se, is key to identifying early emerging risk factors for substance use and disorder, with important implications for identifying risk populations and developmental periods as well as potentially malleable intervention targets. Attention to time sampling in theory-driven research designs and attempts to identify more homogenous groups of individuals who use and eventually abuse substances over time are two examples of ways to better understand some of the complexity underlying the development of addictions. PMID- 24156365 TI - Interaction of endothelial and smooth muscle cells with cobalt-chromium alloy surfaces coated with paclitaxel deposited self-assembled monolayers. AB - The use of self-assembled monolayers (SAMs) as a polymer-free platform to deliver an antiproliferative drug, paclitaxel (PAT), from a stent material cobalt chromium (CoCr) alloy has been previously demonstrated. In this study, the interaction of human aortic endothelial cells (ECs) and human aortic smooth muscle cells (SMCs) with CoCr alloy surfaces coated with SAMs- (SAMs-CoCr) and PAT-deposited SAMs (PAT-SAMs-CoCr) was investigated. A polished CoCr with no coatings was used as a control. The viability, proliferation, morphology, and phenotype of ECs and SMCs were investigated on these samples. SAMs-CoCr significantly enhanced the growth of ECs. Also, the ECs were well spreading with its typical morphological features and showed stronger PECAM-1 expression on SAMs CoCr. This showed that the SAMs-CoCr surface is conducive to endothelialization. For PAT-SAMs-CoCr, although the adhesion of ECs was lower, the cells continued to proliferate with some degree of spreading and limited PECAM-1 expression. For SMCs, a significant decrease in the cell proliferation was observed on SAMs-CoCr when compared with that of Control-CoCr. PAT-SAMs-CoCr showed maximum inhibitory effect on the proliferation of SMCs. Also, the SMCs on PAT-SAMs-CoCr displayed a poorly spread discoid morphology with disarranged alpha-actin filaments. This showed that the PAT released from the SAMs platform successfully inhibited the growth of SMCs. Thus, this study showed the interaction of ECs and SMCs with SAMs CoCr and PAT-SAMs-CoCr for potential uses in stents and other cardiovascular medical devices. PMID- 24156372 TI - Astaxanthin and canthaxanthin (xanthophyll) as supplements in rainbow trout diet: in vivo assessment of residual levels and contributions to human health. AB - Many studies have demonstrated that xanthophylls, such as astaxanthin, have beneficial effects in human health, and their use in food supplements is thus encouraged. Moreover, such nutrients are frequently used in aquaculture to meet consumer demand for salmonoid flesh pigmentation. In this study different xanthophyll administration protocols were tested to verify pigmentation properties and safety of such mixtures of additives in trout diet. Residues of xanthophylls in muscle samples were determined by HPLC-MS/MS, reaching levels of 3.70 +/- 0.04 mg/kg (astaxanthin) and 1.21 +/- 0.06 mg/kg (canthaxanthin) during a 56 day administration period. On the basis of the average fish consumption in the human diet, the highest astaxanthin and canthaxanthin concentrations detected in trout fillets could result in weekly intakes of 1.63 and 0.53 mg, respectively, in humans; these values are not sufficient to achieve the positive effects described by many authors, but their residues could still represent an important source of carotenoids, alternative to the use of synthetic dietary supplements. PMID- 24156370 TI - Parasites as biological tags of fish stocks: a meta-analysis of their discriminatory power. AB - The use of parasites as biological tags to discriminate among marine fish stocks has become a widely accepted method in fisheries management. Here, we first link this approach to its unstated ecological foundation, the decay in the similarity of the species composition of assemblages as a function of increasing distance between them, a phenomenon almost universal in nature. We explain how distance decay of similarity can influence the use of parasites as biological tags. Then, we perform a meta-analysis of 61 uses of parasites as tags of marine fish populations in multivariate discriminant analyses, obtained from 29 articles. Our main finding is that across all studies, the observed overall probability of correct classification of fish based on parasite data was about 71%. This corresponds to a two-fold improvement over the rate of correct classification expected by chance alone, and the average effect size (Zr = 0.463) computed from the original values was also indicative of a medium-to-large effect. However, none of the moderator variables included in the meta-analysis had a significant effect on the proportion of correct classification; these moderators included the total number of fish sampled, the number of parasite species used in the discriminant analysis, the number of localities from which fish were sampled, the minimum and maximum distance between any pair of sampling localities, etc. Therefore, there are no clear-cut situations in which the use of parasites as tags is more useful than others. Finally, we provide recommendations for the future usage of parasites as tags for stock discrimination, to ensure that future applications of the method achieve statistical rigour and a high discriminatory power. PMID- 24156363 TI - Predictive value of in vitro assays depends on the mechanism of toxicity of metal oxide nanoparticles. AB - BACKGROUND: Hazard identification for risk assessment of nanoparticles (NPs) is mainly composed of in vitro cell-based assays and in vivo animal experimentation. The rapidly increasing number and functionalizations of NPs makes in vivo toxicity tests undesirable on both ethical and financial grounds, creating an urgent need for development of in vitro cell-based assays that accurately predict in vivo toxicity and facilitate safe nanotechnology. METHODS: In this study, we used 9 different NPs (CeO2, TiO2, carbon black, SiO2, NiO, Co3O4, Cr2O3, CuO, and ZnO). As an in vivo toxicity endpoint, the acute lung inflammogenicity in a rat instillation model was compared with the in vitro toxicity endpoints comprising cytotoxicity, pro-inflammatory cytokine expression, or haemolytic potential. For in vitro assays, 8 different cell-based assays were used including epithelial cells, monocytic/macrophage cells, human erythrocytes, and combined culture. RESULTS: ZnO and CuO NPs acting via soluble toxic ions showed positive results in most of assays and were consistent with the lung inflammation data. When compared in in vitro assays at the same surface area dose (30 cm2/mL), NPs that were low solubility and therefore acting via surface reactivity had no convincing activity, except for CeO2 NP. Cytotoxicity in differentiated peripheral blood mononuclear cells was the most accurate showing 89% accuracy and 11% false negativity in predicting acute lung inflammogenicity. However, the haemolysis assay showed 100% consistency with the lung inflammation if any dose, having statistical significance was considered positivity. Other cell-based in vitro assays showed a poorer correlation with in vivo inflammogenicity. CONCLUSIONS: Based on the toxicity mechanisms of NPs, two different approaches can be applied for prediction of in vivo lung inflammogenicity. Most in vitro assays were good at detecting NPs that act via soluble ions (i.e., ZnO and CuO NP). However, in vitro assays were limited in detecting NPs acting via surface reactivity as their mechanism of toxicity, except for the haemolysis assay. PMID- 24156367 TI - Moderate intensity supine exercise causes decreased cardiac volumes and increased outer volume variations: a cardiovascular magnetic resonance study. AB - BACKGROUND: The effects on left and right ventricular (LV, RV) volumes during physical exercise remains controversial. Furthermore, no previous study has investigated the effects of exercise on longitudinal contribution to stroke volume (SV) and the outer volume variation of the heart. The aim of this study was to determine if LV, RV and total heart volumes (THV) as well as cardiac pumping mechanisms change during physical exercise compared to rest using cardiovascular magnetic resonance (CMR). METHODS: 26 healthy volunteers (6 women) underwent CMR at rest and exercise. Exercise was performed using a custom built ergometer for one-legged exercise in the supine position during breath hold imaging. Cardiac volumes and atrio-ventricular plane displacement were determined. Heart rate (HR) was obtained from ECG. RESULTS: HR increased during exercise from 60+/-2 to 94+/-2 bpm, (p<0.001). LVEDV remained unchanged (p=0.81) and LVESV decreased with -9+/-18% (p<0.05) causing LVSV to increase with 8+/-3% (p<0.05). RVEDV and RVESV decreased by -7+/-10% and -24+/-14% respectively, (p<0.001) and RVSV increased 5+/-17% during exercise although not statistically significant (p=0.18). Longitudinal contribution to RVSV decreased during exercise by -6+/-15% (p<0.05) but was unchanged for LVSV (p=0.74). THV decreased during exercise by -4+/-1%, (p<0.01) and total heart volume variation (THVV) increased during exercise from 5.9+/-0.5% to 9.7+/-0.6% (p<0.001). CONCLUSIONS: Cardiac volumes and function are significantly altered during supine physical exercise. THV becomes significantly smaller due to decreases in RVEDV whilst LVEDV remains unchanged. THVV and consequently radial pumping increases during exercise which may improve diastolic suction during the rapid filling phase. PMID- 24156376 TI - Wiring-up carbon single wall nanotubes to polycrystalline inorganic semiconductor thin films: low-barrier, copper-free back contact to CdTe solar cells. AB - We have discovered that films of carbon single wall nanotubes (SWNTs) make excellent back contacts to CdTe devices without any modification to the CdTe surface. Efficiencies of SWNT-contacted devices are slightly higher than otherwise identical devices formed with standard Au/Cu back contacts. The SWNT layer is thermally stable and easily applied with a spray process, and SWNT contacted devices show no signs of degradation during accelerated life testing. PMID- 24156371 TI - Narrow therapeutic window of ribavirin as an inhibitor of nitric oxide synthesis is broadened by macromolecular prodrugs. AB - Ribavirin (RBV), a broad-spectrum antiviral agent, is a standard medication against hepatitis C virus (HCV). However, despite the decades of clinical success, the mechanism of action of this drug against HCV remains a subject of debate. Furthermore, the appeal of this therapeutic agent is considerably lessened by unfavorable pharmacokinetics. This interdisciplinary study contributes to the understanding of intracellular effects exerted by RBV and presents a successful design of macromolecular prodrugs of RBV to achieve a safer treatment. Specifically, we demonstrate that RBV exhibits a pronounced anti inflammatory activity in cultured macrophages as is evidenced by a 2-fold decrease in the levels of produced nitric oxide achieved using a clinically relevant concentration of this drug. However, this effect was characterized by a rather narrow therapeutic window with experimental values of EC50 and IC50 being 7 and 19 MUM, respectively. Macromolecular prodrugs were obtained using an acrylate derivative of RBV, RAFT polymerization technique, and N-vinyl pyrrolidone as a partner monomer. The synthesized polymers were characterized with uniform molecular weights, relatively narrow polydispersities, and gradually increasing content of RBV. The resulting polymer therapeutics were effective in delivering their payload to the cultured macrophages and afforded a significantly wider therapeutic window, as much as >1000 MUM (18-fold in relative values). Taken together, this work contributes significantly to the development of safer methods for delivery of RBV, as well as understanding the mechanism of action and origins of the side effects of this broad-spectrum antiviral agent. PMID- 24156366 TI - Protective activity of Panduratin A against thioacetamide-induced oxidative damage: demonstration with in vitro experiments using WRL-68 liver cell line. AB - BACKGROUND: Chalcone Panduratin A (PA) has been known for its antioxidant property, but its merits against oxidative damage in liver cells has yet to be investigated. Hence, the paper aimed at accomplishing this task with normal embryonic cell line WRL-68. METHODS: PA was isolated from Boesenbergia rotunda rhizomes and its 2,2-diphenyl-1-picrylhydrazyl (DPPH) scavenging and ferric reducing power (FRAP) activities were measured in comparison with that of the standard reference drug Silymarin (SI). Oxidative damage was induced by treating the cells with 0.04 g/ml of toxic thioacetamide for 60 minutes followed by treatment with 1, 10 and 100 MUg/ml concentrations of either PA or SI. The severities of oxidative stress in the control and experimental groups of cells were measured by Malondialdehyde (MDA) levels, superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GPx) activities. RESULTS: PA exhibited an acceptable DPPH scavenging and FRAP activities close to that of Silymarin. Treating the injured cells with PA significantly reduced the MDA level and increased the cell viability, comparable to SI. The activities of SOD, CAT and GPx were significantly elevated in the PA-treated cells in a dose dependent manner and again similar to SI. CONCLUSION: Collectively, data suggested that PA has capacity to protect normal liver cells from oxidative damage, most likely via its antioxidant scavenging ability. PMID- 24156375 TI - Principal component analysis in construction of 3D human knee joint models using a statistical shape model method. AB - The statistical shape model (SSM) method that uses 2D images of the knee joint to predict the three-dimensional (3D) joint surface model has been reported in the literature. In this study, we constructed a SSM database using 152 human computed tomography (CT) knee joint models, including the femur, tibia and patella and analysed the characteristics of each principal component of the SSM. The surface models of two in vivo knees were predicted using the SSM and their 2D bi-plane fluoroscopic images. The predicted models were compared to their CT joint models. The differences between the predicted 3D knee joint surfaces and the CT image based surfaces were 0.30 +/- 0.81 mm, 0.34 +/- 0.79 mm and 0.36 +/- 0.59 mm for the femur, tibia and patella, respectively (average +/- standard deviation). The computational time for each bone of the knee joint was within 30 s using a personal computer. The analysis of this study indicated that the SSM method could be a useful tool to construct 3D surface models of the knee with sub-millimeter accuracy in real time. Thus, it may have a broad application in computer-assisted knee surgeries that require 3D surface models of the knee. PMID- 24156368 TI - Suicidal ideation in anxiety-disordered youth: identifying predictors of risk. AB - Evidence is mixed regarding an independent association between anxiety and suicidality. Beyond associations with demographic factors and depression, do anxiety disorders increase risk for suicidality in youth? Given that not all anxiety-disordered youth experience suicidal ideation, potential predictors of risk also require investigation. The present study examined (a) the independent relationship between anxiety and suicidal ideation and (b) emotion dysregulation and distress intolerance as predictors of risk for suicidal ideation in a sample of anxiety-disordered youth aged 7 to 17 (N = 86, M = 11.5). Youth and their parents reported on suicidality, emotion dysregulation, and distress intolerance. Distress tolerance was also measured by a computerized behavioral task. Results support an independent relationship between anxiety symptomatology and youth reported suicidal ideation, controlling for depressive symptoms. Youth self report of emotion dysregulation and distress intolerance predicted higher levels of suicidal ideation in univariate analyses. In a multivariate analysis including all significant predictors, only anxiety symptomatology uniquely predicted suicidal ideation. Results provide recommendations for the assessment and treatment of suicidality in anxiety-disordered youth. Suggestions for future research investigating the relationship between anxiety and suicidal ideation are offered. PMID- 24156378 TI - Gq rather than G11 preferentially mediates nociceptor sensitization. AB - BACKGROUND: The G(q/11)-protein signaling mechanism is essential throughout the nervous system, but little is known about the contribution of the individual G protein GPCR signaling branches towards nociceptor activation and their specific role on nociceptor sensitization. We aimed to unravel the contribution of the G(q/11)-signaling pathway towards nociceptor activation via a variety of classical inflammatory mediators signalling via different G-protein GPCRs and investigated the specific contribution of the individual G(q) and G(11) G Proteins in nociceptors. FINDINGS: Using different transgenic mouse lines, lacking Galpha(q), Galpha(11) or both alpha-subunit of the G-proteins in primary nociceptive neurons, we analyzed the mechanical- and heat-sensitivity upon application of different GPCR-agonists that are known to play an important role under inflammatory conditions (e.g. ATP, Glutamate, Serotonin etc.). We found that the G(q/11)-GPCR signaling branch constitutes a primary role in the manifestation of mechanical allodynia and a minor role in the development of thermal hyperalgesia. Moreover, with respect to the mediators used here, the G(q) protein is the principle G-protein among the G(q/11)-protein family in nociceptive neurons leading to nociceptor sensitization. CONCLUSIONS: Our results demonstrate that the G(q/11) signaling branch plays a primary role in nociceptor sensitization upon stimulation with classical GPCR ligands, contributing primarily towards the development of mechanically allodynia. Moreover, the deletion of the individual G-proteins led to the finding that the G(q)-protein dominates the signalling machinery of the G(q/11) family of G-proteins in nociceptive neurons. PMID- 24156373 TI - Angiopoietin-1 and angiopoietin-2 are altered in polycystic ovarian syndrome (PCOS) during controlled ovarian stimulation. AB - Polycystic ovarian syndrome (PCOS) ovaries are characterized by increased angiogenesis and hypervascularity. While angiopoietin-1 (Ang-1) and its antagonist, angiopoietin-2 (Ang-2), are essential for ovarian function and angiogenesis, the levels of Ang-1 and Ang-2 in PCOS are unknown. This was a prospective cohort study of 14 PCOS women and 14 matched controls undergoing controlled ovarian stimulation (COS). Serum was collected on day 3, hCG and retrieval days. Follicular fluid (FF) was collected on retrieval day. Serum Ang-1 and Ang-2 levels were constant throughout COS, but serum Ang-1 levels were increased at all time points in PCOS women compared with controls (p < 0.05). No differences between groups were found in serum Ang-2 levels or FF Ang-1 levels. However, FF Ang-2 levels were increased almost 2-fold in PCOS women compared with controls (p < 0.01), and correlated positively with number of oocytes retrieved (r = 0.65, p < 0.0001). This study is the first to provide evidence of an alteration in the Ang-1/Ang-2 system in PCOS women. The biological role of Ang-2 in promoting capillary leakage, the increased Ang-2 FF level in PCOS, and its correlation with number of oocytes suggest that Ang-2 may play an important role in the increased risk of ovarian hyperstimulation in PCOS. PMID- 24156355 TI - NADPH oxidases: a perspective on reactive oxygen species production in tumor biology. AB - SIGNIFICANCE: Reactive oxygen species (ROS) promote genomic instability, altered signal transduction, and an environment that can sustain tumor formation and growth. The NOX family of NADPH oxidases, membrane-bound epithelial superoxide and hydrogen peroxide producers, plays a critical role in the maintenance of immune function, cell growth, and apoptosis. The impact of NOX enzymes in carcinogenesis is currently being defined and may directly link chronic inflammation and NOX ROS-mediated tumor formation. RECENT ADVANCES: Increased interest in the function of NOX enzymes in tumor biology has spurred a surge of investigative effort to understand the variability of NOX expression levels in tumors and the effect of NOX activity on tumor cell proliferation. These initial efforts have demonstrated a wide variance in NOX distribution and expression levels across numerous cancers as well as in common tumor cell lines, suggesting that much remains to be discovered about the unique role of NOX-related ROS production within each system. Progression from in vitro cell line studies toward in vivo tumor tissue screening and xenograft models has begun to provide evidence supporting the importance of NOX expression in carcinogenesis. CRITICAL ISSUES: A lack of universally available, isoform-specific antibodies and animal tumor models of inducible knockout or over-expression of NOX isoforms has hindered progress toward the completion of in vivo studies. FUTURE DIRECTIONS: In vivo validation experiments and the use of large, existing gene expression data sets should help define the best model systems for studying the NOX homologues in the context of cancer. PMID- 24156369 TI - MMP-independent role of TIMP-1 at the blood brain barrier during viral encephalomyelitis. AB - Infection of the CNS (central nervous system) with a sublethal neurotropic coronavirus (JHMV) induces a vigorous inflammatory response. CD4+ and CD8+ T cells are essential to control infectious virus but at the cost of tissue damage. An enigma in understanding the contribution of T cell subsets in pathogenesis resides in their distinct migration pattern across the BBB (blood brain barrier). CD4+ T cells transiently accumulate within the perivascular space, whereas CD8+ T cells migrate directly into the CNS parenchyma. As MMPs (matrix metalloproteinases) facilitate migration across the glia limitans, specific expression of the TIMP (tissue inhibitor of MMPs)-1 by CD4+ T cells present in the perivascular cuffs suggested that TIMP-1 is responsible for stalling CD4+ T cell migration into the CNS parenchyma. Using TIMP-1 deficient mice, the present data demonstrate an increase rather than a decrease in CD4+ T cell accumulation within the perivascular space during JHMV infection. Whereas virus control was not affected by perivascular retention of CD4+ T cells, disease severity was decreased and associated with reduced IFNgamma (interferon gamma) production. Moreover, decreased CD4+ T cell recruitment into the CNS parenchyma of TIMP-1 deficient mice was not associated with impaired T cell recruiting chemokines or MMP expression, and no compensation by other TIMP molecules was identified. These data suggest an MMP-independent role of TIMP-1 in regulating CD4+ T cell access into the CNS parenchyma during acute JHMV encephalitis. PMID- 24156379 TI - Steady state vascular imaging with extracellular gadobutrol: evaluation of the additional diagnostic benefit in patients who have undergone a peripheral magnetic resonance angiography protocol. AB - BACKGROUND: To evaluate the feasibility and additional diagnostic benefit of a high-resolution steady state 3D-volume interpolated breath-hold exam (VIBE) sequence between a continuous table movement (CTM) MR angiography of the entire runoff vasculature and a time-resolved (TWIST) MRA of the calves. METHODS: In this retrospective IRB approved study 224 patients (72 women, 152 men, mean age 67.29 +/- 13.9) were included who had undergone a low-dose MR angiographic protocol at 3T (Siemens TimTrio) after injection of 0.1 mmol/kg gadobutrol including a CTM MRA, a time-resolved MRA of the calf station and a steady state 3D VIBE sequence prior to the time-resolved MRA. One board-certified radiologist rated the image quality of the steady state VIBE sequences on an ordinal three point scale (excellent, good, poor) and analyzed the images for additional diagnostic findings of and beyond the vascular system in comparison to the CTM MRA and the time-resolved MRA. Descriptive statistics and demographic patient data were used for further evaluation. RESULTS: The image quality of the steady state imaging of the pelvis, upper and lower leg was excellent in up to 88%, 84% and 47%, respectively, while poor image quality was only detected in the upper (2%) and lower leg (6%). An additional diagnostic benefit was found in 44% of the patients overall. The most common relevant pathologies included inflammatory processes of the soft tissues (26%), thrombi (14%), abscesses (13%) and tumors (11%). In subgroups of patients above the age of 60, 65, 70, 75 and 80 years an additional pathology was found in 50% 33%, 44%, 65% and 58%, respectively. There was no significant difference in terms of additional findings between men and women (46% and 39%, p > 0.05) and inpatients and outpatients (42% and 45%, p > 0.05). CONCLUSION: Steady state imaging is also feasible with extracellular contrast agents with good image quality yielding additional diagnostic findings in up to 44% and above in patients older than 60 years of age irrespective of gender or patient status. Given the short acquisition time of 4 minutes this sequence could be added to all peripheral MRA exams. PMID- 24156374 TI - Evaluation of a curcumin analog as an anti-cancer agent inducing ER stress mediated apoptosis in non-small cell lung cancer cells. AB - BACKGROUND: Recent advances have highlighted the importance of the endoplasmic reticulum (ER) in cell death processes. Pharmacological interventions that effectively enhance tumor cell death through activating ER stress have attracted a great deal of attention for anti-cancer therapy. METHODS: A bio-evaluation on 113 curcumin analogs against four cancer cell lines was performed through MTT assay. Furthermore, real time cell assay and flow cytometer were used to evaluate the apoptotic induction of (1E,4E)-1,5-bis(5-bromo-2-ethoxyphenyl)penta-1,4-dien 3-one (B82). Western blot, RT-qPCR, and siRNA were then utilized to confirm whether B82-induced apoptosis is mediated through activating ER stress pathway. Finally, the in vivo anti-tumor effect of B82 was evaluated. RESULTS: B82 exhibited strong anti-tumor activity in non-small cell lung cancer (NSCLC) H460 cells. Treatment with B82 significantly induced apoptosis in H460 cells in vitro and inhibited H460 tumor growth in vivo. Further studies demonstrated that the B82-induced apoptosis is mediated by activating ER stress both in vitro and in vivo. CONCLUSIONS: A new monocarbonyl analog of curcumin, B82, exhibited anti tumor effects on H460 cells via an ER stress-mediated mechanism. B82 could be further explored as a potential anticancer agent for the treatment of NSCLC. PMID- 24156381 TI - A demographic survey of unwanted horses in Ireland in 2011 and totals for 2012 and a comparison with 2010. AB - This report compiles the available information on unwanted horses in Ireland for 2011 and 2012 and builds upon the previous report for the period 2005 to 2010. Similar trends are present in the high value responsible ownership category and the practicing veterinary profession although extensively involved in horse welfare, euthanises a small proportion of Ireland's unwanted horses. Welfare groups have limited resources and a limited ability to deal with such an extensive problem, which has involved very large numbers of horses. Local authorities continue to have to devote significant efforts and calls on public finances to deal with unwanted horses. Those that they have to deal with are, in the main, not identifiable by either passports or microchips. Category 2 plants and abattoirs continue to provide the principal means of disposal of unwanted horses. The need for abattoirs continues to increase and it is essential that these facilities remain in operation. They processed more than 49,000 horses between 2010 and 2012. The samples they have to submit for Trichinella testing are the most sensitive indicator of the extent of the unwanted horse problem and the most immediate source of information on when it may begin to abate. Trichinella sample numbers and this by inference, horses ponies and donkeys sent to slaughter have fallen by some 35% from 2012 numbers, in the year to date (2013). This may reflect the commercial decision to cease horse slaughter by two slaughterhouses that had hitherto provided this service. Their commercial decision was not in any way related to the identification of fraudulent mislabeled beef in other plants. PMID- 24156380 TI - Low vagal tone magnifies the association between psychosocial stress exposure and internalizing psychopathology in adolescents. AB - Vagal tone is a measure of cardiovascular function that facilitates adaptive responses to environmental challenge. Low vagal tone is associated with poor emotional and attentional regulation in children and has been conceptualized as a marker of sensitivity to stress. We investigated whether the associations of a wide range of psychosocial stressors with internalizing and externalizing psychopathology were magnified in adolescents with low vagal tone. Resting heart period data were collected from a diverse community sample of adolescents (ages 13-17; N = 168). Adolescents completed measures assessing internalizing and externalizing psychopathology and exposure to stressors occurring in family, peer, and community contexts. Respiratory sinus arrhythmia (RSA) was calculated from the interbeat interval time series. We estimated interactions between RSA and stress exposure in predicting internalizing and externalizing symptoms and evaluated whether interactions differed by gender. Exposure to psychosocial stressors was associated strongly with psychopathology. RSA was unrelated to internalizing or externalizing problems. Significant interactions were observed between RSA and child abuse, community violence, peer victimization, and traumatic events in predicting internalizing but not externalizing symptoms. Stressors were positively associated with internalizing symptoms in adolescents with low RSA but not in those with high RSA. Similar patterns were observed for anxiety and depression. These interactions were more consistently observed for male than female individuals. Low vagal tone is associated with internalizing psychopathology in adolescents exposed to high levels of stressors. Measurement of vagal tone in clinical settings might provide useful information about sensitivity to stress in child and adolescent clients. PMID- 24156383 TI - Effect of functional group on the monolayer structures of biodegradable quaternary ammonium surfactants. AB - The monolayer structures and conformational ordering of cationic surfactants including the biodegradable quaternary ammonium molecules have been systematically characterized by pi-A isotherm, surface potential, atomic force microscopy (AFM), X-ray photoelectron spectroscopy (XPS), and sum frequency generation (SFG) vibrational spectroscopy. It was found that the monolayer of the typical dialkyl dimethylammonium on the water surface was less densely packed along with many conformational gauche defects. The packing density and ordering of these monolayers were improved as halide ions were added to the subphase. A similar condensation effect was also observed when amide or ester groups are present in the alkyl tails of the surfactant. These results are discussed on the basis of the repulsive electrostatic interactions between the terminal ammonium moieties, the hydrogen bonding between the functional groups in the alkyl chains, as well as the flexibility of the alkyl chains in these surfactants. The present study is crucial to understanding the relationship between the interfacial structures and the functionalities of the biodegradable quaternary ammonium surfactants. PMID- 24156384 TI - Prevention of diet-induced hyperlipidemia and obesity by caffeic acid in C57BL/6 mice through regulation of hepatic lipogenesis gene expression. AB - This study investigated the influence of phenolic caffeic acid on obesity in mice fed a high fat diet and its underlying mechanisms base on adipose and hepatic lipid lipogenesis. C57BL/6 mice were fed a normal diet or a HFD (20% fat, w/w) with or without caffeic acid (0.02% and 0.08%, w/w) for 6 weeks. The effects of caffeic acid on hyperlipidemia, hyperglycemia, visceral fat accumulation, and related enzyme activities in HFD-mice are examined. The supplementation of caffeic acid significantly lowered body weight, visceral fat mass, plasma GOT and GPT levels, FAS activity, and free fatty acid compared to the HFD group. Caffeic acid also lowered triglyceride and cholesterol concentrations in plasma and liver. Furthermore, we showed that caffeic acid efficiently inhibited cholesterol biosynthesis as evidenced by 3-hydroxy-3-methylglutaryl CoA reductase in the liver. Caffeic acid supplementation suppressed the activity of lipogenesis via sterol regulatory element-binding protein 1 c and its target enzyme fatty acid synthase. In addition, caffeic acid resulted in increased phosphorylation of AMP activated protein kinase and decreased acetyl carboxylase, a downstream target of AMPK, which are related to fatty acid beta-oxidation in the liver. In conclusion, these results indicate that caffeic acid exhibits a significant potential as an antiobesity agent by suppression of lipogenic enzymes and hepatic lipid accumulation. PMID- 24156382 TI - Living-engineered valves for transcatheter venous valve repair. AB - BACKGROUND: Chronic venous insufficiency (CVI) represents a major global health problem with increasing prevalence and morbidity. CVI is due to an incompetence of the venous valves, which causes venous reflux and distal venous hypertension. Several studies have focused on the replacement of diseased venous valves using xeno- and allogenic transplants, so far with moderate success due to immunologic and thromboembolic complications. Autologous cell-derived tissue-engineered venous valves (TEVVs) based on fully biodegradable scaffolds could overcome these limitations by providing non-immunogenic, non-thrombogenic constructs with remodeling and growth potential. METHODS: Tri- and bicuspid venous valves (n=27) based on polyglycolic acid-poly-4-hydroxybutyrate composite scaffolds, integrated into self-expandable nitinol stents, were engineered from autologous ovine bone marrow-derived mesenchymal stem cells (BM-MSCs) and endothelialized. After in vitro conditioning in a (flow) pulse duplicator system, the TEVVs were crimped (n=18) and experimentally delivered (n=7). The effects of crimping on the tissue engineered constructs were investigated using histology, immunohistochemistry, scanning electron microscopy, grating interferometry (GI), and planar fluorescence reflectance imaging. RESULTS: The generated TEVVs showed layered tissue formation with increasing collagen and glycosaminoglycan levels dependent on the duration of in vitro conditioning. After crimping no effects were found on the MSC level in scanning electron microscopy analysis, GI, histology, and extracellular matrix analysis. However, substantial endothelial cell loss was detected after the crimping procedure, which could be reduced by increasing the static conditioning phase. CONCLUSIONS: Autologous living small-diameter TEVVs can be successfully fabricated from ovine BM-MSCs using a (flow) pulse duplicator conditioning approach. These constructs hold the potential to overcome the limitations of currently used non-autologous replacement materials and may open new therapeutic concepts for the treatment of CVI in the future. PMID- 24156385 TI - Comparison of metabolic ratios of urinary estrogens between benign and malignant thyroid tumors in postmenopausal women. AB - BACKGROUND: Estrogen metabolism may be associated with the pathophysiological development of papillary thyroid carcinoma (PTC). METHODS: To evaluate the differential estrogen metabolism between benign and malignant PTCs, estrogen profiling by gas chromatography-mass spectrometry was applied to urine samples from postmenopausal patients with 9 benign tumors and 18 malignant stage I and III/IV PTCs. RESULTS: The urinary concentration of 2-methoxyestradiol was significantly lower in the stage I malignant patients (3.5-fold; P < 0.025) than in the benign group. The metabolic ratios of 16alpha-OH-estrone/estrone and estriol/estradiol, which are responsible for 16alpha-hydroxylase activity, were increased more than 2.5-fold in the advanced-stage malignant PTC (P < 0.02 each). The more than 6.2-fold decrease in the urinary 2-/16alpha-hydroxylase ratio in stage III/IV malignant PTC was consistent with the ratio in postmenopausal patients with endocrine gland cancers. In addition, reductive 17beta hydroxysteroid dehydrogenase (17beta-HSD; estradiol/estrone or estriol/16alpha-OH estrone) was present at significantly higher levels in subjects with stage III/IV malignant PTCs than in benign subjects (>3.5-fold difference; P < 0.002). In particular, the estriol/16alpha-OH-estrone ratio differentiated between the benign and early-stage malignant patients (P < 0.01). CONCLUSIONS: Increased 16alpha-hydroxylation and/or a decreased 2-/16alpha-ratio, as well increased reductive 17beta-HSD, with regard to estrogen metabolism could provide potential biomarkers. The devised profiles could be useful for differentiating malignant thyroid carcinomas from benign adenomas in postmenopausal women. PMID- 24156388 TI - Intraoperative smile in a multiple sclerosis patient with medication-refractory tremor. AB - Deep brain stimulation has been utilized to improve disease symptoms in patients with Parkinson's disease, dystonia, essential tremor, and other neuropsychiatric syndromes such as depression and obsessive compulsive disorder. Deep brain stimulation has also been observed to improve tremor for select patients with multiple sclerosis. During intraoperative stimulation in these multiple sclerosis patients, researchers have observed a wide spectrum of motor and sensory phenomena, but no stimulation-induced emotional responses have been reported. We detailed intraoperative smiling associated with stimulation of the ventralis oralis anterior/ventralis oralis posterior border region of the left thalamus. A single patient with medication-resistant multiple sclerosis tremor experienced smiling, laughing, and subjective euphoria during intraoperative stimulation of the left thalamus. Specifically, during intraoperative stimulation of the left thalamic ventralis oralis anterior border, the patient developed a contralateral smile which progressed to a bilateral smile and was accompanied by a feeling of subjective happiness. The smile habituated in approximately 60 seconds and it was reproducible on a repeat stimulation. The patient could subjectively feel the facial movement, and, at higher voltages, the movement was described as a pulling sensation. Stimulation of the anterior ventralis oralis anterior border of the left thalamus in an multiple sclerosis patient produced a unilateral smile that rapidly developed into a bilateral smile accompanied by euphoria. There were presumed capsular side effects at higher voltages. The exact mechanism by which stimulation of the thalamus produced a smile and mood elevation is unknown, but we speculate that the smile could be induced by stimulation of corticobulbar fibers arising from the caudal cingulate motor area connecting the contralateral facial nerve nucleus. PMID- 24156389 TI - Phase I drug-interaction study of effects of calcium and magnesium infusions on oxaliplatin pharmacokinetics and acute neurotoxicity in colorectal cancer patients. AB - BACKGROUND: Calcium and magnesium (Ca/Mg) infusions have been suggested as an effective intervention for preventing oxaliplatin-induced neurotoxicity, but the effects of Ca/Mg infusions on oxaliplatin pharmacokinetics, motor nerve hyperexcitability and acute neurotoxicity symptoms are unclear. METHODS: In this double blind crossover study, colorectal cancer patients undergoing oxaliplatin based chemotherapy were randomised to receive Ca/Mg (1g Ca Gluconate plus 1g MgSO4) on cycle 1 and placebo (vehicle alone) on cycle 2, or to receive the same treatments in the opposite sequence. Study endpoints included plasma pharmacokinetics of intact oxaliplatin and free platinum; electromyography (EMG) detection of abnormal spontaneous high-frequency motor unit action potential discharges; and patient-reported acute neurotoxicity symptoms and their preferred study treatment for reducing these symptoms. RESULTS: Nineteen of 20 enrolled patients completed the study. Plasma pharmacokinetics of intact oxaliplatin and free platinum were similar when oxaliplatin was given with Ca/Mg or placebo (ratio of geometric means of AUC0-t with Ca/Mg or placebo: intact oxaliplatin, 0.95 (90% CI, 0.90 - 1.01); free platinum, 0.99 (90% CI, 0.94 - 1.05)). EMG motor nerve hyperexcitability scores were similar with Ca/Mg and placebo (mean difference in EMG score between Ca/Mg and placebo: -0.3 (95% CI, -2.2 - 1.6)). Patient-reported acute neurotoxicity symptoms were similar in frequency with Ca/Mg and placebo. For reducing neurotoxic symptoms, fewer patients preferred Ca/Mg than placebo or neither treatment (26% versus 74%; P<0.01). CONCLUSIONS: Ca/Mg infusions do not alter the clinical pharmacokinetics of oxaliplatin and do not seem to reduce its acute neurotoxicity. TRIAL REGISTRATION: Trial registration identifier ACTRN12611000738921. PMID- 24156390 TI - Recent advances in non-ionic surfactant vesicles (niosomes): self-assembly, fabrication, characterization, drug delivery applications and limitations. AB - Non-ionic surfactant vesicles, simply known as niosomes are synthetic vesicles with potential technological applications. Niosomes have the same potential advantages of phospholipid vesicles (liposomes) of being able to accommodate both water soluble and lipid soluble drug molecules control their release and as such serve as versatile drug delivery devices of numerous applications. Additionally, niosomes can be considered as more economically, chemically, and occasionally physically stable alternatives to liposomes. Niosomes can be fabricated using simple methods of preparations and from widely used surfactants in pharmaceutical technology. Many reports have discussed niosomes in terms of physicochemical properties and their applications as drug delivery systems. In this report, a brief and simplified summary of different theories of self-assembly will be given. Furthermore manufacturing methods, physical characterization techniques, bilayer membrane additives, unconventional niosomes (discomes, proniosomes, elastic and polyhedral niosomes), their recent applications as drug delivery systems, limitations and directions for future research will be discussed. PMID- 24156391 TI - Combined finite element and multibody musculoskeletal investigation of a fractured clavicle with reconstruction plate. AB - This paper addresses the evaluation of clavicle fixation devices, by means of computational models. The aim was to develop a method for comparison of stress distribution in various fixation devices, to determine whether the use of multibody musculoskeletal input in such model is applicable and to report the approach. The focus was on realistic loading and the motivation for the work is that the treatment can be enhanced by a better understanding of the loading of the clavicle and fixation device. The method can be used to confirm the strength of customised plates, for optimisation of new plates and to complement experimental studies. A finite element (FE) mesh of the clavicle geometry was created from computed tomography data and imported into the FE solver where the model was subjected to muscle forces and other boundary conditions from a multibody musculoskeletal model performing a typical activity of daily life. A reconstruction plate and screws were also imported into the model. The combination models returned stresses and displacements of plausible magnitudes in all included parts and the result, upon further development and validation, may serve as a design guideline for improved clavicle fixation. PMID- 24156392 TI - Technical indicators of economic performance in dairy sheep farming. AB - In this study, the level of technical efficiency of 58 sheep farms rearing the Chios breed in Greece was measured through the application of the stochastic frontier analysis method. A Translog stochastic frontier production function was estimated using farm accounting data of Chios sheep farms and the impact of various socio-demographic and biophysical factors on the estimated efficiency of the farms was evaluated. The farms were classified into efficiency groups on the basis of the estimated level of efficiency and a technical and economic descriptive analysis was applied in order to illustrate an indicative picture of their structure and productivity. The results of the stochastic frontier model indicate that there are substantial production inefficiencies among the Chios sheep farms and that these farms could increase their production through the improvement of technical efficiency, whereas the results of the inefficiency effects model reveal that the farm-specific explanatory factors can partly explain the observed efficiency differentials. The measurement of technical inefficiency and the detection of its determinants can be used to form the basis of policy recommendations that could contribute to the development of the sector. PMID- 24156393 TI - Synthesis of solid 2-pyridylzinc reagents and their application in Negishi reactions. AB - In search of alternatives to unstable or unreliable 2-pyridylboron reagents, we have explored two new varieties of solid, moderately air-stable 2-pyridylzinc reagents. Both reagents can be manipulated in air and are competent nucleophiles in Negishi cross-coupling reactions. PMID- 24156394 TI - Weighty dynamics: exploring couples' perceptions of post-weight-loss interaction. AB - Although romantic couples can use communication to help one another lose weight and maintain weight loss, the effect of weight loss on partner interaction is less understood. However, an examination of the interpersonal context in which partners manage their weight is important to help partners negotiate their weight, their relationship, and the U.S. obesity epidemic. Guided by systems theory, this study explored partners' perceptions of post-weight-loss interaction in relationships in which one partner lost weight and the other did not. Through qualitative questionnaires of 42 adults (21 romantic couples), the dyadic investigation revealed that while losing weight resulted in positive interaction for many partners (e.g., engaging in a shared healthy lifestyle), shedding weight also yielded some negative consequences (e.g., non-weight-loss partner criticism). The extent to which partners embraced new weight management rules and patterns largely influenced post-weight-loss communication and behavior. PMID- 24156395 TI - Lower A1c among adolescents with lower perceived A1c goal: a cross-sectional survey. AB - BACKGROUND: The International Society for Pediatric and Adolescent Diabetes (ISPAD) and the American Diabetes Association (ADA) have established a hemoglobin A1c (A1c) target of less than 7.5% for adolescents with type 1 diabetes (T1D). However, many adolescents are unaware of their A1c target, and little data exist on how knowledge of this A1c target affects the actual A1c they achieve. We sought to evaluate the relationship between awareness of the A1c target and the actual A1c achieved in adolescents with T1D. METHODS: In a cohort of 240 adolescents with T1D age 13-19 years, we measured A1c and administered a questionnaire to assess their knowledge of the ISPAD guideline for A1c target. RESULTS: Of the total cohort, 42 subjects (18%) had an A1c below target and 198 subjects (82%) had an A1c above target. Almost all subjects (98%) reported that they were told their A1c target by a healthcare provider, and most of those (88%) claimed to know their A1c target, but few (8%) were correct. More subjects with actual A1c below 7.5% thought their A1c goal was lower than the ISPAD target, compared to subjects with A1c above target (75% vs. 59%, p = 0.07), although this did not achieve statistical significance. CONCLUSION: In this cohort of adolescents with T1D, there was a trend toward a lower achieved A1c in those with a lower perceived A1c goal. Further studies should focus on identification of factors influencing an adolescent's ability to achieve a lower A1c. PMID- 24156396 TI - Feasibility of the Enhancing Participation In the Community by improving Wheelchair Skills (EPIC Wheels) program: study protocol for a randomized controlled trial. AB - BACKGROUND: Many older adults rely on a manual wheelchair for mobility but typically receive little, if any, training on how to use their wheelchair effectively and independently. Standardized skill training is an effective intervention, but limited access to clinician trainers is a substantive barrier. Enhancing Participation in the Community by Improving Wheelchair Skills (EPIC Wheels) is a 1-month monitored home training program for improving mobility skills in older novice manual wheelchair users, integrating principles from andragogy and social cognitive theory. The purpose of this study is to determine whether feasibility indicators and primary clinical outcome measures of the EPIC Wheels program are sufficiently robust to justify conducting a subsequent multi site randomized controlled trial. METHODS: A 2 * 2 factorial randomized controlled trial at two sites will compare improvement in wheelchair mobility skills between an EPIC Wheels treatment group and a computer-game control group, with additional wheelchair use introduced as a second factor. A total of 40 community-dwelling manual wheelchair users at least 55 years old and living in two Canadian metropolitan cities (n = 20 * 2) will be recruited. Feasibility indicators related to study process, resources, management, and treatment issues will be collected during data collection and at the end of the study period, and evaluated against proposed criteria. Clinical outcome measures will be collected at baseline (pre-randomization) and post-intervention. The primary clinical outcome measure is wheelchair skill capacity, as determined by the Wheelchair Skills Test, version 4.1. Secondary clinical outcome measures include wheelchair skill safety, satisfaction with performance, wheelchair confidence, life-space mobility, divided-attention, and health-related quality of life. DISCUSSION: The EPIC Wheels training program offers several innovative features. The convenient, portable, economical, and adaptable tablet-based, home program model for wheelchair skills training has great potential for clinical uptake and opportunity for future enhancements. Theory-driven design can foster learning and adherence for older adults. Establishing the feasibility of the study protocol and estimating effect size for the primary clinical outcome measure will be used to develop a multi-site randomized controlled trial to test the guiding hypotheses. TRIAL REGISTRATION: Clinical Trials NCT01740635. PMID- 24156397 TI - Reducing the stigma of mental illness in undergraduate medical education: a randomized controlled trial. AB - BACKGROUND: The stigma of mental illness among medical students is a prevalent concern that has far reaching negative consequences. Attempts to combat this stigma through educational initiatives have had mixed results. This study examined the impact of a one-time contact-based educational intervention on the stigma of mental illness among medical students and compared this with a multimodal undergraduate psychiatry course at the University of Calgary, Canada that integrates contact-based educational strategies. Attitudes towards mental illness were compared with those towards type 2 diabetes mellitus (T2DM). METHOD: A cluster-randomized trial design was used to evaluate the impact of contact based educational interventions delivered at two points in time. The impact was assessed by collecting data at 4 time points using the Opening Minds Scale for Health Care Providers (OMS-HC) to assess changes in stigma. RESULTS: Baseline surveys were completed by 62% (n=111) of students before the start of the course and post-intervention ratings were available from 90 of these. Stigma scores for both groups were significantly reduced upon course completion (p < 0.0001), but were not significantly changed following the one-time contact based educational intervention in the primary analysis. Student confidence in working with people with a mental illness and interest in a psychiatric career was increased at the end of the course. Stigma towards mental illness remained greater than for T2DM at all time points. CONCLUSIONS: Psychiatric education can decrease the stigma of mental illness and increase student confidence. However, one-time, contact-based educational interventions require further evaluation in this context. The key components are postulated to be contact, knowledge and attention to process, where attending to the student's internal experience of working with people with mental illness is an integral factor in modulating perceptions of mental illness and a psychiatric career. PMID- 24156399 TI - Biodelignification of lignocellulose substrates: An intrinsic and sustainable pretreatment strategy for clean energy production. AB - Lignocellulosic biomass (LB) is a promising sugar feedstock for biofuels and other high-value chemical commodities. The recalcitrance of LB, however, impedes carbohydrate accessibility and its conversion into commercially significant products. Two important factors for the overall economization of biofuel production is LB pretreatment to liberate fermentable sugars followed by conversion into ethanol. Sustainable biofuel production must overcome issues such as minimizing water and energy usage, reducing chemical usage and process intensification. Amongst available pretreatment methods, microorganism-mediated pretreatments are the safest, green, and sustainable. Native biodelignifying agents such as Phanerochaete chrysosporium, Pycnoporous cinnabarinus, Ceriporiopsis subvermispora and Cyathus stercoreus can remove lignin, making the remaining substrates amenable for saccharification. The development of a robust, integrated bioprocessing (IBP) approach for economic ethanol production would incorporate all essential steps including pretreatment, cellulase production, enzyme hydrolysis and fermentation of the released sugars into ethanol. IBP represents an inexpensive, environmentally friendly, low energy and low capital approach for second-generation ethanol production. This paper reviews the advancements in microbial-assisted pretreatment for the delignification of lignocellulosic substrates, system metabolic engineering for biorefineries and highlights the possibilities of process integration for sustainable and economic ethanol production. PMID- 24156401 TI - Simultaneous quantitative determination of multiple mycotoxins in cereal and feedstuff samples by a suspension array immunoassay. AB - Mycotoxins produced by different species of fungi may coexist in single cereal and feedstuff samples, which could become highly toxic for humans and animals. In order to quantify four mycotoxins (zearalenone, fumonisin B1, deoxynivalenol, and aflatoxin B1) in cereal and feedstuff samples simultaneously, a new suspension array immunoassay was developed. Antimycotoxin monoclonal antibodies were conjugated to the surface of different encoding microspheres (19#, 37#, 39#, and 49#), and mycotoxin-protein conjugates were then coupled with biotin. Using streptavidin-phycoerythrin as a signal reporter protein, this direct competition multiple suspension array immunoassay was optimized. The results showed that the detection limits for zearalenone, fumonisin B1, deoxynivalenol, and aflatoxin B1 were 0.51, 6.0, 4.3, and 0.56 ng/mL, respectively, with detection ranges of 0.73 6.8, 11.6-110.3, 8.6-108.1, and 1.1-14.1 ng/mL, respectively. For the detection of the spiked samples, the recovery rates were between 92.3% and 115.5%. This method also shows a good correlation coefficient (r = 0.99, P < 0.01) with liquid chromatography-tandem mass spectrometry in the detection of toxins in commercial cereal and feedstuff samples. This suspension array immunoassay was high throughput and accurate for the rapid quantitative detection of multiple mycotoxins in commercial cereal and feedstuff samples. PMID- 24156402 TI - Liposome-coated hydrogel spheres: delivery vehicles with tandem release from distinct compartments. AB - We have fabricated unilamellar lipid bilayer VESicle-COated hydrogel spheres (VESCOgels) by carbodiimide-mediated coupling of liposomes bearing surface amines to core-shell hydrogel spheres bearing surface carboxyls. The amine-containing moiety, 3-O (2-aminoethoxyethyloxyethyl)carbamyl cholesterol (AECHO), was incorporated into large unilamellar vesicles (LUVs), diameter ~100 nm, composed of 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC). The hydrogel, diameter ~ 1 MUm, consisted of a core of poly(N-isopropyl acrylamide) (pNIPAM) and a shell of p(NIPAM-co-acrylic acid (AA)). Activation of these surface displayed carboxyls with N-hydroxysuccinimidyl (NHS) esters permitted amine coupling upon addition of AECHO-containing POPC LUVs. Bilayer integrity of the hydrogel-bound LUVs was maintained, and fusion of LUVs did not occur. Fluorescence assays of the release of cobalt-calcein trapped within hydrogel bound LUVs and of sodium fluorescein trapped within the hydrogel itself showed that each compartment retained its distinct release attributes: fast release from the microgel and slow release from the LUVs. It is envisioned that VESCOgels will be useful, therefore, in applications requiring temporally controlled delivery of distinct drugs. PMID- 24156403 TI - Family-wide characterization of matrix metalloproteinases from Arabidopsis thaliana reveals their distinct proteolytic activity and cleavage site specificity. AB - MMPs (matrix metalloproteases) are a family of zinc-dependent endopeptidases widely distributed throughout all kingdoms of life. In mammals, MMPs play key roles in many physiological and pathological processes, including remodelling of the extracellular matrix. In the genome of the annual plant Arabidopsis thaliana, five MMP-like proteins (At-MMPs) are encoded, but their function is unknown. Previous work on these enzymes was limited to gene expression analysis, and so far proteolytic activity has been shown only for At1-MMP. We expressed and purified the catalytic domains of all five At-MMPs as His-tagged proteins in Escherichia coli cells to delineate the biochemical differences and similarities among the Arabidopsis MMP family members. We demonstrate that all five recombinant At-MMPs are active proteases with distinct preferences for different protease substrates. Furthermore, we performed a family-wide characterization of their biochemical properties and highlight similarities and differences in their cleavage site specificities as well as pH- and temperature-dependent activities. Detailed analysis of their sequence specificity using PICS (proteomic identification of protease cleavage sites) revealed profiles similar to human MMPs with the exception of At5-MMP; homology models of the At-MMP catalytic domains supported these results. Our results suggest that each At-MMP may be involved in different proteolytic processes during plant growth and development. PMID- 24156405 TI - Critical analysis of musculoskeletal modelling complexity in multibody biomechanical models of the upper limb. AB - The inverse dynamics technique applied to musculoskeletal models, and supported by optimisation techniques, is used extensively to estimate muscle and joint reaction forces. However, the solutions of the redundant muscle force sharing problem are sensitive to the detail and modelling assumptions of the models used. This study presents four alternative biomechanical models of the upper limb with different levels of discretisation of muscles by bundles and muscle paths, and their consequences on the estimation of the muscle and joint reaction forces. The muscle force sharing problem is solved for the motions of abduction and anterior flexion, acquired using video imaging, through the minimisation of an objective function describing muscle metabolic energy consumption. While looking for the optimal solution, not only the equations of motion are satisfied but also the stability of the glenohumeral and scapulothoracic joints is preserved. The results show that a lower level of muscle discretisation provides worse estimations regarding the muscle forces. Moreover, the poor discretisation of muscles relevant to the joint in analysis limits the applicability of the biomechanical model. In this study, the biomechanical model of the upper limb describing the infraspinatus by a single bundle could not solve the complete motion of anterior flexion. Despite the small differences in the magnitude of the forces predicted by the biomechanical models with more complex muscular systems, in general, there are no significant variations in the muscular activity of equivalent muscles. PMID- 24156398 TI - Fc-fusion proteins and FcRn: structural insights for longer-lasting and more effective therapeutics. AB - Nearly 350 IgG-based therapeutics are approved for clinical use or are under development for many diseases lacking adequate treatment options. These include molecularly engineered biologicals comprising the IgG Fc-domain fused to various effector molecules (so-called Fc-fusion proteins) that confer the advantages of IgG, including binding to the neonatal Fc receptor (FcRn) to facilitate in vivo stability, and the therapeutic benefit of the specific effector functions. Advances in IgG structure-function relationships and an understanding of FcRn biology have provided therapeutic opportunities for previously unapproachable diseases. This article discusses approved Fc-fusion therapeutics, novel Fc-fusion proteins and FcRn-dependent delivery approaches in development, and how engineering of the FcRn-Fc interaction can generate longer-lasting and more effective therapeutics. PMID- 24156406 TI - Characterization of monomeric Mn(II/III/IV)-hydroxo complexes from X- and Q-band dual mode electron paramagnetic resonance (EPR) spectroscopy. AB - Manganese-hydroxo species have been implicated in C-H bond activation performed by metalloenzymes, but the electronic properties of many of these intermediates are not well characterized. The present work presents a detailed characterization of three Mn(n)-OH complexes (where n = II, III, and IV) of the tris[(N'-tert butylureaylato)-N-ethylene]aminato ([H3buea](3-)) ligand using X- and Q-band dual mode electron paramagnetic resonance (EPR). Quantitative simulations for the [Mn(II)H3buea(OH)](2-) complex demonstrated the ability to characterize similar Mn(II) species commonly present in the resting states of manganese-containing enzymes. The spin states of the Mn(III) and Mn(IV) complexes determined from EPR spectroscopy are S = 2 and 3/2, respectively, as expected for the C3 symmetry imposed by the [H3buea](3-) ligand. Simulations of the spectra indicated the constant presence of two Mn(IV) species in solutions of [Mn(IV)H3buea(OH)] complex. The simulations of perpendicular- and parallel-mode EPR spectra allow determination of zero-field splitting and hyperfine parameters for all complexes. For the Mn(III) and Mn(IV) complexes, density functional theory calculations are used to determine the isotropic Mn hyperfine values, to compare the excited electronic state energies, and to give theoretical estimates of the zero-field energy. PMID- 24156407 TI - Magnetic resonance spectroscopy as a prognostic marker in neonatal hypoxic ischemic encephalopathy: a study protocol for an individual patient data meta analysis. AB - BACKGROUND: The prognostic accuracy of 1H (proton) magnetic resonance spectroscopy (MRS) in neonatal hypoxic-ischemic encephalopathy has been assessed by a criticized study-based meta-analysis. An individual patient data meta analysis may overcome some of the drawbacks encountered in the aggregate data meta-analysis. Moreover, the prognostic marker can be assessed quantitatively and the effect of covariates can be estimated. METHODS: Diagnostic accuracy studies relevant to the study topic were retrieved. The primary authors will be invited to share the raw de-identified study data. These individual patient data will be analyzed using logistic regression analysis. A prediction tool calculating the individualized risk of very adverse outcome will be devised. DISCUSSION: The proposed individual patient data meta-analysis provides several advantages. Inclusion and exclusion criteria can be applied more uniformly. Furthermore, adjustment is possible for confounding factors and subgroup analyses can be conducted. Our goal is to develop a prediction model for outcome in newborns with hypoxic-ischemic encephalopathy. PMID- 24156408 TI - Primary in vitro and in vivo evaluation of norcantharidin-chitosan/poly (vinyl alcohol) for cancer treatment. AB - Two novel polymer-drug conjugates norcantharidin-poly(vinyl alcohol) and norcantharidin-chitosan (NCTD-PVA and NCTD-CS) were synthesized via alcoholysis reaction and characterized by (1)H-NMR and FTIR. NCTD was released from the conjugates via hydrolysis, faster in PBS (pH 5.0) than that in PBS (pH 7.4). NCTD PVA and NCTD-CS inhibited human esophageal carcinoma ECA-109 cell and murine breast cancer EMT6 cell growth in a dose-dependent manner. The IC50 values of NCTD, NCTD-PVA and NCTD-CS on ECA-109 cell at 48 h were 9.4 +/- 0.9, 55.3 +/- 3.0 and 168.8 +/- 8.9 MUg/ml, respectively, and the IC50 values of the three compounds on EMT6 cell were 3.1 +/- 0.3, 30.5 +/- 5.4 and 90.7 +/- 8.1 MUg/ml, respectively. The two conjugates both induced esophageal carcinoma ECA-109 cell apoptosis and arrested cell cycle at the S phase. Caspase-8 and caspase-3 were activated in the ECA-109 cell after incubating with NCTD-PVA or NCTD-CS. The primary in vivo antitumor activity was assessed in the EMT6 tumor-bearing mouse model. NCTD-PVA and NCTD-CS displayed higher tumor inhibition rates than that of free NCTD. PMID- 24156409 TI - Upregulation of Wnt5a promotes epithelial-to-mesenchymal transition and metastasis of pancreatic cancer cells. AB - BACKGROUND: Pancreatic cancer is one of the most lethal cancers worldwide. The aim of this study was to determine the expression pattern, clinical significance, and biological functions of Wnt5a in pancreatic cancer. METHODS: Immunohistochemistry was performed to examine Wnt5a expression in 134 surgically resected pancreatic adenocarcinoma and adjacent normal pancreatic tissues. Associations of Wnt5a expression with clinicopathological factors and cancer specific survival were analyzed. The effects of Wnt5a overexpression or silencing on the invasiveness and epithelial-to-mesenchymal transition (EMT) of pancreatic cancer cells were studied. Silencing of beta-catenin by small interfering RNA was done to determine its role in the Wnt5a-mediated tumor phenotype. RESULTS: The percentage of Wnt5a positive expression showed a bell-shaped pattern in pancreatic cancer tissues, peaking in well-differentiated carcinomas. The median cancer-specific survival was comparable between patients with positive versus negative expression of Wnt5a. Overexpression of Wnt5a promoted the migration and invasion of pancreatic cancer cells, whereas Wnt5a depletion had an inhibitory effect. In an orthotopic pancreatic cancer mouse model, Wnt5a overexpression resulted in increased invasiveness and metastasis, coupled with induction of EMT in tumor cells. Treatment with recombinant Wnt5a elevated the nuclear beta catenin level in pancreatic cancer cells, without altering the Ror2 expression. Targeted reduction of beta-catenin antagonized exogenous Wnt5a-induced EMT and invasiveness in pancreatic cancer cells. CONCLUSION: Upregulation of Wnt5a promotes EMT and metastasis in pancreatic cancer models, which involves activation of beta-catenin-dependent canonical Wnt signaling. These findings warrant further investigation of the clinical relevance of Wnt5 upregulation in pancreatic cancer. PMID- 24156410 TI - Atypical association of semantic dementia, corticobasal syndrome, and 4R tauopathy. AB - A 57-year-old male with no family history was diagnosed with semantic dementia. He also showed some unusual cognitive features such as episodic memory and executive dysfunctions, spatial disorientation, and dyscalculia. Rapidly progressive cognitive and physical decline occurred. About 1.5 years later, he developed clinical features of a corticobasal syndrome. He died at the age of 60. Brain autopsy revealed numerous 4R-tau-positive lesions in the frontal, parietal and temporal lobes, basal ganglia, and brainstem. Neuronal loss was severe in the temporal cortex. Such association of semantic dementia with tauopathy and corticobasal syndrome is highly unusual. These findings are discussed in the light of current knowledge about frontotemporal lobar degeneration. PMID- 24156412 TI - [Membrane-bound cytokine and feedforward regulation]. AB - Feedback and feedforward widely exist in life system, both of them are the basic processes of control system. While the concept of feedback has been widely used in life science, feedforward regulation was systematically studied in neurophysiology, awaiting further evidence and mechanism in molecular biology and cell biology. The authors put forward a hypothesis about the feedforward regulation of membrane bound macrophage colony stimulation factor (mM-CSF) on the basis of their previous work. This hypothesis might provide a new direction for the study on the biological effects of mM-CSF on leukemia and solid tumors, and contribute to the study on other membrane bound cytokines. PMID- 24156411 TI - Molecular docking studies for the identification of novel melatoninergic inhibitors for acetylserotonin-O-methyltransferase using different docking routines. AB - BACKGROUND: N-Acetylserotonin O-methyltransferase (ASMT) is an enzyme which by converting nor-melatonin to melatonin catalyzes the final reaction in melatonin biosynthesis in tryptophan metabolism pathway. High Expression of ASMT gene is evident in PPTs. The presence of abnormally high levels of ASMT in pineal gland could serve as an indication of the existence of pineal parenchymal tumors (PPTs) in the brain (J Neuropathol Exp Neurol 65: 675-684, 2006). Different levels of melatonin are used as a trait marker for prescribing the mood disorders e.g. Seasonal affective disorder, bipolar disorder, or major depressive disorder. In addition, melatonin levels can also be used to calculate the severity of a patient's illness at a given point in time. METHODS: Seventy three melatoninergic inhibitors were docked with acetylserotonin-O-methyltransferase in order to identify the potent inhibitor against the enzyme. The chemical nature of the protein and ligands greatly influence the performance of docking routines. Keeping this fact in view, critical evaluation of the performance of four different commonly used docking routines: AutoDock/Vina, GOLD, FlexX and FRED were performed. An evaluation criterion was based on the binding affinities/docking scores and experimental bioactivities. RESULTS AND CONCLUSION: Results indicated that both hydrogen bonding and hydrophobic interactions contributed significantly for its ligand binding and the compound selected as potent inhibitor is having minimum binding affinity, maximum GoldScore and minimum FlexX energy. The correlation value of r2 = 0. 66 may be useful in the selection of correct docked complexes based on the energy without having prior knowledge of the active site. This may lead to further understanding of structures, their reliability and Biomolecular activity especially in connection with bipolar disorders. PMID- 24156413 TI - [Analysis of correlation between serum thymidine kinase 1 and acute myeloid leukemia]. AB - This study was purposed to investigate the clinical significance of serum thymidine kinase 1 (STK1) level change in acute myeloid leukemia (AML). Peripheral blood samples of 60 newly diagnosed AML patients were collected and the STK1 levels were determined by enhanced chemiluminescent dot-blot method before and at two weeks after start of inductive treatment and in consolidatory treatment. Using non-parametric test, the differences between groups were analyzed. Then the correlation between STK1 level and clinical characteristics was explored by a way of chi-square test. The results indicated that the serum TK1 level in complete remission (CR) or partial remission (PR) AML patients decreased in varying degree as compared to pretreatment (P < 0.05), while there was no significant difference of TK1 level in non-remission (NR) ones (P > 0.05). The serum TK1 level in CR patients remained low level but increased noticeably after relapse into progressive disease (P < 0.05). A significant correlation was found between STK1 level and chromosomal abnormalities, serum LDH level as well as whether had fever in de novo AML patients (P < 0.05). It is concluded that the serum TK1 level change may be applied for reflecting the aggressiveness of disease, monitoring the clinical response to chemotherapy, evaluating the prognosis and predicating the relapse risk. The decrease of TK1 level suggests effective treatment and tumor burden reduction, while its increase indicate poor prognosis and relapse risk. PMID- 24156414 TI - [Expression of survivin in patients with acute myeloid leukemia]. AB - Objective of this study was to detect the expression of Survivin in acute myeloid leukemia (AML) and investigate the relationship of its expression levels with clinical variates and its correlations with BCL-2 ,Bcl-xL and MCL-1. The expression of Survivin, BCL-2, Bcl-xL and MCL-1 were measured by immunohistochemistry in bone marrow biopsy of 63 newly diagnosed AML patients, and the relationship between its expression level and clinical parameters (age, sex, WBC count, diagnosis, prognosis), especially fusion protein AML1/ETO was investigated. The results showed that the expression level of Survivin in newly diagnosed AML patients was higher than that of normal controls (P < 0.01), the expression levels of Survivin did not correlate with age, sex, and WBC counts of patients and so on. There was no significant difference of Survivin expression between different NCCN prognosis groups, either between patients with AML1/ETO or FLT3-ITD mutation and the other patients. Survivin positive patients were got to have lower CR rate but higher relapse rate, however that was not significant in statistics. Indeed, the cumulative survivin rate of Survivin positive patients were lower than that of Survivin negative patients (P = 0.04). Finally, positive correlation between Survivin and MCL-1 was also observed (r = 0.639, P = 0.000). It is concluded that overexpression of Survivin are closely related with occurrence and development of acute leukemia, and may be used as an indicator of prognosis evaluation. In addition, Survivin and MCL-1 may have a relationship of cooperation or interaction. PMID- 24156415 TI - [Expression and significance of stathmin1 in acute leukemia]. AB - This study was aimed to investigate the expression of stathmin1 mRNA and stathmin1 protein in de novo patients with acute leukemia (AL), relapsed patients with AL and complete remission patients with AL, and its clinical significance. The expression of stathmin1 mRNA and stathmin1 protein in peripheral blood samples from 76 cases of AL and 25 healthy persons were examined by fluorescent quantitative PCR (FQ-PCR) and Western blot, respectively. The results showed that the stathmin1 protein expression could not be detected in healthy persons, only the low level of its mRNA could be observed in them. The stathmin1 mRNA expression level in de novo AL patients was higher than that in healthy persons (P < 0.05), the stathmin1 mRNA expression level in relapsed patients with AL was higher than that in de novo patients (P < 0.05), and there was no significant difference of stathmin1 mRNA expression between patients with AML and patients with ALL. The positive rate of stathmin1 protein expression in de novo patients with AL was 89%, while it obviously decreased or did not express in complete remission patients with AL. The stathmin1 protein expression in relapsed patients with AL did not display significant difference as compared with that in de novo patients (P > 0.05). There was no significant difference in stathmin1 protein expression between patients with AML and patients with ALL (P > 0.05). It is concluded that stathmin1 protein and mRNA are overexpressed in de novo patients and relapsed patients, and lowly expressed in complete remission patients. Therefore, the stathmin1 may be a new biological marker for evaluation of minimal residual disease. PMID- 24156416 TI - Reduced expression of PDLIM4 gene correlates with good prognosis in acute myeloid leukemia. AB - This study was aimed to investigate the expression pattern of gene PDLIM4 (PDZ and LIM domain 4) and analyze its clinical correlation with the patients suffered from acute myeloid leukemia (AML). The expression pattern of PDLIM4 in AML was detected by using EvaGreen real-time quantitative PCR (RQ-PCR). The results showed that the PDLIM4 transcript significantly decreased in 94 AML patients, compared with 21 controls (P < 0.01). The decrease of PDLIM4 transcript was found in 42 (45%) AML patients. PDLIM4 low-expression occurred among the subtypes of M1/M2/M3 more frequently than that in M4/M5/M6 (56% vs 20%, P < 0.01). AML patients with PDLIM4 low-expression had an overall survival (OS) higher than that in AML patients without PDLIM4 low-expression (P < 0.05). Analysis with receiver operating characteristic curve (ROC) displayed that PDLIM4 expression possesses the diagnostic value to differentiate AML from controls, with ROC curve area of 0.865 (95% CI: 0.801-0.930). It is concluded that reduced PDLIM4 expression is a common and favorable event for the good prognosis in AML, and can be used as a potential diagnostic biomarker of cancer. PMID- 24156417 TI - [Clinical and laboratorial analysis for 15 adult cases of mixed phenotypic acute leukemia with Ph chromosome and/or positive BCR-ABL]. AB - The purpose of this study was to summary the clinical and laboratorial features in 15 adult cases of mixed phenotypic acute leukemia with Ph chromosome and/or BCR-ABL fusion gene positive (Ph(+)MPAL), 15 adult patients with Ph(+)MPAL were defined by WHO-2008 classification. The clinical characteristics, results of morphology, immunology, cytogenetics and molecular genetic detections and results of follow-up in 15 adult patients with Ph(+)MPAL were analyzed retrospectively. The results showed that 15 patients among 87 cases of MPAL demonstrated Ph(+)MPAL (17.2%; 15/87) (7 males and 8 females), their median age was 51 (range 16-81) year old and median WBC count at diagnosis was 69 (12.7-921)*10(9)/L. Based on FAB criteria, these patients showed different morphologic types, including AML (13.3%; 2/15), ALL (40.0%; 6/15), HAL (46.7%; 7/15). Immunologic analysis indicated that 15 cases of Ph(-)MPAL were all classified as B-lymphoid +myeloid mixed immunophenotype. Except one patient, all expressed CD34 antigen on the surface of leukemia cells with 64.3% strong positive, only Ph (53.3%; 8/15), Ph with additional chromosomal abnormalities (33.3%; 5/15) and normal karyotype (13.3%; 2/15) were cytogenetically identified. BCR-ABL fusion gene transcript positive were detected by multiplex reverse transcription PCR in all cases, with e1a2 subtype (p190) (40.0%; 6/15) and b2a2 or b3a2 (p210) subtype (60.0%; 9/15). Four out of 7 (57.1%) patients were found to have IKZF1 gene deletion, without other common gene mutations. Seven out of 10 cases (70.0%) achieved complete remission (CR) after one cycle of induction chemotherapy. In the induction stage, CR rate seemed higher when tyrosine kinase inhibitors (TKI) were added to chemotherapy (83.3%:50.0%; P = 0.206). Overall survival (OS) in 4 patients received allogeneic hematopoietic stem cell transplantation (allo-HSCT) was longer than that in 4 patients received chemotherapy alone (P = 0.004). It is concluded that Ph(+)MPAL mainly is expressed as B+My phenotype. The majority of patients is older and has CD34 overexpression. In the aspect of molecular genetics, the Ph(+)MPAL is similar to other acute leukemia with Ph chromosome. Ph(+)MPAL is a subtype of acute leukemia with poor prognosis. WBC count at diagnosis is an independent prognostic factor. The combination of TKI and allo HSCT can improve their long-term survival, which needs to be confirmed through carrying out a prospective and multicenter clinical trial for newly diagnosed Ph(+)MPAL. PMID- 24156418 TI - [Anti-human 4-1BBL monoclonal antibody stimulates the nuclear translocation of NF kappaB and the co-location of 4-1BBL/CD28 isoform in U937 cells]. AB - This study was purposed to investigate the molecular mechanism of 4-1BBL reverse signals in the human acute monocytic leukemia cell line of U937. The U937 cell line was used as target cells, and stimulated by the mouse anti-human 4-1BBL monoclonal antibody 1F1. The nuclear translocation of NF-kappaB and the co location of 4-1BBL and CD28i molecules in U937 cells were observed with confocal laser scanning microscopy. The protein and m-RNA expression levels of 4-1BBL and CD28i were detected by flow cytometry and RT-PCR respectively. The results showed that the significant nuclear translocation of NF-kappaB and co-localization of 4 1BBL and CD28i on membrane of U937 cells appeared after being stimulated by mAb1F1. It is concluded that the 4-1BBL reverse signals transduction mediating the growth of U937 cells relates with the nuclear translocation of NF-kappaB. CD28i may be involved in intracellular 4-1BBL reverse signaling pathways. PMID- 24156419 TI - [Establishment of the retrovirus-mediated murine model with MLL-AF9 leukemia]. AB - This study was purposed to establish a retrovirus-mediated murine model with MLL AF9 leukemia, so as to provide a basis for further investigation of the pathogenesis and therapeutic strategy of MLL associated leukemia. Murine (CD45.2) primary hematopoietic precursor positively selected for expression of the progenitor marker c-Kit by means of MACS were transduced with a retrovirus carrying MLL-AF9 fusion gene. After cultured in vitro, the transduced cells were injected intravenously through the tail vein into the lethally irradiated mice (CD45.1). PCR, flow cytometry and morphological observation were employed to evaluate the murine leukemia model system. The results showed that MLL-AF9 fusion gene was expressed in the infected cells, and the cells had a dramatically enhanced potential to generate myeloid colonies with primitive and immature morphology. Flow cytometric analysis revealed that the immortalized cells highly expressed myeloid lineage surface markers Gr-1 and Mac-1. Moreover, the expression levels of Hoxa9 and Meis1 mRNA were significantly higher in the MLL AF9 cells than that in control. The mice transplanted with MLL-AF9 cells displayed typical signs of leukemia within 6-12 weeks. Extensive infiltration leukemic cells was observed in the Wright-Giemsa stained peripheral blood smear and bone marrow, and also in the histology of liver and spleen. Flow cytometric analysis of the bone marrow and spleen cells demonstrated that the CD45.2 populations expressed highly myeloid markers Gr-1 and Mac-1. The leukemic mice died within 12 weeks. It is concluded that the retrovirus-mediated murine model with MLL-AF9 leukemia is successfully established, which can be applied in the subsequent researches. PMID- 24156420 TI - [Cytotoxicity of Naja Naja Actra Venom Component combined with activated immune cells on leukemia cell line KG1a]. AB - This study was aimed to investigate the cytotoxic effect of the Naja Naja Actra Venom Component (NNAVC) combined with activated immune cells on human acute myeloblastic leukemia line KG1a cells. The cytotoxic effects of NNAVC at different concentrations on KG1a cells were measured by CCK-8 method. LDH releasing assay was used to detect the cytotoxic effects of activated immune cells, NNAVC combined with activated immune cells on KG1a cells and the sensitivity of KG1a treated with NNAVC to activated immune cells. The results showed that the inhibitory rate of NNAVC on KG1a cells increased with the concentration enhancement, the cytotoxicity of activated immune cells at the different effector to target (E:T) ratios(6.25:1, 12.5:1, 25:1) on KG1a cells were 12.30%, 24.85% and 52.26%. The cytotoxicity of NNAVC combined with activated immune cells at the different E:T cell ratios (10:1, 20: 1) on KG1a cells were 56.21% and 85.59%, which were higher than that of NNAVC or activated immune cells alone. The cytotoxicity of activated immune cells at the E: T cell ratio of 10:1 on KG1a cells treated with NNAVC at different concentrations were 25.65%, 31.33%, 28.63% and 16.78%, respectively, and that at the E:T cell ratio of 20: 1 were 40.62%, 44.70%, 44.62% and 40.72%. It is concluded that:both of NNAVC and activated immune cells have lethal effect on KG1a cells, and the combination of NNAVC and activated immune cells can strengthen their effect on KG1a. PMID- 24156421 TI - [IL-23 alone or with IL-2 induces the killing effect of hPBMNC on K562 cells]. AB - This study was aimed to explore the killing effect of PBMNC induced by IL-23 alone or combined with IL-2 on K562 cells and its mechanism. The PBMNC were induced in vitro by IL-23 (50 ng/ml) alone or IL-23 combined with IL-2 (100 U/ml) for 72 h, and then were co-cultured with leukemia cell line K562. The CCK-8 method was used to detect the effect of PBMNC induced at different times on K562 cells, the ELISA was performed for detecting IFN-gamma level in culture supernatant, and the perforin and granzymes B were detected by RQ-PCR. The results showed that the killing effect of PBMNC induced by IL-23 alone or IL-23 combined with IL-2 on K562 cells was observed, and obviously enhanced with prolonging of time, moreover, there was statistical difference among different time points (P < 0.05). The IFN-gamma level in supernatant of PBMNC cultured with cytokines significantly increased, and the IFN-gamma levels in group of IL-23 combined with IL-2 were higher than that in other groups (P < 0.05). The mRNA expressions level of perforin and granzymes B of the expanded PBMNC in groups cultured with cytokines were higher than that in control group (P < 0.05), and the mRNA expressions of perforin and granzymes B in group of IL-23 combined with IL-2 were significantly higher than that in others (P < 0.05). It is concluded that IL-23 can promote the killing effect of PBMNC on K562 cells. The combination of IL-2 with IL-23 displays synergic effect and a time-dependent manner. IL-23 also enhances the expression of IFN-gamma, perforin and granzyme B in PBMNC. Its combination with IL-2 displays synergistic effect, suggesting that the anti leukemic activity of IL-23 may be realized through inducing PBMNC to express IFN gamma, perforin and granzyme B. PMID- 24156422 TI - [Analysis of clinical characteristics and prognosis of 13 cases of acute erythroleukemia]. AB - The aim of this study was to investigate the clinical characteristics and prognosis of acute erythroleukemia (AEL, AML-M6). The clinical features and results of morphologic, immunophenotypic, cytogenetic and molecular biologic detections were retrospectively analyzed in 13 cases of AEL from 305 acute leukemia patients hospitalized between October 2007 and October 2012. The results showed that the expression of erythroid and non-erythroid cells increased at the same time. The myeloid antigens mainly expressed CD13/CD33/CD117/CD34, while the erythroid antigens expressed Gly and CD71. The karyotypic detection indicated that there were 1 case with normal karyotype, 3 cases with simple karyotypic abnormality and 2 cases with complex karyotypic abnormality, the other cases were not detected. The molecular biological detection found that the poor prognosis gene existed in 5 cases [38.5% (5/13)], including 3 cases with MLL-MLL fusion gene, 1 case with MLL mutation, and 1 cases with NRAS gene mutation, the abnormal genes were not detected in remainder 8 cases. After chemotherapy with decitabine, the complete remission (CR) rate achieved 53.5% (7/13), partial remission (DR) rate achieved 15.4% (2/13). Finally, 8 patients received allo-HSCT, the median overall survival (OS) was 20.7 months, 3 year survival rate was 79%, 3 year disease-free survival rate was 78%. It is concluded that the acute erythroleukemia is a rare subtype of AML, which is transformed from MDS and has harmful genes and poor prognosis. Allo-HSCT and treatment with decitabine may enhance the survival rate of AEL. PMID- 24156423 TI - [Triptolide inhibits proliferation and induces apoptosis of imatinib resistant K562/G01 cells]. AB - This study was aimed to explore the inhibitory effect of triptolide on proliferation and inducing apoptosis effect of K562/G01 cells and their possible mechanism. MTT assay was used to detect the effect of imatinib or triptolide alone and their combination on K562/G01 proliferation; the cell cycle, apoptosis rate, P-gp protein expression were detected by flow cytometry (FCM); the expression of P-gp was assessed by Western blot; the BCR/ABL gene expression was assayed by real time quantitative PCR. The results showed that triptolide could enhance the effect of imatinib on proliferation inhibition and apoptosis of K562/G01, arrested the cell cycle in G1 phase, down-regulated the expression of BCR/ABL gene and P-gp protein. It is concluded that triptolide induces K562/G01 cell proliferation inhibition and apoptosis, the mechanism may be related to cell cycle arrest, decrease of P-gp protein expression, inhibition of BCR/ABL gene expression. PMID- 24156424 TI - [Detection of SALL4 mRNA expression in leukemia by real-time fluorescent quantitative PCR]. AB - This study was purposed to establish a real-time fluorescent quantitative PCR (FQ PCR) for quantifying SALL4 mRNA and to investigate its expression in different types of leukemia patients. SALL4 mRNA expression were measured in 60 leukemia patients of different periods and 10 normal controls sequentially by FQ-PCR. The results showed that the expression of SALL4 mRNA in de novo leukemia patients and relapsed patients was higher than that in controls (P < 0.05), which was significantly decreased at complete remission (CR). In relapsed patients, the expression of SALL4 mRNA increased slightly higher than that in de novo leukemia group, but the difference was not statistically significant (P > 0.05). However, the expression of SALL4 mRNA was low in CLL, T-ALL and AML-M3. The expression pattern of BMI-1 was same as SALL4, and the expression of BMI-1 positively correlated with that of SALL4 in leukemia (r = 0.825, P < 0.01). It is concluded that the detection of SALL4 gene expression in acute and chronic leukemia by real time gTR-PCR displays high sensitivity and specificity. SALL4 gene may be one of indicators for monitoring the therapeutic outcome of partial leukemia and minimal residual disease. PMID- 24156426 TI - [Expression and clinical significance of Ki-67 in diffuse large B cell lymphoma]. AB - This study was aimed to evaluate the proliferation-associated antigen Ki-67 expression in diffuse large B cell lymphoma (DLBCL) and its clinical significance. The Ki-67 expression and its correlation with prognosis in 50 patients with DLBCL treated with rituximab plus CHOP (R-CHOP) between January 2008 and December 2010 were analyzed retrospectively. The results indicated that there was no significant relationship between Ki-67 expression and clinical features, including age, sex, staging, B symptoms, LDH level, IPI, extranodal site involvement, presence of bulky tumors (>10 cm in diameter), bone marrow involvement, GCG nor GCB type, or response to first line treatment. The median survival was 50 months and 15 months in low Ki-67 expression group (<85%) and in high Ki-67 expression group ( >= 85%) respectively. The overall survival (OS) and progress-free survival (PFS) in low Ki-67 expression group were obviously longer than that in high Ki-67 expression group (P = 0.001; P = 0.027). In univariate analysis, the clinical factors associated with OS included Ann Arbor staging and Ki-67 expression. The clinical factors associated with PFS included Ann Arbor staging. IPI and Ki-67 expression. In multivariate analysis. The Ki-67 expression level was an independent prognostic factor for OS (HR = 4.90; 95% CI, 1.456 16.511; P = 0.0103). It is concluded that Ki-67 expression level seems to be an effective marker for evaluation of DLBCL prognosis. PMID- 24156425 TI - [COX-2 inhibitor celecoxib can suppress the proliferation of FLT3-ITD positive acute myeloid leukemia cells with prominent down regulation of MEK/MCL-1 expression in vitro]. AB - The purpose of this study was to investigate the effects of Celecoxib on the proliferation of the FLT3-ITD positive and negative acute myeloid leukemia cells and its mechanism. The proliferation inhibition effect of Celecoxib with different doses on the FLT3-ITD positive cells MV4-11 and the FLT3-ITD negative K562 cells was detected by CCK-8 method, the cell apoptosis was determined by flow cytometry, and the MEK, Mcl-1, pAKT expression was tested by Western blot. The results showed that Celecoxib inhibited the proliferation of both MV4-11 and K562 cells, but the IC50 for MV4-11 was (29.14 +/- 2.4) umol/L, which was significantly lower than that of K562 cells (39.84 +/- 1.0) umol/L (P < 0.05); The induced apoptosis rate of Celecoxib at 20-80 umol/L on MV4-11 was not observed, but there was apparent influence on K562 at the same concentration. Western blot showed that Celecoxib down-regulated the expression of MEK and Mcl-1 but did not change the expression of pAKT obviously on MV4-11 cells, while the expression of Mcl-1 was reduced a little, but no obvious change were found in the expression of MEK and pAKT on K562 cells. It is concluded that the Celecoxib can inhibit the proliferation of FLT3-ITD positive AML cells distinctly, and the potential mechanism may be related to the inhibition of the MEK/Mcl-1 signaling pathway. PMID- 24156427 TI - [Expression and significance of MMP-26, TIMP-4 and MMP-9 in diffuse large B-cell lymphoma cells]. AB - The aim of this study was to investigate the expression of matrix metalloproteinase 26 (MMP-26), tissue inhibitor of metalloproteinase-4 (TIMP-4) and matrix metalloproteinase 9 (MMP-9) in patients with diffuse large B cell lymphoma (DLBCL) and their correlations with pathogenesis and development of DLBCL. A total of 95 specimens excised from DLBCL patients were prepared. Expression of MMP-26, TIMP-4 and MMP-9 were tested by SABC immunohistochemistry method and its correlation to clinicopathology indexes were analyzed. The results showed that as compared with reactive hyperplasia of lymph nodes, the high expression of MMP-26, TIMP-4 and MMP-9 were found in different types of DLBCL. The positive expression rate of MMP-26 was related to immune typing (P < 0.05). The expression level of MMP-26 in GCB was lower than that in non-GCB, and did not relate to clinical staging, age, sex, diseased region (P > 0.05). The positive expression rate of MMP-9 was related to clinical staging, the positive expression rate of MMP-9 proteins in patient at III and IV stage was obviously higher than that in patients at I and II stage, but did not relate to immune type, age, sex and diseased region of DLBCL (P > 0.05). The expression of TIMP-4 did not relate to immune type, clinical stage, age, sex, disease region (P > 0.05). The expression of MMP-26 in pathologic tissue of DLBCL did not relate to expression of TIMP-4, but positively related to expression of MMP-9 protein (r = 0.486, P < 0.05). It is concluded that MMP-26 and MMP-9 synergically express in DLBCL. MMP 26 may be involve in pathogenesis and invasiveness of DLBCL, the expression of MMP-26 relates to subtypes of DLBCL. The MMP-26 may serve as an indicator for typing of DLBCL and contributes to predict the invasion and metastasis of DLBCL and itself may become a potential target for therapy. PMID- 24156428 TI - [Detection of malignant B lymphocytes in cerebrospinal fluid by using BIOMED-2 PCR]. AB - The purpose of this study was to develop a sensitive method for the detection of malignant B lymphocytes in cerebrospinal fluid (CSF) from patients with diffuse large B-cell lymphoma (DLBCL) who were considered as risk of central nervous system (CNS) involvement. Nine CSF samples were collected and then centrifuged. The cell precipitate was lysed directly. The supernatant was used to detect immunoglobulin heavy chain (IgH) gene rearrangement (characteristic changes of malignant B lymphocytes ) by BIOMED-2 PCR. The sensitivity of this method was compared with that of cytology defection and flow cytometry. In addition, through a series of quantity/concentration of tumor cells, the sensitivity differences caused by two sample handling methods (direct cell lysis vs traditional DNA extraction) were analyzed, and the sensitivity of direct cell lysis combined with BIOMED-2 PCR was evaluated. The results showed that the positive clonality of IgH gene rearrangement were detected by BIOMED-2 PCR in 5 cases, but the positive were detected by cytology defection/flow cytometry only in 2 cases, which indicated that the BIOMED-2 PCR assay gives a better yield. In addition, when combined with BIOMED-2 PCR, direct cell lysis produced sensitivity much higher than DNA extraction. The former can enable clonality detection from a minimum of 0.1%/20 tumor cells. It is concluded the method of direct cell lysis combined with BIOMED-2 PCR is sensitive and suitable for paucicellular CSF detection. It may aid the diagnosis of CNS involvement in patients with DLBCL. PMID- 24156429 TI - [Effect of PCI-32765 and bortezomib on proliferation and apoptosis of B-cell tumor cell lines and its mechanisms]. AB - This study was aimed to investigate the effect of Btk inhibitor PCI-32765 and the proteasome inhibitor bortezomib on Raji and Ramos cell proliferation, apoptosis, and its mechanisms. Raji and Ramos cells were treated with PCI-32765 and bortezomib alone and/or their combination. The cell proliferation and apoptosis were detected by CCK-8 and flow cytometry respectively, the expression level of Btk, NFkappaB, c-IAP1, Bcl-xL and caspase-3 protein were measured by Western blot. The results indicated that: (1) after Raji and Ramos cells were treated with PCI-32765 (0.5, 1.0, 2.0, 3.0, 4.0, 5.0, 6.0 umol/L) alone and bortezomib (10, 20, 30, 40, 50, 60, 80 nmol/L) alone and their combination for 48 h, the cell proliferation and vitality were inhibited in a dose-dependent manner and both had synergistic effect; (2) Raji and Ramos cells were treated with PCI-32765 (2.0 umol/L) and bortezomib (20 nmol/L) alone and their combination for 8, 12, 24, 36, 48 and 72 h, the cell proliferation and vitality were inhibited in a time dependent manner, the two drugs displayed a synergistic effects; (3) the Raji and Ramos cells were treated with PCI-32765 (2.0 umol/L) and bortezomib (20 nmol/L) alone and their combination for 48 h, all these treatments could induce significant apoptosis of Raji and Ramos cells.In Raji cell experiment, the cell apoptosis rate in the control group, PCI-32765 group, bortezomib group and PCI 32765 and bortezomib combination group were 10.34 +/- 0.53%, 24.26 +/- 0.91%, 43.66 +/- 1.08% and 74.06 +/- 0.72% respectively, and the differences was statistically significant among the different groups (P < 0.05). In Ramos cell experiment, the cell apoptosis rate in the control group, PCI-32765 group, bortezomib group and PCI-32765 and bortezomib combination group are 15.16 +/- 1.49%, 71.36 +/- 0.82%, 75.32 +/- 2.36% and 84.30 +/- 0.91% respectively, the differences was statistically significant among the different groups (P < 0.05); (4) PCI-32765 and bortezomib could inhibit the expression level of intracellular Btk, NFkappaB, Bcl-xl and c-IAP1 proteins, but up-regulate the expression level of caspase-3. It is concluded that PCI-32765 and bortezomib can synergistically inhibit the proliferation and induce apoptosis of Raji and Ramos cells, the mechanism may be associated with inhibition of Btk and NFkappaB activity, down regulation of anti-apoptotic proteins expression, such as Bcl-xl and c-IAP1, and increase of caspase-3 expression. PMID- 24156430 TI - [Antiproliferative effects of LY294002 on MCL Jeko-1 cell line and its mechanism]. AB - This study was aimed to investigate the effects of LY294002, a specific inhibitor of phosphatidylinositol 3-kinase, on growth and apoptosis of MCL Jeko-1 cell line and its mechanism. The proliferation inhibitory rate of Jeko-1 cells treated by different doses of LY294002 was assayed by MTT method; the level of apoptosis of Jeko-1 cells was detected by flow cytometry; the expression level of apoptosis related protein Cyclin D1, Bcl-2, procaspase-3 and PI3K/Akt signaling pathway protein phosphorylated-Akt (p-Akt), phosphorylated-TOR (p-mTOR), phosphorylated P70S6K (p-P70S6K) phosphorylated-Akt (p-Akt) in Jeko-1 cells were determined by Western blot. The results showed that the growth of Jeko-1 cell line was inhibited by LY294002. The apoptosis rates of Jeko-1 cells treated with 0, 5, 10 and 20 umol/L of LY294002 for 24 hours were (3.25 +/- 1.27)%, (11.34 +/- 2.35)%, (22.81 +/- 2.74)%, (43.61 +/- 3.48)% respectively, the difference between them was statistically significant (P < 0.01). Phosphorylation levels of PI3K/Akt signaling pathway protein p-Akt, p-mTOR, p-P70S6K decreased, the expression of apoptosis-related protein cyclin D1, Bcl-2, procaspase-3 was down-regulated.It is concluded that the LY294002 can inhibit Jeko-1 cell proliferation, which may be realized through down-regulating the phosphorylation level of p-Akt, p-mTOR, p P70S6K, inhibiting the P13k/Akt signaling pathway, and promoting the cell apoptosis. PMID- 24156431 TI - [Function of peripheral blood Th17 cells in patients with multiple myeloma]. AB - This study was aimed to investigate the effects of peripheral blood Th17 cells and their secreting IL-17, IL-21 in the occurrence and development of multiple myeloma (MM). A total of 55 patients with MM were divided into non-remission group (group A , n = 30), remission group (group B, n = 25); healthy volunteers were used as control group (group C , n = 30). The concentration of IL-17, IL-21 and IL-6 in the peripheral blood mononuclear cell (PBMNC) culture supernatant were determined with ELISA. The ratio of Th7 cells in PBMNC was determined by flow cytometry. The results showed that IL-17, IL-21 levels and ratio of Th17 cells in group A were much higher than those in group B and C (P < 0.05), IL-17, IL-21 and the ratio of Th17 cells between group B and group C were not significantly different (P > 0.05); IL-17 level in non-remission MM group positively correlated with IL-6 level (r = 0.782, P < 0.05), IL-21 level in non remission MM group positively correlated with IL-6 level (r = 0.778, P < 0.05). It is concluded that Th17 cells as a initiating factor may be involved in the immune pathogenesis of MM patients, promoting the progress of the disease. PMID- 24156432 TI - [Cytogenetic abnormalities of 50 MDS patients by FISH detection and conventional karyotype analysis]. AB - This study was purposed to compare detectable rate of cytogenetic abnormalities including -5/5q-, -7/7q-, 20q-,+8, and -Y in MDS by FISH and metaphase cytogenetics, and to investigate the relationship between cytogenetic abnormalities and progression from MDS to acute leukemia. Metaphase cytogenetics and FISH testing for -5/5q-, -7/7q-, 20q-,+8, and -Y were performed in 50 bone marrow samples obtained from patients with MDS diagnosed according to the WHO criteria (2008). Evolution from MDS to AML was followed up for each patient. The results showed that the cytogenetic abnormalities including -5/5q-, -7/7q-, 20q ,+8, and -Y were identified in 25 (50%) of 50 by metaphase cytogenetics, and in 20 (40%) of 50 by FISH. -5/5q-, 7/7q-, 20q- , +8, or -Y was identified by metaphase cytogenetics in 3 (6%) of 50, 13 (26%) of 50, 6 (12%) of 50, 12 (24%) of 50, and 1 (2%) of 50, respectively, and by FISH in 3 (6%) of 50, 10 (20%) 0f 50, 3 (6%) of 50, 10 (20%) of 50, and 1 of 50 (2%), respectively. The detectable rate ranking was -7/7q- >+8>20q->-5/5q->-Y. 47 patients received allogeneic hematopoietic stem cell transplantation. In the IPSS poor prognosis group, 6 (46.2%)of 13 received transplantation before progression to acute leukemia. In the IPSS good prognosis group, 10 (45.5% ) of 22 received transplantation before progression to acute leukemia. In the IPSS intermediate prognosis group, 2 (16.7%) of 12 received trans- plantation before progression to acute leukemia. The rate of progression to acute leukemia was 7.7% (1/13) in the IPSS poor prognosis group, 4.5% (1/22) in the IPSS good prognosis group, and 58.3% (7/12) in the IPSS intermediate prognosis group. The low rate of progression to acute leukemia in the IPSS poor prognosis group might be associated with the high rate of allogeneic hematopoietic stem transplantation. It is concluded that there is higher detectable rate for detecting a certain chromosome by FISH probe than that by metaphase cytogenetics, especially for detecting low clone chromosomal abnormalities and mitotic figures less than 20. There is no difference between IPSS good prognosis group and IPSS poor prognosis group in our study probably because of allogeneic hematopoietic stem cell transplantation. PMID- 24156433 TI - [Application of flow cytometry-fluorescence in situ hybridization in the measurement of relative telomere length of bone marrow CD34(+) cells in patients with myelodysplastic syndrome]. AB - This study was aimed to investigate the feasibility of flow cytometry fluorescence in situ hybridization (Flow-FISH) in measuring the telomere length of bone marrow cell subgroups in patients with myelodysplastic syndrome (MDS). Seven newly diagnosed patients with low-risk MDS and seven nutritional anemia patients who were matched with age and sex, were enrolled in this study. Heparinized bone marrow were sampled. Taking Molt-4 cell line as internal control cells, leukocytes isolated from whole bone marrow were labeled with CD34-Alexa Fluork (r) 647, then denatured by high temperature and hybridized with FITC conjugated telomere probe. The DNA was counterstained and the relative telomere length (RTL) of nucleated cells and CD34(+) cells in bone marrow were measured by four-color flow cytometry. The results showed that CD34(+) cells could be gated for the measurement of RTL in both groups, undergoing the denaturation and hybridization. Primary analysis indicated that the RTL of bone marrow CD34(+) cells in MDS patients was significantly shorter than that of bone marrow nucleated cells (P = 0.001), and the RTL of both CD34(+) cells and nucleated cells in bone marrow of MDS patients were significantly shorter than that of control group (P = 0.020, 0.002). It is concluded that the application of Flow FISH in the measurement of RTL of certain cell subgroup is feasible by labeling the cell with thermostable fluorescence-conjugated antibody, and this technique is worthy to be investigated further. PMID- 24156434 TI - [Abnormal expression of the platelet membrane receptor glycoprotein Ib-IX-V complex in transiently transfected HEK 293T cells]. AB - The structure and function of the glycoprotein (GP) Ib-IX-V complex has been extensively investigated over the decades due to its vital role in platelet activation. For the lack of nucleus in platelets, researchers usually need to study the GPIb-IX-V complex by transfecting wild type or mutant GPIb-IX-V plasmids into other mammalian cell lines, such as CHO or HEK 293T. Therefore, whether the characteristics of the GPIb-IX-V complex in these cell lines can truly represent that in platelets is pivotal to determine whether these cell lines are appropriate for GPIb-IX-V complex studies. In order to determine the most appropriate cell line to study the GPIb-IX-V complex, the surface expression level of the complex in different cell lines was detected and whether difference among cell lines will affect expression of the complex was explored in the present study. The different combinations of the GPIb-IX-V subunits were transfected into cell lines from different species or different tissues, such as CHO, HEK293T and HeLa, and the surface expression levels of the complex were detected by flow cytometry. The results indicated that in both transiently and stably transfected CHO cells, surface expression of GPV depended on the presence of the GPIb-IX complex, which is consistent with that in human platelets. In contrast, GPV could be efficiently expressed on surface in HEK 293T cells even in the absence of GPIb-IX, although the inter-subunit dependence within the GPIb-IX complex is still similar to that in CHO cells or human platelets. Further studies in HeLa, MES13 and HUVEC cell lines revealed that GPV could be efficiently expressed on the surface by itself in HeLa and MES13 cells, but not in HUVEC, suggesting different behaviors of the GPIb-IX-V complex in difference cell lines. It is concluded that this study provides some guidance and advice to future GPIb IX-V complex studies, especially to the choice of suitable cell line. HEK 293T cell line, for example, is likely to provide misleading results since it could not represent the fact in human platelets, thus is not the optimal choice for the GPIb-IX-V complex, particularly the GPV subunit. PMID- 24156435 TI - [Protein kinase C activation induces platelet apoptosis]. AB - Platelet apoptosis elucidated by either physical or chemical compound or platelet storage occurs wildly, which might play important roles in controlling the numbers and functions of circulated platelets, or in the development of some platelet-related diseases. However, up to now, a little is known about the regulatory mechanisms of platelet apoptosis. Protein kinase C (PKC) is highly expressed in platelets and plays central roles in regulating platelet functions. Although there is evidence indicating that PKC is involved in the regulation of apoptosis of nucleated cells, it is still unclear whether PKC plays a role in platelet apoptosis. The aim of this study was to investigate the role of PKC in platelet apoptosis. The effects of PKC on mitochondrial membrane potential (DeltaPsim), phosphatidylserine (PS) exposure, and caspase-3 activation of platelets were analyzed by flow cytometry and Western blot. The results showed that the DeltaPsim depolarization in platelets was induced by PKC activator in time-dependent manner, and the caspase-3 activation in platelets was induced by PKC in concentration-dependent manner. However, the platelets incubated with PKC inhibitor did not results in DeltaPsim depolarization and PS exposure. It is concluded that the PKC activation induces platelet apoptosis through influencing the mitochondrial functions and activating caspase 3. The finds suggest a novel mechanism for PKC in regulating platelet numbers and functions, which has important pathophysiological implications for thrombosis and hemostasis. PMID- 24156436 TI - [Detection of alloantibodies against Factor VIII in plasma of patients with hemophilia A and its relationship with Factor VIIIC domain]. AB - This study was purposed to detect the alloantibodies against Factor VIII (FVIII) by ELISA for estimating the incidence of the alloantibodies against Factor VIII (FVIII) in patients with hemophilia A, and to investigate the relationship between factor VIIIC domain and alloantibodies. Total of 140 patients with hemophilia A and 80 normal controls were enrolled in this study, among them plasma FVIII level of 84 patients was less than 1%, plasma FVIII level of 34 patients was between 1% and 5%, and plasma FVIII level of 22 patients was more than 5%. All patients were treated with plasma-derived FVIII concentrate or plasma before. The ELISA plate was coated with McAb (SZ-132) against FVIII prepared in our laboratory, then human recombinant FVIII concentrates were applied. After incubation in room temperature for 2 hours, diluted plasma samples and HRP-conjugated goat anti-human IgG were added successively, finally A490 was recorded. The threshold of alloantibody of patient plasma was set as mean value>3 SD more than control. The plate was coated with antibody against His, then human recombinant FVIII-C1C2 prepared in our laboratory was added. After incubation in room temperature for 2 hours, diluted plasma samples and HRP-conjugated goat anti human IgG were added successively, finally A490 were recorded. The threshold was set as the mean value>3 SD more than control. The results showed that the alloantibodies against FVIII were found in 56 patients (40%) by ELISA, and 82.1% (46/56) of this kind of alloantibody could interact with the C domain of FVIII. It is concluded that C domain of FVIII is one of the primary binding sites for the alloantibodies against FVIII in Chinese patients with hemophilia A. PMID- 24156437 TI - [Genetic diagnosis of thalassemia mutations with free fetal DNA in pregnant plasma]. AB - This research was aimed to develop a simple, rapid, accurate and non-invasive method by means of flow-through hybridization technology, which can be used for molecular screening and early prenatal diagnosis for detecting common beta thalassemias mutational genotypes. By using PCR technology combined with flow through hybridization of low-density gene chip technology, the 6 sets of PCR primer single tube multiplex PCR system and 29 types of DNA probes were designed, then the mutational thalassemias in foetus DNA was rapidly detected in total of 60 anaemia pregnant women plasma. The results showed that 4 cases with deletional alpha-thalassemias, 3 cases with beta-thalassemias, 1 case with mixed type of alpha & beta-thalassemias were detected in foetus DNA of 60 pregnant women plasmas. It is concluded that the method presented in this study is easy to handle, rapid, reliable and cost-effective for detecting 3 common deletional alpha-thalassemias and 17 common mutational beta-thalassemia. PMID- 24156438 TI - [Introplasmic IFN-gamma level in circulating T cells detected by flow cytomertry and its relation with treatment efficiency in the patients with aplastic anemia]. AB - This study was aimed to investigate the effects of the introplasmic interferon gamma level in circulating T cell of patients with aplastic anemia (AA) and its clinical significance. The interferon-gamma level before and after immuno suppressive therapy was monitored by flow cytometry. The results indicated that the higher interferon-gamma level was detected in 28 out of 50 AA patients, detected rate was 56%. The effective rate of immunosuppressive therapy for AA patients with higher interferon-gamma level was up to 85.7% (24/28). The decrease of interferon-gamma level in these patients positively correlated with hemogram recovery to normal level and obviously earlier than hematologic remission. It is concluded that the immunosuppressive therapy shows better efficacy for AA patients with high interferon-gamma level, moreover the change of interferon gamma level is earlier than hematologic change, that is important for predicting the therapeutic efficacy and relapse of disease. PMID- 24156439 TI - [Clinical analysis of high risk and refractory malignant hematologic diseases treated with haploidentical hematopoietic stem cell transplantation combined with umbilical cord mesenchymal stem cells using modified conditioning regimen]. AB - This study was aimed to investigate the efficacy of haploidentical hematopoietic stem cell transplantation (hi-HSCT) combined with umbilical cord mesenchymal stem cells (MSC) using modified conditioning regimen for the treatment of patients with refractory and relapsed or high risk malignant hematologic diseases, the clinical efficacy in 30 patients with refractory and relapsed or high risk malignant, who voluntarily received HSCT was analyzed. Among the 30 patients there were 4 relapsed cases and 26 cases of high risk malignant hematologic diseases. The above-mentioned patients included 15 AML, 9 ALL, 3 pro T lymphoblast lymphoma/leukemia, 1 spleen boundary zone lymphoma IVB, 1 NK/T lymphoma and 1 Burkitt lymphoma IVB. The results showed that the implantation was achieved in all 30 cases, among them 19 cases (63%) had aGVHD and 6 cases (20%) had III-IV aGVHD, 8 cases (32%) had cGVHD including 1 case of extensive and 7 cases of limited. Three cases relapsed at 300 days (128-455 d) after transplantation. 8 cases died, among them 1 case died of relapse, 2 cases died of IV aGVHD with relapse, 5 cases died of infection and organ failure. It is concluded, the efficacy of hi-HSCT combined with umbilical cord MSC for treatment of patients with refractory and relapsed or high risk malignant hematologic diseases is favorable. PMID- 24156440 TI - [Efficacy of donor's purified CD34(+) cells for treatment of poor graft function following allogeneic hematopoietic stem cell transplantation]. AB - This study was aimed to evaluate the efficacy and safety of donor's purified CD34(+) cells for treatment of secondary poor graft function (PGF) following allogeneic hematopoietic stem cell transplantation (allo-HSCT) . Ten patients suffering from secondary PGF after allo-HSCT in our hospital from January 2009 to December 2011 were treated with the donor's purified and G-CSF mobilized CD34(+) cells. All the patients were observed for infusion-related complication and survival status. CliniMACS system was used to separate cells, the results of sorting purified and recovery rate were calculated and statistically analysed. The results showed that the purified of CD34(+) cells reached to (89.31 +/- 1.73)%, and the recovery rate reached to (93.27 +/- 8.14)%; 10 patients in the process of infusion did not suffer from seriously adverse complications, all of them obtained hematopoietic recovery, neither GVHD nor infection occurred after infusion of donor's purified CD34(+) cells. It is concluded that using CliniMACS system for donor's peripheral CD34(+) separation, both the purified and recovery of CD34(+) cells are satisfied, and the infusion of donor's purified CD34(+) cell is a safe and effective method to treat secondary PGF after allo-HSCT. PMID- 24156441 TI - [Effect of dexamethasone on G-CSF mobilization of peripheral blood stem cells in healthy donors and hematopoietic reconstruction in the recipients]. AB - This study was aimed to investigate the effects of different mobilization methods on mobilization and collection of peripheral blood stem cells in healthy donors and the adverse effect of collection, as well as hematopoietic construction in recipients. A total of 43 donors between January 2008 and May 2013 were divided into the simple mobilization group and the combined mobilization group. The simple group was subcutaneously injected with 5.0-10.0 ug/(kg.d) recombinant human granulocyte colony-stimulating factor (rhG-CSF), and the combined mobilization group was treated with rhG-CSF and intravenously dripped with 10 mg dexamethasone for 2-4 hours before collection. The acquisition and count of MNC and CD34(+) cells in different groups, the relationship between the stem cells and MNC count in blood before collection, and the adverse reactions were analyzed; the hematopoietic reconstruction of recipients was investigated. The results showed that the hematopoietic stem cell number of the two groups meet the demands. The count of MNC and CD34(+) cells in the simple mobilization group was more than that in the combined mobilization group. The MNC count in two groups positively correlated with peripheral blood MNC count before collection. The decline of hemoglobin and platelet levels was more obvious in the simple mobilization group than that in combined mobilization group. The adverse reactions of collection in the simple mobilization group could be well tolerated and reversed. There was no adverse reaction in the combined mobilization group. The differences of conditioning regimens between two groups were not statistically significant and the hematopoietic reconstruction time of combined group was shorter than that in the simple mobilization group.It is concluded that the adverse reactions in process of collection can be reduced, and enough hematopoietic stem cells can be collected by G-CSF plus dexamethasone in mobilization of peripheral blood stem cells. The count of MNC in peripheral blood before collection can be still used as a reference index to evaluate the acquisition of MNC. Especially the combination with dexamethasone for stem cell mobilization can promote the hematopoietic reconstruction of the recipients. PMID- 24156442 TI - [Influence of reactive oxygen species on mouse bone marrow hematopoietic stem cell apoptosis]. AB - Objective of this study was to investigate the mechanism of the biological function damage resulting from increased ROS in peripheral blood stem cells during peripheral blood stem cell transplantation. Bone marrow hematopoietic stem cells (BMHSC) were cultured at the oxygen concentration imitated according to the bone marrow oxygen concentration (5% O2) including mean venous oxygen concentration (12% O2), mean arterial oxygen concentration (20% O2). The ROS level in BMHSC was detected by using fluorescent probe, the percentage of BM-HSC in cell cycle was determined by flow cytometry, the apoptosis rate was assayed by Annexin V/PI double staining, the expression levels of ATM gene and P21 protein were measured by PCR and Western respectively. The results showed that as compared with control group (5% O2), the ROS levels were lower, the percentage of cells in G1, S,G2/M phase increased (P < 0.01), the apoptosis rate of cells obviously increased (P < 0.01), the expression level of ATM gene obviously decreased (P < 0.01), while the expression level of P21 protein significantly was enhanced (P < 0.01) in 12% O2, 20% O2 and 5%-12%-20% O2 groups. It is concluded that ROS results in the apoptosis of BMHSC through inhibiting the expression of ATM gene and activating P21 protein. PMID- 24156443 TI - [Anti-apoptotic effect of Astragalus Polysaccharide on myeloid cells]. AB - This study was aimed to assess the effect of Astragalus Polysaccharide (ASPS) on in-vitro hematopoiesis. CFU-GM assays were used to determine the effect of ASPS and thrombopoietin (TPO) on granulocytic-monocyte progenitor cells. The CFU assays were also used to investigate the effect of ASPS on the proliferation of HL-60 cells.HL-60 cells were cultured with serum-free RPMI 1640 medium and treated with or without of different concentrations of ASPS. After 72 h incubation, the number of cells were counted.In addition, the caspase-3 and JC-1 expression was determined by flow cytometry with Annexin V/PI double staining. The results showed that ASPS (100, 200 ug/ml) and TPO (100 ng/ml) significantly promoted CFU-GM formation in vitro. Various concentrations of ASPS and TPO also promoted the colony formation of HL-60 cells, the largest effect of ASPS was observed at a concentration of 100 ug/ml. There were no synergistic effects between TPO and ASPS on cellular proliferation. The results also showed that ASPS significantly protected HL-60 cells from apoptosis in condition of serum-free medium culture, suppressed caspase 3 activation, and reduced the cell apoptosis. It is concluded that ASPS can significantly promote the formation of bone marrow CFU-GM and the proliferation of HL-60 cells, the optimal concentration of ASPS is at 100 ug/ml. In the absence of serum inducing apoptosis, ASPS also significantly reduced the apoptosis of HL-60 cells via suppressing the activation of caspase-3. PMID- 24156444 TI - [Basic biological characteristics of mesenchymal stem cells derived from bone marrow and human umbilical cord]. AB - Bone marrow (BM) and umbilical cord (UC) are the major sources of mesenchymal stem cells for therapeutics. This study was aimed to compare the basic biologic characteristics of bone marrow-derived and umbilical cord derived-mesenchymal stem cells (BM-MSC and UC-MSC) and their immunosuppressive capability in vitro. The BM-MSC and UC-MSC were cultured and amplified under same culture condition. The growth kinetics, phenotypic characteristics and immunosuppressive effects of UC-MSC were compared with those of BM-MSC.Gene chip was used to compare the genes differentially expressed between UC-MSC and BM-MSC. The results showed that UC MSC shared most of the characteristics of BM-MSC, including morphology and immunophenotype. UC-MSC could be ready expanded for 30 passages without visible changes. However, BM-MSC grew slowly, and the mean doubling time increased notably after passage 6. Both UC-MSC and BM-MSC could inhibit phytohemagglutinin stimulated peripheral blood mononuclear cell proliferation, in which BM-MSC mediated more inhibitory effect. Compared with UC-MSC, BM-MSC expressed more genes associated with immune response. Meanwhile, the categories of up-regulated genes in UC-MSC were concentrated in organ development and growth. It is concluded that the higher proliferation capacity, low human leukocyte antigen-ABC expression and immunosuppression make UC-MSC an excellent alternative to BM-MSC for cell therapy. The differences between BM-MSC and UC-MSC gene expressions can be explained by their ontogeny and different microenvironment in origin tissue. These differences can affect their efficacy in different therapeutic applications. PMID- 24156445 TI - [Serum-free culture of umbilical cord mesenchymal stem cells]. AB - This study was purposed to observe the culture of umbilical cord mesenchymal stem cells (UC-MSC) with serum-free medium, and compared it with the medium containing 10% fetal bovine serum (FBS). The normal umbilical cords were acquired during cesarean section, and then were cultured with MesenCult-XF serum-free medium or medium containing 10% fetal bovine serum (FBS). The morphology, immunophenotype, cell cycle, proliferation and differentiation potential of mesenchymal stem cells and the inhibition of mixed lymphocyte reaction were observed through different medium culture method. The results showed that the MSC cultured with serum-free MesenCult(-)XF medium could transfer and multiply for average of 6.57 +/- 0.7 times, and the serum medium-cultured MSC could transfer and multiply for average of 4.59 +/- 0.45 times (P < 0.05). Two kinds of medium cultured MSC all expressed CD44, CD90, CD73, CD105 antigen, but did not expressed CD31, CD45, HLA-DR and CD34 antigen, and their expression levels were not significantly different. The serum-free medium-cultured MSC (65 +/- 5.2%) were all at Go/G1 phase, and the serum-contained medium-cultured MSC (62+3.1%) were at Go/G1 phase(P > 0.05); the 2 kinds of media-cultured MSC all could differentiate into fat and ossification; when serum-free medium cultured umbilical cord MSC were inoculated at the the density of 10(3), 5*10(3), 10(4), and 2*10(4) cells/well, then co-cultured with the reactant and stimulating cells, the CPM were (6.43 +/- 0.47)*10(4), (4.30 +/- 0.38)*10(4), (1.97 +/- 0.13)*10(4) and (0.24 +/- 0.03)*10(4), respectively, and the serum-containing medium-cultured MSC were incubated with different density of mixed lymphocyte, displaying CPM that were (7.85 +/- 0.07)*10(4), (5.64 +/- 0.12)*10(4), (3.09 +/- 0.18)*10(4) and (1.73 +/- 0.05)*10(4). It is concluded that the serum-free medium has been confirmed to culture MSC, which have potential of transfer and differentiation with count for clinical application, and can avoid foreign protein sensitization. PMID- 24156446 TI - [Influence of CXCR4 overexpressed mesenchymal stem cells on hematopoietic recovery of irradiated mice]. AB - This study was aimed to investigate the homing capacity of CXCR4 overexpressed mesenchymal stem cells (MSC) and their effect on hematopoietic recovery. The 293FT packaging cell line was transfected with the recombinant lentiviral vector LV-CXCR4-IRES-EGFP and LV-IRES-EGFP to produce lentivirus. Mouse MSC were then infected with viral supernatant. Male BALB/c mice were sublethally irradiated and then were injected intravenously with 5*10(5) MSC. General status and survival rate of mice were observed every day. On day 3, 7, 14, 21 and 28, peripheral blood samples were collected to calculate the number of white blood cells (WBC) and red blood cells (RBC), the ratio of reticulocyte to platelet, the number of platelet was detected by flow cytometry. The recovery of bone marrow and spleen was pathologically monitored. The proportion of MSC implantation was analysed by PCR. The results showed that the peripheral blood cells displayed the tendency of firstly increasing and then decreasing to their normal level. Generally, recovery of WBC level was earlier in mice infused with MSC (P < 0.05) . The histopathological examination of spleen and bone marrow showed a faster hematopoietic recovery in CXCR4-MSC group than the other two groups. And the donor MSC could be detected in the recipients on day 7, 14, 21 and 28. It is concluded that infusion of CXCR4-MSC enhances the implantation of hematopoietic stem cells and promotes hematopoietic recovery of the sublethally irradiated mice. PMID- 24156447 TI - [In vitro amplification of CD4(+) CD25(+) regulatory T cells and identification of amplified T cell immunosuppressive function]. AB - This study was purposed to compare the effect of 3 different cell components for expanding CD4(+) CD25(+) Treg in vitro, and identify their immunosuppressive function. CD4(+) T cells, CD4(+) CD25(-)T cells and CD4(+) CD25(+)T cells were isolated from mouse splenocytes by MACS and then expanded in vitro. Phenotype of the T cell lines and expression of the FOXP3 was determined by flow cytometry. The inhibitory effect of expanded CD4(+) CD25(+) T cells on CD4(+) CD25(-)T cells was tested by MLR method. The results showed that the Treg cells from all the three groups were expanded significantly after culture for 2 weeks. In the CD4(+) T cells group, the proliferation rate was (77.8 +/- 5.32) folds with a percentage of Treg cells increasing from (6.61 +/- 1.00)% to (15.33 +/- 1.31)%. The proliferation rate in the CD4(+) CD25(-) T cells group was (95.20 +/- 7.67) folds, with the percentage of CD4(+) CD25(+) T cells raising from (0.37 +/- 0.13)% to (9.84 +/- 0.98)%. The proliferation rate in the CD4(+) CD25(+) T cells group was (41.20 +/- 6.92) folds, the proportion of Treg cells decreased from (86.75 +/- 1.25)% to (85.32 +/- 1.62)%, and the expression of Foxp3 decreased from (76.92 +/- 1.72)% to (75.33 +/- 2.11)% during the culture, there were not significant differences in the cell purity and the expression of Foxp3, compared with pre-amplification. The inhibitory test showed that the expanded CD4(+) CD25(+) T cells could inhibit the proliferation of CD4(+) CD25(-) T cells in vitro in a cell dose-dependent manner. It is concluded that the amplification of CD4(+) CD25(+) Treg cells is successful in vitro, especially in the CD4(+) CD25(+) T cells group, the cell purity and Foxp3 gene is not obviously changes after amplification. PMID- 24156448 TI - [Administration of high dose dexamethasone impairs the function of thymus cells]. AB - This study was purposed to investigate the effects of high-dose dexamethasone on structure and function of thymic epithelial cells (TEC). Male C57BL/6 mice aged 6 to 8 weeks were used as experimental animals. The mice were injected intraperitoneally with dexamethasone (20 mg/kg), and the other mice treated with saline were used as controls. Thymus was harvested at day 5 after treatment. The histological changes of the treated thymus were monitored by HE staining and in situ immunofluorescence staining. The ratio of each subset in the thymus were analyzed by using flow cytometry, and quantitative PCR was applied to detect the expression levels of IL-22 and Foxn1, which represent the regenerative function of thymus. The results showed that compared with control mice, the structure of TEC in mice treated with high-dose dexamethasone was damaged and the thymic cell number was declined dramatically (P < 0.05); the ratios of thymus cell subsets were changed, the number of double positive (DP) thymus cells among these subsets declined sharply (P < 0.05); the expression levels of Foxn1 and IL-22 increased by 34 and 8 folds respectively. It is concluded that the use of high-dose dexamethasone can lead to damage of the structure and function of TEC, and induce up-regulation of the expression of genes related to thymus repair. PMID- 24156449 TI - [Serological characteristics and transfusion efficacy evaluation in 61 cases of autoimmune hemolytic anemia]. AB - This study was aimed to analyze the serological characteristics, efficacy and safety of incompatible RBC transfusion in patients with autoimmune hemolytic anemia (AIHA). The patients with idiopathic or secondary AIHA were analyzed retrospectively, then the serological characteristics and the incidence of adverse transfusion reactions were investigated, and the efficacy and safety of incompatible RBC transfusion were evaluated according to the different autoantibody type and infused different RBC components. The results showed that out of 61 cases of AIHA, 21 cases were idiopathic, and 40 cases were secondary. 8 cases (13.1%) had IgM cold autoantibody, 50 cases (82.0%) had IgG warm autoantibody, and 3 cases (4.9%) had IgM and IgG autoantibodies simultaneously. There were 18 cases (29.5%) combined with alloantibodies. After the exclusion of alloantibodies interference, 113 incompatible RBC transfusions were performed for 36 patients with AIHA, total efficiency rate, total partial efficiency rate and total inefficiency rate were 56.6%, 15.1% and 28.3%, respectively. Incompatible RBC transfusions were divided into non-washed RBC group and washed RBC group. The efficiency rate, partial efficiency rate and inefficiency rate in non-washed RBC group were 57.6%, 13.0% and 29.4%, respectively. The efficiency rate, partial efficiency rate and inefficiency rate in washed RBC group were 53.6%, 21.4% and 25.0%, respectively. There was no significant difference of transfusion efficacy (P > 0.05) in two groups. Incompatible RBC transfusions were also divided into IgM cold autoantibody group and IgG warm autoantibody group. The efficiency rate, partial efficiency rate and inefficiency rate in IgM cold autoantibody group were 46.2%, 30.8% and 29.4%, respectively. The efficiency rate, partial efficiency rate and inefficiency rate in IgG warm autoantibody group were 56.7%, 13.4% and 29.9%, respectively. There was no significant difference of transfusion efficacy (P > 0.05 ) in two groups. Hemolytic transfusion reaction was not observed in all incompatible RBC transfusions. It is concluded that the same ABO type of non washed RBC transfusion and O type washed RBC transfusion are all relatively safe for the AIHA patients with severe anemia after the exclusion of alloantibodies interference. There is no significant difference of transfusion efficacy in two groups. The same ABO type of non-washed RBC transfusion is more convenient and efficient than washed RBC transfusion, and excessive use of type O RBCs can also be avoided. PMID- 24156450 TI - [Rare blood group B (A) detection and safe transfusion]. AB - This study was aimed to investigate the genetic characteristics, identification method and transfusion strategy of rare blood type B(A). The rare blood group B(A) was typed by serological technique, PCR-SSP genotyping and sequencing of exon 6, 7 of ABO blood group. The genetic characteristics and molecular mechanism of B(A) blood group were also analyzed. Blood group compatibility test was conducted between blood donors of B(A) and recipients by clinical transfusion. The results showed that both forward and reverse grouping did not match the 3 cases of serological result in their family survey, while all of the 3 cases were grouped as AB blood group by forward grouping, B blood group by reverse grouping with serological result and B(A)04/001 group were genotyped by ABO genotyping. The patient of B blood group was transfused by 1 bag of washed red blood cells of donor of B(A) under closely monitoring, the patient's condition changed, and a mild adverse transfusion reaction was appeared. Washed red blood cell of O blood group was transfused into B(A) patient without blood transfusion reaction. It is concluded that the forward ABO serological grouping and reverse ABO serological grouping are not compatible, that may be verified by family survey and molecular biological methods. If in some cases transfusion therapy was applied, and group B(A) can not be transfused to the patient with group B or AB. Thus, transfusion compatibility or autologous transfusion can be adopted to transfuse to the patient from group B(A). PMID- 24156451 TI - [Effects of N-Arachidonoylethanolamine on the quality of platelets stored in M sol platelet preservative solution in vitro]. AB - This study was purposed to investigate the effects of N-Arachidonoylethanolamine (ANA) on the quality of platelets (Plt) stored in Plt M-sol preservative solution at 22 +/- 2 degrees C. Samples taken from collecting apheresis Plt by the Amicus instrument and splited into two equal parts were stored in Plt M-sol preservative solution on a shaker at 22 +/- 2 degrees C. Different working concentrations of ANA (from 0.1 to 50 umol/L) were then added into one part of stored Plt as the experimental group, the other without ANA was used as the control group. The viability of Plts stored at 22 +/- 2 degrees C for 7 days was evaluated by MTT colorimetric assay. The most effective concentration of ANA was selected and added to the subsequent experimental group. Plt count (BPC), mean Plt volume (MPV), Plt distribution width (PDW), phosphatidyl serine (PS) and soluble P selectin were detected on the 1(st), 5(th), 7(th), 9(th) and 11(th) day of storage. The results showed that the most effective working concentration of ANA was 0.5 umol/L, which showed significant increasing Plt viability (91.23 +/- 5.44%) compared to the control group (62.54 +/- 4.79%). Thus, ANA concentration at 0.5 umol/L was choose to perform subsequent experiments. During 11 days of storage, the BPC, MPV and PDW were not changed significantly between the experimental group and control group, although there was decreasing trend in the BPC and increasing trends in MPV and PDW in the two groups. The rate of Plt PS positive was enhanced during the storage period: the rate of PS positive in experimental group increased from 7.69 +/- 1.82% to 10.74 +/- 1.78% while it in control group increased from 11.21 +/- 2.03% to 15.37 +/- 1.95%, with significant differences between the two groups (P < 0.05) on the 9(th) and 11(th) day of storage, respectively. Soluble P-selectin contents in experimental group on the 9(th) and 11(th) day of storage were 30.19 +/- 2.03 ng/ml and 34.52 +/- 2.64 ng/mL, respectively, while those in control group were 39.18 +/- 2.66 ng/ml and 43.23 +/- 2.58 ng/ml, respectively, with significant differences between the two groups (P < 0.05). It is concluded that the extended storage of Plt in M-sol treated with low concentration ANA can potentially alleviate Plt storage lesions. PMID- 24156452 TI - [Retrospective analysis of the Gram-positive bacteria-infected cases in the Department of Hematology]. AB - This study was purposed to evaluate the efficacy and safety of linezolid, vancomycin and teicoplanin for the treatment of patients infected by Gram positive bacteria in the Department of Hematology by retrospective analysis. The patients with fever in our department from January to December in 2011 were selected for blood culture with Gram-positive bacteria and treated with linezolid, vancomycin or teicoplanin alone.Various parameters were recorded before and after treatment, such as fever time, respiratory symptoms, physical signs, radiographic changes, blood and biochemical routine, and adverse reactions. The efficacy and safety of linezolid, vancomycin and teicoplanin were compared according to the fever abating time, bacterial clearance rate, clinical efficiencies and adverse events. The patients were divided into linezolid group (15 patients), vancomycin group (17 patients) and teicoplanin group (20 patients). The results showed that the mean time of fever abating in linezolid group was (4.43 +/- 3.15)d, bacterial clearance rate and clinical efficiency in linezolid group were 55.56% and 86.67%, respectively. The above three data in vancomycin group were (6.83 +/- 4.67)d, 54.54% and 76.47% respectively, and were (5.57 +/- 4.16)d, 41.67% and 80.00% in teicoplanin group respectively. There was no statistically significant difference between three groups (P > 0.05). There were one case of diarrhea and two cases of thrombocytopenia in the linezolid group, and one case of nausea and two cases of creatinine increase in the vancomycin group. There were three cases of thrombocytopenia in the teicoplanin group. The thrombocytopenia in five cases and the hemogram drop in patients with leukemia after treatment were overlapped, their drug treatment did not stop, but their thrombocytopoiesis recovered to normal-level, thus the drug treatment were considered as no relation with thrombocytopenia. It is concluded that the treatment efficacy between linezolid, vancomycin and teicoplanin for Gram positive bacterial infections is not statistically different, but linezolid maybe have advantage over vancomycin and teicoplanin in fever abating time, bacterial clearance rate and clinical efficiency. PMID- 24156453 TI - [Application value of procalcitonin and immune inflammatory factors for prediction of bacteraemia in patients with hematologic malignancy combined with febrile neutropenia]. AB - This study was purposed to evaluate the diagnostic value of procalcitonin (PCT), C-reactive protein, interleukin-6 (IL-6), serum amyloid A (SAA) for bacteremia in patients with hematologic malignancy combined with febrile neutropenia. The total of 297 patients with hematologic malignancy combined with febrile neutropenia were analyzed retrospectively from 1253 patients admitted to West China hospital of Sichuan University from March 2011 to October 2012. They were divided into sepsis group (n = 95) and non-sepsis group (n = 202) according to blood culture. The results showed that the levels of PCT, CRP, IL-6 and SAA in sepsis group were higher than those in non-sepsis group, and there was statistically significant difference between these two groups (P < 0.05). The PCT had an AUC value of 0.974 (P < 0.05), and obviously higher than that of CRP (AUC = 0.681, P < 0.05), IL-6 (AUC = 0.661, P < 0.05) and SAA (AUC = 0.605, P < 0.05). When PCT had cut-off value of 1.06 ng/ml, sensitivity of 95.8%, specificity of 92.1%, and the Youden indicator of 0.879, the negative and positive predictive values were 97.8% and 85.0% respectively, the negative and positive likelihood ratios were 0.05 and 12.5 respectively, and all significantly higher than that of CRP, IL-6 and SAA. It is concluded that for patients with hematologic malignancy combined with febrile neutropenia and bacterial infection, the diagnostic value of serum PCT is superior to that of immune inflammatory factors (CRP, IL-6 and SAA), the PCT can predict the bacterium infection, provide laboratory evidence for rational antimicrobial drug usage and mortality reduction. PMID- 24156454 TI - [Detection of fetal RASSF1A gene in maternal plasma for noninvasive prenatal diagnosis]. AB - The aim of this study was to investigate the feasibility of using RASSF1A gene as a universal fetal marker in maternal plasma. Two methods of circulating cell-free fetal DNA (cffDNA) extracted from maternal plasma were compared. The better one was chosen for extraction of cffDNA in the 20 pregnant samples. The SRY gene and the RASSF1A gene treated with methylation-sensitive restriction enzyme were amplificated by RT-PCR and the PCR system was optimized. The results showed that the SRY gene was found in 11 out of the 20 pregnant samples, which was consistent with the postnatal sex. Using the optimized PCR system, the specifically amplified fetal-associated methylated RASSF1A gene was found after treatment with BstUI in 18 of the 20 pregnant samples, while the 2 samples failed in detection. It is concluded that the methylated fetal-specific RASSF1A gene can be used as a universal fetal marker for the presence of cffDNA in maternal plasma without fetal gender restrictions. So, it can be used for noninvasive prenatal diagnosis. PMID- 24156455 TI - [Protective effect of ademetionine 1, 4-butanedisulfonate on liver injury caused by chemotherapeutic agents]. AB - The aim of this study was to observe the protective effect of ademetionine 1, 4 butanedisulfonate on liver injury caused by chemotherapy in patients with leukemia. The clinical data of protective effect were analyzed retrospectively from January 2010 to April 2012. A total of 62 acute leukemia patients were divided into A group (27 cases) and B group (35 cases), the polyene phosphatidyl choline combined with ademetionine or combined with compound glycyrrhizin were given in A and B group, respectively. The changes of liver function were observed after 2 weeks, 5 patients in B group suffered from acute liver injury were treated by ademetionine as rescue therapy. Liver function was compared before and after treatment. The results showed that ALT and AST levels were significantly reduced in A group (P < 0.05), none of the patients (0/27) suffered from acute liver injury, but 14.29% (5/35) patients in B group suffered from acute liver injury, and liver function could be recovered by substitution treatment of ademetionine (the median time is 8 days, 5-14 days). It is concluded that the protective and therapeutic effect of ademetionine against liver injury caused by chemotherapy in patients with leukemia is better than that of compound glycyrrhizin. PMID- 24156456 TI - [Role of LNK gene mutation in pathogenesis of myeloproliferative neoplasms review]. AB - Myeloproliferative neoplasms ( MPN ) is a class of clonal hematopoietic stem cell disease. Studies found that the JAK-STAT signaling pathway is closely related to the pathogenesis of MPN. The lymphocyte-specific adaptor protein (LNK) gene negatively regulates Janus kinase-signal transducer and activator of transcription (JAK-STAT) signaling and may play an important role in the pathogenesis of MPN. Especially in JAK2 mutation-negative MPN, LNK gene specific mutations may be the key to cause MPN subtypes. Certain single nucleotide polymorphism of LNK gene regulation of hematopoietic cells in different directions may also be important influence factors of MPN performance for different subtypes. LNK gene functional changes lead to abnormal activation of the JAK-STAT signaling pathway, and may be a new mechanism of MPN. In this review, the role of LNK gene in MPN pathogenesis is briefly summarized. PMID- 24156457 TI - [Recent advances of studies on role of mTOR signaling in aging of hematopoietic and other organ systems-review]. AB - Mammalian target of rapamycin (mTOR) is a serine/threonine protein kinase, which plays an essential role in cell growth, proliferation and survival. mTOR regulates the transcription of mRNA, synthesis of ribosome and gene expression for metabolism. By forming mTOR complex, it regulates cellular activities by phosphorylating its downstream proteins, such as S6 protein kinase and 4E-BP1. In recent years, the role of mTORC1 in regulating aging is gradually recognized. Studies of physiological function and the regulatory mechanisms of mTOR signaling can not only help to better understand the aging mechanism for cells or organs, but also provide insights as to finding potential new drug targets for aging related diseases. This review focuses on recent advances of mTOR and aging related diseases in hematopoietic and other organ systems. PMID- 24156458 TI - MicroRNA as potential target for gene therapy of multiple myeloma-review. AB - The studies in recent years have found that miRNA play an important role in various biological functions, such as cell differentiation, proliferation, apoptosis, migration, and survival. Many studies considered the abnormally expressed miRNA as significant regulator in the pathogenesis, progression and metastasis of malignant tumors. miRNA can function as oncogenes or tumor suppressors by regulating post-transcriptional factors effecting multi pathways and may even represent target for therapies. This review summarizes the current advancement about the roles of miRNA in the biology of multiple myeloma (MM), including focuses on miRNA signatures relevant to MM, functions of critical miRNA in the mechanisms and development of MM behind their deregulation, the role in the drug-resistance and perspective of their expression in MM. PMID- 24156459 TI - [Current research advance on cellular immunotherapy for leukemia-review]. AB - Despite the chemotherapy is successful in inducing remission of hematologic malignancy, this disease also has a high probability of relapse; besides, the toxicity of chemotherapy for these patients can not be avoided. Researchers have been attempting to eliminate tumor cells by immunotherapy. Recently, various leukemia-associated antigens (LAA) that are recognized by cytotoxic T cell (CTL) in the context of HLA class I molecules have been identified. These LAA include WT1, PR-3, RHAMM, BCR-ABL and Aur-A. On the basis of these findings, various clinical trials of immunotherapy for hematologic malignancy including tumor peptide vaccination, adoptive T cell therapy, NK cell therapy and dendritic cells cytokine induced killer (DC-CIK) cell therapy are on going. In this review, the current status and future feasibility of cellular immunotherapy for leukemia are discussed. PMID- 24156460 TI - [Advances of studies on members of P53 family, interaction and relation with leukemia -review]. AB - The P53 gene has the important functions including induction of apoptosis, regulation of cell cycle, repair of DNA damage. The mutation of the P53 gene exists in more than 50% of human tumors and 13% of hematological malignancies. The P53 gene abnormality is closely related with the clinical course and prognosis of leukemia. The P73 or P63 gene, the member of the P53 family not only possesses similar to P53 activity of inducing apoptosis, activating transcription, but also plays different biological effects according to protein structural diversity, and even antagonises the function of the P53 gene. Researchers found that P73 or P63 gene also has the dual characteristics of the tumor suppressor and oncogene, and shows different expression and function in different types, different stages of leukemia. In this article, P53 family (P53, P73, P63) gene structure, biological function and the relationship of the three genes with the course, prognostic outcome, treatment and other clinical features of the leukemia are reviewed. PMID- 24156461 TI - [New hope of gene therapy results from improvements of lentiviral vectors review]. AB - Gene therapy has been considered as one of the optimal treatments. Although, at the beginning of this century, a series of unexpected side effects brought gene therapy into depression, the improved lentiviral vectors, which characterised by high efficiency transfection, stable expression in target cells and good biosafety, have been applied in clinical trials in recent years and acquired a certain clinical improvements. Nowadays gene therapy becomes an eye-catching field. This review discusses the gene therapy how blocked by lentiviral vectors, the high efficiency and biosafety of lentiviral vectors, the improvement of lentiviral vector preparation and so on. PMID- 24156462 TI - [Relationship between the HOX gene family and the acute myeloid leukemia-review]. AB - In recent years, many studies have shown that the HOX gene family involved in the proliferation, differentiation and maturation of hematopoietic progenitor cells. There is a close relationship between the expression of HOX gene family and acute myeloid leukemia (AML). Most of the HOX genes can promote the proliferation and inhibit the differentiation of the hematopoietic progenitor cells, but the mechanism leading to acute myeloid leukemia remains unknown. This review focuses on the relationship between HOX gene and acute myeloid leukemia and the possible mechanisms leading to acute myeloid leukemia. PMID- 24156463 TI - [NKT cells and graft-versus-host disease-review]. AB - NKT cells (nature killer T cells), as a regulatory cellular compartment in the immune system, express cell surface markers of T cells and NK cells. It secretes a variety of cytokines that stimulate specific antigens. Through regulating the balance of Th1/Th2, the NKT cells play an important role in prevention and treatment of graft-versus-host disease (GVHD). Its antitumor and anti-infectious effects serve as a basis of its application in allogeneic hematopoietic stem cell transplantation. A better understanding of the biological and immunological features of NKT cell, as well as its specific immune regulatory mechanisms, will further justify the rationales of using NKT cells in the management of GVHD for patients. In this review, the biologic properties, classification, differentiation and development, immune activation of NKT cells as well as the NKT cells and GVHD including the related mechanisms of prevention and treatment of GVHD with NKT cells, NKT cells and tumors, NKT cells and infection, and NKT cells and clinical GVHD are summarized. PMID- 24156464 TI - [Progress of microRNA in diagnosis and prognosis of diffuse large B cell lymphoma review]. AB - MicroRNA (miRNA) is a class of naturally occurring short non-coding small molecular RNA with 19-25 nucleotide. MiRNA can regulate gene expression through incompletely binding to complementary sequences in the 3'UTR of target mRNA. MiRNA plays key regulatory role in a diverse rang of pathways, including cell proliferation, differentiation, apoptosis, stem cell development. Many studies have shown that many miRNA have a special role of gene regulation in cancer development and have been used as therapeutic targets and diagnostic markers of cancer. This review focuses on recent advances of studies on miRNA involved in tumorigenesis, and in classification, diagnosis, therapy and prognosis of DLBCL. PMID- 24156465 TI - [Role of chimerism monitoring and donor lymphocyte infusion in eliminating the risk of graft rejection following HSCT in thalassemia patients-review]. AB - One of the major obstacle for hematopoietic stem cell transplantation (HSCT) to treat patients with beta-thalassemia is graft rejection (GR). The proportion of donor-derived cells continually declined in mixed chimerism (MC), finally leading to graft failure. Monitoring chimerism after transplant consecutively can early find unstable mixed chimerism and rejection, which provide the basis for donor lymphocyte infusion (DLI); for imminent risk of graft rejection, escalating doses of DLI is a feasible method for converting unstable MC towards stable MC or full donor chimerism. This review focuses on advancement of chimerism monitoring and DLI after HSCT for patients with beta-thalassemia major. PMID- 24156466 TI - [Mechanism and early evaluation of CNS infiltration in acute lymphocytic leukemia review]. AB - Central nervous system (CNS) is one of places in which direct infiltration and involvement or relapse occur in adult lymphocytic leukemia. The main mechanism of CNS infiltration in leukemia is associated with blood brain barrier (BBB), however the ALL CNS infiltration is difficulty early predicted and evaluated.For this reason, the studies on accurately evaluating the ALL CNS infiltration have important significance for early diagnosis and adjustment of therapeutic regimen, performance of individualised treatment and improvement of ALL patient's prognosis. In this article, the pathway of ALL CNS infiltration and its molecular mechanism, the evaluation methods for BBB function are reviewed. PMID- 24156467 TI - [Preservation and clinical application of umbilical cord blood for personal use review]. AB - Human umbilical cord blood (CB) is one potential source of hematopoietic stem cells (HSC) and progenitor cells, and it has been used to successfully treat leukemia, lymphoma, myelodysplastic syndrome, aplastic anemia, hemoglobinopathies, metabolic storage diseases, and immunodeficiencies. With the establishment of CB bank and increased cases of CB transplantation in clinical use, more and more parents today choice to donate the CB to a public CB bank, or to keep and store the CB in a private bank for potential use in the future. In this article, the current status of CB preservation and clinical application of CB for personal use are reviewed. PMID- 24156468 TI - Portrayals of reproductive and sexual health on prime-time television. AB - Prime-time broadcast television provides health information and establishes norms for millions of people in the United States (Beck, 2004; Brodie et al., 2001; Murphy & Cody, 2003; Rideout, 2008). To understand what people may be learning about reproductive and sexual health, a content analysis was conducted of story lines from the 10 most popular prime-time television programs in 2009, 2010, and 2011. Variables that were measured included the frequency of reproductive and sexual health issues, the level of health information, the type of information portrayed, the gain and loss frames, the presence of stigma, the tone, and the type of role model portrayed. Eighty-seven of the 589 health story lines dealt with reproductive and sexual health, and the most common issues were pre- and postterm pregnancy complications. The majority of these story lines had a moderate or weak level of information and included specifics about treatment and symptoms but not prevention. Just over half of the issues were framed in terms of losses, meaning nonadoption of a behavior change will result in negative outcomes. Twenty-four percent of reproductive and sexual health story lines involved stigma-usually stigma related to sexually transmitted infections (STIs). Most story lines were portrayed as serious and the majority of issues happened to positive role models. The implications of these portrayals for the viewing public are discussed. PMID- 24156470 TI - Stress-induced modification of the boson peak scaling behavior. AB - The scaling behavior of the so-called boson peak in glass-formers and its relation to the elastic properties of the system remains a source of controversy. Here the boson peak in a binary reactive mixture is measured by Raman scattering (i) on cooling the unreacted mixture well below its glass-transition temperature and (ii) after quenching to very low temperature the mixture at different times during isothermal polymerization. We find that the scaling behavior of the boson peak with the properties of the elastic medium - as measured by the Debye frequency - holds for states in which the elastic moduli follow a generalized Cauchy-like relationship, and breaks down in coincidence with the departure from this relation. A possible explanation is given in terms of the development of long-range stresses in glasses. The present study provides new insight into the boson peak behavior and is able to reconcile the apparently conflicting results presented in literature. PMID- 24156469 TI - Acupuncture for dry eye syndrome after refractive surgery: study protocol for a randomized controlled trial. AB - BACKGROUND: Dry eye syndrome is a frequent complication of refractive surgery. Acupuncture has been widely used to alleviate the associated symptoms. However, the use of acupuncture for patients who suffer from dry eye syndrome following refractive surgery has certain drawbacks. This pilot study aims to evaluate the efficacy of acupuncture treatment in treating the signs and symptoms of dry eye syndrome after refractive surgery. METHODS/DESIGN: Forty participants will be randomly assigned to the acupuncture plus usual care group or the usual care control group. The acupuncture plus usual care group will undergo treatments on seventeen acupuncture points, three times per week for four weeks. The control group will receive only usual care during the same period. The primary outcomes will be scores on the Ocular Surface Disease Index (OSDI) and the results of examinations at 1, 3, 5, and 13 weeks. The secondary outcomes will be Tear Film Break-up Time (TBUT), as well as scores on the Schirmer-I test, visual analog scale (VAS), and quality of life (QOL) questionnaire for the self-assessment of ocular discomfort. Digital photographs will be taken to document the pattern of fluorescein staining observed on the corneal surface. The results of the Schirmer I test, TBUT, and fluorescein-stained corneal surface digital photographs will be assessed at the screening and at week 13. VAS scores will be assessed at the screening, as well as at 1, 3, 5, and 13 weeks. QOL will be evaluated at 1, 3, 5, and 13 weeks. DISCUSSION: This trial will provide primary data with which to investigate the clinical effectiveness and safety of acupuncture treatment for dry eye syndrome after refractive surgery. TRIAL REGISTRATION: Current Controlled (Identifier: KCT0000727). PMID- 24156471 TI - Gold nanoparticle inclusion into protein nanotube as a layered wall component. AB - We describe the synthesis, structure, and catalytic activity of human serum albumin (HSA) nanotubes (NTs) including gold nanoparticles (AuNPs) as a layered wall component. The NTs were fabricated as an alternating layer-by-layer assembly of AuNP and HSA admixture (a negatively charged part) and poly-l-arginine (PLA, a positively charged part) into a track-etched polycarbonate membrane (400 nm pore diameter) with subsequent dissolution of the template. SEM images showed the formation of uniform hollow cylinders of (PLA/AuNP-HSA)3 with a 426 +/- 12 nm outer diameter and 65 +/- 7 nm wall thickness. Transmission electron microscopy and energy dispersive X-ray measurements revealed high loading of AuNPs in the tubular wall. HSAs bind strongly onto the individual AuNP (K = 1.25 * 10(9) M( 1)), generating a core-shell AuNP-HSA corona, which is the requirement of the robust NT formation. Calcination of the (PLA/AuNP-HSA)3 NTs at 500 degrees C under air yielded red solid NTs composed of thermally fused AuNPs. From the mass decrease by heat treatment, we calculated the weight of the organic components (PLA and HSA) and thereby constructed a six-layer model of the tube. The (PLA/AuNP-HSA)3 NTs serve as a heterogeneous catalyst for reduction of 4 nitrophenol with sodium borohydrate. Furthermore, implantation of the stiff (PLA/AuNP-HSA)3 NTs vertically onto glass plate produced uniformly cylindrical tube arrays. PMID- 24156472 TI - A study of the effect of a visual arts-based program on the scores of Jefferson Scale for Physician Empathy. AB - BACKGROUND: The effect of visual arts interventions on development of empathy has not been quantitatively investigated. A study was conducted on the effect of a visual arts-based program on the scores of the Jefferson Scale for Physician Empathy (JSPE). METHODS: A total of 110 clerks (n = 92) and first-year postgraduate residents (PGY1s) (n = 18) participating in the program were recruited into this study. The 4-hr program covered the subjects of learning to interpret paintings, interpreting paintings relating to medicine, illness and human suffering, the related-topics of humanitarianism and the other humanities fields and values and meaning. The JSPE was completed at the beginning (pretest) and the end (posttest) of the program. RESULTS: There was no significant difference between the pretest and posttest JSPE scores. The average of the scores for the pretest was lower in the subgroup of PGY1s than the subgroup of clerks (p = 0.0358). An increased but not significantly mean posttest JESPE score was noted for the subgroup of PGY1s. Neither the females nor the males had higher posttest JSPE scores than the pretest scores. CONCLUSIONS: Although using a structured visual arts-based program as an intervention may be useful to enhance medical students' empathy, our results failed to show a positive effect on the JSPE Scores for a group of clerks and PGY1s. This suggests that further experimental studies are needed if quantitative evaluation of the effectiveness of visual-arts based programs on empathy is to be investigated. PMID- 24156473 TI - Chemical tools to probe cellular O-GlcNAc signalling. AB - Protein O-GlcNAcylation is an abundant, dynamic and reversible type of protein post-translational modification in animals that has been implicated in signalling processes linked to innate immunity, stress response, growth factor response, transcription, translation and proteosomal degradation. Only two enzymes, O GlcNAc (O-linked N-acetylglucosamine) transferase and O-GlcNAcase, catalyse the reversible addition of the O-GlcNAc residue to over 1000 target proteins in the human cell. Recent advances in our understanding of the structures and mechanisms of these enzymes have resulted in the development of potent and selective inhibitors. The present review gives an overview of these inhibitors and how they have been used on cell lines, primary cells and animals to modulate O-GlcNAc levels and study the effects on signal transduction. PMID- 24156475 TI - New insights into crystallite size and cell parameters correlation for ZnO nanoparticles obtained from polyol-mediated synthesis. AB - ZnO nanocrystals were prepared from polyol-mediated synthesis. Two key parameters, that is, the zinc precursor concentration and the alcohol mixture chosen as synthesis medium, were varied. The increase of the precursor concentration and the decrease of the permittivity of the alcohol mixture were shown to favor the crystallite growth, leading to crystallite sizes ranging from 5 to 35 nm. The aggregation behavior of the nanocrystal units to form or not polycrystalline spheres, depending on the van der Walls interaction density, was shown and explained. Every sample was accurately characterized by X-ray diffraction; cell parameters were extracted from full pattern matching refinements. A clear correlation between crystallite size and cell parameters, that is, an asymptotic decrease of a and c cell parameters versus the crystallite size, was established. A simple model was also successfully developed to interpret the as-established correlation. PMID- 24156476 TI - Aptamer-nanoparticle bioconjugates enhance intracellular delivery of vinorelbine to breast cancer cells. AB - Targeted uptake of therapeutic nanoparticles in cell- or tissue-specific manner is an attractive technology since they can offer greater efficacy and reduce cytotoxicity on peripheral healthy tissues. In this study, AS1411 (AP), a DNA aptamer specifically binding to nucleolin that is overexpressed on the plasma membrane of breast cancer (BC) cells, was exploited as the targeting ligand of a nanoparticle-based drug delivery system. Vinorelbine (VRL) loaded PLGA-PEG nanoparticles (NP) were formulated by an emulsion/solvent evaporation method, and AP was conjugated to the particle surface using the EDC/NHS technique. The drug loading efficiency and in vitro drug release studies were measured using HPLC. The resulting AP-NP/VRL formed spherical nanoparticles (<200 nm) with drug loading of about 7% and a stable in vitro drug release profile. Fluorescence microscopy was used to confirm the cellular uptake of the particles and targeted drug delivery. Moreover, cytotoxicity studies were carried out in two different cell lines, MDA-MB-231 BC cells and MCF-10A normal epithelial cells. AP-nucleolin interaction significantly enhanced in vitro cytotoxicity to nucleolin overexpressed cells, as compared with non-targeted nanoparticles, while there was no significant difference in cytotoxicity of the two types of nanoparticles on the nucleolin negative cells. The results further support that AS1411 functionalized nanoparticles are potential carrier candidates for targeted drug delivery towards BC. PMID- 24156477 TI - Catalytic intermolecular haloamidation of simple alkenes with N-halophthalimide as both nitrogen and halogen source. AB - A simple, efficient, and highly atom economic haloamidation of simple alkenes has been developed, using AgBF4 or InBr3/AgBF4 (1:3) as catalyst and N halophthalimide as both nitrogen and halogen source. A broad range of olefins can be applied to afford vicinal haloamines in good yields and with high regioselectivity and diastereoselectivity. PMID- 24156478 TI - Using activity-based monitoring systems to detect dairy cows in oestrus: a field evaluation. AB - AIM: To assess the use and performance of activity-based oestrus detection systems (ODS) on two commercial dairy farms using a gold standard based on profiles of concentrations of progesterone in milk, artificial insemination (AI) records and pregnancy diagnosis results. METHODS: Two activity-based ODS were evaluated in mature cows on two large pasture-grazed dairy farms (>500 cows) over the first 3 weeks of AI. Farm 1 (n=286 cows) used a leg-mounted device and cows were drafted automatically based on activity alerts. Decisions regarding AI were then made based on tail-paint and cow history for these cows. Farm 2 (n=345 cows) used a collar-mounted device and activity alerts were used in conjunction with other information, before the farmer manually selected cows for AI. The gold standard to define the timing of oestrus was based on profiles of concentrations of progesterone in milk measured twice-weekly, used in conjunction with AI records and pregnancy diagnosis results. Sensitivity and positive predictive value (PPV) were calculated for the activity-based ODS data only, and then for AI decisions, against the gold standard. RESULTS: Farm 1 had 195 confirmed oestrus events and 209 activity alerts were generated. The sensitivity of the activity based ODS was 89.2% with a PPV of 83.3%. Using tail-paint and cow history to confirm activity-based alerts 175 cows were inseminated, resulting in a sensitivity of 89.2% and an improved PPV of 99.4%. Farm 2 had 343 confirmed oestrus events, and 726 alerts were generated by the activity-based ODS, giving a sensitivity of 69.7% with a PPV of 32.9%. A total of 386 cows had AI records, giving a sensitivity of 81.3% and PPV of 72.3%. CONCLUSIONS: The two activity based ODS were used differently on-farm; one automatically selecting cows and the other supporting the manual selection of cows in oestrus. Only one achieved a performance level suggested to be acceptable as a stand-alone ODS. Use of additional tools, such as observation of tail paint to confirm activity-based oestrus alerts before AI, substantially improved the PPV. CLINICAL RELEVANCE: A well performing activity-based ODS can be a valuable tool in identifying cows in oestrus prior to visual confirmation of oestrus status. However the performance of these ODS technologies varies considerably. PMID- 24156479 TI - Natural regulatory T cells inhibit production of cytotoxic molecules in CD8+ T cells during low-level Friend retrovirus infection. AB - BACKGROUND: Cytotoxic T cells (CTL) play a central role in the control of viral infections. Their antiviral activity can be mediated by at least two cytotoxic pathways, namely the granule exocytosis pathway, involving perforin and granzymes, and the Fas-FasL pathway. It was shown that the level of Friend retrovirus (FV) replication determines the cytotoxic pathway for the control of viral infection. In low-level infection only the Fas pathway is active, whereas cytotoxic molecules are not produced. In the current study, we elucidate the role of CD4+ regulatory T cells (Tregs) in suppressing the exocytosis pathway during an asymptomatic low-level infection. FINDINGS: We show that even a low-level retrovirus infection induced a strong activation and proliferation of natural Tregs. The expanded Tregs suppressed the proliferation of virus-specific CD8+ T cells and the production of cytotoxic molecules by these cells. Not surprisingly, the in vivo killing activity of these CD8+ T cells was rather weak. Selective depletion of Foxp3+ Tregs resulted in de novo granzyme production and augmented virus-specific in vivo killing, but did not affect the low-level virus replication. CONCLUSIONS: Expanded natural Tregs determined the cytotoxic pathways of virus-specific effector CD8+ T cells during the acute phase of retroviral infection. PMID- 24156480 TI - Finite element analysis of a hemi-pelvis: the effect of inclusion of cartilage layer on acetabular stresses and strain. AB - An appropriate method of application of the hip-joint force and stress analysis of the pelvic bone, in particular the acetabulum, is necessary to investigate the changes in load transfer due to implantation and to calculate the reference stimulus for bone remodelling simulations. The purpose of the study is to develop a realistic 3D finite element (FE) model of the hemi-pelvis and to assess stress and strain distribution during a gait cycle. The FE modelling approach of the pelvic bone was based on CT scan data and image segmentation of cortical and cancellous bone boundaries. Application of hip-joint force through an anatomical femoral head having a cartilage layer was found to be more appropriate than a perfectly spherical head, thereby leading to more accurate stress-strain distribution in the acetabulum. Within the acetabulum, equivalent strains varied between 0.1% and 0.7% strain in the cancellous bone. High compressive (15-30 MPa) and low tensile (0-5 MPa) stresses were generated within the acetabulum. The hip joint force is predominantly transferred from the acetabulum through the lateral cortex to the sacroiliac joint and the pubic symphysis. The study is useful to understand the load transfer within the acetabulum and for further investigations on acetabular prosthesis. PMID- 24156481 TI - Assessing resources for implementing a community directed intervention (CDI) strategy in delivering multiple health interventions in urban poor communities in Southwestern Nigeria: a qualitative study. AB - BACKGROUND: Many simple, affordable and effective disease control measures have had limited impact due to poor access especially by the poorer populations (urban and rural) and inadequate community participation. A proven strategy to address the problem of access to health interventions is the Community Directed Interventions (CDI) approach, which has been used successfully in rural areas. This study was carried out to assess resources for the use of a CDI strategy in delivering health interventions in poorly-served urban communities in Ibadan, Nigeria. METHODS: A formative study was carried out in eight urban poor communities in the Ibadan metropolis in the Oyo State. Qualitative methods comprising 12 focus group discussions (FGDs) with community members and 73 key informant interviews (KIIs) with community leaders, programme managers, community based organisations (CBOs), non-government organisations (NGOs) and other stakeholders at federal, state and local government levels were used to collect data to determine prevalent diseases and healthcare delivery services, as well as to explore the potential resources for a CDI strategy. All interviews were audio recorded. Content analysis was used to analyse the data. RESULTS: Malaria, upper respiratory tract infection, diarrhoea and measles were found to be prevalent in children, while hypertension and diabetes topped the list of diseases among adults. Healthcare was financed mainly by out-of-pocket expenses. Cost and location were identified as hindrances to utilisation of health facilities; informal cooperatives (esusu) were available to support those who could not pay for care. Immunisation, nutrition, reproductive health, tuberculosis (TB) and leprosy, environmental health, malaria and HIV/AIDs control programmes were the ongoing interventions. Delivery strategies included house-to-house, home-based treatment, health education and campaigns. Community participation in the planning, implementation and monitoring of development projects was reported as common practice. The resources available for these activities and which constitute potential resources for the CDI process include community volunteers, CBOs and NGOs. Others are landlords; professional, women and youth associations; social clubs, religious organisations and the available health facilities. CONCLUSION: This study's findings support the feasibility of using the CDI process in delivering health interventions in urban poor communities and show that potential resources for the strategy abound in the communities. PMID- 24156482 TI - DNA nanospheres with microfluidics: a promising platform for cancer diagnosis? PMID- 24156483 TI - Nanoflowers: a future therapy for cardiac and ischemic disease? PMID- 24156485 TI - Nanoparticles to target neural stem cell differentiation. PMID- 24156487 TI - Hydrogel nanosensors for biophotonic imaging of chemical analytes. AB - Polymer-based hydrogel nanosensors have been developed and extensively utilized for the imaging and dynamic monitoring of chemical properties, response to external stimulants, and metabolism of cells and tissues, in real time, using optical imaging techniques. A large fraction of these polymeric nanoparticles are based on polyacrylamide (PAA) owing to its excellent properties such as nontoxicity, biocompatibility and flexibility of engineering. The properties of the PAA matrix can be specifically tailored, depending on the application, and the molecules can be loaded into the matrix. Various surface modifications enable one to control its behavior in cells and in vivo, and can be utilized for specific targeting to cells and subcellular organelles. This special report describes the recent advances in the design and application of the latest generation of PAA nanosensors for some physiologically important ions and small molecules. PMID- 24156488 TI - Complementary metal oxide semiconductor-compatible silicon nanowire biofield effect transistors as affinity biosensors. AB - Affinity biosensors use biorecognition elements and transducers to convert a biochemical event into a recordable signal. They provides the molecule binding information, which includes the dynamics of biomolecular association and dissociation, and the equilibrium association constant. Complementary metal oxide semiconductor-compatible silicon (Si) nanowires configured as a field-effect transistor (NW FET) have shown significant advantages for real-time, label-free and highly sensitive detection of a wide range of biomolecules. Most research has focused on reducing the detection limit of Si-NW FETs but has provided less information about the real binding parameters of the biomolecular interactions. Recently, Si-NW FETs have been demonstrated as affinity biosensors to quantify biomolecular binding affinities and kinetics. They open new applications for NW FETs in the nanomedicine field and will bring such sensor technology a step closer to commercial point-of-care applications. This article summarizes the recent advances in bioaffinity measurement using Si-NW FETs, with an emphasis on the different approaches used to address the issues of sensor calibration, regeneration, binding kinetic measurements, limit of detection, sensor surface modification, biomolecule charge screening, reference electrode integration and nonspecific molecular binding. PMID- 24156489 TI - Metallofullerenes: a new class of MRI agents and more? AB - Metallofullerenes have incited research endeavors across many disciplines owing to their wide range of properties obtainable by altering the metal component inside the fullerene cage or by a variety of surface functionalities. With a metal component of gadolinium, gadofullerenes have particularly shown promise in MRI applications owing to their high proton relaxivity and isolation of the metal from the biological environment. This article aims to give a perspective on the development of metallofullerenes as MRI contrast agents and further applications that distinguish them as a new class of imaging agent. PMID- 24156491 TI - Gene delivery techniques for adult stem cell-based regenerative therapy. AB - Over the past decade, stem cells have been considered to be a promising resource to cure and regenerate damaged or diseased tissues with research extending from basic studies to clinical application. Furthermore, genetically modified stem cells have the potential to reduce tumorigenic risks and achieve safe tissue formation. Recent advances in genetic modification of stem cells have rendered these cells more accessible and stable. The successful genetic modification of stem cells relies heavily on designing vector systems, either viral or nonviral vectors, which can efficiently deliver therapeutic genes to the cells with minimum toxicity. Currently, viral vectors showing high transfection efficiencies still raise safety issues, whereas safer nonviral vectors exhibit extremely poor transfection in stem cells. Here, we attempt to review and discuss the main factors raising concern in previous reports, and devise strategies to solve the issues in gene delivery systems for successful stem cell-targeting regenerative therapy. PMID- 24156490 TI - Nonionic surfactant vesicles for delivery of RNAi therapeutics. AB - RNAi is a promising potential therapeutic approach for many diseases. A major barrier to its clinical translation is the lack of efficient delivery systems for siRNA. Among nonviral vectors, nonionic surfactant vesicles (niosomes) have shown a great deal of promise in terms of their efficacy and toxicity profiles. Nonionic surfactants have been shown to be a superior alternative to phospholipids in several studies. There is a large selection of surfactants with various properties that have been incorporated into niosomes. Therefore, there is great potential for innovation in terms of nisome composition. This article summarizes recent advancements in niosome technology for the delivery of siRNA. PMID- 24156493 TI - Characterization of phospholipid molecular species and peptide molecules in wheat sprout hydroalcoholic extract. AB - The phospholipid molecular species and the main peptide molecules of wheat sprout hydroalcoholic extract have been fully characterized by normal-phase high performance liquid chromatography coupled online with positive electrospray ionization tandem mass spectrometry. The extract that resulted was rich in phospholipid molecular species formed by the combination of the two essential fatty acids (alpha-linoleic and alpha-linolenic). These species accounted for 51.7% of total phosphatidic acid, 47.3% of total phosphatidylethanolamine, 37.7% of total phosphatidylcholine, and 14.1% of total phosphatidylinositol. The last one showed the highest amounts of species containing palmitic acid, thus representing the most saturated phospholipid class. The extract was also shown to contain several peptide sequences with both potential antioxidant domains and interaction sites for phospholipids (i.e., H-Ala-Gly-Ser-Met-Met-Cys-NH2, H-Tyr Met-Thr-Val-Val-Ala-Cys-NH2, etc.); this latter finding can have a highly positive impact on the poor peptides bioavailability. Because of the presence of essential fatty acids-rich phospholipids and bioactive peptides, wheat sprout hydroalcoholic extract can be considered a potential functional food ingredient. PMID- 24156499 TI - Measurement of line tension on droplets in the submicrometer range. AB - Wetting is a universal phenomenon in nature and of interest in fundamental research as well as in engineering sciences. Usually, wetting of solid substrates by liquid drops is described by Young's equation, which relates the contact angle between the liquid and the substrate to the three interfacial tensions. This concept has been widely used and confirmed for macroscopic droplets. On the contrary, it is still matter of debate to what extent this concept is able to explain relations on the micrometer scale and below. The so-called extended Young's equation, which takes account of the specific arrangement of the molecules in the three-phase contact line by implementing a term called "line tension", is frequently used to characterize deviations from the "ideal" Young's case. In this work we tried to look into the dependence of measured contact angles of droplets on their size for a close to ideal system. We measured contact angles of ionic liquid droplets with radii between some tens and some hundreds of nanometers by atomic force microscopy on an ideally flat silicon wafer. We found that the contact angles decreased with decreasing droplet size: smaller droplets showed stronger wetting. This dependence of the contact angle on the droplet radius could not be described with the concept of line tension or the modified Young's equation. We propose simple arguments for a possible alternative concept. PMID- 24156496 TI - Identification of barriers to the prevention and treatment of heat-related illness in Latino farmworkers using activity-oriented, participatory rural appraisal focus group methods. AB - BACKGROUND: Heat-related illness (HRI) is an important cause of non-fatal illness and death in farmworkers. We sought to identify potential barriers to HRI prevention and treatment in Latino farmworkers. METHODS: We conducted three semi structured focus group discussions with 35 Latino farmworkers in the Central Washington, USA area using participatory rural appraisal techniques. Interviews were audio taped and transcribed in Spanish. Three researchers reviewed and coded transcripts and field notes, and investigator triangulation was used to identify relevant themes and quotes. RESULTS: Although the majority of participants in our study reported never receiving formal HRI training, most participants were aware that extreme heat can cause illness and were able to accurately describe HRI symptoms, risk factors, and certain prevention strategies. Four main observations regarding farmworkers' HRI-relevant beliefs and attitudes were identified: 1) farmworkers subscribe to varying degrees to the belief that cooling treatments should be avoided after heat exposure, with some believing that such treatments should be avoided after heat exposure, and others encouraging the use of such treatments; 2) the desire to lose weight may be reflected in behaviors that promote increased sweating; 3) highly caffeinated energy drinks are preferred to increase work efficiency and maintain alertness; and 4) the location of drinking water at work (e.g. next to restrooms) and whether water is clean, but not necessarily chemically-treated, are important considerations in deciding whether to drink the water provided at worksites. CONCLUSIONS: We identified potential barriers to HRI prevention and treatment related to hydration, certain HRI treatments, clothing use, and the desire to lose weight among Latino farmworkers. Strategies to address potential barriers to HRI prevention and treatment in this population may include engineering, administrative, and health education and health promotion strategies at individual, workplace, community, and societal levels. Although farmworkers in our study were able to describe HRI risk factors, reported practices were not necessarily consistent with reported knowledge. Further study of potential knowledge-behavior gaps may uncover opportunities for additional HRI prevention strategies. Farmworkers and employers should be included in the development and evaluation of interventions to prevent HRI. PMID- 24156500 TI - Efficacy of in-service nutrition training for mid-level providers to improve feeding practices among HIV-positive children in Tanga, Tanzania: study protocol for a cluster randomized controlled trial. AB - BACKGROUND: Feeding practices and child undernutrition can be improved when trained health workers provide proper nutrition counseling to caregivers. However, this important management component is difficult to achieve in countries where trained health workers are limited; Tanzania is no exception. In rural and semi-urban areas, mid-level providers (MLPs) are left to manage diseases such as HIV/AIDS.Training health workers in nutrition has been shown to be an effective intervention among HIV-negative children elsewhere, but no studies have been conducted among HIV-positive children. Furthermore, in Tanzania and other countries with MLPs, no evidence currently exists demonstrating an improvement in nutrition among children who receive health services given by MLPs. This study thus aims to examine the efficacy of nutrition training of MLPs on feeding practices and the nutrition status of HIV-positive children in Tanga, Tanzania. METHODS/DESIGN: We will conduct a cluster randomized controlled trial in care and treatment centers (CTCs) in Tanga, Tanzania. The CTCs will be the unit of randomization. We will select 16 CTCs out of 32 for this study, of which we will randomly assign 8 to the intervention arm and 8 to the control arm by coin flipping. From the selected CTCs we will attempt to recruit a total of 800 HIV positive children aged 6 months to 14 years, half of whom will be receiving care and/or treatment in the CTCs of the intervention arm, and the other half of whom will be receiving care and/or treatment in the CTCs of the control arm (400 children in each condition).We will provide nutrition training to MLPs of the CTCs selected for the intervention arm. In this intervention, we will use the World Health Organization guidelines on nutrition training of health workers for HIV-positive children aged 6 months to 14 years. The trained MLPs will then provide tailored nutrition counseling to caregivers of children being treated at the 8 CTCs of the intervention arm. We will measure nutrition status and child feeding practices monthly for a total of six months. CONCLUSIONS: Results of this trial will help expanding undernutrition interventions among HIV-positive children in Tanzania and other countries. TRIAL REGISTRATION: Current Controlled Trials: ISRCTN65346364. PMID- 24156501 TI - Older adults' evaluations of middle-aged children's attempts to initiate discussion of care needs. AB - We explored how older adults evaluated the strategies used by an adult child to initiate discussion of future care needs, and subsequently, whether these judgments affected older adults' willingness to engage in discussions about eldercare if approached in a similar fashion by one of their own children. One hundred and thirty older adults were randomly assigned to read one of four scripts depicting efforts by a middle-aged daughter to raise the topic of future care needs with her mother by implementing a variety of facework behaviors. Scripts manipulated the degree to which the daughter conveyed respect for her mother's desires for autonomy (negative face) and connection (positive face). The daughter's facework significantly predicted older parents' evaluation of her as supportive, which in turn predicted their willingness to discuss future care needs with one of their own children if they were to approach the conversation in a similar way. PMID- 24156502 TI - Application of the compensated Arrhenius formalism to explain the dielectric constant dependence of rates for Menschutkin reactions. AB - The dependence of the reaction rate on solvent dielectric constant is examined for the reaction of trihexylamine with 1-bromohexane in a series of 2-ketones over the temperature range 25-80 degrees C. The rate constant data are analyzed using the compensated Arrhenius formalism (CAF), where the rate constant assumes an Arrhenius-like equation that also contains a dielectric constant dependence in the exponential prefactor. The CAF activation energies are substantially higher than those obtained using the simple Arrhenius equation. A master curve of the data is observed by plotting the prefactors against the solvent dielectric constant. The master curve shows that the reaction rate has a weak dependence on dielectric constant for values approximately less than 10 and increases more rapidly for dielectric constant values greater than 10. PMID- 24156503 TI - A UK experience of daycase cochlear implant surgery. AB - OBJECTIVES: This study aims to assess the safety of daycase cochlear implant surgery. METHODS: A retrospective review was conducted on all patients who underwent cochlear implant surgery at a teaching hospital in Oxford, UK between September 2008 and February 2012. RESULTS: One hundred and sixteen patients underwent cochlear implant surgery. This included 73 adults and 43 children. Twenty-six patients underwent the procedure as a daycase procedure. There were no readmissions. DISCUSSION: The demand 'to do more with less' has led to increasing drives for efficiency and cost-effectiveness. Therefore, the role of daycase surgery is becoming increasingly widespread. Daycase surgery has been shown to be advantageous for both patients and hospitals. CONCLUSION: Daycase cochlear implant surgery is feasible and can be safely conducted in a select group of patients. PMID- 24156504 TI - Biologic agents in nail psoriasis: efficacy data and considerations. AB - INTRODUCTION: Nail psoriasis plays a major role in the overall assessment of psoriatic disease. Four biologic agents are officially labeled for the treatment of moderate to severe, stable plaque psoriasis (adalimumab, etanercept, infliximab, ustekinumab) and have enriched subsequently the therapeutic armamentarium against psoriatic nails. However, evidence for the efficacy of these agents for nail psoriasis is under investigation. AREAS COVERED: In this review an effort has been made to summarize evidence regarding the efficacy of biologics in nail psoriasis. A systemic search for reports of biologic agents in psoriatic patients with nail involvement was carried out (MEDLINE and CENTRAL in the Cochrane Library). Relevant data are thoroughly presented. EXPERT OPINION: All four biologic agents have shown efficacy on psoriatic nail disease. However, published data are heterogeneous, based on studies assessing the therapeutic efficacy with different scoring indexes and at different time points, depending on the time table of each drug administration. Therefore, the need for consensus on core outcome to be used is mandatory. Additionally, optimization of the scoring systems and the conduction of further trials of high quality and validity could lead to more accurate conclusions on the efficacy of biologic agents in the treatment of nail psoriasis. PMID- 24156505 TI - Personality disorder and early therapeutic alliance in two time-limited therapies. AB - This study examined the relationship of pre-treatment personality disorder diagnosis to the quality of early therapeutic alliance in 145 patients randomly assigned to either cognitive behavioral therapy or brief relational therapy. The pre-treatment diagnosis was established by DSM-IV (SCID) and Wisconsin Personality Inventory. Quality of the alliance was assessed by patient and therapist reports using the 12-item Working Alliance Inventory, Session Evaluation Questionnaire, and direct questions of ruptures. Results indicated that pre-treatment personality disorder as determined by SCID predicted no variables of early psychotherapy process. Factor scores yielded from a PCA of the WISPI indicated that high impulsivity, dysregulation, and lability were associated with lower patient and therapist ratings of session depth of exploration and higher patient ratings of rupture intensity. PMID- 24156508 TI - Objective classification of scapular kinematics in participants with movement faults of the scapula on clinical assessment. AB - The aim of this study was to assess the potential of employing a classification tool to objectively classify participants with clinically assessed movement faults (MFs) of the scapula. Six participants with a history of shoulder pain with MFs of the scapula and 12 healthy participants with no movement faults (NMFs) performed a flexion movement control test of the scapula, while scapular kinematic data were collected. Principal component scores and discrete kinematic variables were used as input into a classifier. Five out of the six participants with a history of pain were successfully classified as having scapular MFs with an accuracy of 72%. Variables related to the upward rotation of the scapula had the most influence on the classification. The results of the study demonstrate the potential of adopting a multivariate approach in objective classification of participants with altered scapular kinematics in pathological groups. PMID- 24156509 TI - Development of an EMS curriculum. AB - Emergency medical services (EMS) became an American Board of Medical Specialties (ABMS) approved subspecialty of emergency medicine in September 2010. Achieving specialty or subspecialty recognition in an area of medical practice requires a unique body of knowledge, a scientific basis for the practice, a significant number of physicians who dedicate a portion of their practice to the area, and a sufficient number of fellowship programs. To prepare EMS fellows for successful completion of fellowship training, a lifetime of subspecialty practice, and certification examination, a formalized structured fellowship curriculum is necessary. A functional curriculum is one that takes the entire body of knowledge necessary to appropriately practice in the identified area and codifies it into a training blueprint to ensure that all of the items are covered over the prescribed training period. A curriculum can be as detailed as desired but typically all major headings and subheadings of the core content are identified and addressed. Common curricular components, specific to each area of the core content, include goals and objectives, implementation methods, evaluation, and outcomes assessment methods. Implementation methods can include simulation, observations, didactics, and experiential elements. Evaluation and outcomes assessment methods can include direct observation of patient assessment and treatment skills, structured patient simulations, 360 degrees feedback, written and oral testing, and retrospective chart reviews. This paper describes a curriculum that is congruent with the current EMS core content, as well as providing a 12-month format to deploy the curriculum in an EMS fellowship program. Key words: curriculum; education; emergency medical services; fellowships and scholarships. PMID- 24156506 TI - Association of genetic polymorphism of PPARgamma-2, ACE, MTHFR, FABP-2 and FTO genes in risk prediction of type 2 diabetes mellitus. AB - Type 2 diabetes mellitus (T2DM) is a non-autoimmune, complex, heterogeneous and polygenic metabolic disease condition characterized by persistent elevated blood glucose levels (hyperglycemia). India as said to be the diabetic capital of the world is likely to experience the largest increase in T2DM and a greater number of diabetic individuals in the world by the year 2030. Identification of specific genetic variations in a particular ethnic group has a critical role in understanding the risk of developing T2DM in a much efficient way in future. These genetic variations include numerous types of polymorphisms among which single nucleotide polymorphisms (SNPs) is the most frequent. SNPs are basically located within the regulatory elements of several gene sequences. There are scores of genes interacting with various environmental factors affecting various pathways and sometimes even the whole signalling network that cause diseases like T2DM. This review discusses the biomarkers for early risk prediction of T2DM. Such predictions could be used in order to understand the pathogenesis of T2DM and to better diagnostics, treatment, and eventually prevention. PMID- 24156510 TI - Imaging in anatomy: a comparison of imaging techniques in embalmed human cadavers. AB - BACKGROUND: A large variety of imaging techniques is an integral part of modern medicine. Introducing radiological imaging techniques into the dissection course serves as a basis for improved learning of anatomy and multidisciplinary learning in pre-clinical medical education. METHODS: Four different imaging techniques (ultrasound, radiography, computed tomography, and magnetic resonance imaging) were performed in embalmed human body donors to analyse possibilities and limitations of the respective techniques in this peculiar setting. RESULTS: The quality of ultrasound and radiography images was poor, images of computed tomography and magnetic resonance imaging were of good quality. CONCLUSION: Computed tomography and magnetic resonance imaging have a superior image quality in comparison to ultrasound and radiography and offer suitable methods for imaging embalmed human cadavers as a valuable addition to the dissection course. PMID- 24156511 TI - Mixed-spin [2 * 2] Fe4 grid complex optimized for quantum cellular automata. AB - The new pyrazolate-bridged proligand 4-methyl-3,5-bis{6-(2,2'-bipyridyl)}pyrazole ((Me)LH) has been synthesized. Similar to its congener that lacks the backbone methyl substituent ((H)LH) it forms a robust Fe(II)4 grid complex, [(Me)L4Fe(II)4](BF4)4. The molecular structure of [(Me)L4Fe(II)4](BF4)4.2MeCN has been elucidated by X-ray diffraction, revealing two high-spin (HS) and two low spin (LS) ferrous ions at opposite corners of the rhombic metal ion arrangement. SQUID and (57)Fe Mossbauer data for solid material showed that this [HS-LS-HS-LS] configuration persists over a wide temperature range, between 7 and 250 K, while spin-crossover sets in only above 250 K. According to Mossbauer spectroscopy a [1HS-3LS] configuration is present in solution at 80 K. Thus, the methyl substituent in [(Me)L](-) leads to a stronger ligand field compared to parent [(H)L](-) and hence to a higher LS fraction both in the solid state and in solution. Cyclic voltammetry of [(Me)L4Fe(II)4](BF4)4 reveals four sequential oxidations coming in two pairs with pronounced stability of the di-mixed-valence species [(Me)L4Fe(II)2Fe(III)2](6+) (K(C) = 3.35 * 10(8)). The particular [HS-LS HS-LS] configuration as well as the di-mixed-valence configuration, both with identical spin or redox states at diagonally opposed vertices of the grid, make this system attractive as a molecular component for quantum cellular automata. PMID- 24156512 TI - Asymmetric oxidation catalysis by a porphyrin-inspired manganese complex: highly enantioselective sulfoxidation with a wide substrate scope. AB - The first genuinely promising porphyrin-inspired manganese-catalyzed asymmetric sulfoxidation method using hydrogen peroxide has been successfully developed, allowing for rapidly oxidizing (0.5-1.0 h) a wide variety of sulfides in high yields with excellent enantioselectivities (up to >99% ee). PMID- 24156514 TI - Six-helix bundle and triangle DNA origami insulator-based dielectrophoresis. AB - Self-assembled DNA nanostructures have large potential for nanoelectronic circuitry, targeted drug delivery, and intelligent sensing. Their applications require suitable methods for manipulation and nanoscale assembly as well as adequate concentration, purification, and separation methods. Insulator-based dielectrophoresis (iDEP) provides an efficient and matrix-free approach for manipulation of micro- and nanometer-sized objects. In order to exploit iDEP for DNA nanoassemblies, a detailed understanding of the underlying polarization and dielectrophoretic migration is essential. Here, we explore the dielectrophoretic behavior of six-helix bundle and triangle DNA origamis with identical sequence but large topological difference and reveal a characteristic frequency range of iDEP trapping. Moreover, the confinement of triangle origami in the iDEP trap required larger applied electric fields. To elucidate the observed DEP migration and trapping, we discuss polarizability models for the two species according to their structural difference complemented by numerical simulations, revealing a contribution of the electrophoretic transport of the DNA origami species in the iDEP trapping regions. The numerical model showed reasonable agreement with experiments at lower frequency. However, the extension of the iDEP trapping regions observed experimentally deviated considerably at higher frequencies. Our study demonstrates for the first time that DNA origami species can be successfully trapped and manipulated by iDEP and reveals distinctive iDEP behavior of the two DNA origamis. The experimentally observed trapping regimes will facilitate future exploration of DNA origami manipulation and assembly at the nano- and microscale as well as other applications of these nanoassemblies with iDEP. PMID- 24156513 TI - Evolution of the human immunodeficiency virus type 2 envelope in the first years of infection is associated with the dynamics of the neutralizing antibody response. AB - BACKGROUND: Differently from HIV-1, HIV-2 disease progression usually takes decades without antiretroviral therapy and the majority of HIV-2 infected individuals survive as elite controllers with normal CD4+ T cell counts and low or undetectable plasma viral load. Neutralizing antibodies (Nabs) are thought to play a central role in HIV-2 evolution and pathogenesis. However, the dynamic of the Nab response and resulting HIV-2 escape during acute infection and their impact in HIV-2 evolution and disease progression remain largely unknown. Our objective was to characterize the Nab response and the molecular and phenotypic evolution of HIV-2 in association with Nab escape in the first years of infection in two children infected at birth. RESULTS: CD4+ T cells decreased from about 50% to below 30% in both children in the first five years of infection and the infecting R5 viruses were replaced by X4 viruses within the same period. With antiretroviral therapy, viral load in child 1 decreased to undetectable levels and CD4+ T cells recovered to normal levels, which have been sustained at least until the age of 12. In contrast, viral load increased in child 2 and she progressed to AIDS and death at age 9. Beginning in the first year of life, child 1 raised high titers of antibodies that neutralized primary R5 isolates more effectively than X4 isolates, both autologous and heterologous. Child 2 raised a weak X4-specific Nab response that decreased sharply as disease progressed. Rate of evolution, nucleotide and amino acid diversity, and positive selection, were significantly higher in the envelope of child 1 compared to child 2. Rates of R5 to-X4 tropism switch, of V1 and V3 sequence diversification, and of convergence of V3 to a beta-hairpin structure were related with rate of escape from the neutralizing antibodies. CONCLUSION: Our data suggests that the molecular and phenotypic evolution of the human immunodeficiency virus type 2 envelope are related with the dynamics of the neutralizing antibody response providing further support for a model in which Nabs play an important role in HIV-2 pathogenesis. PMID- 24156516 TI - Flow-induced aggregation and breakup of particle clusters controlled by surface nanoroughness. AB - Interactions between colloidal particles are strongly affected by the particle surface chemistry and composition of the liquid phase. Further complexity is introduced when particles are exposed to shear flow, often leading to broad variation of the final properties of formed clusters. Here we discover a new dynamical effect arising in shear-induced aggregation where repeated aggregation and breakup events cause the particle surface roughness to irreversibly increase with time, thus decreasing the bond adhesive energy and the resistance of the aggregates to breakup. This leads to a pronounced overshoot in the time evolution of the aggregate size, which can only be explained with the proposed mechanism. This is demonstrated by good agreement between time evolution of measured light scattering data and those calculated with a population-balance model taking into account the increase in the primary particle nanoroughness caused by repeated breakup events resulting in the decrease of bond adhesive energy as a function of time. Thus, the proposed model is able to reproduce the overshoot phenomenon by taking into account the physicochemical parameters, such as pH, till now not considered in the literature. Overall, this new effect could be exploited in the future to achieve better control over the flow-induced assembly of nanoparticles. PMID- 24156517 TI - Tubular polymersomes: a cross-linker-induced shape transformation. AB - Polymersomes, polymeric vesicles constructed of block copolymers, can undergo a sphere-to-tubule transition under the influence of a chemical modification of the polymeric bilayer. A strain-promoted alkyne-azide cycloaddition (SPAAC) reaction between azide handles inside the hydrophobic domain of the membrane and an excess of a bicyclo[6.1.0]nonyne (BCN)-cross-linker causes the vesicle to stretch in one dimension. Tubular polymersomes up to 2 MUm in length can be obtained with this shape transformation. The introduction of a cleavable cross-linker makes this process reversible and opens the way for future drug delivery applications. PMID- 24156515 TI - Young smokers and non-smokers perceptions of typical users of plain vs. branded cigarette packs: a between-subjects experimental survey. AB - BACKGROUND: In an attempt to minimize the pack design avenue of communication between tobacco producers and smokers and potential smokers, several jurisdictions, including Norway, have considered regulations on cigarette pack design. The main aim of the current study was to investigate how package design affects young people's perceptions of typical smokers of some pre-chosen cigarette brands and brand varieties. METHODS: Based on data from a web survey among 1022 15-22 year-olds, possible effects of plain packaging of cigarettes on adolescents' views about typical cigarette smokers were investigated. The data collection had a between-subjects design, in which participants were allocated to one of three groups, and asked to typify the smokers of selected cigarette packs either in branded, plain or plain with descriptor versions. The sample included boys and girls, and smokers and non-smokers. The smoker characteristics included in the investigation were: gender, glamour, stylishness, popularity, coolness, sophistication and slimness. RESULTS: After creating sum-scores within and across packs and pack versions, analyses indicated that a shift from branded to plain cigarette packaging would result in a reduction in positive user images related to smoking among adolescents and young adults. For girls, this effect held up after controlling for confounders. CONCLUSIONS: To the extent that plain packaging contributes to making smoking images less positive, it can potentially be an efficient aid in reducing smoking uptake among adolescents. PMID- 24156518 TI - Constructing language normativity through the animation of stance in Spanish language medical consultations. AB - The purpose of this study is to examine the construction of language normativity as medical providers interact with patients and animate stance within Spanish language medical consultations. The context of the study is a clinic in which providers use Spanish to communicate with monolingual Spanish-speaking patients. This clinic is in the United States, an English-speaking macro-societal context. Findings indicate that providers who are second-language users of Spanish animate stance and interact with patients in ways such that English is constructed as normative and Spanish as marked. Implications include the need to consider how the construction of language normativity within medical consultations affects health outcomes. PMID- 24156519 TI - Midpoint of sleep on school days is associated with depression among adolescents. AB - Depression is a serious and prevalent disease among adolescents. Identifying possible factors involved with its genesis and presentation is an important task for researchers and clinical practitioners. The individual's chronotype and social jetlag have been associated with depression in different populations. However, information on this is lacking among adolescents. The objective of this cross-sectional study was to examine the relationship between chronotype (midpoint of sleep) and social jetlag with the presence of depression symptoms in young students. We assessed 351 students aged 12-21 years old. They answered a questionnaire on demographic characteristics, the Munich Chronotype Questionnaire (MCTQ) and the Beck Depression Inventory (BDI). Demographic characteristics (age, sex and classes' schedule) and circadian rhythmic variables for school and free days (sunlight exposure, sleep duration, midpoint of sleep and social jetlag) were taken as factors and the presence of at least mild depression symptoms as outcome. In univariate analysis, girls (chi(2) = 5.01, p <= 0.05) and evening students (chi(2) = 6.63, p <= 0.05) were more frequently present among the depressed. Also, the depression group was significantly delayed for both midpoints of sleep during school (t = 2.84, p <= 0.01) and free days (t = 2.20, p <= 0.05). The two groups did not differ in relation to their social jetlag hours (t = -0.68, p = 0.501) neither subjects with two or more hours of social jetlag were more frequent among the depressed (chi(2) = 1.00, p = 0.317). In multivariate analysis, the model that best explained our outcome (R(2) = 0.058, F = 2.318, p <= 0.05) included sex (beta = -0.12, p <= 0.05) and the midpoint of sleep on school days (beta = -0.21, p <= 0.001) as significant predictor variables. A sleep phase delay (later midpoints of sleep for school and free days) was associated with higher levels of depression. However, we were not able to detect similar relationship with the social jetlag hours. This could be attributed to the fact that our sample showed a smaller amount of social jetlag, possibly because even during free days a social routine, this time parents' rules, limited the observation from what could be a natural tendency to sleep later and over. Yet, even when considering the group with more social jetlag, we did not find an association. Perhaps, this variable will only manifest its effect if it is maintained for longer periods throughout life. Additionally, when considering all the variables together, the midpoint of sleep on school days was pointed as the predictor of greatest weight for depression, together with the factor sex. Young girls, possibly earlier types, who are required to study in the evening have more chances of presenting depression symptoms. This study explicit some peculiar characteristics of the assessment of chronobiological variables in the young, such as the presence of an imposed social routine also during free days. Therefore, the expression of chronotype under the influence of the weekly social schedule (midpoint of sleep on school days) could be a more useful marker to measure the stress produced from the mismatch between external and inner rhythms rather than social jetlag. This also reinforces the importance of reconsidering the weekly routine imposed on young people. PMID- 24156521 TI - The effects of season, daylight saving and time of sunrise on serum cortisol in a large population. AB - Cortisol is critical for maintenance of health and homeostasis and factors affecting cortisol levels are of clinical importance. There is conflicting information about the effects of season on morning cortisol and little information on the effects of sunlight on population cortisol assessment. The aim of this study was to assess whether changes in median serum cortisol occurred in a population in conjunction with changing seasons, daylight saving time (DST) or time of sunrise. We analysed serum cortisol results (n = 27,569) from a single large laboratory over a 13-year period. Subjects with confounding medications or medical conditions were excluded and data analysed in 15-minute intervals. We assessed the influence of traditional seasons, seasons determined by equinox/solstice, DST and time of sunrise on median cortisol. The median time of cortisol collection did not vary significantly between seasons. Using traditional seasons, median cortisol was lowest in summer (386 nmol/L) and spring (384 nmol/L) with higher cortisol in autumn (406 nmol/L) and winter (414 nmol/L). Median cortisol was lowest in the summer solstice quarter with significant comparative increases in the spring equinox quarter (3.1%), the autumn equinox quarter (4.5%) and the winter solstice quarter (8.6%). When cortisol was modelled against time, with adjustment for actual sunrise time on day of collection, for each hour delay in sunrise there was a 4.8% increase in median cortisol (95% CI: 3.9-5.7%). In modelling to explain the variation in cortisol over the morning, sunrise time was better than season in explaining seasonal effects. A subtle cyclic pattern in median cortisol also occurred throughout the months of the year. A 3-year trial of DST allowed comparison of cortisol in DST and non DST periods, when clock time differed by one hour. There was modest evidence of a difference in acrophase between DST and non DST cortisol (p = 0.038), with DST peak cortisol estimated to occur 58 minutes later than non-DST peak. In summary, we found that time of sunrise and time of cortisol collection were the most important factors influencing median cortisol. For each hour later that the sun rose there was an almost 5% increase in median cortisol. There was significant seasonal variability with lowest cortisol noted in summer coinciding with the earliest sunrise time. This is an important finding which is consistent with the understanding that light is the major zeitgeber in entrainment of the human circadian cortisol rhythm. Our data suggest this rhythm is resistant to the arbitrary changes in clock time with daylight saving. PMID- 24156520 TI - Bedtime misalignment and progression of breast cancer. AB - Disruption of circadian rhythms, which frequently occurs during night shift work, may be associated with cancer progression. The effect of chronotype (preference for behaviors such as sleep, work, or exercise to occur at particular times of day, with an associated difference in circadian physiology) and alignment of bedtime (preferred vs. habitual), however, have not yet been studied in the context of cancer progression in women with breast cancer. Chronotype and alignment of actual bedtime with preferred chronotype were examined using the Morningness-Eveningness Scale (MEQ) and sleep-wake log among 85 women with metastatic breast cancer. Their association with disease-free interval (DFI) was retrospectively examined using the Cox proportional hazards model. Median DFI was 81.9 months for women with aligned bedtimes ("going to bed at preferred bedtime") (n = 72), and 46.9 months for women with misaligned bedtimes ("going to bed later or earlier than the preferred bedtime") (n = 13) (log rank p = 0.001). In a multivariate Cox proportional hazard model, after controlling for other significant predictors of DFI, including chronotype (morning type/longer DFI; HR = 0.539, 95% CI = 0.320-0.906, p = 0.021), estrogen receptor (ER) status at initial diagnosis (negative/shorter DFI; HR = 2.169, 95% CI = 1.124-4.187, p = 0.028) and level of natural-killer cell count (lower levels/shorter DFI; HR = 1.641, 95% CI = 1.000-2.695, p = 0.050), misaligned bedtimes was associated with shorter DFI, compared to aligned bedtimes (HR = 3.180, 95% CI = 1.327-7.616, p = 0.018). Our data indicate that a misalignment of bedtime on a daily basis, an indication of circadian disruption, is associated with more rapid breast cancer progression as measured by DFI. Considering the limitations of small sample size and study design, a prospective study with a larger sample is necessary to explore their causal relationship and underlying mechanisms. PMID- 24156522 TI - Circadian entrainment by light and host in the Chagas disease vector, Triatoma infestans. AB - Triatoma infestans (Reduviidae: Triatominae, "kissing bug") is the main insect vector of Trypanosoma cruzi, the causative agent of Chagas disease, a chronic trypanosomiasis infecting 10 million people world-wide. This hematophagous bug feeds on diurnal and nocturnal species during each host's quiescent time. As the hosts are also its major predators, kissing bugs are subjected to dual selective pressures from a single source. Therefore, synchronization of feeding with the host's behavior is critical to the insects' survival. We show that nonphotic signals linked to the host eclipse the role of light and dark as the primary circadian zeitgeber for these bugs, although light still strongly inhibits locomotor behavior directly. In nature, this combination provides the insect with great flexibility in organizing physiology and behavior: anticipating a quiescent host or avoiding its potential predation while remaining directly responsive to immediate environmental conditions. Manipulation of nonphotic entrainment could be a useful chronobiotic tool in the control of Chagas disease. PMID- 24156523 TI - Hypothermia after chronic mild stress exposure in rats with a history of postnatal maternal separations. AB - The circadian system develops and changes in a gradual and programmed process over the lifespan. Early in life, maternal care represents an important zeitgeber and thus contributes to the development of circadian rhythmicity. Exposure to early life stress may affect circadian processes and induce a latent circadian disturbance evident after exposure to later life stress. Disturbance of the normal regulation of circadian rhythmicity is surmised to be an etiological factor in depression. We used postnatal maternal separation in rats to investigate how the early life environment might modify the circadian response to later life unpredictable and chronic stress. During postnatal days 2-14, male Wistar rats (n = 8 per group) were daily separated from their mothers for a period of either 180 min (long maternal separation; LMS) or 10 min (brief maternal separation; BMS). In adulthood, rats were exposed to chronic mild stress (CMS) for 4 weeks. Body temperature, locomotor activity and heart rate were measured and compared before and after CMS exposure. LMS offspring showed a delayed body temperature acrophase compared to BMS offspring. Otherwise, adult LMS and BMS offspring demonstrated similar diurnal rhythms of body temperature, locomotor activity and heart rate. Exposure to CMS provoked a stronger and longer lasting hypothermia in LMS rats than in BMS rats. The thermoregulatory response appears to be moderated by maternal care following reunion, an observation made in the LMS group only. The results show that early life stress (LMS) in an early developmental stage induced a thermoregulatory disturbance evident upon exposure to unpredictable adult life stressors. PMID- 24156524 TI - Dynamics in the isotropic phase of nematogens using 2D IR vibrational echo measurements on natural-abundance 13CN and extended lifetime probes. AB - The long time scale orientational relaxation of nematogens in the isotropic phase is associated with the randomization of pseudonematic domains, which have a correlation length that grows as the isotropic-to-nematic phase transition temperature is approached from above. Here we begin to address the fast dynamics of the nematogen molecules within the domains using two-dimensional infrared (2D IR) vibrational echo experiments. The problems of performing ultrafast IR experiments in pure liquids are discussed, and solutions are presented. In addition, the issue of short vibrational lifetimes, which limit the ability of 2D IR experiments to examine dynamics over a wide range of times, is addressed. The experiments were performed on the nematogen 4-cyano-4'-pentylbiphenyl (5CB), with the CN stretch initially used as the vibrational probe. Although the CN stretch has a small transition dipole, because the sample is a pure liquid it is necessary to use an exceedingly thin sample to perform the experiments. The small sample volume leads to massive heating effects that distort the results. In addition, the high concentration in the pure liquid can result in vibrational excitation transfer that interferes with the measurements of structural dynamics, and the CN vibrational lifetime is very short (3.6 ps). These problems were overcome by performing the experiments on the natural-abundance (13)CN stretch (5(13)CB), which greatly reduced the absorbance, eliminating the heating problems; also, this stretch has a longer lifetime (7.9 ps). Experiments were also performed on benzonitrile, which showed that the heating problems associated with pure liquids are not unique to 5CB. Again, the problems were eliminated by conducting measurements on the (13)CN stretch, which has an even longer lifetime (20.2 ps) compared with the (12)CN stretch (5.6 ps). Finally, to extend the range of the dynamical measurements, 4-pentyl-4'-thiocyanobiphenyl (5SCB) was synthesized and studied as a dilute solute in 5CB. The CN stretch of 5SCB has a vibrational lifetime of 103 ps, which permits dynamical measurements to 200 ps, revealing the full range of fast structural dynamics in the isotropic phase of 5CB. It is shown that the 5SCB probe reports essentially the same dynamics as 5(13)CB on the short time scale that is observable with the 5(13)CB vibrational probe. PMID- 24156526 TI - An exploratory study of the relationship between changes in emotion and cognitive processes and treatment outcome in borderline personality disorder. AB - This exploratory study examined specific emotion processes and cognitive problem solving processes in individuals with borderline personality disorder (BPD), and assessed the relationship of these changes to treatment outcome. Emotion and cognitive problem-solving processes were assessed using the Toronto Alexithymia Scale, the Linguistic Inquiry Word Count, the Derogatis Affect Balance Scale, and the Problem Solving Inventory. Participants who showed greater improvements in affect balance, problem solving, and the ability to identify and describe emotions showed greater improvements on treatment outcome, with affect balance remaining statistically significant under the most conservative conditions. The results provide preliminary evidence to support the theory that specific improvements in emotion and cognitive processes are associated with positive treatment outcomes (symptom distress, interpersonal functioning) in BPD. The implications for treatment are discussed. PMID- 24156525 TI - Stakeholder perspectives on implementing accreditation programs: a qualitative study of enabling factors. AB - BACKGROUND: Accreditation programs are complex, system-wide quality and safety interventions. Despite their international popularity, evidence of their effectiveness is weak and contradictory. This may be due to variable implementation in different contexts. However, there is limited research that informs implementation strategies. We aimed to advance knowledge in this area by identifying factors that enable effective implementation of accreditation programs across different healthcare settings. METHODS: We conducted 39 focus groups and eight interviews between 2011 and 2012, involving 258 diverse healthcare stakeholders from every Australian State and Territory. Interviews were semi-structured and focused on the aims, implementation and consequences of three prominent accreditation programs in the aged, primary and acute care sectors. Data were thematically analysed to distil and categorise facilitators of effective implementation. RESULTS: Four factors were identified as critical enablers of effective implementation: the accreditation program is collaborative, valid and uses relevant standards; accreditation is favourably received by health professionals; healthcare organisations are capable of embracing accreditation; and accreditation is appropriately aligned with other regulatory initiatives and supported by relevant incentives. CONCLUSIONS: Strategic implementation of accreditation programs should target the four factors emerging from this study, which may increase the likelihood of accreditation being implemented successfully. PMID- 24156527 TI - Factors associated with facility-based delivery in Mayoyao, Ifugao Province, Philippines. AB - BACKGROUND: The maternal mortality ratio (MMR) in the Philippines is higher than in most other Southeast Asian countries, and home delivery is a major factor contributing to the high MMR. This study aims to explore the determinants for choice of delivery location in Ifugao Province, where people have poor access to health services. FINDINGS: A household interview survey using a structured questionnaire was conducted to identify the factors associated with delivery location among 354 women. In all, 44.4% of the respondents delivered at a health facility. Using logistic regression analysis, parity (odds ratio [OR] 3.0, 95% confidence interval [C.I.] 1.6-5.6), higher education (OR 5.9, 95% C.I. 2.7 12.9), distance to a health facility (OR 6.9, 95% C.I. 3.4-14.2), health problems identified at antenatal care (OR 2.4, 95% C.I. 1.3-4.6), and the person deciding on the delivery location (e.g., for the husband OR 3.2, 95% C.I. 1.1-9.4) were found to be statistically associated with facility-based delivery. CONCLUSION: Involving the husband and other people in the decision regarding delivery location may influence a woman's choice to use facility-based delivery services. Our findings have useful implications for improving the existing Safe Motherhood program in the Philippines. PMID- 24156528 TI - Investigating the molecular structural features of hulless barley (Hordeum vulgare L.) in relation to metabolic characteristics using synchrotron-based fourier transform infrared microspectroscopy. AB - The synchrotron-based Fourier transform infrared microspectroscopy (SR-FTIRM) technique was used to quantify molecular structural features of the four hulless barley lines with altered carbohydrate traits [amylose, 1-40% of dry matter (DM); beta-glucan, 5-10% of DM] in relation to rumen degradation kinetics, intestinal nutrient digestion, and predicted protein supply. Spectral features of beta glucan (both area and heights) in hulless barley lines showed a negative correlation with protein availability in the small intestine, including truly digested protein in the small intestine (DVE) (r = -0.76, P < 0.01; r = -0.84, P < 0.01) and total metabolizable protein (MP) (r = -0.71, P < 0.05; r = -0.84, P < 0.01). Variation in absorption intensities of total carbohydrate (CHO) was observed with negative effects on protein degradation, digestion, and potential protein supply (P < 0.05). Molecular structural features of CHO in hulless barley have negative effects on the supply of true protein to ruminants. The results clearly indicated the impact of the carbohydrate-protein structure and matrix. PMID- 24156529 TI - Synthesis of alkyl aryl(heteroaryl)acetates from N-oxides, 1,1-difluorostyrenes, and alcohols. AB - Derivatives of aryl(heteroaryl)acetic acids or aryl(heteroaryl)methanes are formed from imidazole or thiazole N-oxide, 1,1-difluorostyrene, and an alcohol, amine, or water in a three-component reaction, which probably occurs via 1,3 dipolar cycloaddition. The whole process is a novel method for functionalization of a heterocyclic ring in a position originally occupied by hydrogen. Preliminary experiments show that it occurs for 6-membered N-oxides as well. PMID- 24156530 TI - Warm carbon-chain chemistry. PMID- 24156535 TI - Validation of numerical flow simulations against in vitro phantom measurements in different type B aortic dissection scenarios. AB - An aortic dissection (AD) is a serious condition defined by the splitting of the arterial wall, thus generating a secondary lumen [the false lumen (FL)]. Its management, treatment and follow-up are clinical challenges due to the progressive aortic dilatation and potentially severe complications during follow up. It is well known that the direction and rate of dilatation of the artery wall depend on haemodynamic parameters such as the local velocity profiles, intra luminal pressures and resultant wall stresses. These factors act on the FL and true lumen, triggering remodelling and clinical worsening. In this study, we aimed to validate a computational fluid dynamic (CFD) tool for the haemodynamic characterisation of chronic (type B) ADs. We validated the numerical results, for several dissection geometries, with experimental data obtained from a previous in vitro study performed on idealised dissected physical models. We found a good correlation between CFD simulations and experimental measurements as long as the tear size was large enough so that the effect of the wall compliance was negligible. PMID- 24156537 TI - Drug safety evaluation of certolizumab pegol. AB - INTRODUCTION: The introduction of antibodies directed against tumor necrosis factor (anti-TNF) has dramatically changed our concept of treating both patients with Crohn's disease (CD) and patients with rheumatoid arthritis (RA). Subcutaneous injections with certolizumab pegol (CZP) have been shown efficacious for both CD and RA. In this review, the authors focus on the safety of CZP among other anti-TNF agents. AREAS COVERED: A literature search till June 2013 was performed to identify all trials studying CZP in patients with CD and RA. In addition, abstracts of major congresses were assessed. The authors first focused on the mechanism of action of CZP, and evaluated the efficacy of this drug in both CD and RA. Next, they explored the available safety data on CZP, including infection and malignancy risk, injection site reactions, the development of antibodies against CZP, as well as its use during pregnancy. EXPERT OPINION: Based on the provided literature, CZP seems to have a similar safety profile to other anti-TNF agents. However, in young females considering pregnancy, CZP may be advocated over other anti-TNF agents as it does not actively cross the placenta. PMID- 24156536 TI - Nylon-3 polymers that enable selective culture of endothelial cells. AB - Substrates that selectively encourage the growth of specific cell types are valuable for the engineering of complex tissues. Some cell-selective peptides have been identified from extracellular matrix proteins; these peptides have proven useful for biomaterials-based approaches to tissue repair or regeneration. However, there are very few examples of synthetic materials that display selectivity in supporting cell growth. We describe nylon-3 polymers that support in vitro culture of endothelial cells but do not support the culture of smooth muscle cells or fibroblasts. These materials may be promising for vascular biomaterials applications. PMID- 24156538 TI - Dissecting organ-specific transcriptomes through RNA-sequencing. AB - BACKGROUND: Organ-specific gene expression contains rich information about in vivo biological processes. This kind of information, previously gathered through microarray profiling, has been proven fruitful to the understanding of specific mutants, regulatory events, signaling, and development. With the advent of the next-generation sequencing (NGS) of RNAs, more quantitative and detailed information of gene expressions than previously available can now be collected for each organ or organ developmental stages. The combination of an object oriented experimental design and an efficient treatment of the high volume information generated through a NGS platform may offer a powerful tool for inferring previously intractable developmental processes. RESULTS: We collected transcriptomic data over a Solexa/Illumina platform on samples of Ipomoea leaf, sepal, and petals (at three developmental stages), and presented a method for analyzing transcriptomic variations within and between organs. We demonstrated that in vivo signals of transcriptomes can be retrieved de novo through the NGS techniques, proper data handling, bioinformatic tools, and the current understanding of molecular networks. We found that numbers of transcribed genes from both nuclear and chloroplast genomes decreased by the same order of leaf -> sepal ->petal. Petal resembled leaf in cell division patterns and abundance level of commonly expressed organelle genes. Its chloroplast transcripts constituted a subset of those in leaf. Moreover, reconstructions of multiple metabolic networks for each organ enabled inferences of substance flow, providing transcript evidence for the path of sucrose in leaf to anthocyanin synthesis in petal. CONCLUSION: Our results attest that developmental transcriptomes are highly informative for exploring connections between morphological traits and the associated molecular networks. Significant hypotheses have been developed, including that the petal is a derived organ of leaf and that its color can be modified by fluctuations of substance flow within the associated metabolic networks among organs. PMID- 24156539 TI - Comparative proteomic analysis reveals mechanistic insights into Pseudomonas putida F1 growth on benzoate and citrate. AB - Pseudomonas species are capable to proliferate under diverse environmental conditions and thus have a significant bioremediation potential. To enhance our understanding of their metabolic versatility, this study explores the changes in the proteome and physiology of Pseudomonas putida F1 resulting from its growth on benzoate, a moderate toxic compound that can be catabolized, and citrate, a carbon source that is assimilated through central metabolic pathways. A series of repetitive batch cultivations were performed to ensure a complete adaptation of the bacteria to each of these contrasting carbon sources. After several growth cycles, cell growth stabilized at the maximum level and exhibited a reproducible growth profile. The specific growth rates measured for benzoate (1.01 +/- 0.11 h 1) and citrate (1.11 +/- 0.12 h-1) were similar, while a higher yield was observed for benzoate (0.6 and 0.3 g cell mass per g of benzoate and citrate, respectively), reflecting the different degrees of carbon reduction in the two substrates. Comparative proteomic analysis revealed an enrichment of several oxygenases/dehydrogenases in benzoate-grown cells, indicative of the higher carbon reduction of benzoate. Moreover, the upregulation of all 14 proteins implicated in benzoate degradation via the catechol ortho-cleavage pathway was observed, while several stress-response proteins were increased to aid cells to cope with benzoate toxicity. Unexpectedly, citrate posed more challenges than benzoate in the maintenance of pH homeostasis, as indicated by the enhancement of the Na+/H+ antiporter and carbonic anhydrase. The study provides important mechanistic insights into Pseudomonas adaptation to varying carbon sources that are of great relevance to bioremediation efforts. PMID- 24156540 TI - Properties of bioadhesive ketoprofen liquid suppositories: preparation, determination of gelation temperature, viscosity studies and evaluation of mechanical properties using texture analyzer by 4 * 4 factorial design. AB - CONTEXT: Development and evaluation of thermosensitive and bioadhesive liquid suppositories containing ketoprofen (KP). OBJECTIVE: This study was conducted to develope thermosensitive and bioadhesive liquid suppositories containing KP using poloxamer and different bioadhesive polymers and to investigate their gelation temperature, viscosity and mechanical properties. MATERIALS AND METHODS: Bioadhesive liquid suppositories were prepared by the cold method using poloxamer 407 (P 407), Poloxamer 188 (P 188) and various amounts of different bioadhesive polymers. Their gelation temperatures, viscosity values and mechanical properties were determined using texture analyzer by 4 * 4 factorial design. RESULTS: It was seen that in presence of KP, gelation temperature of formulation P 407/P 188 (4/20%) significantly decreased from 64 to 37.1 degrees C. It is to be noted that addition of increasing concentrations of bioadhesive polymers lowered gelation temperature and its decrease was highest with addition of Carbopol 934 P (C). Results of texture profile analysis (TPA) showed that formulations containing C have significantly higher hardness and adhesiveness values than other bioadhesive formulations. According to TPA, gel structure of liquid suppository formulation F5, containing P 407/P 188/KP/C (4/20/2.5/0.8%), exhibited the greatest hardness, compressibilty, adhesiveness and besides greatest viscosity. DISCUSSION AND CONCLUSION: According to mechanical properties and viscosity values, it was concluded that F5 could be a promising formulation. PMID- 24156541 TI - CO2-stimulated diversiform deformations of polymer assemblies. AB - Use of a given physiological stimulus to delicately deform polymer assemblies is a challenging topic. Here we develop synthetic block copolymers to construct a series of CO2-sensitive self-assembled nanostructures that can simulate controllable deformations of the organelles in different ways. By controlling the CO2 stimulation levels, one can modulate the size, shape, and morphology of the polymer aggregates, which is conducive to understanding the stimuli-triggered dynamic reshaping process of polymer assemblies in aqueous solution. PMID- 24156542 TI - Influence of ester-modified lipids on bilayer structure. AB - Lipid membranes function as barriers for cells to prevent unwanted chemicals from entering the cell and wanted chemicals from leaving. Because of their hydrophobic interior, membranes do not allow water to penetrate beyond the headgroup region. We performed molecular simulations to examine the effects of ester-modified lipids, which contain ester groups along their hydrocarbon chains, on bilayer structure. We chose two lipids from those presented in Menger et al. [J. Am. Chem. Soc. 2006, 128, 14034] with ester groups in (1) the upper half of the lipid chain (MEPC) and (2) the middle and end of the lipid chain (MGPC). MGPC (30%)/POPC bilayers formed stable water pores of diameter 5-7 A, but MGPC (22%)/POPC and MEPC (30%)/POPC bilayers did not form these defects. These pores were similar to those formed during electroporation; i.e., the head groups lined the pore and allowed water and ions to transport across the bilayer. However, we found that lateral organization of the MGPC lipids into clusters, instead of an electric field or charge disparity as in electroporation, was essential for pore formation. On the basis of this, we propose an overall mechanism for pore formation. The similarities between the ester-modified lipids and byproducts of lipid peroxidation with multiple hydrophilic groups in the middle of the chain suggest that free radical reactions with unsaturated lipids and sterols result in fundamental changes that may be similar to what is seen in bilayers with ester modified lipids. PMID- 24156543 TI - Detection of volatile organic compounds in Brucella abortus-seropositive bison. AB - Brucellosis is of great public health and economic importance worldwide. Detection of brucellosis currently relies on serologic testing of an antibody response to Brucella infection, which suffers from cross-sensitivities to other antibody responses. Here we present a new method for identifying Brucella exposure that is based on profiling volatile organic compounds (VOCs) in exhaled breath. Breath samples from Brucella-seropositive bison and controls were chemically analyzed and demonstrated statistically significant differences in the concentration profiles of five VOCs. A point-of-care device incorporating an array of nanomaterial-based sensors could identify VOC patterns indicative of Brucella exposure with excellent discriminative power, using a statistical algorithm. We show that the patterns were not affected by the animals' environment and that the discriminative power of the approach was stable over time. The Brucella-indicative VOCs and collective patterns that were identified in this pilot study could lead to the development of a novel diagnostic screening test for quickly detecting infected animals chute-side, pen-side, or even remotely in populations of free-ranging ungulates. The promising preliminary results presented encourage subsequent larger scale trials in order to further evaluate the proposed method. PMID- 24156544 TI - Use of different subjective health indicators to assess health inequalities in an urban immigrant population in north-western Italy: a cross-sectional study. AB - BACKGROUND: Despite the steady growth of the immigrant population in Italy, data on the health status of immigrants are scarce. Our main goals were to measure Health-Related Quality of Life (HRQoL), Self-Rated Health (SRH) and morbidity among immigrants in Genoa. We aimed to assess the relative contribution of some social, structural and behavioral determinants to "within-group" health disparities. METHODS: We enrolled 502 subjects by means of snowball sampling. The SF-12 questionnaire, integrated with socio-demographic and health-related items, was used. Multivariate logistic and Poisson regression models were applied in order to identify characteristics associated with poor SRH, lower SF-12 scores and prevalence of self-reported morbidities. RESULTS: Subjects showed relatively moderate levels of HRQoL (median physical and mental scores of 51.6 and 47.3, respectively) and about 15% of them rated their health as fair or poor. Lower scores in the physical dimension of HRQoL were associated with the presence of morbidities and immigration for work and religious reasons, while those who had migrated for religious and family reasons displayed a lower probability of lower scores in the mental dimension of HRQoL. Poor SRH was associated with female gender, overweight/obesity and presence of morbidities. Moreover, compared with immigrants from countries with a low human development index, immigrants from highly developed societies showed significantly lower odds of reporting poor SRH. About one-third of respondents reported at least one medical condition, while the prevalence of multi-morbidity was 10%. Females, over 45-year-olds, overweight and long-term immigrants had a higher prevalence of medical conditions. CONCLUSIONS: Our study confirms the presence of health inequalities within a heterogeneous immigrant population. HRQoL, SRH and morbidity are valid, relatively rapid and cheap tools for measuring health inequalities, though they do so in different ways. These indicators should be used with caution and, if possible, simultaneously, as they could help to identify and to monitor more vulnerable subjects among immigrants. PMID- 24156546 TI - Novel computational study on pi-stacking to understand mechanistic interactions of Tryptanthrin analogues with DNA. AB - Based on recently published initial experimental results on the intercalation of a class of broad spectrum antiparasitic compounds, we present a purely theoretical approach for determining if these compounds may preferentially intercalate with guanosine/cytosine (GC)-rich or adenosine/thymidine (TA)-rich regions of DNA. The predictive model presented herein is based upon utilization of density functional theory (DFT) to determine a priori how the best intercalator may energetically and sterically interact with each of the nucleoside base pairs. A potential new method using electrostatic potential maps (EPMs) to visually select the best poses is introduced and compared to the existing brute-force center of mass (COM) approach. The EPM and COM predictions are in agreement with each other, but the EPM method is potentially much more efficient. We report that 4-azatryptantrin, the best intercalator, is predicted to favor pi-stacking with GC over that of TA by approximately 2-4 kcal/mol. This represents a significant difference if one takes into account the Boltzmann distribution at physiological temperature. This theoretical method will be utilized to guide future experimental studies on the elucidation of possible mechanism(s) for the action of these antiparasitic compounds at the molecular level. PMID- 24156545 TI - 90K, an interferon-stimulated gene product, reduces the infectivity of HIV-1. AB - BACKGROUND: In response to viral infections, interferons induce the transcription of several hundred genes in mammalian cells. Specific antiviral functions, however, have only been attributed to a few of them. 90K/LGALS3BP has been reported to be an interferon-stimulated gene that is upregulated in individuals with cancer or HIV-1 infection. RESULTS: Here, we show that 90K expression dose dependently decreased the particle infectivity of HIV-1 progeny. The lower infectivity of released particles correlated with reduced virion incorporation of mature envelope glycoproteins gp120 and gp41. Further, proteolytic processing of the gp160 precursor and surface expression of gp120 in the producer cell were impaired in the presence of 90K expression. In contrast, expression of Gag, Nef and Vpu, and virus release were not grossly affected by 90K expression. 90K imposed restriction occurred in the absence of direct interaction of 90K with HIV 1 Env or entrapment of Env in the ER. The cell-associated, but not the secreted species of 90K, mediated the antiviral effect. A truncated version of human 90K, solely consisting of the two intermediate domains, displayed a similar antiviral activity as the full-length wildtype 90K, indicating that the N-terminal SRCR like domain and the C-terminal domain are dispensable for 90K's antiviral activity. The murine homolog of 90K, CypCAP (Cyclophilin C-associated protein), neither modulated particle infectivity of HIV-1 nor lowered the virion incorporation of mature gp120, suggesting a species-specific mode of action. 90K was expressed at basal levels in TZM-bl cells and in primary macrophages, and at low levels in CD4+ T-cells and PBMCs. 90K's susceptibility to IFN-mediated stimulation of expression was cell type-specific. siRNA-mediated knockdown of 90K in TZM-bl cells and primary macrophages enhanced the incorporation of Env glycoproteins into progeny virions, boosted the particle infectivity of released HIV-1, and accelerated HIV-1 spread. Conversely, treatment of HIV-1 infected macrophages with IFN-alpha induced 90K expression and lowered the particle infectivity of HIV-1. CONCLUSIONS: Thus, 90K constitutes a novel antiviral factor that reduces the particle infectivity of HIV-1, involving interference with the maturation and incorporation of HIV-1 Env molecules into virions. PMID- 24156547 TI - In-vitro methods for testing dermal absorption and penetration of toxic gases. AB - This technical note provides details of an experimental technique for in-vitro skin studies with atmospheric chemical challenge. There appear to be major evidence gaps in relation to dermal exposure of gases. We describe a modification of standard OECD protocols for an atmospheric delivery system which can be used to understand interaction of toxic gases and the skin. The system can be used to examine the mechanisms by which skin uptake occurs. Auxiliary components which allow for parameter variation such as temperature and relative humidity are also described. Methodology presented in this technical note uses examples of gas challenges (ammonia, chlorine) to illustrate its application to gases of differing physicochemical properties. This adapted protocol can be applied in the context of HAZMAT scenarios involving atmospheric toxic chemical release and dermal absorption potential under variable exposure conditions. PMID- 24156548 TI - Association between GSTP1 CpG methylation and the early phase of lead exposure. AB - CONTEXT: GSTP1 is induced by lead, and thus serves as a biomarker of lead exposure. Lead exposure changes DNA methylation status. OBJECTIVE: We attempted to prove that the methylation of the GSTP1 promoter plays an important role in lead toxicity. MATERIALS AND METHODS: We conducted a case-control study of 53 workers from a battery plant and 53 age and sex matched healthy volunteers to determine whether the methylation level of the GSTP1 promoter is associated with the risk of lead poisoning. We employed methylation-specific PCR (MSP) in cell models to determine the relationship between the GSTP1 methylation level and lead exposure. RESULTS: We found no association between GSTP1 methylation and lead exposure. The difference in methylation frequencies between the exposure group and the controls was not statistically significant (p = 0.401), and individuals with the methylated GSTP1 gene was not associated with the risk of lead poisoning (adjusted OR = 1.36, 95% CI, 0.22-8.24). CONCLUSION: This study suggests that GSTP1 methylation is not involved in the early phase of lead toxicity. Further studies should be performed to detect the association between GSTP1 methylation and the risk of lead poisoning in later phases. PMID- 24156549 TI - The CLUES study: a cluster randomized clinical trial for the evaluation of cardiovascular guideline implementation in primary care. AB - BACKGROUND: The appropriate care for people with cardiovascular risk factors can reduce morbidity and mortality. One strategy for improving the care for these patients involves the implementation of evidence-based guidelines. To date, little research concerning the impact of such implementation strategies in our setting has been published. Aims. To evaluate the effectiveness of a multifaceted tailored intervention in the implementation of three cardiovascular risk-related guidelines (hypertension, type 2 diabetes and dyslipidemia) in primary care in the Basque Health Service compared with usual implementation. METHODS/DESIGN: A two-year cluster randomized clinical trial in primary care in two districts in the Basque Health Service. All primary care units are randomized. Data from all patients with diabetes, hypertension and those susceptible to coronary risk screening will be analyzed.Interventions. The control group will receive standard implementation. The experimental group will receive a multifaceted tailored implementation strategy, including a specific web page and workshops for family physicians and nurses.Endpoints. Primary endpoints: annual request for glycosylated hemoglobin, basic laboratory tests for hypertension, cardiovascular risk screening (women between 45-74 and men between 40-74 years old). Secondary endpoints: other process and clinical guideline indicators. ANALYSIS: Data will be extracted from centralized computerized medical records. ANALYSIS will be performed at a primary care unit level weighted by cluster size. DISCUSSION: The main contribution of our study is that it seeks to identify an effective strategy for cardiovascular guideline implementation in primary care in our setting. TRIAL REGISTRATION: Current Controlled Trials, ISRCTN88876909. PMID- 24156550 TI - Electronic and nuclear structural snapshots in ligand dissociation and recombination processes of iron porphyrin in solution: a combined optical/X-ray approach. AB - The photodissociation and recombination of CO and 1-methylimidazole (Im) from iron protoporphyrin IX (FePP-ImCO) dissolved in a 30% v/v aqueous solution of Im was studied using ultrafast optical transient absorption (TA) and X-ray transient absorption (XTA) spectroscopies. FePP-ImCO was shown to lose the CO ligand upon excitation at the Q bands, with 3.8 ps vibrational cooling and 21.6 ps intersystem crossing time constants derived from optical TA experiments, followed by ligation of a second Im on the nanosecond time scale. The penta-coordinate FePP-Im intermediate which forms following CO dissociation adopts a square pyramidal geometry with a "domed" iron center that is reminiscent of that formed upon loss of CO from carbonmonoxymyoglobin (MbCO). Unlike MbCO, which typically retains its newly generated penta-coordinated geometry until CO recombination, FePP can adopt a hexa-coordinate geometry by binding an additional Im ligand (FePP-(Im)2), allowing the porphyrin to exist in the low-spin electronic state even without the CO attached. The second Im ligand remains bound until CO recombination occurs with a time constant of 283 MUs. The photodissociated states of FePP-ImCO and MbCO 100 ps after photoexcitation have similar iron site geometries, implying that the protein matrix in MbCO maintains minimum potential energy in the heme center despite the large-scale reorganization in the protein secondary and tertiary structure that arises from the dynamic active site/matrix interaction. PMID- 24156551 TI - KCTD20, a relative of BTBD10, is a positive regulator of Akt. AB - BACKGROUND: BTBD10 binds to Akt and protein phosphatase 2A (PP2A) and inhibits the PP2A-mediated dephosphorylation of Akt, thereby keeping Akt activated. Previous studies have suggested that BTBD10 plays an important role in preventing motor neuronal death and accelerating the growth of pancreatic beta cells. Because levels of BTBD10 expression are much lower in many non-nervous tissues than nervous tissues, there may be a relative of BTBD10 that has BTBD10-like function in non-neuronal cells. RESULTS: A 419-amino-acid BTBD10-like protein, named KCTD20 (potassium channel tetramerization protein domain containing 20), was to found to bind to all Akt isoforms and PP2A. Overexpression of KCTD20 increased Akt phosphorylation at Thr308, as BTBD10 did, which suggests that KCTD20 as well as BTBD10 positively regulates the function of Akt. KCTD20 was ubiquitously expressed in non-nervous as well as nervous tissues. CONCLUSIONS: KCTD20 is a positive regulator of Akt and may play an important role in regulating the death and growth of some non-nervous and nervous cells. PMID- 24156552 TI - Simple, miniaturized blood plasma extraction method. AB - A rapid plasma extraction technology that collects a 2.5 MUL aliquot of plasma within three minutes from a finger-stick derived drop of blood was evaluated. The utility of the plasma extraction cards used was that a paper collection disc bearing plasma was produced that could be air-dried in fifteen minutes and placed in a mailing envelop for transport to an analytical laboratory. This circumvents the need for venipuncture and blood collection in specialized vials by a phlebotomist along with centrifugation and refrigerated storage. Plasma extraction was achieved by applying a blood drop to a membrane stack through which plasma was drawn by capillary action. During the course of plasma migration to a collection disc at the bottom of the membrane stack blood cells were removed by a combination of adsorption and filtration. After the collection disc filled with an aliquot of plasma the upper membranes were stripped from the collection card and the collection disc was air-dried. Intercard differences in the volume of plasma collected varied approximately 1% while volume variations of less than 2% were seen with hematocrit levels ranging from 20% to 71%. Dried samples bearing metabolites and proteins were then extracted from the disc and analyzed. 25-Hydroxy vitamin D was quantified by LC-MS/MS analysis following derivatization with a secosteroid signal enhancing tag that imparted a permanent positive charge to the vitamin and reduced the limit of quantification (LOQ) to 1 pg of collected vitamin on the disc; comparable to values observed with liquid-liquid extraction (LLE) of a venipuncture sample. A similar study using conventional proteomics methods and spectral counting for quantification was conducted with yeast enolase added to serum as an internal standard. The LOQ with extracted serum samples for enolase was 1 MUM, linear from 1 to 40 MUM, the highest concentration examined. In all respects protein quantification with extracted serum samples was comparable to that observed with serum samples obtained by venipuncture. PMID- 24156553 TI - Numerical investigation of haemodynamics in a helical-type artery bypass graft using non-Newtonian multiphase model. AB - The classic single-phase Newtonian blood flow model ignores the motion of red blood cells (RBCs) and their interaction with plasma. To address these issues, we adopted a multiphase non-Newtonian model to carry out a comparative study between a helical artery bypass graft (ABG) and a conventional ABG in which the blood flow is composed of plasma and RBCs. The investigation focused on the mechanism of RBC buildup in an ABG but the haemodynamic parameters obtained by single-phase and multiphase models were also compared. The aggregation of RBCs along the inside wall of a conventional ABG and at the heel of its distal anastomosis was predicted while a poor aggregation was observed along the helical ABG. In addition, RBCs were observed to gradually sediment along the gravity direction. However, the computed haemodynamic parameters by multiphase model qualitatively agreed well with those by single-phase model. It was concluded that (1) the single-phase computational fluid dynamics (CFD) is reasonable to do the computation of haemodynamic parameters in ABGs; (2) secondary flow does not definitely produce buildup of RBCs in the inside curvature, its configuration played an important role in the movement of RBCs and the dominating one-way rotating flow in a helical ABG guaranteed no buildup of RBCs on its inside wall and (3) gravity direction is important for the movement of RBCs which may help to explain why doing exercise is good for human health. This study helps to shed light on the migration of RBCs in ABGs, which cannot be explored by single-phase CFD models, and provides more understanding of the underlying flow mechanism for ABG failure. PMID- 24156554 TI - Characterization of iprodione resistance in Botrytis cinerea from strawberry and blackberry. AB - Gray mold, caused by the fungal pathogen Botrytis cinerea, is one of the most destructive diseases of strawberry. Control of the disease in commercial fields is largely dependent on the application of fungicides, including the dicarboximide iprodione. Single-spore isolates were collected from strawberry fields in Florida, North Carolina, and South Carolina and subjected to an assay using conidial germination that distinguished sensitive (S) isolates from isolates with various levels of resistance to iprodione. Of the 245 isolates, 1 was highly resistant (HR), 5 were moderately resistant (MR), and 43 had low resistance (LR) to iprodione. LR and MR strains were found in the Florida population and in 9 of 11 locations from North Carolina and South Carolina, indicating that resistance was widespread but accounted for only a relatively small percentage of the B. cinerea population. Sequence analysis of the target gene bos1, which codes for a class III histidine kinase, revealed that the MR phenotype was associated with Q369P and N373S mutations and that the LR phenotype was associated with either a I365S or a I365N mutation. The I365S and I365N mutations were also present in five additionally included HR isolates from North Carolina and South Carolina blackberry fields and one HR isolate from a Virginia strawberry field but no mutation or mutation combinations in bos1 were uniquely associated with the HR phenotype. Expression analysis of bos1 in S and HR isolates did not reveal convincing evidence of the gene's involvement in HR resistance either. The six HR isolates had three different phenotypes with respect to their sensitivity to fludioxonil; two were S, two were LR, and two were MR. The fludioxonil LR and MR isolates were also resistant to tolnaftate, an indication of multidrug efflux pump activity. These data suggest that, in addition to point mutations in bos1, drug efflux pump activity and potentially a third mechanism of resistance may be contributing to the iprodione HR phenotype. Detached fruit studies showed that field rates of Rovral 4 Flowable (iprodione) did not control iprodione MR and HR isolates. PMID- 24156555 TI - Evaluation of the pharmacokinetics and drug interactions of the two recently developed statins, rosuvastatin and pitavastatin. AB - INTRODUCTION: Statins are the cornerstone of lipid-lowering therapy to reduce the risk of coronary heart disease. Rosuvastatin and pitavastatin are the two recently developed statins with less potential for drug interaction resulting in improved safety profiles. AREAS COVERED: This review summarizes the pharmacokinetics and drug interactions of rosuvastatin and pitavastatin. The materials reviewed were identified by searching PubMed for publications using 'rosuvastatin', 'pitavastatin', 'statins', 'pharmacokinetics' and 'drug interaction' as the search terms. EXPERT OPINION: Rosuvastatin and pitavastatin have favorable pharmacokinetic and safety profiles as their disposition does not depend on or is only marginally influenced by cytochrome P450 (CYP) enzymes, thus potentially reducing the risk of drug-drug interactions of these two statins with other drugs known to inhibit CYP enzymes. However, drug transporters play a significant role in the disposition of rosuvastatin and pitavastatin and drug interactions may occur through these. Genetic polymorphisms in drug transporters may also affect the pharmacokinetics, drug interactions and/or the lipid-lowering effect of these statins to a different extent. PMID- 24156557 TI - New insights into inhibition of human immunodeficiency virus type 1 replication through mutant tRNALys3. AB - BACKGROUND: Host cellular tRNA(Lys3) is exclusively utilized by human immunodeficiency virus type 1 (HIV-1) as a primer for the replication step of reverse transcription (RTion). Consequently, the priming step of HIV-1 RT constitutes a potential target for anti-HIV-1 intervention. Previous studies indicated that a mutant tRNA(Lys3) with 7-nucleotide substitutions in the 3' terminus resulted in aberrant HIV-1 RTion from the trans-activation response region (TAR) and inhibition of HIV-1 replication. However, the mutant tRNA(Lys3) also directed HIV-1 RTion from the normal primer-binding site (PBS) with potentially weakened anti-HIV-1 activity. To achieve improved targeting of HIV-1 RTion at sites not including the PBS, a series of mutant tRNA(Lys3) with extended lengths of mutations containing up to 18 bases complementary to their targeting sites were constructed and characterized. RESULTS: A positive correlation between the length of mutation in the 3' PBS-binding region of tRNA(Lys3) and the specificity of HIV-1 RTion initiation from the targeting site was demonstrated, as indicated by the potency of HIV-1 inhibition and results of priming assays. Moreover, two mutant tRNA(Lys3)s that targeted the IN-encoding region and Env gene, respectively, both showed a high anti-HIV-1 activity, suggesting that not only the TAR, but also distant sites downstream of the PBS could be effectively targeted by mutant tRNA(Lys3). To increase the expression of mutant tRNA(Lys3), multiple-copy expression cassettes were introduced into target cells with increased anti-HIV-1 potency. CONCLUSIONS: These results highlight the importance of the length of complementarity between the 3' terminus of the mutant tRNA(Lys3) and its target site, and the feasibility of targeting multiple sites within the HIV-1 genome through mutant tRNA(Lys3). Intervention of the HIV-1 genome conversion through mutant tRNA(Lys3) may constitute an effective approach for development of novel therapeutics against HIV-1 replication and HIV-1-associated diseases. PMID- 24156558 TI - The 40-Something randomized controlled trial to prevent weight gain in mid-age women. AB - BACKGROUND: Obesity prevention is a major public health priority. Despite the health risks associated with weight gain, there has been a distinct lack of research into effective interventions to prevent, rather than treat, obesity particularly at high risk life stages such as menopause in women. This paper describes the rationale for and design of a 2-year randomized controlled trial (RCT) (the 40-Something Study) aimed at testing the feasibility and efficacy of a relatively low intensity intervention designed to achieve weight control in non obese women about to enter the menopause transition. METHODS AND DESIGN: The study is a parallel-group RCT consisting of 12 months of intervention (Phase 1) and 12 months of monitoring (Phase 2). Non-obese pre-menopausal healthy females 44-50 years of age were screened, stratified according to Body Mass Index (BMI) category (18.5-24.9 and 25-29.9 kg/m2) and randomly assigned to one of two groups: motivational interviewing (MI) intervention (n = 28), or a self-directed intervention (SDI) (control) (n = 26). The MI intervention consisted of five consultations with health professionals (four with a Dietitian and one with an Exercise Physiologist) who applied components of MI counselling to consultations with the women over a 12 month period. The SDI was developed as a control and these participants received print materials only. Outcome measures were collected at baseline, three, 12, 18 and 24 months and included weight (primary outcome), waist circumference, body composition, blood pressure, plasma markers of metabolic syndrome risk, dietary intake, physical activity and quality of life. Analysis of covariance will be used to investigate outcomes according to intervention type and duration (comparing baseline, 12 and 24 months). DISCUSSION: The 40-Something study is the first RCT aimed at preventing menopausal weight gain in Australian women. Importantly, this paper describes the methods used to evaluate whether a relatively low intensity, health professional led intervention will achieve better weight control in pre-menopausal women than a self-directed intervention. The results will add to the scant body of literature on obesity prevention methods at an under-researched high-risk life stage, and inform the development of population-based interventions. TRIAL REGISTRATION: ACTRN12611000064909. PMID- 24156559 TI - A clinical study of canine collagen type III glomerulopathy. AB - BACKGROUND: Collagen type III glomerulopathy (Col3GP), also known as collagenofibrotic glomerulonephropathy, is a rare renal disease with unknown pathogenesis that occurs in animals and humans. We recently described a naturally occurring canine autosomal recessive model of Col3GP, and the aim of the present work was to study the clinical features of canine Col3GP and compare with the human phenotype. In humans two different clinical syndromes with different age at onset (child- or adulthood) have been observed. In children a more aggressive course with familial occurrence is described, characterized by progressively increasing proteinuria, nephrotic syndrome, hypertension and chronic renal failure. A markedly increased serum level of the aminoterminal propeptide of type III procollagen (PIIINP) is considered a useful marker for the disease. Since Col3GP and concurrent hypocomplementemia have been observed in humans, we also aimed to investigate if hypocomplementemia was present in Col3GP affected dogs. A litter consisting of seven puppies, four Col3GP affected and three healthy unaffected, was observed from the day of birth until the affected puppies developed a mild or moderate renal azotemia. RESULTS: During the period of observation growth retardation, increasing blood pressure, progressive proteinuria, azotemia, hypoalbuminemia, hypercholesterolemia and increased serum PIIINP were observed in all the affected dogs. Hypocomplementemia was not detected. Affected dogs were euthanized between 109 and 144 days of age, and pathological examinations revealed ascites and massive glomerular accumulations of collagen type III, consistent with Col3GP. CONCLUSIONS: Dogs with Col3GP develop juvenile chronic renal failure, preceded by nephrotic syndrome, elevated serum PIIINP and hypertension, thus have similar clinical features as the juvenile Col3GP in humans. Further studies of this naturally occurring canine phenotype may provide more information on the pathogenesis and genetics of Col3GP in both animals and humans. PMID- 24156561 TI - Synthesis, characterization and reactivity of group 4 metallocene bis(diphenylphosphino)acetylene complexes-a reactivity and bonding study. AB - A study of the coordination chemistry of bis(diphenylphosphino)acetylene, Ph2P C=C-PPh2, with selected group 4 metallocenes is presented. By substitution of the alkyne in complexes of the type Cp'2M(L)(eta(2)-Me3SiC2SiMe3) (M = Ti, no L; M = Zr, L = pyridine; Cp' = substituted or unsubstituted bridged or unbridged eta(5) cyclopentadienyl), the expected mononuclear complexes Cp*2Ti(eta(2)-Ph2PC2PPh2) (4Ti), (rac-ebthi)Ti(eta(2)-Ph2PC2PPh2) (5Ti), and (rac-ebthi)Zr(eta(2) Ph2PC2PPh2) (5Zr) [ebthi = ethylenebis(tetrahydroindenyl)] were obtained. When [Cp2Zr] was used in the reaction of Cp2Zr(py)(eta(2)-Me3SiC2SiMe3) with Ph2P-C=C PPh2, the dinuclear complex [Cp2Zr(eta(2)-Ph2PC2PPh2)]2 (6) was formed and isolated in the solid state. In solution, this complex is in equilibrium with the very spectacular structure of complex 7b as the first example of such a highly strained four-membered heterometallacycle of a group 4 metal, involving the rare R2PCCR' fragment in the cyclic unit. Both the stability and reactivity of heterodisubstituted alkynes X-C=C-X (X = NR2, PR2, SR, SiR3, etc.) themselves and also of their complexes are of general interest. Complex 6 did not react with a second [Cp2Zr] fragment to form a homobimetallic complex. In contrast, for (rac ebthi)Zr(eta(2)-Ph2PC2PPh2) (5Zr) this reaction occurs. In the reaction of complex 4Ti with the Ni(0) complex (Cy3P)2Ni(eta(2)-C2H4) (Cy = cyclohexyl), C-P bond cleavage of the alkyne ligand resulted in the formation of the isolated complex [(Cy3P)Ni(MU-PPh2)]2 (11). The structure and bonding of the complexes were investigated by DFT analysis to compare the different possible coordination modes of the R2P-C=C-PR2 ligand. For compound 7b, a flip-flop coordination of the phosphorus atoms was proposed. Complexes 4Ti, 5Ti, 5Zr, 6, and 11 were characterized by X-ray crystallography. PMID- 24156560 TI - Ruthenium catalyzed hydrohydroxyalkylation of isoprene with heteroaromatic secondary alcohols: isolation and reversible formation of the putative metallacycle intermediate. AB - Heteroaromatic secondary alcohols react with isoprene to form products of hydrohydroxyalkylation in the presence of ruthenium(0) catalysts generated from Ru3(CO)12 and tricyclohexylphosphine, enabling direct conversion of secondary to tertiary alcohols in the absence of premetalated reagents or stoichiometric byproducts. The putative oxaruthenacycle intermediate has been isolated and characterized, and reversible metallacycle formation has been demonstrated. PMID- 24156562 TI - Enhanced antibacterial activity of silver/polyrhodanine-composite-decorated silica nanoparticles. AB - This work describes the synthesis of silver/polyrhodanine-composite-decorated silica nanoparticles and their antibacterial activity. Polymerization of polyrhodanine proceeded preferentially on the surface of the silica nanoparticles where Ag(+) ions were located. In addition, the embedded Ag(+) ions were reduced to form metallic Ag nanoparticles; consequently, silver/polyrhodanine-composite nanoparticles (approximately 7 nm in diameter) were formed on the surface of the silica nanoparticles. The resulting nanostructure was investigated using electron microscopy, Fourier-transform infrared spectroscopy, ultraviolet-visible spectroscopy, and X-ray photoelectron spectroscopy. The silver/polyrhodanine nanocomposite-decorated silica nanoparticles exhibited excellent antimicrobial activity toward gram-negative Escherichia coli and gram-positive Staphylococcus aureus because of the antibacterial effects of the silver nanoparticles and the polyrhodanine. The silver/polyrhodanine-composite nanoparticles may therefore have potential for use as a long-term antibacterial agent. PMID- 24156563 TI - Bioactive components from flowers of Sambucus nigra L. increase glucose uptake in primary porcine myotube cultures and reduce fat accumulation in Caenorhabditis elegans. AB - Obesity and insulin resistance in skeletal muscles are major features of type 2 diabetes. In the present study, we examined the potential of Sambucus nigra flower (elderflowers) extracts to stimulate glucose uptake (GU) in primary porcine myotubes and reduce fat accumulation (FAc) in Caenorhabditis elegans. Bioassay guided chromatographic fractionations of extracts and fractions resulted in the identification of naringenin and 5-O- caffeoylquinic acid exhibiting a significant increase in GU. In addition, phenolic compounds related to those found in elderflowers were also tested, and among these, kaempferol, ferulic acid, p-coumaric acid, and caffeic acid increased GU significantly. FAc was significantly reduced in C. elegans, when treated with elderflower extracts, their fractions and the metabolites naringenin, quercetin-3-O-rutinoside, quercetin-3-O-glucoside, quercetin-3-O-5"-acetylglycoside, kaempferol-3-O rutinoside, isorhamnetin-3-O-rutinoside, and isorhamnetin-3-O-glucoside and the related phenolic compounds kaempferol and ferulic acid. The study indicates that elderflower extracts contain bioactive compounds capable of modulating glucose and lipid metabolism, suitable for nutraceutical and pharmaceutical applications. PMID- 24156564 TI - Synthesis of isoquinolines via Rh(III)-catalyzed C-H activation using hydrazone as a new oxidizing directing group. AB - An efficient and mechanistically interesting method for the synthesis of highly substituted isoquinolines by a Rh(III)-catalyzed hydrazone directed ortho C-H bond activation and annulation without an external oxidant is described. This reaction is accomplished via a C-C and C-N bond formation along with N-N bond cleavage. PMID- 24156565 TI - Reaching "an audience that you would never dream of speaking to": influential public health researchers' views on the role of news media in influencing policy and public understanding. AB - While governments and academic institutions urge researchers to engage with news media, traditional academic values of public disengagement have inhibited many from giving high priority to media activity. In this interview-based study, the authors report on the views about news media engagement and strategies used by 36 peer-voted leading Australian public health researchers in 6 fields. The authors consider their views about the role and importance of media in influencing policy, their reflections on effective or ineffective media communicators, and strategies used by these researchers about how to best retain their credibility and influence while engaging with the news media. A willingness and capacity to engage with the mass media was seen as an essential attribute of influential public health researchers. PMID- 24156566 TI - Once daily glycopyrronium for the treatment of COPD: pooled analysis of the GLOW1 and GLOW2 studies. AB - BACKGROUND: Glycopyrronium is a once daily (o.d.) long-acting muscarinic antagonist that is approved for maintenance treatment of COPD. This post-hoc pooled analysis of two phase III studies, GLycopyrronium bromide in COPD airWays 1 and 2 (GLOW1 and GLOW2), evaluated the effects of glycopyrronium compared with placebo and tiotropium over 26-52 weeks in patients with moderate-to-severe COPD. METHODS: Patients aged>=40 years were randomised to 26 weeks' treatment with glycopyrronium 50 MUg o.d. or placebo (GLOW1) or 52 weeks' treatment with glycopyrronium 50 MUg o.d., placebo, or open-label tiotropium 18 MUg o.d. (GLOW2). The primary efficacy endpoint in both studies was trough forced expiratory volume in one second (FEV1) at Week 12. Other outcomes included additional spirometry endpoints, moderate or severe exacerbations, dyspnoea, health status, rescue medication use and safety. Serial spirometry over 24 hours was conducted in a subset of patients. RESULTS: Of 1888 subjects randomised, 98.2% were analysed (glycopyrronium 1059, tiotropium 267, placebo 528). Least squares mean (LSM) trough FEV1 was significantly higher with glycopyrronium versus placebo at Week 12 (treatment difference+/-standard error [SE]: 103+/-11.2 mL; p<0.001), as well as at Day 1 and Weeks 26 and 52. More patients achieved>=100 mL increase in trough FEV1 from baseline with glycopyrronium versus placebo at all assessments (p<0.001). Glycopyrronium significantly improved FEV1 immediately after the first dose on Day 1 versus placebo (90 mL at 5 minutes, 144 mL at 15 minutes; both p<0.001) and versus tiotropium (43 mL at 5 minutes, 65 mL at 15 minutes; both p<0.001). Glycopyrronium significantly improved other spirometry endpoints and provided clinically meaningful 24 hour bronchodilation versus placebo at most timepoints from Day 1 onwards (p<0.05). Time to first moderate or severe exacerbation was significantly prolonged with glycopyrronium versus placebo over 26 and 52 weeks (36% and 33%, respectively; both p < 0.001). Glycopyrronium provided significantly greater relief of dyspnoea, improved health status and reduced rescue medication use versus placebo. Glycopyrronium was safe and well tolerated. CONCLUSIONS: Glycopyrronium 50 MUg o.d. provided early bronchodilation after the first dose that was sustained for 24 hours, and reduced the risk of exacerbations compared with placebo, with efficacy at least equivalent to tiotropium. TRIAL REGISTRATIONS: NCT01005901 and NCT00929110. PMID- 24156567 TI - Potential-assisted adsorption of bovine serum albumin onto optically transparent carbon electrodes. AB - This article describes the effect of the applied potential on the adsorption of bovine serum albumin (BSA) to optically transparent carbon electrodes (OTCE). To decouple the effect of the applied potential from the high affinity of the protein for the bare surface, the surface of the OTCE was initially saturated with a layer of BSA. Experiments described in the article show that potential values higher than +500 mV induced a secondary adsorption process (not observed at open-circuit potential), yielding significant changes in the thickness (and adsorbed amount) of the BSA layer obtained. Although the process showed a significant dependence on the experimental conditions selected, the application of higher potentials, selection of pH values around the isoelectric point (IEP) of the protein, high concentrations of protein, and low ionic strengths yielded faster kinetics and the accumulation of larger amounts of protein on the substrate. These experiments, obtained around the IEP of the protein, contrast with the traditional hypothesis that enhanced electrostatic interactions between the polarized substrate and the (oppositely charged) protein are solely responsible for the enhanced adsorption. These results suggest that the potential applied to the electrode is able to polarize the adsorbed layer and induce dipole dipole interactions between the adsorbed and the incoming protein. This mechanism could be responsible for the potential-dependent oversaturation of the surface and could bolster to the development of surfaces with enhanced catalytic activity and implants with improved biocompatibility. PMID- 24156569 TI - The anatomy of ulnar nerve branches in anterior transposition. AB - Cubital tunnel syndrome is the second most common nerve entrapment neuropathy. When non-operative treatments fail, surgical intervention is indicated. Although there remains no consensus between simple decompression and anterior transposition, there is a growing recognition of improved clinical outcomes in the latter. Few details of ulnar nerve branches around the elbow are available however and their sacrifice may be necessary to facilitate anterior transposition. Therefore, ten cadaveric upper extremities were dissected to delineate the course and branching pattern of the ulnar nerve around the elbow joint; anterior transposition was also performed in the cadaveric specimens. Digital photographs of the dissection study were analyzed using the Image J package. Results show that distal ulnar nerve branches are distributed more laterally towards the olecranon and may potentially restrict transposition more than has been recognized; proximal branches may also overlap incision lines of such transposition procedures. PMID- 24156568 TI - How well can physicians manage tuberculosis? A public-private sector comparison from Karachi, Pakistan. AB - BACKGROUND: Tuberculosis (TB) is endemic in Pakistan which ranks fifth amongst the twenty two countries designated to be highly burdened by TB according to the World Health Organization. However, there is paucity of data regarding the knowledge of diagnosis of TB and its management amongst public and private practitioners. In this study, we endeavor to identify this gap in knowledge regarding the diagnosis and management of TB between public and private doctors and the factors affecting these knowledge scores in urban Pakistan. METHODS: This cross sectional survey was conducted between June and December 2011. Doctors from public hospitals, private hospitals and private clinics scattered in all eighteen towns of Karachi were included in the study. Qualified MBBS doctors working in any specialty were eligible to participate whereas doctors working in both the public and private sectors were excluded from the study. Vignette based clinical scenarios were given to assess the knowledge score regarding the diagnosis and management of TB. RESULTS: A total of 196 doctors participated in the study. There was a significant difference between private and public physicians in terms of age and years of practice (p-value <0.05). Significant differences in the proportion of knowledge scores were observed between the public and private doctors and National TB Control Program trained and untrained doctors in Karachi. Factors associated with inadequate knowledge scores were being female gender [OR: 2.76 (95% CI: 1.418-5.384)], private employment status [OR: 1.50 (95% CI: 1.258 2.439)], and not trained by NTP [OR: 2.98 (95% CI: 1.286-3.225)] on multivariate logistic regression analysis. CONCLUSION: It is concluded that a knowledge gap exists between the public and private doctors in Karachi. Strengthening of currently implemented public private mix model along with improvement in the trainings of public and private practitioners is highly recommended to control TB in Pakistan. PMID- 24156570 TI - Epidemiology of hand infection--a comparative study between year 2000 and 2009. AB - This study aims to analyze the bacteriology and antibiotic resistance in hand infection between 2000 and 2009 at a local hospital in Asia. It is a retrospective study involving all adult patients with hand infections that were treated surgically, with tissue or wound culture sent. A total of 100 cases in 2000 and 98 cases in 2009 were included in this study. Standard epidemiology information, bacteriology, antibiotic sensitivity and treatment outcome were analyzed. Particular interest was given to diabetic hand infection. There was no significant difference of outcome in hand infection between the two years. The outcome of diabetics was not statistically worse than the non-diabetics. Comparing the patients in 2000 and 2009, more younger patients were affected with hand infection in 2009. While length of stay is shorter in 2009. Mixed infection was more common in diabetics in 2009. There was trend of clindamycin resistance in methicillin-sensitive staphylococcus aureus in 2009. PMID- 24156571 TI - Assessing the variability of injectate distribution following carpal tunnel injection--a cadaveric study. AB - This anatomical study was designed to assess the distribution of a solution (injectate) made up using local anesthetic, steroid and dye into the carpal tunnel using a commonly used injection technique. Dissections were undertaken in 29 embalmed cadaveric wrists. The cadaveric specimens were dissected 24 hours after injection to observe the effect of time on diffusion patterns in both superficial and deep planes. Eighteen of the 29 specimens showed the presence of the injectate in the superficial plane and three preferential patterns of distribution were noted in the deep plane: free in the carpal tunnel, exclusively in the tendon sheath and mixed. This is the first study investigating the delayed diffusion pattern of injectate in the carpal tunnel and illustrates its variability. The findings of variable degree of superficial diffusion and different patterns of intracarpal spread help to offer some explanation regarding the variability of the response following carpal tunnel injection. PMID- 24156572 TI - Retrospective analysis of five-year and longer clinical and electrophysiological results of the world's first endoscopic management for carpal tunnel syndrome. AB - We have analyzed postoperative long-term follow-up results of five years or more from idiopathic carpal tunnel syndrome patients that underwent our complete carpal canal release and decompression procedure that uses the Universal Subcutaneous Endoscope system. In this series, 203 hands were followed up both clinically and electrophysiologically. Final follow-up times were determined by the most recent electrophysiological measurements. Mean follow-up period was nine years. Tingling, pain (using a 3 gm needle) and touch (using a 2 gm von Frey hair) at all median nerve distribution areas recovered to normal in 92.9, 98.2, 95.2%, respectively. Abductor pollicis brevis muscle power improved from preoperative manual muscle testing of 0, 1, 2 to post-operative 4 or 5 in 82.6%. Mean detectable distal sensory latency improved from 4.3 (n = 130) to 3.1 msec (n = 200). Mean detectable distal motor latency improved from 6.2 (n = 189) to 4.1 msec (n = 200). Complication and recurrence rates were 0% and 0.5% respectively. PMID- 24156573 TI - Continuous infraclavicular brachial plexus blockade: effect on survival of replanted digits. AB - In replantation surgery, the use of continuous brachial plexus blockade (CBPB) is popular as it improves postoperative analgesia and vascular flow. The aim of our study was to determine whether CBPB may affect the odds of survivability of replanted digit(s). A four-year retrospective chart review was performed and various parameters affecting replant survival were examined. Outcome was recorded as successful if the transplanted digit(s) survived six months after discharge. All the independent variables were forced into a regression model without using a specific variable selection algorithm. The data for 146 patients was obtained from our chart review. The success rate of replanted digits in the patients reviewed was 65.8%. The logistic regression model showed a relation between the number of digits injured and replanted digit(s) survival. Our study showed that CBPB has no effect on the survivability of the replanted digit(s) till six months after hospital discharge. PMID- 24156574 TI - Beware! The volar ulnar fragment in a comminuted Bartons fracture. AB - The purpose of this study is to highlight a cohort of patients with a comminuted volar shearing type of distal radius fractures (AO B3.3) with the volar ulnar fragment that is prone to re-displace, resulting in volar subluxation of the radiocarpal joint. We report our experience with two such patients with re displacement of the fragment and joint requiring repeat surgery; one of whom required a third procedure to stabilize that fragment. Three subsequent patients were successfully treated with one surgery when particular attention was paid to stabilize the volar ulnar fragment. This highlights the importance of stabilizing this fragment at the primary procedure. PMID- 24156575 TI - Poor results of radio-scaphoid capsulodesis for scapholunate dissociation. AB - We reviewed 17 patients 64 (range 29-123) months after dorsal radioscaphoid capsulodesis for scapholunate dissociation. Mean loss of key pinch was 13%, grip strength 18%, wrist flexion 22% (p < 0.001), and total wrist ROM 17% (p < 0.005). VAS (0 = best; 100 = worst) was 30(+/-28) for pain, 43(+/-30) for function, and 33(+/-33) for general satisfaction with the outcome. Mean Quick-DASH and PRWE scores were 27 and 34, respectively. The mean scapholunate gap was 3.5 mm before surgery, 1.9 mm after surgery, and 3.3 mm at review. The corresponding scapholunate angles were 63 degrees , 46 degrees , and 70 degrees , respectively. The mean radioscaphoid angle with the wrist maximally flexed was 84 degrees (69 99) for the patients and was 91 degrees (77-103) in ten wrists of volunteers. Six patients had changed their jobs because of the wrist. Three patients stated that they would not have consented to operation if they had known the outcome in advance. Radioscaphoid capsulodesis does not prevent volar flexion of the scaphoid. PMID- 24156576 TI - Bioabsorbable fixation of scaphoid fractures and non-unions; analysis of early clinical outcomes. AB - The vast majority of devices used for internal fixation of the scaphoid are metallic. This two-center study aimed to report the results of scaphoid fixation using a cannulated, bioabsorbable device made from a hydroxyapatite and poly-L lactide composite in 29 consecutive patients. Fixation was performed for seven acute fractures and twenty-two established non-unions. Union was achieved in 72.4% of patients. Six of the acute fractures and fifteen of the non-unions united successfully. Modified Mayo Wrist Score ranged between good to excellent in all patients who successfully united, whereas patients who failed to unite ranged between poor to excellent, with one poor and two moderate scores. No adverse biocompatibility reactions were seen. Two failures with broken screws were re-explored and one of these was thought to be due to screw mal-placement. The device used is an alternative to conventional metal implants and produces comparable union rates to metallic devices in the short term. PMID- 24156577 TI - Accurate quantitative measurement of lunate uncovering ratio--is Gilula's semiquantitative test reliable? AB - The Gilula's test suggests the presence of ulnocarpal translation when 50% or more of the lunate lies medial to the ulnar edge of radius. The purpose of this study was to examine the reliability of this semiquantitative test as there was inconsistency between the previous publications in regarding 50% as the cutoff value for the normal lunate uncovering ratio (LUR). We utilized the Picture Archiving and Communication System to investigate radiographs of 299 normal adult wrists and emphasized defined radiographic landmarks for accurate quantitative measurement. Our mean LUR was 35%(SD8) with a range of 8 to 49%. Therefore we re affirmed the reliability of the Gilula's test since none of our normal wrists had a LUR of 50% or greater. PMID- 24156578 TI - High incidence of hamate hook fractures in underwater rugby players: diagnostic and therapeutic implications. AB - Hamate hook fractures are rare injuries but appear to occur frequently in underwater rugby, the reason for which was investigated in this study. High-level underwater rugby players with hook fractures diagnosed during a five-year interval (2005-2010) were studied retrospectively. Medical data on these patients were reviewed for information on the mechanism of injury, type of fracture, radiological imaging, treatment, and outcome. In ten patients, hook fractures of the leading hand were confirmed by computed tomography, all of which were associated with specific injuries during underwater rugby games. Conservative treatment resulted in delayed healing or non-union, wherefore fragment excision and open reduction and internal fixation was performed in ten and five patients, respectively, while two patients declined surgery. After surgery, all patients were able to play underwater rugby again. In underwater rugby, hook fractures occur frequently due to high and repeated forces applied to the leading hand during games. PMID- 24156579 TI - Trapeziectomy with ligament reconstruction and tendon interposition: a minimum 10 year follow-up. AB - PURPOSE: To investigate the long-term (> 10 yrs) outcomes of trapeziectomy with ligament reconstruction and tendon interposition (LRTI). METHODS: We reviewed 15 cases of trapeziectomy with LRTI performed for the treatment trapeziometacarpal osteoarthritis. Mean follow up was 13.5 yrs (range, 10.5-17.5 yrs). We assessed a number of subjective and objective outcomes. A good outcome was a participant who did not require revision surgery, was satisfied with the outcome of their surgery and did not experience rest pain. RESULTS: No patients had revision surgery and only two patients were unsatisfied or very unsatisfied with the outcome of their surgery. Pain with activity was the strongest predictor of participant satisfaction. DISCUSSION: Approximately half the participants in this study experienced good long-term outcomes. Some participants were experiencing long term symptoms, particularly pain, despite reporting that they are satisfied with the outcome of their surgery. Alternative techniques should be investigated that provide superior long-term outcomes. PMID- 24156580 TI - Five to eight years follow-up for trapeziectomy and Weilby ligament reconstruction for the treatment of trapeziometacarpal osteoarthritis. AB - Trapeziectomy and Weilby ligament reconstruction is a recognized treatment for osteoarthritis of the trapeziometacarpal joint. Studies published using this procedure have limited follow-up post-surgery. In this series of 24 cases assessed objectively and 36 subjectively with a minimum follow-up of five years, patients continue to have pain relief and function comparable to the opposite non operated hand. Patient satisfaction is high at 92% and the rate of complications is low. Despite these encouraging results the need for interposition arthroplasty and/or ligament reconstruction in addition to trapeziectomy alone is discussed. PMID- 24156581 TI - Outcome of traction tenolysis in open trigger finger release--a retrospective review. AB - Surgical treatment for trigger finger involves division of the A1 pulley. Some surgeons perform an additional step of traction tenolysis by sequentially bringing the flexor digitorum superficialis and flexor digitorum profundus tendons out of the wound gently with a Ragnell retractor. There is currently no study which states whether flexor tendon traction tenolysis should be routinely performed or not. The objective of this study is to compare the outcome in patients who have traction tenolysis performed (A group) versus those who did not have traction tenolysis (B group) performed. It was noted that even though the mean total active motion (TAM) for the B group in our study was lower preoperatively, it was consistently higher than the A group in all the 3 post operative visits demonstrating a better outcome in the B group. Even though it was not statistically significant, our data also showed that patients with traction tenolysis appeared to have more postoperative pain compared to those without. PMID- 24156582 TI - Peak load resistance of the JuggerKnotTM soft anchor technique compared with other common fixation techniques for large mallet finger fractures. AB - INTRODUCTION: To identify the strongest peak load resistance among four mallet finger fracture fixation methods (Kirschner wire, pull-out wire, tension-band wiring and the JuggerKnotTM (Biomet) soft anchor fixation). METHODS: Fixation techniques were assigned among 24 specimens from six cadaveric human hands in a randomized block fashion. Peak load resistance was tested at 30 degrees , 45 degrees and 60 degrees of flexion of the distal interphalangeal joint. RESULTS: The mean peak load of tension-band wiring was 67.8 N at 60 degrees of flexion which was most superior. The JuggerKnotTM fixation had mean peak loads of 13.35 N (30 degrees ), 22.51 N (45 degrees ) and 32.96 N (60 degrees ). No complications of implant failure or fragmentation of the dorsal fragment was noted. CONCLUSIONS: Tension-band wiring was the strongest fixation method but was most prominent on the skin surface as seen in three specimens. The JuggerKnotTM soft anchor fixation had similar peak load resistance as k-wire fixation and pull-out wiring. PMID- 24156583 TI - Non-union of isolated radial neck fracture using a bone graft and temporary K wire fixation: a case report. AB - INTRODUCTION: Non-union of radial neck fractures is not common in adults, and surgical treatment is rarely required. This case report documents non-union of the radial neck with persistent pain around the elbow joint and tenderness over the neck of the radius, limited range of motion for 12 months. The authors performed an iliac bone graft and temporary K-wire fixation for non-union of the radial neck after an isolated radial neck fracture. CASE PRESENTATION: A 54-year old woman slipped with her hand outstretched 12 months prior to presentation. She was diagnosed with a radial neck fracture, but her injury was eventually diagnosed as a non-union fracture, and she was transferred to our hospital. The patient had tenderness of the radial head and neck and an increasing tendency of pain in the forearm during external rotation with resistance. Flexion was a maximum of 80 degrees , extension was limited to 20 degrees , and internal rotation and external rotation were decreased to 60 degrees . On plain radiographs, a clear radiolucent shadow was present between the bone fragment and radius. After the autogenous iliac bone graft, a temporary K-wire was fixed, and at eight weeks postoperatively, the bone was united. The patient is in the month 24 of postoperative follow-up and is able to perform daily activities without tenderness. CONCLUSION: If elbow joint pain, tenderness, and limitation of range of motion are present in non-union of radial neck fracture, surgical treatment is necessary. If there is no injury to the ligament around the elbow or instability, the authors consider bone graft and temporary K-wire fixation as an excellent treatment option for bony union and early exercise of the joint. PMID- 24156584 TI - Supernumerary flexor carpi ulnaris--case report and review. AB - Anomalies of Flexor carpi ulnaris (FCU) are uncommon and predominantly consist of abnormal insertion or extra tendinous bands. The presence of two separate bellies of FCU muscle with separate tendons has been termed as Digastric FCU. It is a very rare anomaly with only six previously reported cases and no report of clinical use of such anomalous muscle. We describe a case of anomalous FCU found incidentally in a patient operated for complex Post Volkmann's ischemic contracture deficits. On table each head of FCU was found to form separate belly and tendon. One tendon was used for the thumb opposition while the other for index finger flexion. Postoperatively, the patient had independent movement of thumb and index finger. This is the first reported case of clinical application of digastric FCU. We reviewed the literature for supernumerary FCU in general and digastric FCU in particular. We propose a new classification for supernumerary FCUs based on the clinical appearance and the probable embryological basis of the anomaly: Type 1 (Split tendons)--single muscle with two tendons; Type 2 (Digastric FCU)--for each head of FCU forming separate muscle bellies and tendons; and Type 3 (Accessory FCU)--abnormal muscle adjacent to normal FCU with combined features of FCU and Palmaris longus. PMID- 24156585 TI - Primary shortening of the forearm and Sauve-Kapandji for severely comminuted fractures of the distal forearm in elderly patients: a case report. AB - We report a case of an elderly female who sustained a severely comminuted distal radial and ulnar fracture, treated by shortening of the forearm, combined with a primary Sauve-Kapandji procedure and volar plating of the distal radius. PMID- 24156586 TI - Flexor pollicis longus tendon entrapment after performing minimally invasive plate osteosynthesis of a distal radius fracture: a case report. AB - In this study, we report a case of a 60-year-old woman with diabetes mellitus, who had a left distal radius fracture and could not flex the interphalangeal joint of her left thumb after we performed an open reduction and internal fixation procedure using minimally invasive plate osteosynthesis. Nine days after the first operation, we explored her wrist. We observed that the flexor pollicis longus tendon was compressed by the inserted plate. Then revision surgery and tendon repair were performed. Three months later, the fracture was healed and flexor pollicis longus function recovered well without sequelae. Approach through the interval between flexor carpi radialis and radial artery is preferred to prevent tendon entrapement. PMID- 24156587 TI - The rubber band syndrome: the forgotten rubber band in the wrist. AB - A linear constricting scar around the wrist in the presence of a discharging sinus raises clinical suspicion of a forgotten band around the wrist. A 3-year old girl presented with an encircling scar, swelling and discharging sinus over the right wrist since last three months. There were no trophic ulcers and gross sensations were intact. Wrist radiographs showed the "constriction" sign in the radial epiphysis. MRI confirmed the diagnosis of encircling band inside wrist abutting the bone. A coloured rubber band was surgically extracted lying deep to restored and continuous tendons and neurovascular structures. Wound healing was uneventful. Examination at 14 months revealed residual ulnar nerve palsy. If aware, the clinical diagnosis is fairly accurate in rubber band syndrome. MRI aids in establishing diagnosis preoperatively. The reparative potential of a child's tissues is amazing. Although the lesion heals well after extraction of encircling band, the clinician should be wary of residual neurological changes. PMID- 24156588 TI - Carpal tunnel syndrome in patient with hemihypertrophy: case report. AB - Carpal tunnel syndrome is a common condition; however, it has not been previously reported in patients with hemihypertrophy. A 67-year-old woman with left-sided hemihypertrophy presented with carpal tunnel syndrome of the left hand. Magnetic resonance imaging showed enlargement of the median nerve proximal to the transverse carpal ligament. Carpal tunnel decompression was performed, and pain was immediately relieved by decompression of the carpal tunnel. At the six-month follow-up examination, the patient experienced relief from numbness and improvement in thenar muscle atrophy was noted. PMID- 24156589 TI - Flexor tendon rupture of the little finger caused by calcium pyrophosphate dihydrate crystal deposition disease of the pisotriquetrum joint. AB - We report a case of closed rupture of the flexor tendons of the little finger caused by calcium pyrophosphate dihydrate crystal deposition disease of the pisotriquetrum joint. The patient could not flex the little finger and did not have wrist pain. Plain radiographs of the affected wrist joint showed severe arthritic changes of the pisotriquetrum joint and calcification around the joint. At operation, the pisotriquetrum joint capsule was ruptured and involved the flexor tendon of the little finger. The distal stump of the flexor tendon was transferred to the flexor tendon of the ring finger, and the pisiform was resected. Histological examination with polarized light microscopy revealed crystals showing weakly positive birefringence in the calcification. PMID- 24156590 TI - Hamate hook non-union treated with a break-away screw: a case report. AB - Hamate hook non-union is a relatively rare, but on the increase. We encountered a 25-year-old male baseball instructor with hamate hook non-union, and treated it with debridement of the fractured region and osteosynthesis using a break-away screw. Splint fixation was applied for three weeks after surgery, and active/passive range of motion exercises were actively performed thereafter. Bone union was noted three months after surgery. Transient ulnar paralysis resolved, and the patient could return to the same sports activity as that before injury six months after surgery. Since break-away screws are capable of loading a strong pressure on the fractured region and these screws can be inserted by preparing only a surgical field for guide wire insertion, requiring no soft tissue dissection to prepare a region for applying fixation materials, break-away screws are useful for the fixation of small bone fragments and osteosynthesis in a deep surgical field. PMID- 24156591 TI - Successful replantation of a finger in an 8-month old child. AB - A successful replantation of an index fingertip in an 8-month old girl is reported. A literature review of replants in very young children suggests this is one of the youngest patients ever to undergo digital replantation and possibly the youngest finger replant performed. PMID- 24156592 TI - Flexor pulley reconstruction after rupture following corticosteroid injections for trigger thumb: a case report. AB - We report a rare case of limitation of active flexion and subcutaneous bow stringing as a result of flexor pulley rupture after repeated corticosteroid injections for trigger thumb. Complete rupture of the A1 and oblique flexor pulleys was confirmed during surgery, and the pulley system was reconstructed with a "three-loop technique" using a free palmaris longus autograft. This technique provided enough strength to allow early mobilization and prompt recovery to full range of motion. PMID- 24156593 TI - Metallosis of a silastic metacarpophalangeal joint arthroplasty--a case report. AB - Metallosis is a well-documented phenomenon in hip and knee arthroplasty from metal on metal bearing joint replacements. However, few cases of metallosis of metacarpophalangeal joint replacements have been reported. We present the case of a 49-year-old lady with rheumatoid arthritis who had previously undergone MCP joint replacements over 20 years ago. The decision was taken to revise her middle MCP joint after she developed pain and ulnar drift. At revision, the joint exhibited severe metallosis presumably arising from the grommet component of the replacement. This required considerable debridement and removal of the components and revision to a new upsized implant without grommets. It is of note that there were no external signs of metallosis with full flexion of the finger and a good roll up. PMID- 24156594 TI - Salvage of delayed union of a phalangeal fracture with "a hairpin wire". AB - The advantages of using multiple joint sparing antegrade intramedullary wiring for displaced, transverse and short oblique fractures of the small long bones of the hand has been well documented. This technique provides stable three-point fixation and permits early range of motion exercises to prevent hand stiffness. But in some revision cases where there is a breach or deficiency of subchondral bone due to previous intramedullary wiring or in old neglected juxta articular fractures of the metacarpal, proximal phalanx or middle phalanx with disuse osteopenia, there is a high chance of inadvertent joint penetration with intra medullary wiring, inspite of using blunt tipped bent K wires. This could happen intraoperatively or later in the follow up due to collapse of the fracture ends. We describe an innovative fixation technique which ensures stable fixation, no joint penetration and enables early range of motion to prevent hand stiffness. PMID- 24156595 TI - An unusual case of common digital nerve compression caused by a lipoma arising from the flexor tenosynovium. AB - Lipoma of the hand is a common lesion, but lipoma arising from the flexor tenosynovium is a very rare tumor that induces peripheral nerve disorders. Only four cases of synovial lesions that comprised mature fat at the wrist and imitated carpal tunnel syndrome have been described in the literature. We herein report an unusual case of a lipoma arising from the flexor tenosynovium at the level of the ring finger just proximal to the A1 pulley that was responsible for a sensory disturbance of the ring and middle fingers secondary to compression of the common digital nerve at the palm. The patient was completely relieved of the symptoms after lipoma excision. PMID- 24156596 TI - Retiform hemangioendothelioma of the finger: a case report. AB - Retiform hemangioendothelioma is a rare, intermediate-grade, locally aggressive vascular tumour that involves the skin and soft tissues of the trunk and extremities (1-10). Macroscopically it appears as a plaque or an exophytic lesion. Involvement of the hand or upper extremity is rare, with only Three cases reported in the literature (2, 3, 9). Treatment usually involves surgical excision or amputation (2). We present the case of a middle-aged woman with a retiform hemangioendothelioma of the small finger, successfully treated with surgical excision with no signs of recurrence at 4 years of follow-up. PMID- 24156598 TI - On publication of a manuscript: the author, the reviewer and the editor. PMID- 24156601 TI - A computational model for dynamic analysis of the human gait. AB - Biomechanical models are important tools in the study of human motion. This work proposes a computational model to analyse the dynamics of lower limb motion using a kinematic chain to represent the body segments and rotational joints linked by viscoelastic elements. The model uses anthropometric parameters, ground reaction forces and joint Cardan angles from subjects to analyse lower limb motion during the gait. The model allows evaluating these data in each body plane. Six healthy subjects walked on a treadmill to record the kinematic and kinetic data. In addition, anthropometric parameters were recorded to construct the model. The viscoelastic parameter values were fitted for the model joints (hip, knee and ankle). The proposed model demonstrated that manipulating the viscoelastic parameters between the body segments could fit the amplitudes and frequencies of motion. The data collected in this work have viscoelastic parameter values that follow a normal distribution, indicating that these values are directly related to the gait pattern. To validate the model, we used the values of the joint angles to perform a comparison between the model results and previously published data. The model results show a same pattern and range of values found in the literature for the human gait motion. PMID- 24156600 TI - The scale and evolutionary significance of horizontal gene transfer in the choanoflagellate Monosiga brevicollis. AB - BACKGROUND: It is generally agreed that horizontal gene transfer (HGT) is common in phagotrophic protists. However, the overall scale of HGT and the cumulative impact of acquired genes on the evolution of these organisms remain largely unknown. RESULTS: Choanoflagellates are phagotrophs and the closest living relatives of animals. In this study, we performed phylogenomic analyses to investigate the scale of HGT and the evolutionary importance of horizontally acquired genes in the choanoflagellate Monosiga brevicollis. Our analyses identified 405 genes that are likely derived from algae and prokaryotes, accounting for approximately 4.4% of the Monosiga nuclear genome. Many of the horizontally acquired genes identified in Monosiga were probably acquired from food sources, rather than by endosymbiotic gene transfer (EGT) from obsolete endosymbionts or plastids. Of 193 genes identified in our analyses with functional information, 84 (43.5%) are involved in carbohydrate or amino acid metabolism, and 45 (23.3%) are transporters and/or involved in response to oxidative, osmotic, antibiotic, or heavy metal stresses. Some identified genes may also participate in biosynthesis of important metabolites such as vitamins C and K12, porphyrins and phospholipids. CONCLUSIONS: Our results suggest that HGT is frequent in Monosiga brevicollis and might have contributed substantially to its adaptation and evolution. This finding also highlights the importance of HGT in the genome and organismal evolution of phagotrophic eukaryotes. PMID- 24156604 TI - Novel preclinical models of topical PrEP pharmacodynamics provide rationale for combination of drugs with complementary properties. AB - BACKGROUND: The limited success of recent HIV topical pre-exposure prophylaxis clinical trials highlights the need for more predictive models of drug efficacy that better simulate what may happen during sexual exposure. To address this gap, we developed complementary in vitro models to evaluate the ability of drugs to retain anti-HIV activity if cells were washed with seminal plasma (simulating what may happen following exposure to ejaculate), and to protect drug-naive T cells (representing newly recruited immune cells) co-cultured with explants that had been pretreated with drug. We focused on tenofovir disoproxil fumarate (TDF), the non-nucleoside reverse transcriptase inhibitors dapivirine (DPV) and IQP 0528, and the entry inhibitors maraviroc (MVC) and the D-peptide chol-PIE-12 trimer (PIE12). Studies were extended to macaques and the ability of cervical biopsies obtained from animals treated with an intravaginal ring formulation of IQP-0528 to protect ex vivo co-cultured T cells was determined. The antiviral activity of cervicovaginal lavage samples against a primary Clade C isolate was also measured and correlated with drug levels. RESULTS: Cells exposed to TDF were equally protected from HIV whether or not the drug-treated cells were washed with medium or seminal plasma prior to challenge. In contrast, several-fold higher concentrations of NNRTIs and entry inhibitors were needed to attain similar levels of HIV inhibition following a wash with seminal plasma. Conversely, the NNRTIs and PIE12, but not TDF or MVC, were effectively transferred from ex vivo treated explants and protected co-cultured T cells. Biopsies obtained from IQP 0528 ring-treated macaques also protected co-cultured T cells with viral inhibition ranging from 42-72%. Antiviral activity correlated with the concentration of drug recovered. Combinations of TDF with IQP-0528 protected in both in vitro models. CONCLUSIONS: Together, these models suggest that intracellularly retained drugs such as TDF may protect resident immune cells following coitus but sustained delivery may be required to protect immune cells subsequently recruited into the genital tract. Sustained delivery may also be critical for NNRTIs, which are rapidly transported out of cells and could be lost following sexual intercourse. An ideal approach may be a combination of drugs with complementary bioavailability profiles formulated for sustained delivery. PMID- 24156605 TI - Status of selected nutrients in obese dogs undergoing caloric restriction. AB - BACKGROUND: The purpose of this study was to test the hypothesis that dog plasma concentrations of selected nutrients decrease after undergoing caloric restriction for weight loss. Thirty-one overweight dogs that had successfully lost at least 15% of initial body weight were included in the study. Nutrients that had been previously identified to be at potential risk of deficiency during caloric restriction were measured in plasma (choline, amino acids) and urine (selenium) at the initiation and completion of a standardized weight loss regimen in dogs. RESULTS: Dogs remained healthy throughout the study, and no signs attributable to nutrient deficiency were noted. Percentage weight loss was 28.3% (16.0-40.1%) starting body weight, over a period of 250 days (91-674 days). Median energy intake during the weight loss period was 62 (44 to 74) Kcal/kg(0.75) target weight per day. Choline (P = 0.046) and threonine (P = 0.02) decreased after weight loss. Glycine (P = 0.041), and urinary selenium:creatinine ratio (P = 0.006) both increased after weight loss. There were no other significant differences in plasma nutrient concentrations. CONCLUSIONS: Since concentrations of most measured nutrients did not change significantly, the data are not consistent with widespread nutrient deficiency in dogs undergoing caloric restriction using a diet formulated for weight loss. However, the significance of the decrease in plasma choline concentration requires further assessment. PMID- 24156606 TI - Thailand's HIV/AIDS program after weaning-off the global fund's support. AB - BACKGROUND: Though 85% of financing HIV/AIDS program was domestic resources, Global Fund (GF) programs played a significant role in prevention interventions and treatment for non-Thai Key Affected Populations (KAP) and migrants. As upper middle income country, Thailand is not eligible for GF support. This study identified the remaining challenges and funding for prevention interventions for Thai and non-Thai KAP and migrants if GF supports were to curtail. METHODS: Qualitative method was applied including document review and in-depth interviews of 21 key informants who were Principal Recipients, Sub-recipients, provincial level program implementers and policy makers in health financing agencies. A multi-stakeholder consultation workshop was convened to discuss recommendations. RESULTS: The "public financed public services model" where Principal and Agents were the same entities resulted in less accountability than the "contractual agreement" in GF programs where the Principal Recipients, as the Agents were more accountable to the GF as Principal through results based financing. If GF supports were to curtail, impacts on the current programs would be varied from low to high degree of negative consequences. Scale down the scope and targets, while keeping the most critical components were common coping mechanisms. All three, except one, Principal Recipients had difficulties in fund mobilization. Prevention among non-Thai KAP and migrants were identified as the remaining challenge. CONCLUSIONS: A pooled funding mechanism from multiple domestic sources was proposed. Replacing the conventional public-financed-public-service by a contractual model was preferable. The GF should continue funding the non-Thai KAP and migrant as transition mechanism. Multi-countries or regional programs especially at the border areas were priorities. PMID- 24156607 TI - Influence of wood barrels classified by NIRS on the ellagitannin content/composition and on the organoleptic properties of wine. AB - Ellagitannins are extracted from oak wood during wine aging in oak barrels. This research is based on the NIRS (Oakscan) oak wood classification according to their index polyphenolic (IP) (between 21.07 and 70.15). Their level in wood is very variable (between 5.95 and 32.91 mg/g dry wood) and influenced their concentration in red wine (between 2.30 and 32.56 mg/L after 24 months of aging) and thus their impact on wine organoleptic properties. The results show a good correlation between the NIRS classification and the chemical analysis (HPLC-UV-MS and acidic hydrolysis procedure) and with the wood ellagitannin level, the ellagitannin extraction kinetic, and the ellagitannins evolution in red wine (Cabernet Sauvignon). Moreover, a correlation between the NIRS classification and the increasing intensity of some wood aromas (woody, spicy, vanilla, and smoked/toasted), flavors (bitterness and astringency), and a decreasing intensity of fruitiness was also observed. PMID- 24156608 TI - Flexible and practical synthesis of anthracenes through gold-catalyzed cyclization of o-alkynyldiarylmethanes. AB - A concise gold-catalyzed method for the preparation of anthracenes from o alkynyldiarylmethanes has been developed. Under mild reaction conditions, versatile anthracene derivatives were formed in moderate to good yields. The high flexibility, broad substrate scope, and mild nature of this reaction render it a viable alternative for the synthesis of anthracenes. PMID- 24156609 TI - Interconnected tin disulfide nanosheets grown on graphene for Li-ion storage and photocatalytic applications. AB - Reduced graphene oxide (RGO) nanosheet-supported SnS2 nanosheets are prepared by a one-step microwave-assisted technique. These SnS2 nanosheets are linked with each other and dispersed uniformly on RGO surface. The SnS2-RGO sheet-on-sheet nanostructure exhibits good electrochemical performances as an anode material for lithium ion batteries. It shows larger-than-theoretical reversible capacities at 0.1 C and excellent high-rate capability at 1 C and 5 C. The composite is also for the first time identified as an excellent visible light-driven catalyst of rhodamine B and phenol with high degradation efficiencies. The removal rates of rhodamine B and phenol are 100 and 83.2%, respectively, for the SnS2-RGO composite, whereas these values are only 64.8 and 51.5% for pristine SnS2 after the same irradiation times. The outstanding electrochemical or photocatalytic performances of the composite have been attributed to the complementary effect of RGO and SnS2 in the perfect sheet-on-sheet composition nanostructure. PMID- 24156610 TI - Interaction between a cationic surfactant-like peptide and lipid vesicles and its relationship to antimicrobial activity. AB - We investigate the properties of an antimicrobial surfactant-like peptide (Ala)6(Arg), A6R, containing a cationic headgroup. The interaction of this peptide with zwitterionic (DPPC) lipid vesicles is investigated using a range of microscopic, X-ray scattering, spectroscopic, and calorimetric methods. The beta sheet structure adopted by A6R is disrupted in the presence of DPPC. A strong effect on the small-angle X-ray scattering profile is observed: the Bragg peaks from the DPPC bilayers in the vesicle walls are eliminated in the presence of A6R and only bilayer form factor peaks are observed. All of these observations point to the interaction of A6R with DPPC bilayers. These studies provide insight into interactions between a model cationic peptide and vesicles, relevant to understanding the action of antimicrobial peptides on lipid membranes. Notably, peptide A6R exhibits antimicrobial activity without membrane lysis. PMID- 24156611 TI - Label-free quantitative proteomics analysis of antibiotic response in Staphylococcus aureus to oxacillin. AB - Methicillin-resistant Staphylococcus aureus (MRSA) is the leading cause of fatal bacterial infections in hospitals and has become a global health threat. Although the resistance mechanisms of beta-lactam antibiotics have been studied for decades, there are few attempts at systems-wide investigations into how the bacteria respond to antibiotic stress. Spectral counting-based label-free quantitative proteomics has been applied to study global responses in MRSA and methicillin-susceptible S. aureus (MSSA) treated with subinhibitory doses of oxacillin, a model beta-lactam antibiotic. We developed a simple and easily repeated sample preparation procedure that is effective for extracting surface associated proteins. On average, 1025 and 1013 proteins were identified at a false discovery rate threshold of 0.01, for the untreated group of MRSA and MSSA. Upon treatment with oxacillin, 81 proteins (65 up-regulated, 16 down-regulated) were shown differentially expressed in MRSA (p < 0.05). In comparison, 225 proteins (162 up-regulated, 63 down-regulated) were shown differentially expressed in oxacillin-treated MSSA. beta-Lactamase and penicillin-binding protein 2a were observed up-regulated uniquely in oxacillin-treated MRSA, which is consistent with the known beta-lactam resistance mechanisms of S. aureus. More interestingly, the peptidoglycan biosynthesis pathway and the pantothenate and CoA biosynthesis pathway were found to be up-regulated in both oxacillin-treated MRSA and MSSA, and a series of energy metabolism pathways were up-regulated uniquely in oxacillin-treated MSSA. These new data offer a more complete view of the proteome changes in bacteria in response to the antibiotic. This report is the first in using label-free quantitative proteomics to study beta-lactam antibiotic responses in S. aureus. PMID- 24156612 TI - Toward organometallic (99m)Tc imaging agents: synthesis of water-stable (99)Tc NHC complexes. AB - (99)Tc(V)O2-NHC complexes containing monodentate and bidentate N-heterocyclic carbenes (NHCs) have been prepared by the reactions of [TcO(glyc)2](-) (glyc = ethyleneglycolato) with 1,3-dimethylimidazoline-2-ylidene (L1), 1,1'-methylene 3,3'-dimethyl-4,4'-diimidazoline-2,2'-diylidene (L2), and 1,1'-methylene-3,3' diethyl-4,4'-diimidazoline-2,2'-diylidene (L3) in THF. The resulting complexes were fully characterized and their stabilities investigated. While complexes with monodentate NHCs only are hydrolytically unstable, complexes containing bidentate NHCs are water-stable over a broad pH range. The high water stability allows interconversion of the {(99)Tc(V)O2}(+) core into {(99)Tc(V)OCl}(2+) with HCl as the H(+) and Cl(-) source. An alternative procedure to obtain (99)Tc(V)O2-NHC complexes is the in situ deprotonation of imidazolium salts, enabling the preparation of (99)Tc(V)O2-NHC compounds without free NHCs, thus increasing the scope of NHC ligands drastically. The remarkable stability and pH-controllable reactivity of the new complexes underlines the potential of NHCs as stabilizing ligands for (99)Tc complexes and paves the way for the first (99m)Tc-NHC complexes in the future. PMID- 24156613 TI - Estimating lifetime healthcare costs with morbidity data. AB - BACKGROUND: In many developed countries, the economic crisis started in 2008 producing a serious contraction of the financial resources spent on healthcare. Identifying which individuals will require more resources and the moment in their lives these resources have to be allocated becomes essential. It is well known that a small number of individuals with complex healthcare needs consume a high percentage of health expenditures. Conversely, little is known on how morbidity evolves throughout life. The aim of this study is to introduce a longitudinal perspective to chronic disease management. METHODS: Data used relate to the population of the county of Baix Emporda in Catalonia for the period 2004-2007 (average population was N = 88,858). The database included individual information on morbidity, resource consumption, costs and activity records. The population was classified using the Clinical Risk Groups (CRG) model. Future morbidity evolution was simulated under different assumptions using a stationary Markov chain. We obtained morbidity patterns for the lifetime and the distribution function of the random variable lifetime costs. Individual information on acute episodes, chronic conditions and multimorbidity patterns were included in the model. RESULTS: The probability of having a specific health status in the future (healthy, acute process or different combinations of chronic illness) and the distribution function of healthcare costs for the individual lifetime were obtained for the sample population. The mean lifetime cost for women was ?111,936, a third higher than for men, at ?81,566 (all amounts calculated in 2007 Euros). Healthy life expectancy at birth for females was 46.99, lower than for males (50.22). Females also spent 28.41 years of life suffering from some type of chronic disease, a longer period than men (21.9). CONCLUSIONS: Future morbidity and whole population costs can be reasonably predicted, combining stochastic microsimulation with a morbidity classification system. Potential ways of efficiency arose by introducing a time perspective to chronic disease management. PMID- 24156614 TI - Dating human bone: is racemization dating species-specific? AB - Our recently developed dating technique based on the racemization rate of aspartic acid was applied to dating human bone, as well as that of other mammals, utilizing capillary electrophoresis mass spectrometry. First, several well-dated (mostly (14)C-dated and with strong archeological evidence) human bones ranging in age from 150 to ~10,000 years were used to develop a calibration curve for human bone. The D/L ratio of aspartic acid for these specimens ranged from 2.4% to ~10%, with a correlation coefficient of better than 0.99, indicating a strong linear relationship between the d/l ratio of aspartic acid and the age of the specimens. This calibration curve can now be used to date human archeological specimens of unknown age, up to ~10,000 years. However, when the technique was applied to well-dated mixed species of larger mammal bones such as bison, whale, llama, etc., the calibration curve showed a slower rate of racemization with a lower correlation (0.88). As additional large mammal bones with less certain age (i.e., using archeological evidence alone with no (14)C-dating) were dated the correlation coefficient decreased to 0.70. The correlation coefficient decreased further to 0.58 when the racemization data from all mammals (including human) were added to the calibration curve, indicating the importance of using well dated, species-specific specimens for forming a calibration curve. This conclusion is consistent with our previously published calibration curve for a single species of silk (Bombyx mori), which followed the expected reversible first-order kinetics. These results support species specificity of amino acid racemization dating. PMID- 24156615 TI - Risk factors associated with chronic obstructive pulmonary disease early readmission. AB - BACKGROUND: The 31 day readmission rate is deemed to be an important indicator of the quality of medical care in China. The objectives of this study were to identify the readmission rate of acute exacerbation for chronic obstructive pulmonary disease (COPD) and to evaluate associated risk factors. METHODS: We retrospectively reviewed charts for patients with acute exacerbation of COPD (AECOPD) admitted to our hospital between January 2011 and November 2012. The early-readmission group and non-early-readmission group were determined by whether patients were readmitted within 31 days after discharge. Logistic regression analysis was performed to identify risk factors for early readmission following an AECOPD. RESULTS: There were 692 patients with 925 admissions during the 23 month period; 63 (6.8%) admissions met our criteria for early readmission. Multivariate analysis showed that chronic cor pulmonale (odds ratio [OR] 2.14, 95% confidence interval [CI] 1.26-3.64, p = 0.005), hypoproteinemia (OR 2.02, 95% CI 1.03-3.95, p = 0.040) and an elevated PaCO2 (OR 1.03, 95% CI 1.00-1.06, p = 0.027) were identified as risk factors for early readmission of AECOPD. CONCLUSION: The readmission rate for AECOPD was 6.8%. AECOPD patients with chronic cor pulmonale, hypoproteinemia, and a high PaCO2 are at higher risk for readmission with 31 days of hospital discharge, and medical care of these patients warrants greater attention. PMID- 24156616 TI - Effects of an online alcohol education course among college freshmen: an investigation of potential mediators. AB - The authors investigated possible mediating effects of psychosocial variables (perceived drinking norms, positive and negative alcohol expectancies, personal approval of alcohol use, protective behavioral strategies) targeted by an online alcohol education course (AlcoholEdu for College) as part of a 30-campus randomized trial with 2,400 first-year students. Previous multilevel analyses have found significant effects of the AlcoholEdu course on the frequency of past 30-day alcohol use and binge drinking during the fall semester, and the most common types of alcohol-related problems. Exposure to the online AlcoholEdu course was inversely related to perceived drinking norms but was not related to any of the other psychosocial variables. Multilevel analyses indicated at least partial mediating effects of perceived drinking norms on behavioral outcomes. Findings of this study suggest that AlcoholEdu for College affects alcohol use and related consequences indirectly through its effect on student perceptions of drinking norms. Further research is needed to better understand why this online course did not appear to affect other targeted psychosocial variables. PMID- 24156618 TI - Local versus global optimal sports techniques in a group of athletes. AB - Various optimization algorithms have been used to achieve optimal control of sports movements. Nevertheless, no local or global optimization algorithm could be the most effective for solving all optimal control problems. This study aims at comparing local and global optimal solutions in a multistart gradient-based optimization by considering actual repetitive performances of a group of athletes performing a transition move on the uneven bars. Twenty-four trials by eight national-level female gymnasts were recorded using a motion capture system, and then multistart sequential quadratic programming optimizations were performed to obtain global optimal, local optimal and suboptimal solutions. The multistart approach combined with a gradient-based algorithm did not often find the local solution to be the best and proposed several other solutions including global optimal and suboptimal techniques. The qualitative change between actual and optimal techniques provided three directions for training: to increase hip flexion-abduction, to transfer leg and arm angular momentum to the trunk and to straighten hand path to the bar. PMID- 24156617 TI - Weight and body composition changes during oral contraceptive use in obese and normal weight women. AB - BACKGROUND: Oral contraceptive (OC) use seems to have little effect on weight change in normal weight women. Most previous studies have excluded obese women, so the effect of OC use on weight change in obese women is unknown. METHODS: This analysis evaluates weight and body composition change with OC use among obese (body mass index [BMI] 30.0-39.9) and normal weight (BMI 19.0-24.9) women who were randomly assigned to two OC doses: 20 MUg ethinyl estradiol (EE) and 100 MUg levonorgestrel (LNG) OCs or 30 MUg EE and 150 MUg LNG OCs. Follow-up occurred after three to four OC cycles. Weight and body composition were measured at baseline and at follow-up using a bioelectrical impedance analyzer. RESULTS: Among 150 women (54 obese and 96 normal weight) who used OCs for 3 to 4 months, there were no clinically or statistically significant weight or body composition changes in the overall group or by BMI or OC formulation group. CONCLUSIONS: These findings add to evidence that EE/LNG OCs are not associated with short term weight or body composition change for normal weight women and suggest that OCs are also are not associated with short term weight or body composition change in obese women. PMID- 24156619 TI - Results of concurrent chemotherapy and hyperthermia in patients with recurrent cervical cancer after previous chemoradiation. AB - BACKGROUND: Concomitant hyperthermia has been shown to improve response rate after cisplatin in recurrent cervical cancer in previously irradiated patients. It is unclear whether similar response rates can be obtained in patients with a recurrence after previous platinum-containing chemoradiation. OBJECTIVE: This study aimed to evaluate the outcome of cisplatin-based chemotherapy with concurrent hyperthermia in patients with recurrent cervical cancer after radiotherapy and cisplatin. METHODS: Patients with recurrent cervical cancer after cisplatin-based chemoradiation or neoadjuvant chemotherapy followed by surgery and radiotherapy who were treated with concurrent platinum-based chemotherapy and hyperthermia were eligible for this retrospective analysis. All patients received six or eight weekly platinum-based chemotherapy cycles in combination with six or eight weekly hyperthermia sessions. The time-to-event variables were estimated using Kaplan-Meier analysis. P-values less than 0.05 were considered significant. RESULTS: All 38 evaluable patients were selected from the hyperthermia database in the Academic Medical Centre (Amsterdam) and the Erasmus Medical Centre (Rotterdam). Mean age at relapse was 45.7 years (range 27 74). Median time to recurrence after first-line treatment was 15 months. A total of 27 patients had a local and/or regional recurrence; 11 had disease beyond the pelvis. All planned courses of cisplatin chemotherapy and hyperthermia were administered in 17/38 patients. Median follow-up was 6.5 months. One patient died during treatment; response rate was 4/37 (14%), with one complete response. Overall survival was 23% at 12 months and 4% at 24 months. The incidence of grade 3-4 haematological complications did not exceed 10%. CONCLUSION: In this retrospective study, concurrent cisplatin and hyperthermia after first-line cisplatin-containing chemoradiation showed poor response and survival. We do not recommend this treatment for recurrence of locally advanced cervical cancer. PMID- 24156620 TI - Genome-wide association and prediction of direct genomic breeding values for composition of fatty acids in Angus beef cattle. AB - BACKGROUND: As consumers continue to request food products that have health advantages, it will be important for the livestock industry to supply a product that meet these demands. One such nutrient is fatty acids, which have been implicated as playing a role in cardiovascular disease. Therefore, the objective of this study was to determine the extent to which molecular markers could account for variation in fatty acid composition of skeletal muscle and identify genomic regions that harbor genetic variation. RESULTS: Subsets of markers on the Illumina 54K bovine SNPchip were able to account for up to 57% of the variance observed in fatty acid composition. In addition, these markers could be used to calculate a direct genomic breeding values (DGV) for a given fatty acids with an accuracy (measured as simple correlations between DGV and phenotype) ranging from -0.06 to 0.57. Furthermore, 57 1-Mb regions were identified that were associated with at least one fatty acid with a posterior probability of inclusion greater than 0.90. 1-Mb regions on BTA19, BTA26 and BTA29, which harbored fatty acid synthase, Sterol-CoA desaturase and thyroid hormone responsive candidate genes, respectively, explained a high percentage of genetic variance in more than one fatty acid. It was also observed that the correlation between DGV for different fatty acids at a given 1-Mb window ranged from almost 1 to -1. CONCLUSIONS: Further investigations are needed to identify the causal variants harbored within the identified 1-Mb windows. For the first time, Angus breeders have a tool whereby they could select for altered fatty acid composition. Furthermore, these reported results could improve our understanding of the biology of fatty acid metabolism and deposition. PMID- 24156621 TI - The Women's Health Objective Structured Clinical Exam: a multidisciplinary collaboration. AB - PURPOSE: To determine the preliminary benefits of a Women's Health Objective Structured Clinical Exam (OSCE) which integrates psychiatry and obstetrics and gynecology principles into communication-focused doctor-patient paradigms. METHOD: The authors extracted medical student survey data from pre- and post-OSCE program evaluations (n = 193). Using McNemar's tests, the authors compared pre- and post-OSCE proportions of students reporting comfort levels with interactions involving terminally diagnosed patients, domestic violence, breast feeding, and other areas relevant to women's health. RESULTS: The proportion of students reporting comfort with each communication domain increased between pre- and post OSCE assessments. The greatest improvements were observed for discussions related to domestic violence (41% gain), terminal illness (37% gain) and postpartum depression/psychosis (23% gain). Ninety-four percent felt that this Women's Health OSCE was a valuable learning experience. CONCLUSION: The authors conclude that this Women's Health OSCE was a successful addition to the medical student clinical curriculum as measured by student satisfaction and self-reported improved comfort levels with challenging communication paradigms. Future studies will investigate the effect that this learning activity has on competency. PMID- 24156622 TI - Comparison of prenatal and postnatal treatments of spina bifida in Poland--a non randomized, single-center study. AB - OBJECTIVE: The aim of this study was a comparison of the outcomes of intrauterine myelomeningocele (MMC) repairs (IUMR) in type II Chiari malformation (II CM) fetuses with clinical data of newborns and infants operated on postnatally. METHODS: The study group (SG) comprised 46 pregnant women whose type II CM children underwent IUMR, while 47 pregnant women whose type II CM children were operated on postnatally constituted the control group (CG). A total of 24 SG and 20 CG patients reached the endpoint of the study. RESULTS: High incidence of prelabor rupture of membranes (24 (52.2%), CI: 3.74 (1.69-8.26) (p < 0.001) was noted in the group of prenatal surgeries as compared to controls. The need for ventriculoperitoneal shunt implantation was statistically significantly lower (p < 0.008) in the group of children after IUMR as compared to controls (5 (27.8%) and 16 (80%), respectively, CI: 0.35 (0.16-0.75). None of the postnatally treated CG children can walk without adaptive equipment. In contrast, two children from the SG (2 (11.1%) CI: 1.86 (1.00-3.48) p < 0.05) are able to walk independently. CONCLUSIONS: Prenatal MMC closure significantly lowers further adverse evolution of the II CM. Further studies are needed, especially on preventive measures for preterm labor and iatrogenic preterm prelabor rupture of membranes (iPPRM) in the postoperative course of IUMR. PMID- 24156624 TI - Asymptotic structural properties of quasi-random saturated structures of RNA. AB - BACKGROUND: RNA folding depends on the distribution of kinetic traps in the landscape of all secondary structures. Kinetic traps in the Nussinov energy model are precisely those secondary structures that are saturated, meaning that no base pair can be added without introducing either a pseudoknot or base triple. In previous work, we investigated asymptotic combinatorics of both random saturated structures and of quasi-random saturated structures, where the latter are constructed by a natural stochastic process. RESULTS: We prove that for quasi random saturated structures with the uniform distribution, the asymptotic expected number of external loops is O(logn) and the asymptotic expected maximum stem length is O(logn), while under the Zipf distribution, the asymptotic expected number of external loops is O(log2n) and the asymptotic expected maximum stem length is O(logn/log logn). CONCLUSIONS: Quasi-random saturated structures are generated by a stochastic greedy method, which is simple to implement. Structural features of random saturated structures appear to resemble those of quasi-random saturated structures, and the latter appear to constitute a class for which both the generation of sampled structures as well as a combinatorial investigation of structural features may be simpler to undertake. PMID- 24156623 TI - Pubertal high fat diet: effects on mammary cancer development. AB - INTRODUCTION: Epidemiological studies linking dietary fat intake and obesity to breast cancer risk have produced inconsistent results. This may be due to the difficulty of dissociating fat intake from obesity, and/or the lack of defined periods of exposure in these studies. The pubertal mammary gland is highly sensitive to cancer-causing agents. We assessed how high fat diet (HFD) affects inflammation, proliferative, and developmental events in the pubertal gland, since dysregulation of these can promote mammary tumorigenesis. To test the effect of HFD initiated during puberty on tumorigenesis, we utilized BALB/c mice, for which HFD neither induces obesity nor metabolic syndrome, allowing dissociation of HFD effects from other conditions associated with HFD. METHODS: Pubertal BALB/c mice were fed a low fat diet (12% kcal fat) or a HFD (60% kcal fat), and subjected to carcinogen 7,12-dimethylbenz[a]anthracene (DMBA)-induced tumorigenesis. RESULTS: HFD elevated mammary gland expression of inflammatory and growth factor genes at 3 and 4 weeks of diet. Receptor activator of nuclear factor kappa-B ligand (RANKL), robustly induced at 4 weeks, has direct mitogenic activity in mammary epithelial cells and, as a potent inducer of NF-kappaB activity, may induce inflammatory genes. Three weeks of HFD induced a transient influx of eosinophils into the mammary gland, consistent with elevated inflammatory factors. At 10 weeks, prior to the appearance of palpable tumors, there were increased numbers of abnormal mammary epithelial lesions, enhanced cellular proliferation, increased growth factors, chemokines associated with immune-suppressive regulatory T cells, increased vascularization, and elevated M2 macrophages. HFD dramatically reduced tumor latency. Early developing tumors were more proliferative and were associated with increased levels of tumor-related growth factors, including increased plasma levels of HGF in tumor-bearing animals. Early HFD tumors also had increased vascularization, and more intra tumor and stromal M2 macrophages. CONCLUSIONS: Taken together in this non obesogenic context, HFD promotion of inflammatory processes, as well as local and systemically increased growth factor expression, are likely responsible for the enhanced tumorigenesis. It is noteworthy that although DMBA mutagenesis is virtually random in its targeting of genes in tumorigenesis, the short latency tumors arising in animals on HFD showed a unique gene expression profile, highlighting the potent overarching influence of HFD. PMID- 24156626 TI - Association between body mass index and health-related quality of life, and the impact of self-reported long-term conditions - cross-sectional study from the south Yorkshire cohort dataset. AB - BACKGROUND: We sought to quantify the relationship between body mass index (BMI) and health-related quality (HRQoL) of life, as measured by the EQ-5D, whilst controlling for potential confounders. In addition, we hypothesised that certain long-term conditions (LTCs), for which being overweight or obese is a known risk factor, may mediate the association between BMI and HRQoL. Hence the aim of our study was to explore the association between BMI and HRQoL, first controlling for confounders and then exploring the potential impact of LTCs. METHODS: We used baseline data from the South Yorkshire Cohort, a cross-sectional observational study which uses a cohort multiple randomised controlled trial design. For each EQ-5D health dimension we used logistic regression to model the probability of responding as having a problem for each of the five health dimensions. All continuous variables were modelled using fractional polynomials. We examined the impact on the coefficients for BMI of removing LTCs from our model. We considered the self-reported LTCs: diabetes, heart disease, stroke, cancer, osteoarthritis, breathing problems and high blood pressure. RESULTS: The dataset used in our analysis had data for 19,460 individuals, who had a mean EQ-5D score of 0.81 and a mean BMI of 26.3 kg/m2. For each dimension, BMI and all of the LTCs were significant predictors. For overweight or obese individuals (BMI >= 25 kg/m2), each unit increase in BMI was associated with approximately a 3% increase in the odds of reporting a problem for the anxiety/depression dimension, a 8% increase for the mobility dimension, and approximately 6% for the remaining dimension s. Diabetes, heart disease, osteoarthritis and high blood pressure were identified as being potentially mediating variables for all of the dimensions. CONCLUSIONS: Compared to those of a normal weight (18.5 < BMI < 25 kg/m2), overweight and obese individuals had a reduced HRQoL, with each unit increase in BMI associated with approximately a 6% increase in the odds of reporting a problem on any of the EQ-5D health dimensions. There was evidence to suggest that diabetes, heart disease, osteoarthritis and high blood pressure may mediate the association between being overweight and HRQoL. PMID- 24156625 TI - Genetic diversity of the highly variable V1 region interferes with Human Immunodeficiency Virus type 1 envelope functionality. AB - BACKGROUND: The HIV envelope (Env) promotes viral entry in the host cell. During this process, Env undergoes several conformational changes to ensure its function. At the same time, the gp120 component of Env is the protein of the virus presenting the largest genetic diversity. Understanding how the virus maintains the balance between the competing requirements for maintenance of functionality and antigenic variation of this protein is central for the comprehension of its strategies of evolution and can highlight vulnerable aspects of its replication cycle. We focused on the variable domains V1 and V2 of the HIV 1 gp120 that are involved in conformational changes and are critical for viral escape from antibody neutralization. RESULTS: Despite the extensive sequence diversity found in the epidemic for these regions and their location on the external face of the protein, we observed that replacing V1V2 of one primary isolate with that of another severely interferes with Env functionality in more than half of the cases studied. Similar results were obtained for intra- and intersubtype chimeras. These observations are indicative of an interference of genetic diversity in these regions with Env functionality. Therefore, despite the extensive sequence diversity that characterizes these regions in the epidemic, our results show that functional constraints seem to limit their genetic variation. Defects in the V1V2 chimeras were not relieved by the insertion of the V3 region from the same isolate, suggesting that the decrease in functionality is not due to perturbation of potential coevolution networks between V1V2 and V3. Within the V1V2 domain, the sequence of the hypervariable loop of the V1 domain seems to be crucial for the functionality of the protein. CONCLUSIONS: Besides the well-documented role of V1V2 in the interplay with the immune response, this work shows that V1 is also involved in the selection of functional envelopes. By documenting a compromise between the opposing forces of sequence diversification and retention of functionality, these observations improve our understanding of the evolutionary trajectories of the HIV-1 envelope gene. PMID- 24156627 TI - Interface properties of organic para-hexaphenyl/alpha-sexithiophene heterostructures deposited on highly oriented pyrolytic graphite. AB - It was recently reported, that heterostructures of para-hexaphenyl (p-6P) and alpha-sexithiophene (6T) deposited on muscovite mica exhibit the intriguing possibility to prepare lasing nanofibers of tunable emission wavelength. For p 6P/6T heterostructures, two different types of 6T emission have been observed, namely, the well-known red emission of bulk 6T crystals and additionally a green emission connected to the interface between p-6P and 6T. In this study, the origin of the green fluorescence is investigated by photoelectron spectroscopy (PES). As a prerequisite, it is necessary to prepare structurally similar organic crystals on a conductive surface, which leads to the choice of highly oriented pyrolytic graphite (HOPG) as a substrate. The similarity between p-6P/6T heterostructures on muscovite mica and on HOPG is evidenced by X-ray diffraction (XRD), scanning force microscopy (SFM), and optical spectroscopy. PES measurements show that the interface between p-6P and 6T crystals is sharp on a molecular level without any sign of interface dipole formation or chemical interaction between the molecules. We therefore conclude that the different emission colors of the two 6T phases are caused by different types of molecular aggregation. PMID- 24156628 TI - Prostate-specific antigen evolution after photoselective vaporization of the prostate. AB - BACKGROUND: Prostate-specific antigen (PSA) variations after photoselective vaporization of the prostate are an unsolved question. PATIENTS AND METHODS: We included prospectively 323 patients who underwent GreenLight(r) prostate vaporization for prostatic hyperplasia between 2005 and 2013. We excluded patients with prostate cancer and those with concomitant prostate biopsies. Serum PSA levels were measured before and after the procedure at 1, 6, 12, 24, 36, and 48 months. RESULTS: The median preoperative PSA level was 4.50 ng/mL; it decreased to 2.41 ng/mL at 1 month (47% reduction), 2.17 ng/mL at 6 months (52% reduction), 2.30 ng/mL at 1 year (49% reduction), 2.40 ng/mL at 2 years (47% reduction), 2.31 ng/mL at 3 years (49% reduction), and 2.54 ng/mL at 4 years (44% reduction) (P values were all <0.0001). The median PSA nadir at 6 months was significantly different from the median PSA level at 1, 2, 3, and 4 years (respectively P=0.0046, P=0.0017, P=0.0006, and P=0.01). Patients who received <=3000 J/cc had a significant trend to a PSA reascension after 6 months. Patients who received >=4000 J/cc did not show any significant PSA reascension during the 4 years after procedure. Energy was correlated with the PSA reascension in univariate and multivariate analysis. CONCLUSIONS: The PSA level significantly decreased by half 1 month after the procedure, reached its nadir at 6 months, and showed a slight progressive reascension during the 4 following years. Applying an energy rate >=4000 J/cc of prostate induced PSA stability over time whereas energy <=3000 J/cc induced a reascension of the PSA level after 6 months. PMID- 24156629 TI - The Heart Healthy Lenoir project--an intervention to reduce disparities in hypertension control: study protocol. AB - BACKGROUND: Racial disparities in blood pressure control are well established; however the impact of low health literacy (LHL) on blood pressure has garnered less attention. Office based interventions that are created with iterative patient, practice and community stakeholder input and are rolled out incrementally, may help address these disparities in hypertension control. This paper describes our study protocol. METHODS/DESIGN: Using a community based participatory research (CBPR) approach, we designed and implemented a cohort study that includes both a practice level and patient level intervention to enhance the care and support of patients with hypertension in primary care practices in a rural region of eastern North Carolina. The study is divided into a formative phase and an ongoing 2.5 year implementation phase. Our main care enhancement activities include the integration of a community health coach, using home blood pressure monitoring in clinical decision making, standardizing care delivery processes, and working to improve medication adherence. Main outcomes include overall blood pressure change, the differential change in blood pressure by race (African American vs. White) and health literacy level (low vs. higher health literacy). DISCUSSION: Using a community based participatory approach in primary care practice settings has helped to engage patients and practice staff and providers in the research effort and in making practice changes to support hypertension care. Practices have engaged at varying levels, but progress has been made in implementing and iteratively improving upon the interventions to date. TRIAL REGISTRATION: ClinicalTrials.gov NCT01425515. PMID- 24156630 TI - Ladder-type BN-embedded heteroacenes with blue emission. AB - Using a concise synthetic strategy, a series of novel ladder-type BN-embedded heteroacenes were successfully synthesized. Their molecular skeletons render the versatile modification which is desirable for achieving unique physical properties. Organic light-emitting diode devices based on BN-embedded heteroacenes were subsequently fabricated, demonstrating their promising application as blue emitters. PMID- 24156631 TI - Monodisperse Au nanoparticles for selective electrocatalytic reduction of CO2 to CO. AB - We report selective electrocatalytic reduction of carbon dioxide to carbon monoxide on gold nanoparticles (NPs) in 0.5 M KHCO3 at 25 degrees C. Among monodisperse 4, 6, 8, and 10 nm NPs tested, the 8 nm Au NPs show the maximum Faradaic efficiency (FE) (up to 90% at -0.67 V vs reversible hydrogen electrode, RHE). Density functional theory calculations suggest that more edge sites (active for CO evolution) than corner sites (active for the competitive H2 evolution reaction) on the Au NP surface facilitates the stabilization of the reduction intermediates, such as COOH*, and the formation of CO. This mechanism is further supported by the fact that Au NPs embedded in a matrix of butyl-3 methylimidazolium hexafluorophosphate for more efficient COOH* stabilization exhibit even higher reaction activity (3 A/g mass activity) and selectivity (97% FE) at -0.52 V (vs RHE). The work demonstrates the great potentials of using monodisperse Au NPs to optimize the available reaction intermediate binding sites for efficient and selective electrocatalytic reduction of CO2 to CO. PMID- 24156632 TI - Potential of Chilean native corn (Zea mays L.) accessions as natural sources of phenolic antioxidants and in vitro bioactivity for hyperglycemia and hypertension management. AB - Thirty-three Chilean corn accessions were screened for the first time regarding their phenolic profiles, total phenolic contents (TPC), antioxidant capacity (DPPH and ABTS), and in vitro inhibition against key enzymes relevant for hyperglycemia (alpha-amylase and alpha-glucosidase) and hypertension (angiotensin I-converting enzyme, ACE-I) in both free and cell wall-bound fractions. TPC varied from 132.2 to 262.5 mg of gallic acid equivalents/100g dry weight (DW), and around 88% of TPC and antioxidant capacity were found in the bound form. Vanillin, vanillic, protocatechuic, ferulic, and p-coumaric acids were detected by HPLC in free fractions, whereas ferulic and p-coumaric acids were found in the bound form. Pisankalla accession (red kernel) had the highest ferulic acid content (269.5 mg/100g DW). No alpha-amylase and ACE-I inhibition were found; however, all free fractions inhibited alpha-glucosidase (10.8-72.5%). Principal component analysis revealed that darker samples (free fraction) showed higher TPC and antioxidant capacity, while alpha-glucosidase inhibition was related to yellow-colored samples. PMID- 24156633 TI - Numerical model (switchable/dual model) of the human head for rigid body and finite elements applications. AB - In this paper, a methodology for the development and validation of a numerical model of the human head using generic procedures is presented. All steps required, starting with the model generation, model validation and applications will be discussed. The proposed model may be considered as a dual one due to its capabilities to switch from deformable to a rigid body according to the application's requirements. The first step is to generate the numerical model of the human head using geometry files or medical images. The required stiffness and damping for the elastic connection used for the rigid body model are identified by performing a natural frequency analysis. The presented applications for model validation are related to impact analysis. The first case is related to Nahum's (Nahum and Smith 1970) experiments pressure data being evaluated and a pressure map generated using the results from discrete elements. For the second case, the relative displacement between the brain and the skull is evaluated according to Hardy's (Hardy WH, Foster CD, Mason, MJ, Yang KH, King A, Tashman S. 2001.Investigation of head injury mechanisms using neutral density technology and high-speed biplanar X-ray. Stapp Car Crash J. 45:337-368, SAE Paper 2001-22-0016) experiments. The main objective is to validate the rigid model as a quick and versatile tool for acquiring the input data for specific brain analyses. PMID- 24156635 TI - Knowledge about cervical cancer prevention and psychosocial barriers to screening among Mexican women. AB - The objectives of this study were to evaluate: Mexican women's knowledge about cervical cancer prevention; psychosocial barriers to screening; and the relation of both to cervical cancer screening behavior. Three hundred and eighty-four rural and urban women who had achieved a basic or higher educational level were surveyed. Almost 80% of the women had a Pap test but rural women were less likely to have done so. Although most women had received their most recent Pap within the last three years, only 29% had had their first Pap in accordance with the official Mexican norm. Participants showed inadequate knowledge about the risk factors for cervical cancer, especially women with only a basic educational level, irrespective of residence in an urban or rural area. Factors associated with non-screening were poor knowledge about Pap testing and about the risk factors for cervical cancer, as well as the following barriers: believing that Pap testing is too embarrassing; believing that men do not want them to have a Pap test; and believing that the test is painful. In light of these socio cultural influences, our findings could be helpful in designing effective programs to increase Pap screening. PMID- 24156634 TI - Assessment of the risk of blastomere biopsy during preimplantation genetic diagnosis in a mouse model: reducing female ovary function with an increase in age by proteomics method. AB - Preimplantation genetic diagnosis (PGD) is important for screening genetic and chromosome mutations in embryos so that the efficiency of assisted reproductive treatment can be increased and birth defects can be decreased; however, some studies have reported a risk from this technology as well as other assisted reproductive technologies. We have developed a blastomere biopsy mouse model to assess the potential effects of blastomere biopsy that was one key procedure in PGD on the fertility of female mice at different ages. We showed that female fertility was decreased in the biopsied mouse model with an increase in age. Moreover, the ovarian weight, serum hormone levels, and the number of primordial, primary, preantral, and antral stage follicles were also decreased in the middle aged biopsied mouse model. To elucidate the underlying molecular mechanism, we did proteomics analysis on ovarian tissues from puberty biopsied and nonbiopsied mice of the 23 differentially expressed proteins that were screened for in both groups, 3 proteins (PSMB8, ALDH1A1, and HSPA4) were selected and identified by Western blotting and quantitative RT-PCR methods, which showed the 3 proteins to regulate 12 cellular pathways. Furthermore, these three proteins were shown to be located in ovarian tissues, and the dynamic changes of expression profiling in middle-aged biopsied and nonbiopsied mice were demonstrated. The present study showed that blastomere biopsy technology impairs fertility when mice are middle aged, which possibly resulted in abnormal expression profiling of PSMB8, ALDH1A1, and HSPA4 proteins. Thus, additional studies should be performed to assess the overall risk of blastomere biopsies during PGD procedures. PMID- 24156636 TI - Human endogenous retrovirus K (HML-2) RNA and protein expression is a marker for human embryonic and induced pluripotent stem cells. AB - BACKGROUND: Malignant human embryonal carcinoma cells (ECCs) rely on similar transcriptional networks as non-malignant embryonic stem cells (ESCs) to control selfrenewal, maintain pluripotency, and inhibit differentiation. Because re activation of silenced HERV-K(HML-2) loci is a hallmark of ECCs, we asked if this HERV group was also reactivated in ESCs and induced pluripotent stem cells (iPSCs). FINDINGS: Using RT-PCR and Western Blot, we demonstrate HERV-K(HML-2) RNA and protein expression in undifferentiated human ESCs and iPSCs. Induction of differentiation by embryoid body formation resulted in rapid silencing of HERV K(HML-2) provirus expression. Sequencing analysis of a conserved region of the gag gene showed that proviral expression in ESCs and iPSCs represents at least 11 of the 66 nearly full length HERV-K(HML-2) loci, with slightly varying patterns in individual cell lines. These proviruses are human specific integrations and harbor promoter competent long terminal repeats (LTR5hs subgroup). We observed high mRNA levels of the NP9 and Gag encoding proviruses K101(22q11.21) in all and K10(5q33.3) in most of the ECC, ESC, and iPSC lines tested, while K37(11q23.3) mRNA was detected only in ESCs and iPSCs. In addition, we detected expression of proviral mRNA encoding the RNA export adaptor Rec in all cell lines studied. Proviral mRNA originating from the K108(7p22.1) locus, which inter alia codes for functional Rec and Env proteins, was only reactivated in malignant ECC lines, not in benign ESCs or iPSCs. CONCLUSIONS: HERV-K(HML-2) RNA and protein expression is a marker for pluripotent human stem cells. Initiation of differentiation results in rapid down-regulation. Further studies are needed to explore a putative functional role of HERV-K(HML-2) RNA and proteins in pluripotent stem cells. PMID- 24156639 TI - Hydrodynamic chromatography coupled with single particle-inductively coupled plasma mass spectrometry for investigating nanoparticles agglomerates. AB - Studying the environmental fate of engineered or natural colloids requires efficient methods for measuring their size and quantifying them in the environment. For example, an ideal method should maintain its correctness, accuracy, reproducibility, and robustness when applied to samples contained in complex matrixes and distinguish the target particles from the natural colloidal background signals. Since it is expected that a large portion of nanoparticles will form homo- or heteroagglomerates when released into environmental media, it is necessary to differentiate agglomerates from primary particles. At present, most sizing techniques do not fulfill these requirements. In this study, we used online coupling of two promising complementary sizing techniques: hydrodynamic chromatography (HDC) and single-particle ICPMS analysis to analyze gold nanoparticles agglomerated under controlled conditions. We used the single particle mode of the ICPMS detector to detect single particles eluted from an HDC column and determine a mass and an effective diameter for each particle using a double calibration approach. The average agglomerate relative density and fractal dimension were calculated using these data and used to follow the morphological evolution of agglomerates over time during the agglomeration process. The results demonstrate the ability of HDC coupled to single-particle analysis to identify and characterize nanoparticle homoagglomerates and is a very promising technique for the analysis of colloids in complex media. PMID- 24156638 TI - Incidence, predictors and outcomes of congenital diaphragmatic hernia: a population-based study of 32 million births in the United States. AB - OBJECTIVES: To evaluate the incidence, risk factors and neonatal outcomes associated with a congenital diaphragmatic hernia (CDH). STUDY DESIGN: We conducted a population-based cohort study using the CDC's Linked Birth-Infant Death and Fetal Death data files on all births and foetal deaths in USA between 1995 and 2002. We estimated the yearly incidence of CDH and measured its adjusted effect on various outcomes using unconditional logistic regression analysis. RESULTS: About 32,145,448 births during the 8-year study period met the study's inclusion criteria. The incidence of CDH was 1.93/10,000 births. Risk factors for the development of CDH included foetal male gender [OR 1.12, 95% CI: 1.06, 1.17], maternal age beyond 40 [OR 1.51, 95% CI: 1.26, 1.80], Caucasian ethnicity [OR 1.15, 95% CI: 1.10, 1.21], smoking [OR 1.34, 95% CI: 1.22, 1.46] and alcohol use during pregnancy [OR 1.37, 95% CI: 1.05, 1.79]. As compared to foetuses with no CDH, foetuses with CDH were at an increased risk of preterm birth [OR 2.90, 95% CI: 2.72, 3.11], intrauterine growth restriction [OR 3.84, 95% CI: 3.51, 4.18], stillbirth [OR 9.65, 95% CI: 8.20, 11.37] and overall infant death [OR: 94.80, 95% CI: 88.78, 101.23]. The 1-year mortality was 45.89%. CONCLUSION: Congenital diaphragmatic hernia is strongly associated with an increased risk of adverse pregnancy, foetal and neonatal outcomes. These findings may be helpful in counselling pregnancies affected by CDH, and may aid in the understanding of the burden of this condition at the public health level. PMID- 24156637 TI - Reversible, interrelated mRNA and miRNA expression patterns in the transcriptome of Rasless fibroblasts: functional and mechanistic implications. AB - BACKGROUND: 4-Hydroxy-tamoxifen (4OHT) triggers Cre-mediated K-Ras removal in [H Ras-/-; N-Ras-/-; K-Ras lox/lox; RERT ert/ert] fibroblasts, generating growth arrested "Rasless" MEFs which are able to recover their proliferative ability after ectopic expression of Ras oncoproteins or constitutively active BRAF or MEK1. RESULTS: Comparison of the transcriptional profiles of Rasless fibroblasts with those of MEFs lacking only H-Ras and N-Ras identified a series of differentially expressed mRNAs and microRNAs specifically linked to the disappearance of K-Ras from these cells. The rescue of cell cycle progression in Rasless cells by activated BRAF or MEK1 resulted in the reversal of most such transcriptional mRNA and microRNA alterations.Functional analysis of the differentially expressed mRNAs uncovered a significant enrichment in the components of pathways regulating cell division, DNA/RNA processing and response to DNA damage. Consistent with G1/S blockade, Rasless cells displayed repression of a series of cell cycle-related genes, including Cyclins, Cyclin-dependent kinases, Myc and E2F transcription targets, and upregulation of Cyclin-dependent kinase inhibitors. The profile of differentially expressed microRNAs included a specific set of oncomiR families and clusters (repressed miR-17 ~ 92, miR-106a ~ 363, miR-106b ~ 25, miR-212 ~ 132, miR-183 ~ 182, and upregulated miR-335) known for their ability to target a specific set of cellular regulators and checkpoint sensors (including Rb, E2F and Cdkns) able to modulate the interplay between the pro- and anti-proliferative or stress-response pathways that are reversibly altered in Rasless cells. CONCLUSIONS: Our data suggest that the reversible proliferation phenotype of Rasless cells is the pleiotropic result of interplay among distinct pro- and anti-proliferative, and stress-response pathways modulated by a regulatory circuitry constituted by a specific set of differentially expressed mRNAs and microRNAs and preferentially targeting two cross-talking signalling axes: Myc-Rb-E2F-dependent and Cdkns-p53-dependent pathways. PMID- 24156641 TI - Evaluation of the strain-line patterns in a human left ventricle: a simulation study. AB - The aim of this paper is to emphasise the role of the primary strain-line patterns in a human left ventricle (LV) within the complex system that is the heart. In particular, a protocol is proposed for the measurement of the principal strain lines (PSL) in the walls of the LV; this protocol is tested by means of a computational model which resembles a human LV. When the analysis is focused on the epicardial surface, PSL can be used to derive information on the directions of muscle fibres during the entire cardiac cycle, not only the systolic phase. PMID- 24156642 TI - Comparative effectiveness of hypoglycemic medications among veterans. AB - BACKGROUND: The efficacy of diabetic medications among patients with multiple comorbidities is not tested in randomized clinical studies. It is important to monitor the performance of these medications after marketing approvals. OBJECTIVE: To investigate the risk of all-cause mortality associated with prescription of hypoglycemic agents. METHODS: We retrospectively examined data from 17,773 type 2 diabetic patients seen from March 2, 1998, to December 13, 2010, in 3 Veterans Administration medical centers. Severity was measured using patients' inpatient and outpatient comorbidities during the last year of visits. Severity-adjusted logistic regression was used to measure the odds ratio for mortality within the study period. RESULTS: Patients' severity of illness correctly classified mortality for 89.8% of the patients (P less than 0.0001). Being younger, married, and white decreased severity adjusted risk of mortality. Exposure to the following medications increased severity adjusted risk of mortality: glyburide (odds ratio [OR] = 1.804, 95% CI from 1.518 to 2.145), glipizide (OR = 1.566, 95% CI from 1.333 to 1.839), rosiglitazone (OR = 1.805, 95% CI from 1.378 to 2.365), chlorpropamide (OR = 3.026, 95% CI from 1.096 to 8.351), insulin (OR = 2.382, 95% CI from 2.112 to 2.686). None of the other medications (metformin, acarbose, glimepiride, pioglitazone, repaglinide, troglitazone, or dipeptidyl peptidase-4) were associated with excess mortality beyond what could be expected from the patients' severity of illness or demographic characteristics. The reported excess mortality could not be explained away by use of other concurrent, nondiabetic classes of medications. CONCLUSION: Our findings suggest chlorpropamide, glipizide, glyburide, insulin, and rosiglitazone increased severity-adjusted mortality in veterans with type 2 diabetes. A decision aid that could optimize selection of hypoglycemic medications based on patients' comorbidities might increase patients' survival. PMID- 24156640 TI - Evaluation of etoricoxib in patients undergoing total knee replacement surgery in a double-blind, randomized controlled trial. AB - BACKGROUND: Optimal postoperative pain management is important to ensure patient comfort and early mobilization. METHODS: In this double-blind, placebo- and active-controlled, randomized clinical trial, we evaluated postoperative pain following knee replacement in patients receiving placebo, etoricoxib (90 or 120 mg), or ibuprofen 1800 mg daily for 7 days. Patients >=18 years of age who had pain at rest >=5 (0-10 Numerical Rating Scale [NRS]) after unilateral total knee replacement were randomly assigned to placebo (N = 98), etoricoxib 90 mg (N = 224), etoricoxib 120 mg (N = 230), or ibuprofen 1800 mg (N = 224) postoperatively. Co-primary endpoints included Average Pain Intensity Difference at Rest over Days 1-3 (0- to 10-point NRS) and Average Total Daily Dose of Morphine over Days 1-3. Pain upon movement was evaluated using Average Pain Intensity Difference upon Knee Flexion (0- to 10-point NRS). The primary objective was to demonstrate analgesic superiority for the etoricoxib doses vs. placebo; the secondary objective was to demonstrate that the analgesic effect of the etoricoxib doses was non-inferior to ibuprofen. Adverse experiences (AEs) including opioid-related AEs were evaluated. RESULTS: The least squares (LS) mean (95% CI) differences from placebo for Pain Intensity Difference at Rest over Days 1-3 were -0.54 (-0.95, -0.14); -0.49 (-0.89, -0.08); and -0.45 (-0.85, -0.04) for etoricoxib 90 mg, etoricoxib 120 mg, and ibuprofen, respectively (p < 0.05 for etoricoxib vs. placebo). Differences in LS Geometric Mean Ratio morphine use over Days 1-3 from placebo were 0.66 (0.54, 0.82); 0.69 (0.56, 0.85); and 0.66 (0.53, 0.81) for etoricoxib 90 mg, etoricoxib 120 mg, and ibuprofen, respectively (p < 0.001 for etoricoxib vs. placebo). Differences in LS Mean Pain Intensity upon Knee Flexion were -0.37 (-0.85, 0.11); -0.46 (-0.94, 0.01); and -0.42 (-0.90, 0.06) for etoricoxib 90 mg, etoricoxib 120 mg, and ibuprofen, respectively. Opioid-related AEs occurred in 41.8%, 34.7%, 36.5%, and 36.3% of patients on placebo, etoricoxib 90 mg, etoricoxib 120 mg, and ibuprofen, respectively. CONCLUSIONS: Postoperative use of etoricoxib 90 and 120 mg in patients undergoing total knee replacement is both superior to placebo and non-inferior to ibuprofen in reducing pain at rest and also reduces opioid (morphine) consumption. CLINICAL TRIAL REGISTRATION: NCT00820027. PMID- 24156643 TI - Health care decision makers' use of comparative effectiveness research: report from a series of focus groups. AB - BACKGROUND: Comparative effectiveness research (CER) is a helpful approach to improve health outcomes by developing and disseminating evidence-based information to patients, clinicians, and other decision makers about the most effective interventions. OBJECTIVES: To (a) identify the factors necessary to increase the use of the Agency for Healthcare Research and Quality's (AHRQ) CER reviews in hospitals and managed care organizations; (b) assess current awareness and implementation of CER materials in these facilities and organizations; and (c) inform development of content for a workshop on CER. METHODS: Pharmacy and therapeutics (PT) committee members and supportive personnel were recruited to participate in focus groups conducted at national health professional meetings. Prior to the sessions, each participant completed a prefocus group questionnaire evaluating the organization and process of the respondent's PT committee, as well as the respondent's role in the PT committee and awareness of AHRQ CER reports. Each session consisted of a focused discussion about CER and sources of evidence for PT monographs, and each participant completed a ballot to rank topics of importance for inclusion in a CER workshop for health care professionals involved in the PT process. Overarching themes were later identified using qualitative analysis of the transcripts of the focus group sessions. RESULTS: Thirty-nine (68%) pharmacists and 18 (32%) physicians involved in the PT process participated in 1 of 7 focus groups. Almost half of the participants had 6-15 years experience with the PT process. Participants represented health plans, hospitals, and health care systems. Two-thirds indicated they were aware of AHRQ's Effective Health Care Program's CER reviews, yet only 26% reported using the reviews in their organizations. The overarching themes reflected the need for timely and conclusive CER information; the role of the pharmacist as central to evidence synthesis for the PT process; and the need for educational programs in online formats that are designed primarily for pharmacists. CONCLUSION: Health care decision makers identified timeliness as a key factor for facilitating the use of AHRQ CER reviews and guides in hospitals and managed care organizations. To facilitate integration of CER into the decision-making process, it is imperative that key stakeholders have access to comprehensive and timely information. While the majority of participants indicated that they were aware of AHRQ CER reviews, few had used them in the PT process. PMID- 24156644 TI - A systematic review of the economic and humanistic burden of illness in irritable bowel syndrome and chronic constipation. AB - BACKGROUND: Irritable bowel syndrome (IBS) and chronic constipation (CC) are common functional gastrointestinal disorders affecting 14% and 20% of the U.S. population, respectively. Reviews of the evidence on the burden of illness associated with IBS and CC have not been comprehensive in scope and have not provided an assessment of the distribution of health care costs across categories of resource use. OBJECTIVES: To (a) identify studies from any geographic region or country perspective that measure the economic burden of the disease; (b) analyze the direct (medical, drug, and other components) and indirect costs of illness; and (c) assess published evidence of the humanistic burden as measured by quality of life (QOL). METHODS: An electronic literature search was conducted using journal databases, including MEDLINE, The Cochrane Library, EconLit, CINAHL, and Digestive Disease Week meeting abstracts. Specific search terms used were "irritable bowel syndrome" and "chronic constipation." In databases that accommodated Boolean searches, terms related to economic and quality of life outcomes were incorporated. Studies were included if they evaluated patients with an IBS or CC diagnosis and quantitatively measured the economic or humanistic burden of disease. Results were descriptively analyzed. RESULTS: The search identified a total of 882 unique publications. Thirty-five articles and abstracts met the inclusion criteria. Studies included 1,706 IBS-C, 2,264 IBS-D, 2,892 IBS A, 15,830 IBS unclassified, and 1,278 CC patients. Nineteen of 35 studies assessed cost-of-illness endpoints, and from the U.S. perspective, the direct cost per-patient for IBS ranged from $1,562 to $7,547 per year, while direct costs of CC ranged from $1,912 to $7,522 per year. From the U.S. perspective, the indirect costs of IBS ranged from $791 to $7,737 per year, and no study assessed the indirect costs of CC. For IBS, data on the distribution of costs attributable to categories of resource use varied widely, particularly outpatient costs (12.7% to > 50% of total costs), inpatient costs (6.2% to 40.8%), and pharmacy or drug costs (5.9% to 46.6%). Comparable data on CC were not identified. Nineteen studies of IBS patients measured the humanistic burden of disease; 14 studies utilized SF-36; and within-study domain scores were significantly lower in IBS patients compared with non-IBS controls. Only 1 study of CC patients reported humanistic burden of disease. CONCLUSIONS: The studies identified in the systematic review varied in the method used to identify patients with IBS and CC. Results were not typically reported by IBS subtype. We observed a large variation in attributable direct and indirect costs and drivers of these costs. Future research should refine burden of illness estimates to subtypes so that estimates associated with IBS-C and CC are differentiated. PMID- 24156645 TI - The impact of manufacturer coupon use in the statin market. AB - BACKGROUND: Pharmaceutical manufacturer coupons are a rapidly growing promotional activity intended to encourage initiation and continuing use of brand-name medications, but little is known about impacts on medication adherence and expenditures. OBJECTIVE: To understand which patients use manufacturer coupons and the impact of coupons on brand-name statin (atorvastatin and rosuvastatin) use and expenditures 1 year after initiation of statin therapy. METHODS: Using commercially available claims data spanning 3 years and representing 340,350 patients, we compared demographics, statin use, and expenditures of patients initiating generic statins, brand-name statins without manufacturer coupons, and brand-name statins with manufacturer coupons. Differences in user groups were tested using chi-squared statistics and Wilcoxon-Mann-Whitney tests. Main outcome measures included statin fills, adherence, and expenditures, including patient out-of-pocket, payer, and total costs. RESULTS: With the exception of population density, there were no significant demographic differences between new to therapy brand-name statin users filling prescriptions with and without coupons. New to therapy patients using generics were younger and lived in less populated areas compared with new to therapy brand-name statin noncoupon users. The number of statin fills in the 12 months following initiation was highest for coupon users, slightly lower for patients initiating generic statins, and lowest for noncoupon users (7.1 vs. 6.3 vs. 5.8; P < 0.001), with corresponding medication adherence rates (61.1% vs. 60.1% vs. 53.8%; P < 0.001). Coupon users had higher total statin prescription costs than generic initiators and noncoupon users ($798 vs. $92 vs. $678; P < 0.001), and higher precoupon out-of-pocket costs ($339 vs. $53 vs. $169; P < 0.001). Health plan costs for statins excluding rebates were lower for coupon users than noncoupon users ($460 vs. $508; P < 0.001) but were much higher compared with generic statin initiators ($460 vs. $39; P < 0.001). CONCLUSIONS: Brand-name statin initiators using coupons have higher adherence than patients initiating generic statins or brand-name statins without coupons. While the differences in adherence were statistically significant, they may not be clinically significant. Higher adherence among coupon users appears to occur at the expense of higher out-of-pocket and total statin expenditures. PMID- 24156646 TI - Benefit restrictions and gout treatment. AB - BACKGROUND: Gout is a chronic rheumatic disease that can have serious sequelae, including persistent pain, nerve compression, joint destruction and deformities if left untreated. Febuxostat, initially introduced in the United States in 2009, was the first new treatment option for gout in over 40 years. With the introduction of a new drug into a therapeutic class that is composed of generically available options, utilization management will be a common strategy employed in an effort to contain cost; however, the effects of these strategies are not known for chronic gout treatment. OBJECTIVE: To evaluate the effect of utilization management strategies on chronic gout treatment. METHODS: This retrospective analysis examined claims data from a large, national pharmacy benefits manager with a client base that includes commercial HMOs, Medicaid, Medicare Part D, and self-insurers. The study population included patients aged 18 years or older who had at least 1 rejected claim for febuxostat in the 16 month identification period from March 1, 2009, through June 30, 2010. Outcomes of interest were the proportion of patients who filled a febuxostat prescription and proportion of patients who filled a prescription for another chronic gout treatment within 1 month of the febuxostat claim rejection date (the index date). Multivariate logistic regression models were used to assess factors affecting patient response to a rejected febuxostat claim. RESULTS: Of 1,034 patients with rejected febuxostat claims, 95% had claims denied due to utilization management: 36% due to step therapy, 25% due to lack of drug coverage, 18% due to quantity or other limits (i.e., fill limit exceeded, days supply exceeding benefit maximum, or maximum days supply limit exceeded), 16% due to prior authorization requirements, while 5% were due to "other reasons" unrelated to the utilization management strategies of interest. "Other reasons" included over 100 possible rejection reasons such as fill dispensed too soon, missing/invalid days supply, group not having benefit, physician not covered, non-matched group, not a network pharmacy, non-matched member, claim/member birth date not matching, and missing/invalid prescriber identifier. Subsequently, 474 (46%) of these patients filled a febuxostat prescription within 1 month of a rejected claim; 364 (35%) had not filled a prescription for any chronic gout medication within a month of the febuxostat claim rejection. Those filling a febuxostat prescription had higher pre-index total 6-month pharmacy costs than those not filling a chronic gout prescription ($1,718 vs. $988; P < 0.001) . They also had a higher number of pre-index drug claims (25 vs. 18; P < 0.001). The regression model found the following variables to be statistically significant in positively influencing the likelihood of patients filling a febuxostat prescription within a month of a febuxostat claim rejection: (a) self-insured coverage (compared with commercial HMO coverage); (b) pre-index total prescription costs of at least $1,800; (c) claim rejection due to quantity or other limit (compared with lack of drug coverage); (d) claim rejection due to "other reason" (compared with lack of drug coverage); and (e) 1 and >=1 pre-index colchicine claim. Patients with projected febuxostat copay of $100 to $149 were found to be less likely to fill febuxostat compared with patients with a projected copay of $0 to $19. CONCLUSION: Utilization management strategies likely result in gaps in gout treatment; 35% of patients with a denied febuxostat claim in this study population did not fill a prescription for any chronic gout therapy within a month of the claim denial. These findings are important in the consideration of benefit design in gout treatment. PMID- 24156647 TI - Effects on patient care caused by drug shortages: a survey. AB - BACKGROUND: Drug shortages pose a serious challenge for health care institutions, often interfering with patient care. A common practice during a drug shortage is to select an alternate therapeutic; however, these agents often present challenges and may create safety concerns. Patient harms including adverse events and medication errors may occur. Patients may also file complaints because of drug shortages. OBJECTIVE: To measure the effect of drug shortages on patient outcomes, clinical pharmacy operations, patient complaints, and institutional cost. METHODS: An e-mail link to an online survey was sent to pharmacy director members in the MedAssets Pharmacy Group Purchasing Organization. Data were collected within a 3-week period from October 2-23, 2012. The survey focused on 6 different domains: demographics, adverse events, medication errors, patient outcomes, patient complaints, and institutional cost. RESULTS: The survey was sent to 1,516 directors of pharmacy. There were 193 respondents (response rate 13%) who participated in the survey. Approximately 40% of respondents reported between 1 and 5 adverse events probably or possibly associated with drug shortages at their institution. The majority of respondents reported between 1 and 10 medication errors. The most common types of medication errors reported were omission (n = 86, 55.5%), wrong dose dispensed/administered (n = 85, 54.8%), and wrong drug dispensed/administered (n = 54, 34.8%). The most common outcomes reported by respondents were alternative medication used (n=146, 85.3%), delay of therapy (n = 121, 70.8%), and increased patient monitoring necessary (n = 84, 49.1%). Patient complaints were reported by 38% of respondents. The majority of respondents reported an estimated quarterly institutional cost from shortages of less than $100,000, and approximately one quarter of respondents reported adding at least 1 full-time equivalent to manage drug shortages. The majority of participant comments mentioned the increasing institutional costs attributed to drug shortages. CONCLUSIONS: Medication errors and adverse events continue to occur from drug shortages, often resulting in inadequate patient care, high institutional costs, and patient complaints. Delayed care and cancelled care have been reported from shortages. Further research is necessary to better classify medication errors and adverse events during a drug shortage. PMID- 24156648 TI - Cost implications of formulary decisions on oral anticoagulants in nonvalvular atrial fibrillation. AB - BACKGROUND: Nonvalvular atrial fibrillation (AF) is a major public health issue. The major complication of AF is an increased risk of stroke. Warfarin, long used for stroke prophylaxis in AF patients, has a narrow therapeutic window and numerous food and drug interactions necessitating regular laboratory monitoring. New oral anticoagulants (e.g., dabigatran, rivaroxaban, apixaban) may meet the need for predictable anticoagulation with fixed, unmonitored dosing. OBJECTIVE: To review costs of monitoring, bleeding, and stroke in AF patients to analyze costs of anticoagulants for stroke prophylaxis in AF patients. METHODS: A literature search on the costs of treating AF used PubMed/MEDLINE databases (to April 2012) focusing on studies in the United States. Key words or MeSH terms were used, such as "observational studies," "oral anticoagulants," "warfarin," "cost of bleeding," "cost of stroke," and "cost of INR monitoring." RESULTS: The literature focused mainly on short-term, in-hospital expenditures and less on long-term care costs. Annual overall costs per patient for treating AF in the United States ranged from $18,454 to $38,270. Annual incremental costs of treating AF ranged from $8,705 to $16,311. Annual inpatient costs ranged from $7,841 to $22,582 per patient. Annual costs of anticoagulation monitoring ranged from $291 to $943 per patient. Intracranial hemorrhage and major gastrointestinal bleeding with oral anticoagulants were uncommon but expensive: 1-year costs ranged from $7,584 to $193,804. Annual direct costs of stroke in AF patients ranged from $23,143 to $37,620 (incremental cost of $7,824 to $8,232 vs. AF patients without stroke). CONCLUSIONS: AF-associated direct costs are high and can be broken into costs of warfarin monitoring and direct costs of managing consequences of anticoagulant therapy-stroke and bleeding. PMID- 24156649 TI - Budgetary impact on a U.S. health plan adopting abiraterone acetate plus prednisone for the treatment of patients with metastatic castration-resistant prostate cancer. AB - BACKGROUND: Abiraterone acetate, an androgen biosynthesis inhibitor, received FDA approval in 2011 for metastatic castration-resistant prostate cancer (mCRPC) patients who have received prior chemotherapy containing docetaxel. OBJECTIVE: To estimate the projected budgetary impact of adopting abiraterone for mCRPC patients from a U.S. health plan perspective. METHODS: A decision analytic model compared mCRPC treatment cost before and after abiraterone acetate adoption based on a hypothetical 1,000,000-member plan. Plan mCRPC prevalence was derived from prostate cancer incidence reported in U.S. epidemiology statistics and disease progression data from published trials. Market shares for comparator mCRPC treatments (prednisone alone; cabazitaxel + prednisone; mitoxantrone + prednisone; docetaxel retreatment + prednisone) were derived from market research simulation. Abiraterone + prednisone uptake (8% - scenario 1 to 55% - scenario 3) was based on assumptions for illustrative purposes. Treatment costs were computed using prescribing information, treatment duration from phase III trials, and drug costs considering common U.S. cost listing and reimbursement schemes. Prevalence and costs of managing treatment-related toxicities were estimated from literature, treatment guidelines, and expert clinical opinion. The model evaluated the perspectives of a commercial payer with no Medicare beneficiaries and a commercial payer with a subset of Medicare beneficiaries. Sensitivity analyses were conducted to assess changing input values. RESULTS: In each modeled scenario, 57 patients with prior docetaxel therapy received treatment for mCRPC. For the commercial perspective, the incremental per-member-per-month (PMPM) cost attributable to abiraterone ranged from $0.0019 in scenario 1 to $0.0133 in scenario 3. For the commercial/Medicare perspective, the incremental PMPM ranged from $0.0026 in scenario 1 to $0.0176 in scenario 3. The average incremental PMPM cost over 3 scenarios is $0.0112. When testing key sensitivity scenarios, the model indicated that abiraterone treatment duration and cabazitaxel market share were the main drivers of cost. CONCLUSIONS: The model results indicate that reimbursement for abiraterone may have a neutral impact on a U.S. health plan budget given the relatively small size of the eligible prostate cancer population and expected lower toxicity-related costs as compared with chemotherapy. The sensitivity analyses addressing the components of uncertainty in the model show that the budgetary impact of abiraterone is likely low. PMID- 24156651 TI - Characterization of immunoglobulin by mass spectrometry with applications for the clinical laboratory. AB - Studies monitoring immunoglobulin (Ig) antigen specificity have brought to light key Ig biomarkers for immunity, autoimmunity, cancer detection, and immune system function evaluation. A fundamentally new approach to the detection of Igs based on the primary structure of the Ig is beginning to emerge in the literature. This approach has only become feasible in light of advances in proteomics and rapid improvements in mass spectrometry (MS). Driven primarily by the development of Ig pharmaceuticals, Ig MS-based proteomic methods are revealing structural features which were previously unavailable with other characterization techniques. The task of adapting these techniques to clinical chemistry is in its infancy, but these methods have the potential to dramatically alter testing for Ig biomarkers. The purpose of this article is to review the advances that have been made in proteomic characterization of Igs by MS and the early attempts to apply these methods to clinical samples. PMID- 24156650 TI - Biomarkers of lung epithelial injury and inflammation distinguish severe sepsis patients with acute respiratory distress syndrome. AB - INTRODUCTION: Despite recent modifications, the clinical definition of the acute respiratory distress syndrome (ARDS) remains non-specific, leading to under diagnosis and under-treatment. This study was designed to test the hypothesis that a biomarker panel would be useful for biologic confirmation of the clinical diagnosis of ARDS in patients at risk of developing ARDS due to severe sepsis. METHODS: This was a retrospective case control study of 100 patients with severe sepsis and no evidence of ARDS compared to 100 patients with severe sepsis and evidence of ARDS on at least two of their first four ICU days. A panel that included 11 biomarkers of inflammation, fibroblast activation, proteolytic injury, endothelial injury, and lung epithelial injury was measured in plasma from the morning of ICU day two. A backward elimination model building strategy on 1,000 bootstrapped data was used to select the best performing biomarkers for further consideration in a logistic regression model for diagnosis of ARDS. RESULTS: Using the five best-performing biomarkers (surfactant protein-D (SP-D), receptor for advanced glycation end-products (RAGE), interleukin-8 (IL-8), club cell secretory protein (CC-16), and interleukin-6 (IL-6)) the area under the receiver operator characteristic curve (AUC) was 0.75 (95% CI: 0.7 to 0.84) for the diagnosis of ARDS. The AUC improved to 0.82 (95% CI: 0.77 to 0.90) for diagnosis of severe ARDS, defined as ARDS present on all four of the first four ICU days. CONCLUSIONS: Abnormal levels of five plasma biomarkers including three biomarkers generated by lung epithelium (SP-D, RAGE, CC-16) provided excellent discrimination for diagnosis of ARDS in patients with severe sepsis. Altered levels of plasma biomarkers may be useful biologic confirmation of the diagnosis of ARDS in patients with sepsis, and also potentially for selecting patients for clinical trials that are designed to reduce lung epithelial injury. PMID- 24156652 TI - Parkinson's disease, parkinsonism, and traumatic brain injury. AB - We review the relationship between traumatic brain injury (TBI) and the development of idiopathic Parkinson's disease (PD) or secondary parkinsonism. Limited by methodological issues such as recall bias and confounding risk factors, epidemiological studies on the association between TBI and idiopathic PD have so far yielded mixed results. While clinical reports describe parkinsonism - often with lesions in the substantia nigra - secondary to traumatic brain injury, these do not represent cases of idiopathic PD. In laboratory studies, animal models of traumatic brain injury demonstrate neuronal loss in the substantia nigra, altered dopaminergic metabolism, or altered synuclein pathology. While parkinsonism does occur secondary to TBI, the relationship between TBI and subsequent idiopathic PD remains controversial. PMID- 24156653 TI - Body fluid analysis: clinical utility and applicability of published studies to guide interpretation of today's laboratory testing in serous fluids. AB - Requests for testing various analytes in serous fluids (e.g., pleural, peritoneal, pericardial effusions) are submitted daily to clinical laboratories. Testing of these fluids deviates from assay manufacturers' specifications, as most laboratory assays are optimized for testing blood or urine specimens. These requests add a burden to clinical laboratories, which need to validate assay performance characteristics in these fluids to exclude matrix interferences (given the different composition of body fluids) while maintaining regulatory compliance. Body fluid testing for a number of analytes has been reported in the literature; however, understanding the clinical utility of these analytes is critical because laboratories must address the analytic and clinical validation requirements, while educating clinicians on proper test utilization. In this article, we review the published data to evaluate the clinical utility of testing for numerous analytes in body fluid specimens. We also highlight the pre-analytic and analytic variables that need to be considered when reviewing published studies in body fluid testing. Finally, we provide guidance on how published studies might (or might not) guide interpretation of test results in today's clinical laboratories. PMID- 24156654 TI - Electrochemical behavior of flavin adenine dinucleotide adsorbed onto carbon nanotube and nitrogen-doped carbon nanotube electrodes. AB - Flavin adenine dinucleotide (FAD) is a cofactor for many enzymes, but also an informative redox active surface probe for electrode materials such as carbon nanotubes (CNTs) and nitrogen-doped CNTs (N-CNTs). FAD spontaneously adsorbs onto the surface of CNTs and N-CNTs, displaying Langmuir adsorption characteristics. The Langmuir adsorption model provides a means of calculating the electroactive surface area (ESA), the equilibrium constant for the adsorption and desorption processes (K), and the Gibbs free energy of adsorption (DeltaG degrees ). Traditional ESA measurements based on the diffusional flux of a redox active molecule to the electrode surface underestimate the ESA of porous materials because pores are not penetrated. Techniques such as gas adsortion (BET) overestimate the ESA because it includes both electroactive and inactive areas. The ESA determined by extrapolation of the Langmuir adsorption model with the electroactive surface probe FAD will penetrate pores and only include electroactive areas. The redox activity of adsorbed FAD also displays a strong dependency on pH, which provides a means of determining the pKa of the surface confined species. The pKa of FAD decreases as the nitrogen content in the CNTs increases, suggesting a decreased hydrophobicity of the N-CNT surface. FAD desorption at N-CNTs slowly transforms the main FAD surface redox reaction with E1/2 at -0.84 V into two new, reversible, surface confined redox reactions with E1/2 at -0.65 and -0.76 V (vs Hg/Hg2SO4), respectively (1.0 M sodium phosphate buffer pH = 6.75). This is the first time these redox reactions have been observed. The new surface confined redox reactions were not observed during FAD desorption from nondoped CNTs. PMID- 24156655 TI - Insulin therapy and risk of colorectal cancer: an updated meta-analysis of epidemiological studies. AB - OBJECTIVE: An increasing number of studies show that exogenous insulin therapy may promote colorectal carcinogenesis. However, the results of the association between insulin therapy and risk of colorectal cancer (CRC) among type 2 diabetes patients are inconsistent. The purpose of our study is to examine the effect of insulin therapy on CRC risk among patients with type 2 diabetes in an updated meta-analysis. RESEARCH DESIGN AND METHODS: Medline and Embase were searched for the reference lists of pertinent articles published from January 1970 to April 2013. Two investigators independently extracted the data and reached consensus on the inclusion and exclusion criteria. Pooled relative risks and 95% confidence intervals were calculated with a random-effects model. RESULTS: Analysis of six studies, including 374,950 participants, showed that compared with non-insulin or metformin treatment, insulin treatment was associated with an increase of 37% in the risk of colorectal neoplasm among patients with type 2 diabetes, with moderate heterogeneity (I2=40%). The sensitivity analysis showed that exclusion of one small case-control study had no appreciable changes on the pooled results. Subgroup analyses suggested that there were significant positive associations between insulin therapy and risk of CRC in some subgroups, rather than all subgroups. CONCLUSIONS: Our meta-analysis supports a relationship between insulin therapy and increased risk of CRC in patients with type 2 diabetes. Because of bias and confounding of included studies, caution is needed when interpreting our results. Further investigations are needed. PMID- 24156656 TI - 1-Aryl-3-(1H-imidazol-1-yl)propan-1-ol esters: synthesis, anti-Candida potential and molecular modeling studies. AB - BACKGROUND: An increased incidence of fungal infections, both invasive and superficial, has been witnessed over the last two decades. Candida species seem to be the main etiology of nosocomial fungal infections worldwide with Candida albicans, which is commensal in healthy individuals, accounting for the majority of invasive Candida infections with about 30-40% of mortality. RESULTS: New aromatic and heterocyclic esters 5a-k of 1-aryl-3-(1H-imidazol-1-yl)propan-1-ols 4a-d were successfully synthesized and evaluated for their anti-Candida potential. Compound 5a emerged as the most active congener among the newly synthesized compounds 5a-k with MIC value of 0.0833 MUmol/mL as compared with fluconazole (MIC value >1.6325 MUmol/mL). Additionally, molecular modeling studies were conducted on a set of anti-Candida albicans compounds. CONCLUSION: The newly synthesized esters 5a-k showed more potent anti-Candida activities than fluconazole. Compounds 7 and 8 revealed significant anti-Candida albicans activity and were able to effectively satisfy the proposed pharmacophore geometry, using the energy accessible conformers (Econf < 20 kcal/mol). PMID- 24156657 TI - Halophyte-endophyte coupling: a promising bioremediation system for oil contaminated soil in Northwest China. PMID- 24156658 TI - CO2 capture by a rhenium(I) complex with the aid of triethanolamine. AB - A rhenium(I) tricarbonyl diimine complex with a N,N-dimethylformamide ligand captures one CO2 molecule in the presence of triethanolamine (TEOA), giving fac [Re(I)(bpy)(CO)3{R2N-CH2CH2O-COO}] (bpy = 2,2'-bipyridine, R = CH2CH2OH). This could be a predominant complex in various photocatalytic CO2 reduction reactions using [Re(I)(N^N)(CO)3X](n+) (N^N = diimine ligand; X = monodentate ligand; n = 0, 1) type complexes in the presence of TEOA. PMID- 24156659 TI - A route for modulating the diameter of cylindrical silicon nanowires by using thermal self-ordering silver nanoparticles. AB - For the synthesis of uniform sub-80-nm silicon nanowires (Si NWs), we introduce a metal-assisted chemical etching (MCE)-based facile and high-yield route, employing simple thermal annealing and vacuum deposition processes. Under rapid thermal annealing, an ultrathin silver (Ag) film on a Si substrate is self organized into Ag nanoparticles (NPs), which are used for making Si nanoholes through a short MCE process. After sputter deposition of Au (10 nm)/Ag (20 nm) on the caved Si substrate with nanoholes, a nanomesh is obtained. Finally, with the nanomesh as an etching mask, Si NWs are successfully produced through a second MCE process. The size of the Si NWs can be modulated by controlling the thickness of the initial Ag film. The minimum diameter of the synthesized Si NWs is 30 +/- 5 nm, and the maximum diameter is 68 +/- 10 nm. Furthermore, to determine the uniformity of our Si NWs, bottom-gate field-effect transistors were fabricated and the linearity of the on-current level of these transistors with the number of addressed Si NWs was confirmed. PMID- 24156660 TI - The burden of Plasmodium vivax relapses in an Amerindian village in French Guiana. AB - Malaria is a public health problem in French Guiana. Plasmodium vivax is the most frequent parasite. The objective of this analysis was to estimate the proportion of relapses in the burden of vivax malaria using the statistical rule stating that any case of vivax malaria occurring less than 90 days following a first episode is a relapse.A total of 622 subjects were followed for 2,9 years with 336 first single episodes of P. vivax malaria, and a total of 1,226 episodes of vivax malaria among which 559 were relapses (45.5%). For 194 patients having had falciparum malaria followed by vivax malaria it was estimated that 19% of the vivax episodes occurred less than 90 days following the falciparum episode and thus were possibly relapses due to the activation of latent hypnozoites. Despite the number of vivax cases and the number of relapses, there were only 28 recorded primaquine prescriptions (3.4% of vivax episodes, 4.5% of subjects).The present study points out that despite the fact that nearly half of the P. vivax cases, many of which in children, are caused by latent hypnozoites, only a minority of them benefit from primaquine radical cure. The obstacles to this are discussed and suggestions are made to reduce the burden of vivax malaria in Camopi and other remote health centres in French Guiana. PMID- 24156661 TI - Laparoscopic radiofrequency ablation of small renal tumors: long-term oncologic outcomes. AB - INTRODUCTION: Unlike percutaneous radiofrequency ablation (RFA) of small renal tumors, there are limited data assessing the long-term efficacy of laparoscopic RFA. Although the ablation cannot be visualized as reliably as with cryoablation, laparoscopic RFA allows for improved mobilization and placement of probes under direct vision. We reviewed our experience with laparoscopic RFA to assess long term oncologic outcomes. METHODS: We performed a retrospective study of all patients who had undergone laparoscopic RFA for pT1a renal tumors from April 2000 to April 2010. Demographic, clinical, and radiologic data were assessed to determine indications and evidence for recurrence of disease. Radiologic recurrence was defined as any new enhancement (>10 HU) after absence of enhancement on initial negative 6-week computed tomography. RESULTS: Data were available for 79 patients who had 111 small renal masses treated over the 10-year period. The median tumor diameter was 2.2 cm and intraoperative biopsy identified renal cell carcinoma in 77%. The median follow-up was 59 months with an estimated 5-year recurrence-free survival of 93.3%. The overall rate of complications was 8.8% with a 3.8% rate of major complications. CONCLUSIONS: Long-term experience with laparoscopic RFA demonstrates that it is a safe and effective option for the treatment of small renal tumors. Five-year oncologic outcomes appear to be comparable to extirpation. PMID- 24156662 TI - Overcoming challenges to adoption of shared medical appointments. AB - Although research has shown many benefits of Shared Medical Appointments (SMAs) or group visits, uptake by physicians has been quite limited. The objective of this study was to explore the facilitators and barriers to implementing SMAs in a large multispecialty medical group. This was a comparative analysis of SMAs at 3 geographically distinct, semiautonomous divisions of the medical group based on qualitative themes identified in audio recorded key informant interviews with medical and administrative staff (n=12) involved with the implementation of SMAs. Data were collected by conducting key informant interviews focusing on the SMA implementation process, including motivations, history, barriers, and facilitators. Uptake at the 3 divisions was predicated by differing motivations, facilitators, and barriers. Divisions 1 and 2 allocated necessary resources including management support, a physician champion, expert consults, and support staff. These divisions also overcame physician reluctance and financial sustainability challenges. Despite early interest, Division 3 did not devote the time or resources to overcome initial resistance. Without the impetus of management mandate or a champion's enthusiasm, early attempts of SMA implementation faltered and were abandoned. In these cases, a physician champion, management support, and financial sustainability were judged to be the primary enablers of successful implementations of SMAs. Without these enablers and other contributing factors, implementing SMAs was challenging. PMID- 24156663 TI - Sustained economic value of a wellness and disease prevention program: an 8-year longitudinal evaluation. AB - The objective of this study was to determine the sustained economic impact of a health promotion/disease prevention program delivered through a large regional health plan. This was a retrospective analysis of health risk, health claims, and cost using a mixed model factorial design for the years 2002-2009 that compared program participants to nonparticipants. All analyses were adjusted for age, sex, morbidity, and baseline health care costs as appropriate. The findings presented herein indicate a positive return on investment (ROI) for each program year with ratios ranging from a low of 1.16:1 to a high of 2.83:1. The average ROI collapsed across all 8 years was 2.02:1. The 2009 ROI approximated over $6 million in total savings. This study demonstrates the sustained economic value of a comprehensive health promotion program. PMID- 24156664 TI - Results of the promoting effective advance care planning for elders (PEACE) randomized pilot study. AB - The specific aim of the PEACE pilot study was to determine the feasibility of a fully powered study to test the effectiveness of an in-home geriatrics/palliative care interdisciplinary care management intervention for improving measures of utilization, quality of care, and quality of life in enrollees of Ohio's community-based long-term care Medicaid waiver program, PASSPORT. This was a randomized pilot study (n=40 intervention [IG], n=40 usual care) involving new enrollees into PASSPORT who were >60 years old. This was an in-home interdisciplinary chronic illness care management intervention by PASSPORT care managers collaborating with a hospital-based geriatrics/palliative care specialist team and the consumer's primary care physician. This pilot was not powered to test hypotheses; instead, it was hypothesis generating. Primary outcomes measured symptom control, mood, decision making, spirituality, and quality of life. Little difference was seen in primary outcomes; however, utilization favored the IG. At 12 months, the IG had fewer hospital visits (50% vs. 55%, P=0.65) and fewer nursing facility admissions (22.5% vs. 32.5%, P=0.32). Using hospital-based specialists interfacing with a community agency to provide a team-based approach to care of consumers with chronic illnesses was found to be feasible. Lack of change in symptom control or quality of life outcome measures may be related to the tools used, as these were validated in populations closer to the end of life. Data from this pilot study will be used to calculate the sample size needed for a fully powered trial. PMID- 24156665 TI - Cost of schizophrenia in the Medicare program. AB - Medicare beneficiaries diagnosed with non-schizoaffective schizophrenia (MBS) in a 5% national Medicare fee-for-service sample from 2003-2007 were followed for 1 6 years. Medicare population and cost estimates also were made from 2001-2009. Service utilization and Medicare (and beneficiary share) payments for all services except prescription drugs were analyzed. Although adults with schizophrenia make up approximately 1% of the US adult population, they represent about 1.5% of Medicare beneficiaries. MBSs are disproportionately male and minority compared to national data describing the overall schizophrenia population. They also are younger than the general Medicare population (GMB): males are 9 years younger than females on average, and most enter Medicare long before age 65 through eligibility for social security disability, remaining in the program until death. The cost of care for MBSs in 2009 was, on average, 80% higher than for the average GMB per patient year (2010 dollars), and more than 50% of these costs are attributable to a combination of psychiatric and medical hospitalizations, concentrated in about 30% of MBSs with 1 or more hospitalizations per year. From 2004-2009, total estimated Medicare fee-for service payments for MBSs increased from $9.4 billion to $11.5 billion, excluding Part D prescription drugs and payments for services to MBSs in Medicare for less than 1 year. Study results characterize utilization and costs for other services and suggest opportunities for further study to inform policy to improve access and continuity of care and decrease costs to the Medicare program associated with this population. PMID- 24156666 TI - Fluorescence lifetimes of the A1Piu state of C3. AB - The fluorescence lifetimes of 115 vibrational levels of the A1Pi(u) state of C3 have been measured under supersonic molecular beam conditions. Of these, ninety one are Pi(u) vibronic levels, for which the lifetimes lie in the range 190-700 ns. The lifetimes of those Pi(u) levels where only the bending vibration is excited lie in the range 190-235 ns. There is very little variation with bending quantum number, and the lifetimes of the two orbital components of the 1Pi(u) state are essentially the same. When nu1 and nu3 are excited, the lifetimes become longer and/or reach a maximum for levels with v1 + v3 ~ 4. Excitation of the bending vibration in addition to the stretching vibrations shortens the lifetime slightly. Several of the levels show double-exponential decays. Another 23 levels, of Sigma(u)+ vibronic symmetry, mostly have lifetimes that are longer than 300 ns. Interaction with nearby "dark" electronic states, such as B1Sigma(u) , B'1Delta(u), C1Pi(g), and b3Pi(g), is proposed to account for the observed lifetime lengthening. A particularly clear instance of such an interaction is the long lifetime (914 ns) of a perturbing Sigma(u)+ level at 30,181 cm(-1), which is confirmed as belonging to the perturbing B'1Delta(u) state. A single level of Delta(u) symmetry at 29,170 cm(-1), which perturbs one of the Pi(u) levels, is shown to belong to the A state. PMID- 24156667 TI - Maternal magnesium level effect on preterm labor treatment. AB - OBJECTIVE: To compare the initial serum magnesium levels between preterm labor (PL) and control groups and to evaluate MgSO4 treatment response in preterm labor group according to their initial serum magnesium levels. METHODS: Hundred women diagnosed as preterm labor between 28 and 33 weeks of gestation and 100 non complicated pregnant women were enrolled in this prospective study. Total basal serum magnesium levels were measured in both the groups. After a 6 g intravenous bolus of MgSO4, a dose of 2 g/h was given as an infusion in the preterm labor group. RESULTS: Serum magnesium levels were significantly lower in preterm labor group (p < 0.001). The active contractions stopped in 69 (73,4%) preterm patients. The basal Mg level was significantly lower in this preterm group (1.6 versus 1.9, respectively, p < 0.001). Predictive value of basal magnesium level measurement for magnesium tocolysis response was calculated by receiver operating characteristic analyses with 95% confidence interval. Positive predictive and negative predictive values were found as 64.5% and 92.5%, respectively, with 83% accuracy, when cut-off magnesium value was taken as a <1.75 mg/dl (sensitivity = 80%, specificity = 84,1%). CONCLUSIONS: Basal magnesium levels in preterm labor had a predictive value in evaluating MgSO4 tocolysis response. It may help to select patients who are appropriate for MgSO4 tocolysis. PMID- 24156668 TI - A gray-box neural network-based model identification and fault estimation scheme for nonlinear dynamic systems. AB - A novel gray-box neural network model (GBNNM), including multi-layer perception (MLP) neural network (NN) and integrators, is proposed for a model identification and fault estimation (MIFE) scheme. With the GBNNM, both the nonlinearity and dynamics of a class of nonlinear dynamic systems can be approximated. Unlike previous NN-based model identification methods, the GBNNM directly inherits system dynamics and separately models system nonlinearities. This model corresponds well with the object system and is easy to build. The GBNNM is embedded online as a normal model reference to obtain the quantitative residual between the object system output and the GBNNM output. This residual can accurately indicate the fault offset value, so it is suitable for differing fault severities. To further estimate the fault parameters (FPs), an improved extended state observer (ESO) using the same NNs (IESONN) from the GBNNM is proposed to avoid requiring the knowledge of ESO nonlinearity. Then, the proposed MIFE scheme is applied for reaction wheels (RW) in a satellite attitude control system (SACS). The scheme using the GBNNM is compared with other NNs in the same fault scenario, and several partial loss of effect (LOE) faults with different severities are considered to validate the effectiveness of the FP estimation and its superiority. PMID- 24156669 TI - Application of quantum-behaved particle swarm optimization to motor imagery EEG classification. AB - In this study, we propose a recognition system for single-trial analysis of motor imagery (MI) electroencephalogram (EEG) data. Applying event-related brain potential (ERP) data acquired from the sensorimotor cortices, the system chiefly consists of automatic artifact elimination, feature extraction, feature selection and classification. In addition to the use of independent component analysis, a similarity measure is proposed to further remove the electrooculographic (EOG) artifacts automatically. Several potential features, such as wavelet-fractal features, are then extracted for subsequent classification. Next, quantum-behaved particle swarm optimization (QPSO) is used to select features from the feature combination. Finally, selected sub-features are classified by support vector machine (SVM). Compared with without artifact elimination, feature selection using a genetic algorithm (GA) and feature classification with Fisher's linear discriminant (FLD) on MI data from two data sets for eight subjects, the results indicate that the proposed method is promising in brain-computer interface (BCI) applications. PMID- 24156671 TI - Comparison of ictal and interictal EEG signals using fractal features. AB - The feature analysis of epileptic EEG is very significant in diagnosis of epilepsy. This paper introduces two nonlinear features derived from fractal geometry for epileptic EEG analysis. The features of blanket dimension and fractal intercept are extracted to characterize behavior of EEG activities, and then their discriminatory power for ictal and interictal EEGs are compared by means of statistical methods. It is found that there is significant difference of the blanket dimension and fractal intercept between interictal and ictal EEGs, and the difference of the fractal intercept feature between interictal and ictal EEGs is more noticeable than the blanket dimension feature. Furthermore, these two fractal features at multi-scales are combined with support vector machine (SVM) to achieve accuracies of 97.58% for ictal and interictal EEG classification and 97.13% for normal, ictal and interictal EEG classification. PMID- 24156670 TI - Electrophysiological responses from vagus nerve stimulation in rats. AB - The mechanism of action of vagus nerve stimulation (VNS) for pharmacoresistant epilepsy is unknown and the therapeutic outcome is highly variable. We investigated stimulation-induced vagus nerve electrophysiological responses in rats using various stimulation parameters. Conduction velocity, I(50), rheobase and chronaxie were calculated. We identified an early and late component corresponding to an afferent compound action potential (CAP) and a remote laryngeal motor-evoked potential (LMEP), respectively. The conduction velocity (CAP: 26.2 +/- 1.4 m/s; LMEP: 32.4 +/- 2.4 m/s) and I(50) (CAP: 2.4 +/- 0.3 mA; LMEP: 1.8+/-0.2 mA) were significantly different for both components, the rheobase (CAP: 140+/-30 MUA; LMEP: 110+/-26 MUA) and chronaxie (CAP: 66+/-7 MUs; LMEP: 73+/-9 MUs) were not. Using a pulse of 10 MUs, the CAP saturated between 4 5 mA. Our method can be used to record VNS-induced electrophysiological responses in rats and provides an objective biomarker for electrical stimulation with various parameters in an experimental set-up. Our findings are potentially useful for clinical purposes in the sense that combination of VNS and recording of vagal nerve CAPs may help clinicians to determine the individual optimal intensity required to fully activate fast-conducting afferent fibers. PMID- 24156672 TI - Evolving RBF neural networks for adaptive soft-sensor design. AB - This work presents an adaptive framework for building soft-sensors based on radial basis function (RBF) neural network models. The adaptive fuzzy means algorithm is utilized in order to evolve an RBF network, which approximates the unknown system based on input-output data from it. The methodology gradually builds the RBF network model, based on two separate levels of adaptation: On the first level, the structure of the hidden layer is modified by adding or deleting RBF centers, while on the second level, the synaptic weights are adjusted with the recursive least squares with exponential forgetting algorithm. The proposed approach is tested on two different systems, namely a simulated nonlinear DC Motor and a real industrial reactor. The results show that the produced soft sensors can be successfully applied to model the two nonlinear systems. A comparison with two different adaptive modeling techniques, namely a dynamic evolving neural-fuzzy inference system (DENFIS) and neural networks trained with online backpropagation, highlights the advantages of the proposed methodology. PMID- 24156675 TI - T cell response specificity and magnitude against SIVmac239 are not concordant in major histocompatibility complex-matched animals. AB - BACKGROUND: CD8+ T cell responses, restricted by major histocompatibility complex (MHC) class I molecules, are critical to controlling human immunodeficiency virus type 1 (HIV-1) and simian immunodeficiency virus (SIV) replication. Previous studies have used MHC-matched siblings and monozygotic twins to evaluate genetic and stochastic influences on HIV-specific T cell responses and viral evolution. Here we used a genetically restricted population of Mauritian cynomolgus macaques (MCM) to characterize T cell responses within nine pairs of MHC-matched animals. FINDINGS: In MHC-matched animals, there was considerable heterogeneity in the specificity and magnitude of T cell responses detected via individual peptide gamma interferon (IFN-gamma) enzyme-linked immunospot (ELISPOT) assays. These findings were further supported by full proteome pooled peptide matrix ELISPOT data collected from this cohort at 52 weeks post-infection. Interestingly, peptide regions that elicited dominant T cell responses were more commonly shared between MHC-matched MCM than peptide regions that elicited non-dominant T cell responses. CONCLUSIONS: Our findings suggest that, while some T cell responses mounted during chronic infection by MHC-matched MCM are similar, the majority of responses are highly variable. Shared responses detected in this study between MHC-matched MCM were directed against epitopes that had previously elicited relatively dominant responses in MCM with the same MHC class I haplotype, suggesting that the factors that influence dominance may influence the reproducibility of responses as well. This may be an important consideration for future T cell-based vaccines aiming to consistently and reproducibly elicit protective T cell responses. PMID- 24156676 TI - Vascular reactivity of arteria femoralis in adult and aged spontaneously hypertensive and Wistar-Kyoto rats. AB - AIM: The relationship of age and hypertension on endothelial dysfunction and increased responses to vasoconstrictor stimuli. BACKGROUND: Hypertension is a disease accompanied by endothelial dysfunction and is characterized by an impaired vascular reactivity and enhanced activity of sympathetic nervous system. MATERIALS AND METHODS: In our experiment, we used spontaneously hypertensive rats representing model of essential hypertension and the Wistar-Kyoto rats as normotensive strain. Femoral arteries of adult and aged rats were put into the chamber of Mulvany-Halpern isometric myograph. As the nutrient solution, the modified Krebs-Henseleit solution having temperature 37 degrees C and bubbled with O2 was used. After 30 minutes stabilization of blood vessels, a dose dependent curve of norepinephrine response was recorded (concentrations 3x10-8 M, 10-7 M, 3x10-7 M, 10-6 M, 3x10-6 M, 10-5 M, 3x10-5 M, 10-4 M), followed by a dose dependent curve of acetylcholine response (concentrations 3x10-8 M, 10-7 M, 3x10 7 M, 10-6 M, 3x10-6 M). RESULTS: Our experiments recorded an increased reactivity to contraction stimuli in spontaneously hypertensive animals. Vascular reactivity to norepinephrine at 5 month and 12 month old rats from the same group was not significantly affected. Our experiments on the other hand, did not record a reduced endothelium-dependent relaxation in hypertensive compared to normotensive animals, neither in different age groups. CONCLUSIONS: Increased norepinephrine induced contraction occurs even before development of reduced acetylcholine induced relaxation in SHR rats. We predict that in our experiment hypertension plays a bigger role in the development of endothelial dysfunction than aging (Fig. 2, Ref. 22). PMID- 24156677 TI - Cilostazol-induced relaxation of calf cardiac vein and coronary artery during cooling. AB - OBJECTIVE: At present very little is known about the role of endothelial nitric oxide (NO) in the effects of temperature on vascular reactivity. The aim of the present study is to evaluate the influence of cooling (to 28 degrees C) on the vasodilatation induced by cilostazol(10-9-3x10-4M) on carbachol (10-6) precontracted calf cardiac vein and coronary artery and the role of NO in these effects. MATERIALS AND METHODS: Ring preparations of great cardiac vein and the anterior interventricular branch of left coronary artery were used. RESULTS: Cilostazol produced concentration-dependent relaxation of calf cardiac vein and coronary artery rings precontracted with carbachol. During cooling, the pIC50 values, but not the maximal responses to cilostazol were significantly lower than at 37 degrees C in both preparations. Cooling to 28 degrees C in the presence of NG-nitro-L-arginine methyl ester (L-NAME, 10-4 M) did not modify the effect of temperature both in cardiac vein and coronary artery. These results demonstrate for the first time that cooling-induced changes of cilostazol in calf cardiac vein and coronary artery are independent of NO (Tab. 2, Fig. 3, Ref. 32). PMID- 24156678 TI - Does preoperative administration of allopurinol protect the lungs from ischemia reperfusion injury occuring during cardiopulmonary bypass? AB - BACKGROUND: It is investigated whether preoperative allopurinol administration protects lung injury induced by cardiopulmonary bypass (CPB). METHODS: Sixty patients with coronary artery disease who need elective coronary artery bypass grafting operations by using CPB were taken into this study. They were divided into two groups; control and allopurinol. Allopurinol (300 mg/day) was administered to the latter group during the preoperative period of 5 days. Standard CPB procedures were used in all cases. Blood was sampled for TNF-alpha, IL-6, IL-8, IL-10 before anesthesia (T0), after anesthesia and before skin incision (T1), before CPB (T2), after aortic declamping (T3), at the end of CPB (T4), 6 hours after operation (T5), 12 hours after operation (T6), and 24 hours after operation (T7). Pulmonary function test (PFT) was performed before and following the 6th day of operation. RESULTS: TNF-alpha, IL-6, IL-8 increased in both groups at T3, T4, T5 and T6 compared to control (p<0.05). TNF-alpha, IL-6, and IL-8 levels were lower in group A at T3, T4, T5 and T6 (p<0.05). Creatinin phosphokinase (CK) levels were lower in group A at T6 (p<0.05). CK-MB levels were lower in group A than in group C (p<0.05). Pulmonary function test (PFT) did not yield any differences between the groups. CONCLUSIONS: Preoperative allopurinol administration decreases the inflammation and myocardial injury according to biochemical markers of ischemia reperfusion injury. However, this biochemical success does not rebound to PFT (Tab. 5, Ref. 15). PMID- 24156679 TI - Prognostic significance of the preoperative serum levels of soluble form of endoglin in gastric cancer patients. AB - BACKGROUND: Gastric cancer is the second commonest cause of cancer-associated deaths in the world. Its molecular markers can be useful not only for the diagnostic pursuit but also for prognostic purposes. Endoglin was proposed as a marker of neovascularization in solid malignancies. A circulating form of endoglin is referred to as soluble endoglin (sol-end).The purpose of this study was to investigate the clinical importance of serum level of soluble form of sol end in gastric cancer patients. MATERIALS AND METHODS: Serum levels of sol-end were measured in 69 healthy controls and in 60 gastric adenocarcinoma patients with ELISA and serum levels of sol-end were compared with clinicopathological features and outcomes in gastric cancer patients. RESULTS: Serum levels of sol end in gastric adenocancer patients were significantly higher than in control patients (p<0.001). The serum levels of sol-end did not differ relative to clinical and pathologic criteria. CONCLUSION: Presented data suggest that serum levels of sol-end do not seem to be a valuable tool in the assessment of gastric cancer prognosis (Tab. 1, Ref. 11). PMID- 24156680 TI - Importance of systemic mediastinal lymphadenectomy in exact staging of bronchogenic carcinoma. AB - BACKGROUND: Constituent part of radical lung resection for lung cancer is a dissection of mediastinal lymph nodes. Lymphadenectomy is a standard procedure in an assessment of clinical stage of the disease. The aim of the study was to map metastasizing of bronchogenic non-small cell lung carcinoma into homolateral mediastinal lymph nodes and to assess the importance of mediastinal lymphadenectomy for exact staging and survival. METHODS: Study of 31patients with lung resection and systematic mediastinal lymphadenectomy operated from August 2004 to January 2007, with pre-operative stage Ia to IIb (TNM classification) - according to CT without mediastinal lymph nodes invasion and with positive histological finding after systematic mediastinal lymphadenectomy. RESULTS: Tumors in right upper lobe metastasized in 45.5 % into group 1 nodes (stages N1 N4) and group 3 nodes (stages N7) and in 9 % into group 4 nodes (stages N8-N9). Tumors of the right middle lobe metastasized in 100 % into group 3 nodes (stage N7).Tumors of the right lower lobe metastasized in 87.5 % into group 3 nodes (N7) and in 12.5 % into group 4 nodes (stages N8-N9). Tumors of the left upper lobe metastasized in 9.0 % in group 1 nodes (stages N1-N4), in 82 % into group 2 nodes (stages N5-N6) and in 9.0 % were found skip metastases into group 4 nodes (stages N8-N9). Tumors of the left lower lobe metastasized in 26.7 % in group 4 nodes, 46.6 % into group 3 nodes, in 20,0 % into group 2 nodes and in 6,7 % into group 1 nodes. CONCLUSION: Systematic mediastinal lymphadenectomy is crucial for determining the stage of the disease according to the TNM classification. Systematic lymphadenectomy is essential for the diagnosis of stage IIIa disease and setting of additional therapy that prolongs survival (Ref. 17). PMID- 24156681 TI - Growth and obesity and its association with plasma level of steroid hormones and insulin-like growth factor-I (IGF-I) in Slovak female students. AB - The aim of the present study was to examine the possible role of steroid hormones and insulin-like growth factor 1 (IGF-I) in the control of human growth and obesity. We measured plasma level of progesterone, testosterone, estradiol and IGF-I in 301 young women at different stages of their ovarian cycle, and compared them to the standard morphometric indexes of their growth and obesity - body height, body weight, abdomen circumstance and waist to hip ratio (WHR). The ovarian cycle-dependent changes in plasma progesterone and estradiol, but not in testosterone and IGF-I level were found. Young women with higher body height had significantly higher plasma level of estradiol, testosterone and IGF-I, but not of progesterone, compared to subjects with lower body height in both follicular and luteal phases of the ovarian cycle. Subjects with a higher body weight had significantly higher plasma estradiol and progesterone, but not testosterone and IGF-I than subjects with lower body weight in both follicular and luteal phases of ovarian cycle. Women with a higher abdomen circumference had significantly lower plasma estradiol, but not the other hormones than the subjects with lower abdomen circumference. Women with higher WHR index had significantly higher plasma level of estradiol, but not other hormones than subjects with lower WHR index in both follicular and luteal phases of ovarian cycle. The present observations suggests: (1) that luteal phase of the women ovarian cycle is characterised by a dramatically increase in both progesterone and estradiol, but not in testosterone and IGF-I release, (2) that in human females growth can be up regulated by testosterone, estradiol and IGF-I, but not by progesterone, (3) that body mass can be up-regulated by progesterone and estradiol, but not by testosterone or IGF-I, and (4) that women obesity (high WHR, but not abdomen circumference) can be promoted by estradiol, but not by other steroid hormones or IGF-I (Tab. 1, Fig. 4, Ref. 45). PMID- 24156682 TI - Consumption of three strong opioids (morphine, oxycodone and fentanyl) in seven European countries during seven years (2003-2009). AB - PURPOSE: The aim was to analyse the consumption of selected strong opioid analgesics during a seven-year period of 2003-2009 in order to compare Slovak consumption with that in six other European countries and to determine our position. METHODS: Drug consumption data from the State Institute for Drug Control in Slovak Republic were used. As to the data from other countries, annual health statistics published on websites were used in comparison. RESULTS: Obviously the consumption of one of studied opioid drugs with transdermal aplication route, particularly fentanyl, tended to increase in all countries during the observed period. Oxycodone tends to yield a rapid increase in consumption as well. As opposed to the latter drugs, the consumption of morphine was decreasing throughout the observed period. The consumption of these drugs in Slovakia remains low (except for that of fentanyl). CONCLUSION: Our analysis confirmed a clear shift from oral to transdermal therapy as well as usage of newer drugs. Drug consumption data are a relatively new source of information for health research. Our analysis showed increasing trends in fentanyl (patch opioid) consumption in all compared countries as well as an increasing consumption of oxycodone and decreasing consumption of morphine (Fig. 3, Ref. 17). PMID- 24156683 TI - Congenital pulmonary airway malformation. AB - BACKGROUND: Congenital cystic adenomatoid malformations (CCAMs) are considered rare developmental anomalies of the lower respiratory tract. These are hamartomatous abnormalities of the lung with adenomatoid proliferation of cysts resembling bronchioles and ususally occur sporadically occur and unilaterally with single lobe involvement. METHOD: A 6-year-old girl was admitted to our center because of prolonged fever and non-productive cough lasting3 months before admission. RESULTS: The only other complaint was night sweating. She did not have dyspnea and did not mention any respiratory symptoms. On examination, coarse crackle and decreased lung sounds in the left side were detected. White blood cell count was 9.100 /uL, hemoglobin was 11.2 g/dL, erythrocyte sedimentation rate was 50 and C-reactive protein was 1+. IgA and IgM for hydatid cyst were tested and both were raised (14 and 1.4, respectively). CONCLUSION: The patient underwent surgery, with the probable diagnosis of hydatid cyst but in operating room diagnosis was changed and it was adenomatoid cystic malformation. In follow up, she was in good general condition without any post-surgical complaints (Fig. 3, Ref. 11). PMID- 24156684 TI - Transient ischemic attack in the vertebro-basilar circulation due to a hemodynamically significant variation - kinking of the extracranial section of the left vertebral artery. AB - We present a case report of a 74-year old female patient with the clinical diagnosis of transient ischemic attack (TIA) in the vertebro-basilar (VB) circulation, in whom we found bilateral variation of the extracranial section of vertebral arteries on ultrasound, on the left side to the extent of kinking. This finding was later confirmed by magnetic resonance angiography (MRA). We discuss the presumed hemodynamic significance of this variation and its etiological relation to the patient's clinical picture. Ultrasound examination of the carotid and vertebro-basilar circulations is an important examination technique contributing to an early detection of possible aetiology of the cerebral circulation disorders (Fig. 7, Ref. 18). PMID- 24156685 TI - Alleviating travel anxiety through virtual reality and narrated video technology. AB - This study presents an empirical evidence of benefit of narrative video clips in embedded virtual reality websites of hotels for relieving travel anxiety. Even though it was proven that virtual reality functions do provide some relief in travel anxiety, a stronger virtual reality website can be built when narrative video clips that show video clips with narration about important aspects of the hotel. We posit that these important aspects are 1. Escape route and 2. Surrounding neighborhood information, which are derived from the existing research on anxiety disorder as well as travel anxiety. Thus we created a video clip that showed and narrated about the escape route from the hotel room, another video clip that showed and narrated about surrounding neighborhood. We then conducted experiments with this enhanced virtual reality website of a hotel by having human subjects play with the website and fill out a questionnaire. The result confirms our hypothesis that there is a statistically significant relationship between the degree of travel anxiety and psychological relief caused by the use of embedded virtual reality functions with narrative video clips of a hotel website (Tab. 2, Fig. 3, Ref. 26). PMID- 24156686 TI - Malignant schwannoma of the obturator nerve. AB - Lesions of obturator nerve are rare. Tumours and mainly malignant schwannoma of this nerve are extremely rare. The authors describe an unusual case of a gigantic schwannoma of the obturator nerve in 69 year old woman. Due to tumour expansion in the proximal part of the thigh MRI was performed and demonstrated extensive tumour originating most probably from the obturator nerve. The patient had no neurological symptoms. Biopsy from the lesion was taken at the Department of Orthopaedics with the following conclusion: malignant schwannoma. The patient received neoadjuvant chemotherapy due to diffuse metastatic spread on the chest X ray, after which metastatic spread subsided. The main lesion reduced its size by 1 cm. In 4 months after biopsy the patient was referred for operation to neurosurgery. The tumour was removed along its borders and except of minimal weakness of adduction of the right thigh there was no neurological deterioration. She was subsequently referred for further care to oncology and radiotherapy.The goal of this work is to emphasize the extremely rare occurrence of tumours of this nerve and suggest therapeutic options (Fig. 4, Ref. 11). PMID- 24156687 TI - Efficacy of adding the Kinesio Taping method to guideline-endorsed conventional physiotherapy in patients with chronic nonspecific low back pain: a randomised controlled trial. AB - BACKGROUND: Chronic nonspecific low back pain is a significant health condition with high prevalence worldwide and it is associated with enormous costs to society. Clinical practice guidelines show that many interventions are available to treat patients with chronic low back pain, but the vast majority of these interventions have a modest effect in reducing pain and disability. An intervention that has been widespread in recent years is the use of elastic bandages called Kinesio Taping. Although Kinesio Taping has been used extensively in clinical practice, current evidence does not support the use of this intervention; however these conclusions are based on a small number of underpowered studies. Therefore, questions remain about the effectiveness of the Kinesio Taping method as an additional treatment to interventions, such as conventional physiotherapy, that have already been recommended by the current clinical practice guidelines in robust and high-quality randomised controlled trials. We aim to determine the effectiveness of the addition of the use of Kinesio Taping in patients with chronic nonspecific low back pain who receive guideline-endorsed conventional physiotherapy. METHODS/DESIGN: One hundred and forty-eight patients will be randomly allocated to receive either conventional physiotherapy, which consists of a combination of manual therapy techniques, general exercises, and specific stabilisation exercises (Guideline-Endorsed Conventional Physiotherapy Group) or to receive conventional physiotherapy with the addition of Kinesio Taping to the lumbar spine (Conventional Physiotherapy plus Kinesio Taping Group) over a period of 5 weeks (10 sessions of treatment). Clinical outcomes (pain intensity, disability and global perceived effect) will be collected at baseline and at 5 weeks, 3 months, and 6 months after randomisation. We will also collect satisfaction with care and adverse effects after treatment. Data will be collected by a blinded assessor. All statistical analysis will be conducted following the principles of intention to treat, and the effects of treatment will be calculated using Linear Mixed Models. DISCUSSION: The results of this study will provide new information about the usefulness of Kinesio Taping as an additional component of a guideline-endorsed physiotherapy program in patients with chronic nonspecific low back pain. PMID- 24156688 TI - Anisotropic post-yield response of cancellous bone simulated by stress-strain curves of bulk equivalent structures. AB - During the last decade, finite element (FE) modelling has become ubiquitous in understanding complex mechanobiological phenomena, e.g. bone-implant interactions. The extensive computational effort required to achieve biorealistic results when modelling the post-yield behaviour of microstructures like cancellous bone is a major limitation of these techniques. This study describes the anisotropic biomechanical response of cancellous bone through stress-strain curves of equivalent bulk geometries. A cancellous bone segment, reverse engineered by micro computed tomography, was subjected to uniaxial compression. The material's constitutive law, obtained by nano-indentations, was considered during the simulation of the experimental process. A homodimensionally bulk geometry was employed to determine equivalent properties, resulting in a similar anisotropic response to the trabecular structure. The experimental verification of our model sustained that the obtained stress-strain curves can adequately reflect the post-yield behaviour of the sample. The introduced approach facilitates the consideration of nonlinearity and anisotropy of the tissue, while reducing the geometrical complexity of the model to a minimum. PMID- 24156689 TI - Assessment of treatment and monitoring patterns and subsequent outcomes among patients with chronic myeloid leukemia treated with imatinib in a community setting. AB - INTRODUCTION: Real-world treatment and monitoring patterns have not been well documented among imatinib-treated chronic phase chronic myeloid leukemia (CP-CML) patients. Thus, we evaluated these patterns and responses to imatinib in CP-CML patients. METHODS: This retrospective study, based on the Georgia Cancer Specialists' electronic medical record (EMR) system, identified CP-CML patients initiating treatment with imatinib from 01/01/2002 to 11/01/2011 who were subsequently followed for >=6 months. RESULTS: A total of 177 patients met the study criteria. Imatinib dose modification occurred in 59 patients (33%). Rates of treatment interruption, discontinuation, and switching to another therapy were 16%, 24%, and 23%, respectively. Of 27 patients discontinuing imatinib for lack of efficacy, 9 (33%) had initial dose escalation; 26 patients (96%) eventually switched to a second-generation tyrosine kinase inhibitor. By 3 months, 168 patients remained on imatinib, of whom 96 (57%) had undergone cytogenetic and/or molecular testing. The frequency of response monitoring fluctuated over time, with rates as high as 28% for cytogenetic and 69% for molecular testing. Cumulative response rates steadily increased; 18 month rates were 47% for complete cytogenetic response and 26% for major or complete molecular response. There were no cases of progression and/or death among 38 patients who were regularly monitored for molecular response within the first 12 months of imatinib. Ten of 98 patients (10%) not regularly monitored had progressed or died. CONCLUSIONS: Almost one-third of patients initiating imatinib for CP-CML required dose modification, treatment interruption, or discontinuation. Opportunities for improved monitoring in this setting were identified. Limitations include those inherent to retrospective analyses based on EMR and the uncertain extrapolability of the results. PMID- 24156690 TI - Target-triggered cyclic assembly of DNA-protein hybrid nanowires for dual amplified fluorescence anisotropy assay of small molecules. AB - Aptamer-based fluorescence anisotropy (FA) assays have attracted great interest in recent years. However, a key factor that determines FA value is molar mass, thus limiting the utility of this assay for the detection of small molecules. To solve this problem, streptavidin, as a molar mass amplifier, was used in a hybridization chain reaction (HCR) to construct a target-triggered cyclic assembly of DNA-protein hybrid nanowires for highly sensitive detection of small molecules by fluorescence anisotropy. In this assay, one blocking DNA strand is released by target-aptamer recognition. The DNA then serves as an initiator to trigger enzyme-free autonomous cross-opening of hairpin probes via HCR to form a DNA nanowire for further assembly of streptavidin. Using adenosine triphosphate (ATP) as the small molecule target, this novel dual-amplified, aptamer-based FA assay affords high sensitivity with a detection limit of 100 nM. This limit of detection (LOD) is much lower than that of the disassembly approach without HCR amplification or the assembly strategy without streptavidin. In contrast to the previous turn-off disassembly approaches based on nonspecific interactions between the aptamer probe and amplification moieties, the proposed aptamer-based FA assay method exhibits a turn-on response to ATP, which can increase sensing reliability and reduce the risk of false hits. Moreover, because of its resistance to environmental interferences, this FA assay has been successfully applied for direct detection of 0.5 MUM ATP in complex biological samples, including cell media, human urine, and human serum, demonstrating its practicality in real complex biological systems. PMID- 24156691 TI - NOTES for surgical treatment of long-segment hirschsprung's disease: report of three cases. AB - PURPOSE: The aim of this study was to evaluate the feasibility of natural orifice translumenal endoscopic surgery (NOTES((r)); American Society for Gastrointestinal Endoscopy [Oak Brook, IL] and Society of American Gastrointestinal and Endoscopic Surgeons [Los Angeles, CA]) for the surgical management of long-segment Hirschsprung's disease. PATIENTS AND METHODS: Three children with long-segment Hirschsprung's disease were enrolled in this study. In all three cases the transition zone was proximal to the splenic flexure, with too long a segment of distal aganglionic colon to perform an isolated transanal pull through. Our procedure was as follows. A rectal mucosectomy was performed starting 0.5 cm proximal to the dentate line and extending proximally to the level of the intraperitoneal rectum. Three cannulas were inserted through the muscular sleeve into the abdominal cavity. The mesocolon, lateral peritoneum, and greater omentum were ligated and divided in order to mobilize the colon. After mobilization, the aganglionic distal bowel segment was pulled through the anus and resected. Finally the colo-anal anastomosis was created. RESULTS: All three operations were successfully performed without intraoperative complications. No additional ports or conversion to an open procedure was required. The operative times were 242, 195, and 174 minutes, respectively. All three children were discharged without complication with follow-up for at least 1 year. One year after the procedure the 3 patients were stooling one to three times per day, with no fecal soiling or constipation. CONCLUSIONS: This NOTES procedure may be a safe and feasible option for the surgical treatment of long-segment Hirschsprung's disease. PMID- 24156692 TI - Metagenomic approach for the isolation of a thermostable beta-galactosidase with high tolerance of galactose and glucose from soil samples of Turpan Basin. AB - BACKGROUND: beta-Galactosidases can be used to produce low-lactose milk and dairy products for lactose intolerant people. Although commercial beta-galactosidases have outstanding lactose hydrolysis ability, their thermostability is low, and reaction products have strong inhibition to these enzymes. In addition, the beta galactosidases possessing simultaneously high thermostability and tolerance of galactose and glucose are still seldom reported until now. Therefore, identification of novel beta-galactosidases with high thermostability and tolerance to reaction products from unculturable microorganisms accounting for over 99% of microorganisms in the environment via metagenomic strategy is still urgently in demand. RESULTS: In the present study, a novel beta-galactosidase (Gal308) consisting of 658 amino acids was identified from a metagenomic library from soil samples of Turpan Basin in China by functional screening. After being overexpressed in Escherichia coli and purified to homogeneity, the enzymatic properties of Gal308 with N-terminal fusion tag were investigated. The recombinant enzyme displayed a pH optimum of 6.8 and a temperature optimum of 78 degrees C, and was considerably stable in the temperature range of 40 degrees C 70 degrees C with almost unchangeable activity after incubation for 60 min. Furthermore, Gal308 displayed a very high tolerance of galactose and glucose, with the highest inhibition constant K(i,gal) (238 mM) and K(i,glu) (1725 mM) among beta-galactosidases. In addition, Gal308 also exhibited high enzymatic activity for its synthetic substrate o-nitrophenyl-beta-D-galactopyranoside (ONPG, 185 U/mg) and natural substrate lactose (47.6 U/mg). CONCLUSION: This study will enrich the source of beta-galactosidases, and attract some attentions to beta-galactosidases from extreme habitats and metagenomic library. Furthermore, the recombinant Gal308 fused with 156 amino acids exhibits many novel properties including high activity and thermostability at high temperatures, the pH optimum of 6.8, high enzyme activity for lactose, as well as high tolerance of galactose and glucose. These properties make it a good candidate in the production of low-lactose milk and dairy products after further study. PMID- 24156693 TI - Influence of delta-aminolevulinic acid dehydratase gene polymorphism on selected lead exposure biomarkers in a cohort of ex-smelter workers. AB - Lead (Pb) body burden and toxicity may be influenced by genetic polymorphisms. The aim of this study was to investigate the influence of G177C delta aminolevulinic acid dehydratase (ALAD) polymorphism (rs1800435) on selected Pb exposure biomarkers in a population of workers highly exposed to this metal in the past. A cross-sectional survey was conducted between 2007 and 2009 within the cohort of ex-employees of a smelter in the north of France that closed down in 2003. A questionnaire was completed by each participant and blood samples enabled determination of Pb levels and ALAD polymorphism. Five parameters estimating the Pb body burden and its variations were studied: last blood lead level (BLL) during activity, cumulative blood Pb index, BLL at the time of the study, and absolute and percent changes in BLL after cessation of metal exposure. Multiple regression models were used to evaluate links between ALAD polymorphism and the selected Pb exposure biomarkers. Two hundred and four men were included. At the time of inclusion, the median age was 53.5 yr. The median duration of Pb exposure was 25 yr and the median latency since end of exposure was 5.6 yr. The frequency of ALAD-2 allele was 9.3%, with 34 subjects being heterozygous (ALAD1-2) and 2 homozygous (ALAD2-2). According to genotype, there was no significant difference for any of the five selected Pb exposure biomarkers. These results lend support to the notion that ALAD polymorphism exerts no marked impact on Pb body burden. PMID- 24156694 TI - Oxidative stress, inflammatory biomarkers, and toxicity in mouse lung and liver after inhalation exposure to 100% biodiesel or petroleum diesel emissions. AB - Over the past decade, soy biodiesel (BD) has become a first alternative energy source that is economically viable and meets requirements of the Clean Air Act. Due to lower mass emissions and reduced hazardous compounds compared to diesel combustion emissions (CE), BD exposure is proposed to produce fewer adverse health effects. However, considering the broad use of BD and its blends in different industries, this assertion needs to be supported and validated by mechanistic and toxicological data. Here, adverse effects were compared in lungs and liver of BALB/cJ mice after inhalation exposure (0, 50, 150, or 500 MUg/m3; 4 h/d, 5 d/wk, for 4 wk) to CE from 100% biodiesel (B100) and diesel (D100). Compared to D100, B100 CE produced a significant accumulation of oxidatively modified proteins (carbonyls), an increase in 4-hydroxynonenal (4-HNE), a reduction of protein thiols, a depletion of antioxidant gluthatione (GSH), a dose related rise in the levels of biomarkers of tissue damage (lactate dehydrogenase, LDH) in lungs, and inflammation (myeloperoxidase, MPO) in both lungs and liver. Significant differences in the levels of inflammatory cytokines interleukin (IL) 6, IL-10, IL-12p70, monocyte chemoattractant protein (MCP)-1, interferon (IFN) gamma, and tumor necrosis factor (TNF)-alpha were detected in lungs and liver upon B100 and D100 CE exposures. Overall, the tissue damage, oxidative stress, inflammation, and cytokine response were more pronounced in mice exposed to BD CE. Further studies are required to understand what combustion products in BD CE accelerate oxidative and inflammatory responses. PMID- 24156695 TI - Investigation of the pulmonary bioactivity of double-walled carbon nanotubes. AB - Double-walled carbon nanotubes (DWCNT) are a rather new and unexplored variety of carbon nanotubes. Previously conducted studies established that exposure to a variety of carbon nanotubes produced lung inflammation and fibrosis in mice after pharyngeal aspiration. However, the bioactivity of double-walled carbon nanotubes (DWCNT) has not been determined. In this study, the hypothesis that DWCNT would induce pulmonary toxicity was explored by analyzing the pulmonary bioactivity of DWCNT. To test this hypothesis, C57Bl/6 mice were exposed to DWCNT by pharyngeal aspiration. Mice underwent whole-lung lavage (WLL) to assess pulmonary inflammation and injury, and lung tissue was examined histologically for development of pulmonary disease as a function of dose and time. The results showed that DWCNT exposure produced a dose-dependent increase in WLL polymorphonuclear leukocytes (PMN), indicating that DWCNT exposure initiated pulmonary inflammation. DWCNT exposure also produced a dose-dependent rise in lactate dehydrogenase (LDH) activity, as well as albumin levels, in WLL fluid, indicating that DWCNT exposure promoted cytotoxicity as well as decreases in the integrity of the blood-gas barrier in the lung, respectively. In addition, at 7 and 56 d postexposure, the presence of significant alveolitis and fibrosis was noted in mice exposed to 40 MUg/mouse DWCNT. In conclusion, this study provides insight into previously uninvestigated pulmonary bioactivity of DWCNT exposure. Data indicate that DWCNT exposure promotes inflammation, injury, and fibrosis in the lung. PMID- 24156696 TI - Effects of chronic exposure of methomyl on the antioxidant system in kidney of Nile tilapia (Oreochromis niloticus) and recovery pattern. AB - Tilapia were exposed to sublethal methomyl concentrations of 0, 0.2, 2, 20, or 200 MUg/L for 30 d, and then were transferred to methomyl-free water for 18 d. Renal antioxidant parameters, including catalase (CAT), superoxide dismutase (SOD), glutathione S-transferase (GST), glutathione peroxidase (GPx) , glutathione reductase (GR), total glutathione (GSH), and reduced glutathione (GSSG), were examined in tilapia at d 0, 6, 12, 18, 24, and 30 after starting the experiment and at 18 d after transferring to methomyl-free water. There were no significant changes in enzymatic activity and content of antioxidants in kidney of tilapia exposed to 0.2 MUg/L methomyl compared to controls. The results showed significant increases in SOD, CAT, GST, GR, GPx, and level of GSSG accompanied by a decrease in GSH levels following methomyl exposure in tilapia to 2, 20, or 200 MUg/L over the 30-d exposure period, suggesting the presence of oxidative stress. Thus, it would appear the 0.2 MUg/L methomyl might be considered the no-observed adverse-effect level (NOAEL). Recovery data showed that the effects produced by lower concentration of methomyl at 20 MUg/L were reversible but not at the higher 200 MUg/L concentration. PMID- 24156698 TI - A systematic view is key: the successful case of Suzhou Creek rehabilitation. PMID- 24156697 TI - Occupational exposure to aflatoxin B1 in swine production and possible contamination sources. AB - Although the adverse health consequences of ingestion of food contaminated with aflatoxin B1 (AFB1) are known, relatively few studies are available on the adverse effects of exposure in occupational settings. Taking this into consideration, our study was developed aiming to elucidate the possible effects of occupational exposure to AFB1 in Portuguese swine production facilities using a specific biomarker to assess exposure to AFB1. In total, 28 workers participated in this study, providing blood samples, and a control group (n = 30) was composed of subjects without any type of agricultural activity. Fungal contamination was also studied by conventional methods through air, surfaces, and new and used floor coverage. Twenty-one workers (75%) showed detectable levels of AFB1 with values ranging from <1 ng/ml to 8.94 ng/ml and with a mean value of 1.91 +/- 1.68 ng/ml. In the control group, the AFB1 values were all below 1 ng/ml. Twelve different Aspergillus species were identified. Aspergillus versicolor presented the highest airborne spore counts (3210 CFU/m3) and was also detected in higher values in surfaces (>300 CFU/cm2). Data indicate that exposure to AFB1 occurs in swine barns, and this site serves as a contamination source in an occupational setting. PMID- 24156699 TI - Terbium-based coordination polymer nanoparticles for detection of ciprofloxacin in tablets and biological fluids. AB - The metal-organic coordination polymers with tunable structures and properties have been rapidly emerging as very important functional materials. In this work, we prepared terbium (Tb(3+))-based coordination polymer nanoparticles (CPNPs) by employing adenine (Ad) as bridging ligands. The CPNPs was further used as a receptor reagent for ciprofloxacin (CF) detection in aqueous solution. Addition of CF induces a typical emission of Tb(3+) due to the formation of Ad/Tb-CF complex and the sensitization of CF. The fluorescent intensity of Tb(3+) was enhanced linearly with increasing the CF concentration from 60 nM to 14 MUM. The detection limit for CF in aqueous solution is 60 nM. The Ad/Tb CPNPs was successfully applied to detect CF in tablet and urine samples and showed a satisfactory result. Compared with other methods, the proposed method is advantageous because that it provides a very simple strategy for CF detection, which does not require complicated sample pretreatment processes or special reaction media. The proposed strategy could be contributed to expand the potential applications of lanthanide coordination polymers in biological and environmental fields. PMID- 24156700 TI - DC-SIGN, DC-SIGNR and LSECtin: C-type lectins for infection. AB - The C-type lectins DC-SIGN, DC-SIGNR and LSECtin are encoded by the lectin gene cluster on chromosome 19p13.3 and perform cell-adhesion and pathogen recognition functions on dendritic cells, liver cells and lymph node sinusoidal endothelial cells. DC-SIGN and DC-SIGNR share similar overall gene and protein molecule structures, and they exhibit high affinity for high-mannose carbohydrates. LSECtin, a Ca2+-dependent C-type lectin, interacts with mannose, NAcGlc and fucose. These lectins allow pathogen recognition (e.g., viruses, bacteria and allergens) and cell adhesion for dendritic and endothelial cells in different tissues, which may enhance the infection and facilitate the spread of those pathogens. A better understanding of these lectins may yield information about how pathogens are captured by particular cells and how they spread in different tissues. These studies would provide more detail about the physiopathological mechanisms of viral and bacterial infections and may also lead to new strategies to treat or prevent infections. PMID- 24156701 TI - Dynamics of excess electronic charge in aliphatic ionic liquids containing the bis(trifluoromethylsulfonyl)amide anion. AB - In a recent article (J. Am. Chem. Soc. 2011, 133, 20186) we investigated the initial spatial distribution of dry excess electrons in a series of room temperature ionic liquids (RTILs). Perhaps unexpectedly, we found that in some alkylammonium-based systems the excess negative charge resided on anions and not on the positive cations. Following on these results, in the current paper we describe the time evolution of an excess electronic charge introduced in alkylammonium- and pyrrolidinium-based ionic liquids coupled with the bis(trifluoromethylsulfonyl)amide ([Tf2N(-)]) anion. We find that on a 50 fs time scale an initially delocalized excess electron localizes on a single [Tf2N(-)] anion which begins a fragmentation process. Low-energy transitions have a very different physical origin on the several femtoseconds time scale when compared to what occurs on the picosecond time scale. At time zero, these are intraband transitions of the excess electron. However after 40 fs when the excess electronic charge localizes on a single anion, these transitions disappear, and the spectrum is dominated by electron-transfer transitions between the fragments of the doubly charged breaking anion. PMID- 24156703 TI - Growing up with Primary Ciliary Dyskinesia in Bradford, UK: exploring patients experiences as a physiotherapist. AB - Primary Ciliary Dyskinesia (PCD) is a condition which causes impaired mucociliary clearance, resulting in sputum retention and recurrent respiratory tract infections. Physiotherapy, in the form of airway clearance techniques and exercise is recommended to patients with PCD to facilitate sputum clearance. As children diagnosed with PCD develop into adults, understanding their experiences of growing up with this long-term condition and undertaking physiotherapy may help to provide insight to clinicians. No previous research has been published which explores the lived experiences of children and young people with PCD. The prevalence of PCD in Bradford in the North of the UK is unusually high, signifying the importance of understanding the experiences of this patient population. This qualitative study used Interpretive Phenomenological Analysis to allow the researcher, as a physiotherapist, to investigate the lived experiences of five paediatric patients with PCD. While patients' experiences are all unique, three themes emerged across the analysis of the interviews: (1) the experiences of day to day life with the symptoms and treatment burden of PCD; (2) participants' awareness of their own symptoms and knowledge of PCD; and (3) the development of mastery skills and devolution of management from the family to the growing child. The results from this study suggested that facilitation of disease acceptance, strategies to increase patient empowerment, the use of patient centred communication and understanding the contextualisation of patients' experiences may all help to guide clinical practice. PMID- 24156702 TI - Effect of erythropoietin on the incidence of acute kidney injury following complex valvular heart surgery: a double blind, randomized clinical trial of efficacy and safety. AB - INTRODUCTION: Recombinant human erythropoietin (EPO) is known to provide organ protection against ischemia-reperfusion injury through its pleiotropic properties. The aim of this single-site, randomized, case-controlled, and double blind study was to investigate the effect of pre-emptive EPO administration on the incidence of postoperative acute kidney injury (AKI) in patients with risk factors for AKI undergoing complex valvular heart surgery. METHODS: We studied ninety-eight patients with preoperative risk factors for AKI. The patients were randomly allocated to either the EPO group (n = 49) or the control group (n = 49). The EPO group received 300 IU/kg of EPO intravenously after anesthetic induction. The control group received an equivalent volume of normal saline. AKI was defined as an increase in serum creatinine >0.3 mg/dl or >50% from baseline. Biomarkers of renal injury were serially measured until five days postoperatively. RESULTS: Patient characteristics and operative data, including the duration of cardiopulmonary bypass, were similar between the two groups. Incidence of postoperative AKI (32.7% versus 34.7%, P = 0.831) and biomarkers of renal injury including cystatin C and neutrophil gelatinase-associated lipocalin showed no significant differences between the groups. The postoperative increase in interleukin-6 and myeloperoxidase was similar between the groups. None of the patients developed adverse complications related to EPO administration, including thromboembolic events, throughout the study period. CONCLUSIONS: Intravenous administration of 300 IU/kg of EPO did not provide renal protection in patients who are at increased risk of developing AKI after undergoing complex valvular heart surgery. TRIAL REGISTRATION: Clinical Trial.gov, NCT01758861. PMID- 24156704 TI - GagPol-specific CD4+ T-cells increase the antibody response to Env by intrastructural help. AB - BACKGROUND: Immunization of rhesus macaques against Gag of SIV resulted in a more rapid appearance of Env antibodies after infection with SIV or SHIV challenge viruses although the vaccines lacked an Env component. We therefore explored whether T helper cells specific for internal HIV proteins could provide intrastructural help for Env-specific B cells and thus increase the Env antibody response. RESULTS: Mice were immunized by adenoviral vector or DNA vaccines against GagPol and then boosted with virus-like particles (VLP) containing GagPol and Env. Env-specific antibody levels after the VLP booster immunizations were significantly higher in GagPol-immunized mice than in mock-vaccinated controls. Adoptive transfer of CD4+ T cells from GagPol-immunized mice also enhanced the Env antibody response to VLP immunization in the recipient mice. Depending on the presence of VLPs, co-cultivation of CD4+ T cells from GagPol-primed mice with BCR transgenic B cells specific for a protein presented on the surface of the VLPs also resulted in the activation of the B and T cells. CONCLUSIONS: Our study indicates that GagPol-specific T helper cells may provide intrastructural help for Env antibody responses. This cross-talk between immune responses directed against different components of the retroviral particle may be relevant for the immunopathogenesis of retroviral infections and allow to improve virus like particle vaccine approaches against HIV. PMID- 24156705 TI - Ainsliaolide D: a new sesquiterpene lactone from Ainsliaea pertyoides. AB - Ainsliaolide D, a new guaiane-type sesquiterpene lactone, was isolated from the roots of Ainsliaea pertyoides Fr. var. albotomentosa Beauverd. Its structure was determined based on spectral data. PMID- 24156706 TI - Does chronic stress enhance the risk of diseases? AB - OBJECTIVE: In the everyday life, stress is deemed as something unfavorable that may enhance the risk for the development or worsen a disease. However, in its nature, stress is adaptive reaction of the body. Its main characteristic is the activation of the hypothalamic-pituitary-adrenocortical (HPA) axis. Previously, we have shown that activation of the HPA axis plays a gastroprotective role during acute stress. The aim of our study was to clarify the effects of chronic stress and chronically elevated basal corticosterone levels on the gastric ulceration and cardiovascular vulnerability in rats. METHODS: Male Wistar rats were repeatedly restrained 60 min daily for 14 days and examined on day 15th. The gastric ulceration was induced by a s.c. injection of indomethacin (35 mg/kg). The cardiovascular vulnerability was examined in urethane-anaesthetized rats in an experimental angina pectoris model (epinephrine, 10 ug/kg, 30 s later phentolamine, 15 mg/kg, both i.v.). RESULTS: We confirmed the development of chronic stress consequences by changes in several somatic parameters (body weight decrease, thymus involution, adrenal gland hypertrophy), and elevated resting corticosterone levels. However, the gastroprotective effect of chronic stress was not manifested and there was no aggravation of indomethacin-induced gastric ulceration, either. In the experimental angina pectoris model, previous chronic stress did not have any profound effect on the blood pressure, heart rate, and electrocardiogram changes. CONCLUSIONS: In contrast to the general view on the harmfulness nature of the stress, we were unable to find a harmful effect of chronic stress on the internal diseases (gastric ulceration and angina pectoris). However, its protective effect was also missing among present experimental conditions. PMID- 24156707 TI - Bisphenol A alone or in combination with estradiol modulates cell cycle- and apoptosis-related proteins and genes in MCF7 cells. AB - OBJECTIVE: Bisphenol A (BPA) with its estrogenic properties is intensively studied since its presence in the environment and human body. Besides other adverse effects, the compound is suspected of contributing to hormone-related cancers. The present study was aimed to investigate short time (24 h) effects of BPA on the important genes/proteins involved in apoptosis and the cell cycle progression in the breast cancer cells MCF7. The experimental design covered cell treatment with a broad BPA concentration scale: 10-12M corresponding to ubiquitous exposure, 10-9M relevant to human levels, and 10-6M as experimentally usual. We further investigated the combined effects of low BPA dose (10-12M) with physiological concentration of estradiol (E2) (10-9M). METHODS: The expression of particular proteins and genes was studied by Western blotting and real time RT PCR, respectively. RESULTS: Estrogenic effect of BPA was confirmed in the following checkpoints: mRNA expression of estrogen receptor alpha, expression of cyclin D1 and A2 proteins and CCNA2 gene, Bax and Bcl2 protein levels. For both cyclins protein levels, the maximum stimulation was present at 10-9M BPA and the effects resembled the "inverted U"-shape, a nonmonotonic dose-response curve reported for the action of xenoestrogens. The combined effect of low BPA dose with physiological E2 concentration differ from those of individual compounds, the character of stimulatory response is neither additive nor synergistic. CONCLUSIONS: The results obtained strongly support the evidence of BPA and BPA+E2 proliferation-promoting effects in human breast carcinoma cells, even after short time exposure, partially via reduced rate of apoptosis by the action of BPA+E2. PMID- 24156708 TI - Measurement of salivary aldosterone: validation by low-dose ACTH test and gender differences. AB - The aim of the present study was to validate the feasibility of measurement of the salivary aldosterone concentrations by performing a low-dose adrenocorticotropic hormone (ACTH) test. Moreover, the presence of gender differences in salivary aldosterone, considering the phase of the menstrual cycle in women, was verified. The sample consisted of 107 volunteers (60 men, 21 women in the follicular phase and 26 women in the luteal phase of the menstrual cycle). Saliva samples were taken by the subjects themselves around 08:00 AM, at least 60 min after awaking. A separate group of female subjects in the follicular phase underwent low-dose ACTH test (1ug synthetic ACTH i.v.) performed at 08:30 AM with blood and saliva sampling every 30 min for 120 min. Modification of the commercial aldosterone radioimmunoassay methodology for the salivary aldosterone measurement was performed. Salivary aldosterone concentrations rose in response to low-dose ACTH test and positive significant correlation in aldosterone concentrations between plasma and saliva was found. The results showed that women in the luteal phase of the menstrual cycle exhibited significantly higher morning concentrations in salivary aldosterone than men and women in the follicular phase. This study clearly demonstrates suitability of measurement of salivary aldosterone concentrations in the low-dose ACTH test and reveals gender differences in salivary aldosterone levels. The results show high validity of the presented method and its usefulness for assessment of the aldosterone concentrations in saliva. PMID- 24156709 TI - Effects of retinoic acid isomers on proteomic pattern in human breast cancer MCF 7 cell line. AB - Retinoids, acting through their cognate nuclear receptors, are crucial transcriptional regulators of many cellular processes such as differentiation, development, apoptosis, carbohydrate and lipid metabolism, homeostasis, etc. The aim of this study was the exploration of molecular mechanisms in relation to therapy of human breast cancer. One of the efficient strategies is identification of biomarkers as important tools in early cancer diagnosis and advisable treatment. Retinoids have been regarded as important therapeutic agents for many types of cancers, including human breast cancer. The effects of all-trans retinoic acid and 9-cis retinoic acid or their combination on proteomic pattern in human MCF-7 breast cancer line were investigated. The total cell proteins were extracted utilizing a commercially Radio-Immunoprecipitation Assay (RIPA) buffer and separated on 1D sodium dodecyl sulfate polyacrylamide gel electrophoresis (1D SDS-PAGE). The proteins were subsequently digested in-gel by trypsin and identified by matrix assisted laser desorption ionization technique with time of flight mass analyzer (MALDI-TOF/TOF). Our data offer novel information on the proteomic pattern of proteins evaluated after treatment of MCF-7 cells with retinoic acid isomers. PMID- 24156710 TI - Late onset of familial neurogenic diabetes insipidus in monozygotic twins. AB - OBJECTIVE: Autosomal dominant familial diabetes insipidus (FNDI) is a rare disease characterized by polydipsia and polyuria due to deficiency of the antidiuretic hormone, arginine vasopressin (AVP). We report the first Slovak family with the disease. Noteworthy is the concordantly belated debut of the disease symptoms in two monozygotic twin proband girls in the age of 17 years. Because of inconclusive results of water deprivation test consistent with partial diabetes insipidus (DI), missing "bright spot" of posterior pituitary gland in T1 weighted magnetic resonance imaging and family occurrence of polyuria and polydipsia on anamnestic evaluation. METHODS: Molecular genetic testing of the AVP gene was proceeded, because of the inconclusive results of water deprivation test consistent with partial diabetes insipidus, missing "bright spot" of posterior pituitary gland in T1-weighted magnetic resonance imaging and family occurrence of polyuria and polydipsia on anamnestic evaluation. RESULTS: Genetic analysis revealed a heterozygous g.279G>A substitution that predicts a p.Ala19Thr substitution in the signal peptide of the AVP prohormone. The wide intrafamiliar variations (3 to 17 years) in disease onset together with the concordantly delayed debut of polyuria in two monozygotic twin girls suggest that individual differences in genetic influences family environmental factors may modify the penetrance of the mutation of the AVP gene. CONCLUSIONS: The present paper supports the notion that molecular genetic evaluation should be performed in all patients with familial occurrence of DI regardless of the clinical results. PMID- 24156711 TI - Rasopathies - dysmorphic syndromes with short stature and risk of malignancy. AB - OBJECTIVES: The term 'Rasopathies' represents a group of five neurodevelopmental syndromes (Noonan, LEOPARD, Costello, Cardio-facio-cutaneous, and Neurofibromatose-Noonan syndrome) caused by germline mutation in genes encoding proteins involved in RAS/MAPK (rat sarcoma/mitogen-activated protein kinase) signaling pathway. The RAS/MAPK signaling pathway participates in regulation of cell determination, proliferation, differentiation, migration, and senescence and dysregulation of this pathway can lead to the risk of tumorigenesis. In this review, we aim to summarize the current clinical and molecular genetic knowledge on Rasopathies with special attention for the risk of cancer. We propose also clinical and therapeutic approach for patients with malignancy. METHODS: We are reviewing the clinical and molecular basis of Rasopathies based on recent studies, clinical examination, and molecular diagnostics (mutation analysis of causal genes for Rasopathies) in Slovak pediatric patients. RESULTS: Some clinical features, such as short stature, a specific facial dysmorphology and cardiac abnormalities are common to all of Rasopathy syndromes. However, there are unique signs by which the syndromes can differ from each other, especially multiple lentigo in LEOPARD syndrome, increased risk of malignancy in Costello syndrome, dry hyperkeratotic skin in patients with cardio-facio-cutaneous syndrome, and neurofibromas and cafe-au-lait spots in neurofibromatosis-Noonan syndrome. CONCLUSION: Despite the overlapping clinical features, Rasopathy syndromes exhibit unique fenotypical features and the precise molecular diagnostics may lead to confirmation of each syndrome. The molecular diagnostics may allow the detection of pathogenic mutation associated with tumorigenesis. PMID- 24156713 TI - A comparative study on the traditional Indian Shodhana and Chinese processing methods for aconite roots by characterization and determination of the major components. AB - BACKGROUND: Aconitum is an indispensable entity of the traditional medicine therapy in Ayurveda and Traditional Chinese medicine (TCM), in spite of its known fatal toxicity characteristics. The prolonged use of this drug, irrespective of its known lethal effects, is governed by the practice of effective detoxification processes that have been used for decades. However, the processing methods of Ayurveda and TCM are different, and no comparative study has been carried out to evaluate their differences.The objective of the present study was to carry out comparative chemical profiling of the roots of Aconitum heterophyllum Wall, A. carmichaelii Debx., and A. kusnezoffii Reichb. after application of two detoxification methods used in Ayurveda and one method used in TCM . RESULTS: Analysis of the processed samples was carried out by ultra-high performance liquid chromatography combined with quadrupole time-of-flight mass spectrometry (UHPLC-QTOF/MS). The results obtained in the study demonstrate that all three processing methods used in Ayurveda and TCM effectively extract the diester diterpenoid alkaloids and led to their conversion into monoester diterpenoid alkaloids. The efficiency of the processes in reduction of toxic alkaloid contents can be stated as: Processing with water > Shodhana with cow milk > Shodhana with cow urine. The analysis method was validated as per ICH-Q2R1 guidelines and all the parameters were found to comply with the recommendations stated in the guidelines. CONCLUSIONS: There have been no reports till date, to compare the processing methods used in Ayurveda with the methods used in TCM for detoxification of aconite roots. Our study demonstrates that, these methods used in both the traditional systems of medicine, efficiently detoxify the aconite roots. Amongst the three selected procedures, the TCM method of decoction with water is the most efficient. Through experimental evidences, we prove the conversion of toxic diester diterpenoid alkaloids to relatively safer monoester diterpenoid alkaloids. Thus, this study demonstrates that comparative study on the traditional experiences accumulated in different medical systems is useful for expanding their respective applications. PMID- 24156714 TI - What about conventional laparoscopic radical cystectomy? Cost-analysis of open versus laparoscopic radical cystectomy. AB - PURPOSE: To assess direct healthcare costs for open radical cystectomy (ORC) vs laparoscopic radical cystectomy (LRC) with ileal conduit. PATIENTS AND METHODS: A series of 44 and 42 patients undergoing ORC and LRC with ileal conduit were retrospectively analyzed at a single institution from January 2005 to January 2012. The ORC and LRC procedures were performed by two independent surgical teams; there was no selection in patients. Data on patient demographics, perioperative outcome parameters, complications, and readmissions were gathered retrospectively in the ORC series and prospectively in the LRC series. Direct healthcare costs were evaluated for operating room occupation, disposable surgical equipment, blood transfusions, hospital stay according to intensity of care, and readmission days. RESULTS: Mean and median evaluated total direct healthcare costs per patient did not differ significantly and were 17,534? and 16,511? in the LRC group and 22,284? and 15,909? in the ORC group. Excess costs for disposable surgical equipment and operating room occupation within the LRC group were compensated for as a result of shorter hospital stay, lower number of blood transfusions, and intensive-care admissions. Minor and major complication rates were comparable between groups. CONCLUSION: Within our series, LRC is a cost neutral minimally invasive alternative to ORC without comprising quality of care and with beneficial perioperative outcomes. PMID- 24156716 TI - A surprising arrangement pattern and phylogenetic consideration: the complete mitochondrial genome of Belanger's croaker Johnius belangerii (Percoidei: Sciaenidae). AB - The complete mitochondrial genome of Johnius belangerii has been determined for the first time in this article. It was 19,154 base pairs in length, and is composed of 37 genes (13 protein-coding genes, 22 tRNA genes and 2 ribosomal RNA genes). Totally, 5 notable non-coding regions were observed, and a non-coding of 1091 bp was identified as control region based on its location and AT richness. An 800 bp tandem repeat sequence was identified in the fifth non-coding region. We investigated the mitochondrial gene arrangement pattern and found that that the tRNA(Val), 12SrRNA, 16SrRNA and tRNA(Phe) genes of J. belangerii mitogenome were orderly placed at the beginning of heavy strand. This order is different from other croakers. Combine with the phylogenetic reconstruction and genes arrangement pattern of J. belangerii mitochondrial genome, we consider J. belangerii is the most ancient genus within family Sciaenidae. PMID- 24156717 TI - Complete mitochondrial genomes of Tuatara endemic to different islands of New Zealand. AB - Tuatara are the sister taxon to the Squamata (including lizards and snakes) and are regarded as the most distinctive surviving reptilian genus. They are currently inhabits on offshore islands around New Zealand and have been recognized as a species in need of active conservation management. In this study, we report a total number of five nearly complete mitochondrial genomes, which were sequenced by Sanger and Next Generation DNA sequencing methods. Our phylogenomic analysis revealed distinct clustering of tuatara populations from the north and south islands of New Zealand. PMID- 24156715 TI - The efficacy of long-lasting nets with declining physical integrity may be compromised in areas with high levels of pyrethroid resistance. AB - BACKGROUND: Long-lasting insecticide-treated mosquito nets (LLINs) are a primary malaria prevention strategy in sub-Saharan Africa. However, emergence of insecticide resistance threatens the effectiveness of LLINs. METHODS: Cross sectional surveys of LLINs were conducted in houses of seven and four villages in Gem and Bungoma Districts in western Kenya, respectively. Condition (number and area of holes in the nets), number and species of mosquitoes resting inside them, and insecticidal activity of nets were quantified. Mosquitoes collected inside nets were allowed to lay eggs and progeny tested for susceptibility to deltamethrin and permethrin, pyrethoids commonly deployed in LLINs in western Kenya. RESULTS: In Gem, 83.3% of nets were less than three years old and 32.4% had at least one hole of any size; while in Bungoma, 92% were less than three years old and 48% had at least one hole. No anopheline and five Culex spp. mosquitoes were found resting inside nets in Gem regardless of the number and size of holes, while 552 Anopheles gambiae s.l., five Anopheles funestus s.l. and 137 Culex spp. were in nets in Bungoma. The number of mosquitoes resting inside nets increased with hole areas >50 cm in Bungoma. In WHO resistance assays, f1 offspring of samples collected in nets in Bungoma were 94 and 65% resistant to deltamethrin and permethrin, respectively. Nets from Bungoma retained strong activity against a susceptible laboratory strain, but not against f1 offspring of field-collected An. gambiae s.s. All An. gambiae s.s. samples collected in nets were homozygous for the kdr genotype L1014S. CONCLUSIONS: In areas with pyrethroid resistant vectors, LLINs with modest hole areas permit mosquito entry and feeding, providing little protection against the vectors. LLIN formulations develop large holes within three years of use, diminishing their presupposed lifetime effectiveness. PMID- 24156718 TI - Complete mitochondrial genome of the pseudobream, Pseudobrama simoni (Teleostei:Cypriniformes:Cyprinidae). AB - The Pseudobrama simoni (Bleeker) is the only one species within the genus Pseudobrama of the subfamily Xenocyprinae. In this study, we first determined the complete mitochondrial genome sequence of the P. simoni. The whole mitogenome is 16,618 bp in size, consisting of 13 protein-coding genes, 22 transfer RNA (tRNA) genes, 2 ribosomal RNA (rRNA) genes and 1 control region. The gene order and molecule structure are similar to most vertebrates. The complete mitogenome of P. simoni provides the valuable information for the biogeographic and phylogenetic studies on the subfamily Xenocyprinae. PMID- 24156720 TI - Two generations of fall armyworm (Lepidoptera: Noctuidae) contamination by di-n butylphthalate. AB - The effects of di-n-butylphthalate (DnBP) were investigated with respect to bioaccumulation and whether these effects occurred over a second generation in the fall armyworm Spodoptera frugiperda (J.E. Smith, 1797). The concentrations of DnBP in males and females of the second generation were higher than those in first one. However, frequency of mortality of exposed individuals in the second generation was approximately 57% less but the reduction in size and weight was more pronounced than in the first generation. PMID- 24156719 TI - Biological response to nano-scale titanium dioxide (TiO2): role of particle dose, shape, and retention. AB - Titanium dioxide (TiO2) is one of the most widely used nanomaterials, valued for its highly refractive, photocatalytic, and pigmenting properties. TiO2 is also classified by the International Agency for Research on Cancer (IARC) as a possible human carcinogen. The objectives of this study were to (1) establish a lowest-observed-effect level (LOEL) for nano-scale TiO2, (2) determine TiO2 uptake in the lungs, and (3) estimate toxicity based on physicochemical properties and retention in the lungs. In vivo lung toxicity of nano-scale TiO2 using varying forms of well-characterized, highly dispersed TiO2 was assessed. Anatase/rutile P25 spheres (TiO2-P25), pure anatase spheres (TiO2-A), and anatase nanobelts (TiO2-NB) were tested. To determine the effects of dose and particle characteristics, male Sprague-Dawley rats were administered TiO2 (0, 20, 70, or 200 MUg) via intratracheal instillation. Bronchoalveolar lavage fluid (BALF) and lung tissue were obtained for analysis 1 and 7 d post exposure. Despite abundant TiO2 inclusions in all exposed animals, only TiO2-NB displayed any significant degree of inflammation seen in BALF at the 1-d time point. This inflammation resolved by 7 d, although TiO2 particles had not cleared from alveolar macrophages recovered from the lung. Histological examination showed TiO2-NB produced cellular changes at d 1 that were still evident at d 7. Data indicate TiO2-NB is the most inflammatory with a LOEL of 200 MUg at 1 d post instillation. PMID- 24156721 TI - Changes in the incubation by American kestrels (Falco sparverius) during exposure to the polybrominated diphenyl ether (PBDE) mixture DE-71. AB - Polybrominated diphenyl ethers (PBDE) are persistent environmental pollutants that have been detected in wildlife globally. American kestrels exposed to the commercial PBDE mixture DE-71 have previously demonstrated reduced reproductive success and behaviors during courtship and brood rearing; however, it remains unknown whether DE-71 affects incubation. During breeding, captive kestrels were exposed to the DE-71 mixture dissolved in safflower oil at two environmentally relevant concentrations (low: 283.5 +/- 48.2, high: 1104.8 +/- 124.5 ng/g wet weight [ww]) via diet for an average of 75 d. Unexpected low in ovo concentrations of hexabromocyclododecane (HBCD) were also detected (low: 3 +/- 1 ng/g ww, high: 16 +/- 3 ng/g ww). All comparisons are made to control pairs. Kestrel pairs in the low- and high-exposure groups experienced longer incubation periods with increasing exposure to SigmaPBDE and some individual congeners. As incubation progressed, pairs exposed to DE-71 had significantly lower nest temperatures, which were on average 19% lower in low-exposure nests and 35% lower in high-exposure nests during late incubation. The DE-71 exposed pairs (low and high) also demonstrated significantly reduced incubation constancy (defined as percent of temperature readings above the maximum daily ambient temperature) during early incubation compared to controls. Nest temperatures (all pairs) and incubation constancy (high pairs) during early incubation (d 1-3) were significantly and positively associated with the proportion of eggs that hatched per pair. Higher incubation constancy and incubating nest temperatures in the low exposure group were associated with markedly less egg weight loss by mid incubation. These findings demonstrate that exposure to PBDE significantly affected kestrels during incubation, a critical period for embryonic development. PMID- 24156722 TI - Determination of TiO2, ZrO2, and Al2O3 nanoparticles on genotoxic responses in human peripheral blood lymphocytes and cultured embyronic kidney cells. AB - In this study a genotoxic evaluation of titanium dioxide (TiO2, 2.3 nm), zirconium oxide (ZrO2, 6 nm), aluminum oxide (Al2O3, 16.7 nm) nanoparticles (NP) and their ionic forms was conducted using human peripheral blood lymphocytes and cultured human embryonic kidney (HEK293) cells by means of a modified alkaline comet assay with/without the formamidopyrimidine-DNA glycosylase (Fpg) and endonuclease III (Endo III) enzymes. Modifications to the comet assay by using lesion-specific endonucleases, such as Endo III and Fpg, detect DNA bases with oxidative damage. Both human peripheral blood lymphocytes and cultured embryonic kidney cells were incubated with TiO2, ZrO2, or Al2O3 NP at concentrations of 1, 10, or 100 MUg/ml. Our results showed no significant induction in DNA damage by the comet assay with/without the Endo III and Fpg enzymes at all concentrations of ZrO2 and Al2O3. In the case of TiO2 NP only the highest concentration of 100 MUg/ml significantly induced a genotoxic response. Data thus indicate that both ZrO2 and Al2O3 NP were not genotoxic in our system and in the case of TiO2 the lowest-observed-adverse-effect level (LOAEL) for genotoxicity was 100 MUg/ml. Evidence indicates that these metallic NP are considered safe in light of the fact that no genotoxicity was noted with ZrO2 and Al2O3 and that the highest TiO2 concentration is not environmentally relevant. PMID- 24156723 TI - Implications of a possible route of vertical transmission of dengue virus by breast milk. PMID- 24156725 TI - Association of the C242T polymorphism in the NAD(P)H oxidase P22 phox gene with type 2 diabetes mellitus risk: a meta-analysis. AB - OBJECTIVES: A number of epidemiological studies have explored the association between NAD(P)H oxidase P22 phox gene C242T (rs4673) polymorphism and susceptibility to type 2 diabetes mellitus (T2DM), but the results are still debatable. Therefore, we conducted a meta-analysis to assess the potential association between the NAD(P)H oxidase P22 phox gene C242T polymorphism and T2DM risk. METHODS: Electronic literature searches of the PubMed, Embase, Web of Science, CBMdisc, CNKI and Google Scholar were performed up to June 15, 2013. Additionally, hand searching of the references of identified articles was performed. Data analyses were carried out by Stata 11.0. RESULTS: Seven studies were included in the final meta-analysis, covering a total of 1661 T2DM cases and 1265 controls. The results showed evidence for significant association between the NAD(P)H oxidase P22 phox gene C242T polymorphism and T2DM risk (for T/T vs. T/C: OR=1.61, 95% CI=1.14-2.26, p=0.007; for T/T vs. T/C+C/C: OR=1.50, 95% CI=1.10-2.05, p=0.009). In the subgroup analysis, there was also evidence for significant association between the NAD(P)H oxidase P22 phox gene C242T polymorphism and T2DM risk, either for Asians (T/T vs. T/C+C/C: OR=1.74, 95% CI=1.15-2.64, p=0.009) or for non-Asians (for T allele vs C allele: OR=1.30, 95% CI=1.04-1.61, p=0.02). CONCLUSIONS: The present meta-analysis indicates that the NAD(P)H oxidase P22 phox gene 242 T allele might be associated with an increased T2DM risk. PMID- 24156724 TI - Targeted over-expression of endothelin-1 in astrocytes leads to more severe brain damage and vasospasm after subarachnoid hemorrhage. AB - BACKGROUND: Endothelin-1 (ET-1) is a potent vasoconstrictor, and astrocytic ET-1 is reported to play a role in the pathogenesis of cerebral ischemic injury and cytotoxic edema. However, it is still unknown whether astrocytic ET-1 also contributes to vasogenic edema and vasospasm during subarachnoid hemorrhage (SAH). In the present study, transgenic mice with astrocytic endothelin-1 over expression (GET-1 mice) were used to investigate the pathophysiological role of ET-1 in SAH pathogenesis. RESULTS: The GET-1 mice experienced a higher mortality rate and significantly more severe neurological deficits, blood-brain barrier breakdown and vasogenic edema compared to the non-transgenic (Ntg) mice following SAH. Oral administration of vasopressin V1a receptor antagonist, SR 49059, significantly reduced the cerebral water content in the GET-1 mice. Furthermore, the GET-1 mice showed significantly more pronounced middle cerebral arterial (MCA) constriction after SAH. Immunocytochemical analysis showed that the calcium activated potassium channels and the phospho-eNOS were significantly downregulated, whereas PKC-alpha expression was significantly upregulated in the MCA of the GET-1 mice when compared to Ntg mice after SAH. Administration of ABT 627 (ETA receptor antagonist) significantly down-regulated PKC-alpha expression in the MCA of the GET-1 mice following SAH. CONCLUSIONS: The present study suggests that astrocytic ET-1 involves in SAH-induced cerebral injury, edema and vasospasm, through ETA receptor and PKC-mediated potassium channel dysfunction. Administration of ABT-627 (ETA receptor antagonist) and SR 49059 (vasopressin V1a receptor antagonist) resulted in amelioration of edema and vasospasm in mice following SAH. These data provide a strong rationale to investigate SR 49059 and ABT-627 as therapeutic drugs for the treatment of SAH patients. PMID- 24156726 TI - Equatorenes: synthesis and properties of chiral naphthalene, phenanthrene, chrysene, and pyrene possessing bis(1-adamantyl) groups at the peri-position. AB - Chiral polycyclic aromatic hydrocarbons containing bis(1-adamantyl) groups at the peri-positions, named equatorenes, were synthesized in optically pure form starting from optically pure 4,5-bis(1-adamantyl)-8-methoxy-1-naphthol. A sequential Diels-Alder reaction of furan and arynes generated from 1,2 bromotriflates provided tricyclic and tetracyclic epoxides, and acid-catalyzed aromatization gave phenanthrol and chrysenol. Deoxygenation reactions involving the hydrogenolysis of triflates gave 1,8-bis(1-adamantyl)naphthalene, 1,10-bis(1 adamantyl)phenanthrene, and 1,12-bis(1-adamantyl)chrysene. 3,4-Bis(1 adamantyl)pyrene was synthesized from phenanthrol by Sonogashira coupling and Pt catalyzed cyclization. Essentially no racemization occurred during the synthesis. X-ray analysis indicated the distorted naphthalene moiety possessing the peri diadamantyl groups and the flat structure of the other benzene rings. UV-vis analysis of the equatorenes showed considerable redshifts compared with that of the corresponding achiral arenes. Electrochemical analysis of the naphthalene and pyrene indicated that the distortion decreased the highest occupied molecular orbital stability with no marked effect on the lowest unoccupied molecular orbital energy level, and the origin was discussed on the basis of calculation results. PMID- 24156727 TI - Preferences for home delivery in Ethiopia: provider perspectives. AB - More than half of the maternal deaths worldwide occur in sub-Saharan Africa, most commonly during childbirth or the immediate post-partum period. Although delivery in health care facilities can avert maternal deaths, many women in sub-Saharan Africa continue to deliver at home. Factors influencing mothers' decisions to use facility-based delivery services in rural, low-income settings are not well understood. Health care professionals who provide delivery services in these areas may have unique insights about factors specific to such settings. Accordingly, we conducted a qualitative study of health care professionals in rural Ethiopia to determine key factors influencing facility delivery, using in depth interviews and the constant comparative method of data analysis. Results suggest multiple influences on women's decisions to deliver at home, including inadequate resources in facilities; unappealing aspects of delivery in facility settings; and known barriers to accessing services such as distance, transportation and cost. Our findings suggest that local health care providers offer valuable insight into why many rural Ethiopian women deliver their babies at home, despite major efforts to promote facility-based delivery. Their perspectives underscore the importance of a patient-centred approach to delivery services, which is often lacking in low-resource settings but may be fundamental to encouraging facility-based deliveries. PMID- 24156728 TI - Prophylactic titanium elastic nailing (TEN) following femoral lengthening (Lengthening then rodding) with one or two nails reduces the risk for secondary interventions after regenerate fractures: a cohort study in monolateral vs. bilateral lengthening procedures. AB - BACKGROUND: Femoral fracture rates of up to 30% have been reported following lengthening procedures using fixators. "Lengthening then rodding" uses one or two titanium elastic nails (TENs) for prophylactic intramedullary nailing to reduce this complication. The aim of the study was to decide if usage of only one TEN is safe or has it a higher risk of getting a fracture? And we asked if there is a difference between patients with monolateral or bilateral lengthening procedures according to their fracture rate? METHODS: One or two TENs were implanted in two groups of patients (monolateral and bilateral) after femoral lengthening procedures. The regenerate quality was classified using the Li system and fractures were categorized using the Simpson and Kenwright classification. The follow-up period was at least 1 year after removal of the frame. RESULTS: Sixty seven patients with 101 femoral lengthening procedures were included in 2007 2011. Group A included 34 patients with bilateral lengthening due to congenital short stature. Group B consisted of 33 patients with congenital disorders with leg length discrepancies. Seven fractures in six patients were seen in group A and five fractures in group B. One patient had residual shortening of 1 cm, and 11 fractures healed without relevant deviation (< 5 degrees ) or shortening (< 5 mm). A soft-tissue infection in one patient led to early removal of one TEN. CONCLUSIONS: Fractures occurred in both groups of patients in total in 12 of the 101 cases (12%). The rate of secondary interventions was markedly reduced. Usage of one or two TENs did not influence the fracture rate. PMID- 24156729 TI - Comparative analysis of antioxidants against cadmium induced reproductive toxicity in adult male rats. AB - The present study was conducted to compare and evaluate the potential benefits of three different antioxidants in reversing cadmium (Cd)-induced reproductive toxicity in adult male rats. Rats (n = 5) weighing 180 +/- 20 gm were divided into five groups (control, Cd, Cd + sulforaphane, Cd + vitamin E, and Cd + plant extract). Treated groups received CdCl2 (0.2 mg/kg), sulforaphane (25 ug/rat), vitamin E (75 mg/kg), and plant extract (100 mg/kg) for 15 days. Blood samples and testicular tissues were obtained for estimation of testosterone, Zn, and Cd concentration and daily sperm production/efficiency of sperm production. Cadmium exposure caused a significant decrease in final body weight (p < 0.0001). The plasma concentrations of Cd were significantly increased and Zn concentration decreased (p < 0.0001) in the Cd group as compared to the control group. The testicular concentrations of Cd were significantly increased and Zn concentration decreased (p < 0.0001) in the Cd group as compared to the control group. Cadmium exposure caused a significant decrease (p < 0.0001) in plasma testosterone concentrations and daily sperm production as compared to the control group. More significant effects were observed with Cd+sulforaphane, Cd + vitamin E, and Cd + plant extract treated groups in slashing Cd-induced toxicity. Present findings suggest that Ficus religiosa and sulforaphane are more powerful antioxidants as compared to vitamin E in reversing the oxidative stress and can have a protective role against Cd induced reproductive toxicity in adult male rats. Part of the mechanism involved in this protective role seems to be associated with the antioxidant properties of these agents in reducing reproductive damage. PMID- 24156733 TI - Chiropractor perceptions and practices regarding interprofessional service delivery in the Danish primary care context. AB - For the past 20 years, chiropractors have enjoyed access to the Danish health care system and have been free to build integrated health care delivery partnerships. An electronic survey of chiropractic clinics around Denmark was conducted in order to observe interprofessional practice trends. From the available population of 252 practices, 166 responses were received. Ninety-six percent of respondents considered inter-disciplinary/interprofessional practice to be either "very" or "extremely" important in the context of modern Danish health care. Three occupational groups appear to be commonly involved in practice alongside chiropractors, these being massage therapists (82%), physiotherapists (58%) and acupuncturists (37%). Interestingly only 11% considered a medical practitioner to be an active participant in their current interprofessional service delivery. Danish chiropractors consider interprofessional practice to be important and as a group, perceive themselves to be offering such models of service provision. Medical practitioners are perceived as desirable, but under utilized partners. PMID- 24156734 TI - Procalcitonin biomarker kinetics fails to predict treatment response in perioperative abdominal infection with septic shock. AB - INTRODUCTION: Procalcitonin (PCT) biomarker is suggested to tailor antibiotic therapy in the medical intensive care unit (ICU) but studies in perioperative medicine are scarce. The aim of this study was to determine whether PCT reported thresholds are associated with the initial treatment response in perioperative septic shock secondary to intra-abdominal infection. METHODS: This single ICU, observational study included patients with perioperative septic shocks secondary to intra-abdominal infection. Demographics, PCT at days 0, 1, 3, 5, treatment response and outcome were collected. Treatment failure included death related to the initial infection, second source control treatment or a new onset intra abdominal infection. The primary endpoint was to assess whether PCT thresholds (0.5 ng/ml or a drop from the peak of at least 80%) predict the initial treatment response. RESULTS: We included 101 consecutive cases. Initial treatment failed in 36 patients with a subsequent mortality of 75%. Upon admission, PCT was doubled when treatment ultimately failed (21.7 ng/ml +/- 38.7 vs. 41.7 ng/ml +/- 75.7; P = 0.04). Although 95% of the patients in whom PCT dropped down below 0.5 ng/ml responded to treatment, 50% of the patients in whom PCT remained above 0.5 ng/ml also responded successfully to treatment. Moreover, despite a PCT drop of at least 80%, 40% of patients had treatment failure. CONCLUSIONS: In perioperative intra-abdominal infections with shock, PCT decrease to 0.5 ng/ml lacked sensitivity to predict treatment response and its decrease of at least 80% from its peak failed to accurately predict treatment response. Studies in perioperative severe infections are needed before using PCT to tailor antibiotic use in this population. PMID- 24156735 TI - Counting the number of magnesium ions bound to the surface-immobilized thymine oligonucleotides that comprise spherical nucleic acids. AB - Label-free studies carried out under aqueous phase conditions quantify the number of Mg(2+) ions binding to surface-immobilized T40 sequences, the subsequent reordering of DNA on the surface, and the consequences of Mg(2+) binding for DNA DNA interactions. Second harmonic generation measurements indicate that, within error, 18-20 Mg(2+) ions are bound to the T40 strand at saturation and that the metal-DNA interaction is associated with a near 30% length contraction of the strand. Structural reordering, evaluated using vibrational sum frequency generation, atomic force microscopy, and dynamic light scattering, is attributed to increased charge screening as the Mg(2+) ions bind to the negatively charged DNA, reducing repulsive Coulomb forces between nucleotides and allowing the DNA single strands to collapse or coil upon themselves. The impact of Mg(2+) binding on DNA hybridization and duplex stability is assessed with spherical nucleic acid (SNA) gold nanoparticle conjugates in order to determine an optimal working range of Mg(2+) concentrations for DNA-DNA interactions in the absence of NaCl. The findings are consistent with a charge titration effect in which, in the absence of NaCl, (1) hybridization does not occur at room temperature if an average of 17.5 or less Mg(2+) ions are bound per T40 strand, which is not reached until the bulk Mg(2+) concentration approaches 0.5 mM; (2) hybridization proceeds, albeit with low duplex stability having an average Tm of 31(3) degrees C, if an average of 17.5-18.0 Mg(2+) ions are bound; and (3) highly stable duplexes having a Tm of 64(2) degrees C form if 18.5-19.0 Mg(2+) ions are bound, corresponding to saturation of the T40 strand. PMID- 24156736 TI - Engineering biodegradable and multifunctional peptide-based polymers for gene delivery. AB - The complex nature of in vivo gene transfer establishes the need for multifunctional delivery vectors capable of meeting these challenges. An additional consideration for clinical translation of synthetic delivery formulations is reproducibility and scale-up of materials. In this review, we summarize our work over the last five years in developing a modular approach for synthesizing peptide-based polymers. In these materials, bioactive peptides that address various barriers to gene delivery are copolymerized with a hydrophilic backbone of N-(2-hydroxypropyl)methacrylamide (HPMA) using reversible-addition fragmentation chain-transfer (RAFT) polymerization. We demonstrate that this synthetic approach results in well-defined, narrowly-disperse polymers with controllable composition and molecular weight. To date, we have investigated the effectiveness of various bioactive peptides for DNA condensation, endosomal escape, cell targeting, and degradability on gene transfer, as well as the impact of multivalency and polymer architecture on peptide bioactivity. PMID- 24156737 TI - Effort testing in children: can cognitive and symptom validity measures differentiate malingered performances? AB - Recent efforts have contributed to significant advances in the detection of malingered performances in adults during cognitive assessment. However, children's ability to purposefully underperform has received relatively little attention. The purpose of the present investigation was to examine children's performances on common intellectual measures, as well as two symptom validity measures: the Test of Memory Malingering and the Dot-Counting Test. This was accomplished through the administration of measures to children ages 6 to 12 years old in randomly assigned full-effort (control) and poor-effort (treatment) conditions. Prior to randomization, children's general intellectual functioning (i.e., IQ) was estimated via administration of the Kaufman Brief Intellectual Battery-Second Edition (KBIT-2). Multivariate analyses revealed that the conditions significantly differed on some but not all administered measures. Specifically, children's estimated IQ in the treatment condition significantly differed from the full-effort IQ initially obtained from the same children on the KBIT-2, as well as from the IQs obtained in the full-effort control condition. These findings suggest that children are fully capable of willfully underperforming during cognitive testing; however, consistent with prior investigations, some measures evidence greater sensitivity than others in evaluating effort. PMID- 24156739 TI - Designing synthetic biology. AB - Synthetic biology is frequently defined as the application of engineering design principles to biology. Such principles are intended to streamline the practice of biological engineering, to shorten the time required to design, build, and test synthetic gene networks. This streamlining of iterative design cycles can facilitate the future construction of biological systems for a range of applications in the production of fuels, foods, materials, and medicines. The promise of these potential applications as well as the emphasis on design has prompted critical reflection on synthetic biology from design theorists and practicing designers from many fields, who can bring valuable perspectives to the discipline. While interdisciplinary connections between biologists and engineers have built synthetic biology via the science and the technology of biology, interdisciplinary collaboration with artists, designers, and social theorists can provide insight on the connections between technology and society. Such collaborations can open up new avenues and new principles for research and design, as well as shed new light on the challenging context-dependence-both biological and social-that face living technologies at many scales. This review is inspired by the session titled "Design and Synthetic Biology: Connecting People and Technology" at Synthetic Biology 6.0 and covers a range of literature on design practice in synthetic biology and beyond. Critical engagement with how design is used to shape the discipline opens up new possibilities for how we might design the future of synthetic biology. PMID- 24156738 TI - Characterization of simian T-cell leukemia virus type 1 in naturally infected Japanese macaques as a model of HTLV-1 infection. AB - BACKGROUND: Human T-cell leukemia virus type 1 (HTLV-1) causes chronic infection leading to development of adult T-cell leukemia (ATL) and inflammatory diseases. Non-human primates infected with simian T-cell leukemia virus type 1 (STLV-1) are considered to constitute a suitable animal model for HTLV-1 research. However, the function of the regulatory and accessory genes of STLV-1 has not been analyzed in detail. In this study, STLV-1 in naturally infected Japanese macaques was analyzed. RESULTS: We identified spliced transcripts of STLV-1 corresponding to HTLV-1 tax and HTLV-1 bZIP factor (HBZ). STLV-1 Tax activated the NFAT, AP-1 and NF-kappaB signaling pathways, whereas STLV-1 bZIP factor (SBZ) suppressed them. Conversely, SBZ enhanced TGF-beta signaling and induced Foxp3 expression. Furthermore, STLV-1 Tax activated the canonical Wnt pathway while SBZ suppressed it. STLV-1 Tax enhanced the viral promoter activity while SBZ suppressed its activation. Then we addressed the clonal proliferation of STLV-1+ cells by massively sequencing the provirus integration sites. Some clones proliferated distinctively in monkeys with higher STLV-1 proviral loads. Notably, one of the monkeys surveyed in this study developed T-cell lymphoma in the brain; STLV-1 provirus was integrated in the lymphoma cell genome. When anti-CCR4 antibody, mogamulizumab, was administered into STLV-1-infected monkeys, the proviral load decreased dramatically within 2 weeks. We observed that some abundant clones recovered after discontinuation of mogamulizumab administration. CONCLUSIONS: STLV-1 Tax and SBZ have functions similar to those of their counterparts in HTLV 1. This study demonstrates that Japanese macaques naturally infected with STLV-1 resemble HTLV-1 carriers and are a suitable model for the investigation of persistent HTLV-1 infection and asymptomatic HTLV-1 carrier state. Using these animals, we verified that mogamulizumab, which is currently used as a drug for relapsed ATL, is also effective in reducing the proviral load in asymptomatic individuals. PMID- 24156740 TI - Sulfonamides incorporating fluorine and 1,3,5-triazine moieties are effective inhibitors of three beta-class carbonic anhydrases from Mycobacterium tuberculosis. AB - A new series of fluorine containing 1,3,5-triazinyl sulfonamide derivatives obtained from cyanuric fluoride, sulfanilamide/4-aminoethylbenzenesulfonamide followed and incorporating also amin0, amino alcohol and amino acid moieties have been investigated as inhibitors of three beta-carbonic anhydrases (CAs, EC 4.2.1.1) from the bacterial pathogen Mycobacterium tuberculosis, mtCA1 (Rv1284), mtCA 2 (Rv3588c) and mtCA 3 (Rv3273). All three enzymes were efficiently inhibited by these sulfonamides with KI values in the nanomolar or submicromolar range, depending on the substitution of one or both fluorine atoms at the 1,3,5 triazine ring. As some of these enzymes are crucial for the life cycle of this bacterium, the class of beta-CA inhibitors reported in this study may lead to antimycobacterial agents with a different mechanism of action compared to the clinically used such drugs for which the pathogen developed extensive drug resistance. PMID- 24156741 TI - Pharmacokinetic evaluation of C-3 modified 1,8-naphthyridine-3-carboxamide derivatives with potent anticancer activity: lead finding. AB - To develop naphthyridine derivatives as anticancer candidates, pharmacokinetic (PK) evaluations of 10 novel derivatives of 1,4-dihydro-4-oxo-1-proparagyl-1,8 naphthyridine-3-carboxamide, with potent anticancer activity were done using in vitro ADME (absorption, distribution, metabolism, excretion) and pharmacokinetic- pharmcodynamic (PK/PD) assays. Only derivatives 5, 6, 9 and 10 showed better metabolic stability, solubility, permeability, partition coefficient and cytochrome P450 (CYP) inhibition values. PK of derivatives 5, 6, 9 and 10 in rat showed comparable PK profile for derivative 5 (C0 = 6.98 ug/mL) and 6 (C0 = 6.61 ug/mL) with no detectable plasma levels for derivatives 9 and 10 at 5.0 mg/kg i.v. dose. PK/PD assay of derivatives 5 and 6 in tumor-bearing mice (TBM) showed comparable PK but tumor plasma index (TPI) of derivative 6 (4.02) was better than derivative 5 (2.50), suggesting better tumor uptake of derivative 6. Derivative 6, as lead compound, showed highest tumor growth inhibition (TGI) value of 33.6% in human ovary cancer xenograft model. PMID- 24156742 TI - Total monoamine oxidase (MAO) inhibition by chestnut honey, pollen and propolis. AB - Monoamine oxidase (MAO) inhibitors are generally used in the treatment of depressive disorders and some neurodegenerative illnesses, such as Parkinson's disease and Alzheimer's disease. The aim of this preliminary study was to investigate the MAO [MAO (E.C.1.4.3.4)] inhibiting effect of various apitherapeutic products, such as chestnut honey, pollen and propolis. Extracts' MAO inhibition was measured using peroxidase-linked spectrophotometric assay in enzyme isolated from rat liver microsomes, and the values are expressed as the inhibition concentration (IC50) causing 50% inhibition of MAO. The antioxidant activity of the bee products was also determined in terms of total phenolic content (TPC) and ferric reducing/antioxidant power in aquatic extracts. All samples exhibited substantial inhibition of MAO, propolis having the highest. Inhibition was related to samples' TPCs and antioxidant capacities. These results show that bee products possess a sedative effect and may be effective in protecting humans against depression and similar diseases. PMID- 24156743 TI - Synthesis and characterization of quinazoline derivatives: search for hybrid molecule as diuretic and antihypertensive agents. AB - To explore the pharmacological and structure-activity relationship of a series of N-substituted-(4-oxo-2-substituted-phenylquinazolin-3-(4H)-yl), substituted benzene sulfonamide derivatives (1-25) were synthesized from substituted anthranilic acids derived amino quinazolines and substituted benzene sulphonamides. All the synthesized compounds were evaluated for their diuretic (by Lipschitz et al. method), antihypertensive activity by non-invasive blood pressure (NIBP) using the tail-cuff method and anti-diabetic potential in rats. Six compounds showing significantly excellent activity were compared with metolazone, prazosin and diazoxide as standards. Compound N-[7-chloro-2-(4 methoxyphenyl)-4-oxoquinazolin-3(4H)-yl]-4 nitrobenzenesulfonamide (20) exhibited most potent of the series. PMID- 24156744 TI - Docking and molecular dynamics studies of the binding between Peloruside A and tubulin. AB - The molecular docking, MD simulation and binding free energy calculation were performed to explore the probable binding modes between PLA and tubulin. Through docking study, three possible binding sites for PLA were speculated as follows: the taxane site, the alternative site and a new site in alpha-tubulin. Then, 12.0 ns MD simulations show that these binding modes predicted by docking have been changed more or less, whereas the MD simulations offer more reliable binding details. The MM-PBSA binding free-energy calculations reasonably identify that the taxane site is the most favorable binding site of PLA and the alternative site is the secondary one, which can be used to explain some experimental facts. These studies theoretically resolve the priority of binding sites for PLA and offer the reliable binding modes between PLA and tubulin, and thus help to understanding the action mechanism for this kind of inhibitor. PMID- 24156745 TI - Effects of nanoscale surface texture and lubricant molecular structure on boundary lubrication in liquid. AB - Nanoconfinement effects of boundary lubricants can significantly affect the friction behavior of textured solid interfaces. These effects were studied with nanotextured diamond-like carbon (DLC) surfaces using a reciprocating ball-on flat tribometer in liquid lubricants with different molecular structures: n hexadecane and n-pentanol for linear molecular structure and poly(alpha-olefin) and heptamethylnonane for branched molecular structure. It is well-known that liquid lubricants with linear molecular structures can readily form a long-range ordered structure upon nanoconfinement between flat solid surfaces. This long range ordering, often called solidification, causes high friction in the boundary lubrication regime. When the solid surface deforms elastically due to the contact pressure and this deformation depth is larger than the surface roughness, even rough surfaces can exhibit the nanoconfinement effects. However, the liquid entrapped in the depressed region of the nanotextured surface would not solidify, which effectively reduces the solidified lubricant area in the contact region and decreases friction. When liquid lubricants are branched, the nanoconfinement induced solidification does not occur because the molecular structure is not suitable for the long-range ordering. Surface texture, therefore, has an insignificant effect on the boundary lubrication of branched molecules. PMID- 24156747 TI - Solid self-emulsifying drug delivery system (S-SEDDS) for improved dissolution rate of fenofibrate. AB - PURPOSE: The aim of this work was to develop and characterise S-SEDDS containing fenofibrate (FF) for dissolution enhancement. METHODS: The self-emulsifying pre concentrate was prepared by using different proportion of Labrafac WL1349 as oily phase, Cremophor EL as surfactants and Gelucire 44/14 as co-surfactant. The prepared pre-concentrate was solidified with PEG 6000. For comparison, formulations containing TPGS as surfactant and solidifier were prepared and studied. RESULTS: The cremophor/PEG and TPGS based S-SEDDS formulations containing 10 and 15% w/w FF when dispersed in water, formed nanoemulsion with a size range of 150-200 nm. FF was present in the crystalline state in the formulations. The formulations containing 10% w/w FF showed 90-100% dissolution in 60 min whereas the untreated FF showed only 2-4% dissolution. CONCLUSION: A novel S-SEDDS was developed for FF using cremophor/PEG and TPGS. The dissolution of FF was enhanced by approximately 20-fold in SGF pH 1.2. PMID- 24156746 TI - Impact of percutaneous coronary intervention on biomarker levels in patients in the subacute phase following myocardial infarction: the Occluded Artery Trial (OAT) biomarker ancillary study. AB - BACKGROUND: The purpose of the Occluded Artery Trial (OAT) Biomarker substudy was to evaluate the impact of infarct related artery (IRA) revascularization on serial levels of N-terminal prohormone of brain natriuretic peptide (NT-proBNP) and dynamics of other biomarkers related to left ventricular remodeling, fibrosis and angiogenesis. METHODS: Patients were eligible for OAT-Biomarker based on the main OAT criteria. Of 70 patients (age 60.8 +/- 8.8, 25% women) enrolled in the substudy, 37 were randomized to percutaneous coronary intervention (PCI) and 33 to optimal medical therapy alone. Baseline serum samples were obtained prior to OAT randomization with follow up samples taken at one year. The primary outcome was percent change of NT-proBNP from baseline to 1 year. The secondary outcomes were respective changes of matrix metalloproteinases (MMP) 2 and 9, tissue inhibitor of matrix metalloproteinase 2 (TIMP-2), Vascular Endothelial Growth Factor (VEGF), and Galectin-3. RESULTS: Paired (baseline and one-year) serum samples were obtained in 62 subjects. Baseline median NT-proBNP level was 944.8 (455.3, 1533) ng/L and decreased by 69% during follow-up (p < 0.0001). Baseline MMP-2 and TIMP-2 levels increased significantly from baseline to follow-up (p = 0.034, and p = 0.027 respectively), while MMP-9 level decreased from baseline (p = 0.038). Levels of VEGF and Galectin-3 remained stable at one year (p = NS for both). No impact of IRA revascularization on any biomarker dynamics were noted. CONCLUSIONS: There were significant changes in measured biomarkers related to LV remodeling, stress, and fibrosis following MI between 0 and 12 month. Establishing infarct vessel patency utilizing stenting 24 hours-28 days post MI did not however influence the biomarkers' release. PMID- 24156748 TI - Activated carbon mitigates mercury and methylmercury bioavailability in contaminated sediments. AB - There are few available in situ remediation options for Hg contaminated sediments, short of capping. Here we present the first tests of activated carbon and other sorbents as potential in situ amendments for remediation of mercury and methylmercury (MeHg), using a study design that combined 2 L sediment/water microcosms with 14 day bioaccumulation assays. Our key end points were pore water concentrations, and bioaccumulation of total Hg and MeHg by a deposit-feeding oligochaete Lumbriculus variegatus. Four amendments were tested: an activated carbon (AC); CETCO Organoclay MRM (MRM); Thiol-SAMMS (TS), a thiol-functionalized mesoporous silica; and AMBERSEP GT74, an ion-exchange resin. Amendments were tested in four separate microcosm assays using Hg-contaminated sediments from two freshwater and two estuarine sites. AC and TS amendments, added at 2-7% of the dry weight of sediments significantly reduced both MeHg concentrations in pore waters, relative to unamended controls (by 45-95%) and bioaccumulation of MeHg by Lumbriculus (by between 30 and 90%). Both amendments had only small impacts on microcosm surface water, sediment and pore water chemistry, with the exception of significant reductions in pore water dissolved organic matter. The effectiveness of amendments in reducing bioaccumulation was well-correlated with their effectiveness in increasing sediment:water partitioning, especially of MeHg. Sediments with low native sediment:water MeHg partition coefficients were most effectively treated. Thus, in situ sediment sorbent amendments may be able to reduce the risk of biotic Hg and MeHg uptake in contaminated sediments, and subsequent contamination of food webs. PMID- 24156749 TI - Integrated vector management: a critical strategy for combating vector-borne diseases in South Sudan. AB - BACKGROUND: Integrated vector management (IVM) based vector control is encouraged by the World Health Organization (WHO). However, operational experience with the IVM strategy has mostly come from countries with relatively well-established health systems and with malaria control focused programmes. Little is known about deployment of IVM for combating multiple vector-borne diseases in post-emergency settings, where delivery structures are less developed or absent. This manuscript reports on the feasibility of operational IVM for combating vector-borne diseases in South Sudan. CASE DESCRIPTION: A methodical review of published and unpublished documents on vector-borne diseases for South Sudan was conducted via systematic literature search of online electronic databases, Google Scholar, PubMed and WHO, using a combination of search terms. Additional, non-peer reviewed literature was examined for information related to the subject. DISCUSSION: South Sudan is among the heartlands of vector-borne diseases in the world, characterized by enormous infrastructure, human and financial resource constraints and a weak health system against an increasing number of refugees, returnees and internally displaced people. The presence of a multiplicity of vector-borne diseases in this post-conflict situation presents a unique opportunity to explore the potential of a rational IVM strategy for multiple disease control and optimize limited resource utilization, while maximizing the benefits and providing a model for countries in a similar situation. CONCLUSION: The potential of integrating vector-borne disease control is enormous in South Sudan. However, strengthened coordination, intersectoral collaboration and institutional and technical capacity for entomological monitoring and evaluation, including enforcement of appropriate legislation are crucial. PMID- 24156750 TI - Experience with real time continuous glucose monitoring in stabilising fluctuating glycaemia during intensive care of the preterm infant of a diabetic mother. AB - OBJECTIVE: The newborns of diabetic mothers suffer from perinatal complications more frequently than the newborns of healthy women. METHODS: We used for 7 days a real time continuous glucose monitoring system (RT-CGMS) to monitor glucose homeostasis and manage glucose administration in a premature newborn of a diabetic mother. RESULTS: The boy was born at 35 + 5 gestational weeks with typical signs of diabetic fetopathy. RT-CGMS revealed 2 late hypoglycaemia episodes on the 2nd and 4th days. The sensor readings correlated well with glycaemia measured in the laboratory (r = 0.908, p = 0.005). To support conclusions of this case report, we attached the data of five other preterm newborns of diabetic mothers who were later successfully treated according to the RT-CGMS data as well. CONCLUSIONS: This approach allows timely response to glycaemia instability and is applicable even in preterm infants. PMID- 24156751 TI - Copper: a biphasic regulator of caprine sperm forward progression. AB - Copper is essential for spermatogenesis and its presence has been demonstrated in male and female reproductive fluids in several mammalian species. However, little is known about the physiological significance of this trace element in the regulation of forward progression of mammalian sperm cells which is essential for sperm fertility potential in vivo. The purpose of this investigation was to determine the physiological role of the bivalent copper ion (Cu(2+)) on mammalian sperm forward motility using a chemically-defined medium and caprine cauda epididymal sperm model. Sperm forward motility was significantly enhanced by Cu(2+) in a dose-dependent manner; maximal activation (approx 20%) was noted at the 5 uM level of the metal. Above 10 uM Cu(2+) sperm motility decreased, showing that Cu(2+) exerts a biphasic regulation on sperm motility. These findings have been confirmed using a spectrophotometric motility assay, an objective method of motility analysis. At lower concentrations (up to 5 uM), copper enhanced sperm membrane lipid peroxidation as well as the level of intra-sperm cyclic adenosine mono phosphate (c-AMP), but at a higher level it caused marked inhibition of both of the biochemical parameters. The observed correlation of Cu(2+)-dependent biphasic modulation of sperm membrane lipid peroxidation and intrasperm c-AMP with sperm forward motility is consistent with the view that Cu(2+) regulation of sperm motility is mediated by membrane lipid peroxidation, which in turn modulates the level of intra-sperm c-AMP, a well-known activator of sperm motility. PMID- 24156754 TI - Statin therapy correlated CYP2D6 gene polymorphism and hyperlipidemia. AB - PURPOSE: To investigate the distribution of statin therapy correlated gene polymorphism allele CYP2D6*10 (C188T) in Ningxia Hui nationality and to discuss the relationship between the gene polymorphism allele CYP2D6*10 (C188T) and the lipid-lowering efficacy of simvastatin and hyperlipidemia. MATERIALS AND METHODS: One hundred and fifty healthy people (80 males and 70 females) and 200 hyperlipidemia patients (105 males and 95 females) were recruited at Ningxia People's Hospital. Genotypes were determined by using allele-specific amplification (ASA-PCR) in 150 healthy controls and 200 patients with hyperlipidemia. Relationships between genotypes and lipid levels and the lipid lowering efficacy of simvastatin were analyzed. RESULTS: The distribution frequency of the CYP2D6*10 allele was 47.6% in the Ningxia Hui nationality. There was no significant correlation between the CYP2D6*10 allele and hyperlipidemia. At 8 weeks after treatment with simvastatin, total cholesterol (TC) and low density lipoprotein cholesterol (LDL-C) levels were more obviously decreased with the CC genotype than the CT and TT genotypes, with significant differences. CONCLUSION: Distribution of the gene polymorphism of CYP2D6*10 is ethnically and geographical different. The allele T of CYP2D6*10 is not related to hyperlipidemia. CC expression seemed to increase the lipid-lowering effects of simvastatin. The hyperlipidemia patients with CC genotype should take lower doses of simvastatin than those with CT/TT genotype in the Ningxia Hui population. PMID- 24156756 TI - AVISPA: a web tool for the prediction and analysis of alternative splicing. AB - Transcriptome complexity and its relation to numerous diseases underpins the need to predict in silico splice variants and the regulatory elements that affect them. Building upon our recently described splicing code, we developed AVISPA, a Galaxy-based web tool for splicing prediction and analysis. Given an exon and its proximal sequence, the tool predicts whether the exon is alternatively spliced, displays tissue-dependent splicing patterns, and whether it has associated regulatory elements. We assess AVISPA's accuracy on an independent dataset of tissue-dependent exons, and illustrate how the tool can be applied to analyze a gene of interest. AVISPA is available at http://avispa.biociphers.org. PMID- 24156757 TI - Glycerol carbonate as green solvent for pretreatment of sugarcane bagasse. AB - BACKGROUND: Pretreatment of lignocellulosic biomass is a prerequisite for effective saccharification to produce fermentable sugars. In this study, "green" solvent systems based on acidified mixtures of glycerol carbonate (GC) and glycerol were used to treat sugarcane bagasse and the roles of each solvent in deconstructing biomass were determined. RESULTS: Pretreatment of sugarcane bagasse at 90 degrees C for only 30 min with acidified GC produced a solid residue having a glucan digestibility of 90% and a glucose yield of 80%, which were significantly higher than a glucan digestibility of 16% and a glucose yield of 15% obtained for bagasse pretreated with acidified ethylene carbonate (EC). Biomass compositional analyses showed that GC pretreatment removed more lignin than EC pretreatment (84% vs 54%). Scanning electron microscopy (SEM) showed that fluffy and size-reduced fibres were produced from GC pretreatment whereas EC pretreatment produced compact particles of reduced size. The maximal glucan digestibility and glucose yield of GC/glycerol systems were about 7% lower than those of EC/ethylene glycol (EG) systems. Replacing up to 50 wt% of GC with glycerol did not negatively affect glucan digestibility and glucose yield. The results from pretreatment of microcrystalline cellulose (MCC) showed that (1) pretreatment with acidified alkylene glycol (AG) alone increased enzymatic digestibility compared to pretreatments with acidified alkylene carbonate (AC) alone and acidified mixtures of AC and AG, (2) pretreatment with acidified GC alone slightly increased, but with acidified EC alone significantly decreased, enzymatic digestibility compared to untreated MCC, and (3) there was a good positive linear correlation of enzymatic digestibility of treated and untreated MCC samples with congo red (CR) adsorption capacity. CONCLUSIONS: Acidified GC alone was a more effective solvent for pretreatment of sugarcane bagasse than acidified EC alone. The higher glucose yield obtained with GC-pretreated bagasse is possibly due to the presence of one hydroxyl group in the GC molecular structure, resulting in more significant biomass delignification and defibrillation, though both solvent pretreatments reduced bagasse particles to a similar extent. The maximum glucan digestibility of GC/glycerol systems was less than that of EC/EG systems, which is likely attributed to glycerol being less effective than EG in biomass delignification and defibrillation. Acidified AC/AG solvent systems were more effective for pretreatment of lignin-containing biomass than MCC. PMID- 24156758 TI - Molecular dynamics simulations of gas selectivity in amorphous porous molecular solids. AB - Some organic cage molecules have structures with protected, internal pore volume that cannot be in-filled, irrespective of the solid-state packing mode: that is, they are intrinsically porous. Amorphous packings can give higher pore volumes than crystalline packings for these materials, but the precise nature of this additional porosity is hard to understand for disordered solids that cannot be characterized by X-ray diffraction. We describe here a computational methodology for generating structural models of amorphous porous organic cages that are consistent with experimental data. Molecular dynamics simulations rationalize the observed gas selectivity in these amorphous solids and lead to insights regarding self-diffusivities, gas diffusion trajectories, and gas hopping mechanisms. These methods might be suitable for the de novo design of new amorphous porous solids for specific applications, where "rigid host" approximations are not applicable. PMID- 24156755 TI - The interaction of force and repetition on musculoskeletal and neural tissue responses and sensorimotor behavior in a rat model of work-related musculoskeletal disorders. AB - BACKGROUND: We examined the relationship of musculoskeletal risk factors underlying force and repetition on tissue responses in an operant rat model of repetitive reaching and pulling, and if force x repetition interactions were present, indicative of a fatigue failure process. We examined exposure-dependent changes in biochemical, morphological and sensorimotor responses occurring with repeated performance of a handle-pulling task for 12 weeks at one of four repetition and force levels: 1) low repetition with low force, 2) high repetition with low force, 3) low repetition with high force, and 4) high repetition with high force (HRHF). METHODS: Rats underwent initial training for 4-6 weeks, and then performed one of the tasks for 12 weeks, 2 hours/day, 3 days/week. Reflexive grip strength and sensitivity to touch were assayed as functional outcomes. Flexor digitorum muscles and tendons, forelimb bones, and serum were assayed using ELISA for indicators of inflammation, tissue stress and repair, and bone turnover. Histomorphometry was used to assay macrophage infiltration of tissues, spinal cord substance P changes, and tissue adaptative or degradative changes. MicroCT was used to assay bones for changes in bone quality. RESULTS: Several force x repetition interactions were observed for: muscle IL-1alpha and bone IL 1beta; serum TNFalpha, IL-1alpha, and IL-1beta; muscle HSP72, a tissue stress and repair protein; histomorphological evidence of tendon and cartilage degradation; serum biomarkers of bone degradation (CTXI) and bone formation (osteocalcin); and morphological evidence of bone adaptation versus resorption. In most cases, performance of the HRHF task induced the greatest tissue degenerative changes, while performance of moderate level tasks induced bone adaptation and a suggestion of muscle adaptation. Both high force tasks induced median nerve macrophage infiltration, spinal cord sensitization (increased substance P), grip strength declines and forepaw mechanical allodynia by task week 12. CONCLUSIONS: Although not consistent in all tissues, we found several significant interactions between the critical musculoskeletal risk factors of force and repetition, consistent with a fatigue failure process in musculoskeletal tissues. Prolonged performance of HRHF tasks exhibited significantly increased risk for musculoskeletal disorders, while performance of moderate level tasks exhibited adaptation to task demands. PMID- 24156759 TI - A neuropsychological profile of childhood maltreatment within an adolescent inpatient sample. AB - Recent research has begun to identify the neurocognitive and psychological effects of childhood maltreatment, although information is limited on the neuropsychological presentation of maltreatment in psychiatrically hospitalized adolescents. This study examined the executive-functioning and language abilities as well as psychopathological presentation of childhood maltreatment victims in an adolescent psychiatric inpatient setting. The sample consisted of adolescent inpatients (ages 13-19 years old) who completed a neuropsychological/psychological assessment during hospitalization (n = 122). The sample was grouped based on childhood maltreatment history, with one group categorized by maltreatment history (n = 49) and the other group characterized by no maltreatment history (n = 73). Analyses revealed statistically significant differences (p < .01) between maltreatment groups on executive functioning, as well as on measures of self-reported depression and anxiety symptoms. No group differences remained after controlling for posttraumatic stress disorder. Further, distinct neuropsychological profiles were identified for specific types of maltreatment experienced. These findings suggest that while childhood maltreatment is associated with a range of neuropsychological impairments, the specific type of maltreatment experienced may have a significant influence on the type and severity of impairments. These findings contribute to the growing body of research on the significant consequences of childhood maltreatment. PMID- 24156760 TI - An international survey of physicians regarding clinical trials: a comparison between Kyoto University Hospital and Seoul National University Hospital. AB - BACKGROUND: International clinical trials are now rapidly expanding into Asia. However, the proportion of global trials is higher in South Korea compared to Japan despite implementation of similar governmental support in both countries. The difference in clinical trial environment might influence the respective physicians' attitudes and experience towards clinical trials. Therefore, we designed a questionnaire to explore how physicians conceive the issues surrounding clinical trials in both countries. METHODS: A questionnaire survey was conducted at Kyoto University Hospital (KUHP) and Seoul National University Hospital (SNUH) in 2008. The questionnaire consisted of 15 questions and 2 open ended questions on broad key issues relating to clinical trials. RESULTS: The number of responders was 301 at KUHP and 398 at SNUH. Doctors with trial experience were 196 at KUHP and 150 at SNUH. Among them, 12% (24/196) at KUHP and 41% (61/150) at SUNH had global trial experience. Most respondents at both institutions viewed clinical trials favorably and thought that conducting clinical trials contributed to medical advances, which would ultimately lead to new and better treatments. The main reason raised as a hindrance to conducting clinical trials was the lack of personnel support and time. Doctors at both university hospitals thought that more clinical research coordinators were required to conduct clinical trials more efficiently. KUHP doctors were driven mainly by pure academic interest or for their desire to find new treatments, while obtaining credits for board certification and co-authorship on manuscripts also served as motivation factors for doctors at SNUH. CONCLUSIONS: Our results revealed that there might be two different approaches to increase clinical trial activity. One is a social level approach to establish clinical trial infrastructure providing sufficient clinical research professionals. The other is an individual level approach that would provide incentives to encourage doctors to participate in and conduct clinical trials. PMID- 24156762 TI - Creation of cellobiose and xylooligosaccharides-coutilizing Escherichia coli displaying both beta-glucosidase and beta-xylosidase on its cell surface. AB - We demonstrated direct utilization of xylooligosaccharides using beta-xylosidase displaying Escherichia coli. After screening active beta-xylosidases, BSU17580 from Bacillus subtilis or Tfu1616 from Thermobifida fusca YX, were successfully displayed on the E. coli cell surface using Blc or HdeD as anchor proteins, and these transformants directly assimilated xylooligosaccharides as a carbon source. The final OD 600 in minimal medium containing 2% xylooligosaccharides was 1.09 (after 12 h of cultivation) and 1.30 (after 40 h of cultivation). We then constructed an E. coli strain displaying both beta-glucosidase and beta xylosidase. beta-glucosidase- and beta-xylosidase-displaying E. coli was successfully grown on a 1% cellobiose and 1% xylooligosaccharides mixture, and the OD 600 was 1.76 after 10 h of cultivation, which was higher and reached faster than that grown on a glucose/xylose mixture (1.20 after 30 h of cultivation). PMID- 24156764 TI - Neuropsychiatric manifestations of latent toxoplasmosis on mothers and their offspring. AB - Toxoplasmosis is one of the most common parasitic diseases worldwide. It is estimated that approximately one-third of the world's population is latently infected. Infection generally occurs via oral the route and maternal transmission. Damage of the central nervous system is one of the most serious consequences of congenital toxoplasmosis. Moreover, recent investigations proposed that acute and sub-acute congenital toxoplasmosis as well as latent toxoplasmosis during pregnancy; play various roles in the etiology of different neuropsychiatric disorders in mothers and their offspring. This paper reviews new findings about the role of latent toxoplasmosis in the etiology of various neuropsychiatric disorders in mothers and their offspring. PMID- 24156765 TI - Performance map of a cluster detection test using extended power. AB - BACKGROUND: Conventional power studies possess limited ability to assess the performance of cluster detection tests. In particular, they cannot evaluate the accuracy of the cluster location, which is essential in such assessments. Furthermore, they usually estimate power for one or a few particular alternative hypotheses and thus cannot assess performance over an entire region. Takahashi and Tango developed the concept of extended power that indicates both the rate of null hypothesis rejection and the accuracy of the cluster location. We propose a systematic assessment method, using here extended power, to produce a map showing the performance of cluster detection tests over an entire region. METHODS: To explore the behavior of a cluster detection test on identical cluster types at any possible location, we successively applied four different spatial and epidemiological parameters. These parameters determined four cluster collections, each covering the entire study region. We simulated 1,000 datasets for each cluster and analyzed them with Kulldorff's spatial scan statistic. From the area under the extended power curve, we constructed a map for each parameter set showing the performance of the test across the entire region. RESULTS: Consistent with previous studies, the performance of the spatial scan statistic increased with the baseline incidence of disease, the size of the at-risk population and the strength of the cluster (i.e., the relative risk). Performance was heterogeneous, however, even for very similar clusters (i.e., similar with respect to the aforementioned factors), suggesting the influence of other factors. CONCLUSIONS: The area under the extended power curve is a single measure of performance and, although needing further exploration, it is suitable to conduct a systematic spatial evaluation of performance. The performance map we propose enables epidemiologists to assess cluster detection tests across an entire study region. PMID- 24156763 TI - Sequence signatures extracted from proximal promoters can be used to predict distal enhancers. AB - BACKGROUND: Gene expression is controlled by proximal promoters and distal regulatory elements such as enhancers. While the activity of some promoters can be invariant across tissues, enhancers tend to be highly tissue-specific. RESULTS: We compiled sets of tissue-specific promoters based on gene expression profiles of 79 human tissues and cell types. Putative transcription factor binding sites within each set of sequences were used to train a support vector machine classifier capable of distinguishing tissue-specific promoters from control sequences. We obtained reliable classifiers for 92% of the tissues, with an area under the receiver operating characteristic curve between 60% (for subthalamic nucleus promoters) and 98% (for heart promoters). We next used these classifiers to identify tissue-specific enhancers, scanning distal non-coding sequences in the loci of the 200 most highly and lowly expressed genes. Thirty percent of reliable classifiers produced consistent enhancer predictions, with significantly higher densities in the loci of the most highly expressed compared to lowly expressed genes. Liver enhancer predictions were assessed in vivo using the hydrodynamic tail vein injection assay. Fifty-eight percent of the predictions yielded significant enhancer activity in the mouse liver, whereas a control set of five sequences was completely negative. CONCLUSIONS: We conclude that promoters of tissue-specific genes often contain unambiguous tissue-specific signatures that can be learned and used for the de novo prediction of enhancers. PMID- 24156766 TI - Parallel deep transcriptome and proteome analysis of zebrafish larvae. AB - BACKGROUND: Sensitivity and throughput of transcriptomic and proteomic technologies have advanced tremendously in recent years. With the use of deep sequencing of RNA samples (RNA-seq) and mass spectrometry technology for protein identification and quantitation, it is now feasible to compare gene and protein expression on a massive scale and for any organism for which genomic data is available. Although these technologies are currently applied to many research questions in various model systems ranging from cell cultures to the entire organism level, there are few comparative studies of these technologies in the same system, let alone on the same samples. Here we present a comparison between gene and protein expression in embryos of zebrafish, which is an upcoming model in disease studies. RESULTS: We compared Agilent custom made expression microarrays with Illumina deep sequencing for RNA analysis, showing as expected a high degree of correlation of expression of a common set of 18,230 genes. Gene expression was also found to correlate with the abundance of 963 distinct proteins, with several categories of genes as exceptions. These exceptions include ribosomal proteins, histones and vitellogenins, for which biological and technical explanations are discussed. CONCLUSIONS: By comparing state of the art transcriptomic and proteomic technologies on samples derived from the same group of organisms we have for the first time benchmarked the differences in these technologies with regard to sensitivity and bias towards detection of particular gene categories in zebrafish. Our datasets submitted to public repositories are a good starting point for researchers interested in disease progression in zebrafish at a stage of development highly suited for high throughput screening technologies. PMID- 24156767 TI - Plant defense stimulation by natural isolates of bacillus depends on efficient surfactin production. AB - Some plant-associated Bacillus strains produce induced systemic resistance (ISR) in the host, which contributes to their protective effect against phytopathogens. Little is known about the variety of elicitors responsible for ISR that are produced by Bacillus strains. Working with a particular strain, we have previously identified the surfactin lipopeptide as a main compound stimulating plant immune-related responses. However, with the perspective of developing Bacillus strains as biocontrol agents, it is important to establish whether a central role of surfactin is generally true for isolates belonging to the B. subtilis/amyloliquefaciens complex. To that end, we set up a comparative study involving a range of natural strains. Their secretomes were first tested for triggering early defense events in cultured tobacco cells. Six isolates with contrasting activities were further evaluated for ISR in plants, based both on macroscopic disease reduction and on stimulation of the oxylipin pathway as defense mechanism. A strong correlation was found between defense-inducing activity and the amount of surfactin produced by the isolates. These results support the idea of a widespread role for surfactin as a nonvolatile elicitor formed by B. subtilis/amyloliquefaciens, and screening for strong surfactin producers among strains naturally secreting multiple antibiotics could be an efficient approach to select good candidates as biopesticides. PMID- 24156768 TI - Methods to study PAMP-triggered immunity in Brassica species. AB - The first layer of active defense in plants is based on the perception of pathogen-associated molecular patterns (PAMPs) leading to PAMP-triggered immunity (PTI). PTI is increasingly being investigated in crop plants, where it may have potential to provide durable disease resistance in the field. Limiting this work, however, is an absence of reliable bioassays to investigate PAMP responses in some species. Here, we present a series of methods to investigate PTI in Brassica napus. The assays allow measuring early responses such as the oxidative burst, mitogen-activated protein kinase phosphorylation, and PAMP-induced marker gene expression. Illumina-based RNA sequencing analysis produced a genome-wide survey of transcriptional changes upon PAMP treatment seen in both the A and C genomes of the allotetraploid B. napus. Later responses characterized include callose deposition and lignification at the cell wall, seedling growth inhibition, and PAMP-induced resistance to Pseudomonas syringae and Botrytis cinerea. Furthermore, using these assays, we demonstrated substantial variation in PAMP responses within a collection of diverse B. napus cultivars. The assays reported here could have widespread application in B. napus breeding and mapping programs to improve selection for broad-spectrum disease resistance. PMID- 24156769 TI - A bacterial type III secretion assay for delivery of fungal effector proteins into wheat. AB - Large numbers of candidate effectors from fungal pathogens are being identified through whole-genome sequencing and in planta expression studies. Although Agrobacterium-mediated transient expression has enabled high-throughput functional analysis of effectors in dicot plants, this assay is not effective in cereal leaves. Here, we show that a nonpathogenic Pseudomonas fluorescens engineered to express the type III secretion system (T3SS) of P. syringae and the wheat pathogen Xanthomonas translucens can deliver fusion proteins containing T3SS signals from P. syringae (AvrRpm1) and X. campestris (AvrBs2) avirulence (Avr) proteins, respectively, into wheat leaf cells. A calmodulin-dependent adenylate cyclase reporter protein was delivered effectively into wheat and barley by both bacteria. Absence of any disease symptoms with P. fluorescens makes it more suitable than X. translucens for detecting a hypersensitive response (HR) induced by an effector protein with avirulence activity. We further modified the delivery system by removal of the myristoylation site from the AvrRpm1 fusion to prevent its localization to the plasma membrane which could inhibit recognition of an Avr protein. Delivery of the flax rust AvrM protein by the modified delivery system into transgenic tobacco leaves expressing the corresponding M resistance protein induced a strong HR, indicating that the system is capable of delivering a functional rust Avr protein. In a preliminary screen of effectors from the stem rust fungus Puccinia graminis f. sp. tritici, we identified one effector that induced a host genotype-specific HR in wheat. Thus, the modified AvrRpm1:effector-Pseudomonas fluorescens system is an effective tool for large-scale screening of pathogen effectors for recognition in wheat. PMID- 24156770 TI - Membrane-targeted HrpNEa can modulate apple defense gene expression. AB - Fire blight caused by Erwinia amylovora is the major bacterial disease of tribe Maleae, including apple. Among the proteins secreted by this bacterium, HrpNEa, also called harpin, is known to induce hypersensitive response in nonhost plants and to form amyloid oligomers leading to pore opening in the plasma membrane and alteration of membrane homeostasis. To better understand the physiological effects of HrpNEa in the host plant, we produced transgenic apple plants expressing HrpNEa with or without a secretion signal peptide (SP). HrpNEa expressed with a SP was found to be associated within the membrane fraction, in accordance with amyloidogenic properties and the presence of transmembrane domains revealed by in silico analysis. Expression analysis of 28 apple defense related genes revealed gene modulations in the transgenic line expressing membrane-targeted HrpNEa. While apple transgenic trees displaying a high constitutive expression level of SP-HrpNEa showed a slight reduction of infection frequency after E. amylovora inoculation, there was no decrease in the disease severity. Thus HrpNEa seems to act as an elicitor of host defenses, when localized in the host membrane. PMID- 24156771 TI - Hemodynamic observations of tumo yoga practitioners in a Himalayan environment. AB - BACKGROUND: Few attempts have been made to evaluate the physiology of traditional Eastern health practices. The goal of this study was to evaluate the hemodynamic effects of the mysterious Buddhist practice of tumo. Tumo is a meditative practice that produces inner heat through the alleged cultivation of body energy channels. METHODS: This study was performed by members of an international expedition to the Himalayan Mountains in the Republic of India. The study was performed in an unpopulated outdoor mountainous area at an altitude of 16,400 ft with ambient temperatures between -10 and -15( degrees )C. Two (2) cohorts of subjects were studied: healthy non-yogi volunteers and tumo practitioners. All of the subjects were stripped down to their underclothes and exposed to the subzero atmospheric temperatures for 5 minutes. The volunteers were then passively rewarmed while the tumo practitioners performed tumo for up to 10 minutes. Blood pressure, heart rate, and stroke volume index (SVI) and cardiac index were measured noninvasively using a NICOMTM hemodynamic monitor, while carotid blood flow and biventricular performance were determined echocardiographically at each stage of the experiment. The total peripheral resistance index (TPRI), left ventricular ejection fraction (LVEF), and tricuspid annular plane systolic excursion (TAPSE) were determined using standard formula. RESULTS: Fourteen (14) subjects (six volunteers and eight tumo practitioners) completed the study. There was one female subject in each group. With cold exposure, the SVI and carotid blood flow decreased while the TPRI increased significantly in both groups. In the volunteer group, these changes retuned to baseline with rewarming. Following tumo, the cardiac index (4.8+/-0.6 versus 4.0+/-0.5 l/m(2); p<0.01), carotid blood flow (445+/-127 versus 325+/-100 mL/min/m(2), p<0.01), LVEF (68+/-5 versus 64+/-7%; p<0.05) and TAPSE (2.9+/-0.4 versus 2.4+/-0.5 cm; p<0.01) were significantly higher when compared with baseline, while the TPRI was significantly lower (1786+/-189 versus 2173+/-281; p<0.01). CONCLUSIONS: Tumo was associated with a hyperdynamic vasodilated state with increased biventricular performance. We postulate that tumo results in a massive increase in sympathetic activity with activation of brown adipose tissue and marked heat production. The increased heat production may explain the paradoxical vasodilatation in tumo practitioners exposed to subzero temperatures. PMID- 24156772 TI - Effects of classroom animal-assisted activities on social functioning in children with autism spectrum disorder. AB - OBJECTIVE: The objective of this study was to implement and evaluate a classroom based Animal-Assisted Activities (AAA) program on social functioning in children with autism spectrum disorder (ASD). DESIGN: This was a multisite, control-to intervention design study. SETTINGS/LOCATION: The study was conducted in 41 classrooms in 15 schools in Brisbane, Australia. SUBJECTS: Sixty-four (64) 5- to 12-year-old children diagnosed with ASD comprised the study group. INTERVENTION: The AAA program consisted of 8 weeks of animal exposure in the school classroom in addition to 16 20-minute animal-interaction sessions. OUTCOME MEASURES: Teacher- and parent-reported child behavior and social functioning were assessed through standardized instruments at three time points: upon study entry (Time 1), after an 8-week waiting period during the week prior to the AAA program (Time 2), and during the week following the 8-week AAA program (Time 3). RESULTS: Significant improvements were identified in social functioning, including increases in social approach behaviors and social skills, and decreases in social withdrawal behaviors, from before to after the AAA program, but not during the waitlist period. Over half of parents also reported that participants demonstrated an increased interest in attending school during the program. CONCLUSIONS: Results demonstrate the feasibility and potential efficacy of a new classroom-based Animal-Assisted Activities model, which may provide a relatively simple and cost-effective means of helping educators and families to improve the social functioning of children with ASD. PMID- 24156773 TI - Formation of light absorbing organo-nitrogen species from evaporation of droplets containing glyoxal and ammonium sulfate. AB - In the atmosphere, volatile organic compounds such as glyoxal can partition into aqueous droplets containing significant levels of inorganic salts. Upon droplet evaporation, both the organics and inorganic ions become highly concentrated, accelerating reactions between them. To demonstrate this process, we investigated the formation of organo-nitrogen and light absorbing materials in evaporating droplets containing glyoxal and different ammonium salts including (NH4)2SO4, NH4NO3, and NH4Cl. Our results demonstrate that evaporating glyoxal-(NH4)2SO4 droplets produce light absorbing species on a time scale of seconds, which is orders of magnitude faster than observed in bulk solutions. Using aerosol mass spectrometry, we show that particle-phase organics with high N:C ratios were formed when ammonium salts were used, and that the presence of sulfate ions promoted this chemistry. Since sulfate can also significantly enhance the Henry's law partitioning of glyoxal, our results highlight the atmospheric importance of such inorganic-organic interactions in aqueous phase aerosol chemistry. PMID- 24156774 TI - Identification of a suitable and selective inhibitor towards aldehyde oxidase catalyzed reactions. AB - 1. Aldehyde oxidase (AO) is a liver cytosolic molybdoflavoprotein enzyme whose importance in drug metabolism is gaining in the recent. The objective of this work is to find a potent and selective inhibitor for AO activity using phthalazine oxidation as a marker reaction. 2. Among organic solvents tested, it was identified that methanol was not a suitable choice for AO activity even at concentrations less than 0.2% v/v. Acetonitrile and DMSO did not show any effect till 0.5% v/v but thereafter activites tend to decrease. 3. For selectivity, 23 compounds were selected and evaluated for their effects on AO and nine CYP450 enzymes. Among the tested compounds chlorpromazine, estradiol, hydralazine, quetiapine and raloxifene were selected based on their potency of inhibition towards AO activity. 4. Raloxifene was found to be a non-specific inhibitor of all major tested CYP450 enzymes and was excluded as a selective inhibitor for AO. Quetiapine also showed a degree of inhibition towards the major CYP450 tested. Hydralazine used as a specific inhibitor during the past for AO activity demonstrated a stimulation of AO activity at high and low concentrations respectively and the inhibition noted to be time dependent while inhibiting other enzymes like monoamine oxidase. 5. Estradiol showed no inhibition towards the tested CYP450 enzymes and thus proved to be a selective and specific inhibitor for AO activity with an uncompetitive mode of inhibition. PMID- 24156775 TI - Performance of blood glucose meters in compliance with current and future clinical ISO15197 accuracy criteria. AB - Since 2003, blood glucose meters for patient self testing are approved in Europe based on the accuracy performance criteria as defined by the ISO15197 guideline. A new draft ISO guideline is currently under regulatory review, which suggests more strict accuracy acceptance criteria, and which may not be entirely fulfilled by currently commercialized blood glucose meter systems. In order to investigate the compliance of BG*Star and iBG*Star and several other blood glucose meters with the new draft ISO guideline, we performed a post-hoc analysis of data obtained from a recently performed ISO-conforming clinical accuracy performance study. This study was performed with 106 patients, clinically presenting with blood glucose levels distributed over the entire measurement range and in line with the glucose distribution requirements as demanded by the guideline. The YSI 2300 STAT Plus analyzer (glucose oxidase) served as reference method. While all tested meters had been in a high degree of compliance with the current ISO criteria, performance was lower when analyzed in accordance with the new acceptance criteria (95% of readings have to be within +/-15 mg/dL for values <100 mg/dL, and within +/-15% for values >=100 mg/dL). The following meters met the new criteria: Accu-Chek Aviva (95.5%/98.6%), BG*Star (98.5%/97.3%), iBG*Star (98.5%/97.3%), FreeStyle Freedom Lite (95.5%/96.6%), and OneTouch Ultra2 (95.5%/96.5%). One meter failed with low blood glucose values (Contour: 90.9%/95.9%). In conclusion, BG*Star and iBG*Star and several other branded meters met the new draft ISO15197 acceptance criteria, when tested in accordance with the instructions for use and with the ISO accuracy testing protocol in a clinical setting. PMID- 24156776 TI - Enantioselective functionalization of allylic C-H bonds following a strategy of functionalization and diversification. AB - We report the enantioselective functionalization of allylic C-H bonds in terminal alkenes by a strategy involving the installation of a temporary functional group at the terminal carbon atom by C-H bond functionalization, followed by the catalytic diversification of this intermediate with a broad scope of reagents. The method consists of a one-pot sequence of palladium-catalyzed allylic C-H bond oxidation under neutral conditions to form linear allyl benzoates, followed by iridium-catalyzed allylic substitution. This overall transformation forms a variety of chiral products containing a new C-N, C-O, C-S, or C-C bond at the allylic position in good yield with a high branched-to-linear selectivity and excellent enantioselectivity (ee <=97%). The broad scope of the overall process results from separating the oxidation and functionalization steps; by doing so, the scope of nucleophile encompasses those sensitive to direct oxidative functionalization. The high enantioselectivity of the overall process is achieved by developing an allylic oxidation that occurs without acid to form the linear isomer with high selectivity. These allylic functionalization processes are amenable to an iterative sequence leading to (1,n)-functionalized products with catalyst-controlled diastereo- and enantioselectivity. The utility of the method in the synthesis of biologically active molecules has been demonstrated. PMID- 24156777 TI - A therapeutic barium enema is a practical option to control bleeding from the appendix. AB - BACKGROUND: Acute lower gastrointestinal hemorrhage originating from the appendix is rare and often intractable, because it is almost impossible to approach the bleeding point by endoscopy. We herein describe the first case of bleeding from the appendix, which was successively controlled by a therapeutic barium enema administered into the appendix. CASE PRESENTATION: A 71-year-old male visited our hospital because of melena. He has been receiving an anti-coagulation drug, ticlopidine hydrochloride, for 10 years. By an emergency colonoscopy, a hemorrhage was detected in the appendix, and the lesion responsible for the bleeding was regarded to exist in the appendix. Two hundred milliliters of 50 W/V% barium was sprayed into the orifice of the appendix using a spraying tube. The bleeding could thus be immediately stopped, and a radiological examination revealed the accumulation of barium at the cecum and the orifice of the appendix. The barium accumulation disappeared by the next day, and no obvious anal bleeding was observed. Two weeks after stopping the bleeding from the appendix, an appendectomy was performed to prevent any further refractory hemorrhaging. The patient has had no complaints of any abdominal symptoms or anal bleeding for 10 months. CONCLUSIONS: A therapeutic barium enema is a useful procedure to control bleeding from the appendix and to avoid emergency surgery, such as partial cecectomy and hemicolectomy. PMID- 24156778 TI - Policy and provision of WASH in schools for children with disabilities: a case study in Malawi and Uganda. AB - There is a growing body of evidence on the correlation between improving access to water, sanitation and hygiene (WASH) in schools and positive health and educational outcomes for students. Similar evidence on the impact of school WASH facilities on health, enrolment and absence for children with disabilities is not available. The limited data have revealed that children with disabilities are burdened by poor WASH in schools access, and even prevented from attending school due to inaccessible WASH facilities. We conducted two case studies of policy and provision of school WASH services for children with disabilities in Uganda and Malawi. We found a robust policy environment in Uganda and Malawi with policies and guidelines in place for WASH in schools for children with disabilities. However, provision of services and facilities are low and focused primarily on sanitation. PMID- 24156779 TI - Relationship between structure of conjugated oxime esters and their ability to cleave DNA. AB - The size and geometry of polycycles are critical to intercalation into DNA. This work involves the establishment of a new compound library that includes 35 O benzoyl oxime esters with intercalators of five types. These conjugated compounds were synthesized by the condensation of substituted benzoyl chlorides (XC6H4COCl; X = H, Me, CN, F, and NO2) or naphthoyl chlorides with oximes of fluoren-9-one, 9,10-anthraquinone, xanthen-9-one, thioxanthen-9-one, and 9H-thioxanthen-9-one 10,10-dioxide to give the corresponding esters in 80-99% yields. All of these compounds could cleave DNA when photolyzed by UV light. Of these conjugates, 9,10 anthraquinone-O-9-(4-fluorobenzoyl)oxime with a binding constant of 4.49 * 10(4) M(-1) cleaved DNA most efficiently. Examination of the structure-activity relationship supports a conclusion that two factors affect DNA-cleaving potency. These are (1) the planarity of the intercalating moiety, and (2) the size and substituents of the benzoyl ring. The DNA-cleaving ability followed the order 9,10-anthraquinone > fluoren-9-one >= xanthen-9-one ~ thioxanthen-9-one > 9H thioxanthen-9-one 10,10-dioxide. The benzoyl-containing oxime ester conjugates were more active than the corresponding naphthoyl-containing conjugates. The potency that was associated with the different substituents on the benzoyl ring followed the order F > CN >= NO2 > Me ~ H. PMID- 24156780 TI - Chemotherapeutic inhibitors in the treatment of prostate cancer. AB - INTRODUCTION: Prostate cancer being the second leading cause of death in men in Western countries remains a major challenge in healthcare. Several novel agents targeting signaling pathways in prostate cancer have recently been approved by the US Food and Drug Administration (FDA) but there is still an unmet need for new treatment strategies for castration-resistant prostate cancer (CRPC). AREAS COVERED: This review provides a broad overview of prostate cancer therapeutics and highlights key players in the biology of prostate cancer as well as first- and second-line treatments for CRPC. Keywords 'chemotherapeutic agents', 'prostate cancer', 'Phase III clinical trials' and 'US FDA approval' were used for search in PubMed and clinicalTrials.gov databases and the obtained literature was reviewed and summarized. EXPERT OPINION: Owing to the advances in screening and diagnostic techniques, the majority of prostate cancer cases are diagnosed at an early stage resulting in an almost 100% 5-year survival rate. Recently FDA approved novel agents (e.g., abiraterone acetate and enzalutamide) have provided new hope in the fight against prostate cancer. However, CRPC remains an incurable disease. Identification of mechanisms of resistance, new biomarkers, appropriate clinical trial end points and novel treatments holds the key for the future of prostate cancer therapy. PMID- 24156781 TI - Immunopurification of adenomatous polyposis coli (APC) proteins. AB - BACKGROUND: The adenomatous polyposis coli (APC) tumour suppressor gene encodes a 2843 residue (310 kDa) protein. APC is a multifunctional protein involved in the regulation of beta-catenin/Wnt signalling, cytoskeletal dynamics and cell adhesion. APC mutations occur in most colorectal cancers and typically result in truncation of the C-terminal half of the protein. RESULTS: In order to investigate the biophysical properties of APC, we have generated a set of monoclonal antibodies which enable purification of recombinant forms of APC. Here we describe the characterisation of these anti-APC monoclonal antibodies (APC-NT) that specifically recognise endogenous APC both in solution and in fixed cells. Full-length APC(1-2843) and cancer-associated, truncated APC proteins, APC(1 1638) and APC(1-1311) were produced in Sf9 insect cells. CONCLUSIONS: Recombinant APC proteins were purified using a two-step affinity approach using our APC-NT antibodies. The purification of APC proteins provides the basis for detailed structure/function analyses of full-length, cancer-truncated and endogenous forms of the protein. PMID- 24156782 TI - A novel Hsp90 inhibitor AT13387 induces senescence in EBV-positive nasopharyngeal carcinoma cells and suppresses tumor formation. AB - BACKGROUND: Nasopharyngeal carcinoma (NPC) is an epithelial malignancy strongly associated with Epstein-Barr virus (EBV). AT13387 is a novel heat shock protein 90 (Hsp90) inhibitor, which inhibits the chaperone function of Hsp90 and reduces expression of Hsp90-dependent client oncoproteins. This study aimed to evaluate both the in vitro and in vivo antitumor effects of AT13387 in the EBV-positive NPC cell line C666-1. RESULTS: Our results showed that AT13387 inhibited C666-1 cell growth and induced cellular senescence with the downregulation of multiple Hsp90 client oncoproteins EGFR, AKT, CDK4, and restored the protein expression of negative cell cycle regulator p27. We also studied the ability of AT13387 to restore p27 expression by downregulation of AKT and the p27 ubiquitin mediator, Skp2, using AKT inhibitor and Skp2 siRNA. In the functional study, AT13387 inhibited cell migration with downregulation of a cell migration regulator, HDAC6, and increased the acetylation and stabilization of alpha-tubulin. We also examined the effect of AT13387 on putative cancer stem cells (CSC) by 3-D tumor sphere formation assay. AT13387 effectively reduced both the number and size of C666-1 tumor spheres with decreased expression of NPC CSC-like markers CD44 and SOX2. In the in vivo study, AT13387 significantly suppressed tumor formation in C666-1 NPC xenografts. CONCLUSION: AT13387 suppressed cell growth, cell migration, tumor sphere formation and induced cellular senescence on EBV-positive NPC cell line C666-1. Also, the antitumor effect of AT13387 was demonstrated in an in vivo model. This study provided experimental evidence for the preclinical value of using AT13387 as an effective antitumor agent in treatment of NPC. PMID- 24156783 TI - Western European land use regression incorporating satellite- and ground-based measurements of NO2 and PM10. AB - Land use regression (LUR) models typically investigate within-urban variability in air pollution. Recent improvements in data quality and availability, including satellite-derived pollutant measurements, support fine-scale LUR modeling for larger areas. Here, we describe NO2 and PM10 LUR models for Western Europe (years: 2005-2007) based on >1500 EuroAirnet monitoring sites covering background, industrial, and traffic environments. Predictor variables include land use characteristics, population density, and length of major and minor roads in zones from 0.1 km to 10 km, altitude, and distance to sea. We explore models with and without satellite-based NO2 and PM2.5 as predictor variables, and we compare two available land cover data sets (global; European). Model performance (adjusted R(2)) is 0.48-0.58 for NO2 and 0.22-0.50 for PM10. Inclusion of satellite data improved model performance (adjusted R(2)) by, on average, 0.05 for NO2 and 0.11 for PM10. Models were applied on a 100 m grid across Western Europe; to support future research, these data sets are publicly available. PMID- 24156784 TI - Prevalence and predictors of metabolic syndrome among Congolese pre- and postmenopausal women. AB - OBJECTIVES: This study aimed to determine the prevalence and predictors of metabolic syndrome (MetS) among Congolese pre- and postmenopausal women. METHODS: In total, 200 women (100 premenopausal and 100 postmenopausal) were interviewed and underwent clinical and biological investigations searching for lipid and non lipid cardiovascular risk factors. National Cholesterol Education Program-Adult Treatment Panel III (NCEP-ATPIII) criteria were used to define MetS. Multivariate logistic regression analysis was used to evaluate predictors of MetS. RESULTS: There were significant differences between the two groups in terms of age, plasma cholesterol, high density lipoprotein cholesterol and triglyceride levels. MetS was present in 20% and 10% of postmenopausal and premenopausal women (p = 0.07), respectively. The MetS components hypertension, elevated plasma glucose and triglycerides were more frequently observed in post- vs. premenopausal women with MetS. Menopause (adjusted odds ratio (aOR) 2.49; 95% confidence interval (CI) 1.05-5.95), overweight (aOR 6.35; 95% CI 1.66-24.23) and obesity (aOR 14.29; 95% CI: 3.84-53.06) emerged as the main independent predictors of MetS. CONCLUSION: This study showed that MetS is common among Congolese postmenopausal women; menopause and weight gain emerged as its main predictors. This suggests that an integrated therapeutic approach combining hormone replacement therapy and lifestyle change in postmenopausal women should be considered. PMID- 24156785 TI - Marking the 30th anniversary of the first journal in our field. PMID- 24156786 TI - Twelve tips for teaching with ultrasound in the undergraduate curriculum. AB - With ever increasing use of imaging as a diagnostic tool in medicine, medical schools are being urged to further integrate imaging into their curricula. Ultrasound is one such way of doing so-enabling students to bridge the gap between form and function, medical school and clinical practice. As a non invasive imaging technique, with low risk when compared to other methods of imaging, ultrasound is ideal for integration into basic science and clinical teaching. The twelve tips given in this article offer advice on the practicalities of running a successful ultrasound imaging session in an appropriate environment, promoting safety and curriculum integration. PMID- 24156787 TI - pH responsive Janus-like supramolecular fusion proteins for functional protein delivery. AB - A facile, noncovalent solid-phase immobilization platform is described to assemble Janus-like supramolecular fusion proteins that are responsive to external stimuli. A chemically postmodified transporter protein, DHSA, is fused with (imino)biotinylated cargo proteins via an avidin adaptor with a high degree of spatial control. Notably, the derived heterofusion proteins are able to cross cellular membranes, dissociate at acidic pH due to the iminobiotin linker and preserve the enzymatic activity of the cargo proteins beta-galactosidase and the enzymatic subunit of Clostridium botulinum C2 toxin. The mix-and-match strategy described herein opens unique opportunities to access macromolecular architectures of high structural definition and biological activity, thus complementing protein ligation and recombinant protein expression techniques. PMID- 24156788 TI - Annular pancreas concurrent with pancreaticobiliary maljunction presented with symptoms until adult age: case report with comparative data on pediatric cases. AB - BACKGROUND: Annular pancreas (AP) concurrent with pancreaticobiliary maljunction (PBMJ), an unusual coexisted congenital anomaly, often presented symptoms and subjected surgical treatment at the early age of life. We reported the first adult case of concurrent AP with PBMJ presented with symptoms until his twenties, and performed a literature review to analyze the clinicopathological features of such cases comparing with its pediatric counterpart. CASE PRESENTATION: The main clinical features of this case were abdominal pain and increased levels of plasma amylase as well as liver function test. A complete type of annular pancreas with duodenal stenosis was found, and dilated common bile duct with high confluence of pancreaticobiliary ducts was also observed. Meanwhile, extremely high levels of bile amylase were detected both in common bile duct and gallbladder. The patient received duodenojejunostomy (side-to-side anastomosis) as well as choledochojejunostomy (Roux-en-Y anastomosis), and was discharged in a good condition. CONCLUSION: AP concurrent with PBMJ usually presents as duodenal obstruction in infancy, while manifests as pancreatitis in adulthood. Careful long-term follow-up is required for children with AP considering its association with PBMJ which would induce various intractable pathologic conditions in the biliary tract and pancreas. PMID- 24156789 TI - Current and future approaches to treat graft failure after allogeneic hematopoietic stem cell transplantation. AB - INTRODUCTION: One significant obstacle to the success of allogeneic hematopoietic stem cell transplantation (HSCT) is represented by graft failure, defined as either lack of initial engraftment of donor cells (primary graft failure) or loss of donor cells after initial engraftment (secondary graft failure). Graft failure mediated by host immune cells attacking donor stem cells is named graft rejection. Factors associated with graft failure include HLA disparity in the donor/recipient pair, underlying disease, viral infections, type of conditioning regimen and stem cell source employed. AREAS COVERED: In this article, the experts summarize current approaches to treat graft failure/rejection after HSCT, and they discuss new strategies of graft manipulation and immune therapy of particular interest for preventing/treating this complication. EXPERT OPINION: A limited array of options is available to treat graft failure. The experts believe that re-transplantation from another donor or the same donor (if there is no evidence of immunologically mediated graft failure) is the treatment of choice for patients with primary graft failure or acute graft rejection. The experts think that strategies based on innovative approaches of graft manipulation, new agents or cellular therapies could render in the future graft failure a much less relevant problem for HSCT recipients. PMID- 24156790 TI - Re: variants of hepatic arterial supply in a Caribbean population: a computed tomography based study. PMID- 24156791 TI - Re: The FRCR 2B oral examination: is it reliable? A reply. PMID- 24156792 TI - Renal carcinomas associated with Xp11.2 translocations: are CT findings suggestive of the diagnosis? AB - AIM: The purpose of the present study was to summarize the computed tomography (CT) features of renal carcinomas associated with Xp11.2 translocations, and determine whether the diagnosis can be reliably deduced from imaging findings. MATERIALS AND METHODS: Radiological studies of six patients (aged from 9-29 years) with renal carcinoma associated with Xp11.2 translocations were retrospectively analysed. RESULTS: The tumours varied in size from 3.3-11 cm (mean 5.4 cm). Unenhanced CT and cortical, medullary, and pelvic-phase contrast enhanced CT imaging was undertaken in all cases. Unenhanced CT revealed that tumours had a relatively increased radiodensity (4/6, ranged from 45-60 HU) and suggested the possibility of diffuse haemorrhage. Three of the six cases showed irregular and boundary calcification of the lesion. Contrast-enhanced CT showed relatively well demarcated tumours with heterogeneous enhancement (6/6). Prolonged enhancement of tumours might be a common sign (6/6) in Xp11.2 translocations. Three out of the six cases were combined with retroperitoneal lymph nodes metastasis. CONCLUSION: Renal carcinomas associated with Xp11.2 translocations should be considered, particularly in children and young patients, when the lesion has calcification and is hyper-dense on unenhanced CT, and has prolonged enhancement on contrast-enhanced images. PMID- 24156793 TI - Accuracy of multidetector CT in detecting anastomotic leaks following stapled left-sided colonic anastomosis. AB - AIMS: To assess accuracy of multidetector computed tomography (MDCT) and individual radiological signs in the diagnosis of anastomotic leaks. MATERIALS AND METHODS: Patients undergoing anterior resection with a stapled anastomosis over a 2 year period were identified. Electronic and clinical records of these patients were reviewed. Unenhanced and/or enhanced MDCT was performed with intravenous and/or per-rectal contrast medium and read by a radiologist blinded to the patients' clinical details to determine the sensitivity and specificity of specific findings at MDCT for identifying leaks. RESULTS: Seventeen percent (30/170) of the anterior resections were suspected to have an anastomotic leak. Ninety-three percent (28/30) of patients underwent MDCT. Seven point six percent (11+2/170) had a confirmed leak. Two patients underwent surgery without MDCT. A leak was confirmed by MDCT in 91% (10/11) of patients. The sensitivity, specificity, and positive and negative predictive values of MDCT in diagnosing a leak was 0.91, 1, 1, and 0.95, respectively. The sensitivity of peri-anastomotic air, peri-anastomotic collection, extravasation of rectal contrast medium, and staple line integrity was 0.81, 0.63, 0.54, and 0.72, respectively. Use of rectal contrast medium (8/11 cases) increased the subjective ease of diagnosis and was the only sign in one patient. CONCLUSIONS: Presence of peri-anastomotic air is a reliable marker of anastomotic leaks at MDCT. Leakage of rectal contrast medium is highly accurate and increases confidence of diagnosis. The appearance of the staple line itself is not accurate in assessing anastomotic integrity. PMID- 24156794 TI - Preliminary study of whole-brain CT perfusion imaging in patients with intracranial tumours adjacent to large blood vessels. AB - AIM: To explore the value of whole-brain computed tomography perfusion (WBCTP) imaging in patients with intracranial tumours adjacent to large blood vessels. MATERIALS AND METHODS: WBCTP with 320-row CT was performed in 35 patients with clinically and pathologically diagnosed intracranial tumours adjacent to large blood vessels. Three-dimensional CT perfusion (3D-CTP) parameter maps of cerebral blood flow (CBF), cerebral blood volume (CBV), mean transit time (MTT), time to peak (TTP), and dynamic CT angiography (4D-CTA) images were obtained simultaneously. Three-dimensional CT angiography (3D-CTA) images, including volume rendering (VR), minimum intensity projection (MIP), and fusion images of the tumour with CTA, were reconstructed using post-processing techniques. The image quality, CTP and CTA characteristics were analysed. RESULTS: All WBCTP images could be evaluated without artefacts. Abnormal perfusion areas were identified on 3D-CTP maps. Significant differences in CBF and CBV were detected between meningioma (n = 18) and glioma (n = 16; p < 0.05). The blood supplying and draining veins of the tumour could be observed on CTA in 30 cases. The surrounding large arteries were compressed and dislocated by tumours in 18 cases and were wrapped up in six cases. Compression and mild deformation of the venous sinuses were visualized in 10 cases, and in four cases, the superior sagittal sinus was invaded and the vessel lumen was partially blocked. CONCLUSION: Comprehensive evaluation of intracranial tumours adjacent to large blood vessels could be achieved with the WBCTP technique. This technique has great value for the diagnosis of intracranial tumours and for evaluation of the relationship of intracranial tumours to surrounding large blood vessels. PMID- 24156795 TI - Percutaneous transhepatic cholangiobiopsy to determine the pathological cause of anastomotic stenosis after cholangiojejunostomy for malignant obstructive jaundice. AB - AIM: To investigate the feasibility and advantages of cholangiobiopsy during percutaneous transhepatic cholangiography in the histopathological diagnosis of anastomotic stenosis after cholangiojejunostomy for malignant obstructive jaundice. MATERIALS AND METHODS: Using biopsy forceps, specimens were collected from the site of stenosis in patients with recurrent jaundice (n = 24) who had previously undergone cholangiojejunostomy for malignant obstructive jaundice. RESULTS: Stenosis occurred in all patients at the biliary-enteric anastomosis based on percutaneous transhepatic cholangiography, and was the location of the biopsy. Satisfactory specimens were obtained from 22 out of 24 patients. The sensitivity was 91.7% (22/24). Tumour tissue was obtained in 18 cases, confirming disease recurrence. Histopathological changes in four patients were diagnosed as fibroplasia and/or inflammation. These were considered cicatricial stenoses based on histopathological, imaging, and laboratory findings. The remaining two histopathology-negative patients were proven to have recurrent tumour based on imaging, laboratory, and follow-up data. No complications occurred during biopsy, including gastrointestinal haemorrhage or perforation. Either cholangial drainage and/or an inner stent was used following biopsy, which resulted in a noticeable decrease in jaundice postoperatively (p < 0.05). CONCLUSION: Percutaneous transhepatic cholangiobiopsy using biopsy forceps for the diagnosis of anastomotic stenosis after cholangiojejunostomy for malignant biliary obstructive jaundice is easy to perform and safe, with a high level of sensitivity. Interventional therapies, such as percutaneous transhepatic cholangial drainage and stent placement, can be performed concurrently, markedly improving the symptoms of patients with obstructive jaundice. PMID- 24156796 TI - Reduction of dental metallic artefacts in CT: value of a newly developed algorithm for metal artefact reduction (O-MAR). AB - AIM: To evaluate the image quality of O-MAR (Metal Artifact Reduction for Orthopedic Implants) for dental metal artefact reduction. MATERIALS AND METHODS: This prospective study received institutional review board approval and written informed consent was obtained. Thirty patients who had dental implants or dental fillings were included in this study. Computed tomography (CT) images were obtained through the oral cavity and neck during the portal venous phase. The system reconstructed the O-MAR-processed images in addition to the uncorrected images. CT attenuation and image noise of the soft tissue of the oral cavity were compared between the O-MAR and the uncorrected images. Qualitative analysis was undertaken between the two image groups. RESULTS: The image noise of the O-MAR images was significantly lower than that of the uncorrected images (p < 0.01). O MAR offered plausible attenuations of soft tissue compared with non-O-MAR. Better qualitative scores were obtained in the streaking artefacts and the degree of depiction of the oral cavity with O-MAR compared with non-O-MAR. CONCLUSION: O MAR enables the depiction of structures in areas in which this was not previously possible due to dental metallic artefacts in qualitative image analysis. O-MAR images may have a supplementary role in addition to uncorrected images in oral diagnosis. PMID- 24156797 TI - Differentiation between benign and malignant breast lesions using quantitative diffusion-weighted sequence on 3 T MRI. AB - AIM: To investigate the capability and diagnostic accuracy of diffusion-weighted imaging (DWI) in differentiating benign from malignant breast lesions using 3 T magnetic resonance imaging (MRI). MATERIALS AND METHODS: Women with suspicious or indeterminate breast lesions detected at MRI, mammogram and/or ultrasound were recruited for dynamic contrast-enhanced (DCE)-MRI and DWI prior to their biopsy. Image fusion of DCE-MRI with apparent diffusion coefficient (ADC) map was utilized to select the region of interest (ROI) for ADC calculation in the area that showed the most avid enhancement. DWI was performed using two sets of b values at 500 and 1000 s/mm(2), respectively. RESULTS: Fifty women were recruited and the final analysis comprised 44 breast lesions, 31 of which were malignant and 13 were benign. Significant results were obtained between ADC values of benign and malignant lesions (p < 0.001). The cut-off ADC values for benign and malignant lesions were 1.21 * 10(-3) mm(2)/s for b = 500 s/mm(2) and 1.22 * 10( 3) mm(2)/s for b = 1000 s/mm(2), respectively. The sensitivity of DCE-MRI alone was 100% with a specificity of 66.7%. When DCE-MRI was combined with b = 1000 s/mm(2), the specificity rose to 100%, while only mildly affecting sensitivity (90.6%). No significant correlation was found between ADC values and prognostic factors, such as lymph node metastasis, tumour size, oestrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) status, and tumour grades. CONCLUSION: The present study provides consistent evidence to support DWI as a diagnostic tool for breast lesion characterization. A combination of DCE-MRI with DWI is suggested to improve the sensitivity and specificity of lesion characterization. PMID- 24156798 TI - Can biliary-cyst communication be predicted by Gd-EOB-DTPA-enhanced MR cholangiography before treatment for hepatic hydatid disease? AB - AIM: To evaluate the role of gadolinium ethoxybenzyl diethylenetriamine pentaacetic acid (Gd-EOB-DTPA)-enhanced magnetic resonance cholangiography (MRC) in the evaluation of biliary-cyst communication (BCC) before treatment for hepatic hydatid disease (HHD). MATERIAL AND METHODS: Thirty-one patients with clinical and laboratory follow-up for HHD with suspected diagnosis of BCC underwent three-dimensional (3D) T2-weighted MRC and T1-weighted contrast enhanced MRC, dynamic 3D gradient echo (GRE) sequences, using Gd-EOB-DTPA to identify the presence or absence of BCC. A total of 45 hepatic hydatid cysts in the 31 patients were evaluated for cyst diameter, BCC, and the time to contrast enhancement of the hydatid cyst after Gd-EOB-DTPA injection. The surgical and interventional radiological procedures and imaging findings were compared. The sensitivity, specificity, and accuracy of both techniques in identification of BCC were calculated. RESULTS: The accuracy of contrast-enhanced MRC for identifying BCC was superior with a sensitivity of 87.4% and accuracy of 90.5% (p < 0.05). A diameter of >=10 cm was associated with significantly increased risk of BCC on contrast-enhanced MRC images (p < 0.05). CONCLUSION: The use of Gd-EOB DTPA-enhanced MRC yields information that complements T2-weighted MRC findings and improves identification of BCC. The use of T2-weighted MRC, in addition to contrast-enhanced MRC, is recommended to increase preoperative accuracy of identifying BCC. PMID- 24156799 TI - Carotid body size on CTA: correlation with comorbidities. AB - AIM: To test the hypothesis that computed tomographic angiography (CTA) can identify carotid body enlargement in patients with sympathetically mediated diseases. MATERIALS AND METHODS: A retrospective chart review of all patients obtaining CTAs of the cervical vasculature at University of Utah Health Sciences Center over a 6-month period was performed. Widest axial measurements of both carotid bodies were performed on a picture archiving and communication system (PACS). Statistical analysis was then performed to compare the mean carotid body size between control patients and patients with diabetes mellitus, hypertension, and congestive heart failure. RESULTS: Measurements were performed on 288 patients, with 134 controls. Of the remaining 154, 72 patients had diabetes mellitus, 46 had congestive heart failure, and 130 had hypertension. The control patients had a mean carotid body diameter of 2.3 mm. There was a statistically significant (p < 0.01) 20-25% increase in mean diameter with diabetes mellitus (2.8 mm), hypertension (2.7 mm), and congestive heart failure (2.7 mm; p < 0.01). CONCLUSIONS: This study found a 20-25% larger mean carotid body size in patients with diabetes mellitus, hypertension, and congestive heart failure relative to controls. However, this small enlargement should not mimic other carotid body diseases, such as a paraganglionoma. Moreover, these findings further support the proposed functional relationship between the carotid body and sympathetically mediated disease states. PMID- 24156800 TI - Diffusion-weighted imaging in the evaluation of hormonal cyclic changes in abdominal wall endometriomas. AB - AIM: To investigate the utility of diffusion-weighted (DW) magnetic resonance imaging (MRI) in the diagnosis of abdominal wall endometrioma (AWE) and to compare the ADC (apparent diffusion coefficient) values of AWE with those of the uterine endometrium during two different phases of the menstrual cycle. MATERIALS AND METHODS: A total of 22 women aged between 27 and 42 years (mean 32.8 years) and who had regular menstrual cycles were included in the study. These patients had a total of 25 AWE lesions. The mean and standard deviation of the ADC values of the normal endometrium/AWE were calculated for the menstrual and luteal phases. All examinations were performed using a 1.5 T magnet (b-values of 50, 400, and 800 mm/s(2)). The results were analysed using the Shapiro-Wilk test, the Pearson correlation test, the analysis of variance (ANOVA) test, and the paired sample t-test. RESULTS: The ADC values of the endometrium were different in the two phases of the menstrual cycle (menstrual phase: 0.924 +/- 0.171; luteal phase: 1.171 +/- 0.135). Similarly, the ADC values of the AWE were different in these phases (menstrual phase: 0.937 +/- 0.256, luteal phase: 1.256 +/- 0.215). In both AWE and the uterine endometrium, the ADC measurements were significantly lower in the menstrual phase than during the luteal phase. This difference was statistically significant (p < 0.05). There was no significant difference in the ADC values between the endometrial layer and AWE during the same phase (p = 0.216 for menstrual phase, p = 0.104 for luteal phase, paired sample t-test). CONCLUSION: The present study demonstrated that in all patients, the DWI features of AWEs were significantly similar to those of the uterine endometrial tissue. Additionally, the ADC measurements of the patients showed similar cyclical changes. These results suggest that the ADC values of a lesion close to the uterine endometrium may be used to differentiate AWE from the other disease entities of the abdominal wall. PMID- 24156802 TI - Re: variants of hepatic arterial supply in a Caribbean population: a computed tomography based study. A reply. PMID- 24156801 TI - Comparison of 80 and 120 kVp contrast-enhanced CT for attenuation correction in PET/CT, using quantitative analysis and reporter assessment of PET image quality. AB - AIM: To determine the effect of low tube voltage on positron-emission tomography (PET) image quality, quantitative analysis, and radiation dose in a combined PET/computed tomography (CT) study in patients with normal body mass index (BMI). MATERIALS AND METHODS: One hundred and twenty-nine examinations performed in 46 patients (mean age 57 years), who had at least two separate studies were retrospectively evaluated; at least one with 120 kVp and one with 80 kVp. Three independent readers reviewed all PET images and graded the image quality. PET signal and noise were recorded on the liver, spleen, fat, bone marrow, and aorta. CT dose index (CTDI) and the dose-length product (DLP) were used for CT radiation dose estimation. A mixed-effects model analysis was used for comparison of estimated radiation dose and PET data. RESULTS: There was a significant decrease of 15% in the radiation dose estimates between 80 and 120 kVp (DLP 946.2 +/- 189 versus 1157.0 +/- 236, respectively; p < 0.001). There was an increase of 12% in PET signal in the normal liver with 80 kVp. The average score of PET image quality obtained between 80 and 120 kVp was 4.85 +/- 0.42 versus 4.90 +/- 0.27, respectively (p = 0.47). CONCLUSION: PET/80 kVp CT has no statistically significant difference in the PET image quality and quantitative analysis compared to PET/120 kVp and may be used in selected patients to reduce the radiation dose. PMID- 24156803 TI - The difficulties of executing simple algorithms: why brains make mistakes computers don't. AB - It is shown that educated adults routinely make errors in placing stimuli into familiar, well-defined categories such as triangle and odd number. Scalene triangles are often rejected as instances of triangles and 798 is categorized by some as an odd number. These patterns are observed both in timed and untimed tasks, hold for people who can fully express the necessary and sufficient conditions for category membership, and for individuals with varying levels of education. A sizeable minority of people believe that 400 is more even than 798 and that an equilateral triangle is the most "trianglest" of triangles. Such beliefs predict how people instantiate other categories with necessary and sufficient conditions, e.g., grandmother. I argue that the distributed and graded nature of mental representations means that human algorithms, unlike conventional computer algorithms, only approximate rule-based classification and never fully abstract from the specifics of the input. This input-sensitivity is critical to obtaining the kind of cognitive flexibility at which humans excel, but comes at the cost of generally poor abilities to perform context-free computations. If human algorithms cannot be trusted to produce unfuzzy representations of odd numbers, triangles, and grandmothers, the idea that they can be trusted to do the heavy lifting of moment-to-moment cognition that is inherent in the metaphor of mind as digital computer still common in cognitive science, needs to be seriously reconsidered. PMID- 24156804 TI - Burying beetles. PMID- 24156805 TI - Bird brood parasitism. AB - For many animals, the effort to rear their young is considerable. In birds, this often includes building nests, incubating eggs, feeding the chicks, and protecting them from predators. Perhaps for this reason, about 1% of birds (around 100 species) save themselves the effort and cheat instead. They are obligate brood parasites, laying their eggs in the nests of other species and leaving the hosts or foster parents to rear the foreign chicks for them. Some birds also cheat on individuals of the same species (intraspecific brood parasitism). Intraspecific brood parasitism has been reported in around 200 species, but is likely to be higher, as it can often only be detected by genetic analyses. PMID- 24156806 TI - A new galloping gait in an insect. AB - An estimated three million insect species all walk using variations of the alternating tripod gait [1]. At any one time, these animals hold one stable triangle of legs steady while swinging the opposite triangle forward. Here, we report the discovery that three different flightless desert dung beetles use an additional gallop-like gait, which has never been described in any insect before. Like a bounding hare, the beetles propel their body forward by synchronously stepping with both middle legs and then both front legs. Surprisingly, this peculiar galloping gait delivers lower speeds than the alternating tripod gait. Why these beetles have shifted so radically away from the most widely used walking style on our planet is as yet unknown. PMID- 24156807 TI - Badger social networks correlate with tuberculosis infection. AB - Although disease hosts are classically assumed to interact randomly [1], infection is likely to spread across structured and dynamic contact networks [2]. We used social network analyses to investigate contact patterns of group-living European badgers, Meles meles, which are an important wildlife reservoir of bovine tuberculosis (TB). We found that TB test-positive badgers were socially isolated from their own groups but were more important for flow, potentially of infection, between social groups. The distinctive social position of infected badgers may help explain how social stability mitigates, and social perturbation increases, the spread of infection in badgers. PMID- 24156808 TI - The human amygdala drives reflexive orienting towards facial features. AB - The human amygdala is reliably activated by facial expressions [1], but the precise functional relevance of such activity change is not well understood, because most previous studies did not allow for separating effects of the emotional expression from the distribution of specific facial features and neglected corresponding attentional processes. Findings on rare patients with bilateral amygdala damage indicate that the amygdala might be involved in triggering shifts of overt attention towards specific facial features such as the eyes [2]. Moreover, it was reported that healthy individuals show a preference for attending to the eye region across different emotional expressions [3]. This early attentional bias was linked to amygdala activity [4], and was found to be most pronounced for fearful faces and less pronounced for happy facial expressions [3,5]. These findings indicate that healthy individuals show a tendency to automatically attend to facial features that are diagnostic of the current emotional state of conspecifics [6]. Here, we examined an otherwise healthy, male adult individual (MW) with unilateral right-sided amygdala loss in a novel, eye-tracking-based face perception task in order to clarify the functional role of the amygdala complex in driving attentional orienting. Compared to a sample of matched controls, MW showed an isolated deficit in reflexive gaze shifts towards diagnostic emotional facial features during brief stimulus presentations as compared to normal performance during longer viewing periods. These results suggest that the amygdala is implicated in quickly detecting diagnostic facial features in the visual periphery and driving reflexive saccades towards these locations. PMID- 24156809 TI - Perceptual effects of stimulating V5/hMT+ during binocular rivalry are state specific. AB - Binocular rivalry occurs when two distinct visual stimuli are presented separately to each eye, causing perceptual ambiguity. The conscious state of the observer then alternates between the perceptual dominance of one of the stimuli while the other is suppressed, and vice versa. These vivid changes in perception during constant visual stimulation allow the study of brain processes involved in conscious visual experience. There is abundant electrophysiological as well as fMRI evidence that neural activity in stimulus-selective areas of the temporal lobe correlates with perceptual changes during rivalry [1-3]. Yet, almost nothing is known about the causal contribution of these areas to dominance and suppression of their preferred stimulus. We induced binocular rivalry in human observers using moving dots presented to one eye and a static face to the other eye, and applied transcranial magnetic stimulation (TMS) over the motion area V5/hMT+. We show that disrupting activity in V5/hMT+ during rivalry extends periods of motion suppression, with no effect on periods of motion dominance, revealing a state-specific contribution of V5/hMT+ to the competition for awareness in rivalry. PMID- 24156810 TI - Biological clocks: riding the tides. AB - Animals with habitats in the intertidal zone often display biological rhythms that coordinate with both the tidal and the daily environmental cycles. Two recent studies show that the molecular components of the biological clocks mediating tidal rhythms are likely different from the phylogenetically conserved components that mediate circadian (daily) rhythms. PMID- 24156811 TI - Chromosome biology: Wapl spreads its wings. AB - Chromosome segregation requires the removal of cohesion and catenation between sister chromosomes, two physical linkages established during DNA replication. Two new studies reveal that, among other functions, the wings apart-like protein (Wapl) coordinates cohesin removal with decatenation of sister chromosomes during mitosis in mammalian cells. PMID- 24156812 TI - Visual behavior: mice run from overhead danger. AB - Mice show an innate protective behavior to looming shadows approaching from above: they either run for cover or freeze in place. This newly discovered 'looming response' adds to the repertoire of stereotyped behaviors that can be utilized to study visual pathways. PMID- 24156813 TI - Halotropism: turning down the salty date. AB - Plants have a deep-rooted trust in gravity, but it is not unconditional. A new study shows that, if plant roots sense high doses of salt coming up from below, they dump gravity responses and grow away from the salt contamination. PMID- 24156814 TI - Gustatory receptors: not just for good taste. AB - A recent study has found that a Drosophila gustatory receptor is required for thermotaxis. With other fly gustatory receptors having been shown to act in the detection of CO2, nutrients in the brain, and light, the roles of the so-called 'gustatory receptors' clearly go way beyond peripheral detection of non-volatile chemicals. PMID- 24156815 TI - Microtubule disassembly: when a sleeper is activated. AB - Tubulin modifications are emerging as interesting mechanisms to regulate microtubule dynamics. A new study shows that phosphorylation of alpha-tubulin by the atypical kinase PHS1 leads to rapid disassembly of cortical microtubules in plant cells that are under hyperosmotic stresses. PMID- 24156816 TI - Histocompatibility: clarifying fusion confusion. AB - In the colonial tunicate Botryllus schlosseri, a co-dominant trait determines the capacity of adjacent colonies to fuse or reject. An innovative RNA sequencing approach has now identified the gene that predicts the outcomes of this naturally occurring allograft. PMID- 24156817 TI - Network modularity: back to the future in motor control. AB - Optogenetic analysis has revealed the existence of multiple rhythm-generating neural networks that drive leg motoneuron pools in the lumbar spinal cord of rodents. These findings extend the concept of a modular neural network organization for locomotion from invertebrates and lower vertebrates to mammals. PMID- 24156818 TI - Real-time black carbon emission factor measurements from light duty vehicles. AB - Eight light-duty gasoline low emission vehicles (LEV I) were tested on a Chassis dynamometer using the California Unified Cycle (UC) at the Haagen-Smit vehicle test facility at the California Air Resources Board in El Monte, CA during September 2011. The UC includes a cold start phase followed by a hot stabilized running phase. In addition, a light-duty gasoline LEV vehicle and ultralow emission vehicle (ULEV), and a light-duty diesel passenger vehicle and gasoline direct injection (GDI) vehicle were tested on a constant velocity driving cycle. A variety of instruments with response times >=0.1 Hz were used to characterize how the emissions of the major particulate matter components varied for the LEVs during a typical driving cycle. This study focuses primarily on emissions of black carbon (BC). These measurements allowed for the determination of BC emission factors throughout the driving cycle, providing insights into the temporal variability of BC emission factors during different phases of a typical driving cycle. PMID- 24156819 TI - Oxyhalogen-sulfur chemistry: kinetics and mechanism of oxidation of N-acetyl homocysteine thiolactone by acidified bromate and aqueous bromine. AB - N-acetyl homocysteine thiolactone (NAHT), medically known as citiolone, can be used as a mucolytic agent and for the treatment of certain hepatic disorders. We have studied the kinetics and mechanisms of its oxidation by acidic bromate and aqueous bromine. In acidic bromate conditions the reaction is characterized by a very short induction period followed by a sudden and rapid formation of bromine and N-acetyl homocysteine sulfonic acid. The stoichiometry of the bromate-NAHT reaction was deduced to be: BrO3(-) + H2O + CH3CONHCHCH2CH2SCO -> CH3CONHCHCH2CH2(SO3H)COOH + Br(-) (S1) while in excess bromate it was deduced to be: 6BrO3(-) + 5CH3CONHCHCH2CH2SCO + 6H(+) -> 3Br2 + 5CH3CONHCHCH2CH2(SO3H)COOH + 2H2O (S2). For the reaction of NAHT with bromine, a 3:1 stoichiometric ratio of bromine to NAHT was obtained: 3Br2 + CH3CONHCHCH2CH2SCO + 4H2O -> 6Br(-) + CH3CONHCHCH2CH2(SO3H)COOH + 6H(+) (S3). Oxidation occurred only on the sulfur center where it was oxidized to the sulfonic acid. No sulfate formation was observed. The mechanism involved an initial oxidation to a relatively stable sulfoxide without ring-opening. Further oxidation of the sulfoxide involved two pathways: one which involved intermediate formation of an unstable sulfone and the other involves ring-opening coupled with oxidation through to the sulfonic acid. There was oligooscillatory production of aqueous bromine. Bromide produced in S1 reacts with excess bromate to produce aqueous bromine. The special stability associated with the sulfoxide allowed it to coexist with aqueous bromine since its further oxidation to the sulfone was not as facile. The direct reaction of aqueous bromine with NAHT was fast with an estimated lower limit bimolecular rate constant of 2.94 +/- 0.03 * 10(2) M(-1) s(-1). PMID- 24156820 TI - Inspiring trainees to consider a career in medical education. PMID- 24156821 TI - Systematic review of tumor necrosis factor inhibitor discontinuation studies in rheumatoid arthritis. AB - BACKGROUND: Anti-tumor necrosis factor agents (anti-TNFs) have changed the course of rheumatoid arthritis (RA) for more than a decade. Use of these medications often results in remission, or at least low disease activity (LDA), but at a substantial cost. It has been postulated that discontinuation of these medications among patients with RA in remission or LDA may be possible without an associated increase in RA disease activity. OBJECTIVE: The goal of this systematic literature review was to summarize published articles regarding discontinuation of anti-TNFs in patients with RA. METHODS: A systematic literature review was conducted to identify English-language articles indexed in PubMed from July 1999 through June 2013 reporting results regarding anti-TNF discontinuation in patients with RA. Study designs included observational longitudinal studies and clinical trials. Outcomes had to include 1 of the following: time to flare after anti-TNF discontinuation, failure to remain in remission, or proportion of patients in LDA or remission at the end of the study. RESULTS: Ten studies examined discontinuation of anti-TNF therapies in RA. Inclusion criteria varied significantly across studies in terms of disease activity status (remission or LDA) and duration of this disease status (1 year or 1 month) before discontinuation being attempted. Results from larger studies (eg, >100 patients) suggest that the proportion of patients who discontinued anti-TNF and did not have an increase in disease activity ranged from 24% to 81%. In 3 studies that evaluated durability of LDA or remission after anti-TNF discontinuation, the mean time to relapse varied from 15 weeks to 17 months. In studies that analyzed radiographic data, once therapies were reinitiated after an increase in disease activity was detected, patients generally did not experience progression in structural damage. CONCLUSIONS: Discontinuation of anti-TNF therapy is achievable for many RA patients who start in clinical remission or LDA. However, heterogeneous inclusion criteria and highly variable outcome definitions across studies make it difficult to efficiently summarize the literature on this topic or to conduct a meta-analysis. There is a lack of evidence regarding how to best predict which patients have the greatest likelihood of continuing to do well after discontinuation of anti-TNF therapy. PMID- 24156822 TI - Comparison of the performance of carcinogenic HPV typing of the Roche Linear Array and Qiagen LiquiChip(r) HPV assays. AB - BACKGROUND: Cervical cancer is caused by high-risk types of human papillomavirus (HPV). DNA testing of such high-risk types of HPV could improve cervical screening.The aim of the study was to compare the sensitivities and positive predictive values of two commercially available typing assays (Qiagen LQ and Roche LA) and to comparatively assess the distribution of HPV types with these two assays. METHODS: The study population comprised 311 ASCUS + women with abnormal pap tests who were HCII positive and who were admitted to three European referral gynecology clinics between 2007 and 2010 (Madrid, Marseille and Milan). All patients underwent LQ and LA tests. RESULTS: The sensitivity of the two assays for HPV typing was 94% for LQ and 99% for LA (compared with HCII). The overall concordance between LQ and LA was 93%. The three prevalent genotypes, HPV16, HPV18, and HPV31, were identified with a high concordance using the two assays: kappa 0.93, 0.83, and 0.91, respectively. Mixed genotypes were more frequently detected by LA than by LQ: 52% vs. 18%, respectively (p < .0001). CONCLUSIONS: These assays have a good clinical sensitivity for detecting HPV types in CIN2+ patients and allow the virus type to be detected in the same experiment. Our study revealed no significant difference between LQ and LA for CIN2+ or CIN3+ diagnosis, indicating similar distributions of HPV types and a mixed genotype detection that is higher for LA than for LQ. PMID- 24156823 TI - Assessing the effects of treated and untreated urban discharges to estuarine and coastal waters applying selected biomarkers on caged mussels. AB - To assess effects of urban discharges, biomarkers were measured in caged mussels in northern Iberian Peninsula. Lysosomal membrane stability and histopathology of gonad and digestive gland were analysed as general effect biomarkers. Exposure to specific pollutants was evaluated by autometallographical detection of metals, peroxisomal acyl-CoA oxidase activity, micronucleus test and transcription levels of vitellogenin and MT20 genes. Health status of mussels was impaired after 3 days of caging at the untreated outfall discharge and at the waste water treatment plant effluent discharge to the estuary. The most relevant finding was the significant up-regulation of vitellogenin gene transcription in male mussels exposed to the untreated outfall discharge. Metals and xenoestrogenic endocrine disruptors were bioavailable in some discharges and disturbed the health status of mussels. Biomarkers were effective in the assessment of effects of urban discharges and could be implemented in operative controls required to assess the risks associated to effluent discharges. PMID- 24156824 TI - A direct role for small non-coding RNAs in DNA damage response. AB - Historically, the role of cellular RNA has been subordinate and ancillary to DNA. Protein-coding mRNA conveys the information content of DNA, and transfer RNAs and ribosomal RNAs allow the polymerization of amino acids into proteins. The discovery of non-protein-coding RNAs (ncRNAs) provided an additional role for RNA in finely tuning DNA expression. However, it has recently become apparent that the safeguard of DNA integrity depends on small ncRNAs acting at the site of DNA lesions to signal the presence of DNA damage in the cell, and on the genes involved in their biogenesis to achieve accurate DNA repair. I review here evidence supporting a role for small ncRNAs, termed DNA damage-response RNAs (DDRNAs) or double-strand break (DSB)-induced RNAs (diRNAs), that are generated at sites of DNA damage and control the DNA damage response (DDR). I also discuss their biogenesis, potential mechanisms of action, and their relevance in cancer. PMID- 24156826 TI - Relieving the cardiometabolic disease burden: a perspective on phytometabolite functional and chemical annotation for diabetes management. AB - Type 2 diabetes (T2D) is both a complex, multifactorial disease state and an unsolved, intensifying public-health problem. To help reduce disease burden, some T2D patients have embraced plant-derived substances for use with - if not in place of - prescription medicines, a trend based mainly upon historical precedent and anecdotal observations of human health benefit. Preclinical research has emphasized phytometabolite interactions with purported T2D pathogenic targets and the effects of botanical preparations on experimental T2D symptomology as induced in laboratory animals. More holistic, systems-oriented profiling of phytochemicals with functional-biology, omics, and chemical-fingerprinting tools now appears necessary to increase our appreciation of phytometabolite actions potentially beneficial to the T2D patient. The resultant, multidimensional view of phytometabolite pharmacology should help provide a more rational basis for evaluating the potential of natural plant products as T2D pharmacotherapy. Such information may also help substantiate and legitimize (pre)clinical demonstrations of phytochemical health benefits, advance our understanding of T2D pathogenesis, and offer scope for better T2D medicines. Public-private partnerships are invoked for conducting this research with the ultimate aim of improving the global cardiometabolic profile. PMID- 24156825 TI - FFPE tissue as a feasible source for gene expression analysis--a comparison of three reference genes and one tumor marker. AB - BACKGROUND: Formalin-fixation, paraffin-embedding is the standard processing technique for tumor tissue in modern pathology. New techniques such as cryo conservation allow rapid fixation and long-time storage but come along with increased costs and enlarged storage complexity. However, formalin-fixed, paraffin-embedded (FFPE) tissue is available in a large quantity, making it the ideal material for retrospective studies. The following study was designed to investigate the influence of formalin-fixation on the quality of mRNA and applicability of FFPE-derived mRNA for gene expression analysis. Three potential reference genes for pulmonary tumors with neuroendocrine differentiation were included and tested for their robust expression. MATERIALS AND METHODS: Eighty specimens collected from 2005 to 2012 at the Institute of Pathology and Neuropathology at the University Hospital Essen were analyzed for their gene expression by using TaqMan((r)) gene expression assays on demand (AoD). Three distinct potential reference genes (ACTB, GAPDH, HPRT1) were evaluated for their expression, and a proteasome subunit (PSMA1) was included in the analysis as tumor marker and functioned as an internal technical control. CONCLUSION: For GAPDH and ACTB, a highly significant correlation and consistent expression between the investigated entities was found, making them reliable reference genes for further research. Additionally, the feasibility for a FFPE tissue-based gene expression analysis was verified by showing that the mRNA quality is sufficient. When standardized FFPE preparation is performed carefully, sufficient mRNA can be isolated for reliable and successful gene expression analysis. That provides the basis the door for large, retrospective studies that correlate molecular and clinical follow-up data. PMID- 24156827 TI - An audit of a hospital-based Doppler ultrasound quality control protocol using a commercial string Doppler phantom. AB - Results from a four-year audit of a Doppler quality assurance (QA) program using a commercially available Doppler string phantom are presented. The suitability of the phantom was firstly determined and modifications were made to improve the reliability and quality of the measurements. QA of Doppler ultrasound equipment is very important as data obtained from these systems is used in patient management. It was found that if the braided-silk filament of the Doppler phantom was exchanged with an O-ring rubber filament and the velocity range below 50 cm/s was avoided for Doppler quality control (QC) measurements, then the maximum velocity accuracy (MVA) error and intrinsic spectral broadening (ISB) results obtained using this device had a repeatability of 18 +/- 3.3% and 19 +/- 3.5%, respectively. A consistent overestimation of the MVA of between 12% and 56% was found for each of the tested ultrasound systems. Of more concern was the variation of the overestimation within each respective transducer category: MVA errors of the linear, curvilinear and phased array probes were in the range 12.3 20.8%, 32.3-53.8% and 27-40.7%, respectively. There is a dearth of QA data for Doppler ultrasound; it would be beneficial if a multicentre longitudinal study was carried out using the same Doppler ultrasound test object to evaluate sensitivity to deterioration in performance measurements. PMID- 24156828 TI - Modelling the Hofstee method reveals problems. PMID- 24156833 TI - Variables associated with extra uterine growth restriction in very low birth weight infants. AB - OBJECTIVES: To determine the rate of extrauterine growth restriction in very low birth weight infants and to evaluate the influence of perinatal variables, clinical practices, and neonatal morbidities on this outcome. METHODS: A longitudinal study was performed in four neonatal units in the city of Rio de Janeiro. 570 very low birth weight infants were analyzed. The study included perinatal variables, variables related to clinical practices, and incident morbidities in these preterm infants. Extrauterine growth restriction was defined using z-scores for weight or head circumference <= -2 for corrected age. Statistical analysis was performed using the Statistical Package for Social Sciences (SPSS) and R software. RESULTS: This study comprised 570 infants, of which 49% were males, and 33% were small for gestational age (SGA). The mean weight and head circumference at birth were 1,113 +/- 267 g and 27 +/- 2 cm, respectively. The mean z-scores of birth weight and weight at discharge were 0.96 +/- 0.78 and -1.54 +/- 0.75, respectively; for head circumference, the mean z-scores at birth and at discharge were -0.63 +/- 1.18 and -0.45 +/- 0.94, respectively. The rate of extrauterine growth restriction considering the weight was 26% (149/570) and considering the head circumference, 5% (29/570). SGA was the variable with the greatest impact on both growth restriction for weight (PR = 4.33) and for head circumference (PR = 2.11) in adjusted analyses. CONCLUSION: extrauterine growth restriction was high in the population, especially for SGA newborns and those with neonatal morbidities. PMID- 24156834 TI - Extrauterine growth restriction: is it preventable? PMID- 24156835 TI - Physical activity in adolescents: analysis of the social influence of parents and friends. AB - OBJECTIVE: To analyze the association between physical activity and social support from parents and friends on the physical activity level among adolescents. METHODS: Data from 2,361 adolescents (56.6% females; mean age 16.4; SD = 1.2), from public and private high schools were analyzed. The physical activity level of the adolescents, parents, and friends were measured through a questionnaire. Parents' and friends' support and self-efficacy were measured using two previously tested scales. Data analysis was performed using the structural equation modeling in IBM(r) SPSS(r) AmosTM 20.0. RESULTS: Physical activity of friends was directly associated with physical activity level of adolescents. Physical activity of the father was associated with that of their sons, and the physical activity of mother was associated with that of their daughters. An indirect association was identified between the physical activity of parents and friends with physical activity level of the adolescents, mediated by social support. Social support was directly associated with physical activity in adolescents of both genders and indirectly mediated by self-efficacy. CONCLUSIONS: Parents and friends have a social influence on adolescents' level of physical activity through the mechanism of behavior modeling or through social support, mediated by self-efficacy. PMID- 24156836 TI - Portuguese Children's Sleep Habits Questionnaire - validation and cross-cultural comparison. AB - OBJECTIVE: To validate the Portuguese version of the Children's Sleep Habits Questionnaire (CSHQ-PT) and compare it to the versions from other countries. METHODS: The questionnaire was previously adapted to the Portuguese language according to international guidelines. 500 questionnaires were delivered to the parents of a Portuguese community sample of children aged 2 to 10 years old. 370 (74%) valid questionnaires were obtained, 55 children met exclusion criteria and 315 entered in the validation study. RESULTS: The CSHQ-PT internal consistency (Cronbach's alpha) was 0.78 for the total scale and ranged from 0.44 to 0.74 for subscales. The test-retest reliability for subscales (Pearson's correlations, n=58) ranged from 0.59 to 0.85. Our data did not adjust to the original 8 domains structure in Confirmatory Factor Analysis but the Exploratory Factor Analysis extracted 5 factors that have correspondence to CSHQ subscales. CONCLUSION: The CSHQ-PT evidenced psychometric properties that are comparable to the versions from other countries and adequate for the screening of sleep disturbances in children from 2 to 10 years old. PMID- 24156839 TI - Adjuncts to ventilatory support part 1: nitric oxide, surfactants, prostacyclin, steroids, sedation, and neuromuscular blockade. PMID- 24156840 TI - Adjuncts to ventilation part II: monitoring, fluid management, bundles, and positioning. PMID- 24156841 TI - Waveform analysis during mechanical ventilation. PMID- 24156842 TI - Use and titration of positive end-expiratory pressure. PMID- 24156844 TI - Airway pressure release ventilation. PMID- 24156843 TI - Reviewing the studies of the National Heart, Lung, and Blood Institute Acute Respiratory Distress Syndrome Network: outcomes and clinical findings. PMID- 24156845 TI - High-frequency oscillatory ventilation. PMID- 24156846 TI - Initial commitment for inhalation injury. PMID- 24156847 TI - Proportional assist ventilation. PMID- 24156848 TI - Weaning from mechanical ventilation. PMID- 24156849 TI - Benefit, timing, and technique of tracheostomy. PMID- 24156850 TI - Nosocomial pertussis in neonatal units. AB - Pertussis remains a public health concern in many countries despite high vaccination coverage rates. Nosocomial outbreaks of pertussis continue to occur in neonatal units. Neonates and young infants admitted to neonatal intensive care units constitute a pool of susceptible high-risk patients given their prematurity, inadequate immune response and the fact that they are too young to have completed their primary vaccination series against pertussis. This article reviews nosocomial pertussis in neonates and infants, focusing on the role of healthcare workers (HCWs). Outbreaks in neonatal units are often traced to HCWs and are associated with serious morbidity or even a fatal outcome among susceptible young infants. A high index of suspicion is required for early recognition and isolation of patients admitted with suspected or proven pertussis, as well as for HCWs with a compatible clinical syndrome, regardless of vaccination status. Contact investigation is also essential in order to guide administration of post-exposure prophylaxis. Recommendations for a booster vaccination for HCWs are in place in several countries; however, the need of HCWs for lifelong immunity against pertussis cannot be fulfilled by the current vaccine. PMID- 24156851 TI - Endovascular methods for the treatment of intracranial cerebral aneurysms. AB - This article briefly discusses the clinical features, natural history, and epidemiology of intracranial cerebral aneurysms, along with current diagnostic imaging techniques for their detection. The main focus is on the basic techniques used in endovascular coiling of ruptured and nonruptured saccular intracranial cerebral aneurysms. After a discussion of each technique, a short review of the results of each form of treatment is given, concentrating on reported large case series. Specific complications related to the endovascular treatment of saccular intracranial aneurysms are then discussed. PMID- 24156852 TI - Endovascular treatment of cerebral vasospasm: vasodilators and angioplasty. AB - Cerebral vasospasm following aneurysmal subarachnoid hemorrhage (SAH) is a delayed, reversible narrowing of the intracranial vasculature that occurs most commonly 4 to 14 days after aneurysmal SAH and can lead to permanent ischemic injury. Angiographic spasm occurs in up to 70% of patients following SAH, and approximately half become symptomatic. Estimates of patients who are disabled by vasospasm, or die because of it, range from 5% to 9%, with vasospasm accounting for 12% to 17% of all fatalities or cases of disability after SAH. This article discusses the multiple medical and endovascular therapies used to prevent or treat vasospasm. PMID- 24156853 TI - Endovascular treatment of cerebral arteriovenous malformations. AB - Treatment of arteriovenous malformations of the central nervous system requires a multidisciplinary approach with input from vascular neurosurgeons, endovascular interventionalists, and radiation oncologists. Treatment paradigms based on a thorough understanding of the natural history of the lesion and the cumulative risks of multimodality treatment maximize the likelihood of a positive outcome. This article outlines the role of endovascular embolization in the treatment of arteriovenous malformations with specific emphasis on decision making during treatment planning. Technical considerations when treating arteriovenous malformations are discussed, including the choice of embolic agents, potential intraprocedural and periprocedural complications, and postprocedural management of patients. PMID- 24156854 TI - Endovascular treatment of cerebral dural and pial arteriovenous fistulas. AB - Dural arteriovenous fistulas (DAVFs) are arteriovenous shunts from a dural arterial supply to a dural venous channel, typically supplied by pachymeningeal arteries and located near a major venous sinus. Pial arteriovenous fistulas (PAVFs) are composed of one or more arterial feeders draining into a single vein in the absence of an intervening nidus. Fistulas manifesting features of high risk for rupture should be treated aggressively, the spectrum of treatment varies from endovascular, surgical resection, and stereotactic radiosurgery. This article describes the natural history, clinical presentation, and treatment of dural and pial fistulas, with emphasis on endovascular treatment. PMID- 24156855 TI - Endovascular treatment of carotid occlusive disease. AB - Carotid occlusive disease is one of several etiologic factors for stroke. Of all strokes, an estimated 88% are ischemic in nature. Less than 20% of these are caused by atheroma in the carotid bifurcation. Traditionally, carotid artery stenosis has been treated with carotid endarterectomy (CEA); however, carotid artery balloon angioplasty and stent placement has enjoyed significant technological advances over the last decade and can now offer a comparable treatment alternative to CEA. In this review, the authors concentrate their discussion on the treatment of carotid atherosclerotic disease with particular attention on the endovascular treatment. PMID- 24156856 TI - Endovascular treatment of intracranial atherosclerotic disease. AB - Stroke is the third leading cause of death in the United States. Intracranial atherosclerotic disease plays a role in cerebrovascular accidents, with well characterized modifiable and nonmodifiable risk factors. Surgical bypass has so far not proved to be superior to medical therapy. Both medical and endovascular therapies for intracranial atherosclerosis have evolved since the initial off label use of cardiac devices for its treatment. Initial reports on the results of stent placement for symptomatic high-grade intracranial atherosclerotic disease were initially encouraging. However, debate remains as to the optimal treatment of symptomatic intracranial atherosclerotic disease. PMID- 24156857 TI - Spontaneous cervical and cerebral arterial dissections: diagnosis and management. AB - Arterial dissections of head and neck arteries were first identified pathologically in the 1950s, but not until the 1970s and the 1980s did they begin to be widely recognized as a clinical entity. Carotid and vertebral artery dissections account for only 2% of all ischemic strokes, but they account for approximately 20% of thromboembolic strokes in patients younger than 45 years. The cause of supra-aortic dissections can be either spontaneous or traumatic. This article addresses spontaneous cervical and cerebral artery dissections. PMID- 24156858 TI - Endovascular treatment of acute ischemic stroke. AB - Endovascular stroke therapy has revolutionized the management of patients with acute ischemic stroke in the last decade and has facilitated the development of sophisticated stroke imaging techniques and a multitude of thrombectomy devices. This article reviews the scientific basis and current evidence available to support endovascular revascularization and provides brief technical details of the various methods of endovascular thrombectomy with case examples. PMID- 24156859 TI - Intracranial endovascular balloon test occlusion: indications, methods, and predictive value. AB - Abrupt interruption of the internal carotid artery without a balloon test occlusion (BTO) carries a 26% risk of cerebral infarction. BTO is a test used to decrease this risk by evaluating the efficacy of the collateral circulation. Clinical tolerance of parent vessel occlusion can be assessed by a BTO with several variables, including the clinical examination, angiographic assessment, stump pressure, induced hypotension, perfusion scanning, transcranial Doppler ultrasonography, and neurophysiologic monitoring. This review discusses the indications, methods, predictive value, and complications of BTO. PMID- 24156860 TI - Endovascular methods for the treatment of vascular anomalies. AB - Vascular malformations are congenital lesions secondary to errors in the development of arteries, capillaries, veins, or lymphatics. Most of these lesions are sporadic; however, a certain percentage present with syndromes. This article discusses the clinical features, natural history, and epidemiology of these lesions, and the diagnostic imaging features of vascular anomalies of the head and neck are presented. The percutaneous/endovascular treatment of each of the vascular anomalies is described, and surgical and additional treatment options are discussed briefly. The clinical outcomes of the main forms of treatment and level of evidence are presented. PMID- 24156861 TI - Endovascular treatment of adult spinal arteriovenous lesions. AB - Spinal arteriovenous lesions (SAVLs) are rare disorders, the diagnosis of which can be established using various imaging modalities. To discern the various types of SAVL, spinal angiography of the entire neural axis is required. Surgery is the standard treatment of choice; however, ever advancing endovascular technology can provide a viable alternative. This article discusses the normal anatomy, arterial supply, and venous drainage of the spinal cord. The classification, pathophysiology, epidemiology, clinical presentation, natural history, and pathophysiology of SAVLs in adults are reviewed. Finally, endovascular treatment of these lesions is discussed. PMID- 24156862 TI - Spinal arteriovenous shunts in children. AB - Pediatric spinal arteriovenous shunts are rare and, in contrast to those in adults, are often congenital or associated with underlying genetic disorders. These are thought to be a more severe and complete phenotypic spectrum of all spinal arteriovenous shunts seen in the overall spinal shunt population. The pediatric presentation thus accounts for its association with significant morbidity and, in general, a more challenging treatment process compared with the adult presentation. PMID- 24156863 TI - Cerebral arteriovenous shunts in children. AB - Intracranial arteriovenous shunts (AVSs) in children can be divided into pial arteriovenous malformations, vein of Galen malformations, and arteriovenous fistulae (AVF). Dural AVF and dural sinus malformations are rare entities within this group. The relative immaturity of the anatomy and physiology of the neonatal and infant brain results in the inability of the hydrovenous system to compensate in the face of such disorders. Thus, the clinical presentation reflects this difference in the underlying anatomy, physiology, and disorder between children and adults. In this article, we briefly review the presentation, natural history and management of these entities. PMID- 24156864 TI - Pediatric cerebral aneurysms. AB - Childhood intracranial aneurysms differ from those in the adult population in incidence and gender prevalence, cause, location, and clinical presentation. Endovascular treatment of pediatric aneurysms is the suggested approach because it offers both reconstructive and deconstructive techniques and a better clinical outcome compared with surgery; however, the long-term durability of endovascular treatment is still questionable, therefore long-term clinical and imaging follow up is necessary. The clinical presentation, diagnosis, and treatment of intracranial aneurysms in children are discussed, and data from endovascular treatments are presented. PMID- 24156865 TI - Arterial ischemic stroke in children. AB - Acute ischemic stroke affects 3.3 of 100,000 children per year. The causes of AIS in children can be broadly divided into the following 6 categories: cardiac disese, sickle cell disease, moyamoya, arterial dissection, other arteriopathies, and other causes. Approximately 24% of the cases are classified as idiopathic. Magnetic resonance imaging (MRI) and cerebral angiography play an important role in the determining the causes of an AIS in children. Medical approaches, including anticoagulation, anti-inflammatories, and antiplatelet therapies, surgical revascularization and endovascular approaches may have a role in the management of AIS in children. PMID- 24156866 TI - Neuroimaging Clinics of North America. Endovascular management of neurovascular pathology in adults and children. Foreword. PMID- 24156867 TI - Neuroimaging Clinics of North America. Endovascular management of neurovascular pathology in adults and children. Preface. PMID- 24156868 TI - Differential effects of GLP-1 receptor agonists on components of dysglycaemia in individuals with type 2 diabetes mellitus. AB - Metabolic consequences of glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are the result of enhanced glucose-stimulated insulin secretion, inhibition of glucagon release, delayed gastric emptying and increased satiety. These attributes make GLP-1 agonists a treatment option in type 2 diabetes mellitus (T2DM). To optimise treatment choice, a detailed understanding of the effects of GLP-1 RAs on glucose homeostasis in individuals with T2DM is necessary. Although the various GLP-1 RAs share the same basic mechanisms of action, differences in pharmacokinetic/pharmacodynamic characteristics translate into differential effects on parameters of glycaemia. Head-to-head comparisons between long-acting non-prandial (liraglutide once daily and exenatide once weekly) and shorter acting prandial (exenatide twice daily and lixisenatide once daily prandial) GLP 1 RAs confirm their differential effects on fasting plasma glucose (FPG) and post prandial glucose (PPG). Liraglutide once daily and exenatide once weekly demonstrate greater reductions in FPG but lesser impacts on PPG excursions plasma than exenatide twice daily. Prandial GLP-1 RAs have a profound effect on post prandial glycaemia, mediated by delaying gastric emptying, which is not subject to the tachyphylaxis occurring due to the sustained elevated plasma GLP-1 concentrations after treatment with long-acting GLP-1 RAs. Lixisenatide once daily prandial, in contrast to liraglutide, strongly suppresses post-prandial glucagon secretion, further contributing to the more pronounced PPG-lowering effect found with lixisenatide. Evidence suggests that the GLP-1 RAs that predominantly target the prandial glucose excursions, such as exenatide twice daily and lixisenatide once-daily prandial, are therefore best used as combination therapy with basal insulin and will form an important new treatment option for individuals with T2DM. PMID- 24156869 TI - Lupane, friedelane, oleanane, and ursane triterpenes from the stem of Siphonodon celastrineus Griff. AB - Twenty-one triterpenes consisting of a lupane derivative, two friedelanes, an oleanane derivative, and 17 ursane-type triterpenoids, together with three known triterpenes, three sterols, a fatty acid, a sesquiterpene alkaloid, and a glycerol derivative, were isolated from the stem of Siphonodon celastrineus. Their structures were characterized by various spectroscopic techniques, as well as comparison with literature data. Twenty-seven metabolites of these were evaluated for cytotoxic activity against six human cancer cell lines. The biosynthetic formation of a 1,4-dioxane bridge is also discussed. PMID- 24156870 TI - Involuntary social cue integration in patients with obsessive compulsive disorder. AB - OBJECTIVE: Patients with obsessive compulsive disorder (OCD) have inferior social functioning compared to healthy controls, but the exact nature of these social deficits, and the underpinning mechanisms, are unknown. We sought to investigate social functioning in patients with OCD by measuring their involuntary/spontaneous processing of social cues using a specifically designed test, which might reveal deficits in these patients that explicit voluntary tasks do not detect. METHODS: The sample of the study consisted of an OCD group (n = 25) and a control group (n = 26). Both groups performed an adaptation of the Social Distance Judgment Task (SDJT; Jellema et al., 2009), in which participants have to judge the geometrical distance between two human cartoon figures presented on a computer screen. Head/gaze direction and body direction were manipulated to be either compatible, i.e. both directed to the left or to the right (Compatible condition) or incompatible, i.e. body directed toward the observer (frontal view) and head/gaze directed to the left or right (Incompatible condition). RESULTS: In the Compatible condition, controls nor OCD patients were influenced by the social cues in their judgments of the geometrical distances. However, in the Incompatible condition, where the attentional cue was more conspicuous, both groups were influenced by the cues, but the controls to a significantly larger extent than the OCD patients. CONCLUSIONS: This study showed that patients with OCD are less likely, compared to controls, to automatically/spontaneously integrate the other's direction of attention into their visual percept. This may have resulted in their judgments of the geometrical distances between the agents to be more accurate than those of controls. The suggested impairment in automatically integrating social cues may have important repercussions for the social functioning of OCD patients. PMID- 24156871 TI - Tic-related activity restriction as a predictor of emotional functioning and quality of life. AB - OBJECTIVES: Tourette Syndrome (TS) is a chronic neuropsychiatric condition that frequently persists into adulthood. Existing research has identified demographic and symptom-level variables associated with psychopathology and poor quality of life in TS. However, behavior patterns associated with enhanced or adaptive psychological and global functioning among adults with TS have yet to be empirically identified. The current study examined whether tic-specific activity restriction is related to emotional functioning and quality of life in adults with TS. METHODS: Participants were 509 adults from the Tourette Syndrome Impact Survey who completed self-report measures of demographics, tic severity, emotional functioning, quality of life, and tic-related general and social activity restriction. RESULTS: Partial correlations controlling for tic severity indicated that tic-related general and social activity restriction were significantly correlated with lower quality of life and poorer emotional functioning. Hierarchical linear regression models indicated that activity restriction significantly predicted lower quality of life and poorer emotional functioning when controlling for tic severity and demographic variables. CONCLUSIONS: Adults who restrict fewer activities due to tics, regardless of tic severity, experience greater quality of life and better emotional functioning. Clinically, adults with chronic tics may benefit from interventions focused on enhancing engagement in valued life activities. PMID- 24156872 TI - Family history of major depression and residual symptoms in responder and non responder depressed patients. AB - BACKGROUND: Little is known about the extent to which a family history of major depression (MD) affects residual depressive symptoms in responder and non responder patients suffering from MD. METHODS: Nine hundred eighty-six patients with MD were recruited within the context of a large multicenter project. Information about the family history of MD, as well as about total depressive symptoms and specific depressive clusters, was collected and analyzed. RESULTS: No significant difference was observed in overall depressive symptoms between patients with and those without a family history of MD. However, non-responder patients with a family history of MD showed significantly higher scores in core symptoms as compared with responder patients without a family history of MD. CONCLUSIONS: Non-responder MD patients with a positive family history of MD could represent a slightly different sub-group of MD patients with more consistent core depressive symptoms as compared with responder patients without a family history of MD. However, taking into account the retrospective assessment of data, the use of positive or negative family history as a dichotomous indicator of familial loading and the cross-sectional design of the present study, further research is needed to draw more definitive conclusions. PMID- 24156873 TI - Risk factors for suicidal ideation, plans and attempts in Malaysia--results of an epidemiological survey. AB - OBJECTIVE: This is an epidemiological study to determine the prevalence of suicidal behavior and its association with generalised anxiety disorder (GAD) and major depressive disorder (MDD) in a nationally representative sample. METHOD: Suicidal ideation, plans and attempts were assessed in face-to-face interviews of respondents selected by a multistage probability sampling using items on suicidality from the WHO SUPRE-MISS questionnaire. The Mini International Neuropsychiatric Interview (MINI) was used to generate DSM-IV diagnoses of GAD and MDD. A total of 19309 subjects were studied. Multivariate regression analysis was conducted controlling for demographic characteristics such as age, gender and ethnicity. RESULTS: The prevalence estimates for suicide ideation, plans and attempts were 1.7% (95% CI: 1.4-1.9), 0.9% (CI: 0.7-1.1) and 0.5% (CI: 0.4-0.7) respectively. Younger people (16-24 years) had higher risk of suicidal behavior (OR: 2.6, CI: 1.08-6.2). Females (OR: 1.6, CI: 1.2-2.1) and Indians (OR: 3.3, CI: 2.2-4.9) also had higher risk. CONCLUSION: The prevalence of suicidal behavior in Malaysia is low, but it broadly corresponds to the pattern described in other countries. This national study confirms that Malaysians of Indian descent have much higher rates of suicidal behavior than other groups. The younger age group, females and the Indian ethnic group would need focused preventive efforts. PMID- 24156874 TI - ASPECTS is a predictor of favorable CT perfusion in acute ischemic stroke. AB - BACKGROUND AND PURPOSE: Computed tomography perfusion (CTP) is used by some stroke centers to stratify stroke patients who may potentially benefit from endovascular treatment. Our aim is to identify predictors of a favorable CTP in acute ischemic stroke patients evaluated within 8h from symptoms onset for possible endovascular treatment. MATERIALS AND METHODS: We reviewed records of patients who had CTP studies between August 2010 and September 2012. We included all patients with anterior circulation strokes with evidence of large vessel disease. All patients had CT head and CT angiography head and neck as part of our protocol. Favorable CTP was defined as core infarct size less than one third the middle cerebral artery distribution and penumbra>20% of infarct size. The patients were divided into two groups based on favorable CTP or not. Baseline characteristics, time parameters, laboratory data and radiological data were compared between both groups. For statistical analysis, we used independent and Fisher's exact tests and a multivariate logistic regression model. RESULTS: During this period, 60 patients met the inclusion criteria. Patients with favorable CTP were likely to be >= 80 years (33% vs 9%, P = 0.026), have Alberta Stroke Program early CT score (ASPECTS) > 7 (81% v. 21%, P <= 0.001) and lower mean time from symptom onset to CTP (234 +/- 91 vs 305 +/- 122, P = 0.015). On regression analysis, ASPECTS was the only independent predictor of a favorable CTP (OR = 16.2, CI: 4.3-62.2, P < 0.001). CONCLUSION: ASPECT score may be used as a tool to predict a favorable CTP. Larger studies are needed to confirm our findings. PMID- 24156875 TI - Modulation of autophagy by Helicobacter pylori and its role in gastric carcinogenesis. AB - Helicobacter pylori infection represents the strongest known risk factor for the development of gastric cancer. The vacuolating cytotoxin (VacA) plays a key role in disease pathogenesis by exerting pleiotrophic effects on the host. One effect of acute VacA exposure is the induction of autophagy. However, prolonged exposure to the toxin disrupts autophagy by preventing maturation of the autolysosome. Novel insights into the mechanism and consequences of this phenomenon have emerged, but many aspects remain largely unknown. Current evidence supports a scenario in which H. pylori-suppressed autophagy facilitates intracellular survival and persistence of the pathogen, while also generating an environment favoring carcinogenesis. PMID- 24156877 TI - Are IM injections IM in obese and overweight females? A study in injection technique. AB - If given incorrectly, intramuscular injections may result in poor absorption of drug, reduced drug effectiveness, or irritation to surrounding tissues. In this study, IM injection techniques were observed and documented for needle length, injection site, needle insertion, and stretching or bunching of the skin during injection in a population of adult females. The patients' weights and BMIs were recorded to determine the amount of subcutaneous fat at the injection site. In 22 patients of varied weights, 90% of injections were given within current Advisory Committee on Immunization Practice (ACIP) guidelines in normal and underweight patients, and 17% were given within ACIP guidelines in overweight and obese patients. The study concluded that the needle length used is often too short in overweight and obese individuals. PMID- 24156876 TI - Structure and mechanism of energy-coupling factor transporters. AB - Energy-coupling factor (ECF) transporters form a new family of ATP-binding cassette (ABC) transporters and are widely used by prokaryotes to take up micronutrients from the environment. Instead of using the periplasmic solute binding proteins (SBPs), ECF transporters use the membrane S proteins for substrate capture and translocation. In this review, we will focus on structural advances that have been made regarding how substrates are recognized by ECF transporters and possible transport mechanisms employed by the ECF transporters. PMID- 24156878 TI - Anaplastic large cell lymphoma in a reconstructed breast using a silicone implant: a UK case report. AB - We present case of Anaplastic Large Cell Lymphoma discovered as an incidental finding whilst revising an implant based breast reconstruction in a 55 year old woman, whom previously had undergone risk reduction mastectomies and immediate reconstruction. During the procedure a presumed seroma was present but this was macroscopically atypical giving a 'milky' coloured appearance with a pink tinge to it. The atypical fluid was sent for analysis and the diagnosis of ALCL confirmed. Treatment consisted of unilateral capsulectomy on the affected side and bilateral removal of implants with staging scans suggesting the disease being confined to the capsule. She remains in remission 12 months following the original procedure. PMID- 24156880 TI - Rupture of abdominal aortic aneurysm associated with long-term steroid therapy--a case report. AB - We report an autopsy case of bronchial asthma patient with a specific abdominal aortic aneurysm. The aneurysm did not show arteriosclerosis, and a specific saccular morphology was noted above the bifurcation. Histologically, necrosis of the media resembling acute aortic dissociation was observed. However, angiitis was ruled out. In addition, the aneurysm showed a cicatrized, old intimal crack in addition to the rupture site, suggesting repeated failures. The long-term steroid therapy-related fragility of the arterial wall may have been involved in the etiology of the aneurysm. PMID- 24156883 TI - Cross-cultural patterns of the association between varying levels of alcohol consumption and the common mental disorders of depression and anxiety: secondary analysis of the WHO Collaborative Study on Psychological Problems in General Health Care. AB - BACKGROUND: Alcohol consumption is associated with several complications of both physical and mental health. Light or moderate alcohol consumption may have beneficial effects on physical or mental health but this effect is still controversial and research in the mental health field is relatively scarce. Our aim was to investigate the association between varying levels of alcohol consumption and the common mental disorders of depression and anxiety in a large international primary care sample. METHODS: The sample consisted of 5438 primary care attenders from 14 countries who participated in the WHO Collaborative Study of Psychological Problems in General Health Care. Alcohol use was assessed using Alcohol Use Disorders Identification Test (AUDIT) and the mental disorders were assessed with the Composite International Diagnostic Interview (CIDI). RESULTS: Light to moderate alcohol consumption was associated with a lower prevalence of depression and generalized anxiety disorder compared to abstinence while excessive alcohol consumption was associated with a higher prevalence of depression. This non-linear association was not substantially affected after adjustment for a range of possible confounding variables, including the presence of chronic disease and the current physical status of participants and was evident in different drinking cultures. CONCLUSION: The study confirms that excessive drinking is associated with an increased prevalence of depression, but also raises the possibility that light/moderate drinking may be associated with a reduced prevalence of both depression and anxiety. Any causal interpretation of this association is difficult in the context of this cross-sectional study and further longitudinal studies are needed. PMID- 24156881 TI - High resistance of the mechanical properties of the chondrocyte pericellular matrix to proteoglycan digestion by chondroitinase, aggrecanase, or hyaluronidase. AB - In articular cartilage, the extracellular matrix (ECM) and chondrocyte-associated pericellular matrix (PCM) are characterized by a high concentration of proteoglycans (PGs) and their associated glycosaminoglycans (GAGs). These molecules serve important biochemical, structural, and biomechanical roles in the tissue and differences in their regional distributions suggest that different GAG/PG species contribute to the specific biomechanical properties of the ECM and PCM. The objective of this study was to investigate region-specific contributions of aggrecan, chondroitin and dermatan sulfate, and hyaluronan to the micromechanical properties of articular cartilage PCM and ECM in situ. Cryosections of porcine cartilage underwent digestion with ADAMTS-4, chondroitinase ABC, bacterial hyaluronidase or human leukocyte elastase. Guided by immunofluorescence for type VI collagen, AFM stiffness mapping was used to evaluate the elastic properties of matched PCM and ECM regions in paired control and digested cartilage sections. These methods were used to test the hypotheses that specific enzymatic digestion of GAGs or PGs would reduce both PCM and ECM elastic moduli. Elastase, which digests a number of PGs, some types of collagen, and non-collagenous proteins, was used as a positive control. ECM elastic moduli were significantly reduced by all enzyme treatments. However, PCM micromechanical properties were unaffected by enzymatic digestion of aggrecan, chondroitin/dermatan sulfate, and hyaluronan but were significantly reduced by 24% following elastase digestion. Our results provide new evidence for high resistance of PCM micromechanical properties to PG digestion and suggest a potential role for elastase in the degradation of the ECM and PCM. PMID- 24156884 TI - Reasons for Brazilian women to switch from different contraceptives to long acting reversible contraceptives. AB - OBJECTIVES: Long-acting reversible contraceptives (LARCs) include the copper releasing intrauterine device (IUD), the levonorgestrel-releasing intrauterine system (LNG-IUS) and implants. Despite the high contraceptive efficacy of LARCs, their prevalence of use remains low in many countries. The objective of this study was to assess the main reasons for switching from contraceptive methods requiring daily or monthly compliance to LARC methods within a Brazilian cohort. STUDY DESIGN: Women of 18-50 years of age using different contraceptives and wishing to switch to a LARC method answered a questionnaire regarding their motivations for switching from their current contraceptive. Continuation rates were evaluated 1 year after method initiation. Sample size was calculated at 1040 women. Clinical performance was evaluated by life table analysis. The cutoff date for analysis was May 23, 2013. RESULTS: Overall, 1167 women were interviewed; however, after 1 year of use, the medical records of only 1154 women were available for review. The main personal reason for switching, as reported by the women, was "fear of becoming pregnant" while the main medical reasons were nausea and vomiting and unscheduled bleeding. No pregnancies occurred during LARC use, and the main reasons for discontinuation were expulsion (in the case of the IUD and LNG-IUS) and a decision to undergo surgical sterilization (in the case of the etonogestrel-releasing implant). Continuation rate was ~95.0/100 women/year for the three methods. CONCLUSIONS: Most women chose a LARC method for its safety and for practical reasons, and after 1 year of use, most women continued with the method. PMID- 24156882 TI - Variability in the prevalence of adult ADHD in treatment seeking substance use disorder patients: results from an international multi-center study exploring DSM IV and DSM-5 criteria. AB - BACKGROUND: Available studies vary in their estimated prevalence of attention deficit/hyperactivity disorder (ADHD) in substance use disorder (SUD) patients, ranging from 2 to 83%. A better understanding of the possible reasons for this variability and the effect of the change from DSM-IV to DSM-5 is needed. METHODS: A two stage international multi-center, cross-sectional study in 10 countries, among patients form inpatient and outpatient addiction treatment centers for alcohol and/or drug use disorder patients. A total of 3558 treatment seeking SUD patients were screened for adult ADHD. A subsample of 1276 subjects, both screen positive and screen negative patients, participated in a structured diagnostic interview. RESULTS: Prevalence of DSM-IV and DSM-5 adult ADHD varied for DSM-IV from 5.4% (CI 95%: 2.4-8.3) for Hungary to 31.3% (CI 95%:25.2-37.5) for Norway and for DSM-5 from 7.6% (CI 95%: 4.1-11.1) for Hungary to 32.6% (CI 95%: 26.4 38.8) for Norway. Using the same assessment procedures in all countries and centers resulted in substantial reduction of the variability in the prevalence of adult ADHD reported in previous studies among SUD patients (2-83%->5.4-31.3%). The remaining variability was partly explained by primary substance of abuse and by country (Nordic versus non-Nordic countries). Prevalence estimates for DSM-5 were slightly higher than for DSM-IV. CONCLUSIONS: Given the generally high prevalence of adult ADHD, all treatment seeking SUD patients should be screened and, after a confirmed diagnosis, treated for ADHD since the literature indicates poor prognoses of SUD in treatment seeking SUD patients with ADHD. PMID- 24156885 TI - Does an intraabdominally placed LNG-IUS have an adverse effect on fertility? A case report. AB - This case of secondary infertility with an associated intraabdominal levonorgestrel intrauterine system (LNG-IUS) demonstrates the importance of adequate imaging in women with a missing intrauterine contraceptive device and the possible fertility implications of an extrauterine LNG-IUS. PMID- 24156886 TI - Acute pediatric facial nerve paralysis as the first indication for familial cerebral cavernoma: case presentation and literature review. AB - Familial cerebral cavernoma is an autosomal dominant phenotype with incomplete clinical and neuroimaging penetrance. The most common clinical manifestations include seizures and cerebral hemorrhage. We present the case of a 7-year-old boy who developed acute onset facial nerve paralysis secondary to previously unknown familial cerebral cavernoma. Genetic workup revealed a KRIT1 gene deletion which was later confirmed in the patient's asymptomatic father and younger brother. PMID- 24156887 TI - [Intravenous regional anesthesia with long-acting local anesthetics. An update]. AB - Intravenous regional anesthesia is a widely used technique for brief surgical interventions, primarily on the upper limbs and less frequently, on the lower limbs. It began being used at the beginning of the 20th century, when Bier injected procaine as a local anesthetic. The technique to accomplish anesthesia has not changed much since then, although different drugs, particularly long acting local anesthetics, such as ropivacaine and levobupivacaine in low concentrations, were introduced. Additionally, drugs like opioids, muscle relaxants, paracetamol, neostigmine, magnesium, ketamine, clonidine, and ketorolac, have all been investigated as adjuncts to intravenous regional anesthesia, and were found to be fairly useful in terms of an increased onset of operative anesthesia and longer lasting perioperative analgesia. The present article provides an overview of current knowledge with emphasis on long-acting local anesthetic drugs. PMID- 24156888 TI - [Rare problem with the insertion of a SupremeTM laryngeal mask airway device. Case of the trimester]. AB - A breast tumor was resected under general anesthesia. After induction, the airway was managed with a SupremeTM laryngeal mask airway device. The insertion of the laryngeal mask airway device, the insertion of the orogastric tube through the drain tube, as well as the mechanical ventilation, were very difficult from the beginning. On removing the laryngeal mask airway device to solve the problem, it was observed that the drain tube was broken, and the orogastric tube had passed into the anterior, laryngeal part of the device through the split. It was later found out that the laryngeal mask airway device, as well as the whole manufacturing batch, had suffered a design modification: the cuff was constructed with a softer material without reinforcement in the tip, and the drain tube had a heat-sealing defect that facilitated the break. The incident was reported to the local supplier and the manufacturer, and the defective batch of laryngeal mask airway devices was recalled. The incident was also reported to other hospitals via SENSAR, to warn other users of the potential dangers of the design modification in the SupremeTM laryngeal mask airway. PMID- 24156889 TI - The challenge of HIV associated neurocognitive disorder. PMID- 24156890 TI - Corticosteroids for prevention of tuberculosis mortality. PMID- 24156891 TI - Corticosteroids for prevention of tuberculosis mortality. PMID- 24156892 TI - Corticosteroids for prevention of tuberculosis mortality. PMID- 24156893 TI - Corticosteroids for prevention of tuberculosis mortality - Authors' reply. PMID- 24156894 TI - Adjunctive treatment of severe sepsis. PMID- 24156895 TI - Nomenclature of drug-resistant tuberculosis. PMID- 24156896 TI - Rapid diagnostic tests for neurosyphilis. PMID- 24156897 TI - Metabolic disease in HIV infection. AB - The treatment of metabolic disease is becoming an increasingly important component of the long-term management of patients with well controlled HIV on antiretroviral therapy (ART). Metabolic diseases probably develop at the intersection of traditional risk factors (such as obesity, tobacco use, and genetic predisposition) and HIV-specific and ART-specific contributors (including chronic inflammation and immune activation). This Review discusses present knowledge on adipose tissue dysfunction, insulin-glucose homoeostasis, lipid disturbances, and cardiovascular disease risk in people with HIV on ART. Although new antiretroviral drugs are believed to induce fewer short-term metabolic perturbations than do older drugs, the long-term effects of these drugs are not fully understood. Additionally, patients remain at increased risk of cardiovascular disease and other metabolic comorbidities. Research and treatment should focus on selection of ART that is both virologically effective and has minimum metabolic effects, minimisation of traditional risk factors for metabolic disease, and development of novel therapies to treat metabolic disease in patients with HIV, including use of anti-inflammatory and immunomodulatory drugs. PMID- 24156899 TI - Hepatic brucelloma. AB - We present a case of hepatic abscess caused by Brucella melitensis (or hepatic brucelloma) diagnosed in a 59-year-old man 33 years after an episode of acute brucellosis that had completely resolved. Recovery from symptoms and a decrease in lesion size seen on radiological assessment were achieved through prolonged combined antibiotic therapy, without the need for surgery. Hepatic brucelloma is a rare complication of brucellosis, which is the most common zoonosis globally, mainly occurring in specific endemic areas and causing a range of clinical manifestations. In this Grand Round, we review the clinical manifestations, diagnostic approach (through laboratory, radiology, and histology findings), differential diagnosis, treatment, and prognosis of hepatic brucelloma. PMID- 24156900 TI - Ocular syphilis characterised by severe scleritis in a patient infected with HIV. PMID- 24156898 TI - HIV-associated neurocognitive disorder. AB - Neurological involvement in HIV is often associated with cognitive impairment. Although severe and progressive neurocognitive impairment has become rare in HIV clinics in the era of potent antiretroviral therapy, most patients with HIV worldwide have poor outcomes on formal neurocognitive tests. In this Review, we describe the manifestations of HIV-associated neurocognitive disorder in the era of effective HIV therapy, outline diagnosis and treatment recommendations, and explore the research questions that remain. Although comorbid disorders, such as hepatitis C infection or epilepsy, might cause some impairment, their prevalence is insufficient to explain the frequency with which it is encountered. HIV disease markers, such as viral load and CD4 cell counts, are not strongly associated with ongoing impairment on treatment, whereas cardiovascular disease markers and inflammatory markers are. New cerebrospinal fluid and neuroimaging biomarkers are needed to detect and follow impairment. Ongoing research efforts to optimise HIV therapy within the CNS, and potentially to intervene in downstream mechanisms of neurotoxicity, remain important avenues for future investigation. Ultimately, the full control of virus in the brain is a necessary step in the goal of HIV eradication. PMID- 24156902 TI - Madness and crime: historical perspectives on forensic psychiatry. PMID- 24156903 TI - Choking, asphyxiation and the insular seizure. AB - The insular cortex is located deep within the Sylvian fissure, and has rich connections. We describe two patients with focal epilepsy arising from this area, with symptoms of choking and strangulation during consciousness. Clinicians should be aware of this unusual presentation and that interictal electroencephalography can be normal. PMID- 24156901 TI - Striatal abnormalities and spontaneous dyskinesias in non-clinical psychosis. AB - BACKGROUND: Accumulating evidence suggests that individuals experiencing non clinical psychosis (NCP) represent a critical group for improving understanding of etiological factors underlying the broader psychosis continuum. Although a wealth of evidence supports widespread neural dysfunction in formal psychosis, there has been little empirical evidence to inform our understanding of putative vulnerability markers or brain structure in NCP. In this study, we examined the neural correlates of spontaneous movement abnormalities, a biomarker previously detected in NCP that is linked to abnormalities in the striatal dopamine. METHODS: We screened a total of 1285 adolescents/young adults, and those scoring in the upper 15th percentile on a NCP scale were invited to participate; 20 of those invited agreed and these individuals were matched with healthy controls. Participants were administered a structural scan, clinical interviews, and an instrumental motor assessment. RESULTS: The NCP group showed elevated force variability and smaller putamen (but not caudate), and there was a significant relationship between motor dysfunction and striatal abnormalities for the sample. Elevated force variability was associated with both higher positive and negative symptoms, and there was a strong trend (p=.06) to suggest that smaller left putamen volumes were associated with elevated positive symptoms. CONCLUSIONS: The results are among the first to suggest an association between neural structure and a risk marker in NCP. Findings indicate that vulnerabilities seen in schizophrenia also characterize the lower end of the psychosis spectrum. PMID- 24156904 TI - Fusiform aneurysms of the lenticulostriate artery. AB - Lenticulostriate artery aneurysms are rare, can be difficult to diagnoze, and when they rupture they are often associated with deep intraparenchymal hemorrhages. In particular, fusiform, dissecting aneurysms of a distal lenticulostriate artery are extremely rare. Typically, they are usually associated with underlying systemic conditions such as systemic lupus erythematosus, moyamoya disease, and substance abuse. Given their usual small size and location, these aneurysms may be difficult to detect with angiography and can be challenging to treat with either endovascular or microsurgical techniques. We provide background information, review the existing treatment experiences reported in the literature, and present a discussion regarding the optimal management using an illustrative clinical vignette. Parent artery obliteration can be a safe and effective treatment in these rare aneurysms. PMID- 24156905 TI - Acute branch occlusion after Pipeline embolization of intracranial aneurysms. AB - Flow-diverters are used in the treatment of large and complex intracranial aneurysms. One major concern with this concept is the potential for compromise of side branches and perforators covered by the device. We describe three patients treated with the Pipeline embolization device (PED; ev3 Endovascular, Plymouth, MN, USA) who developed immediate compromise of flow into an eloquent side branch covered by the device. Three patients, two with giant posterior circulation aneurysms and one with recurrence of a previously clipped and subsequently coiled middle cerebral artery aneurysm, were each treated by placement of a single PED. Shortly after placement of the devices, despite adequate antiplatelet and anticoagulation regimens, partial or complete occlusion of a major side branch occurred. In all three patients, the occlusion was promptly reversed with intra arterial administration of abciximab with no clinical sequelae. These cases are concerning because branch occlusion occurred even in the setting of patients appropriately premedicated with dual antiplatelet therapy and in whom genetic testing suggested clopidogrel responsiveness. Close monitoring of patients treated with these devices is critical to establish the frequency of this and other unanticipated complications. PMID- 24156906 TI - Vertebral artery dissection after neck extension in an adult patient with Klippel Feil syndrome. AB - The association between Klippel-Feil syndrome and vertebral artery dissection is quite rare. We report an adult patient with vertebral artery dissection and Klippel-Feil syndrome, to our knowledge only the third reported case of its kind. A 45-year-old woman with a known history of Klippel-Feil syndrome presented with occipital head and neck pain following forced neck extension. Diagnostic cerebral angiography revealed a high grade vertebral artery stenosis, consistent with vertebral artery dissection. Following 6 months of medical management, a repeat diagnostic angiogram revealed complete healing of the vessel. While cervical fusion, as seen in Klippel-Feil syndrome, has previously been shown to cause neurologic injury secondary to hypermobility, the association with vertebral artery dissection is incredibly rare. We hypothesize that this hypermobility places abnormal shear force on the vessel, causing intimal injury and dissection. Patients with seemingly spontaneous vertebral artery dissection may benefit from cervical spine radiography, and this predisposition to cerebrovascular injury strongly suggests further evaluation of vascular injury following trauma in patients with Klippel-Feil syndrome or other cervical fusion as clinically warranted. PMID- 24156907 TI - Reducing post-lumbar puncture headaches with small bore atraumatic needles. AB - Lumbar puncture for testing of Alzheimer's disease pathophysiology for diagnostic confirmation is likely to become more common in the coming years. Minimizing adverse effects from this testing will be essential for clinical practice. Small bore, atraumatic needles reduce the occurrence of post-lumbar puncture headache (PLPH). Our goal was to extend this recommendation specifically to a well characterized aging population. We assessed PLPH in the Alzheimer's Disease Neuroimaging Initiative cohort and found that PLPH occurrence was reduced only when using a 24 gauge atraumatic needle. We recommend that lumbar punctures for clinical and research purposes in Alzheimer's disease be conducted with 24 gauge atraumatic needles. PMID- 24156908 TI - Relationship between dimensions of muscles of mastication (masseter and lateral pterygoid) and skeletal dimensions: study of 40 cases. AB - INTRODUCTION: The masticatory muscles play an important part in determining the morphology of the facial skeleton. Skeletal typology and the characteristics of the masticatory muscles are closely linked. Several authors have studied muscle characteristics as related to facial typology. The aim of this work is to study the relationship between vertical and transverse skeletal dimensions and the dimensions (length, width and thickness) of two muscles of mastication, the masseter and the lateral pterygoid. MATERIALS AND METHOD: Our study was based on CT-scan examinations of a sample composed of patients consulting the X-ray department of the Rabat-Sale Teaching Hospital, and for whom a CT-scan had been requested. Forty CT examinations of the skull, performed in the context of sinus explorations or pre-surgical work-ups in the radiology department of the Rabat Sale Teaching Hospital, were selected for this study. The sample comprised 19 women and 21 men aged between 20 and 45, with a mean of 40.9 +/- 12.8. A Siemens 32-row 64-slice spiral CT-scan device was used for spiral acquisition of data around the facial bones, with the mouth closed. The study was carried out in the parenchymal window for the muscle measurements, in the axial and coronal planes. Bone measurements were performed after 3D reconstruction in VRT mode. RESULTS: Our study showed that, for the masseter muscle, thickness is the dimension that correlates significantly with skeletal dimensions in the vertical, transverse and sagittal directions. For the lateral pterygoid muscle, length and width both present significant correlations with transverse skeletal dimensions. Analysis of these results shows that the dimensional characteristics of the masticatory muscles vary according to the vertical and transverse skeletal typology of the subjects concerned. PMID- 24156909 TI - European College of Orthodontics: Commission of Affiliation and Titularisation. AB - Date of birth: 26/08/1994; sex: male. A. PRETREATMENT RECORDS: (01/2006; 11 years 4 months). DIAGNOSIS: Skeletal and dental Class I combined with narrow maxillary dental base and anterior open bite in a normal face pattern and short face typology. TREATMENT: Maxillary disjunction, then bimaxillary multi-bracket appliance and speech therapy. B. POST-TREATMENT RECORDS: (07/2008; 13 years 10 months). RETENTION: Lingual archwire bonded from 33 to 43 with tooth positioner then Hawley maxillary retainer at night. C. POST-RETENTION RECORDS: (11/2009; 15 years 3 months). PMID- 24156912 TI - Association mapping of the PARK10 region for Parkinson's disease susceptibility genes. AB - BACKGROUND: Previous studies indicate that as many as six genes within the PARK10 region (RNF11, UQCRH, HIVEP3, EIF2B3, USP24, ELAVL4) might modify susceptibility or age at onset in Parkinson's disease (PD). METHODS: We sought to identify new PD susceptibility genes and to validate previously nominated candidate genes within the PARK10 region using a two-stage design. We used data from a large, publicly-available genome-wide association study (GWAS) in the discovery stage (n = 2000 cases and 1986 controls) and data from three independent studies for the replication stage (total n = 2113 cases and 2095 controls). Marker density was increased by imputation using HapMap 3 and 1000 Genomes reference panels, and over 40,000 single nucleotide polymorphisms (SNPs) were used in the final analysis. The association between each SNP and PD was modeled using logistic regression with an additive allele dosage effect and adjusted for sex, age, and axes of geographical variation. RESULTS: Although the discovery stage yielded promising findings for SNPs in several novel genes, including DAB1, none of the results were validated in the replication stage. Furthermore, in meta-analyses across all datasets no genes within PARK10 reached significance after accounting for multiple testing. CONCLUSION: Our results suggest that common variation in the PARK10 region is not associated with PD risk. However, additional studies are needed to assess the role of PARK10 in modifying age at onset and to determine whether rare variants in this region might affect PD susceptibility. PMID- 24156913 TI - In vitro analysis of flufenamic acid activity against Candida albicans biofilms. AB - In a recent high-throughput screen against specific Candida albicans drug targets, several compounds that exhibited non-specific antifungal activity were identified, including the non-steroidal anti-inflammatory drug flufenamic acid (FFA). This study sought to determine the effect of different doses of FFA, alone or in combination with fixed concentrations of the standard antifungal agents amphotericin B (AmB), caspofungin (CAS) or fluconazole (FLU), for the prevention and treatment of C. albicans biofilms. Biofilms were formed in a 96-well microplate followed by evaluation of antifungal activity using the XTT assay. FFA concentrations of >=512mg/L demonstrated >80% prevention of biofilm formation. FFA concentrations of 1024mg/L demonstrated >85% reduction of mature biofilms. When FFA (>=8mg/L) was used in combination with FLU (32mg/L), antifungal activity increased to 99% for the prevention of biofilm formation. Similarly, when a FFA concentration of >=8mg/L was used in combination with either AmB (0.25mg/L) or CAS (0.125mg/L), antifungal activity also increased up to 99% for the prevention of biofilm formation. The inhibitory effect of FFA on C. albicans biofilms has not been reported previously, therefore these findings suggest that FFA in combination with traditional antifungals might be useful for the treatment and prevention of C. albicans biofilms. PMID- 24156914 TI - Pathogenesis and clinical implications of optic disk hemorrhage in glaucoma. AB - The association between optic disk hemorrhage and glaucoma has been studied for many years. Recently, randomized clinical trials have confirmed that disk hemorrhage is a risk factor for development and progression of glaucoma. Disk hemorrhage is more commonly detected in open-angle glaucoma with normal tension than in open-angle glaucoma with high tension. Development of disk hemorrhage possibly is associated with the biomechanical properties of the lamina cribrosa and surrounding tissues, including the intraocular pressure (IOP)-cerebrospinal pressure gradient, arterial pressure, and venous pressure. Disk hemorrhage may be a marker of rapid glaucoma progression, in that localized subclinical structural change predisposes to disk hemorrhage, after which subsequent disease progression is accelerated, and recurrent optic disk hemorrhages are related to rapid structural progression of glaucomatous damage. IOP-lowering therapy can be helpful in halting post-hemorrhage glaucoma progression. PMID- 24156915 TI - Trunk neuromuscular responses to a single whole-body vibration session in patients with chronic low back pain: a cross-sectional study. AB - OBJECTIVE: Whole-body vibration (WBV) exercise is progressively adopted as an alternative therapeutic modality for enhancing muscle force and muscle activity via neurogenic potentiation. So far, possible changes in the recruitment patterns of the trunk musculature after WBV remain undetermined. The main objective of this study was to evaluate the short-term effects of a single WBV session on trunk neuromuscular responses in patients with chronic low back pain (cLBP) and healthy participants. METHODS: Twenty patients with cLBP and 21 healthy participants performed 10 trunk flexion-extensions before and after a single WBV session consisting of five 1-minute vibration sets. Surface electromyography (EMG) of erector spinae at L2-L3 and L4-L5 and lumbopelvic kinematic variables were collected during the trials. Data were analyzed using 2-way mixed analysis of variance models. RESULTS: The WBV session led to increased lumbar EMG activity during the flexion and extension phases but yielded no change in the quiet standing and fully flexed phases. Kinematic data showed a decreased contribution to the movement of the lumbar region in the second extension quartile. These effects were not different between patients with cLBP and healthy participants. CONCLUSIONS: Increased lumbar EMG activity after a single WBV session most probably results from potentiation effects of WBV on lumbar muscles reflex responses. Decreased EMG activity in full trunk flexion, usually observed in healthy individuals, was still present after WBV, suggesting that the ability of the spine stabilizing mechanisms to transfer the extension torque from muscles to passive structures was not affected. PMID- 24156916 TI - MicroRNA or NMD: why have two RNA silencing systems? AB - MicroRNA (miRNA)-mediated RNA silencing and nonsense-mediated decay (NMD) are two conserved RNA-level regulatory pathways. Although they are mechanically different, both can regulate target genes by RNA degradation and translational repression. Moreover, studies of individual target genes indicated that these two pathways can be involved in the same processes (e.g., development and stress responses). These facts raise an important question that whether these two systems are cooperative, interchangeable or optimal for regulation of different sorts of genes. We addressed this by comparing miRNA and NMD targets in Arabidopsis thaliana at the genome-wide scale. We find no more overlap in the genes targeted by both systems than expected by chance. Moreover, the sorts of genes or pathways regulated by these systems are categorically different on several cross-correlating fronts. While miRNA targets show enrichment in the process of development, metabolism and transcription, NMD targets are associated with stress responses but otherwise poorly annotated. Validated miRNA targets are more highly expressed, less variably expressed and slower evolving. These differences suggest that the modes of regulation need not be interchangeable. Instead, we suggest that miRNA genes are commonly dose-sensitive and require fine control of levels through weak pull-down by miRNAs. This is consistent with miRNA regulated genes being more likely to be involved in protein-protein interactions. Many NMD-regulated genes, by contrast, have properties consistent with them being rapid emergency response "fire-fighter" genes. If true, the lack of annotation of NMD targets suggests that we poorly understand the emergencies plants face in the wild. PMID- 24156918 TI - Generation and characterization of a transgenic zebrafish expressing the reverse tetracycline transactivator. AB - Conditional expression of a target gene during zebrafish development is a powerful approach to elucidate gene functions. The tetracycline-controlled systems have been successfully used in the modulation of gene expression in mammalian cells, but few lines of zebrafish carrying these systems are currently available. In this study, we had generated a stable transgenic zebrafish line that ubiquitously expressed the second-generation of reverse Tet transactivator (rtTA-M2). Southern blotting analysis and high-throughput genome sequencing verified that a single copy of rtTA-M2 gene had stably integrated into the zebrafish genome. After induction with doxycycline (Dox), a strong green fluorescent protein (GFP) was seen in rtTA-transgenic eggs injected with pTRE EGFP plasmids. The fluorescent signal gradually decreased after the withdrawal of Dox and disappeared. However, leaky expression of GFP was undetectable before Dox induction. Additionally, transgenic embryos expressing rtTA-M2 exhibited no obvious defects in morphological phenotypes, hatching behavior and expression patterns of developmental marker genes, suggesting that rtTA-M2 had little effect on the development of transgenic zebrafish. Moreover, expressed Dickkopf-1 (DKK1) in pTRE-DKK1-injected embryos led to alterations in the expression of marker genes associated with Wnt signaling. Thus, this rtTA-transgenic zebrafish can be utilized to dissect functions of genes in a temporal manner. PMID- 24156917 TI - Nodal promotes mir206 expression to control convergence and extension movements during zebrafish gastrulation. AB - Nodal, a member of the transforming growth factor beta (TGF-beta) superfamily, has been shown to play a role in mesendoderm induction and gastrulation movements. The activity of Nodal signaling can be modulated by microRNAs (miRNAs) as previously reported, but little is known about which miRNAs are regulated by Nodal during gastrulation. In the present study, we found that the expression of mir206, one of the most abundant miRNAs during zebrafish early embryo development, is regulated by Nodal signaling. Abrogation of Nodal signal activity results in defective convergence and extension (CE) movements, and these cell migration defects can be rescued by supplying an excess of mir206, suggesting that mir206 acts downstream of Nodal signaling to regulate CE movements. Furthermore, in mir206 morphants, the expression of cell adhesion molecule E cadherin is significantly increased, while the key transcriptional repressor of E cadherin, snail1a, is depressed. Our study uncovers a novel mechanism by which Nodal-regulated mir206 modulates gastrulation movements in connection with the Snail/E-cadherin pathway. PMID- 24156919 TI - Knockouts of RecA-like proteins RadC1 and RadC2 have distinct responses to DNA damage agents in Sulfolobus islandicus. AB - RecA family recombinases play essential roles in maintaining genome integrity. A group of RecA-like proteins named RadC are present in all archaea, but their in vivo functions remain unclear. In this study, we performed phylogenetic and genetic analysis of two RadC proteins from Sulfolobus islandicus. RadC is closer to the KaiC lineage of cyanobacteria and proteobacteria than to the lineage of the recombinases (RecA, RadA, and Rad51) and the recombinase paralogs (e.g., RadB, Rad55, and Rad51B). Using the recently-established S. islandicus genetic system, we constructed deletion and over-expression strains of radC1 and radC2. Deletion of radC1 rendered the cells more sensitive to DNA damaging agents, methyl methanesulfonate (MMS), hydroxyurea (HU), and ultraviolet (UV) radiation, than the wild type, and a DeltaradC1DeltaradC2 double deletion strain was more sensitive to cisplatin and MMS than the DeltaradC1 single deletion mutant. In addition, ectopic expression of His-tagged RadC1 revealed that RadC1 was co purified with a putative structure-specific nuclease and ATPase, which is highly conserved in archaea. Our results indicate that both RadC1 and RadC2 are involved in DNA repair. RadC1 may play a general or primary role in DNA repair, while RadC2 plays a role in DNA repair in response to specific DNA damages. PMID- 24156920 TI - Positive selection of CAG repeats of the ATXN2 gene in Chinese ethnic groups. PMID- 24156921 TI - Haemophilus influenzae type b (Hib) Vaccination WHO position paper: July 2013 Recommendations. AB - This article presents the World Health Organizations (WHO) evidence and recommendations for the use of Haemophilus influenzae type b vaccination from the WHO position paper on H. influenzae type b (Hib) Vaccination - July 2013 recently published in the Weekly Epidemiological Record [1]. This position paper summarizes the WHO position on the inclusion of Hib vaccines in all national immunization programmes, recent developments in the field and the potential of different Hib immunization schedules to further reduce morbidity and mortality. The current document replaces the position paper on the use of Hib vaccines published in 2006 [2]. Footnotes to this paper provide a number of core references. In accordance with its mandate to provide guidance to Member States on health policy matters, WHO issues a series of regularly updated position papers on vaccines and combinations of vaccines against diseases that have an international public health impact. These papers are concerned primarily with the use of vaccines in large-scale immunization programmes; they summarize essential background information on diseases and vaccines, and conclude with WHO's current position on the use of vaccines in the global context. This paper reflects the recommendations of WHO's Strategic Advisory Group of Experts (SAGE) on immunization. These recommendations were discussed by SAGE at its April 2013 meeting. Evidence presented at the meeting can be accessed at http://www.who.int/immunization/sage/previous/en/index.html. PMID- 24156922 TI - Binding and cleavage (BINACLE) assay for the functional in vitro detection of tetanus toxin: applicability as alternative method for the safety testing of tetanus toxoids during vaccine production. AB - Tetanus toxoids (i.e. chemically inactivated preparations of tetanus neurotoxin) are used for the production of tetanus vaccines. In order to exclude the risk of residual toxicity or of a "reversion to toxicity", each batch of tetanus toxoid is subject to strict safety testing. Up to now, these prescribed safety tests have to be performed as in vivo toxicity tests in guinea pigs. However, as animal tests are generally slow, costly and ethically disputable, a replacement by an in vitro method would be desirable. A suitable alternative method would have to be able to sensitively detect already low concentrations of active tetanus neurotoxin in matrices containing large amounts of inactivated toxoid molecules. We have developed a method which detects active tetanus neurotoxin molecules based on their specific receptor-binding capacity as well as their proteolytic activity. By taking into account two relevant functional characteristics, this combined "BINding And CLEavage" (BINACLE) assay more reliably discriminates between toxic and detoxified molecules than other in vitro assays which solely rely on one single toxin function (e.g. endopeptidase assays). Data from an in house validation show that the BINACLE assay is able to detect active tetanus neurotoxin with a detection limit comparable to the in vivo test. The sensitive detection of active toxin which has been spiked into toxoid samples from different manufacturers could also be demonstrated. Specificity and precision of the method have been shown to be satisfactory. The presented data indicate that for toxoid batches from some of the most relevant European vaccine manufacturers, the BINACLE assay may represent a potential alternative to the prescribed animal safety tests. In addition, this novel method may also provide a convenient tool for monitoring batch-to-batch consistency during toxoid production. PMID- 24156923 TI - Haemophilic arthropathy: long-term outcomes in 107 primary total knee arthroplasties. AB - BACKGROUND: Arthropathy of the knee is a frequent complication in patients with severe bleeding disorders leading to considerable pain and disability. Total knee arthroplasty (TKA) provides marked pain relief. However, a modest functional outcome and a high number of complications due to prosthetic infection and loosening are reported. Data on long-term outcomes are scarce, and most case series include few patients. We have studied clinical outcomes and complications of TKAs with special emphasis on prosthetic survival and periprosthetic infection. METHODS: A consecutive series of 107 TKAs in 74 patients with haemophilic arthropathy were retrospectively reviewed. Follow-up was mean 11.2 years (range 0.8-33.1 years). RESULTS: Five- and 10-year survival rates, with component removal for any reason as the end point, were 92% and 88%, respectively. Twenty-eight TKAs were removed after median 10 years (range 0.8-28 years). The most common cause of failure was aseptic loosening (14 knees) and periprosthetic infection (seven knees). The overall infection rate was 6.5%. The mean postoperative drop in haemoglobin levels was 4.3 g/dL (range 0.5-9.4) with a significant difference between haemophilia A patients with and without inhibitor (6.3 g/dL (range 3.6-9.4) versus 3.7 g/dL (range 0.5-8.1) (p<0.001). A painless knee was reported in 93% of the TKAs at the latest follow-up. CONCLUSIONS: The medium and long-term results of primary TKA in a large haemophilic population show good prosthetic survival at five and 10 years with an excellent relief of pain. Periprosthetic infection is still a major concern compared to the non haemophilic population. LEVEL OF EVIDENCE: Level IV. PMID- 24156924 TI - The double flipped meniscus sign: unusual MRI findings in bucket-handle tear of the lateral meniscus. AB - Bucket-handle meniscal tears are either longitudinal, vertical, or oblique in direction with an attached tear fragment displaced from the meniscus. Magnetic resonance imaging (MRI) signs are widely used in the diagnosis of these tears, including the 'fragment within the intercondylar notch sign', 'flipped meniscus sign', 'double anterior horn sign', 'absence of the bow tie sign', 'double posterior cruciate ligament (PCL) sign', 'posterior double PCL sign', and 'triple PCL sign'. We report an unusual case, not yet described in previous studies, of a bucket-handle tear presenting as a double longitudinal tear of the lateral meniscus (LM). Two longitudinal tears were observed in the white-white zone and the red-white zone of the LM, where both fragments were shown to be displaced and locked within the intercondylar notch. Partial menisectomy was performed for the central fragment and a repair with modified all-inside sutures was performed for the peripheral fragment. PMID- 24156925 TI - Outcomes of a culturally responsive health promotion program for elderly Korean survivors of gastrointestinal cancers: a randomized controlled trial. AB - This single-blind, prospective, randomized controlled trial was designed to evaluate the effects of a culturally responsive health promotion program for elderly Korean (CHP-K) survivors of gastrointestinal (GI) cancers. The program consisted of 8 weeks of Qi exercise and face-to-face counseling on physical and psychological factors. A total of 63 Korean GI cancer survivors, aged >=65 years, who had completed their active cancer treatment, were recruited from a cancer center in South Korea. Outcomes included the amount of exercise, body weight, BMI, the Patient Generated Subjective Global Assessment scale, the M.D. Anderson Symptom Inventory, and self-efficacy and self-esteem scales. Repeated measures MANCOVA revealed a significant difference over time between the groups (Wilks' Lambda F1,62 = 5.361, p = 0.007). Univariate RM-ANCOVA for each outcome measure revealed statistically significant differences between groups. These results suggested that the participation in the CHP-K may have enhanced the health of elderly Korean GI cancer survivors. PMID- 24156926 TI - Modulation of fronto-limbic activity by the psychoeducation in euthymic bipolar patients. A functional MRI study. AB - Bipolar disorders (BD) are mainly characterized by emotional and cognitive processing impairment. The cerebral substrate explaining BD impairment and the action mechanisms of therapies are not completely understood, especially for psychosocial interventions. This fMRI study aims at assessing cerebral correlates of euthymic bipolar patients (EBP) before and after psychoeducation therapy. Sixteen EBP and 16 matched healthy subjects (HS) performed a word-face emotional Stroop task in two separate fMRI sessions at 3-month interval. Between fMRI sessions, EBP underwent psychoeducation. Before psychoeducation, the comparison of EBP vs. HS in fMRI data revealed (a) significant decreased activity of cognitive control regions such as bilateral inferior and left superior frontal gyri, right insula, right fusiform gyrus and bilateral occipital gyri and (b) significant increased activity of emotion-related processing regions such as bilateral hippocampus, parahippocampal gyri and the left middle temporal gyrus. After psychoeducation, EBP showed significant clinical improvement, increased activity of inferior frontal gyri and a tendency toward decreased activity of right hippocampus and parahippocampal gyrus. These results suggest that the imbalance between cognitive control and emotion processing systems characterizing BD acute episodes may persist during euthymic periods. Moreover, this imbalance may be improved by psychoeducation, which enhances the cognitive control and modulates emotional fluctuations in EBP. PMID- 24156927 TI - Central European BRCA2 mutation carriers: birth cohort status correlates with onset of breast cancer. AB - BACKGROUND: Mutations in brca1 and 2 genes lead to a significant increase in the lifetime risk of developing breast (BC) and ovarian cancer (OC). There are indications that birth cohort can influence the cancer risk in brca1 mutation carriers. Therefore, we investigated the risks for BC and OC associated with brca2 mutations in a cohort of female mutation carriers of a genetically heterogeneous Central European population. PATIENTS AND METHODS: This study included 246 women in whom a functional mutation in the brca2 gene had been identified at our institution. At the time of analysis, 153 women had developed cancer (142 BC, 9 OC, 2 BC and OC). Risks were estimated using the product limit method. The log rank test was used to compare different strata. RESULTS: After correction for risk-reducing surgeries, the cumulative risk of developing cancer to age 70 was found to be 88% for BC (95% CI 81-95%) and 31% for OC (95% CI 17 45%). Female brca2 mutation carriers born in 1958 or later were at a significantly higher risk of developing BC at a younger age (p<0.001), while no such age cohort-dependent correlation was found for OC. CONCLUSION: The age cohort-dependent early onset in BC in women born after 1958 strongly suggests the importance of exogenous factors such as lifestyle modification while this does not seem to be the case for OC. Female brca2 mutation carriers should be counseled about their age cohort-dependent breast cancer risk. PMID- 24156928 TI - Modeling nonlinearities of ultrasonic waves for fatigue damage characterization: theory, simulation, and experimental validation. AB - A dedicated modeling technique for comprehending nonlinear characteristics of ultrasonic waves traversing in a fatigued medium was developed, based on a retrofitted constitutive relation of the medium by considering the nonlinearities originated from material, fatigue damage, as well as the "breathing" motion of fatigue cracks. Piezoelectric wafers, for exciting and acquiring ultrasonic waves, were integrated in the model. The extracted nonlinearities were calibrated by virtue of an acoustic nonlinearity parameter. The modeling technique was validated experimentally, and the results showed satisfactory consistency in between, both revealing: the developed modeling approach is able to faithfully simulate fatigue crack-incurred nonlinearities manifested in ultrasonic waves; a cumulative growth of the acoustic nonlinearity parameter with increasing wave propagation distance exists; such a parameter acquired via a sensing path is nonlinearly related to the offset distance from the fatigue crack to that sensing path; and neither the incidence angle of the probing wave nor the length of the sensing path impacts on the parameter significantly. This study has yielded a quantitative characterization strategy for fatigue cracks using embeddable piezoelectric sensor networks, facilitating deployment of structural health monitoring which is capable of identifying small-scale damage at an embryo stage and surveilling its growth continuously. PMID- 24156930 TI - Fear not: manipulating sleep might help you forget. AB - Memory storage is not static - updating is often needed. When it comes to traumatic memories, forgetting may be desired. Two innovative studies recently demonstrated that fear memories can be weakened during sleep using odors associated with fear-learning episodes. New strategies along these lines should be carefully considered for treating unwanted fears. PMID- 24156929 TI - Phase-variance optical coherence tomography: a technique for noninvasive angiography. AB - PURPOSE: Phase-variance optical coherence tomography (PV-OCT) provides volumetric imaging of the retinal vasculature without the need for intravenous injection of a fluorophore. We compare images from PV-OCT and fluorescein angiography (FA) for normal individuals and patients with age-related macular degeneration (AMD) and diabetic retinopathy. DESIGN: This is an evaluation of a diagnostic technology. PARTICIPANTS: Four patients underwent comparative retinovascular imaging using FA and PV-OCT. Imaging was performed on 1 normal individual, 1 patient with dry AMD, 1 patient with exudative AMD, and 1 patient with nonproliferative diabetic retinopathy. METHODS: Fluorescein angiography imaging was performed using a Topcon Corp (Tokyo, Japan) (TRC-50IX) camera with a resolution of 1280 (H) * 1024 (V) pixels. The PV-OCT images were generated by software data processing of the entire cross-sectional image from consecutively acquired B-scans. Bulk axial motion was calculated and corrected for each transverse location, reducing the phase noise introduced from eye motion. Phase variance was calculated through the variance of the motion-corrected phase changes acquired within multiple B-scans at the same position. Repeating these calculations over the entire volumetric scan produced a 3-dimensional PV-OCT representation of the vasculature. MAIN OUTCOME MEASURES: Feasibility of rendering retinal and choroidal microvasculature using PV-OCT was compared qualitatively with FA, the current gold standard for retinovascular imaging. RESULTS: Phase-variance OCT noninvasively rendered a 2 dimensional depth color-coded vasculature map of the retinal and choroidal vasculature. The choriocapillaris was imaged with better resolution of microvascular detail using PV-OCT. Areas of geographic atrophy and choroidal neovascularization imaged by FA were depicted by PV-OCT. Regions of capillary nonperfusion from diabetic retinopathy were shown by both imaging techniques; there was not complete correspondence between microaneurysms shown on FA and PV OCT images. CONCLUSIONS: Phase-variance OCT yields high-resolution imaging of the retinal and choroidal microvasculature that compares favorably with FA. PMID- 24156931 TI - Eukaryotic expression vectors containing genes encoding plant proteins for killing of cancer cells. AB - BACKGROUND: Gene therapy has attracted attention for its potential to specifically and efficiently target cancer cells with minimal toxicity to normal cells. At present, it offers a promising direction for the treatment of cancer patients. Numerous vectors have been engineered for the sole purpose of killing cancer cells, and some have successfully suppressed malignant tumours. Many plant proteins have anticancer properties; consequently, genes encoding some of these proteins are being used to design constructs for the inhibition of multiplying cancer cells. RESULTS: Data addressing the function of vectors harbouring genes specifically encoding ricin, saporin, lunasin, linamarase, and tomato thymidine kinase 1 under the control of different promoters are summarised here. Constructs employing genes to encode cytotoxic proteins as well as constructs employing genes of enzymes that convert a nontoxic prodrug into a toxic drug are considered here. CONCLUSION: Generation of eukaryotic expression vectors containing genes encoding plant proteins for killing of cancer cells may permit the broadening of cancer gene therapy strategy, particularly because of the specific mode of action of anticancer plant proteins. PMID- 24156932 TI - Factors that predict the development of bone metastases due to prostate cancer: Recommendations for follow-up and therapeutic options. AB - CONTEXT: Prostate cancer is a public health problem in Spain and in the Western world. Bone involvement, associated to significant morbidity, is practically constant in the advanced stages of the disease. This work aims to review the prognostic factors used in the usual clinical practice that predict the development of bone metastases and to analyze the follow-up and treatment option in these patient profiles. ACQUIRING OF EVIDENCE: We performed a review of the literature on the useful factors in the context of therapy with intention to cure. We included the classical clinical values in the diagnosis (PSA, clinical stage, Gleason score on the biopsy) pathological factors (pT stage, margins, bladder invasion, tumor volume, lymph node involvement) and PSA kinetics in their different contexts and the histological and molecular parameters. SYNTHESIS OF EVIDENCE: The tumor differentiation "Gleason" score and PSA are the most important predictive factors in the prediction of bone metastases in patients with intention to cure. Kinetic factors such as PSA doubling time (TDPSA) < 8 months or PSA > 10 ng/ml in the case of castration-resistant prostate cancer (CPRC), are predictive factors for the development of metastasis. Zoledronic acid and denosumab have demonstrated their effectiveness for the treatment of bone disease in randomized studies. CONCLUSIONS: There are predictive factors within the usual clinical practice that make it possible to recognize the "patient at risk" to develop bone metastatic disease. The currently available treatments, zoledronic acid or denosumab, can help us in the management of the patient at risk of developing metastasis or metastatic patient, increasing the quality of life and decreasing skeletal events. PMID- 24156933 TI - Results of retrograde intrarenal surgery in the treatment of renal stones greater than 2 cm. AB - OBJECTIVE: To analyze the results of retrograde intrarenal surgery (RIRS) in patients with >=2 cm stones treated in our center. MATERIAL AND METHODS: A retrospective review of 106 patients with renal calculi underwent RIRS >=2 cm (period January 2009-December 2011). The procedures were performed under general anesthesia as a source of fragmentation using the holmium laser (30 W Litho Quantasystem) and flexible ureteroscopes (X2 Flex Storz, Olympus P5) through ureteral access sheaths. It discusses demographic variables (age, medical history, antiplatelet or anticoagulant treatment, treatment of urolithiasis, BMI, ASA), treated stones variables (size, number, Hounsfield units, biochemical composition) and intra-and postoperative variables (operative time, number of pulses, hospital stay, complications) with the completion of a descriptive analysis of the same. To define our results we consider success to the complete absence of fragments or residual <5 mm posterior imaging tests. RESULTS: The mean stone size was 2.46 cm treated, being the only stone in 87.7% of cases. The most frequent location was the renal pelvis stones (44%) followed by the lower calyx (39%). The postoperative complication rate was 6.7%, with all of little relevance. The success rate with a single procedure was 79.4% to 94.1% with retreatment. CONCLUSION: RIRS is a valid alternative for the treatment of kidney stones >=2 cm for its high success rate and few complications if performed in specialized centers. PMID- 24156934 TI - Is minimally invasive transanal surgery an alternative for rectal-urinary fistula correction? PMID- 24156935 TI - Sedentarism and overweight as risk factors for the detection of prostate cancer and its aggressivenes. AB - OBJECTIVE: To analyze the influence of sedentary (SE) and overweight (OW) in the risk of prostate cancer detection (CP) and aggressiveness. MATERIAL AND METHOD: We performed prostate biopsy (PB) to 2,408 consecutive male, 5 ARIs untreated, because of elevated serum PSA above 4.0 ng/mL (91%) or suspicious digital rectal examination (9%). In all ultrasound guided PB, 10 cores were obtained plus 2 to 8 additionals, according to age and prostate volume. Physical activity was assessed using a survey (SE vs non-SE) and calculated body mass index (normal vs OW > 25 kg/cm(2)). The tumor aggressiveness was evaluated according to the Gleason score (high grade "HG": Gleason > 7) and D'Amico risk (high risk "HR": T > 3a or PSA > 20 or Gleason score > 7). RESULTS: We found a significant association between SE (52.5%) and OW (72.9%), P < .001. The overall PC detection rate was 35.2%. In men with SE it was 36.7% and non-SE 33.6%, P = .048. The overall rate of AG tumors was 28.3%, 29.2% in men with SE and 27.1 in non-SE, P = .261. The overall rate of AR tumors was 35%, 39.7% in men with SE and 29.4% non-SE, P < .001. CP was detected in 38.1% of men with normal BMI and 34.3% in men with OW, P = .065. HG tumor rates were 18.1% and 31.4% respectively, P < .001 and AR tumor rates were 22.6% and 39.2% respectively, P < .001. Binary logistic regression showed that SE was an independent predictor of CP, OR .791 (95% CI: .625-.989), P = .030. SE and OW were independent predictors of HG: OR .517 (95% CI: .356-.752), P = .001, and OR 1.635 (95% CI: 1070-2497), p = 0.023. SE and OW were also independent predictors of HR: OR .519 (95% CI .349-.771), P = .001, and OR 1.998 (95% CI 1.281-3.115), P = .002. CONCLUSIONS: In men who met criteria for prostate biopsy an association between sedentary and overweight exist. A sedentary lifestyle is associated with increased risk of PC detection while sedentary and overweight were associated with more aggressive tumors. PMID- 24156936 TI - Erectile dysfunction, metabolic syndrome and arterial disease. Clinical pathological relation by carotid ultrasonography. AB - INTRODUCTION: Different studies have shown the relationship between erectile dysfunction, metabolic syndrome and cardiovascular disease. The objective of this study was to evaluate the presence of arteriopathy performing carotid ultrasound in patients with and without erectile dysfunction. MATERIAL AND METHODS: We conducted a case-control study with 44 patients consulting for erectile dysfunction and 20 controls. All subjects completed the IIEF-5 test and we studied the criteria for metabolic syndrome, and a carotid ultrasound to study the intima-media thickness and the presence of atherosclerotic plaques was performed. RESULTS: Mean intima-media thickness was .71mm+/-.21 for the right and of .71+/-.17 for the left carotid in patients with erectile dysfunction. In the control group, the means were .54+/-0.11 and 0.59+/-0.15mm respectively, statistically significant differences (P=.02 and P=.05 respectively). No plaque was found in any control, but in 25% of both carotid arteries of patients with erectile dysfunction (P=.01). As metabolic syndrome, according to the American Heart Association, were diagnosed 52.8% of patients with erectile dysfunction, and 16.7% of controls, and according to the International Diabetes Federation, 52.3% of patients with erectile dysfunction and 25% of controls met diagnostic criteria. In both cases there were significant differences (P<.01 and P=.02 respectively). We found a positive linear correlation between waist circumference and the intima-media thickness in both carotid (P<.05). CONCLUSIONS: Patients with erectile dysfunction may be at increased risk of cardiovascular disease, as determined by the presence of arterial disease in the carotid arteries, which indicates that we should made a more thorough and comprehensive study of patients with erectile dysfunction. PMID- 24156937 TI - Dimethylaminopyridine derivatives of lupane triterpenoids cause mitochondrial disruption and induce the permeability transition. AB - Triterpenoids are a large class of naturally occurring compounds, and some potentially interesting as anticancer agents have been found to target mitochondria. The objective of the present work was to investigate the mechanisms of mitochondrial toxicity induced by novel dimethylaminopyridine (DMAP) derivatives of pentacyclic triterpenes, which were previously shown to inhibit the growth of melanoma cells in vitro. MCF-7, Hs 578T and BJ cell lines, as well as isolated hepatic mitochondria, were used to investigate direct mitochondrial effects. On isolated mitochondrial hepatic fractions, respiratory parameters, mitochondrial transmembrane electric potential, induction of the mitochondrial permeability transition (MPT) pore and ion transport-dependent osmotic swelling were measured. Our results indicate that the DMAP triterpenoid derivatives lead to fragmentation and depolarization of the mitochondrial network in situ, and to inhibition of uncoupled respiration, induction of the permeability transition pore and depolarization of isolated hepatic mitochondria. The results show that mitochondrial toxicity is an important component of the biological interaction of DMAP derivatives, which can explain the effects observed in cancer cells. PMID- 24156938 TI - The 3,7-diazabicyclo[3.3.1]nonane scaffold for subtype selective nicotinic acetylcholine receptor (nAChR) ligands. Part 1: the influence of different hydrogen bond acceptor systems on alkyl and (hetero)aryl substituents. AB - 3,7-Diazabicyclo[3.3.1]nonane is a naturally occurring scaffold interacting with nicotinic acetylcholine receptors (nAChRs). When one nitrogen of the 3,7 diazabicyclo[3.3.1]nonane scaffold was implemented in a carboxamide motif displaying a hydrogen bond acceptor (HBA) functionality, compounds with higher affinities and subtype selectivity for alpha4beta2(*) were obtained. The nature of the HBA system (carboxamide, sulfonamide, urea) had a strong impact on nAChR interaction. High affinity ligands for alpha4beta2(*) possessed small alkyl chains, small un-substituted hetero-aryl groups or para-substituted phenyl ring systems along with a carboxamide group. Electrophysiological responses of selected 3,7-diazabicyclo[3.3.1]nonane derivatives to Xenopus oocytes expressing various nAChR subtypes showed diverse activation profiles. Compounds with strongest agonistic profiles were obtained with small alkyl groups whereas a shift to partial agonism/antagonism was observed for aryl substituents. PMID- 24156942 TI - A mechanistic comparison of the Varkud satellite and hairpin ribozymes. AB - The hairpin and Varkud satellite ribozymes are two members of the class of nucleolytic ribozymes that catalyze cleavage and ligation reactions at a specific site. Cleavage occurs by a transesterification reaction whereby the 2'-O attacks the adjacent phosphorus with departure of the 5'-O to leave a 2',3'-cyclic phosphate. The structures of both ribozymes are now known. Although the sequences and structures of these ribozymes are generally unrelated, the topological organization and the arrangement of the active sites are the same for both. Both mechanistic and structural data indicate that the ribozymes employ general acid base catalysis to accelerate the transesterification reactions, using guanine and adenine nucleobases as the general base and acid, respectively, in the cleavage reactions. As a class, the nucleolytic ribozymes all appear to use general acid base catalysis; guanine nucleobases in particular are very common participants. PMID- 24156943 TI - HDV family of self-cleaving ribozymes. AB - The hepatitis delta virus (HDV) ribozymes are catalytic RNAs capable of cleaving their own sugar-phosphate backbone. The HDV virus possesses the ribozymes in both sense and antisense genomic transcripts, where they are essential for processing during replication. These ribozymes have been the subject of intense biochemical scrutiny and have yielded a wealth of mechanistic insights. In recent years, many HDV-like ribozymes have been identified in nearly all branches of life. The ribozymes are implicated in a variety of biological events, including episodic memory in mammals and retrotransposition in many eukaryotes. Detailed analysis of additional HDV-like ribozyme isolates will likely reveal many more biological functions and provide information about the evolution of this unique RNA. PMID- 24156940 TI - The hammerhead ribozyme: structure, catalysis, and gene regulation. AB - The hammerhead ribozyme has long been considered a prototype for understanding RNA catalysis, but discrepancies between the earlier crystal structures of a minimal hammerhead self-cleaving motif and various biochemical investigations frustrated attempt to understand hammerhead ribozyme catalysis in terms of structure. With the discovery that a tertiary contact distal from the ribozyme's active site greatly enhances its catalytic prowess, and the emergence of new corresponding crystal structures of full-length hammerhead ribozymes, a unified understanding of catalysis in terms of the structure is now possible. A mechanism in which the invariant residue G12 functions as a general base, and the 2'-OH moiety of the invariant G8, itself forming a tertiary base pair with the invariant C3, is the general acid, appears consistent with both the crystal structure and biochemical experimental results. Originally discovered in the context of plant satellite RNA viruses, the hammerhead more recently has been found embedded in the 3'-untranslated region of mature mammalian mRNAs, suggesting additional biological roles in genetic regulation. PMID- 24156944 TI - The structural and functional uniqueness of the glmS ribozyme. AB - The glmS bacterial ribozyme/riboswitch is found in a number of Gram-positive bacteria, many of which are human pathogens. Investigation of the structure and function of the glmS catalyst will aid in the development of artificial agonists/antagonists that might function as novel antibiotics. The glmS ribozyme is mechanistically unique in that it is the first RNA catalyst identified to require a coenzyme, glucosamine-6-phosphate, for RNA self-cleavage. In addition, it is the first riboswitch identified to utilize self-cleavage as a mode of genetic regulation in metabolism. Significant biochemical and biophysical data exist for the glmS ribozyme and aid in mechanistically understanding the importance of RNA and coenzyme structure to function in acid-base catalysis. PMID- 24156946 TI - Preface. Catalytic RNA. PMID- 24156945 TI - The role of snRNAs in spliceosomal catalysis. AB - The spliceosomes, large ribonucleoprotein (RNP) assemblies that remove the intervening sequences from pre-mRNAs, contain a large number of proteins and five small nuclear RNAs (snRNAs). One snRNA, U6, contains highly conserved sequences that are thought to be the functional counterparts of the RNA elements that form the active site of self-splicing group II intron ribozymes. An in vitro assembled, protein-free complex of U6 with U2, the base-pairing partner in the spliceosomal catalytic core, can catalyze a two-step splicing reaction in the absence of all other spliceosomal factors, suggesting that the two snRNAs may form all or a large share of the spliceosomal active site. On the other hand, several spliceosomal proteins are thought to help in the formation of functionally required RNA-RNA interactions in the catalytic core. Whether they also contribute functional groups to the spliceosomal active site, and thus whether the spliceosomes are RNA or RNP enzymes remain uncertain. PMID- 24156941 TI - Bridging the gap between theory and experiment to derive a detailed understanding of hammerhead ribozyme catalysis. AB - Herein we summarize our progress toward the understanding of hammerhead ribozyme (HHR) catalysis through a multiscale simulation strategy. Simulation results collectively paint a picture of HHR catalysis: HHR first folds to form an electronegative active site pocket to recruit a threshold occupation of cationic charges, either a Mg(2+) ion or multiple monovalent cations. Catalytically active conformations that have good in-line fitness are supported by specific metal ion coordination patterns that involve either a bridging Mg(2+) ion or multiple Na(+) ions, one of which is also in a bridging coordination pattern. In the case of a single Mg(2+) ion bound in the active site, the Mg(2+) ion undergoes a migration that is coupled with deprotonation of the nucleophile (C17:O2'). As the reaction proceeds, the Mg(2+) ion stabilizes the accumulating charge of the leaving group and significantly increases the general acid ability of G8:O2'. Further computational mutagenesis simulations suggest that the disruptions due to mutations may severely impact HHR catalysis at different stages of the reaction. Catalytic mechanisms supported by the simulation results are consistent with available structural and biochemical experiments, and together they advance our understanding of HHR catalysis. PMID- 24156947 TI - Rotavirus vaccines: successes and challenges. AB - Since 2006, the availability of two new rotavirus vaccines has raised enthusiasm to consider the eventual control and elimination of severe rotavirus diarrhea through the global use of vaccines. Rotavirus remains the most severe cause of acute diarrhea in children worldwide responsible for several hundred thousands of deaths in low income countries and up to half of hospital admissions for diarrhea around the world. The new vaccines have been recommended by WHO for all infants and in more than 47 countries, their introduction into routine childhood immunization programs has led to a remarkable decline in hospital admissions and even deaths within 3 years of introduction. Challenges remain with issues of vaccine finance globally and the problem that these live oral vaccines perform less well in low income settings where they are needed most. Ongoing research that will accompany vaccine introduction might help address these issues of efficacy and new vaccines and novel financing schemes may both help make these vaccines universally available and affordable in the decade. PMID- 24156948 TI - Gypsum scaling in pressure retarded osmosis: experiments, mechanisms and implications. AB - Pressure retarded osmosis (PRO) is an osmotically-driven membrane process that can be used to harvest salinity-gradient power. The PRO performance (both water flux and power density) can be severely limited by membrane fouling. The current study, for the first time, investigates PRO scaling in a bench-scale pressurized system using calcium sulfate dihydrate (gypsum) as a model scalant. In addition to the bulk feed solution (FS) saturation index (SI bulk), gypsum scaling was found to be strongly affected by the draw solution (DS) type and concentration, the applied hydraulic pressure, and the membrane orientation. The commonly recommended active layer facing draw solution (AL-DS) orientation was highly prone to internal scaling. In this orientation, severe internal concentration polarization (ICP) of scaling precursors induced gypsum clogging in membrane support layer even when the FS was undersaturated (e.g., SI bulk = 0.8). At higher SI bulk values, external gypsum crystal deposition occurred in addition to internal scaling. More severe scaling was observed when the DS contained scaling precursors such as Ca(2+) or SO4(2-), suggesting that the reverse diffusion of these precursors into the FS can significantly enhanced gypsum scaling. Increasing applied hydraulic pressure could enhance reverse solute diffusion and thus result in more severe gypsum scaling when the DS contained scaling precursors. A conceptual model, capturing the two important PRO scaling mechanisms (ICP of scaling precursors from FS and reverse diffusion of scaling precursors from the DS), is presented to rationalize the experimental results. Our results provide significant implications for PRO scaling control. PMID- 24156949 TI - Suitability of artificial sweeteners as indicators of raw wastewater contamination in surface water and groundwater. AB - There is no quantitative data on the occurrence of artificial sweeteners in the aquatic environment in Southeast Asian countries, particularly no information on their suitability as indicators of raw wastewater contamination on surface water and groundwater. This study provided the first quantitative information on the occurrence of artificial sweeteners in raw wastewater, surface water and groundwater in the urban catchment area in Singapore. Acesulfame, cyclamate, saccharin, and sucralose were ubiquitous in raw wastewater samples at concentrations in the range of ng/L-MUg/L, while other sweeteners were not found or found only in a few of the raw wastewater samples. Residential and commercial effluents were demonstrated to be the two main sources of artificial sweeteners entering the municipal sewer systems. Relatively higher concentrations of the detected sweeteners were frequently found in surface waters at the sampling sites located in the residential/commercial areas. No significant difference in the concentrations of the detected sweeteners in surface water or groundwater was noted between wet and dry weather conditions (unpaired T-test, p> 0.05). Relatively higher concentrations and detection frequencies of acesulfame, cyclamate and saccharin in surface water samples were observed at the potentially impacted sampling sites, while these sweeteners were absent in most of the background surface water samples. Similarly, acesulfame, cyclamate, and saccharin were found in most groundwater samples at the monitoring well (GW6), which is located close to known leaking sewer segment; whereas these were absent in the background monitoring well, which is located in the catchment with no known wastewater sources. Taken together, the results suggest that acesulfame, cyclamate, and saccharin can be used as potential indicators of raw wastewater contamination in surface water and groundwater. PMID- 24156950 TI - Tight ceramic UF membrane as RO pre-treatment: the role of electrostatic interactions on phosphate rejection. AB - Phosphate limitation has been reported as an effective approach to inhibit biofouling in reverse osmosis (RO) systems for water purification. The rejection of dissolved phosphate by negatively charged TiO2 tight ultrafiltration (UF) membranes (1 kDa and 3 kDa) was observed. These membranes can potentially be adopted as an effective process for RO pre-treatment in order to constrain biofouling by phosphate limitation. This paper focuses on electrostatic interactions during tight UF filtration. Despite the larger pore size, the 3 kDa ceramic membrane exhibited greater phosphate rejection than the 1 kDa membrane, because the 3 kDa membrane has a greater negative surface charge and thus greater electrostatic repulsion against phosphate. The increase of pH from 6 to 8.5 led to a substantial increase in phosphate rejection by both membranes due to increased electrostatic repulsion. At pH 8.5, the maximum phosphate rejections achieved by the 1 kDa and 3 kDa membrane were 75% and 86%, respectively. A Debye ratio (ratio of the Debye length to the pore radius) is introduced in order to evaluate double layer overlapping in tight UF membranes. Threshold Debye ratios were determined as 2 and 1 for the 1 kDa and 3 kDa membranes, respectively. A Debye ratio below the threshold Debye ratio leads to dramatically decreased phosphate rejection by tight UF membranes. The phosphate rejection by the tight UF, in combination with chemical phosphate removal by coagulation, might accomplish phosphate-limited conditions for biological growth and thus prevent biofouling in the RO systems. PMID- 24156951 TI - Applicability of dynamic membrane technology in anaerobic membrane bioreactors. AB - This study investigated the applicability of dynamic membrane technology in anaerobic membrane bioreactors for the treatment of high strength wastewaters. A monofilament woven fabric was used as support material for dynamic membrane formation. An anaerobic dynamic membrane bioreactor (AnDMBR) was operated under a variety of operational conditions, including different sludge retention times (SRTs) of 20 and 40 days in order to determine the effect of SRT on both biological performance and dynamic membrane filtration characteristics. High COD removal efficiencies exceeding 99% were achieved during the operation at both SRTs. Higher filtration resistances were measured during the operation at SRT of 40 days in comparison to SRT of 20 days, applying a stable flux of 2.6 L/m(2) h. The higher filtration resistances coincided with lower extracellular polymeric substances concentration in the bulk sludge at SRT of 40 days, likely resulting in a decreased particle flocculation. Results showed that dynamic membrane technology achieved a stable and high quality permeate and AnDMBRs can be used as a reliable and satisfactory technology for treatment of high strength wastewaters. PMID- 24156952 TI - Executive summary of the Consensus Document of GeSIDA and Spanish Secretariat for the National Plan on AIDS on combined antiretroviral treatment in adults infected by the human immunodeficiency virus (January 2013). AB - In the present update of the guidelines, a starting combination antiretroviral treatment (cART) is recommended in symptomatic patients, in pregnant women, in serodiscordant couples with a high risk of transmission, in patients co-infected with hepatitis B virus requiring treatment, and in patients with HIV-related nephropathy. Guidelines on cART are included in the event of a concurrent diagnosis of HIV infection with an AIDS-defining event. In asymptomatic naive patients, cART is recommended if the CD4(+) lymphocyte count is <500cells/MUL; if the CD4(+) lymphocyte count is >500cells/MUL, cART can be delayed, although it may be considered in patients with liver cirrhosis, chronic infection due to hepatitis C virus, high cardiovascular risk, plasma viral load (PVL) >10(5)copies/mL, CD4(+) lymphocyte percentage <14%, cognitive impairment, and age >55 years. cART in naive patients requires a combination of 3 drugs, and its aim is to achieve undetectable PVL. Treatment adherence plays a key role in sustaining a favorable response. cART can, and should be, changed if virological failure occurs, in order to return to undetectable PVL. Approaches to cART in acute HIV infection, in women, in pregnancy, in tuberculosis, and post-exposure prophylaxis are also examined. PMID- 24156956 TI - In vitro power profiles of multifocal simultaneous vision contact lenses. AB - PURPOSE: To evaluate the power profile of multifocal contact lenses (CLs) using a new technology based on quantitative deflectometry. METHODS: The Nimo TR1504 was used to analyze the power distribution of multifocal CLs. The CLs under study were: Air Optix Aqua Multifocal Low, Medium and High Addition and Focus Progressives. Three lenses of each model were considered. RESULTS: All multifocal CLs showed a power profile characterized by a change toward more positive power values when aperture sizes become smaller. The near refractive addition of the lenses under study was +2.61 D, +1.44 D, +1.30 D and +0.30 D for the Focus Progressives, the Air Optix Aqua Multifocal High, Medium Add and Low Add, respectively. The refractive power of the Focus Progressives did not reach the value of the nominal distance power until a radial distance of 0.9 mm from the center of the lens. For the Air Optix Aqua Multifocal Low Add the distance nominal power was reached at a radial distance of 1.5mm from the center of the lens, whereas this occurred at a distance of 1.8mm for the Air Optix Aqua Multifocal Medium and High Add. CONCLUSION: The relation between the pupil diameter of the patients and the power profile of these CLs has a crucial implication on the final distance correction and near addition that these lenses provide to patients. Practitioners should know the power profile of these CLs and measure the pupil diameter of each patient in different situations in order to carry out a customized fitting. PMID- 24156958 TI - The impact of consumer affordability on access to assisted reproductive technologies and embryo transfer practices: an international analysis. AB - OBJECTIVE: To systematically quantify the impact of consumer cost on assisted reproduction technology (ART) utilization and numbers of embryos transferred. DESIGN: Ordinary least squared (OLS) regression models were constructed to measure the independent impact of ART affordability-measured as consumer cost relative to average disposable income-on ART utilization and embryo transfer practices. SETTING: Not applicable. PATIENT(S): Women undergoing ART treatment. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): OLS regression coefficient for ART affordability, which estimates the independent effect of consumer cost relative to income on utilization and number of embryos transferred. RESULT(S): ART affordability was independently and positively associated with ART utilization with a mean OLS coefficient of 0.032. This indicates that, on average, a decrease in the cost of a cycle of 1 percentage point of disposable income predicts a 3.2% increase in utilization. ART affordability was independently and negatively associated with the number of embryos transferred, indicating that a decrease in the cost of a cycle of 10 percentage points of disposable income predicts a 5.1% increase in single-embryo transfer cycles. CONCLUSION(S): The relative cost that consumers pay for ART treatment predicts the level of access and number of embryos transferred. Policies that affect ART funding should be informed by these findings to ensure equitable access to treatment and clinically responsible embryo transfer practices. PMID- 24156959 TI - Targeting ALK in patients with advanced non small cell lung cancer: biology, diagnostic and therapeutic options. AB - The discovery of EML4-ALK fusion gene in a subgroup of patients with lung adenocarcinoma led to the development of a new class of agents, the ALK inhibitors, and dramatically improved the clinical outcome of these patients. The striking results from clinical trials with crizotinib, the first ALK inhibitor evaluated, allowed the accelerated approval of crizotinib from the USA Food and Drug Administration (FDA). Despite the high initial results, patients acquire resistance to crizotinib, and different next generation ALK kinase inhibitors have been developed. In the current review, we will analyze the biology of EML4 ALK gene, the acquired resistance mechanisms to crizotinib, the therapeutic strategies, currently under evaluation, designed to overcome crizotinib resistance, and the open issues that need to be addressed in order to improve outcome in ALK+ Non Small Cell Lung Cancer (NSCLC) patients. PMID- 24156960 TI - Percutaneous coronary intervention versus medical therapy in stable coronary artery disease: the unresolved conundrum. AB - One of the major dilemmas facing physicians is what diagnostic and therapeutic approaches should be recommended to those stable coronary artery disease patients whose symptoms are adequately controlled on medical therapy. This study sought to assess the evidence-based data relating to whether: 1) all patients with significant coronary lesions (i.e., ischemia-producing) should undergo percutaneous coronary intervention (PCI); 2) the best therapeutic approach is optimal medical therapy; or 3) PCI should be performed, but only in certain subsets of patients. We reviewed all recent meta-analyses of prospective randomized trials that compared the outcomes of medical therapy and PCI in stable, symptomatically controlled, coronary artery disease patients. To provide greater insights to the clinician, we then analyzed, in depth, 3 comprehensive and widely quoted randomized trials. Review of recently published (2012) meta analyses, and the detailed analyses of 3 widely quoted individual studies, indicate no difference exists between PCI and medical therapy in nonfatal MI or in all-cause or cardiovascular mortality. Thus, clinical equipoise exists: in other words, there is no evidence-based justification for adopting 1 therapeutic strategy over the other. Therefore, it is not inappropriate, until additional evidence emerges, for the responsible, experienced physician to weigh several sources of information in formulating a recommendation to the patient, even though definitive evidence-based data are not as yet available. Such sources may include assessment of the individual patient's clinical presentation, assessment of the severity of ischemia, and the patient's precise coronary anatomy. Critical for more-reliable decision making will be future development of accurate measures of the individual patient's risk of MI and/or death, whether by biomarker, imaging, or ischemia assessments. PMID- 24156957 TI - The Pregnancy in Polycystic Ovary Syndrome II study: baseline characteristics and effects of obesity from a multicenter randomized clinical trial. AB - OBJECTIVE: To summarize baseline characteristics from a large multicenter infertility clinical trial. DESIGN: Cross-sectional baseline data from a double blind randomized trial of two treatment regimens (letrozole vs. clomiphene). SETTING: Academic Health Centers throughout the United States. PATIENT(S): Seven hundred fifty women with polycystic ovary syndrome (PCOS) and their male partners took part in the study. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Historic, biometric, biochemical, and questionnaire parameters. RESULT(S): Females averaged 30 years and were obese (body mass index [BMI] 35) with ~20% from a racial/ethnic minority. Most (87%) were hirsute and nulligravid (63%). Most of the women had an elevated antral follicle count and enlarged ovarian volume on ultrasound. Women had elevated mean circulating androgens, LH-to-FSH ratio (~2), and antimullerian hormone levels (8.0 ng/mL). In addition, women had evidence for metabolic dysfunction with elevated mean fasting insulin and dyslipidemia. Increasing obesity was associated with decreased LH-to-FSH levels, antimullerian hormone levels, and antral follicle counts but increasing cardiovascular risk factors, including prevalence of the metabolic syndrome. Men were obese (BMI 30) and had normal mean semen parameters. CONCLUSION(S): The treatment groups were well matched at baseline. Obesity exacerbates select female reproductive and most metabolic parameters. We have also established a database and sample repository that will eventually be accessible to investigators. CLINICAL TRIAL REGISTRATION NUMBER: NCT00719186. PMID- 24156961 TI - Five-year clinical and functional multislice computed tomography angiographic results after coronary implantation of the fully resorbable polymeric everolimus eluting scaffold in patients with de novo coronary artery disease: the ABSORB cohort A trial. AB - OBJECTIVES: This study sought to demonstrate the 5-year clinical and functional multislice computed tomography angiographic results after implantation of the fully resorbable everolimus-eluting scaffold (Absorb BVS, Abbott Vascular, Santa Clara, California). BACKGROUND: Multimodality imaging of the first-in-humans trial using a ABSORB BVS scaffold demonstrated at 2 years the bioresorption of the device while preventing restenosis. However, the long-term safety and efficacy of this therapy remain to be documented. METHODS: In the ABSORB cohort A trial (ABSORB Clinical Investigation, Cohort A [ABSORB A] Everolimus-Eluting Coronary Stent System Clinical Investigation), 30 patients with a single de novo coronary artery lesion were treated with the fully resorbable everolimus-eluting Absorb scaffold at 4 centers. As an optional investigation in 3 of the 4 centers, the patients underwent multislice computed tomography (MSCT) angiography at 18 months and 5 years. Acquired MSCT data were analyzed at an independent core laboratory (Cardialysis, Rotterdam, the Netherlands) for quantitative analysis of lumen dimensions and was further processed for calculation of fractional flow reserve (FFR) at another independent core laboratory (Heart Flow, Redwood City, California). RESULTS: Five-year clinical follow-up is available for 29 patients. One patient withdrew consent after 6 months, but the vital status of this patient remains available. At 46 days, 1 patient experienced a single episode of chest pain and underwent a target lesion revascularization with a slight troponin increase after the procedure. At 5 years, the ischemia-driven major adverse cardiac event rate of 3.4% remained unchanged. Clopidogrel was discontinued in all but 1 patient. Scaffold thrombosis was not observed in any patient. Two noncardiac deaths were reported, 1 caused by duodenal perforation and the other from Hodgkin's disease. At 5 years, 18 patients underwent MSCT angiography. All scaffolds were patent, with a median minimal lumen area of 3.25 mm(2) (interquartile range: 2.20 to 4.30). Noninvasive FFR analysis was feasible in 13 of 18 scans, which yielded a median distal FFR of 0.86 (interquartile range: 0.82 to 0.94). CONCLUSIONS: The low event rate at 5 years suggests sustained safety after the implantation of a fully bioresorbable Absorb everolimus-eluting scaffold. Noninvasive assessment of the coronary artery with an option of functional assessment could be an alternative to invasive imaging after treatment of coronary narrowing with such a polymeric bioresorbable scaffold. (ABSORB Clinical Investigation, Cohort A [ABSORB A] Everolimus-Eluting Coronary Stent System Clinical Investigation [ABSORB]; NCT00300131). PMID- 24156962 TI - The synergy between percutaneous therapies and noninvasive diagnostic imaging. PMID- 24156963 TI - Complex coronary artery disease: would outcomes from the SYNTAX (synergy between percutaneous coronary intervention with taxus and cardiac surgery) trial have differed with newer-generation drug-eluting stents? PMID- 24156964 TI - Serial assessment of vessel interactions after drug-eluting stent implantation in unprotected distal left main coronary artery disease using frequency-domain optical coherence tomography. AB - OBJECTIVES: This study sought to assess stent-vessel interactions after drug eluting stent (DES) implantation in unprotected left main coronary artery (ULM) by frequency-domain optical coherence tomography (FD-OCT). BACKGROUND: Percutaneous coronary intervention using DES in ULM has been increasingly performed in routine practice. Recently, FD-OCT assessments of DES-vessel interactions have been used as surrogates for DES safety; however, there are no FD-OCT studies in ULM. METHODS: We prospectively enrolled 33 consecutive patients with ULM disease treated with sirolimus- (n = 11) and everolimus-eluting stents (n = 22). FD-OCT assessments were performed post-percutaneous coronary intervention and at 9-month follow-up. Three different segments of ULM were compared: distal (DIS), bifurcation (BIF), and ostial-body (BODY). The primary endpoints were percentages of uncovered and malapposed struts at 9-month follow up, and the secondary endpoint was neointimal hyperplasia area. RESULTS: We analyzed 25,873 stent struts. Significant differences were demonstrated for percentage of uncovered struts (3.4%, 11.7%, and 18.7%, respectively for DIS, BIF, and BODY; p < 0.05 for all the comparisons). Malapposition was also more common in BODY (5.3%) than in DIS (0.6%) and BIF (2.0%) segments (p < 0.05 for BODY vs. DIS, and BODY vs. BIF). Equivalent neointimal hyperplasia areas were demonstrated in all segments. Acute malapposition rates led to different patterns of DES-vessel interactions at 9-month follow-up. CONCLUSIONS: Distinct patterns of DES-vessel interactions were demonstrated in different segments of ULM. Acute stent strut malapposition affects these findings. PMID- 24156965 TI - Prognostic value of microvascular resistance index immediately after primary percutaneous coronary intervention on left ventricular remodeling in patients with reperfused anterior acute ST-segment elevation myocardial infarction. AB - OBJECTIVES: This study sought to investigate the relationship between the degree of microvascular dysfunction assessed by a dual-sensor guidewire (pressure and Doppler velocity) and left ventricular (LV) remodeling after successful primary percutaneous coronary intervention (PPCI) for a first anterior acute myocardial infarction (AMI). BACKGROUND: Microvascular dysfunction after AMI is associated with progressive LV dilation. METHODS: In 24 consecutive patients, the microvascular resistance index (MVRI) immediately after PPCI was calculated as the ratio of the mean distal pressure to average peak flow velocity during maximal hyperemia. Cardiac magnetic resonance was performed to determine LV volumes at baseline and 8-month follow-up. LV remodeling was defined as an increase in left ventricular end-diastolic volume (LVEDV) of >=20%. RESULTS: In patients with an MVRI greater than the median value of 2.96 mm Hg.cm(-1).s, the LVEDV increased significantly from 117.1 +/- 20.7 ml at baseline to 146.5 +/- 21.4 ml (p = 0.006) at 8 months, whereas it did not change between baseline and 8 months (108.2 +/- 21.2 ml vs. 111.6 +/- 29.9 ml, p = 0.620) in patients with an MVRI <=2.96 mm Hg.cm(-1).s. LV remodeling was more frequent in the group with an MVRI >2.96 mm Hg.cm(-1).s (64% vs. 15%, p = 0.033). Furthermore, there was a positive correlation between MVRI and the percentage of increase or decrease in LVEDV (r = 0.42, p = 0.042). Logistic regression analysis showed that MVRI was the strongest univariate predictor of LV remodeling. The best cutoff value of MVRI was 2.96 mm Hg.cm(-1).s with a sensitivity of 78% and a specificity of 73%. CONCLUSIONS: MVRI immediately after PPCI predicts LV remodeling in patients with reperfused anterior AMI. PMID- 24156966 TI - Remote ischemic post-conditioning of the lower limb during primary percutaneous coronary intervention safely reduces enzymatic infarct size in anterior myocardial infarction: a randomized controlled trial. AB - OBJECTIVES: This study sought to evaluate whether remote ischemic post conditioning (RIPC) could reduce enzymatic infarct size in patients with anterior ST-segment elevation myocardial infarction undergoing primary percutaneous coronary intervention (pPCI). BACKGROUND: Myocardial reperfusion injury may attenuate the benefit of pPCI. In animal models, RIPC mitigates myocardial reperfusion injury. METHODS: One hundred patients with anterior ST-segment elevation myocardial infarction and occluded left anterior descending artery were randomized to pPCI + RIPC (n = 50) or conventional pPCI (n = 50). RIPC consisted of 3 cycles of 5 min/5 min ischemia/reperfusion by cuff inflation/deflation of the lower limb. The primary endpoint was infarct size assessed by the area under the curve of creatinine kinase-myocardial band release (CK-MB). Secondary endpoints included the following: infarct size assessed by cardiac magnetic resonance delayed enhancement volume; T2-weighted edema volume; ST-segment resolution >50%; TIMI (Thrombolysis In Myocardial Infarction) frame count; and myocardial blush grading. RESULTS: Four patients (2 RIPC, 2 controls) were excluded due to missing samples of CK-MB. A total of 96 patients were analyzed; median area under the curve CK-MB was 8,814 (interquartile range [IQR]: 5,567 to 11,325) arbitrary units in the RIPC group and 10,065 (IQR: 7,465 to 14,004) arbitrary units in control subjects (relative reduction: 20%, 95% confidence interval: 0.2% to 28.7%; p = 0.043). Seventy-seven patients underwent a cardiac magnetic resonance scan 3 to 5 days after randomization, and 66 patients repeated a second scan after 4 months. T2-weighted edema volume was 37 +/- 16 cc in RIPC patients and 47 +/- 22 cc in control subjects (p = 0.049). ST-segment resolution >50% was 66% in RIPC and 37% in control subjects (p = 0.015). We observed no significant differences in TIMI frame count, myocardial blush grading, and delayed enhancement volume. CONCLUSIONS: In patients with anterior ST-segment elevation myocardial infarction, RIPC at the time of pPCI reduced enzymatic infarct size and was also associated with an improvement of T2-weighted edema volume and ST-segment resolution >50%. (Remote Postconditioning in Patients With Acute Myocardial Infarction Treated by Primary Percutaneous Coronary Intervention [PCI] [RemPostCon]; NCT00865722). PMID- 24156967 TI - Chronic obstructive pulmonary disease in patients undergoing transcatheter aortic valve implantation: insights on clinical outcomes, prognostic markers, and functional status changes. AB - OBJECTIVES: This study sought to determine the effects of chronic obstructive pulmonary disease (COPD) on clinical outcomes in patients undergoing transcatheter aortic valve implantation (TAVI) and to determine the factors associated with worse outcomes in COPD patients. BACKGROUND: No data exist on the factors determining poorer outcomes in COPD patients undergoing TAVI. METHODS: A total of 319 consecutive patients (29.5% with COPD) who underwent TAVI were studied. Functional status was evaluated by New York Heart Association (NYHA) functional class, Duke Activity Status Index, and the 6-min walk test (6MWT) at baseline and at 6 to 12 months. The TAVI treatment was considered futile if the patient either died or did not improve in NYHA functional class at 6-month follow up. RESULTS: Survival rates at 1 year were 70.6% in COPD patients and 84.5% in patients without COPD (p = 0.008). COPD was an independent predictor of cumulative mortality after TAVI (hazard ratio: 1.84; 95% confidence interval: 1.08 to 3.13; p = 0.026). Improvement in functional status was observed after TAVI (p < 0.001 for NYHA functional class, Duke Activity Status Index, and 6MWT), but COPD patients exhibited less (p = 0.036) improvement in NYHA functional class. Among COPD patients, a shorter 6MWT distance predicted cumulative mortality (p = 0.013), whereas poorer baseline spirometry results (FEV1 [forced expiratory volume in the first second of expiration]) determined a higher rate of periprocedural pulmonary complications (p = 0.040). The TAVI treatment was futile in 40 COPD patients (42.5%) and a baseline 6MWT distance <170 m best determined the lack of benefit after TAVI (p = 0.002). CONCLUSIONS: COPD was associated with a higher rate of mortality at mid-term follow-up. Among COPD patients, a higher degree of airway obstruction and a lower exercise capacity determined a higher risk of pulmonary complications and mortality, respectively. TAVI was futile in more than one-third of the COPD patients, and a shorter distance walked at the 6MWT predicted the lack of benefit after TAVI. These results may help to improve the clinical decision-making process in this challenging group of patients. PMID- 24156968 TI - Does the presence of accessory renal arteries affect the efficacy of renal denervation? AB - OBJECTIVES: This study sought to assess the efficacy of catheter-based renal sympathetic denervation in patients with accessory renal arteries and to compare the blood pressure (BP)-lowering effect with that observed in patients with bilateral single renal arteries after renal denervation. BACKGROUND: Catheter based renal sympathetic denervation causes significant BP reductions in patients with resistant hypertension. METHODS: Seventy-four patients were included in this study. Patients were assigned to 2 main groups: a bilateral single renal arteries group I (n = 54) and an accessory renal arteries group II (n = 20). Group II consisted of 9 patients whose accessory renal arteries were all denervated (group IIa), and 11 patients whose accessory renal arteries were not, or only incompletely, denervated (group IIb). The primary endpoint was the change in office systolic BP after 6 months. RESULTS: The procedure was successful in all patients. Group I: mean BP at baseline was 166.2/89.4 +/- 20.5/14.6 mm Hg and decreased by -16.6 (p < 0.001)/-6.7 (p = 0.016) +/- 16.4/11 mm Hg at 6-month follow-up. Group II: mean BP at baseline was 164.2/89.1 +/- 19.9/15.4 mm Hg and decreased by -6.2 (p = 0.19)/-0.2 (p = 0.5) +/- 19.7/11.3 mm Hg at 6-month follow up. Patients in group IIa had an office BP reduction of -8.8 (p = 0.2)/1.1 +/- 17.9/10.8 mm Hg and patients in group IIb of -4.1 (p = 0.55)/-1.3 +/- 20.8/11.6 mm Hg. Similarly, significant improvements in 24-h mean systolic BP were seen in group I (-8.3 +/- 17.4 mm Hg, p < 0.01), whereas none were seen in group II (-3.7 +/- 8.3 mm Hg, p = 0.38). CONCLUSIONS: BP reduction achieved after renal denervation in patients with accessory renal arteries is less pronounced than in patients with bilateral single renal arteries. PMID- 24156969 TI - Catheter-based renal denervation: the black box procedure. PMID- 24156970 TI - Physicians' radiation exposure in the catheterization lab: does the type of procedure matter? AB - OBJECTIVES: This study sought to evaluate differences in radiation exposure of the operator depending on the type of catheterization lab procedure. BACKGROUND: Invasive cardiologists and angiologists are exposed to long-term, low-dose occupational radiation. Increased workload and specialization require more detailed knowledge of the extent and cause of the radiation exposure. METHODS: In this prospective single-center experience, radiation doses of 3 operators were measured by real-time dosimetry for body, neck, and hand during 284 procedures in 281 patients over a period of 14 weeks. To determine the association between the type of procedure and the doses and to draw a pairwise comparison between the procedures, 3 mixed models were used. RESULTS: The type of procedure, the patient's body mass index, and the fluoroscopy time were independently associated with the operator's radiation exposure. Per procedure, the operators were exposed to a mean effective dose (E) of 2.2 +/- 5.9 MUSv. Compared with coronary angiography, E was 2.3-fold higher in pelvic procedures (95% confidence interval [CI]: 1.7 to 3.0, p < 0.001), 1.7-fold higher in upper limb procedures (95% CI: 1.3 to 2.1, p < 0.001), and 1.4-fold higher in below-the-knee procedures (95% CI: 1.1 to 2.0, p = 0.023). The mean eye dose was 19.1 +/- 37.6 MUSv. Eye doses were significantly higher in peripheral procedures than in coronary angiography procedures. The mean hand dose was 99.6 +/- 196.0 MUSv. Hand doses were significantly higher in pelvic than in coronary angiography, upper limb, and below-the-knee procedures. CONCLUSIONS: Endovascular procedures for pelvic, upper limb, and below-the-knee disease are accompanied with a higher radiation exposure of the operator than with coronary procedures. PMID- 24156971 TI - Percutaneous closure of an aortic pseudoaneurysm due to saphenous vein graft dehiscence with an Amplatzer vascular plug. PMID- 24156973 TI - Surgeons and cardiologists: the indispensable team. PMID- 24156972 TI - Anterograde percutaneous coronary-cameral fistula closure employing a guide-in guide technique. PMID- 24156974 TI - [Neuroleptic associated hypothermia: a new case report and study of spontaneous reports to the French pharmacovigilance network]. AB - INTRODUCTION: Neuroleptics are the main antipsychotic agents used in psychiatric or medicine departments. The occurrence of hyperthermia, particularly in the context of the neuroleptic malignant syndrome, is a well-known side effect of these treatments. Conversely, the occurrence of hypothermia is less known from clinicians. CASE REPORT: We reported a 72-year-old woman, who presented with hypothermia associated with treatment with neuroleptics. This patient had no other medical comorbidities. Because of persistent hypothermia, altered consciousness and bradycardia, exhaustive diagnostic work-up as well as a prolonged hospitalization were necessary. The results of a review of the national French pharmacovigilance database showed that nearly a quarter (153/614) of drug related hypothermia are attributed to psychotropic drug, mainly neuroleptics (99/153). CONCLUSION: A better awareness of hypothermia associated to neuroleptics should facilitate early diagnosis and reporting this side effect of neuroleptics. PMID- 24156975 TI - [Recurrent hemoptysis in a 24-year-old man]. PMID- 24156976 TI - [Myasthenia gravis and autoantibodies: Pathophysiology of the different subtypes]. AB - Myasthenia gravis is characterized by muscle weakness and abnormal fatigability. It is an autoimmune disease caused by the presence of antibodies against components of the muscle membrane localized at the neuromuscular junction. In most cases, the autoantibodies are directed against the acetylcholine receptor (AChR). Recently, other targets have been described, such as muscle-specific kinase protein (MuSK) or lipoprotein related protein 4 (LRP4). The origin of the autoimmune response is not known, but thymic abnormalities and defects in immune regulation certainly play a major role in patients with anti-AChR antibodies. Genetic predisposition probably influences the occurrence of the disease. Sex hormones seem to play a role in the early form of the disease. Muscle weakness is fluctuating and worsens with exercise. Myasthenia gravis could be classified according to the location of the affected muscles (ocular versus generalized), the age of onset of symptoms, thymic abnormalities and profile of autoantibodies. These criteria are used to optimize the management and treatment of patients. In this review, we analyze the latest concepts of the pathophysiology of myasthenia gravis according to the different subgroups of the disease, including a description of the role of immunological, genetic and environmental factors. The potential viral hypothesis of this disease is discussed. Finally, we also discuss the biological assays available to validate the diagnosis. PMID- 24156977 TI - A forceful upper jaw facilitates picking-based prey capture: biomechanics of feeding in a butterflyfish, Chaetodon trichrous. AB - Biomechanical models of feeding mechanisms elucidate how animals capture food in the wild, which, in turn, expands our understanding of their fundamental trophic niche. However, little attention has been given to modeling the protrusible upper jaw apparatus that characterizes many teleost species. We expanded existing biomechanical models to include upper jaw forces using a generalist butterflyfish, Chaetodon trichrous (Chaetodontidae) that produces substantial upper jaw protrusion when feeding on midwater and benthic prey. Laboratory feeding trials for C. trichrous were recorded using high-speed digital imaging; from these sequences we quantified feeding performance parameters to use as inputs for the biomechanical model. According to the model outputs, the upper jaw makes a substantial contribution to the overall forces produced during mouth closing in C. trichrous. Thus, biomechanical models that only consider lower jaw closing forces will underestimate total bite force for this and likely other teleost species. We also quantified and subsequently modeled feeding events for C. trichrous consuming prey from the water column versus picking attached prey from the substrate to investigate whether there is a functional trade-off between prey capture modes. We found that individuals of C. trichrous alter their feeding behavior when consuming different prey types by changing the timing and magnitude of upper and lower jaw movements and that this behavioral modification will affect the forces produced by the jaws during prey capture by dynamically altering the lever mechanics of the jaws. In fact, the slower, lower magnitude movements produced during picking-based prey capture should produce a more forceful bite, which will facilitate feeding on benthic attached prey items, such as corals. Similarities between butterflyfishes and other teleost lineages that also employ picking-based prey capture suggest that a suite of key behavioral and morphological innovations enhances feeding success for benthic attached prey items. PMID- 24156978 TI - Ontogenetic and sexual differences of thermal biology and locomotor performance in a lacertid lizard, Eremias multiocellata. AB - A viviparous lizard, Eremias multiocellata, was used to investigate the possible sexual and ontogenetic effects on selected body temperature, thermal tolerance range and the thermal dependence of locomotor performance. We show that adults are sexually dimorphic and males have larger bodies and heads than females. Adults selected higher body temperatures (34.5 vs. 32.4 degrees C) and could tolerate a broader range of body temperatures (8.1-46.8 vs. 9.1-43.1 degrees C) than juveniles. The sprint speed and maximum sprint distance increased with temperature from 21 degrees C to 33 degrees C, but decreased at 36 degrees C and 39 degrees C in both juveniles and adults. Adults ran faster and longer than juveniles at each tested temperature. Adult locomotor performance was not correlated with snout-vent length (SVL) or sex, and sprint speed was positively correlated with hindlimb length. Juvenile locomotor performance was positively correlated with both SVL and hindlimb length. The ontogenetic variation in selected body temperature, thermal tolerance and locomotor performance in E. multiocellata suggests that the effects of morphology on temperature selection and locomotor performance vary at different ontogenetic stages. PMID- 24156979 TI - Pneumatized septal turbinate. AB - Intumenscentia septi nasi anterior is an anatomical variation in the nasal cavity, first described by Morgagni in 1662; septal turbinate and tuberculum septi nasi anterior are among the various other names attributed to this anatomical structure. It is an expandable vascular network which develops from the septal mucosa. Computed tomography, following history-taking and physical examination, is a valuable tool in diagnosing turbinate pneumatisation. This paper reports the case of a 23-year-old female with nasal stuffiness as her primary complaint, who was found to have pneumatization of the septum mimicking the septal concha. Pneumatization of the septal turbinate may also be a cause of septal enlargement. The symptomatology, diagnosis and treatment options for cases of septal turbinate are discussed. The surgical interventions performed in the presented case are briefly described. The presented patient had a pneumatization of the septal turbinate, like those of the conchae. It is reported for the first time in medical literature, and the histological and functional similarities of the septal turbinate and of the nasal conchae are pointed out. PMID- 24156980 TI - Treatment of displaced mandibular condylar fracture with botulinum toxin A. AB - The aim of this case report is to discuss the effect on condylar reduction of botulinum toxin A treatment used in a child with displaced fracture at condylar neck of mandible. A 3-years old boy was admitted to our clinic for incomplete fracture of mandibular symphysis and displaced condylar fracture at the left side. An asymmetrical occlusal splint with intermaxillary fixation was used instead of open reduction and internal fixation because of incomplete fracture of symphysis and possible complications of condyle surgery. However, it was observed that condylar angulation persisted despite this procedure. Thus, botulinum toxin A was administered to masseter, temporalis and pterygoideus medialis muscles. At the end of first month, it was seen that mandibular condyle was almost completely recovered and that fusion was achieved. In conclusion, Botulinum A toxin injection aiming the suppression of masticatory muscle strength facilitates the reduction in the conservative management of displaced condyle in pediatric patients. PMID- 24156981 TI - In vivo chemistry. PMID- 24156982 TI - Biomonitoring of pyrethroid exposure among rural and urban populations in northern Poland. AB - The aim of this study was to determine for the first time in Poland, levels of exposure to synthetic pyrethroids in preschool and school age children and their parents living in urban and rural areas. For this purpose concentrations of pyrethroid metabolites: 3-phenoxybenzoic acid (3-PBA), 2,2-dibromovinyl-2,2 dimethylcyclopropanecarboxylic acid (Br2CA), cis-3-(2,2-dichlorovinyl)-2,2 dimethylcyclopropane-1-carboxylic acid (cis-Cl2CA) and trans-3-(2,2 dichlorovinyl)-2,2-dimethylcyclopropane-1-carboxylic acid (trans-Cl2CA) were determined in 374 urine samples using a validated GC-MS method. All measured metabolites were detected more frequently and in higher concentrations in rural areas. 3-PBA was detected in 77.4% and 93.8% of samples from urban and rural areas, respectively. Its geometric mean (GM) concentration in rural population was higher than in urban (0.364 vs. 0.223 ng mL(-1) and 0.272 vs. 0.155 MUg g(-1) creatinine, p<0.0001). Among remaining metabolites, only cis- and trans-Cl2CA were detected in more than 50.0% of samples in rural population. Average concentrations of 3-PBA in children were higher than in adults, both in urban and rural areas. Moderate to very strong positive correlations were noticed between concentrations of pairs of pyrethroid metabolites in urine samples. Significant, moderate correlations between the concentrations of particular metabolites in parents and their children were observed in the urban population (range: r=0.2911 0.3919 for non-adjusted and 0.3827-0.4693 for creatinine adjusted concentrations), while in rural areas there were no such relationship. Application of pesticide formulations on pets in the past 6 months was associated with increased 3-PBA urinary concentration. Further studies on pesticide exposure among children in rural areas are needed to identify and possibly reduce or eliminate the sources of exposure. PMID- 24156983 TI - Successful research capacity building in academic nursing and midwifery in Ireland: an exemplar. AB - BACKGROUND: Nursing and midwifery education have comparatively recently moved into academia in Ireland. In 2002, nurse tutors who were qualified to Master's degree level assimilated into the third-level sector. Only 11 of the 35 staff (31%) in one university School held, or were undertaking, a PhD. In 2006, children's nursing and midwifery tutors also moved into third-level institutions. The culture of all assimilating tutors was focussed on teaching, rather than research. OBJECTIVES: The School set ambitious plans to develop the research abilities of all academics, setting the goal that 75% of academic staff would either hold, or be undertaking, a PhD by 2010. Objectives were also set to increase external research funding, peer-reviewed publications and conference presentations. METHODS: A combination of sabbatical leaves, student stipends and periods of reduced teaching load was introduced to provide staff with protected time for doctoral studies. Funding for conference and research expenses was provided, based on the previous year's research output of publications, conference presentations and external funding submissions. RESULTS: By October 2010, 79% of the 66 School staff either had (n=23), or were conducting (n=29), PhDs, surpassing goals set. Peer-reviewed publications and conference presentations had increased by >20% per year and external research funding totalled ?6,351,101 for the previous 5 years. CONCLUSIONS: Strong research leadership, generous support and liberal encouragement can change a predominantly teaching-focussed culture to one of academic research excellence. This increase in research expertise will lead to better patient/client care and improved education of nursing and midwifery students. PMID- 24156984 TI - Management of infertility today. PMID- 24156985 TI - Clinical effects of gynecologic laparoscopy courses in the United Arab Emirates. AB - OBJECTIVE: To evaluate the impact of gynecologic laparoscopy courses on the participants' laparoscopy practice. METHODS: We conducted 5 repeated laparoscopy courses between 2008 and 2012 at the United Arab Emirates University in Al Ain, United Arab Emirates, so as to enhance performance in the operating room. An electronic questionnaire was sent to all participants from each of the courses to evaluate the impact of course attendance on clinical practice. RESULTS: Of 70 participants who were approached to complete the online questionnaire, 38 (54.3%) responded. The majority were female (94.7%) and specialists (65.8%). Half the participants (50.0%) thought they would probably not have started performing laparoscopy without having attended the course. Of the participants, 18.4% thought that their operating skills had greatly improved, 63.2% felt that their operating skills had improved moderately to a lot, and 6/12 participants who had not been performing laparoscopy before attendance of the course began doing so. Overall, the course had no significant impact on the participants' performance of laparoscopy (P=0.51, McNemar test), but the proportion of participants who performed level II laparoscopy was significantly increased after course attendance (10.5% versus 47.4%; P=0.001, McNemar test). CONCLUSION: Gynecologic laparoscopy courses encourage gynecologists to use laparoscopy in clinical practice. PMID- 24156986 TI - Active management of the third stage of labor with and without controlled cord traction. PMID- 24156987 TI - Safety and acceptability of tubal ligation procedures performed by trained clinical officers in rural Uganda. AB - OBJECTIVE: To assess safety associated with tubal ligation performed by trained clinical officers (COs) in rural Uganda. METHODS: Between March and June 2012, 518 women in 4 regions of Uganda were recruited into a prospective cohort study and followed at days 3, 7, and 45 after undergoing tubal ligation performed by a trained CO. Intraoperative and postoperative adverse events (minor, moderate, or major), and acceptability were assessed. RESULTS: Mean age was 36 years (range, 20-49 years) and mean number of living children was 6.7 (range, 0-15). The overall rate of major adverse events was 1.5%: 0.4% intraoperatively; 1.9% at day 3; and 0.2% at day 7. The majority of women who underwent tubal ligation reported a good/very good experience at the facility (range, 94%-99%) and would recommend the health services to a friend (range, 93%-98%). CONCLUSION: In the present study, task sharing of tubal ligation to trained COs in private facilities was safe. Women reported high levels of satisfaction with the procedure. Training COs could be an effective strategy for expanding family-planning services to rural Uganda. PMID- 24156988 TI - Effects of young maternal age and short interpregnancy interval on infant mortality in South Asia. PMID- 24156990 TI - Clinical indications for cesarean delivery in a Cambodian referral hospital. PMID- 24156989 TI - Psychological and ethical implications related to infertility. AB - Being a parent is deeply demanding and one of the most important events in life; parents experience the deepening of human relationships with their partner, within their families, and in society, and moreover the fundamental relationship between parent and child. Every medical, social, and political effort must be made to prevent infertility but also to offer infertile couples the best diagnostic and therapeutic paths. Understanding the suffering of the couple and their families prevents and helps ease the possible psychological and social complications of infertility. Therefore, infertility concerns not only biomedical sciences but also psychological and social ones-ethics and law-in their combined efforts to identify areas of understanding and of research for solutions while respecting the dignity of the couple and unborn child. The Catholic Church offers an ongoing contribution through dialogue in looking for ethical principles guiding scientific and medical research respectful of the true life of human beings. PMID- 24156993 TI - Obstacles of non-heart-beating donor kidney transplantation in Japan to date and future perspectives. AB - In Japan, multiple organ retrieval from brain-dead heart-beating donors has been gradually increasing since the law was adopted in 1997 and amended in 2009. However, almost more than 90% of total deceased donor kidney transplantation (DDKT) in Japan are still obtained from non-heart-beating donors (NHBD). The majority of NHBD are Maastricht categories IV and III. In category IV, we usually place a double balloon arterial and a venous drainage catheter via the femoral vessels after the diagnosis of clinical brain death and acquisition of informed consent from the family. After controlled cardiac arrest, the double balloons are inflated and in situ cold perfusion started as soon as possible to minimize warm ischemic time (WIT), seeking to achieve a zero to within a few minutes WIT in most cases. In category III, it is impossible to place the device prior to cardiac arrest. In these cases, after declaration of cardiac death, cardiopulmonary compression is accompanied by systemic heparinization, immediate laparotomy, and insertion of a cold perfusion catheter at the aortic and caval bifurcations to minimize WIT. NHBD kidney retrieval is critical; extirpation must be performed as rapidly as possible. The results of NHBD kidney transplantation in Japan are excellent, according to the advancement and utilization of in situ cannulation, organ perfusion, and sophisticated retrieval techniques. The patient and graft survival rates of DDKT at 1, 3, and 5 years in most recent 2001 to 2007 era were 95.4%, 92.2%, 89.1% (n = 945) and 89.2%, 83.7%, 77.8% (n = 919), respectively. PMID- 24156991 TI - A qualitative assessment of Ugandan women's perceptions and knowledge of contraception. AB - OBJECTIVE: To determine Ugandan women's perceptions and knowledge of contraception. METHODS: Healthy prepartum women were recruited from a national referral and university teaching hospital to participate in 1 of 5 focus group discussions on contraception. Transcripts were translated and coded by 2 researchers using inductive and deductive methods. RESULTS: Forty-six women participated in the focus group discussions. The major themes that emerged were around family planning as a method to space pregnancies and manage finances, as well as men's roles in decision making regarding contraception. Notable among the many incorrect notions about adverse effects of contraception were fears about cancer and infertility. CONCLUSION: The results indicate that, among the study group of Ugandan women, decision making regarding family planning involves a complex negotiation among women, partners, and families. Furthermore, pervasive myths may hinder a woman's ability to choose safe and effective contraception. These findings are useful to healthcare providers and the greater public-health community. PMID- 24156994 TI - Japanese strategies to maximize heart and lung availabilities: experience from 100 consecutive brain-dead donors. AB - OBJECTIVE: Because the donor shortage is extremely severe in Japan because of a strict organ transplantation law, special strategies have been established to maximize heart and lung transplantations (HTs and LTs, respectively). We reviewed 100 consecutive brain-dead donors to evaluate our strategies to identify and manage heart and lung donors. METHODS: We retrospectively reviewed all 100 consecutive brain-dead donors procured since the law was issued in 1997. There were 56 mens and the overall mean donor age was 43.5 years. The causes of death were cerebrovascular disease (n = 62), head trauma (n = 20), and asphyxia (n = 16): Since November 2002, special transplant management doctors were sent to donor hospitals to assess cardiac and lung functions, seeking to identify transplant opportunities. They stabilized donor hemodynamics and lung function by administering antidiuretic hormone intravenously and performing bronchofibroscopy for pulmonary toilet. RESULTS: Seventy-nine HTs, 1 heart-lung transplantations, and 78 LTs (46 single and 32 bilateral) were performed. By applying these strategies organs per donor were increased from 4.5 to 6.8. Among heart donors, 61/80 were marginal: high inotrope requirement (n = 29), cardiopulmonary resuscitation (n = 28), and/or >55 years old (n = 20). None of the 80 HT recipients died of primary graft failure (PGF). Patient survival rate at 10 years after HT was 95.4%. Among lung donors, 48/65 were marginal: pneumonia (n = 41), chest trauma (n = 4), and >55 years old (n = 9). Only 2/78 LT recipients died of PGF. Patient survival rate at 3 years after LT was 72.2%. After inducing frequent pulmonary toilet, lung procurement and patient survival rates increased significantly after LT. CONCLUSIONS: Although the number of cases was still small, the availability of organs has been greater and the outcomes of HT/LT acceptable. PMID- 24156995 TI - Factors predicting the usefulness of deceased donors. AB - BACKGROUND: Preoperative management for deceased donation is important. Deceased donation can failed for several reasons. We analyzed the clinical data of deceased donation after consent for cadaveric donation to evaluate the reasons of failure of organ procurement. MATERIAL AND METHODS: We retrospectively reviewed the medical records of 112 deceased donors in a single institution between January 1998 and September 2012. There were no organs from cardiac death donors. RESULTS: Of 112 deceased donors, 51 (45.5%) were traumatic brain deaths and 33 (29.5%), nontraumatic brain hemorrhages. The overall mean age was 37.2 (+/-16.6) years with 35 (30.7%) of female gender. There were 15 (13.3%) donation failures for all organs. Significant factors for failure were histories of cardiopulmonary resuscitation (odds ratio [OR], 0.17; 95% confidence interval [CI], 0.05-0.58; P = .005), cardiac arrest (OR, 0.03; 95% CI, 0.006-0.14; P < .001), or acute renal failure (OR, 0.05; 95% CI, 0.006-0.42; P = .006). The nonsignificant factors included the time from intensive care unit to brain death (mean time, 105.1 +/- 153.4); diabetes insipidus; hypotension despite inotrophic therapy, hypothermia (<35 degrees C), arrhythmia, infection, metabolic acidosis, disseminated intravascular coagulopathy, and brain death cause. CONCLUSIONS: Failure of deceased donation was associated with cardiac arrest while awaiting organ procurement and the presence of an history of cardiopulmonary resuscitation or presence of acute renal failure. PMID- 24156996 TI - The "ABO cross-transplantation problem" in liver transplantation in Korea. AB - ABO blood group matching policy between donor and recipients is a chief element of organ allocation. However, O blood group donors may donate to all other blood group recipients, and ABO cross-transplantation has led to excessively long delays for blood group O. To investigate the consequence of this problem, we analyzed the recipients/donor rates according to ABO blood groups and cross transplantation rates among them. Data about deceased donors and liver transplants performed in Korea from January 2008 to September 2012 were reviewed. The proportion of recipient to donor in the O blood group was lower compared to non-O groups (0.61). The percentage of O blood group transplantations in the Korean Network for Organ Sharing (KONOS) status 2B was lower than non-O groups (13.6%). In the status 1 and 2A groups, 44.4% of O blood group donors were allocated to non-O transplantations. Also, 30.7% O blood group donors were allocated to non-O transplantations in the status 2B groups. In conclusion, the ABO cross-transplantation in blood group O donors has led to lower transplantation rates of blood group O in status 1, 2A, and especially, the 2B group. Therefore, the KONOS allocation system should be re-evaluated to address this problem. PMID- 24156997 TI - Does procurement technique affect posttransplant graft function in deceased donor liver transplantation? AB - INTRODUCTION: Various techniques have been described deceased donor liver transplantation (DDLT) procurement. One is a technique whereby almost total dissection is done in the porta hepatis and perihepatic detachment is carried out before cross-clamping the donor aorta. In another approach, after the donor aorta is cross-clamped, rapid and minimal en bloc dissection is performed with minimal manipulation. We evaluated early posttransplant graft function among liver procurement techniques. METHOD: Between January 2008 and August 2012, we performed 45 consecutive adult DDLTs. One patient was excluded from this analysis due to early death from sepsis after transplantation. The 44 included patients were divided into two cohorts according to the procurement technique: A warm dissection (n = 23; 52%) and a cold dissection group (n = 21; 48%). We compared early posttransplant graft function using the aspartate aminotransferase (AST), alanine aminotransferase (ALT), total bilirubin (T-bil), and prothrombin time (PT) values of the two groups from the first to seventh postoperative day. RESULT: The AST values in the warm group were significantly greater than those in the cold group on postoperative days 3 and 5. In addition, the ALT values in the warm group were greater than those in the cold group on postoperative days 4, 5, and 6. Moreover, the T-bil values in the warm group were greater than those in the cold group on postoperative days 2, 3, 4, 5, 6, and 7. However, there were no differences in PT values. CONCLUSION: During liver procurement for DDLT, rapid en bloc procurement with minimal manipulation after clamping the donor aorta achieved better early graft function posttransplantation. PMID- 24156998 TI - Differential function of natural killer cells in the liver graft perfusate of Korean population. AB - BACKGROUND: Liver perfusate (LP) lymphocytes show unique subsets compared with peripheral blood (PB) lymphocytes. LP natural killer (NK) and NKT cells may display unique cytotoxicity and cytokine production, thus leading to distinct roles in liver transplantation. In this study, we sought to evaluate the functions of graft perfusate NK and NKT cells in clinical liver transplantation. METHODS: The living donor right lobe graft was initially washed with 1 L of histidine-tryptophan-ketoglutarate solution to collect the perfusate. We also collected donor PB. Lymphocytes separated by the Ficoll-Hypaque density gradient method underwent immunophenotyping using multicolor flow cytometry. To assess cytokine secretion, we performed the enzyme-linked immunosorbent assay. RESULTS: There were more NK and NKT cells in LP confirming previous reports. In particular, CD56(bright)CD16(low) NK cells accounted for approximately 50% of total NK cells compared with 5% to 10% among PB NK cells. In response to cytokine stimulation LP NK cells produce tumor necrosis factor-alpha at different levels and less interleukin-10 compared with PB NK cells. The major source of interferon gamma production upon stimulation with liver caner cells were CD56(dim) NK cells and CD56(-)CD3(-) cells rather than NKT or T cells. Unlike PB NK cells, LP CD56(bright)CD16(low) NK cells along with CD56(dim)CD16(high) NK cells and NKT cells were efficient killers against Korean liver cancer cells. CONCLUSION: LP NK and NKT cells showed unique functions in cytotoxicity and cytokine production. PMID- 24156999 TI - Post-transplant diabetes mellitus: is it associated with poor allograft outcomes in renal transplants? AB - BACKGROUND: Post-transplant diabetes mellitus (PTDM) is a common metabolic complication whose incidence ranges from 2 to 50%, reflecting wide variations in population type, criteria for diagnosis, and immunosuppressive regimen. PTDM is associated with poor graft outcomes and increased infections and cardiovascular disease following renal transplants. Therefore, we assessed the incidence of PTDM and examined the association between PTDM and graft function after transplantation. MATERIALS AND METHODS: We investigated 565 renal transplants in our center. The patients were divided into 2 groups, depending on the time of surgery: group 1 (n = 228, from January 1990 to December 1995) and group 2 (n = 377, from January 1996 to December 2011). In each group, patients were divided into no diabetes mellitus (non-DM), preexisting diabetes mellitus (pre-DM), and PTDM subgroups. PTDM was defined as fasting plasma glucose >=126 mg/dL. We started treatment by modification of lifestyle and/or antidiabetic medication. All patients in group 1 received cyclosporine (CsA) and patients in group 2 received CsA or tacrolimus. We analyzed the clinical characteristics of recipients, serum creatinine levels, and long-term graft survival. RESULTS: The overall incidence of PTDM was 11.7% (n = 66); 9.2% (n = 21) in group 1, and 13.4% in group 2. There was a higher incidence of PTDM in the recipients who received tacrolimus than in those who received CsA (25.0% vs 9.5%, P < .001) and the delay before the appearance of PTDM was shorter (38.58 +/- 6.94 vs 75.85 +/- 7.67, P = .017). Also the tacrolimus dose (20.4l +/- 4.28 ng/mL) at the time of PTDM diagnosis was above the therapeutic range (5-20 ng/mL). There were no significant differences in infection and cardiovascular complication rates between the non DM, pre-DM, and PTDM patients in group 1. In group 2, the use of tacrolimus significantly increased the incidence of PTDM compared with CsA (P < .001). However, there were no significant differences between subgroups in other variables. Serum creatinine levels 10 years after renal transplantation (P = .756 in group 1 and P = .559 in group 2) and long-term graft survival in those groups were not significantly different (P = .067 in group 1 and P = .125 in group 2). CONCLUSION: Renal function and allograft outcomes are more impaired in patients with PTDM than in either non-DM or pre-DM patients. However, if regular screening of plasma glucose levels, early diagnosis, and appropriate treatment of PTDM are carried out, the risk of complications can be minimized and the long-term allograft outcomes improved. PMID- 24157000 TI - Comparison of QuantiFERON-TB Gold with tuberculin skin test for detection of latent tuberculosis infection before kidney transplantation. AB - INTRODUCTION: Screening for latent tuberculosis infection (LTBI) before kidney transplantation (KT) is an indispensable process, purposes of this study were to compare the QuantiFERON-TB Gold In-Tube test (QFT-GIT) with the tuberculin skin test (TST) for screening of LTBI in kidney transplant recipients (KTRs). METHODS: We compared prospectively the results of QFT-GIT with TST in 97 KTRs screened for LTBI between July 2008 and July 2012. Isoniazid (INH) prophylaxis was applied to KTRs with a positive TST or positive QFT-GIT or clinical risk factors for LTBI. Post-transplant tuberculosis (TB) was diagnosed by clinical evidence. RESULTS: The mean patients follow-up was 24.6 +/- 14.4 months. Positive results on QFT-GIT and TST was obtained among 19 (20.4%) and 12 (12.9%) subjects, respectively, an overall agreement of 79.3% (kappa = 0.27, 95% confidence interval [CI] -0.03 0.50; P < .014). The incidence of TB was 0.52 per 100 person-years (95% CI 0.02 3.68). None of the patients in the INH prophylaxis group developed TB, whereas 1 in the no prophylaxis group developed disease at 14 months after KT. Sensitivity of the 2 tests could not be compared because patients who showed positive results on QFT-GIT or TST did not develop TB. The difference of specificity between QFT GIT (79.3%) and TST (86.9%) was not significant (P = .l67). Abnormal chest radiographs (odds ratio [OR] 27.94, 95% CI 1.22-636.61, P = .037) and positive TST (OR 7.65, 95% CI 1.75-33.30, P = .007) showed significant associations with positive QFT-GIT results. Only positive QFT-GIT (OR 6.03, 95% CI 1.51-24.01, P = .011) showed an association with positive TST results. CONCLUSIONS: QFT-GIT and TST for diagnosis of LTBI in KTRs showed reasonable concordance but no superiority of either test. PMID- 24157001 TI - Impact of flow cytometry crossmatch B-cell positivity on living renal transplantation. AB - BACKGROUND: Various studies have reported poorer graft survival among individuals displaying T-cell-positive flow cytometry crossmatches (FCXM). Good outcomes have been observed in immunologically high-risk patients with the use of rituximab, plasmapheresis, and gamma-globulin. Because the relevance of FCXM B-cell positivity (BCXM (+)) alone remains controversial, we examined its impact on living donor renal transplantations. PATIENTS AND METHODS: We retrospectively studied 146 adult renal transplantation recipients from April 2007 to June 2012, dividing the patients into BCXM (+) (n = 31) versus BCXM (-) recipients (n = 115). We examined patient and graft survivals as well as rejection rates at 0 to 3, 3 to 12, and 12 to 24 months. We also determined the incidence of infectious diseases. We performed stepwise multivariate regression to identify risk factors contributing rejection episodes. RESULTS: One-year patient and graft survivals were 100% in both groups. The BCXM (-) group have a 16.8% rejection probability whereas the BCXM (+) group, 33.2% (P = .201). There were no significantly differences in the incidence of infectious diseases. Only the rate of a sensitizing history was an independent risk factor for a rejection episode. CONCLUSION: BCXM (+) showed only a tendency but not a significant impact on rejection episodes compared with BCXM (-); short-term graft survivals were similar. PMID- 24157002 TI - Implication of donor-recipient age gradient in the prognosis of graft outcome after deceased-donor kidney transplantation. AB - PURPOSE: Successful kidney transplantation leads to greater survival and improved quality of life for patients with end-stage renal disease. Among the most important influences on graft outcomes is donor age. We evaluated the relationships between the donor-recipient age gradient (DRAG) and the graft outcomes after deceased-donor kidney transplantation (DDKT). METHODS: From February 1995 to March 2011, a consecutive series of 526 adult DDKT recipients were analyzed. DRAG values were divided into two groups (negative versus positive years) and then four groups (<=-21, -20 to -1, 0 to 20, and >=21 years). RESULTS: Median age of donors and recipients were 39 (range, 1-75) and 41 (range, 18-74) years, respectively. The degree of DRAG was not associated with episodes of allograft rejection. High or low DRAG had no effect on posttransplant serum creatinine levels or estimated glomerular filtration rates. However, negative levels of DRAG, particularly less than -20 years, were significantly correlated with superior 10-year death-censored graft survival (86.4% and 83.1% vs 72.2% vs 53.9%; overall P = .031), but not increased overall graft or patient survival. CONCLUSION: This study demonstrated that DRAG is a prognostic indicator of long term graft outcomes after DDKT. PMID- 24157003 TI - Can the kidney weight and recipient body weight ratio predict long-term graft outcome in living donor kidney transplantation? AB - We investigated the effect of the donor kidney weight (Kw) to recipient body weight (Rw) ratio (Kw/Rw) on long-term graft function. To investigate the impact of the Kw/Rw ratio on the graft function, we retrospectively collected data from 213 kidney transplant recipients at least 5 years Post-transplantations. Renal function showed a positive correlation with the Kw/Rw ratio until 5 years after transplantation (at 60 months after transplantation, R = 0.158, P = .023); however, this ratio does not affect graft survival (P = .794). We used the mixed effect model to identify the factors that affect the estimated glomerular filtration rate (eGFR) over time. In univariate analysis, donor age, BSA, kidney weight, and Kw/Rw ratio were associated with eGFR. To identify independent factors that affect to the eGFR, multivariate analysis using a mixed model was applied. Donor age (P < .001) and Kw/Rw ratio (P < .001) were independent factors that affected the eGFR. To identify the cutoff values of the Kw/Rw ratio and donor age that affect long-term graft function, multiple testing using a mixed model was applied. The cutoff value for the Kw/Rw ratio was 3.16 (P = .0104) and the cutoff value of donor age was 44 years (P = .0001). Based on our results, we conclude that the Kw/Rw ratio and donor age are important factors for the long term function of graft. PMID- 24157004 TI - Is the graft function of living donor renal transplants associated with renal mass matching by computed tomography angiographic volumetry? AB - BACKGROUND: Donor renal volume, which can be easily measured by computerized tomographic angiography with 3-dimensional reconstruction, may influence graft outcomes. Low functional renal mass and donor kidney-recipient body size mismatch can lead to progressive renal injury and poor graft function. MATERIALS AND METHODS: This single-center retrospective analysis of 51 consecutive living donor renal transplantations performed between January 2005 and December 2011 defined transplant renal volume per unit recipient body surface area (BSA; mL/m(2)). The patients were divided into 2 groups: group I (n = 31, donor-recipient BSA ratio <=1) and group II (n = 20, BSA ratio >1). We analyzed the clinical characteristics and laboratory data of donors and recipients to ascertain correlations with, renal volumes and graft outcomes. RESULTS: The renal volumes of living donors correlated with estimated glomerular filtration ratios (eGFR; r = .314, P = .025). Serum creatinine after renal transplantation correlated with transplanted renal volume at 1, 3, and 12 months (r = -.319, P = .048; r = -.407, P = .010; r = -.472, P = .002). Serum eGFR also correlated with transplanted renal volume at 3 and 12 months after renal transplantation (r = .318, P = .049 and r = .388, P = .015). There were no significant differences between groups for acute or chronic rejection, infection or delayed graft function. However, serum creatinine levels were higher (P = .011, P = .022, and P = .007) and serum eGFR significantly lower in group I at 1, 3, 6, and 12 months after renal transplantation (P = .036, P = .042, P = .042, and P = .049, respectively). There was no significant difference in graft survival. CONCLUSIONS: Renal volume of living donors may reflect renal function and have a significant impact on graft outcomes. Renal volume matching should be considered to select donor-recipient pairs for living donor renal transplantation. PMID- 24157005 TI - Contrast-enhanced magnetic resonance angiography in the early period after kidney transplantation. AB - Our objective was to evaluate the usefulness of three-dimensional (3-D) contrast enhanced (CE) magnetic resonance angiography (MRA) to assess renal parenchyma, arterial inflow stenosis, and peritransplant fluid collections in the early period after kidney transplantation (KT). Between January 2010 and April 2011, we examined a consecutive series of 144 renal transplants using 3-D CE MRA at 14 days after KT. MRA showed parenchyma infarctions (n = 17, 11.8%), arterial inflow stenoses (n = 23, 16%), lymphoceles (n = 14, 9.7%), and hematomas (n = 6, 4.2%). The degree of renal transplant artery inflow stenosis was graded qualitatively based on diameter criterion; <50% = mild, 50% to 70% = moderate, and >70% = severe in 10 (6.9%), 5 (3.5%), and 8 (5.6%) subjects, respectively. The study recipients were divided into 3 groups according to the degree of renal artery inflow stenosis (group I: normal; group II: mild and moderate, <70%; group III: severe, >70%). Among group III patients who underwent digital subtraction angiography, 5 had percutaneous transluminal angioplasty or stenting performed after 1 month. Their mean resume creatinine levels at 1, 6, and 12 months after transplantation were not significantly different from those in the other groups (P = .391, .447, .110). The prevalence of graft loss (n = 2) was high in group III (P = .012), although the frequency of acute rejection episodes was not different among the groups (P = .890). The incidences of renal parenchyma infarction, peritransplant fluid collection and arterial inflow stenosis were unexpectedly high in the early period after KT. Thus, 3-D CE MRA provided a rapid global assessment of the renal parenchyma, transplant arterial system, and peritransplant fluid collection that can be helpful to detect or exclude many causes of renal transplant dysfunction. PMID- 24157006 TI - Comparative analysis of ABO-incompatible living donor kidney transplantation with ABO-compatible grafts: a single-center experience in Korea. AB - INTRODUCTION: Serious organ shortages have necessitated the use of ABO incompatible (ABOi) kidneys transplantation, which has been increasingly preformed in Korea. However there are few detailed comparative data regarding patient and graft survival, graft function, and complications in Korean patients receiving ABO-compatible (ABOc) and ABOi kidney transplants (KT). METHODS: This retrospective study compared 35 consecutive ABOi living donor KTs with 138 ABOc living donor KTs using same immunosuppressive regimens. We examined preoperative demographic factors, immunologic risk factors, patient and graft survivals, postoperative renal function, acute rejection episodes, infections, medical and surgical complications, duration of hospital stay as well as cause for readmission, and their rates. RESULTS: Patient survival, graft survival, and graft function over the 2 years after transplantation were similar between the 2 groups. There were no significant differences in terms of complications with exception of bleeding and BK virus infection. Acute antibody-mediated rejection episodes, bleeding complications, BK virus infections, and preoperative hospital stay were significantly greater in the ABOi group (P = .001, P = .002, P = .005, and P < .001 respectively). CONCLUSIONS: We concluded that, despite some disadvantages, ABOi KT is a viable, safe option for patients whose only available donor is blood group incompatible. PMID- 24157007 TI - The impact of time-zero biopsy on early graft outcomes after living donor kidney transplantation. AB - BACKGROUND: In contrast with deceased donor transplantation, the clinical significance of pathologic findings in time-zero biopsies after living donor kidney transplantation are rarely reported, due to the expectation that histologic findings and renal function are normal. The aim of this study was to identify subclinical pathologic findings in living donors and examine the effect on early graft renal function. METHODS: Between December 2006 and July 2011, 146 living-donor kidney transplant recipients were enrolled in this study. We retrospectively analyzed donor and recipient-related clinical parameters, and post-transplant 6 months and 1 year estimated glomerular filtration rate (eGFR) as early graft renal function. Time-zero biopsies were evaluated using the 2007 Banff criteria. RESULTS: Most abnormal histologic findings were of mild degree as determined by Banff scores. Global glomerulosclerosis (GS, 35.6%), tubular atrophy (CT, 36.3%), interstitial fibrosis (CI, 20.5%), vascular fibrous intimal thickening (CV, 4.1%), arteriolar hyaline thickening (AH, 14.4%), interstitial inflammation (I, 3.4%) were pathologic findings in time-zero biopsies. The univariate analysis revealed that donor age and gender were significantly associated with eGFR at post-transplant 6 months and at 1 year (P < .05). Furthermore, GS and CT were significantly associated with early graft renal function (P < .05). However, multivariate linear regression analysis showed only donor age was significantly associated with early graft renal function (P = .001). CONCLUSION: A mild degree of subclinical, pathologic findings on time-zero biopsy did not affect early graft renal function in living-donor kidney transplantation. PMID- 24157008 TI - Clinical outcomes in kidney transplantation patients from deceased donors with acute kidney injury. AB - BACKGROUND: This single-center study sought to examine the clinical outcomes of kidney transplant recipients from donors displaying acute kidney injury (AKI). METHODS: We analyzed retrospectively the medical records of the donors and recipients of 54 deceased-donor kidney transplantations performed in our center between March 2009 and March 2012. RESULTS: Among the 54 deceased donors, 36 (66.7%) experienced AKI as determined by the final mean serum creatinine levels measured before graft harvest of 2.66 +/- 1.62 mg/dL versus 0.82 +/- 0.28 mg/dL among non-AKI donors. The risks of delayed graft function and slow graft function were increased among the AKI versus non-AKI groups in the early post transplantation period. However, the renal function status of recipients at 3, 6, and 12 months after transplantation was not significantly different between the two groups. Moreover, rejection-free survival rates during the study period were similar. Multivariate analysis revealed an acute rejection episodes (P = .047) and a lower body mass index in the donor relative to the recipient (P = .011) to be independent risk factors predicting poor graft function defined as a 1-year estimated glomerular filtration rate less than 50 mL/min/l.73 m(2). Donor AKI with either a high level (>4.0 mg/dL), an increasing trend of creatinine, or greater severity by the Risk, Injury, Failure, Loss, and End-stage kidney disease (RIFLE) classification was not a significant risk factor. CONCLUSION: Transplantation of kidneys from the AKI donors, namely, patients with severely decreased renal function, displayed excellent short-term outcomes. Accordingly, kidney transplantations from deceased donors with AKI should be considered more actively to expand the donor pool in Korea. PMID- 24157009 TI - Comparison of peritoneal dialysis and hemodialysis after kidney transplant failure. AB - BACKGROUND: Patients with a failed kidney transplant represent a unique chronic kidney disease population that is increasing in number and is at high risk of morbidity and mortality. Among transplant-naive patients, those treated with peritoneal dialysis (PD) show an early survival advantage compared with those treated with hemodialysis (HD). But any advantage of PD after allograft failure is unknown. The aim of this study was to investigate the clinical outcomes of patients with failed allografts according to the type of dialysis modality. METHOD: We reviewed medical records of patients who initiated dialysis after kidney transplant failure from November 1982 to May 2011. Demographics features, clinical data, and survival outcomes were compared between PD and HD patients who had experienced allograft failure. RESULTS: The 182 patients with failed allografts showed the most common cause to be chronic rejection. The median duration of function before allograft failure was 74.0 months. After allograft failure, 145 (79.7%) patients returned to HD and 37 (20.3%) to PD. Twenty-three patients (12.6%) died over the median 69.1 months duration of follow-up. During the observation period, 16 HD (11%) and 7 PD (8.9%) patients died. The survival rates of PD patients at 1 year were 91.2% and 84.4%, respectively, at 1 and 3 years, and those of HD patients 94.8% and 88.9%. There was no significant difference in the survivals of the 2 groups. CONCLUSIONS: The study suggests that the outcome of patients starting PD after kidney transplant failure was similar to those starting HD. Therefore, PD can be regarded to be a good treatment option for patients returning to dialysis after kidney transplant failure. PMID- 24157010 TI - The clinical outcome of end-stage renal disease patients who return to peritoneal dialysis after renal allograft failure. AB - BACKGROUND: With the increased numbers of kidney transplantations, more patients return to dialysis after graft loss (DAGL). The aim of this study was to investigate the safety and efficacy of peritoneal dialysis (PD) after graft loss compared with transplant-naive PD patients (TN-PD). METHOD: This study was conducted on 715 patients who started PD between 1988 and 2009, including 47 who started PD after allograft loss (DAGL-PD) and 668 in the (TN-PD) group. RESULT: The mean ages were 40.8 +/- 10.7 in DAGL-PD group and 51.03 +/- 14.20 in TN-PD group (P < .01). The most common cause of end-stage renal disease in DAGL was primary glomerulonephritis (76.6%), but it was diabetes mellitus (38.9%) in the TN-PD group (P < .05). Patient survival rates at 1, 5, and 10 years were not different: 100%, 86%, and 57% versus 91%, 70%, and 62%, respectively. PD survival rate at 1, 5, and 10 years did not show significant differences: 98%, 95%, and 88% versus 95%, 80%, and 66%, respectively. The most common causes of death in both groups were infection (DAGL, 26.7%; TN-PD, 24.5%) followed by cardiovascular disease (DAGL, 20.0%; TN-PD, 19.6%); the distribution of causes did not differ significantly (P > .05). CONCLUSION: The clinical outcomes of PD in DAGL group were comparable with those of TN-PD patients. Therefore, PD could be considered as a dialysis modality for patients who experience allograft failure. PMID- 24157011 TI - Comparison of the clinical characteristics of renal transplant recipients who underwent early versus late graft nephrectomy. AB - BACKGROUND: Graft nephrectomy is the last-resort option for renal transplant recipients. The aim of this study was to compare the clinical characteristics of patients who underwent graft nephrectomy according to the time after renal transplantation. METHODS: From 2005 to 2012, 42 patients underwent graft nephrectomy after transplant failure. We divided these patients into early (n = 17) and late graft nephrectomy (n = 25) groups based on graft survival to 6 months, comparing their causes for nephrectomy and clinical characteristics. RESULTS: The patients included 29 men and 13 women, with an overall mean age of 45 years (range, 10-71 years). The main causes for early and late graft nephrectomy were irreversible acute rejection (71%) and graft intolerance syndrome (95%), respectively. The clinical characteristics did not significantly differ between the early and late graft nephrectomy groups except for operative related complications. Bleeding was more common among patients who underwent early (n = 10) versus late (n = 3) graft nephrectomy (59% vs 12%; P = .01). Of the 10 patients with perioperative bleeding, 8 had a bleeding tendency, such as low platelet count or prolonged prothrombin time at the time of the operation. These complications occurred after antirejection therapy involving plasma exchange or antithymocyte globulin treatment. Allograft nephrectomy was associated with a mortality rate of 2.38%. CONCLUSIONS: The cause for graft nephrectomy and type of perioperative complication differed according to timing of graft nephrectomy. Antirejection therapy appeared to contribute to postoperative complications such as bleeding. PMID- 24157012 TI - Decreased parathyroid Klotho expression is associated with persistent hyperparathyroidism after kidney transplantation. AB - Although successful kidney transplantation usually corrects hyperparathyroidism, the condition persists in some patients. The present study was designed to determine whether Klotho or fibroblast growth factor 23, the key regulator of parathyroid hormone, is involved in persistent hyperparathyroidism in kidney transplant recipients (KTRs). Nineteen hyperplastic parathyroid glands were obtained from end-stage renal disease (ESRD) patients and KTRs; 6 normal parathyroid glands were used as controls. We compared the expression of Klotho, fibroblast growth factor receptor 1 (FGFR1) and calcium-sensing receptor (CaSR) in the KTRs and ESRD patients. Expressions of Klotho, FGFR1, CaSR and vitamin D receptor, as evaluated by immunohistochemistry, were quantified as the number of positive cells per unit area. The Klotho, FGFR1 and CaSR expressions in parathyroid glands of the post-kidney transplantation (PSKT) and the ESRD groups were significantly decreased compared with normal controls. In the ESRD group, Klotho expression and number of proliferating cell nuclear antigen-positive cells in the parathyroid gland were significantly decreased in parathyroid adenomas as compared with parathyroid hyperplasia. The expression of FGFR1 and CaSR in the parathyroid glands was significantly increased in the PSKT compared with the ESRD group. There was no significant difference in Klotho expression between the PSKT and ESRD groups. Incomplete recovery of Klotho levels in the parathyroid gland may play a role in the pathogenesis of tertiary hyperparathyroidism after kidney transplantation. PMID- 24157013 TI - Impact of vitamin D, bisphosphonate, and combination therapy on bone mineral density in kidney transplant patients. AB - BACKGROUND: Osteoporosis can develop and become aggravated in kidney transplant patients; however, the best preventive options for post-transplantation osteoporosis remain controversial. METHODS: We retrospectively analyzed cohort of 182 renal transplant recipients of mean age 46.7 +/- 12.1 years including 47.3% women. Seventy-three patients received neither vitamin D nor bisphosphonate after transplantation (group 1). The other patients were classified into the following 3 groups: calcium plus vitamin D (group 2; n = 40); bisphosphonate (group 3; n = 18); and both regimens (group 4; n = 51). Bone mineral density (BMD) was evaluated by dual-energy X-ray absorptiometry at baseline and at 1 year after transplantation. RESULTS: At 1 year after transplantation, T-scores of the femoral neck and entire femur were significantly decreased in group 1 (-0.23 +/- 0.65 [P = .004] and -0.21 +/- 0.74 [P = .018], respectively), whereas the lumbar spine was significantly increased in group 4 (0.27 +/- 0.79; P = .020). Post hoc analysis demonstrated that the delta T-score was significantly lower in group 1 than in group 4 (P = .009, 0.035, and 0.031 for lumbar spine, femoral neck, and entire femur, respectively). In a multivariate analysis adjusted by age, sex, body mass index, dialysis duration, diabetes, calcineurin inhibitors, estimated glomerular filtration rate, and persistent hyperparathyroidism, both group 2 and group 4 showed protective effects on BMD reduction (odds ratio [OR], 0.165; 95% confidence interval [CI] 0.032-0.845 [P = .031]; and OR, 0.169; 95% CI, 0.045 0.626 [P = .008]; respectively). However, group 3 did not show a protective effect (OR, 0.777; 95% CI, 0.198-3.054; P = .718), because their incidence of persistent hyperparathyroidism after transplantation was significantly higher (50.0%) than the other groups (P < .001). The incidence of bone fractures did not differ among the groups. CONCLUSIONS: Combination therapy with vitamin D and bisphosphonate was the most effective regimen to improve BMD among kidney recipients. PMID- 24157014 TI - Sirolimus: a switch option for mycophenolate mofetil-induced leukopenia in renal transplant recipients. AB - Mycophenolate mofetil (MMF) is a potent immunosuppressive agent used to prevent acute and chronic rejection in kidney transplantation or for rescue therapy. One side effect of MMF is bone marrow toxicity, including leukopenia, which may necessitate drug withdrawal. We report 2 patients who underwent kidney transplantation and developed leukopenia while receiving MMF and safely switched to sirolimus. A 35-year-old woman underwent deceased donor kidney transplantation. She received basiliximab, tacrolimus, MMF, and a corticosteroid. On postoperative day (POD) 75, her white blood cell (WBC) count was 1800/MUL. A 44-year-old women underwent deceased donor kidney transplantation and received basiliximab, tacrolimus, MMF, valganciclovir, and a corticosteroid. On POD 88, her WBC count was 1320/MUL. MMF was switched to sirolimus, resulting in recovery of WBC count without rejection. Switch from MMF to sirolimus is safe and favorable in MMF-induced leukopenia in renal transplant recipient. PMID- 24157015 TI - Characteristics of testosterone deficiency syndrome in men with chronic kidney disease and male renal transplant recipients: a cross-sectional study. AB - OBJECTIVES: Testosterone deficiency syndrome (TDS) is common among male patients with chronic kidney disease (CKD). We compared the characteristics of TDS in men with CKD versus renal transplantation (RT) with those of age-matched normal controls. MATERIALS AND METHODS: The 129 patients were: RT recipients (n = 25) group I, CKD patients (n = 37) group II, and controls (n = 67). We performed estimates of testosterone, hemoglobin (Hgb), hematocrit (Hct), glucose, creatinine, and lipid profile. Self-assessment questionnaires-International Index of Erectile Function (IIEF), Aging Males' Symptoms (AMS), Center for Epidemiologic Studies Depression Scale-were used to evaluate erectile function, testosterone deficiency, and depression, respectively. We also investigated morning erection as well as the presence and duration of erectile dysfunction (ED). RESULTS: Group I (RT) showed significantly higher serum testosterone levels than group II (CKD), who displayed significantly worse erectile function, more severe testosterone deficiency symptoms, and a greater trend toward depression. Similarly, the prevalences of ED and TDS were significantly greater in group II than group I. Group I and controls differed significantly only in the results of serologic tests, such as serum creatinine, Hgb, and glucose and lipid profiles, but not in serum testosterone levels, scores of self-assessment questionnaires, or prevalence of ED or TDS. Serum testosterone levels correlated significantly with scores on the IIEF and AMS questionnaires in both group II and controls, but not group I. CONCLUSIONS: RT recipients showed higher serum testosterone levels and a lower prevalence of TDS with milder symptom severity than CKD patients. RT recipients beyond the early acute posttransplant period, displayed serum testosterone levels and TDS prevalence similar to those of healthy controls. Unlike CKD patients and normal controls, serum testosterone did not significantly influence TDS symptoms in RT recipients. PMID- 24157016 TI - Clinical courses of renal transplant recipients with high BK viremia. AB - OBJECTIVE: We sought to investigate the clinical courses of renal transplant recipients with plasma BK viral loads >10(4) copies/mL. METHODS: A single-center retrospective review was performed of 88 kidney transplant patients in whom high BK viremia (defined as plasma BKV load >10(4) copies/mL) was detected more than once from January 1, 2004, to December 31, 2011. RESULTS: At the time of transplantation, the mean recipient and donor ages were 44.5 +/- 11.1 and 43.9 +/ 11.3 years, respectively, and 59 subjects (67.0%) were male. The median times to first BK positivity and high BK viremia after transplantation were 44 and 136 days, respectively. Within 3 months after transplantation, we detected, 56 cases of high BK viremia (63.6%). The mean duration of high BK viremia was 8.2 +/- 7.7 months. When plasma BKV load was first >4 logs, the mean log BKV load was 5.50 +/ 1.11 log copies/mL, which rose to a maximum of 5.82 +/- 1.11. At these times, mean serum creatinine concentrations were 1.67 +/- 0.79 and 2.64 +/- 2.78 mg/dL, respectively. There were 31 cases (35%) of biopsy-proven BK nephropathy patients among 51 (58%) biopsies. Treatment modalities included discontinuation or dose reduction of mycophenolic acid drugs (n = 68) and switch from tacrolimus to cyclosporine (n = 9), cidofovir (n = 9), and leflunomide (n = 3). Based on the serum creatinine elevation after high BK viremia, patients were divided into group 1 (n = 27; 30.1%), whose maximal creatinine change was <0.5 mg/dL, and group 2, with a greater alteration. On multivariate logistic regression analysis, the maximal plasma BK viral load was significantly associated with a greater serum creatinine elevation (P < .001). CONCLUSIONS: High BK viremia mostly occurred within 3 months after kidney transplantation. About 30% of renal allograft recipients with high BK viremia maintained stable renal function. Maximal plasma BK viral load was the only independent risk factor for high serum creatinine elevation. PMID- 24157017 TI - Monitoring and treatment for BK virus after kidney transplantation. AB - BACKGROUND: The BK nephropathy (BKN) shows a 10% prevalence among cases of kidney transplantation (KT). We assessed the incidence of BK replication in KT recipients as well as our updated screening strategy and the impact of interventions on BK virus infections. METHODS: Since September 2007, our screening protocol for BK virus included examination of urine cytology or BK virus DNA real-time polymerase chain reaction (PCR) detection on postoperative days 1, 5, 9, 16, 24, 36, 48 weeks up to 1 year. IR present, we tested urine BK virus DNA PCR quantitation. We applied the updated screening protocol from August 2010. It urine BK DNA PCR quantification was above 10(7) copies/mL, we checked regularly blood the BK virus DNA PCR quantification. In addition, if the blood BK virus DNA load was above 10(4) copies/mL and the serum creatinine elevated, we was performed an allograft biopsy. Between September 2007 and December 2011, the 58 recipients who showed BK viremia were enrolled in the present study in 2 groups according to the period of screening protocol (era I, era II). RESULTS: The time between kidney transplantation and BK viremia detection of era II was shorter than that of era I (16 vs 29 weeks; P = .001). Viremia clearance rate at 6 months in era II was significant higher than that of era I (82% vs 36.8%; P = .001) as well as at 12 months (100% vs 61.1%, P < .001) after intervention. Interestingly, viremia clearance at 12 months after intervention was 100% in era II. CONCLUSION: An updated screening protocol for BK virus allowed early detection and accurate diagnosis of BKN. Early detection of BK virus infection enabled early intervention and improved viral clearance rate. PMID- 24157018 TI - Presence of vesicoureteral reflux in the graft kidney does not adversely affect long-term graft outcome in kidney transplant recipients. AB - INTRODUCTION: We studied the incidence of vesicoureteral reflux (VUR) in the graft kidney and its effect on the occurrence of urinary tract infection (UTI) and long-term graft function. METHODS: We performed a retrospective analysis of 64 adult kidney transplant recipients based upon voiding cystourethrography at 12 months post-transplantation. Patients underwent analysis of survival, incidence of UTIs beyond 1 year, and graft function. RESULTS: Thirty-seven male and 27 female patients in the study populations showed a mean age 42 years. VUR in the transplanted kidney at 12 months post-transplant occurred among 78.1% (50/64) of subjects: grade I (n = 6), grade II (n = 30), or grade III (n = 14) reflux. Patients followed for a median 61 months (range 44-74s) showed 11 cases of UTIs in 9 subjects. There were no significant differences in clinical characteristics or incidence of, UTIs according to the presence or severity of VUR (P = .81) or the Serum creatinine and estimated glomerular filtration rate values at 12, 36, 48, or 60 months post-transplantation. CONCLUSIONS: VUR present in 78.1% of patients after kidney transplantation affected neither graft functions or graft survival. The incidence of UTI did not differ according to the presence of VUR. PMID- 24157019 TI - Liver transplantation in lymphoma patients with hepatitis B virus reactivation. AB - BACKGROUND: Acute-on-chronic liver failure (AoCLF) occurs in lymphoma patients because of hepatitis B virus (HBV) reactivation. We aimed to identify characteristics of patients who underwent liver transplantation (OLT) because of AoCLF that occurred due to HBV reactivation in the setting of lymphoma and to compare these patients with AoCLF patients who did not have lymphoma. METHODS: Twenty patients underwent OLT due to AoCLF between February 2009 and June 2011. Among these patients, five were diagnosed with lymphoma before OLT and assigned to group 1. The remaining patients (n = 15) were assigned to group 2. RESULTS: Hospitalization after transplantation in group 2 was longer than in group 1 (P = .014). However, there were no differences in other variables between the two groups. The overall survival rate of group 1 was lower than that of group 2, but there was no difference between the two groups (P = .134). With the exception of one patient, the median time from complete remission to liver transplantation in group 1 was 4.5 months (range, 1-15) in group 1. Lymphoma recurrence occurred in one patient 8 months after transplantation. CONCLUSION: Our study revealed that OLT is a feasible and effective approach in AoCLF due to HBV reactivation in select lymphoma patients. PMID- 24157020 TI - Prognostic value of model for end-stage liver disease scores in patients with fulminant hepatic failure. AB - BACKGROUND: This study was undertaken to investigate risk factors of mortality in patients with fulminant hepatic failure (FHF). METHODS: Fifty-three patients with FHF treated from January 2006 to April 2011 were allocated to a spontaneous survival group (group 1), a death without liver transplantation (LT) group (group 2), and an LT group (group 3). To analyze risk factors associated with mortality in FHF, we excluded group 3 patients. Clinical features, Model for End-Stage Liver Disease (MELD) scores, and King's College Hospital criteria at the time of hepatic encephalopathy in group 2 were compared with those of group 1. RESULTS: The causes of FHF were acute viral infection (n = 29, hepatitis A:B, 28:1), drugs (n = 18; including 4 acetaminophen and 14 herbal medication), autoimmune (n = 4), and miscellaneous (n = 2). Of the 53 patients, 19 were allocated to group 1, 18 to group 2, and 16 to group 3. According to univariate analysis, risk factors for mortality in group 2 were acute renal failure requiring renal replacement therapy and a MELD score >=30 at the time of hepatic encephalopathy. However, by multivariate analysis, a MELD score >=30 was the only independent risk factor for mortality in group 2 (P = .042; hazard ratio, 4.500). CONCLUSIONS: A MELD score >=30 was found to be the only independent risk factor of mortality in FHF patients without LT. Therefore, the findings of this study suggest that these patients may need emergent LT for survival. PMID- 24157021 TI - Survival rates among patients awaiting deceased donor liver transplants at a single high-volume Korean center. AB - BACKGROUND: Since the establishment of the Korean Network for Organ Sharing (KONOS) in 2000, thousands of patients have been enrolled on the waiting list, but only a small proportion have received a deceased donor liver transplantation. This report on waiting list mortality in Korea based on data from a single institution. METHODS: The 1772 patients enrolled on the waiting list between February 2000 and December 2011 either have not yet received at the time of analysis or have died before receiving an organ. Survival information was obtained in February 2012 by reviewing medical records or by telephone. We excluded patients who died immediately after enrollment or after retransplantation. RESULTS: Primary diagnoses of those awaiting transplantation were hepatitis B virus-associated cirrhosis (63.7%), alcoholic liver disease (14.3%), hepatitis C virus-associated cirrhosis (13.8%), and acute liver failure due to other causes (8.1%). The priority status of patients on the waiting list was KONOS status 1 (highest priority) in 3.8%, status 2A in 3.9%, status 2B in 41.9%, status 3 to 7 (lowest priority) in 50.5%. Their median survival periods were 1, 1, 18, and 59 months, respectively. The mean Child-Pugh score was 8.5 +/- 2.5 and Model for End-stage Liver Disease (MELD) score 18.1 +/- 9.8. CONCLUSIONS: Patients with high MELD scores or hepatocellular carcinoma succumbed soon after being entered on to the waiting list. By increasing organ donation rates and developing a risk-based allocation system, it should be possible to reduce mortality among patients on organ waiting lists. PMID- 24157022 TI - Role of hand-assisted laparoscopic surgery in living-donor right liver harvest. AB - OBJECTIVE: The cosmetic aspects of abdominal skin incisions are a matter of concern for both live liver donors and surgeons. We performed a prospective comparative study on the use of minilaparotomy to perform right liver graft harvests with and without hand-assisted laparoscopic surgery (HALS). METHODS: Young donors were indicated for surgery using minilaparotomy with or without HALS. In the non-HALS group (n = 20), a 10-12-cm-long right subcostal incision was used for right liver graft harvest. In the HALS group (n = 20), an 8-cm-sized right subcostal incision was used for hand assistance and 3 laparoscopic holes made for manipulation. The retrohepatic inferior vena cava (IVC) was initially laparoscopically dissected while using air inflation. The skin incision was extended to 10-12 cm, and then hilar dissection and hepatic transection were performed through the skin incision. RESULTS: In all 40 donors in the study cohort, safe uneventful harvesting of the right liver grafts was successfully achieved through the minilaparotomy incisions. The HALS group required an additional 30 minutes for laparoscopic preparation and dissection compared with the non-HALS group. HALS facilitated retrohepatic IVC dissection, and the remaining part of the surgery was the same as that for minimal-incision surgery. The minimal skin incision for the delivery of the liver from the abdomen was an average 10 cm for grafts <500 g and 12 cm for grafts >=700 g. Compared with the patient profiles, there were no differences regarding donor age, body mass index, graft weight, intraoperative blood loss, postoperative increase in peak liver enzymes, total hospital stay, and incidence of postoperative complications. CONCLUSIONS: HALS facilitates the performance of donor hepatectomy with the use of a minimal incision, which probably allows for a wider selection of living donors. PMID- 24157024 TI - Importance of donor-recipient age gradient to the prediction of graft outcome after living donor liver transplantation. AB - PURPOSE: Advanced donor age is a well-known risk factor for poor graft function after living donor liver transplantation (LDLT). In addition, advanced recipient age has a significant impact because of the high prevalence of comorbidities. We investigated the relationship between donor-recipient age gradient (DRAG) and the posttransplant outcomes in LDLT. METHODS: We included 821 consecutive adult recipients who underwent LDLT from June 1997 to May 2011. According to the value of DRAG, they were divided into 2 groups: Negative years (the donor was younger than the recipient) and positive years (the donor was older than the recipient). These groups were further divided into subgroups (<=-21, -20 to -1, 0 to 20, and >=21 years). We collected retrospectively patient characteristics, laboratory results, medical and surgical complications, and graft loss. RESULTS: The positive DRAG group had higher level of posttransplant alkaline phosphatase, but a lower incidence of biliary complications. The negative DRAG group, particularly DRAG <= -21 years was associated with the superior 1-, 3-, 5-, and 10-year graft survivals. Recipients with DRAG >= 21 showed persistently inferior graft survival during the observation period. In cases of young donors, transplants utilizing lower DRAG seen between young donors and older recipients showed more favorable graft survival than that of young-to-young transplants. CONCLUSION: This study demonstrated that DRAG and a fixed donor age limit could be significant factors to predict graft survival after LDLT. Patients should carefully consider the worse graft survival if the donor is older than the recipient by >=20. PMID- 24157023 TI - Unification venoplasty to cope with recipient portal vein anomaly during living donor liver transplantation. AB - PURPOSE: To cope with recipient portal vein (PV) anomalies, such as early branching of the right posterior section (RPS), during living donor liver transplantation (LDLT) surgery, we performed a simulation study to standardize the surgical technique for unification portal venoplasty. METHODS: This study included an observational analysis of conventional methods utilizing RPS PV, simulation-based design of a new surgical technique, and clinical application of this new technique. RESULTS: In a case encountering RPS PV, a mild anastomotic PV stenosis was persistent over 6 months postsurgery, indicating the need for technical refinement. After computational simulation analysis, we found that simple suturing of the PV branch patch automatically resulted in a funnel-shaped elongation. A prospective recipient study (n = 30) indicated that usual PV reconstruction via the PV bifurcation method is feasible in the absence of unusual donor or recipient PV anomaly. Retrospective living donor PV anatomy analysis (n = 20) revealed that 20-mm-long limbs of the first-order PV branches are necessary to make a 10- to l5-mm-long funneled PV stump. This technique of unification venoplasty for an anomalous recipient PV was applied to an adult patient undergoing LDLT with a right liver graft, for which it was shown to be technically feasible and effective. CONCLUSIONS: A simplified unification venoplasty technique was developed to cope with a recipient PV anomaly in adult LDLT. PMID- 24157025 TI - Effect of donor-recipient age gradient on graft outcomes in deceased donor liver transplantation. AB - PURPOSE: Donor age is a well-known factor influencing graft function after deceased donor liver transplantation (DDLT). However, the effect of donors older than recipients on graft outcomes remains unclear. This study investigated the relationship between the donor-recipient age gradient (DRAG) and posttransplant outcomes after DDLT. METHODS: We included 164 adult recipients who underwent DDLT between May 1996 and April 2011. Patients were divided into 2 groups according to the value of DRAG: Negative (DRAG -20 to -1; n = 99) versus positive (DRAG 0-20; n = 65). Medical records were reviewed and laboratory data were retrospectively collected. RESULTS: The median age of donors and recipients was 43 (range, 10-80) and 46 (range, 19-67) years, respectively. The mean follow-up time was 57.4 months. A positive DRAG had a negative effect on levels of alkaline phosphatase until 2 weeks after transplantation. However, the positive group showed a lower incidence of hepatitis B viral disease recurrence. The 1-, 3-, and 5-year graft survival rates were 80.4%, 76.8%, and 71.4% in the negative group, and 65.8%, 58.4%, and 56.3% in the positive group, respectively. The positive DRAG group showed significantly inferior graft survival compared with the negative DRAG group (P = .036). CONCLUSION: This study demonstrated that donors older than recipients had a deleterious effect on graft outcomes. DRAG could be a meaningful determinant of graft survival among DDLT recipients. PMID- 24157026 TI - Comparison of the incidence of de novo malignancy in liver or kidney transplant recipients: analysis of 2673 consecutive cases in a single center. AB - PURPOSE: An increased incidence of de novo malignancy (dM) is an established complication among solid organ transplant (SOT) recipients compared with the general population. The aims of this study were to describe the incidence and cumulative risk for development of dM among our transplanted population, depending on various clinical and pathologic variables. METHODS: We retrospectively reviewed the medical records and pathologic data of SOT recipients performed from February 1995 to December 2010. RESULTS: Among 2673 consecutive SOT recipients, the dM that developed in 66 (2.5%) patients included, 16 (0.6%; 24.2% of overall dM) lymphoid dM and 50 (1.9%; 75.8% of overall dM) nonlymphoid dM. Cumulative incidence of dM in liver was significantly higher than that in kidney transplant recipients. A significantly higher cumulative incidence of dM was observed among living donor versus deceased donor SOT. Although the more frequent development of lymphoid dM was observed during the first year posttransplantation, the cumulative risk of nonlymphoid dM increased year by year, reaching a substantially higher incidence than that of lymphoid dM beyond 5 years after SOT. Comparing the various immunosuppressive regimens, the cumulative incidence was greater among the group with basiliximab induction. However, the hazard of occurrence was unaffected by whether tacrolimus or cyclosporine was used for maintenance immunosuppression. The increased risk of dM was not dependent on recipient age or gender. CONCLUSION: This study demonstrated distinctive cumulative incidences of dM in different clinical and pathologic settings. PMID- 24157027 TI - Characteristics of recipients who achieved spontaneous operational tolerance in adult liver transplantation. AB - BACKGROUND: Chronic immunosuppression is associated with unwanted adverse effects and increased morbidities. Long-term acceptance of transplanted organs without the requirement for immunosuppression, or operational tolerance, remains an important goal in clinical transplantation. METHODS: We reviewed the characteristics of recipients who achieved spontaneous operational tolerance after liver transplantation (OLT) among a consecutive series of 1014 adult recipients in a single center. RESULTS: We observed 5 cases (0.5%) of operational tolerance. All cases were men who underwent transplantations for hepatitis B virus-related liver cirrhosis. The mean time from OLT to achievement of spontaneous operational tolerance was 83.1 +/- 62.9 months (range, 21.3-156.2). Characteristics common to all tolerant recipients were superior graft quality and good pretransplant recipient condition: specifically, high graft-recipient weight ratio (median, 1.18; range, 1.15-2.69), low hepatic macrosteatosis (median, 3; range, 0-15), low score of model for end-stage liver disease (median, 13; range, 7-21), and no history of preoperative intensive care. PMID- 24157028 TI - Graft function measured by transient elastography in living donor liver transplantation: preliminary. AB - INTRODUCTION: Liver stiffness measurements (LSMs) using transient elastography (TE) provide a noninvasive means to assess liver fibrosis that correlate with hepatic cholestasis. However, few studies have examined the correlation of TE to obtain LSMs with perioperative clinical and laboratory parameters in living donor liver transplantation (LDLT). PATIENTS AND METHODS: We retrospectively reviewed forty-eight subjects who underwent LDLT between November 2010 and October 2012. All donors and recipients underwent TE, abdominal computed tomography (CT), and biochemical tests within 1 month before and at 1 week after transplantation. Using a cut-off LSM of 7.5 kPa, which we arbitrarily assigned to be indicative of significant fibrosis, we divided our study population into <=7.5 kPa (group L; n = 15, 31.3%) versus >7.5 kPa; (group H; n = 33, 68.8%). RESULTS: Pretransplantation serum total bilirubin, international normalized ratio, and Model for End-stage Liver Disease scores of recipients were significantly higher in group H than group L. Regarding the pretransplantation donor characteristics, the graft-recipient weight ratio was significantly smaller among those in group H (P = .039). In addition, the post-transplantation 1-week serum total bilirubin level was significantly higher in group H (2.3 mg/dL versus 1.2 mg/dL, P = .015), although neither biliary complications norhepatic congestion was identified by abdominal CT. Among the 1-week post-transplantation laboratory findings, only total bilirubin positively correlated with LSM (P = .044). CONCLUSIONS: This pilot study suggested that a high LSM after LDLT suggests intrahepatic cholestasis and portal hypercirculation in the graft, irrespective of liver fibrosis, outflow obstruction, or biliary obstruction. PMID- 24157029 TI - Long-term survival outcomes for living donor liver transplant recipients with pathologically nonviable hepatocellular carcinoma. AB - PURPOSE: Complete necrosis of hepatocellular carcinoma (HCC) lesions has occasionally been found by explant pathology after pretransplant neoadjuvant treatment. This study sought to investigate the long-term prognostic effect of loss of tumor viability after HCC treatment in living donor liver transplant (LDLT) recipients. METHODS: We reviewed retrospectively the 5-year records of 37 patients who demonstrated nonviable HCC on explant pathology. RESULTS: The most common primary disease was hepatitis-B-virus-associated liver cirrhosis (n = 34). Single explant tumors were found in 29 patients; the mean maximal tumor size was 2.1 +/- 0.9 cm (range: 0.8-4.0). No patients showed microvascular invasion. The median level of alpha-fetoprotein was 12 ng/mL (range: 1-1160). The 1 patient who showed a recurrence at 20 months remains alive more than 6 years after adrenalectomy and repeated pulmonary metastasectomy. The 5-year HCC recurrence rate was thus 2.1%. There were 2 late mortalities, each due to graft failure and recurrent gastric cancer. The overall patient survival rate was 97.3% at 5 and 92.7% at 10 years. CONCLUSIONS: The results of this study revealed that the loss of tumor viability induced by pretransplant neoadjuvant treatment definitely decreased the risk of post-transplant HCC recurrence. Therefore, patients with nonviable HCC can be regarded as members of a superselect group with minimal risk for HCC recurrence, and may be exempted from routine HCC screening. PMID- 24157030 TI - A pilot study on the safety and efficacy of generic mycophenolate agent as conversion maintenance therapy in stable liver transplant recipients. AB - PURPOSE: The patent covering mycophenolate mofetil (MMF) in Korea has expired and, thus, several generic MMF agents are now commercially available. The supply of Cellcept (Roche Korea) was interrupted at the end of 2011, so it was inevitable that a generic MMF would be used instead. During this period, we performed a prospective pilot study to examine the safety and efficacy of a generic mycophenolate agent (Myconol: Hanmi Pharmaceutical, Seoul Korea) for use as conversion maintenance therapy in stable liver transplantation (OLT) recipients. METHODS: OLT recipients, who were treated with MMF on an outpatient basis from January 2012 to March 2012, attended follow-up interviews conducted. The patients had undergone OLT >= 2 years before the study, had tolerated Cellcept, and showed stable liver function. Fifty-three patients were followed up for more than 3 months after conversion to the same dose of Myconol. RESULTS: After conversion to Myconol, 6 patients (11.3%) experienced new side effects, which disappeared when they reverted to Cellcept (n = 5) or stopped taking Myconol medication (n = 1). The side effects associated with Myconol included gastrointestinal symptoms (indigestion and diarrhea; n = 3), skin eruptions (n = 1), pruritus (n = 1), and insomnia (n = 1). The mean mycophenolic acid levels were 1.71 +/- 0.88 MUg/mL for Cellcept and 1.83 +/- 0.91 MUg/mL for Myconol, which showed a strong correlation (r(2) = 0.92, P < .001). CONCLUSIONS: Myconol showed similar pharmacokinetics to those of Celcept, but a small proportion of patients experienced agent-specific side effects; therefore, patients should be closely monitored when taking Myconol. Also, further studies, with a greater number of patients, are required to identify the full spectrum of drug-associated side effects. PMID- 24157031 TI - Long-term outcome of liver transplantation for combined hepatocellular carcinoma and cholangiocarcinoma. AB - PURPOSE: Combined hepatocellular carcinoma (HCC) and cholangiocellular carcinoma (CCC) is a rare pair of intrahepatic malignancies. Differential diagnosis among combined HCC-CCC, HCC, or CCC can be difficult; thus malignancies other than ordinary HCC are occasionally encountered unexpectedly in explanted liver specimens. The present study analyzed the long-term outcomes of liver transplantation (OLT) among patients with HCC-CCC. METHODS: Between January 1999 and December 2009, we performed 2137 adult OLT at our institution including 15 cases of pathologically confirmed HCC-CCC, who all underwent OLT with a pretransplant diagnosis of HCC. We reviewed retrospectively the medical records of these 15 patients. RESULTS: Their mean age was 58.9 +/- 7.2 years. The median preoperative alpha-fetoprotein level was 32.6 ng/mL. Fourteen patients underwent living donor and one deceased donor OLT. The Milan criteria were met in 12 cases. A single tumor was identified in 8 and multiple lesions in 7 patients. The maximal tumor diameter was 2.9 +/- 1.7 cm. Seven patients experienced tumor recurrences: including 6 within the first 12 months. All of the patients who experienced recurrences died at a median 4 months after that diagnosis. The overall patient survival rates were 66.7% at 1 year and 60.0% at 3 and 5 years. Disease-free patient survival rates were 60.0% at 1 year and 53.3% at 3 and 5 years. CONCLUSIONS: Patients with combined HCC-CCC showed a high rate of early recurrences, particularly within the first year. PMID- 24157032 TI - Comparison between resection and transplantation in combined hepatocellular and cholangiocarcinoma. AB - OBJECTIVE: The treatment of choice for combined hepatocellular and cholangiocarcinoma (cHCC-CC) is surgical resection. However, the efficacy of liver transplantation is not clear. We compared the surgical outcome of hepatic resection and liver transplantation for cHCC-CC. PATIENTS AND METHODS: From 1995 to 2012, 89 patients were diagnosed with cHCC-CC after hepatic resection and 8 patients diagnosed with cHCC-CC after liver transplantation. We excluded 21 patients who were American Joint Committee on Cancer Staging Stage III or IV and lost to follow-up. The outcomes were reviewed retrospectively. RESULTS: The poor prognostic factors in cHCC-CC patients who underwent hepatectomy were large tumor size (>5 cm), small safety margin (<2 cm), and low preoperative albumin level. The disease-free survival (DFS) and overall survival (OS) between the hepatectomy group (n = 68) and the liver transplant group (n = 8) was not statistically different (5-year DFS: 26.2% vs 37.5%, P = .333; 5-year OS: 42.1% vs 50%, P = .591). In the small tumor subgroup (tumor size <5 cm), the DFS and OS between the 2 surgical procedures was not different, and in the adequate resection margin subgroup (safety margin >2 cm), survival was comparable. CONCLUSIONS: In well selected cases with small tumor size and with preserved liver function, liver resection should be considered when complete resection is possible. PMID- 24157033 TI - Analysis of S gene mutation of the hepatitis B virus in adult liver transplant recipients showing resistance to hepatitis B immunoglobulin therapy. AB - BACKGROUND: A considerable proportion of recipients of liver transplantations who are presented hepatitis B immunoglobulin (HBIG) monotherapy for hepatitis B virus (HBV) prophylaxis develop HBIG resistance. In this study, we investigated the mutation patterns in the major hydrophilic region (MHR) of amino acid sequences 100 to 160. METHODS: Using the gene sequence analyzer for amino acid sequences 0 to 226 in the S/pre-S region we analyzed blood samples of 15 patients showing HBIG resistance after high-dose HBIG prophylaxis. RESULTS: Various mutations in the MHR were observed in 14/15 samples: Gly145Arg mutation in 8/13 Adr subtype and 1/2 Ayw subtype samples (60%). The next most common mutation was Gly165Trp in 8/13 Adr subtype but neither of 2 Ayw subtype samples (53.3%). Concurrent antiviral resistance was noted in 5 patients: lamivudine (n = 5), or entecavir (n = 3), but not adefovir, suggesting the occurrence of simultaneous, antiviral cross-resistances. Two patients underwent retransplantation due to the progression of HBV infection despite vigorous antiviral therapy. At diagnosis of HBV recurrence, the mean HBV DNA load was 6.5 * 10(6) copies/mL; 4 patients showed paradoxical coexistence of anti-HBs and HBsAg. Currently, 2 subjects show low-level HBV DNA replication in peripheral blood, although the other 12 had no DNA replication after prolonged antiviral therapy. CONCLUSIONS: This study suggested that various mutations in the "a" determinant were associated with HBIG resistance. Since treatment failure to rescue antiviral therapy was often associated with delayed detection of HBV recurrence rather than concurrent antiviral resistance, frequent HBV surveillance using more sensitive screening tests, such as HBeAg and HBV DNA polymerase chain reaction assay, seems to be mandatory. PMID- 24157034 TI - Clinical outcomes and risk factors of hepatitis B virus recurrence in patients who received prophylaxis with entecavir and hepatitis B immunoglobulin following liver transplantation. AB - INTRODUCTION: Although entecavir (ETV) and hepatitis B immunoglobulin (HBIG) have widely been used for prophylaxis of hepatitis B virus (HBV) recurrence following liver transplantation (OLT), there have been few studies about clinical outcomes and risk factors of HBV recurrence. MATERIALS AND METHODS: This study retrospectively assessed clinical outcomes and identified risk factors of post transplant HBV recurrence in 154 patients who received prophylaxis with both ETV and HBIG after OLT. RESULTS: The median follow-up duration was 28.0 months (range, 1.0-57.8). Post-transplant HBV recurrence occurred in 5 patients (3.2%) without any ETV-resistant mutants. The overall rates of HBV recurrence at 1, 2, and 4 years were 0.6%, 1.6%, and 6.2%, respectively. We found that recurrent hepatocellular carcinoma (HCC) was an independent risk factor of HBV recurrence (hazard ratio = 13.5, 95% confidence interval, 2.4-74.4; P = .006). CONCLUSIONS: Prophylaxis with a combination of ETV and HBIG resulted in a low HBV recurrence rate following OLT without any emergence of ETV-resistant mutants. Recurrent HCC was an independent risk factor of HBV recurrence in patients who received prophylaxis with both ETV and HBIG for prophylaxis following OLT. PMID- 24157035 TI - Clinical outcomes of Pneumocystis carinii pneumonia in adult liver transplant recipients. AB - PURPOSE: Pneumocystis carinii pneumonia (PCP) is an opportunistic infection associated with morbidity and mortality in solid-organ transplant recipients. We retrospectively assessed the characteristics and outcomes of liver transplant (OLT) recipients with PCP compared with those of patients with severe non-P carinii pneumonia (non-PCP) who required intensive care with mechanical ventilation. METHODS: During the 2-year period between January 2008 and December 2009, 43 adult OLT recipients had severe pneumonia requiring mechanical ventilation; of these, 8 (19%) had PCP. During this period, routine antibiotic prophylaxis was administered for the first 6 months after OLT. RESULTS: The median period from OLT to development of PCP was 9.5 months (range, 1-67); the 1 year incidence was 0.9%. The 6 and 6 to 12-month incidences of non-PCP were 4.2% and 0.3%, respectively, and those of PCP were 0.3% and 0.6%, respectively. Four of 8 patients (50%) in the PCP group had a recent history of a rejection episode. PCP was associated with a higher incidence of prior antirejection treatment. There were no significant differences between PCP and non-PCP groups in age, gender, preoperative Model for End-stage Liver Disease score, primary diagnosis, graft type, and total number of rejection episodes. CONCLUSIONS: These results indicate that the risk of PCP in OLT recipients is closely related to strong immunosuppressive treatment for acute cellular rejection episodes, suggesting the importance of PCP prophylaxis in these patients. Because most patients developed PCP at around 1 year, it may be advisable to prolong routine post-OLT PCP prophylaxis for 12 months, especially among patients receiving antirejection treatment. PMID- 24157036 TI - Strategies to reduce infectious complication using epidemiologic data analysis in liver transplant recipients. AB - BACKGROUND: Infectious complications are major factors for morbidity and mortality in liver transplant recipients. To establish a proper strategy to reduce infectious complications, we analyzed epidemiologic and risk factors for post-transplant infections. METHODS: We analyzed the medical records of 231 consecutive liver transplant recipients from December 2007 to November 2011, including at least 1-year follow up, for comparison with those from 1996 to 2005. RESULTS: Among 231 patients, 126 (54.5%) experienced 244 infectious episodes, a rate of 1.05 per patient. Among overall mortality of 9.9% (23/231), infections were more prevalent (P = .04). Predominant infections were postoperative intra abdominal problems (36.1%), peritonitis (15.2%), pneumonia (13.5%), bacteremia (4.1%), wound complications (1.6%), viral etiologies (18.0%), and other causes (11.5%). Causative organisms were bacterial (68.9%), viral (14.7%), fungal (7.0%), and unproven ones (9.4%). Multivariate analysis of risks for infection showed significant impacts of Model for End-stage Liver Disease score [P = .027; odds ratio (OR), 1.04], post-transplant biliary complications (P < .001; OR, 3.50), and rejection episodes (P = .023; OR, 3.39). Mortality was related to retransplantation (P = .003), post-transplant dialysis (P = .006), and infection (P = .056) upon univariate analysis, none of which were significant in multivariate analysis. Compared with data from the previous period, overall and infection-related mortality decreased from 24.5% to 9.9% and 52.9% to 26.1%, respectively. There were no significant changes in the types of infection or rate of drug-resistant bacteria, but candidal infections and cytomegalovirus reactivations were more prevalent. CONCLUSION: Our data showed current perioperative antimicrobial regimens need not be changed: however, new strategies are needed to reduce infectious complications after liver transplantation, to reduce biliary complications and to properly manage rejection episodes. PMID- 24157037 TI - Pre-emptive therapy for the cytomegalovirus infection after liver transplantation in endemic areas and its optimal diagnostic method. AB - BACKGROUND: The incidence of positive cytomegalovirus (CMV) IgG tests among Asian populations is high. Both universal prophylaxis and pre-emptive therapy (PT) have been recommended for the moderate-risk group (D+/R+), whose incidence of CMV infection has been reported variously, and for whom the optimal diagnostic method has not been firmly established. Herein, we sought to analyze our experience with CMV infections using PT and to discuss the optimal diagnostic method. METHODS: We retrospectively, analyzed 32 consecutive liver transplant recipients between December 2009 and April 2012 for clinicopathologic data including mortality and rejection rates, comparing 2 diagnostic tools for CMV: pp65 antigen assay and real-time reverse-transcriptase polymerase chain reaction (RT-PCR). RESULTS: Twenty-one patients (65.6%) were positive for the CMV antigen assay, and 13 (40.6%) had positive RT-PCR results. There were no cases of CMV disease during the follow-up and no difference in rejection (P = .529) or mortality (P = .471) rates with regard to PCR positivity. The mean diagnosis time was 26.5 days postoperative. Among the patients who exhibited negative RT-PCR results, 7 (41.18%) were positive on the pp65 antigen assay. CONCLUSION: CMV infection rates were higher when compared to same-risk population from Western countries. As a diagnostic tool for CMV infection, screening with the pp65 antigen assay and confirmation with real-time RT-PCR seemed to provide an optimal diagnostic tool. PMID- 24157038 TI - Post-transplant assessment of consciousness in acute-on-chronic liver failure patients undergoing liver transplantation using bispectral index monitoring. AB - PURPOSE: Deterioration of consciousness is a critical situation for liver transplantation (OLT) recipients. The bispectral (BIS) index based on electroencephalographic parameters, is primarily used to monitor the depth of unconsciousness. The present study sought to assess the usefulness of posttransplant BIS index to monitor acute-on-chronic liver failure patients. METHODS: This 1-year retrospective study of 28 adult patients with acute-on chronic liver failure was performed from July 2011 to June 2012, using post transplant BIS monitoring. RESULTS: The mean patient age was 51 +/- 8 years. Their mean pretransplant Child-Turcotte-Pugh score was 12.3 +/- 1.4, and the mean Model for End-stage Liver Disease score, 36.4 +/- 5.9. After OLT, the mean initial Glasgow Coma Scale (GCS) score and BIS index were 3.4 +/- 1.7 and 43.5 +/ 9.1, respectively. After 6 hours the mean GCS and BIS values rose to 8.6 +/- 4.0 and 52.4 +/- 10.3 and after 12 hours to 9.7 +/- 3.4 and 61.3 +/- 15.7 respectively. Eye opening in response to a voice occurred at a mean of 8.9 +/- 6.7 hours after arrival in the intensive care unit regardless of graft function. The mean GCS and BIS values were 10.6 +/- 2.8 and 69.1 +/- 13.5, respectively. The endotracheal tube was removed after a median of 140 hours; 9 patients required a tracheostomy. Among them 2 died within the first 3 months after OLT. CONCLUSIONS: BIS monitoring is a noninvasive, simple, easy-to-interpret method to measure consciousness among patients intubated with an endotracheal tube. PMID- 24157039 TI - Clinical outcome of idiopathic hepatic parenchymal infarct following living donor liver transplantation. AB - PURPOSE: The aim of the present study was to examine the clinical course of nonvascular hepatic ischemia following adult living donor liver transplantation (LDLT). METHODS: This retrospective study reviewed the medical records of 1782 patients who underwent LDLT from January 2003 to September 2010. Nine subjects (0.5%) suffered idiopathic hepatic parenchymal infarcts (IHPI) classified according to the morphology and extent of the infarcted area as peripheral or central. RESULTS: Increased levels of liver enzymes were observed in all IHPI patients. Liver cell damage closely correlated with the extent of the infarcted area. Most patients with peripheral-type IHPI showed favoarable spontaneous recovery, occasionally requiring liver support with plasmapheresis or a prolonged period. By contrast, 2 patients with central-type IHPI died due to progressive expansion of the infarcted area with subsequent graft failure. CONCLUSIONS: In the present study the incidence of IHPI following LDLT was 0.5%. The severity of the infarct depended upon its location and size; central-type IHPI showed a worse prognosis. Thus, special attention should be paid to patients showing a central type infarction. PMID- 24157040 TI - Risk-based long-term screening for hepatocellular carcinoma recurrence after living donor liver transplantation. AB - BACKGROUND: This study sought to establish an actual risk-based long-term screening protocol for hepatocellular carcinoma (HCC) recurrence after liver transplantation (OLT). METHODS: The study was a retrospective review of medical records from 334 HCC patients who underwent primary living donor OLT and followed up for at least 5 years. RESULTS: Overall 10-year patient survival rate was 67.5%, with a 4.8% perioperative mortality. HCC recurred in 68/318 (21.4%) surviving patients over a mean follow-up of 77 months. HCC recurrence was 20.7% at 5 and 22.2% at 10 years. Annual recurrence rates were 11.4%, 6.6%, and 2.0% during the first, second, and third years, respectively. Among patients within Milan criteria, the annual incidence of HCC recurrence was highest during the first 3 years; thereafter only 6 sporadic recurrences were observed during next 8 years. Among subjects beyond Milan criteria, recurrence was common during, but not after 3 years. In 43 patients (63.2%) increased alpha-fetoprotein (AFP) was an initial indication to perform further imaging studies to diagnosis recurrence, whereas they were detected incidentally on protocol screening imaging among another 25 patients (36.8%) in the absence of an AFP rise. There was a close correlation between pretransplant AFP level and AFP increase after HCC recurrence. CONCLUSIONS: Patients beyond the Milan criteria require frequent tumor marker tests and imaging studies over the first 3 years; and those within Milan criteria require 10-years to follow-up primarily with tumor marker tests. PMID- 24157041 TI - Outcomes of alpha 1,3-GT-knockout porcine heart transplants into a preclinical nonhuman primate model. AB - BACKGROUND: Solid organ xenotransplantation is a potential solution to current organ shortages in allotransplantation. We performed four heart transplantations from alpha1, 3-galactosyltransferase gene-knockout (GT-KO) pigs to cynomolgus monkeys and monitored immunological parameters before and after transplantation. METHODS: After blood typing of the cynomolgus monkeys, we assessed the binding activity of immunoglobulin G (IgG) and IgM of monkey serum and serum toxicity toward porcine peripheral blood mononuclear cells (PBMCs) using flow cytometry. Immunosuppressive protocols consisted of anti-thymocyte globulin (25 mg/kg), rituximab (20 mg/kg), anti-CD154mAb (20 mg/kg), cobra venom factor (0.05 mg/kg), tacrolimus, and steroid. Cynomolgus monkeys with A or AB blood type with the lowest antibody binding and serum toxicity activity on porcine PBMCs were selected as recipients. RESULTS: Absolute numbers of CD3(+) T cells, CD20(+) B cells, and CD3(+)CD95(+) memory T cells in the peripheral blood were suppressed upto 24 days after transplantation. Interferon gamma production of T cells in response to porcine antigens were also significantly suppressed. Heart xenografts from GT-KO pigs survived for upto 24 days without pathologic evidence of rejection. CONCLUSION: We successfully performed 4 heart xenotransplantations using GT-KO pigs. We overcame hyperacute rejection by using GT-KO pigs, and all of the heart xenografts from the GT-KO pigs survived between 11 and 24 days without pathologic evidence of rejection, disseminated intravascular coagulation, or consumptive coagulopathy; however, we need to optimize protocols for immune modulation and postoperative care to attain long-term survival of solid organ xenografts. PMID- 24157043 TI - Optimal device and method for transportation of isolated porcine islet. AB - INTRODUCTION: We investigated the optimal method for transportation of isolated porcine islets from an isolation facility to a transplant hospital or research center in terms of temperature, oxygen supply, and shaking effect. METHODS: Commercially available insulator boxes with thermoregulators exposed for 5 hours under two external temperatures (4 degrees C and 37 degrees C) were monitored using HOBO temperature loggers. To find the optimal transport device, we compared islet counts, viability, quality, and function in conical tubes, gas-permeable bags (GPB) and gas-permeable flasks (GPF) after 1, 3 and 5 hours. To evaluate the effects of shaking on islets, we also analyzed the difference between a control and a shaking group in each device with time. RESULTS: Commercially available Styrofoam insulators with thermoregulators maintained the internal temperature near the target. Islet recovery rate for GPF, which was higher than other devices, was maintained, while those decreased with time for conical tube and GPB containers adenosine diphosphate/adenosine triphosphate (ADP/ATP) ratio for GPF was lower than other devices, albeit not significantly fluoroscein acrimide/propidium iodide (AO/PI) ratio for GPF was higher than other devices after 5 hours. Glucose stimulated index was not different among the devices. In comparison with the control group, shaking yielded comparable islet survival, viability and function. CONCLUSION: Our study demonstrated that the use of commercially available insulator boxes with thermoregulators maintained internal temperature close to the target value and that GPF was more favorable for islet oxygenation during transportation. This study also suggested negligible impact of shaking on isolated porcine islets during transportation. PMID- 24157042 TI - Fabrication of a biodegradable xenoantigen-free rat liver scaffold for potential drug screening applications. AB - BACKGROUND: The increasing market in biological pharmaceuticals raises the demand for human test systems. Although 2-dimensional (2D) models are mostly used for these purposes, these models not mimic responses of 3-dimensional (3D) native tissue. METHODS: After generation of a rat liver scaffold using 0.1% sodium dodecyl sulfate, we characterized the histology, blood vessel integrity, and residual DNA as well as retained amounts of collagen and glycosaminoglycan (GAG). Then, we examined the susceptibility of extracellular matrix (ECM) to enzymatic remodeling. Finally, a mixed lymphocyte reaction (MLR) was performed to evaluate the in vitro immunogenicity of the ECM against human peripheral blood mononuclear cells (PBMCs). RESULTS: Histologic examination of decellularized liver revealed the removal of nuclear and cytoplasmic materials with preservation of architecture. The vascular network was intact after decellularization. Biochemical analysis of ECM components revealed that only a negligible amount of DNA was retained compared with the native liver with preservation of large amounts of GAG and collagen. Scaffolds were degraded in response to collagenase treatment. MLR demonstrated that decellularized matrices did not exert any xenostimulatory response against human PBMCs. CONCLUSION: Our findings suggested that naturally derived rat liver scaffolds show natural biocompatibility besides the ability to preserve the intact 3D structure and components. Because of these characteristics, the whole decellularized rat liver can retain many aspects of native tissue structure and function upon recellularization enabling it to be used for drug screening. PMID- 24157044 TI - Mouse adipose tissue-derived adult stem cells expressed osteogenic specific transcripts of osteocalcin and parathyroid hormone receptor during osteogenesis. AB - INTRODUCTION: Adult mesenchymal stem cells (MSCs) have potential to differentiate into various lineages, replacing cells during normal turnover and tissue regeneration to replace damaged or lost adult tissues during osteoporosis and arthritis, or traumatic injuries. We investigated the osteogenic signature in mouse adipose tissue (AD)- and bone marrow (BM)-derived MSCs. MATERIALS AND METHODS: MSCs from adipose tissue and bone marrow were compared for osteogenic endogenous mRNA markers by reverse-transcription polymerase chain reaction (RT PCR). Cellular proliferation and immunophenotype analyzed by flow cytometry revealed that mouse AD-MSCs and BM-MSCs shared similar characteristics. RESULT: Isolated AD-MSC and BM-MSC showed high proliferation rates and fibroblast morphology. Flow cytometry revealed positive markers for mesenchyme, but negative for primitive hematopoietic and endothelial cells. At day 21, Alizarin red S and Von-kossa staining of differentiated cells showed high calcium deposits compared with undifferentiated cells. After 21 days of osteogenic differentiation, AD-MSCs expressed osteocalcin and parathyroid hormone (PTH) compared with undifferentiated cells. Osteogenic-specific transcript of osteocalcin (OC), bone gamma carboxyglutamate protein, and PTH receptor (PTHr) were detected only in differentiated not undifferentiated cells. Undifferentiated BM-MSCs, expressed all markers at low intensity, which amplified during differentiation. CONCLUSION: Our findings suggest that the OC and PTHr can be used as differentiation markers for osteogenesis of mouse AD-MSC. PMID- 24157045 TI - New culture medium concepts for cell transplantation. AB - BACKGROUND: Before cell or tissue transplantation, cells or tissues have to be maintained for a certain period in vitro using culture medium and methods. Most culture media contain substances such as pH indicators and buffers. It is not known whether some of these substances are safe for subsequent application in the transplantation of cells or tissues into the human body. We investigated culture media and methods with respect to the safety of the components in future transplantation applications. METHODS: A modified culture medium--medical fluid based culture medium (FCM)--was designed by using various fluids and injectable drugs that are already currently permitted for use in clinical medicine. Medium components necessary for optimal cell growth were obtained from approved drugs. FCM was manufactured with adjusted final concentrations of the medium components similar to those in commercial Dulbecco's modified Eagle's medium (DMEM). In particular, 1029.40 mg/L amino acids, approximately 88.85 mg/L vitamins, 13,525.77 mg/L inorganic salts, and 4500 mg/L D-glucose comprise the high-glucose FCM. Next, human fat synovium-derived mesenchymal stem cells and rat H9c2 (2-1) cells were cultured under 2 conditions: (1) DMEM-high glucose (HG), an original commercial medium, and (2) optimized FCM-HG. We assessed the morphologies and proliferation rates of these cells. RESULTS: We observed that FCM-HG was able to induce the growth of FS-MSC and commercially available H9c2 cell. The morphologies and proliferation patterns of these cells cultured under FCM-HG showed no differences compared with cells grown in DMEM-HG. CONCLUSION: Our data suggest that FCM, which we developed for the first time according to the concept of drug repositioning, was a useful culture medium, especially in cultured cells intended for human cell transplantation. PMID- 24157046 TI - Pseudoislet of hybrid cellular spheroids from commercial cell lines. AB - Investigators conducting diabetes-related research have focused on islet transplantation as a radical therapy for type 1 diabetes mellitus. Pancreatic islet isolation, an essential process, is a very demanding work because of the proteolytic enzymes, species, treatment time, and individual difference. Replacement of primary isolated pancreatic islets must be carried out continuously for various in vitro tests, making primary isolated islets a useful tool for cell transplantation research. Hence, we sought to develop pseudoislets from commercial pancreas-derived cell lines. In this study, we used RIN-5F and RIN-m cells, which secrete insulin, somatostatin, or glucagon. To manufacture hybrid cellular spheroids, the cells were cultured under hanging drop plate and nonadhesive plate methods. We observed that hybrid cellular pseudoislets exhibited an oval shape, with sizes ranging from 590 to 1200 MUm. Their morphology was similar to naive islets. Cell line pseudoislets secreted and expressed insulin, glucagon, and somatostatin, as confirmed by reverse transcriptase polymerase chain reaction, enzyme-linked immunosorbent assay, and immunohistochemistry analyses. Thus, the current artificially manufactured biomimetic pseudoislets resembled pancreatic islets of the endocrine system, appearing as cellular aggregates that secreted insulin, glucagon, and somatostatin. Enhanced immunoisolation techniques may lead to the development of new islet sources for pancreatic transplantation through this pseudoislet strategy. PMID- 24157047 TI - Novel supplier of mesenchymal stem cell: subacromial bursa. AB - Mesenchymal stem cells (MSCs) are multipotent stromal elements that can differentiate into a variety of cell types. MSCs are good sources of therapeutic cells for degenerative diseases. For these reason, many researchers have focused on searching for other sources of MSCs. To obtain MSCs for clinical use requires surgery of the donor that therefore can induce donor morbidity, since the common sources at present are bone marrow and adipose tissues. In this study, we investigated the existence of MSCs in postoperative discarded tissues. Subacromial bursal tissues were obtained from the shoulders of 3 injured patients. The cells from the bursa tissues were isolated through treatment with collagenase. The isolated cells were then seeded and expanded by serial passaging under normal culture system. To evaluate MSC characteristics of the cells, their MSC markers were confirmed by mRNA and protein expression. Multipotent ability was assessed using differentiation media and immunohistochemistry. Cells from the bursa expressed MSCs markers-CD29, CD73, CD90, and PDGFRB (platelet-derived growth factor receptor-beta). Moreover, as to their multipotency, bursal cells differentiated into adipocytes (fat cells), osteocytes (bone cells), and chondrocytes (cartilage cells). In summary, we showed that MSCs could be generated from the subacromial bursa, which is medical waste after surgery. PMID- 24157048 TI - Fragmin/protamine microparticle carriers as a drug repositioning strategy for cell transplantation. AB - BACKGROUND: The importance of drug repositioning has been gaining attention in the last few years, allowing existing pharmaceutical products to be reevaluated for potential alternative therapeutic applications. The purpose of this study was to evaluate the effects of fragmin/protamine microparticles (F/P MPs) on cell aggregates under the concept of drug repositioning. METHODS: Mesenchymal stem cells (MSCs) and embryonic rat heart-derived cardiac H9C2 cells were mixed with D PBS, basal medium, fragmin, protamine, and F/P MPs to manufacture aggregates intended for cell transplantation. To evaluate their adhesive properties as cell carriers, we injected combinations of MSC aggregates into cartilage tissue, observing their leakage from the implantation site. RESULTS: Our data demonstrated that MSCs and H9C2 cells mixed with F/P MPs rapidly produced large, viscous cellular aggregates. F/P MPs were bound to the surface of MSCs and H9C2 cells; thus, F/P MPs induced the formation of F/P MP-cell aggregates. Cell aggregates were prevented from leaking from the transplanted site. CONCLUSION: Aggregation induced by F/P MPs may improve the efficiency of cell therapy, a novel method for transplantation. PMID- 24157049 TI - L-carnitine protects against cyclosporine-induced pancreatic and renal injury in rats. AB - BACKGROUND: L-carnitine has protective effects against various types of injury. This study was designed to evaluate the beneficial effects of L-carnitine on pancreatic and renal injuries caused by cyclosporine (CsA). METHODS: Rats maintained on a low sodium diet were given vehicle (olive oil, 1 mL/kg/d), CsA (15 mg/kg/d), L-carnitine (50 or 200 mg/kg/d), or a combination of CsA and L carnitine for 4 weeks. The impact of L-carnitine on pancreatic injury was assessed by blood glucose levels, plasma insulin concentrations, and hemoglobulin A1c (HbA1c). In addition, the protective effects of L-carnitine against CsA induced kidney injury were evaluated in terms of renal function, histopathology (inflammatory cell influx and tubulointerstitial fibrosis), oxidative stress (8 hydroxy 2'-deoxyguanosine, 8-OHdG), transforming growth factor-betal (TGF-beta1), apoptosis (caspase-3), and autophagy (LC3-II). RESULTS: CsA treatment caused diabetes, renal dysfunction, tubulointerstitial inflammation (ED-1-positive cells), and fibrosis, which were accompanied by an increase in 8-OHdG production and upregulation of TGF-beta1, caspase-3, and LC3-II. Concomitant administration of L-carnitine increased plasma insulin concentrations, decreasing plasma glucose and HbA1c levels. In the kidney, L-carnitine induced dose-dependent improvement of renal function, inflammation, and fibrosis in parallel with suppression of the expression of TGF-beta1 and 8-OHdG. Furthermore, the administration of L carnitine at a high dose inhibited the expression of caspase-3 and LC3-II. CONCLUSION: These findings suggest that L-carnitine has a protective effect against CsA-induced pancreatic and renal injuries. PMID- 24157050 TI - No-touch en bloc right lobe living-donor liver transplantation with inferior vena cava replacement for hepatocellular carcinoma close to retrohepatic inferior vena cava: case report. AB - Current studies have shown that living-donor liver transplantation (LDLT) for hepatocelluar carcinoma (HCC) satisfying the Milan criteria does not compromise patient survival or increase HCC recurrence compared with deceased-donor liver transplantation (DDLT). For patients with HCC beyond the Milan criteria, however, worse outcomes are expected after LDLT than after DDLT, despite insufficient data to reach a conclusion. Regarding operative technique, LDLT might be a less optimal cancer operation for HCC located at the hepatic vein confluence and/or paracaval portion. The closeness to the wall of the retrohepatic inferior vena cava (IVC) is greater than in conventional DDLT, rendering it difficult to perform a no-touch en bloc total hepatectomy. An LDLT, which must preserve the native IVC for the piggyback technique during engraftment, may lead to tumor remnants. To reduce recurrences after LDLT, we successfully performed a no-touch en bloc total hepatectomy including the retrohepatic IVC and all 3 hepatic veins. IVC replacement with an artificial vascular graft together with a modified right lobe LDLT was performed for a patient having advanced HCC close to the hepatic vein confluence and paracaval portion. There was no artificial vascular graft related complication, such as thrombosis or infection. Despite the limitations of LDLT, requiring the piggyback technique for graft implantation, IVC replacement using an artificial graft led us to perform a no-touch en bloc total hepatectomy as with a conventional DDLT. PMID- 24157052 TI - A case of everolimus-associated chylothorax in a cardiac transplant recipient. AB - We herein report a case of putative everolimus-associated chylothorax in a cardiac transplant recipient. A 17-year-old Japanese boy with dilated cardiomyopathy and severe cardiac failure requiring left ventricular assist support was determined to be a cardiac transplant candidate in 1992. He underwent overseas heart transplantation in Houston, Texas in October 1992. He was subsequently treated with immunosuppression therapy: Cyclosporine (CSA), azathioprine, and prednisolone (PRD). After several acute rejection episodes requiring steroid therapy, intravascular ultrasonography revealed a moderate degree of transplant coronary arterial vasculopathy (TCAV) with 50% stenosis in 2003. He underwent coronary stenting twice; the immunosuppressive regimen was converted to CSA, mycophenolate mofetil, everolimus (EVL), and PRD in 2006. TCAV has not progressed since then. In October 2008, chest x-ray showed bilateral pleural effusion. As we thought that the pleural effusion was caused by cardiac dysfunction due to moderate mitral regurgitation and TCAV as well as renal impairment, he was treated with diuretics and digoxin. However, the pleural effusion progressed gradually associated with exertional dyspnea and moderate edema of his lower legs. Chest computed tomography showed massive bilateral pleural effusions without evidence of malignancy in 2011. A pleural tap in 2011 revealed chylothorax. Although mammalian target of rapamycin inhibitors were major drugs for lymphoangioleimyomatosis, we believed that the chylothorax was associated with EVL. EVL was discontinued in March 2011: the chylothorax spontaneously resolved in November 2011. PMID- 24157051 TI - Jejunal artery can be a useful option for arterial reconstruction in living donor liver transplantation when the suitable arterial inflow is absent. AB - Successful arterial reconstruction is essential for liver transplantation. In the case of inadequate arterial inflow, an arterial conduit from the aorta using artery graft or re-establishment of arterial flow through other arteries such as the splenic artery, gastroepiploic, or sigmoid artery is considered. Herein we report our experience of 27 cases of hepatic artery reconstruction using alternative methods. The most common cause of hepatic artery reconstruction requiring alternative methods was intimal dissection for which we usually used the gastroepiploic artery. Many patients had a previous operation or transarterial chemoembolization history. Among these cases, hepatic artery reconstruction using the jejunal artery was performed for 2 cases of living donor liver transplantation due to the absence of suitable alternatives. These patients have been followed up with patent hepatic arterial flow until now. Thus, the jejunal artery can be a useful option for arterial reconstruction in living donor liver transplantation when suitable arterial inflow is absent. PMID- 24157053 TI - Successful extracorporeal membrane oxygenation for right heart failure after heart transplantation-2 case reports and literature review. AB - After heart transplantation (HT), transient right heart failure (RHF) is common. If it does not improve with appropriate medical therapy, we must consider mechanical support. Recently, extracorporeal membrane oxygenation (ECMO) has shown better results than a right ventricular assist device or retransplantation. Two HT patients with hypertrophic cardiomyopathy had cold ischemic times beyond >240 minutes. After HT, their right heart function worsened and was unresponsive to medical therapy. After our application of ECMO, weaning was successful and the patients were discharged without complication. Early application of ECMO for RHF after HT is a good option. PMID- 24157055 TI - Effects of antihypertensive treatment in Asian populations: a meta-analysis of prospective randomized controlled studies (CARdiovascular protectioN group in Asia: CARNA). AB - To examine the effects of antihypertensive treatment on cardiovascular disease (CVD) in Asian populations, we systematically evaluated prospective randomized studies carried out in Asia (1991-2013). We identified 18 trials with 23,215 and 21,986 hypertensive patients in the intervention (ie, strict blood pressure [BP] lowering or add-on treatment) and reference groups, respectively (mean age, 65 years; follow-up duration, 3.2 years). Analysis was performed through 1) first subgroup: eight trials that compared active antihypertensive treatment with placebo or intensive with less intensive BP control and 2) second subgroup: 10 trials that compared different antihypertensive treatments. In the first subgroup analysis, BP was reduced from 160.3/87.3 mm Hg to 140.2/78.4 mm Hg in the intervention group with a -6.7/-2.2 mm Hg (P < .001) greater BP reduction than the reference group. Compared with the reference group, the intervention group had a lower risk of composite CVD events (odd ratio [OR], 0.73; 95% confidence interval [CI], 0.66-0.81), myocardial infarction (OR, 0.79; 95% CI, 0.63-1.0), stroke (OR, 0.71; 95% CI, 0.63-0.80), and CVD mortality (OR, 0.81; 95% CI, 0.68 0.97; all P <= .05). In the second subgroup analysis, no difference was found for any outcome between renin-angiotensin blockers and calcium-channel blockers or diuretics. The meta-regression line among the 18 trials indicated that a 10 mm Hg reduction in systolic BP was associated with a reduced risk for composite CVD events (-39.5%) and stroke (-30.0%). Our meta-analysis shows a benefit when a BP target of less than 140/80 mm Hg is achieved in Asian hypertensives. BP reduction itself, regardless of BP lowering agents, is important for achieving CVD risk reduction. PMID- 24157054 TI - Legume growth-promoting rhizobia: an overview on the Mesorhizobium genus. AB - The need for sustainable agricultural practices is revitalizing the interest in biological nitrogen fixation and rhizobia-legumes symbioses, particularly those involving economically important legume crops in terms of food and forage. The genus Mesorhizobium includes species with high geographical dispersion and able to nodulate a wide variety of legumes, including important crop species, like chickpea or biserrula. Some cases of legume-mesorhizobia inoculant introduction represent exceptional opportunities to study the rhizobia genomes evolution and the evolutionary relationships among species. Complete genome sequences revealed that mesorhizobia typically harbour chromosomal symbiosis islands. The phylogenies of symbiosis genes, such as nodC, are not congruent with the phylogenies based on core genes, reflecting rhizobial host range, rather than species affiliation. This agrees with studies showing that Mesorhizobium species are able to exchange symbiosis genes through lateral transfer of chromosomal symbiosis islands, thus acquiring the ability to nodulate new hosts. Phylogenetic analyses of the Mesorhizobium genus based on core and accessory genes reveal complex evolutionary relationships and a high genomic plasticity, rendering the Mesorhizobium genus as a good model to investigate rhizobia genome evolution and adaptation to different host plants. Further investigation of symbiosis genes as well as stress response genes will certainly contribute to understand mesorhizobia-legume symbiosis and to develop more effective mesorhizobia inoculants. PMID- 24157057 TI - Evaluation of colorimetric detection methods for Shigella, Salmonella, and Vibrio cholerae by loop-mediated isothermal amplification. AB - We evaluated loop-mediated isothermal amplification end-point detection methods for Salmonella, Shigella, and Vibrio cholerae. Detection sensitivities were comparable to real-time PCR methods. The colorimetric dyes hydroxynaphthol blue and SYBR Green I showed increased sensitivity when compared to visual and automated turbidity readings. End-point colorimetric dyes promise great utility in developing settings. PMID- 24157056 TI - Is physical disease missed in patients with medically unexplained symptoms? A long-term follow-up of 120 patients diagnosed with bodily distress syndrome. AB - OBJECTIVE: Bodily distress syndrome (BDS) was recently introduced as an empirically based, unifying diagnosis for so-called medically unexplained symptoms and syndromes. BDS relies on a specific symptom pattern rather than on a lack of objective findings, which may increase the risk of overlooking physical disease. We investigated whether physical disease was missed in the first patients diagnosed with BDS. METHOD: The study was a register-based follow-up study of 120 patients diagnosed with BDS at a University Clinic from 2005 to 2007. Median follow-up time was 3.7 years. We used data containing all diagnoses from inpatient, outpatient and emergency admissions supplied by systematic review of hospital records. Medical specialists evaluated all cases of suspected overlooked physical disease. RESULTS: According to registered diagnoses, none of the 120 patients had been misdiagnosed with BDS. In five cases [4.2% (95% confidence interval: 1.4-9.5)] though, we found comorbid medical problems that had not been taken properly care of alongside BDS management. These were disc protrusion, degeneration and prolapsus, hip osteoarthritis, anemia and calcific tendinitis. CONCLUSION: The BDS symptom pattern reliably identified patients with multiple medically unexplained symptoms referred to tertiary care. Nevertheless, differential diagnostics remains important in order to identify comorbid medical problems that require additional treatment. PMID- 24157059 TI - Characterization of multidrug-resistant Klebsiella pneumoniae from Australia carrying blaNDM-1. AB - blaNDM genes, encoding metallo-beta-lactamases providing resistance to carbapenems, have been reported in many locations since the initial report in 2008, including in several Enterobacteriaceae isolates in Australia/New Zealand. Here, we compare 4 additional carbapenem-resistant Klebsiella pneumoniae carrying blaNDM-1 isolated in Australia. Two are sequence type ST147, previously associated with blaNDM in Australia and elsewhere. They carry blaNDM-1 and different 16S rRNA methylase genes (armA or rmtC) on different conjugative plasmids, in 1 case with an IncFIIY replicon. One isolate belongs to the globally important ST11 but did not transfer a plasmid to Escherichia coli. The fourth isolate belongs to the novel ST1068 and transferred blaNDM-1, armA, and an IncA/C plasmid. Amplification and sequencing of ompK porin genes suggest that, unlike the case for other carbapenemase genes, ompK36 defects may not be required for NDM to cause clinically relevant levels of carbapenem resistance. PMID- 24157058 TI - Comparison of rpoB gene sequencing, 16S rRNA gene sequencing, gyrB multiplex PCR, and the VITEK2 system for identification of Acinetobacter clinical isolates. AB - Since accurate identification of species is necessary for proper treatment of Acinetobacter infections, we compared the performances of 4 bacterial identification methods using 167 Acinetobacter clinical isolates to identify the best identification method. To secure more non-baumannii Acinetobacter (NBA) strains as target strains, we first identified Acinetobacter baumannii in a total of 495 Acinetobacter clinical isolates identified using the VITEK 2 system. Because 371 of 495 strains were identified as A. baumannii using gyrB multiplex 1 PCR and blaOXA51-like PCR, we performed rpoB gene sequencing and 16S rRNA gene sequencing on remaining 124 strains belonging to NBA and 52 strains of A. baumannii. For identification of Acinetobacter at the species level, the accuracy rates of rpoB gene sequencing, 16S rRNA gene sequencing, gyrB multiplex PCR, and the VITEK 2 were 98.2%, 93.4%, 77.2%, and 35.9%, respectively. The gyrB multiplex PCR seems to be very useful for the detection of ACB complex because its concordance rates to the final identification of strains of ACB complex were 100%. Both the rpoB gene sequencing and the 16S rRNA gene sequencing may be useful in identifying Acinetobacter. PMID- 24157060 TI - Evaluation of a new real-time reverse transcription polymerase chain reaction assay for detection of norovirus in fecal specimens. AB - A new real-time reverse transcription polymerase chain reaction (RT-PCR) assay, the AccuPower Norovirus Real-time RT-PCR Kit, was evaluated in detection of human norovirus in stool specimens. Studies for detection limit, dynamic range, reproducibility, and cross-reactivity were performed. A total of 281 fecal specimens were tested using the AccuPower Norovirus Real-time RT-PCR Kit, and the results were compared with those obtained using another real-time RT-PCR system. Norovirus positivity and genotype were confirmed by direct sequencing. The lowest mean numbers of genome copies of GI and GII that could be detected by the assay were 12.3 and 5.6 RNA copies/reaction, respectively. The positive, negative, and overall percent agreements between the 2 real-time PCR assays were 99.0% (96/97), 95.1% (175/184), and 96.4% (271/281), respectively. The AccuPower Norovirus Real time RT-PCR system showed good analytical and clinical performance and may be a useful diagnostic tool for norovirus infection. PMID- 24157061 TI - Modelling the role of microtubules in plant cell morphology. AB - Normal plant growth requires the anisotropic expansion of cells and the proper orientation of their divisions. Both are controlled by the architecture of the cortical microtubule array. Cortical microtubules interact through frequent collisions. Several modelling studies have shown that these interactions can be sufficient for spontaneous alignment. Further requirements to this self organization are the homogeneous distribution of microtubule density and reliable control over the array orientation. We review the contribution of computer simulations and mathematical modelling on each of these challenges. These models now provide a good understanding of the basic alignment mechanism and will continue to be very useful tools for investigating more advanced questions, for example how microtubule severing contributes to alignment and array reorientation. PMID- 24157063 TI - Chromosomal aberrations in primary PDGFRA-mutated gastrointestinal stromal tumors. AB - Approximately 15% of gastrointestinal stromal tumors (GISTs) harbor mutations in the platelet-derived growth factor receptor alpha (PDGFRA) gene. Chromosomal aberrations play a crucial role in tumor progression and correlate with clinical behavior. Imbalances, particularly in PDGFRA-mutated GISTs, have not yet been evaluated in larger series. We analyzed 53 PDGFRA-mutated GISTs (including 2 with corresponding metastases) for chromosomal imbalances by conventional comparative genomic hybridization and compared them with a historical collective of 122 KIT mutated GISTs. PDGFRA exon 18 mutations (91% of cases) and exon 12 mutations (9% of cases) correlated significantly with gastric and intestinal sites, respectively. The most common aberrations were identical to those found in KIT mutated GISTs, with -14q in 70%, -1p in 28%, and -22q in 17% of cases. Overall, there were significantly fewer chromosomal aberrations compared with KIT-mutated GISTs, with a mean of 2.8 (0.6 gains, 2.1 losses) aberrations per tumor. There was a statistically significant association of more than 5 chromosomal imbalances with intermediate/high-risk categories. Regarding specific chromosomal aberrations, -9p, -13q, and -22q correlated with intermediate/high risk, and -1p and +8q with poorer survival, although progression occurred in only 2 cases. Altogether, PDGFRA-mutated GISTs display the same chromosomal aberrations as KIT mutated GISTs, although they have a lower degree of chromosomal instability in line with their generally favorable outcome. PMID- 24157062 TI - Enhancement of neuromuscular dynamics and strength behavior using extremely low magnitude mechanical signals in mice. AB - Exercise in general, and mechanical signals in particular, help ameliorate the neuromuscular symptoms of aging and possibly other neurodegenerative disorders by enhancing muscle function. To better understand the salutary mechanisms of such physical stimuli, we evaluated the potential for low intensity mechanical signals to promote enhanced muscle dynamics. The effects of daily brief periods of low intensity vibration (LIV) on neuromuscular functions and behavioral correlates were assessed in mice. Physiological analysis revealed that LIV increased isometric force production in semitendinosus skeletal muscle. This effect was evident in both young and old mice. Isometric force recordings also showed that LIV reduced the fatiguing effects of intensive synaptic muscle stimulation. Furthermore, LIV increased evoked neurotransmitter release at neuromuscular synapses but had no effect on spontaneous end plate potential amplitude or frequency. In behavioral studies, LIV increased mouse grip strength and potentiated initial motor activity in a novel environment. These results provide evidence for the efficacy of LIV in producing changes in the neuromuscular system that translate into performance gains at a behavioral scale. PMID- 24157064 TI - Lobulitis in nonneoplastic breast tissue from breast cancer patients: association with phenotypes that are common in hereditary breast cancer. AB - Lobular inflammation (lobulitis) has been demonstrated in benign breast tissue adjacent to in situ and invasive breast cancers and, more recently, in nonneoplastic tissue from prophylactic mastectomy specimens for hereditary high risk breast carcinoma. The aim of this study is to investigate the incidence of lobulitis in benign breast tissue of patients with breast cancer and associated clinicopathologic features. We reviewed nonneoplastic breast tissue sections from 334 patients with invasive breast carcinoma to study lobulitis in normal breast tissue and to correlate its presence with clinicopathologic features of the associated tumor. Clinical information (age, menopausal status, and follow-up), tumor characteristics (type, grade, size, lymph node status, stage, estrogen and progesterone receptor, HER2), and survival were recorded. Characteristics of women with and without lobulitis were cross-classified with categories of clinical, pathologic, and histologic characteristics, and differences in distributions were tested in univariate and multivariate analysis. Lobulitis was found in 26 (8%) of 334 patients. The lymphocytic infiltrate was predominantly T cell type. In a multivariate model, lobulitis in patients with breast cancer was significantly associated with younger age, triple (estrogen receptor, progesterone receptor, HER2)-negative cancers, and medullary phenotypes. Lobulitis in nonneoplastic breast tissue, away from tumor, is associated with clinicopathologic features more commonly seen in hereditary breast cancer. PMID- 24157065 TI - Lenin's malady--reply. PMID- 24157066 TI - Prostatic atrophy: its spatial proximity to carcinoma and intraepithelial neoplasia based on annotation of digital slides. AB - Whether atrophy is a precursor to high-grade prostatic intraepithelial neoplasia (HGPIN) and cancer is controversial. A virtual slide set comprising 48 prostatectomy cases was used to investigate associations among the amounts and spacing of these entities. Foci of atrophy without inflammation (A), atrophy with inflammation (AI), cancer (by patterns), and HGPIN were digitally annotated. Atrophy's proximity to cancer and HGPIN was assessed with two measurements: abutment (touching) or nearness (<=2 MUm without touching). Area sums per specimen were computed for A, AI, cancer, and HGPIN. Abutment rates of AI and A foci to cancer were 23% versus 21% (p = NS); for nearness, 29% of AI foci were near to cancer versus 12% of A (P = .0001). Abutment or nearness of A and AI to HGPIN were in the 1.4% to 2.4% range. When A, AI, or HGPIN abutted cancer, it was disproportionately to Gleason grade 3 cancer foci even after adjusting for the lesser frequency of higher-grade cancer foci. Area sums of A, AI, or (A + AI) per specimen showed no correlations with those of HGPIN, and mostly negative ones with area sum and with tumor volume of cancer. In conclusion, atrophy with inflammation showed some preferential spatial association to cancer, although area sums of atrophy with or without inflammation correlated negatively with those of cancer. These divergent spatial associations suggest that atrophy and inflammation in biopsy specimens may have clinical relevance. The frequency of inflammatory atrophy (AI) merging with HGPIN was far less than reported previously, weakening the theory that AI gives rise to HGPIN. PMID- 24157067 TI - Low papillary structures in lepidic lung adenocarcinoma: any relationship with micropapillary lung adenocarcinoma?--reply. PMID- 24157068 TI - Correlation analysis of angiotensin-converting enzyme, angiotensinogen, and endothelial nitric oxide synthase gene polymorphisms and the progression of immunoglobulin A nephropathy/membranous nephropathy. AB - The purpose of our study was to evaluate the correlation of polymorphisms in angiotensinogen (AGT), angiotensin-converting enzyme (ACE), and endothelial nitric oxide synthase (eNOS) genes and the development and prognostic implications for immunoglobulin A nephropathy (IgAN)/membranous nephropathy (MN). A polymerase chain reaction was performed for the AGT, ACE, and eNOS genes, followed by DNA sequencing and statistical analysis. There was a difference in ACE gene type II and type I between the IgAN and MN groups (P < .05) and in eNOS gene TT type and T type between the IgAN and MN groups (P < .05 and P < .01). In the IgAN group, significant differences were observed between ACE gene polymorphism and the age group of 20 years or less, male sex group, with/without hematuria, and high blood urea nitrogen (BUN; P < .05 or P < .01); between AGT gene polymorphism and with/without hematuria, high BUN, and pathologic classification (P < .05 or P < .01); and between eNOS gene polymorphism and high BUN and pathologic classification (P < .05 or P < .01). However, in the MN group, significant differences were observed between ACE gene polymorphism and the degree of proteinuria and high BUN (P < .001 and P < .05), between AGT gene polymorphism and with/without hematuria (P < .05), and between eNOS gene polymorphism and the degree of proteinuria and high BUN (P < .05 and P < .01). The ACE, AGT, and eNOS genes were correlated with the development of renal function failure in IgAN, whereas the ACE and eNOS genes were associated with the degree of proteinuria and the development of renal function failure in MN. PMID- 24157069 TI - The ocular vestibular evoked myogenic potential (OVEMP), ten years old. PMID- 24157070 TI - Least-squares deconvolution of evoked potentials and sequence optimization for multiple stimuli under low-jitter conditions. AB - OBJECTIVE: Rapid presentation of stimuli in an evoked response paradigm can lead to overlap of multiple responses and consequently difficulties interpreting waveform morphology. This paper presents a deconvolution method allowing overlapping multiple responses to be disentangled. METHODS: The deconvolution technique uses a least-squared error approach. A methodology is proposed to optimize the stimulus sequence associated with the deconvolution technique under low-jitter conditions. It controls the condition number of the matrices involved in recovering the responses. Simulations were performed using the proposed deconvolution technique. RESULTS: Multiple overlapping responses can be recovered perfectly in noiseless conditions. In the presence of noise, the amount of error introduced by the technique can be controlled a priori by the condition number of the matrix associated with the used stimulus sequence. The simulation results indicate the need for a minimum amount of jitter, as well as a sufficient number of overlap combinations to obtain optimum results. An aperiodic model is recommended to improve reconstruction. CONCLUSIONS: We propose a deconvolution technique allowing multiple overlapping responses to be extracted and a method of choosing the stimulus sequence optimal for response recovery. SIGNIFICANCE: This technique may allow audiologists, psychologists, and electrophysiologists to optimize their experimental designs involving rapidly presented stimuli, and to recover evoked overlapping responses. PMID- 24157071 TI - Ultrasound-assisted triage of ankle trauma can decrease the need for radiographic imaging. AB - BACKGROUND: An ankle sprain is a common injury, and patients are usually examined with plain radiographs to rule out a fracture despite the fact that only a small minority actually have one. PURPOSE: To investigate if ultrasound (US)-guided triage can decrease the need for radiographic imaging in patients with ankle trauma. HYPOTHESIS: Orthopedic surgeons can use point-of-care US with limited training to triage ankle trauma that requires standard radiographs. METHODS: Seven junior orthopedic surgeons underwent a 30-minute standardized training session using a basic US musculoskeletal examination designed to exclude ankle fractures. One-hundred twenty-two patients with ankle trauma were included at the emergency department and underwent clinical investigation, including examination according to the Ottawa ankle rules as well as US and standard ankle radiographs. In this study group, radiographs identified 23 significant fractures. Ultrasound guided triage could not exclude a fracture in 37 patients. All of the 23 fractures seen on radiographs were among the 37 patients where US could not rule out a fracture. Ottawa ankle rules managed to exclude the need for radiographs in 28 of the 122 patients, whereas 85 who underwent the US-guided triage could have avoided a radiograph. Avulsion fractures at the tip of the fibula were not considered significant. CONCLUSION: This study demonstrates that with limited standardized training a junior, an orthopedic surgeon is able to use US-guided triage during the primary examination at the emergency department to exclude at least significant ankle fractures. This practice could decrease the need for radiographic imaging, avoiding a mandatory radiographic investigation in many patients with ankle trauma. It would also make it possible to treat many patients with ankle trauma more rapidly and to reduce costs and radiation exposure. PMID- 24157072 TI - The diminishing role of pelvic x-rays in the management of patients with major torso injuries. AB - INTRODUCTION: A pelvic x-ray (PXR) can be used as an effective screening tool to evaluate pelvic fractures and stability. However, associated intra abdominal/retroperitoneal organ injuries and hemorrhage should also be considered and evaluated in patients with major torso injuries. An abdominal/pelvic computed tomographic (CT) scan may provide higher resolution and more information than a PXR. The role of conventional PXRs was delineated in the current study in the context of the development of the CT scan. MATERIALS AND METHODS: We retrospectively reviewed patients with major torso injuries in our institution. The characteristics of the patients who received different diagnostic modalities (PXR only, CT scan only, or both) were investigated and compared. The characteristics of patients who underwent transcatheter arterial embolization (TAE) for the hemostasis of pelvic fracture-related retroperitoneal hemorrhage were also analyzed. RESULT: There were 726 patients enrolled in current stud. Only 72.0% (523/726) of the patients who had major torso injuries were examined using PXRs, and 69.6% (505/726) of the patients underwent an abdominal/pelvic CT scan. For the patients who were examined using PXRs, there was no significant difference in the usage rate of an additional CT scan between the patients with positive (52.7%, 108/205) and negative (61.0%, 194/318) PXR examinations (P = .070). Four patients underwent TAE immediately following PXR examinations only, without a CT scan. These four patients had unstable pelvic fractures on the PXR examination and significantly a lower systolic blood pressure (61.0 +/- 13.0 mmHg), a lower revised trauma score (3.560 +/- 2.427), a greater requirement for blood transfusions (1750 +/- 957.2 ml) than the patients who underwent TAE after a CT scan. CONCLUSION: For the management of patients with major torso injuries, the role of PXR is diminishing due to the development of the CT scan. However, the PXR is still valuable for patients who are in critical condition and have an obviously high probability of retroperitoneal hemorrhaging. PMID- 24157073 TI - Synthetic drugs: time to ring the warning bell? PMID- 24157074 TI - Trends in financial barriers to medical care for women veterans, 2003-2004 and 2009-2010. AB - INTRODUCTION: Women veterans are a fast-growing segment of the veteran population, yet they face many barriers to medical care. The objective of this study was to examine factors that put women veterans at risk for a financial barrier to medical care. METHODS: We conducted repeated cross-sectional analyses of data from the 2003, 2004, 2009, and 2010 Behavioral Risk Factor Surveillance System. We used weighted logistic regression to examine the risk of a financial barrier to medical care as the primary outcome in a multivariate model controlling for factors in health-related domains. RESULTS: In 2010, there were an estimated 1,719,750 (11.6%) working-aged veterans who needed to see a doctor in the previous 12 months but could not because of cost. For women, 13.4% faced this financial barrier. Over the study period, facing a financial barrier was consistently associated with insurance coverage, physical and mental distress days, and having children in the home. Other associations emerged in particular years, such as binge drinking in 2010. The trends for women veterans relative to men and for younger women veterans relative to older women veterans show reduction in financial barriers to health care. CONCLUSION: The Veteran's Health Administration (VHA) should continue efforts to reduce financial and other barriers, especially among the higher risk groups we identified. This will help meet the VHA's objectives of providing comprehensive care to all veterans including women. PMID- 24157075 TI - Association between leisure-time physical activity and self-reported hypertension among Brazilian adults, 2008. AB - INTRODUCTION: Physical inactivity is a risk factor for hypertension. The objective of this study was to examine the association between self-reported leisure-time physical activity and hypertension among Brazilian adults categorized by sex and body weight. METHODS: The study used data from adult respondents in 26 capital cities and the Federal District to VIGITEL (N = 54,353), Brazil's 2008 national surveillance system for risk and protective factors for chronic diseases. We conducted a multivariate logistic regression analysis to investigate the association between self-reported leisure-time physical activity and hypertension and examined whether sex or body weight modified this relationship. RESULTS: The prevalence of self-reported hypertension was high among women, older people, and people with fewer years of education. Overall, leisure-time physical activity decreased with increasing age, increased with increasing education level, and was higher among men than women. The association for leisure-time physical activity and hypertension was modified by sex but not body weight. Leisure-time physical activity reduced the odds of hypertension in men. CONCLUSION: On the basis of self-reporting, leisure-time physical activity may be protective against hypertension in Brazilian men. Inclusion of other physical activity domains in the analyses may be necessary to fully understand the complex relationship between physical activity and hypertension by sex. In addition, public health priorities in Brazil for improving physical activity can target the entire population and not just those who are overweight or obese. PMID- 24157076 TI - The association between insurance status and cervical cancer screening in community health centers: exploring the potential of electronic health records for population-level surveillance, 2008-2010. AB - INTRODUCTION: Cervical cancer incidence and mortality rates in the United States have decreased 67% over the past 3 decades, a reduction mainly attributed to widespread use of the Papanicolaou (Pap) test for cervical cancer screening. In the general population, receipt of cervical cancer screening is positively associated with having health insurance. Less is known about the role insurance plays among women seeking care in community health centers, where screening services are available regardless of insurance status. The objective of our study was to assess the association between cervical cancer screening and insurance status in Oregon and California community health centers by using data from electronic health records. METHODS: We used bilevel log-binomial regression models to estimate prevalence ratios and 95% confidence intervals for receipt of a Pap test by insurance status, adjusted for patient-level demographic factors and a clinic-level random effect. RESULTS: Insurance status was a significant predictor of cervical cancer screening, but the effect varied by race/ethnicity and age. In our study uninsured non-Hispanic white women were less likely to receive a Pap test than were uninsured women of other races. Young, uninsured Hispanic women were more likely to receive a Pap test than were young, fully insured Hispanic women, a finding not previously reported. CONCLUSION: Electronic health records enable population-level surveillance in community health centers and can reveal factors influencing use of preventive services. Although community health centers provide cervical cancer screening regardless of insurance status, disparities persist in the association between insurance status and receipt of Pap tests. In our study, after adjusting for demographic factors, being continuously insured throughout the study period improved the likelihood of receiving a Pap test for many women. PMID- 24157077 TI - Effect of aerobic exercise on cognition, academic achievement, and psychosocial function in children: a systematic review of randomized control trials. AB - INTRODUCTION: Although the effects of aerobic physical activity (APA) on children's physical health is well characterized, the effect of aerobic physical activity on cognition, academic achievement, and psychosocial function has not yet been established. This systematic review provides an overview of research elucidating the relationship between aerobic physical activity and children's cognition, academic achievement, and psychosocial function. METHODS: A systematic review of English articles was performed in April 2013 using MEDLINE, Cochrane, PsycINFO, SPORTDiscus, and EMBASE. Additional studies were identified through back-searching bibliographies. Only randomized control trials with an intervention of aerobic physical activity in children younger than 19 years that measured psychological, behavioral, cognitive, or academic outcomes were included. RESULTS: We found 8 relevant randomized control trials that met our inclusion criteria and extracted relevant data and evaluated the methodologic quality of the studies. Of the 8 studies identified, 2 studies were crossover randomized control trials studying the effects of acute aerobic physical activity on cognitive performance. Six studies were parallel-group randomized control studies, of which only 2 had a follow-up period of longer than 6 months. All studies showed that APA had a generally positive impact on children's cognition and psychosocial function. However, this relationship was found to be minimal in many studies and in some measures, no significant improvement was seen at all. There was no documentation of APA having any negative impact on children's cognition and psychosocial health, even in cases where school curriculum time was reassigned from classroom teaching to aerobic physical activity. CONCLUSION: APA is positively associated with cognition, academic achievement, behavior, and psychosocial functioning outcomes. More rigorous trials with adequate sample sizes assessing the impact of APA on children's cognitive abilities, psychosocial functioning, behavior, and academic achievement are needed, with standardized interventions, valid and reliable tools of measurement, and long-term follow-up for sustained cognitive and psychosocial outcomes. PMID- 24157078 TI - Technical assistance from state health departments for communities engaged in policy, systems, and environmental change: the ACHIEVE Program. AB - INTRODUCTION: This study assessed the value of technical assistance provided by state health department expert advisors and by the staff of the National Association of Chronic Disease Directors (NACDD) to community groups that participated in the Action Communities for Health, Innovation, and Environmental Change (ACHIEVE) Program, a CDC-funded health promotion program. METHODS: We analyzed quantitative and qualitative data reported by community project coordinators to assess the nature and value of technical assistance provided by expert advisors and NACDD staff and the usefulness of ACHIEVE resources in the development and implementation of community action plans. A grounded theory approach was used to analyze and categorize phrases in text data provided by community coordinators. Open coding placed conceptual labels on text phrases. Frequency distributions of the quantitative data are described and discussed. RESULTS: The most valuable technical assistance and program support resources were those determined to be in the interpersonal domain (ie, interactions with state expert advisors, NACDD staff, and peer-to-peer support). The most valuable technical assistance events were action institutes, coaches' meetings, webinars, and technical assistance conference calls. CONCLUSION: This analysis suggests that ACHIEVE communities valued the management and training assistance provided by expert advisors and NACDD staff. State health department expert advisors provided technical guidance and support, including such skills or knowledge-based services as best-practice strategies, review and discussion of community assessment data, sustainability planning, and identification of possible funding opportunities. NACDD staff led development and implementation of technical assistance events. PMID- 24157080 TI - The changing face of general dentistry has altered specialty practice. PMID- 24157079 TI - The anti-atherosclerotic effect of tanshinone IIA is associated with the inhibition of TNF-alpha-induced VCAM-1, ICAM-1 and CX3CL1 expression. AB - Tanshinone IIA is one of the major diterpenes in Salvia miltiorrhiza. The inhibitory effect of Tanshinone IIA on atherosclerosis has been reported, but the underlying mechanism is not fully understood. The present study aimed to study the anti-atherosclerosis effect of Tanshinone IIA on the adhesion of monocytes to vascular endothelial cells and related mechanism. Results showed that Tanshinone IIA, at the concentrations without cytotoxic effect, dose-dependently inhibited the adhesion of THP-1 monocytes to the TNF-alpha-stimulated human vascular endothelial cells. The expressions of cell adhesion molecules including VCAM-1, ICAM-1 and E-selectin were induced by TNF-alpha in HUVECs at both the mRNA and protein levels. The mRNA and protein expressions of VCAM-1 and ICAM-1, but not E selectin, were both significantly suppressed by Tanshinone IIA in a dose dependent manner. In addition, the TNF-alpha-induced mRNA expression of fractalkine/CX3CL1 and the level of soluble fractalkine were both reduced by Tanshinone IIA. We also found that Tanshinone IIA significantly inhibited TNF alpha-induced nuclear translocation of NF-kappaB which was resulted from the inhibitory effect of Tanshinone IIA on the TNF-alpha-activated phosphorylation of IKKalpha, IKKbeta, IkappaB and NF-kappaB. As one of the major components of Salvia miltiorrhiza, Tanshinone IIA alone exerted more potent effect on inhibiting the adhesion of monocytes to vascular endothelial cells when compared with Salvia miltiorrhiza. All together, these results demonstrate a novel underlying mechanism for the anti-inflammatory effect of Tanshinone IIA by modulating TNF-alpha-induced expression of VCAM-1, ICAM-1 and fractalkine through inhibition of TNF-alpha-induced activation of IKK/NF-kappaB signaling pathway in human vascular endothelial cells. PMID- 24157081 TI - Brain abscess potentially secondary to odontogenic infection: case report. AB - Odontogenic infections are rarely implicated in the causes of brain abscess formation. As such, there are very few reports of brain abscesses secondary to odontogenic infections in the literature. This is due partly to the relative rarity of brain abscesses but also to the difficulty in matching the causative organisms of a brain abscess to an odontogenic source. The authors report a case of a 50-year-old woman whose brain abscess may potentially have been secondary to an odontogenic infection. The patient's early diagnosis, supported by imaging and microbiologic assessment, along with early minicraniotomy and extraction of infected dentition followed by a course of cephalosporins and metronidazole, contributed to a successful outcome. PMID- 24157082 TI - Inefficient exercise gas exchange identifies pulmonary hypertension in chronic thromboembolic obstruction following pulmonary embolism. AB - INTRODUCTION: Persistent obstruction in the pulmonary artery following acute pulmonary embolism (PE) can give rise to both chronic thromboembolic pulmonary hypertension (CTEPH) and chronic thromboembolic disease without PH (CTED). We hypothesised that cardiopulmonary exercise testing (CPET) may be able to differentiate patients with CTEPH and CTED following unresolved PE which may help guide patient assessment. MATERIALS AND METHODS: Fifteen patients with CTEPH and 15 with CTED all diagnosed after PE underwent CT pulmonary angiography, CPET and resting right heart catheterisation. Exercise variables were compared between patients with CTEPH, CTED and 10 sedentary controls and analysed as predictors of a CTEPH diagnosis. Proximal thrombotic burden in CTEPH and CTED was quantified using CT criteria. RESULTS: Physiological dead space (Vd/Vt) (34.5+/-11.4 vs 50.8+/-6.6 %, p<0.001) and alveolar-arterial oxygen gradient (29+/-16 vs 46+/ 12mmHg, p <0.001) at peak exercise strongly differentiated CTED and CTEPH groups respectively. Resting ventilatory efficiency also differed from control subjects. In both univariate and multivariate analyses, peak exercise Vd/Vt predicted a diagnosis of CTEPH (ROC AUC>0.88, 0.67 - 0.97) despite a similar degree of proximal thrombotic obstruction to the CTED group (67.5, 55 - 70% and 72.5, 60 - 80% respectively, p=0.08). CONCLUSIONS: Gas exchange at peak exercise differentiates CTED and CTEPH after PE that can present with no apparent relation to the degree of proximal thrombotic burden. A potential role for CPET exists in guiding further clinical investigations in this setting. PMID- 24157083 TI - New observations on procoagulant properties of amniotic fluid: microparticles (MPs) and tissue factor-bearing MPs (MPs-TF), comparison with maternal blood plasma. AB - INTRODUCTION: Microparticles (MPs) are submicron fragments of the cell membrane affecting many biological processes, e.g. coagulation. The aim of the study was to determine (i) MPs and (ii) tissue factor bearing MPs (MPs-TF) in the amniotic fluid and in blood plasma of parturient women, as well as to assess (iii) TF and TFPI. MATERIAL AND METHODS: The study group consisted of 38 women laboring at term, whereas the control group included 20 non-pregnant women. ELISA method was used to evaluate MPs, MPs-TF, TF and TFPI. RESULTS: The levels of MPs and MPs-TF were significantly higher in the amniotic fluid than in blood plasma of parturient women: the level of MPs was 41.08 times higher (medians: 246.48 nM PS vs. 6.00 nM PS, respectively, p<0.001), and the level of MPs-TF was 18.59 times higher (medians: 90.16pg/ml vs. 4.85pg/ml, respectively) (p<0.001). CONCLUSIONS: 1. Microparticles (MPs) and tissue factor-bearing MPs (MPs-TF) are constituent components of amniotic fluid. 2. It is reasonable to assume that these components together with tissue factor (TF) and its inhibitor (TFPI) can participate in life threatening coagulation disturbances in amniotic fluid embolism, and to take into consideration their impact on fetal development. PMID- 24157084 TI - Short-term prognosis of intracranial haemorrhage in patients on oral anticoagulant or antiplatelet drugs. AB - BACKGROUND: Intracranial haemorrhage (ICH) is the most feared complication of oral vitamin K antagonists (VKAs) and antiplatelet drugs. Little data are available on the clinical course of antithrombotic drug-associated ICHICH. The main aim of the VKA- and Antiplatelet Drug-Associated ICH Prognosis (VAIP) study is to investigate predictors of short-term prognosis in ICH patients, and to analyse characteristics and prognosis of patients with antithrombotic drugs associated ICH. METHODS: VAIP is designed as a retrospective cohort study. Consecutive adult patients with an ICH objectively documented by neuroimaging, occurring during treatment with VKAs or ADs, admitted to the Cuneo hospital, Italy, from 2005 to 2010, were included. For a non-exposed group, we randomly selected patients with ICH not on antithrombotic treatment. RESULTS: Overall, 451 patients were included. In particular, 75 patients were on VKAs and 96 on antiplatelet drugs. The site of haemorrhage was intracerebral in 274 (60.8%) patients, subdural in 156 (34.6%), and subarachnoid in 21 (4.7%). Mortality rate was 35.8%, 4.5%, and 28.6%, respectively. In the multivariate analysis, independent predictors of in-hospital death were: age >80years (hazard ratio [HR] 2.3, 95% confidence interval 1.5-3.5), Glasgow Coma Scale [GCS]<8 (HR 7.8, 5.0 12.1), treatment with VKAs (HR 2.0, 1.2-3.4) and antiplatelet drugs (HR 1.8, 1.1 3.0). Neurosurgical treatment was an independent predictor of survival (HR 0.5, 0.3-1.0). Among patients with VKA-associated ICH, independent predictors of in hospital death for ICH were: age >80years (HR 4.4, 1.6-12.0), GCS <8 (HR 12.0, 4.1-34.8), recent onset of symptoms (HR 4.2, 1.6-11.3), and neurosurgical treatment (HR 0.1, 0.0-0.8). CONCLUSION: Our results suggest that the main predictors of ICH in-hospital prognosis in a tertiary neurosurgical center are advanced age, GCS at admission, previous treatment with VKAs and antiplatelet drugs, and neurosurgical treatment. PMID- 24157085 TI - Anti-beta2GPI/beta2GPI stimulates activation of THP-1 cells through TLR4/MD 2/MyD88 and NF-kappaB signaling pathways. AB - Our previous study demonstrated that Toll-like receptor 4 (TLR4) could act as a co-receptor with annexin A2 (ANX2) mediating anti-beta2-glycoprotein I/beta2- glycoprotein I (anti-beta2GPI/beta2GPI) -induced tissue factor (TF) expression in human acute monocytic leukaemia cell line THP-1. In the current study, we further explored the roles of TLR4 and its adaptors, MD-2 and MyD88, as well as nuclear factor kappa B (NF-kappaB), in anti-beta2GPI/beta2GPI-induced the activation of THP-1 cells, especially on the expression of some proinflammatory molecules. The results showed that treatment of THP-1 cells with anti-beta2GPI (10MUg/ml)/beta2GPI (100MUg/ml) complex could increase IL-6 (interleukin-6), IL-8 (interleukin-8) as well as TNF-alpha (tumor necrosis factor alpha) expression (both mRNA and protein levels). These effects could be blocked by addition of TAK 242 (5MUM), a blocker of signaling transduction mediated by the intracellular domain of TLR4, and also by NF-kappaB inhibitor PDTC (20MUM). Overall, our results indicate that anti-beta2GPI/beta2GPI complex induced IL-6, IL-8 and TNF alpha expression involving TLR4/MD-2/MyD88 and NF-kappaB signaling pathways and this might be associated with pathological mechanisms of antiphospholipid syndrome (APS). PMID- 24157086 TI - Reversed-phase liquid chromatography with octadecylsilyl, immobilized artificial membrane and cholesterol columns in correlation studies with in silico biological descriptors of newly synthesized antiproliferative and analgesic active compounds. AB - Reversed-phase liquid chromatography (RPLC) with different stationary phases, i.e., octadecylsilyl, immobilized artificial membrane and immobilized cholesterol, was used to study lipophilicity of 56 newly-designed 7,8 dihydroimidazo[2,1-c][1,2,4]triazin-4(6H)-ones and 2,6,7,8-tetrahydroimidazo[2,1 c][1,2,4]triazine-3,4-diones with potential anti-proliferative, anti-metastatic and analgesic activities. Extrapolated retention parameters that correspond to pure buffer as the mobile phase, i.e., logkw values are used as chromatographic lipophilicities. The lipophilic properties of compounds also are characterized by computed logP values and basic pharmacokinetic descriptors calculated in silico with the use of ACD/Percepta software according to Abraham's linear solvation energy relationship. Chromatographic and partitioning parameters are compared with biological descriptors using principal component analysis (PCA), and similarities and dissimilarities between variables and compounds are described. Highly significant, predictive relationships between biological descriptors and chromatographic parameters are obtained. Reversed parabolic relationships, which have very good statistical quality between various biological descriptors, i.e., logKsc, logKp, logBB, and logKhsa, and the logkw values, indicate the advantages of a cholesterol column in comparison with immobilized artificial membrane and octadecylsilyl stationary phase. PMID- 24157087 TI - Feasibility of teaching motivational interviewing to parents of young adults with recent-onset schizophrenia and co-occurring cannabis use. AB - This study examined the feasibility of providing motivational interviewing (MI) training to parents of young adults with recent-onset schizophrenia and co occurring cannabis use. The training was offered in a mental health care setting as part of a family motivational intervention (FMI). Ninety-seven parents were randomly assigned to either FMI or routine family support (RFS). To obtain a measure of parent's MI skills at baseline and 3 months after they completed FMI, their role-play interactions with an actor portraying their child were coded. The coding method had satisfactory inter-rater reliability and internal consistency. At follow-up, parents in FMI showed significantly greater adherence to (p=.03) and competence in (p=.04) MI than parents in RFS. Parents in FMI also demonstrated significantly greater increases in expressing empathy (p=.01). These results demonstrate that FMI is a feasible method for increasing MI skills in parents. Additional research is needed to better understand the unique application of MI to parent-child interactions. PMID- 24157088 TI - A 5-year prospective follow-up study of patients with obsessive-compulsive disorder treated with serotonin reuptake inhibitors. AB - BACKGROUND: Although obsessive-compulsive disorder is usually regarded as a chronic illness, there is limited data on the naturalistic long-term outcome of the disorder and on predictors of remission and relapse. The study examines the 5 year course prospectively in outpatients with the primary diagnosis of DSM-IV OCD who were mostly treated with serotonin reuptake inhibitors (SRIs). METHOD: 106 of 115 subjects recruited over a period of 2 years from the outpatient services of an OCD clinic in India were followed periodically up to 5 years. RESULTS: Subjects were moderately ill, mostly self-referred (89%), and less than a half was treatment-naive. Cumulative probability of at least partial remission and full remission at 5 years was 93% and 65% respectively. Most achieved remission by 2 years. In those who achieved either partial or full remission, cumulative probability of relapse by 5 years was 36%. Percentage of time on treatment and treatment-naive status at intake predicted at least partial remission, whereas only percentage of time on treatment predicted full remission. Full remission and doubts/checking dimension predicted lesser likelihood of a relapse. LIMITATIONS: Patients were recruited from a specialty OCD clinic and treatment was not controlled during the follow-up period. CONCLUSIONS: The outcome of OCD seems to be better than generally assumed, at least in moderately ill outpatients. Regular treatment over extended period may enhance likelihood of remission. Full remission should be the goal of treatment since it is associated with lesser propensity for relapse. Most patients remit in the first 2 years of treatment; therefore, early detection and intervention may improve the outcome. PMID- 24157089 TI - Current utility of diagnostic catheter cerebral angiography. AB - BACKGROUND: The role of diagnostic catheter cerebral angiography has been recently thought to have diminished with the increasing use of noninvasive modalities such as computed tomography angiography and magnetic resonance angiography. Because it is invasive and costly, we sought to elucidate the clinical utility of catheter angiography by evaluating the indications, incidence of new and clinically meaningful findings, and its utility compared with noninvasive studies. METHODS: We performed an observational cross-sectional study of consecutive patients undergoing diagnostic cerebral angiography at an urban tertiary care center. We prospectively recorded procedural indications, the findings of previously performed noninvasive studies, the actual angiogram findings, and whether these were new. We defined a new finding as any novel and clinically meaningful piece of anatomic brain vascular information. RESULTS: Of the 200 consecutive studies over 8 months, 55% were for purely diagnostic purposes, whereas the remaining were for surveillance. The most common indications were subarachnoid hemorrhage, ischemic stroke, intracerebral hemorrhage, cerebral aneurysm, and arteriovenous malformation. New findings were detected in 43% of purely diagnostic angiograms and 32% of surveillance studies. We found false-negative rates of 9.9% and false-positive rates of 11.7%. In 23.4% of cases, more precise anatomic information was found that was subjectively deemed clinically meaningful. CONCLUSIONS: Our snapshot of 200 consecutive catheter cerebral angiograms shows that it is used for both primary diagnosis and surveillance in a wide variety of indications. Despite recent imaging trends, diagnostic catheter angiography provides clinically meaningful diagnostic information in enough cases to warrant continued use. PMID- 24157090 TI - Outcomes after tissue plasminogen activator administration under the drip and ship paradigm may differ according to the regional stroke care system. AB - The drip and ship paradigm for stroke patients enhances the rate of using intravenous tissue plasminogen activator (IVT) in community hospitals. The safety and outcomes of patients treated with IVT for acute ischemic stroke (AIS) under the drip and ship paradigm were compared with patients directly treated at a comprehensive stroke center in the Busan metropolitan area of Korea. This was a retrospective study of patients with AIS treated with IVT between January 2009 and January 2012. Information on patients' baseline characteristics, neuroimaging, symptomatic intracerebral hemorrhage (sICH), and outcome 90 days after using IVT was obtained from our stroke registry. We surveyed stroke neurologists regarding their pattern of post-thrombolysis care. During the observation periods, we selected 317 patients using IVT. Among these, 239 patients received IVT at our stroke center, and 78 were treated at 21 community hospitals under the drip and ship paradigm. Initial neurologic deficits and the size of ischemic lesions on magnetic resonance imaging were much more severe in patients treated with IVT under the drip and ship paradigm compared with patients treated at our comprehensive stroke center. The prevalence of a poor outcome (modified Rankin Scale score 3-6) 90 days after IVT was much higher in patients treated with the drip and ship paradigm than in those treated at our comprehensive stroke center. Regarding the occurrence of sICH, there was no significant difference between the 2 groups. The clinical characteristics and outcomes after using IVT under the drip and ship paradigm may differ greatly among stroke care systems. PMID- 24157092 TI - Are biomechanical factors, meniscal pathology, and physical activity risk factors for bone marrow lesions at the knee? A systematic review. AB - OBJECTIVE: To systematically review the literature to determine whether biomechanical factors, meniscal pathology, and physical activity are risk factors for bone marrow lesions (BMLs) at the knee identified from magnetic resonance imaging in pre-osteoarthritis and osteoarthritis populations. METHODS: Electronic searches of MEDLINE and EMBASE were performed from January 1, 1996 to October 31, 2012 using the keywords of bone marrow lesion(s), bone marrow (o)edema, osteoarthritis, and knee. Studies examining biomechanical factors, meniscal pathology, or physical activity in relation to the presence, incidence, or change in BMLs at the knee were included. Two independent reviewers extracted the data and assessed the methodological quality of selected studies. Due to the heterogeneity of the studies, we performed a best evidence synthesis. RESULTS: Fifteen studies were included in this review, of which 9 were considered high quality. The study populations were heterogeneous in terms of the symptoms and radiographic knee osteoarthritis. There was strong evidence for relationships of mechanical knee alignment and meniscal pathology with BMLs in osteoarthritis populations. There was a paucity of evidence for a relationship between physical activity and BMLs. CONCLUSION: Despite the heterogeneity of included studies, these data suggest that mechanical knee alignment and meniscal pathology are risk factors for BMLs in knee osteoarthritis. It suggests that BMLs in individuals with osteoarthritis are more susceptible to mechanical knee alignment. Given the role of BMLs in the pathogenesis of knee osteoarthritis, identifying strategies to modify these risk factors will be important in slowing the progression and reducing the burden of knee osteoarthritis. PMID- 24157091 TI - Th17 cells and IL-17 a--focus on immunopathogenesis and immunotherapeutics. AB - IMPORTANCE: Accumulating evidence suggests that IL-17 A has broad pathogenic roles in multiple autoimmune and immune-mediated inflammatory diseases, including psoriasis and rheumatoid arthritis (RA). The development of new therapies that inhibit IL-17 pathway signaling is of clinical significance. OBJECTIVES: This review aims to summarize the current preclinical evidence on the role of Th17 cells and IL-17 and related cytokines in immune-mediated disease pathophysiology, with a focus on psoriasis and rheumatoid arthritis, as well as to summarize recent clinical trials in these indications with newly developed IL-17 pathway inhibitors. METHODS: A systematic literature search was conducted of PubMed using relevant keywords. Studies were assessed according to recent relevance to IL-17 mediated pathophysiology and clinical IL-17 inhibition. Experimental animal models of autoimmune disease and clinical studies that focused on IL-17 pathway inhibitors were included. RESULTS: Preclinical studies suggest that IL-17A is an attractive therapeutic target. Several IL-17A inhibitors have advanced into clinical trials, including the anti-IL-17A monoclonal antibodies, secukinumab and ixekizumab, and the anti-17RA monoclonal antibody brodalumab. Each has shown variable and sometimes favorable results in proof-of-concept and phase II clinical trials and is currently undergoing further clinical evaluation in a range of immune-mediated diseases. CONCLUSION: Targeting the IL-17 pathway shows promise as strategy to treat immune-mediated diseases ranging from skin to joints. PMID- 24157094 TI - Improvement of sleep-disordered breathing in children is associated with a reduction in overnight blood pressure. AB - OBJECTIVE: Childhood sleep-disordered breathing (SDB) is associated with elevated blood pressure (BP); however, little is known about the long-term outcomes in this population. We aimed to assess long-term changes in overnight BP in children with SDB. METHODS: Forty children with previously diagnosed SDB and 20 nonsnoring control participants underwent repeat overnight polysomnography (PSG) with continuous BP measurement 4years after the original diagnosis. At follow-up, children aged 11-16years were categorized into 2 groups of resolved (absence of snoring and obstructive apnea-hypopnea index [OAHI]?1) or unresolved (continued to snore or had an OAHI >1) SDB. RESULTS: There were no group differences in age, sex, or body mass index (BMI) z score. OAHI was lower at follow-up (P<.05) in both the resolved (n=18) and unresolved (n=22) groups. BP was elevated during wake and sleep in both SDB groups compared to the control group at baseline (P<.01 for all), but it decreased by 5-15mmHg at follow-up during sleep for both SDB groups (P<.05 for all). BP during wake was unchanged in the SDB groups at follow-up but increased in the control group (P<.05). At follow-up, BP did not differ between the control group and the SDB groups during wake or sleep. Improved oxygen saturation (SpO2) during sleep was a significant predictor of a reduction in BP. CONCLUSIONS: SDB improved over the 4-year follow-up and both resolved and unresolved groups exhibited a significant reduction in BP during sleep, with levels similar to the control group. Our study highlights the fact that even small improvements can improve the cardiovascular effects of SDB. PMID- 24157093 TI - Where and how to inject the knee--a systematic review. AB - OBJECTIVES: The knee can be injected at different anatomic sites with or without image-guidance. We undertook a systematic review to determine the accuracy of intra-articular knee injection (IAKI) and whether this varied by site, use of image-guidance, and experience of injectors, and whether accuracy of injection, site, or use of image-guidance influenced outcomes following IAKIs. METHODS: Medline, Embase, AMED, CINAHL, Web of Knowledge, Cochrane Central Registers for Controlled Trials up to Dec 2012 were searched for studies that evaluated either accuracy of IAKIs or outcomes related to accuracy, knee injection sites, or use of image-guidance. Within-study and between-study analyses were performed. RESULTS: Data from 23 publications were included. Within-study analyses suggested IAKIs at the superomedial patellar, medial midpatellar (MMP), superolateral patellar (SLP) and lateral suprapatellar bursae sites were more accurate when using image-guidance than when blinded (ranges of pooled risk difference 0.09 0.19). Pooling data across studies suggested blinded IAKIs at the SLP site were most accurate (87%) while MMP (64%) and anterolateral joint line (ALJL) sites were (70%) least accurate. Overall about one in five blinded IAKIs were inaccurate. There was some evidence that experience of the injector was linked with improved accuracy for blinded though not image-guided injections. Based on a small number of studies, short but not longer-term outcomes for ultrasound-guided were found to be superior to blinded IAKIs. CONCLUSIONS: Image-guided IAKIs are modestly more accurate than blinded IAKIs especially at the MMP and ALJL sites. Blinded injections at SLP site had good accuracy especially if performed by experienced injectors. Further studies are required to address the question whether accurate localization is linked with an improved response. PMID- 24157095 TI - Restless legs syndrome (Willis-Ekbom disease) and growing pains: are they the same thing? A side-by-side comparison of the diagnostic criteria for both and recommendations for future research. AB - There has been no previous side-by-side comparison of the diagnostic criteria for restless legs syndrome (RLS) (Willis-Ekbom disease) and growing pains. In our review, we explore this comparison emphasizing overlaps and disconnects, summarize recent literature exploring the relationship between the 2 entities, and make suggestions for future research. There is considerable overlap in the diagnostic criteria for childhood RLS and growing pains. The literature also indicates that RLS and growing pains more commonly occur together than one would expect based on chance alone, and the family histories of RLS and growing pains often are overlapping. Leg rubbing to obtain relief from leg discomfort is common to both disorders, though walking to obtain relief seems unique to RLS. Childhood RLS also has been reported to be painful in up to 45% of cases. The development of standard diagnostic criteria is necessary to move forward in the field of growing pains research. A quantitative and validated rating scale for growing pains severity already exists. Because of the clinical and genetic similarity between RLS and growing pains, studies that parallel those previously performed in RLS patients are recommended for growing pains patients. For example, a genome wide association study in growing pains patients of all possible genes with particular attention to those identified as related to RLS and a therapeutic trial of medications known to be effective in RLS would be welcome. Abnormalities in vitamin D metabolism also may be common to both disorders. PMID- 24157096 TI - Topography of sensory symptoms in patients with drug-naive restless legs syndrome. AB - OBJECTIVES: We aimed to describe the sensory topography of restless legs syndrome (RLS) sensory symptoms and to identify the relationship between topography and clinical variables. METHODS: Eighty adult patients with drug-naive RLS who had symptoms for more than 1year were consecutively recruited. During face-to-face interviews using a structured paper and pencil questionnaire with all participants, we obtained clinical information and also marked the topography of RLS sensory symptoms on a specified body template, all of which were subsequently inputted into our in-house software. The RLS sensory topography patterns were classified according to localization, lateralization, and symmetry. We investigated if these sensory topography patterns differed according to various clinical variables. RESULTS: The lower extremities only (LE) were the most common location (72.5%), and 76.3% of participants exhibited symmetric sensory topography. Late-onset RLS showed more asymmetric sensory distribution compared with early-onset RLS (P=.024). Patients whose sensory symptoms involved the lower extremities in addition to other body parts (LE-PLUS) showed more severe RLS compared with those involving the LE (P=.037). CONCLUSION: RLS sensory symptoms typically were symmetrically located in the lower extremities. LE-PLUS or an asymmetric distribution more often occurred in patients with more severe RLS symptoms or late-onset RLS. PMID- 24157097 TI - Association analysis of the major histocompatibility complex, class II, DQ beta1 gene, HLA-DQB1, with narcolepsy in Han Chinese patients from Taiwan. AB - BACKGROUND: Narcolepsy is a rare, chronic, disabling neuropsychiatric disorder characterized by excessive daytime sleepiness, cataplexy, hypnagogic hallucinations, sleep paralysis, and abnormal rapid eye movement sleep. It is strongly associated with the HLA-DQB1(*)06:02 allele in various ethnic groups. Our study aimed to investigate the allelic spectrum of HLA-DQB1 in a sample of Han Chinese patients with narcolepsy and control subjects from Taiwan. METHODS: We determined the genotype of the major histocompatibility complex, class II, DQ beta1 gene, HLA-DQB1, in 72 narcolepsy subjects (44 men, 28 women), including 52 narcolepsy subjects with cataplexy (narcolepsy+cataplexy), 20 narcolepsy subjects without cataplexy (narcolepsy-cataplexy), and 194 control subjects (94 men, 100 women) using a sequence-specific oligonucleotide-probe hybridization technique. RESULTS: We found a strong HLA-DQB1(*)06:02 association in narcolepsy+cataplexy subjects (odds ratio [OR], 321.4 [95% confidence interval {CI}, 70.7-1461.4]). The association was less prominent in narcolepsy-cataplexy subjects (OR, 6.9 [95% CI, 2.4-20.1]). In addition to the DQB1(*)06:02, we found that (*)03:01 also was a predisposing allele (OR, 2.0 [95% CI, 1.1-3.7]) in narcolepsy+cataplexy subjects, though the (*)06:01 was a predisposing allele (OR, 2.8 [95% CI, 1.2 6.7]) in narcolepsy-cataplexy subjects. Furthermore, we found a significant overrepresentation of DQB1(*)06:02 homozygotes in narcolepsy+cataplexy subjects. CONCLUSIONS: Our data add further support to the strong association of the HLA DQB1(*)06:02 allele with narcolepsy, especially in narcolepsy+cataplexy patients. Our study also indicates additional HLA-DQB1 alleles may modify the presentation of narcolepsy+cataplexy patients, such as DQB1(*)03:01 and DQB1(*)06:01 in our study. Our results are limited by the small sample size and can only be considered as preliminary findings. PMID- 24157098 TI - Continuous positive airway pressure and noninvasive ventilation adherence in children. AB - BACKGROUND: Adherence to continuous positive airway pressure (CPAP) and noninvasive ventilation (NIV) is crucial for the successful treatment of sleep disordered breathing. The aim of our study was to analyze the adherence of children to long-term home CPAP/NIV treatment. METHODS: We analyzed data from all consecutive patients older than the age of 2years, in whom CPAP/NIV treatment was initiated in a specialized pediatric NIV and in those who were receiving CPAP/NIV treatment at home for at least 1month. Data of the memory cards of the ventilators and nocturnal gas exchange were analyzed during a routine CPAP/NIV overnight control in the hospital. CPAP/NIV adherence during the previous month was analyzed according to patient's age, ventilatory mode, type of interface, nocturnal gas exchange, and duration of treatment. RESULTS: The data of 62 children (mean age, 10+/-5years) with obstructive sleep apnea (n=51) treated with CPAP and neuromuscular disease (n=6) or lung diseases (n=5) treated with NIV were analyzed. Mean adherence was 8:17+/-2:30h:min per night, and the results did not significantly differ between CPAP and NIV adherence. Seventy-two percent of the patients used their device >8h per night. The mean number of nights of CPAP/NIV use during the last month was 26+/-5 nights per month. Treatment adherence was not correlated to age, the type of underlying disease, the type of interface (nasal, facial mask, or nasal cannula), nocturnal gas exchange, and duration of CPAP/NIV treatment. CONCLUSION: Long-term CPAP/NIV adherence at home was extremely high in this group of children followed in a pediatric NIV unit. This finding may explain the lack of effect of the interface, nocturnal gas exchange, and duration of CPAP/NIV treatment. PMID- 24157099 TI - Association between sleep disturbances and falls among the elderly: results from the German Cooperative Health Research in the Region of Augsburg-Age study. AB - OBJECTIVE: We aimed to examine the association between various sleep disturbances and falls among older individuals from the general population while considering the influence of age and dizziness. METHODS: Data were derived from the population-based cross-sectional KORA (Cooperative Health Research in the Region of Augsburg)-Age study, whereby information was conducted in standardized telephone interviews with 4127 men and women aged ?65years in 2008 and 2009. Unstratified and stratified (by age and dizziness) multivariable logistic regression model analyses were performed. RESULTS: The multivariable analysis showed a marginally significant association between trouble staying asleep and ?1 fall in the previous year (odds ratio [OR], 1.23 [95% confidence interval (CI), 1.01-1.50]). This association was more pronounced in participants older than the age of 75years (OR, 1.58 [95% CI, 1.16-2.16]) and in individuals without dizziness (OR, 1.35 [95% CI, 1.04-1.76]). There was no association between daytime sleepiness and falls in the fully-adjusted models, but the odds of falls in the previous year in individuals older than the age of 75years were significantly higher for individuals with difficulty falling asleep. Although sleep duration was not associated with falls in multivariable analyses when stratified by dizziness, sleep duration of 9h daily was significantly associated with higher odds of experiencing at least one fall in the previous year. CONCLUSIONS: Our study suggested that the positive relationship between a trend towards longer sleep duration, trouble falling and staying asleep, and falls is strongest in older individuals and in individuals who did not experience dizziness in the previous year. PMID- 24157100 TI - Increased plasma level of tumor necrosis factor alpha in patients with narcolepsy in Taiwan. AB - BACKGROUND: Narcolepsy is a neuropsychiatric disorder characterized by excessive daytime sleepiness, cataplexy, hypnagogic hallucinations, and abnormal rapid eye movement (REM) sleep. Tumor necrosis factor alpha (TNF alpha) and its cognate receptors have been reported to be involved in the pathophysiology of narcolepsy in addition to the HLA antigen system. Our study aimed to determine if the TNF alpha system was associated with narcolepsy in our patients. METHODS: We first measured the plasma level of TNF alpha in 56 narcoleptic patients and 53 control subjects using a highly sensitive enzyme-linked immunosorbent assay. We next determined the genotype of three single nucleotide polymorphisms (SNPs) (T-1031C, C-863A, and C-857T) at the promoter region of the TNF-alpha gene and one missense SNP (T587G, M196R) at the exon 6 of the tumor necrosis factor receptor 2 gene, TNFR2, in a sample of 75 narcoleptic patients and 201 control subjects by direct sequencing analysis. RESULTS: We found a significant elevation of plasma level of TNF alpha in patients with narcolepsy compared with the control subjects (4.64pg/mL vs 1.06pg/mL; P=.0013). However, we did not find significant differences between these two groups in the allelic and genotypic distributions of the investigated polymorphisms. CONCLUSIONS: Our study suggests that an increased TNF-alpha level was associated with narcolepsy in our patients, and that chronic inflammation due to various factors might have led to the increased TNF-alpha levels found in our patients. PMID- 24157101 TI - Association between morningness-eveningness and the severity of compulsive Internet use: the moderating role of gender and parenting style. AB - BACKGROUND: Eveningness and Internet addiction are major concerns in adolescence and young adulthood. We investigated the relationship between morningness eveningness and compulsive Internet use in young adults and explored the moderating effects of perceived parenting styles and family support on such relationships. METHODS: The participants consisted of 2731 incoming college students (men, 52.4%; mean age, 19.4+/-3.6years) from a National University in Taiwan. Each participant completed the questionnaires, which included the Morningness-Eveningness Scale (MES), the Yale-Brown Obsessive Compulsive Scale modified for Internet use (YBOCS-IU), the Parental Bonding Instrument for parenting style, the Family Adaptation, Partnership, Growth, Affection, and Resolve questionnaire (APGAR) for perceived family support, and the Adult Self Report Inventory-4 (ASRI-4) for psychopathology. The morning (n=459), intermediate (n=1878), and evening (n=394) groups were operationally defined by the MES t scores. RESULTS: The results showed that eveningness was associated with greater weekend sleep compensation, increased compulsive Internet use, more anxiety, poorer parenting styles, and less family support; additionally, the most associated variables for increased compulsive Internet use were the tendency of eveningness, male gender, more anxiety symptoms, less maternal affection/care, and a lower level of perceived family support. The negative association between the morning type and compulsive Internet use severity escalated with increased maternal affection/care and decreased with increased perceived family support. The positive association between the evening type and compulsive Internet use severity declined with increased maternal protection. However, the father's parenting style did not influence the relationship between morningness eveningness and compulsive Internet use severity. CONCLUSIONS: Our findings imply that sleep schedule and the parental and family process should be part of specific measures for prevention and intervention of compulsive Internet use. PMID- 24157102 TI - A 5-year perspective over robotic general surgery: indications, risk factors and learning curves. AB - INTRODUCTION: Robotic surgery has opened a new era in several specialties but the diffusion of medical innovation is slower indigestive surgery than in urology due to considerations related to cost and cost-efficiency. Studies often discuss the launching of the robotic program as well as the technical or clinical data related to specific procedures but there are very few articles evaluating already existing robotic programs. The aims of the present study are to evaluate the results of a five-year robotic program and to assess the evolution of indications in a center with expertise in a wide range of thoracic and abdominal robotic surgery. MATERIAL AND METHODS: All consecutive robotic surgery cases performed in our center since the beginning of the program and prior to the 31st of December 2012 were included in this study, summing up to 734 cases throughout five years of experience in the field. Demographic, clinical, surgical and postoperative variables were recorded and analyzed.Comparative parametric and non-parametric tests, univariate and multivariate analyses and CUSUM analysis were performed. RESULTS: In this group, the average age was 50,31 years. There were 60,9% females and 39,1% males. 55,3% of all interventions were indicated for oncological disease. 36% of all cases of either benign or malignant etiology were pelvic conditions whilst 15,4% were esogastric conditions. Conversion was performed in 18 cases (2,45%). Mean operative time was 179,4A+-86,06 min. Mean docking time was 11,16A+-2,82 min.The mean hospital length of stay was 8,54 (A+-5,1) days. There were 26,2% complications of all Clavien subtypes but important complications (Clavien III-V) only represented 6,2%.Male sex, age over 65 years old, oncological cases and robotic suturing were identified as risk factors for unfavorable outcomes. CONCLUSIONS: The present data support the feasibility of different and complex procedures in a general surgery department as well as the ascending evolution of a well-designed and well-conducted robotic program. From the large variety of surgical interventions, we think that a robotic program could be focused on solving oncologic cases and different types of pelvic and gastroesophageal junction conditions, especially rectal, cervical and endometrial cancer, achalasia and complicated or redo hiatal hernia. PMID- 24157103 TI - Morphological and immunohistochemical criteria of tissue response to radiotherapy in rectal cancer. AB - AIM: Given the context that rectal tumours respond to a certain degree to radiotherapy, a necessity arises for estimating a tumour's capacity to react to radiation from the very moment of diagnostic biopsy. MATERIAL AND METHODS: We have histologically and immunohistochemically analysed tissues coming from 52 patients with rectal adenocarcinomas. RESULTS: Of the studied parameters, the ones presenting significant variation under radiotherapy in terms of statistics(p 0.05) were: colloid type (p=0.001), EGFR in the tumour(p=0.00045), EGFR in the normal epithelium (p=0.0017),VEGF in the tumour (p=0.0132) and VEGF in the tumour stroma (p=0.030). CONCLUSIONS: Our study follows the same trends as the medical literature we have consulted regarding the variation of EGFR and VEGF with radiotherapy, and the distinct note of our study relies in the observation that normal stroma in case of rectal tumors also reacts to radiotherapy, sometimes more aggressively than the tumor itself, especially in which concerns the nerve and muscle fibers. PMID- 24157105 TI - Clinical importance of the determinant-based classification of acute pancreatitis severity. AB - PURPOSE: This classification should eliminate the confusion in terminology occurring over the last 20 years with direct implications in clinical practice. METHOD: The study was based on the web-based consultation of experts worldwide. 528 invitations were sent and 240 responses received from 49 countries from all continents. RESULTS: In an attempt to eliminate many confusions of the old classification, definitions that have built-in modern concepts of the disease have been issued, clinical evaluation of these severity has been improved and a standardized reporting data to objectively evaluate new treatments and to facilitate the communication of data between centers has been created. DISCUSSIONS: An ideal classification should reflect the whole area of clinical and paraclinical changes for one patient, at a given time. In the chosen classification, the main variable that characterizes the degree of severity is only the transitory or persistent organ dysfunction(s) failure(s). CONCLUSIONS: The most significant contribution to this update is redefining local complications based on their content,existence or non-existence of the wall, the place of their appearance and their evolution over time (local determinants).Systemic determinants take into account the presence of organ failures (transient or persistent). The presence of determinant factors has a cumulative effect. PMID- 24157104 TI - Primary tumors of the lateral ventricles of the brain. AB - BACKGROUND: The lateral ventricles are located in the center of the brain. Each ventricle lies in contact with five critical neural structures: the caudate nucleus, the thalamus, the fornix, the corpus callosum, and the genu of internal capsule.The authors report their experience in primary tumors of the lateral ventricles of the brain by analysing the symptomatology,the surgical treatment, the complications and the postoperative results. OBJECTIVE: To determine the importance of the surgical technique on the morbidity and the recurrence of lateral ventricles tumors. Total surgical resection followed by radiotherapy and or chemotherapy had been the main objective in the cases of anaplastic tumors. METHODS: This retrospective study makes reference to 202 primary tumors of the lateral ventricles operated by Leon Danaila between 1982 and 2012. The respective analysis is based on the operative approaches and on the extent of resection. The surgical access routes were the interhemispheric transcallosal approach and the transcortical approach. RESULTS: A number of 177 (87%) of the primary tumors of the lateral ventricles were benign (low grade lesions), while 25(12.37%) of them were anaplastic. The most frequent tumors were ependymomas, astrocytomas, subependymomas, choroid plexus papillomas and meningiomas. Out of the total of 202 tumor cases, 164 (81.18%) were discharged with very good and good results, 35 (17.32%) were left with neurological deficits,and 3 (1.48%) died. A significant proportion of the patients undergoing surgery develop cerebrospinal fluid outflow obstruction, and this fact made the postoperative mounting of a number of ventricular shunts necessary. CONCLUSION: The majority of these tumors were benign, with are latively slow growth rate. Owing to this fact, the preoperative dimensions of the tumors were of several centimeters. The average age of the patients was lower than that of those with similar lesions located intraparenchymatously. The symptoms were determined by the ventricular outflow obstruction and by the affectation of the periventricular structures. Interhemispheric transcallosal and transcortical approaches were the best surgical access routes. PMID- 24157107 TI - Traumatic colon injuries -- factors that influence surgical management. AB - BACKGROUND: This study sought to evaluate current trends in surgical management of colon injuries in a level I urban trauma centre, in the light of our increasing confidence in primary repair. METHODS: Our retrospective study evaluates the results of 116 patients with colon injuries operated at Bucharest Clinical Emergency Hospital, in the light of some of the most commonly cited factors which could influence the surgeon decision-making process towards primary repair or colostomy. RESULTS: Blunt injuries were more common than penetrating injuries (65% vs. 31%). Significant other injuries occurred in 85 (73%) patients. Primary repair was performed in 95 patients (82%). Fecal diversion was used in 21 patients(18%). Multiple factors influence the decision-making process: shock, fecal contamination, associated injuries and higher scores on the Abdominal Trauma Index (ATI) and Colon Injury Scale (CIS). Colon related intra-abdominal complications occurred in 7% of patients in whom the colon injury was closed primarily and in 14% of patients in whom a stoma was created, ATI having a predictive role in their occurrence. The overall mortality rate was 19%. CONCLUSIONS: Primary repair of colon injuries, either by primary suture or resection and anastomosis, is a safe method in the management of the majority of colonic injuries. Colostomy is preferred for patients with ATI >= 30 and CIS >= 4. Surgical judgment remains the final arbiter in decision making. PMID- 24157106 TI - The role of intraoperative ultrasound in establishing the surgical strategy regarding hepato-bilio-pancreatic pathology. AB - Intraoperative ultrasound examination plays a more and more important role in open or laparoscopic abdominal surgery,satisfying the surgeon's need to correctly characterize lesions,bringing various benefits regarding topography and local regional extension, relations between neighbouring structures and, finally, disease staging. Intraoperative ultrasound is used especially in hepato-bilio pancreatic tract interventions, given its diagnostic and therapeutic values. Between 2009-2012 in the IOB First Surgery Clinic 57 intraoperative echo graphies were performed, in patients with hepato-bilio-pancreatic pathologies, leading to intraoperative guided punctures with diagnostic or therapeutic purpose (in case of hepatic abscesses),detection of new hepatic metastases, their ablation under ultrasound guidance, exploration of the local-regional topography with the aim of an optimal hepatic resection. Intraoperative ultrasound allowed radioablation under echographic guidance in 43 patients, the majority presenting multiple hepatic metastases in different areas, this method also enabling control over complete lesional destruction. Also, in 11 cases (22.915), a number of hepatic 20 metastases which had not been visible on preoperative imaging scans were detected, and afterwards treated through RFA; also, in 14 cases intraoperative echography revealed the presence and nature of the hepatic tumours, leading to a correct histopathological diagnostic and an adequate therapy. The method was useful in pancreatic pathologies as well, in complicated forms of acute or chronic pancreatitis, tracking the Wirsung duct within the scleral and calcified mass of pancreatic tissue, through an ultrasound guided puncture, as well as in locating pancreatic cystic masses,determining the optimal puncture or pericystic digestive drainage areas. Intraoperative ultrasound is an inexpensive, easy method, which allows real time exploration throughout the entire surgical process of hepato-bilio-pancreatic lesions, aiding the surgeon in modifying decisions regarding the intervention and preventing complications. PMID- 24157108 TI - Laparoscopic sleeve gastrectomy reduces the predicted coronary heart disease risk and the vascular age in obese subjects. AB - BACKGROUND: Obesity is associated with high prevalence of coronary heart disease (CHD) and long term increased cardiovascular morbi-mortality. There are no data regarding the effect of laparoscopic sleeve gastrectomy (LSG) on long-term CHD - risk. It is known that "a man is as old as his arteries" and this concept is illustrated by Framingham coronary risk score, which can predict vascular age. PURPOSE: To assess the 10-year CHD risk in patients with obesity, preoperatively, and 6 and 12 months after LSG. METHODS: 47 consecutive obese subjects (44.7% males, mean age 39.8 years) scheduled for LSG were prospectively studied before and 6 and 12 months after surgery. The 10 years CHD risk and corresponding vascular age were calculated using Framingham risk score. RESULTS: The body mass index (BMI) decreased from 44.6 +/- 10.6 kg m2 preoperatively to 32.2 +/- 6.9 kg m2 and to 29.4 +/- 5.4 kg m2 at 6 and 12 months follow-up (both p 0.05). Mean excessive weight loss (EWL) was 67.3 +/- 23.7% and 78.3 +/- 23.4% at 6 and 12 months postoperatively. At 6 and 12 months after LSG, there was a marked improvment of lipid profile(decrease of total cholesterol, LDL-cholesterol, triglycerides and increase of HDL-cholesterol) and a significant decrease in prevalence of diabetes mellitus, systemic hypertension and smoking. The 10-year CHD risk reduced from 10.1% preoperatively to 3.5% and to 2.2% at 6 and 12 months after surgery (both p 0.05). Patients' mean vascular age was 65.6 years preoperatively and decreased to 45.8 years 6 month spostoperatively (p 0.05) and to 40.7 years one year after LSG (p 0.05 vs. 6 months postoperatively, p=NS vs.chronological age). CONCLUSIONS: In obese subjects, CHD risk is significantly reduced early, beginning with 6 months after LSG and is diminished with 80% one year postoperatively. Despite the fact that not all patients had achieved the ideal weight yet,mean vascular age is similar to their chronological age one year after surgery. PMID- 24157109 TI - Economic analysis of medical management applied for left colostomy. AB - PURPOSE: This paper presents an analysis of surgical treatment costs for left colostomy, aiming to calculate a medium cost per procedure and to identify the means to maximize the economic management of this type of surgicale procedure. MATERIALS AND METHOD: A retrospective study was conducted on a group of 8 patients hospitalized in the 4th Surgery Department,Emergency University Hospital Bucharest, during the year 2012 for left colic neoplasms with obstruction signs that were operated on with a left colostomy. The followed parameters in the studied group of patients were represented by medical expenses, divided in: preoperative, intra-operative and immediate postoperative (postop. hospitalization). RESULTS: Two major types of colostomy were performed: left loop colostomy with intact tumour for 6 patients and left end colostomy and tumour resection (Hartmann's procedure) for 2 patients. The medium cost of this type of surgical intervention was 4396.807 RON, representing 1068.742 euro. Statistic data analysis didn't reveal average costs to vary with the type of procedure. The age of the study subjects was between 49 and 88, with an average of 61 years, without it being possible to establish a correlation between patient age and the level of medical spendings. CONCLUSIONS: Reducing the costs involved by left colostomy can be efficiently done by decreasing the number of days of hospitalisation in the following ways: preoperative preparation and assessment of the subject in an outpatient regimen; the accuracy of the surgical procedure with the decrease of early postoperative complications and antibiotherapy- the second major cause of increased postoperative costs. PMID- 24157111 TI - Crohn's disease management: conclusions of a comparative study between UK and Romania. AB - Crohn's disease is a chronic inflammatory condition, which may affect any portion of the digestive tract from the mouth to the anus. It is a chronic medical condition which requires surgery when medical treatment fails or complications such as strictures, sepsis or fistulation develop (1,2,3). We retrospectively studied a group of 19 patients with Crohn's disease from "Coltea" Hospital, Bucharest, Romania, and another group of 16 patients with Crohn's disease from Bedford Hospital UK, all of them having undergone surgery; we compared their preoperative and postoperative treatments, including follow up.It was concluded that the implementation of clinical guidelines and protocols for the management of patients with Crohn's disease is needed in Romania. PMID- 24157110 TI - Single-port laparoscopic surgery by use of a surgical glove port: initial experience with 25 cases. AB - BACKGROUND: single-port laparoscopic surgery has gained popularity over the last decade. This technique is used for several surgical procedures. This paper documents a new and cheaper access method known as "surgical glove port" or "homemade single-port", and describes our initial experience with 25 cases. METHOD: Eleven cholecystectomies, eight totally extraperitoneal inguinal hernia repairs, three splenectomies, two gastric wedge resections, and one anti-reflux procedure were performed. RESULTS: Twenty-four procedures out of twenty-five were completed without conversion to open or multiple port techniques. An individual patient who had both cholelithiasis and gastrointestinal stromal tumor underwent both cholecystectomy and gastric wedge resection in the same session with surgical glove port technique. In another case two additional 5-mm incisions were made for hemostasis. The additional operation was required and performed by using surgical glove port for a hiatal hernia repair case, because of postoperative hemorrhage. CONCLUSION: Single-port laparoscopic surgery is an applicable technique for plenty of surgical procedures. Also, surgical glove port is a newer technique and some initial experience shave already published all over the world. Surgical glove port has advantages such as cost-effectiveness, easy and safe port implantation and specimen extraction. SGP can also be used for treating post operative complications. PMID- 24157112 TI - Late results and quality of life after Rives-Stoppa repair for incisional hernias: a prospective clinical study. AB - BACKGROUND: The prosthetic repair of incisional hernias drastically reduced the incidence of recurrence, but increased the associated morbidity. We report a consecutive series of patients with incisional hernias operated by Rives- Stoppa procedure. The aim is to identify the early and late complications associated with the procedure. MATERIAL AND METHODS: 275 patients admitted and operated on between 2002-2006 were prospectively evaluated by direct examination and questionnaire. RESULTS: 171 responded in 2007 and 148 in 2009; direct examination was obtained 143 and 118 patients respectively.Recurrence rate 6.7%. Good and very good comfort rates in 58%. CONCLUSIONS: Similar results with the expert centre. PMID- 24157113 TI - Screening of hepatopulmonary syndrome (HPS) with CEUS and pulse-oximetry in liver cirrhosis patients eligible for liver transplant. AB - BACKGROUND AND AIM: The prevalence of hepatopulmonary syndrome (HPS) in the setting of cirrhosis ranges between 4%-47%. We aimed to detect a correlation between heart and lungs findings on contrast-enhanced ultrasound (CEUS)and pulse oximetry, in order to early detect HPS and thus to improve patients referral to orthotopic liver transplantation(OLT). METHODS: We considered at risk for HPS all patients with delayed left ventricle (LV) enhancement of the contrast agent,at least 3 systolic beats after it appears in the right ventricle(RV). We correlated CEUS results with pulse-oximetry findings,considering to have a positive HPS diagnosis in all patients with both CEUS findings and SaO2 95%. RESULTS: From 186 patients diagnosed with liver cirrhosis, 56 patients (30.10%) had delayed LV enhancement of the contrast agent. Pulse-oximetry showed alterations, such as SaO2 95%and PaO2 70 mmHg in 62 patients (33.33%). Pearson index showed a good correlation between lung and heart CEUS findings and pulse-oximetry (r=0.99) in HPS diagnosis. CONCLUSIONS. Two non-invasive, simple and rapid methods such as CEUS and pulse-oximetry can easily diagnose HPS, a highly fatal complication of liver cirrhosis, and can also guide the future treatment by speeding up OLT recommendations. PMID- 24157114 TI - Minilaparotomy as surgical approach for aortoiliac occlusive disease -- single center initial experience. AB - PURPOSE: The purpose of this study was to emphasize the benefits and indications of performing minilaparotomy as surgical approach for occlusive aortoiliac disease. MATERIAL AND METHOD: From January 2011 to July 2012, a total of 23 patients (19 men and 4 women), with a median age of 60 years (range 49-75) diagnosed with aortoiliac occlusive disease(n=22) or abdominal aneurysm (n=1), were included in a retrospective non-randomized clinical study. Among these patients 11 underwent aortic bypass procedure by minila parotomy approach (ML group) and 12 patients by standard laparotomy(SL group). Demographic and clinical data, operative data, postoperative recovery data and complications were analysed according to these two groups of patients. Follow-up consisted of clinical examination and duplex scanning at 1, 3,6 and 12 months postoperatively. RESULTS: There were no significant differences between the minilaparotomy and standard laparotomy control groups concerning clinical and demographical data. Two surgical conversions to standard laparotomy were necessary (18.18%) in the ML group due to technical difficulties. The mean operative time was shorter in the ML group (124 +/- 22 minutes) and the mean aortic clamping time was similar between the two groups.Major differences between the two lots were observed postoperatively;mean blood loss was more important in the SL group (550 ml) than in the ML group (350 ml) (statistical significance p=0.001, Student test). Patients who have undergone standard laparotomy required more fluids (10000 A+ 2000 ml) in comparison to the other group (6000 +/- 1000 ml) p value=0.0001, while the duration of nasogastric suction and period before resuming a liquid diet was both shorter in the ML group (1.1 +/- 0.5 days) than those from the SL group (2.5 +/- 0.6 days) p value=0.001. The period spent in the ICU was significantly shorter for the ML lot of patients and the median hospitalization time was 5.6 days for patients in ML group,whereas in the SL group the median hospitalization time was 8.9 days (Student test - p value 0.01). We had no 30-day mortality in any of the groups included in the study. One patient from the ML group was readmitted in postoperative day 43 and re-operated on for a prosthetic limb graft thrombosis.Two patients were lost to follow-up and the mean follow-up was 9 +/- 1.5 months. CONCLUSIONS: Minilaparotomy as surgical approach for aortic diseases is a feasible, safe procedure on selected patients. PMID- 24157115 TI - Use of the serratus anterior muscle flap for postoperative empyema -- a single center experience with 25 consecutive cases. AB - OBJECTIVE: The aim of this study is to analyse the possibilities and the results of using the serratus anterior muscle flap during reoperations in patients with a complicated course after major general thoracic procedures. MATERIAL AND METHODS: We performed a retrospective study on 25 consecutive patients operated in a single center between 01.01.2002-01.01.2012, in whom we used the serratus anterior muscle flap during complex thoracomyoplasty procedures for postoperative empyema. In all cases the serratus anterior was mobilized keeping both the thoraco-dorsal branch and the lateral thoracic vessels intact. The following parameters were followed: mortality rate, morbidity rate, hospitalization,viability of the flap and the functional status of the patients at 3 months after surgery. RESULTS: We encountered one postoperative death (4%) and one recurrence of the intrathoracic suppuration (4%). Intensive care unit hospitalization ranged between 1-9 days, with a median of 2 days. Overall postoperative hospitalization ranged between 8-87, with a median of 34 days. We have encountered no post-operative flap necrosis. At 3 months after surgery, 92% of the survivors returned to a normal life. The type of the first thoracotomy incision (postero-lateral versus antero-lateral) had no statistically significant impact on the outcome of the patients' hospitalization or rate of local complications(p 0.05). CONCLUSIONS: As a pure muscular flap, the serratus anterior is extremely useful to treat infectious complications after general thoracic surgery procedures. It can be used during thoracomyoplasty procedures with an acceptable mortality and morbidity and with good functional results. PMID- 24157116 TI - Diagnosis and treatment of limb fractures associated with acute peripheral ischemia. AB - Acute Peripheral Ischemia (API) is the most severe acute complication after both open and closed fractures, as ischemia compromises not only the vitality of the affected limb, but also the patient's life, because metabolic anaerobic changes following ischemia have serious local and general consequences. These explain why early diagnosis of API is very important for the prognosis of the traumatized limb.The authors analyse cases when API was not diagnosed immediately after trauma, but some time after the first examination, due to either low systolic BP or to late onset of API. The patients were analysed concerning the type of the fracture, the reason for delayed diagnosis of API, the moment of API diagnosis and the arterial injury. In all those cases, surgery was performed immediately after API diagnosis, in order to identify and treat the complex injuries(bone and vascular). PMID- 24157117 TI - Conducted healing to treat large skin wounds. AB - BACKGROUND: Improvement of the healing process to provide better aesthetical and functional results continues to be a surgical challenge. This study compared the treatment of skin wounds by means of conducted healing (an original method of treatment by secondary healing) and by the use of autogenous skin grafts. METHOD: Two skin segments, one on each side of the dorsum,were removed from 17 rabbits. The side that served as a graft donor site was left open as to undergo conducted healing (A)and was submitted only to debridement and local care with dressings. The skin removed from the side mentioned above was implanted as a graft (B) to cover the wound on the other side. Thus, each animal received the two types of treatment on its dorsum (A and B). The rabbits were divided into two groups according to the size of the wounds: Group 1 - A and B (4 cm2)and Group 2 - A and B (25 cm2). The healing time was 19 days for Group 1 and 35 days for Group 2. The final macro- and microscopic aspects of the healing process were analysed comparatively among all subgroups. The presence of inflammatory cells, epidermal cysts and of giant cells was evaluated. RESULTS: No macro- or microscopic differences were observed while comparing the wounds that underwent conducted healing and those in which grafting was employed, although the wounds submitted to conducted healing healed more rapidly. CONCLUSIONS: Conducted wound healing was effective for the treatment of skin wounds. PMID- 24157118 TI - Lys751Gln XPD and Arg399Gln XRCC1 in Romanians. Association with sporadic colorectal cancer risk and different stages of carcinomas. AB - BACKGROUND: DNA repair processes involved the removal of modified bases through the base excision repair (BER) pathway and removal of damaged nucleotides through the nucleotide excision repair (NER) pathways. METHODS: in order to determine the association between XPD(Lys751Gln) and XRCC1 (Arg399Gln) SNPs and the risk of CRC as well as tumor grade and stages in Romanians we genotyped using PCR-RFLP methods 150 patients (80 females and 70 males) and 162 controls (100 females and 62 males). RESULTS: The risk (odds ratio - OR) to develop sporadic CRC was 3.02 (p=0.02) and 3.49 (p=0.001), respectively, in association with the homozygous Gln751 Gln751-XPD and Gln399 Gln399-XRCC1 genotypes. Higher risk for carriers of the Gln751 Gln751 - Arg399 Arg399 (OR 4.19, p=0.027),Gln399 Gln399 - Lys751 Lys751 (OR 3.21, p=0.013),Gln399 Gln399 - Lys751 Gln751 (OR 4.5, p=0.05),Lys751 Gln751 - Arg399 Gln399 (OR 3.94, p 0.001) combined genotypes was observed. The lowest risk was observed in carriers of Lys751 Lys751-Arg399 Arg399 genotypes (OR0.24, p 0.001). 2.24-fold (p=0.05) and 3.75-fold (p=0.004)increased risk (OR) for carriers of the Lys751Gln or Arg399Gln variants to be on stage pT2 and pT4, respectively. Patients carriers of Lys751Gln or Arg399Gln variants had 7.7 fold(p=0.002) and 18.94-fold (p 0.001) increased risk (OR) to develop sporadic CRC in stage D. CONCLUSIONS: XPD and XRCC1 variants affect the risk for sporadic CRC in Romanians, seem to be associated with more aggressive forms of sporadic CRC and may be prognostic factors in patients with advanced CRC. PMID- 24157119 TI - Liver transplantation in a patient with unresectable colorectal liver metastases - a case report. AB - BACKGROUND: Due to the lower survival rates achieved, in the early period of liver transplantation era, in patients with colorectal liver metastases, and because of the organ shortage,in the last two decades colorectal liver metastases are considered a contraindication for liver transplantation. However, the increasing number of marginal donors, and the improvements in posttransplant immunossuppresion, chemotherapy and methods to assess the extrahepatic disseminationof colorectal cancer, opened the perspective of liver transplantation to certain patients with malignancies (such as HCC beyond Milan criteria, and selected patients with cholangiocarcinomaor liver metastases from neuroendocrine tumors).Since some of these patients experienced favorable outcomes,in the last years, there were authors that considered a rationalerevisitation of the benefits of liver transplantation in patients with unresectable colorectal liver metastases. Thus, in 2006, a Norwegian group started a study which aims to assess the results of liver transplantation in patients with unresectable colorect alliver metastases. Their results were unexpectedly favorable, revealing that 5-year overall survival rate was 60%, and the quality of life was excellent in the first year following transplantation.However, all the patients presented relapse of the disease in the first two years following transplantation. In the present paper we present the clinico-pathologic characteristics,the pre- and postoperative management and the outcome of a patient with unresectable colorectal liver metastases who underwent liver transplantation in a very advanced state of the disease (when he developed subacute liver failure due to insufficient functional liver parenchyma and toxicity of chemotherapy).We consider useful to present such observations,because collecting the data presented by different centers maybe contributive to identification of a selected group of patients who could benefit from liver transplantation. CASE REPORT: A 42-year old male patient, it was diagnosed with upper rectum cancer and multiple bilobar liver metastases in April 2009. Chemotherapy was started (in another hospital),and because the disease was stable after 7 cycles of FOLFOX and Bevacizumab, the patient was reffered to surgery (for a "two stage" liver resection). In October 2009 it was performed primary tumor resection associated with left lateral section ectomy and segment 4 metastasectomy. Because in November 2009 CT scan re-evaluation revealed progression of liver metastases, the second stage hepatectomy was precluded. Subsequent therapy consisted in radio embolization, multiple lines of chemotherapy,and targeted therapies. After more than 2 years, the liver metastases progressed and the patient developed progressive cholestatic subacute liver failure due to insufficient functional liver parenchyma and chemotherapy toxicity. In this state of the disease, he was admitted in our hospital, being dependant by liver dialysis and plasma exchange procedures. Due to the patients' age, and because the MDCT scan revealed the absence of extrahepatic disease (after almost three years of disease progression), and he could not benefited from any type of antineoplastic treatment due to progressive cholestatic subacute liver failure, liver transplantation with an organ from amarginal donor was considered and performed in January 2012.The postoperative course was uneventful, and the quality of his life improved (being fully reinserted social and professional).The immunosuppressive regimen consisted in Sirolimus and Mycophenolate mofetil, and the adjuvant chemotherapy started two months following liver transplantation. However,the patient developed extrahepatic relapse of the disease (lung metastases and retroperitoneal recurrence), but now, at morethan 20 months following transplantation, he is still alive in agood clinical condition. CONCLUSIONS: In patients with multiple unresectable liver onlycolorectal metastases, liver transplantation may improve overallsurvival and quality of life, by using marginal grafts whichcannot be allocated to the patients with standard indicationsfor liver transplantation. The advent of MDCT and PET CT scan and the use of m-TOR inhibitors may improve the resultsachieved by liver transplantation in patients with CLMs.Further studies could be useful in an attempt to disclosewhether a selected group of patients with unresectable liveronly colorectal metastases could become acceptable candidatesfor liver transplantation. PMID- 24157121 TI - Soft tissue reconstruction in the sacro-gluteal region after excision of a large verrucous carcinoma. AB - Verrucous carcinoma is a slow-growing malignancy which, if neglected, can seriously affect local tissues. We present the case of a 55-year-old male with a 12 9 cm nodular ulcerated lesion in the sacro-gluteal region, poorly defined, with acytologic scrape smear pozitive for squamous cell cacinoma,infiltrating on MRI both gluteal muscles. The initial radiotherapeutic treatment significantly improved local condition facilitating the radical excision of the tumor. The resulting defect, 17 14 cm in size, was covered by V-Y advancement of two fasciocutaneous triangul are flaps based on transmuscular perforators from superior and inferior gluteal arteries. The patient healed completely and the tumor didn't relapse in the past 42 months. PMID- 24157120 TI - Tuberculous lymphadenitis as a cause of obstructive jaundice. AB - Obstructive jaundice secondary to abdominal tuberculosis is extremely rare. We present a patient with jaundice secondary to compression of the common bile duct by TB lymphadenitis. A 49-year-old woman was admitted to our department for nausea,epigastric pain and jaundice. Abdominal ultrasonography and computer tomography scan were suggestive of stenosis of the distal common bile duct caused by a retro pancreatic mass. At laparotomy, an enlarged lymph node behind the head of the pancreas was found, causing compression and stenosis of the distal parts of the choledochus. The lymph node frozen section analysis showed epithelioid granuloma with caseous necrosis,strongly suggesting tuberculous origin. Choledochoduodenal anastomosis was performed. Definitive pathohistological examination confirmed TB lymphadenitis. ATB should be considered as a potential cause of jaundice especially in immuno compromised patients and endemic areas. Diagnosing abdominal tuberculosis can be a challenging task. No satisfactory diagnostic gold standard is available so that in most cases the diagnosis cannot be reached before exploratory laparotomy.Early detection enables successful conservative treatment and eliminates the necessity of surgery. PMID- 24157122 TI - Maxillary solitary recurrent plasmacytoma: a case report. AB - Solitary plasmacytoma is a very rare form of neoplasia, part of the monoclonal gammopathies. It represents a tumoral proliferation of plasma cells in the form of a solitary mass which can be located in the bone marrow or extramedullary.Initial symptoms are vague and nonspecific. Being such a rare affliction, there is little information in the literature. Early diagnosis is difficult but very important due to therapy outcome.A high risk of progression towards a multiple myeloma has been reported. We present a rare case of a 52-year old patient diagnosed with multiple solitary plasmacytomas. The tumours were separated from one another in time, over a 14 years period. The various medullograms did not show any sign of medullary plasma cell infiltrate. Initially, the affliction responded to chemotherapy, but later the haematologist recommended surgical resections followed by reconstruction.The maxillary localization required excision of the tumour with the preservation of the eye bulb despite the destruction of the orbital floor and with the regain of ocular functionality as well as aesthetic rehabilitation. This evolution highlights the benefits of surgical treatment in conjunction with chemotherapy in the treatment of this entity. PMID- 24157123 TI - Calcific uremic arteriolopathy in hemodialyzed patients. AB - In the present article, we discuss the case of 67-year-old female patient diagnosed with inferior limbs calciphylaxis and hemodialyzed since 2006. The clinical manifestations and pathological lab findings are typical for this rare and extremely severe complication in chronic hemodialyzed individuals. The favorable treatment response to sodium thiosulfate, not often used as elected therapy in international studies, represents the particularity of the case. PMID- 24157125 TI - Interaction of parvoviruses with the nuclear envelope. AB - Parvoviruses are serious pathogens but also serve as platforms for gene therapy or for using their lytic activity in experimental cancer treatment. Despite of their growing importance during the last decade little is known on how the viral genome is transported into the nucleus of the infected cell, which is crucial for replication. As nucleic acids are not karyophilic per se nuclear import must be driven by proteins attached to the viral genome. In turn, presence and conformation of these proteins depend upon the entry pathway of the virus into the cell. This review focuses on the trafficking of the parvoviral genome from the cellular periphery to nucleus. Despite of the uncertainties in knowledge about the entry pathway we show that parvoviruses developed a unique strategy to pass the nuclear envelope by hijacking enzymes involved in mitosis. PMID- 24157124 TI - Gallstone ileus: a rare cause of intestinal obstruction -- case report and literature review. AB - Gallstone ileus is an uncommon complication of cholelithiasis with a high morbidity and mortality rate. We report a rare case of small bowel gallstone obstruction in an 87-year-old female patient with cholecystoduodenal fistula. We performed an enterolithotomy, repair of fistula and cholecystectomy. During the postoperative course a wound dehiscence appeared, which required suturing and prolonged hospitalisation. We review the diagnostic and therapeutic aspects, given that the diagnosis of this condition is usually difficult and often made intraoperatively.In fact, here is no standard surgical procedure for this disease. The one-stage procedure should be reserved for stabilized patients, but in cases with associated comorbidities,only enterolithotomy can represent the best option.. PMID- 24157126 TI - Elevated expression of pleiotrophin in pilocarpine-induced seizures of immature rats and in pentylenetetrazole-induced hippocampal astrocytes in vitro. AB - Pleiotrophin (PTN) is a secreted extracellular matrix (ECM)-associated cytokine that has emerged as an important neuromodulator with multiple neuronal functions. In the present study, we detected and compared the dynamic expression of PTN in the hippocampus and adjacent cortex of immature rats with pilocarpine-induced epilepsy. Moreover, we also confirmed the results by examining PTN expression in hippocampal astrocytes cultured in the presence of pentylenetetrazole (PTZ). Immunohistochemistry showed faint immunostaining of PTN in the control hippocampus and adjacent cortex. Notably, PTN immunoreactivity began to increase in relatively small cells in the hippocampus and adjacent cortex at 2h and 3 weeks after seizures, and the labeling intensity reached the maximum level in the hippocampus and adjacent cortex at 8 weeks after seizures. Furthermore, we also found that PTZ treatment significantly reduced astrocytic viability in a dose dependent manner and time-dependently increased expression levels of PTN in hippocampal astrocytes. In conclusion, our data suggest that increased expression of PTN in the brain tissues may be involved in epileptogenesis. PMID- 24157128 TI - Perception of vowels and prosody by cochlear implant recipients in noise. AB - The aim of the present study was to compare the ability of cochlear implant (CI) recipients to recognise speech prosody in the presence of speech-weighted noise to their ability to recognise vowels in the same test paradigm and listening condition. All test materials were recorded from four different speakers (two male, two female). Two prosody recognition tasks were developed, both using single words as stimuli. The first task involved a question/statement distinction, while the second task required listeners to make a judgement about the speaker's attitude. Vowel recognition tests were conducted using vowel pairs selected on the basis of specific acoustic cues (frequencies of the first two formants and duration). Ten CI users and ten normal-hearing controls were tested in both quiet and an adaptive noise condition, using a two-alternative forced choice test paradigm for all the tests. Results indicated that vowel recognition was significantly better than prosody recognition in both listener groups in both quiet and noise, and that question/statement discrimination was the most difficult task for CI listeners in noise. Data from acoustic analyses were used to interpret differences in performance on different tasks and with different speakers. LEARNING OUTCOMES: As a result of this activity, readers will be able to (1) describe suitable methods for comparing vowel and prosody perception in noise, (2) compare performance on vowel and prosody perception tasks in quiet in normal-hearing listeners and cochlear implant recipients, (3) compare performance on vowel and prosody perception tasks in noise in normal-hearing listeners and cochlear implant recipients and (4) relate performance on prosody tasks in quiet to performance on these tasks in noise. PMID- 24157129 TI - Gonadal hormone dependent developmental plasticity of catecholamine:beta2 adrenoceptor signaling complex in male rat thymus: putative implications for thymopoiesis. AB - The study was undertaken considering that: i) androgens affect beta2-adrenoceptor (AR)-mediated catecholamine (CA) action in many tissues; and ii) peripubertal changes in both circulating androgen and thymic CA levels are implicated in rat thymic involution. Its aims were to: i) explore putative effects of the late prepubertal orchidectomy on thymic CA:beta2-AR complex in young adult rats, and ii) delineate the direct effects of testicular hormone withdrawal on the CA:beta2 AR complex from those elicited secondarily through altered influence of this complex components on each other's availability. Upon showing that prepubertal orchidectomy augmented the efficacy of thymopoiesis through increasing the thymocyte surface density of Thy-1, whose expression is negatively regulated by beta2-AR-mediated signaling, we examined the effects of orchidectomy and 14-day long propranolol (PROP) treatment in orchidectomized (ORX) and sham-ORX rats on thymic norepinephrine (NE) concentration and metabolism and beta2-AR expression. Orchidectomy, despite an increase in the average NE amount per thymocyte and total thymocyte NE content, diminished thymic NE concentration. This decrease reflected the diminished density of CA-synthesizing nerve fibers, CD68+ macrophages, cortical (aminopeptidase A+), and medullary (UEA-1+) thymic epithelial cells (TECs) and their CA content (probably due to lessened TH expression accompanied by increased MAO-A expression). Moreover, orchidectomy decreased the surface beta2-AR expression on thymocytes, CD68+ macrophages and OX 62+ dendritic cells, but increased its expression on the TECs. In sham-ORX rats, PROP reduced thymic NE concentration by diminishing TH expression in the thymic cells. Additionally, PROP in thymocytes and thymic stromal cells diminished and enhanced the beta2-AR mRNA expression, respectively. However, in ORX rats PROP did not significantly affect CA(NE):beta2-AR complex components. This indicated that prepubertal orchidectomy affects ability of young adult rats to respond to beta-AR blockade by altering thymic NE and beta2-AR availability. Collectively, the results showed that testicular hormones contribute to alterations in thymus/thymopoiesis during the critical peripubertal period by shaping modulatory sympathetic influence and CA autocrine/paracrine action within the organ. PMID- 24157130 TI - Circulating CD56dim NK cells expressing perforin are increased in progressive multiple sclerosis. AB - In this study we evaluated the percentages of CD3(-)CD56(bright), CD3( )CD56(dim), CD3(-)CD56(bright)perforin(+) and CD3(-)CD56(dim)perforin(+) Natural Killer (NK) cells in peripheral blood from untreated secondary progressive (SP) and primary progressive (PP) multiple sclerosis (MS) patients and age and sex matched healthy subjects. Both PPMS patients and SPMS patients showed increased percentages of circulating CD3(-)CD56(dim)perforin(+) NK cells than healthy subjects. The increased percentage of CD3(-)CD56(dim) NK cells expressing perforin in patients affected by the progressive forms of MS suggests a possible role of this NK cell subpopulation in the pathogenesis of the disease. PMID- 24157127 TI - Gene expression within the extended amygdala of 5 pairs of rat lines selectively bred for high or low ethanol consumption. AB - The objectives of this study were to determine innate differences in gene expression in 2 regions of the extended amygdala between 5 different pairs of lines of male rats selectively bred for high or low ethanol consumption: a) alcohol-preferring (P) vs. alcohol-non-preferring (NP) rats, b) high-alcohol drinking (HAD) vs. low-alcohol-drinking (LAD) rats (replicate line-pairs 1 and 2), c) ALKO alcohol (AA) vs. nonalcohol (ANA) rats, and d) Sardinian alcohol preferring (sP) vs. Sardinian alcohol-nonpreferring (sNP) rats, and then to determine if these differences are common across the line-pairs. Microarray analysis revealed up to 1772 unique named genes in the nucleus accumbens shell (AcbSh) and 494 unique named genes in the central nucleus of the amygdala (CeA) that significantly differed [False Discovery Rate (FDR) = 0.10; fold-change at least 1.2] in expression between the individual line-pairs. Analysis using Gene Ontology (GO) and Ingenuity Pathways information indicated significant categories and networks in common for up to 3 or 4 line-pairs, but not for all 5 line-pairs. However, there were almost no individual genes in common within these categories and networks. ANOVAs of the combined data for the 5 line-pairs indicated 1014 and 731 significant (p < 0.01) differences in expression of named genes in the AcbSh and CeA, respectively. There were 4-6 individual named genes that significantly differed across up to 3 line-pairs in both regions; only 1 gene (Gsta4 in the CeA) differed in as many as 4 line-pairs. Overall, the findings suggest that a) some biological categories or networks (e.g., cell-to-cell signaling, cellular stress response, cellular organization, etc.) may be in common for subsets of line-pairs within either the AcbSh or CeA, and b) regulation of different genes and/or combinations of multiple biological systems may be contributing to the disparate alcohol drinking behaviors of these line-pairs. PMID- 24157131 TI - Sperm attachment and penetration competence in the human oocyte: a possible aetiology of fertilization failure involving the organization of oolemmal lipid raft microdomains influenced by the DeltaPsim of subplasmalemmal mitochondria. AB - The roles of oolemmal lipid raft microdomains enriched in the ganglioside GM1 and the tetraspanin protein CD9 were investigated as causative agents in fertilization failure in human IVF where spermatozoa progress to the oolemma but fail to attach or, if attached, to penetrate. The findings show that specific configurations of GM1 lipid raft microdomains are consistent with attachment and penetration, while microdomains composed of CD9 lipid rafts, a protein known to be critical for penetration, do not appear to have a central role in the initial stages of attachment. The relative magnitude of the potential difference across the inner membrane (DeltaPsim) in mitochondria localized to a stable subplasmalemmal domain appears to influence the organization of GM1 but not CD9 lipid raft microdomains in the corresponding oolemma. The findings present a novel view of how fertilization competence may be established in the human oocyte and a means by which certain fertilization failures that occur after conventional clinical IVF can be identified and explained in the unfortunate instance of fertilization arrest at the oolemma. PMID- 24157132 TI - Reprint of: Uterine plasticity and reproductive fitness. AB - Reproduction in humans is unique in two major aspects. First, the incidence of chromosomally abnormal and developmentally compromised human preimplantation embryos is exceptionally high, and second, the uterus decidualizes spontaneously each cycle, a process also responsible for the menstrual shedding of the endometrium in the absence of pregnancy. Emerging evidence suggests that these distinctive reproductive traits are functionally linked. Thus, the decidual process enables the mother to limit investment in compromised pregnancies, while menstruation imposes a need for constant recruitment of mesenchymal stem cells to regenerate and renew the endometrium each cycle. Endometrial stem cells are immune-privileged compared with other types of adult stem cells, suggesting a role for these cells in accommodating deeply invading semi-allogenic fetal trophoblast. Thus, by coupling reproductive competence to a process of constant tissue renewal, decidualization enables the human uterus to adapt to pregnancy failure and a changing ecology. PMID- 24157134 TI - Osteoporosis and the orthopaedic surgeon. PMID- 24157133 TI - Phase equilibriums, self-assembly and interactions in two-, three- and four medium-chain length component systems. AB - The Scandinavian surface (surfactant) and colloid science owes much of its success to Per Ekwall and Bjorn Lindman. In this review the main topics shared by their research groups at Abo Akademi University in Finland and at Lund University in Sweden are described. The nature of surface active substances (cosolvents, co surfactants and surfactants) and microemulsions are evaluated. It is shown that the properties of medium-chain length surfactants differ dramatically from long chain surfactants. The phase equilibriums of binary systems are related to the phase equilibriums of ternary and quaternary systems referred to as microemulsions or more recently also as nanoemulsions. A distinction is made between hydrotrope liquids, detergentless microemulsions, surfactant mixture systems and microemulsions. Three component systems are assembled to "true" quaternary microemulsions. An exceptionally comprehensive network of thermodynamic parameters describing molecular site exchange and micelle formation are derived and related mutually. Gibbs free energy, enthalpy, entropy, volume, heat capacity, expansivity and compressibility can be used to illustrate the degree of aggregation cooperativity and to evaluate whether micelle formation is of a first-, second- or intermediate order phase transition. Theoretical simulations and experimental results show that the associate structures of medium chain length surfactants are quite open and may be deformed due to small aggregation numbers. The self-assembly occurs over a number of distinct steps at a series of experimentally detectable critical concentrations. Despite the low aggregation tendency their phase behavior equals those of long-chain homologs in surfactant mixture and microemulsion systems. A number of models describing the self-assembly are reviewed. Nuclear magnetic resonance (shift, relaxation rate and diffusion), Laser Raman and infrared spectroscopies were chosen as key instruments for molecular interaction characterization since they were used in the collaboration between the research groups in Abo and in Lund. A new method is introduced in order to evaluate the traditional procedure for extracting limiting parameters which also enables an illustration of the degree of cooperativity. The focus is laid mainly on aqueous, alcoholic, saline and, to a limited extent oil phases of one-, two-, three- and four component systems of water-sodium carboxylates-alcohol-oil. The extensive thermodynamic characterization of these liquid phases and liquid crystalline phases is left out due to space restrictions. PMID- 24157135 TI - Current status and prospect of Chinese arthroplasty. PMID- 24157136 TI - Cervical disc arthroplasty with ProDisc-C artificial disc: 5-year radiographic follow-up results. AB - BACKGROUND: Cervical disc arthroplasty is an alternative surgery to standard cervical decompression and fusion for disc degeneration. Different types of cervical disc prosthesis are used in China. The aim of this study was to evaluate the radiographic outcomes of cervical arthroplasty using the ProDisc-C prosthesis. METHODS: Radiographic evaluation, including static and dynamic flexion-extension lateral images, was performed at baseline and at final follow up. RESULTS: Twenty six patients who had single-level ProDisc-C arthroplasty were followed up for a mean period of 63 months (56-76 months). The range of motion at the operated level was 9.3 degrees +/-3.7 degrees at baseline and 7.3 degrees +/ 3.5 degrees at final follow-up, with a significant difference (P < 0.05). Seventeen of 26 levels (65.4%) developed heterotopic ossification: three were classified as grade II, 13 were classified as grade III, and 1 as grade IV, according to McAfee's classification. Forty nine adjacent segments were evaluated by lateral X-ray and 18 (36.7%) segments developed adjacent segment degenerations. CONCLUSIONS: ProDisc-C arthroplasty had acceptable radiographic results at 5-year follow-up. The range of motion was preserved. However, more than 60% of the patients developed heterotopic ossification. PMID- 24157138 TI - Management of postoperative instrumented spinal wound infection. AB - BACKGROUND: Wound infection following spinal instrumented surgery is a frequent complication. The optimal treatment of acute deep wound infection following spinal instrumentation fusion remains controversial because of variability in cohort identification, definition of an infection, and the instrument used to measure outcomes. This retrospective study evaluated the clinical curative effect for postoperative spinal infection after instrumented spine fusion with extensive debridement, or implant removal. METHODS: From January 2004 to October 2009, 851 patients were identified who underwent surgical treatment of spinal diseases. The medical records of patients who developed infections were reviewed in detail. RESULTS: Of 851 patients, 41 (4.9%) developed an infection. Thirty-three were acute, and eight were delayed. Acute infected cases were managed with antibiotic therapy, and aggressive debridement of the wound and soft tissues leaving all instrumentation in situ in all but one patient. The most common symptoms of acute infection included: posterior incisional drainage (26 of 33 patients), back pain (22 of 33 patients) and fever (13 of 33 patients). Among patients with delayed onset infection, five of eight patients had local pain, four of eight patients had incision drainage, and one patient had a prolonged period of intermittent fever. The most frequent causative organism for postoperative spinal infection following spine surgery is Staphylococcus aureus. Pseudarthrosis was noted in long-term follow-up in four of 41 patients. CONCLUSIONS: We recommend irrigation and debridement, no instrumentation removal, and, if necessary, repeat debridement followed by delayed primary closure for the treatment of acute deep infection with instrumentation. PMID- 24157137 TI - Removal versus preservation of the posterior longitudinal ligament in Bryan cervical disc arthroplasty. AB - BACKGROUND: Bryan cervical disc arthroplasty can be used to restore and maintain the mobility and function of the involved cervical spinal segments. The efficiency of posterior longitudinal ligament (PLL) resection in anterior cervical decompression and fusion has been demonstrated. However, no clinical reports have compared PLL removal with preservation in Bryan cervical disc arthroplasty. This study aimed to assess the role of removal of PLL in Bryan cervical disc arthroplasty at an 18-month follow-up. METHODS: We performed a prospective investigation of clinical and radiological outcomes in patients after Bryan cervical disc arthroplasty. Sixty patients who underwent Bryan cervical disc arthroplasty were included. The PLL was removed in 35 patients (investigational group) and preserved in 25 patients (control group). All of the patients were followed up for more than 18 months. Clinical (Japanese Orthopedic Association score and Visual Analogue Scale pain score) and radiological (functional spinal unit (FSU) angle, range of movement (ROM), and diameter of the spinal cord) parameters were compared between the two groups before and after surgery (18 months). RESULTS: Clinical outcomes in the investigational group were significantly superior to those in the control group. There were no significant differences in the FSU angle and ROM (P = 0.41 and 0.16, respectively) between the two groups. However, the increase in diameter of the spinal cord in the investigational group was significantly greater than that in the control group (P < 0.01). CONCLUSIONS: Removal of the PLL can improve the clinical outcomes of Bryan cervical disc arthroplasty. This procedure does not have a large effect on imbalance and motion of the cervical spine. PMID- 24157139 TI - Clinical results and intramedullary signal changes of posterior decompression with transforaminal interbody fusion for thoracic myelopathy caused by combined ossification of the posterior longitudinal ligament and ligamentum flavum. AB - BACKGROUND: Surgical treatment of thoracic myelopathy caused by ossification of the posterior longitudinal ligament (OPLL) and ossification of the ligamentum flavum (OLF) is technically demanding, and the results tend to be unfavorable. Various operative approaches and treatment strategies have been attempted, and posterior decompression with transforaminal thoracic interbody fusion (PTTIF) may be the optimal method with which the anterior-posterior compression was removed in one step. It is comparatively less traumatic with fewer serious complications. METHODS: Sixteen patients with thoracic myelopathy due to concurrent OLF and OPLL at the same level underwent PTTIF. We investigated clinical outcomes and neurological improvements. Magnetic resonance imaging (MRI) was performed on all patients preoperatively and postoperatively, and intramedullary signal changes were evaluated. RESULTS: The mean operating time was 275 minutes, and the mean operative bleeding amount was 1031 ml. Cerebrospinal fluid leakage occurred in three patients and healed well after repair. Neurological symptom deterioration occurred in one patient, but the patient recovered to nearly the preoperative level after methylprednisolone treatment. The follow-up period ranged from 28 to 47 months. The mean score on the Japanese Orthopedic Association scale improved from 4.3+/-1.2 preoperatively to 7.3+/-1.7 at 3 months postoperatively to 8.5+/ 1.5 at the final follow-up (P < 0.01), with a recovery rate of (63.6+/-20.0)%. Postoperative images showed a significant improvement in local kyphosis (P < 0.01). Eleven patients (68.8%) showed increased signal intensity (ISI) on preoperative T2-weighted MRI. At the final follow-up, the intramedullary ISI totally recovered in five patients. Neurological improvement was worse in patients with persistent ISI than in the other patients (P < 0.05). CONCLUSIONS: PTTIF is an effective therapeutic option for combined OPLL and OLF and provides satisfactory neurological recovery and stabilized thoracic fusion through a single posterior approach. Intramedullary signal changes do not always indicate a poor prognosis; only irreversible ISI is correlated with a poor clinical result. PMID- 24157140 TI - Age-related differences in the biological parameters of vertebral cancellous bone from Chinese women. AB - BACKGROUND: With aging, the human fracture risks gradually increase. This is mainly due to the corresponding changes of the biomechanical parameters of human bone presents with aging. We measured the microstructural parameters of lumbar bone from women in several age groups by micro-computed tomography and scanning electron microscopy. We observed changes in lumbar cancellous bone mineral density and in biomechanical parameters with aging to elucidate the relationship between age and risk of fracture. We provide theoretical support for human pathology, fracture risk increased with age and the individualized of each age group. METHODS: Thirty-two fresh L3 vertebral bodies were donated from 32 women, aged 20-59 years and were divided into four age groups: 20 to 29 years (group A); 30 to 39 years (group B); 40 to 49 years (group C); and 50 to 59 years (group D). Conventional lumbar separation was performed by removing soft tissue and subsidiary structures, leaving only the vertebral body. The vertebral body was cut into halves along the median sagittal plane, maintaining the upper and lower end-plates of each half, and used for biomechanical, morphological, and density measurements. RESULTS: Comparing group A to B, the rod-like trabecular thickness (Tb.Th) decreased; the trabecular spacing (Tb.Sp) increased; the plate-like Tb.Th decreased; bone mineral density, tissue mineral density, bone volume fraction, and bone surface fraction decreased, and the elastic modulus and the ultimate stress decreased (all changes P < 0.05). Similar significant (P < 0.05) trends were obtained when comparing group C to D. With aging, the collagen cross-linking capacity declined, the thickness of the collagen fibrils was variable (ranging from almost the same to loose, sparse, or disordered), and the finer collagen fibrils between the thick filaments were disorganized. CONCLUSIONS: In women aged 20 to 59 years, the rod-like and plate-like Tb.Th of the vertebral body decreased, while Tb.Sp increased. Additionally, the density, elastic modulus, and ultimate stress of the cancellous bone decreased with age. These associated changes in bone microstructure, density, and biomechanics with age may lead to an increasing risk of osteoporosis and fracture. PMID- 24157141 TI - Comprehensive treatment for gas gangrene of the limbs in earthquakes. AB - BACKGROUND: Mortality rates for patients with gas gangrene from trauma or surgery are as high as 25%, but they increase to 50%-80% for patients injured in natural hazards. Early diagnosis and treatment are essential for these patients. METHODS: We retrospectively analyzed the clinical characteristics and therapeutic results of 19 patients with gas gangrene of the limbs, who were injured in the May 2008 earthquake in the Wenchuan district of China's Sichuan province and treated in our hospital, to seek how to best diagnose and treat earthquake-induced gas gangrene. RESULTS: Of 226 patients with limbs open injuries sustained during the earthquake, 53 patients underwent smear analysis of wound exudates and gas gangrene was diagnosed in 19 patients. The average elapsed time from injury to arrival at the hospital was 72 hours, from injury to definitive diagnosis was 4.3 days, and from diagnosis to conversion of negative findings on wound smear analysis to positive findings was 12.7 days. Anaerobic cultures were also obtained before wound closure. The average elapsed time from completion of surgery to recovery of normal vital signs was 6.3 days. Of the 19 patients, 16 were treated with open amputation, two with closed amputation, and 1 with successful limb salvage; 18 patients were successfully treated and one died. CONCLUSIONS: In earthquakes, rapid, accurate screening and isolation are essential to successful treatment of gas gangrene and helpful in preventing nosocomial diffusion. Early and thorough debridement, open amputation, and active supportive treatment can produce satisfactory therapeutic results. PMID- 24157142 TI - Anatomical references for tibial sagittal alignment in total knee arthroplasty: a comparison of three anatomical axes based on 3D reconstructed CT images. AB - BACKGROUND: This study was designed to analyze three tibial axis reference lines including the anterior tibial cortex (ATC) line, the fibular line (FL), and the anatomical axis of tibia (AAT) line, to determine which line most closely parallels the mechanical axis (MA) of the tibia in the sagittal plane. The clinical relevance of the study is that through finding a reliable landmark on the leg, a surgeon may minimize posterior tibial slope measurement errors thereby and improving the technique for assuring proper alignment of total knee arthroplasty. METHODS: The material for this study included CT scans of the tibia from 85 consecutive patients and 168 knees (78 without osteoarthritis (OA) and 90 knees with OA). Measurements of the angles between the tibial mechanical axis and each of three reference lines in the sagittal plane were carried out using 3D imaging software. RESULTS: Mean angles of 168 knees were as follows: aMT (3.96+/ 0.85) degrees , aMF (0.70+/-0.58) degrees , and aMA (1.40+/-0.66) degrees , (aMT: an angle between MA and ATC, aMF: an angle between MA and FL, aMA: an angle between MA and AAT. All abovementioned angles were measured in the sagittal plane of tibia) and the aMF was significantly smaller than the others (P < 0.0001). The mean value of the medial tibial slope angle vs. the MA was (9.19+/-3.97) degrees , and this was significantly larger than the mean lateral slope angle of (6.62+/ 4.23) degrees (P < 0.0001). The difference between aMF without OA and with OA was not statistically significant (P = 0.5015) and the association between the aMT and aMA was strong (r = 0.82, P < 0.01). CONCLUSIONS: FL was more closely parallel to the MA of tibia, and more showed less variation between OA and non- OA controls than ATC and AAT lines. Furthermore, the amount of posterior slope in medial plateau was greater than that in lateral plateau. The findings of this analysis suggest that when using the anterior tibial cortex line as is commonly done with extramedullary tibial resection guides, the tibial resection should be sloped approximately four degrees more posteriorly. PMID- 24157143 TI - Effect of superior retinacular artery damage on osteonecrosis of the femoral head. AB - BACKGROUND: Osteonecrosis of the femoral head (ONFH) is the result of dysfunctional blood supply, but associations between specific damaged arteries, imaging changes and clinical sign require more understanding. We investigated characteristics of ONFH that pertain to blood supply, imaging appearance, and clinical feature to judge the prognosis of ONFH. METHODS: Clinical data were collected for 92 patients (118 hips) with ONFH, including gender, age, duration of pain (from initial clinical presentation to arthroplasty), cause, stage, and classification. Magmatic resonance imaging and X-rays were obtained of all patients to diagnose ONFH. The sizes of lesions were classified by necrotic index. The location of necrosis was classified as Type A, B, or C using the grading system by magmatic resonance imaging and X-rays. All hips were imaged with digital subtraction angiography to visualize their blood-supply characteristics. Hips were divided into groups based on the source artery for femoral head damage: superior retinacular artery (S), inferior retinacular artery (I), and combined superior and inferior retinacular arteries (S+I). Via digital subtraction angiography, imaging appearances and clinical data in three groups were compared. RESULTS: ONFH was caused by damage in either the superior or inferior retinacular artery, or both, in all of 118 hips. The group with only inferior retinacular artery damage reported longer hip pain duration than the other groups. The probability of the lesion extending laterally to the acetabular edge in group S was much more than it in group I. Necrosis indices of the patients in S and S+I were higher than those in group I. CONCLUSIONS: ONFH associated with interruption of the superior and inferior retinacular arteries in this study. When the former alone was damaged, the necrosis of the volume was larger, the risk of femoral head collapse was higher and the time from initial clinical presentation to arthroplasty was shorter. PMID- 24157144 TI - Efficacy of multimodal cocktail periarticular injection with or without steroid in total knee arthroplasty. AB - BACKGROUND: Multimodal cocktail periarticular injection (MCPI) with a large volume of low concentration local anesthetics, adrenaline, and anti-inflammatory agents such as non-steroidal anti-inflammatory drug or steroids have shown good pain control and improvement in range of motion after surgery. This study compares the efficacy of pain control after total knee arthroplasty, using multimodal cocktail periarticular injection with steroid or without steroid. METHODS: This is a prospective, double-blinded, randomized and control study. Seventy-two patients with osteoarthritis that met clinical criteria for total knee arthroplasty were recruited into the study, and were randomized to receive either multimodal cocktail periarticular injection with steroid or without steroid. Pain was assessed by visual analogue scale (VAS) at preoperative and postoperative at rest, and during activity. The range of motion was recorded preoperatively and postoperatively. The amount of daily and cumulative morphine consumption were measured by patient-controlled analgesia in the first 72 hours postoperatively. The duration of celecoxib usage was also recorded at the last follow-up. RESULTS: There were no differences between the non-steroid and steroid groups with regard to VAS at rest and during activity, or range of motion, at any postoperative observation time. The postoperative Knee Society Knee Score in the steroid group improved significantly as compared with that in non-steroid group at the one-month (84.1+/-13.1 and 65.9+/-12.1; P < 0.0045), three-month follow-up (90.2+/-16.3 and 72.5+/-16.6; P < 0.0027), but after postoperative six-month the Knee Society Knee Score showed no significant difference between the groups. There was no significant difference in consumption of the morphine about daily or total consumption within 72 hours between the two groups. The duration of celecoxib usage in patients in the steroid group was significantly shorter than that in the non-steroid group ((7.2+/-0.7) compared with (10.5+/-1.9) weeks; P = 0.012). CONCLUSION: The patients who received the steroid injection had faster rehabilitation and less non-steroidal antiinflammatory drugs consumption. PMID- 24157145 TI - Closed patella fracture combined with cruciate ligament injury: a case control study. AB - BACKGROUND: Patellar fracture and cruciate ligament injury are a common consequence of traumatic knee injury. Patellar fracture combined with cruciate ligament injury is rarely reported, although the mechanisms of two things are similar. This study aimed to evaluate the incidence of closed patella fracture combined with cruciate ligament injury. METHODS: From 2012 March 1 to June 30, magnetic resonance images of 60 patients with unilateral closed patellar fracture were studied in our institution. The mean age of the patients at presentation was 40.2 years (range, 13-64 years) and 48 patients were men. First, patients were divided according to the cause of injury. Twenty-eight patients had high-energy trauma from a falling injury or motor vehicle accident, and 32 patients had low energy trauma resulting from a tumbling injury. Second, according to the fracture pattern, 31 patients had a transverse fracture and 29 patients had a comminuted fracture. RESULTS: We found seven cases of closed patellar fracture combined with cruciate ligament injury among 60 patients, including two cases of a completely ruptured posterior cruciate ligament, two with a partially torn posterior cruciate ligament, and three with a partially torn anterior cruciate ligament. The percentage of this combined injury was 11.6% (7/60). The incidence of a combined injury of the cruciate ligament with a comminuted fracture (6/29, 20.7%) was significantly higher than that with a transverse fracture (1/31, 3.2%, P < 0.05). The most common mechanism of injury in patellar fracture combined with cruciate ligament injury was high-energy trauma from road traffic accidents (94%), whereas in the patellar fracture alone, it was tumbling (62%). The incidence of combined injury with high-energy trauma (6/28, 21.4%) was significantly higher than that with low-energy trauma (1/32, 3.1%, P < 0.05). CONCLUSIONS: These data suggest that high-energy trauma often results in a comminuted patellar fracture, which is often combined with cruciate ligament injury. Traffic accidents are the main risk factor for this combined injury. Understanding the relationship between patellar fracture and cruciate ligament injury for diagnosis and treatment is important. PMID- 24157146 TI - Central tendon splitting combined with SutureBridge double-row technique as a surgical treatment for insertional Achilles tendinopathy. AB - BACKGROUND: Surgical treatment of insertional Achilles tendinopathy should be considered when a variety of conservative measures fail. To achieve a satisfactory outcome, thorough debridement of the Achilles tendon is critical, besides excision of the bursitis and the calcaneal exostosis. Central tendon splitting provides straightforward access to the calcified or degenerative tissue within the Achilles tendon. For Achilles tendon reconstruction if detachment is present, several surgical techniques have been reported. Controversy surrounds the technique can provide maximum security for reattachment of the Achilles tendon. The SutureBridge double-row construct, initially used in rotator cuff repair, is probably a good choice. METHODS: Ten consecutive patients with insertional Achilles tendinopathy underwent tendon reattachment using the SutureBridge technique through a central tendon-splitting approach. We retrospectively evaluated the surgical outcomes, which included pre- and postoperative visual analog scale (VAS), postoperative Maryland Foot Score (MFS), postoperative range of motion of the affected ankle, and related complications. Follow-up was performed in the outpatient department. RESULTS: One patient was lost to follow-up. Nine patients (two male and seven female; 12 feet) were reviewed with a minimum follow-up of six months (range 6-30 months). The postoperative VAS pain scores were markedly lower than the preoperative scores. Postoperative MFS was 92.1+/-8.0 (range 74-100). No intra- or postoperative complications were found, except for one case of delayed healing incision. At last follow-up, all affected ankles achieved their normal range of motion, and patients were able to resume daily activities without any assistive device. CONCLUSIONS: Although a randomized control trial with a larger sample may be necessary to compare the central tendon-splitting combined with the SutureBridge technique with other techniques, our results confirmed that it was a promising alternative for treatment of insertional Achilles tendinopathy. PMID- 24157147 TI - Outcome of contralateral C7 nerve transferring to median nerve. AB - BACKGROUND: Contralateral C7 (cC7) transfer had been widely used in many organizations in the world, but the outcomes were significantly different. So the purpose of the study was to evaluate the outcome of patients treated with cC7 transferring to median nerve and to determine the factors affecting the outcome of this procedure. METHODS: A retrospective review of 51 patients with total root avulsion brachial plexus injuries who underwent cC7 transfer was conducted. All of the surgeries were performed with two surgery stages and median nerve was the recipient nerve. The cC7 nerve was used in three different ways. The entire C7 root was used in 11 patients; the posterior division together with the lateral part of the anterior division was used in 15 patients; the anterior or the posterior division alone was used in 25 patients. The mean follow-up period was 6.9 years. RESULTS: The efficiency of the surgery in these 51 patients was 49.02% in motor and 62.75% in sensory function. The patients with entire C7 root transfer obtained significantly better recovery in both motor and sensory function than the patients with partial C7 transfer. The best function recovery could be induced if the interval between the two surgery stages was 4-8 months. CONCLUSIONS: cC7 transfer is an effective procedure in repairing median nerve. But using the entire C7 root transfer can obtain better recovery; so we emphasize using the entire root as the donor. The optimal interval between two surgery stages is 4-8 months. PMID- 24157148 TI - Association between improved trunk stability and walking capacity using ankle foot orthosis in hemiparetic patients with stroke: evidence from three dimensional gait analysis. AB - BACKGROUND: Restoration of both normal movement of the pelvis and centre of mass is a primary goal of walking rehabilitation in post-stroke patients because these movements are essential components of effective gait. The aim of this study is to quantitatively analyze the effect of ankle-foot orthosis on walking ability, and to investigate the correlation between improvements in trunk motion and walking capacity. METHODS: Walking speed, centre of mass displacement, and pelvic movements were examined in 20 post-stroke hemiparetic patients with and without ankle-foot orthosis using three-dimensional motion analysis. RESULTS: Using ankle foot orthosis improved walking speed, pelvic rotation and tilt, and lateral and vertical displacements of the centre of mass (P < 0.01). Moreover, the gait asymmetry index was significantly decreased (P < 0.01), and the Functional Ambulation Categories score improved significantly when patients used an ankle foot orthosis (P < 0.05). There was significant correlation between improvements in the walking capacity and the displacement of the centre of mass in both vertical and lateral directions (P < 0.01). CONCLUSIONS: Using ankle-foot orthosis improves the walking capacity by improving the stability and concordant of the trunk in hemiplegic patients. The improvement in the walking capacity from using an ankle-foot orthosis may be attributed to its prevention of foot drop and compensation for the instability of the ankle joint. PMID- 24157149 TI - Rotary self-locking intramedullary nail for long tubular bone fractures. AB - BACKGROUND: Intramedullary nails had been widely used in the treatment of long bone fractures because of less interference of fractures and center bearing biomechanical advantage. However, it had been also found many shortcomings such as broken nails, delayed healing and was modified in order to achieve better efficacy and reduce complications. The aim of the present study is to compare the efficacy of rotary self-locking intramedullary nails (RSIN) with that of interlocking intramedullary nails (IIN) in the treatment of long-bone fractures. METHODS: A retrospective study investigated 129 cases with long-bone fractures (36 with femoral fracture, 81 with tibial fracture, and 12 with humeral fracture). The fractures were fixed using either an RSIN or IIN. All patients underwent followup for 12-30 months. RESULTS: All patients in both groups achieved a clinical fracture healing standard and the postoperative affected limb muscle strength and joint function were well restored. The RSIN group required a shorter operative time and the fracture healed faster. There was no significant difference in the hospital stay, intraoperative blood loss or postoperative complications between the two groups. CONCLUSIONS: RSIN is used to treat long bone fractures. Its healing efficacy is equivalent to the IIN. Moreover, the RSIN method is simpler and causes less tissue damage than the IIN, therefore having the advantage of accelerated healing. PMID- 24157150 TI - Up-regulation of Ras/Raf/ERK1/2 signaling in the spinal cord impairs neural cell migration, neurogenesis, synapse formation, and dendritic spine development. AB - BACKGROUND: The Ras/Raf/ERK1/2 signaling pathway controls many cellular responses such as cell proliferation, migration, differentiation, and death. In the nervous system, emerging evidence also points to a death-promoting role for ERK1/2 in both in vitro and in vivo models of neuronal death. To further investigate how Ras/Raf/ERK1/2 up-regulation may lead to the development of spinal cord injury, we developed a cellular model of Raf/ERK up-regulation by overexpressing c-Raf in cultured spinal cord neurons (SCNs) and dorsal root ganglions (DRGs). METHODS: DRGs and SCNs were prepared from C57BL/6J mouse pups. DRGs or SCNs were infected with Ad-Raf-1 or Ad-Null adenovirus alone. Cell adhesion assay and cell migration assay were investigated, DiI labeling was employed to examine the effect of the up-regulation of Ras/Raf/ERK1/2 signaling on the dendritic formation of spinal neurons. We used the TO-PRO-3 staining to examine the apoptotic effect of c-Raf on DRGs or SCNs. The effect on the synapse formation of neurons was measured by using immunofluorescence. RESULTS: We found that Raf/ERK up-regulation stimulates the migration of both SCNs and DRGs, and impairs the formation of excitatory synapses in SCNs. In addition, we found that Raf/ERK up-regulation inhibits the development of mature dendritic spines in SCNs. Investigating the possible mechanisms through which Raf/ERK up-regulation affects the excitatory synapse formation and dendritic spine development, we discovered that Raf/ERK up regulation suppresses the development and maturation of SCNs. CONCLUSION: The up regulation of the Raf/ERK signaling pathway may contribute to the pathogenesis of spinal cord injury through both its impairment of the SCN development and causing neural circuit imbalances. PMID- 24157151 TI - Expression of ectonucleotide pyrophosphatase-1 in end-plate chondrocytes with transforming growth factor beta 1 siRNA interference by cyclic mechanical tension. AB - BACKGROUND: Ectonucleotide pyrophosphatase/phosphodiesterase (ENPP)-1 is a membrane-bound protein that catalyzes the hydrolysis of extracellular nucleoside triphosphates to monophosphate and extracellular inorganic pyrophosphate (ePPi). Mechanical stimulation regulates ENPP-1 expression. This study sought to investigate the changes in ENPP-1 expression after stimulation using cyclic mechanical tension (CMT). METHODS: Rat end-plate chondrocytes were cultured and subjected to CMT (at 3%, 6%, and 9% elongation) for 20, 40, and 60 minutes to observe changes in the expression of ENPP-1. To investigate the pathway, end plate chondrocytes were exposed to 10 ng/ml of transforming growth factor beta 1 (TGF-beta1), TGF-beta1 siRNA, or a specific extracellular signalregulated kinase (ERK)1/2 inhibitor, U0126, in addition to CMT. Changes in ENPP-1 expression were measured by reverse transcription PCR (RT-PCR) and Western blotting. RESULTS: We observed the largest increase in ENPP-1 expression following 3% elongation CMT stimulation. ENPP-1 expression was also increased when end-plate chondrocytes were exposed to 10 ng/ml of TGF-beta1, but decreased after TGF-beta knockdown with siRNA. ERK1/2 phosphorylation was activated after 3% elongation for 40 minutes, and the stimulatory effect of TGF-beta1 on ENPP-1 mRNA and protein expression was inhibited by the suppression of the ERK1/2 pathway using U0126. CONCLUSION: CMT increases the expression of ENPP-1 in end-plate chondrocytes in a manner likely dependent on TGF-beta induction by the ERK1/2 signaling pathway. PMID- 24157152 TI - Compatibility of olfactory ensheathing cells with functionalized self-assembling peptide scaffold in vitro. AB - BACKGROUND: Olfactory ensheathing cell (OEC) transplantation is a promising or potential therapy for spinal cord injury (SCI). However, the effects of injecting OECs directly into SCI site have been limited and unsatisfied due to the complexity of SCI. To improve the outcome, proper biomaterials are thought to be helpful since these materials would allow the cells to grow three-dimensionally and guide cell migration. METHODS: In this study, we made a new peptide hydrogel scaffold named GRGDSPmx by mixing the pure RADA16 and designer peptide RADA16 GRGDSP solution, and we examined the molecular integration of the mixed nanofiber scaffolds using atomic force microscopy. In addition, we have studied the behavior of OECs in GRGDSPmx condition as well as on RADA16 scaffold by analyzing their phenotypes including cell proliferation, apoptosis, survival, and morphology. RESULTS: The experimental results showed that GRGDSPmx could be self assembled to form a hydrogel. Inverted optical microscopic and scanning electron microscopic analyses showed that OECs are viable and they proliferate within the nanostructured environment of the scaffold. Thiazolyl blue (MTT) assay demonstrated that OEC proliferation rate was increased on GRGDSPmx scaffold compared with the pure RADA16 scaffold. In addition, OECs on GRGDSPmx scaffolds also showed less apoptosis and maintained the original spindle-shaped morphology. Calcein-AM/PI fluorescence staining revealed that OECs cultured on GRGDSPmx grew well and the viable cell count was 95%. CONCLUSION: These results suggested that this new hydrogel scaffold provided an ideal substrate for OEC three-dimensional culture and suggested its further application for SCI repair. PMID- 24157153 TI - Hyperbaric oxygen intervention on expression of hypoxia-inducible factor-1alpha and vascular endothelial growth factor in spinal cord injury models in rats. AB - BACKGROUND: Hyperbaric oxygen (HBO) intervention is a main therapeutic method and the curative effect has been certified for spinal cord injury (SCI), but the mechanisms of the neuroprotective effect of HBO on SCI remain elusive. This study aimed to observe the change in expression of hypoxia-inducible factor-1alpha (HIF 1alpha) and vascular endothelial growth factor (VEGF) after SCI at different time points and to investigate the neuroprotective mechanism of HBO on SCI in rats. METHODS: A total of 160 adult Sprague-Dawley rats, weighing between 250 and 300 g, were randomly assigned to four experimental groups (n = 40 per group). SCI group: SCI was created with a special NYU impactor of Allen's by a 25 gramcentimeter impacting energy on T10 of the spinal cord. SCI+HBO group: HBO therapy after SCI model was established. Sham operation (SH) group: only laminectomy of T10 and no impact on the spinal cord was done. SH+HBO group: HBO therapy after sham operation. The hindlimb functional recovery was evaluated using Basso, Beattie, and Bresnahan (BBB) score and the expressions of HIF-1alpha and VEGF were observed with fluorescent quantitation PCR and Western blotting method of six rats picked randomly from each group at different time points of 1, 3, 7, and 14 days after operation. RESULTS: Rats in the SCI group and SCI+HBO group were paralyzed completely after operation with BBB 0-1 score. Rats in the SH group and SH+HBO group could walk after sham operation with BBB 20-21 score. The BBB score of rats in the SCI+HBO group (4.67+/-1.97 and 10.83+/-2.23) was higher than that in the SCI group (1.83+/-0.75 and 6.67+/-2.16) at 7 and 14 days time points obviously (P < 0.05). The expressions of HIF-1a and VEGF in the SCI group and SCI+HBO group were higher than in the SH group and SH+HBO group at any time point obviously (P < 0.05), while the SCI+HBO group presented the least expression of HIF-1alpha mRNA and protein (3.82+/-0.41 and 0.59+/-0.06; 2.26+/ 0.41 and 0.37+/-0.05; 1.58+/-0.26 and 0.29+/-0.05) than that in the SCI group (6.36+/-0.58 and 0.76+/-0.07; 3.55+/-0.47 and 0.51+/-0.07; 2.27+/-0.39 and 0.40+/ 0.06) respectively at 3, 7, and 14 days time points (P < 0.05) with significant difference and more expression of VEGF mRNA and protein (5.83+/-0.77 and 0.72+/ 0.06; 4.59+/-0.51 and 0.63+/-0.06) than that in the SCI group (3.06+/-0.30 and 0.48+/-0.07; 2.25+/-0.24 and 0.39+/-0.09) respectively at 7 and 14 days time points (P < 0.05) with significant difference. CONCLUSIONS: HBO could improve the hind limb functional recovery after SCI in rats. The elevation and duration of the expression of VEGF and the reduction of expression of HIF-1alpha by HBO intervention may be inversely related in the repair of damaged spinal cord and neuroprotective effect. PMID- 24157154 TI - Effects of hyperbaric oxygen preconditioning on ischemia-reperfusion inflammation and skin flap survival. AB - BACKGROUND: Hyperbaric oxygen preconditioning (HBO) is a new method of ischemia preconditioning. In this study, we examined its effects on skin flap survival and the mechanisms involved. METHODS: Thirty-six rats were divided into three groups: HBO preconditioning, control, and sham groups. An extended epigastric adipocutaneous flap based on the right superficial epigastric artery and vein was raised. A 3-hour period of flap ischemia was induced by clamping the pedicle vessels with a microvascular clamp. At the end of ischemia induction, the clamp was removed and the flap was resutured. Rats in the HBO preconditioning group were treated with HBO four times before surgery. Microcirculation in the skin flap was measured on postoperative days 1, 3 and 5. The size of the flap was measured on postoperative day 5, before the animals were sacrificed. Samples of the skin flap were prepared and stained with hematoxylin and eosin. The levels of tumor necrosis factor (TNF)-alpha, interleukin (IL)-1beta, and IL-6 in the flap samples were measured. RESULTS: Surviving flap size was significantly higher in the HBO preconditioning group compared with controls, with a reduced inflammatory response and increased perfusion. IL-1, TNF-alpha, and IL-6 levels in the HBO preconditioning group were lower than in controls. CONCLUSIONS: HBO preconditioning improved flap survival in this ischemia-reperfusion rat model. The mechanisms responsible for this effect may relate to attenuation of the inflammatory response and increased flap perfusion following HBO preconditioning. PMID- 24157156 TI - Thirty-day outcome of carotid artery stenting in Chinese patients: a single center experience. AB - BACKGROUND: Carotid artery stenting (CAS) as a competing treatment modality has had to adhere to limits to gain widespread acceptance in some studies. This study analyzed the clinical data of 1700 consecutive patients after CAS to retrospectively evaluate the 30-day outcome of CAS for internal carotid artery stenosis in a Chinese population. METHODS: Medical records of 1700 patients who underwent CAS at Xuanwu Hospital affiliated to Capital Medical University between January 2001 and August 2012 were reviewed. Postoperative 30-day complication rates were analyzed and compared with those of other studies. Univariate and multivariate Logistic regression analyses were used to identify factors associated with perioperation myocardial infarction (MI), stroke, and death. RESULTS: The overall 30-day rate of MI, stroke, and death after CAS was 2.53%. In univariate analysis, patients who were symptomatic, had a neurological deficit (modified Rankin score (mRS) >=3; P = 0.001), and who were not taking statins experienced a significantly increased rate of MI, stroke, and death (P = 0.017). In multivariate Logistic regression analysis, the presence of symptoms (odds ratio (OR) = 2.485; 95% confidence interval (CI) = 1.267-4.876; P = 0.008) and a neurological deficit (mRS >=3) (OR = 3.025; 95% CI = 1.353-6.763; P = 0.007) were independent risk factors for perioperative MI, stroke, and death. CONCLUSIONS: According to this single-center experience, CAS may effectively prevent and treat carotid artery stenosis that would otherwise lead to stroke. Being symptomatic and having a neurological deficit (mRS >=3) increased the risk of perioperative MI, stroke, and death. PMID- 24157155 TI - A new classification of nevus of Ota. AB - BACKGROUND: The nevus of Ota, is a common benign pigmentary dermatosis, mainly involve innervation area of first and second branch of trigeminal nerve. The classification of nevus of Ota was proposed by Tanino, based on 26 cases of nevus of Ota from 1937 to 1940. Studies about its classification are rarely seen in last 70 years, while it is still practical today. METHODS: Based on the clinical photographs, 1079 consecutive patients with nevus of Ota were verified and reclassified according to the innervation areas of the trigeminal nerve branches. RESULTS: In these 1079 cases, 866 patients were in line with Tanino's classification (80.26%), and 213 patients were not (19.74%). We put forward a new clinical classification (Peking Union Medical College Hospital classification, PUMCH classification) of nevus of Ota based on the innervation area of the trigeminal nerve branches, composed of 5 types and 14 subtypes. The 5 types were as follows: Type I - pigmentation maculeses involving the innervation area of one of the three trigeminal nerve branches, of which there were 424 cases (39.3%), comprising 6 subtypes; Type II - pigmentation macules involving the innervation area of two branches of the three trigeminal nerve branches, of which there were 221 cases (20.48%), comprising 4 subtypes; Type III - pigmentation macules involving the innervation area of all three trigeminal nerve branches, of which there were 361 cases (33.45%), comprising 2 subtypes; Type IV - bilateral type, in which the pigmentation macules involves the bilateral cheek, of which there were 63 cases (5.84%), comprising 2 subtypes; and Type V - complications occurred in the patient, of which there were 10 cases (0.93%). CONCLUSION: The new classification of nevus of Ota is based on the innervation area of the trigeminal nerve branches, and it covers all types of Tanino's classifications; on that basis, some new types and subtypes are brought in and cover almost every clinical condition. PMID- 24157157 TI - Clinicopathological classification and individualized treatment of breast cancer. AB - BACKGROUND: The clinicopathological classification was proposed in the St. Gallen Consensus Report 2011. We conducted a retrospective analysis of breast cancer subtypes, tumor-nodal-metastatic (TNM) staging, and histopathological grade to investigate the value of these parameters in the treatment strategies of invasive breast cancer. METHODS: A retrospective analysis of breast cancer subtypes, TNM staging, and histopathological grading of 213 cases has been performed by the methods recommended in the St. Gallen International Expert Consensus Report 2011. The estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor-2 (HER2), and Ki-67 of 213 tumor samples have been investigated by immunohistochemistry according to methods for classifying breast cancer subtypes proposed in the St. Gallen Consensus Report 2011. RESULTS: The luminal A subtype was found in 53 patients (24.9%), the luminal B subtype was found in 112 patients (52.6%), the HER2-positive subtype was found in 22 patients (10.3%), and the triple-negative subtype was found in 26 patients (12%). Histopathological grade and TNM staging differed significantly among the four subtypes of breast cancer (P < 0.001). CONCLUSION: It is important to consider TNM staging and histopathological grading in the treatment strategies of breast cancer based on the current clinicopathological classification methods. PMID- 24157159 TI - Relapsing polychondritis diagnosed by transbronchial needle aspiration and (18)F fluorodeoxyglucose positron emission tomography/computed tomography. PMID- 24157158 TI - Free triiodothyronine level indicates the degree of myocardial injury in patients with acute ST-elevation myocardial infarction. AB - BACKGROUND: Previous studies have suggested that hypothyroidism correlated with coronary heart diseases (CHD) mortality in long-term cohort, but whether the thyroid function status is associated with myocardial injury in acute ST elevation myocardial infarction (STEMI) has not been investigated sufficiently. METHODS: Five hundred and eighty-two hospitalized patients from January 2010 to December 2011, with the diagnosis of STEMI, were enrolled in this study. All patients underwent testing for thyroid function status, cardiac troponin I (cTnI), cardiac enzymes, C-reactive protein (CRP). We investigated the association between thyroid hormone levels and cardiac markers (creatine kinase MB and cTnI), and thus evaluated the potential role of thyroid function status in predicting the myocardial injury. RESULTS: There were 76 patients (13.06%) who had hypothyroidism including low-T3-syndrome (34 patients, 5.84%), subclinical hypothyroidism (28 patients, 4.81%) and clinical hypothyroidism (14 patients, 2.41%). After adjusting for conventional risk factors (age, gender, smoking, diabetes mellitus, dyslipidemia, hypertension), free triiodothyronine (FT3) was significantly and negatively correlated with log-CKMB (r = -0.244, P < 0.001) and log-cTnI (r = -0.290, P < 0.001), indicating that the lower thyroid hormone level correlates with the severer cardiac injury in STEMI patients. FT3 also had a moderate negative correlation with CRP (r = -0.475, P < 0.001), which might indicate that hypothyroidism may activate the inflammation response. No significant correlation was found between other thyroid parameters (TSH, FT4) and cardiac markers. CONCLUSIONS: As the lower FT3 level correlates with higher level of cardiac markers and lower left ventricular ejection fraction (LVEF), the hypothyroidism may be a predictor for myocardial injury in STEMI. And these results may warrant further study to investigate whether reversing the hypothyroidism could benefit the STEMI patients. PMID- 24157160 TI - Serum cytokine levels in patients with advanced non-small cell lung cancer: correlation with clinical outcome of erlotinib treatment. AB - BACKGROUND: Serum expression of cytokines may provide information about the clinical outcome of advanced non-small cell lung cancer (NSCLC) patients. This study aimed to investigate the relationship between serum cytokine levels and the clinical outcome of erlotinib treatment in a second or third line setting in patients with advanced NSCLC. METHODS: A total of 162 patients with advanced NSCLC who received erlotinib as either second or third line therapy were enrolled in this study. Blood samples were collected before the initiation of erlotinib treatment, and the levels of IL-1, IL- 2R, IL-6, and tumor necrosis factor (TNF) alpha were assessed by enzyme-linked immunosorbent assay (ELISA). Cutoff points were defined as the median levels of IL-1 (low (>=26.5 pg/ml) and high (>26.5 pg/ml)), IL-2R (low ( = 115 pmol/L) and high (>15 pmol/L)), IL-6 (low (<=49.5 pg/ml) and high (>49.5 pg/ml)), and TNF-alpha (low (<=48.5 pg/ml) and high (>48.5 pg/ml)). Kaplan-Meier analysis was used to estimate the survival time, and Cox regression analyses were used to correlate cytokines and baseline clinical characteristics with clinical outcomes, including time to progression (TTP) and overall survival (OS). RESULTS: Between January 2007 and May 2011, 162 patients were enrolled. Their median age was 58 years. In this group, 109 were males and 53 were females, 74 were former or current smokers and 88 were non-smokers. A total of 122 patients had adenocarcinoma, 27 had squamous cell carcinoma, and 13 had tumors with other types of histology. And 139 patients had an Eastern cooperative oncology group (ECOG) performance status of 0-1, while 23 scored at 2 3. Expression of IL-1, IL-2R, and IL-6 was not significantly associated with age, gender, ECOG performance status, smoking status, or histology and stage of tumor. Only TNF-alpha was associated with smoking status (P = 0.045). Survival analysis showed that patients with low levels of either IL-6 or TNF-alpha had a statistically longer TTP and OS than patients with high expression (P < 0.05). These cytokines remained significant upon multivariate analysis (P < 0.05). CONCLUSION: IL-6 or TNF-alpha may serve as potential predictive biomarker for the efficacy of erlotinib. PMID- 24157161 TI - Circulating ghrelin was negatively correlated with pulmonary arterial pressure in atrial septal defect patients. AB - BACKGROUND: Ghrelin was found to attenuate the magnitude of pulmonary arterial hypertension and pulmonary vascular remodeling in rats. The objective of this study was to explore the fasting plasma ghrelin level and the relationships between ghrelin and pulmonary arterial pressure (PAP) in atrial septal defect (ASD) patients with pulmonary arterial hypertension (PAH). METHODS: Fasting plasma ghrelin, obestatin, and insulin levels were measured by enzyme linked immunosorbent assay (ELISA) method in ASD patients with or without PAH according to the manufacturer's instructions. Insulin resistance was calculated by the homeostasis model of assessment for insulin resistance (HOMA-IR) approach, calculated as fasting insulin (microunits/ml)* fasting blood glucose (mmol/L)/22.5. Comparisons between the parameters of patients with PAH and those of patients with normal PAP were performed with an unpaired Student's t test. The relationships between ghrelin and various clinical parameters were examined by bivariate correlations and multiple regression analysis. RESULTS: We found that the fasting plasma ghrelin level and the ratio of ghrelin to obestatin were significantly lower in the PAH group compared with the control group ((582.4+/ 12.8) pg/ml vs. (1045.2+/-95.5) pg/ml, P < 0.05 and 30.5+/-4.9 vs. 70.0+/-9.7, P < 0.01). The fasting plasma obestatin level was higher in the PAH group compared with the control group, but the difference between them was not significant ((23.2+/-3.1) pg/ml vs. (16.3+/-1.6) pg/ml, P > 0.05). In a multiple regression model analysis, only mean PAP was an independent predictor of ghrelin and the ratio of ghrelin to obestatin (standardized coefficient = -0.737, P < 0.001 and standardized coefficient = -0.588, P = 0.006, respectively). CONCLUSION: Ghrelin is negatively correlated with mean PAP and this suggests that circulating ghrelin might predict the severity of pulmonary hypertension in ASD patients with PAH. PMID- 24157163 TI - P1 gene of Mycoplasma pneumoniae in clinical isolates collected in Beijing in 2010 and relationship between genotyping and macrolide resistance. AB - BACKGROUND: Mycoplasma pneumoniae is a common pathogen that caused community acquired pneumonia (CAP). P1 protein served as major adhesion and immunodominant protein in Mycoplasma pneumoniae, but little about P1 gene was learned and the relationship between P1 genotype and macrolide resistance has yet to be explored. METHODS: The DNA sequence of the entire P1 gene from 35 strains isolated from clinical specimens collected in Beijing, China, in 2010 was determined. The resulting sequences were checked for known macrolide resistance mutations, such as A2063G, A2064G, C2617G in domain V of 23S rRNA. Antibiotic susceptibility test was done to further identify macrolide resistant strains. RESULTS: Thirty-four clinical strains were type 1, and were identical to type 1 reference strain MP129. Only one clinical strain, MpYYM22, was type 2, and proved to be variant 2c. One synonymous point mutation in the P1 type 1 gene from two isolates was identified relative to the MP129 P1 sequence at nucleotide position (nt) 552 (C>A), while another two isolates had missense mutations at nt 2504 (G>A). This point mutation caused an amino acid change from glycine to glutamic acid. An AGT tri-nucleotide variable-number tandem repeat (VNTR), coding for serine and repeating 6-11 times, up to 15-16 times, was found in the region between the RepMP4 and RepMP2/3 elements in the 35 isolates examined. All 35 clinical strains, including MpYYM22, demonstrated macrolide resistance with the range of minimum inhibitory concentration (MIC) of erythromycin from 64 to 256 ug/ml, having an A2063G transition in domain V of the 23S rRNA gene. CONCLUSIONS: P1 type 1 was the dominant type of Mycoplasma pneumoniae in Beijing in 2010, although variant 2c strains were present. More samples are needed to determine whether there is a relationship between the P1 genotype and macrolide resistance, as the 35 strains examined did not allow a conclusive result. However, the AGT tri-nucleotide VNTR may be a more informative locus for multi-locus VNTR analysis. PMID- 24157162 TI - Proficiency of virtual reality simulator training in flexible retrograde ureteroscopy renal stone management. AB - BACKGROUND: Minimally invasive flexible ureteroscopy techniques have widely adopted in the management of patients with renal stones. We performed this study to investigate the value of virtual reality simulator training in retrograde flexible ureteroscopy renal stone treatment for catechumen. METHODS: Thirty catechumen, included 17 attending physicians and 13 associate chief physicians, were selected for study. The trainees first underwent 1-hour basic training to get familiar with the instrument and basic procedures, then followed by 4-hour practice on virtual reality simulators. Before and after the 4-hour training, all trainees undertake an assessment with task 7 program (right low pole calyces stone management). We documented for each trainee the total time of procedure, time of progressing from the orifice to stone, stone translocation and fragmentation time, laser operate proficiency scale, total laser energy, maximal size of residual stone fragments, number of trauma from the scopes and tools, damage to the scope and global rating scale (GRS). The proficiency of this training program was analyzed by the comparison of the first and second assessment outcomes. RESULTS: Significant improvement was observed in retrograde flexible ureteroscopy management of renal stone on virtual reality simulators after finishing the 4 hour special-purpose training. This was demonstrated by improvement in total procedure time ((18.37+/-2.59) minutes vs. (38.67+/-1.94) minutes), progressing time from the orifice to stone ((4.00+/-1.08) minutes vs. (13.80+/-2.01) minutes), time of stone translocation ((1.80+/-0.71) minutes vs. (6.57+/-1.01) minutes), fragmentation time ((4.43+/-1.25) minutes vs. (13.53+/ 1.46) minutes), laser operate proficiency scale (8.47+/-0.73 vs. 3.77+/-0.77), total laser energy ((3231.6+/-401.4) W vs. (5329.8+/-448.9) W), maximal size of residual stone fragments ((2.66+/-0.39) mm vs. (5.77+/-0.63) mm), number of trauma from the scopes and tools (3.27+/-1.01 vs. 10.37+/-3.02), damage to the scope (0 vs. 0.97+/-0.76) and GRS (29.27+/-2.95 vs. 9.87+/-2.21). The differences between the first and the second assessment were all statistically significant (all P < 0.01). CONCLUSION: The virtual reality simulator training program can help the trainees to rapidly improve their retrograde flexible ureteroscopy skill in renal stone treatment. PMID- 24157165 TI - Comparison of unipedicular and bipedicular percutaneous kyphoplasty for treating osteoporotic vertebral compression fractures: a meta-analysis. AB - BACKGROUND: Percutaneous vertebroplasty (PKP) has proved its effectiveness regarding minimal invasion, rapid pain reduction, safe cement augmentation, restoring vertebral height, and accelerating complete recovery of osteoporotic vertebral compression fractures (OVCFs). Whether unipedicular or bipedicular PKP provides a better outcome is controversial. METHODS: We searched PubMed, Cochrane Database of Systematic Reviews, Cochrane Central Register of Controlled Trials, Web of Knowledge, Chinese Biomedical Literature Database, and Wanfang Data from January 1980 to March 2013 with "kyphoplasty", "unipedicular", "bipedicular", "compression fracture", and "randomized controlled trial". Risk of bias in the included studies was assessed according to a 12-item scale. Meta-analysis was performed. Dichotomous and continuous variables were calculated using the odds ratio (OR) and standardized mean difference (SMD), respectively. RESULTS: Seven studies involving 440 patients and 559 vertebral bodies met the criteria for inclusion. Among them, one randomized controlled trial had a high risk of bias and six a low risk. The pain visual analogue scale (VAS) SMDs were -0.02 (P = 0.88) for short-term follow-up (<=3 months) and 0.03 (P = 0.82) for long-term follow-up (>= 1 year). Oswestry Disability Index (ODI) SMDs at short- and long term follow-up were not statistically significant (-0.04, P = 0.77 and -0.07, P = 0.74, respectively). This meta-analysis showed greater polymethylmethacrylate volume (SMD -1.08, P = 0.00) and operation time (SMD -2.40, P = 0.00), favoring unipedicular PKP. Radiographic outcomes-preoperative kyphosis angle, restoration rate, reduction angle, loss of reduction angle-were not statistically different between the groups. Pooled analyses of cement leakage and subsequent adjacent OVCFs showed no significant differences between the groups, with OR = 0.82 (P = 0.79) and OR = 1.41 (P = 0.70), respectively. CONCLUSIONS: This meta-analysis comparing unipedicular and bipedicular PKP demonstrated no significant differences regarding VAS, ODI, radiographic outcomes, or complications. Considering the longer operation time and radiation exposure with bipedicular PKP, we recommend unipedicular PKP over bipedicular PKP for treating OVCFs. PMID- 24157166 TI - Comparing minimally invasive and open transforaminal lumbar interbody fusion for treatment of degenerative lumbar disease: a meta-analysis. AB - BACKGROUND: Transforaminal lumbar interbody fusion (TLIF) through a minimally invasive approach (mTLIF) was introduced to reduce soft tissue injury and speed recovery. Studies with small numbers of patients have been carried out, comparing mTLIF with traditional open TLIF (oTLIF), but inconsistent outcomes were reported. METHODS: We conducted a meta-analysis to evaluate the effectiveness of mTLIF and oTLIF in the treatment of degenerative lumbar disease. We searched PubMed, Embase and Cochrane Database of Systematic Reviews in March 2013 for studies directly comparing mTLIF and oTLIF. Patient characteristics, interventions, surgical-related messages, early recovery parameters, long-term clinical outcomes, and complications were extracted and relevant results were pooled. RESULTS: Twelve cohort studies with a total of 830 patients were identified. No significant difference regarding average operating time was observed when comparing mTLIF group with oTLIF group (-0.35 minute, 95% confidence interval (CI): -20.82 to 20.13 minutes). Intraoperative blood loss ( 232.91 ml, 95% CI: -322.48 to -143.33 ml) and postoperative drainage (-111.24.ml, 95% CI: -177.43 to -45.05 ml) were significantly lower in the mTLIF group. A shorter hospital stay by about two days was observed in patients who underwent mTLIF (-2.11 days, 95% CI: -2.76 to -1.45 days). With regard to long-term clinical outcomes, no significant difference in visual analog scale score (-0.25, 95% CI: -0.63 to 0.13) was observed; however, there was a slight improvement in Oswestry Disability Index (-1.42, 95% CI: -2.79 to -0.04) during a minimum of 1 year follow-up between the two groups. The incidence of complications did not differ significantly between the procedures (RR = 1.06, 95% CI: 0.7 to 1.59). Reoperation was more common in patients in mTLIF group than in oTLIF group (5% vs. 2.9%), but this difference was not significant (RR = 1.62, 95% CI: 0.75 to 3.51). CONCLUSION: Current evidence suggests that, compared with traditional open surgery, mTLIF reduces blood loss and allows early postoperative recovery, while achieving comparable or slightly better long-term outcomes, and with a comparable risk of complications. PMID- 24157164 TI - Ischemic preconditioning produces more powerful anti-inflammatory and cardioprotective effects than limb remote ischemic postconditioning in rats with myocardial ischemia-reperfusion injury. AB - BACKGROUND: Both ischemic preconditioning (IPC) and limb remote ischemic postconditioning (LRIPOC) have been shown to possess significantly different cardioprotective effects against the myocardial ischemia reperfusion injury (IRI), but no study has compared the anti-inflammatory effects of IPC and LRIPOC during myocardial IRI process. We hypothesized that IPC and LRIPOC would produce different anti-inflammatory effects in an in vivo rat model with myocardial IRI. METHODS: Eighty rats were randomly allocated into four equal groups: sham group, IRI group, IPC group and LRIPOC group. In 10 rats randomly selected from each group, serum levels of TNF-alpha, HMGB1, ICAM1, IL-1, IL-6 and IL-10 were assessed, and infarct size was determined. In another 10 rats of each group, myocardial levels of TNF-alpha, HMGB1, ICAM1, IL-1, IL-6 and IL-10 in both ischemic and non-ischemic regions were measured. RESULTS: The infarct size was significantly lower in IPC and LRIPOC groups than in IRI group. The serum and myocardial levels of pro-inflammatory cytokines including TNF-alpha, HMGB1, ICAM1, IL-1 and IL-6 during reperfusion were significantly reduced in IPC and LRIPOC groups compared to IRI group. As compared to the IPC group, infarct size, serum level of TNF-alpha at 60 minutes of reperfusion, serum levels of HMGB1 and ICAM1 at 120 minutes of reperfusion, myocardial levels of TNF-alpha, ICAM1, IL-1 and IL-6 in the ischemic region, myocardial levels of ICAM1, IL-1 and IL-6 in the non-ischemic region were significantly increased in the LRIPOC group. CONCLUSIONS: In the rats with myocardial IRI, IPC produces more powerful inhibitory effects on local myocardial and systemic inflammatory responses than LRIPOC. This may be partly attributed to more potent cardioprotection produced by IPC. PMID- 24157167 TI - Advances and disputes of posterior malleolus fracture. AB - OBJECTIVE: The objective of this article is to summarize the development of evaluation and treatment of posterior malleolus fracture (PMF). DATA SOURCES: Data used in this review were mainly from English literature of PubMed data base. Study selection Articles were included in this review if they were related to the PMF or trimalleolar fracture. RESULTS: No consensus was found regarding what sizes of posterior malleolus fragments would lead to ankle instability thus affecting prognosis and should be fixed. X-ray measurement is unreliable, while CT scan is widely recommended and it can recognize the occult posterior malleolus fractures associated with tibia shaft fractures, which are always undetected previously. Direct posterior malleolus fixation is suitable to stabilize syndesmotic injury. The basic and clinical researches support direct reduction and buttress plate fixation of posterior malleolus fracture through the posterolateral approach. Operative indications and timing of weight bearing are still in discussion. CONCLUSIONS: Knowing whether ankle instability occurs and the proper methods to diagnose, evaluate, and operate can help manage the fracture. Further biomechanical research on ankle stability and clinical study to compare various treatment methods are required. PMID- 24157168 TI - Enterprise service bus and standard based hospital integration platform and its application research. PMID- 24157169 TI - Progress of research on the biomechanics of aorta and stent graft. PMID- 24157170 TI - Early graft failure after meniscus allograft transplantation: an unusual cause of using all-inside meniscal repair device. PMID- 24157171 TI - 360 degrees fusion for Charcot spine caused by congenital insensitivity to pain with anhidrosis. PMID- 24157172 TI - Patella infera following patellar tendon contracture after closed trauma. PMID- 24157173 TI - Isolated extramedullary ocular relapse of acute lymphoblastic leukemia after peripheral blood stem cell transplantation. PMID- 24157175 TI - Hold a dialectical view towards creatine kinase. PMID- 24157174 TI - One case of eosinophilia caused by atorvastatin. PMID- 24157176 TI - Successful treatment for neuromyelitis optica with systemic lupus erythematosus. PMID- 24157177 TI - Lymphomatoid papulosis type D in a Chinese young man: a newly recognized variant. PMID- 24157178 TI - Fetal intrapericardial extralobar pulmonary sequestration. PMID- 24157179 TI - T2*-weighted findings in prolonged acute migraine aura. PMID- 24157180 TI - Diagnosis of acromegaly: role of the internist and the other medical professionals. PMID- 24157181 TI - Why patients who die of worsening pulmonary arterial hypertension are not on parenteral prostacyclin analog treatment? PMID- 24157182 TI - An interview with Vishva M. Dixit. PMID- 24157183 TI - [Fertility on women with Turner syndrome]. AB - Spontaneous pregnancies occur in 1.8 to 7.6% among women with Turner syndrome. A genetic counseling is required before conception because only 30 to 40% of these pregnancies lead to the birth of a healthy child. A check-up has to be done before pregnancy, and if authorized, it will be tightly followed-up. Pregnancy is contraindicated if cardiac or aortic malformations exist, except for bicuspid aortic valve. Teams advice single embryo transfer. Rates of pregnancies of 45 to 60% after oocyte donation, but 40 to 60% of spontaneous abortions are noted, due to uterine factors. A study is trying to define patients who could postulate to cryopreservation of ovarian tissue. PMID- 24157184 TI - [Hands cutaneous exam]. AB - There are four different areas to consider: palms, back of the hands, fingers, periungual folds (and nails). Palmoplantar keratodermas are a group of inherited or acquired disorders. Dysidrosis is a peculiar form of eczema on the palms and lateral aspects of the fingers. SAPHO syndrome (Synovitis - Acne - Pustulosis - Hyperostosis - Osteomyelitis) presents pustules on palms. Photo-ageing is frequently noticed on the back of the hands. Paraneoplastic acrokeratosis (Bazex syndrome) affects the nose, ears, and periungual folds of fingers and toes. Spontaneous blue finger syndrome can be a benign process that resolves rapidly. PMID- 24157185 TI - Codex (cognitive disorders examination) for the detection of dementia and mild cognitive impairment. AB - BACKGROUND: Dementia is a major public health problem. Rapid and simple tests, easy to use for screening of dementia and mild cognitive impairment (MCI), are required. AIM: To examine the utility of Codex (cognitive disorders examination), a decision tree, for the detection of dementia and MCI. METHODS: Codex was administered to 105 consecutive patients attending a memory clinic over a six month period. RESULTS: The study showed good sensitivity (0.81) and specificity (0.81) for Codex in identifying patients with dementia. The sensitivity and specificity were 0.68 and 0.90 respectively for the detection of MCI. CONCLUSION: Codex is a simple, quick and reliable test for the detection of dementia, but it is not sufficiently sensitive for the detection of MCI. PMID- 24157186 TI - [Premature ovarian failures]. AB - Premature ovarian failure (POF) is clinically suspected by amenorrhea and confirmed by an elevated FSH serum level above 40 mUI/L (even 20 mUI/L) twice, in a woman before the age of 40. Prevalence of POF is between 1 to 2% in women. In 90% of cases, no aetiology is identified. Obvious causes are chemotherapy, pelvic radiotherapy, ovarian surgery and diethylstilbestrol exposure in utero. A karyotype should be performed as Turner Syndrome is the most frequent genetic cause of POF. Some X abnormalities such as X deletion or X autosome translocation can be found. FMR1 pre-mutation (fragile X syndrome) should be searched for, even though no cases of mental retardation are known, in the family. Other genetic abnormalities can be suggested by associated symptoms (i.e.: FOXL2, SF1 mutations). Auto-immune aetiology can be suspected if other auto-immune features are present, however, there are no reliable auto-antibodies to confirm auto immunity in POF. Treatment of POF is based on hormonal replacement therapy in order to avoid estrogen deficiency, suppress vasomotor symptoms and avoid bone loss as well as cardiovascular risk. Estrogens should be associated with progesterone or a progestin, at least up to the age of 51. Patients with POF should be informed that spontaneous pregnancies may occur (in 5% of cases). In case of desire of pregnancy, the patient should be oriented to a specialized unit for in vitro fertilization with oocyte donation. Psychological support is essential and should be part of the treatment. POF is associated with an increased risk of emotional distress and depression. No preventive treatment of POF is available so far. PMID- 24157187 TI - Recovery of fertility from adult ovarian tissue transplanted into week-old Japanese quail chicks. AB - Fertility of cryopreserved ovarian tissue from immature chickens and Japanese quail has been recovered by transplantation. This is of special importance for non-mammalian vertebrates in which cryopreservation and in vitro maturation of oocytes are challenging because their oogenesis is characterised by vitellogenesis. This study tested whether fertility of adult quail ovarian tissue could be recovered by transplantation. Ovaries were isolated from mature Japanese quail hens, trimmed, cut into 3- to 4-mm2 pieces and transplanted into ovariectomised, week-old chicks. Recipients were administered an immunosuppressant for two weeks. Ten of 12 recipients survived until sexual maturity and seven laid eggs, but all stopped laying by 17 weeks of age. The age at first egg of recipients laying eggs (75.7+/-4.2 days) was greater than that of untreated hens (51.8+/-1.7 days) and egg production of recipients during the laying period (21.7+/-5.7) was less than that of untreated hens (60.8+/-3.5). Recipients were paired with males from the WB line for test mating. Only two hens laid eggs during the test period but both produced 100% donor-derived offspring. This research demonstrated that the reproductive potential of ovarian tissue from adult quail hens can be restored by transplantation. PMID- 24157188 TI - Shorter minimum p-wave duration is associated with paroxysmal lone atrial fibrillation. AB - BACKGROUND AND PURPOSE: Prolonged P-wave dispersion (PWD) and P-wave duration (PWdur) have been found to be associated with common atrial fibrillation (AF), but the association of P-wave indices with lone atrial fibrillation (LAF) is unclear. METHODS: We enrolled 61 paroxysmal LAF cases and 150 controls without AF. P-wave indices were measured from a 12-lead ECG. Multivariable logistic regression was used to assess the association between P-wave indices and LAF. RESULTS: PWD was longer in LAF patients (median, IQR; 54.1 [42.9-63.2] ms) than controls (46.0 [38.5-57.7] ms), P=0.03. MinPWdur was shorter in LAF patients (60.5 [50.7-72.6] ms) than controls (66.0 [55.5-76.4] ms), P=0.03. In multivariable models, only the association between shorter minPWdur and LAF remained statistically significant (OR [95% CI] per tertile increment in minPWdur, 0.64 [0.42-0.95], P=0.03). CONCLUSIONS: Unlike common AF, paroxysmal LAF is independently associated with shorter minPWdur. This finding suggests that both shorter and prolonged PWdur may be associated with increased risk of AF. PMID- 24157189 TI - A new unifying theory of the pathogenesis of tuberculosis. AB - It is set in stone that Mycobacterium tuberculosis is a facultative intracellular bacterial parasite. This axiom drives our knowledge of the host response, the way we design vaccines against the organism by generating protective T cells, and to a lesser extent, the way we try to target anti-microbial drugs. The purpose of this article is to commit total heresy. I believe that M. tuberculosis can equally well be regarded as an extracellular pathogen and may in fact spend a large percentage of its human lung "life-cycle" in this environment. It is of course intracellular as well, but this may well be little more than a brief interlude after infection of a new host during which the bacterium must replicate to increase its chances of transmission and physiologically adapt prior to moving back to an extracellular phase. As a result, by focusing almost completely on just the intracellular phase, we may be making serious strategic errors in the way we try to intervene in this pathogenic process. It is my opinion that when a TB bacillus enters the lungs and starts to reside inside an alveolar macrophage, its central driving force is to switch on a process leading to lung necrosis, since it is only by this process that the local lung tissue can be destroyed and the bacillus can be exhaled and transmitted. I present here a new model of the pathogenesis of the disease that attempts to unify the pathogenic process of infection, disease, persistence [rather than latency], and reactivation. PMID- 24157190 TI - Co-existence of carotid artery disease, renal artery stenosis, and lower extremity peripheral arterial disease in patients with coronary artery disease. AB - In atherosclerosis, carotid artery stenosis (CAS), renal artery stenosis (RAS), lower extremity peripheral arterial disease (PAD), and coronary artery disease (CAD) are common pathologic lesions; their interrelationship is, however, unclear. We studied concomitant multiple atherosclerotic lesions in patients with CAD to understand their prevalence and relations. A cross-sectional analysis was performed on data from consecutive patients who underwent nonemergent coronary angiography. Simultaneous carotid and renal artery Doppler studies and ankle brachial systolic pressure measurements were reviewed to diagnose concomitant lesions and their severity. The study included 1,734 patients (aged 71 +/- 9 years; 70% men), with prevalences of CAS, RAS, lower extremity PAD, and CAD of 6%, 7%, 13%, and 72%, respectively. In patients with CAD (n = 1,253), the prevalences of CAS, RAS, and lower extremity PAD were 7%, 9%, and 16%, respectively; 24% CAD patients had >=1 additional atherosclerotic lesion. Significant interactions among the prevalences of these lesions were found. In addition, the extent of CAD and the prevalences of CAS, RAS, and lower extremity PAD were significantly correlated. Multivariate analysis supported these relationships. In conclusion, the prevalences of CAS, RAS, lower extremity PAD, and CAD were strongly interrelated in the study population; CAD severity was related to that of other atherosclerotic lesions. Additional systematic screening of other concomitant atherosclerotic lesions is recommended, especially in CAD patients having multivessel disease, left main disease, and/or already diagnosed with other concomitant atherosclerotic lesions. PMID- 24157191 TI - Usefulness of preprocedural serum uric acid level to predict restenosis of bare metal stents. AB - Serum uric acid (SUA) level is known as a significant predictor for cardiovascular diseases, partly through increased inflammatory response and smooth muscle cell proliferation. Inflammation and smooth muscle cells play a crucial role in the pathogenesis of in-stent restenosis (ISR). However, the relation between SUA and ISR has not been studied. The aim of the present study was to investigate the predictive value of preprocedural SUA on the development of ISR in patients who undergo coronary bare-metal stent implantation. Clinical, biochemical, and angiographic data from 708 consecutive patients (mean age 60.3 +/- 9.3 years, 71% men) who had undergone bare-metal stent implantation and additional control coronary angiography for stable or unstable angina pectoris were analyzed. Patients were divided into tertiles on the basis of preprocedural SUA levels. Stent restenosis was observed in 54 patients (23%) in the lowest tertile, in 79 (34%) in the middle tertile, and in 109 (46%) in the highest tertile (p <0.001). Using multiple logistic regression analysis, diabetes mellitus, smoking, high-density lipoprotein cholesterol, stent length, C-reactive protein level, and preprocedural SUA level emerged as independent predictors of ISR. On receiver-operating characteristics curve analysis, SUA level >5.5 mg/dl had 75% sensitivity and 71% specificity (area under the curve 0.784, p <0.001) in predicting ISR. In conclusion, higher preprocedural SUA is a powerful and independent predictor of bare-metal stent restenosis in patients with stable and unstable angina pectoris. PMID- 24157192 TI - Comparison of statin alone versus bezafibrate and statin combination in patients with diabetes mellitus and acute coronary syndrome. AB - Acute coronary syndromes (ACS) in patients with diabetes mellitus (DM) are associated with a high risk for major adverse cardiovascular events (MACEs) despite statin treatment. The impact of combined bezafibrate and statin therapy in patients with DM and ACS has not been specifically investigated. The aim of this study was to evaluate the association of combined therapy with 30-day MACEs in patients with DM participating in the nationwide Acute Coronary Syndrome Israeli Surveys (ACSIS). The study population comprised 3,063 patients with DM from the ACSIS 2000, 2002, 2004, 2006, 2008, and 2010 enrollment waves who were alive at discharge and received statins. Of these, 225 (7.3%) received on discharge combined bezafibrate and statin therapy, and 2,838 (92.7%) were treated with statins alone. MACEs were defined as a composite measure of death, recurrent myocardial infarction, recurrent ischemia, stent thrombosis, ischemic stroke, and urgent revascularization. The development of 30-day MACEs was recorded in 8% patients receiving combination therapy and 14.2% of those receiving statins alone (p = 0.01). Crude 1-year mortality and 30-day rehospitalization rates were also significantly lower in patients receiving combination therapy: 4.0% versus 8.1% (p = 0.03) and 13.3% versus 21.6% (p = 0.003), respectively. Multivariate analysis identified combined therapy as an independent predictor of reduced risk for 30-day MACEs, with an odds ratio of 0.56 (95% confidence interval 0.34 to 0.92), corresponding to a 44% relative risk reduction. In conclusion, a significantly lower risk for 30-day MACEs was observed in statin-treated patients with DM who also received bezafibrate after ACS. Signals regarding improvement of 30-day rehospitalization and 1-year mortality rates emerged as well. PMID- 24157193 TI - The Editor's Roundtable: The 10Q Report - Advancing women's heart health through improved research, diagnosis, and treatment. PMID- 24157194 TI - The association between school-to-work programs and school performance. AB - PURPOSE: The School-to-Work (STW) Opportunities Act was passed to aid students in transitioning from education to employment by offering work-based learning opportunities. In the United States, 72% of high schools offer work-based learning opportunities for credit. This is the first study to describe school performance and school-based behaviors among students enrolled in STW programs and compare them with nonworking and other-working students. METHODS: In 2003, a questionnaire was administered to five school districts and one large urban school in Wisconsin. Between 2008 and 2010, analyses were completed to characterize STW students and compare them with other students. RESULTS: Of the 6,519 students aged 14-18 years included in the analyses, 461 were involved in an STW program (7%), 3,108 were non-working (48%), and 2,950 were other-working students (45%). Compared with other students, STW students were less likely to have a grade point average >2.0, more likely to have three or more unexcused absences from school, and more likely to spend <1 hour in school-sponsored activities. Holding multiple jobs also negatively affected a student's academic performance. CONCLUSIONS: School-to-Work students reported poorer academic performance and more unhealthy school-related behaviors compared with nonworking students and other-working students. Whereas many factors have a role in why students perform poorly in school, more research on students enrolled in STW programs is needed to understand whether participating has a negative impact on students' academic achievement. PMID- 24157195 TI - Sexual orientation and sexual and reproductive health among adolescent young women in the United States. AB - PURPOSE: We studied sexual and reproductive health among self-identified bisexual, lesbian, and heterosexual adolescent young women. Prior research has suggested that bisexual and lesbian young women may be at greater risk for many negative health outcomes, including risky sexual and reproductive health behavior. METHODS: Using data from the U.S. nationally representative 2006-2010 National Survey of Family Growth (NSFG), we examined sexual and reproductive health among young women 15-20 years of age as a function of sexual orientation. We used logistic regression and ANCOVA to examine differences in sexual and reproductive health across groups while controlling for demographic group differences. RESULTS: Bisexual and lesbian young women reported elevated sexual and reproductive health risks. Bisexual and lesbian participants reported being younger at heterosexual sexual debut, and having more male and female sexual partners, than did heterosexual participants. Further, they were more likely than heterosexual young women to report having been forced to have sex by a male partner. Bisexual young women reported the earliest sexual debut, highest numbers of male partners, greatest use of emergency contraception, and highest frequency of pregnancy termination. CONCLUSIONS: Overall, sexual minority young women especially those who identified as bisexual-were at higher sexual and reproductive risk than their heterosexual peers. PMID- 24157199 TI - Nocturnal noninvasive positive pressure ventilation in stable COPD: a systematic review and individual patient data meta-analysis. AB - INTRODUCTION: The effects of nocturnal noninvasive positive pressure ventilation (NIPPV) in patients with stable chronic obstructive pulmonary disease (COPD) remain controversial. METHODS: The Cochrane Airways group Register of Trials, MEDLINE, EMBASE and CINAHL were searched up to August 2012. Individual patient data from randomised controlled trials on NIPPV outcomes were selected for two separate meta-analyses: the first with follow-up of 3 months and the second with 12 months of follow-up. Additionally, subgroup analyses within the NIPPV group comparing IPAP levels, compliance and levels of hypercapnia on change in PaCO2 after 3 months were performed. RESULTS: Seven trials (245 patients) were included. All studies were considered of moderate to high quality. No significant difference was found between NIPPV and control groups after 3 or 12 months of follow-up when looking at PaCO2 and PaO2, 6-minute walking distance, health related quality-of-life, forced expiratory volume in 1 s, forced vital capacity, maximal inspiratory pressure and sleep efficiency. Significant differences in change in PaCO2 after 3 months were found for patients ventilated with IPAP levels of at least 18 cm H2O, for patients who used NIPPV for at least 5 h per night as well as for patients with baseline PaCO2 of at least 55 mm Hg when compared to patients with lower IPAP levels, poorer compliance or lower levels of hypercapnia. DISCUSSION: At present, there is insufficient evidence to support the application of routine NIPPV in patients with stable COPD. However, higher IPAP levels, better compliance and higher baseline PaCO2 seem to improve PaCO2. PMID- 24157198 TI - Reflections on agranular architecture: predictive coding in the motor cortex. AB - The agranular architecture of motor cortex lacks a functional interpretation. Here, we consider a 'predictive coding' account of this unique feature based on asymmetries in hierarchical cortical connections. In sensory cortex, layer 4 (the granular layer) is the target of ascending pathways. We theorise that the operation of predictive coding in the motor system (a process termed 'active inference') provides a principled rationale for the apparent recession of the ascending pathway in motor cortex. The extension of this theory to interlaminar circuitry also accounts for a sub-class of 'mirror neuron' in motor cortex--whose activity is suppressed when observing an action--explaining how predictive coding can gate hierarchical processing to switch between perception and action. PMID- 24157200 TI - Prognostic value of six minute walk test in cystic fibrosis adults. AB - BACKGROUND: The 6 min walk test (6MWT) provides prognostic information in various respiratory diseases, but limited data exist in cystic fibrosis (CF) adults. METHODS: Consecutive CF adults who performed 6MWT at Cochin Hospital (Paris, France) over 12 years were analyzed. The cut-off 6 min walking distance (6MWD) value that best predicted a combined endpoint (death without transplant or lung transplant) was established using a receiver operating curve. Determinants of low 6MWD or of desaturation (SpO2 <= 90%) during 6MWT were examined using multivariate logistic regressions. Prognostic value of these variables was assessed using Kaplan-Meier and Cox analyses. RESULTS: 6MWT was performed in 286 CF adults (median: age, 28 yr; FEV1, 45% predicted) of whom 14% (n = 40) had lung transplant and 6% (n = 18) died without transplant. 6MWD correlated with FEV1% predicted (r = 0.43; P < 0.001), but markedly differed in subjects within the same range of FEV1. A 6MWD <= 475 m predicted death or transplant and was mostly found in patients with FEV1 <= 60% predicted. Desaturation during the 6MWT occurred in 29% of patients, exclusively in subjects with FEV1 <= 60% predicted. Both 6MWD <= 475 m and desaturation during the 6MWT were independent predictors of death or transplant. CONCLUSION: The 6MWT provides prognostic information in CF adults, especially in subjects with FEV1 <= 60% predicted. PMID- 24157201 TI - Contrast-enhanced multidetector computed tomography: a new prognosticator in acute pulmonary embolism? PMID- 24157202 TI - Don't kill the messenger: Long-distance trafficking of mRNA molecules. AB - The phloem sap contains numerous macromolecules such as proteins and RNAs, in addition to photoassimilates, amino acids and other small molecules. The transcription profile of messenger RNA (mRNA) molecules in the sieve tubes is unique and does not reflect the transcript profile in the neighboring companion cells. This discovery suggests tight regulation on cell-to-cell movement of mRNA molecules from the companion cells into the sieve tube. Heterografting experiments and RNA-detection methods have provided unequivocal evidence for the trafficking of several specific mRNA molecules between distant organs. Detection of various plant transcripts in their respective plant parasites further confirms this long-distance movement. The finding that several of these trafficked transcripts are involved in the control of developmental processes as well as responses to growth substances or environmental cues has led to a new paradigm that mRNA molecules act as non-cell-autonomous signaling agents operating in the vascular system. Trafficking of these molecules creates a communication network between distant organs that is required for coordinated development of the whole plant under adverse conditions. The generality of this concept, however, is still under debate, because the raison d'etre for long-distance movement of mRNA is not clear. In this review we discuss the identity and potential function of phloem sap mRNA molecules, the factors facilitating RNA transport, and the rationale for their action as long-distance signaling agents in the control of developmental processes. PMID- 24157203 TI - Not to be suppressed? Rethinking the host response at a root-parasite interface. AB - Root-knot nematodes are highly efficient plant parasites that establish permanent feeding sites within host roots. The initiation of this feeding site is critical for parasitic success and requires an interaction with multiple signaling pathways involved in plant development and environmental response. Resistance against root-knot nematodes is relatively rare amongst their broad host range and they remain a major threat to agriculture. The development of effective and sustainable control strategies depends on understanding how host signaling pathways are manipulated during invasion of susceptible hosts. It is generally understood that root-knot nematodes either suppress host defense signaling during infestation or are able to avoid detection altogether, explaining their profound success as parasites. However, when compared to the depth of knowledge from other well-studied pathogen interactions, the published data on host responses to root knot nematode infestation do not yet provide convincing support for this hypothesis and alternative explanations also exist. It is equally possible that defense-like signaling responses are actually induced and required during the early stages of root-knot nematode infestation. We describe how defense-signaling is highly context-dependent and that caution is necessary when interpreting transcriptional responses in the absence of appropriate control data or stringent validation of gene annotation. Further hypothesis-driven studies on host defense like responses are required to account for these limitations and advance our understanding of root-knot nematode parasitism of plants. PMID- 24157204 TI - PaKRP, a cyclin-dependent kinase inhibitor from avocado, may facilitate exit from the cell cycle during fruit growth. AB - Previous studies using 'Hass' avocado cultivar showed that its small-fruit (SF) phenotype is limited by cell number. To explore the molecular components affecting avocado cell production, we isolated four cDNAs encoding: an ICK/KRP protein, known to play cell cycle-regulating roles through modulation of CDK function; two CDK proteins and a D-type cyclin, and monitored their expression patterns, comparing NF (normal fruit) versus SF profiles. The accumulation of PaKRP gradually deceased during growth in both fruit populations. Despite these similarities, SF exhibited higher levels of PaKRP accumulation at early stages of growth. Moreover, in NF, augmented PaKRP expression coincided with a decrease in CDK and PaCYCD1 levels, whereas in SF, enhanced PaKPR expression was coupled with an earlier decline of CDK and PaCYCD1 levels. For both NF and SF, enhanced mesocarp PaKRP transcript accumulation, was associated with elevated abscisic acid (ABA) and ABA catabolites content. Nevertheless, the collective ABA levels, including catabolites, were substantially higher in SF tissues, as compared with NF tissues. Finally, additional expression analysis revealed that in cultured cells, PaKRP could be induced by ABA. Together, our data links PaKRP with exit from the fruit cell cycle and suggest a role for ABA in controlling its expression. PMID- 24157205 TI - Differential expression of cysteine peptidase genes in the inner integument and endosperm of developing seeds of Jatropha curcas L. (Euphorbiaceae). AB - In several plant tissues, programmed cell death (PCD) is mediated by the combined action of cysteine peptidases, namely KDEL-tailed cysteine peptidases (KDEL CysEP) and vacuolar processing enzymes (VPE). Here, we performed a search of the draft genome of Jatropha curcas L. (Euphorbiaceae) and identified 2 genes for KDEL-CysEP (Jc-CysEP1 and Jc-CysEP2) and 3 genes for VPE (Jc-betaVPE, Jc-gammaVPE and Jc-deltaVPE) and determined the expression patterns of these genes by RT-qPCR in integument and cellular endosperm of seeds collected at seven different developmental stages. We were able to demonstrate that the expression of Jc CysEP1, Jc-CysEP2, Jc-betaVPE and Jc-gammaVPE proceeded rapidly from Stage IV, with Jc-CysEP2 displaying the highest relative expression; expression of Jc deltaVPE could not be detected in any of the tissues/developmental stages analyzed. Additionally, we showed that the expression pattern of these peptidases correlates with anatomical changes in integument and cellular endosperm, thus suggesting a role for both classes of peptidases in PCD and in protein processing, both of which occur simultaneously in each of these tissues. PMID- 24157206 TI - Functional analysis of the 5' regulatory region of the maize GALACTINOL SYNTHASE2 gene. AB - Maize (Zea mays) GALACTINOL SYNTHASE (GolS) is a key enzyme in the raffinose biosynthetic pathway. We have previously characterized the maize GolS2 (ZmGolS2) gene as heat shock induced in maize germinating seeds and cultured cells. Here we report the identification, isolation and characterization of the 1.5Kb, 5' regulatory region of the ZmGolS2 gene. The 1.5kb fragment and its deletions were tested for promoter activity by their regulation of the Renilla (Renilla reniformis) luciferase reporter gene expression in maize protoplasts cultured at either 25 degrees C or 42 degrees C for 24h. The expression of a constitutively expressed firefly (Photinus ssp.) luciferase gene in the same vector was used as a reference. One heat shock element (HSE) was identified by comparing the promoter activity of each fragment under normal and heat shock conditions. Deletion or triplication of this HSE motif, abolished or enhanced the heat shock response of the ZmGolS2 promoter, respectively. This HSE motif is specifically bound by proteins in the nuclear extracts of heat shock stressed, but not unstressed maize cells as confirmed by DNA-EMSA. This work helps to understand the regulatory mechanism of the ZmGolS2 gene under stress conditions. PMID- 24157207 TI - Purification and biochemical characterization of Arabidopsis At-NEET, an ancient iron-sulfur protein, reveals a conserved cleavage motif for subcellular localization. AB - CDGSH iron-sulfur domain-containing proteins (CISDs) are newly discovered proteins with electron-accepting and electron-donating moieties. Although the CISDs of plants and animals show high sequence similarity in their CDGSH domain at the C-terminus, their N-terminal peptides have low sequence homology. Here, we show that At-NEET, a recently identified Arabidopsis CISD, contains a cleavable N terminal peptide for chloroplast targeting, which is different from the uncleavable N-terminal peptide of mammal CISDs for mitochondrial outer membrane localization. Using affinity purification to isolate endogenous At-NEET, we identified a consensus sequence for the chloroplast transit peptide cleavage site of V-[R/K]?A-E in At-NEET as well as other plant CISDs. Moreover, chloroplast subfractionation and immunogold labeling experiments showed that At-NEET localizes to the stroma of chloroplast. In addition, biochemical characterization revealed that At-NEET contains a conserved Cys(3)-His(1) ligand in the CDGSH domain, which is essential for coordination of 2Fe-2S clusters and protein folding. Our findings suggest that plant and animal CISDs contain an evolutionarily conserved CDGSH domain. However, they show different subcellular localization patterns that may result in distinct physiological functions. PMID- 24157208 TI - Dehydrins are highly expressed in overwintering buds and enhance drought and freezing tolerance in Gentiana triflora. AB - Gentians, herbaceous perennials, produce overwintering buds (OWBs) to survive the cold season. Although gentians are known to have strong stress tolerances against drought, cold and freezing, the molecular mechanisms of tolerance are unclear. We explored genes more highly expressed in OWBs than in other tissues and identified two gentian orthologs of dehydrins, denoted GtDHN1 and GtDHN2. These GtDHNs possess several ABA or dehydration responsive elements. Furthermore, GtDHN1 and GtDHN2 transcripts in OWBs accumulated during the winter but decreased prior to spring, suggesting that GtDHNs may be induced by dehydration stress during cold periods and may act as a stress protectant mediated by ABA. Likewise, cultured gentian plantlets accumulated GtDHN transcripts in response to ABA as well as cold and drought stresses. Moreover, transgenic gentian plantlets overexpressing GtDHN1 or GtDHN2 showed improved cold and drought stress tolerance. Metabolome analysis revealed that major antioxidants such as glutathione and ascorbate were accumulated in all transgenic plantlets. Overexpression of GtDHNs also affected the activities of the antioxidant enzymes, ascorbate peroxidase and glutathione peroxidase. Based on the results of this study, GtDHNs are induced by ABA and dehydration stress and have an ability to alleviate dehydration stress, probably via activating antioxidant mechanisms. Accumulation of GtDHNs may be part of the strategy for winter survival of gentian OWBs. PMID- 24157210 TI - The Arabidopsis transcriptional repressor ERF9 participates in resistance against necrotrophic fungi. AB - Complex plant defenses that include the hypersensitive response (HR) are mediated by plant hormones, such as salicylic acid (SA), jasmonic acid (JA) and ethylene. We previously isolated the Arabidopsis DEAR1 (DREB AND EAR MOTIF PROTEIN 1) regulator and showed that its overexpression DEAR1 (DEAR1ox) resulted in a dwarf phenotype and lesion-like cell death, accompanied by elevated expression of PR (PATHOGENESIS-RELATED) genes. Here, we show that transgenic Arabidopsis overexpressing DEAR1 (DEAR1ox) has enhanced resistance to the necrotrophic fungus Botrytis cinerea (B. cinerea). This result indicates that DEAR1 represses negative regulators of plant defense responses, including transcriptional repressors belonging to the ERF (ETHYLEN RESPONSE FACTOR) family. Knockout mutants of ERF9 (erf9), which were down-regulated in DEAR1ox plants, showed transcriptional promotion of PDF1.2 (PATHOGEN-INDUCIBLE PLANT DEFENSIN) genes, which serve as positive markers for the ethylene/jasmonic acid (JA) signaling pathway and provide enhanced resistance to B. cinerea. Biochemical assays demonstrated that the ERF9 in capable of binding to the GCC box, a cis-element contained in the promoters of the PDF1.2 gene that possesses trans-repression activity. Moreover, infection with B. cinerea resulted in the promotion of the PDF1.2 expression, coinciding with suppression of the ERF9 gene under the control of the DEAR1 gene. These results indicate that the transcriptional repressor ERF9 participates in plant defense mechanisms against necrotic fungi mediated by the DEAR1-dependent ethylene/JA signaling pathway. PMID- 24157209 TI - Overexpression of a partial fragment of the salt-responsive gene OsNUC1 enhances salt adaptation in transgenic Arabidopsis thaliana and rice (Oryza sativa L.) during salt stress. AB - The rice (Oryza sativa L.) nucleolin gene, OsNUC1, transcripts were expressed in rice leaves, flowers, seeds and roots but differentially expressed within and between two pairs of salt-sensitive and salt-resistant rice lines when subjected to salt stress. Salt-resistant lines exhibited higher OsNUC1 transcript expression levels than salt-sensitive lines during 0.5% (w/v) NaCl salt stress for 6d. Two sizes of OsNUC1 full-length cDNA were found in the rice genome database and northern blot analysis confirmed their existence in rice tissues. The longer transcript (OsNUC1-L) putatively encodes for a protein with a serine rich N-terminal, RNA recognition motifs in the central domain and a glycine- and arginine-rich repeat in the C-terminal domain, while the shorter one (OsNUC1-S) putatively encodes for the similar protein without the N-terminus. Without salt stress, OsNUC1-L expressing Arabidopsis thaliana Atnuc1-L1 plants displayed a substantial but incomplete revertant phenotype, whereas OsNUC1-S expression only induced a weak effect. However, under 0.5% (w/v) NaCl salt stress they displayed a higher relative growth rate, longer root length and a lower H2O2 level than the wild type plants, suggesting a higher salt resistance. Moreover, they displayed elevated AtSOS1 and AtP5CS1 transcript levels. We propose that OsNUC1-S plays an important role in salt resistance during salt stress, a new role for nucleolin in plants. PMID- 24157211 TI - Interactions between Arabidopsis DNA repair genes UVH6, DDB1A, and DDB2 during abiotic stress tolerance and floral development. AB - Plants must protect themselves from a spectrum of abiotic stresses. For example, the sun is a source of heat, intense light, and DNA-damaging ultraviolet (UV) rays. Damaged DNA binding protein 1A (DDB1A), DDB2, and UV hypersensitive 6 (UVH6)/XPD are all involved in the repair of UV-damaged DNA - DDB1A and DDB2 in the initial damage recognition stage, while the UVH6/XPD helicase unwinds the damaged strand. We find that, as predicted, Arabidopsis ddb1a and ddb2 mutants do not affect uvh6/xpd UV tolerance. In addition, uvh6 is heat sensitive, and ddb1a and ddb2 weakly enhance this trait. The uvh6 ddb1a and uvh6 ddb2 double mutants also exhibit sensitivity to oxidative stress, suggesting a role for DDB1 complexes in heat and oxidative stress tolerance. Finally, we describe a new uvh6 phenotype, the low penetrance production of flowers with five petals and five sepals. ddb1a and ddb2 suppress this phenotype in uvh6 mutants. Interestingly, heat treatment also induces five-petalled flowers in the ddb1a and ddb2 single mutants. Thus UVH6, DDB1A, and DDB2 all contribute to UV tolerance, heat tolerance and floral patterning. PMID- 24157212 TI - Separate and combined responses to water deficit and UV-B radiation. AB - Crops and other plants in natural conditions are routinely affected by several stresses acting simultaneously or in sequence. In areas affected by drought, plants may also be exposed to enhanced UV-B radiation (280-315nm). Each of these stress factors differently affects cellular metabolism. A common consequence of plant exposure to the separate action of water deficit and UV-B radiation is the enhanced generation of reactive oxygen species (ROS) causing damage to proteins, lipids, carbohydrates and DNA. Despite this destructive activity, ROS also act as signalling molecules in cellular processes responsible for defence responses. Plants have evolved many physiological and biochemical mechanisms that avoid or tolerate the effects of stress factors. Water deficit avoidance leads to stomatal closure, stimulation of root growth, and accumulation of free proline and other osmolytes. Secondary metabolites (flavonols, flavones and anthocyanins) that accumulate in epidermal cells effectively screen UV-B irradiation and reduce its penetration to mesophyll tissue. The coordinated increased activity of the enzymatic antioxidant defence system such as up-regulation of superoxide dismutase, catalase, guaiacol peroxidase, ascorbate peroxidase and glutathione reductase is an important mechanism of tolerance to water deficit and UV-B radiation. The accumulation of low molecular antioxidants (proline, glycine betaine, ascorbate and glutathione) can also contribute to tolerance to water deficit. Polyamines, tocopherol, carotenoids, alkaloids, flavonoids and other secondary metabolites participate in the removal of ROS under conditions of increased UV-B radiation. The combination of water deficit and UV-B radiation induces responses that can be antagonistic, additive or synergistic in comparison with the action of single stresses. UV-B radiation may enhance resistance to water deficit and vice versa. Hydrogen peroxide, nitric oxide (NO), abscisic acid (ABA), jasmonic acid, ethylene, and salicylic acid participate in the activation of defence mechanisms. The involvement of these molecules in cross-resistance may rely on activation of enzymatic and non-enzymatic antioxidant systems, enzymes of flavonoid biosynthesis and the accumulation of low-molecular-weight osmolytes as well as regulation of stomatal closure. However, under the conditions of prolonged action of stressors or in the case where one of them is severe, the capacity of the defence system becomes exhausted, leading to damage and even death. PMID- 24157213 TI - The tonoplast intrinsic aquaporin (TIP) subfamily of Eucalyptus grandis: Characterization of EgTIP2, a root-specific and osmotic stress-responsive gene. AB - Aquaporins have important roles in various physiological processes in plants, including growth, development and adaptation to stress. In this study, a gene encoding a root-specific tonoplast intrinsic aquaporin (TIP) from Eucalyptus grandis (named EgTIP2) was investigated. The root-specific expression of EgTIP2 was validated over a panel of five eucalyptus organ/tissues. In eucalyptus roots, EgTIP2 expression was significantly induced by osmotic stress imposed by PEG treatment. Histochemical analysis of transgenic tobacco lines (Nicotiana tabacum SR1) harboring an EgTIP2 promoter:GUS reporter cassette revealed major GUS staining in the vasculature and in root tips. Consistent with its osmotic-stress inducible expression in eucalyptus, EgTIP2 promoter activity was up-regulated by mannitol treatment, but was down-regulated by abscisic acid. Taken together, these results suggest that EgTIP2 might be involved in eucalyptus response to drought. Additional searches in the eucalyptus genome revealed the presence of four additional putative TIP coding genes, which could be individually assigned to the classical TIP1-5 groups. PMID- 24157214 TI - Short- and long-term physiological responses of grapevine leaves to UV-B radiation. AB - The present study aimed at evaluating the short- and long-term effects of UV-B radiation on leaves of grapevine Vitis vinifera (cv. Tempranillo). Grapevine fruit-bearing cuttings were exposed to two doses of supplemental biologically effective UV-B radiation (UV-BBE) under glasshouse-controlled conditions: 5.98 and 9.66kJm(-2)d(-1). The treatments were applied either for 20d (from mid veraison to ripeness) or 75d (from fruit set to ripeness). A 0kJm(-2)d(-1) UV-B treatment was included as control. The main effects of UV-B were observed after the short-term exposure (20d) to 9.66kJm(-2)d(-1). Significant decreases in net photosynthesis, stomatal conductance, sub-stomatal CO2 concentration, the actual photosystem II (PSII) efficiency, total soluble proteins and de-epoxidation state of the VAZ cycle were observed, whereas the activities of several antioxidant enzymes increased significantly. UV-B did not markedly affect dark respiration, photorespiration, the maximum potential PSII efficiency (Fv/Fm), non photochemical quenching (NPQ), as well as the intrinsic PSII efficiency. However, after 75d of exposure to 5.98and 9.66kJm(-2)d(-1) UV-B most photosynthetic and biochemical variables were unaffected and there were no sign of oxidative damage in leaves. The results suggest a high long-term acclimation capacity of grapevine to high UV-B levels, associated with a high accumulation of UV-B absorbing compounds in leaves, whereas plants seemed to be tolerant to moderate doses of UV B. PMID- 24157215 TI - Commentary: Hormesis can be used in enhancing plant productivity and health; but not as previously envisaged. AB - Sub-toxic doses of many toxicants have positive, beneficial effects on productivity, or stress resistance (hormesis). Transcriptomic, proteomic, and metabolomic responses to a disparate variety hormetic agents, coupled with bioinformatic analyses, can be used to identify consensus genes, their controlling elements, and their metabolites related to stimulation of growth and/or health. This information can then be used as a method for generating healthier and higher yielding crops using transgenic or other biotechnological techniques. The same bioinformatic information can be used to develop knowledge based, transcriptomic, proteomic and metabolomic high throughput pre-screens using young plants to identify hormetic chemicals that are potentially useful for enhancement of crop health and yield. Such pre-screens preclude the need to use whole plants through maturity. While the hormetic effectors themselves have to date been of limited direct utility, it is clear that they can be used to help pinpoint genes and chemicals that are potentially useful. This is superior to the presently used random screening or even "educated guess" screening of genes and chemicals. PMID- 24157216 TI - Screening and management of cardiovascular disease in Australian adults with HIV infection. AB - BACKGROUND: Cardiovascular disease (CVD) is common in HIV infection. With no specific Australian guidelines for the screening and management of CVD in HIV infected patients, best clinical practice is based on data from the general population. We evaluated adherence to these recommendations by primary care physicians who treat HIV-infected patients. METHODS: Primary care physicians with a special interest in HIV infection were asked to complete details for at least 10 consecutive patient encounters using structured online forms. This included management practices pertaining to blood pressure (BP), blood glucose, electrocardiogram, lipid profile and CVD risk calculations. We assessed overall adherence to screening and follow-up recommendations as suggested by national and international guidelines. RESULTS: Between May 2009 and March 2010, 43 physicians from 25 centres completed reporting for 530 HIV-infected patients, of whom 93% were male, 25% were aged 41-50 years and 83% were treated with antiretrovirals. Risk factors for CVD were common and included smoking (38%), hyperlipidaemia (16%) and hypertension (28%). In men aged >40 years and women aged >50 years without evidence of ischaemic heart disease, only 14% received a CVD risk assessment. Lipid and BP assessments were performed in 87% and 88% of patients, respectively. CONCLUSIONS: This Australian audit provides unique information on the characteristics and management of HIV and CVD in clinical practice. We have found a high burden of risk for CVD in HIV-infected Australians, but current screening and management practices in these patients fall short of contemporary guidelines. PMID- 24157218 TI - Achieving an AIDS-free world: science and implementation. PMID- 24157217 TI - Deficient cognitive control fuels children's exuberant false allegations. AB - In eyewitness studies as in actual investigations, a minority of children generate numerous false (and sometimes incredulous) allegations. To explore the characteristics of these children, we reinterviewed and administered a battery of tasks to 61 children (ages 4-9 years) who had previously participated in an eyewitness study where a man broke a "germ rule" twice when he tried to touch them. Performance on utilization, response conflict (Luria tapping), and theory of mind tasks predicted the number of false reports of touching (with age and time since the event controlled) and correctly classified 90.16% of the children as typical witnesses or exuberant (more than 3) false reporters. Results of a factor analysis pointed to a common process underlying performance on these tasks that accounted for 49% of the variability in false reports. Relations between task performance and testimony confirmed that the mechanisms underlying occasional intrusions are different from those that drive persistent confabulation and that deficient cognitive control fuels young children's exuberant false reports. PMID- 24157219 TI - Molecular diagnostics of cardiovascular diseases in sudden unexplained death. AB - The most challenging type of sudden cardiac death is sudden unexplained death. The etiologies for sudden unexplained death are diverse and not necessarily confined to the cardiovascular system. Nevertheless, certain cardiovascular diseases, particularly cardiac channelopathies and cardiomyopathies, are known to play significant roles in sudden deaths. The purpose of the review is to provide autopsy pathologists with an actionable guide through illuminating the clinically relevant molecular basis of cardiac channelopathies and cardiomyopathies, as well as the changing landscape of molecular diagnostics. PMID- 24157220 TI - Eight years with haemovigilance in Norway. What have we learnt? AB - The purpose of a haemovigilance system is to identify complications related to transfusion or blood donation, analyze them and learn in order to avoid complications in the future. The Norwegian Haemovigilance System (Troll) started as a voluntary, professionally led reporting system in 2004. In 2007 haemovigilance became an authority task, according to the EU blood directive, and reporting of serious adverse reactions and serious adverse events became mandatory. The Norwegian Directorate of Health became responsible for the system and asked The Norwegian Knowledge Centre for the Health Services to run it. Results from the first eight years of reporting are presented. A total of 2607 transfusion complications or incorrect blood component transfused (IBCT) have been reported (127 per 100,000 transfusions). Most transfusion reactions are mild. The most frequently reported are febrile non-hemolytic and mild allergic reactions. Serious adverse reactions such as anaphylaxis, TRALI and hemolytic transfusion reactions occur, but are rare. One incident of bacterial transmission and four incidents of viral transmission have been reported, among them one case of HCV transmission. No incidents of transmission of HIV or hepatitis B have been reported. IBCT was reported 168 times. Our data are comparable with data from other countries. Recommendations from the haemovigilance system are included in local and national guidelines. Increased knowledge of haemovigilance among physicians and nurses can lead to improved transfusion safety. It is safe to receive blood in Norway, but serious adverse reactions do occur. Our reporting system seems to be well accepted. We have not yet been able to document any change of practice that has lead to a reduction in the number of complications. PMID- 24157221 TI - Impaired systolic blood dipping and nocturnal hypertension: an independent predictor of carotid intima-media thickness in type 1 diabetic patients. AB - OBJECTIVE: Type 1 diabetes in children predicts a broad range of later health problems including an increased risk of cardiovascular morbidity and mortality. This study aimed to evaluate whether nocturnal hypertension and impaired nocturnal dipping affect atherosclerosis in children and adolescents with type 1 diabetes and to investigate the relationship between atherogenic risk factors and carotid intima-media thickness (CIMT). METHODS: One hundred fifty-nine type 1 diabetic patients and 100 healthy controls were included in the study. We investigated metabolic and anthropometric parameters such as body mass index (BMI), waist circumference, fasting glucose and insulin, serum lipids, 24h ambulatory blood pressure monitoring (ABPM), and CIMT and compared these with those in control subjects (CS). RESULTS: No difference was found between type 1 diabetic patients and CS in age, weight, waist/hip ratio, triglyceride, HDL cholesterol level. However in children with type 1 diabetes, total cholesterol (p=0.016),and LDL-cholesterol (p=0.002) levels and CIMT (P<0.001) were greater than those of controls. It was determined that 10% of type 1 diabetic patients had dyslipidemia. In 23.2% of type 1 diabetic patients, ABPM showed arterial hypertension. CIMT was significantly higher in the hypertensive group than in the non-hypertensive group (P=0.003). Twenty-three (14.4%) diabetic patients had nocturnal hypertension. CIMT was significantly greater in the nocturnal hypertensive group (p=0.023). Mean systolic blood pressure (SBP) and diastolic blood pressure (DBP) dipping was significantly different in diabetic patients (P<0.001). CIMT was correlated positively with Hba1c (r=0.220, p=0.037), and negatively with SBP dipping (r=-0.362, p=0.020) in the diabetic patients. In stepwise regression analysis, Hba1c and SBP dipping emerged as a significant predictor of CIMT (beta=0.300, p=0.044, beta=0.398 p=0.009) contributing to 15.58% of its variability. CONCLUSION: These results provide additional evidence for the presence of subclinical cardiovascular disease (CVD) and its relation to hypertension in type 1 diabetic patients. They also indicate a significant relation between nocturnal hypertension, SBP dipping and increased arterial stiffness. It is also important to note that our findings reveal significant relationships between HBA1c cardiovascular changes and underline the importance of glucose control to predict CVD. PMID- 24157222 TI - The 'new' biotech industry. PMID- 24157223 TI - Evaluation of noninvasive hemoglobin measurements in trauma patients. AB - BACKGROUND: Reliable, accurate, noninvasive, and continuous determination of hemoglobin would be an important advance in the care of trauma patients. The aim of this study was to evaluate the utility of the Masimo Radical 7 device in severely injured trauma patients. METHODS: Highest level trauma activation patients were enrolled over a 1-year period. Laboratory hemoglobin values were compared with Masimo hemoglobin values using Bland-Altman analysis. RESULTS: A total of 525 patients were enrolled in the study. Comparison of 861 paired values from 418 patients showed a variance of 3.89 to -3.84 g/dL, showing a nonsignificant correlation between Masimo hemoglobin and laboratory hemoglobin values. CONCLUSIONS: The Masimo Radical 7 system evaluated in this study holds promise, but it is not ready to be used as an initial noninvasive evaluation tool in the acute treatment of severely injured trauma patients. There was a poor correlation between Masimo hemoglobin and laboratory hemoglobin and large numbers of missing data. On the basis of the poor correlation, the Masimo Radical 7 device cannot currently be used to guide transfusion therapy. PMID- 24157224 TI - Peritoneal carcinomatosis in patients with gastric cancer, and the role for surgical resection, cytoreductive surgery, and hyperthermic intraperitoneal chemotherapy. AB - BACKGROUND: The aims of this study were to create a model of peritoneal carcinomatosis in patients with gastric cancer and to evaluates outcomes in patients with gastric cancer treated using surgery and hyperthermic intraperitoneal chemotherapy (HIPEC). METHODS: A single-institution cohort of patients with gastric cancer was analyzed according to the development of gastric cancer with peritoneal carcinomatosis (GCPC). Variables were evaluated using regression analysis. Kaplan-Meier analysis was used to evaluate outcomes after surgical resection, cytoreductive surgery, and HIPEC. RESULTS: Age <=60 years and local tumor stage (T3/T4) were significantly associated with GCPC (odds ratio, 3.95 and 3.94, respectively). Thirty-six-month survival was 57% for patients without peritoneal disease and 39% for patients with GCPC. There was no significant trend of improved survival after surgical management or HIPEC. CONCLUSIONS: Age <=60 years and T3/T4 tumor stage are risk factors for GCPC. Intermediate-term survival of patients with GCPC treated with surgical resection or cytoreductive surgery and HIPEC was not improved, though future research should address the possible benefits of aggressive approaches to the treatment of GCRC. PMID- 24157225 TI - Femoral condylar contact points start and remain posterior in high flexing patients. AB - This study compares kinematic patterns of 136 patients following total knee arthroplasty with high post-operative knee flexion (HighFlex) versus kinematics of 114 patients with limited knee flexion (LowFlex) using a blocked stratified random sampling study design to reduce confounding and bias. The kinematics was collected using fluoroscopy and 2D to 3D registration for a weight-bearing deep knee bend activity. Both the lateral and the medial condylar contact positions for the HighFlex subjects were significantly more posterior than the LowFlex subjects at full extension and remained that way at all flexion angles. The amount translation of the contact points, axial orientation angle and axial rotation were found to be similar for the two groups. Lift-off was significantly higher in the LowFlex indicating mid-flexion instability. PMID- 24157226 TI - Incident hepatitis B infection subsequent to the diagnosis of HIV infection in a Melbourne cohort: missed opportunities for prevention. AB - Background The characteristics associated with incident hepatitis B (HBV) infection in HIV-positive individuals are not well described in the Australian setting. The aim of this study is to determine the characteristics of and risk factors for HBV infection within HIV-infected individuals in a Melbourne cohort between 1985 and 2011. METHODS: Individuals susceptible to HBV at their HIV diagnosis were identified using their HBV serology stored within the Victorian HIV database. Within this group, those who had a subsequent positive test for hepatitis B surface antigen or hepatitis B core antibody were identified as infected with HBV after their HIV diagnosis. Incident cases were matched with controls from the initially susceptible group who did not seroconvert for analysis. An incidence rate was calculated from the number of seroconversions and the cumulative time at risk (in 1000 patient-years of follow-up). RESULTS: Of the 4711 patients with HIV seen more than once, 3223 had HBV testing. Of the 174 with positive HBV test results, 39 individuals met the definition of seroconversion after HIV diagnosis, representing the incident cases. The estimated HBV incidence rate was 1.81 (95% confidence interval: 1.28-2.47) per 1000 patient-years at risk. These individuals form the basis of a detailed case series and case-control study. Data collected include demographic details, immunological and virological characteristics, antiretroviral treatment and vaccination history. CONCLUSIONS: HIV-infected individuals should be screened for HBV and monitored for incident infection. Optimal control of HIV and improved vaccination coverage provide the best opportunity for prevention. PMID- 24157227 TI - Improving pain assessment practices and outcomes in long-term care facilities: a mixed methods investigation. AB - An ongoing concern in long-term care (LTC) is that pain problems are often not identified correctly. There is also evidence that behavioral disturbance due to pain is misattributed to psychiatric conditions and consequently frequently treated with psychotropic rather than analgesic medication. This can result in unnecessary polypharmacy and ineffective pain management. In a previous study, implementation of a pain assessment protocol resulted in changes in administration of pro re nata (PRN) medications and positive outcomes. However, there were no changes in regularly scheduled medications suggesting that assessment results were either not communicated to the prescribing physicians or not taken into account. The goal of this study was to determine whether a pain assessment protocol, augmented with communication of the assessment results to the residents' physicians, affects prescriptions of analgesic and psychotropic medication. Psychotropic medication reduction would help address the problem of polypharmacy frequently seen in LTC facilities. PRN medications were also examined. This investigation involved a two group design (control vs. assessment). A mixed methods analysis included both quantitative and qualitative procedures. At the end of the study, residents in the pain assessment group were administered fewer psychotropic medications than patients in the control group, helping address the problem of polypharmacy. Pain levels were comparable between the groups. Health care staff indicated that the protocol resulted in more careful evaluation of residents' pain and greater appropriateness of prescriptions including reductions in polypharmacy. PMID- 24157228 TI - Clinical, ultrasonographic, and endocrinological studies on donkey pregnancy. AB - Although donkey breeding has gained new interest in the past two decades, knowledge about donkey reproduction is still scarce, particularly on jenny pregnancy. The aim of this study was to describe the ultrasonographic and endocrine profiles of the physiological pregnancy in the jenny. The study was performed on 12 pregnancies of 7 Amiata donkeys from Day 10 after ovulation to delivery. Because three pregnancies, respectively at weeks 42, 44, and 45, were considered pathologic and treated pharmacologically, data collected from 2 weeks before diagnosis to the end of pregnancy were removed from the analysis. Average length of the normal pregnancies was 353.4 +/- 13.0 days (range, 339-370 days). Timing, dimensions, and development during the first phases of embryonic growth, evaluated using transrectal ultrasound, were similar to that previously described in jennies and mares: first detection of embryonic vesicle was at 11.8 +/- 1.3 days of gestation and diameter was 6.5 +/- 1.9 mm, loss of spherical shape occurred at 18.5 +/- 1.4 days, and embryo and heart beat were first seen at 22.0 +/- 1.1 and 25 +/- 1.1 days, respectively. The intrauterine growth in the second half of pregnancy, evaluated using the transrectal and transabdominal approach, also showed strong positive correlations, similar to that reported for the mare. The trends of the combined thickness of the utero-placental unit and the echogenicity of the amniotic and allantoic fluids are examples. The diameters (mm) of fetal chest, eye orbit, and aorta increased throughout pregnancy and were 40.6 +/- 2.9, 8.7 +/- 1.5, and 3.5 +/- 0.7, respectively, at week 13, and 190.9 +/- 12.0, 21.4 +/- 1.5, and 30.6 +/- 1.8 at the last evaluation before parturition. In contrast, heart rate decreased as pregnancy progressed. Regression analyses between these parameters and day of gestation were statistically significant (P < 0.001). All fetuses consistently showed some intrauterine activity. Maternal plasma progestagens and estrone sulfate concentrations followed a pattern similar to that seen in mares, although the prepartal progestagen peak was lower in jennies. This study provides a range of ultrasonographic and endocrine values for normal pregnancy in jennies. PMID- 24157229 TI - Successful laparoscopic insemination with a very low number of flow cytometrically sorted boar sperm in field conditions. AB - The aim of this study was to develop a useful procedure for laparoscopic insemination (LI) with sex-sorted boar spermatozoa that yields adequate fertility results in farm conditions. In experiment 1, we evaluated the effects of single (oviducts) and double (oviducts and tips of the uterine horns) LI with X-sorted sperm on the reproductive performance of sows. Sows (N = 109) were inseminated once as follows: (1) single LI with 0.5 * 10(6) unsorted sperm per oviduct; (2) single LI with 0.5 * 10(6) sex-sorted sperm per oviduct; or (3) double LI with 0.5 * 10(6) sex-sorted sperm per oviduct and 0.5 * 10(6) sex-sorted sperm per uterine horn. The farrowing rates were lower (P < 0.05) in sows inseminated with sex-sorted sperm (43.2% and 61.9% for the single and double insemination groups, respectively) than in sows from the unsorted group (91.3%). Within the sex-sorted groups, the farrowing rate tended (P = 0.09) to be greater in sows inseminated using double LI. There were no differences in the litter size among groups. In experiment 2, we evaluated the effect of the number of sex-sorted sperm on the reproductive performance of sows when using double LI. Sows (N = 109) were inseminated with sex-sorted sperm once using double LI with: (1) 0.5 * 10(6) sperm per oviduct and 1 * 10(6) sperm per uterine horn; or (2) 1 * 10(6) sperm per oviduct and 2 * 10(6) sperm per uterine horn. Similarly high pregnancy (90%) and farrowing (80%) rates were achieved in both groups. The sows inseminated with the highest number of sperm tended (P = 0.09) to have more piglets (10.8 +/- 0.7 vs. 9.2 +/- 0.6). A high female proportion (number of female births divided by the total of all births >=0.92) was obtained in both experiments using X-sorted sperm. Our results indicate that the double LI procedure, using between 3 and 6 * 10(6) sex-sorted sperm per sow produces adequate fertility at the farm level, making sperm-sexing technology potentially applicable in elite breeding units. PMID- 24157231 TI - Real increasing incidence of hysterectomy for placenta accreta following previous caesarean section. AB - OBJECTIVE: Placenta accreta, morbid adherence to the uterus to the myometrium, is commonest in association with placenta previa in women previously delivered by caesarean section (CS). It has become proportionally a greater cause of major maternal morbidity and mortality as the frequency of other serious obstetric complications has declined. The aim of this study was to examine the incidence of placenta accreta in the context of a rising caesarean delivery rate. STUDY DESIGN: Retrospective review of the incidence of placenta accreta in parous women during the 36 years 1975-2010. Cases were identified from hospital records and then correlated with pathological reports. The incidence of placenta accreta was analysed in the context of women previously delivered by CS. RESULTS: During the 36-year period in our unit, 157,162 multiparous women delivered, of whom 15,151 (9.6%) had a previous CS scar. The institutional incidence of CS rose from 4.1% in 1975 to 20.7% in 2010. Twenty-five parous women, all with a previous CS, had placenta accreta requiring hysterectomy. The overall incidence of placenta accreta was 1.65 per 1000 parous women with a previous CS, but was low (1.06/1000) until 2002. From 2003 to 2010 the incidence rose to 2.37/1000 previous CS deliveries (OR 2.2; 95% CI 1.05-5.1). CONCLUSION: The frequency of placenta accreta correlated steadily with the CS rate until 2000. Since then, the incidence has nearly doubled in women with previous CS scars, suggesting an additional causative influence on risk. PMID- 24157230 TI - Effect of culture medium type on canine adipose-derived mesenchymal stem cells and developmental competence of interspecies cloned embryos. AB - Canine adipose-derived mesenchymal stem cells (ASCs) are promising as donor cells for somatic cell nuclear transfer (SCNT). It has been suggested that different cell cultures possess different capacities to support pre-implantation development of SCNT embryos. The aim of this study is to investigate whether two culture medium (RCMEP, Dulbecco's modified Eagle's medium [DMEM]) affect gene expression of ASCs, subsequent development of interspecies SCNT (iSCNT) and gene expression of cloned embryos. The RCMEP-cultured cells contained significantly greater amounts of SOX2, NANOG, OCT4, DNMT1, and MeCP2 than DMEM-cultured cells (P < 0.05). In iSCNT, the use of DMEM medium for culturing cells resulted in similar development to the blastocyst stage than those derived from RCMEP cultured cells (4.5% and 3.2%, respectively; P > 0.05). The expression of all transcripts except for DNMT1 in cloned blastocysts from RCMEP cultured cells followed those of cloned blastocysts derived from DMEM cultured cells. The alteration of gene expression in ASCs by culture medium was not manifested in the iSCNT embryos derived from these cells. Although the culture medium can induce changes of gene expression by ASCs, such alterations in donor cells did not affect the developmental competence or gene expression patterns of iSCNT embryos. PMID- 24157232 TI - Diagnosis performance of high sensitivity troponin assay in out-of-hospital cardiac arrest patients. AB - PURPOSE: Early identification of the cause of out-of-hospital cardiac arrest (OHCA) remains a challenge. Our aim was to determine whether high-sensitivity cardiac troponin T (HsTnT) was useful to diagnose a recent coronary artery occlusion as the cause of OHCA. METHODS: Retrospective study including OHCA patients evaluated by systematic coronary angiogram at hospital admission. HsTnT was assessed at ICU admission. Predictive factors of a recent coronary occlusion were identified by logistic regression. Net reclassification improvement (NRI) was calculated to estimate the potential enhancement of prediction with HsTnT. RESULTS: During the 5 year study period, 272 patients (median age 60 y, 76.5% men) were included, and a culprit coronary occlusion was found in 133 (48.9%). The optimum HsTnT cut-off to predict a recent coronary occlusion was 575 ng/l (sensitivity 65.4%, specificity 65.5%). In multivariate analysis, current smoking (OR 3.2 95%, 95%CI 1.62-6.33), time from collapse to BLS<3 min (OR 2.11, 95%CI 1.10-4.05), initial shockable rhythm (OR 5.29, 95%CI 2.06-13.62), ST-segment elevation (OR 2.44, 95%CI 1.18-5.03), post-resuscitation shock onset (OR 2.03, 95%CI 1.01-4.07) and HsTnT>=575 ng/l (OR 2.22, 95%CI 1.16-4.27) were associated with the presence of a recent coronary occlusion. Nevertheless, adding HsTnT to established risk factors of recent coronary occlusion identified above provided a non-significant NRI of -0.43%. CONCLUSIONS: Admission HsTnT is increased after OHCA and is an independent factor of a recent coronary occlusion. However, HsTnT does not seem to be a strong enough diagnostic tool to select candidates for emergent coronary angiogram in OHCA survivors. PMID- 24157233 TI - Electrical cardioversion of atrial fibrillation: evaluation of sedation safety with midazolam by means of EtCO2 and IPI algorithm analysis. AB - BACKGROUND: For several years, the electrical external cardioversion (ECV) has entered into clinical practice without assistance of anesthesiology team. The aim of this study was to evaluate the efficacy and safety of sedation with midazolam in patients undergoing electrical cardioversion of atrial fibrillation (AF) by means of the evaluation of capnometry and pulmonary integrated index (IPI) using the Oridion Capnostream 20. METHODS: We studied 45 consecutive patients (pts) who underwent ECV of AF sedated with midazolam at mean dose of 5mg bolus followed by another 5mg in 2 minutes (min). Maximum dosage was 11 mg (average 8 +/- 2 mg). After cardioversion we infused Anexate 0.5mg bolus followed by 0.5mg in 30 min. All pts were monitored with blood pressure, O2 saturation, cardiac frequency and capnometers. RESULTS: EtCO2 value at baseline was 37.14 +/- 2.7, 35.02 +/- 1.7 after induction of sedation and 36.59 +/- 1.2 after awaking (p<0.05 baseline to induction). IPI index was 9.58 +/- 0.5 at basal 8.09 +/- 0.63 at induction time and 9.02 +/- 0.5 after awaking (p<0.05 basal to induction, induction to awaking and basal to awaking but all data were in normal range). No pts had apnea or hypoxia but there was only one case of hypotension after shock, which lasted 2 min. CONCLUSIONS: Conscious sedation with midazolam for electrical cardioversion of AF appears to be safe and effective because it does not affect adversely the respiratory parameters of pts as demonstrated by the analysis of EtCO2 and IPI index. PMID- 24157234 TI - Sex- and estrogen-dependent regulation of a miRNA network in the healthy and hypertrophied heart. AB - BACKGROUND: In pressure overload, profibrotic gene expression and cardiac fibrosis are more pronounced in males than in females. Sex-specific and estrogen dependent regulation of microRNAs (miRNAs), such as miR-21, may be a potential mechanism leading to sex differences in fibrosis. OBJECTIVES: To analyze the influence of sex, estrogen, and estrogen receptor beta (ERbeta) on the expression of miR-21 and to identify additional miRNAs potentially involved in sex-specific pressure overload-induced cardiac remodeling. METHODS: The sex-specific regulation of fibrosis-related miRNAs was analyzed in male and female wild type and ERbeta-deficient mice after transverse aortic constriction (TAC), in rat fibroblasts, and in a cardiomyocyte-like cell line. RESULTS: We report the sex specific expression of functionally-related miR-21, -24, -27a, -27b, 106a, -106b and the regulation of their expression by estrogen in a sex-specific manner. These effects were abolished in ERbeta-deficient mice. We demonstrate the presence of common functional target sites for these miRNAs on three repressors of the mitogen-activated protein kinase signaling pathway, i.e. Rasa1, Rasa2 and Spry1, which may all lead to cardiac fibrosis. As expected, transfection with miRNA mimics targeting these repressors induced ERK1/2 phosphorylation. CONCLUSIONS: Estrogen regulates a network of miRNAs in a sex-specific manner via ERbeta. Our data suggest that the sex-specific expression of these miRNAs may be related to sex differences in fibrosis after pressure overload. PMID- 24157235 TI - Optical coherence tomography and histopathological assessment of delayed arterial healing after drug-eluting stent implant in a pig coronary model. AB - BACKGROUND: Delayed healing, such as persistent inflammation and fibrin deposition, and vascular dysfunction after drug-eluting stent has been reported. Histological validation of coronary optical coherence tomography (OCT) morphology has not yet been done. METHODS: Sirolimus eluting stents (SES, n=8) and bare metal stents (BMS n=8) were implanted in pig coronary arteries. One month after implantation, an acetylcholine challenge test and OCT were performed. The OCT texture pattern of the neointima was classified into one of the three categories; Layered type, Homo type, and Hetero type. Hearts were harvested for histopathological scoring of inflammation and intramural thrombus. RESULTS: Inflammation and intramural thrombus scores were higher in the Hetero type than in the Layered type and Homo type. OCT intensity of the Homo type was higher than that of the Layered type and Hetero type. Most SES were of the Hetero type. Conversely, most BMS were of the Homo type. SES exhibited higher inflammation and intramural thrombus than BMS (1.72 +/- 0.89 vs 1.00 +/- 0.00, P=0.0003, 2.39 +/- 0.70 vs 0.92 +/- 0.28, P<0.001 respectively). After acetylcholine injection, the diameter change was 4.31 +/- 4.80% for SES versus -3.68 +/- 6.81% for BMS (P=0.024). CONCLUSIONS: The Hetero type texture pattern in OCT images was associated with histological inflammation and intramural thrombus predominantly found in SES, and is related to endothelial dysfunction. PMID- 24157236 TI - Failure of monolateral renal nerve ablation to exert sympathoinhibitory and blood pressure lowering effects in a patient with resistant hypertension: a case report. PMID- 24157237 TI - Bioluminescence imaging of cardiomyogenic and vascular differentiation of cardiac and subcutaneous adipose tissue-derived progenitor cells in fibrin patches in a myocardium infarct model. AB - BACKGROUND: Adipose tissue-derived progenitor cells (ATDPCs) isolated from human cardiac adipose tissue are useful for cardiac regeneration in rodent models. These cells do not express cardiac troponin I (cTnI) and only express low levels of PECAM-1 when cultured under standard conditions. The purpose of the present study was to evaluate changes in cTnI and PECAM-1 gene expression in cardiac ATDPCs following their delivery through a fibrin patch to a murine model of myocardial infarction using a non-invasive bioluminescence imaging procedure. METHODS AND RESULTS: Cardiac and subcutaneous ATDPCs were doubly transduced with lentiviral vectors for the expression of chimerical bioluminescent-fluorescent reporters driven by constitutively active and tissue-specific promoters (cardiac and endothelial for cTnI and PECAM-1, respectively). Labeled cells mixed with fibrin were applied as a 3-D fibrin patch over the infarcted tissue. Both cell types exhibited de novo expression of cTnI, though the levels were remarkably higher in cardiac ATDPCs. Endothelial differentiation was similar in both ATDPCs, though cardiac cells induced vascularization more effectively. The imaging results were corroborated by standard techniques, validating the use of bioluminescence imaging for in vivo analysis of tissue repair strategies. Accordingly, ATDPC treatment translated into detectable functional and morphological improvements in heart function. CONCLUSIONS: Both ATDPCs differentiate to the endothelial lineage at a similar level, cardiac ATDPCs differentiated more readily to the cardiomyogenic lineage than subcutaneous ATDPCs. Non-invasive bioluminescence imaging was a useful tool for real time monitoring of gene expression changes in implanted ATDPCs that could facilitate the development of procedures for tissue repair. PMID- 24157238 TI - Orthostatic function after renal sympathetic denervation in patients with resistant hypertension. AB - INTRODUCTION: Catheter-based renal denervation (RDN) reduces local and whole-body sympathetic activity and blood pressure (BP) in patients with resistant hypertension. However, safety concerns exist concerning the development of orthostatic dysfunction after RDN. METHODS AND RESULTS: In 36 patients (65 +/- 7.6 years, 75% male) with resistant hypertension (office BP 162 +/- 24/91 +/- 14 mm Hg) treated with 4.8 +/- 1.7 antihypertensive drugs, tilt table testing (TTT) was performed before and three months after RDN. Response to RDN was defined as a reduction in office systolic BP (SBP) >= 10 mm Hg three months after RDN. Responders (n=26; 72.2%) and non-responders (n=10; 27.8%) were evaluated separately. After RDN, office SBP and diastolic BP (DBP) were reduced by 29 +/- 6.2/14 +/- 3.6 mm Hg (p<0.0001; p=0.0002) only in responders. During TTT, SBP and DBP in supine position were only reduced in responders. Resting heart rate (HR) decreased in responders but not in non-responders by 5.9 +/- 1.7beats/min (p=0.0016). Mean and minimal SBP were not altered during passive tilting. In the responder group, ?SBP was reduced in the initial phase of tilting. The adaptive increase of HR was preserved in both groups after RDN, while only in responders mean and minimal HR were reduced after passive tilting. Following drug provocation, mean and minimal SBP during all phases of passive tilting remained unchanged. ?SBP, ?HR and total number of (pre-)syncopes were neither influenced by RDN nor differing between responders and non-responders. CONCLUSIONS: In patients with resistant hypertension, RDN reduced office BP, supine BP and HR during TTT without causing orthostatic dysfunction or (pre-)syncopes three months after treatment. PMID- 24157240 TI - The impact of sit-stand office workstations on worker discomfort and productivity: a review. AB - This review examines the effectiveness of sit-stand workstations at reducing worker discomfort without causing a decrease in productivity. Four databases were searched for studies on sit-stand workstations, and five selection criteria were used to identify appropriate articles. Fourteen articles were identified that met at least three of the five selection criteria. Seven of the identified studies reported either local, whole body or both local and whole body subjective discomfort scores. Six of these studies indicated implementing sit-stand workstations in an office environment led to lower levels of reported subjective discomfort (three of which were statistically significant). Therefore, this review concluded that sit-stand workstations are likely effective in reducing perceived discomfort. Eight of the identified studies reported a productivity outcome. Three of these studies reported an increase in productivity during sit stand work, four reported no affect on productivity, and one reported mixed productivity results. Therefore, this review concluded that sit-stand workstations do not cause a decrease in productivity. PMID- 24157239 TI - Phagocytic glial cells: sculpting synaptic circuits in the developing nervous system. AB - In the developing nervous system, synaptic connections are formed in excess and must remodel to achieve the precise synaptic connectivity characteristic of the mature organism. Synaptic pruning is a developmental process in which subsets of synapses are eliminated while the remaining synapses are preserved and strengthened. Recent findings have demonstrated unexpected roles for glial cells in this developmental process. These data demonstrate that phagocytic glia engulf synaptic and/or axonal elements in the developing nervous system and disruptions in this process result in sustained deficits in synaptic connectivity. These new findings highlight the importance of glia for nervous system development and function and may shed new light on mechanisms underlying nervous system disease. PMID- 24157241 TI - The effect of a helmet on cognitive performance is, at worst, marginal: a controlled laboratory study. AB - The present study looked at the effect of a helmet on cognitive performance under demanding conditions, so that small effects would become more detectible. Nineteen participants underwent 30 min of continuous visual vigilance, tracking, and auditory vigilance (VTT + AVT), while seated in a warm environment (27.2 (+/ 0.6) degrees C, humidity 41 (+/-1)%, and 0.5 (+/-0.1) m s(-1) wind speed). The participants wore a helmet in one session and no helmet in the other, in random order. Comfort and temperature perception were measured at the end of each session. Helmet-wearing was associated with reduced comfort (p = 0.001) and increased temperature perception (p < 0.001), compared to not wearing a helmet. Just one out of nine cognitive parameters showed a significant effect of helmet wearing (p = .032), disappearing in a post-hoc comparison. These results resolve previous disparate studies to suggest that, although helmets can be uncomfortable, any effect of wearing a helmet on cognitive performance is at worst marginal. PMID- 24157242 TI - Determining the optimal treatment for metastatic castration-resistant prostate cancer: age should not be a factor. PMID- 24157243 TI - The effect of crystallization of bioactive bioglass 45S5 on apatite formation and degradation. AB - OBJECTIVE: Amorphous bioglass 45S5 has been used for many years as bone substitute material. Bioactive glasses are also suitable as coating materials for implants in order to improve the bone ongrowth behavior. We hypothesize that both the apatite formation on the surface and the chemical stability can be improved by crystallization of the bioglass. METHODS: Synthesized amorphous bioglass 45S5 specimens as well as samples which were crystallized at 1000 degrees C were stored in simulated body fluid for 1, 7, and 14 days. The respective apatite formation was gravimetrically determined and characterized by SEM and XRD analysis. Moreover, the degradation behavior was studied after storage in distilled water. RESULTS: The weight of the crystallized samples decreased 6.3% less than that of the amorphous samples. Calcium silica and calcium carbonate layers were found on amorphous bioglass after 7 and 14 days. However, apatite formation was observed only on the crystallized 45S5 samples after storage. SIGNIFICANCE: We conclude that the chemical resistance can be improved and, in parallel, a pronounced apatite formation on the surface of 45S5 can be obtained by controlled crystallization of the material for the particular test setup. Therefore, crystallized bioactive glasses should be considered to be promising coating material for dental implants. PMID- 24157244 TI - 3D-Finite element analysis of molars restored with endocrowns and posts during masticatory simulation. AB - OBJECTIVE: The objective was to compare equivalent stresses in molars restored with endocrowns as well as posts and cores during masticatory simulation using finite element analysis. METHODS: Four three-dimensional models of first mandibular molars were created: A - intact tooth; B - tooth restored by ceramic endocrown; C - tooth with FRC posts, composite core and ceramic crown; D - tooth with cast post and ceramic crown. The study was performed using finite element analysis, with contact elements. The computer simulations of mastication were conducted. The equivalent stresses of modified von Mises failure criterion (mvM) in models were calculated, Tsai-Wu index for FRC post was determinate. Maximal values of the stresses in the ceramic, cement and dentin were compared between models and to strength of the materials. Contact stresses in the cement-tissue adhesive interface around restorations were considered as well. RESULTS: During masticatory simulation, the lowest mvM stresses in dentin arisen in molar restored with endocrown (Model B). Maximal mvM stress values in structures of restored molar were 23% lower than in the intact tooth. The mvM stresses in the endocrown did not exceed the tensile strength of ceramic. In the molar with an FRC posts (Model C), equivalent stress values in dentin increased by 42% versus Model B. In ceramic crown of Model C the stresses were 31% higher and in the resin luting cement were 61% higher than in the tooth with endocrown. Tensile contact stresses in the adhesive cement-dentin interface around FRC posts achieved 4 times higher values than under endocrown and shear stresses increased twice. The contact stress values around the appliances were several time smaller than cement-dentin bond strength. SIGNIFICANCE: Teeth restored by endocrowns are potentially more resistant to failure than those with FRC posts. Under physiological loads, ceramic endocrowns ideally cemented in molars should not be demaged or debonded. PMID- 24157245 TI - Stereotactic body radiation therapy in octogenarians with stage I lung cancer. AB - BACKGROUND: The purpose of this study was to describe our clinical experience using stereotactic body radiation therapy (SBRT) to treat medically inoperable stage I non-small-cell lung cancer (NSCLC) in very elderly patients. PATIENTS AND METHODS: Twenty-four consecutive octogenarians with stage I NSCLC were treated with SBRT between 2007 and 2011 at a single center. Median prescription dose was 48 Gy (range, 48-56). Follow-up clinical examination and computed tomography (CT) were performed every 2 to 3 months. RESULTS: Median age was 85 years (range, 80 89). Twenty-three (96%) patients had peripheral tumors, and median tumor size was 22 mm (range, 11-49). Tissue diagnosis was obtained in 16 (67%) patients. Median follow-up for all patients was 27.6 months (range, 4.3-61.2). The 24-month disease-free survival was 77% (95% confidence interval [CI], 61%-97%). The 24 month overall survival (OS) was 74% (95% CI, 57%-94%). No local failure (LF) was observed during the period of observation. Nodal failure (NF) and distant failure (DF) occurred in 2 and 4 patients, respectively. The cumulative incidence of competing mortality at 24 months was estimated at 13% (95% CI, 3%-30%). No difference in outcomes with or without tissue diagnosis was observed. No grade >= 3 early or late treatment-related toxicities were observed. CONCLUSION: Octogenarians tolerate SBRT well, which makes it an attractive treatment option. PMID- 24157246 TI - Individual and contextual socioeconomic determinants of knowledge of the ABC approach of preventing the sexual transmission of HIV in Nigeria: a multilevel analysis. AB - BACKGROUND: Nigeria has the highest number of people living with HIV/AIDS in the world after India and South Africa. HIV/AIDS places a considerable burden on society's resources, and its prevention is a cost-beneficial solution to address these consequences. To the best of our knowledge, there has been no multilevel study performed to date that examined the separate and independent associations of individual and community socioeconomic status (SES) with HIV prevention knowledge in Nigeria. METHODS: Multilevel linear regression models were applied to the 2008 Nigeria Demographic and Health Survey on 48871 respondents (Level 1) nested within 886 communities (Level 2) from 37 districts (Level 3). RESULTS: Approximately one-fifth (20%) of respondents were not aware of any of the Abstinence, Being faithful and Condom use (ABC) approach of preventing the sexual transmission of HIV. However, the likelihood of being aware of the ABC approach of preventing the sexual transmission of HIV increased with older age, male gender, greater education attainment, a higher wealth index, living in an urban area and being from least socioeconomically disadvantaged communities. There were significant community and district variations in respondents' knowledge of the ABC approach of preventing the sexual transmission of HIV. CONCLUSION: The present study provides evidence that both individual- and community-level SES factors are important predictors of knowledge of the ABC approach of preventing the sexual transmission of HIV in Nigeria. The findings underscore the need to implement public health prevention strategies not only at the individual level, but also at the community level. PMID- 24157247 TI - Obstetrical complications and Apgar score in subjects at risk of psychosis. AB - The objective of the study was to identify associations between a history of obstetrical complications (OCs) and the future development of symptoms indicating risk of psychosis (At Risk Mental State - ARMS). The frequency of OCs was assessed in 66 ARMS subjects, 50 subjects with the first episode of schizophrenia (FES) and 50 healthy controls. Obstetrical data was obtained from medical documentation and evaluated with the Lewis and Murray Scale. Definite OCs, according to the Lewis and Murray Scale, occurred significantly more frequently in the ARMS group compared to the controls (chi(2) = 7.79, p = 0.005; OR = 4.20, 95% CI = 1.46-12.11), as well as in the FES subjects compared to the controls (chi(2) = 8.39, p = 0.004; OR = 4.64, 95% CI = 1.56-13.20). Apgar scores in the first (Apgar 1) and the fifth minute after birth (Apgar 5) were significantly lower in the FES subjects compared to the controls (for Apgar 1 score Z = 4.439, p < 0.0001; for Apgar 5 score Z = 5.250, p < 0.0001). The ARMS subjects demonstrated significantly lower Apgar 5 scores compared to the healthy controls (Z = 3.458, p = 0.0016). The results indicate that OCs and low Apgar 5 score should be considered important factors in identifying subjects at risk of developing psychosis. PMID- 24157248 TI - Methylation of the dopamine D2 receptor (DRD2) gene promoter in women with a bulimia-spectrum disorder: associations with borderline personality disorder and exposure to childhood abuse. AB - OBJECTIVE: Previous findings indicate that women with Bulimia Nervosa (BN), when compared to women with no eating disorder (NED), tend to display elevated methylation in the promoter region of the DRD2 gene. The preceding would be compatible with evidence of generally reduced dopamine activity in people with BN. However, altered DNA methylation has also been associated with adverse environmental exposures (such as to childhood abuse) and with psychiatric disturbances (such as Borderline Personality Disorder: BPD). In this study, we examined the extent to which DRD2 methylation was associated with the presence or absence of a bulimic eating disorder, to childhood abuse exposure, or to comorbid BPD. METHOD: Women with a bulimia-spectrum disorder (BSD) and women with NED were assessed for childhood traumata, eating-disorder symptoms and BPD, and provided blood samples for methylation analyzes. RESULTS: BSD and NED groups did not differ as to mean percent DRD2 promoter methylation. However, among the women with a BSD, those with BPD showed small, but significant increases in DRD2 methylation levels compared to women with NED (as indicated by Hochberg's post hoc tests). Similarly, women with a BSD who reported a history of childhood sexual abuse showed a trend-level elevation of DRD2 methylation compared to our NED group. DISCUSSION: Our findings imply that, in people with a BSD, increased methylation of the DRD2 gene promoter may be more strongly characteristic of comorbid psychopathology than it is a global correlate of the eating disorder per se. We discuss theoretical implications of our findings. PMID- 24157249 TI - Dissecting diverticulosis database dilemmas. PMID- 24157250 TI - Control of Drosophila embryo patterning by transcriptional co-regulators. AB - A combination of broadly expressed transcriptional activators and spatially restricted repressors are used to pattern embryos into cells of different fate. Transcriptional co-regulators are essential mediators of transcription factor function, and contribute to selective transcriptional responses in embryo development. A two step mechanism of transcriptional regulation is discussed, where remodeling of chromatin is initially required, followed by stimulation of recruitment or release of RNA polymerase from the promoter. Transcriptional co regulators are essential for both of these steps. In particular, most co activators are associated with histone acetylation and co-repressors with histone deacetylation. In the early Drosophila embryo, genome-wide studies have shown that the CBP co-activator has a preference for associating with some transcription factors and regulatory regions. The Groucho, CtBP, Ebi, Atrophin and Brakeless co-repressors are selectively used to limit zygotic gene expression. New findings are summarized which show that different co-repressors are often utilized by a single repressor, that the context in which a co repressor is recruited to DNA can affect its activity, and that co-regulators may switch from co-repressors to co-activators and vice versa. The possibility that co-regulator activity is regulated and plays an instructive role in development is discussed as well. This review highlights how findings in Drosophila embryos have contributed to the understanding of transcriptional regulation in eukaryotes as well as to mechanisms of animal embryo patterning. PMID- 24157252 TI - Surgical repositioning of intraocular lenses after late dislocation: complications, effect on intraocular pressure, and visual outcomes. AB - PURPOSE: To study outcomes after surgery for late intraocular lens (IOL) dislocation and, more specifically, to evaluate different surgical techniques to find predictors of worse visual outcomes, describe postoperative complications, and analyze the effect on intraocular pressure (IOP). SETTING: Department of Ophthalmology, Sahlgrenska University Hospital, Molndal, Sweden. DESIGN: Prospective observational cohort study. METHODS: Medical records from cataract surgery, IOL repositioning, and follow-up examinations were reviewed. RESULTS: Ninety-one eyes with in-the-bag (80) or out-of-the-bag (11) late IOL dislocation were consecutively included. In 94% of eyes, the IOLs were repositioned using scleral sutures; 76% of cases were operated on with a posterior approach, including pars plana vitrectomy. The median follow-up was 17 months. Pseudoexfoliation was detected in 57% of eyes. A significant decrease in IOP (mean 3.0 mm Hg) from preoperative values (P=.028) was seen in glaucoma patients. Thirteen eyes had additional surgical procedures. Three cases of retinal detachment occurred. Of the eyes, 59% obtained a Snellen corrected distance visual acuity (CDVA) of 0.5 or more at follow-up; 23% of eyes had worse CDVA during the follow-up than preoperatively. CONCLUSIONS: Repositioning surgery for late IOL dislocation with a posterior pars plana approach using scleral suturing of the preexisting IOL appears to be a safe and effective method for restoring visual acuity. Postoperative complications were comparable to previous findings in this field. Patients with glaucoma may have improved IOP regulation. PMID- 24157251 TI - Effect of steepest-meridian clear corneal incision for reducing preexisting corneal astigmatism using a meridian-marking method or surgeon's intuition. AB - PURPOSE: To compare the effect of steepest-meridian clear corneal incisions (CCIs) for reducing preexisting corneal astigmatism between a meridian-marking method and a surgeon's-intuition method. SETTING: Hayashi Eye Hospital, Fukuoka, Japan. DESIGN: Randomized controlled trials. METHODS: Eyes scheduled for phacoemulsification were randomized to 1 of 2 groups: a 2.65 mm steepest-meridian CCI using the meridian-marking method or a 2.65 mm steepest-meridian CCI using the surgeon's intuition. Regular and irregular corneal astigmatism, surgically induced astigmatism (SIA) vector, refractive status, higher-order aberrations (HOAs), uncorrected (UDVA) and corrected (CDVA) distance visual acuities, and physical meridian misalignment of the steepest-meridian CCI measured using anterior segment optical coherence tomography were evaluated preoperatively and 1 month and 3 months postoperatively. RESULTS: The mean meridian misalignment of the steepest-meridian CCIs was significantly smaller in the meridian-marking group (4.4 degrees +/- 2.8 [SD]) than in the surgeon's-intuition group (8.6 +/- 4.4 degrees) (P <=.0001). Regular and irregular corneal astigmatism and corneal HOAs did not change significantly postoperatively in either group. No significant difference was found in regular or irregular corneal astigmatism, refractive cylinder, manifest spherical equivalent value, SIA, HOAs, UDVA, or CDVA between the meridian-marking group and the surgeon's-intuition group throughout the follow-up. CONCLUSION: The physical meridian misalignment of steepest-meridian CCI was significantly smaller with the meridian-marking method than with the surgeon's-intuition method; however, the effect of the difference was not large enough to decrease remaining astigmatism and HOAs or to improve the UDVA. PMID- 24157253 TI - Lens-iris diaphragm retropulsion syndrome during phacoemulsification in vitrectomized eyes. AB - PURPOSE: To assess the incidence and associations of lens-iris diaphragm retropulsion syndrome (LIDRS) during phacoemulsification in patients who have had vitrectomy. SETTING: Sunderland Eye Infirmary, Sunderland, United Kingdom. DESIGN: Case series. METHODS: The LIDRS was categorized into none, mild, and moderate/severe. Unadjusted and adjusted odds ratios (ORs) and 95% confidence intervals (CIs) of increased LIDRS severity were estimated. RESULTS: Of the 75 eyes (75 patients) included, 35 (46.7%) had no LIDRS and 40 (53.3%) had LIDRS. The odds of increased LIDRS severity decreased significantly with age (OR = 0.92; 95% CI, 0.88-0.97) (P=.001) and increased with increasing axial length (AL) (OR = 3.26; 95% CI, 2.04-5.20) (P<.001) and anterior chamber depth (OR = 6.90; 95% CI, 2.00-23.8) (P=.002). The odds were greater in extensive vitrectomy than in limited vitrectomy (OR = 4.40; 95% CI, 1.64-11.84) (P=.003) and in men than in women (OR = 3.39; 95% CI, 1.40-8.23) (P=.007). The adjusted odds of increased LIDRS severity were significantly greater in extensive vitrectomy than in limited vitrectomy (adjusted OR = 4.42; 95% CI, 1.19-16.45) (P=.027) and with increasing AL (adjusted OR = 3.05; 95% CI, 1.86-5.01) (P<.001). CONCLUSIONS: Lens-iris diaphragm retropulsion syndrome occurred frequently in eyes with previous vitrectomy. Several identifiable factors had a significant association with the occurrence of LIDRS, and these could be used to help in the preoperative counseling of patients and in surgical planning. PMID- 24157254 TI - Role of hyperthermic intraoperative peritoneal chemotherapy in the management of peritoneal metastases. AB - The peritoneal cavity must be oncologically considered as an organ in its own right and peritoneal metastases (PM) must be treated with the same curative intent (and the same results) as liver metastases. The package combining complete cytoreductive surgery (CCRS) (treating the visible disease) plus hyperthermic intraoperative peritoneal chemotherapy (HIPEC) (treating the remaining non visible disease) achieves cure in many patients. Twenty years of publication allow us to assemble sufficient background information and data to point out the good and poor indications for CCRS+HIPEC. HIPEC is the standard of care for the treatment of peritoneal pseudomyxomas and peritoneal mesotheliomas and also, recently for the treatment of colorectal PM with limited peritoneal extension. HIPEC is in the evaluation phase for gastric PM and ovarian PM after initially disappointing results, but it is highly probable that it will be useful in particular settings. PM from neuroendocrine tumours are in the same situation. HIPEC is not currently indicated for the treatment of PM from sarcomas, from GIST, and for small round-cell desmoplastic tumours, given the poor results obtained. HIPEC can be useful, on a case-by-case basis, to treat rare tumours complicated by isolated peritoneal diffusion (e.g. Frantz's tumours). HIPEC can be used in the prophylactic setting to prevent PM in patients with a high risk of developing PM, and the first results of the 'second-look' approach are promising. Finally, CCRS+HIPEC appear to be indispensable tools in the oncologist's armentarium. PMID- 24157255 TI - Emodin represses TWIST1-induced epithelial-mesenchymal transitions in head and neck squamous cell carcinoma cells by inhibiting the beta-catenin and Akt pathways. AB - Head and neck squamous cell carcinoma (HNSCC) is one of the leading causes of cancer deaths worldwide. In recent studies, a crucial link has been discovered between the acquisition of metastatic traits and tumour-initiating abilities in cancer cells during the epithelial-mesenchymal transition (EMT). Herein, we demonstrated that the ectopic expression of TWIST1, the EMT regulator, in HNSCC FaDu cells triggered EMT and resulted in the acquisition of a mesenchymal phenotype. Moreover, FaDu-pFLAG-TWIST1 cancer cell populations that were induced to EMT displayed an increased proportion of cells with the CD44 marker, which is associated with tumour initiation. Interestingly, we found that emodin treatment reduced the tumour-initiating abilities and inhibited cell migration and invasion in FaDu-pFLAG-TWIST1 cells. Emodin directly inhibited TWIST1 expression, upregulated E-cadherin mRNA and protein expression, and downregulated vimentin mRNA and protein expression. Moreover, we found that emodin inhibited TWIST1 binding to the E-cadherin promoter and repressed E-cadherin transcription activity. We also found that emodin inhibited TWIST1-induced EMT by inhibiting the beta-catenin and Akt pathways. More interestingly, emodin significantly inhibited TWIST1-induced invasion in vivo. Therefore, emodin might be applicable to anticancer therapy and could be a potential new therapeutic drug for HNSCC. PMID- 24157256 TI - The impact of central review and central therapy planning on the treatment of children and adolescents with Hodgkin lymphoma. AB - PURPOSE: The multicentre response-adapted paediatric Hodgkin lymphoma trial GPOH HD95 (1995-2001, 925 patients) was followed by the 'HD-Interval' period (2001 2002, 203 patients). During this period, treatment was recommended according to GPOH-HD95 protocol with only minor changes. Central review and treatment planning as in HD95, however, had to be omitted in the absence of funding. Results of both periods were compared to evaluate the impact of central review on staging, stratification, treatment planning and outcome. METHODS: Pre- and post chemotherapy computed tomography and magnetic resonance imaging of HD-Interval patients were evaluated with respect to reliability of staging, response assessment and subsequent treatment stratification. RESULTS: Despite more favourable patient characteristics and treatment group stratifications, the 10 year progression-free survival (PFS) was inferior in HD-Interval patients compared to GPOH-HD95 patients with nearly identical therapy (86% versus 91%, P=0.01). Of 142 patients without guidance by the reference centre, 56 (39%) received a treatment deviating from protocol recommendations: chemotherapy doses were either lower or higher than recommended in 17% of patients, and deviations concerning radiotherapy dose and treatment volume occurred in 25% and 20%, respectively. In both periods, the 10-year PFS was lower in patients with diminished therapy compared to those with adequate treatment according to the given recommendations (HD-Interval: 72% versus 89%, P=0.02; GPOH-HD95: 80% versus 92%, P=0.04). CONCLUSIONS: Deviations from protocol treatment may influence negatively the outcome in paediatric oncology. Protocol enrolment and compliance including timely and correct treatment are crucial. Central reference and consultation centres offer quality assurance, support protocol adherence, and hence influence PFS. PMID- 24157258 TI - Use of hollow fiber tangential flow filtration for the recovery and concentration of HIV virus-like particles produced in insect cells. AB - Attenuated viruses, inactivated viruses and virus like particles (VLPs) are known to be efficient vaccines partially due to their particulate structure. A potential HIV vaccine candidate engineered as a VLP (HIV gag-VLP) and produced in insect cells is currently under preclinical trials demanding large amounts. Due to their extreme fragility and sensitivity to shear forces the recovery and concentration of these extracellular enveloped particles of approximately 120 nm in size is challenging. The current bench scale gradient ultracentrifugation and precipitation methods have been found unsuitable for larger scale processes. In this study a two-step tangential flow filtration (TFF) process using hollow fibers was developed for the clarification and concentration of HIV gag-VLPs. The first step is microfiltration for cell removal and the second step is ultrafiltration for concentrating the HIV gag-VLPs. The chosen parameters for the microfiltration step were hollow fiber membranes of 0.45 MUm cut off 5000 s(-1) shear force and a flux of 10 LMH. The chosen parameters for the ultrafiltration step were a 500 kDa cut off membrane, 6000 s(-1) shear force and a trans-membrane pressure (TMP) of 1.25 bar. The utilization of these parameters provided with concentrated HIV-gag VLPs from 2L of starting cell suspension within 6h of processing time. These downstream processing conditions are extremely valuable for the further large-scale purification process development for HIV gag-VLPs and other particulate bioproducts. PMID- 24157257 TI - Clinical relevance of cranial nerve injury following carotid endarterectomy. AB - OBJECTIVES: The benefit of carotid endarterectomy (CEA) may be diminished by cranial nerve injury (CNI). Using a quality improvement registry, we aimed to identify the nerves affected, duration of symptoms (transient vs. persistent), and clinical predictors of CNI. METHODS: We identified all patients undergoing CEA in the Vascular Study Group of New England (VSGNE) between 2003 and 2011. Surgeon-observed CNI rate was determined at discharge (postoperative CNI) and at follow-up to determine persistent CNI (CNIs that persisted at routine follow-up visit). Hierarchical multivariable model controlling for surgeon and hospital was used to assess independent predictors for postoperative CNI. RESULTS: A total of 6,878 patients (33.8% symptomatic) were included for analyses. CNI rate at discharge was 5.6% (n = 382). Sixty patients (0.7%) had more than one nerve affected. The hypoglossal nerve was most frequently involved (n = 185, 2.7%), followed by the facial (n = 128, 1.9%), the vagus (n = 49, 0.7%), and the glossopharyngeal (n = 33, 0.5%) nerve. The vast majority of these CNIs were transient; only 47 patients (0.7%) had a persistent CNI at their follow-up visit (median 10.0 months, range 0.3-15.6 months). Patients with perioperative stroke (0.9%, n = 64) had significantly higher risk of CNI (n = 15, CNI risk 23.4%, p < .01). Predictors for CNI were urgent procedures (OR 1.6, 95% CI 1.2-2.1, p < .01), immediate re-exploration after closure under the same anesthetic (OR 2.0, 95% CI 1.3-3.0, p < .01), and return to the operating room for a neurologic event or bleeding (OR 2.3, 95% CI 1.4-3.8, p < .01), but not redo CEA (OR 1.0, 95% CI 0.5-1.9, p = .90) or prior cervical radiation (OR 0.9, 95% CI 0.3-2.5, p = .80). CONCLUSIONS: As patients are currently selected in the VSGNE, persistent CNI after CEA is rare. While conditions of urgency and (sub)acute reintervention carried increased risk for postoperative CNI, a history of prior ipsilateral CEA or cervical radiation was not associated with increased CNI rate. PMID- 24157259 TI - Assessing the impact of neoadjuvant chemotherapy on the management of the breast and axilla in breast cancer. AB - BACKGROUND: Nodal status is a sensitive prognostic indicator in breast cancer. Axillary metastases may be an indication for neoadjuvant systemic therapy. The aims of this study were to compare pathologic response rates to neoadjuvant chemotherapy (NAC) in the breast and axilla across different molecular subtypes of breast cancer and to compare the predictive value of axillary assessment before and after chemotherapy in determining final nodal status in this cohort of patients. PATIENTS AND METHODS: The cohort comprised patients undergoing NAC from 2003 to November 2012. Data regarding patient and tumor characteristics, management, and outcomes were obtained from a prospectively maintained database and analyzed using PASW Statistics, version 18 (SPSS Inc, Chicago, IL). RESULTS: Two hundred two cancers were identified in 196 patients. One hundred thirty-one (65%) diagnostic axillary procedures were performed, 105 (80%) before NAC, of which 93 (89%) were positive. In 28 (30%), downstaging was noted before NAC. Human epidermal growth factor receptor 2 (HER2) subtypes had the highest rate of complete pathologic response (n = 11 [61%]) and negative axillary clearance (AXCn) (n = 11 [69%]). Of 177 AXCns, 68 (38%) were negative before NAC. CONCLUSION: AXCn in patients undergoing NAC remains controversial. HER2 subtypes are less likely to have axillary involvement after NAC and may demand different management. PMID- 24157260 TI - Effects of a health care provider intervention in reduction of sexual risk and related outcomes in economically marginal communities in Mumbai, India. AB - BACKGROUND: The present study assessed the effectiveness of a brief narrative intervention implemented by trained biomedical and Ayurveda, Yoga, Unani, Siddha, Homeopathy (AYUSH) providers from three low-income communities in Mumbai, India. METHODS: A quasi-experimental research design compared attitudinal and behavioural changes among a cohort of 554 patients presenting gupt rog ('secret sexual illnesses') to biomedical and AYUSH providers who were trained in the narrative intervention model (NIM; referred to as 'narrative prevention counseling' in the intervention manual) with those providing standard care (untrained in NIM). Data were analysed using multivariate and longitudinal statistical models. RESULTS: Patients who received treatment for gupt rog from trained providers reported receiving a significantly higher number of services than those receiving services from untrained providers (mean 8.9 vs 7.6 services, respectively; P<0.001). In addition, a higher number of patients seeing the trained providers no longer had gupt rog problems than those seeing untrained providers (42% vs 25%, respectively; P<0.001). Patient-reported sex with a partner who was not the wife decreased significantly from baseline to follow-up for the entire sample but was significantly greater among patients receiving treatment from trained AYUSH providers (from 27% at baseline to 2% at follow up) compared with untrained providers (from 18% at baseline to 5% at follow up; P<0.001). CONCLUSIONS: The results support the effectiveness of brief narrative intervention in primary care settings for reducing sexual risk and associated vulnerabilities among married men. PMID- 24157262 TI - Analysis of a silkworm F1 hybrid with yellow cocoon generated by crossing two white-cocoon strains: further evidences for the roles of Cameo2 and CBP in formation of yellow cocoon. AB - In this report, we examined the gene expression related to carotenoid transport for a silkworm F1 hybrid with yellow cocoon generated by crossing two white cocoon strains, Qiubai and 12-260. Our results showed that, in Qiubai, Cameo2, a transmembrane protein gene belonging to the CD36 family genes, was expressed normally in the silk gland, but no intact carotenoid-binding protein (CBP) mRNA (only the truncated CBP mRNA) was detected in the midgut. In 12-260, we detected the intact CBP mRNA expression in the midgut, but no Cameo2 expression in the silk gland. Regarding the F1 hybrid from crossing Qiubai and 12-260, both Cameo2 and intact CBP mRNA expressed normally in the silk gland and midgut. HPLC detection confirmed that in the F1 hybrid the carotenoids could be absorbed from dietary mulberry leaves through the midgut and transferred to silk gland via the hemolymph, which eventually colored cocoons into yellow. We also identified four CBP mRNA isoforms expressed in the midgut of the F1 hybrid, subsequently named as variants 5-8. Our results provide further evidences for the roles of Cameo2 and CBP in the formation of yellow cocoon of silkworm. PMID- 24157261 TI - ALG1-CDG: a new case with early fatal outcome. AB - Congenital disorders of glycosylation (CDG) are a growing group of inherited metabolic disorders where enzymatic defects in the formation or processing of glycolipids and/or glycoproteins lead to variety of different diseases. The deficiency of GDP-Man:GlcNAc2-PP-dolichol mannosyltransferase, encoded by the human ortholog of ALG1 from yeast, is known as ALG1-CDG (CDG-Ik). The phenotypical, molecular and biochemical analysis of a severely affected ALG1-CDG patient is the focus of this paper. The patient's main symptoms were feeding problems and diarrhea, profound hypoproteinemia with massive ascites, muscular hypertonia, seizures refractory to treatment, recurrent episodes of apnoea, cardiac and hepatic involvement and coagulation anomalies. Compound heterozygosity for the mutations c.1145T>C (M382T) and c.1312C>T (R438W) was detected in the patient's ALG1-coding sequence. In contrast to a previously reported speculation on R438W we confirmed both mutations as disease-causing in ALG1-CDG. PMID- 24157263 TI - Polymorphisms of transcription factor-7-like 2 (TCF7L2) gene in Tunisian women with polycystic ovary syndrome (PCOS). AB - BACKGROUND AND AIMS: Polycystic ovary syndrome (PCOS) is a common endocrine disorder that affects women in their child-bearing age, and is often associated with insulin resistance and type 2 diabetes (T2DM). Given the overlap between PCOS and T2DM, we investigated the association of transcription factor-7-like 2 (TCF7L2) variants rs4506565, rs7903146, rs12243326, and rs12255372 with the susceptibility to PCOS. SUBJECTS AND METHODS: Study subjects comprised 119 Tunisian women with PCOS (mean age 29.8+/-4.7years), and 150 control women (mean age 30.6+/-5.9years). TCF7L2 genotyping was done by the allelic discrimination/real-time PCR method. RESULTS: Minor allele frequencies (MAFs) of rs4506565 (P=0.61), rs7903146 (P=0.68), rs12243326 (P=0.56), and rs12255372 (P=0.60) were comparable between PCOS cases and control subjects. As the four tested TCF7L2 variants were in linkage disequilibrium, 4-locus (rs4506565, rs7903146, rs12243326, rs12255372) haplotype analysis demonstrated that haplotype 2111 was initially negatively associated with PCOS [P=0.035; OR (95% CI)=0.13 (0.02-0.85)], which was later lost upon correcting for multiple comparisons [Pc=0.248]. CONCLUSION: Our data suggest that there is weak or no contribution of TCF7L2 gene polymorphism to PCOS in Tunisian women. Further studies with larger samples are necessary to confirm this observation. PMID- 24157264 TI - The complete sequence of the mitochondrial genome of the African Penguin (Spheniscus demersus). AB - The complete mitochondrial genome of the African Penguin (Spheniscus demersus) was sequenced. The molecule was sequenced via next generation sequencing and primer walking. The size of the genome is 17,346 bp in length. Comparison with the mitochondrial DNA of two other penguin genomes that have so far been reported was conducted namely; Little blue penguin (Eudyptula minor) and the Rockhopper penguin (Eudyptes chrysocome). This analysis made it possible to identify common penguin mitochondrial DNA characteristics. The S. demersus mtDNA genome is very similar, both in composition and length to both the E. chrysocome and E. minor genomes. The gene content of the African penguin mitochondrial genome is typical of vertebrates and all three penguin species have the standard gene order originally identified in the chicken. The control region for S. demersus is located between tRNA-Glu and tRNA-Phe and all three species of penguins contain two sets of similar repeats with varying copy numbers towards the 3' end of the control region, accounting for the size variance. This is the first report of the complete nucleotide sequence for the mitochondrial genome of the African penguin, S. demersus. These results can be subsequently used to provide information for penguin phylogenetic studies and insights into the evolution of genomes. PMID- 24157265 TI - Sticking our neck out: is magnetic resonance imaging needed to clear an obtunded patient's cervical spine? AB - BACKGROUND: Evaluating the cervical spine in the obtunded trauma patient is a subject fraught with controversy. Some authors assert that a negative computed tomography (CT) scan is sufficient. Others argue that CT alone misses occult unstable injuries, and magnetic resonance imaging (MRI) will alter treatment. This study examines the data in an urban, county trauma center to determine if a negative cervical spine CT scan is sufficient to clear the obtunded trauma patient. METHODS: Records of all consecutive patients admitted to a level 1 trauma center from January 2000 to December 2011 were retrospectively analyzed. Patients directly admitted to the intensive care unit with a Glasgow Coma Scale score <=13, contemporaneous CT and MRI, and a negative CT reading were included. The results of the cervical spine MRI were analyzed. RESULTS: A total of 309 patients had both CT and MRI, 107 (35%) of whom had negative CTs. Mean time between CT and MRI was 16 d. Of those patients, seven (7%) had positive acute traumatic findings on MRI. Findings included ligamentous injury, subluxation, and fracture. However, only two of these patients required surgical intervention. None had unstable injuries. CONCLUSIONS: In the obtunded trauma patient with a negative cervical spine CT, obtaining an MRI does not appear to significantly alter management, and no unstable injuries were missed on CT scan. This should be taken into consideration given the current efforts at cost-containment in the health care system. It is one of the larger studies published to date. PMID- 24157266 TI - Frequency dependence of excitation-contraction of multicellular smooth muscle preparations: the relevance to bipolar electrosurgery. AB - BACKGROUND: Bipolar electrosurgical tissue welding uses forceps-like electrodes for grasping the tissues and delivering high-frequency electric current (HFEC) to produce local heat, desiccation, and protein denaturation, resulting in the fusion of the contacting tissues. Although in this technique no electric current is flowing through the whole body to cause electric injury, depending on the frequency of applied energy, it may produce local excitation of intramural nerves, which can propagate beyond the surgical site potentially causing harmful effects. MATERIALS AND METHODS: The effects of varying frequency of HFEC on tissue excitability in bipolar electrosurgical modality were studied in vitro using electric field stimulation (EFS) method on multicellular smooth muscle strips of rat vas deferens. Contractile response to 5-s-long sine wave EFS train was taken as the measure of excitation of intramural nerves. RESULTS: EFS-induced contraction consisted of phasic and tonic components. The amplitude of both components decreased with increasing frequency, with tonic component disappearing at about 10 kHz and phasic component at about 50 kHz. Because components of EFS induced contraction depend on different neurotransmitters, this indicates that various neurotransmitter systems are characterized by distinct frequency dependence, but above 50 kHz they all become inactivated. Bipolar electrosurgical sealing of porcine gut showed no difference in the structure of seal area at HFEC of 67 and 533 kHz. CONCLUSIONS: EFS frequency of 50 kHz represents the upper limit for excitation. HFEC above 50 kHz is safe to use for bipolar electrosurgical tissue welding without concerns of excitation propagating beyond the surgical site. PMID- 24157267 TI - Role of CC chemokine receptor 1 and two of its ligands in human dengue infection. Three approaches under the Cuban situation. AB - Any of the four dengue serotypes can cause a severe disease, partly due to systemic inflammation orchestrated by mediators like cytokines and chemokines. We addressed the role of CCR1 and its ligands CCL3/MIP-1alpha and CCL5/RANTES in dengue infection using three different approaches: an ex vivo model exploring memory immune response in subjects with a well characterized dengue immune background, an in vivo study in patients with primary or secondary dengue infection, and an approach in fatal dengue. CCR1 and CCL3/MIP-1alpha gene expression showed differences after homotypic and heterotypic challenge according to dengue immune background of subjects, in correspondence with previous observations in Cuban dengue outbreaks. CCL5/RANTES gene expression was higher after homotypic challenge. CCR1 and CCL3/MIP-1alpha gene expression was higher in patients with secondary infection during critical days of the dengue disease, while the increase in RANTES expression started earlier than the observed for CCR1 and CCL3/MIP-1alpha. CCR1 and CCL3/MIP-1alpha gene expression was as high in brain as in spleen tissue from necropsy. Our results confirm the strong influence of previous immunity in subsequent dengue infections, and confer a possible pathogenic role to CCR1 and CCL3/MIP-1alpha in dengue disease and a possible protective role for CCL5/RANTES, probably through CCR5 interaction. PMID- 24157269 TI - Plastic litter in the sea. AB - On June 2013 a workshop at the University of Siena (Italy) was organized to review current knowledge and to clarify what is known, and what remains to be investigated, concerning plastic litter in the sea. The content of the workshop was designed to contribute further to the European Marine Strategy Framework Directive (MSFD) following an inaugural workshop in 2012. Here we report a number of statements relevant to policymakers and scientists that was overwhelming agreement from the participants. Many might view this as already providing sufficient grounds for policy action. At the very least, this early warning of the problems that lie ahead should be taken seriously, and serve as a stimulus for further research. PMID- 24157268 TI - Effect of seasonality on oxidative stress responses and metal accumulation in soft tissues of Aulacomya atra, a mussel from the South Atlantic Patagonian coast. AB - This study investigated the effects of pollution and its interaction with temperature on the oxidative status of the ribbed mussel Aulacomya atra in the southern Atlantic Patagonian coast. Animals were collected from four sites with different degree and type of human activity impact, during the summer and winter of 2011. Seawater chromium, copper, manganese, nickel and zinc concentrations were measured, as well as metal accumulation, lipid peroxidation, protein oxidation, reduced glutathione levels, and enzymatic activities of superoxide dismutase and glutathione-S-transferase in gills and digestive glands. Metal bioaccumulation and oxidative stress responses in both tissues were generally higher in mussels from harbor areas. Water temperature had a remarkable effect on gill SOD activity and protein oxidation during winter in mussels from all locations. Methodologically, we conclude that measuring both metal bioaccumulation and oxidative stress responses allowed for a more accurate assessment of the biological effects of metal present in seawater. PMID- 24157271 TI - Hemoglobin level and transfusions in patients on maintenance dialysis: where the rubber meets the road. PMID- 24157272 TI - Past mortality risk and survival: living well and growing up. PMID- 24157270 TI - In vitro moxifloxacin drug interaction with chemotherapeutics: implications for retinoblastoma management. AB - Retinoblastoma (RB) is a common malignant intraocular tumor primarily affecting children. Multidrug resistance (MDR) proteins (P-gp and MRPs) mediated chemoresistance have been considered as a major cause of treatment failure in treatment of RB. Ocular cells have shown good tolerability against moxifloxacin (MFX). Hence, the aim of present study was to investigate the effect of moxifloxacin on the functionality of MDR proteins. Furthermore, we have also examined an interaction of MFX with anticancer agents (Topotecan, etoposide and vinblastine) for RB treatment. For interaction of MFX with efflux transporter, model cell lines transfected with the efflux transporters (MDCK-MDR1 and MDCK MRP2) were used to perform uptake and bi-directional transport experiments. Modulation of anticancer induced cell cytotoxicity, pro-inflammatory cytokines (IL-6 and IL-8) release and caspase-3 enzyme activity in presence of MFX was also evaluated. Result indicates that MFX is a substrate of both MDR1 and MRP2 efflux transporters. Furthermore elevation of anticancer uptake and bi-directional transport, reduction in IC50 cytotoxic value and modulation of antiproliferative and cytokines release in presence of MFX by anticancer agents was observed. Our results demonstrate that MFX may not only modulate the permeability of anticancer agents at efflux sites but it may also potentiate antiproliferative activity of anticancer agents in retinoblastoma cells. This study may be further extended to explore in vivo outcome of this finding. PMID- 24157273 TI - In reply to 'The other side of the central vein stenosis story'. PMID- 24157274 TI - Dialysate calcium concentration and mineral metabolism in long and long-frequent hemodialysis. PMID- 24157275 TI - The other side of the central vein stenosis story. PMID- 24157276 TI - In reply to 'Dialysate calcium concentration and mineral metabolism in long and long-frequent hemodialysis'. PMID- 24157277 TI - To whom shall I tell my grief? PMID- 24157278 TI - Quiz page November 2013: an unusual cause of nephrotic syndrome: minimal change disease (MCD). PMID- 24157279 TI - Suppression of immunoglobulin production in human peripheral blood mononuclear cells by monocytes via secretion of heavy-chain ferritin. AB - In vitro antigen stimulation of peripheral blood mononuclear cells (PBMCs) does not induce immunoglobulin (Ig) production. However, pretreatment of PBMCs with l leucyl-l-leucine methyl ester (LLME) prior to in vitro stimulation removes the suppression of Ig production. In the present study, we attempted to identify the target cells of LLME and determine the mechanisms by which Ig production in PBMCs is suppressed. We found that CD14(+) monocytes are involved in the suppression of Ig production in PBMCs. Furthermore, we confirmed that heavy-chain ferritin derived from CD14(+) monocytes suppresses Ig production in PBMCs, possibly through iron sequestration. PMID- 24157280 TI - Peripheral blood natural killer cells activation status determined by CD69 upregulation predicts implantation outcome in IVF. AB - PROBLEM: NK lymphocytes play critical yet poorly defined role in implantation and during development in early pregnancy. METHODS OF STUDY: Recently, we showed that the proportion of NK that expressed CD69+ after incubation with K562 (CD69(stim)) cells reflected the NK population excitation potential. In the present study, we investigate the significance of NK activation levels in predicting embryo implantation. RESULTS: A qualitative analysis of values distribution in two groups showed that 25/33 (75.8%) women who became pregnant had CD69(stim) levels that were >30 but <60% (conditionally normal zone). In contrast, CD69(stim) levels in patients who failed to become pregnant were either elevated, as in 10/51 (19.6%), or reduced, as in 20/51 (39.2%) of the patients. Accentuated CD69(stim) levels were predictive for implantation failure, extremely significant for decreased (OR 6.9, p=0.0004) and not quite significant for increased CD69(stim) levels (OR 3.9, p=0.062). Accordingly, conditionally normal CD69(stim) levels were favourable for implantation (OR 4.46, p=0.0032). CONCLUSION: We confirm that actual peripheral blood natural killer cells activation status have an influence on embryo implantation. We showed that exactly normal NK cell activity predicting successful implantation. PMID- 24157281 TI - Ovarian masses in children and adolescents - an analysis of 521 clinical cases. AB - OBJECTIVE: To analyze the clinical characteristics of ovarian masses in children and adolescents. MATERIALS AND METHODS: We performed a retrospective analysis of patients less than 20 years of age who were treated at the Obstetrics and Gynecology Hospital of Fudan University between March 2003 and January 2012. Medical records were reviewed for age at operation, including presentation of symptoms and signs; the levels of tumor markers; imaging examinations; pathologic findings; the size of masses; treatment; and outcome. Data management and descriptive analyses were performed using SPSS 16.0. RESULTS: A total of 521 patients were included in this study. Among them, 92 had non-neoplastic lesions, 382 had benign neoplasms, and 47 had malignant tumors. The mean age of the patients was 16.3 +/- 2.2 years. The primary presenting symptoms and signs were abdominal pain (39.5%), menstrual disorder (31.1%), abdominal swelling (5.4%), and an enlarged abdominal perimeter (3.3%). Malignant tumors tended to be larger than benign neoplasms (17.3 +/- 8.6 cm vs 9.0 +/- 5.7 cm; P = .000). There was no age difference between patients with benign neoplasms (16.3 +/- 2.1 y) and those with malignant tumors (15.7 +/- 2.5 y). The operations included salpingo oophorectomy, ovarian cystectomy, and oophorectomy. Two patients with malignant tumors had bilateral salpingo-oophorectomy, and 2 patients who had tumor metastasis underwent a total abdominal hysterectomy and bilateral salpingo oophorectomy. Forty-one cases of malignant tumors received postoperative chemotherapy. CONCLUSIONS: Germ cell tumors are the most common malignancy, and mature teratomas are the most common benign neoplasms in children and adolescents. Abdominal pain and menstrual disorder are the main reasons for doctor's visit. Although examination by ultrasound is the preferred auxiliary in the diagnosis of ovarian pathology, it could not distinguish between benign and malignant tumors. However, tumor size and tumor markers are helpful to identify the properties of masses. Surgery is usually better for treatment, and it is preferable to attempt conservative, fertility-sparing surgery in adolescents. Postoperative chemotherapy is necessary for malignant tumors. PMID- 24157282 TI - Phenolic glycosides from Ficus tikoua and their cytotoxic activities. AB - Four new phenolic glycosides, named 2-ethylene-3,5,6-trimethyl-4-phenol-1-O-beta d-xylopyranosyl-(1->6)-beta-d-glucopyranoside (1), 3-methoxy-4-O-beta-d apiofuranosyl-(1->2)-beta-d-glucopyranosylpropiophenone (2), 3-hydroxy-1-(4-O beta-d-glucopyranosyl-3-methoxyphenyl)propan-1-one (3) and 4-hydroxy-3,5-bis(3' methyl-2-butenyl)benzoic acid-O-beta-d-glucopyranoside (4), were isolated from the ethanol extract of Ficus tikoua, together with six known compounds: 3,4,5 trimethoxyphenol-1-O-beta-d-apiofuranosyl-(1->6)-beta-d-glucopyranoside (5), 3,4,5-trimethoxyphenol-1-O-beta-d-glucopyranoside (6), 3-methoxy-4-O-beta-d apiofuranosyl-(1->6)-beta-d-glucopyranosylpropiophenone (7), baihuaqianhuoside (8), 3,5-dimethoxy-4-hydroxybenzoic acid-O-beta-d-glucopyranoside (9) and 2 methoxy-4-allylphenyl-1-O-beta-d-apiofuranosyl-(1->6)-beta-d-glucopyranoside (10). The structures of the four new compounds were elucidated by chemical methods and MS and IR, as well as 1D and 2D NMR analyses. The cytotoxicities of the 10 compounds against HeLa, K562, HL60 and HepG2 cell lines were assessed. PMID- 24157283 TI - Arsenic induces reactive oxygen species-caused neuronal cell apoptosis through JNK/ERK-mediated mitochondria-dependent and GRP 78/CHOP-regulated pathways. AB - Arsenic (As), a well-known high toxic metal, is an important environmental and industrial contaminant, and it induces oxidative stress, which causes many adverse health effects and diseases in humans, particularly in inorganic As (iAs) more harmful than organic As. Recently, epidemiological studies have suggested a possible relationship between iAs exposure and neurodegenerative disease development. However, the toxicological effects and underlying mechanisms of iAs induced neuronal cell injuries are mostly unknown. The present study demonstrated that iAs significantly decreased cell viability and induced apoptosis in Neuro-2a cells. iAs also increased oxidative stress damage (production of malondialdehyde (MDA) and ROS, and reduction of Nrf2 and thioredoxin protein expression) and induced several features of mitochondria-dependent apoptotic signals, including: mitochondrial dysfunction, the activations of PARP and caspase cascades, and the increase in caspase-3 activity. Pretreatment with the antioxidant N acetylcysteine (NAC) effectively reversed these iAs-induced responses. iAs also increased the phosphorylation of JNK and ERK1/2, but did not that p38-MAPK, in treated Neuro-2a cells. NAC and the specific JNK inhibitor (SP600125) and ERK1/2 inhibitor (PD98059) abrogated iAs-induced cell cytotoxicity, caspase-3/-7 activity, and JNK and ERK1/2 activation. Additionally, exposure of Neuro-2a cells to iAs triggered endoplasmic reticulum (ER) stress identified through several key molecules (GRP 78, CHOP, XBP-1, and caspase-12), which was prevented by NAC. Transfection with GRP 78- and CHOP-specific si-RNA dramatically suppressed GRP 78 and CHOP expression, respectively, and attenuated the activations of caspase-12, 7, and -3 in iAs-exposed cells. Therefore, these results indicate that iAs induces ROS causing neuronal cell death via both JNK/ERK-mediated mitochondria dependent and GRP 78/CHOP-triggered apoptosis pathways. PMID- 24157285 TI - Global bionetworks and challenges in regulating autologous adult stem cells. PMID- 24157284 TI - Atrial fibrillation: food for thought in 2013. PMID- 24157286 TI - Medical residency training and hospital care during and after a natural disaster: Hurricane Sandy and its effects. PMID- 24157287 TI - The innocent bystander: papillary fibroelastoma. PMID- 24157288 TI - Does clinical decision support reduce unwarranted variation in yield of CT pulmonary angiogram? AB - OBJECTIVE: The study objective was to determine whether previously documented effects of clinical decision support on computed tomography for pulmonary embolism in the emergency department (ie, decreased use and increased yield) are due to a decrease in unwarranted variation. We evaluated clinical decision support effect on intra- and inter-physician variability in the yield of pulmonary embolism computed tomography (PE-CT) in this setting. METHODS: The study was performed in an academic adult medical center emergency department with 60,000 annual visits. We enrolled all patients who had PE-CT performed 18 months pre- and post-clinical decision support implementation. Intra- and inter physician variability in yield (% PE-CT positive for acute pulmonary embolism) were assessed. Yield variability was measured using logistic regression accounting for patient characteristics. RESULTS: A total of 1542 PE-CT scans were performed before clinical decision support, and 1349 PE-CT scans were performed after clinical decision support. Use of PE-CT decreased from 26.5 to 24.3 computed tomography scans/1000 patient visits after clinical decision support (P < .02); yield increased from 9.2% to 12.6% (P < .01). Crude inter-physician variability in yield ranged from 2.6% to 20.5% before clinical decision support and from 0% to 38.1% after clinical decision support. After controlling for patient characteristics, the post-clinical decision support period showed significant inter-physician variability (P < .04). Intra-physician variability was significant in 3 of the 25 physicians (P < .04), all with increased yield post-clinical decision support. CONCLUSIONS: Overall PE-CT yield increased after clinical decision support implementation despite significant heterogeneity among physicians. Increased inter-physician variability in yield after clinical decision support was not explained by patient characteristics alone and may be due to variable physician acceptance of clinical decision support. Clinical decision support alone is unlikely to eliminate unwarranted variability, and additional strategies and interventions may be needed to help optimize acceptance of clinical decision support to maximize returns on national investments in health information technology. PMID- 24157289 TI - Increased risk of acute myocardial infarction in systemic sclerosis: a nationwide population-based study. AB - PURPOSE: Systemic sclerosis is a life-threatening autoimmune disease characterized by vasculopathy, which results in myocardial involvement in an extremely high percentage of patients. Nevertheless, there have been no large scale epidemiological studies about the risk of acute myocardial infarction in patients with systemic sclerosis. The aims of this study were to evaluate the hazard ratio (HR) and risk factors of acute myocardial infarction in patients with systemic sclerosis, as well as to compare the risks of acute myocardial infarction among systemic sclerosis patients taking different immunosuppressors. METHODS: The study cohort included 1344 patients with systemic sclerosis and 13,440 (1:10) age-, sex-, and comorbidity-matched controls during the period between 1997 and 2006, from the National Health Insurance Research Database. We compared the risk of acute myocardial infarction between patients with systemic sclerosis and controls and calculated the adjusted HRs for acute myocardial infarction in systemic sclerosis patients taking immunosuppressors and not taking immunosuppressors. RESULTS: The incidence rates of acute myocardial infarction were 535 and 313 cases per 100,000 person-years for systemic sclerosis cohort and reference cohort, respectively (P <.001, unadjusted). After adjusting for age, sex, and underlying medical diseases on Cox proportional hazards model, systemic sclerosis was found to be an independent risk factor for acute myocardial infarction (HR 2.45). Other risk factors included hypertension (HR 2.08) and diabetes (HR 2.14). The multivariate adjusted HR for acute myocardial infarction did not decrease among the systemic sclerosis patients taking systemic steroids, penicillamine, cyclophosphamide, azathioprine, methotrexate, or cyclosporine. CONCLUSION: Systemic sclerosis is independently associated with an increased risk of acute myocardial infarction. Immunosuppressors do not lower the risk of acute myocardial infarction in our study. PMID- 24157290 TI - Testicular choriocarcinoma presenting as hyperthyroidism. PMID- 24157291 TI - Bioresorbable vascular scaffolds in cardiac allograft vasculopathy: a new therapeutic option. PMID- 24157292 TI - Screening and brief intervention for opioid addiction in primary care is not evidence based. PMID- 24157293 TI - The reply. PMID- 24157294 TI - Comments on reducing the health consequences of opioid addiction. PMID- 24157295 TI - The reply. PMID- 24157296 TI - Observed mortality reduction in patients hospitalized with community-acquired pneumonia may well be confounded by disease severity. PMID- 24157297 TI - The reply. PMID- 24157298 TI - How much intravenous iron is utilized for erythropoiesis? PMID- 24157299 TI - The reply. PMID- 24157300 TI - Fifty, febrile, and fatigued: high ferritin as a clue in diagnosis. PMID- 24157301 TI - Therapeutic dilemma in unstable pulmonary embolism. PMID- 24157302 TI - The reply. PMID- 24157303 TI - The association between prior antibiotics and outcome. PMID- 24157304 TI - Uncommon complications of heparin-induced thrombocytopenia. PMID- 24157305 TI - Evans syndrome. PMID- 24157306 TI - Differential effect of p7 inhibitors on hepatitis C virus cell-to-cell transmission. AB - Inhibitors targeting the hepatitis C virus (HCV) encoded viroporin, p7 prevent virus release in vitro. HCV can transmit by cell-free particle infection of new target cells and via cell-to-cell dependent contact with limited exposure to the extracellular environment. The role of assembly inhibitors in preventing HCV transmission via these pathways has not been studied. We compared the efficacy of three published p7 inhibitors to inhibit cell-free and cell-to-cell transmission of two chimeric HCV strains encoding genotype 2 (GT2) or 5 (GT5) p7 using a recently developed single cycle co-culture assay. The inhibitors reduced the infectivity of extracellular GT2 and GT5 virus by 80-90% and GT2 virus cell-to cell transmission by 50%. However, all of the p7 inhibitors had minimal effect on GT5 cell contact dependent transmission. Screening a wider panel of diverse viral genotypes demonstrated that p7 viroporin inhibitors were significantly more effective at blocking cell-free virus than cell-to-cell transmission. These results suggest an altered assembly or trafficking of cell-to-cell transmitted compared to secreted virus. These observations have important implications for the validation, therapeutic design and testing of HCV assembly inhibitors. PMID- 24157307 TI - ATP-binding cassette transporter A1 R219K polymorphism and ischemic stroke risk in the Chinese population: a meta-analysis. AB - Recently, many studies have been focused on the association between the ATP binding cassette transporter A1 (ABCA1) gene R219K polymorphism and ischemic stroke (IS). However, the study results have been inconsistent, especially in the Chinese population. Therefore, we performed a meta-analysis to better clarify the association between the ABCA1 gene and IS. All of the relevant studies used in our meta-analysis were identified using PubMed, OVID, Cochrane Library, Chinese Wan Fang database, Chinese VIP database, China National Knowledge Infrastructure (CNKI), and China Biological Medicine Database (CBM) up to May 2013. Statistical analysis was conducted with STATA software version 11.0. Odds ratios with 95% confidence intervals were applied to evaluate the strength of the association between ABCA1 gene R219K polymorphism and IS. Heterogeneity was evaluated using the Q-test and I(2) statistic. The funnel plots, Begg's and Egger's regression tests were used to assess the publication bias. Our meta-analysis showed the dominant genetic model (OR=0.92, 95% CI: 0.88-0.96), the recessive genetic model (OR=0.73, 95% CI: 0.51-1.05), the homozygote genetic model (OR=0.64, 95% CI: 0.44 0.94), the heterozygote genetic model (OR=0.81, 95% CI: 0.69-0.95), and the allelic genetic model (OR=0.83, 95% CI: 0.69-0.99). For R219K in IS, there were significant associations with these genetic models, but not with the recessive genetic model. Our meta-analysis indicated that the ABCA1 gene R219K polymorphism might be associated with IS and the K allele might be a protective factor in the Chinese population. PMID- 24157308 TI - Acute leukoencephalopathy due to pyrimethamine. An insight into methotrexate neurotoxicity? AB - A unique case of pyrimethamine-related stroke-like leukoencephalopathy is described. The imputability of the drug is discussed as well as the similarities with the well-known methotrexate neurotoxicity. Owing to the same mode of action of both drugs by inhibition of the enzyme dihydrofolate reductase, this case is highly suggestive of the pathogenetic role of methylation pathway blockade on myelin synthesis resulting in delayed demyelination. This complication could be avoided by a concurrent folinic acid supplementation. PMID- 24157309 TI - Early postnatal repeated maternal deprivation causes a transient increase in OMpg and BDNF in rat cerebellum suggesting precocious myelination. AB - Repetitive maternal deprivation (MD) of neonatal rats during early life is known as one of the strongest stressors to pre-weaned animals. There is increasing evidence that the cerebellum is involved in cognition and emotion. In the present study, we examined how neurotrophic factors and myelin-associated molecules and their receptors (NGF, BDNF, OMgp, TrkA, TrkB, p75 NTR, and NgR) in the cerebellum are affected by early postnatal maternal separation. Rat pups were separated from their mothers for 3h/day during postnatal days (PND) 10-15. At PND 16 and 30, the levels of mRNA and protein in the cerebellum were determined using real-time PCR and Western blot analysis. Cerebellar mRNA and protein levels of BDNF, TrkB, and OMgp were significantly increased in MD rats at PND 16. However, by PND 30 these variables normalized to control levels. In contrast, the levels of mRNA and protein for NGF, TrkA, p75 NTR, and NgR were unchanged at both ages examined. Transient enhancement of neurotrophic system and myelin-associated molecule expression may cause interference of normal development of the cerebellum such as precocious myelination, which may lead to functional and cognitive deficits later in life. PMID- 24157310 TI - Stenting below-the-knee bifurcations with dedicated bifurcation stent BiOSS Lim - first in man case report. AB - The best treatment strategy for below the knee bifurcation disease is not known. We present first two cases with successful implantation of dedicated coronary bifurcation sirolimus eluting stent BiOSS Lim (Balton, Poland) in complex bifurcation and trifurcation lesions of tibioperoneal trunk. Both implantations were uncomplicated with sustained short-term result at 30-day control Duplex ultrasound and remarkable clinical improvement. Our report demonstrates feasibility and short-term effectiveness of implantation of dedicated coronary bifurcation stent in below-the-knee bi- and tri-furcations. PMID- 24157312 TI - Ocelot catheter for the recanalization of lower extremity arterial chronic total occlusion. AB - Peripheral arterial disease (PAD) is a growing clinical condition affecting more than 10 million patients in the United States and it is responsible for more than 120,000 amputations annually. The presence of chronic total occlusions (CTO) increases the complexity of endovascular procedures and open surgery may often be the preferred approach. Despite the optimization of the CTO devices and technique, percutaneous CTO revascularization remains a challenging procedure even for experienced operators with important complication rates. The Ocelot(TM) system is a novel CTO device to use real-time optical coherence tomography (OCT) imaging guidance for the recanalization of peripheral CTOs. We review the mechanism of the Ocelot system, the initial results from the multi-center Connect II trial and two cases of Ocelot-assisted CTO recanalization. PMID- 24157311 TI - First- versus second-generation drug-eluting stents for the treatment of coronary bifurcations. AB - BACKGROUND: Randomized controlled trials have demonstrated that second-generation drug-eluting stents (DESs) for the treatment of obstructive coronary artery disease are associated with comparable, if not improved, clinical outcomes as compared to those of their first-generation counterparts. The aim of this study was to compare the long-term clinical outcomes associated with first- versus second-generation DESs for the treatment of coronary bifurcation lesions. METHODS AND MATERIALS: This was a retrospective study of consecutive de novo bifurcation lesions, excluding those at the left main, treated with either second-generation DES (everolimus-eluting or resolute zotarolimus-eluting stents) between October 2006 and October 2011 (199 bifurcation lesions in 192 patients) or first generation DES (sirolimus-eluting or paclitaxel-eluting stents) between April 2002 and December 2005 (289 bifurcation lesions in 273 patients). RESULTS: Second generation DES use in this setting was associated with less major adverse cardiac events (MACE) (23.1% vs. 14.4%, p=0.02) as well as lower target vessel revascularization (TVR) rates (15.5% vs. 8.3%, p=0.01) at 2-year follow-up. Target lesion revascularization, both per patient (12.6% vs. 7.4%, p=0.02) and per bifurcation (11.8% vs. 7.0%, p=0.03), was also improved with second generation DES over the same follow-up period. Propensity-score adjusted analysis suggested that second-generation DES was associated with a lower incidence of MACE (HR, 0.53; 95% CI, 0.33-0.85; p=0.01) and TVR (HR, 0.44; 95% CI, 0.24-0.83; p=0.01). CONCLUSIONS: Our results suggest that the use of second-generation DES for the treatment of bifurcation lesions is associated with better clinical outcomes as compared to first-generation DES, largely due to a lower need for repeat revascularization. PMID- 24157313 TI - The combined effects of size and surface chemistry on the accumulation of boronic acid-rich protein nanoparticles in tumors. AB - The high drug concentration and long-acting time within tumor tissues are a key challenge in cancer treatment. Here we prepare the boronic acid-rich bovine serum albumin nanoparticles with the size of 70 nm, 110 nm and 150 nm, and subsequently decorate particle surface with polyethyleneimine-polyethylene glycol copolymer and cRGD peptide. We demonstrated that the drug accumulation and particle residence time at tumor site can be significantly improved by incorporating boronic acid group into the bovine serum albumin nanoparticles, optimizing particle size and decorating particle surface. We show that the size- and surface chemistry-driven dual-actions lead to the doxorubicin accumulation at tumor site go beyond 12% injected dose per gram of tumor through such delivery system, which is 16-fold higher than that of free doxorubicin injected. Based on the systemic, tissue and cell level analysis, we demonstrated that the incorporated boronic acid group into the nanoparticles enhances the recognition ability of nanoparticles to cancer cells, and prolongs the action time of nanoparticles at tumor sites since the boronic acid group can reversibly and rapidly react with sialic acid residues which are overexpressed in cancer cells. These features make that this drug delivery system not only has significantly superior ability in impeding tumor growth, but also induces distinct shrinkage and apoptosis of tumor. PMID- 24157314 TI - Integrated operation of the photorespiratory cycle and cytosolic metabolism in the modulation of primary nitrogen assimilation and export of organic N-transport compounds from leaves: a hypothesis. AB - Photorespiration is generally considered to be an essentially dissipative process, although it performs some protective and essential functions. A theoretical appraisal indicates that the loss of freshly assimilated CO2 due to photorespiration in well-watered plants may not be as high as generally believed. Even under moderately adverse conditions, these losses may not exceed 10%. The photorespiratory metabolism of the source leaves of well-watered and well nourished crop plants ought to be different from that of other leaves because the fluxes of the export of both carbohydrates and organic N-transport compounds in source leaves is quite high. With a heuristic approach that involved the dovetailing of certain metabolic steps with the photorespiratory cycle (PR cycle), a novel network is proposed to operate in the source-leaves of well watered and well-nourished plants. This network allows for the diversion of metabolites from their cyclic-routes in sizeable quantities. With the removal of considerable quantities of glycine and serine from the cyclic route, the number of RuBP oxygenation events would be several times those of the formation of hydroxypyruvate. Thus, to an extreme extent, photorespiratory metabolism would become open-ended and involve much less futile recycling of glycine and serine. Conversion of glyoxylate to glycine has been proposed to be a crucial step in the determination of the relative rates of the futile (cyclic) and anabolic (open ended) routes. Thus, in the source leaves of well-watered and well-nourished plants, the importance of the cyclic route is limited to the salvaging of photorespiratory intermediates for the regeneration of RuBP. The proposed network is resilient enough to coordinate the rates of the assimilation of carbon and nitrogen in accordance with the moisture and N-fertility statuses of the soil. PMID- 24157315 TI - Assessment of the enzymatic hydrolysis profile of cellulosic substrates based on reducing sugar release. AB - The activity profile of a 1:0.30 mixture of Celluclast 1.5L FG and Novozym 188 (Novozymes) was investigated using Whatman #1 filter paper (W1FP) as a single substrate for hydrolysis. The procedure was based on the ability of the enzymes to release total (RS(Tot)), insoluble (RS(Insol)) and soluble (RS(Sol)) reducing sugars from W1FP. RS(Insol) was used to estimate endoglucanase (EnG) activity whereas exoglucanases (ExG) were assessed by measuring RSSol in the presence of delta-gluconolactone. Finally, the beta-glucosidase (betaG) activity was derived from the difference between RS(Sol) measurements in the presence and absence of delta-gluconolactone. When this analytical procedure was applied to W1FP using 9.64 mg mL(-1) of the enzyme mixture, the relative contributions of EnG, ExG and betaG to the total cellulase activity were 63.28%, 12.02% and 24.70%, respectively. Also, this ratio changed with changes in the enzyme loading, giving a new insight into the synergy that exists among the enzymes. PMID- 24157316 TI - Grouped retinae and tapetal cups in some Teleostian fish: occurrence, structure, and function. AB - This article presents a summary and critical review of what is known about the 'grouped retina', a peculiar type of retinal organization in fish in which groups of photoreceptor cell inner and outer segments are arranged in spatially separated bundles. In most but not all cases, these bundles are embedded in light reflective cups that are formed by the retinal pigment epithelial cells. These cups constitute a specialized type of retinal tapetum (i.e., they are biological 'mirrors' that cause eye shine) and appear to be optimized for different purposes in different fishes. Generally, the large retinal pigment epithelial cells are filled with light-reflecting photonic crystals that consist of guanine, uric acid, or pteridine depending on species, and which ensure that the incoming light becomes directed onto the photoreceptor outer segments. This structural specialization has so far been found in representatives of 17 fish families; of note, not all members of a given family must possess a grouped retina, and the 17 families are not all closely related to each other. In many cases (e.g., in Osteoglossomorpha and Aulopiformes) the inner surface of the cup is formed by three to four layers of strikingly regularly shaped and spaced guanine platelets acting as an optical multilayer. It has been estimated that this provides an up to 10fold increase of the incident light intensity. In certain deep-sea fish (many Aulopiformes and the Polymixidae), small groups of rods are embedded in such 'parabolic mirrors'; most likely, this is an adaptation to the extremely low light intensities available in their habitat. Some of these fishes additionally possess similar tapetal cups that surround individual cones and, very likely, also serve as amplifiers of the weak incident light. In the Osteoglossomorpha, however, that inhabit the turbid water of rivers or streams, the structure of the cups is more complex and undergoes adaptation-dependent changes. At dim daylight, probably representing the usual environmental conditions of the fish, the outer segments of up to 30 cone cells are placed at the bottom of the cup where light intensity is maximized. Strikingly, however, a large number of rod receptor cells are positioned behind each mirroring cup. This peculiar arrangement (i) allows vision at deep red wavelenghts, (ii) matches the sensitivity of rod and cone photoreceptors, and (iii) facilitates the detection of low-contrast and color mixed stimuli, within the dim, turbid habitat. Thus, for these fish the grouped retina appears to aid in reliable and quick detection of large, fast moving, biologically relevant stimuli such as predators. Overall, the grouped retina appears as a peculiar type of general retinal specialization in a variety of fish species that is adaptive in particular habitats such as turbid freshwater but also the deep-sea. The authors were prompted to write this review by working on the retina of Gnathonemus petersii; the data resulting from this work (Landsberger et al., 2008; Kreying et al., 2012) are included in the present review. PMID- 24157318 TI - [Surgical eye whitening. Cosmesis versus safety]. PMID- 24157317 TI - The in vitro anthelmintic effects of plumbagin on newly excysted and 4-weeks-old juvenile parasites of Fasciola gigantica. AB - The effect of plumbagin (PB, 5-hydroxy-2-methyl-1,4-naphthoquinone) against newly excysted juveniles (NEJs) and 4-weeks-old immature parasites of Fasciola gigantica were compared with triclabendazole (TCZ). The anthelmintic efficacy of 1, 10 and 100MUg/ml of PB or TCZ following incubation in vitro for 1-24h was compared using a combination of relative motility (RM), survival index (SI) and larval migration inhibition (LMI) assays for parasite viability. The RM and SI values of the PB-treated group decreased at a more rapid rate than the TCZ treated group. For NEJs, the decreased RM values were first observed at 1h incubation with 1MUg/ml PB, and 90% of flukes were killed at 24h. In contrast, in TCZ-treated groups a 10-fold higher concentration of TCZ (10MUg/ml) resulted in only 9% dead parasites after 24h incubation. In 4-weeks-old juvenile parasites, PB reduced the RM value at 10MUg/ml with 100% of flukes dead after 3h, while TCZ decreased RM values at the concentration of 100MUg/ml but with only 5% of flukes killed at 24h. NEJs treated with PB exhibited 88%, 99% and 100% of LMIs at the concentrations of 1, 10 and 100MUg/ml, respectively. NEJs incubated with TCZ have an LMI of only 32% at the highest concentration of 100MUg/ml. Similarly PB had a significantly greater killing of immature 4weeks juvenile stages than TCZ at all concentrations; however, 4-weeks-old juvenile parasites were more resistant to killing by PB or TCZ at all concentrations when compared to NEJs. Further studies were carried out to investigate the alterations of the parasite tegument by scanning electron microscope (SEM). PB caused similar tegumental alterations in 4 weeks-old juveniles as those observed in TCZ treatment but with greater damage at comparative time points, comprising of swelling, blebbing and rupture of the tegument, loss of spines, and eventual erosion, lesion and desquamation of the total tegument. These data indicate that PB had a greater fasciolicidal effect against immature stages of F. gigantica parasites than TCZ and warrant further studies for use as a potential new anthelmintic against Fasciola infections. PMID- 24157319 TI - [Effect of posterior neodymium:YAG capsulotomy. Safety evaluation of macular foveal thickness, intraocular pressure and endothelial cell loss in pseudophakic patients with posterior capsule opacification]. AB - OBJECTIVE: To determine the effect of posterior capsulotomy on macular thickness, intraocular pressure and endothelial cell loss in pseudophakic patients with posterior capsule opacification using the other eye of every patient as a control. METHODS: An observational prospective study was conducted on 31 pseudophakic patients with posterior capsular opacification in one eye, using the other eye as a control. Patients did not suffer any other ocular pathology. All patients were treated by posterior capsular opacification with Nd:YAG capsulotomy, and followed up for a three-month period. The ocular examination included, best corrected visual acuity (BCVA), intraocular pressure (IOP), macular optical coherence tomography (OCT), and endothelial cell assessment (including densitometry, cell size and coefficient of variation, hexagonal cell percentage and pachymetry), which were determined in both eyes before treatment, and one week, one month and 3 months after capsulotomy. RESULTS: Generalized estimating equations (GEE) were used to assess the capsulotomy effect adjusted by corresponding baseline measurements and time. No association was found between capsulotomy and IOP (P=.597), macular thickness (P=.085) or ECA (densitometry (P=.422), average size of cells (P=.299), variation coefficient (P=.495), hexagonal cell percent (P=.093) and corneal pachymetry (P=.423). A significant increase of 0.15 Snellen units in BCVA was found during the 3-month follow-up period (P<.001). CONCLUSION: This study shows that after Nd:YAG capsulotomy, BCVA improves significantly without any IOP, OCT or ECA changes during the three-month follow-up. Nd:YAG capsulotomy is a safe procedure in pseudophakic patients without any other ocular pathology. PMID- 24157320 TI - [The effects of ocular hypotensive drugs on the cornea: an in vivo analysis with confocal microscopy]. AB - PURPOSE: To evaluate the effects of anti-glaucoma treatments containing benzalconium chloride (BAC) on the human cornea. METHODS: A prospective single masked cohort study was conducted on the 50 eyes of 50 patients. The inclusion criteria were: recently diagnosed glaucoma or ocular hypertension with previous treatment, or ophthalmologist-prescribed anti-glaucoma therapy, and oral consent to participate in the study. The patients were not randomised, as the ophthalmologist decided the best therapy according to clinical criteria. The patients were divided in 2 cohorts: one exposed to BAC (23 patients), and not exposed (27 patients). The mean follow-up period was 22 weeks (range 18-30). The change in cell density before and after therapy was measured in: basal layer epithelium, basal layer of limbal epithelium and endothelium. The change in stromal reflectivity and the number of nerve branches in sub-basal nerve plexus was also measured. BAC exposure was blinded to the main researcher. RESULTS: A greater increase in basal layer epithelium cell density was observed in BAC exposed cohort (P<.05). No significant differences were detected in the endothelium, limbal cell density, stromal reflectivity, or sub-basal nerve plexus. Age, sex, IOP, active ingredient or BAC concentration did not affect the direction or magnitude of the ocular surface alterations found. CONCLUSION: Chronic anti-glaucoma therapy induces changes in the corneal epithelium. Preservative free drops showed less disruption of the ocular surface by confocal microscopy analysis. Further studies should be conducted to evaluate the clinical impact of these histological findings. PMID- 24157321 TI - [Uveal melanoma: clinical characteristics, treatment and survival in a series of 500 patients]. AB - OBJECTIVE: To analyse the clinical features, treatment and survival of uveal melanoma patients diagnosed in a referral Intraocular Tumours Unit over a twenty year period. METHODOLOGY: A prospective study was performed including five hundred patients, diagnosed between January 1992 and December 2011. Clinical tumour characteristics and treatment were collected in a database in Microsoft@ Access@. The numeric variables were expressed as means of frequency and standard deviation, and the quantitative variables using frequency tables. RESULTS: The mean age of the sample was 62.19 years, with 51.2% females, and 64.2% presented with symptoms. The tumours were small in 31.12% of cases, and large in 23.09%, according to COMS criteria. Hazel green was the iris colour in 42.2% of the cases. The initial treatment was episcleral brachytherapy in 42.4% of the total. The overall mortality rate was 17% and 31.3%, and melanoma-related mortality rate was 11.6% and 14.8%, at 5 and 10 years, respectively. CONCLUSIONS: In the serie studied melanomas were more frequent in women, and a higher proportion of darker irides were observed than in other previous studies. Most of the tumours were diagnosed when they became symptomatic and in the early or medium stages, allowing conservative therapies to be used, with brachytherapy being the predominant treatment. The melanoma-related mortality appeared to be lower than previously data published. However, further studies are required on the factors influencing survival. PMID- 24157322 TI - [Morphometric changes of corneal endothelial cells in pseudoexfoliation syndrome and pseudoexfoliation glaucoma]. AB - OBJECTIVE: To evaluate the corneal endothelial morphometry and central corneal thickness (CCT) in pseudoexfoliative (PEX) eyes with and without glaucoma and to compare with normal eyes and eyes with primary open-angle glaucoma (POAG). METHOD: A total of 166 patients were included in this study: 36 eyes with pseudoexfoliation syndrome (PXS), 30 eyes with pseudoexfoliation glaucoma (PXG), 40 eyes with POAG, and 60 normal eyes. Corneal endothelial cell density (ECD), coefficient of variation (CV) in cell size, and percentage of hexagonal cells, were measured using a non-contact specular microscope, whereas CCT was measured with an ultrasonic pachymeter. RESULTS: ECD and percentage of hexagonal cells were lower in PEX groups and in the POAG group compared with normal eyes, while the CV in cell size was greater. There was a tendency for greater cell loss and morphological abnormalities of the corneal endothelial cells in PXG eyes compared to PXS eyes, when all pseudoexfoliative eyes were analyzed together. Changes in endothelial cells increased with age. There were no significant differences in mean CCT between the four groups. CONCLUSION: Endothelial cell density is significantly decreased, and pleomorphism and polymegathism of cells are increased in PEX eyes, particularly when intraocular pressure is high. PMID- 24157323 TI - [Heavy silicone oil (Densiron(r) 68) in proliferative vitreoretinopathy: 4 years of experience]. AB - METHOD: Prospective observational study including 10 patients (age range: 27-74 years) with recurrent retinal detachment (RD) and proliferative vitreoretinopathy (PVR) and 2.8 mean unsatisfactory previous surgeries. Densiron(r) was injected in all patients, with surgical retinectomy being required in 70% of them. Minimum follow-up time was 12 months. RESULTS: The mean length of time before Densiron(r) withdrawal was 4 months. Three patients (30%) presented with a new RD. The main complication detected was cataract development. No relationship was found between re-detachments and tamponade time, baseline disease or RD evolution time. Densiron(r) may be a good option in cases of recurrent RD in which previous treatment with scleral buckle, gas and/or 1,000/5,000 silicone oils has proven to be unsatisfactory. PMID- 24157324 TI - [Acute idiopathic blind spot enlargement syndrome associated with choroidal neovascularization]. AB - CLINICAL CASE: A 17 year old female consulting due to photopsia and a sudden loss of visual field in left eye (OS), with previous contralateral choroidal neovascularization. The examination suggested an acute idiopathic blind spot syndrome. The progress without treatment was favorable, with a reduction in the scotoma and without a worsening of her visual acuity. DISCUSSION: This case report is about an unusual and benign syndrome, typical of young women. Differential diagnosis must be made between the evanescent white dot syndrome and the acute zonal occult outer retinopathy. To our knowledge, this is the first published case associated with choroidal neovascularization, a fact that leads us to question its benignancy. PMID- 24157325 TI - [Neovascular membrane and pregnancy. Treatment with bevacizumab]. PMID- 24157326 TI - [Street vendor glasses]. PMID- 24157327 TI - [Atropos or The fates. Francisco de Goya y Lucientes]. PMID- 24157328 TI - [The photographic look of Edgar Degas]. PMID- 24157329 TI - Effect of aqueous extract of Tournefortia sarmentosa on the regulation of macrophage immune response. AB - Tournefortia sarmentosa, a Chinese herbal medicine, is considered an antioxidant or a detoxicant agent. Recent studies have shown that T. sarmentosa plays an important role in inhibiting low-density-lipoprotein oxidation and attenuating acetaminophen-induced hepatotoxicity. However, information regarding the signaling mechanism of T. sarmentosa-mediated immunoregulation is still limited. Here, we provide evidence that treating macrophages with T. sarmentosa extract leads to a decrease in reactive oxygen species (ROS) production and subsequently suppresses phosphorylated ERK1/2. In contrast, our data revealed that T. sarmentosa extract increases macrophage phagocytosis and adhesion. Also, T. sarmentosa extract activates phosphorylated p38 MAPK in macrophages. We further discovered that T. sarmentosa extract could increase the lipopolysaccharides stimulated IL-6, IL-8, and TNF-alpha production of macrophages. This result suggests that T. sarmentosa extract might enhance inflammation. Taken together, our results suggest that T. sarmentosa extract exerts dual functions on the macrophages: suppressing ROS within cells and enhancing inflammatory responses by improving phagocytic ability and proflammatory cytokine release. PMID- 24157330 TI - Curcumin inhibits agent-induced human neutrophil functions in vitro and lipopolysaccharide-induced neutrophilic infiltration in vivo. AB - Curcumin, extracted from the rhizome of Curcuma longa, is known to possess anti inflammatory activities. Despite the fact that neutrophils are key player cells in inflammation, the role of curcumin on neutrophil cell biology is not well documented and, in particular, how curcumin can alter primed neutrophils is unknown. In addition, the effect of curcumin on agent-induced neutrophilic inflammation is not well documented. Here, we demonstrated that curcumin inhibited formyl-methionyl-leucyl-phenylalanine (fMLP)- or lipopolysaccharide (LPS)-induced suppression of human neutrophil apoptosis. In addition, we found that curcumin reversed the ability of phorbol myristate acetate (PMA) to induce reactive oxygen species as assessed by flow cytometry using the CM-H2DCF-DA probe. Using an antibody array approach, curcumin was found to inhibit LPS induced cytokine production, including MIP-1alpha, MIP-1beta, IL-6, IL-8 (CXCL-8) and GRO-alpha. The inhibitory effect of curcumin on IL-8 production was confirmed by ELISA. Using both an electrophoretic mobility shift assay and a TransFactor p50 NF-kappaB ELISA, we demonstrated that curcumin inhibited LPS-induced NF kappaB activation. In vivo, using the murine air pouch model of acute inflammation, we demonstrated that intraperitoneal administration of curcumin inhibited LPS-induced neutrophilic infiltration in vivo. As assessed by a murine antibody array approach, curcumin was found to decrease the local production of several cytokines/chemokines induced by LPS, including, but not limit to, MIP 1alpha and MIP-1beta. We conclude that curcumin possesses potent modulatory activities on primed or agent-induced human neutrophils in vitro and that it possesses important anti-inflammatory activities in vivo by inhibiting LPS induced neutrophilic inflammation. PMID- 24157331 TI - Cry1Ac protoxin from Bacillus thuringiensis promotes macrophage activation by upregulating CD80 and CD86 and by inducing IL-6, MCP-1 and TNF-alpha cytokines. AB - Bacillus thuringiensis Cry1Ac protoxin (pCry1Ac) is a promising mucosal adjuvant, but its action mechanism is unknown. We examined in vivo whether pCry1Ac promotes the activation of macrophages in the peritoneum, spleen and mesenteric lymph nodes or in the lungs and bronchoalveolar lavage after intraperitoneal or intranasal pCry1Ac administration, respectively, in BALB/c mice. pCry1Ac upregulated the costimulatory molecules CD80 and CD86 in these macrophages, but with distinct kinetics. In vitro stimulation of resident macrophages with pCry1Ac upregulated CD80 and CD86 and enhanced the production of the pro-inflammatory cytokines TNF-alpha, IL-6 and MCP-1. To investigate whether the pCry1Ac-induced activation was mediated through MAPK pathways, we pretreated RAW 264.7 cells with signaling inhibitors of MEK, JNK and p38 MAPKs (PD98059, SP600125 and SB203580, respectively). pCry1Ac-induced upregulation of CD86 and CD80 was partially inhibited by the MEK inhibitor. While LPS-induced upregulation mechanisms of CD80 and CD86 appear to be different; as these were particularly inhibited by MEK and JNK inhibitors, respectively. pCry1Ac-induced IL-6 and MCP-1 production was especially inhibited with the p38 MAPK inhibitor, whereas TNF-alpha was only slightly inhibited upon treatment with JNK and p38 MAPK inhibitors. Therefore macrophage stimulation with pCry1Ac induced the upregulation of CD80 and CD86, and the production of IL-6, TNF-alpha and MCP-1, possibly, through the MEK and p38 MAPK pathways. It also promoted the nuclear translocation of NF-kappaB p50 and p65, the upregulation of MHC-II, and the activation of T CD4+ cells. These results suggest that pCry1Ac induced macrophage activation through mechanisms which differ partially from the LPS-induced. PMID- 24157332 TI - Spectroscopic ellipsometry of Zn(1-x)Cu(x)O thin films based on a modified sol gel dip-coating technique. AB - Nanocrystalline Zn(1-x)Cu(x)O thin films (x=0, 0.01, 0.02, 0.03, 0.04 and 0.05) were synthesized by sol-gel dip-coating technique on a quartz substrate. These films were annealed at 350 degrees C for 2 h. The X-ray diffraction showed a hexagonal crystal structure with high intensity peak for the (002) reflection plane indicating preferential growth along the c-axis of the crystal lattice. The peak position related to the (002) peak was shifted as a result of the copper ion incorporation, confirming the interstitial substitution of the zinc ions by the copper ions. This interstitial substitution leads to a decrease of an average crystallite size and lattice constants and an increase of the micro-strain up to 2 at.% of the copper amount. The surface morphology was explored by scanning electron microscopy which confirmed the homogenous distribution of nanoparticles in the deposited films along the quartz substrates. The energy dispersion X-ray spectroscopy revealed absence of impurities in the as-deposited films. The high resolution electron microscopy and selected area electron diffraction depicted that the films have polycrystalline nature. The film thickness and optical constants of the Zn(1-x)Cu(x)O thin films were estimated by fitting the spectroscopic ellipsometric data (psi and Delta) using three different models. The refractive index was fitted using harmonic oscillator model from which the oscillator and the dispersive energies were found. The dielectric constant, dielectric loss, energy loss functions were also determined. PMID- 24157333 TI - A pair of chiral fluorescent sensors for enantioselective recognition of mandelate in water. AB - A pair of chiral compounds S-1 and R-1 derived from (1S, 2S) or (1R, 2R)-1, 2 diphenylethane-1, 2-diamine were designed and synthesized, the interactions of S 1 and R-1 with mandelate were studied in H2O (0.01 M HEPES buffer, pH=7.4) by fluorescence titration experiments. The sensors S-1 and R-1 were found to present enantioselective fluorescent sensing ability to mandelate. The results indicated that the sensors S-1 and R-1 were very promising to be used as fluorescent sensors in determining the enantiomeric composition of mandelate in H2O. PMID- 24157334 TI - Synthesis and structural study of precursors of novel methylsilanediols by IR and Raman spectroscopies, single-crystal X-ray diffraction and DFT calculations. AB - On the way towards the development of a synthetic route aimed at obtaining new methylsilanediol derivatives with an aminocarbonyl group in beta to silicon (which may have a potential biological interest), we have synthesized, isolated and purified five diphenylic possible precursors, namely chloromethyl(methyl)diphenylsilane, 2-{[methyl(diphenyl)silyl]methyl}-1H isoindole-1,3(2H)-dione, N-[(methyl(diphenyl) silanyl)-methyl]-benzamide, N [(methyl(diphenyl)silyl)-methyl]-acetamide and N-[(methyl(diphenyl)silyl)-methyl] formamide. The conformational landscape of the five species in this study are explored by means of DFT calculations at the B3LYP/6-311++G(**) level. The theoretical molecular structures predicted are confirmed by the reproduction of their respective IR and Raman spectral profiles, that are completely assigned. Some evidence in the vibrational spectra points to the occurrence of conformational mixtures in the samples. Further, single-crystal X-ray diffraction has allowed the elucidation of the crystalline structure of 2 {[methyl(diphenyl)silyl]methyl}-1H-isoindole-1,3(2H)-dione. PMID- 24157335 TI - Differential effects of chronic fluoxetine on the behavior of dominant and subordinate naked mole-rats. AB - Naked mole-rats are eusocial rodents that live in large subterranean colonies with a strict reproductive and social hierarchy. The breeding female (referred to as the queen) and 1 to 3 breeding males are the only reproductive members of the colony. Breeders are socially dominant and all other colony members are non reproductive subordinates. The effects of manipulating the serotonergic neurotransmitter system on aggression and dominance behaviors are well studied in many species, but not in eusocial rodents like the naked mole-rat. The current study investigated how the serotonergic system influences aggressive/dominant behaviors in this species. To do this, two separate but related experiments were conducted: the effects of fluoxetine hydrochloride (FLX) on status-specific behaviors of subordinates (Experiment 1) and dominant queens (Experiment 2) were evaluated both in-colony and in a social-pairing paradigm. In accordance with our main hypothesis, chronic treatment of FLX attenuated the frequency and duration of aggression in queens, but not subordinates, when paired with an unfamiliar conspecific. Further exploration of pharmacological manipulation on status specific behaviors of this eusocial species may elucidate the neurobiological mechanisms underlying their unique and rigid social hierarchy. PMID- 24157336 TI - Effect of prenatal methadone on reinstated behavioral sensitization induced by methamphetamine in adolescent rats. AB - It has been known that methadone maintenance treatment is the standard treatment of choice for pregnant opiate addicts. However, there are few data on newborn outcomes especially in the cross talk with other addictive agents. The present study was to investigate the effect of prenatal exposure to methadone on methamphetamine (METH)-induced behavioral sensitization as an indicator of drug addiction in later life. Pregnant rats received saline or methadone (7 mg/kg, s.c.) twice daily from E3 to E20. To induce behavioral sensitization, offspring (5 weeks old) were treated with METH (1mg/kg, i.p.) or saline once daily for 5 consecutive days. Ninety-six hours (day 9) after the 5th treatment with METH or saline, animals received a single dose of METH (1mg/kg, i.p.) or saline to induce the reinstated behavioral sensitization. Prenatal methadone treatment enhanced the level of development of locomotor behavioral sensitization to METH administration in adolescent rats. Prenatal methadone treatment also enhanced the reinstated locomotor behavioral sensitization in adolescent rats after the administration had ceased for 96 h. These results indicate that prenatal methadone exposure produces a persistent lesion in the dopaminergic system, as indicated by enhanced METH-induced locomotor behavioral sensitization (before drug abstinence) and reinstated locomotor behavioral sensitization (after short term drug abstinence) in adolescent rats. These findings show that prenatal methadone exposure may enhance susceptibility to the development of drug addiction in later life. This could provide a reference for drug usage such as methamphetamine in their offspring of pregnant woman who are treating with methadone. PMID- 24157337 TI - Assessment of behavioral flexibility after middle cerebral artery occlusion in mice. AB - Middle cerebral artery occlusion (MCAO) is the most common animal model of cerebral ischemia and induces various functional impairments. Long-lasting deficits resulting from MCAO however, remain insufficiently characterized, especially regarding cognition. Yet, behavioral flexibility, a prominent cognitive process is found impaired after stroke in humans. We thus used an operant-based task to assess behavioral flexibility in mice after MCAO. Three weeks after 30 min MCAO surgery, mice were subjected to a battery of sensorimotor tests (rotarod, vertical pole test, spontaneous locomotion and grip-strength test). Behavioral flexibility was then assessed in an operant task, in which mice, rewarded according to a FR5 schedule of reinforcement, had to alternate their operant responses between two levers from trial to trial. Regarding sensory and motor functioning, only the pole test yielded a significant difference between MCAO and sham mice. In the operant flexibility task, results showed a behavioral flexibility deficit in MCAO mice; neither the operant response acquisition nor the appeal for food rewards was altered. In conclusion, our operant-based task revealed a long-lasting behavioral flexibility deficit after MCAO in mice. PMID- 24157339 TI - Functional t1rho imaging in panic disorder. AB - BACKGROUND: Abnormal brain pH has been suggested to play a critical role in panic disorder. To investigate this possibility, we employed a pH-sensitive magnetic resonance (MR) imaging strategy (T1 relaxation in the rotating frame [T1rho]) and conventional blood oxygen level-dependent (BOLD) imaging. METHODS: Thirteen panic disorder participants and 13 matched control subjects were enrolled in the study. T1rho and BOLD were used to study the functional response to a visual flashing checkerboard and their relationship to panic symptoms assessed using the Beck Anxiety Inventory. RESULTS: In response to visual stimulation, T1rho imaging revealed a significantly greater increase in the visual cortex of panic disorder participants. T1rho also detected a stimulus-evoked decrease in the anterior cingulate cortex. Blood oxygen level-dependent imaging detected no functional differences between groups. The correspondence between panic symptoms and functional T1rho response identified significant relationships within the left inferior parietal lobe, left middle temporal gyrus, and right insula. No relationships were found between panic symptoms and the BOLD signal. CONCLUSIONS: The data suggest greater activity-evoked T1rho changes in the visual cortex and anterior cingulate cortex of panic disorder participants. These observations are consistent with a pH dysregulation in panic disorder. In addition, our data suggest that T1rho imaging may provide information about panic disorder that is distinct from conventional BOLD imaging and may reflect abnormalities in pH and/or brain metabolism. PMID- 24157340 TI - Heat stress: a major contributor to poor animal welfare associated with long-haul live export voyages. AB - Recent investigations by the Australian Department of Agriculture, Fisheries and Forestry into high mortalities on live export voyages from Australia to the Middle East during the Northern hemisphere summer suggest that animal welfare may be compromised by heat stress. The live export industry has generated a computer model that aims to assess the risk of heat stress and to contain mortality levels on live export ships below certain arbitrary limits. Although the model must be complied with under Australian law, it is not currently available for independent scientific scrutiny, and there is concern that model and the mandated space allowances are inadequate. This review appraises the relevant literature on heat stress in sheep and cattle, including laboratory studies aimed at mimicking the ambient temperatures and humidity levels likely to be encountered on live export voyages. Animal welfare is likely to be very poor as a result of heat stress in some shipments. PMID- 24157338 TI - Increased impulsivity retards the transition to dorsolateral striatal dopamine control of cocaine seeking. AB - BACKGROUND: Development of maladaptive drug-seeking habits occurs in conjunction with a ventral-to-dorsal striatal shift in dopaminergic control over behavior. Although these habits readily develop as drug use continues, high impulsivity predicts loss of control over drug seeking and taking. However, whether impulsivity facilitates the transition to dorsolateral striatum (DLS) dopamine dependent cocaine-seeking habits or whether impulsivity and cocaine-induced intrastriatal shifts are additive processes is unknown. METHODS: High- and low impulsive rats identified in the five-choice serial reaction-time task were trained to self-administer cocaine (.25 mg/infusion) with infusions occurring in the presence of a cue-light conditioned stimulus. Dopamine transmission was blocked in the DLS after three stages of training: early, transition, and late stage, by bilateral intracranial infusions of alpha-flupenthixol (0, 5, 10, or 15 MUg/side) during 15-min cocaine-seeking test sessions in which each response was reinforced by a cocaine-associated conditioned stimulus presentation. RESULTS: In early-stage tests, neither group was affected by DLS dopamine receptor blockade. In transition-stage tests, low-impulsive rats showed a significant dose-dependent reduction in cocaine seeking, whereas high-impulsive rats were still unaffected by alpha-flupenthixol infusions. In the final, late-stage seeking test, both groups showed dose-dependent sensitivity to dopamine receptor blockade. CONCLUSIONS: The results demonstrate that high impulsivity is associated with a delayed transition to DLS-dopamine-dependent control over cocaine seeking. This suggests that, if impulsivity confers an increased propensity to addiction, it is not simply through a more rapid development of habits but instead through interacting corticostriatal and striato-striatal processes that result ultimately in maladaptive drug-seeking habits. PMID- 24157341 TI - Movements of the horse's mouth in relation to horse-rider kinematic variables. AB - The aim of this study was to investigate the behavioural response of horses to rein contact and the movement of the riders' hands through analysis of data from horses ridden at two different head and neck positions. It was hypothesised that the riders' hand movements and rein tension would generate behavioural responses from horses and that these responses would be more marked when horses were ridden 'on the bit' than when unrestrained. Data were collected from seven dressage horse/rider combinations at sitting trot on a high speed treadmill. Kinematics were recorded using a 12-camera, infrared-based opto-electronic system. Three horses wore a rein tension meter. Behavioural registrations were made from video. Behavioural responses included lip movement, mouth movement, open mouth, change in ear position, head tilt and tail movement. Mouth movements were associated with the suspension phase of the trot. Head and neck position was non-significant in the final models, while rein tension and the distance between the rider's hand and the horse's mouth were related to mouth movements. Interactions between horses and riders are complex and highly variable. PMID- 24157342 TI - Mycobacterium bovis infection: everything but the cow. PMID- 24157343 TI - New investigation of distribution imaging and content uniformity of very low dose drugs using hot-melt extrusion method. AB - The content uniformity of low dose drugs in dosage forms is very important for quality assurance. The aim of this study was to prepare uniformly and homogeneously distributed dosage forms of very low-dose drugs using twin screw hot-melt extrusion (HME) and to investigate the distribution of drugs using instrumental analyses. For the feasibility of HME method, a very low amount of coumarin-6, a fluorescent dye, was used to visualize distribution images using confocal laser scanning microscope (CLSM). Limaprost, tamsulosin and glimepiride were then used as low-dose model drugs to study the applicability of HME for content uniformity and distribution behaviors. Hydrophilic thermosensitive polymers with low melting point, such as Poloxamer188 and polyethylene glycol (PEG) 6000, were chosen as carriers. The melt extrusion was carried out around 50 degrees C, at which both carriers were easily dissolved but model drugs remained in solid form. The physicochemical properties of the hot-melt extrudates, including differential scanning calorimetry (DSC), powder X-ray diffraction (PXRD) and Fourier transform infrared spectroscopy (FT-IR), were measured. Content uniformity of the drugs was also checked by HPLC. CLSM imaging showed that model drugs were well distributed throughout the hot-melt extrudate, giving better content uniformity with low batch-to-batch variations compared with simple physical mixtures. DSC, PXRD and FT-IR data showed that there was no interaction or interference between model drugs and thermosensitive polymers. The current HME methods could be used to prepare uniformly distributed and reproducible solid dosage forms containing very low dose drugs for further pharmaceutical applications. PMID- 24157344 TI - HSA nanocapsules functionalized with monoclonal antibodies for targeted drug delivery. AB - The chronic autoimmune disorder rheumatoid arthritis (RA) affects millions of adults and children every year. Chronically activated macrophages secreting enzymes and inflammatory cytokines play a key role in RA. Distinctive marker molecules on the macrophage surface could be used to design a targeted drug delivery device for the treatment of RA without affecting healthy cells and tissues. Here, different methods for covalent attachment of antibodies (mAb) recognizing MHC class II molecules found on macrophages onto human serum albumin (HSA) nanocapsules were compared. HSA nanocapsules were prepared with a hydrodynamic diameter of 500.7 +/- 9.4 nm and a narrow size distribution as indicated by a polydispersity index (PDI) of 0.255 +/- 0.024. This was achieved by using a sonochemical process avoiding toxic cross linking agents and emulsifiers. Covalent binding of mAb on the surface of HSA nanocapsules was realized using polyethyleneglycol (PEG)3000 as spacer molecule. The presence of mAb was confirmed by confocal laser scanning microscopy (CLSM) and enzyme-linked immunosorbent assay (ELISA). Specific binding of mAb-HSA nanocapsules to MHC class II molecules on antigen-presenting cells was demonstrated by flow cytometry analysis. PMID- 24157345 TI - Cationic quaternized aminocalix[4]arenes: cytotoxicity, haemolytic and antibacterial activities. AB - This study reports the characterization of three cationic amphiphillic aminocalix[4]arenes as potential antimicrobial agents in vitro. In cytotoxicity tests on mouse macrophage RAW 264.7 cells aminocalix[4]arenes 1 and 3 showed no toxicity up to 200 and 100 MUM concentrations, respectively, while 2 was non toxic only up to 50 MUM. With regard to the haemolytic activity on rabbit red blood cells, 1 was not active at concentrations up to 100 MUM in contrast to the other two studied macrocycles. Compounds showed negligible ability to protect either mouse macrophage RAW 264.7 cells from anthrax lethal toxin of Bacillus anthracis (B. anthracis) or rabbit red blood cells from alpha-haemolysin of Staphylococcus aureus (S. aureus) in comparison to amino-beta-cyclodextrins. However, all aminocalix[4]arenes showed potential as antimicrobials. Their minimum inhibitory concentrations (MIC) against Escherichia coli (E. coli) and S. aureus were in the 16-32 MUg/ml concentration range, while minimum lethal concentrations (MLC) varied from 16 to 256 MUg/ml depending on the bacteria and aminocalix[4]arene considered. Macrocycle 1 showed partial synergism against S. aureus in tandem with a model antibacterial drug, fusidic acid, at certain concentration combinations. PMID- 24157346 TI - Mucoadhesive hybrid gel improves intraperitoneal platinum delivery. AB - A leading cause of death and suffering in patients with abdominal or pelvic malignancies is progression of peritoneal surface disease. Changes in the use of chemotherapy have shown significant survival benefits for intraperitoneal or combined intraperitoneal and intravenous treatment following optimal surgical cytoreduction. However, broader clinical use of intraperitoneal therapy has not reached its full potential due to limited efficacy, accessibility and nonspecific toxicity. To overcome these problems, we developed a mucoadhesive hybrid gel (HG) for a local, intraperitoneal drug delivery. In vivo studies confirmed reliable adherence and residence of the gel to the peritoneal sidewall for at least 72 h exhibiting no signs of tissue toxicity. Functionally active CDDP was released from HG within 2h and was equal to free CDDP in vitro. Moreover, intraperitoneal application of HG-CDDP significantly enhanced CDDP accumulation in the genomic DNA of peritoneal tissues compared to the same CDDP dose administered intravenously. These findings indicate the potential application of this hybrid gel as a mucoadhesive drug carrier amendable to use for intraperitoneal drug delivery and possible expansion for use on other mucosal surfaces of the female reproductive tract. PMID- 24157347 TI - Variations in clinicopathologic characteristics of thyroid cancer among racial ethnic groups: analysis of a large public city hospital and the SEER database. AB - BACKGROUND: Clinicopathologic variables influence the treatment and prognosis of patients with thyroid cancer. METHODS: A retrospective analysis of public hospital thyroid cancer database and the Surveillance, Epidemiology and End Results 17 database was conducted. Demographic, clinical, and pathologic data were compared across ethnic groups. RESULTS: Within the public hospital database, Hispanics versus non-Hispanic whites were younger and had more lymph node involvement (34% vs 17%, P < .001). Median tumor size was not statistically different across ethnic groups. Similar findings were demonstrated within the Surveillance, Epidemiology and End Results database. African Americans aged <45 years had the largest tumors but were least likely to have lymph node involvement. Asians had the most stage IV disease despite having no differences in tumor size, lymph node involvement, and capsular invasion. CONCLUSIONS: There is considerable variability in the clinical presentation of thyroid cancer across ethnic groups. Such disparities persist within an equal-access health care system. These findings suggest that factors beyond socioeconomics may contribute to such differences. PMID- 24157349 TI - Clinical correlates, outcomes and healthcare costs associated with early mechanical ventilation after kidney transplantation. AB - BACKGROUND: Information is lacking on the frequency, clinical implications, and costs of respiratory failure requiring mechanical ventilation after kidney transplantation. METHODS: U.S. Renal Data System records for Medicare-insured kidney transplant recipients (1995 to 2007; n = 88,392) were examined to identify post-transplantation mechanical ventilation from billing claims within 30 days after transplantation. RESULTS: Post-transplantation mechanical ventilation was required among 2.1% of the cohort. Independent correlates of early mechanical ventilation included recipient age, low body mass index, coronary artery disease, and cerebrovascular disease. Post-transplantation mechanical ventilation was twice as likely with delayed graft function (adjusted odds ratio, 2.13; P < .001) and 35% lower among recipients of living versus deceased donor allografts. Patients needing early mechanical ventilation experienced 5-fold higher 1-year mortality, as well as significantly higher Medicare costs during the transplant hospitalization and first post-transplantation year. CONCLUSIONS: Recognition of patients at risk for post-transplantation respiratory failure may help direct protocols for reducing the incidence and consequences of this complication. PMID- 24157348 TI - Utilization of morning report by acute care surgery teams: results from a qualitative study. AB - BACKGROUND: The rigor of handoffs is increasingly scrutinized in the era of shift based patient care. Acute care surgery (ACS) embraced such a model of care; however, little is known about handoffs in ACS programs. METHODS: Eighteen open ended interviews were conducted with ACS leaders representing diverse geographic and practice settings. Two independent reviewers analyzed interviews using an inductive approach to elucidate themes regarding use of morning report (using NVivo qualitative analysis software). RESULTS: Twelve of 18 respondents reported using morning report, but only 6 of 12 included attending surgeon-to-attending surgeon handoffs. One of 12 incentivized attending surgeons to participate, 2 of 12 included nursing staff members, and 2 of 12 included physician extenders. Cited benefits of morning report were safe and effective information exchange (2 of 12), quality improvement (2 of 12), multidisciplinary discussion (1 of 12), and resident education (2 of 12). Three of 12 respondents cited time commitment as the main limitation of morning report. CONCLUSIONS: Morning report is underused among ACS programs; however, if implemented strategically, it may improve patient care and resident education. PMID- 24157350 TI - Strategies for building an effective mentoring relationship. AB - Mentoring has been recognized as a critical aspect of the professional and/or personal development of the student, resident or faculty member. This career development resource discusses strategies for building effective mentoring relationships and outlines some of the challenges to contemporary mentoring. PMID- 24157351 TI - General surgery career resource. AB - General surgery residency training can lead to a rewarding career in general surgery and serve as the foundation for careers in several surgical subspecialties. It offers broad-based training with exposure to the cognitive and technical aspects of several surgical specialties and prepares graduating residents for a wide range of career paths. This career development resource discusses the training aspects of general surgery. PMID- 24157352 TI - hCG physiology. PMID- 24157353 TI - Laser surgery in twin-twin transfusion syndrome with proximate cord insertions. AB - OBJECTIVE: To estimate the prevalence of proximate cord insertions in twin-twin transfusion syndrome (TTTS) and evaluate the outcome after fetoscopic laser coagulation surgery. METHODS: We included all TTTS cases treated with laser at our center between 2002 and 2013. Placentas were examined after birth and injected with colored dye. TTTS cases without complete placental injection study were excluded. We recorded the presence of proximate cord insertions (distance < 5 cm) after birth and the presence and types of residual anastomoses. We compared the clinical outcome and placental findings in cases with and without proximate cord insertions. RESULTS: The prevalence of proximate cord insertions in TTTS placentas was 2% (4/252). Perinatal mortality in the TTTS group with and without proximate cord insertions was 13% (1/8) and 12% (61/496), respectively (P = 1.0). Residual anastomoses were detected in all placentas with proximate cord insertions (100%, 4/4) compared to 27% (66/248)(P < .01) in TTTS placentas without proximate cord insertions. CONCLUSION: Fetoscopic laser coagulation in TTTS cases with proximate cord insertions is challenging due to technical difficulties in visualizing the vascular equator and results in an increased risk of incomplete laser treatment. PMID- 24157355 TI - Spontaneous coronary artery dissection associated with coughing. PMID- 24157354 TI - Long-term follow-up of cystic fibrosis newborn screening: psychosocial functioning of adolescents and young adults. AB - BACKGROUND: Long-term psychosocial outcomes of cystic fibrosis (CF) patients diagnosed through newborn screening remain unknown. METHODS: This cross-sectional study compared three groups of youths (16 to 22 years): CF patients diagnosed through NBS (CF-NBS, n = 13), CF patients diagnosed through standard practice (CF SP, n = 26) and healthy peers (H, n = 42), plus 72 of their parents. We hypothesized that adolescent psychological functioning would be mediated by parent depression and quality of parent-child communication and cohesiveness. RESULTS: A path analysis showed significantly more depression among CF-NBS group parents (p = .006-.008). Parent-child cohesiveness was related to communication (p < .001). Cohesiveness and communication were associated with youth Internalizing Problems (p = .037, p = .009), Emotional Symptoms (p = 0.018, p = 0.022), and Personal Adjustment (communication only, p = 0.009). Parent depression was related to youth Personal Adjustment (p = 0.022). CONCLUSIONS: CF patients report psychosocial function similar to healthy peers. Parents of children diagnosed with CF through NBS may be at risk for depressive symptoms when their children reach adolescence. PMID- 24157356 TI - Phthiriasis palpebrarum: diagnosis and treatment. AB - INTRODUCTION: Phthiriasis palpebrarum is an ectoparasitosis in which Phthirus pubis infest the eyelashes. It is rare and it can easily be misdiagnosed as blepharitis. The purpose of this study is to describe seven cases of phthiriasis palpebrarum so as to discuss its mode of infestation, diagnosis and treatment. PATIENTS AND METHODS: This is a study of all cases of phthiriasis palpebrarum reported in our laboratory. For each patient, an ophthalmic examination and parasitological examination of the eyelashes were performed. RESULTS: There were five men and two women. Their ages ranged from 4 to 50years with an average of 21.57years. There were four children and three adults. The main symptom was itching of the eyelids. Clinical signs included reddish-brown crusts at the base of the eyelashes in all the cases and visible lice and nits in three cases. Biomicroscopic examination showed lice and nits anchored to the eyelashes in three cases. In the other two cases, the initial diagnosis was felt to be blepharitis. In all cases, the diagnosis of phthiriasis palpebrarum was confirmed by parasitological examination of eyelashes, which revealed the presence of adult and nit forms of Phthirus pubis. The number of adult lice ranged from 1 to 30. In all cases, treatment was based on mechanical removal of both the lice and nits. Outcomes were favorable without recurrence. CONCLUSION: In conclusion, phthiriasis palpebrarum can be easily diagnosed by close examination of the eyelashes and eyelid margins at the slit lamp and can be managed mechanically. Parasitological examination of the eyelashes can confirm the diagnosis. PMID- 24157358 TI - Protein alkylation by the alpha,beta-unsaturated aldehyde acrolein. A reversible mechanism of electrophile signaling? AB - Acrolein, a reactive aldehyde found in cigarette smoke, is thought to induce its biological effects primarily by irreversible adduction to cellular nucleophiles such as cysteine thiols. Here, we demonstrate that acrolein rapidly inactivates the seleno-enzyme thioredoxin reductase (TrxR) in human bronchiolar epithelial HBE1 cells, which recovered over 4-8h by a mechanism depending on the presence of cellular GSH and thioredoxin 1 (Trx1), and corresponding with reversal of protein acrolein adduction. Our findings indicate that acrolein-induced protein alkylation is not necessarily a feature of irreversible protein damage, but may reflect a reversible signaling mechanism that is regulated by GSH and Trx1. PMID- 24157357 TI - Protein engineering strategies for the development of viral vaccines and immunotherapeutics. AB - Vaccines that elicit a protective broadly neutralizing antibody (bNAb) response and monoclonal antibody therapies are critical for the treatment and prevention of viral infections. However, isolation of protective neutralizing antibodies has been challenging for some viruses, notably those with high antigenic diversity or those that do not elicit a bNAb response in the course of natural infection. Here, we discuss recent work that employs protein engineering strategies to design immunogens that elicit bNAbs or engineer novel bNAbs. We highlight the use of rational, computational, and combinatorial strategies and assess the potential of these approaches for the development of new vaccines and immunotherapeutics. PMID- 24157359 TI - FAD C(4a)-hydroxide stabilized in a naturally fused styrene monooxygenase. AB - StyA2B represents a new class of styrene monooxygenases that integrates flavin reductase and styrene-epoxidase activities into a single polypeptide. This naturally-occurring fusion protein offers new avenues for studying and engineering biotechnologically relevant enantioselective biochemical epoxidation reactions. Stopped-flow kinetic studies of StyA2B reported here identify reaction intermediates similar to those reported for the separate reductase and epoxidase components of related two-component systems. Our studies identify substrate epoxidation and elimination of water from the FAD C(4a)-hydroxide as rate limiting steps in the styrene epoxidation reaction. Efforts directed at accelerating these reaction steps are expected to greatly increase catalytic efficiency and the value of StyA2B as biocatalyst. PMID- 24157360 TI - Screening of protein kinase inhibitors and knockdown experiments identified four kinases that affect mitochondrial ATP synthesis activity. AB - Mitochondrial ATP synthase, a major ATP supplier in respiring cells, should be regulated in amount and in activity to respond to the varying demands of cells for ATP. We screened 80 protein kinase inhibitors and found that HeLa cells treated with four inhibitors exhibited reduced mitochondrial ATP synthesis activity. Consistently, knockdown of their target kinases (PKA, PKCdelta, CaMKII and smMLCK) resulted in a decrease in mitochondrial ATP synthesis activity. Among them, mitochondria of smMLCK-knockdown cells contained only a small amount of ATP synthase, while the alpha- and beta-subunits of ATP synthase were produced normally, suggesting that smMLCK affects assembly (or decay) of ATP synthase. PMID- 24157361 TI - Dynamic elements govern the catalytic activity of CapE, a capsular polysaccharide synthesizing enzyme from Staphylococcus aureus. AB - CapE is an essential enzyme for the synthesis of capsular polysaccharide (CP) of pathogenic strains of Staphylococcus aureus. Herein we demonstrate that CapE is a 5-inverting 4,6-dehydratase enzyme. However, in the absence of downstream enzymes, CapE catalyzes an additional reaction (5-back-epimerization) affording a by-product under thermodynamic control. Single-crystal X-ray crystallography was employed to identify the structure of the by-product. The structural analysis reveals a network of coordinated motions away from the active site governing the enzymatic activity of CapE. A second dynamic element (the latch) regulates the enzymatic chemoselectivity. The validity of these mechanisms was evaluated by site-directed mutagenesis. PMID- 24157362 TI - Sperm PLCzeta: from structure to Ca2+ oscillations, egg activation and therapeutic potential. AB - Significant evidence now supports the assertion that cytosolic calcium oscillations during fertilization in mammalian eggs are mediated by a testis specific phospholipase C (PLC), termed PLC-zeta (PLCzeta) that is released into the egg following gamete fusion. Herein, we describe the current paradigm of PLCzeta in this fundamental biological process, summarizing recent important advances in our knowledge of the biochemical and physiological properties of this enzyme. We describe the data suggesting that PLCzeta has distinct features amongst PLCs enabling the hydrolysis of its substrate, phosphatidylinositol 4,5 bisphosphate (PIP2) at low Ca(2+) levels. PLCzeta appears to be unique in its ability to target PIP2 that is present on intracellular vesicles. We also discuss evidence that PLCzeta may be a significant factor in human fertility with potential therapeutic capacity. PMID- 24157363 TI - Site-directed mutagenesis of a fatty acid elongase ELO-like condensing enzyme. AB - The condensation step of fatty acid elongation is the addition of a C2 unit from malonyl-CoA to an acyl primer catalyzed by one of two families of enzymes, the 3 ketoacyl-CoA synthases and the ELO-like condensing enzymes. 3-Ketoacyl-CoA synthases use a Claisen-like reaction mechanism while the mechanism of the ELO catalyzed condensation reaction is unknown. We have used site-directed mutagenesis of Dictyostelium discoideum EloA to identify residues important to catalytic activity and/or structure. Mutation of highly conserved polar residues to alanine resulted in an inactive enzyme strongly suggesting that these residues play a role in the condensation reaction. PMID- 24157365 TI - Design and synthesis of aryl sulfonamide-based nonsteroidal mineralocorticoid receptor antagonists. AB - Hit-to-lead medicinal chemistry efforts are described starting from a screening hit 1, leading to a new class of aryl sulfonamide-based MR antagonist, exemplified by 17, that possesses favourable MR binding affinity, selectivity profile against closely related NHRs, physicochemical properties and metabolic stability. PMID- 24157364 TI - Neutralisation of specific surface carboxylates speeds up translocation of botulinum neurotoxin type B enzymatic domain. AB - Botulinum neurotoxins translocate their enzymatic domain across vesicular membranes. The molecular triggers of this process are unknown. Here, we tested the possibility that this is elicited by protonation of conserved surface carboxylates. Glutamate-48, glutamate-653 and aspartate-877 were identified as possible candidates and changed into amide. This triple mutant showed increased neurotoxicity due to faster cytosolic delivery of the enzymatic domain; membrane translocation could take place at less acidic pH. Thus, neutralisation of specific negative surface charges facilitates membrane contact permitting a faster initiation of the toxin membrane insertion. PMID- 24157366 TI - Discovery and optimization of orally active cyclohexane-based prolylcarboxypeptidase (PrCP) inhibitors. AB - The synthesis, SAR, binding affinities and pharmacokinetic profiles are described for a series of cyclohexane-based prolylcarboxypeptidase (PrCP) inhibitors discovered by high throughput screening. Compounds show high levels of ex vivo target engagement in mouse plasma 20 h post oral dose. PMID- 24157367 TI - Cytidine derivatives as IspF inhibitors of Burkolderia pseudomallei. AB - Published biological data suggest that the methyl erythritol phosphate (MEP) pathway, a non-mevalonate isoprenoid biosynthetic pathway, is essential for certain bacteria and other infectious disease organisms. One highly conserved enzyme in the MEP pathway is 2C-methyl-d-erythritol 2,4-cyclodiphosphate synthase (IspF). Fragment-bound complexes of IspF from Burkholderia pseudomallei were used to design and synthesize a series of molecules linking the cytidine moiety to different zinc pocket fragment binders. Testing by surface plasmon resonance (SPR) found one molecule in the series to possess binding affinity equal to that of cytidine diphosphate, despite lacking any metal-coordinating phosphate groups. Close inspection of the SPR data suggest different binding stoichiometries between IspF and test compounds. Crystallographic analysis shows important variations between the binding mode of one synthesized compound and the pose of the bound fragment from which it was designed. The binding modes of these molecules add to our structural knowledge base for IspF and suggest future refinements in this compound series. PMID- 24157368 TI - Facile preparation of tetrahydro-5H-pyrido[1,2,3-de]-1,4-benzoxazines via reductive cyclization of 2-(8-quinolinyloxy)ethanones and their antioxidant activity. AB - Pd/C-catalyzed reductive cyclization of 1-aryl-2-(8-quinolinyloxy)ethanones opens a facile access to the title compounds in good yields. The scope of this reductive cyclization is explored and the antioxidant activities of the products are studied. PMID- 24157369 TI - Synthesis and biological evaluation of positron emission tomography radiotracers targeting serotonin 4 receptors in brain: [18F]MNI-698 and [18F]MNI-699. AB - Two new benzodioxane derivatives were synthesized as candidates to image the serotonin 4 receptors by positron emission tomography (PET) and radiolabeled with fluorine-18 via a two-step procedure. Competition binding assays demonstrated that MNI-698 and MNI-699 had sub-nanomolar binding affinities against rat striatal 5-HT4 receptors (Ki of 0.20 and 0.07 nM, respectively). PET imaging in rhesus monkey showed that the regional brain distribution of [(18)F]MNI-698 and [(18)F]MNI-699 were consistent with the known densities of 5-HT4 in brain. [(18)F]MNI-698 and [(18)F]MNI-699 are among the first fluorine-18 radiotracers developed for imaging the 5-HT4 receptors in vivo and are currently under preclinical investigation in primates for future human use. PMID- 24157370 TI - The sulfamide moiety affords higher inhibitory activity and oral bioavailability to a series of coumarin dual selective RAF/MEK inhibitors. AB - Introducing a sulfamide moiety to our coumarin derivatives afforded enhanced Raf/MEK inhibitory activity concomitantly with an acceptable PK profile. Novel sulfamide 17 showed potent HCT116 cell growth inhibition (IC50=8 nM) and good PK profile (bioavailability of 51% in mouse), resulting in high in vivo antitumor efficacy in the HCT116 xenograft (ED50=4.8 mg/kg). We confirmed the sulfamide moiety showed no negative impact on tests run on the compound to evaluate DMPK (PK profiles in three animal species, CYP inhibition and CYP induction) and the safety profile (hERG and AMES tests). Sulfamide 17 had favorable properties that warranted further preclinical assessment. PMID- 24157371 TI - Gallic acid is the major component of grape seed extract that inhibits amyloid fibril formation. AB - Many protein misfolding diseases, for example, Alzheimer's, Parkinson's and Huntington's, are characterised by the accumulation of protein aggregates in an amyloid fibrillar form. Natural products which inhibit fibril formation are a promising avenue to explore as therapeutics for the treatment of these diseases. In this study we have shown, using in vitro thioflavin T assays and transmission electron microscopy, that grape seed extract inhibits fibril formation of kappa casein (kappa-CN), a milk protein which forms amyloid fibrils spontaneously under physiological conditions. Among the components of grape seed extract, gallic acid was the most active component at inhibiting kappa-CN fibril formation, by stabilizing kappa-CN to prevent its aggregation. Concomitantly, gallic acid significantly reduced the toxicity of kappa-CN to pheochromocytoma12 cells. Furthermore, gallic acid effectively inhibited fibril formation by the amyloid beta peptide, the putative causative agent in Alzheimer's disease. It is concluded that the gallate moiety has the fibril-inhibitory activity. PMID- 24157372 TI - GPs are key to effective coordination of care for people with chronic conditions, study concludes. PMID- 24157373 TI - Strategy using three layers of surface charge for computing solvation free energy of ions. AB - Continuum solvent model is the common used strategy for computing the solvation free energy. However, the dielectric polarization from Gauss's law differs from that obtained from molecular dynamics simulations. To mimic the dielectric polarization surrounding a solute in molecular dynamics simulations, the first shell water molecule was modeled using a charge distribution of TIP4P molecule in a hard sphere. The dielectric polarization of the first-shell water was modeled as a pair of surface charge layers with a fixed distance between them, but with variable, equal, and opposite charge magnitudes that respond to the electric field on the first-shell water. The water outside the first shell water is treated as a bulk solvent, and the electric effect of the bulk solvent can be modeled as a surface charge. Based on this strategy, the analytical solution describing the solvation free energy of ions was derived, and the values of computed solvation free energy were compared to the values of experiments. PMID- 24157374 TI - Cell shape-dependent early responses of fibroblasts to cyclic strain. AB - Randomly spread fibroblasts on fibronectin-coated elastomeric membranes respond to cyclic strain by a varying degree of focal adhesion assembly and actin reorganization. We speculated that the individual shape of the cells, which is linked to cytoskeletal structure and pre-stress, might tune these integrin dependent mechanotransduction events. To this aim, fibronectin circles, squares and rectangles of identical surface area (2000MUm(2)) were micro-contact printed onto elastomeric substrates. Fibroblasts plated on these patterns occupied the corresponding shapes. Cyclic 10% equibiaxial strain was applied to patterned cells for 30min, and changes in cytoskeleton and cell-matrix adhesions were quantified after fluorescence staining. After strain, megakaryocytic leukemia-1 protein translocated to the nucleus in most cells, indicating efficient RhoA activation independently of cell shape. However, circular and square cells (with radial symmetry) showed a significantly greater increase in the number of actin stress fibers and vinculin-positive focal adhesions after cyclic strain than rectangular (bipolar) cells of identical size. Conversely, cyclic strain induced larger changes in pY397-FAK positive focal complexes and zyxin relocation from focal adhesions to stress fibers in bipolar compared to symmetric cells. Thus, radially symmetric cells responded to cyclic strain with a larger increase in assembly, whereas bipolar cells reacted with more pronounced reorganization of actin stress fibers and matrix contacts. We conclude that integrin-mediated responses to external mechanical strain are differentially modulated in cells that have the same spreading area but different geometries, and do not only depend on mere cell size. PMID- 24157375 TI - Modulation of hepatic sterol regulatory element-binding protein-1c-mediated gene expression contributes to Salacia oblonga root-elicited improvement of fructose induced fatty liver in rats. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Salacia oblonga root (SOR) is a traditionally herbal medicine for obesity and diabetes, which are closely associated with fatty liver. To investigate the molecular mechanisms of SOR in the treatment of dietary induced fatty liver. MATERIALS AND METHODS: Male rats were co-administered with fructose in drinking water and vehicle or the aqueous-ethanolic extract of SOR (by gavage, once daily) for 10 weeks. Biochemical variables were determined enzymatically or by ELISA. Gene expression was analyzed by Real-Time PCR and/or Western blot. RESULTS: SOR treatment (20mg/kg) diminished fructose-induced fatty liver indicated by decreases in excess triglyceride accumulation and the increased vacuolization and Oil Red O staining area in the livers of rats. Importantly, Hepatic gene expression profile revealed that SOR suppressed fructose-stimulated overexpression of sterol regulatory element-binding protein (SREBP)-1/1c mRNA and nuclear protein. In accord, overexpression of SREBP-1c responsive genes, such as fatty acid synthase, acetyl-CoA carboxylase-1 and stearoyl-CoA desaturase-1, was also downregulated. In contrast, overexpressed nuclear protein of carbohydrate response element binding protein and mRNA of its target gene liver pyruvate kinase were not altered. Additionally, SOR also did not affect expression of peroxisome proliferator-activated receptor-gamma- and alpha, as well as their target genes, such as carnitine palmitoyltransferase-1a, acyl-CoA oxidase and CD36. CONCLUSIONS: These results suggest that modulation of hepatic sterol regulatory element-binding protein-1c-mediated gene expression contributes to SOR-elicited improvement of fructose-induced fatty liver in rats. Our findings provide a better understanding of SOR in the treatment of obesity and diabetes. PMID- 24157376 TI - The impact of Zataria multiflora Boiss extract on in vitro and in vivo Th1/Th2 cytokine (IFN-gamma/IL4) balance. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Anti-inflammatory, anti-oxidant and effect of Zataria multiflora on Th1/Th2 balance were previously described. Different therapeutic effects of this plant have been described in Iranian traditional medicine. To evaluate the immune modulatory effects of Zataria multiflora on Th1/Th2 balance, which may be implicated in inflammatory disorders, in vitro and in vivo studies were carried out. MATERIALS AND METHODS: The effects of three concentrations of the extract, dexamethasone, and saline on interleukin 4 (IL-4) and interferon gamma (IFN-gamma) gene expression were evaluated in phytohemagglutinin (PHA) stimulated and non-stimulated human peripheral blood mononuclear cells (hPBMCs). RNA was extracted from the hPBMCs to make cDNA for real time PCR relative quantification. Furthermore, the effect of the extract on serum level of IL-4 and IFN-gamma was assessed in ovalbumin (OA) sensitized guinea pigs (n=6 for each group). RESULTS: Dexamethasone showed significant inhibitory effect on both IFN-gamma and IL-4 gene expression and serum level of the cytokines and significantly enhanced IFN-gamma/IL-4 ratio (p<0.05-p<0.001). The extract inhibited IL-4 and enhance IFN-gamma gene expression and IFN-gamma/IL 4 ratio too (p<0.05-p<0.001). In sensitized animals also serum level of IL-4 were significantly decreased after treatment with both dexamethasone and extract, but serum level of IFN-gamma and IFN-gamma/IL-4 ratio were significantly increased due to extract treatment (p<0.01 for medium and p<0.001 for high concentration). CONCLUSIONS: These results indicated consistent in vitro and in vivo data for selective immune modulatory effect of the extract of Zataria multiflora which increased IFN-gamma, decreased IL-4, and enhanced the ratio of IFN-gamma to IL-4 (Th1/Th2 balance). Therefore, the extract of Zataria multiflora may have therapeutic value in inflammatory responses such as allergy, autoimmunity and infectious diseases associated with Th1/Th2 imbalance. PMID- 24157377 TI - Marsdenia tenacissima extract inhibits gefitinib metabolism in vitro by interfering with human hepatic CYP3A4 and CYP2D6 enzymes. AB - ETHNOPHARMACOLOGICAL RELEVANCE: The stem of Marsdenia tenacissima (Roxb.) Wight et Arn. is mainly produced in Yunnan China and has long been used as a medicine to treat cancer in China. Xiao-Ai-Ping injection, the water-soluble part of the stem of Marsdenia tenacissima, is administrated as an anti-cancer agent in clinics for decades. Our previous study showed that Marsdenia tenacissima extract (MTE) restored gefitinib sensitivity in gefitinib-resistant non-small cell lung cancer (NSCLC) cells, but the mechanism involved is unknown. Gefitinib undergoes hepatic metabolism predominantly through human cytochrome P450 (CYP) 3A4 and CYP2D6 enzymes. This study aims to evaluate whether MTE interferes with gefitinib metabolism via human hepatic P450 enzymes. MATERIAL AND METHODS: A cocktail substrate assay was used to test the effect of MTE on major CYP enzyme activities by incubation of pooled human liver microsomes with specific substrate probes of CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A4 in the absence and presence of MTE. Recombinant human CYP450 enzymes were used to predict in vitro gefitinib metabolic clearance in the absence and presence of MTE. The metabolites of the substrate probes and gefitinib were detected by high-performance liquid chromatographic tandem mass spectrometry (HPLC-MS/MS). Human hepatoma HepG2 cells were used to investigate the effect of gefitinib alone or in combination with MTE on CYP3A4 and CYP2D6 mRNA and protein expression. RESULTS: The cocktail-substrate assay showed that MTE inhibited CYP450 activities in human liver microsomes with the inhibition rate of 3A4>2C9>2C19>1A2>2D6. The co-administration of MTE with gefitinib significantly decreased the in vitro intrinsic clearance (Clint) of gefitinib by 2.6 and 4.0-fold for CYP2D6 and CYP3A4, respectively, but did not affect other CYP450s. CYP2D6 and CYP3A4 mRNA and protein expression in human hepatoma HepG2 cells were greatly reduced in the combined gefitinib and MTE treatment. CONCLUSION: We demonstrate that MTE inhibits gefitinib metabolism by interfering with CYP3A4 and CYP2D6. Meanwhile, MTE combined with gefitinib down regulates the mRNA and protein expression of CYP3A4 and CYP2D6 in the HepG2 cells. Thus, these data suggest that MTE is a promising herbal medicine to enhance gefitinib efficacy through improving its metabolic stability. PMID- 24157378 TI - Antidiarrheal and intestinal antiinflammatory activities of a methanolic extract of Qualea parviflora Mart. in experimental models. AB - ETHNOPHARMACOLOGICAL RELEVANCE: An ethnopharmacological survey indicated that the bark from Qualea parviflora Mart. (Vochysiaceae) could be used to treat gastrointestinal disorders, such as diarrhea and intestinal inflammation. The objective of this study was to evaluate the effects of a methanolic extract from the bark of Qualea parviflora (QP) in an experimental model of diarrhea and intestinal inflammation induced in rodents. MATERIAL AND METHODS: The antidiarrheal and antispasmodic effects of QP were investigated by measuring intestinal motility, diarrhea, and intestinal fluid accumulation in rodents after challenging with a cathartic agent. In addition, the effects of QP on the contractility of the isolated mice-ileum preparation were determined. Acute intestinal inflammation was induced in male Wistar rats by the rectal administration of trinitrobenzenesulfonic acid (TNBS) in 50% ethanol (0.25 mL). QP was administered orally (for 5 days) prior to the induction of inflammation. The colonic injury and extent of inflammation were assessed by macroscopic damage scores and lesion length. The enhanced colonic mucosal injury, inflammatory response, and oxidative stress were evaluated by myeloperoxidase (MPO) activity; the tumor necrosis factor alpha (TNF-alpha), interleukin 1beta (IL1-beta), and malondialdehyde (MDA) levels; and the glutathione (GSH) content. RESULTS: Oral treatment with QP (500 mg/kg) delayed the onset of diarrhea, reduced the amount of liquid stool, and decreased the severity of the diarrhea and the evacuation index in rodents challenged with castor oil (p<0.01). Additionally, QP (150-500 ug/mL) demonstrated effective antispasmodic activity against carbachol-induced contractions of mouse ileum in vitro. Oral treatment (25 and 50 mg/kg/day) with QP significantly reduced the intestinal inflammation induced by TNBS in rats (52% and 45%, respectively). Improvement of colonic mucosal injury by treatment with QP was demonstrated by a decrease in MDA levels and an increase in GSH content in colonic tissue. QP also prevented intestinal inflammation as evidenced by reduced cytokine levels (TNF-alpha and IL1-beta) and low MPO activity. CONCLUSIONS: The ethnopharmacological usefulness of the bark from Qualea parviflora against diarrhea containing blood and mucus was supported by the observed antidiarrheal, antispasmodic, and intestinal antiinflammatory properties of this medicinal plant. PMID- 24157380 TI - Prediction of submucosal gastric cancer by narrow-band imaging magnifying endoscopy. AB - BACKGROUND: The features of gastric submucosal cancer revealed by magnifying endoscopy have not been reported. Aim of our study was to investigate whether magnifying endoscopy could contribute to the diagnosis of submucosal invasion. PATIENTS AND METHODS: In this prospective, cross-sectional study, 197 lesions of gastric differentiated adenocarcinoma, diagnosed as mucosal cancer by conventional endoscopy, were observed by magnifying endoscopy with narrow-band imaging, paying attention to the presence of a blurry mucosal pattern and an irregular mesh pattern. After endoscopic submucosal dissection, all lesions were examined histologically and the areas of two features were estimated. RESULTS: Among the lesions examined, 177 were diagnosed histologically as mucosal cancer and 20 as submucosal cancer. Multivariate logistic regression analysis confirmed that a blurry mucosal pattern (odds ratio 12.15, 95% confidence interval 3.45 42.76, p=0.000) and an irregular mesh pattern (22.55, 4.22-120.45, p=0.000) were independent predictors of submucosal invasion. CONCLUSIONS: Narrow band imaging magnifying endoscopic features are useful for predicting submucosal invasion in gastric cancer. PMID- 24157379 TI - Chronic variable stress in fathers alters paternal and social behavior but not pup development in the biparental California mouse (Peromyscus californicus). AB - Stress and chronically elevated glucocorticoid levels have been shown to disrupt parental behavior in mothers; however, almost no studies have investigated corresponding effects in fathers. The present experiment tested the hypothesis that chronic variable stress inhibits paternal behavior and consequently alters pup development in the monogamous, biparental California mouse (Peromyscus californicus). First-time fathers were assigned to one of three experimental groups: chronic variable stress (CVS, n=8), separation control (SC, n=7), or unmanipulated control (UC, n=8). The CVS paradigm (3 stressors per day for 7 days) successfully stressed mice, as evidenced by increased baseline plasma corticosterone concentrations, increased adrenal mass, decreased thymus mass, and a decrease in body mass over time. CVS altered paternal and social behavior of fathers, but major differences were observed only on day 6 of the 7-day paradigm. At that time point, CVS fathers spent less time with their pairmate and pups, and more time autogrooming, as compared to UC fathers; SC fathers spent more time behaving paternally and grooming the female mate than CVS and UC fathers. Thus, CVS blocked the separation-induced increase in social behaviors observed in the SC fathers. Nonetheless, chronic stress in fathers did not appear to alter survival or development of their offspring: pups from the three experimental conditions did not differ in body mass gain over time, in the day of eye opening, or in basal or post-stress corticosterone levels. These results demonstrate that chronic stress can transiently disrupt paternal and social behavior in P. californicus fathers, but does not alter pup development or survival under controlled, non-challenging laboratory conditions. PMID- 24157381 TI - Eosinophilic myocarditis due to Churg-Strauss syndrome mimicking reversible dilated cardiomyopathy. AB - A 41-year-old woman with a history of asthma arrived at the emergency room of our hospital with dyspnea. The electrocardiogram showed no specific results. Echocardiography defects revealed an obvious decrease in the left ventricular systolic function and enlargement of the left chamber. We initially considered her condition to be dilated cardiomyopathy. However, she had eosinophilia in the peripheral blood and elevated cardiac enzymes. The coronary angiography showed normal coronary arteries. Single photon emission computed tomography (SPECT) showed infiltrative myocardial disease. She was then diagnosed with eosinophil infiltrations. Combined with peripheral nerve injury and lung involvement, she was diagnosed as having Churg-Strauss syndrome. After initiating prednisone treatment, her eosinophilia and rising cardiac enzymes recovered to normal, and both her echocardiographic abnormalities and symptoms noticeably improved. PMID- 24157383 TI - Are we there yet? Electroencephalography as a diagnostic tool for attention deficit/hyperactivity disorder. PMID- 24157384 TI - Appreciating "normal" development: how did we get here? PMID- 24157382 TI - Compliance with pregnancy prevention measures during isotretinoin therapy. AB - BACKGROUND: Approximately 150 women annually become pregnant while taking isotretinoin despite participation in the iPLEDGE program. Noncompliance with the requirement to be abstinent or use 2 contraceptive methods may be a contributing factor. OBJECTIVE: We sought to determine the degree of adherence to contraception or abstinence among women taking isotretinoin. METHODS: We conducted an anonymous survey of women of childbearing potential taking isotretinoin for at least 2 months. RESULTS: Among 75 participants, 21 (28%) chose abstinence as their primary means of pregnancy prevention, of whom 4 (19%) were sexually active during treatment. The most commonly chosen contraceptive methods among the 39 women who were sexually active were condoms (35, 90%) and oral contraceptive pills (18, 46%). Twelve women (31%) admitted to having intercourse at least once using 1 or fewer forms of contraception; 10 failed to use condoms, and 1 reported completely unprotected intercourse. Among sexually active oral contraceptive pill users, 7 (39%) reported missing 1 or more pills in the previous month. LIMITATIONS: Data were self-reported, thus participants may have inaccurately reported contraception use. CONCLUSIONS: Encouraging the use of highly effective, patient-independent contraception and limiting abstinence to women who have never been sexually active may further reduce the rate of isotretinoin-exposed pregnancies. PMID- 24157385 TI - Wraparound, system of care, and child psychiatrists. PMID- 24157386 TI - The delivery of mental health care: where are we and where are we going? PMID- 24157387 TI - Universal mental health screening in pediatrics: toward better knowing, treating, or referring. PMID- 24157388 TI - Universal mental health screening in pediatric primary care: a systematic review. AB - OBJECTIVE: Universal mental health screening in pediatric primary care is recommended, but studies report slow uptake and low rates of patient follow through after referral to specialized services. This review examined possible explanations related to the process of screening, focusing on how parents and youth are engaged, and how providers evaluate and use screening results. METHOD: A narrative synthesis was developed after a systematic review of 3 databases (plus follow-up of citations, expert recommendations, and checks for multiple publications about the same study). Searching identified 1,188 titles, and of these, 186 full-text articles were reviewed. Two authors extracted data from 45 articles meeting inclusion criteria. RESULTS: Published studies report few details about how mental health screens were administered, including how clinicians explain their purpose or confidentiality, or whether help was provided for language, literacy, or disability problems. Although they were not addressed directly in the studies reviewed, uptake and detection rates appeared to vary with means of administration. Screening framed as universal, confidential, and intended to optimize attention to patient concerns increased acceptability. Studies said little about how providers were taught to explore screen results. Screening increased referrals, but many still followed negative screens, in some cases because of parent concerns apparently not reflected by screen results but possibly stemming from screen-prompted discussions. CONCLUSIONS: Little research has addressed the process of engaging patients in mental health screening in pediatric primary care or how clinicians can best use screening results. The literature does offer suggestions for better clinical practice and research that may lead to improvements in uptake and outcome. PMID- 24157389 TI - Gender differences in the relationship between social communication and emotion recognition. AB - OBJECTIVE: To investigate the association between autistic traits and emotion recognition in a large community sample of children using facial and social motion cues, additionally stratifying by gender. METHOD: A general population sample of 3,666 children from the Avon Longitudinal Study of Parents and Children (ALSPAC) were assessed on their ability to correctly recognize emotions using the faces subtest of the Diagnostic Analysis of Non-Verbal Accuracy, and the Emotional Triangles Task, a novel test assessing recognition of emotion from social motion cues. Children with autistic-like social communication difficulties, as assessed by the Social Communication Disorders Checklist, were compared with children without such difficulties. RESULTS: Autistic-like social communication difficulties were associated with poorer recognition of emotion from social motion cues in both genders, but were associated with poorer facial emotion recognition in boys only (odds ratio = 1.9, 95% CI = 1.4, 2.6, p = .0001). This finding must be considered in light of lower power to detect differences in girls. CONCLUSIONS: In this community sample of children, greater deficits in social communication skills are associated with poorer discrimination of emotions, implying there may be an underlying continuum of liability to the association between these characteristics. As a similar degree of association was observed in both genders on a novel test of social motion cues, the relatively good performance of girls on the more familiar task of facial emotion discrimination may be due to compensatory mechanisms. Our study might indicate the existence of a cognitive process by which girls with underlying autistic traits can compensate for their covert deficits in emotion recognition, although this would require further investigation. PMID- 24157390 TI - Overreactive brain responses to sensory stimuli in youth with autism spectrum disorders. AB - OBJECTIVES: Sensory over-responsivity (SOR), defined as a negative response to or avoidance of sensory stimuli, is both highly prevalent and extremely impairing in youth with autism spectrum disorders (ASD), yet little is known about the neurological bases of SOR. This study aimed to examine the functional neural correlates of SOR by comparing brain responses to sensory stimuli in youth with and without ASD. METHOD: A total of 25 high-functioning youth with ASD and 25 age and IQ-equivalent typically developing (TD) youth were presented with mildly aversive auditory and visual stimuli during a functional magnetic resonance imaging (fMRI) scan. Parents provided ratings of children's SOR and anxiety symptom severity. RESULTS: Compared to TD participants, ASD participants displayed greater activation in primary sensory cortical areas as well as amygdala, hippocampus, and orbital-frontal cortex. In both groups, the level of activity in these areas was positively correlated with level of SOR severity as rated by parents, over and above behavioral ratings of anxiety. CONCLUSIONS: This study demonstrates that youth with ASD show neural hyper-responsivity to sensory stimuli, and that behavioral symptoms of SOR may be related to both heightened responsivity in primary sensory regions as well as areas related to emotion processing and regulation. PMID- 24157393 TI - Risk factors and the evolution of psychosis in 22q11.2 deletion syndrome: a longitudinal 2-site study. AB - OBJECTIVE: 22q11.2 Deletion syndrome (22q11.2DS) is associated with high rates of schizophrenia, other neuropsychiatric disorders, and cognitive deficits. The objectives of this 2-center study were to longitudinally assess the trajectories of psychiatric disorders in 22q11.2DS from childhood to adulthood, and to identify risk factors for their emergence. METHOD: A total of 125 children and adults with 22q11.2DS were evaluated at 2 time points, baseline and follow-up (4 years apart), using standardized psychiatric and cognitive measures. RESULTS: The rate of mood disorders tended to decrease during childhood and increase during late adolescence. Statistically significant predictors for the presence of a psychotic disorder as well as the severity of positive symptoms at follow-up were identical, and consisted of an anxiety disorder at baseline, lower baseline Full Scale IQ, and a greater decrease in verbal IQ scores between time points. Nine of 10 individuals with an emerging psychotic disorder had an anxiety disorder at baseline. The age of onset for a psychotic disorder was between 14 and 22 years in 82.6% of cases. CONCLUSIONS: It is important to evaluate the presence of anxiety disorders in children and adolescents with 22q11.2DS, as they are major risk factors for the emergence of psychotic disorders, which usually occur during late adolescence in this at-risk population. PMID- 24157391 TI - A potential electroencephalography and cognitive biosignature for the child behavior checklist-dysregulation profile. AB - OBJECTIVE: The Child Behavior Checklist-Dysregulation Profile (CBCL/DP) identifies youth at increased risk for significant psychopathology. Although the genetic architecture and several biological correlates of the CBCL/DP have been described, little work has elucidated its underlying neurobiology. We examined the potential utility of electroencephalography (EEG), along with behavioral and cognitive assessments, in differentiating individuals based on the CBCL/DP. METHOD: Participants aged 7 to 14 years of age were categorized into 3 age- and sex-matched groups based on clinical assessment and CBCL/DP: typically developing controls without attention-deficit/hyperactivity disorder (ADHD) (n = 38), individuals with ADHD without the CBCL/DP (ADHD/DP-) (n = 38), and individuals with the CBCL/DP (CBCL/DP+) (n = 38). Groups were compared with EEG and measures of clinical phenomenology and cognition. RESULTS: ADHD/DP- and CBCL/DP+ groups had increased inattention, but the CBCL/DP+ group had increased hyperactive/impulsive symptoms, disruptive behavior, mood, and anxiety comorbidities compared with the group with ADHD alone. Cognitive profiles suggested that ADHD/DP-participants had fast impulsive responses, whereas CBCL/DP+ participants were slow and inattentive. On EEG, CBCL/DP+ had a distinct profile of attenuated delta-band and elevated alpha-band spectral power in the central and parietal regions compared to ADHD/DP- and controls. The low delta/high-alpha profile was correlated with measures of emotion and behavior problems and not with inattentive symptomatology or cognitive measures. There were no EEG differences between the ADHD/DP- and control groups. CONCLUSIONS: An EEG/cognitive profile suggests a distinct pattern of underlying neural dysfunction with the CBCL/DP that might ultimately serve as a biosignature. Further work is required to identify potential relationships with clinically defined psychiatric disorders, particularly those of dysregulated mood. PMID- 24157394 TI - Candidate genetic pathways for attention-deficit/hyperactivity disorder (ADHD) show association to hyperactive/impulsive symptoms in children with ADHD. AB - OBJECTIVE: Because multiple genes with small effect sizes are assumed to play a role in attention-deficit/hyperactivity disorder (ADHD) etiology, considering multiple variants within the same analysis likely increases the total explained phenotypic variance, thereby boosting the power of genetic studies. This study investigated whether pathway-based analysis could bring scientists closer to unraveling the biology of ADHD. METHOD: The pathway was described as a predefined gene selection based on a well-established database or literature data. Common genetic variants in pathways involved in dopamine/norepinephrine and serotonin neurotransmission and genes involved in neuritic outgrowth were investigated in cases from the International Multicentre ADHD Genetics (IMAGE) study. Multivariable analysis was performed to combine the effects of single genetic variants within the pathway genes. Phenotypes were DSM-IV symptom counts for inattention and hyperactivity/impulsivity (n = 871) and symptom severity measured with the Conners Parent (n = 930) and Teacher (n = 916) Rating Scales. RESULTS: Summing genetic effects of common genetic variants within the pathways showed a significant association with hyperactive/impulsive symptoms ((p)empirical = .007) but not with inattentive symptoms ((p)empirical = .73). Analysis of parent-rated Conners hyperactive/impulsive symptom scores validated this result ((p)empirical = .0018). Teacher-rated Conners scores were not associated. Post hoc analyses showed a significant contribution of all pathways to the hyperactive/impulsive symptom domain (dopamine/norepinephrine, (p)empirical = .0004; serotonin, (p)empirical = .0149; neuritic outgrowth, (p)empirical = .0452). CONCLUSION: The present analysis shows an association between common variants in 3 genetic pathways and the hyperactive/impulsive component of ADHD. This study demonstrates that pathway-based association analyses, using quantitative measurements of ADHD symptom domains, can increase the power of genetic analyses to identify biological risk factors involved in this disorder. PMID- 24157392 TI - Reduced error-related activation of dorsolateral prefrontal cortex across pediatric anxiety disorders. AB - OBJECTIVE: Abnormalities of cognitive control functions, such as conflict and error monitoring, have been theorized to underlie obsessive-compulsive symptoms but only recently have been considered a potentially relevant psychological construct for understanding other forms of anxiety. The authors sought to determine whether these cognitive control processes elicit the same abnormalities of brain function in patients with pediatric obsessive-compulsive disorder (OCD) as in those with non-OCD anxiety disorders. METHOD: Functional magnetic resonance imaging of the Multisource Interference Task was used to measure conflict- and error-related activations in youth (8-18 years) with OCD (n = 21) and non-OCD anxiety disorders (generalized anxiety disorder, social phobia, separation anxiety disorder; n = 23) compared with age-matched healthy controls (n = 25). RESULTS: There were no differences in performance (accuracy, response times) among groups. However, a significant effect of group was observed in the dorsolateral prefrontal cortex (dlPFC) during error processing, driven by decreased activation in patients with OCD and those with non-OCD anxiety compared with healthy youth. Between patient groups, there was no difference in error related dlPFC activation. CONCLUSIONS: Hypoactive dlPFC response to errors occurs in pediatric patients with OCD and those with non-OCD anxiety. These findings suggest that insufficient error-related engagement of the dlPFC associates with anxiety across traditional diagnostic boundaries and appears during the early stages of illness. PMID- 24157395 TI - Design considerations related to short-term psychodynamic psychotherapy. PMID- 24157396 TI - Dr. Abbass et al. reply:. PMID- 24157398 TI - Practice parameter on disaster preparedness. AB - This Practice Parameter identifies best approaches to the assessment and management of children and adolescents across all phases of a disaster. Delivered within a disaster system of care, many interventions are appropriate for implementation in the weeks and months after a disaster. These include psychological first aid, family outreach, psychoeducation, social support, screening, and anxiety reduction techniques. The clinician should assess and monitor risk and protective factors across all phases of a disaster. Schools are a natural site for conducting assessments and delivering services to children. Multimodal approaches using social support, psychoeducation, and cognitive behavioral techniques have the strongest evidence base. Psychopharmacologic interventions are not generally used but may be necessary as an adjunct to other interventions for children with severe reactions or coexisting psychiatric conditions. PMID- 24157399 TI - Kinematic analysis of upper limb during walking in diplegic children with Cerebral Palsy. AB - Movements of the lower limbs during walking have been widely investigated in literature, while quantification of arm movement during gait is scanty. The aim of the present study was to assess quantitatively the upper limb motion during gait in children with Cerebral Palsy (CP). Sixteen children with diplegic CP were evaluated using a full-body marker set, which allows assessing both the lower and upper limb kinematics. Our results demonstrated that movement of the arms was characterized by an abducted shoulder and a more flexed elbow position at the initial contact of the gait cycle with a quite physiological range of motion if compared to controls. These data showed that gait of children with diplegic CP is generally characterized by abnormal upper limb position which could be considered a strategy to keep balance and posture control during walking. PMID- 24157400 TI - Whole-body vibration training in children with Duchenne muscular dystrophy and spinal muscular atrophy. AB - INTRODUCTION: Whole-body-vibration training is used to improve muscle strength and function and might therefore constitute a potential supportive therapy for neuromuscular diseases. OBJECTIVE: To evaluate safety of whole-body vibration training in ambulatory children with Duchenne muscular dystrophy (DMD) and spinal muscular atrophy (SMA). METHODS: 14 children with DMD and 8 with SMA underwent an 8-week vibration training programme on a Galileo MedM at home (3 * 3 min twice a day, 5 days a week). Primary outcome was safety of the training, assessed clinically and by measuring serum creatine kinase levels. Secondary outcome was efficacy as measured by changes in time function tests, muscle strength and angular degree of dorsiflexion of the ankles. RESULTS: All children showed good clinical tolerance. In boys with DMD, creatine kinase increased by 56% after the first day of training and returned to baseline after 8 weeks of continuous whole body vibration training. No changes in laboratory parameters were observed in children with SMA. Secondary outcomes showed mild, but not significant, improvements with the exception of the distance walked in the 6-min walking test in children with SMA, which rose from 371.3 m to 402.8 m (p < 0.01). INTERPRETATION: Whole-body vibration training is clinically well tolerated in children with DMD and SMA. The relevance of the temporary increase in creatine kinase in DMD during the first days of training is unclear, but it is not related to clinical symptoms or deterioration. PMID- 24157402 TI - mRNA display: from basic principles to macrocycle drug discovery. AB - We describe a new discovery technology that uses mRNA-display to rapidly synthesize and screen macrocyclic peptide libraries to explore a valuable region of chemical space typified by natural products. This technology allows high affinity peptidic macrocycles containing modified backbones and unnatural side chains to be readily selected based on target binding. Success stories covering the first examples of these libraries suggest that they could be used for the discovery of intracellular protein-protein interaction inhibitors, highly selective enzyme inhibitors or synthetic replacements for monoclonal antibodies. The review concludes with a look to the future regarding how this technology might be improved with respect to library design for cell permeability and bioavailability. PMID- 24157401 TI - Sex differences in the neural and behavioral response to intranasal oxytocin and vasopressin during human social interaction. AB - Both oxytocin (OT) and vasopressin (AVP) are known to modulate social behavior, and dysfunction in both systems has been postulated as a potential cause of certain psychiatric disorders that involve social behavioral deficits. In particular, there is growing interest in intranasal OT as a potential treatment for certain psychiatric disorders, and preliminary pre-clinical and clinical studies suggest efficacy in alleviating some of the associated symptoms. However, the vast majority of research participants in these studies have been male, and there is evidence for sexually differentiated effects of nonapeptides in both humans and non-human animals. To date, no study has investigated the effect of intranasal OT on brain function in human males and females within the same paradigm. Previously, in a randomized, placebo-controlled, double-blind fMRI study, we reported effects of intranasal OT and AVP on behavior and brain activity of human males as they played an interactive social game known as the Prisoner's Dilemma Game. Here, we present findings from an identical study in human females, and compare these with our findings from males. Overall, we find that both behavioral and neural responses to intranasal OT and AVP are highly sexually differentiated. In women, AVP increased conciliatory behavior, and both OT and AVP caused women to treat computer partners more like humans. In men, AVP increased reciprocation of cooperation from both human and computer partners. However, no specific drug effects on behavior were shared between men and women. During cooperative interactions, both OT and AVP increased brain activity in men within areas rich in OT and AVP receptors and in areas playing a key role in reward, social bonding, arousal and memory (e.g., the striatum, basal forebrain, insula, amygdala and hippocampus), whereas OT and AVP either had no effect or in some cases actually decreased brain activity in these regions in women. OT treatment rendered neural responses of males more similar to responses of females in the placebo group and vice versa, raising the prospect of an inverted u-shaped dose response to central OT levels. These findings emphasize the need to fully characterize the effects of intranasal OT and AVP in both males and females and at multiple doses before widespread clinical application will be warranted. PMID- 24157403 TI - Effects of calcium and training on the development of bone density in children with Down syndrome. AB - In this study we examined the effects of physical training and calcium intake on the development of bone mineral density (BMD) in children with Down syndrome (DS). A total of 48 children with DS (age 7-12 years old) matched for age and BMD were assigned to four groups exercise and calcium intake (Ex(+)Ca(+)), calcium intake-no-exercise (Ex(-)Ca(+)), exercise no-calcium intake (Ex(+)Ca(-)) and non exercise-no-calcium intake (Ex(-)Ca(-)). The training protocol included 45 min of weight bearing exercise performed 3 sessions per week in addition to dietary calcium rich food intake of enriched cow milk with vitamin D containing 200 mg calcium per serving or no enriched dietary supplement for a duration of 4 months. Data analysis was performed on data by using t-test, one-way ANOVA analysis and Tukey post hoc tests to determine the main and combined effects of training and calcium regiment on BMD. All groups showed greater femoral neck BMD after 4 months. The increase in femoral neck BMD in the Ex(+)Ca(+) group was 5.96% greater than the Ex(+)Ca(-) group (p<0.01). The effect of training was greater than calcium intake alone. The Ex(+)Ca(-) group achieved 3.52% greater BMD than Ex(-)Ca(+) group (p<0.01). In this study, all the experimental groups had greater BMD than the no-calcium-no-exercise group that served as the control group (p<0.01). It was concluded that additional weight bearing exercise and calcium supplementation resulted in a greater increase in BMD in children with DS. PMID- 24157404 TI - Practical and social skills of 16-19-year-olds with Down syndrome: independence still far away. AB - Survival of children with Down syndrome (DS) has improved considerably, but insight into their level of daily functioning upon entering adulthood is lacking. We collected cross-sectional data from a Dutch nationwide cohort of 322 DS adolescents aged 16-19 (response 62.8%) to assess the degree to which they master various practical and social skills, using the Dutch Social competence rating scale and the Children's Social Behavior Questionnaire. Up to 60% mastered some of the skills required for independent functioning, such as maintaining adequate standards of personal hygiene and preparing breakfast. Less than 10% had achieved basic skills such as basic cooking and paying in a shop. It is difficult for DS people to master all the skills necessary to live independently. Ninety percent of adolescents with DS experience significant problems in social functioning. PMID- 24157405 TI - Subsequent axillary surgery after sentinel lymph node biopsy: results from the BreastSurgANZ Quality Audit 2006-2010. AB - OBJECTIVES: To use data from the BreastSurgANZ Quality Audit (BQA) to examine the patterns of completion axillary lymph node dissection (cALND) after sentinel lymph node (SLN) biopsy in women treated for early breast cancer in Australia and New Zealand and to compare it to the Australian and New Zealand guidelines in cases of both positive and negative SLN results. MATERIALS AND METHODS: Patients were sub grouped as having primary tumours <=3 cm and >3 cm and further analysed according to year of surgery, SLN status and final nodal status where cALND was recorded. Multivariate analysis was performed examining tumour size, grade, presence of lymphovascular invasion (LVI), HER2 and oestrogen receptor status, patient age and number of positive sentinel nodes as predictors for subsequent axillary surgery. RESULTS: 14879 patients were identified from 2006 to 2010. 79.8% of patients with a positive SLN result underwent cALND. Age >70 years and a greater number of involved SLN predicted no cALND among SLN positive patients. 10.3% of patients who had a negative SLN result underwent cALND. Younger age, higher grade, lymphovascular invasion and tumour size >3 cm predicted cALND among SLN negative patients. CONCLUSIONS: According to the BQA from 2006 to 2010 the Australian and New Zealand guideline recommendations for SLN positive patients to have cALND and SLN negative patients not to have cALND were adhered to in 79.8% and 89.7% of cases respectively. PMID- 24157407 TI - The Cochrane Collaboration: a 20 year celebration. PMID- 24157406 TI - Influence of gold(I) complexes involving adenine derivatives on major drug-drug interaction pathway. AB - A series of considerably anti-inflammatory active gold(I) mixed-ligand complexes, involving the benzyl-substituted derivatives of N6-benzyladenine (HLn) and triphenylphosphine (PPh3) as ligands and having the general formula [Au(Ln)(PPh3)].xH2O (1-4; n=1-4 and x=0-1), was evaluated for the ability to influence the expression of CYP1A1/2 and CYP3A4 and transcriptional activity of glucocorticoid (GR) and aryl hydrocarbon (AhR) receptors in primary human hepatocytes and HepG2 cells. In both tests, evaluating the ability of the complexes to modulate the expression of CYP1A1, CYP1A2 and CYP3A4 in primary human hepatocytes and influence the transcriptional activity of AhR and GR in the reporter cell lines, no negative influence on the major drug-metabolizing cytochrome P450 isoenzymes and their signaling pathway (through GR and AhR receptors) was observed. These positive findings revealed another substantial evidence that could lead to utilization of the complexes as effective and relatively safe drugs for the treatment of hard-to-treat inflammation-related diseases, such as rheumatoid arthritis, comparable or even better than clinically used gold-containing drug Auranofin. PMID- 24157408 TI - Research in cardiovascular care: a position statement of the Council on Cardiovascular Nursing and Allied Professionals of the European Society of Cardiology. AB - To deliver optimal patient care, evidence-based care is advocated and research is needed to support health care staff of all disciplines in deciding which options to use in their daily practice. Due to the increasing complexity of cardiac care across the life span of patients combined with the increasing opportunities and challenges in multidisciplinary research, the Science Committee of the Council on Cardiovascular Nursing and Allied Professionals (CCNAP) recognised the need for a position statement to guide researchers, policymakers and funding bodies to contribute to the advancement of the body of knowledge that is needed to further improve cardiovascular care. In this paper, knowledge gaps in current research related to cardiovascular patient care are identified, upcoming challenges are explored and recommendations for future research are given. PMID- 24157409 TI - Environmental impact assessment using a utility-based recursive evidential reasoning approach for structural flood mitigation measures in Metro Manila, Philippines. AB - In recent years, the practice of environmental impact assessment (EIA) has created significant awareness on the role of environmentally sound projects in sustainable development. In view of the recent studies on the effects of climate change, the Philippine government has given high priority to the construction of flood control structures to alleviate the destructive effects of unmitigated floods, especially in highly urbanized areas like Metro Manila. EIA thus, should be carefully and effectively carried out to maximize or optimize the potential benefits that can be derived from structural flood mitigation measures (SFMMs). A utility-based environmental assessment approach may significantly aid flood managers and decision-makers in planning for effective and environmentally sound SFMM projects. This study proposes a utility-based assessment approach using the rapid impact assessment matrix (RIAM) technique, coupled with the evidential reasoning approach, to rationally and systematically evaluate the ecological and socio-economic impacts of 4 planned SFMM projects (i.e. 2 river channel improvements and 2 new open channels) in Metro Manila. Results show that the overall environmental effects of each of the planned SFMM projects are positive, which indicate that the utility of the positive impacts would generally outweigh the negative impacts. The results also imply that the planned river channel improvements will yield higher environmental benefits over the planned open channels. This study was able to present a clear and rational approach in the examination of overall environmental effects of SFMMs, which provides valuable insights that can be used by decision-makers and policy makers to improve the EIA practice and evaluation of projects in the Philippines. PMID- 24157410 TI - Removal of groundwater arsenic using a household filter with iron spikes and stainless steel. AB - Arsenic (As) in groundwater for domestic use poses a worldwide threat to public health, most notably in rural areas. The aims of this study were: first, determine groundwater composition in a mining area in central Mexico (Huautla); second, assess As exposure through human groundwater consumption and; third, develop and test a household filter to obtain drinking water for these rural communities. From the 17th century through the 1990s, mines in the area produced Ag-galena and sphalerite from volcanic rock. Groundwater flooded the mines when they were abandoned due to low silver prices. Local households now use the water to meet domestic needs. Water from the mines was found to have high As content (0.04-0.26 mg L(-1)) and Fe, Mn, Pb and Cd were also above Mexican drinking water standards and WHO guidelines. All the population in the Huautla community was exposed to the metalloid through water used in food preparation. The best As removal was obtained with a filter using oxidized commercial fiber (HCl 2N as oxidant). Concentrations in the effluent were below Mexican drinking water standards (0.025 mg As L(-1) water) during the 105-day (2520 h) filter operation, with a maximum As removal efficiency of 95.4%. The household filter was simple, low-cost and may be very attractive for As removal in rural areas in developing countries. PMID- 24157411 TI - Effort for money? Farmers' rationale for participation in agri-environment measures with different implementation complexity. AB - European agri-environment programmes are based on the common principle that farmers deliver environmental services for which society pays. Due to the voluntary nature of agri-environment measures (AEM), the issue of farmers' motives or reasons for participation has been an important topic of investigation in past years. The present paper examines farmers' rationale for participation in AEM against the backdrop of continued debate over whether to develop relatively simple measures that can be readily applied by many farmers or give greater priority to measures that are more targeted - i.e. to the specific management requirement of particular habitats or species - but are often more complex. The paper draws on empirical material from a case study in the Dyle valley, Belgium, including in-depth interviews, expert consultations and a mail survey. It was sought not only to identify and quantify the importance of separate reasons for participation, but also to reveal how these reasons and other elements of relevance were logically interrelated in the explanation that farmers themselves give for their participation. As a result, six modes or styles of participation were identified: opportunistic, calculative, compensatory, optimising, catalysing and engaged. The analyses suggest that there were notable differences in that both separate reasons for and modes of participation do vary with the complexity of the measures' requirements. Overall, the study demonstrates that participation in AEM is not simply a matter of weighing the money against the effort for adoption. Whereas money is an important driver for participation (in particular, for those adopting complex AEM) it plays widely differing roles depending on the level of farmers' reasoning (farm enterprise, single practice or landscape feature) and the importance they give to other considerations (environmental effect, production potential of land, goodness of fit, etc.). Practical implications are drawn for both policy makers and programme managers who develop and make available tailor-made support. PMID- 24157412 TI - Fate of Cryptosporidium parvum oocysts within soil, water, and plant environment. AB - Vegetative Filter Strips (VFS) have long been used to control the movement of agricultural nutrients and prevent them from reaching receiving waters. Earlier studies have shown that VFS also dramatically reduce both the kinetics and extent of Cryptosporidium parvum (C. parvum) oocysts overland transport. In this study, we investigated possible mechanisms responsible for the ability of VFS to reduce oocyst overland transport. Measurement of the kinetics of C. parvum adhesion to individual sand, silt, and clay soil particles revealed that oocysts associate over time, albeit relatively slow, with clay but not silt or sand particles. Measurement of oocyst overland transport kinetics, soil infiltration depth, distance of travel, and adhesion to vegetation on bare and vegetated soil surfaces indicate that oocysts move more slowly, and penetrate the soil profile to a greater extent on a vegetated surface than on a bare soil surface. Furthermore, we demonstrate a small fraction of the oocysts become attached to vegetation at the soil-vegetation interface on VFS. These results suggest VFS function to reduce oocyst overland transport by primarily decreasing oocyst surface flow enough to allow penetration within the soil profile followed by subsequent adhesion to or entrapment within clay particle aggregates, and to a lesser extent, adhesion to the surface vegetation. PMID- 24157413 TI - Multi-scale simulation of electron emission from a triode-type electron source with a carbon-nanotube column array cathode. AB - We have designed and fabricated a new type of field electron source for a novel onboard mass spectrometer. The new electron source, which is a field effect emitter in a triode configuration, consists of a CNT-column array cathode and an extraction gate with holes that are aligned concentrically with respect to the cylindrical CNT columns. In triode mode operation, cathode currents as large as ~420 MUA have been emitted with an anode-to-gate current ratio of ~1.5. To account for the observed emission characteristics of the new electron source, we have carried out multi-scale simulations that combine a three-dimensional (3D) microscopic model in the vicinity of an actual emission site with a two dimensional (2D) macroscopic model that covers the whole device structure. Because the mesh size in the microscopic 3D model is as small as 100 nm, the contributions of the extruding CNT bundle at the top edge of an electron column can be examined in detail. Unlike the macroscopic 2D simulation that shows only small field enhancement at CNT column's top edge, the multi-scale simulation successfully reproduced the local electric field strongly enough to emit the measured cathode currents and the electric field distribution which is consistent with the measured anode-to-gate current ratio. PMID- 24157414 TI - Early treatment during primary infection holds the key to a functional cure for HIV. PMID- 24157415 TI - [Effects of gastric bypass on estimated cardiovascular risk in morbidly obese patients with metabolic syndrome]. AB - INTRODUCTION: The major goal of surgical treatment in morbid obesity is to decrease morbidity and mortality associated with excess weight. In this sense, the main factors of death are cardiovascular disease and metabolic syndrome. The objective of this study is to evaluate the effects of gastric bypass on cardiovascular risk estimation in patients after bariatric surgery. MATERIAL AND METHODS: We retrospectively evaluated pre and postoperative cardiovascular risk estimation of 402 morbidly obese patients who underwent laparoscopic gastric bypass. The major variable studied is the cardiovascular risk estimation that is calculated preoperatively and after 12 months. Cardiovascular risk estimation analysis has been performed with the REGICOR Equation. REGICOR formulation allows calculating a 10 year risk of cardiovascular events adapted to the Spanish population and is expressed in percentages. RESULTS: We reported an overall 4.1+/ 3.0 mean basal REGICOR score. One year after the operation, cardiovascular risk estimation significantly decreased to 2,2+/-1,6 (P<.001). In patients with metabolic syndrome according to ATP-III criteria, basal REGICOR score was 4.8+/ 3.1 whereas in no metabolic syndrome patients 2.2+/-1.8. Evaluation 12 months after surgery, determined a significant reduction in both groups (metabolic syndrome and non metabolic syndrome) with a mean REGICOR score of 2.3+/-1.6 and 1.6+/-1.0 respectively. CONCLUSION: The results of our study demonstrate favorable effects of gastric bypass on the cardiovascular risk factors included in the REGICOR equation. PMID- 24157416 TI - [Intestinal neurilemmoma]. PMID- 24157419 TI - [In Process Citation]. PMID- 24157417 TI - DNA methylation is associated with an increased level of conservation at nondegenerate nucleotides in mammals. AB - DNA methylation at CpG dinucleotides can significantly increase the rate of cytosine-to-thymine mutations and the level of sequence divergence. Although the correlations between DNA methylation and genomic sequence evolution have been widely studied, an unaddressed yet fundamental question is how DNA methylation is associated with the conservation of individual nucleotides in different sequence contexts. Here, we demonstrate that in mammalian exons, the correlations between DNA methylation and the conservation of individual nucleotides are dependent on the type of exonic sequence (coding or untranslated), the degeneracy of coding nucleotides, background selection pressure, and the relative position (first or nonfirst exon in the transcript) where the nucleotides are located. For untranslated and nonzero-fold degenerate nucleotides, methylated sites are less conserved than unmethylated sites regardless of background selection pressure and the relative position of the exon. For zero-fold degenerate (or nondegenerate) nucleotides, however, the reverse trend is observed in nonfirst coding exons and first coding exons that are under stringent background selection pressure. Furthermore, cytosine-to-thymine mutations at methylated zero-fold degenerate nucleotides are predicted to be more detrimental than those that occur at unmethylated nucleotides. As zero-fold and nonzero-fold degenerate nucleotides are very close to each other, our results suggest that the "functional resolution" of DNA methylation may be finer than previously recognized. In addition, the positive correlation between CpG methylation and the level of conservation at zero-fold degenerate nucleotides implies that CpG methylation may serve as an "indicator" of functional importance of these nucleotides. PMID- 24157420 TI - A literature review on oral basaloid squamous cell carcinomas, with special emphasis on etiology. AB - In the recent years, basaloid squamous cell carcinomas (BSCCs) have gained attention because of (1) observation of a relative increase in the number of tumors arising particularly in head and neck sites, (2) identification of human papillomavirus (HPV) in BSCCs arising predominantly in the oropharynx, and (3) controversies that exist regarding the biological aggressiveness of the tumor. The objective of the present review was to address the issues mentioned above by focusing primarily on oral BSCCs, using literature that has been published in the English language up to 2013. According to the literature review, oral BSCCs were found to be relatively more common in elderly patients with a mean age of 64 years. A male predominance with a male/female ratio of 3:1 was observed. The predominant site was the tongue, with almost half of the reported cases occurring at this site, followed by the floor of the mouth and palate. With reference to habit history, majority were found to be tobacco and alcohol users. However, only 3 studies revealed data on HPV status of purely oral BSCC, and according to the results of these studies, of the 17 tumors tested, 4 had harbored high-risk HPV. Furthermore, most oral BSCCs were in an advanced clinical stage, namely, stage III or IV with T3 or T4 lesions and cervical lymph node metastasis at initial presentation, whereas 41% of patients had presented with local recurrences and 45% had died of the disease. In conclusion, although, the present literature review found enough evidence to consider tobacco and alcohol as risk factors for the development of oral BSCC, steps should be taken to fill the gap in our knowledge that exist with reference to contribution of oncoviruses, particularly HPV in the etiology of oral BSCC. PMID- 24157418 TI - Tgfbeta-Smad and MAPK signaling mediate scleraxis and proteoglycan expression in heart valves. AB - Mature heart valves are complex structures consisting of three highly organized extracellular matrix layers primarily composed of collagens, proteoglycans and elastin. Collectively, these diverse matrix components provide all the necessary biomechanical properties for valve function throughout life. In contrast to healthy valves, myxomatous valve disease is the most common cause of mitral valve prolapse in the human population and is characterized by an abnormal abundance of proteoglycans within the valve tri-laminar structure. Despite the clinical significance, the etiology of this phenotype is not known. Scleraxis (Scx) is a basic-helix-loop-helix transcription factor that we previously showed to be required for establishing heart valve structure during remodeling stages of valvulogenesis. In this study, we report that remodeling heart valves from Scx null mice express decreased levels of proteoglycans, particularly chondroitin sulfate proteoglycans (CSPGs), while overexpression in embryonic avian valve precursor cells and adult porcine valve interstitial cells increases CSPGs. Using these systems we further identify that Scx is positively regulated by canonical Tgfbeta2 signaling during this process and this is attenuated by MAPK activity. Finally, we show that Scx is increased in myxomatous valves from human patients and mouse models, and overexpression in human mitral valve interstitial cells modestly increases proteoglycan expression consistent with myxomatous mitral valve phenotypes. Together, these studies identify an important role for Scx in regulating proteoglycans in embryonic and mature valve cells and suggest that imbalanced regulation could influence myxomatous pathogenesis. PMID- 24157421 TI - Effects of molsidomine against doxorubicin-induced cardiotoxicity in rats. AB - PURPOSE: To explore the protective and curative effects of molsidomine (MOL) on doxorubicin (DOX)-induced cardiac damage in the in vivo rat heart. METHODS: Forty rats were randomized into five groups (n = 8): (1) the control group; (2) the MOL group (10 mg/kg for 21 days); (3) the DOX group (a single dose of 20 mg/kg); (4) the DOX + MOL group (3 days after the single dose of DOX, 10 mg/kg MOL continued for 21 days), and (5) the MOL + DOX group (24 h after a 21-day regimen of 10 mg/kg MOL, a single dose of DOX). The rats were monitored for mean arterial blood pressure, heart rate, O2 saturation, and electrocardiography. Heart tissue levels of malondialdehyde (MDA), superoxide dismutase (SOD), catalase (CAT), reduced glutathione (GSH), and nitric oxide (NO) were determined. RESULTS: Blood pressure and O2 saturation values indicated a significant decrease in the DOX group compared with the control group. T negativity was observed in 4 of 8 rats in the DOX group, in 1 of 8 rats in the DOX + MOL group, and in 4 of 8 rats in the MOL + DOX group. MDA levels were significantly higher in the DOX group. SOD, GSH, and NO levels were significantly lower in the DOX group compared with the other groups. There was no statistically significant difference in the CAT levels in any of the study groups compared with controls. DOX treatment induced morphological alterations, such as disorganization of cardiomyocytes, loss of myofibrils, and cytoplasmic vacuolization in the heart. On the other hand, histological damage was significantly reduced in the DOX + MOL and MOL + DOX groups. CONCLUSION: This study implies that there are cardioprotective effects of MOL on DOX-induced cardiotoxicity. PMID- 24157422 TI - Antibody-dependent cellular cytotoxicity in patients on chronic hemodialysis. AB - BACKGROUND: Antibody (Ab)-dependent cellular cytotoxicity (ADCC) is considered to be a relevant mechanism of action of Ab-based tumor therapies. However, knowledge about ADCC capacity of dialysis patients (DP) is limited. The aim of our study was to investigate if ADCC capacity of effector cells obtained from DP differed from those of healthy individuals (HI). METHODS: First, we performed ADCC assays with isolated polymorphonuclear cells (PMN) and peripheral blood mononuclear cells (PBMC), mediated by the epidermal growth factor receptor Ab cetuximab or panitumumab. As cetuximab is of human IgG1 and panitumumab of human IgG2 isotype, both Abs differ in their affinity to Fcgamma receptors and effector cell recruitment. RESULTS: Using PMN as effectors, ADCC levels via panitumumab proved to be higher than via cetuximab, but did not differ between DP and HI. In contrast, IgG2-mediated ADCC with PBMC from DP was significantly enhanced compared to HI. IgG2 Abs predominantly bind to FcgammaRIIa. Within the PBMC, monocytes are the only cytotoxic cells physiologically expressing this receptor. ADCC experiments with isolated monocytes confirmed them to be the pivotal cells for the observed effect. Analysis of monocytes' Fc receptor expression demonstrated no difference between DP and HI, but monocytes of DP proved to be numerically increased and appeared preactivated. CONCLUSION: Our studies implicate that ADCC capacity is not impaired in DP and that it might particularly be reasonable to apply human IgG2 Abs as therapeutics for these patients. PMID- 24157423 TI - The use of alcohol mixed with energy drinks and experiences of sexual victimization among male and female college students. AB - Much research has documented negative associations with the consumption of alcohol mixed with energy drinks (AmED). To date, few research studies have examined the relation between AmED and sexual victimization. Furthermore, research on sexual victimization among men is less studied. The present study employed a sample of 253 men and 545 women to examine the differential associations between AmED consumption and sexual victimization as a function of gender. Results from this study suggest that AmED consumption is robustly associated with being sexually victimized among men, but not women. These results were robust while controlling for demographic factors and other substance use. Results add to the literature on sexual victimization by potentially identifying a new high-risk drinking behavior among males who have been sexually victimized. PMID- 24157424 TI - Application of the protection motivation theory in predicting cigarette smoking among adolescents in China. AB - Reducing tobacco use among adolescents in China represents a significant challenge for global tobacco control. Existing behavioral theories developed in the West - such as the Protection Motivation Theory (PMT) - may be useful tools to help tackle this challenge. We examined the relationships between PMT factors and self-reported cigarette smoking behavior and intention among a random sample of vocational high school students (N=553) in Wuhan, China. Tobacco-related perceptions were assessed using the PMT Scale for Adolescent Smoking. Among the total sample, 45% had initiated cigarette smoking, and 25% smoked in the past month. Among those who never smoked, 15% indicated being likely or very likely to smoke in a year. Multiple regression modeling analysis indicated the significance of the seven PMT constructs, the four PMT perceptions and the two PMT pathways in predicting intention to smoke and actual smoking behavior. Overall, perceived rewards of smoking, especially intrinsic rewards, were consistently positively related to smoking intentions and behavior, and self-efficacy to avoid smoking was negatively related to smoking. The current study suggests the utility of PMT for further research examining adolescent smoking. PMT-based smoking prevention and clinical smoking cessation intervention programs should focus more on adolescents' perceived rewards from smoking and perceived efficacy of not smoking to reduce their intention to and actual use of tobacco. PMID- 24157425 TI - Characteristics of American Indian light smokers. AB - INTRODUCTION: American Indians (AI) have the highest smoking rates of any racial/ethnic group in the U.S. and have more difficulty quitting smoking. Little is known about the smoking characteristics of AI smokers. The present study compared the demographic and smoking characteristics of light (<=10 cigarettes per day; N=206) and moderate/heavy (11+ cigarettes per day; N=86) AI smokers participating in a cross-sectional survey about smoking and health. METHODS: Multiple methods were used to recruit participants in attendance at powwows, health and career fairs, and conferences. A total of 998 AI (76% cooperation rate) completed a survey assessing general health, sociodemographics, traditional and commercial tobacco use, knowledge and attitudes related to cancer, source of health information and care and other health-related behaviors. RESULTS: AI light smokers were younger and less likely to be married or living with a partner compared to moderate/heavy smokers. AI light smokers were less dependent on smoking and more likely to have home smoking restrictions. There were no differences with respect to number of quit attempts in the past year or the average length of their most recent quit attempt by light vs. moderate/heavy smoking. In addition, a similar proportion of light and heavy smokers reported using tobacco for traditional purposes such as ceremonial, spiritual and prayer. CONCLUSIONS: These findings highlight important differences between AI light and heavier smokers. Differences related to smoking characteristics such as level of dependence and home smoking restrictions have important implications for the treatment of AI smokers. PMID- 24157426 TI - Maternal and peer influences on drinking among Latino college students. AB - Previous research on college drinking has paid little attention to Latino students. Social development models (Catalano, Hawkins, & Miller, 1992) suggest that protective influences in one domain (e.g., mothers) can offset negative influences from other domains (e.g., peers) though this possibility has not been explored with respect to Latino college student drinking. The present study had two aims: 1) to determine whether four specific maternal influences (monitoring, positive communication, permissiveness, and modeling) and peer descriptive norms were associated with college drinking and consequences among Latino students, and 2) to determine whether maternal influences moderated the effect of peer norms on college drinking and consequences. A sample of 362 first-year students (69.9% female) completed an online assessment regarding their mothers' monitoring, positive communication, permissiveness, and modeling, peer descriptive norms, and drinking and related consequences. Main effects and two-way interactions (mother*peer) were assessed using separate hierarchical regression models for three separate outcomes: peak drinking, weekly drinking, and alcohol-related consequences. Maternal permissiveness and peer descriptive norms were positively associated with drinking and consequences. Maternal communication was negatively associated with consequences. Findings indicate that previously identified maternal and peer influences are also relevant for Latino students and highlight future directions that would address the dearth of research in this area. PMID- 24157427 TI - Gene expression and reproductive abilities of male Drosophila melanogaster subjected to ELF-EMF exposure. AB - Extremely low frequency electromagnetic field (ELF-EMF) exposure is attracting increased attention as a possible disease-inducing factor. The in vivo effects of short-term and long-term ELF-EMF exposure on male Drosophila melanogaster were studied using transcriptomic analysis for preliminary screening and QRT-PCR for further verification. Transcriptomic analysis indicated that 439 genes were up regulated and 874 genes were down-regulated following short-term exposures and that 514 genes were up-regulated and 1206 genes were down-regulated following long-term exposures (expression >2- or <0.5-fold, respectively). In addition, there are 238 up-regulated genes and 598 down-regulated genes in the intersection of short-term and long-term exposure (expression >2- or <0.5-fold). The DEGs (differentially expressed genes) in D. melanogaster following short-term exposures were involved in metabolic processes, cytoskeletal organization, mitotic spindle organization, cell death, protein modification and proteolysis. Long-term exposure let to changes in expression of genes involved in metabolic processes, response to stress, mitotic spindle organization, aging, cell death and cellular respiration. In the intersection of short-term and long-term exposure, a series of DEGs were related to apoptosis, aging, immunological stress and reproduction. To check the ELF-EMF effects on reproduction, some experiments on male reproduction ability were performed. Their results indicated that short term ELF-EMF exposure may decrease the reproductive ability of males, but long term exposures had no effect on reproductive ability. Down-regulation of ark gene in the exposed males suggests that the decrease in reproductive capacity may be induced by the effects of ELF-EMF exposure on spermatogenesis through the caspase pathway. QRT-PCR analysis confirmed that jra, ark and decay genes were down regulated in males exposed for 1 Generation (1G) and 72 h, which suggests that apoptosis may be inhibited in vivo. ELF-EMF exposure may have accelerated cell senescence, as suggested by the down-regulation of both cat and jra genes and the up-regulation of hsp22 gene. Up-regulation of totA and hsp22 genes during exposure suggests that exposed flies might induce an in vivo immune response to counter the adverse effects encountered during ELF-EMF exposure. Down-regulation of cat genes suggests that the partial oxidative protection system might be restrained, especially during short-term exposures. This study demonstrates the bioeffects of ELF-EMF exposure and provides evidence for understanding the in vivo mechanisms of ELF-EMF exposure on male D. melanogaster. PMID- 24157428 TI - Gonadal hormones differently modulate cutaneous wound healing of chronically stressed mice. AB - Gonadal hormones influence physiological responses to stress and cutaneous wound healing. The aim of this study was to investigate the role of gonadal hormones on cutaneous wound healing in chronically stressed mice. Male and female mice were gonadectomized, and after 25 days, they were spun daily at 115 rpm for 15 min every hour until euthanasia. Twenty-eight days after the gonadectomy, an excisional lesion was created. The animals were killed 7 or 14 days after wounding, and the lesions were collected. Myofibroblast density, macrophage number, catecholamine level, collagen deposition, and blood vessel number were evaluated. In the intact and gonadectomized groups, stress increased the plasma catecholamine levels in both genders. In intact groups, stress impaired wound contraction and re-epithelialization and increased the macrophage number in males but not in females. In addition, stress compromised myofibroblastic differentiation and blood vessel formation and decreased collagen deposition in males but not in females. In contrast to intact mice, wound healing in ovariectomized female mice was affected by stress, while wound healing in castrated male mice was not. In conclusion, gender differences contribute to the cutaneous wound healing of chronically stressed mice. In addition, androgens contribute to the stress-induced impairment of the healing of cutaneous wounds but estrogens inhibit it. PMID- 24157429 TI - The psychoneuroimmunological effects of music: a systematic review and a new model. AB - There has been a growing interest over the past decade into the health benefits of music, in particular examining its psychological and neurological effects. Yet this is the first attempt to systematically review publications on the psychoneuroimmunology of music. Of the selected sixty-three studies published over the past 22 years, a range of effects of music on neurotransmitters, hormones, cytokines, lymphocytes, vital signs and immunoglobulins as well as psychological assessments are cataloged. Research so far points to the pivotal role of stress pathways in linking music to an immune response. However, several challenges to this research are noted: (1) there is very little discussion on the possible mechanisms by which music is achieving its neurological and immunological impact; (2) the studies tend to examine biomarkers in isolation, without taking into consideration the interaction of the biomarkers in question with other physiological or metabolic activities of the body, leading to an unclear understanding of the impact that music may be having; (3) terms are not being defined clearly enough, such as distinctions not being made between different kinds of stress and 'music' being used to encompass a broad spectrum of activities without determining which aspects of musical engagement are responsible for alterations in biomarkers. In light of this, a new model is presented which provides a framework for developing a taxonomy of musical and stress-related variables in research design, and tracing the broad pathways that are involved in its influence on the body. PMID- 24157430 TI - Prenatal nicotine exposure increases anxiety and modifies sensorimotor integration behaviors in adult female mice. AB - Prenatal exposure to nicotine (PNE) has been associated with a myriad of physiological, cognitive, and behavioral effects in the developing offspring. In this study, CD-1 dams were given injections of nicotine or control vehicle throughout gestation and their offspring were raised to 6 months of age. Adult mice were administered a battery of behavioral tests (the Suok test, the elevated platform test, and the elevated plus maze test) to assess anxiety and sensorimotor integration. PNE resulted in a decreased likelihood of jumping during the elevated platform test and decreased directed exploration in the Suok test, both indicative of increased anxiety. Also, PNE mice showed increased numbers of missteps while traversing an elevated rod in the Suok test, demonstrating altered sensorimotor integration. No significant differences were found in falls, segments traveled, latency to leave the central zone, vegetative responses, risk assessment behaviors, or autogroom behaviors. The elevated plus maze test revealed no significant differences between groups. No significant differences in body and brain weights, or cortical thickness within motor, somatosensory, and visual cortices were observed between PNE and control mice. Although neuroanatomical effects of PNE may be rescued as development progresses, defects in sensorimotor integration and increased anxiety persist into adulthood. PMID- 24157431 TI - Sulfated glycans in network rewiring and plasticity after neuronal injuries. AB - Biopolymers in the human body belong to three major classes: polynucleotides (DNA, RNA), polypeptides (proteins) and polysaccharides (glycans). Although striking progress in our understanding of neurobiology has been achieved through a focus on polypeptides as the main players, important biological functions are also expected to be attributable to glycans. Nonetheless, the significance of glycans remains largely unexplored. In this review, we focus on the roles of sulfated glycans. Axonal regeneration/sprouting after injuries does not easily occur in the adult mammalian central nervous system. This is due to the low intrinsic potential of regeneration and the emerging inhibitory molecules. The latter include the sulfated long glycans chondroitin sulfate (CS) and keratan sulfate (KS). Enzymatic ablation of CS or KS, and genetic ablation of KS promote functional recovery after spinal cord injury. Interestingly, the combination of CS and KS ablations exhibits neither additive nor synergistic effects. Thus, KS and CS work in the same pathway in inhibition of axonal regeneration/sprouting. Furthermore, CS has been implicated in neural plasticity as a functional component of the perineuronal nets surrounding inhibitory interneurons. Elucidation of the mechanisms of action for KS and CS will pave the way to treatments to promote network rewiring and plasticity after neuronal injuries. PMID- 24157432 TI - Benefits of exercise training during hemodialysis sessions: a prospective cohort study. AB - BACKGROUND: End-stage renal disease patients can be considered as 'cardiovascular time bombs' due to their tremendous cardiovascular risk. Our study has determined the impact of 3 months of exercise training during dialysis on some of the cardiovascular risk factors (arterial stiffness, body composition and physical performance) in a chronic hemodialyzed population. METHODS: The study group (n = 19) and control group (n = 16) of chronic hemodialysis patients from Timisoara, Romania, were enrolled in a prospective cohort study. The intervention--40 min of exercise training (with non-fistula hand and both lower limbs) during each hemodialysis session for 3 months--was applied only to the study group. The measurements made before and after intervention were aortic pulse wave velocity (PWV), aortic augmentation index, return time and both central and peripheral blood pressure for arterial stiffness evaluation, using the Arteriograph Tensiomed system, body composition by multifrequency bioimpedance and physical performance (Myotest PRO system and hand dynamometer). RESULTS: We found a significant 1-m/s reduction in PWV, a 12-second increase in return time and a 10 mm Hg reduction in both central and systolic blood pressure driven only by the exercise training. Exercise training significantly increased the skeletal muscle mass and the soft lean mass of the study group patients. Physical performance significantly improved in the study group jumping height by 1 cm, lower limbs explosive power by 3 W/kg and non-fistula hand strength prehension by 0.06 bar. CONCLUSIONS: Exercise training during dialysis has a positive effect on arterial stiffness, body composition and physical performance of chronic hemodialyzed patients. PMID- 24157433 TI - The tonal space of contrastive five level tones. AB - Multiple-level tone contrasts are typologically disfavoured because they violate the dispersion principles of maximizing perceptual distance and minimizing articulatory effort. This study investigates the tonal dispersion of a multiple level tone system by exploring the cues used in producing and perceiving the five level tones of Black Miao. Both production and perception experiments show that non-modal phonations are very important cues for these tonal contrasts. Non-modal phonations significantly contribute to the dispersion of the five level tones in two ways: either by enhancing pitch contrasts or by providing an additional contrastive cue. Benefiting from more than one cue, the level tones T11, T33 and T55 are well distinguished in the tonal space; by contrast, the level tones T22 and T44, only contrasting in pitch, are the most confusable tones. The tonal registers model proposed in this article sheds light on the different uses of non modal phonations across languages. PMID- 24157434 TI - From communicative functions to prosodic forms. AB - This is a proposal in favour of proceeding from communicative function to linguistic form, rather than the reverse, for an insightful account of how humans communicate by speech in languages. A functional framework is developed that encompasses argumentation structures, declarative and interrogative functions, and expressive intensification. Such a function orientation can become a powerful tool in comparative prosodic research across the world's languages. The potential of this approach is shown by comparing the prosodic form of Mandarin Chinese data collected in functionally contextualized scenarios with corresponding data from English and German. PMID- 24157435 TI - Danish stod: laryngealization or tone. AB - In the light of previous acoustic analyses of Danish stod and Danish intonation, we discuss two different phonological theories. In one, stod is an autonomous laryngeal syllable prosody. In the other, stod is the phonetic manifestation of an HL tonal pattern compressed within one syllable. The tonal representation is found to be contradicted by the phonetic reality, and it cannot account for the structurally determined alternation between non-stod and stod in inflection and derivation, nor for latent stod or stod in compounds. Furthermore, stod patterns are largely constant across regional varieties of Danish, but tonal patterns over the relevant structural domains are highly variable. Thus, stod may occur on any kind of tonal configuration, anywhere in the speaker's pitch range, a variability which is hard to reconcile with a fixed HL representation. PMID- 24157436 TI - Asymmetries in English vowel perception mirror compression effects. AB - A series of vowel-identification experiments using gated consonant stimuli shows that English listeners are capable of recovering the vocalic context in which a consonant appears from information contained in the consonant alone. This is true for most consonants tested, including liquids, nasals, and stops in onset and coda position. Positional asymmetries in vowel sensitivity go in opposite directions for liquids (coda sensitivity > onset) and stops (onset > coda). Nasals pattern with liquids in terms of vowel sensitivity from consonant steady states alone, but pat- tern more closely with stops when portions outside the steady state are taken into account. It is argued that these asymmetries are related to patterns of cluster-driven vowel compression (also called 'compensatory shortening') in speech production. PMID- 24157437 TI - Listener expectations and gender bias in nonsibilant fricative perception. AB - The nonsibilant English fricatives /f/ and /theta / are known to be acoustically nonrobust. Using /f/ and /theta/ stimuli produced in CV, VCV, and VC syllables in /i alpha u/ contexts spoken by 10 talkers (5 male), we first replicate previous research suggesting that the most robust cues to this contrast are in the formant transitions in adjacent vowels. We also demonstrate vowel and syllable contextual differences that point to the contrast being most robust in /u/ contexts. In a series of perception experiments we go on to demonstrate effects of bias on perception of /f/ and /theta/ that derive from the uninformative nature of the frication noise, making them vulnerable to misperception in general, and especially in low-saliency contexts where the formant transition information is less robust. In experiment 1, listeners' classification of /f/ and /theta/ demonstrated a general bias to respond /f/ for fricatives produced by females and /theta/ for those produced by males. We hypothesize that the perceived concentrations of spectral energy in the fricative are shifted based on the concentration of energy in the vowel, which depend on a talker's gender. In experiment 2, vowel and frication noise portions were cross-spliced to probe this effect, resulting in the same gender-based bias. In a final experiment the vocalic information was removed and only the frication noise was presented to listeners for classification. In this task there was a general bias for /f/, regardless of the talker gender. Overall we demonstrate topdown gender effects in perception that originate in the strong indexical properties of adjacent vowels rather than being present in the frication noise itself. PMID- 24157441 TI - The role of viperin in the innate antiviral response. AB - Viral infection of the cell is able to initiate a signaling cascade of events that ultimately attempts to limit viral replication and prevent escalating infection through expression of host antiviral proteins. Recent work has highlighted the importance of the host antiviral protein viperin in this process, with its ability to limit a large variety of viral infections as well as play a role in the production of type I interferon and the modulation of a number of transcription factor binding sites. Viperin appears to have the ability to modulate varying conditions within the cell and to interfere with proviral host proteins in its attempts to create an unfavorable environment for viral replication. The study of the mechanistic actions of viperin has come a long way in recent years, describing important functional domains of the protein for its antiviral and immune modulator actions as well as demonstrating its role as a member of the radical SAM enzyme family. However, despite the rapid expansion of knowledge regarding the functions of this highly conserved and ancient antiviral protein, there still remains large gaps in our understanding of the precise mechanisms at play for viperin to exert such a wide variety of roles within the cell. PMID- 24157440 TI - Kinetic control in protein folding for light chain amyloidosis and the differential effects of somatic mutations. AB - Light chain amyloidosis is a devastating disease where immunoglobulin light chains form amyloid fibrils, resulting in organ dysfunction and death. Previous studies have shown a direct correlation between the protein thermodynamic stability and the propensity for amyloid formation for some proteins involved in light chain amyloidosis. Here we investigate the effect of somatic mutations on protein stability and in vitro fibril formation of single and double restorative mutants of the protein AL-103 compared to the wild-type germline control protein. A scan rate dependence and hysteresis in the thermal unfolding and refolding was observed for all proteins. This indicates that the unfolding/refolding reaction is kinetically determined with different kinetic constants for unfolding and refolding even though the process remains experimentally reversible. Our structural analysis of AL-103 and AL-103 delP95aIns suggests a kinetic coupling of the unfolding/refolding process with cis-trans prolyl isomerization. Our data reveal that the deletion of proline 95a (AL-103 delP95aIns), which removes the trans-cis di-proline motif present in the patient protein AL-103, results in a dramatic increment in the thermodynamic stability and a significant delay in fibril formation kinetics with respect to AL-103. Fibril formation is pH dependent; all proteins form fibrils at pH2; reactions become slower and more stochastic as the pH increases up to pH7. Based on these results, we propose that, in addition to thermodynamic stability, kinetic stability (possibly influenced by the presence of cis proline 95a) plays a major role in the AL-103 amyloid fibril formation process. PMID- 24157442 TI - Improving catalytic efficiency of endo-beta-1, 4-xylanase from Geobacillus stearothermophilus by directed evolution and H179 saturation mutagenesis. AB - Endo-beta-1, 4-xylanase was cloned from Geobacillus stearothermophilus 1A05583 by PCR. Enzymes with improved catalytic efficiency were obtained using error-prone PCR and a 96-well plate high-throughout screening system. Two variants 1-B8 and 2 H6 were screened from the mutant library containing 9000 colonies, which, when compared with the wild-type enzyme increased the catalytic efficiency (kcat/Km) by 25% and 89%, respectively, acting on beechwood xylan. By sequencing 1-B8 and 2 H6, an identical mutation point H179Y was detected and found to overlap in the active site cleft. Following the introduction of the remaining 19 amino acids into position 179 by site-saturation mutagenesis, the catalytic efficiency of H179F was found to be 3.46-fold that of the wild-type. When Whistidine was substituted by tryptophan, arginine, methionine or proline, the enzyme lost activity. Therefore, the position 179 site may play an important role in regulating the catalytic efficiency. PMID- 24157443 TI - CD44 mediated hyaluronan adhesion of Toxoplasma gondii-infected leukocytes. AB - Toxoplasma gondii is an obligate intracellular apicomplexan parasite that infects humans and animals. Ingested parasites cross the intestinal epithelium, invade leukocytes and are then disseminated to peripheral organs. However, the mechanism of extravasation of the infected leukocytes remains poorly understood. In this study, we demonstrate that T. gondii-invaded human and mouse leukocytes express higher level of CD44, a ligand of hyaluronan (HA), and its expression on myeloid and non-myeloid leukocytes causes T. gondii-invaded human and mouse leukocyte to adhere to HA more effectively than non-invaded leukocytes. The specific adherence of parasite-invaded leukocytes was inhibited by anti CD44 antibody. Leukocytes of CD44 knockout mice did not show parasite-invaded leukocyte specific adhesion. Our results indicate that parasite-invaded leukocytes, regardless of whether myeloid or not, gain higher ability to adhere to HA than non-invaded leukocytes, via upregulation of CD44 expression and/or selective invasion to CD44 highly expressing cells. The difference in ability to adhere to HA between parasite invaded cells and non-invaded neighboring cells might facilitate effective delivery of parasite-invaded leukocytes to the HA-producing endothelial cell surface and/or HA-rich extra cellular matrix. PMID- 24157444 TI - Occurrence of human-pathogenic Enterocytozoon bieneusi, Giardia duodenalis and Cryptosporidium genotypes in laboratory macaques in Guangxi, China. AB - Captive nonhuman primates have been identified as common hosts of Enterocytozoon bieneusi, Giardia duodenalis, Cryptosporidium hominis, and Cyclospora spp., thus are potential reservoirs of some enteric parasites in humans. However, few studies have examined the source and human-infective potential of enteric parasites in laboratory nonhuman primates. In the present work, 205 fecal specimens were collected from three groups of captive Macaca fascicularis kept in different densities in a laboratory animal facility in Guangxi, China, and examined by PCR for E. bieneusi, G. duodenalis, Cryptosporidium spp., and Cyclospora spp. The infection rates of E. bieneusi and G. duodenalis were 11.3% and 1.2% in Group 1 (young animals kept individually; n=168), 72.2% and 11.1% in Group 2 (young animals kept in groups; n=18), and 31.6% and 5.3% in Group 3 (adults kept in groups; n=19), respectively. Sequence analysis of PCR products showed the presence of five E. bieneusi genotypes, with genotype D (in 16/36 genotyped specimens) and a new genotype (in 15/36 genotyped specimens) as the dominant genotypes. All five E. bieneusi genotypes belonged to the zoonotic group (Group 1). The G. duodenalis genotypes (assemblages AII and B) in five specimens and C. hominis subtype (IdA14) in one specimen were also known human-pathogens, although the Cyclospora seen in one animal appeared to be unique to macaque monkeys. The higher infection rate in younger animals reared in groups and common occurrence of zoonotic genotypes indicated that human-pathogenic E. bieneusi could be transmitted efficiently in captive nonhuman primates, and group-housing was a risk factor for transmission of zoonotic pathogens in young nonhuman primates in research facilities. PMID- 24157445 TI - Dietary fiber mixture in pediatric patients with controlled chronic constipation. AB - OBJECTIVES: The aim of the study was to test the clinical efficacy and effect on colonic transit time (CTT) of a dietary fiber mixture given to children with controlled chronic constipation (CC) after the withdrawal of stool softeners and enemas. METHODS: This randomized, placebo-controlled, double-blind clinical trial involved 54 patients aged 4 to 12 years and had CC that was controlled by the use of low-dose stool softeners. The use of these softeners was discontinued when the patients were admitted to the clinical trial. The patients were randomized into 2 groups for the 4-week study period. One group received a dietary fiber mixture and the other group received a placebo (maltodextrin). The primary outcome was therapeutic failure (oral stool softeners or enemas was required to prescribe during the trial). Secondary outcomes included defecation frequency, stool consistency (measured using the Bristol Stool Form Scale), and CTT. RESULTS: Therapeutic failure was observed in 34.6% (9/26) of the patients in the dietary fiber mixture group and in 35.7% (10/28) in the control group (P = 0.933). The mean increase in daily bowel movements was 0.53 in the dietary fiber mixture group and 0.23 in the control group (P = 0.014). The patients in the dietary fiber mixture group (60.0%) passed nonhardened stools more frequently than did those in the control group (16.7%, P = 0.003). The CTT was similar for both groups. CONCLUSIONS: The fiber mixture did not prevent the suspension of stool softeners or lead to reduced CTT; however, the mixture promoted an increased frequency of defecation and an improvement in the stool consistency. PMID- 24157446 TI - Nestle Nutrition Young Investigator Research Development Award: NASPGHAN Foundation report on a 13-year partnership. PMID- 24157447 TI - Occult T-cell acute lymphoblastic leukemia presenting as obstructive pancreatitis. PMID- 24157448 TI - Ghrelin and obestatin levels in children with failure to thrive and obesity. AB - OBJECTIVES: Ghrelin and obestatin are 2 gastric hormones with opposite effects on food intake and body weight. We investigated plasma ghrelin and obestatin in children with failure to thrive (FTT) and obesity as compared with age-matched controls. METHODS: A total of 63 children were included in the study: 13 with FTT, 17 with obesity, and 33 age-matched controls. Children fasted for at least 8 hours before specimen collection. Both hormones were measured using commercially available enzyme immunoassay kits. RESULTS: Ghrelin and obestatin levels in children with FTT were not significantly different from that of the age-matched controls (P >0.05). In children with obesity, the total ghrelin levels were significantly lower (P = 0.0003) and the obestatin levels significantly higher (P = 0.029) compared with those in controls. In the control group, the fasting ghrelin level was significantly higher in the younger (<3 years) than in the older children (>3 years; P = 0.0004). Obestatin levels correlated positively with weight-for-age percentiles in the obese group (P = 0.011) and negatively in the control group >3 years (P = 0.019). CONCLUSIONS: Compared with the levels in age-matched controls, fasting ghrelin and obestatin levels did not differ significantly in children with FTT. In the children with obesity, the decreased ghrelin and increased obestatin levels suggest a possible adaptive process to positive energy balance. Ghrelin had pronounced age-related changes, and obestatin was associated with the weight status. This may suggest that these 2 hormones use different mechanisms to regulate energy balance and weight. PMID- 24157449 TI - Authors' response. PMID- 24157450 TI - Complementary feeding: keeping the message simple. PMID- 24157451 TI - Dietary nitrite improves insulin signaling through GLUT4 translocation. AB - Diabetes mellitus type 2 is a syndrome of disordered metabolism with inappropriate hyperglycemia owing to a reduction in the biological effectiveness of insulin. Type 2 diabetes is associated with an impaired nitric oxide (NO) pathway that probably serves as the key link between metabolic disorders and cardiovascular disease. Insulin-mediated translocation of GLUT4 involves the PI3K/Akt kinase signal cascade that results in activation of endothelial NO synthase (eNOS). eNOS is dysfunctional during diabetes. We hypothesize that loss of eNOS-derived NO terminates the signaling cascade and therefore cannot activate GLUT4 translocation and that dietary nitrite may repair this pathway. In this study, we administered 50mg/L sodium nitrite to db/db diabetic mice for 4 weeks. After 4 weeks treatment, the db/db mice experienced less weight gain, improved fasting glucose levels, and reduced insulin levels. Cell culture experiments using CHO-HIRc-myc-GLUT4eGFP cell lines stably expressing insulin receptor and myc-GLUT4eGFP protein, as well as L6 skeletal muscle cells stably expressing rat GLUT4 with a Myc epitope (L6-GLUT4myc), showed that NO, nitrite, and GSNO stimulate GLUT4 translocation independent of insulin, which is inhibited by NEM. Collectively our data suggest that nitrite improves insulin signaling through restoration of NO-dependent nitrosation of GLUT4 signaling translocation. These data suggest that NO-mediated nitrosation of GLUT4 by nitrite or other nitrosating agents is necessary and sufficient for GLUT4 translocation in target tissue. Description of this pathway may justify a high-nitrate/nitrite diet along with the glycemic index to provide a safe and nutritional regimen for the management and treatment of diabetes. PMID- 24157452 TI - Emergence of autochthonous infections with hepatitis E virus of genotype 4 in Europe. AB - In Europe, autochthonous hepatitis E is caused by genotype 3 hepatitis E virus (HEV) in almost all cases. A total of 15 infections with genotype 4 HEV were diagnosed in France from May 2009 to April 2012, and all but one of the HEV-4 strains implicated in these infections were genetically related and highly similar to HEV-4 sequences isolated from swine in Belgium. In addition, 5 autochthonous HEV-4 infections have been described in the region of Lazio, Italy, during March and April 2011, and these HEV sequences were 100% identical to one another but showed relatively low similarity (74-85%) to HEV-4 RNA samples collected in France. We report 6 additional HEV-4 infections that were diagnosed from May to July 2012 which represented 50% of the HEV infections diagnosed during this period in our clinical microbiology laboratory. Five of these HEV-4 strains were associated with autochthonous infections and were clustered together and with the majority of HEV-4 previously described in France, whereas the sixth strain was genetically divergent. Taken together with reports from other teams, these observations indicate that autochthonous infections with HEV-4 are emerging in Europe and have been transmitted by at least two distinct sources. PMID- 24157453 TI - Is the prognostic impact of tumor location in patients with surgically resected esophageal squamous cell carcinoma affected by surgical approach? AB - AIM: The aim of the present study was to clarify differences in node metastasis mode and clinical outcomes based on tumor location in patients with esophageal squamous cell carcinoma (ESCC). PATIENTS AND METHODS: Participants comprised 228 patients with ESCC who underwent radical esophagectomy without preoperative supplement therapies. Lymph nodes were harvested from three fields: the neck, thorax, and abdomen. Patients were divided into three groups depending on tumor location [upper esophagus (UE), middle esophagus, or lower esophagus (LE)] and analyzed clinicopathologically. RESULTS: The LE group showed significantly more progressive ESCC in terms of tumor invasion (p = 0.025), node metastasis (p = 0.0071), and TNM stage (p = 0.0043). The LE group revealed a tendency to metastasize to extrathoracic (especially abdominal) nodes (p = 0.0008). Recurrent laryngeal node metastasis was increased in the UE group (p = 0.016). However, no prognostic differences were detected between groups according to tumor location. Likewise, subgroup analyses by surgical approach (open thoracotomy vs. thoracoscopy) and cancer stage (stage I/II, III, and IV) did not reveal any significant prognostic impact of tumor location. CONCLUSION: Lymphatic spread varied by tumor location, but no prognostic impact of tumor location could be detected in patients with ESCC in spite of surgical approach or cancer stage. PMID- 24157454 TI - Hepatocyte nuclear factors 1alpha/4alpha and forkhead box A2 regulate the solute carrier 2A2 (Slc2a2) gene expression in the liver and kidney of diabetic rats. AB - AIMS: Solute carrier 2a2 (Slc2a2) gene codifies the glucose transporter GLUT2, a key protein for glucose flux in hepatocytes and renal epithelial cells of proximal tubule. In diabetes mellitus, hepatic and tubular glucose output has been related to Slc2a2/GLUT2 overexpression; and controlling the expression of this gene may be an important adjuvant way to improve glycemic homeostasis. Thus, the present study investigated transcriptional mechanisms involved in the diabetes-induced overexpression of the Slc2a2 gene. MAIN METHODS: Hepatocyte nuclear factors 1alpha and 4alpha (HNF-1alpha and HNF-4alpha), forkhead box A2 (FOXA2), sterol regulatory element binding protein-1c (SREBP-1c) and the CCAAT enhancer-binding protein (C/EBPbeta) mRNA expression (RT-PCR) and binding activity into the Slc2a2 promoter (electrophoretic mobility assay) were analyzed in the liver and kidney of diabetic and 6-day insulin-treated diabetic rats. KEY FINDINGS: Slc2a2/GLUT2 expression increased by more than 50% (P<0.001) in the liver and kidney of diabetic rats, and 6-day insulin treatment restores these values to those observed in non-diabetic animals. Similarly, the mRNA expression and the binding activity of HNF-1alpha, HNF-4alpha and FOXA2 increased by 50 to 100% (P<0.05 to P<0.001), also returning to values of non-diabetic rats after insulin treatment. Neither the Srebf1 and Cebpb mRNA expression, nor the SREBP-1c and C/EBP-beta binding activity was altered in diabetic rats. SIGNIFICANCE: HNF 1alpha, HNF-4alpha and FOXA2 transcriptional factors are involved in diabetes induced overexpression of Slc2a2 gene in the liver and kidney. These data point out that these transcriptional factors are important targets to control GLUT2 expression in these tissues, which can contribute to glycemic homeostasis in diabetes. PMID- 24157455 TI - High-dose tranilast administration to rats creates interstitial cystitis-like symptoms with increased vascular permeability. AB - AIM: We investigated whether the high-dose administration of tranilast could be used to create an animal model of interstitial cystitis (IC). Then, we used this model to assess the relationship between IC and changes in the vascular permeability of the bladder. MAIN METHODS: Female rats were divided into the following 4 groups: a control group, a tranilast group, a carbazochrome group and a combination (tranilast+carbazochrome) group. Continuous cystometry, bladder distension, and the Evans blue dye extravasation test were performed 4weeks after drug administration. Locomotor activity, the plasma TGF-beta1 level, and collagen fibers in the bladder wall were also examined in the control and tranilast groups. KEY FINDINGS: The interval between bladder contractions was shorter and the leakage of Evans blue dye into the bladder wall was greater in the tranilast group than in the control group. Glomerulations of the bladder wall after bladder distention and thinning of the collagen fiber layer in the bladder were observed in the tranilast group. Locomotor activity in darkness and the plasma TGF-beta1 level were both lower in the tranilast group than in the control group. In the combination group, the leakage of Evans blue dye was greater than in the control group; however, it was less prominent than in the tranilast group. SIGNIFICANCE: These results suggest that high-dose administration of tranilast to rats can create an IC-like rat model and that an increase in the vascular permeability of the bladder wall may be one cause of IC symptoms. PMID- 24157456 TI - Chromium modulates expressions of neuronal plasticity markers and glial fibrillary acidic proteins in hypoglycemia-induced brain injury. AB - AIMS: This experiment investigated if chromium (Cr) as Cr-histidinate (CrHis) and Cr29 picolinate (CrPic) have a protective role in rats with hypoglycemia-induced brain injury, assessed by neuronal plasticity and regeneration potential. MAIN METHODS: Male Sprague-Dawley rats were prospectively divided into 2 groups: control and hypoglycemic (induced by insulin administration, 15U/kg, i.p., n=56). Hypoglycemic rats were then received randomly 1) none, 2) dextrose (on the day of sampling), 3) CrHis, or 4) CrPic. Cr-chelates were delivered via drinking water (providing 8MUg elemental Cr per day) for one week prior to the hypoglycemia induction. The expressions of neuroplasticity markers [neural cell adhesion molecule (NCAM), growth-associated protein-43 (GAP-43), glial fibrillary acidic protein (GFAP)], glucose transporters (GLUT), and nuclear transcription proteins [nuclear factor-kappa (NF-kappaB), nuclear factor (erythroid-derived 2)-like 2 (Nrf2), and 4-hydroxyl nonenal (HNE)] were determined using Western blot. KEY FINDINGS: Hypoglycemia caused increases in the expressions of GLUT-1, GLUT-3, GFAP, NF-kappaB and HNE and decreases in the expression of NCAM's, GAP-43 and Nrf2 in the hippocampus, cerebellum, and cortex. Cr-chelates suppressed expressions of GLUTs, GFAP, NF-kappaB and HNE expressions and enhanced expressions of NCAM, GAP-43 and Nrf2, which were more notable for CrHis than for CrPic. SIGNIFICANCE: In conclusion, hypoglycemia leads to cerebral injury and Cr chelates, particularly CrHis have protective and regeneration potential in cerebral tissues through modulating neuroplasticity markers and nuclear transcription proteins as well as facilitating glucose transporters. PMID- 24157457 TI - Serum selenium levels and oxidative balance as differential markers in hepatic damage caused by alcohol. AB - AIMS: Antioxidant system abnormalities have been associated with ethanol consumption. This study examines the effects of chronic ethanol consumption on oxidative balance, including selenium (Se) levels in alcoholic patients with or without liver disease, and if these measurements could be indicative of liver disease. MAIN METHODS: Serum Se levels, antioxidant enzymes' activities, malondialdehyde (MDA) and protein carbonyl (PC) were determined in three groups of patients: alcoholics without liver disease, alcoholics with liver disease, and non-alcoholics with liver disease; and in healthy volunteers. KEY FINDINGS: Serum Se levels were lower in alcoholic patients and in patients affected by liver disease and especially lower in the alcoholic liver disease group. These values were correlated with the activity of glutathione peroxidase (GPx), the antioxidant selenoprotein. The antioxidant activities of the glutathione reductase (GR) and superoxide dismutase (SOD) were also lower in the three non healthy groups. However, GR activity decreased and SOD activity increased in the non-alcoholic liver disease group versus alcoholic groups. Higher concentrations of PC in serum were found in non-healthy groups and were higher in alcoholic patients who also showed higher MDA levels. The highest MDA and PC levels were found in the alcoholic liver disease group. SIGNIFICANCE: We conclude that serum Se levels are drastically decreased in alcoholic liver disease patients, showing that this element has a direct correlation with GPx activity, and lipid oxidation, suggesting that the serum Se/MDA ratio could be an indicator of hepatic damage caused by alcohol consumption, and pointing to Se as a possible antioxidant therapy. PMID- 24157458 TI - Impact of the baseline anti-A/B antibody titer on the clinical outcome in ABO incompatible kidney transplantation. AB - BACKGROUND/AIMS: We investigated the impact of the baseline anti-A/B antibody titer on the clinical outcome in ABO-incompatible kidney transplantation (IKT). METHODS: We included 183 patients who had undergone KT (40 ABO IKT and 143 ABO compatible KT). Eight patients with a baseline titer of >=1:512 were assigned to the high-titer group and 32 patients with a baseline titer of <=1:256 were assigned to the low-titer group. Patients who underwent ABO-compatible KT were used as the control group. We compared the clinical outcomes of the three groups. RESULTS: Before transplantation, the high-titer group displayed more frequent antibody rebound, as shown in a lower titer reduction rate, and more difficulty reaching the target titer (1:16) than the low-titer group. During the postoperative period and out-clinic follow-up, antibody rebound was more frequent, and the rate of acute rejection and infection were significantly higher and allograft function was lower in the high-titer group than in the low-titer and control groups. Multivariate analysis showed that high baseline antibody titer was an independent risk factor for acute rejection. CONCLUSION: ABO IKT in the high-titer group (baseline titer >=1:512) required greater caution compared to the low-titer group because of the higher tendency of antibody rebound and the risk for acute rejection. PMID- 24157459 TI - Bilateral low-frequency repetitive transcranial magnetic stimulation of the auditory cortex in tinnitus patients is not effective: a randomised controlled trial. AB - BACKGROUND: Although some therapies may be beneficial for some patients in reducing tinnitus, there is no curative therapy. Repetitive transcranial magnetic stimulation (rTMS) has been applied as a treatment for chronic tinnitus, but the effect remains controversial. MATERIAL AND METHODS: Fifty patients were treated with rTMS or placebo. Treatment consisted of 2,000 TMS pulses on each auditory cortex, at a rate of 1 Hz and an intensity of 110% of the individual motor threshold, on 5 consecutive days. rTMS and placebo effects were evaluated directly after treatment, after 1 week, and after 1, 3 and 6 months. Primary outcome was the Tinnitus Questionnaire (TQ). Secondary outcomes were the Tinnitus Handicap Inventory (THI) and a visual analogue scale. RESULTS: At none of the follow-up evaluation moments a significant difference between rTMS and placebo was observed with respect to changes in TQ or THI scores relative to pretreatment scores. Multilevel modelling (MLM) analyses did not show a global treatment effect either. Patients with a higher degree of burden showed slightly greater improvement after rTMS (only significant on the THI with MLM analyses). CONCLUSION: Bilateral low-frequency rTMS of the auditory cortex was not effective in treating tinnitus. PMID- 24157460 TI - Filaggrin is a predominant member of the denaturation-resistant nickel-binding proteome of human epidermis. PMID- 24157463 TI - Rothmund-Thomson syndrome and glomerulonephritis in a homozygous C1q-deficient patient due to a Gly164Ser C1qC mutation. PMID- 24157462 TI - IL-1beta drives inflammatory responses to propionibacterium acnes in vitro and in vivo. AB - Acne vulgaris is potentially a severe skin disease associated with colonization of the pilo-sebaceous unit by the commensal bacterium Propionibacterium acnes and inflammation. P. acnes is considered to contribute to inflammation in acne, but the pathways involved are unclear. Here we reveal a mechanism that regulates inflammatory responses to P. acnes. We show that IL-1beta mRNA and the active processed form of IL-1beta are abundant in inflammatory acne lesions. Moreover, we identify P. acnes as a trigger of monocyte-macrophage NLRP3-inflammasome activation, IL-1beta processing and secretion that is dependent on phagocytosis, lysosomal destabilization, reactive oxygen species, and cellular K+ efflux. In mice, inflammation induced by P. acnes is critically dependent on IL-1beta and the NLRP3 inflammasome of myeloid cells. These findings show that the commensal P. acnes-by activating the inflammasome-can trigger an innate immune response in the skin, thus establishing the NLRP3-inflammasome and IL-1beta as possible therapeutic targets in acne. PMID- 24157464 TI - Treatment of cartilage defects of the knee: expanding on the existing algorithm. AB - OBJECTIVE: The purpose of this review is to survey the literature regarding factors used in determining a course of surgical treatment for symptomatic cartilage lesions of the knee to determine which factors affect treatment outcomes and should be incorporated in the treatment algorithm. METHODS: A systematic review was performed using PubMed, Cochrane Review, and SportDiscus databases for studies investigating factors affecting cartilage lesion treatment and outcomes. Inclusion criteria were clinical and basic science studies in English, on human or animal specimens that focus on factors affecting the initiation, progression, and treatment of focal knee chondral defects. RESULTS: Twenty-seven studies examining 1450 human (1416 in vivo; 34 cadaveric) and 90 animal subjects met inclusion criteria. Female sex and higher body mass index (BMI) significantly predicted cartilage loss rates and recovery after microfracture (MFx) and autologous matrix-induced chondrogenesis. Defect size and location significantly predicted treatment outcomes. Sizes >2 to 4 cm demonstrated worse outcomes after MFx treatment. Defect size did not consistently affect autologous chondrocyte implantation or osteochondral autograft transplantation outcomes. Intra-articular lesion location was related to intralesional subchondral bone contact and MFx outcome. Corrected patellofemoral and tibiofemoral alignment improved clinical outcome when realignment procedures were done concurrently with cartilage repair. CONCLUSIONS: Choice of the appropriate repair technique for focal knee cartilage defects is multifactorial. A treatment algorithm should consider frequently used factors such as defect size, location, knee alignment, and patient demand. However, patient sex and BMI could also be considered. Patient age was not significantly associated with clinical outcome. PMID- 24157465 TI - Diagnosis and treatment of triceps tendon injuries: a review of the literature. AB - OBJECTIVE: To elucidate mechanism of injury, nonoperative protocols, surgical techniques, rehabilitation schedules, and return to sports guidelines for partial and complete triceps tendon injuries. DATA SOURCES: The PubMed and OVID databases were searched in 2010 and peer-reviewed English language articles in 2011. MAIN RESULTS: After a fall on an outstretched hand, direct trauma on the elbow, or lifting against resistance, patients often present with pain and weakness of extension. Examination may reveal a palpable tendon gap, and radiographs may reveal a Flake sign. Acute partial injuries have positive outcomes with immobilization in 30-degree flexion for 4 to 6 weeks. Primary repair for complete rupture can restore normal extensor function after 3 to 4 months. Reconstruction returns normal extensor function up to 4 years. Most authors support postoperative immobilization for 2 to 3 weeks at 30- to 40-degree flexion, flexion block bracing for an additional 3 weeks, and unrestricted activity at 6 months. Athletes may be able to return to sports after 4 to 5 weeks of recovery from a partial injury, but return may be delayed if operative tendon repair is performed. CONCLUSIONS: Acute partial triceps tendon injuries may be managed conservatively at first and should be repaired primarily if this fails or if presentation is delayed. Reconstruction should first use the anconeus rotation technique. If the anconeus is devitalized, the Achilles tendon may be the allograft of choice. PMID- 24157466 TI - Rate of injury among youth lacrosse players. AB - OBJECTIVE: This study describes the rate of injury and the types and mechanisms of injuries incurred by girls and boys during youth recreational lacrosse. DESIGN: Prospective cohort study. SETTING: Games were played at a large turf community athletic complex. PARTICIPANTS: Participants included male and female lacrosse players aged 9-15 years. A total of 143 games were played, resulting in 4603 athlete-exposures (AEs). ASSESSMENT OF RISK FACTORS: Youth players were grouped based on sex and 3 age categories: under 11 (U11; 9-10 years), under 13 (U13; 11-12 years), and under 15 (U15; 13-14 years). MAIN OUTCOME MEASURES: Certified athletic trainers collected data on type of injury and injury mechanism. RESULTS: There were 6.3 injuries per 1000 AEs for boys and girls combined. Girls had 7 injuries (3.4 per 1000 AEs) and boys had 22 injuries (8.7 per 1000 AEs). Contusions and lacerations were the most frequent injury (n = 13), and body-to-body contact (n = 10) was the most common injury mechanism. There were 4 concussions among boys (U13 and U15) and none among girls. CONCLUSIONS: Most injuries evaluated in youth lacrosse were contusions/lacerations; however, serious injuries were observed, including concussions in boys in the age group where body contact is allowed. PMID- 24157461 TI - SECTM1 produced by tumor cells attracts human monocytes via CD7-mediated activation of the PI3K pathway. AB - Tumor-associated macrophages (TAMs) have essential roles in tumor progression and metastasis. Tumor cells recruit myeloid progenitors and monocytes to the tumor site, where they differentiate into TAMs; however, this process is not well studied in humans. Here we show that human CD7, a T-cell and NK cell receptor, is highly expressed by monocytes and macrophages. Expression of CD7 decreases in M CSF-differentiated macrophages and in melanoma-conditioned medium-induced macrophages (MCMI/Mphi) in comparison to monocytes. A ligand for CD7, SECTM1 (secreted and transmembrane protein 1), is highly expressed in many tumors, including melanoma cells. We show that SECTM1 binds to CD7 and significantly increases monocyte migration by activation of the PI3K (phosphatidylinositol 3' kinase) pathway. In human melanoma tissues, tumor-infiltrating macrophages expressing CD7 are present. These melanomas, with CD7-positive inflammatory cell infiltrations, frequently highly express SECTM1, including an N-terminal, soluble form, which can be detected in the sera of metastatic melanoma patients but not in normal sera. Taken together, our data demonstrate that CD7 is present on monocytes and tumor macrophages and that its ligand, SECTM1, is frequently expressed in corresponding melanoma tissues, possibly acting as a chemoattractant for monocytes to modulate the melanoma microenvironment. PMID- 24157467 TI - Multiple arterial thromboses associated with anabolic androgenic steroids. AB - The use of supraphysiological doses of anabolic androgenic steroids can have serious side effects. This article reports the case of a young man who suffered potentially life-threatening arterial thromboses following the use of these drugs. PMID- 24157468 TI - Concussion reporting rates at the conclusion of an intercollegiate athletic career. AB - OBJECTIVE: The purpose of this study was to explore the current reported, unreported, and potentially unrecognized concussion rates among collegiate student-athletes who have completed their collegiate athletic career. DESIGN: Retrospective survey. SETTING: College and University athletic training rooms. PARTICIPANTS: One hundred sixty-one collegiate student-athletes (56.5% women; aged 21.5 +/- 1.3; 3.7 +/- 1.0 years of collegiate athletic experience) from 10 institutions who had either completed their intercollegiate athletic eligibility or were no longer participating. MAIN OUTCOME MEASURES: The self-reported concussion rate, the unreported rate and reasons, and the potentially unrecognized concussion rate. RESULTS: The self-reported concussion rate was 33.5% (54/161), and 22.2% (12) self-reported at least 3 concussions. The unreported rate was 11.8% (19/161), and the potentially unrecognized rate was 26.1% (42/161) with the most common unrecognized symptom being "knocked silly/seen stars" (23.6% [38/161]). CONCLUSIONS: Overall, 49.7% of all respondents (80/161) reported 1 acknowledged, unreported, or potential concussion. The unreported rate was lower than previous high school studies; however, the potentially unrecognized rate remains high and should be clinically concerning. These findings suggest educational interventions targeting collegiate student-athletes should remain and continue to focus on identifying concussion symptoms and dispelling the common misconception that "bell ringers" and "dings" are not concussions. PMID- 24157469 TI - Lipid quantification method using FTIR spectroscopy applied on cancer cell extracts. AB - Reprogramming energy metabolism constitutes one of the hallmarks of cancer. Changes in lipid composition of cell membranes also appear early in carcinogenesis. Quantification of various molecules such as lipids evidences the modifications in the metabolism of tumour cells and can serve as potential markers for cancer diagnosis and treatment. Fourier Transform Infrared (FTIR) spectroscopy is a powerful tool used for the detection and characterization of various types of molecules. This technique remains an attractive approach as it is cheap (equipment and reagents), does not require high grade solvents or expensive internal standards, equipment is widely available in standard laboratories and the method is robust and suitable for routine analyses. In this work we established partial least square (PLS) models based on FTIR spectra able to quantify lipids in complex mixtures such as cell extracts. In the first part, we attempted to build PLS models with FTIR spectra of 53 mixtures of 8 well characterized pure lipids. Second, the PLS models were verified using FTIR spectra of mixtures that did not contribute to the calibration. The third step was the validation of the models on lipid cell extracts. In order to obtain reference values for cell extracts, high performance liquid chromatography was carried out by AVANTI. The lipid distribution were globally similar with both techniques, PLS models and chromatography. Finally, the models were applied to determine the lipid composition of cells exposed to four treatments. We could not evidence significant changes in the lipid composition of cell extracts after treatment, in terms of polar head groups. However, the models established in this study appear reliable and could be applied for high throughput measurements. This article is part of a Special Issue entitled Tools to study lipid functions. PMID- 24157470 TI - Carbon nanotube alignment driven rapid actuations. AB - Suspended micro-beams made from aligned carbon nanotubes and parylene deflect reversibly in an ac field and the deflection rate is three orders of magnitude greater than those for existing devices. The direction of beam deflection is determined by the area moment of inertia and the actuation mechanism involves rapid accumulation of charges at tube surfaces, the creation of Coulomb repulsive forces between tubes, beam dilation and the formation of compressive stresses at beam ends. Tube alignment plays a crucial role in the first step as is verified by experimental data and calculation. PMID- 24157471 TI - Substantial proliferation of human renal tubular epithelial cell-reactive CD4+CD28null memory T cells, which is resistant to tacrolimus and everolimus. AB - BACKGROUND: In spite of maintenance treatment with immunosuppressive drugs, tubulitis still occurs and can lead to structural kidney graft damage. We hypothesize that human renal tubular epithelial cells (TECs) trigger selective proliferation of recipient T-cell subsets with variable sensitivity to immunosuppressive drugs. METHODS: Recipient peripheral blood mononuclear cells were cocultured with donor-derived TECs for 7 days. The proliferation of the total CD4 T-cell pool was assessed. Next, we analyzed which CD4 T-cell subset proliferated and how this response was affected by tacrolimus, everolimus, prednisolone, and mycophenolic acid (MPA) in clinically relevant concentrations. RESULTS: CD4 T-cell proliferation upon TEC encounter was mainly executed by memory T cells. Interestingly, 38%+/-7% of the proliferating CD4 T-cell pool showed a CD28 phenotype. These proliferating CD4CD28 memory T cells produced high levels of interferon-gamma, tumor necrosis factor-alpha, and the cytolitic protease granzyme B. TEC-reactive CD4 T-cell proliferation was significantly suppressed by tacrolimus, everolimus, prednisolone, and MPA (P<0.05). Surprisingly and in contrast to prednisolone and MPA, neither tacrolimus nor everolimus could inhibit the CD4CD28 T-cell proliferative response. CONCLUSION: Our data show substantial proliferation of TEC-reactive CD4CD28 memory T cells, which are resistant to tacrolimus and everolimus. This phenomenon might play an important mechanistic role during cellular rejection under full immunosuppression. PMID- 24157472 TI - Elevated bronchoalveolar lavage eosinophilia correlates with poor outcome after lung transplantation. AB - BACKGROUND: Eosinophils are involved in the pathophysiology of many respiratory diseases, but the exact role of eosinophilia in lung transplantation has not been thoroughly investigated. METHODS: We performed a retrospective analysis of our transplanted patients between 2001 and 2011, with a minimum follow-up of 1 year. Using a cutoff of >=2% eosinophilia in bronchoalveolar lavage (BAL) fluid, chronic lung allograft dysfunction (CLAD)-free survival and overall survival was compared between 66 patients demonstrating at least one BAL with eosinophils >=2% and 253 control patients (never BAL >=2%). RESULTS: Patients with increased BAL eosinophilia demonstrated worse CLAD-free and overall survival (both P<0.0001) compared with controls. Eosinophilic BAL predisposed to development of bronchiolitis obliterans syndrome but particularly to restrictive allograft syndrome (P<0.0001). After correction for covariates, the association between eosinophilic BAL and CLAD but equally death remained significant (P=0.0047 and 0.0011). Blood eosinophil and C-reactive protein levels were also elevated at the time of eosinophilic BAL. CONCLUSION: BAL eosinophilia >=2% is associated with poor outcome in our lung transplant patients as demonstrated by worse CLAD-free and overall survival. Interestingly, increased BAL eosinophilia may be specifically associated with the development of restrictive allograft syndrome, which needs further prospective investigation. PMID- 24157473 TI - Chronic rejection associated with antiviral therapy for recurrent hepatitis C after living-donor liver transplantation. AB - BACKGROUND: Chronic rejection (CR) has been reported to be associated with antiviral therapy for recurrent hepatitis C in liver transplant (LT) recipients. The aims of this study were to clarify the details of antiviral therapy associated CR after living-donor liver transplantation (LDLT) and to identify the factors associated with CR. METHODS: A retrospective chart review was performed on 125 recipients who had received antiviral therapy for recurrent hepatitis C after LDLT between January 2001 and September 2012. The characteristics of patients who developed CR during or within 6 months after antiviral therapy were compared with those of 76 patients who did not develop CR despite receiving antiviral therapy for more than 1 year. RESULTS: Seven of 125 (6%) patients developed CR during or within 6 months after the end of antiviral therapy. CR was diagnosed after a median (range) of 9 (1-16) months of antiviral therapy. In five patients, rejection progressed rapidly and resulted in death within 3 months after diagnosis. Analysis revealed two significant factors associated with CR: reduction of the immunosuppressant dose during antiviral therapy and a low fibrosis score as the indication for antiviral therapy. CONCLUSIONS: CR developed in association with antiviral therapy for recurrent hepatitis C after LDLT. This complication may be prevented by ensuring that the immunosuppressant dose is not reduced during antiviral therapy. PMID- 24157475 TI - Redox-active injectable gel using thermo-responsive nanoscale polyion complex flower micelle for noninvasive treatment of local inflammation. AB - Reactive oxygen species (ROS) scavengers have not been widely used for treatment of local inflammatory reactions such as arthritis and periodontal disease because they are rapidly eliminated from the inflamed site, which results in a low therapeutic effect. Therefore, to enhance the local retention time of ROS scavengers, we developed a redox-active injectable gel (RIG) system by using poly[4-(2,2,6,6-tetramethylpiperidine-N-oxyl)aminomethylstyrene]-b-poly(ethylene glycol)-b-poly[4-(2,2,6,6-tetramethylpiperidine-N-oxyl)aminomethylstyrene] (PMNT PEG-PMNT) triblock copolymer, which possesses ROS scavenging nitroxide radicals as side chains of the PMNT segment. Cationic PMNT segment in PMNT-PEG-PMNT forms polyion complexes with anionic poly(acrylic acid) (PAAc) to form a flower-like micelle (ca. 79 nm), which exhibits in situ thermo-irreversible gelation under physiological conditions. We confirmed the prolonged site-specific retention time of RIG by performing in vivo noninvasive electron spin resonance imaging and quantitative evaluation. In contrast to low-molecular-weight nitroxide radical compounds that disappeared from injection sites in less than 1h after subcutaneous injection, 40% of the RIG remained even at 3 days. We also found that RIG inhibits neutrophil infiltration and cytokine production, which leads to suppression of hyperalgesia. These findings indicate the potential of RIG as an innovative approach for treatment of local inflammation. PMID- 24157476 TI - The performance, application and integration of various seabed classification systems suitable for mapping Posidonia oceanica (L.) Delile meadows. AB - In the context of current global environmental changes, mapping and monitoring seagrass meadows have become highly important for management and preservation of coastal zone ecosystems. The purpose of this research was to determine the numerical precision of various cost-effective benthic habitat mapping techniques and their suitability for mapping and monitoring of Posidonia oceanica meadows in the Croatian Adriatic. We selected ultra-high resolution aerial imagery, single beam echo sounder (SBES) seabed classification system from Quester Tangent Co. (QTC), and surface based underwater videography as affordable, non-destructive and simple to use systems for data acquisition. The ultra-high resolution digital imagery was capable of detecting P. oceanica meadows up to 4m depth with 94% accuracy, from 4m to 12.5m depth the accuracy dropped to app. 76%, and from 12.5 to 20 m the system was only capable of distinguishing seabed biota from substrata, though with 97% accuracy. The results of the QTC system showed over 90% detection accuracy for Cymodocea nodosa covered seabed, excellent separation capabilities (>92%) of different sediment types (slightly gravelly sand, gravelly muddy sand and slightly gravelly muddy sand) and reasonable accuracy for mapping underwater vegetation regardless of the bathymetric span. The system proved incapable of separating P. oceanica from dense macroalgae on the same type of substratum. Surface-based underwater videography demonstrated great potential for estimating P. oceanica cover in a sampled region using either a single human rater or a computer estimate. The consistency between two human scorers in evaluating P. oceanica bottom coverage was near perfect (>98%) and high between digital and human scorers (80%). The results indicate that although the selected systems are suitable for mapping seagrasses, they all display limitations in either detection accuracy or spatial coverage, which leads to a conclusion that suitable system integration is essential for producing high quality seagrass spatial distribution maps. PMID- 24157477 TI - Oxidative potential and chemical speciation of size-resolved particulate matter (PM) at near-freeway and urban background sites in the greater Beirut area. AB - To assess particle oxidative potential in the greater Beirut area, size-resolved PM10-2.5, PM2.5-0.25 and PM0.25 samples were collected at near-freeway and urban background sites. Metals and trace elements, including Mn, Cr, Cu, Ba, Mo and Sb, displayed increased levels and crustal enrichment factors at the roadway, indicating their vehicular origin. These elements in addition to Co, V, Ni and Zn were mostly distributed in PM2.5-0.25 and PM0.25 at both sites, with moderate-to high water-solubility (>30%). The presence of these metals, mainly air toxics, in small size ranges constitutes an added health risk. Of particular concern are elements with strong correlations (R >= 0.70) with reactive oxygen species (ROS) activity, measured by a cellular assay. In PM10-2.5, road dust component Mn and soil-related element Co were highly correlated with ROS-activity. In PM2.5-0.25, vehicular abrasion element Cu and soil-derived component Co were highly associated with ROS-activity. In PM0.25, V and Ni, originating from fuel oil combustion, strongly correlated with ROS formation. ROS-activity displayed a particle-size dependency, with lowest activity associated with PM10-2.5. On a per air volume basis, size-resolved ROS-activity was 1.5-2.8 times greater at the roadside than background location, indicating that exposure to redox-active species may be greatest near the freeway. Size-fractionated PM intrinsic activity (i.e. PM mass-normalized) was comparable at both sites, possibly suggesting a similarity in the sources of ROS-active species. Relative to other urban settings, while the intrinsic redox activity of PM10-2.5 in Beirut is comparable to that measured at an urban site in Los Angeles (LA), its PM0.25-induced ROS activity is ~2.3-fold greater. Moreover, the intrinsic ROS-activity of ambient PM2.5 in Beirut is comparable to that reported in Milan-Italy, but 3.1-times PM2.5 activity in the heavily-polluted Lahore-Pakistan. Lastly, findings suggest a dominant role of transition metals in generating ROS compared to organic carbon in the LA area. PMID- 24157478 TI - Direct identification of hazardous elements in ultra-fine and nanominerals from coal fly ash produced during diesel co-firing. AB - This study has provided an initial assessment of the environmental impacts and potential health effects associated with coal fly ash produced during diesel co firing. Many hazardous elements that are typically detected by multifaceted chemical characterization by XRD, petrology, FE-SEM/EDS, and HR-TEM/SEAD/FFT/EDS in ultra-fine compounds and nanominerals from the co-fired coal fly ashes (CFAs). It provided an in-depth understanding of coal ash produced during diesel co firing. Several of the neoformed ultra-fine compounds and nano-minerals found in the coal ashes are the same as those commonly associated with oxidation/transformation of aluminosilicates, carbonates, sulphides and phosphates. PMID- 24157479 TI - Engineering cardiac muscle: new ways to refurbish old hearts? PMID- 24157480 TI - No central venous pressure protein losing enteropathy relation? Blame the albumin. PMID- 24157481 TI - Antegrade stenting of the descending thoracic aorta during DeBakey type 1 acute aortic dissection repair. AB - Several studies have shown that after DeBakey type 1 acute aortic dissection (DB1 AAD) surgery, 70% of the surviving patients still present with a dissected distal aorta that can eventually dilate, rupture, lead to distal malperfusion or require secondary extensive interventions. In order to minimize these complications, different surgeons have advocated total thoracic aorta remodelling procedures during primary aortic repair to promote false-lumen obliteration and distal thrombosis. Such management, which includes arch replacement and antegrade stenting of the dissected descending thoracic aorta (DTA), remains controversial due to its perceived increased operative mortality. Furthermore, the desired long term benefits remain to be confirmed. The present article aimed to evaluate results of antegrade stenting of DTA during surgery for DB1-AAD, focusing on in hospital mortality and morbidity, and long-term survival, occurrence of distal aortic remodelling and freedom from aortic reinterventions. Early results from the identified studies suggested that hybrid repair of DB1-AAD with antegrade DTA stenting was associated with satisfactory in-hospital mortality (10.0%) and stroke (4.8%) rates, while the risk of spinal cord injury appeared to be higher (4.3%) than that reported from historical controls. Furthermore, antegrade stenting of DTA was associated with promising rates of partial/complete thrombosis of the peristent DTA false lumen (88.9%), suggesting that aortic remodelling is highly probable with this approach. Evidence on long-term results after proximal acute dissection repair is still sparse, and mostly jeopardized by limited data beyond 5 years. Further investigations with longer term follow-up and with specifically designed protocols to assess long-term clinical outcomes (late aortic mortality and freedom from distal aortic reinterventions) of total thoracic aortic remodelling procedures vs more conservative management are warranted to reach more definitive conclusions. PMID- 24157482 TI - Reconstruction technique for a short recipient left atrial cuff during lung transplantation. AB - A simple technique for reconstructing a short recipient left atrial cuff during lung transplantation is described. After opening the confluence of the pulmonary veins, the cut ends of the pulmonary veins are sutured together, posteriorly and anteriorly. This effectively lengthens the cuff allowing safe left atrial anastomosis. This technique has been applied in 3 patients with no technique related complications. PMID- 24157483 TI - Triple-layer sealing with absorptive mesh and fibrin glue is effective in preventing air leakage after segmentectomy: results from experiments and clinical study. AB - OBJECTIVES: Fibrin glue in combination with polyglycolic acid (PGA) mesh is effective in preventing air leakage after segmentectomy, but we frequently experienced air leakage with single-layer application. To investigate improved usage, we compared the sealing effect among single-, double- and triple-layer PGA mesh and fibrin glue in both experimental and clinical segmentectomy. METHODS: Ex vivo pig lungs were used for experiments. As a model of segmentectomy, the lateral segment of the left lung was removed using electrocautery. As a model of peripheral lung defect, peripheral lung tissue was resected with scissors. The inter-segmental plane and the peripheral lung defect were sealed using one of the following four methods: (i) fibrin glue alone (Group 1, n = 8), (ii) single-layer with PGA mesh and fibrin glue (Group 2, n = 8), (iii) double-layer (Group 3, n = 8) and (iv) triple-layer (Group 4, n = 8). The seal-breaking pressures among them were compared. In clinical segmentectomy, the periods of chest-tube drainage were compared retrospectively between 17 patients treated by the single-layer and 17 treated by the triple-layer method. RESULTS: In experimental segmentectomy, the seal-breaking pressure in the triple-layer (100 +/- 25 cmH2O) was significantly higher than those in the other methods (26 +/- 17, 48 +/- 12 and 69 +/- 19 cmH2O in the Groups 1, 2 and 3, respectively, P < 0.001-0.05), while there were no significant differences among other methods. For peripheral lung defect, the seal breaking pressures did not differ among the methods. In clinical segmentectomy, the mean chest-drainage period with the triple-layer was 2 +/- 0.9 days, which was significantly shorter than 3.6 +/- 2.8 days with the single-layer (P = 0.009). CONCLUSIONS: Stronger sealants are required to prevent air leakage from inter-segmental planes than from peripheral lung. To prevent air leakage after segmentectomy, triple-layer PGA mesh and fibrin glue is recommended. PMID- 24157484 TI - Gastric conduit cancer after oesophagectomy for oesophageal cancer: incidence and clinical implications. AB - OBJECTIVES: Gastric conduit cancer (GCC), which is a carcinoma that arises in the gastric conduit after oesophagectomy, often negatively affects long-term survivors of oesophageal cancer. The aim of this study was to evaluate the incidence and clinical implications of GCC. METHODS: We reviewed data for 863 patients who underwent an oesophagectomy and a reconstruction of the gastric conduit from 1993 to 2011 for oesophageal cancer. RESULTS: A total of 18 cases of GCC in 18 patients were identified. Cumulative incidence rates of GCC were 2.4% at 5 years and 5.7% at 10 years. The median interval between oesophagectomy and detection of gastric tube cancer was 5.0 years (range, 1-16 years). Ten patients were incidentally diagnosed with GCC under periodic endoscopy. All cases of gastric tube cancer were adenocarcinoma and 12 cases were located at the antrum of the gastric conduit. For GCC treatment, endoscopic submucosal dissection was performed in 6 patients, total gastric conduit gastrectomy with colon interposition in 3 patients and chemotherapy in 6 patients. Five patients received conservative treatment alone. The 5-year survival rate of all patients was 22.2%. The 3-year survival rates of the patients who underwent endoscopic resection, total gastrectomy with colon interposition or chemotherapy or conservative treatment were 100, 50, and 9.1%, respectively (P = 0.003). CONCLUSIONS: Patients had a constant risk of GCC occurrence after oesophagectomy for oesophageal cancer. Endoscopic or surgical resection for early GCC showed favourable outcomes compared with chemotherapy or conservative treatment for advanced GCC. A regular and long-term follow-up, including detailed endoscopy, is essential for the early detection of GCC in patients who underwent oesophagectomy for oesophageal cancer. PMID- 24157485 TI - Ring thrombosis following mitral valve repair. PMID- 24157486 TI - Construction of isogenic mutants in Streptococcus gallolyticus based on the development of new mobilizable vectors. AB - Streptococcus gallolyticus is an emerging cause of infective endocarditis that has been epidemiologically linked to colorectal cancer. S. gallolyticus is poorly transformable using electroporation and no defined mutant has been published yet. Hence, we used mobilization to introduce plasmid DNA from Streptococcus agalactiae into S. gallolyticus using the transfer origin of the conjugative element TnGBS1 (oriTTnGBS1), followed by a classical homologous recombination technique. Two isogenic mutants of S. gallolyticus UCN34, one deleted for the pil1 pilus operon and another for the sortase A gene, were constructed and characterized. This genetic tool should help in unravelling virulence mechanisms of this bacterium. PMID- 24157487 TI - Isolation and chondrogenic differentiation of porcine perichondrial progenitor cells for the purpose of cartilage tissue engineering. AB - In vivo, cartilage has a limited regenerative capacity. Clinical replacement strategies require a suitable cell source to provide a stable chondrocyte phenotype without hypertrophic cartilage development, while being broadly available, and harboring a high proliferative potential. Thus, the aim of this study was to analyze the proliferation and chondrogenic differentiation capacity of porcine perichondrial progenitor cells (PPC) isolated from auricular (ePPC) and tracheal cartilage (tPPC) as an alternative cell source to mesenchymal stem cells (MSC). The proliferative potential of these cell types was analyzed by means of doubling times. Cell pellets were cultured in chondrogenic differentiation medium for 4 weeks. Potential chondrogenic differentiation was investigated by histology and immunohistology in addition to gene expression analysis of the cartilage markers collagen II, aggrecan, cartilage oligomeric matrix protein (COMP), the precartilage marker collagen I, and the hypertrophic cartilage marker collagen X. PPC showed a proliferative behavior comparable to that of MSC. Chondrogenic stimulation resulted in a higher expression of collagen II, aggrecan, and COMP in ePPC as compared to tPPC and MSC, whereas the expression of collagen I was comparable in all cell types independently of differentiation stimulation. Collagen type X, however, could not be detected. The production of cartilage-like extracellular matrix components in PPC pellets was confirmed by histological and immunohistological stains. Elastin, a component of auricular cartilage, however, was not detected in ePPC-derived pellets. Thus, PPC present a promising cell source for tissue engineering of cartilage. Furthermore, ePPC may be more convenient than tPPC due to their higher chondrogenic potential and better accessibility. PMID- 24157488 TI - Is electrode-modiolus distance a prognostic factor for hearing performances after cochlear implant surgery? AB - The aim of this study was to evaluate electrode array position in relation to cochlear anatomy and its influence on hearing performance in cochlear implantees. Twenty-two patients (25 ears) with Med-El cochlear implants were included in this retrospective study. A negative correlation was observed between electrode modiolus distance (EMD) at the cochlear base and monosyllabic word discrimination 6 months after implantation. We found no correlation between EMD and hearing outcome at 12 months. The insertion depth/cochlear perimeter ratio appeared to negatively influence the EMD at the base. Indeed, deep insertions in small cochleae appeared to yield smaller EMD and better hearing performance. This observation supports the idea of preplanning the surgery by adapting the electrode array to the length of the available scala tympani. PMID- 24157489 TI - Fibroblast growth factor-23 levels are associated with vascular calcifications in peritoneal dialysis patients. AB - BACKGROUND: The aim of the study was to assess the relationship between fibroblast growth factor-23 (FGF-23) and vascular calcifications (VC) in peritoneal dialysis (PD) patients. METHODS: A cross-sectional study was performed in 55 PD patients who underwent pelvic X-ray to assess for VC. Patients with and without linear calcifications were recorded. RESULTS: Fifteen patients (27.3%) had linear calcifications on pelvic X-ray. FGF-23 levels were higher in patients with VC (299.5 (30.4-2,410.0) vs. 74.4 (14.8-1,030) pg/ml, p < 0.01). Diabetic patients had lower FGF-23 values (43.2 (14.9-134.0) vs. 103.5 (14.8-2,410) pg/ml, p < 0.01). Patients with residual renal function (RRF) had lower FGF-23 levels (70.6 (14.8-513) vs. 179.5 (30.4-2,410) pg/ml, p = 0.06); however, this did not reach statistical significance. FGF-23 levels, age, creatinine, Ca, dialysis duration and HbA1c were positively correlated with VC, whereas RRF, Ca intake and ALP were negatively associated. Multivariate logistic analysis confirmed FGF-23 levels, age, dialysis duration and RRF to be associated with VC. CONCLUSIONS: FGF 23 levels are associated with VC in PD patients. Further studies are needed to clarify whether it is simply a marker or a potential factor. It may prove to be an important therapeutic target for VC management. PMID- 24157490 TI - Kappa opioid receptor activation decreases inhibitory transmission and antagonizes alcohol effects in rat central amygdala. AB - Activation of the kappa opioid receptor (KOR) system mediates negative emotional states and considerable evidence suggests that KOR and their natural ligand, dynorphin, are involved in ethanol dependence and reward. The central amygdala (CeA) plays a major role in alcohol dependence and reinforcement. Dynorphin peptide and gene expression are activated in the amygdala during acute and chronic administration of alcohol, but the effects of activation or blockade of KOR on inhibitory transmission and ethanol effects have not been studied. We used the slice preparation to investigate the physiological role of KOR and interaction with ethanol on GABA(A) receptor-mediated synaptic transmission. Superfusion of dynorphin or U69593 onto CeA neurons decreased evoked inhibitory postsynaptic potentials (IPSPs) in a concentration-dependent manner, an effect prevented by the KOR antagonist norbinaltorphimine (norBNI). Applied alone, norBNI increased GABAergic transmission, revealing a tonic endogenous activity at KOR. Paired-pulse analysis suggested a presynaptic KOR mechanism. Superfusion of ethanol increased IPSPs and pretreatment with KOR agonists diminished the ethanol effect. Surprisingly, the ethanol-induced augmentation of IPSPs was completely obliterated by KOR blockade. Our results reveal an important role of the dynorphin/KOR system in the regulation of inhibitory transmission and mediation of ethanol effects in the CeA. PMID- 24157492 TI - Spinal inhibitory circuits and their role in motor neuron degeneration. AB - In the spinal cord neuronal activity is controlled by the balance between excitatory and inhibitory neurotransmission, mediated mainly by the neurotransmitters glutamate and GABA/glycine, respectively. Alterations of this equilibrium have been associated with spinal motor neuron hyperexcitability and degeneration, which can be induced by excitotoxicity or by decreasing inhibitory neurotransmission. Here we review the ventral horn neuronal network and the possible involvement of inhibitory circuits in the mechanisms of degeneration of motor neurons characteristic of amyotrophic lateral sclerosis (ALS). Whereas glutamate mediated excitotoxicity seems to be an important factor, recent experimental and histopathological evidence argue in favor of a decreased activity of the inhibitory circuits controlling motor neuron excitability, mainly the recurrent inhibition exerted by Renshaw cells. A decreased Renshaw cell activity may be caused by cell loss or by a reduction of its inhibitory action secondary to a decreased excitation from cholinergic interneurons. Ultimately, inhibitory failure by either mechanism might lead to motor neuron degeneration, and this suggests inhibitory circuits and Renshaw cells as pharmacologic targets for ALS treatment. PMID- 24157491 TI - Nicotine modulation of adolescent dopamine receptor signaling and hypothalamic peptide response. AB - Adolescence is a sensitive developmental period for limbic and dopamine systems that coincides with the typical age for onset of tobacco use. We have previously shown that a 4-day, low-dose nicotine (0.06 mg/kg) pretreatment enhances locomotor and penile response to the D2-like agonist, quinpirole (0.4 mg/kg), in adolescent but not adult rats. The present study is designed to determine mechanisms underlying this effect. Nicotine enhancement of adolescent quinpirole induced locomotion was mediated by D2 receptors (D2Rs) since it was blocked by the D2R antagonist, L-741,626, but not by the D3R and D4R antagonists, NGB 2904 and L-745,870. Enhancement of quinpirole-induced erectile response was blocked by both L-741,626 and NGB 2904, indicating involvement of D3Rs. Whereas D2R binding was unaffected by adolescent nicotine pretreatment, effector coupling in the striatum was increased, as determined by GTPgammaS binding. Nicotine pretreatment enhanced quinpirole-induced c-fos mRNA expression in the hypothalamic paraventricular and supraoptic nuclei in adolescents only. Adolescent nicotine pretreatment enhanced c-fos mRNA expression in corticotropin releasing factor (CRF) cells of the paraventricular nucleus, and enhancement of penile erection was blocked by the CRF-1 receptor antagonist, CP 376,396. These findings suggest that adolescent dopamine and CRF systems are vulnerable to alteration by nicotine. This is the first evidence for a role of CRF in adolescent erectile response. PMID- 24157493 TI - Somatostatin receptor sst2 reduces Akt activity and aggravates hypoxic/ischemic death in cerebral cortical neurons. AB - It is established that growth factors support neuronal survival through the phosphoinositide 3-kinase (PI3K)/Akt pathway but little is known about factors that inhibit Akt signaling in neurons. Given that the sst2 type somatostatin receptor exerts pro-apoptotic effects in tumor cells by inhibiting PI3K/Akt, we examined whether neuronal sst2 has similar effects. In primary cortical cultures heterozygously expressing a sst2 knockout/lacZ knockin allele, beta-galactosidase staining revealed expression of the sst2 gene in the vast majority of the cultured neurons. Somatostatin was identified in a subpopulation of neurons by immunocytochemistry. Immunoblots showed a strong reduction of Akt phosphorylation at S473 in wild type cultures undergoing stimulation with the sst2 agonist BIM 23244. While the sst2 agonist did not cause neuronal death under control conditions, it promoted hypoxic/ischemic neuronal death in cortical cultures subjected to oxygen/glucose deprivation. Treatment of wild type cultures with the sst2 antagonist BIM-23627 and homozygous deletion of the sst2 gene were protective in this paradigm, suggesting that endogenous somatostatin signals through sst2 during hypoxia/ischemia. In fact, examination of sst2 phosphorylation and sst2 internalization provided evidence for sst2 activation in neurons subjected to oxygen/glucose deprivation. Thus, somatostatin acts as a sensor of hypoxia/ischemia, inhibits Akt activity through sst2 and aggravates hypoxic/ischemic neuronal death. sst2-selective antagonists are proposed as neuroprotectants in stroke. PMID- 24157494 TI - Oral misoprostol versus vaginal dinoprostone for labor induction in nulliparous women at term. AB - OBJECTIVE: To compare the efficacy of oral misoprostol to vaginal dinoprostone for labor induction in nulliparous women. STUDY DESIGN: Admissions for labor induction from January 2008 to December 2010 were reviewed. Patients receiving oral misoprostol were compared with those receiving vaginal dinoprostone. The primary outcome was time from induction agent administration to vaginal delivery. Secondary outcomes included vaginal delivery within 24 h, mode of delivery and maternal and fetal outcomes. RESULT: A total of 680 women were included: 483 (71%) received vaginal dinoprostone and 197 (29%) received oral misoprostol. Women who received oral misoprostol had a shorter interval to vaginal delivery (27.2 vs 21.9 h, P<0.0001) and were more likely to deliver vaginally in <24 h (47% vs 64%, P=0.001). There was no increase in the rate of cesarean delivery or adverse maternal or neonatal outcomes. CONCLUSION: Labor induction with oral misoprostol resulted in shorter time to vaginal delivery without increased adverse outcomes in nulliparous women. PMID- 24157495 TI - Breech presentation at delivery: a marker for congenital anomaly? AB - OBJECTIVE: To determine whether congenital anomalies are associated with breech presentation at the time of birth. STUDY DESIGN: A population-based, retrospective cohort study was conducted among 460,147 women with singleton live births using the Missouri Birth Defects Registry, which includes all defects diagnosed during the first year of life. Maternal and obstetric characteristics and outcomes between breech and cephalic presentation groups were compared using chi(2)-square statistic and Student's t-test. Multivariable binary logistic regression analysis was used to estimate adjusted odds ratios (aORs) and 95% confidence intervals (CIs). RESULT: At least one congenital anomaly was more likely present among infants breech at birth (11.7%) than in those with cephalic presentation (5.1%), whether full-term (9.4 vs 4.6%) or preterm (20.1 vs 11.6%). The relationship between breech presentation and congenital anomaly was stronger among full-term births (aOR 2.09, CI 1.96, 2.23, term vs 1.40, CI 1.26, 1.55, preterm), but not in all categories of anomalies. CONCLUSION: Breech presentation at delivery is a marker for the presence of congenital anomaly. Infants delivered breech deserve special scrutiny for the presence of malformation. PMID- 24157496 TI - A risk stratification model to predict adverse neonatal outcome in labor. AB - OBJECTIVE: The development and evaluation of a labor risk model consisting of a combination of antepartum risk factors and intrapartum fetal heart rate (FHR) characteristics that can reliably identify those infants at risk for adverse neonatal outcome in labor. STUDY DESIGN: A nested case-control study of term singleton deliveries at the nine hospitals between March 2007 and December 2009. Eligibility criteria included: gestational age >= 37.0 weeks; singleton pregnancy; documented continuous FHR monitoring for >= 2 h before delivery; assessment of FHR tracing at least every 20 min; and, available maternal and neonatal outcomes. Adverse neonatal outcome was defined as nonanomalous infants admitted to the newborn intensive care unit with either a 5 minute Apgar score <7 or an umbilical artery pH<7.1. Initial risk score was determined using data available at 1 h after admission. Patients with an initial risk score between 7 and 15 were considered high risk. Intrapartum risk scores were then created for these patients using FHR tracing data and labor characteristics. RESULT: A total of 51 244 patients were identified meeting study criteria. Of the antepartum variables evaluated (n=31), 10 were associated with an adverse outcome. The high risk group made up 28% of the population and accounted for 59.8% of the adverse outcomes. Intrapartum characteristics were then evaluated in this high-risk group. Intrapartum evaluation identified the highest risk group with a C/S rate of 40% and adverse outcome rate of 11.3%. CONCLUSION: Incorporation of maternal and antepartum risk factors with FHR analysis can improve the ability to identify the fetus at risk in labor. PMID- 24157498 TI - Cerebral mass in HIV infection. PMID- 24157497 TI - Comparative effectiveness of renin-angiotensin system blockers and other antihypertensive drugs in patients with diabetes: systematic review and bayesian network meta-analysis. AB - OBJECTIVE: To assess the effects of different classes of antihypertensive treatments, including monotherapy and combination therapy, on survival and major renal outcomes in patients with diabetes. DESIGN: Systematic review and bayesian network meta-analysis of randomised clinical trials. DATA SOURCES: Electronic literature search of PubMed, Medline, Scopus, and the Cochrane Library for studies published up to December 2011. STUDY SELECTION: Randomised clinical trials of antihypertensive therapy (angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), alpha blockers, beta blockers, calcium channel blockers, diuretics, and their combinations) in patients with diabetes with a follow-up of at least 12 months, reporting all cause mortality, requirement for dialysis, or doubling of serum creatinine levels. DATA EXTRACTION: Bayesian network meta-analysis combined direct and indirect evidence to estimate the relative effects between treatments as well as the probabilities of ranking for treatments based on their protective effects. RESULTS: 63 trials with 36,917 participants were identified, including 2400 deaths, 766 patients who required dialysis, and 1099 patients whose serum creatinine level had doubled. Compared with placebo, only ACE inhibitors significantly reduced the doubling of serum creatinine levels (odds ratio 0.58, 95% credible interval 0.32 to 0.90), and only beta blockers showed a significant difference in mortality (odds ratio 7.13, 95% credible interval 1.37 to 41.39). Comparisons among all treatments showed no statistical significance in the outcome of dialysis. Although the beneficial effects of ACE inhibitors compared with ARBs did not reach statistical significance, ACE inhibitors consistently showed higher probabilities of being in the superior ranking positions among all three outcomes. Although the protective effect of an ACE inhibitor plus calcium channel blocker compared with placebo was not statistically significant, the treatment ranking identified this combination therapy to have the greatest probability (73.9%) for being the best treatment on reducing mortality, followed by ACE inhibitor plus diuretic (12.5%), ACE inhibitors (2.0%), calcium channel blockers (1.2%), and ARBs (0.4%). CONCLUSIONS: Our analyses show the renoprotective effects and superiority of using ACE inhibitors in patients with diabetes, and available evidence is not able to show a better effect for ARBs compared with ACE inhibitors. Considering the cost of drugs, our findings support the use of ACE inhibitors as the first line antihypertensive agent in patients with diabetes. Calcium channel blockers might be the preferred treatment in combination with ACE inhibitors if adequate blood pressure control cannot be achieved by ACE inhibitors alone. PMID- 24157500 TI - WHO calls for more money to fight tuberculosis. PMID- 24157499 TI - Energy drinks: cause for concern or scaremongering? PMID- 24157501 TI - Patient groups accuse European parliament of putting economic interests ahead of safety on medical devices. PMID- 24157503 TI - LOX-1: a male hormone-regulated scavenger receptor for atherosclerosis. AB - Lectin-like oxidized LDL receptor-1 (LOX-1) is a unique scavenger receptor that mediates the binding and uptake of oxidized LDL (ox-LDL) by vascular cells during the development of atherosclerosis. Exposure to ox-LDL induces LOX-1 expression and LOX-1-dependent biological activities, such as activation of NF-kappaB, a nuclear factor important for signal transduction in inflammation. Accumulating evidence indicates that male hormones may regulate expression of LOX-1 and NF kappaB as well as atherogenesis. Deficiency or low levels of the male hormone testosterone promote LOX-1 expression and NF-kappaB activation, while testosterone replacement therapy reduces the expression of LOX-1 and the activation of NF-kappaB, thereby protecting the arterial wall against atherogenesis. PMID- 24157502 TI - The role of the medial prefrontal cortex in regulating social familiarity-induced anxiolysis. AB - Overcoming specific fears and subsequent anxiety can be greatly enhanced by the presence of familiar social partners, but the neural circuitry that controls this phenomenon remains unclear. To overcome this, the social interaction (SI) habituation test was developed in this lab to systematically investigate the effects of social familiarity on anxiety-like behavior in rats. Here, we show that social familiarity selectively reduced anxiety-like behaviors induced by an ethological anxiogenic stimulus. The anxiolytic effect of social familiarity could be elicited over multiple training sessions and was specific to both the presence of the anxiogenic stimulus and the familiar social partner. In addition, socially familiar conspecifics served as a safety signal, as anxiety-like responses returned in the absence of the familiar partner. The expression of the social familiarity-induced anxiolysis (SFiA) appears dependent on the prefrontal cortex (PFC), an area associated with cortical regulation of fear and anxiety behaviors. Inhibition of the PFC, with bilateral injections of the GABAA agonist muscimol, selectively blocked the expression of SFiA while having no effect on SI with a novel partner. Finally, the effect of D-cycloserine, a cognitive enhancer that clinically enhances behavioral treatments for anxiety, was investigated with SFiA. D-cycloserine, when paired with familiarity training sessions, selectively enhanced the rate at which SFiA was acquired. Collectively, these outcomes suggest that the PFC has a pivotal role in SFiA, a complex behavior involving the integration of social cues of familiarity with contextual and emotional information to regulate anxiety-like behavior. PMID- 24157504 TI - Acute and subacute effects of urban air pollution on cardiopulmonary emergencies and mortality: time series studies in Austrian cities. AB - Daily pollution data (collected in Graz over 16 years and in the Linz over 18 years) were used for time series studies (GAM and case-crossover) on the relationship with daily mortality (overall and specific causes of death). Diagnoses of patients who had been transported to hospitals in Linz were also available on a daily basis from eight years for time series analyses of cardiopulmonary emergencies. Increases in air pollutant levels over several days were followed by increases in mortality and the observed effects increased with the length of the exposure window considered, up to a maximum of 15 days. These mortality changes in Graz and Linz showed similar patterns like the ones found before in Vienna. A significant association of mortality could be demonstrated with NO2, PM2.5 and PM10 even in summer, when concentrations are lower and mainly related to motor traffic. Cardiorespiratory ambulance transports increased with NO2/PM2.5/PM10 by 2.0/6.1/1.7% per 10 ug/m3 on the same day. Monitoring of NO2 (related to motor traffic) and fine particulates at urban background stations predicts acute effects on cardiopulmonary emergencies and extended effects on cardiopulmonary mortality. Both components of urban air pollution are indicators of acute cardiopulmonary health risks, which need to be monitored and reduced, even below current standards. PMID- 24157505 TI - Detection of human impacts by an adaptive energy-based anisotropic algorithm. AB - Boosted by health consequences and the cost of falls in the elderly, this work develops and tests a novel algorithm and methodology to detect human impacts that will act as triggers of a two-layer fall monitor. The two main requirements demanded by socio-healthcare providers--unobtrusiveness and reliability--defined the objectives of the research. We have demonstrated that a very agile, adaptive, and energy-based anisotropic algorithm can provide 100% sensitivity and 78% specificity, in the task of detecting impacts under demanding laboratory conditions. The algorithm works together with an unsupervised real-time learning technique that addresses the adaptive capability, and this is also presented. The work demonstrates the robustness and reliability of our new algorithm, which will be the basis of a smart falling monitor. This is shown in this work to underline the relevance of the results. PMID- 24157507 TI - Domestic water service delivery indicators and frameworks for monitoring, evaluation, policy and planning: a review. AB - Monitoring of water services informs policy and planning for national governments and the international community. Currently, the international monitoring system measures the type of drinking water source that households use. There have been calls for improved monitoring systems over several decades, some advocating use of multiple indicators. We review the literature on water service indicators and frameworks with a view to informing debate on their relevance to national and international monitoring. We describe the evidence concerning the relevance of each identified indicator to public health, economic development and human rights. We analyze the benefits and challenges of using these indicators separately and combined in an index as tools for planning, monitoring, and evaluating water services. We find substantial evidence on the importance of each commonly recommended indicator--service type, safety, quantity, accessibility, reliability or continuity of service, equity, and affordability. Several frameworks have been proposed that give structure to the relationships among individual indicators and some combine multiple indicator scores into a single index but few have been rigorously tested. More research is needed to understand if employing a composite metric of indicators is advantageous and how each indicator might be scored and scaled. PMID- 24157508 TI - Estimating the public health impact of setting targets at the European level for the reduction of zoonotic Salmonella in certain poultry populations. AB - In the European Union (EU), targets are being set for the reduction of certain zoonotic Salmonella serovars in different animal populations, including poultry populations, within the framework of Regulation (EC) No. 2160/2003 on the control of zoonoses. For a three-year transitional period, the EU targets were to cover only Salmonella Enteritidis and S. Typhimurium (and in addition S. Hadar, S. Infantis and S. Virchow for breeding flocks of Gallus gallus). Before the end of that transitional period, the revision of the EU targets was to be considered, including the potentially addition of other serovars with public health significance to the permanent EU targets. This review article aims at providing an overview of the assessments carried out by the Scientific Panel on Biological Hazards of the European Food Safety Authority in the field of setting targets for Salmonella in poultry populations (breeding flocks of Gallus gallus, laying flocks of Gallus gallus, broiler flocks of Gallus gallus and flocks of breeding and fattening turkeys) and their impact in subsequent changes in EU legislation. PMID- 24157506 TI - Smoking behaviour and mental health disorders--mutual influences and implications for therapy. AB - Tobacco use is strongly associated with a variety of psychiatric disorders. Smokers are more likely than non-smokers to meet current criteria for mental health conditions, such as mood disorders, anxiety disorders and psychosis. Evidence also suggest that smokers with psychiatric disorders may have more difficulty quitting, offering at least a partial explanation for why smoking rates are higher in this population. The mechanisms linking mental health conditions and cigarette smoking are complex and likely differ across each of the various disorders. The most commonly held view is that patients with mental health conditions smoke in an effort to regulate the symptoms associated with their disorder. However some recent evidence suggests that quitting smoking may actually improve mental health symptoms. This is particularly true if the tobacco cessation intervention is integrated into the context of ongoing mental health treatment. In this paper we reviewed and summarized the most relevant knowledge about the relationship between tobacco use and dependence and psychiatric disorders. We also reviewed the most effective smoking cessation strategies available for patients with psychiatric comorbidity and the impact of smoking behavior on psychiatric medication. PMID- 24157509 TI - Community perceptions of air pollution and related health risks in Nairobi slums. AB - Air pollution is among the leading global risks for mortality and responsible for increasing risk for chronic diseases. Community perceptions on exposure are critical in determining people's response and acceptance of related policies. Therefore, understanding people' perception is critical in informing the design of appropriate intervention measures. The aim of this paper was to establish levels and associations between perceived pollution and health risk perception among slum residents. A cross-sectional study of 5,317 individuals aged 35+ years was conducted in two slums of Nairobi. Association of perceived score and individual characteristics was assessed using linear regression. Spatial variation in the perceived levels was determined through hot spot analysis using ArcGIS. The average perceived air pollution level was higher among residents in Viwandani compared to those in Korogocho. Perceived air pollution level was positively associated with perceived health risks. The majority of respondents were exposed to air pollution in their place of work with 66% exposed to at least two sources of air pollution. Less than 20% of the respondents in both areas mentioned sources related to indoor pollution. The perceived air pollution level and related health risks in the study community were low among the residents indicating the need for promoting awareness on air pollution sources and related health risks. PMID- 24157511 TI - Drunken environments: a survey of bartenders working in pubs, bars and nightclubs. AB - There is evidence that bartenders play a key role in respect of the health and safety of patrons in nightlife environments. However, little is known of how bartenders themselves are affected by the environments in which they work, especially with regard to their exposure to violence, pressure to drink and stress. We used a cross-sectional survey to assess the experiences of bartenders (n = 424) working in pubs, bars and nightclubs in Denmark. 71% of the respondents reported drinking while working, 6% reported using other drugs than alcohol at work, and 33% reported drinking even when they did not feel like it because of pressure to drink at work. Verbal assaults and threats were common and associated with higher levels of perceived stress. Bartenders' work environment poses a risk for the development of alcohol use disorders. The fact that many bartenders consume significant quantities of alcohol during their working hours may pose a risk not only to their own safety, but also to that of their colleagues and patrons. PMID- 24157512 TI - Stress, health and well-being: the mediating role of employee and organizational commitment. AB - This study investigates the mediating impact of organizational commitment on the relationship between organizational stressors and employee health and well-being. Data were collected from 401 operator level employees working in business process outsourcing organizations (BPOs) based in New Delhi, India. In this research several dimensions from ASSET, which is an organizational stress screening tool, were used to measure employee perceptions of stressors, their commitment to the organization, their perception of the organization's commitment to them, and their health and well-being. Data were analyzed using structural equation modeling on AMOS software. Results of the mediation analysis highlight both employee commitment to their organization and their perceptions of the organization's commitment to them mediate the impact of stressors on physical health and psychological well-being. All indices of the model fit were found to be above standard norms. Implications are discussed with the view to improving standards of health and well-being within the call center industry, which is a sector that has reported higher turnover rates and poor working conditions among its employees internationally. PMID- 24157510 TI - European surveillance for West Nile virus in mosquito populations. AB - A wide range of arthropod-borne viruses threaten both human and animal health either through their presence in Europe or through risk of introduction. Prominent among these is West Nile virus (WNV), primarily an avian virus, which has caused multiple outbreaks associated with human and equine mortality. Endemic outbreaks of West Nile fever have been reported in Italy, Greece, France, Romania, Hungary, Russia and Spain, with further spread expected. Most outbreaks in Western Europe have been due to infection with WNV Lineage 1. In Eastern Europe WNV Lineage 2 has been responsible for human and bird mortality, particularly in Greece, which has experienced extensive outbreaks over three consecutive years. Italy has experienced co-circulation with both virus lineages. The ability to manage this threat in a cost-effective way is dependent on early detection. Targeted surveillance for pathogens within mosquito populations offers the ability to detect viruses prior to their emergence in livestock, equine species or human populations. In addition, it can establish a baseline of mosquito-borne virus activity and allow monitoring of change to this over time. Early detection offers the opportunity to raise disease awareness, initiate vector control and preventative vaccination, now available for horses, and encourage personal protection against mosquito bites. This would have major benefits through financial savings and reduction in equid morbidity/mortality. However, effective surveillance that predicts virus outbreaks is challenged by a range of factors including limited resources, variation in mosquito capture rates (too few or too many), difficulties in mosquito identification, often reliant on specialist entomologists, and the sensitive, rapid detection of viruses in mosquito pools. Surveillance for WNV and other arboviruses within mosquito populations varies between European countries in the extent and focus of the surveillance. This study reviews the current status of WNV in mosquito populations across Europe and how this is informing our understanding of virus epidemiology. Key findings such as detection of virus, presence of vector species and invasive mosquito species are summarized, and some of the difficulties encountered when applying a cost-effective surveillance programme are highlighted. PMID- 24157513 TI - Heterogeneous risk perceptions: the case of poultry meat purchase intentions in Finland. AB - This study focused on the heterogeneity of consumer reactions, measured through poultry meat purchase intentions, when facing three cases of risk. The heterogeneity was analysed by latent class logistic regression that included all three risk cases. Approximately 60% of the respondents belonged to the group of production risk avoiders, in which the intention to purchase risk food was significantly lower than in the second group of risk neutrals. In addition to socio-demographic variables, the purchase intentions were statistically associated with several attitude-based variables. We highlighted some policy implications of the heterogeneity. Overall, the study demonstrated that risk matters to consumers, not all risk is equal, and consumer types react somewhat differently to different types of risk. PMID- 24157514 TI - "We made the rule, we have to stick to it": towards effective management of environmental tobacco smoke in remote Australian Aboriginal communities. AB - Smoking prevalence in remote Australian Aboriginal communities remains extraordinarily high, with rates reported of up to 82%. Widespread exposure to environmental tobacco smoke (ETS) is exacerbated by overcrowded housing. Implementation of existing smoke-free policies is challenged by the normalization of smoking and a lack of appropriate regulation resources. This paper celebrates a grassroots approach to control of environmental tobacco smoke (ETS) in these settings. We report on selected findings from a tobacco intervention study in Arnhem Land, Northern Territory in 2007-2012. In community-level tobacco use surveys at baseline (n = 400 >= 16 years), participants reported concern about the constant exposure of non-smokers to tobacco smoke. Suggestions for action included restricting smoking in private and public spaces. We selected three case studies illustrating management of ETS from observational data during the study's intervention phase. Using a critical realist approach, the context and mechanisms that contributed to specific strategies, or outcomes, were examined in order to develop a hypothesis regarding more effective management of ETS in these environments. Our results suggest that in discrete, disadvantaged communities, enhanced local ownership of smoke-free policies and development of implementation strategies at the grassroots level that acknowledge and incorporate cultural contexts can contribute to more effective management of ETS. PMID- 24157515 TI - Spatial distribution of underweight, overweight and obesity among women and children: results from the 2011 Uganda Demographic and Health Survey. AB - While undernutrition and infectious diseases are still persistent in developing countries, overweight, obesity, and associated comorbidities have become more prevalent. Uganda, a developing sub-Saharan African country, is currently experiencing the public health paradox of undernutrition and overnutrition. We utilized the 2011 Uganda Demographic and Health Survey (DHS) to examine risk factors and hot spots for underweight, overweight, and obesity among adult females (N = 2,420) and their children (N = 1,099) using ordinary least squares and multinomial logit regression and the ArcGIS Getis-Ord Gi* statistic. Overweight and obese women were significantly more likely to have overweight children, and overweight was correlated with being in the highest wealth class (OR = 2.94, 95% CI = 1.99-4.35), and residing in an urban (OR = 1.76, 95% CI = 1.34-2.29) but not a conflict prone (OR = 0.48, 95% CI = 0.29-0.78) area. Underweight clustered significantly in the Northern and Northeastern regions, while overweight females and children clustered in the Southeast. We demonstrate that the DHS can be used to assess geographic clustering and burden of disease, thereby allowing for targeted programs and policies. Further, we pinpoint specific regions and population groups in Uganda for targeted preventive measures and treatment to reduce the burden of overweight and chronic diseases in Uganda. PMID- 24157516 TI - The kinetic signature of toxicity of four heavy metals and their mixtures on MCF7 breast cancer cell line. AB - This study evaluated the kinetic signature of toxicity of four heavy metals known to cause severe health and environmental issues--cadmium (Cd), mercury (Hg) lead (Pb) arsenic (As)--and the mixture of all four metals (Mix) on MCF7 cancer cells, in the presence and absence of the antioxidant glutathione (GSH). The study was carried out using real time cell electronic sensing (RT-CES). RT-CES monitors in real time the electrical impedance changes at the electrode/culture medium interface due to the number of adhered cells, which is used as an index of cell viability. Cells were seeded for 24 h before exposure to the metals and their mixtures. The results showed that in the presence and absence of cellular glutathione, arsenic was the most cytotoxic of all five treatments, inducing cell death after 5 h of exposure. Lead was the least cytotoxic in both scenarios. In the presence of cellular GSH, the cytotoxic trend was As > Cd > MIX > Hg > Pb, while in the absence of GSH, the cytotoxic trend was As > Hg > MIX > Cd > Pb. The findings from this study indicate the significance of glutathione-mediated toxicity of the metals examined--particularly for mercury--and may be clinically relevant for disorders such as autism spectrum disorder where decreased glutathione-based detoxification capacity is associated with increased mercury intoxication. PMID- 24157517 TI - Green synthesis of silver nanoparticles, their characterization, application and antibacterial activity. AB - Our research focused on the production, characterization and application of silver nanoparticles (AgNPs), which can be utilized in biomedical research and environmental cleaning applications. We used an environmentally friendly extracellular biosynthetic technique for the production of the AgNPs. The reducing agents used to produce the nanoparticles were from aqueous extracts made from the leaves of various plants. Synthesis of colloidal AgNPs was monitored by UV-Visible spectroscopy. The UV-Visible spectrum showed a peak between 417 and 425 nm corresponding to the Plasmon absorbance of the AgNPs. The characterization of the AgNPs such as their size and shape was performed by Atom Force Microscopy (AFM), and Transmission Electron Microscopy (TEM) techniques which indicated a size range of 3 to 15 nm. The anti-bacterial activity of AgNPs was investigated at concentrations between 2 and 15 ppm for Gram-negative and Gram-positive bacteria. Staphylococcus aureus and Kocuria rhizophila, Bacillus thuringiensis (Gram-positive organisms); Escherichia coli, Pseudomonas aeruginosa, and Salmonella typhimurium (Gram-negative organisms) were exposed to AgNPs using Bioscreen C. The results indicated that AgNPs at a concentration of 2 and 4 ppm, inhibited bacterial growth. Preliminary evaluation of cytotoxicity of biosynthesized silver nanoparticles was accomplished using the InQTM Cell Research System instrument with HEK 293 cells. This investigation demonstrated that silver nanoparticles with a concentration of 2 ppm and 4 ppm were not toxic for human healthy cells, but inhibit bacterial growth. PMID- 24157518 TI - Computing power and sample size for informational odds ratio. AB - The informational odds ratio (IOR) measures the post-exposure odds divided by the pre-exposure odds (i.e., information gained after knowing exposure status). A desirable property of an adjusted ratio estimate is collapsibility, wherein the combined crude ratio will not change after adjusting for a variable that is not a confounder. Adjusted traditional odds ratios (TORs) are not collapsible. In contrast, Mantel-Haenszel adjusted IORs, analogous to relative risks (RRs) generally are collapsible. IORs are a useful measure of disease association in case-referent studies, especially when the disease is common in the exposed and/or unexposed groups. This paper outlines how to compute power and sample size in the simple case of unadjusted IORs. PMID- 24157519 TI - Effect of the environmental pollutant hexachlorobenzene (HCB) on the neuronal differentiation of mouse embryonic stem cells. AB - Exposure to persistent environmental pollutants may constitute an important factor on the onset of a number of neurological disorders such as autism, Parkinson's disease, and Attention Deficit Disorder (ADD), which have also been linked to reduced GABAergic neuronal function. GABAergic neurons produce gamma aminobutyric acid (GABA), which is the main inhibitory neurotransmitter in the brain. However, the lack of appropriate models has hindered the study of suspected environmental pollutants on GABAergic function. In this work, we have examined the effect of hexachlorobenzene (HCB), a persistent and bioaccumulative environmental pollutant, on the function and morphology of GABAergic neurons generated in vitro from mouse embryonic stem (ES) cells. We observed that: (1) treatment with 0.5 nM HCB did not affect cell viability, but affected the neuronal differentiation of ES cells; (2) HCB induced the production of reactive oxygen species (ROS); and (3) HCB repressed neurite outgrowth in GABAergic neurons, but this effect was reversed by the ROS scavenger N-acetylcysteine (NAC). Our study also revealed that HCB did not significantly interfere with the function of K+ ion channels in the neuronal soma, which indicates that this pollutant does not affect the maturation of the GABAergic neuronal soma. Our results suggest a mechanism by which environmental pollutants interfere with normal GABAergic neuronal function and may promote the onset of a number of neurological disorders such as autism and ADD. PMID- 24157520 TI - Optimization of gold nanoring arrays for biosensing in the fiber-optic communication window. AB - To improve the limit of detection in a nanoplasmonic sensor system, the optical performance of the metal nanostructures should be optimized according to the best spectral window of the measurement instrument. We propose that the spectral window from 1460 to 1610 nm can potentially provide ultrahigh instrumental resolution for biosensing. We optimized gold nanoring arrays such that the extinction peak position is inside the proposed window, the extinction peak is sharp enough to track the peak shift with high resolution and the figure of merit (sensitivity/linewidth) of the array is optimized at the same time. The peak sharpening effect of the array caused by coherent interaction plays a central role in the optimization. The optimized array has a lattice constant in the range [1000 nm,1060 nm], a bulk index sensitivity of around 450 nm/RIU and a figure of merit larger than 4. It is an enabling sensor element for a near-infrared sensor chip with ultrahigh resolution. PMID- 24157522 TI - A novel regulatory element for Shh expression in the lung and gut of mouse embryos. AB - Hedgehog (Hh) signaling plays pivotal roles in morphogenesis of several embryonic tissues, including the primitive gut. In the mouse embryo, Sonic hedgehog (Shh) is expressed in endodermal epithelia from the oral cavity to the intestine, and contributes to cell proliferation in the underlying mesenchyme and subsequent differentiation into the gastrointestinal smooth muscle. Three evolutionary conserved non-coding sequences in the region upstream of the Shh coding sequence contain endoderm-specific enhancers for Shh expression. Although Shh expression in the endodermal epithelial lining is mostly attributed to these three enhancers, none of them regulates gene expression in the gastroesophageal epithelium. Here, we found that a 1.7Kb fragment located 100Kb upstream of the Shh coding sequence contains a functional element for Shh expression in endodermal organs, including the esophagus and stomach. Compared with the three known endodermal enhancers, this novel enhancer shows less evolutionary conservation, even among rodents. In mouse embryonic endodermal tissues, the seamless expression of Shh is achieved by a patchwork of multiple enhancers with different rates of evolution. PMID- 24157521 TI - Eye-specification genes in the bacterial light organ of the bobtail squid Euprymna scolopes, and their expression in response to symbiont cues. AB - The squid Euprymna scolopes has evolved independent sets of tissues capable of light detection, including a complex eye and a photophore or 'light organ', which houses the luminous bacterial symbiont Vibrio fischeri. As the eye and light organ originate from different embryonic tissues, we examined whether the eye specification genes, pax6, eya, six, and dac, are shared by these two organs, and if so, whether they are regulated in the light organ by symbiosis. We obtained sequences of the four genes with PCR, confirmed orthology with phylogenetic analysis, and determined that each was expressed in the eye and light organ. With in situ hybridization (ISH), we localized the gene transcripts in developing embryos, comparing the patterns of expression in the two organs. The four transcripts localized to similar tissues, including those associated with the visual system ~1/4 into embryogenesis (Naef stage 18) and the light organ ~3/4 into embryogenesis (Naef stage 26). We used ISH and quantitative real-time PCR to examine transcript expression and differential regulation in postembryonic light organs in response to the following colonization conditions: wild-type, luminescent V. fischeri; a mutant strain defective in light production; and as a control, no symbiont. In ISH experiments light organs showed down regulation of the pax6, eya, and six transcripts in response to wild-type V. fischeri. Mutant strains also induced down regulation of the pax6 and eya transcripts, but not of the six transcript. Thus, luminescence was required for down regulation of the six transcript. We discuss these results in the context of symbiont-induced light organ development. Our study indicates that the eye-specification genes are expressed in light-interacting tissues independent of their embryonic origin and are capable of responding to bacterial cues. These results offer evidence for evolutionary tinkering or the recruitment of eye development genes for use in a light-sensing photophore. PMID- 24157523 TI - Determination of amantadine in biological fluids using simultaneous derivatization and dispersive liquid-liquid microextraction followed by gas chromatography-flame ionization detection. AB - A one-step derivatization and microextraction technique for the determination of amantadine in the human plasma and urine samples is presented. An appropriate mixture of methanol (disperser solvent), 1,2-dibromoethane (extraction solvent), and butylchloroformate (derivatization agent) is rapidly injected into samples. After centrifuging, the sedimented phase is analyzed by gas chromatography-flame ionization detection (GC-FID). The kind of extraction and disperser solvents and their volumes, amount of derivatization agent and reaction/extraction time which are effective in derivatization/dispersive liquid-liquid microextraction (DLLME) procedure are optimized. Under the optimal conditions, the enrichment factor (EF) of the target analyte was obtained to be 408 and 420, and limit of detection (LOD) 4.2 and 2.7ngmL(-1), in plasma and urine respectively. The linear range is 14-5000 and 8.7-5000ng/mL for plasma and urine, respectively (squared correlation coefficient>=0.990). The relative recoveries obtained for the spiked plasma and urine samples are between 72% and 93%. Moreover, the inter- and intra-day precisions are acceptable at all spiked concentrations (relative standard deviation <7%). Finally the method was successfully applied to determine amantadine in biological samples. PMID- 24157524 TI - Perinatal hyperoxic exposure reconfigures the central respiratory network contributing to intolerance to anoxia in newborn rat pups. AB - Perinatal exposure to hyperoxia (30-60% O2) alters the respiratory control system via modulation of peripheral arterial chemoreceptor development and function. Furthermore, hyperoxic exposure during the first two postnatal weeks of life can alternatively modulate the different phases of the hypoxic ventilatory response. Given the effects of perinatal hyperoxia, the aims of our study were 1) to determine the effect on survival time in response to lethal anoxic stimuli in rat pups and 2) to characterize the output of the isolated central respiratory network in response to acute hypoxic stimuli. We hypothesized that perinatal hyperoxic exposure would modify the neonatal rat ventilatory response to anoxia by affecting a central component of the respiratory network in addition to the maturation of the carotid body chemoreceptors. We found that animals continuously exposed to 60% oxygen up to age 5 days after parturition (P5) have reduced breathing frequency at baseline and within the first 10 min of a fatal anoxic challenge. Hyperoxic rat pups also have a shortened time to last gasp in response to anoxia that is not associated with lung injury or inflammation. This study is the first to demonstrate that these in vivo findings correlate with reduced phrenic burst frequency from the isolated brainstem ex vivo. Thus hyperoxic exposure reduced the phrenic burst frequency at baseline and in response to ex vivo anoxia. Importantly, our data suggest that perinatal hyperoxia alters ventilation and the response to anoxia at P5 in part by altering the frequency of phrenic bursts generated by the central respiratory network. PMID- 24157525 TI - A new method to detect rapid oxygen changes around cells: how quickly do calcium channels sense oxygen in cardiomyocytes? AB - Acute hypoxia is thought to trigger protective responses that, in tissues like heart and carotid body, include rapid (5-10 s) suppression of Ca(2+) and K(+) channels. To gain insight into the mechanism for the suppression of the cardiac l type Ca(2+) channel, we measured O2-dependent fluorescence in the immediate vicinity of voltage-clamped cardiac cells subjected to rapid exchange of solutions with different O2 tensions. This was accomplished with an experimental chamber with a glass bottom that was used as a light guide for excitation of a thin ruthenium-based O2-sensitive ORMOSIL coating. Fluorescence imaging showed that steady-state Po2 was well controlled within the entire stream from an electromagnetically controlled solution "puffer" but that changes were slower at the periphery of the stream (tau1/2 ~ 500 ms) than immediately around the voltage clamped myocyte (tau1/2 ~ 225 ms) where, in turn, firmly attached cells produced an additional local delay of 50-100 ms. Performing simultaneous voltage clamp and O2 measurements, we found that acute hypoxia gradually and reversibly suppressed the Ca(2+) channel (CaV1.2). Using Ba(2+) as charge carrier, the suppression was significant after 1.5 s, reached ~10% after 2.5 s, and was nearly completely reversible in 5 s. The described fluorescence measurements provide the means to check and fine tune solution puffers and suggest that changes in Po2 can be accomplished within ~200 ms. The rapid and reversible suppression of barium current under hypoxia is consistent with the notion that the cardiac Ca(2+) channel is directly modulated by O2. PMID- 24157527 TI - Familial hypercholesterolemia impairs exercise-induced systemic vasodilation due to reduced NO bioavailability. AB - Hypercholesterolemia impairs endothelial function [e.g., the nitric oxide (NO) cyclic GMP-phosphodiesterase 5 (PDE5) pathway], limits shear stress-induced vasodilation, and is therefore expected to reduce exercise-induced vasodilation. To assess the actual effects of hypercholesterolemia on endothelial function and exercise-induced vasodilation, we compared the effects of endothelial NO synthase (eNOS) and PDE5 inhibition in chronically instrumented Yucatan (Control) and Rapacz familial hypercholesterolemic (FH) swine, at rest and during treadmill exercise. The increases in systemic vascular conductance produced by ATP (relative to nitroprusside) and exercise were blunted in FH compared with Control swine. The vasoconstrictor response to eNOS inhibition, with nitro-l-arginine (NLA), was attenuated in FH compared with Control swine, both at rest and during exercise. Furthermore, whereas the vasodilator response to nitroprusside was enhanced slightly, the vasodilator response to PDE5 inhibition, with EMD360527, was reduced in FH compared with Control swine. Finally, in the pulmonary circulation, FH resulted in attenuated vasodilator responses to ATP, while maintaining the responses to both NLA and EMD360527. In conclusion, hypercholesterolemia reduces exercise-induced vasodilation in the systemic but not the pulmonary circulation. This reduction appears to be the principal result of a decrease in NO bioavailability, which is mitigated by a lower PDE5 activity. PMID- 24157526 TI - Angiogenic response to passive movement and active exercise in individuals with peripheral arterial disease. AB - Peripheral arterial disease (PAD) is caused by atherosclerosis and is associated with microcirculatory impairments in skeletal muscle. The present study evaluated the angiogenic response to exercise and passive movement in skeletal muscle of PAD patients compared with healthy control subjects. Twenty-one PAD patients and 17 aged control subjects were randomly assigned to either a passive movement or an active exercise study. Interstitial fluid microdialysate and tissue samples were obtained from the thigh skeletal muscle. Muscle dialysate vascular endothelial growth factor (VEGF) levels were modestly increased in response to either passive movement or active exercise in both subject groups. The basal muscle dialysate level of the angiostatic factor thrombospondin-1 protein was markedly higher (P < 0.05) in PAD patients compared with the control subjects, whereas soluble VEGF receptor-1 dialysate levels were similar in the two groups. The basal VEGF protein content in the muscle tissue samples was ~27% lower (P < 0.05) in the PAD patients compared with the control subjects. Analysis of mRNA expression for a range of angiogenic and angiostatic factors revealed a modest change with active exercise and passive movement in both groups, except for an increase (P < 0.05) in the ratio of angiopoietin-2 to angiopoietin-1 mRNA in the PAD group with both interventions. PAD patients and aged individuals showed a similar limited angiogenic response to active exercise and passive movement. The limited increase in muscle extracellular VEGF combined with an elevated basal level of thrombospondin-1 in muscle extracellular fluid of PAD patients may restrict capillary growth in these patients. PMID- 24157528 TI - Dynamic cerebral autoregulation after bed rest: effects of volume loading and exercise countermeasures. AB - This study assessed effects of head-down-tilt (HDT) bed rest on dynamic cerebral autoregulation (CA) in 21 healthy young adults with volume loading and exercise countermeasures. Of these, seven underwent an 18-day bed rest without exercise countermeasures (sedentary group). Volume loading with dextran infusion was performed after bed rest to restore reduced plasma volume to levels before bed rest. In the other 14 subjects, supine cycling during bed rest was performed to preserve cardiac work from before bed rest (exercise group). Volume loading was also performed in a subgroup of these subjects (Ex+Dex, n = 7). Dynamic CA was estimated by transfer function analysis of changes in arterial pressure and cerebral blood flow (CBF) velocity in the very low (VLF, 0.02-0.07 Hz), low (LF, 0.07-0.20 Hz), and high frequency ranges (HF, 0.20-0.35 Hz). After bed rest, transfer function gain was reduced in the sedentary group (VLF, 0.93 +/- 0.23 to 0.61 +/- 0.23 cm(-1).s(-1).mmHg; P = 0.007) and in the exercise group (LF, 1.22 +/- 0.43 to 0.94 +/- 0.26 cm(-1).s(-1).mmHg; P = 0.005, HF, 1.32 +/- 0.55 to 1.00 +/- 0.32 cm(-1).s(-1).mmHg; P = 0.010). After volume loading, transfer function gain increased in the sedentary group but not in the Ex+Dex group. Taken together, these findings suggest that dynamic CA was preserved or improved after HDT bed rest in both sedentary and exercise subjects. Furthermore, increases of transfer function gain with volume loading suggest that changes in plasma volume may play an important role in CBF regulation. PMID- 24157529 TI - Regulation of oxidative phosphorylation during work transitions results from its kinetic properties. AB - The regulation of oxidative phosphorylation (OXPHOS) during work transitions in skeletal muscle and heart is still not well understood. Different computer models of this process have been developed that are characterized by various kinetic properties. In the present research-polemic theoretical study it is argued that models belonging to one group (Model A), which predict that among OXPHOS complexes complex III keeps almost all of the metabolic control over oxygen consumption (Vo2) and involve a strong complex III activation by inorganic phosphate (Pi), lead to the conclusion that an increase in Pi is the main mechanism responsible for OXPHOS activation (feedback-activation mechanism). Models belonging to another group (Model B), which were developed to take into account an approximately uniform distribution of metabolic control over Vo2 among particular OXPHOS complexes (complex I, complex III, complex IV, ATP synthase, ATP/ADP carrier, phosphate carrier) encountered in experimental studies in isolated mitochondria, predict that all OXPHOS complexes are directly activated in parallel with ATP usage and NADH supply by some external cytosolic factor/mechanism during rest-to-work or low-to-high work transitions in skeletal muscle and heart ("each-step-activation" mechanism). Model B demonstrates that different intensities of each-step activation can account for the very different (slopes of) phenomenological Vo2-ADP relationships observed in various skeletal muscles and heart. Thus they are able to explain the differences in the regulation of OXPHOS during work transitions between skeletal muscle (where moderate changes in ADP take place) and intact heart in vivo (where ADP is essentially constant). PMID- 24157530 TI - Defining the "dose" of altitude training: how high to live for optimal sea level performance enhancement. AB - Chronic living at altitudes of ~2,500 m causes consistent hematological acclimatization in most, but not all, groups of athletes; however, responses of erythropoietin (EPO) and red cell mass to a given altitude show substantial individual variability. We hypothesized that athletes living at higher altitudes would experience greater improvements in sea level performance, secondary to greater hematological acclimatization, compared with athletes living at lower altitudes. After 4 wk of group sea level training and testing, 48 collegiate distance runners (32 men, 16 women) were randomly assigned to one of four living altitudes (1,780, 2,085, 2,454, or 2,800 m). All athletes trained together daily at a common altitude from 1,250-3,000 m following a modified live high-train low model. Subjects completed hematological, metabolic, and performance measures at sea level, before and after altitude training; EPO was assessed at various time points while at altitude. On return from altitude, 3,000-m time trial performance was significantly improved in groups living at the middle two altitudes (2,085 and 2,454 m), but not in groups living at 1,780 and 2,800 m. EPO was significantly higher in all groups at 24 and 48 h, but returned to sea level baseline after 72 h in the 1,780-m group. Erythrocyte volume was significantly higher within all groups after return from altitude and was not different between groups. These data suggest that, when completing a 4-wk altitude camp following the live high-train low model, there is a target altitude between 2,000 and 2,500 m that produces an optimal acclimatization response for sea level performance. PMID- 24157531 TI - Cardiac sympathetic innervation in a patient with catecholaminergic polymorphic ventricular tachycardia. PMID- 24157532 TI - A new procedure for a trans-conduit puncture by grasping the dilator tip with a snare catheter: an alternative access method during catheter ablation of supraventricular tachycardias after an extracardiac Fontan operation. PMID- 24157534 TI - Drug delivery strategies in the therapy of inflammatory bowel disease. AB - Inflammatory bowel disease (IBD) is a frequently occurring disease in young people, which is characterized by a chronic inflammation of the gastrointestinal tract. The therapy of IBD is dominated by the administration of anti-inflammatory and immunosuppressive drugs, which suppress the intestinal inflammatory burden and improve the disease-related symptoms. Established treatment strategies are characterized by a limited therapeutical efficacy and the occurrence of adverse drug reactions. Thus, the development of novel disease-targeted drug delivery strategies is intended for a more effective therapy and demonstrates the potential to address unmet medical needs. This review gives an overview about the established as well as future-oriented drug targeting strategies, including intestine targeting by conventional drug delivery systems (DDS), disease targeted drug delivery by synthetic DDS and disease targeted drug delivery by biological DDS. Furthermore, this review analyses the targeting mechanisms of the respective DDS and discusses the possible field of utilization in IBD. PMID- 24157533 TI - Relative efficacy of catheter ablation vs antiarrhythmic drugs in treating premature ventricular contractions: a single-center retrospective study. AB - BACKGROUND: It is unknown whether radiofrequency ablation (RFA) or antiarrhythmic therapy is superior when treating patients with symptomatic premature ventricular contractions (PVCs). OBJECTIVE: To determine the relative efficacy of RFA and antiarrhythmic drugs (AADs) on PVC burden reduction and increasing left ventricular systolic function. METHODS: Patients with frequent PVCs (>1000/24 h) were treated either by RFA or with AADs from January 2005 through December 2010. Data from 24-hour Holter monitoring and echocardiography before and 6-12 months after treatment were compared between the 2 groups. RESULTS: Of 510 patients identified, 215 (40%) underwent RFA and 295 (60%) received AADs. The reduction in PVC frequency was greater by RFA than with AADs (-21,799/24 h vs -8,376/24 h; P < .001). The left ventricular ejection fraction (LVEF) was increased significantly after RFA (53%-56%; P < .001) but not after AAD (52%- 52%; P = .6) therapy. Of 121 (24%) patients with reduced LVEF, 39 (32%) had LVEF normalization to 50% or greater. LVEF was restored in 25 of 53 (47%) patients in the RFA group compared with 14 of 68 (21%) patients in the AAD group (P = .003). PVC coupling interval less than 450 ms, less impaired left ventricular function, and RFA were independent predictors of LVEF normalization performed by using multivariate analysis. CONCLUSION: RFA appears to be more effective than AADs in PVC reduction and LVEF normalization. PMID- 24157535 TI - Do repeated skin barrier measurements influence each other's results? An explorative study. AB - BACKGROUND: Biophysical skin measurement techniques are widely used to quantify the skin barrier function. In clinical research usually several parameters are subsequently measured in the same skin areas. In this study, possible interfering effects of subsequent measurement procedures on transepidermal water loss (TEWL), stratum corneum hydration (SCH) and skin surface pH were investigated. METHODS: An exploratory study was conducted. Twelve young (mean age 32.9 +/- 7.2 years) and 12 elderly (mean age 68.3 +/- 2.5 years) subjects without any skin diseases were enrolled. The parameters TEWL, skin surface pH, SCH, sebum content, and surface evaluation of living skin were obtained successively in pairs from 4 contralateral volar forearm skin areas. RESULTS: SCH and skin surface pH seemed to be unaffected by previous measurement procedures. TEWL was systematically increased after pH and systematically decreased after stratum corneum measurements. CONCLUSIONS: Measurements per se might interact with the skin, thus changing its characteristics. If several skin barrier function parameters need to be assessed subsequently in the same skin areas, we recommend that TEWL should be measured first followed by all others. PMID- 24157536 TI - No evidence for impaired multisensory integration of low-level audiovisual stimuli in adolescents and young adults with autism spectrum disorders. AB - Abrupt click sounds can improve the visual processing of flashes in several ways. Here, we examined this in high functioning adolescents with Autism Spectrum Disorders (ASD) using three tasks: (1) a task where clicks improve sensitivity for visual temporal order (temporal ventriloquism); (2) a task where a click improves visual search (pip-and-pop), and (3) a task where a click speeds up the visual orienting to a peripheral target (clock reading). Adolescents with ASD were, compared to adolescents with typical development (TD), impaired in judgments of visual temporal order, but they were unimpaired in visual search and orienting. Importantly, in all tasks visual performance of the ASD group improved by the presence of clicks by at least equal amounts as in the TD group. This suggests that adolescents and young adults with ASD show no generalized deficit in the multisensory integration of low-level audiovisual stimuli and/or the phasic alerting by abrupt sounds. PMID- 24157538 TI - Neural correlates of non-verbal social interactions: a dual-EEG study. AB - Successful non-verbal social interaction between human beings requires dynamic and efficient encoding of others' gestures. Our study aimed at identifying neural markers of social interaction and goal variations in a non-verbal task. For this, we recorded simultaneously the electroencephalogram from two participants (dual EEG), an actor and an observer, and their arm/hand kinematics in a real face-to face paradigm. The observer watched "biological actions" performed by the human actor and "non-biological actions" performed by a robot. All actions occurred within an interactive or non-interactive context depending on whether the observer had to perform a complementary action or not (e.g., the actor presents a saucer and the observer either places the corresponding cup or does nothing). We analysed the EEG signals of both participants (i.e., beta (~20 Hz) oscillations as an index of cortical motor activity and motor related potentials (MRPs)). We identified markers of social interactions by synchronising EEG to the onset of the actor's movement. Movement kinematics did not differ in the two context conditions and the MRPs of the actor were similar in the two conditions. For the observer, however, an observation-related MRP was measured in all conditions but was more negative in the interactive context over fronto-central electrodes. Moreover, this feature was specific to biological actions. Concurrently, the suppression of beta oscillations was observed in the actor's EEG and the observer's EEG rapidly after the onset of the actor's movement. Critically, this suppression was stronger in the interactive than in the non-interactive context despite the fact that movement kinematics did not differ in the two context conditions. For the observer, this modulation was observed independently of whether the actor was a human or a robot. Our results suggest that acting in a social context induced analogous modulations of motor and sensorimotor regions in observer and actor. Sharing a common goal during an interaction seems thus to evoke a common representation of the global action that includes both actor and observer movements. PMID- 24157537 TI - Activity reductions in perirhinal cortex predict conceptual priming and familiarity-based recognition. AB - Although it is well established that regions in the medial temporal lobes are critical for explicit memory, recent work has suggested that one medial temporal lobe subregion--the perirhinal cortex (PRC)--may also support conceptual priming, a form of implicit memory. Here, we sought to investigate whether activity reductions in PRC, previously linked to familiarity-based recognition, might also support conceptual implicit memory retrieval. Using a free association priming task, the current study tested the prediction that PRC indexes conceptual priming independent of contributions from perceptual and response repetition. Participants first completed an incidental semantic encoding task outside of the MRI scanner. Next, they were scanned during performance of a free association priming task, followed by a recognition memory test. Results indicated successful conceptual priming was associated with decreased PRC activity, and that an overlapping region within the PRC also exhibited activity reductions that covaried with familiarity during the recognition memory test. Our results demonstrate that the PRC contributes to both conceptual priming and familiarity based recognition, which may reflect a common role of this region in implicit and explicit memory retrieval. PMID- 24157539 TI - The contribution of the right supra-marginal gyrus to sequence learning in eye movements. AB - We investigated the role of the human right Supra-Marginal Gyrus (SMG) in the generation of learned eye movement sequences. Using MRI-guided transcranial magnetic stimulation (TMS) we disrupted neural activity in the SMG whilst human observers performed saccadic eye movements to multiple presentations of either predictable or random target sequences. For the predictable sequences we observed shorter saccadic latencies from the second presentation of the sequence. However, these anticipatory improvements in performance were significantly reduced when TMS was delivered to the right SMG during the inter-trial retention periods. No deficits were induced when TMS was delivered concurrently with the onset of the target visual stimuli. For the random version of the task, neither delivery of TMS to the SMG during the inter-trial period nor during the presentation of the target visual stimuli produced any deficit in performance that was significantly different from the no-TMS or control conditions. These findings demonstrate that neural activity within the right SMG is causally linked to the ability to perform short latency predictive saccades resulting from sequence learning. We conclude that neural activity in rSMG constitutes an instruction set with spatial and temporal directives that are retained and subsequently released for predictive motor planning and responses. PMID- 24157540 TI - Increased response variability as a marker of executive dysfunction in veterans with post-traumatic stress disorder. AB - The stability of cognitive control processes over time can be indexed by trial-to trial variability in reaction time (RT). Greater RT variability has been interpreted as an indicator of executive dysfunction, inhibitory inefficiency, and excessive mental noise. Previous studies have demonstrated that combat veterans with post-traumatic stress disorder (PTSD) show substantial impairments in inhibitory control, but no studies have examined response variability in this population. In the current experiment, RT variability in the Go/NoGo response inhibition task was assessed for 45 veterans with PTSD and 34 control veterans using the intra-individual coefficient of variation (ICV) and ex-Gaussian analysis of RT distributions. Despite having mean RTs that were indistinguishable from controls, the PTSD patients had significantly greater RT variability as measured by ICV. More variable RTs were in turn associated with a greater number of false alarm errors in the patients, suggesting that less consistent performers were less successful at inhibiting inappropriate responses. RT variability was also highly correlated with self-reported symptoms of PTSD, depression, and attentional impulsiveness. Furthermore, response variability predicted diagnosis even when controlling for PTSD symptom severity. In turn, PTSD severity was correlated with self-rated attentional impulsiveness. Deficits in the top-down cognitive control processes that cause greater response variability might contribute to the maintenance of PTSD symptomology. Thus, the distractibility issues that cause more variable reaction times might also result in greater distress related to the trauma. PMID- 24157541 TI - Is it time to rethink how neuropsychological tests are used to diagnose mild forms of HIV-associated neurocognitive disorders? Impact of false-positive rates on prevalence and power. AB - BACKGROUND: Between 0 and 48% of normal HIV-uninfected individuals score below threshold neuropsychological test scores for HIV-associated neurocognitive disorders (HAND) or are false positives. There has been little effort to understand the effect of varied interpretations of research criteria for HAND on false-positive frequencies, prevalence and analytic estimates. METHODS: The proportion of normal individuals scoring below Z score thresholds drawn from research criteria for HAND, or false-positive frequencies, was estimated in a normal Kenyan population and a simulated normal population using varied interpretations of research criteria for HAND. We calculated the impact of false positive frequencies on prevalence estimates and statistical power. RESULTS: False-positive frequencies of 2-74% were observed for asymptomatic neurocognitive impairment/mild neurocognitive disorder and 0-8% for HIV-associated dementia. False-positive frequencies depended on the definition of an abnormal cognitive domain, Z score thresholds and neuropsychological battery size. Misclassification led to clinically important overestimation of prevalence and dramatic decreases in power. CONCLUSIONS: Minimizing false-positive frequencies is critical to decrease bias in prevalence estimates and minimize reductions in power in studies of association, particularly for mild forms of HAND. We recommend changing the Z score threshold to <=-1.5 for mild impairment, limiting analysis to 3-5 cognitive domains and using the average Z score to define an abnormal domain. PMID- 24157542 TI - Efficacy of CytoLyt(r) hemolytic action on ThinPrep(r) LBC using cultured osteosarcoma cell line LM8. AB - OBJECTIVE: The removal of blood components is necessary to improve the quality of the liquid-based cytology (LBC) preparations. In ThinPrep(r) (TP) samples a cell suspension in a methanol-based fixative undergoes a vacuum filtration method, whereas in SurePathTM (SP) samples a cell suspension in an ethanol-based fixative is processed through a density gradient centrifugation system prior to gravity deposition of the specimen onto a glass slide. We compared the cyto-architectural features for the cytologic diagnosis of endometrial adenocarcinoma using parallel TP and SP preparations in a previous publication. STUDY DESIGN: We performed our study on LM8 cells (a cultured osteosarcoma cell line). LM8 cells at a concentration of 1.25 * 10(3) cell/cm(2) were seeded on a 35-mm plate in culture medium, which contained 10% fetal bovine serum (FBS), 100 units/ml penicillin, and 100 MU/ml streptomycin in Dulbecco's modified Eagle's medium (DMEM), and aliquots of the cell suspension obtained in this way were compared after the addition of a hemolytic agent, i.e. Cytolyt(r) (CyL). LBC preparations were then obtained on cell suspensions treated with CyL after different time intervals of hemolysis. RESULTS: Treatment with CyL did not alter the cellularity of the preparation, but reduction of the nuclear area and a tendency towards nuclear chromatin condensation with a subsequent higher brightness were found. Because CyL is a 25% methanol-buffered solution, its alcoholic concentration is low; it was our impression that, while its fixative effect was weak, its hemolytic effect was high. Water influx or efflux through the cell membrane is controlled by osmotic pressure changes induced by the buffer solution in the CyL solution. While CyL was not shown to alter the cell shape, nuclear shrinkage was thought to be probably due to the increasing cell dehydration caused by longer exposure intervals to methanol. CONCLUSION: This study has allowed us to make significant observations on the hemolytic properties of CyL, and on its combined effects with PreservCyt on the cytomorphology of cells suspensions. PMID- 24157543 TI - Evaluation of nanostructured lipid carriers (NLC) and nanoemulsions as carriers for UV-filters: characterization, in vitro penetration and photostability studies. AB - The increased awareness of protection against UV radiation damages has led to a rise in the use of topically applied chemical sunscreen agents and to an increased need of innovative carriers designed to achieve the highest protective effect and reduce the toxicological risk resulting from the percutaneous absorption of these substances. In this paper, nanostructured lipid carriers (NLC) and nanoemulsions (NE) were formulated to optimize the topical application of different and widespread UVA or UVB sun filters (ethyl hexyltriazone (EHT), diethylamino hydroxybenzoyl hexyl benzoate (DHHB), bemotrizinol (Tinosorb S), octylmethoxycinnamate (OMC) and avobenzone (AVO)). The preparation and stability parameters of these nanocarriers have been investigated concerning particle size and zeta potential. The release pattern of the sunscreens from NLC and NE was evaluated in vitro, determining their percutaneous absorption through excised human skin. Additional in vitro studies were performed in order to evaluate, after UVA radiation treatment, the spectral stability of the sunfilters once formulated in NLC or NE. From the results obtained, when incorporated in NLC, the skin permeation abilities of the sun filter were drastically reduced, remaining mainly on the surface of the skin. The photostability studies showed that EHT, DHHB and Tinosorb S still retain their photostability when incorporated in these carriers, while OMC and AVO were not photostable as expected. However, no significant differences in terms of photoprotective efficacy between the two carriers were observed. PMID- 24157544 TI - Synthetic polysulfane derivatives induce cell cycle arrest and apoptotic cell death in human hematopoietic cancer cells. AB - Natural polysulfanes including diallyltrisulfide (DATS) and diallyltetrasulfide (DATTS) from garlic possess antimicrobial, chemopreventive and anticancer properties. However these compounds exhibit chemical instability and reduced solubility, which prevents their potential clinical applicability. We synthesized six DATS and DATTS derivatives, based on the polysulfane motif, expected to exhibit improved physical and chemical properties and verified their biological activity on human leukemia cells. We identified four novel cytotoxic compounds (IC50 values: compound 1, 24.96+/-12.37 MUM; compound 2, 22.82+/-4.20 MUM; compound 3, 3.86+/-1.64 MUM and compound 5, 40.62+/-10.07 MUM, compared to DATTS: IC50: 9.33+/-3.86 MUM). These polysulfanes possess excellent differential toxicity, as they did not affect proliferating mononuclear blood cells from healthy donors. We further demonstrated ability of active compounds to induce apoptosis in leukemia cells by analysis of nuclear fragmentation and of cleavage of effector and executioner caspases. Apoptosis was preceded by accumulation of cells in G2/M phase with a pro-metaphase-like nuclear pattern as well as microtubular alterations. Prolonged and persistent arrest of cancer cells in early mitosis by the benzyl derivative identifies this compound as the most stable and effective one for further mechanistic and in vivo studies. PMID- 24157545 TI - Astaxanthin and omega-3 fatty acids individually and in combination protect against oxidative stress via the Nrf2-ARE pathway. AB - Oxidative stress is a major driver of many diseases, including cancer. The induction of Nrf2-ARE-mediated antioxidant enzymes provides a cellular defense against oxidative stress. Astaxanthin (AST), a red dietary carotenoid, possesses potent antioxidant activity, and inhibits oxidative damages. Polyunsaturated fatty acids (PUFAs), docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA), are important nutritional essentials and potent antioxidants found in fish oil. In the present study, we investigated whether AST in combination with low concentrations of DHA or EPA has a synergistic antioxidant effect in a HepG2-C8 ARE-luciferase cell line system. Using free radical scavenging DPPH assay, AST was more potent DPPH radical scavenger than DHA and EPA. MTS assay revealed that AST was non-toxic up to 100MUM compared with more toxic DHA and EPA. The three compounds alone and in combination elevated cellular GSH levels, increased the total antioxidant activity, induced mRNA expression of Nrf2 and Nrf2 downstream target genes NQO1, HO-1, and GSTM2. Lower concentrations of AST show synergistic effects when combined with DHA or EPA. In summary, our study shows synergistic antioxidant effects of AST and PUFAs at low concentrations. The Nrf2/ARE pathway plays an important role in the antioxidative effects induced by AST, DHA, and EPA. PMID- 24157546 TI - Lipid bilayer preparations of membrane proteins for oriented and magic-angle spinning solid-state NMR samples. AB - Solid-state NMR spectroscopy has been used successfully for characterizing the structure and dynamics of membrane proteins as well as their interactions with other proteins in lipid bilayers. Such an environment is often necessary for achieving native-like structures. Sample preparation is the key to this success. Here we present a detailed description of a robust protocol that results in high quality membrane protein samples for both magic-angle spinning and oriented sample solid-state NMR. The procedure is demonstrated using two proteins: CrgA (two transmembrane helices) and Rv1861 (three transmembrane helices), both from Mycobacterium tuberculosis. The success of this procedure relies on two points. First, for samples for both types of NMR experiment, the reconstitution of the protein from a detergent environment to an environment in which it is incorporated into liposomes results in 'complete' removal of detergent. Second, for the oriented samples, proper dehydration followed by rehydration of the proteoliposomes is essential. By using this protocol, proteoliposome samples for magic-angle spinning NMR and uniformly aligned samples (orientational mosaicity of <1 degrees ) for oriented-sample NMR can be obtained within 10 d. PMID- 24157547 TI - Asymmetric synthesis of amines using tert-butanesulfinamide. AB - Chiral amines are prevalent in many bioactive molecules, including amino acids and pharmaceutical agents. tert-Butanesulfinamide (tBS) is a chiral amine reagent that has enabled the reliable asymmetric synthesis of a very broad range of different amine structures from simple, readily available starting materials. Three steps are commonly applied to the asymmetric synthesis of amines: (i) condensation of tBS with a carbonyl compound, (ii) nucleophile addition and (iii) tert-butanesulfinyl group cleavage. Here we demonstrate these steps with the preparation of a propargylic tertiary carbinamine, one of a class of amines that have been used for many different biological purposes, including click chemistry applications, diversity-oriented synthesis, the preparation of peptide isosteres and the development of protease inhibitors as drug candidates and imaging agents. The process described here can be performed in 3-4 d. PMID- 24157550 TI - High vertical yield InP nanowire growth on Si(111) using a thin buffer layer. AB - We demonstrate the growth of InP nanowires on Si(111) using a thin InP buffer layer. The buffer layer is grown using a two-step procedure. The initial layer formation is ensured by using a very low growth temperature. An extremely high V/III ratio is necessary to prevent In droplet formation at this low temperature. The second layer is grown on the initial layer at a higher temperature and we find that post-growth annealing of the buffer layer does not improve its crystal quality significantly. It is found that the layers inherently have the (111)B polarity. Nanowires grown on this buffer layer have the same morphology and optical properties as nanowires grown on InP (111)B substrates. The vertical yield of the nanowires grown on the buffer layer is over 97% and we also find that crystal defects in the buffer layer do not affect the morphology, vertical yield or optical properties of the nanowires significantly. PMID- 24157548 TI - Genome engineering using the CRISPR-Cas9 system. AB - Targeted nucleases are powerful tools for mediating genome alteration with high precision. The RNA-guided Cas9 nuclease from the microbial clustered regularly interspaced short palindromic repeats (CRISPR) adaptive immune system can be used to facilitate efficient genome engineering in eukaryotic cells by simply specifying a 20-nt targeting sequence within its guide RNA. Here we describe a set of tools for Cas9-mediated genome editing via nonhomologous end joining (NHEJ) or homology-directed repair (HDR) in mammalian cells, as well as generation of modified cell lines for downstream functional studies. To minimize off-target cleavage, we further describe a double-nicking strategy using the Cas9 nickase mutant with paired guide RNAs. This protocol provides experimentally derived guidelines for the selection of target sites, evaluation of cleavage efficiency and analysis of off-target activity. Beginning with target design, gene modifications can be achieved within as little as 1-2 weeks, and modified clonal cell lines can be derived within 2-3 weeks. PMID- 24157549 TI - A three-stage biophysical screening cascade for fragment-based drug discovery. AB - This protocol describes the screening of a library of low-molecular-weight compounds (fragments) using a series of biophysical ligand-binding assays. Fragment-based drug discovery (FBDD) has emerged as a successful method to design high-affinity ligands for biomacromolecules of therapeutic interest. It involves detecting relatively weak interactions between the fragments and a target macromolecule using sensitive biophysical techniques. These weak binders provide a starting point for the development of inhibitors with submicromolar affinity. Here we describe an efficient fragment screening cascade that can identify binding fragments (hits) within weeks. It is divided into three stages: (i) preliminary screening using differential scanning fluorimetry (DSF), (ii) validation by NMR spectroscopy and (iii) characterization of binding fragments by isothermal titration calorimetry (ITC) and X-ray crystallography. Although this protocol is readily applicable in academic settings because of its emphasis on low cost and medium-throughput early-stage screening technologies, the core principle of orthogonal validation makes it robust enough to meet the quality standards of an industrial laboratory. PMID- 24157552 TI - History of transient ischemic attack definition. AB - Transient ischemic attacks have been recognized as a clinical entity for well over a century. Efforts before the availability of modern imaging to establish a diagnosis of inferred ischemic stroke led to acceptance of too long a time period (>24 h) compared with the actual typical events lasting <24 min (usually 5-15 min). Revision of the time period has improved diagnostic yield and discovered many whose image-documented acute infarct is associated with a short clinical course. PMID- 24157551 TI - ETV1 positively regulates transcription of tumor suppressor ARF. AB - ETV1 (ETS variant 1) is a transcription factor from the ETS family and an oncogene in several types of human malignancies. Paradoxically, a predicted inactivating mutation in ETV1 was previously found in a clone of HT1080 cells with reduced activity of p53. We report that elevated expression of ETV1 makes p53-null tumor cells hypersensitive to restoration of said tumor suppressor. Furthermore, elevated levels of either wild-type ETV1 or its truncated derivative, dETV1, which mimics the product of an oncogenic rearrangement in certain tumors, results in increased expression of mRNA for p14ARF, a known activator of p53. Accordingly, expression of a luciferase reporter, which is driven by a putative ARF promoter, was elevated by concomitant expression of either ETV1 or dETV1. Our observations point to yet another example of a tumor suppressor gene being activated by a potentially oncogenic signal. A better understanding of the mechanisms that allow a cell to bypass such safeguards is needed in order to predict and prevent the development of an oncogene-tolerant state during cancer evolution. PMID- 24157553 TI - The concept of acute cerebrovascular syndrome. AB - Early after the onset of transient ischemic attack (TIA), patients are at very high risk of stroke. There is no meaning to differentiate TIA in acute settings from acute ischemic stroke (AIS) only by the duration of symptoms. Acute TIA and AIS are on the same spectrum of acute ischemic syndrome in the central nervous system. We proposed a new concept termed acute cerebrovascular syndrome (ACVS), which includes TIA in acute settings and AIS. The concept of ACVS is comparable to acute coronary syndrome (ACS), which includes unstable angina and acute myocardial infarction. When a focal symptomatic reversible ischemia occurs in the brain, it is called TIA, and when a focal symptomatic irreversible ischemia occurs in the brain, it is called AIS. Patients with ACS share a single pathophysiological mechanism, that is rupture of unstable plaque followed by formation of platelet-rich thrombi to plug up coronary arteries. Unlike ACS, the mechanism of ACVS is complicated, which is not only large artery atherosclerosis similar to ACS but also cardioembolism or small vessel occlusion. In addition, there are no measurable biomarkers for ACVS, while there are practical biomarkers for ACS. Nevertheless, the concept of ACVS is practical to emphasize the importance of immediate evaluation and starting treatment to prevent subsequent stroke in acute settings of TIA. Therefore, TIA in acute settings as well as AIS should be recognized as ACVS, which is a medical emergency. PMID- 24157554 TI - Transient ischemic attack as a medical emergency. AB - Since transient ischemic attack (TIA) is regarded as a medical emergency with high risk for early stroke recurrence, the underlying mechanisms should be immediately clarified to conclude a definitive diagnosis and provide early treatment. Early risk stratification using ABCD(2) scores can predict the risk of ischemic stroke occurring after TIA. Carotid ultrasonography (US) can evaluate the degree of stenosis, plaque properties and flow velocity of ICA lesions. High risk mobile plaques can be classified by carotid US, and aortogenic sources of emboli can be detected by transesophageal echocardiography. Cardiac monitoring and blood findings are thought to play a key role in a diagnosis of cardioembolic TIA. Diffusion-weighted imaging (DWI)-MRI and MR angiography are also indispensable to understand the mechanism of TIA and cerebral circulation. To prevent subsequent stroke arising from TIA, antiplatelet and anticoagulant therapies should be started immediately along with comprehensive management of life-style, hypertension, diabetes mellitus, dyslipidemia and other atherosclerotic diseases. Carotid endarterectomy and endovascular intervention are critical for treating symptomatic patients with significant stenosis of ICA. A novel concept of acute cerebrovascular syndrome (ACVS) has recently been advocated to increase awareness of TIA among citizens, patients and medical professionals. TIA should be recognized as the last opportunity to avoid irreversible ischemic stroke and its sequelae. The clinical relevance of the new concept of ACVS is advocated by early recurrence after TIA, analysis of high-risk TIA, treatment strategies and the optimal management of TIA. Raising TIA awareness should also proceed across many population sectors. PMID- 24157555 TI - TIA clinic: a major advance in management of transient ischemic attacks. AB - Patients with transient ischemic attack (TIA) are at very high risk of imminent stroke. This risk could be decreased by 80% if patients are immediately investigated and treated by stroke specialists. However, because TIA workup includes not only specialist advices but also a wide range of investigations such as brain, arterial and cardiac imaging, management of these patients in emergency required well-organized dedicated health care system, such as TIA clinics. Management of TIA patients in outpatient clinics has been shown to be safe and cost-effective avoiding full hospitalization in most of the cases. PMID- 24157556 TI - Risk scores for transient ischemic attack. AB - The risk of recurrent ischemic stroke after a transient ischemic attack (TIA) has been reported to be 5-10%, and is elevated especially within the first days after the index event. Since TIA primarily has a good outcome without persisting new deficits, interest has been growing to predict stroke recurrence after TIA. This has led to the development of scores, initially for long-term prognosis such as the Stroke Prognosis Instrument (SPI) or the Hankey score, which both have shown a good predictive value at 1 or 2 years after TIA. Risk factors such as age, hypertension or cardiovascular disease were integrated in these systems. Since the early risk prediction for stroke in patients presenting within 24 h after onset of symptoms became clinically more and more relevant in emergency stroke units, the ABCD score (for the predictive factors Age, Blood pressure, Clinical symptoms, Duration of symptoms) was developed. Validation was promising, and hence further scores were developed, which entailed a large number of studies trying to validate these systems or to improve them (e.g. ABCD(2), ABCD(2)I, ABCD(3), ABCD(3)I, CIP model, ASPIRE approach, ABCDE+ etc.). The main approaches were to include imaging results (such as DWI positivity) or etiologic considerations (e.g. carotid stenosis or atrial fibrillation). However, these new scores necessitate an extensive diagnostic workup, and therefore can only be used in large stroke centers. Currently, for acute TIA management, the use of ABCD(2) is recommended in several guidelines. PMID- 24157557 TI - Epidemiology of transient ischemic attack. AB - Few epidemiologic data are available regarding the prevalence and incidence of transient ischemic attack (TIA). Here, the incidence of TIA and that of subsequent stroke events were reviewed. The incidences of TIA in Europe were 0.52 2.37 and 0.05-1.14 in men and women aged 55-64, 0.94-3.39 and 0.71-1.47 in those aged 65-74, and 3.04-7.20 and 2.18-6.06 in those aged 75-84, respectively. The corresponding incidences are similar in the United States, and lower in Japan. Higher incidences were revealed in men compared with women. The incidence of TIA increased very markedly with age, regardless of race or gender. The evidence of risk factors for TIA excluding ischemic strokes is very limited. The ABCD/ABCD(2) score was developed to predict individual risk and to triage patients on the first presentation. In prognostic TIA, the crude rate of stroke risks (%) for general populations were 1.7, 4.8, 6.6, 8.5, and 11.4 at 2 days, 1 week, 1 month, 3 and 6 months, whereas those for hospital patients were 13.7 and 12.4 at 1 and 3 months, respectively. There is very limited evidence of an association between a family history of stroke and the incidence of stroke after TIA, which showed that family history of stroke does not predict the risk of ischemic stroke after TIA. There is also limited evidence of seasonal variation in TIA incidence. TIAs were reported to be most frequent in autumn or spring and less common in winter or spring to summer, and most frequent on Mondays. There seems to be no consensus regarding seasonal differences in TIA incidence. PMID- 24157558 TI - Symptoms of transient ischemic attack. AB - Transient ischemic attack (TIA) is a cerebrovascular disease with temporary (<24 h) neurological symptoms. The symptoms of TIA patients are largely similar to those of ischemic stroke patients and include unilateral limb weakness, speech disturbances, sensory symptoms, visual disturbances, and gait difficulties. As these symptoms are transient, they are frequently evaluated based on patients' subjective reports, which are less precise than those of patients with stroke whose longer-lasting symptoms and signs can be reliably assessed by physicians. Some symptoms, such as monocular blindness, are much more common in TIA than in stroke, and limb shaking occurs almost exclusively in TIA patients. On the other hand, symptoms like hemivisual field defects or limb ataxia are underappreciated in TIA patients. These transient neurological symptoms are not necessarily caused by cerebrovascular diseases, but can be produced by a variety of non-vascular diseases. Careful history taking, examination, and appropriate imaging tests are needed to differentiate these TIA mimics from TIA. Each TIA symptom has a different specificity and sensitivity, and there has been an effort to assess the outcome of the patients through the use of specific clinical features. On top of this, recent developments in imaging techniques have greatly enhanced our ability to predict the outcomes of TIA patients. Perception or recognition of TIA symptoms may differ according to the race, sex, education, and specialty of physicians. Appropriate education of both the general population and physicians with regard to TIA symptoms is important as TIAs need emergent evaluation and treatment. PMID- 24157559 TI - Guidelines for management of patients with transient ischemic attack. AB - A transient ischemic attack (TIA) is a medical emergency that is associated with a high risk of early ischemic stroke and other vascular events. Several evidence based guidelines have been published to provide recommendations for the evaluation and treatment of patients with TIA. These guidelines underline the need for the urgent referral of patients with TIA so that they can access expert evaluation and immediate treatment. The distinction between TIA and ischemic stroke has recently become less important because these two conditions share pathophysiological mechanisms and many of the preventive approaches are applicable to both. Therefore, current guidelines are often described without a distinction between TIA and ischemic stroke. However, the applicability of recommendations for applying treatment for ischemic stroke to TIA has not been proven. Further studies are required to determine the effects of urgent intervention or treatment early after TIA. PMID- 24157560 TI - Radiological examinations of transient ischemic attack. AB - Neuroimaging is critical in the evaluation of patients with TIA. CT and MRI are the two available options for imaging. Head CT is more widely available and commonly used. Diffusion MRI is the recommended modality to image an ischemic lesion. The presence of a diffusion lesion in a patient with transient neurological symptoms is an indicator of a high risk of recurrent stroke. Perfusion imaging with perfusion MRI or CT perfusion may improve the detection of ischemic lesions. Noninvasive vessel imaging may detect a symptomatic vessel lesion associated with an increased risk of stroke. PMID- 24157561 TI - Neurosonological examinations of transient ischemic attack. AB - Cerebrovascular ultrasonography is the only modality that provides real-time information about blood flow in various cervicocerebral arteries. Continuous information can be obtained over extended periods with high resolution and excellent spatial display. Hemodynamic changes in the cerebral circulation due to various physiological or pathological states can be monitored reliably. The information obtained from cerebrovascular ultrasonography carries diagnostic, therapeutic as well as prognostic potential in various conditions. Cervical duplex sonography evaluates blood flow as well as arterial wall characteristics in the major arteries that supply the cerebral vascular bed. Validated criteria for the diagnosis of steno-occlusive disease of carotid or vertebral arteries have high accuracy parameters. Transcranial Doppler (TCD) ultrasonography provides a reliable evaluation of intracranial blood flow patterns in real-time and adds physiological information to the anatomical details obtained from other neuroimaging modalities. Cerebrovascular ultrasonography is relatively cheap, can be performed at bedside, and allows monitoring in acute emergency settings. Extended applications of TCD provide important information about the pathophysiology of cerebrovascular ischemia and risk stratification. Therefore, cerebrovascular ultrasonography has become an integral component of the armamentarium of stroke neurologists for understanding stroke etiopathogenesis, planning and monitoring definitive treatment and determining the prognosis. It has been suggested as an essential component of a comprehensive stroke center. We have reviewed various established applications of ultrasonography in patients with cerebrovascular ischemia. PMID- 24157562 TI - Stroke subtypes and interventional studies for transient ischemic attack. AB - Transient ischemic attack (TIA) is the most important risk factor for ischemic stroke. The risk is the highest in the first hours after symptom onset, and treatment must be initiated in emergency. In the acute phase, antithrombotic agent is probably the most important treatment, but it is not excluded that lipid lowering agents and/or antihypertensive drugs are also important. For current guidelines, monotherapy of antiplatelet agent remains the gold standard in emergency. However, most recent data and meta-analysis support a combination therapy of clopidogrel and aspirin. Data on treatment in the very acute phase of TIA in the different etiologic stroke subtypes are also lacking especially for cardioembolic stroke and the potential benefit of anticoagulant. Long-term prevention mainly derived from large trials, in which TIA and minor stroke patients have constituted the largest part. Patients with non-cardioembolic stroke must be treated with antiplatelet agent in monotherapy, and dual antiplatelet therapy such as clopidogrel plus aspirin should be avoided, particularly in lacunar strokes, whereas anticoagulants are the treatment of choice for patients with cardioembolic stroke. Major advances concerning stroke prevention in patients with atrial fibrillation have emerged with new oral anticoagulant agents that are as effective as vitamin K antagonists and safer, especially with regard to the risk of intracranial hemorrhage. At variance with moderate and severe cerebral infarction, oral anticoagulants can be initiated without delay in TIA patients. Left atrial appendage closure seems to be a promising treatment in patients ineligible for anticoagulation. Aggressive management of vascular risk factors, including blood pressure as low as 130/80 mm Hg, intensive statin treatment, smoking cessation and diabetes control, also plays a major role in the prevention of vascular event. PMID- 24157563 TI - Antithrombotic therapy in transient ischemic attack patients. AB - Historically, studies of antithrombotic therapy in ischemic cerebrovascular disease have included both stroke and transient ischemic attack (TIA). Thus, therapy regimes are very similar. Aspirin (75-325 mg within 48 h after onset of symptoms) is still the standard antithrombotic treatment because other agents have performed similarly (or worse). Combinations of agents have shown mixed results. Aspirin combined with clopidogrel has failed to show a significant reduction of stroke/TIA recurrences but increased the bleeding risk if taken for more than several months. The combination of aspirin and dipyridamole is slightly better than aspirin alone and in particular reduced nonfatal stroke/TIA - hence it is recommended as an alternative and may be used in patients with recurrent events while on regular aspirin. In contrast, combined treatment is regularly recommended after endovascular interventions and if both cardio- and cerebrovascular diseases are present. Warfarin and similar compounds have long been the standard treatment for most patients with permanent, paroxysmal or intermittent non-valvular atrial fibrillation, for which there is excellent evidence in most patients (CHADS-VASc score >1). New compounds have been approved in recent years and shown to reduce either ischemic events, intracranial bleeding complications or both when compared with warfarin. None of them requires regular therapy monitoring. Because there are no head-to-head comparisons of these newer agents, definite recommendations as to which to choose, and when, are hard to make. However, there are some notable differences as well as new approved entities. PMID- 24157564 TI - Studies on left ventricular hypertrabeculation/noncompaction: the need for in depth ultrastructural investigations. PMID- 24157565 TI - Usefulness of clinical, ultrasonographic, hysteroscopic, and immunohistochemical parameters in differentiating endometrial polyps from endometrial cancer. AB - STUDY OBJECTIVE: To evaluate the usefulness of clinical, ultrasonographic, hysteroscopic, and immunohistochemical parameters in differentiating endometrial polyps from endometrial cancer. DESIGN: Cross-sectional study (Canadian Task Force classification II-2). SETTING: Tertiary public hospital, university teaching center. PATIENTS: Eighty-two women who underwent hysteroscopic polypectomy and 20 women who underwent surgery to treat endometrial cancer. INTERVENTIONS: Analysis of medical records and immunohistochemical assessment of estrogen receptors, progesterone receptors, and endothelial markers CD34 and CD105. MEASUREMENTS AND MAIN RESULTS: Among women with endometrial cancer and endometrial polyps, respectively, mean age was 63 and 57 years (p = .01), 89% and 67% were postmenopausal (p < .05), and 85% and 30.5% had postmenopausal bleeding (p < .01). No sonographic parameter enabled differentiation of endometrial polyp from cancer. Of patients with endometrial cancer, 72% exhibited signs suggestive of hyperplasia, and endometrial polyps were diagnosed during hysteroscopy. Estrogen receptors (>= 2 vs >= 1; p < .001) and progesterone receptors (>= 3 vs >= 2; p = .07) were greater in endometrial polyps. There was no significant difference in microvessel density (p > .05). CONCLUSIONS: Ultrasonographic parameters and endothelial markers did not enable differentiation of polyps from endometrial neoplasia. Postmenopausal bleeding and endometrial hypervascularization along with vascular atypia at diagnostic hysteroscopy showed a greater association with endometrial cancer. PMID- 24157566 TI - Postoperative medical therapy after surgical treatment of endometriosis: from adjuvant therapy to tertiary prevention. AB - The high rate of disease recurrence after surgery is critical and frustrating for women with endometriosis. Adjuvant treatments using a 3- to 6-months course of hormone therapy after surgery have been extensively investigated during the last 2 decades; however, results have been unsatisfactory, primarily because the benefits of hormone therapy rapidly vanish once treatment is discontinued. The protective effect is limited to the period of use. Accordingly, it is recognized that suppressive hormone therapy after surgery markedly prevents recurrent episodes only if given over the long term. The emerging view is that estroprogestins do not ameliorate the effects of surgery but demonstrate tertiary prevention of the disease. They prevent ovulation and reduce retrograde menstrual flow, two crucial events in the pathogenesis of endometriosis. The available literature strongly supports the benefits of prolonged administration of estroprogestins after surgery in preventing recurrence of endometriomas and dysmenorrhea. In contrast, data on dyspareunia and nonmenstrual pelvic pain remain scanty and unconvincing, and there is no information about recurrence of other forms of endometriosis such as peritoneal implants and adhesions. Overall, estroprogestin therapy after surgery to treat endometriosis should be recommended in women who do not seek to become pregnant. Further evidence is warranted to better delineate the beneficial effects of this emerging but convincing strategy. PMID- 24157567 TI - Birth-death models and coalescent point processes: the shape and probability of reconstructed phylogenies. AB - Forward-in-time models of diversification (i.e., speciation and extinction) produce phylogenetic trees that grow "vertically" as time goes by. Pruning the extinct lineages out of such trees leads to natural models for reconstructed trees (i.e., phylogenies of extant species). Alternatively, reconstructed trees can be modelled by coalescent point processes (CPPs), where trees grow "horizontally" by the sequential addition of vertical edges. Each new edge starts at some random speciation time and ends at the present time; speciation times are drawn from the same distribution independently. CPPs lead to extremely fast computation of tree likelihoods and simulation of reconstructed trees. Their topology always follows the uniform distribution on ranked tree shapes (URT). We characterize which forward-in-time models lead to URT reconstructed trees and among these, which lead to CPP reconstructed trees. We show that for any "asymmetric" diversification model in which speciation rates only depend on time and extinction rates only depend on time and on a non-heritable trait (e.g., age), the reconstructed tree is CPP, even if extant species are incompletely sampled. If rates additionally depend on the number of species, the reconstructed tree is (only) URT (but not CPP). We characterize the common distribution of speciation times in the CPP description, and discuss incomplete species sampling as well as three special model cases in detail: (1) the extinction rate does not depend on a trait; (2) rates do not depend on time; (3) mass extinctions may happen additionally at certain points in the past. PMID- 24157569 TI - Preceding trauma in childhood hematogenous bone and joint infections. AB - Preceding trauma may play a role in the etiology and pathogenesis of hematogenous bone and joint infections. Among 345 children with an acute hematogenous bone and/or joint infection, 20% reported trauma during a 2-week period leading to infection. Blunt impact, bruises, or excoriations were commonly reported. The rate was similar to that in the general pediatric population obtained from the literature. In the study group, patients with and without trauma were similar in age, serum C-reactive protein and erythrocyte sedimentation rate, length of hospitalization, and late sequelae. Preceding minor trauma did not prove to be significant as an etiological or as a prognostic factor. PMID- 24157568 TI - Mast cell-deficient kit mice develop house dust mite-induced lung inflammation despite impaired eosinophil recruitment. AB - BACKGROUND: Mast cells are implicated in allergic and innate immune responses in asthma, although their role in models using an allergen relevant for human disease is incompletely understood. House dust mite (HDM) allergy is common in asthma patients. Our aim was to investigate the role of mast cells in HDM-induced allergic lung inflammation. METHODS: Wild-type (Wt) and mast cell-deficient Kit(w sh) mice on a C57BL/6 background were repetitively exposed to HDM via the airways. RESULTS: HDM challenge resulted in a rise in tryptase activity in bronchoalveolar lavage fluid (BALF) of Wt mice, indicative of mast cell activation. Kit(w-sh) mice showed a strongly attenuated HDM- induced recruitment of eosinophils in BALF and lung tissue, accompanied by reduced pulmonary levels of the eosinophil chemoattractant eotaxin. Remarkably, Kit(w-sh) mice demonstrated an unaltered capacity to develop lung pathology and increased mucus production in response to HDM. The increased plasma IgE in response to HDM in Wt mice was absent in Kit(w-sh) mice. CONCLUSION: These data contrast with previous reports on the role of mast cells in models using ovalbumin as allergen in that C57BL/6 Kit(w-sh) mice display a selective impairment of eosinophil recruitment without differences in other features of allergic inflammation. PMID- 24157570 TI - Pyomyositis of the obturator internus muscle extending to septic arthritis of the hip in a child: a case report. AB - We report a case of primary pyomyositis in the obturator internus muscle. Pyomyositis involving muscles around the hip needs to be differentiated from septic arthritis because these infections show similar symptoms. Management with antibiotics can avoid the need for surgical intervention. Uncontrolled pyomyosistis can cause sequelae such as septic shock, osteomyelitis of adjacent bone, and septic arthritis. Awareness of this condition will facilitate correct diagnosis and early treatment. PMID- 24157571 TI - Immunometabolism: Mef2 in sickness and in health. PMID- 24157573 TI - Studying immunity to zoonotic diseases in the natural host - keeping it real. AB - Zoonotic viruses that emerge from wildlife and domesticated animals pose a serious threat to human and animal health. In many instances, mouse models have improved our understanding of the human immune response to infection; however, when dealing with emerging zoonotic diseases, they may be of limited use. This is particularly the case when the model fails to reproduce the disease status that is seen in the natural reservoir, transmission species or human host. In this Review, we discuss how researchers are placing more emphasis on the study of the immune response to zoonotic infections in the natural reservoir hosts and spillover species. Such studies will not only lead to a greater understanding of how these infections induce variable disease and immune responses in distinct species but also offer important insights into the evolution of mammalian immune systems. PMID- 24157574 TI - Time and dose-dependent effects of phenobarbital on the rat liver miRNAome. AB - In a previous study we had shown that treatment of male Fischer rats with exogenous chemicals for three months resulted in prominent, mode-of-action dependent effects on liver microRNA (miRNA) (Koufaris et al., 2012). Here we investigated how the effects of chemicals on liver miRNA in male Fischer rats relate to the length and dose of exposure to phenobarbital (PB), a drug with multiple established hepatic effects. Importantly, although acute PB treatment (1 7 days) had significant effects on liver mRNA and the expected effects on the liver phenotype (transient hyperplasia, hepatomegaly, cytochrome P450 induction), limited effects on liver miRNA were observed. However, at 14 days of PB treatment clear dose-dependent effects on miRNA were observed. The main effect of PB treatment from days 1 to 90 on liver miRNA was found to be the persistent, progressive, and highly correlated induction of the miR-200a/200b/429 and miR 96/182 clusters, occurring after the termination of the xenobiotic-induced transient hyperplasia. Moreover, in agreement with their reported functions in the literature we found associations between perturbations of miR-29b and miR 200a/200b by PB with global DNA methylation and zeb1/zeb2 proteins respectively. Our data suggest that miRNA are unlikely to play an important role in the acute responses of the adult rodent liver to PB treatment. However, the miRNA responses to longer PB exposures suggest a potential role for maintaining liver homeostasis in response to sub-chronic and chronic xenobiotic-induced perturbations. Similar studies for more chemicals are needed to clarify whether the temporal and dose pattern of miRNA-toxicant interaction identified here for PB are widely applicable to other xenobiotics. PMID- 24157576 TI - Kinetically controlled self-assembly of redox-active ferrocene-diphenylalanine: from nanospheres to nanofibers. AB - Putting metals into organic compounds such as peptides can lead to many new desirable properties. Here we designed a novel bioorganometallic molecule, ferrocene-diphenylalanine (Fc-FF), and investigated its self-assembly behavior. We directly observed a morphological transition from metastable nanospheres to nanofibers, which led to the formation of a self-supporting hydrogel. The strong hydrophobic interaction of the Fc moiety was suggested to have a key role in this kinetically controlled self-assembly process. Moreover, the redox center of the ferrocene group further allowed us to reversibly control the self-assembly behavior of Fc-FF by altering its redox state. PMID- 24157572 TI - Age-dependent dysregulation of innate immunity. AB - As we age, the innate immune system becomes dysregulated and is characterized by persistent inflammatory responses that involve multiple immune and non-immune cell types and that vary depending on the cell activation state and tissue context. This ageing-associated basal inflammation, particularly in humans, is thought to be induced by several factors, including the reactivation of latent viral infections and the release of endogenous damage-associated ligands of pattern recognition receptors (PRRs). Innate immune cell functions that are required to respond to pathogens or vaccines, such as cell migration and PRR signalling, are also impaired in aged individuals. This immune dysregulation may affect conditions associated with chronic inflammation, such as atherosclerosis and Alzheimer's disease. PMID- 24157575 TI - Inhibition of CXCL12/CXCR4 autocrine/paracrine loop reduces viability of human glioblastoma stem-like cells affecting self-renewal activity. AB - Cancer stem cells (CSCs) or tumor initiating cells (TICs) drive glioblastoma (GBM) development, invasiveness and drug resistance. Distinct molecular pathways might regulate CSC biology as compared to cells in the bulk tumor mass, representing potential therapeutic targets. Chemokine CXCL12 and its receptor CXCR4 control proliferation, invasion and angiogenesis in GBM cell lines and primary cultures, but little is known about their activity in GBM CSCs. We demonstrate that CSCs, isolated from five human GBMs, express CXCR4 and release CXCL12 in vitro, although different levels of expression and secretion were observed in individual cultures, as expected for the heterogeneity of GBMs. CXCL12 treatment induced Akt-mediated significant pro-survival and self-renewal activities, while proliferation was induced at low extent. The role of CXCR4 signaling in CSC survival and self-renewal was further demonstrated using the CXCR4 antagonist AMD3100 that reduced self-renewal and survival with greater efficacy in the cultures that released higher CXCL12 amounts. The specificity of CXCL12 in sustaining CSC survival was demonstrated by the lack of AMD3100 dependent inhibition of viability in differentiated cells derived from the same GBMs. These findings, although performed on a limited number of tumor samples, suggest that the CXCL12/CXCR4 interaction mediates survival and self-renewal in GBM CSCs with high selectivity, thus emerging as a candidate system responsible for maintenance of cancer progenitors, and providing survival benefits to the tumor. PMID- 24157577 TI - Yes, it is time to reconsider how we rate cognitive impairments in HIV disease. PMID- 24157578 TI - The injury response of aged tendons in the absence of biglycan and decorin. AB - Recent studies have demonstrated that the small leucine-rich proteoglycans (SLRPs) biglycan and decorin impact tendon development, aging and healing in mature mice. However, despite the increased risk of tendon injury in the elderly, the role of SLRPs in tendon repair has not been investigated in aged animals. Therefore, our objective was to elucidate the influences of bigylcan and decorin on tendon healing in aged mice to relate our findings to previous work in mature mice. Since the processes of aging and healing are known to interact, our hypothesis was that aging mediates the role of biglycan and decorin on tendon healing. Patellar tendons from wild-type, biglycan-null and decorin-null mice were injured at 270 days using an established model. At 3 and 6 weeks post surgery, structural, mechanical and biochemical analyses were performed and compared to uninjured controls. Early stage healing was inferior in biglycan-null and decorin-null mice as compared to wild type. However, tendons of all genotypes failed to exhibit improved mechanical properties between 3 and 6 weeks post injury. In contrast, in a previous investigation of tendon healing in mature (i.e., 120 day-old) mice, only biglycan-null mice were deficient in early stage healing while decorin-null mice were deficient in late-stage healing. These results confirm that the impact of SLRPs on tendon healing is mediated by age and could inform future age-specific therapies for enhancing tendon healing. PMID- 24157579 TI - Inhibitory effect of ethyl acetate extract of Aristolochia yunnanensis on cardiac fibrosis through extracellular signal-regulated kinases 1/2 and transforming growth factor beta/small mother against decapentaplegic signaling pathways. AB - Aristolochia yunnanensis, known as Nan Mu Xiang in traditional Chinese medicine, has long been used to treat hypertension and chest pain. In this study, the effect of ethyl acetate extract of Nan Mu Xiang (NMX) on cardiac fibrosis was assessed in vitro by cultured adult rat cardiac fibroblasts with angiotensin II (AngII) stimulation, and in vivo by rats with abdominal aorta constriction (AAC). In cultured adult rat cardiac fibroblasts stimulated by AngII, NMX inhibited cardiac fibroblast proliferation, reduced the expression of fibronectin, alpha smooth muscle actin (alpha-SMA), and transforming growth factor beta (TGF-beta) in a dose-dependent manner; and suppressed AngII-induced phosphorylation of extracellular signal-regulated kinase (ERK)1/2, C- rapidly accelerated fibrosarcoma (C-Raf), and small mother against decapentaplegic (Smad) 2. Similar results were also observed in AAC rats with intraperitoneal injection of NMX, which not only ameliorated myocardial fibrosis, but also improved cardiac function. The therapeutic effect of NMX on myocardial fibrosis is attributed mainly to the inhibition of ERK and the TGF-beta/Smad signaling pathways. NMX may be a promising potential drug candidate for myocardial fibrosis. PMID- 24157580 TI - Continued improvement in survival in multiple myeloma: changes in early mortality and outcomes in older patients. AB - Therapy for multiple myeloma (MM) has markedly changed in the past decade with the introduction of new drugs, but it is not clear whether the improvements have been sustained. We studied 1038 patients diagnosed between 2001 and 2010, grouping patients into two 5-year periods by diagnosis, 2001-2005 and 2006-2010. The median estimated follow-up for the cohort was 5.9 years with 47% alive at the last follow-up. The median overall survival (OS) for the entire cohort was 5.2 years: 4.6 years for patients in the 2001-2005 group compared with 6.1 years for the 2006-2010 cohort (P=0.002). The improvement was primarily seen among patients over 65 years, the 6-year OS improving from 31 to 56%, P<0.001. Only 10% of patients died during the first year in the latter group, compared with 16% in the earlier cohort (P<0.01), suggesting improvement in early mortality. The improved outcomes were linked closely to the use of one or more new agents in initial therapy. The current results confirm continued survival improvement in MM and highlight the impact of initial therapy with novel agents. Most importantly, we demonstrate that the improved survival is benefitting older patients and that early mortality in this disease has reduced considerably. PMID- 24157581 TI - The combination of hyper-CVAD plus nelarabine as frontline therapy in adult T cell acute lymphoblastic leukemia and T-lymphoblastic lymphoma: MD Anderson Cancer Center experience. PMID- 24157582 TI - Immunotherapy for chronic lymphocytic leukemia in the era of BTK inhibitors. AB - Understanding the pathogenesis of CLL has uncovered a plethora of novel targets for human application of monoclonal antibodies, engineered T cells, or inhibitors of signal transduction pathways. The B-cell receptor signaling pathway is being actively explored as a therapeutic target in CLL. Ibrutinib, an inhibitor of Bruton's tyrosine kinase is showing impressive responses in heavily pre-treated high-risk CLL, whether alone or in combination with MoAbs or chemotherapy. Other key components of the BCR pathway, namely PI3K-delta, are also being targeted with novel therapies with promising results as well. Future trials would likely evaluate ibrutinib in the front-line setting. Moreover, improvements in allogeneic HCT mostly by continuing to reduce associated toxicity as well as incorporating cellular therapies such as autologous CLL tumor vaccines, among others, will continue to expand. This is also the case for the next generation of chimeric antigen receptor therapy for CLL once genetically modified T cells are available at broad scale and with improved efficacy. As our ability to further refine and integrate these therapies continues to improve, and we gain further knowledge from gene sequencing, we anticipate that treatment algorithms will continue to be revised to a more personalized approach to treat this disease with improved efficacy and devoid of unnecessary toxicity. PMID- 24157584 TI - Modeling human off-site aerosol exposures to polybrominated flame retardants emitted during the land application of sewage sludge. AB - Elevated sewage sludge concentrations of polybrominated diphenyl ethers (PBDEs) are due to their broad utilization in textiles and polymers, their resistance to biological degradation, and also their hydrophobic nature-which drives partitioning into wastewater solids. This study estimated the total U.S. emissions of PBDE due to sewage sludge land application and then determined the human inhalation exposure to sludge-associated PBDEs as a function meteorological conditions and downwind distances from an application site. These aerosol exposures have also been incorporated into pharmacokinetic models to predict contributions to steady-state body burden. Our results suggest that while the amount of PBDEs aerosolized during the land application process is small compared to aerosol emissions associated with product use, the application of sludges onto U.S. soils constitutes a major source of PBDEs entering the outdoor environment. Regarding aerosol exposure to nearby residents, the maximum daily inhalation dosages from a common land application scenario occur immediately after sewage sludges are applied and were 137, 27, 1.9, and 81pg/day for significant congeners PBDE-47, -99, -153 and 209 respectively. These doses are 1-2 orders of magnitude less than the standard daily inhalation exposure to the same PBDEs associated with home indoor air and are similar to doses from inhalation of urban and rural outdoor air. Under the worst-case atmospheric transport scenario, the dosages are reduced by approximately 1 order of magnitude when the setback distance between the sludge aerosolization source and human receptor is increased to 200m. Though the health implications of low-level exposures are not well-understood, these sludge-derived PBDE dosages contribute less than a tenth of 1% to the estimated total body burden of PBDE produced from inhalation of indoor and outdoor air, exposure to house dust, and exposure to PBDE from food and water intake. Overall, the inhalation of PBDE aerosols from sludge-applied fields does not represent a significant contribution to human exposure compared to other common indoor exposures. However, land application is a major environmental source of PBDEs and sludge health impact analyses should focus on the practice's impacts on other exposures, such as biomagnification in aquatic and terrestrial food webs. PMID- 24157583 TI - Whole-exome sequencing identifies a novel somatic mutation in MMP8 associated with a t(1;22)-acute megakaryoblastic leukemia. PMID- 24157585 TI - Investigation of photodynamic therapy optimization for port wine stain using modulation of photosensitizer administration methods. AB - To raise photosensitizer concentration level during the photodynamic therapy process, two new methods of photosensitizer administration were investigated. The first method involves the slow intravenous injection of photosensitizer throughout the first 15 min of irradiation, and the second method involves 30 min fomentation before photosensitizer injection and irradiation. The fluorescence spectra of port wine stain skin were monitored and the therapeutic effect correlated index was calculated with a previously published spectral algorithm. Thirty cases were divided into group A (slow injection of photosensitizer during the first 15 min), group B (fomentation), and group C (control group, traditional injection method), with 10 cases in each group. To analyze the effect of these two new methods, the change of therapeutic effect correlated index values of two photodynamic therapy sessions for each patient were calculated, and the photodynamic therapy outcome was compared. The results showed that the change of therapeutic effect correlated index in group A was slightly more remarkable than that in the control group. The change of therapeutic effect correlated index in group B was similar to that in the control group. Slow injection of photosensitizer during photodynamic therapy has a potential to increase photosensitizer concentration level during photodynamic therapy. However, fomentation before photodynamic therapy has no such potential. There is a need for new methods to be attempted. PMID- 24157586 TI - Toxicological profile of small airway epithelial cells exposed to gold nanoparticles. AB - Gold nanoparticles (AuNPs) have diverse applications in the biomedical industry such as in diagnosis, labeling, delivering and sensing. Despite their prevalent medical use, nanotoxicity induced by AuNPs is still largely unknown. We have previously shown that AuNPs could exert cytotoxic effects on lung fibroblasts. In this study, we investigated the in vitro toxicological effects of AuNPs in small airway epithelial cells (SAECs) which are the first cells of contact for inhaled NPs and compared expression of metallothionein (MT), a reactive oxygen species scavenger, in SAECs and lung fibroblasts in vitro. Transmission electron microscopy (TEM) and energy-dispersive X-ray (EDX) spectroscopy study revealed cellular uptake of aggregates of AuNPs into the cytoplasm at the ultrastructural level. A significant increase in lipid peroxide as well as substantial DNA damage and cytotoxicity was observed in AuNP-treated cells. For MT expression, AuNPs induced down-regulation of the MT-1X isoform in SAECs, but up-regulation of the MT-1X and MT-2 A isoforms in MRC5 lung fibroblasts. The present study suggests that AuNPs could induce oxidative stress-related cytotoxicity and genotoxicity in SAECs. PMID- 24157587 TI - Repair of bone defects using a new biomimetic construction fabricated by adipose derived stem cells, collagen I, and porous beta-tricalcium phosphate scaffolds. AB - Adipose derived stem cells (ASCs) with multilineage differentiation capacities have been demonstrated as an alternative cell candidate for in vitro and in vivo bone regeneration. This suggests that they may be a potential candidate to repair the bone defects. We attempted to demonstrate the use of new biomimetic constructions of undifferentiated rabbit adipose-derived stem cells (rASCs) with fully interconnected porous beta-tricalcium phosphate (beta-TCP) scaffolds encapsulated by collagen I hydrogel in the regeneration of a critical-sized defect of rabbit radii. Critical-sized defects in the left radii of rabbits were prepared and inserted with rASCs/collagen I/beta-TCP scaffold composites or collagen I/beta-TCP scaffold composites. The results were evaluated by histology, radiographs, micro-CT, Emission Computed Tomography (ECT), fluorochrome labeling, western blot, and mechanical testing at 4, 8, and 12 weeks postsurgery. Twelve weeks after implantation, the defects were almost completely repaired as confirmed by the presence of the cortical bone and medullary cavity, which was evaluated through radiologic, histologic, and biomechanical examination. Biodegradation of the biomaterials may be attributed to extracellular liquid dissolution together with cell-mediated phagocytosis. Our study shows that a greater number of rASCs in the porous beta-TCP scaffold encapsulated by collagen I gel enhanced osteogenesis in critical-sized defects. We hope to garner new insight into the engineering of rASCs-based bone tissue for clinical application. PMID- 24157588 TI - Maternal beef and postweaning herring diets increase bone mineral density and strength in mouse offspring. AB - The maternal diet during gestation and lactation affects the long-term health of the offspring. We sought to determine whether maternal and postweaning crossover isocaloric diets based on fish or meat affect the geometry, mineral density, and biomechanical properties of bone in mouse offspring in adulthood. During gestation and lactation, C57BL/6 dams were fed a herring- or beef-based diet. After weaning, half of the pups in each group were fed the same diet as their dams, and half were fed the other diet. Areal bone mineral density (aBMD) and bone mineral content (BMC) of the whole body and lumbar spine were measured in the offspring by dual X-ray absorptiometry at 9 and 21 weeks of age. At 22-26 weeks, tibia bone geometry (length, cortical volumetric (v) BMD, BMC, area and thickness) was analyzed by peripheral quantitative computed tomography, and the biomechanical properties of the tibia were analyzed by the three-point bending test. Plasma insulin-like growth factor-1 was analyzed at 12 weeks. In comparison to the maternal herring diet, the maternal beef diet increased aBMD and BMC in the whole body and lumbar spine of adult offspring, as well as cortical vBMD, BMC, bone area, and thickness at the mid-diaphyseal region of the tibia and the biomechanical properties of tibia strength. In contrast, a postweaning beef diet decreased aBMD in the lumbar spine and BMC in the whole body and lumbar spine compared with a postweaning herring diet, which instead increased plasma insulin like growth factor-1 levels. The change from a maternal beef diet before weaning to a herring diet after weaning decreased body weight and increased the cortical area, vBMD, BMC, thickness, and strength of the tibia. These significant crossover effects indicate that a preweaning maternal beef diet and a postweaning herring diet are optimal for increasing BMC and bone strength in offspring in adulthood. PMID- 24157589 TI - The effects of caloric restriction against ethanol-induced oxidative and nitrosative cardiotoxicity and plasma lipids in rats. AB - Caloric restriction (CR) prevents or delays a wide range of aging-related diseases possibly through alleviation of oxidative stress. The aim of our study was to examine the effect of CR on oxidative and nitrosative cardiac damage in rats, induced by acute ethanol intoxication. Male Wistar rats were divided into following groups: control; calorie-restricted groups with intake of 60-70% (CR60 70) and 40-50% of daily energy needs (CR40-50); ethanol-treated group (E); calorie-restricted, ethanol-treated groups (CR60-70 + E, CR40-50 + E). Ethanol was administered in five doses of 2 g/kg every 12 h, while the duration of CR was five weeks before ethanol treatment. Malondialdehyde level was significantly lower in CR60-70 + E and significantly higher in CR40-50 + E vs. control. Nitrite and nitrate level was significantly higher in CR40-50 + E compared to control group. Activity of total superoxide dismutase (SOD) and its isoenzyme, copper/zinc-SOD (Cu/ZnSOD), was significantly higher in CR60-70 + E and lower in CR40-50 + E vs. control. Activity of manganese-SOD (MnSOD), that is also SOD isoenzyme, was significantly lower in CR40-50 + E compared to control group. Plasma content of sulfhydryl (SH) groups was significantly higher in CR60-70 group vs. control. Plasma concentration of total cholesterol, triacylglycerol, low-density lipoproteins and high-density lipoproteins was significantly lower in CR60-70 group compared to control values. Food restriction to 60-70% of daily energy needs has a protective effect on acute ethanol-induced oxidative and nitrosative cardiac damage, at least partly due to alleviation of ethanol-induced decrease in SOD activity, while restriction to 40-50% of energy needs aggravates lipid peroxidation and nitrosative stress. PMID- 24157590 TI - Preparation and evaluation in vitro and in vivo of docetaxel loaded mixed micelles for oral administration. AB - A mixed micelle that comprised of monomethylol poly(ethylene glycol)-poly(D,L lactic acid) (MPP), D-alpha-tocopheryl polyethylene glycol 1000 succinate (TPGS) and stearic acid grafted chitosan oligosaccharide(CSO-SA) copolymers was developed to enhance the oral absorption of docetaxel (DTX). DTX-loaded MPP/TPGS/CSO-SA mixed polymeric micelles (MPMs) were prepared with thin film hydration method and characterized in terms of morphology, size, zeta potential, encapsulation efficiency, critical micellization concentration, and in vitro stability in media modeling physiological conditions. The in vitro release of docetaxel from the mixed micelles was studied with dialysis method. The oral bioavailability studies were conducted in rats and the pharmacokinetic parameters were evaluated. The results showed that DTX-loaded MPP/TPGS/CSO-SA MPMs had a mean diameter of 34.96 nm and exhibited spherical shape under transmission electron microscopy. The drug loading of DTX in the mixed micelles was 19.15%. The critical micellization concentration of MPP/TPGS/CSO-SA copolymer was 2.11*10(-5) M, and the size of mixed micelles in gastric fluid (pH 1.6) for 2 h and simulated intestinal fluid (pH 6.5) for 6h showed no significant change. The in vitro release study showed that DTX-loaded MPP/TPGS/CSO-SA MPMs exhibited slower release characteristics compared to DTX solution. The oral bioavailability of the DTX-loaded MPP/TPGS/CSO-SA MPMs was increased by 2.52 times compared to that of DTX solution. The current results encourage further development of DTX mixed polymeric micelles as the oral drug delivery system. PMID- 24157592 TI - Clinical profile and prognostic significance of atrial fibrillation in hypertrophic cardiomyopathy. AB - OBJECTIVES: The clinical outcomes of hypertrophic cardiomyopathy (HCM) are largely unpredictable. This study aimed to investigate the relationship between atrial fibrillation (AF) and its prognostic implications in Chinese patients with HCM. METHODS: From 1999 to 2011, 654 unrelated HCM patients were consecutively recruited at Fuwai Hospital. Medical history, including electrocardiographic and echocardiographic data, was analyzed. RESULTS: AF was documented in 158 patients (24%). During follow-up of 4.2 +/- 2.8 years, Kaplan-Meier analysis revealed that the presence of AF was associated with an increased risk for all-cause death (p = 0.001), cardiovascular death (p < 0.001), severe heart failure (p < 0.001) and ischemic stroke (p < 0.001). Multivariate analysis identified AF as an independent predictor of stroke-related death (HR 6.71, 95% CI 1.23-38.58, p = 0.03), advanced heart failure (HR 1.83, 95% CI 1.04-3.22, p = 0.04) and ischemic stroke (HR 9.98, 95% CI 4.06-24.53, p < 0.001). Furthermore, enlarged left atrial diameter was positively related to all-cause death (HR 1.09, 95% CI 1.05-1.13, p < 0.001), cardiovascular death (HR 1.08, 95% CI 1.04-1.20, p < 0.001) and development of advanced heart failure (HR 1.05, 95% CI 1.01-1.10, p = 0.01). CONCLUSIONS: AF predicts poor outcomes for patients with HCM. Left atrial dilation is also related to an adverse prognosis and provides additional prognostic information. PMID- 24157591 TI - Patch-clamp recordings and calcium imaging followed by single-cell PCR reveal the developmental profile of 13 genes in iPSC-derived human neurons. AB - Molecular genetic studies are typically performed on homogenized biological samples, resulting in contamination from non-neuronal cells. To improve expression profiling of neurons we combined patch recordings with single-cell PCR. Two iPSC lines (healthy subject and 22q11.2 deletion) were differentiated into neurons. Patch electrode recordings were performed on 229 human cells from Day-13 to Day-88, followed by capture and single-cell PCR for 13 genes: ACTB, HPRT, vGLUT1, betaTUBIII, COMT, DISC1, GAD1, PAX6, DTNBP1, ERBB4, FOXP1, FOXP2, and GIRK2. Neurons derived from both iPSC lines expressed betaTUBIII, fired action potentials, and experienced spontaneous depolarizations (UP states) ~2 weeks before vGLUT1, GAD1 and GIRK2 appeared. Multisite calcium imaging revealed that these UP states were not synchronized among hESC-H9-derived neurons. The expression of FOXP1, FOXP2 and vGLUT1 was lost after 50 days in culture, in contrast to other continuously expressed genes. When gene expression was combined with electrophysiology, two subsets of genes were apparent; those irrelevant to spontaneous depolarizations (including vGLUT1, GIRK2, FOXP2 and DISC1) and those associated with spontaneous depolarizations (GAD1 and ERBB4). The results demonstrate that in the earliest stages of neuron development, it is useful to combine genetic analysis with physiological characterizations, on a cell-to-cell basis. PMID- 24157593 TI - Analyses of genetic variations at microsatellite loci present in-and-around the Pfcrt gene in Indian Plasmodium falciparum. AB - Evolution and spread of chloroquine resistant (CQR) malaria parasite Plasmodium falciparum have posed great threat in malaria intervention across the globe. The occurrence of K76T mutation in the P. falciparum chloroquine resistance transporter (pfcrt) gene has been widely attributed to CQR with four neighboring mutations providing compensatory fitness benefit to the parasite survival. Understanding evolutionary patterns of the pfcrt gene is of great relevance not only for devising new malaria control measures but also could serve as a model to understand evolution and spread of other human drug-resistant pathogens. Several studies, mainly based on differential patterns of diversities of the microsatellite loci placed in-and-around the pfcrt gene have indicated the role of positive natural selection under the 'hitchhiking' model of molecular evolution. However, the studies were restricted to limited number of microsatellite loci present inside the pfcrt gene. Moreover, comparatively higher level of diversities in microsatellite loci present inside the pfcrt gene than the loci flanking the pfcrt gene are hallmarks of Indian P. falciparum, presenting contrasting evolutionary models to global isolates. With a view to infer evolutionary patterns of the pfcrt gene in Indian P. falciparum, we have adopted a unique sampling scheme of two types of populations (cultured and field collected) and utilized 20 polymorphic microsatellite loci (16 located inside the pfcrt gene and four in the two flanking regions) to disentangle between genetic drift (inbred cultured isolates) and natural selection (field isolates). Data analyses employing different population genetic tests could not straightforwardly explain either the model invoking 'genetic hitchhiking' or 'genetic drift'. However, complex evolutionary models influenced by both demography and natural selection or an alternative model of natural selection (e.g. diversifying/balancing selection) might better explain the observed microsatellite variation in-and-around the pfcrt gene in Indian P. falciparum. PMID- 24157594 TI - Depressing interleukin-1beta contributed to the synergistic effects of tramadol and minocycline on spinal nerve ligation-induced neuropathic pain. AB - Our previous study indicated that coadministration of tramadol and minocycline exerted synergistic effects on spinal nerve ligation (SNL)-induced neuropathic mechanical allodynia. However, the underlying mechanisms are still unclear. Recent reports indicated that spinal proinflammatory factor interleukin-1beta (IL 1beta) contributed to the development of neuropathic pain and the positive feedback communication between neuron and glia. Therefore, the present research is to confirm whether spinal IL-1beta-related pathway response contributes to the synergistic effects of tramadol and minocycline on SNL-induced neuropathic pain. Real-time RT-PCR demonstrated IL-1beta up-expression in the ipsilateral spinal dorsal horn 3 days after lesion, which could be significantly decreased by tramadol and minocycline coadministration. Immunofluorescence and Western blot indicated that SNL-induced microglial phosphorylated p38 (p-p38) upregulation was also inhibited by tramadol and minocycline coapplication. Meanwhile, intrathecal administration of p38 inhibitor SB203580 markedly alleviated mechanical allodynia whilst reducing IL-1beta and Fos expression induced by SNL. Moreover, intrathecal neutralized antibody of IL-1beta could depress SNL-induced mechanical allodynia and Fos expression. These results suggest that depressing SNL-induced aberrant activation of the spinal dorsal horn IL-1beta-related pathway contributes to the underlying mechanism of the synergistic effects of tramadol and minocycline coadministration on SNL-induced neuropathic mechanical allodynia. PMID- 24157595 TI - The effect of age upon the perception of 3-D shape from motion. AB - Two experiments evaluated the ability of 50 older, middle-aged, and younger adults to discriminate the 3-dimensional (3-D) shape of curved surfaces defined by optical motion. In Experiment 1, temporal correspondence was disrupted by limiting the lifetimes of the moving surface points. In order to discriminate 3-D surface shape reliably, the younger and middle-aged adults needed a surface point lifetime of approximately 4 views (in the apparent motion sequences). In contrast, the older adults needed a much longer surface point lifetime of approximately 9 views in order to reliably perform the same task. In Experiment 2, the negative effect of age upon 3-D shape discrimination from motion was replicated. In this experiment, however, the participants' abilities to discriminate grating orientation and speed were also assessed. Edden et al. (2009) have recently demonstrated that behavioral grating orientation discrimination correlates with GABA (gamma aminobutyric acid) concentration in human visual cortex. Our results demonstrate that the negative effect of age upon 3-D shape perception from motion is not caused by impairments in the ability to perceive motion per se, but does correlate significantly with grating orientation discrimination. This result suggests that the age-related decline in 3-D shape discrimination from motion is related to decline in GABA concentration in visual cortex. PMID- 24157597 TI - Evaluation of electronic ambulatory care data for influenza-like illness surveillance, Washington State. AB - A growing number of outpatient providers utilize electronic health records (EHR) to identify patient visits for influenza-like illness (ILI) but no standard query guidance exists. We applied an ILI definition validated for emergency department data to EHR from outpatient networks and found ILI visits highly correlated with influenza laboratory detections. Incorporating ambulatory EHR into our ILI surveillance system increased the capacity by more than 300%. Electronic ambulatory care data could be used to augment or replace public health surveillance systems traditionally reliant on manual reporting. PMID- 24157598 TI - The ultimate limit to the emission linewidth of single nanocrystals. AB - Measurements of the emission linewidth of single nanocrystals are usually limited by spectral diffusion. At cryogenic temperatures, the origin of this instability was revealed to be photo-induced, suggesting that the spectral peak position may be stable in the limit of vanishing optical excitation. Here we test this stability using resonant photoluminescence excitation and find there is persistent spectral broadening, which ultimately limits the emission linewidth in these materials. The spectral broadening is shown to be consistent with spontaneous fluctuations of the local electrostatic field within the disordered environment surrounding the nanocrystal. PMID- 24157602 TI - Validation of stroke prognostic scores: what do clinicians need to know? PMID- 24157596 TI - Crosslinguistic application of English-centric rhythm descriptors in motor speech disorders. AB - BACKGROUND: Rhythmic disturbances are a hallmark of motor speech disorders, in which the motor control deficits interfere with the outward flow of speech and by extension speech understanding. As the functions of rhythm are language-specific, breakdowns in rhythm should have language-specific consequences for communication. OBJECTIVE: The goals of this paper are to (i) provide a review of the cognitive-linguistic role of rhythm in speech perception in a general sense and crosslinguistically; (ii) present new results of lexical segmentation challenges posed by different types of dysarthria in American English, and (iii) offer a framework for crosslinguistic considerations for speech rhythm disturbances in the diagnosis and treatment of communication disorders associated with motor speech disorders. SUMMARY: This review presents theoretical and empirical reasons for considering speech rhythm as a critical component of communication deficits in motor speech disorders, and addresses the need for crosslinguistic research to explore language-universal versus language-specific aspects of motor speech disorders. PMID- 24157603 TI - Effects of exposure time and exposure distance on the degree of cure in light activated pit and fissure sealants. AB - OBJECTIVES: The study aims to measure and compare the effect of different exposure times and exposure distances on the degree of cure (DC) of light hardening resin based pit and fissure sealants. METHODS: A representative selection of 13 commercial sealants brands was chosen. DC of each material (n=6) was measured in real-time by Fourier transform infrared spectroscopy (FTIR) at three clinically relevant exposure times (10, 20, 40s) and two fixed exposure distances (4mm and 7 mm) between sample and light source. Data were analyzed by a multi-variant analysis and partial eta-squared statistic. RESULTS: Factors "material", "exposure time" and "exposure distance" had a significant influence on the DC across all materials (etap(2)=0.927,0.774 and 0.266 respectively) with "material" and "exposure time" showing the strongest effect (significance level alpha <= 0.05). In general, an increased exposure time and reduced exposure distance between sample and light source led to increased DC for all the materials. CONCLUSIONS: Degree of cure is influenced significantly by the brand of sealant and by exposure time. In some cases it is found that DC is also affected significantly by the exposure distance. CLINICAL SIGNIFICANCE: On the basis of this study, an exposure time of at least 20s and a maximum exposure distance of 4mm between curing unit and material surface is recommended. PMID- 24157604 TI - Phosphate wasting and fibroblast growth factor-23. AB - PURPOSE OF REVIEW: The purpose of this study is to review the regulation of phosphate and recent progress in fibroblast growth factor-23 (FGF-23), a key phosphate regulatory hormone. RECENT FINDINGS: Phosphate is required for mineralization of bone, muscle strength and a host of biologic functions. Phosphate is sensed by bone that responds with secretion of FGF-23. The major action of FGF-23 is to stimulate phosphaturia. Feedback loops between FGF-23, 1,25-dihydroxyvitamin D3 and parathyroid hormone maintain phosphate homeostasis. Information about FGF-23 has accumulated from studies in patients with oncogenic osteomalacia and inherited disorders of phosphate wasting rickets that explains the pathophysiology. Exciting new discoveries have highlighted FGF-23 as an independent risk factor for cardiovascular disease in patients with chronic kidney disease. The phosphate sensor triggering FGF-23 production remains to be identified. SUMMARY: Derangements in FGF-23 production, half-life or downstream response are responsible for several disorders of phosphate wasting, rickets and oncogenic osteomalacia. Very high levels of FGF-23 in renal failure are an independent risk for cardiovascular disease. PMID- 24157605 TI - Strong inhibition of thioredoxin reductase by highly cytotoxic gold(I) complexes. DNA binding studies. AB - Biological properties of a series of aminophosphine-thiolate gold(I) complexes [Au(SR)(PPh2NHpy)] [Ph2PNHpy=2-(diphenylphosphinoamino)pyridine; HSR=2 mercaptopyridine (2-HSpy) (3), 2-mercaptonicotinic acid (2-H2-mna) (4), 2 thiouracil (2-HTU) (5) or 2-thiocytosine (2-HTC) (6)] and [Au(SR){PPh2NH(Htrz)}] [Ph2PNH(Htrz)=3-(diphenylphosphinoamino)-1,2,4-triazole]; HSR=2-mercaptopyridine (2-HSpy) (7), 2-thiocytosine (2-HTC) (8) or 6-thioguanine (6-HTG) (9) have been studied. Their antitumor properties have been tested in vitro against two tumor human cell lines, HeLa (derived from cervical cancer) and MCF-7 (derived from breast cancer), using a metabolic activity test (3-(4,5-dimethyl-thiazol-2-yl) 2,5-diphenyl tetrazolium bromide, MTT). Some of them showed excellent cytotoxic activity. With the aim to obtain more information about the mechanisms of action of these derivatives, the interactions of complexes 3, 5, 7 and 9 with thioredoxin reductase in HeLa cells were studied. They showed a potent inhibition of thioredoxin reductase activity. In order to complete this study, interactions of the complexes with calf thymus (CT-) DNA and with different bacterial DNAs, namely the plasmid pEMBL9 and the promoter region of the furA (ferric uptake regulator A) gene from Anabaena sp. PCC 7120 were investigated. Although interactions of complexes with CT-DNA have been verified, none of them cause significant changes in its structure. PMID- 24157606 TI - PIF3 is involved in the primary root growth inhibition of Arabidopsis induced by nitric oxide in the light. AB - PHYTOCHROME INTERACTING FACTOR3 (PIF3) is an important component in the phytochrome signaling pathway and mediates plant responses to various environmental conditions. We found that PIF3 is involved in the inhibition of root growth of Arabidopsis thaliana seedlings induced by nitric oxide (NO) in light. Overexpression of PIF3 partially alleviated the inhibitory effect of NO on root growth, whereas the pif3-1 mutant displayed enhanced sensitivity to NO in terms of root growth. During phytochrome signaling, the photoreceptor PHYB mediates the degradation of PIF3. We found that the phyB-9 mutant had a similar phenotype to that of PIF3ox in terms of responsiveness to NO. Furthermore, NO treatment promoted the accumulation of PHYB, and thus reduced PIF3 content. Our results further show that the activity of PIF3 is regulated by the DELLA protein RGL3[RGA (repressor of ga1-3) LIKE 3]. Therefore, we speculate that PIF3 lies downstream of PHYB and RGL3, and plays an important role in the inhibitory effect of NO on root growth of Arabidopsis seedlings in light. PMID- 24157607 TI - Z-box binding transcription factors (ZBFs): a new class of transcription factors in Arabidopsis seedling development. AB - One set of genes encoding diverse groups of transcription factors that interact with the Z-box (ATACGTGT; a potential Z-DNA forming sequence) is called ZBFs (Z box Binding Factors). ZBFs include ZBF1, ZBF2, and ZBF3, which encode ZBF1/MYC2 (bHLH), ZBF2/GBF1 (bZIP), and ZBF3/CAM7 (Calmodulin) proteins, respectively. With several recent reports, it is becoming increasingly evident that ZBFs play crucial roles in Arabidopsis seedling photomorphogenesis. ZBFs integrate signals from various wavelengths of light to coordinate the regulation of transcriptional networks that affect multiple facets of plant growth and development. The function of each ZBF is qualitatively and quantitatively distinct. The zbf mutants display pleiotropic effects including altered hypocotyl elongation, cotyledon expansion, lateral root development, and flowering time. In this inaugural review, we discuss the identification, molecular functions, and interacting partners of ZBFs in light-mediated Arabidopsis seedling development. PMID- 24157608 TI - Genome-wide DNA binding of GBF1 is modulated by its heterodimerizing protein partners, HY5 and HYH. PMID- 24157609 TI - Heterologous expression of the mevalonic acid pathway in cyanobacteria enhances endogenous carbon partitioning to isoprene. AB - Heterologous expression of the isoprene synthase gene in the cyanobacterium Synechocystis PCC 6803 conferred upon these microorganisms the property of photosynthetic isoprene (C5H8) hydrocarbons production. Continuous production of isoprene from CO2 and H2O was achieved in the light, occurring via the endogenous methylerythritol-phosphate (MEP) pathway, in tandem with the growth of Synechocystis. This work addressed the issue of photosynthetic carbon partitioning between isoprene and biomass in Synechocystis. Evidence is presented to show heterologous genomic integration and cellular expression of the mevalonic acid (MVA) pathway genes in Synechocystis endowing a non-native pathway for carbon flux amplification to isopentenyl-diphosphate (IPP) and dimethylallyl diphosphate (DMAPP) precursors of isoprene. Heterologous expression of the isoprene synthase in combination with the MVA pathway enzymes resulted in photosynthetic isoprene yield improvement by approximately 2.5-fold, compared with that measured in cyanobacteria transformed with the isoprene synthase gene only. These results suggest that the MVA pathway introduces a bypass in the flux of endogenous cellular substrate in Synechocystis to IPP and DMAPP, overcoming flux limitations of the native MEP pathway. The work employed a novel chromosomal integration and expression of synthetic gene operons in Synechocystis, comprising up to four genes under the control of a single promoter, and expressing three operons simultaneously. This is the first time an entire biosynthetic pathway with seven recombinant enzymes has been heterologously expressed in a photosynthetic microorganism. It constitutes contribution to the genetic engineering toolkit of photosynthetic microorganisms and a paradigm in the pursuit of photosynthetic approaches for the renewable generation of high-impact products. PMID- 24157610 TI - The Arabidopsis cysteine-rich GASA5 is a redox-active metalloprotein that suppresses gibberellin responses. PMID- 24157611 TI - High-resolution crystal structure and redox properties of chloroplastic triosephosphate isomerase from Chlamydomonas reinhardtii. AB - Triosephosphate isomerase (TPI) catalyzes the interconversion of glyceraldehyde-3 phosphate to dihydroxyacetone phosphate. Photosynthetic organisms generally contain two isoforms of TPI located in both cytoplasm and chloroplasts. While the cytoplasmic TPI is involved in the glycolysis, the chloroplastic isoform participates in the Calvin-Benson cycle, a key photosynthetic process responsible for carbon fixation. Compared with its cytoplasmic counterpart, the functional features of chloroplastic TPI have been poorly investigated and its three dimensional structure has not been solved. Recently, several studies proposed TPI as a potential target of different redox modifications including dithiol/disulfide interchanges, glutathionylation, and nitrosylation. However, neither the effects on protein activity nor the molecular mechanisms underlying these redox modifications have been investigated. Here, we have produced recombinantly and purified TPI from the unicellular green alga Chlamydomonas reinhardtii (Cr). The biochemical properties of the enzyme were delineated and its crystallographic structure was determined at a resolution of 1.1 A. CrTPI is a homodimer with subunits containing the typical (beta/alpha)8-barrel fold. Although no evidence for TRX regulation was obtained, CrTPI was found to undergo glutathionylation by oxidized glutathione and trans-nitrosylation by nitrosoglutathione, confirming its sensitivity to multiple redox modifications. PMID- 24157612 TI - BRAFV600E immunohistochemistry in conjunction with mismatch repair status predicts survival in patients with colorectal cancer. AB - Immunohistochemistry has recently been validated for the detection of the BRAFV600E mutation across a range of tumor types. In colorectal carcinoma, the presence of the BRAFV600E mutation can be used to virtually exclude Lynch syndrome in mismatch repair-deficient tumors. In mismatch repair-proficient tumors, BRAFV600E mutation assessed by molecular methods has been proposed as a poor prognostic factor. We investigated whether combined BRAFV600E and mismatch repair status assessment by immunohistochemistry alone can be used as a prognostic marker in the routine clinical setting. We performed immunohistochemistry for BRAFV600E, MLH1, PMS2, MSH2, and MSH6 on 1426 consecutive unselected colorectal carcinomas. Ninety-one (6.4%) carcinomas were mismatch repair-proficient and BRAFV600E mutant, and these tumors demonstrated a significantly worse 5-year survival of 49.7% compared with mismatch repair proficient BRAF wild type (74.1% of tumors, 65.4% survival), mismatch repair deficient BRAFV600E mutant (12.9% of tumors, 70.1% survival), and mismatch repair deficient BRAF wild type (6.6% of tumors, 73.6% survival). The poor survival was confirmed by univariate analysis (P<0.01) but fell away in multivariate analysis (P=0.68) because of the strong effect of tumor stage and age on overall survival. We conclude that in addition to its utility in screening for Lynch syndrome, reflex BRAFV600E and mismatch repair assessment by immunohistochemistry can be used as a powerful predictor of all-cause survival. PMID- 24157613 TI - A gold nanoparticles colorimetric assay for label-free detection of protein kinase activity based on phosphorylation protection against exopeptidase cleavage. AB - Protein kinases are significant regulators in the cell signaling pathways, and it is still greatly desirable to achieve simple and quick kinase detection. Herein, we present a novel colorimetric gold nanoparticles (AuNPs)/peptide platform for probing the activity and inhibition of protein kinases based on phosphorylation induced suppression of carboxypeptidase Y (CPY) cleavage. This AuNPs/peptide platform can easily monitor the kinase activity by a UV-vis spectrometer or even by the naked eye. The feasibility of the method has been demonstrated by sensitive measurement of the cAMP-dependent protein kinase (PKA) activity with a low detection limit of 0.232 mU/uL and assessment of kinase inhibition by H-89 with an IC50 value of 18.13 nM. The assay was also successfully put into practice for the detection of kinase activity in cell lysate. Because of its label-free, homogenous and colorimetric merits, the proposed assay presents great potential in high-throughput screening for kinase-targeted drug discovery. PMID- 24157615 TI - Gustatory receptor expression in the labella and tarsi of Aedes aegypti. AB - The yellow-fever mosquito, Aedes aegypti, infects a growing number of people every year with dengue, yellow fever and chikungunya viruses. Contact chemoreception in mosquitoes influences a number of behaviors including host selection, oviposition and feeding. While these behaviors are in many instances well documented, the molecular mechanisms mediating them are not well understood. Here we report the results of sequencing total messenger RNA in the labella and tarsi of both male and female Ae. aegypti to reveal Gustatory Receptor (GR) gene expression profiles in these major gustatory appendages. Gene expression levels in each tissue were verified by RT-qPCR. We discuss potential functions for the GRs revealed here by considering homologous GRs in other insects. Specific GRs provide molecular targets for modification of gustatory-mediated behaviors in this important disease vector. PMID- 24157614 TI - Depletion of hnRNP A2/B1 overrides the nuclear retention of the HIV-1 genomic RNA. AB - hnRNP A2 is a cellular protein that is important for nucleocytoplasmic and cytosolic trafficking of the HIV-1 genomic RNA. Both hnRNP A2's interaction with HIV-1 RNA and its expression levels influence the activities of Rev in mediating nucleocytoplasmic export of the HIV-1 genomic RNA. While the lack of Rev expression during HIV-1 gene expression results in nuclear retention of HIV-1 genomic RNA, we show here by fluorescence in situ hybridization and fractionation studies that the genomic RNA translocates to the cytoplasm when hnRNP A2/B1 are depleted from cells. Polyribosome analyses revealed that the genomic RNA was shunted into a cytoplasmic, dense polyribosomal fraction. This fraction contained several RNA-binding proteins involved in viral gene expression and RNA trafficking but did not contain the translation initiation factor, eIF4G1. Amino acid incorporation into nascent polypeptides in this fraction was also greatly reduced, demonstrating that this fraction contains mRNAs that are poorly translated. These results demonstrate that hnRNP A2/B1 expression plays roles in the nuclear retention of the HIV-1 genomic RNA in the absence of Rev and in the release of the genomic RNA from translationally inactive, cytoplasmic RNP complexes. PMID- 24157616 TI - Impact of a second opinion using expression and molecular analysis of FOXL2 for sex cord-stromal tumors. A study of the GINECO group & the TMRO network. AB - OBJECTIVE: Ovarian sex cord-stromal tumors (SCSTs) are rare and their diagnosis is often difficult to establish. Recently, immunostaining and molecular analysis for Forkhead box L2 (FOXL2) have been developed in this pathology. This study aims to assess the benefit of an algorithm incorporating these new tools for a better diagnosis and classification of SCSTs METHODS: Seventy-two tumors with a potential diagnosis of SCSTs were addressed by 37 different pathologists to one French rare ovarian tumor expert center, member of the Rare Malignant Ovarian Tumor network (TMRO). Then a "second opinion" (SO) through an algorithm incorporating immunostaining (IHC) and molecular analysis of FOXL2 was performed for all these cases. This algorithm was then validated by all pathologists of the TMRO network. RESULTS: After a second opinion including molecular analysis and immunostaining for FOXL2 the initial diagnosis was changed in 15 of 72 samples (21%). FOXL2 mutation was present in 44 out of 47 adult granulosa cell tumors (94%), in 3 out of 8 Thecomas (37%), in 1 out of 10 Sertoli-Leydig cell tumors (SLSTs) (10%) and in 3 out of 5 undifferentiated-SCSTs (Und-SCSTs) (60%). Immunoexpression of FOXL2 was available in 45 cases of SCSTs: FOXL2 was expressed in 44 of them (98%). CONCLUSIONS: A second opinion in an expert center for all cases of SCSTs is fundamental to get an optimal classification of these rare tumors. This second opinion could be performed with an algorithm which integrates FOXL2 mutation and expression status of FOXL2 in order to standardize the practice. PMID- 24157618 TI - Abstracts of the 10th International Congress on Coronary Artery Disease (ICCAD). Florence, Italy. October 13-16, 2013. PMID- 24157617 TI - Detection of cervical cancer recurrence during follow-up: a multivariable comparison of 9 frequently investigated serum biomarkers. AB - OBJECTIVE: To assess the diagnostic accuracy and model the optimal combination of commonly studied serum biomarkers aimed at identifying recurrence in cervical cancer patients. METHODS: From a systematic literature search, nine biomarkers (CA-15.3, CA-125, CEA, CYFRA 21-1, hsCRP, IL-6, SCC-Ag, TNF-alpha and VEGF) were selected for a serum analysis. Samples were derived from a historical cervical cancer cohort. Subjects with serum samples stored in a biobank were included when quality criteria were met, and one sample preceding and at least one following primary treatment were available. In case of recurrence, two additional post recurrence samples were analyzed. Biomarker serum levels were quantified by enzyme linked or chemiluminescence microparticle immunoassays. Logistic regression and receiver operating curve analysis were employed for selection, modeling and comparison on the diagnostic accuracy of the tested biomarkers. RESULTS: 205 samples were analyzed from 75 subjects, of whom 19 (25.3%) had a recurrence. The area under the curve (AUC) of CA-15.3, CA-125, CEA, CYFRA 21-1, IL-6, TNF-alpha and VEGF were all <0.750. Only SCC-Ag and hsCRP were included in the final model with an AUC of 0.822 (95% CI: 0.744-0.900) and 0.831 (95% CI: 0.758-0.905) respectively. Combined AUC was 0.870 (95% CI: 0.805-0.935). Rises in SCC-Ag and hsCRP significantly increased the odds for recurrence. Each ng/ml of SCC-Ag increase, related to an odds ratio (OR) of 1.117 (95% CI: 1.039-1.200). Comparably, the OR for hsCRP (in mg/ml) was 1.025 (95% CI: 1.012-1.038). CONCLUSION: Combined testing of SCC-Ag and hsCRP yields the highest detection rate of disease recurrence during cervical cancer follow-up. PMID- 24157619 TI - The dark lymph node sign on magnetic resonance imaging: a novel finding in patients with sarcoidosis. AB - PURPOSE: The purpose of this study was to describe a characteristic magnetic resonance imaging (MRI) appearance of lymphadenopathy in sarcoidosis--the dark lymph node sign (DLNS)--and to determine its prevalence in a retrospective review of cardiopulmonary MRI examinations obtained in patients with sarcoidosis. MATERIALS AND METHODS: Fifty-one adult patients with a clinical history of sarcoidosis were evaluated with thoracic MRI during a 15-month span; 29 patients were men, and 22 patients were women. The average age of patients was 53.7+/-11.2 years. Patients were considered to have the DLNS on MRI if mediastinal or hilar lymph nodes demonstrated internal low intensity with a peripheral circumferential rim of hyperintensity (relative to paraspinal muscle) on post-gadolinium volume interpolated 3-dimensional gradient echo (3D-GRE/VIBE) and fat-saturated T2 weighted fast spin echo (T2-FSE/BLADE) sequences. Univariate analyses and a logistic regression were used to determine how variables of interest related to the DLNS. RESULTS: Of the 51 patients with sarcoidosis, 49% (25 patients) demonstrated the DLNS. Nodal calcification was present on computed tomography in 45.7% (16/35) of patients with computed tomography scans obtained within 90 days of MRI. The DLNS sign was not more common in those with nodal calcification. When the DLNS occurred in conjunction with calcified nodes, the extent of hypointensity on MRI was not strictly limited to the calcified portions of the lymph node in 71.4% (5/7) of such cases. CONCLUSIONS: The DLNS is commonly present on MRI examinations of patients with sarcoidosis, occurring in approximately half of the participants in our study. PMID- 24157620 TI - Magnetic resonance stress imaging of myocardial perfusion and wall motion. AB - Cardiac magnetic resonance (CMR) imaging is a powerful tool for the detection and management of coronary artery disease. Beyond morphology, CMR imaging can probe relevant physiological parameters such as perfusion and function by means of stress testing. This article reviews current applications of CMR stress imaging with an emphasis upon vasodilators and positive inotropic agents. Further, technical aspects, image interpretation, diagnostic performance, and prognostic value of stress tests will be addressed. PMID- 24157621 TI - Computed tomography and echocardiography in patients with acute pulmonary embolism: part 1: correlation of findings of right ventricular enlargement. AB - PURPOSE: To evaluate the correlation between the computed tomography (CT)-derived right ventricle (RV) to left ventricle (LV) diameter ratio and the RV size determined by echocardiography in patients with acute pulmonary embolism. MATERIALS AND METHODS: Consecutive CT pulmonary angiography examinations (August 2003 to May 2010) from a single, large, urban teaching hospital were retrospectively reviewed. For a cohort of 777 subjects who underwent echocardiography within 48 hours of the CT acquisition, the qualitative RV size (divided into 5 categories) extracted from the echocardiography report was correlated with the CT-derived RV/LV diameter ratio. RESULTS: There was moderate correlation (Spearman rank correlation coefficient=0.54, P<0.001) between the CT derived RV/LV ratio and the RV size as determined by echocardiography. The correlation coefficient and the concordance rate were inversely related to the time difference between the acquisitions of the 2 modalities. CONCLUSIONS: CT and echocardiography findings to assess the RV size after acute pulmonary embolism have moderate correlation. PMID- 24157622 TI - Computed tomography and echocardiography in patients with acute pulmonary embolism: part 2: prognostic value. AB - PURPOSE: The aim of the study was to compare the prognostic value of right ventricular (RV) dysfunction detected on computed tomography pulmonary angiography (CTPA) and transthoracic echocardiography (TTE) in patients with acute pulmonary embolism (PE). MATERIALS AND METHODS: From all consecutive CTPAs performed between August 2003 and May 2010 that were positive for acute PE (n=1744), those with TTE performed within 48 hours of CTPA (n=785) were selected as the study cohort. Multivariate logistic regression analysis was performed to assess the association of CTPA RV/left ventricular (LV) diameter ratio and TTE RV strain with PE-related 30-day mortality, including other associated factors as covariates. The predictive ability (area under the curve) was compared between the model including the CT RV/LV diameter ratio and that including TTE RV strain. Test characteristics of the 2 modalities were calculated. RESULTS: Both CT RV/LV diameter ratio and TTE RV strain were independently associated with PE-related 30 day mortality (adjusted odds ratio=1.14, P=0.023 for 0.1 increment of the CT RV/LV diameter ratio; and odds ratio=2.13, P=0.041 for TTE RV strain). History of congestive heart failure and malignancy were independent predictors of PE-related mortality, while there was significantly lower mortality associated with anticoagulation use. The model including TTE RV strain and that including CT RV/LV had similar predictive ability (area under the curve=0.80 vs. 0.81, P=0.50). The sensitivity, specificity, and positive and negative predictive values of TTE RV strain and CT RV/LV diameter ratio at a cutoff of >=1.0 were similar for PE-related 30-day mortality. CONCLUSIONS: Both RV strain on TTE and an increased CT RV/LV diameter ratio are predictors of PE-related 30-day mortality with similar prognostic significance. PMID- 24157623 TI - Reduction of poor contrast enhancement of the pulmonary artery in computed tomography angiography using an alternative respiratory maneuver. AB - PURPOSE: The aim of the study was to compare the effects of different respiratory maneuvers in computed tomography pulmonary angiography for the diagnosis of pulmonary embolism (PE) on the contrast enhancement of pulmonary circulation and on the quality of lung window images. MATERIALS AND METHODS: A retrospective analysis of 520 examinations, half obtained after deep inspiration followed by breath-holding and half solely during breath-holding. Subjective quality analyses and objective measurements of pulmonary arterial enhancement and lung parenchyma attenuation were performed. RESULTS: Elimination of deep inspiration reduced suboptimal opacification of the pulmonary artery (PA), from 7.3% to 2.7%, with 2.7% of the deep inspiration scans having attenuation values <150 Hounsfield units (HU). The prevalence of PE was similar between the groups (19% vs. 23%, respectively), with excellent interobserver diagnostic agreement (kappa=0.89 to 0.91). Lung windows were compromised in 6.9% of the studies with respiratory pause, and these examinations had a higher attenuation of the lung parenchyma (median: -709.8 HU) compared with deep inspiration (-794.8 HU). A positive correlation between attenuation of the PA and the ascending aorta was observed (r=0.40 to 0.56). CONCLUSIONS: Eliminating deep inspiration before image acquisition had opposite effects with the same magnitude: it caused a reduction in inadequate PA enhancement at the cost of an increased number of nondiagnostic lung images and did not compromise diagnostic consistency for PE. PMID- 24157624 TI - Altered activity of the primary visual area during gaze processing in individuals with high-functioning autistic spectrum disorder: a magnetoencephalography study. AB - BACKGROUND: Individuals with autistic spectrum disorder (ASD) demonstrate an impaired ability to infer the mental states of others from their gaze. Thus, investigating the relationship between ASD and eye gaze processing is crucial for understanding the neural basis of social impairments seen in individuals with ASD. In addition, characteristics of ASD are observed in more comprehensive visual perception tasks. These visual characteristics of ASD have been well explained in terms of the atypical relationship between high- and low-level gaze processing in ASD. METHOD: We studied neural activity during gaze processing in individuals with ASD using magnetoencephalography, with a focus on the relationship between high- and low-level gaze processing both temporally and spatially. Minimum Current Estimate analysis was applied to perform source analysis of magnetic responses to gaze stimuli. RESULTS: The source analysis showed that later activity in the primary visual area (V1) was affected by gaze direction only in the ASD group. Conversely, the right posterior superior temporal sulcus, which is a brain region that processes gaze as a social signal, in the typically developed group showed a tendency toward greater activation during direct compared with averted gaze processing. CONCLUSION: These results suggest that later activity in V1 relating to gaze processing is altered or possibly enhanced in high-functioning individuals with ASD, which may underpin the social cognitive impairments in these individuals. PMID- 24157625 TI - VO2 thermochromic smart window for energy savings and generation. AB - The ability to achieve energy saving in architectures and optimal solar energy utilisation affects the sustainable development of the human race. Traditional smart windows and solar cells cannot be combined into one device for energy saving and electricity generation. A VO2 film can respond to the environmental temperature to intelligently regulate infrared transmittance while maintaining visible transparency, and can be applied as a thermochromic smart window. Herein, we report for the first time a novel VO2-based smart window that partially utilises light scattering to solar cells around the glass panel for electricity generation. This smart window combines energy-saving and generation in one device, and offers potential to intelligently regulate and utilise solar radiation in an efficient manner. PMID- 24157626 TI - The therapeutic effects of human adipose-derived stem cells in Alzheimer's disease mouse models. AB - Alzheimer's disease (AD) is an irreversible neurodegenerative disease, still lacking proper clinical treatment. Therefore, many researchers have focused on the possibility of therapeutic use of stem cells for AD. Adipose-derived stem cells (ASCs), mesenchymal stem cells (MSCs) isolated from adipose tissue, are well known for their pluripotency and their ability to differentiate into multiple tissue types and have immune modulatory properties similar to those of MSCs from other origins. Because of their biological properties, ASCs can be considered for cell therapy and neuroregeneration. Our recent results clearly showed the therapeutic potential of these cells after transplantation into Tg2576 mice (an AD mouse model). Intravenously or intracerebrally transplanted human ASCs (hASCs) greatly improved the memory impairment and the neuropathology, suggesting that hASCs have a high therapeutic potential for AD. PMID- 24157627 TI - What silent mutations say about the human airways. AB - A technique for tracing stem cells and their descendants reveals how the lining of the airways is maintained, and how this process is altered in smokers. PMID- 24157628 TI - Porcine endogenous retrovirus infection changes the expression of inflammation related genes in lipopolysaccharide-stimulated human dermal fibroblasts. AB - BACKGROUND: The present study focuses on explaining the interaction between porcine endogenous retroviruses (PERVs) and human cells in inflammatory conditions. The differences in expression of selected inflammation-related genes in human dermal fibroblasts (NHDF) infected with PERVs with and without lipopolysaccharide stimulation were identified. MATERIAL AND METHODS: The PERV infectivity was analyzed using a co-culture of NHDF and PK15 cells. Quantification of PERV A, B DNA and PERV A, B RNA was performed by real-time QPCR and QRT-PCR. The analysis of the expression profile was performed using HG-U133A 2.0 oligonucleotide microarrays. RESULTS: PERV infection of NHDF cells with LPS stimulation resulted in a statistically significant decrease in the copy number of PERV A DNA, and an increase in the copy number of PERV A RNA compared to fibroblasts without stimulation. There was no statistically significant difference between the copy number of PERV B RNA of LPStreated and untreated NHDF cells. Typing of differentiation genes was performed in a panel of 571 selected transcripts of inflammation-related genes. Among all studied genes, 23 were differentially regulated with a change greater that 1.1-fold and p<0.05 in all studied groups. Of these 23 genes, 3 were found to be regulated by more than 2.0 fold at least in 2 studied groups (IL6, IL8, and IL33). CONCLUSIONS: The interaction between porcine endogenous retroviruses and human cells changes in inflammatory conditions. PERV infection of NHDF cells may alter the expression of inflammation-related genes. Further investigations concerning PERV infection of human cells in different conditions seem to be necessary. PMID- 24157629 TI - IgA deficiency and autoimmunity. AB - IgA is the most abundant immunoglobulin in the human body, and performs a very specialized role which involves mucosal immunity, development of tolerance and protection against infection. IgA is the key immunoglobulin in the respiratory and gastrointestinal tracts, which provide the most intimate interface between the environment and self. Normal levels of IgA are based on early studies consisting of only small numbers of patients. The international consensus definition of IgA deficiency is a level of 0.07g/l after the age of four years in the absence of IgG and IgM deficiencies. The epidemiology of IgA deficiency reveals interesting variances between geographical regions - the incidence in Caucasians being much higher than that in Asians. IgA deficiency has also been found to co-exist with autoimmune diseases, allergies and malignancies. The association with autoimmunity is particularly interesting because it suggests a common genetic linkage that could potentially also explain the diversity in geoepidemiology. Both MHC and non-MHC associations have been described and the 8.1 haplotype has been significantly associated with autoimmunity in IgA deficiency patients over controls. Non-MHC genetic associations include IFIH1 and CLEC16A. The mutations leading to IgA deficiency have not been defined, but in some cases of IgA deficiency it has been suggested that the pathogenesis involves a failure in switched memory B cells that can lead to this cohort experiencing an increased incidence of recurrent bacterial infections or autoimmune diseases. Attempts to investigate the role of cytokines that can induce IgA synthesis in cells of patients with IgA deficiency, such as IL21 or the combination of CD40L/anti-CD40, IL-4 and IL10, are underway. PMID- 24157630 TI - Tablet-based cardiac arrest documentation: a pilot study. AB - AIM: Conventional paper-based resuscitation transcripts are notoriously inaccurate, often lacking the precision that is necessary for recording a fast paced resuscitation. The aim of this study was to evaluate whether a tablet computer-based application could improve upon conventional practices for resuscitation documentation. METHODS: Nurses used either the conventional paper code sheet or a tablet application during simulated resuscitation events. Recorded events were compared to a gold standard record generated from video recordings of the simulations and a CPR-sensing defibrillator/monitor. Events compared included defibrillations, medication deliveries, and other interventions. RESULTS: During the study period, 199 unique interventions were observed in the gold standard record. Of these, 102 occurred during simulations recorded by the tablet application, 78 by the paper code sheet, and 19 during scenarios captured simultaneously by both documentation methods These occurred over 18 simulated resuscitation scenarios, in which 9 nurses participated. The tablet application had a mean sensitivity of 88.0% for all interventions, compared to 67.9% for the paper code sheet (P=0.001). The median time discrepancy was 3s for the tablet, and 77s for the paper code sheet when compared to the gold standard (P<0.001). CONCLUSIONS: Similar to prior studies, we found that conventional paper-based documentation practices are inaccurate, often misreporting intervention delivery times or missing their delivery entirely. However, our study also demonstrated that a tablet-based documentation method may represent a means to substantially improve resuscitation documentation quality, which could have implications for resuscitation quality improvement and research. PMID- 24157631 TI - Low-dose nitroglycerine improves outcome after cardiac arrest in rats. AB - OBJECTIVE: The aim of this study was to evaluate the outcome of intravenously applied nitroglycerine (NTG, 1MUgkg(-1)min(-1) for 1h) after resuscitation from an asphyxia cardiac arrest (ACA) insult. We hypothesized that NTG infused for 1h after the return of spontaneous circulation (ROSC) would improve functional and neuro-morphological outcomes. METHODS: Adult rats were subjected to 8min of ACA followed by resuscitation. There were three treatment groups: ACA, ACA+NTG and sham operated. Vital and blood parameters were monitored during the 1h post resuscitation intensive care phase. After survival times of 3, 6, 12, 24, 72h and 7 days, the neurological deficit score (NDS) was measured. Histological evaluation of the hippocampus, cortex, the thalamic reticular nucleus and the caudate-putamen was performed 7 days post insult. RESULTS: We found that NTG (i) induced significantly higher initial MAP peaks; (ii) resulted in a less pronounced elevation of heart rates after ROSC with significantly faster normalization to baseline levels; and (iii) influenced glucose metabolism, temporarily elevating blood glucose to non-physiological levels. Even so, NTG (iv) improved the neurological outcome and (v) reduced neurodegeneration, mainly in the hippocampal CA1 region. A significant NTG-associated decrease in blood pressure did not occur. CONCLUSION: The effect of low-dosed NTG applied post resuscitation appears to be neuroprotective, demonstrated by reduced hippocampal damage and a better NDS, even with temporarily elevated blood glucose to non physiological levels. Thus, additional studies are needed to evaluate NTG triggered mechanisms and optimized dosages before clinical translation should be considered. Animal study institutional protocol number: 42502-2-2-947-Uni-MD. PMID- 24157632 TI - Might the Bainbridge reflex have a role in resuscitation when chest compression is combined with passive leg raising? PMID- 24157633 TI - Contemplating cough and motility matters. PMID- 24157634 TI - Review of current diagnosis and management of diffuse esophageal spasm, nutcracker esophagus/spastic nutcracker and hypertensive lower esophageal sphincter. AB - PURPOSE OF REVIEW: To cover the diagnosis and management of diffuse esophageal spasm, nutcracker esophagus/spastic nutcracker and hypertensive lower esophageal sphincter. An outline of the presentation and manometric features of these conditions will precede a discussion of therapies. All of these diagnoses are made manometrically, even though they may be suspected by presentation and by findings at video fluoroscopic swallow or gastroscopy testing. RECENT FINDINGS: The advent of high-resolution manometry testing has allowed a better understanding of these motility disorders, and the ability to standardize the diagnoses by the use of the Chicago Classification is a major step forward. Recent developments show that botulinum toxin and perioral myotomy can be an effective treatment for some patients. This should bring more therapies to the fore in the future, but at present there is still the need for more prospective study of best therapies. SUMMARY: The important point to remember for all of these conditions is that unlike achalasia, there is no definite pathological correlation to the manometrically observed abnormalities. This therefore makes the management challenging and means that treatment pathways are not as well set out as for some other upper gastrointestinal motility problems. PMID- 24157635 TI - Chronic cough: a respiratory viewpoint. AB - PURPOSE OF REVIEW: This article reviews the common causes and investigation of chronic cough and explores unexplained cough and its relationship to cough hypersensitivity. RECENT FINDINGS: Cough plays a critical role in airway protection and clearance of secretions. Chronic cough, however, is a debilitating symptom that can significantly interfere with quality of life. Despite their limitations cough guidelines have raised the awareness of chronic cough as an important problem and provided a framework for a logical care pathway. The use of a systematic approach to diagnosis and management in a specialist clinic can result in successful identification as to the cause, with subsequent relief of symptoms. In a proportion of patients no diagnosis is reached or treatment fails. A common finding among these patients is cough reflex hypersensitivity and this is an important feature irrespective of the underlying diagnosis. The majority of patients referred to tertiary cough clinics are females. Women appear to have an intrinsically heightened cough response with augmented cough challenge and a high frequency of ACE-inhibitor cough. SUMMARY: The way in which we review cough has undergone radical change in the last decade. A distinct population of patients with chronic idiopathic cough is emerging in whom cough reflex hypersensitivity is a feature. Extended co-operation between clinicians, scientists and the pharmaceutical industry is required to better understand the pathophysiology of the enhanced cough reflex and the development of more effective antitussive therapies. PMID- 24157636 TI - Management of manifestations of epidermolysis bullosa. AB - PURPOSE OF REVIEW: Children with epidermolysis bullosa can present with disease(s) of the ears, nose, and throat, often related directly to the pathophysiology of their epidermolysis bullosa. Otolaryngologic diseases in children with epidermolysis bullosa have to be managed having a proper understanding of the diagnosis and pathophysiology of epidermolysis bullosa. The purpose of this review is to describe the current nomenclature and diagnostic algorithms for epidermolysis bullosa, and methods for the management of cutaneous and mucosal lesions. RECENT FINDINGS: Characterization of the gene defects leading to epidermolysis bullosa has allowed the utilization of immunofluorescent techniques as the primary method for epidermolysis bullosa diagnosis. Recognizing the difficulty in managing patients with epidermolysis bullosa, several multidisciplinary groups have developed guidelines using meta-analysis of the published literature, or expert panels. Though there are currently no effective treatment modalities for epidermolysis bullosa, techniques for gene and protein replacement show promising results for future use. SUMMARY: Currently, the management of cutaneous and mucosal disease in epidermolysis bullosa is based on the principles of prevention and wound care. Understanding the cause of epidermolysis bullosa types and subtypes, characteristics of skin and mucosal involvement, and prognosis will guide in the development of individualized treatment plans. PMID- 24157637 TI - Lymphatic malformations. AB - PURPOSE OF REVIEW: To update current knowledge of basic science and clinical care of lymphatic malformations. RECENT FINDINGS: Advances in gene sequencing methods have allowed further elucidation of the genetic pathways involved in vascular development. New cell culture techniques are promising the development of practical models to test novel therapeutic interventions. Clinical treatment trends are continuing to shift more away from early surgery and toward sclerotherapy in appropriate cases. New emphasis has been placed upon quality of life analysis of treatment outcomes. SUMMARY: Basic science is increasing the understanding of vascular anomalies in general and may lead us soon toward more effective nonsurgical therapies. Focus on quality of life measures will help to elucidate the most effective therapeutic interventions. PMID- 24157638 TI - Reliability and validity of nasality ratings between a monolingual and bilingual listener for speech samples from English-Spanish-Speaking children. AB - OBJECTIVE: This study sought to determine if a monolingual English listener could rate nasality in English and in Spanish with the same proficiency as a bilingual English-Spanish listener, and to compare nasalance scores with nasality ratings. PATIENTS AND METHODS: Speakers for this study were 26 bilingual English-Spanish speaking children. Speech samples and nasalance scores were obtained simultaneously as each speaker recited one English sentence and one Spanish sentence. A monolingual listener and a bilingual listener rated nasality. RESULTS: For the English sentences, the intrajudge correlation coefficient was r = 0.89 for the monolingual listener and r = 0.89 for the bilingual listener. For the Spanish sentences, the intrajudge correlation coefficient was r = 0.91 for the monolingual listener and r = 0.92 for the bilingual listener. Interjudge agreement was r = 0.86 for rating English sentences and r = 0.78 for rating Spanish sentences. All correlation coefficients were significant (p < 0.001). The correlation coefficients between nasality ratings and nasalance scores were essentially the same for both listeners and both languages. CONCLUSION: A monolingual and a bilingual judge had high agreement on ratings of nasality for English and Spanish speech. The relationship between nasalance and nasality was not different across languages. PMID- 24157639 TI - Many Indian HIV patients drop out of healthcare before they qualify for antiretrovirals, study finds. PMID- 24157640 TI - The saviour of Hunter's collection. PMID- 24157641 TI - Childhood mortality varies threefold across different UK local authorities, report shows. PMID- 24157642 TI - Concerns are raised over professors detained in Egypt since military coup. PMID- 24157643 TI - Affordable Care Act's lower than projected premiums will save $190bn more over decade, report says. PMID- 24157645 TI - Short to midterm clinical and radiographic outcomes of the Salto total ankle prosthesis. AB - BACKGROUND: Total ankle arthroplasty (TAA) has become an increasingly effective treatment option for tibiotalar arthritis. The purpose of this study was to evaluate the short to midterm clinical and radiographic outcomes of the Salto fixed bearing total ankle prosthesis. METHODS: We retrospectively reviewed the radiographs and patient records of 74 consecutive patients with 75 TAA implants from January 2007 to April 2011. The average age was 60.6 years (range, 41-82) with 41 females and 33 males. The average clinical follow-up was 43 months (range, 24-73 months). Radiographs were reviewed for areas of radiolucency and cystic changes around the talar and tibial implants, as well as for implant migration using standardized tibal, talar, talocalcaneal, and tibial slope angular measurements. The validated Foot and Ankle Outcome Score (FAOS), Short Form-12 (SF-12), and Visual Analog Scale (VAS) were used as subjective patient outcome measures. Kaplan Meier (K-M) curves were created for implant survivorship with revision of components as an endpoint and for return to the operating room for any reason. RESULTS: Total ankle survivorship was 98%. Thirteen patients returned to the operating room for any reason. There was 1 deep infection, and no ankles were converted to an arthrodesis. Average ankle dorsiflexion and plantarflexion improved from 4.3 +/- 3.3 to 8.7 +/- 5.6 degrees (P = .0008) and 24 +/- 11 to 29 +/- 7 degrees (P = .04), respectively. Patients showed significant improvements in all subscales of the FAOS (P < .0001). The physical component of the SF-12 significantly improved from 30 +/- 8 to 41 +/- 13 (P < .0001), but this was not observed with the mental component (52 +/- 1 vs 53 +/- 1, P = .55). The mean VAS for patient satisfaction was 9 (range, 2-10). Two patients had component migration (1 tibial and 1 talar component), neither of which required a revision procedure. Six ankles had a total of 9 radiolucent lines with a radiographically stable implant, and no patients had cystic changes. CONCLUSION: This is one of the first articles to report clinical and radiographic outcome data for the fixed bearing version of this prosthesis. We observed significant improvements in subjective outcome measures and range of motion with a 98% component survivorship at short to midterm follow-up. Longer follow-up will be necessary to determine the durability of this implant. LEVEL OF EVIDENCE: Level IV, case series. PMID- 24157647 TI - Glutathione transferases immobilized on nanoporous alumina: flow system kinetics, screening, and stability. AB - The previously uncharacterized Drosophila melanogaster Epsilon-class glutathione transferases E6 and E7 were immobilized on nanoporous alumina. The nanoporous anodized alumina membranes were derivatized with 3-aminopropyl-triethoxysilane, and the amino groups were activated with carbonyldiimidazole to allow coupling of the enzymes via epsilon-amino groups. Kinetic analyses of the immobilized enzymes were carried out in a circulating flow system using CDNB (1-chloro-2,4 dinitrobenzene) as substrate, followed by specificity screening with alternative substrates. A good correlation was observed between the substrate screening data for immobilized enzyme and corresponding data for the enzyme in solution. A limited kinetic study was also carried out on immobilized human GST S1-1 (also known as hematopoietic prostaglandin D synthase). The stability of the immobilized enzymes was virtually identical to that of enzymes in solution, and no leakage of enzyme from the matrix could be observed. PMID- 24157648 TI - 'Bucky gel' of multiwalled carbon nanotubes as electrodes for high performance, flexible electric double layer capacitors. AB - We report the preparation of a gelled form of multiwalled carbon nanotubes (MWCNTs) with an ionic liquid 1-butyl-1-methyl pyrrolidinium bis(trifluoromethane sulfonyl)imide (BMPTFSI)), referred to as 'bucky gel', to be used as binderless electrodes in electrical double layer capacitors (EDLCs). The characteristics of gelled MWCNTs are compared with pristine MWCNTs using transmission electron microscopy, x-ray diffraction and Raman studies. A gel polymer electrolyte film consisting of a blend of poly(vinylidene fluoride-co-hexafluoropropylene) and BMPTFSI, exhibiting a room temperature ionic conductivity of 1.5 * 10(-3) S cm( 1), shows its suitability as an electrolyte/separator in flexible EDLCs. The performance of EDLCs, assembled with bucky gel electrodes, using impedance spectroscopy, cyclic voltammetry and charge-discharge analyses, are compared with those fabricated with pristine MWCNT-electrodes. An improvement in specific capacitance (from 19.6 to 51.3 F g(-1)) is noted when pristine MWCNTs are replaced by gelled MWCNT-binderless electrodes. Although the rate performance of the EDLCs with gelled MWCNT-electrodes is reduced, the pulse power of the device is sufficiently high (~10.5 kW kg(-1)). The gelled electrodes offer improvements in energy and power densities from 2.8 to 8.0 Wh kg(-1) and 2.0 to 4.7 kW kg(-1), respectively. Studies indicate that the gel formation of MWCNTs with ionic liquid is an excellent route to obtain high-performance EDLCs. PMID- 24157646 TI - A high-throughput screen identifies miRNA inhibitors regulating lung cancer cell survival and response to paclitaxel. AB - microRNAs (miRNAs) are small RNAs endogenously expressed in multiple organisms that regulate gene expression largely by decreasing levels of target messenger RNAs (mRNAs). Over the past few years, numerous studies have demonstrated critical roles for miRNAs in the pathogenesis of many cancers, including lung cancer. Cellular miRNA levels can be easily manipulated, showing the promise of developing miRNA-targeted oligos as next-generation therapeutic agents. In a comprehensive effort to identify novel miRNA-based therapeutic agents for lung cancer treatment, we combined a high-throughput screening platform with a library of chemically synthesized miRNA inhibitors to systematically identify miRNA inhibitors that reduce lung cancer cell survival and those that sensitize cells to paclitaxel. By screening three lung cancer cell lines with different genetic backgrounds, we identified miRNA inhibitors that potentially have a universal cytotoxic effect on lung cancer cells and miRNA inhibitors that sensitize cells to paclitaxel treatment, suggesting the potential of developing these miRNA inhibitors as therapeutic agents for lung cancer. We then focused on characterizing the inhibitors of three miRNAs (miR-133a/b, miR-361-3p, and miR 346) that have the most potent effect on cell survival. We demonstrated that two of the miRNA inhibitors (miR-133a/b and miR-361-3p) decrease cell survival by activating caspase-3/7-dependent apoptotic pathways and inducing cell cycle arrest in S phase. Future studies are certainly needed to define the mechanisms by which the identified miRNA inhibitors regulate cell survival and drug response, and to explore the potential of translating the current findings into clinical applications. PMID- 24157649 TI - EHR-based medication support and nurse-led medication therapy management: rationale and design for a three-arm clinic randomized trial. AB - BACKGROUND: Patients with chronic conditions often use complex medical regimens. A nurse-led strategy to support medication therapy management incorporated into primary care teams may lead to improved use of medications for disease control. Electronic health record (EHR) tools may offer a lower-cost, less intensive approach to improving medication management. METHODS AND RESULTS: The Northwestern and Access Community Health Network Medication Education Study is a health center-level cluster-randomized trial being conducted within a network of federally qualified community health centers. Health centers have been enrolled in groups of 3 and randomized to (1) usual care, (2) EHR-based medication management tools alone, or (3) EHR tools plus nurse-led medication therapy management. Patients with uncontrolled hypertension who are prescribed >= 3 medications of any kind are recruited from the centers. EHR tools include a printed medication list to prompt review at each visit and automated plain language medication information within the after-visit summary to encourage proper medication use. In the nurse-led intervention, patients receive one-on-one counseling about their medication regimens to clarify medication discrepancies and identify drug-related concerns, safety issues, and nonadherence. Nurses also provide follow-up telephone calls following new prescriptions and periodically to perform medication review. The primary study outcome is systolic blood pressure after 1 year. Secondary outcomes include measures of understanding of dosing instructions, discrepancies between patient-reported medications and the medical record, adherence, and intervention costs. CONCLUSIONS: The Northwestern and Access Community Health Network Medication Education Study will assess the effects of 2 approaches to support outpatient medication management among patients with uncontrolled hypertension in federally qualified health center settings. PMID- 24157650 TI - Cardiovascular disease hospitalizations in relation to exposure to the September 11, 2001 World Trade Center disaster and posttraumatic stress disorder. AB - BACKGROUND: A cohort study found that 9/11-related environmental exposures and posttraumatic stress disorder increased self-reported cardiovascular disease risk. We attempted to replicate these findings using objectively defined cardiovascular disease hospitalizations in the same cohort. METHODS AND RESULTS: Data for adult World Trade Center Health Registry enrollees residing in New York State on enrollment and no cardiovascular disease history (n = 46,346) were linked to a New York State hospital discharge-reporting system. Follow-up began at Registry enrollment (2003-2004) and ended at the first cerebrovascular or heart disease (HD) hospitalization, death, or December 31, 2010, whichever was earliest. We used proportional hazards models to estimate adjusted hazard ratios (AHRs) for HD (n = 1151) and cerebrovascular disease (n = 284) hospitalization during 302,742 person-years of observation (mean follow-up, 6.5 years per person), accounting for other factors including age, race/ethnicity, smoking, and diabetes. An elevated risk of HD hospitalization was observed among women (AHR 1.32, 95% CI 1.01 to 1.71) but not men (AHR 1.16, 95% CI 0.97 to 1.40) with posttraumatic stress disorder at enrollment. A high overall level of World Trade Center rescue and recovery-related exposure was associated with an elevated HD hospitalization risk in men (AHR 1.82, 95% CI 1.06 to 3.13; P for trend = 0.05), but findings in women were inconclusive (AHR 3.29, 95% CI 0.85 to 12.69; P for trend = 0.09). Similar associations were observed specifically with coronary artery disease hospitalization. Posttraumatic stress disorder increased the cerebrovascular disease hospitalization risk in men but not in women. CONCLUSIONS: 9/11-related exposures and posttraumatic stress disorder appeared to increase the risk of subsequent hospitalization for HD and cerebrovascular disease. This is consistent with findings based on self-reported outcomes. PMID- 24157651 TI - Posttraumatic stress disorder and cardiometabolic disease. AB - The need for addressing posttraumatic stress disorder (PTSD) among combat veterans returning from Afghanistan and Iraq is a growing public health concern. Current PTSD management addresses psychiatric parameters of this condition. However, PTSD is not simply a psychiatric disorder. Traumatic stress increases the risk for inflammation-related somatic diseases and early mortality. The metabolic syndrome reflects the increased health risk associated with combat stress and PTSD. Obesity, dyslipidemia, hypertension, diabetes mellitus, and cardiovascular disease are prevalent among PTSD patients. However, there has been little appreciation for the need to address these somatic PTSD comorbidities. Medical professionals treating this vulnerable population should screen patients for cardiometabolic risk factors and avail themselves of existing preventive diet, exercise, and pharmacologic modalities that will reduce such risk factors and improve overall long-term health outcomes and quality of life. There is the promise that cardiometabolic preventive therapy complementing psychiatric intervention may, in turn, help improve the posttraumatic stress system dysregulation and favorably impact psychiatric and neurologic function. (c) 2013 S. Karger AG, Basel. PMID- 24157652 TI - Acute intracerebroventricular inositol does not reverse the effect of chronic lithium treatment in the forced swim test. AB - BACKGROUND: Lithium has numerous biochemical effects but it is difficult to dissect which of these is responsible for its therapeutic action in bipolar disorder. In the current study we aimed to address one of the major hypotheses, the inositol depletion hypothesis. This hypothesis postulates that lithium's mood stabilizing effect is mediated by the depletion of brain inositol levels and the subsequent effect on cellular signaling. METHODS: We studied whether acute intracerebroventricular (ICV) administration of myo-inositol could reverse the antidepressant-like effect of chronic lithium treatment in the forced swim test (FST). RESULTS: In contrast with our prediction, acute myo-inositol administration did not reverse the effect of chronic lithium to decrease immobility in the FST. CONCLUSIONS: The results of the present study are limited due to the following: (1) inositol was given acutely while possible events downstream of inositol depletion might require a longer period and (2) ICV inositol may not have reached those areas of the brain involved in the FST. PMID- 24157653 TI - EGG and acoustic analyses of different voice samples: comparison between perceptual evaluation and voice activity and participation profile. AB - OBJECTIVE: This study investigated whether different electroglottographic (EGG) parameters may be used to estimate voice quality and loading related to it, and whether voice quality is related to self-estimation of voice problems and laryngeal status. The effect of sample type was also considered. METHODS: EGG and acoustic signals of a sustained vowel [a:] (90 dB6 cm) and text reading during noise exposure were recorded from 93 female kindergarten teachers. Analyses were made from the sustained vowel and vowel [a:] from a stressed word. Contact quotient (CQ) was calculated. Maximum velocity of increase in contact area inferred from derivative (MDEGG) was examined. Fundamental frequency was calculated from the EGG signal. From the acoustic signal sound pressure level (SPL) was computed and pressedness in voice quality was evaluated perceptually. Self-evaluation was made with Voice Activity and Participation Profile (VAPP). Indirect laryngoscopy was also performed. RESULTS: Pressedness in voice correlated with EGG results only for the sustained vowel, and better with MDEGG than CQ values. VAPP and laryngeal evaluation did not correlate with the acoustic or EGG parameters or with perception. CONCLUSIONS: MDEGG is worth testing as an indicator of impact stress. Sustained vowel at a controlled SPL is more suitable for voice quality evaluation than a long stressed vowel from connected speech. PMID- 24157654 TI - Promoter methylation of CYP19A1 gene in Chinese polycystic ovary syndrome patients. AB - AIMS: This study aimed to examine the methylation status of the CYP19A1 promoter region in Chinese polycystic ovary syndrome (PCOS) patients. METHODS: A case control study was designed that involved 10 PCOS patients and 10 controls. Ovary tissues obtained from 10 women with PCOS and 10 healthy controls were matched for body mass index and age. Methylation of CYP19A1 promoter was detected by methylation-specific PCR. CYP19A1 expression was measured by real-time PCR and Western blotting. RESULTS: The methylation level of CYP19A1 promoter in PCOS samples was significantly higher than in controls (0.698 +/- 0.192 vs. 0.210 +/- 0.064, p < 0.01). A significant downregulation of CYP19A1 mRNA and protein expression levels was observed in PCOS ovary tissues. Furthermore, the scatter plot revealed that promoter methylation was inversely correlated with CYP19A1 mRNA level (Pearson's correlation -0.820, p < 0.01). CONCLUSION: CYP19A1 expression is frequently repressed in PCOS ovaries due to the promoter hypermethylation. CYP19A1 promoter hypermethylation may play a key role in the pathogenesis of PCOS. (c) 2013 S. Karger AG, Basel. PMID- 24157656 TI - Structure and RNA-binding properties of the type III-A CRISPR-associated protein Csm3. AB - The prokaryotic adaptive immune system is based on the incorporation of genome fragments of invading viral genetic elements into clusters of regulatory interspaced short palindromic repeats (CRISPRs). The CRISPR loci are transcribed and processed into crRNAs, which are then used to target the invading nucleic acid for degradation. The large family of CRISPR-associated (Cas) proteins mediates this interference response. We have characterized Methanopyrus kandleri Csm3, a protein of the type III-A CRISPR-Cas complex. The 2.4 A resolution crystal structure shows an elaborate four-domain fold organized around a core RRM like domain. The overall architecture highlights the structural homology to Cas7, the Cas protein that forms the backbone of type I interference complexes. Csm3 binds unstructured RNAs in a sequence non-specific manner, suggesting that it interacts with the variable spacer sequence of the crRNA. The structural and biochemical data provide insights into the similarities and differences in this group of Cas proteins. PMID- 24157658 TI - Global variation in elevational diversity patterns. AB - While horizontal gradients of biodiversity have been examined extensively in the past, vertical diversity gradients (elevation, water depth) are attracting increasing attention. We compiled data from 443 elevational gradients involving diverse organisms worldwide to investigate how elevational diversity patterns may vary between the Northern and Southern hemispheres and across latitudes. Our results show that most elevational diversity curves are positively skewed (maximum diversity below the middle of the gradient) and the elevation of the peak in diversity increases with the elevation of lower sampling limits and to a lesser extent with upper limit. Mountains with greater elevational extents, and taxonomic groups that are more inclusive, show proportionally more unimodal patterns whereas other ranges and taxa show highly variable gradients. The two hemispheres share some interesting similarities but also remarkable differences, likely reflecting differences in landmass and mountain configurations. Different taxonomic groups exhibit diversity peaks at different elevations, probably reflecting both physical and physiological constraints. PMID- 24157657 TI - There might be a role for CD200 in the pathogenesis of autoimmune and inflammatory skin disorders. AB - BACKGROUND: Soluble CD200 (sCD200) is a novel immuno-effective molecule, which acts to regulate inflammatory and acquired immune responses. Recently, our study group showed that sCD200 was present in serum and blister fluid in a patient with bullous pemphigoid and a patient with toxic epidermal necrolysis. We therefore planned this study to evaluate the sCD200 levels of autoimmune and inflammatory skin disorder patients and to compare them with that of healthy controls. MATERIAL/METHODS: Our study included 30 consecutive patients with psoriasis vulgaris, 15 with pemphigus vulgaris, and 15 healthy controls. Clinical examination and laboratory tests were performed on the same day. Psoriasis patients were also assessed with the Psoriasis Area and Severity Index (PASI) and pemphigus patients were assessed using the Pemphigus Disease Area Index (PDAI). Levels of sCD200 in the serum samples were quantified using ELISA kits. RESULTS: The serum sCD200 level was observed to be statistically significantly higher in patients with psoriasis vulgaris (96.7+/-15.8) compared to patients with pemphigus vulgaris (76.2+/-14.6), (p<0.001) and healthy controls (26.8+/-7.0) (p<0.001). The serum sCD200 levels were observed to be statistically significantly higher in patients with pemphigus vulgaris compared with that in healthy controls (p<0.001). In addition, there was a statistically significant correlation between serum sCD200 levels and PDAI (r=0.987, p=0.001). Nevertheless, there was no statistically significant correlation between serum sCD200 levels and PASI (r=0.154, p=0.407). CONCLUSIONS: sCD200 might play a role in immune response in the pathogenesis of autoimmune and inflammatory skin disorders. However, it remains to be fully elucidated how sCD200 can orchestrate inflammatory response in psoriasis and pemphigus. PMID- 24157655 TI - Avian circadian organization: a chorus of clocks. AB - In birds, biological clock function pervades all aspects of biology, controlling daily changes in sleep: wake, visual function, song, migratory patterns and orientation, as well as seasonal patterns of reproduction, song and migration. The molecular bases for circadian clocks are highly conserved, and it is likely the avian molecular mechanisms are similar to those expressed in mammals, including humans. The central pacemakers in the avian pineal gland, retinae and SCN dynamically interact to maintain stable phase relationships and then influence downstream rhythms through entrainment of peripheral oscillators in the brain controlling behavior and peripheral tissues. Birds represent an excellent model for the role played by biological clocks in human neurobiology; unlike most rodent models, they are diurnal, they exhibit cognitively complex social interactions, and their circadian clocks are more sensitive to the hormone melatonin than are those of nocturnal rodents. PMID- 24157660 TI - Molecular switches from benzene derivatives adsorbed on metal surfaces. AB - Transient precursor states are often experimentally observed for molecules adsorbing on surfaces. However, such precursor states are typically rather short lived, quickly yielding to more stable adsorption configurations. Here we employ first-principles calculations to systematically explore the interaction mechanism for benzene derivatives on metal surfaces, enabling us to selectively tune the stability and the barrier between two metastable adsorption states. In particular, in the case of the tetrachloropyrazine molecule, two equally stable adsorption states are identified with a moderate and conceivably reversible barrier between them. We address the feasibility of experimentally detecting the predicted bistable behaviour and discuss its potential usefulness in a molecular switch. PMID- 24157659 TI - Recombinant anti-monkey CD3 immunotoxin depletes peripheral lymph node T lymphocytes more effectively than rabbit anti-thymocyte globulin in naive baboons. AB - T cell depletion is an important procedure for both experimental and therapeutic immune modulation. Rabbit anti-thymocyte globulin (ATG), which is a commonly used T cell depletion antibody in clinical organ and cell transplantation protocols, is effective in temporarily depleting peripheral blood T lymphocytes but only moderately effective in depleting peripheral lymph node T cells which comprise the majority of T lymphocytes. A recombinant anti-CD3 immunotoxin, A-dmDT390 scfbDb (C207), has been developed and shown in an initial study to retain the lymph node depleting properties of conjugated CD3 immunotoxin. This agent could potentially be used synergistically with or as a replacement for rabbit ATG in preclinical primate models of transplantation. We directly compared the peripheral blood and lymph node depleting abilities of this recombinant anti-CD3 immunotoxin and rabbit ATG in naive animals at clinically tolerated doses. Baboons were treated with a full course of either rabbit ATG (n=2) or CD3 immunotoxin (n=3). Peripheral blood and lymph node T lymphocytes were measured before and following treatment. Peripheral blood CD3+ cells fell below 100cells/MUL in every animal. In the two animals receiving ATG, CD3+ cells represented 53% and 68% of lymph node cells two days following a full course of rabbit ATG. In contrast, CD3+ cells represented 3%, 5%, and 38% in lymph nodes following a full course of CD3-IT. Thus, recombinant anti-monkey CD3 immunotoxin showed improved peripheral lymph node T lymphocyte depletion to rabbit ATG and spared other immune cells. PMID- 24157662 TI - Structural and thermodynamic studies of two centrin isoforms from Blastocladiella emersonii upon calcium binding. AB - Centrins are calcium-binding proteins associated with microtubules organizing centers. Members of two divergent subfamilies of centrins were found in the aquatic fungus Blastocladiella emersonii, contrasting with the occurrence of only one member known for the better explored terrestrial fungi. BeCen1 shows greatest identity with human centrins HsCen1, HsCen2 and green algae centrin CrCenp, while BeCen3 records largest identity with human centrin HsCen3 and yeast centrin Cdc31p. Following the discovery of this unique feature, BeCen1 and BeCen3 centrins were produced to study whether these proteins had distinct features upon calcium binding. Circular dichroism showed opposite calcium binding effects on the alpha-helix arrangement of the secondary structure. The spectra indicated a decrease in alpha-helix signal for holo-BeCen1 contrasting with an increase for holo-BeCen3. In addition, only BeCen1 refolds after being de-natured. The fluorescence emission of the hydrophobic probe ANS increases for both proteins likely due to hydrophobic exposure, however, only BeCen1 presents a clear blue shift when calcium is added. ITC experiments identified four calcium binding sites for both proteins. In contrast to calcium binding to BeCen1, which is mainly endothermic, binding to BeCen3 is mainly exothermic. Light-scattering evidenced the formation of large particles in solution for BeCen1 and BeCen3 at temperatures above 30 degrees C and 40 degrees C, respectively. Atomic force microscopy confirmed the presence of supramolecular structures, which differ in the compactness and branching degree. Binding of calcium leads to different structural changes in BeCen1 and BeCen3 and the thermodynamic characteristics of the interaction also differ. PMID- 24157666 TI - Changing of the guard: new nurse administrators take the helm. PMID- 24157661 TI - Role of the ubiquitin-proteasome system in brain ischemia: friend or foe? AB - The ubiquitin-proteasome system (UPS) is a catalytic machinery that targets numerous cellular proteins for degradation, thus being essential to control a wide range of basic cellular processes and cell survival. Degradation of intracellular proteins via the UPS is a tightly regulated process initiated by tagging a target protein with a specific ubiquitin chain. Neurons are particularly vulnerable to any change in protein composition, and therefore the UPS is a key regulator of neuronal physiology. Alterations in UPS activity may induce pathological responses, ultimately leading to neuronal cell death. Brain ischemia triggers a complex series of biochemical and molecular mechanisms, such as an inflammatory response, an exacerbated production of misfolded and oxidized proteins, due to oxidative stress, and the breakdown of cellular integrity mainly mediated by excitotoxic glutamatergic signaling. Brain ischemia also damages protein degradation pathways which, together with the overproduction of damaged proteins and consequent upregulation of ubiquitin-conjugated proteins, contribute to the accumulation of ubiquitin-containing proteinaceous deposits. Despite recent advances, the factors leading to deposition of such aggregates after cerebral ischemic injury remain poorly understood. This review discusses the current knowledge on the role of the UPS in brain function and the molecular mechanisms contributing to UPS dysfunction in brain ischemia with consequent accumulation of ubiquitin-containing proteins. Chemical inhibitors of the proteasome and small molecule inhibitors of deubiquitinating enzymes, which promote the degradation of proteins by the proteasome, were both shown to provide neuroprotection in brain ischemia, and this apparent contradiction is also discussed in this review. PMID- 24157667 TI - Thoughts regarding innovations in nursing education, part 2. AB - Many new nursing leaders assuming deanships or assistant or interim deanships have limited education, experience, or background to prepare them for the job. To assist new deans and those aspiring to be deans, the authors of this department offer survival tips based on their personal experiences and insights. They address common issues, challenges, and opportunities that face academic executive teams, such as negotiating an executive contract, obtaining faculty lines, building effective work teams, managing difficult employees, and creating nimble organizational structure to respond to changing consumer, healthcare delivery, and community needs. The authors welcome counterpoint discussions with readers. PMID- 24157668 TI - Igniting interest in learning theory. PMID- 24157669 TI - Creating a new view of aging. PMID- 24157671 TI - Unfolding multicourse case study: developing students' administrative competencies. AB - Providing students with learning opportunities that integrate disparate data into meaningful constructs can be a challenge for faculty. The author discusses an unfolding case study that provided simulated learning opportunities related to administrative student competencies, staged to increase in complexity and scope over time while affording multiple student evaluation opportunities. A hybrid delivery format was used, including Blackboard Learn e-technology, to support individual student assignments and small group collaboration, cloud technology for shared student document development, Excel budget manipulation, and face-to face classroom interactions. PMID- 24157670 TI - Using film, television, and other media to teach management and leadership concepts. PMID- 24157672 TI - Developing a sense of community among nursing students. AB - For beginning students, becoming a member of the nursing profession starts with experiences in nursing school. Better understanding of the experiences that contribute to sense of community for students can guide faculty efforts and curricular decisions. Using the sense of community model as a framework, the authors assessed the influence of a freshman-level class and other leadership and student organization experiences on the students' perceptions of the school of nursing as community. The authors discuss the study and its outcomes. PMID- 24157673 TI - Developing scholarly thinking using mind maps in graduate nursing education. AB - Two broad issues that beginning graduate nursing students face are identifying a research focus and learning how to organize complex information. Developing a mind map is 1 strategy to help students clarify their thinking and lay the foundation for in-depth expertise related to their research focus, review of the literature, and conceptual framework. The authors discuss their use of mind mapping combined with feedback using a fishbowl technique. PMID- 24157674 TI - Assessing and maintaining quality and rigor in an online DNP program. AB - Although the number and diversity of online programs in graduate nursing education have proliferated, they have often outpaced the development of evaluation methods to ensure the quality of those offerings. Questions surrounding rigor remain, particularly with postmaster's programs and students without advanced practice degrees. In this article, the authors explore the issue of rigor and describe some methods used to ensure rigor in a new DNP program conveyed to an online audience. PMID- 24157675 TI - Implementation of an interprofessional educational model. AB - Despite literature that supports the benefits of interprofessional collaboration among healthcare practitioners, such as better patient outcomes and more efficient use of resources, many education programs continue to educate in silos, leading to a lack of awareness of the role of other disciplines. The nurse practitioner role, as example, requires positive collaboration with other healthcare providers, including physicians. The authors describe the development, implementation, and evaluation of an innovative interprofessional clinical educational model that was integrated into a nurse practitioner curriculum, as well as lessons learned during the first 2 years this program has been in place. PMID- 24157676 TI - Effectiveness of a reference accuracy strategy for peer-reviewed journal articles. AB - Dissemination of information through peer-reviewed journal articles is an important requirement of success in academia. Despite the importance of publishing articles, about 25% to 45% of articles published in nursing journals have at least 1 reference error in the reference list. The authors discuss the implementation and outcomes of an internal copyeditor strategy aimed at reducing reference inaccuracy in faculty-authored journal articles. PMID- 24157677 TI - Weaving the tapestry of learning: simulation, standardized patients, and virtual communities. AB - Using situated cognition learning theory, nursing faculty developed simulated clinical learning experiences integrating virtual communities and standardized patients. These learning experiences provide authenticity and realism not easily achieved using the individual techniques in isolation. The authors describe the process of weaving these strategies into a rich learning experience for students. PMID- 24157679 TI - Association of anthropometric measures with cardiovascular risk factors and metabolic syndrome in normal-weight children and adolescents: the CASPIAN III study. AB - OBJECTIVE: This nationwide study was conducted to determine the association of anthropometric measures with cardiovascular risk factors and metabolic syndrome (MetS) in Iranian normal-weight children and adolescents. METHODS: We analyzed the data of 3,565 children and adolescents (50.3% boys), aged 10-18 years, with a normal BMI (5th-84th percentile) obtained from the third survey of 'Childhood and Adolescence Surveillance and Prevention of Adult Non-communicable Disease' (CASPIAN III) study. The diagnostic criteria for MetS were defined by the International Diabetes Federation consensus. RESULTS: The prevalence of MetS for 10- to 13.9-year-old boys, 14- to 18-year-old boys, 10- to 13.9-year-old girls, and 14- to 18-year-old girls were 1.4, 2.8, 2.3, and 3.3%, respectively. After adjustment for age and sex, each unit increase in BMI (within normal range) and waist circumference increased the odds of MetS from 6 to 72% and from 1 to 20%, respectively. The dominant pattern of dyslipidemia among the participants was high triglycerides and low high-density lipoprotein cholesterol. CONCLUSION: This study complements recent research about the high frequency of metabolic risk factors among normal-weight individuals in the pediatric age group. PMID- 24157680 TI - Is biomass fractionation by Organosolv-like processes economically viable? A conceptual design study. AB - In this work, the conceptual designs of the established Organosolv process and a novel biphasic, so-called Organocat process are developed and analyzed. Solvent recycling and energy integration are emphasized to properly assess economic viability. Both processes show a similar energy consumption (approximately 5 MJ/kg(dry biomass)). However, they still show a lack of economic attractiveness even at larger scale. The Organocat process is more favorable due to more efficient lignin separation. The analysis uncovers the remaining challenges toward an economically viable design. They largely originate from by-products formation, product isolation, and solvent recycling. Necessary improvements in process chemistry, equipment design, energy efficiency and process design are discussed to establish economically attractive Organosolv-like processes of moderate capacity as a building block of a future biorefinery. PMID- 24157681 TI - Chemical and morphological changes in hydrochars derived from microcrystalline cellulose and investigated by chromatographic, spectroscopic and adsorption techniques. AB - Hydrothermal carbonization (HTC) can be used for converting the biomass into a carbon-rich material, whose application as a fuel requires higher heating value, whereas soil amendment needs stable carbon. This work was focused on the characterization of hydrochars derived from microcrystalline cellulose. The chars were investigated using elemental analysis, Brunauer-Emmett-Teller technique, nuclear magnetic resonance spectroscopy, Raman, Fourier transform infrared, and electron spin resonance spectroscopy. Severity in temperature between 230 and 270 degrees C with reaction times between 2 and 10 h only affect the carbon content moderately. The results show that aromatization of HTC chars correlates well with temperature, which was further supported by the increase of organic radicals with decreasing g values at higher temperatures. Based on these results, the energetic use of chars favors mild HTC (T<230 degrees C and t<=6 h), while the soil amendement favors serve conditions (T>=230 degrees C, and t>6 h). PMID- 24157682 TI - Enzymatic hydrolysis and production of bioethanol from common macrophytic green alga Ulva fasciata Delile. AB - The green seaweed Ulva which proliferates fast and occurs abundantly worldwide was used as a feedstock for production of ethanol following enzymatic hydrolysis. Among the different cellulases investigated for efficient saccharification, cellulase 22119 showed the highest conversion efficiency of biomass into reducing sugars than Viscozyme L, Cellulase 22086 and 22128. Pre-heat treatment of biomass in aqueous medium at 120 degrees C for 1h followed by incubation in 2% (v/v) enzyme for 36 h at 45 degrees C gave a maximum yield of sugar 206.82+/-14.96 mg/g. The fermentation of hydrolysate gave ethanol yield of 0.45 g/g reducing sugar accounting for 88.2% conversion efficiency. These values are substantially higher than those of reported so far for both agarophytes and carrageenophytes. It was also confirmed that enzyme can be used twice without compromising on the saccharification efficiency. The findings of this study reveal that Ulva can be a potential feedstock for bioethanol production. PMID- 24157683 TI - Autotrophic nitrogen removal from domestic sewage in MBR-CANON system and the biodiversity of functional microbes. AB - The feasibility of completely autotrophic nitrogen removal over nitrite (CANON) process for treating domestic sewage was investigated in membrane bioreactor (MBR), for which conventional activated sludge was seeded at ambient temperature. By gradually decreasing hydraulic retention time under the oxygen-limited condition, CANON was successfully started-up for 78 days. Finally the MBR-CANON system was adopted for treating domestic sewage, nitrogen and COD removal achieved to 0.97 kg m(-3) d(-1), 80%, respectively, with the effluent turbidity below 1.0 NTU. DGGE profiles showed a distinct community shift of the functional bacteria after seeded to the reactor, and phylogenetic results indicated the predominance of Nitrosomonas and Candidatus Kuenenia stuttgartiensis for nitrogen removal in the reactor. FISH results showed the predominance of aerobic ammonia oxidizing bacteria (AerAOB) and anaerobic ammonia oxidizing bacteria (AnAOB) in the system, both of whose proportion reduced when treated domestic sewage. PMID- 24157684 TI - Emergency and trauma care in Pakistan: a cross-sectional study of healthcare levels. AB - BACKGROUND: The importance of emergency medical care for the successful functioning of health systems has been increasingly recognised. This study aimed to evaluate emergency and trauma care facilities in four districts of the province of Sindh, Pakistan. METHOD: We conducted a cross-sectional health facility survey in four districts of the province of Sindh in Pakistan using a modified version of WHO's Guidelines for essential trauma care. 93 public health facilities (81 primary care facilities, nine secondary care hospitals, three tertiary hospitals) and 12 large private hospitals were surveyed. Interviews of healthcare providers and visual inspections of essential equipment and supplies as per guidelines were performed. A total of 141 physicians providing various levels of care were tested for their knowledge of basic emergency care using a validated instrument. RESULTS: Only 4 (44%) public secondary, 3 (25%) private secondary hospitals and all three tertiary care hospitals had designated emergency rooms. The majority of primary care health facilities had less than 60% of all essential equipments overall. Most of the secondary level public hospitals (78%) had less than 60% of essential equipments, and none had 80% or more. A fourth of private secondary care facilities and all tertiary care hospitals (n=3; 100%) had 80% or more essential equipments. The average percentage score on the physician knowledge test was 30%. None of the physicians scored above 60% correct responses. CONCLUSIONS: The study findings demonstrated a gap in both essential equipment and provider knowledge necessary for effective emergency and trauma care. PMID- 24157685 TI - Failure of fourth-generation enzyme immunoassay in HIV screening and plasma HIV-1 RNA detection in recent high-risk behavior. AB - Acute HIV infection was not detected in a young man presenting symptoms of sexual disease infection using fourth-generation screening tests combining HIV-specific antibody and p24 antigen. Detection of plasma HIV-1 RNA concomitant with screening tests may be proposed in individuals presenting with a symptomatic sexually transmitted infection. PMID- 24157686 TI - Atomic-layer triangular WSe2 sheets: synthesis and layer-dependent photoluminescence property. AB - The exotic band structures and distinctive physical properties of two-dimensional materials have exhibited great potential for fundamental research and technical applications in spintronics, electronics, photonics, optoelectronics, and so forth. Facing the challenge of effective synthesis of WSe2 two-dimensional sheets, for the first time we demonstrate a straightforward catalyst-free vapor solid (VS) growth method to synthesize ultrathin, even monolayer, WSe2 sheets with high yield, regular shapes and high quality optical properties on sapphire substrates. By detailed layer-number-dependent photoluminescence measurements at a low temperature of 40 K, we find the spin-orbit splitting at the K point of the WSe2 valence band with a fixed energy difference of 0.36 eV independent of layer number and the transition of indirect-to-direct gap when the thickness decreases to monolayer. These results, comparable to those of mechanically peeled WSe2 sheets, further prove the high optical and crystal quality of our WSe2 nanosheets via the VS growth approach. Our efforts may open up new exciting opportunities in future valley-based electronics, optoelectronics and photonics. PMID- 24157687 TI - Antipsychotic discontinuation in patients with dementia: a systematic review and meta-analysis of published randomized controlled studies. AB - BACKGROUND: There is a lack of clarity in the literature on the impact of antipsychotic discontinuation in dementia. METHOD: We conducted a systematic review and meta-analysis of published randomized controlled studies comparing the effects of antipsychotic discontinuation versus continuation in dementia. MEDLINE, EMBASE, PsycInfo, Cochrane Library and CINAHL were searched. Severity change of behavioral and psychological symptoms of dementia (BPSD) was the primary outcome. RESULTS: Ten studies were included in the systematic review and 9 studies in the meta-analysis. The results showed that the antipsychotic discontinuation group had no statistically significant difference in BPSD severity change compared to the continuation group (n = 214, standardized mean difference: 0.19, 95% CI: -0.20 to 0.58). Secondary outcome analyses revealed that the discontinuation group included a statistically significantly higher proportion of subjects whose BPSD severity worsened (n = 366, risk ratio: 1.78, 95% CI: 1.31-2.41). Although not statistically significant, the discontinuation group appeared to have higher early study termination rates and a lower mortality during follow-up. CONCLUSIONS: This meta-analysis showed that antipsychotic discontinuation resulted in no statistically significant difference in BPSD severity change, early study terminations and mortality. However, a statistically significantly higher proportion of subjects with BPSD worsened in this group compared to the continuation group. Further studies are needed to explore the effects of antipsychotic discontinuation on BPSD. (c) 2013 S. Karger AG, Basel. PMID- 24157688 TI - Identification of a treatment-resistant, ketamine-sensitive genetic line in the chick anxiety-depression model. AB - The introduction of pharmacotherapies for treatment-resistant depression is hindered by translational challenges with existing preclinical screening models that fail to adequately model the clinical features of this syndrome. This research sought to screen antidepressants in two selected genetic lines previously identified as stress-vulnerable and -resilient in the chick anxiety depression model. Separate groups of socially-raised 5-6 day-old Black Australorps (stress-vulnerable) and Production Reds (stress-resilient) were administered imipramine (0-20 mg/kg), fluoxetine (0-10 mg/kg), maprotiline (0-10 mg/kg) or ketamine 0-15 mg/kg) IP (1 ml/kg) and placed into isolation for 90 min. Distress vocalizations (DVoc) were recorded. Onset of behavioral despair and Dvoc rates during the depression-like phase (30-90 min) were calculated. Black Australorps entered behavioral despair approximately 25% faster than Productions Reds highlighting stress-vulnerability in this Black Australorp line. In the depression-like phase, Black Australorps were insensitive to imipramine and fluoxetine but sensitive to ketamine, a finding that parallels stress-vulnerable, treatment resistant depressive disorder. The chick anxiety-depression model using the Black Australorp line may prove useful in pre-clinical screening of novel antidepressant targets for use in treatment-resistant depression. PMID- 24157689 TI - Intestinal selenoprotein P in epithelial cells and in plasma cells. AB - The micronutrient selenium and selenium-containing selenoproteins are involved in prevention of inflammation and carcinogenesis in the gut. Selenoprotein P (Sepp1), the plasma selenium transport protein, is secreted primarily from hepatocytes, but Sepp1 mRNA is also abundant in the intestine. By immunofluorescence analysis, we show that Sepp1 levels in epithelial cells of the rat jejunum increase along the crypt-to-villus axis. A different Sepp1 distribution pattern was observed in the rat colon, where the epithelial cells located at the base and at the top of the crypts were similarly positive for Sepp1. In addition, we found pronounced Sepp1 immunoreactivity in CD138-positive plasma cells scattered within the lamina propria of the colon. This hitherto unrecognized presence in terminally differentiated B-cells was corroborated by detection of Sepp1 in plasma cells residing in the rat spleen. Following supplementation with dietary selenium compounds, polarized intestinal epithelial Caco-2 cells secreted Sepp1 into the culture medium across the basolateral membrane. Our data suggest that Sepp1 secreted from epithelial cells may support the intestinal immune system by providing immune cells (including plasma cells) with selenium for the biosynthesis of endogenous selenoproteins. PMID- 24157690 TI - A light-activated NO donor attenuates anchorage independent growth of cancer cells: Important role of a cross talk between NO and other reactive oxygen species. AB - It is established that high concentrations of nitric oxide(1) (NO), as released from activated macrophages, induce apoptosis in breast cancer cells. In this study, we assessed the potential of a light-activated NO donor [(Me2bpb)Ru(NO)(Resf)], a recently reported apoptototic agent, in suppressing the anchorage independent growth potentials of an aggressive human breast cancer cell line. Our results demonstrated the down regulation of anchorage independent growth by light activated NO treatment in the aggressive human breast cancer cell line MDA-MB-231 and afforded insight into the associated mechanism(s). The investigation revealed an up-regulation of the bioactivity of catalase with an accompanied reduction in the endogenous levels of H2O2, a direct substrate of catalase and a recently identified endogenous growth modulator in breast cancer cells. An earlier publication reported that endogenous superoxide (O2(-)) in human breast cancer cells constitutively inhibits catalase bioactivity (at the level of its protein), resulting in increased H2O2 levels. Interestingly in this study, O2(-) was also found to be down- regulated following NO treatment providing a basis for the observed increase in catalase bioactivity. Cells silenced for the catalase gene exhibited compromised reduction in anchorage independent growth upon light activated NO treatment. Collectively this study detailed a mechanistic cross talk between exogenous NO and endogenous ROS in attenuating anchorage independent growth. PMID- 24157692 TI - Controlling the influence of Auger recombination on the performance of quantum dot light-emitting diodes. AB - Development of light-emitting diodes (LEDs) based on colloidal quantum dots is driven by attractive properties of these fluorophores such as spectrally narrow, tunable emission and facile processibility via solution-based methods. A current obstacle towards improved LED performance is an incomplete understanding of the roles of extrinsic factors, such as non-radiative recombination at surface defects, versus intrinsic processes, such as multicarrier Auger recombination or electron-hole separation due to applied electric field. Here we address this problem with studies that correlate the excited state dynamics of structurally engineered quantum dots with their emissive performance within LEDs. We find that because of significant charging of quantum dots with extra electrons, Auger recombination greatly impacts both LED efficiency and the onset of efficiency roll-off at high currents. Further, we demonstrate two specific approaches for mitigating this problem using heterostructured quantum dots, either by suppressing Auger decay through the introduction of an intermediate alloyed layer, or by using an additional shell that impedes electron transfer into the quantum dot to help balance electron and hole injection. PMID- 24157691 TI - Novel SCN3A variants associated with focal epilepsy in children. AB - Voltage-gated sodium (NaV) channels are essential for initiating and propagating action potentials in the brain. More than 800 mutations in genes encoding neuronal NaV channels including SCN1A and SCN2A have been associated with human epilepsy. Only one epilepsy-associated mutation has been identified in SCN3A encoding the NaV1.3 neuronal sodium channel. We performed a genetic screen of pediatric patients with focal epilepsy of unknown cause and identified four novel SCN3A missense variants: R357Q, D766N, E1111K and M1323V. We determined the functional consequences of these variants along with the previously reported K354Q mutation using heterologously expressed human NaV1.3. Functional defects were heterogeneous among the variants. The most severely affected was R357Q, which had a significantly smaller current density and slower activation than the wild-type (WT) channel as well as depolarized voltage dependences of activation and inactivation. Also notable was E1111K, which evoked a significantly greater level of persistent sodium current than WT channels. Interestingly, a common feature shared by all variant channels was increased current activation in response to depolarizing voltage ramps revealing a functional property consistent with conferring neuronal hyper-excitability. Discovery of a common biophysical defect among variants identified in unrelated pediatric epilepsy patients suggests that SCN3A may contribute to neuronal hyperexcitability and epilepsy. PMID- 24157694 TI - Tunable hydrogel composite with two-step processing in combination with innovative hardware upgrade for cell-based three-dimensional bioprinting. AB - Three-dimensional (3-D) bioprinting is the layer-by-layer deposition of biological material with the aim of achieving stable 3-D constructs for application in tissue engineering. It is a powerful tool for the spatially directed placement of multiple materials and/or cells within the 3-D sample. Encapsulated cells are protected by the bioink during the printing process. Very few materials are available that fulfill requirements for bioprinting as well as provide adequate properties for cell encapsulation during and after the printing process. A hydrogel composite including alginate and gelatin precursors was tuned with different concentrations of hydroxyapatite (HA) and characterized in terms of rheology, swelling behavior and mechanical properties to assess the versatility of the system. Instantaneous as well as long-term structural integrity of the printed hydrogel was achieved with a two-step mechanism combining the thermosensitive properties of gelatin with chemical crosslinking of alginate. Novel syringe tip heaters were developed for improved temperature control of the bioink to avoid clogging. Human mesenchymal stem cells mixed into the hydrogel precursor survived the printing process and showed high cell viability of 85% living cells after 3 days of subsequent in vitro culture. HA enabled the visualization of the printed structures with micro-computed tomography. The inclusion of HA also favors the use of the bioink for bone tissue engineering applications. By adding factors other than HA, the composite could be used as a bioink for applications in drug delivery, microsphere deposition or soft tissue engineering. PMID- 24157693 TI - Tunable drug-loading capability of chitosan hydrogels with varied network architectures. AB - Advanced bioactive systems with defined macroscopic properties and spatio temporal sequestration of extracellular biomacromolecules are highly desirable for next generation therapeutics. Here, chitosan (CT) hydrogels were prepared with neutral or negatively charged cross-linkers in order to promote selective electrostatic complexation with charged drugs. CT was functionalized with varied dicarboxylic acids, such as tartaric acid, poly(ethylene glycol) bis(carboxymethyl) ether, 1,4-phenylenediacetic acid and 5-sulfoisophthalic acid monosodium salt (PhS), whereby PhS was hypothesized to act as a simple mimetic of heparin. Attenuated total reflectance Fourier transform infrared spectroscopy showed the presence of CO amide I, N-H amide II and CO ester bands, providing evidence of covalent network formation. The cross-linker content was reversely quantified by proton nuclear magnetic resonance on partially degraded network oligomers, so that 18 mol.% PhS was exemplarily determined. Swellability (SR: 299 +/- 65-1054 +/- 121 wt.%), compressibility (E: 2.1 +/- 0.9-9.2 +/- 2.3 kPa), material morphology and drug-loading capability were successfully adjusted based on the selected network architecture. Here, hydrogel incubation with model drugs of varied electrostatic charge, i.e. allura red (AR, doubly negatively charged), methyl orange (MO, negatively charged) or methylene blue (MB, positively charged), resulted in direct hydrogel-dye electrostatic complexation. Importantly, the cationic compound, MB, showed different incorporation behaviours, depending on the electrostatic character of the selected cross linker. In light of this tunable drug-loading capability, these CT hydrogels would be highly attractive as drug reservoirs towards e.g. the fabrication of tissue models in vitro. PMID- 24157696 TI - Provisional CDC guidelines for the use and safety monitoring of bedaquiline fumarate (Sirturo) for the treatment of multidrug-resistant tuberculosis. AB - Multidrug-resistant tuberculosis (MDR TB) is caused by Mycobacterium tuberculosis that is resistant to at least isoniazid and rifampin, the two most effective of the four first-line TB drugs (the other two drugs being ethambutol and pyrazinamide). MDR TB includes the subcategory of extensively drug-resistant TB (XDR TB), which is MDR TB with additional resistance to any fluoroquinolone and to at least one of three injectable anti-TB drugs (i.e., kanamycin, capreomycin, or amikacin). MDR TB is difficult to cure, requiring 18-24 months of treatment after sputum culture conversion with a regimen that consists of four to six medications with toxic side effects, and carries a mortality risk greater than that of drug-susceptible TB. Bedaquiline fumarate (Sirturo or bedaquiline) is an oral diarylquinoline. On December 28, 2012, on the basis of data from two Phase IIb trials (i.e., well-controlled trials to evaluate the efficacy and safety of drugs in patients with a disease or condition to be treated, diagnosed, or prevented), the Food and Drug Administration (FDA) approved use of bedaquiline under the provisions of the accelerated approval regulations for "serious or life threatening illnesses" (21CFR314.500) (Cox EM. FDA accelerated approval letter to Janssen Research and Development. Available at http://www.accessdata.fda.gov/drugsatfda_docs/appletter/2012/204384Orig1s000ltr.p f). This report provides provisional CDC guidelines for FDA-approved and unapproved, or off-label, uses of bedaquiline in certain populations, such as children, pregnant women, or persons with extrapulmonary MDR TB who were not included in the clinical trials for the drug. CDC's Division of TB Elimination developed these guidelines on the basis of expert opinion informed by data from systematic reviews and literature searches. This approach is different from the statutory standards that FDA uses when approving drugs and drug labeling. These guidelines are intended for health-care professionals who might use bedaquiline for the treatment of MDR TB for indicated and off-label uses. Aspects of these guidelines are not identical to current FDA-approved labeling for bedaquiline. Bedaquiline should be used with clinical expert consultation as part of combination therapy (minimum four-drug treatment regimen) and administered by direct observation to adults aged >=18 years with a diagnosis of pulmonary MDR TB (Food and Drug Administration. SIRTURO [bedaquiline] tablets label. Available at http://www.accessdata.fda.gov/drugsatfda_docs/label/2012/204384s000lbl.pdf). Use of the drug also can be considered for individual patients in other categories (e.g., persons with extrapulmonary TB, children, pregnant women, or persons with HIV or other comorbid conditions) when treatment options are limited. However, further study is required before routine use of bedaquiline can be recommended in these populations. A registry for persons treated with bedaquiline is being implemented by Janssen Therapeutics to track patient outcomes, adverse reactions, laboratory testing results (e.g., diagnosis, drug susceptibility, and development of drug resistance), use of concomitant medications, and presence of other comorbid conditions. Suspected adverse reactions (i.e., any adverse event for which there is a reasonable possibility that the drug caused the adverse event) and serious adverse events (i.e., any adverse event that results in an outcome such as death, hospitalization, permanent disability, or a life-threatening situation) should be reported to Janssen Therapeutics at telephone 1-800-526 7736, to FDA at telephone 1-800-332-1088 or at http://www.fda.gov/medwatch, and to CDC's Emergency Operations Center at telephone 1-770-488-7100. PMID- 24157695 TI - Mussel-inspired bioceramics with self-assembled Ca-P/polydopamine composite nanolayer: preparation, formation mechanism, improved cellular bioactivity and osteogenic differentiation of bone marrow stromal cells. AB - The nanostructured surface of biomaterials plays an important role in improving their in vitro cellular bioactivity as well as stimulating in vivo tissue regeneration. Inspired by the mussel's adhesive versatility, which is thought to be due to the plaque-substrate interface being rich in 3,4-dihydroxy-l phenylalamine (DOPA) and lysine amino acids, in this study we developed a self assembly method to prepare a uniform calcium phosphate (Ca-P)/polydopamine composite nanolayer on the surface of beta-tricalcium phosphate (beta-TCP) bioceramics by soaking beta-TCP bioceramics in Tris-dopamine solution. It was found that the addition of dopamine, reaction temperature and reaction time are three key factors inducing the formation of a uniform Ca-P/polydopamine composite nanolayer. The formation mechanism of a Ca-P/polydopamine composite nanolayer involved two important steps: (i) the addition of dopamine to Tris-HCl solution decreases the pH value and accelerates Ca and P ionic dissolution from the crystal boundaries of beta-TCP ceramics; (ii) dopamine is polymerized to form self-assembled polydopamine film and, at the same time, nanosized Ca-P particles are mineralized with the assistance of polydopamine, in which the formation of polydopamine occurs simultaneously with Ca-P mineralization (formation of nanosized microparticles composed of calcium phosphate-based materials), and finally a self-assembled Ca-P/polydopamine composite nanolayer forms on the surface of the beta-TCP ceramics. Furthermore, the formed self-assembled Ca P/polydopamine composite nanolayer significantly enhances the surface roughness and hydrophilicity of beta-TCP ceramics, and stimulates the attachment, proliferation, alkaline phosphate (ALP) activity and bone-related gene expression (ALP, OCN, COL1 and Runx2) of human bone marrow stromal cells. Our results suggest that the preparation of self-assembled Ca-P/polydopamine composite nanolayers is a viable method to modify the surface of biomaterials by significantly improving their surface physicochemical properties and cellular bioactivity for bone regeneration application. PMID- 24157697 TI - The hemocompatibility of oxidized diamond nanocrystals for biomedical applications. AB - Low-dimensional carbon-based nanomaterials have recently received enormous attention for biomedical applications. However, increasing evidence indicates that they are cytotoxic and can cause inflammatory responses in the body. Here, we show that monocrystalline nanodiamonds (NDs) synthesized by high-pressure-high temperature (HPHT) methods and purified by air oxidation and strong oxidative acid treatments have excellent hemocompatibility with negligible hemolytic and thrombogenic activities. Cell viability assays with human primary endothelial cells suggested that the oxidized HPHT-NDs (dimensions of 35-500 nm) are non cytotoxic. No significant elevation of the inflammatory cytokine levels of IL 1beta and IL-6 was detected in mice after intravenous injection of the nanocrystals in vivo. Using a hindlimb-ischemia mouse model, we demonstrated that 35-nm NDs after covalent conjugation with polyarginine are useful as a drug delivery vehicle of heparin for prolonged anticoagulation treatment. The present study lays a solid foundation for further therapeutic applications of NDs in biomedicine. PMID- 24157698 TI - Approaching mathematical model of the immune network based DNA Strand Displacement system. AB - One biggest obstacle in molecular programming is that there is still no direct method to compile any existed mathematical model into biochemical reaction in order to solve a computational problem. In this paper, the implementation of DNA Strand Displacement system based on nature-inspired computation is observed. By using the Immune Network Theory and Chemical Reaction Network, the compilation of DNA-based operation is defined and the formulation of its mathematical model is derived. Furthermore, the implementation on this system is compared with the conventional implementation by using silicon-based programming. From the obtained results, we can see a positive correlation between both. One possible application from this DNA-based model is for a decision making scheme of intelligent computer or molecular robot. PMID- 24157699 TI - Assessing the effect of zooprophylaxis on zoonotic cutaneous leishmaniasis transmission: a system dynamics approach. AB - Capturing or diverting the disease carrying vector from humans can reduce the transmission of vector borne diseases such as leishmaniasis. The use of animals that act as dead-end hosts to relieve the vector (sandfly) bites on humans is called zooprophylaxis. However, as the number of blood meal providers especially domestic animals increases, the sandflies enhanced availability of blood meals will improve its number and survival, thereby countering the impact of diverting bites from humans. Thus, the transmission model exhibits the structure of a feedback loop characterizing complex dynamic systems. In order to rigorously assess the effect of zooprophylaxis, we propose a system dynamic model for zoonotic cutaneous leishmaniasis transmission with 3 blood-meal hosts: domestic animals, humans, and a reservoir (rodents). In this context, a simulation study of the proposed model with a follow-up period of 1000 days was performed. We explored how perturbations in the parameters characterizing the transmission, essentially the vector biting rates and the size of the domestic animal population, affect the zooprophylaxis outcome. The results show that the basic reproductive number R0 and the disease incidence in humans are decreasing function of the relative size of the domestic animal population. The speed of this decrease depends also on the vector biting rates of the different mammal species. The key factors influencing the magnitude of zooprophylaxis are: the sizes of the vector, rodent, and domestic animal populations, as well as, the biting rates which incorporate relative attraction and accessibility of the vectors to the mammalian populations. PMID- 24157700 TI - Does aridity influence the morphology, distribution and accumulation of calcium oxalate crystals in Acacia (Leguminosae: Mimosoideae)? AB - Calcium oxalate (CaOx) crystals are a common natural feature of many plant families, including the Leguminosae. The functional role of crystals and the mechanisms that underlie their deposition remain largely unresolved. In several species, the seasonal deposition of crystals has been observed. To gain insight into the effects of rainfall on crystal formation, the morphology, distribution and accumulation of calcium oxalate crystals in phyllodes of the leguminous Acacia sect. Juliflorae (Benth.) C. Moore & Betche from four climate zones along an aridity gradient, was investigated. The shapes of crystals, which include rare Rosanoffian morphologies, were constant between species from different climate zones, implying that morphology was not affected by rainfall. The distribution and accumulation of CaOx crystals, however, did appear to be climate-related. Distribution was primarily governed by vein density, an architectural trait which has evolved in higher plants in response to increasing aridity. Furthermore, crystals were more abundant in acacias from low rainfall areas, and in phyllodes containing high concentrations of calcium, suggesting that both aridity and soil calcium levels play important roles in the precipitation of CaOx. As crystal formation appears to be calcium-induced, we propose that CaOx crystals in Acacia most likely function in bulk calcium regulation. PMID- 24157701 TI - Comparison of ascorbic acid biosynthesis in different tissues of three non heading Chinese cabbage cultivars. AB - Ascorbic acid (L-AsA) is an important antioxidant in plants and humans. Vegetables are one of the main sources of ascorbic acid for humans. For instance, non-heading Chinese cabbage (Brassica campestris ssp. chinensis Makino) is considered as one of the most important vegetables in south China. To elucidate the mechanism by which AsA accumulates, we systematically investigated the expression profiles of D-mannose/L-galactose pathway-related genes. We also investigated the recycling-related genes and AsA contents in different tissues of three non-heading Chinese cabbage cultivars, 'Suzhouqing', 'Wutacai' and 'Erqing' containing different amounts of AsA. Our results showed that six genes [D-mannose 6-phosphate isomerase 1 (PMI1), GDP-L-galactose phosphorylase 1 (GGP1), GGP2, GGP4, GDP-mannose-3', 5'-epimerase1 (GME1), and GME2] were expressed at high level and ascorbate oxidase (AAO) was expressed at low level. This expression pattern contributes, at least partially, to higher AsA accumulation in the leaves and petioles than in the roots. Eight genes (PMI1, GME, GGP, L-galactose-1 phosphate phosphatase, L-galactose dehydrogenase, L-galactono-1, 4-lactone dehydrogenase, monodehydroascorbate reductase 1, and glutathione reductase1) were also expressed at high level; AAO and ascorbate peroxidase (APX) were expressed at low level. This expression pattern may similarly contribute to higher AsA accumulation in 'Wutacai' and 'Suzhouqing' than in 'Erqing'. Therefore, the high expression levels of PMI, GME, and GGP and the low expression level of AAO contributed to the high AsA accumulation in non-heading Chinese cabbage. PMID- 24157702 TI - Radiofrequency ablation for selective reduction in complicated monochorionic multiple pregnancies. AB - OBJECTIVE: To evaluate the perinatal outcome of monochorionic (MC) multiple pregnancies after selective reduction by radiofrequency ablation (RFA). METHODS: A case series of all MC multiple pregnancies with selective reduction by RFA in one single institution was reviewed. RESULTS: Ten consecutive patients with an MC pregnancy (9 pairs of twins and 1 set of triplets) underwent RFA. The median gestational age at the time of the procedure was 15.6 weeks (range, 12.3-19.6). The indications for selective reduction included discordance for fetal anomalies (4 cases), twin reversed arterial perfusion sequence (3 cases), selective intrauterine growth restriction (2 cases) and severe twin-twin transfusion syndrome (1 case). All procedures were technically successful in achieving selective reduction. The overall survival rate of the co-twin was 81.8% (9/11), and the median gestational age at delivery was 35.9 weeks (range, 32.4-38.6). There was one preterm delivery before 34 weeks of gestation (11.1%). Preterm premature rupture of the membranes occurred in 2 patients (20%); however, this was not observed within 4 weeks postoperatively, nor did they deliver before 32 weeks. CONCLUSIONS: RFA is a promising technique for selective reduction in complicated MC multiple pregnancies with a high survival rate and low complication rate. PMID- 24157703 TI - Effects of volitional walking control on postexercise changes in motor cortical excitability. AB - To explore the effects of qualitative or quantitative changes in walking on motor cortical excitability, a transcranial magnetic stimulation procedure was used to examine the alterations of motor-evoked potential (MEP) amplitude following walking. Eight healthy participants completed a series of two walking tasks on a treadmill at 2 km/h. The ratio of the left stance duration to the right stance duration was 1 : 2 in the asymmetrical walking task and 1 : 1 in the symmetrical walking task. In each task, walking for 10 min followed by MEP measurement for ~4 min was repeated three times. MEP measurements were also performed before a walking task as a baseline and continued every 10 min for a further 30 min after the completion of the walking task. During slight voluntary contraction of the left tibialis anterior muscle, MEP measurements were conducted four times. Although a significant MEP depression was found after the asymmetrical walking task with increasing amount of walking, no significant decrease in MEP below baseline was observed after the symmetrical walking task throughout all measurement sessions. This MEP depression was the prominent response to the asymmetrical walking task compared with the symmetrical walking task. These findings indicate that the intentional control of walking pattern has both temporal and task-specific influences on excitability changes in the cerebral cortex, and suggest that motor cortical excitability may be altered by controlling the amount of central commands to the legs even during gait exercise. PMID- 24157704 TI - Intrasubthalamic cell transplants for epilepsy therapy: hopes and concerns. AB - The mainstay of treatment of patients suffering from epilepsies involves antiepileptic drug therapy. However, about one-third of patients continue to have seizures or show intolerable adverse effects despite appropriate medication. Neuronal transplantation into key brain regions involved in seizure generation, propagation, or modulation is a promising alternative experimental approach to treat drug-resistant epilepsies. Especially for patients with multiple-epileptic foci, or without a clear focal onset, therapeutic manipulation of brain structures remote to the focus but significantly involved in seizure modulation may be a more advantageous strategy. Using animal experiments, we recently showed that the subthalamic nucleus (STN) may be an auspicious target region in this respect. The STN repeatedly showed up to be highly sensitive to changes in GABAergic transmission, which can be achieved by localized microinjection of GABA elevating drugs or by grafting GABA-releasing cells. However, there are many hurdles to overcome and questions to resolve before clinical translation of this approach appears realistic. This commentary discusses potential benefits as well as concerns associated with grafting of inhibitory cells into the STN. PMID- 24157705 TI - T273 plays an important role in the activity and structural stability of arginine kinase. AB - Arginine kinase (AK) is a key enzyme for cellular energy metabolism, catalyzing the reversible phosphoryl transfer from phosphoarginine to ADP in invertebrates. The amino acid residue C271 is involved in keeping AK's activity and constraining the orientation of the substrate arginine. However, the roles of the C271 interaction amino acid residues in AK's substrate synergism, activity and structural stability are still unclear. The crystal structure of AK implied that the amino acid residue T273 interacted with the residue C271 and might play vital roles in keeping AK's activity, substrate synergism and structural stability. The mutations T273G and T273A led to significantly loss of activity, obviously decreased of substrate synergism and structural stability. Furthermore, spectroscopic experiments indicated that mutations T273G and T273A impaired the structure of AK and led them to a partially unfolded state. The inability to fold to the functional state made the mutations prone to aggregate under environmental stresses. Moreover, the mutations T273S and T273D almost had no effects on AK's activity and structural stability. This study herein indicated that the residue T273 played key roles in AK's activity, substrate synergism and structural stability. PMID- 24157706 TI - Cost analysis of early psychosocial intervention in Alzheimer's disease. AB - BACKGROUND/AIM: To investigate the impact of early psychosocial intervention aimed at patients with Alzheimer's disease (AD) and their caregivers on resource use and costs from a societal perspective. METHODS: Dyads of patients and their primary caregiver were randomised to intervention (n = 163) or control (n = 167) and followed for 3 years. Health care use was extracted from national registers, and the Resource Utilisation in Dementia questionnaire was used to measure informal care and productivity loss. Multiple imputation was used to replace missing data, and non-parametric bootstrapping was used to estimate standard errors. RESULTS: Overall, there were no statistically significant differences because of large variation in the observations. The average additional cost of psychosocial intervention provision was estimated at EUR 3,401 per patient. This cost masked a reduced use of formal health care and an increased use of informal care. CONCLUSIONS: Early psychosocial intervention in AD could be cost-saving from a health care perspective, whereas the opposite seems to be true from a broader societal perspective. PMID- 24157708 TI - Precise organization of metal nanoparticles on DNA origami template. AB - Nanoscale assemblies of metal nanoparticles in one dimension (1D) to three dimensions (3D) can exhibit novel phenomena that are not observed in the amorphous state. Bottom-up assembly technique is expected to overcome the resolution limit of top-down method and casts a new light on the nanofabrication field. DNA origami, which is mainly used to construct discrete and addressable nanostructures, can be utilized to assemble functional colloidal nanoparticles into delicate geometries with interesting properties. This review aims to summarize the methods that use DNA origami structures as templates to precisely organize metal nanoparticles, such as gold nanospheres (AuNSs) gold nanorods (AuNRs) and silver nanoparticles (AgNPs). The potential applications and the perspective are also discussed. PMID- 24157707 TI - Invasive candidiasis as a cause of sepsis in the critically ill patient. AB - Invasive fungal infections are an increasingly frequent etiology of sepsis in critically ill patients causing substantial morbidity and mortality. Candida species are by far the predominant agent of fungal sepsis accounting for 10% to 15% of health-care associated infections, about 5% of all cases of severe sepsis and septic shock and are the fourth most common bloodstream isolates in the United States. One-third of all episodes of candidemia occur in the intensive care setting. Early diagnosis of invasive candidiasis is critical in order to initiate antifungal agents promptly. Delay in the administration of appropriate therapy increases mortality. Unfortunately, risk factors, clinical and radiological manifestations are quite unspecific and conventional culture methods are suboptimal. Non-culture based methods (such as mannan, anti-mannan, beta-d glucan, and polymerase chain reaction) have emerged but remain investigational or require additional testing in the ICU setting. Few prophylactic or pre-emptive studies have been performed in critically ill patients. They tended to be underpowered and their clinical usefulness remains to be established under most circumstances. The antifungal armamentarium has expanded considerably with the advent of lipid formulations of amphotericin B, the newest triazoles and the echinocandins. Clinical trials have shown that the triazoles and echinocandins are efficacious and well tolerated antifungal therapies. Clinical practice guidelines for the management of invasive candidiasis have been published by the European Society for Clinical Microbiology and Infectious Diseases and the Infectious Diseases Society of North America. PMID- 24157711 TI - Molecular imaging of tumors and metastases using chemical exchange saturation transfer (CEST) MRI. AB - The two glucose analogs 2-deoxy-D-glucose (2-DG) and 2-fluoro-2-deoxy-D-glucose (FDG) are preferentially taken up by cancer cells, undergo phosphorylation and accumulate in the cells. Owing to their exchangeable protons on their hydroxyl residues they exhibit significant chemical exchange saturation transfer (CEST) effect in MRI. Here we report CEST-MRI on mice bearing orthotopic mammary tumors injected with 2-DG or FDG. The tumor exhibited an enhanced CEST effect of up to 30% that persisted for over one hour. Thus 2-DG/FDG CEST MRI can replace PET/CT or PET/MRI for cancer research in laboratory animals, but also has the potential to be used in the clinic for the detection of tumors and metastases, distinguishing between malignant and benign tumors and monitoring tumor response to therapy as well as tumors metabolism noninvasively by using MRI, without the need for radio-labeled isotopes. PMID- 24157710 TI - Surveillance of influenza vaccination coverage--United States, 2007-08 through 2011-12 influenza seasons. AB - PROBLEM/CONDITION: Substantial improvement in annual influenza vaccination of recommended groups is needed to reduce the health effects of influenza and reach Healthy People 2020 targets. No single data source provides season-specific estimates of influenza vaccination coverage and related information on place of influenza vaccination and concerns related to influenza and influenza vaccination. REPORTING PERIOD: 2007-08 through 2011-12 influenza seasons. DESCRIPTION OF SYSTEMS: CDC uses multiple data sources to obtain estimates of vaccination coverage and related data that can guide program and policy decisions to improve coverage. These data sources include the National Health Interview Survey (NHIS), the Behavioral Risk Factor Surveillance System (BRFSS), the National Flu Survey (NFS), the National Immunization Survey (NIS), the Immunization Information Systems (IIS) eight sentinel sites, Internet panel surveys of health-care personnel and pregnant women, and the Pregnancy Risk Assessment and Monitoring System (PRAMS). RESULTS: National influenza vaccination coverage among children aged 6 months-17 years increased from 31.1% during 2007 08 to 56.7% during the 2011-12 influenza season as measured by NHIS. Vaccination coverage among children aged 6 months-17 years varied by state as measured by NIS. Changes from season to season differed as measured by NIS and NHIS. According to IIS sentinel site data, full vaccination (having either one or two seasonal influenza vaccinations, as recommended by the Advisory Committee on Immunization Practices for each influenza season, based on the child's influenza vaccination history) with up to two recommended doses for the 2011-12 season was 27.1% among children aged 6 months-8 years and was 44.3% for the youngest children (aged 6-23 months). Influenza vaccination coverage among adults aged >=18 years increased from 33.0% during 2007-08 to 38.3% during the 2011-12 influenza season as measured by NHIS. Vaccination coverage by age group for the 2011-12 season as measured by BRFSS was <5 percentage points different from NHIS estimates, whereas NFS estimates were 6-8 percentage points higher than BRFSS estimates. Vaccination coverage among persons aged >=18 years varied by state as measured by BRFSS. For adults aged >=18 years, a doctor's office was the most common place for receipt of influenza vaccination (38.4%, BRFSS; 32.5%, NFS) followed by a pharmacy (20.1%, BRFSS; 19.7%, NFS). Overall, 66.9% of health-care personnel (HCP) reported having been vaccinated during the 2011-12 season, as measured by an Internet panel survey of HCP, compared with 62.4%, as estimated through NHIS. Vaccination coverage among pregnant women was 47.0%, as measured by an Internet panel survey of women pregnant during the influenza season, and 43.0%, as measured by BRFSS during the 2011-12 influenza season. Overall, as measured by NFS, 86.8% of adults aged >=18 years rated the influenza vaccine as very or somewhat effective, and 46.5% of adults aged >=18 years believed their risk for getting sick with influenza if unvaccinated was high or somewhat high. INTERPRETATION: During the 2011-12 season, influenza vaccination coverage varied by state, age group, and selected populations (e.g., HCP and pregnant women), with coverage estimates well below the Healthy People 2020 goal of 70% for children aged 6 months-17 years, 70% for adults aged >=18 years, and 90% for HCP. PUBLIC HEALTH ACTIONS: Continued efforts are needed to encourage health-care providers to offer influenza vaccination and to promote public health education efforts among various populations to improve vaccination coverage. Ongoing surveillance to obtain coverage estimates and information regarding other issues related to influenza vaccination (e.g., knowledge, attitudes, and beliefs) is needed to guide program and policy improvements to reduce morbidity and mortality associated with influenza by increasing vaccination rates. Ongoing comparisons of telephone and Internet panel surveys with in-person surveys such as NHIS are needed for appropriate interpretation of data and resulting public health actions. Examination of results from all data sources is necessary to fully assess the various components of influenza vaccination coverage among different populations in the United States. PMID- 24157709 TI - Differential regulation of the REGgamma-proteasome pathway by p53/TGF-beta signalling and mutant p53 in cancer cells. AB - Proteasome activity is frequently enhanced in cancer to accelerate metastasis and tumorigenesis. REGgamma, a proteasome activator known to promote p53/p21/p16 degradation, is often overexpressed in cancer cells. Here we show that p53/TGF beta signalling inhibits the REGgamma-20S proteasome pathway by repressing REGgamma expression. Smad3 and p53 interact on the REGgamma promoter via the p53RE/SBE region. Conversely, mutant p53 binds to the REGgamma promoter and recruits p300. Importantly, mutant p53 prevents Smad3/N-CoR complex formation on the REGgamma promoter, which enhances the activity of the REGgamma-20S proteasome pathway and contributes to mutant p53 gain of function. Depletion of REGgamma alters the cellular response to p53/TGF-beta signalling in drug resistance, proliferation, cell cycle progression and proteasome activity. Moreover, p53 mutations show a positive correlation with REGgamma expression in cancer samples. These findings suggest that targeting REGgamma-20S proteasome for cancer therapy may be applicable to human tumours with abnormal p53/Smad protein status. Furthermore, this study demonstrates a link between p53/TGF-beta signalling and the REGgamma-20S proteasome pathway, and provides insight into the REGgamma/p53 feedback loop. PMID- 24157712 TI - Understanding translational control mechanisms of the mTOR pathway in CHO cells by polysome profiling. AB - The mammalian target of rapamycin (mTOR) pathway plays essential roles in the regulation of translational activity in many eukaryotes. Thus, from a bioprocessing point of view, understanding its molecular mechanisms may provide potential avenues for improving cell culture performance. Toward this end, the mTOR pathway of CHO cells in batch cultures was subjected to rapamycin treatment (inhibition) or nutrient supplementation (induction) and translational activities of CHO cells producing a monoclonal antibody (mAb) were evaluated with polysome profiling technology. Expectedly, rapamycin induced a shift of mRNAs from polysomes towards monosomes, thus reducing maximum cellular growth rate by 30%, while feeding additional nutrients extended mTOR pathway activity during the stationary growth phase in control batch culture, thereby contributing to an increase in global translation activity by up to 2-fold, and up to 5-fold higher specific translation of the heavy and light chains of the recombinant mAb. These increases in translation activity correlated with a 5-day extension in cellular growth and a 4-fold higher final product titer observed upon nutrient feeding. This first study of the relationship between the mTOR pathway and translational activity in CHO cultures provides key insights into the role of translational control in supporting greater productivity, which will lead to further enhancement of CHO cultures. PMID- 24157713 TI - Enhanced bioproduction of poly-3-hydroxybutyrate from wheat straw lignocellulosic hydrolysates. AB - Polyhydroxyalkanoates (PHAs) are bioplastics that can replace conventional petroleum-derived products in various applications. One of the major barriers for their widespread introduction in the market is the higher production costs compared with their petrochemical counterparts. In this work, a process was successfully implemented with high productivity based on wheat straw, a cheap and readily available agricultural residue, as raw material. The strain Burkholderia sacchari DSM 17165 which is able to metabolise glucose, xylose and arabinose, the main sugars present in wheat straw hydrolysates (WSHs), was used. Results in shake flask showed that B. sacchari cells accumulated about 70%gpoly(3 hydroxybutyrate)(P(3HB))/g cell dry weight (CDW) with a yield of polymer on sugars (YP/S) of 0.18g/g when grown on a mixture of commercial C6 and C5 sugars (control), while these values reached about 60%gP(3HB)/g CDW and 0.19g/g, respectively, when WSHs were used as carbon source. In fed-batch cultures carried out in 2L stirred-tank reactors (STRs) on WSH, a maximum polymer concentration of 105 g/L was reached after 61 hours of cultivation corresponding to an accumulation of 72% of CDW. Polymer yield and productivity were 0.22 gP(3HB)/g total sugar consumed and 1.6g/L hour, respectively. The selected feeding strategy successfully overcame the carbon catabolite repression (CCR) phenomenon observed with sugar mixtures containing hexoses and pentoses. This is the first work describing fed-batch cultivations aiming at PHA production using real lignocellulosic hydrolysates. Additionally, the P(3HB) volumetric productivities attained are by far the highest ever achieved on agricultural waste hydrolysates. PMID- 24157714 TI - Myostatin inhibitors as therapies for muscle wasting associated with cancer and other disorders. AB - PURPOSE OF REVIEW: This review summarizes recent progress in the development of myostatin inhibitors for the treatment of muscle wasting disorders. It also focuses on findings in myostatin biology that may have implications for the development of antimyostatin therapies. RECENT FINDINGS: There has been progress in evaluating antimyostatin therapies in animal models of muscle wasting disorders. Some programs have progressed into clinical development with initial results showing positive impact on muscle volume.In normal mice myostatin deficiency results in enlarged muscles with increased total force but decreased specific force (total force/total mass). An increase in myofibrillar protein synthesis without concomitant satellite cell proliferation and fusion leads to muscle hypertrophy with unchanged myonuclear number. A specific force reduction is not observed when atrophied muscle, the predominant therapeutic target of myostatin inhibitor therapy, is made myostatindeficient.Myostatin has been shown to be expressed by a number of tumor cell lines in mice and man. SUMMARY: Myostatin inhibition remains a promising therapeutic strategy for a range of muscle wasting disorders. PMID- 24157716 TI - Immunological and hormonal effects of exercise: implications for cancer cachexia. AB - PURPOSE OF REVIEW: There is increasing interest in the use of therapeutic exercise for cancer cachexia. Apart from the directly beneficial effects on muscle, exercise has the potential to attenuate some of the immunological and hormonal abnormalities found in cachexia. This review summarizes the findings of recent studies, which have explored such effects in patients with cancer, and discusses their relevance to patients with cancer cachexia. RECENT FINDINGS: Our search identified 11 studies in patients with breast, colorectal, lung, and prostate cancer, predominantly with early stage disease or following primary curative treatment. Overall, exercise was associated with reduced levels of C reactive protein (CRP), but not other markers of systemic inflammation. There was no consistent impact on levels of glucose, insulin or measures of insulin sensitivity or, in patients with prostate cancer, on levels of testosterone. SUMMARY: There is limited scope to extrapolate these findings to patients with cancer cachexia, who are more likely to have advanced disease, higher levels of systemic inflammation, and greater degrees of metabolic dysfunction. Studies specific to this group are required to explore what, if any, changes exercise can make to levels of CRP and other immune and hormonal biomarkers, along with their potential clinical relevance. PMID- 24157717 TI - Personalized, patient-centred cancer cachexia management: lessons to be learnt from oncology and to be taught to oncology. PMID- 24157715 TI - Gut barrier dysfunction and microbial translocation in cancer cachexia: a new therapeutic target. AB - PURPOSE OF REVIEW: Cachexia is a complex metabolic syndrome characterized by skeletal muscle and adipose tissue loss and is frequently associated with emaciation, anorexia, systemic inflammation, and metabolic dysfunction. Lack of a clear understanding of the cause of cancer cachexia has impeded progress in identifying effective therapeutic agents. This review summarizes recent publications on the role of gut barrier function, intestinal microbiota, and inflammation in the etiology of cancer cachexia and new therapeutic interventions that may benefit treatment strategies. RECENT FINDINGS: Significant advances have been made in understanding the composition and metabolic capabilities of the intestinal microbiota and its impact on gut barrier function with implications for certain inflammatory-based diseases. Recent studies reported associations between intestinal permeability and endotoxemia with development of cancer cachexia and other metabolic disorders. Improvements in intestinal function and weight gain along with decreased inflammation have been reported for potential therapeutic agents such as eicosapentaenoic acid, immunoglobulin isolates, and probiotics. SUMMARY: Continued progress in the scientific understanding of the complex interplay between the intestinal microbiota, gut barrier function, and host inflammatory responses will uncover new therapeutic targets to help avoid the serious metabolic alterations associated with cachexia. PMID- 24157718 TI - Bindings of hMRP1 transmembrane peptides with dodecylphosphocholine and dodecyl beta-d-maltoside micelles: a molecular dynamics simulation study. AB - In this paper, we describe molecular dynamics simulation results of the interactions between four peptides (mTM10, mTM16, TM17 and KTM17) with micelles of dodecylphosphocholine (DPC) and dodecyl-beta-d-maltoside (DDM). These peptides represent three transmembrane fragments (TM10, 16 and 17) from the MSD1 and MSD2 membrane-spanning domains of an ABC membrane protein (hMRP1), which play roles in the protein functions. The peptide-micelle complex structures, including the tryptophan accessibility and dynamics were compared to circular dichroism and fluorescence studies obtained in water, trifluoroethanol and with micelles. Our work provides additional results not directly accessible by experiments that give further support to the fact that these peptides adopt an interfacial conformation within the micelles. We also show that the peptides are more buried in DDM than in DPC, and consequently, that they have a larger surface exposure to water in DPC than in DDM. As noted previously by simulations and experiments we have also observed formation of cation-pi bonds between the phosphocholine DPC headgroup and Trp peptide residue. Concerning the peptide secondary structures (SS), we find that in TFE their initial helical conformations are maintained during the simulation, whereas in water their initial SS are lost after few nanoseconds of simulation. An intermediate situation is observed with micelles, where the peptides remain partially folded and more structured in DDM than in DPC. Finally, our results show no sign of beta-strand structure formation as invoked by far-UV CD experiments even when three identical peptides are simulated either in water or with micelles. PMID- 24157720 TI - Acute exacerbations of idiopathic pulmonary fibrosis. AB - Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive and ultimately fatal disease, with a highly variable course in individual patients. Episodes of rapid deterioration are not uncommon, often following a period of stability. In cases of uncertain etiology, with typical clinical and high-resolution computed tomography (HRCT) features, the term 'acute exacerbation of IPF' (AE-IPF) has been coined to describe a combination of diffuse alveolar damage and preexisting usual interstitial pneumonia. In 2007, a consensus definition and diagnostic criteria were proposed. Although the presence of overt infection is currently an exclusion criterion, it appears likely that occult infection, reflux and thoracic surgical procedures are all trigger factors for AE-IPF. The development of new, usually bilateral infiltrates (ground-glass attenuation with variable admixed consolidation) is a defining HRCT feature. The outcome is poor with a short-term mortality in excess of 50% despite therapy. A number of pathophysiologic pathways are activated, with immunologic dysregulation, epithelial damage and circulating fibrocytes all believed to play a pathogenetic role. Acute exacerbations are less prevalent in other fibrotic lung diseases than in IPF and may have a better outcome, with the exception of acute exacerbations of rheumatoid lung. In AE-IPF, the exclusion of alternative causes of rapid deterioration, including heart failure and infection, is the main goal of investigation. Empirical high-dose corticosteroid steroid therapy is generally used in AE-IPF, without proven benefit. PMID- 24157719 TI - Oxidative stress among SOD-1 genotypes in rainbow trout (Oncorhynchus mykiss). AB - Natural variation in the antioxidant-enzyme SOD-1 (superoxide dismutase) is known to alter the impacts of oxidative damage at both the cellular and organismal levels. Using three homozygous clonal lines of rainbow trout [Hot Creek (n=30), Arlee (n=21), and Swanson (n=10)], which differ for single nucleotide polymorphisms (SNPs) and amino acid substitutions at the SOD-1 locus, we investigated the functional effects of this variation on SOD-1 activity during ozone stress and subsequent levels of oxidative damage to DNA and cell membranes. Fish from each line were subjected to either control conditions or 24h of ozone stress, after which tissues were analyzed for antioxidant status and oxidative damage. Liver SOD-1 activity was lower in ozonated vs. control fish in the Hot Creek line, and among ozonated fish, Hot Creek was lower than Arlee. Total erythrocyte SOD activity was not significantly impacted by ozonation; however significant differences in total erythrocyte SOD activity were measured among clonal lines, driven primarily by lower activity in the Hot Creek line. Ozone had a significant treatment effect in all oxidative damage parameters assessed: it increased DNA lesions in erythrocytes and levels of lipid peroxidation in gill tissue and plasma. Among lines, Swanson showed higher lipid peroxidation levels in gill tissue after ozonation than Arlee or Hot Creek. Conversely, Swanson control and treatment fish had significantly lower plasma lipid peroxidation levels than did fish from the other lines. Overall, the among-line differences in SOD and SOD-1 activity and oxidative damage provide evidence that SOD-1 genotypes differ functionally under both oxidative stress and control conditions; however, other genetic differences among lines should be investigated in order to further explain the phenotypic differences in SOD enzyme activity and oxidative damage described here. PMID- 24157721 TI - Microsurgical resection of intramedullary spinal cord hemangioblastomas: 3 dimensional operative video. PMID- 24157722 TI - Yeast cells with impaired drug resistance accumulate glycerol and glucose. AB - Multiple drug resistance (MDR) in yeast is effected by two major superfamilies of membrane transporters: the major facilitator superfamily (MFS) and the ATP binding cassette (ABC) superfamily. In the present work, we investigated the cellular responses to disruptions in both MFS (by deleting the transporter gene, QDR3) and ABC (by deleting the gene for the Pdr3 transcription factor) transporter systems by growing diploid homozygous deletion yeast strains in glucose- or ammonium-limited continuous cultures. The transcriptome and the metabolome profiles of these strains, as well as the flux distributions in the optimal solution space, reveal novel insights into the underlying mechanisms of action of QDR3 and PDR3. Our results show how cells rearrange their metabolism to cope with the problems that arise from the loss of these drug-resistance genes, which likely evolved to combat chemical attack from bacterial or fungal competitors. This is achieved through the accumulation of intracellular glucose, glycerol, and inorganic phosphate, as well as by repurposing genes that are known to function in other parts of metabolism in order to minimise the effects of toxic compounds. PMID- 24157723 TI - MicroRNAs in plasma and cerebrospinal fluid as potential markers for Alzheimer's disease. AB - The development of Alzheimer's disease (AD) biomarkers remains an unmet challenge, and new approaches that can improve current AD biomarker strategies are needed. Recent reports suggested that microRNA (miRNA) profiling of biological fluids has emerged as a diagnostic tool for several pathologic conditions. In this study, we measured six candidate miRNAs (miR-9, miR-29a, miR 29b, miR-34a, miR-125b, and miR-146a) in plasma and cerebrospinal fluid (CSF) of AD and normal subjects by using quantitative reverse transcriptase-polymerase chain reaction (qRT-PCR) to evaluate their potential usability as AD biomarkers. The qRT-PCR results showed that plasma miR-34a and miR-146a levels, and CSF miR 34a, miR-125b, and miR-146a levels in AD patients were significantly lower than in control subjects. On the other hand, CSF miR-29a and miR-29b levels were significantly higher than in control subjects. Our results provide a possibility that miRNAs detected in plasma and CSF can serve as biomarkers for AD. PMID- 24157724 TI - The benefits of errorless learning for serial reaction time performance in Alzheimer's disease. AB - Identifying the conditions favoring new procedural skill learning in Alzheimer's disease (AD) could be important for patients' autonomy. It has been suggested that error elimination is beneficial during skill learning, but no study has explored the advantage of this method in sequential learning situations. In this study, we examined the acquisition of a 6-element perceptual-motor sequence by AD patients and healthy older adults (control group). We compared the impact of two preliminary sequence learning conditions (Errorless versus Errorful) on Serial Reaction Time performance at two different points in the learning process. A significant difference in reaction times for the learned sequence and a new sequence was observed in both conditions in healthy older participants; in AD patients, the difference was significant only in the errorless condition. The learning effect was greater in the errorless than the errorful condition in both groups. However, while the errorless advantage was found at two different times in the learning process in the AD group, in the control group this advantage was observed only at the halfway point. These results support the hypothesis that errorless learning allows for faster automation of a procedure than errorful learning in both AD and healthy older subjects. PMID- 24157725 TI - What are people with Parkinson's disease really impaired on when it comes to making decisions? A meta-analysis of the evidence. AB - Parkinson's disease (PD) is associated with motor and cognitive impairment caused by dopamine dysregulation in the basal ganglia. Amongst a host of cognitive deficits, evidence suggests that decision-making is impaired in patients with PD, but the exact scope of this impairment is still unclear. The aim of this review was to establish which experimental manipulations commonly associated with studies involving decision-making tasks were most likely to generate impairments in performance in PD patients. This allowed us to address the question of the exact scope of the decision-making deficits in PD and to hypothesize about the role of the basal ganglia in decision-making processes. We conducted a meta analysis of available literature, which revealed that the two key predictors of impairment in PD were the feedback structure of the decision-making task and the medication status of patients while performing the tasks. Rather than a global impairment in decision-making ability, these findings suggest that deficiencies in choice-behaviour in patients with PD stem from dysfunctions at the outcome evaluation stage of the decision-making process. PMID- 24157726 TI - Mind the blind brain to understand the sighted one! Is there a supramodal cortical functional architecture? AB - While most of the research in blind individuals classically has focused on the compensatory plastic rearrangements that follow loss of sight, novel behavioral, anatomical and functional brain studies in individuals born deprived of sight represent a powerful tool to understand to what extent the brain functional architecture is programmed to develop independently from any visual experience. Here we review work from our lab and others, conducted in sighted and congenitally blind individuals, whose results indicate that vision is not a mandatory prerequisite for the brain cortical organization to develop and function. Similar cortical networks subtend visual and/or non-visual perception of form, space and movement, as well as action recognition, both in sighted and in congenitally blind individuals. These findings support the hypothesis of a modality independent, supramodal cortical organization. Visual experience, however, does play a role in shaping specific cortical sub-regions, as loss of sight is accompanied also by cross-modal plastic phenomena. Altogether, studying the blind brain is opening our eyes on how the brain develops and works. PMID- 24157727 TI - Brainnetome-wide association studies in schizophrenia: the advances and future. AB - Convergent evidence suggests that psychiatric disorders are the result of faulty brain networks. To understand the pathophysiological network mechanisms of psychiatric disorders, it is necessary to integrate multi-level network features obtained using various functional and anatomical brain imaging technologies on different scales. We have proposed a new concept, the brainnetome, to represent this integrative framework. In the present review, we use schizophrenia, a disorder characterized by dysconnectivity, to demonstrate how the brainnetome concept can be applied to the study of psychiatric disorders. We first review studies of abnormal brain networks in schizophrenia that are based on single regions of interest. We then present some advances and challenges in understanding the malfunctions of specific brain networks in schizophrenia. Some recent advances and challenges in understanding abnormal whole brain networks in schizophrenia are also presented. We next briefly introduce a few studies that show how genes related to the risk for schizophrenia affect brain networks. Finally, we present a brief discussion about how the brainnetome concept may influence future research and provide a perspective on challenges in this field. PMID- 24157728 TI - Abstracts of the German, Austrian, and Swiss Society for Hematology and Oncology. October 18-22, 2013. Vienna, Austria. PMID- 24157729 TI - Synthesis and biological studies of steroidal pyran based derivatives. AB - Steroid based cancer chemotherapeutic agents of the type 2'-amino-3'-cyanocholest 6-eno[5,7-de]4H-pyrans (1c-3c) have been synthesized and characterized by the various spectroscopic and analytical techniques. The DNA binding studies of compounds (1c-3c) with CT DNA were carried out by UV-vis and fluorescence spectroscopy and gel electrophoresis. The compounds (1c-3c) bind to DNA preferentially through electrostatic and hydrophobic interactions with Kb values found to be 5.4 * 10(3), 2.3 * 10(3)M(-1) and 1.97 * 10(3)M(-1), respectively indicating the higher binding affinity of compound (1c) towards DNA. The molecular docking study suggested that the electrostatic interaction of compounds (1c-3c) in between the nucleotide base pairs is due to the presence of pyran moiety in steroid molecule. All the compounds (1c-3c) cleave supercoiled pBR322 DNA via hydrolytic pathway, as validated by T4 DNA ligase assay. The compounds (1c-3c) were screened for in vitro cytotoxicity against the cancer and non-cancer cells SW480, A549, HepG2, HeLa, MCF-7, HL-60, DU-145, NL-20, HPC and HPLF by MTT assay. The compounds (1c-3c) were tested for genotoxicity (comet assay) involving apoptotic degradation of DNA and was analyzed by agarose gel electrophoresis and visualized by ethidium bromide staining. The results revealed that compound (1c) has better prospectus to act as cancer chemotherapeutic candidate which warrants further in vivo anticancer investigations. PMID- 24157730 TI - Prevalence of depression among recently admitted long-term care patients in Norwegian nursing homes: associations with diagnostic workup and use of antidepressants. AB - AIMS: We aimed to establish the prevalence of depression among recently admitted long-term care patients and to examine associations with diagnostic initiatives and treatment as recorded in patients' medical records. MATERIALS AND METHODS: Eighty-eight long-term care patients were included. Depression was diagnosed according to the ICD-10 criteria; patients were screened for depression using the Cornell Scale for Depression in Dementia (CSDD) and for dementia with the Clinical Dementia Rating (CDR) scale. RESULTS: Depression was found in 25% of the patients according to the ICD-10 criteria and in 31% according to a CSDD sum score of >= 8. Diagnostic initiatives were documented in the medical records of half of the patients with depression. Forty-four percent of the patients were prescribed antidepressants and 23% actually received them for the treatment of depression. CONCLUSION: Depression was prevalent among recently admitted long term care patients, but diagnostic initiatives were too rarely used. Antidepressants were commonly prescribed, but depression was the indication for treatment in only half of the cases. Screening for depression should be mandatory on admission. PMID- 24157733 TI - Emergency cervical internal carotid artery stenting in combination with intracranial thrombectomy in acute stroke. AB - BACKGROUND AND PURPOSE: In past years, thrombectomy has become a widely used procedure in interventional neuroradiology for the treatment of acute intracranial occlusions. However, in 10-20% of patients, there are additional occlusions or stenotic lesions of the ipsilateral cervical internal carotid artery. The purpose of this study was to evaluate the feasibility of emergency carotid artery stent placement in combination with intracranial thrombectomy and the clinical outcome of the treated patients. MATERIALS AND METHODS: We analyzed clinical and angiographic data of patients who underwent emergency cervical ICA stent placement and intracranial thrombectomy with stent-retriever devices in our institution between November 2009 and July 2012. Recanalization was assessed according to the Thrombolysis in Cerebral-Infarction score. Clinical outcome was evaluated at discharge (NIHSS) and after 3 months (mRS). RESULTS: Overall, 24 patients were treated. The mean age was 67.2 years; mean occlusion time, 230.2 minutes. On admission, the median NIHSS score was 18. In all patients, the Thrombolysis in Cerebral Infarction score was zero before the procedure. Stent implantation was feasible in all cases. In 15 patients (62.5%), a Thrombolysis in Cerebral Infarction score >= 2b could be achieved. Six patients (25%) improved >=10 NIHSS points between admission and discharge. After 90 days, the median mRS score was 3.0. Seven patients (29.2%) had a good clinical outcome (mRS 0-2), and 4 patients (16.6%) died, 1 due to fatal intracranial hemorrhage. Overall, symptomatic intracranial hemorrhage occurred in 4 patients (16.6%). CONCLUSIONS: Emergency ICA stent implantation was technically feasible in all patients, and the intracranial recanalization Thrombolysis in Cerebral Infarction score of >=2b was reached in a high number of patients. Clinical outcome and mortality seem to be acceptable for a cohort with severe stroke. However, a high rate of symptomatic intracranial hemorrhage occurred in our study. PMID- 24157731 TI - The contribution of group A streptococcal virulence determinants to the pathogenesis of sepsis. AB - Streptococcus pyogenes (group A streptococcus, GAS) is responsible for a wide range of pathologies ranging from mild pharyngitis and impetigo to severe invasive soft tissue infections. Despite the continuing susceptibility of the bacterium to beta-lactam antibiotics there has been an unexplained resurgence in the prevalence of invasive GAS infection over the past 30 years. Of particular importance was the emergence of a GAS-associated sepsis syndrome that is analogous to the systemic toxicosis associated with TSST-1 producing strains of Staphylococcus aureus. Despite being recognized for over 20 years, the etiology of GAS associated sepsis and the streptococcal toxic shock syndrome remains poorly understood. Here we review the virulence factors that contribute to the etiology of GAS associated sepsis with a particular focus on coagulation system interactions and the role of the superantigens in the development of streptococcal toxic shock syndrome. PMID- 24157732 TI - Semiconductor-based DNA sequencing of histone modification states. AB - The recent development of a semiconductor-based, non-optical DNA sequencing technology promises scalable, low-cost and rapid sequence data production. The technology has previously been applied mainly to genomic sequencing and targeted re-sequencing. Here we demonstrate the utility of Ion Torrent semiconductor-based sequencing for sensitive, efficient and rapid chromatin immunoprecipitation followed by sequencing (ChIP-seq) through the application of sample preparation methods that are optimized for ChIP-seq on the Ion Torrent platform. We leverage this method for epigenetic profiling of tumour tissues. PMID- 24157734 TI - Stent retrievers in acute ischemic stroke: complications and failures during the perioperative period. AB - BACKGROUND AND PURPOSE: Stent retriever-assisted thrombectomy promotes high recanalization rates in acute ischemic stroke. Nevertheless, complications and failures occur in more than 10% of procedures; hence, there is a need for further investigation. MATERIALS AND METHODS: A total of 144 patients with ischemic stroke presenting with large-vessel occlusion were prospectively included. Patients were treated with stent retriever-assisted thrombectomy +/- IV fibrinolysis. Baseline clinical and imaging characteristics were incorporated in univariate and multivariate analyses. Predictors of recanalization failure (TICI 0, 1, 2a), and of embolic and hemorrhagic complications were reported. The relationship between complication occurrence and periprocedural mortality rate was studied. RESULTS: Median age was 69.5 years, and median NIHSS score was 18 at presentation. Fifty patients (34.7%) received stand-alone thrombectomy, and 94 (65.3%) received combined therapy. The procedural failure rate was 13.9%. Embolic complications were recorded in 12.5% and symptomatic intracranial hemorrhage in 7.6%. The overall rate of failure, complications, and/or death was 39.6%. The perioperative mortality rate was 18.4% in the overall cohort but was higher in cases of failure (45%; P = .003), embolic complications (38.9%; P = .0176), symptomatic intracranial hemorrhages (45.5%; P = .0236), and intracranial stenosis (50%; P = .0176). Concomitant fibrinolytic therapy did not influence the rate of recanalization or embolic complication, or the intracranial hemorrhage rate. Age was the only significant predictive factor of intracranial hemorrhage (P = .043). CONCLUSIONS: The rate of perioperative mortality was significantly increased in cases of embolic and hemorrhagic complications, as well as in cases of failure and underlying intracranial stenoses. Adjunctive fibrinolytic therapy did not improve the recanalization rate or collateral embolic complication rate. The rate of symptomatic intracranial hemorrhage was not increased in cases of combined treatment. PMID- 24157735 TI - Local and global fiber tractography in patients with epilepsy. AB - BACKGROUND AND PURPOSE: Fiber tractography is increasingly used in the preoperative evaluation of endangered fiber bundles. From a clinical point of view, an accurate and methodologically transparent procedure is desired. Our aim was to evaluate the recently described global tracking algorithm compared with other established methods, such as deterministic and probabilistic tractography. MATERIALS AND METHODS: Twenty patients, candidates for excision of epileptogenic lesions, were subjected to higher-angular resolution diffusion imaging-based fiber tractography. Seed points were created without manual bias, predominantly by FreeSurfer and voxel-based atlases. We focused on 2 important fiber bundles, namely the descending motor pathways and the optic radiation. Postoperatively, the accuracy of the predicted fiber route was controlled by structural MR imaging and by inflicted functional deficits. RESULTS: Among the 3 evaluated methods, global tracking was the only method capable of reconstructing the full extent of the descending motor pathways, including corticobulbar fibers from the area of face representation. Still, probabilistic tractography depicted the optic radiation better, especially the Meyer loop. The deterministic algorithm performed less adequately. CONCLUSIONS: The probabilistic method seems to be the best balance between computational time and effectiveness and seems to be the best choice in most cases, particularly for the optic radiation. If, however, a detailed depiction of the fiber anatomy is intended and tract crossings are implicated, then the computationally time-consuming global tracking should be preferred. PMID- 24157737 TI - Correlation between fissured fibrous cap and contrast enhancement: preliminary results with the use of CTA and histologic validation. AB - BACKGROUND AND PURPOSE: Previous studies demonstrated that carotid plaques analyzed by CTA can show contrast plaque enhancement. The purpose of this preliminary work was to evaluate the possible association between the fissured fibrous cap and contrast plaque enhancement. MATERIALS AND METHODS: Forty-seven consecutive (men = 25; average age = 66.8 +/- 9 years) symptomatic patients studied by use of a multidetector row CT scanner were prospectively analyzed. CTA was performed before and after contrast and radiation doses were recorded; analysis of contrast plaque enhancement was performed. Patients underwent carotid endarterectomy en bloc; histologic sections were prepared and evaluated for fissured fibrous cap and microvessel attenuation. The Mann-Whitney test was performed to evaluate the differences between the 2 groups. A multiple logistic regression analysis was performed to assess the effect of fissured fibrous cap and microvessel attenuation on contrast plaque enhancement. Receiver operating characteristic curve and area under the curve were also calculated. RESULTS: Twelve patients had fissured fibrous cap. In 92% (11/12) of fissured fibrous cap positive plaques, we found contrast plaque enhancement, whereas in 69% (24/35) of the plaques without fissured fibrous cap contrast plaque enhancement was found. The Mann-Whitney test showed a statistically significant difference between the contrast enhancement in plaques with fissured fibrous cap (Hounsfield units = 22.6) and without fissured fibrous cap (Hounsfield units = 12.9) (P = .011). On the regression analysis, both fissured fibrous cap and neovascularization were associated with contrast plaque enhancement (P = .0366 and P = .0001). The receiver operating characteristic curve confirmed an association between fissured fibrous cap and contrast plaque enhancement with an area under the curve of 0.749 (P = .005). CONCLUSIONS: The presence of fissured fibrous cap is associated with contrast plaque enhancement. Histologic analysis showed that the presence of fissured fibrous cap is associated with a larger contrast plaque enhancement compared with the contrast plaque enhancement of plaques without fissured fibrous cap. PMID- 24157736 TI - Neurointerventions in children: radiation exposure and its import. AB - BACKGROUND AND PURPOSE: Neurointerventions in children have dramatically improved the clinical outlook for patients with previously intractable cerebrovascular conditions, such as vein of Galen malformations and complex arteriovenous fistulas. However, these complex and sometimes lengthy procedures are performed under fluoroscopic guidance and thus unavoidably expose vulnerable pediatric patients to the effects of ionizing radiation. Recent epidemiologic evidence from a national registry of children who underwent CT scans suggests a higher-than expected incidence of secondary tumors. We sought to calculate the predicted risk of secondary tumors in a large cohort of pediatric neurointerventional patients. MATERIALS AND METHODS: We reviewed our cohort of pediatric neurointerventions, tabulated radiation dose delivered to the skin, and calculated the range of likely brain-absorbed doses by use of previously developed mathematical models. The predicted risk of secondary tumor development as a function of brain-absorbed dose in this cohort was then generated by use of the head CT registry findings. RESULTS: Maximal skin dose and brain-absorbed doses in our cohort were substantially lower than have been previously described. However, we found 1) a statistically significant correlation between radiation dose and age at procedure, as well as number and type of procedures, and 2) a substantial increase in lifetime predicted risk of tumor above baseline in the cohort of young children who undergo neurointerventions. CONCLUSIONS: Although neurointerventional procedures have dramatically improved the prognosis of children facing serious cerebrovascular conditions, the predicted risk of secondary tumors, particularly in the youngest patients and those undergoing multiple procedures, is sobering. PMID- 24157738 TI - Bacterial co-expression of the alpha and beta protomers of human l-asparaginase 3: Achieving essential N-terminal exposure of a catalytically critical threonine located in the beta-subunit. AB - l-asparaginases hydrolyze l-asparagine to l-aspartic acid and ammonia. Enzymes of bacterial origin are used as therapeutic agents for the treatment of acute lymphoblastic leukemia. Recently, the structure of a human homolog, hASNase3, which possesses l-asparaginase activity, was solved setting the basis for the development of an anti-leukemic protein drug of human origin. Being an N-terminal hydrolase, hASNase3 undergoes intramolecular self-cleavage generating two protomers (subunits alpha and beta) which remain non-covalently associated and constitute the catalytically active form of the enzyme. However, recombinant expression of full-length hASNase3 in Escherichiacoli results in only partial processing towards the active enzyme. We developed a co-expression system for the two subunits that allowed production of the beta-subunit complexed to the alpha subunit such that the N-terminal methionine is removed by endogenous methionine aminopeptidase to expose the catalytically essential threonine residue at the N terminus of the beta-subunit. The enzyme produced by this co-expression strategy is fully active, thus obviating the necessity of self-activation by slow autoproteolytic cleavage. PMID- 24157739 TI - Selective optical assembly of highly uniform nanoparticles by doughnut-shaped beams. AB - A highly efficient natural light-harvesting antenna has a ring-like structure consisting of dye molecules whose absorption band changes through selective evolutionary processes driven by external stimuli, i.e., sunlight depending on its territory and thermal fluctuations. Inspired by this fact, here, we experimentally and theoretically demonstrate the selective assembling of ring like arrangements of many silver nanorods with particular shapes and orientations onto a substrate by the light-induced force of doughnut beams with different colours (wavelengths) and polarizations in conjunction with thermal fluctuations at room temperature. Furthermore, the majority of nanorods are electromagnetically coupled to form a prominent red-shifted collective mode of localized surface plasmons resonant with the wavelength of the irradiated light, where a spectral broadening also appears for the efficient broadband optical response. The discovered principle is a promising route for "bio-inspired selective optical assembly" of various nanomaterials that can be used in the wide field of nanotechnology. PMID- 24157740 TI - It's the environment, stupid. PMID- 24157741 TI - Critical feedback. PMID- 24157742 TI - An effective pipeline. PMID- 24157743 TI - HPV concern. PMID- 24157744 TI - Doubtful wisdom. PMID- 24157758 TI - Micro-educational opportunities in outreach clinical dental education. AB - Outreach education at the University of Portsmouth Dental Academy is providing a valuable platform to offer students 'micro-educational opportunities'. Some of these are highly innovative experiences, which allow senior students across the dental team to take short periods of time away from the clinic to broaden their life experience. The maturity of senior students generates a significant added value to their educational experiences with minimal loss of clinical time. Another important outcome, which echoes the Marmot review on Health Inequalities (2010), is the population of the City of Portsmouth, particularly the socially deprived, gain better access to oral health advice, prevention and treatment. Our experience suggests these opportunities enhance the undergraduate experience, equipping our new colleagues for a professional life in a changing and challenging environment. PMID- 24157759 TI - Oral surgery: part 4. Minimising and managing nerve injuries and other complications. AB - Many post-operative complications can be avoided with good patient selection, training and surgical planning. Obtaining explicit patient consent is also an essential component of treatment. The most significant complications from oral surgical interventions are iatrogenic trigeminal nerve injuries, which can result in permanent altered sensation and pain, causing considerable functional and psychological disability. This paper provides some useful suggestions on minimising the risks of these injuries. By understanding the risk factors and modifying the resulting intervention, more of these injuries may be prevented. PMID- 24157760 TI - Surfing the spectrum - what is on the horizon? AB - Diagnostic imaging techniques have evolved with technological advancements - but how far? The objective of this article was to explore the electromagnetic spectrum to find imaging techniques which may deliver diagnostic information of equal, or improved, standing to conventional radiographs and to explore any developments within radiography which may yield improved diagnostic data. A comprehensive literature search was performed using Medline, Web of Knowledge, Science Direct and PubMed Databases. Boolean Operators were used and key-terms included (not exclusively): terahertz, X-ray, ultraviolet, visible, infra-red, magnetic resonance, dental, diagnostic, caries and periodontal. Radiographic techniques are primarily used for diagnostic imaging in dentistry, and continued developments in X-ray imaging include: phase contrast, darkfield and spectral imaging. Other modalities have potential application, for example, terahertz, laser doppler and optical techniques, but require further development. In particular, infra-red imaging has regenerated interest with caries detection in vitro, due to improved quality and accessibility of cameras. Non-ionising imaging techniques, for example, infra-red, are becoming more commensurate with traditional radiographic techniques for caries detection. Nevertheless, X-rays continue to be the leading diagnostic image for dentists, with improved diagnostic potential for lower radiation dose becoming a reality. PMID- 24157765 TI - Summary of: a school-based oral health intervention in East London: the Happy Teeth fluoride varnish programme. AB - BACKGROUND: The Community Dental Services of Barts Health NHS Trust in City and Hackney and Tower Hamlets PCTs in East London have provided a school-based oral health intervention since 2009. OBJECTIVE: The aim of this paper is to present the programme development, outcomes and evaluation. SUBJECTS AND METHODS: The programme consists of fluoride varnish (FV) applications linked to school dental screenings for three- to six-year-olds, combined with oral health promotion for parents/carers. An outreach linkworker works closely with schools to help identify and support vulnerable families into the programme. RESULTS: In the first year of the programme 160 of the target children (42%) had one FV application and 81 children (21%) had two applications. In the second year 149 children (39%) had one FV application, and 113 (29%) had two applications. Amendments to the protocol increased programme participation in the third year, with 1,822 of the target children (61%) having one FV application and 1,586 (53%) having two applications. CONCLUSIONS: The programme proved acceptable to the school staff, participating parents/carers and children. The Happy Teeth programme is proposed as a model for school-based fluoride varnish programmes. PMID- 24157766 TI - 'Vacation for your teeth' - dental tourists in Hungary from the perspective of Hungarian dentists. AB - BACKGROUND: Hungary has become a popular destination for foreign patients in the last two decades, particularly in dental care. Since 2008, increasing prices in Western Europe coupled with Hungary's accessibility and availability of dental treatment, has meant the country has become a leader in 'dental tourism'. As the quality of care in Hungary is high and prices are more affordable than in Western Europe, and due to the freedom of movement of people, services and goods within the EU, patient flow into Hungary has increased progressively. OBJECTIVES: The aim of this article is to provide comprehensive empirical evidence from the perspective of a recipient country in dental tourism. METHODS: A questionnaire survey was conducted among Hungarian dentists (n = 273). Qualitative in-depth interviews were conducted with representatives of dental professional bodies (n = 10). Both research methods aimed to elicit dentists' views on the presence of dental tourism - particularly the push and pull factors (for example, source countries, competitors, information sources, patient motivation). RESULTS: The findings show that there are several reasons why Hungary could maintain a leading position in dental tourism. First, the cost/benefit ratio is outstanding. The affordable price and value for money were already recognised in the early 1990s and were appreciated even before Hungary joined the EU. Secondly, the high quality of Hungary's dental profession: a) dental professionals in Hungary are well-qualified dental practitioners who have received high level dental training; b) dental professional standards are up-to-date and often supervised; c) in Hungary dental technology, the quality of materials and equipment used in dental practices is of European level quality. The rate of complications in dental care is around 5%, similar to other European countries. Finally, previous treatment experiences are positive and patient satisfaction levels are high. More and more patients seek care in Hungary, and more and more patients state that they would be willing to return for further treatment in the future. PMID- 24157781 TI - Iain Chapple: 'as a clinician, you assume that people know what periodontitis is'. AB - Iain Chapple talks to the BDJ about implant failure, the teaching predicament for UK dental schools and why we must teach the public about the dangers of periodontitis. PMID- 24157788 TI - A school-based oral health intervention in East London: the Happy Teeth fluoride varnish programme. AB - BACKGROUND: The Community Dental Services of Barts Health NHS Trust in City and Hackney and Tower Hamlets PCTs in East London have provided a school-based oral health intervention since 2009. OBJECTIVE: The aim of this paper is to present the programme development, outcomes and evaluation. SUBJECTS AND METHODS: The programme consists of fluoride varnish applications linked to school dental screenings for three to six-year-olds, combined with oral health promotion for parents/carers. An outreach linkworker works closely with schools to help identify and support vulnerable families into the programme. RESULTS: In the first year of the programme 160 of the target children (42%) had one FV application and 81 children (21%) had two applications. In the second year 149 children (39%) had one FV application, and 113 (29%) had two applications. Amendments to the protocol increased programme participation in the third year, with 1,822 of the target children (61%) having one FV application and 1,586 (53%) having two applications. CONCLUSIONS: The programme proved acceptable to the school staff, participating parents/carers and children. The Happy Teeth programme is proposed as a model for school-based fluoride varnish programmes. PMID- 24157789 TI - A pilot of a school-based dental treatment programme for vulnerable children with possible dental neglect: the Back2School programme. AB - BACKGROUND: The general dental practitioners and community dental services of Barts Health NHS Trust in City and Hackney and Tower Hamlets PCTs in East London currently provide a school-based oral health prevention programme. The programme provides dental screening for three- to six-year-olds, fluoride varnish application twice during the school year and engaging with the families to encourage dental attendance. An evaluation of the programme suggested that children with a dental treatment need, identified by the screening, were not being taken for further dental care. OBJECTIVE: The aim of this 'Back2School' pilot was to evaluate the use of mobile dental units in the provision of care to this group of children. The objectives were to assess if this care was acceptable to the children and their families, to evaluate dental treatment provided, patient attendance, costs of the service and whether it would be a viable method to provide dental care. METHODS: The rotation of the mobile dental unit in this pilot offered ten sessions of dental care over five days in three different locations. The locations were chosen near the five schools covered by the community dental service. RESULTS: A total of 63 children were seen; 33 females and 30 males, which included 7 walk-in patients. Five children had extractions and the number of fillings ranged from one to six. Of the 63 children seen only 8 (13%) had attended a dentist before, 59 (93%) of the children were rated 'high risk' for dental disease, 61 (97%) of the children received a fluoride varnish application and 95.2 UDAs were achieved. Feedback was positive overall. CONCLUSIONS: The use of a community-based mobile dental unit has the potential to be a cost-effective method to remove barriers to dental care access, both for the treatment of vulnerable children and as a first point of contact in the dental care pathway. PMID- 24157790 TI - Peptidomic comparison and characterization of the major components of the venom of the giant ant Dinoponera quadriceps collected in four different areas of Brazil. AB - Despite the noxious effects inflicted by Dinoponera ant's envenomation, the information about the biological properties and composition of their venom is still very limited. Ants from the genus Dinoponera are believed to be the world's largest living ants with a body length of 3cm. Their occurrence is restricted to tropical areas of South America. In this work, we study the venom of the giant Dinoponera quadriceps ant collected in 4 different regions of Brazil. By using a combination of complementary mass spectrometric approaches, we aim at: (i) characterizing the venom composition of these ants; (ii) establishing a comparative analysis of the venom from four geographically different regions in Brazil. This approach demonstrates that ant venom is a copious source of new compounds. Several peptides were identified and selected for "de novo sequencing". Since most of the new peptides showed similarities with antimicrobial peptides (AMPs), antimicrobial assays were performed with the purpose of evaluating their activity. In regard to the comparative study of the four regions, we observed not only major differences in the venom compositions, but also that the venoms collected in closest areas are more similar than the ones collected in distant regions. These observations seem to highlight an adaption of the ant venoms to the local environment. Concerning the biological assays, the peptides called Dq-3162 and Da-3177 showed a wide-ranging antimicrobial activity. The characterization of new AMPs with a broad spectrum of activity and different scaffolds may aid scientists to design new therapeutic agents and understand the mechanisms of those peptides to interact with microbial membranes. The results obtained betoken the biotechnological potential of ant's venom. BIOLOGICAL SIGNIFICANCE: For the first time this manuscript describes an extensive proteomics characterization of the D. quadriceps venom. In addition this study reports the variation in venom composition of primitive ants from 4 geographically different areas of Brazil. The results reveal the presence of ~335 compounds for each venom/area and inter-colony variations were observed. 16 new peptides were characterized and 2 of them were synthesized and biologically assayed. These findings highlight the considerable and still unexplored diversity of ant's venom which could be used as valuable research tools in different areas of knowledge. PMID- 24157791 TI - MiR-145 is downregulated in human ovarian cancer and modulates cell growth and invasion by targeting p70S6K1 and MUC1. AB - MicroRNAs (miRNAs) are a family of small non-coding RNA molecules that regulate gene expression at post-transcriptional levels. Previous studies have shown that miR-145 is downregulated in human ovarian cancer; however, the roles of miR-145 in ovarian cancer growth and invasion have not been fully demonstrated. In the present study, Northern blot and qRT-PCR analysis indicate that miR-145 is downregulated in ovarian cancer tissues and cell lines, as well as in serum samples of ovarian cancer, compared to healthy ovarian tissues, cell lines and serum samples. Functional studies suggest that miR-145 overexpression leads to the inhibition of colony formation, cell proliferation, cell growth viability and invasion, and the induction of cell apoptosis. In accordance with the effect of miR-145 on cell growth, miR-145 suppresses tumor growth in vivo. MiR-145 is found to negatively regulate P70S6K1 and MUC1 protein levels by directly targeting their 3'UTRs. Importantly, the overexpression of p70S6K1 and MUC1 can restore the cell colony formation and invasion abilities that are reduced by miR-145, respectively. MiR-145 expression is increased after 5-aza-CdR treatment, and 5 aza-CdR treatment results in the same phenotype as the effect of miR-145 overexpression. Our study suggests that miR-145 modulates ovarian cancer growth and invasion by suppressing p70S6K1 and MUC1, functioning as a tumor suppressor. Moreover, our data imply that miR-145 has potential as a miRNA-based therapeutic target for ovarian cancer. PMID- 24157792 TI - Serum-induced up-regulation of hepcidin expression involves the bone morphogenetic protein signaling pathway. AB - Hepcidin is a peptide hormone that is secreted by the liver and that functions as the central regulator of systemic iron metabolism in mammals. Its expression is regulated at the transcriptional level by changes in iron status and iron requirements, and by inflammatory cues. There is considerable interest in understanding the mechanisms that influence hepcidin expression because dysregulation of hepcidin production is associated with a number of disease states and can lead to iron overload or iron-restricted anemia. In order to shed light on the factors that alter hepcidin expression, we carried out experiments with HepG2 and HuH7, human hepatoma cell lines that are widely used for this purpose. We found that the addition of heat-inactivated fetal calf serum to these cells resulted in a significant dose- and time-dependent up-regulation of hepcidin expression. Serum also activated signaling events known to be downstream of bone morphogenetic proteins (BMPs), a group of molecules that have been implicated previously in hepcidin regulation. Inhibition of these signals with dorsomorphin significantly suppressed serum-induced hepcidin up-regulation. Our results indicate that a BMP or BMP-like molecule present in serum may play an important role in regulating hepcidin expression. PMID- 24157793 TI - Blockade of SOCE protects HT22 cells from hydrogen peroxide-induced apoptosis. AB - Oxidative stress is an established event in the pathology of neurobiological diseases. Previous studies indicated that store-operated Ca(2+) entry (SOCE) has been involved in oxidative stress. The present study was carried out to investigate the effects of SOCE inhibition on neuronal oxidative stress injury induced by hydrogen peroxide (H2O2) in HT22 cells, a murine hippocampal neuronal model. H2O2 insult induced significant intracellular Ca(2+) overload, mitochondrial dysfunction and cell viability decrease. Inhibition of SOCE by pharmacological inhibitor and STIM1 RNAi significantly alleviated intracellular Ca(2+) overload, restored the mitochondrial membrane potential (MMP), decreased cytochrome C release and eventually inhibited H2O2-induced cell apoptosis. These findings suggest that SOCE inhibition exhibited neuroprotection against oxidative stress induced by H2O2 and SOCE might be a useful therapeutic target in neurobiological disorders. PMID- 24157794 TI - Dynamic modulation of FGFR1-5-HT1A heteroreceptor complexes. Agonist treatment enhances participation of FGFR1 and 5-HT1A homodimers and recruitment of beta arrestin2. AB - New findings show that neurotrophic and antidepressant effects of 5-HT in brain can, in part, be mediated by activation of the 5-HT1A receptor protomer in the hippocampal and raphe FGFR1-5-HT1A heteroreceptor complexes enhancing the FGFR1 signaling. The dynamic agonist modulation of the FGFR1-5-HT1A heteroreceptor complexes and their recruitment of beta-arrestin is now determined in cellular models with focus on its impact on 5-HT1AR and FGFR1 homodimerization in the heteroreceptor complexes based on BRET(2) assays. The findings show that coagonist treatment with 8-OH-DPAT and FGF2 but not treatment with the 5-HT1A agonist alone markedly increases the BRETmax values and significantly reduces the BRET50 values of 5HT1A homodimerization. The effects of FGF2 or FGF20 with or without the 5-HT1A agonist were also studied on the FGFR1 homodimerization of the heteroreceptor complexes. FGF2 produced a marked and rapid increase in FGFR1 homodimerization which partially declined over a 10min period. Cotreatment with FGF2 and 5-HT1A agonist blocked this decline in FGFR1 homodimerization. Furthermore, FGF2 alone produced a small increase in the BRET(2) signal from the 5-HT1A-beta-arrestin2 receptor-protein complex which was additive to the marked effect of 8-OH-DPAT alone. Taken together, the participation of 5-HT1A and FGFR1 homodimers and recruitment of beta-arrestin2 was demonstrated in the FGFR1-5-HT1A heteroreceptor complexes upon agonist treatments. PMID- 24157796 TI - Nursing must stop "eating its young". PMID- 24157795 TI - Insights into the carboxyltransferase reaction of pyruvate carboxylase from the structures of bound product and intermediate analogs. AB - Pyruvate carboxylase (PC) is a biotin-dependent enzyme that catalyzes the MgATP- and bicarbonate-dependent carboxylation of pyruvate to oxaloacetate, an important anaplerotic reaction in central metabolism. The carboxyltransferase (CT) domain of PC catalyzes the transfer of a carboxyl group from carboxybiotin to the accepting substrate, pyruvate. It has been hypothesized that the reactive enolpyruvate intermediate is stabilized through a bidentate interaction with the metal ion in the CT domain active site. Whereas bidentate ligands are commonly observed in enzymes catalyzing reactions proceeding through an enolpyruvate intermediate, no bidentate interaction has yet been observed in the CT domain of PC. Here, we report three X-ray crystal structures of the Rhizobium etli PC CT domain with the bound inhibitors oxalate, 3-hydroxypyruvate, and 3-bromopyruvate. Oxalate, a stereoelectronic mimic of the enolpyruvate intermediate, does not interact directly with the metal ion. Instead, oxalate is buried in a pocket formed by several positively charged amino acid residues and the metal ion. Furthermore, both 3-hydroxypyruvate and 3-bromopyruvate, analogs of the reaction product oxaloacetate, bind in an identical manner to oxalate suggesting that the substrate maintains its orientation in the active site throughout catalysis. Together, these structures indicate that the substrates, products and intermediates in the PC-catalyzed reaction are not oriented in the active site as previously assumed. The absence of a bidentate interaction with the active site metal appears to be a unique mechanistic feature among the small group of biotin dependent enzymes that act on alpha-keto acid substrates. PMID- 24157797 TI - A portrait of the bedside: clinical nurse leaders complete the picture. PMID- 24157798 TI - Salutogenesis: the origin of health. PMID- 24157799 TI - Early warning signs and the EHR: at the intersection of technology and care. PMID- 24157800 TI - Get smart with smart pumps. PMID- 24157801 TI - The balancing act. PMID- 24157802 TI - Rekindling the flame: using mindfulness to end nursing burnout. PMID- 24157804 TI - The great healthcare debate: for-profit vs. not-for-profit. PMID- 24157805 TI - Consider the children: pediatric disaster planning. PMID- 24157806 TI - The cure for workplace bullying. PMID- 24157807 TI - Leadership Q&A. PMID- 24157808 TI - Increased activation and differentiated localization of native and phosphorylated STAT3 in nasal polyps. AB - BACKGROUND: Chronic rhinosinusitis with nasal polyps (CRSwNP) is a multifactorial disease; the underlying mechanisms of cell signalling are not fully understood. STAT3 (signal transducer and activator of transcription 3) is a phosphokinase and a key signalling molecule implicated in cell cycle regulation. We studied the distribution and expression of STAT3 to examine the role of STAT3 in the pathogenesis of CRSwNP. METHODS: We investigated tissue samples of the nasal polyps and inferior turbinate of patients with CRSwNP as well as samples of the inferior turbinate of subjects without chronic sinusitis. The expression levels of STAT3 and its activated form pSTAT3 were analysed using Western blotting, protein array, DNA microarray and immunohistochemistry. RESULTS: No significant differences were found in STAT3-mRNA levels between the samples of nasal polyps and inferior turbinates of the same patient. However, the amount of pSTAT3 was increased in the polyp tissue compared to the inferior turbinates from both CRSwNP patients and control subjects (p < 0.01), indicating an activation of STAT3 in polyps. We identified a varying distribution pattern of pSTAT3; pSTAT3 was primarily found in superficial epithelial cells but not in the basal layer of the epithelium of the turbinate, whereas pSTAT3 was located in all layers of the epithelium of the polyp and mostly noted in the basal layer. CONCLUSIONS: Our results of the activation and varying localisation of STAT3 and its phosphorylated form in nasal polyps suggest that pSTAT3 plays a crucial role in the proliferative development of nasal polyps. PMID- 24157809 TI - Focussed ion beam serial sectioning and imaging of monolithic materials for 3D reconstruction and morphological parameter evaluation. AB - A new characterisation method, based on the utilisation of focussed ion beam scanning electron microscopy (FIB-SEM), has been employed for the evaluation of morphological parameters in porous monolithic materials. Sample FIB serial sectioning, SEM imaging and image processing techniques were used to extract the pore boundaries and reconstruct the 3D porous structure of carbon and silica based monoliths. Since silica is a non-conducting material, a commercial silica monolith modified with activated carbon was employed instead to minimise the charge build-up during FIB sectioning. This work therefore presents a novel methodology that can be successfully employed for 3D reconstruction of porous monolithic materials which are or can be made conductive through surface or bulk modification. Furthermore, the 3D reconstructions were used for calculation of the monolith macroporosity, which was in good agreement with the porosity values obtained by mercury intrusion porosimetry (MIP). PMID- 24157810 TI - Identification of tumor antigens that elicit a humoral immune response in the sera of Chinese esophageal squamous cell carcinoma patients by modified serological proteome analysis. AB - Our aim was to identify novel tumor-associated antigens from the esophageal squamous cell carcinoma (ESCC) cell line EC0156, and related autoantibodies in sera from patients with ESCC. We used modified serological proteome analysis, involving one- and two-dimensional electrophoresis, Western blot, and MALDI TOF/TOF-MS to identify 6 ESCC-associated antigens. From these, 105 kDa heat shock protein (HSP105) and triosephosphate isomerase (TIM) were further evaluated and we determined they could induce autoantibody responses in ESCC sera and are highly expressed in ESCC tissues. Anti-HSP105 and anti-TIM autoantibodies were found in 39.1% (18/46) and 34.8% (16/46) of patients with ESCC, respectively, but only in two controls. A receiver operating characteristic curve constructed with HSP105 and TIM gave a sensitivity of 54.3% and 95% (38/40) specificity in discriminating ESCC from matched controls. Interestingly, we found that autoantibodies against TIM in ESCC serum mainly reacted with glycosylated but not deglycosylated TIM. The preliminary results suggest the potential utility of screening autoantibodies in sera for use as biomarkers for cancer diagnosis. PMID- 24157811 TI - One mouse, one patient paradigm: New avatars of personalized cancer therapy. AB - Over the last few decades, study of cancer in mouse models has gained popularity. Sophisticated genetic manipulation technologies and commercialization of these murine systems have made it possible to generate mice to study human disease. Given the large socio-economic burden of cancer, both on academic research and the health care industry, there is a need for in vivo animal cancer models that can provide a rationale that is translatable to the clinic. Such a bench-to bedside transition will facilitate a long term robust strategy that is economically feasible and clinically effective to manage cancer. The major hurdles in considering mouse models as a translational platform are the lack of tumor heterogeneity and genetic diversity, which are a hallmark of human cancers. The present review, while critical of these pitfalls, discusses two newly emerging concepts of personalized mouse models called "Mouse Avatars" and Co clinical Trials. Development of "Mouse Avatars" entails implantation of patient tumor samples in mice for subsequent use in drug efficacy studies. These avatars allow for each patient to have their own tumor growing in an in vivo system, thereby allowing the identification of a personalized therapeutic regimen, eliminating the cost and toxicity associated with non-targeted chemotherapeutic measures. In Co-clinical Trials, genetically engineered mouse models (GEMMs) are used to guide therapy in an ongoing human patient trial. Murine and patient trials are conducted concurrently, and information obtained from the murine system is applied towards future clinical management of the patient's tumor. The concurrent trials allow for a real-time integration of the murine and human tumor data. In combination with several molecular profiling techniques, the "Mouse Avatar" and Co-clinical Trial concepts have the potential to revolutionize the drug development and health care process. The present review outlines the current status, challenges and the future potential of these two new in vivo approaches in the field of personalized oncology. PMID- 24157814 TI - Correction. PMID- 24157813 TI - Association between genetic variations in MTNR1A and MTNR1B genes and gestational diabetes mellitus in Han Chinese women. AB - BACKGROUND/AIMS: The purpose of this study was to investigate the association between MTNR1A and MTNR1B gene polymorphisms and gestational diabetes mellitus (GDM) in Han Chinese women. METHODS: Study participants included 350 patients with GDM and 480 control subjects. Three single-nucleotide polymorphisms (SNPs; rs2119882 in MTNR1A and rs10830963 and rs10830962 in MTNR1B) were genotyped using direct sequencing. Genotype and allele distributions of SNPs in cases of GDM and controls were analyzed. Association of the MTNR1A and MTNR1B gene variants with plasma glucose and insulin levels as well as blood lipid levels was further investigated. RESULTS: The frequencies of genotypes and allele types of rs2119882 in MTNR1A and rs10830963 in MTNR1B were significantly different between women with GDM and controls (p < 0.05). Moreover, in the GDM group, these SNPs were associated with increased fasting plasma glucose concentrations (p < 0.001) and increased homeostasis model assessment of insulin resistance (p < 0.001). The rs10830962 polymorphism in MTNR1B was not associated with an increased risk of developing GDM or any of the clinical or metabolic characteristics in patients with GDM (p > 0.05). CONCLUSION: The genetic polymorphisms rs2119882 in MTNR1A and rs10830963 in MTNR1B are associated with an increased risk of developing GDM and insulin resistance in Han Chinese women. PMID- 24157812 TI - Osteopontin-a alters glucose homeostasis in anchorage-independent breast cancer cells. AB - Invasive breast tumor cells generate three splice variants of the metastasis gene osteopontin, while non-invasive breast cells express only the unspliced form or no osteopontin at all. One role for osteopontin in tumor progression is the support of anchorage-independence. Here we show that the full-length gene product, osteopontin-a, induces a gene expression profile that is associated with tissue remodeling and directed movement/sprouting. This occurs via signals through STAT1 and STAT3 to sn-glycero-3-phosphocholine. Osteopontin-a upregulates the levels of glucose in breast cancer cells, likely through STAT3 and its transcriptional targets apolipoprotein D and IGFBP5. The splice variants osteopontin-a and osteopontin-c may synergize, with each form activating signal transduction pathways that are distinct from the other. The elevated glucose is used by osteopontin-c dependent signals to generate chemical energy (Shi et al. submitted for publication). The splice variant-specific metabolic effects of osteopontin add a novel aspect to the pro-metastatic functions of this molecule. PMID- 24157815 TI - Development of a risk assessment tool for contact tracing people after contact with infectious patients while travelling by bus or other public ground transport: a Delphi consensus approach. AB - BACKGROUND: Tracing persons who have been in contact with an infectious patient may be very effective in preventing the spread of communicable diseases. However, criteria to decide when to conduct contact tracing are not well established. We have investigated the available evidence for contact tracing with a focus on public ground transport aiming to give guidance in what situations contact tracing should be considered. METHODS: Relevant infectious diseases suitable for contact tracing in ground transport and a set of disease-specific epidemiological criteria were defined through literature search and structured multistep expert consultations. We developed continuous scales for each criterion to be rated for its relevance to contact tracing in ground transport. We used the Delphi method with an international expert panel to position the values of criteria on the respective scales. RESULTS: The study led to the development of the 'Contact Tracing-Risk Assessment Profile' (CT-RAP), a decision-making instrument, taking into account pathogen-specific as well as situation-specific criteria. This report describes the methodology of this instrument and presents two examples of ready-to-use CT-RAP for tuberculosis and for meningococcal disease in public ground transport. DISCUSSION: The systematic and transparent use of the CT-RAP for tuberculosis and meningococcal disease is likely to facilitate reasonable, efficient and user-friendly decisions with respect to contact tracing. New CT RAPs for additional pathogens and different settings such as schools and kindergartens are being planned. PMID- 24157817 TI - Correction. PMID- 24157816 TI - Cardiovascular health knowledge, attitude and practice/behaviour in an urbanising community of Nepal: a population-based cross-sectional study from Jhaukhel Duwakot Health Demographic Surveillance Site. AB - OBJECTIVES: This study determined the knowledge, attitude and practice/behaviour of cardiovascular health in residents of a semiurban community of Nepal. DESIGN: To increase the understanding of knowledge, attitude and practice/behaviour towards cardiovascular health, we conducted in-home interviews using a questionnaire based on the WHO STEPwise approach to surveillance and other resources, scoring all responses. We also recorded blood pressure and took anthropometric measurements. SETTING: Our study was conducted as part of the Heart-Health-Associated Research and Dissemination in the Community project in the Jhaukhel-Duwakot Health Demographic Surveillance Site in two urbanising villages near Kathmandu. PARTICIPANTS: The study population included 777 respondents from six randomly selected clusters in both villages. RESULTS: Seventy per cent of all participants were women and 26.9% lacked formal education. The burden of cardiovascular risk factors was high; 20.1% were current smokers, 43.3% exhibited low physical activity and 21.6% were hypertensive. Participants showed only poor knowledge of heart disease causes; 29.7% identified hypertension and 11% identified overweight and physical activity as causes, whereas only 2.2% identified high blood sugar as causative. Around 60% of respondents did not know any heart attack symptoms compared with 20% who knew 2-4 symptoms. Median percentage scores for knowledge, attitude and practice/behaviour were 79.3, 74.3 and 48, respectively. Nearly 44% of respondents had insufficient knowledge and less than 20% had highly satisfactory knowledge. Among those with highly satisfactory knowledge, only 14.7% had a highly satisfactory attitude and 19.5% and 13.9% had satisfactory and highly satisfactory practices, respectively. CONCLUSIONS: Our study demonstrates a gap between cardiovascular health knowledge, attitude and practice/behaviour in a semiurban community in a low income nation, even among those already affected by cardiovascular disease. PMID- 24157818 TI - Vitamin D status in recently arrived immigrants from Africa and Asia: a cross sectional study from Norway of children, adolescents and adults. AB - OBJECTIVES: To estimate the prevalence of vitamin D deficiency (25(OH)D) <50 nmol/L among recently arrived immigrants from Africa and Asia in Oslo, and to explore 25(OH)D levels according to origin, gender and age. DESIGN: A cross sectional study. SETTING: Primary healthcare unit in Oslo, Norway, offering family immigrants, asylum seekers, United Nations (UN) refugees or individuals granted asylum a free medical examination on arrival. PARTICIPANTS: All individuals from African and Asian countries (n=591) referred to the Centre of Migrant Health, Health Agency, Oslo, Norway in 2010, estimated to cover 60% of the targeted population. RESULTS: 25(OH)D <50 nmol/L was very prevalent in immigrants from the Middle East (81% (95% CI 75.4% to 86.6%)), South Sahara Africa (73% (CI 67.5% to 78.5%)) and South Asia (75% (CI 64.0% to 86.0%)), in contrast to East Asians (24% (CI 12.6% to 35.4%)), p<0.001 for differences. The prevalence of 25(OH)D<25 nmol/L was lower but followed the same pattern (Middle East: 38% (CI 31.1% to 45.0%), South Sahara Africa: 24% (CI 18.7% to 29.3%) and South Asia: 35% (CI 22.9% to 47.1%), although it was not observed in East Asians (p<0.001 for differences)). The ethnic differences persisted after adjusting for the duration of residence, seasonality and residence status in multiple linear regression analyses. Female adolescents from South Asia, the Middle East and South Sahara Africa had the lowest levels of 25(OH)D. Further, country-specific median levels of 25(OH)D were low (24-38 nmol/L) among groups from Somalia, Eritrea, Afghanistan and Iraq, the countries with the largest number of immigrants in our study. CONCLUSIONS: The majority of recently settled immigrant groups from the Middle East, South Asia and Africa had 25(OH)D <50 nmol/L, in contrast to East Asians. Female adolescents from these regions had the lowest levels of 25(OH)D. PMID- 24157819 TI - Randomised controlled trial of vitamin D supplementation in sarcoidosis. AB - OBJECTIVES: The role vitamin D intake/production plays in sarcoidosis-associated hypercalcaemia is uncertain. However, authoritative reviews have recommended avoiding sunlight exposure and vitamin D supplements, which might lead to adverse skeletal outcomes from vitamin D insufficiency. We investigated the effects of vitamin D supplementation on surrogate measures of skeletal health in patients with sarcoidosis and vitamin D insufficiency. DESIGN: Randomised, placebo controlled trial. SETTING: Clinical research centre. PARTICIPANTS: 27 normocalcaemic patients with sarcoidosis and 25-hydroxyvitamin D (25OHD) <50 nmol/L. INTERVENTION: 50 000 IU weekly cholecalciferol for 4 weeks, then 50 000 IU monthly for 11 months or placebo. PRIMARY AND SECONDARY OUTCOME MEASURES: The primary endpoint was the change in serum calcium over 12 months, and secondary endpoints included measurements of calcitropic hormones, bone turnover markers and bone mineral density (BMD). RESULTS: The mean age of participants was 57 years and 70% were women. The mean (SD) screening 25OHD was 35 (12) and 38 (9) nmol/L in the treatment and control groups, respectively. Vitamin D supplementation increased 25OHD to 94 nmol/L after 4 weeks, 84 nmol/L at 6 months and 78 nmol/L at 12 months, while levels remained stable in the control group. 1,25-Dihydroxy vitamin D levels were significantly different between the groups at 4 weeks, but not at 6 or 12 months. There were no between-groups differences in albumin-adjusted serum calcium, 24 h urine calcium, markers of bone turnover, parathyroid hormone or BMD over the trial. One participant developed significant hypercalcaemia after 6 weeks (total cholecalciferol dose 250 000 IU). CONCLUSIONS: In patients with sarcoidosis and 25OHD <50 nmol/L, vitamin D supplements did not alter average serum calcium or urine calcium, but had no benefit on surrogate markers of skeletal health and caused one case of significant hypercalcaemia. TRIAL REGISTRATION: This trial is registered at the Australian New Zealand Clinical Trials Registry (http://www.anzctr.org.au). The registration number is ACTRN12607000364471, date of registration 5/7/2007. PMID- 24157820 TI - Service providers' perspectives, attitudes and beliefs on health services delivery for Aboriginal people receiving haemodialysis in rural Australia: a qualitative study. AB - OBJECTIVE: Providing services to rural dwelling minority cultural groups with serious chronic disease is challenging due to access to care and cultural differences. This study aimed to describe service providers' perspectives on health services delivery for Aboriginal people receiving haemodialysis for end stage kidney disease in rural Australia. DESIGN: Semistructured interviews, thematic analysis SETTING: A health district in rural New South Wales, Australia PARTICIPANTS: Using purposive sampling, 29 renal and allied service providers were recruited, including nephrologists, renal nurses, community nurses, Aboriginal health workers, social workers and managers. Six were Aboriginal and 23 non-Aboriginal. RESULTS: Improving cultural understanding within the healthcare system was central to five themes identified: rigidity of service design (outreach, inevitable home treatment failures, pressure of system overload, limited efficacy of cultural awareness training and conflicting priorities in acute care); responding to social complexities (respecting but challenged by family obligations, assumptions about socioeconomic status and individualised care); promoting empowerment, trust and rapport (bridging gaps in cultural understanding, acknowledging the relationship between land, people and environment, and being time poor); distress at late diagnosis (lost opportunities and prioritise prevention); and contending with discrimination and racism (inherent judgement of lifestyle choices, inadequate cultural awareness, pervasive multilevel institutionalised racism and managing patient distrust). CONCLUSIONS: Service providers believe current services are not designed to address cultural needs and Aboriginality, and that caring for Aboriginal patients receiving haemodialysis should be family focused and culturally safer. An Aboriginal-specific predialysis pathway, building staff cultural awareness and enhancing cultural safety within hospitals are the measures recommended. Increasing patient support for home haemodialysis may improve health and the quality of care outcomes. PMID- 24157821 TI - Comparative study of the effects of room air and sulfur hexafluoride gas tamponade on functional and morphological recovery after macular hole surgery: a retrospective study. AB - BACKGROUND: To compare the effects of room air and sulfur hexafluoride (SF6) gas tamponade on functional and morphological macular recovery after vitrectomy for the treatment of idiopathic macular hole (MH). METHODS: A total of 22 eyes of 22 patients with preoperative diameter of MH smaller than 500 um were retrospectively studied. Pars plana vitrectomy with internal limiting membrane peeling was performed, followed by fluid-air exchange with room air or 20% SF6. Surgical outcomes were analyzed, regarding best-corrected visual acuity (BCVA) and spectral domain optical coherence tomography images. RESULTS: The primary closure rate was 100% in both groups, while there was a statistically significant difference in the prone posturing period between the SF6 group (7.0 +/- 1.6 days) and the air group (3.7 +/- 0.6 days; p < 0.0001, unpaired t test). Mean BCVA at baseline, month 1 and month 3 was 0.25, 0.63 and 0.77 in decimal units in the SF6 group and 0.32, 0.60 and 0.73 in the air group, respectively. CONCLUSIONS: This study suggests that room air tamponade may provide equally prompt functional and morphological recovery as well as a comparable rate of MH closure with even a shorter prone posturing period compared with SF6 gas tamponade, at least for MH with relatively small diameters. PMID- 24157823 TI - Cultural adaptation, standardization and clinical validity of the test your memory dementia screening instrument in Greek. AB - BACKGROUND/AIMS: To adapt and standardize the Test Your Memory (TYM) dementia screening instrument in Greek. METHODS: Normative data on the Greek version of the TYM were obtained from a community sample of 239 adults aged 21-92 years. Clinical validity was assessed in a cohort of 134 Neurology Clinic patients. Concurrent validity was examined through comparisons with the Mini-Mental State Examination (MMSE) and the Greek Everyday Function Scale. RESULTS: Correlations between the TYM and the MMSE were 0.73 and 0.82 in the community and patient samples, respectively. Scores on both tests were moderately associated with everyday functional capacity. Using age- and education-corrected cutoff scores ranging from 26/50 to 45/50 points, the sensitivity of the TYM for Alzheimer's disease detection was found to be higher than that of the MMSE (0.82 vs. 0.70), although its specificity was lower (0.71 vs. 0.90). CONCLUSION: Findings are consistent with previous reports in a variety of cultural settings supporting the potential utility of the TYM as a dementia screening tool. PMID- 24157824 TI - CCL5/RANTES, sVCAM-1, and sICAM-1 in chronic spontaneous urticaria. AB - BACKGROUND: Chronic urticaria (CU) is a common disease characterized by recurrent itchy wheals and/or angioedema for more than 6 weeks. We aimed to investigate the potential involvement of chemotactic mediators and soluble adhesion molecules as markers of endothelial dysfunction in the pathogenesis of chronic spontaneous urticaria (CSU). The potential relevance of these soluble mediators in the evaluation of disease activity was also investigated. METHODS: We measured the levels of CCL5/RANTES, CXCL8/IL-8, sVCAM-1, and sICAM-1 in the sera of 87 patients with CSU and 61 normal healthy subjects (NHS) using ELISA assays. According to the results of autologous serum skin tests (ASST), CSU patients were classified into ASST-positive and ASST-negative subgroups. Furthermore, we investigated in 4 patients whether H1-antihistamine therapy decreases sVCAM-1 and sICAM-1 levels. RESULTS: We detected a significantly higher concentration of CCL5/RANTES (p < 0.0001) but not of CXCL8/IL-8 in CSU patients compared to NHS. The serum levels of sICAM-1 and sVCAM-1 were significantly increased in CSU patients compared to NHS (p = 0.0121 and p = 0.0043, respectively). No difference in chemokine or soluble adhesion molecule levels was detected between the ASST positive and ASST-negative subgroups. A positive correlation was found between sICAM-1 and sVCAM-1 (p = 0.0022) but not between these and CCL5/RANTES. After H1 antihistamine therapy, sVCAM-1 and sICAM-1 levels did not decrease in the 4 CSU patients tested. CONCLUSIONS: Our study suggests that CCL5/RANTES, sICAM-1, and sVCAM-1 play a potential role in the pathogenesis of CSU but they do not parallel disease activity and are not predictive of the response to H1-antihistamine therapy. PMID- 24157825 TI - The effect of metformin on apoptosis in a breast cancer presurgical trial. AB - BACKGROUND: Metformin has been associated with antitumour activity in breast cancer (BC) but its mechanism remains unclear. We determined whether metformin induced a modulation of apoptosis by terminal deoxynucleotidyl transferase dUTP nick end labelling (TUNEL) overall and by insulin resistance status in a presurgical trial. METHODS: Apoptosis was analysed in core biopsies and in surgical samples from 100 non-diabetic BC patients participating in a randomised trial of metformin vs placebo given for 4 weeks before surgery. RESULTS: Eighty seven subjects (45 on metformin and 42 on placebo) were assessable for TUNEL measurement at both time points. TUNEL levels at surgery were higher than that at baseline core biopsy (P<0.0001), although no difference between arms was noted (metformin arm: median difference surgery-biopsy levels +4%, interquartile range (IQR): 2-12; placebo arm: +2%, IQR: 0-8, P=0.2). Ki67 labelling index and TUNEL levels were directly correlated both at baseline and surgery (Spearman's r=0.51, P<0.0001). In the 59 women without insulin resistance (HOMA index<2.8) ,there was a higher level of TUNEL at surgery on metformin vs placebo (median difference on metformin +4%, IQR: 2-14 vs +2%, IQR: 0-7 on placebo), whereas an opposite trend was found in the 28 women with insulin resistance (median difference on metformin +2%, IQR: 0-6, vs +5%, IQR: 0-15 on placebo, P-interaction=0.1). CONCLUSION: Overall, we found no significant modulation of apoptosis by metformin, although there was a trend to a different effect according to insulin resistance status, with a pattern resembling Ki67 changes. Apoptosis was significantly higher in the surgical specimens compared with baseline biopsy and was directly correlated with Ki67. Our findings provide additional evidence for a dual effect of metformin on BC growth according to insulin resistance status. PMID- 24157826 TI - ING4 regulates JWA in angiogenesis and their prognostic value in melanoma patients. AB - BACKGROUND: We previously showed that inhibitor of growth family member 4 (ING4) inhibits melanoma angiogenesis, and JWA suppresses the metastasis of melanoma cells. As angiogenesis is essential for tumour metastasis, further investigation of the function of ING4 and JWA in melanoma angiogenesis is needed, and their prognostic value are of great interest. METHODS: Western blot, tube-formation assays and luciferase assays were used to investigate the correlation between ING4 and JWA in melanoma angiogenesis. JWA and integrin-linked kinase (ILK) expression was determined on a tissue microarray constructed from 175 biopsies. RESULTS: ING4 promoted JWA expression by activating JWA promoter. Furthermore, the regulation of growth and tube formation of endothelial cells by ING4 was partially JWA dependent. Also, ING4 inhibited the ILK-induced angiogenesis signalling pathway via JWA. Moreover, reduced JWA, or increased ILK, expression was closely associated with 5-year disease-specific survival of melanoma patients (P=0.001 and 0.007, respectively). There was also a positive correlation between ING4 and JWA yet a negative correlation between ING4 and ILK. Importantly, their concomitant expressions were significantly related to 5-year survival of melanoma patients (P=0.002 and 0.003, respectively). CONCLUSION: JWA has an important role in ING4-regulated melanoma angiogenesis, and ING4/JWA/ILK are promising prognostic markers and may be used as anti-angiogenic therapeutic targets for melanoma. PMID- 24157827 TI - Genetic variation in the GSTM3 promoter confer risk and prognosis of renal cell carcinoma by reducing gene expression. AB - BACKGROUND: Glutathione S-transferase mu 3 (GSTM3) has been proven to be downregulated in renal cell carcinoma (RCC). We aimed to characterise the role of GSTM3 and its genetic predisposition on the occurrence and postoperative prognosis of RCC. METHODS: The effect of GSTM3 on RCC aggressiveness was examined using transfection and silencing methods. Glutathione S-transferase mu 3 expression in renal tissues was examined by immunohistochemistry. The associations of rs1332018 (A-63C) and rs7483 (V224I) polymorphisms with RCC risk were examined using 400 RCC patients and 802 healthy controls. The factors contributing to postoperative disease-specific survival of RCC patients were evaluated using the Cox proportional hazard model. RESULTS: Glutathione S transferase mu 3 silencing increased the invasion and anchorage-independent growth of RCC cell lines. rs1332018 (AC+CC vs AA), which correlated with low expression of GSTM3 in kidney, was associated with RCC risk (odds ratio, 1.446; 95% confidence interval (CI), 1.111-1.882). rs1332018 variants and low GSTM3 expression significantly predicted unfavourable postoperative survivals of RCC patients (P<0.05). rs1332018 variants independently predicted a poor prognosis (hazard ratio, 2.119; 95% CI, 1.043-4.307). CONCLUSION: Glutathione S-transferase mu 3 may function as a tumour suppressor in RCC. rs1332018 genetic variants predispose the host to downregulating GSTM3 expression in kidney, facilitate carcinogenesis, and predict an unfavourable postoperative prognosis of RCC. PMID- 24157829 TI - Reply: Comment on 'Histopathologic evaluation of liver metastases from colorectal cancer patients treated with FOLFOXIRI plus bevacizumab'. PMID- 24157828 TI - The EndoPredict score provides prognostic information on late distant metastases in ER+/HER2- breast cancer patients. AB - BACKGROUND: ER+/HER2- breast cancers have a proclivity for late recurrence. A personalised estimate of relapse risk after 5 years of endocrine treatment can improve patient selection for extended hormonal therapy. METHODS: A total of 1702 postmenopausal ER+/HER2- breast cancer patients from two adjuvant phase III trials (ABCSG6, ABCSG8) treated with 5 years of endocrine therapy participated in this study. The multigene test EndoPredict (EP) and the EPclin score (which combines EP with tumour size and nodal status) were predefined in independent training cohorts. All patients were retrospectively assigned to risk categories based on gene expression and on clinical parameters. The primary end point was distant metastasis (DM). Kaplan-Meier method and Cox regression analysis were used in an early (0-5 years) and late time interval (>5 years post diagnosis). RESULTS: EP is a significant, independent, prognostic parameter in the early and late time interval. The expression levels of proliferative and ER signalling genes contribute differentially to the underlying biology of early and late DM. The EPclin stratified 64% of patients at risk after 5 years into a low-risk subgroup with an absolute 1.8% of late DM at 10 years of follow-up. CONCLUSION: The EP test provides additional prognostic information for the identification of early and late DM beyond what can be achieved by combining the commonly used clinical parameters. The EPclin reliably identified a subgroup of patients who have an excellent long-term prognosis after 5 years of endocrine therapy. The side effects of extended therapy should be weighed against this projected outcome. PMID- 24157830 TI - Tumour hypoxia determines the potential of combining mTOR and autophagy inhibitors to treat mammary tumours. AB - BACKGROUND: Hypoxia can activate autophagy, a self-digest adaptive process that maintains cell turnover. Mammalian target of rapamycin (mTOR) inhibitors are used to treat cancer but also stimulate autophagy. METHODS: Human mammary cancer cells and derived xenografts were used to examine whether hypoxia could exacerbate autophagy-mediated resistance to the mTOR inhibitor rapamycin. RESULTS: Rapamycin exerted potent antitumour effects in MCF-7 and MDA-MB-231 mammary tumours through a marked inhibition of angiogenesis, but the autophagy inhibitor chloroquine (CQ) failed to further sensitise tumours to mTOR inhibition. Rapamycin treatment actually led to tumour reoxygenation, thereby preventing the development of autophagy. Chloroquine alone, however, blocked the growth of MCF-7 tumours and in vitro blunted the hypoxia-induced component of autophagy in these cells. Finally, when initiating CQ treatment in large, hypoxic tumours, a robust antitumour effect could be observed, which also further increased the antiproliferative effects of rapamycin. CONCLUSION: The mTOR inhibitor rapamycin significantly contributes to tumour growth inhibition and normalisation of the tumour vasculature through potent antiangiogenic effects. The resulting reduction in hypoxia accounts for a lack of sensitisation by the autophagy inhibitor CQ, except if the tumours are already at an advanced stage, and thus largely hypoxic at the initiation of the combination of rapamycin and CQ treatment. PMID- 24157831 TI - Comment on 'Histopathologic evaluation of liver metastases from colorectal cancer in patients treated with FOLFOXIRI plus bevacizumab'. PMID- 24157833 TI - An optimized streptavidin-binding RNA aptamer for purification of ribonucleoprotein complexes identifies novel ARE-binding proteins. AB - Determining the composition of messenger ribonucleoprotein (mRNP) particles is essential for a comprehensive understanding of the complex mechanisms underlying mRNA regulation, but is technically challenging. Here we present an RNA-based method to identify RNP components using a modified streptavidin (SA)-binding RNA aptamer termed S1m. By optimizing the RNA aptamer S1 in structure and repeat conformation, we improved its affinity for SA and found a 4-fold repeat of S1m (4*S1m) to be more efficient than the established MS2 and PP7 systems from bacteriophages. We then attached the AU-rich element (ARE) of tumor necrosis factor alpha (TNFalpha), a well-known RNA motif that induces mRNA degradation, via 4*S1m to a SA matrix, and used the resulting RNA affinity column to purify ARE-binding proteins (BPs) from cellular extracts. By quantitative mass spectrometry using differential dimethyl labeling, we identified the majority of established ARE-BPs and detected several RNA-BPs that had previously not been associated with AREs. For two of these proteins, Rbms1 and Roxan, we confirmed specific binding to the TNFalpha ARE. The optimized 4*S1m aptamer, therefore, provides a powerful tool for the discovery of mRNP components in a single affinity purification step. PMID- 24157832 TI - Deep sequencing analyses expands the Pseudomonas aeruginosa AmpR regulon to include small RNA-mediated regulation of iron acquisition, heat shock and oxidative stress response. AB - Pathogenicity of Pseudomonas aeruginosa, a major cause of many acute and chronic human infections, is determined by tightly regulated expression of multiple virulence factors. Quorum sensing (QS) controls expression of many of these pathogenic determinants. Previous microarray studies have shown that the AmpC beta-lactamase regulator AmpR, a member of the LysR family of transcription factors, also controls non-beta-lactam resistance and multiple virulence mechanisms. Using RNA-Seq and complementary assays, this study further expands the AmpR regulon to include diverse processes such as oxidative stress, heat shock and iron uptake. Importantly, AmpR affects many of these phenotypes, in part, by regulating expression of non-coding RNAs such as rgP32, asRgsA, asPrrF1 and rgRsmZ. AmpR positively regulates expression of the major QS regulators LasR, RhlR and MvfR, and genes of the Pseudomonas quinolone system. Chromatin immunoprecipitation (ChIP)-Seq and ChIP-quantitative real-time polymerase chain reaction studies show that AmpR binds to the ampC promoter both in the absence and presence of beta-lactams. In addition, AmpR directly binds the lasR promoter, encoding the QS master regulator. Comparison of the AmpR-binding sequences from the transcriptome and ChIP-Seq analyses identified an AT-rich consensus-binding motif. This study further attests to the role of AmpR in regulating virulence and physiological processes in P. aeruginosa. PMID- 24157834 TI - Nuclease-mediated gene editing by homologous recombination of the human globin locus. AB - Tal-effector nucleases (TALENs) are engineered proteins that can stimulate precise genome editing through specific DNA double-strand breaks. Sickle cell disease and beta-thalassemia are common genetic disorders caused by mutations in beta-globin, and we engineered a pair of highly active TALENs that induce modification of 54% of human beta-globin alleles near the site of the sickle mutation. These TALENS stimulate targeted integration of therapeutic, full-length beta-globin cDNA to the endogenous beta-globin locus in 19% of cells prior to selection as quantified by single molecule real-time sequencing. We also developed highly active TALENs to human gamma-globin, a pharmacologic target in sickle cell disease therapy. Using the beta-globin and gamma-globin TALENs, we generated cell lines that express GFP under the control of the endogenous beta globin promoter and tdTomato under the control of the endogenous gamma-globin promoter. With these fluorescent reporter cell lines, we screened a library of small molecule compounds for their differential effect on the transcriptional activity of the endogenous beta- and gamma-globin genes and identified several that preferentially upregulate gamma-globin expression. PMID- 24157835 TI - Engineered reversal of drug resistance in cancer cells--metastases suppressor factors as change agents. AB - Building molecular correlates of drug resistance in cancer and exploiting them for therapeutic intervention remains a pressing clinical need. To identify factors that impact drug resistance herein we built a model that couples inherent cell-based response toward drugs with transcriptomes of resistant/sensitive cells. To test this model, we focused on a group of genes called metastasis suppressor genes (MSGs) that influence aggressiveness and metastatic potential of cancers. Interestingly, modeling of 84 000 drug response transcriptome combinations predicted multiple MSGs to be associated with resistance of different cell types and drugs. As a case study, on inducing MSG levels in a drug resistant breast cancer line resistance to anticancer drugs caerulomycin, camptothecin and topotecan decreased by more than 50-60%, in both culture conditions and also in tumors generated in mice, in contrast to control un induced cells. To our knowledge, this is the first demonstration of engineered reversal of drug resistance in cancer cells based on a model that exploits inherent cellular response profiles. PMID- 24157837 TI - MEROPS: the database of proteolytic enzymes, their substrates and inhibitors. AB - Peptidases, their substrates and inhibitors are of great relevance to biology, medicine and biotechnology. The MEROPS database (http://merops.sanger.ac.uk) aims to fulfill the need for an integrated source of information about these. The database has hierarchical classifications in which homologous sets of peptidases and protein inhibitors are grouped into protein species, which are grouped into families, which are in turn grouped into clans. Recent developments include the following. A community annotation project has been instigated in which acknowledged experts are invited to contribute summaries for peptidases. Software has been written to provide an Internet-based data entry form. Contributors are acknowledged on the relevant web page. A new display showing the intron/exon structures of eukaryote peptidase genes and the phasing of the junctions has been implemented. It is now possible to filter the list of peptidases from a completely sequenced bacterial genome for a particular strain of the organism. The MEROPS filing pipeline has been altered to circumvent the restrictions imposed on non-interactive blastp searches, and a HMMER search using specially generated alignments to maximize the distribution of organisms returned in the search results has been added. PMID- 24157836 TI - Nuclear ubiquitination by FBXL5 modulates Snail1 DNA binding and stability. AB - The zinc finger transcription factor Snail1 regulates epithelial to mesenchymal transition, repressing epithelial markers and activating mesenchymal genes. Snail1 is an extremely labile protein degraded by the cytoplasmic ubiquitin ligases beta-TrCP1/FBXW1 and Ppa/FBXL14. Using a short hairpin RNA screening, we have identified FBXL5 as a novel Snail1 ubiquitin ligase. FBXL5 is located in the nucleus where it interacts with Snail1 promoting its polyubiquitination and affecting Snail1 protein stability and function by impairing DNA binding. Snail1 downregulation by FBXL5 is prevented by Lats2, a protein kinase that phosphorylates Snail1 precluding its nuclear export but not its polyubiquitination. Actually, although polyubiquitination by FBXL5 takes place in the nucleus, Snail1 is degraded in the cytosol. Finally, FBXL5 is highly sensitive to stress conditions and is downregulated by iron depletion and gamma irradiation, explaining Snail1 stabilization in these conditions. These results characterize a novel nuclear ubiquitin ligase controlling Snail1 protein stability and provide the molecular basis for understanding how radiotherapy upregulates the epithelial to mesenchymal transition-inducer Snail1. PMID- 24157838 TI - Next-generation sequencing reveals how RNA catalysts evolve from random space. AB - Catalytic RNAs are attractive objects for studying molecular evolution. To understand how RNA libraries can evolve from randomness toward highly active catalysts, we analyze the original samples that led to the discovery of Diels Alderase ribozymes by next-generation sequencing. Known structure-activity relationships are used to correlate abundance with catalytic performance. We find that efficient catalysts arose not just from selection for reactivity among the members of the starting library, but from improvement of less potent precursors by mutations. We observe changes in the ribozyme population in response to increasing selection pressure. Surprisingly, even after many rounds of enrichment, the libraries are highly diverse, suggesting that potential catalysts are more abundant in random space than generally thought. To highlight the use of next-generation sequencing as a tool for in vitro selections, we also apply this technique to a recent, less characterized ribozyme selection. Making use of the correlation between sequence evolution and catalytic activity, we predict mutations that improve ribozyme activity and validate them biochemically. Our study reveals principles underlying ribozyme in vitro selections and provides guidelines to render future selections more efficient, as well as to predict the conservation of key structural elements, allowing the rational improvement of catalysts. PMID- 24157839 TI - Structure-dependent inhibition of the ETS-family transcription factor PU.1 by novel heterocyclic diamidines. AB - ETS transcription factors mediate a wide array of cellular functions and are attractive targets for pharmacological control of gene regulation. We report the inhibition of the ETS-family member PU.1 with a panel of novel heterocyclic diamidines. These diamidines are derivatives of furamidine (DB75) in which the central furan has been replaced with selenophene and/or one or both of the bridging phenyl has been replaced with benzimidazole. Like all ETS proteins, PU.1 binds sequence specifically to 10-bp sites by inserting a recognition helix into the major groove of a 5'-GGAA-3' consensus, accompanied by contacts with the flanking minor groove. We showed that diamidines target the minor groove of AT rich sequences on one or both sides of the consensus and disrupt PU.1 binding. Although all of the diamidines bind to one or both of the expected sequences within the binding site, considerable heterogeneity exists in terms of stoichiometry, site-site interactions and induced DNA conformation. We also showed that these compounds accumulate in live cell nuclei and inhibit PU.1 dependent gene transactivation. This study demonstrates that heterocyclic diamidines are capable of inhibiting PU.1 by targeting the flanking sequences and supports future efforts to develop agents for inhibiting specific members of the ETS family. PMID- 24157842 TI - Super-stretchable, transparent carbon nanotube-based capacitive strain sensors for human motion detection. AB - Realization of advanced bio-interactive electronic devices requires mechanically compliant sensors with the ability to detect extremely large strain. Here, we design a new multifunctional carbon nanotube (CNT) based capacitive strain sensors which can detect strains up to 300% with excellent durability even after thousands of cycles. The CNT-based strain gauge devices exhibit deterministic and linear capacitive response throughout the whole strain range with a gauge factor very close to the predicted value (strictly 1), representing the highest sensitivity value. The strain tests reveal the presented strain gauge with excellent dynamic sensing ability without overshoot or relaxation, and ultrafast response at sub-second scale. Coupling these superior sensing capabilities to the high transparency, physical robustness and flexibility, we believe the designed stretchable multifunctional CNT-based strain gauge may have various potential applications in human friendly and wearable smart electronics, subsequently demonstrated by our prototypical data glove and respiration monitor. PMID- 24157841 TI - Inference of sigma factor controlled networks by using numerical modeling applied to microarray time series data of the germinating prokaryote. AB - A computational model of gene expression was applied to a novel test set of microarray time series measurements to reveal regulatory interactions between transcriptional regulators represented by 45 sigma factors and the genes expressed during germination of a prokaryote Streptomyces coelicolor. Using microarrays, the first 5.5 h of the process was recorded in 13 time points, which provided a database of gene expression time series on genome-wide scale. The computational modeling of the kinetic relations between the sigma factors, individual genes and genes clustered according to the similarity of their expression kinetics identified kinetically plausible sigma factor-controlled networks. Using genome sequence annotations, functional groups of genes that were predominantly controlled by specific sigma factors were identified. Using external binding data complementing the modeling approach, specific genes involved in the control of the studied process were identified and their function suggested. PMID- 24157840 TI - Characterization of the interaction between HMGB1 and H3-a possible means of positioning HMGB1 in chromatin. AB - High mobility group protein B1 (HMGB1) binds to the internucleosomal linker DNA in chromatin and abuts the nucleosome. Bending and untwisting of the linker DNA results in transmission of strain to the nucleosome core, disrupting histone/DNA contacts. An interaction between H3 and HMGB1 has been reported. Here we confirm and characterize the interaction of HMGB1 with H3, which lies close to the DNA entry/exit points around the nucleosome dyad, and may be responsible for positioning of HMGB1 on the linker DNA. We show that the interaction is between the N-terminal unstructured tail of H3 and the C-terminal unstructured acidic tail of HMGB1, which are presumably displaced from DNA and the HMG boxes, respectively, in the HMGB1-nucleosome complex. We have characterized the interaction by nuclear magnetic resonance spectroscopy and show that it is extensive for both peptides, and appears not to result in the acquisition of significant secondary structure by either partner. PMID- 24157843 TI - Skin lipid structure controls water permeability in snake molts. AB - The role of lipids in controlling water exchange is fundamentally a matter of molecular organization. In the present study we have observed that in snake molt the water permeability drastically varies among species living in different climates and habitats. The analysis of molts from four snake species: tiger snake, Notechis scutatus, gabon viper, Bitis gabonica, rattle snake, Crotalus atrox, and grass snake, Natrix natrix, revealed correlations between the molecular composition and the structural organization of the lipid-rich mesos layer with control in water exchange as a function of temperature. It was discovered, merging data from micro-diffraction and micro-spectroscopy with those from thermal, NMR and chromatographic analyses, that this control is generated from a sophisticated structural organization that changes size and phase distribution of crystalline domains of specific lipid molecules as a function of temperature. Thus, the results of this research on four snake species suggest that in snake skins different structured lipid layers have evolved and adapted to different climates. Moreover, these lipid structures can protect, "safety", the snakes from water lost even at temperatures higher than those of their usual habitat. PMID- 24157844 TI - Life expectancy and human capital: evidence from the international epidemiological transition. AB - Exploiting preintervention variation in mortality from various infectious diseases, together with the time variation arising from medical breakthroughs in the late 1940s and the 1950s, this study examines how a large positive shock to life expectancy influenced the formation of human capital within countries during the second half of the 20th century. The results establish that the rise in life expectancy was behind a significant part of the increase in human capital over this period. According to the baseline estimate, for one additional year of life expectancy, years of schooling increase by 0.17 year. Moreover, the evidence suggests that declines in pneumonia mortality are the underlying cause of this finding, indicating that improved childhood health increases human capital investments. PMID- 24157845 TI - Empowering clinicians, containing costs through decision support software. PMID- 24157846 TI - Managing clinical alarms: using data to drive change. PMID- 24157847 TI - 10 Leadership principles for IT activation. PMID- 24157848 TI - Are effects of the symmetric and asymmetric tonic neck reflexes still visible in healthy adults? AB - When a cat's head is rotated in a transverse plane to one side, the legs on that side of the body extend, while on the other side, they flex (asymmetric tonic neck reflexes ATNR). On the contrary, when the head is rotated in a sagittal plane both legs flex when the head flexes, and extend when the head extends (symmetric tonic neck reflexes STNR). These reflexes have also been found in newborn babies and are thought to be a motor primitive, which is suppressed later in life. Still, using a test in which children sit on hand and knees, the ATNR and STNR can be found in children up to 9 years of age. This may suggest that these reflexes may still be involved in motor control in these children. Whether this is also the case in full-grown adults has thus far only been studied using coarse methods. Thus, for the current study, we set out to measure in detail whether the ATNR/STNR can still be evoked in healthy adult subjects. We measured 10 subjects who were asked to sit on their hands and knees while (1) their head was rotated left and right by an experimenter, (2) their head was flexed and extended by an experimenter. Kinematics was registered using a Vicon system. Elbow and head angles were detrended, and a regression analysis was performed, to investigate the effects of head angle on elbow angle. Results clearly showed the existence of the ATNR and STNR in adult subjects. A next step will be to assess the effects of the ATNR and STNR during everyday motor control tasks, such as making head rotations while driving a bike. PMID- 24157849 TI - Attentional demands of postural control during single leg stance in patients with anterior cruciate ligament reconstruction. AB - The aim of this study was to investigate the amount of attention demands of postural control in patients with anterior cruciate ligament-reconstruction (ACL R), by comparing the pattern of posture-cognition interaction between two groups of ACL-R patients (n=25) and healthy matched controls (n=25). All participants were examined during single-leg stance on a balance board under both single- and dual-task conditions in 4 dynamic balance tests. These tests were standing on the injured and uninjured legs with straight or flexed knees. The corresponding dominant and non-dominant legs of healthy group were considered as controls. Contact frequency and contact time were acquired as a measure of postural performance. Cognitive performance was assessed by counting the number of errors in a silent backward digit span task. The results of analysis of variance showed a significant higher contact frequency and longer contact time in patients with ACL-R compared to healthy matched controls (p<0.02). Moreover, the ACL-R patients showed a significantly higher contact frequency and longer contact time during dual-task compared to single-task conditions (p<0.01). This pattern of posture cognition interference was not observed in the healthy control group. In conclusion, patients who had undergone ACL-R surgery demonstrated poorer balance stability during single-leg stance than healthy controls. Also, simultaneous execution of the cognitive task during standing caused a significant deterioration in postural stability which indicates decreased automaticity (increased attention demanding) of postural control in patients with ACL-R compared to healthy controls. PMID- 24157850 TI - Small-worldness and modularity of the resting-state functional brain network decrease with aging. AB - The human brain is a complex network that is known to be affected by normal aging. Graph-based analysis has been used to estimate functional brain network efficiency and effects of normal aging on small-worldness have been reported. This relationship is further investigated here along with network modularity, a statistic reflecting how well a network is organized into modules of densely interconnected nodes. Modularity has previously been observed to vary as a function of working memory capacity, therefore we hypothesized that both small worldness and modularity would show age-related declines. We found that both small-worldness and modularity were negatively correlated with increasing age but that this decline was relatively slow. PMID- 24157851 TI - Individual contributions to (re-)stabilizing interpersonal movement coordination. AB - Interpersonal movement coordination is characterized by stable coordination patterns. We examined the extent to which the two individuals within a dyad contributed to the stabilization of a shared coordination pattern. Within each dyad, the two participants coordinated rhythmic movements of their right lower arms in either in-phase or antiphase. We analyzed the responses to precisely controlled mechanical perturbations to one of the arms that disrupted the coordination pattern. Return to the original coordination pattern did not only involve phase adaptations in the perturbed arm, but in the unperturbed arm as well. Hence, the coupling between the companions was bidirectional and subserved the coordinative stability. Moreover, for both coordination patterns the interpersonal coupling was near symmetrical, with both actors (perturbed and unperturbed) contributing to the same extents to the restabilization of the coordination between them. The applied methodology provides a new entry point to examine asymmetries in interpersonal coupling, due to, for instance, social impairments, differences in social competence, or particular task setting. PMID- 24157852 TI - Systemic treatment with D-fenfluramine, but not sibutramine, blocks cue-induced reinstatement of food-seeking behavior in the rat. AB - Individuals struggling with obesity often have difficulty maintaining dietary regimens. One source of dietary relapse is the reinstatement of previous feeding behaviors following the presentation of cues indicating the availability of palatable but highly caloric food reward. The drugs fenfluramine and sibutramine have previously been prescribed because they enhance satiety mechanisms and decrease meal size. However, it is unclear whether these anorectic agents are also effective in blocking the cue-induced reinstatement of food-seeking behaviors. In these three experiments, we compared the effects of systemic treatment of d-fenfluramine (3mg/kg; N=10) and sibutramine (3mg/kg; N=11) with that of the D1 antagonist SCH 23390 (6MUg/kg; N=11) at a dose that has previously been shown to attenuate cue-induced reinstatement. d-Fenfluramine treatment blocked the cue's ability to reinstate lever pressing as compared to the saline injection day. In contrast, sibutramine had no effect on cue-induced reinstatement; all animals reinstated their lever pressing during the first reinstatement test, and this was unaffected by sibutramine treatment. SCH 23390 treatment did not significantly reduce cue-induced reinstatement in this set of experiments. The results suggest that the motivational effects of d-fenfluramine is not limited to the promotion of satiety once a meal has been initiated, and demonstrate that some anorectic treatments may inhibit the effectiveness of conditioned cues to elicit relapse of food-seeking behavior. PMID- 24157853 TI - Does the type of somatosensory information from the contralateral finger touch affect grip force control while lifting an object? AB - The magnitude of grip force used to lift and transport a hand-held object is decreased if a light finger touch from the contralateral arm is provided to the wrist of the target arm. We investigated whether the type of contralateral arm sensory input that became available with the finger touch to the target arm affects the way grip force is reduced. Nine healthy subjects performed the same task of lifting and transporting an instrumented object with no involvement of the contralateral arm and when an index finger touch of the contralateral arm was provided to the wrist, elbow, and shoulder. Touching the wrist and elbow involved movements of the contralateral arm; no movements were produced while touching the shoulder. Grip force was reduced by approximately the same amount in all conditions with the finger touch compared to the no touch condition. This suggests that information from the muscle and joint receptors of the contralateral arm is used in control of grip force when a finger touch is provided to the wrist and elbow, and cutaneous information is utilized when lifting an object while touching the shoulder. The results of the study provide additional evidence to support the use of a second arm in the performance of activities of daily living and stress the importance of future studies investigating contralateral arm sensory input in grip force control. PMID- 24157854 TI - Electro-acupuncture at points of Zusanli and Quchi exerts anti-apoptotic effect through the modulation of PI3K/Akt signaling pathway. AB - We evaluated the neuroprotective effect of electro-acupuncture (EA) on cerebral ischemia-reperfusion (IR) injury and deeply investigated the relationship between this neuroprotective effect and PI3K/Akt pathway. Rats underwent focal cerebral IR injured by suture method and received the in vivo therapeutic efficacy of EA at points of Zusanli(ST36) and Quchi(LI11) after the operation. We found that the EA treatment significantly (p<0.05) improved neurological deficit and cerebral infarction. Furthermore, EA profoundly activated PI3K/Akt signaling resulted in the inhibition of cerebral cell apoptosis in the ischemic penumbra. Simultaneously EA increased the expression of PI3K, p-Akt, p-Bad and Bcl-2 at the protein level and the expression of Bcl-2 at the mRNA level. On the contrary, EA inhibited the Bax and cleaved Caspase-3-positive expression. The selective PI3K inhibitor LY294002 compromised EA-induced neuroprotective effects and reduced the elevation of p-Akt, p-Bad and Bcl-2 levels. Our data suggested that the PI3K/Akt pathway played a critical role in mediating the neuroprotective effects of EA treatment at points of Zusanli and Quchi after the ischemic stroke. PMID- 24157855 TI - Non-viable Borrelia burgdorferi induce inflammatory mediators and apoptosis in human oligodendrocytes. AB - In previous studies, exposure to live Borrelia burgdorferi was shown to induce inflammation and apoptosis of human oligodendrocytes. In this study we assessed the ability of non-viable bacteria (heat killed or sonicated) to induce inflammatory mediators and cell death. Both heat-killed and sonicated bacteria induced release of CCL2, IL-6, and CXCL8 from oligodendrocytes in a dose dependent manner. In addition, non-viable B. burgdorferi also induced cell death as evaluated by terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) and another cell viability assay. These results suggest that spirochetal residues left after bacterial demise, due to treatment or otherwise, may continue to be pathogenic to the central nervous system. PMID- 24157856 TI - Lipopolysaccharide can induce errors in anatomical measures of neuronal plasticity by increasing tracing efficacy. AB - Evidence suggests that activating certain components of the immune system may increase regeneration and plasticity in the injured central nervous system. Investigating the effect of lipopolysaccharide (LPS), a potent endotoxin and immune activator, on neuronal plasticity in rat models of spinal cord injury, we discovered that systemic administration of LPS can increase the number of descending motor axons that transport neuronal tracers anterogradely to the spinal cord. This effect of LPS was not observed across all motor tracts traced in two different experiments, but was significant for two different tracers administered to corticospinal tract neurons. Densitometry measurement of traced corticospinal axons within the cervical gray matter revealed that normalization to the number of traced axons is crucial to avoid false-positive reports of increased plasticity following LPS injection. These findings indicate that assessments of neuronal growth based on neuronal tracing techniques should be normalized when inflammation or immune activation is an experimental variable. PMID- 24157857 TI - Amelioration of beta-amyloid-induced cognitive dysfunction and hippocampal axon degeneration by curcumin is associated with suppression of CRMP-2 hyperphosphorylation. AB - The Alzheimer's disease (AD) brain is characterized by beta-amyloid deposition, hyperphosphorylation of microtubule-associated proteins, formation of senile plaques and neurofibrillary tangles, and degeneration of specific neuronal populations. Collapsin response mediator protein 2 (CRMP-2) hyperphosphorylation has been implicated in AD-associated neural process regression and neurofibrillary tangle formation. Curcumin is a promising AD drug with incompletely defined therapeutic mechanisms. One possibility is that curcumin prevents beta-amyloid-induced CRMP-2 hyperphosphorylation, thereby protecting against axonal regression and (or) promoting axonal regrowth. We examined spatial learning in the Morris water maze, hippocampal expression levels of CRMP-2 and phosphorylated CRMP-2 (p-CRMP-2) by Western blot, and NF-200 (an axon-specific marker) by immunohistochemistry in Sprague-Dawley rats subjected to a single intrahippocampal injection of Abeta1-40 alone or Abeta1-40 followed by curcumin (i.p. daily for 7 days). Compared to controls, spatial learning was significantly impaired in these Abeta1-40-injected AD model rats (P<0.05). In addition, hippocampal expression levels of CRMP-2 and NF-200 were reduced while p-CRMP-2 expression was significantly enhanced (P<0.05 for all). Overexpression of p-CRMP 2 was correlated with NF-200 underexpression (r(2)=-0.67308, P<0.05), suggesting that Abeta1-40 damaged hippocampal axons. Spatial learning deficits were reversed, CRMP-2 and NF-200 expression levels increased, and p-CRMP-2 expression reduced in curcumin-treated rats (all P<0.05). We propose that curcumin improves spatial learning by inhibiting CRMP-2 hyperphosphorylation, thus protecting against beta-amyloid-induced hippocampal damage or promoting regeneration. PMID- 24157858 TI - Regulation of dopamine presynaptic markers and receptors in the striatum of DJ-1 and Pink1 knockout rats. AB - Pathogenic autosomal recessive mutations in the DJ-1 (Park7) or the PTEN-induced putative kinase 1 (Pink1 or PARK6) genes are associated with familial Parkinson's disease (PD). It is not well known regarding the pathological mechanisms involving the DJ-1 and Pink1 mutations. Here we characterized DJ-1 and Pink1 knockout rats both through expression profiling and using quantitative autoradiography to measure the densities of the dopamine D1, D2, D3 receptors, vesicular monoamine transporter type-2 (VMAT2) and dopamine transporter (DAT) in the striatum of transgenic rats and wild type controls. Expression profiling with a commercially available array of 84 genes known to be involved in PD indicated that only the target gene was significantly downregulated in each transgenic rat model. D1 receptor, VMAT2, and DAT were measured using [(3)H]SCH23390, [(3)H]dihydrotetrabenazine, and [(3)H]WIN35428, respectively. No significant changes were observed in the density of DAT in either model. Although the densities of VMAT2 and D1 receptor were unchanged in Pink1 knockout, but both were increased in DJ-1 knockout rats. The densities of D2 and D3 receptors, determined by mathematical analysis of binding of radioligands [(3)H]WC-10 and [(3)H]raclopride, were significantly increased in both knockout models. These distinctive changes in the expression of dopamine presynaptic markers and receptors in the striatum may reflect different compensatory regulation of dopamine system in DJ-1 versus Pink1 knockout rat models of familial PD. PMID- 24157859 TI - Thymic stromal lymphopoietin induces corticosteroid resistance in natural helper cells during airway inflammation. AB - Type-2 innate immune responses that occur in airways and are accompanied by goblet-cell hyperplasia and mucus production are largely driven by interleukin-33 (IL-33) and natural helper (NH) cells, a member of group 2 innate lymphoid cells (ILC2s) and the major target of IL-33. Here we report that the corticosteroid resistance observed as a result of airway inflammation triggered by sensitization and exposure to allergen is induced via the IL-33/NH-cell axis. Thymic stromal lymphopoietin (TSLP) synthesized during airway inflammation plays a pivotal role in the induction of NH-cell corticosteroid resistance in vitro and in vivo, by controlling phosphorylation of STAT5 and expression of Bcl-xL in NH cells. Blockade of TSLP with a neutralizing antibody or blocking the TSLP/STAT5 signalling pathway with low molecular-weight STAT5 inhibitors such as pimozide restores corticosteroid sensitivity. Thus, the TSLP-STAT5 pathway could be a new therapeutic target in severe, corticosteroid-resistant asthma. PMID- 24157860 TI - Angioimmunoblastic T cell lymphoma: an unusual presentation of posttransplant lymphoproliferative disorder in a pediatric patient. AB - Posttransplant lymphoproliferative disorders (PTLD) are a potentially life threatening complication of immunosuppression in transplant recipients. The majority of cases are Epstein-Barr virus-associated lesions of B cell origin. T cell PTLD is rare, particularly in pediatric patients. We present an unusual case of monomorphic T cell PTLD with features of angioimmunoblastic T cell lymphoma in an 8-year-old heart transplant patient, presenting with cranial nerve palsy. PMID- 24157861 TI - Clustering strategies for optimal trial selection in multisensor environments. An eigenvector based approach. AB - BACKGROUND: Quite often, magnetoencephalography (MEG) measurements are contaminated by a series of artifacts that degrade the quality of the various source localization methods applied to them. In particular, eye blinking, minor head movement and related activities are a constant source of measurement contamination. In order to solve this problem, trial selection and rejection is applied, a task that is usually performed manually. NEW METHOD: The present work shows an automatic trial selection and rejection algorithm based on clustering techniques. These techniques employ a measurement of the dissimilarity of the items belonging to a set. This measure, based on the projection of the eigenvector corresponding to the largest eigenvalue of the covariance matrix, is provided and its rationale is explained. Subsequently, covariance matrices belonging to the selected cluster are averaged and used in the well-known Linearly Constrained Minimum Variance (LCMV) Beamformer. RESULTS: The results show a marked improvement of the specificity of the localization algorithm compared to the application of the LCMV without clustering. COMPARISON WITH EXISTING METHOD(S): The method shows a marked reduction in computational cost compared with other data cleaning procedure widely used: Independent Component Analysis (ICA). CONCLUSIONS: Thus, we propose clustering techniques to be used in brain localization activity algorithms. PMID- 24157863 TI - Anterior segment optical coherence tomography for imaging the sub-Tenon space. AB - In this study, we report the ability of anterior segment optical coherence tomography (AS OCT) in imaging the sub-Tenon space and its clinical application. High-speed AS OCT (Carl Zeiss Meditec, Dublin, Calif., USA) was used to visualize the sub-Tenon space during sub-Tenon injection. The sub-Tenon spaces, Tenon thickness, conjunctiva-Tenon thickness, injecting cannula position in relation to the sub-Tenon space and drug localization/distribution in the sub-Tenon space were analyzed. The sub-Tenon spaces of 12 of 11 patients were visualized with OCT during sub-Tenon injection up to 10-13 mm from the limbus. The mean conjunctiva Tenon and Tenon thickness were 0.38 +/- 0.08 and 0.21 +/- 0.07 mm, respectively. The drug was tracked as bright white fluid. There was no conjunctival chemosis, subconjunctival drug or scleral perforation. Anterior segment OCT can be used for imaging the sub-Tenon space, especially during depot injections for confirmation of drug localization. PMID- 24157862 TI - Biophysical and pharmacological characterization of alpha6-containing nicotinic acetylcholine receptors expressed in HEK293 cells. AB - Nicotinic acetylcholine receptors (nAChR's) containing the alpha6 subunit (alpha6) are putative drug targets of relevance to Parkinson's disease and nicotine addiction. However, heterologous expression of alpha6 receptors has proven challenging which has stifled drug discovery efforts. Here, we investigate potential new avenues for achieving functional alpha6 receptor expression. Combinations of chimeric and mutated alpha6, beta2 and beta3 subunits were co expressed in the human HEK293 cell line and receptor expression was assessed using Ca(2+)-imaging (FLIPRTM) and whole-cell patch-clamp electrophysiology. Transient transfections of a chimeric alpha6/alpha3 subunit construct in combination with beta2 and beta3(V9'S) gave rise to significant acetylcholine evoked whole-cell currents. Increasing the beta3(V9'S):beta2:alpha6/alpha3 cDNA ratio, resulted in a significantly higher fraction of cells with robust current levels. Using an excess of wild-type beta3, significant functional expression of alpha6/alpha3beta2beta3 was also demonstrated. Comparing the acetylcholine concentration-response relationship of alpha6/alpha3beta2beta3(V9'S) to that of alpha6/alpha3beta2beta3 revealed the beta3 point mutation to result in decreased current decay rate and increased ACh agonist potency. Ca(2+)-imaging experiments showed preservation of basic alpha6 receptor pharmacology. Our results establish that alpha6/alpha3beta2beta3(V9'S) replicate several basic features of native alpha6 receptors but also highlight several caveats associated with using this construct and may therefore provide guidance for future drug hunting efforts. PMID- 24157864 TI - Influence of adjustments to amputation and artificial limb on quality of life in patients following lower limb amputation. AB - The objectives of this study are to investigate the relationship between adjustments to amputation and artificial limb, and quality of life (QoL), and to analyse the influence of sociodemographic, medical and amputation-related factors on this relationship. Patients with unilateral and noncongenital lower limb amputation who were using artificial limb were interviewed (n=368) using structured questionnaires. The Trinity Amputation and Prosthesis Experience Scales (TAPES) were used to assess adjustments to amputation and artificial limb and the MOS Short-Form Health Survey (SF-36) was used to assess the physical (PCS) and mental (MCS) component summary of QoL. Absence of comorbidity and residual stump pain, being employed, young age, less functional restriction, being more adjusted to limitation, increased social adjustment and less restriction in athletic activity were related to better PCS scores. Absence of comorbidity and phantom limb pain, nonuse of assistive device, being more adjusted to limitation, increased social adjustment and being less functionally restricted were related to higher MCS scores. Comorbidity had a modifying effect on both PCS and MCS scores. In addition, age, being employed and residual stump pain had a modifying influence on PCS, whereas assistive device use and phantom limb pain had a modifying influence on MCS. Our findings show that TAPES subscales have a modifying effect on the associations between several background (sociodemographic and amputation characteristics) and QoL (PCS and MCS). This indicates that adjustments to amputation and artificial limb are the key determinants of QoL in individuals following lower limb amputation. PMID- 24157865 TI - Age is predictive of immediate postoperative urinary continence after radical retropubic prostatectomy. AB - INTRODUCTION: Immediate continence is a goal to take into consideration for better patient satisfaction after radical prostatectomy. Factors predicting urinary continence at catheter removal were investigated. MATERIALS AND METHODS: We evaluated preoperative, operative, clinical, hormonal and pathological variables in a homogeneous series of radical retropubic prostatectomies (RRPs) following the principles of urinary sphincter restoration technique. RESULTS: The study included 201 patients who underwent RRP. The overall immediate continence rate at catheter removal was 67.7% (136 patients); 28.8% (58 patients) were using one protective pad daily and 3.5% (7 patients) were incontinent. At 6-month follow-up incontinence had reached the lowest level of 2.5% (5 patients) and at 12 months the patients using one pad daily had decreased to 11.9% (24 patients). Multivariate logistic analysis showed that the only two factors independently associated with immediate continence were age <65 years (OR = 2.63, 95% CI 1.13 5.88, p = 0.02) and potency (OR = 3.6, 95% CI 1.2-10.7, p = 0.01) adjusting for D'Amico risk group, surgical margins, extracapsular extension, clinical stage, PSA, testosterone, LH and FSH. No significant association was noted for PSA, hormonal levels, hospital stay, prostate size, clinical stage, risk group, TNM stage, pathological Gleason score or extracapsular extension. CONCLUSIONS: In our series age <65 years was associated with immediate continence after RRP. Moreover, patients who were immediately continent had a 3.6-fold probability to be potent within 12 months. PMID- 24157866 TI - Tumor suppressor PDCD4 modulates miR-184-mediated direct suppression of C-MYC and BCL2 blocking cell growth and survival in nasopharyngeal carcinoma. AB - Programmed cell death 4 (PDCD4), a novel tumor suppressor, inhibits cell proliferation, migration and invasion as well as promotes cell apoptosis in tumors. However, the molecular mechanism of its tumor-suppressive function remains largely unknown in tumors including nasopharyngeal carcinoma (NPC). In this study, downregulated PDCD4 expression was significantly associated with the status of NPC progression and poor prognosis. PDCD4 markedly suppressed the ability of cell proliferation and cell survival by modulating C-MYC-controlled cell cycle and BCL-2-mediated mitochondrion apoptosis resistance signals, and oncogenic transcription factor C-JUN in NPC. Furthermore, miR-184, a tumor suppressive miRNA modulated by PDCD4 directly targeting BCL2 and C-MYC, participated in PDCD4-mediated suppression of cell proliferation and survival in NPC. Further, we found that PDCD4 decreased the binding of C-Jun to the AP-1 element on the miR-184 promoter regions by PI3K/AKT/JNK/C-Jun pathway and stimulated miR-184 expression. In clinical fresh specimens, reduced PDCD4 mRNA level was positively correlated with miR-184 expression in NPC. Our studies are the first to demonstrate that PDCD4 as tumor suppressor regulated miR-184 mediated direct targeting of BCL2 and C-MYC via PI3K/AKT and JNK/C-Jun pathway attenuating cell proliferation and survival in NPC. PMID- 24157867 TI - Drosophila ref(2)P is required for the parkin-mediated suppression of mitochondrial dysfunction in pink1 mutants. AB - Autophagy is a critical regulator of organellar homeostasis, particularly of mitochondria. Upon the loss of membrane potential, dysfunctional mitochondria are selectively removed by autophagy through recruitment of the E3 ligase Parkin by the PTEN-induced kinase 1 (PINK1) and subsequent ubiquitination of mitochondrial membrane proteins. Mammalian sequestrome-1 (p62/SQSTM1) is an autophagy adaptor, which has been proposed to shuttle ubiquitinated cargo for autophagic degradation downstream of Parkin. Here, we show that loss of ref(2)P, the Drosophila orthologue of mammalian P62, results in abnormalities, including mitochondrial defects and an accumulation of mitochondrial DNA with heteroplasmic mutations, correlated with locomotor defects. Furthermore, we show that expression of Ref(2)P is able to ameliorate the defects caused by loss of Pink1 and that this depends on the presence of functional Parkin. Finally, we show that both the PB1 and UBA domains of Ref(2)P are crucial for mitochondrial clustering. We conclude that Ref(2)P is a crucial downstream effector of a pathway involving Pink1 and Parkin and is responsible for the maintenance of a viable pool of cellular mitochondria by promoting their aggregation and autophagic clearance. PMID- 24157868 TI - Zinc chelation: a metallothionein 2A's mechanism of action involved in osteosarcoma cell death and chemotherapy resistance. AB - Osteosarcoma is the most common primary tumor of bone occurring in children and adolescents. The histological response to chemotherapy represents a key clinical factor related to survival. We previously showed that statins exhibit antitumor effects in vitro, inducing apoptotic cell death, reducing cell migration and invasion capacities and strengthening cytotoxic effects in combination with standard drugs. Comparative transcriptomic analysis between control and statin treated cells revealed strong expression of several genes, including metallothionein (MT) 2A. MT2A overexpression by lentiviral transduction reduced bioavailable zinc levels, an effect associated with reduced osteosarcoma cell viability and enhanced cell differentiation. In contrast, MT2A silencing did not modify cell viability but strongly inhibited expression of osteoblastic markers and differentiation process. MT2A overexpression induced chemoresistance to cytotoxic drugs through direct chelation of platinum-containing drugs and indirect action on p53 zinc-dependent activity. In contrast, abrogation of MT2A enhanced cytotoxic action of chemotherapeutic drugs on osteosarcoma cells. Finally, clinical samples derived from chemonaive biopsies revealed that tumor cells expressing low MT2A levels correspond to good prognostic (good responder patients with longer survival rate), whereas high MT2A levels were associated with adverse prognosis (poor responder patients). Taken together, these data show that MT2A contributes to chemotherapy resistance in osteosarcoma, an effect partially mediated by zinc chelation. The data also suggest that MT2A may be a potential new prognostic marker for osteosarcoma sensitivity to chemotherapy. PMID- 24157869 TI - Acquisition of epithelial-mesenchymal transition and cancer stem cell phenotypes is associated with activation of the PI3K/Akt/mTOR pathway in prostate cancer radioresistance. AB - Radioresistance is a major challenge in prostate cancer (CaP) radiotherapy (RT). In this study, we investigated the role and association of epithelial-mesenchymal transition (EMT), cancer stem cells (CSCs) and the PI3K/Akt/mTOR signaling pathway in CaP radioresistance. We developed three novel CaP radioresistant (RR) cell lines (PC-3RR, DU145RR and LNCaPRR) by radiation treatment and confirmed their radioresistance using a clonogenic survival assay. Compared with untreated CaP-control cells, the CaP-RR cells had increased colony formation, invasion ability and spheroid formation capability (P<0.05). In addition, enhanced EMT/CSC phenotypes and activation of the checkpoint proteins (Chk1 and Chk2) and the PI3K/Akt/mTOR signaling pathway proteins were also found in CaP-RR cells using immunofluorescence, western blotting and quantitative real-time PCR (qRT-PCR). Furthermore, combination of a dual PI3K/mTOR inhibitor (BEZ235) with RT effectively increased radiosensitivity and induced more apoptosis in CaP-RR cells, concomitantly correlated with the reduced expression of EMT/CSC markers and the PI3K/Akt/mTOR signaling pathway proteins compared with RT alone. Our findings indicate that CaP radioresistance is associated with EMT and enhanced CSC phenotypes via activation of the PI3K/Akt/mTOR signaling pathway, and that the combination of BEZ235 with RT is a promising modality to overcome radioresistance in the treatment of CaP. This combination approach warrants future in vivo animal study and clinical trials. PMID- 24157870 TI - O6-methylguanine DNA methyltransferase as a promising target for the treatment of temozolomide-resistant gliomas. AB - Temozolomide (TMZ) is an alkylating agent currently used as first-line therapy for gliomas treatment due to its DNA-damaging effect. However, drug resistance occurs, preventing multi-cycle use of this chemotherapeutic agent. One of the major mechanisms of cancer drug resistance is enhanced activity of a DNA repair enzyme, O(6)-methylguanine-DNA-methyltransferase (MGMT), which counteracts chemotherapy-induced DNA alkylation and is a key component of chemoresistance. MGMT repairs TMZ-induced DNA lesions, O(6)-meG, by transferring the alkyl group from guanine to a cysteine residue. This review provides an overview of recent advances in the field, with particular emphasis on the inhibitors of MGMT and underlying mechanisms. Literature search was performed through PubMed and all relevant articles were reviewed, with particular attention to MGMT, its role in TMZ-resistant gliomas, effects of MGMT inhibitors and the underlying mechanisms. Several strategies are currently being pursued to improve the therapeutic efficacy of TMZ via inhibition of MGMT to reduce chemoresistance and improve overall survival. MGMT may be a promising target for the treatment of TMZ resistant gliomas. PMID- 24157871 TI - Contribution of serine, folate and glycine metabolism to the ATP, NADPH and purine requirements of cancer cells. AB - Recent observations on cancer cell metabolism indicate increased serine synthesis from glucose as a marker of poor prognosis. We have predicted that a fraction of the synthesized serine is routed to a pathway for ATP production. The pathway is composed by reactions from serine synthesis, one-carbon (folate) metabolism and the glycine cleavage system (SOG pathway). Here we show that the SOG pathway is upregulated at the level of gene expression in a subset of human tumors and that its level of expression correlates with gene signatures of cell proliferation and Myc target activation. We have also estimated the SOG pathway metabolic flux in the NCI60 tumor-derived cell lines, using previously reported exchange fluxes and a personalized model of cell metabolism. We find that the estimated rates of reactions in the SOG pathway are highly correlated with the proliferation rates of these cell lines. We also observe that the SOG pathway contributes significantly to the energy requirements of biosynthesis, to the NADPH requirement for fatty acid synthesis and to the synthesis of purines. Finally, when the PC-3 prostate cancer cell line is treated with the antifolate methotrexate, we observe a decrease in the ATP levels, AMP kinase activation and a decrease in ribonucleotides and fatty acids synthesized from [1,2-(13)C2]-D glucose as the single tracer. Taken together our results indicate that the SOG pathway activity increases with the rate of cell proliferation and it contributes to the biosynthetic requirements of purines, ATP and NADPH of cancer cells. PMID- 24157872 TI - Panobinostat synergizes with zoledronic acid in prostate cancer and multiple myeloma models by increasing ROS and modulating mevalonate and p38-MAPK pathways. AB - Patients with advanced prostate cancer (PCa) and multiple myeloma (MM) have limited long-term responses to available therapies. The histone deacetylase inhibitor panobinostat has shown significant preclinical and clinical anticancer activity in both hematological and solid malignancies and is currently in phase III trials for relapsed MM. Bisphosphonates (BPs), such as zoledronic acid (ZOL), inhibit osteoclast-mediated bone resorption and are indicated for the treatment of bone metastasis. BPs, including ZOL, have also shown anticancer activity in several preclinical and clinical studies. In the present report, we found a potent synergistic antiproliferative effect of panobinostat/ZOL treatment in three PCa and three MM cell lines as well as in a PCa ZOL-resistant subline, independently of p53/KRAS status, androgen dependency, or the schedule of administration. The synergistic effect was also observed in an anchorage independent agar assay in both ZOL-sensitive and ZOL-resistant cells and was confirmed in vivo in a PCa xenograft model. The co-administration of the antioxidant N-acetyl-L-cysteine blocked the increased reactive oxygen species generation and apoptosis observed in the combination setting compared with control or single-agent treatments, suggesting that oxidative injury plays a functional role in the synergism. Proapoptotic synergy was also partially antagonized by the addition of geranyl-geraniol, which bypasses the inhibition of farnesylpyrophosphate synthase by ZOL in the mevalonate pathway, supporting the involvement of this pathway in the synergy. Finally, at the molecular level, the inhibition of basal and ZOL-induced activation of p38-MAPK by panobinostat in sensitive and ZOL-resistant cells and in tumor xenografts could explain, at least in part, the observed synergism. PMID- 24157873 TI - Transcriptional regulation of immediate-early gene response by THOC5, a member of mRNA export complex, contributes to the M-CSF-induced macrophage differentiation. AB - Hematopoiesis and commitment to a restricted lineage are guided by a timely expressed set of cytokine receptors and their downstream transcription factors. A member of the mRNA export complex, THOC5 (suppressors of the transcriptional defects of hpr1 delta by overexpression complex 5) is a substrate for several tyrosine kinases such as macrophage colony-stimulating factor (M-CSF) receptor and various leukemogenic tyrosine kinases, such as Bcr-Abl, or NPM-ALK. THOC5 tyrosine phosphorylation is elevated in stem cells from patients with chronic myeloid leukemia, suggesting that THOC5 may be involved in leukemia development. THOC5 is also an essential element in the maintenance of hematopoiesis in adult mice. In this report, we show that THOC5 is located in the nuclear speckles, and that it is translocated from the nucleus to cytoplasm during M-CSF-induced bone marrow-derived macrophage differentiation. Furthermore, we have identified THOC5 target genes by trancriptome analysis, using tamoxifen-inducible THOC5 knockout macrophages. Although only 99 genes were downregulated in THOC5-depleted macrophages, half of the genes are involved in differentiation and/or migration. These include well-known regulators of myeloid differentiation inhibitor of DNA binding (Id)1, Id3, Smad family member 6 (Smad6) and Homeobox (Hox)A1. In addition, a subset of M-CSF-inducible genes, such as Ets family mRNAs are THOC5 target mRNAs. Upon depletion of THOC5, unspliced v-ets erythroblastosis virus E26 oncogene homolog (Ets1) mRNA was accumulated in the nucleus. Furthermore, THOC5 was recruited to chromatin where Ets1 was transcribed and bound to unspliced and spliced Ets1 transcripts, indicating that THOC5 has a role in processing/export of M-CSF-inducible genes. In conclusion, regulation of immediate-early gene response by THOC5, a member of mRNA export complex contributes to the M-CSF induced macrophage differentiation. PMID- 24157874 TI - Purported Mcl-1 inhibitor marinopyrrole A fails to show selective cytotoxicity for Mcl-1-dependent cell lines. PMID- 24157875 TI - APR-246/PRIMA-1MET inhibits thioredoxin reductase 1 and converts the enzyme to a dedicated NADPH oxidase. AB - The low-molecular-weight compound APR-246 (PRIMA-1(MET)) restores wild-type conformation and function to mutant p53, and triggers apoptosis in tumor cells. We show here that APR-246 also targets the selenoprotein thioredoxin reductase 1 (TrxR1), a key regulator of cellular redox balance. APR-246 inhibited both recombinant TrxR1 in vitro and TrxR1 in cells. A Sec-to-Cys mutant of TrxR1 was not inhibited by APR-246, suggesting targeting of the selenocysteine residue in wild-type TrxR1. Preheated APR-246 and its conversion product methylene quinuclidinone (MQ) were much more efficient TrxR1 inhibitors than APR-246 itself, indicating that MQ is the active compound responsible for TrxR1 enzyme inhibition. TrxR1 inhibited by MQ was still functional as a pro-oxidant NADPH oxidase. Knockdown of TrxR1 caused a partial and reproducible attenuation of APR 246-induced tumor cell death independently of p53 status. Cellular TrxR1 activity was also inhibited by APR-246 irrespective of p53 status. We show that APR-246 can directly affect cellular redox status via targeting of TrxR1. Our findings provide an explanation for the previously observed effects of APR-246 on tumor cells lacking mutant p53. PMID- 24157876 TI - LHX6 acts as a novel potential tumour suppressor with epigenetic inactivation in lung cancer. AB - LIM homeobox domain 6 (LHX6) is a putative transcriptional regulator that controls the differentiation and development of neural and lymphoid cells. However, the function of LHX6 in cancer development remains largely unclear. Recently, we found that LHX6 is hypermethylated in lung cancer. In this study, we analysed its epigenetic regulation, biological functions, and related molecular mechanisms in lung cancer. Methylation status was evaluated by methylation specific PCR and bisulfite genomic sequencing. LHX6 mRNA levels were measured in relation to the methylation status. The effects of LHX6 expression on tumourigenesis were studied in vitro and in vivo. LHX6 was readily expressed in normal lung tissues without methylation, but was downregulated or silenced in lung cancer cell lines and tissues with hypermethylation status. Treatment of lung cancer cells with the demethylating agent 5-aza-2'-deoxycytidine restored LHX6 expression. Moreover, LHX6 hypermethylation was detected in 56% (52/93) of primary lung cancers compared with none (0/20) of the tested normal lung tissues. In lung cancer cell lines 95D and H358, forced expression of LHX6 suppressed cell viability, colony formation, and migration, induced apoptosis and G1/S arrest, and inhibited their tumorigenicity in nude mice. On the other hand, knockdown of LHX6 expression by RNA interference increased cell proliferation and inhibited apoptosis and cell cycle arrest. These effects were associated with upregulation of p21 and p53, and downregulation of Bcl-2, cyclinD1, c-myc, CD44, and MMP7. In conclusion, our results suggest that LHX6 is a putative tumour suppressor gene with epigenetic silencing in lung cancer. PMID- 24157877 TI - Implication of transcriptional repression in compound C-induced apoptosis in cancer cells. AB - Compound C, a well-known inhibitor of AMP-activated protein kinase (AMPK), has been reported to induce apoptosis in some types of cells. However, the underlying mechanisms remain largely unclear. Using a DNA microarray analysis, we found that the expression of many genes was downregulated upon treatment with compound C. Importantly, compound C caused transcriptional repression with the induction of p53, a well-known marker of transcriptional stress response, in several cancer cell lines. Compound C did not induce the phosphorylation of p53 but dramatically increased the protein level of p53 similar to some other transcriptional inhibitors, including 5,6-dichloro-1-beta-D-ribobenzimidazole (DRB). Consistent with previous reports, we found that compound C initiated apoptotic death of cancer cells in an AMPK-independent manner. Similar to DRB and actinomycin D (ActD), two classic transcription inhibitors, compound C not only resulted in the loss of Bcl-2 and Bcl-xl protein but also induced the phosphorylation of eukaryotic initiation factor-alpha (eIF2alpha) on Ser51. Hence, the phosphorylation of eIF2alpha might be a novel marker of transcriptional inhibition. It is noteworthy that compound C-mediated apoptosis of cancer cells is correlated with decreased expression of Bcl-2 and Bcl-xl and the phosphorylation of eIF2alpha on Ser51. Remarkably, compound C exhibits potent anticancer activities in vivo. Taken together, our data suggest that compound C may be an attractive candidate for anticancer drug development. PMID- 24157878 TI - The epigenetic modifier trichostatin A, a histone deacetylase inhibitor, suppresses proliferation and epithelial-mesenchymal transition of lens epithelial cells. AB - Proliferation and epithelial-mesenchymal transition (EMT) of lens epithelium cells (LECs) may contribute to anterior subcapsular cataract (ASC) and posterior capsule opacification (PCO), which are important causes of visual impairment. Histone deacetylases (HDACs)-mediated epigenetic mechanism has a central role in controlling cell cycle regulation, cell proliferation and differentiation in a variety of cells and the pathogenesis of some diseases. However, whether HDACs are involved in the regulation of proliferation and EMT in LECs remain unknown. In this study, we evaluated the expression profile of HDAC family (18 genes) and found that class I and II HDACs were upregulated in transforming growth factor beta2 (TGFbeta2)-induced EMT in human LEC lines SRA01/04 and HLEB3. Tricostatin A (TSA), a class I and II HDAC inhibitor, suppressed the proliferation of LECs by G1 phase cell cycle arrest not only through inhibition of cyclin/CDK complexes and induction of p21 and p27, but also inactivation of the phosphatidylinositol-3 kinase/Akt, p38MAPK and ERK1/2 pathways. Meanwhile, TSA strongly prevented TGFbeta2-induced upregulation of fibronectin, collagen type I, collagen type IV, N-cadherin, Snail and Slug. We also demonstrated that the underlying mechanism of TSA affects EMT in LECs through inhibiting the canonical TGFbeta/Smad2 and the Jagged/Notch signaling pathways. Finally, we found that TSA completely prevented TGFbeta2-induced ASC in the whole lens culture semi-in vivo model. Therefore, this study may provide a new insight into the pathogenesis of ASC and PCO, and suggests that epigenetic treatment with HDAC inhibitors may be a novel therapeutic approach for the prevention and treatment of ASC, PCO and other fibrotic diseases. PMID- 24157881 TI - A need to discover the world of giant viruses. PMID- 24157880 TI - Increased plasma levels of CK-18 as potential cell death biomarker in patients with HELLP syndrome. AB - HELLP (hemolysis, elevated liver enzymes, low platelets) syndrome represents a life-threatening pregnancy disorder with high fetal and maternal mortality, but its underlying molecular mechanisms remain unknown. Although apoptosis has been implicated in HELLP syndrome, its pathogenic role remains largely unclear. In the present study, we investigated whether the detection of apoptosis by novel plasma biomarkers is of diagnostic value in HELLP patients. For this purpose, we analyzed two biomarkers that specifically detect apoptosis or overall cell death of epithelial cells, such as hepatocytes or placental trophoblasts, through the release of caspase-cleaved or total (caspase-cleaved and uncleaved) cytokeratin 18 (CK-18) in plasma of HELLP patients compared with pregnant as well as non pregnant healthy women. In addition, caspase activation and cell death were determined in placental tissues of HELLP patients and individuals with normal pregnancy. In contrast to pregnant or non-pregnant healthy controls, we observed significantly increased levels of both caspase-cleaved and total CK-18 in plasma of HELLP patients. Following delivery, CK-18 levels rapidly decreased in HELLP patients. Caspase activation and cell death were also elevated in placental tissues from HELLP patients compared with healthy pregnant women. These data demonstrate not only that apoptosis is increased in HELLP syndrome, but also that caspase-cleaved or total CK-18 are promising plasma biomarkers to identify patients with HELLP syndrome. Thus, further studies are warranted to evaluate the utility of these biomarkers for monitoring disease activity in HELLP syndrome. PMID- 24157879 TI - Epoxyeicosatrienoic acids protect cardiac cells during starvation by modulating an autophagic response. AB - Epoxyeicosatrienoic acids (EETs) are cytochrome P450 epoxygenase metabolites of arachidonic acid involved in regulating pathways promoting cellular protection. We have previously shown that EETs trigger a protective response limiting mitochondrial dysfunction and reducing cellular death. Considering it is unknown how EETs regulate cell death processes, the major focus of the current study was to investigate their role in the autophagic response of HL-1 cells and neonatal cardiomyocytes (NCMs) during starvation. We employed a dual-acting synthetic analog UA-8 (13-(3-propylureido)tridec-8-enoic acid), possessing both EET-mimetic and soluble epoxide hydrolase (sEH) inhibitory properties, or 14,15-EET as model EET molecules. We demonstrated that EETs significantly improved viability and recovery of starved cardiac cells, whereas they lowered cellular stress responses such as caspase-3 and proteasome activities. Furthermore, treatment with EETs resulted in preservation of mitochondrial functional activity in starved cells. The protective effects of EETs were abolished by autophagy-related gene 7 (Atg7) short hairpin RNA (shRNA) or pharmacological inhibition of autophagy. Mechanistic evidence demonstrated that sarcolemmal ATP-sensitive potassium channels (pmKATP) and enhanced activation of AMP-activated protein kinase (AMPK) played a crucial role in the EET-mediated effect. Our data suggest that the protective effects of EETs involve regulating the autophagic response, which results in a healthier pool of mitochondria in the starved cardiac cells, thereby representing a novel mechanism of promoting survival of cardiac cells. Thus, we provide new evidence highlighting a central role of the autophagic response in linking EETs with promoting cell survival during deep metabolic stress such as starvation. PMID- 24157882 TI - A decade of improvements in Mimiviridae and Marseilleviridae isolation from amoeba. AB - Since the isolation of the first giant virus, the Mimivirus, by T.J. Rowbotham in a cooling tower in Bradford, UK, and after its characterisation by our group in 2003, we have continued to develop novel strategies to isolate additional strains. By first focusing on cooling towers using our original time-consuming procedure, we were able to isolate a new lineage of giant virus called Marseillevirus and a new Mimivirus strain called Mamavirus. In the following years, we have accumulated the world's largest unique collection of giant viruses by improving the use of antibiotic combinations to avoid bacterial contamination of amoeba, developing strategies of preliminary screening of samples by molecular methods, and using a high-throughput isolation method developed by our group. Based on the inoculation of nearly 7,000 samples, our collection currently contains 43 strains of Mimiviridae (14 in lineage A, 6 in lineage B, and 23 in lineage C) and 17 strains of Marseilleviridae isolated from various environments, including 3 of human origin. This study details the procedures used to build this collection and paves the way for the high-throughput isolation of new isolates to improve the record of giant virus distribution in the environment and the determination of their pangenome. PMID- 24157883 TI - Codon usage, amino acid usage, transfer RNA and amino-acyl-tRNA synthetases in Mimiviruses. AB - Mimiviruses are giant viruses that infect phagocytic protists, including Acanthamoebae spp., which were discovered during the past decade. They are the current record holder among viruses for their large particle and genome sizes. One group is composed of three lineages, referred to as A, B and C, which include the vast majority of the Mimiviridae members. Cafeteria roenbergensis virus represents a second group, though the Mimiviridae family is still expanding. We analyzed the codon and amino acid usages in mimiviruses, as well as both the transfer RNA (tRNA) and amino acyl-tRNA synthetases. We confirmed that the codon and amino acid usages of these giant viruses are highly dissimilar to those in their amoebal host Acanthamoeba castellanii and are instead correlated with the high adenine and thymine (AT) content of Mimivirus genomes. We further describe that the set of tRNAs and amino acyl-tRNA synthetases in mimiviruses is globally not adapted to the codon and amino acid usages of these viruses. Notwithstanding, Leu(TAA)tRNA, present in several Mimivirus genomes and in multiple copies in some viral genomes, may complement the amoebal tRNA pool and may contribute to accommodate the viral AT-rich codons. In addition, we found that the genes most highly expressed at the beginning of the Mimivirus replicative cycle have a nucleotide content more adapted to the codon usage in A.castellanii. PMID- 24157884 TI - Giant viruses of amoebae as potential human pathogens. AB - Giant viruses infecting phagocytic protists are composed of mimiviruses, the record holders of particle and genome size amongst viruses, and marseilleviruses. Since the discovery in 2003 at our laboratory of the first of these giant viruses, the Mimivirus, a growing body of data has revealed that they are common inhabitants of our biosphere. Moreover, from the outset, the story of Mimivirus has been linked to that of patients exhibiting pneumonia and it was shown that patients developed antibodies to this amoebal pathogen. Since then, there have been several proven cases of human infection or colonization with giant viruses of amoebae, which are known to host several bacteria that are human pathogens. Mimiviruses and marseilleviruses represent a major challenge in human pathology, as virological procedures implemented to date have not used appropriate media to allow their culture, and molecular techniques have used filtration steps that likely prevented their detection. Nevertheless, there is an increasing body of evidence that mimiviruses might cause pneumonia and that humans carry marseilleviruses, and re-analyses of metagenomic databases have provided evidence that these giant viruses can be common in human samples. The proportion of human infections related to these giant mimiviruses and marseilleviruses and the precise short- and long-term consequences of these infections have been scarcely investigated so far and should be the subject of future works. PMID- 24157885 TI - First isolation of a Marseillevirus in the Diptera Syrphidae Eristalis tenax. AB - OBJECTIVE: Giant viruses and amoebae are common in freshwater, where they can coexist with various insects. We screened insect larvae to detect giant viruses using a high-throughput method. METHODS: We analyzed 86 Eristalis tenax larvae obtained from stagnant water reservoirs in Tunisia. The larvae were decontaminated and then dissected to remove internal parts for coculture with Acanthamoeba polyphaga. Genome sequencing of isolated viruses was performed on a 454 Roche instrument, and comparative genomics were performed. RESULTS: One Marseillevirus, named Insectomime virus, was isolated. The genome assembly generated two scaffolds, which were 382,776 and 3,855 bp in length. Among the 477 identified predicted proteins, the best hit for 435 of the identified proteins was a Marseillevirus or Lausannevirus protein. Tunisvirus was the most closely related to Insectomime, with 446 orthologs. One Insectomime protein shared with Lausannevirus and Tunisvirus showed the highest similarity with a protein from an aphid. CONCLUSION: The isolation of a Marseillevirus from an insect expands the diversity of environments in which giant viruses have been isolated. The coexistence of larvae and giant viruses in stagnant water may explain the presence of the giant virus in the larva internal structures. This study illustrates the putative role of amoeba in lateral gene transfer not only between the organisms it phagocytoses, but also between organisms living in the same environment. (c) 2013 S. Karger AG, Basel. PMID- 24157886 TI - Describing the silent human virome with an emphasis on giant viruses. AB - Viruses are the most abundant obligate intracellular entities in our body. Until recently, they were only considered to be pathogens that caused a broad array of pathologies, ranging from mild disease to deaths in the most severe cases. However, recent advances in unbiased mass sequencing techniques as well as increasing epidemiological evidence have indicated that the human body is home to diverse viral species under non-pathological conditions. Despite these studies, the description of the presumably healthy viral flora, i.e. the normal human virome, is still in its infancy regarding viral composition and dynamics. This review summarizes our current knowledge of the human virome under non pathological conditions. PMID- 24157887 TI - Real-time PCR systems targeting giant viruses of amoebae and their virophages. AB - Giant viruses that infect amoebae, including mimiviruses and marseilleviruses, were first described in 2003. Virophages were subsequently described that infect mimiviruses. Culture isolation with Acanthamoeba spp. and metagenomic studies have shown that these giant viruses are common inhabitants of our biosphere and have enabled the recent detection of these viruses in human samples. However, the genomes of these viruses display substantial genetic diversity, making it a challenge to examine their presence in environmental and clinical samples using conventional and real-time PCR. We designed and evaluated the performance of PCR systems capable of detecting all currently isolated mimiviruses, marseilleviruses and virophages to assess their prevalence in various samples. Our real-time PCR assays accurately detected all or most of the members of the currently delineated lineages of giant viruses infecting acanthamoebae as well as the mimivirus virophages, and enabled accurate classification of the mimiviruses of amoebae in lineages A, B or C. We were able to detect four new mimiviruses directly from environmental samples and correctly classified these viruses within mimivirus lineage C. This was subsequently confirmed by culture on amoebae followed by partial Sanger sequencing. PCR systems such as those implemented here may contribute to an improved understanding of the prevalence of mimiviruses, their virophages and marseilleviruses in humans. PMID- 24157888 TI - Shan virus: a new mimivirus isolated from the stool of a Tunisian patient with pneumonia. AB - OBJECTIVE: Following the isolation of a Marseillevirus from the stool of a healthy young Senegalese and a Mimivirus from a Tunisian patient with pneumonia, we attempted to isolate other giant viruses of amoebae from a large human stool collection. METHODS: During the period 2010-2011, a total of 1,605 stool samples, including 115 from Tunisian patients with pneumonia, were cultured on amoebae. We used a recently developed high-throughput isolation system to detect amoebae plaque lysis on agar plates; this method allows for the testing of 100 samples per plate per week. The giant virus was identified by sequencing of genes conserved in Megavirales. RESULTS: A single giant virus, called Shan, was isolated from the stool of a Tunisian patient with pneumonia who responded poorly to antibiotics. This virus has an icosahedral shape typical of members of the family Mimiviridae and a size of 640 +/- 10 nm. Phylogenetic analyses showed that Shan virus was classified as a member of Mimivirus lineage C that infects amoebae. CONCLUSION: Only one isolate was obtained in this study, suggesting that giant viruses of amoebae are rare in human stool. The isolation of Shan virus from a patient with pneumonia brings into question the etiological role of this virus and its subsequent release in stool. PMID- 24157889 TI - Lausannevirus seroprevalence among asymptomatic young adults. AB - OBJECTIVES: The giant Lausannevirus was recently identified as a parasite of amoeba that replicates rapidly in these professional phagocytes. This study aimed at assessing Lausannevirus seroprevalence among asymptomatic young men in Switzerland and hopefully identifying possible sources of contact with this giant virus. METHODS: The presence of anti-Lausannevirus antibodies was assessed in sera from 517 asymptomatic volunteers who filled a detailed questionnaire. The coreactivity between Lausannevirus and amoeba-resisting bacteria was assessed. RESULTS: Lausannevirus prevalence ranged from 1.74 to 2.51%. Sporadic condom use or multiple sexual partners, although frequent (53.97 and 60.35%, respectively), were not associated with anti-Lausannevirus antibodies. On the contrary, frequent outdoor sport practice as well as milk consumption were significantly associated with positive Lausannevirus serologies (p = 0.0066 and 0.028, respectively). Coreactivity analyses revealed an association between Criblamydia sequanensis (an amoeba-resisting bacterium present in water environments) and Lausannevirus seropositivity (p = 0.001). CONCLUSIONS: Lausannevirus seroprevalence is low in asymptomatic Swiss men. However, the association between virus seropositivity and frequent sport practice suggests that this member of the Megavirales may be transmitted by aerosols and/or exposure to specific outdoor environments. Milk intake was also associated with seropositivity. Whether the coreactivity observed for C. sequanensis and Lausannevirus reflects a common mode of acquisition or some unexpected cross-reactivity remains to be determined. PMID- 24157890 TI - Alcohol disinfection procedure for isolating giant viruses from contaminated samples. AB - OBJECTIVE: Giant viruses of the Megavirales order have been neglected in the literature because they are removed from samples during viral purification for viral metagenomic studies. Isolation via amoeba coculture has low efficiency and is extremely time-consuming. Thus, our objective was to improve Megavirales detection and recovery by using a new protocol that will eliminate most bacteria present in environmental samples while preserving giant virus viability. METHODS: In this study, we tested the ability of a number of disinfection protocols to kill contaminating bacteria. These treatments were ethanol, UV irradiation, desiccation, glutaraldehyde and thermal shock. RESULTS: Of all the treatments, a brief ethanol treatment did not significantly reduce the titer of viable viral particles of Acanthamoeba polyphaga mimivirus or Marseillevirus, whereas it efficiently killed Escherichia coli. This treatment was applied to environmental samples that previously tested positive for giant viruses and was shown to eliminate contaminating bacteria, whereas it allowed for the isolation of the giant viruses. CONCLUSION: Our results demonstrate that ethanol treatment can be used to evaluate large collections of environmental samples for the presence of giant viruses and to provide insight into understanding their ecology. This study should also facilitate the isolation of giant viruses using other species of protozoa in addition to Acanthamoeba spp. PMID- 24157891 TI - Health economic analysis on a psychosocial intervention for family caregivers of persons with dementia. AB - BACKGROUND/AIMS: Psychosocial intervention has shown positive effects on the caregivers' burden and satisfaction. The aims of this study were to describe the cost and cost-effectiveness of such an intervention. METHODS: We analyzed resource use and costs of formal care for 308 persons with dementia and their caregivers' health-related quality of life (HRQoL). RESULTS: The costs of home help services were lower in the subgroup of spouse caregivers in the intervention group and the cost of nursing home placement was lower in the intervention group. While the person with dementia lived at home, caregivers in the intervention group reported a higher HRQoL (p < 0.01). After the person with dementia had moved to a nursing home, spouses in the control group had a lower HRQoL (p < 0.001). CONCLUSION: The result can be interpreted as a positive effect of the intervention focusing on the identified specific needs of the family caregivers. PMID- 24157892 TI - Autophagy inhibition suppresses pulmonary metastasis of HCC in mice via impairing anoikis resistance and colonization of HCC cells. AB - Metastasis is one of the main causes of poor prognosis for hepatocellular carcinoma (HCC), which has been linked to cell-death resistance. Autophagy is an important survival mechanism under conditions of cell stress. We hypothesized that autophagy may play a role in HCC metastasis due to its prosurvival effect. Highly metastatic HCC cell lines with stable autophagy inhibition were established via lentivirus-mediated silencing of BECN1 and ATG5 genes. Mouse models of pulmonary metastasis were then developed using the cells with or without autophagy inhibition. The analysis of lung metastasis by histopathological examination and small animal imaging showed that autophagy inhibition significantly decreased the incidence of pulmonary metastases in vivo. Further invasion, migration, detachment, lung colonization, and epithelial mesenchymal transition (EMT) assays indicated that autophagy inhibition did not affect cell invasiveness, migration or EMT but attenuated the anoikis-resistance and lung colonization of HCC cells. Investigation of the molecular mechanisms underlying showed that the autophagy-inhibition-mediated anoikis-resistance attenuation was associated with the regulation of apoptotic signaling. As autophagy inhibition was shown to be able to suppress HCC metastasis, an autophagy-based HCC tissue-specific target therapy system (AFP-Cre/LoxP-shRNA) was constructed. In vitro and in vivo analyses showed that the system was able to efficiently inhibit autophagy of HCC cells and tissue in a tissue-specific manner. Further in vivo metastasis assay showed that intratumoral administration of the system could significantly suppress lung metastasis. Together, our findings suggest that autophagy may be involved in HCC metastasis through facilitating anoikis resistance and lung colonization of HCC cells. Autophagy based HCC tissue-specific target therapy may be a new strategy for the management of HCC metastasis. PMID- 24157893 TI - Introducing Bridging the Gaps: a new form of special commentary for PAIN(r). PMID- 24157894 TI - 'Inhibition of IL-6 signaling: a novel therapeutic approach to treating spinal cord injury pain' by Guptarak et al. PMID- 24157895 TI - Authors' response. PMID- 24157896 TI - Box-covering algorithm for fractal dimension of weighted networks. AB - Box-covering algorithm is a widely used method to measure the fractal dimension of complex networks. Existing researches mainly deal with the fractal dimension of unweighted networks. Here, the classical box covering algorithm is modified to deal with the fractal dimension of weighted networks. Box size length is obtained by accumulating the distance between two nodes connected directly and graph coloring algorithm is based on the node strength. The proposed method is applied to calculate the fractal dimensions of the "Sierpinski" weighted fractal networks, the E.coli network, the Scientific collaboration network, the C.elegans network and the USAir97 network. Our results show that the proposed method is efficient when dealing with the fractal dimension problem of complex networks. We find that the fractal property is influenced by the edge-weight in weighted networks. The possible variation of fractal dimension due to changes in edge weights of weighted networks is also discussed. PMID- 24157897 TI - Median effective dose (ED50) of paracetamol and morphine for postoperative pain: a study of interaction. AB - BACKGROUND: Paracetamol is widely used to treat postoperative pain and is well known for its morphine-sparing effect. Therefore, the effect of morphine paracetamol combination can be synergistic, additive, or infra-additive. The primary aim of our study is to define the median effective analgesic doses (ED50s) of paracetamol, morphine, and the combination of both. Also, the nature of the interaction for postoperative pain after moderately painful surgery using an up-and-down method and isobolographic analysis was determined. METHODS: Ninety patients, undergoing moderately painful surgery, were included in one of the three groups. Determination of the median ED50s was performed by the Dixon and Mood up-and-down method. Initial doses were 1.5 g and 5 mg, with dose adjustment intervals of 0.5 g and 1 mg, in the paracetamol and morphine groups, respectively. The initial doses of paracetamol and morphine were 1.5 g and 3 mg, in the paracetamol-morphine combination group with dose adjustment intervals of 0.25 g for paracetamol and 0.5 mg for morphine. Analgesic efficacy was defined as a reduction to or <3 on a 0-10 numeric rating scale, 45 min after the beginning of drug administration. Isobolographic analysis was used to define the nature of their interaction. RESULTS: The median ED50s of paracetamol and morphine were 2.1 g and 5 mg, respectively. The median ED50 of the combination was 1.3 g for paracetamol and 2.7 mg for morphine. CONCLUSIONS: Our study showed that the combination of the paracetamol and morphine produces an additive analgesic effect. Clinical trial registration NCT01366313. PMID- 24157898 TI - Distinct regulation of Th2 and Th17 responses to allergens by pulmonary antigen presenting cells in vivo. AB - Accumulating evidence demonstrates that both Th2 and Th17 responses are involved in the pathogenesis of allergic airway inflammation in animals as well as in humans. The lung contains diverse types of antigen presenting cells. However, the mechanism by which these antigen presenting cells regulate Th2 versus Th17 responses in the lung remains incompletely understood. Here, we show that intranasal administration of fungal protease allergen induced both Th2 and Th17 responses in the lung with different kinetics. Notably, depletion of CD11c(+) cells or macrophages greatly diminished the numbers of allergen-specific Th2 cells in the lung, the infiltration of eosinophils into the airway and airway hyperreactivity. In sharp contrast, depletion of the same antigen presenting cells significantly increased the numbers of allergen-specific Th17 cells in the lung and the infiltration of neutrophils into the airway. Moreover, although a subpopulation of lung epithelial cells express MHC II, lack of MHC II expression in parenchymal cells did not alter pulmonary Th2 and Th17 responses. Our results demonstrate that antigen presenting cells differentially regulate the generation of pulmonary Th2 and Th17 cells in response to intranasal protease allergens. PMID- 24157899 TI - Gated cardiac SPECT: can it be used for serial assessment of left ventricular function in oncology patients? PMID- 24157900 TI - Ring-enhancing brain lesions, clinical presentation of focal seizures, and inconclusive anatomical neuroimaging features: can 18F-FDG-PET/CT play an adjunct role in bettering diagnosis in this setting? PMID- 24157902 TI - Universal health coverage and HIV in resource-constrained countries: a critical juncture for research and action. PMID- 24157903 TI - Moxifloxacin for Buruli ulcer/HIV coinfected patients: kill two birds with one stone? PMID- 24157904 TI - Progression to and spontaneous regression of high-grade anal squamous intraepithelial lesions in HIV-infected and uninfected men. AB - OBJECTIVE: To quantify incidence of, and risk factors for, progression to and spontaneous regression of high-grade anal squamous intraepithelial lesions (ASILs). DESIGN: Retrospective review of patients at St Vincent's Hospital Anal Cancer Screening Clinic during a period when high-grade ASILs were not routinely treated (2004-2011). METHODS: All patients who had an anal Papanicolaou smear or high-resolution anoscopy were included, except for patients with previous anal cancer. High-grade anal intraepithelial neoplasia (HGAIN) was defined as a composite of histologically confirmed grade 2 or 3 anal intraepithelial neoplasia (AIN2/3) and/or high-grade squamous intraepithelial lesion on anal cytology. Analyses were repeated restricting to histologically confirmed AIN3. RESULTS: There were 574 patients: median age 45 years (interquartile range, IQR 36-51), 99.3% male and 73.0% HIV-infected [median HIV duration was 13.8 years (IQR 6.4 19.8), median CD4+ T-lymphocyte count was 500 cells/MUl (IQR 357-662), 83.5% had undetectable plasma HIV viral load]. Median follow-up was 1.1 years (IQR 0.26 2.76). Progression rate to HGAIN was 7.4/100 person-years (95% confidence interval, CI 4.73-11.63). No risk factor for progression to HGAIN was identified; progression to AIN3 was more likely with increasing age (Ptrend = 0.004) and in those who were HIV-infected [hazard ratio 2.8 (95% CI 1.18-6.68) versus HIV uninfected; P = 0.019], particularly in those whose nadir CD4+ T-lymphocyte count was less than 200 cells/MUl (Ptrend = 0.003). In 101 patients with HGAIN, 24 (23.8%) patients had spontaneous regression [rate 23.5/100 person-years (95% CI 15.73-35.02)], mostly to AIN1. Regression was less likely in older patients (Ptrend = 0.048). Two patients with HGAIN developed anal cancer. CONCLUSION: High grade ASILs frequently spontaneously regress. Longer-term, prospective studies are required to determine whether these regressions are sustained. PMID- 24157906 TI - Comparison of HIV DNA and RNA in gut-associated lymphoid tissue of HIV-infected controllers and noncontrollers. AB - OBJECTIVES: HIV-infected controllers have provided novel insights into mechanisms of viral control. We investigated the degree to which HIV DNA and RNA are present in gut-associated lymphoid tissue (GALT) of controllers. DESIGN: Cross-sectional cohort study. METHODS: Colorectal biopsy pieces were obtained from five untreated noncontrollers, five ART-suppressed patients, and nine untreated controllers. RESULTS: Rectal HIV DNA was lower in controllers (median 496 copies/10(6) CD4 T cells) than in untreated noncontrollers (117483 copies/10(6) CD4+ T cells, P = 0.001) and ART-suppressed patients (6116 copies/10(6) CD4 T cells, P = 0.004). Similarly, rectal HIV RNA was lower in controllers (19 copies/10(6) CD4 T cells) than in noncontrollers (15210 copies/10(6) CD4+ T cells, P = 0.001) and ART suppressed patients (1625 copies/10(6) CD4+ T cells, P = 0.0599). Rectal HIV RNA/DNA ratios were not statistically different between the three groups. CONCLUSION: Despite being able to maintain very low plasma HIV RNA levels in the absence of antiretroviral therapy (ART), HIV-infected controllers have readily measurable levels of HIV DNA and RNA in GALT. As expected, controllers had lower rectal HIV DNA and RNA compared with untreated noncontrollers and ART-suppressed individuals. Compared with the mechanisms of 'natural' viral control of controllers, long-term ART does not reduce the total HIV reservoir to the level of controllers. PMID- 24157907 TI - Cell-to-cell vs. cell-free HIV-1 transmission from macrophages to CD4+ T lymphocytes: lessons from the virology textbook. PMID- 24157908 TI - Characterization of CRF56_cpx, a new circulating B/CRF02/G recombinant form identified in MSM in France. AB - Several B/CRF02_AG Unique Recombinant Forms (URFs) have previously been identified in France. Here we show that one of them (URF5_B/02/G) is emerging in MSM, a high-risk population where HIV incidence and number of superinfections are increasing. We describe this new Circulating Recombinant Form, CRF56_cpx, estimate the time to its most recent common ancestor, investigate its origins and show that it probably shares common ancestors with strains from the East Mediterranean. PMID- 24157909 TI - Clinical, radiological and laboratory features of human metapneumovirus lower respiratory tract infection in HIV-positive patients: a case series. PMID- 24157910 TI - Response to Lancaster et al. Generalizability and scalability of HIV 'treatment as prevention'. PMID- 24157905 TI - The impact of HIV-1 reverse transcriptase polymorphisms on responses to first line nonnucleoside reverse transcriptase inhibitor-based therapy in HIV-1 infected adults. AB - OBJECTIVE: HIV-1 genetic variability may influence antiretroviral therapy (ART) outcomes. The study aim was to determine the impact of polymorphisms in regions known to harbor major nonnucleoside reverse transcriptase inhibitor (NNRTI) resistance mutations (codons 90-108, 135-138, 179-190, 225-348) on virologic responses to first-line NNRTI-based ART. METHODS: Reverse transcriptase sequences from ART-naive individuals who commenced efavirenz (EFV) or nevirapine (NVP) with at least two nucleos(t)ide reverse transcriptase inhibitors (NRTIs) without major drug resistance mutations were analyzed. The impact of polymorphisms on week 4 viral load decrease and time to virologic failure was measured over a median 97 weeks. RESULTS: Among 4528 patients, most were infected with HIV-1 subtype B (67%) and commenced EFV-based ART (84%). Overall, 2598 (57%) had at least one polymorphism, most frequently at codons 90, 98, 101, 103, 106, 135, 138, 179, and 238. Virologic failure rates were increased in patients with two (n = 597) or more than two (n = 72) polymorphisms [adjusted hazard ratio 1.43; 95% confidence interval (CI) 1.07-1.92; P = 0.016]. Polymorphisms associated with virologic failure occurred at codons 90 (mostly V90I), 98 (mostly A98S), and 103 (mostly K103R), with adjusted hazard ratios of 1.78 (1.15-2.73; P = 0.009), 1.55 (1.16 2.08; P = 0.003), and 1.75 (1.00-3.05: P = 0.049), respectively. Polymorphisms at codon 179, especially V179D/E/T, predicted reduced week 4 responses (P = 0.001) but not virologic failure. CONCLUSION: The occurrence of multiple polymorphisms, though uncommon, was associated with a small increase in the risk of NNRTI treatment failure; significant effects were seen with polymorphisms at codon 90, 98, and 103. The mechanisms underlying the slower suppression seen with V179D/E/T deserve further investigation. PMID- 24157911 TI - The management of antiretroviral treatments in Europe: the Italian experience. PMID- 24157912 TI - Reply: To PMID 23722610. PMID- 24157913 TI - Clinical significance of redundant nerve roots of the cauda equina. PMID- 24157914 TI - Intraoperative imaging and assessment of cerebral blood flow in cerebrovascular surgery: hybrid operating rooms, intraoperative angiography and magnetic resonance imaging, Doppler ultrasound, cerebral blood flow probes, endoscopic assistance, indocyanine green videography, and laser speckle contrast imaging. PMID- 24157915 TI - The World Federation of Neurosurgical Societies Rabat Reference Center for Training African Neurosurgeons: an experience worthy of duplication. PMID- 24157916 TI - Standard performance measures for adult stroke patients. PMID- 24157917 TI - Carotid endarterectomy: minimizing unplanned readmissions. PMID- 24157918 TI - VEGF gene polymorphism and response to intravitreal ranibizumab in neovascular age-related macular degeneration. AB - BACKGROUND/AIMS: To investigate the association between VEGF gene polymorphism and response to ranibizumab in neovascular age-related macular degeneration (AMD). METHODS: A total of 92 patients were genotyped for the VEGF rs1413711 single nucleotide polymorphism. Patients with neovascular AMD initially received 3 monthly ranibizumab intravitreal injections and were retreated as needed. Visual acuity (VA) and central retinal thickness (CRT) were measured before and 1, 3, 6 and 12 months after treatment. RESULTS: For patients with TT and CT genotypes, paired comparisons of mean VA showed improvement when the data obtained at all visits were compared with baseline values, in contrast to patients with the CC genotype. CRT statistically improved at all visits for all genotypes. CONCLUSION: Patients with the CC genotype showed poorer long-term functional and anatomical response to anti-VEGF therapy. PMID- 24157919 TI - Bod1 regulates protein phosphatase 2A at mitotic kinetochores. AB - Mitotic entry and progression require the activation of several mitotic kinases and the proper regulation and localization of several phosphatases. The activity and localization of each of these enzymes is tightly controlled through a series of specific activators, inhibitors and regulatory subunits. Two proteins, Ensa and Arpp-19, were recently identified as specific inhibitors of PP2A-B55 and are critical for allowing full activity of Cdk1/cyclin B and entry into mitosis. Here we show that Bod1, a protein required for proper chromosome alignment at mitosis, shares sequence similarity with Ensa and Arpp-19 and specifically inhibits the kinetochore-associated PP2A-B56 holoenzyme. PP2A-B56 regulates the stability of kinetochore-microtubule attachments by dephosphorylating several kinetochore proteins. Loss of Bod1 changes the balance of phosphorylation at kinetochores, causing defects in kinetochore function. Bod1, Ensa and Arpp-19 define a family of specific PP2A inhibitors that regulate specific PP2A holoenzymes at distinct locations and points in the cell cycle. PMID- 24157920 TI - Detection of functional connectivity in the resting mouse brain. AB - Resting-state functional connectivity, manifested as spontaneous synchronous activity in the brain, has been detected by functional MRI (fMRI) across species such as humans, monkeys, and rats. Yet, most networks, especially the classical bilateral connectivity between hemispheres, have not been reliably found in the mouse brain. This could be due to anesthetic effects on neural activity and difficulty in maintaining proper physiology and neurovascular coupling in anesthetized mouse. For example, alpha2 adrenoceptor agonist, medetomidine, is a sedative for longitudinal mouse fMRI. However, the higher dosage needed compared to rats may suppress the functional synchrony and lead to unilateral connectivity. In this study, we investigated the influence of medetomidine dosage on neural activation and resting-state networks in mouse brain. We show that mouse can be stabilized with dosage as low as 0.1mg/kg/h. The stimulation-induced somatosensory activation was unchanged when medetomidine was increased from 0.1 to 6 and 10 folds. Especially, robust bilateral connectivity can be observed in the primary, secondary somatosensory and visual cortices, as well as the hippocampus, caudate putamen, and thalamus at low dose of medetomidine. Significant suppression of inter-hemispheric correlation was seen in the thalamus, where the receptor density is high, under 0.6mg/kg/h, and in all regions except the caudate, where the receptor density is low, under 1.0mg/kg/h. Furthermore, in mice whose activation was weaker or took longer time to detect, the bilateral connectivity was lower. This demonstrates that, with proper sedation and conservation of neurovascular coupling, similar bilateral networks like other species can be detected in the mouse brain. PMID- 24157921 TI - Automated longitudinal intra-subject analysis (ALISA) for diffusion MRI tractography. AB - Fiber tractography (FT), which aims to reconstruct the three-dimensional trajectories of white matter (WM) fibers non-invasively, is one of the most popular approaches for analyzing diffusion tensor imaging (DTI) data given its high inter- and intra-rater reliability and scan-rescan reproducibility. The major disadvantage of manual FT segmentations, unfortunately, is that placing regions-of-interest for tract selection can be very labor-intensive and time consuming. Although there are several methods that can identify specific WM fiber bundles in an automated way, manual FT segmentations across multiple subjects performed by a trained rater with neuroanatomical expertise are generally assumed to be more accurate. However, for longitudinal DTI analyses it may still be beneficial to automate the FT segmentation across multiple time points, but then for each individual subject separately. Both the inter-subject and intra-subject automation in this situation are intended for subjects without gross pathology. In this work, we propose such an automated longitudinal intra-subject analysis (dubbed ALISA) approach, and assessed whether ALISA could preserve the same level of reliability as obtained with manual FT segmentations. In addition, we compared ALISA with an automated inter-subject analysis. Based on DTI data sets from (i) ten healthy subjects that were scanned five times (six-month intervals, aged 7.6 8.6years at the first scan) and (ii) one control subject that was scanned ten times (weekly intervals, 12.2years at the first scan), we demonstrate that the increased efficiency provided by ALISA does not compromise the high degrees of precision and accuracy that can be achieved with manual FT segmentations. Further automation for inter-subject analyses, however, did not provide similarly accurate FT segmentations. PMID- 24157922 TI - Celastrol inhibits lipopolysaccharide-induced angiogenesis by suppressing TLR4 triggered nuclear factor-kappa B activation. AB - Celastrol is an active compound extracted from the root bark of the traditional Chinese medicine Tripterygium wilfordii Hook F. In this study, we investigated the effect of celastrol on lipopolysaccharide (LPS)-activated LP-1 human multiple myeloma cell-induced angiogenesis, and identified its molecular mechanism of action. Migration of human umbilical vein endothelial cells (HUVECs) was tested using a wound-healing assay. HUVEC invasion was assayed using a Transwell chamber. Cell surface expression of Toll-like receptor 4 (TLR4) was analyzed by flow cytometry. Angiogenic factor vascular endothelial growth factor (VEGF) level was quantified by LUMINEX and protein expression was analyzed by Western blot. Translocation of nuclear factor-kappa B (NF-kappaB) was observed by fluorescence microscopy. Celastrol inhibited LPS-stimulated LP-1 human multiple myeloma induced HUVEC migration and invasion in a concentration-dependent manner. Wound diameters increased by 72.9, 165.4 and 246.2% at 0.025, 0.05 and 0.1 MUM, respectively, compared to LPS alone. A 45-74% inhibition of LPS-dependent cell invasion was achieved in the presence of 0.025-0.1 MUM celastrol. Celastrol significantly downregulated LPS-induced TLR4 expression and inhibited LPS-induced VEGF secretion in LP-1 cells. VEGF levels decreased by 64.8, 84.4 and 92.9% after coexposure to celastrol at 0.025, 0.05 and 0.1 MUM, respectively, compared to LPS alone. Celastrol also inhibited the IkappaB kinase (IKK)/NF-kappaB pathway induced by LPS. Protein levels of NF-kappaB p65, IKKalpha and IkappaB-alpha decreased in a dose-dependent manner after coexposure to celastrol. Celastrol also blocked nuclear translocation of the p65 subunit. These results suggest that celastrol inhibits LPS-induced angiogenesis by suppressing TLR4-triggered NF kappaB activation. PMID- 24157923 TI - Downregulation of G3BPs inhibits the growth, migration and invasion of human lung carcinoma H1299 cells by suppressing the Src/FAK-associated signaling pathway. AB - G3BP is a RasGAP binding protein that is overexpressed in many human cancers. We previously reported that downregulation of G3BP suppressed cell growth and induced apoptosis in HCT116 cells. Here we report that both transient and stable knockdown of G3BP suppressed the growth, migration and invasion capability of human lung carcinoma H1299 cells. Moreover, downregulation of G3BP significantly inhibited the phosphorylation of Src, FAK and ERK, and the levels of NF-kappaB were also markedly decreased in H1299 cells. Knockdown of G3BP also decreased the expression of matrix metalloproteinase-2 (MMP-2), MMP-9 and plasminogen activator (uPA), and in vivo data demonstrated that downregulation of G3BP markedly inhibited the growth of H1299 tumor xenografts. Together, these data revealed that knockdown of G3BP inhibited the migration and invasion of human lung carcinoma cells through the inhibition of Src, FAK, ERK and NF-kappaB and decreased levels of MMP-2, MMP-9 and uPA. PMID- 24157924 TI - Recent advances and developments in the antitumor effect of the HVJ envelope vector on malignant melanoma: from the bench to clinical application. AB - Inactivated Sendai virus particles (hemagglutinating virus of Japan envelope; HVJ E) are considered to be safe and efficient non-viral vectors used for drug delivery, since they can incorporate DNA, RNA, proteins and drugs. We have recently found that HVJ-E has a novel antitumor immune effect using a colon cancer model. HVJ-E has also been shown to have both direct and immune-mediated indirect actions against malignancy. Intratumoral injection of an inactivated HVJ E solution significantly reduced the tumor volume and prevented spontaneous lung metastasis, leading to an increased overall survival in C57/BL6 mice transplanted with B16/BL6 mouse melanoma cells, and even in immunodeficient mice transplanted with Mewo human melanoma cells. No severe adverse effects including laboratory data abnormalities or anaphylactic reactions were observed. The comprehensive mechanism(s) underlying the immunological effects of HVJ-E appear to include not only enhanced effector T cell- and/or natural killer (NK) cell-mediated immunity, but also rescue from regulatory T cell (Treg)-mediated immunosuppression, presumably through the interleukin-6 secretion from dendritic cells stimulated by HVJ-E. Since a protocol for a clinical study of HVJ-E in malignant melanoma was approved in 2009 by the ethics committee of Osaka University and of the Medical Center for Translational Research in Osaka University Hospital, a phase I/IIa study for advanced malignant melanoma patients was just started. In this review, we show several favorable results regarding the antitumor effects of HVJ-E and describe the novel mechanism underlying this tumor immune response. Since we are conducting a phase I/IIa clinical trial using HVJ-E in advanced melanoma patients on the basis of preclinical results, detailed clinical information and immune monitoring data are also introduced. The development of new therapeutic modalities for advanced melanoma patients is urgently needed, and we hope that HVJ-E may provide one such treatment. PMID- 24157925 TI - Inhibition of Rho-associated coiled-coil-forming kinase increases efficacy of measles virotherapy. AB - RhoA and its downstream effector Rho-associated coiled-coil-forming kinase (ROCK) are known regulators of the formation of actin cytoskeleton in cells. Actin cytoskeleton is involved in paramyxovirus infection; we, therefore, examined the effect of ROCK inhibition on measles virus (MV) cytopathic effect and replication. Treatment with the ROCK inhibitor, Y27632, significantly increased syncytia size in tumor cell lines following MV infection, associated with cytoskeleton disruption as demonstrated by actin staining. Treatment of prostate cancer, breast cancer and glioblastoma tumor cell lines with Y27632 following MV infection resulted in increased cytopathic effect, as assessed by trypan blue exclusion assays. In addition, there was a significant increase in viral proliferation by at least one log or more as tested in one-step viral growth curves. Increased viral replication was also observed in athymic nude mice bearing MDA-MB-231 xenografts following combination treatment with MV and Y27632. In summary, inhibition of the ROCK kinase by Y27632 enhanced the oncolytic effect of MV and viral proliferation; this approach merits further translational investigation. PMID- 24157926 TI - Affinities of bispyridinium non-oxime compounds to [(3)H]epibatidine binding sites of Torpedo californica nicotinic acetylcholine receptors depend on linker length. AB - The toxicity of organophosphorus nerve agents or pesticides arises from accumulation of acetylcholine and overstimulation of both muscarinic and nicotinic acetylcholine receptors (mAChRs and nAChRs) due to inhibition of acetylcholinesterase (AChE). Standard treatment by administration of atropine and oximes, e.g., obidoxime or pralidoxime, focuses on antagonism of mAChRs and reactivation of AChE, whereas nicotinic malfunction is not directly treated. An alternative approach would be to use nAChR active substances to counteract the effects of accumulated acetylcholine. Promising in vitro and in vivo results were obtained with the bispyridinium compounds SAD-128 (1,1'-oxydimethylene bis(4-tert butylpyridinium) dichloride) and MB327 (1,1'-(propane-1,3-diyl)bis(4-tert butylpyridinium) di(iodide)), which were partly attributed to their interaction with nAChRs. In this study, a homologous series of unsubstituted and 4-tert-butyl substituted bispyridinium compounds with different alkane linker lengths was investigated in competition binding experiments using [(3)H]epibatidine as a reporter ligand. Additionally, the effect of the well-characterised MB327 on the [(3)H]epibatidine equilibrium dissociation (KD) constant in different buffers was determined. This study demonstrated that divalent cations increased the affinity of [(3)H]epibatidine. Since quaternary ammonium molecules are known to inhibit AChE, the obtained affinity constants of the tested bispyridinium compounds were compared with the inhibition of human AChE. In competition experiments, bispyridinium derivatives of longer linker length displaced [(3)H]epibatidine and inhibited AChE strongly. Bispyridinium compounds with short linkers, at most, have an allosteric interaction with the [(3)H]epibatidine binding sites and barely inhibited AChE. In dependence on alkane linker length, the bispyridinium compounds seemed to interact at different binding sites. However, the exact binding sites of the bispyridinium compounds responsible for the positive pharmacological effects have still not been identified, making predictive drug design difficult. PMID- 24157927 TI - Physical exercise during pregnancy improves object recognition memory in adult offspring. AB - Exercising during pregnancy has been shown to improve spatial learning and short term memory, as well as increase brain-derived neurotrophic factor mRNA levels and hippocampal cell survival in juvenile offspring. However, it remains unknown if these effects endure into adulthood. In addition, few studies have considered how maternal exercise can impact cognitive functions that do not rely on the hippocampus. To address these issues, the present study tested the effects of maternal exercise during pregnancy on object recognition memory, which relies on the perirhinal cortex (PER), in adult offspring. Pregnant rats were given access to a running wheel throughout gestation and the adult male offspring were subsequently tested in an object recognition memory task at three different time points, each spaced 2-weeks apart, beginning at 60 days of age. At each time point, offspring from exercising mothers were able to successfully discriminate between novel and familiar objects in that they spent more time exploring the novel object than the familiar object. The offspring of non-exercising mothers were not able to successfully discriminate between objects and spent an equal amount of time with both objects. A subset of rats was euthanized 1h after the final object recognition test to assess c-FOS expression in the PER. The offspring of exercising mothers had more c-FOS expression in the PER than the offspring of non-exercising mothers. By comparison, c-FOS levels in the adjacent auditory cortex did not differ between groups. These results indicate that maternal exercise during pregnancy can improve object recognition memory in adult male offspring and increase c-FOS expression in the PER; suggesting that exercise during the gestational period may enhance brain function of the offspring. PMID- 24157928 TI - Differential S-nitrosylation of proteins in Alzheimer's disease. AB - Numerous studies have provided evidence regarding the involvement of protein S nitrosylation in the progression of Alzheimer's disease (AD) pathology and its implication in the formation and accumulation of misfolded protein aggregates. The identification of S-nitrosylated proteins can be a major step toward the understanding of mechanisms leading to neuronal degeneration. The present study targeted S-nitrosylated proteins in AD hippocampus, substantia nigra and cortex using the following work-flow that combines S-nitrosothiol-specific antibody detection, classical biotin switch method labeled with fluorescence dye followed by electrospray ionization quadrupole time of flight tandem MS (ESI-QTOF MS/MS) identification. Endogenous nitrosocysteines were identified in 45 proteins, mainly involved in metabolism, signaling pathways, apoptosis and redox regulation as assigned by REACTOME and KEGG pathway database analysis. Superoxide dismutase (SOD2) [Mn], fructose-bisphosphate aldolase C (ALDOC) and voltage-dependent anion selective channel protein 2 (VDAC2) showed differential S-nitrosylation signal, not previously reported in AD regions. Extensive neuronal atrophy with increased protein S-nitrosylation in AD regions is also evident from immunofluorescence studies using S-nitrosocysteine antibody. A number of plausible cysteine modification sites were predicted via Group-based Prediction System-S nitrosothiols (GPS-SNO) 1.0 while STRING 8.3 analysis revealed functional annotations in the modified proteins. The findings are helpful in characterization of functional abnormalities and may facilitate the understanding of molecular mechanisms and biological function of S-nitrosylation in AD pathology. PMID- 24157929 TI - Intracellular Nogo-A facilitates initiation of neurite formation in mouse midbrain neurons in vitro. AB - Nogo-A is a transmembrane protein originally discovered in myelin, produced by postnatal CNS oligodendrocytes. Nogo-A induces growth cone collapse and inhibition of axonal growth in the injured adult CNS. In the intact CNS, Nogo-A functions as a negative regulator of growth and plasticity. Nogo-A is also expressed by certain neurons. Neuronal Nogo-A depresses long-term potentiation in the hippocampus and modulates neurite adhesion and fasciculation during development in mice. Here we show that Nogo-A is present in neurons derived from human midbrain (Lund human mesencephalic (LUHMES) cell line), as well as in embryonic and postnatal mouse midbrain (dopaminergic) neurons. In LUHMES cells, Nogo-A was upregulated threefold upon differentiation and neurite extension. Nogo A was localized intracellularly in differentiated LUHMES cells. Cultured midbrain (dopaminergic) neurons from Nogo-A knock-out mice exhibited decreased numbers of neurites and branches when compared with neurons from wild-type (WT) mice. However, this phenotype was not observed when the cultures from WT mice were treated with an antibody neutralizing plasma membrane Nogo-A. In vivo, neither the regeneration of nigrostriatal tyrosine hydroxylase fibers, nor the survival of nigral dopaminergic neurons after partial 6-hydroxydopamine lesions was affected by Nogo-A deletion. These results indicate that during maturation of cultured midbrain (dopaminergic) neurons, intracellular Nogo-A supports neurite growth initiation and branch formation. PMID- 24157930 TI - Neurosteroids modulate epileptiform activity and associated high-frequency oscillations in the piriform cortex. AB - Allotetrahydrodeoxycorticosterone (THDOC) belongs to a class of pregnane neurosteroidal compounds that enhance brain inhibition by interacting directly with GABAA signaling, mainly through an increase in tonic inhibitory current. Here, we addressed the role of THDOC in the modulation of interictal- and ictal like activity and associated high-frequency oscillations (HFOs, 80-500 Hz; ripples: 80-200 Hz, fast ripples: 250-500 Hz) recorded in vitro in the rat piriform cortex, a highly excitable brain structure that is implicated in seizure generation and maintenance. We found that THDOC: (i) increased the duration of interictal discharges in the anterior piriform cortex while decreasing ictal discharge duration in both anterior and posterior piriform cortices; (ii) reduced the occurrence of HFOs associated to both interictal and ictal discharges; and (iii) prolonged the duration of 4-aminopyridine-induced, glutamatergic independent synchronous field potentials that are known to mainly result from the activation of GABAA receptors. Our results indicate that THDOC can modulate epileptiform synchronization in the piriform cortex presumably by potentiating GABAA receptor-mediated signaling. This evidence supports the view that neurosteroids regulate neuronal excitability and thus control the occurrence of seizures. PMID- 24157931 TI - Plasticity in human pitch perception induced by tonotopically mismatched electro acoustic stimulation. AB - Under normal conditions, the acoustic pitch percept of a pure tone is determined mainly by the tonotopic place of the stimulation along the cochlea. Unlike acoustic stimulation, electric stimulation of a cochlear implant (CI) allows for the direct manipulation of the place of stimulation in human subjects. CI sound processors analyze the range of frequencies needed for speech perception and allocate portions of this range to the small number of electrodes distributed in the cochlea. Because the allocation is assigned independently of the original resonant frequency of the basilar membrane associated with the location of each electrode, CI users who have access to residual hearing in either or both ears often have tonotopic mismatches between the acoustic and electric stimulation. Here we demonstrate plasticity of place pitch representations of up to three octaves in Hybrid CI users after experience with combined electro-acoustic stimulation. The pitch percept evoked by single CI electrodes, measured relative to acoustic tones presented to the non-implanted ear, changed over time in directions that reduced the electro-acoustic pitch mismatch introduced by the CI programming. This trend was particularly apparent when the allocations of stimulus frequencies to electrodes were changed over time, with pitch changes even reversing direction in some subjects. These findings show that pitch plasticity can occur more rapidly and on a greater scale in the mature auditory system than previously thought possible. Overall, the results suggest that the adult auditory system can impose perceptual order on disordered arrays of inputs. PMID- 24157933 TI - Developmental alpha2-adrenergic regulation of noradrenergic synaptic facilitation at cerebellar GABAergic synapses. AB - In the central nervous system, the normal development of neuronal circuits requires adequate temporal activation of receptors for individual neurotransmitters. Previous studies have demonstrated that alpha2-adrenoceptor (alpha2-AR) activation eliminates spontaneous action potentials of interneurons in the cerebellar molecular layer (MLIs) and subsequently reduces the frequency of spontaneous inhibitory postsynaptic currents (sIPSCs) in Purkinje cells (PCs) after the second postnatal week. The magnitude of the alpha2-adrenergic reduction in sIPSC frequency is enhanced during the third postnatal week because of an increase in firing-derived sIPSCs. However, little is known about the effects of alpha2-AR activation by noradrenaline (NA) on cerebellar GABAergic synaptic transmission that is accompanied by the activation of other AR subtypes, alpha1- and beta-ARs. Here, we developmentally examined the roles of alpha2-AR activation in the noradrenergic facilitation of sIPSCs in cerebellar PCs. Until the second postnatal week, when substantial inhibitory effects of alpha2-ARs are absent, NA potentiated sIPSCs and maintained the increased sIPSC frequency, suggesting that NA causes long-lasting facilitation of GABAergic synaptic transmission through alpha1- and beta-AR activation. After the second postnatal week, NA transiently increased the sIPSC frequency, whereas blocking alpha2-ARs sustained the noradrenergic sIPSC facilitation and increase in the firing rate of MLIs, suggesting that alpha2-AR activation suppresses the noradrenergic facilitation of GABAergic synaptic transmission. The simultaneous activation of alpha1- and beta ARs by their specific agonists mimicked the persistent facilitation of sIPSC frequency, which required extracellular signal-regulated kinase 1/2 activation. These findings indicate that NA acts as a neurotrophic factor that strengthens GABAergic synaptic transmission in the developing cerebellar cortex and that alpha2-ARs temporally restrain the noradrenergic facilitation of sIPSCs after GABAergic synaptogenesis. PMID- 24157935 TI - Disease-specific self-efficacy in the eosinophilic gastrointestinal disorders. AB - Eosinophilic gastrointestinal disorders (EGIDs) are chronic inflammatory conditions with increasing global prevalence. Self-efficacy is important for patients' ability to manage chronic disease. We sought to evaluate disease specific self-efficacy in the EGIDs via a modified version of the Inflammatory Bowel Disease Self-Efficacy Scale (IBD-SES). Ninety-one Participants reported demographic, clinical, and psychosocial variables. The IBD-SES demonstrated excellent reliability and validity in this population. Self-efficacy was higher in men, patients with less severe disease, and those who had consulted a dietitian. The IBD-SES is a useful measure of disease-specific self-efficacy in the EGIDs. Further research is necessary to understand the role of self-efficacy in the management of these illnesses. PMID- 24157932 TI - MiR-7-1 potentiated estrogen receptor agonists for functional neuroprotection in VSC4.1 motoneurons. AB - Protection of motoneurons is an important goal in the treatment of spinal cord injury (SCI). We tested whether neuroprotective microRNAs (miRs) like miR-206, miR-17, miR-21, miR-7-1, and miR-106a could enhance efficacy of estrogen receptor (ER) agonists such as 1,3,5-tris (4-hydroxyphenyl)-4-propyl-1H-pyrazole (PPT, ERalpha agonist), Way200070 (WAY, ERbeta agonist), and estrogen (EST, ERalpha and ERbeta agonist) in preventing apoptosis in the calcium ionophore (CI)-insulted ventral spinal cord 4.1 (VSC4.1) motoneurons. We determined that 200 nM CI induced 70% cell death. Treatment with 50 nM PPT, 100 nM WAY, and 150 nM EST induced overexpression of ERalpha, ERbeta, and both receptors, respectively, at mRNA and protein levels. Treatment with ER agonists significantly upregulated miR 206, miR-17, and miR-7-1 in the CI-insulted VSC4.1 motoneurons. Transfection with miR-206, miR-17, or miR-7-1 mimic potentiated WAY or EST to inhibit apoptosis in the CI-insulted VSC4.1 motoneurons. Overexpression of miR-7-1 maximally increased efficacy of WAY and EST for down regulation of pro-apoptotic Bax and upregulation of anti-apoptotic Bcl-2. A search using microRNA database (miRDB) indicated that miR-7-1 could inhibit the expression of L-type Ca(2+) channel protein alpha 1C (CPalpha1C). miR-7-1 overexpression and WAY or EST treatment down regulated CPalpha1C but upregulated p-Akt to trigger cell survival signaling. The same therapeutic strategy increased expression of the Ca(2+)/calmodulin-dependent protein kinase II beta (CaMKIIbeta) and the phosphorylated cAMP response element binding protein (p-CREB) so as to promote Bcl-2 transcription. Whole cell membrane potential and mitochondrial membrane potential studies indicated that miR-7-1 highly potentiated EST to preserve functionality in the CI-insulted VSC4.1 motoneurons. In conclusion, our data indicated that miR-7-1 most significantly potentiated efficacy of EST for functional neuroprotection and this therapeutic strategy could be used in the future to attenuate apoptosis of motoneurons in SCI. PMID- 24157938 TI - High tau levels in cerebrospinal fluid predict rapid decline and increased dementia mortality in Alzheimer's disease. AB - OBJECTIVE: Cerebrospinal fluid (CSF) amyloid beta42 (Abeta42), total tau (t-tau) and phosphorylated tau (p-tau) are useful as predictors of conversion from mild cognitive impairment (MCI) to Alzheimer's disease (AD) dementia. However, results are contradictory as to whether these biomarkers reflect the future rate of clinical decline. METHODS: This is a retrospective study on 196 patients with AD [mild/moderate AD (n = 72) or AD-MCI (n = 124) at baseline] with a follow-up period of 2-9 years' duration (median 6 years). Lumbar punctures were performed at baseline as a part of the diagnostic procedure. RESULTS: We found an increased risk of rapid cognitive decline defined as a drop in the Mini-Mental State Examination score of >= 4 points/year in patients with CSF t-tau concentrations above the median (OR 3.31, 95% CI 1.53-7.16) and CSF p-tau above the median (OR 2.53, 95% CI 1.21-5.26). Patients with CSF t-tau in the highest quartile had a higher risk of dying in severe dementia (HR 4.67, 95% CI 1.16-18.82). CONCLUSIONS: In this large AD cohort, we found an association between high levels of CSF t-tau and p-tau and a more aggressive course of the disease, measured as a rapid cognitive decline and a higher risk of dying in severe dementia. PMID- 24157937 TI - The significance of microscopic mass spectrometry with high resolution in the visualisation of drug distribution. AB - The visualisation and quantitative analysis of the native drug distribution in a pre-clinical or clinical setting are desirable for evaluating drug effects and optimising drug design. Here, using matrix-assisted laser desorption ionisation imaging mass spectrometry (MALDI-IMS) with enhanced resolution and sensitivity, we compared the distribution of a paclitaxel (PTX)-incorporating micelle (NK105) with that of PTX alone after injection into tumour-bearing mice. We demonstrated optically and quantitatively that NK105 delivered more PTX to the tumour, including the centre of the tumour, while delivering less PTX to normal neural tissue, compared with injection with PTX alone. NK105 treatment yielded a greater antitumour effect and less neural toxicity in mice than did PTX treatment. The use of high-resolution MALDI-IMS may be an innovative approach for pharmacological evaluation and drug design support. PMID- 24157936 TI - Conceptualizing prognostic awareness in advanced cancer: a systematic review. AB - This systematic review synthesizes the complex literature on prognostic awareness in cancer. A total of 37 studies examining cancer patients' understanding of their prognosis were included. Prognostic awareness definitions and assessment methods were inconsistent across studies. A surprisingly high percentage of patients (up to 75%) were unaware of their poor prognosis, and in several studies, even their cancer diagnosis (up to 96%), particularly in studies conducted outside of North America. This review highlights surprisingly low rates of prognostic awareness in patients with advanced cancer as well as discrepancies in prognostic awareness assessment, suggesting the need for empirically validated measures of prognostic awareness. PMID- 24157939 TI - Modeling amyotrophic lateral sclerosis in hSOD1 transgenic swine. AB - Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease that occurs in two clinically indistinguishable forms: sporadic (SALS) and familial (FALS), the latter linked to several gene mutations, mostly inheritable in a dominant manner. Nearly 20% of FALS forms are linked to mutations in the Cu/Zn superoxide dismutase (SOD1) gene. Research on ALS relies on transgenic models and particularly on mice carrying a glycine-to-alanine conversion at the 93rd codon (G93A) of the hSOD1 gene. Although G93A transgenic mice have been widely employed in clinical trials and basic research, doubts have been recently raised from numerous reliable sources about their suitability to faithfully reproduce human disease. Besides, the scientific community has already foreseen swine as an attractive and alternative model to nonhuman primates for modeling human diseases due to closer anatomical, physiological and biochemical features of swine rather than rodents to humans. On this basis, we have produced the first swine ALS model by in vitro transfection of cultured somatic cells combined with somatic cell nuclear transfer (SCNT). To achieve this goal we developed a SOD1(G93A) (superoxide dismutase 1 mutated in Gly93-Ala) vector, capable of promoting a high and stable transgene expression in primary porcine adult male fibroblasts (PAF). After transfection, clonal selection and transgene expression level assessment, selected SOD1(G93A) PAF colonies were used as nuclei donors in SCNT procedures. SOD1(G93A) embryos were transferred in recipient sows, and pregnancies developed to term. A total of 5 piglets survived artificial hand raising and weaning and developed normally, reaching adulthood. Preliminary analysis revealed transgene integration and hSOD1(G93A) expression in swine tissues and 360 degrees phenotypical characterization is ongoing. We believe that our SOD1(G93A) swine would provide an essential bridge between the fundamental work done in rodent models and the reality of treating ALS. PMID- 24157941 TI - Adiponectin and metformin additively attenuate IL1beta-induced malignant potential of colon cancer. AB - Both adiponectin (AD) and metformin (Met) have been proposed to downregulate cell proliferation of colon cancer cells, but whether their effect might be additive has not been studied to date. Genetic studies in humans have suggested an important role for interleukin 1beta (IL1beta) in cancer pathogenesis. Direct evidence that IL1beta contributes to the development of colon cancer has not yet been fully confirmed and no previous studies have evaluated how IL1beta may interact with AD and/or Met to regulate malignant potential and intracellular signaling pathways in human and mouse colon cancer cells. We conducted in vitro studies using human (LoVo) and mouse (MCA38) colon cancer cell lines to evaluate whether AD and Met alone or in combination may antagonize IL1beta-regulated malignant potential in human and mouse colon cancer cell lines. IL1beta increased malignant potential and regulated the expression of tumor suppressor (p53) and cell cycle regulatory genes (p21, p27, and cyclin E2) in human and mouse colon cancer cell lines. These effects were reversed by co-administration of AD and/or Met and were additively altered by AD and Met in combination in a STAT3- and AMPK/LKB1-dependent manner. We also observed using fluorescence activated cell sorter analysis that IL1beta-regulated cell cycle progression is altered by AD and Met alone or in combination. Our novel mechanistic studies provide evidence for an important role for IL1beta in colon cancer and suggest that AD and/or Met might be useful agents in the management or chemoprevention of IL1beta-induced colon carcinogenesis. PMID- 24157940 TI - Altered MENIN expression disrupts the MAFA differentiation pathway in insulinoma. AB - The protein MENIN is the product of the multiple endocrine neoplasia type I (MEN1) gene. Altered MENIN expression is one of the few events that are clearly associated with foregut neuroendocrine tumours (NETs), classical oncogenes or tumour suppressors being not involved. One of the current challenges is to understand how alteration of MENIN expression contributes to the development of these tumours. We hypothesised that MENIN might regulate factors maintaining endocrine-differentiated functions. We chose the insulinoma model, a paradigmatic example of well-differentiated pancreatic NETs, to study whether MENIN interferes with the expression of v-MAF musculoaponeurotic fibrosarcoma oncogene homologue A (MAFA), a master glucose-dependent transcription factor in differentiated beta cells. Immunohistochemical analysis of a series of human insulinomas revealed a correlated decrease in both MENIN and MAFA. Decreased MAFA expression resulting from targeted Men1 ablation was also consistently observed in mouse insulinomas. In vitro analyses using insulinoma cell lines showed that MENIN regulated MAFA protein and mRNA levels, and bound to Mafa promoter sequences. MENIN knockdown concomitantly decreased mRNA expression of both Mafa and beta-cell differentiation markers (Ins1/2, Gck, Slc2a2 and Pdx1) and, in parallel, increased the proliferation rate of tumours as measured by bromodeoxyuridine incorporation. Interestingly, MAFA knockdown alone also increased proliferation rate but did not affect the expression of candidate proliferation genes regulated by MENIN. Finally, MENIN variants with missense mutations detected in patients with MEN1 lost the WT MENIN properties to regulate MAFA. Together, our findings unveil a previously unsuspected MENIN/MAFA connection regarding control of the beta-cell differentiation/proliferation balance, which could contribute to tumorigenesis. PMID- 24157942 TI - Safety and antitumor efficacy of (153)Sm-EDTMP and docetaxel administered sequentially to patients with metastatic castration-resistant prostate cancer. AB - BACKGROUND: Bone metastases are responsible for most of the morbidity associated with metastatic castration-resistant prostate cancer (mCRPC). Bone-seeking radiopharmaceuticals have been approved for palliation of painful skeletal metastases, but their clinical use is limited by concerns of toxicities both when administered alone and especially when combined with chemotherapy agents. OBJECTIVE: We investigated whether docetaxel administered to mCRPC patients after treatment with samarium-153-labeled ethylene-diamine-tetra-methylene-phosphonic acid (Sm-EDTMP) has increased toxicity and/or reduced antitumor efficacy. MATERIALS AND METHODS: Thirty mCRPC patients with skeletal metastases were enrolled. Patients received standard therapy with docetaxel (75 mg/m intravenously every 21 days for at least six cycles) on average 6 weeks after Sm EDTMP (37 MBq/kg). Patients were monitored for the presence of toxicities, and antitumor efficacy was assessed by changes in serum prostate-specific antigen levels. Besides standard descriptive statistical analysis, progression-free survival and overall survival were defined using the Kaplan-Meier method. RESULTS: Over 80% of the patients showed favorable biochemical responses. Median time to progression was 9.1 months (mean 9.8, 95% confidence interval 7.8-9.9), and median overall survival was 19.9 months (mean 24.5, 95% confidence interval 16.9-22.8); five patients were still alive over 5 years after enrollment. No additional hematological toxicities were observed when docetaxel was administered after Sm-EDTMP other than those expected when administering the agent alone. CONCLUSION: Prior administration of Sm-EDTMP does not cause additional toxicities for subsequent treatment with docetaxel and does not reduce the antitumor efficacy of the latter. This work justifies further investigations on the possible synergistic effects of combined strategies with the two agents. PMID- 24157944 TI - Using synthetic templates to design an unbiased multiplex PCR assay. AB - T and B cell receptor loci undergo combinatorial rearrangement, generating a diverse immune receptor repertoire, which is vital for recognition of potential antigens. Here we use a multiplex PCR with a mixture of primers targeting the rearranged variable and joining segments to capture receptor diversity. Differential hybridization kinetics can introduce significant amplification biases that alter the composition of sequence libraries prepared by multiplex PCR. Using a synthetic immune receptor repertoire, we identify and minimize such biases and computationally remove residual bias after sequencing. We apply this method to a multiplex T cell receptor gamma sequencing assay. To demonstrate accuracy in a biological setting, we apply the method to monitor minimal residual disease in acute lymphoblastic leukaemia patients. A similar methodology can be extended to any adaptive immune locus. PMID- 24157943 TI - Gene-gene interactions in APOL1-associated nephropathy. AB - BACKGROUND: Two APOL1 nephropathy variants confer substantial risk for non diabetic end-stage kidney disease (ESKD) in African Americans (AAs). Since not all genetically high-risk individuals develop ESKD, modifying factors likely contribute. Forty-two potentially interactive single nucleotide polymorphisms (SNPs) from a genome-wide association study in non-diabetic ESKD were tested for interaction with APOL1 to identify genes modifying risk for non-diabetic nephropathy. METHODS: SNPs were examined in an expanded sample of 1367 AA non diabetic ESKD cases and 1504 AA non-nephropathy controls, with validation in an independent family-based cohort containing 608 first-degree relatives of index cases with non-diabetic ESKD. Logistic regression and mixed models were fitted to test for interaction effects with APOL1 on ESKD, estimated kidney function and albuminuria. RESULTS: Among ESKD samples, 14 of 42 SNPs demonstrated suggestive APOL1 interaction with P-values <0.05. After Bonferroni correction, significant interactions with APOL1 were seen with SNPs in podocin (rs16854341; NPHS2, P = 8.0 * 10(-4)), in SDCCAG8 (rs2802723; P = 5.0 * 10(-4)) and near BMP4 (rs8014363; P = 1.0 * 10(-3)); with trends for ENOX1 (rs9533534; P = 2.2 * 10(-3)) and near TRIB1 (rs4457349; P = 5.7 * 10(-3)). The minor allele in NPHS2 markedly changed the APOL1-ESKD association odds ratio (OR) from 7.03 to 1.76 (~50% reduction in effect per copy of the minor allele), rs2802723 changed the OR from 5.1 to 10.5, and rs8014363 increased the OR from 4.8 to 9.5. NPHS2 (P = 0.05) and SDCCAG8 (P = 0.03) SNPs demonstrated APOL1 interaction with albuminuria in independent family based samples. CONCLUSIONS: Variants in NPHS2, SDCCAG8 and near BMP4 appear to interact with APOL1 to modulate the risk for non-diabetic ESKD in AAs. PMID- 24157945 TI - Characterisation and expression of myogenesis regulatory factors during in vitro myoblast development and in vivo fasting in the gilthead sea bream (Sparus aurata). AB - The aim of this study was to characterise a primary cell culture isolated from fast skeletal muscle of the gilthead sea bream. Gene expression profiles during culture maturation were compared with those obtained from a fasting-refeeding model which is widely used to modulate myogenesis in vivo. Myogenesis is controlled by numerous extracellular signals together with intracellular transcriptional factors whose coordinated expression is critical for the appropriate development of muscle fibres. Full-length cDNAs for the transcription factors Myf5, Mrf4, Pax7 and Sox8 were cloned and sequenced for gilthead sea bream. Pax7, sox8, myod2 and myf5 levels were up-regulated during the proliferating phase of the myogenic cultures coincident with the highest expression of proliferating cell nuclear antigen (PCNA). In contrast, myogenin and mrf4 transcript abundance was highest during the differentiation phase of the culture when myotubes were present, and was correlated with increased myosin heavy chain (mhc) and desmin expression. In vivo, 30days of fasting resulted in muscle fibre atrophy, a reduction in myod2, myf5 and igf1 expression, lower number of Myod-positive cells, and decreased PCNA protein expression, whereas myogenin expression was not significantly affected. Myostatin1 (mstn1) and pax7 expression were up-regulated in fasted relative to well-fed individuals, consistent with a role for Pax7 in the reduction of myogenic cell activity with fasting. The primary cell cultures and fasting-feeding experiments described provide a foundation for the future investigations on the regulation of muscle growth in gilthead sea bream. PMID- 24157946 TI - Tightly controlled WRKY23 expression mediates Arabidopsis embryo development. AB - The development of a multicellular embryo from a single zygote is a complex and highly organized process that is far from understood. In higher plants, apical basal patterning mechanisms are crucial to correctly specify root and shoot stem cell niches that will sustain and drive post-embryonic plant growth and development. The auxin-responsive AtWRKY23 transcription factor is expressed from early embryogenesis onwards and the timing and localization of its expression overlaps with the root stem cell niche. Knocking down WRKY23 transcript levels or expression of a dominant-negative WRKY23 version via a translational fusion with the SRDX repressor domain affected both apical-basal axis formation as well as installation of the root stem cell niche. WRKY23 expression is affected by two well-known root stem cell specification mechanisms, that is, SHORTROOT and MONOPTEROS-BODENLOS signalling and can partially rescue the root-forming inability of mp embryos. On the basis of these results, we postulate that a tightly controlled WRKY23 expression is involved in the regulation of both auxin dependent and auxin-independent signalling pathways towards stem cell specification. PMID- 24157947 TI - Remodelling without a power stroke. PMID- 24157948 TI - Piezo1-dependent stretch-activated channels are inhibited by Polycystin-2 in renal tubular epithelial cells. AB - Mechanical forces associated with fluid flow and/or circumferential stretch are sensed by renal epithelial cells and contribute to both adaptive or disease states. Non-selective stretch-activated ion channels (SACs), characterized by a lack of inactivation and a remarkably slow deactivation, are active at the basolateral side of renal proximal convoluted tubules. Knockdown of Piezo1 strongly reduces SAC activity in proximal convoluted tubule epithelial cells. Similarly, overexpression of Polycystin-2 (PC2) or, to a greater extent its pathogenic mutant PC2-740X, impairs native SACs. Moreover, PC2 inhibits exogenous Piezo1 SAC activity. PC2 coimmunoprecipitates with Piezo1 and deletion of its N terminal domain prevents both this interaction and inhibition of SAC activity. These findings indicate that renal SACs depend on Piezo1, but are critically conditioned by PC2. PMID- 24157950 TI - Tiling array study of MNNG treated Escherichia coli reveals a widespread transcriptional response. AB - The alkylating agent N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) is known to trigger the adaptive response by inducing the ada-regulon - consisting of three DNA repair enzymes Ada, AlkB, AlkA and the enigmatic AidB. We have applied custom designed tiling arrays to study transcriptional changes in Escherichia coli following a MNNG challenge. Along with the expected upregulation of the adaptive response genes (ada, alkA and alkB), we identified a number of differentially expressed transcripts, both novel and annotated. This indicates a wider regulatory response than previously documented. There were 250 differentially expressed and 2275 similarly-expressed unannotated transcripts. We found novel upregulation of several stress-induced transcripts, including the SOS inducible genes recN and tisAB, indicating a novel role for these genes in alkylation repair. Furthermore, the ada-regulon A and B boxes were found to be insufficient to explain the regulation of the adaptive response genes after MNNG exposure, suggesting that additional regulatory elements must be involved. PMID- 24157949 TI - Ldb1 is essential for development of Nkx2.1 lineage derived GABAergic and cholinergic neurons in the telencephalon. AB - The progenitor zones of the embryonic mouse ventral telencephalon give rise to GABAergic and cholinergic neurons. We have shown previously that two LIM homeodomain (LIM-HD) transcription factors, Lhx6 and Lhx8, that are downstream of Nkx2.1, are critical for the development of telencephalic GABAergic and cholinergic neurons. Here we investigate the role of Ldb1, a nuclear protein that binds directly to all LIM-HD factors, in the development of these ventral telencephalon derived neurons. We show that Ldb1 is expressed in the Nkx2.1 cell lineage during embryonic development and in mature neurons. Conditional deletion of Ldb1 causes defects in the expression of a series of genes in the ventral telencephalon and severe impairment in the tangential migration of cortical interneurons from the ventral telencephalon. Similar to the phenotypes observed in Lhx6 or Lhx8 mutant mice, the Ldb1 conditional mutants show a reduction in the number of both GABAergic and cholinergic neurons in the telencephalon. Furthermore, our analysis reveals defects in the development of the parvalbumin positive neurons in the globus pallidus and striatum of the Ldb1 mutants. These results provide evidence that Ldb1 plays an essential role as a transcription co regulator of Lhx6 and Lhx8 in the control of mammalian telencephalon development. PMID- 24157951 TI - Aqualase(r) revisited: endothelial cell loss strongly depends on lens density. AB - PURPOSE: To analyze the dependence between corneal endothelial cell loss by Aqualase(r) cataract surgery and the nuclear opalescence grade of the lens. PATIENTS AND METHODS: A total of 100 eyes of 92 patients were enrolled in this prospective, single-center study. Patients were randomly assigned to the Aqualase (50 eyes) or the phacoemulsification group (50 eyes). The nuclear density was classified with the Lens Opacities Classification System III. All procedures were performed by the same surgeon. Preoperatively and 1 week postoperatively, endothelial cell counts were obtained using a noncontact specular microscope (Konan, Japan). RESULTS: (1) Aqualase group: the group of patients with a nuclear density of 1-2 (17 patients) showed no significant endothelial cell loss (4.1%, p = 0.163). The endothelial cell loss in grade 3 cataracts (28 eyes) was 13.9% (p = 0.004) and in grade 4 cataracts (5 eyes) 69.1% (p = 0.043), being statistically significant in both groups. (2) Phacoemulsification group: in nuclear density groups 1 and 2, endothelial cell loss was 6.3% (p = 0.41), in group 3 it was 17.6% (p = 0.001) and in group 4 it was 14.9% (p = 0.08). Only in nuclear opalescence grade 4 there was a significant difference between the Aqualase and the phacoemulsification procedure (p = 0.008). CONCLUSION: Endothelial cell loss by Aqualase technology depends strongly on the nuclear opalescence grade. In low- and medium-density cataracts, Aqualase does not seem to provoke significant endothelial cell loss. Due to very high endothelial loss in hard nuclei, Aqualase is unsuitable for these cataracts. PMID- 24157952 TI - Systematic review and meta-analysis of autologous stem cell transplantation in peripheral T cell lymphoma. PMID- 24157953 TI - Substance P receptor antagonist in lateral habenula improves rat depression-like behavior. AB - Substance P (SP) levels are closely related with the pathogenesis of depression. Recent work has focused on antidepressive effect of substance P receptor antagonist (SPA), however, its action site and mechanism remain largely unresolved. Our previous results showed that the lateral habenula (LHb) plays a key role in the pathogenesis of depression. The current study investigated the effects of SPA microinjected into LHb on the behavioral responses of two rat models that exhibit depression-like behavior. To produce adult rats that exhibit depression-like behavior, rats were either exposed to chronic mild stress (CMS), or chronically administered clomipramine (CLI), a tricyclic antidepressant, during the neonatal state of life. The forced-swimming test (FST) was used to evaluate behavioral responses. Furthermore, we measured serotonin (5-HT) levels in dorsal raphe nucleus (DRN) using microdialysis. The FST showed a decreased immobility time and an increased climbing time after SPA injection into the LHb of depression-like behavior rats. In addition, 5-HT levels in DRN increased after SPA was microinjected into LHb of the rats that exhibited depression-like behavior. This study demonstrates that LHb mediates antidepressive effect of SPA by increasing 5-HT levels in the DRN, suggesting that the LHb may be a potential target of antidepressant. PMID- 24157954 TI - Balb/c mice treated with D-cycloserine arouse increased social interest in conspecifics. AB - The genetically inbred Balb/cJ (Balb/c) mouse with functional alteration of its endogenous tone of NMDA receptor-mediated neurotransmission displays impaired sociability in a standard paradigm; this mouse strain has been proposed as a model of autism spectrum disorders (ASDs). Prior work showed that treatment of the Balb/c mouse with a centrally effective dose of D-cycloserine, a partial glycineB NMDA receptor agonist, improved several measures of its sociability. Additionally, D-cycloserine-treated Balb/c mice show greater preference for a social stimulus mouse than an inanimate object. We wondered if treatment with D cycloserine also improved the social salience of the Balb/c mouse for "normally" sociable comparator strains. The current experiments explored whether C57Bl/6J (B6) and ICR mouse strains prefer D-cycloserine-treated to vehicle-treated Balb/c stimulus mice in a paradigm that evaluated social preference. The results showed that B6 mice prefer D-cycloserine-treated Balb/c mice to vehicle-treated Balb/c mice, suggesting that treatment could have resulted in normalization of "emitted" social cues. PMID- 24157955 TI - Low-dose estrogen is as effective as high-dose treatment in rats with postmenopausal hypertension. AB - : This study was conducted to test the hypothesis that 17beta-estradiol therapy improves redox balance by decreasing reactive oxygen species production and increasing nitric oxide (NO) bioavailability, favoring Akt pathway activation and resulting in a better autonomic vascular control. Ovariectomized female Wistar rats were divided into 4 groups: (1) vehicle (VL) and animals treated with a pellet of 17beta-estradiol for 21 days; (2) low dose (LE; 0.05 mg); (3) medium dose (ME; 0.2 mg); and (4) high dose (HE; 0.5 mg). Arterial pressure and its sympathetic nervous system modulation were evaluated by spectral analysis. Nitric oxide synthase and NADPH oxidase (Nox) activities, H2O2 concentration, redox status (GSH/GSSG), protein expression of Trx-1 and p-Akt/Akt were evaluated in the aorta, whereas NO metabolites were measured in the serum. Estrogen-treated groups showed a significant decrease in arterial pressure and sympathetic vascular drive. Redox status was significantly improved and NADPH oxidase and H2O2 were decreased in all estrogen-treated groups. Estrogen also induced an enhancement in NO metabolites, nitric oxide synthase activity, and Akt phosphorylation. This study demonstrated that estrogen treatment to ovariectomized rats induced cardioprotection, which was evidenced by reduced blood pressure variability and vascular sympathetic drive. These effects were associated with an improved redox balance and Akt activation, resulting in an enhanced NO bioavailability. PMID- 24157956 TI - Fenofibrate modulates cytochrome P450 and arachidonic acid metabolism in the heart and protects against isoproterenol-induced cardiac hypertrophy. AB - It has been previously shown that the cytochrome P450 (P450) modulator, fenofibrate, protects against cardiovascular diseases. P450 and their metabolites, epoxyeicosatrienoic acids (EETs) and 20-hydroxyeicosatetraenoic acid (20-HETE) were found to play an important role in cardiovascular diseases. Therefore, it is important to examine whether fenofibrate would modulate the cardiac P450 and its associated arachidonic acid metabolites and whether this modulation protects against isoproterenol-induced cardiac hypertrophy. For this purpose, male Sprague-Dawley rats were treated with fenofibrate (30 mg.kg.d), isoproterenol (4.2 mg.kg.d), or the combination of both. The expression of hypertrophic markers and different P450s along with their metabolites was determined. Our results showed that fenofibrate significantly induced the cardiac P450 epoxygenases, such as CYP2B1, CYP2B2, CYP2C11, and CYP2C23, whereas it decreased the cardiac omega-hydroxylase, CYP4A3. Moreover, fenofibrate significantly increased the formation of 14,15-EET, 11,12-EET, and 8,9-EET, whereas it decreased the formation of 20-HETE in the heart. Furthermore, fenofibrate significantly decreased the hypertrophic markers and the increase in heart-to-body weight ratio induced by isoproterenol. This study demonstrates that fenofibrate alters the expression of cardiac P450s and their metabolites and partially protects against isoproterenol-induced cardiac hypertrophy, which further confirms the role of P450s, EETs, and 20-HETE in the development of cardiac hypertrophy. PMID- 24157957 TI - The effect of aleglitazar on the pharmacokinetics and pharmacodynamics of S- and R-warfarin in healthy male subjects. AB - : Aleglitazar acts through balanced activation of peroxisome proliferator activated receptors alpha and gamma; warfarin is a commonly prescribed anticoagulant. Given the extent of cardiovascular disease in patients with type 2 diabetes, cotreatment with aleglitazar and warfarin is likely in this population. This open-label, randomized, 2-period, crossover study in 12 healthy male subjects investigated the potential for drug-drug interactions between warfarin and aleglitazar (final data drawn from 11 white subjects). The primary objective was to investigate the effect of aleglitazar on the pharmacokinetic properties of S-warfarin and on the pharmacodynamics of the racemic mixture; the secondary objectives included the effect of aleglitazar on R-warfarin pharmacokinetics and of racemic warfarin on aleglitazar pharmacokinetics. Subjects were randomized to single-dose warfarin on day 1 or aleglitazar once daily (12 days) plus single dose warfarin on day 6 followed by a 14-day washout period, then crossover. Coadministration of aleglitazar reduced S- and R-warfarin exposure (AUC0 infinity) by 18% and 13%, respectively, but did not change its pharmacodynamic effects (prothrombin time and factor VII activity). After warfarin dosing, aleglitazar trough concentrations remained within the same range. These findings indicate that coadministration of aleglitazar and warfarin is unlikely to affect the efficacy or safety of either agent. PMID- 24157958 TI - The effect of urban-area unemployment on the mental health of citizens differs between Slovak and Dutch cities. AB - Conclusive evidence on the association of mental health problems (MHP) with area unemployment is lacking in regard to Central European cities. We obtained data on residents aged 19-64 from Slovak and Dutch cities from the FP7 EURO-URHIS 2 project. Multilevel logistic regression showed that the association between MHP (GHQ-12-total score >=2) and area unemployment was strong in the Netherlands, but absent in Slovakia. Slovak citizens from the most favourable neighbourhoods had nearly double the risk of MHP than their Dutch counterparts. Individual-level socioeconomic characteristics did not explain area differences. The effect of urban-area unemployment seems to differ between Central European and Western European countries. PMID- 24157959 TI - Order-disorder transition in a two-dimensional boron-carbon-nitride alloy. AB - Two-dimensional boron-carbon-nitride materials exhibit a spectrum of electronic properties ranging from insulating to semimetallic, depending on their composition and geometry. Detailed experimental insights into the phase separation and ordering in such alloy are currently lacking. Here we report the mixing and demixing of boron-nitrogen and carbon phases on ruthenium (0001) and found that energetics for such processes are modified by the metal substrate. The brick-and-mortar patchwork observed of stoichiometrically percolated hexagonal boron-carbon-nitride domains surrounded by a network of segregated graphene nanoribbons can be described within the Blume-Emery-Griffiths model applied to a honeycomb lattice. The isostructural boron nitride and graphene assumes remarkable fluidity and can be exchanged entirely into one another by a catalytically assistant substitution. Visualizing the dynamics of phase separation at the atomic level provides the premise for enabling structural control in a two-dimensional network for broad nanotechnology applications. PMID- 24157960 TI - Argon plasma coagulation of gastric inlet patches for the treatment of globus sensation: it is an effective therapy in the long term. AB - AIM: To determine the long-term effect of argon plasma coagulation (APC) of gastric inlet patches in the cervical esophagus for patients suffering from globus sensation. METHODS: We intended to follow up all patients between 2004 and 2011 (n = 49) who received argon plasma ablation of gastric inlet patches for globus sensation at our clinic. Symptoms were assessed by a visual analogue scale (VAS) in 31 of 49 patients. Follow-up endoscopy of the upper gastrointestinal tract was performed to confirm residual or relapsed cervical inlet patches. RESULTS: After a median period of 27 months, APC was assessed as a successful therapy in 23 of 31 patients (74%). VAS scores decreased significantly from 7.6 to 4.0 in the long term. Twenty-two of 31 patients were willing to undergo follow up endoscopy. Endoscopy revealed recurrent/residual gastric inlet patches after APC in 11 of 22 cases. These patients suffered from a significant relapse of symptoms in the postinterventional period (p < 0.001). CONCLUSION: This retrospective study indicates that APC of gastric inlet patches for the treatment of globus sensation might be a sufficient therapy option. Recurrences or residual heterotopic gastric mucosa are possible and seem to be associated with a relapse of symptoms. Therefore, endoscopic follow-up and retreatment might be necessary if globus sensation is not sufficiently eliminated. PMID- 24157961 TI - Iron metabolism: bedside to bench and back. PMID- 24157962 TI - Hemochromatosis and iron overload: from bench to clinic. PMID- 24157963 TI - An update on iron homeostasis: make new friends, but keep the old. AB - A classic Girl Scout song says, "Make new friends/but keep the old/One is silver/and the other gold." This review focuses on the past decade of discovery in the field of iron homeostasis, which has identified "new friends" or key modifiers of the critical systemic iron regulator, hepcidin antimicrobial peptide. The foundation for these discoveries has been the identification of mutated genes in well-characterized cohorts of patients with inherited hemochromatosis from across the globe. Transgenic mouse models of iron overload and iron-restricted anemia have also contributed to understanding molecular pathophysiology in ways that could never be accomplished in human subjects alone. The majority of these newly discovered molecules coordinate signaling through the bone morphogenetic protein pathway of ligands, receptors and coreceptors, intracellular signaling and transcription. The discovery of these proteins and their interactions with "old friends," such as the 1st known hereditary hemochromatosis gene product, HFE and transferrin receptor, has opened the field of iron homeostasis to include regulatory networks involving signal transduction pathways, in particular, the mitogen-activated protein kinase and Smad pathways. These newly discovered partnerships have also made way for opportunities to develop novel therapeutics for the treatment of iron regulatory disorders, including hemochromatosis. PMID- 24157964 TI - Sternal mass presenting as a first manifestation of lung cancer. PMID- 24157965 TI - Atypical Rocky Mountain spotted fever with polyarticular arthritis. AB - BACKGROUND: Rocky Mountain spotted fever (RMSF) is an acute, serious tick borne illness caused by Rickettsia rickettsi. Frequently, RMSF is manifested by headache, a typical rash and fever but atypical disease is common, making diagnosis difficult. Inflammatory arthritis as a manifestation is rare. The purpose of this study is to describe a patient with serologically proven RMSF who presented in an atypical manner with inflammatory arthritis of the small joints of the hands and to review the previously reported patients with rickettsial infection and inflammatory arthritis. METHODS: An 18-year-old woman presented with a rash that began on the distal extremities and spread centrally, along with hand pain and swelling. She had tenderness and swelling of the metacarpophlangeal joints on examination in addition to an erythematosus macular rash and occasional fever. RESULTS: Acute and convalescent serology demonstrated R rickettsi infection. She was successfully treated with doxycycline. CONCLUSIONS: Inflammatory arthritis is a rare manifestation of RMSF or other rickettsial infection with 8 previously reported patients, only 1 of whom had RMSF. Physician must have a high index of suspicion for RMSF because of atypical presentations. PMID- 24157966 TI - A rare case of double parathyroid lipoadenoma with hyperparathyroidism. AB - A rare case of double lipoadenomas of parathyroid glands with hyperparathyroidism is described. A 56-year-old woman was referred for management of diabetes. Work up revealed: serum Calcium (Ca) =11.9 mg/dl, glomerular filtration rate (GFR) = 103 ml/min/m2, parathyroid hormone (PTH) = 60 pg/ml, Phosphorus = 3.0 mg/dl, 25 hydroxy vitamin D (25 OH D) =16.5 ng/ml, 24 h urine Calcium =179 mg/day. Parathyroid sestamibi scan showed increased activity in the left thyroid and right thyroid lobe. Single photon emission computed tomography demonstrated uptake in inferior left and right thyroid lobes. Her serum calcium following successful bilateral parathyroidectomy was 9.3 mg/dl. Pathology showed double parathyroid lipoadenomas. After surgery, her serum Calcium and PTH normalized to 9.8 mg/dl and 32 pg/ml respectively. Lipoadenoma has been described as a very rare lesion of the parathyroid gland and is most commonly non-functional. PubMed search failed to reveal any case of hyperparathyroidism due to double parathyroid lipoadenomas. PMID- 24157967 TI - Emergent transcutaneous embolization in an advanced carcinosarcoma. AB - Active hemorrhage is a life-threatening complication of advanced tumors. It often signifies the terminal stage of the disease and therefore is usually treated with palliative care. Transcutaneous arterial embolization (TAE) is a safe, noninvasive procedure that halts acute tumor-related bleeding thereby providing effective life-saving treatment for patients with non-operable tumors. Carcinosarcoma is an uncommon tumor that generally affects the head and neck, respiratory tract, colon, uterus, ovaries, and fallopian tubes. The authors present an interesting case of a rare manifestation in an unusual location. A 60 year-old Caucasian male, who presented with abdominal and groin pain, was found to have a large carcinosarcoma in the retroperitoneal space. The tumor was complicated with an active bleed. Since he was not a candidate for surgical intervention, a TAE was performed. Two days later, the patient was discharged to hospice where he was able to live out the rest of his life. PMID- 24157968 TI - Purinergic receptor X7 is a key modulator of metabolic oxidative stress-mediated autophagy and inflammation in experimental nonalcoholic steatohepatitis. AB - Recent studies indicate that metabolic oxidative stress, autophagy, and inflammation are hallmarks of nonalcoholic steatohepatitis (NASH) progression. However, the molecular mechanisms that link these important events in NASH remain unclear. In this study, we investigated the mechanistic role of purinergic receptor X7 (P2X7) in modulating autophagy and resultant inflammation in NASH in response to metabolic oxidative stress. The study uses two rodent models of NASH. In one of them, a CYP2E1 substrate bromodichloromethane is used to induce metabolic oxidative stress and NASH. Methyl choline-deficient diet feeding is used for the other NASH model. CYP2E1 and P2X7 receptor gene-deleted mice are used to establish their roles in regulating metabolic oxidative stress and autophagy. Autophagy gene expression, protein levels, confocal microscopy based immunolocalization of lysosome-associated membrane protein (LAMP)2A and histopathological analysis were performed. CYP2E1-dependent metabolic oxidative stress induced increases in P2X7 receptor expression and chaperone-mediated autophagy markers LAMP2A and heat shock cognate 70 but caused depletion of light chain 3 isoform B (LC3B) protein levels. P2X7 receptor gene deletion significantly decreased LAMP2A and inflammatory indicators while significantly increasing LC3B protein levels compared with wild-type mice treated with bromodichloromethane. P2X7 receptor-deleted mice were also protected from NASH pathology as evidenced by decreased inflammation and fibrosis. Our studies establish that P2X7 receptor is a key regulator of autophagy induced by metabolic oxidative stress in NASH, thereby modulating hepatic inflammation. Furthermore, our findings presented here form a basis for P2X7 receptor as a potential therapeutic target in the treatment for NASH. PMID- 24157969 TI - Increased PDE5 activity and decreased Rho kinase and PKC activities in colonic muscle from caveolin-1-/- mice impair the peristaltic reflex and propulsion. AB - Caveolae are specialized regions of the plasma membrane that concentrate receptors and associated signaling molecules critical in regulation of cellular response to transmitters and hormones. We have determined the effects of caveolin 1 (Cav-1) deletion, caveolin-1 siRNA, and caveolar disruption in mice on the signaling pathways that mediate contraction and relaxation in colonic smooth muscle and on the components of the peristaltic reflex in isolated tissue and propulsion in intact colonic segments. In Cav-1-/- mice, both relaxation and contraction were decreased in smooth muscle cells and muscle strips, as well as during both phases of the peristaltic reflex and colonic propulsion. The decrease in relaxation in response to the nitric oxide (NO) donor was accompanied by a decrease in cGMP levels and an increase in phosphodiesterase 5 (PDE5) activity. Relaxation by a PDE5-resistant cGMP analog was not affected in smooth muscle of Cav-1-/- mice, suggesting that inhibition of relaxation was due to augmentation of PDE5 activity. Similar effects on relaxation, PDE5 and cGMP were obtained in muscle cells upon disruption of caveolae by methyl-beta-cyclodextrin or suppression of Cav-1. Sustained contraction mediated via inhibition of myosin light chain phosphatase (MLCP) activity is regulated by Rho kinase and PKC via phosphorylation of two endogenous inhibitors of MLCP: myosin phosphatase targeting subunit (MYPT1) and 17-kDa PKC-potentiated protein phosphatase 1 inhibitor protein (CPI-17), respectively. The activity of both enzymes and phosphorylation of MYPT1 and CPI-17 were decreased in smooth muscle from Cav-1-/- mice. We conclude that the integrity of caveolae is essential for contractile and relaxant activity in colonic smooth muscle and the maintenance of neuromuscular function at organ level. PMID- 24157971 TI - Raw bovine milk improves gut responses to feeding relative to infant formula in preterm piglets. AB - For preterm neonates, the quality of the first milk is crucial for intestinal maturation and resistance to necrotizing enterocolitis (NEC). Among other factors, milk quality is determined by the stage of lactation and processing. We hypothesized that unprocessed mature bovine milk (BM; raw bovine milk) would have less bioactivity than corresponding bovine colostrum (BC) in a preterm pig model, but have improved bioactivity relative to its homogenized, pasteurized, spray dried equivalent, whole milk powder (WMP), or a bovine milk protein-based infant formula (IF). For 5 days, newborn preterm pigs received parenteral and enteral nutrition consisting of IF (n = 13), BM (n = 13), or BC (n = 14). In a second study, WMP (n = 15) was compared with IF (n = 10) and BM (n = 9). Compared with pigs fed IF, pigs that were fed BM had significantly improved intestinal structure (mucosal weight, villus height) and function (increased nutrient absorption and enzyme activities, decreased gut permeability, nutrient fermentation, and NEC severity). BC further improved these effects relative to BM (lactase activity, lactose absorption, plasma citrulline, and tissue interleukin 8). WMP induced similar effects as BM, except for lactase activity and lactose absorption. In conclusion, the maturational and protective effects on the immature intestine decreased in the order BC>BM>WMP, but all three intact bovine milk diets were markedly better than IF. The stage of lactation (colostrum vs. mature milk) and milk processing (e.g., homogenization, fractionation, pasteurization, spray-drying) are important factors in determining milk quality during the early postnatal period of preterm neonates. PMID- 24157970 TI - Evidence for and against epithelial-to-mesenchymal transition in the liver. AB - The outcome of liver injury is determined by the success of repair. Liver repair involves replacement of damaged liver tissue with healthy liver epithelial cells (including both hepatocytes and cholangiocytes) and reconstruction of normal liver structure and function. Current dogma posits that replication of surviving mature hepatocytes and cholangiocytes drives the regeneration of liver epithelium after injury, whereas failure of liver repair commonly leads to fibrosis, a scarring condition in which hepatic stellate cells, the main liver-resident mesenchymal cells, play the major role. The present review discusses other mechanisms that might be responsible for the regeneration of new liver epithelial cells and outgrowth of matrix-producing mesenchymal cells during hepatic injury. This theory proposes that, during liver injury, some epithelial cells undergo epithelial-to-mesenchymal transition (EMT), acquire myofibroblastic phenotypes/features, and contribute to fibrogenesis, whereas certain mesenchymal cells (namely hepatic stellate cells and stellate cell-derived myofibroblasts) undergo mesenchymal-to-epithelial transition (MET), revert to epithelial cells, and ultimately differentiate into either hepatocytes or cholangiocytes. Although this theory is highly controversial, it suggests that the balance between EMT and MET modulates the outcome of liver injury. This review summarizes recent advances that support or refute the concept that certain types of liver cells are capable of phenotype transition (i.e., EMT and MET) during both culture conditions and chronic liver injury. PMID- 24157972 TI - Antibiotics modulate intestinal immunity and prevent necrotizing enterocolitis in preterm neonatal piglets. AB - Preterm birth, bacterial colonization, and formula feeding predispose to necrotizing enterocolitis (NEC). Antibiotics are commonly administered to prevent sepsis in preterm infants, but it is not known whether this affects intestinal immunity and NEC resistance. We hypothesized that broad-spectrum antibiotic treatment improves NEC resistance and intestinal structure, function, and immunity in neonates. Caesarean-delivered preterm pigs were fed 3 days of parenteral nutrition followed by 2 days of enteral formula. Immediately after birth, they were assigned to receive either antibiotics (oral and parenteral doses of gentamycin, ampicillin, and metronidazole, ANTI, n = 11) or saline in the control group (CON, n = 13), given twice daily. NEC lesions and intestinal structure, function, microbiology, and immunity markers were recorded. None of the ANTI but 85% of the CON pigs developed NEC lesions by day 5 (0/11 vs. 11/13, P < 0.05). ANTI pigs had higher intestinal villi (+60%), digestive enzyme activities (+53-73%), and goblet cell densities (+110%) and lower myeloperoxidase (-51%) and colonic microbial density (10(5) vs. 10(10) colony-forming units, all P < 0.05). Microarray transcriptomics showed strong downregulation of genes related to inflammation and innate immune response to microbiota and marked upregulation of genes related to amino acid metabolism, in particular threonine, glucose transport systems, and cell cycle in 5-day-old ANTI pigs. In a follow-up experiment, 5 days of antibiotics prevented NEC at least until day 10. Neonatal prophylactic antibiotics effectively reduced gut bacterial load, prevented NEC, intestinal atrophy, dysfunction, and inflammation and enhanced expression of genes related to gut metabolism and immunity in preterm pigs. PMID- 24157973 TI - Association of HSD17B3 and HSD3B1 polymorphisms with acne vulgaris in Southwestern Han Chinese. AB - Acne vulgaris is a very common skin disorder. Previous studies have indicated that genetic background factors play key roles in the onset of acne. Our previous investigation implicated several genes in the androgen metabolism pathway with acne vulgaris in the Han Chinese population. Thus, we further investigated genes and genetic variants that play important roles in this pathway for their relationship with the pathology of acne. In this study, a total of 610 subjects, including 403 acne patients and 207 healthy controls, were genotyped for 15 single-nucleotide polymorphisms in HSD3B1 and HSD17B3 genes. This study shows that rs6428829 in HSD3B1 was associated with acne vulgaris in Han patients from Southwest China, even after adjusting for age and sex. The GG genotype was associated with an increased risk of acne vulgaris (p < 0.05) and G allele carriers were associated with an increased risk of acne vulgaris (p < 0.05). In addition, the haplotype AAT in HSD3B1 significantly increased the risk of acne vulgaris in the case-control study (p < 0.05). Furthermore, for another gene in this pathway, HSD17B3, the haplotype H8 was significantly associated with an increased risk of acne vulgaris. Based on these analyses, our study indicates that the cutaneous androgen metabolism-regulated genes HSD3B1 and HSD17B3 increase the susceptibility to acne vulgaris in Han Chinese from Southwest China. PMID- 24157975 TI - Conditioned flavor avoidance and conditioned gaping: rat models of conditioned nausea. AB - Although rats are incapable of vomiting, they demonstrate profound avoidance of a flavor previously paired with an emetic drug. They also display conditioned gaping reactions during re-exposure to the flavor. This robust learning occurs in a single trial and with long delays (hours) between consumption of a novel flavor and the emetic treatment. However, conditioned flavor avoidance learning is not a selective measure of the emetic properties of drugs, because non-emetic treatments (even highly rewarding treatments) produce conditioned avoidance, and anti-emetic treatments are generally ineffective in suppressing conditioned avoidance produced by an emetic drug. On the other hand, conditioned gaping reactions are consistently produced by emetic drugs and are prevented by anti emetic drugs, indicating that they may be a more selective measure of conditioned malaise in rats. Here we review the literature on the use of conditioned flavor avoidance and conditioned gaping reactions as rat measures of conditioned nausea, as well as the neuropharmacology and neuroanatomy of conditioned gaping reactions in rats. PMID- 24157974 TI - Different regulatory effects of hydrogen sulfide and nitric oxide on gastric motility in mice. AB - NO and H2S are gaseous signaling molecules that modulate smooth muscle motility. We aimed to identify expressions of enzymes that catalyze H2S and NO generation in mouse gastric smooth muscle, and determine relationships between endogenous H2S and NO in regulation of smooth muscle motility. Western blotting and immunocytochemistry methods were used to track expressions of neuronal nitric oxide synthase (nNOS), endothelial nitric oxide synthase (eNOS), cystathionine beta-synthase (CBS) and cystathionine gamma-lyase (CSE) in gastric smooth muscles. Smooth muscle motility was recorded by isometric force transducers. cGMP production was measured by a specific radioimmunoassay. We found that CBS, CSE, eNOS, and nNOS were all expressed in mice gastric antral smooth muscle tissues, and in cultured gastric antral smooth muscle cells. AOAA significantly inhibited smooth muscle contractions in the gastric antrum, which was significantly recovered by NaHS, while PAG had no significant effect. l-NAME enhanced contractions. NaHS at low concentrations increased basal tension but decreased it at high concentrations. SNP significantly inhibited the contractions, which could be recovered by NaHS both in the absence and presence of CuSO4. ODQ did not block NaHS-induced excitatory effect, while IBMX partially blocked this effect. cGMP production in smooth muscle was significantly increased by SNP but was not affected by NaHS. All these results suggest that endogenous H2S and NO appear to play opposite roles in regulating gastric motility and their effects may be via separate signal transduction pathways. Intracellular H2S/NO levels may be maintained in a state of balance to warrant normal smooth muscle motility. PMID- 24157977 TI - Prognostic factors for chemotherapy induced nausea and vomiting. AB - PURPOSE: to review the topic of prognostic factors for chemotherapy-induced nausea and vomiting. Multiple patient factors such as age, gender and alcohol intake have been found that affect the likelihood of emesis with a given chemotherapy. Pharmacogenomics has also been explored as a cause for variation in emetic response. In theory these risk factors could be used to optimize antiemetic therapy for individual patients but guidelines for prophylactic antiemetics are based solely upon the type of chemotherapy administered. Attempts to identify subgroups of patients for whom guidelines recommendations are suboptimal have thus far been unsuccessful except for those with a poor experience in a previous cycle of the same chemotherapy. At present, there is no basis for deviating from evidence-based guidelines when prescribing antiemetics prior to the first cycle of chemotherapy. PMID- 24157978 TI - Involvement of IP3-receptor activation in endothelin-1-induced Ca(2+) influx in rat pulmonary small artery. AB - We examined the endothelin-1 (ET-1)-induced increase in the intracellular free Ca(2+) concentration ([Ca(2+)]i) in fura-2-loaded rat pulmonary small arteries. ET-1 (30 nM) elicited a long-lasting increase in [Ca(2+)]i in physiological salt solution (PSS). In subsequent experiments, arteries were pretreated with BQ-788, an ETB-specific blocker, to allow us to focus on responses mediated via the ETA receptor, the existence of which was confirmed by immunohistochemistry. In Ca(2+) free PSS, ET-1 evoked a small transient increase in [Ca(2+)]i, indicating Ca(2+) release from the SR (sarcoplasmic reticulum). After a switch to PSS (containing 2mM CaCl2), ET-1 elicited a long-lasting increase in [Ca(2+)]i that was not inhibited by 1 MUM nicardipine, an L-type Ca(2+)-channel inhibitor, suggesting involvement of a Ca(2+)-influx pathway independent of that channel. In arteries preincubated with 30 MUM cyclopiazonic acid (CPA) or 2 MUM thapsigargin (TG), the ET-1-induced Ca(2+)-release was greatly reduced, and the induced Ca(2+)-influx was attenuated. U-73122, a phospholipase C (PLC) inhibitor, had inhibitory effects similar to those of CPA and TG on the ET-1-induced Ca(2+)-release and Ca(2+)-influx, whereas U-73343, an inactive analogue of U-73122, had no such effects. Two putative membrane-permeable IP3-receptor blockers, 2 aminoethoxydiphenyl borate (2APB, 50 MUM) and Xestospongin C (20 MUM), (a) almost completely inhibited the ET-1-induced Ca(2+)-release and Ca(2+)-influx, and (b) reduced the ET-1-induced contraction. These results indicate that in rat pulmonary small arteries, ET-1 induces receptor-operated Ca(2+) influx via the ETA receptor, and that this influx interacts with InsP3-receptor activation. PMID- 24157976 TI - Additive antiemetic efficacy of low-doses of the cannabinoid CB(1/2) receptor agonist Delta(9)-THC with ultralow-doses of the vanilloid TRPV1 receptor agonist resiniferatoxin in the least shrew (Cryptotis parva). AB - Previous studies have shown that cannabinoid CB1/2 and vanilloid TRPV1 agonists (delta-9-tetrahydrocannabinol (Delta(9)-THC) and resiniferatoxin (RTX), respectively) can attenuate the emetic effects of chemotherapeutic agents such as cisplatin. In this study we used the least shrew to demonstrate whether combinations of varying doses of Delta(9)-THC with resiniferatoxin can produce additive antiemetic efficacy against cisplatin-induced vomiting. RTX by itself caused vomiting in a bell-shaped dose-dependent manner with maximal vomiting at 18 MUg/kg when administered subcutaneously (s.c.) but not intraperitoneally (i.p.). Delta(9)-THC up to 10 mg/kg provides only 80% protection of least shrews from cisplatin-induced emesis with an ID50 of 0.3-1.8 mg/kg. Combinations of 1 or 5 MUg/kg RTX with varying doses of Delta(9)-THC completely suppressed both the frequency and the percentage of shrews vomiting with ID50 dose values 5-50 times lower than Delta(9)-THC doses tested alone against cisplatin. A less potent TRPV1 agonist, capsaicin, by itself did not cause emesis (i.p. or s.c.), but it did significantly reduce vomiting induced by cisplatin given after 30 min but not at 2 h. The TRPV1-receptor antagonist, ruthenium red, attenuated cisplatin-induced emesis at 5mg/kg; however, another TRPV1-receptor antagonist, capsazepine, did not. In summary, we present evidence that combination of CB1/2 and TRPV1 agonists have the capacity to completely abolish cisplatin-induced emesis at doses that are ineffective when used individually. PMID- 24157979 TI - Opioid induced nausea and vomiting. AB - Opioids are broad spectrum analgesics that are an integral part of the therapeutic armamentarium to combat pain in the palliative care population. Unfortunately, among the adverse effects of opioids that may be experienced along with analgesia is nausea, vomiting, and/or retching. Although it is conceivable that in the future, using combination agents (opioids combined with agents which may nullify emetic effects), currently nausea/vomiting remains a significant issue for certain patients. However, there exists potential current strategies that may be useful in efforts to diminish the frequency and/or intensity of opioid-induced nausea/vomiting (OINV). PMID- 24157980 TI - Alleviation of transient global ischemia/reperfusion-induced brain injury in rats with 1,2,3,4,6-penta-O-galloyl-beta-d-glucopyranose isolated from Mangifera indica. AB - Present study was undertaken to evaluate the protective effect of 1,2,3,4,6-penta O-galloyl-beta-d-glucopyranose (PGG) against transient global ischemia/reperfusion (I/R)-induced brain injury in rats. Sixty minutes of global ischemia, followed by 24h of reperfusion caused significant alterations in cognition and memory (p<0.01), significant deterioration of motor coordination, grip strength, and limb tone (P<0.01) associated with neurological deficit. In addition, significant decrease in catalase (P<0.01), and superoxide dismutase (SOD) (P<0.01) activities, increase in lipid peroxidation (P<0.01), depletion of reduced glutathione (GSH) (P<0.01), and increase in brain volume (P<0.01) was observed. Additionally, I/R insult has aggravated the cerebral infarct formation (P<0.01), and the histopathology of brain showed congestion of blood vessels, edema of brain parenchyma, leukocyte infiltration as signs of neuroinflammation, and necrosis of brain tissue. Interestingly, pre-treatment with quercetin (20mg/kg, i.p.), and PGG (5 and 10mg/kg, i.p.) for 7 days showed significant, and dose dependent protection against I/R-induced brain injury by alleviating all the behavioral, neurological, morphological, and histological changes induced by I/R. Besides, PGG is a well-known antioxidant, and its protective effect against I/R induced brain injury is thought to be due to its potent antioxidant property. PMID- 24157981 TI - Nausea and the quest for the perfect anti-emetic. AB - The discovery of anti-emetic agents is reviewed to illustrate the large database (>129,000 papers in PubMed) available for potential data mining and to provide a background to the shift in interest to nausea from vomiting. Research on nausea extends to identification of biomarkers for diagnosis/clinical trials and to understanding why nausea is such a common dose-limiting toxicity of diverse therapeutic agents. The lessons learned for translation from animals to humans, from the discovery of the anti-vomiting effects of 5-HT3 and NK1 receptor antagonists, is discussed in terms of the similarities between the emetic pathways and their pharmacology, and also in terms of the limitations of rodent models of "nausea" (pica, conditioned taste aversion, conditioned gaping and disgust). The review focuses on the established view that anti-emetics are more efficacious against vomiting than nausea. In particular we examine studies of 5 HT3, NK1 and D2 receptor antagonists, gabapentin and various receptor agonists. The potential for targeting anti-nausea agents is then considered, by targeting mechanisms which correct delayed gastric emptying (prokinetics), the rise in plasma vasopressin (AVP) and/or act at central targets revealed by the growing knowledge of cortical regions activated/inhibited in subjects reporting nausea. Modulation of the projections from the brainstem to the cortical areas responsible for the genesis of the sensation of nausea provides the most likely approach to a target at which an anti-nausea drug could be targeted with the expectation that it would affect nausea from multiple causes. PMID- 24157983 TI - Radiation induced nausea and vomiting. AB - Radiation induced nausea and vomiting (RINV) is a frequent complication of radiotherapy and still often underestimated by radiation oncologists. Fractionated RT may involve up to 40 fractions over a 6-8 weeks period, and prolonged symptoms of nausea and vomiting affect quality of life. Approximately, 50-80 percent of patients undergoing radiotherapy (RT) will experience these symptoms if no appropriate prophylaxis is applied. The incidence and severity are influenced by the specific RT regimen and by patient-specific factors. Patients should receive antiemetic prophylaxis as suggested by the international antiemetic guidelines based upon a risk assessment, taking especially into account the planned radiotherapy regimen. In this field the guideline from the Multinational Association of Supportive Care in Cancer (MASCC)/European Society of Clinical Oncology (ESMO) and the American Society of Medical Oncology (ASCO) guidelines are wildly endorsed. The emetogenicity of radiotherapy regimens and recommendations for the appropriate use of antiemetics including 5 hydroxytryptamine (5-HT3) receptor antagonists and steroids will be discussed in regard to the applied radiotherapy or radiochemotherapy regimen. PMID- 24157984 TI - International antiemetic guidelines on chemotherapy induced nausea and vomiting (CINV): content and implementation in daily routine practice. AB - Over the past decades major improvements in the management of chemotherapy induced nausea and vomiting (CINV) were obtained. With the correct use of antiemetic drugs, CINV can be prevented in almost 70%, and even up to, 80% of patients. Treatment guidelines enable physicians to integrate the latest clinical research into their daily practice. The large volume of rapidly evolving clinical data has been summarised and incorporated into treatment recommendations by well known and reliable institutions. These organisations include the Multinational Association of Supportive Care in Cancer (MASCC), the European Society of Medical Oncology (ESMO), the American Society for Clinical Oncology (ASCO), and National Comprehensive Cancer Network (NCCN). However, despite the availability of these guidelines, there is an emerging evidence that adherence to, and implementation of, treatment recommendations is less than optimal. This review will especially focus on the content of the current antiemetic guidelines and will address the important question of how these guidelines are implemented in routine practice. PMID- 24157982 TI - Anticipatory nausea and vomiting due to chemotherapy. AB - As a specific variation of chemotherapy-induced nausea and vomiting, anticipatory nausea and vomiting (ANV) appears particularly linked to psychological processes. The three predominant factors related to ANV are classical conditioning; demographic and treatment-related factors; and anxiety or negative expectancies. Laboratory models have provided some support for these underlying mechanisms for ANV. ANV may be treated with medical or pharmacological interventions, including benzodiazepines and other psychotropic medications. However, behavioral treatments, including systematic desensitization, remain first line options for addressing ANV. Some complementary treatment approaches have shown promise in reducing ANV symptoms. Additional research into these approaches is needed. This review will address the underlying models of ANV and provide a discussion of these various treatment options. PMID- 24157985 TI - Olanzapine for the prevention and treatment of chronic nausea and chemotherapy induced nausea and vomiting. AB - Olanzapine is an atypical antipsychotic agent of the thiobenzodiazepine class. It blocks multiple neurotransmitter receptors including dopaminergic at D1, D2, D3, D4 brain receptors, serotonergic at 5-HT2a, 5-HT2c, 5-HT3, 5-HT6 receptors, catecholamines at alpha1 adrenergic receptors, acetylcholine at muscarinic receptors, and histamine at H1 receptors. Olanzapine has five times the affinity for 5-HT2 receptors than D2 receptors and has been used to treat schizophrenia and delirium. Olanzapine's activity at multiple receptors, particularly at the D2, 5-HT2c, and 5-HT3 receptors which appear to be involved in nausea and emesis, has prompted its use in the treatment of nausea and vomiting refractory to standard antiemetics. Case reports and formal clinical trials have demonstrated its efficacy in the treatment of chronic nausea, the prevention of chemotherapy induced nausea and emesis, and the treatment of breakthrough chemotherapy-induced nausea and emesis. Phase II and phase III clinical trials have demonstrated that there is a significant improvement in nausea when olanzapine is added to guideline directed prophylactic antiemetic agents 5-HT3 receptor antagonists and tachykinin NK1 receptor antagonists in patients receiving moderately or highly emetogenic chemotherapy Common side effects of olanzapine when used over a period of months include weight gain as well as an association with the onset of diabetes mellitus, but these effects have not been seen with short term use of daily doses of less than one week. PMID- 24157986 TI - Are you satisfied working as a specialist in a New Zealand public hospital? PMID- 24157987 TI - Sources of satisfaction and dissatisfaction among specialists within the public and private health sectors. AB - AIM: As in many countries, medical and surgical specialists in New Zealand have the opportunity of working in the public sector, the private sector or both. This study aimed to explore the level and sources of satisfaction and dissatisfaction of specialists in New Zealand with working in the two sectors. Such information can assist workforce planning, management and policy and may inform the wider debate about the relationship between the two sectors. METHOD: A postal survey was conducted of 1983 registered specialists throughout New Zealand. Respondents were asked to assess 14 sources of satisfaction and 9 sources of dissatisfaction according to a 5-point Likert scale. Means and standard deviations were calculated for the total sample, and for procedural and non-procedural specialties. Differences between the means of each source of satisfaction and dissatisfaction were also calculated. RESULTS: Completed surveys were received from 943 specialists (47% response rate). Overall mean levels of satisfaction were higher in the private sector than the public sector while levels of dissatisfaction were lower. While the public system is valued for its opportunities for further education and professional development, key sources of dissatisfaction are workload pressures, mentally demanding work and managerial interference. In the private sector specialists value the opportunity to work independently and apply their own ideas in the workplace. CONCLUSION: Sources of job satisfaction and dissatisfaction amongst specialists are different for the public and private sectors. Allowing specialists more freedom to work independently and to apply their own ideas in the workplace may enhance recruitment and retention of specialists in the public health system. PMID- 24157988 TI - Prevalence of diabetic retinopathy and maculopathy in Northland, New Zealand: 2011-2012. AB - AIM: To determine the prevalence of diabetic retinopathy and maculopathy in the Northland Diabetic Retinopathy Screening Programme. METHOD: Retrospective analysis of the latest and most severe retinopathy and maculopathy grades from each patient in the programme. RESULTS: Data from 7098 screenings from 5647 diabetics were obtained, which represented approximately 77% of the total number of diagnosed diabetics in Northland. The two main ethnic groups in our study were New Zealand European (56.5%) and Maori (39.3%). Retinopathy was present in 19% of the Northland diabetic screening population: 13.6% had minimal non-proliferative diabetic retinopathy (NPDR), 5.4% had NPDR and 0.4% had Proliferative Diabetic Retinopathy (PDR). Ethnicity data for NPDR was 57% Maori, 38% European, and PDR 50% Maori, 45% European. Maculopathy was present in 11%. Maculopathy requiring treatment was present in 1.4% (Maori 48%, European 44%). The mean failure-to attend rate was 31%. CONCLUSION: Rates of retinopathy and maculopathy detected by the Northland screening programme were comparable to rates reported in Waikato, lower than Wellington rates and lower than international averages. Maori were over-represented in patients with retinopathy and maculopathy, but underrepresented within the screening population. The success of this programme was undermined by the high failure-to-attend rate despite attempts to improve access. PMID- 24157989 TI - A retrospective review of notified human cryptosporidiosis cases in the Waikato region of New Zealand, 2004 to 2011. AB - AIM: To retrospectively review notified human cryptosporidiosis cases in the Waikato region of New Zealand between 2004 and 2011 and to identify risk factors for human cryptosporidiosis infection. METHOD: Waikato cryptosporidiosis notification data for the period 1 January 2004 to 31 December 2011 were analysed to identify any trends in the rates and distribution of key variables. A comparison was made between urban and rural dwelling cases. RESULTS: Annual Waikato cryptosporidiosis notification rates were consistently higher than national rates. Analysis showed a seasonal peak centred around September with most cases having direct or indirect contact with cattle. Comparisons between urban and rural cases showed similar probable causes of infection and higher rates of infection in rural cases. CONCLUSION: Those who have contact with animals continue to be at risk of infection from Cryptosporidium. The data suggests that children who live on rural properties and have contact with animal faeces, either directly or via a contaminated drinking water supply, are at the highest risk of infection. PMID- 24157990 TI - Review of capacity assessments and recommendations for examining capacity. AB - AIM: To audit the capacity assessments performed since December 2007 by Community Geriatric Services (CGS), Middlemore Hospital, and to develop a resource kit for training health professionals. METHOD: 1343 clinical letters were reviewed. Demographic data, reason for assessment and outcome of assessment were recorded. Data was analysed to reveal trends. RESULTS: There were 87 capacity assessments on 82 unique patients. The numbers of referrals for capacity assessments have increased since December 2007. 63% of patients were female, and the majority were European (75.6%). The mean age was 80.3 years. 66.7% of patients were referred by their general practitioner (GP). Dementia was the most common diagnosis. Fifty patients had more than one reason for referral. Thirty-seven were assessed for appointing an enduring power of attorney (EPOA), 44 for financial welfare, 73 for personal welfare, and two for testamentary capacity. Forty-five lacked capacity for all aspects assessed. Twenty-three did not have an EPOA and appointment of a guardian was recommended for 16 patients. CONCLUSION: The CGS is performing more capacity assessments over time. The majority of the patients are elderly and have dementia. There is a need to train specialist nurses and general practitioners to perform capacity assessments. A resource kit has been developed for this purpose. PMID- 24157991 TI - Factors affecting vaginal birth after caesarean section at Middlemore Hospital, Auckland, New Zealand. AB - AIMS: To determine factors associated with vaginal birth after caesarean section (VBAC) in women delivering at Middlemore Hospital (MMH). METHOD: Retrospective descriptive study. All women in 2008-2009 who had a previous caesarean section and was deemed suitable for a trial of labour (TOL). RESULTS: Of the 1543 women who had one or more previous caesarean sections, 806 (52.2%) were deemed suitable for a TOL by an obstetrician and self-selected to have a VBAC. Of the 806 women who had a TOL, 592 (73%) had a VBAC. Of women who had a previous VBAC, 257 (91%) delivered vaginally again compared to 332 (64%) without such a history (OR 3.69; 95%CI 1.83-7.43). Increasing parity increased the chances of another vaginal delivery. Variables that led to a failed VBAC were: a BMI =25 in women of single parity (OR 0.47, 95%CI 0.24-0.91), labour augmentation (OR 0.63, 95%CI 0.43-0.93) and epidural analgesia (OR 0.18, 95%CI 0.12-0.28). CONCLUSION: The VBAC rate at MMH in 2008-2009 was 73% and was higher in women who had a previous VBAC. The VBAC rate is lower in women with a high BMI of single parity and where progress of labour was slow. This information is important in counselling women with a previous caesarean section who are considering a VBAC. PMID- 24157992 TI - Futility of medical treatment in current medical practice. AB - Intensive care provides support for acute reversible organ failure and most patients who receive intensive care recover from their illness. In some patients organ failure may become irreversible and in these patients further treatment or organ support may be considered futile. Emerging technologies and expertise can enable the medical profession to prolong life / death indefinitely without curing or controlling the underlying disease process. Introduction of ultramodern organ supports such as extracorporeal life-support systems, ventricular assist devices and organ transplantation surgeries have introduced some degree of ambiguity in defining futility of care. Furthermore medico legal implications of futility of care introduce further complexities in defining and instituting futile treatments. In this review we discuss the evolution of the concept of futility of care, review the various meanings of the term "futility of care", explore the complexities of management when care is considered futile, offer suggestions as to how such patients and their families could be managed. We also review the legal framework when consensus is not achieved. PMID- 24157993 TI - Point-of-care testing governance in New Zealand: a national framework. AB - Point-of-care testing (POCT) devices are in-vitro diagnostic devices used near the patient and for the most part distant from the pathology laboratory. By definition they have a large scope of settings and user profiles. POCT optimises care pathways and overcomes geographical barriers but has a high potential for adverse incidents. A successful POCT service needs good clinical governance and a comprehensive quality management system. In New Zealand, Medsafe regulates medical devices including POCT devices in accordance with the Medicines Act 1981. A number of regulations impact on the use of devices but none address analytical and clinical performance. In 2015 PHARMAC will assume responsibility for management of medical devices. We propose a governance framework that optimises patient safety and maximises benefit from this indispensable technology. This is the first of two articles; the second will address point-of-care governance at healthcare provider level. PMID- 24157994 TI - Beware of paracetamol use in alcohol abusers: a potential cause of acute liver injury. AB - There may be under-recognition of acute liver injury following reported therapeutic use of paracetamol in alcoholics. We present the case of an alcoholic patient who developed acute liver injury suspicious for chronic paracetamol toxicity on two occasions. The likely contribution of chronic paracetamol was not recognised at her second presentation, reflecting a need for increased awareness of this potential cause of acute liver injury. The biochemical hallmark of the syndrome is the 'towering' aspartate-aminotransferase (AST), often in the thousands; transaminases above 500 U/L should never be dismissed as secondary to alcoholic liver disease alone. Whether alcoholics are at increased risk of toxicity from therapeutic doses of paracetamol remains controversial, although many cases have been described for over 30 years. Randomised controlled trials to date have failed to show significant hepatic derangement in newly abstinent alcoholics exposed to short courses of paracetamol. We argue that these studies do not reflect the realities of paracetamol use in this population. In addition, alcoholics are at risk of accidental 'staggered overdoses', or repeated supra therapeutic ingestions. In cases of suspected paracetamol toxicity, administration of the antidote n-acetyl cysteine (NAC) should be considered, even when the patient's serum paracetamol level is normal. PMID- 24157995 TI - Kikuchi-Fujimoto disease--an unusual mimicker? AB - We describe the case of a 27-year-old Chinese female diagnosed with Kikuchi Fujimoto disease in Ireland. It principally occurs in Asian populations, but is being increasingly reported in non-Asian populations. This rare, benign disease may potentially be misdiagnosed as lymphoma, and has an association with the subsequent development of systemic lupus erythematosus. Clinicians and pathologists need to be aware of the clinical and histological features of this rare disorder to avoid misdiagnosis. PMID- 24157996 TI - Medical image. Retroperitoneal liposarcoma. Giant retroperitoneal mass occupying nearly the whole abdomen. PMID- 24157997 TI - The sickness of the USA model of healthcare--is it a contagious disease? PMID- 24157998 TI - Prostate cancer screening in New Zealand. PMID- 24157999 TI - Doctors discussing PSA screening with their male patients. PMID- 24158000 TI - Usage of renal function equations to guide prescribing in general medicine. PMID- 24158001 TI - How do adolescents perceive plain packaging? PMID- 24158002 TI - Response to Hadorn et al on increasing recruitment into randomised clinical trials. PMID- 24158003 TI - Combination treatment with 2-methoxyestradiol overcomes bortezomib resistance of multiple myeloma cells. AB - Bortezomib is a proteasome inhibitor used for the treatment of relapsed/refractory multiple myeloma (MM). However, intrinsic and acquired resistance to bortezomib has already been observed in MM patients. In a previous report, we demonstrated that changes in the expression of mitochondrial genes lead to changes in mitochondrial activity and bortezomib susceptibility or resistance, and their combined effects contribute to the differential sensitivity or resistance of MM cells to bortezomib. Here we report that the combination treatment of bortezomib and 2-methoxyestradiol (2ME), a natural estrogen metabolite, induces mitochondria-mediated apoptotic cell death of bortezomib resistant MM KMS20 cells via mitochondrial reactive oxygen species (ROS) overproduction. Bortezomib plus 2ME treatment induces a higher level of cell death compared with treatment with bortezomib alone and increases mitochondrial ROS and Ca(2+) levels in KMS20 cells. Pretreatment with the antioxidant N-acetyl L-cysteine scavenges mitochondrial ROS and decreases cell death after treatment with bortezomib plus 2ME in KMS20 cells. Moreover, we observed that treatment with bortezomib plus 2ME maintains the activation of c-Jun N-terminal kinase (JNK) and mitogen-activated protein kinase kinase kinase 4/7 (MKK4/7). Collectively, combination treatment with bortezomib and 2ME induces cell death via JNK-MKK4/7 activation by overproduction of mitochondrial ROS. Therefore, combination therapy with specific mitochondrial-targeting drugs may prove useful to the development of novel strategies for the treatment of bortezomib-resistant MM patients. PMID- 24158004 TI - A bumblebee (Bombus ignitus) venom serine protease inhibitor that acts as a microbial serine protease inhibitor. AB - Serine protease inhibitors from bumblebee venom have been shown to block plasmin activity. In this study, we identified the protein BiVSPI from the venom of Bombus ignitus to be a serine protease inhibitor and an antimicrobial factor. BiVSPI is a 55-amino acid mature peptide with ten conserved cysteine residues and a P1 methionine residue. BiVSPI is expressed in the venom gland and also found in the venom as an 8-kDa peptide. Recombinant BiVSPI that was expressed in baculovirus-infected insect cells exhibited inhibitory activity against chymotrypsin but not trypsin. BiVSPI also inhibited microbial serine proteases, such as subtilisin A (Ki=6.57nM) and proteinase K (Ki=7.11nM). In addition, BiVSPI was shown to bind directly to Bacillus subtilis, Bacillus thuringiensis, and Beauveria bassiana but not to Escherichia coli. Consistent with these results, BiVSPI exhibited antimicrobial activity against Gram-positive bacteria and fungi. These findings provide evidence for a novel serine protease inhibitor in bumblebee venom that has antimicrobial functions. PMID- 24158005 TI - Rhegmatogenous retinal detachment: a reappraisal of its pathophysiology and treatment. AB - This article represents a synthesis of an extensive literature review and the authors' decades-long personal experience with both scleral buckling (SB) and vitrectomy for rhegmatogenous retinal detachment (RD). Presenting a coherent understanding of the pathophysiology and treatment of RD, the authors confirm numerous findings described in earlier publications but also challenge certain long-standing dogmas. The key argument made here is that it is extremely rare for the chain of events leading to an RD to start with a retinal pathology. Rather, the initial pathology is syneresis of the vitreous, which then allows gel movement (intraocular currents). At the point of vitreoretinal adhesion, dynamic traction is exerted on the retina, which may be sufficient to tear it. If the tear is operculated and the dynamic traction overcomes the forces keeping the neuroretina and retinal pigment epithelium (RPE) together, the heretofore virtual subretinal space becomes accessible through the retinal tear. The intraocular currents allow the free (nonbound) intravitreal fluid to enter the subretinal space, and once the amount of the incoming fluid overwhelms the draining capacity of the RPE, an RD ensues. Detachment of the posterior cortical vitreous (PVD) is not a necessary prerequisite to RD development; furthermore, PVD cannot be diagnosed preoperatively with adequate certainty with current technology such as biomicroscopy, ultrasonography or optical coherence tomography. The surgeon should expect no or only partial (anomalous) PVD at the time of surgical repair in over half of eyes. The treatment's primary goal must thus be weakening (pneumatic retinopexy, SB) or eliminating (vitrectomy) this dynamic traction. If vitrectomy is employed, it must be a truly complete vitreous removal. This includes a surgically induced PVD if one is not present, close shaving at the periphery, and removing the vitreous immediately behind the lens. The vitrectomy is followed by the creation of a chorioretinal scar around the tear and aided by some form of intraocular tamponade. The main function of the tamponade is not to temporarily cover the break but to significantly reduce the intraocular currents and thus prevent fluid entry through the break until the chorioretinal adhesion will have become sufficiently strong to seal the retinal edge around the tear; postoperative positioning is therefore not as important as currently assumed. PMID- 24158006 TI - Autologous stem cell transplantation as the first-line treatment for peripheral T cell lymphoma: results of a comprehensive meta-analysis. AB - OBJECTIVE: In view of the poor prognosis of most peripheral T cell lymphoma (PTCL) subtypes treated with conventional chemotherapy such as CHOP/CHOP-like regimens, high-dose chemotherapy followed by autologous stem cell transplantation (HDT/ASCT) seems a reasonable option in eligible patients. Nevertheless, owing to the small size of the study and the heterogeneity of most published series, a consensus on the role of ASCT as the first-line consolidation therapy for high risk PTCL patients has not been reached so far. STUDY DESIGN: We searched MEDLINE, EMBASE, EBSCO, Web of Science, clinicaltrials.gov and the Cochrane Library. Hazard ratio (HR) and 95% confidence intervals (CIs) were calculated by a fixed/random effect model. RESULTS: Twenty-one studies were eligible. Although no statistical significance was observed in these studies, there was a trend toward survival advantage for the HDT/ASCT group as compared to the historical control group (HR 0.81, 95% CI 0.31-2.13). Statistical differences were confirmed in terms of overall survival (OS) between complete remission (CR) and non-CR patients (HR 3.17, 95% CI 0.92-5.42), patients with good and poor risk according to the International Prognostic Index (IPI; HR 0.36, 95% CI 0.22-0.60, I(2) 49%) and Prognostic Index for PTCL (PIT; HR 0.31, 95% CI 0.17-0.58; HR 0.31, 95% CI 0.18-0.54). CONCLUSION: The clear and convincing proof of the effects of up-front HDT/ASCT still depends on sufficient large PTCL-restricted randomized trials in the future. Patients who failed to attain CR before transplant exhibited a worse prognosis; patients with good risk of IPI or PIT had a substantially better OS after ASCT. PMID- 24158007 TI - Serotonin syndrome after the use of tramadol and ziprasidone in a patient with a deep brain stimulator for Parkinson disease. AB - Serotonin syndrome (SS) is a life-threatening adverse reaction that can result from the therapeutic use of serotonergic drugs or accidental drug interactions. Tramadol is a drug that is widely prescribed because of its low abuse potential, but physicians need to be aware of its significant potential to cause SS because it inhibits serotonin reuptake. Ziprasidone is an atypical antipsychotic that can also cause dangerous interactions to cause SS because it is not only a potent 5 HT1A agonist but also has been reported to inhibit serotonin reuptake with an affinity similar to tricyclic antidepressants, in addition to inhibiting reuptake of norepinephrine. We are describing the clinical characteristics of a gentleman with bipolar disorder and Parkinson disease who presented with SS, despite having a deep brain stimulator in the subthalamic nucleus, which decreases central serotonin levels, and a discussion of the factors that contributed to his presentation. PMID- 24158008 TI - Localized cell stimulation by nitric oxide using a photoactive porous coordination polymer platform. AB - Functional cellular substrates for localized cell stimulation by small molecules provide an opportunity to control and monitor cell signalling networks chemically in time and space. However, despite improvements in the controlled delivery of bioactive compounds, the precise localization of gaseous biomolecules at the single-cell level remains challenging. Here we target nitric oxide, a crucial signalling molecule with site-specific and concentration-dependent activities, and we report a synthetic strategy for developing spatiotemporally controllable nitric oxide-releasing platforms based on photoactive porous coordination polymers. By organizing molecules with poor reactivity into polymer structures, we observe increased photoreactivity and adjustable release using light irradiation. We embed photoactive polymer crystals in a biocompatible matrix and achieve precisely controlled nitric oxide delivery at the cellular level via localized two-photon laser activation. The biological relevance of the exogenous nitric oxide produced by this strategy is evidenced by an intracellular change in calcium concentration, mediated by nitric oxide-responsive plasma membrane channel proteins. PMID- 24158009 TI - Body-related cognitions, affect and post-event processing in body dysmorphic disorder. AB - BACKGROUND AND OBJECTIVES: Cognitive behavioural models postulate that individuals with BDD engage in negative appearance-related appraisals and affect. External representations of one's appearance are thought to activate a specific mode of processing characterized by increased self-focused attention and an activation of negative appraisals and affect. METHODS: The present study used a think-aloud approach including an in vivo body exposure to examine body-related cognitions and affect in individuals with BDD (n = 30), as compared to individuals with major depression (n = 30) and healthy controls (n = 30). Participants were instructed to think aloud during baseline, exposure and follow up trials. RESULTS: Individuals with BDD verbalized more body-related and more negative body-related cognitions during all trials and reported higher degrees of negative affect than both control groups. A weaker increase of positive body related cognitions during exposure, a stronger increase of sadness and anger after exposure and higher levels of post-event processing, were specific processes in individuals with BDD. LIMITATIONS: Individuals with major depression were not excluded from the BDD group. This is associated with a reduction of internal validity, as the two clinical groups are somewhat interwoven. Key findings need to be replicated. CONCLUSION: The findings indicate that outcomes such as negative appearance-related cognitions and affect are specific to individuals with BDD. An external representation of one's appearance activates a specific mode of processing in BDD, manifesting itself in the absence of positive body-related cognitions, increased anger and sadness, and high levels of post event processing. These specific processes may contribute toward maintenance of BDD psychopathology. PMID- 24158013 TI - Highly functionalized 2-oxopiperazine-based peptidomimetics: an approach to PAR1 antagonists. AB - A series of pseudodipeptide-based chiral 1,3,4,5-tetrasubstituted-2 oxopiperazines has been designed and synthesized as potential PAR1 antagonists. These highly functionalized piperazines were synthesized from aromatic and basic amino acid derived Psi[CH(CN)NH]pseudodipeptides through a four step pathway that involves reduction of the cyano group to build the 2-oxopiperazine ring, followed by selective functionalization at the N4-, N1-positions, and at the exocyclic moiety at position C5. This regioselective functionalization required the fine tuning of reaction conditions. All new compounds were screened as inhibitors of human platelet aggregation induced by the PAR1 agonist SFLLRN and as cytotoxic agents in human cancer cell lines. Some of the compounds displayed moderate PAR1 antagonist activity, while, others were cytotoxic at MUM concentration. No correlation was observed between both types of activities. PMID- 24158012 TI - Scorpiand-like azamacrocycles prevent the chronic establishment of Trypanosoma cruzi in a murine model. AB - Chagas disease is today one of the most important neglected diseases for its upcoming expansion to non-endemic areas and has become a threat to blood recipients in many countries. In this study, the trypanocidal activity of ten derivatives of a family of aza-scorpiand like macrocycles is evaluated against Trypanosoma cruzi in vitro and in vivo murine model in which the acute and chronic phases of Chagas disease were analyzed. The compounds 4, 3 and 1 were found to be more active against the parasite and less toxic against Vero cells than the reference drug benznidazole, 4 being the most active compound, particularly in the chronic phase. While all these compounds showed a remarkable degree of inhibition of the Fe-SOD enzyme of the epimastigote forms of T. cruzi, they produced a negligible inhibition of human CuZn-SOD and Mn-SOD from Escherichia coli. The modifications observed by (1)H NMR and the amounts of excreted catabolites by the parasites after treatment suggested that the mechanism of action could be based on interactions of the side chains of the compounds with enzymes of the parasite metabolism. The ultrastructural alterations observed in treated epimastigote forms confirmed that the compounds having the highest activity are those causing the largest cell damage. A complementary histopathological analysis confirmed that the compounds tested were significantly less toxic to mammals than the reference drug. PMID- 24158014 TI - New derivative of carnosine for nanoparticle assemblies. AB - Carnosine (beta-alanyl-l-histidine) is an endogenous dipeptide, extensively studied owing to its multifunctional activity exhibited in tissues of several animal species. This natural compound may act as a physiological buffer, ion chelating agent (especially for copper(II) and zinc(II)), antioxidant and antiglycating agent. The main limit for the therapeutical uses of carnosine is the rapid hydrolysis mostly in human plasma by carnosinase. The chemical derivatization of carnosine is a promising strategy to improve the bioavailability of the dipeptide and facilitating the site-specific transport to different tissues. On this basis, a new carnosine derivative with biotin was synthesized and structurally characterized by NMR and MS measurements, with aim of exploiting the avidin-biotin technology that offers a universal system for selective delivery of any biotinylated agent. The stability of the new carnosine derivative towards the hydrolytic action of serum carnosinase as well as the copper(II) binding ability of the carnosine-biotin conjugate were also assessed. The binding affinity of the new molecular entity to avidin and streptavidin, investigated by a spectrophotometric assay, was exploited to functionalize avidin and streptavidin-gold nanoparticles with the carnosine-biotin conjugate. PMID- 24158015 TI - A stereoselective approach to peptidomimetic BACE1 inhibitors. AB - Aiming at identifying new scaffolds to generate beta-secretase (BACE1) inhibitors we developed peptidomimetics based on a 1,4-benzodiazepine core (3a-d), their seco-analogs (4a-b), and linear analogs (5a-h), by stereoselective approaches. We herein discuss the synthesis, molecular modeling and in vitro studies for the newly developed ligands. Compounds 5c and 5h behaved as BACE1 inhibitors on the isolated enzyme and in cellular studies. Particularly, for its low molecular weight, inhibitor 5h is a prototypic hit to develop a series of BACE1 inhibitors more potent and active on whole-cells. PMID- 24158016 TI - Generation and analysis of draft sequences of 'stolbur' phytoplasma from multiple displacement amplification templates. AB - Phytoplasma-associated diseases are reported for more than 1,000 plant species worldwide. Only a few genome sequences are available in contrast to the economical importance of these bacterial pathogens. A new strategy was used to retrieve phytoplasma strain-specific genome data. Multiple displacement amplification was performed on DNA obtained from <3 g of plant tissue from tobacco and parsley samples infected with 'stolbur' strains. Random hexamers and Phi29 polymerase were evaluated with and without supplementation by group assigned oligonucleotides providing templates for Illumina's sequencing approach. Metagenomic drafts derived from individual and pooled strain-specific de novo assemblies were analyzed. Supplementation of the Phi29 reaction with the group assigned oligonucleotides resulted in an about 2-fold enrichment of the percentage of phytoplasma-assigned reads and thereby improved assembly results. The obtained genomic drafts represent the largest datasets available from 'stolbur' phytoplasmas. Sequences of the two strains (558 kb, 448 proteins and 516 kb, 346 proteins, respectively) were annotated allowing the identification of prominent membrane proteins and reconstruction of core pathways. Analysis of a putative truncated sucrose phosphorylase provides hints on sugar degradation. Furthermore, it is shown that drafts obtained from repetitive-rich genomes allow only limited analysis on multicopy regions and genome completeness. PMID- 24158017 TI - LDL but not HDL increases adiponectin release of primary human adipocytes. AB - Adipocytes in obesity have inappropriately low cholesterol while adiponectin release is reduced. Cholesterol shortage may contribute to low adiponectin and 3T3-L1 cells treated with lovastatin have diminished adiponectin in cell supernatants. LDL and HDL deliver cholesterol to adipocytes. LDL but not HDL increases adiponectin in cell supernatants of primary human adipocytes. The effect of LDL is not blocked by receptor associated protein suggesting that members of the LDL-receptor family are not involved. To evaluate whether these in vitro observations translate into changes in systemic adiponectin, adiponectin was measured in serum of three patients before, immediately after and 3d after LDL-apheresis. Whereas circulating lipoproteins are reduced immediately after apheresis adiponectin is not changed. Therefore, acute lowering of lipoproteins does not affect systemic adiponectin also excluding that plenty of adiponectin is bound to lipoprotein particles. Accordingly, levels of adiponectin in purified lipoproteins are quite low. Familial hypobetalipoproteinemia (FHBL) is a rare disorder associated with low plasma LDL. Serum adiponectin is, however, similar compared to healthy controls. Thus, neither LDL nor HDL directly contributes to circulating adiponectin concentrations. PMID- 24158019 TI - Clozapine-associated asterixis: case report. PMID- 24158018 TI - Deep sequencing and Circos analyses of antibody libraries reveal antigen-driven selection of Ig VH genes during HIV-1 infection. AB - The vast diversity of antibody repertoires is largely attributed to heavy chain (V(H)) recombination of variable (V), diversity (D) and joining (J) gene segments. We used 454 sequencing information of the variable domains of the antibody heavy chain repertoires from neonates, normal adults and an HIV-1 infected individual, to analyze, with Circos software, the VDJ pairing patterns at birth, adulthood and a time-dependent response to HIV-1 infection. Our comparative analyses of the Ig VDJ repertoires from these libraries indicated that, from birth to adulthood, VDJ recombination patterns remain the same with some slight changes, whereas some V(H) families are selected and preferentially expressed after long-term infection with HIV-1. We also demonstrated that the immune system responds to HIV-1 chronic infection by selectively expanding certain HV families in an attempt to combat infection. Our findings may have implications for understanding immune responses in pathology as well as for development of new therapeutics and vaccines. PMID- 24158020 TI - Use and safety of antipsychotics in behavioral disorders in elderly people with dementia. AB - In recent years, the use of antipsychotics has been widely debated for reasons concerning their safety in elderly patients affected with dementia. To update the use of antipsychotics in elderly demented people, a MEDLINE search was conducted using the following terms: elderly, conventional and atypical antipsychotics, adverse events, dementia, and behavioral and psychotic symptoms in dementia (BPSD). Owing to the large amounts of studies on antipsychotics, we mostly restricted the field of research to the last 10 years. Conventional antipsychotics have been widely used for BPSD; some studies showed they have an efficacy superior to placebo only at high doses, but they are associated with several and severe adverse effects. Atypical antipsychotics showed an efficacy superior to placebo in randomized studies in BPSD treatment, with a better tolerability profile versus conventional drugs. However, in 2002, trials with risperidone and olanzapine in elderly patients affected with dementia-related psychoses suggested the possible increase in cerebrovascular adverse events. Drug regulatory agencies issued specific recommendations for underlining that treatment of BPSD with atypical antipsychotics is "off-label." Conventional antipsychotics showed the same likelihood to increase the risk of death in the elderly as atypical agents, and they should not replace the atypical agents discontinued by Food and Drug Administration warnings. Before prescribing an antipsychotic drug, the following are factors to be seriously considered: the presence of cardiovascular diseases, QTc interval on electrocardiogram, electrolytic imbalances, familiar history for torsades des pointes, concomitant treatments, and use of drugs able to lengthen QTc. Use of antipsychotics in dementia needs a careful case-by-case assessment, together with the possible drug drug, drug-disease, and drug-food interactions. PMID- 24158021 TI - Pyroglutamate-modified amyloid-beta protein demonstrates similar properties in an Alzheimer's disease familial mutant knock-in mouse and Alzheimer's disease brain. AB - BACKGROUND: N-terminally truncated, pyroglutamate-modified amyloid-beta (Abeta) peptides are major constituents of amyloid deposits in Alzheimer's disease (AD). METHODS: Using a newly developed ELISA for Abeta modified at glutamate 3 with a pyroglutamate (pE3Abeta), brain pE3Abeta was characterized in human AD in an AD mouse model harboring double knock-in amyloid precursor protein (APP)-KM670/671NL and presenilin 1 (PS1)-P264L (APP/PS1-dKI) mutations, and in a second mouse model with transgenic overexpression of human APP695 with APP-KM670/671NL (Tg2576). RESULTS: pE3Abeta increased in the AD brain versus age-matched controls, with pE3Abeta/total Abeta at 45 and 10%, respectively. Compared to controls, the AD brain demonstrated 8.5-fold increased pE3Abeta compared to non-pE3Abeta species, which increased 2.7-fold. In the APP/PS1-dKI brain, pE3Abeta/total Abeta increased from 7% at 3 months to 16 and 19% at 15 and 19 months, respectively. In Tg2576, pE3Abeta/total Abeta was only 1.5% at 19 months, suggesting that APP/PS1 dKI, despite less total Abeta compared to Tg2576 at comparable ages, more closely mimics AD brain pathology. CONCLUSION: This report supports a significant role for pE3Abeta in AD pathogenesis by confirming that pE3Abeta represents a large fraction of Abeta within the AD brain. Compared to the age-matched control brain, pE3Abeta increased to a greater extent compared to Abeta species without this N terminal modification. Further, the APP/PS1-dKI model more closely resembles the AD brain in this regard, compared to the Tg2576 model. PMID- 24158022 TI - Long-term efficacy of latanoprost in primary congenital glaucoma. AB - PURPOSE: To investigate the success (glaucoma control) of latanoprost therapy of primary congenital glaucoma (PCG) and factors affecting the long-term outcome. METHODS: Patients with PCG treated with latanoprost were re-examined. At study visit and from clinical charts, we evaluated: intraocular pressure, length of glaucoma control with latanoprost, need of further medication or glaucoma surgery, systemic and topical side effects. Multivariate analysis was used to test factors related to the final outcome of the treatment. RESULTS: Eighty-one eyes of 44 patients with PCG, and 42 eyes of 29 patients with previous glaucoma surgery, had received latanoprost therapy. In the first group, a success (glaucoma control by latanoprost therapy) was found in 24 eyes (29.6%), whereas 57 eyes (70.4%) had received surgery (45 eyes (55.6%) in the first year); among the eyes with previous surgery, a success was found in 12 eyes (28.6%), 13 eyes (31%) required an additional therapy, and 17 eyes (40.5%) had received further glaucoma surgery. No patient discontinued the treatment because of side effects. Factors related to the failure of the latanoprost treatment were: the high score of severity of glaucoma (P=0.014) and low age at PCG presentation (P=0.042). CONCLUSIONS: Long-term treatment with latanoprost is effective in about 30% of the eyes; factors related to failure were severe glaucomatous alterations, and young age at PCG presentation. PMID- 24158023 TI - The Royal College of Ophthalmologists Guidelines on AMD: Executive Summary. PMID- 24158025 TI - [A geography of nursing for critical times: between spiders and dreams]. PMID- 24158024 TI - What research is being done on prenatal alcohol exposure and fetal alcohol spectrum disorders in the Russian research community? AB - AIMS: Although Russia has one of the highest rates of alcohol consumption and alcohol-attributable burden of disease, little is known about the existing research on prenatal alcohol exposure (PAE) and Fetal Alcohol Spectrum Disorders (FASDs) in this country. The objective of this study was to locate and review published and unpublished studies related to any aspect of PAE and FASD conducted in or using study populations from Russia. METHODS: A systematic literature search was conducted in multiple English and Russian electronic bibliographic databases. In addition, a manual search was conducted in several major libraries in Moscow. RESULTS: The search revealed a small pool of existing research studies related to PAE and/or FASD in Russia (126: 22 in English and 104 in Russian). Existing epidemiological data indicate a high prevalence of PAE and FASD, which underlines the strong negative impact that alcohol has on mortality, morbidity and disability in Russia. High levels of alcohol consumption by women of childbearing age, low levels of contraception use, and low levels of knowledge by health and other professionals regarding the harmful effects of PAE put this country at great risk of further alcohol-affected pregnancies. CONCLUSIONS: Alcohol preventive measures in Russia warrant immediate attention. More research focused on alcohol prevention and policy is needed in order to reduce alcohol related harm, especially in the field of FASD. PMID- 24158026 TI - [Invasive and non-invasive ventilation: impact on nursing workload]. AB - INTRODUCTION: Non invasive ventilation (NIV) is increasingly used in intensive and non intensive wards. OBJECTIVE: To detect the impact of ventilation modes on nursing workload. METHODS: Retrospective observational study of 200 patients admitted to a general Intensive Care Unit (ICU). Nursing Activities Score (NAS) was used to measure the nursing workload. Patients enrolled were treated with the following ventilation modes: oxygen therapy without positive end-expiratory pressure (PEEP), helmet Continuous Positive Airway Pressure (CPAP), controlled mechanical ventilation, Invasive pressure support ventilation (I-PSV). RESULTS: The overall mean NAS score of patients was 74.3% (SD +/-8.88 - range 39/143) corresponding to an ideal nurse/patient ratio of 0.7 and varied with the different ventilation modes. In the days in oxygen therapy, the average NAS was 64.5% (+/-11.9), with helmet CPAP 69.7% (+/-12.7), with controlled mechanical ventilation 86.1% (SD +/-15.1) and with invasive assisted ventilation 76.4% (+/ 11.4) [p=0.0001]. In patients with helmet CPAP the NAS increased of 14% when FiO2 >0.6 and PEEP >10 compared to oxygen therapy. The average NAS score of the 15 patients (7.5%) with mask-PSV was 80.2% (+/-12:5). CONCLUSIONS: Overall, the nursing workload of patient with helmet CPAP was lower than with invasive ventilation. In Helmet CPAP, with FiO2 >0.6 and PEEP level >10 cmH2O and mask PSV, the nursing workload is similar to that of patients with invasive ventilation. NAS scores in patients with Invasive ventilation in the controlled mode is higher than with assisted mode. PMID- 24158027 TI - [Skin antisepsis with 0.05% sodium hypochlorite before the insertion of a peripheral venous catheter in adults, children and newborns]. AB - INTRODUCTION: Antisepsis of the skin of adults, children and newborns before the insertion of a peripheral venous catheter (PVC) reduces the risk of catheter related infections (CRI). Data on the effectiveness of electrolytic sodium hypochlorite are missing. METHODS: An explorative study was conducted on children, adults and newborns admitted to hospital and with skin antisepsis with sodium hypoclorite 0.057g with active chlorine 0.055g in 100ml (Amukine Med(r)) to assess the level of contamination of PVC tips, as surrogate sign of infection. Quantitative methods were used and the catheter tip was considered colonized if >1000 CFU (colony forming Units)/catheter segment. RESULTS: In the sample of 42 adults, 51 children and 52 newborns, 16.7%, 7.8% and 3.8% of catheter tips were contaminated respectively. No catheter related phlebites were observed. CONCLUSIONS: Skin antisepsis with Amukine Med(r) seems effective in preventing CRIs but further comparative studies are needed with the antiseptics recommended by guidelines. PMID- 24158028 TI - [Nursing competences and basic education: descriptive study on new-graduate nurses]. AB - The pressing need by the health organizations of new-graduate nurses immediately able to take full charge of the ward, together with the radical changes of nursing education, led the professional community to discuss the education of new graduate nurses. AIM: To describe if new-graduate nurses at the Nursing Degree Course in Reggio Emilia, have the competences adequate to the demands of the health care organizations. METHODS: Fifty ward Nursing Manager of a National health Service, where new-graduate nurses of the 2009-2010 academic year were emploied by at least one month were interviewed by phone. A list of 34 competences were identified and grouped into six skill areas (taking care, technical, managerial, communication, professional ethics, education and professional updating); for each, respondents had to rank the level of compentence on a Likert scale from 1 not able to 5 fully able. RESULTS: According to Nursing Managers new-graduate nurses are able to identify the patient care problems (mean score 4.1+0.8), to perform nursing techniques (mean score 4.4+0.7) and to meet the deadlines of the organizations (mean score 4.2+0.8). All Nursing Managers agree that new-graduate nurses have required skills and knowledge to work in their units. DISCUSSION: The level of expertise of by new-graduates in the areas investigated appears adequate to fulfill the role of nurse in health care organizations after a short period of coaching by a senior nurse. PMID- 24158029 TI - [The future of the National Institute for health and Clinical Excellence]. AB - The change of the former director of the National Institute for health and Clinical Excellence (NICE) is the occasion for envisaging a strategy and a vision for the future of the NICE. The main contents of the letter of the outgoing director and his vision for the future and the development of the NICE are reported. PMID- 24158030 TI - [The shortage of nurses: a reversing trend?]. AB - With fewer people becoming nurses, projections of the past years indicated a declining in the size of nursing workforce and forecast a shortage of up to 1 million of nurses. This trend seems revolving as in the US, due to a series of public and private initiatives, the number of applicants for nursing courses more than doubled since 1985. While the number of nurses is increasing, in some European countries, hospitals are facing a severe shortage of nurses, for costs constraints due to the economic crisis and a mismatch between health and NHS priorities and policies. PMID- 24158031 TI - [The stamina case]. AB - The Stamina method is proposed by the non-profit Stamina Foundation and envisages the conversion of mesenchymal stem cells, which normally generate bone, cartilage and adipose tissue, into neurons after brief exposure to ethanol and retinoic acid. The reactions of the scientific community and the implications of the case are briefly explored. PMID- 24158032 TI - [Malala]. AB - Pakistani school girl Malala Yousafzai has addressed the United Nations as part of her campaign to ensure free compulsory education for every child. She celebrated her 16th birthday by delivering the speech at the UN headquarters in New York. Malala was shot by a Taliban hit man in Pakistan on October 9, 2012 after speaking out in favor of girls' education. In her speech Malala called on world leaders to provide free, compulsory education for every child,reminding that education, and rights, must be respected, guaranteed and protected. PMID- 24158033 TI - Dysplasia features of myelodysplastic syndrome in ethnically Chinese people. AB - OBJECTIVE: It was our aim to study the diagnostic significances of various dysplasia characteristics in myelodysplastic syndrome (MDS). METHODS: We analyzed 160 cases of primary MDS and a control group including 28 cases of paroxysmal nocturnal hemoglobinuria (PNH), 104 cases of idiopathic thrombocytopenic purpura (ITP), 53 cases of non-severe aplastic anemia (NSAA), 40 cases of megaloblastic anemia and 50 cases of infectious and autoimmune diseases. Peripheral blood smears and bone marrow morphology were reviewed. RESULTS: There was no significant difference in the occurrence rates of a variety of dysplasias in three lineages among MDS, megaloblastic anemia and PNH; however, changes in qualities and quantities in three lineages between NSAA and MDS were significantly different. ITP and MDS showed statistical differences in multiple changes in myeloid and erythroid cells. Significant differences also existed in multiple changes in erythroid series and megakaryocytes between infectious and autoimmune diseases and MDS. Morphological abnormalities highly related with MDS included multinucleated erythroblasts, ringed sideroblasts, poikilocytosis and gigantocytes, pseudo-Pelger neutrophils, ring-shaped nucleus, and micromegakaryocytes. CONCLUSIONS: It is difficult to discriminate megaloblastic anemia and PNH from MDS by means of cell morphology. Different dysplasias of MDS have specific diagnostic values. PMID- 24158034 TI - Negishi coupling reactions as a valuable tool for [11C]methyl-arene formation; first proof of principle. AB - The Negishi coupling reaction between arylzinc halide reagents and (11)CH3I has been used to synthesise (11)C-methylated arene species via a palladium-mediated process. The metabotropic glutamate receptor subtype-5 radiotracer [(11)C]MPEP has been radiolabelled using this technique. PMID- 24158035 TI - Anti-ghrelin immunoglobulins modulate ghrelin stability and its orexigenic effect in obese mice and humans. AB - Obese individuals often have increased appetite despite normal plasma levels of the main orexigenic hormone ghrelin. Here we show that ghrelin degradation in the plasma is inhibited by ghrelin-reactive IgG immunoglobulins, which display increased binding affinity to ghrelin in obese patients and mice. Co administration of ghrelin together with IgG from obese individuals, but not with IgG from anorectic or control patients, increases food intake in rats. Similarly, chronic injections of ghrelin together with IgG from ob/ob mice increase food intake, meal frequency and total lean body mass of mice. These data reveal that in both obese humans and mice, IgG with increased affinity for ghrelin enhances ghrelin's orexigenic effect, which may contribute to increased appetite and overeating. PMID- 24158036 TI - Cuffed and uncuffed tubes and the geometric correlation with pediatric airway. PMID- 24158038 TI - Editorial: a toxicological transition. PMID- 24158037 TI - Microperimetry of subretinal drusenoid deposits. AB - PURPOSE: To investigate light sensitivity in eyes presenting with subretinal drusenoid deposits (SDD). METHODS: All consecutive patients with SDD only seen between January 2012 and July 2012 were included. A control group of consecutive age- and sex-matched control subjects presenting at least one eye with early age related macular degeneration was considered. In all cases best-corrected visual acuity (BCVA), color fundus photography, fundus autofluorescence imaging and spectral-domain-optical coherence tomography with integrated microperimetry were performed. RESULTS: Twenty-one eyes (21 patients, 9 females, 12 males, mean age 69.2 +/- 5.3 years, mean BCVA 0.18 +/- 0.14 LogMAR) were included in the SDD group. Twenty eyes of 20 patients (13 females, 7 males, mean age 69.1 +/- 3.9 years, mean BCVA 0.16 +/- 0.15 LogMAR) were included in the control group. In eyes with SDD the choroid was thinner at the subfoveal location, and at 1,500 MUm superior, inferior, temporal and nasal to the fovea (p < 0.05). In eyes with SDD, the overall mean light sensitivity in the central macula (4.21 +/- 2.46 dB) was significantly reduced when compared to the control group (6.81 +/- 2.12 dB, p = 0.001), while stable fixation was present in both groups. Correlation between BCVA and mean light sensitivity in the central 7 * 7 mm square was low in the SDD group (Pearson's rho = 0.4, p = 0.01), while it was good in the control group (Pearson's rho = 0.7, p = 0.001). CONCLUSIONS: Eyes with SDD showed reduced sensitivity despite preserved BCVA. Reduced choroidal thickness could be involved in reduction of light sensitivity. PMID- 24158039 TI - To breathe or not to breathe: negative data on ozone and vascular function in an established research model. PMID- 24158043 TI - A shift in the balance of regulatory T and T helper 17 cells in rheumatic heart disease. AB - BACKGROUND: Autoimmunity plays an essential role in the pathogenesis of rheumatic heart disease (RHD); however, cellular mechanisms of autoimmune response are unclear. Whereas T helper 17 (TH17) and regulatory T cells (Treg) cells share a common differentiation pathway, they play opposite roles in the immune tolerance and autoimmune diseases. Although high TH17/Treg ratio has been shown in several autoimmune diseases, no data are available in RHD. This study investigated the balance between TH17 and Treg in rheumatic mitral valve disease (MVD). METHODS: Forty patients with rheumatic MVD and 23 control subjects were enrolled into the study. All subjects underwent clinical, electrocardiographic, and echocardiographic evaluation. The percentages of circulating TH17 and Treg cells were analyzed by flow cytometry. Serum levels of high-sensitivity C-reactive protein (hs-CRP) and cytokines were assessed by enzyme-linked immunosorbent assay. RESULTS: As compared with control subjects, rheumatic MVD patients showed significant increase in peripheral TH17 percentage, high serum levels of TH17 related cytokine interleukin 17A, and an obvious decrease in the percentage of Treg cells. T helper 17/Treg ratio was significantly high in rheumatic MVD patients compared with control subjects (P = 0.0001). Serum concentrations of hs CRP in rheumatic MVD group were higher than those of the control subjects, and hs CRP levels correlated with the TH17/Treg ratio (r = 0.71, P = 0.0001). Serum levels of transforming growth factor beta1 were increased in rheumatic MVD group compared with those of the control subjects. CONCLUSIONS: The results indicated that high TH17/Treg ratio exists inrheumatic MVD. This imbalance may play a role in the pathogenesis, and TH17/Treg balance may be a promising therapeutic approach in RHD. PMID- 24158044 TI - Clinical implications in the prevalence and associated cardiovascular factors of elevated serum alanine aminotransferase levels among elderly agricultural and fishing population in Taipei, Taiwan: experience at a teaching hospital. AB - AIM: To discuss the prevalence and associated factors related to an elevated serum alanine aminotransferase (ALT) level among the elderly agricultural and fishing population. METHODS: A total of 6542 (3989 males and 2553 females) healthy adults voluntarily admitted to a teaching hospital for a physical checkup in 2010 in Taipei, Taiwan. Fasting blood samples were drawn via venipuncture, and clinical nurses interviewed the study participants using a structured questionnaire from. RESULTS: The overall prevalence of an elevated serum ALT level was 18.2% and revealed a statistically significant decrease with increasing age (P < 0.001). The men exhibited a higher prevalence than the women (19.7% vs 15.9%; P < 0.001). Male sex; younger age; and presence of obesity, hypertension, hyperuricemia, and hypoalbuminemia were significantly associated with an elevated serum ALT level. Sex-related differences were also revealed. For the men, type 2 diabetes (odds ratio [OR], 1.23; 95% confidence interval [CI], 1.02-1.57), hypercholesterolemia (OR, 1.78; 95% CI, 1.22-2.83), hypertriglyceridemia (OR, 1.32; 95% CI, 1.04-1.73), and low high-density lipoprotein (OR, 1.26; 95% CI, 1.05-1.51) were significantly related to an elevated serum ALT level, but this was not so for the women. The disparity of ALT in age groups was revealed. CONCLUSION: Several sex-related differences were indicated pertaining to the prevalence of an elevated serum ALT level among elderly specific occupational population. PMID- 24158045 TI - Modeling of indoor radon concentration from radon exhalation rates of building materials and validation through measurements. AB - Building materials are the second major source of indoor radon after soil. The contribution of building materials towards indoor radon depends upon the radium content and exhalation rates and can be used as a primary index for radon levels in the dwellings. The radon flux data from the building materials was used for calculation of the indoor radon concentrations and doses by many researchers using one and two dimensional model suggested by various researchers. In addition to radium content, the radon wall flux from a surface strongly depends upon the radon diffusion length (L) and thickness of the wall (2d). In the present work the indoor radon concentrations from the measured radon exhalation rate of building materials calculated using different models available in literature and validation of models was made through measurement. The variation in the predicted radon flux from different models was compared with d/L value for wall and roofs of different dwellings. The results showed that the radon concentrations predicted by models agree with experimental value. The applicability of different model with d/L ratio was discussed. The work aims to select a more appropriate and general model among available models in literature for the prediction of indoor radon. PMID- 24158046 TI - The use of portable equipment for the activity concentration index determination of building materials: method validation and survey of building materials on the Belgian market. AB - The Euratom BSS requires that in the near future (2015) the building materials for application in dwellings or buildings such as offices or workshops are screened for NORM nuclides. The screening tool is the activity concentration index (ACI). Therefore it is expected that a large number of building materials will be screened for NORM and thus require ACI determination. Nowadays, the proposed standard for determination of building material ACI is a laboratory analyses technique with high purity germanium spectrometry and 21 days equilibrium delay. In this paper, the B-NORM method for determination of building material ACI is assessed as a faster method that can be performed on-site, alternative to the aforementioned standard method. The B-NORM method utilizes a LaBr3(Ce) scintillation probe to obtain the spectral data. Commercially available software was applied to comprehensively take into account the factors determining the counting efficiency. The ACI was determined by interpreting the gamma spectrum from (226)Ra and its progeny; (232)Th progeny and (40)K. In order to assess the accuracy of the B-NORM method, a large selection of samples was analyzed by a certified laboratory and the results were compared with the B-NORM results. The results obtained with the B-NORM method were in good correlation with the results obtained by the certified laboratory, indicating that the B-NORM method is an appropriate screening method to assess building material ACI. The B NORM method was applied to analyze more than 120 building materials on the Belgian market. No building materials that exceed the proposed reference level of 1 mSv/year were encountered. PMID- 24158047 TI - Friedel-Crafts functionalization of the cyclopentadienyl ligand in buckymetallocenes. AB - Acylated buckyferrocene and ruthenocene, Fe(eta(5)-C60Me5)(eta(5)-C5H4COR) (R = Me, Ph, and CH[double bond, length as m-dash]CHPh) and Ru(eta(5)-C60Me5)(eta(5) C5H4COR) (R = Me and Ph), were obtained by Friedel-Crafts acylation of the parent buckymetallocenes with the corresponding acid chlorides and aluminum chloride in carbon disulfide at ambient temperature. The electron withdrawing and sterically hindered nature of the acyl groups were revealed by X-ray crystallography, infrared spectroscopy and electrochemical measurements. The possibility of further derivatizing the acylated products was illustrated by the conversion of the acetyl buckyruthenocene into the corresponding hydroxy and acetoxy compounds Ru(eta(5)-C60Me5)(eta(5)-C5H4CH(OH)Me) and Ru(eta(5)-C60Me5)(eta(5) C5H4CH(OAc)Me). PMID- 24158048 TI - Mechanisms of cholesterol-lowering effects of lactobacilli and bifidobacteria strains as potential probiotics with their bsh gene analysis. AB - The bile salt hydrolase (BSH) enzyme activities of human-derived lactic acid bacteria and bifidobacteria were evaluated. The highest enzyme activity was identified as 1.76 +/- 0.23 U/mg protein for Bifidobacterium breve A26 and 1.42 +/- 0.11 U/mg protein for Lactobacillus plantarum LA3. The bile salt deconjugation ability of the 6 isolates representing the highest BSH enzyme activity was calculated as the release of cholic acid and was between the range of 2.03 +/- 0.22 and 1.05 +/- 0.25 mM. The strains with high BSH enzyme activity also showed high deconjugation ability (p < 0.01). The effect of increasing bile concentrations on the growth of bacteria and their cholesterol removal abilities based on cholesterol precipitation were determined. Cholesterol removal in control medium was between 22.6 +/- 0.4 and 26.5 +/- 0.4%. The highest value was recorded at a 0.2% bile concentration. As the biliary concentration increased, a decrease in cholesterol removal and viability of the bacteria was noted in all strains. The percent of similarity of the bsh gene region between different genes was specified. The results may throw some light on proving the ability of these probiotics either as a novel alternative or as adjuvants to chemical drugs in treating hypercholesterolemia. PMID- 24158049 TI - Postoperative changes in sleep-disordered breathing and sleep architecture in patients with obstructive sleep apnea. AB - BACKGROUND: Anesthetics, analgesics, and surgery may profoundly affect sleep architecture and aggravate sleep-related breathing disturbances. The authors hypothesized that patients with preoperative polysomnographic evidence of obstructive sleep apnea (OSA) would experience greater changes in these parameters than patients without OSA. METHODS: After obtaining approvals from the Institutional Review Boards, consented patients underwent portable polysomnography preoperatively and on postoperative nights (N) 1, 3, 5, and 7 at home or in hospital. The primary and secondary outcome measurements were polysomnographic parameters of sleep-disordered breathing and sleep architecture. RESULTS: Of the 58 patients completed the study, 38 patients had OSA (apnea hypopnea index [AHI] >5) with median preoperative AHI of 18 events per hour and 20 non-OSA patients had median preoperative AHI of 2. AHI was increased after surgery in both OSA and non-OSA patients (P < 0.05), with peak increase on postoperative N3 (OSA vs. non-OSA, 29 [14, 57] vs. 8 [2, 18], median [25th, 75th percentile], P < 0.05). Hypopnea index accounted for 72% of the postoperative increase in AHI. The central apnea index was low (median = 0) but was significantly increased on postoperative N1 in only non-OSA patients. Sleep efficiency, rapid eye movement sleep, and slow-wave sleep were decreased on N1 in both groups, with gradual recovery. CONCLUSIONS: Postoperatively, sleep architecture was disturbed and AHI was increased in both OSA and non-OSA patients. Although the disturbances in sleep architecture were greatest on postoperative N1, breathing disturbances during sleep were greatest on postoperative N3. PMID- 24158050 TI - Factors associated with postoperative exacerbation of sleep-disordered breathing. AB - INTRODUCTION: The knowledge on the mechanism of the postoperative exacerbation of sleep-disordered breathing may direct the perioperative management of patients with obstructive sleep apnea. The objective of this study is to investigate the factors associated with postoperative severity of sleep-disordered breathing. METHODS: After obtaining approvals from Institutional Review Boards, consenting patients underwent portable polysomnography preoperatively, and on postoperative nights 1 and 3 in hospital or at home. The primary outcomes were polysomnography parameters measuring the sleep-disordered breathing. They were treated as repeated measurement variables and analyzed for associated factors by mixed models. RESULTS: Three hundred seventy-six patients, 168 men and 208 women, completed polysomnography on preoperative and postoperative night 1. Age was 59 +/- 12 yr (mean +/- SD). Preoperative apnea-hypopnea index (AHI) was 12 (4, 26) (median [25th, 75th percentile]) events per hour. Thirty-five patients had minor surgeries, 292 intermediate surgeries, and 49 major surgeries, with 210 general anesthesia and 166 regional anesthesia. The 72-h opioid dose was 55 (14, 85) mg intravenous morphine-equivalent dose. Preoperative AHI, age, and 72-h opioid dose were associated with postoperative AHI. Preoperative central apnea index, male sex, and general anesthesia were associated with postoperative central apnea index. Slow wave sleep percentage was inversely associated with postoperative AHI and central apnea index. CONCLUSIONS: Patients with a higher preoperative AHI were predicted to have a higher postoperative AHI. Preoperative AHI, age, and 72 h opioid dose were positively associated with postoperative AHI. Preoperative central apnea, male sex, and general anesthesia were associated with postoperative central apnea index. PMID- 24158052 TI - Competency-based education in anesthesiology: history and challenges. AB - The Accreditation Council for Graduate Medical Education is transitioning to a competency-based system with milestones to measure progress and define success of residents. The confines of the time-based residency will be relaxed. Curriculum must be redesigned and assessments will need to be precise and in-depth. Core anesthesiology faculty will be identified and will be the "trained observers" of the residents' progress. There will be logistic challenges requiring creative management by program directors. There may be residents who achieve "expert" status earlier than the required 36 months of clinical anesthesia education, whereas others may struggle to achieve acceptable status and will require additional education time. Faculty must accept both extremes without judgment. Innovative new educational opportunities will need to be created for fast learners. Finally, it will be important that residents embrace this change. This will require programs to clearly define the specific aims and measurement endpoints for advancement and success. PMID- 24158051 TI - Isoflurane-induced apoptosis of neurons and oligodendrocytes in the fetal rhesus macaque brain. AB - BACKGROUND: The authors have previously shown that exposure of the neonatal nonhuman primate (NHP) brain to isoflurane for 5 h causes widespread acute apoptotic degeneration of neurons and oligodendrocyte. The current study explored the potential apoptogenic action of isoflurane in the fetal NHP brain. METHODS: Fetal rhesus macaques at gestational age of 120 days (G120) were exposed in utero for 5 h to isoflurane anesthesia (n = 5) or to no anesthesia (control condition; n = 4), and all regions of the brain were systematically evaluated 3 h later for evidence of apoptotic degeneration of neurons or glia. RESULTS: Exposure of the G120 fetal NHP brain to isoflurane caused a significant increase in apoptosis of neurons and of oligodendrocytes at a stage when oligodendrocytes were just beginning to myelinate axons. The neuroapoptosis response was most prominent in the cerebellum, caudate, putamen, amygdala, and several cerebrocortical regions. Oligodendrocyte apoptosis was diffusely distributed over many white matter regions. The total number of apoptotic profiles (neurons + oligodendrocytes) in the isoflurane-exposed brains was increased 4.1-fold, compared with the brains from drug-naive controls. The total number of oligodendrocytes deleted by isoflurane was higher than the number of neurons deleted. CONCLUSIONS: Isoflurane anesthesia for 5 h causes death of neurons and oligodendrocytes in the G120 fetal NHP brain. In the fetal brain, as the authors previously found in the neonatal NHP brain, oligodendrocytes become vulnerable when they are just achieving myelination competence. The neurotoxic potential of isoflurane increases between the third trimester (G120) and the neonatal period in the NHP brain. PMID- 24158053 TI - An oxygen-17 dynamic NMR study of the Pr-DOTA complex. AB - The complex between (17)O-enriched DOTA (tetraazacyclododecanetetraacetic acid) and praseodymium(III) (Pr(3+)) was studied in aqueous solution by variable temperature (17)O NMR at 14.1 T. pH effects as well as the influence of metal ions free in solution were investigated. At low temperature, the so-called TSAP and SAP conformations give rise to distinct signals for the oxygen atoms coordinated to the metal ion (O2); coalescence occurs between 20 and 30 degrees C. In contrast, a single signal was detected for the noncoordinated oxygen atoms (O1) in the entire investigated temperature range, i.e. between -3 and 135 degrees C. At high temperature, the spectra exhibit signal broadening that reveals the interchange of the O1 and O2 oxygen atoms of the carboxylate groups. The linewidths measured for O1 were deconvolved into contributions from quadrupole relaxation and chemical exchange, allowing the corresponding activation barriers to be determined. The present (17)O dynamic NMR study provides the first quantitative experimental data characterizing the interchange of the oxygen atoms in a DOTA chelate of a lanthanide metal ion. The activation entropy of this process is negligible and the activation enthalpy is found to range between 66 and 77 kJ mol(-1), depending on the pH and the presence of free Pr(3+) ions in solution. These data support the results of a previous computational study according to which the exchange mechanism involves the internal rotation of the carboxylate groups. PMID- 24158054 TI - Informed consent for return of incidental findings in genomic research. AB - PURPOSE: Researchers face the dilemma of how to obtain consent for return of incidental findings from genomic research. We surveyed and interviewed investigators and study participants, with the goal of providing suggestions for how to shape the consent process. METHODS: We performed an online survey of 254 US genetic researchers identified through the NIH RePORTER database, abstracts from the 2011 American Society of Human Genetics meeting, and qualitative semi structured interviews with 28 genomic researchers and 20 research participants. RESULTS: Most researchers and participants endorsed disclosure of a wide range of information about return of incidental findings, including risks, benefits, impact on family members, data security, and procedures, for return of results in the event of death or incapacity and for recontact. However, most researchers were willing to devote 30 min or less to this process and expressed concerns that disclosed information would overwhelm participants, a concern shared by many participants themselves. CONCLUSION: There is a disjunction between the views of investigators and participants about the amount of information that should be disclosed and the practical realities of the research setting, including the time available for consent discussions. This strongly suggests the need for innovative approaches to the informed consent process. PMID- 24158055 TI - Estimates of cancer burden in Piedmont and Aosta Valley. AB - AIMS AND BACKGROUND: Cancer registration in Piedmont currently covers the city of Turin and the province of Biella, together representing 24% of the regional population. The objective of this paper is to provide estimates of the incidence and mortality rates and prevalence proportions for cancer of the lung, breast, cervix, prostate, colon-rectum and stomach and melanoma of the skin for 2012 and the time trends up to 2015 for the Piedmont and Aosta Valley regions. METHODS: The estimates were obtained by applying the MIAMOD method, a statistical back calculation approach to derive incidence and prevalence figures starting from mortality and relative survival data. Published data from the Italian cancer registries were modeled in order to estimate the regional cancer survival. The MIAMOD estimates were also compared with those obtained by applying a method based on the mortality-incidence and prevalence-incidence ratios. RESULTS: The most frequently diagnosed cancers in absolute terms were prostate, colorectal, breast and lung cancer with about 5,000, 4,700, 3,300, and 2,900 new cases, respectively, in 2012. Incidence rates were rising for melanoma in both sexes and lung cancer in women, while they diminished for cervical and stomach cancer. For prostate cancer and male lung cancer the rates initially increased but were estimated to decrease in the most recent period. Colorectal cancer also increased up to the 1990s but was estimated to reach a plateau in the final years of estimation. Prevalence increased for all the considered cancers with the exception of cervical cancer. Mortality was declining for all considered cancers with the exception of lung cancer in women. CONCLUSIONS: Monitoring indicators of the cancer burden is crucial for setting priorities among possible health system activities in a limited-resource setting. Piedmont has long invested in organized, population-based screening programs: these will have to be extended and accompanied by greater efforts in primary prevention. PMID- 24158056 TI - Estimates of cancer burden in Lombardy. AB - AIMS AND BACKGROUND: Cancer registration in Lombardy covers almost half of the regional population and started in 1976 in the Varese province. The aim of this paper is to provide estimates of the incidence, mortality and prevalence of seven major cancers for the entire Lombardy region in the period 1970-2015. METHODS: The estimates were obtained by applying the MIAMOD method, a statistical back calculation approach to derive incidence and prevalence figures starting from mortality and relative survival data. Published data from the Italian cancer registries were modeled in order to estimate the regional cancer survival. RESULTS: In Lombardy, about 9,000 new cases of breast cancer, 8,500 of colorectal cancer, 7,200 of prostate cancer and 6,700 of lung cancer were expected to be diagnosed in the year 2012. Incidence rates are still rising for female breast cancer, skin melanoma in both sexes, and lung cancer in women. By contrast, the rates have been declining for cervix and stomach cancer. For lung cancer in men, prostate cancer and colorectal cancer the rates increased, reaching a peak in different periods, and then decreased. Prevalence increased for all cancers considered except cervix cancer. The rise was less pronounced in stomach cancer due to the impressive reduction of its incidence and was striking for breast and prostate cancer, with 116,000 and 58,900 prevalent cases in 2012. Mortality dropped for all considered cancers with the only exception of lung cancer in women. CONCLUSION: This up-to-date picture of the cancer risk and burden in Lombardy shows the increasing demand for oncology services as one of the major challenges for the region. However, primary prevention is still the only way to simultaneously reduce incidence, prevalence and mortality rates, thus saving further lives and preserving health resources. PMID- 24158057 TI - Estimates of cancer burden in Liguria. AB - AIMS AND BACKGROUND: The regional health care system of Liguria caters for a resident population which is among the oldest in Europe. One population-based cancer registry is present in the region, providing incidence and survival data for the Genoa province (covering 55% of the regional population). This paper will estimate the incidence, prevalence and mortality in the Liguria region for cancers of the lung, breast, prostate, colon-rectum, stomach and uterine cervix and melanoma of the skin in 1970-2015. METHODS: The estimated figures were obtained by applying the MIAMOD method. Starting from mortality and survival data, incidence and prevalence were derived using a statistical back-calculation approach. Survival was modeled on the basis of published data from the Italian cancer registries. The MIAMOD method was applied also to estimate the colorectal cancer incidence, mortality and prevalence rates in the Ligurian provinces in the period 1988-2015. RESULTS: In 2012 about 1,500 new cases of breast cancer were expected in Ligurian women. The estimates for the other cancer sites were considerably lower, ranging from 839 (colon-rectum) to 54 (cervix). In men about 1,400 new cases were estimated for prostate cancer, while the incidence for the other sites ranged from 1,118 (colon-rectum) to 208 (skin melanoma). The breast cancer prevalence rate was more than 10 times the incidence rate in women, and the lung cancer prevalence rate was more than double the incidence rate in both sexes. Mortality rates were highest for lung cancer in men and breast cancer in women; the lowest rates were estimated for melanoma and cancer of the uterine cervix. CONCLUSION: In Liguria a large portion of the health expenditure has been devoted to diagnostic and therapeutic resources. This may have contributed to the reduction of mortality rates and to the improvement of cancer survival. This phenomenon, added to population aging, will inflate the cancer prevalence. One of the major challenges for the Liguria region is to face the increasing demand for oncology services. PMID- 24158058 TI - Estimates of cancer burden in Trentino-Alto Adige. AB - AIMS AND BACKGROUND: The Trentino-Alto Adige region is composed of two autonomous provinces (Trento and Bolzano), each with its own cancer registry. The registries' total coverage is 100% of the regional population. The main difference between the two provinces in terms of cancer epidemiology is related to the prostate cancer incidence and survival, with higher values in Bolzano. This paper provides an update until 2015 of the basic epidemiological indicators for seven major cancers for the entire region. METHODS: The indicators were estimated by means of the MIAMOD method, a statistical back-calculation approach to derive incidence and prevalence figures starting from mortality and relative survival data. Mortality data were provided by ISTAT for the period 1970-2002 while survival was modeled on the basis of published data from the Italian cancer registries. RESULTS: The estimates for 2012 show that breast cancer was the most common cancer in women and prostate cancer was most common in men. Incidence and mortality were decreasing for cervix cancer and stomach cancer in both genders during the whole study period. The lung cancer incidence and mortality were decreasing in men but increasing in women. The colorectal cancer incidence rose in both genders while the mortality was decreasing in women. The incidence of skin melanoma increased in both sexes, while the mortality remained very low. The breast cancer incidence was increasing up to 2015 while the mortality was declining since 1986. The prostate cancer incidence increased up to 2006, thereafter the rates stabilized while mortality started to decrease in the early 2000s. The highest mortality rates were estimated for lung cancer in men and breast cancer in women. CONCLUSIONS: Lifestyle plays an important role in cancer trends, as does organized screening for early detection of cervix, breast and colorectal cancer. The provincial data on risk factor distribution and adherence to and coverage of organized screening are satisfactory and their optimization may allow additional benefits in terms of public health. PMID- 24158059 TI - Estimates of cancer burden in Veneto. AB - AIMS AND BACKGROUND: In Veneto a regional cancer registry has been operating since 1987 which provides incidence and survival data for the region. It currently covers 48% of the regional population. The aim of this paper is to provide estimates of the incidence, mortality and prevalence of the major cancers for the whole Veneto region in the period 1970-2015. METHODS: The estimates were obtained by applying the MIAMOD method, a statistical back-calculation approach to derive incidence and prevalence figures starting from mortality and relative survival data. Survival was modeled on the basis of published data from the Italian cancer registries. RESULTS: In 2012 the most frequent cancer sites were colon-rectum, prostate and breast with 4,677, 3,760 and 3,729 new diagnosed cases, respectively. The incidence rates were estimated to increase constantly for female lung cancer, prostate cancer, colorectal cancer and melanoma, while they were decreasing for cervical cancer and stomach cancer. For male lung cancer and female breast cancer the rates increased, reaching a peak, and then decreased. In the last years of the period of analysis, mortality declined for all cancers: the highest number of deaths (2,390 in both sexes) was estimated for lung cancer in 2012. Prevalence was increasing for all the considered cancer sites with the exception of lung cancer in men, for which the prevalence was estimated to increase until 2007 and then stabilize. By contrast, the cervical cancer decreased during the whole period. In 2012 breast cancer had the highest prevalence, with about 52,000 cases. CONCLUSION: This paper provides a description of the burden of the major cancers in Veneto until 2015. The estimates highlight the continuing reduction of cancer mortality. This decline can be related to the improvement of clinical treatments and to multidisciplinary treatment approaches. In order for this positive trend to continue, implementation and reinforcement of the screening programs is needed, especially for breast and colorectal cancer. PMID- 24158060 TI - Cancer estimates up to 2015 in Friuli Venezia Giulia. AB - AIMS AND BACKGROUND: This analysis intended to estimate the incidence, mortality and prevalence time trends for the major cancer sites up to 2015 in the Friuli Venezia Giulia region, northeastern Italy, where a population-based cancer registry has been covering the whole area since 1995. METHODS: The MIAMOD method, a statistical back-calculation approach, was applied to estimate incidence, mortality and prevalence figures, in the period 1970-2015, using mortality data from the Italian National Institute of Statistics and relative survival data from Italian cancer registries. RESULTS: We estimated that the cancer sites with the highest incidence rates in the forthcoming years will be breast in women (with an age-standardized incidence rate of 130 per 100,000 in 2015), prostate in men (97 per 100,000) and colon-rectum in both sexes (85 and 42 per 100,000 in men and women, respectively). The incidence rates for lung cancer will continue to decrease only in men (down to 43 per 100,000 in 2015). Although the decline in the mortality rates of lung, breast and colorectal cancers is likely to persist, these tumors will remain the big killers in the near future. The number of people living in Friuli Venezia Giulia after a cancer diagnosis is expected to continue to rise in particular for breast cancer (with a crude prevalence of 3,000 per 100,000 women in 2015), prostate cancer (1,700 per 100,000 men) and colorectal cancer (1,100 and 800 per 100,000 in men and women, respectively). CONCLUSION: These estimates confirmed the epidemiological patterns in time trends of major cancer sites recorded in Friuli Venezia Giulia. They highlighted in particular the increasing number of people living after a cancer diagnosis as a result of population aging, earlier diagnosis and better prognosis, which warrants adequate public health policies. PMID- 24158061 TI - Estimates of cancer burden in Emilia-Romagna. AB - AIMS AND BACKGROUND: This paper aims to provide a comprehensive overview of mid term epidemiological trends for the major cancer sites in the Emilia-Romagna region of northern Italy (population 4,400,000). METHODS: The MIAMOD method, a back-calculation approach to estimate and project the incidence of chronic diseases from mortality and patient survival, was used for the estimation of incidence and prevalence by calendar year (from 1970 to 2015) and age (from 0 to 99). Survival estimates were taken from cancer registries of northeastern Italy. RESULTS: The estimated incidence of stomach cancer decreased by approximately 75% for both sexes. Trends in incidence of colorectal cancer differed between males and females. For females, the rate increased moderately until the year 2000 with a slow decrease thereafter, whereas the male colorectal cancer incidence showed a regular increase until 2010 followed by a substantial leveling off. Among males the lung cancer incidence and mortality rates showed a steep increase until the late 1980s and a rapid decrease thereafter. Among females, the trends were increasing over the entire study period. The estimated incidence of female breast cancer rose sharply between 1970 and 2001, but from that year onwards a slightly decreasing trend was observed. Mortality peaked in 1988 and has fallen since. The incidence of prostate cancer showed a 3-fold increase. After 2005, the rate is expected to stabilize. Among females, the estimated prevalence increased for breast cancer (52,700 cases expected in 2015), colorectal cancer, lung cancer and melanoma, while decreasing for stomach cancer and cervical cancer. Among males, the estimates showed an upward trend for prostate cancer (32,100 cases expected in 2015) and colorectal cancer, and a leveling off for lung cancer after 2010. CONCLUSION: The estimates were fairly consistent with previous data from several epidemiological sources. The MIAMOD method provided a picture of the impressive increase in the prevalence of breast cancer and prostate cancer over the 45-year period studied. PMID- 24158062 TI - Estimates of cancer burden in Tuscany. AB - AIMS AND BACKGROUND: The Tuscan cancer registry has been operating since 1985, providing cancer incidence and survival data in Tuscany; it covers about 33% of the regional population. The purpose of this paper is to provide incidence, prevalence and mortality estimates for the major cancers in the whole Tuscany region for the period 1970-2015. METHODS: The estimated figures were obtained by applying the MIAMOD method. Starting from mortality and survival data, incidence and prevalence were derived using a statistical back-calculation approach. Survival was modeled on the basis of published data from the Italian cancer registries. RESULTS: According to the estimates, the most frequent cancer sites were colon-rectum in both genders, prostate in men and breast in women, with 4,188, 3,082 and 3,092 new diagnoses, respectively, in 2012. The incidence rates were steadily increasing for lung cancer in women and melanoma in both sexes, while they were decreasing for uterine cervix cancer in women, lung cancer in men and stomach cancer in both sexes. For colorectal cancer a small reduction in incidence was estimated for both sexes in recent years. The incidence rates for prostate cancer, after a steep increase and subsequent stabilization, were estimated to increase slightly in the last years. The breast cancer incidence was estimated to stabilize in the last 10 years. The mortality trends were decreasing for all considered cancers except female lung cancer. Prevalence increased for most of the studied cancers except stomach cancer in both sexes, lung cancer in men and cervix cancer in women. The highest prevalence was estimated for breast cancer, with over 42,000 cases in 2012. CONCLUSION: This paper provides an updated description of the cancer burden in Tuscany until 2015. These trends will have a significant impact on the regional health services and it is therefore important to enhance both primary prevention, for reducing the cancer incidence, and oncological surveillance, for evaluating the care and assistance of cancer patients. PMID- 24158063 TI - Estimates of cancer burden in Umbria. AB - AIMS AND BACKGROUND: Model-based estimates and projections of epidemiological indicators related to cancer are important tools to support public health policies and planning. The aim of the present study is to produce projections of cancer incidence, mortality and prevalence for the Umbria region (900,000 inhabitants) in central Italy. METHODS: The estimations were obtained by applying the MIAMOD method, a statistical back-calculation approach to derive incidence and prevalence figures starting from mortality and relative survival data. Published data from the Italian cancer registries were modeled in order to estimate regional cancer survival. Estimated incidence rates were validated with observed incidence rates obtained from the Umbria regional cancer registry. RESULTS: The most frequent cancer sites estimated were colon-rectum, prostate and breast in women, with 970, 615 and 729 new diagnoses, respectively, in 2012. The incidence rates were increasing for female lung cancer, male colorectal cancer, and melanoma. By contrast, the rates have been declining for cervix and stomach cancer. For lung cancer and prostate cancer in men and colorectal cancer in women the rates increased, reaching a peak in different periods, and then decreased. The incidence rates of breast cancer rose, reaching a plateau in the mid 2010s. Favorable mortality trends were predicted for all cancers except skin melanoma and lung cancer in women. The prevalence of cancer was increasing with the only exception of cervical cancer in women and lung cancer in men in the most recent estimation period. CONCLUSION: The scenario found for cancer incidence and prevalence was largely influenced by screening activities, so that increasing or stable incidence rates may reflect active preventive efforts. Aging, screening, and more complex and costly treatments pose a problem of sustainability and selection of interventions to the regional oncology system. Evaluation of effectiveness of intervention and cost-benefit analyses will be important to ensure cancer control in the future. PMID- 24158064 TI - Estimates of cancer burden in Marche. AB - AIMS AND BACKGROUND: The aim of this paper is to provide estimates of the incidence, mortality and prevalence of seven major cancers in the Marche region for the period 1970-2015. METHODS: The MIAMOD method, a statistical back calculation approach, was applied to derive incidence and prevalence figures from mortality and relative survival data. Published data from the Italian cancer registries were used as the basis for survival modeling. RESULTS: Colorectal, breast and prostate cancer were the most frequent cancers in 2012, with 1,563, 1,215 and 1,191 estimated incident cases, and leading to 539, 224 and 228 deaths, respectively. Age-standardized rates were estimated to decrease for stomach and cervical cancer and to increase for skin melanoma and female lung cancer. In men, the lung cancer incidence rates reached their maximum level during the late 1980s and decreased thereafter. The colorectal cancer trend showed an initially increasing pattern, followed by a decrease in the last decade, both for men and women. The estimated incidence rates of prostate cancer presented a very steep rise in the period 1985-2002 and then remained stable at the high levels reached in 2003. The largest increases in prevalence were for breast, colorectal and prostate cancer, for which 17,098, 11,844 and 9,269 cases were estimated, respectively, in 2012. CONCLUSION. This paper provides a description of the burden of the major cancers in the Marche region until 2015. The estimates were fairly consistent with previously published data by the Macerata province cancer registry. The MIAMOD method provides a picture of the impressive increase in the prevalence of breast cancer and prostate cancer over the period studied, thereby allowing to foresee an increasing demand for cancer care services as one of the major challenges for the regional health care system. PMID- 24158065 TI - Estimates of cancer burden in Lazio. AB - AIMS AND BACKGROUND: Since 1983 a population-based cancer registry has been operating in Lazio which provides incidence and survival data and covers the entire Latina province, amounting to 10% of the regional population. The aim of this paper is to provide estimates of the incidence, mortality and prevalence for seven major cancers in the Lazio region for the period 1970-2015. METHODS: The estimates were obtained by applying the MIAMOD method, a statistical back calculation approach to derive incidence and prevalence figures starting from mortality and relative survival data. Survival was modeled on the basis of published data from the Italian cancer registries. RESULTS: In 2012 the most frequent cancer sites were breast, colon-rectum and prostate with 5,529, 5,315 and 4,759 new diagnosed cases, respectively. The cancers with increasing incidence trends were breast cancer, lung cancer and skin melanoma in women, and prostate cancer, colorectal cancer and melanoma in men. The incidence rates of uterine cervix and stomach cancer decreased. The male lung cancer rates increased, reaching a peak in the late 1980s, and then decreased. Prevalence increased for all the considered cancers except cervix cancer. In 2012 breast, colorectal and prostate cancer had the highest prevalence, with 68,239, 36,617 and 33,934 prevalent cases, respectively. In the final period of the study the mortality declined for all cancers except female lung cancer. In 2012, the highest mortality rates were estimated for lung cancer in both men and women, with 89 and 40 deaths per 100,000, respectively. CONCLUSION: These estimates give a useful description of the present and future cancer patterns in the Lazio region. Incidence, mortality and prevalence projections provide new information for health resource planning. Furthermore, they point to the need to reinforce the organized screening programs, especially for breast and colorectal cancer. PMID- 24158066 TI - Estimates of cancer burden in Abruzzo and Molise. AB - AIMS AND BACKGROUND: Abruzzo and Molise are two regions located in the south of Italy, currently without population-based cancer registries. The aim of this paper is to provide estimates of cancer incidence, mortality and prevalence for the Abruzzo and Molise regions combined. METHODS: The MIAMOD method, a back calculation approach to estimate and project the incidence of chronic diseases from mortality and patient survival, was used for the estimation of incidence and prevalence by calendar year (from 1970 to 2015) and age (from 0 to 99). The survival estimates are based on cancer registry data of southern Italy. RESULTS: The most frequently diagnosed cancers were those of the colon and rectum, breast and prostate, with 1,394, 1,341 and 698 new diagnosed cases, respectively, estimated in 2012. Incidence rates were estimated to increase constantly for female breast cancer, colorectal cancer in men and melanoma in both sexes. For prostate cancer and male lung cancer, the incidence rates increased, reaching a peak, and then decreased. In women the incidence of colorectal and lung cancer stabilized after an initial increase. For stomach and cervical cancers, the incidence rates showed a constant decrease. Prevalence was increasing for all the considered cancer sites with the exception of the cervix uteri. The highest prevalence values were estimated for breast and colorectal cancer with about 12,300 and over 8,200 cases in 2012, respectively. In the 2000s the mortality rates declined for all cancers except skin melanoma and female lung cancer, for which the mortality was almost stable. CONCLUSION: This paper provides a description of the burden of the major cancers in Abruzzo and Molise until 2015. The increase in cancer survival, added to population aging, will inflate the cancer prevalence. In order to better evaluate the cancer burden in the two regions, it would be important to implement cancer registration. PMID- 24158067 TI - Estimates of cancer burden in Campania. AB - AIMS AND BACKGROUND: In Campania two cancer registries have been operating since 1996, covering part of the province of Naples and the province of Salerno, and amounting to 29% of the regional population. The aim of this paper is to provide estimates of the incidence, mortality and prevalence of seven major cancers for the entire Campania region. METHODS: The estimates were obtained by applying the MIAMOD method, a statistical back-calculation approach to derive incidence and prevalence figures starting from mortality and relative survival data. Survival was modeled on the basis of published data from the Italian cancer registries. RESULTS: In 2012 the most frequent cancers were colorectal, breast and lung cancer with 3,969, 3,675 and 3,629 new diagnosed cases, respectively. The cancers with increasing incidence trends were breast cancer, lung cancer and skin melanoma in women, and colorectal cancer and skin melanoma in men. By contrast, the incidence rates of uterine cervix cancer and stomach cancer were decreasing. In men the lung and prostate cancer incidence rates increased, reaching a peak in different periods, and then decreased and stabilized, respectively. Prevalence was increasing for all considered cancers with the exception of cervical cancer. The highest values in 2012 were estimated for breast and colorectal cancer (34,000 and 22,000 prevalent cases, respectively). In the final period under study there was a decline in mortality for all cancers except female lung cancer. The highest crude mortality rates in 2012 were estimated for lung cancer in men and breast cancer in women: 80 and 31 per 100,000, respectively. CONCLUSION: This paper provides a description of the burden of the major cancers in Campania until 2015. The estimates highlight the need to reinforce organized screening, especially for breast and colorectal cancer, and to support evidence-based prevention campaigns against female smoking. All these aspects require continuous and updated monitoring of the main epidemiological indicators in the Campania population. PMID- 24158068 TI - Estimates of cancer burden in Puglia. AB - AIMS AND BACKGROUND: A regional population-based cancer registry that provides incidence and survival data has become active only recently. Since it is important to know the time trends of basic epidemiological indicators to understand the cancer burden in the region, this paper will provide incidence, prevalence and mortality estimates in the region for seven major cancers for the period 1970-2015. METHODS: The estimates were obtained by applying the MIAMOD method, a statistical back-calculation approach to derive incidence and prevalence figures starting from mortality and relative survival data. Survival was modeled on the basis of published data from the Italian cancer registries. RESULTS: The incidence rates are estimated to be still increasing for female breast cancer, colorectal cancer in men and skin melanoma in both sexes. By contrast, the incidence rates indicate a decreasing trend for cervix uteri cancer and stomach cancer, the latter both in men and women. For these cancers an analogous trend is observed for mortality, confirming the reduction of the risk factors related to these cancer types. The incidence rates for lung cancer and prostate cancer in men were estimated to rise, reach a peak, and then decrease in the last part of the considered period. Prevalence increased for all the considered cancers except cervix cancer. The increase was striking for breast cancer and less pronounced for stomach cancer in both genders. CONCLUSION: This paper provides a description of the burden of the major cancers until 2015. The results highlight the need to reinforce effective preventive measures to contrast cancers related to an unhealthy lifestyle and to increase the compliance with organized screening programs to reduce the colorectal and breast cancer burden. PMID- 24158069 TI - Estimates of cancer burden in Basilicata and Calabria. AB - AIMS AND BACKGROUND: Basilicata and Calabria are two neighboring, low income regions of southern peninsular Italy with an overall population of about 2.5 million in 2010. Cancer registration has covered the entire Basilicata population since 2005 and the province of Catanzaro (18.3% of the Calabria population) since 2003. This paper will provide estimates and projections for the period 1970-2015 of the basic epidemiological indicators - incidence, prevalence and mortality - in the Basilicata and Calabria regions for the major cancers (lung, colon and rectum, stomach, skin mela-noma, breast, cervix and prostate). METHODS: The indicators were estimated by applying the MIAMOD statistical back-calculation method to the 1970-2002 official mortality data, and to the 1985-2002 relative survival data collected by population-based registries of the southern regions of Italy. RESULTS: The incidence rates were estimated to be still rising for breast, prostate and colorectal cancer, and for skin melanoma in men. By contrast, they were estimated to be declining for cervix and stomach cancer. The incidence increased, reaching a peak, and subsequently decreased for lung cancer in men and for skin melanoma in women. The age-standardized mortality rates were estimated to decrease for all considered cancers except prostate cancer in men and lung cancer in women, which presented quite stable mortality rates from the mid 2000s onwards. Except for cervix cancer, prevalence was increasing for all considered cancers, particularly those of the breast and prostate. CONCLUSION: These data support the need for health policies focused on primary and secondary prevention, which is the main way to reduce the overall impact of cancer and to preserve health care resources, as well as on actions aimed at ensuring equal access to cancer care and at transferring innovation into clinical practice. PMID- 24158070 TI - Estimates of cancer burden in Sicily. AB - AIMS AND BACKGROUND: Estimates are complementary epidemiological measures which allow to present data on cancer burden, especially in geographical areas where measurements of cancer occurrence are not supported by exhaustive statistics on incidence, mortality and survival. The aim of this paper is to provide cancer incidence, mortality and prevalence estimates and projections for the major cancers in the period 1970-2015 for the entire region of Sicily. METHODS: The estimates were computed by applying the MIAMOD method, a statistical back calculation approach to derive incidence and prevalence figures starting from mortality and relative survival data. Published data from the Italian cancer registries were modeled in order to estimate the regional cancer survival. RESULTS: In 2012 the most common cancers were breast cancer in women, colorectal cancer in both sexes, and prostate cancer in men, with about 4,000, 3,500 and 3,000 estimated new cases, respectively. The highest crude mortality rates were estimated for lung cancer in men (63.6 per 100,000) and breast cancer in women (30.8 per 100,000) and the lowest for skin melanoma (both sexes) and cancer of the cervix uteri. For colorectal, lung and stomach cancer and skin melanoma, all the indicators were higher in men than women. The prevalence figures in women were more than 9 times the incidence figures for breast cancer and more than 10 times the incidence figures for skin melanoma. The prevalence was twice the incidence for lung cancer in both sexes. The prevalence increased for all the considered cancers except cervical cancer. CONCLUSION: According to our analyses in Sicily we expect about 14,000 new diagnoses and 5,500 deaths for the major cancer types in a year, while about 92,000 persons with a diagnosis of the considered cancers were alive in 2012. We expect an increase in cancer survival and contemporary aging of the population: both expectations will inflate the cancer prevalence, causing more demand for oncology facilities. PMID- 24158071 TI - Estimates of cancer burden in Sardinia. AB - AIMS AND BACKGROUND: Cancer registration in Sardinia covers 43% of the population and started in 1992 in the Sassari province. The aim of this paper is to provide estimates of the incidence, mortality and prevalence of seven major cancers for the entire region in the period 1970-2015. METHODS: The estimates were obtained by applying the MIAMOD method, a statistical back-calculation approach to derive incidence and prevalence figures starting from mortality and relative survival data. Estimates were compared with the available observed data. RESULTS: In 2012 the lowest incidence was estimated for stomach cancer and melanoma among men, with 140 and 74 new cases, respectively, per 100,000. The mortality rates were highest for lung cancer and were very close to the incidence rates (77 and 95 per 100,000, respectively). In women, breast was by far the most frequent cancer site both in terms of incidence (1,512 new cases) and mortality (295 deaths), followed by colon-rectum (493 cases and 201 deaths), lung (205 cases and 167 deaths), melanoma (106 cases and 15 deaths), stomach (82 cases and 61 deaths), and uterine cervix (36 cases and 19 deaths). The highest prevalence was estimated for breast cancer (15,180 cases), followed by colorectal cancer with about 7,300 prevalent cases in both sexes. CONCLUSION: This paper provides a description of the burden of the major cancers in Sardinia until 2015. The comparisons between the estimated age-standardized incidence rates and those observed in the Sassari registry indicate good agreement. The estimates show a general decrease in cancer mortality, with the exception of female lung cancer. By contrast, the prevalence is steeply increasing for all considered cancers (with the only exception of cancer of the uterine cervix). This points to the need for more strongly supporting evidence-based prevention campaigns focused on contrasting female smoking, unhealthy nutrition and sun exposure. PMID- 24158072 TI - Estimates of cancer burden in Italy. AB - AIMS AND BACKGROUND: This paper presents updated estimates of the incidence, prevalence and mortality of stomach, colorectal, lung, breast, uterine cervix and prostate cancer and skin melanoma in the Italian population. In particular, point estimates for 2012 and time trends from 1970 to 2015 will be provided. METHODS: The presented figures were obtained by summing up the regional epidemiological indicator estimates presented in the other papers of this monographic issue, which were derived by applying the MIAMOD statistical back-calculation method to cancer registries survival data and official mortality rates. RESULTS: Our findings indicate that breast, colon-rectum and prostate will be the cancer sites with the highest incidence rates in the forthcoming years. The incidence rates still tend to increase for breast, male colorectal cancer and female lung cancer as well as for skin melanoma. By contrast, the incidence of stomach cancer, cervical cancer and male lung cancer, by far the most common tumor sites up to the early 1990s, will continue to decrease. The mortality estimates showed a decreasing trend for all considered cancers with the only exception of lung cancer in women. CONCLUSION: These results point to the need to reinforce prevention activities by developing more effective preventive measures for population groups at risk. There is also a need to support timely and continuous cancer surveillance in the Italian population through cancer registries in order to monitor the spread of the cancer risk and to evaluate the impact of prevention policies and therapeutic advances. PMID- 24158073 TI - Useful indicators to interpret the cancer burden in Italy. AB - INTRODUCTION: In the last decades the demographics of most Western countries have undergone a deep transformation, which has caused a steady increase in degenerative chronic diseases and has made maintaining health and social support by the welfare system difficult. This paper aims to present a set of indicators pertaining to the health status of the Italian population and to the national economic and social systems, as an aid to a better interpretation of the cancer burden impact and of its future tendencies. MATERIAL AND METHODS: All indicators were derived from the ISTAT Health for All database. They were presented by region or macro area, globally or by gender, considering the most recent regional distribution and their time trends. The following features of the Italian population were chosen: percent of people aged over 65 years; life expectancy at birth; birth rate; crude and age-standardized overall mortality rates; dependency ratio; percent of single persons; percent of people with no more than a junior high school diploma; percent of people attaining at least the short first university degree; percent of people employed in the service and tertiary sectors; unemployment rate; incidence of poverty; total health expenditure (THE) as an absolute value and as percent of GDP; percent of public THE; percent of out of-pocket THE of households; percent of smokers; proportion of overweight and obese people aged >=18 years. RESULTS: Italy presented an unbalanced demographic situation with an increasingly old population, a decreasing middle-aged age group, a low birth rate, high crude overall mortality rates, and decreasing standardized overall mortality rates. The Italian population is characterized by a constant increase in the dependency ratio and in the percentage of people living alone, together with increasing expenses for health care, both at the public and households levels. Smoking has reduced its impact in men but not yet in women. The increasing proportion of overweight and obese people may explain the convergence in time of the mortality rates of the different Italian macro areas. DISCUSSION AND CONCLUSION: The Italian situation seems to be not well fitted to face the expected growing cancer burden. Along with the aging of the population, the corresponding lowering of the national GDP due to the persisting global economic crisis will lead the public sector and families to reduce health expenditure, while the number of people affected by cancer is bound to increase. Moreover, the social support provided by family members and the advantages of the Mediterranean dietary habits are declining. The strategies for facing the challenging evolution of the future should focus on successful primary prevention and a wider application of evidence-based medicine to optimize the choice of diagnostic and therapeutic procedures offered to citizens. PMID- 24158074 TI - Cancer burden estimates and forecasts: uses and cautions. AB - Incidence, prevalence and mortality indicators, as provided in this monographic issue for each of the Italian regions and for the major cancers (stomach, colorectal, lung, breast, uterine cervix, prostate cancer and skin melanoma), provide necessary information for cancer control activities. In Italy, these activities are mainly organized on a regional level. Incidence depends on the distribution of risk factors in the population and is monitored to assess the efficacy of primary prevention programs as well as to measure the effect of screening activities. Mortality is a summary indicator incorporating the effects of both occurrence and survival. Finally, the prevalence of people with a diagnosis of cancer within a population is a direct measure of the demand for health care and social services. When taken separately, each of these indicators provides a partial view of the cancer phenomenon and should therefore be interpreted with caution. In this paper we give some examples of the uses of these indicators, and also of the interpretation difficulties by relating the regional cancer incidence to tobacco use, overweight and residence in polluted sites. We comment on the observed mortality trends in terms of their contribution to incidence and survival. We associate the estimated trends in cancer prevalence from 1990 to 2015 with the gross domestic product, an indicator of the resources available in Italy. The simultaneous consideration of all three indicators, as was done throughout this monograph by means of a unique methodology, is suggested for public health use. PMID- 24158075 TI - Fatal hypersensitivity pneumonitis associated with docetaxel. AB - We present a patient with advanced breast cancer treated with three cycles of docetaxel who developed repeated episodes of hypersensitivity pneumonitis, progressed to respiratory failure and death despite treatment with corticosteroids and supportive care. Docetaxel-induced hypersensitivity pneumonitis was diagnosed by excluding infection and tumor spread with bronchoalveolar lavage and lung biopsy. Physicians should consider such a condition in all patients who present with interstitial pneumonitis and respiratory failure when they are receiving docetaxel and treat them aggressively with steroids and supportive care, as it can be fatal. PMID- 24158077 TI - Metastases to the thyroid gland from renal cancer. AB - AIMS AND BACKGROUND: Metastases to the thyroid gland from renal cancer pose a challenge to physicians, due in part to the rarity of the phenomenon, the prolonged time interval between removal of the primary renal cancer and the appearance of metastases, the difficulty in diagnosis, and the uncertainty regarding long-term prognosis. We report our experience with diagnosis and management of patients affected by thyroid metastases from renal clear cell carcinoma. STUDY DESIGN: We report herein three clinical cases of thyroid metastases from renal clear cell carcinoma. We also present a review of the literature and examine common features of clinical presentation and management recommendations. RESULTS: Over the past 17 years, 918 patients underewent surgery for thyroid cancer in our institution. Histological examination demonstrated a thyroid secondary malignancy from kidney cancer in 3 cases. Two patients underwent total thyroidectomy, whereas in the third patient a palliative right lobectomy with homolateral latero-cervical lymphoadenectomy was performed. At a 5 year follow-up, only one patient survived and was disease-free. CONCLUSIONS: Thyroid metastases from renal clear cell carcinoma are a rare occurrence but should be taken into consideration in the differential diagnosis of a thyroid nodule. Preoperative diagnosis is often difficult. Nevertheless, an extensive diagnostic workup is recommended because the subsequent therapy must be tailored on the basis of the local extension of metastases. Surgical treatment of solitary thyroid metastases is recommended. However, patients with disseminated disease have a poor prognosis, and palliative care is the indicated recommendation. In these patients and in surgically untreatable patients, prolonged survival may be achieved by adjuvant medical therapy. PMID- 24158076 TI - Ewing's sarcoma/primitive neuroectodermal tumor arising from the adrenal gland: a case report and literature review. AB - We report a rare case of Ewing's sarcoma (ES)/primitive neuroectodermal tumor (PNET) arising from the adrenal gland. A 17-year-old Japanese woman presented with left upper abdominal pain and high fever. Computed tomography and magnetic resonance imaging revealed a 15 * 10 cm tumor replacing the adrenal gland. Preoperative diagnosis was an adrenocortical carcinoma. Resection of the tumor was performed. We obtained the final diagnosis of ES/PNET by immunohistochemical molecular study with positive staining for the MIC2 gene product (CD99) and a Ewing sarcoma breakpoint region 1 (EWSR1) gene rearrangement. Local recurrence was observed one month after the surgery. The patient was then treated with systemic chemotherapy and localized radiotherapy. PMID- 24158078 TI - Primary renal angiosarcoma: radiologic-pathologic correlation and literature review. AB - We present a case of primary renal angiosarcoma. We focus on the characteristic striated pattern of the tumor on T2-w MR sequence as well as on other radiological features and correlate them with the pathologic findings. A review of the imaging characteristics of cases published in the literature was subsequently performed. PMID- 24158079 TI - The case of a patient affected by primary gliosarcoma and neuroendocrine pancreatic cancer with prolonged survival. AB - Primary gliosarcoma (PGS) is a rare neoplasm with a poor prognosis. It is considered as a variant of glioblastoma multiforme (GBM) and as a grade IV neoplasm. There is little evidence on the optimal therapy for this disease: treatment of PGS includes surgery, radiotherapy and chemotherapy, and often the same treatment used for GBM is employed for PGS. Several studies have demonstrated that somatostatin receptors are overexpressed in gliomas; somatostatin analogues could therefore also be employed in this mixed form but to date the experience reported in the literature is unclear and there are no studies about the use of these agents in PGS. We present the case of a patient affected by both PGS and neuroendocrine pancreatic cancer. The case is interesting for the prolonged survival and for the stabilization of disease obtained during therapy with somatostatin analogues. PMID- 24158081 TI - Retreatment with icotinib in a patient with metastatic lung adenocarcinoma. AB - A patient with advanced non-small cell lung cancer (NSCLC) was successfully treated with icotinib. The tumor relapsed after a partial response and the patient was retreated with icotinib after temporary cessation. Surprisingly we found that the tumor responded to icotinib again. The exact mechanism of this phenomenon is still unclear. A better understanding of the biological basis of involved events will help us to improve treatment of advanced NSCLC. PMID- 24158080 TI - Volumetric-modulated arc therapy for a pelvic lymph node metastasis from prostate cancer: a case report. AB - A 50-year-old patient had an early biochemical recurrence after radical prostatectomy and androgen deprivation therapy and castration. An anti-1-amino-3 [18F] fluorocyclobutane-1-carboxylic acid positron emission tomography/computed tomography scan showed a single pelvic lymph node metastasis. The patient was given volume-modulated arc therapy with a cumulative dose of 50 Gy for the volume with pelvic lymph nodes and 78 Gy to the boost volume for the lymph node metastasis. He experienced only a transitory mild toxicity from the rectum and the urinary bladder and had a partial remission for 16 months. PMID- 24158082 TI - Unusual long-lasting cutaneous complete response to lapatinib and capecitabine in a heavily pretreated HER2-positive plurimetastatic breast cancer patient. AB - Lapatinib, in combination with capecitabine, has shown clinical activity in both first-line and refractory disease in patients with HER2-positive advanced breast cancer. Herein we describe the case of a plurimetastatic, heavily pretreated, HER2-positive breast cancer patient who experienced multiple cutaneous metastases successfully treated with lapatinib and capecitabine. An early complete response was obtained on all skin lesions, and no evidence of disease progression at other metastatic sites was observed for 22 months. The treatment was well tolerated, without dose-reductions or delays. In advanced breast cancer patients with skin metastases overexpressing HER2, previously treated with anthracyclines, taxanes and trastuzumab, lapatinib and capecitabine may represent a very active, safe and well-tolerated treatment option. PMID- 24158083 TI - Long-term disease control with lapatinib and capecitabine in a patient with HER2 positive metastatic breast cancer pretreated with trastuzumab and trastuzumab emtansine. AB - We describe the case of a woman who has been undergoing treatment for HER2 positive metastatic breast cancer since 2002. She presented liver metastasis at diagnosis in February 2002. Combination therapy with docetaxel and trastuzumab was administered as first-line treatment, and a complete response of the hepatic lesion and a partial response at the breast primary cancer site were achieved. After 6 cycles of therapy, the patient underwent surgical excision of the breast and then received trastuzumab alone until progression, which occurred in March 2010 with the development of a right chest wall lesion. The patient progressed after therapy with trastuzumab emtansine (T-DM1) received as second-line treatment. Subsequently, a combination of lapatinib and capecitabine was started in April 2011. At this writing, the patient is still receiving treatment (24 months) and is showing a long-lasting response with a favorable safety profile. PMID- 24158085 TI - Improvement of quality of life in third-line chemotherapy with lapatinib in a case of metastatic breast cancer. AB - We describe a case of a 72-year-old patient suffering from metastatic breast cancer. The disease had progressed slowly and was almost asymptomatic for a significant time. Toxicity, following third-line treatment with lapatinib, was not significant, and side effects were well controlled. The case is an excellent example of a chronic neoplastic disease in a patient who could be defined as "long-surviving". PMID- 24158084 TI - Lapatinib and renal impairment: a case report. AB - This clinical report describes durable control of disease in a postmenopausal patient receiving hemodialysis and letrozole plus lapatinib since the diagnosis of HER2-positive, estrogen receptor-positive liver metastasis from breast cancer after anastrozole plus trastuzumab failure. PMID- 24158087 TI - Metastatic signet ring cell carcinoma presenting as a thyroid diffuse involvement: report of a case studied with Q-elastographic and acoustic radiation force impulse imaging features. AB - Metastatic carcinomas to the thyroid are rare in daily clinical practice. However, when encountered they represent a diagnostic challenge, since it is difficult to distinguish them from primary thyroid lesions, especially when occurring in patients with occult malignant history. Nevertheless, it is critical to differentiate a metastatic tumor from primary thyroid lesions, as the clinical management and the prognosis are different for the two entities. More recently, elastosonography opened new possibilities to ultrasound in different fields, such as thyroid nodule differentiation. Herein, we report a case of metastatic signet ring cell carcinoma to the thyroid studied with quantitative elastography and acoustic radiation force impulse imaging. PMID- 24158088 TI - Early recurrence and progression of a rare rectal squamous cell carcinoma after initial response to primary chemoradiotherapy. AB - Rectal squamous cell carcinomas represent an extremely rare malignancy which carries a significant morbidity and mortality. Diagnosis requires distinction from squamous cell carcinoma of the anus and colonic adenocarcinoma by endoscopy and histopathological examination of a biopsy. Due to the rarity of the pathology, available evidence is limited and optimum management has yet to be elucidated. Older reports favored radical surgical management, but recent reports in the literature recommend judicious use of primary chemoradiotherapy. We herein report the diagnosis and management of a male patient with an aggressive, locally advanced rectal squamous cell carcinoma treated with good results with primary chemoradiotherapy. Six months after completion of therapy, however, extensive recurrence and metastases were diagnosed. This case highlights the need for stringent clinical and radiological follow-up. PMID- 24158089 TI - A case of long-term survival after repeated response to oxaliplatin-based chemotherapy and repeated thermoablation of liver metastases from colorectal cancer. Should we introduce the concept of oxaliplatin-resistant tumors? AB - BACKGROUND: The management of advanced colorectal cancer patients differs among cancer centers. International guidelines recommend offering all the recognized active regimens in order to obtain survival advantage, but little information is given about the sequence and combination in which such regimens should be administered. CASE REPORT: We report the case of a man with multiple liver metastasis from colorectal cancer followed for more than 78 months at our Institution. Repeated response to the same oxaliplatin, 5-fluorouracil and folinic acid chemotherapy schedule was achieved, and repeated radiofrequency ablation of liver metastases was performed until progression of lung and brain disease at 50 and 72 months, respectively, after the diagnosis of advanced disease. Although the tumor became oxaliplatin and chemo-resistant after the onset of extra-hepatic disease, a more aggressive chemotherapy regimen, including a doublet with a biological, halted tumor growth. CONCLUSIONS: The patient survived for more than 78 months without experiencing a major impact on his quality of life. This case reflects the importance of following tumor biology in the therapeutic decision-making process, reintroducing oxaliplatin whenever possible, and adopting a more aggressive strategy when the tumor becomes oxaliplatin-resistant. PMID- 24158090 TI - Chylothorax in a patient with Hodgkin's lymphoma: a case report and review of the literature. AB - BACKGROUND: Chylothorax is defined as chyle entering the pleural space. The most common causes of chylothorax are lymphoma followed by bronchogenic carcinoma and trauma. CASE REPORT: We report a case of chylothorax in a patient with Hodgkin's lymphoma. A 28-year old man was admitted to the hospital with exertional dyspnea and dry cough. A chest X-ray showed the large opacity on the left side suggesting to the presence of pleural effusion. METHODS: The effusion was drained, and biochemical tests of the pleural fluid revealed high contents of triglycerides and, hence, confirmed the diagnosis of chylothorax. Cytology of the pleural fluid showed no evidence of Hodgkin's cells. Computer tomography scans of the chest and abdomen exhibited the presence of a soft tissue mass located in the left mediastinum. Mediastinal mass biopsy led to diagnosis of Hodgkin's lymphoma of the nodular sclerosis subtype. The patient received the standard treatment with two cycles of chemotherapy with prednisolone, doxorubicin, cyclophosphamide, vincristine, bleomycin, procarbazine, and etoposide (BEACOPP), followed by an additional two cycles of therapy with doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD). RESULTS: After one cycle of chemotherapy, chylothorax initially decreased. Unfortunately, during the following courses of chemotherapy, the pleural effusion reoccurred and repeated pleural taps were necessary. According to the treatment protocol, radiation of the mediastinal bulk was performed after chemotherapy. Now, nearly one year after completion of radiotherapy, the chylothorax has significantly regressed and no further thoracocenteses were necessary. CONCLUSION: The case reveals an example of left sided chylothorax as the first manifestation of Hodgkin's lymphoma in a young patient. In this case, radiotherapy was shown to be an effective treatment option for lymphoma-associated chylothorax unresponsive to chemotherapy. PMID- 24158091 TI - Mining clinical text for signals of adverse drug-drug interactions. AB - BACKGROUND AND OBJECTIVE: Electronic health records (EHRs) are increasingly being used to complement the FDA Adverse Event Reporting System (FAERS) and to enable active pharmacovigilance. Over 30% of all adverse drug reactions are caused by drug-drug interactions (DDIs) and result in significant morbidity every year, making their early identification vital. We present an approach for identifying DDI signals directly from the textual portion of EHRs. METHODS: We recognize mentions of drug and event concepts from over 50 million clinical notes from two sites to create a timeline of concept mentions for each patient. We then use adjusted disproportionality ratios to identify significant drug-drug-event associations among 1165 drugs and 14 adverse events. To validate our results, we evaluate our performance on a gold standard of 1698 DDIs curated from existing knowledge bases, as well as with signaling DDI associations directly from FAERS using established methods. RESULTS: Our method achieves good performance, as measured by our gold standard (area under the receiver operator characteristic (ROC) curve >80%), on two independent EHR datasets and the performance is comparable to that of signaling DDIs from FAERS. We demonstrate the utility of our method for early detection of DDIs and for identifying alternatives for risky drug combinations. Finally, we publish a first of its kind database of population event rates among patients on drug combinations based on an EHR corpus. CONCLUSIONS: It is feasible to identify DDI signals and estimate the rate of adverse events among patients on drug combinations, directly from clinical text; this could have utility in prioritizing drug interaction surveillance as well as in clinical decision support. PMID- 24158092 TI - Attosecond nonlinear optics using gigawatt-scale isolated attosecond pulses. AB - High-energy isolated attosecond pulses required for the most intriguing nonlinear attosecond experiments as well as for attosecond-pump/attosecond-probe spectroscopy are still lacking at present. Here we propose and demonstrate a robust generation method of intense isolated attosecond pulses, which enable us to perform a nonlinear attosecond optics experiment. By combining a two-colour field synthesis and an energy-scaling method of high-order harmonic generation, the maximum pulse energy of the isolated attosecond pulse reaches as high as 1.3 MUJ. The generated pulse with a duration of 500 as, as characterized by a nonlinear autocorrelation measurement, is the shortest and highest-energy pulse ever with the ability to induce nonlinear phenomena. The peak power of our tabletop light source reaches 2.6 GW, which even surpasses that of an extreme ultraviolet free-electron laser. PMID- 24158093 TI - An intact immune system is required for the anticancer activities of histone deacetylase inhibitors. AB - Cell-intrinsic effects such as induction of apoptosis and/or inhibition of cell proliferation have been proposed as the major antitumor responses to histone deacetylase inhibitors (HDACi). These compounds can also mediate immune modulatory effects that may contribute to their anticancer effects. However, HDACi can also induce anti-inflammatory, and potentially immunosuppressive, outcomes. We therefore sought to clarify the role of the immune system in mediating the efficacy of HDACi in a physiologic setting, using preclinical, syngeneic murine models of hematologic malignancies and solid tumors. We showed an intact immune system was required for the robust anticancer effects of the HDACi vorinostat and panobinostat against a colon adenocarcinoma and two aggressive models of leukemia/lymphoma. Importantly, although HDACi-treated immunocompromised mice bearing established lymphoma succumbed to disease significantly earlier than tumor bearing, HDACi-treated wild-type (WT) mice, treatment with the conventional chemotherapeutic etoposide equivalently enhanced the survival of both strains. IFN-gamma and tumor cell signaling through IFN gammaR were particularly important for the anticancer effects of HDACi, and vorinostat and IFN-gamma acted in concert to enhance the immunogenicity of tumor cells. Furthermore, we show that a combination of vorinostat with alpha galactosylceramide (alpha-GalCer), an IFN-gamma-inducing agent, was significantly more potent against established lymphoma than vorinostat treatment alone. Intriguingly, B cells, but not natural killer cells or CD8(+) T cells, were implicated as effectors of the vorinostat antitumor immune response. Together, our data suggest HDACi are immunostimulatory during cancer treatment and that combinatorial therapeutic regimes with immunotherapies should be considered in the clinic. PMID- 24158094 TI - Lenalidomide inhibits lymphangiogenesis in preclinical models of mantle cell lymphoma. AB - Lymphomas originate in and spread primarily along the lymphatic system. However, whether lymphatic vessels contribute to the growth and spreading of lymphomas is largely unclear. Mantle cell lymphoma (MCL) represents an aggressive non Hodgkin's lymphoma. We found that MCL exhibited abundant intratumor lymphatic vessels. Our results demonstrated that the immunomodulatory drug lenalidomide potently inhibited the growth and dissemination of MCL in a xenograft MCL mouse model, at least in part, by inhibiting functional tumor lymphangiogenesis. Significant numbers of tumor-associated macrophages expressing vascular endothelial growth factor-C were found in both human MCL and mouse MCL xenograft samples. Lenalidomide treatment resulted in a significant reduction in the number of MCL-associated macrophages. In addition, in vivo depletion of monocytes/macrophages impaired functional tumor lymphangiogenesis and inhibited MCL growth and dissemination. Taken together, our results indicate that tumor lymphangiogenesis contributes to the progression of MCL and that lenalidomide is effective in decreasing MCL growth and metastasis most likely by inhibiting recruitment of MCL-associated macrophages. PMID- 24158095 TI - 3'-UTR poly(T/U) tract deletions and altered expression of EWSR1 are a hallmark of mismatch repair-deficient cancers. AB - The genome-wide accumulation of DNA replication errors known as microsatellite instability (MSI) is the hallmark lesion of DNA mismatch repair (MMR)-deficient cancers. Although testing for MSI is widely used to guide clinical management, the contribution of MSI at distinct genic loci to the phenotype remains largely unexplored. Here, we report that a mononucleotide (T/U)16 tract located in the 3' untranslated region (3'-UTR) of the Ewing sarcoma breakpoint region 1 (EWSR1) gene is a novel MSI target locus that shows perfect sensitivity and specificity in detecting mismatch repair-deficient cancers in two independent populations. We further found a striking relocalization of the EWSR1 protein from nucleus to cytoplasm in MMR-deficient cancers and that the nonprotein-coding MSI target locus itself has a modulatory effect on EWSR1 gene expression through alternative 3' end processing of the EWSR1 gene. Our results point to a MSI target gene specific effect in MMR-deficient cancers. PMID- 24158096 TI - Advancing forensic correctional nursing. PMID- 24158097 TI - Exploring work-life issues in provincial corrections settings. AB - Correctional nurses hold a unique position within the nursing profession as their work environment combines the demands of two systems, corrections and health care. Nurses working within these settings must be constantly aware of security issues while ensuring that quality care is provided. The primary role of nurses in correctional health care underscores the importance of understanding nurses' perceptions about their work. The purpose of this study was to examine the work environment of nurses working in provincial correctional facilities. A mixed methods design was used. Interviews were conducted with 13 nurses and healthcare managers (HCMs) from five facilities. Surveys were distributed to 511 nurses and HCMs in all provincial facilities across the province of Ontario, Canada. The final sample consisted of 270 nurses and 27 HCMs with completed surveys. Participants identified several key issues in their work environments, including inadequate staffing and heavy workloads, limited control over practice and scope of practice, limited resources, and challenging workplace relationships. Work environment interventions are needed to address these issues and subsequently improve the recruitment and retention of correctional nurses. PMID- 24158098 TI - A critical exploration of the management of self-harm in a male custodial setting: qualitative findings of a comparative analysis of prison staff views on self-harm. AB - There are a growing number of prisoners who self-harm in prisons in England and Wales despite adopting a safer custody ethos. An in-depth study of staff views of self-harm from various agencies within the prison and the integration of their different forms of expertise and perspectives to address this problem is lacking. Negative attitudes to self-harm have been identified as an additional risk factor to this problematic behavior. AIM: This study identified and compared relevant attitudinal dimensions of custodial and healthcare staff on prisoners who self harm in an Adult Male "Local" Category B prisons (referred to as the study prison) where self-harm was twice the national average (14%). METHOD: Semistructured interviews were conducted with 37 prison staff (14 nurses and 23 prison officers) as part of a mixed methods research study where documentary evidence and a self-harm questionnaire were also used. This paper discusses and presents the findings for the thematic analysis of the semistructured interviews. FINDINGS: The key themes identified were understanding self-harm, building relationships, organizational issues, occupational issues, and care management of self-harm. The findings suggest that most prison staff felt unsupported and inadequately equipped to manage self-harm, and reported interdisciplinary conflict on its collective management. PMID- 24158099 TI - Care and companionship in an isolating environment: inmates attending to dying peers. AB - The purpose of this study was to examine the values, beliefs, and perceptions of end-of-life (EOL) care held by inmates caring for peers approaching the end of their lives. The study is part of a broader participatory action research project to infuse enhanced EOL care into state prisons. Face-to-face interviews using a semistructured discussion guide were conducted with 17 male prisoners who were providing care for peers with advanced chronic illness and approaching end of life. Qualitative data were analyzed using content and thematic analyses. Key themes were getting involved, living the role, and transforming self through caring for others. As well, contextual features at the organizational, peer, and personal levels were identified, which either facilitated or impeded inmate caregiving. Provision of enhanced EOL care by inmate peers shows promise for improving prison community relations and morale, reducing suffering, and demonstrating care and compassion within the harsh prison environment. This study provides clear evidence that providing compassionate care for dying peers may result in transformative experiences for inmate caregivers. Implications for correctional nursing practice include providing training for inmate caregivers, including them in team meetings, and implementing grief support programs. Also, upholding nursing's code of ethics and watching for predatory behavior are critical. PMID- 24158100 TI - Nurses leading care in custody suite environments: a qualitative study from Scotland. AB - This paper outlines the qualitative findings of a recent multimethod study exploring the impact of nurses assuming leadership roles in delivering primary health care to detainees within police custody suites in Scotland. The full multimethod study was conducted within a framework of realistic evaluation with key findings indicating that the nurse-led model of service delivery offers positive outcomes for all key stakeholders. Findings from the qualitative component of the study showed that the quality of clinical care for detainees improved, policing concerns for detainee safety were mitigated, and forensic medical examiners were able to expand their specialist roles. Key supporting mechanisms in achieving these outcomes included generating collaborative practices, enacting clinical leadership, and providing a forensic nursing educational program to empower nurses to generate service provision and grow professional autonomy. PMID- 24158101 TI - Cardiovascular risk factors among prisoners: an integrative review. AB - BACKGROUND AND AIM: Incarceration is characterized by inequalities in disease burden and an increased risk for cardiovascular disease (CVD). The aim of this review was to critique published empirical research studies on cardiovascular risk factors among prisoners and to summarize and synthesize current knowledge and findings across these studies. DESIGN AND REVIEW METHOD: An integrative review of the studies was conducted. Cooper's five stage method was used as a framework to guide data collection, analysis, and synthesis. Quality appraisal of retrieved studies was done using a combined evaluation tool for quantitative research studies and a checklist. The following databases were searched: CINAHL, MEDLINE, PubMed, Cochrane, Indigenous Studies Portal (iPortal), Native Health Database, Criminal Justice Abstracts, and PsychInfo using keywords. Inclusion criteria were used to select published papers. RESULTS AND CONCLUSION: A total of 12 studies that met the inclusion criteria were identified and analyzed. Hypertension, among other CVD risk factors such as smoking, physical inactivity and obesity, was one of the three most common CVD risk factors found in prisoners. Women and young offenders had a higher prevalence of hypercholesterolemia. Identifying prevalent risks factors among prisoners might influence the development of CVD prevention strategies that are specifically directed to at risk prisoners. PMID- 24158103 TI - The ROCK inhibitor Y-26732 enhances the survival and proliferation of human embryonic stem cell-derived neural progenitor cells upon dissociation. AB - Human neural progenitor cells (hNPCs) are the starting material required for neuronal subtype differentiation. Proliferation of hNPCs allows researchers to study the mechanistic complexities and microenvironments present during neural differentiation and to explore potential applications for hNPCs in cell therapies. The use of enzymatic dissociation during hNPC proliferation causes dissociation-induced apoptosis; therefore, in the present study, we examined the effect of the p-160-Rho-associated coiled-coil kinase (ROCK) inhibitor Y-26732 on dissociation-induced apoptosis of hNPCs. We generated hNPCs via embryoid body formation using serum-free culture medium supplemented with noggin. The established hNPCs were characterized and the effect of the ROCK inhibitor on hNPC dissociation was studied. We demonstrated that supplementation of the culture media with 10 MUM Y-26732 efficiently reduced apoptosis of dissociated hNPCs; this supplementation was effective when the inhibitor was applied either at (i) 24 h before dissociation of the cells and at 24 h after plating the cells or (ii) at 24 h after plating of the cells only. In addition to reducing apoptosis, both supplementation conditions with Y-26732 enhanced the proliferation of dissociated hNPCs. Our findings provide the optimal time window for ROCK treatment of hNPC dissociation in respect to apoptosis and cell proliferation. PMID- 24158104 TI - Glomerular angiotensin-converting enzyme 2 in pediatric IgA nephropathy. AB - BACKGROUND: Angiotensin-converting enzyme (ACE) 2 is a homolog of ACE and is thought to be a potent counter-regulator against ACE activity. However, the role of ACE2 has not been investigated in pediatric patients with IgA nephropathy (IgAN). This study was performed to examine the relationship between ACE2 expression and the development of pediatric IgAN. METHODS: We performed immunohistochemical analysis of ACE2 and ACE in 39 patients with pediatric IgAN and 14 patients with minor glomerular abnormalities, and elucidated the effects of various cytokines on ACE2 expression in cultured human mesangial cells. RESULTS: ACE2 expression levels in glomeruli and tubules were positively correlated with the mesangial hypercellularity score, while ACE expression levels in glomeruli and tubules are not. Multiple regression analysis showed that the mesangial hypercellularity score correlated with the ACE2 expression level in glomeruli and the urinary protein-creatinine ratio. In IgAN patients not treated with a renin-angiotensin system blocker, ACE2 expression levels in glomeruli were significantly increased compared to patients with minor glomerular abnormalities. IgAN patients treated with a renin-angiotensin system blocker did not show this increase in ACE2 expression. Furthermore, cultured human MC showed increased ACE2 mRNA and protein after treatment with IL-1beta, a pro-inflammatory cytokine in IgAN. In fact, glomerular expressions of IL-1beta were remarkably increased in patients with IgAN. CONCLUSION: These data indicate that ACE2 expression in glomeruli is associated with mesangial hypercellularity in early lesions of pediatric IgAN. PMID- 24158105 TI - Silver-catalyzed C-C bond formation with carbon dioxide: significant synthesis of dihydroisobenzofurans. AB - The silver salt catalyzed the C-C bond forming reaction of o-alkynylacetophenone derivatives and carbon dioxide. In this reaction, a carbonyl group and a furan skeleton were successively constructed to afford the corresponding dihydroisobenzofuran derivatives. PMID- 24158106 TI - Clinical, psychosocial, and central correlates of quality of life in myotonic dystrophy type 1 patients. AB - AIMS: To identify sociodemographic, clinical, and central correlates of health related quality of life (HRQoL) in DM1 patients. METHODS: 200 DM1 patients had assessments of muscular impairment, CTG repeats, and intelligence. Validated instruments were used to assess sociodemographic and clinical factors as well as social support, social participation, daytime sleepiness, fatigue, personality, mood, and quality of life. Regression analysis was used to identify correlates of SF-36 physical and mental component summary scores. RESULTS: Patients scored lower on all SF-36 physical health subscales compared with normative data but did not differ with respect to mental health function. Regression analysis revealed that psychological distress, fatigue, severe muscular impairment, emotional stability, not having worked within the last 12 months, and lower intellectual quotient were associated with lower scores in physical health function. Moreover, neuroticism, daytime sleepiness, dissatisfaction with social participation, and lower conscientiousness were associated with lower scores in mental health function. CONCLUSION: DM1 has an impact on SF-36 physical summary scores but not on mental summary scores. Factors such as fatigue, daytime sleepiness, psychological distress, unemployment, and social participation dissatisfaction that significantly affect HRQoL in DM1 are amenable to treatment and psychosocial interventions, namely by providing care that integrate health, social, and community services. PMID- 24158107 TI - Analysis of the complete genomes of Acholeplasma brassicae, A. palmae and A. laidlawii and their comparison to the obligate parasites from 'Candidatus Phytoplasma'. AB - Analysis of the completely determined genomes of the plant-derived Acholeplasma brassicae strain O502 and A. palmae strain J233 revealed that the circular chromosomes are 1,877,792 and 1,554,229 bp in size, have a G + C content of 36 and 29%, and encode 1,690 and 1,439 proteins, respectively. Comparative analysis of these sequences and previously published genomes of A. laidlawii strain PG-8, 'Candidatus Phytoplasma asteris' strains, 'Ca. P. australiense' and 'Ca. P. mali' show a limited shared basic genetic repertoire. The acholeplasma genomes are characterized by a low number of rearrangements, duplication and integration events. Exceptions are the unusual duplication of rRNA operons in A. brassicae and an independently introduced second gene for a single-stranded binding protein in both genera. In contrast to phytoplasmas, the acholeplasma genomes differ by encoding the cell division protein FtsZ, a wide variety of ABC transporters, the F0F1 ATP synthase, the Rnf-complex, SecG of the Sec-dependent secretion system, a richly equipped repertoire for carbohydrate metabolism, fatty acid, isoprenoid and partial amino acid metabolism. Conserved metabolic proteins encoded in phytoplasma genomes such as the malate dehydrogenase SfcA, several transporters and proteins involved in host-interaction, and virulence-associated effectors were not predicted for the acholeplasmas. PMID- 24158108 TI - Mutual impacts of wheat (Triticum aestivum L.) and earthworms (Eisenia fetida) on the bioavailability of perfluoroalkyl substances (PFASs) in soil. AB - Wheat and earthworms were exposed individually and together to soils contaminated with 11 perfluoroalkyl substances (PFASs). Wheat accumulated PFASs from soil with root concentration factors and bioconcentration factors that decreased as the number of perfluorinated carbons in the molecule increased. Earthworms accumulated PFASs from soil with biota-to-soil accumulation factors that increased with the number of carbons. Translocation factors (TF) of perfluorinated carboxylates (PFCAs) in wheat peaked at perfluorohexanoic acid and decreased significantly as the number of carbons increased or decreased. Perfluorohexane sulfonate produced the greatest TF of the three perfluorinated sulfonates (PFSAs) examined. Wheat increased the bioaccumulation of all 11 PFASs in earthworms and earthworms increased the bioaccumulation in wheat of PFCAs containing seven or less perfluorinated carbons, decreased bioaccumulation of PFCAs with more than seven carbons, and decreased bioaccumulation of PFSAs. In general, the co-presence of wheat and earthworms enhanced the bioavailability of PFASs in soil. PMID- 24158109 TI - Multivoxel 1H MR spectroscopy is superior to contrast-enhanced MRI for response assessment after anti-angiogenic treatment of orthotopic human glioma xenografts and provides handles for metabolic targeting. AB - BACKGROUND: Anti-angiogenic treatment of glioblastoma characteristically results in therapy resistance and tumor progression via diffuse infiltration. Monitoring tumor progression in these patients is thwarted because therapy results in tumor invisibility in contrast-enhanced (CE) MRI. To address this problem, we examined whether tumor progression could be monitored by metabolic mapping using (1)H MR spectroscopic imaging (MRSI). METHODS: We treated groups of BALB/c nu/nu mice carrying different orthotopic diffuse-infiltrative glioblastoma xenografts with bevacizumab (anti-vascular endothelial growth factor [VEGF] antibody, n = 13), cabozantinib (combined VEGF receptor 2/c-Met tyrosine kinase inhibitor, n = 11), or placebo (n = 15) and compared CE-MRI with MRS-derived metabolic maps before, during, and after treatment. Metabolic maps and CE-MRIs were subsequently correlated to histology and immunohistochemistry. RESULTS: In vivo imaging of choline/n-acetyl aspartate ratios via multivoxel MRS is better able to evaluate response to therapy than CE-MRI. Lactate imaging revealed that diffuse infiltrative areas in glioblastoma xenografts did not present with excessive glycolysis. In contrast, glycolysis was observed in hypoxic areas in angiogenesis dependent compact regions of glioma only, especially after anti-angiogenic treatment. CONCLUSION: Our data present MRSI as a powerful and feasible approach that is superior to CE-MRI and may provide handles for optimizing treatment of glioma. Furthermore, we show that glycolysis is more prominent in hypoxic areas than in areas of diffuse infiltrative growth. The Warburg hypothesis of persisting glycolysis in tumors under normoxic conditions may thus not be valid for diffuse glioma. PMID- 24158110 TI - Primary glioblastoma with oligodendroglial differentiation has better clinical outcome but no difference in common biological markers compared with other types of glioblastoma. AB - BACKGROUND: Glioblastoma multiforme with an oligodendroglial component (GBMO) has been recognized in the World Health Organization classification-however, the diagnostic criteria, molecular biology, and clinical outcome of primary GBMO remain unclear. Our aim was to investigate whether primary GBMO is a distinct clinicopathological subgroup of GBM and to determine the relative frequency of prognostic markers such as loss of heterozygosity (LOH) on 1p and/or 19q, O(6) methylguanine-DNA methyltransferase (MGMT) promoter methylation, and isocitrate dehydrogenase 1 (IDH1) mutation. METHODS: We examined 288 cases of primary GBM and assessed the molecular markers in 57 GBMO and 50 cases of other primary GBM, correlating the data with clinical parameters and outcome. RESULTS: GBMO comprised 21.5% of our GBM specimens and showed significantly longer survival compared with our other GBM (12 mo vs 5.8 mo, P = .006); there was also a strong correlation with younger age at diagnosis (56.4 y vs 60.6 y, P = .005). Singular LOH of 19q (P = .04) conferred a 1.9-fold increased hazard of shorter survival. There was no difference in the frequencies of 1p or 19q deletion, MGMT promoter methylation, or IDH1 mutation (P = .8, P = 1.0, P = 1.0, respectively). CONCLUSIONS: Primary GBMO is a subgroup of GBM associated with longer survival and a younger age group but shows no difference in the frequency of LOH of 1p/19q, MGMT, and IDH1 mutation compared with other primary GBM. PMID- 24158113 TI - Can Giardia lamblia infection lower the risk of acute diarrhea among preschool children? AB - There are inconsistent findings concerning the role of Giardia lamblia in pediatric diarrhea. A prospective cohort study of the incidence of acute diarrhea among Israeli Arab preschool children offered the opportunity to examine the association between G. lamblia infection (at baseline) and subsequent diarrhea. Following baseline screening by light microscopy for the presence of Giardia in their stools, a cohort was assembled of 142 children who were followed between October 2003 and August 2004 for the incidence of diarrhea. Surveillance was performed through maternal interviews. At baseline, 21 children tested Giardia positive. During the prospective surveillance, acute diarrhea occurred less often among Giardia-positive children (9.5%) than among children who were not infected with Giardia (26.5%). G. lamblia infection was associated with lower risk of acute diarrhea; adjusted odds ratio of 0.18 (95% confidence interval 0.04-0.93) (p = 0.041). This prospective study provides additional evidence that Giardia may lower the risk of subsequent acute diarrhea among preschool children. PMID- 24158111 TI - A miR-297/hypoxia/DGK-alpha axis regulating glioblastoma survival. AB - BACKGROUND: Despite advances in the treatment of the most aggressive form of brain tumor, glioblastoma, patient prognosis remains disappointing. This failure in treatment has been attributed to dysregulated oncogenic pathways, as observed in other tumors. We and others have suggested the use of microRNAs (miRs) as therapeutic tools able to target multiple pathways in glioblastoma. METHODS: This work features PCR quantification of miRs and transient transfection of many glioblastoma cell lines with miRs, followed by cell number analysis, trypan blue staining, alamarBlue assay of cell viability, caspase-3/-7 activity assay, immunoblot of cleaved poly(ADP-ribose) polymerase and fluorescence activated cell sorting and imaging of apoptotic nuclei, cell invasion assays, MRIs of glioblastoma xenografts in mice using transiently transfected cells as well as posttumor treatment with lentiviral vector encoding miR-297, and analysis of miR 297 target diacylglycerol kinase (DGK)-alpha including immunoblot, 3'UTR luciferase activity, and rescue with DGK-alpha overexpression. Cell counts and DGK-alpha immunoblot were also analyzed in the context of hypoxia and with overexpression of heterogeneous ribonucleoprotein L (hnRNPL). RESULTS: We identified miR-297 as a highly cytotoxic microRNA in glioblastoma, with minimal cytotoxicity to normal astrocytes. miR-297 overexpression reduced in vitro invasiveness and in vivo tumor formation. DGK-alpha is shown to be a miR-297 target with a critical role in miR-297 toxicity. In addition, hypoxia and its mediator hnRNPL upregulated DGK-alpha and buffered the cytotoxic effects of miR 297. CONCLUSION: This work shows miR-297 as a novel and physiologic regulator of cancer cell survival, largely through targeting of DGK-alpha, and also indicates that hypoxia ameliorates miR-297 toxicity to cancer cells. PMID- 24158114 TI - A new case of successful outcome of pregnancy in a carrier of homozygous type II (L99F) antithrombin deficiency. AB - Inherited antithrombin deficiency is associated with an increased risk of venous thromboembolism. There is no consensus about pregnancy management in antithrombin deficiency patients because there are very few cases published in the literature. We report a successful pregnancy in a 32-year-old female carrier of a homozygous type II (L99F) antithrombin deficiency who developed a spontaneous deep vein thrombosis at the age of 27 years. PMID- 24158112 TI - Experimental validation of 5 in-silico predicted glioma biomarkers. AB - BACKGROUND: Glioblastoma multiforme (GBM) is a high-grade glioma with poor prognosis. Identification of new biomarkers specific to GBM could help in disease diagnosis. We have developed and validated a bioinformatics method to predict proteins likely to be suitable as glioma biomarkers via a global microarray meta analysis to identify uncharacterized genes consistently coexpressed with known glioma-associated genes. METHODS: A novel bioinformatics method was implemented called global microarray meta-analysis, using approximately 16,000 microarray experiments to identify uncharacterized genes consistently coexpressed with known glioma-associated genes. These novel biomarkers were validated as proteins highly expressed in human gliomas varying in tumor grades using immunohistochemistry. Glioma gene databases were used to assess delineation of expression of these markers in varying glioma grades and subtypes of GBM. RESULTS: We have identified 5 potential biomarkers-spondin1, Plexin-B2, SLIT3, fibulin-1, and LINGO1-that were validated as proteins highly expressed on the surface of human gliomas using immunohistochemistry. Expression of spondin1, Plexin-B2, and SLIT3 was significantly higher (P < .01) in high-grade gliomas than in low-grade gliomas. These biomarkers were significant discriminators in grade IV gliomas compared with either grade III or II tumors and also distinguished between GBM subclasses. CONCLUSIONS: This study strongly suggests that this type of bioinformatics approach has high translational potential to rapidly discern which poorly characterized proteins may be of clinical relevance. PMID- 24158115 TI - Clinical performance of anticardiolipin and antibeta2 glycoprotein I antibodies using a new automated chemiluminescent assay: superior thrombotic prediction of combined results measured by two different methods. AB - The anticardiolipin (aCL) and antibeta2-glycoprotein I (abeta2GPI) antibodies are used to diagnosis antiphospholipid syndrome. It would be possible to use two or more methods to improve the diagnostic sensitivity of aCL and abeta2GPI. In this study, we investigated the laboratory performance of a new chemiluminescent assay and explored whether the combined results of aCL and abeta2GPI measured by two different methods predict thrombotic risk better. The cut-off values were assessed with 99 healthy controls. The coefficient of variations was determined using control materials. Using the plasma of 109 patients, AcuStar chemiluminescent assay and QUANTA Lite ELISA were carried out according to the manufacturers' instructions. The AcuStar cut-off points were 13.5 U/ml for aCL IgG, 19.1 U/ml for aCL IgM, 16.3 U/ml for abeta2GPI IgG and 12.6 U/ml for abeta2GPI IgM. Total coefficient of variations ranged from 4.6 to 8.8%. For both aCL and abeta2GPI, the AcuStar odds ratio for thrombosis prediction was higher than that of QUANTA Lite. When the results for both AcuStar and QUANTA Lite are positive, the odds ratios of aCL and abeta2GPI were higher than that interpreted by a single positive result each. The new automated chemiluminescent assay exhibited good precision, concordance rate, and clinical performance. The combined results of aCL and abeta2GPI as measured by two different methods are expected to increase the prediction power for thrombosis. PMID- 24158116 TI - Three polymorphisms in promoter of protein C gene with endothelial protein c receptor gene and risk of venous thrombosis. AB - The primary abnormalities that are associated with a risk of venous thrombosis are the deficiencies of protein C. Protein C (PROC), encoded by the PROC gene, acts through its affinity for binding to its transmembrane endothelial cell protein C receptor (EPCR) encoded by the EPCR gene. The objective of the study was to analyze the link between three polymorphisms in the promoter of PROC gene, the polymorphism in the EPCR gene and the occurrence of venous thrombosis. We genotyped 135 individuals - 51 cases with documented venous thrombosis and 84 healthy volunteers without a history of venous thrombosis. The occurrence of the TAA haplotype of PROC gene was significantly more frequent in the controls (N = 48; 57.1%), compared with the patients (N = 18; 35.3%), (P = 0.0206). The healthy individuals were also significantly often carriers of the TAA haplotype and the standard genotype AA of EPCR gene (50 vs. 25.5%) than the patients (P = 0.0066). The frequency of haplotypes CAA and CGT of PROC gene was insignificantly higher in the patients (15.7 and 21.6%, respectively) than in the control group (9.5 and 13.1%). The combination of haplotype CAA/CAA of PROC gene and variant genotype AG of EPCR gene was confirmed with a higher frequency in the group of patients (3.9 vs. 1.2%).This analysis showed that the PROC haplotype associated with a high protein C level (TAA) and the EPCR AA genotype was significantly more frequent in the healthy volunteers (P = 0.0066). Haplotypes associated with a low production of protein C (CAA or CGT) were more frequent in patients with venous thrombosis. PMID- 24158117 TI - The preliminary study on the antithrombotic mechanism of glycosaminoglycan from mactra veneriformis. AB - The effect of glycosaminoglycan from Mactra veneriformis on deep venous thrombosis of rats was observed, and the preliminary antithrombotic mechanism of glycosaminoglycan was explained. The results showed that when the glycosaminoglycan was injected intravenously into rats within the dose range of 0.0313-1 mg/kg, the antithrombotic effect increased as the dose increased. When the dose was increased to and exceeded 0.125 mg/kg, deep venous thrombosis caused by blood stagnation was inhibited significantly or extremely remarkably (P < 0.05, P < 0.01), while the intensity was similar to that of the tool drug heparin sodium at the same dose and weaker than that of heparin calcium of low molecular weight at three times' dose in clinics. Three doses (0.1, 0.4 and 1.6 mg/kg) of glycosaminoglycan were intravenously injected via mice tail, resulting in an extremely significant increase of activated partial thromboplastin time (APTT) and thrombin time (TT) (P < 0.01), no significant change of prothrombin time (PT) (P > 0.05), and a weaker anticoagulant effect than that of heparin sodium. In vitro experiments demonstrated that except for the 2 MUg/ml of glycosaminoglycan (P > 0.05), other final concentration groups significantly or extremely significantly prolonged the APPT, TT and PT of rabbits (P < 0.05, P < 0.01), but with a slightly weaker anticoagulant effect than that of heparin sodium; The antiplatelet aggregation experiments using big-eared rabbits manifested that glycosaminoglycan markedly decreased the maximum aggregation percentage of rabbits blood platelet (P < 0.01), which indicated that it had good antiplatelet aggregation effect, but the intensity was weaker than the positive control drug, Ozagrel sodium. PMID- 24158118 TI - A novel mutation c.1048A>T at codon 350(Lys>Stop) in PROC gene causing neonatal purpura fulminans. AB - Purpura fulminans in the neonatal period due to severe congenital protein C deficiency (protein C activity <1 IU/dl) is a rare autosomal recessive disorder. If untreated, it is fatal. Early identification of such patients may be lifesaving. Acquired deficiency of protein C caused by increased consumption as overt disseminated intravascular coagulation (DIC) and severe infection creates a diagnostic dilemma. Mutation analysis plays a critical role in confirming the diagnosis of the disease and offering prenatal diagnosis. In this report, we describe a newborn who presented with purpura fulminans and DIC, molecular analysis showed a novel c.1048A>T transversion in a homozygous state at codon 350 (Lys>Stop) of protein C (PROC) gene. Prenatal diagnosis in subsequent pregnancy was done which revealed the affected fetus had the same mutation in homozygous form. PMID- 24158119 TI - Surgical interventions in childhood rare factor deficiencies: a single-center experience from Turkey. AB - Congenital rare factor deficiencies may present in infancy by life-threatening bleedings or may not show any symptoms until adulthood. It is reported more commonly in countries having consanguineous marriages. Data regarding surgical interventions of rare congenital factor deficiencies are based on case reports and records of guidelines. There are no well documented and separately prepared directories related to pre-surgical and prophylactic approaches of surgical interventions of these deficiencies. Our retrospective study consisted of 171 rare factor deficiencies that were followed up in our clinic, and of whom 61 had 88 surgical interventions between 1990 and 2012. Of these patients, 45 were having factor VII deficiency, and factor V, X, XI, XIII and fibrinogen deficiencies were present in five, four, three, two and two patients, respectively. In 23 patients, factor coagulant activities were under 5% (37.7%), in 15 it was between 5 and 30% (24.6%), and in 23 between 30 and 50% (37.7%). Twenty-eight were symptomatic and 33 were asymptomatic. Information of 51 (83.6%) male and 10 (16.4%) female patients with an age range of 5-25 years (13 +/- 5.27), whose age at presentation ranged between 3 weeks and 18 years (7 +/- 4.66), were retrieved from patient records and from the records contained in the data-processing environment introduced in 2005. The rate of familial consanguinity was 49.2%. Of the surgical interventions, 24 (27.3%) were major, 24 (27.3%) were minor and 40 (45.4%) were circumcision. We used fresh frozen plasma in 32, recombinant factor (rF)VIIa in 20, prothrombin complex concentrate in five and fibrinogen in three patients during surgical interventions. In 18 patients, antifibrinolytic agents were also used. In 27 patients, surgical interventions were applied without any replacement therapy. No additional doses were required after surgical prophylaxis doses. Thrombotic events were not observed. Antibody occurrence was not detected in these patients. In our study, we evaluated preparation for surgical procedures, factor replacement therapy before surgical intervention and postoperative follow-up in patients with rare coagulation factor deficiency. PMID- 24158120 TI - Circulating leptin concentrations in patients with chronic obstructive pulmonary disease: a systematic review and meta-analysis. AB - BACKGROUND: Weight loss is a clinically important risk factor indicating a poor prognosis in chronic obstructive pulmonary disease (COPD). Leptin is an important regulator of food intake and energy expenditure. OBJECTIVES: To conduct a meta analysis to determine whether the level of leptin is related to the disease status of COPD. METHODS: Studies published before December 2012 were identified by searching PubMed, Embase and the Cochrane Database. Observational studies comparing circulating leptin levels between COPD patients and healthy controls were included. Data were independently extracted by two investigators and analyzed using Stata 12.0 software. RESULTS: Ten articles were included in the meta-analysis. Circulating leptin levels were correlated with the body mass index (BMI) as well as percent fat mass in stable COPD patients. The correlation coefficient tended to be weaker during exacerbation. A positive correlation between leptin and tumor necrosis factor (TNF)-alpha levels was found in COPD exacerbations, while it disappeared in patients with stable disease. Most studies indicated that circulating leptin levels in stable COPD patients were not significantly different from those in healthy controls when adjusted for gender and BMI, whilst leptin levels tended to elevate in exacerbation groups. CONCLUSIONS: The normal regulatory mechanism of leptin is maintained in stable COPD patients despite weight loss. The additional correlation between leptin and TNF-alpha during exacerbations may support the closer association of leptin with changes in nutritional parameters and suggests its valuable role in the evaluation of systemic inflammatory responses in COPD patients during exacerbation, which merits further study. PMID- 24158122 TI - Skipping breakfast and overweight in 2- and 5-year-old Dutch children-the GECKO Drenthe cohort. AB - Skipping breakfast is associated with higher BMI in children aged 5 years and older. However, not much is known about this association in younger children. In the Dutch GECKO Drenthe birth cohort we examined the association between breakfast skipping and objectively measured overweight at the age of 2 (n=1488) and 5 (n=1366) years. At 2 years, 124 (8.3%) children were overweight and 44 (3.0%) did not eat breakfast daily. At 5 years, 180 (13.2%) children were overweight and 73 (5.3%) did not eat breakfast daily. Children belonging to families of non-Dutch origin, those with lower educated parents and those with single parents skipped breakfast more often. Breakfast skipping in 2- and 5-year olds is rare in the Netherlands. We found no association between skipping breakfast and overweight, neither at age 2 (odds ratio (OR): 1.85 (95% confidence interval (CI): 0.61-5.64)) nor at age 5 (OR: 0.46 (95% CI: 0.19-1.11)). Also the type of breakfast was not related to overweight at 5 years. An explanation for this finding might be that skipping breakfast is not (yet) an issue in these children. PMID- 24158123 TI - Involvement of protein kinase A and C in norepinephrine- and angiotensin II induced modulation of cardiac IKs. AB - BACKGROUND/AIMS: The slow component of the delayed rectifier K(+) current (IKs) is one of the major repolarizing currents in the heart. Yet, the signaling mechanisms for norepinephrine- and angiotensin II-induced modulation of IKs in cardiac myocytes are far from being well understood. METHODS: The whole-cell patch clamp technique was used to study the effects of norepinephrine and angiotensin II on IKs in guinea pig cardiac myocytes. RESULTS: Both the alpha1- and beta-adrenoceptor inhibitors attenuated norepinephrine-induced enhancement of IKs, which was also significantly depressed by inhibitors of protein kinase A and C. Angiotensin II-induced inhibition of the IKs was inhibited by angiotensin type 1 receptor blocker losartan and protein kinase C inhibitor. CONCLUSIONS: Norepinephrine and angiotensin II modulated IKs with opposite effects and distinct mechanisms. The activation of protein kinase A was the major component of the norepinephrine-induced activation of IKs while the activation of protein kinase C was responsible for the angiotensin II-induced inhibition of IKs. There was crosstalk between the alpha1- and beta-adrenoceptor that also contributed to the norepinephrine-induced enhancement of IKs. This current study provides new insight into the cellular signaling mechanisms of norepinephrine and angiotensin II, the two important modulators of cardiovascular function. PMID- 24158121 TI - Newborns of obese parents have altered DNA methylation patterns at imprinted genes. AB - BACKGROUND: Several epidemiologic studies have demonstrated associations between periconceptional environmental exposures and health status of the offspring in later life. Although these environmentally related effects have been attributed to epigenetic changes, such as DNA methylation shifts at imprinted genes, little is known about the potential effects of maternal and paternal preconceptional overnutrition or obesity. OBJECTIVE: We examined parental preconceptional obesity in relation to DNA methylation profiles at multiple human imprinted genes important in normal growth and development, such as: maternally expressed gene 3 (MEG3), mesoderm-specific transcript (MEST), paternally expressed gene 3 (PEG3), pleiomorphic adenoma gene-like 1 (PLAGL1), epsilon sarcoglycan and paternally expressed gene 10 (SGCE/PEG10) and neuronatin (NNAT). METHODS: We measured methylation percentages at the differentially methylated regions (DMRs) by bisulfite pyrosequencing in DNA extracted from umbilical cord blood leukocytes of 92 newborns. Preconceptional obesity, defined as BMI ?30 kg m(-2), was ascertained through standardized questionnaires. RESULTS: After adjusting for potential confounders and cluster effects, paternal obesity was significantly associated with lower methylation levels at the MEST (beta=-2.57; s.e.=0.95; P=0.008), PEG3 (beta=-1.71; s.e.=0.61; P=0.005) and NNAT (beta=-3.59; s.e.=1.76; P=0.04) DMRs. Changes related to maternal obesity detected at other loci were as follows: beta-coefficient was +2.58 (s.e.=1.00; P=0.01) at the PLAGL1 DMR and 3.42 (s.e.=1.69; P=0.04) at the MEG3 DMR. CONCLUSION: We found altered methylation outcomes at multiple imprint regulatory regions in children born to obese parents, compared with children born to non-obese parents. In spite of the small sample size, our data suggest a preconceptional influence of parental life style or overnutrition on the (re)programming of imprint marks during gametogenesis and early development. More specifically, the significant and independent association between paternal obesity and the offspring's methylation status suggests the susceptibility of the developing sperm for environmental insults. The acquired imprint instability may be carried onto the next generation and increase the risk for chronic diseases in adulthood. PMID- 24158124 TI - The role of fibroblast growth factor 23 in chronic kidney disease-mineral and bone disorder. AB - Fibroblast Growth Factor 23 (FGF-23) is a bone-derived hormone involved in the regulation of phosphate homeostasis. FGF-23 levels are extremely elevated in Chronic Kidney Disease (CKD) and there is evidence supporting the role of this hormone in the pathogenesis of Chronic Kidney Disease-Mineral and Bone Disorder (CKD-MBD). Furthermore, recent data associates FGF-23 with the pathogenesis of systemic complications of CKD-MBD. The increasing evidence that the consequences of abnormal mineral metabolism are not restricted to bone disease changed the approach to the pathophysiology and treatment of disturbed bone and mineral metabolism in CKD patients. FGF-23 has been proposed to be the initial adaptive response in early CKD to protect the organism from the adverse effects of phosphate retention. Increased levels of FGF-23 observed in CKD patients are associated with cardiovascular mortality risk and was shown to mediate direct, "off-target" toxicity to the heart. This report aims to review the relevant aspects of the physiology of FGF-23 in bone biology and mineral homeostasis and the role of FGF-23 in the pathophysiology of CKD-BMD and its clinical implications. PMID- 24158125 TI - MicroRNAs in the kidney: novel biomarkers of acute kidney injury. AB - microRNAs are small, endogenous RNA molecules which are critical for a new step in the regulation of the gene expression. They have become the most critical biological mediators characterized in the last ten years. microRNAs participate in almost every cellular process, therefore their deregulation is associated with the development of a wide range of pathologies, including kidney diseases. Increasing evidence demonstrates that microRNAs are key regulators of the normal kidney function and development, but they are also at the basis of several renal diseases. Recent works have established that these molecules can be secreted to extracellular environments, enabling their detection in peripheral body fluids such as urine and serum. Moreover, circulating miRNAs detected in body fluids turn into suitable biomarkers of kidney diseases, including acute kidney injury. This new generation of renal biomarkers could have a great impact in the clinical practice, significantly contributing to improve patient management. In this review, we discuss over the implication of microRNAs in normal kidney function and homeostasis as well as the role of circulating miRNAs as novel biomarkers of kidney diseases, focusing on their potential usefulness in acute kidney injury management. PMID- 24158126 TI - Perspective on rhabdomyolysis-induced acute kidney injury and new treatment options. AB - AIM: The purpose of this study was to assess the role of caspase-dependent apoptosis, caspase 1, calpain 1, inducible nitric oxide synthase (iNOS) and endothelial nitric oxide synthase (eNOS) and the protective effect of grape seed proanthocyanidin extract (GSPE) in the development of rhabdomyolysis-induced acute kidney injury (AKI). MATERIALS AND METHODS: Twenty-one rats were divided into 3 groups - control, rhabdomyolysis and rhabdomyolysis + GSPE. Rhabdomyolysis was induced in the rhabdomyolysis and rhabdomyolysis + GSPE groups with the injection into both hind limbs of 10 ml/kg hypertonic (50%) glycerol following 24 hour dehydration on the 6th day. The rhabdomyolysis + GSPE group was given GSPE at 100 mg/kg by gavage for 7 days. The experiment was concluded 48 h after glycerol injection. Blood specimens were collected, and kidney tissues were extracted for histopathological examination. RESULTS: We identified an increase in blood urea nitrogen, creatinine, histopathological score, iNOS, caspase 3, caspase 1 and calpain 1 expression in the rhabdomyolysis group compared to the controls and a decrease in eNOS expression. In the rhabdomyolysis + GSPE group, however, there was a decrease in these mediators, together with an increase in eNOS expression. CONCLUSION: This study shows for the first time in the literature that calpain 1 is involved in the pathogenesis of rhabdomyolysis induced AKI, and that GSPE may have a renoprotective effect. PMID- 24158127 TI - With care and compassion: adolescent sexual assault victims' experiences in Sexual Assault Nurse Examiner programs. AB - In this study, we conducted in-depth qualitative interviews with 20 adolescent sexual assault patients aged 14-17 years who sought postassault medical forensic examinations at one of two Midwestern Sexual Assault Nurse Examiner programs. Our goals were to examine how adolescent victims characterized the quality of the emotional/interpersonal care they received and to identify specific aspects of Sexual Assault Nurse Examiner nursing practice that were helpful and healing. Overall, the patients had very positive experiences with both programs. The nurses were sensitive to their patients' physical and emotional needs throughout the examination. The adolescents also noted that the nurses were compassionate, caring, and personable. Finally, the survivors deeply appreciated that the nurses believed and validated their accounts of the assault. These findings suggest that compassionate care must be developmentally informed, such that basic patient centered practices (e.g., belief and validation) are age sensitive and age appropriate. PMID- 24158128 TI - A comparative analysis of victims of sexual assault with and without mental health histories: acute and follow-up care characteristics. AB - Sexual assault is a common and serious health issue that is underreported and has low follow-up rates. The myriad of psychological sequelae of sexual assault are well documented; however, there is a dearth of literature on the prevalence of preexisting mental health issues in survivors of sexual assault. This exploratory study compares victims seen at a sexual assault treatment center with and without preexisting self-reported mental health histories. The rates of preexisting mental illness in sexual assault victims are significant. Implications for clinical practice and research are discussed. PMID- 24158129 TI - Injury patterns and causal mechanisms of bruising in physical elder abuse. AB - The recognition of injury patterns can aid forensic nurses to identify victims of elder abuse. This study examined the mechanism of injury of bruises endured by physical elder abuse victims. A sample of 67 elders aged 65 years and older who reported to Adult Protective Services for physical elder abuse was included in the analysis. A research nurse conducted assessments and documented the presence and characteristics of all bruises. Data regarding the abusive incident were collected through victim descriptions and the Revised Conflicts Tactic Scales (CTS2) physical assault scale. The most common bruising locations were the lateral/anterior arms (n = 23, 34.3%), head and neck (n = 10, 14.9%), and posterior torso (n = 7, 10.4%). Victims' odds of having head and neck bruises were greater when reporting being choked (OR = 7.71, 95% CI [1.29, 45.90], p = 0.039), punched (OR = 13.53, 95% CI [2.55, 71.80], p = 0.001), and beaten up (OR = 5.60, 95% CI [3.26, 74.45], p = 0.001). The odds of having lateral/anterior arm bruises were eight times greater when the victim reported being grabbed (OR = 8.43, 95% CI [2.67, 26.65], p < 0.001). The findings suggest similarities between injuries experienced in elder abuse and those in intimate partner violence. Findings highlight injury patterns that elder abuse victims sustain and can be informative for forensic nurses. PMID- 24158130 TI - Evaluation of personality disorder workshops in Essex, England: reported impacts on clinical practice. AB - In this paper we examine the background and context for training related to working with people with personality disorders in England. People with a diagnosis of personality disorder often feel excluded from mainstream health, social and employment contexts, and sometimes experience negative and stigmatizing attitudes from people, including health and social care workers. An evaluation of a program of workshops for forensic nurses and other practitioners was carried out to ascertain how effective the workshops were in challenging attitudes and also in potentially promoting better practice in working with this client group. The evaluation was designed utilizing the principles of illuminative evaluation and involved an analysis of workshop evaluation forms and telephone interviews with course participants. The course received very positive evaluations and participants described how it challenged their beliefs, promoting therapeutic optimism, understanding, and more positive partnerships. Key factors in achieving this were adopting a team approach to the training and service user participation in the workshops. Drawing on our experiences and a wide range of literature, we illustrate the importance of service user involvement in teaching and promoting more positive attitudes, and we outline further areas for investigation. PMID- 24158131 TI - The evolution of a labyrinth walking program in corrections. AB - The development and expansion of labyrinth walking in corrections has signaled a milestone in the treatment of offenders, particularly those incarcerated for substance abuse-related offenses. In this article we describe the evolution of the labyrinth walking program from its inception highlighting: curriculum development and refinement, evidence-based and program evaluation findings. Methods used in working with key stakeholders are illustrated to both implement and evaluate labyrinth walking, and to identify future directions. PMID- 24158132 TI - Advocating for pregnant women in prison: the role of the correctional nurse. AB - On any given day, approximately 6%-10% of women who are incarcerated in prisons and jails in the United States are pregnant. Although incarcerated pregnant women have been identified as a high-risk group because of compromised physical and emotional health when they enter these settings, their specific healthcare needs are frequently unmet or partially met during their imprisonment. Stressors imposed by prison life and separation from their newborn at birth often exacerbate existing mental health issues including posttraumatic stress disorder, depression, anxiety, and insomnia. Nurses in correctional settings play a strategic role in improving the health care of this population by promoting teamwork, incorporating standards of care, and advocating for changes in policies. Collaboration with the warden, physician or nurse practitioner, correctional officers, and social workers can lead to positive changes in health outcomes. Given the national emphasis on gender responsive treatment in prisons and jails, a window of opportunity exists to be a voice for these women and make significant changes in health care for this largely underserved [corrected] population. PMID- 24158133 TI - Stress management techniques in the prison setting. AB - BACKGROUND: The percentage of incarcerated individuals in the United States is currently close to an all time high, and more stressful places than prisons are hard to find. Because registered nurses and advance practice nurses are often the only healthcare providers readily available to prison inmates, nurses need a repertoire of effective strategies to minimize prisoners' stress-related symptoms and behaviors. PURPOSE: The purpose of this critical literature review was to identify the state of knowledge about using stress management techniques (SMTs) in the prison setting for reducing psychological problems and/or behavioral problems in male and female adult prison populations. METHODS: A comprehensive, systematic integrated literature search was performed using multiple relevant databases to identify studies using various SMTs for incarcerated adults. FINDINGS: Although clinical practice recommendations for the use of SMTs in the prison setting cannot be made with strong certainty, nurses working in the prison setting should continue to incorporate muscle relaxation, Transcendental Meditation, and certain Eastern meditative practices in the care of their clients because of the safety and possible positive impacts and practicality these methods have in this setting. PMID- 24158134 TI - Development of the Commonwealth of Puerto Rico National Protocol for the Management of Victims of Sexual Violence: Adults/Adolescents. AB - Sexual violence is a public health problem in Puerto Rico (PR), with an incidence of 7.4 cases for every 10,000 people during 2005-2006 (Departamento de Salud Secretaria Auxiliar de Salud Familiar y Servicios Integrados, 2007). Findings from the literature review indicated that the traditional model of care provided to the victims of sexual violence in the Emergency Department is incomplete; furthermore, it may cause revictimization because of the attitudes, behaviors, and practices of the community service providers, resulting in additional trauma. Emerging evidence demonstrates that Sexual Assault Nurse Examiner (SANE) programs are providing effective quality care. In PR, SANEs do not intervene in sexual assault cases; nevertheless, the Department of Health of PR has recognized the importance of SANE intervention. Consequently, there is a need for current evidence-based protocols and standards of care to describe the procedures, roles, and responsibilities for the provision of quality care to victims. This project involves the implementation of the Stufflebeam's Context-Input-Process-Product Model in the creation of the Commonwealth of Puerto Rico National Protocol for the Management of Victims of Sexual Violence: Adults/Adolescents. PMID- 24158136 TI - Promoting ethical integrity in publishing. PMID- 24158137 TI - Tuning a layer to a pillared-layer metal-organic framework for adsorption and separation of light hydrocarbons. AB - Rational assembly from a layer structure to a pillared-layer metal-organic framework affords an ideal microporous material with large Langmuir surface area for highly selective separation of hydrocarbons. PMID- 24158139 TI - Chitosan confinement enhances hydrogen photogeneration from a mimic of the diiron subsite of [FeFe]-hydrogenase. AB - Nature has created [FeFe]-hydrogenase enzyme as a hydrogen-forming catalyst with a high turnover rate. However, it does not meet the demands of economically usable catalytic agents because of its limited stability and the cost of its production and purification. Synthetic chemistry has allowed the preparation of remarkably close mimics of [FeFe]-hydrogenase but so far failed to reproduce its catalytic activity. Most models of the active site represent mimics of the inorganic cofactor only, and the enzyme-like reaction that proceeds within restricted environments is less well understood. Here we report that chitosan, a natural polysaccharide, improves the efficiency and durability of a typical mimic of the diiron subsite of [FeFe]-hydrogenase for photocatalytic hydrogen evolution. The turnover number of the self-assembling system increases ~4,000 fold compared with the same system in the absence of chitosan. Such significant improvements to the activity and stability of artificial [FeFe]-hydrogenase-like systems have, to our knowledge, not been reported to date. PMID- 24158138 TI - Correlation between ABCD, ABCD2 scores and craniocervical artery stenosis in patients with transient ischemic attack. AB - BACKGROUND AND PURPOSE: Craniocervical artery stenosis is an important etiology for transient ischemic attack (TIA). We hypothesized ABCD and ABCD2 scores can predict craniocervical artery stenosis in patients with TIA. METHODS: ABCD and ABCD2 scores were calculated in a total of 479 consecutive first-ever TIA patients in Nanjing Stroke Registry Program and compared with angiographic imaging derived from MRI or invasive catheter-based angiography. RESULTS: Overall craniocervical artery (O-CA) stenosis was found in 197 (41.1%) patients. Extracranial craniocervical artery (E-CA) and intracranial craniocervical artery (I-CA) stenosis was found in 101 (21.1%) and 110 (23%) cases, respectively. ABCD and ABCD2 scores with similar accuracy for O-CA (AUCABCD 0.71, AUCABCD2 0.70), E CA (AUCABCD 0.72, AUCABCD2 0.72) and I-CA stenosis (AUCABCD 0.62, AUCABCD2 0.62) were both independent predictors for various categories of artery stenosis after being adjusted for non-ABCD2 parameters. The cut-off points were equally 4 in both predicting rules. For ABCD, sensitivity was 57.4, 65.3 and 52.7% and specificity 77.0, 70.4 and 67.5% for O-CA/E-CA/I-CA, respectively. For ABCD2, sensitivity was 61.9, 69.3 and 58.2% and specificity 72.3, 65.6 and 63.1%. CONCLUSIONS: In patients with TIA, despite an association between ABCD and ABCD2 scores and underlying craniocervical artery stenosis, the clinical utility was limited by unsatisfactory sensitivity and specificity. PMID- 24158140 TI - 5-Hydroxytryptamine 1A and 2B serotonin receptors in neurite outgrowth: involvement of early growth response protein 1. AB - Neurotransmitters play important roles in neurogenesis; in particular, acetylcholine and serotonin may regulate neurite elongation. Acetylcholine may also activate transcription factors such as early growth response protein 1 (EGR 1), which plays a role in neurite extension. N18TG2 neuroblastoma cells (which do not produce neurotransmitters and constitutively express muscarinic acetylcholine receptors) were transfected with constructs containing the cDNA for choline acetyltransferase, 5-hydroxytryptamine 1A (5-HT1A) and 5-HT2B serotonin receptors to study acetylcholine and serotonin interplay in neurite outgrowth. 5-HT1A receptor stimulation causes a decrease in EGR-1 levels and inhibition of neurite outgrowth; 5-HT2B stimulation, however, has no effect. Muscarinic cholinergic stimulation, on the other end, increases EGR-1 levels and fiber outgrowth. Inhibition of EGR-1 binding reduces fiber outgrowth activity. When both cholinergic and 5-HT1A receptors are stimulated, fiber outgrowth is restored; therefore, acetylcholine counterbalances the inhibitory effect of serotonin on neurite outgrowth. These results suggest that EGR-1 plays a role in the interplay of acetylcholine and serotonin in the regulation of neurite extension during development. PMID- 24158141 TI - Botulinum toxin A inhibits salivary secretion of rabbit submandibular gland. AB - Botulinum toxin A (BTXA) has been used in several clinical trials to treat excessive glandular secretion; however, the precise mechanism of its action on the secretory function of salivary gland has not been fully elucidated. In this study, we aimed to investigate the effect of BTXA on secretion of submandibular gland in rabbits and to identify its mechanism of action on the secretory function of salivary gland. At 12 weeks after injection with 5 units of BTXA, we found a significant decrease in the saliva flow from submandibular glands, while the salivary amylase concentration increased. Morphological analysis revealed reduction in the size of acinar cells with intracellular accumulation of secretory granules that coalesced to form a large ovoid structure. Expression of M3-muscarinic acetylcholine receptor (M3 receptor) and aquaporin-5 (AQP5) mRNA decreased after BTXA treatment, and distribution of AQP5 in the apical membrane was reduced at 1, 2 and 4 weeks after BTXA injection. Furthermore, BTXA injection was found to induce apoptosis of acini. These results indicate that BTXA decreases the fluid secretion of submandibular glands and increases the concentration of amylase in saliva. Decreased expression of M3 receptor and AQP5, inhibition of AQP5 translocation, and cell apoptosis might involve in BTXA reduced fluid secretion of submandibular glands. PMID- 24158142 TI - Effect of colouring green stage zirconia on the adhesion of veneering ceramics with different thermal expansion coefficients. AB - This study evaluated the adhesion of zirconia core ceramics with their corresponding veneering ceramics, having different thermal expansion coefficients (TECs), when zirconia ceramics were coloured at green stage. Zirconia blocks (N=240; 6 mm*7 mm*7 mm) were manufactured from two materials namely, ICE Zirconia (Group 1) and Prettau Zirconia (Group 2). In their green stage, they were randomly divided into two groups. Half of the specimens were coloured with colouring liquid (shade A2). Three different veneering ceramics with different TEC (ICE Ceramic, GC Initial Zr and IPS e.max Ceram) were fired on both coloured and non-coloured zirconia cores. Specimens of high noble alloys (Esteticor Plus) veneered with ceramic (VM 13) (n=16) acted as the control group. Core-veneer interface of the specimens were subjected to shear force in the Universal Testing Machine (0.5 mm?min(-1)). Neither the zirconia core material (P=0.318) nor colouring (P=0.188) significantly affected the results (three-way analysis of variance, Tukey's test). But the results were significantly affected by the veneering ceramic (P=0.000). Control group exhibited significantly higher mean bond strength values (45.7+/-8) MPa than all other tested groups ((27.1+/-4.1) (39.7+/-4.7) and (27.4+/-5.6)-(35.9+/-4.7) MPa with and without colouring, respectively) (P<0.001). While in zirconia-veneer test groups, predominantly mixed type of failures were observed with the veneering ceramic covering <1/3 of the substrate surface, in the metal-ceramic group, veneering ceramic was left adhered >1/3 of the metal surface. Colouring zirconia did not impair adhesion of veneering ceramic, but veneering ceramic had a significant influence on the core veneer adhesion. Metal-ceramic adhesion was more reliable than all zirconia veneer ceramics tested. PMID- 24158143 TI - Interferon-gamma and interleukin-4 detected in serum and saliva from patients with oral lichen planus. AB - Our previous salivary study had demonstrated an apparent T helper 2 (Th2) predominance in saliva of oral lichen planus (OLP) patients and suggested a potential of salivary interleukin-4 (IL-4) as a biomarker for monitoring disease severity. To further determine the consistency of Th1/Th2 bias of OLP, this study investigated the expression profile of interferon-gamma (IFN-gamma) and IL-4 in serum and the relationship of the serum levels of these cytokines with their saliva partners. Sixty ethnic Chinese patients with OLP (40 of the erythematous/ulcerative form and 20 of the reticular form) were recruited for this study, with 40 age-sex-matched healthy volunteers as control group. IFN gamma and IL-4 levels in serum and paired saliva samples were screened by enzyme linked immunosorbent assay. OLP patient showed a low-level IFN-gamma but high level IL-4 expression profile in both serum and saliva, with a lower IFN-gamma/IL 4 ratio. Serum IL-4 level in the erythematous/ulcerative group was significantly higher than that in the reticular group. Serum levels of IFN-gamma and IL-4 were significantly and positively correlated with their saliva partners. These results provided more evidence for Th2 cytokine-predominant immune imbalance in OLP, as well as the potential of IL-4 as the biomarker for monitoring severity of OLP. PMID- 24158145 TI - Attenuated plaque is associated with plaque prolapse accompanied by cardiac enzyme elevation after drug-eluting stent implantation. AB - OBJECTIVES: This study aimed to evaluate the relationship between grayscale intravascular ultrasound-attenuated plaque (AP) and poststenting plaque prolapse (PP) as well as their influence on creatine kinase-myocardial band (CK-MB) elevation after drug-eluting stent (DES) implantation. BACKGROUND: The relationship between baseline AP and poststenting PP and their impacts on percutaneous coronary intervention (PCI) are not well known. PATIENTS AND METHODS: A total of 141 single, native, de-novo coronary lesions in 141 patients with normal pre-PCI CK-MB levels who underwent intravascular ultrasound before and after DES implantation were studied. RESULTS: AP was found in 72 (51.1%) lesions and PP occurred in 43 (30.5%) lesions. Baseline AP was associated with greater plaque area, lesion eccentricity, and positive remodeling, and was associated with higher frequency of poststenting PP (47.2 vs. 13.0%, P<0.001) as well as greater poststenting PP volume (2.2+/-1.3 vs. 1.9+/-1.1 mm, P=0.045). Elevated CK-MB levels were observed in 34 (24.1%) lesions and significantly more frequently in patients with baseline AP and poststenting PP than without both of these findings. Multivariate analysis indicated that AP with PP was the predictor of post-PCI CK-MB elevation. CONCLUSION: Baseline AP was associated with high risk characteristics, higher frequency, and greater volume of poststenting PP accompanied by CK-MB elevation in patients with DES implantation. PMID- 24158146 TI - Inactivation of pyruvate kinase or the phosphoenolpyruvate: sugar phosphotransferase system increases shikimic and dehydroshikimic acid yields from glucose in Bacillus subtilis. AB - The glycolytic intermediate phosphoenolpyruvate (PEP) is a precursor of several cellular components, including various aromatic compounds. Modifications to the PEP node such as PEP:sugar phosphotransferase system (PTS) or pyruvate kinase inactivation have been shown to have a positive effect on aromatics production capacity in Escherichia coli and Bacillus subtilis. In this study, pyruvate kinase and PTS-deficient B. subtilis strains were employed for the construction of derivatives lacking shikimate kinase activity that accumulate two industrially valuable chemicals, the intermediates of the common aromatic pathway, shikimic and dehydroshikimic acids. The pyruvate kinase-deficient strain (CLC6-PYKA) showed the best production parameters under resting-cell conditions. Compared to the PTS-deficient strain, the shikimic and dehydroshikimic acids specific production rates for CLC6-PYKA were 1.8- and 1.7-fold higher, respectively. A batch fermentor culture using complex media supplemented with 83 g/l of glucose was developed with strain CLC6-PYKA, where final titers of 4.67 g/l (shikimic acid) and 6.2 g/l (dehydroshikimic acid) were produced after 42 h. PMID- 24158144 TI - KDM6B epigenetically regulates odontogenic differentiation of dental mesenchymal stem cells. AB - Mesenchymal stem cells (MSCs) have been identified and isolated from dental tissues, including stem cells from apical papilla, which demonstrated the ability to differentiate into dentin-forming odontoblasts. The histone demethylase KDM6B (also known as JMJD3) was shown to play a key role in promoting osteogenic commitment by removing epigenetic marks H3K27me3 from the promoters of osteogenic genes. Whether KDM6B is involved in odontogenic differentiation of dental MSCs, however, is not known. Here, we explored the role of KDM6B in dental MSC fate determination into the odontogenic lineage. Using shRNA-expressing lentivirus, we performed KDM6B knockdown in dental MSCs and observed that KDM6B depletion leads to a significant reduction in alkaline phosphate (ALP) activity and in formation of mineralized nodules assessed by Alizarin Red staining. Additionally, mRNA expression of odontogenic marker gene SP7 (osterix, OSX), as well as extracellular matrix genes BGLAP (osteoclacin, OCN) and SPP1 (osteopontin, OPN), was suppressed by KDM6B depletion. When KDM6B was overexpressed in KDM6B knockdown MSCs, odontogenic differentiation was restored, further confirming the facilitating role of KDM6B in odontogenic commitment. Mechanistically, KDM6B was recruited to bone morphogenic protein 2 (BMP2) promoters and the subsequent removal of silencing H3K27me3 marks led to the activation of this odontogenic master transcription gene. Taken together, our results demonstrated the critical role of a histone demethylase in the epigenetic regulation of odontogenic differentiation of dental MSCs. KDM6B may present as a potential therapeutic target in the regeneration of tooth structures and the repair of craniofacial defects. PMID- 24158147 TI - A large aspergilloma. PMID- 24158148 TI - Gene flow and genetic diversity in cultivated and wild cacao (Theobroma cacao) in Bolivia. AB - PREMISE OF THE STUDY: The role of pollen flow within and between cultivated and wild tropical crop species is little known. To study the pollen flow of cacao, we estimated the degree of self-pollination and pollen dispersal distances as well as gene flow between wild and cultivated cacao (Theobroma cacao L.). METHODS: We studied pollen flow and genetic diversity of cultivated and wild cacao populations by genotyping 143 wild and 86 cultivated mature plants and 374 seedlings raised from 19 wild and 25 cultivated trees at nine microsatellite loci. KEY RESULTS: A principal component analysis distinguished wild and cultivated cacao trees, supporting the notion that Bolivia harbors truly wild cacao populations. Cultivated cacao had a higher level of genetic diversity than wild cacao, presumably reflecting the varied origin of cultivated plants. Both cacao types had high outcrossing rates, but the paternity analysis revealed 7-14% self-pollination in wild and cultivated cacao. Despite the tiny size of the pollinators, pollen was transported distances up to 3 km; wild cacao showed longer distances (mean = 922 m) than cultivated cacao (826 m). Our data revealed that 16-20% of pollination events occurred between cultivated and wild populations. CONCLUSIONS: We found evidence of self-pollination in both wild and cultivated cacao. Pollination distances are larger than those typically reported in tropical understory tree species. The relatively high pollen exchange from cultivated to wild cacao compromises genetic identity of wild populations, calling for the protection of extensive natural forest tracts to protect wild cacao in Bolivia. PMID- 24158149 TI - Crafting moral communities in forensic nursing. PMID- 24158150 TI - "She was truly an angel": Women with disabilities' satisfaction with hospital based sexual assault and domestic violence services. AB - INTRODUCTION: Little is known about the characteristics of women with disabilities who have experienced abuse and their satisfaction with care received from specialized healthcare providers working in hospital-based violence services. METHOD: To address this gap, we surveyed clients presenting to 30 sexual assault/domestic violence treatment centers (SA/DVTCs) in Ontario. RESULTS: Of the 920 women aged 12 years or older who completed a survey, 194 (21%) reported having a disability. Bivariate analyses revealed that women with a disability who experienced abuse were more likely than those without a disability to be older, separated, widowed or divorced, and unemployed; to live alone or to be homeless or living in a shelter; and to report less support from family and friends or colleagues. Women with disabilities were less likely to have been assaulted by acquaintances known for < 24 hours, to be students, and to have been accompanied to the SA/DVTC by another person. Women with disabilities were also more likely than those without disabilities to sustain physical injuries in the assault. Despite these significant differences, almost all women with disabilities rated the care received as excellent or good (97%) and reported that they received the care needed (98%); were able to choose the preferred care (95%); felt safe during the visit (96%); and were treated sensitively (97%), respectfully (96%), and in a nonjudgmental manner (96%). Furthermore, 96% stated that they would recommend the services to others. CONCLUSION: Women with disabilities were overwhelmingly satisfied with SA/DVTC services. However, given their distinct vulnerabilities and increased risk of being injured, attending health providers should receive training relevant to working with this population. PMID- 24158151 TI - Use of an alternative light source to assess strangulation victims. AB - Alternative light sources (ALSs) are commonly used at crime scenes and in forensic laboratories to collect evidence such as latent fingerprints, body fluids, hair, and fibers. This article describes the use of this technology to reveal soft tissue injuries that are not visible to the naked or unaided eye in patients who report strangulation. The value of this information to the medical, nursing, and judicial systems is discussed. The records of the 172 strangulation patients seen in our forensic nurse examiner program between 2009 and 2010 were reviewed. The SPEX Crimescope (SPEX Forensics, Edison, New Jersey) was used during the assessment of all of them. Ninety-three percent of the patients had no visible evidence of external injuries on physical examination. The ALS revealed positive findings of intradermal injuries in 98% of that group. Information obtained with ALS devices helps medical and nursing practitioners understand the gravity of patients' injuries, influences medical treatment decisions and follow up care, and supports the prosecution of the perpetrators of crimes of violence. Educational programs about the application of ALS and the interpretation of its findings are valuable for medical, nursing, and other forensic disciplines. PMID- 24158152 TI - Intersection of HPV and sexual assault: an opportunity for practice change. AB - BACKGROUND: An opportunity exists for nurses to integrate HPV education and prevention strategies into the care for adolescent and young adult sexual assault patients. STUDY DESIGN: An exploratory, cross-sectional, E-mail survey was conducted to explore forensic nurses' (1) level of support and (2) facilitators and barriers that may influence nurses' level of support regarding incorporating HPV preventative strategies into their care. Eligibility for inclusion was nurse members of the International Association of Forensic Nurses who are stakeholders in the care of sexual assault patients. RESULTS: 541 nurses completed the survey. 98% were supportive of at least providing patients with written educational information regarding HPV and the HPV vaccine; 86% were supportive of providing written information plus making changes to the discharge instructions to incorporate HPV vaccination recommendations; and 53% were supportive of providing written information, making changes to the discharge instructions, and initiating HPV vaccination at the point of care. The strongest predictor of level of support was having positive perceived benefits for HPV vaccination. A one standard deviation increase in perceived benefit was associated with a 50% increased odds of having the highest level of support (OR = 1.5, CI [1.1, 1.9]). CONCLUSIONS: Nurses provide care for many adolescent and young adult sexual assault patients who are at risk for acquiring HPV and are within the age range for HPV vaccination. There is an opportunity to update current practice guidelines and recommendations. The nurses in this national sample were overwhelmingly supportive of integrating HPV prevention strategies into care. PMID- 24158153 TI - Total control: a critical analysis of mandatory HIV testing in U.S. prisons. AB - The aim of this paper is to explore the relationship between mandatory HIV testing and the institutional management of inmates in U.S. prisons. Mandatory HIV testing has been largely overlooked by the nursing community even though it has important human rights and ethical implications. Drawing on the work of Goffman (1990) on the inner workings of total institutions, the present article critically examines the deployment of mandatory HIV testing in U.S. prisons. To set the stage, we define mandatory HIV testing and describe the methods of HIV testing currently used in U.S. prison settings. Then, we provide a brief overview of the concept of total institution and the mortification process. Finally, we expand on the relationship between mandatory HIV testing and much larger institutional objectives of total control, total structuring, total isolation, and separation of inmates from society (as summarized by Farrington, 1992). And lastly, we provide a brief discussion on the implications of mandatory HIV testing (as a method of HIV testing) from a nursing perspective. PMID- 24158155 TI - Standards of practice for forensic mental health nurses--identifying contemporary practice. AB - Forensic mental health nursing is a recognized field of nursing in most countries. Despite a growing body of literature describing aspects of practice, no publication has been found that captures the core knowledge, skills, and attitudes of forensic mental health nurses. One group of nurses in Australia have pooled their knowledge of relevant literature and their own clinical experience and have written standards of practice for forensic mental health nursing. This paper identifies the need for standards, provides a summary of the standards of practice for forensic mental health nurses, and concludes with how these standards can be used and can articulate to others the desired and achievable level of performance in the specialty area. PMID- 24158154 TI - Understanding correlates of hepatitis C virus infection among homeless recently paroled men. AB - This cross-sectional study assessed predictors of Hepatitis C virus (HCV) positivity with baseline data collected on recently released male parolees (N = 157) participating in a randomized trial focused on reduction of drug use, recidivism, and risk for hepatitis and HIV infections. In this sample, the prevalence of HCV was 25%. The logistic regression analysis revealed that being an injection drug user was significantly related to HCV infection. However, contrary to most of the current literature, being Black had significantly lower odds of contracting HCV than their White counterparts. Moreover, having lived on the streets, not being part of a close family in childhood, and being older were also associated with HCV infection. These findings highlight the need for skilled assessments that target the vulnerabilities of homeless adults, especially those who have been incarcerated. Understanding drug use patterns, childhood networks, and family relationships, may assist in the design of interventions to reduce risky drug use and address behaviors derived from disadvantaged childhood. PMID- 24158156 TI - Recantation: a case study. AB - This case study explores the problem of recantation, the act of publically declaring that a former disclosure is untrue. Recantation in child sexual abuse cases can be devastating for forensic teams who work with victims of sexual abuse and put the victims of CSA at increased risk of further child sexual abuse. Recanting complicates efforts to protect victims, or other potential victims. When recantation occurs, victims are often placed back in the situation where the abuse occurred, the perpetrator has continued access to the victim and the abuse continues. To prevent recantation, Forensic nurses should be involved in case from the time of disclosure until the case is completed. PMID- 24158157 TI - Forensic nursing interventions with patients with personality disorder: a holistic approach. AB - Research findings suggest that nursing assessment and care and psychotherapy of forensic patients with personality disorder should be based on a holistic approach that addresses a wide range of their needs. Such an approach should be in collaboration with patients, informal carers, and other professionals and informed by appropriate education, training, clinical supervision, and support. Holistic care includes areas (such as physical health, cultural, spiritual, and psychosexual needs) that are addressed to a limited extent in the literature on patients with personality disorder. Despite limitations in research evidence, findings suggest that some patients with personality disorder benefit from psychotherapies, sometimes facilitated by nurse-therapists, and therapeutic community principles. These interventions should take account of patients' cultural and spiritual needs and perspectives. Helping patients to manage anger has potentially positive consequences for their physical health, personal and work relationships, and other areas. Research is needed to consider how to deliver holistic care with limited resources and in organizations, such as prisons, with conflicting goals. PMID- 24158159 TI - A stable 16-electron iridium(III) hydride complex grafted on SBA-15: a single site catalyst for alkene hydrogenation. AB - The dihydride pincer complex [IrH2(POCOP)] reacts with surface silanols of mesoporous silica (SBA-15) to give the coordinatively unsaturated, yet stable hydridesiloxo Ir(III) species [IrH(O-SBA-15)(POCOP)]. The silica-grafted complex catalyses the hydrogenation of ethene and propene at low temperature and pressure without prior activation. PMID- 24158160 TI - Albuminuria and carotid atherosclerosis as predictors of cognitive function in a general population. AB - BACKGROUND/AIMS: Albuminuria and carotid atherosclerosis are predictors of cardiovascular disease and potential predictors of cognitive decline. Our aim was to study whether albuminuria was an early predictor of cognitive function independent of carotid atherosclerosis in a general population. METHODS: The study population comprised 1,577 adults without self-reported stroke. In 1994 and 2007 all were screened for cardiovascular risk factors, urinary albumin creatinine ratio (ACR), carotid intima-media thickness and carotid total plaque area (TPA). Endpoints were neuropsychological test results in 2007 from the digit symbol test, the finger-tapping test, the Mini Mental Status Examination and the 12-word test parts 1 and 2. Multivariate linear regression was used to assess associations. RESULTS: Higher ACR, DeltaACR, intima-media thickness, TPA and DeltaTPA independently predicted a lower score on the digit symbol test. Higher DeltaACR and DeltaTPA predicted a lower score on the finger-tapping test. Higher TPA predicted a lower score on the 12-word test part 1 (immediate recall). Smoking predicted lower scores on the digit symbol and finger-tapping tests independent of albuminuria and carotid atherosclerosis. CONCLUSIONS: Our results suggest that albuminuria, carotid atherosclerosis and smoking are independent predictors of executive function and motor tempo. PMID- 24158161 TI - Mycophenolate mofetil and valsartan inhibit podocyte apoptosis in streptozotocin induced diabetic rats. AB - AIM: To investigate the effects of mycophenolate mofetil on apoptosis and the expression of Bax and Bcl-2 of podocytes in rats with diabetic nephropathy. METHODS: A total of 40 male rats were randomly divided into two groups: healthy control group (NC, n = 8) and diabetic nephropathy group (DN, n = 32). The diabetic rat models were induced by streptozotocin, which was injected intraperitoneally. After the DN model was established successfully, the DN group was subdivided into four groups: (1) group treated with the dissolvent (DN), (2) group treated with mycophenolate mofetil (DN + M), (3) group treated with valsartan (DN + V) and (4) group treated with mycophenolate mofetil and valsartan (DN + MV). After 16 weeks of treatment, kidney and body weight, urinary protein level and serum glucose were measured. Histomorphology of renal tissue was observed by an optical microscope. Apoptosis of podocytes was determined by transferase-mediated dUTP nick-end labeling (TUNEL) test. The expression of nephrin and Wilms' tumor suppressor gene (WT1) were detected by immunohistochemistry and real-time PCR, and the protein expression of Bax and Bcl 2 were examined by Western blot. RESULTS: The mRNA and protein expression of nephrin and WT1 were both downregulated. The apoptosis rate, the expression of Bax, caspase-3 activity and cleavage increased, while the expression of Bcl-2 decreased in the DN group compared with the NC group. However, they were all improved in the groups treated with either mycophenolate mofetil or valsartan. CONCLUSION: Mycophenolate mofetil can protect renal function by increasing Bcl-2 expression and decreasing Bax expression and podocyte apoptosis rate, thereby reducing proteinuria. PMID- 24158162 TI - Impact of flow cytometry in thyroid cytopathology. AB - BACKGROUND: Fine-needle aspiration (FNA) is a useful diagnostic tool for preoperative evaluation of thyroid nodules. However, cytomorphology alone has poor accuracy for the diagnosis of lymphoproliferative disorders involving the thyroid. This study reviews our experience with flow cytometry on thyroid FNA and correlation with surgical follow-up at The Johns Hopkins Hospital. METHODS: The 11,118 thyroid FNAs performed over a 20-year period were reviewed for clinical flow cytometry data (n = 62) or a subsequent diagnosis of lymphoma in the thyroid without flow cytometry data (n = 2). RESULT: Sixty-four cases (0.6%) were included out of 11,118 thyroid FNAs collected over a 20-year period. Lymphoma was diagnosed 13 times. In 8 cases, both cytomorphology and flow cytometry arrived at the correct diagnosis. Cytomorphology alone made the correct diagnosis twice in the absence of flow cytometric results; flow cytometry made the diagnosis once in the absence of suspicious morphology. Neither flow cytometry nor cytomorphology made the correct diagnosis in 2 sparsely cellular cases. CONCLUSION: The combination of cytomorphology and flow cytometry is a useful diagnostic modality for the work-up of lymphocyte-rich thyroid nodules that show atypical lymphocyte populations. PMID- 24158163 TI - Measuring long-range carrier diffusion across multiple grains in polycrystalline semiconductors by photoluminescence imaging. AB - Thin-film polycrystalline semiconductors are currently at the forefront of inexpensive large-area solar cell and integrated circuit technologies because of their reduced processing and substrate selection constraints. Understanding the extent to which structural and electronic defects influence carrier transport in these materials is critical to controlling the optoelectronic properties, yet many measurement techniques are only capable of indirectly probing their effects. Here we apply a novel photoluminescence imaging technique to directly observe the low temperature diffusion of photocarriers through and across defect states in polycrystalline CdTe thin films. Our measurements show that an inhomogeneous distribution of localized defect states mediates long-range hole transport across multiple grain boundaries to locations exceeding 10 MUm from the point of photogeneration. These results provide new insight into the key role deep trap states have in low temperature carrier transport in polycrystalline CdTe by revealing their propensity to act as networks for hopping conduction. PMID- 24158164 TI - Plasma biomarkers for acute respiratory distress syndrome: a systematic review and meta-analysis*. AB - OBJECTIVE: Numerous studies have focused on biomarkers for acute lung injury and acute respiratory distress syndrome. Although several biomarkers have been identified, their relative performance is unclear. We aim to provide a quantitative overview of plasma-derived biomarkers associated with acute respiratory distress syndrome diagnosis or mortality. DATA SOURCES: MEDLINE (inception to January 2012) and personal databases. STUDY SELECTION: English language studies on plasma biomarkers associated with acute respiratory distress syndrome diagnosis or mortality. DATA EXTRACTION: Demographic variables, plasma levels of biomarker, statistical data, acute respiratory distress syndrome occurrence, and mortality rates were retrieved. The methodological quality was assessed with the Quality Assessment of Diagnostic Accuracy Studies score. Clinical outcomes included 1) diagnosis of acute respiratory distress syndrome in the at-risk population and 2) mortality in acute respiratory distress syndrome patients. For each biomarker, pooled odds ratios for clinical outcome were calculated by meta-analysis, and biomarkers were ranked according to pooled odds ratio. DATA SYNTHESIS: Fifty-four studies appeared eligible for meta-analysis, together including 3,753 patients. We identified 20 biomarkers for diagnosis of acute respiratory distress syndrome in the at-risk population and 19 biomarkers for mortality of acute respiratory distress syndrome patients. The biomarkers most strongly associated with acute respiratory distress syndrome diagnosis in the at-risk population, when increased, were Krebs von den Lungen-6 (odds ratio [95% CI], 6.1 [3.0-12.1]), lactate dehydrogenase (5.7 [1.7-19.1]), soluble receptor for advanced glycation end products (3.5 [1.7-7.2]), and von Willebrand Factor (3.1 [2.0-5.2]). The biomarkers most strongly associated with acute respiratory distress syndrome mortality, when increased, were interleukin-4 (18.0 [6.0-54.2]), interleukin-2 (11.8 [4.3-32.2]), angiopoietin-2 (6.4 [1.3-30.4]), and Krebs von den Lungen-6 (5.1 [3.0-12.2]). Decreased levels of Protein C were associated with increased odds for acute respiratory distress syndrome diagnosis and mortality. CONCLUSIONS: This meta-analysis provides a unique ranking of plasma biomarkers according to their strength of association with acute respiratory distress syndrome diagnosis or acute respiratory distress syndrome mortality. The relative performance of biomarkers among studies shown in this ranking may help to improve acute respiratory distress syndrome diagnosis and outcome prediction. PMID- 24158165 TI - Effects of viscosity on cerebral blood flow after cardiac arrest. AB - OBJECTIVES: To determine blood viscosity in adult comatose patients treated with mild therapeutic hypothermia after cardiac arrest and to assess the relation between blood viscosity, cerebral blood flow, and cerebral oxygen extraction. DESIGN: Observational study. SETTING: Tertiary care university hospital. PATIENTS: Ten comatose patients with return of spontaneous circulation after out of-hospital cardiac arrest. INTERVENTION: Treatment with mild therapeutic hypothermia for 24 hours followed by passive rewarming to normothermia. MEASUREMENTS AND MAIN RESULTS: Median viscosity at shear rate 50/s was 5.27 mPa . s (4.29-5.91 mPa . s) at admission; it remained relatively stable during the first 12 hours and decreased significantly to 3.00 mPa . s (2.72-3.58 mPa . s) at 72 hours (p < 0.001). Median mean flow velocity in the middle cerebral artery was low (27.0 cm/s [23.8-30.5 cm/s]) at admission and significantly increased to 63.0 cm/s (51.0-80.0 cm/s) at 72 hours. Median jugular bulb saturation at the start of the study was 61.5% (55.5-75.3%) and significantly increased to 73.0% (69.0 81.0%) at 72 hours. Median hematocrit was 0.41 L/L (0.36-0.44 L/L) at admission and subsequently decreased significantly to 0.32 L/L (0.27-0.35 L/L) at 72 hours. Median C-reactive protein concentration was low at admission (2.5 mg/L [2.5-6.5 mg/L]) and increased to 101 mg/L (65-113.3 mg/L) in the following hours. Median fibrinogen concentration was increased at admission 2,795 mg/L (2,503-3,565 mg/L) and subsequently further increased to 6,195 mg/L (5,843-7,368 mg/L) at 72 hours. There was a significant negative association between blood viscosity and the mean flow velocity in the middle cerebral artery (p = 0.0008). CONCLUSIONS: Changes in blood viscosity in vivo are associated with changes in flow velocity in the middle cerebral artery. High viscosity early after cardiac arrest may reduce cerebral blood flow and may contribute to secondary brain injury. Further studies are needed to determine the optimal viscosity during the different stages of the postcardiac arrest syndrome. PMID- 24158166 TI - Impact of distinct definitions of acute lung injury on its incidence and outcomes in Brazilian ICUs: prospective evaluation of 7,133 patients*. AB - OBJECTIVES: Evaluation of prevalence and outcomes of acute lung injury in a large cohort of critically ill patients in Brazil and comparison of predictive receiver operating characteristic curve mortality of American European Consensus conference definition with new Berlin definition of acute respiratory distress syndrome. DESIGN: A 15-month prospective, multicenter, observational study. SETTING: Fourteen medical ICUs in Espirito Santo, a state of Brazil. PATIENTS: Mechanically ventilated patients who fulfilled American European Consensus conference criteria of acute lung injury or Berlin definition of acute respiratory distress syndrome. INTERVENTIONS: Clinical and respiratory data were collected for 7 consecutive days and on the 14 and 28 days. Twenty-eight day mortality, hospital mortality, and predictive receiver operating characteristic curve mortality were calculated. MEASUREMENTS AND MAIN RESULTS: Of 7,133 patients, 130 patients (1.8%) fulfilled criteria for acute lung injury (American European Consensus conference) or acute respiratory distress syndrome (Berlin definition). Median time for diagnosis was 2 days (interquartile range, 0-3 d). Main risk factors were pneumonia (35.3%) and nonpulmonary sepsis (31.5%). Mean age was 44.2 +/- 15.9 years, and 61.5% were men. Mean Acute Physiology and Chronic Health Evaluation II score was 20.7 +/- 7.9. Mean PaO2/FIO2 was 206 +/- 61.5, significantly lower in nonsurvivors on day 7 (p = 0.003). Mean mechanical ventilation time was 21 +/- 15 days. Length of ICU stay was 26.4 +/- 18.7 days. Twenty-eight-day mortality was 38.5% (95% CI, 30.1-46.8); hospital mortality was 49.2% (95% CI, 40.6-57.8). Predictive 28-day mortality area under the receiver operating characteristic curve for American European Consensus conference definition was 0.5625 (95% CI, 0.4783-0.6467) and for the Berlin definition 0.5664 (95% CI, 0.4759-0.6568; p = 0.9510). CONCLUSIONS: In our population, prevalence of acute lung injury was low, most cases were diagnosed 2 days after ICU admission, and Berlin definition was not different from American European Consensus conference definition in predicting mortality. There are still several problems with the global epidemiology, definition, and mortality predictive indices that should be added to the classification of this still lethal syndrome to improve its predictive mortality power in the future. PMID- 24158168 TI - Mechanical ventilation during cardiopulmonary resuscitation with intermittent positive-pressure ventilation, bilevel ventilation, or chest compression synchronized ventilation in a pig model. AB - OBJECTIVE: Mechanical ventilation with an automated ventilator is recommended during cardiopulmonary resuscitation with a secured airway. We investigated the influence of intermittent positive-pressure ventilation, bilevel ventilation, and the novel ventilator mode chest compression synchronized ventilation, a pressure controlled ventilation triggered by each chest compression, on gas exchange, hemodynamics, and return of spontaneous circulation in a pig model. DESIGN: Animal study. SETTING: University laboratory. SUBJECTS: Twenty-four three-month old female domestic pigs. INTERVENTIONS: The study was performed on pigs under general anesthesia with endotracheal intubation. Arterial and central venous catheters were inserted and IV rocuronium (1 mg/kg) was injected. After 3 minutes of cardiac arrest (ventricular fibrillation at t = 0 min), animals were randomized into intermittent positive-pressure ventilation (control group), bilevel, or chest compression synchronized ventilation group. Following 10 minute uninterrupted chest compressions and mechanical ventilation, advanced life support was performed (100% O2, up to six defibrillations, vasopressors). MEASUREMENTS AND MAIN RESULTS: Blood gas samples were drawn at 0, 4 and 13 minutes. At 13 minutes, hemodynamics was analyzed beat-to-beat in the end inspiratory and end-expiratory cycle comparing the IPPV with the bilevel group and the CCSV group. Data were analyzed with the Mann-Whitney U test. Return of spontaneous circulation was achieved in five of eight (intermittent positive pressure ventilation), six of eight (bilevel), and four of seven (chest compression synchronized ventilation) pigs. The results of arterial blood gas analyses at t = 4 minutes and t = 13 minutes (torr) were as follows: PaO2 intermittent positive-pressure ventilation, 143 (76/256) and 262 (81/340); bilevel, 261 (109/386) (p = 0.195 vs intermittent positive-pressure ventilation) and 236 (86/364) (p = 0.878 vs intermittent positive-pressure ventilation); and chest compression synchronized ventilation, 598 (471/650) (p < 0.001 vs intermittent positive-pressure ventilation) and 634 (115/693) (p = 0.054 vs intermittent positive-pressure ventilation); PaCO2 intermittent positive-pressure ventilation, 40 (38/43) and 45 (36/52); bilevel, 39 (35/41) (p = 0.574 vs intermittent positive-pressure ventilation) and 46 (42/49) (p = 0.798); and chest compression synchronized ventilation, 28 (27/32) (p = 0.001 vs intermittent positive-pressure ventilation) and 26 (18/29) (p = 0.004); mixed venous pH intermittent positive-pressure ventilation, 7.34 (7.31/7.35) and 7.26 (7.25/7.31); bilevel, 7.35 (7.29/7.37) (p = 0.645 vs intermittent positive pressure ventilation) and 7.27 (7.17/7.31) (p = 0.645 vs intermittent positive pressure ventilation); and chest compression synchronized ventilation, 7.34 (7.33/7.39) (p = 0.189 vs intermittent positive-pressure ventilation) and 7.35 (7.34/7.36) (p = 0.006 vs intermittent positive-pressure ventilation). Mean end inspiratory and end-expiratory arterial pressures at t = 13 minutes (mm Hg) were as follows: intermittent positive-pressure ventilation, 28.0 (25.0/29.6) and 27.9 (24.4/30.0); bilevel, 29.1 (25.6/37.1) (p = 0.574 vs intermittent positive pressure ventilation) and 28.7 (24.2/36.5) (p = 0.721 vs intermittent positive pressure ventilation); and chest compression synchronized ventilation, 32.7 (30.4/33.4) (p = 0.021 vs intermittent positive-pressure ventilation) and 27.0 (24.5/27.7) (p = 0.779 vs intermittent positive-pressure ventilation). CONCLUSIONS: Both intermittent positive-pressure ventilation and bilevel provided similar oxygenation and ventilation during cardiopulmonary resuscitation. Chest compression synchronized ventilation elicited the highest mean arterial pressure, best oxygenation, and a normal mixed venous pH during cardiopulmonary resuscitation. PMID- 24158167 TI - Prevalence, risk factors, and mortality for ventilator-associated pneumonia in middle-aged, old, and very old critically ill patients*. AB - OBJECTIVE: We investigated the epidemiology of ventilator-associated pneumonia in elderly ICU patients. More precisely, we assessed prevalence, risk factors, signs and symptoms, causative bacterial pathogens, and associated outcomes. DESIGN: Secondary analysis of a multicenter prospective cohort (EU-VAP project). SETTING: Twenty-seven European ICUs. PATIENTS: Patients who were mechanically ventilated for greater than or equal to 48 hours. We compared middle-aged (45-64 yr; n = 670), old (65-74 yr; n = 549), and very old patients (>= 75 yr; n= 516). MEASUREMENTS AND MAIN RESULTS: Ventilator-associated pneumonia occurred in 103 middle-aged (14.6%), 104 old (17.0%), and 73 very old patients (12.8%). The prevalence (n ventilator-associated pneumonia/1,000 ventilation days) was 13.7 in middle-aged patients, 16.6 in old patients, and 13.0 in very old patients. Logistic regression analysis could not demonstrate older age as a risk factor for ventilator-associated pneumonia. Ventilator-associated pneumonia in elderly patients was more frequently caused by Enterobacteriaceae (24% in middle-aged, 32% in old, and 43% in very old patients; p = 0.042). Regarding clinical signs and symptoms at ventilator-associated pneumonia onset, new temperature rise was less frequent among very old patients (59% vs 76% and 74% for middle-aged and old patients, respectively; p = 0.035). Mortality among patients with ventilator associated pneumonia was higher among elderly patients: 35% in middle-aged patients versus 51% in old and very old patients (p = 0.036). Logistic regression analysis confirmed the importance of older age in the risk of death (adjusted odds ratio for old age, 2.1; 95% CI, 1.2-3.9 and adjusted odds ratio for very old age, 2.3; 95% CI, 1.2-4.4). Other risk factors for mortality in ventilator associated pneumonia were diabetes mellitus, septic shock, and a high-risk pathogen as causative agent. CONCLUSIONS: In this multicenter cohort study, ventilator-associated pneumonia did not occur more frequently among elderly, but the associated mortality in these patients was higher. New temperature rise was less common in elderly patients with ventilator-associated pneumonia, whereas more episodes among elderly patients were caused by Enterobacteriaceae. PMID- 24158169 TI - Microvascular perfusion as a target for fluid resuscitation in experimental circulatory shock. AB - OBJECTIVES: To study regional perfusion during experimental endotoxemic and obstructive shock and compare the effect of initial cardiac output-targeted fluid resuscitation with optimal cardiac output-targeted resuscitation on different peripheral tissues. DESIGN: Controlled experimental study. SETTING: University affiliated research laboratory. SUBJECTS: Fourteen fasted anesthetized mechanically ventilated domestic pigs. INTERVENTIONS: Domestic pigs were randomly assigned to the endotoxemic (n = 7) or obstructive shock (n = 7) model. Central and regional perfusion parameters were obtained at baseline, during greater than or equal to 50% reduction of cardiac output (T1), after initial resuscitation to baseline (T2), and after optimization of cardiac output (T3). MEASUREMENTS AND MAIN RESULTS: Regional perfusion was assessed in the sublingual, intestinal, and muscle vascular beds at the different time points and included visualization of the microcirculation, measurement of tissue oxygenation, and indirect assessments of peripheral skin perfusion. Hypodynamic shock (T1) simultaneously decreased all regional perfusion variables in both models. In the obstructive model, these variables returned to baseline levels at T2 and remained in this range after T3, similar to cardiac output. In the endotoxemic model, however, the different regional perfusion variables were only normalized at T3 associated with the hyperdynamic state at this point. The magnitude of changes over time between the different vascular beds was similar in both models, but the endotoxemic model displayed greater heterogeneity between tissues. CONCLUSIONS: This study demonstrates that the relationship between the systemic and regional perfusion is dependent on the underlying cause of circulatory shock. Further research will have to demonstrate whether different microvascular perfusion variables can be used as additional resuscitation endpoints. PMID- 24158170 TI - Improving code team performance and survival outcomes: implementation of pediatric resuscitation team training. AB - OBJECTIVE: To determine whether implementation of Composite Resuscitation Team Training is associated with improvement in survival to discharge and code team performance after pediatric in-hospital cardiopulmonary arrest. DESIGN, SETTING, AND SUBJECTS: We conducted a prospective observational study with historical controls at a 302-bed, quaternary care, academic children's hospital. Inpatients who experienced cardiopulmonary arrest between January 1, 2006, and December 31, 2009, were included in the control group (123 patients experienced 183 cardiopulmonary arrests) and between July 1, 2010, and June 30, 2011, were included in the intervention group (46 patients experienced 65 cardiopulmonary arrests). INTERVENTION: Code team members were introduced to Composite Resuscitation Team Training and continued training throughout the intervention period (January 1, 2010-June 30, 2011). Training was integrated via in situ code blue simulations (n = 16). Simulations were videotaped and participants were debriefed for education and process improvement. Primary outcome was survival to discharge after cardiopulmonary arrest. Secondary outcome measures were 1) change in neurologic morbidity from admission to discharge, measured by Pediatric Cerebral Performance Category, and 2) code team adherence to resuscitation Standard Operating Performance variables. MEASUREMENTS AND MAIN RESULTS: The intervention group was more likely to survive than the control group (60.9% vs 40.3%) (unadjusted odds ratio, 2.3 [95% CI, 1.15-4.60]) and had no significant change in neurologic morbidity (mean change in Pediatric Cerebral Performance Category 0.11 vs 0.27; p = 0.37). Code teams exposed to Composite Resuscitation Team Training were more likely than control group to adhere to resuscitation Standard Operating Performance (35.9% vs 20.8%) (unadjusted odds ratio, 2.14 [95% CI, 1.15-3.99]). After adjusting for adherence to Standard Operating Performance, survival remained improved in the intervention period (odds ratio, 2.13 [95% CI, 1.06-4.36]). CONCLUSION: With implementation of Composite Resuscitation Team Training, survival to discharge after pediatric cardiopulmonary arrest improved, as did code team performance. Demonstration of improved survival after adjusting for code team adherence to resuscitation standards suggests that this may be a valuable resuscitation training program. Further studies are needed to determine causality and generalizability. PMID- 24158171 TI - Neurologic recovery from profound accidental hypothermia after 5 hours of cardiopulmonary resuscitation. AB - OBJECTIVE: To describe the successful neurologic recovery from profound accidental hypothermia with cardiac arrest despite the longest reported duration of cardiopulmonary resuscitation. DESIGN: Case report. SETTING: Mountain. PATIENT: A 57-year-old woman experienced profound accidental hypothermia (16.9 degrees C) in a mountainous region of Grenoble. She was unconscious and had extreme bradycardia (6 beats/min) at presentation. A cardiac arrest occurred at the mobilization that was not responsive to electrical shocks or epinephrine. INTERVENTION: Cardiopulmonary resuscitation was continued for 307 minutes after rescue until venoarterial extracorporeal membrane oxygenation blood flow had been established at the emergency department. MEASUREMENTS AND MAIN RESULTS: At a 3 month follow-up, the patient showed good physical and mental recovery. CONCLUSION: With no evidence of trauma or asphyxia, profound accidental hypothermia with cardiac arrest represents a specific condition for which successful neurologic recovery is feasible despite prolonged cardiopulmonary resuscitation. PMID- 24158173 TI - Inhaled anticoagulation regimens for the treatment of smoke inhalation-associated acute lung injury: a systematic review. AB - OBJECTIVE: Inhaled anticoagulation regimens are increasingly being used to manage smoke inhalation-associated acute lung injury. We systematically reviewed published and unpublished preclinical and clinical trial data to elucidate the effects of these regimens on lung injury severity, airway obstruction, ventilation, oxygenation, pulmonary infections, bleeding complications, and survival. DATA SOURCES: PubMed, Scopus, EMBASE, and Web of Science were searched to identify relevant published studies. Relevant unpublished studies were identified by searching the Australian and New Zealand Clinical Trials Registry, World Health Organization International Clinical Trials Registry Platform, Cochrane Library, ClinicalTrials.gov, MINDCULL.com, Current Controlled Trials, and Google. STUDY SELECTION: Inclusion criteria were any preclinical or clinical study in which 1) animals or subjects experienced smoke inhalation exposure, 2) they were treated with nebulized or aerosolized anticoagulation regimens, including heparin, heparinoids, antithrombins, or fibrinolytics (e.g., tissue plasminogen activator), 3) a control and/or sham group was described for preclinical studies, and 4) a concurrent or historical control group described for clinical studies. Exclusion criteria were 1) the absence of a group treated with a nebulized or aerosolized anticoagulation regimen, 2) the absence of a control or sham group, and 3) case reports. DATA EXTRACTION: Ninety-nine potentially relevant references were identified. Twenty-seven references met inclusion criteria including 19 preclinical references reporting 18 studies and eight clinical references reporting five clinical studies. DATA SYNTHESIS: A systematic review of the literature is provided. Both clinical and methodological diversity precluded combining these studies in a meta-analysis. CONCLUSIONS: The high mortality associated with smoke inhalation-associated acute lung injury results from airway damage, mucosal dysfunction, neutrophil infiltration, airway coagulopathy with cast formation, ventilation-perfusion mismatching with shunt, and barotrauma. Inhaled anticoagulation regimens in both preclinical and clinical studies improve survival and decrease morbidity without altering systemic markers of clotting and anticoagulation. In some preclinical and clinical studies, inhaled anticoagulants were associated with a favorable effect on survival. This approach appears sufficiently promising to merit a well-designed prospective study to validate its use in patients with severe smoke inhalation-associated acute lung injury requiring mechanical ventilation. PMID- 24158174 TI - Comparison of the Mortality Probability Admission Model III, National Quality Forum, and Acute Physiology and Chronic Health Evaluation IV hospital mortality models: implications for national benchmarking*. AB - OBJECTIVE: To examine the accuracy of the original Mortality Probability Admission Model III, ICU Outcomes Model/National Quality Forum modification of Mortality Probability Admission Model III, and Acute Physiology and Chronic Health Evaluation IVa models for comparing observed and risk-adjusted hospital mortality predictions. DESIGN: Retrospective paired analyses of day 1 hospital mortality predictions using three prognostic models. SETTING: Fifty-five ICUs at 38 U.S. hospitals from January 2008 to December 2012. PATIENTS: Among 174,001 intensive care admissions, 109,926 met model inclusion criteria and 55,304 had data for mortality prediction using all three models. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: We compared patient exclusions and the discrimination, calibration, and accuracy for each model. Acute Physiology and Chronic Health Evaluation IVa excluded 10.7% of all patients, ICU Outcomes Model/National Quality Forum 20.1%, and Mortality Probability Admission Model III 24.1%. Discrimination of Acute Physiology and Chronic Health Evaluation IVa was superior with area under receiver operating curve (0.88) compared with Mortality Probability Admission Model III (0.81) and ICU Outcomes Model/National Quality Forum (0.80). Acute Physiology and Chronic Health Evaluation IVa was better calibrated (lowest Hosmer-Lemeshow statistic). The accuracy of Acute Physiology and Chronic Health Evaluation IVa was superior (adjusted Brier score = 31.0%) to that for Mortality Probability Admission Model III (16.1%) and ICU Outcomes Model/National Quality Forum (17.8%). Compared with observed mortality, Acute Physiology and Chronic Health Evaluation IVa overpredicted mortality by 1.5% and Mortality Probability Admission Model III by 3.1%; ICU Outcomes Model/National Quality Forum underpredicted mortality by 1.2%. Calibration curves showed that Acute Physiology and Chronic Health Evaluation performed well over the entire risk range, unlike the Mortality Probability Admission Model and ICU Outcomes Model/National Quality Forum models. Acute Physiology and Chronic Health Evaluation IVa had better accuracy within patient subgroups and for specific admission diagnoses. CONCLUSIONS: Acute Physiology and Chronic Health Evaluation IVa offered the best discrimination and calibration on a large common dataset and excluded fewer patients than Mortality Probability Admission Model III or ICU Outcomes Model/National Quality Forum. The choice of ICU performance benchmarks should be based on a comparison of model accuracy using data for identical patients. PMID- 24158175 TI - Macrolides and mortality in critically ill patients with community-acquired pneumonia: a systematic review and meta-analysis. AB - OBJECTIVE: Some studies suggest better outcomes with macrolide therapy for critically ill patients with community-acquired pneumonia. To further explore this, we performed a systematic review of studies with mortality endpoints that compared macrolide therapy with other regimens in critically ill patients with community-acquired pneumonia. DATA SOURCES: Studies were identified via electronic databases, grey literature, and conference proceedings through May 2013. STUDY SELECTION: Using prespecified criteria, two reviewers selected studies; studies of outpatients and hospitalized noncritically ill patients were excluded. DATA EXTRACTION: Two reviewers extracted data and evaluated bias using the Newcastle-Ottawa Scale. Random effects models were used to generate pooled risk ratios and evaluate heterogeneity (I). DATA SYNTHESIS: Twenty-eight observational studies (no randomized control trials) were included. Average age ranged from 58 to 78 years and 14-49% were women. In our primary analysis of 9,850 patients, macrolide use was associated with statistically significant lower mortality compared with nonmacrolides (21% [846 of 4,036 patients] vs 24% [1,369 of 5,814]; risk ratio, 0.82; 95% CI, 0.70-0.97; p = 0.02; I = 63%). When macrolide monotherapy was excluded, the macrolide mortality benefit was maintained (21% [737 of 3,447 patients] vs 23% [1,245 of 5,425]; risk ratio, 0.84; 95% CI, 0.71-1.00; p = 0.05; I = 60%). When broadly guideline-concordant regimens were compared, there was a trend to improved mortality and heterogeneity was reduced (20% [511 of 2,561 patients] mortality with beta-lactam/macrolide therapy vs 23% [386 of 1,680] with beta-lactam/fluoroquinolone; risk ratio, 0.83; 95% CI, 0.67-1.03; p = 0.09; I = 25%). When adjusted risk estimates were pooled from eight studies, macrolide therapy was still associated with a significant reduction in mortality (risk ratio, 0.75; 95% CI, 0.58-0.96; p = 0.02; I = 57%). CONCLUSIONS: In observational studies of almost 10,000 critically ill patients with community-acquired pneumonia, macrolide use was associated with a significant 18% relative (3% absolute) reduction in mortality compared with nonmacrolide therapies. After pooling data from studies that provided adjusted risk estimates, an even larger mortality reduction was observed. These results suggest that macrolides be considered first-line combination treatment in critically ill patients with community-acquired pneumonia and support current guidelines. PMID- 24158172 TI - Delirium in the ICU and subsequent long-term disability among survivors of mechanical ventilation. AB - OBJECTIVE: Survivors of critical illness are frequently left with long-lasting disability. The association between delirium and disability in critically ill patients has not been described. We hypothesized that the duration of delirium in the ICU would be associated with subsequent disability and worse physical health status following a critical illness. DESIGN: Prospective cohort study nested within a randomized controlled trial of a paired sedation and ventilator weaning strategy. SETTING: A single-center tertiary-care hospital. PATIENTS: One hundred twenty-six survivors of a critical illness. MEASUREMENTS AND MAIN RESULTS: Confusion Assessment Method for the ICU, Katz activities of daily living, Functional Activities Questionnaire (measuring instrumental activities of daily living), Medical Outcomes Study 36-item Short Form General Health Survey Physical Components Score, and Awareness Questionnaire were used. Associations between delirium duration and outcomes were determined via proportional odds logistic regression with generalized estimating equations (for Katz activities of daily living and Functional Activities Questionnaire scores) or via generalized least squares regression (for Medical Outcomes Study 36-item Short Form General Health Survey Physical Components Score and Awareness Questionnaire scores). Excluding patients who died prior to follow-up but including those who withdrew or were lost to follow-up, we assessed 80 of 99 patients (81%) at 3 months and 63 of 87 patients (72%) at 12 months. After adjusting for covariates, delirium duration was associated with worse activities of daily living scores (p = 0.002) over the course of the 12-month study period but was not associated with worse instrumental activities of daily living scores (p = 0.15) or worse Medical Outcomes Study 36-item Short Form General Health Survey Physical Components Score (p = 0.58). Duration of delirium was also associated with lower Awareness Questionnaire Motor/Sensory Factors scores (p 0.02). CONCLUSION: In the setting of critical illness, longer delirium duration is independently associated with increased odds of disability in activities of daily living and worse motor sensory function in the following year. These data point to a need for further study into the determinants of functional outcomes in ICU survivors. PMID- 24158176 TI - The influence of Pluronics nanovehicles on dark cytotoxicity, photocytotoxicity and localization of four model photosensitizers in cancer cells. AB - Many photosensitizers (PSs) for use in photodynamic therapy (PDT) are characterized by poor solubility and a tendency to aggregate in aqueous environments. Nanovehicles of Pluronics block copolymers may be used for drug delivery of antineoplastic agents and may also exert a separate effect in enhancing drug efficiency. The objective of this study was to determine the effects of selected Pluronics (F127, P123, L44 and F68) on the dark cytotoxicity, photocytotoxicity and localization of four model photosensitizers, tetraphenyl porphyrins 4-substituted on the phenyl groups with trimethylamine (TAPP), hydroxyl (THPP), sulfonate (TSPP) and carboxyl (TCPP) in cancer cells. The selected PSs showed a 3 log range in sensitivity to cellular photoinactivation. Pluronics were found to efficiently deaggregate the PSs and improve PS solubility as analyzed by fluorescence spectroscopy and dynamic light scattering. The Pluronics had moderate to profound effects on intracellular localization of the PSs and cellular sensitivity to photoinactivation. Confocal microscopy was used to determine the localization of PSs in colon adenocarcinoma cell line (WiDr), guided by co-staining with nuclear (Hoechst 33342) and endolysosomal (LysoTracker Green DND(r) 26 and Dextran Alexa Fluor(r) 488) markers. Of the most significant effects P123 and F127 strongly attenuated the uptake and photocytotoxicity of THPP and redirected the cellular uptake to endocytosis. P123 stimulated translocation of TAPP from endocytic vesicles to a cytosolic and nuclear localization followed by an enhanced phototoxicity. In the absence of Pluronics TCPP was found to localize partly in endocytic vesicles and partly in the cytosol and nucleus, while P123 and F127 lowered the fraction in endocytic vesicles followed by a reduced sensitivity to photoinactivation. F68 had only moderate effects on intracellular localization of the evaluated PSs with the exception of a higher endocytic accumulation of TCPP and lowered photocytotoxicity of TCPP and THPP. In conclusion, Pluronics are attractive solubilizers of porphyrin-based PSs which have in many cases substantial effects on intracellular localization and efficacy of the PSs. PMID- 24158177 TI - Effect of combined bevacizumab and temozolomide treatment on intramedullary spinal cord tumor. AB - STUDY DESIGN: C6 glioma cells and an intramedullary spinal cord tumor model were used to evaluate the effect of bevacizumab (Avastin) or temozolomide (TMZ). OBJECTIVE: In this study, we hypothesized that treatment with bevacizumab accelerates the therapeutic effect of TMZ on intramedullary gliomas in an animal model. SUMMARY OF BACKGROUND DATA: Recently therapies for the management of intramedullary malignant gliomas include surgery, chemotherapy, and radiotherapy. Concurrent or adjuvant TMZ has been considered an emerging new treatment for intramedullary malignant gliomas; however, high-dose application of TMZ has limitation of side effect. METHODS: C6 glioma cells were injected into the T5 level of the spinal cord, and TMZ and bevacizumab were administered 5 days after C6 inoculation (n = 7 for each group). Tumor size was analyzed using histology and magnetic resonance imaging at 13 days after tumor inoculation. RESULTS: Histological analyses and magnetic resonance imaging findings showed that combined treatment with TMZ and bevacizumab reduced tumor mass. The tumor volume of control group was 2.8-fold higher than combined therapy (P < 0.05). Neurological outcomes demonstrated that combined therapy improved hind limb function more than TMZ-alone group or control group (P < 0.05). CONCLUSION: This study shows that bevacizumab could be useful in combination with TMZ to increase the therapeutic benefits of TMZ for intramedullary spinal cord tumors. LEVEL OF EVIDENCE: N/A. PMID- 24158179 TI - Experience with intrawound vancomycin powder for spinal deformity surgery. AB - STUDY DESIGN: Retrospective cohort study. OBJECTIVE: To evaluate the ability of local vancomycin powder to prevent deep wound infection after thoracolumbar and lumbar spinal fusion for open deformity cases. SUMMARY OF BACKGROUND DATA: Recent studies report that local delivery of vancomycin powder is associated with a decrease in spinal surgical site infection (SSI). This study compares deformity fusion cases before and after the routine application of spinal vancomycin powder. METHODS: Posterior spinal deformity surgical procedures by a single institution were reviewed from January 2011 to April 2013. Routine application of vancomycin powder started in April 2012. Inclusion criteria included adult patients who underwent posterior fusion for deformity pathologies, including spondylolisthesis, kyphosis, sagittal imbalance, and scoliosis. Each cohort's baseline characteristics including infection risk factors, operative data, and rates of wound infection were compared. Associations between infection and vancomycin powder, with and without propensity score adjustment for risk factors were determined using logistic regression. RESULTS: A total of 306 patients were included in the study. All measured baseline and operative variables were statistically similar between untreated (n = 150) and those who received vancomycin powder (n = 156). No significant change in deep wound infection rate was seen between the control (5.3%) and intervention group (5.1%, P = 0.936). Logistic regression with and without propensity score adjusted for risk factors demonstrated that the use of vancomycin powder did not impact the development of SSI (odds ratio [95% confidence interval]: 1.01 [0.36-2.79], P = 0.9910) and (odds ratio [95% confidence interval]: 0.87 [0.31-2.42], P = 0.7876), respectively. CONCLUSION: The local application of powdered vancomycin was not associated with a significant difference in the rate of deep SSI after spinal deformity surgery, and other treatment modalities are necessary to limit infection for this high-risk group. This study is in contrary to prior studies, which have reported a decrease in SSI with vancomycin powder. LEVEL OF EVIDENCE: 2. PMID- 24158180 TI - Imagine.... PMID- 24158181 TI - Improving patient satisfaction in the orthopaedic trauma population. AB - OBJECTIVES: Patient satisfaction is a key determinant of the quality of care and an important component of pay for performance metrics. The purpose of this study was to evaluate the impact of a simple intervention aimed to increase patients' understanding of their orthopaedic trauma surgeon and improve patient satisfaction with the overall quality of inpatient care delivered by the attending surgeon. DESIGN: Prospective quality improvement initiative using a randomized intervention. SETTING: Level 1 academic trauma center. PATIENTS/PARTICIPANTS: Two hundred twelve patients were eligible; 100 patients were randomized to the intervention group, and 112 patients were randomized to the control group. Overall, 76 patients could be reached for follow-up satisfaction survey, including 34 patients in the intervention group and 42 patients in the control group. INTERVENTION: Patients randomized to the intervention group received an attending biosketch card, which included a picture of the attending orthopaedic surgeon with a brief synopsis of his educational background, specialty, surgical interests, and research interests. MAIN OUTCOME MEASURES: Our primary outcome measure was a patient satisfaction survey assessing patients' rating of the overall quality of inpatient care delivered by the attending surgeon. RESULTS: Overall, 25 (74%) of 34 patients who received an attending biosketch card reported "excellent overall quality of doctor care," whereas only 22 (52%) of 42 patients in the control group reported "excellent overall quality of doctor care" (P = 0.05). Age, gender, race, education, insurance status, primary injury type, and the length of hospital stay were not significant with reference to "excellent" outcome. CONCLUSIONS: Clinically significant improvements in satisfaction with the overall quality of inpatient care by the attending surgeon were identified in patients who received a biosketch card of his or her attending orthopaedic surgeon. PMID- 24158183 TI - Femoral suspension devices for anterior cruciate ligament reconstruction: do adjustable loops lengthen? AB - BACKGROUND: Cortical suspension devices are commonly used for femoral graft fixation during anterior cruciate ligament (ACL) reconstructive surgery. Adjustable-length fixation devices provide technical advantages over fixed-length loops but may be more susceptible to lengthening during cyclic loading. HYPOTHESIS: Both fixed-length and adjustable-length femoral cortical suspension devices would withstand ultimate loads greater than those normally experienced by the native ACL and would prevent clinically significant lengthening during prolonged cyclic loading. STUDY DESIGN: Controlled laboratory study. METHODS: Mechanical testing was performed on 3 ACL graft cortical suspensory devices by use of an extended cyclic loading (4500 cycles at 10-250 N) and pull-to-failure protocol. Two adjustable-length devices were additionally tested with the free suture ends tied. RESULTS: Total displacement after 4500 cycles of tensioning at variable loads (expressed as mean +/- SD) was 42.45 mm (+/-7.01 mm) for the Arthrex TightRope RT, 5.76 mm (+/-0.35 mm) for the Biomet ToggleLoc, and 1.34 mm (+/-0.03 mm) for the Smith & Nephew EndoButton CL Ultra (P < .001). The Arthrex TightRope reached clinical failure of 3 mm lengthening after fewer cycles (1349 +/- 316) than the Biomet ToggleLoc (2576 +/- 73) (P < .001). The Smith & Nephew EndoButton did not reach clinical failure during cyclic testing. With the free suture ends tied, after 4500 cycles, the Arthrex TightRope had a significant decrease in lengthening to 13.36 +/- 1.86 mm (P < .037) There was also a significant difference in ultimate load between the TightRope (809.11 +/- 52.94 N) and the other 2 constructs (P < .001). CONCLUSION: The ultimate load of all graft-fixation devices exceeded the forces likely to be experienced in a patient's knee during the early postoperative rehabilitation period. However, the adjustable-length fixation devices experienced a clinically significant increase in loop lengthening during cyclic testing. This lengthening is partially caused by suture slippage into the adjustable-length loop. CLINICAL RELEVANCE: Adjustable-length ACL graft cortical suspension devices lengthen under cyclic loads because free suture ends are pulled into the adjustable loop. This may allow for graft-fixation device lengthening during the acute postoperative period. PMID- 24158182 TI - The novel fusion protein sTRAIL-TMTP1 exhibits a targeted inhibition of primary tumors and metastases. AB - Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) can selectively kill tumor cells and enhance therapy in vivo. However, concerns regarding its considerable liver toxicity limit its use in humans as a cancer therapy. Tumor molecular targeted peptide 1 (TMTP1) has previously been reported by our laboratory to target primary tumors and metastatic foci. Here, we report a novel recombinant fusion protein, sTRAIL-TMTP1, which not only induced apoptosis in cancer cells in vitro but also inhibited tumor growth and metastases in vivo. Moreover, sTRAIL-TMTP1 impacted tumor angiogenesis. The biodistribution results demonstrated that sTRAIL-TMTP1 accumulation peaked 6 h after injection and persisted for 24 h in the tumor, while faint sTRAIL-TMTP1 accumulation was detected in normal organs in tumor-bearing mice. Thus, combining sTRAIL with TMTP1 resulted in high anti-tumor activity and low toxicity. In conclusion, the novel fusion protein sTRAIL-TMTP1 was successfully developed in our laboratory and was observed to induce apoptosis both in primary and metastatic cancer, which may lead to the development of novel, targeted anticancer agents. KEY MESSAGE: Construction, purification, and characterization of the novel recombinant fusion protein, sTRAIL-TMTP1. sTRAIL-TMTP1 not only induce apoptosis in cancer cells but inhibit tumor growth and metastasis. sTRAIL-TMTP1 showed an impact on caspase activity and tumor angiogenesis. sTRAIL-TMTP1's accumulate in tumor with little accumulation in normal organs. PMID- 24158184 TI - Diagnostic accuracy of (68)Ga-DOTANOC PET/CT imaging in pheochromocytoma. AB - PURPOSE: The purpose of the present study was to evaluate the diagnostic accuracy of (68)Ga-DOTANOC positron emission tomography (PET)/CT in patients with suspicion of pheochromocytoma. METHODS: Data of 62 patients [age 34.3 +/- 16.1 years, 14 with multiple endocrine neoplasia type 2 (MEN2)] with clinical/biochemical suspicion of pheochromocytoma and suspicious adrenal lesion on contrast CT (n = 70), who had undergone (68)Ga-DOTANOC PET/CT, were retrospectively analyzed. PET/CT images were analyzed visually as well as semiquantitatively, with measurement of maximum standardized uptake value (SUVmax), SUVmean, SUVmax/SUVliver, and SUVmean/SUVliver. Results of PET/CT were compared with (131)I-metaiodobenzylguanidine (MIBG) imaging, which was available in 40 patients (45 lesions). Histopathology and/or imaging/clinical/biochemical follow-up (minimum 6 months) was used as reference standard. RESULTS: The sensitivity, specificity, and accuracy of (68)Ga-DOTANOC PET/CT was 90.4, 85, and 88.7%, respectively, on patient-based analysis and 92, 85, and 90%, respectively, on lesion-based analysis. (68)Ga-DOTANOC PET/CT showed 100% accuracy in patients with MEN2 syndrome and malignant pheochromocytoma. On direct comparison, lesion based accuracy of (68)Ga-DOTANOC PET/CT for pheochromocytoma was significantly higher than (131)I-MIBG imaging (91.1 vs 66.6%, p = 0.035). SUVmax was higher for pheochromocytomas than other adrenal lesions (p = 0.005), MEN2-associated vs sporadic pheochromocytoma (p = 0.012), but no difference was seen between benign vs malignant pheochromocytoma (p = 0.269). CONCLUSION: (68)Ga-DOTANOC PET/CT shows high diagnostic accuracy in patients with suspicion of pheochromocytoma and is superior to (131)I-MIBG imaging for this purpose. Best results of (68)Ga DOTANOC PET/CT are seen in patients with MEN2-associated and malignant pheochromocytoma. PMID- 24158185 TI - Imaging acute spinal myelitis with 18F-FDG PET/CT. PMID- 24158188 TI - Spectroscopic properties of Zn(salphenazine) complexes and their application in small molecule organic solar cells. AB - A new family of salphen based complexes, viz. Zn(salphenazine)s, has been prepared and is characterized by a larger pi-surface compared to previously reported Zn(salphen) complexes. The spectroscopic properties of these Zn(salphenazine)s have been studied in detail using UV-Vis and fluorescence spectroscopy, and further investigated by computational methods. The first application of a Zn(salphenazine) complex in a small molecule organic solar cell (smOSC) is presented showing the potential of salphenazine systems in this area. PMID- 24158189 TI - Epicardial fat thickness is independently associated with psoriasis. AB - BACKGROUND: Several studies have showed an association between psoriasis and cardiovascular (CV) diseases and metabolic syndrome (MS). Assessment of CV risk in patients with psoriasis has become an important issue. Epicardial fat thickness (EFT) is an emerging cardiometabolic risk factor and has been shown to be related to atherosclerosis. EFT has not been studied in the context of psoriasis. OBJECTIVE: To compare the EFT in psoriasis patients with that in control subjects. METHODS: 31 patients with psoriasis and 32 control subjects were included in this case-control study. EFT was evaluated by two-dimensional transthoracic echocardiography. RESULTS: EFT was significantly higher in psoriasis patients compared to controls (p = 0.027). Multiple linear regression analysis showed that the association of EFT with psoriasis was independent of MS and age. CONCLUSION: EFT, which has been suggested as a cardiometabolic risk factor in various diseases, is also independently associated with psoriasis. PMID- 24158191 TI - S.T.A.R.T.T.: development of a national, multidisciplinary trauma crisis resource management curriculum-results from the pilot course. AB - BACKGROUND: Most medical errors are nontechnical and include failures in team communication, situational awareness, resource use, and leadership. Other high risk industries have adopted team-based crisis resource management (CRM) training strategies to address "nontechnical" skills and to improve human error and safety. Here, we describe the development and evaluation of a national multidisciplinary trauma CRM curriculum. METHODS: A needs analysis survey was distributed to general surgery program directors across Canada. With the use of this feedback, a course called STARTT [Standardized Trauma and Resuscitation Team Training] was developed and held in conjunction with the Canadian Surgery Forum. Participants completed a precourse and postcourse evaluation exploring changes in attitudes toward simulation and CRM principles using previously validated instruments. RESULTS: Twenty surgical residents, 6 nurses, 4 respiratory therapists, and 11 instructors (trauma surgeons, emergency physicians, nurses, and intensivists) participated. Of the participants, 100% completed the survey. Satisfaction was very high, with 97.5% of the participants rating the course as "good" or "excellent" and 97.5% recommending it to others. The presurvey and postsurvey showed statistically significant improvement in attitudes toward simulation and overall CRM principles (136.3 vs. 140.3 of 170, p = 0.004) following the course, primarily in the domain of teamwork (69.1 vs. 72.0 of 85, p = 0.002). CONCLUSION: Creation of a national multidisciplinary trauma CRM curriculum is feasible, has high satisfaction among participants, and can improve attitudes toward the importance of simulation and CRM principles with the ultimate goal of improving patient safety and care. PMID- 24158192 TI - Evaluation of resuscitation fluids on endothelial glycocalyx, venular blood flow, and coagulation function after hemorrhagic shock in rats. AB - BACKGROUND: Endothelial glycocalyx (EG) plays an essential role in endothelium integrity and may be compromised by hemorrhagic shock. The effects of currently available resuscitation fluids such as Hextend (HEX) or lactated Ringer's solution (LR) on vascular function and coagulation are not well understood. The aim of the present study was to compare the effects of fresh frozen plasma (FFP) with HEX or LR in their ability to repair EG structure, promote volume expansion, increase blood flow, and prevent coagulopathy. METHODS: A total of 121 microvessels from cremaster muscle were studied in 32 anesthetized instrumented rats. After baseline systemic and microvascular measurements, 40% hemorrhage followed by resuscitation was performed, and measurements were repeated. Coagulation was evaluated using ROTEM to assay clot formation time, clotting time, firmness, strength, and lysis. Velocity and "platelet component" of strength were calculated. Fluorescein isothiocyanate or Texas Red bound to Dextrans was injected to estimate EG thickness in vivo. RESULTS: Respiratory rate, blood pH, base excess, and lactate returned to near-baseline levels in all treatments. Hemodilution caused by LR and HEX decreased firmness, prolonged clotting time, and lowered platelet counts. EG thickness in HEX- and LR-treated rats was 50% lower, and plasma syndecan 1 was 50% higher than sham and FFP groups. Blood flow and shear rate were restored in the HEX group. Resuscitation with FFP improved coagulation and blood flow. CONCLUSION: Our findings support the concept of cardiovascular and microvascular stabilization by infused FFP, in which the increase in microvascular perfusion associated with restored EG is essential for an optimal resuscitation strategy. PMID- 24158193 TI - Group VIB Ca(2+)-independent phospholipase A(2gamma) is associated with acute lung injury following trauma and hemorrhagic shock. AB - BACKGROUND: Gut-derived mediators are carried via mesenteric lymph duct into systemic circulation after trauma/hemorrhagic shock (T/HS), thus leading to acute lung injury (ALI)/multiple-organ dysfunction syndrome. Phospholipase A2 (PLA(2)) is a key enzyme for the production of lipid mediators in posthemorrhagic shock mesenteric lymph (PHSML). However, the precise functions of PLA(2) subtype, such as cytosolic PLA(2), secretory PLA(2), and Ca-independent PLA(2), in the acute phase of inflammation have remained unclear. Our previous study has suggested that the activation of Group VIB Ca-independent PLA(2gamma) (PLA(2gamma)) may be associated with increased lyso-phosphatidylcholines (LPCs) in the PHSML. Therefore, our purpose was to verify the role of iPLA(2gamma) on the production of 2-polyunsaturated LPC species and the pathogenesis of T/HS-induced ALI using an iPLA(2gamma)-specific inhibitor, R-(E)-6-(bromoethylene)-3-(1-naphthalenyl)-2H tetrahydropyran-2-one (R-BEL). METHODS: Male Sprague-Dawley rats were anesthetized and cannulated in blood vessels and mesenteric lymph duct. Animals in the T/HS group underwent a midline laparotomy plus hemorrhagic shock (mean arterial pressure, 35 mm Hg, 30 minutes) and 2-hour resuscitation with shed blood and 2* normal saline. Trauma/sham shock rats were performed the identical procedure without hemorrhage. R-BEL or DMSO was administered 30 minutes before T/HS or trauma/sham shock. Polyunsaturated LPCs and arachidonic acid in the PHSML were analyzed with a liquid chromatography/electrospray ionization-mass spectrometry. Furthermore, ALI was assessed by lung vascular permeability, myeloperoxidase activity, and histology. RESULTS: T/HS increased 2 polyunsaturated LPCs and arachidonic acid in the PHSML. The R-BEL pretreatment significantly decreased these lipids and also inhibited ALI. CONCLUSION: The iPLA(2gamma) enzyme is possibly involved in the pathogenesis of ALI following T/HS through the mesenteric lymph pathway. PMID- 24158194 TI - Pulsed dosed delivery of oxygen in mechanically ventilated pigs with acute lung injury. AB - BACKGROUND: Acute lung injury (ALI) is a condition that leads to impaired oxygen delivery. We demonstrated previously that using a portable oxygen concentrator (POC) with pulsed dose delivery of oxygen is an alternative option to conserve oxygen while still maintaining adequate oxygen delivery in a mechanical model. We hypothesized that using a modified POC, pulsed dose oxygen delivery can provide adequate oxygenation in an animal model. METHODS: In a crossover study, we induced ALI in 15 pigs using an oleic acid model. We ventilated the pigs using equipment that is used by Critical Care Air Transport Teams of the US Air Force. We compared oxygen delivery using a POC in both continuous flow and pulsed dose modes, while in both volume-control and pressure-control mechanical ventilation. RESULTS: The PaO(2)/FIO(2) ratios were increased in both the continuous flow and pulsed dose delivery for volume control and pressure control. In volume control, the pulsed dose demonstrated a significant increase in the PaO(2)/FIO(2) ratio (168.8 [96.1] vs. 91.7 [65.4], p = 0.002) compared with continuous flow. However, this was not seen in pressure-control ventilation (89.0 [74.5] vs. 79.1 [65.4], p = 0.67). CONCLUSION: We were able to demonstrate that oxygen delivery using a POC in mechanically ventilated pigs with ALI is feasible. We were also able to demonstrate that pulsed dose delivery from a POC is superior to continuous flow oxygen delivery for oxygenation in ALI, when using volume control. We propose that this is a safe alternative to conserve oxygen in the transport of critically ill patients. PMID- 24158195 TI - Traumatic brain injury-induced alterations in peripheral immunity. AB - BACKGROUND: The complex alterations that occur in peripheral immunity after traumatic brain injury (TBI) have been poorly characterized to date. The purpose of this study was to determine the temporal changes in the peripheral immune response after TBI in a murine model of closed head injury. METHODS: C57Bl/6 mice underwent closed head injury via a weight drop technique (n = 5) versus sham injury (n = 3) per time point. Blood, spleen, and thymus were collected, and immune phenotype, cytokine expression, and antibody production were determined via flow cytometry and multiplex immunoassays at 1, 3, 7, 14, 30, and 60 days after injury. RESULTS: TBI results in acute and chronic changes in both the innate and adaptive immune response. TBI resulted in a striking loss of thymocytes as early as 3 days after injury (2.1 * 10 TBI vs. 5.6 * 10 sham, p = 0.001). Similarly, blood monocyte counts were markedly diminished as early as 24 hours after TBI (372 per deciliter TBI vs. 1359 per deciliter sham, p = 0.002) and remained suppressed throughout the first month after injury. At 60 days after injury, monocytes were polarized toward an anti-inflammatory (M2) phenotype. TBI also resulted in diminished interleukin 12 expression from Day 14 after injury throughout the remainder of the observation period. CONCLUSION: TBI results in temporal changes in both the peripheral and the central immune systems culminating in an overall immune suppressed phenotype and anti-inflammatory milieu. PMID- 24158196 TI - Basic fibroblast growth factor/vascular endothelial growth factor in the serum from severe burn patients stimulates the proliferation of cultured human umbilical cord mesenchymal stem cells via activation of Notch signaling pathways. AB - BACKGROUND: Mesenchymal stem cells (MSCs) are the leading cellular constituents used in regenerative medicine. MSCs repair and reconstruct wounds of acute traumata and radiation-induced burns through proliferation, differentiation, and trophic activity. However, repair effect of MSCs on severe burn wounds remain to be clarified because severe burns are much more complex traumata than radiation induced burns. Survival and proliferation of MSCs in microenvironments affected by severe burns are very important for improving wound repair/regeneration. This study aimed to elucidate the survival and proliferation effects and the potential proliferation mechanism of serum from severe burn patients (BPS) on human umbilical cord MSCs (hUCMSCs) in vitro. METHODS: The hUCMSCs were isolated, cultured, and identified. Next, we evaluated the effects of BPS on cell numbers, cell cycle progression, cyclin D expression, and key proteins and genes of the Notch signaling pathway. Putative mechanisms underlying the proliferation of hUCMSCs were investigated. RESULTS: BPS markedly increased the number of hUCMSCs, and the results of the cell cycle studies indicated that BPS induced cell cycle progression into the M phase. Cyclin D expression was higher with BPS than in the control group. Moreover, Notch-1, a key determinant of hUCMSC activation and proliferation, and its target gene Hes-1 were overexpressed after BPS treatment. Proliferation numbers of hUCMSC, rate of proliferation period (G2/M+S), and the expression of cyclin D, Notch-1, and Hes-1 were markedly decreased by Notch signaling inhibitors (DAPT/GSI). In the case of BPS, basic fibroblast growth factor and vascular endothelial growth factor were the key factors that promoted hUCMSC proliferation. CONCLUSION: This study provides novel evidence for the role of BPS in the survival and rapid proliferation of hUCMSCs and suggests that these cells could be used for cell therapy-based clinical applications for treating severe burns. Furthermore, hUCMSC proliferation was induced by basic fibroblast growth factor/vascular endothelial growth factor in BPS through activation of Notch signal. PMID- 24158197 TI - Restraint stress aggravates rat kidney injury caused by a crush injury through endoplasmic reticulum stress. AB - BACKGROUND: The present study aimed to determine whether restraint stress aggravates kidney injury caused by a crush injury through endoplasmic reticulum stress (ERS). METHODS: In this study, Sprague-Dawley rat restraint stress, crush injury, and stressful injury models consisting of restraint stress and crush injury were established. An ERS inhibitor, Salubrinal (Sal), was administered intraperitoneally 30 minutes before induction of daily injury in the stressful injury group. At the end of the experimental procedures, plasma levels of noradrenaline and adrenaline, creatine phosphokinase, creatinine, and blood urea nitrogen were measured. Kidneys were harvested, and paraffin-embedded sections of kidney tissues were processed for hematoxylin-eosin staining and TUNEL assay to verify pathologic changes. Western blot was used to determine the protein levels of glucose-regulated protein 78, CCAAT/enhancer-binding protein-homologous protein, caspase 12, caspase 3, and MCP-1 in kidney specimens. RESULTS: Compared with crush injury, the most significant changes in kidney injury occurred in the stressful injury group, which was inhibited by Sal. The results suggested that restraint stress aggravates kidney injury caused by a crush injury, and the mechanism might involve ERS. Further study showed that double attacks induced a significant increase in the levels of glucose-regulated protein 78, CCAAT/enhancer-binding protein-homologous protein, caspase 12, and caspase 3, which was inhibited by Sal. The same changes were observed using the TUNEL assay. Double attacks also induced an increased expression of the proinflammatory cytokine, MCP-1, which was inhibited by Sal. CONCLUSION: Apoptosis and inflammation induced by ERS are important mechanisms by which restraint stress aggravates kidney injury caused by a crush injury. PMID- 24158199 TI - Brain-type natriuretic peptide and right ventricular end-diastolic volume index measurements are imprecise estimates of circulating blood volume in critically ill subjects. AB - BACKGROUND: Surrogate indicators have often been used to estimate intravascular volume to guide fluid management. Brain-type natriuretic peptide (BNP) has been used as a noninvasive adjunct in the diagnosis of fluid overload and as a marker of response to therapy, especially in individuals with congestive heart failure. Similarly, right ventricular end-diastolic volume index (RVEDVI) measurements represent another parameter used to guide fluid resuscitation. The aim of this study was to evaluate whether BNP and RVEDVI are clinically valuable parameters that can distinguish among hypovolemia, euvolemia, and hypervolemia, as measured by blood volume (BV) analysis in critically ill surgical subjects. METHODS: This observational study was part of a prospective, randomized controlled trial. Subjects with pulmonary artery catheters for the treatment of traumatic injuries, severe sepsis/septic shock, cardiovascular collapse, adult respiratory distress syndrome, and postsurgical care were studied. Circulating BV was measured by a radioisotope dilution technique using the BVA-100 Analyzer (Daxor Corporation, New York, NY) within the first 24 hours of acute resuscitation. BV results were reported as percent deviation from the patient's ideal BV based on height and percent deviation from optimum weight. Hypovolemia was defined as less than 0%, euvolemia was defined as 0% to +16%, and hypervolemia was defined as greater than +16% deviation from ideal BV. RVEDVI was measured by continuous cardiac output pulmonary artery catheters (Edwards Lifesciences, Irvine, CA). BNP and RVEDVI measurements obtained with BV analysis were evaluated with Fisher's exact test and regression analysis. RESULTS: In 81 subjects, there was no difference in BV status between those with BNP of 500 pg/mL or greater and BNP of less than 500 pg/mL (p = 0.82) or in those with RVEDVI of 140 mL/m or greater and RVEDVI of less than 140 mL/m (p = 0.43). No linear relationship existed between BV and these parameters. CONCLUSION: In critically ill surgical patients, BNP and RVEDVI were not associated with intravascular volume status, although they may be useful as indices that reflect increased cardiac preload. LEVEL OF EVIDENCE: Diagnostic study, level III. PMID- 24158198 TI - The deleterious effect of red blood cell storage on microvascular response to transfusion. AB - BACKGROUND: The transfusion of relatively older red blood cells (RBCs) has been associated with both morbidity and mortality in trauma patients in observational studies. Although the mechanisms responsible for this phenomenon remain unclear, alterations in the microcirculation as a result of the transfusion of relatively older blood may be a causative factor. To assess this hypothesis, we evaluated microvascular perfusion in trauma patients during RBC transfusion. METHODS: Anemic but otherwise stable trauma intensive care unit patients with orders for transfusion were identified. Thenar muscle tissue oxygen saturation (StO(2)) was measured continuously by near-infrared spectroscopy during the course of transfusion of one RBC unit. Sublingual microcirculation was observed by sidestream dark-field illumination microscopy before and after transfusion of one RBC unit. Thenar muscle StO(2) was recorded during the course of transfusion. Pretransfusion and posttransfusion perfused capillary vascular density (PCD) was determined by semiquantitative image analysis. Changes in StO(2) and PCD relative to age of RBC unit were evaluated using mixed models that adjusted for baseline StO(2) and Spearman correlation, respectively. RESULTS: Overall, 93 patients were recruited for study participation, 69% were male, and average Injury Severity Score (ISS) was 26.4. The average pretransfusion hemoglobin was 7.5 mg/dL, and the average age of RBC unit transfused was 29.4 days. The average peritransfusion StO(2) was negatively associated with increasing RBC age (slope, -0.11; p = 0.0014). Change in PCD from pretransfusion to posttransfusion period was found to correlate negatively with RBC storage age (Spearman correlation, -0.27; p = 0.037). CONCLUSION: The transfusion of relatively older RBC units was associated with a decline in both StO(2) and PCD. Collectively, these observations demonstrate that transfusions of older RBC units are associated with the inhibition of regional microvascular perfusion. In patients requiring multiple units of RBCs, alteration of the microcirculation by relatively older units could potentially contribute to adverse outcomes. LEVEL OF EVIDENCE: Prognostic study, level III. PMID- 24158200 TI - Predicting surgical exploration in renal trauma: assessment and modification of an established nomogram. AB - BACKGROUND: This study aimed to externally validate a previously described nomogram that predicts the need for renal exploration in the trauma setting. METHODS: The predicted probability of nephrectomy was manually calculated using prospectively collected data from consecutive patients with renal trauma who presented to our institution between May 2001 and January 2010. To assess nomogram performance, receiver operating characteristic curves against the observed exploration rate were generated, and areas under the curve were calculated. Calibration curves were generated to assess performance across the range of predicted probabilities. Logistic regression modeling was used to determine clinical factors predicting exploration in a contemporary setting, and a nomogram was derived and internally validated using bootstrapping. RESULTS: The established nomogram was applied to the 320 patients who presented during the 9 year period. The global performance of the established nomogram was very high, with an area under the curve of 0.95. However, the model performance was poor for higher predicted probabilities, thus lacking predictive ability in the population where the model has the greatest potential utility. A clinical tool was generated to better predict trauma nephrectomy in our contemporary population, using platelet transfusion within the first 24 hours, blood urea nitrogen, hemoglobin, and heart rate on admission. The global accuracy for the new model was similar to the previous nomogram, but it was significantly better calibrated for patients with higher probabilities of nephrectomy, with good predictive accuracy even in patients with Grade 5 injuries. CONCLUSION: Older nomogram fails to accurately predict renal exploration in high-grade injuries in the contemporary setting. A new nomogram that more accurately predicts the need for exploration is presented. LEVEL OF EVIDENCE: Therapeutic study, level IV; prognostic study, level III. PMID- 24158201 TI - Surgical management of traumatic isolated sternal fracture and manubriosternal dislocation. AB - BACKGROUND: The aim of this study was to evaluate the surgical procedures of osteosynthesis and the respective costs in isolated sternal fractures and manubriosternal dislocations. METHODS: Between January 2006 and July 2011, we treated 47 patients with an isolated fracture and 18 patients with a dislocation of the sternum surgically. In case of sternal fracture, the titanium plate was used in 30 (64%), steel plate in 12 (25%), and steel wire in 5 patients (11%). The stabilization after traumatic luxation was obtained with steel wire in 4 patients (22%) and titanium plate associated with demineralized bone matrix in 14 patients (78%). The quality adjusted life years (QALYs) was analyzed, as well as the incremental cost-effectiveness ratio based on QALYs. RESULTS: In the sternal fractures, titanium plate showed a decreased time of intervention (30 [2] minutes), length of stay (3 [1] days), and total cost (&OV0556;2,277.10) compared with steel plate (&OV0556;2,667.70) and steel wire (&OV0556;2,801.60) procedures, displaying an excellent difference in QALYs (0.825 and 1.615, respectively). In the sternal dislocation, steel wire technique highlighted a poor QALYs, although this approach was less expensive than titanium plate with demineralized bone matrix (&OV0556;3,553.60 vs. &OV0556;6,047.80). Incremental cost-effectiveness ratio revealed that the titanium plate costs were &OV0556;623.55 more than the steel wire per QALYs gained. CONCLUSION: The rigid titanium plate application ensured a safe and easy management of traumatic sternal lesions with a good prognosis of patients, justified by the improved QALYs compared with other methods. LEVEL OF EVIDENCE: Therapeutic study, level IV; economic analysis, level IV. PMID- 24158202 TI - Vancomycin and nephrotoxicity: just another myth? AB - BACKGROUND: Vancomycin is considered the drug of choice for methicillin-resistant Staphylococcus aureus infection; however, it has also been linked with nephrotoxicity in the past, sometimes leading to its substitution with linezolid. We hypothesized that patients treated with vancomycin for gram-positive (GP) infections would have an increased incidence of rise in creatinine and need for hemodialysis (HD) compared with patients receiving linezolid. METHODS: This was a retrospective cohort study of a prospectively maintained database of all surgical patients treated with either vancomycin or linezolid for GP infections in a single intensive care unit from 2001 to 2008 and managed under a cycling antibiotic protocol. Patients were followed up until hospital discharge. Categorical and continuous variables were evaluated. Multivariable logistic regression was performed. RESULTS: A total of 545 patients were treated for 1,046 GP infections (571 with vancomycin, 475 with linezolid) over 7 years. Patient demographics were similar between groups; however, the vancomycin group was associated with a longer treatment course (16.2 [0.5] days vs. 14.3 [0.5] days; p = 0.022). Unadjusted outcomes were similar between groups. Multivariable analysis revealed that Acute Physiology and Chronic Health Evaluation II score predicted an increase in creatinine levels greater than 1.0 following antibiotic therapy (relative risk [RR], 3.01; 95% confidence interval [CI], 1.22-7.42) and subsequent need for HD (RR, 3.07; 95% CI, 1.23-7.62). In addition, initial creatinine level predicted an increase in creatinine levels greater than 1.0 following antibiotic therapy (RR, 4.36; 95% CI, 1.46-12.99) and subsequent need for HD (RR, 10.83; 95% CI, 3.19-36.77). Linezolid was found to be protective regarding rise in creatinine levels greater than 1.0 following antibiotic therapy; however, this was only experienced when vancomycin trough levels greater than 20 were encountered (RR, 5.4;95% CI, 1.19-24.51). CONCLUSION: These data suggest that vancomycin is minimally nephrotoxic and has a similar nephrotoxic profile as compared with linezolid when appropriate dosing is used, even among critically ill patients with complex infections. LEVEL OF EVIDENCE: Therapeutic/care management, level II. PMID- 24158203 TI - The role of serious concomitant injuries in the treatment and outcome of pediatric severe traumatic brain injury. AB - BACKGROUND: The study objective was to describe the epidemiology of serious concomitant injuries and their effects on outcome in pediatric severe traumatic brain injury (sTBI). METHODS: A retrospective cohort of all severely injured (Injury Severity Score [ISS] >= 12) pediatric patients (<18 years) admitted to our pediatric intensive care unit, between 2000 and 2011, after experiencing an sTBI (Glasgow Coma Scale [GCS] score <= 8 and head Abbreviated Injury Scale [AIS] >= 4) were included. Two groups were compared based on the presence of serious concomitant injuries (maximum AIS score >= 3). Multivariate logistic regression was undertaken to determine variable associations with mortality. RESULTS: Of the 180 patients with sTBI, 113 (63%) sustained serious concomitant injuries. Chest was the most commonly injured extracranial body region (84%), with lung being the most often injured. Patients with serious concomitant injuries had increased age, weight, and injury severity (p < 0.001) and were more likely injured in a motor vehicle collision (91% vs. 48%, p < 0.001). Those with serious concomitant injuries had worse sTBI, based on lower presedation GCS (p = 0.031), higher frequency of fixed pupils (p = 0.006), and increased imaging abnormalities (SAH and DAI, p <= 0.01). Non-neurosurgical operations and blood transfusions were more frequent in the serious concomitant injury group (p < 0.01). The differences in mortality for the two groups failed to reach statistical significant (p = 0.053), but patients with serious concomitant injuries had higher rates of infection and acute central diabetes insipidus, fewer ventilator-free days, and greater length of stays (p < 0.05). Multivariate analyses revealed fixed pupillary response (odd ratio [OR], 63.58; p < 0.001), presedation motor GCS (OR, 0.23; p = 0.001), blood transfusion (OR, 5.80; p = 0.008), and hypotension (OR, 4.82; p = 0.025) were associated with mortality, but serious concomitant injuries was not (p = 0.283). CONCLUSION: Head injury is the most important prognostic factor in mortality for sTBI pediatric patients, but the presence of serious concomitant injuries does contribute to greater morbidity, including longer stays, more infections, fewer ventilator-free days, and a higher level of care required on discharge from hospital. LEVEL OF EVIDENCE: Prognostic and epidemiologic study, level III. PMID- 24158204 TI - Spinal cord injury without radiologic abnormality in children imaged with magnetic resonance imaging. AB - BACKGROUND: This study aimed to compare children diagnosed with cervical spinal cord injury without radiographic abnormality (SCIWORA) relative to whether there is evidence of cervical spinal cord abnormalities on magnetic resonance imaging (MRI). METHODS: We conducted a planned subanalysis of a cohort of children younger than 16 years with blunt cervical spine injury presenting to Pediatric Emergency Care Applied Research Network centers from January 2000 to December 2004 who underwent cervical MRI and did not have bony or ligamentous injury identified on neuroimaging. We defined SCIWORA with normal MRI finding as children with clinical evidence of cervical cord injury and a normal MRI finding and compared them with children with SCIWORA who had cervical cord signal changes on MRI (abnormal MRI finding). RESULTS: Of the children diagnosed with cervical spine injury, 55% (297 of 540) were imaged with MRI; 69 had no bony or ligamentous injuries and were diagnosed with SCIWORA by clinical evaluation; 54 (78%) had normal MRI finding, and 15 (22%) had cervical cord signal changes on MRI (abnormal MRI finding). Children with abnormal MRI findings were more likely to receive operative stabilization (0% normal MRI finding vs. 20% abnormal MRI finding) and have persistent neurologic deficits at initial hospital discharge (6% normal MRI finding vs. 67% abnormal MRI finding). CONCLUSION: Children diagnosed with SCIWORA but with normal MRI finding in our cohort presented differently and had substantially more favorable clinical outcomes than those with cervical cord abnormalities on MRI. LEVEL OF EVIDENCE: Epidemiologic study, level III. PMID- 24158205 TI - Incidental findings in patients with multiple injuries: how to proceed? AB - BACKGROUND: Multislice computed tomography (MSCT) is the diagnostic criterion standard for the initial evaluation of patients with suspected multiple injuries. Besides scanning for injuries directly related to the initial trauma, MSCT scans can reveal pathologies unrelated to the trauma of clinical relevance.The aim of the present study was to determine the frequency and follow-up course of incidental findings in patients with multiple injuries. METHODS: This is a retrospective analysis of prospectively collected data on 2,242 patients with suspected multiple injuries at a Level I trauma center from 2006 to 2010.The MSCT reports were retrospectively reviewed regarding abnormal findings not related to trauma. These incidental findings were classified on a four-point level scoring system with respect to clinical importance and urgency for further diagnostic and therapeutic procedures. RESULTS: During initial trauma center evaluation in the emergency department, 2,246 patients met our inclusion criteria. A total of 2,036 patients (90.7%) underwent MSCT; 1,142 (50.9%) of the patients had one or more incidental findings. A total of 2,844 incidental findings were detected. Overall, 349 tumor findings were noted (12.3% of all incidental findings); 113 findings were suspicious for malignant processes or metastasis. According to our classification, 168 (5.9%) of the incidental findings required urgent follow-up (Level 4), and 527 (18.5%) of the incidental findings required a follow-up before discharge (Level 3). CONCLUSION: MSCT in patients with multiple injuries reveals one or more incidental findings in more than one of two patients. A scoring system classifying for relevance of incidental findings was introduced and could be applied in routine trauma care in the future. LEVEL OF EVIDENCE: Epidemiologic study, level III. PMID- 24158206 TI - Early abdominal closure improves long-term outcomes after damage-control laparotomy. AB - BACKGROUND: The impact of initial clinical decisions on the long-term quality of life and functional outcome of patients who undergo damage-control laparotomy (DCL) is unknown. We hypothesized that early abdominal closure after DCL improves long-term outcomes. METHODS: Patients (2005-2011) who underwent DCL (n = 140) at our Level I trauma center were identified. A total of 108 patients survived their hospitalization, and 15 died following discharge. Of the remaining 93 survivors, 59 were unreachable and not present in the social security death index. Our final study population of 34 survivors prospectively completed a standardized study questionnaire, the SF-36 health survey, and inpatient and outpatient records were reviewed. Survivors were compared on the basis of time with final abdominal closure (early, <7 days vs. late, >7 days; either primary closure or Vicryl mesh), and study variables were analyzed. A p < 0.05 was considered significant. RESULTS: Our study population was primarily male (82%) of varying age (36 [13]) and mechanism (blunt 56%, penetrating 44%) with severe injuries (mean [SD] Injury Severity Score [ISS], 17 [8]). Despite no differences in age, sex, mechanism, ISS, admission Glasgow Coma Scale (GCS) score, or admission systolic blood pressure, early-closure patients (n = 13) had shorter hospital (25 days vs. 57 days) and intensive care unit (12 days vs. 20 days) stays and, upon long-term follow-up, higher physical (54 vs. 18), emotional (86 vs. 44), and general health (66 vs. 50) SF-36 scores than late-closure patients (n = 21) (all p < 0.05). Early-closure patients had less daily pain (38% vs. 95%), had higher overall SF 36 scores (66 vs. 46), and were more likely to return to work (54% vs. 10%) than late-closure patients (all p < 0.05). CONCLUSION: Early clinical decisions impact the lives of critically injured patients. Abdominal closure within 7 days of DCL improves long-term quality of life and functional outcome. LEVEL OF EVIDENCE: Therapeutic study, level IV. PMID- 24158207 TI - Contemporary acute care surgery percutaneous endoscopic gastrostomy tube placement: an extreme bumper height and complications. AB - BACKGROUND: As the role of acute care surgery (ACS) becomes more prevalent, clinicians in this specialty will be placing more percutaneous endoscopic gastrostomy (PEG) tubes. In this contemporary series of ACS PEG procedures, we hypothesized that technical aspects of PEG tube placement may play an important role. METHODS: For our retrospective study, we queried our tertiary Level I trauma center's prospectively maintained ACS database for PEG tube placement. Our study period was from July 1, 2010, through June 30, 2012. We excluded patients who underwent "push" PEG placement, an outpatient PEG tube placement, or an open or laparoscopic gastrostomy tube operation. We conducted a multivariate logistic regression analysis of factors contributing to complications. RESULTS: During our 24-month study period, of 184 patients, 133 underwent "pull" PEG tube placement with sufficient data for analysis. The mean (SD) age was 56 (22) years; 66% were male. Overall, 33 (25%) experienced complications: 13 (10%) were major and 20 (15%) were minor complications. In our multivariate logistic regression analysis, we found that an extreme bumper height (<2 or >5 cm) (odds ratio, 1.57; 95% confidence interval, 1.14-2.16) and upper aerodigestive tract malignancy as the operative indication (odds ratio, 1.54; 95% confidence interval, 1.06-2.26) were significantly associated with complications. CONCLUSION: Although pull PEG tube placement is typically a straightforward procedure, morbidity can be significant. Bumper height is an easily modifiable variable; obtaining the proper height for each patient could decrease complications after PEG tube placement. LEVEL OF EVIDENCE: Therapeutic study, level IV. PMID- 24158208 TI - Long-term outcome analysis of liver transplantation for severe hepatic trauma. AB - BACKGROUND: Liver transplantation (LTX) for severe hepatic trauma and its sequelae is a rare but potentially lifesaving option at the far end of the operative spectrum. METHODS: This study analyzes 12 cases with LTX for hepatic trauma and its consequences from two transplant centers. A total of 2,701 consecutive liver transplants unrelated to trauma served as a control group. chi and Mann-Whitney U-tests, Kaplan-Meier analysis with log-rank tests, and Cox regression analysis were applied. Addressed were issues before, during, and after LTX. Major study end points were patient and graft survival. RESULTS: The posttrauma transplant recipients are significantly younger (p = 0.014), with a significantly shorter graft survival (p = 0.038), resulting in a significantly higher retransplantation rate (p = 0.043). Of the 12 patients, 11 underwent surgical treatment for hepatic trauma before LTX with 7 of 12 patients experiencing liver necrosis at the time of LTX. Short-term survival and long-term survival are not significantly different between trauma and nontrauma patients. Severity of liver trauma (Moore Score) and concomitant injuries (Injury Severity Score [ISS]) have no significant impact on patient and graft survival. Four patients with hepatic trauma were treated with two-stage LTX with anhepatic phases between 14 hours and 28 hours. Two of those patients reached long-term survival (20-22 years). CONCLUSION: LTX for severe liver trauma and its consequences seems justified in extreme cases. The high frequency of liver necrosis at the time of LTX may indicate possible shortcomings in liver packing technique or liver resection for hemorrhage control. Thus, severe hepatic trauma requires treatment by experienced liver surgeons and emergency physicians. LEVEL OF EVIDENCE: Therapeutic study, level IV. PMID- 24158209 TI - Burden of hospitalizations for bicycling injuries by motor vehicle involvement: United States, 2002 to 2009. AB - BACKGROUND: Bicycling and bicycling injuries have increased during the past decade in the United States, but research on the extent and outcomes of injuries has lagged behind. This study aimed to estimate the current burden of injury from bicycling injury hospitalizations by motor vehicle crash (MVC) and non-MVC in the United States. METHODS: We included patients with primary or secondary diagnosis e-codes corresponding to MVC or non-MVC bicycle injury, drawn from the US Nationwide Inpatient Sample (2002-2009). Descriptive statistics, linear regression, and logistic regression were used to examine patient and hospital characteristics (length of stay, total charges, nonroutine discharges, and demographics) associated with hospitalizations for bicycling injuries by motor vehicle involvement. RESULTS: On average, from 2002 to 2009, there were an annually estimated 6,877 MVC and 18,457 non-MVC bicycle injury hospitalizations nationwide. This translates to more than $1 billion of hospital charges overall, $425 million for MVC and $588 million for non-MVC per year. After controlling for covariates, MVC bicycling injury hospitalizations had an average length of stay that was 2 days longer (95% confidence interval [CI], 1.8-2.3) and an average hospitalization charge of $23,424 more (95% CI, $21,360-$25,538) than non-MVC. Those with MVC bicycling injuries were more than two times as likely to have a nonroutine hospital discharge than non-MVC (odds ratio, 2.22; 95% CI, 2.06-2.39). CONCLUSION: The burden of injury from bicycle crashes is large overall, and MVC related bicycling injuries result in longer hospital stays, higher costs, and more nonroutine hospital discharges than non-MVC, despite the fact that non-MVC hospitalizations are more frequent and result in higher total charges, overall. To have the greatest impact on reducing the burden of injury from bicycle crashes, educational interventions, policy, and infrastructure changes should include all age groups and prioritize reducing bicycle-motor vehicle collisions. LEVEL OF EVIDENCE: Epidemiologic study, level III. PMID- 24158210 TI - Helmet use is associated with safer bicycling behaviors and reduced hospital resource use following injury. AB - BACKGROUND: While the efficacy of helmet use in the prevention of head injury is well described, helmet use as it relates to bicyclists' behaviors and hospital resource use following injury is less defined. The objective of this study was to compare the demographics, behaviors, hospital workups, and outcomes of bicyclists based on helmet use. METHODS: This study was a subset analysis of a 2.5-year prospective cohort study of vulnerable roadway users conducted at Bellevue Hospital Center, a New York City Level 1 trauma center. All bicyclists with known helmet status were included. Demographics, insurance type, traffic law compliance, alcohol use, Glasgow Coma Scale (GCS) score, initial imaging studies, Abbreviated Injury Scale (AIS) score, Injury Severity Score (ISS), admission status, length of stay, disposition, and mortality were assessed. Information was obtained primarily from patients; witnesses and first responders provided additional information. RESULTS: Of 374 patients, 113 (30.2%) were wearing helmets. White bicyclists were more likely to wear helmets; black bicyclists were less likely (p = 0.037). Patients with private insurance were more likely to wear helmets, those with Medicaid or no insurance were less likely (p = 0.027). Helmeted bicyclists were more likely to ride with the flow of traffic (97.2%) and within bike lanes (83.7%) (p < 0.001 and p = 0.013, respectively). Nonhelmeted bicyclists were more likely to ride against traffic flow (p = 0.003). There were no statistically significant differences in mean GCS score, AIS score, and mean ISS for helmeted versus nonhelmeted bicyclists. Nonhelmeted patients were more likely to have head computed tomographic scans (p = 0.049) and to be admitted (p = 0.030). CONCLUSION: Helmet use is an indicator of safe riding practices, although most injured bicyclists do not wear them. In this study, helmet use was associated with lower likelihood of head CTs and admission, leading to less hospital resource use. Injured riders failing to wear helmets should be targeted for educational programs. LEVEL OF EVIDENCE: Epidemiologic study, level III. PMID- 24158212 TI - Hemorrhagic shock. PMID- 24158211 TI - External fixation for acute pelvic ring injuries: decision making and technical options. PMID- 24158213 TI - Endovascular stent repair of traumatic cervical internal carotid artery injuries. PMID- 24158214 TI - What is the evidence of utility for intraosseous blood transfusion in damage control resuscitation? PMID- 24158215 TI - Extracorporeal life support in patients with multiple injuries and severe respiratory failure: a single-center experience? AB - BACKGROUND: The use of extracorporeal life support in trauma casualties is limited by concerns regarding hemorrhage, particularly in the presence of traumatic brain injury (TBI). We report the use of extracorporeal membrane oxygenation (ECMO)/interventional lung assist (iLA) as salvage therapy in trauma patients. High-flow technique without anticoagulation was used in patients with coagulopathy or TBI. METHODS: Data were collected from all adult trauma patients referred to one center for ECMO/iLA treatment owing to severe hypoxemic respiratory failure. RESULTS: Ten casualties had a mean (SD) Injury Severity Score (ISS) of 50.3 (10.5) (mean [SD] age, 29.8 [7.7] years; 60% male) and were supported 9.5 (4.5) days on ECMO (n = 5) and 7.6 (6.5) days on iLA (n = 5). All experienced blunt injury with severe chest injuries, including one cardiac perforation. Most were coagulopathic before initiation of ECMO/iLA support. Among the seven patients with TBI, four had active intracranial hemorrhage. Complications directly related to support therapy were not lethal; these included hemorrhage from a cannulation site (n = 1), accidental removal of a cannula (n = 1), and pressure sores (n = 3). Deaths occurred owing to septic (n = 2) and cardiogenic shock (n = 1). Survival rates were 60% and 80% on ECMO and iLA, respectively. Follow-up of survivors detected no neurologic deterioration. CONCLUSION: ECMO/iLA therapy can be used as a rescue therapy in adult trauma patients with severe hypoxemic respiratory failure, even in the presence of coagulopathy and/or brain injury. The benefits of rewarming, acid-base correction, oxygenation, and circulatory support must be weighed individually against the risk of hemorrhage. Further research should determine whether ECMO therapy also confers survival benefit. LEVEL OF EVIDENCE: Therapeutic study, level V. PMID- 24158216 TI - The value of digital rectal examination in assessing for pelvic fracture associated urethral injury: what defines a high-riding or nonpalpable prostate? AB - BACKGROUND: The Advanced Trauma Life Support Manual (8th ed.) recommend a digital rectal examination (DRE) as part of the initial evaluation of all trauma patients. A "high-riding" or "nonpalpable" prostate is a contraindication to urethral catheterization and an indication for urethrography. However, there are no published guidelines on, definitions of, or predictive values for high riding. Moreover, prostate evaluation can be difficult in the supine/trauma position. METHODS: A total of 100 patients underwent DRE in lateral decubitus position. Prostate size and distance from anal verge to the prostate apex were recorded. DRE in the supine position was then performed, noting the most proximal part of the prostate that was palpable. High-riding prostate was defined as the apex being one or more SDs farther from the anal verge than the mean. Fifty index finger lengths were measured to ensure that DRE findings were applicable to the average examiner. RESULTS: A total of 100 prostates were evaluated. Mean (SD) distance from the anal verge to the prostate apex in patients with palpable prostates was 4.86 (1.38) cm (range, 2.5-8 cm). The prostate was nonpalpable in the decubitus position in 8 of the 100 patients and in the supine position in 42 of the 100 patients. Mean (SD) body mass index in the nonpalpable group was 32.6 (5.8) kg/m versus palpable group with 28.1 (5.7) kg/m (p < 0.01). Of the 100 patients, 26 had prostates that were "high riding" (defined as >6.2 cm from the anal verge), 2 of which were palpable in the supine position. Palpable prostates were closer to the anal verge at 4.13 cm compared with nonpalpable at 6.15 cm (p < 0.01). Mean (SD) index finger length is 7.3 (0.60) cm. CONCLUSION: DRE in the pelvic fracture trauma setting to evaluate for urethral disruption is unreliable. Patients with a larger body mass index were less likely to have a palpable prostate. The use of the criteria of "nonpalpable" prostate has a high false positive rate. Our objective definition of high-riding prostate should be incorporated into all trauma protocols. LEVEL OF EVIDENCE: Epidemiologic study, level V. PMID- 24158217 TI - From the barn to the operating room and back: the Amish way of life leads to improved throughput and outcomes following trauma. AB - BACKGROUND: The Amish culture is known for simple living, reluctance to use modern technology, and a heavy emphasis on church and family relationships. We hypothesized that the strong work ethic and social structure of the Amish would lead to improved outcome following trauma. METHODS: Trauma registry was queried for all patients from years 2000 to 2010. Patients separated into Amish versus non-Amish. Groups were compared using univariate logistic regression, with the first outcome variable being mortality and the second being hospital length of stay (LOS) greater than 5 days. Factors significant on univariate analysis were included in the multivariate models for the same dependent variables. RESULTS: From 2000 to 2010, our Level II trauma center admitted 18,337 trauma patients, 802 (4.4%) of whom were Amish. When adjusted for age of 65 years or older, Injury Severity Score (ISS) of 16 or greater, and the occurrence of at least one complication, the Amish are at 96% lower odds for having an overall hospital LOS greater than 5 days (odds ratio, 0.51; 95% confidence interval, 0.40-0.66; p < 0.001). The Amish have a 72% lower odds of dying following trauma, when controlling for age of 65 years or older, Glasgow Coma Scale (GCS) score of 13 or less, ISS of 16 or greater, and Revised Trauma Score (RTS) of 7 or less (odds ratio, 0.58; 95% confidence interval, 0.33-0.96; p = 0.036). The hospital LOS model had a receiver operating characteristic curve of 0.77, and the mortality model had a receiver operating characteristic curve of 0.88. CONCLUSION: When adjusted for injury severity, age, and physiology, the Amish have a 72% lower odds of dying following trauma than their non-Amish counterparts. When adjusted for injury severity, age, physiology, and complications, the Amish have a 96% lower odds of having an extended hospital LOS than their non-Amish counterparts. Understanding the unique social structure of the Amish population may allow scarce social services' resources to be shifted to more underserved areas. LEVEL OF EVIDENCE: Epidemiologic, level III. PMID- 24158218 TI - The significance of splenectomy in experimental swine models of controlled hemorrhagic shock. PMID- 24158219 TI - Re: The significance of splenectomy in experimental swine models of hemorrhagic shock. PMID- 24158220 TI - Re: The significance of splenectomy in experimental swine models of hemorrhagic shock. PMID- 24158221 TI - Reducing pediatric firearm injury must start with stronger gun regulations. PMID- 24158222 TI - "Firing" the stapler in emergency general surgery patients: not so fast! PMID- 24158223 TI - Re: "Firing" the stapler in emergency general surgery patients. PMID- 24158226 TI - Internet cigarette vendor compliance with credit card payment and shipping bans. AB - INTRODUCTION: Most Internet cigarette sales have violated taxation and youth access laws, leading to landmark 2005 agreements with credit card companies, PayPal, and private shippers (United Parcel Service, Federal Express, DHL) to cease participation in these transactions. Despite their promise at the time, loopholes allowed for check payment and U.S. Postal Service (USPS) shipping. This study assessed actual vendor compliance with the payment and shipping bans using a purchase survey. METHODS: In late 2007 and early 2008, an adult buyer attempted to order cigarettes from the 97 most popular Internet cigarette vendors (ICVs) using banned payment and shipping methods. When banned payment or shipping methods were unavailable, purchases were attempted with alternate methods (e.g., checks, e-checks, USPS). RESULTS: Twenty-seven of 100 orders were placed with (banned) credit cards; 23 were successfully received. Seventy-one orders were placed with checks (60 successfully received). Four orders were delivered using banned shippers; 79 of 83 successfully received orders were delivered by the USPS. CONCLUSIONS: About a quarter of ICVs violated the payment ban, others adapted by accepting checks. Most vendors complied with the shipping ban, perhaps because USPS was an easy substitute shipping option. Better enforcement of the bans is needed; the 2009 Prevent All Cigarette Trafficking Act closed the USPS loophole by making cigarettes nonmailable material; evaluation of enforcement efforts and adaptations by vendors are needed. These sorts of bans are a promising approach to controlling the sale of restricted goods online. PMID- 24158227 TI - Smoking cessation in homeless populations: who participates and who does not. AB - INTRODUCTION: Although homeless individuals smoke at an alarmingly high rate, few smoking cessation clinical trials have focused on this vulnerable population. Little is known about recruitment efforts and suitable eligibility criteria for tobacco control research in homeless populations. METHODS: The aim of this article is to describe the recruitment, eligibility, and enrollment of homeless smokers who participated in the Power to Quit smoking study, a randomized smoking cessation clinical trial funded by the National Institutes of Health. The study compared motivational interviewing and standard counseling while participants received an 8-week treatment of the nicotine patch. RESULTS: Working with local emergency shelters, a total of 839 adult smokers were screened for study eligibility, 580 of whom (69.1%) met eligibility criteria. Of those eligible, 430 (74.1%) returned for randomization. Those who returned for randomization were older and more likely to have a phone number compared with eligible participants not enrolled. The most common reasons for exclusion included exhaled carbon monoxide levels less than or equal to 5 parts per million (indicating nonsmoking status), use of smoking cessation aid during the past 30 days, and not meeting the study definition of homelessness. CONCLUSION: Knowledge of these factors may help researchers tailor criteria that accurately identify and include homeless smokers in future research. PMID- 24158228 TI - Heaviness of smoking predicts smoking relapse only in the first weeks of a quit attempt: findings from the International Tobacco Control Four-Country Survey. AB - INTRODUCTION: The Heaviness of Smoking Index (HSI) is the measure of dependence most strongly predictive of relapse. However, recent research suggests it may not be predictive of longer-term relapse. Our aim was to examine its predictive power over the first 2 years after quitting and explore whether use of stop-smoking medications is a moderator. METHODS: Data (n = 7,093) came from the first 7 waves (2002-2009) of the International Tobacco Control Four-Country Survey, an annual cohort survey of smokers in Canada, the United States, the United Kingdom, and Australia. HSI and its 2 components (cigarettes per day [CPD] and time to first cigarette [TTFC]) were used to predict smoking relapse risk in the 2 years after the start of a quit attempt. RESULTS: Scores on HSI and its components all strongly predicted relapse, but there was an interaction with time (p < .001). These measures were strong predictors of relapse within the first week of quitting (hazard ratios [HR] = 1.17, 1.24, and 1.30 for HSI, CPD, and TTFC, respectively; all p < .001), less predictive of relapse occurring between 1 week and 1 month, and not clearly predictive beyond 1 month. Among those using medication to quit, hazard ratio for HSI (HR = 1.11, p < .001) was significantly lower than for those not using (HR = 1.24, p < .001) in the first week but not beyond. CONCLUSIONS: HSI and its 2 components are strong predictors of short-term smoking relapse, but they rapidly lose predictive power over the first weeks of an attempt, becoming marginally significant at around 1 month and not clearly predictive beyond then. PMID- 24158229 TI - Statins in chronic kidney disease: what do meta-analyses tell us? AB - Dyslipidemia is common in patients with chronic kidney disease (CKD), and previous reports indicate that a significant number of CKD patients with dyslipidemia do not receive statin therapy. This article reviews two recent meta analyses on statin therapy in CKD which summarize results from randomized controlled trials that have reported on hard clinical outcomes and major adverse events. Despite differences in methodology, both meta-analyses show that statin therapy is safe and effective in preventing mortality and major cardiovascular events in non-dialysis-dependent CKD patients. However, there is very limited evidence to support the use of statins in patients on dialysis, and statin therapy was not found to be effective in reducing the risk of kidney failure or decline in kidney function. PMID- 24158230 TI - Loculated fluid collections evidenced by peritoneal scintigraphy. PMID- 24158231 TI - Comprehensive analysis of oncogenic mutations in lung squamous cell carcinoma with minor glandular component. AB - BACKGROUND: The mutations in oncogenic genes, such as EGFR, ALK, BRAF, HER2, DDR2, RET, and AKT1, defined subsets of non-small cell lung cancers (NSCLCs) with potential sensitivity to targeted therapies. At present, the mutational spectrum, prevalence, and clinicopathologic characteristics in squamous cell carcinomas with minor (<10%) glandular component (SQCC-mGCs) are not well established. METHODS: Three hundred ten surgically resected lung squamous cell carcinoma (SQCC) specimens were collected. The histology of all cases was reevaluated using hematoxylin-eosin and immunohistochemistry staining. EGFR, KRAS, HER2, BRAF, PIK3CA, AKT1, and DDR2 mutations, as well as ALK and RET rearrangements, were examined in 310 SQCCs by directed sequencing. RESULTS: Ninety-five SQCC-mGCs (30.6%) and 215 pure SQCCs (69.4%) were identified. Of the 95 SQCC-mGCs, 26 (27.4%; 95% CI, 18.7%-37.4%) were found to harbor known oncogenic mutations, including 10 with EGFR, seven with KRAS, three with PIK3CA, one with BRAF, one with HER2, one each with EGFR/PIK3CA and KRAS/PIK3CA double mutations, and two with EML4-ALK fusions. Ten of 215 pure SQCCs (4.7%; 95% CI, 2.3%-8.4%) harbored mutations, including seven with PIK3CA, and each with AKT1, DDR2, and EGFR. No RET rearrangements were detected in SQCCs. SQCC-mGCs had a significantly higher rate of mutations in known oncogenic genes than that in pure SQCCs (27.4% vs 4.7%, P<.001). All KRAS mutations occurred in SQCC-mGCs. CONCLUSIONS: Our results demonstrated that oncogenic mutations in EGFR, KRAS, BRAF, HER2, and ALK were extremely rare or absent in patients with pure SQCC, whereas SQCC-mGC had a relatively high frequency of EGFR, ALK, or KRAS mutations. Prospective identification of these known oncogenic mutations in SQCC-mGC before the initiation of treatment is an essential step to identify which patient could benefit from targeted therapies. PMID- 24158232 TI - Is a small-bore catheter efficient for most pleural pathologies? AB - PURPOSE: Chest tubes are used for drainage of the pleural cavity. Traditionally, large-bore catheters are inserted for all indications, but there has been a recent tendency to use small-bore catheters. We share the results of our experience of using small-bore catheters for almost all indications routinely in our clinic. METHODS: A collective total of 309 small-bore chest catheters (10 F) were inserted via the Seldinger technique in 287 patients during a 5-year-period. Malignant pleural effusion and pneumothorax were the most common indications for chest tube insertion. RESULTS: The mean catheter duration was 5.6 days, being 5 days for pneumothorax and 6 days for malignant pleural effusion. Pleurodesis was performed effectively for malignant pleural effusions. In this series, the failure rate of small-bore catheters was 7.2 %. CONCLUSION: Based on our clinical experience of using small-bore catheters, we believe that they are potentially effective for almost all pleural pathologies. Our results concur with those in the literature, but this series also includes different pleural diseases requiring chest tube insertion. PMID- 24158233 TI - Differences in cognitive and emotional outcomes between patients with perimesencephalic and aneurysmal subarachnoid haemorrhage. AB - OBJECTIVES: To compare cognitive and emotional outcomes between patients with aneurysmal and perimesencephalic subarachnoid haemorrhage and norm scores. DESIGN: First measurement in prospective cohort study. PATIENTS: Sixty-seven patients with subarachnoid haemorrhage, were divided into perimesencephalic (n = 8) and aneurysmal (n = 59) subarachnoid haemorrhage groups. METHODS: Patients completed several questionnaires within the first year after haemorrhage. Depression was measured with the Center for Epidemiologic Studies Depression scale, fatigue with the Fatigue Severity Scale, and objective cognitive functioning with the Trail Making Test. Glasgow Coma Scale scores were collected at hospital admission. RESULTS: Perimesencephalic patients had lower depression (p = 0.006) and lower fatigue scores (p = 0.029) and were faster on the Trail Making Test A (p = 0.002) than aneurysmal patients. No differences between the groups were found on Trail Making Test B (p = 0.112) and presence of fatigue (p = 0.105). Compared with norm scores, aneurysmal patients scored significantly worse on all outcomes, whereas perimesencephalic patients scored worse on Trail Making Test B (p < 0.008), fatigue (p = 0.073) and presence of fatigue (p = 0.058). CONCLUSION: Perimesencephalic patients may experience problems in complex cognitive functioning and fatigue. In this respect, they have similar sequelae as aneurysmal patients, which may interfere with daily activities and social participation. These findings are of clinical relevance, as perimesencephalic patients often are discharged from hospital without long-term follow-up. PMID- 24158235 TI - Improved evaluation of calcified segments on coronary CT angiography: a feasibility study of coronary calcium subtraction. AB - We explore the feasibility of coronary calcium subtraction computed tomography angiography (CCTA) in patients with high calcium scores using invasive coronary angiography as the gold standard. Eleven patients with calcium scores of >400 underwent CCTA using a subtraction protocol followed by invasive coronary angiography. In addition to standard reconstructions, subtracted images were obtained using a dedicated subtraction algorithm. A total of 55 calcified segments were evaluated for image quality [using a 4-point scale ranging from 1 (uninterpretable) to 4 (good)] and the presence of significant (>= 50 %) luminal stenosis. Conventional and subtracted CCTA were compared using quantitative coronary angiography (QCA) as the gold standard. The average image quality of conventional CCTA was 2.5 +/- 0.6 versus 3.1 +/- 0.6 on subtraction CCTA (P < 0.001). The percentage of segments with a score 1 or 2 was reduced from 41.8 to 12.7 % after coronary calcium subtraction (P = 0.002). On QCA, significant stenosis was observed in 16 segments. The area under the receiver operating characteristics curve to detect >= 50 % stenosis on QCA increased from 0.741 [95 % confidence interval (CI) 0.598-0.885] for conventional CCTA to 0.905 (95 % CI 0.791-1.000) for subtraction CCTA (P = 0.003). In patients with extensive calcifications undergoing CCTA, coronary calcium subtraction may improve the evaluation of calcified segments. PMID- 24158236 TI - In vivo diagnosis of basal cell carcinoma subtype by reflectance confocal microscopy. AB - BACKGROUND: Reflectance confocal microscopy (RCM) is a noninvasive imaging technique. Currently, RCM is mainly used for the diagnosis of melanoma and nonmelanoma skin cancer including basal cell carcinoma (BCC). Until now, it has not been possible to distinguish between subtypes of BCC using RCM. OBJECTIVE: To establish the RCM features for subtypes of BCC. METHODS: 57 lesions were selected for RCM imaging. Clinical and dermatoscopic pictures were taken and a 3-mm biopsy was obtained. RESULTS: It was demonstrated that tumor nests with peripheral palisading, branch-like structures, fibrotic septa and increase in vascular diameter were characteristic RCM features for nodular and micronodular BCC. The size and shape of the tumor nests allowed further distinction between these BCCs. Solar elastosis and tumor nests connected with the basal cell layer characterize superficial BCC. CONCLUSION: This study presents RCM features for BCC, which might allow in vivo diagnosis of the nodular, micronodular and superficial subtype of BCC. This could prevent a skin biopsy, resulting in direct proper treatment. Further, RCM allows to evaluate the total lesion, which makes it possible to detect mixed-type BCCs. PMID- 24158237 TI - A case of lung metastasis in myxoinflammatory fibroblastic sarcoma: analytical review of one hundred and thirty eight cases. AB - PURPOSE: Myxoinflammatory fibroblastic sarcoma (MIFS) is a rare soft tissue tumour first identified at the end of the 1990s. This study presents our experience and literature reviews focusing on risk of recurrence. METHODS: Rizzoli Orthopaedic Institute database and literature were searched for patients with MIFS observed from 1997 to 2012. Data were analysed in a new database. RESULTS: Five patients underwent surgery at our institute, and 133 cases were retrieved from the literature. Not all clinicopathological data were available: 76/138 were men (55%), median age was 45 [interquartile range (IQR) 34-56] years, median tumour size was three (IQR two to five) centimetres. Common sites of occurrence were hand (24%), fingers (23%) and foot (20%). Pain was present at diagnosis in 14/82 patients (17%), with a median duration of seven (IQR three to 12) months. Surgery was performed for a suspected benign tumour in 88 patients (74%). Resection was incomplete in 45/71 cases (63%); re-excision was performed in 32/45 (71%). At a median follow-up of 26 months, 26/118 patients (22%) developed recurrent disease; median time to recurrence was 15 months (IQR seven to 26). Actuarial relapse-free survival (RFS) at one, three and five years was 93%, 72% and 67%, respectively. At univariate analysis, only symptom duration of six months or less was significantly associated with a worse RFS (p = 0.046). Metastatic disease to lymph nodes and/or lungs was observed in four patients (3%). CONCLUSIONS: Clinicopathological findings confirm the low-grade nature of MIFS. However, local recurrence occurs, and patients may be affected by aggressive forms with a potential for distant metastases. Follow-up is strongly advised. PMID- 24158238 TI - Radiological evaluation for conflict of the femoral tunnel entrance area prior to anterior cruciate ligament revision surgery. AB - PURPOSE: Anterior cruciate ligament (ACL) revision surgery is a demanding procedure and requires meticulous pre-operative clinical and radiological assessment. In clinical practice the position of the femoral tunnel is identified mainly using plain radiographs (XR). Two-dimensional computed tomography (2D-CT) and magnetic resonance imaging (MRI) are not yet routine imaging methods and are only performed in specific clinical indications or in the scientific setting. Several measurement methods describe the femoral tunnel after ACL reconstruction and indicate 'ideal or wrong' placement to the surgeon. The aim of this study is to provide a reliable measurement method to predict potential conflict between the pre-existing and the planned femoral tunnel entrance area (FTEA). METHODS: Ten patients with primary ACL reconstruction served as a reference group to describe our desired FTEA. Their femoral tunnel positioning was measured on XR and 2D-CT according to published measurement methods. These results were compared to the FTEA measured with a new technique on 3-dimensionally reconstructed CT images (3D-CT) based on intra-operative landmarks. Twenty patients requiring ACL revision surgery underwent identical radiological examination. The mean values of the reference group were compared to each measurement of the patients requiring revision surgery. RESULTS: 3D-CT measurements found potential conflicts in nine out of 20 patients, which all proved to be true during arthroscopic revision surgery. Only one of these patients was identified in all XR and 2D-CT measurements. In 12 out of all 30 patients some measurements on XR or 2D-CT could not be recorded. CONCLUSION: 3D-CT reconstruction shows the most accuracy in depicting conflict of the pre-existing and desired femoral tunnel prior to ACL revision surgery. The desired FTEA must be defined for each surgeon and his individual technique. In contrast, precision of conventional measurement techniques on XR and 2D-CT is low and does not qualify for this purpose. PMID- 24158239 TI - Clinical outcomes of Kyocera Modular Limb Salvage system after resection of bone sarcoma of the distal part of the femur: the Japanese Musculoskeletal Oncology Group study. AB - PURPOSE: The Japanese Musculoskeletal Oncology Group have developed an original prosthesis called the Kyocera Modular Limb Salvage system (KMLS system). This prosthesis has a semi-rotating hinge joint and is particularly designed for people with an Asian body type. The metallic parts of the prosthesis are made entirely of titanium alloy. The purpose of this study is to evaluate the clinical outcomes of treatment using this system following tumour resection of primary bone sarcoma of the distal femur. METHODS: Between 2002 and 2010, 82 patients with primary bone sarcomas of the distal femur were treated. Seventeen patients underwent stem cementation, while 65 patients were treated with cementless prostheses. The mean follow-up period after surgery was 61 months. RESULTS: Complications were observed in 28 of the 82 patients. Forty-one complications occurred in these 28 patients. Thirteen prostheses (16%) required revision surgery due to complications, including five cases of stem breakage, three deep infections, three cases of aseptic loosening, one case of displacement of the shaft cap and one case of breakage of the tibial tray. The five-year overall prosthetic survival rate was 80.0%. Four of the 82 patients underwent subsequent amputation due to local recurrence. The five-year limb salvage rate was 94.5%. The mean function score according to the scoring system of the Musculoskeletal Tumour Society was 21.8 points (72.5%). CONCLUSIONS: Although further follow-up is required to determine the performance, this prosthesis is considered to be satisfactory for reconstruction of the distal femur after resection of bone sarcoma. PMID- 24158240 TI - gamma-AApeptide-based small-molecule ligands that inhibit Abeta aggregation. AB - We report the design, synthesis, characterization and evaluation of a novel class of gamma-AApeptide one-bead-one-compound (OBOC) library, from which a small gamma AApeptide was identified to effectively prevent and disassemble Abeta aggregation. PMID- 24158241 TI - Factor analysis of the pediatric symptom checklist in a population of children with voiding dysfunction and/or nocturnal enuresis. AB - The research objective was to identify the factor structure of the pediatric symptom checklist (PSC) in children with voiding dysfunction and/or nocturnal enuresis who were seen in a pediatric urology clinic. Retrospective chart reviews were conducted for 498 consecutive patients, ages 6-16, who were seen over a 13 month period. The PSC, a 35-item measure used to screen for psychosocial difficulties, was completed by the patient's caregiver. Confirmatory factor analyses using three previous models were conducted. A four factor model comprised of internalizing, externalizing, attention problems, and chronic illness factors represented the best fit to the data. Within this population, the PSC appears to capture internalizing and externalizing problems, difficulties with attention, and possible side effects of a medical condition. This information could aid clinicians in assessing adjustment difficulties within this population and concurrently allow researchers to examine whether these specific factors are related to other relevant outcomes. PMID- 24158242 TI - Health-related outcomes associated with patterns of risk factors in primary care patients. AB - It is important to find ways to identify prevalent co-occurring health risk factors to help facilitate treatment programming. One method is to use electronic medical record (EMR) data. Funderburk et al. (J Behav Med 31:525-535, 2008) used such data and latent class analysis to identify three classes of individuals based on standard health screens administered in Veterans Affairs primary care clinics. The present study extended these results by examining the health-related outcomes for each of these identified classes. Follow-up data were collected from a subgroup of the original sample (N = 4,132). Analyses showed that class assignment predicted number of diagnoses associated with the diseases that the health screens target and number of primary care behavioral health, and emergency room encounters. The findings illustrate one way an EMR can be used to identify clusters of individuals presenting with multiple health risk factors and where the healthcare system comes in contact with them. PMID- 24158243 TI - Anterior superior iliac spine avulsion fracture presenting as meralgia paraesthetica in an adolescent sprinter. AB - OBJECTIVE: We report here a rare case of anterior superior iliac spine avulsion fracture that presented initially as meralgia paraesthetica. CASE REPORT: A 14 year-old male sprinter presented with anterior superior iliac spine avulsion fracture, which was not observed on initial plain radiograph of the hip, but was diagnosed by ultrasound. Both clinical presentations and electrophysiological studies indicated meralgia paraesthetica. The lateral femoral cutaneous nerve of the thigh was probably compressed by an inguinal haematoma resulting from sartorius muscle strain, which was detected on musculoskeletal ultrasound. Computed tomography of the pelvis confirmed anterior superior iliac spine avulsion fracture. CONCLUSION: Meralgia paraesthetica in adolescents can be due to anterior superior iliac spine avulsion fracture. Sonography is a valuable tool for screening for muscular haematoma and occult fractures, which may allow clinicians to diagnose the nature of the muscle injury, and thus guide the most appropriate therapeutic strategy. PMID- 24158244 TI - Reply to letter received from Prof Michael Bohnert regarding article on "Tongue protrusion as an indicator of vital burning". PMID- 24158245 TI - Anterior video-assisted approach to the craniovertebral junction: transnasal or transoral? A cadaver study. AB - BACKGROUND: Endoscopy represents both an alternative and useful complement to the standard microsurgical approach to the anterior craniovertebral junction (CVJ). Nevertheless, few studies provide an experimental comparison between transnasal and transoral endoscopic control on CVJ. We compared the surgical exposition angle and the working channel volume of both the transnasal and transoral approaches in the cadaver. METHODS: Eleven fresh non-perfused cadavers were studied. Transnasal and transoral linear and angled exposure of the CVJ were evaluated by means of X-ray and CT scan both in sagittal and lateral planes. RESULTS: The transoral endoscopic surgical exposition was wider compared with the transnasal in anterior and lateral projections:(1)in the sagittal plane, both in vertical exposition (transnasal inferior to transoral from 5.89 % to 76.48 %, average 35.89 %) and in vertical surgical angle (from 22 % to 77.42 %, average 56.53 %); (2)in the coronal plane, both in coronal exposition (transnasal inferior to transoral from 50.77 % to 83.88 %, average 70.34 %) and in coronal surgical angle (from 65.58 % to 86.71 %, average 76.70 %). The sagittal surgical domain was found to spanning from the inferior third of the clivus to C3 with the transoral and from the middle third of the clivus to the nasopalatal line (NPL) with the transnasal approach. The overlapping surgical domain area was found to be the inferior third of the clivus. CONCLUSIONS: The endoscope assisted transoral approach allows a better surgical control of the CVJ. It provides a better CVJ exposure, in sagittal and transverse planes, providing a larger working channel and an easier manoeuvrability. The transnasal approach is limited in caudal direction down to the NPL, otherwise the transoral approach is limited in the rostral direction with a maximum to the foramen magnum in normal specimen. In every individual case, pros and cons of the appropriate approach have to be taken into account as well as the choice of a combined transnasal and transoral approaches strategy. PMID- 24158246 TI - Transcranial segment of the trigeminal nerve: macro-/microscopic anatomical study using sheet plastination. AB - BACKGROUND: Trigeminal neuralgia (TN) may be caused by the mechanical compression of the trigeminal nerve. In the studies on the location of mechanical irritation and entrapment of the nerve, attention has been paid mostly to vascular structures in the subarachnoid space. Few studies have explored the relationship between the trigeminal nerve and its surrounding structures along its course in the skull base. The aim of this study was to examine and trace the root, ganglion and three divisions of the trigeminal nerve and their relationships with surrounding soft and bony structures in the skull base, and to identify the likely mechanical compression points. METHODS: A total of 26 adult cadavers (ten females, 16 males; age range, 45-81 years) were examined in this study, eight for dissection and 16 for sheet plastination study. RESULTS: Anatomical structures that may make the trigeminal nerve susceptible to entrapment in the skull base were located at (1) the inferolateral edge of the mouth of Meckel's cave, (2) the middle cranial fossa dura and the lateral wall of the anterior intracavernous portion of the internal carotid artery, (3) the ridge of the medial wall of the foramen rotundum, and (4) the twisted periosteum and venous plexus of the foramen ovale. CONCLUSION: This study identified four likely mechanical compression points along the course of the trigeminal nerve in the skull base. Knowledge of these TN-susceptible sites may be useful to both skull base surgeon and TN-animal model researcher, particularly when they study TN without vascular compression. PMID- 24158247 TI - Duration of benefit in patients with autoimmune pulmonary alveolar proteinosis after inhaled granulocyte-macrophage colony-stimulating factor therapy. AB - BACKGROUND: Treatment of autoimmune pulmonary alveolar proteinosis (aPAP) by subcutaneous injection or inhaled therapy of granulocyte-macrophage colony stimulating factor (GM-CSF) has been demonstrated to be safe and efficacious in several reports. However, some reports of subcutaneous injection described transient benefit in most instances. The durability of response to inhaled GM-CSF therapy is not well characterized. METHODS: To elucidate the risk factors for recurrence of aPAP after GM-CSF inhalation, 35 patients were followed up, monitoring for the use of any additional PAP therapies and disease severity score every 6 months. Physiologic, serologic, and radiologic features of the patients were analyzed for the findings of 30-month observation after the end of inhalation therapy. RESULTS: During the observation, 23 patients remained free from additional treatments, and twelve patients required additional treatments. There were no significant differences in age, sex, symptoms, oxygenation indexes, or anti-GM-CSF antibody levels at the beginning of treatment between the two groups. Baseline vital capacity (% predicted, %VC) were higher among those who required additional treatment (P<.01). Those patients not requiring additional treatment maintained the improved disease severity score initially achieved. A significant difference in the time to additional treatment between the high %VC group (%VC>=80.5) and the low %VC group was seen by a Kaplan-Meier analysis and a log-rank test (P<.0005). CONCLUSIONS: These results demonstrate that inhaled GM CSF therapy sustained remission of aPAP in more than one-half of cases, and baseline %VC might be a prognostic factor for disease recurrence. TRIAL REGISTRY: ISRCTN Register and JMACCT Clinical Trial Registry; No.: ISRCTN18931678 and JMAIIA00013; URL: http://www.isrctn.org and http://www.jmacct.med.or.jp. PMID- 24158248 TI - Eicosapentaenoic Acid combined with optimal statin therapy improves endothelial dysfunction in patients with coronary artery disease. AB - PURPOSE: Eicosapentaenoic acid (EPA) has been reported to augment endothelial function and improve clinical outcomes in patients with coronary artery disease (CAD). The purpose of this study was to determine whether EPA could improve residual endothelial dysfunction despite adequate lipid-lowering with statin in CAD patients. METHODS: Eighty patients with established CAD, who had been on statin treatment and had serum low-density lipoprotein cholesterol (LDL-C) levels <100 mg/dl, were randomly assigned to receive either 1,800 mg of EPA daily plus statin (EPA group, n = 40) or statin alone (Control group, n = 40). Lipid profiles and flow-mediated dilation (FMD) were assessed just before and after more than 3 months of treatment in both groups. Only patients who had impaired FMD (<6 %) before randomization were enrolled. RESULTS: After treatment for 5.2 +/- 1.7 months, the EPA group showed a significant increase in the serum concentration of EPA and EPA to arachidonic acid (AA) (EPA/AA) ratio (62.5 +/- 38.1 to 159.8 +/- 53.8 MUg/ml, 0.45 +/- 0.34 to 1.20 +/- 0.55, p < 0.01 for both). In the EPA group, serum triglycerides significantly decreased (150.7 +/- 92.9 to 119.3 +/- 60.7 mg/dl, p = 0.02), whereas no significant change was seen in the Control group. FMD, the primary study endpoint, showed a significant improvement in the EPA group (2.6 +/- 1.6 % to 3.2 +/- 1.6%, p = 0.02), whereas no significant change was observed in the Control group (2.7 +/- 1.6% to 2.4 +/- 1.7 %, p = 0.29). CONCLUSIONS: EPA improved endothelial function and impaired FMD in patients with established CAD who were on optimal statin therapy. PMID- 24158249 TI - Mapping and genomic targeting of the major leaf shape gene (L) in Upland cotton (Gossypium hirsutum L.). AB - KEY MESSAGE: A major leaf shape locus (L) was mapped with molecular markers and genomically targeted to a small region in the D-genome of cotton. By using expression analysis and candidate gene mapping, two LMI1 -like genes are identified as possible candidates for leaf shape trait in cotton. Leaf shape in cotton is an important trait that influences yield, flowering rates, disease resistance, lint trash, and the efficacy of foliar chemical application. The leaves of okra leaf cotton display a significantly enhanced lobing pattern, as well as ectopic outgrowths along the lobe margins when compared with normal leaf cotton. These phenotypes are the hallmark characteristics of mutations in various known modifiers of leaf shape that culminate in the mis/over-expression of Class I KNOX genes. To better understand the molecular and genetic processes underlying leaf shape in cotton, a normal leaf accession (PI607650) was crossed to an okra leaf breeding line (NC05AZ21). An F2 population of 236 individuals confirmed the incompletely dominant single gene nature of the okra leaf shape trait in Gossypium hirsutum L. Molecular mapping with simple sequence repeat markers localized the leaf shape gene to 5.4 cM interval in the distal region of the short arm of chromosome 15. Orthologous mapping of the closely linked markers with the sequenced diploid D-genome (Gossypium raimondii) tentatively resolved the leaf shape locus to a small genomic region. RT-PCR-based expression analysis and candidate gene mapping indicated that the okra leaf shape gene (L (o) ) in cotton might be an upstream regulator of Class I KNOX genes. The linked molecular markers and delineated genomic region in the sequenced diploid D-genome will assist in the future high-resolution mapping and map-based cloning of the leaf shape gene in cotton. PMID- 24158250 TI - Characterization and genetic mapping of a Photoperiod-sensitive dwarf 1 locus in rice (Oryza sativa L.). AB - Plant height is an important agronomic trait for crop architecture and yield. Most known factors determining plant height function in gibberellin or brassinosteroid biosynthesis or signal transduction. Here, we report a japonica rice (Oryza sativa ssp. japonica) dominant dwarf mutant, Photoperiod-sensitive dwarf 1 (Psd1). The Psd1 mutant showed impaired cell division and elongation, and a severe dwarf phenotype under long-day conditions, but nearly normal growth in short-day. The plant height of Psd1 mutant could not be rescued by gibberellin or brassinosteroid treatment. Genetic analysis with R1 and F2 populations determined that Psd1 phenotype was controlled by a single dominant locus. Linkage analysis with 101 tall F2 plants grown in a long-day season, which were derived from a cross between Psd1 and an indica cultivar, located Psd1 locus on chromosome 1. Further fine-mapping with 1017 tall F2 plants determined this locus on an 11.5-kb region. Sequencing analysis of this region detected a mutation site in a gene encoding a putative lipid transfer protein; the mutation produces a truncated C terminus of the protein. This study establishes the genetic foundation for understanding the molecular mechanisms regulating plant cell division and elongation mediated by interaction between genetic and environmental factors. PMID- 24158252 TI - Validation of non-contact and point-to-point mapping in a single electroanatomic map. PMID- 24158251 TI - Genome-wide marker development for the wheat D genome based on single nucleotide polymorphisms identified from transcripts in the wild wheat progenitor Aegilops tauschii. AB - KEY MESSAGE: 13,347 high-confidence SNPs were discovered through transcriptome sequencing of Aegilops tauschii, which are useful for genomic analysis and molecular breeding of hexaploid wheat. In organisms with large and complex genomes, such as wheat, RNA-seq analysis is cost-effective for discovery of genome-wide single nucleotide polymorphisms (SNPs). In this study, deep sequencing of the spike transcriptome from two Aegilops tauschii accessions representing two major lineages led to the discovery of 13,347 high-confidence (HC) SNPs in 4,872 contigs. After removing redundant SNPs detected in the leaf transcriptome from the same accessions in an earlier study, 10,589 new SNPs were discovered. In total, 5,642 out of 5,808 contigs with HC SNPs were assigned to the Ae. tauschii draft genome sequence. On average, 732 HC polymorphic contigs were mapped in silico to each Ae. tauschii chromosome. Based on the polymorphic data, we developed markers to target the short arm of chromosome 2D and validated the polymorphisms using 20 Ae. tauschii accessions. Of the 29 polymorphic markers, 28 were successfully mapped to 2DS in the diploid F2 population of Ae. tauschii. Among ten hexaploid wheat lines, which included wheat synthetics and common wheat cultivars, 25 of the 43 markers were polymorphic. In the hexaploid F2 population between a common wheat cultivar and a synthetic wheat line, 23 of the 25 polymorphic markers between the parents were available for genotyping of the F2 plants and 22 markers mapped to chromosome 2DS. These results indicate that molecular markers that developed from polymorphisms between two distinct lineages of Ae. tauschii might be useful for analysis not only of the diploid, but also of the hexaploid wheat genome. PMID- 24158253 TI - Atrial fibrillation patients do not benefit from acetylsalicylic acid. AB - AIMS: Oral anticoagulation is the recommended treatment for stroke prevention in patients with atrial fibrillation. Notwithstanding, many patients are treated with acetylsalicylic acid (ASA) as monotherapy. Our objective was to investigate if atrial fibrillation patients benefit from ASA as monotherapy for stroke prevention. METHODS AND RESULTS: Retrospective study of patients with a clinical diagnosis of atrial fibrillation between 1 July 2005 and 1 January 2009 in the National Swedish Patient register, matched with data from the National Prescribed Drugs register. Endpoints were ischaemic stroke, thrombo-embolic event, intracranial haemorrhage, and major bleeding. The study population consisted of 115 185 patients with atrial fibrillation, of whom 58 671 were treated with ASA as monotherapy and 56 514 were without any antithrombotic treatment at baseline. Mean follow-up was 1.5 years. Treatment with ASA was associated with higher risk of ischaemic stroke and thrombo-embolic events compared with no antithrombotic treatment. CONCLUSION: Acetylsalicylic acid as monotherapy in stroke prevention of atrial fibrillation has no discernable protective effect against stroke, and may even increase the risk of ischaemic stroke in elderly patients. Thus, our data support the new European guidelines recommendation that ASA as monotherapy should not be used as stroke prevention in atrial fibrillation. PMID- 24158254 TI - What is the next step after a failed standard radiofrequency ablation of atrioventricular nodal tachycardia? PMID- 24158255 TI - Role of extended external loop recorders for the diagnosis of unexplained syncope, pre-syncope, and sustained palpitations. AB - AIMS: To assess the diagnostic yield of new external loop recorders (ELRs) in patients with history of syncope, pre-syncope, and sustained palpitations. METHODS AND RESULTS: Since 2005, we have established a registry including patients who consecutively received ELR monitoring for unexplained syncope or pre syncope/palpitations. The registry included 307 patients (61% females, age 58 +/- 19 years, range 8-94 years) monitored by high-capacity memory ELR of two subsequent generations: SpiderFlash-A((r)) (SFA((r)), Sorin CRM), storing two lead electrocardiogram (ECG) patient-activated recordings by loop-recording technique (191 patients, 54 patients with syncope, years 2005-09), and SpiderFlash-T((r)) (SFT((r))), adding auto-trigger detection for pauses, bradycardia, and supraventricular/ventricular arrhythmias (116 patients, 38 patients with syncope, years 2009-12). All the patients previously underwent routine workup for syncope or palpitation, including one or more 24 h Holter, not conclusive for diagnosis. Mean monitoring duration was 24.1 +/- 8.9 days. Among 215 patients with palpitations, a conclusive diagnosis was obtained in 184 patients (86% diagnostic yield for palpitation). Among 92 patients with syncope, a conclusive diagnosis was obtained in 16 patients (17% clinical diagnostic yield for syncope), with recording during syncope of significant arrhythmias in 9 patients, and sinus rhythm in 7 patients. Furthermore, asymptomatic arrhythmias were de novo detected in 12 patients (13%), mainly by auto-trigger detection, suggesting an arrhythmic origin of the syncope. CONCLUSIONS: The diagnostic yield of ELR in patients with syncope, pre-syncope, or palpitation of unknown origin after routine workup was similar to implantable loop recorder (ILR) within the same timeframe, therefore, ELR could be considered for patients candidate for long-term ECG monitoring, stepwise before ILR. PMID- 24158256 TI - Coronary artery reperfusion for ST elevation myocardial infarction is associated with shorter cycle length ventricular tachycardia and fewer spontaneous arrhythmias. AB - AIMS: Ventricular tachycardia (VT) induction at electrophysiological (EP) study early after ST elevation myocardial infarction (STEMI) has been a predictor of spontaneous ventricular arrhythmia. Reperfusion therapy for STEMI may have resulted in altered VT character. We attempted to determine differences in VT cycle length (CL) and VT recurrence rates, in patients who received early and late reperfusion treatment for STEMI. METHODS AND RESULTS: Of 180 consecutive patients with left ventricular ejection fraction < 40%, 77 patients had positive EP studies. Forty-nine patients receiving early reperfusion treatment (group 1, n = 49) were compared with 28 patients who received late reperfusion (group 2; n = 28). Seventy-five patients had defibrillators implanted for primary prevention of sudden death. Patients were followed for up to 6 years to assess long-term rates of spontaneous ventricular tachyarrhythmia. Patients who received early reperfusion demonstrated shorter CL inducible VT (231 +/- 43 ms vs. 252 +/- 56 ms; P = 0.016). They also had fewer spontaneous arrhythmias (adjusted hazard ratio of 2.94, 95% confidence interval: 1.07-8.13; P = 0.03) with shorter CL spontaneous VT (266 +/- 54 ms vs. 320 +/- 80 ms; P = 0.02) at 53 +/- 33 months. Ventricular tachycardia CL was the only independent predictor of spontaneous arrhythmia or sudden cardiac death (1.22, 1.07-1.47; P = 0.016). CONCLUSIONS: Patients receiving early reperfusion for STEMI had faster inducible and spontaneous VT and fewer spontaneous recurrences. This may be due to changes in the myocardial substrate as a result of early coronary artery reperfusion. PMID- 24158257 TI - Adenosine reveals dormant conduction of an arrhythmogenic thoracic vein despite the absence of previous ablation. PMID- 24158258 TI - Remote magnetic ablation of atrial fibrillation is safe and feasible in the presence of a left atrial appendage closure device. PMID- 24158259 TI - Intra-isthmus reentry: diagnosis at-a-glance. PMID- 24158260 TI - Response of chlorophyll d-containing cyanobacterium Acaryochloris marina to UV and visible irradiations. AB - We have previously investigated the response mechanisms of photosystem II complexes from spinach to strong UV and visible irradiations (Wei et al J Photochem Photobiol B 104:118-125, 2011). In this work, we extend our study to the effects of strong light on the unusual cyanobacterium Acaryochloris marina, which is able to use chlorophyll d (Chl d) to harvest solar energy at a longer wavelength (740 nm). We found that ultraviolet (UV) or high level of visible and near-far red light is harmful to A. marina. Treatment with strong white light (1,200 MUmol quanta m(-2) s(-1)) caused a parallel decrease in PSII oxygen evolution of intact cells and in extracted pigments Chl d, zeaxanthin, and alpha carotene analyzed by high-performance liquid chromatography, with severe loss after 6 h. When cells were irradiated with 700 nm of light (100 MUmol quanta m( 2) s(-1)) there was also bleaching of Chl d and loss of photosynthetic activity. Interestingly, UVB radiation (138 MUmol quanta m(-2) s(-1)) caused a loss of photosynthetic activity without reduction in Chl d. Excess absorption of light by Chl d (visible or 700 nm) causes a reduction in photosynthesis and loss of pigments in light harvesting and photoprotection, likely by photoinhibition and inactivation of photosystem II, while inhibition of photosynthesis by UVB radiation may occur by release of Mn ion(s) in Mn4CaO5 center in photosystem II. PMID- 24158261 TI - Factors associated with impaired quality of life in adult patients suffering from ichthyosis. PMID- 24158262 TI - Phase ordering kinetics in uniaxial nematic liquid crystals with second- and fourth-rank interactions. AB - We present comprehensive results of the Monte Carlo (MC) simulations of the phase ordering dynamics in d = 2 nematic liquid crystals. We study a system of size N (2)(N = 512) with molecules confined to a 512*512 square lattice and report the results for two LC Hamiltonians: generalized Lebwohl-Lasher (GLL) model and r(-6) dependent anisotropic dispersion interaction potential. In these Hamiltonians a fourth-rank Legendre polynomial P4 interaction term is added to the usual second rank P2 term. We find that in both the cases the presence of the P4 interaction term significantly influences the nematic domains morphology. Our numerical data show a diffusive growth law with a logarithmic correction: L(t) ~ (t/ln t)(1/2). PMID- 24158263 TI - Phenomenological and statistical analyses of turbulence in forced convection with temperature-dependent viscosity under non-Boussinesq condition. AB - In this work, Thermal Large Eddy Simulation (TLES) is performed to study the behavior of weakly compressible Newtonian fluids with anisotropic temperature dependent viscosity in forced convection turbulent flow. A systematic analysis of variable-viscosity effects, isolated from gravity, with relevance to industrial cooling/heating applications is being carried out. A LES of a planar channel flow with significant heat transfer at a low Mach number was performed to study effects of fluid property variation on the near-wall turbulence structure. In this flow configuration the top wall is maintained at a higher temperature (T hot ) than the bottom wall (T cold ). The temperature ratio (R theta = T hot /T cold ) is fixed at 1.01, 2 and 3 to study the effects of property variations at low Mach number. Results indicate that average and turbulent fields undergo significant changes. Compared with isothermal flow with constant viscosity, we observe that turbulence is enhanced in the cold side of the channel, characterized by locally lower viscosity whereas a decrease of turbulent kinetic energy is found at the hot wall. The turbulent structures near the cold wall are very short and densely populated vortices but near the hot wall there seems to be a long streaky structure or large elongated vortices. Spectral study reveals that turbulence is completely suppressed at the hot side of the channel at a large temperature ratio because no inertial zone is obtained (i.e. index of Kolmogorov scaling law is zero) from the spectra in these region. PMID- 24158264 TI - Noise-induced regime shifts: A quantitative characterization. AB - Diverse complex dynamical systems are known to exhibit abrupt regime shifts at bifurcation points of the saddle-node type. The dynamics of most of these systems, however, have a stochastic component resulting in noise-driven regime shifts even if the system is away from the bifurcation points. In this paper, we propose a new quantitative measure, namely, the propensity transition point as an indicator of stochastic regime shifts. The concepts and the methodology are illustrated for the one-variable May model, a well-known model in ecology and the genetic toggle, a two-variable model of a simple genetic circuit. The general applicability and usefulness of the method for the analysis of regime shifts is further demonstrated in the case of the mycobacterial switch to persistence for which experimental data are available. PMID- 24158265 TI - Electro-hydrodynamic instability of stressed viscoelastic polymer films. AB - We study the stability of a viscoelastic thin polymer film under two destabilization factors: the application of an electric field normal to the surface--as in typical electro-hydrodynamic destabilization experiments--and the presence of a frozen-in internal residual stress, stemming from the preparation process of the film, typically spin-coating. At the film-substrate interface we consider a general boundary condition, containing perfect gliding on slippery substrates, as well as perfect sticking of the film to the substrate as limiting cases. We show that the interplay of the two sources of stress, the viscoelasticity and the boundary condition, leads to a rich behavior, especially as far as the fastest growing wave number (or wavelength) is concerned. The latter determines the initial growth of the instability, and often also the final pattern obtained in small capacitor gaps, and is the main experimental observable. PMID- 24158266 TI - Phase separation and disorder in doped nematic elastomers. AB - We formulate and analyse a model describing the combined effect of mechanical deformation, dynamics of the nematic order parameter, and concentration inhomogeneities in an elastomeric mixture of a mesogenic and an isotropic component. The uniform nematic state may exhibit a long-wave instability corresponding to nematic-isotropic demixing. Numerical simulations starting from either a perfectly ordered nematic state or a quenched isotropic state show that coupling between the mesogen concentration and the nematic order parameter influences the shape and orientation of the domains formed during the demixing process. PMID- 24158267 TI - Chemo-, regio-, and stereoselective iron-catalysed hydroboration of alkenes and alkynes. AB - The highly chemo-, regio-, and stereoselective synthesis of alkyl- and vinyl boronic esters with good functional group tolerance has been developed using in situ activation of a bench-stable iron(II) pre-catalyst and pinacolborane (16 examples, 45-95% yield, TOF up to 30,000 mol h(-1)). The first iron-catalysed alkene hydrogermylation is also reported. PMID- 24158268 TI - Real-time monitoring of (E)-beta-farnesene emission in colonies of the pea aphid, Acyrthosiphon pisum, under lacewing and ladybird predation. AB - Aphids (Homoptera) are constantly under attack by a variety of predators and parasitoids. Upon attack, most aphids release alarm pheromone that induces escape behavior in other colony members, such as dropping off the host plant. In the pea aphid, Acyrthosiphon pisum Harris (Aphididae), the only component of this alarm pheromone is the sesquiterpene (E)-beta-farnesene (EBF). EBF is thought to act as a kairomone by attracting various species of parasitoids and predators including lacewings and ladybirds. Lately, it also was proposed that EBF is constantly emitted in low quantities and used by aphids as a social cue. No study has focused on emission dynamics of this compound over a long time period. Here, we present the first long-time monitoring of EBF emission in aphid colonies using real-time monitoring. We used a zNose(TM) to analyze the headspace of colonies of the pea aphid, under lacewing (Neuroptera: Chrysopidae) and ladybird (Coleoptera: Coccinellidae) predation, over 24 hr. We found no emission of EBF in the absence of predation. When either a ladybird adult or a lacewing larva was placed in an aphid colony, EBF was detected in the headspace of the colonies in the form of emission blocks; i.e., periods in which EBF was emitted alternating with periods without EBF emission. The number of emission blocks correlated well with the number of predation events that were determined at the end of each experiment. There was no circadian rhythm in alarm pheromone emission, and both predators were active during both night and day. Our results show that alarm pheromone emission pattern within an aphid colony is driven by the feeding behavior of a predator. PMID- 24158269 TI - Effects of stocking rate on the variability of peak standing crop in a desert steppe of Eurasia grassland. AB - Proper grazing management practices can generate corresponding compensatory effects on plant community production, which may reduce inter-annual variability of productivity in some grassland ecosystems. However, it remains unclear how grazing influences plant community attributes and the variability of standing crop. We examined the effects of sheep grazing at four stocking rate treatments [control, 0 sheep ha(-1) month(-1); light (LG), 0.15 sheep ha(-1 )month(-1); moderate (MG), 0.30 sheep ha(-1) month(-1); and heavy (HG), 0.45 sheep ha(-1) month(-1)] on standing crop at the community level and partitioned by species and functional groups, in the desert steppe of Inner Mongolia, China. The treatments were arranged in a completely randomized block design over a 9-year period. Standing crop was measured every August from 2004 to 2012. Peak standing crop decreased (P < 0.05) with increasing stocking rate; peak standing crop in the HG treatment decreased 40 % compared to the control. May-July precipitation explained at least 76 % of the variation in peak standing crop. MG and HG treatments resulted in a decrease (P < 0.05) in shrubs, semi-shrubs, and perennials forbs, and an increase (P < 0.05) in perennial bunchgrasses compared to the control. The coefficients of variation at plant functional group and species level in the LG and MG treatments were lower (P < 0.05) than in the control and HG treatments. Peak standing crop variability of the control and HG community were greatest, which suggested that LG and MG have greater ecosystem stability. PMID- 24158270 TI - Extended phenotype description and new molecular findings in late onset glycogen storage disease type II: a northern Italy population study and review of the literature. AB - Glycogen storage disease type II (GSDII) is a lysosomal storage disorder caused by acid alpha-1,4-glucosidase deficiency and associated with recessive mutations in its coding gene GAA. Few studies have provided so far a detailed phenotypical characterization in late onset GSDII (LO-GSDII) patients. Genotype-phenotype correlation has been previously attempted with controversial results. We aim to provide an in-depth description of a cohort (n = 36) of LO-GSDII patients coming from the north of Italy and compare our population's findings to the literature. We performed a clinical record-based retrospective and prospective study of our patients. LO-GSDII in our cohort covers a large variability of phenotype including subtle clinical presentation and did not differ significantly from previous data. In all patients, molecular analysis disclosed GAA mutations, five of them being novel. To assess potential genotype-phenotype correlations we divided IVS1-32-13T>G heterozygous patients into two groups following the severity of the mutations on the second allele. Our patients harbouring "severe" mutations (n = 21) presented a strong tendency to have more severe phenotypes and more disability, more severe phenotypes and more disability, higher prevalence of assisted ventilation and a shorter time of evolution to show it. The determination of prognostic factors is mandatory in order to refine the accuracy of prognostic information, to develop follow-up strategy and, more importantly, to improve the decision algorithm for enzyme replacement therapy administration. The demonstration of genotype-phenotype correlations could help to reach this objective. Clinical assessment homogeneity is required to overcome limitations due to the lack of power of most studies. PMID- 24158272 TI - Selective hyposmia in Parkinson's disease? PMID- 24158271 TI - The cost-effectiveness of deep brain stimulation in combination with best medical therapy, versus best medical therapy alone, in advanced Parkinson's disease. AB - Parkinson's disease (PD) is a complex progressive movement disorder leading to motor and non-motor symptoms that become increasingly debilitating as the disease advances, considerably reducing quality of life. Advanced treatment options include deep brain stimulation (DBS). While clinical effectiveness of DBS has been demonstrated in a number of randomised controlled trials (RCT), evidence on cost-effectiveness is limited. The cost-effectiveness of DBS combined with BMT, versus BMT alone, was evaluated from a UK payer perspective. Individual patient level data on the effect of DBS on PD symptom progression from a large 6-month RCT were used to develop a Markov model representing clinical progression and capture treatment effect and costs. A 5-year time horizon was used, and an incremental cost-effectiveness ratio (ICER) was calculated in terms of cost per quality-adjusted life-years (QALY) and uncertainty assessed in deterministic sensitivity analyses. Total discounted costs in the DBS and BMT groups over 5 years were L68,970 and L48,243, respectively, with QALYs of 2.21 and 1.21, giving an incremental cost-effectiveness ratio of L20,678 per QALY gained. Utility weights in each health state and costs of on-going medication appear to be the key drivers of uncertainty in the model. The results suggest that DBS is a cost effective intervention in patients with advanced PD who are eligible for surgery, providing good value for money to health care payers. PMID- 24158273 TI - Juvenile parkinsonism as an initial manifestation of gliomatosis cerebri. PMID- 24158274 TI - Striatal hand in Parkinson's disease: the re-evaluation of an old clinical sign. AB - Among postural abnormalities in Parkinson's disease (PD), striatal hand (SH) is a particularly underexplored phenomenon. It leads to extreme abnormalities of hand posture, causing altered dexterity, pain and disfigurement. In our study, three blinded investigators examined several pictures of the hands of individuals with PD (N = 40) and controls (N = 15). The investigators quantified postural alterations using the Striatal Hand Score. Demographic and clinical data were also collected. As no differences were detected among investigators agreement, a final Hand Score (HS, range 0-4) was obtained for each hand. The Striatal Hand Score in both the left and right hand was significantly different in PD compared to controls (p < 0.001 for both left and right hand). Striatal hand was significantly worse on the side of PD onset, and on the side with greater PD symptomatology. The finding of a striatal hand was 100 % specific for a diagnosis of PD. Nine PD subjects were evaluated both on and off medication, and dopaminergic treatment did not significantly change the Striatal Hand Score. Our findings suggest that in patients without any explanation for hand deformities other than PD, striatal hand occurs very often, and is highly specific for the side of worst PD involvement. We recommend including an evaluation for SH as part of routine practice. This study emphasizes the importance of a careful observation of the patient in order to improve diagnostic accuracy. PMID- 24158275 TI - Differential diagnoses to MS: experiences from an optic neuritis clinic. AB - Optic neuritis (ON) is closely linked to multiple sclerosis (MS). It may, however, also be associated to a range of autoimmune or infectious diseases. The purpose of this study was to assess the differential diagnoses in patients with suspected ON. In this retrospective study, we reviewed the files of all patients referred to the Clinic of Optic Neuritis, Glostrup Hospital, University of Copenhagen, Denmark, between January 2000 and November 2011. All patients were referred by ophthalmologists with possible ON. Patients diagnosed with MS prior to referral were excluded from the study. A total of 643 patients were included in the study. Apart from ON, the most frequent diagnoses were tumors (n = 15), ischemic or hypertensive neuropathies (n = 13), and retinal or choroid disorders (n = 9). Six patients were diagnosed with neuromyelitis optica. Rarer causes of visual loss were infections (n = 5), giant cell arteritis (n = 4), sarcoidosis (n = 3), thyrotoxicosis (n = 2), and hereditary or toxic neuropathies (n = 2). Nine percent of patients referred to the Clinic of Optic Neuritis had symptoms caused by medical, neurosurgical or ophthalmic disorders, and 0.9 % of our patients had NMO. Though most of these conditions are rare, it is of importance to keep them in mind upon encountering patients with symptoms of ON. PMID- 24158276 TI - Johann Hoffmann (1857-1919). PMID- 24158280 TI - Letters: Comment on "Effects of multi-scattering on the performance of a single beam acoustic manipulation device". AB - The concern addressed in the present commentary is to point out the omission of the azimuthal component Fphi of the axial acoustic radiation force provided in M. Azarpeyvand, M. A. Alibakhshi, R. Self, "Effects of multi-scattering on the performance of a single-beam acoustic manipulation device," IEEE Trans. Ultrason. Ferroelectr. Freq. Control, vol. 59, no. 8, pp. 1741-1749, 2012, which may suggest a miscalculation of the radiation force function Ym and its related numerical computations. PMID- 24158279 TI - Serial repetitive transcranial magnetic stimulation (rTMS) decreases BDNF serum levels in healthy male volunteers. AB - Although repetitive transcranial magnetic stimulation (rTMS) is established in the treatment of depression, there is little knowledge about the underlying molecular mechanisms. In the last decade, the neurotrophic hypothesis of depression entailed a plethora of studies on the role of neurogenesis-associated factors in affective disorders and rTMS treatment. In the present study, we hypothesised a sham-controlled increase of peripheral brain-derived neurotrophic factor (BDNF) levels following serial rTMS stimulations in healthy individuals. We investigated the influence of a cycle of nine daily high-frequency (HF)-rTMS (25 Hz) stimulations over the left dorsolateral prefrontal cortex (DLPFC) on serum levels of BDNF in 44 young healthy male volunteers. BDNF serum concentrations were measured at baseline, on day 5 and on day 10. Overall, the statistical analyses showed that the active and sham group differed significantly regarding their responses of BDNF serum levels. Contrary to our expectations, there was a significant decrease of BDNF only during active treatment. Following the treatment period, significantly lower BDNF serum levels were quantified in the active group on day 10, when compared to the sham group. The participants' smoking status affected this effect. Our results suggest that serial HF-rTMS stimulations over the left DLPFC decrease serum BDNF levels in healthy male volunteers. This provides further evidence for an involvement of BDNF in clinical rTMS effects. PMID- 24158281 TI - High-resolution frequency measurement method with a wide-frequency range based on a quantized phase step law. AB - A wide-frequency and high-resolution frequency measurement method based on the quantized phase step law is presented in this paper. Utilizing a variation law of the phase differences, the direct different frequency phase processing, and the phase group synchronization phenomenon, combining an A/D converter and the adaptive phase shifting principle, a counter gate is established in the phase coincidences at one-group intervals, which eliminates the +/-1 counter error in the traditional frequency measurement method. More importantly, the direct phase comparison, the measurement, and the control between any periodic signals have been realized without frequency normalization in this method. Experimental results show that sub-picosecond resolution can be easily obtained in the frequency measurement, the frequency standard comparison, and the phase-locked control based on the phase quantization processing technique. The method may be widely used in navigation positioning, space techniques, communication, radar, astronomy, atomic frequency standards, and other high-tech fields. PMID- 24158282 TI - Width-modulated square-wave pulses for ultrasound applications. AB - A method of output pressure control for ultrasound transducers using switched excitation is described. The method generates width-modulated square-wave pulse sequences that are suitable for driving ultrasound transducers using MOSFETs or similar devices. Sequences are encoded using an optimized level-shifted, carrier comparison, pulse-width modulation (PWM) strategy derived from existing PWM theory, and modified specifically for ultrasound applications. The modifications are: a reduction in carrier frequency so that the smallest number of pulses are generated and minimal switching is necessary; alteration of a linear carrier form to follow a trigonometric relationship in accordance with the expected fundamental output; and application of frequency modulation to the carrier when generating frequency-modulated, amplitude- tapered signals. The PWM method permits control of output pressure for arbitrary waveform sequences at diagnostic frequencies (approximately 5 MHz) when sampled at 100 MHz, and is applicable to pulse shaping and array apodization. Arbitrary waveform generation capability is demonstrated in simulation using convolution with a transducer's impulse response, and experimentally with hydrophone measurement. Benefits in coded imaging are demonstrated when compared with fixed-width square-wave (pseudo chirp) excitation in coded imaging, including reduction in image artifacts and peak side-lobe levels for two cases, showing 10 and 8 dB reduction in peak side lobe level experimentally, compared with 11 and 7 dB reduction in simulation. In all cases, the experimental observations correlate strongly with simulated data. PMID- 24158283 TI - Dependence of the reversibility of focused- ultrasound-induced blood-brain barrier opening on pressure and pulse length in vivo. AB - The most challenging aspect of intravenously-administered drugs currently developed to treat central nervous system (CNS) diseases is their impermeability through the blood-brain barrier (BBB), a specialized vasculature system protecting the brain microenvironment. Focused ultrasound (FUS) in conjunction with systemically administered microbubbles has been shown to open the BBB locally, noninvasively, and reversibly. The objective of this study was to investigate the effect of FUS (center frequency: 1.5 MHz) pulse length (PL), ranging here from 67 MUs to 6.7 ms, on the physiology of the FUS-induced BBB opening. Dynamic contrast-enhanced (DCE) and T1-weighted magnetic resonance imaging (MRI) were used to quantify the permeability changes using transfer rate (Ktrans) mapping, the volume of BBB opening (VBBB) and the reversibility timeline of the FUS-induced BBB opening, with the systemic administration of microbubbles at different acoustic pressures, ranging from 0.30 to 0.60 MPa. Permeability and volume of opening were both found to increase with the acoustic pressure and pulse length. At 67-MUs PL, the opening pressure threshold was 0.45 MPa, with BBB opening characteristics similar to those induced with 0.60 MPa at the same PL, as well as with 0.67-ms PL/0.30 MPa. On average, these cases had Ktrans = 0.0049 +/- 0.0014 min-1 and VBBB = 3.7 +/- 4.3 mm(3), and closing occurred within 8 h. The 6.7-ms PL/0.30 MPa induced similar opening with 0.67-ms PL/0.45 MPa, and a closing timeline of 24 to 48 h. On average, Ktrans was 0.0091 +/- 0.0029 min-1 and VBBB was 14.13 +/- 7.7 mm(3) in these cases. Also, there were no significant differences between the 6.7-ms PL/0.45 MPa, 0.67-ms PL/0.60 MPa and 6.7-ms PL/0.60 MPa cases, yielding on average a Ktrans of 0.0100 +/- 0.0023 min-1 and VBBB equal to 20.1 +/- 5.7 mm(3). Closing occurred within 48 to 72 h in these cases. Stacked histograms of the Ktrans provided further insight to the nonuniform spatial distribution of permeability changes and revealed a correlation with the closing timeline. These results also suggest a beneficial complementary relationship between the elongation of the PL and the decrease of the peak negative acoustic pressures, and vice versa. Linear regression between Ktrans and VBBB showed a good correlation fit. Also, the time required for closing linearly increased with VBBB. The volume rate of decrease was measured to be 11.4 +/- 4.0 mm3 per day, suggesting that the closing timeline could be predicted from the initial volume of opening. Finally, no histological damage was detected in any of the cases 7 d post-FUS, indicating the safety of the methodology and parameters used. PMID- 24158284 TI - Phase-based direct average strain estimation for elastography. AB - In this paper, a phase-based direct average strain estimation method is developed. A mathematical model is presented to calculate axial strain directly from the phase of the zero-lag cross-correlation function between the windowed precompression and stretched post-compression analytic signals. Unlike phase based conventional strain estimators, for which strain is computed from the displacement field, strain in this paper is computed in one step using the secant algorithm by exploiting the direct phase-strain relationship. To maintain strain continuity, instead of using the instantaneous phase of the interrogative window alone, an average phase function is defined using the phases of the neighboring windows with the assumption that the strain is essentially similar in a close physical proximity to the interrogative window. This method accounts for the effect of lateral shift but without requiring a prior estimate of the applied strain. Moreover, the strain can be computed both in the compression and relaxation phases of the applied pressure. The performance of the proposed strain estimator is analyzed in terms of the quality metrics elastographic signal-to noise ratio (SNRe), elastographic contrast-to-noise ratio (CNRe), and mean structural similarity (MSSIM), using a finite element modeling simulation phantom. The results reveal that the proposed method performs satisfactorily in terms of all the three indices for up to 2.5% applied strain. Comparative results using simulation and experimental phantom data, and in vivo breast data of benign and malignant masses also demonstrate that the strain image quality of our method is better than the other reported techniques. PMID- 24158285 TI - A multiplicative model for improving microvascular flow estimation in dynamic contrast-enhanced ultrasound (DCE-US): theory and experimental validation. AB - Perfusion parameter estimation from dynamic contrast-enhanced ultrasound (DCE-US) data relies on fitting parametric models of flow to curves describing linear echo power as a function of time. The least squares criterion is generally used to fit these models to data. This criterion is optimal in the sense of maximum likelihood under the assumption of an additive white Gaussian noise. In the current work, it is demonstrated that this assumption is not held for DCEUS. A better-adapted maximum likelihood criterion based on a multiplicative model is proposed. It is tested on simulated bolus perfusion data and on 11 sequences acquired in vivo during bolus perfusion of contrast agent in the cortex of healthy murine kidney, an area where the perfusion is expected to be approximately homogeneous. Results on simulated data show a significant improvement (p < 0.05) of the precision and the accuracy for the estimations of perfusion parameters time to peak (TTP), wash-in rate (WiR), and mean transit time (MTT). On the 11 in vivo sequences, the new method leads to a significant reduction (p < 0.05) in the variation of parametric maps for 9 sequences for TTP and 10 sequences for WiR and MTT. The mean percent decreases of the coefficient of variation are 40%, 25%, and 59% for TTP, WiR, and MTT, respectively. This method should contribute to a more robust and accurate estimation of perfusion parameters and an improved resolution of parametric imaging. PMID- 24158287 TI - Implementation of parallel transmit beamforming using orthogonal frequency division multiplexing--achievable resolution and interbeam interference. AB - The speed of sound in the human body limits the achievable data acquisition rate of pulsed ultrasound scanners. To overcome this limitation, parallel beamforming techniques are used in ultrasound 2-D and 3-D imaging systems. Different parallel beamforming approaches have been proposed. They may be grouped into two major categories: parallel beamforming in reception and parallel beamforming in transmission. The first category is not optimal for harmonic imaging; the second category may be more easily applied to harmonic imaging. However, inter-beam interference represents an issue. To overcome these shortcomings and exploit the benefit of combining harmonic imaging and high data acquisition rate, a new approach has been recently presented which relies on orthogonal frequency division multiplexing (OFDM) to perform parallel beamforming in transmission. In this paper, parallel transmit beamforming using OFDM is implemented for the first time on an ultrasound scanner. An advanced open platform for ultrasound research is used to investigate the axial resolution and interbeam interference achievable with parallel transmit beamforming using OFDM. Both fundamental and second harmonic imaging modalities have been considered. Results show that, for fundamental imaging, axial resolution in the order of 2 mm can be achieved in combination with interbeam interference in the order of -30 dB. For second harmonic imaging, axial resolution in the order of 1 mm can be achieved in combination with interbeam interference in the order of -35 dB. PMID- 24158286 TI - Super-resolution imaging using multi- electrode CMUTs: theoretical design and simulation using point targets. AB - This paper investigates a low computational cost, super-resolution ultrasound imaging method that leverages the asymmetric vibration mode of CMUTs. Instead of focusing on the broadband received signal on the entire CMUT membrane, we utilize the differential signal received on the left and right part of the membrane obtained by a multi-electrode CMUT structure. The differential signal reflects the asymmetric vibration mode of the CMUT cell excited by the nonuniform acoustic pressure field impinging on the membrane, and has a resonant component in immersion. To improve the resolution, we propose an imaging method as follows: a set of manifold matrices of CMUT responses for multiple focal directions are constructed off-line with a grid of hypothetical point targets. During the subsequent imaging process, the array sequentially steers to multiple angles, and the amplitudes (weights) of all hypothetical targets at each angle are estimated in a maximum a posteriori (MAP) process with the manifold matrix corresponding to that angle. Then, the weight vector undergoes a directional pruning process to remove the false estimation at other angles caused by the side lobe energy. Ultrasound imaging simulation is performed on ring and linear arrays with a simulation program adapted with a multi-electrode CMUT structure capable of obtaining both average and differential received signals. Because the differential signals from all receiving channels form a more distinctive temporal pattern than the average signals, better MAP estimation results are expected than using the average signals. The imaging simulation shows that using differential signals alone or in combination with the average signals produces better lateral resolution than the traditional phased array or using the average signals alone. This study is an exploration into the potential benefits of asymmetric CMUT responses for super-resolution imaging. PMID- 24158288 TI - Comparison of three scattering models for ultrasound blood characterization. AB - Ultrasonic backscattered signals from blood contain frequency-dependent information that can be used to obtain quantitative parameters reflecting the aggregation level of red blood cells (RBCs). The approach is based on estimating structural aggregate parameters by fitting the spectrum of the backscattered radio-frequency echoes from blood to an estimated spectrum considering a theoretical scattering model. In this study, three scattering models were examined: a new implementation of the Gaussian model (GM), the structure factor size estimator (SFSE), and the new effective medium theory combined with the structure factor model (EMTSFM). The accuracy of the three scattering models in determining mean aggregate size and compactness was compared by 2-D and 3-D computer simulations in which RBC structural parameters were controlled. Two clustering conditions were studied: 1) the aggregate size varied and the aggregate compactness was fixed in both 2-D and 3-D cases, and 2) the aggregate size was fixed and the aggregate compactness varied in the 2-D case. For both clustering conditions, the EMTSFM was found to be more suitable than GM and SFSE for characterizing RBC aggregation. PMID- 24158289 TI - Fast and mechanistic ultrasound simulation using a point source/receiver approach. AB - Ultrasound simulators relying on impulse response methods are faithful to the mechanisms of image formation from the underlying radio-frequency signals, but as a result tend to be relatively slow. At the other extreme are fast techniques, often motivated by the development of teaching and training simulators, which approximate the image formation processes rather than rigorously modeling the underlying physics. Previously, we have shown that transmit field distributions from linear phased-array transducers can be modeled accurately and efficiently using arrays of point sources. This approach is now extended to point sources/receivers, which allows for simulation of the transmit/receive fields, and thus the physical processes underlying ultrasound image formation. Field distributions and fast-time signals are shown to compare favorably to those obtained using the impulse response method. Doppler spectrogram and B-mode images derived from these signals also show excellent agreement with the results obtained using the impulse response method, but with a computational savings of nearly two orders of magnitude. Because of the inherent simplicity of our Fast and Mechanistic Ultrasound Simulation (FAMUS) approach, CPU parallelization was readily achieved, and further orders of magnitude speed improvements, and thus real-time performance, can be anticipated via extension to modern graphics processing units. PMID- 24158290 TI - Harmonic tracking of acoustic radiation force-induced displacements. AB - Ultrasound-based elasticity imaging methods rely upon accurate estimates of tissue deformation to characterize the mechanical properties of soft tissues. These methods are corrupted by clutter, which can bias and/or increase variance in displacement estimates. Harmonic imaging methods are routinely used for clutter suppression and improved image quality in conventional B-mode ultrasound, but have not been utilized in ultrasound-based elasticity imaging methods. We introduce a novel, fully-sampled pulse-inversion harmonic method for tracking tissue displacements that corrects the loss in temporal sampling frequency associated with conventional pulse-inversion techniques. The method is implemented with acoustic radiation force impulse (ARFI) imaging to monitor the displacements induced by an impulsive acoustic radiation force excitation. Custom pulse sequences were implemented on a diagnostic ultrasound scanner to collect spatially-matched fundamental and harmonic information within a single acquisition. B-mode and ARFI images created from fundamental data collected at 4 MHz and 8 MHz are compared with 8-MHz harmonic images created using a band-pass filter approach and the fully sampled pulse-inversion method. In homogeneous, tissue-mimicking phantoms, where no visible clutter was observed, there was little difference in the axial displacements, estimated jitter, and normalized cross-correlation among the fundamental and harmonic tracking methods. The similarity of the lower- and higher-frequency methods suggests that any improvement resulting from the increased frequency of the harmonic components is negligible. The harmonic tracking methods demonstrated a marked improvement in B mode and ARFI image quality of in vivo carotid arteries. Improved feature detection and decreased variance in estimated displacements were observed in the arterial walls of harmonic ARFI images, especially in the pulse-inversion harmonic ARFI images. Within the lumen, the harmonic tracking methods improved the discrimination of the blood-vessel interface, making it easier to visualize plaque boundaries. Improvements in harmonic ARFI images in vivo were consistent with suppressed clutter supported by improved contrast and contrast-to-noise ratio (CNR) in the matched harmonic B-mode images compared with the fundamental B mode images. These results suggest that harmonic tracking methods can improve the clinical utility and diagnostic accuracy of ultrasound-based elasticity imaging methods. PMID- 24158292 TI - An analysis of thickness-shear vibrations of doubly-rotated quartz crystal plates with the corrected first-order Mindlin plate equations. AB - The Mindlin plate equations have been widely used in the analysis of high frequency vibrations of quartz crystal resonators with accurate solutions, as demonstrated by the design procedure based on analytical results in terms of frequency, mode shapes, and optimal parameters for the AT-cut quartz crystal plate, which is the core element in a resonator structure. Earlier studies have been focused on the AT-cut (which is one type of rotated Y-cut) quartz crystal plates because it is widely produced and has relatively simple couplings of vibration modes at thickness-shear frequencies of the fundamental and overtone modes. The simplified equations through the truncation, correction, and modification of the Mindlin plate equations have been widely accepted for practical applications, and further efforts to expand their applications to similar problems of other material types, such as doubly-rotated quartz crystals, with the SC-cut being a typical and popular one, are also naturally expected. We have found out that the Mindlin plate theory can be truncated and corrected for the SC-cut quartz crystal plates in a manner similar to the AT-cut plates. The analytical results show that the corrected Mindlin plate equations are equally accurate and convenient for obtaining essential design parameters of resonators for the thickness-shear vibrations of SC-cut quartz crystal plates. PMID- 24158291 TI - Ultrasound vibrometry using orthogonal- frequency-based vibration pulses. AB - New vibration pulses are developed for shear wave generation in a tissue region with preferred spectral distributions for ultrasound vibrometry applications. The primary objective of this work is to increase the frequency range of detectable harmonics of the shear wave. The secondary objective is to reduce the required peak intensity of transmitted pulses that induce the vibrations and shear waves. Unlike the periodic binary vibration pulses, the new vibration pulses have multiple pulses in one fundamental period of the vibration. The pulses are generated from an orthogonal-frequency wave composed of several sinusoidal signals, the amplitudes of which increase with frequency to compensate for higher loss at higher frequency in tissues. The new method has been evaluated by studying the shear wave propagation in in vitro chicken and swine liver. The experimental results show that the new vibration pulses significantly increase tissue vibration with a reduced peak ultrasound intensity, compared with the binary vibration pulses. PMID- 24158293 TI - Experimental study on the pressure and pulse wave propagation in viscoelastic vessel tubes-effects of liquid viscosity and tube stiffness. AB - A pulse wave is the displacement wave which arises because of ejection of blood from the heart and reflection at vascular bed and distal point. The investigation of pressure waves leads to understanding the propagation characteristics of a pulse wave. To investigate the pulse wave behavior, an experimental study was performed using an artificial polymer tube and viscous liquid. A polyurethane tube and glycerin solution were used to simulate a blood vessel and blood, respectively. In the case of the 40 wt% glycerin solution, which corresponds to the viscosity of ordinary blood, the attenuation coefficient of a pressure wave in the tube decreased from 4.3 to 1.6 dB/m because of the tube stiffness (Young's modulus: 60 to 200 kPa). When the viscosity of liquid increased from approximately 4 to 10 mPa.s (the range of human blood viscosity) in the stiff tube, the attenuation coefficient of the pressure wave changed from 1.6 to 3.2 dB/m. The hardening of the blood vessel caused by aging and the increase of blood viscosity caused by illness possibly have opposite effects on the intravascular pressure wave. The effect of the viscosity of a liquid on the amplitude of a pressure wave was then considered using a phantom simulating human blood vessels. As a result, in the typical range of blood viscosity, the amplitude ratio of the waves obtained by the experiments with water and glycerin solution became 1:0.83. In comparison with clinical data, this value is much smaller than that seen from blood vessel hardening. Thus, it can be concluded that the blood viscosity seldom affects the attenuation of a pulse wave. PMID- 24158294 TI - Electro-thermo-mechanical model for bulk acoustic wave resonators. AB - We present the electro-thermo-mechanical constitutive relations, expanded up to the third order, for a BAW resonator. The relations obtained are implemented into a circuit model, which is validated with extensive linear and nonlinear measurements. The mathematical analysis, along with the modeling, allows us to identify the dominant terms, which are the material temperature derivatives and two intrinsic nonlinear terms, and explain, for the first time, all observable effects in a BAW resonator by use of a unified physical description. Moreover, the terms that are responsible for the second-harmonic generation and the frequency shift with dc voltage are shown to be the same. PMID- 24158295 TI - Measurement and FEM/BEM simulation of transverse effects in SAW resonators on lithium tantalate. AB - It is well known that transverse effects contribute significantly to the loss of SAW resonators on lithium tantalate. In particular, for frequencies above resonance, the surface wave is not guided inside the transducer and radiates into the busbars. In addition, because bulk modes can also be excited, scalar models are not sufficient to accurately predict transverse effects. It is also known that the layout of a SAW resonator (electrode gaps and dummy electrodes) has a strong impact on the transverse effects. In this paper, a periodic FEM/BEM model is presented and is used to simulate the transverse effects for various SAW resonator layouts. Test devices matching those simulated are fabricated and measured; the measured results are compared with the simulated results and show good agreement. By analyzing the dispersion curves produced from the FEM/BEM model in the different regions of the device, several frequency bands corresponding to different transverse behaviors are identified. These results are consistent with the elastic displacements, also computed by the FEM/BEM model. It is further shown that guided conditions in the gap between the transducer and the busbar occur for a frequency range above resonance. This result is in agreement with measurements showing that resonators with smaller gaps exhibit smaller spurious responses in their admittance. PMID- 24158296 TI - Producing acoustic frozen waves: simulated experiments. AB - In this paper, we show how appropriate superpositions of Bessel beams can be successfully used to obtain arbitrary longitudinal intensity patterns of nondiffracting ultrasonic wave fields with very high transverse localization. More precisely, the method here described allows generation of longitudinal acoustic pressure fields whose longitudinal intensity patterns can assume, in principle, any desired shape within a freely chosen interval 0 <= z <= L of the propagation axis, and that can be endowed in particular with a static envelope (within which only the carrier wave propagates). Indeed, it is here demonstrated by computer evaluations that these very special beams of nonattenuated ultrasonic field can be generated in water-like media by means of annular transducers. Such fields at rest have been called by us acoustic frozen waves (FWs). The paper presents various cases of FWs in water, and investigates their aperture characteristics, such as minimum required size and ring dimensioning, as well as the influence they have on the proper generation of the desired FW patterns. The FWs are particular localized solutions to the wave equation that can be used in many applications, such as new kinds of devices, e.g., acoustic tweezers or scalpels, and especially in various ultrasound medical apparatus. PMID- 24158297 TI - A large-signal model for CMUT arrays with arbitrary membrane geometry operating in non-collapsed mode. AB - A large-signal, transient model has been developed to predict the output characteristics of a CMUT array operated in the non-collapse mode. The model is based on separation of the nonlinear electrostatic voltage-to-force relation and the linear acoustic array response. For modeling of linear acoustic radiation and crosstalk effects, the boundary element method is used. The stiffness matrix in the vibroacoustics calculations is obtained using static finite element analysis of a single membrane which can have arbitrary geometry and boundary conditions. A lumped modeling approach is used to reduce the order of the system for modeling the transient nonlinear electrostatic actuation. To accurately capture the dynamics of the non-uniform electrostatic force distribution over the CMUT electrode during large deflections, the membrane electrode is divided into patches shaped to match higher order membrane modes, each introducing a variable to the system model. This reduced order nonlinear lumped model is solved in the time domain using commercial software. The model has two linear blocks to calculate the displacement profile of the electrode patches and the output pressure for a given force distribution over the array. The force-to-array displacement block uses the linear acoustic model, and the Rayleigh integral is evaluated to calculate the pressure at any field point. Using the model, the time domain transmitted pressure can be simulated for different large drive signal configurations. The acoustic model is verified by comparison to harmonic FEA in vacuum and fluid for high- and low-aspect-ratio membranes as well as mass-loaded membranes. The overall software model is verified by comparison to transient 3-D finite element analysis and experimental results for different large drive signals, and an example for a phased array simulation is given. PMID- 24158298 TI - Grooved backing structure for CMUTs. AB - Capacitive micromachined ultrasonic transducers (CMUTs) manufactured on silicon substrates need an acoustic backing to suppress substrate ringing when such transducers are in operation. The acoustic backing most often used for ultrasound transducers is a composite of epoxy and tungsten powder. To absorb the acoustic energy, the backing of a CMUT should have an acoustic impedance that matches that of the silicon substrate and it should be lossy. If the backing is thick enough, it will absorb the acoustic wave in the backing without reflecting it back to the transducer, and thus will not create any trailing echoes. However, if we intend to use the transducer in applications in which there is no room for a thick backing, for example in intravascular ultrasound (IVUS), a grooved backing structure might be used. The grooves at the bottom of the backing provide extra attenuation by scattering the waves in different directions so that a thinner backing is sufficient. The scattering removes power from the specular reflection from the back surface which otherwise degrades the image quality. It has been shown that this type of structure reduces the specular reflection for a range of frequencies. When CMUTs are used in practical applications, the propagation of waves from a fluid medium into the backing or vice versa is blocked to some degree by total reflection, except for a range of steering angles around broadside. This is due to the difference in acoustic velocities of silicon and the fluid medium. This blocking is accompanied by the generation of surface waves in the silicon substrate, which also may impact the imaging and therefore must be controlled. In this paper, we investigate the acoustic signal transmitted into the backing relative to the signal transmitted into the fluid medium when CMUT arrays on top of the silicon substrate are excited. Furthermore, the performance of the grooved backing structure is studied for the waves traveling in normal as well as in oblique directions to the bottom surface of the backing. PMID- 24158299 TI - Correspondence: Spatial variations of viscoelastic properties of porcine vitreous humors. AB - Using a microbubble-based acoustic radiation force approach, spatial variations of Young's modulus and shear viscosity of the porcine vitreous humors in two groups--young pigs (6 months old) and mature pigs (2 to 3 years old)--were measured in situ. The measurements in these groups (4 specimens in each group) were performed in several positions along an anterior-to-posterior direction. At each position, microbubbles were generated by focusing a nanosecond pulsed laser beam and the displacement of each microbubble in response to an impulsive acoustic radiation force was measured every 10 us using a custom-made high-pulse repetition-frequency ultrasound system. Based on measured dynamics of the microbubble, Young's modulus and shear viscosity at various locations of the vitreous were reconstructed. Young's moduli of the young and mature porcine vitreous at anterior region were the highest, whereas the central region had the lowest values, indicating the clear spatial variations in the vitreous humor elasticity in both groups. PMID- 24158300 TI - Complete abolition of reading and writing ability with a third ventricle colloid cyst: implications for surgical intervention and proposed neural substrates of visual recognition and visual imaging ability. AB - We report a rare case of a patient unable to read (alexic) and write (agraphic) after a mild head injury. He had preserved speech and comprehension, could spell aloud, identify words spelt aloud and copy letter features. He was unable to visualise letters but showed no problems with digits. Neuropsychological testing revealed general visual memory, processing speed and imaging deficits. Imaging data revealed an 8 mm colloid cyst of the third ventricle that splayed the fornix. Little is known about functions mediated by fornical connectivity, but this region is thought to contribute to memory recall. Other regions thought to mediate letter recognition and letter imagery, visual word form area and visual pathways were intact. We remediated reading and writing by multimodal letter retraining. The study raises issues about the neural substrates of reading, role of fornical tracts to selective memory in the absence of other pathology, and effective remediation strategies for selective functional deficits. PMID- 24158301 TI - Multivessel spontaneous coronary artery dissection of left and right coronary systems. AB - Spontaneous coronary artery dissection (SCAD) involving multiple coronary arteries simultaneously is extremely rare. It should be considered in younger patients, especially who do not have traditional cardiac risk factors. We present a case of young male patient presenting with acute coronary syndrome associated with ST segments elevation on ECG following physical stress whose coronary angiography revealed SCAD of the left anterior descending as well as the right coronary artery and discuss the therapeutic options with a brief review of the limited evidence. PMID- 24158302 TI - Osteolitic and osteoblastic lesions of the skull. PMID- 24158303 TI - Successful percutaneous angioembolisation of bleeding jejunal varix by acrylate glue and coils. AB - Portal hypertension is a common disease worldwide. One of its rare complications is bleeding jejunal varices which is usually asymptomatic and may present with gastrointestinal bleeding. We present a case of a jejunal bleeding that was successfully embolised with acrylate glue and embolisation coils. A middle-aged woman with a history of multiple abdominal surgeries for adenocarcinoma of right ovary, presented to us with multiple episodes of haematochezia. On a CT scan of the abdomen, she was diagnosed with chronic liver disease with portal hypertension, multiple varices at porto-systemic anastomosis and ectopic jejunal varix. She was treated by interventional radiologists by percutaneous embolisation of bleeding varix using glue and embolisation coils through a portal venous approach. PMID- 24158304 TI - Longitudinal development of mother-infant interaction during the first year of life among mothers with substance abuse and psychiatric problems and their infants. AB - The quality of mother-infant interaction during the first year may be hampered by maternal substance abuse and co-existing non-optimal factors such as psychiatric problems and difficult relational experiences. In the present study three groups of women were recruited during pregnancy: One group with substance abuse problems from residential treatment centers (n = 28), a second group from psychiatric outpatient treatment centers (n = 22), and a third group from well-baby clinics (n = 30). Four maternal optimality indexes were assessed (substance abuse, psychiatric problems, relational experiences and SES). Mother-infant interaction was observed at 3 and 12 months. The substance abuse group showed the most disturbed mother-infant interaction at 12 months. Low maternal optimality as well as impairments in maternal affective involvement at 3 months influenced negatively both on infant and dyadic affective behavior in interaction at 12 months. Long-term interventions are needed to promote affective reciprocity among mother-baby pairs with low optimality. PMID- 24158305 TI - The emotional and cognitive impact of unexpected simulated patient death: a randomized controlled trial. AB - BACKGROUND: Observational studies suggest that emotions experienced during simulation training may affect cognitive load and learning outcomes. The objective of this study was to manipulate emotions during simulation training and assess the impact on cognitive load and learning. METHODS: In this prospective randomized trial, 116 final-year medical students received training in a simulated scenario of a 70-year-old woman presenting with reduced consciousness due to aminosalicylic acid ingestion. Training groups were randomly allocated to one of two endings for the scenario: The patient was transferred to another service, or she experienced a cardiorespiratory arrest and died. Participants rated their emotions and cognitive load after training. Three months later, we evaluated their performance on a simulation Objective Structured Clinical Examination station of a 60-year-old man presenting with reduced consciousness due to ethylene glycol ingestion. RESULTS: Emotions tended to be more negative for students in training groups where the simulated patient died. These students also reported a higher cognitive load (mean +/- SD, 7.63 +/- 0.97 vs 7.25 +/- 0.84; P = .03; d = 0.42) and were less likely to be rated as competent to diagnose and manage a patient with reduced consciousness due to toxin ingestion (OR, 0.37; 95% CI, 0.14-0.95; P = 0.04) 3 months later. CONCLUSIONS: Students exposed to unexpected simulated patient death reported increased cognitive load and had poorer learning outcomes. Educators need to expose learners to negative experiences; therefore, further studies are needed on how best to use negative emotional experiences during simulation training. PMID- 24158307 TI - Efficacy and safety of systemic treatments for psoriasis in elderly patients. AB - Management of psoriasis in elderly patients can be challenging, because of the impairment of immune system efficiency and the presence of comorbidities that contra-indicate systemic therapies. We studied the safety and efficacy of systemic traditional and biological treatments in 187 consecutive psoriatic patients aged > 65 years. At week 12 of therapy, Psoriasis Area and Severity Index 75 was achieved by 49%, 27%, 46% and 31% of patients who received methotrexate, acitretin, cyclosporine or PUVA, and 64.1%, 64.7%, 93.3%, 57.1% and 100% of patients who received etanercept, adalimumab, infliximab, efalizumab and ustekinumab. The rate of adverse events was 0.12, 0.32, 1.4 and 0.5 per patient year in the methotrexate, acitretin, cyclosporine and PUVA groups and 0.11, 0.35, 0.19, 0.3 and 0.26 in the etanercept, adalimumab, infliximab, efalizumab and ustekinumab groups. Traditional drugs were less effective than biologics in our elderly population. Etanercept was associated with a lower rate of adverse events compared with other treatments. PMID- 24158308 TI - Thermal responsive microgels as recyclable carriers to immobilize active proteins with enhanced nonaqueous biocatalytic performance. AB - We describe the preparation of a thermoresponsive microgel, which can non covalently immobilize active proteins with enhanced biocatalytic performance in organic solvents and easy reusability due to the porous microstructure and temperature responsive property. PMID- 24158306 TI - Disruption of neurogenesis by hypothalamic inflammation in obesity or aging. AB - Adult neural stem cells contribute to neurogenesis and plasticity of the brain which is essential for central regulation of systemic homeostasis. Damage to these homeostatic components, depending on locations in the brain, poses threat to impaired neurogenesis, neurodegeneration, cognitive loss and energy imbalance. Recent research has identified brain metabolic inflammation via proinflammatory IkappaB kinase-beta (IKKbeta) and its downstream nuclear transcription factor NF kappaB pathway as a non-classical linker of metabolic and neurodegenerative disorders. Chronic activation of the pathway results in impairment of energy balance and nutrient metabolism, impediment of neurogenesis, neural stem cell proliferation and differentiation, collectively converging on metabolic and cognitive decline. Hypothalamic IKKbeta/NF-kappaB via inflammatory crosstalk between microglia and neurons has been discovered to direct systemic aging by inhibiting the production of gonadotropin-releasing hormone (GnRH) and inhibition of inflammation or GnRH therapy could revert aging related degenerative symptoms at least in part. This article reviews the crucial role of hypothalamic inflammation in affecting neural stem cells which mediates the neurodegenerative mechanisms of causing metabolic derangements as well as aging-associated disorders or diseases. PMID- 24158309 TI - Patterns of work injuries: cases admitted to emergency room treatment compared to cases reported to the Danish Working Environment Authority during 2003-2010. AB - OBJECTIVE: To compare work injuries treated in an emergency department (ED) and injuries reported to the Danish Working Environment Authority (DWEA). METHODS: Work injuries of the ED, Odense University Hospital, and injuries from the geographical catchment area reported to the DWEA between 2003 and 2010 were included. The injuries included in both datasets were identified by merging the ED file and the DWEA file using the civil registry number and injury date information as key. RESULTS: Approximately 50 000 work injuries occurred in the catchment area of the ED. The intersection between the two injury registration systems was 16%. A major discordance concerned the type of injuries, as some injuries were seen frequently in the ED but not reported to the DWEA to any significant extent, for example 'eye injuries' and 'superficial lacerations or wounds'. On the other hand, some injuries are rarely seen in the ED, but often reported to the DWEA, for example 'low back pain'. Additionally, younger workers visit the ED more often than older workers, and injuries in the high risk sectors have the lowest reporting proportion. CONCLUSIONS: Neither the ED nor DWEA injury files alone give a complete picture of work injuries. But merged, they represent a significant number of injuries, taking into account differences in data sources, for example concerning uneven distribution of age, sex, type of injury and type of industry. Obviously, not all serious work related ED injuries resulting in lost work time are reported to the DWEA. PMID- 24158311 TI - Prevention of recurrent sickness absence in workers with common mental disorders: results of a cluster-randomised controlled trial. AB - OBJECTIVES: Workers with common mental disorders (CMDs) frequently experience recurrent sickness absence but interventions to prevent this are lacking. The goal of this study was to evaluate the effectiveness of the Stimulating Healthy participation And Relapse Prevention at work intervention in preventing recurrent sickness absence in workers who returned to work after sickness absence due to CMDs. METHODS: We performed a cluster-randomised controlled trial with 3 months, 6 months and 12 months follow-up. Treatment providers were randomised to either a 2-day training in the Stimulating Healthy participation And Relapse Prevention at work intervention, that is, a problem-solving intervention, or usual care. Primary outcome measures were the incidence of recurrent sickness absence and time to recurrent sickness absence. Secondary outcome measures were mental health complaints, work functioning and coping behaviour. RESULTS: 80 participants were randomised in the intervention group and 78 in the control group. The adjusted OR for the incidence of recurrent sickness absence was 0.40 (95% CI 0.20 to 0.81) and the adjusted HR for time to recurrent sickness absence was 0.53 (95% CI 0.33 to 0.86) for the intervention group compared with care as usual. CONCLUSIONS: This study demonstrates the 12-month effectiveness of a problem-solving intervention for reducing recurrent sickness absence in workers with CMDs and emphasises the importance of continuous attention in the post return to work phase for workers who have been on sickness absence due to CMDs. PMID- 24158310 TI - Estimated prevalence of exposure to occupational carcinogens in Australia (2011 2012). AB - BACKGROUND AND OBJECTIVES: Although past studies of workplace exposures have contributed greatly to our understanding of carcinogens, significant knowledge gaps still exist with regard to the actual extent of exposure among current workers, with no routinely collected population-based data being available in most countries. This study, the Australian Work Exposures Study (AWES), aimed to investigate the current prevalence of occupational exposure to carcinogens. METHODS: A random sample of men and women aged between 18 and 65, who were currently in paid employment, were invited to participate in a telephone interview collecting information about their current job and various demographic factors. Interviews were conducted using a web-based application (OccIDEAS). OccIDEAS uses the expert exposure method in which participants are asked about their job tasks and predefined algorithms are used to automatically assign exposures. Responses were obtained from 5023 eligible Australian residents, resulting in an overall response rate of 53%. RESULTS: 1879 respondents (37.6%) were assessed as being exposed to at least one occupational carcinogen in their current job. Extrapolation of these figures to the Australian working population suggested 3.6 million (40.3%) current workers could be exposed to carcinogens in their workplace. Exposure prevalence was highest among farmers, drivers, miners and transport workers, as well as men and those residing in regional areas. CONCLUSIONS: This study demonstrates a practical, web-based approach to collecting population information on occupational exposure to carcinogens and documents the high prevalence of current exposure to occupational carcinogens in the general population. PMID- 24158312 TI - Enantioselective Friedel-Crafts alkylation for synthesis of 2-substituted indole derivatives. AB - An efficient catalytic asymmetric intermolecular C2 Friedel-Crafts alkylation reaction between N-methyl skatole and beta,gamma-unsaturated alpha-ketoesters has been realized by a chiral N,N'-dioxide-Ni(II) complex. The corresponding indole derivatives were obtained in good yield (up to 96%) with excellent enantioselectivities (up to 99% ee) under mild reaction conditions. PMID- 24158313 TI - A prospective randomized single-blind control study of volume threshold for chest tube removal following lobectomy. AB - BACKGROUND: The aim of the current study was to assess the feasibility and safety of a new volume threshold for chest tube removal following lobectomy. METHODS: The prospective randomized single-blind control study included 90 consecutive patients who underwent lobectomy or bilobectomy for pathological conditions between March 2012 and September 2012. Eligible patients were randomized into two groups: early removal group (chest tube removal at the drainage volume of 300 ml/24 h or less) and traditional management group (chest tube removal when the drainage volume is less than 100 ml/24 h). Criteria for the early removal group were established and met prior to chest tube removal. The volume and characteristics of drainage, time of drainage tube extraction, and postoperative hospital stay were recorded. All patients received standard care while in the hospital and a follow-up visit was performed 7 days after discharge from hospital. RESULTS: In accordance with the exit criteria, 20 patients were excluded from the study. The remaining 70 patients included in the final analysis were divided into two groups: early removal group (n = 41) and traditional management group (n = 29). There was no difference between the two groups in terms of age, sex, comorbidities, and pathological evaluation of resection specimens. In eligible patients (n = 70), the mean volume of drainage 24 h after surgery was 300 ml, while the mean volume of drainage 48 h after surgery was 250 ml. The average daily drainage 48 h after surgery was significantly different than the average daily drainage 24 h after surgery (Z = -2.059, P = 0.039). The mean duration of chest tube placement was 44 h in the early removal group and 67 h in the traditional management group (P = 0.004). Patients who underwent early removal management had a shorter postoperative hospital stay compared to the traditional management group (5 vs. 6 days, P < 0.01). No statistically significant differences were observed between the rates of pleural effusion development, thoracentesis, and postoperative complications 1 week after hospital discharge. CONCLUSION: Early removal of the chest tube after lobectomy is feasible and safe and may shorten patient hospital stay and reduce morbidity without the added risk of postoperative complications. PMID- 24158314 TI - School effects on risk of non-fatal suicidal behaviour: a national multilevel cohort study. AB - OBJECTIVE: Research has demonstrated school effects on health, over and above the effects of students' individual characteristics. This approach has however been uncommon in mental health research. The aim of the study was to assess whether there are any school-contextual effects related to socioeconomic characteristics and academic performance, on the risk of hospitalization from non-fatal suicidal behaviour (NFSB). METHODS: A Swedish national cohort of 447,929 subjects was followed prospectively in the National Patient Discharge Register from the completion of compulsory school in 1989-93 (~16 years) until 2001. Multilevel logistic regression was used to assess the association between school-level characteristics and NFSB. RESULTS: A small but significant share of variation in NFSB was accounted for by the school context (variance partition coefficient <1%, median odds ratio = 1.26). The risk of NFSB was positively associated with the school's proportion of students from low socioeconomic status (SES), single parent household, and the school's average academic performance. School effects varied, in part, by school location. CONCLUSION: NFSB seems to be explained mainly by individual-level characteristics. Nevertheless, a concentration of children from disadvantaged backgrounds in schools appears to negatively affect mental health, regardless of whether or not they are exposed to such problems themselves. Thus, school SES should be considered when planning prevention of mental health problems in children and adolescents. PMID- 24158315 TI - Probing solute-solvent interaction in 1-ethyl-3-methylimidazolium-based room temperature ionic liquids: A time-resolved fluorescence anisotropy study. AB - Rotational diffusion of two organic solutes, coumarin153 (C153) and 4 aminophthalimide (AP) has been investigated in four ionic liquids (ILs), viz. 1 ethyl-3-methylimidazolium trifluoroacetate (EMIMTFA), 1-ethyl-3-methylimidazolium ethylsulfate (EMIMESU), 1-ethyl-3-methylimidazolium tetrafluoroborate (EMIMTFB) and 1-ethyl-3-methylimidazolium tetracyanoborate (EMIMTCB), as a function of temperature. Between the two probes, AP can act as hydrogen-bond-donor to the solvents having hydrogen bond acceptor ability. The results indicate that the rotational dynamics of C153 is mainly governed by the viscosity of the medium. On the other hand, the rotational motion of AP is found to be significantly hindered in the ILs depending on the nature of anions of the ILs. Rotational coupling constant values for AP in the ILs follow the order TFA > ESU > TCB > TFB. The slower rotational motion of AP in these ILs has been attributed to the specific hydrogen bonding interaction between AP and anions of ILs. PMID- 24158316 TI - Patient hospital choice for hip replacement: empirical evidence from the Netherlands. AB - In the Dutch health care system, hospitals are expected to compete. A necessary condition for competition among hospitals is that patients do not automatically choose the nearest hospital, but are-at least to some extent-sensitive to differences in hospital quality. In this study, an analysis is performed on the underlying features of patient hospital choice in a setting where prices do not matter for patients as a result of health insurance coverage. Using claims data from all Dutch hospitals over the years 2008-2010, a conditional logit model examines the relationship between patient characteristics (age, gender and reoperations) and hospital attributes (hospital quality information, waiting times on treatments and travel time for patients to the hospitals) in the market for general non-emergency hip replacement treatments. The results show that travel time is the most important determinant in patient hospital choice. From our analysis, however, it follows that publicly available hospital quality ratings and waiting times also have a significant impact on patient hospital choice. The panel data used for this study (2008-2010) is rather short, which may explain why no coherent and persistent changes in patient hospital choice behaviour over time are found. PMID- 24158317 TI - Adolescent perceptions of cigarette appearance. AB - BACKGROUND: To reduce the possibility of cigarette appearance misleading consumers about harm caused by the product, the European Commission's draft Tobacco Products Directive proposed banning cigarettes <7.5 mm in diameter. It appears however, following a plenary vote in the European Parliament, that this will not be part of the final Tobacco Products Directive. To reduce the appeal of cigarettes, the Australian Government banned the use of branding on cigarettes and stipulated a maximum cigarette length as part of the Tobacco Plain Packaging Act. We explored the role, if any, of cigarette appearance on perceptions of appeal and harm among adolescents. METHODS: Focus group research with 15-year olds (N = 48) was conducted in Glasgow (Scotland) to explore young people's perceptions of eight cigarettes differing in length, diameter, colour and decorative design. RESULTS: Slim and superslim cigarettes with white filter tips and decorative features were viewed most favourably and rated most attractive across gender and socio-economic groups. The slimmer diameters of these cigarettes communicated weaker tasting and less harmful looking cigarettes. This was closely linked to appeal as thinness implied a more pleasant and palatable smoke for young smokers. A long brown cigarette was viewed as particularly unattractive and communicated a stronger and more harmful product. CONCLUSION: This exploratory study provides some support that standardising cigarette appearance could reduce the appeal of cigarettes in adolescents and reduce the opportunity for stick design to mislead young smokers in terms of harm. PMID- 24158318 TI - Effectiveness of interventions to increase hepatitis C testing uptake among high risk groups: a systematic review. AB - BACKGROUND: People who inject drugs are at the greatest risk of acquiring hepatitis C virus infection in many high-income countries, including those in Europe. Our review examined the effectiveness of interventions aimed at increasing hepatitis C virus testing uptake. METHODS: We undertook a systematic review of controlled studies. Searches of 13 databases were supplemented with citation searching, and manual searches of reference lists and websites. Studies of interventions that aimed to increase testing uptake among high-risk groups were included. Testing uptake was our primary outcome measure of interest and secondary outcomes were engagement in follow-up services and treatment. A narrative synthesis was undertaken. RESULTS: Eight controlled studies were included. Three studies examined interventions in primary care; one examined dried blood spot testing as an alternative method of testing, and two examined outreach provision. Two further studies examined interventions to improve hepatitis C management. Targeted case finding in primary care, support and training for primary care practitioners, offering alternative testing and provision of outreach testing all increased uptake of testing; however, intervention effects were variable. CONCLUSIONS: Evidence from the available studies suggests that increases in testing uptake can be achieved. Careful attention needs to be paid to the resource implications associated with implementation of interventions in primary care settings and also of the potential for interventions to improve outcomes once a positive diagnosis has been made. Further research on the cost-effectiveness of the intervention approaches examined in this review is required. PMID- 24158319 TI - Distribution, sources, and ecological risks of organochlorine pesticides in surface sediments from the Yellow River Estuary, China. AB - Thirty-four surface sediment samples were analyzed for organochlorine pesticides (OCPs), in order to provide information on levels, distribution and sources of these compounds in the Yellow River Estuary, China. The levels of the organochlorine pesticides in samples were detected by the technique of soxhlet extraction followed by analysis by gas chromatography (GC) coupled with a mass selective detector. Total concentrations of OCPs ranged widely from 0.06 to 53.4 ng g(-1), with a mean value of 44.84 ng g(-1), at the mid level of pesticide concentrations compared to those reported in other regions worldwide. HCHs were the predominant species in the study area. The ratios of alpha-HCH/gamma-HCH indicated that the technical HCH contamination was mainly due to a recent input of lindane in upper reach of Yellow River Estuary. The ratios of (DDD + DDE)/DDTs and DDD/DDE suggested that DDTs in sediments came mainly from the degradation of historical DDT in the environment, and DDT could be much easier to degrade into DDD under anaerobic conditions. Principal component analysis (PCA) could conclude that most of the OCPs came from early input and historical degradation products in the study area. Based on the sediment quality guidelines, gamma-HCH and p'p DDE would be of more concern for the ecotoxicological risk in this study area. PMID- 24158320 TI - Gastrointestinal parasitic burdens in UK tortoises: a survey of tortoise owners and potential risk factors. AB - Despite gastrointestinal parasites being commonly diagnosed in captive tortoises throughout the UK, there is a lack of data regarding the prevalence. The aims of this study were to investigate the prevalence of gastrointestinal parasites in tortoises in the UK, and to investigate the factors affecting the prevalence of these parasites. Owners were invited to submit a faecal sample from their tortoise in conjunction with a completed questionnaire covering details of signalment and husbandry. Data from the questionnaires were analysed at the end of the study. Faecal analysis was performed on samples from Testudo hermanni, Testudo graeca and Testudo horsfieldii. This involved examination of direct wet preparations, a modified McMaster technique, passive NaCl flotation and Cryptosporidium staining. Of the 142 samples used, 130 were examined by the first three methods. 49 per cent were positive for one or more parasites. Of the positive samples, 67 per cent were positive for oxyurids, 28 per cent were positive for ascarids and 28 per cent were positive for protozoa (Balantidium, Nyctotherus or flagellates). Only 1/113 (0.8 per cent) samples was positive for Cryptosporidium. The most important risk factors for parasites were sex (F) and length of time (<5 years) in owner's possession. This survey showed that gastrointestinal parasites are frequently detected in the faecal samples of captive tortoises in the UK, but their prevalence may be influenced by various factors including sex, length of time owned, age and species. PMID- 24158321 TI - Bovine respiratory syncytial virus: infection dynamics within and between herds. AB - The infection dynamics of bovine respiratory syncytial virus (BRSV) were studied in randomly selected Norwegian dairy herds. A total of 134 herds were tested twice, six months apart. The herds were classified as positive for BRSV if at least one animal between 150 and 365 days old tested positive for antibodies against BRSV, thereby representing herds that had most likely had the virus present during the previous year. The prevalence of positive herds at the first and second sampling was 34 per cent and at 41 per cent, respectively, but varied greatly between regions. Negative herds were found in close proximity to positive herds. Some of these herds remained negative despite several new infections nearby. Of the herds initially being negative, 42 per cent changed status to positive during the six months. This occurred at the same rate during summer as winter, but a higher rate of animals in the herds was positive if it took place during winter. Of the herds initially being positive, 33 per cent changed to negative. This indicates that an effective strategy to lower the prevalence and the impact of BRSV could be to employ close surveillance and place a high biosecurity focus on the negative herds. PMID- 24158322 TI - Serum haptoglobin concentrations in dogs with liver disease. AB - Dogs with liver disease have been shown to have increased serum C-reactive protein (CRP) concentrations. However, it is unclear whether dogs with liver disease also have increased serum haptoglobin concentrations. The aim of the study was to measure serum haptoglobin concentrations in healthy dogs, hospitalised dogs and dogs with liver diseases. Haptoglobin concentrations were measured in 30 healthy dogs, 47 hospitalised dogs with non-hepatic illness, 46 dogs with congenital portosystemic shunt (cPSS) and 11 dogs with primary hepatopathy. Haptoglobin concentrations were not significantly different between cPSS dogs with and without hepatic encephalopathy (HE), thus all cPSS dogs were considered as one group. Haptoglobin concentrations were significantly different between the remaining groups (P<0.0001). Hospitalised ill dogs had significantly higher haptoglobin concentrations than healthy dogs (P<0.001), dogs with cPSS (P<0.001) and dogs with primary hepatopathy (P<0.05). There was no significant difference between haptoglobin concentrations in healthy dogs, dogs with cPSS and dogs with primary hepatopathy. Haptoglobin concentrations were not significantly increased in dogs with liver diseases or in dogs with cPSS and HE. This is in contrast with the previously reported CRP results. This study demonstrates that liver function should be considered when interpreting haptoglobin concentrations in dogs. PMID- 24158323 TI - Meticillin-resistant commensal staphylococci in the oral cavity of healthy cats: a reservoir of meticillin resistance. PMID- 24158324 TI - Comparison of rectal, tympanic membrane and axillary temperature measurement methods in dogs. AB - The aim of this study was to compare axillary and tympanic membrane (TM) temperature measurements to rectal temperature in a large group of clinical canine patients. We also sought to ascertain whether certain factors affected the differences between the measurements and to compare the ease of measurement. Axillary temperatures were easy to obtain but tended to be lower than rectal readings (median difference 0.6 degrees C). In 54.7 per cent of dogs there was a difference of >0.5 degrees C between the two readings. Weight, coat length, body condition score and breed size were significantly associated with the difference between the rectal and axillary temperature. TM temperatures were more similar to rectal temperatures (median difference 0 degrees C) but in 25 per cent of dogs, there was a difference of >0.5 degrees C between rectal and TM readings. TM measurements were less well tolerated than axillary measurements. None of the factors assessed were associated with the difference between the rectal and TM temperature. As a difference of >0.5 degrees C has previously been described as unacceptable for different methods of temperature measurement, neither axillary nor TM temperatures are interchangeable with rectal temperatures for the measurement of body temperature. PMID- 24158325 TI - Horizontal transmission of bovine leukemia virus from lymphocytotic cattle, and beneficial effects of insect vector control. PMID- 24158326 TI - Different volumes of injectate using electrostimulator and blinded techniques for brachial plexus block in dogs. AB - To compare different volumes of injectate using electrostimulator (ES)-guided and blind brachial plexus blockade (BPB) techniques in dogs. Prospective, randomised, blinded study. Fifty-eight healthy adult purpose-bred beagle dogs. Animals were randomised into 4 groups based on the volume of methylene blue 0.1 per cent administered for BPB, three using ES technique: E1 (0.2 ml/kg, n=22), E2 (0.6 ml/kg, n=22), and E3 (1.0 ml/kg, n=14), and one using blinded technique B4 (1.0 ml/kg, n=14). After euthanasia, the axillary region was dissected and nerves identified by a blinded evaluator. Success was defined as 3/4 nerves stained, or presence of dye in the tissue immediately surrounding the plexus. There were no significant differences between groups when total nerve count, adjacent staining, success rate (92.8-100 per cent), or rate of haematoma were evaluated. The musculocutaneous nerve was significantly more targeted in B4 than E1 and E2, but not E3. Electrostimulator-guided BPB using lower volumes of injectate had similar success rate as the blinded technique using higher volume, thus, lower volumes can be used without compromising success. When an ES is not available, the blind technique with 1 ml/kg is also acceptable. However, when performing an ES-guided BPB, volumes as low as 0.2 ml/kg can be used. As volume is increased, the musculocutaneous nerve becomes more likely to be targeted. PMID- 24158327 TI - Prevalence and antimicrobial resistance of canine urinary tract pathogens. AB - This study aims to describe the incidence and risk factors for positive urinary tract culture, the prevalence of urinary tract pathogens in single organism and mixed cultures and changes in their antimicrobial resistance over 10 years. A retrospective review of computer records detailing canine urine samples submitted between August 1999 and September 2009 for culture and sensitivity in a UK tertiary referral hospital is described. 17.5 per cent of 5923 samples (670 of 4530 dogs) were positive cultures. 85.3 per cent of cultures yielded a single isolate. The prevalence of bacterial species differed between mixed and single isolate cultures. Entire and neutered female dogs were more likely to return positive cultures than male dogs (OR=2.5 and 1.5, respectively). Escherichia coli was most commonly isolated (53.9 per cent) and affected female dogs, older dogs and neutered dogs more. There was an increase in the antimicrobial resistance of Enterococcus faecalis and Pseudomonas Aeruginosa, and a decrease in the effectiveness of enrofloxacin, cephalexin and oxytetracycline. The prevalence of urinary bacterial isolates is described for a large group of dogs. Monitoring changes in antimicrobial efficacy and microbial resistance guides the empirical use of antimicrobials for the treatment of urinary tract infection and helps formulate strategic plans to limit drug resistance. PMID- 24158328 TI - Reduced-size microchips for identification of horses: response to implantation and readability during a six-month period. AB - In this study, readability of reduced-size microchips in horses and the response to implantation were analysed. It was hypothesised that small microchips can be implanted stress-free but are less readable than larger microchips. Adult mares (n=40) were implanted with a reduced-size microchip (10.9*1.6 mm) at the left side of the neck (size of conventional microchips 11.4*2.2 mm). Microchips were identified with three different scanners (A, B, C) immediately, and at 6, 12 and 28 weeks after implantation. Twelve out of the 40 mares were submitted to microchip implantation and control treatments and cortisol, heart rate and heart rate variability (HRV) were determined. From the chip-bearing side of the neck, microchips were identified with all scanners in all horses at all times. From the contralateral side, correct readings were always 100 per cent with scanner C and with scanners A and B ranged between 60 and 100 per cent. Heart rate and HRV variable sd of beat-to-beat interval increased slightly (P<0.01) at microchip implantation and control treatment, but cortisol concentration did not increase. In conclusion, reduced-size microchips are highly reliable for identification of horses. Compared with conventional microchips, the reduction in size did not impair readability. Microchip implantation is no pronounced stressor for horses. PMID- 24158330 TI - Development of transgenic sweet potato with multiple virus resistance in South Africa (SA). AB - Multiple infections of Sweet potato feathery mottle virus (SPFMV), Sweet potato chlorotic stunt virus (SPCSV), Sweet potato virus G (SPVG) and Sweet potato mild mottle virus (SPMMV) cause a devastating synergistic disease complex of sweet potato (Ipomoea batatas Lam.) in KwaZulu-Natal, South Africa. In order to address the problem of multiple virus infections and synergism, this study aimed to develop transgenic sweet potato (cv. Blesbok) plants with broad virus resistance. Coat protein gene segments of SPFMV, SPCSV, SPVG and SPMMV were used to induce gene silencing in transgenic sweet potato. Transformation of apical tips of sweet potato cv. Blesbok was achieved by using Agrobacterium tumefaciens strain LBA4404 harboring the expression cassette. Polymerase chain reaction and Southern blot analyses showed integration of the transgenes occurred in six of the 24 putative transgenic plants and that all plants seemed to correspond to the same transformation event. The six transgenic plants were challenged by graft inoculation with SPFMV, SPCSV, SPVG and SPMMV-infected Ipomoea setosa Ker. Although virus presence was detected using nitrocellulose enzyme-linked immunosorbent assay, all transgenic plants displayed delayed and milder symptoms of chlorosis and mottling of lower leaves when compared to the untransformed control plants. These results warrant further investigation on resistance to virus infection under field conditions. PMID- 24158329 TI - Utility of three-dimensional computed tomography in general thoracic surgery. AB - It is important for general thoracic surgeons to understand the relationship between tumors and surrounding organs during surgery; however, many anatomical variations are possible in the thorax, which can complicate this goal. Multidetector computed tomography (MDCT) is the latest technical breakthrough in CT imaging. MDCT permits rapid scanning of large areas of the body with multiple detectors, thereby allowing for simultaneous acquisition of an increased number of transaxial CT slices, which reduce motion artifacts. Three-dimensional (3D) rendering involves the creation of two-dimensional images that convey the 3D relationship of objects. The 3D reconstruction allows for enormous quantity of data to be utilized intuitively and effectively. The final images can reveal various lesions or organs of interest with high anatomical detail and accuracy to the general thoracic surgeon, which is helpful in performing safer surgeries. Surgeries for the following can benefit from this technology: lung lobectomy or segmentectomy, pulmonary sequestration, cardiovascular malformation, tracheobronchial tree, mediastinum, and chest wall. This article reviews the utility of 3D-MDCT imaging in the field of general thoracic surgery. PMID- 24158331 TI - Reconstructive procedures for treating peri-implantitis: a systematic review. AB - This review aimed at evaluating the effectiveness of reconstructive procedures for treating peri-implantitis. Searches of electronic databases and cross referencing were performed for human comparative clinical trials with >= 10 implants for >= 12 months of follow-up, reporting radiographic defect fill and at least one of the following parameters: probing depth reduction, clinical attachment level gain, bleeding on probing reduction, and mucosal recession. The searches retrieved 430 citations. Only 1 randomized controlled trial was identified, which compared reconstructive therapy and open flap debridement. Case series studies were also included to evaluate the overall performance of the reconstructive procedures. Twelve studies were finally included. Meta-analysis revealed that the weighted mean radiographic defect fill was 2.17 mm (95% confidence interval [CI]: 1.46-2.87 mm), probing depth reduction was 2.97 mm (95% CI: 2.38-3.56 mm), clinical attachment level gain was 1.65 mm (95% CI: 1.17-2.13 mm), and bleeding on probing reduction was 45.8% (95% CI: 38.5%-53.3%). Great variability in reparative outcomes was found, attributed to patient factors, defect morphology, and reconstructive agents used. Currently, there is a lack of evidence for supporting additional benefit of reconstructive procedures to the other treatment modalities for managing peri-implantitis. PMID- 24158332 TI - Long-term stability of early implant placement with contour augmentation. AB - In this prospective case series study, 20 patients with an implant-borne single crown following early implant placement with simultaneous contour augmentation were followed for 6 years. Clinical, radiologic, and esthetic parameters were assessed. In addition, cone beam computed tomography (CBCT) was used at 6 years to examine the facial bone wall. During the study period, all 20 implants were successfully integrated, and the clinical parameters remained stable over time. Pleasing esthetic outcomes were noted, as assessed by the pink esthetic scores. None of the implants developed mucosal recession of 1 mm or more. The periapical radiographs yielded stable peri-implant bone levels, with a mean DIB of 0.44 mm at 6 years. The CBCT scans showed that all 20 implants had a detectable facial bone wall at 6 years, with a mean thickness of around 1.9 mm. In summary, this prospective case series study demonstrated stable peri-implant hard and soft tissues for all 20 implants, and pleasing esthetic outcomes overall. The follow up of 6 years confirmed that the risk for mucosal recession is low with early implant placement. In addition, contour augmentation with guided bone regeneration (GBR) was able to establish and maintain a facial bone wall in all 20 patients. PMID- 24158333 TI - Influence of platform switching on bone-level alterations: a three-year randomized clinical trial. AB - The concept of platform switching has been introduced to implant dentistry based on clinical observations of reduced peri-implant crestal bone loss. However, published data are controversial, and most studies are limited to 12 months. The aim of the present randomized clinical trial was to test the hypothesis that platform switching has a positive impact on crestal bone-level changes after 3 years. Two implants with a diameter of 4 mm were inserted crestally in the posterior mandible of 25 patients. The intraindividual allocation of platform switching (3.3-mm platform) and the standard implant (4-mm platform) was randomized. After 3 months of submerged healing, single-tooth crowns were cemented. Patients were followed up at short intervals for monitoring of healing and oral hygiene. Statistical analysis for the influence of time and platform type on bone levels employed the Brunner-Langer model. At 3 years, the mean radiographic peri-implant bone loss was 0.69 +/- 0.43 mm (platform switching) and 0.74 +/- 0.57 mm (standard platform). The mean intraindividual difference was 0.05 +/- 0.58 mm (95% confidence interval: -0.19, 0.29). Crestal bone-level alteration depended on time (p < .001) but not on platform type (p = .363). The present randomized clinical trial could not confirm the hypothesis of a reduced peri-implant crestal bone loss, when implants had been restored according to the concept of platform switching. PMID- 24158334 TI - Genetic networks in osseointegration. AB - Osseointegration-based dental implants have become a well-accepted treatment modality for complete and partial edentulism. The success of this treatment largely depends on the stable integration and maintenance of implant fixtures in alveolar bone; however, the molecular and cellular mechanisms regulating this unique tissue reaction have not yet been fully uncovered. Radiographic and histologic observations suggest the sustained retention of peri-implant bone without an apparent susceptibility to catabolic bone remodeling; therefore, implant-induced bone formation continues to be intensively investigated. Increasing numbers of whole-genome transcriptome studies suggest complex molecular pathways that may play putative roles in osseointegration. This review highlights genetic networks related to bone quality, the transient chondrogenic phase, the vitamin D axis, and the peripheral circadian rhythm to elute the regulatory mechanisms underlying the establishment and maintenance of osseointegration. PMID- 24158335 TI - Do implant overdentures improve dietary intake? A randomized clinical trial. AB - People wearing mandibular two-implant overdentures (IOD) chew food with less difficulty than those wearing conventional complete dentures (CD). However, there is still controversy over whether or not this results in better dietary intake. In this randomized clinical trials (RCT), the amounts of total dietary fiber (TDF), macronutrients, 9 micronutrients, and energy in diets consumed by persons with IOD and CD were compared. Male and female edentate patients >= 65 yrs (n = 255) were randomly divided into 2 groups and assigned to receive a maxillary CD and either a mandibular IOD or a CD. One year following prosthesis delivery, 217 participants (CD = 114, IOD = 103) reported the food and quantities they consumed to a registered dietician through a standard 24-hour dietary recall method. The mean and median values of TDF, macro- and micronutrients, and energy consumed by both groups were calculated and compared analytically. No significant between group differences were found (ps > .05). Despite quality-of-life benefits from IODs, this adequately powered study reveals no evidence of nutritional advantages for independently living medically healthy edentate elders wearing two-implant mandibular overdentures over those wearing conventional complete dentures in their dietary intake at one year following prosthesis delivery. PMID- 24158336 TI - Dental implants installed in irradiated jaws: a systematic review. AB - The aim of this study was to assess the survival rate of titanium implants placed in irradiated jaws. MEDLINE, EMBASE, and CENTRAL were searched for studies assessing implants that had been placed in nongrafted sites of irradiated patients. Random effects meta-analyses assessed implant loss in irradiated versus nonirradiated patients and in irradiated patients treated with hyperbaric oxygen (HBO) therapy. Of 1,051 potentially eligible publications, 15 were included. A total of 10,150 implants were assessed in the included studies, and of these, 1,689 (14.3%) had been placed in irradiated jaws. The mean survival rate in the studies ranged from 46.3% to 98.0%. The pooled estimates indicated a significant increase in the risk of implant failure in irradiated patients (risk ratio: 2.74; 95% confidence interval: 1.86, 4.05; p < .00001) and in maxillary sites (risk ratio: 5.96; 95% confidence interval: 2.71, 13.12; p < .00001). Conversely, HBO therapy did not reduce the risk of implant failure (risk ratio: 1.28; 95% confidence interval: 0.19, 8.82; p = .80). Radiotherapy was linked to higher implant failure in the maxilla, and HBO therapy did not improve implant survival. Most included publications reported data on machined implants, and only 3 studies on HBO therapy were included. Overall, implant therapy appears to be a viable treatment option for reestablishing adequate occlusion and masticatory conditions in irradiated patients. PMID- 24158337 TI - Release of bone markers in immediately loaded and nonloaded dental implants: a randomized clinical trial. AB - The aim of this study was to compare the release of bone markers during osseointegration of immediately loaded and nonloaded implants. Forty patients who were indicated for rehabilitation with dental implants randomly received either implant and prosthesis placement within 72 hours (group IM) or implant insertion and no prosthesis placement (group NL). Peri-implant crevicular fluid was collected immediately after implant insertion and 7, 15, 30, 60, 90, and 120 days after surgery and levels of osteoprotegerin, transforming growth factors, osteocalcin, osteopontin, and parathyroid hormone were evaluated using Luminex assay. Bleeding index and peri-implantar sulcus depth were also evaluated. The data were compared using statistical tests (alpha = 5%). No statistical difference was found regarding demographic and clinical parameters (p > .05). Transforming growth factors, osteoprotegerin, osteopontin, and parathyroid hormone presented an earlier release peak in group IM than in NL group (p < .05). Osteocalcin achieved higher levels in group IM versus group NL between 7 and 30 days of evaluation (p < .05). It may be concluded that earlier loading positively modulates bone mediators release around immediately loaded implants when compared with nonloaded dental implants. PMID- 24158338 TI - Cost-effectiveness of anterior implants versus fixed dental prostheses. AB - For the restoration of an anterior missing tooth, implant-supported single crowns (ISCs) or fixed dental prostheses (FDPs) are indicated, but it is not clear which type of restoration is more cost-effective. A self-selected trial was performed with 15 patients with ISCs and 11 with FDPs. Patient preferences were recorded with visual analog scales before treatment, 1 month following restoration, and then annually. Quality-adjusted tooth years (QATYs) were estimated by considering the type of reconstruction for replacing the missing tooth and its effect on the adjacent teeth. A stochastic cost-effectiveness model was developed using Monte Carlo simulation. The expected costs and QATYs were summarized in cost effectiveness acceptability curves. ISC was the dominant strategy, with a QATY increase of 0.01 over 3 years and 0.04 over 10 years with a higher probability of being cost-effective. While both treatment options provided satisfactory long term results from the patient's perspective, the lower initial costs, particularly laboratory fees, were responsible for the dominance of ISCs over FDPs. PMID- 24158339 TI - Investigational clinical research in implant dentistry: beyond observational and descriptive studies. PMID- 24158340 TI - Ridge alterations post-extraction in the esthetic zone: a 3D analysis with CBCT. AB - Dimensional alterations of the facial bone wall following tooth extractions in the esthetic zone have a profound effect on treatment outcomes. This prospective study in 39 patients is the first to investigate three-dimensional (3D) alterations of facial bone in the esthetic zone during the initial 8 wks following flapless tooth extraction. A novel 3D analysis was carried out, based on 2 consecutive cone beam computed tomographies (CBCTs). A risk zone for significant bone resorption was identified in central areas, whereas proximal areas yielded only minor changes. Correlation analysis identified a facial bone wall thickness of <= 1 mm as a critical factor associated with the extent of bone resorption. Thin-wall phenotypes displayed pronounced vertical bone resorption, with a median bone loss of 7.5 mm, as compared with thick-wall phenotypes, which decreased by only 1.1 mm. For the first time, 3D analysis has allowed for documentation of dimensional alterations of the facial bone wall in the esthetic zone of humans following extraction. It also characterized a risk zone prone to pronounced bone resorption in thin-wall phenotypes. Vertical bone loss was 3.5 times more severe than findings reported in the existing literature. PMID- 24158341 TI - Patient-specific analysis of periodontal and peri-implant microbiomes. AB - Periodontally involved teeth have been implicated as 'microbial reservoirs' in the etiology of peri-implant diseases. Therefore, the purpose of this investigation was to use a deep-sequencing approach to identify the degree of congruence between adjacent peri-implant and periodontal microbiomes in states of health and disease. Subgingival and peri-implant biofilm samples were collected from 81 partially edentulous individuals with periodontal and peri-implant health and disease. Bacterial DNA was isolated, and the 16S rRNA gene was amplified and sequenced by pyrotag sequencing. Chimera-depleted sequences were compared against a locally hosted curated database for bacterial identification. Statistical significance was determined by paired Student's t tests between tooth-implant pairs. The 1.9 million sequences identified represented 523 species. Sixty percent of individuals shared less than 50% of all species between their periodontal and peri-implant biofilms, and 85% of individuals shared less than 8% of abundant species between tooth and implant. Additionally, the periodontal microbiome demonstrated significantly higher diversity than the implant, and distinct bacterial lineages were associated with health and disease in each ecosystem. Analysis of our data suggests that simple geographic proximity is not a sufficient determinant of colonization of topographically distinct niches, and that the peri-implant and periodontal microbiomes represent microbiologically distinct ecosystems. PMID- 24158342 TI - Implant-supported mandibular overdentures in very old adults: a randomized controlled trial. AB - The purpose of this study was (1) to investigate denture satisfaction following the conversion of existing mandibular complete dentures to implant overdentures (IOD) in very old edentulous patients who depend on help for activities of daily living and (2) to evaluate secondary end points, such as functional, structural, nutritional, and patient-centered aspects. For this randomized clinical trial, 2 interforaminal short implants were placed in the intervention group (n = 16, 85.0 +/- 6.19 yrs) to retain mandibular IODs; the control group (n = 18, 84.1 +/- 5.55 yrs) received conventional relines. During the first year, no implant was lost; however, 2 patients died. IODs proved more stable, and participants in the intervention group demonstrated significantly higher denture satisfaction as well as an increased oral health-related quality of life compared to the control group. Maximum voluntary bite force improved significantly with IODs, yet the chewing efficiency was not different between groups. Masseter muscle thickness increased with IODs, mainly on the preferred chewing side. Body mass index decreased in both groups, but the decline tended to be smaller in the intervention group; blood markers and the Mini Nutritional Assessment did not confirm this tendency. These results indicate that edentulous patients who depend on help for activities of daily living may benefit from IODs even late in life. PMID- 24158343 TI - A retrospective study of implant-abutment connections on crestal bone level. AB - This study compared the effects of external hex, internal octagon, and internal Morse taper implant-abutment connections on the peri-implant bone level before and after the occlusal loading of dental implants. Periapical radiographs of 103 implants (63 patients) placed between 2002 and 2010 were collected, digitized, standardized, and classified into groups based on the type of implant-abutment connection. These radiographs were then analyzed with image-processing software to measure the peri-implant crestal bone change during the healing phase (4 months after implant placement) and at loading phases 1 and 2 (3 and 6 months after occlusal loading, respectively). A generalized estimating equation method was employed for statistical analysis. The amount of peri-implant crestal bone change differed significantly among all time-phase pairs for all 3 types of implant-abutment connection, being greater in the healing phase than in loading phase 1 or 2. However, the peri-implant crestal bone change did not differ significantly among the 3 types of implant-abutment connections during the healing phase, loading phase 1, or loading phase 2. This retrospective clinical study reveals that the design of the implant-abutment connection appears to have no significant impact on short-term peri-implant crestal bone change. PMID- 24158344 TI - Mastication improvement after partial implant-supported prosthesis use. AB - Partially edentulous patients may be rehabilitated by the placement of removable dental prostheses, implant-supported removable dental prostheses, or partial implant fixed dental prostheses. However, it is unclear the impact of each prosthesis type over the masticatory aspects, which represents the objective of this paired clinical trial. Twelve patients sequentially received and used each of these 3 prosthesis types for 2 months, after which maximum bite force was assessed by a strain sensor and food comminution index was determined with the sieving method. Masseter and temporal muscle thicknesses during rest and maximal clenching were also evaluated by ultrasonography. Each maxillary arch received a new complete denture that was used throughout the study. Data were analyzed by analysis of variance for repeated measures, followed by the Tukey test (p < .05). Maximum bite force and food comminution index increased (p < .0001) after implant supported dental prosthesis and implant fixed dental prosthesis use, with the higher improvement found after the latter's use. Regardless of implant-retained prosthesis type, masseter muscle thickness during maximal clenching also increased (p < .05) after implant insertion. Partial implant-supported prostheses significantly improved masseter muscle thickness and mastication, and the magnitude of this effect was related to prosthesis type. PMID- 24158346 TI - The role of microRNAs in hepatitis C virus RNA replication. AB - Replication of hepatitis C virus (HCV) RNA is influenced by a variety of microRNAs, with the main player being the liver-specific microRNA-122 (miR-122). Binding of miR-122 to two binding sites near the 5' end of the 5' untranslated region (UTR) of the HCV genomic RNA results in at least two different effects. On the one hand, binding of miR-122 and the resulting recruitment of protein complexes containing Argonaute (Ago) proteins appears to mask the viral RNA's 5' end and stabilizes the viral RNA against nucleolytic degradation. On the other hand, this interaction of miR-122 with the 5'-UTR also stimulates HCV RNA translation directed by the internal ribosome entry site (IRES) located downstream of the miR-122 binding sites. However, it is suspected that additional, yet undefined roles of miR-122 in HCV replication may also contribute to HCV propagation. Accordingly, miR-122 is considered to contribute to the liver tropism of the virus. Besides miR-122, let-7b, miR-196, miR-199a* and miR-448 have also been reported to interact directly with the HCV RNA. However, the latter microRNAs inhibit HCV replication, and it has been speculated that miR 199a* contributes indirectly to HCV tissue tropism, since it is mostly expressed in cells other than hepatocytes. Other microRNAs influence HCV replication indirectly. Some of those are advantageous for HCV propagation, while others suppress HCV replication. Consequently, HCV up-regulates or down-regulates, respectively, the expression of most of these miRNAs. PMID- 24158345 TI - Detection of rotavirus in children with acute gastroenteritis in Porto Velho, Rondonia, Brazil. AB - Rotavirus group A (RVA) infection was ascertained in 591 fecal samples from children 0 to 6 years old with acute gastroenteritis. The vaccination status was also verified in all 591 subjects, with 302 (51.0 % +/- 4.0 %) participants fully vaccinated against rotavirus. Forty-two of the vaccinated children (13.9 % +/- 3.9 %) tested positive for RVA infection. Of the 289 unvaccinated children (49.0 % +/- 4.0 %), 61 (21.1 % +/- 4.7 %) had stools positive for RVA. This study suggests that the proportion of acute diarrhea cases caused by rotavirus was low and that the incidence of rotavirus diarrhea decreased over the study period in both vaccinated and unvaccinated children. PMID- 24158347 TI - Enterovirus 71 pathogenicity in monkeys and cotton rats. AB - Enterovirus 71 (EV71) is a neurovirulent non-polio enterovirus that can cause severe central nervous system (CNS) infection in infants. Vervet monkeys infected intracerebrally or intramuscularly with EV71 isolates from the Bulgarian outbreak of 1975 developed clinical manifestations and pathological signs of encephalomyelitis and spinal poliomyelitis that were similar to EV71 neuroinfection in children. In addition, vervet monkeys with encephalomyelitis had severe alterations in the choroid plexus. EV71 neuroinfection could also be reproduced in young (3- to 4-week old) cotton rats with clinical and pathological signs comparable with those observed in vervet monkeys. PMID- 24158348 TI - Cloning, expression and purification of duck hepatitis B virus (DHBV) core protein and its use in the development of an indirect ELISA for serologic detection of DHBV infection. AB - Infecting ducks with duck hepatitis B virus (DHBV) is widely accepted as a relevant model for studying aspects of human HBV infection. However, efficient and sensitive diagnostic methods for the various infection models are limited. In order to provide a more simple and convenient method for serologic diagnosis, we improved the production of recombinant DHBV viral capsid protein (core protein) and then used it to develop an indirect enzyme-linked immunosorbent assay (ELISA) for detecting anti-DHBc antibodies (DHBcAg ELISA) in DHBV-infected ducks. Given the positive/negative cut-off value, the maximum dilution of duck sera in which anti-DHBc antibodies could be detected was 1:12,800. In addition, the DHBcAg ELISA displayed no cross reactivity with duck antisera against duck circovirus (DuCV), duck plague virus (DPV), duck hepatitis virus (DHV), duck swollen head septicemia virus (DSHSV), avian influenza virus (AIV), Riemerella anatipestifer, Salmonella anatum, or Escherichia coli. Furthermore, the coefficients of variation (CVs) of inter-assay and intra-assay experiments were both below than 10 %. When compared to PCR for accuracy on clinical samples from cases of suspected DHBV infection, the DHBcAg showed 95.45 % coincidence with PCR. In conclusion, recombinant DHBc was readily produced and used to establish a simple DHBcAg ELISA that provided a highly specific and sensitive method for analysis of clinical samples. PMID- 24158349 TI - Do grandmaternal smoking patterns influence the etiology of childhood asthma? AB - BACKGROUND: Animal data suggest that tobacco smoke exposure of a mother when she is in utero influences DNA methylation patterns in her offspring and that there is an effect on the respiratory system, particularly airway responsiveness. The only study, to our knowledge, in humans suggests that there is a similar effect on asthma. The present study tests whether an association with respiratory problems can be confirmed in a large population study and aims to determine whether in utero exposure of the father has similar effects on his offspring. METHODS: Information from the Avon Longitudinal Study of Parents and Children was used to compare the offspring of women and of men who had themselves been exposed to cigarette smoke in utero; separate analyses were performed for children of women smokers and nonsmokers. The outcome measures were trajectories of history of early wheezing, doctor-diagnosed asthma by age 7 years, and results of lung function and methacholine challenge tests at 8 years. A variety of social and environmental factors were taken into account; offspring sexes were examined separately. RESULTS: There was no association with any outcome in relation to maternal prenatal exposure. There was some evidence of an increase in asthma risk with paternal prenatal exposure when the study mother was a nonsmoker (adjusted OR, 1.17; 95% CI, 0.97-1.41). This was particularly strong for girls (adjusted OR, 1.39; 95% CI, 1.04-1.86). CONCLUSIONS: We did not find that maternal prenatal exposure to her mother's smoking had any effect on her children's respiratory outcomes. There was suggestive evidence of paternal prenatal exposure being associated with asthma and persistent wheezing in the granddaughters. PMID- 24158350 TI - Methotrexate-induced accelerated nodulosis in a patient with rheumatoid arthritis and scleroderma. PMID- 24158351 TI - Is there a relationship between symptoms of patients and tomographic characteristics of styloid process? AB - OBJECTIVES: To investigate the angulations and length of the styloid process (SP) on three-dimensional computed tomography (3D-CT) images between the patients having elongated SP complaints and those without any stylalgia symptoms. PATIENTS AND METHODS: One hundred patients underwent 3D-CT evaluation of the bilateral temporomandibular joints to investigate for symptomatic elongated styloid process (ESP) at our institution. The differences between the mean angulations and lengths of the SP and comparisons between patient and control groups were analyzed by student t test. RESULTS: In study group, mean length of styloid processes was 40.7 +/- 10.8 mm on the right and 40.3 +/- 10.9 mm on the left. Mean medial angles of SP were measured as 22.60 +/- 4.0 on the right side and 22.60 +/- 4.5 on the left side. In the same group, mean anterior angles of SP were 16.10 +/- 6.9 on the right and 16.70 +/- 7.1 on the left side. The "in group" comparisons of lengths, medial and anterior angles did not produce statistically significant results. The comparison of medial angulations between the symptomatic and asymptomatic patients was the only statistically meaningful result in our study. CONCLUSION: 3D-CT has several advantages according to conventional tomography for visualization of head and neck anatomy. The increase of medial angulation of SP may be responsible for the development of complaints in ESP. PMID- 24158352 TI - A rare muscular variation in the superficial region of the popliteal fossa. AB - We found a rare muscular variation in the superficial region of the popliteal fossa in a 61-year-old Korean male cadaver whose cause of death was laryngeal carcinoma during routine dissection course for medical students. The muscle ran transversely between the medial head of the gastrocnemius muscle and the tendon of the long head of biceps femoris muscle, covering the neurovascular structures in the popliteal fossa. The muscle received its nerve supply from the tibial nerve. Based on its innervation, we speculated that the anomalous muscle might be a very specific type of variation related to the gastrocnemius tertius rather than another superficial muscle in the popliteal fossa. PMID- 24158353 TI - Spatially resolved microrheology of heterogeneous biopolymer hydrogels using covalently bound microspheres. AB - Characterization of the rheological properties of heterogeneous biopolymers is important not only to understand the effect of substrate elasticity on cell behaviors, but also to provide insights into mechanical changes during cellular remodeling of the environment. Conventional particle-tracking microrheology (PTM) techniques are compromised by probe-network slippage and cage-hopping problems, and require a priori knowledge of network mesh size in order to determine a suitable probe size. We demonstrated here the usefulness of covalently bound probes for PTM of biopolymers to overcome the above limitations. We showed that, in a well-defined system like polyacrylamide gels, surface-modified probe particles using a zero-length crosslinker provided more reliable measurements of network mechanics as compared to standard carboxylated probes. We further demonstrated that appropriate surface modification of microspheres for PTM circumvented the requirement of using microspheres larger than the network mesh, an approach typically considered to be ideal. Using the method presented in this study, we found the local network at the leading edge of a typical C6 glioma cell to be stiffer as compared to the side. Our findings established that permanent interaction between the probe and network is crucial to reliably measure the local network mechanics in reconstituted, heterogeneous networks using PTM. PMID- 24158355 TI - The influence of black carbon on the sorption and desorption of two model PAHs in natural soils. AB - Black carbons (BC) which result from the incomplete combustion of farm waste [man made (burned) BC] are highly absorbent. In Taiwan, the burning of farm waste known as slash and burn is common. The BCs from the burning may present an environmental challenge. Little is known about the effect of BCs on the transport of hydrophobic organic contaminants (HOC). This study investigates the sorption of anthracene and naphthalene to BCs in soil and efficiency of the surfactants Tween 80 and Triton X-100 in their removal. Both surfactants demonstrated 2-6 times increased solubility in the soils with the addiction of BC. Column experiments were performed to imitate the transportation of these contaminants in groundwater through soils before and after adding BC produced by burning farm waste in the lab. We found significantly increased sorption of anthracene in soil added with BCs produced in the lab, suggesting that fraction of organic carbon (foc) can contribute to sorption of such HOCs. Sorption of naphthalene was increased but not significantly. Comparing the concentrations of contaminants, we found the soil containing BC from burned farm waste absorbed HOC more efficiently than the organic BC (naturally-occurring) in the original soil. Therefore, sorption capacity and influence on the transport of HOC cannot be estimated simply by the foc of the soil because the two BCs differ greatly in their sorption ability. BC from farm waste absorbs more contaminants than naturally occurring BC in the soil. PMID- 24158356 TI - Characterization and risk assessment of exposure to volatile organic compounds in apartment buildings in Harbin, China. AB - This study analyzed the risk of exposure to volatile organic compounds (VOCs) in the apartment buildings (including bedrooms, living rooms, kitchens and study rooms) in Harbin, China. The concentration of total VOCs in bedrooms showed the lowest value with an average of 482.6 mg/m(3). 32.33 % of total measured VOCs correspond to aromatic hydrocarbons. The major chemical forms of the identified VOCs in other 3 types of rooms were alcohols which contributed to 30.66 % (in living rooms), 36.55 % (in kitchens) and 35.43 % (in study rooms) separately. Formaldehyde was the pollutant of highest concern given its high chronic toxic and carcinogenic risk levels according to the health assessment. Other pollutants of concern for human heal risks were benzene and naphthalene. The non-cancer risk by the exposure to naphthalene ranged from 2.39 to 2.80 in 4 target groups, which is more than 1.0 considered as a hazarded level to human health. PMID- 24158354 TI - The roles of HLH transcription factors in epithelial mesenchymal transition and multiple molecular mechanisms. AB - Epithelial-to-mesenchymal transition (EMT) is presently recognized as an important event and the initiating stage for tumor invasion and metastasis. Several EMT inducers have been identified, among which the big family of helix loop-helix (HLH) transcription factors are rising as a novel and promising family of proteins in EMT mediation, such as Twist1, Twist2, E47, and HIFs, etc. Due to the variety and complexities of HLH members, the pathways and mechanisms they employ to promote EMT are also complex and characteristic. In this review, we will discuss the roles of various HLH proteins in the regulation and sustenance of the EMT and multiple cellular mechanisms, attempting to provide a novel and broadened view towards the link between HLH proteins and EMT. PMID- 24158357 TI - Anticoagulant rodenticides in red-tailed hawks, Buteo jamaicensis, and great horned owls, Bubo virginianus, from New Jersey, USA, 2008-2010. AB - Liver samples from red-tailed hawks (Buteo jamaicensis) and great horned owls (Bubo virginianus) were analyzed for anticoagulant rodenticides. Residues of one or more second generation anticoagulant rodenticides (SGARs) were detected in 81 % of red-tailed hawks and 82 % of great horned owls. The most frequently detected SGAR was brodifacoum, which was detected in 76 % of red-tailed hawks and 73 % of great horned owls. Bromadiolone was detected in 20 % of red-tailed hawks and 27 % of great horned owls. Difenacoum was detected in one great horned owl. No other ARs were detected. There were no significant differences between species in the frequency of detection or concentration of brodifacoum or bromadiolone. There was a marginally significant difference (p = 0.0497) between total SGAR residues in red-tailed hawks (0.117 mg/kg) and great horned owls (0.070 mg/kg). There were no seasonal differences in the frequency of detection or concentration of brodifacoum in red-tailed hawks. The data suggest that SGARs pose a significant risk of poisoning to predatory birds in New Jersey. PMID- 24158358 TI - Gene editing a constitutively active OsRac1 by homologous recombination-based gene targeting induces immune responses in rice. AB - OsRac1 is a member of the plant small GTPase Rac/Rop family and plays a key role in rice immunity. The constitutively active (CA) G19V mutation of OsRac1 was previously shown to induce reactive oxygen species production, phytoalexin synthesis and defense gene activation, leading to resistance to rice blast infection. To study further the effect of the G19V mutation in disease resistance, we introduced a single base substitution by gene targeting and removed the selectable marker using Cre-loxP site-specific recombination. The CA OsRac1 gene generated by gene targeting was termed CA-gOsRac1. The G19V mutation was transferred from a targeting vector to the OsRac1 locus and stably transmitted to the next generation. In the leaf blade of homozygous CA-gOsRac1 plants, mutant transcript levels were much lower than in those of wild-type plants. In contrast, mutant transcripts in roots, leaf sheaths and panicles were more abundant than those in leaf blades. However, upon chitin treatment, the expression of defense-related genes PAL1 and PBZ1 in the cell culture was greater in the mutants compared with wild-type plants. Furthermore, induction of hypersensitive response (HR)-like cell death was observed in the leaf sheaths of mutant plants infected with a compatible race of rice blast fungus. In the CA gOsRac1 plants, a number of genes previously shown to be induced by Magnaporthe oryzae and Xanthomonas oryzae pv. oryzae (Xoo) infection were induced in the leaf sheath without pathogen infection. These results suggest that gene targeting will provide mutations useful for gene function studies and crop improvement. PMID- 24158360 TI - Models of service delivery for cancer genetic risk assessment and counseling. AB - Increasing awareness of and the potentially concomitant increasing demand for cancer genetic services is driving the need to explore more efficient models of service delivery. The aims of this study were to determine which service delivery models are most commonly used by genetic counselors, assess how often they are used, compare the efficiency of each model as well as impact on access to services, and investigate the perceived benefits and barriers of each. Full members of the NSGC Familial Cancer Special Interest Group who subscribe to its listserv were invited to participate in a web-based survey. Eligible respondents were asked which of ten defined service delivery models they use and specific questions related to aspects of model use. One-hundred ninety-two of the approximately 450 members of the listserv responded (42.7%); 177 (92.2%) had provided clinical service in the last year and were eligible to complete all sections of the survey. The four direct care models most commonly used were the (traditional) face-to-face pre- and post-test model (92.2%), the face-to-face pretest without face-to-face post-test model (86.5%), the post-test counseling only for complex results model (36.2%), and the post test counseling for all results model (18.3%). Those using the face-to-face pretest only, post-test all, and post-test complex models reported seeing more new patients than when they used the traditional model and these differences were statistically significantly. There were no significant differences in appointment wait times or distances traveled by patients when comparing use of the traditional model to the other three models. Respondents recognize that a benefit of using alternative service delivery models is increased access to services; however, some are concerned that this may affect quality of care. PMID- 24158359 TI - Genotypic characterization by spoligotyping and VNTR typing of Mycobacterium bovis and Mycobacterium caprae isolates from cattle of Tunisia. AB - This work is an approach to the molecular epidemiology of Mycobacterium tuberculosis complex (MTBC) bovine infections in Tunisia. A total of 35 MTBC isolates from both lateral retropharyngeal lymph node samples of cattle slaughtered in different Tunisian regions were genotyped by spoligotyping and variable number tandem repeat typing (VNTR)-typing. Spoligotyping allowed to identify two profiles not previously registered, namely SB2024, a Mycobacterium caprae isolate from Nabeul Region (North East Tunisia), the first description of this species in the country, and SB2025 (Mycobacterium bovis) from Sfax Region (Southern Tunisia). A second M. caprae isolate with a spoligotyping profile previously described in Europe mainland, SB0418, was also isolated from a bovine of Sfax region. Both isolates suggest the possibility of a widespread distribution of this species in the country. The predominant spoligotype was SB0120, present in all Tunisian regions selected for the study but Nabeul. Molecular typing also allowed to describe a mixed infection caused by two different M. bovis isolates (SB0120 and SB0848) in the same animal. VNTR typing was highly discriminant by testing a panel of six loci. Loci QUB3232 and QUB11b were the most discriminant, whereas ETR-D and QUB11a had the lower diversity index. The value of allelic diversity can significantly vary among countries; thus, it is important to standardize a panel of loci for future inter-laboratory comparisons. Although VNTR typing proved to be useful for an efficient discrimination among MTBC isolates, especially in combination with spoligotyping, further studies are needed in order to assess the genetic diversity of the MTBC in Tunisia. PMID- 24158361 TI - Iron catalysed nitrosation of olefins to oximes. AB - Fe(BF4)2.6H2O/2,6-pyridinedicarboxylic acid catalysed nitrosation of a wide variety of substituted styrenes has been developed in the presence of t BuONO/NaBH4 under H2 pressure (10 bar) in MeOH-H2O (5 : 1) to afford corresponding oximes in good to excellent yields. PMID- 24158363 TI - Metabolic surgery for type 2 diabetes: appraisal of clinical evidence and review of randomized controlled clinical trials comparing surgery with medical therapy. AB - Bariatric surgical procedures were originally developed to treat morbid obesity where their benefits certainly outweigh their potential side effects. Although they are very beneficial in improving metabolic control in type 2 diabetes, there are many medical treatments that are also effective. The role of bariatric surgery as primary therapy for type 2 diabetes depends on whether the benefit exceeds the surgical and nutritional complications, which are significant. The ultimate role for bariatric surgery in treating type 2 diabetes can only be determined by large, long-term randomized clinical trials which compare clinical outcomes of bariatric surgery with those of current intensive medical treatment. The four reported small, mostly 1-year trials have shown superior glycemic control by surgery as compared with medical treatment, but at the expense of significant surgical complications and unknown nutritional liability. They show that future trials will have to be much larger and last for at least 5-10 years. PMID- 24158364 TI - MEAT SCIENCE AND MUSCLE BIOLOGY SYMPOSIUM--implant and beta agonist impacts on beef palatability. AB - The use of anabolic implants has a long-standing place in the cattle feeding industry, due to their positive impact on growth performance and subsequent profitability. However, implants can have adverse effects on carcass quality, shear force, and eating quality depending on the dose and frequency, or what some refer to as the aggressiveness of the implant regimen administered. Within the past decade, a new class of growth promotants, known as beta-adrenergic agonists (betaAA), has emerged in the beef feeding industry in the United States. Currently, 2 have gained U.S. Food and Drug Administration approval for use in beef finishing diets to improve performance and carcass yields. Much like anabolic implants, these repartitioning agents can have negative effects on Warner-Bratzler shear force (WBSF), but the differences do not necessarily translate directly to consumer responses for palatability and acceptance in some instances, especially when tenderness is managed through proper postmortem aging. As researchers continued to investigate the mechanisms responsible for the impact of betaAA, inevitably this led to consideration of the interaction between betaAA and anabolic implants. Early work combining zilpaterol hydrochloride (ZH) with anabolic implants improved performance, carcass yield, and meat yield with additive negative effects on WBSF. Similar results were produced when pairing ZH with anabolic steroids equipped with various release patterns. As with any tool, the key to success is proper management. Certain cattle populations may be better suited to receive growth promotants such as implants and betaAA, and postmortem management of subprimal cuts becomes vital when producers take more aggressive approaches to improve performance and yield. The objective of this review is to overview research findings related to the impact of growth promotant technologies on beef palatability, focusing specifically on the role of implants and betaAA on carcass quality, beef tenderness, and consumer responses for meat palatability. PMID- 24158365 TI - Variance components of aggressive behavior in genetically highly connected Pietrain populations kept under two different housing conditions. AB - Mixing of unfamiliar pigs is a standard management procedure in commercial pig production and is often associated with a period of intense and physically damaging aggression. Aggression is considered a problem for animal welfare and production. The objective of the present paper was to investigate the genetic background of aggressive behavior traits at mixing of unfamiliar gilts under 2 different housing conditions. Therefore, a total of 543 purebred Pietrain gilts, from 2 nucleus farms (farm A: n = 302; farm B: n = 241) of 1 breeding company, were tested at an average age of 214 d (SD 12.2 d) for aggressive behavior by 1 observer. Observations included the frequencies of aggressive attack and reciprocal fighting during mixing with unfamiliar gilts. On farm A 41% of the gilts were purebred Pietrains, whereas 59% were purebred Landrace or Duroc gilts. On the farm B 42% of the gilts were purebred Pietrains, and 58% purebred Large White gilts. The average size of the newly mixed groups of gilts was 28 animals on farm A and 18 animals on farm B. The Pietrain gilts from the 2 herds were genetically closely linked. They were the offspring of 96 sires, with 64% of these sires having tested progeny in both farms. There were clear differences in the housing of the animals between the 2 farms. The test pen on farm A had a solid concrete floor littered with wooden shavings and was equipped with a dry feeder. On farm B there was a partly slatted floor, and the gilts were fed by an electronic sow feeder. Mean space allowance was 2.6 m(2)/gilt on farm A and 3.9 m(2)/gilt on farm B. Although large interindividual differences existed, gilts from farm B performed numerically more aggressive attack (mean 1.12, SD 1.42 vs. mean 0.71, SD 1.20) and reciprocal fighting (mean 0.78, SD 0.98 vs. mean 0.44, SD 0.82) when compared with gilts from farm A. The heritabilities and additive genetic variances for behavioral traits were estimated with a linear animal model and were on a low level in farm A (h(2) = 0.11, SE = 0.07, and sigma(2)a = 0.12 for aggressive attack and h(2) = 0.04, SE = 0.07, and sigma(2)a = 0.02 for reciprocal fighting) and on a moderate level in farm B (h(2) = 0.29, SE = 0.13, and sigma(2)a = 0.44 for aggressive attack and h(2) = 0.33, SE = 0.12, and sigma(2)a = 0.27 for reciprocal fighting). For both aggressive attack and reciprocal fighting, genetic correlation of the same trait between farm A and farm B was 1.0. Therefore, aggressive behavior does not seem to be influenced by genotype * environment interactions. Under these circumstances aggressions in group housing can be reduced by genetic selection against aggressive behavior. Therewith, the welfare and health of sows will ultimately increase. PMID- 24158362 TI - Endothelial microRNAs and atherosclerosis. AB - The vascular endothelium, a thin layer of endothelial cells (ECs) that line the inner surface of blood vessels, is a critical interface between blood and all tissues. EC activation, dysfunction, and vascular inflammation occur when the endothelium is exposed to various insults such as proinflammatory cytokines, oxidative stress, hypertension, hyperglycemia, aging, and shear stress. These insults lead to the pathogenesis of a range of disease states, including atherosclerosis. Several signaling pathways, especially nuclear factor kappaB mediated signaling, play crucial roles in these pathophysiological processes. Recently, microRNAs (miRNAs) have emerged as important regulators of EC function by fine-tuning gene expression. In this review, we discuss how miRNAs regulate EC function and vascular inflammation in response to a variety of pathophysiologic stimuli. An understanding of the role of miRNAs in EC activation and dysfunction may provide novel targets and therapeutic opportunities for controlling atherosclerosis and other chronic inflammatory disease states. PMID- 24158366 TI - Effect of intravenous or oral sodium chlorate administration on the fecal shedding of Escherichia coli in sheep. AB - The effect of gavage or intravenous (i.v.) administration of sodium chlorate salts on the fecal shedding of generic Escherichia coli in wether lambs was studied. To this end, 9 lambs (27 +/- 2.5 kg) were administered 150 mg NaClO3/kg BW by gavage or i.v. infusion in a crossover design with saline-dosed controls. The crossover design allowed each animal to receive each treatment during 1 of 3 trial periods, resulting in 9 observations for each treatment. Immediately before and subsequent to dosing, jugular blood and rectal fecal samples were collected at 4, 8, 16, 24, and 36 h. Endpoints measured were fecal generic E. coli concentrations, blood packed cell volume (PCV), blood methemoglobin concentration, and serum and fecal sodium chlorate concentrations. Sodium chlorate had no effects (P > 0.05) on blood PVC or methemoglobin. Fecal generic E. coli concentrations were decreased (P < 0.05) approximately 2 log units (99%) relative to controls 16 and 24 h after sodium chlorate infusion and 24 h after sodium chlorate gavage. Within and across time and treatment, fecal chlorate concentrations were highly variable for both gavage and i.v. lambs. Average fecal sodium chlorate concentrations never exceeded 100 ug/g and were typically less than 60 ug/g from 4 to 24 h after dosing. Times of maximal average fecal sodium chlorate concentration did not correspond with times of lowered average generic E. coli concentrations. Within route of administration, serum sodium chlorate concentrations were greatest (P < 0.01) 4 h after dosing; at the same time point, serum chlorate was greater (P< 0.01) in i.v.-dosed lambs than gavaged lambs but not at 16 or 24 h (P > 0.05). At 8 h, serum chlorate concentrations of gavaged lambs were greater (P < 0.05) than in i.v.-dosed lambs. Serum chlorate data are consistent with earlier studies indicating very rapid transfer of orally dosed chlorate to systemic circulation, and fecal chlorate data are consistent with earlier data showing the excretion of low to marginal concentrations of sodium chlorate in orally dosed animals. Efficacy of sodium chlorate at reducing fecal E. coli concentrations after i.v. infusion suggests that low concentrations of chlorate in gastrointestinal contents, delivered by biliary excretion, intestinal cell sloughing, or simple diffusion, are effective at reducing fecal E. coli levels. Alternatively, chlorate could be eliciting systemic effects that influence fecal E. coli populations. PMID- 24158367 TI - Technical note: A method for quantification of saliva secretion and salivary flux of metabolites in dairy cows. AB - Salivary flow and net jugular flux of metabolites were studied during resting and rumination in 3 lactating dairy cows (BW 548 +/- 17.2 kg, days in milk 113 +/- 4 d). The method was based on the concentration difference between arterial and jugular blood, and jugular blood flow measured by downstream dilution of p aminohippuric acid (pAH). Cows were surgically prepared with a permanent arterial catheter in A. intercostales dorsales before the trial. On sampling days, cows were prepared with left and right side jugular, and ear vein catheters for blood sampling and infusion of pAH, respectively. Blood was sampled simultaneously from the 2 jugular veins and artery during periods of rest and rumination. Secretion of saliva was set equal to the net water extraction calculated from the increased hemoglobin concentration in jugular blood compared with arterial blood. Arterial and jugular blood flow summed for both sides of the head doubled (P < 0.001) during rumination (437 +/- 19, 424 +/- 18 L/h, respectively) compared with resting (210 +/- 19, 202 +/- 18 L/h, respectively), consequently doubling the saliva secretion (P < 0.001, resting = 7.6 +/- 0.8 L/h, rumination = 13.8 +/- 0.8 L/h). The extraction of inorganic phosphate (Pi) from arterial blood during resting periods was greater compared with rumination (P = 0.004; resting = 21.7% +/- 0.9%; rumination = 15.6% +/- 0.9%), resulting in a greater Pi concentration in saliva secreted during resting. The concentrations of Pi in saliva were 4.5 +/ 0.3 and 3.7 +/- 0.3 times the arterial concentration during resting and rumination (P = 0.09), respectively. The urea concentration in saliva was 0.63 +/ 0.04 times the arterial level, showing that urea is less efficiently transferred from blood than water, resulting in a greater numerical urea concentration in jugular compared with arterial blood. The water extraction method presented in the present paper offers an alternative way of estimating saliva secretion without the chewing activity constraints associated with other methods, for example, allowing for determination of saliva flow during rumination. PMID- 24158368 TI - Duration of time that beef cattle are fed a high-grain diet affects the recovery from a bout of ruminal acidosis: short-chain fatty acid and lactate absorption, saliva production, and blood metabolites. AB - This study was conducted to determine if the duration of time that beef cattle are fed a high-grain diet affects short-chain fatty acid (SCFA) absorption, saliva production, and blood metabolites before, during, and following an induced bout of ruminal acidosis. Sixteen Angus heifers were assigned to 1 of 4 blocks and within block to 1 of 2 treatments designated as long adapted (LA) or short adapted (SA). Long adapted and SA heifers were fed a backgrounding diet [forage:concentrate (F:C) = 60:40] for 33 and 7 d, respectively, and then transitioned over 20 d to a high-grain diet (F:C = 9:91) with the timing of dietary transition staggered such that the LA and SA heifers were fed the high grain diet for 34 and 8 d, respectively, before inducing ruminal acidosis. Ruminal acidosis was induced by restricting feed to 50% of DMI:BW for 24 h followed by an intraruminal infusion of ground barley at 10% DMI:BW. Heifers were then given their regular diet allocation 1 h after the intraruminal infusion. Data were collected during an 8 d baseline period (BASE), on the day of the acidosis challenge (CHAL), and during 2 consecutive 8 d recovery periods (REC1 and REC2). When pooled across periods, the fractional rates of propionate (42 vs. 34%/h; P = 0.045) and butyrate (45 vs. 36%/h; P = 0.019) absorption, measured using the isolated and washed reticulorumen technique, were greater for LA than SA heifers. Moreover, overall, LA heifers tended to have greater absolute rates of butyrate absorption (94 vs. 79 mmol/h; P = 0.087) and fractional rates of total SCFA absorption (37 vs. 32%/h; P = 0.100). Treatment * period interactions for lactate absorption (P = 0.024) and serum D-lactate concentration (P = 0.003) were detected with LA heifers having greater D-lactate concentrations during CHAL and greater fractional rates of lactate absorption during REC1 than SA. The absolute and fractional absorption of acetate, propionate, and butyrate increased between REC1 and REC2, with intermediate values for BASE (P <= 0.05). Although fractional rates of SCFA absorption were low during REC1, saliva production (P = 0.018) increased between BASE and REC1, with intermediate values for REC2. These results suggest that the duration of time that animals are fed a high-grain diet may increase propionate, butyrate, and lactate absorption, and that cattle may decrease SCFA absorption and increase saliva production shortly after an acute bout of ruminal acidosis. PMID- 24158369 TI - The duration of time that beef cattle are fed a high-grain diet affects the recovery from a bout of ruminal acidosis: dry matter intake and ruminal fermentation. AB - This study was conducted to determine if the duration of time cattle are fed a high-grain diet affects their susceptibility to and recovery from ruminal acidosis. Sixteen Angus heifers (BW +/- SEM, 261 +/- 6.1 kg) were assigned to 1 of 4 blocks and fed a backgrounding diet consisting of 60% barley silage, 30% barley grain, and 10% supplement (DM basis). Within block, cattle were randomly assigned to 1 of 2 treatments differing in the number of days they were fed the high-grain diet before an acidosis challenge: 34 d for long adapted (LA) and 8 d for short adapted (SA). All heifers were exposed to the same 20 d dietary transition to a high-grain diet containing 9% barley silage, 81% barley grain, and 10% supplement (DM basis). Ruminal acidosis was induced by restricting feed to 50% of DMI:BW for 24 h followed by an intraruminal infusion of ground barley at 10% DMI:BW. Heifers were then given their regular diet allocation 1 h after the intraruminal infusion. Data were collected during an 8-d baseline period (BASE), on the day of the acidosis challenge (CHAL), and during 2 consecutive 8-d recovery periods (REC1 and REC2). Acidosis induction increased daily duration (531 to 1,020 min/d; P < 0.001) and area (176 to 595 (min * pH)/d; P < 0.001) that ruminal pH was <5.5 relative to BASE. Relative to BASE, inducing acidosis also increased the daily mean (0.3 to 11.4 mM; P = 0.013) and maximum (1.3 to 29.3 mM; P = 0.008) ruminal fluid lactate concentrations. There was no effect of dietary treatment on ruminal pH, lactate, or short-chain fatty acid (SCFA) concentrations (P > 0.050). However, during BASE and CHAL, SA heifers experienced greater linear (P = 0.031), quadratic (P = 0.016), and cubic (P = 0.008) coefficients for the duration of time that pH was <5.5. In addition, a treatment * day interaction for the duration that pH was <5.5 during REC1 suggested that LA cattle tended to recover from the challenge more rapidly than SA cattle (P = 0.085). Regression analysis confirmed that the LA heifers experienced a quicker linear (P = 0.019) recovery from induced acidosis over time. These results indicate adaptation of the ruminal epithelium continues with advancing time as evidenced by more stable ruminal pH both before and after an induced bout of acute ruminal acidosis but does not affect susceptibility of cattle to ruminal acidosis. PMID- 24158370 TI - High mobilization of arsenic, metals and rare earth elements in seepage waters driven by respiration of old allochthonous organic carbon. AB - Metal and metalloid mobilization processes within seepage water are of major concern in a range of water reservoir systems. The mobilization process of arsenic and heavy metals within a dam and sediments of a drinking water reservoir was investigated. Principle component analysis (PCA) on time series data of seepage water showed a clear positive correlation of arsenic with iron and DOC (dissolved organic carbon), and a negative correlation with nitrate due to respiratory processes. A relationship of reductive metal and metalloid mobilization with respiration of old carbon was shown. The system is influenced by sediment layers as well as a recent DOC input from degraded ombrotrophic peatbogs in the catchment area. The isotopic composition ((12)C, (13)C and (14)C) of DOC is altered along the path from basin to seepage water, but no significant changes in structural parameters (LC-OCD-OND, FT-IR) could be seen. DIC (dissolved inorganic carbon) in seepage water partly originates from respiratory processes, and a higher relationship of it with sediment carbon than with the DOC inventory of infiltrating water was found. This study revealed the interaction of respiratory processes with metal and metalloid mobilization in sediment water flows. In contrast to the presumption that emerging DOC via respiratory processes mainly controls arsenic and metal mobilization it could be shown that the presence of aged carbon compounds is essential. The findings emphasize the importance of aged organic carbon for DOC, DIC, arsenic and metal turnover. PMID- 24158371 TI - Comparing accommodative function between the dominant and non-dominant eye. AB - BACKGROUND: To compare the accommodative amplitude (AA), facility (AF), and lag between dominant and non-dominant eyes. METHODS: Seventy students [mean (SD) age: 21.2 (1.7) years, range 18-25] from Zahedan University of Medical Sciences were selected. Retinoscopy and subjective refraction was used to determine the refractive error. The hole-in-the card method was used to determine eye dominance. The accommodative amplitude (AA) was measured in the dominant and non dominant eye using the push-up method, and accommodative facility (AF) using +/ 2.00 dioptre flipper lenses at 40 cm. Accommodative lag was determined using monocular estimate method (MEM) retinoscopy at 40 cm. RESULTS: The right eye was dominant in 53 subjects (75.7 %). There was no significant difference in refractive error (sphere, cylinder, and spherical equivalent) between dominant and non-dominant eyes. The mean (SD) for the AA, AF, and lag in dominant eyes was 12.48 (2.56) dioptres, 12.45 (4.83) cycles per minute, and 0.80 (0.27) dioptres respectively. The mean (SD) for the AA, AF, and lag in non-dominant eyes was 12.16 (2.37) dioptres, 12.20 (4.88) cycles per minute, and 0.83 (0.28) dioptres respectively. The mean (SD) difference in AA, AF, and lag between dominant and non dominant eyes was 0.32 (0.75) dioptres (P = 0.001), 0.25 (1.05) cycles per minute (P = 0.04), and -0.02 (0.11) dioptres (P = 0.10) respectively. The AA and AF was statistically better (P < 0.05) in the dominant eye group than in the non dominant eye group. These data provided little evidence of any difference in the accommodative lag between dominant and non-dominant eyes (P > 0.05). CONCLUSION: The right eye was dominant in 76 % of subjects. Superior AA and AF was found in the dominant eye as determined by hole-in-the card method in young healthy adults, although these differences are perhaps not of clinical significance (<0.50 dioptres and <2 cycles per minute). PMID- 24158372 TI - En face enhanced depth imaging optical coherence tomography features in adult onset foveomacular vitelliform dystrophy. AB - BACKGROUND: Our purpose was to describe the different morphological features in adult onset foveomacular vitelliform dystrophy (AOFVD), using en face enhanced depth imaging (EDI) spectral-domain optical coherence tomography (SD-OCT). METHODS: Thirty eyes of 22 consecutive patients presenting with diagnosis of AOFVD were enrolled. Diagnosis of AOFVD was concluded based on fundus examination, autofluorescence imaging, fluorescein angiography and SD-OCT. En face OCT imaging was obtained with the Spectralis EDI SD-OCT; 97 inverted sections (nine averaged B-scans per image) were acquired. RESULTS: On en face OCT, vitelliform lesions appeared as regular concentric rings of different reflectivity. From the periphery to center of the ring, we observed: (1) the hypereflective ring representing the inner segment/ outer segment (IS/OS) junction, which was continuous in 23 out of 30 eyes, and (2) a well-detectable hyporeflective ring between the IS/OS junction and vitelliform material in 20 out of 30 eyes; the innermost composant of the lesion was hypereflective, and it corresponded to vitelliform material. In eight out of 30 eyes, a hyporeflective "croissant"-shaped lesion with inferior concavity in the upper part of the hyperreflective material was present. Hypereflective retinal pigment epithelium (RPE) elevations or bumps were detected in 25 out of 30 eyes. These areas of focal RPE thickening or bumps appeared to be intensely hypereflective on infrared reflectance imaging. CONCLUSION: En face imaging of the retina helps visualizing the distribution of vitelliform material in AOFVD. The sedimentation of vitelliform lesions is characterized by a upper "croissant"-shaped hypoflectivity. The bumps/thickening of RPE appeared as hypereflective lesions on IR imaging. PMID- 24158373 TI - Macular buckling for previously untreated and recurrent retinal detachment due to high myopic macular hole: a 12-month comparative study. AB - PURPOSE: To evaluate postoperative outcomes after macular buckling together with pars plana vitrectomy (PPV) in previously untreated and recurrent retinal detachment secondary to macular hole (MH) in highly myopic eyes. METHODS: In a retrospective cohort study, 42 eyes of 42 high myopic patients with retinal detachment due to MH were evaluated. Patients were divided into previously untreated retinal detachment (group 1, 21 eyes) and recurrent retinal detachment (group 2, 21 eyes). Macular buckling and PPV were performed in all patients. Main outcomes included retinal reattachment rate, macular hole closure rate and best corrected visual acuity (BCVA) at 3, 6, and 12 months. Optical coherence tomography (OCT) was performed both pre- and postoperatively in all patients to assess the anatomical status of the macula. RESULTS: Primary retinal reattachment rate in group 1 was 95% (20/21), which increased to 100% (21/21) after a second surgery. MH closure was achieved in 81% of patients (17/21) after one surgery. The mean preoperative BCVA (logarithm of the minimum angle of resolution, LogMAR) improved from 1.32 (95% CI 1.19;1.44) to 0.76 (95% CI 0.56;0.96) 12 months postoperatively. In all except one case, gas tamponade was preferred. Primary reattachment and MH closure rate in group 2 were 90.5% (19/21) and 57% (12/21) respectively, and did not improve after a second surgery. Preoperative BCVA (LogMAR) was 1.39 (95% CI 1.29;1.49) and improved to 0.95 (95% CI 0.75;1.15) at 12 months. Silicone oil tamponade was used in seven of 21 patients, and finally was removed in five of them. CONCLUSIONS: Macular buckling combined with PPV should be considered a preferred surgical approach both in primary and recurrent retinal detachment secondary to MH in high myopic eyes. Nevertheless, visual outcomes seem to be better when macular buckling is chosen as first-line treatment. PMID- 24158374 TI - Trabectome surgery for primary and secondary open angle glaucomas. AB - PURPOSE: In most forms of open angle glaucoma, the trabecular meshwork is the main barrier for aqueous humor outflow, causing elevated intraocular pressure (IOP). The Trabectome is a minimal invasive device for the surgical treatment of open angle glaucoma, particularly eliminating the juxtacanalicular meshwork. This study was conducted to compare the effectiveness and complication profile among different glaucoma subgroups. METHODS: Single center prospective observational study. There were 557 consecutive eyes of 487 patients included in this study. Trabectome surgery was performed either alone or in combination with cataract surgery. Intraoperative and postoperative complications were documented systematically. Main outcome measures were IOP reduction over time and the preoperative and postoperative number of IOP-lowering medications. Due to subgroup sizes, only data from eyes with primary open angle glaucoma and pseudoexfoliation glaucoma were processed for statistical analysis. RESULTS: For the 261 eyes classified as primary open angle glaucoma, preoperative IOP was 24 +/- 5.5 mmHg (mean +/- SD) under 2.1 +/- 1.3 IOP-lowering medications. After a mean follow-up of 204 +/- 238 days, IOP was reduced to 18 +/- 6.1 mmHg, and medication was reduced to 1.2 +/- 1.1. For the 173 eyes classified as pseudoexfoliation glaucoma, after a mean follow-up of 200 +/- 278 days, IOP was reduced from 25 +/- 5.9 mmHg to 18 +/- 8.2 mmHg, and medication was reduced from 2.0 +/- 1.2 to 1.1 +/- 1.1. A Cox proportional hazards model hinted forward superiority of the combined surgery cases (Trabectome + Phaco + intraocular lens) in comparison to Trabectome surgery only in phakic or pseudophakic eyes. No serious complications were observed. CONCLUSIONS: Minimal invasive glaucoma surgery with the Trabectome seems to be safe and effective. The subgroup analysis of different kinds of open angle glaucomas presented in this study may help in first-line patient selection. The lack of ocular surface alterations makes it a valuable addition to glaucoma surgery. PMID- 24158376 TI - Classical macroautophagy in Lobivia rauschii (Cactaceae) and possible plastidial autophagy in Tillandsia albida (Bromeliaceae) tapetum cells. AB - The tapetum in anthers is a tissue that undergoes programmed cell death (PCD) during the production of pollen. We observed two types of autophagy prior to cell death. In Lobivia rauschii (Cactaceae), tapetum cells showed plant-type autophagosomes-autolysosomes, which have been found previously exclusively in root meristem cells. The autophagic structures were formed by a network of tubules which apparently merged laterally, thereby sequestering a portion of the cytoplasm. The organelles observed in the sequestered material included multilamellar bodies, which have not been reported earlier in these organelles. By contrast, Tillandsia albida (Bromeliaceae) tapetum cells contained no such organelles but showed plastids that might possibly carry out autophagy, as they contained portions of the cytoplasm similar to the phenomenon reported earlier in Phaseolus and Dendrobium. However, the ultrastructure of the T. albida plastids was different from that in the previous reports. It is concluded that in L. rauschii classical plant macroautophagy was involved in degradation of the cytoplasm, while in T. albida such classical macroautophagy was not observed. Instead, the data in T. albida suggested the hypothesis that plastids are able to carry out degradation of the cytoplasm. PMID- 24158375 TI - Chloroplast molecular farming: efficient production of a thermostable xylanase by Nicotiana tabacum plants and long-term conservation of the recombinant enzyme. AB - The high cost of recombinant enzymes for the production of biofuel from ligno cellulosic biomass is a crucial factor affecting the economic sustainability of the process. The use of plants as biofactories for the production of the suitable recombinant enzymes might be an alternative to microbial fermentation. In the case of enzyme accumulation in chloroplasts, it is fundamental to focus on the issue of full photosynthetic efficiency of transplastomic plants in the field where they might be exposed to abiotic stress such as high light intensity and high temperature. Xylanases (EC 3.2.1.8), a group of enzymes that hydrolyse linear polysaccharides of beta-1,4-xylan into xylose, find an application in the biofuel industry favouring biomass saccharification along with other cell-wall degrading enzymes. In the present study, we analysed how a high level of accumulation of a thermostable xylanase in tobacco chloroplasts does not impact on photosynthetic performance of transplastomic plants grown outdoors. The recombinant enzyme was found to be stable during plant development, ex planta and after long-term storage. PMID- 24158377 TI - In vitro evaluation of mitochondrial-chloroplast subcellular localization of heme oxygenase1 (HO1) in Glycine max. AB - Heme oxygenase1 (HO1) catalyzes the degradation of heme in to biliverdin, carbon monoxide, and ferrous ions. Its role in higher plants has been found as an antioxidant and precursor of phytochrome synthesis. The present study focuses on subcellular localization of HO1 in leaves of soybean has been investigated. Most activity appeared to be located within chloroplast due to its role in phytochrome synthesis but mitochondria also share its localization. Mitochondrial location of HO1 might be on its inner membranous space due to its role in the synthesis of electron donor species which facilitates HO1 catalyzed reaction. Study reports the co-localization of HO1 in both chloroplast and mitochondria. PMID- 24158378 TI - A molecular logical switching beacon controlled by thiolated DNA signals. AB - A logical switching MB is established, with an "ON/OFF" switching function. In this study, thiolated DNA can participate as a switching controller to regulate the fluorescent increments of other DNA input signals. Assisted by gold nanoparticles and DNA branch migration, one and two-switch systems have been achieved. PMID- 24158379 TI - Laboratory and clinical acute effects of active and passive indoor group water pipe (narghile) smoking. AB - BACKGROUND: Indoor group water-pipe tobacco smoking, commonly referred to as water-pipe smoking (WPS), especially in coffee shops, has gained worldwide popularity. We performed a comprehensive laboratory and clinical evaluation of the acute effects of active and passive indoor group WPS. METHODS: This comparative study evaluated pre- and post-30-min active and passive indoor group WPS. The outcome parameters were carboxyhemoglobin (COHb), nicotine, and cotinine levels; CBC count; and cardiorespiratory parameters. Exhaled breath condensate (EBC) cytokines and endothelial function (using the EndoPat device [Itamar Medical Ltd]) were measured only in active smokers. Statistical methods used were Student t test, Wilcoxon signed rank test, Fisher exact test, analysis of variance, and Newman-Keuls post hoc test where relevant. RESULTS: Sixty-two volunteers aged 24.9+/-6.2 years were included; 47 were active smokers, and 15 were passive smokers. COHb level increased postactive WPS (active smokers, 2.0%+/ 2.9% vs 17.6%+/-8.8%; P<.00001); six subjects (12.7%) had a >25% increase, and two subjects (4.2%) had a >40% increase. Plasma nicotine level increased postactive WPS (active smokers, 1.2+/-4.3 ng/mL vs 18.8+/-13.9 ng/mL; P<.0001); plasma cotinine and urinary nicotine and cotinine levels also increased significantly. EBC IL-4, IL-5, IL-10, IL-17, and gamma-interferon decreased significantly with postactive smoking; endothelial function did not change. WPS was associated with adverse cardiorespiratory changes. In passive smokers, COHb level increased (0.8%+/-0.25% vs 1.2%+/-0.8%, respectively, P=.003) as did respiratory rate. CONCLUSIONS: One session of active indoor group WPS resulted in significant increases in COHb and serum nicotine levels (eightfold and 18-fold, respectively) and was associated with adverse cardiorespiratory health effects. The minor effects found in passive smokers suggest that they too may be affected adversely by exposure to WPS. The results call for action to limit the continuing global spread of WPS in coffee shops. TRIAL REGISTRY: ClinicalTrials.gov; No.: NCT1237548; URL: www.clinicaltrials.gov. PMID- 24158380 TI - Qualitative assessment of HIV prevention challenges and opportunities among Latino immigrant men in a new receiving city. AB - Changing demographics in new receiving communities contributes to a lag time between the arrival of new immigrants and the development of appropriate services. This scarcity of services can exacerbate existing disparities in health conditions such as HIV, which disproportionately affects Latinos. Focus groups were conducted in Baltimore with 59 Latino men who had immigrated to the U.S. within the past 10 years to explore the challenges and opportunities to accessing HIV testing and preventative services. Transcripts were analyzed through a modified thematic constant comparison approach. Four thematic categories emerged: information about HIV, HIV fear and stigma, barriers to accessing healthcare, and opportunities for intervention approaches. Information and communication technology provides an opportunity to improve access to HIV testing and prevention services. Individualized interventions, though, must be disseminated in collaboration with community-, structural-, and policy-level interventions that address HIV risk, HIV/AIDS stigma, and healthcare access among Latino immigrants. PMID- 24158381 TI - Emergency communications within the limited English proficient Chinese community. AB - Limited English speaking communities face communication challenges during emergencies. Our objective was to investigate Chinese limited English proficiency individuals' perceptions of and inclination to interact with emergency communication systems. A telephone survey was conducted in Mandarin or Cantonese with 250 ethnic Chinese individuals who spoke little or no English. Respondents who spoke no English were less likely to name 9-1-1 as their first source of help for a medical emergency than those who spoke some English (p < 0.01). Those reporting higher levels of confidence in handling the situation were more likely to name 9-1-1 as their first source of help, as were those who listed 9-1-1 as their most trusted source of help (p < 0.01). For this group, the results indicate that calling 9-1-1 may require a sense of self-efficacy. Not calling 9-1 1 in a medical emergency can have serious health consequences, thus interventions are needed to increase confidence in accessing 9-1-1. PMID- 24158382 TI - Atmospheric deposition of current use pesticides in the Arctic: snow core records from the Devon Island Ice Cap, Nunavut, Canada. AB - Current use pesticides (CUPs) have been detected in the Arctic, even though there are no direct sources and their long range atmospheric transport potential is generally lower than that of legacy pesticides. Data on the deposition of CUPs in the Arctic are required to assess the impact of their global usage and emission. In this study, selected CUPs were measured in the layers of a snow pit sampled on the Devon Ice Cap, Nunavut, Canada. The oldest sampled layers correspond to deposition from the early 1990s. Dacthal and endosulfan sulfate were most frequently detected, with peak deposition fluxes of 1.0 and 0.4 pg cm(-2) per year. While endosulfan sulfate was more abundant than its parent compounds in most years, endosulfan (sum of alpha and beta isomers) was predominant in 2003 and 2006, which together with air mass backward trajectories suggests a possible origin from ongoing use in Eurasia. The interannual variation in CUP deposition fluxes could not be explained with annual variations in the extent of air mass origin over agricultural lands, suggesting that other factors, such as the interannual variation in pesticide use, play a role in affecting the long range transport of CUPs to the Arctic. The very high variability in the concentrations of CUPs in the horizontal layers of Arctic ice caps is most plausibly explained by the highly episodic nature of long range atmospheric transport and deposition. While this strong influence of rare events limits the suitability of ice caps as reliable records of historical trends in Arctic contaminant deposition with annual resolution, the presence of concentration peaks in the ice record is proof of the possibility of such transport and deposition. PMID- 24158383 TI - Autonomic deficit not the cause of death in West Nile virus neurological disease. AB - INTRODUCTION: Some West Nile virus (WNV)-infected patients have been reported to manifest disease signs consistent with autonomic dysfunction. Moreover, WNV infection in hamsters causes reduced electromyography amplitudes of the gastrointestinal tract and diaphragm, and they have reduced heart rate variability (HRV), a read-out for the parasympathetic autonomic function. METHODS: HRV was measured in both hamsters and mice using radiotelemetry to identify autonomic deficits. To identify areas of WNV infection within the medulla oblongata mapping to the dorsal motor nucleus of vagus (DMNV) and the nucleus ambiguus (NA), fluorogold dye was injected into the cervical trunk of the vagus nerve of hamsters. As a measurement of the loss of parasympathetic function, tachycardia was monitored contiguously over the time course of the disease. RESULTS: Decrease of HRV did not occur in all animals that died, which is not consistent with autonomic function being the mechanism of death. Fluorogold-stained cells in the DMNV were not stained for WNV envelope protein. Fourteen percent of WNV-stained cells were co-localized with fluorogold-stained cells in the NA. These data, however, did not suggest a fatal loss of autonomic functions because tachycardia was not observed in WNV-infected hamsters. CONCLUSION: Parasympathetic autonomic function deficit was not a likely mechanism of death in WNV-infected rodents and possibly in human patients with fatal WN neurological disease. PMID- 24158385 TI - MiR-125b regulates cell proliferation and survival in neonatal megakaryocytes. PMID- 24158384 TI - Changes in renal function in congestive heart failure. AB - Both cardiovascular and renal diseases are common and frequently coexist in the same patient. Indeed, renal dysfunction has been shown to be a more powerful independent predictor of poor outcomes in heart failure (HF) than left ventricular ejection fraction or functional class. Furthermore, acute kidney injury is a frequent therapeutic concern in heart failure. Consequently, there has been much interest in developing new renoprotective treatments and novel biomarkers to monitor renal function. Additionally, given the crucial cardiorenal interaction and interdependence, the concept of a cardiorenal syndrome with five different subtypes has been advanced to better categorize patients and facilitate research. PMID- 24158386 TI - GEM-P chemotherapy is active in the treatment of relapsed Hodgkin lymphoma. AB - Hodgkin lymphoma (HL) is a relatively chemosensitive malignancy. However, for those who relapse, high-dose chemotherapy with autologous stem cell transplant is the treatment of choice which relies on adequate disease control with salvage chemotherapy. Regimens commonly used often require inpatient administration and can be difficult to deliver due to toxicity. Gemcitabine and cisplatin have activity in HL, non-overlapping toxicity with first-line chemotherapeutics, and may be delivered in an outpatient setting. In this retrospective single-centre analysis, patients with relapsed or refractory HL treated with gemcitabine 1,000 mg/m(2) day (D)1, D8 and D15; methylprednisolone 1,000 mg D1-5; and cisplatin 100 mg/m(2) D15, every 28 days (GEM-P) were included. Demographic, survival, response and toxicity data were recorded. Forty-one eligible patients were identified: median age 27. One hundred and twenty-two cycles of GEM-P were administered in total (median 3 cycles; range 1-6). Twenty of 41 (48 %) patients received GEM-P as second-line treatment and 11/41 (27 %) as third-line therapy. Overall response rate (ORR) to GEM-P in the entire cohort was 80 % (complete response (CR) 37 %, partial response 44 %) with 14/15 CR confirmed as a metabolic CR on PET and ORR of 85 % in the 20 second-line patients. The most common grade 3/4 toxicities were haematological: neutropenia 54 % and thrombocytopenia 51 %. Median follow-up from the start of GEM-P was 4.5 years. Following GEM-P, 5-year progression-free survival was 46 % (95 % confidence interval (CI), 30-62 %) and 5-year overall survival was 59 % (95 % CI, 43-74 %). Fourteen of 41 patients proceeded directly to autologous transplant. GEM-P is a salvage chemotherapy with relatively high response rates, leading to successful transplantation in appropriate patients, in the treatment of relapsed or refractory HL. PMID- 24158388 TI - [Bone substitution materials in therapy of cystic tumors of the immature skeleton]. AB - The primary goal in the treatment of cystic bone tumors in children is the restoration of bone integrity and normal function. It is assumed that filling of the cavity defect after removal of the tumor will facilitate bone healing. In order to reduce the complications observed with autografts and allografts use bone graft substitutes were developed. The current literature review shows that the application of substances with potential immunogenic, toxic or cancerogenic properties should be avoided. Among the purely synthetic mineral materials, tricalcium phosphate has the biochemical properties most compatible with new bone formation and calcium phosphate cements can be used to provide immediate stability in cases of existing or imminent fractures. However, there is currently insufficient evidence that the use of bone grafts or bone graft substitutes provides a real benefit to the patient, especially in comparison with no graft at all. Prospective randomized studies are necessary in order to delineate the indications for bone grafting or use of bone graft substitutes for the treatment of cystic bone tumors in children. PMID- 24158387 TI - Protein Z/protein Z-dependent protease inhibitor system in loco in human gastric cancer. AB - In gastric cancer, hemostatic system components contribute to cancer progression, as activation of factor X (FX) was observed. The protein Z (PZ)/protein Z dependent protease inhibitor (ZPI) complex inhibits factor Xa proteolytic activity. The purpose of this study was to determine the distribution of ZPI and PZ in relation to FX, and prothrombin fragment (F1 + 2), a standard marker for blood coagulation activation, in human gastric cancer tissue. ABC procedures and a double staining method employed polyclonal antibodies against PZ, FX, and F1 + 2 and a monoclonal antibody against ZPI. In situ hybridization (ISH) methods employed biotin-labeled 25-nucleotide single-stranded DNA probes directed to either PZ or ZPI mRNAs. FX and components of PZ/ZPI coagulation inhibitory system were observed in cancer cells. F1 + 2 was observed in gastric cancer cells as well. Double staining studies revealed FX/PZ, FX/ZPI, and PZ/ZPI co-localization on gastric cancer cells. ISH studies demonstrated the presence of PZ mRNA and ZPI mRNA in gastric cancer cells indicating induced synthesis of these proteins. The co-localization of PZ/ZPI and FX in gastric cancer cells indicates in loco that these proteins may play a role in anticoagulant events at the tumor tissue. PMID- 24158389 TI - [Osseous and soft tissue operations for treatment of joint malpositioning in infantile cerebral palsy]. AB - If untreated infantile cerebral palsy (ICP) leads to a progressive shortening of muscles and to progressive joint malpositioning. In addition a number of other disorders also result, in particular sensory disorders, intelligence deficits and epilepsy. In order to optimally treat as many as possible of the problems of multi-handicapped children with ICP it is of immanent importance that physiotherapists, occupational therapists, speech therapists, orthopedic technicians, pediatric orthopedists as well as neuropediatricians and social pediatricians work as a team. Surgical measures to correct joint malpositioning serve to improve the function and also to avoid or alleviate pain. Functional improvement measures are ideally undertaken during or shortly before elementary school age, thus enabling a further verticalization/straightening and mobilization. To improve symmetry and therefore the sitting posture, surgery is also indicated for profoundly disabled patients, sometimes making foot operations necessary. It is only in this way that maximum participation can be guaranteed and if necessary utilizing additional aids, such as Zimmer frames or E wheelchairs. PMID- 24158390 TI - Purification and partial characterization of NAD aminohydrolase from Aspergillus oryzae NRRL447. AB - Aspergillus oryzae aminohydrolase free acid phosphodiesterase catalyzes nicotinamide adenine dinucleotide to deamino-NAD and ammonia. The enzyme was purified to homogeneity by a combination of acetone precipitation, anion exchange chromatography and gel filtration chromatography. The enzyme was purified 230.5 fold. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis of the purified enzyme showed a single protein band of MW 94 kDa. The enzyme displayed maximum activity at pH 5 and 40 degrees C with NAD as substrate. The enzyme activity appeared to be stable up to 40 degrees C. The enzyme activity was enhanced slightly by addition of Na+ and K+, whereas inhibited strongly by addition of Ag+, Mn2+, Hg2+ and Cu2+ to the reaction mixtures. The enzyme hydrolyzes several substrates, suggesting a probable non-specific nature. The enzyme catalyzes the hydrolytic cleavage of amino group of NAD, adenosine, AMP, CMP, GMP, adenosine, cytidine and cytosine to the corresponding nucleotides, nucleosides or bases and ammonia. The substrate concentration-activity relationship is the hyperbolic type and the apparent Km and Kcat for the tested substrates were calculated. PMID- 24158391 TI - Herbicides induce change in metabolic and genetic diversity of bacterial community from a cold oligotrophic lake. AB - Pristine cold oligotrophic lakes show unique physical and chemical characteristics with permanent fluctuation in temperature and carbon source availability. Incorporation of organic toxic matters to these ecosystems could alter the bacterial community composition. Our goal was to assess the effects of simazine (Sz) and 2,4 dichlorophenoxyacetic acid (2,4-D) upon the metabolic and genetic diversity of the bacterial community in sediment samples from a pristine cold oligotrophic lake. Sediment samples were collected in winter and summer season, and microcosms were prepared using a ration 1:10 (sediments:water). The microcosms were supplemented with 0.1 mM 2,4-D or 0.5 mM Sz and incubated for 20 days at 10 degrees C. Metabolic diversity was evaluated by using the Biolog EcoplateTM system and genetic diversity by 16S rDNA amplification followed by denaturing gradient gel electrophoresis analysis. Total bacterial counts and live/dead ratio were determined by epifluorescence microscopy. The control microcosms showed no significant differences (P > 0.05) in both metabolic and genetic diversity between summer and winter samples. On the other hand, the addition of 2,4-D or Sz to microcosms induces statistical significant differences (P < 0.05) in metabolic and genetic diversity showing the prevalence of Actinobacteria group which are usually not detected in the sediments of these non contaminated lacustrine systems. The obtained results suggest that contaminations of cold pristine lakes with organic toxic compounds of anthropic origin alter their homeostasis by inhibiting specific susceptible bacterial groups. The concomitant increase of usually low representative bacterial groups modifies the bacterial composition commonly found in this pristine lake. PMID- 24158392 TI - Inflorescences in Eriocaulaceae: taxonomic relevance and practical implications. AB - BACKGROUND AND AIMS: Inflorescences are thought to be of enormous taxonomic relevance; however, at the same time they are regarded as being notoriously difficult. This is partly due to the conflicting needs of floristics and evolutionary botany, but partly also due to the complicated and confusing terminology introduced by W. Troll and his school. METHODS: The branching patterns of representatives of the genera Eriocaulon, Syngonanthus and Paepalanthus have been studied in the field and from preserved material by scanning electron microscopy. Branching patterns and formation sequences have been analysed and documented in longitudinal schemes and diagrams. Repetitive units of different levels are detected and related to the body plans of other species of the family. KEY RESULTS: The repetition of very few different branching patterns on different levels of complexity may lead to highly complex inflorescences. However, terms are needed only for patterns; levels may be numbered consecutively. While complex inflorescences are often described as additions or aggregations of units, there is some evidence that complex inflorescences are often the result of fractionation of inflorescence meristems. CONCLUSIONS: Precise descriptions of inflorescences useful for diagnostics and phylogenetics can be much simpler than they often are today. If complex inflorescences are the result of meristem fractionation, intermediate morphotypes cannot be expected. On the other hand, such intermediate morphotypes should occur if a complex inflorescence is formed following an aggregation pathway. Unless the repetitive patterns shown here are not correlated to complementary gene activities the inflorescences are not fully understood. PMID- 24158393 TI - Immunosuppressive and cytotoxic cells in invasive vs. non-invasive Bowen's disease. PMID- 24158394 TI - Expression of mutant CHMP2B, an ESCRT-III component involved in frontotemporal dementia, causes eye deformities due to Notch misregulation in Drosophila. AB - Endosomal sorting complexes required for transport (ESCRTs) mediate sorting of ubiquitinated membrane proteins into multivesicular bodies en route to lysosomes for degradation. A mutation in CHMP2B (CHMP2B(Intron5), an ESCRT-III component) that is associated with a hereditary form of frontotemporal dementia (FTD3) disrupts the endosomal-lysosomal pathway and causes accumulation of autophagosomes and multilamellar structures. We previously demonstrated that expression of CHMP2B(Intron5) in the Drosophila eye using GMR-Gal4 causes misregulation of the Toll receptor pathway. Here, we show that ectopic expression of CHMP2B(Intron5) using eyeless-Gal4 (ey>CHMP2B(Intron5)), a driver with different spatiotemporal expression attributes than GMR-Gal4 in the Drosophila eye, causes eye deformities when compared to expression of wild-type CHMP2B (CHMP2B(WT)) and the Drosophila homologue of CHMP2B (CG4618). In addition, ey>CHMP2B(Intron5) flies showed defects in photoreceptor cell patterning and phototactic behavior. Furthermore, ey>CHMP2B(Intron5) flies showed accumulation of Notch in enlarged endosomes and up-regulation of Notch activity. Partial loss of Notch activity in ey>CHMP2B(Intron5) flies significantly rescued eye deformities, photoreceptor patterning defect, and phototactic behavior defect, indicating that these defects are primarily due to Notch misregulation. These results demonstrate that CHMP2B(Intron5) preferentially affects different receptor signaling pathways in a cellular and developmental context-dependent manner. PMID- 24158395 TI - Sphingosine phosphate lyase regulates myogenic differentiation via S1P receptor mediated effects on myogenic microRNA expression. AB - S1P lyase (SPL) catalyzes the irreversible degradation of sphingosine-1-phosphate (S1P), a bioactive lipid whose signaling activities regulate muscle differentiation, homeostasis, and satellite cell (SC) activation. By regulating S1P levels, SPL also controls SC recruitment and muscle regeneration, representing a potential therapeutic target for muscular dystrophy. We found that SPL is induced during myoblast differentiation. To investigate SPL's role in myogenesis at the cellular level, we generated and characterized a murine myoblast SPL-knockdown (SPL-KD) cell line lacking SPL. SPL-KD cells accumulated intracellular and extracellular S1P and failed to form myotubes under conditions that normally stimulate myogenic differentiation. Under differentiation conditions, SPL-KD cells also demonstrated delayed induction of 3 myogenic microRNAs (miRNAs), miR-1, miR-206, and miR-486. SPL-KD cells successfully differentiated when treated with an S1P1 agonist, S1P2 antagonist, and combination treatments, which also increased myogenic miRNA levels. SPL-KD cells transfected with mimics for miR-1 or miR-206 also overcame the differentiation block. Thus, we show for the first time that the S1P/SPL/S1P-receptor axis regulates the expression of a number of miRNAs, thereby contributing to myogenic differentiation. PMID- 24158396 TI - S-nitrosylation of ascorbate peroxidase is part of programmed cell death signaling in tobacco Bright Yellow-2 cells. AB - Nitric oxide (NO) is a small redox molecule that acts as a signal in different physiological and stress-related processes in plants. Recent evidence suggests that the biological activity of NO is also mediated by S-nitrosylation, a well known redox-based posttranslational protein modification. Here, we show that during programmed cell death (PCD), induced by both heat shock (HS) or hydrogen peroxide (H2O2) in tobacco (Nicotiana tabacum) Bright Yellow-2 cells, an increase in S-nitrosylating agents occurred. NO increased in both experimentally induced PCDs, although with different intensities. In H2O2-treated cells, the increase in NO was lower than in cells exposed to HS. However, a simultaneous increase in S nitrosoglutathione (GSNO), another NO source for S-nitrosylation, occurred in H2O2-treated cells, while a decrease in this metabolite was evident after HS. Consistently, different levels of activity and expression of GSNO reductase, the enzyme responsible for GSNO removal, were found in cells subjected to the two different PCD-inducing stimuli: low in H2O2-treated cells and high in the heat shocked ones. Irrespective of the type of S-nitrosylating agent, S-nitrosylated proteins formed upon exposure to both of the PCD-inducing stimuli. Interestingly, cytosolic ascorbate peroxidase (cAPX), a key enzyme controlling H2O2 levels in plants, was found to be S-nitrosylated at the onset of both PCDs. In vivo and in vitro experiments showed that S-nitrosylation of cAPX was responsible for the rapid decrease in its activity. The possibility that S-nitrosylation induces cAPX ubiquitination and degradation and acts as part of the signaling pathway leading to PCD is discussed. PMID- 24158397 TI - Different functions of the common P/V/W and V-specific domains of rinderpest virus V protein in blocking IFN signalling. AB - The V proteins of paramyxoviruses are composed of two evolutionarily distinct domains, the N-terminal 75 % being common to the viral P, V and W proteins, and not highly conserved between viruses, whilst the remaining 25 % consists of a cysteine-rich V-specific domain, which is conserved across almost all paramyxoviruses. There is evidence supporting a number of different functions of the V proteins of morbilliviruses in blocking the signalling pathways of type I and II IFNs, but it is not clear which domains of V are responsible for which activities and whether all these activities are required for effective blockade of IFN signalling. We have shown here that the two domains of rinderpest virus V protein have distinct functions: the N-terminal domain acted to bind STAT1, whilst the C-terminal V-specific domain interacted with the IFN receptor associated kinases Jak1 and Tyk2. Effective blockade of IFN signalling required the intact V protein. PMID- 24158398 TI - Toxic effects of octylphenol on the expression of genes in liver identified by suppression subtractive hybridization of Rana chensinensis. AB - Octylphenol (OP) is the degradative product of alkylphenol ethoxylates that are widely used to produce rubber, pesticides, and paints. It is chemically stable substance and demonstrates estrogenic effects, toxicity and carcinogenic effects in the environment. The toxin accumulates rapidly in the liver where it exerts most of its damage, but the molecular mechanisms behind its toxicity remain unclear. Due to limited information concerning the effect of OP on liver, this study investigates how OP causes hepatotoxicity in liver. Here, suppression subtractive hybridization was used to identify the alterations in gene transcription of the frog (Rana chensinensis) after exposure to OP. After hybridization and cloning, the subtractive cDNA libraries were obtained. At random, 207 positive clones were selected and sequenced from the subtractive libraries, which gave a total of 75 gene fragment sequences. The screening identified numerous genes involved in apoptosis, signal transduction, cytoskeletal remodeling, innate immunity, material and energy metabolism, translation and transcription which were extensively discussed. Two sequenced genes were analyzed further using real time quantitative PCR. The two genes from the library were found to be transcriptionally up-regulated. These results confirmed the successful construction of the subtractive cDNA library that was enriched for the genes that were differentially transcribed in the amphibian liver challenged with OP, and for the first time present the basic data on toxicity effect of OP on liver. PMID- 24158399 TI - Interactive effects of elevated ozone and UV-B radiation on soil nematode diversity. AB - Ultraviolet-B (UV-B) radiation and elevated tropospheric ozone may cause reductions in the productivity and quality of important agricultural crops. However, research regarding their interactive effect is still scarce, especially on the belowground processes. Using the open top chambers experimental setup, we monitored the response of soil nematodes to the elevated O3 and UV-B radiation individually as well as in combination. Our results indicated that elevated O3 and UV-B radiation have impact not only on the belowground biomass of plants, but also on the community structure and functional diversity of soil nematodes. The canonical correspondence analysis suggested that soil pH, shoot biomass and microbial biomass C and N were relevant parameters that influencing soil nematode distribution. The interactive effects of elevated O3 and UV-B radiation was only observed on the abundance of bacterivores. UV-B radiation significantly increased the abundance of total nematodes and bacterivores in comparison with the control at pod-filling stage of soybean. Following elevated O3, nematode diversity index decreased and dominance index increased relative to the control at pod-filling stage of soybean. Nematode functional diversity showed response to the effects of elevated O3 and UV-B radiation at pod-bearing stage. Higher enrichment index and lower structure index in the treatment with both elevated O3 and UV-B radiation indicated a stressed soil condition and degraded soil food web. However, the ratios of nematode trophic groups suggested that the negative effects of elevated O3 on soil food web may be weakened by the UV-B radiations. PMID- 24158400 TI - The plant extracellular transglutaminase: what mammal analogues tell. AB - The extracellular transglutaminases (TGs) in eukaryotes are responsible for the post-translational modification of proteins through different reactions, cross linking being the best known. In higher plants, extracellular TG appears to be involved in roles similar to those performed by the mammalian counterparties. Since TGs are pleiotropic enzymes, to fully understand the role of plant enzymes it is possible to compare them with animal TGs, the most studied being TG of type 2 (TG2). The extracellular form of TG2 stabilizes the matrix and modulates the interaction of the integrin-fibronectin receptor, causing the adhesion of cells to the extracellular matrix; TG2 plays a role also in the pathogenicity. Extracellular TGs have also been identified in the cell wall of fungi, such as Candida and Saccharomyces, where they cross-link structural glycoproteins, and in Phytophthora, where they are involved in pathogenicity; in the alga Chlamydomonas, TGs link polyamines to glycoproteins thereby favouring the strengthening of cell wall. In higher plants, TG localized in the cell wall of flower petals appears to be involved in the structural reinforcement as well as senescence and cell death of the flower corolla. In the pollen cell wall an extracellular TG co-localizes with substrates and cross-linked products; it is required for the apical growth of pollen tubes. The pollen TG is also secreted into the extracellular matrix possibly allowing the migration of pollen tubes during fertilisation. Although pollen TGs seem to be secreted via vesicles transported along actin filaments, a different mechanism from the classical ER Golgi pathway is possible, similar to TG2. PMID- 24158401 TI - Immature male gibbons produce female-specific songs. AB - Gibbons are apes that are well known to produce characteristic species-specific loud calls, referred to as "songs." Of particular interest is the sex specificity of the "great calls" heard in gibbon songs. However, little is known about the development of such calls. While great calls are given by female gibbons of various ages, they have never been recorded from males. Here, we report two observations of immature male gibbons from two different species, wild Hylobates agilis and captive H. lar, which spontaneously sang female-specific great calls. Based on the video clips, we conclude that immature males also have the potential to produce great calls. Our observations led us to propose a new hypothesis for the development of sexual differentiation in the songs of gibbons, and its implications for the general issue of sex-specific behavior in primates. PMID- 24158402 TI - Serum creatinine and creatinine clearance for predicting plasma methotrexate concentrations after high-dose methotrexate chemotherapy for the treatment for childhood lymphoblastic malignancies. AB - PURPOSE: Monitoring of plasma methotrexate (MTX) concentrations allows for therapeutic adjustments in treating childhood acute lymphoblastic leukemia (ALL) or non-Hodgkin lymphoma (NHL) with high-dose MTX (HDMTX). We tested the hypothesis that assessment of creatinine clearance (CrCl) and/or serum Cr may be a suitable means of monitoring plasma MTX concentrations. METHODS: All children in the study had ALL or NHL, were in complete remission, and received HDMTX (3 or 5 g/m(2))+leucovorin. Plasma MTX concentrations were measured at 24, 48, and 96 h. CrCl was determined at 24 and 48 h. Correlations between 24- and 48-h plasma MTX concentrations and CrCl and serum Cr concentrations were determined. CrCl and serum Cr concentrations were compared over time between children who had delayed and non-delayed MTX elimination. RESULTS: A total of 105 children were included. There were significant negative correlations between CrCl at 24 and 48 h and plasma MTX concentrations at 24 (both p < 0.001) and 48 h (both p < 0.001). There were significant positive correlations between serum Cr concentrations at both 24 and 48 h and plasma MTX concentrations at 24 (both p < 0.001) and 48 h (both p < 0.001). There were 88 (30.2 %) instances of elimination delay. Children with elimination delay had significantly lower CrCl and higher Cr concentrations at 24 and 48 h compared with children without elimination delay (all p < 0.05). CONCLUSION: Our findings suggest that, with further refinement, assessment of renal function may be a useful means of monitoring plasma MTX concentrations during HDMTX for ALL and NHL. PMID- 24158403 TI - The functional and molecular entities underlying amino acid and peptide transport by the mammary gland under different physiological and pathological conditions. AB - This review describes the properties and regulation of the membrane transport proteins which supply the mammary gland with aminonitrogen to support metabolism under different physiological conditions (i.e. pregnancy, lactation and involution). Early studies focussed on characterising amino acid and peptide transport pathways with respect to substrate specificity, kinetics and hormonal regulation to allow a broad picture of the systems within the gland to be established. Recent investigations have concentrated on identifying the individual transporters at the molecular level (i.e. mRNA and protein). Many of the latter studies have identified the molecular correlates of the transport systems uncovered in the earlier functional investigations but in turn have also highlighted the need for more amino acid transport studies to be performed. The transporters function as either cotransporters and exchangers (or both) and act in a coordinated and regulated fashion to support the metabolic needs of the gland. However, it is apparent that a physiological role for a number of the transport proteins has yet to be elucidated. This article highlights the many gaps in our knowledge regarding the precise cellular location of a number of amino acid transporters within the gland. We also describe the role of amino acid transport in mammary cell volume regulation. Finally, the important role that individual mammary transport proteins may have in the growth and proliferation of mammary tumours is discussed. PMID- 24158404 TI - Spatial vascular volume fraction imaging for quantitative assessment of angiogenesis. AB - PURPOSE: The purpose of this study is to set up a quantitative imaging strategy for therapeutic angiogenesis and monitoring the spatial distribution and survival of the transplanted mesenchymal stem cells (MSCs) in vivo simultaneously. PROCEDURES: Mouse adipose-derived MSCs (AD-MSCs) were isolated from firefly luciferase and enhanced green fluorescent protein positive transgenic mice, and implanted intramuscularly into hindlimbs of C57BL/6 mice. Serial spatial vascular volume fraction (SVVF) imaging was performed to quantitatively assess angiogenesis by calculating the spatially explicit vascular volume. The hybrid microcomputed tomography angiography/bioluminescence tomography (micro-CTA/BLT) was used to track the fate of AD-MSCs in vivo. Laser Doppler perfusion imaging (LDPI) was used to evaluate blood perfusion. Ex vivo conventional methods were performed to cross-validate the therapeutic angiogenesis. RESULTS: There was a linear correlation relation between the cell number and Fluc/Fluc protein signal intensity in AD-MSCs via BLT. LDPI showed improved perfusion rate in mice treated with cytotherapy, compared to control mice. Furthermore, angiogenesis assessed by SVVF was 10.67 +/- 0.41 %, 13.99 +/- 0.28 %, and 23.50 +/- 1.23 % on days 7, 14, and 28 post-transplantation of AD-MSCs, respectively. Vascular densities of the longitudinally monitored ischemic hindlimbs were significantly higher than those at early time points and controls, which was also confirmed by vascular corrosion casting, scanning electron microscopic imaging, and histological analysis. CONCLUSIONS: Hybrid high-resolution micro-CTA/BLT enabled monitoring and quantitative assessment of cytotherapeutically induced angiogenesis in vivo. PMID- 24158405 TI - Multiple myeloma: Defining the high-risk patient and determining the optimal treatment strategy. AB - Multiple Myeloma (MM) is the second most common hematologic malignancy, with approximately 21,000 new diagnoses each year. The prognosis for MM is variable and depends on several factors. This chapter highlights the clinical and pathological features of multiple myeloma to help define the "high-risk" patient. The authors also review clinical trial data in an effort to delineate the optimal treatment strategy for this group of patients. While more research in this field is needed, the available evidence supports the use of bortezomib as induction therapy and maintenance for high-risk patients with multiple myeloma. PMID- 24158406 TI - Treatment of micro air bubbles in rat adipose tissue at 25 kPa altitude exposures with perfluorocarbon emulsions and nitric oxide. AB - INTRODUCTION: Perfluorocarbon emulsions (PFC) and nitric oxide (NO) releasing agents have on experimental basis demonstrated therapeutic properties in treating and preventing the formation of venous gas embolism as well as increased survival rate during decompression sickness from diving. The effect is ascribed to an increased solubility and transport capacity of respiratory gases in the PFC emulsion and possibly enhanced nitrogen washout through NO-increased blood flow rate and/or the removal of endothelial micro bubble nuclei precursors. Previous reports have shown that metabolic gases (i.e., oxygen in particular) and water vapor contribute to bubble growth and stabilization during altitude exposures. Accordingly, we hypothesize that the administration of PFC and NO donors upon hypobaric pressure exposures either (1) enhance the bubble disappearance rate through faster desaturation of nitrogen, or in contrast (2) promote bubble growth and stabilization through an increased oxygen supply. METHODS: In anesthetized rats, micro air bubbles (containing 79% nitrogen) of 4-500 nl were injected into exposed abdominal adipose tissue. Rats were decompressed in 36 min to 25 kPa (~10,376 m above sea level) and bubbles studied for 210 min during continued oxygen breathing (FIO2 = 1). Rats were administered PFC, NO, or combined PFC and NO. RESULTS: In all groups, most bubbles grew transiently, followed by a stabilization phase. There were no differences in the overall bubble growth or decay between groups or when compared with previous data during oxygen breathing alone at 25 kPa. CONCLUSION: During extreme altitude exposures, the contribution of metabolic gases to bubble growth compromises the therapeutic effects of PFC and NO, but PFC and NO do not induce additional bubble growth. PMID- 24158407 TI - Central and peripheral adjustments during high-intensity exercise following cold water immersion. AB - PURPOSE: We investigated the acute effects of cold water immersion (CWI) or passive recovery (PAS) on physiological responses during high-intensity interval training (HIIT). METHODS: In a crossover design, 14 cyclists completed 2 HIIT sessions (HIIT1 and HIIT2) separated by 30 min. Between HIIT sessions, they stood in cold water (10 degrees C) up to their umbilicus, or at room temperature (27 degrees C) for 5 min. The natural logarithm of square-root of mean squared differences of successive R-R intervals (ln rMSSD) was assessed pre- and post HIIT1 and HIIT2. Stroke volume (SV), cardiac output (Q), O2 uptake (VO2), total muscle hemoglobin (t Hb) and oxygenation of the vastus lateralis were recorded (using near infrared spectroscopy); heart rate, Q, and VO2 on-kinetics (i.e., mean response time, MRT), muscle de-oxygenation rate, and anaerobic contribution to exercise were calculated for HIIT1 and HIIT2. RESULTS: ln rMSSD was likely higher [between-trial difference (90% confidence interval) [+13.2% (3.3; 24.0)] after CWI compared with PAS. CWI also likely increased SV [+5.9% (-0.1; 12.1)], possibly increased Q [+4.4% (-1.0; 10.3)], possibly slowed Q MRT [+18.3% (-4.1; 46.0)], very likely slowed VO2 MRT [+16.5% (5.8; 28.4)], and likely increased the anaerobic contribution to exercise [+9.7% (-1.7; 22.5)]. CONCLUSION: CWI between HIIT slowed VO2 on-kinetics, leading to increased anaerobic contribution during HIIT2. This detrimental effect of CWI was likely related to peripheral adjustments, because the slowing of VO2 on-kinetics was twofold greater than that of central delivery of O2 (i.e., Q). CWI has detrimental effects on high intensity aerobic exercise performance that persist for >= 45 min. PMID- 24158408 TI - Mild eczema affects self-perceived health among pre-adolescent girls. AB - The aim was to assess the impact of eczema on health-related quality of life in the population-based birth cohort BAMSE with 2,756 pre-adolescent children. All answered the following questions on self-perceived health; "How are you feeling?", "How healthy do you consider yourself to be?" and "How happy are you with your life right now?". Children with ongoing eczema answered the "Children's Dermatology Life Quality Index (CDLQI)" questionnaire. In total, 350 (12.7%) of the children had eczema. Girls with eczema reported impaired self-perceived health as evaluated in the 3 questions; adjusted OR 1.72 (95% CI 1.16-2.55), 1.89 (95% CI 1.29-2.76) and 1.69 (95% CI 1.18-2.42). Eczema among boys was not associated with impairment of self-perceived health. The mean CDLQI score was 3.98 (95% CI 3.37-4.58). Since eczema affects up to 20% of pre-adolescent girls, the findings have implications both for health care providers and for society as a whole. PMID- 24158409 TI - Improved clinical and economic outcomes in severe bronchiolitis with pre-emptive nCPAP ventilatory strategy. AB - PURPOSE: Severe bronchiolitis is the leading cause of admission to the pediatric intensive care unit (PICU). Nasal continuous positive airway pressure (nCPAP) has become the primary respiratory support, replacing invasive mechanical ventilation (MV). Our objective was to evaluate the economic and clinical consequences following implementation of this respiratory strategy in our unit. METHODS: This was a retrospective cohort analysis of 525 infants with bronchiolitis requiring respiratory support and successively treated during two distinct periods with invasive MV between 1996 and 2000, P1 (n = 193) and nCPAP between 2006 and 2010, P2 (n = 332). Costs were estimated using the hospital cost billing reports. RESULTS: Patients' baseline characteristics were similar between the two periods. P2 is associated with a significant decrease in the length of ventilation (LOV) (4.1 +/- 3.5 versus 6.9 +/- 4.6 days, p < 0.001), PICU length of stay (LOS) (6.2 +/- 4.6 versus 9.7 +/- 5.5 days, p < 0.001) and hospital LOS. nCPAP was independently associated with a shorter duration of ventilatory support than MV (hazard ratio 1.8, 95% CI 1.5-2.2, p < 0.001). nCPAP was also associated with a significant decrease in ventilation-associated complications, and less invasive management. The mean cost of acute viral bronchiolitis-related PICU hospitalizations was significantly decreased, from 17,451 to 11,205 ? (p < 0.001). Implementation of nCPAP led to a reduction of the total annual cost of acute viral bronchiolitis hospitalizations of 715,000 ?. CONCLUSION: nCPAP in severe bronchiolitis is associated with a significant improvement in patient management as shown by the reduction in invasive care, LOV, PICU LOS, hospital LOS, and economic burden. PMID- 24158410 TI - Impact of lung ultrasound on clinical decision making in critically ill patients. AB - PURPOSE: To assess the impact of lung ultrasound (LU) on clinical decision making in mechanically ventilated critically ill patients. METHODS: One hundred and eighty-nine patients took part in this prospective study. The patients were enrolled in the study when LU was requested by the primary physician for (1) unexplained deterioration of arterial blood gases and (2) a suspected pathologic entity [pneumothorax, significant pleural effusion (including parapneumonic effusion, empyema, or hemothorax), unilateral atelectasis (lobar or total), pneumonia and diffuse interstitial syndrome (pulmonary edema)]. RESULTS: Two hundred and fifty-three LU examinations were performed; 108 studies (42.7%) were performed for unexplained deterioration of arterial blood gases, and 145 (57.3%) for a suspected pathologic entity (60 for pneumothorax, 34 for significant pleural effusion, 22 for diffuse interstitial syndrome, 15 for unilateral lobar or total lung atelectasis, and 14 for pneumonia). The net reclassification index was 85.6%, indicating that LU significantly influenced the decision-making process. The management was changed directly as a result of information provided by the LU in 119 out of 253 cases (47%). In 81 cases, the change in patient management involved invasive interventions (chest tube, bronchoscopy, diagnostic thoracentesis/fluid drainage, continuous venous-venous hemofiltration, abdominal decompression, tracheotomy), and in 38 cases, non-invasive (PEEP change/titration, recruitment maneuver, diuretics, physiotherapy, change in bed position, antibiotics initiation/change). In 53 out of 253 cases (21%), LU revealed findings which supported diagnoses not suspected by the primary physician (7 cases of pneumothorax, 9 of significant pleural effusion, 9 of pneumonia, 16 of unilateral atelectasis, and 12 of diffuse interstitial syndrome). CONCLUSION: Our study shows that LU has a significant impact on decision making and therapeutic management. PMID- 24158412 TI - Appropriate antibiotic use for patients with urinary tract infections reduces length of hospital stay. AB - BACKGROUND: To define appropriate antibiotic use for patients with a complicated urinary tract infection (UTI), we developed in a previous study a key set of 4 valid, guideline-based quality indicators (QIs). In the current study, we evaluated the association between appropriate antibiotic use for patients with a complicated UTI, as defined by these QIs, and length of hospital stay (LOS). METHODS: A retrospective, observational multicenter study included 1252 patients with a complicated UTI, hospitalized at internal medicine and urology departments of 19 university and nonuniversity Dutch hospitals. Data from the patients' medical charts were used to calculate QI performance scores. Multilevel mixed model analyses were performed to relate LOS to QI performance (appropriate use or not). We controlled for the potential confounders sex, age, (urological) comorbidity, febrile UTI, and intensive care unit admission <24 hours. RESULTS: Prescribing therapy in accordance with local hospital guidelines was associated with a shorter LOS (7.3 days vs 8.7 days; P = .02), as was early intravenous-oral switching (4.8 days vs 9.1 days; P < .001). There was an inverse relationship between the proportion of appropriate use in a patient (QI sum score/number of applicable QIs) and LOS (9.3 days for lower tertile vs 7.2 days for upper tertile; overall P < .05). CONCLUSIONS: Appropriate antibiotic use in patients with a complicated UTI seems to reduce length of hospital stay and therefore favors patient outcome and healthcare costs. In particular, adherence to the total set of QIs showed a significant dose-response relationship with a shorter LOS. PMID- 24158411 TI - Dual HER2 inhibition in combination with anti-VEGF treatment is active in heavily pretreated HER2-positive breast cancer. AB - BACKGROUND: Preclinical data indicate that dual HER2 inhibition overcomes trastuzumab resistance and that use of an HER2 inhibitor with an anti-angiogenic agent may augment responses. PATIENTS AND METHODS: We conducted a dose escalation, phase I study of a combination of trastuzumab, lapatinib and bevacizumab. The subset of patients with metastatic breast cancer was analyzed for safety and response. RESULTS: Twenty-six patients with metastatic breast cancer (median = 7 prior systemic therapies) (all with prior trastuzumab; 23 with prior lapatinib; one with prior bevacizumab) received treatment on a range of dose levels. The most common treatment-related grade 2 or higher toxicities were diarrhea (n = 11, 42%) and skin rash (n = 2, 8%). The recommended phase 2 dose was determined to be the full Food and Drug Administration (FDA) approved doses for all the three agents (trastuzumab 8 mg/kg loading dose, 6 mg/kg maintenance dose, intravenously every 3 weeks; lapatinib 1250 mg daily, bevacizumab 15 mg/kg intravenously every 3 weeks). The overall rate of stable disease (SD) >=6 months and partial or complete remission (PR/CR) was 50% (five patients with SD >=6 months; seven PRs (including one unconfirmed); one CR). The rate of SD >=6 months/PR/CR was not compromised in patients who had previously received study drugs, those with brain metastases, and patients treated at lower dose levels. CONCLUSIONS: The combination of trastuzumab, lapatinib and bevacizumab was well tolerated at maximally approved doses of each drug, and its activity in heavily pretreated patients with metastatic breast cancer suggests that it warrants further investigation. CLINTRIALSGOV ID: NCT00543504. PMID- 24158413 TI - Persistence of intracellular bacteria in the urinary bladder. PMID- 24158414 TI - Human monkeypox. AB - Human monkeypox is a zoonotic Orthopoxvirus with a presentation similar to smallpox. Clinical differentiation of the disease from smallpox and varicella is difficult. Laboratory diagnostics are principal components to identification and surveillance of disease, and new tests are needed for a more precise and rapid diagnosis. The majority of human infections occur in Central Africa, where surveillance in rural areas with poor infrastructure is difficult but can be accomplished with evidence-guided tools and educational materials to inform public health workers of important principles. Contemporary epidemiological studies are needed now that populations do not receive routine smallpox vaccination. New therapeutics and vaccines offer hope for the treatment and prevention of monkeypox; however, more research must be done before they are ready to be deployed in an endemic setting. There is a need for more research in the epidemiology, ecology, and biology of the virus in endemic areas to better understand and prevent human infections. PMID- 24158415 TI - Reply to Kaye and Sobel. PMID- 24158416 TI - Editorial commentary: linking process measures to outcome for patients with complicated urinary tract infection: it's complicated. PMID- 24158417 TI - [Informed consent to the insertion of a PEG tube in a 53-year-old male patient with highly advanced dementia]. AB - In patients with advanced dementia and dysphagia, regular fluid- and food intake together with oral medication can be guaranteed by insertion of a PEG tube. Consent to a treatment in a patient without legal capacity requires nomination of a legal substitute by an Austrian court. The following case report describes the problems associated with this particular situation exposing additional psychosocial stress to closest relatives and to the palliative care team in charge for the patient. This case report describes the legal options together with the finally chosen path of medical treatment which in clinical praxis may not always match. PMID- 24158418 TI - [Palliative sedation for psycho-existential suffering]. AB - Sedation in palliative care is generally considered as an important therapy in terminally ill patients with refractory symptoms. However the sedation of patients with intractable psycho-existential suffering is still under discussion. This paper discusses the case of a 56-year-old patient in the final phase of carcinoma of the ovaries, who required palliative sedation for refractory, mainly psycho-existential suffering. It describes the course on our ward and the difficult process of decision-making. We discuss our approach based on literature. PMID- 24158419 TI - Expensive therapies in children: benefit versus cost of combined treatment of recombinant human growth hormone and gonadotropin-releasing hormone analogue in girls with poor height potential. AB - OBJECTIVE: The combination therapy of gonadotropin-releasing hormone analogues (GnRHa) and recombinant human growth hormone (rhGH) has been used to increase growth in children with premature sexual maturation and attenuated growth. The aim of this report was to study the benefit over cost of combined treatment in girls with central precocious puberty (CPP) and poor height prognosis and in girls with idiopathic short stature (ISS) and early puberty. Should this expensive treatment be given to such patients? SUBJECTS AND METHODS: Two patient groups were included: five girls with central precocious puberty (CPP) who reached final height (FH) at 16.3+/-1.2 years and eight girls with ISS who reached FH at 14.7+/-0.8 years. Patients were treated for 3.5+/-0.6 years. RESULTS: In both groups, FH improved significantly; in CPP from -1.3 to -0.5 standard deviation score (SDS) (p=0.030) and in ISS from -2.6 to -1.7 SDS (p=0.012). Only girls with CPP reached their target height (-0.5 vs. -0.6 SDS) (p=0.500). CONCLUSIONS: Both groups had a total height gain of 5 cm. Each centimetre cost about ?2700 per patient. This treatment should be considered only in patients with extremely low height prediction and very early pubertal onset. PMID- 24158420 TI - A common thyroid peroxidase gene mutation (G319R) in Turkish patients with congenital hypothyroidism could be due to a founder effect. AB - The most common congenital endocrine disorder is congenital hypothyroidism (CH), which can lead to mental retardation if untreated. Majority of the patients have been found to have defects in thyroid development and migration disorders (dysgenesis), and the remaining ones have thyroid hormone synthesis defects (dyshormonogenesis). One of the most common mechanisms to cause dyshormonogenesis is a defect in the thyroid peroxidase (TPO) enzyme. In familial cases, mutations in the TPO gene are fairly prevalent. To date, more than 80 mutations have been identified, which result in variably decreasing TPO bioactivities. Clinical manifestations of TPO defects are typically permanent CH and with or without goiter. In this report, we presented two children with CH who were born to consanguineous parents and were homozygous carriers of a missense (G319R) TPO mutation, the mutation segregated with the disease status in the families confirming its pathogenicity. G319R mutation seemed to be a common cause of CH in Turkish population, which could originate from a common founder ancestor. Moreover, our results also confirmed the phenotypic variability associated with different TPO mutations. PMID- 24158421 TI - Endocytic Rabs in membrane trafficking and signaling. AB - The endolysosomal system controls the trafficking of proteins between the plasma membrane and the degradative environment of the lysosome. The early endosomal Rab5 and the late endosomal Rab7 GTPases have a key role in the transport along the endocytic pathway by recruiting tethering factors such as the hexameric CORVET and HOPS complexes that promote membrane fusion. Both Rabs are also involved in signaling at endosomal membranes and linked to amino acid sensing and autophagy, indicating that their role in trafficking may be connected to signal transduction and adaptation during cell stress. Here, we will summarize the current knowledge on the role of both Rab GTPases on both processes and discuss the possible crosstalk between them. PMID- 24158422 TI - Detection of unamplified HCV RNA in serum using a novel two metallic nanoparticle platform. AB - BACKGROUND: The unique properties of metallic nanoparticles have enabled their utilization in biosensing applications. A novel assay for the detection of hepatitis C virus (HCV) RNA in serum specimens has been developed using magnetic nanoparticles and unmodified cationic gold nanoparticles (AuNPs). METHODS: HCV RNA was extracted using magnetic nanoparticles functionalized with an oligonucleotide specific to HCV RNA. Extracted RNA is reacted with oligonucleotide sequence specific for HCV RNA in presence of unmodified cationic AuNPs. In positive samples, AuNPs are aligned onto the phosphate backbone of the RNA and their aggregation changes the solution color from red to blue. In the absence of target, solution color remains red. The assay has been tested on 50 serum clinical samples (25 HCV positive and 25 controls). RESULTS: The dual nanoparticles assay detected HCV RNA in serum and generated comparable results to real-time PCR. The assay had specificity and a sensitivity of 96% and 96.5%, respectively, and a detection limit of 15 IU/mL. CONCLUSIONS: The developed colorimetric dual nanoparticles HCV RNA assay is simple and inexpensive and can be used for rapid detection of unamplified HCV RNA in serum. Similar sensing platforms can be developed to detect other nucleic acid targets. PMID- 24158423 TI - Quantification of linezolid in serum by LC-MS/MS using semi-automated sample preparation and isotope dilution internal standardization. AB - BACKGROUND: Linezolid serum concentrations have been shown to be highly variable in critically ill patients with often sub-therapeutic drug levels regarding minimal inhibitory concentrations for relevant pathogens. Consequently, therapeutic drug monitoring of linezolid must be considered, requiring a reliable and convenient analytical method. We therefore developed and validated an LC MS/MS method applying isotope dilution internal standardization and on-line solid phase extraction for serum linezolid quantification. METHODS: Sample preparation was based on protein precipitation and on-line solid phase extraction with two dimensional liquid chromatography and column switching. Three-fold deuterated linezolid was used as the internal standard. The method was validated involving two separate LC-MS/MS systems covering the concentration range of 0.13-32 mg/L. The run time was 4 min. RESULTS: Validation revealed good analytical performance, with inaccuracy <6% and imprecision of <7.3% (CV) for six quality control samples (0.38-16.0 mg/L). The method was found to be robust during the validation process and during a pharmacokinetic study so far involving 600 samples. Comparative measurements on two LC-MS/MS systems revealed close agreement. CONCLUSIONS: This LC-MS/MS assay described herein is a convenient, robust and reliable method for linezolid quantification in serum which can be routinely applied using different LC-MS/MS systems. The method can be used for clinical studies and subsequent TDM of linezolid. PMID- 24158424 TI - Positive airway pressure treatment for opioid-related central sleep apnea, where are we now? PMID- 24158425 TI - Treatment considerations for HIV-infected individuals with severe mental illness. AB - There has been a general recognition of a syndemic that includes HIV/AIDS and serve mental illnesses including schizophrenia, major depression, bipolar disorder, post-traumatic stress disorder, and others. The pathophysiology and direction of effects between severe mental illness and HIV infection is less clear however, and relatively little work has been done on prevention and treatment for people with these complex, co-occurring conditions. Here we present the most recent work that has been published on HIV and mental illness. Further, we describe the need for better treatments for "triply diagnosed persons"; those with HIV, mental illness, and substance abuse and dependence. Finally, we describe the potential drug-drug interactions between psychotropic medications and anti-retrovirals, and the need for better treatment guidelines in this area. We describe one example of an individually tailored intervention for persons with serious mental illness and HIV (PATH+) that shows that integrated community-based treatments using advanced practice nurses (APNs) as health navigators can be successful in improving health-related quality of life and reducing the burden of disease in these persons. PMID- 24158426 TI - Perceived usefulness of data entry tools in medical encounters: a survey. AB - Electronic Health Records allows direct data entry and is an important factor for accurate diagnosis. However, two drawbacks of this system is the time needed to create them, which can reduce health care professional productivity, and the fact that it is error prone. It is important, therefore, to select the most appropriate methods and tools for data entry by the health care providers at the point of care in order to minimize a loss of productivity. The study aims to understand health care professionals' perceptions of the data entry process, and determine the appropriate methods, tools and functions that would facilitate the process, minimize loss of productivity and improve quality. A questionnaire which consisting of 18 basic questions (including demographic data) was posted on a web site which hosts questionnaires, on an established online community space and also mailed to health care professionals who are working in various hospitals for a duration of 10 months. Totally, 533 medical care professionals who are primarily from Turkey participated in the survey, of which 284 were medical doctors, 127 were nurses and the rest, other medical professionals. While the clear majority of participants involved in data entry use keyboard and mouse, most expressed a preference for more convenient methods, such as voice recognition or touch screen. Furthermore, physicians reported rarely spending more than 15 min for each consultation and conducting 21-30 examinations a day. The main motivation for creating an efficient direct data entry is to increase time allowed for patient examination, and to improve accuracy of diagnosis. Despite a heavy workload, health care professionals are very receptive to the idea of using a convenient data entry tool and keeping electronic patient records. Emergent data entry technologies in health sector can improve the quality of examinations, physicians' productivity and can decrease the percentage of medical misdiagnosis. PMID- 24158427 TI - Privacy preserving index for encrypted electronic medical records. AB - With the development of electronic systems, privacy has become an important security issue in real-life. In medical systems, privacy of patients' electronic medical records (EMRs) must be fully protected. However, to combine the efficiency and privacy, privacy preserving index is introduced to preserve the privacy, where the EMR can be efficiently accessed by this patient or specific doctor. In the literature, Goh first proposed a secure index scheme with keyword search over encrypted data based on a well-known primitive, Bloom filter. In this paper, we propose a new privacy preserving index scheme, called position index (P index), with keyword search over the encrypted data. The proposed index scheme is semantically secure against the adaptive chosen keyword attack, and it also provides flexible space, lower false positive rate, and search privacy. Moreover, it does not rely on pairing, a complicate computation, and thus can search over encrypted electronic medical records from the cloud server efficiently. PMID- 24158428 TI - Can mobile health technologies transform health care? PMID- 24158429 TI - Inhibitors of second messenger pathways and Ca(2+)-induced exposure of phosphatidylserine in red blood cells of patients with sickle cell disease. AB - The present work investigates the contribution of various second messenger systems to Ca(2+)-induced phosphatidylserine (PS) exposure in red blood cells (RBCs) from sickle cell disease (SCD) patients. The Ca(2+) dependence of PS exposure was confirmed using the Ca(2+) ionophore bromo-A23187 to clamp intracellular Ca(2+) over 4 orders of magnitude in high or low potassium containing (HK or LK) saline. The percentage of RBCs showing PS exposure was significantly increased in LK over HK saline. This effect was reduced by the Gardos channel inhibitors, clotrimazole and charybdotoxin. Nevertheless, although Ca(2+) loading in the presence of an outwardly directed electrochemical gradient for K(+) stimulated PS exposure, substantial exposure still occurred in HK saline. Under the conditions used inhibitors of other second messenger systems (ABT491, quinacrine, acetylsalicylic acid, 3,4-dichloroisocoumarin, GW4869 and zVAD-fmk) did not inhibit the relationship between [Ca(2+)] and PS exposure. Inhibitors of phospholipase A2, cyclooxygenase, platelet-activating factor, sphingomyelinase and caspases, therefore, were without effect on Ca(2+)-induced PS exposure in RBCs, incubated in either HK or LK saline. PMID- 24158431 TI - Intra-articular entrapment of the ulnar nerve after acute elbow dislocation: a rare cause of flexion contracture. PMID- 24158430 TI - BK channel activation by tungstate requires the beta1 subunit extracellular loop residues essential to modulate voltage sensor function and channel gating. AB - Tungstate, a compound with antidiabetic, antiobesity, and antihypertensive properties, activates the large-conductance voltage- and Ca(2+)-dependent K(+) (BK) channel containing either beta1 or beta4 subunits. The BK activation by tungstate is Mg(2+)-dependent and promotes arterial vasodilation, but only in precontracted mouse arteries expressing beta1. In this study, we further explored how the beta1 subunit participates in tungstate activation of BK channels. Activation of heterologously expressed human BKalphabeta1 channels in inside-out patches is fully dependent on the Mg(2+) sensitivity of the BK alpha channel subunit even at high (10 MUM) cytosolic Ca(2+) concentration. Alanine mutagenesis of beta1 extracellular residues Y74 or S104, which destabilize the active voltage sensor, greatly decreased the tungstate-induced left-shift of the BKalphabeta1 G V curves in either the absence or presence of physiologically relevant cytosolic Ca(2+) levels (10 MUM). The weakened tungstate activation of the BKalphabeta1Y74A and BKalphabeta1S104A mutant channels was not related to decreased Mg(2+) sensitivity. These results, together with previously published reports, support the idea that the putative binding site for tungstate-mediated BK channel activation is located in the pore-forming alpha channel subunit, around the Mg(2+) binding site. The role of beta1 in tungstate-induced channel activation seems to rely on its interaction with the BK alpha subunit to modulate channel activity. Loop residues that are essential for the regulation of voltage sensor activation and gating of the BK channel are also relevant for BK activation by tungstate. PMID- 24158432 TI - Tibialis spastic varus foot without tarsal coalition: a report of two cases. PMID- 24158433 TI - Pedicle versus free frozen autograft for reconstruction in malignant bone and soft tissue tumors of the lower extremities. AB - BACKGROUND: Of the biological reconstruction methods for malignant bone and soft tissue tumors, reconstruction with liquid nitrogen has the advantage of maintaining continuity on the distal side of the tumor bone site (pedicle freezing procedure; PFP). This method is expected to result in early blood flow recovery, with early union and low complication rate. The purpose of this study was to compare the outcomes of the PFP and free freezing procedure (FFP) in the lower extremities. METHODS: The study included 20 patients (12 men and 8 women) with frozen autografts (FFP, 13 cases; PFP, 7 cases). The mean age of the subjects was 36.3 years (range 11-79 years), and the mean follow-up period was 56.4 months (range 12-142 months). RESULTS: Final bone union occurred in 11 patients in the FFP group (84.6%) and in 7 patients in the PFP group (100%). The mean union period in patients who did not need additional surgery was 9.8 months (range 4-21 months) in the FFP group and 4.8 months (range 2-7 months) in the PFP group. Postoperative complications occurred in 8 cases: infection in 3 cases, fracture in 3 cases, and joint destruction in 2 cases. Six FFP patients, and 2 PFP patients (two cases of fracture), developed postoperative complications. CONCLUSIONS: The union period was shorter and the rate of postoperative complications was lower with the PFP than with the FFP. We considered that early blood flow recovery might have led to the above results in the PFP. PMID- 24158434 TI - Whole grain and refined grain consumption and the risk of type 2 diabetes: a systematic review and dose-response meta-analysis of cohort studies. AB - Several studies have suggested a protective effect of intake of whole grains, but not refined grains on type 2 diabetes risk, but the dose-response relationship between different types of grains and type 2 diabetes has not been established. We conducted a systematic review and meta-analysis of prospective studies of grain intake and type 2 diabetes. We searched the PubMed database for studies of grain intake and risk of type 2 diabetes, up to June 5th, 2013. Summary relative risks were calculated using a random effects model. Sixteen cohort studies were included in the analyses. The summary relative risk per 3 servings per day was 0.68 (95% CI 0.58-0.81, I(2) = 82%, n = 10) for whole grains and 0.95 (95% CI 0.88-1.04, I(2) = 53%, n = 6) for refined grains. A nonlinear association was observed for whole grains, p nonlinearity < 0.0001, but not for refined grains, p nonlinearity = 0.10. Inverse associations were observed for subtypes of whole grains including whole grain bread, whole grain cereals, wheat bran and brown rice, but these results were based on few studies, while white rice was associated with increased risk. Our meta-analysis suggests that a high whole grain intake, but not refined grains, is associated with reduced type 2 diabetes risk. However, a positive association with intake of white rice and inverse associations between several specific types of whole grains and type 2 diabetes warrant further investigations. Our results support public health recommendations to replace refined grains with whole grains and suggest that at least two servings of whole grains per day should be consumed to reduce type 2 diabetes risk. PMID- 24158435 TI - Phosphorylation of the cryptochrome 1 C-terminal tail regulates circadian period length. AB - The Cryptochrome (CRY) proteins are critical components of the mammalian circadian clock and act to rhythmically repress the activity of the transcriptional activators CLOCK and BMAL1 at the heart of the clock mechanism. The CRY proteins are part of a large repressive complex, the components of which are not completely known. Using mass spectroscopy, we identified the catalytic subunit of DNA-dependent protein kinase as a CRY-interacting protein and found that loss or inhibition of this kinase results in circadian rhythms with abnormally long periods. We then identified serine 588 in the C-terminal tail of mouse CRY1 as a potential DNA-PK phosphorylation site but surprisingly found that the phosphomimetic mutation S588D also results in long period rhythms, similar to the loss of DNA-PK. Consistent with this, we found that phosphorylation of this site is increased in cells lacking DNA-PK, suggesting that DNA-PK negatively regulates the phosphorylation of this site most likely through indirect means. Furthermore, we found that phosphorylation of this site increases the stability of the CRY1 protein and prevents FBXL3-mediated degradation. The phosphorylation of this site is robustly rhythmic in mouse liver nuclei, peaking in the middle of the circadian day at a time when CRY1 levels are declining. Therefore, these data suggest a new role for the C-terminal tail of CRY1 in which phosphorylation rhythmically regulates CRY1 stability and contributes to the proper circadian period length. PMID- 24158436 TI - Multi-step loading of human minichromosome maintenance proteins in live human cells. AB - Once-per-cell cycle replication is regulated through the assembly onto chromatin of multisubunit protein complexes that license DNA for a further round of replication. Licensing consists of the loading of the hexameric MCM2-7 complex onto chromatin during G1 phase and is dependent on the licensing factor Cdt1. In vitro experiments have suggested a two-step binding mode for minichromosome maintenance (MCM) proteins, with transient initial interactions converted to stable chromatin loading. Here, we assess MCM loading in live human cells using an in vivo licensing assay on the basis of fluorescence recovery after photobleaching of GFP-tagged MCM protein subunits through the cell cycle. We show that, in telophase, MCM2 and MCM4 maintain transient interactions with chromatin, exhibiting kinetics similar to Cdt1. These are converted to stable interactions from early G1 phase. The immobile fraction of MCM2 and MCM4 increases during G1 phase, suggestive of reiterative licensing. In late G1 phase, a large fraction of MCM proteins are loaded onto chromatin, with maximal licensing observed just prior to S phase onset. Fluorescence loss in photobleaching experiments show subnuclear concentrations of MCM-chromatin interactions that differ as G1 phase progresses and do not colocalize with sites of DNA synthesis in S phase. PMID- 24158437 TI - Glycolytic ATP fuels the plasma membrane calcium pump critical for pancreatic cancer cell survival. AB - Pancreatic cancer is an aggressive cancer with poor prognosis and limited treatment options. Cancer cells rapidly proliferate and are resistant to cell death due, in part, to a shift from mitochondrial metabolism to glycolysis. We hypothesized that this shift is important in regulating cytosolic Ca(2+) ([Ca(2+)]i), as the ATP-dependent plasma membrane Ca(2+) ATPase (PMCA) is critical for maintaining low [Ca(2+)]i and thus cell survival. The present study aimed to determine the relative contribution of mitochondrial versus glycolytic ATP in fuelling the PMCA in human pancreatic cancer cells. We report that glycolytic inhibition induced profound ATP depletion, PMCA inhibition, [Ca(2+)]i overload, and cell death in PANC1 and MIA PaCa-2 cells. Conversely, inhibition of mitochondrial metabolism had no effect, suggesting that glycolytic ATP is critical for [Ca(2+)]i homeostasis and thus survival. Targeting the glycolytic regulation of the PMCA may, therefore, be an effective strategy for selectively killing pancreatic cancer while sparing healthy cells. PMID- 24158438 TI - Activation of intracellular calcium by multiple Wnt ligands and translocation of beta-catenin into the nucleus: a convergent model of Wnt/Ca2+ and Wnt/beta catenin pathways. AB - Ca(2+) and beta-catenin, a 92-kDa negatively charged transcription factor, transduce Wnt signaling via the non-canonical, Wnt/Ca(2+) and canonical, Wnt/beta catenin pathways independently. The nuclear envelope is a barrier to large protein entry, and this process is regulated by intracellular calcium [Ca(2+)]i and trans-nuclear potential. How beta-catenin traverses the nuclear envelope is not well known. We hypothesized that Wnt/Ca(2+) and Wnt/beta-catenin pathways act in a coordinated manner and that [Ca(2+)]i release facilitates beta-catenin entry into the nucleus in mammalian cells. In a live assay using calcium dyes in PC3 prostate cancer cells, six Wnt peptides (3A, 4, 5A, 7A, 9B, and 10B) mobilized [Ca(2+)]i but Wnt11 did not. Based upon dwell time (range = 15-30 s) of the calcium waveform, these Wnts could be classified into three classes: short, 3A and 5A; long, 7A and 10B; and very long, 4 and 9B. Wnt-activated [Ca(2+)]i release was followed by an increase in intranuclear calcium and the depolarization of both the cell and nuclear membranes, determined by using FM4 64. In cells treated with Wnts 5A, 9B, and 10B, paradigm substrates for each Wnt class, increased [Ca(2+)]i was followed by beta-catenin translocation into the nucleus in PC3, MCF7, and 253J, prostate, breast, and bladder cancer cell lines; both the increase in Wnt 5A, 9B, and 10B induced [Ca(2+)]i release and beta catenin translocation are suppressed by thapsigargin in PC3 cell line. We propose a convergent model of Wnt signaling network where Ca(2+) and beta-catenin pathways may act in a coordinated, interdependent, rather than independent, manner. PMID- 24158439 TI - Structures of the Bacillus subtilis glutamine synthetase dodecamer reveal large intersubunit catalytic conformational changes linked to a unique feedback inhibition mechanism. AB - Glutamine synthetase (GS), which catalyzes the production of glutamine, plays essential roles in nitrogen metabolism. There are two main bacterial GS isoenzymes, GSI-alpha and GSI-beta. GSI-alpha enzymes, which have not been structurally characterized, are uniquely feedback-inhibited by Gln. To gain insight into GSI-alpha function, we performed biochemical and cellular studies and obtained structures for all GSI-alpha catalytic and regulatory states. GSI alpha forms a massive 600-kDa dodecameric machine. Unlike other characterized GS, the Bacillus subtilis enzyme undergoes dramatic intersubunit conformational alterations during formation of the transition state. Remarkably, these changes are required for active site construction. Feedback inhibition arises from a hydrogen bond network between Gln, the catalytic glutamate, and the GSI-alpha specific residue, Arg(62), from an adjacent subunit. Notably, Arg(62) must be ejected for proper active site reorganization. Consistent with these findings, an R62A mutation abrogates Gln feedback inhibition but does not affect catalysis. Thus, these data reveal a heretofore unseen restructuring of an enzyme active site that is coupled with an isoenzyme-specific regulatory mechanism. This GSI alpha-specific regulatory network could be exploited for inhibitor design against Gram-positive pathogens. PMID- 24158440 TI - Preservation of protein dynamics in dihydrofolate reductase evolution. AB - The hydride transfer reaction catalyzed by dihydrofolate reductase (DHFR) is a model for examining how protein dynamics contribute to enzymatic function. The relationship between functional motions and enzyme evolution has attracted significant attention. Recent studies on N23PP Escherichia coli DHFR (ecDHFR) mutant, designed to resemble parts of the human enzyme, indicated a reduced single turnover rate. NMR relaxation dispersion experiments with that enzyme showed rigidification of millisecond Met-20 loop motions (Bhabha, G., Lee, J., Ekiert, D. C., Gam, J., Wilson, I. A., Dyson, H. J., Benkovic, S. J., and Wright, P. E. (2011) Science 332, 234-238). A more recent study of this mutant, however, indicated that fast motions along the reaction coordinate are actually more dispersed than for wild-type ecDHFR (WT). Furthermore, a double mutant (N23PP/G51PEKN) that better mimics the human enzyme seems to restore both the single turnover rates and narrow distribution of fast dynamics (Liu, C. T., Hanoian, P., French, T. H., Hammes-Schiffer, S., and Benkovic, S. J. (2013) Proc. Natl. Acad. Sci. U.S.A. 110, 10159-11064). Here, we measured intrinsic kinetic isotope effects for both N23PP and N23PP/G51PEKN double mutant DHFRs over a temperature range. The findings indicate that although the C-H->C transfer and dynamics along the reaction coordinate are impaired in the altered N23PP mutant, both seem to be restored in the N23PP/G51PEKN double mutant. This indicates that the evolution of G51PEKN, although remote from the Met-20 loop, alleviated the loop rigidification that would have been caused by N23PP, enabling WT-like H tunneling. The correlation between the calculated dynamics, the nature of C-H->C transfer, and a phylogenetic analysis of DHFR sequences are consistent with evolutionary preservation of the protein dynamics to enable H-tunneling from well reorganized active sites. PMID- 24158441 TI - Tyr728 in the kinase domain of the murine kinase suppressor of RAS 1 regulates binding and activation of the mitogen-activated protein kinase kinase. AB - In metazoans, the highly conserved MAPK signaling pathway regulates cell fate decision. Aberrant activation of this pathway has been implicated in multiple human cancers and some developmental disorders. KSR1 functions as an essential scaffold that binds the individual components of the cascade and coordinates their assembly into multiprotein signaling platforms. The mechanism of KSR1 regulation is highly complex and not completely understood. In this study, we identified Tyr(728) as a novel regulatory phosphorylation site in KSR1. We show that Tyr(728) is phosphorylated by LCK, uncovering an additional and unexpected link between Src kinases and MAPK signaling. To understand how phosphorylation of Tyr(728) may regulate the role of KSR1 in signal transduction, we integrated structural modeling and biochemical studies. We demonstrate that Tyr(728) is involved in maintaining the conformation of the KSR1 kinase domain required for binding to MEK. It also affects phosphorylation and activation of MEK by RAF kinases and consequently influences cell proliferation. Moreover, our studies suggest that phosphorylation of Tyr(728) may affect the intrinsic kinase activity of KSR1. Together, we propose that phosphorylation of Tyr(728) may regulate the transition between the scaffolding and the catalytic function of KSR1 serving as a control point used to fine-tune cellular responses. PMID- 24158442 TI - Transition state analogues of Plasmodium falciparum and human orotate phosphoribosyltransferases. AB - The survival and proliferation of Plasmodium falciparum parasites and human cancer cells require de novo pyrimidine synthesis to supply RNA and DNA precursors. Orotate phosphoribosyltransferase (OPRT) is an indispensible component in this metabolic pathway and is a target for antimalarials and antitumor drugs. P. falciparum (Pf) and Homo sapiens (Hs) OPRTs are characterized by highly dissociative transition states with ribocation character. On the basis of the geometrical and electrostatic features of the PfOPRT and HsOPRT transition states, analogues were designed, synthesized, and tested as inhibitors. Iminoribitol mimics of the ribocation transition state in linkage to pyrimidine mimics using methylene or ethylene linkers gave dissociation constants (Kd) as low as 80 nM. Inhibitors with pyrrolidine groups as ribocation mimics displayed slightly weaker binding affinities for OPRTs. Interestingly, p-nitrophenyl riboside 5'-phosphate bound to OPRTs with Kd values near 40 nM. Analogues designed with a C5-pyrimidine carbon-carbon bond to ribocation mimics gave Kd values in the range of 80-500 nM. Acyclic inhibitors with achiral serinol groups as the ribocation mimics also displayed nanomolar inhibition against OPRTs. In comparison with the nucleoside derivatives, inhibition constants of their corresponding 5'-phosphorylated transition state analogues are largely unchanged, an unusual property for a nucleotide-binding site. In silico docking of the best inhibitor into the HsOPRT active site supported an extensive hydrogen bond network associated with the tight binding affinity. These OPRT transition state analogues identify crucial components of potent inhibitors targeting OPRT enzymes. Despite their tight binding to the targets, the inhibitors did not kill cultured P. falciparum. PMID- 24158443 TI - Translational regulation of Yersinia enterocolitica mRNA encoding a type III secretion substrate. AB - Yersinia enterocolitica type III secretion machines transport YopQ and other Yop effectors into host immune cells. YopD and its chaperone LcrH are essential components of the Yersinia type III pathway, enabling effector translocation into host cells. YopD, LcrH, and YscM1 also regulate yop expression post transcriptionally in response to environmental signals; however, the molecular mechanisms for this regulation and Yop secretion are unknown. We show here that YopD associates with 30 S ribosomal particles in a manner requiring LcrH. When added to ribosomes, YopD, LcrH, and YscM1 block the translation of yopQ mRNA. We propose a model whereby LcrH-dependent association of YopD with 30 S ribosomal particles enables YscM1 to block yopQ translation unless type III machines are induced to secrete the effector. PMID- 24158444 TI - The E3 ubiquitin ligase UBE3C enhances proteasome processivity by ubiquitinating partially proteolyzed substrates. AB - To maintain protein homeostasis, cells must balance protein synthesis with protein degradation. Accumulation of misfolded or partially degraded proteins can lead to the formation of pathological protein aggregates. Here we report the use of destabilizing domains, proteins whose folding state can be reversibly tuned using a high affinity ligand, as model substrates to interrogate cellular protein quality control mechanisms in mammalian cells using a forward genetic screen. Upon knockdown of UBE3C, an E3 ubiquitin ligase, a reporter protein consisting of a destabilizing domain fused to GFP is degraded more slowly and incompletely by the proteasome. Partial proteolysis is also observed when UBE3C is present but cannot ubiquitinate substrates because its active site has been mutated, it is unable to bind to the proteasome, or the substrate lacks lysine residues. UBE3C knockdown also results in less substrate polyubiquitination. Finally, knockdown renders cells more susceptible to the Hsp90 inhibitor 17-AAG, suggesting that UBE3C protects against the harmful accumulation of protein fragments arising from incompletely degraded proteasome substrates. PMID- 24158445 TI - Promiscuous activation of transient receptor potential vanilloid 1 (TRPV1) channels by negatively charged intracellular lipids: the key role of endogenous phosphoinositides in maintaining channel activity. AB - The regulation of the heat- and capsaicin-activated transient receptor potential vanilloid 1 (TRPV1) channels by phosphoinositides is controversial. Data in cellular systems support the dependence of TRPV1 activity on phosphoinositides. The purified TRPV1, however, was recently shown to be fully functional in artificial liposomes in the absence of phosphoinositides. Here, we show that several other negatively charged phospholipids, including phosphatidylglycerol, can also support TRPV1 activity in excised patches at high concentrations. When we incorporated TRPV1 into planar lipid bilayers consisting of neutral lipids, capsaicin-induced activity depended on phosphatidylinositol 4,5-bisphosphate. We also found that TRPV1 activity in excised patches ran down and that MgATP reactivated the channel. Inhibition of phosphatidylinositol 4-kinases or enzymatic removal of phosphatidylinositol abolished this effect of MgATP, suggesting that it activated TRPV1 by generating endogenous phosphoinositides. We conclude that endogenous phosphoinositides are positive cofactors for TRPV1 activity. Our data highlight the importance of specificity in lipid regulation of ion channels and may reconcile discordant data obtained in various experimental settings. PMID- 24158446 TI - Structural insights of tBid, the caspase-8-activated Bid, and its BH3 domain. AB - The Bcl-2 family proteins regulate mitochondria-mediated apoptosis through intricate molecular mechanisms. One of the pro-apoptotic proteins, tBid, can induce apoptosis by promoting Bax activation, Bax homo-oligomerization, and mitochondrial outer membrane permeabilization. Association of tBid on the mitochondrial outer membrane is key to its biological function. Therefore knowing the conformation of tBid on the membrane will be the first step toward understanding its crucial role in triggering apoptosis. Here, we present NMR characterization of the structure and dynamics of human tBid in 1-palmitoyl-2 hydroxy-sn-glycero-3-[phospho-RAC-(1-glycerol)] micelles. Our data showed that tBid is monomeric with six well defined alpha-helices in the micelles. Compared with the full-length Bid structure, a longer flexible loop between tBid helix alpha4 and alpha5 was observed. Helices in tBid do not pack into a compact-fold but form an extended structure with a C-shape configuration in the micelles. All six tBid helices were shown to interact with LPPG micelles, with helix alpha6 and alpha7 being more embedded. Of note, the BH3-containing helix alpha3, which was previously believed to be exposed above the membrane surface, is also membrane associated, suggesting an "on the membrane" binding mode for tBid interaction with Bax. Our data provided structural details on the membrane-associated state of tBid and the functional implications of its membrane-associated BH3 domain. PMID- 24158447 TI - Membrane Na+-pyrophosphatases can transport protons at low sodium concentrations. AB - Membrane-bound Na(+)-pyrophosphatase (Na(+)-PPase), working in parallel with the corresponding ATP-energized pumps, catalyzes active Na(+) transport in bacteria and archaea. Each ~75-kDa subunit of homodimeric Na(+)-PPase forms an unusual funnel-like structure with a catalytic site in the cytoplasmic part and a hydrophilic gated channel in the membrane. Here, we show that at subphysiological Na(+) concentrations (<5 mM), the Na(+)-PPases of Chlorobium limicola, four other bacteria, and one archaeon additionally exhibit an H(+)-pumping activity in inverted membrane vesicles prepared from recombinant Escherichia coli strains. H(+) accumulation in vesicles was measured with fluorescent pH indicators. At pH 6.2-8.2, H(+) transport activity was high at 0.1 mM Na(+) but decreased progressively with increasing Na(+) concentrations until virtually disappearing at 5 mM Na(+). In contrast, (22)Na(+) transport activity changed little over a Na(+) concentration range of 0.05-10 mM. Conservative substitutions of gate Glu(242) and nearby Ser(243) and Asn(677) residues reduced the catalytic and transport functions of the enzyme but did not affect the Na(+) dependence of H(+) transport, whereas a Lys(681) substitution abolished H(+) (but not Na(+)) transport. All four substitutions markedly decreased PPase affinity for the activating Na(+) ion. These results are interpreted in terms of a model that assumes the presence of two Na(+)-binding sites in the channel: one associated with the gate and controlling all enzyme activities and the other located at a distance and controlling only H(+) transport activity. The inherent H(+) transport activity of Na(+)-PPase provides a rationale for its easy evolution toward specific H(+) transport. PMID- 24158448 TI - A two- and five-year follow-up of clinical outcome after ACL reconstruction using BPTB or hamstring tendon grafts: a prospective intervention outcome study. AB - PURPOSE: The aim of the present study was to evaluate and compare objective and subjective outcome in patients 2 and 5 years after anterior cruciate ligament (ACL) reconstruction with either bone-patellar tendon-bone (BPTB) or hamstring grafts. The second aim was to report the prevalence of re- and contralateral ACL ruptures. METHODS: Sixty-eight patients (BPTB, n = 34 and hamstring graft, n = 34) were evaluated preoperatively, 2 and 5 years after ACL reconstruction. Anterior knee laxity and rotational knee joint stability, muscle torque, hop length, anterior knee pain, activity level and self-reported knee function and quality of life were evaluated within and between groups. The prevalence of re- and contralateral ACL ruptures was also recorded. RESULTS: No significant difference in anterior knee laxity, rotational knee joint stability, hop length anterior knee pain or knee function and quality of life were noted at the 5-year follow-up. No significant differences in concentric or eccentric quadriceps torque at 90 degrees /s and 230 degrees /s were found at any of the follow-ups between and within grafts. A significant group difference in hamstring torque 1.05 (0.02) for BPTB and 0.89 (0.02) for hamstring grafts, and in hop length (leg symmetry index) follow-up 0.94 (0.07) for BPTB compared to 0.99 (0.07) for hamstring grafts (P = 0.002) was found at the 2 year follow-up in favour of the BPTB graft, but not at the 5 year follow-up. A significant improvement over time, irrespective of graft, was found in the KOOS's subscales Sport/Rec and quality of life (P < 0.001). None of the patients, irrespective of group, returned to their pre-injury level of sport (P < 0.05). Over the five postoperative years, one man and eight women (13 %) (hamstring graft, n = 5 and BPTB graft, n = 4), sustained a total of 11 (16.2 %) new ACL ruptures: seven (10.2 %) re-ruptures and four (5.9 %) ruptures of the contralateral ACL. CONCLUSIONS: At the 5-year follow-up, there were no significant differences in terms of anterior knee laxity, rotational knee joint stability, muscle torque, anterior knee pain, hop performance, quality of life or activity level between patients who had undergone reconstruction with BPTB or hamstring grafts. None of the patients, irrespective of group, had returned to their pre-injury level of activity. Eight out of the nine patients who had sustained a second ACL rupture were women. PMID- 24158451 TI - Hypohidrosis plays a crucial role in the vicious circle of bathing suit ichthyosis: a case with summer exacerbation. PMID- 24158449 TI - Influence of intentional femoral component flexion in navigated TKA on gap balance and sagittal anatomy. AB - PURPOSE: Navigation has proven its ability to accurately restore coronal leg axis; however, for a good clinical outcome, other factors such as sagittal anatomy and balanced gaps are at least as important. In a gap-balanced technique, the size of the flexion gap is equalled to that of the extension gap. Flexion of the femoral component has been described as a theoretical possibility to balance flexion and extension gap. Aim of this study was to assess whether intentional femoral component flexion is helpful in balancing TKA gaps and in restoring sagittal anatomy. METHODS: One hundred and thirty-one patients with TKA were included in this study. Implantation was performed in a navigated, gap-balanced, tibia-first technique. The femoral component flexion needed to equal flexion to extension gap was calculated based upon the navigation data. The sagittal diameter, the anterior and posterior offset were measured pre- and postoperatively based on the lateral radiographs. Medial and lateral gaps in extension and flexion as well as flexion/extension gap differences pre- and postoperatively were analysed. Additionally range of motion (ROM) and patient satisfaction (SF 12) were obtained. RESULTS: To achieve equal flexion and extension gap, the femoral component was flexed in 120 out of 131 patients showing mean flexion of 2.9 degrees (SD 2.2 degrees ; navigation data) and 3.1 degrees (SD 2.0 degrees ; radiological analysis), respectively. Based on this technique, it was possible to balance the extension gap (<2 mm difference) in 130 out of 131 patients (99%) and the flexion gap in 119 out of 131 (91%). The difference between extension and flexion gap was reduced from 39 to 24 out of 131 patients (81%) on the medial side and from 69 to 28 on the lateral side (79%). The sagittal diameter was restored in 114 out of 131 cases (87%); however, anterior offset was significantly reduced by 1.3 mm (SD 3.9 degrees ), and posterior offset was significantly increased by 1.6 mm (SD 3.3 degrees ). No correlation between any navigation and radiological parameter was found with ROM and SF 12. CONCLUSIONS: The navigation-based, gap-balanced technique allows intentional flexion of the femoral component in order to balance gaps in more than 90% of primary TKA cases. Simultaneously, the sagittal diameter is restored in 87% of patients. However, to achieve equal gaps, the posterior offset is significantly increased by 1.6 mm and the femoral component is flexed by 3 degrees . To evaluate the effect of this technique on the clinical outcome, future studies are needed. LEVEL OF EVIDENCE: II. PMID- 24158452 TI - Outcome of conventional treatment for adult amblyopia. AB - PURPOSE: To ascertain whether conventional treatment can improve visual function in adults with amblyopia. METHODS: Sixteen patients aged 21-67 years old were instructed to wear glasses for refractive correction and to patch the non amblyopic eye for at least 1 h per day. Visual acuity, measured with crowded optotypes for distance and near acuity, was checked every 3 months, and followed for a mean (SD) of 14.1 (4.2) months. Prognostic factors related to the subsequent results, an improvement of 3 or more lines logMAR in distance visual acuity, were evaluated. RESULTS: Of 16 patients, 5 (31 %) improved 3 or more lines of distance and 5 (31 %) in near acuity. The mean improvement in distance was 2.4 lines logMAR (95 % CI 1.4-3.5) and 2.4 lines logMAR for near acuity (95 % CI 1.5-3.3). Patients aged under 45 years (p = 0.0357) and with severe amblyopia (p = 0.0337), defined as a corrected distance visual acuity of worse than -0.699 logMAR, were associated with a good response. CONCLUSIONS: Conventional treatment may improve the visual acuity of amblyopic eyes even in adult patients. PMID- 24158453 TI - High throughput and miniaturised systems for biodegradability assessments. AB - The society demands safer products with a better ecological profile. Regulatory criteria have been developed to prevent risks for human health and the environment, for example, within the framework of the European regulation REACH (Regulation (EC) No 1907, 2006). This has driven industry to consider the development of high throughput screening methodologies for assessing chemical biodegradability. These new screening methodologies must be scalable for miniaturisation, reproducible and as reliable as existing procedures for enhanced biodegradability assessment. Here, we evaluate two alternative systems that can be scaled for high throughput screening and conveniently miniaturised to limit costs in comparison with traditional testing. These systems are based on two dyes as follows: an invasive fluorescent dyes that serves as a cellular activity marker (a resazurin-like dye reagent) and a noninvasive fluorescent oxygen optosensor dye (an optical sensor). The advantages and limitations of these platforms for biodegradability assessment are presented. Our results confirm the feasibility of these systems for evaluating and screening chemicals for ready biodegradability. The optosensor is a miniaturised version of a component already used in traditional ready biodegradability testing, whereas the resazurin dye offers an interesting new screening mechanism for chemical concentrations greater than 10 mg/l that are not amenable to traditional closed bottle tests. The use of these approaches allows generalisation of high throughput screening methodologies to meet the need of developing new compounds with a favourable ecological profile and also assessment for regulatory purpose. PMID- 24158455 TI - Blood pressure levels and stroke: J-curve phenomenon? AB - The blood pressure J-curve discussion has been ongoing for more than 30 years, yet there are still questions in need of definitive answers. On one hand, existing antihypertensive therapy studies provide strong evidence for J-curve shaped relationships between both diastolic and systolic blood pressure and primary outcomes in the general hypertensive patient population, as well as in high-risk populations, including subjects with coronary artery disease, diabetes mellitus, left ventricular hypertrophy, and the elderly. On the other hand, we have very limited data on the relationship between systolic and diastolic blood pressure and stroke prevention. Moreover, it seems that this outcome is more a case of "the lower the better." Further large, well-designed studies are necessary in order to clarify this issue, especially as existing available studies are observational, and randomized trials either did not have or lost statistical power and were thus inconclusive. PMID- 24158457 TI - Linear collagen naevus: an unusual connective tissue disorder. PMID- 24158456 TI - A modeling approach for compounds affecting body composition. AB - Body composition and body mass are pivotal clinical endpoints in studies of welfare diseases. We present a combined effort of established and new mathematical models based on rigorous monitoring of energy intake (EI) and body mass in mice. Specifically, we parameterize a mechanistic turnover model based on the law of energy conservation coupled to a drug mechanism model. Key model variables are fat-free mass (FFM) and fat mass (FM), governed by EI and energy expenditure (EE). An empirical Forbes curve relating FFM to FM was derived experimentally for female C57BL/6 mice. The Forbes curve differs from a previously reported curve for male C57BL/6 mice, and we thoroughly analyse how the choice of Forbes curve impacts model predictions. The drug mechanism function acts on EI or EE, or both. Drug mechanism parameters (two to three parameters) and system parameters (up to six free parameters) could be estimated with good precision (coefficients of variation typically <20 % and not greater than 40 % in our analyses). Model simulations were done to predict the EE and FM change at different drug provocations in mice. In addition, we simulated body mass and FM changes at different drug provocations using a similar model for man. Surprisingly, model simulations indicate that an increase in EI (e.g. 10 %) was more efficient than an equal lowering of EI. Also, the relative change in body mass and FM is greater in man than in mouse at the same relative change in either EI or EE. We acknowledge that this assumes the same drug mechanism impact across the two species. A set of recommendations regarding the Forbes curve, vehicle control groups, dual action on EI and loss, and translational aspects are discussed. This quantitative approach significantly improves data interpretation, disease system understanding, safety assessment and translation across species. PMID- 24158454 TI - Blood pressure control and primary prevention of stroke: summary of the recent clinical trial data and meta-analyses. AB - Stroke is the second most common cause of death worldwide and of adult disability, but in the near future the global burden of cerebrovascular diseases will rise due to ageing and adverse lifestyle changes in populations worldwide. The risk of stroke increases at blood pressure levels above 115/75 mm Hg and high blood pressure (BP) is the most important modifiable risk factor for stroke, associated with 54 % episodes of stroke worldwide. There is strong evidence from clinical trials that antihypertensive therapy reduces substantially the risk of any type of stroke, as well as stroke-related death and disability. The risk attributed to BP is associated not only with absolute values but also with certain parameters describing BP diurnal pattern as well as short-term and long term variability. Many studies reported that certain features of BP like nocturnal hypertension, morning surge or increased variability predict an increased stroke risk. However, there is no accepted effective modality for correction of these disturbances (chronotherapy, certain classes of antihypertensive drugs). In the elderly, who are mostly affected by stroke, the primary prevention guidelines recommend treatment with diuretics and calcium channel blockers to lower blood pressure to the standard level. PMID- 24158458 TI - The supraclavicular artery island flap in head and neck reconstruction: applications and limitations. AB - IMPORTANCE: The supraclavicular artery island (SAI) rotational flap may have advantages compared with free-tissue transfer in head and neck reconstruction. Because this flap has not been extensively described for head and neck reconstruction of oncologic defects, guidelines for its indications would benefit the reconstructive surgeon. OBJECTIVE: To describe the applications and limitations of the SAI flap as an alternative to free-tissue transfer in reconstruction of head and neck defects. DESIGN, SETTING, AND PARTICIPANTS: Retrospective case series of 45 patients with defects related to malignant and nonmalignant disease undergoing reconstructive surgery from August 18, 2010, through September 28, 2012, at an academic, tertiary referral center. Each defect was deemed unsuitable for primary or local flap closure and would require regional tissue or free-tissue transfer. Mean follow-up was 10.3 (range, 1-31) months. INTERVENTION: Use of the SAI flap for reconstruction of soft-tissue defects of the head and neck. MAIN OUTCOMES AND MEASURES: Defect site, flap dimensions, time to raise the flap, and complications. RESULTS: Defects of the oral cavity, oropharynx, laryngopharynx, esophagus, trachea, temporal bone, and cervicofacial skin underwent reconstruction. Mean flap dimensions were 6.1 cm wide and 21.4 cm long, with a mean skin paddle length of 7.9 cm. Harvest time was less than 1 hour. Donor-site complications included minor dehiscence in 6 patients and prolonged wound care in 2. Partial skin flap necrosis occurred in 8 patients, whereas 2 had complete loss of the skin paddle. Seven patients developed a salivary fistula, 4 of which healed spontaneously. Flap length greater than 22 cm correlated with flap necrosis (P = .02). A history positive for smoking correlated with an increased risk of flap dehiscence (P = .02). CONCLUSIONS AND RELEVANCE: The SAI flap provides an alternative to free-tissue transfer for soft-tissue reconstruction after head and neck oncologic surgery. This flap is easy to harvest and versatile. However, the SAI flap has limitations in length and, because it is a rotational flap, is less capable of reconstructing some complex head and neck defects. PMID- 24158459 TI - Natural and anthropogenic controls on sediment composition of an arid coastal environment: Sharm Obhur, Red Sea, Saudi Arabia. AB - The present study investigated the natural and anthropogenic processes that control the composition of the bottom sediments of Sharm Obhur, Red Sea. Mineralogical analysis using XRD indicated that the sediments consist of carbonate and non-carbonate minerals. Elemental interrelationships allowed differentiating two groups of elements of different sources and origin. Elements that are in the same group are positively correlated, while they correlate negatively with elements of the other group. The first group includes silicon, Al, Fe, Mn, Mg, vanadium (V), chromium (Cr), Co, Ni, Cu, and Zn, whereas the other group includes Ca, Sr, and CaCO3. The highest concentration levels of the first group and the highest content of non-carbonate minerals were obtained from the sediments near the head of the sharm (zone A), whereas the sediments near the mouth of the sharm (zone B) yielded high concentrations of second group and carbonate minerals. Metal enrichment and contamination factors and pollution load index were calculated. The values of these indices differentiate two groups of metals: lithogenic and non-lithogenic. Except for lead (Pb) at one sampling site, metals in zone A sediments are of lithogenic source, supplied to the sharm either naturally by aeolian transportation and through Wadi Al-Kuraa'a during rare but major floods or by human activities such as dumping and shore protection. Non lithogenic Cr, Pb, V, and Mn were documented from some sampling sites in zone B, and their occurrences are related to waste disposal and fossil fuel combustion. PMID- 24158460 TI - The impact of meal composition on the release of fatty acids from salmon during in vitro gastrointestinal digestion. AB - We hypothesize that the rate of release of lipids from salmon muscle during in vitro digestion is altered by additional meal components. In vitro digestion of salmon was performed using a mixture of porcine gastrointestinal enzymes and bile salts. Broccoli and barley were also added to the digestion simulating a meal. The extent of lipolysis was determined by measuring the release of fatty acids (FAs) during sampling at the simulated gastric phase endpoint (60 minutes) and 20, 40, 60, 80, 110 and 140 minutes simulated small intestinal phase, using solid phase extraction and GC-FID. Adding barley resulted in a lower overall release of FA from salmon, whereas broccoli caused an initial delay followed by increased release from 80-140 min when lipid digestion of salmon alone plateaued. The impact of broccoli and barley on the release of peptides and digesta viscosity were also measured. The effect of different components in the meal shown by this in vitro study suggests that it would be possible to make dietary changes affecting the lipolysis, further triggering specific responses in the gastrointestinal tract. However, these observations need to be validated in vivo, and the mechanisms need to be further examined. PMID- 24158461 TI - Ottowia shaoguanensis sp. nov., isolated from coking wastewater. AB - A Gram-negative, short rod-shaped, floc-forming bacterial strain J5-66(T) without any flagellum was isolated from coking wastewater collected from Shaoguan, Guangdong, China. It was capable of optimal growth at pH 7, 30 degrees C, and 1 2 % (w/v) NaCl. Phylogenetic analysis based on 16S rRNA gene sequences showed that this strain belonged to the genus Ottowia in Comamonadaceae, and the highest 16S rRNA gene sequence similarity was 96.2 % with Ottowia pentelensis DSM 21699(T). The major cellular fatty acids of strain J5-66(T) were C16:1omega7c/C16:1 omega6c (45.0 %), C16:0 (21.1 %), C18:1 omega7c or/and C18:1 omega6c (19.2 %). The polar lipids were phosphatidylethanolamine, phosphatidylglycerol, phosphatidylmonomethylethanolamine, glycolipid and two unidentified phospholipids (PL1 and PL2). The predominant ubiquinone was Q-8, and the G+C content of the genome DNA was 64.4 mol%. On the basis of genetic, phenotypic and chemotaxonomic analyses, strain J5-66(T) represents a novel species of the genus Ottowia for which the name Ottowia shaoguanensis sp. nov. is proposed. The type strain is J5-66(T) (=CGMCC 1.12431(T) =LMG 27408(T)). PMID- 24158462 TI - Anticholinergic medication use for female overactive bladder in the ambulatory setting in the United States. AB - INTRODUCTION AND HYPOTHESIS: Our objective was to estimate the prevalence and sociodemographic factors associated with anticholinergic medication use by adult women for overactive bladder (OAB) in the United States. METHODS: We conducted a cross-sectional study using the 2009 National Ambulatory Medical Care Survey database (NAMCS). We included women aged 18 years and older and identified visits for which anticholinergic medications for OAB were in active use. We evaluated the prevalence of medications used and estimated the use of short-acting versus long-acting drugs. We also assessed variables associated with anticholinergic use, (age, race/ethnicity, insurance, geographic location) using survey weights in the analysis to estimate national data. RESULTS: In 2009, adult women made 516.8 million outpatient office visits. Of these, 8.1 million (1.6 %) were associated with an OAB anticholinergic medication (annual rate 68 per 1,000 women). Women who used anticholinergics were predominantly insured by Medicare (61.0 %) and were older than those not using anticholinergic medications (70.0 +/ 1.1 vs. 53.0 +/- 0.5, p < 0.001). No racial or ethnic differences were evident between the two groups. Tolterodine (33.8 %) and oxybutynin (33.1 %) were the most commonly reported medications, followed by solifenacin (19.5 %), darifenacin (9.3 %), and trospium (4.4 %). Long-acting anticholinergics were used more often than short-acting medications (53.8 % vs. 46.3 %, respectively, p < 0.001). CONCLUSIONS: Annually, more than 8 million outpatient visits occur in which adult women in the United States are using an OAB anticholinergic medication. Despite the abundance of newer-generation medications, tolterodine and oxybutynin remain the most commonly prescribed anticholinergic drugs for OAB. Solifenacin is the most popular newer-generation anticholinergic drug. PMID- 24158463 TI - Voltage-controlled enzyme-catalyzed glucose-gluconolactone conversion using a field-effect enzymatic detector. AB - The field-effect enzymatic detection (FEED) technique was used to control the kinetics of the enzymatic conversion of glucose to gluconolactone. The glucose gluconolactone conversion occurring at an enzyme-immobilized electrode, a well studied process, was confirmed using mass spectrometry. Electrochemical studies showed that the glucose oxidation current depends on the gating voltage VG and the ion concentration of the sample solution. Additionally, the depletion of glucose in the sample also showed a dependence on VG. FEED was used to detect H2O2 on the zepto-molar level in order to show the ultrasensitive detection capability of the technique. These results, while providing evidence for the proposed mechanism of FEED, indicate that VG controls the conversion process. The effect of VG on the glucose-gluconolactone conversion was demonstrated by the observed VG-dependent kinetic parameters of the conversion process. PMID- 24158464 TI - Clinician Documentation on Receipt of Trauma-Focused Evidence-Based Psychotherapies in a VA PTSD Clinic. AB - The U.S. Department of Veterans Affairs (VA) is implementing two trauma-focused, evidence-based psychotherapies (TF-EBPs) for posttraumatic stress disorder (PTSD): cognitive processing therapy and prolonged exposure therapy (PE). Veterans with PTSD often do not receive these treatments, and little is known about the reasons veterans may not receive TF-EBPs. The aim of this qualitative study was to summarize clinician-reported reasons in medical records for nonreceipt of TF-EBPs. All veterans (N = 63) identified through PTSD screening who were newly engaged in mental health care and received individual evaluations in a PTSD specialty clinic in fiscal year 2008 were included in the sample. Content analysis of electronic medical records revealed multiple potential reasons for nonreceipt of TF-EBPs including referral to other PTSD treatments, other clinical priorities, poor engagement in care, practical barriers, negative beliefs, and receipt of care in other settings. Eight veterans (13%) initiated TF EBPs. Further interventions to promote engagement in PTSD treatment are warranted. PMID- 24158465 TI - Nutrient availability affects the response of the calcifying chlorophyte Halimeda opuntia (L.) J.V. Lamouroux to low pH. AB - Atmospheric carbon dioxide emissions cause a decrease in the pH and aragonite saturation state of surface ocean water. As a result, calcifying organisms are expected to suffer under future ocean conditions, but their physiological responses may depend on their nutrient status. Because many coral reefs experience high inorganic nutrient loads or seasonal changes in nutrient availability, reef organisms in localized areas will have to cope with elevated carbon dioxide and changes in inorganic nutrients. Halimeda opuntia is a dominant calcifying primary producer on coral reefs that contributes to coral reef accretion. Therefore, we investigated the carbon and nutrient balance of H. opuntia exposed to elevated carbon dioxide and inorganic nutrients. We measured tissue nitrogen, phosphorus and carbon content as well as the activity of enzymes involved in inorganic carbon uptake and nitrogen assimilation (external carbonic anhydrase and nitrate reductase, respectively). Inorganic carbon content was lower in algae exposed to high CO2, but calcification rates were not significantly affected by CO2 or inorganic nutrients. Organic carbon was positively correlated to external carbonic anhydrase activity, while inorganic carbon showed the opposite correlation. Carbon dioxide had a significant effect on tissue nitrogen and organic carbon content, while inorganic nutrients affected tissue phosphorus and N:P ratios. Nitrate reductase activity was highest in algae grown under elevated CO2 and inorganic nutrient conditions and lowest when phosphate was limiting. In general, we found that enzymatic responses were strongly influenced by nutrient availability, indicating its important role in dictating the local responses of the calcifying primary producer H. opuntia to ocean acidification. PMID- 24158466 TI - A green mesostructured vanadosilicate catalyst and its unprecedented catalytic activity for the selective synthesis of 2,6-disubstituted p-benzoquinones. AB - We have developed a green method for the production of 2,6-disubstituted p benzoquinones (DSBQs) by liquid-phase oxidations of di/tri-substituted phenols using two-dimensional hexagonally thick-walled mesoporous vanadosilicate catalysts. In particular, 2,6-di-tert-butyl-p-benzoquinone was synthesized by the oxidation of 2,6-di-tert-butylphenol, using various reaction parameters, over mesoporous VSBA-15 catalysts synthesized with various vanadium contents. A promising chemical treatment method for the preparation of green mesoporous VSBA 15(5) or W-VSBA-15(5) (W: washed) catalysts was successfully used in the presence of ammonium acetate solution to remove moderately toxic non-framework V2O5 crystallite species from the active surface, and the catalytic activity of the recovered green mesoporous VSBA-15(5) catalyst was determined. To confirm the green aspects, recyclability and hot-catalytic filtration experiments were performed. The combined results show that the green mesoporous VSBA-15(5) is a highly active, recyclable, and promising heterogeneous catalyst for the selective synthesis of DSBQs (98-100%), and has unprecedented catalytic activity compared with other mesoporous vanadosilicate catalysts. PMID- 24158467 TI - Repeat cytoreductive surgery and heated intraperitoneal chemotherapy may offer survival benefit for intraperitoneal mesothelioma: a single institution experience. AB - INTRODUCTION: Cytoreduction with heated intraperitoneal chemotherapy (HIPEC) has demonstrated improved overall survival (OS) in malignant peritoneal mesothelioma (MPM). The role of repeated HIPEC for MPM is less clear. METHODS: An institutional review board-approved database of MPM patients was analyzed for clinical factors and outcomes. RESULTS: From June 2004 to March 2012, 29 patients underwent surgical treatment for mesothelioma. HIPEC was aborted in 3 and completed in 26; 8 underwent additional repeat HIPEC. The majority was male (62 %), median age 66 years. There was no significant difference in surgery duration, blood loss, or hospital-stay-duration between initial and repeat HIPEC. Cisplatin was the chemotherapy used. Complications occurred in 17 (65 %) initial and 6 (50 %) repeat HIPEC, with wound complications being most common. Reoperation was less common (4 % initial and 25 % repeat), and perioperative death was rare (4 % initial, 0 % repeat). Fourteen (54 %) initial and seven (58 %) repeat HIPEC patients received adjuvant chemotherapy. Median time from HIPEC to initiation of chemotherapy was not different between initial and repeat HIPEC (8.8 and 4.6 months, respectively, p = 0.68). Median treatment-free time (time from initial to repeat HIPEC or chemotherapy) also was not different between initial and repeat HIPEC (8.8 and 6.3 months, respectively, p = 0.92). Median OS for the cohort was 41.2 months. Patients who underwent repeat HIPEC had improved median OS (80 months) versus single HIPEC (27.2 months; p = 0.007). A lower peritoneal carcinoma index and complete cytoreduction were associated positively with OS. CONCLUSIONS: Cytoreduction and HIPEC for MPM are associated with longer OS. Patients who are candidates for repeat HIPEC may derive an even greater OS advantage. PMID- 24158468 TI - Electromagnetic thermotherapy system with needle arrays: a practical tool for the removal of cancerous tumors. AB - Thermotherapy has been a promising method to treat tumor. In recent years, electromagnetic thermotherapy (EMT) has been extensively investigated and holds the potential for a variety of medical applications including for cancer treatment when combined with minimally invasive surgery approach. In this study, an alternating electromagnetic frequency was provided by an EMT system to heat up stainless steel needle arrays which were inserted into the target tumor to a high temperature, therefore leading to local ablation of the tumor. A new two-section needle-array apparatus was further demonstrated to encompass the tumor to prevent the tumor cells to spread after the treatment process. By using the needle-array insertion apparatus, there is no limitation of the treatment area; this method could, therefore, be applied for tumors that are larger than 6 cm. It was first successfully demonstrated in the in vitro experiments on porcine livers. Then an in vivo experiment was directly conducted on pigs. The two-section needle array incorporated with the needle-array apparatus and EMT was demonstrated to be promising for no-touch isolation treatment of cancerous tumors. PMID- 24158469 TI - Tumor localization using magnetic nanoparticle-induced acoustic signals. AB - Cancer is a major public health problem worldwide, especially in developed countries. Early detection of cancer can greatly increase both survival rates and quality of life for patients. A magnetoacoustic-based method had been previously proposed for early tumor detection, in a minimal invasive procedure, using magnetic nanoparticles (MNPs). This paper presents a supporting localization algorithm that can provide the clinician with essential tumor location data and could enable a sequential biopsy. It provides localization algorithm development, as well as its validation in both computerized simulations and in vitro experiments. Three-dimensional (3-D) tumor localization is demonstrated with an error of 2.14 mm and an overlapping volume of 84% of the actual tumor. The obtained results are promising and prove the feasibility of tumor localization using a time difference of arrival algorithm along with a magnetoacoustic detection scheme. PMID- 24158470 TI - Attenuation of systolic blood pressure and pulse transit time hysteresis during exercise and recovery in cardiovascular patients. AB - Pulse transit time (PTT) is a cardiovascular parameter of emerging interest due to its potential to estimate blood pressure (BP) continuously and without a cuff. Both linear and nonlinear equations have been used in the estimation of BP based on PTT. This study, however, demonstrates that there is a hysteresis phenomenon between BP and PTT during and after dynamic exercise. A total of 46 subjects including 16 healthy subjects, 13 subjects with one or more cardiovascular risk factors, and 17 patients with cardiovascular disease underwent graded exercise stress test. PTT was measured from electrocardiogram and photoplethysmogram of the left index finger of the subject, i.e., a pathway that includes predominately aorta, brachial, and radial arteries. The results of this study showed that, for the same systolic BP (SBP), PTT measured during exercise was significantly larger than PTT measured during recovery for all subject groups. This hysteresis was further quantified as both normalized area bounded by the SBP-PTT relationship (AreaN) and SBP difference at PTT during peak exercise plus 20 ms (DeltaSBP20). Significant attenuation of both AreaN (p <; 0.05) and DeltaSBP20 (p <; 0.01) is observed in cardiovascular patients compared with healthy subjects, independent of resting BP. Since the SBP-PTT relationship are determined by the mechanical properties of arterial wall, which is predominately mediated by the sympathetic nervous system through altered vascular smooth muscle (VSM) tone during exercise, results of this study are consistent with the previous findings of autonomic nervous dysfunction in cardiovascular patients. We further conclude that VSM tone has a nonnegligible influence on the BP-PTT relationship and thus should be considered in the PTT-based BP estimation. PMID- 24158471 TI - Report from the inaugural Australian pruritus symposium, Sydney, Australia, August 10, 2013. PMID- 24158472 TI - A fluorescent probe for the biological signaling molecule H2S based on a specific H2S trap group. AB - A fluorescent turn-on probe for H2S was exploited based on a H2S-induced substitution-cyclization cascade reaction towards the bis-electrophilic centers of a new H2S trap group 2-(iodomethyl)benzoate. PMID- 24158474 TI - Real-time scalable depth sensing with hybrid structured light illumination. AB - Time multiplexing (TM) and spatial neighborhood (SN) are two mainstream structured light techniques widely used for depth sensing. The former is well known for its high accuracy and the latter for its low delay. In this paper, we explore a new paradigm of scalable depth sensing to integrate the advantages of both the TM and SN methods. Our contribution is twofold. First, we design a set of hybrid structured light patterns composed of phase-shifted fringe and pseudo random speckle. Under the illumination of the hybrid patterns, depth can be decently reconstructed either from a few consecutive frames with the TM principle for static scenes or from a single frame with the SN principle for dynamic scenes. Second, we propose a scene-adaptive depth sensing framework based on which a global or region-wise optimal depth map can be generated through motion detection. To validate the proposed scalable paradigm, we develop a real-time (20 fps) depth sensing system. Experimental results demonstrate that our method achieves an efficient balance between accuracy and speed during depth sensing that has rarely been exploited before. PMID- 24158473 TI - Severe hypocalcemia after denosumab in a patient with acquired Fanconi syndrome. AB - We report the case of a 48-year-old man with acquired Fanconi syndrome due to IgG kappa monoclonal gammopathy, who received a single dose of denosumab 60 mg for secondary prevention of skeletal fractures, in conjunction with oral calcium and vitamin D supplementation. The treatment was complicated with a severe, symptomatic hypocalcemia occurring 1 month after the injection and necessitating 4 weeks of intravenous calcium gluconate therapy. Similarly to bisphosphonates, inhibitors of the receptor activator of nuclear factor kappa-B ligand may not be appropriate for the treatment of acquired Fanconi syndrome and other forms of osteomalacia regardless of the degree of renal insufficiency and vitamin D levels. Clinicians should carefully interpret the radiographic and bone densitometry results in light of diverse mechanisms of bone demineralization and potential dependence of calcium homeostasis on high bone turnover. PMID- 24158475 TI - Integrated segmentation and interpolation of sparse data. AB - We address the two inherently related problems of segmentation and interpolation of 3D and 4D sparse data and propose a new method to integrate these stages in a level set framework. The interpolation process uses segmentation information rather than pixel intensities for increased robustness and accuracy. The method supports any spatial configurations of sets of 2D slices having arbitrary positions and orientations. We achieve this by introducing a new level set scheme based on the interpolation of the level set function by radial basis functions. The proposed method is validated quantitatively and/or subjectively on artificial data and MRI and CT scans and is compared against the traditional sequential approach, which interpolates the images first, using a state-of-the-art image interpolation method, and then segments the interpolated volume in 3D or 4D. In our experiments, the proposed framework yielded similar segmentation results to the sequential approach but provided a more robust and accurate interpolation. In particular, the interpolation was more satisfactory in cases of large gaps, due to the method taking into account the global shape of the object, and it recovered better topologies at the extremities of the shapes where the objects disappear from the image slices. As a result, the complete integrated framework provided more satisfactory shape reconstructions than the sequential approach. PMID- 24158476 TI - Linear time distances between fuzzy sets with applications to pattern matching and classification. AB - We present four novel point-to-set distances defined for fuzzy or gray-level image data, two based on integration over alpha-cuts and two based on the fuzzy distance transform. We explore their theoretical properties. Inserting the proposed point-to-set distances in existing definitions of set-to-set distances, among which are the Hausdorff distance and the sum of minimal distances, we define a number of distances between fuzzy sets. These set distances are directly applicable for comparing gray-level images or fuzzy segmented objects, but also for detecting patterns and matching parts of images. The distance measures integrate shape and intensity/membership of observed entities, providing a highly applicable tool for image processing and analysis. Performance evaluation of derived set distances in real image processing tasks is conducted and presented. It is shown that the considered distances have a number of appealing theoretical properties and exhibit very good performance in template matching and object classification for fuzzy segmented images as well as when applied directly on gray-level intensity images. Examples include recognition of hand written digits and identification of virus particles. The proposed set distances perform excellently on the MNIST digit classification task, achieving the best reported error rate for classification using only rigid body transformations and a kNN classifier. PMID- 24158477 TI - Spatial statistics of image features for performance comparison. AB - When matching images for applications such as mosaicking and homography estimation, the distribution of features across the overlap region affects the accuracy of the result. This paper uses the spatial statistics of these features, measured by Ripley's K-function, to assess whether feature matches are clustered together or spread around the overlap region. A comparison of the performances of a dozen state-of-the-art feature detectors is then carried out using analysis of variance and a large image database. Results show that SFOP introduces significantly less aggregation than the other detectors tested. When the detectors are rank-ordered by this performance measure, the order is broadly similar to those obtained by other means, suggesting that the ordering reflects genuine performance differences. Experiments on stitching images into mosaics confirm that better coverage values yield better quality outputs. PMID- 24158478 TI - Atomic-level functional model of dengue virus Envelope protein infectivity. AB - A number of structures have been solved for the Envelope (E) protein from dengue virus and closely related flaviviruses, providing detailed pictures of the conformational states of the protein at different stages of infectivity. However, the key functional residues responsible for mediating the dynamic changes between these structures remain largely unknown. Using a comprehensive library of functional point mutations covering all 390 residues of the dengue virus E protein ectodomain, we identified residues that are critical for virus infectivity, but that do not affect E protein expression, folding, virion assembly, or budding. The locations and atomic interactions of these critical residues within different structures representing distinct fusogenic conformations help to explain how E protein (i) regulates fusion-loop exposure by shielding, tethering, and triggering its release; (ii) enables hinge movements between E domain interfaces during triggered structural transformations; and (iii) drives membrane fusion through late-stage zipper contacts with stem. These results provide structural targets for drug and vaccine development and integrate the findings from structural studies and isolated mutagenesis efforts into a cohesive model that explains how specific residues in this class II viral fusion protein enable virus infectivity. PMID- 24158480 TI - Balancing the developmental niches within the lung. PMID- 24158479 TI - MicroRNA 4423 is a primate-specific regulator of airway epithelial cell differentiation and lung carcinogenesis. AB - Smoking is a significant risk factor for lung cancer, the leading cause of cancer related deaths worldwide. Although microRNAs are regulators of many airway gene expression changes induced by smoking, their role in modulating changes associated with lung cancer in these cells remains unknown. Here, we use next generation sequencing of small RNAs in the airway to identify microRNA 4423 (miR 4423) as a primate-specific microRNA associated with lung cancer and expressed primarily in mucociliary epithelium. The endogenous expression of miR-4423 increases as bronchial epithelial cells undergo differentiation into mucociliary epithelium in vitro, and its overexpression during this process causes an increase in the number of ciliated cells. Furthermore, expression of miR-4423 is reduced in most lung tumors and in cytologically normal epithelium of the mainstem bronchus of smokers with lung cancer. In addition, ectopic expression of miR-4423 in a subset of lung cancer cell lines reduces their anchorage independent growth and significantly decreases the size of the tumors formed in a mouse xenograft model. Consistent with these phenotypes, overexpression of miR 4423 induces a differentiated-like pattern of airway epithelium gene expression and reverses the expression of many genes that are altered in lung cancer. Together, our results indicate that miR-4423 is a regulator of airway epithelium differentiation and that the abrogation of its function contributes to lung carcinogenesis. PMID- 24158482 TI - Profile of Thomas Sudhof, James Rothman, And Randy Schekman, 2013 Nobel Laureates in Physiology or Medicine. PMID- 24158481 TI - Single-molecule superresolution imaging allows quantitative analysis of RAF multimer formation and signaling. AB - The RAF serine/threonine kinases regulate cell growth through the MAPK pathway, and are targeted by small-molecule RAF inhibitors (RAFis) in human cancer. It is now apparent that protein multimers play an important role in RAF activation and tumor response to RAFis. However, the exact stoichiometry and cellular location of these multimers remain unclear because of the lack of technologies to visualize them. In the present work, we demonstrate that photoactivated localization microscopy (PALM), in combination with quantitative spatial analysis, provides sufficient resolution to directly visualize protein multimers in cells. Quantitative PALM imaging showed that CRAF exists predominantly as cytoplasmic monomers under resting conditions but forms dimers as well as trimers and tetramers at the cell membrane in the presence of active RAS. In contrast, N terminal truncated CRAF (CatC) lacking autoinhibitory domains forms constitutive dimers and occasional tetramers in the cytoplasm, whereas a CatC mutant with a disrupted CRAF-CRAF dimer interface does not. Finally, artificially forcing CRAF to the membrane by fusion to a RAS CAAX motif induces multimer formation but activates RAF/MAPK only if the dimer interface is intact. Together, these quantitative results directly confirm the existence of RAF dimers and potentially higher-order multimers and their involvement in cell signaling, and showed that RAF multimer formation can result from multiple mechanisms and is a critical but not sufficient step for RAF activation. PMID- 24158483 TI - Pheromone discrimination by a pH-tuned polymorphism of the Bombyx mori pheromone binding protein. AB - The Bombyx mori pheromone-binding protein (BmorPBP) is known to adopt two different conformations. These are BmorPBP(A), where a regular helix formed by the C-terminal dodecapeptide segment, alpha7, occupies the ligand-binding cavity, and BmorPBP(B), where the binding site is free to accept ligands. NMR spectra of delipidated BmorPBP solutions at the physiological pH of the bulk sensillum lymph near pH 6.5 show only BmorPBP(A), and in mixtures, the two species are in slow exchange on the chemical shift frequency scale. This equilibrium has been monitored at variable pH and ligand concentrations, demonstrating that it is an intrinsic property of BmorPBP that is strongly affected by pH variation and ligand binding. This polymorphism tunes BmorPBP for optimal selective pheromone transport: Competition between alpha7 and lipophilic ligands for its binding cavity enables selective uptake of bombykol at the pore endings in the sensillum wall, whereas compounds with lower binding affinity can only be bound in the bulk sensillum lymph. After transport across the bulk sensillum lymph into the lower pH area near the dendritic membrane surface, bombykol is ejected near the receptor, whereas compounds with lower binding affinity are ejected before reaching the olfactory receptor, rendering them susceptible to degradation by enzymes present in the sensillum lymph. PMID- 24158484 TI - How optimal foragers should respond to habitat changes: a reanalysis of the Marginal Value Theorem. AB - The Marginal Value Theorem (MVT) is a cornerstone of biological theory. It connects the quality and distribution of patches in a fragmented habitat to the optimal time an individual should spend exploiting them, and thus its optimal rate of movement. However, predictions regarding how habitat alterations should impact optimal strategies have remained elusive, with heavy reliance on graphical arguments. Here we derive the sensitivity of realized fitness and optimal residence times to general habitat attributes, for homogeneous and heterogeneous habitats, retaining the level of generality of the MVT. We provide new predictions on how altering travel times, patch qualities and/or relative abundances should affect optimal strategies, and study the consequences of habitat heterogeneity. We show that knowledge of average characteristics is in general not sufficient to predict the change in the average rate of movement. We apply our results to examine the conditions under which the optimal strategies are invariant to scaling. We prove a previously conjectured form of invariance in homogeneous habitats, but show that invariances to scaling are not generic in heterogeneous habitats. We also consider the relative exploitation of patches that differ in quality, clarifying the conditions under which it is adaptive to stay longer on poorer patches. PMID- 24158485 TI - At home and away: gay men and high risk sexual practices. AB - We aimed to describe HIV risk practices of gay men who travel locally, regionally and overseas. We analysed data from the Sydney Gay Community Periodic Survey 2009 about high-risk sexual practices in four locations (locally, while travelling in NSW, Australia and overseas) and with partners of HIV positive, negative and unknown serostatus in each location. Analyses of associations used generalized log-binomial estimation procedures with Type I error of 5 %. Of 1,839 sexually active participants, 70.1 % reported having sex locally. 19.7 % elsewhere in NSW, 20.1 % interstate and 18 % overseas. Unprotected anal intercourse (UAI) was reported by 29.9, 28.6, 21.3 and 19.3 % of men in each location respectively. There was no difference in the levels of UAI locally and elsewhere in NSW, but UAI levels were lower in other Australian locations [adjusted prevalence rate ratio (APRR) = 0.76; 95 % confidence interval (95 % CI) 0.66-0.88] and overseas (APRR = 0.76; 95 % CI 0.65-0.89). UAI was more likely if partners were seroconcordant HIV positive (APRR = 1.67; 95 % CI 1.32-2.11) and less likely if partners were of different HIV serostatus (APRR = 0.39; 95 % CI 0.33-0.47) as compared to seroconcordant HIV negative partners. UAI was associated with group sex and use of party drugs. In this community sample, UAI levels were higher in the local context than in travel destinations, suggesting that familiarity between partners may play a role. High-risk sexual practices can nevertheless contribute to bridging different HIV epidemics and HIV transmission across borders. HIV prevention programs should develop effective approaches to target sexually adventurous gay men and HIV transmission associated with travel. PMID- 24158486 TI - HIV transmission risk behavior among HIV-positive patients receiving antiretroviral therapy in KwaZulu-Natal, South Africa. AB - The aim of this investigation was to identify factors associated with HIV transmission risk behavior among HIV-positive women and men receiving antiretroviral therapy (ART) in KwaZulu-Natal, South Africa. Across 16 clinics, 1,890 HIV+ patients on ART completed a risk-focused audio computer-assisted self interview upon enrolling in a prevention-with-positives intervention trial. Results demonstrated that 62 % of HIV-positive patients' recent unprotected sexual acts involved HIV-negative or HIV status unknown partners. For HIV positive women, multivariable correlates of unprotected sex with HIV-negative or HIV status unknown partners were indicative of poor HIV prevention-related information and of sexual partnership-associated behavioral skills barriers. For HIV-positive men, multivariable correlates represented motivational barriers, characterized by negative condom attitudes and the experience of depressive symptomatology, as well as possible underlying information deficits. Findings suggest that interventions addressing gender-specific and culturally-relevant information, motivation, and behavioral skills barriers could help reduce HIV transmission risk behavior among HIV-positive South Africans. PMID- 24158487 TI - Vicious circle of perceived stigma, enacted stigma and depressive symptoms among children affected by HIV/AIDS in China. AB - Previous research has found a deleterious impact of stigma on the mental health of children affected by HIV/AIDS. Little is known about the longitudinal relationship of stigma and children's mental health. This study explores the longitudinal reciprocal effects of depressive symptoms and stigma, specifically enacted stigma and perceived stigma, among children affected by HIV/AIDS aged 6 12. Longitudinal data were collected from 272 children orphaned by AIDS and 249 children of HIV-positive parents in rural China. Cross-lagged panel analysis was conducted in the study. Results showed that the autoregressive effects were stable for depressive symptoms, perceived stigma and enacted stigma suggesting the substantially stable individual differences over time. The cross-lagged effects indicated a vicious circle among the three variables in an order of enacted stigma -> depressive symptom -> perceived stigma -> enacted stigma. The possibility of employing equal constraints on cross-lagged paths suggested that the cross-lagged effects were repeatable over time. The dynamic interplay of enacted stigma, perceived stigma and depressive symptoms suggests the need of a multilevel intervention in stigma reduction programming to promote mental health of children affected by HIV/AIDS. PMID- 24158488 TI - Effects of partnership change on microbicide gel adherence in a clinical trial (HPTN 035). AB - Use of HIV prevention methods may vary for women by types of sexual partners. In a microbicide safety and effectiveness trial (HPTN 035) differences in adherence to a microbicide study gel were compared between women with new versus ongoing partnerships over time. 1,757 women in the three HPTN 035 trial's arms completed the Follow-up Partner Status (FPS) questionnaire at their last study visit. Women married at baseline were asked if they had the same husband, new husband or new partner. Unmarried women were asked if they had changed partners or married. Self reported gel adherence during the last sex act was compared at each quarterly visit between women with ongoing versus new partners. High gel adherence was compared with low gel adherence (85-100 vs. <85 % of last vaginal sex acts reported with gel use, respectively) in multivariable models to assess associations with partner change. Overall 7 % of women (n = 123) reported a new partner and 41 % (51) of those reported a new husband. Median gel adherence was reported to be 100 % in women with ongoing partners and 75 % for women with new partners (p < 0.001). In women reporting no gel use in their last sex act, only 12.5 % of the women with a new partner and none of those with an ongoing partner reported using condoms (p < 0.001). Fewer women with new partners reported using both the gel and condom during the last sex act as compared to women with ongoing partners (median 50 vs. 71.4 %, p < 0.001). After adjusting for age, site, education level, and sexual frequency, women with ongoing partners were more likely to report high gel adherence than those with new partners (AOR 2.5, 95 % CI 1.6, 3.9). This pattern persisted when gel use over time was compared between women with new versus ongoing partners. In the HPTN 035 trial, women with new partners had higher HIV incidence and reported less gel use and higher condom use. Specific counseling and support are needed to help women use potential HIV prevention methods, including microbicides, when they are changing partners. PMID- 24158489 TI - Synergy of ferrous ion on 5-aminolevulinic acid-mediated growth inhibition of Plasmodium falciparum. AB - Haem biosynthesis appeared to be a target of malaria therapy because 5 aminolevulinic acid (ALA), a haem biosynthesis starting material, with light exposure or a high amount of ALA alone reduced Plasmodium falciparum growth to undetectable level. However, the administration of a high dose of ALA is unrealistic for clinical therapy. We found that Fe(2+) enhanced P. falciparum killing potency of ALA and significantly inhibited the parasite growth. The intermediates of haem biosynthesis localized to the parasite organelles, and coproporphyrin III was the most accumulated intermediate. These novel findings may lead to development of a new anti-malarial drug using ALA and Fe(2+). PMID- 24158491 TI - Accurate and Reliable Gait Cycle Detection in Parkinson's Disease. AB - There is a growing interest in the use of Inertial Measurement Unit (IMU)-based systems that employ gyroscopes for gait analysis. We describe an improved IMU based gait analysis processing method that uses gyroscope angular rate reversal to identify the start of each gait cycle during walking. In validation tests with six subjects with Parkinson disease (PD), including those with severe shuffling gait patterns, and seven controls, the probability of True-Positive event detection and False-Positive event detection was 100% and 0%, respectively. Stride time validation tests using high-speed cameras yielded a standard deviation of 6.6 ms for controls and 11.8 ms for those with PD. These data demonstrate that the use of our angular rate reversal algorithm leads to improvements over previous gyroscope-based gait analysis systems. Highly accurate and reliable stride time measurements enabled us to detect subtle changes in stride time variability following a Parkinson's exercise class. We found unacceptable measurement accuracy for stride length when using the Aminian et al gyro-based biomechanical algorithm, with errors as high as 30% in PD subjects. An alternative method, using synchronized infrared timing gates to measure velocity, combined with accurate mean stride time from our angular rate reversal algorithm, more accurately calculates mean stride length. PMID- 24158492 TI - Ground state spectroscopy of hydroxyquinolines: evidence for the formation of protonated species in water-rich dioxane-water mixtures. AB - We have recently used 6-, 7-, and 8-hydroxyquinolines (HQs) as fluorescent probes to study the binding mechanism in one of the drug binding sites of human serum albumin. In the present work we study the absorption spectra of the HQ molecules in neat and binary mixtures of dioxane and water in order to identify the different tautomeric species in the ground state. This study should help in identifying the environment in nanocavities of macromolecules when HQs are used as local reporters. The enol form is shown to be the only tautomer for the three HQs in dioxane and water, with the exception of 7HQ in which both the enol and the zwitterion tautomers exist in equilibrium in water. The results are confirmed by the density functional theory (DFT) calculations using the B3LYP method with a 6-311++G(2d,p) basis set. In water-rich dioxane mixtures, all HQs are protonated. The results were confirmed by comparing the absorption spectra in binary solvents with those in acidic and basic aqueous solutions, and by DFT calculations of the Franck-Condon S1 <- S0 transitions. The number of water molecules solvating the polar sites in each HQ molecule was estimated from the spectral change in the binary solvent mixtures, and structures were calculated by DFT. Mapping the water density around the polar sites in each HQ using molecular dynamics (MD) simulations shows well-defined hydrogen bonds around the N-heteroatom in each HQ molecule. Water density is only well-defined around the hydroxyl group in 8HQ. The MD simulations indicate free rotation of the OH group in 6HQ and 7HQ, and the stability of the cis-isomer in 8HQ. The results point to the unique spectral signatures of 7HQ in water which make this molecule a potential probe to detect the presence of water in nanocavities of macromolecules, and to the ability of the three HQs to detect acidic media in binding sites. PMID- 24158493 TI - Intranasal topical local anesthetic and decongestant for flexible nasendoscopy in children: a randomized, double-blind, placebo-controlled trial. AB - IMPORTANCE: To our knowledge, the present study is the first double-blind, randomized, placebo-controlled trial in children to compare nasal preparation sprays administered before flexible nasendoscopy with placebo. OBJECTIVE: To compare the degree of pain experienced by children undergoing flexible nasendoscopy after 1 of 3 intranasal sprays: placebo, decongestant with topical local anesthetic (TLA), or decongestant without TLA. DESIGN, SETTING, AND PARTICIPANTS: A randomized placebo-controlled trial with blinding of participants, caregivers, observers, and otolaryngologists was conducted in a tertiary pediatric otolaryngology ambulatory clinic. Participants included a consecutive sample of children aged 3 to 12 years requiring flexible nasendoscopy. Exclusion criteria included concomitant respiratory tract infection, known allergy to a trial agent, or previous flexible nasendoscopy. One hundred fifty-one children were assessed for eligibility; 24 eligible children refused participation and 69 were included and block-randomized. All completed the study, and there were no adverse events. INTERVENTIONS: Nasal spray administration of placebo (normal saline); xylometazoline hydrochloride, 0.05% (decongestant); or lidocaine hydrochloride, 1%, with xylometazoline hydrochloride, 0.05% (TLA with decongestant) was performed 10 minutes before flexible nasendoscopy. MAIN OUTCOMES AND MEASURES: Primary outcome measure was the child-reported Wong-Baker Faces Pain (WBFP) scale. Secondary outcomes included the caregiver-proxy WBFP scale; the Face, Legs, Activity, Cry, and Consolability (FLACC) scale; and the physician-reported Difficulty of Procedure Visual Analog Scale (DPVAS). RESULTS: Twenty-three children were recruited in each of the intervention arms. Baseline characteristics were comparable between groups. The mean child-rated WBFP scale scores were 2.4, 1.8, and 2.2 for the placebo, decongestant, and TLA with decongestant groups, respectively (P = .45). Although the finding was statistically nonsignificant, decongestant had the lowest mean caregiver-proxy WBFP scale score, lowest observer-rated FLACC scale score, and highest physician-rated DPVAS score. Subgroup analysis did not demonstrate any correlation between the outcomes and age or sex. CONCLUSIONS AND RELEVANCE: This study revealed no statistically significant difference in the discomfort experienced by children undergoing flexible nasendoscopy after placebo, decongestant, or TLA with decongestant. Decongestant was associated with the least discomfort (on child, caregiver, and observer-rated pain scale scores) and the lowest rating for difficulty of procedure. With these findings, the study suggests that there is no significant benefit of topical decongestant with or without TLA compared with placebo in reducing pain associated with pediatric flexible nasendoscopy. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT01351298. PMID- 24158494 TI - The KLK5 protease suppresses breast cancer by repressing the mevalonate pathway. AB - Kallikrein-related peptidase 5 (KLK5) displays aberrant expression in cancer. However, any functional association is missing. Here, we show that reconstitution of KLK5 expression in non-expressing MDA-MB-231 breast cancer cells suppresses malignancy in vitro and in vivo dose-dependently. Reactivation of KLK5 suppressed key EMT genes. Unexpectedly, we identified altered expression of genes encoding enzymes of the mevalonate pathway typical of those observed upon cholesterol starvation. Consistently, we found that SREBF1, the master regulator of the mevalonate pathway was induced. KLK5 re-expression leads to reduced cellular cholesterol and fatty acid synthesis and enhanced uptake of LDL-cholesterol. Suppression of the mevalonate pathway in KLK5 transfectants was further shown by reduced synthesis of isoprenoids. Indeed, we found diminished levels of active RhoA, a signaling oncoprotein that requires prenylation for activation. We propose that reduced RhoA activation plays a dominant role in suppression of malignancy by KLK5, since geranylgeranyl pyrophosphate restored active RhoA in KLK5-reverted cells resulting in increased malignancy. For the first time, we suggest that a protease may suppress breast cancer by modulating the mevalonate pathway. PMID- 24158495 TI - Ligand-gated purinergic receptors regulate HIV-1 Tat and morphine related neurotoxicity in primary mouse striatal neuron-glia co-cultures. AB - Emerging evidence suggests that opioid drugs, such as morphine and heroin, can exacerbate neuroAIDS. Microglia are the principal neuroimmune effectors thought to be responsible for neuron damage in HIV-infected individuals, and evidence suggests that opioid drugs acting via MU opioid receptors in microglia aggravate the neuropathophysiological effects of HIV. Key aspects of microglial function are regulated by the P2X family of ATP activated ligand-gated ion channels. In addition, opioid-dependent microglial activation has been reported to be mediated through P2X4 signaling, which prompted us to investigate whether the cation permeable P2X receptors contribute to the neurotoxic effects of HIV and morphine. To address this question, neuron survival, as well as other endpoints including changes in dendritic length, extracellular ATP levels, and intracellular calcium levels, were assayed in primary neuron-glia co-cultures from mouse striatum. Treatment with TNP-ATP, a non-selective P2X antagonist, prevented the neurotoxic effects of exposure to morphine and/or HIV Tat, or ATP alone, suggesting P2X receptors mediate the neurotoxic effects of these insults in striatal neurons. Although P2X7, and perhaps P2X1, receptor activation decreases neuron survival, neither P2X1, P2X3, nor P2X7 selective receptor antagonists prevented Tat and/or morphine-induced neurotoxicity. These and other experiments indicate the P2X receptor family contributes to Tat- and morphine- related neuronal injury, and provide circumstantial evidence implicating P2X4 receptors in particular. Our findings reveal that members of the P2X receptor family, especially P2X4, may be novel therapeutic targets for restricting the synaptodendritic injury and neurodegeneration that accompanies neuroAIDS and opiate abuse. PMID- 24158497 TI - Epigenetic identification of receptor tyrosine kinase-like orphan receptor 2 as a functional tumor suppressor inhibiting beta-catenin and AKT signaling but frequently methylated in common carcinomas. AB - Through subtraction of tumor-specific CpG methylation, we identified receptor tyrosine kinase-like orphan receptor 2 (ROR2) as a candidate tumor suppressor gene (TSG). ROR2 is a specific receptor or co-receptor for WNT5A, involved in canonical and non-canonical WNT signaling, with its role in tumorigenesis controversial. We characterized its functions and related cell signaling in common carcinomas. ROR2 was frequently silenced by promoter CpG methylation in multiple carcinomas including nasopharyngeal, esophageal, gastric, colorectal, hepatocellular, lung, and breast cancers, while no direct correlation of ROR2 and WNT5A expression was observed. Ectopic expression of ROR2 resulted in tumor suppression independent of WNT5A status, through inhibiting tumor cell growth and inducing cell cycle arrest and apoptosis. ROR2 further suppressed epithelial mesenchymal transition and tumor cell stemness through repressing beta-catenin and AKT signaling, leading to further inhibition of tumor cell migration/invasion and increased chemo-sensitivity. Thus ROR2, as an epigenetically inactivated TSG, antagonizes both beta-catenin and AKT signaling in multiple tumorigenesis. Its epigenetic silencing could be a potential tumor biomarker and therapeutic target for carcinomas. PMID- 24158498 TI - Specificities and pH profiles of adenine and hypoxanthine-guanine-xanthine phosphoribosyltransferases (nucleotide synthases) of the thermoacidophile archaeon Sulfolobus solfataricus. AB - Two open reading frames in the genome of Sulfolobus solfataricus (SSO2342 [corrected] and SSO2424) were cloned and expressed in E. coli. The protein products were purified and their enzymatic activity characterized. Although SSO2342 [corrected] was annotated as a gene (gpT-1) encoding a 6-oxopurine phosphoribosyltransferase (PRTase), the protein product turned out to be a PRTase highly specific for adenine and we suggest that the reading frame should be renamed apT. The other reading frame SSO2424 (gpT-2) proved to be a true 6 oxopurine PRTase active with hypoxanthine, xanthine and guanine as substrates, and we suggest that the gene should be renamed gpT. Both enzymes exhibited unusual profiles of activity versus pH. The adenine PRTase showed the highest activity at pH 7.5-8.5, but had a distinct peak of activity also at pH 4.5. The 6 oxo PRTase showed maximal activity with hypoxanthine and guanine around pH 4.5, while maximal activity with xanthine was observed at pH 7.5. We discuss likely reasons why SSO2342 [corrected] in S. solfataricus and similar open reading frames in other Crenarchaeota could not be identified as genes encoding APRTase. PMID- 24158499 TI - Neuro-ophthalmologic complications of neoplastic leptomeningeal disease. AB - Neoplastic leptomeningeal disease (NLD), which encompasses both primary and secondary leptomeningeal tumors, has a devastating impact on the life of cancer patients. The present diagnostic technical armamentarium is insufficient for early diagnosis of NLD. However, NLD may present with subtle neuro-ophthalmic features at a time of relatively small tumor burden, which gives the provider first encountering these patients the window of opportunity for early diagnosis and consequently improved life expectancy and quality of life of these patients. Therefore, familiarity with early, often subtle neuro-ophthalmic features is an essential tool for diagnosing these patients prior to the development of fixed deficits, which usually portend a dismal prognosis. Future evolving laboratory and neuroimaging technologies are expected to advance our understanding of underlying pathophysiology and early detection of NLD. This paper provides an up to-date review and synthesis of the current literature with focus on neuro ophthalmic features and their underlying pathophysiology. PMID- 24158496 TI - Natural history of mesenchymal stem cells, from vessel walls to culture vessels. AB - Mesenchymal stem/stromal cells (MSCs) can regenerate tissues by direct differentiation or indirectly by stimulating angiogenesis, limiting inflammation, and recruiting tissue-specific progenitor cells. MSCs emerge and multiply in long term cultures of total cells from the bone marrow or multiple other organs. Such a derivation in vitro is simple and convenient, hence popular, but has long precluded understanding of the native identity, tissue distribution, frequency, and natural role of MSCs, which have been defined and validated exclusively in terms of surface marker expression and developmental potential in culture into bone, cartilage, and fat. Such simple, widely accepted criteria uniformly typify MSCs, even though some differences in potential exist, depending on tissue sources. Combined immunohistochemistry, flow cytometry, and cell culture have allowed tracking the artifactual cultured mesenchymal stem/stromal cells back to perivascular anatomical regions. Presently, both pericytes enveloping microvessels and adventitial cells surrounding larger arteries and veins have been described as possible MSC forerunners. While such a vascular association would explain why MSCs have been isolated from virtually all tissues tested, the origin of the MSCs grown from umbilical cord blood remains unknown. In fact, most aspects of the biology of perivascular MSCs are still obscure, from the emergence of these cells in the embryo to the molecular control of their activity in adult tissues. Such dark areas have not compromised intents to use these cells in clinical settings though, in which purified perivascular cells already exhibit decisive advantages over conventional MSCs, including purity, thorough characterization and, principally, total independence from in vitro culture. A growing body of experimental data is currently paving the way to the medical usage of autologous sorted perivascular cells for indications in which MSCs have been previously contemplated or actually used, such as bone regeneration and cardiovascular tissue repair. PMID- 24158500 TI - Cloning and expression analysis of a novel high-mobility group box 2 homologue from Lampetra japonica. AB - High-mobility group box 2 (HMGB2) is a nonhistone architectural protein that plays important roles in many biological processes. In this study, we cloned a homologue of the HMGB2 from the lymphocyte-like cells of Lampetra japonica (L. japonica). Sequence analysis reveals that L. japonica HMGB2 contains two highly conserved motifs and shares more than 70 % identity with the homologues from other vertebrate species. Subsequently, Lj-HMGB2 was subcloned into the pET 28a(+) and pIRES2 AcGFP1-Nuc vector and expressed in Rosetta blue (DE3) and Hela cell lines, respectively. The recombinant L. japonica HMGB2 (rLj-HMGB2) with apparent molecular mass of 22 kDa was further purified by His-Bind affinity chromatography. Real-time quantitative PCR indicates that the expression level of Lj-HMGB2 was particularly up-regulated in intestines after challenged with lipopolysaccharide, while up-regulated in lymphocyte-like cells and heart after challenged with concanavalin A in vivo. In addition, rLj-HMGB2 could induce the generation of proinflammatory mediators in the activated human acute monocytic leukemia cell line (THP1), which suggested that Lj-HMGB2 may participate in the immune response of the lampreys. PMID- 24158501 TI - MDMA enhances hippocampal-dependent learning and memory under restrictive conditions, and modifies hippocampal spine density. AB - OBJECTIVES: Addictive drugs produce forms of structural plasticity in the nucleus accumbens and prefrontal cortex. The aim of this study was to investigate the impact of chronic MDMA exposure on pyramidal neurons in the CA1 region of hippocampus and drug-related spatial learning and memory changes. METHODS AND RESULTS: Adolescent rats were exposed to saline or MDMA in a regime that mimicked chronic administration. One week later, when acquisition or reference memory was evaluated in a standard Morris water maze (MWM), no differences were obtained between groups. However, MDMA-exposed animals performed better when the MWM was implemented under more difficult conditions. Animals of MDMA group were less anxious and were more prepared to take risks, as in the open field test they ventured more frequently into the central area. We have demonstrated that MDMA caused an increase in brain-derived neurotrophic factor (BDNF) expression. When spine density was evaluated, MDMA-treated rats presented a reduced density when compared with saline, but overall, training increased the total number of spines, concluding that in MDMA-group, training prevented a reduction in spine density or induced its recovery. CONCLUSIONS: This study provides support for the conclusion that binge administration of MDMA, known to be associated to neurotoxic damage of hippocampal serotonergic terminals, increases BDNF expression and stimulates synaptic plasticity when associated with training. In these conditions, adolescent rats perform better in a more difficult water maze task under restricted conditions of learning and memory. The effect on this task could be modulated by other behavioural changes provoked by MDMA. PMID- 24158503 TI - Assessing the economic impact of paternal involvement: a comparison of the generalized linear model versus decision analysis trees. AB - Lack of paternal involvement has been shown to be associated with adverse pregnancy outcomes, including infant morbidity and mortality, but the impact on health care costs is unknown. Various methodological approaches have been used in cost minimization and cost effectiveness analyses and it remains unclear how cost estimates vary according to the analytic strategy adopted. We illustrate a methodological comparison of decision analysis modeling and generalized linear modeling (GLM) techniques using a case study that assesses the cost-effectiveness of potential father involvement interventions. We conducted a 12-year retrospective cohort study using a statewide enhanced maternal-infant database that contains both clinical and nonclinical information. A missing name for the father on the infant's birth certificate was used as a proxy for lack of paternal involvement, the main exposure of this study. Using decision analysis modeling and GLM, we compared all infant inpatient hospitalization costs over the first year of life. Costs were calculated from hospital charges using department-level cost-to-charge ratios and were adjusted for inflation. In our cohort of 2,243,891 infants, 9.2% had a father uninvolved during pregnancy. Lack of paternal involvement was associated with higher rates of preterm birth, small-for gestational age, and infant morbidity and mortality. Both analytic approaches estimate significantly higher per-infant costs for father uninvolved pregnancies (decision analysis model: $1,827, GLM: $1,139). This paper provides sufficient evidence that healthcare costs could be significantly reduced through enhanced father involvement during pregnancy, and buttresses the call for a national program to involve fathers in antenatal care. PMID- 24158502 TI - Effect of sex on ethanol consumption and conditioned taste aversion in adolescent and adult rats. AB - RATIONALE: Vulnerability to alcoholism is determined by many factors, including the balance of pleasurable vs. aversive alcohol-induced sensations: pleasurable sensations increase intake, while aversive sensations decrease it. Female sex and adolescent age are associated with lower sensitivity to intake-reducing effects and more rapid development of alcohol abuse. OBJECTIVES: This study assessed voluntary drinking and the aversive effects of alcohol to determine whether these measures are inversely related across the sexes and development. METHODS: Voluntary drinking of 20 % ethanol in an every-other-day (EOD) availability pattern and the dose-response relationship of ethanol conditioned taste aversion (CTA) were assessed in male and female adolescent and adult rats. RESULTS: CTA was sex specific in adult but not adolescent rats, with adult females exhibiting less aversion. Voluntary ethanol consumption varied according to age and individual differences but was not sex specific. Adolescents initially drank more than adults, exhibited greater day-to-day variation in consumption, were more susceptible to the alcohol deprivation effect, and took longer to establish individual differences in consumption patterns. CONCLUSIONS: These results show that the emergence of intake patterns differs between adolescents and adults. Adolescents as a group initiate drinking at high levels but decrease intake as they mature. A subset of adolescents maintained high drinking levels into adulthood. In contrast, most adults consumed at steady, low levels, but a small subset quickly established and maintained high-consumption patterns. Adolescents also showed marked deprivation-induced increases. Sex differences were not observed in EOD drinking during either adolescence or adulthood. PMID- 24158504 TI - Disclosure and impact of maternal HIV+ serostatus on mothers and children in rural Haiti. AB - Mothers living with HIV (MLWHs) in the United States have reported that one of their main challenges is the decision to disclose their HIV serostatus to their children and the potential consequences of their disclosure. Little is known about the experiences of MLWHs regarding disclosing their HIV serostatus to their children and the impact of maternal HIV serostatus disclosure in the island nations of the Caribbean. Study objectives were to identify the factors influencing maternal HIV serostatus disclosure, examine the breadth of maternal HIV serostatus, and understand the impact of disclosure on mothers and the children. Baseline interviews were conducted between 2006 and 2007 with 25 HIV positive mothers and 26 children ages 10-17 participating in a pilot psychosocial support intervention for HIV-affected youth and their caregivers in Haiti. Interviews were transcribed verbatim and coded for topical themes by two investigators. Analysis of the interviews yielded several themes relevant to reasons for disclosure, including children's experience of HIV stigma in the community, social support and encouragement from psychosocial intervention workers. The main themes related to breadth of disclosure were brief disclosure and explicit disclosure with some mothers sharing information about how they learned about their illness diagnosis and their medication. Themes related to impacts of disclosure included emotional reactions of children and mothers, and children's desire to assist mothers with illness and become involved. These findings suggest the need to provide more psychosocial support to HIV-affected families in the Caribbean region. PMID- 24158505 TI - Closing the gap in maternal and child health: a qualitative study examining health needs of migrant mothers in Dandenong, Victoria, Australia. AB - We conducted a qualitative study that explored the views and perceptions of migrant women in, Dandenong, Victoria, Australia about sociocultural barriers and health needs during pregnancy and in the postnatal period. The study was informed by the Social Identity Theory and the Acculturation Theory. It involved five focus group discussions with 35 migrant mothers from Afghanistan, Africa, China, Palestine, Lebanon, Syria, Iran and Jordan. Five themes emerged from the analysis: (1) the need for family support and complex social environments; (2) dealing with two cultural identities; (3) the health of mother and offspring; (4) access to the health system; and (5) life-skills for better health. Pregnancy and motherhood are challenges that are made more difficult by migration. The findings point towards the need for policies and interventions: (1) to reduce the negative impact of social isolation and lack of support during pregnancy and postnatally; (2) to support greater fathers' involvement in childcare; and (3) to reconcile different practices and expectations between traditional cultures and Australian norms. They also suggest a need to test culturally competent interventions that address health and lifestyle needs in migrant women and education programs for mothers that effectively address their concerns about maternal and child health. PMID- 24158506 TI - Discussions about intimate partner violence during prenatal care in the United States: the role of race/ethnicity and insurance status. AB - Over 1.5 million women are physically, sexually, and emotionally abused by intimate partners in the U.S. each year. Despite the severe health consequences and costs associated with intimate partner violence (IPV), most health providers fail to assess patients for abuse. It was of interest to examine the occurrence of IPV discussions during prenatal care (PNC) visits among women who experienced IPV. This study analyzed data from the 2004-2008 National Pregnancy Risk Assessment Monitoring System which included 195,687 women who delivered a live birth in the U.S. IPV victimization was measured using four items that addressed physical abuse by a current or former husband/partner in the 12 months before or during pregnancy. Responses were categorized as preconception, prenatal, preconception and prenatal, and preconception and/or prenatal IPV. The outcome was IPV discussions by health providers during PNC. Separate logistic regression models provided odds ratios and 95% confidence intervals. Women who reported prenatal IPV were less likely to have IPV discussions during PNC (OR = 0.81, 95% CI = 0.70-0.94). Results were similar for women experiencing IPV during the prenatal and preconception periods. Among racial/ethnic minorities, women who experienced preconception IPV were less likely to have discussions about IPV during PNC. Further, Medicaid recipients who reported preconception and/or prenatal IPV were less likely to report IPV discussions (OR = 0.75, 95% CI = 0.69 0.82). This study underscores a public health problem and missed opportunity to connect battered victims to necessary services and care. It elucidates the state of current clinical practice and better informs policies on incorporating universal IPV screening. PMID- 24158507 TI - Breast milk sharing via the internet: the practice and health and safety considerations. AB - To characterize the practice of breast milk sharing via the internet in the US and examine factors associated with participants' communication regarding potential health and safety risks. This cross-sectional study examined all original postings (n = 254) placed during 1 week in 2011 on four websites to facilitate the sharing of breast milk. Postings were characterized for intent and health and safety topics (i.e., selling vs. donating milk, hygiene/handling practices, infectious disease screening, diet/exercise habits, substance and pharmaceutical use, milk quality claims, price) communicated between milk providers and recipients. Approximately 69% of postings were providing milk and 31% were seeking milk; 47% included identifiers. Few provider postings reflected measures to potentially reduce risks to recipients: 20% mentioned using a healthy handling/hygiene practice, 11% offered specifics about infectious disease screening, 51% mentioned limiting/abstaining from 1+ substances. The presence of indications about handling/hygiene, diet/exercise, and abstaining from substances were strongly positively associated with each other (ORs 7.42-13.80), with the odds of selling (ORs 6.03-infinity), and with making quality claims (ORs 3.14 13.54), but not with disease screening. One-fifth of recipients sought milk for a child with a medical condition or poor birth outcome. Most recipients (90%) did not specify any health and safety practices of a provider in their posting. Health behaviors and screening for diseases that may affect milk safety are not prominent topics in postings seeking to share milk. This lack of communication may exacerbate the health risks to recipient infants, especially infants at increased risk due to pre-existing health conditions. PMID- 24158508 TI - Adolescent childbearing and women's attitudes towards wife beating in 25 sub Saharan African countries. AB - Preventing unwanted adolescent pregnancy is key for keeping girls in school, leading to a more productive and healthier workforce in sub-Saharan Africa. Gender norms are an important indicator of the status of women and more conservative gender norms are associated with experiencing domestic violence, and poorer maternal and reproductive health care. This paper examines the association between adolescent childbearing and norms towards wife beating in sub-Saharan Africa, and the role of education in moderating this association. Data come from the most recent Demographic and Health Surveys-nationally representative cross sectional surveys conducted every 5 years. Country-by-country multivariable logistic regressions were conducted in 25 countries, and country and regional estimates were obtained using meta-analytical techniques. More than half of sub Saharan African adolescents have a child, with levels ranging from 23% in Rwanda to 69% in Niger. Between 12 and 87% of women believed wife beating is acceptable. In 20 of the 25 countries, women with a birth during adolescence were significantly more likely to believe wife beating is justified [OR = 1.39; 95% confidence interval (CI) 130-1.39]. After multivariate adjustment, the overall finding remains statistically significant [AOR = 1.09; 95% CI 105-1:13]. Education attenuates the observed association. Overall, the effects are strongest and most consistent in West Africa. Results suggest that women who have an adolescent birth more likely to hold more conservative attitudes. Working with adolescents to improve their attitudes on relationship expectations and the importance of furthering their education even after a pregnancy could be integrated into life skills and sexual education curricula. PMID- 24158509 TI - Shape-preserving preprocessing for human pulse signals based on adaptive parameter determination. AB - The use of the human pulse signal for medical diagnosis is a mainstay in the practice of traditional Chinese medicine. Computer processing of this signal may be used to automate diagnostic procedures and to reveal sources of information in the waveform that have been used by both eastern and western physicians for more than two millennia. A new method for preprocessing of the human pulse signal significantly improves feature extraction and classification of the waveform. Baseline distortion is first removed using the dual-tree complex wavelet transform (DT-CWT) and cubic spline interpolation, then a novel filtering method removes the residual background noise. Filtering is implemented in two stages. In the initial pass, a majority of the noise is eliminated by an adaptive mean filter whose sliding window duration is selected automatically based on a chain code and the DT-CWT. In the second pass, residual high frequency noise is removed using the DT-CWT with a new threshold determination. Experimental results demonstrate effective removal of background disturbances with excellent preservation of pulse peak information essential for proper parametric representation and classification of the waveform. PMID- 24158510 TI - Migration of intraocular silicone oil into the brain. PMID- 24158512 TI - Optical properties of free-standing gelatin-Si nanoparticle composite films and gelatin-Si-Au nanoparticle composite films. AB - A free-standing fluorescent gelatin-Si nanoparticle composite thin film is facilely prepared by means of a filtration technique assisted by porous copper hydroxide nanostrands as a sacrificial layer. The as-prepared gelatin-Si nanoparticle composite film is greatly portable, flexible, transparent and free standing. The most important advantage is its robust storage stability stored in ambient air, which make it promising for various applications. Meanwhile, a gelatin-Si-Au nanoparticle composite film is also successfully prepared by the formation of Au NPs in a gelatin-Si nanoparticle composite film through the in situ reduction of HAuCl4 at room temperature. The photoluminescence (PL) quenching and blue shift in the peak of the emission spectra occur due to the energy transfer from Si NPs to Au NPs. By varying the amount and size of Au NPs incorporated into the gelatin-Si nanoparticle composite film, the energy transfer efficiency can be controlled. This is a general method to prepare metal semiconductor hybrid fluorescent nanomaterials, which offers the possibility of tuning the luminescence intensity and wavelength of the emitted light. PMID- 24158511 TI - Detecting EGFR alterations in clinical specimens-pitfalls and necessities. AB - We investigated the epidermal growth factor receptor (EGFR) status in early stage lung cancer in Southern Sweden, a population for which there are no previous reports on the EGFR mutation frequency. Three hundred fifty small cell lung cancers, adenocarcinomas (AC), squamous cell carcinomas (SqCC), and large cell carcinomas were analyzed using a combination of techniques for the analysis of protein expression, gene copy numbers, and mutations. Immunohistochemical (IHC) staining with antibodies for the EGFR mutations L858R and del E746-A750 revealed intratumoral heterogeneity and several discrepant cases when compared to mutation specific polymerase chain reaction (PCR)-based analysis. The frequencies of these two mutations, when considering IHC staining with mutation-specific antibodies in a cohort of 298 cases and subsequent confirmation by PCR, were 10 % in AC and <2 % in SqCC. Furthermore, screening by sequencing of EGFR in a cohort of 52 lung AC and squamous carcinomas demonstrated a more diverse mutation spectrum, not covered by the mutation-specific antibodies. High expression of total EGFR protein was correlated to high gene copy numbers but did not reflect the mutational status of the tumors. We believe that the mutation spectra in a Southern Swedish population is too diverse to be covered by the mutation-specific antibodies, and we also raise some other issues regarding the use of the mutation specific antibodies, for example concerning heterogeneous expression of the mutated protein, optimal antibody dilution, and discrepancies between staining results and PCR. PMID- 24158513 TI - Globotriaosylceramide induces lysosomal degradation of endothelial KCa3.1 in fabry disease. AB - OBJECTIVE: Globotriaosylceramide (Gb3) induces KCa3.1 downregulation in Fabry disease (FD). We investigated whether Gb3 induces KCa3.1 endocytosis and degradation. APPROACH AND RESULTS: KCa3.1, especially plasma membrane-localized KCa3.1, was downregulated in both Gb3-treated mouse aortic endothelial cells (MAECs) and human umbilical vein endothelial cells. Gb3-induced KCa3.1 downregulation was prevented by lysosomal inhibitors but not by a proteosomal inhibitor. Endoplasmic reticulum stress-inducing agents did not induce KCa3.1 downregulation. Gb3 upregulated the protein levels of early endosome antigen 1 and lysosomal-associated membrane protein 2 in MAECs. Compared with MAECs from age-matched wild-type mice, those from aged alpha-galactosidase A (Gla)-knockout mice, an animal model of FD, showed downregulated KCa3.1 expression and upregulated early endosome antigen 1 and lysosomal-associated membrane protein 2 expression. In contrast, no significant difference was found in early endosome antigen 1 and lysosomal-associated membrane protein 2 expression between young Gla-knockout and wild-type MAECs. In aged Gla-knockout MAECs, clathrin was translocated close to the cell border and clathrin knockdown recovered KCa3.1 expression. Rab5, an effector of early endosome antigen 1, was upregulated, and Rab5 knockdown restored KCa3.1 expression, the current, and endothelium-dependent relaxation. CONCLUSIONS: -Gb3 accelerates the endocytosis and lysosomal degradation of endothelial KCa3.1 via a clathrin-dependent process, leading to endothelial dysfunction in FD. PMID- 24158514 TI - The critical role of mRNA destabilizing protein heterogeneous nuclear ribonucleoprotein d in 3' untranslated region-mediated decay of low-density lipoprotein receptor mRNA in liver tissue. AB - OBJECTIVE: Previous studies showed that low-density lipoprotein receptor (LDLR) mRNA 3' untranslated region (UTR) contains regulatory elements responsible for rapid mRNA turnover in hepatic cells and mediates the mRNA stabilization induced by berberine (BBR). Here, we elucidate the underlying mechanism of BBR's action by characterizing mRNA-binding proteins that modulate LDLR mRNA decay via 3'UTR in liver tissue in vivo. APPROACH AND RESULTS: We generated a transgenic mouse model (Alb-Luc-UTR) that expresses Luc-LDLR3'UTR reporter gene driven by the albumin promoter to study 3'UTR function in mediating LDLR mRNA decay in liver tissue. We show that treating Alb-Luc-UTR mice with BBR led to significant increases in hepatic bioluminescence signals, Luc-UTR mRNA, and LDLR mRNA levels as compared with control mice. These effects were accompanied by specific reductions of mRNA decay-promoting factor heterogeneous nuclear ribonucleoprotein D (hnRNP D) in liver of BBR-treated mice. Knockdown and overexpression studies further demonstrated that hnRNP D p37 isoform plays a major role in promoting hepatic LDLR mRNA degradation. In addition, we examined LDLR mRNA half-life, Luc UTR reporter activity, and hnRNP D expression levels in cell lines derived from extrahepatic tissues. We demonstrated that strengths of 3'UTR in promoting mRNA degradation correlate with hnRNP D cellular abundances in nonhepatic cell lines, thereby suggesting its involvement in LDLR mRNA degradation beyond liver tissue. CONCLUSIONS: hnRNP D is critically involved in LDLR mRNA degradation in liver tissue in vivo. The inverse relationship of hnRNP D abundance with LDLR mRNA levels after BBR treatment suggests the potential of hnRNP D of being a novel therapeutic target for LDL cholesterol lowering. PMID- 24158515 TI - Mice heterozygous for the xanthine oxidoreductase gene facilitate lipid accumulation in adipocytes. AB - OBJECTIVE: Xanthine oxidoreductase (XOR) catalyzes the production of uric acid with concomitant generation of reactive oxygen species. XOR has been shown to regulate adipogenesis through the control of peroxisome proliferator-activated receptor gamma, but its role in adipose tissue remains unclear. The aim of this study was to examine the role of XOR in adipose tissue using XOR genetically modified mice. APPROACH AND RESULTS: Experiments were performed using 2-, 4-, and 18-month-old XOR heterozygous mice (XOR(+/-)) and their wild-type littermates to evaluate the physiological role of XOR as the mice aged. Stromal vascular fraction cells were prepared from epididymal white adipose tissue in 2-month-old XOR mice to assess adipogenesis. At 18 months, XOR(+/)- mice had significantly higher body weight, higher systolic blood pressure, and higher incidence of insulin resistance compared with wild-type mice. At 4 months, blood glucose and the expressions of CCAAT enhancer-binding protein beta, peroxisome proliferator activated receptor gamma, monocyte chemoattractant protein-1, and tumor necrosis factor alpha mRNA in epididymal white adipose tissue were significantly higher in XOR(+/-) than in wild-type mice. Furthermore, histological analysis of epididymal white adipose tissue in XOR(+/-) mice revealed that adipocyte size and the F4/80 positive macrophage count were increased. Experiments with a high-fat diet exhibited that body weight gain was also significantly higher in XOR(+/-) than in wild-type mice. In stromal vascular fraction cells derived from XOR(+/-) mice, the levels of peroxisome proliferator-activated receptor gamma, fatty acid binding protein 4, and CCAAT enhancer-binding protein alpha mRNA were upregulated, and oxidative stress levels were elevated during differentiation into adipocytes. CONCLUSIONS: These results suggest that the reduction in XOR gene expression in mice augments lipid accumulation in adipocytes, accompanied by an increase in oxidative stress, and induces obesity with insulin resistance in older age. PMID- 24158516 TI - Essential role of CD11a in CD8+ T-cell accumulation and activation in adipose tissue. AB - OBJECTIVE: T cells, particularly CD8(+) T cells, are major participants in obesity-linked adipose tissue (AT) inflammation. We examined the mechanisms of CD8(+) T-cell accumulation and activation in AT and the role of CD11a, a beta2 integrin. APPROACH AND RESULTS: CD8(+) T cells in AT of obese mice showed activated phenotypes with increased proliferation and interferon-gamma expression. In vitro, CD8(+) T cells from mouse AT displayed increased interferon gamma expression and proliferation to stimulation with interleukin-12 and interleukin-18, which were increased in obese AT. CD11a was upregulated in CD8(+) T cells in obese mice. Ablation of CD11a in obese mice dramatically reduced T cell accumulation, activation, and proliferation in AT. Adoptive transfer showed that CD8(+) T cells from wild-type mice, but not from CD11a-deficient mice, infiltrated into AT of recipient obese wild-type mice. CD11a deficiency also reduced tumor necrosis factor-alpha-producing and interleukin-12-producing macrophages in AT and improved insulin resistance. CONCLUSIONS: Combined action of cytokines in obese AT induces proliferative response of CD8(+) T cells locally, which, along with increased infiltration, contributes to CD8(+) T-cell accumulation and activation in AT. CD11a plays a crucial role in AT inflammation by participating in T-cell infiltration and activation. PMID- 24158517 TI - Functionality of endothelial cells and pericytes from human pluripotent stem cells demonstrated in cultured vascular plexus and zebrafish xenografts. AB - OBJECTIVE: Endothelial cells (ECs), pericytes, and vascular smooth muscle cells (vSMCs) are essential for vascular development, and their dysfunction causes multiple cardiovascular diseases. Primary vascular cells for research are, however, difficult to obtain. Human-induced pluripotent stem cells (hiPSCs) derived from somatic tissue are a renewable source of ECs and vSMCs; however, their use as disease models has been limited by low and inconsistent efficiencies of differentiation and the lack of phenotypic bioassays. APPROACH AND RESULTS: Here, we developed defined conditions for simultaneous derivation of ECs and pericytes with high efficiency from hiPSCs of different tissue origin. The protocol was equally efficient for all lines and human embryonic stem cells (hESCs). The ECs could undergo sequential passage and were phenotypically indistinguishable, exhibiting features of arterial-like embryonic ECs. Moreover, hiPSC-derived ECs formed an authentic vascular plexus when cocultured with hiPSC derived pericytes. The coculture system recapitulated (1) major steps of vascular development including EC proliferation and primary plexus remodeling, and (2) EC mediated maturation and acquisition of contractile vSMC phenotype by pericytes. In addition, hiPSC-derived ECs integrated into developing vasculature as xenografts in zebrafish. This contrasts with more widely used ECs from human umbilical vein, which form only unstable vasculature and were completely unable to integrate into zebrafish blood vessels. CONCLUSIONS: We demonstrate that vascular derivatives of hiPSC, such as ECs and pericytes, are fully functional and can be used to study defective endothelia-pericyte interactions in vitro for disease modeling and studies on tumor angiogenesis. PMID- 24158518 TI - Matrix metalloproteinase-8 promotes vascular smooth muscle cell proliferation and neointima formation. AB - OBJECTIVE: We investigated the role of matrix metalloproteinase-8 (MMP8) in neointima formation and in vascular smooth muscle cell (VSMC) migration and proliferation. APPROACH AND RESULTS: After carotid artery wire injuring, MMP8(-/ )/apoE(-/-) mice had fewer proliferating cells in neointimal lesions and smaller lesion sizes. Ex vivo assays comparing VSMCs isolated from MMP8 knockout and wild type mice showed that MMP8 knockout decreased proliferation and migration. Proteomics analysis revealed that a disintegrin and metalloproteinase domain containing protein 10 (ADAM10) had lower concentrations in MMP8 knockout VSMC culture media than in MMP8 wild-type VSMC culture media. Western blot, flow cytometric, and immunocytochemical analyses showed that MMP8 knockout VSMCs contained more pro-ADAM10 but less mature ADAM10, more N-cadherin, and beta catenin in the plasma membrane but less beta-catenin in the nucleus and less cyclin D1. Treatment of MMP8 wild-type VSMCs with an ADAM10 inhibitor, GI254023X, or siRNA knockdown of ADAM10 in MMP8 wild-type VSMCs inhibited proliferation and migration, increased N-cadherin and beta-catenin in the plasma membrane, reduced beta-catenin in the nucleus, and decreased cyclin D1 expression. Incubation of MMP8 knockout VSMCs with a recombinant ADAM10 rescued the proliferative and migratory ability of MMP8 knockout VSMCs and increased cyclin D1 expression. Furthermore, immunohistochemical analyses showed colocalization of ADAM10 with VSMCs and N-cadherin, and nuclear accumulation of beta-catenin in the neointima in apoE(-/-)/MMP8(+/+) mice. CONCLUSIONS: MMP8 enhances VSMC proliferation via an ADAM10, N-cadherin, and beta-catenin-mediated pathway and plays an important role in neointima formation. PMID- 24158519 TI - Peroxisome proliferator-activated receptor delta agonist GW1516 attenuates diet induced aortic inflammation, insulin resistance, and atherosclerosis in low density lipoprotein receptor knockout mice. AB - OBJECTIVE: The peroxisome proliferator-activated receptor (PPAR) delta regulates systemic lipid homeostasis and inflammation. However, the ability of PPARdelta agonists to improve the pathology of pre-established lesions and whether PPARdelta activation is atheroprotective in the setting of insulin resistance have not been reported. Here, we examine whether intervention with a selective PPARdelta agonist corrects metabolic dysregulation and attenuates aortic inflammation and atherosclerosis. APPROACH AND RESULTS: Low-density lipoprotein receptor knockout mice were fed a chow or a high-fat, high-cholesterol (HFHC) diet (42% fat, 0.2% cholesterol) for 4 weeks. For a further 8 weeks, the HFHC group was fed either HFHC or HFHC plus GW1516 (3 mg/kg per day). GW1516 significantly attenuated pre-established fasting hyperlipidemia, hyperglycemia, and hyperinsulinemia, as well as glucose and insulin intolerance. GW1516 intervention markedly reduced aortic sinus lesions and lesion macrophages, whereas smooth muscle alpha-actin was unchanged and collagen deposition enhanced. In aortae, GW1516 increased the expression of the PPARdelta-specific gene Adfp but not PPARalpha- or gamma-specific genes. GW1516 intervention decreased the expression of aortic proinflammatory M1 cytokines, increased the expression of the anti-inflammatory M2 cytokine Arg1, and attenuated the iNos/Arg1 ratio. Enhanced mitogen-activated protein kinase signaling, known to induce inflammatory cytokine expression in vitro, was enhanced in aortae of HFHC-fed mice. Furthermore, the HFHC diet impaired aortic insulin signaling through Akt and forkhead box O1, which was associated with elevated endoplasmic reticulum stress markers CCAAT-enhancer-binding protein homologous protein and 78kDa glucose regulated protein. GW1516 intervention normalized mitogen-activated protein kinase activation, insulin signaling, and endoplasmic reticulum stress. CONCLUSIONS: Intervention with a PPARdelta agonist inhibits aortic inflammation and attenuates the progression of pre-established atherosclerosis. PMID- 24158520 TI - Effects of a reward system on resident research productivity. AB - IMPORTANCE: With the changing academic medical environment, nontraditional methods may need to be considered to foster research and scholarly activity during the otolaryngology residency experience. OBJECTIVE: To evaluate the results of a reward system on resident research activity. DESIGN, SETTING, AND PARTICIPANTS: Retrospective review of publications and approved institutional review board (IRB) projects between July 1, 1997, and June 30, 2011, among otolaryngology residents at a single otolaryngology residency program at the University of Missouri. INTERVENTION: A resident reward system, which awards points for research efforts for each progressive step along the research path from project design to acceptance for publication, was implemented on July 1, 2004. Residents can convert points to a monetary amount to be used for academic enrichment. MAIN OUTCOMES AND MEASURES: Publication rate and IRB approval rate were compared before and after institution of the reward system. Study design types that were published and study design types that received IRB approval were evaluated as well. We hypothesized that the reward system would increase research quantity and quality. RESULTS: The mean publication output per resident per year increased from 0.13 (95% CI, 0.03-0.23) before commencement of the reward system to 0.43 (95% CI, 0.26-0.60) after implementation of the reward system (P = .004). Significantly more case reports were published compared with other study design types. The number of approved IRB projects before institution of the reward system was 0.47 (95% CI, 0.18-0.75) per resident per year. After instituting the reward system, this increased significantly to 1.29 (95% CI, 0.96-1.63) per resident per year (P = .007). Significant increases in IRB-approved case reports and retrospective clinical studies were noted. CONCLUSIONS AND RELEVANCE: After implementation of a point-based reward system, resident research activity increased. The data suggest that this system may encourage resident research, although further refinement may be required to promote higher-quality research endeavors. PMID- 24158522 TI - Dialogue on sustainable development as part of engineering education: the relevance of the Finnish case : commentary on "a national collaboration process: Finnish engineering education for the benefit of people and environment". AB - Society invests in the education of engineers because it is expected that the works of engineers will bring good results for society. Because the work of engineers is not value free or neutral, it is important that engineers are educated in the important principles of the social sciences and humanities. This education is essential for the awareness and understanding of what is good for society. Therefore the concept of sustainable development should be part of an education in engineering but only when the social sciences are also a part of it. PMID- 24158523 TI - Sustainable development as a challenge for undergraduate students: the module "Science bears responsibility" in the Leuphana bachelor's programme : commentary on "a case study of teaching social responsibility to doctoral students in the climate sciences". AB - The Leuphana Semester at Leuphana University Luneburg, together with the module "Science bears responsibility" demonstrate how innovative methods of teaching and learning can be combined with the topic of sustainable development and how new forms of university teaching can be introduced. With regard to module content, it has become apparent that, due to the complexity of the field of sustainability, a single discipline alone is unable to provide analyses and solutions. If teaching in higher education is to adequately deal with this complexity, then it is necessary to develop inter- and transdisciplinary approaches that go beyond a purely specialist orientation. PMID- 24158521 TI - A century of optocardiography. AB - In the past decade, optical mapping provided crucial mechanistic insight into electromechanical function and the mechanism of ventricular fibrillation. Therefore, to date, optical mapping dominates experimental cardiac electrophysiology. The first cardiac measurements involving optics were done in the early 1900s using the fast cinematograph that later evolved into methods for high-resolution activation and repolarization mapping and stimulation of specific cardiac cell types. The field of "optocardiography," therefore, emerged as the use of light for recording or interfering with cardiac physiology. In this review, we discuss how optocardiography developed into the dominant research technique in experimental cardiology. Furthermore, we envision how optocardiographic methods can be used in clinical cardiology. PMID- 24158525 TI - Deriving a ranking from hesitant fuzzy preference relations under group decision making. AB - In this paper, we explore the ranking methods with hesitant fuzzy preference relations (HFPRs) in the group decision making environments. As basic elements of hesitant fuzzy sets, hesitant fuzzy elements (HFEs) usually have different numbers of possible values. In order to compute or compare HFEs, we have two principles to normalize them, i.e., the alpha -normalization and the beta normalization. Based on the alpha -normalization, we develop a new hesitant goal programming model to derive priorities from HFPRs. On the basis of the beta normalization, we develop the consistency measures of HFPRs, establish the consistency thresholds to measure whether or not an HFPR is of acceptable consistency, and then use the hesitant aggregation operators to aggregate preferences in HFPRs to obtain the ranking results. PMID- 24158524 TI - The siRNA cocktail targeting VEGF and HER2 inhibition on the proliferation and induced apoptosis of gastric cancer cell. AB - The aim of this study was to investigate the inhibitory effect of a siRNA cocktail targeting Vascular endothelial growth factor (VEGF) and Human epidermal growth factor receptor 2 (HER2) on cell proliferation, induced apoptosis and the expression of VEGF and HER2 in human gastric carcinoma cell. The silencing rate of pre-designed siRNAs that targeted VEGF and HER2 was detected by Real-time Quantitative PCR (RT-QPCR) analysis. Furthermore, the best silencing siRNA that targeted VEGF and HER2 was prepared as a cocktail to co-knockdown VEGF and HER2 expression at both mRNA and protein levels which were detected by RT-QPCR and Western blot analysis. Cell proliferation inhibition rates were determined by CCK8 assay. The effect of siRNA cocktail on cell apoptosis was determined by flow cytometry. The migration inhibition of siRNA cocktail was analyzed by wound healing assay. The ability of VEGF to induce endothelial cells to proliferate was examined in HUVECs by the method of tube formation assay. The pre-designed siRNAs could inhibit VEGF and HER2 mRNA level. siRNA cocktail, and co-downregulation of VEGF and HER2 result in significant inhibition of gastric cancer growth and migration in vitro. The inhibition of VEGF and HER2 expressions can induce apoptosis of SGC-7901 cells. PMID- 24158526 TI - Density sensitive hashing. AB - Nearest neighbor search is a fundamental problem in various research fields like machine learning, data mining and pattern recognition. Recently, hashing-based approaches, for example, locality sensitive hashing (LSH), are proved to be effective for scalable high dimensional nearest neighbor search. Many hashing algorithms found their theoretic root in random projection. Since these algorithms generate the hash tables (projections) randomly, a large number of hash tables (i.e., long codewords) are required in order to achieve both high precision and recall. To address this limitation, we propose a novel hashing algorithm called density sensitive hashing (DSH) in this paper. DSH can be regarded as an extension of LSH. By exploring the geometric structure of the data, DSH avoids the purely random projections selection and uses those projective functions which best agree with the distribution of the data. Extensive experimental results on real-world data sets have shown that the proposed method achieves better performance compared to the state-of-the-art hashing approaches. PMID- 24158527 TI - hobo-brothers elements and their time and place for horizontal transfer. AB - Transposable elements (TEs) are ubiquitous components of nearly all genomes studied. These elements are highly variable in copy number, molecular structure and transposition strategies. They can move within and between genomes, thus increasing their copy numbers and avoiding being eliminated by stochastic and deterministic processes. hobo is a class II element isolated from Drosophila melanogaster. Previous phylogenetic analyses have shown that the canonical hobo element from D. melanogaster has a sister group formed by sequences found in D. willistoni (called howilli2) and D. mojavensis (called homo1). In the present study, we investigated 36 Drosophilidae species for sequences similar to howilli2 and homo1 using degenerate primers. Additionally, in silico searches were performed in 21 available Drosophila genomes. The obtained sequences formed a monophyletic sister group with the canonical hobo element; we termed these sequences 'hobo-brothers' elements. These elements showed a patch distribution and incongruities with the TE and host species phylogenies, suggesting possible cases of horizontal transfer (HT). Species that possess hobo-brothers sequences are from the New World, mainly Neotropical areas. In addition, the estimated divergence of the sequences found showed that these elements are or were recently active; the large number of HT events observed suggests that these elements could be experiencing an expansion process in Neotropical genomes. A comparison of these results with the literature is discussed with regard to the importance of the time and location of horizontal transposon transfer events. PMID- 24158530 TI - Electronic, ductile, phase transition and mechanical properties of Lu monopnictides under high pressures. AB - The structural, elastic and electronic properties of lutatium-pnictides (LuN, LuP, LuAs, LuSb, and LuBi) were analyzed by using full-potential linearized augmented plane wave within generalized gradient approximation in the stable rock salt structure (B1 phase) with space group Fm-3m and high-pressure CsCl structure (B2 phase) with space group Pm-3m. Hubbard-U and spin-orbit coupling were included to predict correctly the semiconducting band gap of LuN. Under compression, these materials undergo first-order structural transitions from B1 to B2 phases at 241, 98, 56.82, 25.2 and 32.3 GPa, respectively. The computed elastic properties show that LuBi is ductile by nature. The electronic structure calculations show that LuN is semiconductor at ambient conditions with an indirect band gap of 1.55 eV while other Lu-pnictides are metallic. It was observed that LuN shows metallization at high pressures. The structural properties, viz, equilibrium lattice constant, bulk modulus and its pressure derivative, transition pressure, equation of state, volume collapse, band gap and elastic moduli, show good agreement with available data. PMID- 24158528 TI - Non-invasive evaluation of liver fibrosis: a comparison of ultrasound-based transient elastography and MR elastography in patients with viral hepatitis B and C. AB - OBJECTIVE: To compare the diagnostic accuracy of TE and MRE and establish cutoff levels and diagnostic strategies for both techniques, enabling selection of patients for liver biopsy. METHODS: One hundred three patients with chronic hepatitis B or C and liver biopsy were prospectively included. Areas under curves (AUROC) were compared for TE and MRE for METAVIR fibrosis grade >= F2 and >=F3. We defined cutoff values for selection of patients with F0-F1 (sensitivity >95%) and for significant fibrosis F2-F4 (specificity >95%). RESULTS: Following exclusions, 85 patients were analysed (65 CHB, 19 CHC, 1 co-infected). Fibrosis stages were F0 (n = 3), F1 (n = 53), F2 (n = 15), F3 (n = 8) and F4 (n = 6). TE and MRE accuracy were comparable [AUROCTE >= F2: 0.914 (95% CI: 0.857-0.972) vs. AUROCMRE >= F2: 0.909 (0.840-0.977), P = 0.89; AUROCTE >= F3: 0.895 (0.816-0.974) vs. AUROCMRE >= F3: 0.928 (0.874-0.982), P = 0.42]. Cutoff values of <5.2 and >=8.9 kPa (TE) and <1.66 and >=2.18 kPa (MRE) diagnosed 64% and 66% of patients correctly as F0-F1 or F2-F4. A conditional strategy in inconclusive test results increased diagnostic yield to 80%. CONCLUSION: TE and MRE have comparable accuracy for detecting significant fibrosis, which was reliably detected or excluded in two-thirds of patients. A conditional strategy further increased diagnostic yield to 80%. KEY POINTS: * Both ultrasound-based transient elastography and magnetic resonance elastography can assess hepatic fibrosis. * Both have comparable accuracy for detecting liver fibrosis in viral hepatitis. * The individual techniques reliably detect or exclude significant liver fibrosis in 66 %. * A conditional strategy for inconclusive findings increases the number of correct diagnoses. PMID- 24158531 TI - Bimanual motor deficits in older adults predicted by diffusion tensor imaging metrics of corpus callosum subregions. AB - Age-related changes in the microstructural organization of the corpus callosum (CC) may explain declines in bimanual motor performance associated with normal aging. We used diffusion tensor imaging in young (n = 33) and older (n = 33) adults to investigate the microstructural organization of seven specific CC subregions (prefrontal, premotor, primary motor, primary sensory, parietal, temporal and occipital). A set of bimanual tasks was used to assess various aspects of bimanual motor functioning: the Purdue Pegboard test, simultaneous and alternating finger tapping, a choice reaction time test and a complex visuomotor tracking task. The older adults showed age-related deficits on all measures of bimanual motor performance. Correlation analyses within the older group showed that white matter fractional anisotropy of the CC occipital region was associated with bimanual fine manipulation skills (Purdue Pegboard test), whereas better performance on the other bimanual tasks was related to higher fractional anisotropy in the more anterior premotor, primary motor and primary sensory CC subregions. Such associations were less prominent in the younger group. Our findings suggest that structural alterations of subregional callosal fibers may account for bimanual motor declines in normal aging. PMID- 24158532 TI - Tabrizicola aquatica gen. nov. sp. nov., a novel alphaproteobacterium isolated from Qurugol Lake nearby Tabriz city, Iran. AB - A novel Gram-negative, aerobic, non-motile and rod-shaped bacterium was isolated from Qurugol Lake near Tabriz city. The bacterium grew chemoorganolheterotrophically and chemolithoautotrophically. However, photo organoheterotrophic, photo-lithoautotrophic and fermentative growth could not be demonstrated. The presence of photosynthesis genes pufL and pufM was not shown and photosynthesis pigments were not formed. Strain RCRI19(T) grew without NaCl and tolerated up to 3 % NaCl. Growth occurred at pH 6-9 (optimum, pH 7) and 15-55 degrees C (optimum 40-45 degrees C). Vitamins were not required for growth. The major fatty acids are C18:1 omega7C, 11-methyl C18:1 omega7C, C18:0 3-OH. The predominant respiratory quinone is ubiquinone Q-10. The G+C content of genomic DNA is 65.9 mol%. Analysis of 16S rRNA sequences showed that strain RCRI19(T) has the highest similarities with uncultured environmental sequences followed by members of the genera Rhodobacter (<=95.75 %), Haematobacter (<=95.53 %), Gemmobacter (<=95.17 %) and Falsirhodobacter (94.60 %) in the family Rhodobacteraceae. DNA-DNA relatedness between strain RCRI19(T) and the closest phylogenetically related strain, Rhodobacter blasticus LMG 4305(T), was 20 %. Based on its phenotypic and chemotaxonomic characteristics and considering that it does not form photosynthetic pigments and is unable to grow phototrophically, it is concluded that strain RCRI19(T) cannot be included into the genus Rhodobacter and any of the other related genera. Therefore, we propose to place the new bacterium into a new genus and species for which the name Tabrizicola aquatica gen. nov. and sp. nov. is proposed. The type strain is RCRI19(T) (=BCCM/LMG 25773(T )= JCM 17277(T )= KCTC 23724(T)). PMID- 24158533 TI - Bacillus xiamenensis sp. nov., isolated from intestinal tract contents of a flathead mullet (Mugil cephalus). AB - A taxonomic study was carried out on strain HYC-10(T), which was isolated from the intestinal tract contents of a flathead mullet, Mugil cephalus, captured from the sea off Xiamen Island, China. The bacterium was observed to be Gram positive, oxidase and catalase positive, rod shaped, and motile by subpolar flagella. The bacterium was found to grow at salinities of 0-12 % and at temperatures of 8-45 degrees C. The isolate was found to hydrolyze aesculin and gelatin, but was unable to reduce nitrate to nitrite. Phylogenetic analysis based on 16S rRNA gene sequences indicated that strain HYC-10(T) belongs to the genus Bacillus, with highest sequence similarity (99.3 %) to Bacillus aerophilus 28K(T), Bacillus stratosphericus 41KF2a(T) and Bacillus altitudinis DSM 21631(T), followed by Bacillus safensis DSM 19292(T) (99.5 %) and Bacillus pumilus DSM 27(T) (99.5 %), while the sequence similarities to others were all below 97.6 %. The genomic ANIm values between strain HYC-10(T) and three type strains (B. altitudinis DSM 21631(T), B. safensis DSM 19292(T) and B. pumilus DSM 27(T)) were determined to range from 89.11 to 91.53 %. The DNA-DNA hybridization estimate values between strain HYC-10(T) and the three type strains were from 36.60 to 44.00 %. The principal fatty acids identified were iso-C15:0 (39.1 %), anteiso-C15:0 (22.7 %), iso-C17:0 (13.1 %), C16:0 (6.1 %), anteiso-C17:0 (5.8 %) and iso-C16:0 (5.1 %). The G+C content of the chromosomal DNA was determined from the draft genome sequence to be 41.3 mol%. The respiratory quinone was determined to be MK-7 (100 %). Phosphatidylglycerol, diphosphatidylglycerol, aminoglycolipid, two glycolipids and two unknown phospholipids were found to be present. The combined genotypic and phenotypic data show that strain HYC-10(T) represents a novel species of the genus Bacillus, for which the name Bacillus xiamenensis sp. nov. is proposed, with the type strain HYC-10(T) (=CGMCC NO.1.12326(T) = LMG 27143(T) = MCCC 1A00008(T)). PMID- 24158534 TI - Response surface optimization for enhanced production of cellulases with improved functional characteristics by newly isolated Aspergillus niger HN-2. AB - Fungi isolated from partially decayed wood log samples showing characteristic diversity for spore colour, colony morphology and arrangement of spores were assessed for cellulolytic enzyme production. Isolates showing a cellulolytic index of >=2.0 were assayed for filter paper (FP) cellulase and beta-glucosidase (BGL) production. Molecular characterization confirmed the identity of the selected cellulolytic isolate as a strain of Aspergillus niger (A. niger HN-2). Addition of 2 % (w/v) urea enhanced FP and BGL activity by about 20 and 60 %, respectively. Validation studies conducted at parameters (29 degrees C, pH 5.4, moisture content 72 % and 66 h) optimized through response surface methodology in a solid-state static tray fermentation resulted in FP, BGL, cellobiohydrolase I (CBHI), endoglucanase (EG), xylanase activity and protein content of 25.3 FPU/g ds, 750 IU/g ds, 13.2 IU/g ds, 190 IU/g ds, 2890 IU/g ds and 0.9 mg/ml, respectively. In comparison, A. niger N402 which is a model organism for growth and development studies, produced significantly lower FP, BGL, CBHI, EG, xylanase activity and protein content of 10.0 FPU/g ds, 100 IU/g ds, 2.3 IU/g ds, 50 IU/g ds, 500 IU/g ds and 0.75 mg/ml, respectively under the same process conditions as were used for A. niger HN-2. Process optimization led to nearly 1.8- and 2.2-fold increase in FP and BGL activity, respectively showing promise for cellulase production by A. niger HN-2 at a higher scale of operation. Zymogram analysis revealed two isoforms each for EG and cellobiohydrolase and three isoforms for BGL. Crude cellulase complex produced by A. niger HN-2 exhibited thermostability under acidic conditions showing potential for use in biofuel industry. PMID- 24158535 TI - Salinarubrum litoreum gen. nov., sp. nov.: a new member of the family Halobacteriaceae isolated from Chinese marine solar salterns. AB - Three halophilic archaeal strains, XD46(T), YJ-63-S1 and ZS-1-H, were isolated from three Chinese marine solar salterns. All were observed to have pleomorphic cells that lysed in distilled water, stained Gram-negative and formed red pigmented colonies. They were found to grow optimally at 37 degrees C, at pH 7.0 and in the presence of 2.6 M NaCl and 0.05 M Mg(2+). The major polar lipids were identified as those typical for members of the Halobacteriaceae but also included major glycolipids chromatographically identical to sulfated mannosyl glucosyl diether (S-DGD-1), mannosyl glucosyl diether (DGD-1) and two unidentified ones. The 16S rRNA gene sequences of the three strains were 99.8-100 % identical, showing most similarity to sequences of members of the family Halobacteriaceae, and clustering together as a distinct clade in phylogenetic tree reconstructions. The rpoB' gene similarities between the three strains were 98.7-100 % and lower to the sequences of other halobacteria. Their DNA G+C contents were determined to be 65.1-65.5 mol%. The phenotypic, chemotaxonomic and phylogenetic properties suggest that strains XD46(T) (=CGMCC 1.12237(T) = JCM 18649(T)), YJ-63-S1 (=CGMCC 1.12574) and ZS-1-H (=CGMCC 1.12544) represent a novel species in a new genus within the family Halobacteriaceae, for which the name Salinarubrum litoreum gen. nov., sp. nov. is proposed. PMID- 24158536 TI - Prognostic significance of basaloid squamous cell carcinoma in head and neck cancer. AB - IMPORTANCE: Head and neck basaloid squamous cell carcinoma (BSCC) has been considered a more aggressive variant of squamous cell carcinoma (SCC) with a poorer prognosis, although case-control studies have reached conflicting conclusions. OBJECTIVE: To examine the prognostic significance of head and neck BSCC on overall survival in a large population-based registry. DESIGN AND SETTING: Retrospective data review of a population-based registry from the Surveillance, Epidemiology, and End Results database. PARTICIPANTS: Individual case data for 34,196 patients treated between January 2004 and December 2009 with head and neck primary SCC (n = 33,554) and BSCC (n = 642) of the oral cavity, oropharyx, larynx, or hypopharynx. Patients with metastatic disease, incomplete staging information, and those who did not receive surgery or radiation were excluded. INTERVENTIONS: Patients had been treated with surgery, radiation, or both. MAIN OUTCOMES AND MEASURES: Distribution of patient characteristics between patients of each histology. Hazard ratios, 3-year overall survival, subgroup, and multivariate analysis of patient and treatment characteristics were investigated. RESULTS: Across each cohort, patients with BSCC more often had high-grade tumors and treatment with lymph node dissection. Multivariate analysis found that group stage, T stage, N stage, size, lymph node dissection, and age statistically significantly influenced overall survival. In multivariate analysis, the hazard ratio for death for patients with BSCC in the oral cavity and larynx and hypopharynx was not statistically significantly different from that for SCC. In the oropharynx, the hazard ratio for death for BSCC histology compared with SCC histology was 0.73 (P = .03). CONCLUSIONS AND RELEVANCE: Compared with SCC, BSCC is not an independent adverse prognostic factor for patients with head and neck cancer. The Surveillance, Epidemiology, and End Results analysis has limits, including lack of information regarding chemotherapy, but after controlling for disease and treatment variables, including neck dissection and radiotherapy, BSCC histology did not have an independent adverse prognostic effect on overall survival. The reported association between human papillomavirus and BSCC histology may explain the lower hazard ratio for death in patients with oropharynx BSCC. PMID- 24158537 TI - Induction of apoptosis by directing oncogenic Bcr-Abl into the nucleus. AB - The chimeric Bcr-Abl oncoprotein, which causes chronic myeloid leukemia, mainly localizes in the cytoplasm, and loses its ability to transform cells after moving into the nucleus. Here we report a new strategy to convert Bcr-Abl to be an apoptotic inducer by altering its subcellular localization. We show that a rapalog nuclear transport system (RNTS) containing six nuclear localization signals directs Bcr-Abl into the nucleus and that nuclear entrapped Bcr-Abl induces apoptosis and inhibits proliferation of CML cells by activating p73 and shutting down cytoplasmic oncogenic signals mediated by Bcr-Abl. Coupling cytoplasmic depletion with nuclear entrapment of Bcr-Abl synergistically enhances the inhibitory effect of nuclear Bcr-Abl on its oncogenicity in mice. These results provide evidence that direction of cytoplasmic Bcr-Abl to the nucleus offers an alternative CML therapy. PMID- 24158538 TI - An efficient, nonlinear stability analysis for detecting pattern formation in reaction diffusion systems. AB - Reaction diffusion systems are often used to study pattern formation in biological systems. However, most methods for understanding their behavior are challenging and can rarely be applied to complex systems common in biological applications. I present a relatively simple and efficient, nonlinear stability technique that greatly aids such analysis when rates of diffusion are substantially different. This technique reduces a system of reaction diffusion equations to a system of ordinary differential equations tracking the evolution of a large amplitude, spatially localized perturbation of a homogeneous steady state. Stability properties of this system, determined using standard bifurcation techniques and software, describe both linear and nonlinear patterning regimes of the reaction diffusion system. I describe the class of systems this method can be applied to and demonstrate its application. Analysis of Schnakenberg and substrate inhibition models is performed to demonstrate the methods capabilities in simplified settings and show that even these simple models have nonlinear patterning regimes not previously detected. The real power of this technique, however, is its simplicity and applicability to larger complex systems where other nonlinear methods become intractable. This is demonstrated through analysis of a chemotaxis regulatory network comprised of interacting proteins and phospholipids. In each case, predictions of this method are verified against results of numerical simulation, linear stability, asymptotic, and/or full PDE bifurcation analyses. PMID- 24158539 TI - Cochrane in CORR(r): Arthroplasties (with and without bone cement) for proximal femoral fractures in adults. PMID- 24158540 TI - Cochrane in CORR (r): Joint lavage for osteoarthritis of the knee. PMID- 24158541 TI - How does external rotation bracing influence motion and functional scores after arthroscopic shoulder stabilization? AB - BACKGROUND: After arthroscopic shoulder stabilization, the loss of motion or delayed recovery of motion remains a clinical problem and may lead to poor patient satisfaction. There remains no consensus regarding the optimal position for postoperative immobilization and it is not known whether the position for shoulder immobilization has an effect on motion and functional recovery. QUESTIONS/PURPOSES: We asked: (1) Do patients treated with external rotation (ER) bracing after arthroscopic anterior shoulder stabilization reliably regain ROM and shoulder function? And (2) what is the frequency of recurrent instability and brace-related complications associated with the use of ER bracing? METHODS: Forty consecutive patients with a primary diagnosis of anterior shoulder instability underwent arthroscopic stabilization and received postoperative ER bracing; 33 patients (83%; mean age, 23 years; range, 13-44 years) were followed for at least 1 year postoperatively and seven patients were lost to followup. Shoulder ROM and functional scores were recorded preoperatively and at 2 weeks, 12 weeks, 6 months, and greater than 1 year (mean, 16 months) after surgery. RESULTS: All patients recovered their preoperative ROM and most patients achieved normal ROM by 3 months after surgery. Significant improvements in American Shoulder and Elbow Surgeons (ASES) and Western Ontario Shoulder Instability (WOSI) scores were observed at each postoperative time point. The mean (+/- SD) final scores were 95 +/- 9 for the ASES and 87% +/- 17% for the WOSI (p < 0.001 compared to preoperative scores). One patient (3%) developed recurrent instability. No patients underwent reoperation for the injured shoulder for any reason during the followup period. CONCLUSIONS: ER bracing after arthroscopic shoulder stabilization is associated with a predictable recovery of ROM and functional score improvement. Future studies comparing ER bracing to traditional sling use should be conducted to determine the optimal method of postoperative immobilization. LEVEL OF EVIDENCE: Level IV, therapeutic study. See Instructions for Authors for a complete description of levels of evidence. PMID- 24158542 TI - Cochrane in CORR(r): Surgical interventions for treating acute Achilles tendon ruptures (Review). PMID- 24158543 TI - Reply to the Letter to the Editor: Mid-America Orthopaedic Association Physician in Training Award: Surgical technique: Pediatric supracondylar humerus fractures: a technique to aid closed reduction. PMID- 24158544 TI - A combined experimental and computational study of the catalytic dehydration of glycerol on microporous zeolites: an investigation of the reaction mechanism and acrolein selectivity. AB - The catalytic activity and the acrolein selectivity for liquid phase glycerol dehydration on beta zeolites (HNa-beta-k) were found to be dependent on the reaction temperature as well as on the amount of acid sites on the zeolites. An increase in the reaction temperature favors the acrolein selectivity. The acrolein selectivity increases with the Na(+)/H(+) ratio and the glycerol conversion decreases with it so that a maximum acrolein yield is obtained when a certain amount of acidic sites are replaced by non-active Na(+) sites. The computational results indicate that 3-hydoxylpropanal (HPA) is an important intermediate that determines the final product selectivity. The relative rates of the different reaction pathways for HAP can be affected by the amount of water molecules involved in its homogeneous reaction. Based on the reaction mechanism proposed, it was hypothesized that smaller pores reduce activity but increase selectivity to acrolein, and results of the H-MFI zeolite were consistent with this hypothesis. Our work provides important insight into the overall landscape of the reaction mechanism and can be used to help design reaction systems that have good acrolein selectivity for the liquid phase glycerol dehydration reactions. PMID- 24158548 TI - Asymmetric reductive amination. AB - Asymmetric reductive amination (ARA) affords synthetically valuable chiral amines straightforwardly. This chapter reviews the recent advances made in the area, focusing on ARA by hydrogenation, transfer hydrogenation, organocatalytic reduction, and biocatalytic reduction. PMID- 24158546 TI - Characterization of human placental glycosaminoglycans and regional binding to VAR2CSA in malaria infected erythrocytes. AB - Placental malaria is a serious problem in sub-Saharan Africa. Young women are particular susceptible to contracting this form of malaria during their first or second pregnancy despite previously acquired immunity from past infections. Placental malaria is caused by Plasmodium falciparum parasites expressing VAR2CSA on the erythrocyte surface. This protein adheres to a low-sulfated chondroitin sulfate-A found in placental tissue causing great harm to both mother and developing fetus. In rare cases, the localization of infected erythrocytes to the placenta can even result in the vertical transmission of malaria. In an effort to better understand this infection, chondroitin sulfate was isolated from the cotyledon part of the placenta, which should be accessible for parasite adhesion, as well as two non-accessible parts of the placenta to serve as controls. The placental chondroitin sulfate structures and their VAR2CSA binding were characterized. All portions of human placenta contained sufficient amounts of the appropriate low-sulfated chondroitin sulfate-A to display high-affinity binding to a recombinant truncated VAR2CSA construct, as determined using surface plasmon resonance. The cotyledon is the only placental tissue accessible to parasites in the bloodstream, suggesting it is the primary receptor for parasite infected red blood cells. PMID- 24158549 TI - Genome Sequence of Rhodococcus sp. Strain BCP1, a Biodegrader of Alkanes and Chlorinated Compounds. AB - Rhodococcus sp. strain BCP1 cometabolizes chlorinated compounds and mineralizes a broad range of alkanes, as it is highly tolerant to them. The high-quality draft genome sequence of Rhodococcus sp. strain BCP1, consisting of 6,231,823 bp, with a G+C content of 70.4%, 5,902 protein-coding genes, and 58 RNA genes, is presented here. PMID- 24158550 TI - A divergent variant of the eleventh human polyomavirus species, saint louis polyomavirus. AB - Saint Louis polyomavirus (STLPyV) was recently discovered in human feces. Using random-primed rolling circle amplification combined with deep sequencing, we have found a divergent variant of STLPyV in a sanitized human skin wart specimen. The result strongly suggests that STLPyV directly infects humans and is not simply a dietary contaminant. PMID- 24158551 TI - Draft Genome Sequence of the Novel Peptoniphilus sp. Strain ChDC B134, Isolated from a Human Periapical Abscess Lesion. AB - The genus Peptoniphilus comprises butyrate-producing, nonsaccharolytic species that use peptone and amino acids as major energy sources. The novel Peptoniphilus sp. strain ChDC B134 (=KCOM 1628) was isolated from a human periapical abscess lesion. Here, we report the draft genome sequence of the strain. PMID- 24158552 TI - Draft Genome Sequences of Bordetella hinzii and Bordetella trematum. AB - Bordetella hinzii colonizes the respiratory tracts of poultry but can also infect immunocompromised humans. Bordetella trematum, however, only infects humans, causing ear and wound infections. Here, we present the first draft genome sequences of strains B. hinzii ATCC 51730 and B. trematum CCUG 13902. PMID- 24158553 TI - Complete Genome Sequence of an Avian Bornavirus Isolated from a Healthy Canadian Goose (Branta canadensis). AB - A recent survey among wild birds demonstrated the presence of a unique genotype of avian bornavirus (ABV) in wild geese and swans in North America. Here, we report the first complete genome sequence of an avian bornavirus of the goose genotype. PMID- 24158554 TI - Genome of the Root-Associated Plant Growth-Promoting Bacterium Variovorax paradoxus Strain EPS. AB - Variovorax paradoxus is a ubiquitous betaproteobacterium involved in plant growth promotion, the degradation of xenobiotics, and quorum-quenching activity. The genome of V. paradoxus strain EPS consists of a single circular chromosome of 6,550,056 bp, with a 66.48% G+C content. PMID- 24158555 TI - Complete Genome Sequences of Five Chrysodeixis chalcites Nucleopolyhedrovirus Genotypes from a Canary Islands Isolate. AB - The Chrysodeixis chalcites single nucleopolyhedrovirus (ChchSNPV) infects and kills C. chalcites larvae, an important pest of banana crops in the Canary Islands. Five genotypes present in the most prevalent and widespread isolate in the Canary Islands were sequenced, providing genetic data relevant to the genotypic and phenotypic diversity of this virus. PMID- 24158556 TI - Genome Sequence of Growth-Improving Paenibacillus mucilaginosus Strain KNP414. AB - Paenibacillus mucilaginosus is a critical growth-improving silicate bacterium. Here, we report the complete genome sequence of P. mucilaginosus strain KNP414. This information will provide us with the opportunity to understand its molecular mechanisms and develop more effective utilization of the strain. PMID- 24158557 TI - Complete Genome Sequence of an H12N8 Avian Influenza Virus Isolated from Wild Bird Feces in Hunan East Dongting Lake National Nature Reserve. AB - An H12N8 subtype avian influenza virus (AIV) was isolated from a wild bird in China in 2011. It is the first report of isolation of the H12N8 subtype AIV in Asia. Phylogenetic analysis results suggested it is a reassortant, and all eight gene segments belong to the Eurasian gene pool. PMID- 24158558 TI - Complete Genome Sequence of a UL96 Mutant Cytomegalovirus Towne-BAC (Bacterial Artificial Chromosome) Isolate Passaged in Fibroblasts To Allow Accumulation of Compensatory Mutations. AB - Here, we present the complete genome sequence of a cytomegalovirus Towne-BAC (bacterial artificial chromosome) isolate that we first genetically engineered to mutate the UL96 gene and then serially passaged in human fibroblasts to allow for the accumulation of compensatory mutations. A total of 17 single-base substitutions were discovered in the passaged genome compared to the reference sequence (KF493877). PMID- 24158559 TI - Draft Genome Sequence of Bacillus sp. Strain NSP2.1, a Nonhalophilic Bacterium Isolated from the Salt Marsh of the Great Rann of Kutch, India. AB - The 5.52-Mbp draft genome sequence of Bacillus sp. strain NSP2.1, a nonhalophilic bacterium isolated from the salt marsh of the Great Rann of Kutch, India, is reported here. An analysis of the genome of this organism will facilitate the understanding of its survival in the salt marsh. PMID- 24158560 TI - Complete Genome Sequence of the Escherichia coli PMV-1 Strain, a Model Extraintestinal Pathogenic E. coli Strain Used for Host-Pathogen Interaction Studies. AB - Escherichia coli is a highly versatile species, causing diverse intestinal and extraintestinal infections. Here, we present the complete genome sequence of PMV 1, an O18:K1 extraintestinal pathogenic E. coli (ExPEC) strain that is used as a model for peritonitis in mice and was useful for deciphering the innate immune response triggered by ExPEC infections. PMID- 24158561 TI - Chemoresistance to gemcitabine in hepatoma cells induces epithelial-mesenchymal transition and involves activation of PDGF-D pathway. AB - Hepatocellular carcinoma (HCC) is one of the common malignances in the world and has high mortality in part due to development of acquired drug resistance. Therefore, it is urgent to investigate the molecular mechanism of drug resistance in HCC. To explore the underlying mechanism of drug resistance in HCC, we developed gemcitabine-resistant (GR) HCC cells. We used multiple methods to achieve our goal including RT-PCR, Western blotting analysis, transfection, Wound healing assay, migration and invasion assay. We observed that gemcitabine resistant cells acquired epithelial-mesenchymal transition (EMT) phenotype. Moreover, we found that PDGF-D is highly expressed in GR cells. Furthermore, down regulation of PDGF-D in GR cells led to partial reversal of the EMT phenotype. Our findings demonstrated that targeting PDGF-D could be a novel strategy to overcome gemcitabine resistance in HCC. PMID- 24158563 TI - Ferromagnetic interaction and slow magnetic relaxation in a Co3 cluster-based three-dimensional framework. AB - A Co3 cluster-based three-dimensional (3D) framework, [Co3(4 ptz)4(N3)2(H2O)2].4DMF (1; 4-Hptz = 4-(1H-tetrazol-5-yl)pyridine), exhibits ferromagnetic interactions and slow-magnetic relaxation behavior. PMID- 24158562 TI - [Waiting times for cancer care in four most frequent cancers in several French regions in 2011 and 2012]. AB - Measuring waiting times is a good indicator of quality of cancer care and could reveal inequalities in cancer care access. AIMS: To determine the most representative waiting times in breast, lung, colon and prostate cancer care in several regions of France. To analyze the influence of individual, medical or health care system factors on those waiting times. METHODS: This study was piloted by the French Cancer Institute in partnership with the National Federation of the Regional Health Observatories and was driven by the Regional Oncology Networks and the Regional Health Observatories. In 2011, 2,530 women with breast cancer and 1,945 patient with lung cancer were included in eight regions, and in 2012, 3,248 patients with colon cancer and 4,207 men with prostate cancer were included in 13 regions, two of which were overseas departments. Data were analyzed from multidisciplinary discussion reports and from medical records. RESULTS: The mean time intervals (+/- standard deviation) for the various components of access to care were as follows in breast cancer: mammography to pathologist diagnosis, 17,7 days (+/-15,9); diagnosis (or treatment proposal) to surgery, 22,9 days (+/-13,9). In lung cancer: first suspect medical image to pathologist diagnosis, 21,5 days (+/-17,6); diagnosis to treatment proposal, 13,5 days (+/-10,7). In colon cancer: coloscopy to pathologist diagnosis, 4,5 days (+/-4,1); diagnosis to surgery, 18,9 days (+/ 14,9). In prostate cancer: pathologist diagnosis to treatment proposal, 36,5 days (+/-26,5); treatment proposal to surgery, 45,2 days (+/-30,1). Data collection was particularly difficult because of very heterogeneous way in medical records filling by care centers, so the data collection method used in the study could not be used in routine procedures. Waiting times measured in the four cancers had an important variability. In fact, age, circumstance of diagnosis, tumor stage and category of care center had an influence. After considering those different factors, differences between regions remained from range 2 to 4. Those regional differences could be explained by organizational factors but were not explored in our study. In the same way, data on individual factors (social vulnerability, category of employment) were not available to measure their effects on this study. Besides, our results were comparable to those in international publications or national recommendations in other countries. CONCLUSION: These results suggest that waiting times could be good indicators and could reveal inequalities in cancer care access. Measuring them would lead to characterize those inequalities and to propose actions to improve access to cancer care whose impact could be measured. PMID- 24158564 TI - Diagnosis of obstructive sleep apnea by peripheral arterial tonometry: meta analysis. AB - IMPORTANCE: Efficient diagnosis and early treatment of obstructive sleep apnea may help prevent the development of related morbidity and mortality. Compared with polysomnography (PSG), ambulatory sleep study devices offer the possibility of an accurate diagnosis with convenience and low cost. OBJECTIVE: To assess the correlation between sleep indexes measured by a portable sleep-testing device (peripheral arterial tonometry [PAT]) and those measured by PSG. DATA SOURCES: We searched PubMed, MEDLINE, the Cochrane Trial Registry (through May 2013), and relevant article bibliographies. STUDY SELECTION: Systematic review and meta analysis of studies assessing correlation of sleep indexes between PAT devices and PSG in adults (aged >18 years). Included studies provided a bivariate correlation coefficient for sleep indexes, specifically the respiratory disturbance index (RDI), apnea-hypopnea index (AHI), and oxygen desaturation index (ODI). DATA EXTRACTION AND SYNTHESIS: Included studies were reviewed by 2 independent reviewers. Reported correlation values for the RDI, AHI, and ODI between a commercially available PAT device (WatchPAT) and PSG were systematically reviewed. A comprehensive meta-analysis software package was used for statistical analysis. MAIN OUTCOMES AND MEASURES: Assessment of the correlation between PAT and PSG as measured by AHI, RDI, and ODI. RESULTS: Fourteen studies met inclusion criteria and had data suitable for pooling (909 patients). Of these, 13 studies had blinded study designs, with PAT and PSG conducted simultaneously in the home or the laboratory setting. One study contained 2 trial phases for the same patient group (n = 29), one laboratory based and the other home based, which were analyzed separately. One study contained 2 different study groups based on age. Overall, correlation of the RDI and AHI was high (r = 0.889 [95% CI, 0.862-0.911]; P < .001). Studies comparing the RDI between PAT and PSG had a combined correlation of 0.879 (95% CI, 0.849 0.904; P < .001); those comparing the AHI, 0.893 (0.857-0.920; P < .001); and those comparing the ODI, 0.942 (0.894-0.969; P < .001). Analysis of publication bias revealed a nonsignificant Egger regression intercept. CONCLUSIONS AND RELEVANCE: Respiratory indexes calculated using PAT-based portable devices positively correlated with those calculated from the scoring of PSG. Strengthened by the blinded design of most of the included studies, this technology represents a viable alternative to PSG for confirmation of clinically suspected sleep apnea. PMID- 24158565 TI - Facilitators and barriers to service user involvement in mental health guidelines: lessons from the Netherlands. AB - This study is the first in-depth qualitative study of service user involvement in the development of multidisciplinary mental health guidelines in the Netherlands. The study comprised a desk study of guidelines (n = 12) and case studies of service user involvement in five guidelines using document analysis, interviews (n = 24) and observations. The desk study shows that all multidisciplinary mental health guidelines have taken service user perspectives into account to some extent. The five guideline case studies led to the identification of ten main themes. Findings will assist guideline developers in making early, informed decisions on involving service users effectively. PMID- 24158566 TI - Direct catalytic asymmetric addition of acetonitrile to N-thiophosphinoylimines. AB - Direct catalytic addition of acetonitrile pronucleophiles to thiophosphinoylimines is described. Soft Lewis acid-hard Bronsted base cooperative catalysis is crucial to promote this elusive carbon-carbon bond forming reaction in an enantioselective fashion. PMID- 24158567 TI - Elastomeric microvalves as tunable nanochannels for concentration polarization. AB - Elastomeric microvalves in poly(dimethylsiloxane) (PDMS) devices are today's paradigm for massively parallel microfluidic operations. Here, we report that such valves can act as nanochannels upon closure. When tuning nanospace heights between ~55 nm and ~7 nm, the nanofluidic phenomenon of concentration polarization could be induced. A wide range of concentration polarization regimes (anodic and cathodic analyte focusing and stacking) was achieved simply by valve pressure actuation. Electro-osmotic flow generated a counterpressure which also could be used to actuate between concentration polarization regimes. 1000-fold preconcentration of fluorescein was achieved in just 100 s in the anodic focusing regime. After valve opening, a concentrated sample plug could be transported through the valve, though at the cost of some defocusing. Reversible nanochannels open new avenues for integrating electrokinetic operations and assays in large scale integrated microfluidics. PMID- 24158568 TI - Donor-acceptor conjugated polymers based on a pentacyclic aromatic lactam acceptor unit for polymer solar cells. AB - A series of donor-acceptor (D-A) conjugated polymers P1-P4 was synthesized by copolymerization of a novel pentacyclic aromatic lactam acceptor unit, thieno[20,30:5,6]pyrido[3,4-g]thieno[3,2-c]-isoquinoline-5,11(4H,10H)-dione (TPTI), with a donor unit, benzo-[1,2-b:4,5-b0]dithiophene (BDT) or dithieno[3,2 b:20,30-d]silole (DTS). The effect of the donor units and the side chains on TPTI on polymer properties and solar cell performance was investigated. Bulk heterojunction solar cells based on P1 and PC71BM afforded the highest power conversion efficiency (PCE) of 5.30%. PMID- 24158569 TI - Nickel induces interleukin-1beta secretion via the NLRP3-ASC-caspase-1 pathway. AB - Exposure to nickel (Ni(2+)) can trigger allergic reactions in susceptible individuals, which is widely accepted as the major cause of allergic contact hypersensitivity (CHS) worldwide. Although Ni(2+)-induced proinflammatory responses clearly play a pivotal role in CHS, the underlying molecular mechanism has not been fully defined. Here we report that Ni(2+) activates the NLRP3-ASC caspase-1 immune signaling pathway in antigen-presenting cells, leading to the proteolytic processing and secretion of a proinflammatory cytokine, interleukin 1beta (IL-1beta). The activation of this signaling axis is independent of phagolysosome-cathepsin B pathway. Instead, Ni(2+) induces mitochondrial reactive oxygen species accumulation and cation fluxes, both of which are required for activating the NLRP3-ASC-caspase-1 pathway. Together, these results identified a novel innate immune signaling pathway (NLRP3-ASC-caspase-1-IL-1beta) activated by Ni(2+) and provided a mechanistic basis for optimizing the therapeutic intervention against Ni(2+)-induced allergy in patients. PMID- 24158571 TI - MicroRNA-dependent control of the cardiac fibroblast secretome. PMID- 24158570 TI - Influence of hyperoxia and mechanical ventilation in lung inflammation and diaphragm function in aged versus adult rats. AB - Although assist ventilation with FIO2 0.21 is the preferable mode of ventilation in the intensive care unit, sometimes controlled ventilation with hyperoxia is needed. But the impact of this setting has not been extensively studied in elderly subjects. We hypothesized that a high fraction of inspired oxygen (FiO(2)) and controlled mechanical ventilation (CMV) is associated with greater deleterious effects in old compared to adult subjects. Adult and old rats were submitted to CMV with low tidal volume (6 ml/kg) and FiO(2) 1 during 3 or 6 h. Arterial blood gas samples were measured at 0, 60 and 180 min (four groups: old and adult rats, 3 or 6 h of CMV), and additionally at 360 min (two groups: old and adult rats, 6 h of CMV). Furthermore, total protein content (TPC) and tumor necrosis factor-alpha (TNF-alpha) in bronchoalveolar lavage were assessed; lung tissue was used for malondialdehyde and histological analyses, and the diaphragm for measurement of contractile function. Arterial blood gas analysis showed an initial (60 min) greater PaO(2) in elderly versus adult animals; after that time, elderly animals had lowers pH and PaO(2), and greater PaCO(2). After 3 h of CMV, TPC and TNF-alpha levels were higher in the old compared with the adult group (P < 0.05). After 6 h of MV, malondialdehyde was significantly higher in elderly compared with the adult animals (P < 0.05). Histological analysis showed leukocyte infiltration and edema, greater in old animals. In diaphragm, twitch contraction with caffeine significantly declined after 6 h of CMV only for the elderly group. These data support the hypothesis that relatively short-term CMV with low tidal volume and hyperoxia has greatest impact in elderly rats, decreasing diaphragmatic contractile function and increasing lung inflammation. PMID- 24158572 TI - miR-663 and the miRaculous vascular smooth muscle phenotypic switch. PMID- 24158573 TI - A twist of proepicardial fate. PMID- 24158574 TI - Heart regeneration: a tale of cell reprogramming. PMID- 24158575 TI - Classic studies of cultured cardiac myocyte hypertrophy: interview with a transformer. PMID- 24158576 TI - RyR-NCX-SERCA local cross-talk ensures pacemaker cell function at rest and during the fight-or-flight reflex. AB - RATIONALE: A recent study published in Circulation Research by Gao et al used sinoatrial node (SAN)-targeted, incomplete Ncx1 knockout in mice to explore the role of the Na(+)/Ca(2+) exchanger (NCX) in cardiac pacemaker. The authors concluded that NCX is required for increasing sinus rates, but not for maintaining resting heart rate. This conclusion was based, in part, on numeric model simulations performed by Gao et al that reproduced their experimental results of unchanged action potentials in the knockout SAN cells. The authors, however, did not simulate the NCX current (INCX), that is, the subject of the study. OBJECTIVE: We extended numeric examinations to simulate INCX in their incomplete knockout SAN cells that is crucial to interpret the study results. METHODS AND RESULTS: INCX and Ca(2+) dynamics were simulated using different contemporary numeric models of SAN cells. We found that minimum diastolic Ca(2+) levels and INCX amplitudes generated by remaining NCX molecules (only 20% of control) remained almost unchanged. Simulations using a new local Ca(2+) control model indicate that these powerful compensatory mechanisms involve complex local cross-talk of Ca(2+) cycling proteins and NCX. Specifically, lower NCX expression facilitates Ca(2+)-induced Ca(2+) release and larger local Ca(2+) releases that stabilize diastolic INCX. Further reduction of NCX expression results in arrhythmia and halt of automaticity. CONCLUSIONS: Remaining NCX molecules in the incomplete knockout model likely produce almost the same diastolic INCX as in wild-type cells. INCX contribution is crucially important for both basal automaticity of SAN cells and during the fight-or-flight reflex. PMID- 24158577 TI - A method for the determination of D-kynurenine in biological tissues. AB - D-kynurenine (D-KYN), a metabolite of D-tryptophan, can serve as the bioprecursor of kynurenic acid (KYNA) and 3-hydroxykynurenine, two neuroactive compounds that are believed to play a role in the pathophysiology of several neurological and psychiatric diseases. In order to investigate the possible presence of D-KYN in biological tissues, we developed a novel assay based on the conversion of D-KYN to KYNA by purified D-amino acid oxidase (D-AAO). Samples were incubated with D AAO under optimal conditions for measuring D-AAO activity (100 mM borate buffer, pH 9.0), and newly produced KYNA was detected by high-performance liquid chromatography (HPLC) with fluorimetric detection. The detection limit for D-KYN was 300 fmol, and linearity of the assay was ascertained up to 300 pmol. No assay interference was noted when other D-amino acids, including D-serine and D aspartate, were present in the incubation mixture at 50-fold higher concentrations than D-KYN. Using this new method, D-KYN was readily detected in the brain, liver, and plasma of mice treated systemically with D-KYN (300 mg/kg). In these experiments, enantioselectivity was confirmed by determining total kynurenine levels in the same samples using a conventional HPLC assay. Availability of a sensitive, specific, and simple method for D-KYN measurement will be instrumental for evaluating whether D-KYN should be considered for a role in physiology and pathology. PMID- 24158578 TI - Occurrence, degradation, and effect of polymer-based materials in the environment. AB - There is now a plethora of polymer-based materials (PBMs) on the market, because of the increasing demand for cheaper consumable goods, and light-weight industrial materials. Each PBM constitutes a mixture of their representative polymer/sand their various chemical additives. The major polymer types are polyethylene, polypropylene,and polyvinyl chloride, with natural rubber and biodegradable polymers becoming increasingly more important. The most important additives are those that are biologically active, because to be effective such chemicals often have properties that make them resistant to photo-degradation and biodegradation. During their lifecycle,PBMs can be released into the environment form a variety of sources. The principal introduction routes being general littering, dumping of unwanted waste materials,migration from landfills and emission during refuse collection. Once in the environment,PBMs are primarily broken down by photo-degradation processes, but due to the complex chemical makeup of PBMs, receiving environments are potentially exposed to a mixture of macro-, meso-, and micro-size polymer fragments, leached additives, and subsequent degradation products. In environments where sunlight is absent (i.e., soils and the deep sea) degradation for most PBMs is minimal .The majority of literature to date that has addressed the environmental contamination or disposition of PBMs has focused on the marine environment. This is because the oceans are identified as the major sink for macro PBMs, where they are known to present a hazard to wildlife via entanglement and ingestion. The published literature has established the occurrence of microplastics in marine environment and beach sediments, but is inadequate as regards contamination of soils and freshwater sediments. The uptake of microplastics for a limited range of aquatic organisms has also been established, but there is a lack of information regarding soil organisms, and the long-term effects of microplastic uptake are also less well understood.There is currently a need to establish appropriate degradation test strategies consistent with realistic environmental conditions, because the complexity of environmental systems is lost when only one process (e.g., hydrolysis) is assessed in isolation. Enhanced methodologies are also needed to evaluate the impact of PBMs to soil and freshwater environments. PMID- 24158579 TI - Effects of addictive substances during pregnancy and infancy and their analysis in biological materials. AB - The use of addictive substances during pregnancy is a serious social problem, not only because of effects on the health of the woman and child, but also because drug or alcohol dependency detracts from child care and enhances the prospect of child neglect and family breakdown. Developing additive substance abuse treatment programs for pregnant women is socially important and can help ensure the health of babies, prevent subsequent developmental and behavioral problems (i.e., from intake of alcohol or other additive substances such as methamphetamine, cocaine,or heroine) and can reduce addiction costs to society. Because women of childbearing age often abuse controlled substances during their pregnancy, it is important to undertake biomonitoring of these substances in biological samples taken from the pregnant or nursing mother (e.g., blood, urine,hair, breast milk, sweat, oral fluids, etc.), from the fetus and newborn (e.g., meconium,cord blood, neonatal hair and urine) and from both the mother and fetus (i.e.,amniotic fluids and placenta). The choice of specimens to be analyzed is determined by many factors; however, the most important is knowledge of the chemical and physical characteristics of a substance and the route of it administration. Maternal and neonatal biological materials reflect exposures that occur over a specific time period, and each of these biological specimens has different advantages and disadvantages,in terms of accuracy, time window of exposure and cost/benefit ratio.Sampling the placenta may be the most important biomonitoring choice for assessing in utero exposure to addictive substances. The use of the placenta in scientific research causes a minimum of ethical problems, partly because its sampling is noninvasive, causes no harm to mother or child, and partly because, in any case,placentas are discarded and incinerated after birth. Such samples, when properly analyzed, may provide key essential information about fetal exposure to toxic substances, and may provide the groundwork for protecting the fetus or newborn and the mother from further damage.Several sensitive and specific bioanalytical methods are commonly utilized to accurately measure for drug biomarkers of in utero drug exposure. Moreover, several immunoassay methods are used to rapidly screen for drugs in many biological specimen types. However, results from immunoassays should be carefully interpreted,and should be confirmed by more specific and sensitive chromatographic methods, such as GC-MS or LC-MS. Although techniques for analysis of addictive substances are still being developed or are being refined, current methods are efficient and sensitive and provide valuable information on human exposures to addictive substances and their metabolites. PMID- 24158580 TI - Genetic structure and diversity of animal populations exposed to metal pollution. AB - Studying the genetic diversity of wild populations that are affected by pollution provides a basis for estimating the risks of environmental contamination to both wildlife, and indirectly to humans. Such research strives to produce both a better understanding of the underlying mechanisms by which genetic diversity is affected,and the long-term effects of the pollutants involved.In this review, we summarize key aspects of the field of genetic ecotoxicology that encompasses using genetic patterns to examine metal pollutants as environmental stressors of natural animal populations. We address genetic changes that result from xenobiotic exposure versus genetic alterations that result from natural ecological processes. We also describe the relationship between metal exposure and changes in the genetic diversity of chronically exposed populations, and how the affected populations respond to environmental stress. Further, we assess the genetic diversity of animal populations that were exposed to metals, focusing on the literature that has been published since the year 2000.Our review disclosed that the most common metals found in aquatic and terrestrial ecosystems were Cd, Zn, Cu and Pb; however, differences in the occurrence between aquatic (Cd=Zn>Cu>Pb>Hg) and terrestrial (Cu>Cd>Pb>Zn>Ni)environments were observed. Several molecular markers were used to assess genetic diversity in impacted populations, the order of the most common ones of which were SSR's > allozyme > RAPD's > mtDNA sequencing> other molecular markers.Genetic diversity was reduced for nearly all animal populations that were exposed to a single metal, or a mixture of metals in aquatic ecosystems (except in Hyalella azteca, Littorina littorea, Salmo trutta, and Gobio gobio); however, the pattern was less clear when terrestrial ecosystems were analyzed.We propose that future research in the topic area of this paper emphasizes seven key areas of activity that pertain to the methodological design of genetic ecotoxicological studies. Collectively, these points are designed to provide more accurate data and a deeper understanding of the relationship between alterations in genetic diversity of impacted populations and metal exposures. In particular, we believe that the exact nature of all tested chemical pollutants be clearly described, biomarkers be included, sentinel organisms be used, testing be performed at multiple experimental sites, reference populations be sampled in close geographical proximity to where pollution occurs, and genetic structure parameters and high throughput technology be more actively employed. Furthermore, we propose a new class of biomarkers,termed "biomarkers of permanent effect," which may include measures of genetic variability in impacted populations. PMID- 24158581 TI - Bioamplification as a bioaccumulation mechanism for persistent organic pollutants (POPs) in wildlife. AB - Persistent organic pollutant bioaccumulation models have generally been formulated to predict bioconcentration and biomagnification. A third bioaccumulation process that can mediate chemical fugacity in an organism is bioamplification.Bioamplification occurs when an organism loses body weight and the chemical partitioning capacity occurs at a rate that is faster than the chemical can be eliminated.Although bioamplification has not been widely recognized as a bioaccumulation process, the potential consequences of this process are significant. Bioamplification causes an increase in chemical fugacity in the animal's tissues and results in there distribution of contaminants from inert storage sites to more toxicologically sensitive tissues. By reviewing laboratory and field studies, we have shown in this paper that bioamplification occurs across taxonomic groups that include, invertebrates,amphibians, fishes, birds, and mammals. Two case studies are presented, and constitute multi-life stage non-steady state bioaccumulation models calibrated for yellow perch and herring gulls. These case studies were used to demonstrate that bioamplification is predicted to occur under realistic scenarios of animal growth and seasonal weight loss. Bioamplification greatly enhances POP concentrations and chemical fugacities during critical physiological and behavioral events in an animal's life history, e.g., embryo development, juvenile stages, metamorphosis, reproduction, migration, overwintering, hibernation, and disease. Consequently,understanding the dynamics of bioamplification, and how different life history scenario scan alter tissue residues, may be helpful and important in assessing wildlife hazards and risks. PMID- 24158582 TI - Three-dimensional analysis of initial biofilm formation on polytetrafluoroethylene in the oral cavity. AB - AIM: There is published evidence that polytetrafluoroethylene (PTFE) exhibits beneficial surface characteristics by means of long-term biofilm accumulation. The purpose of this study was to investigate and compare early biofilm formation on polytetrafluoroethylene, ceramic-reinforced polytetrafluoroethylene and as the control group, stainless steel. MATERIALS AND METHODS: This study comprised 10 healthy volunteers (5 females and 5 males) with a mean age of 27.3 +/- 3.7 years. Three different slabs (two PTFE coatings: one pure and one ceramic-reinforced polytetrafluoroethylene, and stainless steel) were placed in random order on a splint in the mandibular molar region. Intraoral splints were inserted for 48 h. After 48 h, we removed the slabs from the splints and stained the biofilm with a two-color fluorescence assay for bacterial viability (LIVE/DEAD BacLight Bacterial Viability Kit 7012, Invitrogen, Mount Waverley, Australia). The amount of biofilm accumulation was assessed using confocal laser scanning microscopy (CLSM). RESULTS: The biofilm surface coverage was 55.8 +/- 39.8% on pure PTFE coated probes, 55.9 +/- 35.0% on ceramic-reinforced PTFE-coated probes, and 33.3 +/- 37.8% on stainless steel. The differences among the three groups were not significant (p = 0.301). Biofilm depth was 5.6 +/- 5.4 MUm on pure PTFE-coated probes, 5.2 +/- 3.8 MUm on ceramic-reinforced PTFE-coated probes, and 2.4 +/- 2.9 MUm on stainless steel. The Friedman test revealed a significant difference in biofilm depth (p = 0.002). Pairwise comparison of biofilm accumulation yielded a significant difference between pure PTFE and ceramic-reinforced PTFE compared to stainless steel (p = 0.017; p = 0.005). CONCLUSION: Our results indicate that the beneficial surface characteristics of PTFE coatings by reducing long-term biofilm are not a result of inhibiting initial bacterial adhesion. PMID- 24158583 TI - In vivo effectiveness of enamel sealants around orthodontic brackets. AB - OBJECTIVE: In this randomized study, the caries-protective effect on vestibular enamel of two fluoride-containing sealants (Protecto(r) and Light Bond(r)) during multibracket treatment was investigated. MATERIALS AND METHODS: In all, 40 orthodontic patients about to receive a multibracket appliance with the brackets bonded to the vestibular tooth surfaces were randomly included in this study. Each one was randomly assigned to one of four groups. A crossover design was selected in which a sealed quadrant was contralateral to an unsealed quadrant, then choosing the reverse configuration in the opposite jaw. Two sealants were, thus, tested on vestibular enamel on left and right anterior teeth and premolars in both jaws of each patient over 6 months of multibracket treatment. A DIAGNOdent(r) pen measuring laser fluorescence was used to analyze the relevant enamel surfaces both at baseline and after 6 months. RESULTS: Neither the incidence nor the characteristics of the demineralization we observed during the study differed between the 4 groups. CONCLUSION: Single application of smooth surface sealants did not protect enamel around brackets from incipient carious lesions during the first 6 months of multibracket treatment. PMID- 24158586 TI - Mandibular cortical shape index in non-standardised panoramic radiographs for identifying patients with osteoporosis as defined by the German Osteology Organization. PMID- 24158584 TI - Radiographic assessment of maxillary incisor position after rapid maxillary expansion in children with clinical signs of eruption disorder. AB - BACKGROUND AND OBJECTIVE: In this study we assessed the influence of rapid maxillary expansion (RME) on the intraosseous vertical position and inclination of the impacted incisors diagnosed at an early developmental stage on panoramic radiographs and subsequently treated by surgical removal of the obstacle. MATERIALS AND METHODS: Following surgical removal of the obstacles to incisor eruption (T1), a group of 34 subjects (mean age 8 years 11 months +/- 11 months) underwent RME, while a group of 28 subjects (mean age 9 years 1 month +/- 1 year) was monitored after surgery without further treatment. At T2 (on average 10 months after T1), the prevalence rate of subjects with erupted incisors was recorded. The measurements were taken on the panoramic radiographs at T1 and T2 to assess the vertical position and angulation of delayed unerupted incisors. RESULTS: At T2, impacted incisors erupted in 82.4% of the patients in the RME group versus 39.3% of those in the monitored group (chi(2) =8.45, p<0.001). All the patients treated with RME showed an improvement in the vertical and angular position of the unerupted teeth. Logistic regression revealed RME therapy as the only significant predictive variable (p<0.001) for successful eruption of the delayed incisors at T2. CONCLUSION: RME in early mixed dentition appears to be an effective procedure to increase the prevalence rate of impacted maxillary incisor eruption. PMID- 24158587 TI - Dimensional alterations of extraction sites after different alveolar ridge preservation techniques-a volumetric study. PMID- 24158589 TI - Molecular docking and molecular dynamics study on the effect of ERCC1 deleterious polymorphisms in ERCC1-XPF heterodimer. AB - Excision repair cross complementation group 1 (ERCC1) is an important protein in the nucleotide excision repair (NER) pathway, which is responsible for removing DNA adducts induced by platinum based compounds. The heterodimer ERCC1-XPF is one of two endonucleases required for NER. Genetic variations or polymorphisms in ERCC1 gene alter DNA repair capacity. Reduced DNA repair (NER) capacity may result in tumors and enhances cisplatin chemotherapy in cancer patients, which functions by causing DNA damage. Therefore, ERCC1 variants have the potential to be used as a strong candidate biomarker in cancer treatments. In this study we identified five variants V116M, R156Q, A199T, S267P, and R322C of ERCC1 gene as highly deleterious. Further structural and functional analysis has been conducted for ERCC1 protein in the presence of three variants V116M, R156Q, and A199T. Occurrence of theses variations adversely affected the regular interaction between ERCC1 and XPF protein. Analysis of 20 ns molecular dynamics simulation trajectories reveals that the predicted deleterious variants altered the ERCC1 XPF complex stability, flexibility, and surface area. Notably, the number of hydrogen bonds in ERCC1-XPF mutant complexes decreased in the molecular dynamic simulation periods. Overall, this study explores the link between the ERCC1 deleterious variants and cisplatin chemotherapy for various cancers with the help of molecular docking and molecular dynamic approaches. PMID- 24158590 TI - Aerosol-assisted plasma deposition of hydrophobic polycations makes surfaces highly antimicrobial. AB - The currently used multistep chemical synthesis for making surfaces antimicrobial by attaching to them hydrophobic polycations is replaced herein by an aerosol assisted plasma deposition procedure. To this end, N,N-hexyl,methyl-PEI (HMPEI) is directly plasma-coated onto a glass surface. The resultant immobilized HMPEI coating has been thoroughly characterized and shown to be robust, bactericidal against Escherichia coli, and virucidal against human influenza virus. PMID- 24158591 TI - Maternal flu or fever, medications use in the first trimester and the risk for neural tube defects: a hospital-based case-control study in China. AB - PURPOSE: This study aims to evaluate the effects of maternal flu or fever, and medications (antibiotics and antipyretics) use in the first trimester on neural tube defects (NTDs) risk in offspring. METHODS: Data came from a hospital-based case-control study conducted between 2006 and 2008 in Shandong/Shanxi provinces including 459 mothers with NTD-affected births and 459 mothers without NTD affected births. Logistic regression models were used to evaluate the effects of maternal flu, fever, and medications use on NTD risk. The effects were evaluated by adjusted odds ratio (OR) and 95 % confidence intervals (CIs) with SAS9.1.3.software. RESULTS: NTDs risks were significantly associated with maternal flu or fever (OR = 2.63, 95 % CI = 1.64-4.23) and antipyretics use (OR = 3.38, 95 % CI = 1.68-6.79), but not with antibiotics use (OR = 1.82, 95 % CI = 0.85-3.93). The risk effect of antipyretics use on anencephaly (OR = 7.81, 95 % CI = 1.96-31.13) was markedly higher than on spina bifida (OR = 3.02, 95 % CI = 1.08-8.42). Maternal flu or fever together with antipyretics use showed a higher OR for total NTDs (3.27 vs.1.87), anencephaly (7.38 vs.2.08), and spina bifida (2.97 vs.2.07) than maternal flu or fever with no antipyretics use. CONCLUSIONS: Maternal flu or fever and antipyretics use in the first trimester were risk for NTDs. Maternal flu or fever together with antipyretics use increased NTD risk than only maternal flu or fever. PMID- 24158592 TI - Ectopic choroid plexus found in fetal sections: a case report with literature consideration. AB - We incidentally found an ectopic choroid plexus (CP) attached to the posterior side of the cervicothoracic spinal cord (C4-T6) in a 16-week aborted fetus. The cytoarchitecture of the cord and segmental nerves showed normal development. The fourth ventricle did not contain the usual CP but a red blood cell cluster due to hemorrhage, although the cause, whether spontaneous or traumatic, was unknown. The ectopic CP was associated with thick neuroepithelium that was strongly positive for glial fibrillary acidic protein, vimentin, nestin, and proliferating cell nuclear antigen, but did not contain any CD34-positive vessels. Thus, the ectopic neuroepithelium seemed not to carry growth factor for vascular development. On the inferior side of the ectopic CP, the lower thoracic cord was wavy, folded, and packed in a limited space as a folding fan. Despite the strange gross appearance, however, we found no abnormality in the dorsal root ganglion, the spinal nerve root, or the cytoarchitecture of the lower thoracic cord. Therefore, the abnormality in the lower thoracic cord seemed to be secondarily induced by trophic factor(s) from the ectopic CP and/or the associated neuroepithelium. This may be the first report on an ectopic CP associated with ectopic neuroepithelium. PMID- 24158593 TI - Unexpected finding of delayed-onset seizures in HIV-positive, treatment experienced subjects in the Phase IIb evaluation of fosdevirine (GSK2248761). AB - BACKGROUND: Fosdevirine (GSK2248761) is a non-nucleoside reverse transcriptase inhibitor with HIV-1 activity against common efavirenz-resistant strains. Two partially blind, randomized, Phase IIb studies were initiated (1 in treatment naive and 1 in treatment-experienced subjects with HIV) to select a once-daily dose of fosdevirine for Phase III trials. METHODS: In the SIGNET study, treatment naive subjects were randomized 1:1:1 to receive once-daily fosdevirine 100 or 200 mg or efavirenz 600 mg, each along with tenofovir disoproxil fumarate/emtricitabine 300 mg/200 mg or abacavir/lamivudine 600 mg/300 mg. In the SONNET study, treatment-experienced subjects with non-nucleoside reverse transcriptase inhibitor-resistant HIV-1 were randomized 1:1:1 to treatment with fosdevirine 100 or 200 mg once daily or etravirine 200 mg twice daily, each along with twice-daily darunavir/ritonavir 600/100 mg and raltegravir 400 mg. The primary efficacy end point was the proportion of subjects with HIV-1 RNA<50 copies/ml. Safety and pharmacokinetics were also addressed. RESULTS: A total of 35 subjects were exposed to fosdevirine 100 or 200 mg. Trials were halted when 5 treatment-experienced subjects (1 receiving fosdevirine 100 mg, 4 receiving fosdevirine 200 mg) developed new-onset seizures after >=4 weeks of exposure to fosdevirine. There was no clear association between seizures and fosdevirine plasma drug levels. Time to seizure onset ranged from 28 to 81 days, and all 5 subjects experienced >=1 seizure after drug discontinuation. CONCLUSIONS: The delayed onset of seizures after fosdevirine exposure and persistence after discontinuation is without precedent in antiretroviral drug development, leading to additional investigation and underscoring the need for careful subject monitoring. PMID- 24158594 TI - Spectroelectrochemical investigation of Bu4N[Fe(CO)3(NO)]: identification of a reversible EC-mechanism. AB - Bu4N[Fe(CO)3(NO)] displays unique catalytic properties in electron-transfer catalysis such as in allylic substitutions, hydrosilylation, transesterifications, or carbene transfer chemistry. Herein we present a detailed spectroelectrochemical investigation of this complex that unravels an interesting electrochemical-chemical transformation in which two parts of [Fe(CO)3(NO)](-) are oxidized and undergo a disproportionation in the presence of CO to [Fe(CO)5] and [Fe(CO)2(NO)2]. Upon re-reduction the former two complexes regenerate [Fe(CO)3(NO)](-) to about 85%. PMID- 24158595 TI - Stability of midface fracture repair using absorbable plate and screw system pilot holes drilled and pin placement at angles other than 90 degrees . AB - IMPORTANCE: Conventional plating systems use titanium plates for fixation of fractures, with benefits of strength and biocompatibility. However, titanium plates require that screws be placed at a 90 degrees angle to the pilot holes. In the midface, this becomes extremely difficult. Today, a variety of craniomaxillofacial osteosynthesis systems are available, including resorbable plating systems. Specifically, the KLS Martin Sonic Weld system ultrasonically fuses the plate and the head of the pin when placed and will fill the pilot hole grooves completely even at less than 90 degrees angles, which provides a tremendous advantage in midface fracture repair. OBJECTIVE: To determine if the KLS Martin Sonic Weld system provides plate-screw construct stability in human heads even when placed at acute angles at the midface buttresses. DESIGN, SETTING, AND SPECIMENS: Twenty cadaveric head specimens with the mandible removed were prepared by creating osteotomies in the midface buttresses bilaterally. Specimens were defleshed and placed in a 2-part testing rig to hold and position the head for testing in a standard material testing system. Testing was performed at the Wayne State University Bioengineering test laboratories, Detroit, Michigan, using an Instron device and high-speed camera. Specimens were plated on one side of the midface using the KLS Martin Sonic Weld system with pilot holes and pins placed at 90 degrees angles. On the contralateral side, the buttresses were plated with the KLS Martin Sonic Weld system at 60 degrees , 45 degrees , and 30 degrees angles. Data were collected using the TDAS data acquisition system and were compared with matched pairs within each specimen. MAIN OUTCOMES AND MEASURES: Ultrasonically vibrated pins placed into absorbable mini-plates at less than 90 degrees angles with the KLS Martin Sonic Weld system were compared with the same amount of stress as the system placed at a 90 degrees angle before demonstrating plate-screw construct failure. RESULTS Fifty-seven paired tests were collected, with 114 total tests. Twenty failures were due to bone breakage, and 94 fixations failed as a result of the plate-screw construct breaking. Fractures fixated with the ultrasonic absorbable plating system placed with screws at all tested angles failed at similar loads to our control plates with pins placed at 90 degrees angles. These results lend the surgeon to successfully reduce fractures in the midface fragments in difficult-to-reach areas and possibly cut down on operative time while improving the chance of achieving a long-lasting adequate reduction. CONCLUSIONS AND RELEVANCE: Although there is a measured difference in the laboratory, no clinical difference is observed because the maximum force is not usually encountered. Overall, the clinical scenario indicates absorbable plates to be a viable option in less accessible areas. LEVEL OF EVIDENCE: NA. PMID- 24158596 TI - [Bone targeted therapies: new agents]. AB - The development of bisphosphonates and anti-RANK/RANKL agents was associated with a better understanding of physiological and pathological processes of bone remodeling. New agents are now developed in this context targeting factors associated with osteoclastogenesis (TGFbeta, PTHrP), with signaling pathways activated during bone remodeling (Src, Cathepsin K) or with tumor cells homing into bone (chemokines). This review aims to present the underlying rationale for these developments as well as the clinical results. The emergence of new bone targeting therapies is discussed. PMID- 24158597 TI - Paired diagnostic and pharmacodynamic analysis of rare non-small cell lung cancer cells enabled by the VerIFAST platform. AB - Lung cancer is the leading cause of cancer-related deaths in the United States and worldwide. This has led to major research initiatives focusing on improving early diagnosis rate, as well as the development of pharmacodynamic biomarkers. However, broad clinical integration of these approaches is limited due to the invasive nature of lung biopsies, needle aspirates and resections. Recently, an advance for sampling suspicious lung nodules to collect mini-bronchoalveolar lavage (mBAL) samples was shown to be diagnostically relevant but limited by standard cytology techniques leading to low sensitivity and specificity. In addition, a second non-invasive method that holds great promise is the collection of circulating tumor cells, a rare population of tumor cells that have shed into peripheral circulation from primary or metastatic tumor sites, from blood. Here, we utilize a recently published platform, VerIFAST, for the capture and proteomic analysis of rare cells, to isolate cells of interest from lung cancer patients using both mBAL and blood samples. The VerIFAST platform leverages surface tension at the microscale to pin aqueous and oil fluids in adjacent chambers to create a virtual filter between two aqueous fluids. In this manuscript, the VerIFAST was further enhanced to include oil pinning, which allowed on-device tumbling, further eliminating a laborious and time consuming step that could result in increased sample loss. Finally, we further developed the base assays used in standard histopathologic assays for diagnostic and pharmacodynamic analysis of these rare lung cancer cells. Specifically, we examined thyroid transcription factor-1 (TTF-1) signal intensity, in which loss is associated with more aggressive disease, and epidermal growth factor receptor (EGFR) signal intensity, which is a high value therapeutic target in lung cancer. PMID- 24158598 TI - A role for TRAIL/TRAIL-R2 in radiation-induced apoptosis and radiation-induced bystander response of human neural stem cells. AB - Adult neurons, which are terminally differentiated cells, demonstrate substantial radioresistance. In contrast, human neural stem cells (NSC), which have a significant proliferative capacity, are highly sensitive to ionizing radiation. Cranial irradiation that is widely used for treatment of brain tumors may induce death of NSC and further cause substantial cognitive deficits such as impairing learning and memory. The main goal of our study was to determine a mechanism of NSC radiosensitivity. We observed a constitutive high-level expression of TRAIL R2 in human NSC. On the other hand, ionizing radiation through generation of reactive oxygen species targeted cell signaling pathways and dramatically changed the pattern of gene expression, including upregulation of TRAIL. A significant increase of endogenous expression and secretion of TRAIL could induce autocrine/paracrine stimulation of the TRAIL-R2-mediated signaling cascade with activation of caspase-3-driven apoptosis. Furthermore, paracrine stimulation could initiate bystander response of non-targeted NSC that is driven by death ligands produced by directly irradiated NSC. Experiments with media transfer from directly irradiated NSC to non-targeted (bystander) NSC confirmed a role of secreted TRAIL for induction of a death signaling cascade in non-targeted NSC. Subsequently, TRAIL production through elimination of bystander TRAIL-R-positive NSC might substantially restrict a final yield of differentiating young neurons. Radiation-induced TRAIL-mediated apoptosis could be partially suppressed by anti TRAIL antibody added to the cell media. Interestingly, direct gamma-irradiation of SK-N-SH human neuroblastoma cells using clinical doses (2-5 Gy) resulted in low levels of apoptosis in cancer cells that was accompanied however by induction of a strong bystander response in non-targeted NSC. Numerous protective mechanisms were involved in the maintenance of radioresistance of neuroblastoma cells, including constitutive PI3K-AKT over-activation and endogenous synthesis of TGFbeta1. Specific blockage of these survival pathways was accompanied by a dramatic increase in radiosensitivity of neuroblastoma cells. Intercellular communication between cancer cells and NSC could potentially be involved in amplification of cancer pathology in the brain. PMID- 24158599 TI - Fast pairwise IBD association testing in genome-wide association studies. AB - MOTIVATION: Recently, investigators have proposed state-of-the-art Identity-by descent (IBD) mapping methods to detect IBD segments between purportedly unrelated individuals. The IBD information can then be used for association testing in genetic association studies. One approach for this IBD association testing strategy is to test for excessive IBD between pairs of cases ('pairwise method'). However, this approach is inefficient because it requires a large number of permutations. Moreover, a limited number of permutations define a lower bound for P-values, which makes fine-mapping of associated regions difficult because, in practice, a much larger genomic region is implicated than the region that is actually associated. RESULTS: In this article, we introduce a new pairwise method 'Fast-Pairwise'. Fast-Pairwise uses importance sampling to improve efficiency and enable approximation of extremely small P-values. Fast Pairwise method takes only days to complete a genome-wide scan. In the application to the WTCCC type 1 diabetes data, Fast-Pairwise successfully fine maps a known human leukocyte antigen gene that is known to cause the disease. AVAILABILITY: Fast-Pairwise is publicly available at: http://genetics.cs.ucla.edu/graphibd. PMID- 24158601 TI - Enhanced proportion of radiative excitons in non-doped electro-fluorescence generated from an imidazole derivative with an orthogonal donor-acceptor structure. AB - A greatly enhanced proportion of radiative excitons in non-doped blue electroluminescence with a maximum exciton utilizing efficiency (EUE) of 85% is harvested in the orthogonal cyano substituted, charge transfer (CT) emitter TPMCN, in comparison to the localized emission (LE)-like emitter TPM with a low EUE of 16%. PMID- 24158600 TI - Mouse model phenotypes provide information about human drug targets. AB - MOTIVATION: Methods for computational drug target identification use information from diverse information sources to predict or prioritize drug targets for known drugs. One set of resources that has been relatively neglected for drug repurposing is animal model phenotype. RESULTS: We investigate the use of mouse model phenotypes for drug target identification. To achieve this goal, we first integrate mouse model phenotypes and drug effects, and then systematically compare the phenotypic similarity between mouse models and drug effect profiles. We find a high similarity between phenotypes resulting from loss-of-function mutations and drug effects resulting from the inhibition of a protein through a drug action, and demonstrate how this approach can be used to suggest candidate drug targets. AVAILABILITY AND IMPLEMENTATION: Analysis code and supplementary data files are available on the project Web site at https://drugeffects.googlecode.com. PMID- 24158602 TI - Nucleation and growth of epitaxial metal-oxide films based on polymer-assisted deposition. AB - Polymer-assisted deposition (PAD) is one of the chemical solution deposition methods which have been successfully used to grow films, form coatings, and synthesize nanostructured materials. In comparison with other conventional solution-based deposition techniques, PAD differs in its use of water-soluble polymers in the solution that prevent the metal ions from unwanted chemical reactions and keep the solution stable. Furthermore, filtration to remove non coordinated cations and anions in the PAD process ensures well controlled nucleation, which enables the growth of high quality epitaxial films with desired structural and physical properties. The precursor solution is prepared by mixing water-soluble polymer(s) with salt(s). Thermal treatment of the precursor films in a controlled environment leads to the formation of desired materials. Using BaTiO3 grown on SrTiO3 and LaMnO3 on LaAlO3 as model systems, we show the effect of filtration on the nucleation and growth of epitaxial complex metal-oxide films based on the PAD process. PMID- 24158603 TI - Treatment of astrocytoma grade III with Photofrin II as a radiosensitizer. A case report. AB - INTRODUCTION: Astrocytomas are neoplasms that originate from glial cells. Anaplastic astrocytoma is classified as WHO III, with 27 % of the individuals with grade III astrocytoma living for at least 5 years even after treatment (radiation and chemotherapy). Photofrin II has been demonstrated to serve as a specific and selective radiosensitizing agent in both in vitro and in vivo tumor models. MATERIAL AND METHODS: This case report presents a woman suffering from an inoperable astrocytoma WHO III since 2004. The patient was treated with radiation therapy and Photofrin II as a radiosensitiser. The patient underwent irradiation with 40 + 20 Gy boost. The patient was given a single intravenous dose of 1 mg/kg Photofrin II 24 h prior to the initiation of radiation therapy. RESULTS: The patient is still alive without any significant side effect with a follow up of 106 months. MRI shows no evidence of disease. CONCLUSION: The follow-up results are encouraging regarding the application of Photofrin II as an effective radiosensitizing agent in the treatment of inoperable WHO III astrocytoma. PMID- 24158604 TI - Blisters - an unusual effect during radiotherapy. AB - The skin reaction to radiation is regularly monitored in order to detect enhanced radiosensitivity of the patient, unexpected interactions (e.g. with drugs) or any inadvertent overdosage. It is important to distinguish secondary disease from radiation reaction to provide adequate treatment and to avoid unnecessary discontinuation of radiotherapy. A case of bullous eruption or blisters during radiotherapy of the breast is presented. Differential diagnoses bullous pemphigoid, pemphigus vulgaris, and bullous impetigo are discussed and treatment described. PMID- 24158605 TI - [Prognosis of pregnant women with primary breast cancer]. PMID- 24158607 TI - Human sensitivity to vertical self-motion. AB - Perceiving vertical self-motion is crucial for maintaining balance as well as for controlling an aircraft. Whereas heave absolute thresholds have been exhaustively studied, little work has been done in investigating how vertical sensitivity depends on motion intensity (i.e., differential thresholds). Here we measure human sensitivity for 1-Hz sinusoidal accelerations for 10 participants in darkness. Absolute and differential thresholds are measured for upward and downward translations independently at 5 different peak amplitudes ranging from 0 to 2 m/s(2). Overall vertical differential thresholds are higher than horizontal differential thresholds found in the literature. Psychometric functions are fit in linear and logarithmic space, with goodness of fit being similar in both cases. Differential thresholds are higher for upward as compared to downward motion and increase with stimulus intensity following a trend best described by two power laws. The power laws' exponents of 0.60 and 0.42 for upward and downward motion, respectively, deviate from Weber's Law in that thresholds increase less than expected at high stimulus intensity. We speculate that increased sensitivity at high accelerations and greater sensitivity to downward than upward self-motion may reflect adaptations to avoid falling. PMID- 24158608 TI - Fifteen novel mutations in the mitochondrial NADH dehydrogenase subunit 1, 2, 3, 4, 4L, 5 and 6 genes from Iranian patients with Leber's hereditary optic neuropathy (LHON). AB - Leber's hereditary optic neuropathy (LHON) is an optic nerve dysfunction resulting from mutations in mitochondrial DNA (mtDNA), which is transmitted in a maternal pattern of inheritance. It is caused by three primary point mutations: G11778A, G3460A and T14484C; in the mitochondrial genome. These mutations are sufficient to induce the disease, accounting for the majority of LHON cases, and affect genes that encode for the different subunits of mitochondrial complexes I and III of the mitochondrial respiratory chain. Other mutations are secondary mutations associated with the primary mutations. The purpose of this study was to determine MT-ND variations in Iranian patients with LHON. In order to determine the prevalence and distribution of mitochondrial mutations in the LHON patients, their DNA was studied using PCR and DNA sequencing analysis. Sequencing of MT-ND genes from 35 LHON patients revealed a total of 44 nucleotide variations, in which fifteen novel variations-A14020G, A13663G, C10399T, C4932A, C3893G, C10557A, C12012A, C13934T, G4596A, T12851A, T4539A, T4941A, T13255A, T14353C and del A 4513-were observed in 27 LHON patients. However, eight patients showed no variation in the ND genes. These mutations contribute to the current database of mtDNA polymorphisms in LHON patients and may facilitate the definition of disease related mutations in human mtDNA. This research may help to understand the disease mechanism and open up new diagnostic opportunities for LHON. PMID- 24158609 TI - Association of the interleukin-12 polymorphic variants with the development of antibodies to surface antigen of hepatitis B virus in hemodialysis patients in response to vaccination or infection. AB - Cytokines, involved in the T-helper 1 system, play a role in the regulation of hepatitis B virus (HBV) clearance and the immune response to HBV antigens during natural infection or planned vaccination. Our aim was to examine whether the polymorphic variants of IL-12 are equally associated with development of antibodies to HBV surface antigen (anti-HBs) in hemodialysis (HD) patients in the case of HBV vaccination or HBV infection. The IL-12A rs568408 and IL-12B rs3212227 polymorphisms were analyzed in relation to anti-HBs development in 602 HD patients with negative antibodies to HBV core antigen (anti-HBc) who were hepatitis B vaccinated (group I) as well as in 237 anti-HBc positive HD patients who were infected with HBV in the past (group II). In group I, 199 patients did not develop an anti-HBs titre >10 IU/L (subgroup Ia), whereas in group II, 55 patients did not develop an anti-HBs titre >10 IU/L (subgroup IIa). Patients of groups I and II that developed an anti-HBs >10 IU/L were included into subgroups Ib and IIb, respectively. In hepatitis B vaccinated HD patients, development of a protective anti-HBs titre was positively associated with vintage of renal replacement therapy (RRT), chronic glomerulonephritis as a cause of RRT, and GA rs 568408 IL-12A (OR 1.6, 95 % CI 1.0-2.5, P = 0.035), but a frequency distribution of this genotype between responders and non-responders was not significant when the Bonferroni correction was applied. In HBV infected HD patients, anti-HBs development was positively associated with AC rs3212227 IL-12B (OR 8.0, 95 % CI 2.6-24.9, P < 0.001), whereas HBsAg positivity, AA rs3212227 IL 12B (OR 0.3, 95 % CI 0.1-0.7, P = 0.007), and CC rs3212227 IL-12B (OR 0.1, 95 % CI 0.03-0.6, P = 0.011) were negative predictors of positive anti-HBs phenotype. When the Bonferroni correction was applied, if appropriate, these associations remained significant. In HD patients, the studied IL-12 polymorphic variants seem to be associated with the anti-HBs phenotype (a) with borderline significance for IL-12A in hepatitis B vaccinated patients, and (b) significantly for IL-12B in patients who underwent natural HBV infection. PMID- 24158610 TI - SNPs of MYPN and TTN genes are associated to meat and carcass traits in Italian Large White and Italian Duroc pigs. AB - Myopalladin (MYPN) and titin (TTN) play key roles in skeletal muscle structural organisation and for this reason they may be functional candidates for meat production traits in pigs. We analysed by PCR-RFLP two polymorphisms previously identified and described in the 3'UTR of MYPN and TTN genes in a group of Italian Large White (ILW) and Italian Duroc (ID) pigs with extreme divergent estimated breeding values for some production traits. Significant allele frequency differences were observed for lean cuts (LC) at the MYPN locus in ILW breed and for visible intermuscular fat (VIF) at MYPN and TTN loci in ID breed. Moreover, association analysis between the two genes and some production traits (average daily gain, LC, backfat thickness, ham weight, feed conversion ratio and VIF) was performed in a sample of 409 ILW and 381 ID pigs. On the whole, the results showed significant effects of both genes on some of the considered traits in ID breed, and for TTN gene in ILW animals. These results indicate that both genes can be considered as candidates for meat and carcass traits in ID pigs. PMID- 24158611 TI - Identification of four novel connexin 26 mutations in non-syndromic deaf patients: genotype-phenotype analysis in moderate cases. AB - This paper presents a mutation as well as a genotype-phenotype analysis of the GJB2 and GJB6 genes in 476 samples from non-syndromic unrelated Argentinean deaf patients (104 familial and 372 sporadic cases). Most of them were of prelingual onset (82 %) and 27 % were cochlear implanted. Variation of sequences was detected in 171 of the 474 patients (36 %). Overall, 43 different sequence variations were identified in GJB2 and GJB6. Four of them are reported for the first time in GJB2: c.233dupG, p.Ala78Ser, p.Val190Asp and p.Cys211Tyr. Mutations in GJB6 were detected in 3 % of patients [nine del(GJB6-D13S1830) and three del(GJB6-D13S1854)]. Of the 43 different variations identified in GJB2, 6 were polymorphisms and of the others, 10 (27 %) were truncating and 27 (73 %) were nontruncating. Patients with two truncating mutations had significantly worse hearing impairment than all other groups. Moderate phenotypes were observed in a group of patients carrying biallelic mutations (23 %). This work shows the high prevalence of GJB2 mutations in the Argentinean population and presents an analysis of moderate phenotypes in our cohort. PMID- 24158612 TI - Proangiogenic TIE2(+)/CD31 (+) macrophages are the predominant population of tumor-associated macrophages infiltrating metastatic lymph nodes. AB - Tumor-associated macrophages (TAMs) accumulate in various cancers and promote tumor angiogenesis and metastasis, and thus may be ideal targets for the clinical diagnosis of tumor metastasis with high specificity. However, there are few specific markers to distinguish between TAMs and normal or inflammatory macrophages. Here, we show that TAMs localize in green fluorescent protein labeled tumors of metastatic lymph nodes (MLNs) from B16F1 melanoma cells but not in necrotic tumor regions, suggesting that TAMs may promote the growth of tumor cells and the progression of tumor metastasis. Furthermore, we isolated pure populations of TAMs from MLNs and characterized their gene expression signatures compared to peritoneal macrophages (PMs), and found that TAMs significantly overexpress immunosuppressive cytokines such as IL-4, IL-10, and TGF-beta as well as proangiogenic factors such as VEGF, TIE2, and CD31. Notably, immunological analysis revealed that TIE2(+)/CD31(+) macrophages constitute the predominant population of TAMs that infiltrate MLNs, distinct from tissue or inflammatory macrophages. Importantly, these TIE2(+)/CD31(+) macrophages also heavily infiltrated MLNs from human breast cancer biopsies but not reactive hyperplastic LNs. Thus, TIE2(+)/ CD31(+) macrophages may be a unique histopathological biomarker for detecting metastasis in clinical diagnosis, and a novel and promising target for TAM-specific cancer therapy. PMID- 24158613 TI - Impact of tamsulosin exposure on late complications following cataract surgery: retrospective cohort study. AB - The purpose of this study is to measure the impact of tamsulosin intake on five postoperative cataract surgery complications (toxic anterior segment syndrome, rebound uveitis, retinal detachment, macular edema, and postoperative endophthalmitis). This retrospective cohort study was conducted at University Hospital of Henares. The study included 660-eyes of 660 patients submitted to cataract surgery at the ophthalmology unit of Hospital del Henares (Madrid) between 2 March 2009 and 28 February 2010. Extracapsular cataract extraction, combined glaucoma and cataract surgery phacovitrectomy, posterior capsule rupture and zonular damage were considered exclusion criteria. Clinical charts were reviewed during July 2012. Patients were divided in two groups (exposed and non exposed to tamsulosin). Cumulative incidence of toxic anterior segment syndrome, rebound uveitis, retinal detachment, macular edema and postoperative endophthalmitis were compared in both groups. Rebound uveitis (relative risk [RR] 3.39; confidence interval [CI] 1.63-7.08) and macular edema (RR 4.15; CI 1.06 16.22) were more common in the tamsulosin-exposed group. Retinal detachment had a similar incidence in both groups. We observed no cases of endophthalmitis or toxic anterior segment syndrome in either of the two groups. Tamsulosin exposure in this cohort was associated with a higher risk of rebound uveitis and macular edema but the other three studied postoperative complications had a similar incidence in both groups. PMID- 24158614 TI - Value of preoperative optical coherence tomography for predicting visual outcome after epiretinal membrane surgery. AB - We assessed the value of preoperative optical coherence tomography (OCT) for predicting the visual outcome for patients undergoing macular surgery for epiretinal membranes (ERMs). In a retrospective trial, we analyzed the medical charts of patients who had received surgery for ERMs between January and August 2011. The best-corrected pre- and postoperative logMAR visual acuity was assessed. We pre- and postoperatively measured the central foveal thickness with high-resolution spectral-domain OCT and analyzed the structure of the outer retinal layers (retinal pigment epithelium, photoreceptors, and external limiting membrane) before and after surgery. The study included 49 patients (23 male, 27 female) with an average age of 69 years (SD 6.7) who had received macular surgery during the above-mentioned period. For phakic eyes (n = 34), treatment had also included phacoemulsification and intraocular lens implantation. Postoperative follow-up examinations and OCT controls had been conducted after an average of 9 weeks (SD 5). The mean improvement in visual acuity was 2.4 lines (SD 2.3; p < 0.001). For patients with phakic eyes, the combination of vitrectomy and cataract surgery resulted in a slightly better, but insignificant increase in visual acuity than for patients with primary pseudophakia (Delta = 0.05, p = 0.46). On average, central foveal thickness regressed by 94 MUm (SD 129 MUm). Linear regression showed a significant linear relationship between the reduction of central foveal thickness and improvement of visual acuity (R (2) = 0.16, B = 0.71, p = 0.004). A decrease in foveal thickness by 100 MUm resulted in an increase in visual acuity by 0.71 lines. Visual improvement did not significantly differ between the group of patients with intact outer retinal layers before surgery and the group of patients with preoperative defects of the retina (p = 0.085). We found a significant linear relationship between the reduction of central foveal thickness and improvement of visual acuity for patients undergoing surgery for ERM. However, the preoperative OCT status (intact vs. broken) of the outer retinal layers did not correlate with the change in visual acuity. PMID- 24158615 TI - Effects of oral propranolol on circumscribed choroidal hemangioma: a pilot study. AB - IMPORTANCE: Oral propranolol hydrochloride treatment has been proven effective for infantile hemangiomas. To our knowledge, this study is the first to report multiple cases in which oral propranolol therapy was used for patients with circumscribed choroidal hemangioma. OBSERVATIONS: Five patients with circumscribed choroidal hemangioma were treated at Nagoya Medical Center, Nagoya, Japan, from 2011 to 2012. Oral propranolol hydrochloride was initiated at 10 mg 3 times a day and was increased monthly by 30 mg/d until the desired effects were observed. The mean (SD) height of the tumor (based on the B-mode at the end of the study) was 84.5% (13.6%) relative to the initial height. Similarly, the mean (SD) tumor area (based on indocyanine green angiography) was 94.2% (6.0%), the mean (SD) visual acuity was 0.04 (0.21) logMAR, and the mean (SD) Humphrey visual field mean deviation was -0.98 (1.1) dB. In 3 patients with macular edema, the mean (SD) foveal thickness (measured with optical coherence tomography) was 114.0% (13.9%). CONCLUSIONS AND RELEVANCE: Although oral propranolol therapy may partially improve the condition of patients with circumscribed choroidal hemangioma, it does not seem to have a critical therapeutic effect, at least at blood concentrations lower than 50 to 100 ng/mL. TRIAL REGISTRATION: umin.ac.jp/ctr Identifier: UMIN000006623. PMID- 24158616 TI - Monitoring environmental Aspergillus spp. contamination and meteorological factors in a haematological unit. AB - The opportunistic pathogens belonging to the Aspergillus genus are present in almost all seasons of the year, and their concentration is related to meteorological conditions. The high density of Aspergillus spp. conidia in a haematological hospital ward may be a significant risk factor for developing invasive fungal diseases in immunocompromised patients. Aim of the present study was to evaluate the variability of airborne Aspergillus spp. conidia contamination in a Haematological Unit (HU) within a period of 16 months in relation with some meteorological parameters. An environmental Aspergillus surveillance was conducted in the HU in four rooms and their bathrooms, in the corridor and in three external sites using an agar impact sampler. During each sampling, temperature and relative humidity at each site were recorded and current wind speed and rainfall events were taken from the official weather service. Aspergillus spp. conidia concentration differed significantly across the sampling sites. Internal Aspergillus spp. loads were significantly dependent on temperature, internal relative humidity and rain. External conidia concentrations were significantly influenced by outdoor temperature and relative humidity. A suitable indicator was introduced to evaluate the seasonal distribution of Aspergillus spp. conidia in the sampling sites, and a significant dependence on this indicator was observed inside the HU. Seventeen different fungal species belonging to the Aspergillus genus were detected during the sampling period. Aspergillus fumigatus was the most frequently isolated species and its distribution depended significantly on the seasonal indicator both inside and outside the hospital ward. PMID- 24158617 TI - Keratitis due to the wood saprobic ascomycete, Auerswaldia lignicola (Family Botryosphaeriaceae), in a carpenter in India. AB - Keratitis due to Auerswaldia lignicola in a 32-year-old Indian male carpenter is described. At presentation, the patient reported persistent pain and tearing (left eye) in spite of topical antimicrobial therapy for more than 3 weeks. Clinically, mycotic keratitis was suspected, and direct microscopy of corneal scrapings stained by lactophenol cotton blue and Gram stains revealed broad septate hyphae. Intensive topical antifungal therapy was then given for 15 days. The keratitis continued to progress, necessitating therapeutic penetrating keratoplasty. Following the keratoplasty, there was rapid reduction in inflammation and gradual quietening of the eye. Brown-black fungal colonies resembling Lasiodiplodia theobromae were isolated from corneal scrape and corneal button (post-surgery) material on Sabouraud glucose-neopeptone agar; however, sporulation did not occur, so the morphological identification could not be confirmed. Sequence analysis of the 18S rRNA region of extracted fungal genomic DNA yielded an identification of A. lignicola Ariyawansa, J.K. Liu & K.D. Hyde; the sequence data have been deposited in GenBank (A. lignicola strain DK/V4, accession number KC866317.1). Medical management of keratitis due to such rarely reported fungal species may be difficult, necessitating surgical procedures. PMID- 24158618 TI - [Inhibition of RANK ligand to treat bone metastases]. AB - Bone is the most common metastatic site. The skeleton is also the preferential initial metastatic site in breast and prostate carcinomas. Objective complications of bone metastases are named " skeletal-related events " (SREs) and generally include the need for radiotherapy on bone, surgery to bone, pathologic fracture and spinal cord compression. Recent phase III double-blind trials have demonstrated the superiority of denosumab to zoledronic acid for delaying the time to first SRE in patients with breast or prostate cancer and bone metastases. Non-inferiority was shown in the trial including other solid tumors and multiple myeloma. The overall burden of the disease was also significantly reduced in the breast and prostate cancer studies, and in the pre-specified integrated analysis that included all three comparative trials. Denosumab is conveniently administered by subcutaneous injections and is devoid of renal toxicity. However, denosumab induces more cases of hypocalcaemia than zoledronate. Calcium and vitamin D supplementation is recommended during therapy and it is advised to regularly monitor calcium levels during denosumab long-term treatment. There are numerically more cases of osteonecrosis of the jaw, but the differences are not statistically significant between zoledronate and denosumab, whether in the individual studies or in the integrated analysis. Treatment with these potent inhibitors of bone resorption should be progressively 'individualized' to better define the place of intermittent treatments, to decrease the occurrence of toxic effects and to improve the cost-effectiveness ratio of new compounds. PMID- 24158620 TI - Sodium tanshinone IIA sulfonate inhibits porcine reproductive and respiratory syndrome virus via suppressing N gene expression and blocking virus-induced apoptosis. AB - BACKGROUND: Porcine reproductive and respiratory syndrome virus (PRRSV) causes significant economic loss in the swine industry. Currently, there is no effective way to prevent PRRSV infection. Sodium tanshinone IIA sulfonate (STS), a natural compound derived from Salvia miltiorrhiza, was shown to possess anti-PRRSV activity, but the underlying mechanisms remain unclear. The objective of this study was to investigate the effect of STS on PRRSV-induced cell apoptosis and PRRSV N protein expression pattern. METHODS: Relative quantification real-time PCR was used to evaluate the inhibition of STS on N gene expression. Simultaneously indirect immunofluorescence assay (IFA) and western blot were used to assess the effect on N protein expression. Apoptosis was analysed using fluorescence microscope with an annexin V-EGFP kit. The effect of STS on caspase 3 cleaving was assessed by western blot. RESULTS: Our results showed that STS could inhibit viral N gene expression at both the messenger RNA stage and at the protein level in PRRSV-infected cells in a dose-dependent manner. In addition, STS could also rescue PRRSV-induced apoptosis. CONCLUSIONS: Our data suggest that STS may serve as a base compound for developing more effective drugs against PRRSV infection. PMID- 24158621 TI - Effects of aluminum and extremely low frequency electromagnetic radiation on oxidative stress and memory in brain of mice. AB - This study was aimed to investigate the effect of aluminum and extremely low frequency magnetic fields (ELF-MF) on oxidative stress and memory of SPF Kunming mice. Sixty male SPF Kunming mice were divided randomly into four groups: control group, ELF-MF group (2 mT, 4 h/day), load aluminum group (200 mg aluminum/kg, 0.1 ml/10 g), and ELF-MF + aluminum group (2 mT, 4 h/day, 200 mg aluminum/kg). After 8 weeks of treatment, the mice of three experiment groups (ELF-MF group, load aluminum group, and ELF-MF + aluminum group) exhibited firstly the learning memory impairment, appearing that the escaping latency to the platform was prolonged and percentage in the platform quadrant was reduced in the Morris water maze (MWM) task. Secondly are the pathologic abnormalities including neuronal cell loss and overexpression of phosphorylated tau protein in the hippocampus and cerebral cortex. On the other hand, the markers of oxidative stress were determined in mice brain and serum. The results showed a statistically significant decrease in superoxide dismutase activity and increase in the levels of malondialdehyde in the ELF-MF group (P < 0.05 or P < 0.01), load aluminum group (P < 0.01), and ELF-MF + aluminum group (P < 0.01). However, the treatment with ELF-MF + aluminum induced no more damage than ELF-MF and aluminum did, respectively. In conclusion, both aluminum and ELF-MF could impact on learning memory and pro-oxidative function in Kunming mice. However, there was no evidence of any association between ELF-MF exposure with aluminum loading. PMID- 24158622 TI - Through-space charge transfer and emission color tuning of di-o-carborane substituted benzene. AB - 1,4-Di-(1-Ar-o-carboran-2-yl)benzene (Ar = 3,5-bis(trifluoromethyl)phenyl (1), phenyl (2), 4-n-butylphenyl (3), 4-N,N-dimethylaniline (4)) compounds that are electronically modulated at the C1-position of o-carborane with the electron withdrawing or -donating aryl groups were prepared and characterized. The X-ray crystal structures of 1, 3, and 4 reveal that the two aryl groups on the C1 carborane carbon atoms are oppositely positioned, featuring overall C2-symmetry, and the C1-C2 bond length of carborane increases with the increasing order of electron-donating effect of an aryl group. UV-vis absorption spectra exhibit small low-energy absorption bands at around 275-300 nm for 1-3 while 4 shows a broad absorption tail at 350-400 nm. Although 1-4 show virtually no emission in solution, an intense aggregation-induced emission over the region ranging from 400-700 nm is observed in the solid state. Importantly, the emission wavelengths of 1-4 exhibit an apparent red-shift upon changing the aryl substituent from the CF3 to the NMe2 group (from 1 to 4). TD-DFT calculations suggest that the low energy electronic transition is attributed to the intramolecular "through-space" charge transfer between the appended aryl group (HOMO) and the central phenylene ring (LUMO), and the greater change in the HOMO level by the substituent than that in the LUMO is responsible for the emission color tuning. PMID- 24158623 TI - Brain metastases from colorectal cancer: main clinical factors conditioning outcome. AB - BACKGROUND: The aim of our study is to evaluate the outcome of patients affected by brain metastases from colorectal cancer and to correlate the outcome with prognostic factors. METHODS: Patients were retrospectively evaluated. Survival distributions were estimated by using the Kaplan-Meier method. The log-rank test was used to assess the impact on survival of individual factors. RESULTS: Among 41 patients (25M and 16F; median age 58), 58.5 % had rectal cancer and 39 % synchronous metastatic disease; 95 % had extracranial metastases, most common site was lung (87.8 %). Seven patients had synchronous brain metastases. Median overall survival after diagnosis of brain metastases was 5 months [95 % confidence interval 3-12 months]. Median survival from brain metastases diagnosis was 4.2 months in patients treated with radiotherapy (29.3 %), 11.9 months in those with radio- and chemotherapy (21.9 %) and 21.4 months in those with surgery with/without radiotherapy or chemotherapy (29.3 %) (P < 0.0001). On multivariate analysis, no independent prognostic factors were found for disease-free interval from diagnosis to brain metastases and overall survival; amount of chemotherapy before brain metastases have no statistically significant relation to brain metastases-free-interval even if patients who received more than one line of chemotherapy have a longer median brain-metastases-free-interval than those who received less than one. KRAS was found mutated in 17/28 patients without statistically significant correlation to outcome due to the small sample size. CONCLUSIONS: Prognosis of brain-metastases-patients is poor. An interesting tool is to evaluate the correlation of KRAS status and brain metastases with aim to tailor treatment and follow-up. PMID- 24158624 TI - Phylogenetic diversity of the enteric pathogen Salmonella enterica subsp. enterica inferred from genome-wide reference-free SNP characters. AB - The enteric pathogen Salmonella enterica is one of the leading causes of foodborne illness in the world. The species is extremely diverse, containing more than 2,500 named serovars that are designated for their unique antigen characters and pathogenicity profiles-some are known to be virulent pathogens, while others are not. Questions regarding the evolution of pathogenicity, significance of antigen characters, diversity of clustered regularly interspaced short palindromic repeat (CRISPR) loci, among others, will remain elusive until a strong evolutionary framework is established. We present the first large-scale S. enterica subsp. enterica phylogeny inferred from a new reference-free k-mer approach of gathering single nucleotide polymorphisms (SNPs) from whole genomes. The phylogeny of 156 isolates representing 78 serovars (102 were newly sequenced) reveals two major lineages, each with many strongly supported sublineages. One of these lineages is the S. Typhi group; well nested within the phylogeny. Lineage through-time analyses suggest there have been two instances of accelerated rates of diversification within the subspecies. We also found that antigen characters and CRISPR loci reveal different evolutionary patterns than that of the phylogeny, suggesting that a horizontal gene transfer or possibly a shared environmental acquisition might have influenced the present character distribution. Our study also shows the ability to extract reference-free SNPs from a large set of genomes and then to use these SNPs for phylogenetic reconstruction. This automated, annotation-free approach is an important step forward for bacterial disease tracking and in efficiently elucidating the evolutionary history of highly clonal organisms. PMID- 24158628 TI - The genetic architecture of chemosensory cues involved in species recognition: a behavioral approach in the house mouse. AB - The genetics of chemical signals is poorly understood. We addressed this issue in two subspecies of mice, Mus musculus musculus and M. m. domesticus, comparing their odor phenotypes with that of their hybrids. Earlier studies indicated that these subspecies could be discriminated on the basis of their urinary odor. We assessed male odor phenotypes from perception of musculus mice acting as olfactometers. Our results point to a complex genetic determinism. Reciprocal F1 hybrids produced a distinct odor phenotype, with shared characteristics distinguishing them from their parents, and stronger similarity to domesticus than to musculus. These results are consistent with implications of genes with partial dominance and a parent of origin effect. Further, similarities between reciprocal F2 allowed us to reject a direct role of the Y-chromosome in shaping the odor phenotype. However we show that the X-chromosome could be involved in explaining domesticus phenotype, while epistasis between genes on the sex chromosomes and the autosomes might influence musculus phenotype. PMID- 24158629 TI - Synthesis of atomic metal clusters on nanoporous alumina. AB - The synthesis of atomic metal (gold and nickel) clusters by pulsed galvanostatic electrodeposition on nanoporous alumina is presented. The method allows the production of clusters with an average diameter of 0.7 nm for gold and 1.1 nm for nickel, while the size can be controlled through the current density applied. This strategy represents a simple and efficient method for the construction of heterogeneous catalysts and sub-nanometre electrode arrays exemplified here by the reduction of 4-nitrophenol and the electrochemical response to ferrocyanide. PMID- 24158626 TI - Depressive symptom trajectories during and after adjuvant treatment for breast cancer. AB - BACKGROUND: The course of depressive symptoms during and after breast cancer treatment is not well understood. PURPOSE: We identified patient subgroups based on distinct trajectories of depressive symptoms and determined whether subgroups could be distinguished by personal characteristics and coping strategies. METHODS: Breast cancer patients completed the Center for Epidemiologic Studies Depression Scale on clinically meaningful occasions and during the posttreatment period. The Illness Management Questionnaire was completed prior to treatment. RESULTS: A three-class mixture model provided the best fit to the data. Subgroup membership was significantly (p < .05) associated with marital status, history of depression, and focusing on symptoms. In multivariate analysis, marital status and focusing on symptoms remained significant (p < .05) predictors of subgroup membership. CONCLUSIONS: Distinct trajectories can be identified during and after adjuvant breast cancer therapy. Predictors of these trajectories have implications for addressing depressive symptoms in this clinical population and for future research. PMID- 24158625 TI - An evolutionary screen highlights canonical and noncanonical candidate antiviral genes within the primate TRIM gene family. AB - Recurrent viral pressure has acted on host-encoded antiviral genes during primate and mammalian evolution. This selective pressure has resulted in dramatic episodes of adaptation in host antiviral genes, often detected via positive selection. These evolutionary signatures of adaptation have the potential to highlight previously unrecognized antiviral genes (also called restriction factors). Although the TRIM multigene family is recognized for encoding several bona fide restriction factors (e.g., TRIM5alpha), most members of this expansive gene family remain uncharacterized. Here, we investigated the TRIM multigene family for signatures of positive selection to identify novel candidate antiviral genes. Our analysis reveals previously undocumented signatures of positive selection in 17 TRIM genes, 10 of which represent novel candidate restriction factors. These include the unusual TRIM52 gene, which has evolved under strong positive selection despite its encoded protein lacking a putative viral recognition (B30.2) domain. We show that TRIM52 arose via gene duplication from the TRIM41 gene. Both TRIM52 and TRIM41 have dramatically expanded RING domains compared with the rest of the TRIM multigene family, yet this domain has evolved under positive selection only in primate TRIM52, suggesting that it represents a novel host-virus interaction interface. Our evolutionary-based screen not only documents positive selection in known TRIM restriction factors but also highlights candidate novel restriction factors, providing insight into the interfaces of host-pathogen interactions mediated by the TRIM multigene family. PMID- 24158630 TI - Investigational analysis reveals a potential role for neutrophils in giant-cell arteritis disease progression. AB - RATIONALE: Giant-cell arteritis (GCA) is a large-vessel vasculitis characterized by immune cell infiltration, yet the potential involvement of neutrophils has rarely been studied. OBJECTIVE: We investigated whether alterations in neutrophil reactivity occurred in the pathogenesis of GCA or during its clinical management with a canonical glucocorticoid dose regimen during a 6-month period. METHODS AND RESULTS: Blood samples were taken within 48 hours of therapy commencement and at weeks 1, 4, and 24 after glucocorticoid dose. Flow cytometric analysis revealed 3 distinct neutrophil populations and phenotypes. Within 48 hours of steroid treatment, neutrophils displayed an AnxA1(hi)CD62L(lo)CD11b(hi) phenotype, whereas week 1 neutrophils were AnxA1(hi)CD62L(lo)CD11b(lo) and displayed minimal adhesion to endothelial monolayers under flow, and week 24 (i.e., lowest glucocorticoid dose) neutrophils were AnxA1(hi)CD62L(hi)CD11b(hi) with increased endothelial adhesion under flow. Week 24 plasma analyses showed high levels of C X-C motif chemokine ligand 5, interleukin (IL) 8, IL-17, and IL-6. Importantly, comparison of week 1 and week 24 samples revealed a suppressive neutrophil effect on T-cell proliferation at the former time point only. Finally, in vitro incubation of naive neutrophils with concentrations of IL-6 and IL-17 quantified in GCA plasma at weeks 1 and 24 replicated this differential modulation of lymphocyte proliferation. CONCLUSIONS: This translational study highlights a novel clinical manifestation of GCA, with evidence for a neutrophil component and an escaped proinflammatory phenotype when glucocorticoid therapy is tapered. These results indicate potential involvement of neutrophils in GCA pathogenesis. PMID- 24158632 TI - Retraction note: Quality of life of patients with rheumatoid arthritis in Argentina: reliability, validity, and sensitivity to change of a Spanish version of the Rheumatoid Arthritis Quality of Life questionnaire. PMID- 24158633 TI - Palladium-catalyzed reductive homocoupling of N'-tosyl arylhydrazines. AB - A novel procedure for the preparation of biaryl compounds by Pd-catalyzed homocoupling of N'-tosyl arylhydrazine has been described. N'-Tosyl arylhydrazine, as a readily available and stable coupling partner, demonstrated its generality in the homocoupling reactions. The scope of the reaction and possible mechanism have also been investigated. PMID- 24158631 TI - Directional diffusion of corticospinal tract supports therapy decisions in idiopathic normal-pressure hydrocephalus. AB - INTRODUCTION: Gait disturbance in patients with idiopathic normal pressure hydrocephalus (iNPH) may be caused by alterations of the corticospinal tract that we aimed to measure with diffusion tensor imaging (DTI). The directional diffusion parameters axial diffusivity and fractional anisotropy (FA) reflect axon integrity, whereas mean diffusivity, radial diffusivity and magnetization transfer ratio (MTR) reflect myelin content. METHODS: Twenty-six patients with probable iNPH were grouped into drainage responders (n = 12) and drainage non responders (n = 14) according to their improvement on gait assessment tests after a 3-day lumbar CSF drainage. We measured DTI and MTR of the corticospinal tract and, as reference, of the superior longitudinal fascicle before and after CSF withdrawal in iNPH and in ten age-matched controls. Drainage responders were re examined after ventricoperitoneal shunting. Differences before any intervention and changes upon CSF withdrawal were evaluated. RESULTS: Axial diffusivity in corticospinal tract and superior longitudinal fascicle was higher in both patient groups compared to controls (p < 0.001). Only in the corticospinal tract of drainage responders was FA higher compared to controls, and both FA and axial diffusivity decreased after shunting. For axial diffusivity upon CSF drainage, a decrease of >0.7 % discriminated drainage responders from drainage non-responders with 82 % sensitivity, and a decrease of >1 % predicted overall improvement after shunting with 87.5 % sensitivity and 75 % specificity. The specificity to discriminate responders/non-responders was low for all DTI values (max. 69 % for FA values). CONCLUSION: High values of directional diffusion parameters in the corticospinal tract are found in iNPH patients indicating affection of its axons. Increased values and their decrease upon CSF drainage may facilitate treatment decisions in clinically uncertain cases. PMID- 24158634 TI - Intensity-modulated radiation therapy for T4 nasopharyngeal carcinoma. Treatment results and locoregional recurrence. AB - PURPOSE: The purpose of this work was to examine outcomes in patients with T4 nasopharyngeal carcinoma (NPC) treated with intensity-modulated radiation therapy (IMRT). METHODS AND MATERIALS: Between 2007 and 2010, 154 patients with nonmetastatic T4 NPC were treated with IMRT to a total dose of 70 Gy in 33-35 fractions. In addition, 97% of patients received concurrent platinum-based chemotherapy. The median follow-up time was 52.8 months. RESULTS: The rates of 5 year actuarial locoregional control, distant metastasis-free survival, progression free-survival, and overall survival (OS) were 81.2, 72.2, 61.9, and 78.1%, respectively. A total of 27 patients had locoregional recurrence: 85.2% in field failures, 11.1% marginal failures, and 3.7% out-of-field failures. Fourteen patients with locoregional recurrence received aggressive treatments, including nasopharyngectomy, neck dissection, or re-irradiation, and the 5-year OS rate tended to be better (61.9%) compared to those receiving conservative treatment (32.0%, p=0.051). In patients treated with 1 course of radiotherapy, grade >=3 toxicities of ototoxicity, neck fibrosis, xerostomia, epistaxis, and radiographic temporal lobe necrosis occurred in 18.2, 9.8, 6.3, 2.1, and 5.6% of patients, respectively. Increased ototoxicity, osteonecrosis, severe nasal bleeding, and temporal necrosis were observed in patients treated by re-irradiation. CONCLUSION: IMRT offers good locoregional control in patients with T4 NPC. For patients with locoregional recurrence after definitive radiotherapy, aggressive local treatment may be considered for a better outcome. PMID- 24158635 TI - [Risks of unfavorable cosmetic and toxicity after percutaneous accelerated partial breast irradiation (APBI). Interim analysis from the Canadian RAPID trial]. PMID- 24158636 TI - [Stereotactic body radiotherapy for the treatment of hepatocellular cancer. Pooled analysis of two phase I/II trials]. PMID- 24158637 TI - Adenoid cystic carcinoma of the breast. The double face of an exocrine gland carcinoma. PMID- 24158638 TI - [Radiotherapy with rectangular fields compared to conformal fields. Fewer clinical failures in high-risk prostate cancer patients]. PMID- 24158639 TI - [Laryngeal preservation with induction chemotherapy for hypopharyngeal squamous cell carcinoma]. PMID- 24158640 TI - Efficacy and safety of trabeculectomy vs nonpenetrating surgical procedures: a systematic review and meta-analysis. AB - IMPORTANCE: To date, only a few studies have directly compared nonpenetrating surgery (NPS) and trabeculectomy (TE). Therefore, there is no strong evidence as to which surgical technique leads to the best results in terms of ocular hypotensive effect and safety. OBJECTIVE: To compare the hypotensive effect and safety of NPS and TE in terms of intraocular pressure (IOP) reduction and incidence of complications. DATA SOURCES: The MEDLINE and EMBASE databases were searched for studies potentially eligible in any language published up to March 31, 2013. STUDY SELECTION: Systematic review and meta-analysis of comparative studies of 2 or more surgical techniques (1 of which had to be TE), including patients with open-angle glaucoma. DATA EXTRACTION AND SYNTHESIS: The considered interventions were TE, deep sclerectomy (DS), viscocanalostomy, and canaloplasty. MAIN OUTCOMES AND MEASURES: The primary outcome was the mean between-group difference in the reduction in diurnal IOP from baseline to the 6- or 12-month follow-up evaluation. We also considered the incidence of complications, expressed as relative risk. RESULTS: Eighteen articles, accounting for 20 comparisons, were selected for data extraction and analysis. Analysis of the 6 month follow-up data showed that the pooled estimate of the mean between-group difference was -2.15 mm Hg (95% CI, -2.85 to -1.44) in favor of TE. There was no difference between the NPS subgroups. In the subgroup antimetabolite analysis, the addition of mitomycin C to TE and DS decreased the difference in the reduction in IOP (TE and DS without mitomycin C: -2.65 mm Hg [95% CI, -3.90 to 1.39]; TE and DS with mitomycin C: -0.83 mm Hg [95% CI, -2.40 to 0.74]). In the subgroup analysis by implant addition, no significant difference induced by DS with or without drainage devices was detected (test for subgroup differences: chi(2)(1) = 0.24; P = .62). The absolute risk of hypotony, choroidal effusion, cataract, and flat or shallow anterior chamber was higher in the TE group than in the NPS group. CONCLUSIONS AND RELEVANCE: Trabeculectomy seems to be the most effective surgical procedure for reducing IOP in patients with open-angle glaucoma. However, as expected, it was associated with a higher incidence of complications when compared with NPS. PMID- 24158641 TI - [Biomarkers of bone remodelling]. AB - Bone is a frequent site for metastases patients with advanced solid tumors. Metastatic bone disease alters bone homeostasis and biochemical markers of bone turnover are studied in patients with cancer. These markers include bone matrix synthesis and degradation products, or enzymes expressed by osteoblasts or osteoclasts. Thus, the use of these biochemical markers of bone metabolism is being evaluated in screening for development of bone metastases, in predicting risk of skeletal-related events and survival in patients with bone metastases, and in monitoring response to antiresorptive therapy. Bone markers have potential to provide information, but their routine use in the clinic cannot be recommended yet. PMID- 24158643 TI - Porous titanium and zirconium oxo carboxylates at the interface between sol-gel and metal-organic framework structures. AB - Reaction of Ti(OiPr)4 with several tri- and tetracarboxylic acids, followed by hydrolysis, resulted in microporous, structured materials, with microporous surface areas up to 340 m(2) g(-1). Depending on the kind of carboxylic acid, the Ti : COOH ratio and the Ti : H2O ratio, either pillared layered or surface fractal 3D structures were obtained according to SAXS measurements. The most pronounced layered structure was found for 1,2,4,5-benzenetetrabenzoic acid and a Ti : H2O ratio of 4, while a Ti : H2O ratio of 2 resulted in a 3D structure. The use of 1,3,5-benzenetricarboxylic acid or 1,3,5-benzenetribenzoic acid resulted in similar structures which, however, were less pronounced and less ordered. The reaction of tetrakis(4-carboxyphenyl)silicon with Ti(OiPr)4 or benzenetribenzoic acid with Zr(OiPr)4 gave 3D structures for all Ti : H2O ratios. PMID- 24158642 TI - Affective, biological, and cognitive predictors of depressive symptom trajectories in adolescence. AB - Heterogeneity in the longitudinal course of depressive symptoms was examined using latent growth mixture modeling among a community sample of 382 U.S. youth from ages 11 to 18 (52.1 % female). Three latent trajectory classes were identified: Stable Low (51 %; displayed low depressive symptoms at all assessments), Increasing (37 %; reported low depressive symptoms at age 11, but then significantly higher depressive symptoms than the Stable Low class at ages 13, 15, and 18), and Early High (12 %; reported high early depressive symptoms at age 11, followed by symptoms that declined over time yet remained significantly higher than those of the Stable Low class at ages 13, 15, and 18). By age 15, rates of Major Depressive Disorder diagnoses among the Early High (25.0 %) and Increasing (20.4 %) classes were more than twice that observed among the Stable Low class (8.8 %). Affective (negative affectivity), biological (pubertal timing, sex) and cognitive (cognitive style, rumination) factors were examined as predictors of class membership. Results indicated general risk factors for both high-risk trajectories as well as specific risk factors unique to each trajectory. Being female and high infant negative affectivity predicted membership in the Increasing class. Early puberty, high infant negative affectivity for boys, and high rumination for girls predicted membership in the Early High class. Results highlight the importance of examining heterogeneity in depression trajectories in adolescence as well as simultaneously considering risk factors across multiple domains. PMID- 24158644 TI - Validity of the Functional Gait Assessment in patients with Parkinson disease: construct, concurrent, and predictive validity. AB - BACKGROUND: The Functional Gait Assessment (FGA) is a validated measurement of gait-related activities in certain populations and may be potentially useful to assess balance and gait disorders in patients with Parkinson disease (PD). OBJECTIVE: The purpose of this study was to determine the construct, concurrent, and predictive validity of the FGA in inpatients with PD. DESIGN: This was a prospective cohort study. METHODS: One hundred twenty-one inpatients with PD were prospectively enrolled. The FGA and other relevant appraisals of gait, balance, disease severity, and activities of daily living were performed. Six months later, the patients were interviewed by telephone to have their fall information collected. Principal component analysis was used to determine construct validity. Spearman correlation coefficients were used to determine concurrent validity between the FGA and other measures. Cutoff point, sensitivity, specificity, and positive likelihood ratio were calculated for predictive validity based on the receiver operating characteristic curve. RESULTS: One common factor was extracted for construct validity, which cumulatively explained 64.0% of the total variance. Correlation coefficients for the FGA compared with other measures ranged from .57 to .85. The cutoff point for predicting falls was 18, with sensitivity of 80.6%, specificity of 80.0%, and positive likelihood ratio of 4.03. LIMITATIONS: This study was limited by the length of time of follow-up and self-reports of falls without the requirement of a fall diary. Medication adjustment after the FGA evaluation may have led to a different cutoff score for identifying those patients who were at risk of falling. CONCLUSIONS: The FGA demonstrated good construct validity in patients with PD. It had moderate to strong correlations with other balance and gait appraisals. The FGA can be used to predict falls within the subsequent 6 months. PMID- 24158645 TI - The contralateral extremity has also benefit from the locally administered bone marrow-derived mononuclear cells and cord blood serum in diabetic ischemic wound healing. AB - OBJECTIVE: Impaired wound healing could be a disaster especially in diabetes and amputation is the major risk. The aim of this study was to evaluate the benefit of BMMCs and CBS on wound healing. METHODS: Diabetic rats were underwent bilateral limb ischemia and wounding of skin defects on both extremities. The groups were formed as BMMCs (group A), BMMCs and CBS (group B), only CBS (group C), and phosphate buffer solution (group D) that were injected into wounds on right legs. RESULTS: The complete recovery of right legs was established as a mean of 21.4 +/- 1.1 days, 12.9 +/- 1.5 days, 30.0 +/- 0.0 days and 38.1 +/- 1.5 days according to Groups A, B, C, and D (p < 0.05). The recovery of left legs were calculated as a mean of 27.0 +/- 0.0 days, 24.0 +/- 0.0 days, 35.6 +/- 1.1 days and 37.3 +/- 1.6 days according to Groups A, B, C and D (p < 0.05). At the end of the recovery, the HE staining showed that vascularity was increased in groups A and B. CONCLUSION: Transplantation of BMMCs and CBS to the ischemic wounds of the diabetic rats accelerate the repair. The recovery was also superior in the same group although the treatment was not applied to the left extremity directly. PMID- 24158646 TI - Detection of the G3 genotype of Echinococcus granulosus from hydatid cysts of Chilean cattle using COX1 and ND1 mitochondrial markers. AB - For a deeper understanding of the phylogenetic relationships of Echinococcus genotypes and species in different intermediate hosts, we analyzed samples from human and bovine hydatid cysts. For this, segments of the cytochrome oxidase (COX1) and NADH dehydrogenase (ND1) mitochondrial genes were used. To obtain sufficient amounts of the ND1 marker to be sequenced properly, a new variant of the PCR assay was implemented. Phylogenetic analysis with both markers showed that most of the analyzed samples correspond to genotype G1. However, a sample from cysts of a bovine lung (Q21), with the COX1 marker, was grouped in a node together with a sample belonging to genotype G3. In the phylogenetic tree obtained with the ND1 marker, this sample was grouped with sequences of genotypes G3, G2, and G4. Analyzing the single nucleotide polymorphic (SNP) sites of both markers, it was observed that the Q21 sequence is almost identical to the G3 sequence and differ in only one SNP from the G2 sequence, and is completely different from G4. These results are noteworthy, since neither G2 nor G3 genotypes have been described previously in Chile, raising the possibility that the G3 genotype is present in these latitudes. This information is highly relevant; it can be employed to uncover additional unknown details of transmission cycles of this important parasite. PMID- 24158647 TI - Strong larvicidal potential of Artemisia annua leaf extract against malaria (Anopheles stephensi Liston) and dengue (Aedes aegypti L.) vectors and bioassay driven isolation of the marker compounds. AB - Malaria and dengue are the two most important vector-borne human diseases caused by mosquito vectors Anopheles stephensi and Aedes aegypti, respectively. Of the various strategies adopted for eliminating these diseases, controlling of vectors through herbs has been reckoned as one of the important measures for preventing their resurgence. Artemisia annua leaf chloroform extract when tried against larvae of A. stephensi and A. aegypti has shown a strong larvicidal activity against both of these vectors, their respective LC50 and LC90 values being 0.84 and 4.91 ppm for A. stephensi and 0.67 and 5.84 ppm for A. aegypti. The crude extract when separated through column chromatography using petroleum ether-ethyl acetate gradient (0-100%) yielded 76 fractions which were pooled into three different active fractions A, B and C on the basis of same or nearly similar R f values. The aforesaid pooled fractions when assayed against the larvae of A. stephensi too reported a strong larvicidal activity. The respective marker compound purified from the individual fractions A, B and C, were Artemisinin, Arteannuin B and Artemisinic acid, as confirmed and characterized through FT-IR and NMR. This is our first report of strong mortality of A. annua leaf chloroform extract against vectors of two deadly diseases. This technology can be scaled up for commercial exploitation. PMID- 24158648 TI - Health-related quality of life experienced by children with chromosomal abnormalities and congenital heart defects. AB - Long-term outcomes are fundamental in advising parents about the potential future of their children with congenital heart disease (CHD). No published reports have described the health-related quality of life (HRQL) experienced by children with chromosomal abnormalities who had surgery in early infancy for CHD. A study was undertaken to assess HRQL among children with chromosomal abnormalities and CHD. The authors hypothesized that these children have a worse HRQL than healthy children or a cohort of children matched for CHD diagnosis. Infants with chromosomal abnormalities undergoing cardiac surgery for CHD at 6 weeks of age or younger at the Stollery Children's Hospital between July 2000 and June 2005 were included in the study. The HRQL of these infants was assessed using the Pediatric Quality of Life Inventory (PedsQL) 4.0 Generic Core Scales completed by their parents at a 4-year follow-up evaluation. The study compared the scores for 16 children with normative data. The children with chromosomal abnormalities and CHD had significantly lower mean total PedsQL (71.3 vs. 87.3; p < 0.0001), Psychosocial Summary (70.3 vs. 86.1; p < 0.0001), and Physical Summary (74.3 vs. 89.2; p = 0.0006) scores. Compared with the matched children, those with chromosomal abnormalities had a significantly lower median total PedsQL (75.0 vs. 84.6; p = 0.03), Physical Summary (79.5 vs. 96.9; p = 0.007), and School Functioning (68.5 vs. 83.0; p = 0.03) scores. A better understanding of the mechanisms and determinants of HRQL in these children has the potential to yield important implications for clinical practice including clarity for treatment decision making as well as determination of targeted supports and services to meet the needs of these children and their families differentially. PMID- 24158649 TI - Prediction of therapeutic effectiveness according to CT findings after therapeutic lymphangiography for lymphatic leakage. AB - PURPOSE: To evaluate the correlation between computed tomography (CT) findings after therapeutic lymphangiography for lymphatic leakage and the clinical course of lymphatic leakage. MATERIALS AND METHODS: Therapeutic lymphangiography for lymphatic leakage was performed in 14 patients. In all patients, CT was performed 0.5-26 h (mean 6.9 h) after lymphangiography and results were retrospectively evaluated. RESULTS: In 8 of the 14 patients (57 %), lymphatic leakage stopped after lymphangiography. Lymphatic leakage was detected on CT in 9 of the 14 patients (64 %) and had either a nodular (n = 4) or beaded appearance (n = 5). The amount of drainage had decreased the day after lymphangiography, and leakage finally stopped in all 4 patients in whom the leakage had a nodular appearance. However, leakage did not stop in 3 of the 5 patients having leakage with a beaded appearance. CONCLUSION: A nodular appearance of leakage might predict success of therapeutic lymphangiography. PMID- 24158650 TI - Potentially symptomatic fabella: MR imaging review. AB - Fabella, a small ossicle at the posterolateral aspect of the knee, is potentially a source of knee pain. Although fabella syndrome is a rare cause of knee symptoms in young adults, osteocartilaginous degeneration prominent in the fabellofemoral joint on magnetic resonance imaging may be commonly seen in elderly patients. PMID- 24158651 TI - Red grape berry-cultured cells reduce blood pressure in rats with metabolic-like syndrome. AB - PURPOSE: Cumulative evidence suggests that moderate red wine consumption protects the cardiovascular system. The effect of cultured cells derived from red grape berry (RGC) on blood pressure (BP) has not been investigated. We therefore studied the antihypertensive effects of oral consumption of RGC in experimental rat model of metabolic-like syndrome and assessed its effect on human umbilical vein endothelial cells (HUVECs). METHODS: Forty male Sprague-Dawley rats were fed for 5 weeks with either a high fructose diet (HFD) (n = 10) or HFD supplemented, during the last 2 weeks, with different doses (200, 400 and 800 mg/kg/day) of RGC suspended in their food (n = 30). BP, plasma triglycerides, insulin and adiponectin levels were measured at the beginning and after 3 and 5 weeks of diet. RGC effect on vasodilatation was evaluated by its ability to affect endothelin-1 (ET-1) production and endothelial nitric oxide synthase (eNOS) expression in HUVECs. RESULTS: BP, plasma triglycerides, insulin and adiponectin increased significantly in rats fed with a HFD. The increase in BP, plasma triglycerides and insulin was attenuated by RGC supplementation. Incubation of HUVECs with RGC demonstrated a concentration-dependent inhibition of ET-1 secretion and increase in the level of eNOS, signaling a positive effect of RGC on vasodilatation. CONCLUSION: In rats with metabolic-like syndrome, RGC decreased BP and improved metabolic parameters. These beneficial effects may be mediated by the cell constituents, highly rich with polyphenols and resveratrol, reside in their natural state. PMID- 24158652 TI - Plasma kinetics of chylomicron-like emulsion and lipid transfers to high-density lipoprotein (HDL) in lacto-ovo vegetarian and in omnivorous subjects. AB - PURPOSE: Previously, it was showed that vegan diet improves the metabolism of triglyceride-rich lipoproteins by increasing the plasma clearance of atherogenic remnants. The aim of the current study was to investigate this metabolism in lacto-ovo vegetarians whose diet is less strict, allowing the ingestion of eggs and milk. Transfer of lipids to HDL, an important step in HDL metabolism, was tested in vitro. METHODS: Eighteen lacto-ovo vegetarians and 29 omnivorous subjects, all eutrophic and normolipidemic, were intravenously injected with triglyceride-rich emulsions labeled with 14C-cholesterol oleate and 3H-triolein. Fractional clearance rates (FCR, in min-1) were calculated from samples collected during 60 min. Lipid transfer to HDL was assayed by incubating plasma samples with a donor nanoemulsion labeled with radioactive lipids. RESULTS: LDL cholesterol was lower in vegetarians than in omnivores (2.1 +/- 0.8 and 2.7 +/- 0.7 mmol/L, respectively, p < 0.05), but HDL cholesterol and triglycerides were equal. Cholesteryl ester FCR was greater in vegetarians than in omnivores (0.016 +/- 0.012, 0.003 +/- 0.003, p < 0.01), whereas triglyceride FCR was equal. Cholesteryl ester transfer to HDL was lower in vegetarians than in omnivores (2.7 +/- 0.6, 3.5 +/- 1.5 %, p < 0.05), but free cholesterol, triglyceride and phospholipid transfers and HDL size were equal. CONCLUSION: Similarly to vegans, lacto-ovo vegetarian diet increases remnant removal, as indicated by cholesteryl oleate FCR, which may favor atherosclerosis prevention, and has the ability to change lipid transfer to HDL. PMID- 24158654 TI - ["Book of life" : On course for personalized anesthesia?]. PMID- 24158653 TI - Bioavailability of phenolics from an oleuropein-rich olive (Olea europaea) leaf extract and its acute effect on plasma antioxidant status: comparison between pre and postmenopausal women. AB - PURPOSE: Preclinical studies suggest a potential protective effect of oleuropein in osteoporosis, and one of the proposed mechanisms is the modulation of the oxidative stress. Oleuropein bioavailability and its effect on antioxidant status in pre- and postmenopausal women are unknown. The aim of the present study was to investigate the oral bioavailability of an olive leaf extract rich in oleuropein (40 %) and its effect on antioxidant status in postmenopausal women compared to premenopausal women. METHODS: Premenopausal (n = 8) and postmenopausal women (n = 8) received 250 mg of olive leaf extract, blood samples (t = 0, 1, 2, 3, 4, 6, 8, 12, 16 and 24 h) were taken, and 24-h urine divided into five fractions was collected. Olive-leaf-extract-derived metabolites were analyzed in plasma and urine by HPLC-ESI-QTOF and UPLC-ESI-QqQ, and pharmacokinetics parameters were determined. Ferric reducing antioxidant ability and malondialdehyde levels were measured in plasma. RESULTS: Plasma levels of hydroxytyrosol glucuronide, hydroxytyrosol sulfate, oleuropein aglycon glucuronide and oleuropein aglycon derivative 1 were higher in postmenopausal women. MDA levels were significantly decreased (32%) in postmenopausal women and inversely correlated with hydroxytyrosol sulfate levels. Postmenopausal women excreted less sulfated metabolites in urine than premenopausal women. CONCLUSIONS: Our results suggest that postmenopausal women could be a target population for the intake of olive phenolics in order to prevent age-related and oxidative stress-related processes such as osteoporosis. PMID- 24158656 TI - A case report of extended neurogenic muscular atrophy related to SAPHO syndrome. PMID- 24158657 TI - Dental hygiene internationally: the 19th International Symposium on Dental Hygiene. PMID- 24158655 TI - Variation in chromatin accessibility in human kidney cancer links H3K36 methyltransferase loss with widespread RNA processing defects. AB - Comprehensive sequencing of human cancers has identified recurrent mutations in genes encoding chromatin regulatory proteins. For clear cell renal cell carcinoma (ccRCC), three of the five commonly mutated genes encode the chromatin regulators PBRM1, SETD2, and BAP1. How these mutations alter the chromatin landscape and transcriptional program in ccRCC or other cancers is not understood. Here, we identified alterations in chromatin organization and transcript profiles associated with mutations in chromatin regulators in a large cohort of primary human kidney tumors. By associating variation in chromatin organization with mutations in SETD2, which encodes the enzyme responsible for H3K36 trimethylation, we found that changes in chromatin accessibility occurred primarily within actively transcribed genes. This increase in chromatin accessibility was linked with widespread alterations in RNA processing, including intron retention and aberrant splicing, affecting ~25% of all expressed genes. Furthermore, decreased nucleosome occupancy proximal to misspliced exons was observed in tumors lacking H3K36me3. These results directly link mutations in SETD2 to chromatin accessibility changes and RNA processing defects in cancer. Detecting the functional consequences of specific mutations in chromatin regulatory proteins in primary human samples could ultimately inform the therapeutic application of an emerging class of chromatin-targeted compounds. PMID- 24158658 TI - Evidence-based considerations for the clinical use of locally delivered, controlled-release antimicrobials in periodontal therapy. AB - PURPOSE: Locally delivered, controlled-release antimicrobials have long been available in dentistry. Their utilization in routine clinical practice, however, has been slow, perhaps because of concerns about clinical benefits or costs or possibly due to a lack of understanding of their efficacy or proper use. In this paper the evidence regarding locally delivered, controlled-released antimicrobials is considered, and some of the controversies surrounding these agents are discussed. Evidence-based considerations regarding their use are also summarized. Scaling and root planing (SRP) procedures are the backbone of non surgical periodontal therapy. Since a number of well designed clinical trials have demonstrated that adjunctive, locally delivered, controlled-release antimicrobials make SRP significantly more effective to reduce clinical signs of chronic periodontitis with a known safety profile, and since SRP procedures have previously been considered the standard of care for non-surgical periodontal therapy, a case is made that SRP in combination with adjunctive therapy, administered in a manner consistent with the approved full prescribing information, could be considered a new standard. PMID- 24158659 TI - Strategies for service-learning assessment in dental hygiene education. AB - PURPOSE: A large body of literature exists on the instructional pedagogy known as service-learning. Service-learning is a teaching and learning approach characterized by the dental hygiene student's practical application of academic studies and occurs within a community setting, to the benefit of both the student and community. Dental hygiene educators use service-learning to enhance student knowledge and application of oral health curriculum. This manuscript reports on the importance of service-learning assessment to the National Dental Hygiene Research Agenda as well as the future of the profession of dental hygiene and the successful strategies in service-learning evaluation available for utilization by dental hygiene educators. PMID- 24158660 TI - Access to oral health care in the Georgia prison system. AB - PURPOSE: The Eighth Amendment of the U.S. Constitution establishes the basis for inmates' rights to health care and includes both routine and emergency medical, dental and psychiatric treatment. According to Georgia's Correctional Standards of Health Care, inmates should receive a dental examination within 30 days of incarceration, instructions in oral hygiene and other care by a dentist when medically necessary. The July, August and September 2011 Georgia Department of Corrections' profiles of active inmates in the Georgia prison system reveal a need for both dental and dental hygiene services. The purpose of this article is to provide an overview of the access to oral health care of inmates in the Georgia prison system. Potential barriers to dental and dental hygiene services are identified and suggestions are offered to improve access to care for inmates. PMID- 24158661 TI - A qualitative case study of the legislative process of the hygienist-therapist bill in a large Midwestern state. AB - PURPOSE: Inequitable access to dental care contributes to oral health disparities. Midlevel dental provider models are utilized across the globe as a way to bridge the gap between preventive and restorative dental professionals and increase access to dental care. The purpose of this study was threefold: to examine lessons learned from the state legislative process related to creation of the hygienist-therapist in a Midwestern state, to improve understanding of the relationship between alternative oral health delivery models and public policy and to inform the development and passage of future policies aimed at addressing the unmet dental needs of the public. METHODS: This research investigation utilized a qualitative research methodology to examine the process of legislation relating to an alternative oral health delivery model (hygienist-therapist) through the eyes of key stakeholders. Interview data was analyzed and then triangulated with 3 data sources: interviews with key stakeholders, documents and researcher participant field notes. RESULTS: Data analysis resulted in consensus on 3 emergent themes with accompanying categories. The themes that emerged included social justice, partnerships and coalitions, and the legislative process. CONCLUSION: This qualitative case study suggests that the creation of a new oral health workforce model was a long and arduous process involving multiple stakeholders and negotiation between the parties involved. The creation of this new workforce model was recognized as a necessary step to increasing access to dental care at the state and national level. The research in this case study may serve to inform advocates of access to oral health care as other states pursue their own workforce models. PMID- 24158662 TI - Extending oral health care services to underserved children through a school based collaboration: Part 3--a cost analysis. AB - PURPOSE: The purpose of this manuscript was to conduct a cost analysis of the Miles of Smiles Program, a collaboration between the University of Missouri Kansas City School of Dentistry and the Olathe School District in Kansas. This preventive program was implemented to improve the access to oral health care for low income children within the school district. METHODS: An inventory list and de identified patient records were used to determine the costs associated with operating the program to serve 339 elementary school students during the 2008 to 2009 school term. Costs related to equipment, supplies and personnel were included. The costs were then compared to the amount of Medicaid reimbursement obtained for the services provided. Additionally, the cost of operating a similar program, if staffed by dental professionals rather than supervised dental hygiene students, was estimated. RESULTS: The cost of operating the program during the 2008 to 2009 school term was $107,515.74. The program received Medicaid reimbursement for approximately 1.5% of the total operating cost of and approximately 6.3% of the total billable services, however, challenges with submitting and billing Medicaid claims for the first time contributed to this low rate of reimbursement. If a similar program that utilized dental professionals was implemented and treated the same number of patients, the cost would be approximately $37,529.65 more due to higher expenses associated with personnel and supplies. CONCLUSION: The program is not self-sustainable based on Medicaid government-funded insurance reimbursement alone, and therefore continuous external sources of funding or a change in the program design would be necessary for long-term sustainability of the program. PMID- 24158663 TI - Public health dental hygiene: an option for improved quality of care and quality of life. AB - PURPOSE: The purpose of this research was to document quality of life (QoL) and quality of care (QoC) measures for families receiving care from dental hygienists within public health departments, and to consider if oral health for families with economic disparities and cultural differences was improved. METHODS: A descriptive research study using a retrospective record review was conducted considering QoC. A review of state epid "Do preventive oral health programs based in local health departments provide quality care services, thus impacting QoL for underserved populations?" RESULTS: A dental hygienist working in public health made significant contributions to improving access to care and QoL in a rural, socioeconomically disadvantaged community. A total of 2,364 children received education, 1,745 received oral screenings and 1,511 received dental sealants. Of these, 804 children with caries were referred, with 463 receiving restorations and follow-up care. QoL metrics basis assessed Health Outcomes & Health Determinants. Initial QoL data was ranked in the bottom half of the state, while 70% of original determinant data was also ranked in the bottom half of reported metrics. CONCLUSION: Dental hygienists in public health settings can positively affect patients offering preventive care outreach services. Education and sealant placement were considered effective as measured by access, delivery and, when required, referral for restorative care. Improvement in QoL for individuals was noted through improved health outcomes and determinant metrics. PMID- 24158664 TI - Accuracy of digital arm and wrist manometers: clinical implications for the dental hygienist. AB - PURPOSE: Utilization of digital manometers chairside is fast becoming a standard of care in dental hygiene education. It is imperative to ensure accurate blood pressure measurements regardless of modality to avoid medical emergencies in the dental chair. This study sought to determine the accuracy of the automated digital arm and wrist cuffs utilized by students in the University of Maine at Augusta, Bangor Campus Dental Health Programs' dental hygiene clinic. METHODS: After institutional review board approval, 121 subjects were recruited, with 21 excluded for a total of 100 subjects. Subjects were randomly assigned to different test modalities upon check-in. Initial blood pressure measurements were taken with a calibrated aneroid control device by a principal investigator. A second measurement was taken with the randomized arm or wrist manometer 5 minutes later. Investigators were blinded to the modality of test manometer and measurements obtained from the second reading. All readings were taken according to manufacturers' instructions to ensure technique consistency. RESULTS: Data indicated lower readings for each modality from the control for both systolic and diastolic measurements. The differences in the systolic and diastolic readings for the wrist modality were significantly lower than the control with (p= 0.000) and (p=0.000), respectively. CONCLUSION: Automated digital manometers should be used with caution as a screening tool in the dental setting, particularly when administration of pharmacological agents such as local anesthesia may be used during the course of treatment. These automated modalities should not be used for patients with cardiac or hypertensive conditions. PMID- 24158665 TI - Stereospecific synthesis of a twinned alanine ester. AB - Reaction between 1,2-bis(2-hydroxyphenyl)-ethylenediamine (hpen) and methyl pyruvate gives the diaza-Cope rearrangement product with good yield and excellent stereospecificity. The product containing two chiral quaternary carbon centers is characterized by high performance liquid chromatography and X-ray crystallography. DFT computation provides insight into why the diaza-Cope rearrangement takes place readily with methyl pyruvate but not with other ketones like acetone and substituted acetophenones. PMID- 24158667 TI - Porous Mg thin films for Mg-air batteries. AB - An alkaline primary Mg-air battery made from a porous Mg thin film displayed superior discharge performances, including a flat discharge plateau, a high open circuit voltage of 1.41 V and a large discharge capacity of 821 mAh g(-1), suggesting that the electrochemical performances of Mg-air batteries can be improved by controlling the Mg anode morphology. PMID- 24158666 TI - Clinical pharmacokinetic drug interactions associated with artemisinin derivatives and HIV-antivirals. AB - Management of HIV and malaria co-infection is challenging due to potential drug drug interactions between antimalarial and HIV-antiviral drugs. Little is known of the clinical significance of these drug interactions, and this review provides a comprehensive summary and critical evaluation of the literature. Specifically, drug interactions between WHO-recommended artemisinin combination therapies (ACT) and HIV-antivirals are discussed. An extensive literature search produced eight articles detailing n = 44 individual pharmacokinetic interactions. Only data pertaining to artemether-lumefantrine and two other artesunate combinations are available, but most of the interactions are characterized on at least two occasions by two different groups. Overall, protease inhibitors (PIs) tended to increase the exposure of lumefantrine and decrease the exposures of artemether and dihydroartemisinin, a pharmacologically active metabolite of artemether. Non nucleoside reverse transcriptase inhibitors (NNRTIs) tended to decrease the exposures of artemether, dihydroartemisinin, and lumefantrine when co administered with artemether-lumefantrine. Fewer studies characterized the effects of PIs or NNRTIs on artesunate combinations, but nevirapine increased artesunate exposure and ritonavir decreased dihydroartemisinin exposure. On the other hand, artemether-lumefantrine or artesunate combinations had little effect on the pharmacokinetics of HIV-antivirals, with the exception of decreased nevirapine exposure from artemether-lumefantrine or increased ritonavir exposure from pyronaridine/artesunate co-administration. In general, pharmacokinetic interactions can be explained by the metabolic properties of the co-administered drugs. Despite several limitations to the studies, these data do provide valuable insights into the potential pharmacokinetic perturbations, and the consistently marked elevation or reduction in ACT exposure in some cases cannot be overlooked. PMID- 24158668 TI - [Bone targeting agents: bisphosphonates]. AB - Malignant tumor osteolysis is a frequent complication in many cancers. It can cause skeletal-related events with alteration of quality of life and survival. Bisphosphonates play an important role in the management of this malignant osteolysis, via an inhibition of osteoclast-mediated bone resorption, and a potential direct antitumor activity. Their use constitutes an important therapeutic advance in patients with bone metastases so as to reduce or delay the appearance of these skeletal events. They are also useful for the treatment of hypercalcemia, which could arise in these patients. Their interest as adjuvant therapy before the onset of bone metastases is currently being evaluated. PMID- 24158669 TI - Risk factors for early death after surgery in patients with brain metastases: reevaluation of the indications for and role of surgery. AB - Surgical resection remains an important option for the treatment of brain metastases despite recent advancements in radiotherapy and systemic therapy. When selecting surgical candidates, it is important to exclude terminal cases who will receive neither a survival benefit nor an improvement in their quality of life. We reviewed a total of 264 surgical cases of brain metastases and analyzed the clinical characteristics of early death in order to clarify the indication for and the role of surgery. The median survival time (MST) after surgery in all cases was 12.4 months. Early death was defined as death within 6 months, and 23% (62 cases) of this series were succumbed to this. A decrease in postoperative Karnofsky performance status (KPS) (<70) (P = 0.041), lack of systemic therapy after surgery (P < 0.0001), and uncontrolled extracranial malignancies (P = 0.0022) were significantly related to early death in multivariate analysis, while preoperative KPS (<70) and recursive partitioning analysis (RPA) class were related to early death only in univariate analysis (P < 0.05). When analyzing patients with uncontrolled extracranial malignancies and those with a postoperative KPS score of 70 or greater (who were generally candidates for systemic therapy), the MST was significantly longer in the systemic therapy (+) group compared with the systemic therapy (-) group (12.5 vs. 5.6 months; P = 0.0026). Our data indicate that the postoperative RPA class and treatment strategy were associated with early death. Deterioration of patients by surgery should be avoided in the treatment of brain metastases. PMID- 24158670 TI - Risk factors and long-term survival in adult patients with primary malignant spinal cord astrocytomas. AB - Primary intramedullary spinal cord tumors are a rare entity, comprising 4-10 %of all spinal cord tumors. The current report presents data on intramedullary spinal cord anaplastic astrocytomas and glioblastomas in adults using the national surveillance, epidemiology, and end results database (1973-2008), and evaluates the impact of demographic and treatment factors on survival. Eighty nine adults were evaluated (mean age of 43 years); 49 % of patients had anaplastic astrocytoma and 51 % of patients had glioblastoma.88 % of patients had surgical intervention and 85 % of patients had radiotherapy. In univariate analysis, male gender (HR = 0.50, CI: 0.29-0.86, P = 0.01), surgical treatment (HR = 0.37, CI: 0.15-0.93, P = 0.03), and tumor histology (HR = 1.83, CI: 1.06-3.18, P = 0.03) were significant predictors of survival. Results remained significant or marginally significant after multivariate adjustment analyses. Adjuvant radiotherapy and age at diagnosis did not have a significant influence on survival. Future prospective studies from collaborative institutions combining richer detail in perioperative treatment, radiotherapy dosing, chemotherapy treatment, neurologic examinations, functional outcomes, and quality of life measures would contribute to more concrete, evidence-based treatment protocols for adult patients with primary malignant spinal cord astrocytomas. PMID- 24158671 TI - Glyoxalase 1 is up-regulated in hepatocellular carcinoma and is essential for HCC cell proliferation. AB - Glyoxalase 1 (Glo1), belonging to the glyoxalase system, participates in the detoxification of methylglyoxal (MG), a byproduct of glycolysis. Glo1 is associated with the progression of many human malignancies. However, the role of Glo1 in hepatocellular carcinoma (HCC) is unclear. We have discovered that the expression of Glo1 is up-regulated in HCC tissues compared with adjacent non tumorous tissues, and knockdown of Glo1 expression by RNA interference significantly inhibited the proliferation of human HCC cell lines. Glo1 knockdown resulted in the accumulation of its cytotoxic substrate, MG. Overall, thus Glo1 might be essential for HCC progression and can be designated as a potential therapeutic target for HCC in the future. PMID- 24158673 TI - A new approach for discovering cold-active enzymes in a cell mixture of pure cultured bacteria. AB - To overcome the intrinsic problems of conventional approaches, such as the unavailability of source microorganisms in metagenomic libraries and the production of inactive aggregates, a new method was tested for discovering new enzymes (e.g. cold-active chitinase). A metagenome-like library was constructed using genomes extracted from a cell mixture of pure-cultured chitinolytic bacteria, followed by activity-based screening for Escherichia coli clones that exhibit chitinase activity on selective medium. Within one positive chitinolytic clone, one chitinase gene (chi22718_III) was detected and assigned to the arctic marine bacterium, Pseudoalteromonas issachenkonii PAMC 22718, by colony-PCR with chi22718_III-specific primers. When expressed in E. coli, recombinant R Chi22718_III lost 85 % of its enzyme activity when pre-incubated at 40 degrees C for 1 h, whereas its mesophilic counterpart R-ChiK only lost 10 % of its activity under the same conditions indicating that R-Chi22718_III is thermolabile, a characteristic of cold-active enzymes. PMID- 24158674 TI - Comparison of extraction phases for a two-phase culture of a recombinant E. coli producing retinoids. AB - To prevent degradation of intracellular retinoids through in situ extraction from the cells, a two-phase culture system was performed. Several organic solvents, including n-alkanes, mineral oils and cosmetic raw materials, were applied as the extraction phase. Of the n-alkanes, n-decane had the highest retinoid production as 134 mg/l after 72 h. For mineral oil, light and heavy mineral oil gave retinoid productions of 158 and 174 mg/l after 96 h, respectively. Of other materials, isopropyl myristate gave the highest retinoid production of 181 mg/l. These results indicate that many types of oils can be applied for retinoid production, and optimization of the in situ extraction process will lead to further improve of economical production for the industrial purpose. PMID- 24158675 TI - Efficient targeting of FATS at a common fragile site in mice through TALEN mediated double-hit genome modification. AB - Transcription activator-like effector nucleases (TALENs) have emerged as a newly developed approach for genome editing. However, its application in targeting specific genomic loci susceptible to DNA damage remains obscure. Here, we report a modified approach for TALENs-based targeting of FATS, a fragile-site gene whose major introns have AT-rich sequence and di-nucleotide repeats. Two pairs of FATS TALENs were designed to cleave two sites specifically at a coding exon of FATS. After in vitro transcription, the mRNA from FATS-TALEN pairs was microinjected into mouse zygotes. The targeting efficiency of two FATS-TALEN pairs in vivo was more than threefold higher than that of one FATS-TALEN pair. Moreover, large-size DNA deletions were detected, which were heritable and easily detectable by PCR. Our study indicates that the double-hit TALEN approach enhances targeting efficiency in vivo and provides convenience for monitoring germline transmission of mutations by PCR, which will facilitate the functional research on fragile site genes. PMID- 24158676 TI - Production of fructose from highly concentrated date extracts using Saccharomyces cerevisiae. AB - Large amounts of low-quality dates produced worldwide are wasted. Here, highly concentrated fructose syrups were produced via selective fermentation of date extracts with Saccharomyces cerevisiae. Syrups with 95.4-99.9 % (w/w) fructose yields were obtained from date extracts having an initial sugar range of 49-374 g/l without media supplementation; the corresponding ethanol yields were between 69 and 52 % (w/w). At 470 g initial sugars/l, fructose and ethanol yields were 84 and 47 % (w/w), respectively, and the product contained 62 % (w/w) fructose, which is higher than the widely available commercial 42 and 55 % (w/w) high fructose corn syrups. The commercial potential for conversion of waste dates to high-value products is thus demonstrated. PMID- 24158677 TI - Tumorsphere assay provides more accurate prediction of in vivo responses to chemotherapeutics. AB - Although the sphere culture system has been widely used in stem cell biology, its application for drug screening is limited due to lack of standardized, rapid analytical tools. To optimize sphere cultures for in vitro screening of drugs, we evaluated the properties of primary tumor cells growing as tumorspheres and compared their chemosensitivity to those of cells growing in monolayer. Most cells in tumorsphere cultures were quiescent whereas cells in monolayer culture had a high mitotic index. Moreover, doxorubicin showed better cytotoxicity than paclitaxel in the sphere cultures, but their efficacy was reversed in the monolayer cultures. Importantly, the response of cytotoxic outcomes for suspension cultures matched the in vivo response better than monolayer cultures, providing support for the use of short term suspension cultures of primary cells as a model for drug testing. PMID- 24158678 TI - Exact second virial coefficient for dipolar hard spheres. AB - The second virial coefficient B2 for a fluid of dipolar hard spheres has been given several approximate forms valid in the limits of weak and strong interactions. They have been formulated as asymptotic expressions in a dimensionless interaction parameter lambda. In this paper, B2 is determined exactly for all values of lambda in both the three-dimensional case, where spheres may access the whole space and their dipole moments may be oriented in all directions, and in the quasi-two-dimensional case, where spheres have their centres bound to glide on a plane, while their dipole moments are still freely orientable in space. PMID- 24158680 TI - Postsecondary pathways and persistence for STEM versus non-STEM majors: among college students with an autism spectrum disorder. AB - Little is known about postsecondary pathways and persistence among college students with an autism spectrum disorder (ASD). This study analyzed data from the National Longitudinal Transition Study-2, 2001-2009, a nationally representative sample of students in special education with an ASD who progressed from high school to postsecondary education. Findings suggest that most college students with an ASD enrolled in a 2-year community college at some point in the postsecondary careers (81%). Those in science, technology, engineering and mathematics (STEM) fields were more likely to persist in a 2-year community college and were twice as likely to transfer from a 2-year community college to a 4-year university than their peers in the non-STEM fields. College persistence rates varied by gender, race, parent education level, and college pathway and major. Educational policy implications are discussed. PMID- 24158679 TI - Measuring anxiety as a treatment endpoint in youth with autism spectrum disorder. AB - Despite the high rate of anxiety in individuals with autism spectrum disorder (ASD), measuring anxiety in ASD is fraught with uncertainty. This is due, in part, to incomplete consensus on the manifestations of anxiety in this population. Autism Speaks assembled a panel of experts to conduct a systematic review of available measures for anxiety in youth with ASD. To complete the review, the panel held monthly conference calls and two face-to-face meetings over a fourteen-month period. Thirty eight published studies were reviewed and ten assessment measures were examined: four were deemed appropriate for use in clinical trials, although with conditions; three were judged to be potentially appropriate, while three were considered not useful for clinical trials assessing anxiety. Despite recent advances, additional relevant, reliable and valid outcome measures are needed to evaluate treatments for anxiety in ASD. PMID- 24158681 TI - Corneal changes in neurosurgically induced neurotrophic keratitis. AB - IMPORTANCE: Neurotrophic keratitis (NK) represents a sight-threatening complication after trigeminal impairment. To our knowledge, the duration for which trigeminal injury may affect corneal structures and function has not been investigated previously. OBJECTIVE: To describe the long-term clinical, morphological, and functional outcomes of NK after neurosurgical trigeminal damage. DESIGN, SETTING, AND PARTICIPANTS: Observational case series performed at a corneal and ocular surface diseases referral center in 2010. Eight consecutive patients with monolateral NK from 1 to 19 years after neurosurgery and 20 age- and sex-matched healthy participants were included. MAIN OUTCOMES AND MEASURES: Complete eye examination, tear film function tests, corneal staining, and Cochet Bonnet esthesiometry were performed. The number and density of corneal nerves, number of hyperreflective keratocytes, and corneal epithelial, endothelial, and keratocyte cell densities were evaluated by in vivo slit scanning confocal microscopy. Clinical and morphological data were compared with the contralateral unaffected eyes and with the eyes of healthy control participants. RESULTS: All patients showed superficial punctate keratitis and dry eye in the NK eye and a healthy contralateral eye. Decreased corneal sensitivity was observed in all affected eyes (mean [SD], 2.0 [1.9] mm in the affected eyes vs 5.8 [0.3] mm in the contralateral unaffected eyes; P = .01) and was related to decreased subbasal nerve length (P = .04; R = 0.895). Corneal epithelial and endothelial cell densities were significantly decreased and the number of hyperreflective keratocytes was significantly increased in NK eyes compared with contralateral unaffected eyes and with the eyes of healthy participants. A longer duration of NK was associated with lower endothelial cell density (P = .046; R = -0.715). CONCLUSIONS AND RELEVANCE: Corneal morphology and function were impaired even years after neurosurgical trigeminal damage, suggesting that assessment of tear film and corneal sensitivity as well as in vivo confocal microscopy examination should be performed in all patients with trigeminal impairment. PMID- 24158683 TI - Tuberculosis and sudden death. PMID- 24158682 TI - Maximizing postmortem oral-facial data to assist identification following severe incineration. AB - PURPOSE: This paper reviews the literature for methods of maximizing the postmortem oral-facial information available for a comparison to be made for identification following an incident resulting in incineration. METHOD: A search was initially instigated utilizing PubMed, Scopus, and Google Scholar, with further library searches and correspondences among peers around the world leading to a comprehensive review of the literature. CONCLUSION: Maximizing postmortem dental evidence in a severe incineration event requires correct recognition and recording of dental data. Odontologists should attend the scene to facilitate this recognition. The information should be documented, photographed, and stabilized before retrieval. Wrapping, padding, and further support of the remains during transportation to the examination mortuary will aid this process. Examination at the mortuary requires further photography, complete charting, and radiographic examination of any dental material available, as well as awareness of other possible medical evidence, to enable identification of the human remains. PMID- 24158684 TI - The evolution of supportive care needs trajectories in women with advanced breast cancer during the 12 months following diagnosis. AB - PURPOSE: This longitudinal study examined if the evolution of supportive care needs differed over the first year following the diagnosis of advanced breast cancer and examined factors differentiating these trajectories. METHODS: Two hundred twenty-eight of 276 Chinese women with advanced breast cancer were assessed while they were awaiting or receiving initial chemotherapy, then again at 6 weeks, 3 months, 6 months, and 12 months post-baseline. Supportive care needs (SCNS-34-Ch), psychological distress (Hospital Anxiety and Depression scale), symptom distress (MSAS-Ch), and patient satisfaction (PSEQ-9) were assessed at baseline; supportive care needs were reassessed at each follow-up assessment. Latent growth mixture modeling explored if trajectories differed within each of four need domains: health system, information, and patient support (HSIPS); psychological; physical daily living (PDL); and sexuality needs. Logistic regression identified factors predicting trajectory patterns. RESULTS: Two distinct trajectories were identified for HSIPS and sexuality need domains and three distinct trajectories for psychological and physical daily living need domains. Most women showed stable low levels of HSIPS (78.9 %), psychological (82.4 %), PDL (83.7 %), and sexuality (97.4 %) supportive care needs. One in five and one in eight women showed high initial supportive care needs in HSIPS and psychological and PDL domains, respectively. With the exception of sexuality needs, trajectory patterns were predicted by physical symptom distress. Women in the high-decline group reported greater physical symptom distress. CONCLUSIONS: Most Chinese women with advanced breast cancer showed low stable supportive care needs. Physical symptom distress predicted high supportive care needs. Interventions should focus on optimizing symptom assessment and management. PMID- 24158685 TI - Administration of teriparatide treatment for a challenging case of nonunion of periprosthetic fracture after total knee arthroplasty. AB - INTRODUCTION: Management of a periprosthetic fracture after total knee arthroplasty is often challenging because it typically occurs in elderly patients, who often have osteoporotic bone with a high risk of delayed union and nonunion. Thus, administration of a medication that could effectively accelerate fracture healing to prevent a delayed union or nonunion should significantly improve treatment outcome and patient's quality of life. CASE PRESENTATION: We report the case of a 74-year-old rheumatoid arthritis woman with nonunion of a periprosthetic fracture after total knee arthroplasty, in whom bone union could not be achieved even after she underwent internal fixation and bone grafting twice; however, successful bone fusion was achieved after simple once-weekly administration of teriparatide for 6 months. DISCUSSION: Although we report only one patient, the present case may suggest the advantage of preventive administration of teriparatide in addition to surgical procedures for treating nonunion of a periprosthetic fracture after total knee arthroplasty. PMID- 24158686 TI - Association between susceptibility to photodynamic oxidation and the genetic background of Staphylococcus aureus. AB - Multidrug resistant strains of Staphylococcus aureus are a major cause of skin and soft tissue infections requiring the development of novel and alternative therapeutic options. Photodynamic oxidation is the cornerstone of antimicrobial photodynamic therapy (aPDT) involving the combined use of light and a photosensitizer, which, in the presence of oxygen, originates cytotoxic species capable of oxidizing biological molecules and leads to inactivation of target cells. We have previously shown that susceptibility to aPDT differs significantly across S. aureus isolates and could be associated with several genetic elements. However, the effect of the photodynamic process regarding the S. aureus genetic background has never been reported. We have compared the genetic backgrounds of the strains (SCCmec types, spa types and main clonal complexes) with respect to their susceptibility to protoporphyrin IX-mediated photodynamic inactivation. SCCmec typing revealed no differences in response to photoinactivation. However, detection of spa types and clonal complexes clustered the studied population of MRSA strains according to their response to photodynamic oxidation. Clonal complex 1 (CC1) accounted for elevated resistance and CC30 (ST36) for susceptibility to photoinactivation. Moreover, spa typing identified isolates resistant (t032) and susceptible to photodynamic oxidation (t051, t015). The very tight association between clonal lineages and response to photodynamic inactivation indicates the important role of genetic background for aPDT efficacy. These results make a case for the development of a diagnostic tool with the predictive value of aPDT efficacy according to an identified genetic background of S. aureus isolates. PMID- 24158687 TI - Association between polymorphisms in the csrRS two-component regulatory system and invasive group A streptococcal infection. AB - The csrRS two-component regulatory system is an important element in the pathogenesis of group A Streptococcus (GAS). The main goal of this study is to understand the association between csrRS polymorphisms and GAS infection. We sequenced the csrRS genes from 172 clinical isolates, including 81 invasive and 91 noninvasive isolates, and then employed phylogenetic analyses to determine the consequences of the csrRS polymorphisms. In total, 13 and 26 polymorphic loci were detected in the csrR and csrS genes, respectively. These polymorphisms constituted 14 csrR and 25 csrS alleles, producing two CsrR and seven CsrS variants, respectively. Three invasive isolates contained an indel in csrS, but no indel was identified in csrR. The frequency and distribution of polymorphisms in csrR and csrS was significantly different between the invasive and noninvasive infection isolates (p < 0.001). For CsrR, only one noninvasive isolate was identified to have a V29I mutation. The amino acid substitutions in CsrS included S32P (0.6 %), E265G (0.6 %), E265K (0.6 %), I332V (1.7 %), and N498K (82.6 %). Isolates with an N498K single mutation were more likely to be associated with invasive infections (p < 0.001). The dN/dS ratio indicated that both csrR and csrS were under purifying selection. The fixation index suggested a moderate evolutionary differentiation of the csrR and csrS alleles between invasive and noninvasive isolates. The identification of these genetic differences within the csrRS loci will provide a better understanding of the pathogenesis of GAS. PMID- 24158688 TI - Trophic structure of amoeba communities near roots of Medicago sativa after contamination with fuel oil no. 6. AB - Root exudation increases microbial activity, selecting bacterial and fungal communities that metabolize organic matter such as hydrocarbons. However, a strong contamination pulse of hydrocarbons around plant roots may reorganize the soil's microbial trophic structure toward amoebae feeding on bacteria. We conducted a microcosm experiment to elucidate the effect of Medicago sativa on the trophic structure of naked amoebae after a strong pulse of pollution (50,000 ppm of fuel oil no. 6, which is a mixture of long chains ranging from C10 to C28). Plants were seeded 24 h after contamination and species of amoebae in the microcosms were identified at 1, 30, and 60 days after pollution. Several species from three trophic groups of naked amoeba were still alive 24 h after the hydrocarbon pulse. Non-planted microcosms harbored three trophic groups after 60 days, while planted ones nourished four groups. The bacterivore group was the most diverse in all microcosms, followed by protist-eaters and omnivores. The quantity of amoebae was significantly higher (3.4*10(3) organisms/g soil) in the planted pots than in the non-planted ones (1.3*10(3) organisms/g soil after 30 days of pollution (P <= 0.01). The shortest hydrocarbon chains (C10-C14) disappeared or diminished in all microcosms, and the longest ones increased in the planted ones. M. sativa thus exerted a positive effect on species richness, quantity, and the composition of amoebae trophic groups in contaminated soil. This indirect effect on bacterial predators is another key factor underlying hydrocarbon assimilation by living organisms during phytoremediation. PMID- 24158689 TI - Seasonal dynamics of prokaryotic abundance and activities in relation to environmental parameters in a transitional aquatic ecosystem (Cape Peloro, Italy). AB - This study examines the effects of temporal changes on microbial parameters in a brackish aquatic ecosystem. To this aim, the abundances of prokaryotes and vibrios together with the rates of enzymatic hydrolysis of proteins by leucine aminopeptidase (LAP), polysaccharides by beta-glucosidase (GLU) and organic phosphates by alkaline phosphatase (AP), heterotrophic prokaryotic production (HPP), respiration (R), were seasonally investigated, during a 2-year period in the coastal area of Cape Peloro (Messina, Italy), constituted by two brackish lakes (Faro and Ganzirri). In addition, physical and chemical parameters (temperature, salinity, nutrients) and particulate organic carbon and nitrogen (POC, PN) were measured. The influence of multiple factors on prokaryotic abundances and activities was analysed. The results showed that Cape Peloro area is characterised by high seasonal variability of the microbial parameters that is higher than the spatial one. Combined changes in particulate matter and temperature (T), could explain the variability in vibrios abundance, GLU and R activities in both lakes, indicating a direct stimulation of the warm season on the heterotrophic prokaryotic metabolism. Positive correlations between T (from 13.3 to 29.6 degrees C) and HPP, LAP, AP, POC, PN are also observed in Ganzirri Lake. Moreover, the trophic status index and most of the microbial parameters show significant seasonal differences. This study demonstrates that vibrios abundance and microbial activities are responsive to the spatial and seasonal changes of examined area. The combined effects of temperature and trophic conditions on the microbial parameters lead us to suggest their use as potential indicators of the prokaryotic response to climate changes in temperate brackish areas. PMID- 24158690 TI - Defining the niche of Vibrio parahaemolyticus during pre- and post-monsoon seasons in the coastal Arabian Sea. AB - The bacteria Vibrio parahaemolyticus is an important component of coastal ecosystems worldwide, and in recent years, V. parahaemolyticus has caused several cases of food-borne gastroenteritis. However, research investigating which parameters are important in regulating V. parahaemolyticus abundance in tropical areas with relatively stable temperatures and salinity are largely lacking. The objective here was to investigate which environmental forces are driving elevated abundances of V. parahaemolyticus in a tropical oligotrophic coastal area in the Arabian Sea. We analysed a large number of environmental parameters in parallel with cell densities of V. parahaemolyticus and Vibrio spp. Abundance data was obtained using real-time PCR, during two different sampling periods, representative for two distinct seasons. Water temperature and salinity were stable during and between sampling periods, but V. parahaemolyticus abundances were on average six times higher during the first sampling period in December, compared to the second period in February-March. V. parahaemolyticus abundance was found to be positively correlated to inorganic phosphate concentration and copepod abundance. We thus hypothesise that these are important factors regulating V. parahaemolyticus abundance in coastal tropical areas during these periods. PMID- 24158691 TI - Olodaterol: first global approval. AB - Olodaterol (Striverdi((r)) Respimat((r))) is a novel, long-acting, beta2 adrenergic receptor agonist developed by Boehringer Ingelheim for the treatment of chronic obstructive pulmonary disease (COPD). The drug is delivered via the Respimat((r)) Soft MistTM inhaler. Olodaterol received its first global approval for the once-daily maintenance treatment of COPD in Canada and Russia, and submissions for regulatory approval have also been made in the USA, the EU and elsewhere. Phase II trials have been conducted in patients with asthma. The company is also developing a fixed-dose combination of olodaterol with tiotropium bromide, a long-acting anti-muscarinic agent, for the treatment of COPD. This article summarizes the milestones in the development of olodaterol leading to this first approval for COPD. PMID- 24158692 TI - Redox balance and cardioprotection. AB - Coronary artery disease is a major cause of morbidity and mortality in the Western countries. Acute myocardial infarction is a serious and often lethal consequence of coronary artery disease, resulting in contractile dysfunction and cell death. It is well known that unbalanced and high steady state levels of reactive oxygen and nitrogen species (ROS/RNS) are responsible for cytotoxicity, which in heart leads to contractile dysfunction and cell death. Pre- and post conditioning of the myocardium are two treatment strategies that reduce contractile dysfunction and the amount of cell death considerably. Paradoxically, ROS and RNS have been identified as a part of cardioprotective signaling molecules, which are essential in pre- and post-conditioning processes. S nitrosylation of proteins is a specific posttranslational modification that plays an important role in cardioprotection, especially within mitochondria. In fact, mitochondria are of paramount importance in either promoting or limiting ROS/RNS generation and reperfusion injury, and in triggering kinase activation by ROS/RNS signaling in cardioprotection. These organelles are also the targets of acidosis, which prevents mitochondrial transition pore opening, thus avoiding ROS-induced ROS release. Therefore, we will consider mitochondria as either targets of damage or protection from it. The origin of ROS/RNS and the cardioprotective signaling pathways involved in ROS/RNS-based pre- and post-conditioning will be explored in this article. A particular emphasis will be given to new aspects concerning the processes of S-nitrosylation in the cardioprotective scenario. PMID- 24158693 TI - Cardiac aquaporins. AB - Aquaporins are a group of proteins with high-selective permeability for water. A subgroup called aquaglyceroporins is also permeable to glycerol, urea and a few other solutes. Aquaporin function has mainly been studied in the brain, kidney, glands and skeletal muscle, while the information about aquaporins in the heart is still scarce. The current review explores the recent advances in this field, bringing aquaporins into focus in the context of myocardial ischemia, reperfusion, and blood osmolarity disturbances. Since the amount of data on aquaporins in the heart is still limited, examples and comparisons from better studied areas of aquaporin biology have been used. The human heart expresses aquaporin-1, -3, -4 and -7 at the protein level. The potential roles of aquaporins in the heart are discussed, and some general phenomena that the myocardial aquaporins share with aquaporins in other organs are elaborated. Cardiac aquaporin-1 is mostly distributed in the microvasculature. Its main role is transcellular water flux across the endothelial membranes. Aquaporin-4 is expressed in myocytes, both in cardiac and in skeletal muscle. In addition to water flux, its function is connected to the calcium signaling machinery. It may play a role in ischemia-reperfusion injury. Aquaglyceroporins, especially aquaporin-7, may serve as a novel pathway for nutrient delivery into the heart. They also mediate toxicity of various poisons. Aquaporins cannot influence permeability by gating, therefore, their function is regulated by changes of expression-on the levels of transcription, translation (by microRNAs), post translational modification, membrane trafficking, ubiquitination and subsequent degradation. Studies using mice genetically deficient for aquaporins have shown rather modest changes in the heart. However, they might still prove to be attractive targets for therapy directed to reduce myocardial edema and injury caused by ischemia and reperfusion. PMID- 24158694 TI - Synthesis of rac-Lindenene via a thermally induced cyclopropanation reaction. AB - The first synthesis of the sesquiterpene Lindenene is described. A novel non catalysed intramolecular cyclopropanation reaction between a diazoketone and an unactivated alkene was utilised to construct the relatively labile ketone precursor with complete stereocontrol. This ketone was transformed in three steps into Lindenene. PMID- 24158695 TI - All-trans-retinoic acid rescues neurons after global ischemia by attenuating neuroinflammatory reactions. AB - Retinoic acid (RA) plays an important role in the developing mammalian nervous system. Based on this concept, some studies have demonstrated the beneficial effects of RA administration on neurogenesis in neuropathological diseases. Some investigations have revealed the anti-inflammatory effects of RA treatment in multiple systems, in addition to its role in neurogenesis. To date, however, the neuroprotective efficacy of RA after cerebral ischemia, especially in the context of its anti-inflammatory effects, has been poorly demonstrated. Additionally, to the best of our knowledge, experiments of the therapeutic efficacy of RA treatment in a transient global ischemic model in the Mongolian gerbil have been lacking worldwide. Here, we studied the neuroprotective effects and neurobehavioral outcomes of intraperitoneally administered all-trans-RA (ATRA; a synthetic form of RA) on brains with transient global ischemia that was induced with the bilateral common carotid artery occlusion and reperfusion (BCCAO/R) model in the gerbil. In order to identify whether these neuroprotective mechanisms were due to the anti-inflammatory effects of ATRA, in vivo hippocampal expression of proinflammatory cytokines including tissue necrosis factor-alpha (TNF-alpha), and interleukin-6 (IL-6) after ATRA injection and in vitro levels of release of nitric oxide, TNF-alpha and IL-6 from lipopolysaccharide (LPS) stimulated BV2 microglial cells after ATRA treatment were evaluated. The results showed that ATRA can protect pyramidal neurons in the hippocampal CA1 region against BCCAO-induced neuronal apoptosis and significantly reduce the extent of astrocytosis and microglial activation. In addition, the ischemia-induced neurobehavioral changes were normalized by ATRA injection. Consistent with these phenotypic data, we observed the diminishing effects of ATRA treatment on the production of proinflammatory mediators (e.g., TNF-alpha and IL-6) in hippocampal homogenates and LPS-stimulated BV2 cells, and these effects were dose-dependent. These results suggest a beneficial role of ATRA in the attenuation of global cerebral ischemia due to its anti-inflammatory properties, resulting in, at least partly, the inhibition of microglial secretion of variable proinflammatory cytokines. PMID- 24158696 TI - 24-hour intraocular pressure rhythm in young healthy subjects evaluated with continuous monitoring using a contact lens sensor. AB - IMPORTANCE: This study evaluates a new device that has been proposed to continuously monitor intraocular pressure (IOP) over 24 hours. OBJECTIVE: To evaluate 24-hour IOP rhythm reproducibility during repeated continuous 24-hour IOP monitoring with noncontact tonometry (NCT) and a contact lens sensor (CLS) in healthy participants. DESIGN, SETTING, AND PARTICIPANTS: Cross-sectional study of 12 young healthy volunteers at a referral center of chronobiology. INTERVENTIONS: Participants were housed in a sleep laboratory and underwent four 24-hour sessions of IOP measurements over a 6-month period. After initial randomized attribution, the IOP of the first eye was continuously monitored using a CLS and the IOP of the fellow eye was measured hourly using NCT. Two sessions with NCT measurements in 1 eye and CLS measurements in the fellow eye, 1 session with CLS measurements in only 1 eye, and 1 session with NCT measurements in both eyes were performed. MAIN OUTCOMES AND MEASURES: A nonlinear least squares, dual-harmonic regression analysis was used to model the 24-hour IOP rhythm. Comparison of acrophase, bathyphase, amplitude, midline estimating statistic of rhythm, IOP values, IOP changes, and agreement were evaluated in the 3 tonometry methods. RESULTS: A significant nyctohemeral IOP rhythm was found in 31 of 36 sessions (86%) using NCT and in all sessions (100%) using CLS. Hourly awakening during NCT IOP measurements did not significantly change the mean phases of the 24-hour IOP pattern evaluated using CLS in the contralateral eye. Throughout the sessions, intraclass correlation coefficients of the CLS acrophase (0.6 [95% CI, 0.0 to 0.9]; P = .03), CLS bathyphase (0.7 [95% CI, 0.1 to 0.9]; P = .01), NCT amplitude (0.7 [95% CI, 0.1 to 0.9]; P = .01), and NCT midline estimating statistic of rhythm (0.9 [95% CI, 0.9 to 1.0]; P < .01) were significant. When performing NCT measurements in 1 eye and CLS measurements in the contralateral eye, the IOP change at each point normalized from the first measurement (9 am) was not symmetric individually or within the population. CONCLUSIONS AND RELEVANCE: The CLS is an accurate and reproducible method to characterize the nyctohemeral IOP rhythm in healthy participants but does not allow for estimating the IOP value in millimeters of mercury corresponding to the relative variation of the electrical signal measured. PMID- 24158697 TI - Root endophyte symbiosis in vitro between the ectomycorrhizal basidiomycete Tricholoma matsutake and the arbuscular mycorrhizal plant Prunus speciosa. AB - We previously reported that Tricholoma matsutake and Tricholoma fulvocastaneum, ectomycorrhizal basidiomycetes that associate with Pinaceae and Fagaceae, respectively, in the Northern Hemisphere, could interact in vitro as a root endophyte of somatic plants of Cedrela odorata (Meliaceae), which naturally harbors arbuscular mycorrhizal fungi in South America, to form a characteristic rhizospheric colony or "shiro". We questioned whether this phenomenon could have occurred because of plant-microbe interactions between geographically separated species that never encounter one another in nature. In the present study, we document that these fungi formed root endophyte interactions and shiro within 140 days of inoculation with somatic plants of Prunus speciosa (=Cerasus speciosa, Rosaceae), a wild cherry tree that naturally harbors arbuscular mycorrhizal fungi in Japan. Compared with C. odorata, infected P. speciosa plants had less mycelial sheath surrounding the exodermis, and the older the roots, especially main roots, the more hyphae penetrated. In addition, a large number of juvenile roots were not associated with hyphae. We concluded that such root endophyte interactions were not events isolated to the interactions between exotic plants and microbes but could occur generally in vitro. Our pure culture system with a somatic plant allowed these fungi to express symbiosis-related phenotypes that varied with the plant host; these traits are innately programmed but suppressed in nature and could be useful in genetic analyses of plant-fungal symbiosis. PMID- 24158699 TI - Pituitary metastasis of colon adenocarcinoma: a rare occurrence. PMID- 24158698 TI - EGCG inhibit chemical reactivity of iron through forming an Ngal-EGCG-iron complex. AB - Accumulated evidence indicates that the interconversion of iron between ferric (Fe(3+)) and ferrous (Fe(2+)) can be realized through interaction with reactive oxygen species in the Fenton and Haber-Weiss reactions and thereby physiologically effects redox cycling. The imbalance of iron and ROS may eventually cause tissue damage such as renal proximal tubule injury and necrosis. Many approaches were exploited to ameliorate the oxidative stress caused by the imbalance. (-)-Epigallocatechin-3-gallate, the most active and most abundant catechin in tea, was found to be involved in the protection of a spectrum of renal injuries caused by oxidative stress. Most of studies suggested that EGCG works as an antioxidant. In this paper, Multivariate analysis of the LC-MS data of tea extracts and binding assays showed that the tea polyphenol EGCG can form stable complex with iron through the protein Ngal, a biomarker of acute kidney injury. UV-Vis and Luminescence spectrum methods showed that Ngal can inhibit the chemical reactivity of iron and EGCG through forming an Ngal-EGCG-iron complex. In thinking of the interaction of iron and ROS, we proposed that EGCG may work as both antioxidant and Ngal binding siderphore in protection of kidney from injuries. PMID- 24158700 TI - [Radiotherapy of bone metastases]. AB - Sixty percent of cancer patients have or develop bone metastases during the development of their cancer. Bone metastases are the most common cause of cancer related pain. External radiation therapy is the standard treatment of uncomplicated bone metastases, for the treatment of pain, the prevention of fracture, and for tumor control. Fractionation schedules (one session of 8 Gy or several sessions, typically 30 Gy in 10 fractions) vary in terms of efficacy with however more retreatments after a single session. The treatment of spinal cord compression is classically based on radiotherapy associated or not with surgery with indications assessed in emergency by a multidisciplinary team. The use of prognostic scores and prospective studies including patients corresponding to the daily practice and the work of groups like the GEMO aim to harmonize and optimize the management of bone metastases. PMID- 24158701 TI - The Janus kinases inhibitor AZD1480 attenuates growth of small cell lung cancers in vitro and in vivo. AB - PURPOSE: The prognosis of small cell lung cancer (SCLC) is poor, and there has been very little progress in the medical treatment of SCLC in the past two decades. We investigated the potential of Janus-activated kinases (JAK) inhibitor, AZD1480, for treatment of SCLC in vitro and in vivo. EXPERIMENTAL DESIGN: JAK1 and JAK2 were inhibited by AZD1480 or siRNAs, and the effect of inhibition of JAK gene family on SCLC cell viability was evaluated. The effect of AZD1480 on cell-cycle distribution and apoptosis induction was studied. Antitumor effects of AZD1480 in tumor xenografts were assessed. RESULTS: AZD1480 significantly inhibited growth of six out of 13 SCLC cells with IC50s ranging from 0.73 to 3.08 MUmol/L. Knocking down of JAK2 and JAK1 inhibited proliferation of Jak2-positive/Jak1-negative H82 cells and Jak1-positive/Jak2-negative GLC4 cells, respectively. Treatment of SCLC cells with AZD1480 for 24 hours resulted in an increase of 4N DNA content and histone 3 serine 10 phosphorylation, indicative of G2-M phase arrest. Moreover, SCLCs underwent apoptosis after AZD1480 treatment as exemplified by the downregulation of MCL1, the accumulation of cleaved caspase 3, cleaved PARP, and increase of annexin-V-positive cells. Finally, xenograft experiments showed that AZD1480 attenuated the growth of H82 and GLC4 tumors in mice, and we observed stronger apoptosis as well as decreased CD31-positive endothelial cells in H82 and GLC4 xenografts upon AZD1480 treatment. CONCLUSIONS: JAK inhibitor AZD1480 attenuated growth of SCLC cells in vitro and in vivo. Clinical development of anti-JAKs therapies in SCLC warrants further investigation. PMID- 24158703 TI - Public health and the common good. PMID- 24158705 TI - Charge order and possible bias-induced metastable state in the organic conductor beta-(meso-DMBEDT-TTF)2PF6: effects of structural distortion. AB - We theoretically investigate charge order and nonlinear conduction in the quasi two-dimensional organic conductor beta-(meso-DMBEDT-TTF)2PF6 (DMBEDT TTF=dimethylbis(ethylenedithio)tetrathiafulvalene). Within the Hartree-Fock approximation, we study the effects of structural distortion on the experimentally observed checkerboard charge order and its bias-induced melting by using an extended Hubbard model with Peierls- and Holstein-types of electron lattice interactions. The structural distortion is important in realizing the charge order. The current-voltage characteristics obtained by a nonequilibrium Green's function method indicate that a charge-ordered insulating state changes into a conductive state. Although the charge order and lattice distortions are largely suppressed at a threshold voltage, they remain finite even in the conductive state. We discuss the relevance of the results to experimental observations, especially to a possible bias-induced metastable state. PMID- 24158702 TI - Molecular pathways: sterols and receptor signaling in cancer. AB - Accelerated cholesterol and lipid metabolism are the hallmarks of cancer and contribute to malignant transformation due to the obligatory requirement for cholesterol for the function of eukaryotic membranes. To build new membranes and maintain active signaling, cancer cells depend on high intensity of endogenous cholesterol biosynthesis and uptake of lipid particles. This metabolic dependency of cancer cells on cholesterol and other lipids is tightly regulated by the cholesterol homeostasis network, including (i) sterol response element-binding proteins (SREBP), master transcriptional regulators of cholesterol and fatty acid pathway genes; (ii) nuclear sterol receptors (liver X receptors, LXR), which coordinate growth with the availability of cholesterol; and (iii) lipid particle receptors, such as low-density lipid particle (LDL) receptor, providing exogenous sterol and lipids to cancer cells. In addition, activity of oncogenic receptors, such as MUC1 or EGFR, accelerates sterol uptake and biosynthesis. Therefore, a general strategy of reducing the cholesterol pool in cancer cells is challenged by the highly efficient feedback loops compensating for a blockade at a single point in the cholesterol homeostatic network. Besides the well-established structural role of cholesterol in membranes, recent studies have uncovered potent biologic activities of certain cholesterol metabolic precursors and its oxidized derivatives, oxysterols. The former, meiosis-activating sterols, exert effects on trafficking and signaling of oncogenic EGF receptor (EGFR). Cholesterol epoxides, the highly active products of cholesterol oxidation, are being neutralized by the distal sterol pathway enzymes, emopamyl-binding protein (EBP) and dehydrocholesterol-7 reductase (DHCR7). These recently discovered "moonlighting" activities of the cholesterol pathway genes and metabolites expand our understanding of the uniquely conserved roles these sterol molecules play in the regulation of cellular proliferation and in cancer. PMID- 24158706 TI - How can we engage more fully with clinicians in less economically developed countries? PMID- 24158704 TI - Smoking cessation in the first trimester reduces most obstetric risks, but not the risks of major congenital anomalies and admission to neonatal care: a population-based cohort study of 1,164,953 singleton pregnancies in Finland. AB - BACKGROUND: In industrialised countries, approximately 5-20% of women smoke during pregnancy. We aim to study the association between smoking during pregnancy and adverse perinatal outcomes. METHODS: A retrospective population based cohort study using data on all singleton births between 1991 and 2010 (n=1,164,953) derived from the Finnish Medical Birth Register. RESULTS: Of all the mothers included, 82.3% were non-smokers, 2.6% quit smoking during the first trimester of pregnancy, 12.5% smoked throughout pregnancy and 2.7% had no information on smoking. Continuing smoking after the first trimester of the pregnancy was associated with an increased prevalence of admission to a neonatal intensive care unit, stillbirth, preterm birth (<37 gestational weeks), low birth weight (LBW, <2500 g), small for gestational age (SGA, < -2 SDs) and major congenital anomaly compared with non-smokers. Smoking cessation reduced the risk of prematurity, stillbirth, LBW and SGA close to or at similar levels as those of non-smokers. Tobacco exposure in early pregnancy resulted in a 19% increased prevalence of admission to neonatal intensive care unit and a 22% increased prevalence of major congenital anomaly compared with non-smokers. CONCLUSIONS: Smoking cessation appeared to reduce pregnancy risks close to those of non smoking peers. Exposure to early pregnancy smoking was, however, associated with an increased admission to neonatal intensive care and an increased prevalence of major congenital anomalies. PMID- 24158707 TI - Commentary on Sapienza et al. Flexor tendon excursion and load during passive and active simulated motion: a cadaver study. PMID- 24158708 TI - Commentary on Al-Qattan et al. The diaphysial axis-metacarpal head angle in the management of fractures of the base of the proximal phalanx in children. PMID- 24158709 TI - Re: del Pinal F. Editorial: I have a dream ... reflex sympathetic dystrophy (RSD or Complex Regional Pain Syndrome--CRPS 1) does not exist. J Hand Surg Eur. 2013, 38: 595-7. PMID- 24158710 TI - FESSH and European Accreditation in Hand Surgery. PMID- 24158711 TI - [Cells of the tumor front : a potential therapeutic target in head and neck cancer therapy?]. AB - BACKGROUND: With a frequency of about 90 %, head and neck squamous cell carcinomas (HNSCCs) are the most common malignancies of the upper aerodigestive tract. The cancer stem cell (CSC) hypothesis postulates that CSCs are the dangerous part of the tumor and are relevant to metastasis, invasiveness and resistance to chemotherapy. METHODS: Tissue samples taken from HNSCCs and normal mucosa were tested for the expression of several established CSC markers. The expression and activity of the matrix metalloproteinase MMP-9 was also investigated. RESULTS: Cells of the invasive tumor front expressed the basal stem cell markers CD44, ALDH1 and CK14. However, in contrast to the noninvasive basal cell layer of normal mucosa, HNSCC samples were also positive for active MMP-9, which lends the tumor its gelatinolytic activity. CONCLUSION: These observations suggest a model in which cells of the invasive front are derived from the basal cell layer of normal mucosa and harbour the CSCs. Future studies should thus focus on the cells of the invasive front in particular, since the activity of these cells may form the basis for tumor recurrence and therapy resistance. PMID- 24158712 TI - [Surgical therapy of secondary elephantoid lymphedema of the eyelids]. AB - Because of the disfiguring changes they cause, prominent secondary lymphedemas of the face represent an extreme burden for afflicted patients. Many of these patients already have considerable restrictions imposed upon their quality of life as a consequence of the primary cancer therapy. Therapeutic options are often limited, mainly comprising physical therapy and pharmacological interventions. Only in exceptional cases is surgical therapy a treatment facility. We report the successful surgical treatment of a patient with secondary elephantoid lymphedema following primary radiochemotherapy for squamous cell cancer of the base of the tongue. PMID- 24158713 TI - [Speech and general development in children receiving early cochlear implants]. AB - BACKGROUND: After cochlear implantation, most parents expect a normal speech and general development of their child. However, it remains unclear how quickly after early cochlear implantation these children can compensate for their deficits compared to normal-hearing children. METHODS: This study retrospectively analyzed ELFRA-1 questionnaire data from 40 children with borderline deafness or high grade hearing loss (without other known impairments) who had undergone cochlear implantation at a university medical center before reaching 2 years of age. ELFRA 1 questionnaires were filled out parents assisted by specialists 12 months after implantation. Questions assessed the children's speech production and comprehension, as well as their use of gestures and fine motoric skills. RESULTS: At an average hearing-age of 12 months, the children achieved normal values in all of the subgroups that were comparable to those of 12-month-old children without hearing impairments. A significant correlation (p = 0.01) between the individual subgroups of the ELFRA-1 (speech production, speech comprehension, gestures and fine motor skills) was observed. Unilingual educated children performed significantly better overall. CONCLUSION: Within 12 months of receiving a cochlear implant, all children passed the four categories of the ELFRA-1. This demonstrates a rapid compensation of deficits in speech, motor skills and gesture development by children undergoing early cochlear implantation. PMID- 24158714 TI - [Newly arising defect of the hard and soft palate in an adult patient]. PMID- 24158715 TI - [Headaches, meningeal thickening and exudate in the mastoid process]. PMID- 24158716 TI - Deferasirox treatment improved hematopoiesis and led to complete remission in a patient with pure red cell aplasia. AB - A 64-year-old woman developed pure red cell aplasia (PRCA) 4 years after thymectomy for thymoma. During anti-thymocyte globulin treatment, the patient developed cytomegalovirus pneumonia and was thus unable to continue immunosuppressive therapy and became transfusion dependent. Deferasirox was started for treatment with iron overload when serum ferritin increased to >1000 ng/mL. Seven months after initiation of deferasirox treatment, serum ferritin level decreased the normal range and the patient has remained transfusion independent thereafter. Deferasirox was discontinued when serum ferritin level decreased below 500 ng/mL, and she has maintained in complete remission over the last 15 months. Hypotheses have been raised regarding the improvement of hematopoiesis by deferasirox treatment, but the mechanism whereby this might be achieved remains unclear. Deferasirox treatment may be clinically beneficial both by reducing iron overload and by improving hematopoiesis in patients with PRCA. PMID- 24158717 TI - Lateral organization of biological membranes: role of long-range interactions. AB - The lateral organization of biological membranes is of great importance in many biological processes, both for the formation of specific structures such as super complexes and for function as observed in signal transduction systems. Over the last years, AFM studies, particularly of bacterial photosynthetic membranes, have revealed that certain proteins are able to segregate into functional domains with a specific organization. Furthermore, the extended non-random nature of the organization has been suggested to be important for the energy and redox transport properties of these specialized membranes. In the work reported here, using a coarse-grained Monte Carlo approach, we have investigated the nature of interaction potentials able to drive the formation and segregation of specialized membrane domains from the rest of the membrane and furthermore how the internal organization of the segregated domains can be modulated by the interaction potentials. These simulations show that long-range interactions are necessary to allow formation of membrane domains of realistic structure. We suggest that such possibly non-specific interactions may be of great importance in the lateral organization of biological membranes in general and in photosynthetic systems in particular. Finally, we consider the possible molecular origins of such interactions and suggest a fundamental role for lipid-mediated interactions in driving the formation of specialized photosynthetic membrane domains. We call these lipid-mediated interactions a 'lipophobic effect.' PMID- 24158718 TI - Disorder-specific volumetric brain difference in adolescent major depressive disorder and bipolar depression. AB - Structural abnormalities in frontal, limbic and subcortical regions have been noted in adults with both major depressive disorder (MDD) and bipolar disorder (BD). In the current study, we examined regional brain morphology in youth with MDD and BD as compared to controls. Regional brain volumes were measured in 32 MDD subjects (15.7 +/- 2.1 years), 14 BD subjects (16.0 +/- 2.4 years) and 22 healthy controls (16.0 +/- 2.8 years) using magnetic resonance imaging (MRI). Regions of interest included the hippocampus, dorsolateral prefrontal cortex (DLPFC), anterior cingulate cortex (ACC), caudate, putamen and thalamus. Volumetric differences between groups were significant (F26,80 = 1.80, p = 0.02). Post-hoc analyses indicated that individuals with MDD showed reduced left hippocampus volumes (p = 0.048) as well as right ACC white and gray matter volumes (p = 0.003; p = 0.01) compared to controls. BD participants also displayed reduced left hippocampal and right/left putamen volumes compared to controls (p < 0.001; p = 0.015; p = 0.046 respectively). Interestingly, right and left ACC white matter volumes were smaller in MDD than in BD participants (p = 0.019; p = 0.045 respectively). No volumetric group differences were observed for the DLPFC and thalamus. Discriminant analysis was able to correctly classify 81.0 % of subjects as having BD or as MDD based on imaging data. Confirmation and extension of our findings requires larger sample sizes. Our findings provide new evidence of distinct, specific regional brain volumetric differences between MDD and BD that may be used to distinguish the two disorders. PMID- 24158719 TI - Clinical comparison between double-row and transosseous-equivalent repairs for medium to large size rotator cuff tears. AB - BACKGROUND: The transosseous-equivalent (TOE) repair of the rotator cuff tears was invented to make up for several shortcomings of the double-row (DR) repair. However, no studies have compared the clinical aspects of the DR repair and the TOE technique, supporting the superior results of the TOE technique over the DR repair, including the benefit of minimizing surgical steps. We asked whether differences existed between the two repairs regarding clinical outcomes, time and costs. MATERIALS AND METHODS: Subjects included 55 using the DR repair and 119 using the TOE repair for the medium to large sized rotator cuff tears. Clinical outcomes were measured with a Visual Analog Scale, American Shoulder and Elbow Surgeons score, Constant score, and shoulder strength. For practical aspects, operative time and number of suture anchors used for the medial and lateral rows were compared. RESULTS: Both repairs brought substantial improvements in pain and function. However, significant differences were not detected between the repairs in all the clinical measurements. Regarding operative time and costs, in the medium size tears, a statistical difference was found only in the anchors used for the lateral row. In the large size tears, the DR repair required more operation time than the TOE repair, while the TOE repair used more anchors for the lateral row. CONCLUSION: This study failed to demonstrate clinical differences between the techniques. However, when stratifying rotator cuff tears according to the tear sizes, significant differences were found in operative time and cost: the DR repair had the advantage of cost effectiveness by saving anchors for the lateral row, while the TOE repair required less operative time with more anchors used for the lateral row in the large size tears. This finding provides evidence to support the use of the TOE repair to reduce surgical steps. PMID- 24158720 TI - Inhibition studies on Mycobacterium tuberculosis N-acetylglucosamine-1-phosphate uridyltransferase (GlmU). AB - Peptidoglycan is an essential component of the cell wall of bacteria, including Mycobacterium tuberculosis, that provides structural strength and rigidity to enable internal osmotic pressure to be withstood. The first committed step in the biosynthesis of peptidoglycan involves the formation of uridine diphosphate-N acetylglucosamine (UDP-GlcNAc) from uridine triphosphate (UTP) and GlcNAc-1 phosphate. This reaction is catalysed by N-acetylglucosamine-1-phosphate uridyltransferase (GlmU), a bifunctional enzyme with two independent active sites that possess acetyltransferase and uridyltransferase activities. Herein, we report the first inhibition study targeted against the uridyltransferase activity of M. tuberculosis GlmU. A number of potential inhibitors were initially prepared leading to the discovery of active aminoquinazoline-based compounds. The most potent inhibitor in this series exhibited an IC50 of 74 MUM against GlmU uridyltransferase activity and serves as a promising starting point for the discovery of more potent inhibitors. PMID- 24158721 TI - Comment on: "Clomiphene Citrate co-treatment with low dose urinary FSH versus urinary FSH for clomiphene resistant PCOS: randomized controlled trial." by Ghanem et al. PMID- 24158722 TI - Effect of low-level laser therapy on allergic asthma in rats. AB - Asthma is a complex chronic inflammatory disease of the airways that involves the activation of many inflammatory and other types of cells. We investigated the effect of low-level laser therapy (LLLT) on allergic asthma in rats and compared its effect with that of the glucocorticoid budesonide. Asthma was induced by challenge and repeated exposure to ovalbumin. Asthmatic rats were then treated with LLLT or budesonide suspension. LLLT at 8 J/cm(2) once daily for 21 days could relieve pathological damage and airway inflammation in asthmatic rats. LLLT could decrease the total numbers of cells and eosinophils in bronchoalveolar lavage fluid. LLLT could reduce levels of IL-4 and increase IFN-gamma levels in bronchoalveolar lavage fluid and serum, meanwhile reduce serum IgE levels. Flow cytometry assay showed that LLLT can regulate the Th1/Th2 imbalance of asthmatic rats. LLLT had a similar effect to that of budesonide. These findings suggest that the mechanism of LLLT treatment of asthma is by adjustment of Th1/Th2 imbalance. Thus, LLLT could take over some of the effects of budesonide for the treatment of asthma, thereby reducing some of the side effects of budesonide. PMID- 24158724 TI - Changing the brain, changing the society: clinical and ethical implications of neuromodulation techniques in neurology and psychiatry. AB - New neurotechnologies for modulating brain functions are becoming increasingly powerful and applicable to diverse diseases, but raise new questions for clinicians, ethicists, policy makers, and laymen. This issue of Brain Topography gathers several papers exploring the clinical and ethical implications of several invasive and noninvasive neuromodulation approaches. The opportunities and challenges associated with the emergence of neuro-engineering solutions to brain research and brain repair require a close dialogue between multiple disciplines, as well as open discussion with the general public. PMID- 24158726 TI - [Surgical treatment of vertebral metastases]. AB - The multiplicity of clinical presentations and the lack of consensus explain that the treatment of spine metastasis remains controversial. Optimal treatment requires a truly multidisciplinary approach, involving oncologists, interventional radiologists, radiation oncologists, rheumatologists and spine surgeons. Recent progress in all these areas have allowed to provide safe and effective therapeutic solutions tailored to each situation. We remind, in this work, the main progress in the surgical field, specifying the role of surgery in the current therapeutic arsenal. PMID- 24158727 TI - Recent advances in lipid-based formulation technology. PMID- 24158725 TI - The five myths of MMN: redefining how to use MMN in basic and clinical research. AB - The goal of this review article is to redefine what the mismatch negativity (MMN) component of event-related potentials reflects in auditory scene analysis, and to provide an overview of how the MMN serves as a valuable tool in Cognitive Neuroscience research. In doing so, some of the old beliefs (five common 'myths') about MMN will be dispelled, such as the notion that MMN is a simple feature discriminator and that attention itself modulates MMN elicitation. A revised description of what MMN truly reflects will be provided, which includes a principal focus onto the highly context-dependent nature of MMN elicitation and new terminology to discuss MMN and attention. This revised framework will help clarify what has been a long line of seemingly contradictory results from studies in which behavioral ability to hear differences between sounds and passive elicitation of MMN have been inconsistent. Understanding what MMN is will also benefit clinical research efforts by providing a new picture of how to design appropriate paradigms suited to various clinical populations. PMID- 24158728 TI - Binary blend of glyceryl monooleate and glyceryl monostearate for magnetically induced thermo-responsive local drug delivery system. AB - PURPOSE: To develop a novel monoglycerides-based thermal-sensitive drug delivery system, specifically for local intracavitary chemotherapy. METHODS: Lipid matrices containing mixtures of glyceryl monooleate (GMO) and glyceryl monostearate (GMS) were evaluated for their potential application as magnetically induced thermo-responsive local drug delivery systems using a poorly water soluble model drug, nifedipine (NF). Oleic acid-modified iron oxide (OA-Fe3O4) nanoparticles were embedded into the GMO-GMS matrix for remote activation of the drug release using an alternating magnetic field (AMF). RESULTS: The crystallization behavior of binary blends of GMO and GMS as characterized by DSC did show temperature dependent phase transition. GMO-GMS (75:25 wt%) blend showed a melting (T m ) and crystallization (T c ) points at 42 degrees C and 37 degrees C, respectively indicating the potential of the matrix to act as an 'on-demand' drug release. The matrix released only 35% of the loaded drug slowly in 10 days at 37 degrees C whereas 96% release was obtained at 42 degrees C. A concentration of 0.5% OA-Fe3O4 heated the matrix to 42.3 and 45.5 degrees C within 5 min and 10 min of AMF exposure, respectively. CONCLUSIONS: The in vitro NF release profiles form the monoglycerides matrix containing 0.5% OA-Fe3O4 nanoparticles after AMF activation confirmed the thermo-responsive nature of the matrix that could provide pulsatile drug release 'on-demand'. PMID- 24158729 TI - Branch retinal vein occlusion: natural history of visual outcome. AB - IMPORTANCE: Understanding the natural history of visual outcome in branch retinal vein occlusion (BRVO) is fundamental to its management. OBJECTIVE: To investigate the natural history of visual outcome in major and macular BRVO. DESIGN, SETTING, AND PARTICIPANTS: Observational cohort study at a university-based referral practice from 1973 until 1999. The study comprised 216 consecutive eyes with BRVO (144 eyes with major and 72 eyes with macular BRVO) seen within 3 months of onset. INTERVENTION: At first visit, all patients had a detailed ophthalmic and medical history and comprehensive ophthalmic evaluation. Ophthalmic evaluation at initial and follow-up visits included recording best-corrected visual acuity (VA) using the Snellen VA chart and visual fields with a Goldmann perimeter. MAIN OUTCOMES AND MEASURES: Best-corrected VA and visual field outcome on follow-up. RESULTS: The median time to macular edema resolution was 21 months in those with major BRVO and 18 months in those with macular BRVO. Overall, for eyes with initial VA of 20/60 or better, VA improved or remained stable in 75% (95% CI, 63% 86%) for major BRVO and 86% (95% CI, 73%-95%) for macular BRVO. In those with initial VA of 20/70 or worse, VA improved in 69% (95% CI, 56%-80%) for major BRVO and in 53% (95% CI, 27%-79%) for macular BRVO, with median final VA of 20/60 for both BRVO types. CONCLUSIONS AND RELEVANCE: Major and macular BRVOs are 2 distinct clinical entities, and initial visual status and final visual outcome in the 2 types are quite different. Overall, on resolution of macular edema, our study suggests that in both major and macular BRVO, VA and visual fields improved to a variable degree in the majority of eyes without any treatment. PMID- 24158730 TI - Hsa-miR-132 regulates apoptosis in non-small cell lung cancer independent of acetylcholinesterase. AB - MiR-132 is enriched in the central nerve system and is thought to be involved in neuronal development, maturation and function, and to be associated with several neurological disorders including Alzheimer's disease. In addition to its documented neuronal functions, an emerging role for miR-132 in tumorigenesis has been suggested. Recently, hsa-miR-132 was shown to be modulated in different tumor types. However, its role in non-small cell lung cancer (NSCLC) remains unclear. Here, we show that hsa-miR-132 can initiate apoptosis in NSCLC cells to dramatically attenuate tumor formation in nude mice independent of its effect on the proliferation/apoptosis-associated gene, acetylcholinesterase (AChE). Interestingly, hsa-miR-132 has no pro-apoptotic effect in normal pulmonary trachea epithelium. Taken together, these results suggest that hsa-miR-132 represses NSCLC growth by inducing apoptosis independent of AChE. PMID- 24158731 TI - Identification and characterization of human MIBP1 gene in glioma cell differentiation. AB - Malignant gliomas are the most common and lethal intracranial tumors; differentiation therapy is a promising candidate for their treatment. In order to reveal the mechanisms related to glioma differentiation, after confirming that differentiation was induced by sodium phenylbutyrate in SHG-44 human glioma cells, RNA arbitrary primer differential display was used to screen differentially expressed genes. One gene was found to be upregulated by differential display, and this was also confirmed by reverse northern blot and quantitative real-time PCR analysis. After it was cloned and sequenced, the 505 bp fragment was identified as the MIBP1 (c-myc intron-binding protein 1) gene, also named Hivep2/MBP-2/Schnurri-2. Quantitative real-time PCR analysis of 30 human tissue samples revealed that the expression of MIBP1 tended to decrease with increasing WHO grade and was significantly depressed in the high malignancy gliomas group (WHO grade IV). We cloned and sequenced the MIBP1 gene, which was accepted by GenBank as number DQ231041. Finally, transfection of MIBP1 in a reverse transcription vector into glioma cells inhibited cell growth, induced differentiation, and blocked the cell cycle. Here, we identify and describe the structure and function of a differentiation-related gene, human MIBP1, in human glioma. PMID- 24158733 TI - Extraordinary magnetoresistance in graphite: experimental evidence for the time reversal symmetry breaking. AB - We report a highly anisotropic in-plane magnetoresistance (MR) in graphite that possesses in-plane parallel line-like structural defects. In a current direction perpendicular to the line defects (LD), MR is negative and linear in low fields with a crossover to a positive MR at higher fields, while in a current direction parallel to LD, we observed a giant super-linear positive MR. These extraordinary MRs are respectively explained by a hopping magnetoresistance via non-zero angular momentum orbitals, and by the magnetoresistance of inhomogeneous media. The linear negative orbital MR is a unique signature of the broken time-reversal symmetry (TRS). We discuss the origin of the disorder-induced TRS-breaking in graphite. PMID- 24158732 TI - Photoaffinity labeling of nicotinic receptors: diversity of drug binding sites! AB - For almost 30 years, photoaffinity labeling and protein microsequencing techniques have been providing novel insights about the structure of nicotinic acetylcholine receptors (nAChR) and the diversity of nAChR drug binding sites. Photoaffinity labeling allows direct identification of amino acid residues contributing to a drug binding site without prior knowledge of the location of the binding site within the nAChR or the orientation of the ligand within the binding site. It also distinguishes amino acids that contribute to allosteric binding sites from those involved in allosteric modulation of gating. While photoaffinity labeling was used initially to identify amino acids contributing to the agonist binding sites and the ion channel, it has been used recently to identify binding sites for allosteric modulators at subunit interfaces in the extracellular and the transmembrane domains, and within a subunit's transmembrane helix bundle. In this article, we review the different types of photoaffinity probes that have been used and the various binding sites that have been identified within the structure of nAChR, with emphasis on our recent studies of allosteric modulator binding sites. PMID- 24158734 TI - Novel mechanisms of biotransformation of p-tert-amylphenol by bacteria and fungi with special degradation abilities and simultaneous detoxification of the disinfectant. AB - The compound p-tert-amylphenol (p-(1,1-dimethylpropyl)phenol) is a widely used disinfectant belonging to the group of short branched-chain alkylphenols. It is produced in or imported into the USA with more than one million pounds per year and can be found in the environment in surface water, sediments, and soil. We have investigated for the first time the biotransformation of this disinfectant and the accumulation of metabolites by five bacterial strains, three yeast strains, and three filamentous fungi, selected because of their ability to transform either aromatic or branched-chain compounds. Of the 11 microorganisms tested, one yeast strain and three bacteria could not transform the disinfectant despite of a very low concentration applied (0.005%). None of the other seven organisms was able to degrade the short branched alkyl chain of p-tert amylphenol. However, two yeast strains, two filamentous fungi, and two bacterial strains attacked the aromatic ring system of the disinfectant via the hydroxylated intermediate 4-(1,1-dimethyl-propyl)-benzene-1,2-diol resulting in two hitherto unknown ring fission products with pyran and furan structures, 4 (1,1-dimethyl-propyl)-6-oxo-6-H-pyran-2-carboxylic acid and 2-[3-(1,1-dimethyl propyl)-5-oxo-2H-furan-2-yl]acetic acid. While the disinfectant was toxic to the organisms applied, one of the ring cleavage products was not. Thus, a detoxification of the disinfectant was achieved by ring cleavage. Furthermore, one filamentous fungus formed sugar conjugates with p-tert-amylphenol as another mechanism of detoxification of toxic environmental pollutants. With this work, we can also contribute to the allocation of unknown chemical compounds within environmental samples to their parent compounds. PMID- 24158735 TI - Anti-microbial and cytotoxic 1,6-dihydroxyphenazine-5,10-dioxide (iodinin) produced by Streptosporangium sp. DSM 45942 isolated from the fjord sediment. AB - Phenazine natural products/compounds possess a range of biological activities, including anti-microbial and cytotoxic, making them valuable starting materials for drug development in several therapeutic areas. These compounds are biosynthesized almost exclusively by eubacteria of both terrestrial and marine origins from erythrose 4-phosphate and phosphoenol pyruvate via the shikimate pathway. In this paper, we report isolation of actinomycete bacteria from marine sediment collected in the Trondheimfjord, Norway. Screening of the isolates for biological activity produced several "hits", one of which was followed up by identification and purification of the active compound from the actinomycete bacterium Streptosporangium sp. The purified compound, identified as 1,6 dihydroxyphenazine-5,10-dioxide (iodinin), was subjected to extended tests for biological activity against bacteria, fungi and mammalian cells. In these tests, the iodinin demonstrated high anti-microbial and cytotoxic activity, and was particularly potent against leukaemia cell lines. This is the first report on the isolation of iodinin from a marine-derived Streptosporangium. PMID- 24158736 TI - Vitamin D improves endometrial thickness in PCOS women who need intrauterine insemination: a randomized double-blind placebo-controlled trial. AB - PURPOSE: To determine whether administration of vitamin D affects the success rates of intra uterine insemination (IUI) in infertile polycystic ovarian syndrome (PCOS) women and their endometrial thickness. METHODS: This randomized, double-blind, placebo-controlled trial was conducted in an infertility clinic of Women's Hospital, and 110 infertile PCOS patients undergoing IUI were randomly divided to receive vitamin D or placebo. Endometrial thickness, IUI results, number of dominant follicles, duration of IUI cycle, and dose of HMG used in IUI were determined. RESULTS: The endometrial thickness was significantly different in the group treated with vitamin D versus the placebo group (p = 0.003). There was no statistical difference in pregnancy out come between the two groups (RR = 1.167, CI 95 % 0.70-1.93). No statistical difference was found in number of dominant follicles (p = 0.96), duration of IUI cycles (p = 0.70) and dose of HMG used for IUI (p = 0.95). CONCLUSIONS: It seems that administration of vitamin D induces endometrial proliferation in PCOS women during IUI cycle. The study was recorded in Iranian Registry of Clinical Trials(IRCT201104216246N1). PMID- 24158737 TI - Microscopic modeling of Pais grape seed extract absorption in the small intestine. AB - The concentration profiles and the absorbed fraction (F) of the Pais grape seed extract in the human small intestine were obtained using a microscopic model simulation that accounts for the extracts' dissolution and absorption. To apply this model, the physical and chemical parameters of the grape seed extract solubility (C s), density (rho), global mass transfer coefficient between the intestinal and blood content (k) (effective permeability), and diffusion coefficient (D) were experimentally evaluated. The diffusion coefficient (D = 3.45 * 10(-6) +/- 5 * 10(-8) cm(2)/s) was approximately on the same order of magnitude as the coefficients of the relevant constituents. These results were chemically validated to discover that only the compounds with low molecular weights diffused across the membrane (mainly the (+)-catechin and (-)-epicatechin compounds). The model demonstrated that for the Pais grape seed extract, the dissolution process would proceed at a faster rate than the convective process. In addition, the absorbed fraction was elevated (F = 85.3%). The global mass transfer coefficient (k = 1.53 * 10(-4) +/- 5 * 10(-6) cm/s) was a critical parameter in the absorption process, and minor changes drastically modified the prediction of the extract absorption. The simulation and experimental results show that the grape seed extract possesses the qualities of a potential phytodrug. PMID- 24158738 TI - Gastric histopathology in laparoscopic sleeve gastrectomy: pre- and post operative comparison. AB - BACKGROUND: Sleeve gastrectomy (SG) produces excellent results in weight reduction and resolution of comorbidities. The histology of the gastric mucosa can be affected by the surgical procedure, with alterations of inflammatory patterns. The objective of this study is to evaluate alterations of the inflammatory patterns of the gastric mucosa in SG and the results in weight loss and resolution of comorbidities. METHODS: Morbidly obese patients were selected to undergo SG. Endoscopies were performed pre-operatively and post-operatively after 6 months, with an incisura and 3 cm before the pylorus biopsies. Data on weight, height, and associated diseases were collected. The data were compared, and the biopsies evaluate the inflammatory patterns. RESULTS: There was a reduction of body weight with a pre-operative weight of 132.5 +/- 15.7 kg and a post-operative weight of 95.8 +/-10.6 kg with a p < 0.001. Also, the body mass index (BMI) was reduced significantly with a mean pre-operative of 42.6 +/- 10.6 kg/m(2) and a post-operative of 30.9 +/- 3.2 kg/m(2) with a p < 0.001. The comorbidities were all resolved or improved. The pattern of gastric histology showed chronic gastritis with inflammatory activity associated with Helicobacter pylori in 33.3 % of the patients, along with foveolar hyperplasia at 58.3 %. The chronic gastritis with discrete inflammatory activity was reduced by 16.7 %, and the foveolar hyperplasia was reduced by 33.3 %. CONCLUSION: The inflammatory alterations in the pre-operative period were mainly foveolar hyperplasia and chronic gastritis associated with H. pylori, and they were reduced in the post operative period. A significant reduction of weight and BMI occurred, and a resolution of comorbidities was observed. PMID- 24158740 TI - When and how to operate on thoracic and lumbar spine fractures? AB - PURPOSE: To discuss when and how to operate on thoracic and lumbar spine fractures. PATIENTS AND METHODS: We retrospectively studied 77 consecutive patients with thoracic and lumbar spine fractures treated from 2000 to 2011; 28 patients experienced high-energy spinal trauma and 49 low-energy spinal trauma. Mean follow-up was 5 years (1-11 years). Surgical treatment was done in 15 patients with neurological deficits, and in 16 neurologically intact patients with fractures-dislocations, burst fractures and fractures with marked deformity. Non-surgical treatment was done in 46 neurologically intact patients with simple fracture configurations. Clinical and imaging examination and the Oswestry Disability Index (O.D.I.) questionnaire were obtained. RESULTS: All patients treated surgically maintained spinal alignment; patients with long fusion maintained the best alignment; however, they experienced back stiffness and moderate low back pain. Patients with combined posterior fusion and kyphoplasty experienced earlier recovery and improved sagittal correction. Mean O.D.I. was 22.4 and 14.2% at 3 and 12 months postoperatively. Thirty six (78%) patients treated non-surgically were asymptomatic, 22 (48%) experienced mild residual kyphosis, 10 (22 %) developed marked deformity during their follow-up and were finally operated; mean O.D.I. was 28.6 and 12.1% at 3 and 12 months. No difference in O.D.I. was observed between patients who had surgical and non surgical treatment. CONCLUSIONS: Progressive neurological deficits and/or mechanical instability of the spine are absolute indications for early surgical treatment. Younger patients with high-energy spinal trauma, unstable fractures and neurological deficits should be treated surgically in order to provide optimum conditions for neurologic recovery, early mobilization and possibly ambulation. Most cases can be adequately operated through a posterior only surgical approach; an anterior or combined approach is usually indicated for burst and thoracic spine fractures. Postoperative complications, more common infection and neurological deterioration may occur. Elderly, neurologically intact patients with low-energy, stable spinal fractures without marked spinal deformity may be successfully treated conservatively. Most of these patients will do well; however, follow-up for progressive posttraumatic deformity is required. PMID- 24158741 TI - Free non-vascularized fibular strut bone graft for treatment of post-traumatic lower extremity large bone loss. AB - Post-traumatic large bone defects of more than 4 cm occur sometimes in open lower extremity fractures. Management of this kind trauma can be a challenge to orthopedic surgeons. We have managed this kind of bone defect by the use of free non-vascularized fibular strut bone grafts (FNVFG) harvested subperiosteally and held by screw fixation of the strut ends to the ends of the bone defect. Ten patients, eight males and two females, with a mean age of 44 years (range 26-76 years) underwent this procedure. The length of defect was 7.0 cm on average (ranging from 4 to 8 cm). Ten grafts (100%) united at both ends within an average of 6 months (range 5-9 months). Nine patients walked independently, and one patient walked with a stick. FNVFG is a simple procedure and a reliable method to bridge huge bone loss due to open fractures of lower extremities successfully in selected cases. PMID- 24158742 TI - Safety profile of sural nerve in posterolateral approach to the ankle joint: MRI study. AB - The posterolateral approach to ankle joint is well suited for ORIF of posterior malleolar fractures. There are no major neurovascular structures endangering this approach other than the sural nerve. The sural nerve is often used as an autologous peripheral nerve graft and provides sensation to the lateral aspect of the foot. The aim of this paper is to measure the precise distance of the sural nerve from surrounding soft tissue structures so as to enable safe placement of skin incision in posterolateral approach. This is a retrospective image review study involving 64 MRI scans. All measurements were made from Axial T1 slices. The key findings of the paper is the safety window for the sural nerve from the lateral border of tendoachilles (TA) is 7 mm, 1.3 cm and 2 cm at 3 cm above ankle joint, at the ankle joint and at the distal tip of fibula respectively. Our study demonstrates the close relationship of the nerve in relation to TA and fibula in terms of exact measurements. The safety margins established in this study should enable the surgeon in preventing endangerment of the sural nerve encountered in this approach. PMID- 24158739 TI - Relapsed and refractory pediatric acute myeloid leukemia: current and emerging treatments. AB - Survival rates for children with acute myeloid leukemia (AML) exceed 60 % when modern, intensified chemotherapeutic regimens and enhanced supportive care measures are employed. Despite well-recognized improvements in outcomes, primary refractory or relapsed pediatric AML yields significant morbidity and mortality, and improved understanding of this obstinate population along with refined treatment protocols are urgently needed. Although a significant number of patients with refractory or relapsed disease will achieve remission, long-term survival rates remain poor, and efforts to identify therapies which will improve OS are under continuous investigation. The current fundamental goal of such investigation is the achievement of as complete a remission as possible without dose-limiting toxicities, and the progression to hematopoietic stem cell transplantation thereafter. In this review the scope of the problem of relapsed and refractory AML as well as current and emerging chemotherapy options will be discussed. PMID- 24158743 TI - Amputation versus functional reconstruction in the management of complex hind foot injuries caused by land-mine explosions: a long-term retrospective comparison. AB - The purpose of this study is to compare the long-term clinical outcomes of patients who were treated with either hind foot reconstruction or amputation in complex hind foot injuries accompanied with bone and soft tissue loss due to land mine explosions. Between 1994 and 2004, all patients with hind foot complex injuries due to land-mine explosion, who were operated in our clinic, were enrolled to the study. All patients were evaluated with Short-Form 36 (SF-36), Foot and Ankle Disability Index (FADI) and Body Image Quality of Life Inventory (BIQLI) after a mean of 15.1 +/- 2.2 (range 9-19) years of follow-up. Demographic characteristics, number of operations, necessity of psychiatric treatment and all complications were compared between groups. There were a total of 42 patients [21 in reconstruction group (Gr I) and 21 in amputation group (Gr II)]. The mean age at the time of final follow-up was 38.4 +/- 3.04 years in Gr I and 38.2 +/- 4.24 years in Gr II (p = 0.732). The mean follow-up duration was 15.7 +/- 2.07 years in Gr I and 14.57 +/- 2.29 years in Gr II (p = 0.081). The number of operations was significantly higher in Gr I (8.66 +/- 10.2 times vs. 4.42 +/- 7.7 times, respectively, p = 0.001). The mean FADI score at the final follow-up was 64.3 +/- 18.1 in Gr I. In amputation group, more patients needed psychotherapy due to major depression (12 patients vs. 4 patients, p = 0.012). Major complications in Gr I were musculocutaneous flap atrophy in calcaneal region (n = 8 patients), limited ankle motion (n = 11) and painful osteophytes on plantar region (n = 6). In Gr II, stump problems were dominating (pain and tenderness n = 10, ulcer n = 2, allergic skin lesions n = 7, painful neuroma n = 10, bony spur n = 5, paresthesia n = 1, excessive sweating n = 12). At the final visit, although SF-36 scores were similar between groups (p = 0.182), extremity reconstruction group had significantly higher BIQLI scores than the amputation group (p = 0.016). If the dorsalis pedis is intact and midfoot and forefoot is relatively protected, hind foot reconstruction should be attempted. Long-term outcomes of hind foot reconstruction are satisfactory with minor complications and better BIQLI. PMID- 24158744 TI - [Minutes of the second ESTRO forum held in Geneva (Switzerland), 19-23 April 2013]. PMID- 24158746 TI - Pediatric hand injuries: essentials you need to know. AB - The hand is a common site of injury in children and adolescents. The most common mechanism of injury in younger children is crush injury resulting from the hand caught in a closing door while most fractures in teenagers result from recreational sports. Accurate diagnosis of hand fractures is a requisite for timely management of these injuries in order to restore normal function and achieve a satisfactory outcome since poorly treated injuries can have significant functional consequences. Metacarpal and phalangeal fractures can be difficult to diagnose at radiography due to their relatively small size leading to potential delays in treatment. Recognition of common fracture locations and patterns is essential in ensuring prompt and appropriate treatment. PMID- 24158745 TI - Novel anti-plasmodial hits identified by virtual screening of the ZINC database. AB - Increased resistance of Plasmodium falciparum to most available drugs challenges the control of malaria. Studies with protease inhibitors have suggested important roles for the falcipain family of cysteine proteases. These enzymes act in concert with other proteases to hydrolyze host erythrocyte hemoglobin in the parasite food vacuole. In order to find potential new antimalarial drugs, we screened in silico the ZINC database using two different protocols involving structure- and ligand-based methodologies. Our search identified 19 novel low micromolar inhibitors of cultured chloroquine resistant P. falciparum. The most active compound presented an IC50 value of 0.5 MUM against cultured parasites and it also inhibited the cysteine protease falcipain-2 (IC50 = 25.5 MUM). These results identify novel classes of antimalarials that are structurally different from those currently in use and which can be further derivatized to deliver leads suitable for optimisation. PMID- 24158747 TI - Lifetime prevalence of multiple victimizations and its impact on children's mental health. AB - This study sought to document lifetime experiences of individual categories of victimizations and polyvictimization using the Juvenile Victimization Questionnaire among children from the province of Quebec (Canada) to examine whether polyvictimization predicts mental health symptoms and to assess whether categories of victimization still contribute to mental health symptoms after considering polyvictimization. Polyvictimization accounted for the most variability in scores for depression, anxiety, and anger/aggression compared with individual victimization categories. None of the individual categories of victimization made an independent contribution to the prediction of trauma scores, once polyvictimization was considered. PMID- 24158749 TI - Non-covalent duplex to duplex crosslinking of DNA in solution revealed by single molecule force spectroscopy. AB - Small molecules that interact with DNA, disrupting the binding of transcription factors or crosslinking DNA into larger structures, have significant potential as cancer therapies and in nanotechnology. Bisintercalators, including natural products such as echinomycin and rationally designed molecules such as the bis-9 aminoacridine-4-carboxamides, are key examples. There is little knowledge of the propensity of these molecules to crosslink duplex DNA. Here we use single molecule force spectroscopy to assay the crosslinking capabilities of bisintercalators. We show that bis-9-aminoacridine-4-carboxamides with both rigid and flexible linkers are able to crosslink duplex strands of DNA, and estimate the equilibrium free energy of a 9-aminoacridine-4-carboxamide bisintercalator from DNA at 5.03 kJ mol(-1). Unexpectedly, we find that echinomycin and its synthetic analogue TANDEM are capable of sequence-specific crosslinking of the terminal base pairs of two duplex DNA strands. In the crowded environment of the nucleosome, small molecules that crosslink neighbouring DNA strands may be expected to have significant effects on transcription, while a small molecule that facilitates sequence-specific blunt-end ligation of DNA may find applications in the developing field of DNA nanotechnology. PMID- 24158751 TI - The effect of serotonin 1A receptor polymorphism on the cognitive function of premenstrual dysphoric disorder. AB - Estrogen and serotonin play vital roles in the mechanism of premenstrual dysphoric disorder (PMDD). Cognitive deficit in the premenstrual phase contributes to impaired life function among women with PMDD. The aim of this study was to evaluate the difficulties in cognitive control and working memory (WM) in PMDD and to explore the effects of gonadotropic hormone and polymorphism of serotonin 1A receptor (HTR1A; rs6295) on cognitive deficit in PMDD. Women with PMDD completed diagnostic interviewing, questionnaire assessment, the Go/Nogo task, 2-back and 3-back tasks, and gonadotropic hormone analysis in the premenstrual and follicular phases. Further, they were followed up for two menstrual cycles to confirm two consecutive symptomatic cycles. A total of 59 subjects with PMDD and 74 controls completed all evaluation, fulfilled the criteria, and entered into the final analysis. The results demonstrated cognitive control and WM decline in the premenstrual among women with PMDD. The G/G genotype of HTR1A (rs6295) was found to be associated with impaired WM in the premenstrual phase and premenstrual decline of cognitive function. It also contributed to the vulnerability of cognitive function to the menstrual cycle effect and PMDD effect. As the G/G genotype of HTR1A (rs6295) involves in reducing serotonin neurotransmission, our results provide insight into the serotonin mechanism of cognitive function among women with PMDD. PMID- 24158752 TI - Conservation genetics and the implication for recovery of the endangered Mitchell's satyr Butterfly, Neonympha mitchellii mitchellii. AB - The modern delineation of taxonomic groups is often aided by analyses of molecular data, which can also help inform conservation biology. Two subspecies of the butterfly Neonympha mitchellii are classified as federally endangered in the United States: Neonympha mitchellii mitchellii, the Mitchell's satyr, and Neonympha mitchellii francisi, the Saint Francis's satyr. The recent discovery of additional disjunct populations of N. mitchellii in the southeastern US could have important implications for both legal protection and management decisions. We elucidated the relationships among 48 individuals representing 5 N. mitchellii populations using 6 molecular markers (5 nuclear and 1 mitochondrial) under a variety of analytical frameworks. Phylogenetic analysis resulted in moderately supported clades that corresponded with the geographic region where samples originated. Clustering analyses identified 3 groups, wherein the 2 named subspecies formed separate clusters. Coalescent analyses indicated evolutionary divergence between N. m. mitchellii and all other populations but weakly supported divergence among N. m. francisi and the recently discovered populations. Hence, the 2 currently accepted subspecies were clearly different from one another, but the recently discovered populations could not be completely distinguished from N. m. francisi or each other. We propose that N. m. mitchellii and N. m. francisi continue to be managed as separate endangered species. PMID- 24158750 TI - Engineering Gd-loaded nanoparticles to enhance MRI sensitivity via T(1) shortening. AB - Magnetic resonance imaging (MRI) is a noninvasive imaging technique capable of obtaining high-resolution anatomical images of the body. Major drawbacks of MRI are the low contrast agent sensitivity and inability to distinguish healthy tissue from diseased tissue, making early detection challenging. To address this technological hurdle, paramagnetic contrast agents have been developed to increase the longitudinal relaxivity, leading to an increased signal-to-noise ratio. This review focuses on methods and principles that enabled the design and engineering of nanoparticles to deliver contrast agents with enhanced ionic relaxivities. Different engineering strategies and nanoparticle platforms will be compared in terms of their manufacturability, biocompatibility properties, and their overall potential to make an impact in clinical MR imaging. PMID- 24158753 TI - The natural course of bridging osteophyte formation in diffuse idiopathic skeletal hyperostosis: retrospective analysis of consecutive CT examinations over 10 years. AB - OBJECTIVE: The aim of this study was to evaluate the natural progression of bridging osteophyte formation in diffuse idiopathic skeletal hyperostosis (DISH) on CT by a newly proposed scoring system. METHODS: CT examinations of the thoracic/lumbar spine of DISH patients (Resnick criteria) obtained at two or more time points within a minimum of 3 years were evaluated. Twenty-six patients (mean age at first CT 57 years, 21 males) fulfilled the entry criteria. A semi quantitative scoring system for osteophyte progression was evaluated for intra- and interreader reliability on 68 vertebral units (VUs) in five patients. CT sagittal reformates of all 26 study patients were scored by two readers in consensus. RESULTS: Scoring intra- and interobserver intraclass correlation coefficient values were high (0.971 and 0.893, respectively). The average time points per patient was 3.6 in 398 VUs analysed for 93 time points. The average time between the first and last scans was 5.6 years (range 3-10). The scores of six patients were unchanged. The scores of 20 patients increased by 3 units in 48 VUs over 5.6 (s.d. 3.1) years. The time for a DISH score to increase by 1 scoring unit was 1.6 (s.d. 0.4) years. Two bridging patterns were observed: osteophyte fusion associated with a calcified anterior longitudinal ligament (ALL, 66%) and osteophyte fusion without apparent ALL calcification (33%). Both patterns were observed concomitantly in 15 patients. CONCLUSION: The new scoring system may enable earlier diagnosis and help predict disease progression into its final confluent osteophyte form. The two described patterns may indicate an underlying inflammatory rather than a degenerative pathogenesis. PMID- 24158754 TI - Endomyocardial fibrosis in patients with confirmed Churg-Strauss syndrome. PMID- 24158755 TI - Long-term mortality in frail elderly subjects with osteoarthritis. AB - OBJECTIVE: Elderly subjects are characterized by a high prevalence of OA and clinical frailty. This study aimed to examine the predictive role of clinical frailty on long-term mortality in elderly subjects with and without OA. METHODS: Mortality was evaluated after a 12-year follow-up in 698 subjects with and 590 subjects without OA recruited in 1992. Clinical frailty was assessed according to the Frailty Staging System and stratified in tertiles. RESULTS: After a 12-year follow-up, mortality was 42.2% in subjects without and 55.8% in subjects with OA (P = 0.256). With increasing frailty, mortality increased by 30.5% (P for trend < 0.001) in subjects without and by 45.6% in subjects with OA (P for trend < 0.001). Multivariate analysis showed that frailty [hazard ratio (HR) = 1.49 for each unit of increase, 95% CI 1.32, 1.94, P < 0.001) but not OA (HR = 1.28, 95% CI 0.987, 1.39, P = 0.412) was predictive of long-term mortality. Moreover, when Cox regression analysis was performed, frailty enhanced the risk of long-term mortality for each unit of increase by 32% (HR = 1.32, 95% CI 1.06, 1.65, P = 0.03) in the absence of OA and by 98% in the presence (HR = 1.98, 95% CI 1.63, 2.95, P < 0.01) of OA. CONCLUSION: Clinical frailty significantly predicts mortality in subjects without OA and even more in those with OA. Thus clinical frailty may be considered a new prognostic factor to identify subjects with OA at high risk of mortality. PMID- 24158756 TI - MicroRNA-361-5p facilitates cervical cancer progression through mediation of epithelial-to-mesenchymal transition. AB - The epithelial-to-mesenchymal transition (EMT) promotes cervical cancer progression, and microRNAs have been found to be master regulators of EMT. The aim of the present study was to investigate the functional roles of miR-361-5p in EMT and cervical cancer progression. Differentially expressed miRNAs were screened with microarray analysis in SiHa and CasKi cells; cellular and animal studies were used to observe the impact of miR-361-5p on cell proliferation; invasion and migration ability of cervical cancer cells were investigated by Transwell and wound-healing studies; enzyme-linked immunosorbent assay and Western blot methods were used to test protein levels; miR-361-5p level in cervical cancer specimens was detected with in situ hybridization. MicroRNA-361 5p (miR-361-5p) was found to be the most upregulated microRNA in transferred cervical cancer cells. MiR-361-5p acts as an oncogene to enhance cell proliferation and promote cell invasion, and these changes were accompanied by the characteristics of EMT. miR-361-5p is increasingly elevated during cervical carcinoma progression and inversely correlated with E-cadherin, a marker of EMT. These findings suggest that miR-361-5p is an oncomicroRNA and an important factor in the progression of cervical cancer. PMID- 24158757 TI - Plasma proteomics analysis of tamoxifen resistance in breast cancer. AB - Due to ease accessibility, exploring plasma for candidate cancer biomarkers is of great interest to molecular biologist and physicians. In breast cancer, the development of tamoxifen resistance (TR) is among the major causes of recurrence and mortality. Therefore, the identification of novel biomarkers that are linked to TR is of great interest and the subject of intensive research. Here, we exploited the power of two-dimensional gel electrophoresis coupled with protein identification using tandem mass spectrometry to identify plasma proteome signatures associated with TR. Comparative proteomics analysis resulted in the identification of 15 statistically significant spots, which were up /downregulated after tamoxifen therapy. MASCOT search of the mass spectrometry generated spectral data resulted in the identification of 9 proteins. Several differentially expressed proteins such as clusterin, serum amyloid A, serpin B4, and transthyretin are already known to be involved in cancer incidence and progression. The possible involvement of these candidate proteins in conferring TR and their potential usefulness as plasma biomarkers for predicting response to tamoxifen treatment has been discussed. PMID- 24158758 TI - Newborn blood spot screening for sickle cell disease by using tandem mass spectrometry: implementation of a protocol to identify only the disease states of sickle cell disease. AB - BACKGROUND: The currently recommended technologies of HPLC and isoelectric focusing for newborn blood spot screening for sickle cell disease (SCD) identify both the disease and carrier states, resulting in large numbers of infants being followed up unnecessarily. Analysis of blood spot tryptic peptides performed by using tandem mass spectrometry (MS/MS) is an alternative technology to detect hemoglobin (Hb) variant disorders. METHODS: We analyzed 2154 residual newborn blood spots and 675 newborn blood spots from infants with Hb variants by using MS/MS after trypsin digestion. Screening cutoffs were developed by using the ratio between the variant peptide-to-wild-type peptide abundance for HbS, C, D(Punjab), O(Arab), Lepore, and E peptides. A postanalytical data analysis protocol was developed using these cutoffs to detect only the disease states of SCD and not to identify carrier states. A parallel study of 13 249 newborn blood spots from a high-prevalence SCD area were analyzed by both MS/MS and HPLC. RESULTS: Screening cutoffs developed distinguished the infants with the disease states of SCD, infants who were carriers of SCD, and infants with normal Hb. In the parallel study no false-negative results were identified, and all clinically relevant cases were correctly identified using the MS/MS protocol. Unblinding the data revealed a total of 328 carrier infants that were successfully excluded by the protocol. CONCLUSIONS: The screening protocol developed correctly identified infants with the disease states of SCD. Furthermore, large numbers of sickle cell carrier infants were successfully not identified, thereby avoiding unnecessary follow-up testing and referral for genetic counseling. PMID- 24158759 TI - Validation of Rosner-Colditz breast cancer incidence model using an independent data set, the California Teachers Study. AB - To validate an established breast cancer incidence model in an independent prospective data set. After aligning time periods for follow-up, we restricted populations to comparable age ranges (47-74 years), and followed them for incident invasive breast cancer (follow-up 1994-2008, Nurses' Health Study [NHS]; and 1995-2009, California Teachers Study [CTS]). We identified 2026 cases during 540,617 person years of follow-up in NHS, and 1,400 cases during 288,111 person years in CTS. We fit the Rosner-Colditz log-incidence model and the Gail model using baseline data. We imputed future use of hormones based on type and prior duration of use and other covariates. We assessed performance using area under the curve (AUC) and calibration methods. Participants in the CTS had fewer children, were leaner, consumed more alcohol, and were more frequent users of postmenopausal hormones. Incidence rate ratios for breast cancer showed significantly higher breast cancer in the CTS (IRR = 1.32, 95 % CI 1.24-1.42). Parameters for the log-incidence model were comparable across the two cohorts. Overall, the NHS model performed equally well when applied in the CTS. In the NHS the AUC was 0.60 (s.e. 0.006) and applying the NHS betas to the CTS the performance in the independent data set (validation) was 0.586 (s.e. 0.009). The Gail model gave values of 0.547 (s.e. 0.008), a significant 4 % lower, p < 0.0001. For women 47-69 the AUC values for the log-incidence model are 0.608 in NHS and 0.609 in CTS; and for Gail are 0.569 and 0.572. In both cohorts, performance of both models dropped off in older women 70-87, and later in follow up (6-12 years). Calibration showed good estimation against SEER with a non significant 4 % underestimate of overall breast cancer incidence when applying the model in the CTS population (p = 0.098). The Rosner-Colditz model performs consistently well when applied in an independent data set. Performance is stronger predicting incidence among women 47-69 and over a 5-year time interval. AUC values exceed those for Gail by 3-5 % based on AUC when both are applied to the independent validation data set. Models may be further improved with addition of breast density or other markers of risk beyond the current model. PMID- 24158760 TI - Closing an on-going clinical trial: when is it betrayal of participants? PMID- 24158761 TI - Testosterone induces erythrocytosis via increased erythropoietin and suppressed hepcidin: evidence for a new erythropoietin/hemoglobin set point. AB - BACKGROUND: The mechanisms by which testosterone increases hemoglobin and hematocrit remain unclear. METHODS: We assessed the hormonal and hematologic responses to testosterone administration in a clinical trial in which older men with mobility limitation were randomized to either placebo or testosterone gel daily for 6 months. RESULTS: The 7%-10% increase in hemoglobin and hematocrit, respectively, with testosterone administration was associated with significantly increased erythropoietin (EPO) levels and decreased ferritin and hepcidin levels at 1 and 3 months. At 6 months, EPO and hepcidin levels returned toward baseline in spite of continued testosterone administration, but EPO levels remained nonsuppressed even though elevated hemoglobin and hematocrit higher than at baseline, suggesting a new set point. Consistent with increased iron utilization, soluble transferrin receptor (sTR) levels and ratio of sTR/log ferritin increased significantly in testosterone-treated men. Hormonal and hematologic responses were similar in anemic participants. The majority of testosterone-treated anemic participants increased their hemoglobin into normal range. CONCLUSIONS: Testosterone-induced increase in hemoglobin and hematocrit is associated with stimulation of EPO and reduced ferritin and hepcidin concentrations. We propose that testosterone stimulates erythropoiesis by stimulating EPO and recalibrating the set point of EPO in relation to hemoglobin and by increasing iron utilization for erythropoiesis. PMID- 24158762 TI - Postprandial activation of p53-dependent DNA repair is modified by Mediterranean diet supplemented with coenzyme Q10 in elderly subjects. AB - BACKGROUND: Alterations in the expression levels of genes and proteins involved in oxidative stress and DNA damage response underlie the phenotypic changes associated with aging. We have investigated whether the quality of dietary fat alters postprandial gene expression and protein levels involved in p53-dependent DNA repair and whether the supplementation with Coenzyme Q10 improves this situation in an elderly population. METHODS: Twenty participants were randomized to receive three isocaloric diets each for 4 weeks: Mediterranean diet supplemented with Coenzyme Q10, Mediterranean diet, saturated fatty acid-rich diet. After a 12-hour fast, volunteers consumed a breakfast with a fat composition similar to that consumed in each of the diets. Gadd45a, Gadd45b, OGG1, APE-1/Ref-1, DNApolbeta, and XPC gene expression and nuclear Gadd45a, APE 1/Ref-1, and DNApolbeta protein levels were determined in peripheral blood mononuclear cells. RESULTS: Mediterranean diet and Mediterranean diet supplemented with Coenzyme Q10diets downregulated Gadd45a protein levels compared with the saturated fatty acid-rich diet. Moreover, Mediterranean diet supplemented with Coenzyme Q10diet evoked lower postprandial Gadd45a, Gadd45b, XPC, DNApolbeta and OGG1 gene expression and lower APE-1/Ref-1 and DNApolbeta protein levels than the saturated fatty acid-rich diet. CONCLUSIONS: Our results support a beneficial effect of Mediterranean diet and Mediterranean diet supplemented with Coenzyme Q10 on DNA damage as compared to the detrimental action of a saturated fatty acid-rich diet, which triggers the p53-dependent DNA repair machinery. PMID- 24158763 TI - Impact of climate change on elder health. AB - Demographers predict human life expectancy will continue to increase over the coming century. These forecasts are based on two critical assumptions: advances in medical technology will continue apace and the environment that sustains us will remain unchanged. The consensus of the scientific community is that human activity contributes to global climate change. That change will degrade air and water quality, and global temperature could rise 11.5 degrees F by 2100. If nothing is done to alter this climatic trajectory, humans will be confronted by a broad spectrum of radical environmental challenges. Historically, children and the elderly adults account for most of the death toll during times of severe environmental stress. This article makes an assessment from a geriatric viewpoint of the adverse health consequences that global climate change will bring to the older segments of future populations in the United States. PMID- 24158764 TI - Validation study of the body adiposity index as a predictor of percent body fat in older individuals: findings from the BLSA. AB - A new body adiposity index (BAI = (hip circumference)/((height)(1.5)) - 18) has been developed and validated in adult populations. We aimed to assess the validity of BAI in an older population. We compared the concordance correlation coefficient between BAI, body mass index (BMI), and percent body fat (fat%; by dual-energy X-ray absorptiometry) in an older population (n = 954) participating in the Baltimore Longitudinal Study of Aging. BAI was more strongly correlated with fat% than BMI (r of .7 vs .6 for BAI vs BMI and fat%, respectively, p < .01) and exhibited a smaller mean difference from fat% (-5.2 vs -7.6 for BAI vs BMI and fat%, respectively, p < .01) indicating better agreement. In men, however, BMI was in better agreement with fat% (r of .6 vs .7 for BAI vs BMI and fat%, respectively, p < .01) with a smaller mean difference from fat% (-3.0 vs -2.2 for BAI vs BMI and fat%, respectively, p < .01). Finally, BAI did not accurately predict fat% in people with a fat% below 15%. BAI provides valid estimation of body adiposity in an older adult population; however, BMI may be a better index for older men. Finally, BAI is not accurate in people with extremely low or high body fat percentages. PMID- 24158765 TI - Older adults with limited literacy are at increased risk for likely dementia. AB - BACKGROUND: Low literacy is common among the elderly and possibly more reflective of educational attainment than years of school completed. We examined the association between literacy and risk of likely dementia in older adults. METHODS: Participants were 2,458 black and white elders (aged 71-82) from the Health, Aging and Body Composition study, who completed the Rapid Estimate of Adult Literacy in Medicine and were followed for 8 years. Participants were free of dementia at baseline; incidence of likely dementia was defined by hospital records, prescription for dementia medication, or decline in Modified Mini-Mental State Examination score. We conducted Cox proportional hazard models to evaluate the association between literacy and incidence of likely dementia. Demographics, education, income, comorbidities, lifestyle variables, and apolipoprotein E (APOE) epsilon4 status were included in adjusted analyses. RESULTS: Twenty-three percent of participants had limited literacy (<9th-grade level). Limited literacy, as opposed to adequate literacy (>=9th-grade level), was associated with greater incidence of likely dementia (25.5% vs17.0%; unadjusted hazard ratio [HR] = 1.75, 95% confidence interval 1.44-2.13); this association remained significant after adjustment. There was a trend for an interaction between literacy and APOE epsilon4 status (p = .07); the association between limited literacy and greater incidence of likely dementia was strong among epsilon4 noncarriers (unadjusted HR = 1.85) but nonsignificant among epsilon4 carriers (unadjusted HR = 1.25). CONCLUSIONS: Limited literacy is an important risk factor for likely dementia, especially among APOE epsilon4-negative older adults, and may prove fruitful to target in interventions aimed at reducing dementia risk. PMID- 24158767 TI - How do we better translate adherence research into improvements in patient care? PMID- 24158766 TI - Is HIV a model of accelerated or accentuated aging? AB - BACKGROUND: Antiretroviral therapy has reduced the incidence of adverse events and early mortality in HIV-infected persons. Despite these benefits, important comorbidities that increase with age (eg, diabetes, cardiovascular disease, cancer, liver disease, and neurocognitive impairment) are more prevalent in HIV infected persons than in HIV-uninfected persons at every age, and geriatric syndromes such as falls and frailty occur earlier in HIV-infected persons. This raises a critical research question: Does HIV accelerate aging through pathways and mechanisms common to the aging process or is HIV simply an additional risk factor for a wide number of chronic conditions, thus accentuating aging? METHODS: Extensive literature review. RESULTS: The purpose of this review is to briefly outline the evidence that age-related clinical syndromes are exacerbated by HIV, examine the ways in which HIV is similar, and dissimilar from natural aging, and assess the validity of HIV as a model of premature aging. Specific biomarkers of aging are limited in HIV-infected hosts and impacted by antiretroviral therapy, and a high rate of modifiable life style confounders (eg, smoking, substance abuse, alcohol) and coinfections (eg, hepatitis) in HIV-infected participants. CONCLUSIONS: There is a need for validated biomarkers of aging in the context of HIV. Despite these differences, welldesigned studies of HIV-infected participants are likely to provide new opportunities to better understand the mechanisms that lead to aging and age-related diseases. PMID- 24158768 TI - Vitamin D receptor BsmI polymorphism modulates soy intake and 25-hydroxyvitamin D supplementation benefits in cardiovascular disease risk factors profile. AB - Vitamin D receptor polymorphisms may predispose that not all individuals could have benefits from the nutritional supplementation of 25-hydroxyvitamin D. Furthermore, vitamin D-related cardiovascular effects may also be influenced by soy isoflavones considered endocrine regulators of cardiovascular homeostasis. To find possible gene-diet interactions by evaluating individualized lipid metabolism benefits from an increase in soy and 25-hydroxyvitamin D intake, 106 healthy individuals, genotyped for vitamin D receptor (VDR) gene polymorphism rs1544410 (BsmI) were randomly assigned to either no intake, to daily 250 mL or 500 mL of a 25-hydroxyvitamin D supplemented SB for 2 months. The soybean beverage induced differences in cardiovascular risk factors (lipid profile, blood pressure, TNFalpha and MCP-1), as well as vitamin D metabolites in a dose-gene dependent relation. Thus, VDR BsmI polymorphism affected individual response being the GG genotype the ones that showed dose-dependent manner responsiveness in the reduction in total cholesterol, LDL and triglycerides in comparison with the AA/AG genotype. These differences were associated with increased plasma levels of 1alpha,25-dyhydroxyvitamin D3 in the carriers of the GG genotype. It was concluded that metabolic response to 25-hydroxyvitamin D and soybean supplementation is dependent on VDR BsmI GG genotype due to a higher conversion rate from vitamin D precursors. PMID- 24158769 TI - Phospholipid transfer protein deficiency decreases the content of S1P in HDL via the loss of its transfer capability. AB - Sphingosine-1-phosphate (S1P) is an amphiphilic signaling molecule, which is enriched in functional high density lipoprotein (HDL) and shows arterial protection. The distribution of S1P is changed with increased plasma phospholipid transfer protein (PLTP) activity and impaired HDL function in patients with coronary heart diseases. Therefore, we hypothesized that PLTP might transfer S1P among cells or lipoproteins. We found that plasma S1P contents were decreased by 60.1 % in PLTP knockout mice (PLTP-/-, N = 5) compared with their wild type littermates (WT, N = 5) (151.70 +/- 38.59 vs. 379.32 +/- 59.90 nmol/l, P<0.01). S1P content in HDL fraction (HDL-S1P) from PLTP-/- was decreased by 64.7 % compared with WT (49.36 +/- 1.49 vs. 139.76 +/- 2.94 nmol/l, P<0.01). The results of the S1P transfer assay indicated that PLTP could facilitate S1P transport from erythrocytes to HDL at 37 degrees C in D-Hanks buffer. Plasma content of apolipoprotein M, a specific adaptor of S1P, was not changed in PLTP-/- compared with WT. Therefore, we concluded that PLTP was a key factor to maintain plasma HDL-S1P, and PLTP deficiency could decrease the S1P content in plasma lipoproteins, which involves its capability of transferring S1P from erythrocyte to HDL. PMID- 24158770 TI - Intra-articular fibroma of tendon sheath arising in the acromioclavicular joint. AB - Fibroma of the tendon sheath, a rare benign soft tissue tumor that most often occurs in the distal upper extremities (hands and wrist), is exceedingly rare to present as an intraarticular mass. Presented here is the first case in the English literature, to our knowledge, of a fibroma of the tendon sheath arising in the acromioclavicular joint. The patient presented with recurrent shoulder pain with activity without antecedent trauma. Radiographs were essentially normal. MR images demonstrated a lobulated, heterogeneous mass with contrast enhancement arising from the acromioclavicular joint. Following surgical resection, histopathology revealed hypocellular collagen matrix with spindle shaped fibroblasts, confirming the diagnosis of fibroma of tendon sheath. The imaging features of the fibroma of the tendon sheath and a brief review of the literature are presented. PMID- 24158771 TI - Systematic literature review of the costs of pregnancy in the US. AB - BACKGROUND: The cost of pregnancy is increasing over time despite the decline in pregnancy rates. OBJECTIVE: To fully elucidate and evaluate the cost drivers of pregnancy in the US for payers, a systematic review was conducted to understand the main cost components and primary factors that contribute to the direct costs of pregnancy, pregnancy-related complications and unintended pregnancy among women of childbearing age (15-44 years). DATA SOURCES: We performed electronic searches in the PubMed database from January 2000 to December 2012, and major women's health and pharmacoeconomics conference proceedings from 2011 to 2012. STUDY SELECTION: The systematic review is comprised of studies that reported pregnancy, pregnancy-related complications, unplanned pregnancy, and pregnancy induced monetary costs. The review excluded narrative reports, systematic reviews, model-derived cost of pregnancy papers, non-US-based studies, and reports based solely on expert opinions. STUDY APPRAISAL AND SYNTHESIS METHODS: Two reviewers independently applied the inclusion criteria and assessed the quality of the data collected. Disagreements between reviewers were resolved by consensus or by arbitration through a third party, with reference to the original sources. We collected information on the study design and outcomes for each included study. We used the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines in designing, performing, and reporting of the systematic review. RESULTS: We identified 40 studies from electronic and handsearching methods. We classified studies based on the primary research topic focusing on the overall cost of pregnancy (N = 10), cost of pregnancy-related complications (N = 26), cost of unintended pregnancy (N = 2), cost of planned pregnancy (N = 1), or cost of pregnancy by facilities (N = 1). In the quality assessment, randomized, non-randomized, and retrospective database studies had low to moderate risk of bias. We determined primary cost drivers based on the highest cost reported in each study. The identified cost drivers were inpatient care, pregnancy delivery, multiple births, complicated cesarean sections, high risk pregnancy, preterm birth, low birth weight, complications due to conditions such as hypertension, diabetes, anemia, and cancer, and in vitro fertilization. In 2008, the overall mean cost per hospital stay for pregnancy-related incidence ranged from $3,306 to $9,234 in 2012 dollars. The mean cost of pregnancy-related complications that led to preterm birth was as high as $326,953 for an infant born at 25 weeks. It is estimated that over 50 % of live births were unintended in the US. The difference in the cost of unintended pregnancy and intended pregnancy was approximately $536 million. LIMITATIONS: One limitation of the systematic review was the exclusion of model-based cost studies which were excluded because of the high level of variation and heterogeneity across sources of reported cost. Another limitation of the review is that the cost of pregnancy perspective is restricted to the US. CONCLUSION: Preventing pregnancy-related complications and reducing unintended pregnancies may lower the overall economic burden of pregnancy on the US health care system. PMID- 24158774 TI - Changes in weight and BMI following the diagnosis of type 1 diabetes in children and adolescents. AB - The aim of this study was to study weight and body mass index (BMI) before, at, and after diagnosis of type 1 diabetes (T1D) and to identify factors associated with weight gain. Studied retrospectively were 209 children <18 years with T1D followed for 6 years. Data collected included clinical and laboratory data before diagnosis, at diagnosis, and during 6 years of follow-up. Anthropometric parameters of patients were compared along follow-up and with those of their parents and siblings. Mean BMI-standard deviation score (SDS) was below average at diagnosis (-0.66 +/- 1.27), had increased to 0.37 +/- 0.93 at 3 months, and decreased to a nadir at 6 months in females and 12 months in males; between 1 and 3 years, there was a slight increase and between 3 and 6 years a further increase only in the females. BMI-SDS at 6 years was significantly higher than pre diabetes BMI-SDS (0.35 +/- 0.83 vs. -0.04 +/- 1.23, p < 0.001). Patients' BMI-SDS at 6 years was similar to that of their parents and siblings, was higher in the females (0.53 +/- 0.74 vs. 0.27 +/- 0.82, p = 0.02) and in those keeping diabetes a secret (0.66 +/- 0.82 vs. 0.33 +/- 0.78, p = 0.027), and was not associated with age or pubertal stage at diagnosis, ethnicity, or metabolic control. A longer duration of insulin pump therapy was associated with a lower BMI-SDS (r = 0.2375, p < 0.025). BMI-SDS increased during the 6 years following diagnosis of T1D in pediatric patients, especially in the females, but remained in the normal range and was similar to that of other family members. PMID- 24158772 TI - Gemcitabine and vinorelbine as second-line or beyond treatment in patients with malignant pleural mesothelioma pretreated with platinum plus pemetrexed chemotherapy. AB - BACKGROUND: Malignant pleural mesothelioma (MPM) is an aggressive neoplasm that responds poorly to chemotherapy. Although treatment with pemetrexed in combination with cisplatin serves as first-line chemotherapy for MPM, the optimal second-line and beyond therapy has not yet been fully examined. METHODS: Between March 2008 and October 2011, 17 consecutive Japanese patients pretreated with at least one regimen of platinum plus pemetrexed chemotherapy received gemcitabine and vinorelbine. Responses, survival time, and toxicity were retrospectively evaluated. RESULTS: Response [partial response (PR) + complete response (CR)] and disease control [stable disease (SD) + PR + CR] rates were 18 and 82 %, respectively. The median progression-free survival (PFS) after combination chemotherapy was 6.0 months, whereas the median overall survival (OS) was 11.2 months. Grade 3 or 4 neutropenia and anemia were observed in 41 and 29 % of patients, respectively, and one patient experienced febrile neutropenia. Grade 3 or 4 nonhematologic toxicities included constipation (6 %) and phlebitis (6 %). CONCLUSION: Combination chemotherapy using gemcitabine with vinorelbine was shown to have moderate activity in Japanese MPM patients pretreated with platinum plus pemetrexed chemotherapy. A further multicenter phase II trial is warranted to confirm the efficacy and safety of this combination treatment. PMID- 24158773 TI - The complex relationship of realspace events and messages in cyberspace: case study of influenza and pertussis using tweets. AB - BACKGROUND: Surveillance plays a vital role in disease detection, but traditional methods of collecting patient data, reporting to health officials, and compiling reports are costly and time consuming. In recent years, syndromic surveillance tools have expanded and researchers are able to exploit the vast amount of data available in real time on the Internet at minimal cost. Many data sources for infoveillance exist, but this study focuses on status updates (tweets) from the Twitter microblogging website. OBJECTIVE: The aim of this study was to explore the interaction between cyberspace message activity, measured by keyword-specific tweets, and real world occurrences of influenza and pertussis. Tweets were aggregated by week and compared to weekly influenza-like illness (ILI) and weekly pertussis incidence. The potential effect of tweet type was analyzed by categorizing tweets into 4 categories: nonretweets, retweets, tweets with a URL Web address, and tweets without a URL Web address. METHODS: Tweets were collected within a 17-mile radius of 11 US cities chosen on the basis of population size and the availability of disease data. Influenza analysis involved all 11 cities. Pertussis analysis was based on the 2 cities nearest to the Washington State pertussis outbreak (Seattle, WA and Portland, OR). Tweet collection resulted in 161,821 flu, 6174 influenza, 160 pertussis, and 1167 whooping cough tweets. The correlation coefficients between tweets or subgroups of tweets and disease occurrence were calculated and trends were presented graphically. RESULTS: Correlations between weekly aggregated tweets and disease occurrence varied greatly, but were relatively strong in some areas. In general, correlation coefficients were stronger in the flu analysis compared to the pertussis analysis. Within each analysis, flu tweets were more strongly correlated with ILI rates than influenza tweets, and whooping cough tweets correlated more strongly with pertussis incidence than pertussis tweets. Nonretweets correlated more with disease occurrence than retweets, and tweets without a URL Web address correlated better with actual incidence than those with a URL Web address primarily for the flu tweets. CONCLUSIONS: This study demonstrates that not only does keyword choice play an important role in how well tweets correlate with disease occurrence, but that the subgroup of tweets used for analysis is also important. This exploratory work shows potential in the use of tweets for infoveillance, but continued efforts are needed to further refine research methods in this field. PMID- 24158775 TI - GLP-1 receptor agonist-induced polyarthritis: a case report. AB - Occasional cases of bilateral, symmetrical, seronegative polyarthritis have been reported in patients treated with dipeptidyl peptidase-4 inhibitors (Crickx et al. in Rheumatol Int, 2013). We report here a similar case observed during treatment with a GLP-1 receptor agonist. A 42-year-old man with type 2 diabetes treated with metformin 1,500 mg/day and liraglutide 1.8 mg/day. After 6 months from the beginning of treatment, the patient complained of bilateral arthralgia (hands, feet, ankles, knees, and hips). Erythrocyte sedimentation rate (ESR), C reactive protein (CRP), and leukocytes were increased. Rheumatoid factor, anticyclic citrullinated protein antibody, antinuclear antibodies, anti-Borrelia, and burgdorferi antibodies were all negative, and myoglobin and calcitonin were normal. Liraglutide was withdrawn, and the symptoms completely disappeared within 1 week, with normalization of ESR, CRP, fibrinogen, and leukocytes. Previously described cases of polyarthritis associated with DPP4 inhibitors had been attributed to a direct effect of the drugs on inflammatory cells expressing the enzyme. The present case, occurred during treatment with a GLP-1 receptor agonists, suggests a possibly different mechanism, mediated by GLP-1 receptor stimulation, which deserved further investigation. PMID- 24158776 TI - Deterministic growth of AgTCNQ and CuTCNQ nanowires on large-area reduced graphene oxide films for flexible optoelectronics. AB - We describe a synchronous reduction and assembly procedure to directly produce large-area reduced graphene oxide (rGO) films sandwiched by a high density of metal nanoparticles (silver and copper). Further, by using the sandwiched metal NPs as sources, networks consisting of AgTCNQ and CuTCNQ nanowires were deterministically grown from the rGO films, forming structurally and functionally integrated rGO/metal-TCNQ hybrid films with outstanding flexibility, bending endurance, and electrical stability. Interestingly, due to the p-type nature of the rGO film and the n-type nature of the metal-TCNQ NWs, the hybrid films are essentially thin-film p-n junctions which are useful in ubiquitous electronics and optoelectronics. Measurements of the optoelectronic properties demonstrate that the rGO/metal-TCNQ hybrid films exhibit substantial photoconductivity and highly reproducible photoswitching behaviours. The present approach may open the door to the versatile and deterministic integration of functional nanostructures into flexible conducting substrates and provide an important step towards producing low-cost and high-performance soft electronic and optoelectronic devices. PMID- 24158778 TI - Trends in smoking in Canada from 1950 to 2011: progression of the tobacco epidemic according to socioeconomic status and geography. AB - PURPOSE: Smoking has declined in Canada in recent years. However, it is not clear whether differences in current smoking by socioeconomic status have increased, decreased, or remained unchanged in Canada. METHODS: We examined rates of current smoking by sex, education, and province from 1950 to 2011. Differences in current smoking, initiation, and cessation were summarized using relative and absolute measures. RESULTS: Between 1950 and 2011, the prevalence of current smoking (including daily and non-daily) among adults aged 20 years and older decreased steadily in men from 68.9 % (95 % CI 63.9-73.3) to 18.6 % (14.9-22.1) but in women increased slightly from 38.2 % (32.3-42.2) in 1950 to 39.1 % (36.4-41.2) in 1959 before declining to 15.4 % (11.9-18.9) in 2011. Among men, there was an inverse association between educational attainment and smoking which was consistent from 1950 to 2011. A similar gradient emerged in the mid-1960s in women. Absolute differences in rates of smoking across levels of education increased despite overall declines in smoking across all levels of education. Rates of smoking in women and men were higher in the Atlantic Provinces and Quebec, although in men these differences have declined since the 1990s. In a subset of data from 1999 to 2011, those with lower levels of education had higher levels of smoking initiation and lower levels of cessation. CONCLUSIONS: Smoking rates have fallen over time but socioeconomic differences have increased. Smoking prevalence peaked later in lower socioeconomic status (SES) groups, and rates of decline in lower SES groups and certain provinces have been less steep. This suggests that SES gradients emerge rapidly in later stages of the tobacco epidemic and may have increased through greater efficacy of tobacco control policies in reducing smoking among those of higher SES compared to those of lower SES. Tailored approaches may be required to reduce smoking rates in those of lower SES and narrow SES differences. PMID- 24158779 TI - A case-control study of lifetime light intensity physical activity and breast cancer risk. AB - PURPOSE: Physical activity reduces breast cancer risk, although most evidence is for activity in the moderate-to-vigorous intensity range. The effect of light intensity physical activity (LIPA) is unknown. We aimed to determine the association between self-reported lifetime LIPA and pre- and post-menopausal breast cancer risk. Our secondary objective was to analyze risk stratified by estrogen and progesterone tumor receptor status. METHODS: Data were from a case control study of 1,110 incident breast cancer cases (388 pre-menopausal; 722 post menopausal) and 1,172 controls (442 pre-menopausal; 730 post-menopausal) recruited at two Canadian sites. Lifetime leisure-time, household, and occupational physical activity and covariates were assessed by questionnaire. Mean minutes per day of LIPA for each of the age periods 12-17, 18-34, 35-49, >=50, and the total lifetime were calculated. Odds ratios were calculated using unconditional logistic regression for overall breast cancer risk and using polytomous logistic regression for estrogen receptor (ER)/progesterone receptor (PR)-defined tumor subtypes and were adjusted for moderate-to-vigorous physical activity and other confounders. RESULTS: LIPA was not associated with breast cancer risk at any age period across the life course: odds ratio (OR) = 0.81; 95 % CI 0.53-1.24 for pre-menopausal women and OR = 0.87; 95 % CI 0.64-1.19 for post menopausal women in the highest vs. lowest categories of total lifetime LIPA. No heterogeneity in risk by ER/PR tumor status was observed. CONCLUSIONS: Our results suggest that light intensity physical activity is not associated with breast cancer risk reduction. This finding is important for physical activity recommendations for breast cancer prevention. PMID- 24158780 TI - Lifestyle factors and health-related quality of life in colorectal cancer survivors. AB - PURPOSE: This study investigates the association between a postdiagnosis lifestyle score and health-related quality of life (HrQol) in long-term colorectal cancer (CRC) survivors. METHODS: A cross-sectional study of 1,389 long term CRC survivors in Northern Germany was analyzed. On average 7.2 years after CRC diagnosis, HrQol was assessed with the EORTC QLQ-C30, and lifestyle factors, including weight, height, diet, physical activity, and smoking were obtained using self-administered questionnaires. A lifestyle score (BMI <30 kg/m2, healthy diet, recreationally active, and not smoking) was applied. Participants were categorized in adhering to at most one, two, three, or all recommended lifestyle factors, categorizing unfavorable behaviors with 0 and favorable with 1 point. Multivariable logistic regression models were used to investigate the association between the lifestyle score and HrQol as a binary variable. RESULTS: Approximately 10 % had at most one, 30 % two, 38 % three, and 23 % all favorable factors. Compared to participants with one or zero factors, the odds ratio (OR) for a low global HrQol (gHrQol) decreased with stronger adherence to the score. The OR (95% CI) for a low gHrQol was 0.50 (0.33-0.76) for participants with all favorable lifestyle factors compared to participants with one or zero. Clinical and socio-demographic factors had little impact on these associations, with exception of living arrangement which showed a statistically significant interaction. Associations were stronger for functioning domains, representing mobility rather than mental health. CONCLUSIONS: Favorable lifestyle behaviors might be associated with HrQol in CRC long-term survivors. More research in prospective studies is needed. PMID- 24158777 TI - Glycogen synthase kinase 3 beta (GSK3beta) at the tip of neuronal development and regeneration. AB - Gaining a basic understanding of the inhibitory molecules and the intracellular signaling involved in axon development and repulsion after neural lesions is of clear biomedical interest. In recent years, numerous studies have described new molecules and intracellular mechanisms that impair axonal outgrowth after injury. In this scenario, the role of glycogen synthase kinase 3 beta (GSK3beta) in the axonal responses that occur after central nervous system (CNS) lesions began to be elucidated. GSK3beta function in the nervous tissue is associated with neural development, neuron polarization, and, more recently, neurodegeneration. In fact, GSK3beta has been considered as a putative therapeutic target for promoting functional recovery in injured or degenerative CNS. In this review, we summarize current understanding of the role of GSK3beta during neuronal development and regeneration. In particular, we discuss GSK3beta activity levels and their possible impact on cytoskeleton dynamics during both processes. PMID- 24158781 TI - CXCR4 pathway associated with family history of melanoma. AB - PURPOSE: Genetic predisposition plays a major role in the etiology of melanoma, but known genetic markers only account for a limited fraction of family-history associated melanoma cases. Expression microarrays have offered the opportunity to identify further genomic profiles correlated with family history of melanoma. We aimed to distinguish mRNA expression signatures between melanoma cases with and without a family history of melanoma. METHODS: Based on the Nurses' Health Study, family history was defined as having one or more first-degree family members diagnosed with melanoma. Melanoma diagnosis was confirmed by reviewing pathology reports, and tumor blocks were collected by mail from across the USA. Genomic interrogation was accomplished through evaluating expression profiling of formalin-fixed paraffin-embedded tissues from 78 primary cutaneous invasive melanoma cases, on either a 6K or whole-genome (24K) Illumina gene chip. Gene set enrichment analysis was performed for each batch to determine the differentially enriched pathways and key contributing genes. RESULTS: The CXC chemokine receptor 4 (CXCR4) pathway was consistently up-regulated within cases of familial melanoma in both platforms. Leading edge analysis showed four genes from the CXCR4 pathway, including MAPK1, PLCG1, CRK, and PTK2, were among the core members that contributed to the enrichment of this pathway. There was no association between the enrichment of CXCR4 pathway and NRAS, BRAF mutation, or Breslow thickness of the primary melanoma cases. CONCLUSIONS: We found that the CXCR4 pathway might constitute a novel susceptibility pathway associated with family history of melanoma in first-degree relatives. PMID- 24158782 TI - Efficacy, usability and tolerability of a dynamic elbow orthosis after collateral ligament reconstruction: a prospective randomized study. AB - PURPOSE: To assess the efficacy, usability and tolerability of a dynamic orthosis compared with a standard plaster splint after the reconstruction of elbow medial or lateral collateral ligaments (MCL, LCL). METHODS: Twenty-six subjects undergoing MCL (n = 23) or LCL (n = 3) reconstruction were randomly assigned to immobilization with an orthosis (n = 13; group A "Innovator X") or with a plaster splint (n = 13; group B "Plaster splint"). Outcome measures were visual analogue scale pain score, mid-arm (MA) circumference, grip strength, Oxford elbow score (OES) and range of motion (ROM). Patients were assessed at baseline and at 2, 6, 12 and 24 weeks. RESULTS: Significant pain reduction was reported by all patients at 6, 12 and 24 weeks (p < 0.05). Mean MA circumference was significantly higher in group A at all time points (all p < 0.05). Mean grip strength was greater in group A on weeks 2 and 6 (p < 0.05), whereas the difference found on weeks 12 and 24 was not significant. The OES and passive ROM values of the two groups were not significantly different at any time point. CONCLUSIONS: The dynamic orthosis and the plaster splint both provided effective and safe elbow immobilization after MCL or LCL reconstruction. The orthosis provided greater pain reduction, faster recovery of muscle trophism and grip strength, and was better tolerated. PMID- 24158783 TI - Prevalence and location of bone bruises associated with anterior cruciate ligament injury and implications for mechanism of injury: a systematic review. AB - BACKGROUND: Bone bruising is commonly observed on magnetic resonance imaging (MRI) after non-contact anterior cruciate ligament (ACL) injury. OBJECTIVES: The primary objective of this study was to determine if the location and prevalence of tibial and femoral bone bruises after ACL injury can be explained by specific injury mechanism(s). The secondary objective was to determine whether the bone bruise literature supports sex-specific injury mechanism(s). We hypothesized that most studies would report bone bruising in the lateral femoral condyle (LFC) and on the posterior lateral tibial plateau (LTP). METHODS: MEDLINE, PubMed, and SCOPUS were searched for studies that reported bone bruise prevalence and location in ACL-injured subjects. Sex differences in bone-bruise patterns were assessed. Time from injury to imaging was assessed to account for confounding effects on bone-bruise size and location. RESULTS: Thirty-eight studies met the inclusion/exclusion criteria. Anterior-posterior location of bone bruises within the tibiofemoral compartment was assessed in 11 studies. Only five of these studies reported bone-bruise locations on both the tibia and the femur. The most common bone-bruise combination in all five studies was on the LFC and the posterior LTP. Sex differences were only assessed in three studies, and only one reported significantly greater prevalence of LTP bruising in females. CONCLUSION: Bone-bruise patterns in the current literature support a valgus-driven ACL injury mechanism; however, more studies should report the specific locations of tibial and femoral bone bruises. There is insufficient evidence in the literature to determine whether there are sex-specific bone-bruise patterns in ACL-injured subjects. PMID- 24158784 TI - Home health care nurse perceptions of geriatric depression and disability care management. AB - PURPOSE OF THE STUDY: Psychosocial interventions alone or combined with antidepressant medication can effectively treat mild to moderate geriatric depression. However, most home health care patients with depression and disability do not receive these interventions. Moreover, relatively little is known about home health care nurse views about depression management. Therefore, our research purpose was to provide a deeper understanding about how home health care nurses perceive and experience depression detection and evaluation within the context of caring for geriatric patients with disabilities. DESIGN AND METHODS: This qualitative descriptive study involved 2 focus groups and 16 semistructured interviews with nurses providing care to geriatric home health care patients followed by observation during 25 nurse home visits to geriatric patients who had depression and disability. FINDINGS: Nurses demonstrated confidence in caring for elderly patients with disabilities. However, they expressed different views about the nature of depression and the integration of depression and disability care in daily practice. Evidence points to a need for advanced training that supports an enhanced role for generalist homecare nurses in providing depression care management for this vulnerable geriatric population. IMPLICATIONS: Policy challenges are associated with ways in which home health care is fiscally organized primarily to address patients' physical and acute skilled care needs and not depression. PMID- 24158785 TI - Anti-cytokine autoantibodies preceding onset of autoimmune polyendocrine syndrome type I features in early childhood. AB - PURPOSE: Almost all patients with autoimmune polyendocrine syndrome (APS)-I have high titer neutralizing autoantibodies to type I interferons (IFN), especially IFN-omega and IFN-alpha2, whatever their clinical features and onset-ages. About 90 % also have antibodies to interleukin (IL)-17A, IL-17F and/or IL-22; they correlate with the chronic mucocutaneous candidiasis (CMC) that affects ~90 % of patients. Our aim was to explore how early the manifestations and endocrine and cytokine autoantibodies appear in young APS-I patients. That may hold clues to very early events in the autoimmunization process in these patients. METHODS: Clinical investigations and autoantibody measurements in 13 APS-I patients sampled before age 7 years, and 3 pre-symptomatic siblings with AIRE-mutations in both alleles. RESULTS: Antibody titers were already high against IFN-alpha2 and IFN-omega at age 6 months in one sibling-8 months before onset of APS-I-and also against IL-22 at 7 months in another (still unaffected at age 5 years). In 12 of the 13 APS-I patients, antibody levels were high against IFN-omega and/or IL-22 when first tested, but only modestly positive against IFN-omega in one patient who had only hypo-parathyroidism. Endocrine organ-specific antibodies were present at age 6 months in one sibling, and as early as 36 and 48 months in two of the six informative subjects. CONCLUSION: This is the first study to collate the onset of clinical features, cytokine and endocrine autoantibodies in APS-I infants and siblings. The highly restricted early autoantibody responses and clinical features they show are not easily explained by mere loss of broad specific self-tolerance inducing mechanisms, but hint at some more sharply focused early event(s) in autoimmunization. PMID- 24158786 TI - Significantly enhanced photoresponse in carbon nanotube film/TiO2 nanotube array heterojunctions by pre-electroforming. AB - Traditional TiO2 based photodetectors (PDs) suffer from high dark resistance, which increases loss of photoexcited charge carriers. Here, we report a new and simple way to improve the performance of PDs based on double-walled carbon nanotube (DWCNT)/TiO2 nanotube heterojunctions. Highly ordered TiO2 nanotube arrays were fabricated using a two-step anodic oxidation method, and coated with a DWCNT film, which functioned as a semitransparent electrode and a photoactive layer. Via pre-electroforming, the device was switched from a high resistance state (HRS) to a low resistance state (LRS). At an applied bias of 1 V, the dark resistance was reduced from 926 to 0.67 kOmega, as a result of the formation of oxygen vacancy related conducting filaments. The photoresponse (DeltaI = Ip - Id, where Ip and Id represents photocurrent and dark current, respectively) of the PD in LRS reached 816.76 MUA W(-1) under 532 nm laser illumination and 802.89 MUA W( 1) under 1064 nm laser irradiation, which is 965 and 3980 times higher, respectively, than those obtained from the HRS device under the same conditions. This strategy for enhancing the photoresponse of TiO2 based PDs may have applications in further improving the power conversion efficiency of dye sensitized solar cells. PMID- 24158788 TI - Progressive resistance strength training and the related injuries in older adults: the susceptibility of the shoulder. AB - The benefits of progressive resistance training (PRT) among the older adults are evident, especially in the prevention of sarcopenia and improving muscle strength, which reverse the age-related loss of functional ability. However, PRT carries some risk, particularly when participants are older adults with a certain degree of muscle weakness. The purpose of this article is to discuss the PRT related injuries, and present an overview of documented shoulder injuries among the elderly, discerning possible mechanisms of injury and risk factors. A literature search was conducted in the PUBMED database to identify the relevant literature using combinations of keywords: strength-training injuries, resistance training injuries, sports injuries in the elderly, shoulder complex, shoulder injury, and shoulder disorder. Acute and chronic injuries attributed to PRT have been cited in the epidemiological literature. The shoulder complex, has been alluded to as one of the most prevalent regions of injury, particularly in exercises that place the arm extended above the head and posterior to the trunk. However, the risk for injuries appears to be higher for testing than for training itself. One-repetition maximum strength testing may result in a greater injury risk. This technique, though acceptable, needs additional precautions in inexperience older adults to prevent injury. Thus, the best treatment for PRT age related injuries is prevention. Appropriate and individualized training programs, the use of safe equipment, careful warming up and cooling down, correct range of motion, progressive intensity training, cardiovascular and musculoskeletal fitness are essential aspects of injury prevention among the elderly. PMID- 24158787 TI - Everolimus plus exemestane in postmenopausal patients with HR(+) breast cancer: BOLERO-2 final progression-free survival analysis. AB - INTRODUCTION: Effective treatments for hormone-receptor-positive (HR(+)) breast cancer (BC) following relapse/progression on nonsteroidal aromatase inhibitor (NSAI) therapy are needed. Initial Breast Cancer Trials of OraL EveROlimus-2 (BOLERO-2) trial data demonstrated that everolimus and exemestane significantly prolonged progression-free survival (PFS) versus placebo plus exemestane alone in this patient population. METHODS: BOLERO-2 is a phase 3, double-blind, randomized, international trial comparing everolimus (10 mg/day) plus exemestane (25 mg/day) versus placebo plus exemestane in postmenopausal women with HR(+) advanced BC with recurrence/progression during or after NSAIs. The primary endpoint was PFS by local investigator review, and was confirmed by independent central radiology review. Overall survival, response rate, and clinical benefit rate were secondary endpoints. RESULTS: Final study results with median 18-month follow-up show that median PFS remained significantly longer with everolimus plus exemestane versus placebo plus exemestane [investigator review: 7.8 versus 3.2 months, respectively; hazard ratio = 0.45 (95% confidence interval 0.38-0.54); log-rank P < 0.0001; central review: 11.0 versus 4.1 months, respectively; hazard ratio = 0.38 (95% confidence interval 0.31-0.48); log-rank P < 0.0001] in the overall population and in all prospectively defined subgroups, including patients with visceral metastases, [corrected] and irrespective of age. The incidence and severity of adverse events were consistent with those reported at the interim analysis and in other everolimus trials. CONCLUSION: The addition of everolimus to exemestane markedly prolonged PFS in patients with HR(+) advanced BC with disease recurrence/progression following prior NSAIs. These results further support the use of everolimus plus exemestane in this patient population. ClinicalTrials.gov #NCT00863655. PMID- 24158789 TI - The complexities of resynchronizing scar. PMID- 24158790 TI - Bootstrap methods for estimating PET image noise: experimental validation and an application to evaluation of image reconstruction algorithms. AB - OBJECTIVE: Accurate and validated methods for estimating regional PET image noise are helpful for optimizing image processing. The bootstrap is a data-based simulation method for statistical inference, which can be used to estimate the PET image noise without repeated measurements. The aim of this study was to experimentally validate bootstrap-based methods as a tool for estimating PET image noise and demonstrate its usefulness for evaluating image reconstruction algorithms. METHODS: Two bootstrap-based method, the list-mode data bootstrap (LMBS) and the sinogram bootstrap (SNBS), were implemented on a clinical PET scanner. A uniform cylindrical phantom filled with (18)F solution was scanned using list-mode acquisition. A reference standard deviation (SD) map was calculated from 60 statistically independent measured list-mode data. Using one of the 60 list-mode data, 60 bootstrap replicates were generated and used to calculate bootstrap SD maps. Brain (18)F-FDG data from a healthy volunteer were also processed as an example of the bootstrap application. Three reconstruction algorithms, FBP 2D and both 2D and 3D versions of dynamic row-action maximum likelihood algorithm (DRAMA), were assessed. RESULTS: For all the reconstruction algorithms used, the bootstrap SD maps agreed well with the reference SD map, confirming the validity of the bootstrap methods for assessing image noise. The two bootstrap methods were equivalent with respect to the performance of image noise estimation. The bootstrap analysis of the FDG data showed the better contrast-noise relation curve for DRAMA 3D compared to DRAMA 2D and FBP 2D. CONCLUSIONS: The bootstrap methods provide the estimates of image noise for various reconstruction algorithms with reasonable accuracy, require only a single measurement, not repeated measures, and are, therefore, applicable for a human PET study. PMID- 24158791 TI - miR-139-5p is a regulator of metastatic pathways in breast cancer. AB - Metastasis is a complex, multistep process involved in the progression of cancer from a localized primary tissue to distant sites, often characteristic of the more aggressive forms of this disease. Despite being studied in great detail in recent years, the mechanisms that govern this process remain poorly understood. In this study, we identify a novel role for miR-139-5p in the inhibition of breast cancer progression. We highlight its clinical relevance by reviewing miR 139-5p expression across a wide variety of breast cancer subtypes using in-house generated and online data sets to show that it is most frequently lost in invasive tumors. A biotin pull-down approach was then used to identify the mRNA targets of miR-139-5p in the breast cancer cell line MCF7. Functional enrichment analysis of the pulled-down targets showed significant enrichment of genes in pathways previously implicated in breast cancer metastasis (P < 0.05). Further bioinformatic analysis revealed a predicted disruption to the TGFbeta, Wnt, Rho, and MAPK/PI3K signaling cascades, implying a potential role for miR-139-5p in regulating the ability of cells to invade and migrate. To corroborate this finding, using the MDA-MB-231 breast cancer cell line, we show that overexpression of miR-139-5p results in suppression of these cellular phenotypes. Furthermore, we validate the interaction between miR-139-5p and predicted targets involved in these pathways. Collectively, these results suggest a significant functional role for miR-139-5p in breast cancer cell motility and invasion and its potential to be used as a prognostic marker for the aggressive forms of breast cancer. PMID- 24158792 TI - Kinetic mechanism of nick sealing by T4 RNA ligase 2 and effects of 3'-OH base mispairs and damaged base lesions. AB - T4 RNA ligase 2 (Rnl2) repairs 3'-OH/5'-PO4 nicks in duplex nucleic acids in which the broken 3'-OH strand is RNA. Ligation entails three chemical steps: reaction of Rnl2 with ATP to form a covalent Rnl2-(lysyl-Nzeta)-AMP intermediate (step 1); transfer of AMP to the 5'-PO4 of the nick to form an activated AppN- intermediate (step 2); and attack by the nick 3'-OH on the AppN- strand to form a 3'-5' phosphodiester (step 3). Here we used rapid mix-quench methods to analyze the kinetic mechanism and fidelity of single-turnover nick sealing by Rnl2-AMP. For substrates with correctly base-paired 3'-OH nick termini, kstep2 was fast (9.5 to 17.9 sec(-1)) and similar in magnitude to kstep3 (7.9 to 32 sec(-1)). Rnl2 fidelity was enforced mainly at the level of step 2 catalysis, whereby 3'-OH base mispairs and oxoguanine, oxoadenine, or abasic lesions opposite the nick 3' OH elicited severe decrements in the rate of 5'-adenylylation and relatively modest slowing of the rate of phosphodiester synthesis. The exception was the noncanonical A:oxoG base pair, which Rnl2 accepted as a correctly paired end for rapid sealing. These results underscore (1) how Rnl2 requires proper positioning of the 3'-terminal ribonucleoside at the nick for optimal 5'-adenylylation and (2) the potential for nick-sealing ligases to embed mutations during the repair of oxidative damage. PMID- 24158793 TI - Structural and thermodynamic signatures that define pseudotriloop RNA hairpins. AB - Pseudotriloop (PTL) structures in RNAs have been recognized as essential elements in RNA folding and recognition of proteins. PTL structures are derived from hexaloops by formation of a cross-loop base pair leaving a triloop and 3' bulged out residue. Despite their common presence and functional importance, insufficient structural and thermodynamic data are available that can be used to predict formation of PTLs from sequence alone. Using NMR spectroscopy and UV melting data we established factors that contribute to the formation and stability of PTL structures derived from hepatitis B virus and human foamy virus. The NMR data show that, besides the cross-loop base pair, also a 3' pyrimidine bulge and a G-C loop-closing base pair are primary determinants of PTL formation. By changing the G-C closing base pair into C-G, the PTL switches into a hexaloop. Comparison of these rules with regular triloop hairpins and PTLs from other sources is discussed as well as the conservation of a PTL in human foamy virus and other spumaretroviruses. PMID- 24158794 TI - A good reason to measure 24-hour urine creatinine excretion, but not to assess kidney function. PMID- 24158795 TI - Financial incentives for living kidney donation: ethics and evidence. PMID- 24158796 TI - Urine creatinine excretion and clinical outcomes in CKD. AB - BACKGROUND AND OBJECTIVES: Twenty-four-hour urine creatinine excretion is a reliable approximation of muscle mass. Whether changes in urine creatinine predict clinical outcomes in persons with CKD is unknown. This work studied the relationship between urine creatinine and patient and renal survival in people with CKD not requiring renal replacement therapy. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: This longitudinal cohort study included incident stages 3-5 CKD patients referred to the renal clinic at the University Federico II in Naples between January of 1995 and December of 2005. Clinical data and urine creatinine were updated at each visit. Main outcomes were all-cause mortality and kidney failure requiring dialysis. RESULTS: This study enrolled 525 individuals and followed them for a median of 6 years (range of 4 months to 15 years). Urine creatinine excretion declined by 16 mg/d per year (95% confidence interval, 14 to 19) in participants with CKD stages 3a, 3b, and 4, and it remained stable in participants with stage 5 CKD. Per each 20 mg/d decline in urine creatinine, mortality increased by 3% (adjusted hazard ratio, 1.03; 95% confidence interval, 1.01 to 1.05), and the risk of initiating dialysis increased by 2% (adjusted hazard ratio, 1.02; 95% confidence interval, 1.01 to 1.03). These associations were independent of body mass index and GFR. CONCLUSIONS: In persons with CKD stages 3 and 4, urine creatinine declines at a rate of 16 mg/d per year. Lower urine creatinine excretion predicts greater risk of kidney failure and patient mortality. PMID- 24158798 TI - The GPCR crystallography boom: providing an invaluable source of structural information and expanding the scope of homology modeling. AB - G protein-coupled receptors (GPCRs) are integral membrane proteins of high pharmaceutical interest. Until relatively recently, their structures have been particularly elusive, and rhodopsin has been for many years the only member of the superfamily with experimentally elucidated structures. However, a number of recent technical and scientific advancements made the determination of GPCR structures more feasible, thus leading to the solution of the structures of several receptors. Besides providing direct structural information, these experimental GPCR structures also provide templates for the construction of GPCR models. In depth studies have been performed to probe the accuracy of these models, in particular with respect to the interactions with their ligands, and to assess their applicability the rational discovery of GPCR modulators. Given the current state of the art and the pace of the field, the future of GPCR structural studies is likely to be characterized by a landscape populated by an increasingly higher number of experimental and theoretical structures. PMID- 24158797 TI - The cost-effectiveness of using payment to increase living donor kidneys for transplantation. AB - BACKGROUND AND OBJECTIVES: For eligible candidates, transplantation is considered the optimal treatment compared with dialysis for patients with ESRD. The growing number of patients with ESRD requires new strategies to increase the pool of potential donors. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Using decision analysis modeling, this study compared a strategy of paying living kidney donors to waitlisted recipients on dialysis with the current organ donation system. In the base case estimate, this study assumed that the number of donors would increase by 5% with a payment of $10,000. Quality of life estimates, resource use, and costs (2010 Canadian dollars) were based on the best available published data. RESULTS: Compared with the current organ donation system, a strategy of increasing the number of kidneys for transplantation by 5% by paying living donors $10,000 has an incremental cost-savings of $340 and a gain of 0.11 quality adjusted life years. Increasing the number of kidneys for transplantation by 10% and 20% would translate into incremental cost-savings of $1640 and $4030 and incremental quality-adjusted life years gain of 0.21 and 0.39, respectively. CONCLUSION: Although the impact is uncertain, this model suggests that a strategy of paying living donors to increase the number of kidneys available for transplantation could be cost-effective, even with a transplant rate increase of only 5%. Future work needs to examine the feasibility, legal policy, ethics, and public perception of a strategy to pay living donors. PMID- 24158799 TI - Modeling of G protein-coupled receptors using crystal structures: from monomers to signaling complexes. AB - G protein-coupled receptors constitute a large and functionally diverse family of transmembrane proteins. They are fundamental in the transfer of extracellular stimuli to intracellular signaling pathways and are among the most targeted proteins in drug discovery. Recent advances in crystallization methods have permitted to resolve the molecular structure of several members of the family. This chapter focuses on the impact of these structures in the use of homology modeling techniques for building three-dimensional models of homologous G protein coupled receptors, higher order oligomers, and their complexes with ligands and signaling proteins. PMID- 24158800 TI - Structure and dynamics of G-protein coupled receptors. AB - G-protein coupled receptors (GPCRs) are seven helical transmembrane proteins that mediate cell-to-cell communication. They also form the largest superfamily of drug targets. Hence detailed studies of the three dimensional structure and dynamics are critical to understanding the functional role of GPCRs in signal transduction pathways, and for drug design. In this chapter we compare the features of the crystal structures of various biogenic amine receptors, such as beta1 and beta2 adrenergic receptors, dopamine D3 receptor, M2 and M3 muscarinic acetylcholine receptors. This analysis revealed that conserved residues are located facing the inside of the transmembrane domain in these GPCRs improving the efficiency of packing of these structures. The NMR structure of the chemokine receptor CXCR1 without any ligand bound, shows significant dynamics of the transmembrane domain, especially the helical kink angle on the transmembrane helix6. The activation mechanism of the beta2-adrenergic receptor has been studied using multiscale computational methods. The results of these studies showed that the receptor without any ligand bound, samples conformations that resemble some of the structural characteristics of the active state of the receptor. Ligand binding stabilizes some of the conformations already sampled by the apo receptor. This was later observed in the NMR study of the dynamics of human beta2-adrenergic receptor. The dynamic nature of GPCRs leads to a challenge in obtaining purified receptors for biophysical studies. Deriving thermostable mutants of GPCRs has been a successful strategy to reduce the conformational heterogeneity and stabilize the receptors. This has lead to several crystal structures of GPCRs. However, the cause of how these mutations lead to thermostability is not clear. Computational studies are beginning to shed some insight into the possible structural basis for the thermostability. Molecular Dynamics simulations studying the conformational ensemble of thermostable mutants have shown that the stability could arise from both enthalpic and entropic factors. There are regions of high stress in the wild type GPCR that gets relieved upon mutation conferring thermostability. PMID- 24158801 TI - How the dynamic properties and functional mechanisms of GPCRs are modulated by their coupling to the membrane environment. AB - Experimental observations of the dependence of function and organization of G protein-coupled receptors (GPCRs) on their lipid environment have stimulated new quantitative studies of the coupling between the proteins and the membrane. It is important to develop such a quantitative understanding at the molecular level because the effects of the coupling are seen to be physiologically and clinically significant. Here we review findings that offer insight into how membrane-GPCR coupling is connected to the structural characteristics of the GPCR, from sequence to 3D structural detail, and how this coupling is involved in the actions of ligands on the receptor. The application of a recently developed computational approach designed for quantitative evaluation of membrane remodeling and the energetics of membrane-protein interactions brings to light the importance of the radial asymmetry of the membrane-facing surface of GPCRs in their interaction with the surrounding membrane. As the radial asymmetry creates adjacencies of hydrophobic and polar residues at specific sites of the GPCR, the ability of membrane remodeling to achieve complete hydrophobic matching is limited, and the residual mismatch carries a significant energy cost. The adjacencies are shown to be affected by ligand-induced conformational changes. Thus, functionally important organization of GPCRs in the cell membrane can depend both on ligand-determined properties and on the lipid composition of various membrane regions with different remodeling capacities. That this functionally important reorganization can be driven by oligomerization patterns that reduce the energy cost of the residual mismatch, suggests a new perspective on GPCR dimerization and ligand-GPCR interactions. The relation between the modulatory effects on GPCRs from the binding of specific cell-membrane components, e.g., cholesterol, and those produced by the non-local energetics of hydrophobic mismatch are discussed in this context. PMID- 24158804 TI - From three-dimensional GPCR structure to rational ligand discovery. AB - This chapter will focus on G protein-coupled receptor structure-based virtual screening and ligand design. A generic virtual screening workflow and its individual elements will be introduced, covering amongst others the use of experimental data to steer the virtual screening process, ligand binding mode prediction, virtual screening for novel ligands, and rational structure-based virtual screening hit optimization. An overview of recent successful structure based ligand discovery and design studies shows that receptor models, despite structural inaccuracies, can be efficiently used to find novel ligands for GPCRs. Moreover, the recently solved GPCR crystal structures have further increased the opportunities in structure-based ligand discovery for this pharmaceutically important protein family. The current chapter will discuss several challenges in rational ligand discovery based on GPCR structures including: (i) structure-based identification of ligands with specific effects on GPCR mediated signaling pathways, and (ii) virtual screening and structure-based optimization of fragment like molecules. PMID- 24158802 TI - Coarse-grained molecular dynamics provides insight into the interactions of lipids and cholesterol with rhodopsin. AB - Protein function is a complicated interplay between structure and dynamics, which can be heavily influenced by environmental factors and conditions. This is particularly true in the case of membrane proteins, such as the visual receptor rhodopsin. It has been well documented that lipid headgroups, polyunsaturated tails, and the concentration of cholesterol in membranes all play a role in the function of rhodopsin. Recently, we used all-atom simulations to demonstrate that different lipid species have preferential interactions and possible binding sites on rhodopsin's surface, consistent with experiment. However, the limited timescales of the simulations meant that the statistical uncertainty of these results was substantial. Accordingly, we present here 32 independent 1.6 MUs coarse-grained simulations exploring lipids and cholesterols surrounding rhodopsin and opsin, in lipid bilayers mimicking those found naturally. Our results agree with those found experimentally and in previous simulations, but with far better statistical certainty. The results demonstrate the value of combining all-atom and coarse-grained models with experiment to provide a well rounded view of lipid-protein interactions. PMID- 24158805 TI - Mathematical modeling of G protein-coupled receptor function: what can we learn from empirical and mechanistic models? AB - Empirical and mechanistic models differ in their approaches to the analysis of pharmacological effect. Whereas the parameters of the former are not physical constants those of the latter embody the nature, often complex, of biology. Empirical models are exclusively used for curve fitting, merely to characterize the shape of the E/[A] curves. Mechanistic models, on the contrary, enable the examination of mechanistic hypotheses by parameter simulation. Regretfully, the many parameters that mechanistic models may include can represent a great difficulty for curve fitting, representing, thus, a challenge for computational method development. In the present study some empirical and mechanistic models are shown and the connections, which may appear in a number of cases between them, are analyzed from the curves they yield. It may be concluded that systematic and careful curve shape analysis can be extremely useful for the understanding of receptor function, ligand classification and drug discovery, thus providing a common language for the communication between pharmacologists and medicinal chemists. PMID- 24158806 TI - GPCR & company: databases and servers for GPCRs and interacting partners. AB - G-protein-coupled receptors (GPCRs) are a large superfamily of membrane receptors that are involved in a wide range of signaling pathways. To fulfill their tasks, GPCRs interact with a variety of partners, including small molecules, lipids and proteins. They are accompanied by different proteins during all phases of their life cycle. Therefore, GPCR interactions with their partners are of great interest in basic cell-signaling research and in drug discovery.Due to the rapid development of computers and internet communication, knowledge and data can be easily shared within the worldwide research community via freely available databases and servers. These provide an abundance of biological, chemical and pharmacological information.This chapter describes the available web resources for investigating GPCR interactions. We review about 40 freely available databases and servers, and provide a few sentences about the essence and the data they supply. For simplification, the databases and servers were grouped under the following topics: general GPCR-ligand interactions; particular families of GPCRs and their ligands; GPCR oligomerization; GPCR interactions with intracellular partners; and structural information on GPCRs. In conclusion, a multitude of useful tools are currently available. Summary tables are provided to ease navigation between the numerous and partially overlapping resources. Suggestions for future enhancements of the online tools include the addition of links from general to specialized databases and enabling usage of user-supplied template for GPCR structural modeling. PMID- 24158803 TI - Beyond standard molecular dynamics: investigating the molecular mechanisms of G protein-coupled receptors with enhanced molecular dynamics methods. AB - The majority of biological processes mediated by G Protein-Coupled Receptors (GPCRs) take place on timescales that are not conveniently accessible to standard molecular dynamics (MD) approaches, notwithstanding the current availability of specialized parallel computer architectures, and efficient simulation algorithms. Enhanced MD-based methods have started to assume an important role in the study of the rugged energy landscape of GPCRs by providing mechanistic details of complex receptor processes such as ligand recognition, activation, and oligomerization. We provide here an overview of these methods in their most recent application to the field. PMID- 24158807 TI - Bioinformatics tools for predicting GPCR gene functions. AB - The automatic classification of GPCRs by bioinformatics methodology can provide functional information for new GPCRs in the whole 'GPCR proteome' and this information is important for the development of novel drugs. Since GPCR proteome is classified hierarchically, general ways for GPCR function prediction are based on hierarchical classification. Various computational tools have been developed to predict GPCR functions; those tools use not simple sequence searches but more powerful methods, such as alignment-free methods, statistical model methods, and machine learning methods used in protein sequence analysis, based on learning datasets. The first stage of hierarchical function prediction involves the discrimination of GPCRs from non-GPCRs and the second stage involves the classification of the predicted GPCR candidates into family, subfamily, and sub subfamily levels. Then, further classification is performed according to their protein-protein interaction type: binding G-protein type, oligomerized partner type, etc. Those methods have achieved predictive accuracies of around 90 %. Finally, I described the future subject of research of the bioinformatics technique about functional prediction of GPCR. PMID- 24158808 TI - Through-knee amputation for a patient with proximal femur focal deficiency and tibial hemimelia: surgical anatomy and clinical implications. AB - Tibial hemimelia is a rare anomaly of unknown etiology. This condition can occur sporadically or may have a familial inheritance. It is characterized by deficiency of the tibia with a relatively intact fibula. The anomaly may be unilateral or bilateral. We report a case of a 2-year-old girl who presented with right lower limb deformity since birth. She was diagnosed with proximal femur focal deficiency with absence of the ipsilateral tibia. She presented with a shorter right lower limb and a deformed foot. She was treated with a through-knee amputation. Anatomical dissection of the amputated limb was carried out to verify the anomalies. The dissection showed that the distal phalanx of the great toe was trifid. The anatomical and clinical significance of this interesting case is discussed. PMID- 24158809 TI - Virion attachment and entry: HIV gp120 Env biotinylation, gp120 Env, or integrin ligand-binding assay. AB - The HIV-1 entry receptors are CD4 and a chemokine receptor (CCR5 or CXCR4). In addition it has recently been demonstrated that HIV-1 gp120 binds to and signals through integrin alpha4beta7, the gut-homing receptor (Arthos et al., Nat Immunol 9(3):301-309, 2008). Integrin alpha4beta7 is not an entry receptor for HIV-1, although it can facilitate virion attachment to target cells (Arthos et al., Nat Immunol 9(3):301-309, 2008; Cicala et al., Proc Natl Acad Sci U S A 106:20877 20882, 2009). Recombinant HIV-1 gp120s bind to integrin alpha4beta7 in a manner similar to its natural ligands (MAdCAM-1, V-CAM-1, fibronectin) (Andrew et al., J Immunol 153:3847-3861, 1994). gp120-alpha4beta7 interactions are detected in a manner similar to assays developed for the natural ligands of alpha4beta7. In this chapter we describe a method for the analysis of integrin-gp120 binding via a cell-based binding assay. In vitro ligand-integrin affinity can be modified by the presence of divalent cations (Mn(2+), Mg(2+), Ca(2+)) (Leitinger et al., Leitinger Biochim Biophys Acta 1498:91-98, 2000). Here we describe a protocol to detect biotinylated recombinant HIV-1 gp120 binding to integrin alpha4beta7 in both primary cells and cell lines expressing the gut-homing receptor. PMID- 24158810 TI - CryoEM analysis of capsid assembly and structural changes upon interactions with a host restriction factor, TRIM5alpha. AB - After virus fusion with a target cell, the viral core is released into the host cell cytoplasm and undergoes a controlled disassembly process, termed uncoating, before or as reverse transcription takes place. The cellular protein TRIM5alpha is a host cell restriction factor that blocks HIV-1 infection in rhesus macaque cells by targeting the viral capsid and inducing premature uncoating. The molecular mechanism of the interaction between capsid and TRIM5alpha remains unclear. Here, we describe an approach that utilizes cryo-electron microscopy (cryoEM) to examine the structural changes exerted on HIV-1 capsid (CA) assembly by TRIM5alpha binding. The TRIM5alpha interaction sites on CA assembly were further dissected by combining cryoEM with pair-wise cysteine mutations that crosslink CA either within a CA hexamer or between CA hexamers. Based on the structural information from cryoEM and crosslinking results from in vitro CA assemblies and purified intact HIV-1 cores, we demonstrate that direct binding of TRIM5alpha CC-SPRY domains to the viral capsid results in disruption and fragmentation of the surface lattice of HIV-1 capsid, specifically at inter hexamer interfaces. The method described here can be easily adopted to study other important interactions in multi-protein complexes. PMID- 24158811 TI - The fate of HIV-1 capsid: a biochemical assay for HIV-1 uncoating. AB - The uncoating process of HIV-1 is a poorly understood process, so the development of a reliable assay to study uncoating is critical for moving the field forward. Here we describe an uncoating assay that currently represents the state-of-the art biochemical procedure for monitoring uncoating and core stability during infection. This assay is based on the biochemical separation of soluble capsid protein from particulate capsid cores and provides information about the fate of the capsid during infection. PMID- 24158812 TI - The cyclosporin A washout assay to detect HIV-1 uncoating in infected cells. AB - Uncoating is an early step of HIV-1 replication in which the viral capsid disassembles by p24 capsid (p24(CA)) protein dissociating from the viral complex. Although uncoating is required for HIV-1 replication, many questions remain about the mechanism of this process as well as its impact on other steps in viral replication. Here we describe a recently developed assay to study the process of uncoating in HIV-1-infected cells. The CsA washout assay is a cell-based assay that utilizes the HIV-1 restriction factor TRIM-CypA to detect and inhibit infection of coated viral complexes. Owl monkey kidney (OMK) cells are infected with a GFP reporter virus and TRIM-CypA restriction is switched on at various times postinfection allowing the kinetics of uncoating to be monitored in infected cells. This assay also can be used to examine the effect of different viral or cellular factors on the process of uncoating. PMID- 24158813 TI - Imaging HIV-1 nuclear pre-integration complexes. AB - Advancements in fluorescent microscopy techniques now permit investigation of HIV 1 biology exploiting tools alternative to conventional molecular biology. Here we describe a novel, fluorescence-based method to visualize HIV-1 viral particles within intact nuclei of infected cells. This method allows investigating the localization of pre-integration complexes within the nuclear compartment with respect to the nuclear envelope and the chromatin territories. PMID- 24158814 TI - HIV-1 reverse transcription. AB - Reverse transcription is an obligatory step in retrovirus replication in the course of which the retroviral RNA/DNA-dependent DNA polymerase (RT) copies the single-stranded positive sense RNA genome to synthesize the double-stranded viral DNA. At the same time the RT-associated RNaseH activity degrades the genomic RNA template, which has just been copied. The viral nucleocapsid protein NCp7 is an obligatory partner of RT, chaperoning synthesis of the complete viral DNA flanked by the two long-terminal repeats (LTR), required for viral DNA integration into the host genome and its expression. Here we describe assays for in vitro and ex vivo monitoring of reverse transcription and the chaperoning role of the nucleocapsid protein (NC). PMID- 24158815 TI - RNase H: specificity, mechanisms of action, and antiviral target. AB - The Ribonuclease (RNase) H is one of the four enzymes encoded by all retroviruses, including HIV. Its main activity is the hydrolysis of the RNA moiety in RNA-DNA hybrids. The RNase H ribonuclease is essential in the retroviral life cycle, since it generates and removes primers needed by the Reverse Transcriptase (RT) for initiation of DNA synthesis. Retroviruses lacking RNase H activity are noninfectious. Despite its importance, RNase H is the only enzyme of HIV not yet targeted by antiretroviral therapy. Here, we describe functions and mechanisms of RNase H during the HIV life cycle and describe a cleavage assay, which is suitable to determine RNase H activity in samples of various kinds. In this assay, an artificial, fluorescence-labeled RNA-DNA hybrid is cleaved in vitro by an RT/RNase H enzyme. Cleavage products are analyzed by denaturing polyacrylamide gel electrophoresis (PAGE). This assay may be used to detect the RNase H, assess the effect of inhibitors, or even activators, of the RNase H, as we have described, as candidates for novel antiretroviral agents. PMID- 24158816 TI - HIV-1 chromatin, transcription, and the regulatory protein Tat. AB - Upon integration into the host cell genome, the nucleosomal organization and epigenetic control of the HIV-1 provirus play an active role in its transcriptional regulation. Therefore, characterization of the chromatin changes that occur in the viral promoter region in response to different cellular stimuli or drug treatments represents an important aspect of our understanding of HIV-1 transcription. Moreover, the viral transactivator Tat protein potently activates HIV-1 transcription by recruiting the cellular positive transcription elongation factor p-TEFb to the TAR element located at the 5' end of all nascent viral transcripts, thereby promoting efficient elongation. This chapter describes two complementary techniques for analyzing chromatin structure. The first technique is called indirect end-labeling and uses DNase I, micrococcal nuclease (MNase) or specific restriction enzymes to provide a view of nucleosome positions and of nucleosome-free regions within genes that are usually associated with transcriptional regulatory elements. The second technique, called chromatin immunoprecipitation (ChIP), provides a detailed analysis of chromatin structure by determining the pattern of histone modification marks in the DNA region of interest and by identifying the transcription factors as well as the components of the transcriptional initiation and elongation machineries that are recruited in vivo to this chromosomal region. PMID- 24158817 TI - HIV-1 Rev function and RNA nuclear-cytoplasmic export. AB - The requirement of HIV-1 and HTLV-1 to export incompletely spliced mRNAs has necessitated the evolution of Rev and Rex, respectively, to overcome host cellular mechanism that block nuclear-cytoplasmic export of incompletely processed mRNAs. Evaluating the function of these viral factors can be done at multiple levels: examining the functional consequence of Rev/Rex on viral gene expression, monitoring the movement of these proteins between the nucleus and cytoplasm or the subcellular distribution of the viral mRNAs. Here, I describe procedures to evaluate each of these aspects of Rev/Rex function. PMID- 24158818 TI - HIV-1 accessory proteins: Nef. AB - Nef is a multifunctional protein encoded by all primate lentiviruses that modulates cell surface expression of a variety of cellular receptors and increases the infectivity of progeny virons. Here, we describe the use of bicistronic HIV-1 constructs that coexpress Nef and fluorescent proteins via an internal ribosome entry site to quantify Nef-mediated receptor modulation in virally infected cells. We also report how such proviral constructs and indicator cell lines can be used to quantify the effect of Nef on virion infectivity. PMID- 24158819 TI - HIV-1 accessory proteins: VpR. AB - HIV-1 viral protein R (VpR) is a multifunctional protein that plays specific roles at multiple stages of the HIV-1 viral life cycle and affects anti-HIV functions of the immune cells. VpR is required for efficient viral replication in nondividing cells such as macrophages, and it promotes, to some extent, viral replication in the proliferating target CD4+ T cells. A number of specific activities that may contribute to these effects of VpR have been proposed. In this chapter, we describe two best characterized activities of VpR, nuclear import of the HIV-1 preintegration complex (PIC) and induction of cell cycle G2 arrest, focusing on the methods used for their demonstration. PMID- 24158820 TI - HIV-1 accessory proteins: Vpu and Vif. AB - HIV-1 Vif and Vpu are accessory factors involved in late stages of viral replication. Vif regulates viral infectivity by preventing virion incorporation of APOBEC3G and other members of the family of cytidine deaminases, while Vpu causes degradation of CD4 and promotes virus release by functionally inactivating the host factor BST-2. This chapter described techniques used for the characterization of Vif and Vpu and their functional interaction with host factors. Many of the techniques are, however, applicable to the functional analysis of other viral proteins. PMID- 24158821 TI - SIVSM/HIV-2 Vpx proteins: function and uses in the infection of primary myeloid cells. AB - Vpx is coded almost exclusively by members of the SIVSM/HIV-2 lineage of primate lentiviruses, it is incorporated into virion particles and is thus present during the early phases of infection of target cells. While Vpx exerts no detectable function during the infection of most cell types, it potently counteracts a cellular restriction that targets incoming lentiviruses specifically in myeloid cells. As a consequence of this function, Vpx improves the efficiency of lentiviral infection of dendritic cells (DCs), macrophages, and monocytes. Here, we describe how the positive function exerted by Vpx during the early phases of infection of myeloid cells can be used to augment the efficiency of lentiviral vector-mediated gene transfer in these cells. PMID- 24158822 TI - Imaging of HIV assembly and release. AB - Assembly, release and maturation of HIV-1 particles comprise a highly dynamic sequence of events, characterized by a series of dramatic rearrangements of the viral structural proteins and overall virion architecture. HIV-1 morphogenesis is a relatively rapid and asynchronous process, showing high variability between cells and individual virions. Therefore, bulk biochemical methods are not ideally suited to study specific aspects of this process in detail. In contrast, imaging represents a direct approach to analyze individual particles and events. While live-cell imaging can reveal the dynamics of intracellular events with high temporal resolution, it falls short in revealing ultra-structural details. Thus, live-cell fluorescence microscopy and electron microscopy (EM) can complement each other to gain insight into both the dynamics of assembly and the structures detected at HIV-1 assembly sites. In this chapter we describe microscopic setups, tools, and methods for live-cell fluorescence microscopy as well as for different EM techniques, which have been successfully used by us and others to study HIV-1 assembly at the host cell plasma membrane. These methods can be used in a complementary manner to investigate the effects of cellular factors, mutations in the viral genome or antiviral drugs on dynamic and structural aspects of HIV-1 morphogenesis. PMID- 24158823 TI - HIV-1 isolation from infected peripheral blood mononuclear cells. AB - Human immunodeficiency virus 1 (HIV-1) isolation from peripheral blood mononuclear cells (PBMCs) allows retrieval of replication-competent viral variants. In order to impose the smallest possible selective pressure on the viral isolates, isolation must be carried out in primary cultures of cells and not in tumor derived cell lines. The procedure involves culture of PBMCs from an infected patient with phytohemagglutinin (PHA)-stimulated PBMC from seronegative donors, which provide susceptible target cells for HIV replication. HIV can be isolated from the bulk population of PBMCs or after cloning of the cells to obtain viral biological clones. Viral production is determined with p24 antigen (Ag) detection assays or with reverse transcriptase (RT) activity assay. Once isolated, HIV-1 can be propagated by infecting PHA-stimulated PBMCs from healthy donors. Aliquots from culture with a high production of virus are stored for later use. PMID- 24158824 TI - Determination of HIV-1 co-receptor usage. AB - Human immunodeficiency virus type I (HIV-1) infects target cells through interaction with the CD4 molecule and chemokine receptors, mainly the beta chemokine receptor 5 (CCR5) and the alpha-chemokine receptor 4 (CXCR4). Viral isolates can be phenotypically classified based on the co-receptor they utilize to infect target cells. In this chapter, methods to determine the co-receptor usage of HIV-1 variants are described. PMID- 24158825 TI - The macrophage and HIV: basic concepts and methodologies. AB - Along with CD4+ T-lymphocytes, macrophage lineage cells serve as primary hosts for HIV replication in vivo. In some tissues such as brain, where T-cell infection is essentially absent, the development of HIV-associated disease is mediated through infection of macrophages. This fact underscores the importance of experimental methods that yield results and conclusions that accurately reflect the mechanisms operational in vivo. Unfortunately, our understanding of key aspects of HIV-macrophage interactions, most notably, features of viral entry, replication, latency and persistence, lags behind that of T-cell infection. While some questions are best approached by direct examination of patient specimens using methods such as immunohistochemistry and phylogenetics, experiments based on HIV infection of macrophages in vitro can, necessarily, identify and elucidate the events, molecular mechanisms, and pathological consequences associated with this infection. In addition, macrophage culture methods can provide for the isolation of infectious HIV from patient blood monocytes and tissue macrophages, as well as subsequent continued propagation of these isolates in their host cell of origin. Maintenance of the host cell pedigree limits the possibility of alteration of viral properties such as chemokine coreceptor usage that may then no longer reflect the situation in vivo. This chapter focuses on HIV infection of macrophages. We describe methods for the cultivation of human blood monocyte-derived macrophages, their infection with HIV and subsequent maintenance, and the isolation of infectious HIV from them. Also included is a protocol using accutase for macrophage detachment. Accutase is a relatively new dissociation medium, used primarily in stem cell research. In our laboratory, it has far out-performed all other methods by providing for the gentle, yet thorough, detachment of macrophages without the need for scraping, and without loss of surface antigens or viability. PMID- 24158826 TI - HIV infection of dendritic cells. AB - Dendritic cells (DC) present in the genital tract are one of the first cells to encounter HIV during sexual mucosal transmission. In addition they are able to efficiently transfer the virus to its main target cells, CD4(+) T-lymphocytes. As such an understanding of how HIV interacts with and manipulates DCs is of key importance for the design of mucosal vaccines and microbicides. However working with these cells is difficult for several reasons. Firstly, immature DCs are difficult to infect due to their high endocytic capacity and mature DCs are usually resistant to infection. Secondly, tissue DCs are inherently difficult to isolate, which results in small yields and the cells are prone to maturation as a result of extraction. Here we describe how to isolate CD1a expressing Langerhans cells from the epidermis and CD1a(+), CD14(+) and perhaps BDCA3(+) DCs from the dermis. We also describe how to produce the model monocyte-derived DC (MDDC) by cytokine stimulation of CD14(+) monocytes, which results in the production of large numbers of immature cells. We also describe methods by which high titer HIV stocks can be generated to infect a significant proportion of DCs and also methods for determining the titer of such stocks. PMID- 24158827 TI - Histocultures (tissue explants) in human retrovirology. AB - Viral pathogenesis is studied predominantly in cultures of primary isolated cells or cell lines. Many retroviruses efficiently replicate only in activated cells. Therefore, in order to become efficient viral producers cells should be artificially activated, a procedure which significantly changes cell physiology. However, for many viral diseases, like HIV-1 and other retroviruses' diseases, critical pathogenic events occur in tissues. Therefore, cell isolation from their native microenvironment prevents single-cell cultures from faithfully reflecting important aspects of cell-cell and cell-pathogen interactions that occur in the context of complex tissue cytoarchitecture. Tissue explants (histocultures) that retain tissue cytoarchitecture and many aspects of cell-cell interactions more faithfully represent in vivo tissue features. Human histocultures constitute an adequate model for studying viral pathogenesis under controlled laboratory conditions. Protocols for various human histocultures as applied to study retroviral pathogenesis, in particular of HIV-1, have been refined by our laboratory and are described in the present publication. Histocultures of human tonsils and lymph nodes, as well as of recto-sigmoid and cervicovaginal tissues can be used to study viral transmission, pathogenesis and as a preclinical platform for antivirals evaluation. PMID- 24158828 TI - Single-copy quantification of HIV-1 in clinical samples. AB - HIV replication in humans proceeds with substantial viral RNA levels in plasma. Antiretroviral therapy results in suppression but not eradication of HIV infection. Continuous therapy is essential for durable clinical responses. Discontinuing antiretroviral therapy results in prompt rebound in viremia. The source of HIV during suppressive therapy and mechanisms of persistence remain uncertain. Sensitive assays for HIV have been useful in quantifying viremia in response to antiretroviral therapy and in experimental studies of drug intensification, drug simplification, and potential anatomic sanctuary site investigations. As clinical eradication strategies move forward, robust, sensitive quantitative assays for HIV at low levels represent essential laboratory support modalities. Here we describe in detail an assay for HIV-1 RNA with single-copy sensitivity. PMID- 24158829 TI - Quantification of total HIV1-DNA in peripheral blood mononuclear cells. AB - HIV reservoir measurement in patients is one of the challenges at the time of testing new treatment approaches aiming at eradicating HIV infection. HIV reservoirs are complex and disseminated in a large number of organs and lymphoid tissues. We chose to quantify total cell-associated HIV-DNA in PBMC as a marker of HIV reservoirs and described the method we developed. The marker was used in large cohort studies at different stages of HIV disease and in therapeutical trials. Our results show how informative is this marker, as well as that plasma HIV-RNA and CD4 T cell count are representative of each patient when measured in blood. Such a series of results might help to adapt simplification or structured interruption strategies, design new clinical trials targeting HIV reservoirs, and select populations that could benefit of such new treatments. PMID- 24158830 TI - HIV-1-based lentiviral vectors. AB - Numerous viral vectors have been developed for the delivery of transgenes to specific target cells. For persistent transgene expression, vectors based on retroviruses are attractive delivery vehicles because of their ability to stably integrate their DNA into the host cell genome. Initially, vectors based on simple retroviruses were the vector of choice for such applications. However, these vectors can only transduce actively dividing cells. Therefore, much interest has turned to retroviral vectors based on the lentivirus genus because of their ability to transduce both dividing and non-dividing cells. The best characterized lentiviral vectors are derived from the human immunodeficiency virus type 1 (HIV 1). This chapter describes the basic features of the HIV-1 replication cycle and the many improvements reported for the lentiviral vector systems to increase the safety and efficiency. We also provide practical information on the production of HIV-1 derived lentiviral vectors, the cell transduction protocol and a method to determine the transduction titers of a lentiviral vector. PMID- 24158831 TI - Quantification of miRNA by poly(A)-RT-qPCR arrays and verification of target sites in HIV-1 using a one-LTR infectious molecular clone. AB - Quantitative PCR (qPCR) provides a robust method for quantifying DNA species. By combining modern qPCR techniques with the isolation of small RNA, the polyadenylation of the RNA, and the use of reverse transcriptase to create miRNA derived cDNA, it is now possible to use qPCR to quantify miRNA. This method is scalable and provides a useful addition to the retrovirologists' toolbox. Here, we also describe the use of one-LTR infectious molecular clones to verify miRNA target sites within the retroviral LTR. PMID- 24158832 TI - Investigating human T cell lymphotropic retrovirus (HTLV) Tax function with molecular and immunophenotypic techniques. AB - Human T cell Lymphotropic Viruses 1 and 2 (HTLV-1 and HTLV-2) are the first described human retroviruses. HTLV-1 is the causative agent of an aggressive malignancy of CD4+ T lymphocytes named adult T-cell leukemia/lymphoma (ATLL) and of a chronic neurological disease known as HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). HTLV-2 shares many similarities with HTLV-1, but displays lower or absent association to diseases. Among the proteins encoded by HTLVs, the viral transactivator Tax exerts an essential role in viral transcription as well as in cell transformation. Different experimental methods to study Tax activity on HTLV-LTR promoter and Tax subcellular distribution are described. Emphasis is given to the functional and physical interaction between Tax-1/Tax-2 and cellular cofactors which may have an impact on the infectivity process of the HTLVs and on the capacity of cell transformation. PMID- 24158833 TI - Proviral load determination of HTLV-1 and HTLV-2 in patients' peripheral blood mononuclear cells by real-time PCR. AB - TaqMan real-time PCR assays were developed to determine the proviral load (PVL) of human T-cell leukemia viruses type 1 and 2 (HTLV-1 and HTLV-2) in peripheral blood mononuclear cells (PBMCs) of infected subjects. In particular, separate single-plex assays for HTLV-1 tax-1, and HTLV-2 tax-2 and pol-2 genes were designed for quantitation of HTLV-1 and HTLV-2 PVLs. The specificity of both tax 2 and pol-2 assays was verified by testing the DNA extracted from C10, a chronically HTLV-1-infected cell line, used as a negative control. As far as HTLV 2 assay, the specificity was checked by testing C344 cells which are stably infected by HTLV-2. Quantitative determination of HTLV PVLs was obtained by performing standard reference curves by a serial dilution of DNA extracted from C10 and C344 cells, assuming one proviral genome per C10 cell and two per C344 cell. The human albumin gene, of which there are 2 copies per cell, was quantified in the same reactions to normalize the results. Intra-assay reproducibility was checked by running 30 replicates of the same sample in a plate (coefficient of variance <6 %), while inter-assay reproducibility was measured by amplifying the same sample in three independent experiments (coefficient of variance <6 %). PMID- 24158834 TI - Quantitative analysis of human T-lymphotropic virus type 1 (HTLV-1) gene expression using nucleo-cytoplasmic fractionation and splice junction-specific real-time RT-PCR (qRT-PCR). AB - Like other complex retroviruses such as HIV-1, HTLV-1 encodes several regulatory and auxiliary non-structural proteins from overlapping open reading frames through the generation of alternatively spliced mRNAs. HTLV-1 expression is orchestrated by the Tax and Rex regulatory proteins; Tax drives the transcription of the viral genome, while Rex acts at the posttranscriptional level by enhancing the nuclear export and expression of unspliced and incompletely spliced mRNAs. The present chapter is focused on the techniques employed to quantitate HTLV-1 mRNAs in the nuclear and cytoplasmic compartments. To ensure a quantitative transcript-specific detection of the levels of individual HTLV-1 mRNAs in a complex mixture of closely related species, splice junction-specific primers and TaqMan probes were used. As HTLV-1 gene regulation is based on the controlled nucleo-cytoplasmic export of the different viral mRNAs, we quantitated the individual viral transcripts in the nuclear and cytoplasmic fractions. PMID- 24158835 TI - Effects of electroacupuncture on oxaliplatin-induced neuropathic cold hypersensitivity in rats. AB - This study investigated whether and how electroacupuncture (EA) attenuates cold hypersensitivity (allodynia) in a rat model of oxaliplatin-induced neuropathic pain. Cold allodynia [evaluated by immersing the tail into cold water (4 degrees C) and measuring the withdrawal latency] was induced 3 days after an oxaliplatin administration (6 mg/kg, i.p.). EA stimulation (2/100 Hz, 0.3-ms pulse duration, 0.2-0.3 mA) was delivered to ST36 acupoint or non-acupoint for 20 min. Low frequency (2 Hz) EA at ST36 relieved cold allodynia more effectively than high frequency EA at ST36 or low-frequency EA at non-acupoint. Naloxone (opioid antagonist, 2 mg/kg, i.p.) completely blocked such EA-induced anti-allodynia, whereas phentolamine (alpha-adrenergic antagonist, 2 mg/kg, i.p.) did not. Moreover, plasma beta-endorphin levels significantly increased right after the end of EA and subsequently decreased. These results indicate that low-frequency EA at ST36 in rats has a marked relieving effect on oxaliplatin-induced cold allodynia that is mediated by the endogenous opioid, but not noradrenergic, system. PMID- 24158836 TI - RAvariome: a genetic risk variants database for rheumatoid arthritis based on assessment of reproducibility between or within human populations. AB - Rheumatoid arthritis (RA) is a common autoimmune inflammatory disease of the joints and is caused by both genetic and environmental factors. In the past six years, genome-wide association studies (GWASs) have identified many risk variants associated with RA. However, not all associations reported from GWASs are reproduced when tested in follow-up studies. To establish a reliable set of RA risk variants, we systematically classified common variants identified in GWASs by the degree of reproducibility among independent studies. We collected comprehensive genetic associations from 90 papers of GWASs and meta-analysis. The genetic variants were assessed according to the statistical significance and reproducibility between or within nine geographical populations. As a result, 82 and 19 single nucleotide polymorphisms (SNPs) were confirmed as intra- and inter population-reproduced variants, respectively. Interestingly, majority of the intra-population-reproduced variants from European and East Asian populations were not common in two populations, but their nearby genes appeared to be the components of common pathways. Furthermore, a tool to predict the individual's genetic risk of RA was developed to facilitate personalized medicine and preventive health care. For further clinical researches, the list of reliable genetic variants of RA and the genetic risk prediction tool are provided by open access database RAvariome. DATABASE URL: http://hinv.jp/hinv/rav/. PMID- 24158837 TI - Use of intravitreal rituximab for treatment of vitreoretinal lymphoma. AB - AIM: Vitreoretinal lymphoma is a diffuse large B cell non-Hodgkin lymphoma. Targeting malignant cells with rituximab is being used increasingly as local chemotherapy, but information on this treatment is scant. We aimed to describe current therapeutic approaches, as well as responses to and complications of, intravitreal rituximab in patients with vitreoretinal lymphoma. METHODS: Clinical data were collected in a standardised manner retrospectively on patients with vitreoretinal lymphoma treated with intravitreal rituximab. RESULTS: 48 eyes (34 patients) with vitreoretinal lymphoma were treated with a median of 3.5 intravitreal injections of rituximab (1 mg/0.1 mL) for new diagnosis (68.8%), progressive disease (29.9%) and maintenance therapy (2.1%). Intravitreal rituximab+/-methotrexate was the sole treatment in 19 eyes (39.6%). 31 eyes (64.6%) eyes achieved complete remission, after a median of 3 injections; 7 of these eyes developed recurrent disease. 11 eyes (22.9%) achieved partial remission. Although rituximab may have contributed to complications reported in 12 eyes (25.0%), a 2-line loss of Snellen visual acuity occurred in only 2 of those eyes (4.2%). CONCLUSIONS: Approaches in rituximab-based intravitreal chemotherapy vary widely, but our findings suggest that this treatment may be safe and effective in inducing remission in a majority of eyes with vitreoretinal lymphoma. PMID- 24158838 TI - Surgical simulators in cataract surgery training. AB - BACKGROUND: Virtual simulators have been widely implemented in medical and surgical training, including ophthalmology. The increasing number of published articles in this field mandates a review of the available results to assess current technology and explore future opportunities. METHOD: A PubMed search was conducted and a total of 10 articles were reviewed. RESULTS: Virtual simulators have shown construct validity in many modules, successfully differentiating user experience levels during simulated phacoemulsification surgery. Simulators have also shown improvements in wet-lab performance. The implementation of simulators in the residency training has been associated with a decrease in cataract surgery complication rates. CONCLUSIONS: Virtual reality simulators are an effective tool in measuring performance and differentiating trainee skill level. Additionally, they may be useful in improving surgical skill and patient outcomes in cataract surgery. Future opportunities rely on taking advantage of technical improvements in simulators for education and research. PMID- 24158839 TI - The relationship between retinal and choroidal thickness and visual acuity in highly myopic eyes. PMID- 24158840 TI - Identification of ocular surface squamous neoplasia by in vivo staining with methylene blue. AB - AIM: To evaluate the diagnostic accuracy of methylene blue used as a non-invasive in vivo stain to detect ocular surface squamous neoplasia (OSSN). METHODS: A test validation study was performed according to Standards for the reporting of diagnostic accuracy studies (STARD) guidelines on 75 consecutive patients who presented with ocular surface lesions suspicious of OSSN. Methylene blue 1% was instilled in vivo following local anaesthetic. Stain results were documented photographically and read by an independent observer. Lesions were excised at the same visit and evaluated histologically by pathologists who were blind to the stain results. Sensitivity, specificity, positive and negative predictive values were determined. RESULTS: Thirty-three patients had histologically malignant lesions, of which 32 stained with methylene blue, and 42 patients had benign or premalignant lesions, of which 21 stained with methylene blue. Methylene blue had a sensitivity of 97%, specificity of 50% and positive and negative predictive values of 60% and 96%, respectively. CONCLUSIONS: The topical application of methylene blue is a simple, inexpensive, non-invasive diagnostic test that can be helpful in excluding malignant ocular surface lesions but cannot replace histology as gold standard for diagnosis of OSSN. PMID- 24158841 TI - Comparison between femtosecond laser mushroom configuration and manual trephine straight-edge configuration deep anterior lamellar keratoplasty. AB - AIM: To compare outcomes and complications of femtosecond laser (FSL) mushroom configuration and manual trephine (MT) straight-edge configuration deep anterior lamellar keratoplasty (DALK). METHODS: A cohort of 19 consecutive eyes that underwent FSL DALK was compared with 19 consecutive eyes that underwent MT DALK. Surgery was performed for eyes with keratoconus, corneal ectasia and scarring. Patient demographics, best-corrected visual acuities (BCVAs), refraction and complications were compared. RESULTS: Groups were comparable for age, gender and preoperative BCVA. Rates of intraoperative and postoperative complications were low and comparable between the groups. These included intraoperative Descemet's membrane (DM) perforation which did not require conversion to penetrating keratoplasty; stromal rejection successfully treated with topical steroids; postoperative DM detachment; delayed epithelial healing and increased intraocular pressure which resolved with topical anti-glaucoma drops. At 3 months, the mean BCVA was significantly better in the FSL group compared with the MT group (p=0.00002). At 6 months and 1 year, there was no significant difference between mean BCVA between the two groups. Mean spherical equivalent, cylindrical astigmatism and keratometric cylinder preoperatively and at 3, 6 and 12 months postoperatively were similar between the two groups. CONCLUSIONS: FSL or trephine DALK are viable options for keratoconus, ectasia and corneal scars. Earlier visual recovery occurs with FSL mushroom configuration compared with MT straight edge DALK. PMID- 24158843 TI - Pterygium: are we any closer to the cause? PMID- 24158842 TI - How to help children with neurodevelopmental and visual problems: a scoping review. AB - Children with visual impairment and a condition affecting their neurodevelopment (children with VND) may require extensive and specialised help but evidence on the most effective strategies for visual improvement is lacking. We defined a PICO format (Population, Intervention, Comparator, Outcome) for a scoping review and systematically searched 13 databases. Two reviewers assessed the abstracts for inclusion and a third arbitrated in cases of disagreement. We abstracted data from included studies. We found 4450 abstracts from which we identified 107 papers for inclusion. Of these, 42 related to interventions involving a change in visual input or function: 5 controlled trials, 8 before and after studies and 29 case reports. The strongest evidence supported the provision of spectacles to improve distance or near vision and the use of ultraviolet light as environmental modification for training. Less strong but suggestive evidence supported training/practice routines to improve acuity or oculomotor control. Interventions exist to help children with VND and current recommendations that they are assessed by a vision specialist are supported by the evidence. More information is needed on the effectiveness of training/practice programmes which may promote improved function, and of environmental modifications to facilitate engagement of children with VND with the surroundings. PMID- 24158844 TI - Fourier-domain optical coherence tomography evaluation of retinal and optic nerve head neovascularisation in proliferative diabetic retinopathy. AB - AIM: To describe the in vivo spatial and morphological vitreoretinal relationships associated with diabetic retinal neovascularisation using Fourier domain optical coherence tomography (FD-OCT). METHODS: Qualitative assessment of macula, retina and optic disc head FD-OCT (Topcon 3D OCT-1000) imaging of patients with treatment-naive and laser-treated proliferative diabetic retinopathy (PDR). The morphology and plane of retinal neovascularisation at the disc (NVD) and elsewhere in the retina (NVE) were examined, and the posterior vitreous relationships were evaluated. The FD-OCT characteristics of clinical versus subclinical PDR disease were correlated with conventional and wide-field Optos fundus fluorescein angiography. RESULTS: 50 eyes of 50 patients were evaluated in this retrospective study. Retinal neovascularisation appears as a hyper-reflective complex, with NVE arising from inner retina with disruption through the internal limiting membrane to attach to the posterior hyaloid surface. FD-OCT detected subclinical hyper-reflective NVD complexes that were subvisible on colour fundus imaging. We describe retinoschisis, vitreoretinal adhesions and pegs, zones of separation, and intraretinal tractional elements in untreated PDR patients using high resolution FD-OCT. CONCLUSIONS: FD-OCT can non invasively characterise retinal and optic nerve head neovascular complexes at different stages of the proliferative disease process. In clinical practice, FD OCT can monitor the in vivo serial changes of retinal neovascularisation over time. PMID- 24158845 TI - New light for old eyes: comparing melanopsin-mediated non-visual benefits of blue light and UV-blocking intraocular lenses. AB - BACKGROUND/AIMS: Melanopsin-expressing photosensitive retinal ganglion cells form a blue-light-sensitive non-visual system mediating diverse physiological effects including circadian entrainment and cognitive alertness. Reduced blue wavelength retinal illumination through cataract formation is thought to blunt these responses while cataract surgery and intraocular lens (IOL) implantation have been shown to have beneficial effects on sleep and cognition. We aimed to use the reaction time (RT) task and the Epworth Sleepiness Score (ESS) as a validated objective platform to compare non-visual benefits of UV- and blue-blocking IOLs. METHODS: Patients were prospectively randomised to receive either a UV- or blue blocking IOL, performing an RT test and ESS questionnaire before and after surgery. Optical blurring at the second test controlled for visual improvement. Non-operative age-matched controls were recruited for comparison. RESULTS: 80 participants completed the study. Those undergoing first-eye phacoemulsification demonstrated significant improvements in RT over control (p=0.001) and second-eye surgery patients (p=0.03). Moreover, reduced daytime sleepiness was measured by ESS for the first-eye surgery group (p=0.008) but not for the second-eye group (p=0.09). Choice of UV- or blue-blocking IOL made no significant difference to magnitude of cognitive improvement (p=0.272). CONCLUSIONS: Phacoemulsification, particularly first-eye surgery, has a strong positive effect on cognition and daytime alertness, regardless of IOL type. PMID- 24158846 TI - Intracameral bevacizumab as an adjunct to trabeculectomy: a 1-year prospective, randomised study. AB - AIMS: To investigate the efficacy and safety of a single intracameral bevacizumab injection to improve the outcome of trabeculectomy. METHODS: A 12-month, prospective, randomised, double-masked, placebo-controlled trial. Patients with medically uncontrolled open-angle glaucoma scheduled for a primary trabeculectomy were recruited and randomised to receive 50 uL of either bevacizumab (1.25 mg) or placebo (balanced salt solution) peroperatively. Absolute success was defined as intraocular pressure (IOP) <=18 mm Hg and >5 mm Hg with at least 30% reduction from baseline and no loss of light perception. Success through the use of additional medical and/or surgical IOP-lowering treatments was defined as qualified success. RESULTS: 138 patients completed a 12-month follow-up, 69 of whom were in the bevacizumab treated group. IOP at 1 year postoperatively was significantly lower than baseline (placebo: 25.6+/-9.9 mm Hg vs 11.5+/-3.9 mm Hg, p<0.01; bevacizumab: 24.8+/-8.1 mm Hg vs 11.9+/-3.8 mm Hg, p<0.01), with no difference between treatment groups (p=0.69). However, absolute success was higher in the bevacizumab group (71% vs 51%, p=0.02), with the need for IOP lowering interventions (needlings) being lower in this group (12% vs 33%, p=0.003). Complication rates were low and comparable between groups. CONCLUSIONS: Peroperative administration of intracameral bevacizumab significantly reduces the need for additional interventions during the follow-up of patients undergoing trabeculectomy. PMID- 24158847 TI - High-fat diet induced an oxidative stress in white adipose tissue and disturbed plasma transition metals in rat: prevention by grape seed and skin extract. AB - Obesity is a public health problem characterized by increased accumulation of fat into adipose tissues leading to oxidative stress, dyslipidemia, and chronic inflammatory status. We used an experimental model of high-fat diet-induced obesity to analyze the link between dyslipidemia, oxidative stress, and fat accumulation into adipose tissue of rats, as well as the involvement of intracellular mediators such as transition metals on signal transduction. We also looked at the ability of a grape seed and skin extract (GSSE) from a Tunisian cultivar to prevent fat-induced disturbances. Data showed that a high-fat diet (HFD) provoked dyslipidemia into plasma which is linked to an oxidative stress, an accumulation of transition metals such as manganese, copper, and zinc and a depletion of iron. GSSE prevented dyslipidemia by modulating lipase activity, together with increased antioxidant capacity and depletion of transition metals as well as of free radicals such as O2 (-) and OH. These data indicated that GSSE has important preventive effects on HFD-induced obesity and oxidative stress whose transduction seems to involve transition metals. GSSE should be used as a safe anti-obesity agent that could find potential applications in metabolic disorders involving transition metals dyshomeostasis. PMID- 24158849 TI - The CYP27B1 variant associated with an increased risk of autoimmune disease is underexpressed in tolerizing dendritic cells. AB - Genome-wide association studies have identified a linkage disequilibrium (LD) block on chromosome 12 associated with multiple sclerosis (MS), type 1 diabetes and other autoimmune diseases. This block contains CYP27B1, which catalyzes the conversion of 25 vitamin D3 (VitD3) to 1,25VitD3. Fine-mapping analysis has failed to identify which of the 17 genes in this block is most associated with MS. We have previously used a functional approach to identify the causal gene. We showed that the expression of several genes in this block in whole blood is highly associated with the MS risk allele, but not CYP27B1. Here, we show that CYP27B1 is predominantly expressed in dendritic cells (DCs). Its expression in these cells is necessary for their response to VitD, which is known to upregulate pathways involved in generating a tolerogenic DC phenotype. Here, we utilize a differentiation protocol to generate inflammatory (DC1) and tolerogenic (DC2) DCs, and show that for the MS risk allele CYP27B1 is underexpressed in DCs, especially DC2s. Of the other Chr12 LD block genes expressed in these cells, only METT21B expression was as affected by the genotype. Another gene associated with autoimmune diseases, CYP24A1, catabolizes 1,25 VitD3, and is predominantly expressed in DCs, but equally between DC1s and DC2s. Overall, these data are consistent with the hypothesis that reduced VitD pathway gene upregulation in DC2s of carriers of the risk haplotype of CYP27B1 contributes to autoimmune diseases. These data support therapeutic approaches aimed at targeting VitD effects on DCs. PMID- 24158851 TI - FOXO3 determines the accumulation of alpha-synuclein and controls the fate of dopaminergic neurons in the substantia nigra. AB - Parkinson's disease (PD) is characterized by the selective degeneration of neuronal populations presumably due to pathogenic interactions between aging and predisposing factors such as increased levels of alpha-synuclein. Here, we genetically modulate the activity of the transcription factor Forkhead box protein O3 (FOXO3) in adult nigral dopaminergic neurons using viral vectors and explore how this determinant of longevity impacts on neuronal fate in normal and diseased conditions. We find that dopaminergic neurons are particularly vulnerable to changes in FOXO3 activity in the substantia nigra. While constitutive activation has proapoptotic effects leading to neuronal loss, inhibition of FOXO-mediated transcription by a dominant-negative competitor causes oxidative damage and is detrimental at high vector dose. To address the role of FOXO3 in PD, we modulate its activity in dopaminergic neurons overexpressing human alpha-synuclein. In this pathogenic condition, we find that FOXO inhibition has protective effects, suggesting that this transcription factor ultimately contributes to neuronal cell death. Nevertheless, mild FOXO3 activity also protects nigral neurons against the accumulation of human alpha-synuclein, albeit to a lesser extent. FOXO3 reduces the amount of alpha-synuclein present in the soluble protein fraction and promotes the coalescence of dense proteinase K resistant aggregates, with an accumulation of autophagic vacuoles containing lipofuscin. Consistent with these in vivo observations, we find that FOXO3 controls autophagic flux in neuronal cells. Altogether, these results point to FOXO3 as an important determinant of neuronal survival in the substantia nigra, which may oppose alpha-synuclein accumulation and proteotoxicity. PMID- 24158850 TI - Lipid-enriched diet rescues lethality and slows down progression in a murine model of VCP-associated disease. AB - Valosin-containing protein (VCP)-associated disease caused by mutations in the VCP gene includes combinations of a phenotypically heterogeneous group of disorders such as hereditary inclusion body myopathy, Paget's disease of bone, frontotemporal dementia and amyotrophic lateral sclerosis. Currently, there are no effective treatments for VCP myopathy or dementia. VCP mouse models carrying the common R155H mutation include several of the features typical of the human disease. In our previous investigation, VCP(R155H/R155H) homozygous mice exhibited progressive weakness and accelerated pathology prior to their early demise. Herein, we report that feeding pregnant VCP(R155H/+) heterozygous dams with a lipid-enriched diet (LED) results in the reversal of the lethal phenotype in VCP(R155H/R155H) homozygous offspring. We examined the effects of this diet on homozygous and wild-type mice from birth until 9 months of age. The LED regimen improved survival, motor activity, muscle pathology and the autophagy cascade. A targeted lipidomic analysis of skeletal muscle and liver revealed elevations in tissue levels of non-esterified palmitic acid and ceramide (d18:1/16:0), two lipotoxic substances, in the homozygous mice. The ability to reverse lethality, increase survival, and ameliorate myopathy and lipids deficits in the VCP(R155H/R155H) homozygous animals suggests that lipid supplementation may be a promising therapeutic strategy for patients with VCP-associated neurodegenerative diseases. PMID- 24158852 TI - ACAD9, a complex I assembly factor with a moonlighting function in fatty acid oxidation deficiencies. AB - Oxidative phosphorylation and fatty acid oxidation are two major metabolic pathways in mitochondria. Acyl-CoA dehydrogenase 9 (ACAD9), an enzyme assumed to play a role in fatty acid oxidation, was recently identified as a factor involved in complex I biogenesis. Here we further investigated the role of ACAD9's enzymatic activity in fatty acid oxidation and complex I biogenesis. We provide evidence indicating that ACAD9 displays enzyme activity in vivo. Knockdown experiments in very-long-chain acyl-CoA dehydrogenase (VLCAD)-deficient fibroblasts revealed that ACAD9 is responsible for the production of C14:1 carnitine from oleate and C12-carnitine from palmitate. These results explain the origin of these obscure acylcarnitines that are used to diagnose VLCAD deficiency in humans. Knockdown of ACAD9 in control fibroblasts did not reveal changes in the acylcarnitine profiles upon fatty acid loading. Next, we investigated whether catalytic activity of ACAD9 was necessary for complex I biogenesis. Catalytically inactive ACAD9 gave partial-to-complete rescue of complex I biogenesis in ACAD9 deficient cells and was incorporated in high-molecular-weight assembly intermediates. Our results underscore the importance of the ACAD9 protein in complex I assembly and suggest that the enzymatic activity is a rudiment of the duplication event. PMID- 24158854 TI - Elective use of an uncuffed small-bore cricothyrotomy tube with balloon occlusion of the subglottic airway. AB - PURPOSE: To conduct a qualitative observational study on positive pressure ventilation through a percutaneous uncuffed small-bore cricothyrotomy tube with balloon occlusion of the subglottic airway to minimize supraglottic leak. CLINICAL FEATURES: Ten consecutive procedures were performed in the nine men enrolled in this study. The demographics of the participants were: aged 50-73 yr, weight 48-87 kg, American Society of Anesthesiologists class I-II, and scheduled for endoscopic submucosal dissection via flexible endoscopy for en bloc resection of superficial meso- and hypopharyngeal cancer. The airway was initially secured with a supraglottic airway (SGA) under sevoflurane-based anesthesia, and a cricothyrotomy was then performed using a Portex((r)) Minitrach II uncuffed cricothyrotomy tube (4-mm internal diameter). Following SGA removal, a Coopdech((r)) bronchial blocker was orally or nasally inserted, and the balloon was inflated to occlude the trachea immediately beneath the glottis. The ventilator setting was initially based on observation of chest motion and end tidal carbon dioxide tension and then readjusted according to arterial blood gas levels. All procedures were completed within a median time of 149 min. Effective ventilation was achieved in all patients despite mild hypercapnia (PaCO2 of 58 mmHg at maximum) in some patients. SpO2 levels were maintained at >= 98%. CONCLUSION: This technique provides effective intraoperative ventilation and easy endoscopic access, and it countermeasures against the likely complication of postoperative laryngeal edema. Moreover, there is no need for conventional tracheostomy or prolonged intubation. This approach establishes a curative and less invasive pharyngeal cancer therapy. Certain adverse outcomes can be avoided, including impaired speech and swallowing, possible delayed closure of the stoma, or a compromised cosmetic outcome. PMID- 24158855 TI - [To improve minimally invasive gastrointestinal surgery based on high quality in China]. AB - Laparoscopic surgery for gastrointestinal diseases had a remarkable achievement in the past 20 years. To ensure the high quality of minimally invasive gastrointestinal surgery, several issues should be addressed, including correct guidelines and standard based on the consensus, high quality evidence from multi center randomized control studies, proper training system for the technique, and constant innovations to improve the technique. We believe that with the great efforts of gastrointestinal surgeons, the minimally invasive gastrointestinal surgery in China is promising in the near future. PMID- 24158853 TI - Spread of X-chromosome inactivation into autosomal sequences: role for DNA elements, chromatin features and chromosomal domains. AB - X-chromosome inactivation results in dosage equivalence between the X chromosome in males and females; however, over 15% of human X-linked genes escape silencing and these genes are enriched on the evolutionarily younger short arm of the X chromosome. The spread of inactivation onto translocated autosomal material allows the study of inactivation without the confounding evolutionary history of the X chromosome. The heterogeneity and reduced extent of silencing on autosomes are evidence for the importance of DNA elements underlying the spread of silencing. We have assessed DNA methylation in six unbalanced X-autosome translocations using the Illumina Infinium HumanMethylation450 array. Two to 42% of translocated autosomal genes showed this mark of silencing, with the highest degree of inactivation observed for trisomic autosomal regions. Generally, the extent of silencing was greatest close to the translocation breakpoint; however, silencing was detected well over 100 kb into the autosomal DNA. Alu elements were found to be enriched at autosomal genes that escaped from inactivation while L1s were enriched at subject genes. In cells without the translocation, there was enrichment of heterochromatic features such as EZH2 and H3K27me3 for those genes that become silenced when translocated, suggesting that underlying chromatin structure predisposes genes towards silencing. Additionally, the analysis of topological domains indicated physical clustering of autosomal genes of common inactivation status. Overall, our analysis indicated a complex interaction between DNA sequence, chromatin features and the three-dimensional structure of the chromosome. PMID- 24158856 TI - [Problems and strategies of laparoendoscopic single site surgery in gastrointestinal surgery]. AB - Laparoendoscopic single site surgery(LESS), which has been applied in gastrointestinal surgery domestically and abroad, is the most feasible "scarless" operation at present. Combined with our expierience the problems and strategies of laparoendoscopic single site surgery in gastrointestinal surgery are reviewed and discussed in this paper. Inline vision, chopsticks effect and equipment congestion are the difficulties in LESS, especially when it is used in gastrointestinal surgery. Improving skills, selecting appropriate apparatus, fixed operating team and flexible exposure method can ensure the safety of LESS. In order to ensure that LESS is accepted, the safety and effectiveness of LESS used in the operation of gastric and colorectal cancer need assessment. As a new surgical technique, the further development of LESS in gastrointestinal surgery is not possible without concept recognition, breakthrough of technical limitation and equipment innovation. PMID- 24158857 TI - [Practical skills of harmonic scalpel in laparoscopic gastrointestinal surgery]. AB - Harmonic scalpel, one of the most commonly used energy tools, have been recognized as an important revolutionary development in surgical device. Due to its convenience in cutting, coagulating, and dissecting harmonic scalpel has been increasingly used to performed surgery by more and more surgeons. In gastrointestinal surgeries, however, many manipulationssuch as dissecting soft connective tissues off the stomach or colon, isolating and cutting particular vessels, would require proper techniques in handling harmonic scalpels. Thus, based on our experiences of using harmonic scalpel in laparoscopic gastrointestinal surgeries, we summarized a "nine-word tactics", which may be helpful for beginners to use harmonic scalpels in a proper and efficient manner. PMID- 24158858 TI - [Laparoscopic education and training: considerations and feedback from our 10 year experience]. AB - Laparoscopic surgery for gastrointestinal tumors have been conducted in the Department of General Surgery of Nanfang Hospital since 2002. Within the past decade, the education and training courses of laparoscopic surgical techniques were given to over 2,000 gastrointestinal surgeons. From these experience, we believed that efficient and high quality laparoscopic surgical training program should combine the following philosophies: thorough understanding of anatomy under laparoscopic view was the cornerstone; skilled cooperation between surgeon, assistant and laparoscopist would ensure the safety and fluency of the surgery; training course should be designed according to the laparoscopic skills of the trainee. Based on these understandings of laparoscopic education and training, we would further perfect and standardize our training system so as to contribute to the future development and popularization of laparoscopic gastrointestinal surgery in China. PMID- 24158859 TI - [Evaluation of robotic gastrectomy for gastric cancer based on the current evidence]. AB - Surgical modality undoubtedly has been developing rapidly resulting from the improvement of minimally invasive approach and instruments. Robotic gastrectomy for gastric cancer, as one of the most common performed operations worldwide, is playing a key role in maximizing potential benefits for both patients and surgeons. Most studies have demonstrated its satisfactory short-term outcomes including fast postoperative recovery course and similar oncological adequacy, while followed by several disadvantages or pitfall such as longer operation time, relatively high costs, and uncertain long-term outcome. However, the role of robotic gastrectomy is still controversial. This article is a review about robotic gastrectomy for treating gastric cancer based on the current evidence in terms of technology, application, clinical trials, and future prospects. PMID- 24158860 TI - [Strategy and prospect of laparoscopic lymph node dissection for locally advanced upper-third gastric cancer]. AB - Laparoscopic D2 lymphadenectomy for locally advanced upper-third gastric cancer(LAUGC) must follow the same lymph node dissection extent with open surgery. Following the surgical steps can make the operation process more smoothly and achieve en bloc resection. Laparoscopic spleen-preserving splenic hilar lymph node dissection is the difficult point during total gastrectomy for LAUGC. Selecting the right surgical approach, mastering spleen vascular anatomical types, and the cooperation of surgical team can help to shorten the learning curve of the operation. Although laparoscopic lymph node dissection for LAUGC is still in the exploratory stage, we believe that with the emergence of evidence-based medicine, it is expected to become one of the standard operations for LAUGC. PMID- 24158861 TI - [Laparoscopy-assisted distal gastrectomy for gastric cancer]. AB - Laparoscopy-assisted distal gastrectomy (LADG) is a minimally invasive surgical technique, and also an important development of modern surgery. According to Japanese Gastric Cancer Treatment Guideline, indications of LADG must be strictly limited in early gastric cancer patients, while it should be investigated in advanced gastric cancer. Based on available studies, the short-term advantage of LADG for early gastric cancer has been generally accepted, but the totally laparoscopic technique for early gastric cancer is still to be further studied. LADG for advanced gastric cancer continues to be controversial, which needs the relevant final results of randomized controlled trials from China, Japanese, and Korean to determine, although some current studies have demonstrated similar efficacy of LADG plus D2 lymphadenectomy as compared to open gastrectomy. PMID- 24158862 TI - [Laparoscopic surgery of gastric gastrointestinal stromal tumor]. AB - Gastric gastrointestinal stromal tumor(GIST) is the most common mesenchymal neoplasms of the gastro-intestinal tract.For its unique biological behavior with KIT gene expression and the particular clinical characteristics with the recurrent nature, surgery and molecular targeted therapy is the main treatment of gastric GIST. Laparoscopic technology has been used in the surgical treatment of gastric GIST and is the future trend. In this article, we shed some light on the standardize surgical procedures of radical laparoscopic gastrectomy, obeying the surgical principles, accurate intraoperative localization, and surgery combined with targeted therapy. PMID- 24158863 TI - [Current status and prevention of complications after laparoscopic radical gastrectomy]. AB - It is the most important for surgeons to achieve surgical safety and oncological clearance in laparoscopic surgery for gastric cancer. With the widespread adoption oflaparoscopic surgery for gastric cancer, surgeons make great efforts to achieve better safety andlower morbidity. Common abdominal complications (intraoperative and postoperative) after laparoscopic radical gastrectomy include bleeding, anastomotic leakage, anastomotic stenosis, iatrogenic organ injury, pancreatic leakage, etc. The causes and prevention of the complications related with laparoscopic radical gastrectomy was discussed in this article. PMID- 24158864 TI - [Measures to anatomic variations of the colonic vessels in laparoscopic operations]. AB - In laparoscopic colorectal resection, the poor blood supply of the anastomosis after tumor excision is difficult to be determined during the operations sometimes. The change in blood supply of the bowel is mainly due to the mesenteric anatomy and the operative techniques. The direct blood supply of colon is the marginal vessels in the mesentery. The integrity and patency of the marginal vessels determine the vitality of the bowel. However, the marginal vessels are different in diameter, pulsation or even discontinue in various areas, affecting the excision of the colon and following anastomosis. The most common three dangerous areas to anastomosis include:(1)area between ileocolic artery and right colonic artery; (2)area between middle colonic artery and left colonic artery-the Griffiths point. (3)area between the terminal branch of sigmoid colonic artery and superior rectal artery-Sudeck dangerous area. In laparoscopic colorectal resection, one should pay attention to protect the blood supply of the bowel and the marginal blood vessels, and be vigilant to the three vascular variations above mentioned. The vessels should be ligated accurately to ensure sufficient blood supply to the anastomosis and consequent normal healing of the rectal and colonic anastomosis. More attention should be paid to the elderly, morbid, and diabetic patients. If the safety of the anastomosis is unsure, prophylactic ileostomy should be performed. PMID- 24158865 TI - [Quality control of laparoscopic surgery for gastric cancer]. AB - As the improvement of technique and accumulation of experience in the past decade, the development of laparoscopic surgery has been in the advanced phase for the minimally invasive surgery for the management of gastric cancer. Even laparoscopic surgery has severaladvantages such as faster recovery courses and improved quality of life, however, surgical quality control for oncology must always be the most important consideration. The quality control system consists of accurate clinical staging, patient selection, intraoperative standard operating procedure, proper education and training course, data management for clinicopathologic information, and evidence-based studies. PMID- 24158866 TI - [Three major problems and solutions in laparoscopic abdominoperineal resection for rectal carcinoma]. AB - OBJECTIVE: To investigate the three major problems and solutions in laparoscopic abdominoperineal resection(APR) for rectal carcinoma. METHODS: A retrospective study of 60 low rectal carcinoma cases undergoing selective laparoscopic APR from September 2010 to May 2013 in our hospital was undertaken. A laparoscopic sigmoid stoma was performed through the extraperitoneal route at the left lower abdomen puncture point after lymphadenectomy and tumor excision during operation. Using the unique intracorporeal suture technique of transanal endoscopic microsurgery(TEM), the pelvic peritoneum was closed by continuous suture with TEM needle-forceps and absorbable suture. Those patients with the successful pelvic peritoneum closure received continuous irrigation of presacral space from the third postoperative day to prevent perineal incision infection. RESULTS: Only one patient (1.7%) was converted to laparotomy. Fifty-nine patients underwent laparoscopic APR and laparoscopic sigmoid stoma was successfully performed through the extraperitoneal route without abdominal incision, and the incidence of stoma complication was only 3.4%. Out of 59 patients undergoing laparoscopic APR, the pelvic peritoneum of 56 patients(94.9%) was closed successfully. The median time of closing the pelvic peritoneum was 15 min. Fifty-seven patients with pelvic peritoneum successfully closed by laparotomy or laparoscopic approach received continuous irrigation of presacral space and the median time of presacral drainage tube placement was 7.8 days. No patient developed postoperative intestinal obstruction. The rate of perineal wound healing in grade A, B and C was 87.7%, 8.8% and 3.5%, respectively. In the 3 patients whose pelvic peritoneum failed to be closed with simple drainage of presacral space, one developed postoperative intestinal obstruction and one had a grade C perineal wound healing. CONCLUSIONS: Laparoscopic sigmoid stoma through the extraperitoneal route during laparoscopic APR for rectal carcinoma is feasible and safe. It is convenient and effective to close pelvic peritoneum by using TEM intracorporeal suture technique. It is worth discussing the role of continuous irrigation of presacral space postoperatively to prevent perineal incision infection. PMID- 24158867 TI - [Clinical application of reverse puncture device(RPD) in laparascopic esophagogastrectomy (esophagojejunostomy): a report of 18 cases]. AB - OBJECTIVE: The authors report the newly developed reconstruction technique after laparoscopic total gastrectomy (LTG) or laparoscopic distal gastrectomy (LDG): intracorporeal circular stapling esophagojejunostomy(esophagojejunostomy) using the reverse puncture device(RPD). METHODS: After LTG or LDG, The anvil is then transorally inserted into the esophagus by using the RPD system. Double-stapling esophagojejunostomy with a circular stapler is performed intracorporeally, and the jejunal stump is closed with an Echelon. RESULTS: There was no intraoperative complication or conversion to open surgery, the mean operation time was 155 min and blood loss was 75 ml. Postoperative fluorography revealed no anastomosis leakage or stenosis Patients resumed an oral liquid diet on postoperative day 2, and discharged at day 8. CONCLUSIONS: We have successfully performed LTG or LDG, reconstruction using our technique in 18 patients without any anastomosis complications. We believe that our procedure is a safe and reliable reconstruction method, which is especially useful in obese patients, in whom conventional extracorporeal anastomosis is often difficult. PMID- 24158868 TI - [Application of laparoscopic technique in acute abdomen of gastrointestinal surgery]. AB - OBJECTIVE: To explore the clinical application of laparoscopy in gastrointestinal abdominal emergency. METHODS: Clinical data of 44 cases with undefined acute abdomen undergoing laparoscopic surgery from October 2008 to October 2011 were analyzed retrospectively. Sixty-five cases treated by regular surgery during the same period were enrolled as controls. RESULTS: In laparoscopic surgery group, 42 cases were diagnosed under laparoscopy(95.5%, 42/44). Thirty-four (77.3%,34/44) patients received operation successfully after diagnosis, including 20 of total laparoscopy, 14 of assistant small incision. Compared with control group, laparoscopic group had shorter length of incision[(6.7+/-2.2) cm vs. (15.8+/-3.4) cm], less blood loss[(51.4+/-30.3) ml vs. (117.9+/-49.5) ml], faster recovery of postoperative gastrointestinal function[postoperative oral intake(15.0+/-6.1) d vs. (30.5+/-8.4) d], shorter hospital stay[(5.6+/-4.2) d vs. (8.4+/-4.8) d] (all P<0.05), lower complication rate, and less surgical cost(P>0.05). CONCLUSION: Laparoscopy is safe and effective in treating gastrointestinal abdominal emergency and therapeutic operation can be performed after a definite diagnosis. PMID- 24158869 TI - [Intracorporeal Roux-en-Y reconstruction after laparoscopic distal gastrectomy: a report of 20 cases]. AB - OBJECTIVE: To investigate the safety and feasibility of intracorporeal Roux-en-Y reconstruction after laparoscopic distal gastrectomy. METHODS: Clinical data of 20 patients undergoing laparoscopic distal gastrectomy and intracorporeal Roux-en Y reconstruction in our hospital from August 2012 to March 2013 were analyzed retrospectively. RESULTS: Totally laparoscopic distal gastrectomy was successfully performed in all the patients. The mean operation time was (190.8+/ 53.6) min, the mean operative blood loss was(122.4+/-57.7) ml, and mean number of harvested lymph node was 31.2+/-5.7. Tumor-free proximal margin was confirmed by pathological examination in all the patients. The mean time to first flatus and hospital stay were (2.6+/-1.6) d and (8.1+/-2.0) d. One case developed pulmonary infection postoperatively, but no anastomosis related complication was observed. CONCLUSION: Intracorporeal Roux-en-Y reconstruction after laparoscopic distal gastrectomy is safe and feasible. PMID- 24158870 TI - [Clinical analysis of 25 gastric cancer cases undergoing totally laparoscopic distal gastrectomy]. AB - OBJECTIVE: To investigate the feasibility and safety of totally laparoscopic distal gastrectomy. METHODS: Clinical data of 25 patients with distal gastric cancer undergoing totally laparoscopic distal gastrectomy between December 2011 and January 2013 were analyzed retrospectively. Only laparoscopic linear stapler was used in intracorporeal delta-shaped or Roux-en-Y anastomosis for reconstruction. RESULTS: No patient required conversion to laparoscopy-assisted or open surgery. The mean total operative time and anastomotic time were (256+/ 23.6) min and (35.7+/-8.4) min respectively in patients with delta-shaped anastomosis, and (287+/-11.5) min and (46.4+/-12.1) min in those with Roux-en-Y anastomosis. The mean blood loss was(109.6+/-42.3) ml, and the mean number of stapler used was 5.6. The mean time to the first flatus was (2.8+/-1.2) d, and mean time liquid diet to resume was (3.5+/-0.9) d. Postoperative complication occurred in 3 patients(12.0%). CONCLUSION: Totally laparoscopic distal gastrectomy with intracorporeal anastomosis using laparoscopic linear stapler is safe and feasible. PMID- 24158871 TI - [Analysis of lymph node dissection patterns in D2 radical gastrectomy by hand assisted laparoscopic technique]. AB - OBJECTIVE: To summarize the experience of lymph node dissection patterns in hand assisted laparoscopic radical gastrectomy. METHODS: One hundred and eleven patients with gastric carcinoma between December 2010 and September 2012 were operated by hand-assisted laparoscopic system designed by us. Clinical data were analyzed retrospectively. The lymph nodes were dissected from left to right together with total tumor resection(reverse lymph nodes scavenge pattern), then digestive tract was reconstructed. RESULTS: Total gastrectomy, distal gastrectomy and proximal gastrectomy were performed in 57, 46 and 8 cases respectively. Combined cholecystectomy and lateral segment of left liver lobe were needed in 4 and 2 patients respectively, and 1 case underwent combined splenectomy and pancreatic body and tail resection. TNM staging of patients in I(, II(, III(A, III(B, and IIII( were 16, 8, 35, 14, and 38, respectively. Histological type was poorly differentiated in 78 cases, moderate differentiation in 26 cases and good differentiation in 7 cases. The incision length was(6.8+/-0.3) cm, blood loss was(238.4+/-113.6) ml, operative time was (171.9+/-23.3) min, number of removed lymph node was 17.2+/-5.7, hospital stay was (10.1+/-3.7) d, postoperative complication rate was 9.0%. One case died during perioperative time. CONCLUSIONS: Hand-assisted laparoscopic D2 radical gastrectomy(reverse lymph nodes scavenge pattern) can avoid the multiple conversion of open-laparoscopic operation model, and is beneficial to the standardization for surgical procedure. PMID- 24158872 TI - [Systemic review of the safety and efficacy of fast-track surgery combined with laparoscopy in radical gastrectomy for gastric cancer]. AB - OBJECTIVE: To conduct a systemic review of the safety and efficacy of fast-track surgery combined with laparoscopy in radical gastrectomy for gastric cancer. METHODS: The databases, including CNKI, Wangfang, VIP, PubMed, EMBASE and Cochrane Library, were searched to collect randomized controlled trials(RCTs) or clinical controlled trials(CCTs) on the comparison of fast-track surgery combined with laparoscopy versus fast-track surgery or laparoscopy separately used in radical gastrectomy for gastric cancer between January 1994 and December 2012. After data were extracted, meta-analysis was conducted by using RevMan 5.1.0 software. RESULTS: A total of 3 RCTs and 2 CCTs, involving 524 patients, were included. There were 257 patients in the study group and 267 patients in the control group. Compared with the control group, the study group had earlier first flatus(SMD=-1.29, 95%CI:-2.17 to -0.40, P<0.05), shorter postoperative hospital stay(WMD=-1.72,95%CI:-2.56 to -0.89, P<0.05) and lower postoperative complication rate(OR=0.51, 95%CI:0.31 to 0.84, P<0.05). However, no significant differences were found in operation time, harvested lymph node number, intraoperative blood loss and hospital charge(P>0.05). CONCLUSION: Fast-track surgery combined with laparoscopy in radical gastrectomy for gastric cancer can accelerate postoperative rehabilitation by promoting postoperative bowel function recovery, and decreasing postoperative hospital stay and complication rate. PMID- 24158873 TI - [Re-optimized technology of protective ileostomy with no need of reversal]. AB - OBJECTIVE: To explore the clinical application of aoptimizedtechniquebased onpreviouslyreported protecting stoma with no need forreversal. METHODS: Thetechniquealso used "the assembly of drainage device" to performprotecting ileostomy. The original method includes enterotomy at the terminal ileum to placedrainage device, which was optimized as follows: two intestinal pursestring with 0.5 cm distance were placed 5 cm away from the ileocecal valve. Transverse enterotomy was performed in the anti-mesenteric side. The assembly was placed at the root of the appendix between two pursestring, and then the intestine purse suture was tighten. Ligation of the small intestine anastomosis between the anastomosis ring at both ends was carried out, and theanastomosis ring was deployed. From the root of the appendix in the cecum wall, the assembly was embedded about 2 cm and pulled out of abdominal cavitythough the Trocar hole. RESULTS: Seventeen cases of ultra-low rectal cancer completed protecting stoma, including 11 cases through ileocecal protective stoma. All the anastomosis healed well. Defecation drainage tube was removed 3-5 weeks after anastomosis ring degradation. Drainage nozzle healed after 3 to 5 days, and no complications occurred. CONCLUSION: The optimized ileocecal protective ileostomy has the following advantages: (1)wound healing time is significantly shorter. (2)secondary intestinal fistula can be prevented. (3)no need to fix ileum and less chance of subsequent volvulus, intestinal obstruction. PMID- 24158874 TI - [Manufacture and application of laparoscopic extraperitoneal sigmoid colostomy]. AB - OBJECTIVE: To investigate the safety and feasibility of laparoscopic extraperitoneal sigmoid colostomy. METHODS: Thirty-six patients with low rectal cancer undergoing laproscopic abdominoperineal resection from July 2011 to July 2012 were prospectively enrolled in the study and randomly divided into extraperitoneal colostomy group(EPC, n=18) and internal peritoneal colostomy group(IPC, n=18). Follow-up period was 4-16 (median, 7) months and postoperative complications were compared between two groups. RESULTS: One case in EPC group was converted to IPC because of poor blood supply of the proximal sigmoid, who was eliminated from the subsequent analysis. Compared with the IPC group, the surgery time was longer in EPC group [(25.3+/-8.5) min vs. (14.7+/-6.4) min], while the difference was not statistically significant(P>0.05). Each group had 1 case of stoma ischemia, who both received the colostomy reconstructive surgery. The incidence of stoma edema was significantly higher in EPC group[35.3%(6/17) vs. 0, P<0.05). The early postoperative complications rate did not significantly different between the two groups[58.8%(10/17) vs. 27.8%(5/18), P>0.05]. The late postoperative complications rate was 22.2%(4/18) in IPC group, including 1 case of stoma prolapse, 1 case of stoma stenosis and 2 cases of parastomal hernia. No later postoperative complication occurred in EPC group. CONCLUSION: Extraperitoneal sigmoid colostomy is an easy and safe procedure with lower late complications as compared to internal peritoneal sigmoid colostomy. PMID- 24158875 TI - [Effect of laparoscopic proctectomy and open proctectomy on plasma levels of vascular endothelial growth factor]. AB - OBJECTIVE: To investigate the effect of laparoscopic and open proctectomy on plasma levels of vascular endothelial growth factor (VEGF). METHODS: From January 2011 to December 2012, 100 rectal cancer patients in Shantou Central Hospital were enrolled in the study. Patients were divided into laparoscopic (LR) group and open (OR) group based on the decision of the patients. There were 63 patients in the LR group (44 cases undergoing low anterior resection and 19 abdominoperineal resection) and 37 patients in the OR group(26 cases undergoing low anterior resection and 11 abdominoperineal resection). Double antibody sandwich enzyme-linked immunohistochemistry was used to detect the level of VEGF on 1-day before and 1-day, 3-day, 7-day after operation. RESULTS: In the LR group, the postoperative levels of VEGF increased slowly, and the level of VEGF was significantly higher than that before operation until the 7-day after operation(P<0.05) regardless of the procedure. In the OR group, all the postoperative levels of VEGF were significantly increased(P<0.05). There was no significant difference of the VEGF level on 1-day before and 1-day after operation between the two groups(all P>0.05). The VEGF level in the OR group was significantly higher than that in the LR group on the day 3 and day 7 after operation(P<0.05). CONCLUSION: Compared with open approach, laparoscopic proctectomy has smaller short-term impact on the plasma level of VEGF in rectal cancer patients. PMID- 24158876 TI - [Perioperative managment of laparoscopic sleeve gastrectomy]. AB - OBJECTIVE: To summarize the surgical technique and perioperative management of laparoscopic sleeve gastrectomy (LSG). METHODS: A total of 57 morbid obesity patients undergoing LSG surgery from May 2010 to December 2012 were enrolled in the study, whose clinical data in perioperative period were analyzed retrospectively. These patients had more than 1 year of follow-up. All the patients received preoperative preparation and postoperative management, and postoperative excess weight loss(EWL%) and improvement of preoperative complications was evaluated. RESULTS: All the cases completed the operation under laparoscopy, except 1 case because of the abdominal extensive adhesion. The average operation time was(102.0+/-15.2) min and the mean intraoperative blood loss (132.3+/-45.6) ml. Of 2 postoperative hemorrhage patients, 1 case received conservative treatment, and another one underwent laparoscopic exploration. The EWL% at 3 months, 6 months and 1 year after procedure was (54.9+/-13.8)%, (79.0+/ 23.6)% and (106.9+/-25.1)% respectively. The preoperative complications were improved in some degree. There were no operative death, and anastomotic leak, anastomotic stenosis, or surgical site infection occurred. CONCLUSION: LSG is a safe and effective surgical technique, whose safety and efficacy may be increased by improving the perioperative management. PMID- 24158877 TI - [Evaluation of the application of laparoscopic sleeve gastrectomy in bariatric and metabolic surgery]. AB - Bariatric surgery is one of the most effective treatment options for obesity and type 2 diabetes mellitus. In recent years, laparoscopic sleeve gastrectomy has become increasingly popular due to simple operation, high safety and significant efficacy. In this article, the progress and the application evaluation of laparoscopic sleeve gastrectomy for the treatment of obesity and type 2 diabetes mellitus in the field of bariatric and metabolic surgery are reviewed. PMID- 24158878 TI - Carbetocin at elective Cesarean delivery: a randomized controlled trial to determine the effective dose, part 2. AB - PURPOSE: The aim of this study was to determine the intravenous dose of carbetocin required to produce effective uterine contraction in 95% of women (ED95) undergoing elective Cesarean delivery under spinal anesthesia. METHODS: One hundred and twenty term pregnant women at low risk for postpartum hemorrhage (PPH) undergoing elective Cesarean delivery under spinal anesthesia were randomly allocated to receive carbetocin in doses of 20, 40, 60, 80, or 100 MUg iv upon delivery of the fetus. The obstetrician evaluated the efficacy of uterine tone as satisfactory or unsatisfactory, and in case of unsatisfactory tone, additional uterotonics were administered as per routine institutional practice. The primary outcome measure was satisfactory uterine tone at two minutes after carbetocin administration, and the secondary outcomes were the estimated blood loss, need for additional uterotonic agents within 24 hr, and side effects. RESULTS: Overall satisfactory uterine tone at two minutes was observed in 94.2% (113/120) of the women, and there was no difference across the different study groups. It was not possible to calculate the ED95 of carbetocin due to the even distribution of women with unsatisfactory uterine tone at two minutes across all dose groups (P = 0.60). Additional uterotonics within 24 hr were required in 13% (16/120) of the women. Side effects were similar across all dose groups, with an overall 42.5% incidence of hypotension following the administration of carbetocin. CONCLUSIONS: In women at low risk for PPH undergoing elective Cesarean delivery under spinal anesthesia, carbetocin is similarly effective in doses of 20-100 MUg. There is a high incidence of hypotension associated with carbetocin in these doses. Further dose-finding studies are warranted, including doses lower than 20 MUg. This trial was registered at www.clinicaltrials.gov (NCT01428817). PMID- 24158879 TI - Perinatal nutrition programs the hypothalamic melanocortin system in offspring. AB - Epidemiological studies initially suggested that maternal undernutrition leading to low birth weight may predispose for long-lasting energy balance disorders. High birth weight due to maternal obesity or diabetes, inappropriate early postnatal nutrition, and rapid catch-up growth, may also sensitize to increased risk of obesity. As stated by the Developmental Origin of Health and Disease concept, the perinatal perturbation of fetus/neonate nutrient supply might be a crucial determinant of individual programming of body weight set-point. The hypothalamic melanocortin system composed of the melanocortin receptor 4, its agonist alpha-melanin-stimulating hormone (alpha-MSH), and its antagonist agouti related protein (AgRP) is considered as the main central anorexigenic pathway controlling energy homeostasis. Studies in numerous animal models demonstrated that this system is a prime target of developmental programming by maternal nutritional manipulation. In rodents, the perinatal period of life corresponds largely to the period of brain maturation (i. e., melanocortin neuronal differentiation and development of their neural projections). In contrast, these phenomena essentially take place before birth in bigger mammals. Despite these different developmental time windows, altricial and precocial species share several common offspring programming mechanisms. Offspring from malnourished dams present a hypothalamic melanocortin system with a series of alterations: impaired neurogenesis and neuronal functionality, disorganization of feeding pathways, modified glucose sensing, and leptin/insulin resistance. Overall, these alterations may account for the long-lasting dysregulation of energy balance and obesity. Following maternal malnutrition, hormonal and epigenetic mechanisms might be responsible for melanocortin system programming in offspring. PMID- 24158880 TI - Long-term incidence of depression and predictors of depressive symptoms in older stroke survivors. AB - BACKGROUND: Depression is common and an important consequence of stroke but there is limited information on the longer-term relationship between these conditions. AIMS: To identify the prevalence, incidence and predictors of depression in a secondary-care-based cohort of stroke survivors aged over 75 years, from 3 months to up to 10 years post-stroke. METHOD: Depression was assessed annually by three methods: major depression by DSM-IV criteria, the self-rated Geriatric Depression Scale (GDS) and the observer-rated Cornell scale. RESULTS: We found the highest rates, 31.7% baseline prevalence, of depressive symptoms with the GDS compared with 9.7% using the Cornell scale and 1.2% using DSM-IV criteria. Incidence rates were 36.9, 5.90 and 4.18 episodes per 100 person years respectively. Baseline GDS score was the most consistent predictor of depressive symptoms at all time points in both univariate and multivariate analyses. Other predictors included cognitive impairment, impaired activities of daily living and in the early period, vascular risk factor burden and dementia. CONCLUSIONS: Our results emphasise the importance of psychiatric follow-up for those with early-onset post-stroke depression and long-term monitoring of mood in people who have had a stroke and remain at high risk of depression. PMID- 24158881 TI - Epidemiology of hoarding disorder. AB - BACKGROUND: Hoarding disorder is typified by persistent difficulties discarding possessions, resulting in significant clutter that obstructs the individual's living environment and produces considerable functional impairment. The prevalence of hoarding disorder, as defined in DSM-5, is currently unknown. AIMS: To provide a prevalence estimate specific to DSM-5 hoarding disorder and to delineate the demographic, behavioural and health features that characterise individuals with the disorder. METHOD: We conducted a two-wave epidemiological study of 1698 adult individuals, originally recruited via the South East London Community Health (SELCoH) study. Participants screening positively for hoarding difficulties in wave 1, and who agreed to be re-contacted for wave 2 (n = 99), underwent in-home psychiatric interviews and completed a battery of self-report questionnaires. Current DSM-5 diagnoses were made via consensus diagnostic procedure. RESULTS: In total, 19 individuals met DSM-5 criteria for hoarding disorder at the time of interview, corresponding to a weighted prevalence of 1.5% (95% CI 0.7-2.2). Those with hoarding disorder were older and more often unmarried (67%). Members of this group were also more likely to be impaired by a current physical health condition (52.6%) or comorbid mental disorder (58%), and to claim benefits as a result of these issues (47.4%). Individuals with hoarding disorder were also more likely to report lifetime use of mental health services, although access in the past year was less frequent. CONCLUSIONS: With a lower bound prevalence of approximately 1.5%, hoarding disorder presents as a condition that affects people of both genders and is associated with substantial adversity. PMID- 24158882 TI - Dilatative uropathy as a manifestation of neurohypophyseal diabetes insipidus due to a novel mutation in the arginine vasopressin-neurophysin-II gene. AB - Polydypsia and polyuria are frequent symptoms in patients with sellar masses caused by neurohypophyseal diabetes insipidus. Autosomal dominant familial neurohypophyseal diabetes insipidus (adFNDI), a disorder caused by mutations in the arginine vasopressin (AVP) -neurophysin II (NPII) gene, should be considered as a rare differential diagnosis. A delayed diagnosis bears the risk of life threatening electrolyte imbalances and permanent urinary tract damage, leading to impaired quality of life.We present a Caucasian kindred of at least 4 generations with FNDI.Clinical histories, endocrine para-meters, and results of molecular analyses of the AVP gene are presented with a review of the literature on diabetes insipidus (DI) related urinary tract dilatation.Polyuria and polydipsia were only reported based on explicit and thorough interrogation after more than 4 years of clinical follow-up. A novel heterozygous mutation in the AVP gene was found in all examined symptomatic subjects (c.1-33_c.4del37nt). A literature review revealed that non-obstructive hydronephrosis (NOH) is a rare but known complication of DI.Since increased fluid intake is often a typical familial pattern in adFNDI, it is frequently missed as being pathologic in affected patients, therefore a detailed clinical history of drinking volumes is of critical importance. AVP gene testing is an important component in the confirmation of the diagnosis. Otherwise unexplainable NOH should lead to further investigations and evaluation of rare diseases like FNDI. PMID- 24158883 TI - YouTube as a source of information for children with paroxysmal episodes. AB - Whereas to date the internet is a main source of information for many parents, there are no restrictions regarding data presentation. Thus, the aim of this study was to assess the quality of internet material concerning paroxysmal episodes.We rated videos on YouTube for several conditions like infantile spasms, absence seizures, Sandifer syndrome, sleep myoclonus, and shuddering attacks. Videos were classified into different categories of certainty of diagnosis according to expert opinion based on a 4 point Likert scale followed by calculation of interrater reliability. Also the quality of supplemental information was assessed, as well as whether videos were helpful from a neuropaediatrican's point of view in counselling patients and their parents.In sleep myoclonus, absences and infantile spasms correlation between title of videos and classification by expert opinion was good. There was more discrepancy with the videos concerning Sandifer syndrome and shuddering attacks. Interrater reliability was low for Sandifer syndrome, fair for absences, shuddering attacks and sleep myoclonus and moderate for infantile spasms. Some supplemental information was rated to be helpful but other information was found to be misleading or even unsettling for patients and their parents.We consider that video material on YouTube can generally not be considered as helpful for parents because of a significant disagreement between experts, even for the most well defined disorders in our study. PMID- 24158884 TI - Testicular germ cell tumors in boys <10 years: results of the protocol MAHO 98 in respect to surgery and watch & wait strategy. AB - In 1982 the GPOH opened the 1st protocol for germ cell tumors (GCTs) of the testis (MAHO 82). Here the results of the 5th version (MAHO 98) will be offered for boys <10 year of age.In MAHO 98 watch and wait (w&w) strategy after inguinal tumororchiectomy was widened from 2 to 10-year-old boys with YST stage IA (group I); other invasive measures were omitted. Thus the prognostic impact of a non recommended surgery like transscrotal operation +/- conventional biopsy (group II) can be evaluated.Clinical diagnosis and staging by ultrasound and tumor marker. In blurry cases, a frozen section was recommended to confirm the diagnosis by histology intraoperatively. Indications for adjuvant chemotherapy were: YST stage IA without elevated AFP, YST stage>IA and all mixed malignant GCTs.From 1998 till 2005 128 boys <10 years with a testicular GCT were registered. HISTOLOGY: YST n=76, teratoma n=46, mixed malignant GCT n=6. Tumor stage IA: n=101. All teratoma patients survive event-free. At all, only 19/82 patients with a malignant GCT received chemotherapy including 5 patients with a tumor progress after w&w (2/49 group I and 3/15 group II patients, respectively) and 1 patient (YST IIIA) with relapse after adjuvant chemotherapy. Transscrotal surgery (n=18) or tumorenucleation (n=6) remained without event. Indeed all patients survived.Prognosis of boys <10 year with a testicular GCT is excellent as ~80% will be cured by high inguinal tumororchiectomy alone. w&w is feasible and safe even after not recommended surgery if suitable follow-up is assured at least in stage IA cases. PMID- 24158885 TI - Genotype-phenotype and genotype-origin correlations in children with mediterranean fever in Germany - an AID-net study. AB - Familial Mediterranean fever (FMF) is the most inherited common autoinflammatory disease (AID) with mutations in the MEFV (MEditerraneanFeVer) gene.The Mor- and Pras-Score modified for children and C-reactive protein (CRP) were used to assess FMF disease severity in Germany. We evaluate the applicability of the 2 severity scores and the correlations between ethnic origin, phenotype, and genotype.Among 242 children (median 5 age at diagnosis), we detected 431 pyrin mutations and 22 different sequence variants, including one new mutation (p.Gly488Asp). The 5 most -frequent alterations were p.Met694Val (55.2%), p.Met680lle (11.8%), p.Val726Ala (10%), p.Glu148Gln (7.9%) and p.Met694IIe (2.3%). The prevailing ancestries of 223 cases were Turkish (82.5%) and Lebanese (8.1%). Homozygous p.Met694Val substitution (30.2%) was associated with a more severe disease activity by Mor Score, as well as with a higher mean CRP (74 mg/l) compared to patients with other mutations. Indeed, Mor- and Pras-Score were inconsistent with each other. A typical distribution of mutations in different ethnic populations was obvious, but not statistically verifiable due to the low number of cases.The homozygous p.Met694Val substitution was associated with a more severe disease activity in our German cohort. The common severity scores were inconsistent in -children. PMID- 24158886 TI - Impact of cranial irradiation and brain tumor location on fertility: a survey. AB - As survival rates of patients with childhood brain tumors have increased to 75%, treatment related side effects are of particular importance. The present study evaluated questionnaire-based fertility characteristics in cancer survivors treated with irradiation to the hypo-thalamic-pituitary-axis.A nationwide survey was conducted in collaboration with the German Childhood Cancer Registry. Questionnaire and treatment data could be retrieved for 1110 former childhood cancer patients with cranial irradiation and/or chemotherapy.Survivors receiving >=30 gray vs. 18-29 gray and 0-17 gray to the pituitary gland reported less pregnancies or less with their partners (7.4% vs. 32.8% vs. 12.4%; p<0.001), were more often infertile (40% vs. 9.4% vs. 12.5%; p<0.001) and the female participants, had a higher frequency of permanent amenorrhea (16.7% vs. 1.7% vs. 0%; p<0.001).Irradiation of the pituitary gland >= 30 gray seemed to be associated with less pregnancies and increased permanent amenorrhea in women. Future studies need to be conducted to confirm these results. Increased knowledge of treatment related side effects might help brain tumor patients to improve their family planning if necessary by gonadotropine replacement. PMID- 24158887 TI - Extra-appendiceal neuroendocrine neoplasms in children - data from the GPOH-MET 97 Study. AB - Neuroendocrine neoplasms (NEN) in children are rare. In Germany, children with NEN of the gastroenteropancreatic system are prospectively registered since 1997. The objective of this study was to evaluate diagnostics, treatment and outcome in children with extra-appendiceal NEN.Clinical data of 39 patients with NEN registered in the GPOH-MET 97 trial from 1997 to 2012 were analyzed. Children with NEN of the appendix were excluded.14 patients with pancreatic, 12 patients with bronchial, 6 patients with gastrointestinal, 2 patients with nasopharyngeal and 5 patients with NEN of unknown primary were registered. About half of the patients had localized disease and rather low grade tumors, including all bronchial NEN, 5 of 14 pancreatic and 2 of 6 gastrointestinal tumors. Metastatic disease and high grade tumors were stated in cases with nasopharyngeal tumors, NEN of unknown -primary and in part of pancreatic and gastrointestinal NEN. Complete surgical resection was performed in patients with localized NEN with an overall survival of 100%. In contrast, overall survival in metastatic disease was 26%.Outcome in children with low grade NEN and localized disease is excellent. Management of high grade tumors and metastatic disease remains challenging. Establishing international registries is inevitable for further improvements. PMID- 24158888 TI - Safety of blood transfusions using 27 gauge neonatal PICC lines: an in vitro study on hemolysis. AB - Blood transfusions are required by the majority of extremely premature infants. Packed red blood cells (PRBCs) are usually applied via simple peripheral cannulas. In situations where no peripheral venous access is achievable, 27 Gauge (G) neonatal PICC lines - that are ideally exclusively dedicated to application of parenteral nutrition - may represent a useful alternative access for PRBC transfusions. However, transfusion via small scaled catheters may damage PRBCs and lead to hemolysis. We here evaluate whether transfusion of irradiated PRBCs via 27 G PICC lines leads to hemolysis in vitro.Experimental transfusions of gamma-irradiated PRBCs were performed at increasing velocities (2.5, 3.7, 5 ml/h; full force manual push approximating 30 ml/h) via 27 G PICC lines of 20 and 30 cm length. Parameters of hemolysis (lactate dehydrogenase, potassium and free hemoglobin) were measured from the supernatants of transfused PRBCs and the percentage of hemolysis was calculated.Potassium and lactate dehydrogenase after transfusion at increasing velocities did not differ significantly from negative controls. Free hemoglobin levels showed a small but significant increase at the slowest transfusion speed (2.5 ml/h) using the 30 cm 27 G PICC line, with a relative hemolysis of only 0.13%. A manual push (approximating 30 ml/h) showed no significant changes of parameters from baseline.We conclude that transfusion of gamma-irradiated PRBCs using a 27 G neonatal PICC line does not cause clinically relevant hemolysis in vitro. Clinical studies are needed to confirm the feasibility and safety of the approach in vivo. PMID- 24158889 TI - Short-term morbidities in moderate and late preterm infants. AB - OBJECTIVE: To determine (1) the association between neonatal morbidity and gestational age and (2) the impact of pre-existing maternal medical conditions, pregnancy and birth complications on neonatal outcome in moderate and late preterm infants (32-36 completed weeks). METHODS: Retrospective single-centre cohort study including all moderate and late preterm infants without congenital anomalies born at the Children's and Maternity Hospital Linz, Austria, between January 2007 and June 2010. Stepwise regression analysis was used to determine significant associations between morbidities, maternal and perinatal complications and the gestational age. RESULTS: Of 870 infants included the incidence of neonatal morbidities increased from 24% at 36 weeks to 43% at 35 weeks', 55% at 34 weeks', 75% at 33 weeks' and 93% at 32 weeks' gestation. Infants at 32 weeks had a 4-fold (RR: 3.88; 95% CI: 1.87-8.06) increased risk compared with those at 36 weeks, and infants of 32 weeks were 16 times (RR: 16.01; 95% CI: 9.82-26.09) more likely to be admitted to the NICU than infants of 36 weeks'. Hyperbilirubinemia (29%) and respiratory morbidity (14.3%) were the most common neonatal diagnoses. Intrauterine growth restriction, preeclampsia, preterm premature rupture of the membranes, lack of antenatal steroid administration, antepartum hemorrhage, multiple pregnancy and male gender were all associated with any kind of neonatal morbidity, admission rate to the NICU and length of hospital stay (p<0.05). CONCLUSION: Nearly half of all infants suffered from any morbidity, and several risk factors were identified being significantly associated with NICU admission rate and length of hospitalization. PMID- 24158890 TI - X-linked agammaglobulinemia in community-acquired pneumonia cases revealed by immunoglobulin level screening at hospital admission. AB - In children with primary immunodeficiencies, the onset of symptoms precedes the diagnosis and the initiation of appropriate treatment by months or years. This delay in diagnosis is due to the fact that while these disorders are rare, some of the infections seen in immunodeficient patients are common. Defective antibody production represents the largest group among these disorders, with otitis, sinusitis and pneumonia as the most frequent initial manifestation. We performed a prospective study of humoral immunity in children hospitalized due to community acquired pneumonia in tertiary care hospital. Out of 254 patients (131 boys, 123 girls, median age 4.5 years) recruited over 3 years, we found 2 boys (age 11 and 21 months) lacking serum immunoglobulins and circulating B cells. Subsequent genetic analysis confirmed diagnosis of X-linked agammaglobulinemia. Despite their immunodeficiency, the pneumonia was uncomplicated in both patients and did not call for immunological evaluation. However, the immunoglobulin screening at admission allowed for an early diagnosis of the immunodeficiency and timely initiation of immunoglobulin substitution, the key prerequisite for a favorable course of the disease.Simple and inexpensive immuno-globulin measurement during the manage-ment of hospitalized children with community-acquired pneumonia may help in early identification of patients with compromised humoral immunity and prevent serious complications. PMID- 24158891 TI - [Pneumothorax during mechanical ventilation--therapeutic options in term and preterm neonates]. AB - A pneumothorax (PTX) is a potentially life threatening event during mechanical ventilation. Aim of this study was to analyse 3 different ways of management: expectant treatment, once-only pleural puncture and thoracic drainage.Retrospective data analysis in term and preterm neonates admitted to the NICU of the Medical University of Graz (between 2000-2010) and Innsbruck (2002 2010) who suffered from a PTX during continuous positive airway pressure (CPAP) or conventional mechanical ventilation (CMV).104 neonates, 33 term and 71 preterm neonates with PTX were included. 33 term neonates: 52% were treated expectantly, 36% with thoracic drainage and 12% with once-only pleural puncture (100% thoracic drainage after pleural puncture). 71 preterm neonates: 25% were treated expectantly, 52% with thoracic drainage and 23% with pleural puncture (63% thoracic drainage after pleural puncture). In CPAP-subgroup (n=64), term neonates were treated in 60% expectantly and in 40% with thoracic drain-age, preterm neonates in 33% expectantly, in 47% with thoracic drainage and in 20% with pleural puncture (50% thoracic drainage after pleural puncture). In CMV-subgroup (n=40), term neonates were treated in 44% expectantly, in 33% with thoracic drainage and in 22% with pleural puncture (100% thoracic drainage after pleural puncture), preterm neonates in 9% expectantly, in 64% with thoracic drainage and in 27% with pleural puncture (83% thoracic drain-age after pleural puncture).Present data show that expectant treatment is feasible. If invasive intervention is needed, once-only pleural puncture was not successful, as often thoracic drainage was necessary in addition. PMID- 24158892 TI - Torsion of extralobar lung sequestration - lack of contrast medium enhancement could facilitate MRI-based diagnosis. PMID- 24158893 TI - Herpes simplex virus reactivation and disease during treatment for childhood acute lymphoblastic leukemia. PMID- 24158894 TI - Reactive pituitary enlargement mimicking a sellar mass. PMID- 24158895 TI - Myeloid and plasmacytoid dendritic cells: reference ranges in the peripheral blood of healthy children. AB - To date, few publications report on dendritic cells values in healthy children and mostly are found as control groups in studies focused on either allergic and autoimmune diseases or malignancies. This report provides an overview of 8 publications regarding absolute dendritic cells quantification in the peripheral blood of healthy children by using minimum manipulated samples processed within 24 hours. PMID- 24158896 TI - Homozygous R127H mutation in the GJB2 gene in a boy with initial unilateral severe hearing loss. PMID- 24158897 TI - Severe hypertriglyceridemia in a 6-year-old boy with ALL relapse: successfully treated with plasmapheresis. PMID- 24158898 TI - Sequential therapy versus standard triple-drug therapy for Helicobacter pylori eradication: a randomized study. AB - BACKGROUND: Antimicrobial resistance has decreased eradication rates for Helicobacter pylori infection worldwide. A sequential treatment schedule has been reported to be effective, but studies published to date were performed in Italy. We undertook this study to determine whether these results could be replicated in India. METHODS: A randomized, open-labeled, prospective controlled trial comparing sequential vs. standard triple-drug therapy was carried out at Lokmanya Tilak Municipal General Hospital, Mumbai. Two hundred and thirty-one patients with dyspepsia were randomized to a 10-day sequential regimen (40 mg of pantoprazole, 1 g of amoxicillin, each administered twice daily for the first 5 days, followed by 40 mg of pantoprazole, 500 mg of clarithromycin, and 500 mg of tinidazole, each administered twice daily for the remaining 5 days) or to standard 14-day therapy (40 mg of pantoprazole, 500 mg of clarithromycin, and 1 g of amoxicillin, each administered twice daily). RESULTS: The eradication rate achieved with the sequential regimen was significantly greater than that obtained with the triple therapy. Per-protocol eradication rate of sequential therapy was 92.4% (95% CI 85.8-96.1%) vs. 81.8% (95% CI 73.9-87.8%) (p = 0.027) for standard drug therapy. Intention-to-treat eradication rates were 88.2% (95% CI 80.9-93.0%) vs. 79.1% (95% CI 71.1-85.4%), p = 0.029, respectively. The incidence of major and minor side effects between therapy groups was not significantly different (14.6% in the triple therapy group vs. 23.5% in sequential group, p = 0.12). Follow up was incomplete in 3.3% and 4.7% patients in standard and sequential therapy groups, respectively. Sequential therapy includes one additional antibiotic (tinidazole) that is not contained in standard therapy. CONCLUSIONS: Sequential therapy was significantly better than standard therapy for eradicating H. pylori infection. PMID- 24158899 TI - Endoscopic "crossroads" in the management of malignant hilar strictures. PMID- 24158900 TI - Endonasal endoscopic release of a delayed tension pneumocephalus after craniofacial resection of a tumor of the anterior skull base. AB - Tension pneumocephalus is a rare complication that can occur after craniofacial resection of lesions of the anterior skull base. Early diagnosis is important to avoid potential serious neurologic deficits, including death. It has been associated with the perioperative placement of a lumbar drainage and with esthesioneuroblastoma. Therapy consists of evacuation of the intracranial air as well as conservative measures. Here we report a case of a patient with an ethmoidal esthesioneuroblastoma who underwent a traditional microsurgical craniofacial resection and developed a delayed epidural tension pneumocephalus. This was treated by performing an incision in the pericranial flap covering the anterior cranial base defect using an endonasal endoscopic approach. To our knowledge, this particular treatment technique has not been reported before in this context. PMID- 24158901 TI - Longitudinal stent deformation elongating to left main trunk. AB - A 67-year-old woman was admitted with an acute coronary syndrome. Angiographic examination revealed diffuse severe stenosis of the left circumflex artery. A Pressure Wire Certus (St. Jude Medical, St. Paul, MN, USA) was passed to the second post-lateral (PL) branch. To prevent side-branch occlusion, a SION wire (Asahi Intecc Co., Aichi, Japan) was left in the first PL branch, and a SION blue wire (Asahi Intecc) was placed in the second obtuse marginal branch. We implanted an everolimus-eluting stent (PROMUS Element 2.5 * 24 mm, Boston Scientific, Natick, MA, USA) in the culprit lesion. After retrieving the protection wire in first PL branch with resistance, we performed post-dilatation. However, the intravascular ultrasound images showed that the proximal portion of the implanted stent had elongated approximately 2 mm to the left main trunk (LMT), although the position of the distal edge of the stent was unchanged. We decided to additionally place a stent from the ostium of the LMT to the proximal left anterior descending coronary artery, and a biolimus-eluting stent (NOBORI 3.0 * 18 mm, Terumo Co., Tokyo, Japan) was implanted successfully. Longitudinal stent elongation might be caused by the small number of links between the hoops of a stent, originally intended to improve deliverability. PMID- 24158902 TI - Wound drainage after axillary dissection for carcinoma of the breast. AB - BACKGROUND: Axillary dissection is commonly performed for breast carcinoma. It is uncertain whether insertion of a drain reduces complication rates. OBJECTIVES: To assess the effects of wound drainage after axillary dissection for breast carcinoma on the incidence of postoperative seroma formation. Secondary outcome measures include the incidence of infection and length of hospital stay. SEARCH METHODS: We searched the Cochrane Wound and Breast Cancer Group's Specialised Registers (22 February 2013), MEDLINE (1950 to 22 February 2013), EMBASE (1966 to 22 February 2013), the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP) and ClinicalTrials.gov (22 February 2013) for all prospectively registered and ongoing trials (22 February 2013). Reference lists of included studies were handsearched by two independent review authors to look for additional eligible trials. SELECTION CRITERIA: All randomised controlled trials (RCTs) comparing wound drainage versus no wound drainage in individuals after axillary dissection for the treatment of breast carcinoma were included. All disease stages were considered. Breast-conserving surgery and mastectomy were considered. Patients undergoing sentinel node biopsy without axillary dissection were not included. No limits were applied to language or study location. Two review authors independently determined the eligibility of each study. DATA COLLECTION AND ANALYSIS: Two review authors independently extracted data for each included study using a predesigned data extraction proforma and assessed risk of bias using The Cochrane Collaboration's 'Risk of bias' tool. Discrepancies were resolved by consensus discussion with a third review author. Dichotomous variables were analysed using a Mantel-Haenszel model to produce odds ratios (ORs). Continuous variables were analysed using an inverse variance model to produce a mean difference (MD). MAIN RESULTS: Seven RCTs including 960 participants were identified. The quality of trials was generally low, with several studies at risk of selection bias, and no studies used blinding during treatment or outcome assessment. There was a high level of statistical variation between the studies, which therefore reduces the reliability of the evidence. The OR for seroma formation was 0.46 (95% confidence interval (CI) 0.23 to 0.91, P = 0.03) in favour of a reduced incidence of seroma in participants with drains inserted. There was no significant difference in infection rates between drainage and no drainage groups (OR = 0.70; 95% CI 0.44 to 1.12, P = 0.14). The mean difference in length of hospital stay, reported in four trials consisting of 600 participants, was 1.47 days greater in the drained population (95% CI 0.67 to 2.28, P = 0.0003). A mean difference of 0.79 fewer postoperative seroma aspirations was found in the drained population (95% CI 1.23 to 0.35 fewer, P = 0.0004) in two trials including 212 participants. No significant difference in volume of seroma aspirations was reported (MD -19.44, 95% CI -59.45 to 20.57, P = 0.34) in three trials including 519 participants. No significant difference in the incidence of lymphoedema was noted (OR 2.31 favouring no drainage, 95% CI 0.47 to 11.37, P = 0.30), with only six instances reported in three trials of 360 participants, nor was any significant difference in the incidence of haematoma observed (OR 1.68, 95% CI 0.33 to 8.51, P = 0.53), with only five instances reported in two trials of 314 participants. AUTHORS' CONCLUSIONS: There is limited quality evidence that insertion of a drain following axillary lymphadenectomy reduced the odds of developing a seroma and reduced the number of post-operative seroma aspirations. These benefits should be balanced against an increased length of hospital stay in the drained population. PMID- 24158903 TI - Health-related information exchange experiences of Jordanian women at breast cancer diagnosis. AB - The aim of this study was to explore Jordanian women's experiences of information exchange following diagnosis of early stage breast cancer. A purposive sample of 28 women who had surgery for early stage breast cancer within 6 months prior to the interview and had treatment at three hospitals in Central and Northern Jordan was recruited for the study. Data were collected using semi-structured individual interviews focused on women's communication experiences at diagnosis and during cancer treatment. Interviews were audio taped, transcribed verbatim in Arabic, and analyzed using conventional content analysis. Three main themes associated with information exchange were revealed as follows: (1) knowledge about breast cancer and its treatment, (2) communication of cancer diagnosis and treatment, and (3) educating on treatment side effects. Misconceptions about breast cancer risk factors, consequences of breast cancer treatment, and breast cancer-related symptoms were common among participants. Women made important health-related decisions based on misconceptions. Physician's information giving, availability, and responses to women's questions varied by their level of education and the type and location of treatment facility. Informational exchange experiences vary among Jordanian women diagnosed with breast cancer and raise concern over opportunities offered these women to engage in informed decision making. Findings suggest a need for nurses to assess the information needs of Jordanian women newly diagnosed with breast cancer and provide education tailored to individual needs. There is also a need to develop Arabic educational materials and make these available for patients at treatment facilities in all regions of Jordan. PMID- 24158905 TI - A thermoelectric heat engine with ultracold atoms. AB - Thermoelectric effects, such as the generation of a particle current by a temperature gradient, have their origin in a reversible coupling between heat and particle flows. These effects are fundamental probes for materials and have applications to cooling and power generation. Here, we demonstrate thermoelectricity in a fermionic cold atoms channel in the ballistic and diffusive regimes, connected to two reservoirs. We show that the magnitude of the effect and the efficiency of energy conversion can be optimized by controlling the geometry or disorder strength. Our observations are in quantitative agreement with a theoretical model based on the Landauer-Buttiker formalism. Our device provides a controllable model system to explore mechanisms of energy conversion and realizes a cold atom-based heat engine. PMID- 24158904 TI - Identification and rescue of alpha-synuclein toxicity in Parkinson patient derived neurons. AB - The induced pluripotent stem (iPS) cell field holds promise for in vitro disease modeling. However, identifying innate cellular pathologies, particularly for age related neurodegenerative diseases, has been challenging. Here, we exploited mutation correction of iPS cells and conserved proteotoxic mechanisms from yeast to humans to discover and reverse phenotypic responses to alpha-synuclein (alphasyn), a key protein involved in Parkinson's disease (PD). We generated cortical neurons from iPS cells of patients harboring alphasyn mutations, who are at high risk of developing PD dementia. Genetic modifiers from unbiased screens in a yeast model of alphasyn toxicity led to identification of early pathogenic phenotypes in patient neurons. These included nitrosative stress, accumulation of endoplasmic reticulum (ER)-associated degradation substrates, and ER stress. A small molecule identified in a yeast screen (NAB2), and the ubiquitin ligase Nedd4 it affects, reversed pathologic phenotypes in these neurons. PMID- 24158906 TI - The role of surface oxygen in the growth of large single-crystal graphene on copper. AB - The growth of high-quality single crystals of graphene by chemical vapor deposition on copper (Cu) has not always achieved control over domain size and morphology, and the results vary from lab to lab under presumably similar growth conditions. We discovered that oxygen (O) on the Cu surface substantially decreased the graphene nucleation density by passivating Cu surface active sites. Control of surface O enabled repeatable growth of centimeter-scale single-crystal graphene domains. Oxygen also accelerated graphene domain growth and shifted the growth kinetics from edge-attachment-limited to diffusion-limited. Correspondingly, the compact graphene domain shapes became dendritic. The electrical quality of the graphene films was equivalent to that of mechanically exfoliated graphene, in spite of being grown in the presence of O. PMID- 24158907 TI - ERF115 controls root quiescent center cell division and stem cell replenishment. AB - The quiescent center (QC) plays an essential role during root development by creating a microenvironment that preserves the stem cell fate of its surrounding cells. Despite being surrounded by highly mitotic active cells, QC cells self renew at a low proliferation rate. Here, we identified the ERF115 transcription factor as a rate-limiting factor of QC cell division, acting as a transcriptional activator of the phytosulfokine PSK5 peptide hormone. ERF115 marks QC cell division but is restrained through proteolysis by the APC/C(CCS52A2) ubiquitin ligase, whereas QC proliferation is driven by brassinosteroid-dependent ERF115 expression. Together, these two antagonistic mechanisms delimit ERF115 activity, which is called upon when surrounding stem cells are damaged, revealing a cell cycle regulatory mechanism accounting for stem cell niche longevity. PMID- 24158908 TI - High-resolution mapping of the spatial organization of a bacterial chromosome. AB - Chromosomes must be highly compacted and organized within cells, but how this is achieved in vivo remains poorly understood. We report the use of chromosome conformation capture coupled with deep sequencing (Hi-C) to map the structure of bacterial chromosomes. Analysis of Hi-C data and polymer modeling indicates that the Caulobacter crescentus chromosome consists of multiple, largely independent spatial domains that are probably composed of supercoiled plectonemes arrayed into a bottle brush-like fiber. These domains are stable throughout the cell cycle and are reestablished concomitantly with DNA replication. We provide evidence that domain boundaries are established by highly expressed genes and the formation of plectoneme-free regions, whereas the histone-like protein HU and SMC (structural maintenance of chromosomes) promote short-range compaction and the colinearity of chromosomal arms, respectively. Collectively, our results reveal general principles for the organization and structure of chromosomes in vivo. PMID- 24158909 TI - Yeast reveal a "druggable" Rsp5/Nedd4 network that ameliorates alpha-synuclein toxicity in neurons. AB - alpha-Synuclein (alpha-syn) is a small lipid-binding protein implicated in several neurodegenerative diseases, including Parkinson's disease, whose pathobiology is conserved from yeast to man. There are no therapies targeting these underlying cellular pathologies, or indeed those of any major neurodegenerative disease. Using unbiased phenotypic screens as an alternative to target-based approaches, we discovered an N-aryl benzimidazole (NAB) that strongly and selectively protected diverse cell types from alpha-syn toxicity. Three chemical genetic screens in wild-type yeast cells established that NAB promoted endosomal transport events dependent on the E3 ubiquitin ligase Rsp5/Nedd4. These same steps were perturbed by alpha-syn itself. Thus, NAB identifies a druggable node in the biology of alpha-syn that can correct multiple aspects of its underlying pathology, including dysfunctional endosomal and endoplasmic reticulum-to-Golgi vesicle trafficking. PMID- 24158910 TI - TP53 alterations and colorectal cancer predisposition in south Indian population: a case-control study. AB - The objective of the present study was to investigate the association between TP53 gene single nucleotide polymorphisms (SNPs) and colorectal cancer (CRC) predisposition in south Indian population and to evaluate the role of TP53 expression in the pathophysiology of CRC. A genetic association study was conducted in 103 CRC cases and 107 controls of south Indian origin. We genotyped ten selected TP53 SNPs by polymerase chain reaction-sequencing analysis. Haplotype frequencies for multiple loci and the standardized disequilibrium coefficient (D') for pairwise linkage disequilibrium (LD) were assessed by Haploview Software. In addition, to better understand the role of TP53 in the pathophysiology of CRC, the expression pattern was evaluated in analogous tumor and normal tissues from 23 CRC patients by Western blot analysis. The frequencies of Pro72Pro (P = 0.0033) genotype and Ser47/Pro72 (P = 0.00171) haplotype were significantly higher in patients as compared to controls. Strong LD was observed between codon 47 and 72 in cases (D' = 0.32) as compared to controls (D' = 0.21). The polymorphism was not observe at the remaining eight SNPs loci analyzed. Furthermore, increased TP53 expression was observed in tumor tissue than in analogous normal tissue of CRC patients. Interestingly, advanced stage tumors showed more elevated TP53 expression compared to early stage tumors. In conclusion, the TP53 Pro72Pro genotype and Ser47/Pro72 haplotype has an increased risk for CRC predisposition in south Indian population. In addition, elevated TP53 expression appears to be useful prognostic marker for CRC. PMID- 24158913 TI - Medical discovery in the age of breaking news. PMID- 24158914 TI - Reducing risks to the unborn child. PMID- 24158915 TI - Response to 'Anaemia in the older surgical patient'. PMID- 24158912 TI - Animal models of Parkinson's disease: a gateway to therapeutics? AB - Parkinson's disease (PD) is a progressive, neurodegenerative disorder of unknown etiology, although a complex interaction between environmental and genetic factors has been implicated as a pathogenic mechanism of selected neuronal loss. A better understanding of the etiology, pathogenesis, and molecular mechanisms underlying the disease process may be gained from research on animal models. While cell and tissue models are helpful in unraveling involved molecular pathways, animal models are much better suited to study the pathogenesis and potential treatment strategies. The animal models most relevant to PD include those generated by neurotoxic chemicals that selectively disrupt the catecholaminergic system such as 6-hydroxydopamine; 1-methyl-1,2,3,6 tetrahydropiridine; agricultural pesticide toxins, such as rotenone and paraquat; the ubiquitin proteasome system inhibitors; inflammatory modulators; and several genetically manipulated models, such as alpha-synuclein, DJ-1, PINK1, Parkin, and leucine-rich repeat kinase 2 transgenic or knock-out animals. Genetic and nongenetic animal models have their own unique advantages and limitations, which must be considered when they are employed in the study of pathogenesis or treatment approaches. This review provides a summary and a critical review of our current knowledge about various in vivo models of PD used to test novel therapeutic strategies. PMID- 24158917 TI - How dramatic were the effects of handwashing on maternal mortality observed by Ignaz Semmelweis? PMID- 24158918 TI - Ignaz Phillip Semmelweis' studies of death in childbirth. PMID- 24158922 TI - A critical systematic review of budget impact analyses on drugs in the EU countries. AB - BACKGROUND: Budget impact analysis (BIA) is a relatively recent technique that is supposed to be complementary to more established economic evaluations (EEs). OBJECTIVE: We reviewed the BIAs published on drugs in the EU since December 2008, to assess whether these studies have improved in quality in the last few years. METHODS: We conducted a literature search on the international databases PubMed and EMBASE. The selected articles were screened using a two-step approach to assess (1) their main methodological characteristics and (2) the level of adherence to the latest BIA definition. The assessment was made by two independent reviewers and any disagreement was resolved through discussion. RESULTS: Eventually, 17 articles were reviewed. Thirteen referred to a stand alone BIA not accompanying a full EE, only nine focussed on a new treatment, 15 were sponsored by the manufacturer of the drug of reference, all but one claiming savings for healthcare budgets. The quality of methods was poor in many of the studies, and only a few of them attempted to estimate real local costs in a credible way. Therefore, the crucial items that in theory make a BIA different from other types of EEs were often the major points of weakness of the studies reviewed. CONCLUSIONS: Our review confirmed that the BIA is not yet a well established technique in the literature and many published studies still fail to reach an acceptable quality. In particular, BIAs funded by pharmaceutical companies appear to be tailored to show short-term savings induced by new, highly priced products. PMID- 24158923 TI - Dietary supplements for preventing postnatal depression. AB - BACKGROUND: Postnatal depression is a medical condition that affects many women and the development of their infants. There is a lack of evidence for treatment and prevention strategies that are safe for mothers and infants. Certain dietary deficiencies in a pregnant or postnatal woman's diet may cause postnatal depression. By correcting these deficiencies postnatal depression could be prevented in some women. Specific examples of dietary supplements aimed at preventing postnatal depression include: omega-3 fatty acids, iron, folate, s adenosyl-L-methionine, cobalamin, pyridoxine, riboflavin, vitamin D and calcium. OBJECTIVES: To assess the benefits of dietary supplements for preventing postnatal depression either in the antenatal period, postnatal period, or both. SEARCH METHODS: We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (30 April 2013). SELECTION CRITERIA: Randomised controlled trials, involving women who were pregnant or who had given birth in the previous six weeks, who were not depressed or taking antidepressants at the commencement of the trials. The trials could use as intervention any dietary supplementation alone or in combination with another treatment compared with any other preventive treatment, or placebo, or standard clinical care. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed trials for inclusion and assessed the risk of bias for the two included studies. Two review authors extracted data and the data were checked for accuracy. MAIN RESULTS: We included two randomised controlled trials.One trial compared oral 100 microgram (ug) selenium yeast tablets with placebo, taken from the first trimester until birth. The trial randomised 179 women but outcome data were only provided for 85 women. Eighty three women were randomised to each arm of the trial. Sixty-one women completed the selenium arm, 44 of whom completed an Edinburgh Postnatal Depression Scale (EPDS). In the placebo arm, 64 women completed the trial, 41 of whom completed an EPDS. This included study (n = 85) found selenium had an effect on EPDS scores but did not reach statistical significance (P = 0.07). There was a mean difference (MD) of -1.90 (95% confidence interval (CI) -3.92 to 0.12) of the self reported EPDS completed by participants within eight weeks of delivery. There was a high risk of attrition bias due to a large proportion of women withdrawing from the study or not completing an EPDS. This included study did not report on any of the secondary outcomes of this review.The other trial compared docosahexanoic acid (DHA) and eicosapentaenoic acid (EPA) with placebo. The trial randomised 126 women at risk of postpartum depression to three arms: 42 were allocated to EPA, 42 to DHA, and 42 to placebo. Three women in the EPA arm, four in the DHA arm, and one woman in the placebo arm were lost to follow-up. Women who were found to have major depressive disorder, bipolar disorder, current substance abuse or dependence, suicidal ideation or schizophrenia at recruitment were excluded from the study. The women who discontinued the intervention (five in the EPA arm, four in the DHA arm and seven in the placebo arm) were included in the intention-to treat analysis, while those who were lost to follow-up were not. Women received supplements or placebo from recruitment at a gestational age of 12 to 20 weeks until their final review visit six to eight weeks postpartum. The primary outcome measure was the Beck Depression Inventory (BDI) score at the fifth visit (six to eight weeks postpartum). No benefit was found for EPA-rich fish oil (MD 0.70, 95% CI -1.78 to 3.18) or DHA-rich fish oil supplementation (MD 0.90, 95% CI -1.33 to 3.13) in preventing postpartum depression. No difference was found in the effect on postnatal depression comparing EPA with DHA (MD -0.20, 95% CI -2.61 to 2.21). No benefit or significant effect was found in terms of the secondary outcomes of the presence of major depressive disorder at six to eight weeks postpartum, the number of women who commenced antidepressants, maternal estimated blood loss at delivery or admission of neonates to the neonatal intensive care unit. AUTHORS' CONCLUSIONS: There is insufficient evidence to conclude that selenium, DHA or EPA prevent postnatal depression. There is currently no evidence to recommend any other dietary supplement for prevention of postnatal depression. PMID- 24158924 TI - ICRU Report No. 87: Radiation dose and image-quality assessment in computed tomography. AB - Computed tomography has experienced a number of significant technological advances over the past decade, and these have had pronounced impacts on the accuracy of radiation dosimetry and the assessment of image quality. After reviewing CT technology and clinical applications, this Report describes and discusses existing dosimetry methods and then presents new methods for radiation dosimetry, including the evaluation of beam quality, and measurement of CT scanner output in air and in phantoms. Many of the proposed dosemetric quantities can be measured quickly using a real-time ionization chamber, which is introduced here. Traditional measurements of image quality for computed tomography rely upon simple and subjective observations. A more rigorous approach is proposed, including routine use of the modulation-transfer function for describing spatial resolution along all axes, and of the noise-power spectrum for describing the noise amplitude and texture properties of CT images. This Report focuses on new but practical methods for the assessment of radiation dose and image quality for CT scanners. PMID- 24158940 TI - Pharmacokinetics, safety and tolerability of DA-6034, an anti-inflammatory agent, after single and multiple oral administrations in healthy volunteers. AB - BACKGROUND AND OBJECTIVES: Inflammatory bowel disease (IBD) is a chronic inflammatory disorder of the gastrointestinal tract. DA-6034 has been shown to be effective in an IBD model and has demonstrated a good toxicological profile in preclinical studies. This study evaluated the tolerability, safety and pharmacokinetics of DA-6034 in healthy volunteers. METHODS: A double-blind, randomized, placebo-controlled, ascending-dose study was conducted in 67 healthy volunteers. In the single-ascending-dose study, 10, 20, 50, 100 or 200 mg of DA 6034 was administered orally to 40 subjects; in the multiple-ascending-dose study, 40, 100 or 200 mg/day of DA-6034 was administered orally to 27 subjects for 7 days. Serial blood and urine samples were taken for pharmacokinetic analysis. Plasma drug concentrations were determined by high-performance liquid chromatography. Safety and tolerability were assessed throughout the study. RESULTS: DA-6034 had minimal absorption, and the pharmacokinetic parameters were highly variable among subjects. For both the single- and multiple-dose administrations, the coefficients of variation of the area under the plasma concentration-time curve to the last observation (AUClast) and the area under the plasma concentration-time curve over the dosing interval at steady state (AUCss,tau) ranged from 16.0 to 125.0 %. At doses of up to 200 mg of DA-6034, the mean maximum plasma concentration (C max) was <3 ng/mL, and the urine recovery ratio was 0.3 % of the dose, indicating a lack of absorption. Twenty-two mild adverse events were reported in 14 subjects. There were no serious adverse events and no significant changes in the safety assessment. CONCLUSION: DA-6034 was well tolerated and minimally absorbed in healthy volunteers. The non-systemic, local exposure of the gastrointestinal tract to DA-6034 may be advantageous for IBD treatment. PMID- 24158941 TI - Kola nut: so much more than just a nut. PMID- 24158942 TI - Opt-out organ donation: on evidence and public policy. PMID- 24158943 TI - Glaciihabitans tibetensis gen. nov., sp. nov., a psychrotolerant bacterium of the family Microbacteriaceae, isolated from glacier ice water. AB - A Gram-stain-positive, aerobic, non-spore-forming, short-rod-shaped bacterium, designated strain MP203(T), was isolated from ice water of Midui Glacier in Tibet Autonomous Region, China. The strain was psychrotolerant, growing at 0-25 degrees C. 16S rRNA gene sequence analysis showed that strain MP203(T) was most similar to Frigoribacterium faeni NBRC 103066(T), Compostimonas suwonensis KACC 13354(T), Frigoribacterium mesophilum KCTC 19311(T), Marisediminicola antarctica CCTCC AB 209077(T) and Alpinimonas psychrophila JCM 18951(T), with similarities of 97.4, 97.2, 97.2, 97.1 and 97.1%, respectively. The maximum-likelihood phylogenetic tree indicated that strain MP203(T) clustered with nine genera of the family Microbacteriaceae, namely Frigoribacterium, Compostimonas, Marisediminicola, Alpinimonas, Frondihabitans, Clavibacter, Subtercola, Klugiella and Agreia. However, bootstrap analysis showed that there was no significance in the branching pattern of the linage comprising strain MP203(T) and any existing generic lineage of the family Microbacteriaceae. DNA-DNA hybridization results indicated levels of relatedness between strain MP203(T) and Marisediminicola antarctica CCTCC AB 209077(T), Frigoribacterium faeni NBRC 103066(T), Frigoribacterium mesophilum KCTC 19311(T), Compostimonas suwonensis KACC 13354(T) and Alpinimonas psychrophila JCM 18951(T) were 25.8 +/- 7.3, 29.6 +/- 7.6, 19.7 +/- 6.7, 16.0 +/- 4.2 and 12.4 +/- 5.1 % (mean +/- SD), respectively. The G+C content of the genomic DNA was 64.1 mol%. Analysis of the cell-wall peptidoglycan revealed that the peptidoglycan structure of strain MP203(T) was B10 type with Gly[l-Hse]-D-Glu-D-DAB, containing 2, 4-diaminobutyric acid (DAB) as a diagnostic amino acid. The cell-wall sugars were rhamnose, ribose, mannose and glucose. The major fatty acids were anteiso-C(15 : 0), iso-C(16 : 0) and anteiso A-C(15 : 1). An unusual compound identified as anteiso-C(15 : 0)-DMA (1,1-dimethoxy-anteiso pentadecane) was also present in strain MP203(T). The predominant menaquinone was MK-10. Diphosphatidylglycerol (DPG), phosphatidylglycerol (PG), one unknown glycolipid and four unknown lipids were detected in the polar lipid extracts. As strain MP203(T) was distinguishable from phylogenetically related genera in the family Microbacteriaceae in terms of its physiological and chemotaxonomic characteristics and phylogenetic position, it was considered to represent a novel species of a new genus. Thus, the name Glaciihabitans tibetensis gen. nov., sp. nov. is proposed. The type strain of Glaciihabitans tibetensis is MP203(T) ( = CGMCC 1.12484(T) = KCTC 29148(T)). PMID- 24158944 TI - Yarrowia divulgata f.a., sp. nov., a yeast species from animal-related and marine sources. AB - Five yeast strains, phenotypically indistinguishable from Yarrowia lipolytica and Yarrowia deformans, were recovered from different animal-related samples. One strain was isolated from a bacon processing plant in Denmark, two strains from chicken liver in the USA, one strain from chicken breast in Hungary and one from minced beef in Hungary. Comparisons of the sequences of their large subunit rRNA gene D1/D2 domain and the internal transcribed spacer (ITS) regions revealed that, despite their phenotypic similarity, they represent a novel yeast species of the Yarrowia clade with Y. deformans being the genotypically closest relative (LSU rRNA gene D1/D2 and ITS region similarity of 97.0 and 93.7 %, respectively). Yarrowia divulgata f.a., sp. nov. is proposed to accommodate these strains with F6-17(T) ( = CBS 11013(T) = CCUG 56725(T)) as the type strain. Some D1/D2 sequences of yeasts from marine habitats were found in the GenBank database that were identical to those of the strains of Y. divulgata f.a., sp. nov. Unfortunately, these strains were not available for our study. PMID- 24158945 TI - Bifidobacterium moukalabense sp. nov., isolated from the faeces of wild west lowland gorilla (Gorilla gorilla gorilla). AB - Gram-staining-positive anaerobic rods were isolated from the faeces of a wild lowland gorilla (Gorilla gorilla gorilla) in Moukalaba-Doudou National Park, Gabon, and strain GG01(T) was taxonomically investigated. Based on phylogenetic analyses and specific phenotypic characteristics, the strain belonged to the genus Bifidobacterium. Phylogenetic analysis of its 16S rRNA gene sequence revealed that strain GG01(T) formed a single monophyletic cluster and had a distinct line of descent. Based on 16S rRNA gene sequence similarity, the type strains of Bifidobacterium catenulatum JCM 1194(T) (98.3%) and Bifidobacterium pseudocatenulatum (98.1%) JCM 1200(T) were the most closely related to this novel strain, although it was clear that they belonged to different species. hsp60 sequences also supported these relationships. The DNA G+C content of this novel strain was 60.1 mol%. Bifidobacterium moukalabense sp. nov. (type strain GG01(T) = JCM 18751(T) = DSM 27321(T)) is proposed. PMID- 24158946 TI - Novosphingobium arabidopsis sp. nov., a DDT-resistant bacterium isolated from the rhizosphere of Arabidopsis thaliana. AB - An aerobic, Gram-stain-negative, rod-shaped, DDT-resistant bacterium, designated strain CC-ALB-2(T), was isolated from the Arabidopsis thaliana rhizosphere. Strain CC-ALB-2(T) was able to grow at 25-37 degrees C, at pH 5.0-8.0, with 1.0% (w/v) NaCl and tolerate up to 200 mg l(-1) DDT. 16S rRNA gene sequence analysis of strain CC-ALB-2(T) showed highest sequence similarity to Novosphingobium stygium KCTC 2891(T) (97.1%) and Novosphingobium soli DSM 22821(T) (96.8%), and lower levels of similarity (<97.0%) to other species of the genus Novosphingobium. The major fatty acid profile consisted of C14 : 0 2-OH (13.1%), C16 : 0 (10.0%), C(15 : 0) iso 3-OH (5.8%), C(16: 1)omega7c/C(16 :1)omega6c (summed feature 3, 24.7%) and C(18 : 1)omega7c/C(18 : 1)omega6c (summed feature 8, 42.4%). The polar lipid profile constitutes sphingoglycolipid, glycolipid, diphosphatidylglycerol, phosphatidylethanolamine, phosphatidyldimethylethanolamine, phosphatidylglycerol and phosphatidylcholine. The polyamine pattern showed a predominance of spermidine as the major polyamine. The predominant quinone system was ubiquinone (Q-10). The DNA G+C content was 68.9 +/- 0.1 mol%. Based on the phylogenetic, phenotypic and chemotaxonomic features, strain CC-ALB-2(T) is proposed to represent a novel species of the genus Novosphingobium for which the name Novosphingobium arabidopsis sp. nov. is proposed. The type strain is CC-ALB-2(T) ( = BCRC 80571(T) = JCM 18896(T)). PMID- 24158947 TI - Emended description of Actinoplanes friuliensis and description of Actinoplanes nipponensis sp. nov., antibiotic-producing species of the genus Actinoplanes. AB - In 2000, an actinomycete strain that showed strong antibacterial activity in culture extracts was isolated from a soil sample. The antibiotic activity corresponds to a lipopeptide complex that was named friulimycin, as the producing micro-organism was isolated from a soil sample from the region of Friaul in Italy. Taxonomic investigations showed that the producer strain belonged to a novel species of the genus Actinoplanes, for which the name Actinoplanes friuliensis was proposed. During further taxonomic studies, another antibiotic producing isolate belonging to the genus Actinoplanes, FH 2241(T), was characterized; in a patent, the name 'Actinoplanes nipponensis' was proposed for this strain. This organism was shown to be related to A. friuliensis. 'A. nipponensis' was never described in detail and the name was never validly published. Here we present a complete description of Actinoplanes nipponensis sp. Nov. (type strain FH 2241(T) = ATCC 31145(T) = DSM 43867(T)) and an emended description of Actinoplanes friuliensis (type strain HAG 010964(T) = DSM 45797(T) = CCUG 63250(T)). PMID- 24158948 TI - Falsiporphyromonas endometrii gen. nov., sp. nov., isolated from the post-partum bovine uterus, and emended description of the genus Porphyromonas Shah and Collins 1988. AB - Two black-pigmented, anaerobic bacterial strains, designated LMM 40(T) and LMM 41, were isolated from the bovine post-partum endometrium of two Holstein cows. The 16S rRNA gene sequences of the two strains were identical and showed the highest similarity to the 16S rRNA gene sequence of the type strain of Porphyromonas crevioricanis (90.2%) but only 85.1% 16S rRNA gene sequence similarity to the type strain of the type species of the genus Porphyromonas, Porphyromonas asaccharolytica. The major fatty acid profiles of the two strains were similar to those of species of the genus Porphyromonas, containing iso-C(15 : 0) as the major component and moderate amounts of anteiso-C(15 : 0), iso-C(13 : 0), C(15 : 0) and C(16 : 0). Hydroxylated fatty acids, such as iso-C(14 : 0) 3 OH, iso-C(16 : 0) 3-OH and iso-C(17 : 0) 3-OH, were also detected. The quinone profiles were dominated by the menaquinones MK-8 and MK-9, while spermidine was the major polyamine. The polar lipid profiles contained major amounts of phosphatidylethanolamine, an unidentified phospholipid, an unidentified aminophospholipid and two unidentified lipids and minor amounts of phosphatidylglycerol, an unidentified aminolipid, a second unidentified aminophospholipid and an unidentified glycolipid. The cell-wall peptidoglycan contained meso-diaminopimelic acid. The genomic DNA G+C contents of LMM 40(T) and LMM 41 were 40.7 and 41.3 mol%, respectively. Based on a polyphasic approach, including phylogenetic analysis, physiological and biochemical tests as well as metabolic fingerprinting, it is proposed that the two strains are members of a novel genus and species, for which the name Falsiporphyromonas endometrii gen. nov., sp. nov. is proposed. The type strain of Falsiporphyromonas endometrii is LMM 40(T) ( = DSM 27210(T) = CCUG 64267(T)). An emended description of the genus Porphyromonas is also presented. PMID- 24158949 TI - Altererythrobacter xiamenensis sp. nov., an algicidal bacterium isolated from red tide seawater. AB - A Gram-stain-negative, yellow-pigmented, aerobic bacterial strain, designated LY02(T), was isolated from red tide seawater in Xiamen, Fujian Province, China. Growth was observed at temperatures from 4 to 44 degrees C, at salinities from 0 to 9% and at pH from 6 to 10. Phylogenetic analysis based on 16S rRNA gene sequencing revealed that the isolate was a member of the genus Altererythrobacter, which belongs to the family Erythrobacteraceae. Strain LY02(T) was related most closely to Altererythrobacter marensis MSW-14(T) (97.2% 16S rRNA gene sequence similarity), followed by Altererythrobacter ishigakiensis JPCCMB0017(T) (97.1%), Altererythrobacter epoxidivorans JCS350(T) (97.1%) and Altererythrobacter luteolus SW-109(T) (97.0%). The dominant fatty acids were C(18 : 1)omega7c, C(17 : 1)omega6c and summed feature 3 (comprising C(16 : 1)omega7c and/or C(16 : 1)omega6c). DNA-DNA hybridization showed that strain LY02(T) possessed low DNA-DNA relatedness to A. marensis MSW-14(T), A. ishigakiensis JPCCMB0017(T), A. epoxidivorans JCS350(T) and A. luteolus SW-109(T) (mean +/- SD of 33.2 +/- 1.3, 32.1 +/- 1.0, 26.7 +/- 0.7 and 25.2 +/- 1.1 %, respectively). The G+C content of the chromosomal DNA was 61.2 mol%. The predominant respiratory quinone was ubiquinone-10 (Q-10). According to its morphology, physiology, fatty acid composition and 16S rRNA gene sequence data, the novel strain most appropriately belongs to the genus Altererythrobacter, but can readily be distinguished from recognized species. The name Altererythrobacter xiamenensis sp. nov. is proposed (type strain LY02(T) = CGMCC 1.12494(T) = KCTC 32398(T) = NBRC 109638(T)). PMID- 24158950 TI - Myroides xuanwuensis sp. nov., a mineral-weathering bacterium isolated from forest soil. AB - A Gram-reaction-negative, aerobic, non-motile, yellow-pigmented, rod-shaped bacterium, designated strain TH-19(T), was isolated from a forest soil sample in Jiangsu province, China. On the basis of 16S rRNA gene sequence similarity, strain TH-19(T) was shown to belong to the genus Myroides, a member of the phylum Bacteroidetes, and was related to Myroides odoratimimus LMG 4029(T) (98.7% similarity), Myroides profundi D25(T) (98.2%) and Myroides marinus JS-08(T) (97.5%). Strain TH-19(T) contained menaquinone-6 (MK-6) as the predominant menaquinone, and the dominant fatty acids were iso-C(15 : 0) and iso-C(17 : 0) 3 OH. The DNA G+C content of strain TH-19(T) was 37.2 mol%. The DNA-DNA relatedness values of strain TH-19(T) with Myroides odoratimimus JCM 7460(T), Myroides profundi D25(T) and Myroides marinus JS-08(T) were below 70%. Based on phenotypic, genotypic and phylogenetic evidence, it is suggested that strain TH 19(T) represents a novel species of the genus Myroides, for which the name Myroides xuanwuensis sp. nov. is proposed. The type strain is TH-19(T) ( = CCTCC AB 2013145(T) = JCM 19200(T)). PMID- 24158951 TI - Methanospirillum psychrodurum sp. nov., isolated from wetland soil. AB - A psychrotolerant methanogenic strain, X-18(T), was isolated from the soil of the Madoi wetland at Qinghai, Tibetan plateau, China. Cells were wavy rods (11-62 um long) with blunt tapered ends and Gram-stain-negative. Strain X-18(T) grew strictly anaerobically and produced methane exclusively from H2/CO2. Growth occurred in the temperature range of 4-32 degrees C and optimally at 25 degrees C. Growth pH ranged from 6.5 to 8.0 and the optimum was 7.0. The G+C content of the genomic DNA of strain X-18(T) was 44.4 mol%. Phylogenetic analysis based on 16S rRNA gene sequences and the alpha subunit of methyl-coenzyme M reductase indicated that strain X-18(T) was affiliated to the genus Methanospirillum and was most closely related to Methanospirillum lacunae Ki8-1(T), with 96.3% 16S rRNA gene sequence similarity. However, strain X-18(T) could be distinguished from the existing species of the genus Methanospirillum by its lower growth temperature and obligate hydrogenotrophic methanogenesis. On the basis of phenotypic characteristics and phylogenetic analysis, strain X-18(T) represents a novel species of the genus Methanospirillum, for which the name Methanospirillum psychrodurum sp. nov. is proposed and strain X-18(T) is assigned as the type strain ( = CGMCC 1.5186(T) = JCM 19216(T)). PMID- 24158952 TI - Photobacterium aestuarii sp. nov., a marine bacterium isolated from a tidal flat. AB - A Gram-staining-negative, motile, weakly halophilic and facultatively aerobic bacterium, designated strain YA11(T), was isolated from tidal flat sediment at Yeongam Bay, South Korea. Strain YA11(T) grew at 10-30 degrees C (optimum, 20 degrees C), at pH 6.0-10.0 (optimum, pH 6.5-7.5) and in the presence of 1-6% (w/v) NaCl (optimum, 2-3%). The major cellular fatty acids of the strain were summed feature 3 (C(16 : 1)omega7c and/or C(16 : 1)omega6c), summed feature 8 (C(18 : 1)omega7c and/or C(18 : 1)omega6c) and C(16 : 0). The DNA G+C content of the genomic DNA was 44.2 mol%. Strain YA11(T) contained Q-8 as the sole respiratory quinone. A phylogenetic tree based on 16S rRNA gene sequences showed that strain YA11(T) formed a distinct phyletic lineage within the genus Photobacterium and the 16S rRNA gene sequence similarities between strain YA11(T) and the type strains of species of the genus Photobacterium ranged between 94.0 and 96.4%. Based on the phenotypic, chemotaxonomic and molecular properties, strain YA11(T) represents a novel species of the genus Photobacterium, for which the name Photobacterium aestuarii sp. nov. is proposed, with strain YA11(T)( = KACC 16912(T) = JCM 18592(T)) as the type strain. PMID- 24158953 TI - Thermus caliditerrae sp. nov., a novel thermophilic species isolated from a geothermal area. AB - Two thermophilic bacterial strains, designated YIM 77925(T) and YIM 77777, were isolated from two hot springs, one in the Hydrothermal Explosion (Shuirebaozhaqu) area and Frog Mouth Spring in Tengchong county, Yunnan province, south-western China. The taxonomic positions of the two isolates were investigated by a polyphasic approach. Cells of the two strains were Gram-stain-negative, aerobic and rod-shaped. They were able to grow at 50-70 degrees C, pH 6.0-8.0 and with a NaCl tolerance up to 0.5% (w/v). Colonies are circular, convex, non-transparent and produce yellow pigment. Phylogenetic analyses based on 16S rRNA gene sequences comparison clearly demonstrated that strains YIM 77925(T) and YIM 77777 represent members of the genus Thermus, and they also detected low-level similarities of 16S rRNA gene sequences (below 97%) compared with all other species in this genus. Their predominant menaquinone was MK-8. The genomic DNA G+C contents of strains YIM 77925(T) and YIM 77777 were 65.6 mol% and 67.2 mol%, respectively. Based on the results of physiological and biochemical tests and phylogenetic analyses, strains YIM 77925(T) and YIM 77777 could not be classified as representing any species of the genus Thermus with a validly published name. Thus the two strains are considered to represent a novel species of the genus Thermus, for which the name Thermus caliditerrae sp. nov. is proposed. The type strain is YIM 77925(T) ( = DSM 25901(T) = CCTCC 2012061(T)). PMID- 24158956 TI - Influenza A(H5N1) vaccines: are we better prepared for the next pandemic? PMID- 24158955 TI - Human gene variants linked to enhanced NLRP3 activity limit intramacrophage growth of Mycobacterium tuberculosis. AB - Activation of the NLRP3 inflammasome and subsequent generation of interleukin 1beta is initiated in macrophages upon recognition of several stimuli. In the present work, we show that gain-of-function gene variants of inflammasome components known to predispose individuals to inflammatory disorders have a host protective role during infection with Mycobacterium tuberculosis. By isolation of macrophages from patients and healthy blood donors with genetic variants in NLRP3 and CARD8 and subsequent infection of the cells with virulent M. tuberculosis, we show that these gene variants, combined, are associated with increased control of bacterial growth in human macrophages. PMID- 24158954 TI - Confounding roles for type I interferons during bacterial and viral pathogenesis. AB - Although type I interferons (IFN-I) were initially defined as potent antiviral agents, they can also cause decreased host resistance to some bacterial and viral infections. The many antiviral functions of the IFN-I include direct suppression of viral replication and activation of the immune response against viruses. In addition to their antiviral effects, IFN-I are also protective against several extracellular bacterial infections, in part, by promoting the induction of TNF alpha and nitric oxide. In contrast, there is a negative effect of IFN-I on host resistance during chronic infection with lymphocytic choriomeningitis virus (LCMV) and acute infections with intracellular bacteria. In the case of LCMV, chronic IFN-I signaling induces adaptive immune system suppression. Blockade of IFN-I signaling removes the suppression and allows CD4 T-cell- and IFN-gamma mediated resolution of the infection. During acute intracellular bacterial infection, IFN-I suppress innate immunity by at least two defined mechanisms. During Francisella infection, IFN-I prevent IL-17 upregulation on gammadelta T cells and neutrophil recruitment. Following Listeria infection, IFN-I promote the cell death of macrophages and lymphocytes, which leads to innate immune suppression. These divergent findings for the role of IFN-I on pathogen control emphasize the complexity of the interferons system and force more mechanistic evaluation of its role in pathogenesis. This review evaluates IFN-I during infection with an emphasis on work carried out IFN-I-receptor-deficient mice. PMID- 24158957 TI - Functional polymorphisms in the gene encoding macrophage migration inhibitory factor are associated with Gram-negative bacteremia in older adults. AB - Macrophage migration inhibitory factor (MIF) is an immune mediator encoded in a functionally polymorphic locus. We found the genotype conferring low expression of MIF to be enriched in a cohort of 180 patients with gram-negative bacteremia, compared with 229 healthy controls (odds ratio [OR], 2.4; P = .04), an association that was more pronounced in older adults (OR, 4.6; P = .01). Among older subjects, those with low expression of MIF demonstrated 20% reduced MIF production from lipopolysaccharide-stimulated peripheral blood monocytes and 30% lower monocyte surface Toll-like receptor 4, compared with those with high expression. Our work suggests that older adults with low expression of MIF may be predisposed to hyporesponsiveness to lipopolysaccharide and gram-negative bacterial infection. PMID- 24158958 TI - Immune responses to pertussis vaccines and disease. AB - In this article we discuss the following: (1) acellular vaccines are immunogenic, but responses vary by vaccine; (2) pertussis antibody levels rapidly wane but promptly increase after vaccination; (3) whole-cell vaccines vary in immunogenicity and efficacy; (4) whole-cell vaccines and naturally occurring pertussis generate predominantly T-helper 1 (Th1) responses, whereas acellular vaccines generate mixed Th1/Th2 responses; (5) active transplacental transport of pertussis antibody is documented; (6) neonatal immunization with diphtheria toxoid, tetanus toxoid, and acellular pertussis vaccine has been associated with some suppression of pertussis antibody, but suppression has been seen less often with acellular vaccines; (7) memory B cells persist in both acellular vaccine- and whole cell vaccine-primed children; and (8) in acellular vaccine-primed children, T-cell responses remain elevated and do not increase with vaccine boosters, whereas in whole-cell vaccine-primed children, these responses can be increased by vaccine boosting and natural exposure. Despite these findings, challenges remain in understanding the immune response to pertussis vaccines. PMID- 24158959 TI - Differential potentiation of the virulence of the Pseudomonas aeruginosa cystic fibrosis liverpool epidemic strain by oral commensal Streptococci. AB - BACKGROUND: The Pseudomonas aeruginosa Liverpool epidemic strain (LES) is an important cystic fibrosis (CF) pathogen and is associated with increased morbidity and a worsened prognosis, compared with other CF-associated strains. However, interactions of common LES phenotypic variants with other members of the polymicrobial biofilms associated with chronic CF respiratory disease, such as oral commensal streptococci, have not been investigated. METHODS: Biofilm population dynamics, virulence factor production, and pathogenicity in Galleria mellonella larvae of common LES phenotypes (ie, low production, intermediate production, and overproduction of pyocyanin) in the presence or absence of anginosus group streptococci (AGS) were compared. RESULTS: AGS populations isolated from biofilm cocultures were P. aeruginosa phenotypic variant dependent, with higher AGS cell densities than those in monoculture frequently observed. Coexistence of AGS with a producer of low or intermediate levels of pyocyanin was found to result in enhancement of virulence factor production. In addition, the LES formed pathogenic partnerships with AGS in the G. mellonella infection model, with killing dependent on LES phenotype and AGS species. CONCLUSIONS: The pathogenic potential of LES phenotypic variants can be enhanced by the presence of oral commensal streptococci. As adaptive mutations leading to reduced virulence factor production are commonplace, the observations made are relevant in the general context of the biology of P. aeruginosa infection during CF. PMID- 24158960 TI - Cytokine and chemokine responses in the acute phase of hepatitis B virus replication in naive and previously vaccinated blood and plasma donors. AB - BACKGROUND: Blood and plasma donor screening for hepatitis B virus (HBV) DNA, HBV surface antigen (HBsAg), and antibodies to surface (anti-HBs) and core (anti-HBc) antigens allows identification of individuals who acquired HBV despite previous HBV vaccination. METHODS: Of 14 HBV acute infection donor panels (HBV-DNA positive/anti-HBc-negative), 6 donors were previously vaccinated (anti-HBs+). We investigated the differences in viral kinetics and immune responses in vaccinated and nonvaccinated individuals. Serial specimens were characterized for HBV DNA and serological markers and 39 cytokines. RESULTS: The rate of viral load increase was blunted, and virus was cleared more rapidly in vaccinated individuals (P = .004). In unvaccinated individuals, induced protein 10 (IP-10), interleukin 10 (IL-10), macrophage inflammatory protein 1beta (MIP-1beta), and soluble interleukin 2Ralpha (sIL-2Ralpha) levels were commonly elevated at the time of peak viremia. In contrast, vaccinated individuals had earlier peaks in IL 10 and IP-10 responses that occurred at much lower viral loads and coincided with anamnestic anti-hepatitis B surface (HBs) responses and clearance of viremia. CONCLUSION: There is earlier engagement of innate and adaptive immunity in infected subjects with previous vaccination, possibly explaining suppressed viremia in vaccine breakthrough infections. Although breakthrough infections occur in partially protected vaccine recipients, vaccination likely contributes to early control of replication, limiting immune activation and preventing development of clinically significant acute and chronic HBV infection. PMID- 24158963 TI - Paternalism in the name of autonomy. AB - Different ideas of the normative relevance of autonomy can give rise to profoundly different action-guiding principles in healthcare. If autonomy is seen as a value rather than as a right, it can be argued that patients' decisions should sometimes be overruled in order to protect or promote their own autonomy. We refer to this as paternalism in the name of autonomy. In this paper, we discuss different elements of autonomy (decision-making capacity, efficiency, and authenticity) and arguments in favor of paternalism for the sake of autonomy that have been proposed in the bioethical debate. We argue that if autonomy is valuable, then paternalism for the sake of autonomy may be justified. However, policies allowing paternalism in the name of autonomy may be self-defeating. PMID- 24158962 TI - An LC/MS/MS method for stable isotope dilution studies of beta-carotene bioavailability, bioconversion, and vitamin A status in humans. AB - Isotope dilution is currently the most accurate technique in humans to determine vitamin A status and bioavailability/bioconversion of provitamin A carotenoids such as beta-carotene. However, limits of MS detection, coupled with extensive isolation procedures, have hindered investigations of physiologically-relevant doses of stable isotopes in large intervention trials. Here, a sensitive liquid chromatography-tandem mass spectrometry (LC/MS/MS) analytical method was developed to study the plasma response from coadministered oral doses of 2 mg [(13)C10]beta-carotene and 1 mg [(13)C10]retinyl acetate in human subjects over a 2 week period. A reverse phase C18 column and binary mobile phase solvent system separated beta-carotene, retinol, retinyl acetate, retinyl linoleate, retinyl palmitate/retinyl oleate, and retinyl stearate within a 7 min run time. Selected reaction monitoring of analytes was performed under atmospheric pressure chemical ionization in positive mode at m/z 537->321 and m/z 269->93 for respective [(12)C]beta-carotene and [(12)C] retinoids; m/z 547->330 and m/z 274->98 for [(13)C10]beta-carotene and [(13)C5] cleavage products; and m/z 279->100 for metabolites of [(13)C10]retinyl acetate. A single one-phase solvent extraction, with no saponification or purification steps, left retinyl esters intact for determination of intestinally-derived retinol in chylomicrons versus retinol from the liver bound to retinol binding protein. Coadministration of [(13)C10]retinyl acetate with [(13)C10]beta-carotene not only acts as a reference dose for inter individual variations in absorption and chylomicron clearance rates, but also allows for simultaneous determination of an individual's vitamin A status. PMID- 24158964 TI - Innovative surgery and the precautionary principle. AB - Surgical innovation involves practices, such as new devices, technologies, procedures, or applications, which are novel and untested. Although innovative practices are believed to offer an improvement on the standard surgical approach, they may prove to be inefficacious or even dangerous. This article considers how surgeons considering innovation should reason in the conditions of uncertainty that characterize innovative surgery. What attitude to the unknown risks of innovative surgery should they take? The answer to this question involves value judgments about the acceptability of risk taking when satisfactory scientific information is not available. This question has been confronted in legal contexts, where risk aversion in the form of the precautionary principle has become increasingly influential as a regulatory response to innovative technologies that pose uncertain future hazards. This article considers whether it is appropriate to apply a precautionary approach when making decisions about innovative surgery. PMID- 24158966 TI - A decade of progress for patients with metastatic colorectal cancer: a new decade in which obstacles loom. PMID- 24158961 TI - HIV-1 envelope-receptor interactions required for macrophage infection and implications for current HIV-1 cure strategies. AB - Myeloid cells residing in the CNS and lymphoid tissues are targets for productive HIV-1 replication, and their infection contributes to the pathological manifestations of HIV-1 infection. The Envs can adopt altered configurations to overcome entry restrictions in macrophages via a more efficient and/or altered mechanism of engagement with cellular receptors. This review highlights evidence supporting an important role for macrophages in HIV-1 pathogenesis and persistence, which need to be considered for strategies aimed at achieving a functional or sterilizing cure. We also highlight that the molecular mechanisms underlying HIV-1 tropism for macrophages are complex, involving enhanced and/or altered interactions with CD4, CCR5, and/or CXCR4, and that the nature of these interactions may depend on the anatomical location of the virus. PMID- 24158967 TI - Emerging treatments in recurrent and metastatic colorectal cancer. AB - Metastatic colorectal cancer (mCRC) is a prevalent disease for which many new therapies have been developed over the past decade. Currently, standard of care chemotherapeutic regimens for mCRC include doublet cytotoxic chemotherapy with or without the anti-vascular endothelial growth factor (VEGF) monoclonal antibody bevacizumab, anti-epidermal growth factor receptor (EGFR) monoclonal antibodies such as cetuximab and panitumumab with or without chemotherapy, and single-agent cytotoxic chemotherapy or targeted therapy for patients intolerant of combination regimens. Recent studies have investigated the efficacy of triplet cytotoxic chemotherapeutic regimens, bevacizumab in combination with chemotherapy beyond first-line therapy disease progression, dual anti-VEGF and anti-EGFR antibody therapy, and the more novel agents ziv-aflibercept and regorafenib for treatment of mCRC. Furthermore, molecular profiling of CRC has identified several genetic alterations for which targeted therapies are currently being developed. Optimal drug combinations and treatment sequences have yet to be defined, but an expanding armamentarium of therapies with which to treat CRC offers a promising future. PMID- 24158968 TI - Sequencing of treatment in advanced unresectable colorectal cancer. AB - This article reviews the various systemic therapy options for patients with metastatic colorectal cancer (CRC) that is judged to be noncurable. The choice of initial therapy depends on patient preferences, treatment goals, performance status, and presence of comorbid conditions. Whether surgical resection of the primary tumor should be considered in patients who present with metastatic CRC is a matter of controversy. The components of the initial systemic regimen influence the options for second- and third-line options when disease progression occurs during therapy. The standard of practice is often to continue chemotherapy until progression, unacceptable side effects, or death. In patients with incurable CRC, the balance between efficacy, toxicity, and repeated hospital or clinic visits must be discussed with the patient. Although continuous treatment may be appropriate for some patients, intermittent treatment strategies or maintenance with the least toxic agents may be preferable for others. If disease progression occurs during a chemotherapy break or while the patient is on maintenance therapy, previously used agents may be reintroduced provided that preexisting toxicities have resolved. PMID- 24158969 TI - Synchronous metastatic rectal cancer completely resected after multidisciplinary planning and treatment: a case report. AB - Colorectal cancer is a common and significant public health concern. The liver is the most common site of metastasis, and colorectal cancer liver metastases (CRLM) may affect up to 60% of patients at some time during the course of their disease. Approximately 25% of patients are found to have synchronous CRLM at the time of diagnosis, and these patients have a worse prognosis than those who develop metastases later in their disease course. In the absence of extrahepatic disease, resection of CRLM with negative margins along with chemotherapy can lead to a 5 year overall survival rate of up to 60%. This report presents the case of a 48 year-old man diagnosed with rectal cancer and synchronous liver metastases that a multidisciplinary tumor board initially deemed to be unresectable because of large size and insufficient future liver remnant. The patient underwent FOLFOX chemotherapy with bevacizumab and experienced conversion to resectable hepatic disease. After neoadjuvant short-course radiation treatment to the rectum, the patient underwent combined low anterior resection of the rectum and a right hepatectomy and was rendered disease-free. The management of the patient's clinical course with correlation to the NCCN Clinical Practice Guidelines in Oncology for Rectal Cancer is presented in this report, including discussion of the role of chemotherapy in the conversion of CRLM to resectable status, the role of surgical metastasectomy, and postoperative surveillance of patients with colorectal cancer. PMID- 24158970 TI - Joining together to improve outcomes: integrating specialty palliative care into the care of patients with cancer. AB - This article addresses the misconception that patients with cancer should undergo a definitive "transition" to palliative care at some point in their trajectory, and instead proposes that a gradual shift should occur from primary palliative care provided by the oncologist to specialty palliative care when the need exists. The goal is to help practitioners identify which patients are in need of specialty palliative care, suggest when oncologists should consider making a referral, and offer a model for sharing the responsibilities of care once palliative care clinicians become involved. This model enhances the patient and family experience through improving symptom control and quality of life, and may even prolong survival. It also minimizes patients' perception of abandonment at the end of life, while reducing the risk of physician burnout in practicing oncologists. Lastly, the misconceptions of oncologists are addressed regarding how patients and families will accept the idea of a palliative care consultation, and suggestions are offered for responding to patient and/or family resistance to referral when it arises. PMID- 24158971 TI - Multigene assays in metastatic colorectal cancer. AB - Specific genomic colorectal cancer alterations are increasingly linked to prognosis and/or response to specific anticancer agents. The identification of KRAS mutations as markers of resistance to epidermal growth factor receptor (EGFR) inhibitors has paved the way to the interrogation of numerous other markers of resistance to anti-EGFR therapy, such as NRAS, BRAF, and PI3KCA mutations. Other genomic and protein expression alterations have recently been identified as potential targets of treatment or as markers of chemotherapy or targeted-therapy resistance, including ERCC1 expression, c-Met expression, PTEN expression, HER2 amplification, HER3 expression, and rare KRAS mutations. As the number of distinct validated intratumor genomic assays increases, numerous molecular assays will need to be compiled into one multigene panel assay. Several companies and academic centers are now offering multigene assays to patients with metastatic colorectal cancer and other solid tumors. This article discusses the technology behind multigene assays, its limitations, its current advantages, and its potential in the clinical care of metastatic colorectal cancer. PMID- 24158972 TI - Biobehavioral measures as outcomes: a cautionary tale. AB - This article discusses the use of biobehavioral measures as outcomes for health care intervention studies. Effect size (ES) values for salivary cortisol and observation-based measures of pain and agitation were examined. Effects pre to post treatment were assessed separately for nursing home residents with and without acute psychotic symptoms. This study revealed large positive effects on both pain and agitation measures in the group with acute psychotic symptoms and small-to-medium positive effects on these same measures in the group without acute psychotic symptoms. In both of these groups, the ES values were not consistently positive on the cortisol measures. Prior to determining whether a measure can be used to estimate minimum clinically important differences, it is essential to consider if the biomarker will be responsive to therapy in the populations and contexts being studied. PMID- 24158973 TI - Differential immunoglobulin class-mediated responses to components of the U1 small nuclear ribonucleoprotein particle in systemic lupus erythematosus and mixed connective tissue disease. AB - OBJECTIVE: The objective of this paper is to determine whether patients with systemic lupus erythematosus (SLE) and mixed connective tissue disease (MCTD) possess differential IgM- and IgG-specific reactivity against peptides from the U1 small nuclear ribonucleoprotein particle (U1 snRNP). METHODS: The IgM- and IgG mediated responses against 15 peptides from subunits of the U1 snRNP were assessed by indirect enzyme linked immunosorbent assays (ELISAs) in sera from patients with SLE and MCTD and healthy individuals (n = 81, 41, and 31, respectively). Additionally, 42 laboratory tests and 40 clinical symptoms were evaluated to uncover potential differences. Binomial logistic regression analyses (BLR) were performed to construct models to support the independent nature of SLE and MCTD. Receiver operating characteristic (ROC) curves corroborated the classification power of the models. RESULTS: We analyzed IgM and IgG anti-U1 snRNP titers to classify SLE and MCTD patients. IgG anti-U1 snRNP reactivity segregates SLE and MCTD from nondisease controls with an accuracy of 94.1% while IgM-specific anti-U1 snRNP responses distinguish SLE from MCTD patients with an accuracy of 71.3%. Comparison of the IgG and IgM anti-U1 snRNP approach with clinical tests used for diagnosing SLE and MCTD revealed that our method is the best classification tool of those analyzed (p <= 0.0001). CONCLUSIONS: Our IgM anti-U1 snRNP system along with lab tests and symptoms provide additional molecular and clinical evidence to support the hypothesis that SLE and MCTD may be distinct syndromes. PMID- 24158975 TI - Morphology controlled synthesis of nanoporous Co3O4 nanostructures and their charge storage characteristics in supercapacitors. AB - Cubic spinel Co3O4 nanoparticles with spherical (0D) and hexagonal platelet (2D) morphologies were synthesized using a simple solvothermal method by tuning the reaction time. XRD and HRTEM analyses revealed pure phase with growth of Co3O4 particles along [111] and [110] directions. UV-vis studies showed two clear optical absorption peaks corresponding to two optical band gaps in the range of 400-500 nm and 700-800 nm, respectively, related to the ligand to metal charge transfer events (O(2-) -> Co(2+,3+)). Under the electrochemical study in two electrode assembly system (Co3O4/KOH/Co3O4) without adding any large area support or a conductive filler, the hexagonal platelet Co3O4 particles exhibited comparatively better characteristics with high specific capacitance (476 F g( 1)), energy density 42.3 Wh kg(-1) and power density 1.56 kW kg(-1) at current density of 0.5 Ag(-1), that suited for potential applications in supercapacitors. The observed better electrochemical properties of the nanoporous Co3O4 particles is attributed to the layered platelet structural arrangement of the hexagonal platelet and the presence of exceptionally high numbers of regularly ordered pores. PMID- 24158976 TI - Brain temperature in multiple sclerosis. PMID- 24158977 TI - Fatty fish intake is associated with decreased occurrence of multiple sclerosis. AB - BACKGROUND: High vitamin D levels have been associated with a decreased risk of developing multiple sclerosis (MS). The most important source of dietary vitamin D is fatty fish. OBJECTIVE: The objective of this paper is to investigate the association between fish consumption and the risk of MS, including the interaction between fish intake and ultraviolet radiation (UVR) exposure habits. METHODS: This study is based on the project Epidemiological Investigation of MS (EIMS), which is a Swedish population-based case-control study. The analysis included 1879 incident cases of MS and 4135 controls. Subjects who reported high fatty fish intake were compared regarding occurrence of MS with those who reported low intake by calculating odds ratio (OR) with 95% confidence interval (CI). RESULTS: Frequent fatty fish intake was associated with decreased occurrence of MS (adjusted OR 0.82 (95% CI 0.68-0.98). There was no significant association between intake of lean fish and MS. CONCLUSION: Fatty fish intake might decrease the risk for MS. A hypothetical explanation is that intake of fatty fish may compensate for vitamin D deficiency that is associated with increased MS risk. PMID- 24158978 TI - Effects of exercise on fitness and cognition in progressive MS: a randomized, controlled pilot trial. AB - BACKGROUND: Exercise may have beneficial effects on both well-being and walking ability in multiple sclerosis (MS). Exercise is shown to be neuroprotective in rodents and may also enhance cognitive function in humans. It may, therefore, be particularly useful for MS patients with pronounced neurodegeneration. OBJECTIVE: To investigate the potential of standardized exercise as a therapeutic intervention for progressive MS, in a randomized-controlled pilot trial. METHODS: Patients with progressive MS and moderate disability (Expanded Disability Status Scale (EDSS) of 4-6) were randomized to one of three exercise interventions (arm ergometry, rowing, bicycle ergometry) for 8-10 weeks or a waitlist control group. We analyzed the drop-out rate as a measure of feasibility. The primary endpoint of the study was aerobic fitness. Secondary endpoints were walking ability, cognitive function as measured by a neuropsychological test battery, depression and fatigue. RESULTS: A total of 42 patients completed the trial (10.6% drop-out rate). Significant improvements were seen in aerobic fitness. In addition, exercise improved walking ability, depressive symptoms, fatigue and several domains of cognitive function. CONCLUSION: This study indicated that aerobic training is feasible and could be beneficial for patients with progressive MS. Larger exercise studies are needed to confirm the effect on cognition. TRIAL REGISTRATION: ISRCTN (trial number 76467492) http://isrctn.org. PMID- 24158979 TI - First-line trastuzumab plus taxane-based chemotherapy for metastatic breast cancer: cost-minimization analysis. AB - AIM: To carry out a cost-minimization analysis including a comparison of the costs arising from first-line treatment by trastuzumab plus docetaxel versus trastuzumab plus paclitaxel in patients with metastatic breast cancer. METHODS: All consecutive patients with human epidermal growth receptor 2-postive metastatic breast cancer who were treated at Besancon University Hospital and Saint Vincent private hospital between 2001 and 2010 by first-line therapy containing trastuzumab plus taxane were retrospectively studied. Economic analysis took into account costs related to drugs, hospitalization, and healthcare travel. RESULTS: Progression-free survival difference between the two treatments was not significant (p = 0.65). First-line treatment by trastuzumab plus taxane was estimated at approximately ?68,000 (p = 0.74). The drug costs represented around 70-75% of the total cost, mainly related to the use of trastuzumab. CONCLUSION: Our economic analysis shows that although the costs of the two trastuzumab plus taxane regimens are similar, they may contribute to the on-going debate about the availability and use of innovative chemotherapy drugs, in particular in human epidermal growth factor receptor 2-positive metastatic breast cancer with new therapies such as trastuzumab-DM1 and pertuzumab. PMID- 24158980 TI - Sunitinib-induced severe hypoglycemia in a diabetic patient. AB - INTRODUCTION: Sunitinib is an oral inhibitor of tyrosine kinase that was used for the treatment of mRCC. The general side effects are fatigue, asthenia, diarrhea, mucositis, nausea, vomiting, skin changes, hypertension, hypothyroidism and hematologic side effects. In addition, sunitinib-induced hypoglycemia has also been reported. There are limited number of case reports related to sunitinib induced hypoglycemia. CASE PRESENTATION: In this case report, we have presented a patient with type 2 diabetes mellitus (DM) with emerging severe hypoglycemia after sunitinib treatment. It was shown that blood glucose levels were normalized two weeks after the interruption of sunitinib. CONCLUSION: Although the underlying mechanism of sunitinib-induced hypoglycemia is not completely understood, sunitinib can be regarded to have an antidiabetic effect. In the literature, there are some reports about sunitinib/other TKI induced hypoglycemia; however, life threatening hypoglycemia is rare. There is no case report of severe hypoglycemia due to imatinib; however, there are two case reports with severe hypoglycemia due to sunitinib treatment. Symptomatic hypoglycemic episodes due to sunitinib may lead to hospital admission. Diabetic patients may develop severe hypoglycaemia and it should be kept in mind that the discontinuation of antihyperglycemic treatment may be required. Therefore, blood glucose levels should be closely monitored in diabetic patients with mRCC during sunitinib therapy. PMID- 24158981 TI - A bioinformatics approach identifies signal transducer and activator of transcription-3 and checkpoint kinase 1 as upstream regulators of kidney injury molecule-1 after kidney injury. AB - Kidney injury molecule-1 (KIM-1)/T cell Ig and mucin domain-containing protein-1 (TIM-1) is upregulated more than other proteins after AKI, and it is highly expressed in renal damage of various etiologies. In this capacity, KIM-1/TIM-1 acts as a phosphatidylserine receptor on the surface of injured proximal tubular epithelial cells, mediating phagocytosis of apoptotic cells, and it may also act as a costimulatory molecule for immune cells. Despite recognition of KIM-1 as an important therapeutic target for kidney disease, the regulators of KIM-1 transcription in the kidney remain unknown. Using a bioinformatics approach, we identified upstream regulators of KIM-1 after AKI. In response to tubular injury in rat and human kidneys or oxidant stress in human proximal tubular epithelial cells (HPTECs), KIM-1 expression increased significantly in a manner that corresponded temporally and regionally with increased phosphorylation of checkpoint kinase 1 (Chk1) and STAT3. Both ischemic and oxidant stress resulted in a dramatic increase in reactive oxygen species that phosphorylated and activated Chk1, which subsequently bound to STAT3, phosphorylating it at S727. Furthermore, STAT3 bound to the KIM-1 promoter after ischemic and oxidant stress, and pharmacological or genetic induction of STAT3 in HPTECs increased KIM-1 mRNA and protein levels. Conversely, inhibition of STAT3 using siRNAs or dominant negative mutants reduced KIM-1 expression in a kidney cancer cell line (769-P) that expresses high basal levels of KIM-1. These observations highlight Chk1 and STAT3 as critical upstream regulators of KIM-1 expression after AKI and may suggest novel approaches for therapeutic intervention. PMID- 24158982 TI - Adenylyl cyclase 6 deficiency ameliorates polycystic kidney disease. AB - cAMP is an important mediator of cystogenesis in polycystic kidney disease (PKD). Several adenylyl cyclase (AC) isoforms could mediate cAMP accumulation in PKD, and identification of a specific pathogenic AC isoform is of therapeutic interest. We investigated the role of AC6 in a mouse model of PKD that is homozygous for the loxP-flanked PKD1 gene and heterozygous for an aquaporin-2-Cre recombinase transgene to achieve collecting duct-specific gene targeting. Collecting duct-specific knockout of polycystin-1 caused massive renal cyst formation, kidney enlargement, and severe kidney failure, with a mean survival time of 2 months. In contrast, coincident collecting duct-specific knockout of polycystin-1 and AC6 (also homozygous for the floxed ADCY6 gene) markedly decreased kidney size and cystogenesis, improved renal function, reduced activation of the B-Raf/ERK/MEK pathway, and greatly increased survival. Absence of collecting duct AC6 did not alter urinary cAMP excretion or kidney cAMP concentration. In conclusion, AC6 is a key mediator of cyst formation and renal injury in a model of PKD. PMID- 24158983 TI - Nurse practitioner care improves renal outcome in patients with CKD. AB - Treatment goals for patients with CKD are often unrealized for many reasons, but support by nurse practitioners may improve risk factor levels in these patients. Here, we analyzed renal endpoints of the Multifactorial Approach and Superior Treatment Efficacy in Renal Patients with the Aid of Nurse Practitioners (MASTERPLAN) study after extended follow-up to determine whether strict implementation of current CKD guidelines through the aid of nurse practitioners improves renal outcome. In total, 788 patients with moderate to severe CKD were randomized to receive nurse practitioner support added to physician care (intervention group) or physician care alone (control group). Median follow-up was 5.7 years. Renal outcome was a secondary endpoint of the MASTERPLAN study. We used a composite renal endpoint of death, ESRD, and 50% increase in serum creatinine. Event rates were compared with adjustment for baseline serum creatinine concentration and changes in estimated GFR were determined. During the randomized phase, there were small but significant differences between the groups in BP, proteinuria, LDL cholesterol, and use of aspirin, statins, active vitamin D, and antihypertensive medications, in favor of the intervention group. The intervention reduced the incidence of the composite renal endpoint by 20% (hazard ratio, 0.80; 95% confidence interval, 0.66 to 0.98; P=0.03). In the intervention group, the decrease in estimated GFR was 0.45 ml/min per 1.73 m(2) per year less than in the control group (P=0.01). In conclusion, additional support by nurse practitioners attenuated the decline of kidney function and improved renal outcome in patients with CKD. PMID- 24158984 TI - MicroRNA-155 a new therapeutic target in crescentic GN. PMID- 24158985 TI - MicroRNA-214 antagonism protects against renal fibrosis. AB - Renal tubulointerstitial fibrosis is the common end point of progressive renal disease. MicroRNA (miR)-214 and miR-21 are upregulated in models of renal injury, but the function of miR-214 in this setting and the effect of its manipulation remain unknown. We assessed the effect of inhibiting miR-214 in an animal model of renal fibrosis. In mice, genetic deletion of miR-214 significantly attenuated interstitial fibrosis induced by unilateral ureteral obstruction (UUO). Treatment of wild-type mice with an anti-miR directed against miR-214 (anti-miR-214) before UUO resulted in similar antifibrotic effects, and in vivo biodistribution studies demonstrated that anti-miR-214 accumulated at the highest levels in the kidney. Notably, in vivo inhibition of canonical TGF-beta signaling did not alter the regulation of endogenous miR-214 or miR-21. Whereas miR-21 antagonism blocked Smad 2/3 activation, miR-214 antagonism did not, suggesting that miR-214 induces antifibrotic effects independent of Smad 2/3. Furthermore, TGF-beta blockade combined with miR-214 deletion afforded additional renal protection. These phenotypic effects of miR-214 depletion were mediated through broad regulation of the transcriptional response to injury, as evidenced by microarray analysis. In human kidney tissue, miR-214 was detected in cells of the glomerulus and tubules as well as in infiltrating immune cells in diseased tissue. These studies demonstrate that miR-214 functions to promote fibrosis in renal injury independent of TGF-beta signaling in vivo and that antagonism of miR-214 may represent a novel antifibrotic treatment in the kidney. PMID- 24158987 TI - Association between body composition and frailty among prevalent hemodialysis patients: a US Renal Data System special study. AB - Studies of frailty among patients on hemodialysis have relied on definitions that substitute self-reported functioning for measures of physical performance and omit weight loss or substitute alternate criteria. We examined the association between body composition and a definition of frailty that includes measured physical performance and weight loss in a cross-sectional analysis of 638 adult patients receiving maintenance hemodialysis at 14 centers. Frailty was defined as having three of following characteristics: weight loss, weakness, exhaustion, low physical activity, and slow gait speed. We performed logistic regression with body mass index (BMI) and bioelectrical impedance spectroscopy (BIS)-derived estimates of intracellular water (ICW), fat mass, and extracellular water (ECW) as the main predictors, and age, sex, race, and comorbidity as covariates. Overall, 30% of participants were frail. Older age (odds ratio [OR], 1.31 per 10 years; 95% confidence interval [95% CI], 1.14 to 1.50), diabetes (OR, 1.65; 95% CI, 1.13 to 2.40), higher fat mass (OR, 1.18; 95% CI, 1.02 to 1.37), and higher ECW (OR, 1.33; 95% CI, 1.20 to 1.47) associated with higher odds of frailty. Higher ICW associated with lower odds of frailty (OR, 0.80 per kg; 95% CI, 0.73 to 0.87). The addition of BMI data did not change the area under the receiver operating characteristics curve (AUC; AUC=0.66 versus 0.66; P=0.71), but the addition of BIS data did change the AUC (AUC=0.72; P<0.001). Thus, individual components of body composition but not BMI associate strongly with frailty in this cohort of patients receiving hemodialysis. PMID- 24158986 TI - Fibroblast growth factor-23 and cardiovascular events in CKD. AB - An elevated level of fibroblast growth factor-23 (FGF-23) is the earliest abnormality of mineral metabolism in CKD. High FGF-23 levels promote left ventricular hypertrophy but not coronary artery calcification. We used survival analysis to determine whether elevated FGF-23 is associated with greater risk of adjudicated congestive heart failure (CHF) and atherosclerotic events (myocardial infarction, stroke, and peripheral vascular disease) in a prospective cohort of 3860 participants with CKD stages 2-4 (baseline estimated GFR [eGFR], 44+/-15 ml/min per 1.73 m(2)). During a median follow-up of 3.7 years, 360 participants were hospitalized for CHF (27 events/1000 person-years) and 287 had an atherosclerotic event (22 events/1000 person-years). After adjustment for demographic characteristics, kidney function, traditional cardiovascular risk factors, and medications, higher FGF-23 was independently associated with graded risk of CHF (hazard ratio [HR], 1.45 per doubling [95% confidence interval (CI), 1.28 to 1.65]; HR for highest versus lowest quartile, 2.98 [95% CI, 1.97 to 4.52]) and atherosclerotic events (HR per doubling, 1.24 [95% CI, 1.09 to 1.40]; HR for highest versus lowest quartile, 1.76 [95% CI, 1.20 to 2.59]). Elevated FGF 23 was associated more strongly with CHF than with atherosclerotic events (P=0.02), and uniformly was associated with greater risk of CHF events across subgroups stratified by eGFR, proteinuria, prior heart disease, diabetes, BP control, anemia, sodium intake, income, fat-free mass, left ventricular mass index, and ejection fraction. Thus, higher FGF-23 is independently associated with greater risk of cardiovascular events, particularly CHF, in patients with CKD stages 2-4. PMID- 24158990 TI - Endothelial-podocyte crosstalk: the missing link between endothelial dysfunction and albuminuria in diabetes. AB - Although diabetes is the most common cause of end-stage renal disease (ESRD) worldwide, most people with diabetic nephropathy will never develop ESRD but will instead die of cardiovascular (CV) disease (CVD). The first evidence of kidney injury in diabetes is often microalbuminuria, itself also an independent risk marker for CVD. Although the two processes are closely associated, the recent failure of antialbuminuric therapies to affect CV outcomes has encouraged a reconsideration of how albuminuria may occur in diabetes and how increased urinary albumin excretion may be indicative of CV risk. The relationship between CVD and urinary albumin content (even within the normal range) is widely considered to reflect the common underlying pathology of endothelial dysfunction. At the same time, recent years have witnessed a growing appreciation that diabetic albuminuria commonly arises from damage to glomerular podocytes, specialized epithelial cells acting as the final barrier to macromolecular flow into the urinary filtrate. These superficially discordant paradigms can be assimilated by the emerging concept of endothelial-podocyte crosstalk across the glomerular filtration barrier, whereby the actions of one type of cell may profoundly influence the function of the other. The bidirectional nature of this paracrine network is illustrated by the actions of the vascular endothelial growth factor-A (VEGF-A)/VEGF receptor-2 and activated protein C systems, among others. Identification of novel mediators of endothelial-podocyte crosstalk may lead to the development of more effective treatments for diabetic nephropathy and its sequelae. PMID- 24158991 TI - The compelling case for anti-CD3 in type 1 diabetes. PMID- 24158988 TI - Predialysis health, dialysis timing, and outcomes among older United States adults. AB - Studies of dialysis initiation timing have not accounted for predialysis clinical factors that could impact postdialysis outcomes. We examined the association of predialysis health with timing of dialysis initiation in older adult patients in the United States and contrasted morbidity and mortality outcomes among patients with early [estimated GFR (eGFR)>=10 ml/min per 1.73 m(2)] versus later (eGFR<10 ml/min per 1.73 m(2)) initiation. We included all patients from the US Renal Data System who initiated dialysis between 2006 and 2008, were >=67 years old, and had >=2 years of prior Medicare coverage (n=84,654). We calculated patients' propensity to initiate dialysis early and matched patients by propensity scores. Cox models were used to compare risks of mortality and hospitalization among initiation groups. The majority (58%) of patients initiated dialysis early. Early initiators were more likely to have had AKI, multiple congestive heart failure admissions, and other hospitalizations preceding initiation. Among propensity matched patients (n=61,930), early initiation associated with greater all-cause (hazard ratio [HR], 1.11; 95% confidence interval [95% CI], 1.08 to 1.14), cardiovascular (CV; HR, 1.13; 95% CI, 1.09 to 1.17), and infectious (HR, 1.13; 95% CI, 1.06 to 1.22) mortality and greater all-cause (HR, 1.03; 95% CI, 1.01 to 1.05) and infectious (HR, 1.10; 95% CI, 1.07 to 1.13) hospitalizations. There was no difference in CV hospitalizations. Among these older adults, early dialysis initiation associates with greater mortality and hospitalizations, even after accounting for predialysis clinical factors. These findings do not support the common practice of early dialysis initiation in the United States. PMID- 24158992 TI - Location, location, location?: is the pain of diabetic neuropathy generated by hyperactive sensory neurons? PMID- 24158993 TI - Cholesterol accumulation in podocytes: a potential novel targetable pathway in diabetic nephropathy. PMID- 24158994 TI - How does pioglitazone prevent progression of impaired glucose tolerance to diabetes? PMID- 24158995 TI - ATP and sulfonylurea linkage in the K(ATP) channel solves a diabetes puzzler. PMID- 24158996 TI - Depleting T cells in newly diagnosed autoimmune (type 1) diabetes--are we getting anywhere? PMID- 24158997 TI - Going with the flow: adaptation of beta-cell function to glucose fluxes after bariatric surgery. PMID- 24158998 TI - GABAergic system in beta-cells: from autoimmunity target to regeneration tool. PMID- 24158999 TI - Assessing decreased sensation and increased sensory phenomena in diabetic polyneuropathies. AB - Loss of sensation and increased sensory phenomena are major expressions of varieties of diabetic polyneuropathies needing improved assessments for clinical and research purposes. We provide a neurobiological explanation for the apparent paradox between decreased sensation and increased sensory phenomena. Strongly endorsed is the use of the 10-g monofilaments for screening of feet to detect sensation loss, with the goal of improving diabetic management and prevention of foot ulcers and neurogenic arthropathy. We describe improved methods to assess for the kind, severity, and distribution of both large- and small-fiber sensory loss and which approaches and techniques may be useful for conducting therapeutic trials. The abnormality of attributes of nerve conduction may be used to validate the dysfunction of large sensory fibers. The abnormality of epidermal nerve fibers/1 mm may be used as a surrogate measure of small-fiber sensory loss but appear not to correlate closely with severity of pain. Increased sensory phenomena are recognized by the characteristic words patients use to describe them and by the severity and persistence of these symptoms. Tests of tactile and thermal hyperalgesia are additional markers of neural hyperactivity that are useful for diagnosis and disease management. PMID- 24159003 TI - Do men's and women's accounts of surviving a stroke conform to Frank's narrative genres? AB - We compared the illness narratives of 9 male and 9 female United Kingdom stroke survivors using Frank's typologies of illness narratives. Most respondents presented a single dominant narrative genre ("quest memoir," "restitution," "chaos," or a new "despair" genre); none presented quest manifesto or automythology narratives of social action or self-reinvention. We found no gender differences apparent in which genres respondents presented. Stroke severity and the degree of anticipated or actual recovery largely influenced which genre predominated in individual accounts. Contrary to some sociological understandings of gender and health, gender appeared to be less influential on stroke survivors' illness accounts than aspects of the illness, such as its severity. PMID- 24159000 TI - Myocardial loss of IRS1 and IRS2 causes heart failure and is controlled by p38alpha MAPK during insulin resistance. AB - Cardiac failure is a major cause of death in patients with type 2 diabetes, but the molecular mechanism that links diabetes to heart failure remains unclear. Insulin resistance is a hallmark of type 2 diabetes, and insulin receptor substrates 1 and 2 (IRS1 and IRS2) are the major insulin-signaling components regulating cellular metabolism and survival. To determine the role of IRS1 and IRS2 in the heart and examine whether hyperinsulinemia causes myocardial insulin resistance and cellular dysfunction via IRS1 and IRS2, we generated heart specific IRS1 and IRS2 gene double-knockout (H-DKO) mice and liver-specific IRS1 and IRS2 double-knockout (L-DKO) mice. H-DKO mice had reduced ventricular mass; developed cardiac apoptosis, fibrosis, and failure; and showed diminished Akt >forkhead box class O-1 signaling that was accompanied by impaired cardiac metabolic gene expression and reduced ATP content. L-DKO mice had decreased cardiac IRS1 and IRS2 proteins and exhibited features of heart failure, with impaired cardiac energy metabolism gene expression and activation of p38alpha mitogen-activated protein kinase (p38). Using neonatal rat ventricular cardiomyocytes, we further found that chronic insulin exposure reduced IRS1 and IRS2 proteins and prevented insulin action through activation of p38, revealing a fundamental mechanism of cardiac dysfunction during insulin resistance and type 2 diabetes. PMID- 24159004 TI - The weight of the word: knowing silences in obesity research. AB - In this article, we examine the ethical and methodological tensions entailed in doing qualitative research in obesity studies. Framing our own embodied engagements through critical social theory, we consider how cultural meanings associated with obesity are silenced and negotiated in the research process. This negotiation is fraught with linguistic and corporeal challenges, beginning with the decision to use (or not use) the word obesity in research materials. Obesity is a visible stigma, and we argue that silencing language does not erase the tacit judgments that accompany discursive categorization. It is in a broader context of power relations that we examine the relationship between researcher and participant bodies and the ways in which collective knowingness about fat bodies underpins methodological engagement. The simultaneous presence and absence of obesity have a significant impact on the research process, in shaping both participants' experiences and the researcher's actions and interpretations. PMID- 24159005 TI - Sanitoriums and the Canadian colonial legacy: the untold experiences of tuberculosis treatment. AB - Sanitoriums served a much-needed purpose in the age prior to antituberculosis drugs: They removed the infected patient from wider society and created an environment that promoted recovery. We aimed to (a) describe sanitoriums from the perspective of a First Nations reserve community in northern Canada and (b) understand the impact of the sanitorium experience at a community level. Semistructured interviews (n = 15) were conducted in a First Nations reserve community with a high incidence of tuberculosis. Purposive and snowball sampling were used to obtain the sample. Data collection and analysis were iterative, using qualitative content analysis. Participants described the exclusion resulting within and because of sanitoriums. Exclusion within sanitoriums was categorized into (a) the exclusion of Aboriginal culture and practices of healing from the treatment of tuberculosis and (b) the internal exclusion, in which members of the community internally labeled the healed individual postsanitorium as an outsider. PMID- 24159006 TI - Practice tips and tools for the successful use of U-500 regular human insulin: the diabetes educator is key. AB - This review provides information to equip diabetes educators to instruct and guide patients in using U-500 human regular insulin (U-500R). The article includes an overview of U-500R pharmacology and clinical data, strategies for outpatient and inpatient use, and tools for patient education. U-500R is useful for treating patients with any type of diabetes who require high doses of insulin. U-500R alleviates the volume-related problems associated with high doses of U-100 insulin, making treatment with high doses of insulin more feasible (because of the need for fewer injections for patients) as well as more cost efficient and potentially more effective. These tools can help diabetes educators feel more comfortable and confident as they advise and educate patients who receive high-dose U-500R as part of their overall diabetes care plan. The diabetes educator plays a vital role in helping patients use U-500R safely and successfully. PMID- 24159008 TI - Server-based enterprise collaboration software improves safety and quality in high-volume PET/CT practice. AB - With increasing volumes of complex imaging cases and rising economic pressure on physician staffing, timely reporting will become progressively challenging. Current and planned iterations of PACS and electronic medical record systems do not offer workflow management tools to coordinate delivery of imaging interpretations with the needs of the patient and ordering physician. The adoption of a server-based enterprise collaboration software system by our Division of Nuclear Medicine has significantly improved our efficiency and quality of service. PMID- 24159007 TI - Impact of a focused nutrition educational intervention coupled with improved access to fresh produce on purchasing behavior and consumption of fruits and vegetables in overweight patients with diabetes mellitus. AB - PURPOSE: The purpose of this study was to test the impact of distributing coupons redeemable at farmers markets plus an educational intervention on fruit and vegetable (F&V) purchase and consumption in overweight patients with type 2 diabetes (T2DM). METHODS: Seventy-eight participants with T2DM being followed at Jacobi Medical Center, a large public hospital in the Bronx, New York, were randomized to receive the standard of care or a 1-hour session focused on benefits of F&V consumption and $6 in coupons. Questionnaires assessed demographics, F&V intake, and farmers market purchasing at baseline and 12 weeks. Clinical parameters were obtained through chart review at baseline and at 12 weeks. RESULTS: Participants were predominantly Latino, females, and low income. At 12 weeks, there was a statistically significant increase in the number of participants in the intervention arm who reported purchasing from a farmers market. In addition, there was a minimal increase in fresh fruit intake in the intervention arm at 12 weeks. CONCLUSION: Focused education combined with a small economic incentive resulted in an increase in purchasing behavior and fresh fruit intake per day. A more intense behavioral intervention combined with increased access may result in a significant impact on obesity and diabetes, particularly among low-income and racially diverse communities. PMID- 24159009 TI - The role of scintigraphy in confirmation of suspected brain death. AB - We present a case illustrating how cerebral perfusion scintigraphy can be used to assist in crucial medical decision making in the intensive care setting for patients who are maintained on life support but are clinically suspected to have brain death. Cerebral perfusion scintigraphy can confirm brain death but cannot be used to diagnose it. (99m)Tc-HMPAO and (99m)Tc-ethylcysteinate dimer are the preferred imaging agents since they cross the blood-brain barrier. PMID- 24159010 TI - The added clinical value of 18F-FDG PET/CT in evaluating intratracheal recurrence of differentiated thyroid carcinoma: implications for planning surgery, assessing its completeness, and planning radioiodine therapy. AB - In selected patients with differentiated thyroid carcinoma, (18)F-FDG PET/CT has been shown to have added value. We present 2 clinical examples in the settings of both iodine-concentrating and non-iodine-concentrating lesions with tracheal involvement with special reference to its importance in planning of surgery or radioiodine therapy and assessing completeness of surgery. We believe that the use of PET/CT should be considered on a case-by-case basis and specifically when SPECT/CT is unavailable or has inconclusive findings. PMID- 24159011 TI - Evaluation of tumor-induced osteomalacia with 111In-pentetreotide scintigraphy. AB - In cases of nonhereditary osteomalacia associated with hypophosphatemia and inadequate response to vitamin D supplementation, one should consider the possibility of tumor-induced osteomalacia, a paraneoplastic syndrome caused by small mesenchymal tumors often found in obscure locations. We present a case of tumor-induced osteomalacia in which (111)In-pentetreotide scintigraphy aided in accurate localization of the culprit brachial plexus tumor and cure after resection. PMID- 24159012 TI - Comparison of a noise-weighted filtered backprojection algorithm with the Standard MLEM algorithm for poisson noise. AB - Iterative maximum-likelihood expectation maximization and ordered-subset expectation maximization algorithms are excellent for image reconstruction and usually provide better images than filtered backprojection (FBP). Recently, an FBP algorithm able to incorporate noise weighting during reconstruction was developed. This paper compares the performance of the noise-weighted FBP algorithm and the iterative maximum-likelihood expectation maximization algorithm with Poisson noise-corrupted emission data generated by computer simulations and a SPECT experimental study. The results show comparable performance for these 2 algorithms. PMID- 24159013 TI - From Kraepelin to a modern and integrative scientific discipline: the development of transcultural psychiatry in Germany. AB - The roots of transcultural psychiatry in Germany can be traced back to Emil Kraepelin, who made the first culturally comparative observations on mental disorders in Southeast Asia at the start of the 20th century. Since the beginning of the 1970s, contributors to the literature of transcultural psychiatry in Germany have been predominantly concerned with the mental health of migrant workers from Mediterranean countries, particularly the practical difficulties and therapeutic implications of inpatient psychiatric treatment of these migrant groups. The inauguration of the Section on Transcultural Psychiatry of the German Association for Psychiatry and Psychotherapy 20 years ago reflected an increasing scientific interest in this topic. In addition to the psychic impact of migration, research into transcultural care is currently focused on disparities in the utilization of health care and conjectured barriers to access to health and mental health care among migrants. Furthermore, studies based on epidemiological approaches have been carried out in order to resolve the question of whether migrants are as affected by mental disorders as the ethnic German population, and which issues contribute to the so-called "healthy migrant" effect. Other topics that have been explored in the last 10 years are the particular psychosocial situation of asylum seekers and refugees in Germany, and the effects of inadequate integration and discrimination on their mental health. In summary, after a short historical and theoretical overview, this article reviews the current major themes in transcultural research in German contemporary psychiatry, and concludes with an overview of future developments in this field. PMID- 24159014 TI - Bricks and MOOCs. PMID- 24159019 TI - Genomes. Ancient DNA links Native Americans with Europe. PMID- 24159021 TI - Astronomy. Earliest known galaxy formed stars at a breakneck pace. PMID- 24159020 TI - Science funding. U.S. shutdown ends, but not budget anxiety. PMID- 24159022 TI - Newsmaker interview: Mark Walport. U.K. science adviser faces emotionally charged issues and uncertain science. PMID- 24159023 TI - Infectious disease. Immune suppressant unexpectedly boosts flu vaccine. PMID- 24159024 TI - Tropical medicine. Surprising new dengue virus throws a spanner in disease control efforts. PMID- 24159025 TI - Varmus's second act. PMID- 24159026 TI - A cancer to-do list. PMID- 24159027 TI - Ecosystem services: accounting standards. PMID- 24159028 TI - Ecosystem services: the farmers' challenge. PMID- 24159029 TI - Ecosystem services: nature's balance sheet. PMID- 24159030 TI - Ecosystem services: response. PMID- 24159031 TI - Conservation. Biodiversity risks from fossil fuel extraction. PMID- 24159032 TI - Economics. Women, fertility, and the rise of modern capitalism. PMID- 24159033 TI - Evolution. Natural selection and pain meet at a sodium channel. PMID- 24159034 TI - Chemistry. Expanding the scope of fluorine tags for PET imaging. PMID- 24159035 TI - Geophysics. The new core paradox. PMID- 24159036 TI - Immunology. Mucus coat, a dress code for tolerance. PMID- 24159037 TI - Environmental science. Blooms bite the hand that feeds them. PMID- 24159038 TI - IBI* series winner. Radiation and atomic literacy for nonscientists. PMID- 24159040 TI - Observation of Floquet-Bloch states on the surface of a topological insulator. AB - The unique electronic properties of the surface electrons in a topological insulator are protected by time-reversal symmetry. Circularly polarized light naturally breaks time-reversal symmetry, which may lead to an exotic surface quantum Hall state. Using time- and angle-resolved photoemission spectroscopy, we show that an intense ultrashort midinfrared pulse with energy below the bulk band gap hybridizes with the surface Dirac fermions of a topological insulator to form Floquet-Bloch bands. These photon-dressed surface bands exhibit polarization dependent band gaps at avoided crossings. Circularly polarized photons induce an additional gap at the Dirac point, which is a signature of broken time-reversal symmetry on the surface. These observations establish the Floquet-Bloch bands in solids and pave the way for optical manipulation of topological quantum states of matter. PMID- 24159041 TI - From few to many: observing the formation of a Fermi sea one atom at a time. AB - Knowing when a physical system has reached sufficient size for its macroscopic properties to be well described by many-body theory is difficult. We investigated the crossover from few- to many-body physics by studying quasi-one-dimensional systems of ultracold atoms consisting of a single impurity interacting with an increasing number of identical fermions. We measured the interaction energy of such a system as a function of the number of majority atoms for different strengths of the interparticle interaction. As we increased the number of majority atoms one by one, we observed fast convergence of the normalized interaction energy toward a many-body limit calculated for a single impurity immersed in a Fermi sea of majority particles. PMID- 24159039 TI - Voltage-gated sodium channel in grasshopper mice defends against bark scorpion toxin. AB - Painful venoms are used to deter predators. Pain itself, however, can signal damage and thus serves an important adaptive function. Evolution to reduce general pain responses, although valuable for preying on venomous species, is rare, likely because it comes with the risk of reduced response to tissue damage. Bark scorpions capitalize on the protective pain pathway of predators by inflicting intensely painful stings. However, grasshopper mice regularly attack and consume bark scorpions, grooming only briefly when stung. Bark scorpion venom induces pain in many mammals (house mice, rats, humans) by activating the voltage gated Na(+) channel Nav1.7, but has no effect on Nav1.8. Grasshopper mice Nav1.8 has amino acid variants that bind bark scorpion toxins and inhibit Na(+) currents, blocking action potential propagation and inducing analgesia. Thus, grasshopper mice have solved the predator-pain problem by using a toxin bound to a nontarget channel to block transmission of the pain signals the venom itself is initiating. PMID- 24159042 TI - Stabilizing liquid drops in nonequilibrium shapes by the interfacial jamming of nanoparticles. AB - Nanoparticles assemble at the interface between two fluids into disordered, liquid-like arrays where the nanoparticles can diffuse laterally at the interface. Using nanoparticles dispersed in water and amine end-capped polymers in oil, nanoparticle surfactants are generated in situ at the interface overcoming the inherent weak forces governing the interfacial adsorption of nanoparticles. When the shape of the liquid domain is deformed by an external field, the surface area increases and more nanoparticles adsorb to the interface. Upon releasing the field, the interfacial area decreases, jamming the nanoparticle surfactants and arresting further shape change. The jammed nanoparticles remain disordered and liquid-like, enabling multiple, consecutive deformation and jamming events. Further stabilization is realized by replacing monofunctional ligands with difunctional versions that cross-link the assemblies. The ability to generate and stabilize liquids with a prescribed shape poses opportunities for reactive liquid systems, packaging, delivery, and storage. PMID- 24159043 TI - Mass-independent oxygen isotopic partitioning during gas-phase SiO2 formation. AB - Meteorites contain a wide range of oxygen isotopic compositions that are interpreted as heterogeneity in solar nebula. The anomalous oxygen isotopic compositions of refractory mineral phases may reflect a chemical fractionation process in the nebula, but there are no experiments to demonstrate this isotope effect during particle formation through gas-phase reactions. We report experimental results of gas-to-particle conversion during oxidation of silicon monoxide that define a mass-independent line (slope one) in oxygen three-isotope space of (18)O/(16)O versus (17)O/(16)O. This mass-independent chemical reaction is a potentially initiating step in nebular meteorite formation, which would be capable of producing silicate reservoirs with anomalous oxygen isotopic compositions. PMID- 24159044 TI - Atypical combinations and scientific impact. AB - Novelty is an essential feature of creative ideas, yet the building blocks of new ideas are often embodied in existing knowledge. From this perspective, balancing atypical knowledge with conventional knowledge may be critical to the link between innovativeness and impact. Our analysis of 17.9 million papers spanning all scientific fields suggests that science follows a nearly universal pattern: The highest-impact science is primarily grounded in exceptionally conventional combinations of prior work yet simultaneously features an intrusion of unusual combinations. Papers of this type were twice as likely to be highly cited works. Novel combinations of prior work are rare, yet teams are 37.7% more likely than solo authors to insert novel combinations into familiar knowledge domains. PMID- 24159045 TI - A radical intermediate in tyrosine scission to the CO and CN- ligands of FeFe hydrogenase. AB - The radical S-adenosylmethionine (SAM) enzyme HydG lyses free l-tyrosine to produce CO and CN(-) for the assembly of the catalytic H cluster of FeFe hydrogenase. We used electron paramagnetic resonance spectroscopy to detect and characterize HydG reaction intermediates generated with a set of (2)H, (13)C, and (15)N nuclear spin-labeled tyrosine substrates. We propose a detailed reaction mechanism in which the radical SAM reaction, initiated at an N-terminal 4Fe-4S cluster, generates a tyrosine radical bound to a C-terminal 4Fe-4S cluster. Heterolytic cleavage of this tyrosine radical at the Calpha-Cbeta bond forms a transient 4-oxidobenzyl (4OB(*)) radical and a dehydroglycine bound to the C terminal 4Fe-4S cluster. Electron and proton transfer to this 4OB(*) radical forms p-cresol, with the conversion of this dehydroglycine ligand to Fe-bound CO and CN(-), a key intermediate in the assembly of the 2Fe subunit of the H cluster. PMID- 24159047 TI - Role of O-(2-18F-fluoroethyl)-L-tyrosine PET as a diagnostic tool for detection of malignant progression in patients with low-grade glioma. AB - In patients with low-grade glioma (LGG) of World Health Organization (WHO) grade II, early detection of progression to WHO grade III or IV is of high clinical importance because the initiation of a specific treatment depends mainly on the WHO grade. In a significant number of patients with LGG, however, information on tumor activity and malignant progression cannot be obtained on the basis of clinical or conventional MR imaging findings only. We here investigated the potential of O-(2-(18)F-fluoroethyl)-L-tyrosine ((18)F-FET) PET to noninvasively detect malignant progression in patients with LGG. METHODS: Twenty-seven patients (mean age +/- SD, 44 +/- 15 y) with histologically proven LGG (WHO grade II) were investigated longitudinally twice using dynamic (18)F-FET PET and routine MR imaging. Initially, MR imaging and PET scans were performed, and diagnosis was confirmed on the basis of biopsy. Subsequently, PET scans were obtained when clinical findings or contrast-enhanced MR imaging suggested malignant progression. Maximum and mean tumor-to-brain ratios (20-40 min after injection) (TBRmax and TBRmean, respectively) of (18)F-FET uptake as well as tracer uptake kinetics (i.e., time to peak [TTP] and patterns of the time-activity curves) were determined. The diagnostic accuracy of imaging parameters for the detection of malignant progression was evaluated by receiver-operating-characteristic analyses and by Fisher exact test for 2 * 2 contingency tables. RESULTS: In patients with histologically proven malignant progression toward WHO grade III or IV (n = 18), TBRmax and TBRmean increased significantly, compared with baseline (TBRmax, 3.8 +/- 1.0 vs. 2.4 +/- 1.0; TBRmean, 2.2 +/- 0.3 vs. 1.6 +/- 0.6; both P < 0.001), whereas TTP decreased significantly (median TTP, 35 vs. 23 min; P < 0.001). Furthermore, time-activity curve patterns changed significantly in 10 of 18 patients (P < 0.001). The combined analysis of (18)F-FET PET parameters (i.e., changes of TBRmax, TTP, or time-activity curve pattern) yielded a significantly higher diagnostic accuracy for the detection of malignant progression than changes of contrast enhancement in MR imaging (accuracy, 81% vs. 63%; P = 0.003). CONCLUSION: Both tumor-to-brain ratio and kinetic parameters of (18)F-FET PET uptake provide valuable diagnostic information for the noninvasive detection of malignant progression of LGG. Thus, repeated (18)F-FET PET may be helpful for further treatment decisions. PMID- 24159048 TI - Brain glucose transport and phosphorylation under acute insulin-induced hypoglycemia in mice: an 18F-FDG PET study. AB - We addressed the questions of how cerebral glucose transport and phosphorylation change under acute hypoglycemia and what the underlying mechanisms of adaptation are. METHODS: Quantitative (18)F-FDG PET combined with the acquisition of real time arterial input function was performed on mice. Hypoglycemia was induced and maintained by insulin infusion. PET data were analyzed with the 2-tissue compartment model for (18)F-FDG, and the results were evaluated with Michaelis Menten saturation kinetics. RESULTS: Glucose clearance from plasma to brain (K1,glc) and the phosphorylation rate constant increased with decreasing plasma glucose (Gp), in particular at a Gp of less than 2.5 mmol/L. Estimated cerebral glucose extraction ratios taking into account an increased cerebral blood flow (CBF) at a Gp of less than 2 mmol/L were between 0.14 and 0.79. CBF-normalized K1,glc values were in agreement with saturation kinetics. Phosphorylation rate constants indicated intracellular glucose depletion at a Gp of less than 2-3 mmol/L. When brain regions were compared, glucose transport under hypoglycemia was lowest in the hypothalamus. CONCLUSION: Alterations in glucose transport and phosphorylation, as well as intracellular glucose depletion, under acute hypoglycemia can be modeled by saturation kinetics taking into account an increase in CBF. Distinct transport kinetics in the hypothalamus may be involved in its glucose-sensing function. PMID- 24159049 TI - Parallel programming of saccades during natural scene viewing: evidence from eye movement positions. AB - Previous studies have shown that saccade plans during natural scene viewing can be programmed in parallel. This evidence comes mainly from temporal indicators, i.e., fixation durations and latencies. In the current study, we asked whether eye movement positions recorded during scene viewing also reflect parallel programming of saccades. As participants viewed scenes in preparation for a memory task, their inspection of the scene was suddenly disrupted by a transition to another scene. We examined whether saccades after the transition were invariably directed immediately toward the center or were contingent on saccade onset times relative to the transition. The results, which showed a dissociation in eye movement behavior between two groups of saccades after the scene transition, supported the parallel programming account. Saccades with relatively long onset times (>100 ms) after the transition were directed immediately toward the center of the scene, probably to restart scene exploration. Saccades with short onset times (<100 ms) moved to the center only one saccade later. Our data on eye movement positions provide novel evidence of parallel programming of saccades during scene viewing. Additionally, results from the analyses of intersaccadic intervals were also consistent with the parallel programming hypothesis. PMID- 24159046 TI - Fine tuning of craniofacial morphology by distant-acting enhancers. AB - The shape of the human face and skull is largely genetically determined. However, the genomic basis of craniofacial morphology is incompletely understood and hypothesized to involve protein-coding genes, as well as gene regulatory sequences. We used a combination of epigenomic profiling, in vivo characterization of candidate enhancer sequences in transgenic mice, and targeted deletion experiments to examine the role of distant-acting enhancers in craniofacial development. We identified complex regulatory landscapes consisting of enhancers that drive spatially complex developmental expression patterns. Analysis of mouse lines in which individual craniofacial enhancers had been deleted revealed significant alterations of craniofacial shape, demonstrating the functional importance of enhancers in defining face and skull morphology. These results demonstrate that enhancers are involved in craniofacial development and suggest that enhancer sequence variation contributes to the diversity of human facial morphology. PMID- 24159050 TI - The DSM-5 changes and ADHD: More than a tweak of terms. PMID- 24159051 TI - Metacognitive training for patients with schizophrenia: preliminary evidence for a targeted, single-module programme. AB - OBJECTIVE: Metacognitive training is an eight-module, group-based treatment programme for people with schizophrenia that targets the cognitive biases (i.e. problematic thinking styles) thought to contribute to the genesis and maintenance of delusions. The present article is an investigation into the efficacy of a shorter, more targeted, single-module metacognitive training programme, administered individually, which focuses specifically on improving cognitive biases that are thought to be driven by a 'hypersalience of evidence-hypothesis matches' mechanism (e.g. jumping to conclusions, belief inflexibility, reasoning heuristics, illusions of control). It was hypothesised that a more targeted metacognitive training module could still improve performance on these bias tasks and reduce delusional ideation, while improving insight and quality of life. METHOD: A sample of 28 patients diagnosed with schizophrenia and mild delusions either participated in the hour-long, single-session, targeted metacognitive training programme (n = 14), or continued treatment as usual (n = 14). All patients were assessed using clinical measures gauging overall positive symptomology, delusional ideation, quality of life and insight, and completed two cognitive bias tasks designed to elucidate the representativeness and illusion of control biases. RESULTS: After a 2-week, post-treatment interval, targeted metacognitive training patients exhibited significant decreases in delusional severity and conviction, significantly improved clinical insight, and significant improvements on the cognitive bias tasks, relative to the treatment-as-usual controls. Performance improvements on the cognitive bias tasks significantly correlated with the observed reductions in overall positive symptomology. Patients also evaluated the training positively. CONCLUSIONS: Although interpretations of these results are limited due to the lack of an optimally designed, randomised controlled trial and a small sample size, the results are promising and warrant further investigation into targeted versions of the metacognitive training programme. PMID- 24159052 TI - Social media, social avatars and the psyche: is Facebook good for us? AB - OBJECTIVE: This paper aims to explore how social media users represent themselves online, and to consider whether this process has inherent potential to impact upon the psyche of the individual. CONCLUSIONS: Advanced thinking around social media may exist on an organizational level, but on an individual level there exists a need to catch up, as the psychological dimensions of going online are significant and deserve consideration. Inherent to the experience of using social media is the self selection of favorable material to represent the individual. This process is cumulative, and effectively creates a socially-derived and socially-driven, composite online image ('social avatar'). Humans notably select their best aspects for presentation to others and the social avatar reflects this tendency, effectively facilitating the creation of a 'gap' between online image (representation) and offline identity (substance). The creation of a social avatar should therefore be an important and conscious consideration for all users of social media, not just those individuals already struggling with the task of integrating the multiple facets which make up modern personal identity. Social avatars appear to be an important factor in understanding the inherent potential for social media to affect the psyche/contribute to psychopathology within the individual. PMID- 24159054 TI - Effects of inflammation on the innervation of the colon. AB - Inflammatory bowel diseases (IBD) such as ulcerative colitis and Crohn's disease lead to altered gastrointestinal (GI) function as a consequence of the effects of inflammation on the tissues that comprise the GI tract. Among these tissues are several types of neurons that detect the state of the GI tract, transmit pain, and regulate functions such as motility, secretion, and blood flow. This review article describes the structure and function of the enteric nervous system, which is embedded within the gut wall, the sympathetic motor innervation of the colon and the extrinsic afferent innervation of the colon, and considers the evidence that colitis alters these important sensory and motor systems. These alterations may contribute to the pain and altered bowel habits that accompany IBD. PMID- 24159053 TI - Associations between observed neighborhood characteristics and physical activity: findings from a multiethnic urban community. AB - BACKGROUND: There is growing interest in the contributions of characteristics of the neighborhood environment to inequalities in physical activity. However, few studies have examined the relationship between observed neighborhood environmental characteristics and physical activity in a multiethnic urban area. PURPOSE: The purpose of this study was to assess relationships between neighborhood environments and physical activity and the extent to which these associations varied by demographic characteristics or perceptions of the physical and social environment. METHODS: Cross-sectional analyses drew upon data collected from a stratified proportional probability sample of non-Hispanic Black, Hispanic and non-Hispanic White (NHW) adults (n = 919) in low-to-moderate income neighborhoods in Detroit, Michigan. Physical activity was assessed as self reported duration and frequency of vigorous and moderate physical activity. Observed physical environment was assessed through systematic social observation by trained observers on blocks adjacent to survey respondents' residences. RESULTS: We find a positive association of sidewalk condition with physical activity, with stronger effects for younger compared with older residents. In addition, physical disorder was more negatively associated with physical activity among NHW and older residents. CONCLUSIONS: These findings suggest that sidewalk improvements and reductions in physical disorder in urban communities may promote greater equity in physical activity. PMID- 24159055 TI - Overview of the pancreatic toxicity and carcinogenesis session. AB - The theme of the Society of Toxicologic Pathology Annual Symposium 2013 was "Toxicologic Pathology of the Digestive Tract and Pancreas." The last session focused on pancreatic toxicity and carcinogenesis. This overview highlights the various presentations in this session, focusing on pancreatic toxicologic pathology, responses of the pancreas to xenobiotics, and current understanding on pancreatic carcinogenesis. The objective of this symposium overview and the subsequent articles from this session is to enable the audience to develop a better appreciation for the pancreas as a target organ in toxicological studies. PMID- 24159058 TI - Hypothesis generation for childhood cancer communication research: results of a secondary analysis. AB - Secondary analysis of existing qualitative datasets offers an opportunity to efficiently use these difficult-to-collect data to generate hypotheses for future research and expand understanding of the phenomena under study. We conducted a retrospective interpretation of two qualitative datasets regarding childhood cancer treatment decision making to elaborate themes regarding parents' cancer communication (information sharing and involvement of their children in treatment decision making) that were not fully developed in the original analyses. We identified broad variability in parents' cancer communication that was not entirely dependent upon the age of their ill child. We were able to generate multiple hypotheses to help guide our future research. PMID- 24159060 TI - CLOTBUST-Hands Free: pilot safety study of a novel operator-independent ultrasound device in patients with acute ischemic stroke. AB - BACKGROUND AND PURPOSE: The Combined Lysis of Thrombus in Brain Ischemia With Transcranial Ultrasound and Systemic T-PA-Hands-Free (CLOTBUST-HF) study is a first-in-human, National Institutes of Health-sponsored, multicenter, open-label, pilot safety trial of tissue-type plasminogen activator (tPA) plus a novel operator-independent ultrasound device in patients with ischemic stroke caused by proximal intracranial occlusion. METHODS: All patients received standard-dose intravenous tPA, and shortly after tPA bolus, the CLOTBUST-HF device delivered 2 hour therapeutic exposure to 2-MHz pulsed-wave ultrasound. Primary outcome was occurrence of symptomatic intracerebral hemorrhage. All patients underwent pretreatment and post-treatment transcranial Doppler ultrasound or CT angiography. National Institutes of Health Stroke Scale scores were collected at 2 hours and modified Rankin scale at 90 days. RESULTS: Summary characteristics of all 20 enrolled patients were 60% men, mean age of 63 (SD=14) years, and median National Institutes of Health Stroke Scale of 15. Sites of pretreatment occlusion were as follows: 14 of 20 (70%) middle cerebral artery, 3 of 20 (15%) terminal internal carotid artery, and 3 of 20 (15%) vertebral artery. The median (interquartile range) time to tPA at the beginning of sonothrombolysis was 22 (13.5-29.0) minutes. All patients tolerated the entire 2 hours of insonation, and none developed symptomatic intracerebral hemorrhage. No serious adverse events were related to the study device. Rates of 2-hour recanalization were as follows: 8 of 20 (40%; 95% confidence interval, 19%-64%) complete and 2 of 20 (10%; 95% confidence interval, 1%-32%) partial. Middle cerebral artery occlusions demonstrated the greatest complete recanalization rate: 8 of 14 (57%; 95% confidence interval, 29%-82%). At 90 days, 5 of 20 (25%, 95% confidence interval, 7%-49) patients had a modified Rankin scale of 0 to 1. CONCLUSIONS: Sonothrombolysis using a novel, operator-independent device, in combination with systemic tPA, seems safe, and recanalization rates warrant evaluation in a phase III efficacy trial. CLINICAL TRIAL REGISTRATION URL: http://www.clinicaltrials.gov. Unique identifier: CLOTBUST-HF NCT01240356. PMID- 24159061 TI - Dietary patterns are associated with incident stroke and contribute to excess risk of stroke in black Americans. AB - BACKGROUND AND PURPOSE: Black Americans and residents of the Southeastern United States are at increased risk of stroke. Diet is one of many potential factors proposed that might explain these racial and regional disparities. METHODS: Between 2003 and 2007, the REasons for Geographic and Racial Differences in Stroke (REGARDS) cohort study enrolled 30 239 black and white Americans aged>=45 years. Dietary patterns were derived using factor analysis and foods from food frequency data. Incident strokes were adjudicated using medical records by a team of physicians. Cox-proportional hazards models were used to examine risk of stroke. RESULTS: During 5.7 years, 490 incident strokes were observed. In a multivariable-adjusted analysis, greater adherence to the plant-based pattern was associated with lower stroke risk (hazard ratio, 0.71; 95% confidence interval, 0.56-0.91; Ptrend=0.005). This association was attenuated after addition of income, education, total energy intake, smoking, and sedentary behavior. Participants with a higher adherence to the Southern pattern experienced a 39% increased risk of stroke (hazard ratio, 1.39; 95% confidence interval, 1.05, 1.84), with a significant (P=0.009) trend across quartiles. Including Southern pattern in the model mediated the black-white risk of stroke by 63%. CONCLUSIONS: These data suggest that adherence to a Southern style diet may increase the risk of stroke, whereas adherence to a more plant-based diet may reduce stroke risk. Given the consistency of finding a dietary effect on stroke risk across studies, discussing nutrition patterns during risk screening may be an important step in reducing stroke. PMID- 24159065 TI - Type 2 (non-insulin-dependent) diabetes mellitus: the thrifty phenotype hypothesis. 1992. PMID- 24159066 TI - Commentary: The thrifty phenotype and the hierarchical preservation of tissues under stress. PMID- 24159062 TI - Activated protein C analog protects from ischemic stroke and extends the therapeutic window of tissue-type plasminogen activator in aged female mice and hypertensive rats. AB - BACKGROUND AND PURPOSE: 3K3A-activated protein C (APC) protects young, healthy male rodents after ischemic stroke. 3K3A-APC is currently under development as a neuroprotectant for acute ischemic stroke in humans. Stroke Therapy Academic Industry Roundtable recommends that after initial studies in young, healthy male animals, further studies should be performed in females, aged animals, and animals with comorbid conditions. Here, we studied the effects of delayed 3KA-APC therapy alone and with tissue-type plasminogen activator (tPA) in aged female mice and spontaneously hypertensive rats. METHODS: We used Stroke Therapy Academic Industry Roundtable recommendations for ensuring good scientific inquiry. Murine recombinant 3K3A-APC (0.2 mg/kg) alone or with recombinant tPA (10 mg/kg) was given intravenously 4 hours after transient middle cerebral artery occlusion in aged female mice and rats and after embolic stroke in spontaneously hypertensive rat. 3K3A-APC was additionally administered within 3 to 7 days after stroke. The neuropathological analysis and neurological scores, foot-fault, forelimb asymmetry, and adhesive removal tests were performed within 7 and 28 days of stroke. RESULTS: In all models, tPA alone had no effects on the infarct volume or behavior. 3K3A-APC alone or with tPA reduced the infarct volume 7 days after the middle cerebral artery occlusion in aged female mice and embolic stroke in spontaneously hypertensive rat by 62% to 66% and 50% to 53%, respectively, significantly improved (P<0.05) behavior, and eliminated tPA-induced intracerebral microhemorrhages. In aged female mice, 3K3A-APC was protective within 4 weeks of stroke. CONCLUSIONS: 3K3A-APC protects from ischemic stroke and extends the therapeutic window of tPA in aged female mice and in spontaneously hypertensive rat with a comorbid condition. PMID- 24159067 TI - Commentary: Thrifty phenotype: 20 years later. PMID- 24159068 TI - Commentary: The meaning of thrift. PMID- 24159069 TI - Commentary: The developmental origins of health and disease: an appreciation of the life and work of Professor David J.P. Barker, 1938-2013. PMID- 24159070 TI - On the supposed influence of offensive trades on mortality. 1856. PMID- 24159071 TI - Commentary: Snow's paper on 'offensive trades'--with the benefit of 150 years of hindsight. PMID- 24159072 TI - Commentary: On 'On the supposed influence of offensive trades on mortality'. PMID- 24159073 TI - Commentary: John Snow's 'On the supposed influence of offensive trades on mortality': the 'Snow paradigm'. PMID- 24159074 TI - The Public Health and Nuisances Removal Bill: Dr. Snow's evidence. 1855. PMID- 24159075 TI - Influence of offensive trades on the public health. 1856. PMID- 24159076 TI - Profile: Manhica Health Research Centre (Manhica HDSS). AB - The Manhica Health Research Centre, established in 1996 in a rural area of southern Mozambique, currently follows around 92 000 individuals living in approximately 20 000 enumerated and geo-positioned households. Its main strength is the possibility of linking demographic data and clinical data to promote and conduct biomedical research in priority health areas. Socio-demographic data are updated twice a year and clinical data are collected on a daily basis. The data collected in Manhica HDSS comprises household and individual characteristics, household socio-economic assets, vital data, migration, individual health history and cause of death, among others. Studies conducted in this HDSS contributed to guide the health authorities and decision-making bodies to define or adjust health policies such as the introduction of Mozambique's expanded programme of immunization with different vaccines (Haemophilus influenzae type b, Pneumococcus) or the development of the concept of Intermittent Preventive Treatment for Infants (IPTi) that led to the World Health Organization recommendation of this method as best practice for the control of malaria among infants. Manhica's data can be accessed through a formal request to Diana Quelhas (diana.quelhas@manhica.net) accompanied by a proposal that will be analysed by the Manhica HDSS internal scientific and ethics committees. PMID- 24159077 TI - Parental smoking during pregnancy and cardiovascular structures and function in childhood: the Generation R Study. AB - BACKGROUND: Foetal smoke exposure might lead to foetal developmental adaptations that permanently affect the cardiovascular system. We assessed the associations of both maternal and paternal smoking during pregnancy with childhood cardiovascular structures and function. METHOD: In a prospective cohort study among 5565 children, we examined whether maternal and paternal smoking during pregnancy are associated with blood pressure, carotid-femoral pulse wave velocity and left cardiac structures and function in 6-year-old children. RESULTS: As compared with children from non-smoking mothers, children from mothers who smoked more than 10 cigarettes per day had a higher diastolic blood pressure [difference 1.43 mmHg (95% confidence interval: 0.22, 2.63)]. Maternal smoking during pregnancy was not associated with systolic blood pressure, childhood carotid femoral pulse wave velocity or left cardiac structures. Maternal smoking of 10 or more cigarettes per day was associated with a higher fractional shortening in childhood [difference 1.01% (95% confidence interval: 0.18, 1.84)]. Among mothers who did not smoke during pregnancy, paternal smoking was associated with aortic root diameter but not with other cardiovascular outcomes. CONCLUSIONS: Maternal smoking during pregnancy is associated with higher diastolic blood pressure and fractional shortening, although the effect estimates are small. The stronger effect estimates for maternal smoking compared with paternal smoking might suggest that direct intrauterine adaptive responses are involved as underlying mechanisms. PMID- 24159078 TI - Calculating statistical power in Mendelian randomization studies. AB - In Mendelian randomization (MR) studies, where genetic variants are used as proxy measures for an exposure trait of interest, obtaining adequate statistical power is frequently a concern due to the small amount of variation in a phenotypic trait that is typically explained by genetic variants. A range of power estimates based on simulations and specific parameters for two-stage least squares (2SLS) MR analyses based on continuous variables has previously been published. However there are presently no specific equations or software tools one can implement for calculating power of a given MR study. Using asymptotic theory, we show that in the case of continuous variables and a single instrument, for example a single nucleotide polymorphism (SNP) or multiple SNP predictor, statistical power for a fixed sample size is a function of two parameters: the proportion of variation in the exposure variable explained by the genetic predictor and the true causal association between the exposure and outcome variable. We demonstrate that power for 2SLS MR can be derived using the non-centrality parameter (NCP) of the statistical test that is employed to test whether the 2SLS regression coefficient is zero. We show that the previously published power estimates from simulations can be represented theoretically using this NCP-based approach, with similar estimates observed when the simulation-based estimates are compared with our NCP based approach. General equations for calculating statistical power for 2SLS MR using the NCP are provided in this note, and we implement the calculations in a web-based application. PMID- 24159079 TI - Cohort effects explain the increase in autism diagnosis among children born from 1992 to 2003 in California. PMID- 24159080 TI - Authors' Response to: Cohort effects explain the increase in autism diagnosis among children born from 1992 to 2003 in California. PMID- 24159081 TI - Current status and future prospects of epidemiology and public health training and research in the WHO African region. PMID- 24159086 TI - A study of the short-term effect of artificial tears on contrast sensitivity in patients with Sjogren's syndrome. AB - PURPOSE: Primary Sjogren's syndrome often includes dry eye manifestations, including a reduction in optical quality from the compromised ocular surface. This study was designed to measure the effect of different artificial tears on the contrast sensitivity of Sjogren's syndrome patients from 5 minutes to 4 hours after instillation. METHODS: Ten normal subjects and 10 subjects with ocular manifestations of Sjogren's syndrome were compared at baseline, including staining scores, a dry eye questionnaire, and contrast sensitivity testing. Changes in contrast sensitivity in the Sjogren's syndrome group were measured over a 4-hour period after instillation of a variety of artificial tears. RESULTS: Statistically significant differences in staining, subjective questionnaire scores, and contrast sensitivity were measured between the normal and Sjogren's syndrome groups. Statistically significant changes in contrast sensitivity were measured over time after artificial tear instillation, with the greatest effect at 3 to 6 cycles/deg. The more mucoadhesive artificial tears demonstrated a significantly greater effect. CONCLUSIONS: The effects of artificial tears on measured contrast sensitivity in dry eye patients in the postinstillation period of 5 minutes to 4 hours appear limited, but an artificial tear with more mucoadhesive properties showed more benefit than those that do not. Modest effects on contrast sensitivity, primarily at medium spatial frequencies, were observed with the more mucoadhesive formulations. PMID- 24159087 TI - Assessment of acute mild hypoxia on retinal oxygen saturation using snapshot retinal oximetry. AB - PURPOSE: To study the effect of acute mild hypoxia on retinal oxygen saturation. METHODS: Spectral retinal images were acquired under normoxic and hypoxic conditions for 10 healthy human volunteers (six male, four female, aged 25 +/- 5 years [mean +/- SD]) using a modified fundus camera fitted with an image replicating imaging spectrometer (IRIS). Acute, mild hypoxia was induced by changing the oxygen saturation of inhaled air from 21% to 15% using a hypoxia generator with subjects breathing the hypoxic gas mixture for 10 minutes. Peripheral arterial oxygen saturation of the subjects was monitored using fingertip-pulse oximetry. Images were processed to calculate oxygen saturation, arteriovenous difference in oxygen saturation, and vessel diameter. Data are presented as mean +/- SD and were analyzed using paired sample t-test with significance accepted at P < 0.05. RESULTS: The retinal arterial and venous oxygen saturation was 98.5% +/- 1.6% and 70.7% +/- 2.7% during normoxia. A reduction in the fraction of inspired oxygen resulted in a decline (P < 0.001) in both retinal-arterial and venous oxygen saturation to 90.3% +/- 2.0% and 62.4% +/ 2.2%, respectively. The arteriovenous oxygen saturation difference in normoxia (27.8% +/- 2.9%) and hypoxia (27.9% +/- 2.1%) did not change. Retinal arteriolar and venular diameters increased (P < 0.001) by 4% and 3%, respectively, under hypoxia. CONCLUSIONS: The acute inhalation of a hypoxic gas mixture resulted in a decline in both retinal-arterial and venous saturation, while arteriovenous oxygen difference was maintained with an accompanying significant increase in retinal vessel diameter. This may suggest an autoregulatory response to acute mild hypoxia. PMID- 24159089 TI - The economic cost of myopia in adults aged over 40 years in Singapore. AB - PURPOSE: To estimate the economic cost of myopia among adults aged 40 years and older in Singapore. METHODS: A substudy of 113 Singaporean adults aged 40 years and older with myopia (spherical equivalent refraction of at least -0.5 diopters) in the population-based ancillary study of Singapore Chinese Eye Study (SCES) was conducted. A health expenditure questionnaire was used to assess the direct cost of myopia. RESULTS: A total of 113 (90.4%) of 125 myopic subjects participated in the survey. The mean cost was approximately SGD$900 (USD$709) per person per year. The lifetime per capita cost ranged from SGD$295 (USD$232) for those with 0 year's duration to SGD$21,616 (USD$17,020) for those with 80 years' duration. Costs of spectacles, contact lenses, and optometry services were the major cost drivers, contributing to an average of 65% of total costs. Seven subjects (6.2%) had undergone LASIK surgery, resulting in a cost of SGD$4891 (USD$3851) per patient per year. Three subjects (2.7%) reported annual costs of (SGD$33 or USD$26) for complications due to LASIK surgery or contact lenses. There was an increasing cost of myopia in adults who started to wear glasses at earlier ages. By applying our cost data to age-specific myopia prevalence data in the whole population in the country, the total cost was estimated to be approximately SGD$959 (USD$755) million per year in Singapore. CONCLUSIONS: Myopia is associated with substantial out-of-pocket expenditure, imposing considerable economic burden for patients. Myopia is a disorder with immense societal costs and public health impact. PMID- 24159088 TI - Marginal corneal vascular arcades. AB - PURPOSE: To determine the metrics of the marginal corneal vascular arcades (MCA). METHODS: The MCA and filling pattern was investigated using indocyanine green dye angiography (ICGA) in the fellow eye of patients with treated unilateral keratitis. Images were acquired using a scanning laser ophthalmoscope. Five contiguous squares (100 pixels) were aligned beyond the inner row of vessels extending approximately 700 MUm into the limbal region and spanning an arc length of approximately 4 mm of the peripheral cornea. Geometrical properties of the MCA were determined using programs written in a numerical computing environment. RESULTS: A total of 17 patients (24-88 years) were included. Filling of the inferior corneal quadrant occurred first, followed by superior, nasal, and temporal quadrants. Mean area of a vascular loop of the MCA was 11.87 * 10-3 mm2 (SD: 10.44 * 10-3 mm2) skewed (2.20) toward smaller sizes. Mean circumference of a vascular loop was 422.5 MUm (SD: 218.7 MUm) with major and minor axes of 158.9 MUm and 90.8 MUm. There were five (SD: 1.8) branches per loop with a segment length of 89.5 um (SD 163.8 MUm). Vessels were tortuous (mean 0.19, SD: 0.16) with a fractal number of 1.51 (0.12). There were significant differences between subjects in vessel loop area (P = 0.003) and number of branches (P = 0.002). Speed of flow was circumferential along the innermost row and measured at 0.22 mm/s in one subject. CONCLUSIONS: The MCA comprise a network of branched interlinked elliptical loops supporting circumferential blood flow in the corneal periphery. There was no definable change in vascular pattern extending into the limbal region. PMID- 24159085 TI - Myopia stabilization and associated factors among participants in the Correction of Myopia Evaluation Trial (COMET). AB - PURPOSE: To use the Gompertz function to estimate the age and the amount of myopia at stabilization and to evaluate associated factors in the Correction of Myopia Evaluation Trial (COMET) cohort, a large ethnically diverse group of myopic children. METHODS: The COMET enrolled 469 ethnically diverse children aged 6 to younger than 12 years with spherical equivalent refraction between -1.25 and -4.50 diopters (D). Noncycloplegic refraction was measured semiannually for 4 years and annually thereafter. Right eye data were fit to individual Gompertz functions in participants with at least 6 years of follow-up and at least seven refraction measurements over 11 years. Function parameters were estimated using a nonlinear least squares procedure. Associated factors were evaluated using linear regression. RESULTS: In total, 426 participants (91%) had valid Gompertz curve fits. The mean (SD) age at myopia stabilization was 15.61 (4.17) years, and the mean (SD) amount of myopia at stabilization was -4.87 (2.01) D. Ethnicity (P < 0.0001) but not sex or the number of myopic parents was associated with the age at stabilization. Ethnicity (P = 0.02) and the number of myopic parents (P = 0.01) but not sex were associated with myopia magnitude at stabilization. At stabilization, African Americans were youngest (mean age, 13.82 years) and had the least myopia (mean, -4.36 D). Participants with two versus no myopic parents had approximately 1.00 D more myopia at stabilization. The age and the amount of myopia at stabilization were correlated (r = -0.60, P < 0.0001). CONCLUSIONS: The Gompertz function provides estimates of the age and the amount of myopia at stabilization in an ethnically diverse cohort. These findings should provide guidance on the time course of myopia and on decisions regarding the type and timing of interventions. PMID- 24159090 TI - Analysis of macrophage phenotype in rejected corneal allografts. AB - PURPOSE: We investigated the phenotype of macrophages infiltrating rejected corneal allografts. METHODS: We performed allogeneic or syngeneic corneal transplantation in mice, and humanely killed animals at day 28 during allograft rejection when 60% of corneal allografts were rejected. We divided allografts into two groups: grafts with rejection as rejectors and grafts without rejection as nonrejectors, and analyzed for macrophage infiltration and their phenotype using immunohistochemistry. In addition, we investigated the time course of proinflammatory cytokines and chemokines by analyzing corneal grafts at days 7, 28, and 42 using real-time RT-PCR. Also, we assayed human corneal allografts with chronic graft failure. RESULTS: We found that a large number of CD11b(+), F4/80(+), or inducible nitrous oxide synthase cells (iNOS(+)) infiltrated corneal allografts during rejection in mice, while the cells were found rarely in syngeneic or allogeneic grafts that were not rejected. There were rare CD11c(+) cells in rejectors and nonrejectors. Many mannose receptor cells (MRC(+)) were present in nonrejectors, but not in rejectors. The levels of Th1 cytokines, IFN gamma, and IL-2 were highly increased in rejectors at day 28, indicating immune rejection. Also, the levels of IL-12a, IL-1beta, TNF-alpha, CCL3, and iNOS that are produced by activated macrophages were markedly increased in rejectors at day 28, compared to syngeneic grafts or nonrejectors. Similarly, human corneal allografts with chronic graft failure had higher levels of IL-12a, IL-1beta, CCL3, and iNOS than controls. CONCLUSIONS: Increased numbers of macrophages in rejected corneal allografts implicate that these cells might contribute to the immunopathogenesis of corneal graft rejection. PMID- 24159091 TI - Comparison of swollen and dextran deswollen organ-cultured corneas for Descemet membrane dissection preparation: histological and ultrastructural findings. AB - PURPOSE: To compare the use of swollen tissue versus tissue deswollen by addition of dextran to the medium in the dissection of organ-cultured Descemet membrane (DM) with regard to preparation-related characteristics and ultrastructural findings to optimize transplantation in Descemet membrane endothelial keratoplasty (DMEK). METHODS: DMs of 20 corneoscleral rims were separated using organ-cultured groups, one immersed in culture medium without dextran (group A) and the other in medium with added dextran for 24 hours (group B). The preparation details were noted. The difficulty of preparation was analyzed using a scoring system (0 = impossible, 10 = easy). By means of a micrometer, ultrathin sections of endothelial layer were obtained. Presence of any residual stroma, thickness of the DM, thickness of the endothelial cell layer, and the smoothness of the lamella were analyzed. RESULTS: In both group A and group B, all 10 usable DMs were available. Mean preparation time was 6.5 +/- 1.4 minutes in group A and 6.1 +/- 0.9 minutes in group B (P = 0.399). The difficulty score was 7.9 +/- 1.9 in group A and 8.0 +/- 2.0 in group B (P = 0.726). The total mean thickness of the DM (without the endothelial cell layer) was 13.58 +/- 2.81 MUm in group A and 12.69 +/- 2.06 MUm in group B (P = 0.474). The total mean thickness of the endothelial cell layer was 3.99 +/- 0.62 in group A and 3.98 +/- 0.52 in group B (P = 0.989). Light microscopy and transmission electron microscopy revealed no evidence of any adherent remnants of corneal stroma on any specimen in each group. CONCLUSIONS: DM-endothelium grafts for transplantation in DMEK procedures can be surgically prepared from organ-cultured corneal rims in swollen and deswollen conditions. Both separation methods seem to be equivalent in regard to the preparation characteristics of the obtained DM. Nevertheless, clinical studies are still necessary in order to confirm these findings. PMID- 24159092 TI - Response of small heat shock proteins in diabetic rat retina. AB - PURPOSE: Small heat shock proteins (sHsps) have a critical role under stress conditions to maintain cellular homeostasis by their involvement in protein folding and cytoprotection. The hyperglycemia in diabetes may impose cellular stress on the retina. Therefore, we investigated the expression of sHsps, phosphoregulation of alphaB-crystallin (alphaBC), and their localization in the diabetic rat retina. METHODS: Diabetes was induced in rats and maintained on hyperglycemia for a period of 12 weeks. The expression of sHsps, HSFs, and phosphorylated sHsps was analyzed by quantitative (q) RT-PCR and immunoblotting. The solubility of sHsps was analyzed by detergent solubility assay. Cellular localization of sHsps and phosphorylated alphaBCs was examined by immunohistochemistry. RESULTS: Of 10 sHsps, five sHsps were detected in the rat retina. Among those, increased expression for alphaA-crystallin (alphaAC), alphaBC, and Hsp22, and decreased expression for Hsp20 were seen in the diabetic retina, whereas Hsp27 mRNA levels were increased, while protein levels were decreased. While the expression of HSFs was either unaltered or decreased, expression of hypoxia inducible factor-1alpha (HIF-1alpha) was increased in the diabetic retina. The phosphorylation of alphaBC at Ser45 and Ser19 was increased in the retina of diabetic rats. However, phosphorylation of alphaBC at Ser59 was decreased in the soluble fraction with a concomitant increase in the insoluble fraction. Moreover, diabetes activated the p38MAPK signaling cascade by increasing the p-p38 MAPK in the retina. Further, diabetes induced the aggregation of Hsp27, alphaAC, alphaBC, and pS59-alphaBC in the retina. A strong immunoreactivity of Hsp27, alphaAC, alphaBC, and phosphorylated alphaBC was localized in different retinal layers of diabetic rats. CONCLUSIONS: The results indicate an upregulation of alphaAC, alphaBC, and Hsp22, but their solubility was compromised in the diabetic retina. There was increased phosphorylation at Ser59, Ser45, and Ser19 of alphaBC under diabetic conditions. Localization of sHsps and their phosphorylated forms was dispersed to many layers of the retina in diabetes. These results suggest that sHsps may be protecting the retinal neurons in chronic diabetes. PMID- 24159093 TI - Ulnar-sided wrist pain is not the only cause of TFCC injury: a clinical perspective on other diagnoses in the sport setting. PMID- 24159094 TI - Republished research: non-steroidal anti-inflammatory drugs (NSAIDs). PMID- 24159095 TI - Kinesio taping for sports injuries. PMID- 24159153 TI - Short versus prolonged courses of antibiotic therapy for children with uncomplicated Gram-negative bacteraemia. AB - OBJECTIVES: The optimal duration of antibiotic therapy for uncomplicated Gram negative bacteraemia remains undefined. Our objective was to compare clinical outcomes of receiving short (7-10 days) versus prolonged (>10 days) durations of antibiotic therapy for children with uncomplicated Gram-negative bacteraemia. METHODS: We conducted a retrospective cohort study of children with uncomplicated Gram-negative bacteraemia at The Johns Hopkins Hospital between 2002 and 2012. We estimated the risk of bacteraemic relapse among children who received short versus prolonged durations of antibiotic therapy using 1:1 nearest neighbour propensity score matching without replacement prior to performing regression analysis. RESULTS: There were 170 matched pairs that were well balanced on baseline covariates. The median duration of therapy in the short and prolonged courses was 10 days (IQR 10-10) and 14 days (IQR 14-17), respectively. The 30 day mortality was similar between the groups (OR 1.12; 95% CI 0.96-1.21). A prolonged duration of antibiotic therapy did not reduce the relapse risk compared with shorter durations (adjusted hazard ratio 0.67; 95% CI 0.35-1.27). Similarly, each additional day of antibiotic therapy was not protective against relapse risk (adjusted hazard ratio 0.99 per additional day; 95% CI 0.92-1.03). There was a trend towards an increased subsequent risk of candidaemia in children receiving longer treatment durations (hazard ratio 2.44; 95% CI 0.97-6.19). CONCLUSIONS: Antibiotic treatment for more than 10 days for uncomplicated bacteraemia in children does not reduce the risk of microbiological relapse compared with shorter-course therapy, but may be associated with an increased risk of candidaemia. Our findings need to be confirmed in a larger, prospective study. PMID- 24159154 TI - Fighting the spread of AmpC-hyperproducing Enterobacteriaceae: beneficial effect of replacing ceftriaxone with cefotaxime. AB - OBJECTIVES: Considering the hypothesis that the high biliary elimination of ceftriaxone could be responsible for the selection of Enterobacteriaceae harbouring high-level AmpC beta-lactamase (HL-CASE), the use of ceftriaxone was discontinued in our hospital in 2006 and replaced with cefotaxime. METHODS: Antibiotic consumption, expressed as defined daily dose (DDD)/1000 patient-days (PD), and HL-CASE incidence, expressed as the number of patients carrying HL CASE/1000 PD, were compared between the pre-intervention period (Period 1, 2001 05) and the post-intervention period (Period 2, 2006-12) using an interrupted time series analysis. RESULTS: The incidence of HL-CASE increased significantly from 0.32 to 0.69/1000 PD during Period 1 (coefficient = 0.082, P < 0.01). A significant inflection of the slope in the incidence curve occurred in Period 2 (coefficient = -0.061, P = 0.05), mainly owing to the stabilization of the HL CASE incidence of Enterobacteriaceae harbouring chromosomally inducible cephalosporinase (Period 1, 0.27 to 0.64/1000 PD; Period 2, 0.58 to 0.61/1000 PD) and especially for Enterobacter cloacae (Period 1, 0.09 to 0.30/1000 PD; Period 2, 0.26 to 0.27/1000 PD). This deceleration was observed despite a significant increase in the slope of cefotaxime consumption over Period 2 (coefficient = 2.97, P < 0.01). CONCLUSION: Despite the disadvantages of using cefotaxime compared with ceftriaxone (administration three times daily versus once a day), the ecological benefits of this substitution seem sufficiently convincing to preferentially use cefotaxime. Control of HL-CASE incidence is crucial to limiting carbapenem use and preventing the selection of carbapenemase-producing Enterobacteriaceae. PMID- 24159155 TI - Metronidazole increases the emergence of ciprofloxacin- and amikacin-resistant Pseudomonas aeruginosa by inducing the SOS response. PMID- 24159156 TI - Isolation of KPC-2-producing Klebsiella pneumoniae strains belonging to the high risk multiresistant clonal complex 11 (ST437 and ST340) in urban rivers. PMID- 24159157 TI - The new commentary section: a venture into the middle distance. PMID- 24159160 TI - Found: a cellular activating ligand for NKp44. AB - In this issue of Blood, Baychelier et al identify a ligand for a major natural killer (NK) cell receptor that mediates natural cytotoxicity toward tumor cells, thus ending a search that lasted well over a decade. PMID- 24159161 TI - Gnawing at Metchnikoff's paradigm. AB - In this issue of Blood, Rossi et al provide convincing evidence that extends and generalizes the importance of trogocytosis, a process in which effector cells use Fcg receptors to remove Immunoglobulin G (IgG)-chelated antigens from donor cells. Their work suggests that the process may be beneficial in the context of epratuzumab treatment of autoimmune diseases. PMID- 24159162 TI - HIV, EBV, and monoclonal gammopathy. AB - In this issue of Blood, Ouedraogo et al have investigated the role of HIV and Epstein-Barr virus (EBV) replication in the persistence of monoclonal gammopathy.1 It has been known for some time that patients with HIV infection have an increased incidence of monoclonal gammopathy and plasma cell dyscrasias.2,3 The exact mechanism of monoclonal gammopathy in patients with HIV infection is unknown, but in many patients the monoclonal gammopathy and other B cell abnormalities can be reversed with antiretroviral therapy. However, a proportion of patients will have persistent monoclonal gammopathy. PMID- 24159163 TI - Flying without a net in MDS. AB - In this issue of Blood, Malcovati et al discuss the findings of an expert panel of the European LeukemiaNet (ELN) and their recommendations for treating myelodysplastic syndromes (MDS). PMID- 24159164 TI - Redirecting traffic using the XPO1 police. AB - In this issue of Blood, Walker et al investigate the preclinical potential of KPT 330, an exportin-1 (XPO1, also known as chromosome maintenance protein 1 [CRM1]) inhibitor, against both accelerated phase (AP) and blast crisis chronic myeloid leukemia (CML-BC) and against Philadelphia chromosome-positive (Ph1) acute lymphoblastic leukemia (ALL), all of which are diseases of significant unmet clinical need.1 The authors provide encouraging data from both a leukemic mouse model and a single CML-AP patient, corroborating mechanistic studies suggesting that KPT-330 efficacy relies on targeting abundantly expressed XPO1, followed by the reactivation of protein phosphatase 2A (PP2A). PMID- 24159165 TI - An open-and-shut case? PMID- 24159166 TI - Anti-hepcidin therapy for iron-restricted anemias. AB - In this issue of Blood, Cooke et al demonstrate the potential of a fully human anti-hepcidin antibody as a novel therapeutic for iron-restricted anemias such as anemia of inflammation, cancer, or chronic kidney disease (formerly known as "anemia of chronic diseases"). PMID- 24159167 TI - Reversible lymph node follicular hyperplasia associated with dasatinib treatment of chronic myeloid leukemia in chronic phase. PMID- 24159168 TI - BRAF V600E is also seen in unclassifiable splenic B-cell lymphoma/leukemia, a potential mimic of hairy cell leukemia. PMID- 24159169 TI - Activity of omacetaxine mepesuccinate against ponatinib-resistant BCR-ABL positive cells. PMID- 24159170 TI - Effect of congenital upregulation of hypoxia inducible factors on percentage of fetal hemoglobin in the blood. PMID- 24159171 TI - Longitudinal trajectory of sexual functioning after hematopoietic cell transplantation: impact of chronic graft-versus-host disease and total body irradiation. AB - This prospective study described the trajectory of sexual well-being from before hematopoietic cell transplantation (HCT) to 3 years after in 131 allogeneic and 146 autologous HCT recipients using Derogatis Interview for Sexual Function and Derogatis Global Sexual Satisfaction Index. Sixty-one percent of men and 37% of women were sexually active pre-HCT; the prevalence declined to 51% (P = .01) in men and increased to 48% (P = .02) in women at 3 years post-HCT. After HCT, sexual satisfaction declined in both sexes (P < .001). All sexual function domains were worse in women compared with men (P <= .001). Orgasm (P = .002) and drive/relationship (P < .001) declined in men, but sexual cognition/fantasy (P = .01) and sexual behavior/experience (P = .01) improved in women. Older age negatively impacted sexual function post-HCT in both sexes (P < .01). Chronic graft-versus-host disease was associated with lower sexual cognition/fantasy (P = .003) and orgasm (P = .006) in men and sexual arousal (P = .05) and sexual satisfaction (P = .005) in women. All male sexual function domains declined after total body irradiation (P < .05). This study identifies vulnerable subpopulations that could benefit from interventional strategies to improve sexual well-being. PMID- 24159172 TI - Desmolaris, a novel factor XIa anticoagulant from the salivary gland of the vampire bat (Desmodus rotundus) inhibits inflammation and thrombosis in vivo. AB - The identity of vampire bat saliva anticoagulant remained elusive for almost a century. Sequencing the salivary gland genes from the vampire bat Desmodus rotundus identified Desmolaris as a novel 21.5-kDa naturally deleted (Kunitz 1 domainless) form of tissue factor pathway inhibitor. Recombinant Desmolaris was expressed in HEK293 cells and characterized as a slow, tight, and noncompetitive inhibitor of factor (F) XIa by a mechanism modulated by heparin. Desmolaris also inhibits FXa with lower affinity, independently of protein S. In addition, Desmolaris binds kallikrein and reduces bradykinin generation in plasma activated with kaolin. Truncated and mutated forms of Desmolaris determined that Arg32 in the Kunitz-1 domain is critical for protease inhibition. Moreover, Kunitz-2 and the carboxyl-terminus domains mediate interaction of Desmolaris with heparin and are required for optimal inhibition of FXIa and FXa. Notably, Desmolaris (100 MUg/kg) inhibited FeCl3-induced carotid artery thrombus without impairing hemostasis. These results imply that FXIa is the primary in vivo target for Desmolaris at antithrombotic concentrations. Desmolaris also reduces the polyphosphate-induced increase in vascular permeability and collagen- and epinephrine-mediated thromboembolism in mice. Desmolaris emerges as a novel anticoagulant targeting FXIa under conditions in which the coagulation activation, particularly the contact pathway, plays a major pathological role. PMID- 24159173 TI - IL-21 signalling via STAT3 primes human naive B cells to respond to IL-2 to enhance their differentiation into plasmablasts. AB - B-cell responses are guided by the integration of signals through the B-cell receptor (BCR), CD40, and cytokine receptors. The common gamma chain (gammac) binding cytokine interleukin (IL)-21 drives humoral immune responses via STAT3 dependent induction of transcription factors required for plasma cell generation. We investigated additional mechanisms by which IL-21/STAT3 signaling modulates human B-cell responses by studying patients with STAT3 mutations. IL-21 strongly induced CD25 (IL-2Ralpha) in normal, but not STAT3-deficient, CD40L-stimulated naive B cells. Chromatin immunoprecipitation confirmed IL2RA as a direct target of STAT3. IL-21-induced CD25 expression was also impaired on B cells from patients with IL2RG or IL21R mutations, confirming a requirement for intact IL 21R signaling in this process. IL-2 increased plasmablast generation and immunoglobulin secretion from normal, but not CD25-deficient, naive B cells stimulated with CD40L/IL-21. IL-2 and IL-21 were produced by T follicular helper cells, and neutralizing both cytokines abolished the B-cell helper capacity of these cells. Our results demonstrate that IL-21, via STAT3, sensitizes B cells to the stimulatory effects of IL-2. Thus, IL-2 may play an adjunctive role in IL-21 induced B-cell differentiation. Lack of this secondary effect of IL-21 may amplify the humoral immunodeficiency in patients with mutations in STAT3, IL2RG, or IL21R due to impaired responsiveness to IL-21. PMID- 24159174 TI - Tropomodulin3-null mice are embryonic lethal with anemia due to impaired erythroid terminal differentiation in the fetal liver. AB - Tropomodulin (Tmod) is a protein that binds and caps the pointed ends of actin filaments in erythroid and nonerythoid cell types. Targeted deletion of mouse tropomodulin3 (Tmod3) leads to embryonic lethality at E14.5-E18.5, with anemia due to defects in definitive erythropoiesis in the fetal liver. Erythroid burst forming unit and colony-forming unit numbers are greatly reduced, indicating defects in progenitor populations. Flow cytometry of fetal liver erythroblasts shows that late-stage populations are also decreased, including reduced percentages of enucleated cells. Annexin V staining indicates increased apoptosis of Tmod3(-/-) erythroblasts, and cell-cycle analysis reveals that there are more Ter119(hi) cells in S-phase in Tmod3(-/-) embryos. Notably, enucleating Tmod3(-/ ) erythroblasts are still in the process of proliferation, suggesting impaired cell-cycle exit during terminal differentiation. Tmod3(-/-) late erythroblasts often exhibit multilobular nuclear morphologies and aberrant F-actin assembly during enucleation. Furthermore, native erythroblastic island formation was impaired in Tmod3(-/-) fetal livers, with Tmod3 required in both erythroblasts and macrophages. In conclusion, disruption of Tmod3 leads to impaired definitive erythropoiesis due to reduced progenitors, impaired erythroblastic island formation, and defective erythroblast cell-cycle progression and enucleation. Tmod3-mediated actin remodeling may be required for erythroblast-macrophage adhesion, coordination of cell cycle with differentiation, and F-actin assembly and remodeling during erythroblast enucleation. PMID- 24159175 TI - Genome-wide methylation analyses of primary human leukocyte subsets identifies functionally important cell-type-specific hypomethylated regions. AB - DNA methylation is an important mechanism by which gene transcription and hence cellular function are regulated. Here, we provide detailed functional genome-wide methylome maps of 5 primary peripheral blood leukocyte subsets including T cells, B cells, monocytes/macrophages, and neutrophils obtained from healthy individuals. A comparison of these methylomes revealed highly specific cell lineage and cell-subset methylation profiles. DNA hypomethylation is known to be permissive for gene expression and we identified cell-subset-specific hypomethylated regions (HMRs) that strongly correlate with gene transcription levels suggesting these HMRs may regulate corresponding cell functions. Single nucleotide polymorphisms associated with immune-mediated disease in genome-wide association studies preferentially localized to these cell-specific regulatory HMRs, offering insight into pathogenesis by highlighting cell subsets in which specific epigenetic changes may drive disease. Our data provide a valuable reference tool for researchers aiming to investigate the role of DNA methylation in regulating primary leukocyte function in health and immune-mediated disease. PMID- 24159178 TI - The challenging chase for nutrigenetic predictors of metabolic responses to dietary interventions. PMID- 24159176 TI - Germline and somatic genetic variations of TNFAIP3 in lymphoma complicating primary Sjogren's syndrome. AB - Several autoimmune diseases, including primary Sjogren's syndrome (pSS), are associated with an increased risk for lymphoma. Polymorphisms of TNFAIP3, which encodes the A20 protein that plays a key role in controlling nuclear factor kappaB activation, have been associated with several autoimmune diseases. Somatic mutations of TNFAIP3 have been observed in the mucosa-associated lymphoid tissue lymphoma subtype frequently associated with pSS. We studied germline and somatic abnormalities of TNFAIP3 in 574 patients with pSS, including 25 with lymphoma. Nineteen additional patients with pSS and lymphoma were available for exome sequence analysis. Functional abnormalities of A20 were assessed by gene reporter assays. The rs2230926 exonic variant was associated with an increased risk for pSS complicated by lymphoma (odds ratio, 3.36 [95% confidence interval, 1.34 8.42], and odds ratio, 3.26 [95% confidence interval, 1.31-8.12], vs controls and pSS patients without lymphoma, respectively; P = .011). Twelve (60%) of the 20 patients with paired germline and lymphoma TNFAIP3 sequence data had functional abnormalities of A20: 6 in germline DNA, 5 in lymphoma DNA, and 1 in both. The frequency was even higher (77%) among pSS patients with mucosa-associated lymphoid tissue lymphoma. Some of these variants showed impaired control of nuclear factor kappaB activation. These results support a key role for germline and somatic variations of A20 in the transformation between autoimmunity and lymphoma. PMID- 24159179 TI - Age at menarche and type 2 diabetes risk: the EPIC-InterAct study. AB - OBJECTIVE: Younger age at menarche, a marker of pubertal timing in girls, is associated with higher risk of later type 2 diabetes. We aimed to confirm this association and to examine whether it is explained by adiposity. RESEARCH DESIGN AND METHODS: The prospective European Prospective Investigation into Cancer and Nutrition (EPIC)-InterAct case-cohort study consists of 12,403 incident type 2 diabetes cases and a stratified subcohort of 16,154 individuals from 26 research centers across eight European countries. We tested the association between age at menarche and incident type 2 diabetes using Prentice-weighted Cox regression in 15,168 women (n = 5,995 cases). Models were adjusted in a sequential manner for potential confounding and mediating factors, including adult BMI. RESULTS: Mean menarcheal age ranged from 12.6 to 13.6 years across InterAct countries. Each year later menarche was associated with 0.32 kg/m2 lower adult BMI. Women in the earliest menarche quintile (8-11 years, n = 2,418) had 70% higher incidence of type 2 diabetes compared with those in the middle quintile (13 years, n = 3,634), adjusting for age at recruitment, research center, and a range of lifestyle and reproductive factors (hazard ratio [HR], 1.70; 95% CI, 1.49-1.94; P < 0.001). Adjustment for BMI partially attenuated this association (HR, 1.42; 95% CI, 1.18 1.71; P < 0.001). Later menarche beyond the median age was not protective against type 2 diabetes. CONCLUSIONS: Women with history of early menarche have higher risk of type 2 diabetes in adulthood. Less than half of this association appears to be mediated by higher adult BMI, suggesting that early pubertal development also may directly increase type 2 diabetes risk. PMID- 24159180 TI - Disproportionate body composition and neonatal outcome in offspring of mothers with and without gestational diabetes mellitus. AB - OBJECTIVE: High birth weight is a risk factor for neonatal complications. It is not known if the risk differs with body proportionality. The primary aim of this study was to determine the risk of adverse pregnancy outcome in relation to body proportionality in large-for-gestational-age (LGA) infants stratified by maternal gestational diabetes mellitus (GDM). RESEARCH DESIGN AND METHODS: Population based study of all LGA (birth weight [BW] >90th percentile) infants born to women with GDM (n = 1,547) in 1998-2007. The reference group comprised LGA infants (n = 83,493) born to mothers without diabetes. Data were obtained from the Swedish Birth Registry. Infants were categorized as proportionate (P-LGA) if ponderal index (PI) (BW in grams/length in cm(3)) was <=90th percentile and as disproportionate (D-LGA) if PI >90th percentile. The primary outcome was a composite morbidity: Apgar score 0-3 at 5 min, birth trauma, respiratory disorders, hypoglycemia, or hyperbilirubinemia. Logistic regression analysis was used to obtain odds ratios (ORs) for adverse outcomes. RESULTS: The risk of composite neonatal morbidity was increased in GDM pregnancies versus control subjects but comparable between P- and D-LGA in both groups. D-LGA infants born to mothers without diabetes had significantly increased risk of birth trauma (OR 1.19 [95% CI 1.09-1.30]) and hypoglycemia (1.23 [1.11-1.37]). D-LGA infants in both groups had significantly increased odds of Cesarean section. CONCLUSIONS: The risk of composite neonatal morbidity is significantly increased in GDM offspring. In pregnancies both with and without GDM, the risk of composite neonatal morbidity is comparable between P- and D-LGA. PMID- 24159183 TI - Diagnosis of gestational diabetes mellitus: a different paradigm to consider. PMID- 24159181 TI - Barriers and potential solutions to providing optimal guideline-driven care to patients with diabetes in the U.S. AB - The cost of diabetes, driven primarily by the cost of preventable diabetes complications, will continue to increase with the epidemic rise in its prevalence in the U.S. The Diabetes Working Group (DWG), a consortium of professional organizations and individuals, was created to examine the barriers to better diabetes care and to recommend mitigating solutions. We consolidated three sets of guidelines promulgated by national professional organizations into 29 standards of optimal care and empanelled independent groups of diabetes care professionals to estimate the minimum and maximum time needed to achieve those standards of care for each of six clinical vignettes representing typical patients seen by diabetes care providers. We used a standards-of-care economic model to compare provider costs with reimbursement and calculated "reimbursement gaps." The reimbursement gap was calculated using the maximum and minimum provider cost estimate (reflecting the baseline- and best-case provider time estimates from the panels). The cost of guideline-driven care greatly exceeded reimbursement in almost all vignettes, resulting in estimated provider "losses" of 470,000-750,000 USD/year depending on the case mix. Such "losses" dissuade providers of diabetes care from using best practices as recommended by national diabetes organizations. The DWG recommendations include enhancements in care management, workforce supply, and payment reform. PMID- 24159184 TI - Sharing insulin pens: are you putting patients at risk? PMID- 24159185 TI - Comment on: Wing et al. Effect of intensive lifestyle intervention on sexual dysfunction in women with type 2 diabetes: results from an ancillary Look AHEAD Study. Diabetes care 2013;36:2937-2944. PMID- 24159186 TI - Response to Comment on: Wing et al. Effect of intensive lifestyle intervention on sexual dysfunction in women with type 2 diabetes: results from an ancillary Look AHEAD Study. Diabetes care 2013;36:2937-2944. PMID- 24159187 TI - Comment on: Raz et al. Personalized management of hyperglycemia in type 2 diabetes: reflections from a Diabetes Care Editors' Expert Forum. Diabetes care 2013;36:1779-1788. PMID- 24159188 TI - A missense mutation accelerating the gating of the lysosomal Cl-/H+-exchanger ClC 7/Ostm1 causes osteopetrosis with gingival hamartomas in cattle. AB - Chloride-proton exchange by the lysosomal anion transporter ClC-7/Ostm1 is of pivotal importance for the physiology of lysosomes and bone resorption. Mice lacking either ClC-7 or Ostm1 develop a lysosomal storage disease and mutations in either protein have been found to underlie osteopetrosis in mice and humans. Some human disease-causing CLCN7 mutations accelerate the usually slow voltage dependent gating of ClC-7/Ostm1. However, it has remained unclear whether the fastened kinetics is indeed causative for the disease. Here we identified and characterized a new deleterious ClC-7 mutation in Belgian Blue cattle with a severe symptomatology including perinatal lethality and in most cases gingival hamartomas. By autozygosity mapping and genome-wide sequencing we found a handful of candidate variants, including a cluster of three private SNPs causing the substitution of a conserved tyrosine in the CBS2 domain of ClC-7 by glutamine. The case for ClC-7 was strengthened by subsequent examination of affected calves that revealed severe osteopetrosis. The Y750Q mutation largely preserved the lysosomal localization and assembly of ClC-7/Ostm1, but drastically accelerated its activation by membrane depolarization. These data provide first evidence that accelerated ClC-7/Ostm1 gating per se is deleterious, highlighting a physiological importance of the slow voltage-activation of ClC-7/Ostm1 in lysosomal function and bone resorption. PMID- 24159190 TI - Genome-wide association study on dimethylarginines reveals novel AGXT2 variants associated with heart rate variability but not with overall mortality. AB - AIMS: The purpose of this study was to identify novel genetic variants influencing circulating asymmetric dimethylarginine (ADMA) and symmetric dimethylarginine (SDMA) levels and to evaluate whether they have a prognostic value on cardiovascular mortality. METHODS AND RESULTS: We conducted a genome wide association study on the methylarginine traits and investigated the predictive value of the new discovered variants on mortality. Our meta-analyses replicated the previously known locus for ADMA levels in DDAH1 (rs997251; P = 1.4 * 10(-40)), identified two non-synomyous polymorphisms for SDMA levels in AGXT2 (rs37369; P = 1.4 * 10(-40) and rs16899974; P = 1.5 * 10(-38)) and one in SLC25A45 (rs34400381; P = 2.5 * 10(-10)). We also fine-mapped the AGXT2 locus for further independent association signals. The two non-synonymous AGXT2 variants independently associated with SDMA levels were also significantly related with short-term heart rate variability (HRV) indices in young adults. The major allele (C) of the novel non-synonymous rs16899974 (V498L) variant associated with decreased SDMA levels and an increase in the ratio between the low- and high frequency spectral components of HRV (P = 0.00047). Furthermore, the SDMA decreasing allele (G) of the non-synomyous SLC25A45 (R285C) variant was associated with a lower resting mean heart rate during the HRV measurements (P = 0.0046), but not with the HRV indices. None of the studied genome-wide significant variants had any major effect on cardiovascular or total mortality in patients referred for coronary angiography. CONCLUSIONS: AGXT2 has an important role in SDMA metabolism in humans. AGXT2 may additionally have an unanticipated role in the autonomic nervous system regulation of cardiac function. PMID- 24159189 TI - Oleoylethanolamide enhances beta-adrenergic-mediated thermogenesis and white-to brown adipocyte phenotype in epididymal white adipose tissue in rat. AB - beta-adrenergic receptor activation promotes brown adipose tissue (BAT) beta oxidation and thermogenesis by burning fatty acids during uncoupling respiration. Oleoylethanolamide (OEA) can inhibit feeding and stimulate lipolysis by activating peroxisome proliferator-activating receptor-alpha (PPARalpha) in white adipose tissue (WAT). Here we explore whether PPARalpha activation potentiates the effect of beta3-adrenergic stimulation on energy balance mediated by the respective agonists OEA and CL316243. The effect of this pharmacological association on feeding, thermogenesis, beta-oxidation, and lipid and cholesterol metabolism in epididymal (e)WAT was monitored. CL316243 (1 mg/kg) and OEA (5 mg/kg) co-administration over 6 days enhanced the reduction of both food intake and body weight gain, increased the energy expenditure and reduced the respiratory quotient (VCO2/VO2). This negative energy balance agreed with decreased fat mass and increased BAT weight and temperature, as well as with lowered plasma levels of triglycerides, cholesterol, nonessential fatty acids (NEFAs), and the adipokines leptin and TNF-alpha. Regarding eWAT, CL316243 and OEA treatment elevated levels of the thermogenic factors PPARalpha and UCP1, reduced p38-MAPK phosphorylation, and promoted brown-like features in the white adipocytes: the mitochondrial (Cox4i1, Cox4i2) and BAT (Fgf21, Prdm16) genes were overexpressed in eWAT. The enhancement of the fatty-acid beta-oxidation factors Cpt1b and Acox1 in eWAT was accompanied by an upregulation of de novo lipogenesis and reduced expression of the unsaturated-fatty-acid-synthesis enzyme gene, Scd1. We propose that the combination of beta-adrenergic and PPARalpha receptor agonists promotes therapeutic adipocyte remodelling in eWAT, and therefore has a potential clinical utility in the treatment of obesity. PMID- 24159200 TI - Fail fast. PMID- 24159191 TI - Maternal and foetal angiogenic imbalance in congenital heart defects. AB - AIMS: Animal models showed that angiogenesis is related to abnormal heart development. Our objectives were to ascertain whether a relationship exists between congenital heart defects (CHDs) and angiogenic/anti-angiogenic imbalance in maternal and foetal blood and study the expression of angiogenic factors in the foetal heart. METHODS AND RESULTS: Maternal and cord blood placental growth factor (PlGF), soluble fms-like tyrosine kinase-1 (sFlt-1) and soluble endoglin (sEng) were compared in 65 cases of CHD and 204 normal controls. Angiogenic factor expression and markers of hypoxia were measured in heart tissue from 23 CHD foetuses and 8 controls. In the CHD group, compared with controls, plasma PlGF levels were significantly lower (367 +/- 33 vs. 566 +/- 26 pg/mL; P < 0.0001) and sFlt-1 significantly higher (2726 +/- 450 vs. 1971 +/- 130 pg/mL, P = 0.0438). Foetuses with CHD had higher cord plasma sFlt-1 (442 +/- 76 vs. 274 +/- 26 pg/mL; P = 0.0285) and sEng (6.76 +/- 0.42 vs. 4.99 +/- 0.49 ng/mL, P = 0.0041) levels. Expression of vascular endothelial growth factor (VEGF), sFlt-1, markers of chronic hypoxia, and antioxidant activity were significantly higher in heart tissue from CHD foetuses compared with normal hearts (VEGF, 1.59-fold; sFlt 1, 1.92-fold; hypoxia inducible factor (HIF)-2alpha, 1.45-fold; HO-1, 1.62-fold; SOD1, 1.31-fold). CONCLUSION: An intrinsically angiogenic impairment exists in CHD that appears to be present in both the maternal and foetal circulation and foetal heart. Our data suggest that an imbalance of angiogenic-antiangiogenic factors is associated with developmental defects of the human heart. PMID- 24159201 TI - CAPE outcomes 2013: Building on two decades of advances to guide the future of pharmacy education. PMID- 24159202 TI - Medication insecurity and the need for more involvement. PMID- 24159203 TI - Center for the Advancement of Pharmacy Education 2013 educational outcomes. AB - An initiative of the Center for the Advancement of Pharmacy Education (formerly the Center for the Advancement of Pharmaceutical Education) (CAPE), the CAPE Educational Outcomes are intended to be the target toward which the evolving pharmacy curriculum should be aimed. Their development was guided by an advisory panel composed of educators and practitioners nominated for participation by practitioner organizations. CAPE 2013 represents the fourth iteration of the Educational Outcomes, preceded by CAPE 1992, CAPE 1998 and CAPE 2004 respectively. The CAPE 2013 Educational Outcomes were released at the AACP July 2013 Annual meeting and have been revised to include 4 broad domains, 15 subdomains, and example learning objectives. PMID- 24159204 TI - Learning styles and teaching perspectives of Canadian pharmacy practice residents and faculty preceptors. AB - OBJECTIVE: To characterize and compare learning styles of pharmacy practice residents and their faculty preceptors, and identify teaching perspectives of faculty preceptors. METHODS: Twenty-nine pharmacy residents and 306 pharmacy faculty members in British Columbia were invited to complete the Pharmacists' Inventory of Learning Styles (PILS). Faculty preceptors also were asked to complete the Teaching Perspectives Inventory (TPI). RESULTS: One hundred percent of residents and 61% of faculty members completed the PILS, and 31% of faculty members completed the TPI. The most common dominant learning style among residents and faculty preceptors was assimilator, and 93% were assimilators, convergers, or both. The distribution of dominant learning styles between residents and faculty members was not different (p=0.77). The most common dominant teaching perspective among faculty members was apprenticeship. CONCLUSION: Residents and preceptors mostly exhibited learning styles associated with abstract over concrete thinking or watching over doing. Residency programs should steer residents more toward active learning and doing, and maximize interactions with patients and other caregivers. PMID- 24159205 TI - Potential cost avoidance of pharmacy students' patient care activities during advanced pharmacy practice experiences. AB - OBJECTIVES: To evaluate the potential cost avoidance of student interventions documented by fourth-year (P4) student pharmacists during advanced pharmacy practice experiences (APPEs) in outpatient and inpatient settings. METHODS: The school-wide Web-based intervention database was retrospectively analyzed to review characteristics of interventions documented during the 2011-2012 APPE cycle. Potential cost avoidance for interventions was derived from a comprehensive literature review and adjusted to 2011 dollars based on the consumer price index for medical care. RESULTS: Eighty-seven students (71% of the graduating class) documented 5,775 interventions over 36 weeks, with an estimated potential total cost avoidance of $908,800. The intervention categories associated with the greatest cost avoidance were prevention of adverse drug events, provider education, and patient education. CONCLUSIONS: Fourth-year student pharmacists and their preceptors had a positive impact, contributing to potential cost avoidance in both the inpatient and outpatient pharmacy settings. PMID- 24159207 TI - Assessment of students' critical-thinking and problem-solving abilities across a 6-year doctor of pharmacy program. AB - OBJECTIVE: To determine the feasibility of using a validated set of assessment rubrics to assess students' critical-thinking and problem-solving abilities across a doctor of pharmacy (PharmD) curriculum. METHODS: Trained faculty assessors used validated rubrics to assess student work samples for critical thinking and problem-solving abilities. Assessment scores were collected and analyzed to determine student achievement of these 2 ability outcomes across the curriculum. Feasibility of the process was evaluated in terms of time and resources used. RESULTS: One hundred sixty-one samples were assessed for critical thinking, and 159 samples were assessed for problem-solving. Rubric scoring allowed assessors to evaluate four 5- to 7-page work samples per hour. The analysis indicated that overall critical-thinking scores improved over the curriculum. Although low yield for problem-solving samples precluded meaningful data analysis, it was informative for identifying potentially needed curricular improvements. CONCLUSIONS: Use of assessment rubrics for program ability outcomes was deemed authentic and feasible. Problem-solving was identified as a curricular area that may need improving. This assessment method has great potential to inform continuous quality improvement of a PharmD program. PMID- 24159206 TI - Student and faculty perceptions of lecture recording in a doctor of pharmacy curriculum. AB - OBJECTIVE: To describe students' and faculty members' perceptions of the impact of lecture recording in a doctor of pharmacy (PharmD) curriculum. METHODS: Second and third-year pharmacy students and faculty members completed an anonymous survey instrument regarding their perceptions of lecture recording with 2 classroom lecture capture software programs, Camtasia Studio and Wimba Classroom. RESULTS: Most students (82%) responded that Camtasia was very helpful and almost half (49%) responded that Wimba Classroom was helpful (p<0.001). Forty-six percent of the students reported being more likely to miss a class that was recorded; however, few students (10%) reported using recordings as a substitute for attending class. The most common concern of faculty members was decreased student attendance (27%). CONCLUSION: Pharmacy students consider lecture recordings beneficial, and they use the recordings primarily to review the lecture. While faculty members reported concerns with decreased attendance, few students reported using recordings as an alternative to class attendance. PMID- 24159208 TI - Quantifying published scholarly works of experiential education directors. AB - OBJECTIVE: To determine the amount and potential impact of scholarly works that directors of experiential education in US colleges and schools of pharmacy have published since 2001. METHODS: A search in Web of Science was used to identify publications and citations for the years 2001-2011 by experiential education directors as identified by the American Association of Colleges of Pharmacy (AACP) Roster of Faculty and Professional Staff in 2011. Publication productivity was analyzed by position title, faculty rank, and type of institution (public vs private, research vs nonresearch-intensive). Types of published works were characterized, related citations were identified, and a reported h-index was collected for each person who published during this period. RESULTS: Ninety-seven of 226 (43%) experiential education directors published 344 scholarly works which had received 1841 citations, for an average of 1 publication every 3 years and an average citation rate of 5.3 per publication. Directors at publicly funded and research-intensive institutions published slightly more than did their counterparts at private and nonresearch-intensive schools. Publications were concentrated in 6 journals with a weighted mean publication impact factor of 1.5. CONCLUSION: Many experiential education directors have published scholarly works even though their titles and ranks vary widely. While the quantity of such works may not be large, the impact is similar to that of other pharmacy practice faculty members. These results could be used to characterize the scholarly performance of experiential education directors in recent years as well as to establish a culture of scholarship in this emerging career track within pharmacy education. PMID- 24159209 TI - Improving reliability of a residency interview process. AB - OBJECTIVE: To improve the reliability and discrimination of a pharmacy resident interview evaluation form, and thereby improve the reliability of the interview process. METHODS: In phase 1 of the study, authors used a Many-Facet Rasch Measurement model to optimize an existing evaluation form for reliability and discrimination. In phase 2, interviewer pairs used the modified evaluation form within 4 separate interview stations. In phase 3, 8 interviewers individually evaluated each candidate in one-on-one interviews. RESULTS: In phase 1, the evaluation form had a reliability of 0.98 with person separation of 6.56; reproducibly, the form separated applicants into 6 distinct groups. Using that form in phase 2 and 3, our largest variation source was candidates, while content specificity was the next largest variation source. The phase 2 g-coefficient was 0.787, while confirmatory phase 3 was 0.922. Process reliability improved with more stations despite fewer interviewers per station-impact of content specificity was greatly reduced with more interview stations. CONCLUSION: A more reliable, discriminating evaluation form was developed to evaluate candidates during resident interviews, and a process was designed that reduced the impact from content specificity. PMID- 24159211 TI - Online debates to enhance critical thinking in pharmacotherapy. AB - OBJECTIVES: To assess the impact of teaching strategies on the complexity and structure of students' arguments and type of informal reasoning used in arguments. DESIGN: Students were given an introduction to argumentation followed by 2 formal debates, with feedback provided in between. ASSESSMENT: Four debate groups were randomly selected for evaluation. In debate 1, all groups posted 1 argument, and all 4 arguments were rationalistic and ranked as high-level arguments. In debate 2, members of the 4 groups posted a total of 33 arguments, which were evaluated and received an overall median ranking lower than that for debate 1. All debates were categorized as rationalistic. CONCLUSION: Students were able to formulate rationalistic arguments to therapeutic controversies; however, their level of argumentation decreased over the course of the study. Changes planned for the future include conducting the debates in the context of patient scenarios to increase practical applicability. PMID- 24159210 TI - Critical thinking and reflection exercises in a biochemistry course to improve prospective health professions students' attitudes toward physician-pharmacist collaboration. AB - OBJECTIVE: To determine the impact of performing critical-thinking and reflection assignments within interdisciplinary learning teams in a biochemistry course on pharmacy students' and prospective health professions students' collaboration scores. DESIGN: Pharmacy students and prospective medical, dental, and other health professions students enrolled in a sequence of 2 required biochemistry courses. They were randomly assigned to interdisciplinary learning teams in which they were required to complete case assignments, thinking and reflection exercises, and a team service-learning project. ASSESSMENT: Students were asked to complete the Scale of Attitudes Toward Physician-Pharmacist Collaboration prior to the first course, following the first course, and following the second course. The physician-pharmacist collaboration scores of prospective health professions students increased significantly (p<0.001). CONCLUSIONS: Having prospective health professions students work in teams with pharmacy students to think and reflect in and outside the classroom improves their attitudes toward physician-pharmacist collaboration. PMID- 24159212 TI - Correlation between active-learning coursework and student retention of core content during advanced pharmacy practice experiences. AB - OBJECTIVE: To implement an active-learning approach in a pharmacotherapy course sequence in the second year (P2) and third (P3) year of a doctor of pharmacy (PharmD) program and determine whether the pedagogical changes correlated with retention of core content in the fourth year (P4). DESIGN: Class sessions were transitioned from slides-based lectures to discussion-based active-learning pedagogy. ASSESSMENT: A comprehensive examination was created and administered to assess student retention of therapeutic topics taught. Students demonstrated significantly improved overall scores on questions derived from the active learning pedagogy used in Pharmacotherapy II and III compared to those derived from Pharmacotherapy I in which content was delivered by lecture. CONCLUSION: The use of active-learning strategies over lecture-based methods in pharmacotherapy courses resulted in higher retention of core content. Students' performance in areas taught using the discussion-based methodology was superior to that which was taught using lecture-based slide presentations. PMID- 24159213 TI - A virtual patient software program to improve pharmacy student learning in a comprehensive disease management course. AB - OBJECTIVE: To implement and assess the impact of a virtual patient pilot program on pharmacy students' clinical competence skills. DESIGN: Pharmacy students completed interactive software-based patient case scenarios embedded with drug therapy problems as part of a course requirement at the end of their third year. ASSESSMENT: Assessments included drug-therapy problem competency achievement, performance on a pretest and posttest, and pilot evaluation survey instrument. Significant improvements in students' posttest scores demonstrated advancement of clinical skills involving drug-therapy problem solving. Students agreed that completing the pilot program improved their chronic disease management skills and the program summarized the course series well. CONCLUSION: Using virtual patient technology allowed for assessment of student competencies and improved learning outcomes. PMID- 24159214 TI - Home medication reviews in a patient care experience for undergraduate pharmacy students. AB - OBJECTIVES: To evaluate the effectiveness of conducting medication management reviews (MMRs) and home medication reviews (HMRs) on improving undergraduate pharmacy students' pharmaceutical care skills and clinical knowledge. DESIGN: Fifth-year bachelor of science in pharmacy students were enrolled in a structured course in which MMR cases based on real patient scenarios were completed, findings were discussed in groups, and comprehensive feedback was provided by course instructors. Each student was then asked to recruit a real patient through a community pharmacy and conduct an HMR. ASSESSMENT: Students' pre- and post course scores on the same MMR case improved significantly, with 84.6% of students passing the post-course assessment. Students also completed a new post-course MMR case and 74.8% received a passing score. Students' answers on a post-course self assessment showed a significant improvement in their scores regarding knowledge and skills in conducting MMRs and HMRs. CONCLUSION: Medication management reviews and home medication reviews are excellent tools for educating pharmacy students and providing them with needed actual clinical practice experience. PMID- 24159215 TI - The use of social networking to improve the quality of interprofessional education. AB - OBJECTIVE: To evaluate the feasibility and effectiveness of using an online social networking platform for interprofessional education. DESIGN: Three groups of 6 students were formed with 1 student in each group from medicine, nursing, dentistry, pharmacy, veterinary medicine, and public health. Each group followed a different collaborative educational model with a unique pedagogical structure. Students in all groups interacted via an online social networking platform for a minimum of 15 weeks and met in person once at the end of the 15-week experience for a focus group session. The students were tasked with developing a collaborative recommendation for using social networking in interprofessional education programs. ASSESSMENT: Most of the students who reported in a post experience survey that their expectations were not met were in the minimally structured group. Almost all students in the facilitated and highly structured groups indicated that this experience positively impacted their knowledge of other health professions. Most students stated that interacting within a social networking space for 15 weeks with other members of the university's health professions programs was a positive and effective interprofessional education experience. CONCLUSION: Social networking is feasible and can be used effectively within an overall strategy for interprofessional education, but design and placement within a core content course is critical to success. PMID- 24159216 TI - A pharmacogenetics service experience for pharmacy students, residents, and fellows. AB - OBJECTIVE: To utilize a comprehensive, pharmacist-led warfarin pharmacogenetics service to provide pharmacy students, residents, and fellows with clinical and research experiences involving genotype-guided therapy. DESIGN: First-year (P1) through fourth-year (P4) pharmacy students, pharmacy residents, and pharmacy fellows participated in a newly implemented warfarin pharmacogenetics service in a hospital setting. Students, residents, and fellows provided genotype-guided dosing recommendations as part of clinical care, or analyzed samples and data collected from patients on the service for research purposes. ASSESSMENT: Students', residents', and fellows' achievement of learning objectives was assessed using a checklist based on established core competencies in pharmacogenetics. The mean competency score of the students, residents, and fellows who completed a clinical and/or research experience with the service was 97% +/-3%. CONCLUSION: A comprehensive warfarin pharmacogenetics service provided unique experiential and research opportunities for pharmacy students, residents, and fellows and sufficiently addressed a number of core competencies in pharmacogenetics. PMID- 24159217 TI - Student scientific inquiry in the core curriculum. AB - OBJECTIVE: To design and implement a required student-driven research program as a capstone experience in the doctor of pharmacy (PharmD) curriculum. DESIGN: A research proposal in the form of a competitive grant application was required for each of 65 fourth-year students in an inaugural PharmD class at Touro College of Pharmacy in New York. The focus of the proposals was on hypothesis-driven research in basic science, clinical research, health outcomes, and public health. ASSESSMENT: Students' research proposals were graded using a standardized grading instrument. On a post-experience survey, most students rated the overall experience positively, indicating increased confidence in their research skills. About two-thirds of faculty members were satisfied with their students' performance, and the great majority thought the experience would be useful in the students' careers. CONCLUSION: The capstone research project was a positive experience for fourth-year students. PMID- 24159218 TI - Best practices for implementing team-based learning in pharmacy education. AB - Colleges and schools of pharmacy are incorporating more team-based learning (TBL) into their curriculum. Published resources are available to assist instructors with implementing TBL and describing it in the health professions literature. The 7 core elements include: team formation, readiness assurance, immediate feedback, sequencing of in-class problem solving, the 4 "S" structure for developing team application exercises (significant problem, same problem, specific answer choice, simultaneous reporting), incentive structure, and peer evaluation. This paper summarizes best practices related to implementation of TBL in pharmacy education, including courses taught using teaching teams. PMID- 24159219 TI - Caveat lector. PMID- 24159220 TI - Comparison of growth rates in the enrollments and numbers of graduates for US medical and pharmacy schools. PMID- 24159221 TI - Developing effective study groups in the quest for the "Holy Grail": critical thinking. PMID- 24159222 TI - CAPE educational outcomes: a student's perspective. PMID- 24159227 TI - Ultrasmooth metallic films with buried nanostructures for backside reflection mode plasmonic biosensing. AB - We present a new plasmonic device architecture based on ultrasmooth metallic surfaces with buried plasmonic nanostructures. Using template-stripping techniques, ultrathin gold films with less than 5 A surface roughness are optically coupled to an arbitrary arrangement of buried metallic gratings, rings, and nanodots. As a prototypical example, we present linear plasmonic gratings buried under an ultrasmooth 20 nm thick gold surface for biosensing. The optical illumination and collection are completely decoupled from the microfluidic delivery of liquid samples due to the backside, reflection-mode geometry. This allows for sensing with opaque or highly scattering liquids. With the buried nanostructure design, we maintain high sensitivity and decoupled backside (reflective) optical access as with traditional prism-based surface plasmon resonance (SPR) sensors. In addition, we also gain the benefits offered by nanoplasmonic sensors such as spectral tunability and high-resolution, wide-field SPR imaging with normal-incidence epi-illumination that is simple to construct and align. Beyond sensing, our buried plasmonic nanostructures with ultrasmooth metallic surfaces can benefit nanophotonic waveguides, surface-enhanced spectroscopy, nanolithography, and optical trapping. PMID- 24159228 TI - What will make hospital pharmacists successful as they take on an expanded scope of practice? PMID- 24159229 TI - [Not Available]. PMID- 24159230 TI - Retrospective analysis of opioid medication incidents requiring administration of naloxone. AB - BACKGROUND: Opioid analgesics are high-alert medications known to cause adverse drug events. OBJECTIVES: The purpose of this study was to determine the cause of opioid incidents requiring administration of naloxone, an opioid reversal agent. The specific objectives were to determine the number of opioid incidents and the proportion of incidents documented through occurrence reporting and to characterize the incidents by phase in the medication-use process, by type of incident, and by drug responsible for toxic effects. METHODS: A retrospective chart analysis was conducted using records from 2 acute care centres in the Regina Qu'Appelle Health Region. The study included inpatients who received naloxone for reversal of opioid toxicity resulting from licit, in-hospital opioid use. Cases were classified as preventable or nonpreventable. Preventable cases were analyzed to determine the phase of the medication-use process during which the incident occurred. These cases were also grouped thematically by the type of incident. The drug most likely responsible for opioid toxicity was determined for each case. The proportion of cases documented by occurrence reporting was also noted. RESULTS: Thirty-six cases involving administration of naloxone were identified, of which 29 (81%) were deemed preventable. Of these 29 preventable cases, the primary medication incident occurred most frequently in the prescribing phase (23 [79%]), but multiple phases were often involved. The cases were grouped into 6 themes according to the type of incident. Morphine was the drug that most frequently resulted in toxic effects (18 cases [50%]). Only two of the cases (5.6%) were documented by occurrence reports. CONCLUSION: Preventable opioid incidents occurred in the acute care centres under study. A combination of medication safety initiatives involving multiple disciplines may be required to decrease the incidence of these events and to better document their occurrence. PMID- 24159231 TI - Personality traits of hospital pharmacists: toward a better understanding of factors influencing pharmacy practice change. AB - BACKGROUND: The profession of pharmacy has adopted a mandate to become more patient-centred; however, significant change in this direction has not been achieved. OBJECTIVE: To characterize the personality traits of hospital pharmacists in one Canadian province, to provide insights into potential barriers to practice change. METHODS: A cross-sectional survey of hospital pharmacists was conducted in Alberta, Canada. An invitation to participate was sent to all 766 hospital pharmacists practising in the province's 2 health service organizations. The survey was based on the Big Five Inventory, a validated, reliable instrument that uses a 5-point Likert scale to measure the traits of extraversion, agreeableness, conscientiousness, neuroticism, and openness. RESULTS: Of the 347 pharmacists who completed the survey (45% response rate), the majority (297 [86%]) were staff pharmacists working full time in an urban setting. The average age of respondents was 41 years (standard deviation [SD] 11 years), and the average period in practice was 17 years (SD 11 years). Respondents' mean scores were 3.2 (SD 0.7) on extraversion, 3.8 (SD 0.4) on agreeableness, 4.0 (SD 0.4) on conscientiousness, 2.5 (SD 0.7) on neuroticism, and 3.5 (SD 0.6) on openness. Total frequency counts revealed that respondents tended toward stronger expression of extraversion, agreeableness, conscientiousness, and openness and low levels of neuroticism (with the latter indicating stability). CONCLUSION: The Big Five Inventory represents a novel approach to examining pharmacists' change related behaviours. Improving understanding of hospital pharmacists' personality traits will provide insights for the development of training and support programs tailored specifically to this group. PMID- 24159232 TI - Management of stroke prevention in canadian patients with atrial fibrillation at moderate to high risk of stroke. AB - BACKGROUND: Many patients with atrial fibrillation who are at moderate to high risk of stroke do not receive anticoagulation with vitamin K antagonists (VKAs) in accordance with recommendations. OBJECTIVE: To determine (1) why Canadian patients with atrial fibrillation who are potentially eligible for VKA do not receive this therapy, (2) why Canadian primary care physicians discontinue VKA therapy, and (3) why VKA therapy is perceived as difficult to manage. METHODS: The study involved a chart review of 3 cohorts of patients with nonvalvular atrial fibrillation at moderate to high risk of stroke: patients who had never received VKA treatment (VKA-naive), those whose treatment had been discontinued, and those whose VKA treatment was considered difficult to manage. RESULTS: Charts for 187 patients (mean age 78.4 years, standard deviation 8.9 years) treated at 39 primary care sites were reviewed (62 treatment-naive, 42 with therapy discontinued, and 83 whose therapy was considered difficult to manage). Atrial fibrillation was paroxysmal in 82 (44%) of the patients, persistent in 47 patients (25%), and permanent in 58 (31%). One patient in each of the 3 cohorts had experienced a stroke during the 6 months before study participation. Bleeding events were more frequent among patients who had discontinued VKA therapy than in the other 2 groups. Among those whose therapy was discontinued and those whose therapy was difficult to manage, the mean time in the therapeutic range was 46.3% and 56.4%, respectively. The most common reason for not initiating VKA therapy in treatment-naive patients was the transient nature of atrial fibrillation (25/62 [40%]). The most common reason for discontinuation of VKA therapy was a bleeding event (10/42 [24%]). The presence of a concomitant chronic disease was the most common reason that a patient's therapy was considered difficult to manage (46/83 [55%]). CONCLUSIONS: VKA therapy was not initiated or was discontinued for various reasons. Multiple comorbid conditions made management of VKA therapy more difficult. These findings reflect the challenges that primary care physicians experience in managing the care of patients with atrial fibrillation. PMID- 24159233 TI - Assessing the impact of an expanded scope of practice for pharmacists at a community hospital. PMID- 24159234 TI - Physical Incompatibility between Parenteral Cloxacillin and Vancomycin. PMID- 24159235 TI - Development of a training program for handling hazardous drugs. PMID- 24159236 TI - Use of the 2008 basel consensus statements to assess, realign, and monitor pharmacy practice at a tertiary care hospital in northern Uganda: illustrative case study. PMID- 24159237 TI - Should azithromycin no longer be considered a drug of choice for community acquired pneumonia because of its potential to cause cardiovascular death? PMID- 24159238 TI - Physical Compatibility of Ranitidine and Metoclopramide in 50-mL Minibags of Normal Saline. PMID- 24159239 TI - Acting on adherence: better sooner than later. PMID- 24159240 TI - [Not Available]. PMID- 24159241 TI - How is CSHP Supporting Hospital Pharmacists? PMID- 24159242 TI - WHERE AND HOW TO DRAW THE LINE BETWEEN REASONABLE CORPORAL PUNISHMENT AND ABUSE. PMID- 24159244 TI - On the Evaluation of the Elastic Modulus of Soft Materials Using Beams with Unknown Initial Curvature. AB - A nonlinear optimization procedure is established to determine the elastic modulus of slender, soft materials using beams with unknown initial curvature in the presence of large rotations. Specifically, the deflection of clamped-free beams under self-weight - measured at different orientations with respect to gravity - is used to determine the modulus of elasticity and the intrinsic curvature in the unloaded state. The approach is validated with experiments on a number of different materials - steel, polyetherimide, rubber and pig skin. Since the loading is limited to self-weight, the strain levels attained in these tests are small enough to assume a linear elastic material behavior. This nondestructive methodology is also applicable to engineered tissues and extremely delicate materials in order to obtain a quick estimate of the material's elastic modulus. PMID- 24159243 TI - Shedding Light on Structure-Property Relationships for Conjugated Microporous Polymers: The Importance of Rings and Strain. AB - The photophysical properties of insoluble porous pyrene networks, which are central to their function, differ strongly from those of analogous soluble linear and branched polymers and dendrimers. This can be rationalized by the presence of strained closed rings in the networks. A combined experimental and computational approach was used to obtain atomic scale insight into the structure of amorphous conjugated microporous polymers. The optical absorption and fluorescence spectra of a series of pyrene-based materials were compared with theoretical time dependent density functional theory predictions for model clusters. Comparison of computation and experiment sheds light on the probable structural chromophores in the various materials. PMID- 24159245 TI - A cytotoxic dimeric furanoheliangolide from Piptocoma rufescens. AB - A new sesquiterpene lactone, rufescenolide C (1), the first furanoheliangolide dimer, was isolated from the leaves of Piptocoma rufescens, collected in the Dominican Republic. Its structure was determined by analysis of its spectroscopic data, with the absolute configuration being established by analysis of the CD spectrum. A plausible biogenesis of this dimer is proposed. This compound showed potent cytotoxicity with an IC50 value of 150 nM, when tested against HT-29 human colon cancer cells. PMID- 24159246 TI - Network Sampling with Memory: A proposal for more efficient sampling from social networks. AB - Techniques for sampling from networks have grown into an important area of research across several fields. For sociologists, the possibility of sampling from a network is appealing for two reasons: (1) A network sample can yield substantively interesting data about network structures and social interactions, and (2) it is useful in situations where study populations are difficult or impossible to survey with traditional sampling approaches because of the lack of a sampling frame. Despite its appeal, methodological concerns about the precision and accuracy of network-based sampling methods remain. In particular, recent research has shown that sampling from a network using a random walk based approach such as Respondent Driven Sampling (RDS) can result in high design effects (DE)-the ratio of the sampling variance to the sampling variance of simple random sampling (SRS). A high design effect means that more cases must be collected to achieve the same level of precision as SRS. In this paper we propose an alternative strategy, Network Sampling with Memory (NSM), which collects network data from respondents in order to reduce design effects and, correspondingly, the number of interviews needed to achieve a given level of statistical power. NSM combines a "List" mode, where all individuals on the revealed network list are sampled with the same cumulative probability, with a "Search" mode, which gives priority to bridge nodes connecting the current sample to unexplored parts of the network. We test the relative efficiency of NSM compared to RDS and SRS on 162 school and university networks from Add Health and Facebook that range in size from 110 to 16,278 nodes. The results show that the average design effect for NSM on these 162 networks is 1.16, which is very close to the efficiency of a simple random sample (DE=1), and 98.5% lower than the average DE we observed for RDS. PMID- 24159247 TI - Is Openness to Using Empirically Supported Treatments Related to Organizational Culture and Climate? AB - The overall purpose of this study is to investigate workers' openness towards implementing a new empirically supported treatment (EST) and whether the workers' openness scores relate to their workplace culture and climate scores. Participants in this study (N=1273) worked in a total of 55 different programs in a large child and family services organization and completed a survey measuring their attitudes toward ESTs. Results indicate that work groups that measure themselves as being more open to using ESTs rated their organizational cultures as being significantly more proficient and significantly less resistant to change. With ESTs becoming the gold standard for professional social work practices, it is important to have accessible pathways to EST implementation. PMID- 24159248 TI - Effects of age and ability on components of cognitive change. AB - Prior experience with a cognitive task is often associated with higher performance on a second assessment, and these experience effects can complicate the interpretation of cognitive change. The current study was designed to investigate experience effects by obtaining measures of cognitive performance separated by days and by years. The analyses were based on data from 2017 adults with two longitudinal occasions, of whom 948 had also completed a third occasion, with each occasion consisting of three parallel versions of the tests on separate sessions. Change across short intervals was typically positive, and greater among older adults and adults with low levels of cognitive ability, whereas change over intervals of approximately three years was often negative, particularly at older ages. In contrast to the expectation that change over short intervals might be informative about change over longer intervals, relations between short-term change and long-term change were negative, as the individuals who gained the most with assessments separated by days tended to experience the greatest losses across assessments separated by years. PMID- 24159249 TI - Optimizing parameters in clinical trials with a randomized start or withdrawal design. AB - Disease-modifying (DM) trials on chronic diseases such as Alzheimer's disease (AD) require a randomized start or withdrawal design. The analysis and optimization of such trials remain poorly understood, even for the simplest scenario in which only three repeated efficacy assessments are planned for each subject: one at the baseline, one at the end of the trial, and the other at the time when the treatments are switched. Under the assumption that the repeated measures across subjects follow a trivariate distribution whose mean and covariance matrix exist, the DM efficacy hypothesis is formulated by comparing the change of efficacy outcome between treatment arms with and without a treatment switch. Using a minimax criterion, a methodology is developed to optimally determine the sample size allocations to individual treatment arms as well as the optimum time when treatments are switched. The sensitivity of the optimum designs with respect to various model parameters is further assessed. An intersection-union test (IUT) is proposed to test the DM hypothesis, and determine the asymptotic size and the power of the IUT. Finally, the proposed methodology is demonstrated by using reported statistics on the placebo arms from several recently published symptomatic trials on AD to estimate necessary parameters and then deriving the optimum sample sizes and the time of treatment switch for future DM trials on AD. PMID- 24159250 TI - High pressure homogenization to improve the stability of casein - hydroxypropyl cellulose aqueous systems. AB - The effect of high pressure homogenization on the improvement of the stability hydroxypropyl cellulose (HPC) and micellar casein was investigated. HPC with two molecular weights (80 and 1150 kDa) and micellar casein were mixed in water to a concentration leading to phase separation (0.45% w/v HPC and 3% w/v casein) and immediately subjected to high pressure homogenization ranging from 0 to 300 MPa, in 100 MPa increments. The various dispersions were evaluated for stability, particle size, turbidity, protein content, and viscosity over a period of two weeks and Scanning Transmission Electron Microscopy (STEM) at the end of the storage period. The stability of casein-HPC complexes was enhanced with the increasing homogenization pressure, especially for the complex containing high molecular weight HPC. The apparent particle size of complexes was reduced from ~200nm to ~130nm when using 300 MPa, corresponding to the sharp decrease of absorbance when compared to the non-homogenized controls. High pressure homogenization reduced the viscosity of HPC-casein complexes regardless of the molecular weight of HPC and STEM imagines revealed aggregates consistent with nano-scale protein polysaccharide interactions. PMID- 24159251 TI - Ya33 'give' as a valency increaser in Jinghpo nuclear serialization: from benefactive to malefactive. AB - This paper analyzes serial verb constructions in Jinghpo formed by ya33 'give', arguing that it has the function of a valency-increasing device in nuclear serialization: the use of ya33 allows the licensing of an additional beneficiary argument as a core argument to the lexical verb. In a new twist, however, on the evolution of give verbs, we demonstrate that the benefactive usage is extended to malefactive semantics in a distinct, derived structure, conditioned via the expression of possession, a type of malefactive that is not well-documented in current literature on this domain. Furthermore, the existence of two distinct constructions for the benefactive and the malefactive in Jinghpo conforms to Radetzky & Smith's claim (2010: 116) that this is an areal feature comprising the Indian subcontinent, Southeast and East Asia, and thus contrasts strongly with the conflation of both types of construction in many European languages. Finally, we propose that the nuclear type of serialization, integral to the typological profile of Jinghpo, a SOV language, is a determining factor in the reanalysis of ya33 . This feature is subsequently invoked to explain why the malefactive usage of ya33 constitutes a separate development from the well-attested pathway for give verbs leading to permissive causative verbs and adversative passive markers, which, while blocked in Jinghpo, is commonly found in many other East and Southeast Asian languages with core serialization. The present analysis is based on the variety of Jinghpo spoken in Luxi county, Yunnan province, China, using in the main natural discourse data collected in the field. PMID- 24159252 TI - Does Mandated Treatment Benefit Youth? A Prospective Investigation of Adolescent Justice System Involvement, Treatment Motivation, and Substance Use Outcomes. AB - BACKGROUND: The majority of adolescents treated for substance use disorder (SUD) in the United States are now referred by the criminal justice system. Little is known, however, regarding how justice-system involvement relates to adolescent community treatment outcomes. Controversy exists, also, over the extent to which justice system involvement reflects a lack of intrinsic motivation for treatment. This study examined the relation between justice system referral and reported reason for treatment entry and tested the extent to which each predicted treatment response and outcome. METHOD: Adolescent outpatients (N = 127; M age = 16.7, 24% female) with varying levels of justice-system involvement (i.e., no justice system involvement [No-JSI; n = 63], justice-system involved [JSI; n = 40], justice system involved-mandated [JSI-M; n = 24]) and motivation levels (i.e., self-motivated [n = 40], externally-motivated [n = 87]) were compared at treatment intake. Multilevel mixed models tested these groups' effects on percent days abstinent (PDA) and odds of heavy drinking (HD) over 12 months. RESULTS: JSI M were less likely to be self-motivated compared to No-JSI or JSI (p = 0.009). JSI-M had higher PDA overall, but with significant declines over time, relative to no-JSI. Self-motivated patients did not differ from externally-motivated patients on PDA or HD. CONCLUSIONS: Mandated adolescent outpatients were substantially less likely to report self-motivated treatment entry. Despite the notion that self-motivated treatment entry would be likely to produce better outcomes, a judicial mandate appears to predict an initially stronger treatment response, although this diminishes over time. Ongoing monitoring and/or treatment may be necessary to help maintain treatment gains for justice system-involved adolescents. PMID- 24159253 TI - People Believe That They Are Prototypically Good or Bad. AB - People have been shown to view their beliefs as being prototypical (modal) but their abilities as (falsely) unique (above or below average). It is possible that these two viewpoints - self as prototypical and self as unique - can be reconciled. If the distribution of ability for a given skill is skewed such that many others have high (low) ability and few others have low (high) ability, it is possible that a majority of peoples' self-assessments can be above (below) average. Participants in 5 studies demonstrated an understanding that various skills have skewed ability distributions and their self-assessments were related to distribution shape: high when negatively skewed and low when positively skewed. Further, participants tended to place themselves near the mode of their perceived skill distribution. Participants were most likely to think that they were good at skills for which they thought that most others were also good. PMID- 24159254 TI - A randomized clinical trial comparing the effect of different haemostatic agents for haemostasis of the liver after hepatic resection. AB - Introduction. Operative blood loss is still a great obstacle to liver resection, and various topical hemostatic agents were introduced to reduce it. The aim of the current study is to evaluate effects of 3 different types of these agents. Methods. In this randomized clinical trial, 45 patients undergoing liver resection were assigned to receive TachoSil, Surgicel, and Glubran 2 for controlling bleeding. Intraoperative and postoperative findings were compared between groups. Results. Postoperative bleeding (0 versus 33.3%, P = 0.04) and drainage volume first day after surgery (281.33 +/- 103.98 versus 150.00 +/- 60.82 mL, P = 0.02) were significantly higher in Surgicel than in TachoSil group. Postoperative complications included bile leak (3 cases in Surgicel, 1 case in TachoSil and Glubran 2), noninfectious collection (2 cases in TachoSil and Surgicel and 1 case in Glubran 2), perihepatic abscess, and massive hematoma around hepatectomy site both in Surgicel group. There was no death during the study period. Conclusion. Due to higher complications in Surgicel group, its application as hemostatic agent after liver resection is not recommended. Better results in TachoSil in comparison to the other two are indicative of its better efficacy and superiority in controlling hemostasis. PMID- 24159255 TI - Assessing the measurement error properties of interviewer observations of neighbourhood characteristics. AB - Interviewer observations made during the process of data collection are currently used to inform responsive design decisions, to expand the set of covariates for nonresponse adjustments, to explain participation in surveys, and to assess nonresponse bias. However, little effort has been made to assess the quality of such interviewer observations. Using data from the Los Angeles Family and Neighbourhood Survey (L.A.FANS), this paper examines measurement error properties of interviewer observations of neighbourhood characteristics. Block level and interviewer covariates are used in multilevel models to explain interviewer variation in the observations of neighbourhood features. PMID- 24159256 TI - Relations among Teachers' Emotion Socialization Beliefs and Practices, and Preschoolers' Emotional Competence. AB - RESEARCH FINDINGS: Utilizing a three-part model of emotion socialization that includes Modeling, Contingent Responding, and Teaching, this study examined the associations between 44 teachers' self-reported and observed emotion socialization practices and 326 preschoolers' emotion knowledge and observed emotional behavior. Multi-level analyses revealed that the majority of the variance in the children's emotion knowledge scores and observed emotional behavior was predicted by factors within, rather than between, classrooms. Teachers' use of all three emotion socialization techniques did contribute to the prediction of the children's scores; however, the nature of these associations differed by children's age and gender. PRACTICE OR POLICY: The development of children's emotional competence is a complex, multi-faceted process in which many interaction partners play a role; early childhood teachers act as emotion socialization agents for the children in their care by modeling emotions, responding either supportively or punitively to children's expressions of emotions, and engaging in direct instruction regarding emotional experience. This research may provide a basis for potential future interventions designed to assist teachers in developing their own emotion socialization skills so that they can be more effective emotion socialization agents for the children in their care. PMID- 24159257 TI - Synthesis and crystal structure of a phenazine N-oxide. AB - The preparation and crystal structure of 8-chloro-1H-pyrrolo[2,3-b]phenazine 5 oxide (1) are described. Compound 1 formed dark purple crystals from deeply colored solution in methanol. Crystal plates were in the triclinic system, P-1 space group with unit cell parameters a = 6.9514(8), b = 9.1568(10), c = 10.2067(11), alpha = 84.509(2), beta = 82.936(2), gamma = 72.357(2) and a cell volume of 613.25(12) A-3. The title compound which contains the first example of the extensively conjugated pyrrolo-phenazine N-oxide system exhibits strong light absorption in the green to cyan wavelength range which disappears upon protonation. PMID- 24159258 TI - SOSPES: SPIRIVA(r) observational study measuring SGRQ score in routine medical practice in Central and Eastern Europe. AB - PURPOSE: The long-acting inhaled anticholinergic agent, tiotropium, is recommended as first-line maintenance therapy for moderate to very severe Chronic Obstructive Pulmonary Disease (COPD) to improve symptoms, exercise tolerance, health status, and to reduce exacerbations. Few studies have evaluated the therapeutic efficacy of tiotropium in patients in routine clinical conditions. The current study was designed to investigate the therapeutic efficacy of tiotropium delivered via the HandiHaler(r) device on the health status of patients with COPD with Global initiative for chronic Obstructive Lung Disease (GOLD) disease classification 2-4 in six central and eastern European countries in a real-life clinical setting. METHODS: The study was an open-label, prospective, uncontrolled, and single-arm surveillance study with three clinic visits during a 6-month observation period (baseline, and months 3 and 6). Health status was measured using the disease-specific St George's Respiratory Questionnaire (SGRQ). The primary efficacy endpoint was the mean change from baseline in SGRQ total score at the end of the 6-month observational period. RESULTS: Patients treated with tiotropium 18 MUg once daily showed statistically significant and clinically meaningful reduction (improvement) of 21.7 units in the SGRQ total score, regardless of smoking status or cardiac comorbidities at enrollment (P < 0.0001). The analysis also showed that age, treatment compliance, and GOLD disease classification were significant factors that impact the health status of patients with COPD differently. CONCLUSION: These results provide further support for the use of the tiotropium HandiHaler(r) as first-line maintenance treatment of patients with COPD with a clinician-assessed disease. PMID- 24159260 TI - Budget impact analysis of conversion from cyclosporine to sirolimus as immunosuppressive medication in renal transplantation therapy. AB - OBJECTIVES: The aim of this study was to determine budget impact of conversion from cyclosporine (CsA) to sirolimus (SRL) in renal transplant therapy (RTT) from the perspective of insurance organizations in Iran. METHODS: An Excel-based model was developed to determine cost of RTT, comparing current CsA based therapy to an mTOR inhibitor-based therapy regimen. Total cost included both cost of immunosuppressive agents and relative adverse events. The inputs were derived from database of Ministry of Health and insurance organizations, hospital and pharmacy based registries, and available literature that were varied through a one-way sensitivity analysis. According to the model, there were almost 17,000 patients receiving RTT in Iran, out of which about 2,200 patients underwent the operation within the study year. The model was constructed based on the results of a local RCT, in which test and control groups received CsA, SRL, and steroids over the first 3 months posttransplantation and, from the fourth month on, CsA, mycophenolate mofetil (MMF), and steroids were used in the CsA group and SRL, MMF, and steroids were administered in the SRL group, respectively. RESULTS: The estimated cost of RTT with CsA was US$4,850,000 versus US$4,300,000 receiving SRL. These costs corresponded to the cost saving of almost US$550,000 for the payers. CONCLUSION: To evaluate the financial consequence of adding mTOR inhibitors to the insurers' formulary, in the present study, a budget impact analysis was conducted on sirolimus. Fewer cases of costly adverse events along with lower required doses of MMF related to SRL based therapies were major reasons for this saving budgetary impact. PMID- 24159259 TI - Efficacy and safety of QVA149 compared to the concurrent administration of its monocomponents indacaterol and glycopyrronium: the BEACON study. AB - INTRODUCTION: The BEACON study evaluated the efficacy and safety of QVA149, a once-daily dual bronchodilator containing a fixed-dose combination of the long acting beta2-agonist (LABA) indacaterol and long-acting muscarinic antagonist (LAMA) glycopyrronium (NVA237), in development for the treatment of patients with chronic obstructive pulmonary disease (COPD), compared with the free-dose concurrent administration of indacaterol plus glycopyrronium (IND+GLY). METHODS: In this multicenter, double-blind, parallel group study, patients with stage II or stage III COPD (Global initiative for chronic Obstructive Lung Disease [GOLD] 2010) were randomized (1:1) to once-daily QVA149 (110 MUg indacaterol/50 MUg glycopyrronium) or concurrent administration of indacaterol (150 MUg) and glycopyrronium (50 MUg) via the Breezhaler(r) device (Novartis AG, Basel, Switzerland) for 4 weeks. The primary endpoint was to evaluate the noninferiority of QVA149 as compared with concurrent administration of IND+GLY, for trough forced expiratory volume in 1 second (FEV1) after 4 weeks of treatment. The other assessments included FEV1 area under the curve from 0 to 4 hours (AUC0-4 hours) at day 1 and week 4, symptom scores, rescue medication use, safety, and tolerability over the 4-week study period. RESULTS: Of 193 patients randomized, 187 (96.9%) completed the study.Trough FEV1 at week 4 for QVA149 and IND+GLY was 1.5 L +/- 0.02 [DOSAGE ERROR CORRECTED] and 1.46 L +/- 0.18, respectively. The FEV1 AUC0-4 hours at day 1 and week 4 were similar between the two treatment groups. Both treatment groups had a similar reduction in symptom scores and rescue medication use for the 4-week treatment period. Overall, 25.6% of patients in QVA149 group and 25.2% in the IND+GLY group experienced an adverse event, with the majority being mild-to-moderate in severity. No deaths were reported during the study or during the 30 days follow-up period. CONCLUSION: The BEACON study demonstrated that once-daily QVA149 provides an efficacy and safety profile similar to the concurrent administration of its monocomponents indacaterol and glycopyrronium. PMID- 24159261 TI - Dubowitz syndrome: common findings and peculiar urine odor. AB - BACKGROUND: Dubowitz syndrome is a rare, autosomal recessive disorder characterized by intrauterine and postnatal growth retardation, severe microcephaly, psychomotor retardation, hyperactivity, eczema, and characteristic dysmorphic facial features. Although many cases have been reported, the cause of this disease is still unknown. CASE: We present here the case of a Lebanese girl with Dubowitz syndrome in whom an unpleasant urine odor was persistently reported since birth. CONCLUSION: Although Dubowitz syndrome has been largely described in the medical literature, this is the first time that a peculiar urine odor was reported. This case report adds a new and unusual feature to the numerous findings related to this rare polymorphous syndrome. PMID- 24159263 TI - Unusual case of contralateral Horner's syndrome following stellate-ganglion block: a case report and review of the literature. AB - Stellate-ganglion block (SGB) is a commonly performed procedure for the treatment of numerous conditions, including upper-extremity complex regional pain syndromes and arterial insufficiency. The appropriate response to SGB includes ipsilateral Horner's syndrome and temperature elevation of affected extremity. Contralateral and bilateral Horner's syndrome following SGB are rarely seen, with only six prior cases reported. We describe a case of a 47-year-old female with right-hand pain secondary to Raynaud's phenomenon who underwent SGB with subsequent contralateral Horner's syndrome and review the literature of this rare phenomenon. PMID- 24159262 TI - Developments in the treatment of hemophilia B: focus on emerging gene therapy. AB - Hemophilia B is a genetic disorder that is characterized by a deficiency of clotting factor IX (FIX) and excessive bleeding. Advanced understanding of the pathophysiology of the disease has led to the development of improved treatment strategies that aim to minimize the acute and long-term complications of the disease. Patients with hemophilia B are ideal candidates for gene therapy, mostly because a small increase in protein production can lead to significantly decreased bleeding diathesis. Although human clotting FIX was cloned and sequenced over 30 years ago, progress toward achieving real success in human clinical trials has been slow, with long-term, therapeutically relevant gene expression only achieved in one trial published in 2011. The history of this extensive research effort has revealed the importance of the interactions between gene therapy vectors and multiple arms of the host immune system at multiple stages of the transduction process. Different viral vector systems each have unique properties that influence their ability to deliver genes to different tissues, and the data generated in several clinical trials testing different vectors for hemophilia have guided our understanding toward development of optimal configurations for treating hemophilia B. The recent clinical success implementing a novel adeno-associated virus vector demonstrated sufficient FIX expression in patients to convert a severe hemophilia phenotype to mild, an achievement which has the potential to profoundly alter the impact of this disease on human society. Continued research should lead to vector designs that result in higher FIX activity at lower vector doses and with reduced host immune responses to the vector and the transgene product. PMID- 24159264 TI - The REDIH experience: an emerging design to develop an effective training program for graduate students in reproductive science. AB - BACKGROUND: A training program in Reproduction, Early Development, and the Impact on Health (REDIH) was initiated in 2009 by researchers specializing in biomedical, clinical, population health, and ethics research from seven collaborating universities in Quebec and Ontario, and Health Canada. This paper reports the findings from the first three years of the 6-year program. OBJECTIVES: The objective of the REDIH program is to provide increased opportunities for excellent training in reproduction and early development for graduate students and fellows, in order to build research, clinical, regulatory, decision-making, and industry capacity in Canada. METHODS: A mixed methods approach was used to evaluate the REDIH training program, so as to combine the strengths of both qualitative and quantitative studies. A total of four focus groups (two with mentors and two with trainees) were run during the June 2012 REDIH meeting. Surveys were administered directly after each training module. The W(e)Learn framework was used as a guide to design and evaluate the program and answer the research questions. RESULTS: The data from the analysis of the focus group interviews, in corroboration with the survey data, suggested trainees enjoyed and benefited from the REDIH experience. Trainees provided several examples of new knowledge and skills they had acquired from REDIH sessions, regarding reproductive and early developmental biology, and health. A few trainees who had been in the program for over a year provided examples of knowledge and skills acquired during the REDIH session that they were using in their place of work. Next steps will include following up on REDIH graduates to see if the program has had any impact on trainees' employment opportunities and career development. CONCLUSION: Trainees and mentors concluded that the curricular design, which focuses on modules in 2-day learning sessions over a 6 year period, with opportunities for application in the workplace, enabled the sessions to be tailored to the outcomes of the formative evaluation. By sharing our experiences with REDIH, we hope that others can benefit from this unique emerging design, which focuses on the flexibility and receptivity of the mentors, and results in a program that lends itself to curriculum modification and tailoring as learners' needs are solicited and addressed. PMID- 24159265 TI - Effect of year of study on stress levels in male undergraduate dental students. AB - OBJECTIVE: Stress among dental students can be a significant threat, resulting in physical and/or mental illness, and have a negative effect on students' performance and the professional practice of dentistry. Stress can occur from different sources. The purpose of this study is to test whether the year of study has an effect on the stress levels of dental students. METHOD: Our study consisted of a cross-sectional survey using a modified version of the Dental Environment Stress (DES) questionnaire. The questionnaires were filled out by male undergraduate dental students at King Saud University in Riyadh City during the 2010-2011 academic year (n = 214). RESULTS: THE RESULTS SHOW THE MOST COMMON SOURCES OF STRESS: examinations and completing clinical requirements. Moreover, in the five-year lecture-based traditional curriculum, the third year students reported the highest level of stress, whereas the first year reported the lowest level of stress. CONCLUSION: Third year undergraduate dental students reported the highest level of stress. This stress could be reduced by reviewing and modifying the dental curriculum by allowing students to have contact with patients more gradually, starting from the first year, in addition to adding stress prevention and intervention programs in dental curricula. PMID- 24159266 TI - Correlation of psychomotor skills and didactic performance among dental students in Saudi Arabia. AB - OBJECTIVES: The objective of this study is to investigate the correlation between the psychomotor skills and the academic performance of dental students. METHODS: Didactic and preclinical scores were collected for students who graduated from the Faculty of Dentistry, King Abdulaziz University, Jeddah, Saudi Arabia, in 2011. Three courses (Dental Anatomy, Removable Prosthodontic Denture, and Orthodontics) were selected. Correlations comparing didactic and practical scores were done for the total samples, then for the males and females separately. RESULTS: There was no significant correlation between the practical and didactic scores for the three courses for the total sample. There was a significant correlation between all three subjects in the didactic scores. For females, the results showed that there was only a significant correlation between the practical and didactic scores for Dental Anatomy. For males, no correlation was observed between the practical and didactic scores for all subjects. CONCLUSION: In the present sample, didactic performance did not correlate well with the students' psychomotor performance. PMID- 24159267 TI - Therapeutic Assessment of Complex Trauma: A Single-Case Time-Series Study. AB - The cumulative effect of repeated traumatic experiences in early childhood incrementally increases the risk of adjustment problems later in life. Surviving traumatic environments can lead to the development of an interrelated constellation of emotional and interpersonal symptoms termed complex posttraumatic stress disorder (CPTSD). Effective treatment of trauma begins with a multimethod psychological assessment and requires the use of several evidence based therapeutic processes, including establishing a safe therapeutic environment, reprocessing the trauma, constructing a new narrative, and managing emotional dysregulation. Therapeutic Assessment (TA) is a semistructured, brief intervention that uses psychological testing to promote positive change. The case study of Kelly, a middle-aged woman with a history of repeated interpersonal trauma, illustrates delivery of the TA model for CPTSD. Results of this single case time-series experiment indicate statistically significant symptom improvement as a result of participating in TA. We discuss the implications of these findings for assessing and treating trauma-related concerns, such as CPTSD. PMID- 24159268 TI - Cultural Adaptation for Ethnic Diversity: A Review of Obesity Interventions for Preschool Children. AB - Obesity disproportionately affects U.S. ethnic minority preschool children, placing them at risk for obesity related co-morbidities and premature death. Effective culturally appropriate interventions are needed to improve health behaviors and reduce obesity in young high-risk minority children, while their behaviors are still developing. All known obesity intervention studies (e.g., diet and physical activity) since 2000 targeting U.S. ethnic minority preschool children were reviewed. Five electronic databases and eight published literature reviews were used to identify the studies. Intervention studies without identified ethnic minority participants were excluded. Ten obesity interventions studies met the review criteria. Published cultural adaptation guidelines were used to develop a mechanism to analyze, score, and rank the intervention adaptations. Cultural adaptations varied widely in rigor, depth, and breadth. Results indicated a relative absence of appropriately adapted obesity interventions for ethnic minority groups, suggesting a need for more rigorous cultural adaptation guidelines when designing obesity interventions for diverse ethnicities. Culturally appropriate adaptations appeared to enhance intervention relevance, effectiveness, and feasibility. The purpose of this literature review was to evaluate 1) the type and extent of cultural adaptations strategies applied to the interventions, and 2) how these adaptations related to the study outcomes. PMID- 24159269 TI - Digital family histories for data mining. AB - As we move closer to ubiquitous electronic health records (EHRs), genetic, familial, and clinical information will need to be incorporated into EHRs as structured data that can be used for data mining and clinical decision support. While the Human Genome Project has produced new and exciting genomic data, the cost to sequence the human personal genome is high, and significant controversies regarding how to interpret genomic data exist. Many experts feel that the family history is a surrogate marker for genetic information and should be part of any paper-based or electronic health record. A digital family history is now part of the Meaningful Use Stage 2 menu objectives for EHR reimbursement, projected for 2014. In this study, a secure online family history questionnaire was designed to collect data on a unique cohort of Vietnam-era repatriated male veterans and a comparison group in order to compare participant and family disease rates on common medical disorders with a genetic component. This article describes our approach to create the digital questionnaire and the results of analyzing family history data on 319 male participants. PMID- 24159270 TI - Exploration of ICD-9-CM coding of chronic disease within the Elixhauser Comorbidity Measure in patients with chronic heart failure. AB - INTRODUCTION: International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) codes capture comorbidities that can be used to risk adjust nonrandom patient groups. We explored the accuracy of capturing comorbidities associated with one risk adjustment method, the Elixhauser Comorbidity Measure (ECM), in patients with chronic heart failure (CHF) at one Veterans Affairs (VA) medical center. We explored potential reasons for the differences found between the original codes assigned and conditions found through retrospective review. METHODS: This descriptive, retrospective study used a cohort of patients discharged with a principal diagnosis coded as CHF from one VA medical center in 2003. One admission per patient was used in the study; with multiple admissions, only the first admission was analyzed. We compared the assignment of original codes assigned to conditions found in a retrospective, manual review of the medical record conducted by an investigator with coding expertise as well as by physicians. Members of the team experienced with assigning ICD-9-CM codes and VA coding processes developed themes related to systemic reasons why chronic conditions were not coded in VA records using applied thematic techniques. RESULTS: In the 181-patient cohort, 388 comorbid conditions were identified; 305 of these were chronic conditions, originally coded at the time of discharge with an average of 1.7 comorbidities related to the ECM per patient. The review by an investigator with coding expertise revealed a total of 937 comorbidities resulting in 618 chronic comorbid conditions with an average of 3.4 per patient; physician review found 872 total comorbidities with 562 chronic conditions (average 3.1 per patient). The agreement between the original and the retrospective coding review was 88 percent. The kappa statistic for the original and the retrospective coding review was 0.375 with a 95 percent confidence interval (CI) of 0.352 to 0.398. The kappa statistic for the retrospective coding review and physician review was 0.849 (CI, 0.823-0.875). The kappa statistic for the original coding and the physician review was 0.340 (CI, 0.316-0.364). Several systemic factors were identified, including familiarity with inpatient VA and non-VA guidelines, the quality of documentation, and operational requirements to complete the coding process within short time frames and to identify the reasons for movement within a given facility. CONCLUSION: Comorbidities within the ECM representing chronic conditions were significantly underrepresented in the original code assignment. Contributing factors potentially include prioritization of codes related to acute conditions over chronic conditions; coders' professional training, educational level, and experience; and the limited number of codes allowed in initial coding software. This study highlights the need to evaluate systemic causes of underrepresentation of chronic conditions to improve the accuracy of risk adjustment used for health services research, resource allocation, and performance measurement. PMID- 24159271 TI - Impact of electronic health record systems on information integrity: quality and safety implications. AB - While the adoption of electronic health record (EHR) systems promises a number of substantial benefits, including better care and decreased healthcare costs, serious unintended consequences from the implementation of these systems have emerged. Poor EHR system design and improper use can cause EHR-related errors that jeopardize the integrity of the information in the EHR, leading to errors that endanger patient safety or decrease the quality of care. These unintended consequences also may increase fraud and abuse and can have serious legal implications. This literature review examines the impact of unintended consequences of the use of EHR systems on the quality of care and proposed solutions to address EHR-related errors. This analysis of the literature on EHR risks is intended to serve as an impetus for further research on the prevalence of these risks, their impact on quality and safety of patient care, and strategies for reducing them. PMID- 24159272 TI - Impact of radio-frequency identification (RFID) technologies on the hospital supply chain: a literature review. AB - Supply costs account for more than one-third of the average operating budget and constitute the second largest expenditure in hospitals. As hospitals have sought to reduce these costs, radio-frequency identification (RFID) technology has emerged as a solution. This study reviews existing literature to gauge the recent and potential impact and direction of the implementation of RFID in the hospital supply chain to determine current benefits and barriers of adoption. Findings show that the application of RFID to medical equipment and supplies tracking has resulted in efficiency increases in hospitals with lower costs and increased service quality. RFID technology can reduce costs, improve patient safety, and improve supply chain management effectiveness by increasing the ability to track and locate equipment, as well as monitoring theft prevention, distribution management, and patient billing. Despite ongoing RFID implementation in the hospital supply chain, barriers to widespread and rapid adoption include significant total expenditures, unclear return on investment, and competition with other strategic imperatives. PMID- 24159273 TI - Long-term care and health information technology: opportunities and responsibilities for long-term and post-acute care providers. AB - Long-term and post-acute care providers (LTPAC) need to understand the multiple aspects of health information technology (HIT) in the context of health systems transformation in order to be a viable participant. The issues with moving to HIT are not just technical and funding, but include legal and policy, technical and business operations, and very significantly, governance. There are many unanswered questions. However, changes in payment methodologies, service delivery models, consumer expectations, and regulatory requirements necessitate that LTPAC providers begin their journey. PMID- 24159274 TI - Registry-based diabetes risk detection schema for the systematic identification of patients at risk for diabetes in West Virginia primary care centers. AB - Approximately 466,000 West Virginians, or about 25 percent of the state population, have prediabetes and are at high risk for developing type 2 diabetes. Appropriate lifestyle intervention can prevent or delay the onset of type 2 diabetes if individuals at risk are identified and treated early. The West Virginia Diabetes Prevention and Control Program and the West Virginia University Office of Health Services Research are developing a systematic approach to diabetes prevention within primary care. This study aims to demonstrate the viability of patient registry software for the analysis of disparate electronic health record (EHR) data sets and standardized identification of at-risk patients for early detection and intervention. Preliminary analysis revealed that of 94,283 patients without a documented diagnosis of diabetes or prediabetes, 10,673 (11.3 percent) meet one or more of the risk criteria. This study indicates that EHR data can be repurposed into an actionable registry for prevention. This model supports meaningful use of EHRs, the Patient-Centered Medical Home program, and improved care through enhanced data management. PMID- 24159275 TI - The role of information and communication technology in community outreach, academic and research collaboration, and education and support services (IT CARES). AB - INTRODUCTION: The purpose of this study is to examine the role of information and communication technology (ICT) in enhancing community outreach, academic and research collaboration, and education and support services (IT-CARES) in an academic setting. METHODS: A survey was deployed to assess the ICT needs in an academic setting. The survey was developed using the Delphi methodology. Questionnaire development was initiated by asking key stakeholders involved in community outreach, academic, research, education, and support to provide feedback on current ICT issues and future recommendations for relevant ICT tools that would be beneficial to them in their job, and to capture current ICT issues. Participants were asked to rate the level of importance of each ICT question on five-point Likert scales. RESULTS: The survey was sent to 359 participants, including faculty, staff, and students. The total number of respondents was 96, for a 27 percent response rate. The majority of the participants (54.1 percent, n = 46) placed a high importance on learning the available research capabilities of the college. The majority of the participants placed moderate (43.5 percent, n = 37) to high importance (40 percent, n = 34) on having an intranet that could support collaborative grant writing. A majority of the participants attributed high importance to learning to interact with the online learning management system Blackboard. A majority of the participants agreed that social media should being more actively utilized for diverse activities for academic and research purposes. CONCLUSION: The study helped to identify the current needs and challenges faced by professionals and students when interacting with ICT. More research is needed in order to effectively integrate the use of ICT in the field of higher education, especially related to the modern global public health context. PMID- 24159276 TI - Unexpected Retirement from Full Time Work after Age 62: Consequences for Life Satisfaction in older Americans. AB - Recent policy shifts in the United States have resulted in an increase in the number of older workers remaining in the labor force. Increases in the retirement age for receiving full Social Security benefits coupled with declining pension funds and the erosion of employer retiree health benefits, mean that current cohorts of older workers may fully expect to work longer than previous generations. Yet, working longer may not always be possible due to health problems, outdated skills, economic insecurity, and competing obligations. We examine the consequences of unmet expectations for full time work after age 62 for life satisfaction in a nationally representative sample of older Americans. With longitudinal data from the Health and Retirement Study (1998-2008), this paper uses repeated measures of expectations for later life work among a cohort of Americans (N=1684) gathered prospectively over an eight year period, and examines the effects of unfulfilled expectations on subsequent life satisfaction. Using generalized growth mixture modeling three latent classes of individuals were identified with distinct trajectories of later life work expectations (low expectations, high expectations, and neutral expectations for full time work after age 62). A majority of men had generally high expectations to work full time past age 62, whereas the majority of women reported a low probability of working full time after age 62. When comparing expectations to actual full time work past age 62, we found no effects of unmet expectations for women. But men with less job stability (reflected by shorter job tenure and lower incomes) generally had high expectations to work longer, and their life satisfaction scores were significantly lower when these expectations were not realized. The hazards of missed expectations for later life work have consequences for subjective well-being in older adults. PMID- 24159277 TI - Prebiotic inulin: Useful dietary adjuncts to manipulate the livestock gut microflora. AB - In recent years, there has been a growing appreciation on the relevance of gastrointestinal microflora in both ruminants and non-ruminants owing to revelation of their role in several physiological functions including digestion, nutrient utilization, pathogen exclusion, gastrointestinal development, immunity system, gut gene expression and quality of animal products. The ban imposed on the use of antibiotics and hormones in feed has compelled animal researchers in finding an alternative which could overcome the issues of conventional feed additives. Though the concept of prebiotic was evolved keeping in mind the gastrointestinal flora of human beings, presently animal researchers are exploring the efficiency of prebiotic (inulin) for modulating the gut ecosystem of both ruminants and non-ruminants. It was revealed that prebiotic inulin is found to exhibit desirable changes in the gut of non-ruminants like poultry, swine, rabbit etc for augmenting gut health and improvement of product quality. Similarly, in ruminants the prebiotic reduces rumen ammonia nitrogen, methane production, increase microbial protein synthesis and live weight gains in calves. Unlike other feed additives, prebiotic exhibits its effect in multipronged ways for overall increase in the performances of the animals. In coming days, it is expected that prebiotics could be the part of diets in both ruminants and non ruminants for enabling modulation of gut microflora vis a vis animals productivity in ecological ways. PMID- 24159278 TI - Molecular identification of Lactobacillus spp. associated with puba, a Brazilian fermented cassava food. AB - Puba or carima is a Brazilian staple food obtained by spontaneous submerged fermentation of cassava roots. A total of 116 lactobacilli and three cocci isolates from 20 commercial puba samples were recovered on de Man, Rogosa and Sharpe agar (MRS); they were characterized for their antagonistic activity against foodborne pathogens and identified taxonomically by classical and molecular methods. In all samples, lactic acid bacteria were recovered as the dominant microbiota (7.86 +/- 0.41 log10 CFU/g). 16S-23S rRNA ARDRA pattern assigned 116 isolates to the Lactobacillus genus, represented by the species Lactobacillus fermentum (59 isolates), Lactobacillus delbrueckii (18 isolates), Lactobacillus casei (9 isolates), Lactobacillus reuteri (6 isolates), Lactobacillus brevis (3 isolates), Lactobacillus gasseri (2 isolates), Lactobacillus nagelii (1 isolate), and Lactobacillus plantarum group (18 isolates). recA gene-multiplex PCR analysis revealed that L. plantarum group isolates belonged to Lactobacillus plantarum (15 isolates) and Lactobacillus paraplantarum (3 isolates). Genomic diversity was investigated by molecular typing with rep (repetitive sequence)-based PCR using the primer ERIC2 (enterobacterial repetitive intergenic consensus). The Lactobacillus isolates exhibited genetic heterogeneity and species-specific fingerprint patterns. All the isolates showed antagonistic activity against the foodborne pathogenic bacteria tested. This antibacterial effect was attributed to acid production, except in the cases of three isolates that apparently produced bacteriocin-like inhibitory substances. This study provides the first insight into the genetic diversity of Lactobacillus spp. of puba. PMID- 24159279 TI - Prediction of acid lactic-bacteria growth in turkey ham processed by high hydrostatic pressure. AB - High hydrostatic pressure (HHP) has been investigated and industrially applied to extend shelf life of meat-based products. Traditional ham packaged under microaerophilic conditions may sometimes present high lactic acid bacteria population during refrigerated storage, which limits shelf life due to development of unpleasant odor and greenish and sticky appearance. This study aimed at evaluating the shelf life of turkey ham pressurized at 400 MPa for 15 min and stored at 4, 8 and 12 degrees C, in comparison to the non pressurized product. The lactic acid bacteria population up to 10(7) CFU/g of product was set as the criteria to determine the limiting shelf life According to such parameter the pressurized sample achieved a commercial viability within 75 days when stored at 4 degrees C while the control lasted only 45 days. Predictive microbiology using Gompertz and Baranyi and Roberts models fitted well both for the pressurized and control samples. The results indicated that the high hydrostatic pressure treatment greatly increased the turkey ham commercial viability in comparison to the usual length, by slowing down the growth of microorganisms in the product. PMID- 24159280 TI - Influence of carvacrol and thymol on the physiological attributes, enterotoxin production and surface characteristics of Staphylococcus aureus strains isolated from foods. AB - This study evaluated the influence of the phenolic compounds carvacrol (CAR) and thymol (THY) on some physiological characteristics and on the modulation of the secretion of some staphylococcal virulence factors, that is, coagulase and enterotoxin. This study also investigated possible mechanisms for the establishment of the anti-staphylococcal activity of these compounds. Sublethal concentrations (0.3 and 0.15 MUL/mL) of CAR and THY inhibited the activity of the enzymes coagulase and lipase and led to a decrease in salt tolerance. At the tested sublethal concentrations, both CAR and THY led to a total suppression of enterotoxin production. The loss of a 260-nm-absorbing material and an efflux of potassium ions occurred immediately after the addition of CAR and THY at 0.6 and 1.2 MUL/mL and increased up to 120 min of exposure. Electron microscopy of cells exposed to CAR and THY (0.6 MUL/mL) revealed that individual cells appeared to be deformed, with projections of cellular material. The observations of leakage of cellular material and an altered cell surface suggest that gross damage to a cell's cytoplasmic membrane, which results in a disruption in protein secretion, could be responsible for the anti-staphylococcal properties of CAR and THY. PMID- 24159281 TI - Detection of Salmonella spp, Salmonella Enteritidis and Typhimurium in naturally infected broiler chickens by a multiplex PCR-based assay. AB - The presence of Salmonella in the intestinal tract, on the chickens skin and among their feathers, may cause carcasses contamination during slaughtering and processing and possibly it is responsible by the introduction of this microorganism in the slaughterhouses. A rapid method to identify and monitor Salmonella and their sorovars in farm is becoming necessary. A pre-enriched multiplex polymerase chain reaction (m-PCR) assay employing specific primers was developed and used to detect Salmonella at the genus level and to identify the Salmonella enterica serovar Enteritidis (S. Enteritidis) and Salmonella enterica serovar Typhimurium (S. Typhimurium) in broiler chicken swab samples. The method was validated by testing DNA extract from 90 fresh culture cloacal swab samples from poultry chicken cultured in phosphate buffer peptone water at 37 degrees C for 18 h. The final results showed the presence of Salmonella spp. in 25% of samples, S. Enteritidis was present in 12% of the Salmonella-positive samples and S. Typhimurium in 3% of the samples. The m-PCR assay developed in this study is a specific and rapid alternative method for the identification of Salmonella spp. and allowed the observation of specific serovar contamination in the field conditions within the locations where these chickens are typically raised. PMID- 24159282 TI - Bio-preservation of ground beef meat by Enterococcus faecalis CECT7121. AB - Meat and particularly ground beef is frequently associated with Food Poisoning episodes and breeches in Food Safety. The main goal of this research was to evaluate the bactericide effect of the probiotic Enterococcus faecalis CECT7121, against different pathogens as: Escherichia coli O157:H7, Staphylococcus aureus, Clostridium perfringens and Listeria monocytogenes, inoculated in ground beef meat. Three studies were performed to evaluate the inhibition of E. faecalis CECT7121 on ground beef meat samples inoculated with pathogens: Study I: Samples (100 g meat) were inoculated with pathogens (10(3) CFU/g)) and E. faecalis CECT7121 (10(4) CFU/g) simultaneously. Study II: Samples were inoculated with E. faecalis CECT7121 24 h before the pathogens. Study III: E. faecalis CECT7121were inoculated 24 h after pathogens. The viable counts were performed at 0, 24, 48 and 72 h post-inoculation. The simultaneous inoculation of E. faecalis CECT7121 with E. coli O157:H7 strains resulted in the absence of viable counts of bacteria at 72 h post-treatment. However, when the probiotic was added 24 h before and 24 h after the pathogen E. coli O157:H7, viable cells were not detected at 24 h and 48 h post-treatment, respectively. Consistently, neither S. aureus nor Cl. perfringens viable bacteria were detected at 48 h in whole assays when inoculated with E. faecalis CECT7121. The same trend than described before was obtained after applying the 3 models assayed for L. monocytogenes. The current assays demonstrated the bactericide activity of E. faecalis CECT7121 strain on bacterial pathogens in ground beef meat. PMID- 24159283 TI - Formation of biofilm by Listeria monocytogenes ATCC 19112 at different incubation temperatures and concentrations of sodium chloride. AB - Biofilm formation can lead to various consequences in the food processing line such as contamination and equipment breakdowns. Since formation of biofilm can occur in various conditions; this study was carried out using L. monocytogenes ATCC 19112 and its biofilm formation ability tested under various concentrations of sodium chloride and temperatures. Cultures of L. monocytogenes ATCC 19112 were placed in 96-well microtitre plate containing concentration of sodium chloride from 1-10% (w/v) and incubated at different temperature of 4 degrees C, 30 degrees C and 45 degrees C for up to 60 h. Absorbance reading of crystal violet staining showed the density of biofilm formed in the 96-well microtitre plates was significantly higher when incubated in 4 degrees C. The formation of biofilm also occurs at a faster rate at 4 degrees C and higher optical density (OD 570 nm) was observed at 45 degrees C. This shows that storage under formation of biofilm that may lead to a higher contamination along the processing line in the food industry. Formation of biofilm was found to be more dependent on temperature compared to sodium chloride stress. PMID- 24159284 TI - Antagonistic activity of Lactobacillus acidophilus LA10 against Salmonella enterica serovar Enteritidis SE86 in mice. AB - Salmonella enterica serovar Enteritidis is one of the main pathogens responsible for foodborne illness in Brazil. Probiotic bacteria can play a role in defense and recovery from enteropathogenic infections. In this study, the ability of Lactobacillus acidophilus LA10 to colonise and exert antagonistic effects in the gastrointestinal tract was tested before and during experimental infection in conventional mice contaminated with S. Enteritidis (SE86). A dose of 0.1 mL containing 10(8) viable cells of SE86 and L. acidophilus LA10 was orally administered by gavage to mice. The experiment was divided into groups. As a negative control, Group 1 was administered only sterile saline solution. As a positive control, Group 2 was administered only SE86. Group 3 was first administered SE86, and after 10 days, treated with L. acidophilus LA10. Group 4 was first administered L. acidophilus LA10, and after 10 days, challenged with SE86. The results demonstrated that a significant number of SE86 cells were able to colonize the gastrointestinal tract of mice, specifically in the colon and ileum. L. acidophilus LA10 demonstrated an antagonistic effect against SE86, with better results observed for Group 3 over Group 4. Thus, L. acidophilus LA10 shows potential antagonistic effects against S. Enteritidis SE86, especially if administered after infection. PMID- 24159285 TI - Antibacterial efficacy of Nisin, Pediocin 34 and Enterocin FH99 against Listeria monocytogenes and cross resistance of its bacteriocin resistant variants to common food preservatives. AB - Antilisterial efficiency of three bacteriocins, viz, Nisin, Pediocin 34 and Enterocin FH99 was tested individually and in combination against Listeria mononcytogenes ATCC 53135. A greater antibacterial effect was observed when the bacteriocins were combined in pairs, indicating that the use of more than one LAB bacteriocin in combination have a higher antibacterial action than when used individually. Variants of Listeria monocytogenes ATCC 53135 resistant to Nisin, Pediocin 34 and Enterocin FH99 were developed. Bacteriocin cross-resistance of wild type and their corresponding resistant variants were assessed and results showed that resistance to a bacteriocin may extend to other bacteriocins within the same class. Resistance to Pediocin 34 conferred cross resistance to Enterocin FH 99 but not to Nisin. Similarly resistance to Enterocin FH99 conferred cross resistance to Pediocin 34 but not to Nisin. Also, the sensitivity of Nisin, Pediocin 34 and Enterocin FH99 resistant variants of Listeria monocytogenes to low pH, salt, sodium nitrite, and potassium sorbate was assayed in broth and compared to the parental wild-type strain. The Nisin, Pediocin 34 and Enterocin FH99 resistant variants did not have intrinsic resistance to low pH, sodium chloride, potassium sorbate, or sodium nitrite. In no case were the bacteriocin resistant Listeria monocytogenes variants examined were more resistant to inhibitors than the parental strains. PMID- 24159286 TI - Reduction of Aeromonas hidrophyla biofilm on stainless stell surface by essential oils. AB - This study demonstrates the possibility of using sanitizing detergents based on natural products for the elimination and/or reduction of Aeromonas hydrophila biofilm formed on stainless steel surfaces. The goal of this work was to determine the reduction effect of sanitizing detergents containing essential oils of Thymus vulgaris (thyme) and Cymbopogon citratus (lemongrass) on biofilm formed by A. hydrophila on AISI 304 stainless steel coupons, using UHT skimmed milk as substratum. There was adhesion and biofilm formation by A. hydrophila at 28 degrees C, presenting 7.60 log cfu.cm(-2) after the fourth day of cultivation. There was no significant difference between the lemongrass treatment and that of the thyme oil (p < 0.05). However, both treatments significantly reduced the biofilm, differing significantly from the NaOH control (p > 0.05). The treatment with lemongrass solution reduced the biofilm by 4.51 log cfu cm(-2) at 25 degrees C. The thyme detergent also reduced the number of cfu cm(-2) by 3.84 log cycles at 25 degrees C. The use of the lemongrass and thyme solutions efficiently reduced the A. hydrophila biofilm. PMID- 24159287 TI - Occurrence of Brettanomyces/Dekkera in Brazilian red wines and its correlation with ethylphenols. AB - The yeast Brettanomyces/Dekkera can cause important spoilage in wines, with the production of ethylphenols and other off-flavor compounds. This study aimed at determining the presence of this yeast and the ethylphenols produced by them in Brazilian red wines, establishing their relationship with other chemical characteristics. Isolates of Brettanomyces/Dekkera were quantified by plating 126 samples of dry red wine in selective culture medium, while ethylphenols were analyzed by solid phase extraction and GC/FID. Free and total SO2, alcohol, total dry extract, residual sugar, total and volatile acidity, and pH were also determined. Brettanomyces/Dekkera was present in 27% of samples. Ethylphenols were detected in most samples, with amounts higher than the threshold limit of 426 MUg/L found in 46.03% of samples. The majority of wine samples showed inadequate levels of SO2 and residual sugars, facts that might facilitate microbial spoilage. The passage in barrels and the grape varieties (Cabernet Sauvignon and Merlot), did not show any influence on the levels of contamination or ethylphenols contents. The prevalence of Brettanomyces/Dekkera and the concentrations of ethylphenols were high considering the sensory impact they can cause. The growth of Brettanomyces/Dekkera was dependent on the levels of SO2 and alcohol of wines. Knowledge of the contamination, the presence of ethylphenols, and their relationship with the chemical characteristics of wines can entice effective measures to prevent Brettanomyces/Dekkera and contribute to improve the general quality of Brazilian red wines. PMID- 24159288 TI - Fusarium species and fumonisins associated with maize kernels produced in Rio Grande do Sul State for the 2008/09 and 2009/10 growing seasons. AB - Ear rots caused by Fusarium spp. are among the main fungal diseases that contribute to poor quality and the contamination of maize grains with mycotoxins. This study aimed to determine the visual incidence of fungal-damaged kernels (FDKs), the incidence of two main Gibberella (a teleomorph of Fusarium) complexes (G. fujikuroi and G. zeae) associated with maize using a seed health blotter test, and the fumonisin levels, using high performance liquid chromatography, in samples of maize grains grown across 23 municipalities during the 2008/09 and 2009/10 growing seasons. Additionally, 104 strains that were representative of all of the analysed samples were identified to species using PCR assays. The mean FDK was seven per cent, and only six of the samples had levels greater than six per cent. Fusarium spp. of the G. fujikuroi complex were present in 96% of the samples, and G. zeae was present in 18% of the samples (5/27). The mean incidence of G. fujikuroi was 58%, and the incidence of G. zeae varied from 2 to 6%. FB1 was found in 58.6%, FB2 in 37.9%, and both toxins in 37.9% of the samples. The FB1 and FB2 levels were below the quantification limits for 41.3% of the samples, and the mean FB1 levels (0.66 MUg/g) were higher than the mean FB2 levels (0.42 MUg/g). The PCR identification separated the 104 isolates into three of the G. fujikuroi complex: F. verticillioides (76%), F. subglutinans (4%) and F. proliferatum (2%); and G. zeae (anamorph = F. graminearum) (18%). Our results confirmed the dominance of F. verticillioides, similar to other regions of Brazil, but they differed due to the relatively higher incidence of F. graminearum. Total fumonisin levels were below the maximum limit determined by current Brazilian regulations. PMID- 24159289 TI - Fecal indicators and bacterial pathogens in bottled water from Dhaka, Bangladesh. AB - Forty-six bottled water samples representing 16 brands from Dhaka, Bangladesh were tested for the numbers of total coliforms, fecal indicator bacteria (i.e., thermotolerant Escherichia coli and Enterococcus spp.) and potential bacterial pathogens (i.e., Aeromonas hydrophila, Pseudomonas aeruginosa, Salmonella spp., and Shigella spp.). Among the 16 brands tested, 14 (86%), ten (63%) and seven (44%) were positive for total coliforms, E. coil and Enterococcus spp., respectively. Additionally, a further nine (56%), eight (50%), six (37%), and four (25%) brands were PCR positive for A. hydrophila lip, P. aeruginosa ETA, Salmonella spp. invA, and Shigella spp. ipaH genes, respectively. The numbers of bacterial pathogens in bottled water samples ranged from 28 +/- 12 to 600 +/- 45 (A. hydrophila lip gene), 180 +/- 40 to 900 +/- 200 (Salmonella spp. invA gene), 180 +/- 40 to 1,300 +/- 400 (P. aeruginosa ETA gene) genomic units per L of water. Shigella spp. ipaH gene was not quantifiable. Discrepancies were observed in terms of the occurrence of fecal indicators and bacterial pathogens. No correlations were observed between fecal indicators numbers and presence/absence of A. hydrophila lip (p = 0.245), Salmonella spp. invA (p = 0.433), Shigella spp. ipaH gene (p = 0.078), and P. aeruginosa ETA (p = 0.059) genes. Our results suggest that microbiological quality of bottled waters sold in Dhaka, Bangladesh is highly variable. To protect public health, stringent quality control is recommended for the bottled water industry in Bangladesh. PMID- 24159290 TI - Microbial spoilage of portuguese chourico along shelf life period. AB - Microbial flora of portuguese chourico (Alentejano (A) and Ribatejano (R)) with abnormal sensorial characteristics along shelf life was studied. Mesophilic anaerobic bacteria, enterococci, mesophilic sporeformers, coliforms, coagulase positive staphylococci, sulphite reducing clostridia, Clostridium perfringens, moulds and yeasts were the most representative in both types of chourico. PMID- 24159291 TI - Comparison of phenotypic and molecular tests to identify lactic acid bacteria. AB - Twenty-nine lactic acid bacteria (LAB) isolates were submitted for identification using Biolog, API50CHL, 16S rDNA sequencing, and species-specific PCR reactions. The identification results were compared, and it was concluded that a polyphasic approach is necessary for proper LAB identification, being the molecular analyzes the most reliable. PMID- 24159292 TI - Identification and assessment of kefir yeast potential for sugar/ethanol resistance. AB - Biochemical and molecular analysis was used for identification of different kefir yeasts species from Brazil, Canada and the United States of America. The sugar/ethanol-resistant activity of the yeasts was evaluated. Saccharomyces cerevisiae and Kluyveromyces marxianus had the highest growth rates, suggesting biotechnological applications possible for these strains. PMID- 24159293 TI - Comparison of methods for the detection of biofilm formation by Staphylococcus aureus isolated from bovine subclinical mastitis. AB - Biofilm formation is considered to be a selective advantage for Staphylococcus aureus mastitis isolates by facilitating bacterial persistence in the udder. It requires attachment to mammary epithelium, proliferation and accumulation of cells in multilayers. The objective of this study was to determine the sensitivity and specificity of three techniques for the detection of S. aureus biofilm-positive strains. Two phenotypic tests, including growth on microtitre plates and Congo red agar, were compared with a PCR technique using 94 S. aureus strains obtained from cows with subclinical mastitis from two farms in the state of Sao Paulo. These strains were characterised by in vitro slime production on Congo red agar, biofilm formation on microtitre plates and the presence of the icaA and icaD genes. The results revealed that 85% of the isolates tested produced slime on the Congo red agar, 98.9% of the isolates produced biofilms in vitro by adhering to sterile 96-well "U" bottom polystyrene tissue culture plates, and 95.7% of the isolates carried the icaA and icaD genes. The results of the phenotypic tests for biofilm formation were compared with those of the molecular analysis, and the sensitivity and specificity of the Congo red agar test were 88.9% and 100%, respectively, while those of the microtitre plate test were 100% and 25%, respectively. When the phenotypic methods for the detection of biofilm producers, namely growth on microtitre plates and Congo red agar, were compared, the sensitivity and specificity were 86% and 100%, respectively. Therefore, growth on Congo red agar and the microtitre plate test are methods that could be used to determine whether an isolate has the potential for biofilm production. PMID- 24159294 TI - Zoonoses in humans from small rural properties in Jataizinho, Parana, Brazil. AB - The aim of this study was to conduct a serological survey for Lyme diseases, brucellosis, leptospirosis and toxoplasmosis and identify the risk variables related to these zoonoses in humans living in the rural area of Jataizinho, state of Parana, Brazil. A total of 63 rural properties were surveyed. Additionally, 207 serum samples collected from these rural area inhabitants were tested for indirect immunofluorescence (IFI) and western blots (WB) were performed to detect Borrelia burgdorferi (sensu lato); a tamponated acidified antigen test (AAT) and 2-mercaptoethanol (2-ME) were used to detect antibodies of Brucella abortus; the microscopic agglutination test (MAT) was carried out to detect antibodies anti Leptospira spp. and IFI was used to find antibodies of Toxoplasma gondii. Two of the samples (0.96%) were reactive for Lyme borreliosis, three (1.4%) for brucellosis, 25 (12.1%) for leptospirosis and 143 (69.1%) for toxoplasmosis. Although the town of Jataizinho has a human development index (IDH) that was considered to be average (0.733) in the state of Parana, the low social, economic and cultural conditions of the population from small rural properties have resulted in lack of basic information on animal health and direct or indirect contact with the various species of domestic animals, wildlife and ticks have probably contributed to the prevalence levels found. These results show the need for additional regional studies in order to determine the epidemiological characteristics of these diseases as well as their respective vectors and reservoirs so that effective prophylaxis can be administered in the human population. PMID- 24159295 TI - Detection of toxins A/B and isolation of Clostridium difficile and Clostridium perfringens from dogs in Minas Gerais, Brazil. AB - The objective of this study was to detect C. difficile A/B toxins and to isolate strains of C. perfringens and C. difficile from diarrheic and non-diarrheic dogs in Brazil. Stool samples were collected from 57 dogs, 35 of which were apparently healthy, and 22 of which were diarrheic. C. difficile A/B toxins were detected by ELISA, and C. perfringens and C. difficile were identified by multiplex PCR. C. difficile A/B toxins were detected in 21 samples (36.8%). Of these, 16 (76.2%) were from diarrheic dogs, and five (23.8%) were from non-diarrheic dogs. Twelve C. difficile strains (21.1%) were isolated, of which ten were A(+)B(+) and two were A(-)B(-). All non-toxigenic strains were isolated from non-diarrheic animals. The binary toxin gene cdtB was found in one strain, which was A(+)B(+) and was derived from a non-diarrheic dog. C. perfringens strains were isolated from 40 samples (70.2%). Of these, 18 (45%) were from the diarrheic group, and 22 (55%) belonged to the non-diarrheic group. All isolates were classified as C. perfringens type A and there was an association between the detection of the cpe gene and the presence of diarrhea. Interestingly, ten strains (25%) were positive for the presence of the cpb2 gene. The high rate of detection of the A/B toxins in non-diarrheic dogs suggests the occurrence of subclinical disease in dogs or carriage of its toxins without disease. More studies are needed to elucidate the epidemiology of C. difficile and C. perfringens in dogs and to better our understanding of C. difficile as a zoonotic agent. This is the first study to report the binary toxin gene in C. difficile strains isolated from dogs in Brazil. PMID- 24159296 TI - Clinical and mycological analysis of dog's oral cavity. AB - The oral microbiota of humans and animals is made up of a wide variety of yeasts and bacteria, but microbiota of dogs is not totally described. Although such identification is an important step to establish the etiopathogenesis and adequate therapy for the periodontal disease The aim of this study was to evaluate and correlate oral alterations with the presence of yeasts in oral cavity of female dogs. After clinical evaluation samples from healthy and from dogs with oral diseases were obtained from three different oral sites by swabs, curettes, millimeter periodontal probes and HA membrane tip in cellulose ester. Yeast identification was performed through macroscopic and microscopic colony features and biochemical tests. Dental calculus was the most prevalent occurrence in the oral cavity of 59 females. However, the isolation of yeasts was significantly higher (p < 0.05) in animals suffering from halitosis. Eleven yeast species were identified, namely: Malassezia pachydermatis, Rhodotorula spp., Candida albicans, C. catenulata, C. famata, C. guilliermondii, C. parapsilosis, C. intermedia, Trichosporon asahii, T. mucoides and Cryptococcus albidus. It could be concluded that the yeasts are part of the microbiota from the different sites of the oral cavity of the female canines studied without causing any significant alterations except halitosis. PMID- 24159297 TI - The prevalence of swine enteropathogens in Brazilian grower and finish herds. AB - Diarrhoea among growing and finishing pigs is an important problem in many herds. The prevalence of L. intracellularis, B. pilosicoli, B. hyodysenteriae, Salmonella spp., enterotoxigenic E. coli, Trichuris suis and the occurrence of mixed infection were investigated. Fecal samples for forty-six herds with diarrhea or a history of diarrhea were randomly collected in Minas Gerais state, Brazil. The enteric pathogens were detected by culture (E. coli and Salmonella sp.), PCR (L. intracellularis and Brachyspira spp.) and eggs counts (T. suis). The overall herd prevalence of L. intracellularis, Salmonella enterica serotype Typhimurium and enterotoxigenic E. coli were 19.56%, 6.52%, 10.86% respectively. Mixed infection was diagnosed in 30.43% of herds, and L. intracellularis and Salmonella enterica serotype Typhimurium are main pathogens association (10.87%). B. pilosicoli was diagnosed only in two herds, always associated with mixed infections. B. hyodysenteriae and T. suis were not demonstrated in any sample. These pathogens have been reported world-wide but studies regarding epidemiology in Brazil are few. This study contributes to establish of prevention programs for the control enteropathogens in grower finish herds in Brazil. PMID- 24159298 TI - Relationship between Paratuberculosis and the microelements Copper, Zinc, Iron, Selenium and Molybdenum in Beef Cattle. AB - To study the deficiency of minerals and its relationship with Paratuberculosis, blood, serum, and fecal samples were obtained from 75 adult bovines without clinical symptoms of the disease and from two bovines with clinical symptoms of the disease, from two beef herds with a previous history of Paratuberculosis in the Province of Buenos Aires, Argentina. Serum samples were processed by ELISA and feces were cultured in Herrolds medium. Copper, zinc and iron in serum were quantified by spectrophotometry and selenium was measured by the activity of glutathione peroxidase. We also determined copper, zinc, iron and molybdenum concentrations in pastures and the concentration of sulfate in water. Mycobacterium avium subsp paratuberculosis (Map) was isolated from 17.3% of fecal samples of asymptomatic animals and from the fecal samples from the two animals with clinical symptoms. All the Map-positive animals were also ELISA-positive or suspect, and among them, 84.6% presented low or marginal values of selenium and 69.2% presented low or marginal values of copper. The two animals with clinical symptoms, and isolation of Map from feces and organs were selenium-deficient and had the lowest activity of glutathione peroxidase of all the animals from both herds. All the animals negative to Map in feces and negative to ELISA had normal values of Se, while 13.8% of animals with positive ELISA or suspect and culture negative presented low levels of Se. Half of the animals that were negative both for ELISA and culture in feces were deficient in copper but none of them presented low values of selenium. The content of molybdenum and iron in pasture was high, 2.5 ppm and 1.13 ppm in one herd and 2.5 ppm and 2.02 ppm in the other, respectively, whereas the copper:molybdenum ratio was 1.5 and 5.2, respectively. These results do not confirm an interaction between imbalances of the micronutrients and clinical Paratuberculosis, but show evidence of the relationship between selenium deficiencies in animals with Map infection and ELISA positive results. PMID- 24159299 TI - Identification and antimicrobial susceptibility patterns of Pasteurella multocida isolated from chickens and japanese quails in Brazil. AB - A study was performed to verify the presence of Pasteurella multocida in eight different poultry groups of 90 birds each. Groups I to IV were chickens (I being > 6 weeks of age with a history of respiratory illness, II > 6 weeks of age and free of respiratory illness, III < 6 weeks of age with respiratory illness and IV being < 6 weeks of age and with no respiratory illness. Groups V to VIII had the matching characteristics of Groups I to V but consisted of Japanese Quails. The P. multocida isolation rate from the groups was as follows; Group I 56/90 (62.3%) Group II 18/90 (20.0%), Group III 12/90 (13.3%), Group IV 3/90 (3.33%), Group V 8/90 (8.88%), Group VI 2/90 (2.22%) Group VII 2/90 (2.22%) and Group VIII 1/90 (1.11%). These isolation rates were not significantly different within the groups of a bird type but the overall chicken isolation rate was significantly higher than the quail isolation rate (p < 0.01). All isolates were examined for their sensitivity to four antimicrobial agents. The results showed only low levels of resistance to the agents tested. The highest level of resistance detected was to cephalothin (5.1% of isolates) followed by amikacin (3.4%). PMID- 24159300 TI - Characterization of a virulent Leptospira interrogans strain isolated from an abandoned swimming pool. AB - Pathogenic Leptospira spp. are the etiological agents of leptospirosis, an important disease of both humans and animals. In urban settings, L. interrogans serovars are the predominant cause of disease in humans. The purpose of this study was to characterize a novel Leptospira isolate recovered from an abandoned swimming pool. Molecular characterization through sequencing of the rpoB gene revealed 100% identity with L. interrogans and variable-number tandem-repeat (VNTR) analysis resulted in a banding pattern identical to L. interrogans serogroup Icterohaemorrhagiae, serovar Copenhageni or Icterohaemorrhagiae. The virulence of the strain was determined in a hamster model of lethal leptospirosis. The lethal dose 50% (LD50) was calculated to be two leptospires in female hamsters and a histopathological examination of infected animals found typical lesions associated with severe leptospirosis, including renal epithelium degeneration, hepatic karyomegaly, liver-plate disarray and lymphocyte infiltration. This highly virulent strain is now available for use in further studies, especially evaluation of vaccine candidates. PMID- 24159301 TI - Isolation of dermatophytes in wild felids from screening centers. AB - The aim of this study was detect the presence of dermatophyte fungi on wild felids from screening centers. Samples were taken from 30 animals, assembled in two groups: "free-ranging" and "transitory captivity". The dermatophytes (Trichophyton genus), isolated from two felids (6.6%), both of the group "free ranging". PMID- 24159302 TI - Susceptibility variation of Malassezia pachydermatis to antifungal agents according to isolate source. AB - Malassezia pachydermatis is associated with dermatomycoses and otomycosis in dogs and cats. This study compared the susceptibility of M. pachydermatis isolates from sick (G1) and healthy (G2) animals to azole and polyene antifungals using the M27-A3 protocol. Isolates from G1 animals were less sensitive to amphotericin B, nystatin, fluconazole, clotrimazole and miconazole. PMID- 24159303 TI - Assessment of the effectiveness of the PPD-mallein produced in Brazil for diagnosing glanders in mules. AB - To assess the potency of the PPD-mallein produced in Brazil, five animals were from a property identified as a focus of glanders. These animals had suggestive clinical signs of the disease and the other five, from a property free from glanders, showed no clinical signs and were serology negative (control group). PPD-mallein from Burkholderia mallei was obtained by precipitation with trichloroacetic acid and ammonium sulfate. The animals were inoculated according to the criteria established by Department of Agriculture, Livestock and Supply (MAPA) for the diagnosis of glanders. After 48 h of application of PPD-mallein, there was swelling in the area of application, presence of ocular secretion and tears in sick animals. The control group showed no inflammatory reaction at the site of inoculation of PPD-mallein. This immunogen produced in Brazil and still being tested was effective for identifying the infection in true positive animals and excluding the truly negative ones, being a new possibility for diagnosis and control of glanders. PMID- 24159304 TI - Submerged fermentation of Lactobacillus rhamnosus YS9 for gamma-aminobutyric acid (GABA) production. AB - gamma-Aminobutyric acid (GABA) is a major inhibitory neurotransmitter in central nervous system, and its application in drugs and functional foods has attracted great attention. To enhance production of gamma-aminobutyric acid, Lactobacillus rhamnosus YS9, a strain isolated from Chinese traditional fermented food pickled vegetable, was grown under submerged fermentation. Its cultivation conditions were investigated. When culture pH condition was adjusted to the optimal pH of glutamate decarboxylase activity, culture of Lb. rhamnosus YS9 in medium supplemented with 200 mM of monosodium glutamate and 200 MUM of pyridoxal phosphate (PLP), produced 187 mM of GABA. PMID- 24159305 TI - Enhancement of chitosanase production by cell immobilization of Gongronella sp. JG. AB - Chitosanase production of Gongronella sp. JG cells immobilized in calcium alginate gel and polyurethane foam was compared with that of the free cells, there was a 60% increase in the enzyme yield (2429 U/L) compared to the highest yield obtained from free cells (1513 U/L). The optimal immobilization parameters (concentrations of sodium alginate, calcium chloride, bead inoculums, bead diameter, etc) for the enhanced production of chitosanase were determined as: sodium alginate 2% (w/v), 0.1 M calcium chloride, inoculum 10 mL beads to 100 mL production media and 2.7 mm bead diameter. Maximum chitosanase production was achieved with initial pH of 5.5 and temperature of 30 degrees C. The alginate beads had well stability, retained 85% ability of enzyme production even after 7 cycles of repeated batch fermentation. These results showed the immobilization technique was a feasible and economical method for chitosansase production by Gongronella sp. JG. PMID- 24159306 TI - Minerals consumption by Acetobacter xylinum on cultivation medium on coconut water. AB - The objective of this work is to verifying the consume of the minerals K, Na, Fe, Mg, P, S-SO4 (-2), B, N Total Kjedahl (NTK), NO3 (-)-N, and NH4 (+)-N in the production of bacterial cellulose by Acetobacter xylinum, according to the medium and the manner of cultivation. The fermentative process was in ripe and green coconut water. K and Na were determined by flame emission photometry, Mg and Fe by atomic absorption spectrophotometry, P by molecular absorption spectrophotometry, S-SO4 (-2) by barium sulphate turbidimetry, B by Azomethin-H method, NTK by Kjeldahl method, N-NO3 (-) and N-NH4 (+) by vapor distillation with magnesium oxide and Devarda's alloy, respectively. In Fermentation of ripe coconut water there were higher consumption of K (69%), Fe (84,3%), P (97,4%), S SO2 (-2) (64,9%), B (56,1%), N-NO3 (-) (94,7%) and N-NH4 (+) (95,2%), whereas coconut water of green fruit the most consumed ions were Na (94,5%), Mg (67,7%) and NTK (56,6%). The cultivation under agitation showed higher mineral consumption. The higher bacterial cellulose production, 6 g.L(-1), was verified in the coconut water fermentative in ripe fruit, added KH2PO4, FeSO4 and NaH2PO4 kept under agitation. PMID- 24159307 TI - Secretion of laccase and manganese peroxidase by Pleurotus strains cultivate in solid-state using Pinus spp. sawdust. AB - Pleurotus species secrete phenol oxidase enzymes: laccase (Lcc) and manganese peroxidase (MnP). New genotypes of these species show potential to be used in processes aiming at the degradation of phenolic compounds, polycyclic aromatic hydrocarbons and dyes. Hence, a screening of some strains of Pleurotus towards Lcc and MnP production was performed in this work. Ten strains were grown through solid-state fermentation on a medium based on Pinus spp. sawdust, wheat bran and calcium carbonate. High Lcc and MnP activities were found with these strains. Highest Lcc activity, 741 +/- 245 U gdm(-1) of solid state-cultivation medium, was detected on strain IB11 after 32 days, while the highest MnP activity occurred with strains IB05, IB09, and IB11 (5,333 +/- 357; 4,701 +/- 652; 5,999 +/- 1,078 U gdm(-1), respectively). The results obtained here highlight the importance of further experiments with lignocellulolytic enzymes present in different strains of Pleurotus species. Such results also indicate the possibility of selecting more valuable strains for future biotechnological applications, in soil bioremediation and biological biomass pre-treatment in biofuels production, for instance, as well as obtaining value-added products from mushrooms, like phenol oxidase enzymes. PMID- 24159309 TI - Bioethanol production from rice straw residues. AB - A rice straw - cellulose utilizing mold was isolated from rotted rice straw residues. The efficient rice straw degrading microorganism was identified as Trichoderma reesei. The results showed that different carbon sources in liquid culture such as rice straw, carboxymethyl cellulose, filter paper, sugar cane bagasse, cotton stalk and banana stalk induced T. reesei cellulase production whereas glucose or Potato Dextrose repressed the synthesis of cellulase. T. reesei cellulase was produced by the solid state culture on rice straw medium. The optimal pH and temperature for T. reesei cellulase production were 6 and 25 degrees C, respectively. Rice straw exhibited different susceptibilities towards cellulase to their conversion to reducing sugars. The present study showed also that, the general trend of rice straw bioconversion with cellulase was more than the general trend by T. reesei. This enzyme effectively led to enzymatic conversion of acid, alkali and ultrasonic pretreated cellulose from rice straw into glucose, followed by fermentation into ethanol. The combined method of acid pretreatment with ultrasound and subsequent enzyme treatment resulted the highest conversion of lignocellulose in rice straw to sugar and consequently, highest ethanol concentration after 7 days fermentation with S. cerevisae yeast. The ethanol yield in this study was about 10 and 11 g.L(-1). PMID- 24159308 TI - Optimizing a culture medium for biomass and phenolic compounds production using Ganoderma lucidum. AB - The present work was aimed at optimizing a culture medium for biomass production and phenolic compounds by using Ganoderma lucidum. The culture was optimized in two stages; a Plackett-Burman design was used in the first one for identifying key components in the medium and a central composite design was used in the second one for optimizing their concentration. Both responses (biomass and phenolic compounds) were simultaneously optimized by the latter methodology regarding desirability, and the optimal concentrations obtained were 50.00 g/L sucrose, 13.29 g/L yeast extract and 2.99 g/L olive oil. Maximum biomass production identified in these optimal conditions was 9.5 g/L and that for phenolic compounds was 0.0452 g/L, this being 100% better than that obtained in the media usually used in the laboratory. Similar patterns regarding chemical characterization and biological activity towards Aspergillus sp., from both fruiting body and mycelium-derived secondary metabolites and extracts obtained in the proposed medium were observed. It was shown that such statistical methodologies are useful for optimizing fermentation and, in the specific case of G. lucidum, optimizing processes for its production and its metabolites in submerged culture as an alternative to traditional culture. PMID- 24159310 TI - Production and partial characterization of serine and metallo peptidases secreted by Aspergillus fumigatus Fresenius in submerged and solid state fermentation. AB - Enzyme production varies in different fermentation systems. Enzyme expression in different fermentation systems yields important information for improving our understanding of enzymatic production induction. Comparative studies between solid-state fermentation (SSF) using agro-industrial waste wheat bran and submerged fermentation (SmF) using synthetic media were carried out to determinate the best parameters for peptidase production by the fungus Aspergillus fumigatus Fresen. Variables tested include: the concentration of carbon and protein nitrogen sources, the size of the inoculum, the pH of the media, temperature, and the length of the fermentation process. The best peptidase production during SSF was obtained after 96 hours using wheat bran at 30 degrees C with an inoculum of 1 * 10(6) spores and yielded 1500 active units (U/mL). The best peptidase production using SmF was obtained after periods of 72 and 96 hours of fermentation in media containing 0.5% and 0.25% of casein, respectively, at a pH of 6.0 and at 30 degrees C and yielded 40 U/mL. We also found examples of catabolite repression of peptidase production under SmF conditions. Biochemical characterization of the peptidases produced by both fermentative processes showed optimum activity at pH 8.0 and 50 degrees C, and also showed that their proteolytic activity is modulated by surfactants. The enzymatic inhibition profile using phenylmethylsulfonyl fluoride (PMSF) in SmF and SSF indicated that both fermentative processes produced a serine peptidase. Additionally, the inhibitory effect of the ethylene-diaminetetraacetic acid (EDTA) chelating agent on the peptidase produced by SmF indicated that this fermentative process also produced a metallopeptidase. PMID- 24159311 TI - Computation of interactive effects and optimization of process parameters for alkaline lipase production by mutant strain of Pseudomonas aeruginosa using response surface methodology. AB - Alkaline lipase production by mutant strain of Pseudomonas aeruginosa MTCC 10,055 was optimized in shake flask batch fermentation using response surface methodology. An empirical model was developed through Box-Behnken experimental design to describe the relationship among tested variables (pH, temperature, castor oil, starch and triton-X-100). The second-order quadratic model determined the optimum conditions as castor oil, 1.77 mL.L(-1); starch, 15.0 g.L(-1); triton X-100, 0.93 mL.L(-1); incubation temperature, 34.12 degrees C and pH 8.1 resulting into maximum alkaline lipase production (3142.57 U.mL(-1)). The quadratic model was in satisfactory adjustment with the experimental data as evidenced by a high coefficient of determination (R(2)) value (0.9987). The RSM facilitated the analysis and interpretation of experimental data to ascertain the optimum conditions of the variables for the process and recognized the contribution of individual variables to assess the response under optimal conditions. Hence Box-Behnken approach could fruitfully be applied for process optimization. PMID- 24159312 TI - Phenotypic and genotypic characterization of Streptococcus agalactiae in pregnant women. First study in a province of Argentina. AB - Group B Streptococcus (GBS) is the leading cause of neonatal infections. Our purpose was to characterize GBS colonization in pregnant women, current serotypes, resistance phenotypes and genes associated with virulence. In Misiones, Argentina, there are no previous data on this topic. Vaginal-rectal swabs from 3125 pregnant women were studied between 2004 and 2010. GBS strains were identified by conventional and serological methods (Phadebact Strep B Test, ETC International, Bactus AB, Sweden). Serotypes were detected using Strep-B Latex (Statens Serum Institut, Denmark). Resistance phenotypes were determined by the double-disk test. Genes were studied by PCR. Maternal colonization was 9.38%. Resistance to erythromycin was 11.6%, and the constitutive phenotype was the predominant one. Serotype Ia was the most frequent, whereas serotypes IV, VI, VII and VIII were not detected. The lmb, bca and hylB genes were detected in more than 79% of the strains. In this study, the colonization rate with GBS and the serotype distribution were compared with studies reported in other areas of the country. The high resistance to erythromycin in Misiones justifies performing antibiotic susceptibility testing. The serotype distribution, the genes encoding putative virulence factors, and the patterns of resistance phenotypes of GBS may vary in different areas. They thus need to be evaluated in each place to devise strategies for prevention. PMID- 24159313 TI - Effect of sub-minimum inhibitory concentrations of ciprofloxacin, amikacin and colistin on biofilm formation and virulence factors of Escherichia coli planktonic and biofilm forms isolated from human urine. AB - The aim of this study was to determine the effect of subinhibitory concentrations (sub-MICs) of ciprofloxacin, amikacin and colistin on biofilm formation, motility, curli fimbriae formation by planktonic and biofilm cells of E. coli strains isolated from the urine of patients with various urinary system infections. Quantification of biofilm formation was carried out using a microtiter plate assay and a spectrophotometric method. Bacterial enumeration was used to assess the viability of bacteria in the biofilm. Curli expression was determined by using YESCA agar supplemented with congo red. Using motility agar the ability to move was examined. All the antibiotics used at sub-MICs reduced biofilm formation in vitro, decreased the survival of bacteria, but had no effect on the motility of planktonic as well as biofilm cells. The inhibitory effect of sub-MICs of antimicrobial agents on curli fimbriae formation was dependent on the form in which the bacteria occurred, incubation time and antibiotic used. Our results clearly show that all the three antibiotics tested reduce biofilm production, interfere with curli expression but do not influence motility. This study suggests that ciprofloxacin, amikacin and colistin may be useful in the treatment of biofilm-associated infections caused by E. coli strains. PMID- 24159314 TI - EsxA might as a virulence factor induce antibodies in patients with Staphylococcus aureus infection. AB - Staphylococcus aureus (S. aureus) is an important human pathogen, which commonly causes the acquired infectious diseases in the hospital and community. Effective and simple antibiotic treatment against S. aureus-related disease becomes increasingly difficult. Developing a safe and effective vaccine against S. aureus has become one of the world's hot spots once again. The key issue of developing the vaccine of S. aureus is how to find an ideal key pathogenic gene of S. aureus. It was previously suggested that EsxA might be a very important factor in S. aureus abscess formation in mice, but clinical experimental evidence was lacking. We therefore expressed EsxA protein through prokaryotic expression system and purified EsxA protein by Ni-affinity chromatography. ELISA was used to detect the anti-EsxA antibodies in sera of 78 patients with S. aureus infection and results showed that the anti-EsxA antibodies were positive in the sera of 19 patients. We further analyzed the EsxA positive antibodies related strains by antimicrobial susceptibility assay and found that all of the corresponding strains were multi-drug resistant. Among those multi-drug resistant strains, 73.7% were resistant to MRSA. The results indicated EsxA is very important in the pathogenesis of S. aureus. We suggested that the EsxA is very valuable as vaccine candidate target antigens for prevention and control of S. aureus infection. PMID- 24159315 TI - Molecular basis of high-level ciprofloxacin resistance in Neisseria gonorrhoeae strains from Shandong Province, China. AB - In the study, the ciprofloxacin resistance rate was 100%. High-level ciprofloxacin resistance rate was 63.55%. Sixteen different mutation patterns involved in the formation of ciprofloxacin resistance were identified. The most prevalent were patterns P7 (25.2%), P8 (15.0%), P9 (11.2%), P1 (10.3%), and P5 (10.3%). All of the 107 NG isolates analyzed for mutations in the study have demonstrated a change of Ser-91 -> Phe in the gyrA gene, and all except one have demonstrated a change in position 95 of the amino acid sequence. All of the 68 high-level QRNG isolates had double mutations in gyrA gene combined with a single or two mutations in parC gene. It is most important that a new mutation site of Ile-97 -> Met in gyrA and a new mutation of Leu-106 -> Ile in parC were found in the study, both leading to high-level ciprofloxacin resistance (MIC values, 8 MUg/mL, 32 MUg/mL, respectively). Therefore, we confim that gyrA mutations are necessary for the fluoroquinolone resistance phenotype and parC mutations are correlated intimately with high-level fluoroquinolone resistance. In China fluoroquinolone resistance in Neisseria gonorrhoeae strains is very serious and the new mutation sites in the fluoroquinolone resistance-determining regions emerge more and more quickly. Hence, in China fluoroquinolones, which are used to treat gonorrhoea presently, should be substituted by a new antibiotics. PMID- 24159316 TI - Detection of Staphylococcus aureus with an intermediate profile to vancomycin (VISA) isolate from Santa Maria, RS. AB - Twenty-three isolates of Staphylococcus aureus resistant to methicillin have been analyzed, being found a clinical isolate of VISA through microdilution technique. The others techniques were unable to detect such isolates. This is the first study that shows the presence of VISA in clinical isolates in the city of Santa Maria-RS. PMID- 24159317 TI - Comparison of resazurin microtiter assay performance and BACTEC MGIT 960 in the susceptibility testing of Brazilian clinical isolates of Mycobacterium tuberculosis to four first-line drugs. AB - We assessed the performance of REMA in comparison with BACTEC MGIT 960 in the susceptibility testing of 80 Mycobacterium tuberculosis clinical isolates from Clemente Ferreira Institute against four drugs. REMA proved to be a rapid and accurate method, providing excellent correlation with BACTEC MGIT 960, with the exception of results for the ethambutol drug. PMID- 24159318 TI - Measuring of Mycobacterium tuberculosis growth. A correlation of the optical measurements with colony forming units. AB - The quantification of colony forming units (cfu), turbidity, and optical density at 600 nm (OD600) measurements were used to evaluate Mycobacterium tuberculosis growth. Turbidity and OD600 measurements displayed similar growth curves, while cfu quantification showed a continuous growth curve. We determined the cfu equivalents to McFarland and OD600 units. PMID- 24159319 TI - Properties of catechol 1,2-dioxygenase in the cell free extract and immobilized extract of Mycobacterium fortuitum. AB - Polycyclic aromatic hydrocarbons (PAH) are carcinogenic compounds which contaminate water and soil, and the enzymes can be used for bioremediation of these environments. This study aimed to evaluate some environmental conditions that affect the production and activity of the catechol 1,2-dioxygenase (C12O) by Mycobacterium fortuitum in the cell free and immobilized extract in sodium alginate. The bacterium was grown in mineral medium and LB broth containing 250 mg L(-1) of anthracene (PAH). The optimum conditions of pH (4.0-9.0), temperature (5-70 degrees C), reaction time (10-90 min) and the effect of ions in the enzyme activity were determined. The Mycobacterium cultivated in LB shown higher growth and the C12O activity was two-fold higher to that in the mineral medium. To both extracts the highest enzyme activity was at pH 8.0, however, the immobilized extract promoted the increase in the C12O activity in a pH range between 4.0 and 8.5. The immobilized extract increased the enzymatic activity time and showed the highest C12O activity at 45 degrees C, 20 degrees C higher than the greatest temperature in the cell free extract. The enzyme activity in both extracts was stimulated by Fe(3+), Hg(2+) and Mn(2+) and inhibited by NH(4+) and Cu(2+), but the immobilization protected the enzyme against the deleterious effects of K(+) and Mg(2+) in tested concentrations. The catechol 1,2-dioxygenase of Mycobacterium fortuitum in the immobilized extract has greater stability to the variations of pH, temperature and reaction time, and show higher activity in presence of ions, comparing to the cell free extract. PMID- 24159320 TI - Mucorales from the semiarid of Pernambuco, Brazil. AB - Nineteen taxa of Mucorales, belonging to Absidia, Apophysomyces, Cunninghamella, Fennellomyces, Lichtheimia, Mucor, Mycotypha, Rhizopus and Syncephalastrum were isolated from 36 composite soil samples in three semiarid areas in the State of Pernambuco (Triunfo, Cabrobo and Belem de Sao Francisco), Northeast Brazil, which are characterized by Caatinga vegetation. Triunfo is preserved, whereas Cabroro and Belem de Sao Francisco are experiencing low and severe desertification processes, respectively. Mucorales were isolated in Petri dishes in triplicate from 5 mg samples of soil placed on the surface of wheat germ agar plus chloramphenicol and Cercobin [Dimethyl 4,49-(103 phenylene) bis (3 thioallophanate)] medium. The plates were left on a bench at room temperature (28 +/- 2 degrees C) for 72 h of alternating dark and light periods. Absidia cylindrospora presented the highest amount of CFU/g of soil, followed by L. hyalospora, C. phaeospora and C. echinulata var. echinulata. The latter, and R. microsporus var. microsporus, presented the highest frequencies of occurrence. Soils from Triunfo showed higher diversity of Mucorales than the samples from the other areas, although without differing statistically in relation to species richness. The communities of Mucorales from the degraded areas were more similar, while that from the preserved area was quite different. Most of the identified specimens have been commonly isolated from soil in other Brazilian regions, which indicates that they are not endemic of the semiarid. Eleven taxa are registered for the first time in this ecosystem, while F. heterothallicus is reported for the first time in Brazil. PMID- 24159321 TI - Hexavalent chromium reduction by aerobic heterotrophic bacteria indigenous to chromite mine overburden. AB - Microbiological analysis of overburden samples collected from chromite mining areas of Orissa, India revealed that they are rich in microbial density as well as diversity and dominated by Gram-negative (58%) bacteria. The phenotypically distinguishable bacterial isolates (130) showed wide degree of tolerance to chromium (2-8 mM) when tested in peptone yeast extract glucose agar medium. Isolates (92) tolerating 2 mM chromium exhibited different degrees of Cr(+6) reducing activity in chemically defined Vogel Bonner (VB) broth and complex KSC medium. Three potent isolates, two belonging to Arthrobacter spp. and one to Pseudomonas sp. were able to reduce more than 50 and 80% of 2 mM chromium in defined and complex media respectively. Along with Cr(+6) (MIC 8.6-17.8 mM), the isolates showed tolerance to Ni(+2), Fe(+3), Cu(+2) and Co(+2) but were extremely sensitive to Hg(+2) followed by Cd(+2), Mn(+2) and Zn(+2). In addition, they were resistant to antibiotics like penicillin, methicillin, ampicillin, neomycin and polymyxin B. During growth under shake-flask conditions, Arthrobacter SUK 1201 and SUK 1205 showed 100% reduction of 2 mM Cr(+6) in KSC medium with simultaneous formation of insoluble precipitates of chromium salts. Both the isolates were also equally capable of completely reducing the Cr(+6) present in mine seepage when grown in mine seepage supplemented with VB concentrate. PMID- 24159322 TI - Isolation, morphological and molecular characterization of phytate-hydrolysing fungi by 18S rDNA sequence analysis. AB - Phytate is the primary storage form of phosphate in plants. Monogastric animals like poultry, pigs and fishes have very low or no phytase activities in their digestive tracts therefore, are incapable to efficiently utilize phytate phosphorus from the feed. Phytase from microbial sources are supplemented to feedstuff of these to increase the uptake of phytate phosphorus. In the present work efforts were made to isolate and characterize proficient phytase producing fungi from soil. Phytase producing fungi were isolated using phytate specific medium. Fungal isolates were selected according to their higher phytase activities. These isolates were further characterized and identified by morphological and microscopic analysis and confirmed by amplification of 18S rRNA gene, using specific primers. This gene was subsequently sequenced and phylogenetic affiliations were assigned. Fungal isolates were identified as various species of Aspergillus. Phytases from these fungi could be utilized as a feed additive in poultry and swine industries. PMID- 24159323 TI - 16S rRNA gene-based identification of microbiota associated with the parthenogenetic troglobiont sand fly Deanemyia maruaga (Diptera, Psychodidae) from central Amazon, Brazil. AB - Bacteria associated with the parthenogenetic troglobiont sand fly Deanemyia maruaga were characterized by sequencing cloned 16S rDNA PCR products. Eleven novel partial 16S rDNA sequences, with varying degrees of similarity to Actinobacteria, were identified. None of the sequences identified had homology to those known from parthenogenesis-inducing bacteria. PMID- 24159324 TI - Diversity of the candidate phylum Poribacteria in the marine sponge Aplysina fulva. AB - Poribacterial clone libraries constructed for Aplysina fulva sponge specimens were analysed with respect to diversity and phylogeny. Results imply the coexistence of several, prevalently "intra-specific" poribacterial genotypes in a single sponge host, and suggest quantitative analysis as a desirable approach in studies of the diversity and distribution of poribacterial cohorts in marine sponges. PMID- 24159325 TI - Human coronavirus ocurrence in different populations of Sao Paulo: A comprehensive nine-year study using a pancoronavirus RT-PCR assay. AB - Human coronaviruses (HCoVs) are considered one of the most common respiratory viruses associated with respiratory tract illnesses. An emergent human coronavirus was identified as the causal agent of an epidemic of severe acute respiratory syndrome (SARS) during 2002-2003. The severity of the disease combined with its rapid spread requires the continuous surveillance of coronaviruses in worldwide populations. Epidemiological and clinical data of HCoVs infectious in the Brazilian population are scarce and restricted to one or two groups of patients. Our study aimed to investigate retrospectively the presence of HCoVs in different populations of Sao Paulo presenting acute respiratory tract infections (ARIs) during the years of 2001-2010. A pancoronavirus RT-PCR was performed in this study. Coronaviruses were detected in 126 (11.5%) of 1,087 specimens. Peaks detection frequency was observed during 2002-2004 and 2008-2009, with the highest detection in 2008. The prevalence of HCoVs was higher among children with heart diseases (24.6%), patients under stem cell transplantation program (24.3%) and renal transplanted patients (20.2%). Coryza, cough and fever were the most common symptoms at presentation of positive cases and wheezing, a lower respiratory tract infection symptom was reported by 12% of the total, and 27% of high at-risk patients. HCoVs may have an important role among patients with underlying conditions and transplanted ones. PMID- 24159326 TI - Skin parameter map retrieval from a dedicated multispectral imaging system applied to dermatology/cosmetology. AB - In vivo quantitative assessment of skin lesions is an important step in the evaluation of skin condition. An objective measurement device can help as a valuable tool for skin analysis. We propose an explorative new multispectral camera specifically developed for dermatology/cosmetology applications. The multispectral imaging system provides images of skin reflectance at different wavebands covering visible and near-infrared domain. It is coupled with a neural network-based algorithm for the reconstruction of reflectance cube of cutaneous data. This cube contains only skin optical reflectance spectrum in each pixel of the bidimensional spatial information. The reflectance cube is analyzed by an algorithm based on a Kubelka-Munk model combined with evolutionary algorithm. The technique allows quantitative measure of cutaneous tissue and retrieves five skin parameter maps: melanin concentration, epidermis/dermis thickness, haemoglobin concentration, and the oxygenated hemoglobin. The results retrieved on healthy participants by the algorithm are in good accordance with the data from the literature. The usefulness of the developed technique was proved during two experiments: a clinical study based on vitiligo and melasma skin lesions and a skin oxygenation experiment (induced ischemia) with healthy participant where normal tissues are recorded at normal state and when temporary ischemia is induced. PMID- 24159327 TI - The effect of weight loss in obese patients with chronic stable plaque-type psoriasis. AB - Background. Chronic plaque psoriasis is frequently associated with obesity. The effect of a low-calorie diet on psoriasis has not been investigated. Objective. The objective was to investigate whether moderate weight loss increases the therapeutic response to topical treatment in obese patients with chronic stable plaque-type psoriasis. Material and Method. A 24-week clinical trial was conducted in 10 patients. The efficacy of a low-calorie diet with topical treatment was compared with baseline in obese patients with chronic stable plaque type psoriasis. The primary measure of clinical response was the Psoriasis Area and Severity Index at weeks 12 and 24. Results. At week 12, the mean reduction in body weight was 9.6 percent. There was an improvement from baseline of 50 percent or more in the Psoriasis Area and Severity Index in 50 percent of the patients. The responses as measured by improvements in the Psoriasis Area and Severity Index were paralleled by improvements in global assessments by the physician and the patients and in the Dermatology Life Quality Index. Conclusion. Obese patients with chronic stable plaque-type psoriasis increase their response to a low-calorie diet. Lifestyle modifications, including a low-calorie diet, may supplement the pharmacologic treatment of obese psoriasis patients. PMID- 24159328 TI - Cutis Verticis Gyrata in Men Affected by HIV-Related Lipodystrophy. AB - We report the occurrence of cutis verticis gyrata (CVG), a disfiguring dermatological condition, in four patients with HIV-related lipodystrophy (HIVLD). These four patients had abnormal metabolic and hormonal lab values which we compare with metabolic and hormonal perturbations cited in previous HIVLD cohorts. In addition, we describe the sole use of poly-L-lactic acid as a potential treatment for decreasing the appearance of CVG-associated ridges. PMID- 24159329 TI - Abdominal Pain: A Comparison between Neurogenic Bowel Dysfunction and Chronic Idiopathic Constipation. AB - Introduction. Most spinal-cord-injured patients have constipation. One-third develop chronic abdominal pain 10 years or more after injury. Nevertheless, very little is known about the nature of abdominal pain after spinal cord injury (SCI). It may be neuropathic or caused by constipation. Aim. To compare characteristics of abdominal pain in SCI with able-bodied with chronic idiopathic constipation (CIC). Subjects and Methods. 21 SCI and 15 CIC patients were referred for treatment of bowel symptoms. Constipation-related symptoms were assessed with the Cleveland Constipation Scoring System and the International Spinal Cord Injury Basic Bowel Function Data Set. Characteristics of abdominal pain were described using the Brief Danish Pain Questionnaire. Total gastrointestinal transit times (GITT) were measured by radiopaque markers. Results. Seventeen (81%) SCI and 14 (93%) CIC patients reported abdominal pain or discomfort within the last month (P = 0.38). Pain was considered more intense by CIC than by SCI patients (P < 0.05). Only minor differences were found in patient's qualitative description of abdominal pain or in the location of pain. In neither SCI nor CIC was pain associated with GITT. Conclusion. Most characteristics of abdominal pain among SCI patients resemble those of CIC. This indicates that constipation is a major cause of pain after SCI. PMID- 24159330 TI - Recent Advances in NSAIDs-Induced Enteropathy Therapeutics: New Options, New Challenges. AB - The injurious effects of NSAIDs on the small intestine were not fully appreciated until the widespread use of capsule endoscopy. It is estimated that over two thirds of regular NSAID users develop injury in the small intestinal injuries and that these injuries are more common than gastroduodenal mucosal injuries. Recently, chronic low-dose aspirin consumption was found to be associated with injury to the lower gut and to be a significant contributing factor in small bowel ulceration, hemorrhage, and strictures. The ability of aspirin and NSAIDs to inhibit the activities of cyclooxygenase (COX) contributes to the cytotoxicity of these drugs in the gastrointestinal tract. However, many studies found that, in the small intestine, COX-independent mechanisms are the main contributors to NSAID cytotoxicity. Bile and Gram-negative bacteria are important factors in the pathogenesis of NSAID enteropathy. Here, we focus on a promising strategy to prevent NSAID-induced small intestine injury. Selective COX-2 inhibitors, prostaglandin derivatives, mucoprotective drugs, phosphatidylcholine-NSAIDs, and probiotics have potential protective effects on NSAID enteropathy. PMID- 24159331 TI - Serum testosterone level, testosterone replacement treatment, and prostate cancer. AB - There has been an increase in the number of individuals seeking testosterone (T) replacement treatment (TRT) due to a decrease in their blood T levels. Prostate cancer (PCa) is also an important issue in the same age group. However, we, urologists, are anxious about PCa development after T treatment. This is because it has been assumed that T may cause PCa or exacerbate insidious PCa which is already present. In this paper, recent developments regarding the relationship between serum levels of sex hormone and prostate tissue, the causal relationship between T and development of PCa, the effect of TRT on the group of patients who are at high risk of developing PCa, the suitability of TRT for patients who have already been diagnosed with PCa, and the effect of TRT on serum prostate-specific antigen level are analyzed. PMID- 24159332 TI - Correction of hypothyroidism seems to have no effect on body fat. AB - Aim. We aimed to observe the effects of L-thyroxine replacement therapy on body fat content determined with various anthropometric methods and a bioelectrical impedance analysis method in patients with hypothyroidism. Methods. Forty-two women with naive autoimmune hypothyroidism were included. Also, 40 healthy participants were enrolled as a control group. Weight, body mass index, waist circumference, and subscapulary, suprailiac, femur, biceps, and triceps skin fold thicknesses were measured. Body fat percentages were calculated and body fat measurements were performed. Euthyroidism was maintained with L-thyroxine. At the 6th and 18th month, of therapy, measurements were reperformed. Results. Mean TSH levels were 57.49 +/- 36.46 mIU/L in hypothyroid group and 1.94 +/- 1.12 mIU/L in control subjects at admission. In hypothyroid patients, calculated body fat percentages were greater than those of the control subjects during follow-up. Body fat percentage of each hypothyroid case decreased at 6- and 18-month controls, but the decrements were statistically insignificant. Although skin fold thicknesses measured from all sites were observed to decline, only those obtained from femur and biceps showed a significant decrease (P = 0.03 and P = 0.01, resp.). Discussion. Correction of hypothyroidism did not cause any improvement in body weight and body fat percentage. The decrease in skin fold thicknesses might probably result from the reduction in subcutaneous mucopolysaccharide deposits. PMID- 24159333 TI - Systemic siRNA Delivery via Peptide-Tagged Polymeric Nanoparticles, Targeting PLK1 Gene in a Mouse Xenograft Model of Colorectal Cancer. AB - Polymeric nanoparticles were developed from a series of chemical reactions using chitosan, polyethylene glycol, and a cell-targeting peptide (CP15). The nanoparticles were complexed with PLK1-siRNA. The optimal siRNA loading was achieved at an N : P ratio of 129.2 yielding a nanoparticle size of >200 nm. These nanoparticles were delivered intraperitoneally and tested for efficient delivery, cytotoxicity, and biodistribution in a mouse xenograft model of colorectal cancer. Both unmodified and modified chitosan nanoparticles showed enhanced accumulation at the tumor site. However, the modified chitosan nanoparticles showed considerably, less distribution in other organs. The relative gene expression as evaluated showed efficient delivery of PLK1-siRNA (0.5 mg/kg) with 50.7 +/- 19.5% knockdown (P = 0.031) of PLK1 gene. The in vivo data reveals no systemic toxicity in the animals, when tested for systemic inflammation and liver toxicity. These results indicate a potential of using peptide-tagged nanoparticles for systemic delivery of siRNA at the targeted tumor site. PMID- 24159336 TI - A New Horizon: Oxytocin as a Novel Therapeutic Option for Obesity and Diabetes. AB - The story of oxytocin (OXT) began long ago in evolutionary terms with its recognition as a classical neurohypophyseal hormone important for lactation and uterine contraction. With the recent discovery of its local actions in the brain, its previously-unappreciated diverse functions in regulating social behaviors and metabolic physiology are emerging. In light of metabolic control, OXT has been shown to induce feeding restriction and body weight lowering through acting on brain regulatory regions, in particular the hypothalamus. Studies from pharmacologic interventions and genetic manipulations demonstrated that OXT can play significant roles in affecting glucose metabolism as well as insulin secretion and lipolysis, many of those functions being regulated both centrally and peripherally. Also excitingly, recent therapeutic success was obtained in clinical endeavor showing that OXT nasal spray effectively induced weight loss and metabolic improvement in human patients with obesity, thus further indicating OXT as a tangible drug target for treating obesity and metabolic complications. In addition to the native form, OXT-derived analogues have been found effective in inducing body weight control and glucose balance. Altogether, all recent advances in studying OXT and metabolic regulation has promoted a promising foundation for the therapeutic strategy of developing innovative OXT peptidyl drugs for the treatment of obesity and related metabolic diseases. PMID- 24159337 TI - Investigating the effects of three needling parameters (manipulation, retention time, and insertion site) on needling sensation and pain profiles: a study of eight deep needling interventions. AB - Introduction. In traditional Chinese acupuncture, needle sensation (deqi) is purported to contribute to a therapeutic outcome. While researchers have attempted to define deqi qualitatively, few have examined the effects of needling parameters on its intensity. Methods. 24 healthy subjects completed eight interventions scheduled at least one week apart, which involved manual acupuncture to LI4 or a designated nonacupoint (NAP) on the hand, with real or simulated manipulation each three minutes and needle retentions of one or 21 minutes. Intensities of needling sensation and pain were reported every three minutes and sensation qualities were reported post-intervention. Results. Immediately after needle insertion, similar levels of mean needle sensation and of pain were reported independent of intervention. At subsequent measurement times, only two interventions (one at LI4 and one at NAP) maintained statistically significantly elevated needle sensation and pain scores and reported higher numbers of needle sensation descriptors. For both, the needle was retained for 21 minutes and manipulated every three minutes. Neither intervention differed significantly in terms of levels of pain, and needle sensation or numbers and qualities of needle sensation described. Conclusion. In this group of healthy subjects, the initial needling for all eight interventions elicited similar levels of needle sensation and pain. These levels were only maintained if there was ongoing of needle manipulation and retention of the needle. By contrast, the strength of needle sensation or pain experienced was independent of insertion site. PMID- 24159335 TI - Trimeric tau is toxic to human neuronal cells at low nanomolar concentrations. AB - In Alzheimer's disease (AD), tau aggregates into fibrils and higher order neurofibrillary tangles, a key histopathological feature of AD. However, soluble oligomeric tau species may play a more critical role in AD progression since these tau species correlate better with neuronal loss and cognitive dysfunction. Recent studies show that extracellular oligomeric tau can inhibit memory formation and synaptic function and also transmit pathology to neighboring neurons. However, the specific forms of oligomeric tau involved in toxicity are still unknown. Here, we used two splice variants of recombinant human tau and generated monomeric, dimeric, and trimeric fractions of each isoform. The composition of each fraction was verified chromatographically and also by atomic force microscopy. The toxicity of each fraction toward both human neuroblastoma cells and cholinergic-like neurons was assessed. Trimeric, but not monomeric or dimeric, tau oligomers of both splice variants were neurotoxic at low nanomolar concentrations. Further characterization of tau oligomer species with disease specific modifications and morphologies is necessary to identify the best targets for the development of biomarker and therapeutic development for AD and related tauopathies. PMID- 24159334 TI - RNA splicing: a new player in the DNA damage response. AB - It is widely accepted that tumorigenesis is a multistep process characterized by the sequential accumulation of genetic alterations. However, the molecular basis of genomic instability in cancer is still partially understood. The observation that hereditary cancers are often characterized by mutations in DNA repair and checkpoint genes suggests that accumulation of DNA damage is a major contributor to the oncogenic transformation. It is therefore of great interest to identify all the cellular pathways that contribute to the response to DNA damage. Recently, RNA processing has emerged as a novel pathway that may contribute to the maintenance of genome stability. In this review, we illustrate several different mechanisms through which pre-mRNA splicing and genomic stability can influence each other. We specifically focus on the role of splicing factors in the DNA damage response and describe how, in turn, activation of the DDR can influence the activity of splicing factors. PMID- 24159338 TI - Efficacy of acupuncture for primary insomnia: a randomized controlled clinical trial. AB - Objectives. To investigate the six-week influence of acupuncture on sleep quality and daytime functioning in primary insomnia. Methods. The study was a double dummy, single-blinded, randomized, placebo-controlled clinical trial. A total of 180 patients with primary insomnia were randomly assigned to 3 groups: verum group underwent verum acupuncture plus placebo; estazolam group underwent estazolam plus sham acupuncture; sham group underwent sham acupuncture plus placebo. The outcome was measured by Pittsburgh Sleep Quality Index (PSQI), Epworth Sleepiness Scale (ESS), and the 36-item short-form health survey (SF-36). Results. The three groups showed significant improvement compared with the pretreatment baseline. Compared with the other two groups, the verum group reported improved sleep quality (SQ) and vitality (VT), decreased daytime dysfunction (DD) and sleepiness (ESS score). The differences were kept from the treatment period to the end of the trial. Discussion. Verum acupuncture appeared to be more effective in increasing sleep quality and daytime functioning than sham acupuncture and estazolam. Trial Registration. The trial is registeded with ClinicalTrials.gov ISRCTN12585433. PMID- 24159339 TI - Immunomodulatory Activity and Protective Effects of Polysaccharide from Eupatorium adenophorum Leaf Extract on Highly Pathogenic H5N1 Influenza Infection. AB - The development of novel broad-spectrum, antiviral agents against H5N1 infection is urgently needed. In this study, we evaluated the immunomodulatory activities and protective effect of Eupatorium adenophorum polysaccharide (EAP) against the highly pathogenic H5N1 subtype influenza virus. EAP treatment significantly increased the production of IL-6, TNF- alpha , and IFN- gamma both in vivo and in vitro as measured by qPCR and ELISA. In a mouse infection model, intranasal administration of EAP at a dose of 25 mg/kg body weight prior to H5N1 viral challenge efficiently inhibited viral replication, decreased lung lesions, and increased survival rate. We further evaluated the innate immune recognition of EAP, as this process is regulated primarily Dectin-1 and mannose receptor (MR). These results indicate that EAP may have immunomodulatory properties and a potential prophylactic effect against H5N1 influenza infection. Our investigation suggests an alternative strategy for the development of novel antiinfluenza agents and benefits of E. adenophorum products. PMID- 24159342 TI - Comment on "chinese herbal medicine for osteoporosis: a systematic review of randomized controlled trails". PMID- 24159340 TI - Electroacupuncture at 2/100 hz activates antinociceptive spinal mechanisms different from those activated by electroacupuncture at 2 and 100 hz in responder rats. AB - We examined the effects of intrathecal injection of desipramine and fluoxetine (selective inhibitors of norepinephrine and 5-HT uptake, resp.), thiorphan and neostigmine (inhibitors of enkephalinase and acetylcholinesterase, resp.), gabapentin (a GABA releaser), and vigabatrin (an inhibitor of GABA-transaminase) on the antinociception induced by 2 Hz, 100 Hz, or 2/100 Hz electroacupuncture (EA) applied bilaterally to the Zusanli (ST36) and Sanyinjiao (SP6) acupoints using the rat tail-flick test. We show that 2 Hz EA antinociception lasts longer after the administration of drugs that increase the spinal availability of norepinephrine, acetylcholine, or GABA; 100 Hz EA antinociception lasts longer after drug that increases the spinal availability of norepinephrine; 2/100 Hz EA antinociception lasts longer after drugs that increase the spinal availability of endogenous opioids or GABA. We conclude that the antinociceptive effect of 2/100 Hz EA is different from the synergistic effect of alternate stimulation at 2 and 100 Hz because the effect of the former is not changed by increasing the spinal availability of serotonin and lasts longer after the administration of vigabatrin. The combination of EA with drugs that increase the availability of spinal neurotransmitters involved in the modulation of nociceptive inputs may result in a synergistic antinociceptive effect in the rat tail-flick test. PMID- 24159341 TI - Moxibustion for the correction of nonvertex presentation: a systematic review and meta-analysis of randomized controlled trials. AB - Objectives. This study aims to assess the effectiveness and safety of moxibustion for the correction of nonvertex presentation. Methods. Records without language restrictions were searched up to February 2013 for randomized controlled trials (RCTs) comparing moxibustion with other therapies in women with a singleton nonvertex presentation. Cochrane risk of bias criteria were used to assess the methodological quality of the trials. Results. Seven of 392 potentially relevant studies met the inclusion criteria. When moxibustion was compared with other interventions, a meta-analysis revealed a significant difference in favor of moxibustion on the correction of nonvertex presentation at delivery (risk ratio (RR) 1.29, 95% confidence interval (CI) 1.12 to 1.49, and I (2) = 0). The same findings applied to the cephalic presentation after cessation of treatment (RR 1.36, 95% CI 1.08 to 1.71, and I (2) = 80%). A subgroup analysis that excluded two trials with a high risk of bias also indicated favorable effects (RR 1.63, 95% CI 1.42 to 1.86, and I (2) = 0%). With respect to safety, moxibustion resulted in decreased use of oxytocin. Conclusion. Our systematic review and meta analysis suggested that moxibustion may be an effective treatment for the correction of nonvertex presentation. Moreover, moxibustion might reduce the need for oxytocin. PMID- 24159343 TI - Availability of tongue diagnosis system for assessing tongue coating thickness in patients with functional dyspepsia. AB - Tongue diagnosis is an important procedure in traditional Korean medicine (TKM). In particular, tongue coating thickness (TCT) is deemed to show the progression of the disease. However, conventional tongue diagnosis has limitations because of various external factors. Therefore, it is necessary to investigate the availability of tongue diagnosis system (TDS) in the assessment of TCT. This study has been designed as a prospective clinical trial involving 60 patients with functional dyspepsia. Tongue images will be obtained by TDS twice with a 30 min interval. The system will measure the percentage of TCT and classify it as either no coating, thin coating, or thick coating according to the existing diagnostic criteria. After finishing the collection of 60 patients' tongue images, TCT on the images will be simultaneously evaluated by the conventional method to establish the gold standard for assessing TCT by 5 well-trained clinicians. The evaluation will be repeated by the same clinicians after 2 weeks, but the order of the images will be changed. This trial is expected to provide clinical evidence for the availability of TDS as a diagnostic tool and to contribute to the standardization of the diagnosis system used in TKM. This trial is registered with ClinicalTrials.gov NCT01864837. PMID- 24159344 TI - The mechanism of moxibustion: ancient theory and modern research. AB - THE MOXIBUSTION HAS A DUAL EFFECT OF TONIFICATION AND PURGATION IN TCM THEORIES, WHICH ARE BASED ON TWO ASPECTS: the actions of the meridian system and the roles of moxa and fire. Modern research works of the moxibustion mechanism mainly relate to the thermal effects, radiation effects, and pharmacological actions of moxa and its combustion products. Experimental results showed that moxibustion thermal stimulation affects both shallow and deep tissues of the skin, and the warm-heat effects of moxibustion have a close relation to the warm receptors or/and the polymodal receptor. The burning moxa radiation spectrum ranges from 0.8 to 5.6 MU m; peak is nearby 1.5 MU m, lying within the near infrared portion. There is an amazing consistency in the infrared spectrums of three types of indirect moxibustion and the unified spectrum of acupoints; all have their peaks of radiation near 10 MU m. Lots of ingredients had been identified from mugwort leaves and moxa smoke, which have a variety of biological activities; they were considered to participate in the comprehensive effects of moxibustion. Although lots of research works have been carried out and made some progress, there is still a great distance from fully understanding the mechanism of moxibustion. PMID- 24159345 TI - Antiherpetic Effects of Gynura procumbens. AB - The ethanol extract of Gynura procumbens showed virucidal and antireplicative actions against herpes simplex virus HSV-1 and HSV-2. It was further chromatographed on MCI gel CHP20P column giving the extract fractions F1 (water), F2 (water-methanol) F3 (methanol), and F4 (ethyl acetate). All but F1 had virucidal action against both viral types. We reported here the active compounds from F2 and F3. The antiherpetic compounds of F2 was a mixture of dicaffeoylquinic acids with virucidal and antireplicative actions against HSV-2 (IC50 96.0 and 61.0 MU g/mL, resp.) Virucidal compounds of F3 were a mixture of beta -sitosterol and stigmasterol (IC50 250.0 MU g/mL against HSV-1), a mixture of beta -sitosteryl and stigmasteryl glucosides (IC50 50.0 MU g/mL against HSV 2) and 1, 2-bis-dodecanoyl-3- alpha -D-glucopyranosyl-sn-glycerol (IC50 of 40.0 MU g/mL against HSV-2). Herbal products containing 1 and 2% of standardized ethanol extract were prepared. Double-blind randomized controlled clinical trial of the products was performed in patients with recurrent herpes labialis. Results showed that the number of patients, whose lesions healed within 7 days and the average healing time of both groups differed insignificantly. Viral culture on D7 indicated a decrease of infected patients from 48.7% to 7.69% in treated group whereas in placebo group the infected patients decreased from 31.25% to 20.00%. The viral reduction in treated group indicated the benefit of the product. Insignificant result might arise from a low number of participated patients and insufficient concentration of plant extract in herbal product. PMID- 24159347 TI - Potential Therapeutic Role of Hispidulin in Gastric Cancer through Induction of Apoptosis via NAG-1 Signaling. AB - Gastric cancer is one of the most common malignant cancers due to poor prognoses and high mortality rates worldwide. However, an effective chemotherapeutic drug without side effects remains lacking. Saussurea involucrata (SI) Kar. et Kir., also known as snow lotus, grows in mountainous rocky habitats at 2600 m elevation in the Tian Shan and A'er Tai regions of China. The ethyl acetate extract of SI had been shown to inhibit proliferation and induce apoptosis in various tumor cells. In this study, we demonstrated that Hispidulin, active ingredients in SI, inhibits the growth of AGS gastric cancer cells. After Hispidulin treatment, NAG 1 remained highly expressed, whereas COX-2 expression was downregulated. Flow cytometric analysis indicated that Hispidulin induces G1/S phase arrest and apoptosis in time- and concentration-dependent manners. G1/S arrest correlated with upregulated p21/WAF1 and p16 and downregulated cyclin D1 and cyclin E, independent of p53 pathway. In addition, Hispidulin can elevate Egr-1 expression and ERK1/2 activity, whereas ERK1/2 inhibitor markedly attenuated NAG-1 mediated apoptosis. Taken together, Hispidulin can efficiently activate ERK1/2 signaling followed by NAG-1 constitutive expression and trigger cell cycle arrest as well as apoptosis in cancer cell. It can be a potential compound for combination therapy of gastric cancer in the future. PMID- 24159346 TI - Tai chi chuan in medicine and health promotion. AB - Tai Chi Chuan (Tai Chi) is a Chinese traditional mind-body exercise and recently, it becomes popular worldwide. During the practice of Tai Chi, deep diaphragmatic breathing is integrated into body motions to achieve a harmonious balance between body and mind and to facilitate the flow of internal energy (Qi). Participants can choose to perform a complete set of Tai Chi or selected movements according to their needs. Previous research substantiates that Tai Chi has significant benefits to health promotion, and regularly practicing Tai Chi improves aerobic capacity, muscular strength, balance, health-related quality of life, and psychological well-being. Recent studies also prove that Tai Chi is safe and effective for patients with neurological diseases (e.g., stroke, Parkinson's disease, traumatic brain injury, multiple sclerosis, cognitive dysfunction), rheumatological disease (e.g., rheumatoid arthritis, ankylosing spondylitis, and fibromyalgia), orthopedic diseases (e.g., osteoarthritis, osteoporosis, low-back pain, and musculoskeletal disorder), cardiovascular diseases (e.g., acute myocardial infarction, coronary artery bypass grafting surgery, and heart failure), chronic obstructive pulmonary diseases, and breast cancers. Tai Chi is an aerobic exercise with mild-to-moderate intensity and is appropriate for implementation in the community. This paper reviews the existing literature on Tai Chi and introduces its health-promotion effect and the potential clinical applications. PMID- 24159348 TI - Metabolic Signatures of Kidney Yang Deficiency Syndrome and Protective Effects of Two Herbal Extracts in Rats Using GC/TOF MS. AB - Kidney Yang Deficiency Syndrome (KDS-Yang), a typical condition in Chinese medicine, shares similar clinical signs of the glucocorticoid withdrawal syndrome. To date, the underlying mechanism of KDS-Yang has been remained unclear, especially at the metabolic level. In this study, we report a metabolomic profiling study on a classical model of KDS-Yang in rats induced by hydrocortisone injection to characterize the metabolic transformation using gas chromatography/time-of-flight mass spectrometry. WKY1, a polysaccharide extract from Astragalus membranaceus and Lycium barbarum, and WKY2, an aqueous extract from a similar formula containing Astragalus membranaceus, Lycium barbarum, Morinda officinalis, Taraxacum mongolicum, and Cinnamomum cassia presl, were used separately for protective treatments of KDS-Yang. The changes of serum metabolic profiles indicated that significant alterations of key metabolic pathways in response to abrupt hydrocortisone perturbation, including decreased energy metabolism (lactic acid, acetylcarnitine), lipid metabolism (free fatty acids, 1 monolinoleoylglycerol, and cholesterol), gut microbiota metabolism (indole-3 propionic acid), biosynthesis of catecholamine (norepinephrine), and elevated alanine metabolism, were attenuated or normalized with different degrees by the pretreatment of WKY1 or WKY2, which is consistent with the observations in which the two herbal agents could ameliorate biochemical markers of serum cortisone, adrenocorticotropic (ACTH), and urine 17-hydroxycorticosteroids (17-OHCS). PMID- 24159349 TI - Protective Mechanisms of S. lycopersicum Aqueous Fraction (Nucleosides and Flavonoids) on Platelet Activation and Thrombus Formation: In Vitro, Ex Vivo and In Vivo Studies. AB - The purpose of this research was to investigate mechanisms of antiplatelet action of bioactive principle from S. lycopersicum. Aqueous fraction had a high content of nucleosides (adenosine, guanosine, and adenosine 5'-monophosphate) by HPLC analysis. Also aqueous fraction presented flavonoids content. Aqueous fraction inhibited platelet activation by 15 +/- 6% (P < 0.05). Fully spread of human platelets on collagen in the presence of aqueous fraction was inhibited from 15 +/- 1 to 9 +/- 1 MU m(2) (P < 0.001). After incubation of whole blood with aqueous fraction, the platelet coverage was inhibited by 55 +/- 12% (P < 0.001). Platelet ATP secretion and aggregation were significantly inhibited by the aqueous fraction. At the same concentrations that aqueous fraction inhibits platelet aggregation, levels of sCD40L significantly decreased and the intraplatelet cAMP levels increased. In addition, SQ22536, an adenylate cyclase inhibitor, attenuated the effect of aqueous fraction toward ADP-induced platelet aggregation and intraplatelet level of cAMP. Platelet aggregation ex vivo (human study) and thrombosis formation in vivo (murine model) were inhibited by aqueous fraction. Finally, aqueous fraction may be used as a functional ingredient adding antiplatelet activities (nucleosides and flavonoids) to processed foods. PMID- 24159350 TI - Evaluation of Antimicrobial and Wound Healing Potential of Justicia flava and Lannea welwitschii. AB - Microbial infections of various types of wounds are a challenge to the treatment of wounds and wound healing. The aim of the study is to determine the antimicrobial, antioxidant, and in vivo wound healing properties of methanol leaf extracts of Justicia flava and Lannea welwitschii. The antimicrobial activity was investigated using agar well diffusion and microdilution methods. The free radical scavenging activity of the methanol leaf extracts was performed using 1,1 diphenyl-2-picryl-hydrazyl (DPPH). The rate of wound contraction was determined using excision model. The test organisms used were Escherichia coli ATCC 25922, Pseudomonas aeruginosa ATCC 4853, Bacillus subtilis NTCC 10073, Staphylococcus aureus ATCC 25923, and clinical strains of Candida albicans. The MICs of methanol leaf extract of J. flava against test organisms were E. coli (7.5 mg/mL); P. aeruginosa (7.5 mg/mL); S. aureus (5 mg/mL); B. subtilis (7.5 mg/mL); and C. albicans (5 mg/mL). The MICs of methanol leaf extract of L. welwitschii against test organisms were E. coli (5 mg/mL); P. aeruginosa (10 mg/mL); S. aureus (5 mg/mL); B. subtilis (2.5 mg/mL); and C. albicans (2.5 mg/mL). The MBC/MFC of the extract was between 10 and 50 mg/mL. The IC50 of the reference antioxidant, alpha -tocopherol, was 1.5 MU g/mL and the methanol leaf extracts of J. flava and L. welwitschii had IC50 of 65.3 MU g/mL and 81.8 MU g/mL, respectively. The methanol leaf extracts of J. flava and L. welwitschii gave a significant reduction in wound size as compared to the untreated. The rates of wound closure after the application of the extracts (7.5% w/w) were compared to the untreated wounds. On the 9th day, J. flava extract had a percentage wound closure of 99% (P < 0.01) and that of L. welwitschii exhibited wound closure of 95% (P < 0.05) on the 13th day compared to the untreated wounds. The two extracts significantly (P < 0.01) increased the tensile strength of wounds compared to the untreated wounds. The extracts treated wound tissues showed improved angiogenesis, collagenation, and reepithelialization compared to the untreated wound tissues. The preliminary phytochemical screening of J. flava and L. welwitschii leaf extracts revealed the presence of tannins, alkaloids, flavonoids, and glycosides. The above results indicate that methanol leaf extracts of J. flava and L. welwitschii possess antimicrobial and wound healing properties which may justify the traditional uses of J. flava and L. welwitschii in the treatment of wounds and infections. PMID- 24159351 TI - Observational studies on evaluating the safety and adverse effects of traditional chinese medicine. AB - Background. This study aims to share our experiences when carrying out observational studies of traditional Chinese medicine (TCM). Methods. We have proactively monitored the safety profiles of Duhuo Jisheng Tang (DJT), Suan Zao Ren Tang (SZRT), and TMN-1. A list of adverse events (AEs), complete blood counts, and liver and kidney function tests were obtained from the participants during their scheduled hospital visits. Retrospective observational studies were conducted based on the reimbursement database of the National Health Insurance system, Taiwan, to explore the relationship between the use of TCM that have been adulterated by aristolochic acid and the risk from both nephrotoxins and carcinogens. Results. A total of 221, 287, and 203 AEs were detected after SZRT, DJT, and TMN-1 had been taken, respectively. Dizziness, headache, stomach ache, and diarrhea were judged to be probably related to SZRT treatment. Retrospective observational studies found an association between the consumption of aristolochic acid-containing Chinese formulae such as Mu Tong and an increased risk of CKD, ESRD, and urinary tract cancer. Conclusion. Prospective and retrospective observational studies seem to have specific advantages when investigating the safety and adverse effects of TCM therapies, as well as possibly other alternative/complementary therapies. PMID- 24159352 TI - Evaluation of a salutogenetic concept for inpatient psychosomatic treatment. AB - The increase of psychosomatic disorders due to cultural changes requires enhanced therapeutic models. This study investigated a salutogenetic treatment concept for inpatient psychosomatic treatment, based on data from more than 11000 patients of a psychosomatic clinic in Germany. The clinic aims at supporting patients' health improvement by fostering values such as humanity, community, and mindfulness. Most of patients found these values realized in the clinical environment. Self assessment questionnaires addressing physical and mental health as well as symptom ratings were available for analysis of pre-post-treatment effects and long-term stability using one-year follow-up data, as well as for a comparison with other clinics. With respect to different diagnoses, symptoms improved in self-ratings with average effect sizes between 0.60 and 0.98. About 80% of positive changes could be sustained as determined in a 1-year follow-up survey. Patients with a lower concordance with the values of the clinic showed less health improvement. Compared to 14 other German psychosomatic clinics, the investigated treatment concept resulted in slightly higher decrease in symptoms (e.g., depression scale) and a higher self-rated mental and physical improvement in health. The data suggest that a successfully implemented salutogenetic clinical treatment concept not only has positive influence on treatment effects but also provides long-term stability. PMID- 24159353 TI - Pomegranate Supplementation Protects against Memory Dysfunction after Heart Surgery: A Pilot Study. AB - Memory dysfunction is a common complaint following heart surgery and may be related to a diffuse ischemic state induced by microemboli dislodged during the procedure. Ischemia can induce damage by a number of mechanisms, including oxidative stress. Because pomegranates contain a variety of polyphenols with antioxidant and other potentially beneficial effects, we tested whether supplementation with a pomegranate extract before and after heart surgery could protect against postoperative cognitive dysfunction. Patients undergoing elective coronary artery bypass graft and/or valve surgery were given either 2 g of pomegranate extract (in 2 POMx pills) or placebo (pills containing no pomegranate ingredients) per day from one week before surgery to 6 weeks after surgery. The patients were also administered a battery of neuropsychological tests to assess memory function at 1 week before surgery (baseline), 2 weeks after surgery, and 6 weeks after surgery. The placebo group had significant deficits in postsurgery memory retention, and the pomegranate treatment not only protected against this effect, but also actually improved memory retention performance for up to 6 weeks after surgery as compared to presurgery baseline performance. PMID- 24159354 TI - Anti-Proliferative Effect of an Aqueous Extract of Prunella vulgaris in Vascular Smooth Muscle Cells. AB - The abnormal proliferation of vascular smooth muscle cells (VSMCs) in arterial walls is an important pathogenic factor of vascular disorders such as diabetic atherosclerosis. We have reported the anti-inflammatory effect of an aqueous extract from Prunella vulgaris (APV) in vascular endothelial cell. In the present study, APV exhibited inhibitory effects on high glucose-stimulated VSMC proliferation, migration, and invasion activities, inducing G1 cell cycle arrest with downregulation of cyclins and CDKs and upregulation of the CKIs, p21(waf1/cip1) and p27(kip1). Furthermore, APV dose dependently suppressed the high glucose-induced matrix metalloproteinase activity. High glucose-induced phosphorylation of ERK, p38 MAPK, was decreased by the pretreatment of APV. NF- kappa B activation by high glucose was attenuated by APV, as an antioxidant. APV attenuated the high glucose-induced decrease of nuclear factor E2-related factor 2 (Nrf2) translocation and heme oxygenase-1 (HO-1) expression. Intracellular cGMP level was also increased by APV treatment. These results demonstrate that APV may inhibit VSMC proliferation via downregulating ROS/NF- kappa B /ERK/p38 MAPK pathways. In addition, APV has a beneficial effect by the interaction of Nrf2 mediated NO/cGMP with HO-1, suggesting that Prunella vulgaris may be useful in preventing diabetic atherosclerosis. PMID- 24159355 TI - Antioxidant and Antiproliferative Activities of Leaf Extracts from Plukenetia volubilis Linneo (Euphorbiaceae). AB - Plukenetia volubilis Linneo, or Sacha inca, is an oleaginous plant from the Euphorbiaceae family. The aim of this work was to perform a chemical and biological analysis of different leaf extracts from P. volubilis such as aqueous extract (AEL), methanol (MEL), ethanol (EEL), chloroform (CEL), and hexane (HEL). Thin layer chromatography analysis revealed the presence of phenolic compounds, steroids, and/or terpenoides. Furthermore, the antioxidant activities were analyzed by in vitro assays and their effects on cell lineages by in vivo assays. The Total Antioxidant Capacity (TCA) was expressed as equivalent ascorbic acid (EEA/g) and it was observed that the extracts showed values ranging from 59.31 to 97.76 EAA/g. Furthermore, the DPPH assay values ranged from 62.8% to 88.3%. The cell viability assay showed that the extracts were able to reduce viability from cancer cells such as HeLa and A549 cells. The extracts MEL and HEL (250 ug/mL) were able to reduce the proliferation of HeLa cells up to 54.3% and 48.5%, respectively. The flow cytometer results showed that these extracts induce cell death via the apoptosis pathway. On the other hand, the extracts HEL and AEL were able to induce cell proliferation of normal fibroblast 3T3 cells. PMID- 24159356 TI - Epimedium extract promotes peripheral nerve regeneration in rats. AB - Effects of Epimedium extract and its constituent icariin on peripheral nerve repair were investigated in a crush injury rat model. Animals were divided into four groups: sham, control, Epimedium extract, and icariin groups. At postoperative weeks 1, 2, 4, and 8, nerve regeneration and functional recovery were evaluated by sciatic functional index (SFI), nerve electrophysiology, nerve pinch test, and muscle wet weight. Results showed that at 2 and 4 weeks after surgery rats in the Epimedium group displayed a better recovery of nerve function than that in the icariin and control groups, with better recovery in the icariin group than in the control group. The nerve pinch test showed that nerve regeneration was greater in the Epimedium group and the icariin group as compared to the control group. In addition, the muscle wet weight in the Epimedium group was significantly improved when compared with the icariin group, and the improvement in the icariin group was better than that in the control group at 8 weeks after operation. Our findings suggest that Epimedium extract effectively promotes peripheral nerve regeneration and improves the function of damaged nerves. PMID- 24159357 TI - Effect of Laser Irradiation at Different Wavelengths (940, 808, and 658 nm) on Pressure Ulcer Healing: Results from a Clinical Study. AB - THE AIM OF THE STUDY WAS TO ASSESS THE EFFICACY OF LASER THERAPY (AT DIFFERENT WAVELENGTHS: 940, 808, and 658 nm) for treating pressure ulcers. The primary endpoint in this trial included both the percentage reduction of the ulcer surface area and the percentage of completely healed wounds after one month of therapy (ulcer healing rate). The secondary endpoint was the ulcer healing rate at the follow-up evaluation (3 months after the end of the study). In total, 72 patients with stage II and III pressure ulcers received laser therapy once daily, 5 times per week for 1 month using a (GaAlAs) diode laser with a maximum output power of 50 mW and continuous radiation emission. Three separate wavelengths were used for the laser treatment: 940 nm (group I), 808 nm (group II), and 658 nm (group III). An average dose of 4 J/cm(2) was applied. In group IV, a placebo was applied (laser device was turned off). The laser therapy at a wavelength of 658 nm appeared to be effective at healing pressure ulcers. The wavelengths of 808 and 940 nm did not have any effect in our study. PMID- 24159358 TI - P90RSK and Nrf2 Activation via MEK1/2-ERK1/2 Pathways Mediated by Notoginsenoside R2 to Prevent 6-Hydroxydopamine-Induced Apoptotic Death in SH-SY5Y Cells. AB - 6-Hydroxydopamine (6-OHDA) is known to contribute to neuronal death in Parkinson's disease. In this study, we found that the preincubation of SH-SY5Y cells for 24 h with 20 MU M notoginsenoside R2 (NGR2), which is a newly isolated notoginsenoside from Panax notoginseng, showed neuroprotective effects against 6 OHDA-induced oxidative stress and apoptosis. NGR2 incubation successively resulted in the activation of P90RSK, inactivation of BAD, and inhibition of 6 OHDA-induced mitochondrial membrane depolarization, thus preventing the mitochondrial apoptosis pathway. NGR2 incubation also led to the activation of Nrf2 and subsequent activity enhancement of phase II detoxifying enzymes, thus suppressing 6-OHDA-induced oxidative stress, and these effects could be removed by Nrf2 siRNA. We also found that the upstream activators of P90RSK and Nrf2 were the MEK1/2-ERK1/2 pathways but not the JNK, P38, or PI3K/Akt pathways. Interestingly, NGR2 incubation could also activate MEK1/2 and ERK1/2. Most importantly, NGR2-mediated P90RSK and Nrf2 activation, respective downstream target activation, and neuroprotection were reversed by the genetic silencing of MEK1/2 and ERK1/2 by using siRNA and PD98059 application. These results suggested that the neuroprotection elicited by NGR2 against 6-OHDA-induced neurotoxicity was associated with NGR2-mediated P90RSK and Nrf2 activation through MEK1/2 ERK1/2 pathways. PMID- 24159359 TI - Ficus carica L. (Moraceae): Phytochemistry, Traditional Uses and Biological Activities. AB - This paper describes the botanical features of Ficus carica L. (Moraceae), its wide variety of chemical constituents, its use in traditional medicine as remedies for many health problems, and its biological activities. The plant has been used traditionally to treat various ailments such as gastric problems, inflammation, and cancer. Phytochemical studies on the leaves and fruits of the plant have shown that they are rich in phenolics, organic acids, and volatile compounds. However, there is little information on the phytochemicals present in the stem and root. Reports on the biological activities of the plant are mainly on its crude extracts which have been proven to possess many biological activities. Some of the most interesting therapeutic effects include anticancer, hepatoprotective, hypoglycemic, hypolipidemic, and antimicrobial activities. Thus, studies related to identification of the bioactive compounds and correlating them to their biological activities are very useful for further research to explore the potential of F. carica as a source of therapeutic agents. PMID- 24159360 TI - Left to their own devices: Post-ELSI, ethical equipment and the International Genetically Engineered Machine (iGEM) Competition. AB - In this article, we evaluate a novel method for post-ELSI (ethical, legal and social implications) collaboration, drawing on 'human practices' (HP) to develop a form of reflexive ethical equipment that we termed 'sociotechnical circuits'. We draw on a case study of working collaboratively in the International Genetically Engineered Machine Competition (iGEM) and relate this to the parts based agenda of synthetic biology. We use qualitative methods to explore the experience of undergraduate students in the Competition, focussing on the 2010 University of Sheffield team. We examine how teams work collaboratively across disciplines to produce novel microorganisms. The Competition involves a HP component and we examine the way in which this has been narrowly defined within the ELSI framework. We argue that this is a much impoverished style of HP when compared with its original articulation as the development of 'ethical equipment'. Inspired by this more theoretically rich HP framework, we explore the relations established between team members and how these were shaped by the norms, materials and practices of the Competition. We highlight the importance of care in the context of post-ELSI collaborations and report on the implications of our case study for such efforts and for the relation of the social sciences to the life sciences more generally. PMID- 24159361 TI - Partial molecular cloning of the JHK retrovirus using gammaretrovirus consensus PCR primers. AB - The JHK virus (JHKV) was previously described as a type C retrovirus that has some distinctive ultrastructural features and replicates constitutively in a human B-lymphoblastoid cell line, JHK-3. In order to facilitate the cloning of sequences from JHKV, a series of partially degenerate consensus retroviral PCR primers were created by a data-driven design approach based on an alignment of 14 diverse gammaretroviral genomes. These primers were used in the PCR amplification of purified JHK virion cDNA, and ana lysis of the resulting amplified sequence indicates that the JHKV is in the murine leukemia virus (MLV) family. The JHK sequence is nearly identical to the corresponding region of the Bxv-1 endogenous mouse retrovirus (GenBank accession AC115959) and distinct from XMRV. JHKV gag specific amplification was demonstrated with nucleic acids from uncultivated, frozen, peripheral blood mononuclear cells (PBMCs) of the index patient, but not in PBMCs from nine healthy blood donors. Unlike earlier reports, in which MLV like sequences were identified in human source material, which may have been due to murine contamination, budding retrovirions were demonstrated repeatedly by electron microscopy in uncultivated lymphocytes of the index patient that were morphologically identical in their development to the virions in the JHK-3 cells, and immunological evidence was obtained that the index patient produced IgG antibodies that bound to the budding viral particles in patient PBMCs and in the JHK-3 cells. These data indicate that the patient had been infected by JHKV, lending significance to the demonstration of JHKV amplicons in nucleic acids of the patient's PBMCs. In future studies, the PCR primer sets described herein may expand the detection of an amplifiable subset of viruses related to MLV. PMID- 24159363 TI - Encapsulation of Fluidic Tubing and Microelectrodes in Microfluidic Devices: Integrating Off-Chip Process and Coupling Conventional Capillary Electrophoresis with Electrochemical Detection. AB - In this paper, an approach to fabricate epoxy or polystyrene microdevices with encapsulated tubing and electrodes is described. Key features of this approach include a fixed alignment between the fluidic tubing and electrodes, the ability to polish the device when desired, and the low dead volume nature of the fluidic interconnects. It is shown that a variety of tubing can be encapsulated with this approach, including fused silica capillary, polyetheretherketone (PEEK), and perfluoroalkoxy (PFA), with the resulting tubing/microchip interface not leading to significant band broadening or plug dilution. The applicability of the devices with embedded tubing is demonstrated by integrating several off-chip analytical methods to the microchip. This includes droplet transfer, droplet desegmentation, and microchip-based flow injection analysis. Off-chip generated droplets can be transferred to the microchip with minimal coalescence, while flow injection studies showed improved peak shape and sensitivity when compared to the use of fluidic interconnects with an appreciable dead volume. Importantly, it is shown that this low dead volume approach can be extended to also enable the integration of conventional capillary electrophoresis (CE) with electrochemical detection. This is accomplished by embedding fused silica capillary along with palladium (for grounding the electrophoresis voltage) and platinum (for detection) electrodes. With this approach, up to 128,000 theoretical plates for dopamine was possible. In all cases, the tubing and electrodes are housed in a rigid base; this results in extremely robust devices that will be of interest to researchers wanting to develop microchips for use by non-experts. PMID- 24159362 TI - Triggered Nanoparticles as Therapeutics. AB - Drug delivery systems (DDSs) face several challenges including site-specific delivery, stability, and the programmed release of drugs. Engineered nanoparticle (NP) surfaces with responsive moieties can enhance the efficacy of DDSs for in vitro and in vivo systems. This triggering process can be achieved through both endogenous (biologically controlled release) and exogenous (external stimuli controlled release) activation. In this review, we will highlight recent examples of the use of triggered release strategies of engineered nanomaterials for in vitro and in vivo applications. PMID- 24159364 TI - Asymmetric Addition of Cyanide to beta-Nitroalkenes Catalysed by Chiral Salen Complexes of Titanium(IV) and Vanadium(V). AB - Structurally well-defined bimetallic titanium(IV) (salen) and monometallic vanadium(V) (salen) complexes have been used as catalysts for the asymmetric addition of trimethylsilyl cyanide to beta-nitroalkenes to produce chiral nitronitriles with ee values in the range of 79-89 % and conversions up to 100 % at 0 degrees C. The reaction conditions (solvent, temperature, time and vanadium complex counter-ion) were optimised, and it was shown that the catalyst loading could be significantly reduced (20 to 2 mol %) and the reaction temperature increased (-40 to 0 degrees C) compared to previous studies that used an in situ prepared catalyst. The results are compared and contrasted with previous results obtained by using the same catalysts for the asymmetric addition of trimethylsilyl cyanide to aldehydes, and a transition-state structure for the asymmetric addition of trimethylsilyl cyanide to nitroalkenes is proposed to account for the observed stereochemistry. PMID- 24159366 TI - Electron Beam-Induced Writing of Nanoscale Iron Wires on a Functional Metal Oxide. AB - Electron beam-induced surface activation (EBISA) has been used to grow wires of iron on rutile TiO2(110)-(1 * 1) in ultrahigh vacuum. The wires have a width down to ~20 nm and hence have potential utility as interconnects on this dielectric substrate. Wire formation was achieved using an electron beam from a scanning electron microscope to activate the surface, which was subsequently exposed to Fe(CO)5. On the basis of scanning tunneling microscopy and Auger electron spectroscopy measurements, the activation mechanism involves electron beam induced surface reduction and restructuring. PMID- 24159365 TI - Sand fly-Leishmania interactions: long relationships are not necessarily easy. AB - Sand fly and Leishmania are one of the best studied vector-parasite models. Much is known about the development of these parasites within the sand fly, and how transmission to a suitable vertebrate host takes place. Various molecules secreted by the vector assist the establishment of the infection in a vertebrate, and changes to the vector are promoted by the parasites in order to facilitate or enhance transmission. Despite a generally accepted view that sand flies and Leishmania are also one of the oldest vector-pathogen pairs known, such long history has not been translated into a harmonic relationship. Leishmania are faced with many barriers to the establishment of a successful infection within the sand fly vector, and specific associations have been developed which are thought to represent aspects of a co-evolution between the parasite and its vectors. In this review, we highlight the journey taken by Leishmania during its development within the vector, and describe the issues associated with the natural barriers encountered by the parasite. Recent data revealed sexual replication of Leishmania within the sand fly, but it is yet unknown if such reproduction affects disease outcome. New approaches targeting sand fly molecules to prevent parasite transmission are being sought, and various techniques related to genetic manipulation of sand flies are being utilized. PMID- 24159367 TI - Obesity and Black Women: Special Considerations Related to Genesis and Therapeutic Approaches. AB - Black women in the United States are disproportionately affected by obesity, with almost two-thirds considered obese based on body mass index. Obesity has been directly linked to cardiovascular morbidity and mortality in black women. Therefore, understanding contributors to the genesis of obesity in black women is imperative. While biologic differences likely result in varying obesity prevalence across racial/ethnic groups, behaviors such as post-partum weight retention and limited leisure-time physical activity, may especially contribute to obesity in black women. Black women also appear to be particularly susceptible to cultural, psychosocial, and environmental factors that can promote weight gain. Therapeutic interventions are being tailored to specifically address these social determinants of health and to foster lifestyle modification; however, more work is needed to understand barriers to behavior change for black women. Knowledge gaps also remain in identifying mechanisms by which pharmacologic and surgical treatments for obesity modify cardiovascular risk in black women. PMID- 24159368 TI - Pharmacokinetics, metabolism, and in vivo efficacy of the antimalarial natural product bromophycolide A. AB - A suite of pharmacokinetic and pharmacological studies show that bromophycolide A (1), an inhibitor of drug-sensitive and drug-resistant Plasmodium falciparum, displays a typical small molecule profile with low toxicity and good bioavailability. Despite susceptibility to liver metabolism and a short in vivo half-life, 1 significantly decreased parasitemia in a malaria mouse model. Combining these data with prior SAR analyses, we demonstrate the potential for future development of 1 and its bioactive ester analogs. PMID- 24159369 TI - Differential transcription of virulence genes in Aggregatibacter actinomycetemcomitans serotypes. AB - BACKGROUND: Aggregatibacter actinomycetemcomitans serotypes are clearly associated with periodontitis or health, which suggests distinct strategies for survival within the host. OBJECTIVE: We investigated the transcription profile of virulence-associated genes in A. actinomycetemcomitans serotype b (JP2 and SUNY 465) strains associated with disease and serotype a (ATCC 29523) strain associated with health. DESIGN: Bacteria were co-cultured with immortalized gingival epithelial cells (OBA-9). The adhesion efficiency after 2 hours and the relative transcription of 13 genes were evaluated after 2 and 24 hours of interaction. RESULTS: All strains were able to adhere to OBA-9, and this contact induced transcription of pgA for polysaccharide biosynthesis in all tested strains. Genes encoding virulence factors as Omp29, Omp100, leukotoxin, and CagE (apoptotic protein) were more transcribed by serotype b strains than by serotype a. ltxA and omp29, encoding the leukotoxin and the highly antigenic Omp29, were induced in serotype b by interaction with epithelial cells. Factors related to colonization (aae, flp, apaH, and pgA) and cdtB were upregulated in serotype a strain after prolonged interaction with OBA-9. CONCLUSION: Genes relevant for surface colonization and interaction with the immune system are regulated differently among the strains, which may help explaining their differences in association with disease. PMID- 24159370 TI - Ovine fetal renal development impacted by multiple fetuses and uterine space restriction. AB - Intrauterine growth restriction (IUGR) from uteroplacental dysfunction causes impaired nephrogenesis and ultimately hypertension, but it is unknown whether IUGR caused by insufficient space for placental development seen in uterine anomalies and/or multifetal gestation exerts the same effects. Fetal renal development and metabolism were studied in an ovine space-restriction model by combining unilateral horn surgical ligation and/or multifetal gestation. Reduced placental attachment sites and placental weight per fetus defined space restricted (USR) v. control nonrestricted (NSR) fetuses. Space-restricted fetuses exhibited evidence for decreased plasma volume, with higher hematocrit and plasma albumin at gestational day (GD) 120, followed by lower blood pO2, and higher osmolarity and creatinine at GD130, P < 0.05 for all. By combining treatments, fetal kidney weight relative to fetal weight was inversely related to both fetal weight and plasma creatinine levels, P < 0.05 for both. At GD130, space restricted fetal kidney weights, cortical depths and glomerular generations were decreased, P < 0.05 for all. Space-restricted kidneys underwent an adaptive response by prolonging active nephrogenesis and increasing maculae densa number, P < 0.05 for both. The major renal adaptations in space-restricted IUGR fetuses included immaturity in both development and endocrine function, with evidence for impaired renal excretory function. PMID- 24159372 TI - Assessing DNA Damage from Enzyme-Oxidized Single-Walled Carbon Nanotubes. AB - Peroxidase enzyme digests of oxidized single-wall carbon nanotubes (SWCNT) were shown to damage DNA in potentially genotoxic reactions for the first time using an electro-optical array with and without metabolic activation. PMID- 24159371 TI - Lipid metabolism emerges as a promising target for malignant glioma therapy. AB - Malignant gliomas are one of the most treatment-refractory cancers. Development of resistance to chemo- and radio-therapies contributes to these tumors' aggressive phenotypes. Elevated lipid levels in gliomas have been reported for the last 50 years. However, the molecular mechanisms of how tumor tissues obtain lipids and utilize them are not well understood. Recently, the oncogenic signaling EGFR/PI3K/Akt pathway has been shown to enhance lipid synthesis and uptake by upregulating SREBP-1, a master transcriptional factor, to control lipid metabolism. This article discusses the analytical chemistry results of lipid components in glioma tissues from different research groups. The molecular mechanisms that link oncogenes with lipid programming, and identification of the key molecular targets and development of effective drugs to inhibit lipid metabolism in malignant gliomas will be discussed. PMID- 24159373 TI - Asymmetric synthesis of alpha-alkenyl homoallylic primary amines via 1,2-addition of Grignard reagent to alpha,beta-unsaturated phosphonyl imines. AB - A series of chiral N-phosphonyl protected alpha-alkenyl homoallylic primary amines were synthesized by asymmetric addition of allylmagnesium bromide Grignard reagent towards chiral alpha,beta-unsaturated imines. Only 1,2-adduct was obtained for all the imines with good yields and excellent diastereoselectivities. The chiral auxiliary could be easily removed under simple conditions, giving free multiple functionalized primary amines. PMID- 24159374 TI - Selective Delivery of an Anticancer Drug with Aptamer-Functionalized Liposomes to Breast Cancer Cells in Vitro and in Vivo. AB - Selective targeting of cancer cells is a critical step in cancer diagnosis and therapy. To address this need, DNA aptamers have attracted significant attention as possible targeting ligands. However, while their use in targeting cancer cells in vitro has been reported, their effectiveness has rarely been established in vivo. Here we report the development of a liposomal drug delivery system for targeted anticancer chemotherapy. Liposomes were prepared containing doxorubicin as a payload, and functionalized with AS1411, a DNA aptamer with strong binding affinity for nucleolin. AS1411 aptamer-functionalized liposomes increased cellular internalization and cytotoxicity to MCF-7 breast cancer cells as compared to non-targeting liposomes. Furthermore, targeted liposomal doxorubicin improved antitumor efficacy against xenograft MCF-7 breast tumors in athymic nude mice, attributable to their enhanced tumor tissue penetration. This study suggests that AS1411 aptamer-functionalized liposomes can recognize nucleolin overexpressed on MCF-7 cell surface, and therefore enable drug delivery with high specificity and selectivity. PMID- 24159375 TI - Endoplasmic Reticulum Stress Activation during Total Knee Arthroplasty. AB - Total knee arthroplasty (TKA) is the most common remediation for knee pain from osteoarthritis (OA) and is performed 650,000 annually in the U.S. A tourniquet is commonly used during TKA which causes ischemia and reperfusion (I/R) to the lower limb but the effects of I/R on muscle are not fully understood. Previous reports suggest upregulation of cell-stress and catabolism and downregulation of markers of cap-dependent translation during and after TKA. I/R has also been shown to cause endoplasmic reticulum (ER) stress and induce the unfolded protein response (UPR). We hypothesized that the UPR would be activated in response to ER stress during TKA. We obtained muscle biopsies from the vastus lateralis at baseline, before TKA; at maximal ischemia, prior to tourniquet deflation; and during reperfusion in the operating room. Phosphorylation of 4E-BP1 and AKT decreased during ischemia (-28%, p < .05; -20%, p < .05 respectively) along with an increase in eIF2alpha phosphorylation (64%, p < .05) suggesting decreased translation initiation. Cleaved ATF6 protein increased in ischemia (39%, p = .056) but returned to baseline during reperfusion. CASP3 activation increased during reperfusion compared to baseline (23%, p < .05). XBP1 splicing assays revealed an increase in spliced transcript during ischemia (31%, p < .05) which diminished during reperfusion. These results suggest that in response to I/R during TKA all three branches of the ER stress response are activated. PMID- 24159377 TI - Evidence for the involvement of NADPH oxidase in adenosine receptors-mediated control of coronary flow using A1 and A3 knockout mice. AB - The NADPH oxidase (Nox) subunits 1, 2 (gp91 phox) and 4 are the major sources for reactive oxygen species (ROS) in cardiovascular system. In conditions such as ischemia-reperfusion injury and hypoxia, both ROS and adenosine are released suggesting a possible interaction. We hypothesized that ROS generated through Nox is involved in adenosine-induced coronary flow (CF) responses. Adenosine (10-8-10 5.5 M) increased CF in isolated hearts from wild type (WT; C57/BL6), A1 adenosine receptor (AR) knockout (A1KO), A3AR KO (A3KO) and A1 and A3AR double KO (A1/A3DKO) mice. The Nox inhibitors apocynin (10-5 M) and gp91 ds-tat (10-6 M) or the SOD and catalase-mimicking agent EUK134 (50 MUM) decreased the adenosine enhanced CF in the WT and all the KOs. Additionally, adenosine increased phosphorylation of p47-phox subunit and ERK 1/2 without changing protein expression of Nox isoforms in WT. Moreover, intracellular superoxide production was increased by adenosine and CGS-21680 (a selective A2A agonist), but not BAY 60-6583 (a selective A2B agonist), in mouse coronary artery smooth muscle cells (CASMCs) and endothelial cells (CAECs). This superoxide increase was inhibited by the gp91 ds-tat and ERK 1/2 inhibitor (PD98059). In conclusion, adenosine-induced increase in CF in isolated heart involves Nox2-generated superoxide, possibly through ERK 1/2 phosphorylation with subsequent p47-phox subunit phosphorylation. This adenosine/Nox/ROS interaction occurs in both CASMCs and CAECs, and involves neither A1 nor A3 ARs, but possibly A2A ARs in mouse. PMID- 24159376 TI - Matrix Metalloproteinase Inhibition Mitigates Renovascular Remodeling in Salt Sensitive Hypertension. AB - Extracellular matrix (ECM) remodeling is the hallmark of hypertensive nephropathy. Uncontrolled proteolytic activity due to an imbalance between matrix metalloproteinases and tissue inhibitors of metalloproteinases (MMPs/TIMPs) has been implicated in renovascular fibrosis. We hypothesized that inhibition of MMPs will reduce excess ECM deposition and modulate autophagy to attenuate hypertension. Dahl-salt sensitive (Dahl/SS) and Lewis rats were fed on high salt diet and treated without or with 1.2 mg/kg b.w. of GM6001 (MMP inhibitor) by intra-peritoneal injection on alternate days for 4 weeks. Blood pressure, renal cortical blood flow, vascular density, collagen, elastin and MMPs/TIMPs were measured. GM6001 treatment significantly reduced mean blood pressure in hypertensive Dahl/SS rats. Renal resistive index was increased in hypertensive Dahl/SS rats and Doppler flowmetry showed reduced cortical perfusion. Barium angiography demonstrated a reduction in terminal branches of renal vasculature. Inhibition of MMPs by GM6001 resulted in a significant improvement in all the parameters including renal function. In hypertensive Dahl/SS rats, protein levels of MMP-9, -2 and -13 were increased including the activity of MMP-9 and -2; TIMP 1 and -2 levels were increased whereas, TIMP-3 levels were similar to Lewis controls. Administration of GM6001 reduced the activity of MMPs and increased the levels of TIMP-1, -2 and -3. MMP inhibition reduced type -1 collagen deposition and increased elastin in the intra-renal vessels indicating reduced fibrosis. Autophagy markers were decreased in hypertensive Dahl/SS rats and GM6001 treatment enhanced their levels. We conclude that MMP inhibition (GM6001) reduces adverse renovascular remodeling in hypertension by modulating ECM turnover and stimulating autophagy. PMID- 24159378 TI - Obese melanocortin-4 receptor-deficient rats exhibit augmented angiogenic balance and vasorelaxation during pregnancy. AB - While obesity is a major risk factor for preeclampsia, the mechanisms linking obesity and hypertension during preeclampsia remain unclear. Hypertension in preeclampsia is associated with placental ischemia-induced release of anti angiogenic soluble fms-like tyrosine kinase (sFlt-1) into the maternal circulation, which antagonizes vascular endothelial growth factor (VEGF) promoting endothelial dysfunction. Haploinsufficiency, defined as loss of one copy of a gene via a mutation, of the melanocortin-4 receptor (MC4R) is the most common cause of monogenetic obesity in humans. The purpose of our study was to determine the effects of genetic obesity on angiogenic balance, endothelial function, and blood pressure in pregnant MC4R+/- and MC4R+/+ rats. At gestational day (GD) 18, body weight and total body fat mass were greater in MC4R+/- than MC4R+/+ rats. On GD 19, plasma sFlt-1 was not significantly different between groups. Interestingly, circulating VEGF was greater in the obese rats with the source being adipose tissue and not the placenta. Wire myography showed in third order mesenteric arteries that sensitivity (logEC50) to endothelial dependent and nitric oxide donor-induced vasorelaxation was greater in MC4R+/- versus MC4R+/+. Mean arterial blood pressure was similar between groups. In conclusion, under normal pregnant conditions, genetically obese pregnant animals have greater angiogenic balance and dependency of vasorelaxation on nitric oxide signaling protecting against the development of hypertension. However, we speculate that, in the face of reduced uterine perfusion, a rise in circulating placental factors that target and reduce nitric oxide bioavailability exposes the susceptibility of genetically obese animals to greater hypertension in pregnancy. PMID- 24159379 TI - Afferent Arteriolar Responses to beta,gamma-methylene ATP and 20-HETE are not Blocked by ENaC Inhibition. AB - Afferent arteriolar myogenic and tubuloglomerular feedback responses are critical for the proper maintenance of renal hemodynamics and water and electrolyte homeostasis. adenosine triphosphate (ATP) P2X receptor activation and 20 hydroxyeicosatetraenoic (20-HETE) have been implicated in afferent arteriolar autoregulatory responses. Besides these two participants, members of the degenerin/epithelial Na+ channel (DEG/ENaC) family have been demonstrated to play a pivotal role in the afferent arteriolar myogenic response. The aim of the present study was to determine if ENaC contributes to P2X receptor- or 20-HETE mediated afferent arteriolar vasoconstriction. As previously demonstrated, afferent arteriolar diameter responses to increasing perfusion pressure from 100 to 160 mmHg were abolished by ENaC inhibitors amiloride or benzamil. Afferent arteriolar diameter decreased by 29% under control conditions and by 1 and 5% in the presence of amiloride or benzamil, respectively. The P2X receptor agonist beta,gamma-methylene ATP decreased afferent arteriolar diameter by 3 +/- 1%, 7 +/ 1%, 12 +/- 2%, and 17 +/- 3% in response to 0.1, 1, 10, and 100MUmol/L, respectively. ENaC inhibition did not alter the afferent arteriolar vasoconstrictor response to the P2X receptor agonist beta,gamma-methylene ATP. Like P2X receptor activation, 20-HETE dose-dependently decreased afferent arteriolar diameter and this vasoconstrictor response was not altered by the presence of ENaC inhibitors amiloride or benzamil. These results suggest that DEG/ENaC channels are required for afferent arteriolar autoregulatory responses; however, DEG/ENaC channels do not contribute to P2X receptor- or 20-HETE-mediated afferent arteriolar vasoconstriction. PMID- 24159380 TI - Circulating Porphyromonas gingivalis lipopolysaccharide resets cardiac homeostasis in mice through a matrix metalloproteinase-9-dependent mechanism. AB - Porphyromonas gingivalis lipopolysaccharide (Pg-LPS) circulates systemically in over 50% of periodontal disease (PD) patients and is associated with increased matrix metalloproteinase (MMP)-9. We hypothesized that low systemic Pg-LPS would stimulate an inflammatory response in the left ventricle (LV) through MMP-9, leading to a decrease in cardiac function. Wild-type (WT) and MMP-9 null mice (4 7 months old) were exposed for 1 or 28 days to low dose Pg-LPS or saline (n >= 6/group). MMP-9 significantly increased in WT mice LV at 1 and 28 days of exposure, compared to control (P < 0.05 for both). Fractional shortening decreased subtly yet significantly in WT mice by day 28 (31 +/- 1%) compared to control (35 +/- 1%; P < 0.05), and this decrease was attenuated in null (34 +/- 1%) mice. Plasma cardiac troponin I levels were elevated in WT mice at day 28. Macrophage-related factors increased over twofold in WT plasma and LV after day 1 (monocyte chemoattractant protein-5, macrophage inflammatory protein (MIP) 1alpha, MIP-1gamma, stem cell factor, Ccl12, Ccl9, Il8rb, Icam1, Itgb2, and Spp1; all P < 0.05), indicating a moderate inflammatory response. Levels returned to baseline by day 28, suggesting tolerance to Pg-LPS. In contrast, macrophage related factors remained elevated in day 28 null mice, indicating a sustained defense against Pg-LPS stimulation. Consistent with these findings, LV macrophage numbers increased in both groups at day 1 and returned to baseline by day 28 in the WT mice only. Major histocompatibility complex (MCH) II remained elevated in the null group at day 28, confirming Pg-tolerance in the WT. Interestingly Il 1alpha, a regulator of macrophage immunosuppression, increased in the plasma of WT mice only on day 28, suggesting that Il-1alpha plays a role in tolerance in a MMP-9-dependent manner. In conclusion, circulating Pg-LPS induced tolerance in WT mice, resulting in significant LV changes and subtle cardiac dysfunction. MMP-9 played a major role in the regulation of chronic systemic inflammation and associated cardiac dysfunction. PMID- 24159381 TI - Purification and Properties of Polygalacturonase Produced by Thermophilic Fungus Thermoascus aurantiacus CBMAI-756 on Solid-State Fermentation. AB - Polygalacturonases are enzymes involved in the degradation of pectic substances, being extensively used in food industries, textile processing, degumming of plant rough fibres, and treatment of pectic wastewaters. Polygalacturonase (PG) production by thermophilic fungus Thermoascus aurantiacus on solid-state fermentation was carried out in culture media containing sugar cane bagasse and orange bagasse in proportions of 30% and 70% (w/w) at 45 degrees C for 4 days. PG obtained was purified by gel filtration and ion-exchange chromatography. The highest activity was found between pH 4.5 and 5.5, and the enzyme preserved more than 80% of its activity at pH values between 5.0 and 6.5. At pH values between 3.0 and 4.5, PG retained about 73% of the original activity, whereas at pH 10.0 it remained around 44%. The optimum temperature was 60-65 degrees C. The enzyme was completely stable when incubated for 1 hour at 50 degrees C. At 55 degrees C and 60 degrees C, the activity decreased 55% and 90%, respectively. The apparent molecular weight was 29.3 kDa, K m of 1.58 mg/mL and V max of 1553.1 MU mol/min/mg. The presence of Zn(+2), Mn(+2), and Hg(+2) inhibited 59%, 77%, and 100% of enzyme activity, respectively. The hydrolysis product suggests that polygalacturonase was shown to be an endo/exoenzyme. PMID- 24159382 TI - Purification and Characterization of Phenylalanine Ammonia Lyase from Trichosporon cutaneum. AB - Trichosporon cutaneum phenylalanine ammonia lyase was selected as a model to investigate the dual substrate activity of this family of enzymes. Sequencing of the PAL gene identified an extensive intron region at the N-terminus. Five amino acid residues differing from a prior report were identified. Highest Phe : Tyr activities (1.6 +/- 0.3 : 0.4 +/- 0.1 MU mol/h g wet weight) were induced by Tyr. The enzyme has a temperature optimum of 32 degrees C and a pH optimum of 8 8.5 and shows no metal cofactor dependence. Michaelis-Menten kinetics (Phe, K m 5.0 +/- 1.1 mM) and positive allostery (Tyr, K' 2.4 +/- 0.6 mM, Hill coefficient 1.9 +/- 0.5) were observed. Anion exchange chromatography gave a purification fold of 50 with 20% yield. The His-Gln motif (substrate selectivity switch region) indicates the enzyme's ability to act on both substrates. PMID- 24159383 TI - Smartphone Delivery of Mobile HIV Risk Reduction Education. AB - We sought to develop and deploy a video-based smartphone-delivered mobile HIV Risk Reduction (mHIVRR) intervention to individuals in an addiction treatment clinic. We developed 3 video modules that consisted of a 10-minute HIVRR video, 11 acceptability questions, and 3 knowledge questions and deployed them as a secondary study within a larger study of ecological momentary and geographical momentary assessments. All 24 individuals who remained in the main study long enough completed the mHIVRR secondary study. All 3 videos met our a priori criteria for acceptability "as is" in the population: they achieved median scores of <=2.5 on a 5-point Likert scale; <=20% of the individuals gave them the most negative rating on the scale; a majority of the individuals stated that they would not prefer other formats over video-based smartphone-delivered one (all P < 0.05). Additionally, all of our video modules met our a priori criteria for feasibility: <=20% of data were missing due to participant noncompliance and <=20% were missing due to technical failure. We concluded that video-based mHIVRR education delivered via smartphone is acceptable, feasible and may increase HIV/STD risk reduction knowledge. Future studies, with pre-intervention assessments of knowledge and random assignment, are needed to confirm these findings. PMID- 24159384 TI - Point-of-Care HIV Testing and Linkage in an Urban Cohort in the Southern US. AB - The Southern states experience the highest rates of HIV and AIDS in the US, and point-of-care (POC) testing outside of primary care may contribute to status awareness in medically underserved populations in this region. To evaluate POC screening and linkage to care at an urban south site, analyses were performed on a dataset of 3,651 individuals from an integrated rapid-result HIV testing and linkage program to describe this test-seeking cohort and determine trends associated with screening, results, and linkage to care. Four percent of the population had positive results. We observed significant differences by test result for age, race and gender, reported risk behaviors, test location, and motivation for screening. The overall linkage rate was 86%, and we found significant differences for clients who were linked to HIV care versus persons whose linkage could not be confirmed with respect to race and gender, location, and motivation. The linkage rate for POC testing that included a comprehensive intake visit and colocated primary care services for in-state residents was 97%. Additional research on integrated POC screening and linkage methodologies that provide intake services at time of testing is essential for increasing status awareness and improving linkage to HIV care in the US. PMID- 24159385 TI - Epilepsy surgery: factors that affect patient decision-making in choosing or deferring a procedure. AB - Surgical resection for well-selected patients with refractory epilepsy provides seizure freedom approximately two-thirds of the time. Despite this, many good candidates for surgery, after a presurgical workup, ultimately do not consent to a procedure. The reasons why patients decline potentially effective surgery are not completely understood. We explored the socio cultural, medical, personal, and psychological differences between candidates who chose (n = 23) and those who declined surgical intervention (n = 9). We created a novel questionnaire addressing a range of possible factors important in patient decision making. We found that patients who declined surgery were less bothered by their epilepsy (despite comparable severity), more anxious about surgery, and less likely to listen to their doctors (and others) and had more comorbid psychiatric disease. Patients who chose surgery were more embarrassed by their seizures, more interested in being "seizure-free", and less anxious about specific aspects of surgery. Patient attitudes, beliefs, and anxiety serve as barriers to ideal care. These results can provide opportunities for education, treatment, and intervention. Additionally, patients who fit a profile of someone who is likely to defer surgery may not be appropriate for risky and expensive presurgical testing. PMID- 24159387 TI - Screening prior to Breast Cancer Diagnosis: The More Things Change, the More They Stay the Same. AB - Purpose. In November 2009, the U.S. Preventative Service Task Force (USPSTF) revised their breast cancer screening guidelines. We evaluated the pattern of screening subsequent to the altered guidelines in a cohort of women. Methods. Our database was queried for the following variables: age, race, method of diagnosis, mass palpability, screening frequency, histology, and stage. Statistical analyses were performed using Pearson's chi-square and Fisher's exact tests. Results. 1112 women were diagnosed with breast cancer from January 2010 to 2012. The median age at diagnosis was 60 years. Most cancers were detected on mammography (61%). The majority of patients had invasive ductal carcinoma (59%), stage 0 (23%), and stage 1 (50%) cancers. The frequency of screening did not change significantly over time (P = 0.30). However, nonregular screeners had an increased risk of being diagnosed with later stage breast cancer (P < 0.001) and were more likely to present with a palpable mass compared to regular screeners (56% versus 21%; P < 0.001). Conclusions. In our study, screening behavior did not significantly change in the years following the USPSTF guidelines. These results suggest that women who are not screened annually are at increased risk of a delay in breast cancer diagnosis, which may impact treatment options and outcomes. PMID- 24159388 TI - Synergistic Effects of Nonthermal Plasma and Disinfecting Agents against Dental Biofilms In Vitro. AB - Aim. Dental biofilms play a major role in the pathogenesis of many dental diseases. In this study, we evaluated the synergistic effect of atmospheric pressure plasma and different agents in dentistry on the reduction of biofilms. Methods and Results. We used monospecies (S. mutans) and multispecies dental biofilm models grown on titanium discs in vitro. After treatment with one of the agents, the biofilms were treated with plasma. Efficacy of treatment was determined by the number of colony forming units (CFU) and by live-dead staining. For S. mutans biofilms no colonies could be detected after treatment with NaOCl or H2O2. For multispecies biofilms the combination with plasma achieved a higher CFU reduction than each agent alone. We found an additive antimicrobial effect between argon plasma and agents irrespective of the treatment order with cultivation technique. For EDTA and octenidine, antimicrobial efficacy assessed by live-dead staining differed significantly between the two treatment orders (P < 0.05). Conclusions. The effective treatment of dental biofilms on titanium discs with atmospheric pressure plasma could be increased by adding agents in vitro. PMID- 24159386 TI - How sleep activates epileptic networks? AB - Background. The relationship between sleep and epilepsy has been long ago studied, and several excellent reviews are available. However, recent development in sleep research, the network concept in epilepsy, and the recognition of high frequency oscillations in epilepsy and more new results may put this matter in a new light. Aim. The review address the multifold interrelationships between sleep and epilepsy networks and with networks of cognitive functions. Material and Methods. The work is a conceptual update of the available clinical data and relevant studies. Results and Conclusions. Studies exploring dynamic microstructure of sleep have found important gating mechanisms for epileptic activation. As a general rule interictal epileptic manifestations seem to be linked to the slow oscillations of sleep and especially to the reactive delta bouts characterized by A1 subtype in the CAP system. Important link between epilepsy and sleep is the interference of epileptiform discharges with the plastic functions in NREM sleep. This is the main reason of cognitive impairment in different forms of early epileptic encephalopathies affecting the brain in a special developmental window. The impairment of cognitive functions via sleep is present especially in epileptic networks involving the thalamocortical system and the hippocampocortical memory encoding system. PMID- 24159390 TI - Effect of Patency File on Transportation and Curve Straightening in Canal Preparation with ProTaper System. AB - The aim of this ex vivo study was to evaluate the effect of using a patency file on apical transportation and curve straightening during canal instrumentation with the ProTaper rotary system. Seventy permanent mandibular first molars with mesiobuccal canals, measuring 18-23 mm in length and with a 25-40 degrees curvature (according to the Schneider method), were selected. The working lengths were determined and the teeth were mounted and divided into two experimental groups: (A) prepared by the ProTaper system without using a patency file (n = 35) and (B) prepared by the ProTaper system using a patency file (n = 35). Radiographs taken before and after the preparation were imported into Photoshop software and the apical transportation, and curve straightening were measured. Data were analyzed using independent t-test. Partial correlation analysis was performed to evaluate the relationship between the initial curvature, transportation, and curve straightening (alpha = 0.05). Using a patency file during canal preparation significantly decreased both apical transportation and curve straightening (P < 0.001). There were significant relationships between the angle of curvature, transportation and curve straightening in pairs (P < 0.001). Apical patency is recommended during root canal preparation with the ProTaper rotary system. PMID- 24159391 TI - Portal hypertension and myeloproliferative neoplasms: a relationship revealed. AB - Background/Objectives. Patients with myeloproliferative neoplasms have a well established increased risk of thrombosis. Many trials report identification of an underlying myeloproliferative neoplasm by investigation of the patients developing portal hypertensive esophagus and/or fundus variceal hemorrhage in the absence of any known etiology. This trial was designed to investigate the association between myeloproliferative neoplasms and portal hypertension and to detect the frequency of portal hypertension development in this subset of patients. Methodology. Twenty-nine patients previously diagnosed with polycythemia vera, essential thrombocytopenia, and primary myelofibrosis, who were under followup at the hematology outpatient clinic of our hospital, were included in the trial. Results. In our trial, we detected portal hypertension in 13.8% of the patients (n = 4), as a finding that was similar to those obtained in other studies performed to date. Conclusions. Considering the fact that diagnosis of myeloproliferative neoplasms usually takes a long time, treatment should be started (while, on the other hand, assessing the investigational and therapeutical choices for the complications) right after the bone marrow biopsy or cytogenetic studies required for establishing the final diagnosis have been performed. PMID- 24159389 TI - Dental enamel development: proteinases and their enamel matrix substrates. AB - This review focuses on recent discoveries and delves in detail about what is known about each of the proteins (amelogenin, ameloblastin, and enamelin) and proteinases (matrix metalloproteinase-20 and kallikrein-related peptidase-4) that are secreted into the enamel matrix. After an overview of enamel development, this review focuses on these enamel proteins by describing their nomenclature, tissue expression, functions, proteinase activation, and proteinase substrate specificity. These proteins and their respective null mice and human mutations are also evaluated to shed light on the mechanisms that cause nonsyndromic enamel malformations termed amelogenesis imperfecta. Pertinent controversies are addressed. For example, do any of these proteins have a critical function in addition to their role in enamel development? Does amelogenin initiate crystallite growth, does it inhibit crystallite growth in width and thickness, or does it do neither? Detailed examination of the null mouse literature provides unmistakable clues and/or answers to these questions, and this data is thoroughly analyzed. Striking conclusions from this analysis reveal that widely held paradigms of enamel formation are inadequate. The final section of this review weaves the recent data into a plausible new mechanism by which these enamel matrix proteins support and promote enamel development. PMID- 24159392 TI - Skin photoaging and the role of antioxidants in its prevention. AB - Photoaging of the skin depends primarily on the degree of ultraviolet radiation (UVR) and on an amount of melanin in the skin (skin phototype). In addition to direct or indirect DNA damage, UVR activates cell surface receptors of keratinocytes and fibroblasts in the skin, which leads to a breakdown of collagen in the extracellular matrix and a shutdown of new collagen synthesis. It is hypothesized that dermal collagen breakdown is followed by imperfect repair that yields a deficit in the structural integrity of the skin, formation of a solar scar, and ultimately clinically visible skin atrophy and wrinkles. Many studies confirmed that acute exposure of human skin to UVR leads to oxidation of cellular biomolecules that could be prevented by prior antioxidant treatment and to depletion of endogenous antioxidants. Skin has a network of all major endogenous enzymatic and nonenzymatic protective antioxidants, but their role in protecting cells against oxidative damage generated by UV radiation has not been elucidated. It seems that skin's antioxidative defence is also influenced by vitamins and nutritive factors and that combination of different antioxidants simultaneously provides synergistic effect. PMID- 24159393 TI - Diagnostic value of the combined measurement of serum hcy, serum cys C, and urinary microalbumin in type 2 diabetes mellitus with early complicating diabetic nephropathy. AB - Diabetic nephropathy (DN) is a major cause of end-stage kidney disease, and therefore early diagnosis and intervention may help reverse renal damage. One hundred and sixty-eight patients with T2DM and 56 healthy volunteers (control group) were enrolled at Shandong University Qilu Hospital between April 2010 and October 2012. All subjects underwent blood sampling for sera homocysteine (Hcy) and cystatin C (Cys C) assays and a urine microalbumin test. The patients were divided into three groups according to the urine microalbumin excretion rate (UMAER): the simple DM group (SDM group, n = 51), the early-stage DN group (EDN group, n = 60), and the clinical DN and renal failure group (CDN group, n = 57). Correlation analysis was performed to examine the association between sera Hcy and Cys C levels with UMAER. Our findings showed that sera Hcy level, Cys C level, and UMAER increased significantly in the SDM group (P < 0.05, P < 0.01), the EDN group (P < 0.01), and the CDN group (P < 0.01) as compared with the control group. These three biochemical markers also increased significantly with DN progression (P < 0.01). Correlation analysis showed that sera Hcy and Cys C levels were positively correlated with UMAER (r = 0.702, P < 0.01; r = 0.873, P < 0.01). In conclusion, our results showed that sera Hcy and Cys C levels increased consistently with the development and progression of DN as indicated by UMAER. Sera Hcy and Cys C are sensitive biomarkers for the detection of early-stage DN and monitoring its progression. PMID- 24159394 TI - SPECT-CT Assessment of Pseudarthrosis after Spinal Fusion: Diagnostic Pitfall due to a Broken Screw. AB - A 43-year-old drug addicted female was referred for a L5-S1 posterolateral in situ fixation with autologous graft because of an L5/S1 severe discopathy with listhesis. After six months, low back pain recurred. A Tc-99m HDP SPECT-CT diagnosed a pseudarthrosis with intense uptake of the L5-S1 endplates and a fracture of the right S1 screw just outside the metal-bone interface without any uptake or bone resorption around the screw. The absence of uptake around a broken screw is a pitfall that the physician should be aware of. PMID- 24159395 TI - Pigmented villonodular synovitis of the thoracic vertebra presenting with progressive spastic paraparesis. AB - Pigmented villonodular synovitis (PVNS) is a proliferative benign lesion originating from the synovium and commonly affects large joints of the extremities. PVNS can arise from any synovium in the whole body and rarely affects the zygapophyseal joints of the spine. Spinal PVNS is diagnosed mostly after resection of the mass. In our case we present a 22-year-old male patient showing progressive spastic paraparesis with insidious onset of back pain and difficulty of walking in a relatively short period of 1 month. After gross excision of the mass, diagnosis was established through histopathology. Two years of follow-up period reveals complete resolution of the patient's complaints and no recurrence on radiologic images. PMID- 24159396 TI - A case of primary submandibular gland oncocytic carcinoma. AB - Primary submandibular gland oncocytic carcinoma is a rare pathology, with only 10 cases being reported to date. We encountered a case of primary submandibular gland oncocytic carcinoma and report it herein. The patient was a 69-year-old man who came to our hospital with right submandibular cancer as the main complaint. Based on the results of computed tomography and magnetic resonance imaging, submandibular gland tumor was diagnosed. Preoperative cytodiagnosis suggested class III oncocytic carcinoma. Resection of the right submandibular tumor was performed along with right neck dissection. Postoperative histopathological diagnosis was oncocytic carcinoma. As of 3 years following surgery, no recurrence has been identified. PMID- 24159397 TI - Optimal postoperative treatment for composite laryngeal small cell carcinoma. AB - Small cell carcinoma (SmCC) most commonly occurs in the lung and rarely arises from the head and neck region. Further, composite SmCC is extremely rare. Therefore, no postoperative treatment strategy has been established. We report a 59-year-old male patient referred to our outpatient clinic for further examination and treatment of a laryngeal tumor. Biopsy from the tumor revealed squamous cell carcinoma (SCC). The preoperative diagnosis was supraglottic SCC (T3N2bM0), and total laryngectomy and bilateral neck dissection were performed. Pathological examination revealed 2 individual cancer components: SmCC and SCC. Postoperative chemoradiotherapy (2 courses of cisplatin (CDDP) and etoposide (VP 16)) was indicated. Following the postoperative chemoradiotherapy, 2 courses of adjuvant chemotherapy were administered. The patient is currently alive with no evidence of disease at 36 months following the completion of therapy. Postoperative chemoradiotherapy and adjuvant chemotherapy are optimal treatment strategies for laryngeal composite SmCC. PMID- 24159398 TI - A rare case of suppurative aspergillosis of the thyroid. AB - Suppurative fungal infection of the thyroid is an extremely rare condition even more so in an immunocompetent patient. Fungal infections of the thyroid usually occur in immunocompromised patients with hematological malignancies, recipients of bone marrow and solid organ allografts on immunosuppression, and patients with AIDS. A 65-year-old male presented with swelling in the front of the neck for 2 years. Examination revealed a 4 * 4 cm non-tender, firm swelling of the right lobe of the thyroid. The patient was taken up for a subtotal thyroidectomy. Intra operatively, an abscess cavity with pus was found in the right lobe of the thyroid. Histopathology revealed features of fungal abscess and staining demonstrated fungal hyphae characteristic of Aspergillus ssp. PMID- 24159399 TI - Squamous cell papilloma of the urinary bladder endoscopically mimicking cancer. AB - Squamous cell lesions of the urinary bladder are generally rare. Herein we describe a case of 74-year-old male patient with a benign squamous cell papilloma. Histologically, the tumor presented extensive keratinization at its surface and showed no nuclear atypia or stromal invasion. The tumor cells were negative for HPV DNA. These lesions are extremely rare, and even though they are considered benign and non-HPV related, they should be followed, since recurrence has been reported. PMID- 24159400 TI - Septicemia in a Neonate following Therapeutic Hypothermia: The Literature Review of Evidence. AB - We report a term neonate with hypoxic ischemic encephalopathy who underwent a 72 hour therapeutic hypothermia. He developed unstable body temperature associated with coagulase negative staphylococcus septicemia 2 weeks later which was promptly treated with intravenous antibiotics and made a good recovery. PubMed (a service of the U.S. National Library of Medicine) was searched for the terms "therapeutic hypothermia" and "septicemia," with limits activated (humans, English, age 0-18 years). There were only 6 randomized controlled trials, 1 non randomized controlled trial, 1 retrospective cohort, and 1 case-control trial, which showed no definite evidence of increased risk of septicemia or neutrophil dysfunction in infants following hypothermia therapy. PMID- 24159401 TI - Congenital lumbar hernia with lumbocostovertebral syndrome: a case report and review of the literature. AB - Introduction. Congenital lumbar hernia is one of the rare types of hernias. Anomalies of the ribs, spine, and muscles which constitute the lumbocostovertebral syndrome in association with congenital lumbar hernia make it the rarest of entities. In addition, a multitude of other organ systems may be involved. Case Report. A case of congenital lumbar hernia associated with lumbocostovertebral syndrome is presented in view of its rarity and diagnostic and therapeutic challenges. Discussion. Anatomical background of congenital lumbar hernia associated with various other anomalies especially of the musculoskeletal structures is discussed. All cases of congenital lumbar hernia should be investigated for other congenital anomalies. Both open and laparoscopic approaches have been described for surgical treatment. Conclusion. Open surgical intervention is the mainstay of treatment taking into consideration the technical challenges posed by distorted anatomy due to the associated congenital anomalies. PMID- 24159402 TI - Pulmonary thromboembolism in a child with sickle cell hemoglobin d disease in the setting of acute chest syndrome. AB - Introduction. Sickle cell hemoglobin D disease (HbSD) is a rare variant of sickle cell disease (SCD). Incidence of pulmonary thromboembolism (PE) and deep venous thrombosis (DVT) in children with HbSD is unknown. PE and DVT are known complications of SCD in adults but have not been reported in the literature in children with HbSD. Case Report. We are reporting a case of a 12-year-old boy with HbSD with acute chest syndrome (ACS) complicated by complete thrombosis of the branch of the right pulmonary artery and multiple small pulmonary artery emboli seen on computed tomography (CT) pulmonary angiogram and thrombosis of the right brachial vein seen on Doppler ultrasound. Our patient responded to treatment with anticoagulant therapy. Conclusion. There are no cases reported in children with HbSD disease presenting as ACS with pulmonary thromboembolism. We suggest that PE should be suspected in patients presenting with ACS who do not show improvement with standard management. CT pulmonary angiogram should be utilized for early diagnosis and appropriate management as there is no current protocol for management of PE/DVT in pediatric patients with SCD. PMID- 24159403 TI - Multifocal extranodal involvement of diffuse large B-cell lymphoma. AB - Endobronchial involvement of extrapulmonary malignant tumors is uncommon and mostly associated with breast, kidney, colon, and rectum carcinomas. A 68-year old male with a prior diagnosis of colon non-Hodgkin lymphoma (NHL) was admitted to the hospital with a complaint of cough, sputum, and dyspnea. The chest radiograph showed right hilar enlargement and opacity at the right middle zone suggestive of a mass lesion. Computed tomography of thorax revealed a right-sided mass lesion extending to thoracic wall with the destruction of the third and the fourth ribs and a right hilar mass lesion. Fiberoptic bronchoscopy was performed in order to evaluate endobronchial involvement and showed stenosis with mucosal tumor infiltration in right upper lobe bronchus. The pathological examination of bronchoscopic biopsy specimen reported diffuse large B-cell lymphoma and the patient was accepted as the endobronchial recurrence of sigmoid colon NHL. The patient is still under treatment of R-ICE (rituximab-ifosfamide-carboplatin etoposide) chemotherapy and partial regression of pulmonary lesions was noted after 3 courses of treatment. PMID- 24159404 TI - Reversed halo sign in tuberous sclerosis complex. AB - We describe a reversed halo sign in a teenage girl with tuberous sclerosis complex (TSC). Lung manifestations of TSC include lung cysts corresponding to lymphangioleiomyomatosis and small nodules indicating multifocal micronodular pneumocyte hyperplasia (MMPH). However, a reversed halo sign in TSC has never been reported. The lesion was microscopically consistent with MMPH. Immunohistological findings also supported the notion that the lesion is associated with TSC. PMID- 24159405 TI - Vascular supply to the liver: a report of a rare arterial variant. AB - In the classic description of hepatic arterial supply, the common hepatic artery originates from the coeliac trunk. However, there are numerous variations to this classic pattern. We report a rare variant pattern of hepatic arterial supply and discuss the clinical significance of this variation. PMID- 24159406 TI - Repair of a post-hepatectomy posterior sectoral duct injury secondary to anomalous bile duct anatomy using a novel combined surgical-interventional radiologic approach. AB - A 64-year-old woman with a completely transected posterior sectoral duct following extended hepatectomy underwent a combined operative procedure with interventional radiology and surgery to restore biliary-enteric drainage. The anterior and posterior sectoral ducts were identified, and catheters were inserted into both systems. The posterior sectoral catheter was placed intraoperatively through a preoperatively placed sheath, and a new tunnel was created through the regenerated liver surface. Biliary-enteric anastomoses were created over the stents. PMID- 24159407 TI - Metastasis of thyroid cancer to the sternum after total thyroidectomy and laryngectomy. AB - Metastasis of thyroid cancer to the sternum is rare. Ablation is the therapy of choice for patients with metastasizing differentiated thyroid cancer, while surgical resection is an option for those with resectable bony metastasis. This report describes a case of a 65-year-old woman with a sternal tumor. The patient was treated by partial sternal resection and sternal reconstruction with new material polypropylene/expanded polytetrafluoroethylene (ePTFE) composite. The postoperative course was uneventful, and she was free of recurrence after 1 year of follow-up. We conclude that surgery should be used to manage solid bony metastasis from thyroid papillary carcinoma. Further more, a polypropylene/ePTFE composite may be useful for sternal reconstruction after thoracotomy. PMID- 24159409 TI - Mesothelial cyst of the round ligament misdiagnosed as irreducible inguinal hernia. AB - We report the case of a 36-year-old woman who presented with signs and symptoms of an irreducible inguinal hernia. Surgical exploration revealed a mesothelial cyst of the round ligament of the uterus. Mesothelial cysts of the round ligament are rare lesions, frequently masquerading as inguinal hernias, and should be included in the differential diagnosis of any inguinal mass. Clinical findings are those of a groin mass, discomfort, and bulging. Ultrasound and CT scans often demonstrate an aperistaltic cystic mass. Definitive diagnosis is usually made intraoperatively and confirmed histopathologically. PMID- 24159408 TI - En masse resection of pancreas, spleen, celiac axis, stomach, kidney, adrenal, and colon for invasive pancreatic corpus and tail tumor. AB - Providing a more comfortable life and a longer survival for pancreatic corpus/tail tumors without metastasis depends on the complete resection. Recently, distal pancreatectomy with celiac axis resection was reported as a feasible and favorable method in selected pancreatic corpus/tail tumors which had invaded the celiac axis. Additional organ resections to the celiac axis were rarely required, and when necessary it was included only a single extra organ resection such as adrenal or intestine. Here, we described a distal pancreatic tumor invading most of the neighboring organs-stomach, celiac axis, left renal vein, left adrenal gland, and splenic flexure were treated by en bloc resection of all these organs. The patient was a 60-year-old man without any severe medical comorbidities. Postoperative course of the patient was uneventful, and he was discharged on postoperative day eight without any complication. Histopathology and stage of the tumor were adenocarcinoma and T4 N1 M0, respectively. Preoperative back pain of the patient was completely relieved in the postoperative period. As a result, celiac axis resection for pancreatic cancer is an extensive surgery, and a combined en masse resection of the invaded neighboring organs is a more extensive surgery than the celiac axis resection alone. This more extensive surgery is safe and feasible for selected patients with pancreatic cancer. PMID- 24159410 TI - Early rupture of an ultralow duodenal stump after extended surgery for gastric cancer with duodenal invasion managed by tube duodenostomy and cholangiostomy. AB - When dealing with gastric cancer with duodenal invasion, gastrectomy with distal resection of the duodenum is necessary to achieve negative distal margin. However, rupture of an ultralow duodenal stump necessitates advanced surgical skills and close postoperative observation. The present study reports a case of an early duodenal stump rupture after subtotal gastrectomy with resection of the whole first part of the duodenum, complete omentectomy, bursectomy, and D2+ lymphadenectomy performed for a pT3pN2pM1 (+ number 13 lymph nodes) adenocarcinoma of the antrum. Duodenal stump rupture was managed successfully by end tube duodenostomy, without omental patching, and tube cholangiostomy. Close assessment of clinical, physical, and radiological signs, output volume, and enzyme concentration of the tube duodenostomy, T-tube, and closed suction drain, which was placed near the tube duodenostomy site to drain the leak around the catheter, dictated postoperative management of the external duodenal fistula. PMID- 24159411 TI - Internal hernia in a liver transplant recipien: a case report. AB - Biliary complications have great importance for liver transplant recipients because of affecting long-term prognosis. In rare situations, an internal hernia of the Roux-en-Y loop cause graft injury. A 42-year-old woman with a history of living donor liver transplantation 6 years ago presented with prolonged graft injury during the past 6 months. She suddenly developed ileus of the small bowel with internal hernia through the defect of the mesentery around the Roux-en-Y limb of the hepaticojejunostomy. Emergent surgery was performed to reduce the hernia and volvulus; also the mesenteric rent was closed with interrupted suture of silk. Internal hernia of the small bowel after liver transplantation is rare but causes graft injury due to associated biliary complications and rapid deterioration of patient's condition. PMID- 24159413 TI - Spontaneous regression of primary malignant lymphoma of the prostate. AB - We herein report a case of primary lymphoma of the prostate, which arose in an 85 year-old male with dysuria. CT and MRI examinations demonstrated a large mass in the prostate. A transrectal ultrasound-guided biopsy of the prostate was performed. The histological examination showed diffuse large B-cell lymphoma. The large lesion in the prostate showed spontaneous regression. Spontaneous regression of primary lymphoma of the prostate has not been reported previously. The spontaneous regression of primary lymphoma of the prostate observed in this patient suggests that observation may represent a viable treatment option following a biopsy that has provided a histopathological diagnosis. PMID- 24159412 TI - Intra-abdominal localisation of a buschke-lowenstein tumour: case presentation and review of the literature. AB - Giant condyloma acuminatum or Buschke-Lowenstein tumour is a very rare disease which usually is located in the genital, anorectal, and perianal regions. It is regarded as a type of verrucous carcinoma occurring on anogenital mucosal surfaces where it is locally invasive but displays a benign cytology. We describe a case of a 24-year-old woman with persisting condyloma acuminata progressing to a large intra-abdominal Buschke-Lowenstein tumour. To our knowledge such an advanced stage has only been reported once before. The severity and extent of the tumour both determine the treatment and patient outcome. Treatment was impeded by cachexia, an immunosuppressive state after kidney transplantation and difficulties in establishing a reliable diagnose. Interferon treatment was started which initially led to tumour reduction but was complicated by an interferon-induced pancreatitis, pneumonia, and fasciitis necroticans resulting in death. We present a literature overview on the treatment options for a Buschke Lowenstein tumour, with emphasis on interferon therapy, with all the advantages and disadvantages. PMID- 24159414 TI - A bladder wall angiomyolipoma as a manifestation of tuberous sclerosis: first case report. AB - A 21-year-old female patient admitted to the emergency department complaining of left side pain. Hypovolemic shock, which was probably caused by retroperitoneal bleeding from left sided renal angiomyolipoma, was developed. Abdominal computed tomography showed multiple fat containing lesions in different, regions including right bladder wall, lower pole of left kidney, and right kidney. Some lesions compatible with tuberous sclerosis such as angiofibromas, Shagreen patches, myocardial, and brain hamartomas were also detected. Bladder wall mass showing intra- and extravesical extensions was seen at exploration. We removed the tumor completely preserving bladder trigone. Angiomyolipoma located at lower pole of left kidney was also removed. Diagnosis of bladder angiomyolipoma was confirmed by the immunohistochemical examination. Recurrent or residual mass was not detected at the three-months-follow-up. We report the first case of bladder angiomyolipoma confirmed by histopathologically as a tuberous sclerosis. PMID- 24159415 TI - A rare entity of benign recurring mesenchymal tumor of the female urethra. AB - This is a case report of a 51-year-old female patient with benign mesenchymal tumors of paraurethral region which caused lower urinary tract symptoms. The pathological examination of the lesion was reported as angiomyxoma which is a distinct soft tissue tumor characterized by the presence of prominent myxoid matrix and numerous thin-walled blood vessels. This tumor has a predilection for the trunk, head and neck, extremities, and genitalia. It is a benign tumor, and total excision is curative. Recurrence is rare except for aggressive angiomyxomas. PMID- 24159416 TI - A rare presentation of imperforate hymen: a case report. AB - Introduction. Acute urinary retention in a child is rare. Haematocolpos can cause a mechanical obstruction, resulting in acute urinary retention. Case Report. A 12 year-old girl presented to the surgical department with a one-day history of acute urinary retention and suprapubic tenderness. She had not started menses but had described period-like pains every month for the past six months. On examination, she had a palpable bladder with over 500 mls of residual urine and a bluish-grey bulge posterior to her urethral meatus. An US scan showed a large mass posterior to her bladder resembling a haematocolpos, and this was confirmed with an MRI scan. She was catheterised and eventually underwent a hymenectomy using a cruciate incision. She made a good recovery postoperatively. Conclusion. In the case of a peripubertal female presenting with acute urinary retention, haematocolpos should be considered as a diagnosis. PMID- 24159417 TI - Pilonidal cyst of the penis mimicking carcinoma. AB - Pilonidal sinus is a long-standing chronic inflammatory condition consisting of a sinus tract from the skin-lined orifice extending into subcutaneous tissue, with hairs attached to the wall of the tract and projecting outside of the opening. Penile location is rare, and differential diagnosis with severe balanoposthitis, epidermal cysts, and neoplasms can be difficult. We report a rare case of pilonidal cyst located between coronal sulcus and prepuce which, due to its ulcerated aspect and absence of a tract with projecting hairs, simulated a penile carcinoma. PMID- 24159418 TI - Acetylcholinesterase inhibitors promote angiogenesis in chick chorioallantoic membrane and inhibit apoptosis of endothelial cells. AB - Alzheimer's disease (AD) is one of the most common causes of dementia in the elderly. Recently, a great attention has been paid to the possible role of vascular changes in the pathogenesis of AD. Reduced microvascular density and degeneration of the endothelium are of structural cerebrovascular changes in AD. Acetylcholinesterase (AChE) inhibitors are widely used for the improvement of AD symptoms. Until now, however, the effects of AChE inhibitors on vascular changes including angiogenesis and endothelial cell apoptosis are not fully understood. In the present work, the effects of three AChE inhibitors (donepezil, rivastigmine, and galantamine) were tested on H2O2-induced apoptosis in human umbilical vein endothelial cells (HUVECs) and on angiogenesis in chicken chorioallantoic membrane model. Incubation of HUVEC with H2O2 led to a significant decrease in cell viability and an increase in the percentage of apoptotic cells. The tested drugs, at concentrations of 1-100 MU M, significantly inhibited the H2O2-induced toxicity. Also, all donepezil, rivastigmine and galantamine significantly increased the number of vessels in the chorioallantoic membrane when injected into fertilized eggs. In conclusion, AChE inhibitors possess angiogenesis-accelerating properties and have antiapoptotic effects on endothelial cells. These effects of AChE inhibitors may be involved in their beneficial effects on AD. PMID- 24159419 TI - Cumulative effect of depression on dementia risk. AB - Objective. To analyze a potential cumulative effect of life-time depression on dementia and Alzheimer's disease (AD), with control of vascular factors (VFs). Methods. This study was a subanalysis of the Neurological Disorders in Central Spain (NEDICES) study. Past and present depression, VFs, dementia status, and dementia due to AD were documented at study inception. Dementia status was also documented after three years. Four groups were created according to baseline data: never depression (nD), past depression (pD), present depression (prD), and present and past depression (prpD). Logistic regression was used. Results. Data of 1,807 subjects were investigated at baseline (mean age 74.3, 59.3% women), and 1,376 (81.6%) subjects were evaluated after three years. The prevalence of dementia at baseline was 6.7%, and dementia incidence was 6.3%. An effect of depression was observed on dementia prevalence (OR [CI 95%] 1.84 [1.01-3.35] for prD and 2.73 [1.08-6.87] for prpD), and on dementia due to AD (OR 1.98 [0.98 3.99] for prD and OR 3.98 [1.48-10.71] for prpD) (fully adjusted models, nD as reference). Depression did not influence dementia incidence. Conclusions. Present depression and, particularly, present and past depression are associated with dementia at old age. Multiple mechanisms, including toxic effect of depression on hippocampal neurons, plausibly explain these associations. PMID- 24159420 TI - Neuroprotective Role of a Novel Copper Chelator against Abeta 42 Induced Neurotoxicity. AB - Alzheimer's disease (AD) is a progressive neurodegenerative disease and associated with the extracellular deposits of amyloid- beta peptide in hippocampus region. Metal ions like Cu, Fe and Zn are known to associate with the amyloid beta (A beta ) at high concentration and interaction of these ions with soluble and aggregated forms of A beta peptide help in development of AD. Here we showed Cu mediated neurotoxicity in the eye tissues of transgenic Drosophila expressing human amyloid beta and its rescue through a novel Cu chelator. In this context, we have synthesised and characterized the compound L 2,6 Pyridinedicarboxylic acid, 2,6-bis[2-[(4-carboxyphenyl) methylene] hydrazide] by Mass spectra (MS) and Elemental analysis (EA). The Cu chelation potential of the compound L is tested in vivo in Drosophila. Oral administration of Copper to the transgenic larvae resulted in severe degeneration in eye tissues, which was rescued by the supplementation of compound L. The levels of anti-oxidant markers like SOD and MDA were measured in compound L treated flies and found a significant rescue (P < 0.001). Further rescue of the eye degeneration phenotypes as revealed by SEM affirm the role of copper in A beta toxicity. Hence, use of compound L, an amidoamine derivative, could be a possible therapeutic measure for A beta induced neurotoxicity. PMID- 24159421 TI - Statin Modulation of Human T-Cell Proliferation, IL-1beta and IL-17 Production, and IFN-gamma T Cell Expression: Synergy with Conventional Immunosuppressive Agents. AB - HMG-CoA reductase inhibitors (statins) have been demonstrated to be immunomodulatory for human immune-mediated disease and in experimental models. The aim of this study was to compare statin-mediated immunosuppressive effects on human T-cell responses in vitro with those of conventional immunosuppressives (dexamethasone, cyclosporin A (CsA), mycophenolate, and rapamycin). Statins (atorvastatin, lovastatin, and simvastatin) were investigated for their modulatory effects on human PBMC viability, cytokine profiles, and T-cell proliferation. At concentrations that inhibited anti-CD3/28-stimulated T-cell proliferation (P < 0.01), simvastatin significantly decreased intracellular CD4(+) T-cell expression of IFN-gamma (P < 0.01) to levels similar to those induced by conventional immunosuppressives. Atorvastatin and lovastatin also decreased IFN-gamma expression, although to a lesser degree (P < 0.05). All three statins reduced levels of IL-17 production (P < 0.01). However, in response to anti-CD3/28 stimulation, simvastatin significantly upregulated IL-1beta production (P < 0.05). The profile of cytokines produced in response to anti CD3/28 stimulation was similar when both atorvastatin and dexamethasone were added as compared with dexamethasone alone, suggesting that atorvastatin can synergise with dexamethasone with respect to immunomodulation of cytokines. This data supports the hypothesis of selective statin-mediated immunomodulatory effects on human immune cells. PMID- 24159422 TI - Triangulation in Youth Sport: Healthy Partnerships among Parents, Coaches, and Practitioners. AB - Youth sport is unique because it involves communication, coordination, and maintenance of relationships among multiple adults, all of whom are vested stakeholders in a child-athlete's sport experience. This dynamic becomes even more complex when a sport psychology practitioner is added; therefore, the purpose of this paper is to provide guidelines and considerations to assist sport psychology practitioners in managing the triangulation of adults who are involved in the consultation process with youth athletes. We first discuss specific dyads and considerations for the practitioner and then highlight recommendations for practitioners regarding transparency and confidentiality issues specific to youth athletes. PMID- 24159423 TI - Absence of Nitric Oxide Synthase 3 Increases Amyloid beta-Protein Pathology in Tg 5xFAD Mice. AB - AIM: The abnormal accumulation, assembly and deposition of the amyloid beta protein (Abeta) are prominent pathological features of patients with Alzheimer's disease (AD) and related disorders. A number of factors in the brain can influence Abeta accumulation and associated pathologies. The aim of the present study was to determine the consequences of deleting nitric oxide synthase (NOS) 3, the endothelial form of NOS, in Tg-5xFAD mice, a model of parenchymal AD-like amyloid pathology. METHODS: Tg-5xFAD mice were bred with NOS3-/- mice. Cohorts of Tg-5xFAD mice and bigenic Tg-5xFAD/NOS3-/- mice were aged to six months followed by collection of the blood and brain tissues from the mice for biochemical and pathological analyses. RESULTS: ELISA analyses show that the absence of NOS3 results in elevated levels of cerebral and plasma Abeta peptides in Tg-5xFAD mice. Immunohistochemical analyses show that the absence of NOS3 increased the amount of parenchymal Abeta deposition and fibrillar amyloid accumulation in Tg 5xFAD mice. The elevated levels of Abeta were not due to changes in the expression levels of transgene encoded human amyloid precursor protein (APP), endogenous beta-secretase, or increased proteolytic processing of APP. CONCLUSIONS: The results from this study suggest that the loss of NOS3 activity enhances Abeta pathology in Tg-5xFAD mice. These findings are similar to previous studies of NOS2 deletion suggesting that reduced NOS activity and NO levels enhance amyloid-associated pathologies in human APP transgenic mice. PMID- 24159424 TI - Alternating ROMP copolymers containing charge-transfer units. AB - Alternating copolymers derived from the ring-opening metathesis polymerization (ROMP) of functionalized cyclobutene esters (CBE) and cyclohexenes (CH) are described. The copolymer poly(CBE-alt-CH)n contains alternating side-chains based on dialcoxynaphthalene (DAN) and pyromellitc dianhydride (PDI). Characterization by UV-Vis spectroscopy showed that the copolymers exhibit an increase in charge transfer intensity in comparison to previously reported alternating copolymers. The bulky side-chains inhibit backbiting during the polymerization and allow for enhanced control over the polymerization in comparison to copolymers functionalized with linear alkyl groups. PMID- 24159425 TI - PEG-Polypeptide Dual Brush Block Copolymers: Synthesis and Application in Nanoparticle Surface PEGylation. AB - Amphiphilic polypeptide-containing hybrid dual brush block copolymers with controlled molecular weights and narrow molecular weight distributions were synthesized in one pot via ring-opening metathesis polymerization of sequentially added norbornyl-PEG and N-(2-((trimethylsilyl)amino)ethyl)-5-norbornene-endo-2,3 dicarboximide (M1) followed by ring-opening polymerization of amino acid N carboxyanhydrides. Polylactide nanoparticles coated with these am phiphilic dual brush block copolymers showed significantly improved stability in PBS solution compared to those coated with amphiphilic linear block copolymers such as PEG polylactide and PEG-polypeptides. PMID- 24159426 TI - Essential Elements to Consider for MRI Cell Tracking Studies with Iron Oxide based Labeling Agents. AB - Personalized diagnosis and treatment with allogenic or autologous cells have been intensively investigated over the past decade. Despite the promising findings in preclinical studies, the clinical results to date have been largely disappointing. Some critical issues remain to be solved, such as how to monitor the migration, homing, survival, and function of the transplanted cells in vivo. In the past years, imaging techniques have been introduced to solve these issues based on a concept that cells can be transformed to a cellular imaging agent following labeling of the cells with an imaging agent. For this purpose, magnetic resonance imaging (MRI) is so far the first choice imaging modality and iron oxide-based nanoparticles are the most frequently applied labeling agents. However, most MRI cell tracking studies are currently still limited in in vivo visualization of the labeled cells, some critical elements for cell tracking studies are often incompletely characterized, which makes it difficult to validate and meta-analyze the data generated from different studies. Incomplete information on preclinical studies also slows the transition of the findings to clinical practice. A robust protocol of MRI cell tracking studies is apparently critical to deal with these issues. In this review, we first briefly discuss the limitations of MRI cell tracking based on iron oxide nanoparticles and then recommend a minimum set of essential elements that should be considered in MRI cell tracking studies at preclinical stage. PMID- 24159427 TI - Translational Molecular Imaging of Prostate Cancer. AB - Prostate cancer is a heterogeneous disease, and its management is now evolving to become more personalized and to incorporate new targeted therapies. With these new changes comes a demand for molecular imaging techniques that can not only detect disease but also assess biology and treatment response. This review article summarizes current molecular imaging approaches in prostate cancer (e.g. 99mTc bone scintigraphy and 18F-fluorodeoxyglucose positron emission tomography) and highlights emerging clinical and preclinical imaging agents, with an emphasis on mechanism and clinical application. Emerging agents at various stages of clinical translation include radiolabeled analogs of lipid, amino acid, and nucleoside metabolism, as well as agents more specifically targeting prostate cancer biomarkers including androgen receptor, prostate-specific membrane antigen and others. We also highlight new techniques and targeted contrast agents for magnetic resonance imaging and spectroscopy. For all these imaging techniques, a growing and important unmet need is for well-designed prospective clinical trials to establish clear indications with clinical benefit in prostate cancer. PMID- 24159428 TI - Biobanking: The Melding of Research with Clinical Care. AB - The number of biobanks around the world has increased dramatically, owing in part, to the need for researchers to have access to large numbers of samples for genomic research. Policies for enrolling participants, returning research results and obtaining samples and data can have a far reaching impact on the type of research that can be performed with each biobank. Research using biobank samples includes studies of the impact of environmental and other risk exposures on health, understanding genetic risks for common disease, identification of biomarkers in disease progression and prognosis, and implementation of personalized medicine projects. This research has been instrumental in the progress of genetic and genomic research and translational medicine. This article will highlight some of the controversies and recent research associated with biobanking over the past year. PMID- 24159430 TI - Congratulatory message. PMID- 24159431 TI - Congratulatory message. PMID- 24159432 TI - Congratulatory message. PMID- 24159429 TI - Promises and Challenges of Nanoplasmonic Devices for Refractometric Biosensing. AB - Optical biosensors based on surface plasmon resonance (SPR) in metallic thin films are currently standard tools for measuring molecular binding kinetics and affinities - an important task for biophysical studies and pharmaceutical development. Motivated by recent progress in the design and fabrication of metallic nanostructures, such as nanoparticles or nanoholes of various shapes, researchers have been pursuing a new generation of biosensors harnessing tailored plasmonic effects in these engineered nanostructures. Nanoplasmonic devices, while demanding nanofabrication, offer tunability with respect to sensor dimension and physical properties, thereby enabling novel biological interfacing opportunities and extreme miniaturization. Here we provide an integrated overview of refractometric biosensing with nanoplasmonic devices and highlight some recent examples of nanoplasmonic sensors capable of unique functions that are difficult to accomplish with conventional SPR. For example, since the local field strength and spatial distribution can be readily tuned by varying the shape and arrangement of nanostructures, biomolecular interactions can be controlled to occur in regions of high field strength. This may improve signal-to-noise and also enable sensing a small number of molecules. Furthermore, the nanoscale plasmonic sensor elements may, in combination with nanofabrication and materials selective surface-modifications, make it possible to merge affinity biosensing with nanofluidic liquid handling. PMID- 24159433 TI - The effect of global warming on infectious diseases. AB - Global warming has various effects on human health. The main indirect effects are on infectious diseases. Although the effects on infectious diseases will be detected worldwide, the degree and types of the effect are different, depending on the location of the respective countries and socioeconomical situations. Among infectious diseases, water- and foodborne infectious diseases and vector-borne infectious diseases are two main categories that are forecasted to be most affected. The effect on vector-borne infectious diseases such as malaria and dengue fever is mainly because of the expansion of the infested areas of vector mosquitoes and increase in the number and feeding activity of infected mosquitoes. There will be increase in the number of cases with water- and foodborne diarrhoeal diseases. Even with the strongest mitigation procedures, global warming cannot be avoided for decades. Therefore, implementation of adaptation measures to the effect of global warming is the most practical action we can take. It is generally accepted that the impacts of global warming on infectious diseases have not been apparent at this point yet in East Asia. However, these impacts will appear in one form or another if global warming continues to progress in future. Further research on the impacts of global warming on infectious diseases and on future prospects should be conducted. PMID- 24159434 TI - Molecular Classification of Human Adenovirus Type 7 Isolated From Acute Respiratory Disease Outbreak (ARD) in Korea, 2005-2006. AB - OBJECTIVES: To assess the genomic characteristics of human adenoviruses (HAdVs) that caused small-scale epidemics in Korea and compare sequence analysis and restriction fragment length polymorphism (RFLP). METHODS: Two hundred sixty-two throat swabs were collected from geographically distinct two cohabitation facilities during outbreaks in August 2005 and February-May 2006. 148 isolates were obtained using the adenocarcinomic human alveolar basal epithelial cells (A549 cells) from 262 specimens. The sequences of 448 bp partial hexon gene of isolates were analized and compared with serotype results using neutralizing test. The hexon (1.2 kb), fiber, and E4 ORF 6/7 34.7 kDa protein (2.1 kb) genes were further analysed in 10 randomly selected specimens. RFLP of the genomic DNA for genotyping was also performed and compared with sequence information. RESULTS: All the isolates were localized into the same cluster when phylogenetic tree was generated based on hexon gene using Clustal W. While fiber and E4 ORF 6/7 34.7 kDa protein genes were analysed, the tree was divided into two clusters. Interestingly, isolates with same genetic characteristics of hexon gene did not show identical RFLP patterns in accordance with their origin of episode, rather phylogenetic analysis of fiber and E4 ORF 6/7 34.7 kDa protein genes were correlated with RFLP patterns. CONCLUSION: These results indicate that serotype classification based on hexon gene might not be enough to discriminate HAdV serotype, and additional genetic characteristics including fiber and/or E4 ORF 6/7 should be recruited to dispose subgroup of HAdV serotype. PMID- 24159435 TI - Serum Homocysteine and Folate Levels are Associated With Late-life Dementia in a Korean Population. AB - OBJECTIVES: We aimed to determine whether serum levels of homocysteine (Hcy) and its biological determinants, folate and vitamin B12, are related to cognitive decline in elderly people. METHODS: The concentrations of total Hcy, folate, and vitamin B12 were measured in serum samples from 424 cognitively normal controls, 382 mild cognitive impairment patients, and 56 dementia patients from Ansan Geriatric cohort. The Consortium to Establish a Registry for Alzheimer's Disease (CERAD) neuropsychological battery was used to evaluate cognitive functions. RESULTS: The dementia patients had higher serum Hcy (dementia, 17.6 +/- 6.9 MUmol/L; control, 12.9 +/- 5.0 MUmol/L; p < 0.001) and lower serum folate (dementia, 7.9 +/- 4.8 ng/mL; control, 10.0 +/- 7.1 ng/mL; p = 0.034) levels compared with controls. There was an inverse relationship between Hcy levels and serum folate or vitamin B12 concentrations. The cognitive status as measured by the (CERAD) score was inversely related to Hcy levels. The adjusted odds ratio of dementia was 5.18 (95% confidence interval: 1.91-14.10; p = 0.001) for moderate (30 >= Hcy > 15) hyperhomocysteinemia compared with normal Hcy levels (<=15 MUmol/L). In addition, there was weak association between low serum folate (<3.0 ng/mL) and the risk for dementia (crude odds ratio = 3.68; 95% confidence interval: 1.07-12.69; p = 0.039). CONCLUSION: Elevated serum Hcy and decreased serum folate concentrations are associated with the risk of dementia in Korean elders. PMID- 24159436 TI - Surveillance and control of rubella in the republic of Korea from 2001 to 2009: the necessity for enhanced surveillance to monitor congenital rubella syndrome. AB - OBJECTIVES: The aim of this study was to review the epidemiologic data of rubella and congenital rubella syndrome (CRS) supplied by surveillance systems from 2001 to 2009 and to propose measures to improve the quality of the surveillance system in the Republic of Korea. METHODS: The epidemiological data for rubella and CRS cases reported to the Korea Centers for Disease Control and Prevention from 2001 to 2009 were retrospectively reviewed, and insurance reimbursement data from the Korea National Health Insurance Review Agency were collected for comparison. RESULTS: The number of yearly reported rubella cases to the Korea Centers for Disease Control and Prevention from 2001 to 2009 was 128, 24, 8, 24, 15, 12, 35, 30, and 36, respectively. The occurrence of rubella shifted to a slightly higher age group during the 9-year period, i.e. from 0-9 years to 10-19 years. Among the 309 reported rubella cases, three were confirmed cases of CRS. In addition, according to data sourced from Health Insurance Review Agency, 24, 19, 19, 9, and 5 CRS cases were reported for medical insurance reimbursement from 2005 to 2009, respectively. CONCLUSION: According to available surveillance data, the reported cases of rubella and CRS were not high, but a more detailed surveillance with emphasis on susceptible women of childbearing age is necessary for better monitoring and control of rubella and CRS in the Republic of Korea. PMID- 24159437 TI - Distribution of Virulence Genes and Their Association of Serotypes in Pathogenic Escherichia coli Isolates From Diarrheal Patients in Korea. AB - OBJECTIVES: To characterise the genetic and serological diversity of pathogenic Escherichia coli, we tested 111 E coli strains isolated from diarrhoeal patients in Korea between 2003 and 2006. METHODS: The isolates were tested through polymerase chain reaction (PCR) and slide agglutination method for the detection of virulence genes and serotypes, respectively. To compare the expression of Shiga toxin (stx)-1 and stx2 genes, real-time quantitative reverse-transcriptase PCR and rapid exprssion assay, reversed-passive latex agglutination, were performed. RESULTS: Forty-nine Shiga toxin-producing E coli (STEC) strains and 62 non-STEC strains, including 20 enteropathogenic E coli, 20 enterotoxigenic E coli, 20 enteroaggregative E coli, and 2 enteroinvasive E coli were randomly chosen from the strains isolated from diarrhoeal patients in Korea between 2003 and 2006. PCR analysis indicated that locus of enterocyte effacement pathogenicity island, that is, eaeA, espADB, and tir genes were present in STEC, enteropathogenic E coli, and enteroinvasive E coli. Quorum sensing-related gene luxS was detected in most of pathogenic E coli strains. Major serotypes of the STEC strains were O157 (26%) and O26 (20%), whereas the non-STEC strains possessed various serotypes. Especially, all the strains with serotype O157 carried stx2 and the tested virulence factors. Of the STEC strains, the data of real-time quantitative reverse-transcriptase PCR and reversed-passive latex agglutination tests showed that messenger RNA- and protein expression of stx2 gene were higher than those of stx1 gene. CONCLUSION: Our results provide the epidemiological information regarding the trend of STEC and non-STEC infections in the general population and show the fundamental data in association of serotypes with virulence genes in diarrhoeagenic E coli strains from Korea. PMID- 24159438 TI - Gene Expression and Identification Related to Fluconazole Resistance of Candida glabrata Strains. AB - OBJECTIVES: Candida glabrata has become one of the most common causes of Candida bloodstream infections worldwide. Some strains of C. glabrata may be intermediately resistant to all azoles. The several possible mechanisms of azole resistance have been reported previously, but the exact resistant mechanism is not clear. In this study, we identified differentially expressed genes (DEGs) of fluconazole-resistant C. glabrata and compared the gene expression of fluconazole resistant strains with that of fluconazole-susceptible strains to identify gene corresponding to fluconazole resistance. METHODS: Using antifungal susceptibility test, several C. glabrata strains were selected and used for further study. The expression of CgCDR1 and CgCDR2 genes was investigated by slot hybridization against fluconazole-susceptible, -resistant, and resistant-induced strains. In addition, ERG3 and ERG11 genes were sequenced to analyze DNA base substitution. DEGs were identified by reverse transcription-polymerase chain reaction using DEG kit composed of 120 random primers. RESULTS: In slot hybridization, CgCDR1 gene was expressed more than CgCDR2 gene in resistant strains. Though base substitution of ERG11 and ERG3 genes was observed in several base sequences, just one amino acid change was identified in resistant strain. In the results of reverse transcription-polymerase chain reaction, 44 genes were upregulated and 34 genes were downregulated. Among them, adenosine triphosphate-binding cassette transporter-related genes, fatty acid desaturase, lyase, and hypothetical protein genes were upregulated and aldehyde dehydrogenase, oxidoreductase, and prohibitin like protein genes were downregulated. Other DEGs were also identified. CONCLUSION: This study showed that CgCDR1 gene was more closely related to fluconazole resistance of C. glabrata than CgCDR2 gene. In addition, several other genes related with fluconazole resistance of C. glabrata were identified. PMID- 24159439 TI - Prevalence of Clonorchis sinensis Infections Along the Five Major Rivers in Republic of Korea, 2007. AB - OBJECTIVES: The prevalence of Clonorchis sinensis infection was investigated among residents of the five major river basins, that is, Hangang, Nakdonggang, Seomjingang, Yeongsangang, and Geumgang River basins in Korea. METHODS: From January to December 2007, a total of 31,268 stool samples were collected from 29 localities and examined by the formalin-ether sedimentation technique. RESULTS: Intestinal parasite eggs and/or protozoan cysts were detected from 2957 (9.5%) inhabitants. Number of residents harbouring helminth eggs in the faeces was 2542 (8.1%) for C. sinensis, 255 (0.8%) for Heterophyes spp., 36 (0.1%) for Echinostoma spp., 30 (0.1%) for Trichuris trichiura, 8 (0.03%) for Ascaris lumbricoides, 7 (0.02%) for Gymnophalloide seoi, and 50 (0.02%) for Trichostrongylus orientalis. Number of residents harbouring protozoan cysts in the faeces was 133 (1.3%) for Entamoeba spp. and 50 (0.2%) for Giardia lamblia. The positive rates of C. sinensis in Nakdonggang, Seomjingang, Yeongsangang, Geumgang, and Hangang River basins were 12.2%, 9.5%, 3.3%, 3.0%, and 1.0%, respectively. The egg positive rate of C. sinensis was higher in male (10.6%) than in female (6.1%), and the age group of 50s had the highest positive rate (10.4%). CONCLUSION: The result of this study revealed little decrease in positive rate of C. sinensis compared with the result of southern endemic areas of Korea in 2006. PMID- 24159440 TI - Trends in water- and foodborne disease outbreaks in Korea, 2007-2009. AB - OBJECTIVES: In Korea, every outbreak of acute gastroenteritis in two or more patients who are epidemiologically related is investigated by local public health centres to determine causative agents and control the outbreak with the support of the Korean Centers for Disease Control and Prevention. The findings and conclusions of each outbreak investigation have been summarized annually since 2007 to make reports and statistics of water- and foodborne disease outbreaks. METHODS: All outbreaks reported to Korean Centers for Disease Control and Prevention from 2007 to 2009 were included in the study. We analysed the trends and epidemiologic aspects of outbreaks by month, year, and location. RESULTS: The total number of outbreaks decreased steadily each year for the period the study covered, whereas the number of patients per outbreak continued to increase resulting from a dramatic increase in the number of patients per outbreak in food service establishments. The outbreaks occurred in the period of June to September, when temperature and humidity are relatively high, which accounted for 44.3% of total outbreaks. The monthly number of outbreaks decreased steadily until November after peaking in May 2009. The most common causative agent was norovirus (16.5%) followed by pathogenic Escherichia coli. The rate of causative agent identification was 60.1%, with higher identification rates in larger outbreaks. CONCLUSIONS: Although a decreasing trend of outbreaks by year was observed in the study, the food services in schools and companies require more attention to hygiene and sanitation to prevent large outbreaks. The ability to establish the cause of an outbreak should be further improved. PMID- 24159441 TI - Epidemiological characteristics of scrub typhus in Korea, 2009. AB - OBJECTIVES: Currently, the incidence of scrub typhus has increased in urban areas. In this study, we described the epidemiological characteristics of scrub typhus cases reported in the urban areas of Korea in 2009. METHODS: We analysed the case investigation reports of scrub typhus cases that were collected in Korea in 2009. Specially, the different risk factors such as fieldwork and outdoor activity were compared to urban and rural areas, and six urban cities. Statistical analysis was performed using chi(2) test. RESULTS: A total of 4,461 cases (including 1,663 suspected cases) were analysed in this study. Among these, the case reports of 4,254 cases had complete addresses. The cases with outdoor activities were 720 (85.2%) in urban areas. In Daegu and Daejeon, the number of cases participated in outdoor activities was 32 (34.4%) and 23 (31.5%), respectively. In other urban areas, cases with outdoor activities were more than 85%. CONCLUSION: The most common infection risk factor was outdoor activity in urban areas. However, the proportion and distribution of outdoor activities were different in urban areas. These results will be used to establish strategies for effective prevention and management in urban areas. PMID- 24159442 TI - The road less traveled. PMID- 24159444 TI - Genotypic Characterization of Vibrio vulnificus Clinical Isolates in Korea. AB - OBJECTIVES: Vibrio vunificus is known to cause septicemia and severe wound infections in patients with chronic liver diseases or an immuno-compromised condition. We carried out the molecular characterization of V. vulnificus isolates from human Vibrio septicemia cases based on pulsed-field gel electrophoresis (PFGE) using NotI and SfiI. METHODS AND RESULTS: PFGE was used to characterize a total of 78 strains from clinical cases after NotI or SfiI digestion. The geographical distribution of PFGE patterns for the strains from the southern part of Korea, a high-risk region for Vibrio septicemia, indicated that the isolates from southeastern Korea showed a comparatively higher degree of homology than those from southwestern Korea. CONCLUSIONS: We report the genetic distribution of V. vulnficus isolated from Vibrio septicemia cases during 2000 2004 in Korea. This method has potential use as a subspecies-typing tool for V. vulnificus strains isolated from distant geographic regions. PMID- 24159443 TI - Incubation period of ebola hemorrhagic virus subtype zaire. AB - OBJECTIVES: Ebola hemorrhagic fever has killed over 1300 people, mostly in equatorial Africa. There is still uncertainty about the natural reservoir of the virus and about some of the factors involved in disease transmission. Until now, a maximum incubation period of 21 days has been assumed. METHODS: We analyzed data collected during the Ebola outbreak (subtype Zaire) in Kikwit, Democratic Republic of the Congo, in 1995 using maximum likelihood inference and assuming a log-normally distributed incubation period. RESULTS: The mean incubation period was estimated to be 12.7 days (standard deviation 4.31 days), indicating that about 4.1% of patients may have incubation periods longer than 21 days. CONCLUSION: If the risk of new cases is to be reduced to 1% then 25 days should be used when investigating the source of an outbreak, when determining the duration of surveillance for contacts, and when declaring the end of an outbreak. PMID- 24159445 TI - Pathogenesis and Chronologic Localization of the Human Influenza A (H1N1) Virus in Cotton Rats. AB - OBJECTIVES: We aimed to evaluate the pathogenesis and chronologic localization of human influenza A (H1N1) virus in experimentally infected cotton rats. METHODS: The animals were intranasally inoculated with 10(7) plaque-forming units of A/Solomon Islands/3/2006 (H1N1) influenza virus and evaluated for pathogenicity for a period of 28 days. Virus replication kinetics and pathological properties were assessed chronologically. Acute antiviral responses were evaluated by mean of real-time polymerase chain reaction. RESULTS: Cotton rats infected with A/Solomon Islands/3/2006 virus lost weight until 6 days post-inoculation (DPI) and showed decreased activity until 3 DPI. At necropsy, focal areas of redness and consolidation of lungs were evident at 1, 2, and 3 DPI. Lung histopathology showed moderate to severe interstitial pneumonia, alveolitis and bronchiolitis. Influenza A specific viral protein was detected in bronchiolar epithelial cells, alveolar septa and pneumocytes. Influenza viruses were recovered from the lungs during the early period of infection and the titer peaked at 1 DPI. Viral proteins were detected from 4 hours to 6 hours DPI. These trends correlate with the up-regulation of mRNA expression of the IFN-alpha, Mx1, and Mx2 genes that play critical roles in the anti-influenza response at the early stage of infection. CONCLUSION: Our results provide evidence that supports the use of cotton rats for the study of influenza virus pathogenesis and the immune response. PMID- 24159446 TI - Infectivity of Homologous Recombinant HIV-1 Pseudo-virus with Reverse Transcriptase Inhibitor-related Mutations from Highly Active Antiretroviral Therapy Experienced Patients. AB - OBJECTIVES: In this study, the viral fitness of pseudo-viruses with a drug resistant site in the reverse transcriptase (RT) region of the genome was investigated. The pseudo-viruses were derived from highly active antiretroviral therapy (HAART)-experienced HIV/AIDS patients. METHODS: HIV-1 RNA was extracted from the plasma of HAART-experienced (KRB9149, KRB7021, KRC1097) and HAART-naive (KRC5180, KRC5123) HIV-1 patients. The RT gene from the extracted viral RNA was amplified and the polymerase chain reaction product was cloned from the pHXB2Delta2-261 RT vector. C8166 and TZM-bl cell lines were used as the HIV-1 replication capacity measurement system. To quantify the infectivity of homologous recombinant HIV-1, the infectivity derived from each pseudo-virus was compared with the infectivity of the reference strain HXB2. RESULTS: Patient derived HIV-1 was cotransfected into C8166 cells and the expression level of the p24 antigen was measured. The expression was high in the HIV-1 isolates from patients KRC5180 and KRB9149 and low in patients KRB7021, KRC5123, and KRC1097, when compared with the reference strain. The infectivity of the pseudo-virus measured in TZM-bl cells decreased in the order, reference strain HXB2 > KRC5180 > KRC5123 > KRB9149 > KRB7021 > KRC1097. CONCLUSION: In this study, HIV-1 infectivity of the drug-resistant strain isolated from HAART-experienced patients with HIV/AIDS was found to be lower than the infectivity of the reference strain HXB2. This study provides useful data for the phenotypic susceptibility assay in HAART-experienced patients infected with HIV-1. PMID- 24159447 TI - Serological detection of lyme borreliosis agents in patients from Korea, 2005 2009. AB - OBJECTIVES: Laboratory tests are now being used to identify seropositive cases in patients suspected of having a Lyme borreliosis (LB) infection. From 2005 to 2009, we analyzed the serological and epidemiological characteristics of 53 LB positive cases in Korea using immunoblot assay. METHODS: During the five-year study period, a total of 1897 serum samples from suspected LB cases were referred to us for further laboratory diagnosis. The bacterial strains Borrelia afzeli pKo, Borrelia garinii 935T and Borrelia burgdorferi B31 were used for indirect immunofluorescent antibody assay. Immunoblot assay was performed using the recomBlot Borrelia. RESULTS: Based on the information from the clinicians, the main symptoms of LB infection were rash and fever (66.0%), neurological symptoms (30.2%), and arthritis (5.7%). Of the 53 cases, 16 (30.2%) were infected abroad and the remaining 37 cases (69.8%) were suspected to have been infected in Korea. Immunoblot assays detected high levels of the antigens p41 (FlaB) of B. burgdorferi and OspC of B. garinii in infected samples. CONCLUSIONS: The causative bacteria of LB were not isolated from humans yet but from vector ticks and rodents in Korea, and a few cases were reported with serological diagnosis. Our results suggest that LB is present in all areas of Korea and indicate that B. garinii and B. burgdorferi may be the predominant bacteria in patients with LB. However, further studies are needed to isolate and identify the causative bacteria for LB in patients. PMID- 24159448 TI - Identification of Dengue Type 1 Virus (DENV-1) in Koreans Traveling Abroad. AB - OBJECTIVES: To date, no indigenous dengue virus (DENV) transmissions have been reported in Korea. However, imported dengue infections have been diagnosed in travelers returning from endemic areas. This study presents the first virological evidence of travel-associated DENV importation into South Korea. METHODS: From January 2004 to June 2006, a total of 278 serum samples from 245 patients with suspected dengue fever were tested using the Panbio Dengue Duo IgM/IgG Rapid Strip Test. We selected 11 of the early symptomatic-phase sera that were negative for IgM and retrospectively studied them by virus isolation and reverse transcription-polymerase chain reaction. RESULTS: All 11 serum samples were found to be DENV positive by reverse transcription-polymerase chain reaction and viruses were successfully isolated from seven of the 11 serum samples. All the isolates were identified as DENV serotype-1. CONCLUSION: We successfully isolated seven DENV serotype-1 strains for the first time in South Korea from imported infections. Considering that the vector mosquito, Aedes albopictus, already exists in South Korea, we propose that a vector surveillance program for dengue is urgently needed. PMID- 24159449 TI - Prevalence of Antibiotic Resistance in Escherichia coli Fecal Isolates From Healthy Persons and Patients With Diarrhea. AB - OBJECTIVES: This study aimed to investigate the prevalence of antibiotic resistance in fecal Escherichia coli isolates from healthy persons and patients with diarrhea. METHODS: E. coli isolates (n = 428) were obtained from fecal samples of apparently healthy volunteers and hospitalized patients with diarrhea. Susceptibility patterns of isolates to 16 antimicrobial agents were determined by agar disc diffusion. RESULTS: Most E. coli isolates exhibited less than 10% resistance against imipenem, cefotetan, aztreonam, cefepime, cefoxitin, amikacin and netilamicin, although greater than 65% were resistant to ampicillin and tetracycline. No significant difference in resistance rates for all tested antibiotics was found between isolates from the healthy-and diarrheal-patient groups, including for multi-drug resistance (p = 0.22). The highest number of resistant antibiotics was 12 antibiotics. No significant differences in antibiotic resistance were found among the sex and age strata for isolates from healthy individuals. However, antibiotic resistance rates to cefoxitin, cefotaxime, amikacin, and netilamicin were significantly higher in the isolates of men than those of women (p < 0.05) in isolates from patients with diarrhea. Furthermore, isolates from patients with diarrhea older than 40-years of age showed higher resistance to cefepime and aztreonam (p < 0.05). CONCLUSION: High resistance to the antibiotics most frequently prescribed for diarrhea was found in isolates from patients with diarrhea and apparently healthy individuals without any significant difference. PMID- 24159450 TI - Seroprevalence of hepatitis a and e viruses based on the third Korea national health and nutrition survey in Korea. AB - OBJECTIVES: The purpose of this study was to investigate the seroprevalence of hepatitis A virus (HAV) and hepatitis E virus (HEV) in Korea during 2005. METHODS: Study subjects were selected from across Korea using a stratified multistage probability sampling design, and HAV and HEV seroprevalence was compared on the basis of sex, age, and residency. A total of 497 rural and urban people aged 10-99 years of age (mean +/- SD age = 28.87 +/- 17.63 years) were selected by two-stage cluster sampling and tested serologically for anti-HAV and anti-HEV IgG using an enzyme-linked immunosorbent assay. RESULTS: Among this population, the overall seroprevalence of HAV was 63.80% (55.21% aged in their 20s and 95.92% in their 30s, p < 0.01) and that of HEV was 9.40% (5.21% aged in their 20s and 7.14% in their 30s, p < 0.01). Seroprevalence also varied according to area of residence. HEV prevalence in rural areas was higher than that of urban regions based on the anti-HEV antibody, odds ratio 3.22 (95% confidence interval: 1.46-7.10, p < 0.01). There were no significant differences between male and female against anti-HAV/HEV antibodies. CONCLUSION: Our study suggested that the seropositive rates of HAV and HEV might be related to age and environmental conditions. PMID- 24159451 TI - Mathematical Modeling of Vibrio vulnificus Infection in Korea and the Influence of Global Warming. AB - OBJECTIVES: To investigate the possible link between Vibrio vulnificus population size in seawater and water temperature. METHODS: We collected incidence and water temperature data in coastal regions of Korea and constructed a mathematical model that consisted of three classes; susceptible fish, infected fish available to humans, and infected humans. RESULTS: We developed a mathematical model to connect V. vulnificus incidence with water temperature using estimated bacterial population sizes and actual coastal water temperatures. CONCLUSION: Increased V. vulnificus population sizes in marine environments may increase the risk of infection in people who eat at coastal restaurants in Korea. Furthermore, we estimated the near-future number of infected patients using our model, which will help to establish a public-health policy to reduce the disease burden. PMID- 24159452 TI - The influence of dietary patterns on the nutritional profile in a korean child cohort study. AB - OBJECTIVES: The aim of the present study was to identify the major dietary patterns of seven- and eight-year-old Korean children and to examine the relationship between dietary patterns and obesity, nutrient intake, and diet quality. METHODS: The subjects were 284 seven- and eight-year-old children who participated in the Gwacheon child cohort study. Three dietary patterns emerged from the factor analysis: Korean, modified Western, and Western. Cluster analysis was used to classify the subjects into two dietary groups: Korean and Western diet patterns. RESULTS: The two different dietary patterns were closely related to dietary quality which in turn was related to health risks. The Western diet group had a lower fiber intake, a higher intake of energy, fat and calcium and a higher dietary diversity score (DDS) than the Korean diet group. The number of days when fruit, milk and dairy products were omitted from the diet was higher for the Korean diet group than for the Western group. CONCLUSIONS: Dietary patterns and related diet quality should be considered when designing nutrition policy and intervention programs for children. PMID- 24159453 TI - National action plan for response to poliovirus importation. AB - The Division of Vaccine-Preventable Disease Control and National Immunization Program of the Korea Centers for Disease Control and Prevention has prepared a plan of action as a guide for key actions that will be taken if a poliovirus outbreak occurs in the Republic of Korea. The history of poliomyelitis and vaccination against poliovirus in the nation was reviewed and the routine surveillance procedures that are currently in place were described. The principles and specific actions for an effective response to a poliovirus outbreak were prepared. The guidelines clearly outline the actions to be taken in case of a polio outbreak. When a suspected case of poliovirus infection is reported, an immediate epidemiological investigation is to be conducted. The response to a poliovirus outbreak includes case isolation, management of potential contacts and immunization. All stakeholders are to be made aware of what key actions should be taken at each stage of the response to a poliovirus outbreak in the nation. PMID- 24159454 TI - A tale of two fields: mathematical and statistical modeling of infectious diseases. PMID- 24159455 TI - Development of a predictive model for type 2 diabetes mellitus using genetic and clinical data. AB - OBJECTIVES: Recent genetic association studies have provided convincing evidence that several novel loci and single nucleotide polymorphisms (SNPs) are associated with the risk of developing type 2 diabetes mellitus (T2DM). The aims of this study were: 1) to develop a predictive model of T2DM using genetic and clinical data; and 2) to compare misclassification rates of different models. METHODS: We selected 212 individuals with newly diagnosed T2DM and 472 controls aged in their 60s from the Korean Genome and Epidemiology Study. A total of 499 known SNPs from 87 T2DM-related genes were genotyped using germline DNA. SNPs were analyzed for significant association with T2DM using various classification algorithms including Quest (Quick, Unbiased, Efficient, Statistical tree), Support Vector Machine, C4.5, logistic regression, and K-nearest neighbor. RESULTS: We tested these models using the complete Korean Genome and Epidemiology Study cohort (n = 10,038) and computed the T2DM misclassification rates for each model. Average misclassification rates ranged at 28.2-52.7%. The misclassification rates for the logistic and machine-learning algorithms were lower than the statistical tree algorithms. Using 1-to-1 matched data, the misclassification rate of the statistical tree QUEST algorithm using body mass index and SNP variables was the lowest, but overall the logistic regression performed best. CONCLUSIONS: The K nearest neighbor method exhibited more robust results than other algorithms. For clinical and genetic data, our "multistage adjustment" model outperformed other models in yielding lower rates of misclassification. To improve the performance of these models, further studies using warranted, strategies to estimate better classifiers for the quantification of SNPs need to be developed. PMID- 24159456 TI - Plasma calcium and risk of hypertension: propensity score analysis using data from the korean genome and epidemiology study. AB - OBJECTIVE: To investigate associations between plasma calcium and future incidence of hypertension in a healthy population. METHODS: We used prospective data from Ansung and Ansan cohorts (n = 10,038) of the Korean Genome and Epidemiology Study. Data from baseline (2001-02) to the fourth study (2007-08) were used. After excluding hypertensive cases at baseline, missing data, and outliers, 5560 participants were analyzed. Propensity scores for having higher plasma calcium (>=2.37 mmol/L) were created for each participant. After propensity score matching (1:1 nearest neighbor matching within caliper), 2153 pairs were left for analysis. Factors that were significantly different between the lower and higher plasma calcium groups before matching either became nonsignificant or the difference decreased in size. RESULTS: Using multivariable Cox proportional hazard models with robust standard errors accounting for clustering of matched pairs, higher plasma calcium was associated with higher incidence of hypertension (adjusted HR, 1.24; robust 95%CI, 1.07-1.43). Among those with higher plasma calcium, low dietary calcium intake increased the development of hypertension, but the effect was not significant. Sensitivity analysis showed that our results were robust to hidden bias. CONCLUSIONS: Plasma calcium was positively associated with incidence of hypertension. These results expand on cross-sectional associations between hypercalcemia and the metabolic syndrome, and extend the link to future risk of hypertension. PMID- 24159457 TI - Modeling for Estimating Influenza Patients from ILI Surveillance Data in Korea. AB - OBJECTIVE: Prediction of influenza incidence among outpatients from an influenza surveillance system is important for public influenza strategy. METHODS: We developed two influenza prediction models through influenza surveillance data of the Korea Centers for Disease Control and Prevention (each year, each province and metropolitan city; total reported patients with influenza-like illness stratified by age) for 6 years from 2005 to 2010 and disease-specific data (influenza code J09-J11, monthly number of influenza patients, total number of outpatients and hospital visits) from the Health Insurance Review and Assessment service. RESULTS: Incidence of influenza in each area, year, and month was estimated from our prediction models, which were validated by simulation processes. For example, in November 2009, Seoul and Joenbuk, the final number of influenza patients calculated by prediction models A and B underestimated actual reported cases by 64 and 833 patients, respectively, in Seoul and 6 and 9 patients, respectively, in Joenbuk. R-square demonstrated that prediction model A was more suitable than model B for estimating the number of influenza patients. CONCLUSION: Our prediction models from the influenza surveillance system could estimate the nationwide incidence of influenza. This prediction will provide important basic data for national quarantine activities and distributing medical resources in future pandemics. PMID- 24159458 TI - Increased Prevalence of low High-density Lipoprotein Cholesterol (HDL-C) Levels in Korean Adults: Analysis of the Three Korean National Health and Nutrition Examination Surveys (KNHANES 1998-2005). AB - OBJECTIVES: High-density lipoprotein cholesterol (HDL-C) is an independent risk factor for cardiovascular diseases that has shown a remarkable increase, but little is known about the prevalence of low HDL-C in Korea. This study aimed to evaluate changing trends of low HDL-C prevalence, and indicate other risk factors associated with low HDL-C. METHODS: We selected subjects aged >=20 years from the Korean National Health and Nutrition Examination Survey (KNHANES) 1998, 2001, and 2005 (n = 7962, 6436, and 6412). The mean level of HDL-C and the prevalence of low HDL-C was calculated, and cardiovascular risk factors associated with low HDL C, as well as demographic, anthropometric, lifestyle, and nutrition factors, were assessed using the KNHANES 2005 data. RESULTS: Mean HDL-C levels in men and women between KNHANES 1998 and 2005 decreased significantly, from 48.1 to 42.3 and from 51.6 to 47.1 mg/dL, respectively (both p < 0.001). The decrease was slightly less for women compared with men for the same period, and women had higher HDL-C levels at all periods. Covariate-adjusted OR revealed that body mass index, waist circumference, and non-alcohol drinker in both men and women were associated with low HDL-C levels by KNHANES 2005, as were employed and light physical activity in men and low fat intake in women. CONCLUSION: The prevalence of low HDL-C increased significantly from KNHANES 1998 to 2001 and 2005 (p < 0.001) in both men and women. body mass index, waist circumference, and non-alcohol drinker were identified as associated with low HDL-C in Korean adults. PMID- 24159459 TI - Estimation of HIV Seroprevalence in Colorectal Hospitals by Questionnaire Survey in Korea, 2002-2007. AB - OBJECTIVES: The incidence of anal disease is higher among persons with human immunodeficiency virus (HIV) infection than among the general population. We surveyed the status of seroprevalence in colorectal hospitals in Korea. METHODS: The survey was conducted in colorectal hospitals in Korea from November to December 2008. The questionnaire was comprised of six topics about the status of HIV testing in colorectal hospitals. We gathered the data by website (http://hivqa.nih.go.kr/risk) or fax. RESULTS: Among 774 colorectal hospitals contacted, 109 (14%) hospitals participated in the survey. Among these, 48 hospitals (44%) performed HIV tests in their own hospitals and 11 (23%) took HIV testing by rapid method. The main reason for recommending an HIV test was surgical operation (54%) followed by endoscope (11%) and health checkup (9%). The annual number of HIV tests increased from 58,647 (at 21 hospitals) in 2002 to 246,709 (at 58 hospitals) in 2007. HIV seroprevalence was >3.0 per 10,000 individuals during 2002-2005, decreased to 2.2 per 10,000 individuals in 2006 and rose to 2.8 per 10,000 individuals in 2007. CONCLUSIONS: HIV seroprevalence of colorectal hospitals was more than twice that of general hospitals in Korea. HIV surveillance systems based on colorectal hospitals for HIV/AIDS transmission prevention by early HIV diagnosis are needed. PMID- 24159460 TI - Ingenol Protects Human T Cells From HIV-1 Infection. AB - OBJECTIVES: Many natural compounds have been investigated as drug candidates to prevent human immunodeficiency virus (HIV) with low cytotoxicity. We tested whether ingenol from Euphorbia ingens exerts anti-HIV effects in human T cell lines. METHODS AND RESULTS: Ingenol effectively maintained high cell viability (CD50, >1 mM) in H9 and MT4 T cells. The efficacy of ingenol to inhibit HIV-1 infection was dose dependent. ED50 for 100 and 200 TCID50 of HIV-1 was 5.06 and 16.87 MUM, respectively. Gag p24 antigen production in ingenol-treated MT4 cells was reduced by 24.5% on day 6 post-infection. While p24 antigen was reduced in ingenol-treated cells, levels of cytokines such as TNF-alpha and IL-6 and chemokines such as RANTES and MCP-1 were increased. dUTP level related to late apoptotic events was increased on day 2 post-infection of HIV by ingenol treatment, whereas expression of annexin V was unchanged. Reduced levels of iNOS and ZAP-70 after HIV infection were recovered by ingenol treatment. CONCLUSION: Ingenol helps T cells to survive longer against viremia after HIV-1 infection, without exerting cytotoxic effects. Ingenol can be considered a safe and efficacious candidate for immune-boosting therapy for AIDS patients. PMID- 24159461 TI - Multilocus Sequence Analysis of Housekeeping Genes and Antigenic Determinant Genes in Bordetella pertussis Strains Isolated in Korea. AB - OBJECTIVES: To confirm genotype diversities of clinical isolates of Bordetella pertussis and to evaluate the risk of pertussis outbreak in Korea. METHODS: Seven housekeeping genes and 10 antigenic determinant genes from clinical B. pertussis isolates were analyzed by Multilocus sequence typing (MLST). RESULTS: More variant pattern was observed in antigenic determinant genes. Especially, PtxS1 gene was the most variant gene; five genotypes were observed from eight global genotypes. In the bacterial type, the number of observed sequence types in the isolates was seven and the most frequent form was type 1 (79.6%). This major sequence type also showed a time-dependent transition pattern. Older isolates (1968 and 1975) showed type 1 and 6 in housekeeping genes and antigenic determinant genes, respectively. However, these were changed to type 2 and 1 in isolates 1999-2008. This transition was mainly attributed to genotype change of PtxS1 and Fim3 gene; the tendency of genotype change was to avoid vaccine-derived genotype. In addition, there was second transition in 2009. In this period, only the sequence type of antigenic determinant genes was changed to type 2. Based Upon Related Sequence Types (BURST) analysis confirmed that there were two clonal complexes (ACCI and ACCII) in the Korean isolates. Moreover, the recently increased sequence type was revealed as AST2 derived from AST 3 in ACCI. CONCLUSIONS: Genotype changes in Korean distributing strains are still progressing and there was a specific driving force in antigenic determinant genes. Therefore continuous surveillance of genotype change of the distributing strains should be performed to confirm interrelationship of genotype change with vaccine immunity. PMID- 24159462 TI - Improved HPLC Method Using 2,3-naphthalenedicarboxaldehyde as Fluorescent Labeling Agent for Quantification of Histamine in Human Immunoglobulin Preparations. AB - OBJECTIVES: To develop and optimize quantitative HPLC method using 2,3 naphthalenedicarboxaldehyde (NDA) after simple and efficient solid phase extraction to determine the histamine in a biopharmaceutical (HistobulinTM). METHODS: The HPLC method was established using NDA-induced Histobulin and compared with the recently reported HPLC method using o-phthaldehyde (OPA). The validated NDA-applied HPLC method was adjusted to 15 lots of Histobulin and compared by the current lot-release-test method using fluorimetry in recovery of histamine and reproducibility. RESULTS: Analyses of six HPLC chromatograms using NDA and OPA each were compared. NDA produced a more stable chromatogram baseline than OPA, and showed better stability. The HPLC analysis was validated in accuracy (91-103%), precision (interday/intraday assay CV <=2.30%), and linearity of dose-response curve (R(2) >= 0.9919). The detection limit was 0.0076 MUg/mL and the quantitative limit was 0.0229 MUg/mL. The amount of histamine per 12 mg of immunoglobulin was determined to be 0.17 +/- 0.016 MUg by the HPLC and 0.025 +/- 0.013 MUg by the current lot-release-test method using fluorimetry. CONCLUSION: NDA derivatization showed better stability compared with the OPA method. Therefore the newly established NDA-derivatizated HPLC method may be more suitable than the fluorimetric method in lot-release-tests of biopharmaceuticals. PMID- 24159463 TI - A note on obesity as epidemic in Korea. AB - OBJECTIVE: To analyze the incidence of obesity in adults aged 19-59 years in Korea and predict its trend in the future. METHODS: We considered a two compartmental deterministic mathematical model Susceptible-Infected-Susceptible (SIS), a system of difference equations, to predict the evolution of obesity in the population and to propose strategies to reduce its incidence. RESULTS: The prevention strategy on normal-weight individuals produced a greater improvement than that produced by treatment strategies. CONCLUSIONS: Mathematical model sensitivity analysis suggests that obesity prevention strategies are more effective than obesity treatment strategies in controlling the increase of adult obesity in Korea. PMID- 24159464 TI - Registration of human embryonic stem cell lines: Korea, 2010. AB - In an effort to increase the credibility of human embryonic stem cell (hESC) lines established in Korea, obligatory registration was introduced by the Bioethics and Safety Act 2008, effective as of January 1, 2010. The DNA fingerprint, chromosome stability, expression of pluripotency markers, and contamination of mycoplasma of the submitted lines were analyzed by Korea Centers for Disease Control and Prevention (KCDC). The characterization data and ethical aspects, such as informed consent for donation of surplus embryos, were reviewed by a 10-member advisory review committee for stem cell registry. A total of 55 domestic hESC lines were submitted for registration in 2010; among them 51 were registered. Among these submitted lines, 26 were additionally characterized by KCDC, while 25 lines previously characterized by the Ministry of Education, Science and Technology were not additionally analyzed by KCDC. Registration completed an oversight system for embryo research by registering the products of licensed embryo research projects, making embryo research more transparent in Korea. Information about hESC lines is available at the website of the Korea Stem Cell Registry (kscr.nih.go.kr). PMID- 24159465 TI - Is the public transportation system safe from a public health perspective? PMID- 24159466 TI - Neutralizing Antibody Responses and Evolution of the Viral Envelope in the Course of HIV-1 Korean Clade B Infection. AB - OBJECTIVES: HIV is able to continuously adapt to and evade the evolving neutralizing antibody responses of the host. We investigated the ability of HIV variants to evade neutralizing antibodies in order to understand the distinct characteristics of HIV-1 Korean clade B. METHODS: Three drug-naive subjects were enrolled in this study who were infected with HIV-1 Korean clade B. Neutralizations were performed using autologous plasma and pseudovirion-based assays in order to analyze and compare changes in the env gene. RESULTS: In the early phase of infection, neutralizing activities against autologous virus variants gradually increased, which was followed by a decline in the humoral immune response against the subsequent viral escape variants. The amino acids lengths and number of potential N-linked glycosylation sites (PNGS) in HIV-1 env gene was positively correlated with neutralized antibody responses during the early stages of infection. CONCLUSION: This study suggests that change within the env domains over the course of infection influences reactivities to neutralized antibodies and may also have an impact on host immune responses. This is the first longitudinal study of HIV-1 humoral immunity that took place over the entire course of HIV-1 Korean clade B infection. PMID- 24159467 TI - Longitudinal and Cross-Sectional Genetic Diversity in the Korean Peninsula Based on the P vivax Merozoite Surface Protein Gene. AB - OBJECTIVES: Vivax malaria has reemerged and become endemic in Korea. Our study aimed to analyze by both longitudinal and cross-sectional genetic diversity of this malaria based on the P vivax Merozoite Surface Protein (PvMSP) gene parasites recently found in the Korean peninsula. METHODS: PvMSP-1 gene sequence analysis from P vivax isolates (n = 835) during the 1996-2010 period were longitudinally analyzed and the isolates from the Korean peninsula through South Korea, the demilitarized zone and North Korea collected in 2008-2010 were enrolled in an overall analysis of MSP-1 gene diversity. RESULTS: New recombinant subtypes and severe multiple-cloneinfection rates were observed in recent vivax parasites. Regional variation was also observed in the study sites. CONCLUSION: This study revealed the great complexity of genetic variation and rapid dissemination of genes in P vivax. It also showed interesting patterns of diversity depending, on the region in the Korean Peninsula. Understanding the parasiteninsula. Under genetic variation may help to analyze trends and assess the extent of endemic malaria in Korea. PMID- 24159469 TI - Cyclophilin A Cpr1 Protein Modulates the Response of Antioxidant Molecules to Menadione-induced Oxidative Stress in Saccharomyces cerevisiae KNU5377Y. AB - OBJECTIVES: The cellular function of cyclophilin A (CypA) differs between organisms, even though CypA is conserved in both prokaryotes and eukaryotes. The purpose of this study was to elucidate the role of activated CypA isoform CPR1 in the antioxidative mechanisms of Saccharomyces cerevisiae under menadione (MD) induced oxidative stress. METHODS: Four S. cerevisiae strains, KNU5377Y (kwt) and BY4741 (bwt), and their isogenic cpr1? mutant strains (kc1 and bc1), were treated with MD, at a concentration ranging between 0.25 and 0.4 mM. Cpr1-mediated antioxidative effects were analyzed by measuring the levels of cellular glutathione (GSH) and ascorbate (AsA)-like molecules in yeast. RESULTS: GSH and AsA-like reductant molecule concentrations were more reduced in the presence of MD in the kc1 strain than in the kwt strain; whereas, there was no significant difference between the bwt and bc1 strains under the same conditions. In kc1 strain samples, we observed a reduction in the expression of proteins related both to GSH synthesis and the recycling system, and simultaneously, downregulation of GSH synthetase and GSH reductase activities were also evident. Oxidative stress in the kc1 strain was alleviated by the application of the GSH and AsA analog. CONCLUSION: These results indicate that activated Cpr1 modulates the response of antioxidant molecules involved in cellular redox homeostasis of KNU5377Y during oxidative stress induced by MD. PMID- 24159468 TI - Alterations of gyrA, gyrB, and parC and Activity of Efflux Pump in Fluoroquinolone-resistant Acinetobacter baumannii. AB - OBJECTIVES: This study investigated the fluoroquinolone-resistant mechanism of 56 clinical cases of A baumannii infection from 23 non-tertiary hospitals, collected between 2004 and 2006. METHODS: Susceptibility testing was performed by broth microdilution and Epsilometer test. Analyses of quinolone resistance-determining region (QRDR) were done by sequencing. The activity of the efflux pump was measured using inhibitors. RESULTS: The sequences from selected 56 isolates were divided into seven groups (I-VII) on the basis of mutations in gyrA (S83L), parC (S80L, S80W and S84K) and gyrB (containing the novel mutations E679D, D644Y and A677V). The 27 isolates with triple mutations in gyrA, gyrB and parC (groups IV VII) showed higher levels of resistance to ciprofloxacin (minimal inhibitory concentration [MIC] of 16-256 MUg/mL) than the 26 isolates with double mutations in gyrA and parC (groups II and III, MIC of 8-64 MU g/mL; p < 0.05). Alterations in the efflux pump were observed in four isolates with the parC S80L mutation (group II) or E84K mutation (group VII), but no effect was observed in an isolate with the parC S80 W mutation (group III). CONCLUSION: These results suggest that triple mutations in clinical isolates of A baumannii contribute to the development of high levels of resistance to fluoroquinolones and that mutations in parC S80L or E84K (groups II and VII) may contribute to alterations in efflux pump activity in A baumannii. PMID- 24159470 TI - The Emergence of Oseltamivir-Resistant Seasonal Influenza A (H1N1) Virus in Korea During the 2008-2009 Season. AB - OBJECTIVES: To monitor antiviral drug resistance among seasonal influenza viruses isolated in Korea during the 2008-2009 influenza season, we examined influenza isolates collected through Korea Influenza Surveillance Scheme for antiviral drug susceptibility. METHODS: For genetic analysis of antiviral drug resistance, the matrix (M2) and neuraminidase (NA) genes of each isolate were amplified by reverse transcription-polymerase chain reaction and followed by nucleotide sequencing. For phylogenetic analyses, the sequences of hemagglutinin (HA) and NA genes of each isolate were aligned using multiple alignment program. For phenotypic analysis of antiviral drug resistance, drug susceptibilities against M2 inhibitor (amantadine) and NA inhibitors (oseltavimir and zanamivir) were determined by virus yield reduction assay and fluorometric NA inhibition assay, respectively. RESULTS: In Korea, the resistant influenza viruses against oseltamivir were first detected in sealsonal influenza A(H1N1) viruses on Week 48 of 2008. Since then, the number of oseltamivir-resistant A(H1N1) viruses was continuously increased and had reached the highest peak on Week 52 of 2008. 533 (99.8%) of 534 A(H1N1) viruses were resistant to oseltamivir and all of them harbored the H275Y mutation in the NA gene during the 2008-2009 season. The oseltamivir resistance identified by sequencing was confirmed by NA inhibition assay. Genetic analysis based on HA gene of the resistant A(H1N1) viruses revealed that the viruses were identified as A/Brisbane/10/2007-like strain which was vaccine strain for the 2008-2009 season. CONCLUSIONS: The oseltamivir resistant A(H1N1) viruses were first emerged in Europe in November 2007 and then circulated globally. One year later, the oseltamivir-resistant A(H1N1) viruses were first detected in Korea in November 2008 and continued circulating until the Week 7 of 2009 during the 2008-2009 season. Considering the pandemic preparedness, it should be continued to monitor the emergence and the characterization of antiviral drug resistant influenza viruses. PMID- 24159471 TI - Serum MicroRNA Expression Profiling in Mice Infected with Rabies Virus. AB - OBJECTIVES: Serum or plasma microRNAs (miRNAs) are potential biomarkers for the diagnosis for cancer and prenatal diseases. This study was conducted to investigate whether rabies virus causes a change in serum miRNA expression. METHODS: ICR mice were intramuscularly inoculated with rabies virus and were sacrificed weekly to collect serum and brain tissue for 4 weeks postinoculation. Mice were assigned to four groups based on the results of indirect immunofluorescent assays, enzyme-linked immunosorbent assay, and nested reverse transcription-polymerase chain reaction and the expression profiles of serum miRNAs were compared using a commercial mouse miRNA expression profiling assay. RESULTS: The expression levels of miRNAs changed significantly with the different stages of the disease. The expression level of 94 serum miRNAs in infected mice changed at least twofold. Seven microRNAs of them were significantly upregulated or downregulated in all infected mice regardless of disease status. The number of miRNAs with an expression level change decreased with the progression of the disease. In a hierarchical cluster analysis, infected mice clustered into a group separate from uninfected control mice. CONCLUSIONS: Based on the relationship of miRNAs to gene expression regulation, miRNAs may be candidates for the study of viral pathogenesis and could have potential as biomarkers. PMID- 24159472 TI - Food and nutrient intakes according to income in korean men and women. AB - OBJECTIVES: The present study investigated associations between income and intake of nutrients and food in adults (n = 11,063) from the fourth Korea National Health and Nutrition Examination Survey 2007-2009. METHODS: To examine relationships between individual dietary intake and anthropometric measures and family income, multiple linear regression models were constructed for each outcome variable. All models were adjusted for age, education, energy intake, smoking, body mass index, and physical activity. RESULTS: For men, intakes of protein, calcium, phosphorus, potassium, and vitamin C were lower in low-income compared to high-income groups. For women, intakes of protein and niacin were lower in low-income groups. Lowest income group ate less dairy products in men and less fruits and fishes or shellfishes in women. CONCLUSION: Low-income groups had severe food insecurity and low diet quality compared to high-income groups. The study results will provide direction for public health efforts regarding dietary intakes according to economic status among Korean men and women. PMID- 24159473 TI - Prevalence of Farm and Slaughterhouse Workers Carrying Shiga Toxin-Producing Escherichia coli in Korea. AB - OBJECTIVES: The aim of this study was to investigate the distribution of Shiga toxin (Stx) gene-positive stool samples from dairy farmer and slaughterhouse workers in Gyeonggi-Do province. METHODS: A total of 621 samples from healthy farmers and 198 samples from slaughterhouse workers were screened by polymerase chain reaction (PCR) for Shiga toxigenic Escherichia coli (STEC) infection on stool samples. RESULTS: The PCR product of Stx-encoding genes was detected in 21 (3.4%) of 621 farmers and 15 (7.6%) of 198 slaughterhouse workers' stool samples. Distribution of the Stx PCR positive workers by age increment revealed an increase in STEC infection with age increment in both workers. Distribution of the Stx PCR positive workers by working years revealed an increase in STEC infection with working years in farmers. CONCLUSION: These results of the study show that slaughterhouse workers are at higher risk of STEC infection than farmers. In addition, slaughterhouse workers have a more potential source of food contamination of STEC and transmission. PMID- 24159475 TI - Sensitivity Analysis of the Parameters of Korea's Pandemic Influenza Preparedness Plan. AB - OBJECTIVES: Our aim was to evaluate Korea's Pandemic Influenza Preparedness Plan. METHODS: We conducted a sensitivity analysis on the expected number of outpatients and hospital bed occupancy, with 1,000,000 parameter combinations, in a situation of pandemic influenza, using the mathematical simulation program InfluSim. RESULTS: Given the available resources in Korea, antiviral treatment and social distancing must be combined to reduce the number of outpatients and hospitalizations sufficiently; any single intervention is not enough. The antiviral stockpile of 4-6% is sufficient for the expected eligible number of cases to be treated. However, the eligible number assumed (30% for severe cases and 26% for extremely severe cases) is very low compared to the corresponding number in European countries, where up to 90% of the population are assumed to be eligible for antiviral treatment. CONCLUSIONS: A combination of antiviral treatment and social distancing can mitigate a pandemic, but will only bring it under control for the most optimistic parameter combinations. PMID- 24159474 TI - A diversity of Antibiotic-resistant Staphylococcus spp. in a Public Transportation System. AB - OBJECTIVES: Our goal was to determine the diversity and abundance of Staphylococcus bacteria on different components of a public transportation system in a mid-sized US city (Portland, Oregon) and to examine the level of drug resistance in these bacteria. METHODS: We collected 70 samples from 2 cm * 4 cm sections from seven different areas on buses and trains in Portland, USA, taking 10 samples from each area. We isolated a subset of 14 suspected Staphylococcus spp. colonies based on phenotype, and constructed a phylogeny from16S rRNA sequences to assist in identification. We used the Kirbye-Bauer disk diffusion method to determine resistance levels to six common antibiotics. RESULTS: We found a range of pathogenic Staphylococcus species. The mean bacterial colony counts were 97.1 on bus and train floors, 80.1 in cloth seats, 9.5 on handrails, 8.6 on seats and armrests at bus stops, 3.8 on the underside of seats, 2.2 on windows, and 1.8 on vinyl seats per 8 cm(2) sample area. These differences were significant (p < 0.001). Of the 14 isolates sequenced, 11 were staphylococci, and of these, five were resistant to penicillin and ampicillin, while only two displayed intermediate resistance to bacitracin. All 11 isolates were sensitive to trimethoprim-sulfamethoxazole, vancomycin, and tetracycline. CONCLUSIONS: We found six different strains of Staphylococcus, and while there were varying levels of drug resistance, we did not find extensive levels of multidrug resistant bacteria, and no S. aureus was found. We found floors and cloth seats to be areas on buses and trains that showed particularly high levels of bacteria. PMID- 24159477 TI - The name of the game. PMID- 24159476 TI - A Contribution of MdfA to Resistance to Fluoroquinolones in Shigella flexneri. AB - In this study, we measured the drug resistance conferred by mdfA mutations in two Shigella flexneri strains. A mutant in mdfA genes was constructed by polymerase chain reaction-based, one-step inactivation of chromosomal genes. The antimicrobial susceptibility of parent and mutant strains to fluoroquinolones was determined by minimal inhibitory concentration (MICs). The ?mdfA mutants were somewhat more susceptible to fluoroquinolones than the parent strains. The low level changes in MICs of the ?mdfA mutants suggest that mdfA contributed the fluoroquinolone resistance in S flexneri. This finding found that the increased expression level of an MdfA efflux pump mediated fluoroquinolone resistance, but it is not likely a major effecter of higher resistance levels. PMID- 24159478 TI - Human diseases 101: nature versus nurture. PMID- 24159479 TI - Study on the correlation of premises condition index and the presence of larvae of aedes species mosquitoes in human dwellings of the cuddalore district of Tamil Nadu, India. AB - CONCLUSIONS: It is concluded that this study helps in conducting rapid survey to identify the presence of Aedes larvae with a minimum number of staff for both inspection and treatment of Aedes larvae during the epidemic situation. OBJECTIVES: To predict dwellings for the presence of Aedes larvae rapidly based on Premises Condition Index (PCI) factors, we studied the possible presence of Aedes species mosquitoes larvae among houses in the Chidambaram urban of Cuddalore District in Tamil Nadu, India based on the scores of variables in PCI, namely House, Yard and degree of shadow. Data of these variables were collected in September and October 2006 from 1813 houses in the Chidambaram urban area during the intensive vector control activities employed for the prevention and control of Chikungunya. METHODS: The association between presence of larvae and the variables of PCI was tested by Chi-square and Correlation. The predictability of the presence of Aedes larvae based on PCI factors was computed by logistic regression. RESULTS: The study shows 301 containers in 132 houses were found positive with Aedes species out of 1813 houses surveyed. It was further observed that the probability of presence of positive premises was four times higher in the premises with 75% shadow compared with premises with a 25% shadow. These findings showed a significant association (p < 0.001) with positive premises. PMID- 24159480 TI - Viral Interferon Regulatory Factor 1 of Kaposi's Sarcoma-Associated Herpesvirus Interacts with a Translocation Liposarcoma Protein-Associated Serine-Arginine Protein. AB - OBJECTIVES: To confirm that Kaposi's sarcoma-associated herpes virus openreading frame K9, viral interferon regulatory factor 1 (vIRF1), interacts with splicing factor, translocation liposarcoma protein-associated serine-arginine protein (TASR), in vivo and to establish whether interactions between vIRF1 and TASRs influence alternative splicing. METHODS: Association between vIRF1 and TASRs was confirmed with the glutathione S-transferase pull-down assay and coimmunoprecipitation. Further colocalization was shown by immunofluorescence. The in vivo splicing assay was performed to confirm the alterations in the splicing pattern. RESULTS: vIRF1 interacts with both TASR1 and 2 in vivo. vIRF1 has been shown to colocalize with TASR proteins in 293 T cells. However, an in vivo splicing revealed no alterations in the splicing pattern via interaction. CONCLUSIONS: The study data suggest that vIRF1 interacts with the TASR protein. However, vIRF1 interactions do not affect TASR-mediated alternative splicing. PMID- 24159481 TI - Epidemiologic features of animal bite cases occurring in rabies-endemic areas of Korea, 2005 to 2009. AB - OBJECTIVES: Human rabies is a reemerging infectious disease in Korea. There was no human rabies case for 14 years until the disease had reoccurred in 1999. To prevent occurrence of human rabies, surveillance for animal bite patients in rabies endemic areas in Korea was conducted since 2005 as a part of a human rabies control program. The animal bite cases were analyzed to determine whether patients were treated according to the post-exposure prophylaxis (PEP) guideline of the Korea Centers for Disease Control and Prevention. METHODS: Information of animal bite cases that occurred from 2005 to 2009 in rabies high-risk regions were collected by cooperation with Regional Public Health Centers in 18 cities/districts of rabies endemic areas. RESULTS: A total of 2458 animal bite cases were reported. Dogs accounted for 86% of animal bites and 67% of the animals were not vaccinated against rabies virus. For PEP, among rabies vaccinated animals, 92.7% were observed for clinical signs and 1.4% underwent necropsy. Among unvaccinated animals, 72.7% were observed for clinical signs and 4.1% underwent necropsy. The remaining animals were not available for examination. Of the animal bite patients, 32.5% received PEP and 51.6% were treated by first aid or by washing the wound. CONCLUSIONS: Given that no human rabies cases were reported since 2005 and animal rabies was continuously reported in endemic areas of Korea, the human rabies control program implemented in 2005 appears to have a significant role in the prevention and control of human rabies. PMID- 24159482 TI - Application of the microagglutination test for serologic diagnosis of human brucellosis. AB - OBJECTIVES: Brucellosis is one of the most common zoonoses in the world, and occurs mainly in farmers, slaughterhouse workers, and veterinarians via direct or indirect contact with infected animals or their products. The clinical symptoms of human brucellosis are nonspecific, such as fever, headache, chills, and sweating. Diagnosis and treatment of brucellosis requires laboratory tests. Although the serum tube agglutination test (SAT) is the standardized gold method, it is laborious, time consuming, and requires a number of reagents. A microagglutination test (MAT) variant of the SAT or enzyme-linked immunosorbent assay (ELISA) is recommended for serological diagnoses. For the simple and rapid diagnosis of brucellosis, the MAT was standardized using samples for the SAT to define positive and negative categories, and we then compared the sensitivity and specificity of the MAT and ELISA. METHODS: Thirty SAT-positive sera and 60 SAT negative sera were used in this study. Antibody titers of >=1:160 were considered positive readings in both the SAT and MAT. Brucella abortus antigens and Brucella positive control antiserum were used in the SAT and MAT. ELISAs of IgM and IgG were performed according to the manufacturers' instructions. RESULTS: The titers of the MAT differed according to antigen concentration. The optimal concentration of B abortus antigen was determined to compare the sensitivity and specificity between the MAT and SAT. The sensitivity and specificity of the MAT were 93.3% and 96.7%, respectively, for IgG with reference to ELISA, and 96.7% and 98.3%, respectively, for IgM. CONCLUSIONS: The optimal concentration of antigen for the MAT was 1:10. The MAT is less time consuming and requires less antigen and serum than the SAT. The results of the MAT showed good agreement with those of ELISA. The results of this study suggest that the MAT could be useful for diagnosis of brucellosis. PMID- 24159483 TI - HIV/AIDS Knowledge, Stigmatizing Attitudes, and Related Behaviors and Factors that Affect Stigmatizing Attitudes against HIV/AIDS among Korean Adolescents. AB - OBJECTIVES: This study examined the sex differentials for specific aspects of knowledge regarding HIV, stigmatizing attitudes toward people with HIV/AIDS (PWHAs) and sexual behavior. In addition, the factors that affect stigmatizing attitudes toward PWHAs were investigated. METHODS: The population of this study comprised of senior high students in Seoul, Korea. Eight high schools were selected randomly and 1566 adolescents participated in the survey. A total sample of 1548 cases (18 cases were excluded) was used for analysis. A self-administered questionnaire measuring their general and transmission and discriminatory attitudes was used. RESULTS: The level of HIV/AIDS knowledge among Korean adolescents was low, as indicated by a correct response rate of 54% (7.0 out of 13). The students answered correctly about HIV transmission by kissing at 50.2%, toilets at 59.4%, cup sharing at 57.4%, and daily school life at 60.5%. The level of discriminatory attitudes towards HIV-infected persons was high. Boys reported a higher proportion of sexual experience (7.0% vs. 2.6%, OR=2.89, p < 0.001). Only 39.0% used a condom during their last sexual encounter and more girls (53.3%) than boys (35.3%) reported using a condom. CONCLUSIONS: These findings highlight the need for increasing HIV knowledge, reducing HIV stigma, and providing sex education focusing on safer sex practices. PMID- 24159484 TI - Seroepidemiology of hepatitis a infection in northeastern china, Korea, and Japan. AB - OBJECTIVES: The epidemiological patterns of endemic hepatitis A virus (HAV) are unclear in northeastern Asia depending on the ethnicity of the country in question. The purpose of this study was to investigate the seroprevalence of HAV in northeastern China, South Korea, and Japan. METHODS: A total of 1,500 serum samples were collected from five groups of inhabitants (300 each) who were over 40 years of age (Korean Chinese, indigenous Chinese, South Korean, Korean living in Japan, and indigenous Japanese). The samples were screened for antibodies to HAV using an enzyme-linked immunosorbent assay. RESULTS: Positivity for HAV antibodies was 93.7% (95% confidence interval [CI]: 90.9-96.4) in Koreans living in northeastern China, 99.7% (95% CI: 99.0-100.3) in indigenous Chinese, 98.0% (95% CI: 96.4-99.6) in indigenous Koreans, 33.3% (95% CI: 28.0-38.7) in Koreans living in Japan, and 20.4% (95% CI: 15.8-25.0) in indigenous Japanese persons. The overall anti-HAV prevalence was not significantly different between northeastern China and South Korea, but it was different in Japan. CONCLUSIONS: These results indicate that differences in seroprevalence can be attributed to geological, environmental, and socioeconomic conditions rather than ethnicity. PMID- 24159485 TI - Phylogenetic Analysis of the Rotavirus Genotypes Originated from Children < 5 Years of Age in 16 Cities in South Korea, between 2000 and 2004. AB - OBJECTIVES: The purpose of this study was to examine the diversity of the G and P types of human rotavirus strains isolated in South Korea during 2000 to 2004. METHODS: We selected 38 Group A rotavirus isolates among 652 fecal samples, which were collected from infants and children < 5 years of age with acute gastroenteritis or diarrhea admitted in 8 hospitals representative of five provinces of South Korea between 2000 and 2004. Rotavirus P- and G-genotypes were determined by nucleotide sequencing and phylogenetic analysis was performed. RESULTS: One G1P[4] consisted G1-Id-P[4]-V; one G1P[6] consisted G1-Id-P[6]-Ia; nine G1P[8] consisted G1-Ib-P[8]-Ia (n=3), G1-Ic-P[8]-Ia (n=1), and G1-Id-P[8]-Ia (n=5); 13 G2P[4] consisted G2-V-P[4]-V; two G3P[4] consisted G3-IIId-P[4]-V; five G3P[8] consisted G3-IIId-P[8]-Ia; four G4P[6] consisted G4-Ie-P[6]-Ia; two G4P[8] consisted G4-Ie-P[8]-II; one G9P[6] consisted G9-III-P[6]-Ia. CONCLUSIONS: A considerable amount of rotavirus genotypic diversity was detected in South Korea from 2000 to 2004. These findings are important to develop the effective vaccines and to undertake epidemiologic studies. PMID- 24159486 TI - Enteropathogenic Escherichia coli Outbreak and its Incubation Period: Is it Short or Long? AB - OBJECTIVES: The aim of this study is to determine the incubation period of enteropathogenic Escherichia coli (EPEC), which creates several outbreaks in a year in South Korea. METHODS: We reviewed all water and food-borne outbreaks data reported to the Korea Centers for Disease Control and Prevention (KCDC) from 2009 to 2010 and determined their characteristics. Through this process, we can presume the incubation period of EPEC among outbreaks in South Korea. RESULTS: A total of 497 water and food-borne outbreaks were reported to KCDC and 66 (13.28%) are defined as E coli-origin outbreaks. EPEC was the most common subtype of E coli, being confirmed as a causative organism in 26 outbreaks. Overall attack rate was 15.85% (range 0.9-100). The subjects were eight outbreaks that have a clear history of single exposure and we can estimate the incubation time of EPEC as minimum 0.5 hours to maximum 34.0 hours with a mean 12.9 hours (range 4.5 24.0). The cases of those cannot completely rule out the chance of multiple exposure from same source or place have minimum 1.0 hour, to a maximum of 195.5 hours and a mean 30.5 (range 22.7-61.0) hours of incubation period. CONCLUSIONS: This serial analysis suggests that EPEC has actually shorter mean incubation period as much as 12 hours. When this period is longer than 1 day or over, then the epidemiologic investigator should consider the chance of repeated or continuous exposure by making it clear whether there is any chance of any other exposure in common. PMID- 24159487 TI - In vivo Noninvasive Small Animal Molecular Imaging. AB - The remarkable efforts that are made on molecular imaging technologies demonstrate its potential importance and range of applications. The generation of disease-specific animal models, and the developments of target-specific probes and genetically encoded reporters are another important component. Continued improvements in the instrumentation, the identification of novel targets and genes, and the availability of improved imaging probes should be made. Multimodal imaging probes should provide easier transitions between laboratory studies, including small animal studies and clinical applications. Here, we reviewed basic strategies of noninvasive in vivo imaging methods in small animals to introducing the concept of molecular imaging. PMID- 24159492 TI - Can stigma still distort the spectrum of a disease? PMID- 24159493 TI - Effect of maternal immune status on responsiveness of bacillus calmette-gurin vaccination in mouse neonates. AB - OBJECTIVES: Bacillus Calmette-Guerin (BCG) vaccination has proven to be efficient in immunologically naive infants; however, it has not been investigated that maternal natural exposure to Mycobacterium and/or BCG vaccine could influence the characteristics of immune responses to BCG in newborns. In this study, we analyzed whether the maternal immune status to M tuberculosis (M tb) can affect neonatal immunity to BCG using a mouse model. METHODS: Neonates were obtained from mice that were previously exposed to live BCG, to live M avium, or to heat killed M tb H37Rv, and from naive control mothers. One week after birth, the neonates were divided into two subgroups: one group immunized with live BCG via the subcutaneous route and the other group of neonates sham-treated. Interferon gamma (IFNgamma) secretion in response to in vitro stimulation with heat-killed BCG or purified protein derivative (PPD) was examined. Protection against M tb infection was evaluated by challenging mice nasally with live M tb H37Rv followed by counting colonies from spleen and lung homogenates. RESULTS: BCG-immunized neonates showed increased IFNgamma secretion in response to heat-killed BCG or PPD. All mice in BCG-immunized neonates subgroups showed reduced bacterial burden (colony forming unit) in the lungs when compared with control naive neonate mice. However, no statistically significant difference was observed when comparing BCG immunized mice born from mothers previously exposed to M avium or immunized with either heat-killed H37Rv or live BCG and mice born from naive mothers. CONCLUSION: The maternal immune status to M tb does not appear to impact on the immunogenicity of BCG vaccine in their progeny in our experimental conditions. PMID- 24159494 TI - Proteomic Analysis of Cellular and Membrane Proteins in Fluconazole-Resistant Candida glabrata. AB - OBJECTIVES: Candida glabrata is one of the most common causes of Candida bloodstream infections worldwide. Some isolates of C glabrata may be intermediately resistant to azoles, with some strains developing resistance during therapy or prophylaxis with fluconazole. In this study, we used a proteomic approach to identify differentially expressed proteins between fluconazoleresistant and -susceptible strains. METHODS: Membrane and cellular proteins were extracted from fluconazolesusceptible and fluconazole-resistant C glabrata strains. Differentially expressed proteins were compared using two dimensional sodium dodecyl sulfate polyacrylamide gel electrophoresis. Proteins with >1.5-fold difference in expression were identified by liquid chromatography tandem mass spectrometry (LC-MS/MS). RESULTS: A total of 65 proteins were differentially expressed in the cellular and membrane fractions. Among the 39 cellular proteins, 11 were upregulated and 28 were downregulated in fluconazole resistant strains in comparison with fluconazole-susceptible strains. In the membrane fraction, a total of 26 proteins were found, of which 19 were upregulated and seven were downregulated. A total of 31 proteins were identified by LC-MS/MS that are involved in glycolysis, carbohydrate transport, energy transfer, and other metabolic pathways. Heat shock proteins were identified in various spots. CONCLUSION: Heat shock and stress response proteins were upregulated in the membrane fraction of the fluconazole-resistant C glabrata strain. Compared with susceptible strains, fluconazole-resistant strains showed increased expression of membrane proteins and decreased expression of cellular proteins. PMID- 24159495 TI - Non-chromatographic Method for the Hepatitis B Virus X Protein Using Elastin-Like Polypeptide Fusion Protein. AB - OBJECTIVES: Hepatitis B virus (HBV) is a member of the hepadnavirus family. The HBV genome contains four genes designated as S, C, P, and X. The HBV X (HBx) gene encodes for a 16.5-kDa regulatory protein that enhances HBV replication and exerts multifunctional activities. The aim of this study is to describe the rapid and easy purification of HBx using ELP (elastin-like polypeptide) fusion protein. METHODS: The ELP-HBx fusion protein was overexpressed in Escherichia coli. Environmental sensitivity was demonstrated via turbidity and dynamic light scattering as a function of temperature. HBx was purified as an ELP fusion protein. ELPs are biopolymers of the pentapeptide repeat Val-Pro-Gly-Xaa-Gly that undergo an inverse temperature phase transition. ELP follows in temperature and salt consistency, precipitation, and solution repetition (inverse transition cycling) with polypeptide, where it purifies the protein in a simple manner. RESULTS: Fusion proteins underwent supramolecular aggregation at 40 C in 1 M NaCl and slowly resolubilized at subphysiologic temperatures. ELP domain proteolysis liberated a peptide of comparable size and immunoreactivity to the commercial HBx. CONCLUSION: This study suggests that HBx can be purified rapidly and easily using inverse transition cycling, and that this method can be applied in determination of HBx 3D structures and HBx stability study. PMID- 24159496 TI - Improvements in the metabolic syndrome and stages of change for lifestyle behaviors in korean older adults. AB - OBJECTIVES: This study aims to examine the effectiveness of a 6-month lifestyle modification program on the improvement in metabolic syndrome (MetS) status and in stages of change for lifestyle behaviors associated with MetS among Korean older adults. METHODS: A lifestyle modification program was developed based on the transtheoretical model. The program consisted of health counseling, education classes, a self-management handbook, newsletters and a health diary. Older adults aged >=60 (n = 480) with MetS were randomly assigned to the intervention group (IG) or the comparison group (CG). The IG received a comprehensive 6-month lifestyle modification intervention, while the CG received minimal information on MetS and lifestyle modification. Health examination and selfadministered survey were conducted before and after the intervention to determine the effectiveness of the program. RESULTS: After the intervention, the prevalence of MetS decreased to 38.1% in the IG and 52.4% in the CG (p = 0.046). The IG improved abdominal obesity (p = 0.016), blood pressure (p = 0.030), and triglyceride (p = 0.005) more than the CG did. The IG demonstrated significant improvements in the behavioral stages for portion control (p = 0.021), balanced diet (p < 0.001) and adequate intake of fruits and vegetables (p = 0.012). The IG reduced the prevalence of abdominal obesity (OR = 2.34) and improved MetS status (OR = 1.79) better than the CG. The IG were more likely to advance from preaction stages at baseline to action stage at post-intervention for portion control (OR = 3.29) and adequate intake of fruits and vegetables (OR = 2.06). CONCLUSION: Lifestyle modification can improve the MetS status and behavioral stages in older adults. PMID- 24159497 TI - Improving Service Quality in Long-term Care Hospitals: National Evaluation on Long-term Care Hospitals and Employees Perception of Quality Dimensions. AB - OBJECTIVES: To investigate predictors for specific dimensions of service quality perceived by hospital employees in long-term care hospitals. METHODS: Data collected from a survey of 298 hospital employees in 18 long-term care hospitals were analysed. Multivariate ordinary least squares regression analysis with hospital fixed effects was used to determine the predictors of service quality using respondents' and organizational characteristics. RESULTS: The most significant predictors of employee-perceived service quality were job satisfaction and degree of consent on national evaluation criteria. National evaluation results on long-term care hospitals and work environment also had positive effects on service quality. CONCLUSION: The findings of the study show that organizational characteristics are significant determinants of service quality in long-term care hospitals. Assessment of the extent to which hospitals address factors related to employeeperceived quality of services could be the first step in quality improvement activities. Results have implications for efforts to improve service quality in longterm care hospitals and designing more comprehensive national evaluation criteria. PMID- 24159498 TI - Epidemiological and Immunological Characteristics at the Time of HIV Diagnosis for HIV/AIDS Cohort Registrants Representative of HIV-Infected Populations in Korea. AB - OBJECTIVES: The Korea HIV/AIDS cohort was constructed with 18 hospitals that care for HIV-infected individuals in 2006. We compared the epidemiological and immunological characteristics of the cohort registrants with those of the HIVinfected population at the time of HIV diagnosis. METHODS: This study was conducted on 5717 people living with HIV/AIDS from 1985 to 2009, of which 789 individuals registered with the Korea HIV/AIDS cohort study. Individuals who had data from initial CD4+ T-cell counts measured within 6 months following HIV diagnosis were selected as study participants to predict the status of disease progression at the time of HIV diagnosis. A total of 2886 patients (50%) were selected from people living with HIV/AIDS, of whom 424 individuals (54%) were cohort registrants. The chi(2) test and Wilcoxon rank sum test were used for analysis. RESULTS: The distributions of age, marital status, diagnosed regions, reason for HIV testing, and screening site were similar between the HIV-infected population and the cohort registrants. In 1985-2004, the male ratio for the cohort registrants (94.3%) was significantly higher than that measured for the HIV-infected population (89.5%) (p = 0.0339). With regard to transmission route, homosexual contact of cohort registrants (46.6%) was higher than that of the HIV infected population (40.1%) (p = 0.022) in 2005-2009. No statistical difference in CD4+ T-cell counts at the time of HIV diagnosis was found between the HIVinfected population and cohort registrants (p = 0.2195). CONCLUSION: The Korea HIV/AIDS cohort registrants represent the HIV-infected population, and the data collected from this cohort could be used as a foundation for national statistics. PMID- 24159499 TI - Changes in Human Immunodeficiency Virusrelated Knowledge and Stigmatizing Attitudes among Korean Adolescents from 2006 to 2011. AB - OBJECTIVES: This study assessed the prevalence and changes of human immunodeficiency virus (HIV) knowledge and stigmatizing attitudes in 2006, 2008, and 2011. METHODS: Three cross-sectional surveys were conducted in 2006, 2008, and 2011. A cross-sectional sample of high school students in Seoul, South Korea was targeted. A self-administered questionnaire measuring general and transmission and discriminatory attitudes was used. RESULTS: Misconceptions about casual contact were widespread, even though the proportion responding incorrectly decreased significantly over the 5-year period. The respondents in all surveys displayed a high level of discrimination against those with HIV/AIDS in some situations, particularly in the idea of HIV/AIDS making the respondent feel disgusted (63.3% in 2006, 57.5% in 2008, and 52.6% in 2011), avoiding sitting with people with HIV/AIDS (50.6% in 2006, 50.5% in 2008, and 48.5% in 2011), and blaming those with HIV for becoming infected (46.6% in 2006, 42.8% in 2008, and 43.0% in 2011). Even though respondents had a high level of stigmatizing attitudes, the survey showed that the stigma has declined over the 5-year period. CONCLUSION: The survey results showed that public health policy should recognize that HIV stigmatizing attitudes persist in Korea. This finding has implications for the development of intervention programs focusing on reducing the levels of discrimination. PMID- 24159502 TI - Basis for korean genome study. PMID- 24159500 TI - Multiplex Real-Time Polymerase Chain Reaction-Based Method for the Rapid Detection of gyrA and parC Mutations in Quinolone-Resistant Escherichia coli and Shigella spp. AB - Two real-time polymerase chain reaction assays were developed to detect mutations in codons 83 and 87 in gyrA and in codons 80 and 91 in parC, the main sites that causes quinolone resistance in pathogenic Escherichia coli and Shigella spp. isolates. These assays can be employed as a useful method for controlling infections caused by quinolone-resistant E coli and Shigella isolates. PMID- 24159503 TI - Early detection of nosocomial outbreaks caused by rare pathogens: a case study employing score prediction interval. AB - OBJECTIVES: Nosocomial outbreaks involve only a small number of cases and limited baseline data. The present study proposes a method to detect the nosocomial outbreaks caused by rare pathogens, exploiting score prediction interval of a Poisson distribution. METHODS: THE PROPOSED METHOD WAS APPLIED TO THREE EMPIRICAL DATASETS OF NOSOCOMIAL OUTBREAKS IN JAPAN: outbreaks of (1) multidrug-resistant Acinetobacter baumannii (n = 46) from 2009 to 2010, (2) multidrug-resistant Pseudomonas aerginosa (n = 18) from 2009 to 2010, and (3) Serratia marcescens (n = 226) from 1999 to 2000. RESULTS: The proposed method successfully detected all three outbreaks during the first 2 months. Both the model-based and empirically derived threshold values indicated that the nosocomial outbreak of rare infectious disease may be declared upon diagnosis of index case(s), although the sensitivity and specificity were highly variable. CONCLUSION: The findings support the practical notion that, upon diagnosis of index patient(s), one should immediately start the outbreak investigation of nosocomial outbreak caused by a rare pathogen. The proposed score prediction interval can permit easy computation of outbreak threshold in hospital settings among healthcare experts. PMID- 24159504 TI - Optimal Control Strategy of Plasmodium vivax Malaria Transmission in Korea. AB - OBJECTIVE: To investigate the optimal control strategy for Plasmodium vivax malaria transmission in Korea. METHODS: A Plasmodium vivax malaria transmission model with optimal control terms using a deterministic system of differential equations is presented, and analyzed mathematically and numerically. RESULTS: If the cost of reducing the reproduction rate of the mosquito population is more than that of prevention measures to minimize mosquito-human contacts, the control of mosquito-human contacts needs to be taken for a longer time, comparing the other situations. More knowledge about the actual effectiveness and costs of control intervention measures would give more realistic control strategies. CONCLUSION: Mathematical model and numerical simulations suggest that the use of mosquito-reduction strategies is more effective than personal protection in some cases but not always. PMID- 24159505 TI - Dynamics of Constructs in Successful Aging of Korean Elderly: Modified Rowe and Kahn's Model. AB - OBJECTIVES: This study examined components in Rowe and Kahn's successful aging model to investigate their hierarchical order and led to a modification of the previous hierarchical order. METHODS: To examine the hierarchical order of components, we constructed a structural equation model and verified those paths that have discrepancies in studies and/or potential inclusion or omission errors in the model. For this purpose, we analyzed 556 cases out of stratified and purposively sampled 600 elderly people living in the city of Jeonju during the study period (2011). RESULTS: The paths with inclusion errors such as H3 [self reported health -> productive activity (SRH -> PA)]: the effect of SRH on PA, and H6 [social network (SN) -> PA]: the effect of SN on PA, were not directly but indirectly supported. The path with discrepancy, H4 [SN -> physical-cognitive function (PCF)]: the effect of SN on PCFs, was statistically significant. The path with inclusion error and discrepancy, H8 (PCF -> PA): the effect of PCF on PA, was not directly but indirectly supported. Also the path with the omission error, H2 [SRH -> psychological trait (PT)]: the effect of SRH on PT, was statistically significant. The other paths in the hierarchical order of the model reported in previous studies were statistically significant. CONCLUSION: We verified new dynamics of constructs involved in successful aging, which would provide better understanding of Rowe and Kahn's successful aging model for Korean elderly people living in a medium-sized city. PMID- 24159506 TI - Surveillance and vector control of lymphatic filariasis in the republic of Korea. AB - OBJECTIVES: Until the early 2000s, lymphatic filariasis would commonly break out in the coastal areas in Korea. Through steady efforts combining investigation and treatment, filariasis was officially declared eradicated in 2008. This study surveyed the density of vector species of filariasis in past endemic areas, and inspected filariasis DNA from collected mosquitoes for protection against the reemergence of filariasis. METHODS: Between May and October 2009, mosquitoes were caught using the black night trap in past endemic coastal areas: Gyeongsangnam do, Jeollanamdo, and Jeju-do. The collected mosquitoes were identified, and the extracted DNA from the collected vector mosquitoes was tested by polymerase chain reaction for Brugia malayi filariasis. RESULTS: Ochletotatus togoi, Anophel es (Hyrcanus) group and Culex pipiens were most frequently caught in Jeollanam-do (Geomun Island, Bogil Island, Heuksan Island), Jeju-do (Namone-ri, Wimi-ri). and Gyeongsangnam-do (Maemul Island). DNA of B malayi was not found in Och Togoi and An (Hyrcanus) group as main vectors of filariasis. CONCLUSION: Lymphatic filariasis was not found in the vector mosquitoes collected in past endemic areas. However, considering that the proportion of vector species is quite high, there is a potential risk that filariasis could be reemerging through overseas travel or trade. Thus, there is a need to continuously monitor vector mosquitoes of lymphatic filariasis. PMID- 24159507 TI - Comparison of Antimicrobial Resistance in Escherichia coli Strains Isolated From Healthy Poultry and Swine Farm Workers Using Antibiotics in Korea. AB - OBJECTIVES: The aim of this study is to compare the antibiotic resistance of Escherichia coli isolates from faecal samples of workers who often use antibiotics. METHODS: A total of 163E coli strains isolated from faecal samples of livestock workers (poultry and swine farm workers) and restaurant workers in the same regions as a control group were analyzed by agar disc diffusion to determine their susceptibility patterns to 16 antimicrobial agents. RESULTS: Most of the tested isolates showed high antimicrobial resistance to ampicillin and tetracycline. The isolates showed higher resistance to cephalothin than other antibiotics among the cephems. Among the aminoglycosides, the resistance to gentamicin and tobramycin occurred at higher frequencies compared with resistance to amikacin and netilmicin. Our data indicated that faecal E coli isolates of livestock workers showed higher antibiotic resistances than nonlivestock workers (restaurant workers), especially cephalothin, gentamicin, and tobramycin (p < 0.05). Moreover, the rates of the livestock workers in the association of multidrug resistance were also higher than the rates of the restaurant workers. CONCLUSION: This study implies that usage of antibiotics may contribute to the prevalence of antibiotic resistance in commensal E coli strains of humans. PMID- 24159508 TI - Knowledge, Attitudes, and Sexual Behaviors in HIV/AIDS and Predictors Affecting Condom Use among Men Who Have Sex with Men in South Korea. AB - OBJECTIVES: In South Korea, men who have sex with men (MSM) are rather understudied, but are known to be at high risk for human immunodeficiency virus infection (HIV)/acquired immunodeficiency syndrome (AIDS). This study was to access HIV/AIDS knowledge, attitudes, and risk behaviors, and to identify the factors of condom use in HIV prevention. METHODS: We recruited 1070 MSM in Korea, using the Internet to maximize the confidentiality of the MSM. RESULTS: The prevalence of self-reported and sexually transmitted infections and HIV in the total sample was 10.7% and 2.7%, respectively. Factual knowledge and phobias regarding HIV/AIDS and self-efficacy were relatively high among the MSM. After controlling for age, education, marital status, and sexual identity, predictors of condom use at most recent anal sex included knowledge (OR = 1.25; p < 0.0001); self-efficacy (OR = 1.33; p = 0.02), additionally, having HIV testing (OR = 1.45; p = 0.02); and having a regular partner (OR = 0.53; p < 0.0001) were also positively associated with condom use. CONCLUSION: The intervention programs for MSM in Korea may need to take the idiosyncratic societal and cultural pressures of the region into consideration in order to reduce infection risk. PMID- 24159509 TI - JXTA: A Technology Facilitating Mobile P2P Health Management System. AB - OBJECTIVES: Mobile JXTA (Juxtapose) gaining momentum and has attracted the interest of doctors and patients through P2P service that transmits messages. Audio and video can also be transmitted through JXTA. The use of mobile streaming mechanism with the support of mobile hospital management and healthcare system would enable better interaction between doctors, nurses, and the hospital. Experimental results demonstrate good performance in comparison with conventional systems. This study evaluates P2P JXTA/JXME (JXTA functionality to MIDP devices.) which facilitates peer-to-peer application+ using mobile-constraint devices. Also a proven learning algorithm was used to automatically send and process sorted patient data to nurses. METHODS: From December 2010 to December 2011, a total of 500 patients were referred to our hospital due to minor health problems and were monitored. We selected all of the peer groups and the control server, which controlled the BMO (Block Medical Officer) peer groups and BMO through the doctor peer groups, and prescriptions were delivered to the patient's mobile phones through the JXTA/ JXME network. RESULTS: All 500 patients were registered in the JXTA network. Among these, 300 patient histories were referred to the record peer group by the doctors, 100 patients were referred to the external doctor peer group, and 100 patients were registered as new users in the JXTA/JXME network. CONCLUSION: This system was developed for mobile streaming applications and was designed to support the mobile health management system using JXTA/ JXME. The simulated results show that this system can carry out streaming audio and video applications. Controlling and monitoring by the doctor peer group makes the system more flexible and structured. Enhanced studies are needed to improve knowledge mining and cloud-based M health management technology in comparison with the traditional system. PMID- 24159510 TI - Serological Correlate of Protection in Guinea Pigs for a Recombinant Protective Antigen Anthrax Vaccine Produced from Bacillus brevis. AB - OBJECTIVE: Recombinant protective antigen (rPA) is the active pharmaceutical ingredient of a second generation anthrax vaccine undergoing clinical trials both in Korea and the USA. By using the rPA produced from Bacillus brevis pNU212 expression system, correlations of serological immune response to anthrax protection efficacy were analyzed in a guinea pig model. METHODS: Serological responses of rPA anthrax vaccine were investigated in guinea pigs that were given single or two injections (interval of 4 weeks) of various amounts of rPA combined with aluminumhydroxide adjuvant. Guinea pigs were subsequently challenged by the intramuscular injection with 30 half-lethal doses (30LD50) of virulent Bacillus anthracis spores. Serumantibody titerswere determined by anti-PA IgGELISA and the ability of antibodies to neutralize the cytotoxicity of lethal toxin on J774A.1 cell was measured through the toxin neutralizing antibody (TNA) assay. RESULTS: To examine correlations between survival rate and antibody titers, correlation between neutralizing antibody titers and the extent of protection was determined. Toxin neutralization titers of at least 1176 were sufficient to confer protection against a dose of 30LD50 of virulent anthrax spores of the H9401 strain. Such consistency in the correlation was not observed from those antibody titers determined by ELISA. CONCLUSION: Neutralizing-antibody titers can be used as a surrogate marker. PMID- 24159511 TI - Opening of the national biobank of Korea as the infrastructure of future biomedical science in Korea. AB - On April 26, 2012, the Korea National Institute of Health officially held the opening ceremony of newly dedicated biobank building, 'NationalBiobank of Korea'. The stocked biospecimens and related information have been distributed for medical and public health researches. The Korea Biobank Project, which was initiated in 2008, constructed the Korea Biobank Network consisting of the National Biobank of Korea (NBK) with 17 regional biobanks in Korea. As of December 2011, a total of 525,416 biospecimens with related information have been secured: 325,952 biospecimens from the general population obtained through cohort studies and 199,464 biospecimens of patients from regional biobanks. A large scale genomic study, Korea Association Resource (KARE) and many researches utilized the biospecimens secured through Korea Genome Epidemiology Study (KoGES) and Korea Biobank Project (KBP). Construction of 'National Biobank of Korea', a dedicated biobank building at Osong means that NBK can manage and check quality of the biospecimens with promising distribution of 26 million vials of biospecimen, which provide the infrastructure for the development of health technology in Korea. The NBK and the National Library of Medicine (to be constructed in 2014) will play a central role in future biomedical research in Korea. PMID- 24159512 TI - National Biobank of Korea: Quality control Programs of Collected-human Biospecimens. AB - Personalized medicine is emerging as a main paradigm for risk prediction, pre diagnosis, and effective prevention and treatment of disease. A large number of human biospecimens and their clinical data are essential resources for the success of personalized medicine as well as other biomedical research. The National Biobank of Korea (NBK) has collected well-annotated and high quality human biospecimens, and distributes them to the Korean biomedical scientists, through the Korea Biobank Project (KBP). The ultimate goal of NBK activities is to promote biomedical research and public health. As of December- 2011, the NBK has collected various human biospecimens from 525,416 participants including 325,952 Korean populations and 199,464 patients. The purpose of this paper is to introduce the KBP and quality control programs for collection of human biospecimens with high quality of NBK. PMID- 24159513 TI - A New Statistical Approach to Analyze Plasmodium vivax Malaria Endemic in Korea. PMID- 24159514 TI - Spatial and Temporal Distribution of Plasmodium vivax Malaria in Korea Estimated with a Hierarchical Generalized Linear Model. AB - OBJECTIVES: The spatial and temporal correlations were estimated to determine Plasmodium vivax malarial transmission pattern in Korea from 2001-2011 with the hierarchical generalized linear model. METHODS: Malaria cases reported to the Korea Centers for Disease Control and Prevention from 2001 to 2011 were analyzed with descriptive statistics and the incidence was estimated according to age, sex, and year by the hierarchical generalized linear model. Spatial and temporal correlation was estimated and the best model was selected from nine models. Results were presented as diseases map according to age and sex. RESULTS: The incidence according to age was highest in the 20-25-year-old group (244.52 infections/100,000). Mean ages of infected males and females were 31.0 years and 45.3 years with incidences 7.8 infections/100,000 and 7.1 infections/100,000 after estimation. The mean month for infection was mid-July with incidence 10.4 infections/100,000. The best-fit model showed that there was a spatial and temporal correlation in the malarial transmission. Incidence was very low or negligible in areas distant from the demilitarized zone between Republic of Korea and Democratic People's Republic of Korea (North Korea) if the 20-29-year-old male group was omitted in the diseases map. CONCLUSION: Malarial transmission in a region in Korea was influenced by the incidence in adjacent regions in recent years. Since malaria in Korea mainly originates from mosquitoes from North Korea, there will be continuous decrease if there is no further outbreak in North Korea. PMID- 24159515 TI - Dietary patterns and osteoporosis risk in postmenopausal korean women. AB - OBJECTIVES: The prevalence of osteoporosis and related fractures has increased rapidly in Korean women. Proper nutrition intake is associated with the prevention of osteoporosis. We analyzed the association between dietary patterns and the risk of osteoporosis during a 4-year follow-up in postmenopausal Korean women. METHODS: Postmenopausal women (n = 1,725) who participated in the Korean Genome and Epidemiology Study were enrolled. Food intake was assessed using a validated semiquantitative food frequency questionnaire, and a quantitative ultrasound device was used to measure the speed of sound at the radius and tibia. RESULTS: THREE MAJOR DIETARY PATTERNS WERE IDENTIFIED USING FACTOR ANALYSIS BASED ON BASELINE INTAKE DATA: traditional (high intake of rice, kimchi, and vegetables), dairy (high intake of milk, dairy products, and green tea), and western (high intake of sugar, fat, and bread). Multivariate Cox proportional hazards models were used to estimate relative risk for osteoporosis. An inverse association was detected between the dairy dietary pattern and the osteoporosis incidence [relative risk (RR): 0.63, 95% confidence interval (CI): 0.42-0.93, p trend=0.055 in radius; RR: 0.56, 95% CI: 0.35-0.90, p-trend=0.048 in tibia]. Individuals in the highest quintile for the traditional dietary pattern (p-trend = 0.009 in tibia) and western dietary pattern (p-trend = 0.043 in radius) demonstrated a higher risk of osteoporosis incidence than those in the lowest quintile. CONCLUSION: These results suggested that high consumption of milk, dairy products, and green tea may reduce the risk of osteoporosis in postmenopausal Korean women. PMID- 24159516 TI - Acute health effects among military personnel participating in the cleanup of the hebei spirit oil spill, 2007, in taean county, Korea. AB - OBJECTIVES: This study was conducted to investigate acute health effects and its related factors among military personnel participating in the cleanup of the 2007 Hebei Spirit oil spill accident in Taean county, Korea. METHODS: We collected data on acute symptoms during the cleanup and their predictors using a self administered questionnaire to 2624 military personnel. Selfreported symptoms included six neurologic symptoms, five respiratory symptoms, two dermatologic symptoms, three ophthalmic symptoms, and three general symptoms. Independent variables were demographic factors (gender, age, education level, and rank), health behavioral factors (smoking history and usage of the personal protective equipment such as masks and gloves), and occupational history such as where and for how long individuals participated in cleanup. RESULTS: The duration of work days was significantly associated with 17 acute symptoms except for itchiness and red skin.Working in Taean county also increased the risk of most acute symptoms except headache and back pain. In regard to personal protective equipment, wearing masks was mainly related to the development of respiratory symptoms such as sore throat and wearing other protective equipment was related to the development of sore throat, back pain, headache, and cough. Military personnel younger than 25 years reported 4.66 times more hot flushing and 5.39 times more itchiness than those older than 25 years. CONCLUSION: It should be emphasized that for early-stage cleanup the number of workers should be minimized, sufficient personal protective equipment with approved quality for blocking noxious gas should be supplied, and systematic health care for the workers should be provided. Health effects could be diminished by providing adequate education regarding the appropriate use of protective equipment, especially to nonprofessionals such as residents and volunteers. To make disaster response expeditious, a national and regional preparedness plans and a professional response team for emergency environmental assessment and emergency action should be established beforehand to make prompt decisions. PMID- 24159517 TI - Prevalence of tick-borne encephalitis virus in ixodid ticks collected from the republic of Korea during 2011-2012. AB - OBJECTIVES: In this study, we demonstrated that TBEV-infected ticks have been distributed in the ROK, combined with our previous results. These results suggest that TBEV may exist in the ROK, and H. longicornis, H. flava, and I. nipponensis may be potential vectors of TBEV. In addition, these results emphasize the need for further epidemiological research of TBEV. METHODS: We examined for the presence of RNA of TBEV by reverse transcriptase-nested polymerase chain reaction (RT-nested PCR) using ixodid ticks captured in 25 localities of 10 provinces. Ticks were collected by the flagging and dragging method or using sentinel BG traps at forests, grass thickets, and grassland. A total of 13,053 ticks belonging to two genera and four species were collected and pooled (1292 pools), according to collection site, species of tick, and developmental stage. RESULTS: Among 1292 pools, the envelope (E) protein gene of TBEV was detected using RT nested PCR in 10 pools (3 pools of the 1,331 adult ticks and 7 pools of the 11,169 nymph ticks) collected from Gangwon-do province, Jeonrabuk-do province, and Jeju Island. The minimum infection rates for TBEV of Haemaphysalis longicornis, Haemaphysalis flava, and Ixodes nipponensis were 0.06%, 0.17%, and 2.38%, respectively. Phylogenetic analysis based on the partial E protein gene was performed to identify relationships between the TBEV strains. This showed that 10 Korean strains clustered with the Western subtype. CONCLUSION: In this study, we investigated the prevalence of tick-borne encephalitis virus (TBEV) in ixodid ticks from various regions of the Republic of Korea (ROK) during 2011-2012 to identify whether TBEV is circulating and to determine the endemic regions of TBEV. PMID- 24159518 TI - Enhanced Type III Secretion System Expression of Atypical Shigella flexneri II:(3)4,7(8). AB - OBJECTIVES: We aimed at evaluating the virulence of atypical Shigella flexneri II:(3)4,7(8) by DNA microarray and invasion assay. METHODS: We used a customized S. flexneri DNA microarray to analyze an atypical S. flexneri II:(3)4,7(8) gene expression profile and compared it with that of the S. flexneri 2b strain. RESULTS: Approximately one-quarter of the atypical S. flexneri II:(3)4,7(8) strain genes showed significantly altered expression profiles; 344 genes were more than two-fold upregulated, and 442 genes were more than 0.5-fold downregulated. The upregulated genes were divided into the category of 21 clusters of orthologous groups (COGs), and the "not in COGs" category included 170 genes. This category had virulence plasmid genes, including the ipa-mxi-spa genes required for invasion of colorectal epithelium (type III secretion system). Quantitative reverse-transcription polymerase chain reaction results also showed the same pattern in two more atypical S. flexneri II:(3)4,7(8) strains. Atypical S. flexneri II:(3)4,7(8) showed four times increased invasion activity in Caco-2 cells than that of typical strains. CONCLUSION: Our results provide the intracellularly regulated genes that may be important for adaptation and growth strategies of this atypical S. flexneri. PMID- 24159519 TI - Hematological Evidence of Occupational Exposure to Chemicals and Other Factors among Auto-Repair Workers in Rawalpindi, Pakistan. AB - OBJECTIVES: Occupational exposure to aromatic solvents causes many serious health hazards to workers, especially if an ambient environment increases the exposure during routine working hours. This study was conducted on two related groups, i.e., automobile mechanics (MCs) and automobile spray painters (PNs), with an effort to analyze effects of chemical exposure on hematological parameters, keeping a focus on environmental parameters and workers' personal behavioral characteristics that could be held responsible for increasing exposure risk. METHODS: A preliminary survey of various chemicals used in these places was done, and 78 blood samples were collected from three groups (control, n = 24; mechanics, n = 25; painters, n = 29). Demographic features of workers were recorded through a short questionnaire. RESULTS: Results showed that mean red blood cell (RBC) count was lower both in MCs [t(51) = 2.38, p < 0.021, r = 0.32] and in PNs [t(47) = 2.12, p < 0.03, r = 0.29], whereas mean hemoglobin (Hb) was significantly lower in MCs [t(51) = 2.5, p = 0.017, r = 0.33]. Combined data for exposed groups for smokers (SMs) versus nonsmokers (NSs) showed that SMs had a significantly lower number (RBC count: t(52) = 2.28, p < 0.027, r = 0.25; Hb count: t(52) = 2.71, p < 0.009, r = 0.30] of these parameters than NSs, even compared to the control group. Moreover, logistic regression results showed that smoking is a significant predictor of reduction in RBC and Hb counts, besides occupational exposure and work experience to a little extent among exposed workers. Mean white blood cell count [t(47) = 2.63, p < 0.01, r=0.35], mean corpuscle volume [t(47)= -2.82, p = 0.007, r = 0.29], and packed cell volume [t(47)= -2.28, p = 0.027, r = 31] were higher exclusively in painters, which could be related to exposure to benzene in addition to isocyanate. CONCLUSION: It appeared that workplace exposure may be complex due to interaction of multiple factors and PNs face much more exposure to isocyanate and aromatic solvents than MCs, which had significant effects on their hematopoiesis. Smoking enhances exposure risk manifolds, and among MCs it showed combined effects along with occupational exposure. There is a need to create awareness among these workers to adopt self-safety measures during routine tasks and also of a separate study to elucidate actual occupational exposure among them, eliminating confounding factors. PMID- 24159520 TI - Resistance to Fluoroquinolone by a Combination of Efflux and Target Site Mutations in Enteroaggregative Escherichia coli Isolated in Korea. AB - OBJECTIVES: Enteroaggregative Escherichia coli (EAEC) was recently reported as a major diarrheagenic pathogen in infant and adult travelers, both in developing and developed countries. EAEC strains are known to be highly resistant to antibiotics including quinolones. Therefore in this study we have determined the various mechanisms of quinolone resistance in EAEC strains isolated in Korea. METHODS: For 26 EAEC strains highly resistant to fluoroquinolone, minimal inhibitory concentrations for fluoroquinolones were determined, mutations in the quinolone target genes were identified by PCR and sequencing, the presence of transferable quinolone resistance mechanism were identified by PCR, and the contribution of the efflux pump was determined by synergy tests using a proton pump inhibitor. The expression levels of efflux pump-related genes were identified by relative quantification using real-time PCR. RESULTS: Apart from two, all tested isolates had common mutations on GyrA (Ser83Leu and Ser87Gly) and ParC (Ser80Gln). Isolates EACR24 and EACR39 had mutations that have not been reported previously: Ala81Pro in ParC and Arg157Gly in GyrA, respectively. Increased susceptibility of all the tested isolates to ciprofloxacin and norfloxacin in the presence of the pump inhibitor implies that efflux pumps contributed to the resistance against fluoroquinolones. Expression of the efflux pump-related genes, tolC, mdfA, and ydhE, were induced in isolates EACR 07, EACR 29, and EACR 33 in the presence of ciprofloxacin. CONCLUSION: These results indicate that quinolone resistance of EAEC strains mainly results from the combination of mutations in the target enzyme and an increased expression of efflux pump-related genes. The mutations Ala81Pro in ParC and Arg157Gly in GyrA have not been reported previously the exact influence of these mutations should be investigated further. PMID- 24159521 TI - Immune status and epidemiological characteristics of human immunodeficiency virus seroconverters in Korea, 1999-2009. AB - OBJECTIVES: The detection of HIV seroconverters increased annually since HIV antigen/antibody testing kits have been available widely in South Korea. This study aimed to identify the epidemiological characteristics of HIV seroconverters and their immune level at HIV diagnosis. METHOD: We analyzed the epidemiological and immunological characteristics of 341 HIV seroconverters among 6,008 HIV diagnosed individuals from 1999 and 2009. The analysis of immune level and epidemiological factors of HIV seroconverters was conducted by using chi-square test on SAS version 9.1. RESULTS: The seroconverters among newly-identified HIV cases each year increased from 0.5% in 1999 to over 5% or in 2009. The sex ratio of seroconverters was 18:1 (male:female), and 33% were in their 30s, and 28% were in their 20s. Reasons for HIV testing were involvement in voluntary test due to risky behaviors (43%), and health check-up (36%). Discovery of HIV infection occurred primarily in hospitals (84%). Among seroconverters, 55 percent had a CD4 T-cell count of more than 350/MUl. CONCLUSION: Korean HIV seroconverters tended to be younger at diagnosis, diagnosed during a voluntary test, and their CD4+ T cell counts at HIV diagnosis were higher than those of non-seroconverters aall HIV-infected individuals. This study of HIV seroconverters will be important foundational in future studies on HIV incidence, disease progress, and survival rate. PMID- 24159522 TI - The Geographical and Economical Impact of Scrub Typus, the Fastest-growing Vector borne Disease in Korea. PMID- 24159523 TI - Spatial distribution analysis of scrub typhus in Korea. AB - OBJECTIVE: This study analyzes the spatial distribution of scrub typhus in Korea. METHODS: A spatial distribution of Orientia tsutsugamushi occurrence using a geographic information system (GIS) is presented, and analyzed by means of spatial clustering and correlations. RESULTS: The provinces of Gangwon-do and Gyeongsangbuk-do show a low incidence throughout the year. Some districts have almost identical environmental conditions of scrub typhus incidence. The land use change of districts does not directly affect the incidence rate. CONCLUSION: GIS analysis shows the spatial characteristics of scrub typhus. This research can be used to construct a spatial-temporal model to understand the epidemic tsutsugamushi. PMID- 24159524 TI - Willingness to pay for avoiding infection of climate change diseases, in particular tsutsugamushi disease. AB - OBJECTIVES: As the prevalence of tsutsugamushi disease has tripled over the past decade to affect 8307 people in October 2012, this study is conducted to estimate the willingness to pay (WTP) to avoid infection of tsutsugamushi disease in order to analyze the loss of value caused by climate change diseases. METHODS: The double-bounded dichotomous choice of contingent valuation method was used to estimate the WTP to avoid infection of tsutsugamushi disease, through surveys conducted in the patient group (n = 120) and the control group (n = 240). RESULTS: More young people in the family, higher level of awareness of risks caused by climate change, more male members (as opposed to female), higher income, lower suggested bid, and greater WTP, is better positioned to avoid infection of disease. The mean of the amount of WTP has been estimated to be 3689 Kwon per month. CONCLUSION: As people have become increasingly aware of climate change diseases, WTP to avoid infection of tsutsugamushi disease has increased accordingly. The implicit loss of value due to climate change diseases is becoming increasingly higher. Therefore, there should be stronger and more aggressive promotional activities to prevent people from being infected with tsutsugamushi disease and to build a healthier society free from climate change diseases. PMID- 24159525 TI - Prevalence and Risk Factors of Clonorchiasis among the Populations Served by Primary Healthcare Posts along Five Major Rivers in South Korea. AB - OBJECTIVES: Clonorchiasis is an infectious disease caused by the Chinese liver fluke Clonorchis sinensis. In this study, we investigated the prevalence and risk factors of clonorchiasis among the populations served by primary healthcare posts along five major rivers in South Korea. METHODS: Forty primary healthcare posts that are located less than 5 km from one of the five rivers were selected from 26 counties. For the purpose of the survey, community health practitioners selected the nearest villages from the riversides in their own catchment area. From January to May 2009, a total of 2788 stool samples were collected and examined using the formalin-ether sedimentation technique. Village inhabitants were also interviewed by means of questionnaires in order to obtain information on potential risk factors. RESULTS: THE PREVALENCE RATES OF CLONORCHIASIS AT VARIOUS RIVER BASINS WERE AS FOLLOWS: Seomjin River, 21.3%; Nakdong River, 13.5%; Geum River, 9.2%; Han River, 7.6%; and Yeongsan River, 4.9%. The total number of people infected with C. sinensis was 329 (11.3%). By gender, 14.3% of males and 7.6% of females were infected. In case of both males and females, the prevalence rate was highest in those in their 40s. Consumption of raw freshwater fish was confirmed as a risk factor based on a logistic regression analysis. CONCLUSION: The present findings suggest that clonorchiasis is still highly prevalent among the inhabitants of riverside areas in southern Korea, and, accordingly, it is necessary to implement a systematic control program in the endemic areas. PMID- 24159526 TI - A Comparison of Subtyping Methods for Differentiating Salmonella enterica Serovar Enteritidis Isolates Obtained from Food and Human Sources. AB - PURPOSE: To evaluate the abilities of these subtyping methods, we distinguished Salmonella Enteritidis (S. Enteritidis) isolated from food products and human clinical samples between 2009 and 2010 in Seoul using five subtyping methods. METHODS: We determined the subtypes of 20 S. Enteritidis isolates from food and human sources using phage typing, antimicrobial susceptibility, pulsed-field gel electrophoresis (PFGE), repetitive sequence-based PCR (rep-PCR), and multi-locus sequence typing (MLST). RESULTS: A total of 20 tested isolates were differentiated into six antimicrobial susceptibility patterns, three different phage types, four different PFGE profiles, seven rep-PCR patterns, and one MLST type. Food isolates were considerably more susceptible to antibiotics than human isolates. We were best able to discriminate among S. Enteritidis isolates using rep-PCR, and obtained the highest Simpson's diversity index of 0.82, whereas other methods produced indices that were less than 0.71. PFGE pattern appeared to be more related to antimicrobial resistance and phage types of S. Enteritidis isolates than rep-PCR. MLST revealed identical alleles in all isolates at all seven loci examined, indicating no resolution. CONCLUSION: The results of this study suggest that rep-PCR provided the best discriminatory power for phenotypically similar S. Enteritidis isolates of food and human origins, whereas the discriminatory ability of MLST may be problematic because of the high sequence conservation of the targeted genes. PMID- 24159527 TI - Epidemiological characteristics of serologically confirmed q Fever cases in South Korea, 2006-2011. AB - OBJECTIVES: Q fever has been reported worldwide; however, there was almost no official report of Q fever in Korea. In this study, we describe the current status of human Q fever occurrence in Korea. METHODS: Demographic data of Q fever patients were collected from the National Notifiable Diseases Surveillance System from 2006 to 2011. Case investigation reports from regional public health departments were used for additional information, like risk factors and clinical manifestation, of the patients since 2008. RESULTS: There were 65 serologically confirmed cases during the study period. The annual notification rate of Q fever was 0.22 cases per million persons. The majority of cases were men (87.7%), adults (98.5%), and urban inhabitants (67.7%). Relevant exposures to risk factors were identified in 45.7% of patients. The most common symptoms of acute Q fever were fever (89.3%), myalgia (67.9%) and asthenia (53.6%). Two cases with endocarditis were identified in chronic Q fever. CONCLUSION: This study suggests that Q fever has a low endemicity in Korea. However, management and research at national level is required for prevention of a future epidemic. PMID- 24159528 TI - Are there spatial and temporal correlations in the incidence distribution of scrub typhus in Korea? AB - OBJECTIVES: A hierarchical generalized linear model (HGLM) was applied to estimate the transmission pattern of scrub typhus from 2001 to 2011 in the Republic of Korea, based on spatial and temporal correlation. METHODS: Based on the descriptive statistics of scrub typhus incidence from 2001 to 2011 reported to the Korean Centers for Disease Control and Prevention, the spatial and temporal correlations were estimated by HGLM. Incidences according to age, sex, and year were also estimated by the best-fit model out of nine HGLMs. A disease map was drawn to view the annual regional spread of the disease. RESULTS: The total number of scrub typhus cases reported from 2001 to 2011 was 51,136: male, 18,628 (36.4%); female, 32,508 (63.6%). The best-fit model selected was a combination of the spatial model (Markov random-field model) and temporal model (first order autoregressive model) of scrub typhus transmission. The peak incidence was 28.80 per 100,000 persons in early October and the peak incidence was 40.17 per 100,000 persons in those aged 63.3 years old by the best-fit HGLM. The disease map showed the spread of disease from the southern central area to a nationwide area, excepting Gangwon-do (province), Gyeongsangbuk-do (province), and Seoul. CONCLUSION: In the transmission of scrub typhus in Korea, there was a correlation to the incidence of adjacent areas, as well as that of the previous year. According to the disease map, we are unlikely to see any decrease in the incidence in the near future, unless ongoing aggressive measures to prevent the exposure to the vector, chigger mites, in rural areas, are put into place. PMID- 24159529 TI - Statistical Evaluation of Two Microbiological Diagnostic Methods of Pulmonary Tuberculosis After Implementation of a Directly Observed Treatment Short-course Program. AB - OBJECTIVES: To evaluate the diagnostic accuracy of smear and culture tests of clinical samples of pulmonary tuberculosis after the introduction of the directly observed treatment short-course (DOTS) program. METHODS: Using sputum samples from 572 individuals as a self-selected population, both Ziehl-Neelsen staining and culturing on Lowenstein-Jensen medium were carried out as diagnostic procedures. Using Bayes' rule, the obtained data set was analyzed. RESULTS: Of the 572 samples, 33 (0.05769) were true positive (results of both tests positive) cases; 22 samples (0.03846) were false positive (smear test positive and culture test negative) cases; 62 samples (0.10839) were false negative (smear test negative and culture test positive) cases; and 455 samples (0.79545) were true negative (results of both tests negative) cases. Values of test statistics, sensitivity, and specificity were used to compute several inherent other Bayesian test statistics. The a priori probability or prevalence value of tuberculosis in the targeted population was 0.166. The a posteriori probability value computed arithmetically was 0.6614 and that obtained by the graphical method was 0.62. CONCLUSIONS: The smear test was found to be dependable for 95.4% with stable TB infections, and it was not dependable for 34.7% without stable TB infections. The culture test could be regarded as the gold standard for 96.15% as seen with the data set, which was obtained after the implementation of the DOTS program. PMID- 24159530 TI - Autochthonous lyme borreliosis in humans and ticks in Korea. AB - OBJECTIVE: This study aimed at finding epidemiological and clinical features of autochthonous Lyme borreliosis in humans through epidemiological investigations and identifying its vectors and pathogens through analysis of ticks. METHOD: Epidemiological investigations, including review of the retrospective medical records and patient interviews, were conducted in two cases that occurred in 2012. To identify the vectors and pathogens, ticks were collected between September 23 and October 6, 2012 from the area where the tick bite in the first patient occurred. The ticks were classified, and polymerase chain reaction (PCR) tests and cultures were performed. RESULTS: The first patient, a 46-year-old female, visited a forest in Gangwon province, which was 900 m above sea level, where the tick bite occurred. Two weeks after the tick bite, erythema migrans (12 * 6 cm(2) in size) appeared on the site of tick bite, along with fever, chill, fatigue, myalgia, and arthralgia on shoulders, knees, and hips. The second patient, a 44-year-old male, visited a mountain in Gangwon province, which was 1200 m above sea level, where a tick bite occurred. One month after the tick bite, erythema migrans appeared at the site of the tick bite, along with fatigue, myalgia, and arthralgia on the right shoulder and temporomandibular joint. Indirect fluorescent antibody testing and Western blotting were carried out in these two cases for diagnosis, and positive findings were obtained. As a result, Lyme borreliosis could be confirmed. To estimate the pathogens and vectors, the ticks were collected. A total of 122 ticks were collected and only two species, Haemaphysalis japonica and Haemaphysalis flava, were identified. PCR and culture were performed on ticks. However, Borrelia burgdo rferi sensu lato was not isolated from any collected ticks. CONCLUSIONS: This study is significant to confirm Lyme borreliosis officially at first by the national surveillance system, although identification of the mites and pathogens failed. PMID- 24159532 TI - Fires in the neighborhood. PMID- 24159531 TI - Prion diseases as transmissible zoonotic diseases. AB - Prion diseases, also called transmissible spongiform encephalopathies (TSEs), lead to neurological dysfunction in animals and are fatal. Infectious prion proteins are causative agents of many mammalian TSEs, including scrapie (in sheep), chronic wasting disease (in deer and elk), bovine spongiform encephalopathy (BSE; in cattle), and Creutzfeldt-Jakob disease (CJD; in humans). BSE, better known as mad cow disease, is among the many recently discovered zoonotic diseases. BSE cases were first reported in the United Kingdom in 1986. Variant CJD (vCJD) is a disease that was first detected in 1996, which affects humans and is linked to the BSE epidemic in cattle. vCJD is presumed to be caused by consumption of contaminated meat and other food products derived from affected cattle. The BSE epidemic peaked in 1992 and decreased thereafter; this decline is continuing sharply owing to intensive surveillance and screening programs in the Western world. However, there are still new outbreaks and/or progression of prion diseases, including atypical BSE, and iatrogenic CJD and vCJD via organ transplantation and blood transfusion. This paper summarizes studies on prions, particularly on prion molecular mechanisms, BSE, vCJD, and diagnostic procedures. Risk perception and communication policies of the European Union for the prevention of prion diseases are also addressed to provide recommendations for appropriate government policies in Korea. PMID- 24159533 TI - Availability of clean tap water and medical services prevents the incidence of typhoid Fever. AB - OBJECTIVE: In this study, the factors that induced a decrease in the incidence of typhoid fever were analyzed. Based on the study results, we propose a quantitative and concrete solution to reduce the incidence of typhoid fever. METHODS: We analyzed the incidence and fatality rate of typhoid fever in Korea. Tap water service rate and the number of pharmacies, which affect the incidence rate of typhoid fever, were used as environmental factors. RESULTS: To prevent typhoid fever in the community, it is necessary to provide clean tap water service to 35.5% of the population, with an individual requiring 173 L of clean water daily. Appropriate access to clean water (51% service coverage, 307 L) helped the population to maintain individual hygiene and food safety practices, which brought about a decrease in the incidence of typhoid fever, and subsequently a decrease in fatality rate, which was achieved twice. During the 8 year study period, the fatality rate decreased to 1% when the population has access to proper medical service. CONCLUSION: The fatality rate was primarily affected by the availability of medical services as well as by the incidence of typhoid fever. However, an analysis of the study results showed that the incidence of typhoid fever was affected only by the availability of clean water through the tap water system. PMID- 24159534 TI - Prevalence of Antimicrobial Resistance in Escherichia coli Strains Isolated from Fishery Workers. AB - OBJECTIVES: This study aimed to characterize the prevalence of antibiotic resistance in Escherichia coli isolates from the fecal samples of fishery workers who work in fish farms and often use antibiotics for the feeding fishes. METHODS: Seventy-three E. coli strains isolated from the fecal samples of fishery workers and 180 isolates from a control group of restaurant workers were tested for antibiotic resistance by agar disk diffusion with 16 antimicrobial agents. RESULTS: About 30% of isolates from each group showed antimicrobial resistance to ampicillin, and 60% of isolates from fishery workers and 41% from restaurant workers were resistant to tetracycline. The isolates showed higher resistance to cephalothin and cefoxitin than to other cephem antibiotics and to gentamicin than to other aminogycosides. Our data indicated that fecal E. coli isolates from fishery workers showed higher antibiotic resistance than those of non-fishery workers (restaurant workers), especially to cephalothin, tetracycline, and trimethoprim-sulfamethoxazole (p < 0.05). However, rates of multidrug resistance were similar among the fishery workers and restaurant workers. CONCLUSION: Frequent use of antibiotics may cause increased antibiotic resistance in the human microbiome. PMID- 24159535 TI - Susceptibility and Resistance of Field Populations of Anopheles sinensis (Diptera: Culicidae) Collected from Paju to 13 Insecticides. AB - OBJECTIVES: Over 20% of all malaria cases reported annually in the Republic of Korea (ROK) occur in Paju, Gyeonggi Province. Vector control for malaria management is essential, but the insecticide resistance of the vector, Anopheles mosquitoes, has been a major obstacle in implementing effective control. In this study, the insecticide resistance of the vector mosquitoes was evaluated and compared with that of vector mosquitoes collected from the same locality in 2001 and 2009. METHODS: The insecticide resistance of Anopheles sinensis s.s. collected from Paju, Gyeonggi Province in the ROK was evaluated under laboratory conditions with a micro-application method using 13 insecticides currently used by local public health centers and pest control operators in the ROK. RESULTS: Based on median lethal dose (LC50) values, An. sinensis s.s. were most susceptible to the insecticides bifenthrin, cyfluthrin, and etofenprox in that order, and least susceptible to permethrin. An. sinensis showed higher susceptibility to pyrethroids than organophosphates, except for fenthion and permethrin. In a comparative resistance test, the resistance ratios (RRs) of An. sinensis collected in 2012 (AS12) to the 13 insecticides were compared to the RRs of two strains of An. sinensis collected from the same locality in 2001 (AS01) and 2008 (AS08). With some exceptions, AS12 demonstrated higher resistance to all tested insecticides compared to AS01 and AS08, and less resistance to bifenthrin, cyfluthrin, and cypermethrin compared to AS01. CONCLUSION: These results indicate that careful selection and rotation of these insecticides may result in continued satisfactory control of field populations of An. sinensis s.s. for effective malaria management in Paju. PMID- 24159536 TI - The effects of religious attendance and obesity on health by race/ethnicity. AB - OBJECTIVES: The objectives of this paper are to examine the effects of religion and obesity on health and determine how the relationship varies by racial/ethnic groups with data from the Panel Study of American Race and Ethnicity (PS-ARE). METHODS: Using ordinal logistic regression, the effects of religion and obesity on self-rated health and how the relationship varies by racial/ethnic groups are investigated. Additionally, to determine whether certain ethnic groups are more impacted by the frequency of religious attendance and obesity, whites, blacks, and Hispanics are analyzed separately with ordinal logistic regression. RESULTS: When obesity was added in focal relationship between religious services attendance and self-rated health strengthened this focal relationship which is a suppression effect between religious services attending and self-rated health adding obesity. For BMI is also significantly associated with decreased odds of reporting better health-normal weight (OR = 2.99; 95% CI = 2.43-3.67) and overweight (OR = 2.19; 95% CI = 1.79-2.68) compared to obese. Subjects who attend religious services 1-2 time a year (OR = 1.30; 95% CI = 1.04-1.62) and 1-3 times a month (OR = 1.28; 95% CI = 1.05-1.57) are associated with increased odds of reporting better health. In whites, attending religious services 1-2 times a year are associated with increased odds of reporting better health (OR = 1.48; 95% CI = 1.09-2.00) and 1-3 times a month are also associated with increased odds of reporting health (OR = 1.34; 95% CI = 1.02-1.78) compared to never attending religious attendance. The frequency of religious services attendance of blacks and Hispanics are not associated with self-rated health. For BMI, being white is more positively associated with increased odds of reporting better health than black and Hispanic subjects. Although white subjects are less likely to attend religious services more frequently than black and Hispanic subjects, the influence on self-rated health in white subjects is more evidenced than other racial/ethnic groups. CONCLUSIONS: Although it was not proven that the association between participation in religious services and self-rated health is mediated by obesity, the research shows the suppression effect of obesity between participation in religious services and self-rated health. PMID- 24159537 TI - The first outbreak of giardiasis with drinking water in Korea. AB - OBJECTIVES: To identify the pathogen of the diarrhea outbreak in a village in Jeollabuk province in Korea in April 2010. METHODS: DNA extraction was performed from the 120 L of collected water, which was centrifuged at 10,000 x g for 30 min. PCR reactions were conducted in a total of 25 ul, which included PCR premix (GenDEPOT, Barker, TX, USA), 2 ul (~100 ng) of extracted DNA, and 10 pmol of each primer. RESULTS: Nine people out of 25 had a symptom of abdominal pain accompanied by diarrhea after they used stored valley water in a water tank as a provisional water supply source without chlorine sterilization. Among them Giardia lamblia was detected in fecal samples of 7 people using the polymerase chain reaction method. Although G. lamblia was also detected from water provided by the provisional water supply system stored in the water tank and used as drinking water, it was not detected in the water tank itself. This water-borne outbreak is considered to have occurred when the provisional water supply tube was destroyed under a building construction and contaminated by G. lamblia, but its precise cause has not been clarified. CONCLUSION: This outbreak resulting from G. lamblia is very meaningful as the first outbreak of an infection by a water-borne parasite in Korea. PMID- 24159538 TI - Factors related to completed status and seropositivity of hepatitis a immunization among children aged 1-3 years and 6-8 years in South Korea. AB - This study was designed to identify factors associated with hepatitis A immunization status and seropositivity in Korean children. In-person interviews, reviewing their vaccination cards and testing hepatitis A antibody were conducted with 389 children aged 1-3 years and 544 children aged 6-8 years. In all age groups, earlier birth order was the only significant factor in children receiving either single or both doses of the vaccination. And completion of the second dose of vaccination was a prerequisite for increased seropositivity. Additionally, household income had a positive impact on seropositivity only in children aged 6 8 years. Our findings suggest that presence of an economic barrier is the underlying cause of the decreased hepatitis A vaccination services in Korea. Therefore, hepatitis A vaccine should be included in the essential National Immunization Program. PMID- 24159539 TI - Peer-to-Peer JXTA Architecture for Continuing Mobile Medical Education Incorporated in Rural Public Health Centers. AB - OBJECTIVES: Mobile technology helps to improve continuing medical education; this includes all aspects of public health care as well as keeping one's knowledge up to-date. The program of continuing medical and health education is intertwined with mobile health technology, which forms an imperative component of national strategies in health. Continuing mobile medical education (CMME) programs are designed to ensure that all medical and health-care professionals stay up-to-date with the knowledge required through mobile JXTA to appraise modernized strategies so as to achieve national goals of health-care information distribution. METHODS: In this study, a 20-item questionnaire was distributed to 280 health professionals practicing traditional training learning methodologies (180 nurses, 60 doctors, and 40 health inspectors) in 25 rural hospitals. Among the 83% respondents, 56% are eager to take new learning methodologies as part of their evaluation, which is considered for promotion to higher grades, increments, or as part of their work-related activities. RESULTS: The proposed model was executed in five public health centers in which nurses and health inspectors registered in the JXTA network were referred to the record peer group by administrators. A mobile training program on immunization was conducted through the ADVT, with the lectures delivered on their mobiles. Credits are given after taking the course and completing an evaluation test. The system is faster compared with traditional learning. CONCLUSION: Medical knowledge management and mobile-streaming application support the CMME system through JXTA. The mobile system includes online lectures and practice quizzes, as well as assignments and interactions with health professionals. Evaluation and assessments are done online and credits certificates are provided based on the score the student obtains. The acceptance of mobile JXTA peer-to-peer learning has created a drastic change in learning methods among rural health professionals. The professionals undergo training and should pass an exam in order to obtain the credits. The system is controlled and monitored by the administrator peer group, which makes it more flexible and structured. Compared with traditional learning system, enhanced study improves cloud-based mobile medical education technology. PMID- 24159540 TI - A strategic plan for the second phase (2013-2015) of the Korea biobank project. AB - The Korea Biobank Project (KBP) was led by the Ministry of Health and Welfare to establish a network between the National Biobank of Korea and biobanks run by university-affiliated general hospitals (regional biobanks). The Ministry of Health and Welfare started the project to enhance medical and health technology by collecting, managing, and providing researchers with high-quality human bioresources. The National Biobank of Korea, under the leadership of the Ministry of Health and Welfare, collects specimens through various cohorts and regional biobanks within university hospitals gather specimens from patients. The project began in 2008, and the first phase ended in 2012, which meant that there needed to be a plan for the second phase that begins in 2013. Consequently, professionals from within and outside the project were gathered to develop a plan for the second phase. Under the leadership of the planning committee, six working groups were formed to formulate a practical plan. By conducting two workshops with experts in the six working groups and the planning committee and three forums in 2011 and 2012, they have developed a strategic plan for the second phase of the KBP. This document presents a brief report of the second phase of the project based on a discussion with them. During the first phase of the project (2008-2012), a network was set up between the National Biobank of Korea and 17 biobanks at university-affiliated hospitals in an effort to unify informatics and governance among the participating biobanks. The biobanks within the network manage data on their biospecimens with a unified Biobank Information Management System. Continuous efforts are being made to develop a common standard operating procedure for resource collection, management, distribution, and personal information security, and currently, management of these data is carried out in a somewhat unified manner. In addition, the KBP has trained and educated professionals to work within the biobanks, and has also carried out various publicity promotions to the public and researchers. During the first phase, biospecimens from more than 300,000 participants through various cohorts and biospecimens from more than 200,000 patients from hospitals were collected, which were distributed to approximately 600 research projects. The planning committee for the second phase evaluated that the first phase of the KBP was successful. However, the first phase of the project was meant to allow autonomy to the individual biobanks. The biobanks were able to choose the kind of specimens they were going to collect and the amount of specimen they would set as a goal, as well as being allowed to choose their own methods to manage their biobanks (autonomy). Therefore, some biobanks collected resources that were easy to collect and the resources needed by researchers were not strategically collected. In addition, there was also a low distribution rate to researchers outside of hospitals, who do not have as much access to specimens and cases as those in hospitals. There were also many cases in which researchers were not aware of the KBP, and the distribution processes were not set up to be convenient to the demands of researchers. Accordingly, the second phase of the KBP will be focused on increasing the integration and cooperation between the biobanks within the network. The KBP plans to set goals for the strategic collection of the needed human bioresources. Although the main principle of the first phase was to establish infrastructure and resource collection, the key objective of the second phase is the efficient utilization of gathered resources. In order to fully utilize the gathered resources in an efficient way, distribution systems and policies must be improved. Vitalization of distribution, securing of high-value resource and related clinical and laboratory information, international standardization of resource management systems, and establishment of a virtuous cycle between research and development (R&D) and biobanks are the four main strategies. Based on these strategies, 12 related objectives have been set and are planned to be executed. PMID- 24159541 TI - Revision of the national action plan in response to poliovirus importation in Korea. AB - The polio outbreak in China in 2011 makes it necessary to revise the 2010 polio National Action Plan (NAP) in Korea. The revised plan was provided after evaluation of the 2010 NAP, literature reviews, and expert advice. It was discussed and confirmed by the Polio National Certificate Committee (NCC). The revised NAP (2012 NAP) has structured the action to take by patient phase and the role of each institution. It also provides the specified classification and management actions on the contacts. It includes a new recommendation of onetime additional immunization for the contacts regardless of the immunization history. The 2012 NAP could provide an effective countermeasure if there are imported poliomyelitis patients in Korea. PMID- 24159542 TI - Years of Epidemics (2009-2011): Pandemic Influenza and Foot-and-Mouth Disease Epidemic in Korea. PMID- 24159543 TI - Estimation of the Infection Window for the 2010/2011 Korean Foot-and-Mouth Disease Outbreak. AB - OBJECTIVES: This study aims to develop a method for calculating infection time lines for disease outbreaks on farms was developed using the 2010/2011 foot-and mouth disease (FMD) epidemic in the Republic of Korea. METHODS: Data on farm demography, the detection date of FMD, the clinical history for the manifestation of lesions, the presence of antibodies against FMD virus (including antibodies against the structural and nonstructural proteins of serotype O), vaccination status (O1 Manisa strain), the number of reactors and information on the slaughter of infected animals were utilized in this method. RESULTS: Based on estimates of the most likely infection date, a cumulative detection probability that an infected farm would be identified on a specific day was determined. Peak infection was observed between late December and early January, but peak detection occurred in mid-January. The early detection probability was highest for pigs, followed by cattle (dairy, then beef) and small ruminants. Nearly 90% of the infected pig farms were detected by Day 11 post-infection while 13 days were required for detection for both dairy and beef cattle farms, and 21 days were necessary for small ruminant (goat and deer) farms. On average, 8.1 +/- 3.1 days passed prior to detecting the presence of FMD virus on a farm. The interval between infection and detection of FMD was inversely associated with the intensity of farming. CONCLUSION: The results of our study emphasize the importance of intensive clinical inspection, which is the quickest method of detecting FMD infection and minimizing the damage caused by an epidemic. PMID- 24159544 TI - Multiplex Real-time Polymerase Chain Reaction Assays for Simultaneous Detection of Vibrio cholerae, Vibrio parahaemolyticus, and Vibrio vulnificus. AB - OBJECTIVES: A multiplex real-time polymerase chain reaction (RT-PCR) method was developed for the identification of three Vibrio species: Vibrio cholerae, Vibrio parahaemolyticus, and Vibrio vulnificus. METHODS: Specific primers and probes targeting the hlyA, tlh, and vvhA genes were selected and used for multiplex real time PCR to confirm the identification of V. cholerae, V. parahaemolyticus, and V. vulnificus, respectively. This method was applied to screen Vibrio species from environmental samples and combining it with a culture-based method, its effectiveness was evaluated in comparison with culture-based methods alone. RESULTS: Specific PCR fragments were obtained from isolates belonging to the target species, indicating a high specificity of this multiplex real-time PCR. No cross-reactivity with the assay was observed between the tested bacteria. The sensitivity of the multiplex real-time PCR was found to have a lower limit of 10(4) colony-forming units/reaction for all three Vibrio species. The combination strategy raised the isolation ratio of all three Vibrio species 1.26- to 2.75 fold. CONCLUSION: This assay provides a rapid, sensitive, and specific technique to detect these three Vibrio species in the environment. PMID- 24159545 TI - Impacts of heavy rain and typhoon on allergic disease. AB - OBJECTIVES: Allergic disease may be increased by climate change. Recent reports have shown that typhoon and heavy rain increase allergic disease locally by concentration of airborne allergens of pollen, ozone, and fungus, which are causes of allergic disease. The objective of this study was to determine whether typhoon and heavy rain increase allergic disease in Korea. METHODS: This study included allergic disease patients of the area declared as a special disaster zone due to storms and heavy rains from 2003 to 2009. The study used information from the Korea Meteorological Administration, and from the National Health Insurance Service for allergic diseases (asthma, allergic rhinitis, and atopic dermatitis). RESULTS: During a storm period, the numbers of allergy rhinitis and atopic dermatitis outpatients increased [rate ratio (RR) = 1.191; range, 1.150 1.232] on the sixth lag day. However, the number of asthma outpatients decreased (RR = 0.900; range, 0.862-0.937) on the sixth lag day after a disaster period. During a storm period, the numbers of allergic rhinitis outpatients (RR = 1.075; range, 1.018-1.132) and atopy outpatients increased (RR = 1.134; range, 1.113 1.155) on the seventh lag day. However, the number of asthma outpatients decreased to RR value of 0.968 (range, 0.902-1.035) on the fifth lag day. CONCLUSION: This study suggests that typhoon and heavy rain increase allergic disease apart from asthma. More study is needed to explain the decrease in asthma. PMID- 24159547 TI - Study on Entomological Surveillance and its Significance during a Dengue Outbreak in the District of Tirunelveli in Tamil Nadu, India. AB - OBJECTIVES: TO STUDY THE SIGNIFICANCE OF ENTOMOLOGICAL SURVEILLANCE, THE HOUSE INDEX (HI), CONTAINER INDEX (CI), AND BRETEAU INDEX (BI) WERE DETERMINED TO ESTIMATE THE DEGREE OF A MAJOR DENGUE OUTBREAK IN TIRUNELVELI, TAMIL NADU, INDIA (LATITUDE: 8 degrees 42'N; Longitude: 77 degrees 42'E) in May 2012. METHODS: The HI, CI, and BI were determined in a primary health center (PHC) in the village of Maruthamputhur (Pappakudi taluk, Tirunelveli) by carrying out an antilarval (AL) work that involved door-to-door search for immature stages of Aedes spp. mosquitoes by trained field workers and volunteers. The work of field workers was evaluated by a junior and senior entomologist the following day. RESULTS: Before the AL work, the reported numbers of fever cases from Week 1 to 5 in Maruthamputhur were 211, 394, 244, 222, and 144 with two deaths. By contrast, after the AL work, these numbers were considerably reduced and there was no fever related death (the HI was reduced from 48.2% to 1.6%, the CI from 28.6% to 0.4%, and the BI from 48.2 to 1.6). CONCLUSION: Because no specific medicine and vaccines are available to treat dengue fever and dengue hemorrhagic fever, entomological surveillance and its significance can be used to halt the outbreak of dengue as shown in this study. PMID- 24159546 TI - Development of a Diagnostic Kit to Detect Cryptosporidium parvum and Giardia lamblia. AB - OBJECTIVES: This study aims to develop a high-sensitivity antibody diagnostic kit that will enable a rapid and accurate detection of Cryptospofidium parvum and Giardia lamblia in patients with diarrhea. METHODS: The cultivated C. parvum oocysts and G. lamblia cysts in each calf and dog were injected to mice to obtain antibodies, which were titrated. Spleen cells of the immunized mouse were separated and blended with myelomas to produce hybrid cell lines that form monoclonal antibodies. Using ELISA method, antibodies that specifically respond to C. parvum and G.lamblia were then selected. The cells were injected into the abdominal cavity of a BALB/c mouse to isolate hydrops abdominis containing high level of antibodies. The IgG antibody was purified using protein G gel. RESULTS: The detection limit of monoclonal antibodies for Cryptosporidium parvum and Giardia lamblia was 125 oocysts/mL and 1250 cysts/mL, respectively. In addition, during testing they did not show cross-reactivity to viruses (n = 15), bacteria (n =17), and parasites (n = 9). CONCLUSION: The rapid diagnostic antibody kit developed in this study, which specifically responds to C. parvum and G. lamblia, will be useful in detecting and monitoring diarrheal infections. PMID- 24159548 TI - Epidemiological characteristics of imported shigellosis in Korea, 2010-2011. AB - Shigellosis is a global disease as food poisoning by infection of Shigella spp (S. dysenteriae, S. flexneri, S. boydii and S. sonnei). In Korea, approximately 500 cases of shigellosis have reported every year since 2004, and imported shigellosis is increasing gradually from 2006 in particular. According to increase of numbers of overseas travelers, the numbers of patients diseased with imported shigellosis is also increasing. We need continuous surveillance studies network (SSN) for control of imported shigellosis. We studied epidemiological characteristic of imported shigellosis by using database of Korea Centers for Disease Control and Prevention (KCDC) from 2010 to 2011. The imported shigellosis is analyzed on correlation with variable factors such as sex, age, symptom, visited country as well as Shigella spp in the database. Total 399 patients diseased with shigellosis have been reported between 2010 and 2011, The 212 patients (53.1%) among them were disease with imported shigellosis and the 205 patients (96.7%) were diagnosed as definite shigellosis. Shigella sonnei (65.6%) and Shigella flexneri (20.3%) were isolated in order. Clinical symptoms of the shigellosis were diarrhea (96.5%), abdominal pain (54.7%), fever (52.8%), chill (31.6%), and weakness (21.7% etc) in order. Duration of diarrhea was 1 to 5 days, the number of diarrhea was mostly more than 10 times, and type of stool was almost yellow stool. Almost shigellosis was occurred in the travelers visited to Asia (98.1%). Particularly, the occurrence rate of shigellosis was highest in traveler visited to Southeast Asia which is India (21.7%), Cambodia (19.8%), Philippines (17.9%), and Vietnam (9.0%) in order. According to increase of traveler to Southeast Asia, imported Shigellosis also increased. We need to strengthen the public health and hygiene, which is infection prevention rules, eating properly-cook food, washing hands, drinking boiled water, for traveler to Asia. The quarantine and surveillance system to control imported shigellosis is need continually in Korea. PMID- 24159549 TI - Trends in the incidence of scrub typhus: the fastest growing vector-borne disease in Korea. AB - Scrub typhus, also called tsutsugamushi disease, is classified as a Group 3 disease in Korea according to the National Notifiable Diseases Surveillance Systems. It is an infectious disease transmitted to humans through the bite of mites that are infected with an intracellular parasite called Orientia tsutsugamushi (Family: Rickettsiaceae). This study aims to identify the demographic characteristics of the infected cases according to profession, region, gender, and onset period and provide a basic data for prevention and control of the disease in the infected patients. Between 2001 and 2010, 16,741 men (36.3%) and 29,373 women (63.7%) were reported to have been infected with scrub typhus, with men being 1.6 times less infected than women. When classified according to age, it was found that 4421 persons (9.6%) were under 40 years of age; 6601 (13.1%) in their 40s; 9714 (21.1%) in their 50s; 13,067 (28.3%) in 60s; 10,128 (22.0%) in their 70s; and 2723 (5.9%) aged 80 or more. The elderly (60 years or older) represented more than half of the infected cases. When the infections were classified according to region, it was found that the county residents had the major share of infection, with a total of 1583 infected cases (59.85). PMID- 24159552 TI - Was the mass vaccination effective during the influenza pandemic 2009-2010 in Korea? PMID- 24159550 TI - Travel-Associated Chikungunya Cases in South Korea during 2009-2010. AB - OBJECTIVES: Chikungunya (CHIK) has been classified as a communicable disease group IV in South Korea since late 2010. Based on this, we investigated the extent of imported cases of CHIK in dengue-suspected individuals returning from dengue-endemic regions. METHODS: A total of 486 dengue-suspected serum samples were screened for CHIK by enzyme-linked immunosorbent assay (ELISA) and reverse transcription-polymerase chain reaction (RT-PCR) analysis. Further RT-PCR positive samples were used for the viral culture, and CHIK was subsequently confirmed by sequence analysis of the culture samples. RESULTS: Five out of 107 dengue-positive samples were found to be positive for CHIK and 15 out of 379 dengue-negative samples were found to be positive for CHIK by immunoglobulin M ELISA. Further, a CHIK virus was isolated from one of the two RT-PCR-positive sera by cell culture and confirmed by sequence analysis. CONCLUSION: The present study documents the first evidence of travel-associated CHIK infection in South Korea. Considering the intense international traffic between countries, our finding emphasizes the urgent need for active patient and vector surveillance for timely response to reduce the introduction of CHIK in Korea. PMID- 24159553 TI - Association between serum vitamin d and metabolic risk factors in korean schoolgirls. AB - OBJECTIVES: Vitamin D, a key regulator of bone metabolism, has been recently been linked with energy homeostasis and metabolic disorders in western countries. However, few studies have focused on the association of vitamin D with metabolic risk factors among Asian children. We studied the prevalence of vitamin D insufficiency and the association of 25-hydroxyvitamin D [25(OH)D] with metabolic risk factors in Korean schoolgirls. METHODS: The sample consisted of 320 13-year old girls recruited from two middle schools in the city of Gwacheon, Korea (latitude 37 degrees N), in July 2011. Anthropometric and blood biochemistry data were obtained for this cross-sectional observational study. We also obtained lifestyle data from questionnaires and dietary data from 3-day food diaries. RESULTS: Vitamin D deficiency [25(OH)D < 20 ng/mL] was noted in 63.8% of participants. The mean 25(OH)D level was not significantly lower in the overweight group. Level of physical activity and vitamin D intake did not significantly affect 25(OH)D. However, 25(OH)D levels were positively correlated with milk intake and negatively correlated with soft drink intake. Serum 25(OH)D had a negative relationship with fasting glucose and insulin resistance index (homeostasis model assessment-insulin resistance; HOMA-IR) after adjustment for physical activity and body mass index z score (r = -0.144, p = 0.015), and with metabolic risk score similarly (r = -0.141, p = 0.012). Levels of insulin, HOMA IR, and systolic blood pressure were higher in girls with deficient 25(OH)D levels than in those with sufficient levels. CONCLUSION: We found that low 25(OH)D levels were associated with higher blood glucose and insulin resistance. Korean girls with low 25(OH)D levels could be at increased risk for metabolic disorders. PMID- 24159554 TI - Obesity and asian americans in the United States: systematic literature review. AB - OBJECTIVES: Obesity is one of the most serious health problems in the world today. Asian Americans are usually less overweight and obese than African Americans and Hispanic Americans, but the rate of obesity in Asian Americans is still increasing, especially in younger generations. This research examines Asian American obesity using existing research, as a means of finding the need for greater emphasis on Asian American obesity intervention research. METHODS: In this research literature review, Asian American obesity using existing research as a means of finding the need for greater emphasis on Asian American obesity intervention research is examined. A systematic review is done in order to find Asian American obesity research, due to the minimal amount of existing studies. In total, there were only nine papers which were not duplicates and which still met the criteria for inclusion, from an initial 106 papers. RESULTS: There is very little research on obesity in Asian Americans. Although the rate of obesity among Asian Americans is increasing, there are few related articles, projects, and surveys, and there is little information. There is a need for more specific and in-depth analysis of Asian American obesity. Asian Americans are associated with a lower waist circumference (WC) and BMI, while Hawaiian/Pacific Islanders are associated with a higher WC and BMI. Typically, Asian Americans who were born in the United States (US) tend to be overweight and more obese than those born in foreign countries. CONCLUSION: Based on this literature review, it is concluded that there is a shortage of Asian American obesity research, even though there is an evident need for particular obesity intervention programs that target Asian Americans. PMID- 24159555 TI - Instability at Short Tandem Repeats in Lymphoblastoid Cell Lines. AB - OBJECTIVES: Epstein Barr virus (EBV)-transformed lymphoblastoid cell lines (LCLs) are a useful biological resource, however, genomic variations can happen during the generation and immortalization processes of LCLs. The purpose of this study was to identify genomic variations in LCL DNA compared with matched blood DNA using short tandem repeats (STRs) analysis. METHODS: We analyzed 15 STRs with blood DNA and their matched LCL DNA samples from 6645 unrelated healthy individuals. RESULTS: Mutations (such as repeat variations and triallelic patterns) of 15 STR loci were detected in 612 LCL DNAs (9.2% of total) without mutations in their matched blood DNA. The repeat variations of 15 STRs were detected in 526 LCL DNAs (mutation rate = 0.0792) and triallelic patterns were identified in 123 (mutation rate = 0.0185). Among 15 STRs, the most common repeat variations (n = 214, mutation rate = 0.0322) and triallelic patterns (n = 17, mutation rate = 0.0026) were found at FGA locus. CONCLUSION: Our study shows that mutations in STRs can occur during generation and immortalization of LCLs. PMID- 24159556 TI - Comparison of Breast Cancer Screening Results in Korean Middle-Aged Women: A Hospital-based Prospective Cohort Study. AB - OBJECTIVES: The aim of this hospital-based prospective study was to evaluate the diagnostic ability of breast cancer screening in Korean middle-aged women using age, ultrasonography, mammography, and magnification mammography, which are commonly used in most hospitals. METHODS: A total of 21 patents were examined using ultrasonography, mammography, and magnification mammography, and their data were prospectively analyzed from August 2011 to March 2013. All patients were divided into benign and malignant groups and the screening results were classified using the American College of Radiology Breast Imaging Reporting and Data System (BI-RADS). The final pathology report was used as the reference standard and the sensitivity and specificity of ultrasonography, mammography, and magnification mammography were evaluated using receiver-operating characteristics (ROC) analysis. RESULTS: The analysis included 21 patients who underwent biopsy. Among them, three (14.3%) were positive and 18 (85.7%) negative for breast cancer. The average age was 50.5 years (range = 38-61 years). The sensitivity was the same for ultrasonography and magnification mammography and the specificity of magnification mammography was higher than that of ultrasonography. The highest area under the ROC curve (AUC) was observed in the combination of age and magnification mammography (1.000) and the decreasing order of AUC in others was magnification mammography (0.833), ultrasonography (0.787), mammography (0.667), and age (0.648). CONCLUSIONS: In Korean women, the diagnostic accuracy of magnification mammography was better than that of ultrasonography and mammography. The combination of age and magnification mammography increased the sensitivity and diagnostic accuracy. PMID- 24159557 TI - The influence of media communication on risk perception and behavior related to mad cow disease in South Korea. AB - OBJECTIVES: The purpose of this study was to ascertain the influence of media communication on risk behavior related to mad cow disease (MCD). METHODS: Mothers of elementary school students in Seoul were recruited as the survey participants of this study. RESULTS: Media reports affected risk behavior related to MCD. Also, knowledge and attitude toward MCD affects risk behavior. CONCLUSION: Risk related information provided by the media should maintain consistency and objectivity. For effective risk communication, there should be an open communication between the government and public, experts, and related industries, who should all collaborate. PMID- 24159558 TI - Evaluation of the Effectiveness of Pandemic Influenza A(H1N1) 2009 Vaccine Based on an Outbreak Investigation During the 2010-2011 Season in Korean Military Camps. AB - OBJECTIVES: In December 2010, there was an outbreak of acute febrile respiratory disease in many Korean military camps that were not geographically related. A laboratory analysis confirmed a number of these cases to be infected by the pandemic influenza A(H1N1) 2009 (H1N1pdm09) virus. Because mass vaccination against H1N1pdm09 was implemented at the infected military camps eleven months ago, the outbreak areas in which both vaccinated and nonvaccinated individuals were well mixed, gave us an opportunity to evaluate the effectiveness of H1N1pdm09 vaccine through a retrospective cohort study design. METHODS: A self administered questionnaire was distributed to the three military camps in which the outbreak occurred for case detection, determination of vaccination status, and characterization of other risk factors. The overall response rate was 86.8% (395/455). Case was defined as fever (>=38 degrees C) with cough or sore throat, influenza-like illness (ILI), and vaccination status verified by vaccination registry. Crude vaccine effectiveness (VE) was calculated as "1 - attack rate in vaccinated individuals/attack rate in nonvaccinated individuals", and adjusted VE was calculated as "1 - odds ratio" using logistic regression adjusted for potential confounding factor. A number of ILI definitions were used to test the robustness of the result. RESULTS: The attack rate of ILI was 12.8% in register verified vaccinated individuals and 24.0% in nonvaccinated individuals. The crude VE was thus calculated to be 46.8% [95% confidence interval (CI): 14.5-66.9]. The adjusted VE rate was 46.8% (95% CI: -9.4 to 74.1). Various combinations of ILI symptoms also showed similar VE rates. CONCLUSION: We evaluated the effectiveness of H1N1pdm09 vaccine in the 2010-2011 season in an outbreak setting. Although the result was not sensitive to any analytical method used and ILI case definition, the magnitude of effectiveness was lower than estimated in the 2009-2010 season. PMID- 24159559 TI - Epidemic intelligence service officers and field epidemiology training program in Korea. AB - Korea has adopted Epidemic Intelligence Service (EIS) officers through the Field Epidemiology Training Program (FETP) since 1999 for systematic control of emerging and re-emerging infectious diseases. Graduates of medical schools in Korea are selected and serve as public health doctors (PHDs) for their mandatory military service. The duration of service is 3 years and PHDs comprise general practitioners and specialists. Some PHDs are selected as EIS officers with 3 weeks basic FETP training and work for central and provincial public health authorities to conduct epidemiological investigations. The total number of EIS officers is 31 as of 2012. The Korea Centers for Disease Control and Prevention (KCDC) has 12 specialists, whereas specialists and each province has one or two EIS officers to administer local epidemiological investigations in 253 public health centers. The Korean EIS officers have successfully responded and prevented infectious diseases, but there is a unique limitation: the number of PHDs in Korea is decreasing and PHDs are not allowed to stay outside Korea, which makes it difficult to cope with overseas infectious diseases. Furthermore, after 3 years service, they quit and their experiences are not accumulated. KCDC has hired full-time EIS officers since 2012 to overcome this limitation. PMID- 24159560 TI - Computational modeling of transcranial direct current stimulation (tDCS) in obesity: Impact of head fat and dose guidelines. AB - Recent studies show that acute neuromodulation of the prefrontal cortex with transcranial direct current stimulation (tDCS) can decrease food craving, attentional bias to food, and actual food intake. These data suggest potential clinical applications for tDCS in the field of obesity. However, optimal stimulation parameters in obese individuals are uncertain. One fundamental concern is whether a thick, low-conductivity layer of subcutaneous fat around the head can affect current density distribution and require dose adjustments during tDCS administration. The aim of this study was to investigate the role of head fat on the distribution of current during tDCS and evaluate whether dosing standards for tDCS developed for adult individuals in general are adequate for the obese population. We used MRI-derived high-resolution computational models that delineated fat layers in five human heads from subjects with body mass index (BMI) ranging from "normal-lean" to "super-obese" (20.9 to 53.5 kg/m(2)). Data derived from these simulations suggest that head fat influences tDCS current density across the brain, but its relative contribution is small when other components of head anatomy are added. Current density variability between subjects does not appear to have a direct and/or simple link to BMI. These results indicate that guidelines for the use of tDCS can be extrapolated to obese subjects without sacrificing efficacy and/or treatment safety; the recommended standard parameters can lead to the delivery of adequate current flow to induce neuromodulation of brain activity in the obese population. PMID- 24159561 TI - Multi-delay multi-parametric arterial spin-labeled perfusion MRI in acute ischemic stroke - Comparison with dynamic susceptibility contrast enhanced perfusion imaging. AB - The purpose of the present study was to present a multi-delay multi-parametric pseudo-continuous arterial spin labeling (pCASL) protocol with background suppressed 3D GRASE (gradient and spin echo) readout for perfusion imaging in acute ischemic stroke. PCASL data at 4 post-labeling delay times (PLD = 1.5, 2, 2.5, 3 s) were acquired within 4.5 min in 24 patients (mean age 79.7 +/- 11.4 years; 11 men) with acute middle cerebral artery (MCA) stroke who also underwent dynamic susceptibility contrast (DSC) enhanced perfusion imaging. Arterial transit times (ATT) were estimated through the calculation of weighted delays across the 4 PLDs, which were included in the calculation of cerebral blood flow (CBF) and arterial cerebral blood volume (CBV). Mean perfusion parameters derived using pCASL and DSC were measured within MCA territories and infarct regions identified on diffusion weighted MRI. The results showed highly significant correlations between pCASL and DSC CBF measurements (r > = 0.70, p < = 0.0001) and moderately significant correlations between pCASL and DSC CBV measurements (r > = 0.45, p < = 0.027) in both MCA territories and infarct regions. ASL ATT showed correlations with DSC time to the maximum of tissue residual function (Tmax)(r = 0.66, p = 0.0005) and mean transit time (MTT)(r = 0.59, p = 0.0023) in leptomeningeal MCA territories. The present study demonstrated the feasibility for noninvasive multi-parametric perfusion imaging using ASL for acute stroke imaging. PMID- 24159562 TI - Thyroid function in heart failure and impact on mortality. AB - OBJECTIVES: The aim of this study was to investigate whether patients with systolic heart failure (HF) and abnormal thyroid function are at increased risk for death. BACKGROUND: Thyroid hormone homeostasis is vital to the optimal functioning of the cardiovascular system, but an independent prognostic effect of thyroid abnormalities in patients with HF has not been established. METHODS: In SCD-HeFT (Sudden Cardiac Death in Heart Failure Trial), which randomized patients with ischemic or nonischemic HF to placebo or amiodarone or implantable cardioverter-defibrillator therapy, thyroid-stimulating hormone (TSH) was measured at baseline and at 6-month intervals throughout the 5-year study. RESULTS: Of 2,225 patients, the majority (87%) had normal TSH levels (0.3 to 5.0 MUU/ml) at baseline, 12% had values suggestive of hypothyroidism, and 1% had values consistent with hyperthyroidism. Compared with euthyroid patients, those hypothyroid at baseline were older and included more women and Caucasians (all p values <0.05). Over the median follow-up period of 45.5 months, among patients euthyroid at baseline, 89 developed abnormally low TSH levels, and 341 developed abnormally high values. Patients randomized to amiodarone (median dose 300 mg) had an elevated risk for developing abnormal TSH levels compared with implantable cardioverter-defibrillator therapy or placebo (p < 0.0001). Patients with baseline or new-onset abnormal thyroid function had a higher mortality than those with normal thyroid function, even after controlling for other known mortality predictors (hazard ratio: 1.58; 95% confidence interval: 1.29 to 1.94; p < 0.0001 for hypothyroid; hazard ratio: 1.85; 95% confidence interval: 1.21 to 2.83; p = 0.0048 for hyperthyroid). Implantable cardioverter-defibrillator benefit did not vary with thyroid function. CONCLUSIONS: Abnormal thyroid function in patients with symptomatic HF and ejection fractions <=35% is associated with significantly increased risk for death, even after controlling for known mortality predictors. PMID- 24159563 TI - Moving toward comprehensive acute heart failure risk assessment in the emergency department: the importance of self-care and shared decision making. AB - Nearly 700,000 emergency department (ED) visits were due to acute heart failure (AHF) in 2009. Most visits result in a hospital admission and account for the largest proportion of a projected $70 billion to be spent on heart failure care by 2030. ED-based risk prediction tools in AHF rarely impact disposition decision making. This is a major factor contributing to the 80% admission rate for ED patients with AHF, which has remained unchanged over the last several years. Self care behaviors such as symptom monitoring, medication taking, dietary adherence, and exercise have been associated with decreased hospital readmissions, yet self care remains largely unaddressed in ED patients with AHF and thus represents a significant lost opportunity to improve patient care and decrease ED visits and hospitalizations. Furthermore, shared decision making encourages collaborative interaction between patients, caregivers, and providers to drive a care path based on mutual agreement. The observation that "difficult decisions now will simplify difficult decisions later" has particular relevance to the ED, given this is the venue for many such issues. We hypothesize patients as complex and heterogeneous as ED patients with AHF may need both an objective evaluation of physiologic risk as well as an evaluation of barriers to ideal self-care, along with strategies to overcome these barriers. Combining physician gestalt, physiologic risk prediction instruments, an evaluation of self-care, and an information exchange between patient and provider using shared decision making may provide the critical inertia necessary to discharge patients home after a brief ED evaluation. PMID- 24159566 TI - Welcome to the first issue of liver cancer. PMID- 24159565 TI - Serum VEGF-D a concentration as a biomarker of lymphangioleiomyomatosis severity and treatment response: a prospective analysis of the Multicenter International Lymphangioleiomyomatosis Efficacy of Sirolimus (MILES) trial. AB - BACKGROUND: VEGF-D is a lymphangiogenic growth factor that has a key role in tumour metastasis. Serum VEGF-D concentrations are increased in most patients with lymphangioleiomyomatosis, a rare neoplasm associated with mTOR-activating tuberous sclerosis gene mutations, lymphadenopathy, metastatic spread, and pulmonary cyst formation. We used data from the Multicenter International Lymphangioleiomyomatosis Efficacy of Sirolimus (MILES) trial to assess the usefulness of serum VEGF-D concentration as a marker of severity and therapeutic response to sirolimus in patients with lymphangioleiomyomatosis. METHODS: In the MILES trial, patients with lymphangioleiomyomatosis who had forced expiratory volume in 1 second (FEV1) of 70% or less of predicted were randomly assigned (1:1) to 12 months masked treatment with sirolimus or placebo. Serum VEGF-D concentrations were measured at baseline, 6 months, and 12 months. We used a linear regression model to assess associations of baseline VEGF-D concentrations with markers of disease severity, and a linear mixed effects model to assess the associations of VEGF-D concentrations with between-group differences in clinical, physiological, and patient-reported outcomes. FINDINGS: We included 42 patients from the placebo group and 45 from the sirolimus group in our analysis. Baseline VEGF-D concentrations in individual patients varied from 0.34 ng/mL to 16.7 ng/mL. Baseline VEGF-D concentrations were higher in patients who needed supplemental oxygen than in those who did not need supplemental oxygen (1.7 ng/mL [IQR 0.99-3.36] vs 0.84 ng/mL [0.52-1.39]; p<0.0001) and in those who had a bronchodilator response than in those who did not (2.01 ng/mL [0.99-2.86] vs 1.00 ng/mL [0.61-2.15]; 0.0273). Median serum VEGF-D concentrations were similar at baseline in the sirolimus and placebo groups, and fell from baseline at 6 and 12 months in the sirolimus group but remained roughly stable in the placebo group. Each one-unit increase in baseline log(VEGF-D) was associated with a between group difference in baseline-to-12-month FEV1 change of 134 mL (p=0.0007). In the sirolimus group, improvement in baseline-to-12-month FEV1 occurred in 15 of 23 (65%) VEGF-D responders (ie, those in whom baseline-to-12-month VEGF-D concentrations decreased by more than they did in any patients in the placebo group) and four of 15 (27%) VEGF-D non-responders (p=0.0448). INTERPRETATION: Serum VEGF-D is a biologically plausible and useful biomarker in lymphangioleiomyomatosis that correlates with disease severity and treatment response. Measurement of serum VEGF-D concentrations could inform the risk benefit analysis of sirolimus therapy in patients with lymphangioleiomyomatosis and reduce the numbers of patients needed for clinical trials. FUNDING: National Institutes of Health, US Department of Defense. PMID- 24159564 TI - Prevention of atrial fibrillation by bucindolol is dependent on the beta1389 Arg/Gly adrenergic receptor polymorphism. AB - OBJECTIVES: This study assessed the impact of bucindolol, a beta blocker/sympatholytic agent, on the development of atrial fibrillation (AF) in advanced chronic heart failure with reduced left ventricular ejection fraction (HFREF) patients enrolled in the BEST (Beta-Blocker Evaluation of Survival Trial). BACKGROUND: beta-blockers have modest efficacy for AF prevention in HFREF patients. Bucindolol's effects on HF and ventricular arrhythmic endpoints are genetically modulated by beta1- and alpha(2c)-adrenergic receptor (AR) polymorphisms that can be used to subdivide HFREF populations into those with bucindolol effectiveness levels that are enhanced, unchanged, or lost. METHODS: BEST enrolled 2,708 New York Heart Association (NYHA) class III to IV HFREF patients. A substudy in which 1,040 patients' DNA was genotyped for the beta1-AR position 389 Arg/Gly and the alpha(2c)322-325 wild type (Wt)/deletion (Del) polymorphisms, and new-onset AF was assessed from adverse event case report forms or electrocardiograms at baseline and at 3 and 12 months. RESULTS: In the entire cohort, bucindolol reduced the rate of new-onset AF compared to placebo by 41% (hazard ratio [HR]: 0.59 [95% confidence interval (CI): 0.44 to 0.79], p = 0.0004). In the 493 beta1389 arginine homozygotes (Arg/Arg) in the DNA substudy, bucindolol reduced new-onset AF by 74% (HR: 0.26 [95% CI: 0.12 to 0.57]), with no effect in beta1389 Gly carriers (HR: 1.01 [95% CI: 0.56 to 1.84], interaction test = 0.008). When beta1389 Gly carriers were subdivided by alpha(2c) Wt homozygotes (n = 413, HR: 0.94 [95% CI: 0.48 to 1.82], p = 0.84) or Del variant carriers (n = 134, HR: 1.33 [95% CI: 0.32 to 5.64], p = 0.70), there was a positive interaction test (p = 0.016) when analyzed with beta1389 Arg homozygotes. CONCLUSIONS: Bucindolol prevented new-onset AF; beta1 and alpha(2c) polymorphisms predicted therapeutic response; and the 47% of patients who were beta1389 Arg homozygotes had an enhanced effect size of 74%. (Beta-Blocker Evaluation in Survival Trial [BEST]; NCT00000560) PMID- 24159567 TI - Epidemiology and surveillance of hepatocellular carcinoma. AB - Hepatocellular carcinoma (HCC) is one of the most frequently occurring malignancies and has a high mortality rate. The incidence of HCC differs greatly according to the geographic area. East and Southeast Asia, as well as middle and West Africas have the highest prevalence of HCC. The risk factors for developing HCC are well known and include cirrhosis, hepatitis B virus (HBV) infection, hepatitis C virus (HCV) infection, alcohol consumption, smoking, diabetes, and nonalcoholic steatohepatitis. Cirrhosis is the most significant risk factor, and there is a correlation between the degree of noninvasively measured liver fibrosis and the risk of HCC occurrence. HBV exerts carcinogenic effects by several mechanisms, including host genome integration, and studies have revealed that HBV replication predicts HCC development. HCV induces multistep carcinogenesis from inflammation, to fibrosis and liver cancer. HCC is an appropriate target for surveillance programs for early cancer detection. Currently, liver ultrasonography (US) combined with serum alpha-fetoprotein (AFP, a biomarker of HCC) measurement every 6 months is the standard method of HCC surveillance. Although US is the most widely used tool, its sensitivity in detecting early HCC (i.e., within the Milan criteria) during surveillance is only 63%. AFP is the representative biomarker for both HCC surveillance and diagnosis; however, the unsatisfactory performance of AFP as a surveillance tool means that a novel biomarker or combination with other serum markers is required. Des-gamma carboxy prothrombin and AFP-L3 are candidate biomarkers that are complementary to AFP. The strategies of HCC surveillance vary in different countries according to the healthcare system, the resources available, and health insurance coverage. Many studies have shown that the rate of early cancer detection and rate of application of curative therapies were increased, as was the survival time, by HCC surveillance, which should now become a part of standard care, rather than just a recommendation. Improved US technology and the discovery of new biomarkers are necessary to make further progress in HCC surveillance. PMID- 24159568 TI - Clinical application of fluorescence imaging of liver cancer using indocyanine green. AB - Recently, fluorescence imaging using indocyanine green (ICG) has been applied to hepatobiliary surgery, not only to visualize the bile ducts, but also to identify liver cancer during surgery. In this technique, ICG is administered intravenously at a dose of 0.5 mg/kg body weight for routine liver function testing before surgery. Intraoperatively, liver cancer can be readily identified by fluorescence imaging on the liver surface before resection and on the cut surface of the resected specimen. This is achieved by visualizing fluorescence from the area of impaired bile excretion in hepatocellular cancer tissue and in the liver parenchyma surrounding metastatic liver cancers. Liver cancer navigation surgery, first developed in Japan, is also possible, and it represents one of the few fluorescence imaging techniques for cancer that have reached the stage of clinical application; with further developments in basic research, fluorescence imaging is expected to become an indispensable technique for the diagnosis and treatment of liver cancer. PMID- 24159570 TI - Chemoembolization in patients with hepatocellular carcinoma. AB - Transcatheter arterial chemoembolization (TACE) is the standard of care for nonsurgical patients with preserved liver function with large or multinodular noninvasive hepatocellular carcinoma (HCC) confined to the liver. The administration of an anticancer-in-oil emulsion followed by embolic agents is the most popular TACE technique; however, the introduction of embolic, drug-eluting beads (DEB) has provided an alternative to conventional regimens. Experimental studies have shown that DEB-TACE results in a safe pharmacokinetic profile and effective tumor killing in animal models. Clinical experiences have confirmed that DEB-TACE provides a combined ischemic and cytotoxic effect locally, with significantly reduced drug-related toxicity and liver toxicity compared with conventional TACE. The addition of molecular targeted drugs to the therapeutic armamentarium for HCC has prompted the design of clinical trials aimed at investigating the synergies between TACE and systemic treatments. Combining TACE with antiangiogenic agents represents a promising strategy because TACE is thought to cause local hypoxia, resulting in a temporary increase in levels of vascular endothelial growth factor. Recently, a large phase 2, randomized, double blind, placebo-controlled trial (the SPACE study) indicated that the concurrent administration of DEB-TACE and sorafenib has a manageable safety profile and suggested that the time to progression (TTP) and time to vascular invasion or extrahepatic spread may be improved compared with DEB-TACE alone. These data support the further evaluation of molecular targeted, systemically active agents in combination with DEB-TACE in a phase 3 setting. PMID- 24159572 TI - Why does every hepatocellular carcinoma clinical trial using molecular targeted agents fail? PMID- 24159569 TI - Recent Advances in CT and MR Imaging for Evaluation of Hepatocellular Carcinoma. AB - Hepatocellular carcinoma (HCC) is one of the most common malignancies worldwide. Accurate diagnosis and assessment of disease extent are crucial for proper management of patients with HCC. Imaging plays a crucial role in early detection, accurate staging, and the planning of management strategies. A variety of imaging modalities are currently used in evaluating patients with suspected HCC; these include ultrasound, computed tomography (CT), magnetic resonance imaging (MRI), nuclear medicine, and angiography. Among these modalities, dynamic MRI and CT are regarded as the best imaging techniques available for the noninvasive diagnosis of HCC. Recent improvements in CT and MRI technology have made noninvasive and reliable diagnostic assessment of hepatocellular nodules possible in the cirrhotic liver, and biopsy is frequently not required prior to treatment. Until now, the major challenge for radiologists in imaging cirrhosis has been the characterization of small cirrhotic nodules smaller than 2 cm in diameter. Further technological advancement will undoubtedly have a major impact on liver tumor imaging. The increased speed of data acquisition in CT and MRI has allowed improvements in both spatial and temporal resolution, which have made possible a more precise evaluation of the hemodynamics of liver nodules. Furthermore, the development of new, tissue-specific contrast agents such as gadoxetic acid has improved HCC detection on MRI. In this review, we discuss the role of CT and MRI in the diagnosis and staging of HCC, recent technological advances, and the strengths and limitations of these imaging modalities. PMID- 24159571 TI - Noninvasive diagnosis of hepatocellular carcinoma in cirrhotic liver: current guidelines and future prospects for radiological imaging. AB - Noninvasive imaging has become the standard for hepatocellular carcinoma (HCC) diagnosis in cirrhotic patients. Typical imaging features of HCC such as arterial wash-in and venous wash-out deliver very high specificity and acceptable sensitivity even in nodules from 1 to 2 cm in diameter. However, limitations apply specifically in hypovascular HCC, for which the addition of new techniques such as diffusion-weighted magnetic resonance imaging (DW-MRI) or hepatobiliary MRI is helpful. Whereas DW-MRI adds to both the sensitivity and specificity, hepatobiliary MRI additionally contributes valuable information in cirrhotic patients on the histopathology of small lesions, including early HCC and high grade dysplastic nodules. Biopsy of small, atypical lesions is associated with a high rate of false-negative findings and should be used only after careful consideration in selected patients. Here, we review the current international guidelines on HCC diagnosis as well as the latest developments in imaging that may contribute to safe detection and accurate characterization of suspicious nodules in patients with liver cirrhosis. PMID- 24159573 TI - Asia-pacific primary liver cancer expert meetings. PMID- 24159574 TI - Treatment of advanced hepatocellular carcinoma with emphasis on hepatic arterial infusion chemotherapy and molecular targeted therapy. AB - Advanced hepatocellular carcinoma is defined as liver cancer with vascular invasion or extrahepatic metastasis that is untreatable by local therapy. In Japan, hepatic arterial infusion chemotherapy (HAIC) with interferon plus 5 fluorouracil (5-FU) or a combination of low-dose 5-FU and cisplatin, referred to as low-dose FP, is administered for treating advanced liver cancer and yields favorable outcomes. Outside Japan, the molecular targeted agent, sorafenib, is used as a first-line treatment for advanced liver cancer. New drug development for advanced liver cancer and clinical trials on combination therapy with sorafenib and HAIC are currently underway. The prognosis of advanced liver cancer will significantly improve if these clinical trials yield positive results. PMID- 24159575 TI - Liver resection and transplantation in hepatocellular carcinoma. AB - Liver resection is the most available, efficient treatment for patients with hepatocellular carcinoma. Better liver function assessment, increased understanding of segmental liver anatomy using more accurate imaging studies, and surgical technical progress are the most important factors that have led to reduced mortality, with an expected 5 year survival of 70%. Impairment of liver function and the risk of tumor recurrence lead to consideration of liver transplantation (LT) as the ideal treatment for removal of the existing tumor and the preneoplastic underlying liver tissue. However, LT, which is not available in many countries, is restricted to patients with minimum risk of tumor recurrence under immunosuppression. Limited availability of grafts as well as the risk and the cost of the LT procedure has led to considerable interest in combined treatment involving resection and LT. An increasing amount of evidence has shown that initial liver resection in transplantable patients with a single limited tumor and good liver function is a valid indication. Histological analysis of specimens allows identification of the subgroup of patients who could benefit from follow-up with LT in case of recurrence. PMID- 24159576 TI - Emerging signaling pathways in hepatocellular carcinoma. AB - Signaling pathways have become a major source of targets for novel therapies in hepatocellular carcinoma (HCC). Survival benefits achieved with sorafenib, a multikinase inhibitor, are unprecedented and underscore the importance of improving our understanding of how signaling networks interact in transformed cells. Numerous signaling modules are de-regulated in HCC, including some related to growth factor signaling (e.g., IGF, EGF, PDGF, FGF, HGF), cell differentiation (WNT, Hedgehog, Notch), and angiogenesis (VEGF). Intracellular mediators such as RAS and AKT/MTOR may also play a role in HCC development and progression. Different molecular mechanisms have been shown to induce aberrant pathway activation. These include point mutations, chromosomal aberrations, and epigenetically driven down-regulation. The use of novel molecular technologies such as next-generation sequencing in HCC research has enabled the identification of novel pathways previously underexplored in the HCC field, such as chromatin remodeling and autophagy. Considering recent failures of molecular therapies in advanced clinical trials (e.g., sunitinib, brivanib), survey of these and other new pathways may provide alternative therapeutic targets. PMID- 24159578 TI - Japan's Successful Model of Nationwide Hepatocellular Carcinoma Surveillance Highlighting the Urgent Need for Global Surveillance. PMID- 24159577 TI - New paradigm for management of hepatocellular carcinoma by imaging. AB - Based on recent clinical practice guidelines, imaging is largely replacing pathology as the preferred diagnostic method for determination of hepatocellular carcinoma (HCC). A variety of imaging modalities, including ultrasound (US), computed tomography (CT), magnetic resonance imaging (MRI), nuclear medicine, and angiography, are currently used to examine patients with chronic liver disease and suspected HCC. Advancements in imaging techniques such as perfusion imaging, diffusion imaging, and elastography along with the development of new contrast media will further improve the ability to detect and characterize HCC. Early diagnosis of HCC is essential for prompt treatment, which may in turn improve prognosis. Considering the process of hepatocarcinogenesis, it is important to evaluate sequential changes via imaging which would help to differentiate HCC from premalignant or benign lesions. Recent innovations including multiphasic examinations, high-resolution imaging, and the increased functional capabilities available with contrast-enhanced US, multidetector row CT, and MRI have raised the standards for HCC diagnosis. Although hemodynamic features of nodules in the cirrhotic liver remain the main diagnostic criterion, newly developed cellspecific contrast agents have shown great possibilities for improved HCC diagnosis and may overcome the diagnostic dilemma associated with small or borderline hepatocellular lesions. In the 20th century paradigm of medical imaging, radiological diagnosis was based on morphological characteristics, but in the 21st century, a paradigm shift to include biomedical, physiological, functional, and genetic imaging is needed. A multidisciplinary team approach is necessary to foster an integrated approach to HCC imaging. By developing and combining new imaging modalities, all phases of HCC patient care, including screening, diagnosis, treatment, and therapy, can be dramatically improved. PMID- 24159581 TI - Perspectives on the design of clinical trials combining transarterial chemoembolization and molecular targeted therapy. AB - Transarterial chemoembolization (TACE) moderately prolongs the survival of patients with intermediate-stage hepatocellular carcinoma. Molecular targeted therapy (MTT) may improve the efficacy of TACE. However, the findings of clinical trials evaluating the efficacy of a combination of TACE and MTT are conflicting. We hypothesized that this disparity can be prevented using alternative study designs. In this review, we classify the pertinent issues of study designs into five domains: primary endpoints, patients, TACE procedures, timing of randomization, and drug administration. Furthermore, we discuss the methods for increasing the success rate by minimizing potentially confounding factors within these five domains. Transarterial chemoembolization (TACE) is the current standard therapy for patients with Barcelona Clinic Liver Cancer (BCLC) intermediate-stage hepatocellular carcinoma (HCC) [1, 2, 3]. The survival benefit of TACE is supported by the results of meta-analysis of clinical trials comparing TACE with other conservative treatments in patients with inoperable HCC [4]. The results showed that the median survival of patients improved from approximately 16 to 20 months following TACE [4, 5]. Although advances in TACE techniques and the use of new embolization agents may improve the efficacy of TACE [6, 7], other approaches are needed to further improve the outcome in HCC patients treated using TACE. Molecular targeted therapy (MTT) has improved the survival of patients with advanced-stage HCC [5, 8]. Therefore, combining MTT and TACE may additionally improve the survival in patients with intermediate-stage HCC. Many molecular targeted agents (MTA) are currently undergoing evaluation in randomized trials (table 1). However, the designs of these trials differ significantly. The results of two trials combining sorafenib and TACE were recently reported. Both trials failed to demonstrate a therapeutic benefit of the combination therapy for time to tumor progression (TTP) or overall survival (OS) [9, 10]. However, specific subgroups of patients who received treatment for more than 6 months exhibited significantly better survival (table 2). Because median survival can be greater than 2 years in patients with intermediate-stage HCC, it is likely that an extended exposure period is necessary for MTA effects to reach the biological threshold at which survival benefit becomes measurable. Therefore, early discontinuation of study drug treatment may significantly undermine the statistical power of efficacy analysis in randomized trials (fig. 1). Clinical trials should be designed to minimize confounding factors that could lead to early discontinuation of study drug [1, 2, 3, 11, 12]. Factors that are crucial in this regard can be categorized into five domains: (1) selection of primary endpoints, (2) selection of patient population, (3) selection of TACE procedures, (4) timing of randomization, and (5) study drug administration. In this review we discuss the confounding effects potentially associated with each domain and the possible interactions among domains in trials combining TACE and MTA. We also discuss strategies that can help improve sensitivity and accuracy measurements of MTA efficacy. PMID- 24159580 TI - Portal vein embolization for hepatocellular carcinoma. AB - Portal vein embolization (PVE) improves the safety of major hepatectomy through hypertrophy of the future liver remnant (FLR), atrophy of the liver volume to be resected, and improvement in patient selection. Because most patients with hepatocellular carcinoma (HCC) have liver parenchymal injury due to underlying viral hepatitis or alcoholic liver fibrosis/cirrhosis, indication of PVE is relatively complex and sequential procedures, including transarterial chemoembolization, are required to maximize the effect of PVE as well as to minimize tumor progression due to increased arterial flow after PVE. PVE is currently indicated for patients with relatively well-preserved hepatic function [Child-Pugh A and indocyanine green tolerance test (ICG-R15) <20%) to achieve minimal FLR volume for safe major hepatectomy. FLR volume >40% is the minimal requirement for patients with chronic hepatitis or cirrhosis, and further strict criteria (FLR volume >50%) have been recommended for patients with marginal liver functional reserve (ICG-R15, 10-20%). Recent clinical results have suggested that PVE can be safely performed in patients with HCC and that it contributes to improved survival after major hepatectomy. PMID- 24159579 TI - Treatment of hepatocellular carcinoma: a systematic review. AB - Hepatocellular carcinoma (HCC) is one of the most common malignancies, with an increasing incidence. With advances in surgical techniques and instrumentation and the development of molecular-target drugs, a number of potentially curative treatments have become available. Management of HCC patients depends on the stage of their tumor. Liver resection remains the first choice for very early-stage HCC, but it is being challenged by local ablative therapy. For early-stage HCC that meet the Milan criteria, liver transplantation still offers a better outcome; however, local ablative therapy can be a substitute when transplantation is not feasible. Local ablation is also used as a bridging therapy toward liver transplantation. HCC recurrence is the main obstacle to successful treatment, and there is currently no effective means of preventing or treating HCC recurrence. Transarterial therapy is considered suitable for intermediate-stage HCC, while sorafenib is recommended for advanced-stage HCC. This stage-based approach to therapy not only provides acceptable outcomes but also improves the quality of life of HCC patients. Because of the complexity of HCC, therapeutic approaches must be adapted according to the characteristics of each individual patient. This review discusses the current standards and trends in the treatment of HCC. PMID- 24159582 TI - Are Tumor Exposure and Anatomical Resection Antithetical during Surgery for Hepatocellular Carcinoma? A Critical Review. AB - Hepatic resection is the most potentially curative local therapy for patients with hepatocelluar carcinoma (HCC). However, the high rate of postoperative recurrence, 50-70% at 3 years, remains a major concern. Such recurrences usually occur in the liver owing to the high propensity of HCC to invade the portal vein branches and the underlying liver cirrhosis, which is the ideal background for HCC development. Two pivotal surgical techniques are commonly used to reduce such recurrences: anatomical resection (AR) and achievement of negative margins. However, controversies exist about the definition of anatomical resection and the requisite width of negative margins. Consequently, a consensus on these issues is far from being achieved in the specialized surgical community. Review of the literature and author's discernment support AR for HCC larger than 2cm, and tumor exposure when the tumor is in contact with major vessels. Therefore, tumor exposure is not a contradiction to an AR properly carried out. PMID- 24159583 TI - Liver transplantation for hepatocellular carcinoma: an appraisal of current controversies. AB - Cost-effective and efficacious approaches to the management of hepatocellular carcinoma (HCC) must be developed in response to the rising incidence of this disease worldwide. While surgical resection is the current standard of care, most patients afflicted with HCC are unresectable at diagnosis. Developing good therapy for these patients is thus imperative. Liver transplantation offers the possibility of extirpation of not only the tumor but also the remaining cirrhotic liver. Transplantation is hence an ideal treatment option for early HCC patients with poor liver function. When transplantation occurs within the established Milan criteria, the outcomes are good (5-year survival >60%). Current efforts are under way to expand the indications for transplantation beyond the Milan criteria. The resulting surge of new algorithms may potentially shape a new system of transplantation criteria based on personalized parameter calculations. However, this change in criteria is not without controversy, and data remains inconclusive. Current bridging strategies have been similarly hindered by lack of consensus because of the lack of randomized, controlled trials demonstrating their efficacy. In addition, debate continues on the role of transplantation in early (resectable) HCC with good liver function. Issues of reimbursement, the paucity of available donor livers, and governmental funding (or lack thereof) continue to complicate the situation. In this review, issues preventing or facilitating globally consistent treatment strategies for HCC are discussed. PMID- 24159584 TI - Comparison of international guidelines for noninvasive diagnosis of hepatocellular carcinoma. AB - The aim of this review is to present the similarities and differences between the latest guidelines for noninvasive diagnosis of hepatocelullar carcinoma (HCC) of American Association for the Study of Liver Diseases (AASLD), European Association for the Study of the Liver (EASL), Asian Pacific Association for the Study of the Liver (APASL), and Japanese Society of Hepatology. All the four guidelines defined a typical HCC vascular pattern as the homogeneous hyperenhancement (wash-in) in the arterial phase followed by wash-out in the venous or late phase. The AASLD and EASL guidelines accept only four-phase computed tomography and dynamic contrast magnetic resonance imaging (MRI) for HCC diagnosis, whereas the APASL and Japanese guidelines also accept contrast enhanced ultrasound (CEUS). Regarding CEUS, the APASL guidelines accept the use of Levovist or Sonazoid as contrast agents, whereas the Japanese guidelines accept only the use of Sonazoid. The AASLD and EASL guidelines recommend using only extracellular contrast agents such as gadolinium for MRI, whereas the APASL guidelines also included the use of super paramagnetic iron oxid-MRI, and the Japanese guidelines recommended the use of gadolinium-ethoxybenzyl diethylentriamine pentaacetic acid-MRI. The AASLD and EASL guidelines propos a diagnostic algorithm starting from the tumor size, whereas the APASL and Japanese guidelines recommend an algorithm starting from arterial tumor vascularity (hyper or hypovascular in the arterial phase). In conclusion, important differences exist among the Western and Eastern guidelines for noninvasive HCC diagnosis. PMID- 24159585 TI - Combination of local transcatheter arterial chemoembolization and systemic anti angiogenic therapy for unresectable hepatocellular carcinoma. AB - The pathophysiologic complexity of hepatocellular carcinoma (HCC) and underlying hepatic cirrhosis, make optimal treatment choice a clinical challenge. The radical change in the treatment algorithm of patients with advanced unresectable HCC over the past 7 years, with the introduction of anti-angiogenic agents in patients with only preserved liver function reflect this challenge. Even though data from studies on the combination of transcatheter arterial chemoembolization and anti-angiogenic agents demonstrate a survival advantage in selected patients, this combination is not straightforward. In this review, we'll examine current data of administering anti-angiogenic therapy in combination with transcatheter arterial chemoembolization and critically evaluate the progress and gaps in current knowledge. PMID- 24159586 TI - Application of Radiotherapeutic Strategies in the BCLC-Defined Stages of Hepatocellular Carcinoma. AB - The Barcelona Clinic Liver Cancer (BCLC) staging system is the method currently used to stage hepatocellular carcinoma (HCC) and therefore plays an important role in deciding on an appropriate course of treatment. BCLC takes into consideration the extent of the disease as well as patient factors such as hepatic function and performance status. However, it does not propose solutions for all clinical situations. Although radiotherapy (RT) is not included in the BCLC guidelines, the potent local antitumor effect of RT should be considered seriously as a part of the treatment strategy. Novel RT technologies introduced during the last decade have made it possible to deliver higher doses of radiation to the tumor while avoiding damage to critical normal tissues adjacent to the tumor. Because of the growing interest in using RT for HCC patients unfit for or progressed beyond standard treatments, the role of RT for HCC patients needs to be specified within the BCLC staging system. Curative RT can be used for patients with either very early or early stage BCLC; focal high dose RTs, such as stereotactic body RT, are especially useful. Intermediate or advanced stage disease confined to the liver can be managed safely and effectively by localized RT in conjunction with other treatment modalities such as transarterial chemoembolization or concurrent or adjuvant chemotherapy. In this review, the efficacy of RT in each BCLC stage of HCC will be discussed. PMID- 24159587 TI - Immunotherapeutic approaches to hepatocellular carcinoma treatment. AB - Liver cancer, the most common form of which is hepatocellular carcinoma (HCC), is one of the most deadly cancers worldwide. As of 2008, in men, HCC was the fifth most common cancer (approximately 450,000 new cases per year) and the second most frequent cause of death from cancer (around 416,000 deaths per year), whereas in women, it was the seventh most frequently diagnosed cancer (150,000 new cases per year) and the sixth most frequent cause of cancer deaths (140,000 deaths per year) [1]. Overall, HCC is the third leading cause of death from cancer globally [2, 3]. Worldwide, the incidence of HCC in males is more than twice that in females. The etiology of HCC is diverse; however, approximately 80% of HCCs occur secondary to chronic infection with hepatitis B virus (HBV) and/or hepatitis C virus (HCV) [4]. The geographic distribution of HCC is such that the high incidence regions of Eastern Asia and sub-Saharan Africa bear a disproportionate HCC burden, amounting to more than 80% of the global burden [4]. However, even in areas considered low-incidence regions-North America and Europe-the incidence of HCC is on the rise [4]. In the US, HCC incidence has risen more than threefold in the past 30 years, and it is now the ninth most frequent cause of death from cancer. The major reasons for the increased incidence of HCC in the US are the increasing prevalence of chronic HCV infection, increased immigration from high incidence countries in Asia and Africa, and the increase in the number of individuals with cirrhosis due to obesity-related fatty liver disease. Most HCCs are diagnosed at an advanced stage for which there is no curative option. Sorafenib, the only agent specifically approved for HCC treatment, is of limited efficacy in this setting. Therefore, an urgent need for improved HCC therapy exists. In this review, we discuss the available data on the development and use of immunotherapy for HCC, with a particular focus on recent results and novel approaches. PMID- 24159588 TI - Clinical impact of ultrasound-related techniques on the diagnosis of focal liver lesions. AB - Since its introduction in clinical practice, ultrasound technology has greatly impacted patient management, particularly in the case of liver diseases, where hepatologists usually perform ultrasound examinations. Clinicians are increasingly aware of the great potential of ultrasound waves and of the recent innovations that exploit the mechanical properties of ultrasound waves. Thus, at present, not only B-mode ultrasound but also contrast-enhanced ultrasound and, more recently, elastosonography are used worldwide in various settings. This review aims to describe why clinicians should be aware of ultrasound-based techniques, how they should use these techniques for assessing focal liver lesions, and how these techniques impact patient management. We will review the clinical potential of ultrasound-related techniques, starting from lesion detection, moving to characterization, and concluding with their utility in guiding treatments and analyzing their effects. PMID- 24159589 TI - Current and Future Treatment Strategies for Patients with Advanced Hepatocellular Carcinoma: Role of mTOR Inhibition. AB - Hepatocellular carcinoma (HCC) is a common cancer that has the third highest cancer-related mortality rate worldwide. Although potentially curable by transplantation if detected early, the majority of cases are diagnosed at an advanced stage of disease for which limited treatment options are available. The only proven systemic therapy for advanced HCC is sorafenib, a multi-kinase inhibitor that has demonstrated modest efficacy and reasonable tolerability in patients with advanced HCC. Five years after the approval of sorafenib, no other agent has been proven to be beneficial in the first- or second-line setting in advanced HCC. While molecular studies have highlighted various potential targets in HCC, the mammalian target of rapamycin (mTOR) has emerged as an exciting target for cancer therapy including HCC. Laboratory data have linked the phosphatidylinositol 3-kinase/AKT/mTOR axis to various oncogenic processes, including survival and angiogenesis. Historically, mTOR inhibitors have been used for their immunosuppressive properties, but more recently they have been approved as anticancer agents. Retrospective HCC studies suggest that the inclusion of mTOR inhibition as part of an immunosuppressant regimen after transplantation may reduce HCC recurrence compared with other immunosuppressive agents such as calcineurin inhibitors. More recently, single-arm, phase I/II studies have shown that mTOR inhibitors also have activity as monotherapy in cases of recurrent HCC or de novo advanced HCC. This article will review the rationale for targeting the mTOR pathway in HCC, and the currently available clinical data supporting its development for HCC. PMID- 24159590 TI - Delayed Diagnosis of HCC with Chronic Alcoholic Liver Disease. AB - BACKGROUND: Adherence to surveillance recommendations for patients at risk of developing hepatocellular carcinoma (HCC) is influenced by several factors, including the etiology of chronic liver disease. AIM: The aim of this study was to analyze whether tumor stage at diagnosis and prognosis differ in patients with alcohol-related HCC compared to those with chronic viral hepatitis-related HCC. PATIENTS AND METHODS: Medical records of 650 patients diagnosed with HCC between 1994 and 2011 were analyzed retrospectively. Groups were formed from patients having either alcohol abuse or viral hepatitis (chronic hepatitis B or C virus infection) as the only known HCC risk factors. Demographic data (age and gender), tumor stage at diagnosis, survival, liver function [Child-Pugh-Turcotte (CPT) score] in patients with liver cirrhosis, complications of liver cirrhosis, and serologic parameters were compared between the two groups. RESULTS: A total of 393 HCC cases (male 84%, median age 65 years) were identified, with alcohol abuse as the causative factor in 76.8% and chronic viral hepatitis in 23.2%. In patients with alcohol abuse, 278 (92.1%) were diagnosed with liver cirrhosis (CPT A 49.3%, CPT B 31.1%, CPT C 9.6%), while in patients with viral hepatitis, 84 (92.3%) suffered from liver cirrhosis (CPT A 59.3%, CPT B 23.1%, CPT C 8.8%). Tumor stage in patients with alcohol abuse was Barcelona Clinic Liver Cancer (BCLC) C in 43.7%, BCLC B in 30.5%, and BCLC A in 14.6%. Patients with viral hepatitis showed a trend toward diagnosis at an earlier tumor stage (BCLC B 35.2%, BCLC C 34.1%, BCLC A 22.2%). Etiology of liver cirrhosis did not significantly influence survival in intermediate and advanced tumor stages, but BCLC-A patients with alcohol-related disease demonstrated prolonged survival compared to patients with viral hepatitis. CONCLUSION: Tumor stage at diagnosis of HCC is influenced by the etiology of underlying chronic liver disease and is more progressed in patients having a disease with alcoholic etiology. Majority of HCC patients are not diagnosed at a curable stage, which underlines the need for specialized care for all patients with chronic liver disease, independent of etiology and consequent adherence to current surveillance guidelines. PMID- 24159591 TI - Adopting Gayet's Techniques of Totally Laparoscopic Liver Surgery in the United States. AB - Professor Brice Gayet of the Institut Mutualiste Montsouris in Paris, France, has developed totally laparoscopic techniques for all segments of the liver. As a pioneer in the field of minimally invasive hepato-pancreato-biliary surgery, he started a Minimally Invasive Hepato-Pancreato-Biliary Fellowship in 2006. A retrospective review of all hepatic cases performed by a single surgeon since completing this Fellowship was undertaken. From November 2007 to October 2012, a total of 80 liver resections were done, of which 73 were begun with the intention of completing the case laparoscopically. Of these, more than 90% were completed laparoscopically and 88% were for malignant disease. One of the foundations of Professor Gayet's techniques is the low lithotomy or 'French' position and the utilization of a small robotically controlled laparoscope holder that is sterilizeable and considerably more economic than complete surgical systems. Prototypes exist of robotically controlled hand-held laparoscopic instruments that, unlike the complete surgical system, enable surgeons to maintain a sense of touch (haptics). Proper training in minimally invasive hepato-pancreato-biliary techniques can be obtained with surgeons able to independently perform laparoscopic major hepatectomies without senior minimally invasive backup. Furthermore, miniature and more affordable robotics may enable more surgeons to enjoy the benefits of minimally invasive surgery while maintaining patient safety and minimizing the rising burden of health-care costs worldwide. PMID- 24159592 TI - Intraoperative ultrasound in patients with hepatocellular carcinoma: from daily practice to future trends. AB - Starting from the end of the 1970s, intraoperative ultrasound was introduced and developed to stage liver disease and guide the surgical interventions in patients with hepatocellular carcinoma. Without intraoperative ultrasound, it would probably be impossible to correctly define the hepatic segments as well as the limits of a tumor, also because of the existing wide variations in the anatomy. More importantly, intraoperative ultrasound allows for three-dimensional reconstruction of the relationships between the tumor, hepatic veins, and Glissonian pedicles. Such reconstruction is essential for planning the surgical strategy, which should be individualized in each patient with the aim to spare functional liver parenchyma. This work focuses on the role of intraoperative ultrasound to stage liver disease and to plan surgical resection, describing the most recent technical achievements. PMID- 24159593 TI - Laparoscopic liver resection for hepatocellular carcinoma: korean experiences. AB - The development of laparoscopic liver resection (LLR) has been slow due to technical difficulties. Therefore, LLR has been limited to easily accessible lesions. Recently, this procedure has been well applied to hepatocellular carcinoma. However, until now, the indications for LLR have been tumors in the peripheral portion of the anterolateral segments of the liver (segments II, III, V and VI and the inferior part of IV according to the classification of Couinaud). Due to the growing interest in LLR, there have been many attempts to apply this technique in difficult locations. The lesions in the posterior or superior part of the liver (segments I, VII, VIII and the superior part of IV), which are considered to be poor indications for LLR, have been reported to be successfully operated on by laparoscopic surgery. Accordingly, this laparoscopic approach has become similar to open surgery in many ways. One of the major advancements of LLR is anatomic liver resection including major and minor resection. Laparoscopic mono- and bisegmentectomies have also become possible with growing experience. There are a variety of monosegmentectomies and bisegmentectomies. The common representatives of bisegmentectomies are left lateral sectionectomy, right anterior sectionectomy and right posterior sectionectomy. The common operative types of monosegmentectomies are S4, S5, and S6 monosegmentectomies, etc. Central bi-sectionectomy will also be discussed. The Glissonian approach has been useful for these types of anatomic liver resection. The difficulty of controlling hemorrhage has been overcome by performing meticulous surgical techniques with newly developed instruments, and intraoperative sonography has been used to locate the lesions and guide the resection plane even for deep-seated or invisible lesions. Further accumulation of experience and technical refinements will make theses challenging procedures more reproducible and safer. PMID- 24159595 TI - Adjuvant therapy after curative resection for hepatocellular carcinoma associated with hepatitis virus. AB - The outcome after curative resection for hepatocellular carcinoma (HCC) is still unsatisfactory because of the high rate of recurrence of HCC, including intrahepatic metastasis originating from the primary carcinoma and multicentric carcinogenesis after surgery. The rate of recurrence, particularly of multicentric carcinogenesis after surgery, is affected by persistent active hepatitis and hepatic fibrosis caused by chronic hepatitis B or C. In patients with hepatitis B virus (HBV)-related HCC, a high viral load is a strong risk factor for HCC recurrence. Nucleos(t)ide analogues improve the outcome after curative resection for HBV-related HCC. Interferon therapy improves the outcome after curative resection for hepatitis C virus (HCV)-related HCC by decreasing recurrence and preserving or improving liver function when treatment is successful. Low-dose intermittent interferon therapy has also been reported to be effective in suppressing HCC recurrence. New antiviral agents including protease or polymerase inhibitors are expected to be effective because these agents can eradicate HCV in most patients who receive such treatment. PMID- 24159594 TI - Biomarkers: evaluation of screening for and early diagnosis of hepatocellular carcinoma in Japan and china. AB - Over the past few decades, the screening for and early diagnosis of hepatocellular carcinoma (HCC) has attracted attention worldwide, and especially in Asian countries such as Japan and China. Such approaches can help detecting HCC at an earlier stage when curable interventions can be offered to achieve long term disease-free survival for patients. Biomarkers have been used to screen for and diagnose HCC in various countries. In Japan, the combined tests of des-Gamma carboxyprothrombin (DCP) and alpha-fetoprotein (AFP) or Lens culinaris agglutinin reactive fraction of AFP (AFP-L3) have been shown to achieve a high level of sensitivity and specificity. These tests have routinely been used to screen for HCC and are covered by Japan's national health insurance. Due to the routine practice of screening for HCC among high-risk patients, HCC nodules have been detected in the early stages in more than 60% of patients in Japan. In contrast, although several remarkable advances in the management of HCC have been made in China over the past few decades, most HCC patients still present with advanced stage disease. AFP is the only serum biomarker that has widely been used to screen for and diagnose HCC in China. In recent years, several molecular biological studies have further investigated the clinical usefulness of DCP, and they have found that it may facilitate the screening for and diagnosis of HCC and assist with the assessment of HCC progression. DCP can serve as a biomarker to detect HCC in an early stage and facilitate definitive treatment. The wide implementation of DCP is expected, especially in China where 55% of HCC cases worldwide live. PMID- 24159596 TI - Surgical strategy for liver cancers in the era of effective chemotherapy. AB - Systemic chemotherapy is the only option for advanced and/or disseminated disease in patients with hepatocellular carcinoma (HCC). For decades, various systemic therapies have been explored for the treatment of advanced HCC. Nevertheless, no satisfactory results have been obtained in cytotoxic chemotherapy so far. However, with the recent introduction of effective chemotherapy agents including sorafenib, the role of systemic therapy for the treatment of HCC is changing. The goals of systemic therapy include prolongation of survival with stabilization of disease progression and, in selected patients, downsizing of primarily unresectable tumors. In the era of effective chemotherapy, patients with advanced HCC should be managed with individualized approaches to optimize outcome. PMID- 24159597 TI - A worldwide survey of the current daily practice in liver surgery. AB - BACKGROUND: Liver resection remains the mainstay of curative treatment for liver malignancies. A variety of preoperative assessments and surgical techniques have improved the short- and long-term outcomes of liver resection in patients with liver tumors. Recently, laparoscopic hepatectomies have been increasingly performed. The aim of the present study is to survey the current practice of liver surgery in high-volume centers in the world. METHODS: A questionnaire on the preoperative assessment for liver surgery, open hepatectomy, and laparoscopic hepatectomy was sent to 94 liver centers in the world. RESULTS: Forty-two centers (45%) responded to this survey (29 Asian, 9 European, and 4 North American centers). All but one of the centers evaluated the future liver remnant (FLR) volume, and 95% of them performed preoperative portal vein embolization to increase the FLR volume. In half of the centers, the required FLR volume was over 30% in patients with normal liver and 50% in patients with cirrhotic liver. To reduce the intraoperative blood loss, half of the centers routinely used Pringle's maneuver, and 85% restricted the intraoperative fluid infusion to reduce the central venous pressure. More than 10 laparoscopic hepatectomies were performed per year in 62% of the centers, and more than 30 were performed in 26%, respectively. Laparoscopic major hepatectomies were performed in 24%. Two-thirds answered that the laparoscopic approach would be feasible in donor hepatectomy. CONCLUSION: The evaluation of FLR volume in patients with normal or cirrhotic liver and the usage of preoperative portal vein embolization have become essential practice in more than 90% of the centers. Reduced blood loss has been achieved using Pringle's maneuver, restriction of fluid infusion, and a variety of surgical devises. The laparoscopic approach is increasingly extended to major hepatectomy or donor hepatectomy. PMID- 24159598 TI - Early hepatocellular carcinoma: definition and diagnosis. PMID- 24159599 TI - Local ablation for hepatocellular carcinoma in taiwan. AB - Hepatocellular carcinoma (HCC) is the second commonest cancer in Taiwan. The national surveillance program can detect HCC in its early stages, and various curative modalities (including surgical resection, orthotopic liver transplantation, and local ablation) are employed for the treatment of small HCC. Local ablation therapies are currently advocated for early-stage HCC that is unresectable because of co-morbidities, the need to preserve liver function, or refusal of resection. Among the various local ablation therapies, the most commonly used modalities include percutaneous ethanol injection and radiofrequency ablation (RFA); percutaneous acetic acid injection and microwave ablation are used less often. RFA is more commonly employed than other local ablative modalities in Taiwan because the technique is highly effective, minimally invasive, and requires fewer sessions. RFA is therefore advocated in Taiwan as the first-line curative therapy for unresectable HCC or even for resectable HCC. However, current RFA procedures are less effective against tumors that are in high-risk or difficult-to-ablate locations, are poorly visualized on ultrasonography (US), or are large. Recent advancements in RFA in Taiwan can resolve these issues by the creation of artificial ascites or pleural effusion, application of real-time virtual US assistance, use of combination therapy before RFA, or use of switching RF controllers with multiple electrodes. This review article provides updates on the clinical outcomes and advances in local ablative modalities (mostly RFA) for HCC in Taiwan. PMID- 24159600 TI - Hepatic progenitor cells: their role and functional significance in the new classification of primary liver cancers. AB - Hepatic progenitor cells (HPCs) are bipotential cells residing in normal liver. Their proliferation is observed in reactive conditions of the liver and in primary liver cancers. The observation that some hepatocellular carcinomas (HCCs) express a biliary-like immunophenotype has led to the identification of HPCs in HCC. Accumulating evidence suggests that HPCs play a role as the cell of origin in a variety of primary liver cancers. This has led to the development of revolutionary concepts in hepatocarcinogenesis. In this article, the role and significance of HPCs in HCC, including its classification, are summarized and discussed. PMID- 24159601 TI - Predictive biomarkers of antiangiogenic therapy for advanced hepatocellular carcinoma: where are we? AB - Antiangiogenic therapy, especially treatment with sorafenib, is the primary treatment for patients with advanced hepatocellular carcinoma (HCC). However, the efficacy of such therapy is modest, with low objective response rates and limited prolongation of survival times. Several researchers have investigated predictive biomarkers to help identify patients who can benefit most from antiangiogenic therapy. The largest study on this topic to date was based on the pivotal phase III study of sorafenib (the SHARP study) and did not find any plasma markers that could predict the efficacy of sorafenib. Other studies based on single-arm phase II clinical trials found some potential predictive markers, such as early alpha fetoprotein response, the serum insulin-like growth factor-1 level at baseline, and the volume transfer constants of dynamic contrast-enhanced magnetic resonance imaging. These findings require validation by further studies. Identifying predictive biomarkers of antiangiogenic therapy for HCC remains challenging and warrants further investigations. PMID- 24159605 TI - Professional societies: Come together. PMID- 24159602 TI - The roles of fibroblast growth factors in the testicular development and tumor. AB - Fibroblast growth factors (FGFs) are classically known as hormonal factors and recent studies have revealed that FGFs have a key role in regulating growth and development of several reproductive organs, including the testis. The testis is mainly consisted of germ cells, Sertoli cells and Leydig cells to develop and maintain the male phenotype and reproduction. This review summarizes the structure and fuctions of testis, the roles of FGFs on testicular development and potential involvement in testicular tumor and its regulatory mechanism. Among 23 members of FGFs, the FGF-1, FGF-2, FGF-4, FGF-8, FGF-9, and FGF-21 were involved and describe in details. Understanding the roles and mechanism of FGFs is the foundation to modeling testicular development and treatments in testicular disease. Therefore, in the last part, the potential therapy with FGFs for the testis of cancer and diabetes was also discussed. PMID- 24159604 TI - Reply: To PMID 24028520. PMID- 24159603 TI - Advanced diabetic nephropathy with nephrotic range proteinuria: a pilot study of the long-term efficacy of subcutaneous ACTH gel on proteinuria, progression of CKD, and urinary levels of VEGF and MCP-1. AB - BACKGROUND AND OBJECTIVE: Adrenocorticotropic hormone (ACTH) is able to reduce proteinuria in nondiabetic glomerulopathies through activation of melanocortin receptors (MCR) expressed in the podocyte. To determine the efficacy of ACTH, we conducted a randomized, open-label pilot trial of ACTH gel in patients with advanced diabetic nephropathy. STUDY DESIGN: Twenty-three (23) patients with diabetic nephropathy were randomized to daily subcutaneous (SQ) injections of 16 or 32 units of ACTH gel for six months. Outcome. The primary endpoint was the percentage of patients achieving a complete remission (<300 mg/24 hours) within 6 months. Exploratory endpoints included the percentage of partial (50% reduction) remissions, changes in Cr, and urinary cytokine markers. RESULTS: After 6 months of ACTH gel therapy, 8 of 14 (57%) patients achieved a complete (n = 1) or partial (n = 7) remission. In the low-dose ACTH gel group (16 units), urinary protein fell from 6709 + 953 to 2224 + 489 mg/24 hrs (P < 0.001). In contrast, 2 of 6 patients in the 32-unit group achieved partial remission, but aggregate proteinuria (5324 + 751 to 5154 + 853 mg/24 hours) did not change. Urinary VEGF increased from 388 to 1346 pg/mg urinary creatinine (P < 0.02) in the low-dose group but remained unchanged in the high-dose group. CONCLUSION: ACTH gel stabilizes renal function and reduces urinary protein for up to 6 months after treatment. The ClinTrials.gov identifier is NCT01028287. PMID- 24159606 TI - Tony Pawson (1952-2013). PMID- 24159607 TI - Regarding: Travnik L, Djordjevic S, Rozman S, Hribernik M, Dahmane R (2013) Muscles within muscles: a tensiomyographic and histochemical analysis of the normal human vastus medialis longus and vastus medialis obliquus muscles. J Anat 222, 580-587. doi: 10.1111/joa.12045. PMID- 24159608 TI - Radium-223 in prostate cancer. PMID- 24159610 TI - Welcome to the Swedish theme issue: putting exercise into sports medicine. PMID- 24159609 TI - Genome-wide genotype-based risk model for survival in acute myeloid leukaemia patients with normal karyotype. AB - Single nucleotide polymorphisms (SNP) are inter-individual genetic variations that could explain inter-individual differences of response/survival to chemotherapy. The present study was performed to build up a risk model for survival in 247 patients with acute myeloid leukaemia (AML) with normal karyotype (AML-NK). Genome-wide Affymetrix SNP array 6.0 was used for genotyping in discovery set (n = 118). After identifying significant SNPs for overall survival (OS) in single SNP analysis, a risk model was constructed. Out of 632 957 autosomal SNPs analysed, finally four SNPs (rs2826063, rs12791420, rs11623492 and rs2575369) were introduced into the risk model. The model could stratify the patients according to their OS in discovery set (P = 1.053656 * 10-4). Replication was performed using Sequenom platform for genotyping in the validation cohort (n = 129). The model incorporated with clinical and four SNP risk score was successfully replicated in a validation set (P = 5.38206 * 10-3). The integration of four SNPs and clinical factors into the risk model showed higher area under the curve (AUC) reults than in the model incorporating only clinical or only four SNPs, suggesting improved prognostic stratification power by combination of four SNPs and clinical factors. In conclusion, a genome-wide SNP-based risk model in 247 patients with AML-NK can identify a group of high risk patients with poor survival. PMID- 24159611 TI - 2nd World Congress of Cutaneous Lymphomas & 6th International Symposium on the Biology and Immunology of Cutaneous Lymphoma. PMID- 24159612 TI - Reply by authors. PMID- 24159613 TI - Invited commentary. PMID- 24159614 TI - Invited commentary. PMID- 24159615 TI - Authors' response. PMID- 24159616 TI - Invited Commentary. PMID- 24159617 TI - Dr Drew and colleagues respond. PMID- 24159618 TI - Dr Freeman and colleagues respond. PMID- 24159619 TI - High maintenance. PMID- 24159621 TI - Magnetic map. PMID- 24159620 TI - End harassment. PMID- 24159622 TI - Politics: The long shadow of the shutdown. PMID- 24159623 TI - Policy: Set research priorities in a time of recession. PMID- 24159624 TI - Knowledge of medication use and factors influencing the utilisation of public health clinics. AB - BACKGROUND: This study aimed to determine knowledge of medication use, to investigate the treatment-seeking pattern and to identify factors affecting the use of public health clinics among the study population. METHODS: A survey was conducted in Mantin Town of Malaysia using a structured questionnaire based on a literature review. Households were recruited through a three-stage sampling technique. RESULTS: Of 183 respondents (mean age 44.6 [+/-16.9] years; 115 [62.8%] women), 157 (85.8%) did not know about the term 'generic name' and 159 (86.9%) were not sure about the difference in price between a generic medicine and a branded medicine. The majority sought healthcare from the public health clinics (102/183; 55.7%). In the multivariate analysis, higher education level of respondents (p = 0.028), good quality of services in public health clinics (p = 0.001) and short distances between their residences and the public health clinics (p<0.001) were the significant variables for predicting the use of a public health clinic. CONCLUSION: This study highlights that health education on the use of generic drugs needs to be scaled up. These findings are important to the health policy makers who may need to consider addressing factors such as quality of care and physical distance to the clinic in the design and implementation of health facilities and the selection of the catchment areas. PMID- 24159625 TI - CHADS2 score: its predictive capacity in clinical practice. Reply. PMID- 24159626 TI - Cardiac dysfunction related to cirrhosis. Reply. PMID- 24159627 TI - LIBEFP: A new parallel implementation of the effective fragment potential method as a portable software library. AB - A new high performance parallel implementation of the general Effective Fragment Potential (EFP) method in a form of a portable software library called libefp is presented. The libefp library was designed to provide developers of various quantum chemistry software packages with an easy way to add EFP functionality to the program of their choice. The general overview of the library is presented and various aspects of interfacing the library with third party quantum chemistry packages are considered. The reference implementation of common methods of computational chemistry such as geometry optimization and molecular dynamics on top of libefp is delivered in the form of efpmd program. Results of molecular dynamics simulation of liquid water using the developed software are described. PMID- 24159628 TI - New implementation of high-level correlated methods using a general block tensor library for high-performance electronic structure calculations. AB - This article presents an open-source object-oriented C++ library of classes and routines to perform tensor algebra.The primary purpose of the library is to enable post-Hartree-Fock electronic structure methods; however, the code is general enough to be applicable in other areas of physical and computational sciences. The library supports tensors of arbitrary order (dimensionality), size, and symmetry. Implemented data structures and algorithms operate on large tensors by splitting them into smaller blocks, storing them both in core memory and in files on disk, and applying divide-and-conquer-type parallel algorithms to perform tensor algebra. The library offers a set of general tensor symmetry algorithms and a full implementation of tensor symmetries typically found in electronic structure theory: permutational, spin, and molecular point group symmetry. The Q-Chem electronic structure software uses this library to drive coupled-cluster, equation-of-motion, and algebraic-diagrammatic construction methods. PMID- 24159629 TI - Grcarma: A fully automated task-oriented interface for the analysis of molecular dynamics trajectories. AB - We report the availability of grcarma, a program encoding for a fully automated set of tasks aiming to simplify the analysis of molecular dynamics trajectories of biological macromolecules. It is a cross-platform, Perl/Tk-based front-end to the program carma and is designed to facilitate the needs of the novice as well as those of the expert user, while at the same time maintaining a user-friendly and intuitive design. Particular emphasis was given to the automation of several tedious tasks, such as extraction of clusters of structures based on dihedral and Cartesian principal component analysis, secondary structure analysis, calculation and display of root-meansquare deviation (RMSD) matrices, calculation of entropy, calculation and analysis of variance-covariance matrices, calculation of the fraction of native contacts, etc. The program is free-open source software available immediately for download. PMID- 24159630 TI - Retraction. Effect of pretransplantation hemoglobin blood concentration on renal allograft survival and function: Transplantation Proceedings, volume 42, number 3, pages 760-2, April 2010. PMID- 24159631 TI - On balance. Fall prevention starts with stability. PMID- 24159632 TI - A new way of life. How three people control type 2 diabetes with diet and exercise alone. PMID- 24159633 TI - Healthy harvest. PMID- 24159634 TI - Widening indications for CRT implants: not necessarily 'the more the merrier'? PMID- 24159635 TI - Controversies in rectal cancer. PMID- 24159636 TI - Who should be treating rectal cancer in 2013? PMID- 24159637 TI - LOREC: the English Low Rectal Cancer National Development Programme. PMID- 24159638 TI - Extra-levator abdomino-perineal excision in advanced low rectal cancer surgery. PMID- 24159639 TI - A Papillon patient's journey. PMID- 24159640 TI - Local excision of rectal tumours by minimally invasive transanal surgery. PMID- 24159641 TI - Contact radiotherapy for elderly patients with early low rectal cancers. PMID- 24159642 TI - Artificial hydration in the terminally ill patient. PMID- 24159643 TI - The first issue of the British Journal of Surgery. PMID- 24159645 TI - Pain in the neck: a rare complication of carbimazole therapy. PMID- 24159644 TI - Experiences and challenges in achieving sustainable quality improvement in two UK hospitals. PMID- 24159646 TI - Mallory-Weiss tears occurring during upper gastrointestinal endoscopy. PMID- 24159647 TI - Return of the spleens. PMID- 24159648 TI - Haemoptysis and liver dysfunction. PMID- 24159649 TI - A physics lesson for physicians. PMID- 24159650 TI - Irreversible apical ballooning may also occur. PMID- 24159651 TI - Authors' reply. PMID- 24159653 TI - To reach out or not: is critical care outreach as valuable as it seems? PMID- 24159654 TI - Whose fault is it anyway? PMID- 24159655 TI - Net costs of hospital-acquired and pre-admission PUs among older people hospitalised in Ontario. AB - OBJECTIVE: To determine the net cost of hospital-acquired and pre-admission pressure ulcers (PUs) in an acute-care setting in Ontario, Canada. METHOD: Cases of PUs were identified among hospitalised patients using Ontario Case Costing Initiative (OCCI) data from 2002-2006. Inpatient costs included direct and overhead costs.To determine the net cost of PUs, cases were matched controlling for age, gender, most responsible diagnosis and comorbidity. Mean net costs were estimated using Bayesian linear mixed models methods. Results were also reported by PU severity. RESULTS: In our study, there were 1351 cases of hospital-acquired PUs and 2523 cases of preadmission PUs over 5 years. Net cost of hospital acquired PU ranged between CA$44000 for a category II PU to CA$90000 for a category IV PU. For pre-admission PU net cost was between CA$11 000 to CA$18500 for category II and category IV PU, respectively.The net cost of treating hospital-acquired PU is higher than pre-admission PU. Costs increase with increasing PU severity. CONCLUSION: The total net adjusted hospitalisation cost of a hospital-acquired PU in Ontario was CA$44000-90000, compared with CA$11 000 18500 for a pre-admission PU. Future studies should determine the attributable cost of PU using patient-level data to verify the accuracy of the study results. PMID- 24159656 TI - An evaluation of dehydrated human amniotic membrane allografts in patients with DFUs. AB - OBJECTIVE: To evaluate healing of chronic diabetic foot ulcers (DFUs) with use of dehydrated human amniotic membrane (dHAM) in patients failing under standard of care treatment. METHOD: The study population was identified from patients with chronic DFUs enrolled in a randomised trial comparing standard care with standard care with the addition of dHAM. The present study included patients that failed to heal (defined as < 50% decrease in wound size after 6 weeks, or not completely healed by 12 weeks of treatment) with standard care. One week after withdrawal from the randomised trial, these patients were offered treatment with standard care and bi-weekly application of dHAM. Subsequent evaluation of clinical records was made with IRB approval and patient consent. Each patient was used as their own control to compare wound size reduction between treatment periods, and healing rates within the 12-week dHAM treatment period. RESULTS: Eleven patients were included in the study. Mean wound chronicity was 21.1 +/- 12.4 weeks (range 11-54 weeks) and mean wound size was 4.7 +/- 5.0cm2, at baseline. Complete healing was achieved in 55% by 4 weeks, 64% by 6 weeks and 91% by 12 weeks with bi-weekly dHAM application. Mean weeks to complete healing was 4.2 +/- 3.1 weeks for the 10 patients healed. After 4 weeks of standard care, wounds had decreased in size an average of 26.8 +/- 45.3% versus 87.6 +/- 16.0% after 4 weeks of dHAM treatment (two applications; p < 0.001). CONCLUSION: This study provides evidence that the incorporation of dHAM into standard of care for patients with chronic DFUs can be beneficial. The results suggest that dHAM is a viable option for the treatment of recalcitrant DFUs. PMID- 24159657 TI - Coping with an exulcerated breast carcinoma: an interpretative phenomenological study. AB - OBJECTIVE: To explore how women living at home with a malignant fungating wound (MFW) cope with such wounds. METHOD: To explore coping through the lived experiences of patients a methodological framework, using Heideggerian hermeneutic phenomenology and semi-structured interviews. Nine patients were interviewed from January until November 2009. RESULTS: The results are divided into two categories: 'living with a MFW' and 'feeling different'. These categories demonstrate how it is to live with the unpredictability, and uncontrollability of a MFW due to symptoms such as malodour, bleeding, exudate, pain and itching. The loss of control of the body boundary due to uncontrollable symptoms led to significant levels of distress and suffering for the patients. Different coping strategies were used to live with this wound. CONCLUSION: This study demonstrates how difficult it is to live and cope with a malignant fungating wound. Coping strategies, including going into isolation, or denying any issues, were used. When taking care of patients with MFWs, strategies need to integrate a palliative, holistic, empathic approach. PMID- 24159658 TI - A review of PU prevalence and incidence across Scandinavia, Iceland and Ireland (Part I). AB - OBJECTIVE: To provide a critical appraisal and synthesis of the published literature pertaining to pressure ulcer (PU) prevalence, incidence and prevention practices from the context of Scandinavia, Iceland and Ireland. METHOD: An integrative research review following Cooper's five stages. Studies published in peer-reviewed journals, involving any study design, but specifically exploring PU prevalence or incidence in adults or children, in any care setting, were included. RESULTS: Fifty-five papers were data extracted, quality appraised and included in the qualitative synthesis of the review. Mean prevalence in Norway was 17% (4.8-29%) in Ireland was 16% (4-37%), in Denmark was 15% (2.2-35.5%) and in Sweden was 25%, (0.04-42.7%). Prevalence in Iceland was 8.9%. In acute care, mean prevalence was 21% (0-42.7%) and in long stay was 12% (2.4-23.7%). Prevalence among hospice patients was 35.7%, and in community care was 0.04% and 4%. No incidence study from Iceland was identified; the single incidence study from Norway noted a figure of 16.4%. The mean incidence from Ireland was 11% (8 14.4%) from Sweden was 20% (3.1-49%) and Denmark was 1.8% (1.4-2.7%). Mean incidence in acute care setting was 17.6%, (1.4-49%); in long stay was 6.63% (3.1 8.4%). Incidence in the hospice setting was 20.4%. No study reported PU incidence figures from the community setting. CONCLUSION: Figures for both prevalence and incidence were similar in Ireland and Norway and highest in Sweden, whereas Denmark demonstrated the lowest incidence rates and Iceland demonstrated the lowest prevalence rates. Figures were consistently highest in acute care and hospice settings, and lowest in the care of the older person setting. PMID- 24159659 TI - Collagen matrix wound dressings and the treatment of DFUs. PMID- 24159660 TI - Management of post road traffic accident compound leg defects using fasciocutaneous flaps. AB - OBJECTIVE: To highlight the role of fasciocutaneous flaps in the management of leg and foot defects sustained after trauma, in rural India. METHOD: This was a prospective study conducted on patients with traumatic defects of the leg and foot, admitted between May 2001 and April 2007. Selection of flaps was done on the basis of defect size, site and condition of surrounding tissue. Ipsilateral flaps (proximally- and distally-based), contralateral-leg flaps and free flaps (anterolateral thigh and radial forearm) were raised according to standard techniques and wounds resurfaced accordingly. The outcome was considered 'excellent' when there was no flap necrosis and no donor site morbidity, 'good' when there was some infection, either at the donor or recipient site, but no necrosis, 'satisfactory' when partial flap necrosis and 'poor' when there was flap loss. RESULTS: One-hundred and ten patients (86 males and 24 females) with post-traumatic leg defects underwent reconstruction with different fasciocutaneous flaps. The ages of the patients ranged from 6 years to 58 years, with a mean age of 28.2 +/- 11.5 years. Forty cases (37%) underwent immediate reconstruction within the first 72 hours and in 70 cases (63%) delayed reconstruction was done. Hospital stay of the patients ranged from 8 days to 54 days, with a mean of 20.2 +/- 1.9 days. There were no complications recorded at donor site. The overall results were considered excellent in 92 cases (84%), good in 12 (11%), satisfactory in four (3.6%) and poor in two cases (1.8%), where flap necrosis occurred. CONCLUSION: Our results suggest fasciocutaneous flaps are convenient, simple, reliable and easy to manage. The majority of compound leg defects can be reconstructed with fasciocutaneous flaps either from the ipsilateral leg, contralateral leg or in the form of free flaps. PMID- 24159661 TI - Treatment of ulcerated necrobiosis lipoidica with ovine forestomach matrix. AB - Necrobiosis lipoidica (NL) results from degradation of the collagen extracellular matrix; these recurring ulcerated lesions are an especially challenging condition to treat. Ovine forestomach matrix (OFM) is a decellularised extracellular matrix and was used to successfully close a pretibial ulcer resulting from NL. Complete closure of the wound was achieved in 22 weeks, after four applications of OFM. This suggests OFM may be considered for the treatment of these challenging wounds. PMID- 24159662 TI - [Treatment of endocarditis and spondylitis caused by Enterococcus faecalis with continuous intravenous infusion of ampicillin]. PMID- 24159664 TI - Outbreak news. Wild poliovirus in the Horn of Africa. PMID- 24159663 TI - [Emergency hospitalization caused by fever-70's woman with short bowel syndrome]. PMID- 24159665 TI - Meeting of the International Task Force for Disease Eradication - July 2013. PMID- 24159666 TI - WHO Statement on the third meeting of the IHR Emergency committee concerning Middle East respiratory syndrome coronavirus (MERS-CoV). PMID- 24159667 TI - Recommended composition of influenza virus vaccines for use in the 2014 southern hemisphere influenza season. PMID- 24159668 TI - Antigenic and genetic characteristics of zoonotic influenza viruses and development of candidate vaccine viruses for pandemic preparedness. PMID- 24159669 TI - Monthly report on dracunculiasis cases, January - August 2013. PMID- 24159670 TI - [Relationship and bonding]. PMID- 24159672 TI - Perspectives. PMID- 24159673 TI - Diffusion model applied to postfeeding larval dispersal in blowflies (Diptera:Calliphoridae). AB - This paper presents a diffusion model of larval dispersal specifically designed to account for particular aspects of postfeeding larval dispersal from the food source in organisms such as blowflies. In these organisms the dispersal of immatures includes two groups of individuals, those that are actively migrating and those that have initiated the pupation process. The classical diffusion equation in one dimension was modified to incorporate a function which describes the burying of larvae to become pupae. The analytical solution of this equation predicts oscillatory and monotonic dispersal behaviors, which are observed in experimental populations of blowfly species. PMID- 24159674 TI - Behavior of Biomphalaria glabrata Say, 1818 (Gastropoda: Planorbidae) - 1. Morphophysiology of the mantle cavity. AB - Using longitudinal and transverse anatomical sections, we observed that the three cristae of the mantle of Biomphalaria glabrata (renal, rectal and dorsolateral cristae) divide the mantle cavity into three chambers which we designated air or pulmonary chamber, water inflow chamber and water outflow chamber. Using videotape filming, we observed the inflow and outflow of air and water into and from the mantle cavity and we related their probable functions such as flotation, oxygen reservoir and transport, excreta circulation and elimination, water skeleton, and modification of specific weight. To determine whether the air bubble may function as a physical gill in this species we submitted three groups of snails to different systems in which water contained the same level of dissolved oxygen whereas the gas phases were atmospheric air, pure nitrogen or pure oxygen. We observed the following parameters: timer of permanence on the surface, time of immersion, and frequency at which the snails reached the surface. These results did not demonstrate a physical gill function; morphological analysis of the mantle cavity indicates this possibility. PMID- 24159675 TI - [Guidelines for iodinated contrast in a patient with CKD 2012]. PMID- 24159676 TI - Knock their socks off! A nurse practitioner's approach to care. PMID- 24159677 TI - The importance of continuing education. PMID- 24159678 TI - Chatter with a CE junkie. PMID- 24159679 TI - Know & tell. The top 5 sexual harassment pitfalls. PMID- 24159680 TI - Rallying for dentistry: Perception is reality. PMID- 24159681 TI - Informative and motivational insights regarding mid-level care providers in dentistry. PMID- 24159682 TI - One is never too old to learn. PMID- 24159683 TI - Sinus floor elevation with crestal approach and immediately loaded post extraction implants. AB - Alveolar ridges in the posterior maxilla are often compromised by reduced bone volume. This anatomic condition often limits dental implant placement, mostly because of limited vertical bone availability without prior or simultaneous sinus augmentation. When at least 5 mm of residual bone are present, osteotome techniques are used as a less invasive alternative to the lateral window approach to increase bone volume in the posterior posterior region of the maxillary jaw. Implants are generally placed simultaneously for four to six months after performing osteotome-mediated sinus floor elevation, depending upon the residual crestal bone remaining beneath the sinus floor. However, unlike common indications, in order to shorten the treatment period, this report aims to show a challenging case where, through a thorough surgical protocol, two compromised maxillary teeth were replaced by two immediately loaded post-extraction implants contextually to an osteotome-mediated sinus floor elevation. PMID- 24159684 TI - Operation: stand down. Indiana dentists donate oral heclth to veterans. PMID- 24159685 TI - Three guidelines for avoiding dental malpractice. PMID- 24159686 TI - ...and the pursuit of Happiness. PMID- 24159687 TI - Cytotoxic effect of aspartame (diet sweet) on the histological and genetic structures of female albino rats and their offspring. AB - The present study evaluated the effect of aspartame intake on the histological and genetic structures of mother albino rats and their offspring. Sixty adult female albino rats and 180 of their offspring were equally divided into two groups (control and treated), each group divided into three subgroups. Each subgroup consisted of 10 pregnant rats and 30 of their offspring. The experimental design divided into three periods: (1) the gestation period (subgroup one), (2) the gestation period and three weeks after delivery (subgroup two) and (3) animals in the third subgroup treated as subgroup two then left till the end of the ninth week after delivery. Each pregnant rat in the treated subgroups was given a single daily dose of 1 mL aspartame solution (50.4 mg) by gastric gavage throughout the time intervals of experimental design. At the end of each experimental period for control and treated subgroups, the liver of half of both control and treated groups were subjected for histological study while the liver and bone marrow of the other halves were subjected for cytogenetic studies. Body weight of both groups were recorded individually twice weekly in the morning before offering the diet. The results revealed that the rats and their offspring in the subgroups of control animals showed increases in body weight, normal histological sections, low chromosomal aberration and low DNA fragmentation. The treated animals in the three subgroups rats and their offspring revealed decreases in body weight, high histological lesions, increases in the chromosomal aberration and DNA fragmentation compared with control groups. In conclusion, the consumption of aspartame leads to histopathological lesions in the liver and alterations of the genetic system in the liver and bone marrow of mother albino rats and their offspring. These toxicological changes were directly proportional to the duration of its administration and improved after its withdrawal. PMID- 24159688 TI - Biodiversity of microalgae in Western and Eastern Ghats, India. AB - The systematic study was conducted on the microalgal flora of Western Ghats and other parts of Eastern Ghats revealed a rich wetland algal resource for biotechnological exploration. The present study reveals with the diversity of microalgal flora in the region of Kodaikanal (10 degrees 14' N, 77 degrees 28' E), Gudalur (9 degrees 19'N 77 degrees 12'E), Agasthiyar falls (9 degrees 58'N, 78 degrees 10'E) and Kolli hills (10 degrees 12'N, 77 degrees 56'E) located in Western and Eastern Ghats of Tamilnadu, India collected in May 2011. In total, 97 species of micro algae belonging to three taxonomic groups were identified, of which 41 species belonging to Cyanophyceae, 38 species from Chlorophyceae and 18 species from Bacillariophyceae. The predominant species in Cyanophyceae were Aphanothece microscopica, Chroococcus minutus, Coelospharium dubium, Hydrococcus rivularism, Oscillatoria princeps, Nostoc muscorum, Nostoc puncteforme, Nostoc commune, Gleotricha gausii, Calothrix braunii, Rivellaria sp., Tolypothrix tenuis, Scytonema schmidtii, whereas in Chlorophyceae, Chlorella sp., Scenedesmus sp., Pediastrum duplex, Cosmarium consperum, Euastrum elagans, Micrasterias americana and in Bacillariophyceae, Navicula hallophyla, Rhophaldia gebrella, Fragellaria intermedia, Pinnularia virdis, Nitzchia palliate. Physicochemical nature of water samples were analyzed and correlated with the total microalgal diversity. Based on the correlation coefficient data, the micro algae showed positive relationship with dissolved oxygen, salinity, nutrients and negative relationship with temperature and turbidity. The species diversity index (H'), Species Richness (SR) and species evenness (J') were calculated and analyzed for microalgal population dynamic variation in the Western and Eastern Ghats. PMID- 24159689 TI - Geographic distributions and ecology of ornamental Curcuma (Zingiberaceae) in Northeastern Thailand. AB - The genus Curcuma is a very important economic plant. Members of this genus were used as food, medicine and ornament plants. The objectives of this study were to examine the geographic distributions and ecological conditions in the natural habitats of Curcuma in Northeastern Thailand. Species diversity was examined using the line transect method. Ecological conditions of the species were examined using a sampling plot of 20 x 20 m. A total of five species were found including Curcuma angustifolia Roxb., C. alismatifolia Gagnep., C. gracillima Gagnep., C. parviflora Wall. and C. rhabdota. These species were in an altitudinal range between 290 m and 831 m above sea level. Four species (C. angustifolia, C. alismatifolia, C. gracillima and C. rhabdota) were distributed in open gaps in dry dipterocarp forest. One species, C. parviflora was found in the contact zone between dry dipterocarp and bamboo (Gigantochloa sp.) forest. C. rhabdota was found only in a habitat with high humidity and shading along the Thailand-Lao PDR border. Significant ecological conditions of the natural habitats of these Curcuma species were identified. Altitude is the most important factor when determining the geographic distributions of these Curcuma species in Northeastern Thailand. PMID- 24159690 TI - Effect of vitamins A, E and C on liver enzyme activity in rats exposed to organophosphate pesticide diazinon. AB - Diazinon, a commonly used organophosphorus pesticide, has been widely used throughout the world in agriculture and horticulture to control insects that feed on crops, ornamentals, lawns, fruits, vegetables and other food products. The toxicity of the DZN causes adverse effects on many organs. The purpose of this study was to examine the protective effect of vitamins A, E and C on liver enzymes alanine transaminase (ALT), Aspartate aminotransferase (AST) and Lactate Dehydrogenase (LDH) in rats exposed to diazinon. In this study, male wistar rats were randomly divided into 10 different groups. The groups were administered normal saline, soybean oil (as the solvent for diazinon and fat-soluble vitamins), diazinon, (30 mg kg(-1), vitamins E, C and A (100, 500 mg kg(-1) and 400 IU kg(-1), respectively) and a combination of diazinon with the same dose of each vitamin intraperitoneally i.p.daily for 14 days. Seven days after the final injection, the animals were anesthetized and blood samples were taken. The photometric method was used to measure the activity of the enzymes. The activities of ALT and AST in the diazinon group were significantly higher than that observed in the control group; however, the diazinon/vitamin E, A, C group displayed significant reduction in ALT and AST activities compared to the diazinon group. The lowest level of LDH enzyme activity was observed in the dazinon/vitamin C group and this was statistically lower than the diazinon group. The results of this study revealed that vitamin E, A and C have a potent protective effect against diazinon-induced hepatotoxicity in rats, which may be due to the scavenging of free radicals and increased antioxidant status. PMID- 24159691 TI - Effect of hysteroscopy before intra uterine insemination on fertility in infertile couples. AB - Uterine disorders like usual infertility factors (male factor, ovarian and tubal problems of women) may affect the outcome of infertility treatment in infertile patients. In our clinical trial, 110 couples diagnosed with infertility were candidate for intra uterine insemination (IUI). The patients were divided randomly into two equal groups (n = 55): In group one (control group), patients without hysteroscopy underwent ovulation induction by clomiphene citrate and hCG followed by intrauterine insemination. The second group (experiment group), patients were undergoing hysteroscopy before intra uterine insemination on the day 21 of the cycle and due to abnormal findings, going under surgical treatment if they needed. The rates of pregnancy complications in patients were evaluated. The age, BMI, kind of infertility, duration of infertility, number of previous trial, duration of stimulation, the type of procedures used and semen analysis (TMC, Motility and morphology of sperm) were similar for both groups and no statistically significant differences emerged at all between them. In experimental group, hysteroscopy revealed pathology in the uterine cavity in 26 out of 55 cases. The overall rates of clinical pregnancy were higher in experimental group compared to the control group. The findings from this study showed that the use of hysteroscopy as a diagnostic or therapeutic procedure before IUI, can increase the rate of pregnancy and finally decrease the failure rate of infertility treatment and perinatal complications in infertile couples. PMID- 24159692 TI - Lipid profile of women using oral contraceptive pills. AB - Oral contraceptives (OCs) are the most popular type of birth control pills. The study was designed to examine the biochemical changes which occur due to the use of oral contraceptive pills (OCs). The study was based on the questionnaire for having the information of any reproductive history fasting, age, health, nature of menstrual cycle, bleeding, disease etc and blood profiling for biochemical analysis of the women includes high density lipoprotein cholesterol (HDL-C), low density lipoprotein cholesterol (LDL-C), total cholesterol (TC) and triglycerides (TG). Lipid profiling was carried out by using a commercially available diagnostic test kits. SPSS was used to analyze the data. The results showed statistically significant differences among users of OCs compared to non-users. Total cholesterol (242.92 +/- 2.842 mg dL(-1)), HDL-C (58.65 +/- 1.098 mg dL( 1)), LDL-C (115.84 +/- 1.266 mg dL(-1)) and triglycerides (105.56 +/- 2.341 mg dL(-1)) were significantly higher compared to the non-users (Total cholesterol 218.49 +/- 1.762, HDL-C 48.17 +/- 0.543, LDL-C 100.321 +/- 0.951 and triglycerides 83.77 +/- 2.299 mg dL(-1)). The result suggests that OCs increase the level of high density lipoprotein cholesterol (HDL-C), low density lipoprotein cholesterol (LDL-C), total cholesterol (TC) and triglycerides (TG). PMID- 24159693 TI - Preliminarily comparison of nutritional composition of some fresh and processed seafood. AB - Processing made fish less susceptible to spoilage. Fish are rich in protein content but the protein content is reduced with processing gave a better result when long-time preservation was carried out. Aim of this study was comparison of proximate analysis of some fresh and processed seafoods. Raw materials and processed seafoods (canned mackerel tuna, frozen Sea-Bream and Pressed caviar) were obtained from different firms and analyzed. Analysis carried out according AOAC methods. Moisture, protein and fat values of tuna fish were estimated to be 51, 23.9 and 21.4%, respectively. In this study, moisture content of pressed caviar was 36%, protein content was 34.4% and fat content was 16.7%, carbohydrate and energy values were 4.9% and 316 kcal/100 g, respectively. Pressed and smoked seafoods contained lower amount of moisture but higher amounts of the other components than raw materials (p < 0.05). Canned mackerel tuna, frozen sea bream and pressed caviar also contained higher amounts of fat, carbohydrate and energy, respectively (p < 0.05) than raw material. Except canning with water, all processing technologies decreased the moisture content but increased energy values (p < 0.05) of the fish. It is concluded that processed seafoods are rich in chemical components and very nutritive. Canned tuna with salted water may be advised for low-calorie diets. Caviar pressed was one the best sea foods that was produced in Iran. Since fishes are consumed as a major protein source in food, it is very important that the protein content should not be compromised during table preparation. PMID- 24159694 TI - In praise of MOM. PMID- 24159695 TI - Excited about the MOM. PMID- 24159696 TI - Grateful patients at MOM. PMID- 24159697 TI - Doesn't support fluoridation. PMID- 24159698 TI - Tips for school lunches that will keep your child smiling. PMID- 24159699 TI - Will we accept change? PMID- 24159700 TI - Providing dental records to patients with past-due accounts. PMID- 24159701 TI - Survey says.... PMID- 24159702 TI - Caring for former patients at a new practice. PMID- 24159703 TI - 10 ways you can lead by example. PMID- 24159704 TI - Why the Mission of Mercy matters? PMID- 24159705 TI - Dental management of patients taking oral bisphosphonates and other antiresorptive agents. PMID- 24159706 TI - Atypical presentation of bilateral maxillary supplemental lateral incisors: A rare case report. AB - Hyperdontia presents as a unique dental condition which may or may not require immediate corrective therapy. Supplemental teeth in the permanent dentitian comprises only 4% of all the supernumeraries, and bilateral supplemental teeth are even rarer entities. We present a rare case report of non-syndromic bilateral supplemental maxillary lateral incisors. PMID- 24159707 TI - When it comes to practice space, owning is better. PMID- 24159708 TI - [PMS and PMDD]. AB - The symptoms of premenstrual syndrome (PMS) and premenstrual dysphoric disorder (PMDD) significantly impair daily functioning. Symptoms occur in the late luteal phase. There must be a symptom-free interval between the end of menstruation and the time of ovulation. A two-month daily rating of symptoms is required for the diagnosis. The etiology is not well-known. Premenstrual disorders do not occur in anovulatory states. Hormonal therapy suppressing ovulation and selective serotonin reuptake inhibitors (SSRIs) are effective treatments. PMS and PMDD can be successfully managed in general practice. PMID- 24159709 TI - [Autoimmune hepatitis]. AB - Autoimmune hepatitis is chronic liver disease with two subtypes, type 1 with anti nuclear or smooth muscle antibodies and type 2 with LKM1 or LC1 antibodies, and both with hypergammaglobulinemia and typical histology. Prevalence of AIH is between 10 to 17 per 100000 in Europe. Up to 20-40 % of cases present with acute hepatitis. Budesonide can be used as a first line induction therapy in non cirrhotic patients, and tiopurines, mercaptopurine or mycophenolic acid as maintenance therapies. Patients not responding to conventional therapy can be treated with ciclosporin, tacrolimus or rituximab or finally with liver transplantation. PMID- 24159710 TI - [Virtual support for problem gamblers]. AB - Low threshold virtual support is an emerging form of treatment for problem gamblers. The advantages of virtual support are cost-efficacy and good availability. A special advantage of web-environment is the possibility to modify the virtual support programs separately for diverse subgroups of problem gamblers. PMID- 24159712 TI - [Update on current care guideline: gestational diabetes]. AB - Gestational diabetes screening using a 75 g oral glucose tolerance test should be offered to all pregnant women, except those who are at low risk. 10-15% of gestational diabetes is caused by LADA (Latent Autoimmune Diabetes in Adults) or MODY (Maturity Onset Diabetes in the Young), in which mothers generally sustain a normal body weight. The diagnostic criteria for gestational diabetes are venous plasma glucose levels > or = 5.3 mmol/l (fasting), > or = 10.0 mmol/I (1 h) and > or = 8.6 mmol/l (2 h). Achieving a normal body weight is crucially important to mothers after delivery. PMID- 24159711 TI - [Tuberous sclerosis]. AB - Tuberous sclerosis is a polymorphic, dominantly inherited syndrome caused by an inactivating mutation in a tumor suppressor gene. The disease involves benign tumors in several distinct organs such as the skin, kidneys, heart and central nervous system. The tumors interfere with organ function, but only some exhibit a significant tendency to grow. The clinical picture of tuberous sclerosis varies from nearly symptomless to a severe disease. Treatment of growing tumors associated with tuberous sclerosis is changing significantly, since their growth can be suppressed with rapamycin and its derivatives. PMID- 24159713 TI - [Chronic pain conditions in foot and ankle region]. AB - New starting points are available for the diagnosis, classification and treatment of prolonged pain conditions in the foot and ankle region. Mechanisms maintaining the pain should be clarified, and a comprehensive patient interview must be conducted. Physical examination shall include static observation, functional tests, passive movement tests as well as provocative and mapping tests. By careful examination and treatment of motor control and movement disorders it is possible to completely refrain from surgical treatment. If surgery has instead been decided upon, the loading defect underlying the problem must also be treated. PMID- 24159714 TI - [Lower limb pain of arterial origin]. AB - With the ageing population and increasing incidence of diabetes, arterial occlusive disease will become more common as cause of lower limb pain. In the diagnosis of limb pain of arterial origin it is essential to distinguish rest pain from intermittent claudication. Rest pain is associated with high risk of amputation and is therefore an indication for examinations within specialized care. First-line treatment of intermittent claudication instead consists of the management of risk factors and guided exercise. Specialized care consultation is required only in case of intermittent claudication which is refractory to conservative treatment and threatening the ability to work and function. Acute lower limb ischemia is always an indication for emergency assessment. PMID- 24159715 TI - [Spinal claudication]. AB - Spinal claudication refers to symptoms caused by nerve compression in the spinal canal brought on during strain. The symptoms are felt as lower limb pain, numbness or fatigue, but back pain that becomes worse under stress is also common. The symptoms are usually associated with the erect position and relieved when sitting or laying down. The underlying condition is most commonly narrowing of the spinal canal. While the diagnosis is often clear, MRI imaging is worth conducting if the symptoms are atypical or cause a clear-cut disability or functional limitation. Most patients are treated conservatively. PMID- 24159716 TI - [Skin problems in a swollen lower limb]. AB - Swollen lower limb is a diagnostic challenge for a physician. Common conditions causing swelling of lower extremities are chronic venous insufficiency and abnormalities in lymph drainage. Stasis dermatitis and lymphedema are manifestations of these defects. The most important therapy of both stasis dermatitis and lymphedema is adequate compression therapy. Patient education is important in order to achieve good compliance with compression therapy. The mainstay therapies of skin eczema are corticosteroids and tacrolimus ointment. Patients with stasis dermatitis have a higher risk for contact sensitization, which is important to remember when prescribing topical treatments. PMID- 24159717 TI - [Venous edema]. AB - Findings of venous insufficiency in the lower limb can usually be detected in connection with venous edema. Realization of compression therapy requires a prescription for stockings, motivation and guidance. In specialized care, correlating the edema and venous symptoms with color Doppler ultrasonography findings is essential. In addition to the assessment of the venous status, functioning of the calf muscle pump should be assessed more profoundly. Impeding symptoms of venous insufficiency or a complicated situation are an indication for invasive treatment. Venous return found in connection with mere edema symptoms or lymphedema is not an indication for invasive treatment. PMID- 24159718 TI - [Dependency syndrome]. AB - The most common causes of lower limb edema include cardiac insufficiency, venous insufficiency, insufficiency of lymph flow, and side effects of drugs. It can also be due to dependency syndrome, in which the edema and skin changes can only be explained by a passive calf muscle pump and the resulting venous hypertension. Underlying the drop foot is always immobilization for one reason or other. The patient must be given an explanation about the situation, activated to move if possible, and in any case guided to the use of support stockings and postural therapy. PMID- 24159719 TI - [Systemic disease as cause of leg swelling]. AB - Symmetrical leg swelling formed in the course of the years is a common and in most cases benign phenomenon that is mostly encountered in the aged population, especially in women. Venous insufficiency of the lower limbs is the most common cause of symmetrical leg swelling among those over 50 years of age. Diseases of the essential organs such as the heart, the liver and the kidneys are excluded during the initial stage. Pitting edema occurs both in venous insufficiency and in right-sided heart failure. Basic tests and drug history are usually sufficient to exclude a host of general causes of the edema. PMID- 24159720 TI - A win for HROs. Employing high-reliability organization characteristics in EMS. AB - Was I insubordinate, arrogant or disrespectful? You may feel that I was. But in reality, I was educated to a level that could have been validated and should have been respected by command. I was, in fact, practicing a key aspect of HRO. I was stopping an obvious dangerous condition before it could harm or kill emergency responders. My IC colleague knew it from the facts presented and, in fact, joked with me about my "subtle sarcasm" and moved the perimeter to the recommended half mile distance. Did I win, or did a proactive HRO win? Actually, HRO won and potentially saved 30 lives. I simply presented the hazards of CFC inhalation. A high-reliability organization must not rely on only one source of data when detailed information on a hazard isn't immediately available, or if it isn't very informative during an emergency decision-making process. Read "EMS & High Reliability Organizing: Achieving safety & reliability in the dynamic, high-risk environment and practice its important principles," pp. 60-63. It's really common sense, not rocket science, and may save you, your crews or others in your community. PMID- 24159721 TI - Re: Provider to patient: One EMT's close call offers lessons for all providers. PMID- 24159722 TI - Kicked in the chest. PMID- 24159723 TI - What's the buzz? Industry buzzwords have crept their way into the EMS world. PMID- 24159724 TI - Rural Colorado care. West Routt Fire Protection District provides BLS & ALS. PMID- 24159725 TI - Dumbness. Are we stuck in heavy-land? PMID- 24159726 TI - One-pill killers. One dose of adult medication can be deadly to children. PMID- 24159727 TI - International EMS. How demand is shifting around the world. AB - The panelists agreed that prehospital systems around the world might very well begin seeing higher demand and lower acuity. However, the unique aspects of each culture that create different prehospital concerns also create different solutions to these needs. U.S. providers must consider for-profit organizations when attempting to reduce fragmentation to gain one lobbying voice, while EMS providers in some nations, such as in Latin America and India, must consider integrating their treatments with local shamens to gain patient acceptance. In Franco-German systems, efficient doctor training has allowed placement of anesthesiologists on ambulances, while prehospital providers in Vietnam have basic concerns, such as whether prehospital care can be sustained in the hospital environment. The shift in EMS around the world will Sdepend more on the expectations and demands of the customers in each nation. It will also depend on the ability of its EMS leaders and administrators to come up with solutions that get customers the most appropriate care in the most affordable manner. To learn more, go to www.jems.com/2020vision. PMID- 24159728 TI - Consortium of care. PMID- 24159729 TI - Scene-safe mantra. Why this common & popular safety assessment should be replaced. PMID- 24159730 TI - EMS & high reliability organizing. Achieving safety & reliability in the dynamic, high-risk environment. AB - Enactment describes how we engage the situation to make sense of it. But by our engagement, we also change the situation. Our presence, alone, will change the situation. At times, we may fail to act. Here, we are at risk of interpreting this as a sense of personal "limitation" in what we can do. This will inhibit us in engaging in other incidents. Rather, we should understand that while we may often fail after engaging, acting is part of performing in uncertainty. In EMS, the system, as it's set up, can lead people to fail to act. For reasons specific to a system, the EMT or paramedic may not act for fear of doing something wrong. This failure to act reinforces the limitations one feels. When you avoid acting, you don't learn. By avoiding testing ourselves, we conclude that constraints exist. This is contrary to the historical approach public safety and EMS personnel use to learn. In the past, it was accepted that we learn what works through action. We also perceive, or sensemake, through interaction with the environment. We watch for responsiveness to our actions, such as cooperation from bystanders vs. defiance. However, this is influenced by how we approach the scene. One EMS provider may obtain cooperation while another experiences defiance. We bracket this information by placing it in context. This interaction is difficult to communicate to those not present at the incident, because they don't know when one "story" begins and when another leaves off. HROs have developed in organizations that adapted to time constraints in uncertain and hazardous environments. There, lessons were actually learned through the blood of live-or-die situations. Academics have codified these principles and concepts that are accessible to EMS caregivers. EMS can benefit from the principles and concepts of HRO through improved performance by individuals and stronger organizations. PMID- 24159731 TI - Eating healthy. Shopping tips to help busy EMS personnel. PMID- 24159732 TI - Whu'sat you say? A lesson in treating deaf & hard of hearing patients. PMID- 24159733 TI - R.I.P. squad bench. European ambulances designed around the patient, not the vehicle. AB - You can see and hear more about my journey throughout Germany and England in a special, archived, free Webcast on jems.com. And in future articles, videos and Web presentations, you'll see and learn about the different EMS delivery models I saw, the men and women whom I met and rode with on calls, and, most importantly, their impressive attitude about patient care, customer service and safety. Progressive American and Canadian ambulance manufacturers now agree with safety experts and forward-thinking ambulance operators that the squad bench is dead. These manufacturers now offer innovative seats that are much safer and functional than those coffin-like obstructions that gobbled up so much space in our rigs for the past three decades. Design your next ambulance around the needs and safety of your crews and their patients, and spec a patient compartment that is laid out logiclaly and efficient. PMID- 24159734 TI - Ambulance safety. Seeking a system to analyze & prevent emergency vehicle crashes. PMID- 24159735 TI - Vehicle checks are easy. Start with the essentials. PMID- 24159736 TI - The swelling airway. Angioedema is not always caused by allergic reaction. AB - The case detailed here is relatively rare but can be life-threatening. EMS personnel identified the case, provided the appropriate treatment presuming it to be an allergic reaction. Later, it was determined to have been caused by angioedema, but the staff believed that the prehospital care led to a more rapid diagnosis and subsequent care. PMID- 24159737 TI - Heat trap. How to treat vehicular hyperthermia in children. PMID- 24159738 TI - No child locked inside. The role of EMS in raising awareness about the dangers of leaving children in hot vehicles. PMID- 24159739 TI - Improving morale from the ground up. Grassroots tips to make your workplace better. AB - In our profession, where we help people every single day, there's no reason to not enjoy coming to work Remind yourself of that as long as it takes to feel it inherently. Keep a positive attitude and make sure you don't feed the workplace morale problem yourself. By keeping an eye on your own needs and making sure you're keeping yourself happy, maintaining this positive attitude can be effortless. Setting the example by your own behavior will induce change in the moods of those around you, whether you know it or not. Good luck, stay safe and have fun out there. PMID- 24159740 TI - Squad to the rescue. Unique EMS/rescue agency uses new heavy-rescue to expand response capability. PMID- 24159741 TI - Delicate condition: Assessing & treating common pregnancy complications. PMID- 24159742 TI - Conversation starters. The missing protocol for alternative pain & anxiety management. PMID- 24159743 TI - Increasing cardiac arrest survival by using data & process improvement measures. PMID- 24159745 TI - The ups & downs of EMS. PMID- 24159744 TI - Seriously? When 9-1-1 callers don't use common sense. PMID- 24159746 TI - [Clinical guidelines, protocols and behavioral rules]. PMID- 24159747 TI - [Fentolamin to prevent bite incidence?]. PMID- 24159748 TI - [Loss of permanent teeth in children]. PMID- 24159749 TI - [Dental focus examination: a proposal for a more nuanced approach]. AB - Oral and maxillofacial surgeons and hospital dentists are often requested to perform a dental focus examination in patients (to be) admitted in a hospital and for whom the state of their teeth is of importance for a medical treatment or situation. The main reasons for a dental focus examination include unexplained fever, heart surgery, chemotherapy, organ or artificial joint transplants, use of oral or intravenous bisphosphonates and radiotherapy of the head and neck. In daily practice, there is a need for a clear algorithm which is easy to apply for the diagnosis and treatment of dentalfoci for the various medical indications. The medical conditions described above have in common that subclinical infections can lead to complications under exceptional conditions. The influence and the nature of the development ofa dental infection varies in each of the situations mentioned. This has consequences for the need to eliminate dentalfoci. The diagnosis and treatment of dental foci in relation to various medical situations therefore requires a nuanced approach. PMID- 24159750 TI - [Oral manifestations of systemic sclerosis]. AB - Systemic sclerosis is a relatively rare connective tissue disorder, in which a severe and progressive fibrosis of the skin and sometimes also of internal organs often develops as a result of an increased deposition of collagen. Fibrosis of the salivary glands may cause hyposalivation and xerostomia. Fibrosis of the perioral skin reduces the maximum opening of the mouth, thereby hampering dental treatment and the maintenance of oral hygiene. Periodontitis and bone resorption ofthe jaws are more frequently observed in systemic sclerosis patients. PMID- 24159751 TI - [Sialendoscopy: endoscopic approach to obstructive salivary gland disease]. AB - Sialendoscopy: endoscopic approach to obstructive salivary gland defects Obstructive defects of the parotid and the submandibular gland often present themselves clinically by mealtime-related swelling of the affected salivary gland, the so-called 'mealtime syndrome'. Salivary ductal obstruction of the parotid and submandibular gland is predominantly caused by the presence of a salivary stone, a mucous plug, or by ductal stenosis. Until recently, diagnostic and treatment options for these obstructive salivary gland defects were restricted. Surgical removal of the affected salivary gland was often the treatment of choice. By applying sialendoscopy, a minimally invasive, semi rigid optical technique, it is possible to diagnose and treat obstructions which are found in the salivary ductal system. In many cases, therefore, the surgical removal of the salivary gland becomes unnecessary. PMID- 24159752 TI - [Three dimensional technology and reconstructions of large defects of the jaw]. AB - 3D technology is increasingly being applied in dentistry and in oral and maxillofacial surgery. An important field of application is reconstructive surgery, especially in the reconstruction of large defects ofthe jaw. In such cases of reconstruction, the goal is the restoration of both the continuity of the defective area and its function. For the functional restoration implant supported dental structures are often employed. In such cases, CAD/CAM superstructures, 3D printed drill and saw templates, anatomical models, wafers and surgical outcome models are used. The combination of the digital planning and the digital fabrication ofsuperstructures and surgical aids offers many preoperative advantages. The use of saw, drill and positioning templates provides for accurate segmentation and implant positioning, by means of which the reconstruction can be carried out in a predictable way. PMID- 24159753 TI - [Maxillomandibular advancement surgery as an optional therapy for patiens with severe obstructive sleep apnoea]. AB - Obstructive sleep apnoea (OSA) is a common chronic disorder which often requires lifelong treatment. Its prevalence in the Netherlands is estimated to be around 300.000 people. In this study 12 patients with severe OSA were treated with maxillomandibular advancement surgery between 2011 and 2012. The mean advancement during surgery was 8.7 mm and the mean postoperative admission was 4 days. All patients underwent polysomnography at 3 months. Three months after surgical treatment, the apnoea-hypopnea index had decreased with 74.9% (57.3 to 14.4). The subjective sleepiness of the patients had also decreased with a mean of 57.5%. The literature indicates comparable results in patients with severe OSAS, specifically a reduction of the apnoea-hypopnea index of 80-90%. Considering the successful results following maxillomandibular advancement surgery, this therapy is an appropriate alternative for patients who cannot cope with 'continuous positive airway pressure' or patients who want a permanent therapeutic solution. Further research is recommended to achieve higher levels ofevidence for maxillomandibular advancement surgery in patients with OSA. PMID- 24159754 TI - [Oral medicine 9. Lichen planus and lichenoid lesions of the oral mucosa]. AB - The general dentist is sometimes confronted with white lesions of the oral mucosa. Oral lichen planus is the most common oral white lesion. The diagnosis can usually be made on the basis of the clinical aspect, but is sometimes made more difficult by certain abnormalities in the oral mucosa which clinically resemble oral lichen planus or by abnormalities which cannot be distinguished from oral lichen planus but have a different origin. Those lesions are classified as oral lichenoid lesions. Malignant deterioration has been described in allforms of oral lichen planus lesions and oral lichenoid lesions. There is no known method to predict or prevent malignant transformation. Nor are there any studies examining the efficacy of frequent follow-up visits. It seems sensible, in keeping with the tendency in recent literature, to schedule annual check-ups for patients to be on the safe side. These follow-up visits may reasonably be performed in a general dental practice. PMID- 24159755 TI - [Dentistry and healthcare legislation 5. Confidentiality and privacy]. AB - The right to confidentiality and privacy is established in various laws and in many cases the violation of these laws provokes a reaction in the form of severe sanctions. Nevertheless, patients complain relatively seldom about violations ofprivacy laws by dentists. The right to privacy consists of a requirement of confidentiality on the part of those carrying out treatment and the patients' right to be treated without being observed by third parties. 'Third parties' do not include those involved in the treatment or someone who represents the patient. The right to confidentiality can be violated if a patient grants consent, in cases of a legal requirement or in cases ofa conflict of requirements. A separate regulation exists concerning the confidentiality and privacy of patients in the context of scientific research. PMID- 24159756 TI - [Analysis of the results of urinary incontinence treatment in women using free suburethral synthetic sling: the experience of 1000 operations]. AB - The study presents an analysis of the experience of treatment of urinary incontinence in women using free synthetic suburethral sling. Between 2001 and 2008, 1081 patients underwent surgery. Of these, 841 (77.8%) suffered from stress urinary incontinence, 202 (18.62%) suffered from the mixed form of urinary incontinence with a predominance of the stress component, and 38 (3.52%) had recurrent urinary incontinence. Group 1 included patients with stress urinary incontinence who underwent surgery using suburethral synthetic sling with retropubic access (TVT operation); Group 2 included patients, who underwent surgery using suburethral sling implanted with transobturator access (TVT-O operation). Group 3 consisted of patients with mixed urinary incontinence, who underwent TVT-O operation. Retropubic suburethral TVT sling was implanted in 273 (25.25%) patients, transobturator TVT-O sling--in 740 (68,45%) patients, and other synthetic suburethral slings--in 68 (6.3%) patients. The average follow-up period was 50.1, 31.1 and 32,6 months in each group, respectively. Cough test was used for the objective evaluation of the effectiveness, and visual analogue scale -for the subjective evaluation of effectiveness. In the TVT group, the negative cough test in the postoperative period remained at 85.58% of the patients, and in in TVT-O group--in 84.36% of patients. Analysis of the frequency of intraoperative complications showed that the probability of occurrence of complications was not associated with age, body mass index and obstetric history of patients. It was noted that the perforation of the bladder and pelvic hematoma were more likely to occur when using the retropubic access. Transobturator access is associated with a higher risk of injury of the lateral vaginal fornix, although bladder injury is not ruled out. Objective and subjective indicators of efficacy of treatment of mixed form of urinary incontinence were 86.15 and 87.69%, respectively. The study suggests that the operations using suburethral TVT and TVT-O slings are safe and effective methods of treatment of stress urinary incontinence in women. PMID- 24159757 TI - [Erosions of the vaginal, bladder and urethral mucosa after transvaginal correction of genital prolapse and stress urinary incontinence using synthetic materials]. AB - The article presents the results of treatment of 13 women with erosion of the vaginal mucosa with an exposure of the part of prosthesis and 4 women with the migration of fragments of the prosthesis into the lumen of the bladder or urethra after surgical correction of genital prolapse and stress urinary incontinence with the use of synthetic materials (Prolift, TVT operations). Interventions included the removal of part or all prosthesis from zone of erosion of the vaginal mucosa and removal of prosthesis migrated into the lumen of the bladder or urethra. Good results of operations were achieved in all cases. 8-12 months after surgery, recurrence of erosion and migration of prosthesis into the lumen of urinary organs were not observed. PMID- 24159758 TI - [The microbial spectrum of urine and bladder bioptic samples in women with chronic recurrent cystitis]. AB - The evaluation of urine and bladder bioptic samples (bacteriological examination and polymerase chain reaction) of 28 women with chronic cystitis was performed. In 85.7% of cases, mixed infections with predominance of nonclostridial anaerobes in the urine was detected. Herpes simplex virus type 1 was detected in 7.1% of cases. In the same manner as in urine, predominance of nonclostridial anaerobes in bladder bioptic samples (85.7%) was observed. Identical bacteria in urine and bladder bioptic samples were revealed in 64.3% of patients. Herpes viruses and papillomaviruses were frequently registered (p < 0.05) in the bioptic samples. PMID- 24159759 TI - [Rehabilitation of patients with urolithiasis after minimally invasive procedures on the kidneys]. AB - Minimally invasive surgeries in patients with urolithiasis are not always successful. Prevention of inflammatory and cicatrical-sclerotic complications in the postoperative period plays an important role. 49 patients with urolithiasis divided into two groups were followed-up. The study group included 25 patients who underwent percutaneous puncture nephrolitholapaxy. The control group consisted of 24 patients with a history of percutaneous puncture nephrolitholapaxy. In postoperative period, active prevention of inflammation and cicatrical-sclerotic complications using drug Longidaza in combination with magnetic-laser therapy was performed in study group. The control group received standard treatment. 6 months after surgery, 1 (4%) patient in the study group had pyeloectasis approximately 2 cm and obstruction of UPJ of operated kidney, which required re-treatment with Longidaza. In the control group, pyeloectasis and violation of passage through the upper urinary tract were recorded in 4 (16.7%) patients. These data allow to recommend a comprehensive prevention of postoperative inflammation and cicatrical-sclerotic complications using Longidaza and magnetic-laser therapy in patients undergoing minimally invasive surgery of the kidney. PMID- 24159760 TI - [The structure of urological disorders in athletes]. AB - According to the data of preventive medical examinations since the end of 2009 to April 2012, data on the urological incidence in 654 athletes surveyed during this period were collected and analyzed. Among the diseases identified in athletes, the main place is occupied by varicocele (5.35%), urethritis (5.04%), urolithiasis without clinical manifestation of acute inflammation (1.37%). PMID- 24159762 TI - [The results of the 10-year study of efficacy and safety of Serenoa repens extract in patients at risk of progression of benign prostatic hyperplasia]. AB - The article presents the results of an open, noncomparative, observational study of the efficacy and safety of continued use of the Serenoa repens (prostamol uno) plant extract at a dose of 320 mg 1 time a day for 10 years in 38 patients with early manifestations of BPH and the risk of its progression. The results of study showed the absence of progression, both on subjective criteria (IPSS, and QoL scores), and objective criteria (prostate volume, the rate of urination, residual urine volume). Furthermore, patients had no undesirable effects directly related to the use of this drug. PMID- 24159761 TI - [Efficiency of uroprofit in women with chronic cystitis]. AB - From September 2011 to December 2011, 40 women aged 20-68 years with chronic cystitis were examined. All patients were divided into two groups of 20 people depending on the type of treatment. Control group of patients received monotherapy with fosfomycin (monural), main group of patients--complex therapy with fosfomycin and biologically active supplement uroprofit. The results were evaluated at 1 and 2 months after initiation of therapy. Before and after treatment, all patients were examined, including standard laboratory tests, uroflowmetry, cystometry, and cystoscopy. It was shown that patients in main group have a rapid normalization of clinical manifestations and laboratory parameters, improvement of dynamics of the endoscopic picture. Thus, uroprofit has antibacterial, anti-inflammatory action, contributes to the normalization of urodynamics of the lower urinary tract, reduces the risk of relapses of chronic cystitis and can be recommended as a component of the treatment of acute exacerbations of chronic cystitis, as well as a drug for the prevention of disease in the disease-free interval. PMID- 24159763 TI - [Experience of male transobturator AdVance sling implantation in patients with stress urinary incontinence after radical prostatectomy]. AB - For the period from April 2008 to March 2012, 12 men with mild-to-moderate and severe stress urinary incontinence underwent transobturator AdVance sling implantation. In the preoperative period, all patients underwent assessment, including history taking, physical, and instrumental and laboratory examination. Daily pad test was used as an objective method for the assessment of the degree of urinary incontinence. The use no more than one pad a day was considered as recovery, no more than 2 pads or reduction of the loss of urine by more than 50%- as an improvement. Median follow-up period was 28 months. The success of the operation was achieved in 91.7% of cases. Implantation of the sling led to the significant decrease of urine loss, the number of used pads and improvement of quality of life of patients. Infectious and inflammatory complications of acute urinary retention were not observed. Implantation of male transobturator AdVance sling is effective and safe treatment for patients with stress urinary incontinence after radical prostatectomy. PMID- 24159764 TI - [Application of udenafil for the correction of endothelial disorders in patients with stress-induced erectile dysfunction]. AB - The study was aimed to the evaluation of vascular endothelium status in patients with stress-induced arterial hypertension, coupled with erectile dysfunction (ED). 51 patients underwent examination. Laurent--Segal Male Copulative Function Questionnaire (MCF), and International Index of Erectile Function (IIEF) were used for the detection of ED and assessment of its severity. Microcirculation in penile vessels was evaluated by laser Doppler flowmetry. Markers of endothelial function--endothelin 1 and asymmetric dimethylarginine-were measured. For the correction of violations identified, the drug udenafil (zydena) was used at a dose of 50 mg daily for 1 month. Against the background of therapy with udenafil, restoration of function of endothelial cells was detected. This suggested the functional nature of the violations in the genital sphere, and was regarded as a manifestation of stress-induced ED. Elimination of endothelial dysfunction led to significant reduction in ED symptoms. PMID- 24159765 TI - [Experience of the use of silodosin in acute urinary retention caused by benign prostatic hyperplasia]. AB - For the treatment of acute urinary retention (AUR) as one of the most serious complications of adenoma of the prostate (BPH), alpha-adrenoblockers are widely used. The article presents an experience of the use of the new uroselective alpha adrenoblocker silodosin approved for the treatment of patients with urination disorders caused by BPH. Its pharmacological profile has a number of advantages, including the highest uroselectiveness at the present day, immediate action, the potential for the use of standard dose of 8 mg 1 time a day, which does not require a correction depending on the age, and the possibility of the simultaneous application with antihypertensive drugs. PMID- 24159766 TI - [Endothelium-dependent and endothelium-independent vasodilation in patients with chronic prostatitis]. AB - Using laser Doppler flowmetry, basal blood flow in patients with chronic prostatitis was evaluated. 90 men with chronic prostatitis and 30 healthy men of reproductive age underwent examination. For the assessment of endothelial vasomotor function, ionophoretic tests with 5% acetylcholine and 5% sodium nitroprusside were performed. Results of the study suggested a violations of the skin vasomotor activity in patients studied, which indicated a decrease in reserve capacity of the microvasculature both in bacterial and abacterial genesis of chronic prostatitis. PMID- 24159767 TI - [Destructive changes in the mice testes in retrograde infection with herpes simplex virus]. AB - Herpes simplex virus (HSV) causes inflammatory diseases of the genitourinary system of males, infects male sex cells, and its presence in the ejaculate is associated with infertility. However, information on the pathways of HSV in the testicles, the extent of damage of spermatogenic tissue and the effect on spermatogenesis are insufficient. This work was aimed to the evaluation of effect of HSV on mice spermatogenesis in retrograde infection with the virus. Molecular (RT-PCR), virologic, morphological and immunohistochemical methods were used. Analysis showed that after virus inoculation directly into seminiferous tubules the viral protein is found in all layers of seminiferous epithelium. On the third day of infection the proportion of tubules containing HSV protein was 4.9%, reached a maximum on day 6 - 23,5 and 18% for the high and low doses of HSV, respectively, and then decreased; viral protein was not detected on 21th and 45th day. HSV DNA was detected in the testes at all stages of infection. Since the 14th day after infection, testes weight was significantly reduced compared to the control: 7,9-fold decrease at 45th day with a high dose of HSV, and 4,9-fold decrease with low dose. The infection with HSV led to the development of orchitis and considerable destructive changes in the spermatogenic tissue. The proportion of morphologically normal tubules was reduced to 6 and 15% at day 14 and remained at a low level up to 45th day. Approximately half of the seminiferous tubules (46.5%) at the 14th and 21th day had no somatic Sertoli cells needed for the restoration of spermatogenic tissue. These data suggests that retrograde infection of male gonads with HSV leads to the structure damage of testis and death of germ and somatic cells, indicating the irreversibility of degenerative changes in infected testes. PMID- 24159768 TI - [Extracorporeal partial nephrectomy for kidney neoplasms]. AB - The results of 11 extracorporeal partial nephrectomies for neoplasm with subsequent autologous transplantation of kidney are presented. In 4 patients, resection was performed ex vivo in the presence of a large centrally located tumor in a solitary kidney. Another two patients had bilateral tumor process. In 2 patients, a large, centrally located tumor in solitary kidney was the indication for extracorporeal resection. 3 patients had elective indications for the operation. Early postoperative complications occurred in 5 patients. 3 patients had oligoanuria. One patient developed postoperative bleeding; one patient developed obliteration of the upper third of ureter. Recurrence of renal cell cancer has not been identified; the functional state of the kidney vessels and vessels of upper urinary tract was regarded as satisfactory. Good results of these operations indicate the feasibility of expanding the indications for extracorporeal organ-sparing surgery. PMID- 24159769 TI - [Laparoscopic transperitoneal and retroperitoneal partial nephrectomy]. AB - The article presents a modern approach to partial nephrectomy, and evaluation of individual results of laparoscopic partial nephrectomies. The study included 38 patients who underwent laparoscopic partial nephrectomy in the period from 2006 to 2011. Kidney cancer was diagnosed in 30 patients, other diseases--in 8. Mean duration of surgery was 225 min. Warm ischemia time was less than 36 minutes. The average postoperative period was 8,7 days. Despite the technical difficulties in the development and implementation of laparoscopic partial nephrectomy, the benefits of minimally invasive techniques are obvious, and the operation can comply with all the principles of oncology and become an alternative to open surgery. PMID- 24159770 TI - [Laparoscopic partial nephrectomy using local ischemia]. AB - Oncological outcomes of laparoscopic partial nephrectomy are no worse than those after open sparing operation for kidney cancer. However, laparoscopic procedures are accompanied by a longer warm ischemia. In order to reduce the ischemic injury, local ischemia by isolation and temporary clamping of the individual branches of the renal artery was used. From January 2009 to June 2012, 60 laparoscopic partial nephrectomies were performed in the clinic, including 34 resections with temporary clipping of renal artery and 26 resections with temporary clipping of secondary and tertiary segmental and subsegmental branches. Functions of affected kidney were evaluated before and after surgery in both groups of patients. At 3 months after surgery, significantly lower decline of the function of affected kidney was observed in patients who underwent resection with the use of local ischemia compared with patients who received the intervention accompanied by a temporary clamping the renal artery. Partial nephrectomy using local ischemia can significantly expand the indications for laparoscopic and retroperitoneoscopic sparing operation for renal cell cancer. PMID- 24159771 TI - [The use of laser vaporization for the treatment of benign prostatic hyperplasia]. AB - Results of use of UroBeam laser diode in 72 patients with benign prostatic hyperplasia (BPH) were analyzed. Average prostate volume was 67.29 +/- 26.72 cm3, the duration of vaporization--69.2 +/- 23.7 min. Blood loss was minimal. In the period from 2 weeks to 4 months after surgery, 9 patients have developed acute urinary retention. In the early postoperative period, acute prostatitis was diagnosed in 7 patients and was jugulated using drug treatment. The laser vaporization of BPH led to a three-fold reduction in the severity of urinary disorders and increase the urinary flow rate. The combination of laser vaporization of the prostate with transurethral resection of the prostate allow to improve the recovery of urination after surgery. PMID- 24159772 TI - [Potentials for the conservative therapy in the complex treatment of varicocele in adolescents]. AB - The article presents the results of the evaluation of the influence of varicocele on the reproductive system of adolescents from the perspective of involvement of periprostatic venous plexus and prostatovesicular complex in the pathological process. The study involved 90 adolescents 16-18 years old with left varicocele and disturbances in ejaculate parameters, of which 60 had pelvic congestion. Patients and control group received a comprehensive treatment, including preoperative trophic and flebotonic therapy, laparoscopic surgical clipping of the internal spermatic vein and post-operative rehabilitation. Patients of the study group along with this treatment received prostatotropic drug Vitaprost. According to the results of study, it was found that in patients with varicocele, attention should pay to the status of the venous outflow from the pelvic organs, which leads to the pelvic congestion and causes degenerative changes in the prostate in half of cases, which in turn negatively affects the spermogram parameters and increases the risk of subfertility. The use of prostatotropic drugs in the treatment of patients suffering from varicoceles with pelvic congestion is appropriate and pathogenetically justified, as it promotes a more rapid restoration of the structure and function of the prostate. PMID- 24159773 TI - [Suprapubic transvesical adenomectomy of external glands of prostate with blind suture of bladder]. AB - The article presents the experience of 524 open suprapubic transvesical prostatectomies with blind suture of bladder and hemostasis of adenoma bed by removable catgut ligatures. The advantages of this type of operation include early recovery of urethral urination (2 to 4th day), the normalization of urodynamic parameters, the restoration of anatomical and functional status of the upper urinary tract (91% of patients), rapid epithelialization of adenoma bed and low incidence of inflammatory and obstructive complications. PMID- 24159774 TI - [Retrograde nephrolithotripsy in patient with an abnormality of the urinary system]. PMID- 24159775 TI - [Orally dissolving tablet levitra--a new step in the treatment of patients with erectile dysfunction]. PMID- 24159776 TI - [Chronic prostatitis, benign prostatic hyperplasia and immunity: the disorders and correction]. PMID- 24159778 TI - [Arterial stiffness and blood levels of glycation end-products in patients with arterial hypertension and carotid atherosclerosis]. AB - Combination of arterial hypertension (AH) and carotid atherosclerosis significantly increases the risk of cardiovascular complications. Arterial stiffness is believed to be a key risk factor of the development of such complications. This paper described peculiarities of this condition, methods for its assessment in patients with AH and carotid atherosclerosis, and importance of characteristics of regional and local stiffness for estimation of cardiovascular risks. The role of glycation end-products in damaging arterial walls and triggering pathogenetic mechanisms of atherosclerosis is discussed. PMID- 24159777 TI - [Incidental renal cell carcinoma]. PMID- 24159779 TI - [Bronchial hyper-reactivity and chronic obstructive pulmonary disease]. AB - Bronchial hyper-reactivity (BHR) is a highly sensitive indicator of bronchial asthma, a main predictor of obligatory property of this disease. Modern studies show that BHR occurs in 55-87% of the patients with chronic obstructive pulmonary disease (COPD). Recent epidemiological studies demonstrated that BHR is an independent predictor of COPD risk and the second most important risk factor of COPD after smoking. BHR is believed to modify effects of BHR on the clinical course of COPD and thereby accelerate conversion of obstructive lesions into high mortality rate. Literature data give reason to regard BHR not only as a marker of unfavourable prognosis and severe COPD but also as a pathogenetic and phenotypic characteristic of the disease responsible for variability of its symptoms and therapeutic reaction. PMID- 24159780 TI - [Drug interaction of proton pump inhibitors and clopidogrel taken together]. AB - Current clinical practice lays special emphasis on drug interactions. High rates of cardiovascular morbidity and acid-dependent diseases dictates the necessity of antiaggregation and antisecretory therapy. The former uses a variety of medicines with acetylsalicylic acid (ASA) and clopidogrel being the most popular ones. Therapy using drugs with different mechanisms of action on the thrombocytic component of homeostasis appears to be especially promising as having synergic antiplatelet effect. The most common variant of antiplatelet therapy is a combination of ASA and clopidogrel usually referred to as double antiplatelet therapy (DAP). Current consensus recommends intake of proton pump inhibitors (PPI) during DAP to reduce the risk of gastrointestinal complications. However, recent studies showed that this approach is fraught with severe cardiovascular disorders, such as myocardial infarction, stroke, unstable angina, necessity of repeat coronary interventions, and coronary death. Hence, the importance of differential application of PPI in patients treated with ASA and clopidogrel. A comprehensive review of this problem is presented along with results of investigations of PPI action on clinical outcome of clopidrogel therapy. PMID- 24159781 TI - [Current concepts of pathogenesis, clinical course and treatment of hepatitis delta (35 years since its discovery)]. AB - Chronic HDV infection is a most serious and rapidly progressing hepatic disease with high risk of liver cirrhosis and hepato cellular carcinoma (HCC). Many aspects of its pathogenesis, virus biology and treatment remain unknown 35 years after the discovery of the disease. HDV is significantly different from HCV and HBV despite common route of infection. HDV as a satellite pathogen realizes its pathological action in an organism with compromised immune system that proved unable to eliminate HBEV. Hepatic lesions induced by HBV create favourable conditions for HDV propagation that causes rapid development of cirrhosis and its complications. The low efficacy of IFN-alpha therapy is due to the properties of HDV that inhibits the immune response. In most cases, decompensation and hepatic insufficiency determine prognosis of and mortality from HDV infection rather than HCC as in HBV and HCV. PMID- 24159782 TI - [Survival and working ability in men after coronary bypass surgery (analysis of registry data)]. AB - This retrospective study was focused on the survival and working ability in 2169 men (mean age 54.5 +/- 5.8 yr) included in the registry after they underwent coronary bypass surgery in 2000-2009. Three, five and ten-year survival rates were 91, 87 and 74% respectively. Independent factors influencing long-term survival were correction of valve defects (OR 3, 1, 95%, CI 1.9-4.8; p < 0.001) and left ventricular ejection fraction (OR 2, 9, 95% CI 2.1-3.8; p < 0.001). 34.2 and 60.2% of the patients were disabled before and after surgery respectively. This rise is attributed to the poorly developed system of postoperative rehabilitation. Occupational status was not an independent factor affecting long term survival. PMID- 24159783 TI - [Immune status of patients with persistent atrial fibrillation and coronary heart disease]. AB - We estimated the strength of immune response to chlamydial infection in patients with CHD. It was most pronounced in CHD patients with atrial fibrillation (AF). There was close relationship between past chlamydial infection and markers of inflammation (CRP and TNF-alpha). The study demonstrated high prognostic value of these markers for the development of AF during CHD and their relationship with characteristics of structural and functional remodeling of myocardium during CHD with AF. The study confirmed the role of inflammation in pathogenesis of AF in CHD patients. PMID- 24159784 TI - [Ten-year risk of osteoporotic fractures in patients with chronic obstructive pulmonary disease estimated by FRAX method]. AB - The study included 104 long-smoking men with COPD. The 10-year risk of osteoporotic fractures was estimated using the FRAX software. It was shown that patients with grade 2 COPD were at minimal risk of fractures of forearm, arm and vertebrae while those with COPD-4 were at maximum risk. The risk of fractures in COPD-2 was significantly different from that in COPD-3 and 4. The 10-year risk of osteoporotic fractures significantly correlated with BMI and DLCO. It is concluded that the use of FRAX makes it possible to reveal patients with COPD at risk of osteoporotic fractures. PMID- 24159785 TI - [Application of heated oxygen-helium mixture for combined treatment of community acquired pneumonia]. AB - Community-acquired pneumonia (CAP) is the commonest infectious disease characterized by the high lethality rate. The aim of this work was to estimate the efficacy of introducing inhalation of heated oxygen-helium mixture (thermoheliox) into standard therapy of CAP. The study included 50 patients with moderately severe CAP 25 patients of group 1 were given standard therapy plus thermoheliox, those of group 2 were treated by standard method. Group 1 showed faster disappearance of symptoms and physical signs including inflammatory changes (chemiluminescence of whole blood) and cardiac rhythm variability as well as more complete recovery of pneumonia upon X-ray examination. It is concluded that thermoheliox is an effective agent for pathogenetic therapy of community acquired pneumonia. PMID- 24159786 TI - [The role of gastric APUD system in progression of chronic Helicobacter gastritis]. AB - The study included 60 patients with chronic Halicobacter gastritis (30 with chronic non-atrophic and 30 with atrophic Halicobacter gastritis (CNAHG and CAHG)). The control group was comprised of 15 practically healthy subjects. The aim of the work was to elucidate the role of Helicobacter infection, disturbances of regeneration, endothelin-1 and melatonin-secreting neuroendocrine cells of gastric antrum in progression of chronic Helicobacter gastritis (CHG). It was shown that CHG is due to H. pylori persistence and that patients with CNAHG undergo grade III microbial contamination while in CAHG patients atrophic changes are accompanied by metaplasia of gastric mucosa (GM) and inflammation of different severity. Patients with CNAHG has an increased number of melatonin positive gastric cells and enhanced apoptotic activity of GM epitheliocytes. Patients with CAHG experience a reduction of melatonin-positive cells correlated with enhanced apoptotic activity of GM epitheliocytes. The number of endothelin-1 positive cells in patients with CNAHG and CAHG was similar to that in controls. Adequate eradication promoted normalization of the number of gastric endothelin-1 and melatonin-secreting neuroendocrine cells in patients with CHG. The apoptotic index reached the control value within 1 month after eradication in CNAHG patients but remained relatively high in CAHG patients. PMID- 24159787 TI - [Predicting side effects of the treatment of chronic hepatitis with peginterferon alpha-2A with ribaverin]. AB - The aim of the study was to monitor the commonest side effects of the treatment of chronic hepatitis with peginterferon alpha-2A (PEG-IFN) and ribaverin (RBV) and the influence of various factors on their development. The work was done in the Department of Infectious Disease, Erevan State Medical University. Monitoring 16 adverse reactions was carried out with the use of special tables within 1, 2, 4 and 6 months after the onset of therapy in patients with genotypes 2 and 3 and in addition after 8, 10 and 12 months in patients with genotype 1. The influence of independent prognostic factors was estimated by logistic regression analysis. The commonest side effects of PEG-IFN plus RBV therapy were leukopenia, thrombocytopenia, weight loss, depression, fatigue, and insomnia that occurred at one time or another in more than half of the patients. Weight loss during therapy amounted to 8.36 kg (95% CI 6.7-10) (maximum 21 kg). Myalgia, anorexia, arthralgia, headache, alopecia, and vomiting were documented in 20-50% of the cases. Anemia, pruritis, eruption, erythema, and hair shedding at injection sites occurred in 1/4 of the patients. It is concluded that logistic regression analysis with matching selected prognostic factors permits to estimate the probability of such side effects as weight loss, flu-like syndrome, and myalgia. PMID- 24159788 TI - [Long-term dynamics of gastrointestinal symptoms after cholecystectomy for the treatment of cholelithiasis]. AB - The aim of the work was to analyse dynamics of gastrointestinal symptoms and risk factors at different periods after cholecystectomy (CCE) in patients with cholelithiasis (CL). It was a prospective open cohort observational study with interviewing the patients before, 6 and 36 months after cholecystectomy for the treatment of CL. The pain symptom of CL persisted in 65.9% of the patients till the 6th month after CCE and in 57.3% of the patients till the 36th month. The logistic univariant analysis showed high probability of persistence and/or appearance of biliary pain within 6 months after surgery in patients suffering biliary colic before it (OR = 5.3, p = 0.01) and having hereditary aggravation of CL (OR = 2.7, p = 0.38). The relationship between biliary pain and planned surgical intervention for the treatment of CL was documented 3 years after the operation (OR = 2.6, p = 0.018). Similar relationship was revealed after 6 and 36 months (OR = 3.8, p = 0.002). Biliary pain within 6 months after CL was an independent prognostic factor of its development within the next 3 years. Other increasingly severe gastrointestinal symptoms were heartburn, intolerance of greasy food, and disturbed intestinal passage as a result of biliary insufficiency or disordered intestinal motility. The above relationships between gastrointestinal symptoms may be used to predict their appearance within 6 months after CL. PMID- 24159789 TI - [Clinical and functional symptoms of funicular myelosis and chronic gastritis in patients with B12-deficiency anemia]. AB - The aim of this work was to study clinical and functional symptoms of funicular myelosis (FM) and chronic gastritis (CG) in patients with B12-deficiency anemia. A total of 77 patients with diagnosis verified by finding megaloblasts in bone marrow biopsies were examined. Clinical symptoms of FM were found in 57% of the patients. The most characteristic subjective ones were paresthesia (83.3%) and limb weakness (60%) while objective symptoms included impaired limb sensitivity (100%). All patients suffered CG with lesions in both antrum and fundus. PMID- 24159790 TI - [Effectiveness of immunomodulating therapy of pulmonary tuberculosis with cycloferon]. AB - Cycloferon was used to treat newly diagnosed, recurrent and long-standing pulmonary TB. The dose of 7,5 g combined with antibacterial therapy caused no complications. The effectiveness of this therapy based on the generally-accepted criteria was significantly higher than standard treatment but varied depending on the character of pathological process. It is recommended to use cycloferon in the intense phase of the basal treatment. PMID- 24159791 TI - [Additional advantages of mexicor used in combined therapy of coronary heat disease and diabetes mellitus of 2nd type]. AB - This open prospective randomized 16-week study of combined therapy of coronary heat disease (CHD) and and diabetes mellitus of 2nd type (DM2) with secondary non alcoholic fatty liver disease (NAFLD) including mexicor was designed to estimate structural and functional liver characteristics. Mexicor was shown to act as a hepatoprotector reducing the frequency of cytolithic syndrome when used together with statins in combined therapy of atherogenic dyslipidemia. It also significantly decreased the number of patients with elevated levels of gamma glutamyltranspeptidase. These changes suggest favourable prognosis for patients with CHD and DM2 because enhanced activity of this enzyme is believed to be a predictor of high cardiovascular risk. Mexicor promoted combined hypolipidemic effect, reduced the degree of insulin resistance, improved hepatic metabolism, and lowered cardiovascular risks in patients with CHD and DM2. PMID- 24159793 TI - [Magnetic resonance tomography in diagnostics of coronary heart disease]. AB - Contrast-enhanced magnetic resonance tomography (1.5 Tl) was used to examine 101 patients with coronary heart disease. It was shown that angina of effort was associated with disturbed myocardial perfusion manifest during the first passage of the contrast agent at sites with a hypointense signal. Patients with acute myocardial infarction exhibited, besides defective perfusion, hyperintense edematous regions on T2-weighted images as well as hyperintense sites of delayed contrast enhancement. The main symptoms of post-infarction cardiosclerosis in hyperintense zones of delayed contrast enhancement related to cicatrical lesions in myocardium. Disturbances of local contractility depending on the severity of ischemia and cicatrical lesions resulted in the impairment of overall left ventricular contractility. PMID- 24159792 TI - [Impact of combined therapy using glucosamine sulfate and anti-inflammatory agent on pain severity in patients with osteoarthritis: prospective, non-controlled postmarketing study]. AB - Pain is one of the major symptoms of the osteoarthritis (OA). The objective of the study was to evaluate impact of combined therapy with diclofenac, aescin and original glucosamine sulfate on pain severity in patients with OA of different localizations in real life clinical settings in Russia and Ukraine. METHODS: Design--prospective, non-controlled, before and after post-marketing study. Study was performed in 38 cities across Russia and Ukraine in 2012. Registered anti inflammatory and symptomatic slow acting drugs were used according to the registered indications and dosages. In Russian sites combined therapy A using diclofenac ("Dorosan" formulation, Rottapharm S.p.A., aerosole 1%, 3-4 times/day) for two weeks, original glucosamine sulfate ("Dona" formulation, Rottapharm S.p.A.) intramuscular (ampule 200 mg/ml, 2 ml 3 times/week) for 4 weeks and per os (powder 1500 mg, once/day) for 8 weeks was used. In Ukraine sites (scheme B) diclofenac was substituted with topical aescin ("Reparil-Gel" formulation, Madaus AG, tube 400 mg, 2-3 times/day) anti-inflammatory product. Physicians were free to change therapy and study organizers had no impact on prescribing and management practice. Patients with OA of different localizations were included into the study. Pain severity was assessed using numeric rating scale. Total duration of the study was 8 weeks. Questionnaires were distributed to patients via physician out-patient offices. The only endpoint was the difference in median pain severity at the end of the study compared with the baseline level. RESULTS: In total 4931 patients were included into the study (mean age 57 +/- 12 years, 75% were females). Scheme A was used in 3956 patients and scheme B in 975 patients. The median pain severity decreased from 0.7 at the baseline (interquartile range +/- 0.2) to 0.2 (interquartile range +/- 0.2) after 8 weeks of the study in both treatment regimens (p < 0.001). Limitations of the study include absence of the control group, collection of the questionnaires from physician offices, rather than directly from patients, limited range of clinical data collected and use of single instrument to assess pain severity. CONCLUSIONS: Post-marketing study of combined therapy of OA of different localizations using diclofenac, aescin and original glucosamine sulfate in Russia and Ukraine demonstrated decrease of the pain severity, assessed by numeric rating scale, after 8 weeks of the treatment. PMID- 24159794 TI - [Development of the metod of percussion in the period of the war of 1812]. PMID- 24159795 TI - [125th birth anniversary of the outstanding botanist Peter Mikhailovich Zhukovsky]. AB - Peter Mikhailovich Zhykovsky--botanist, monograph of the genus Aegilops, closest associate of N.N. Vavilov, Director of the All-Union Institute of Plant Industry, Academic Secretary of the Department of Agriculture of VASKhNIL, and the first Editor-in-Chief of the Genetika journal. He postulated a theory on host-parasite coevolution at their common place of origin, and put forward the concept on Megagene centers of origin of cultivated plants and their endemic Microgene centers. He discovered and described the new wheat species Triticum timopheevii (Zhuk.) Zhuk. This species is unique with respect to its immunity to diseases and pests, and is the carrier of the genes for cytoplasmic male sterility. PMID- 24159796 TI - [Organization and maintenance features of IncP-7 naphthalene degradation plasmid pFME5 basic replicon]. AB - A basic replicon of the naphthalene degradation plasmid pFME5 (80 kb, IncP-7) has been constructed and sequenced. The nucleotide sequence of pFME5mini is almost identical to replicons of the pND6-1 subgroup, which was separated based on the reA-oriV homology in our previous work. The basic replicon of pFME5 is capable of replication and stable maintenance exclusively in Pseudomonas species. An analysis of the deletion mutation indicated that, in contrast to the parWAB region, the parC gene is not essential for the stability of pFME5mini and can be a common feature of IncP-7 replicons. We revealed that par-defective mutants of pFME5mini were slowly eliminated from the bacterial population in a nonselective medium compared to their pCAR1-based counterparts. Designed primers specific to the repA and parC genes can be used to detect IncP-7 plasmids, while primers specific to two variants of parA can be used for intragroup classification. PMID- 24159797 TI - [Genetic differentiation of common wheat cultivars using multiple alleles of gliadin-coding loci]. AB - The alleles ofgliadin-coding loci have been identified in 105 spring common wheat cultivars bred in Omsk and Saratov by polyacrylamide gel electrophoresis. It has been shown that 49% of the Omsk cultivars and 40% of the Saratov cultivars are heterogeneous, i.e., composed of several biotypes that differ in alleles of the gliadin-coding loci. A total of 278 genotypes have been determined (170 in the Saratov cultivars and 112 in the Omsk cultivars); in these two groups of cultivars, four genotypes are identical. Due to this heterogeneity, the cultivars bred in Omsk and Saratov can be differentiated in a statistically significant manner despite their close kinship, which allows them to be ascribed an accession to a particular breeding center based on the gliadin pattern and the number or frequency of biotypes, as well as to determine its species affiliation with a 95% probability. Close relations prevent 5% of the Saratov cultivars and 4.4% of the Omsk cultivars from being distinguished within populations, since they have identical alleles of gliadin-coding loci. PMID- 24159798 TI - [Genetic diversity of larch at the north of Primorskii Krai and distribution limits of Larix olgensis A. Henry]. AB - The genetic diversity of four mtDNA fragments and five microsatellite loci of ctDNA was examined in six larch samples from the territory of the Sikhote-Alin Nature Reserve (northern Primor'e). In order to identify possible species specific differences between the samples, the latter were collected at transects along the shore of the Sea of Japan and at different distances from the sea. Based on a number of morphological characters, some authors suggest that Olgan larch grows in the shoreline part of the reserve and, moving inland, it is replaced by Gmelin larch. According to the other data, the northern border of the Olgan larch range does not reach the reserve territory. The data obtained were compared to those obtained previously for three samples from the south of Primor'e, including those for the locus classicus of Olgan larch. In the examined larch accessions (186, for mtDNA and 200, for ctDNA), a total of five mitotypes and 52 chlorotypes were recovered. According to the results of the AMOVA test, the proportion of variations accounted for the differences among all Larix samples examined over both types of markers was higher (N(ST) = 0.435, for mtDNA and R(ST) = 0.041, for ctDNA) than that for the differences among the samples within the reserve (N(ST) = 0.079, for mtDNA and R(ST) = 0.005, for ctDNA). No differences were detected between the groups of shoreline and continental populations. PMID- 24159799 TI - [Effect of constitutive expression of ARGOS-LIKE gene on dimensions of cells and organs of transgenic tobacco plants]. AB - Transgenic tobacco plants that overexpress the ARGOS-LIKE (ARL) gene of Arabidopsis thaliana have been developed. The transgenic plants possessed increased dimensions of leaves and stem, whereas the magnitude of flowers was modified to a lesser degree. The increase in the organ dimensions was a result of stimulation of cell expansion; the cell quantity in the organ was even decreased. Ectopic expression of the ARL gene was promoted in order to increase in the level of mRNA of tobacco expansine NtEXPA5. It has been shown that the ARL gene of A. thaliana can be used to obtain transgenic plants with increased sizes of the leaves and stem. PMID- 24159800 TI - [Mapping of meiotic genes in rye (Secale cereale L.): localization of sy19 mutation, impairing homologous synapsis, by means of isozyme and microsatellite markers]. AB - The sy19 mutation, which impairs the homology of meiotic chromosome synapsis in rye, were mapped using a specially created F2 population by means of isozyme Acph 1 locus and microsatellite (SSR) markers. The sy19gene was localized in the chromosome 7R in the pericentromeric region of long armbased on the linked inheritance with the Acph 1 locus. The locus was linked with five rye SSR markers, with the Xrems 1234 locus being located closest to the sy19 gene (6.4 cM). The genetic map of the analyzed chromosome 7R region includes ten markers and the sy19 locus. A possible function of the Sy1 and Sy19 genes based on the data on comparative genomics is discussed. PMID- 24159801 TI - [Effect of Triton X-100 on genetic segregation and associated monocotyledonous and dicotyledonous traits in sugarbeet (Beta vulgaris L.)]. AB - The effect of Triton X-100 (TX-100) on the ratio of phenotypic classes and the expression of morphological traits in the progeny of sugar beet hybrids (N12 and N2) was investigated. It was shown that the TX-100 exposition on the unopened flower buds of sugar beets has different effects on hybrid progenies. In agamospermic progeny of hybrid plant No 12km-4, a significant decrease in the heteroallelic (heterozygous) phenotypic classes of alcohol dehydrogenase (ADH1) fraction was determined in the nonagamospermic progeny of hybrid plant No 2km-2 appearance of sugar beet seedlings with one cotyledon leaf was detected. The obtained results indicate the high efficiency of the epimutagenic effect of TX 100 on the early stages of plant ontogenesis. PMID- 24159802 TI - [Expression of cecropin P1 gene increases resistance of Camelina sativa (L.) plants to microbial phytopathogenes]. AB - Transgenic plants of camelina (Camelina sativa (L.) Crantz) with the synthetic gene of antimicrobial peptide cecropin P1 (cecP1) were obtained. Agrobacterium mediated transformation is performed using the binary vector pGA482::cecP1 by vacuum infiltration of flower buds. The presence of the cecP1 gene in the genome of plants was confirmed by PCR. cecP1 gene expression in transgenic plants was shown by Western blot analysis and by antimicrobial activity of plant extracts against the bacterial phytopathogene Erwinia carotovora. The plants of F0 and F1 generations had the normal phenotype and retained the ability to form viable seeds in self-pollination. cecP1 plants exhibit enhanced resistance to bacterial and fungal phytopathogens: Erwinia carotovora and Fusarium sporotrichioides. The increased sustainability of cecropin P1-expressing plants against salt stress is shown. The possibility of the integration of the cecP1 gene into the overall protective system of plants against biotic and abiotic stresses is discussed. PMID- 24159803 TI - [Analysis of allelic content of genes responsible for baking properties in allocytoplasmic wheat hybrids]. AB - A collection comprised of allocytoplasmic hybrids of mild wheat (ACPH) was screened for the allelic state of genes responsible for baking properties (high molecular glutenins, puroindolines, and Waxy). The possibility of the introgression of the Waxy gene of T. timopheevii into the mild wheat genome was demonstrated in several ACPH samples using the set of molecular markers. Allelic gene variants responsible for the baking properties were revealed for 22 ACPH samples, which make it possible to detect the most challenging samples for both molecular-genetic research and applied science. PMID- 24159804 TI - Molecular characterization and population genetic diversity of Limonium sinense based on nuclear ribosomal DNA and ISSR. AB - The single nucleotide polymorphism (SNP) and amplification refractory mutation system (ARMS) have been applied to authenticate Limonium species and their corresponding herb samples. One species specific primer was designed and the amplification product is 200 bp (Limonium sinense) by using this primer. No band was observed with other Limonium species. The phylogenetic relationship of Limonium species were studied using ribosomal DNA ITS and the adulterants (L. bicolor, L. aureum and L. wrightii) were clustered with L. sinense in NJ tree. Inter simple sequence repeat (ISSR) was used to assess genetic diversity and population structure of L. sinense and a high level of genetic diversity was detected (H(E) = 0.2573, PPB = 85.71%) with POPGENE. Based on AMOVA analysis, there was moderate variation between pairs of populations with phi(ST) from 0.1744 to 0.5131 and on average 28.81% of the genetic variation occurred among populations. Five main clusters were shown in UPGMA dendrogram using TFPGA. The results showed that SNP and ARMS could be used to authenticate not only Limonium species but related herbs on rDNA internal transcribed spacer region. Possible strategies should be implemented for conservation of this endemic herb. PMID- 24159805 TI - [Influence of Vrn-B1a and Vrn-B1c alleles on length of developmental phases of substitution and near-isogenic lines of common wheat]. AB - The influence of Vrn-B1a and Vrn-B1c alleles on the length of developmental phases in lines of winter cv. Sava with intervarietal substitution of chromosomes 5B and near-isogenic lines (NILs) with these loci in the genetic background of winter cv. Bezostaya 1 is studied. We have confirmed that effects of Vrn genes appear on the tillering phase and that the response to vernalization and shortening of day length can change the duration of this phase. We have shown that, after vernalization and under short-day conditions, the Vrn-B1a allele has the strongest effect on the length of the tillering phase. After vernalization, in the late substitution line Sava (Diamant II 5B) with the Vrn-B1a allele, the length of the tillering decreased more strongly after 6 days than in the earlier Sava line (Saratovskaya 29 5B) with the Vrn-B1c allele. After the length of the day shortens, in late NIL i:Bez1 Vrn-B1a, the length of the tillering phase and period of stem elongation--heading increased more strongly for 13 and 5 days, respectively than in the early i:Bez1 Vrn-B1c line. The study of F1 hybrids between substitution and isogenic lines, the growth habits of which are determined by both Vrn-B1a and Vrn-B1c alleles, had shown the dominance of the trait lateness, which is determined by the line with the Vrn-B1a allele. In F1 hybrids, between substitution lines, the length of tillering was similar to that of the line with Vrn-B1a and, in F1 hybrids between NILs, the length of tillering was intermediate between the parental lines. PMID- 24159806 TI - [Genomic diversity in cattle breeds assessed using polymorphism of intermicrosatellite markers]. AB - Using (AG)9C and (GA)9C primers and analysis of multilocus profile of intermicrosatellite polymorphism (ISSR-PCR), in 19 cattle breeds, a total of 66 PCR products were revealed. The statistical processing of the data obtained using standard software programs enabled the identification of the ISSR markers, the polymorphism of which made the greatest contribution to the total genomic diversity of both individual breeds and the species Bos taurus in general. These DNA fragments deserve special interest for the further analysis of their localization and functions. PMID- 24159807 TI - [Genetic diversity of Chionomys genus (Mammalia, Arvicolinae) and comparative phylogeography of snow voles]. AB - In the present study, the genetic polymorphism of the Chionomys genus was examined based on the sequencing of the mitochondrial cytb gene and two nuclear exons, including CHR exon 10 and BRCA1 exon 11. The distinct subdivision of the genus of snow voles into five lineages, including Ch. nivalis, Ch. gud, Ch. roberti, and Ch. aff. nivalis from Turkey, as well as Ch. aff. gud from Turkey, was demonstrated. The branching order in the trees constructed based on the data for different genes was ambiguous, which was probably the consequence of recent and rapid radiation of the major lineages from a common ancestor. However, the data of the mitochondrial and nuclear gene analyses definitely indicated that the genetic and taxonomic diversity of the Chionomys genus was higher than it was expected before. The genetic divergence of some populations was so deep that they probably deserved the statuses of independent species. Despite that the range of the European snow vole Ch. nivalis is larger and more fragmented than the Gudaur vole Ch, gud, the latter species with its relatively small range, which is limited to the Caucasian and Pontic Mountains, was characterized by a similarly expressed phylogenetic structure. At the same time, Robert's vole Ch. roberti was less structured genetically than the first two species. The data obtained supported the Near Eastern, rather than the European origin of the Chionomys genus. PMID- 24159808 TI - [From pendulum to DNA]. AB - In the review the results on the modeling of angular oscillations of the nitrous bases in short and long (in the limit - infinite) fragments of polynucleotide DNA chains are collected and systematized. The material is arranged so to represent the results of investigations in the course of development beginning from those obtained first for elementary models as the pendulum or a pair of coupled unequal pendulums, and then for more complex DNA models. The description of dynamic behavior features of all considered model systems is executed in the uniform mathematical language representing a state of model system as a point, moving along a certain trajectory in the phase space. PMID- 24159809 TI - [Thermoadsorptive separation of DNA by size using a polymeric sorbent]. AB - The article describes theoretical aspects of isolation and separation of DNA fragments by size using a polymeric sorbent. On this basis we presented a theoretical model of thermal desorption of DNA fragments of different length. Assuming that, under certain pH, interaction of DNA with the polymer sorbent is of an ion-dipole character and moving dipoles interact with the sorbent according to the Boltzmann distribution with the total charge of the DNA fragment in its pore, the expression for the interaction energy as a function of temperature is obtained. Equating the thermal energy to the interaction energy of the ion-dipole character, we have found the critical temperature of DNA separation from the sorbent. Account of the conformation of single-stranded DNA in the coil form leads to the dependence of DNA separation temperature, i.e., desorption, on the length of the DNA chain. The temperature for desorption increases symbatically to the contour length of DNA. PMID- 24159811 TI - [Structure of crambin in solution, crystal and in the trajectories of molecular dynamics simulations]. AB - The mechanisms of the three-dimensional crambin structure alterations in the crystalline environments and in the trajectories of the molecular dynamics simulations in the vacuum and crystal surroundings have been analyzed. In the crystalline state and in the solution the partial regrouping of remote intramolecular packing contacts, involved in the formation and stabilization of the tertiary structure of the crambin molecule, occurs in NMR structures. In the crystalline state it is initiated by the formation of the intermolecular contacts, the conformational influence of its appearance is distributed over the structure. The changes of the conformations and positions of the residues of the loop segments, where the intermolecular contacts of the crystal surroundings are preferably concentrated, are most observable. Under the influence of these contacts the principal change of the regular secondary structure of crambin is taking place: extension of the two-strand beta structure to the three-strand structure with the participation of the single last residue N46 of the C-terminal loop. In comparison with the C-terminal loop the more profound changes are observed in the conformation and the atomic positions of the backbone atoms and in the solvent accessibility of the residues of the interhelical loop. In the solution of the ensemble of the 8 NMR structures relative accessibility to the solvent differs more noticeably also in the region of the loop segments and rather markedly in the interhelical loop. In the crambin cryogenic crystal structures the positions of the atoms of the backbone and/or side chain of 14-18 of 46 residues are discretely disordered. The disorganizations of at least 8 of 14 residues occur directly in the regions of the intermolecular contacts and another 5 residues are disordered indirectly through the intramolecular contacts with the residues of the intermolecular contacts. Upon the molecular dynamics simulation in the vacuum surrounding as in the solution of the crystalline structure of crambin the essential changes of the backbone conformation are caused by the intermolecular contacts absence, but partly masked by the structure changes owing to the nonpolar H atoms absence on the simulated structure. The intermolecular contact absence is partly manifested upon the molecular dynamics simulation of the crambin crystal with one protein molecule. Compared to the crystal structure the lengths of the interpeptide hydrogen bonds and other interresidue contacts in an average solution NMR structure are somewhat shorter and accordingly the energy of the interpeptide hydrogen bonds is better. This length shortening can occur at the stage of the refinement of the NMR structures of the crambin and other proteins by its energy minimizations in the vacuum surroundings and not exist in the solution protein structures. PMID- 24159810 TI - [Investigation of interaction of thrombin-binding aptamer with thrombin and prethrombin-2 by simulation of molecular dynamics]. AB - Thrombin is a major component of blood clotting and involved in the formation of a fibrin clot. One of the precursors during thrombin maturation is prethrombin-2, with the presence of Arg363-Ile364 bond between the light and heavy chain of protein, the only distinction from thrombin. Prethrombin-2 is able to interact with less efficiency with a 15-mer thrombin-binding aptamer (TBA). We investigate the interaction of both known conformers of TBA with thrombin and prethrombin-2 by simulation of molecular dynamics. It was shown that TBA could interact with thrombin in both conformations with similar efficiency, although a stable complex of prethrombin-2 with TBA was found only in conformation identical with the aptamer structure, pdb 1HAO. Analysis of molecular dynamics of complexes offered an assumption that the motion of the exosite-1 forming loop Lys428-Ile438 determined the difference in affinity of the complexes of TBA with thrombin and prethrombin-2. PMID- 24159812 TI - [Effect of inorganic salts on free radicals production by near UV irradiation of frozen aqueous solutions of adenine and its derivatives]. AB - The addition of Na and Ca chlorides to adenine (A), adenosine (Ado) and adenosine diphosphate solutions at pH 5.3 has been shown to result in intensification of EPR signals in samples irradiated by near UV at 77 K and appearance of signals of Cl2-* and peroxyl radicals. The peroxyl radicals contribution can exceed 30% of total amount of paramagnetic products. The addition of inorganic phosphate reduces the contribution of peroxyl radicals. Possible mechanisms of the processes involved are discussed. PMID- 24159813 TI - [Electrochemical measurement of intraprorein and interprotein electron transfer]. AB - Intramolecular and intermolecular direct (unmediated) electron transfer was studied by means of electrochemical techniques in flavohemoprotein cytochrome P450 BM3 (CYP102A1 from Bacillius megaterium) and between cytochrome b5 and cytochrome c. Flavohemoprotein cytochrome P450 BM3 was immobilized on a screen printed graphite electrode, modified with a biocompatible nanocomposite material based on the didodecyldimethylammonium bromide DDAB and gold nanoparticles. Analytical characterictics of DDAB/Au/P450 BM3 electrodes were studied with cyclic voltammetry and square wave voltammetry. It was shown that intramolecular electron transfer was realized between diflavin (FAD/FMN) and heme domain of CYP102A1. An electron transport chain of flavohemoprotein P450 BM3 immobilized at nanostructued electrode is realized as: electrode --> FAD --> FMN --> heme. Electron transfer occurs inside the protein, and it is an evidence of functional interaction between diflavin and heme domains. The effect of a substrate (lauric acid) or inhibitors (metyrapone or imidazole) binding on the electrochemical parameters of flavohemoprotein P450 BM3 was also studied. Interprotein electron transfer was analyzed between cytochrome b5 and cytochrome c. Electrochemical analysis revealed that electron transfer takes place in protein-protein complexes with participants possessing different redox potentials. PMID- 24159814 TI - [Analysis of intermolecular interaction energy inputs in benzene-imidazole and imidazole-imidazole systems in parallel displaced and T-configuration]. AB - Intermolecular interactions in several dimer aromatic systems were analyzed to determine how various energy contributions (electrostatic, exchange, repulsion, and polarization) change depending on the value of monomers separation. Different contributions to the intermolecular energy interactions between imidazole imidazole and benzene-imidazole dimers are studied using the aug-cc-pVDZ basis set in the framework of ab initio Hartree-Fock and second-order Moller-Plesset perturbation theory methods. Special attention is paid to the exchange and dispersion energy binding contributions. PMID- 24159815 TI - [Influence of a variation potential on photosynthesis in pumpkin seedlings (Cucurbita pepo L.)]. AB - The influence of a variation potential on photosynthesis in pumpkin seedlings (Cucurbita pepo L.) was investigated in our work. It was shown that the variation potential induced by cotyledon burning propagates into a leaf. It decreases CO2 assimilation and transpiration as well as increases nonphotochemical quenching. Investigation of isolated chloroplasts showed that lowering of the pH in incubation medium from 6.9-7.2 to 6.5 increases nonphotochemical quenching. It was proposed that lowering of the cytoplasmic pH induced by the variation potential takes place in the photosynthetic response development. PMID- 24159816 TI - [Changes of dipole potential of phospholipid membranes resulted from flavonoid adsorption]. AB - The effects of flavonoids, phloridzin, quercetin, myricetin and biochanin A on the dipole potential of planar lipid bilayers formed from dioleylphosphoethanolamine, dioleylphosphoserine, dioleoylphosphocholine, and diphytanoylphosphocholine are investigated. The characteristic parameters of the Langmuir adsorption isotherm, the maximum changes in the membrane dipole potential at an infinitely large concentration of flavonoid and its dissociation constant, which reflects the affinity of flavonoid to the membrane lipids, are determined. Modifying effects of chalcones, flavonols and isoflavones are compared. The influence of the surface charge of the lipid bilayer and the spontaneous curvature of the membrane-forming phospholipids on the adsorption of flavonoids on the model membranes is discussed. PMID- 24159817 TI - [Interaction of free fatty acids with mitochondria during uncoupling of oxidative phosphorylation]. AB - The activity of free saturated fatty acids (caprylic, capric, lauric, myristic, palmitic and stearic) as inducers and regulators of uncoupling of oxidative phosphorylation with participation of ADP/ATP antiporter, aspartate/glutamate antiporter and cyclosporin A-sensitive structure was investigated in experiments on rat liver mitochondria. It is established that at equal uncoupling activity of fatty acids the regulatory effect is minimal for caprylic acid and raised with increasing the hydrophobicity of fatty acids reaching the maximum value for stearic acid. There exists the linear dependence of the regulatory effect value of fatty acids on fatty acids content in the hydrophobic region of the inner membrane. The model that describes the interaction of fatty acids with the hydrophobic region of the mitochondrial inner membrane preserving functional activity of organelles is developed. It is established that if molecules of various fatty acids being in the hydrophobic region of the membrane are equally effective as uncoupling regulators, their specific uncoupling activity is different. Caprylic acid, a short-chain fatty acid, possesses the highest uncoupling activity. As the acyl chain length increases, the specific uncoupling activity of fatty acids reduces exponentially. Under these conditions components of the uncoupling activity sensitive to glutamate and carboxyatractylate and glutamate and insensitive to these reagents (but sensitive to cyclosporin A) change approximately equally. PMID- 24159818 TI - [Magnetic dipole interaction of endogenous magnetic nanoparticles with magnetoliposomes for targeted drug delivery]. AB - Dynamics of magnetoliposomes binding to the tumor cells and the efficiency of their recognition for targeted drug delivery is largely determined by physical interaction. In this paper we assess the strength of magnetic dipole interaction that occurs between endogenous magnetic nanoparticles in tumor cells and exogenous magnetic nanoparticles as a component of magnetoliposomes, and compare it with the forces of specific binding of the antigen-antibody complex. To assess the strength of magnetic dipole interaction the model of chains of identical particles was used, and an order of magnitude, 9(-10) N, was obtained. Thus, the indicated force has an order of magnitude close to the forces of specific binding, and even more. The force of magnetic dipole interaction between a magnetically marked dosage form and tumor cells is virtually the additional specific binding force--"passive targeting" for targeted drug delivery in consequence of the fact that tumor cells tend to contain the number of biogenic nanoparticles of magnetite (Fe3O4) by an order of magnitude greater than normal. PMID- 24159819 TI - [Study of the influence of gold nanoparticles on activation of human blood neutrophils]. AB - Activation of neutrophils in the presence of gold nanoparticles is accompanied by the formation of free radical peroxidation products recording the flash of chemiluminescence. The basis for the activation mechanism has its origins most likely in the influence of the gold particles on the surface membrane potential of neutrophils. Investigation of changes in the fluorescence intensity of the negatively charged ANS probe on the surface of model membranes by adding different concentrations of gold nanoparticles indicates the change in the membrane surface charge density that can cause cell activation. PMID- 24159820 TI - [3-Dimensional microscopy as a method for volume measurement in cells undergoing apoptosis]. AB - Different patterns of cell volume perturbations are commonly used for modes of cell death: necrosis (cell swelling) and apoptosis (cell shrinkage). In this study we employed recently developed three dimensional microscopy for the measurement of the volume of attached vascular smooth muscle cells transfected with E1A-adenoviral protein. These cells undergo rapid apoptosis in the absence of growth factors or in the presence of staurosporine. In 30-60 min of serum deprivation the volume of these cells is increased by -40% that corresponds to the time point of maximal activation of caspase 3 and chromatin cleavage. In 10 15 min swollen cells exhibit morphological collapse indicated by formation of apoptotic bodies. In contrast to serum-deprived cells, staurosporine leads to attenuation of cell volume by 30%. In this case, apoptotic bodies are detected in -2.5 hr after maximal shrinkage. Thus, our results show that cell shrinkage can not be considered as universal hallmark of apoptosis. The role of stimulus specific cell volume perturbation in the triggering of the cell death machinery should be examined further. PMID- 24159821 TI - [The influence of physical-chemical characteristics of surface modified copper nanoparticles on E. coli cell population growth suppression and on electrostatic properties of their membranes]. AB - The biological activity of copper nanoparticles, able to suppress growth of E. coli cells population under contact interactions, was explored. Three types of samples with oxide layers of various sizes, thickness and composition were used in experiments. It was found out, that an increase in electron density on the external membrane of E. coli correlated with copper nanoparticles suppression capability and with lower activation energy of electron transfer on bacteria. The analysis of experimental data helps to correct conditions for obtaining nanoparticles with certain properties of their surface oxide layers. The character of temperature dependence of electron density reveals the electron type of conductivity in contact area of E. coli and nanoparticles. These results help to find approach to understanding the nature of toxic influence of copper nanoparticles on E. coli cells under contact interaction. PMID- 24159822 TI - [Influence of lateral diffusion on depression of neural cholinsensitivity]. AB - Using mathematical model a comparative analysis of the influence of receptor lateral diffusion, endocytosis and exocytosis of receptors on the change in the number of membrane receptors at rhythmical local applications of a mediator on neural soma was performed. The results allow us to estimate quantitatively the effect of these processes on the length of the period between mediator applications. The necessity of considering the change in the rate of receptor lateral diffusion, while studying the effect of some protein kinases and protein phosphatases on the change in the number of receptors, became evident. The model also provided the effect of "after stimulus efficiency". PMID- 24159823 TI - [The interaction between nerve cells and carbon nanotube networks made by CVD process investigation]. AB - In this research we investigate neuroblastoma cells cultivated on single-walled carbon nanotubes networks made by CVD method on silicon substrates. The complex analysis of grown cells made by atomic force, electron microscopy and Raman spectroscopy was carried out and the effect of nanotube growth process on proliferation factor was investigated. It is shown that despite of a weak decrease in proliferation, cell morphology remains unchanged and no physical or chemical interaction between carbon nanotubes and cells is observed. The results of the research can be used to investigate the interaction between conductive nanomaterials and cells for the development of neural replacement implants. Also they can be useful in bio-electronic interface investigation of signal propagation in neurons. PMID- 24159824 TI - [Interaction between muscle cell and external mechanical field: a model study]. AB - We have suggested a mathematical model of the muscle cell membrane on the basis of the thin elastic rods theory which takes external mechanic effects into account. We have also performed a quantitative analysis of deformation of rodent shin muscles when exposed to hindlimb suspension. Maximal deformation is shown to be typical for soleus muscle fibers and their magnitude is connected with stiffness of the cortical cytoskeleton. PMID- 24159825 TI - [Anti-inflammatory effect of therapeutic and low-frequency ultrasound on a rat model of inflammatory process]. AB - The results of experimental investigations of the anti-inflammatory effect of ultrasound on the inflammatory process on a rat model of carrageenan-induced edema of the hind limb are given in this article. The technique used in the experiment showing ultrasound exposure parameters and how to control characteristics of the inflammatory process is described. The anti-inflammatory effect of ultrasound is established. PMID- 24159826 TI - [Modeling of localization phenomena of the auditory image caused by brain regions dysfunctions]. AB - This paper focuses on the modeling of the neural representations of subjective auditory image motion characters that can be induced by bilateral brain dysfunctions. The modeling is based on a biologically inspired computational model that simulates the behavior of bilaterally located populations of binaural auditory neurons. To assess neural model responses in terms of psychophysical data, a special method is designed. The application of the method reveals the inertness of auditory image motion perception. The results of the modeling show stable influence of both value and bilateral location of the noises (which mimic effect of different brain part dysfunctions) on phenomena of auditory image localization. PMID- 24159827 TI - [Geomagnetic storm decreases coherence of electric oscillations of human brain while working at the computer]. AB - The effect of geomagnetic storms at the latitude of Moscow on the electric oscillations of the human brain cerebral cortex was studied. In course of electroencephalogram measurements it was shown that when the voluntary persons at the age of 18-23 years old were performing tasks using a computer during moderate magnetic storm or no later than 24 hrs after it, the value of the coherence function of electric oscillations of the human brain in the frontal and occipital areas in a range of 4.0-7.9 Hz (so-called the theta rhythm oscillations of the human brain) decreased by a factor of two or more, sometimes reaching zero, although arterial blood pressure, respiratory rate and the electrocardiogram registered during electroencephalogram measurements remained within the standard values. PMID- 24159828 TI - Towards malaria elimination in the Greater Mekong Subregion. PMID- 24159829 TI - Greater Mekong Subregion (GMS): context. AB - The epidemiology and outcome of malaria control initiatives are affected by a great diversity of factors including environment, economy and politics, to name but a few. Nowhere is this more obvious than in the GMS, where the rapid pace of economic development that has occurred over the past decade has brought with it a raft of changes to environment, employment, transport, communication, and demography and wealth patterns. The GMS, as a subregion, continues to gain increasing political and economic significance and has the potential to become one of the fastest growing regions in the world. While the pace of change is impressive, it has also brought with it new challenges in the fight against malaria. On the one hand, improvement in transport networks such as roads and railways, facilitates increased cross-border trade and development, on the other hand such improvements are likely to result in a massive increase in population movements across borders. As travel becomes easier the numbers of migrant workers moving between areas of high and low transmission, also expands, further increasing the risk of the spread of resistant malaria strains. In addition, the increase in large infrastructure projects such as the construction of dams, as well as agricultural plantations, also potentially lead to changes in vector behavior with unknown consequences for malaria transmission. Effectively addressing the new challenges to malaria control will require renewed commitment, coordination and better collaboration between all sectors from governments and non government organizations in the GMS. PMID- 24159830 TI - Malaria situation in the Greater Mekong Subregion. AB - The epidemiology of malaria in the Greater Mekong Subregion is complex and rapidly evolving. Malaria control and elimination efforts face a daunting array of challenges including multidrug-resistant parasites. This review presents secondary data collected by the national malaria control programs in the six countries between 1998 and 2010 and examines trends over the last decade. This data has a number of limitations: it is derived exclusively from public sector health facilities; falciparum-specific and then pan-specific rapid diagnostic tests were introduced during the period under review; and, recently there has been a massive increase in case detection capability as a result of increased funding. It therefore requires cautious interpretation. A series of maps are presented showing trends in incidence, mortality and proportion of cases caused by Plasmodium falciparum over the last decade. A brief overview of institutional and implementation arrangements, historical background, demographics and key issues affecting malaria epidemiology is provided for each country. National malaria statistics for 2010 are presented and their robustness discussed in terms of the public sector's share of cases and other influencing factors such as inter country variations in risk stratification, changes in diagnostic approach and immigration. Targets are presented for malaria control and where appropriate for elimination. Each country's artemisinin resistance status is described. The epidemiological trends presented reflect the improvement in the malaria situation, however the true malaria burden is as yet unknown. There is a need for continuing strengthening and updating of surveillance and response systems. PMID- 24159831 TI - Malaria vectors in the Greater Mekong Subregion: overview of malaria vectors and remaining challenges. AB - Malaria transmission in the Greater Mekong Subregion depends on, among other factors, vector behavior and ecology, and the degree of contact between humans and the Anopheles mosquitoes. This chapter will review and update knowledge presented in the 2003 Mekong Malaria monograph for planning and implementing evidence-based vector control programs. Collation of 150 publications and reports showed that the highest number of vector species reported included An. minimus Theobald complex (26.74%), An. dirus Peyton and Harrison (14.26%), An. sundaicus (Rodenwaldt) (5.65%), An. sinensis Wiedemann (4.29%), An. maculatus Theobald (4.23%), An. philippinensis Ludlow (1.62%), An. annularis Van der Wulp (0.37%), An. campestris Reid (0.25%), and An. lesteri Baisas and Hu (=anthropophagus) (0.045%). Other Anopheles species accounted for 44.44%. Anopheles dirus was incriminated as a vector of Plasmodium knowlesi malaria in Viet Nam for the first time, but remained a suspected simian vector in other countries in the region. Well-designed trials of innovative strategies in intractable and difficult situations are needed, including a better understanding of the various causal relations and interactions between physiology, environment, and vector bionomics. While current front-line vector control interventions have contributed significantly to a worldwide decrease of malaria, indoor residual spraying and insecticide-treated bednets/ long lasting insecticidal bednets have had variable impact on exophilic/exophagic and/or early biting vectors. As vectors' responses to control measures vary in different areas, entomological studies on the efficacy of insecticide-treated bednets and other innovative control tools to ensure that strategies are tailored to local circumstances. Given that current tools are insufficient to break transmission cycles, more strategic investments into research on outdoor transmission, monitoring of insecticide resistance, vector species identities, vector mapping, target profiles of new control technologies and delivery systems are required. PMID- 24159832 TI - Migration and malaria. AB - Migration is an important global issue as poorly managed migration can result in a diversity of problems, including an increase in the transmission of diseases such as malaria. There is evidence to suggest that malaria is no longer a forest dependent disease and may largely be affected by population movements, mostly to agricultural areas. While internal and transnational migration has different legal implications in most countries, both types of migration occur for the same reasons; economic and/ or safety. Although migration in itself is not a definitive risk for malaria, several factors can put, migrants and local communities alike, in vulnerable situations. In particular, infrastructure and rural development, deforestation for logging and economic farming, political movements, and natural disasters are some of the major factors that push and pull people in and out of malaria-endemic areas. Therefore, understanding the changing socio-environmental situation as well as population movements and their associated risks for malaria infection, is critical for malaria control, containment, and elimination. Efforts to address these issues should include advocacy, mapping exercises and expanded/ strengthened surveillance to also include migrant health information systems. Malaria related information, prevention measures, and early diagnosis and appropriate treatment should be made easily accessible for migrants regardless of their migration status; not only to ensure that they are equipped with appropriate knowledge and devices to protect themselves, but also to ensure that they are properly diagnosed and treated, to prevent further transmission, and to ensure that they are captured by the surveillance system. PMID- 24159834 TI - Malaria research in the Greater Mekong Subregion: an overview. AB - The Greater Mekong Subregion (GMS) has low transmission of Plasmodium falciparum and P. vivax and is a prime region for malaria elimination based on evidence. The extent of GMS based research is unknown. Pub Med-identified research articles from the GMS were selected based on defined criteria and classified into 24 research areas. A research questionnaire was sent to WHO country offices, national malaria control programs (NMCPs), national research institutes and non governmental organizations (NGOs). Two thousand eight hundred ninety of 3,319 identified publications were included, dating from 1933 to June 2012; 1,485 (51.8%) of 2,890 since 2000. Ten research areas accounted for 2,264 (78.3%) publications: drug resistance 12.8% (n=371), entomology 11.42% (n=330), clinical trials 10.45% (n=302), pathophysiology 9.34% (n=270), epidemiology 8.96% (n=259), pharmacology 6.06% (n=175), parasite biology 5.19% (n=150), malaria control 4.88% (n=141), diagnosis/diagnostics 4.6% (n=133) and clinical studies 4.6% (n=133). Thailand produced most publications, 1,684 (58.27%), followed by Viet Nam (365, 12.63%), Cambodia (139, 4.81%), Myanmar (132, 4.57%), Yunnan Province, China (124, 4.3%) and Lao PDR (79, 2.73%). Other publications were multicountry, including >or=1 GMS country (n=269), or reviews (n=98). Publication numbers increased significantly over time. Eleven questionnaires were received. Principal research areas were treatment seeking behavior, knowledge, attitude and practice surveys, bed net use, access to treatment by migrants, and malaria diagnostics. Research in GMS is broad. Biomedical research dominates peer reviewed publications. NMCP and NGOs focus more on downstream malaria implementation issues. The challenge is to engage GMS research capacity to build quality evidence for malaria elimination. PMID- 24159833 TI - Monitoring antimalarial drug efficacy in the Greater Mekong Subregion: an overview of in vivo results from 2008 to 2010. AB - In vivo Therapeutic Efficacy Studies (TES) have been routinely conducted in the Greater Mekong Subregion (GMS) for decades. Results from the last 10 years have contributed to update national antimalarial drug policies, to identify hotspots of multi-drug resistance and from 2008 onwards, to stimulate ambitious multi country programs and innovative research projects to contain and eliminate artemisinin resistant Plasmodium falciparum strains in the subregion. This paper describes the results of TES of first-line antimalarials in six countries of the GMS from 2008-2010 using the WHO in vivo standard protocol. A total of 91 studies were conducted at 32 sentinel sites testing dihydroartemisinin-piperaquine (DHA PIP), artesunate+mefloquine (A+M), and artemether-lumefantrine (AL) against P. falciparum malaria, as well as chloroquine and DHA-PIP against P vivax. Overall, artemisinin-based combination therapies (ACTs) remained efficacious against falciparum malaria with some exceptions. The 42-day adequate clinical and parasitological response (ACPR) for DHA-PIP dropped significantly to 73% (95% CI 53-87) in 2010 in the same hotspot area of western Cambodia known to harbor artemisinin resistant P. falciparum strains. Because P falciparum sensitivity to artemisinin is a major concern, especially on the Cambodia-Thailand border, attempts were also made to strengthen the monitoring of parasite clearance time elsewhere in the region and globally. The proportion of patients still blood smear positive on Day 3 above 10% is considered a proxy indicator to strongly suspect the appearance of falciparum resistance to artesunate. This has led to substantial extra measures to confirm the suspicion and eventually set up interventions to eliminate artemisinin resistant parasites. Notably, increasing proportions (>10%) of Day 3 positives among falciparum malaria patients treated with DHA-PIP have been observed in western Cambodia, Myanmar, Viet Nam and China from 2008. Percent Day 3 parasitemia associated with A+M has increased along the Thailand-Myanmar border to surpass 10% at several sites, adding to the known pool of sites with 'suspected' artemisinin resistance in the GMS. Chloroquine remains highly effective against P. vivax except for northeastern and north-central Cambodia. TES results from this subregional-wide monitoring of antimalarial efficacy have influenced the changes of 1st line drugs against both P. falciparum and P. vivax in Cambodia, against P. falciparum in selected areas in Thailand, and pinpointed hotspot areas elsewhere that should be closely monitored in order to take action in a timely manner. PMID- 24159835 TI - Malaria control in the Greater Mekong Subregion: an overview of the current response and its limitations. AB - The malaria burden in the Greater Mekong Subregion has been dramatically reduced over the last 20 years but the disease remains an important public health issue in all six countries. This chapter introduces the standard tools for malaria control (long lasting insecticidal nets; indoor residual spraying; early diagnosis and appropriate treatment; epidemic surveillance and response; and, communication) and presents the evidence base supporting the use of each of these tools in the Subregion. Targeting approaches and delivery mechanisms for these tools are presented and discussed country by country. The technical limitations of these standard tools and delivery mechanisms are then discussed in the context of local variations in the epidemiology of the disease. The challenges presented by the feeding and resting habits of local vectors, by the characteristics and behavior of different human population groups, and by particular species and drug resistant strains of malaria parasites are considered. A range of innovative tools and delivery mechanism that have been developed to address these problems are presented and moves to bring these various innovations together to provide a comprehensive package of malaria control services for each risk group are discussed. Implementation arrangements are introduced and an overview of the stakeholder landscape at regional and country level is provided. Finally, remaining programmatic gaps (which include limited coverage, declining funds, drug resistance, weak surveillance and weak health systems) are highlighted and areas in need of further action (including the need for continued innovation) are discussed. PMID- 24159837 TI - [Measurements of stable isotopes in atmospheric CO2 and H2O by open-path Fourier transform infrared spectrometry]. AB - The development of spectroscopic techniques has offered continuous measurement of stable isotopes in the ambient air. The method of measuring environmental stable isotopes based on Fourier transform infrared spectrometry (FTIR) is described. In order to verify the feasibility of the method for continuous measurement of the stable isotopes, an open-path FTIR system was used to measure stable isotopes of CO2 and H2O in ambient air directly in a seven-day field experiment, including 12CO2, 3CO2, H2 16O and HD16 O. Also, the time course of carbon isotopic ratio delta13 C and deuterium isotope composition deltaD was calculated. The measurement precision is about 1.08 per thousand for delta13 C and 1.32 per thousand for deltaD. The measured stable isotopes of CO2 and H2O were analyzed on different time scales by Keeling plot methods, and the deuterium isotopic ratios of evapotranspiration were determined. The results of the field experiment demonstrate the potential of the open-path FTIR system for continuous measurement of stable isotopes in the air. PMID- 24159838 TI - [Extracting municipal solid waste dumps based on high resolution images]. AB - The dramatically increasing informal MSW dumps are endangering the urban environment. Remote sensing (RS) technologies are more efficient to monitor and manage municipal solid wastes (MSW) than traditional survey-based methods. In high spatial resolution remotely sensed images, these irregularly distributed dumps have complex compositions and strong heterogeneities, thus it is still hard to extract them automatically no matter the pixel-or object-based image analysis method is used. Therefore, based on the analysis of MSW characteristics, the present study develops a multiresolution strategy to extract MSW dumps by combining image features at both high resolution and resampled low heterogeneity images, while the high resolution images can provide detailed information and the low resolution images can suppress the strong heterogeneities of informal MSW dumps. Taking the QuickBird image covering part of Beijing as an example, this multi-resolution strategy produced a high accuracy (75%), indicating that this multi-resolution strategy is quite effective for extracting the open-air informal MSW dumps. PMID- 24159839 TI - [Enhancing stimulated Raman scattering of water and heavy water lattice vibration by laser induced plasma]. AB - Stimulated Raman scattering was studied in water and heavy water using pulse laser at the wavelength of 532nm, not only obtaining the stimulated Raman of O-H and O-D stretching vibration, but also obtaining the stimulated Raman lattice vibration. When the laser energy was 130 mJ, the low frequency Stokes and anti Stokes 313 cm(-1) line of water could be observed; When the laser energy was 160 mJ, the low frequnecy Stokes and anti-Stokes 280 cm(-1) line of heavy water could be observed. The results were explained by physics mechanism of laser induced plasma. PMID- 24159840 TI - [Spectroscopic study of dilute magnetic semiconductors Zn(1-x) Fe(x)O nanoparticles]. AB - Diluted magnetic semiconductors Zn(1-x) Fe(x)O nanoparticles with different content (x = 0, 0.01, 0.05, 0.10 and 0.20) were successfully synthesized via hydrothermal method. The X-ray diffraction (XRD) shows that the samples are wurtzite structure and metallic Fe or other secondary phases were not found in the samples. The transmission electron microscopy (TEM) shows that the morphology is nanoparticles with good dispersion, and the lattice is clearly visible. Raman scattering spectrum (Raman spectra) shows that E2 (High) mode broadened, shifted towards the high-frequencies side and decreased the peak intensity. Photoluminescence spectra (PL) shows that the peaks moved to lower energy and the photoluminescence intensity was quenched with increasing Fe doping concentration. The ultraviolet-visible spectrophotometry (UV-Vis) indicates that the optical band gap decreased and red shift occured. All the results indicate that Fe3+ ions successfully substituted for Zn2+ and were incorporated into the crystal lattice of ZnO. PMID- 24159841 TI - [Effect of flat-mirror device on laser-induced plasma radiation characteristics]. AB - To improve the quality of laser-induced breakdown spectroscopy, flat-mirror device was proposed. The effects of flat-mirror device on the radiation characteristics of laser-induced plasma were studied. The experimental results showed that when the device consisted of three flat-mirrors placed around the plasma, the spectral line intensity of Mg, Fe, Ba, Ti and Al increases by about 116.2%, 96.43%, 90.93%, 102.1% and 98.57% than that without flat-mirror device, and the signal-to-noise raises by around 39.17%, 32.48%, 38.07%, 39.95% and 21.30%,respectively. By measuring the plasma parameters, the mechanism of the radiation enhancement obtained with the device consisting of three flat-mirrors was explained. This method was an effective way to improve the detection capacity of LIBS. PMID- 24159842 TI - [Spectroscopic diagnosis of dielectric barrier discharge in long gap under low presssure]. AB - In the present paper, a dielectric barrier discharge (DBD) plasma was generated at low pressure in a DBD device with the eletrode distance of 10cm and using Ar as working gas. The changes in electronic temperature and density in the discharge cavum were studied by means of emission spectrometry. The changes in electronic temperature measured by using corona model were obtained. The variations in electronic density were analyzed using 750.4 nm line intensity. It was found that the plasma electronic temperature and density is various at different positions in the discharge cavum. With the measuring point moving from cathode to anode, the electronic temperature firstly increases slowly, then decreases quickly. While the electronic density increases slowly at first, and then rapidly. PMID- 24159843 TI - [Measurement of nonuniform temperature and concentration distribution by absorption spectroscopy based on least-square fitting]. AB - The measurement of nonuniform temperature and concentration distributions was investigated based on tunable diode laser absorption spectroscopy technology. Through direct scanning multiple absorption lines of H2O, two zones for temperature and concentration distribution were achieved by solving nonlinear equations by least-square fitting from numerical and experimental studies. The numerical results show that the calculated temperature and concentration have relative errors of 8.3% and 7.6% compared to the model, respectively. The calculating accuracy can be improved by increasing the number of absorption lines and reduction in unknown numbers. Compared with the thermocouple readings, the high and low temperatures have relative errors of 13.8% and 3.5% respectively. The numerical results are in agreement with the experimental results. PMID- 24159844 TI - [Effect of substrate temperature on structure and photoluminescence of ZnMgO films]. AB - ZnMgO films were deposited on quartz glass substrates by the ultrasonic spray pyrolysis at different substrate temperatures (450-550 degrees C). The structural, surface morphological and optical properties of the samples were investigated by X-ray diffraction (XRD), scanning electron microscope (SEM) and photoluminescence (PL) spectroscopy. The results demonstrate that the substrate temperature has important effect on structural and optical characteristics. All the films have hexagonal wurtzite polycrystalline structures and the c-axis preferential orientation has an optimum temperature of 530 degrees C. The sample prepared at this temperature owns uniform grain size, smooth surface morphology and better crystalline quality. The width of deep-level emission decreases and the near band edge (NBE) ultraviolet emission peak appears with the increase in temperature by the PL spectrum. When the temperature arrives to 530 degrees C, a distinct NBE emission peak can be observed at 374. 5 nm, while the deep level emission is almost undetectable. PMID- 24159845 TI - [Color-tunable nano-material alpha-NaYF4 : Yb, Er, Tm prepared by microemulsion hydrothermal method]. AB - NaYF4 : Yb3+, Er3+, Tm3+ nanoparticles were prepared by microemulsion hydrothermal method. Crystal phase, morphology and structure of the samples were characterized by X-ray diffraction (XRD) and scanning electron microscopy (SEM). The luminescence properties were studied by up-conversional fluorescence spectroscopy. The XRD patterns of as-prepared samples were in agreement with the PDF # 77-2042 of cubic NaYF4. SEM images of the particles showed that the samples were cotton-like spherical in shape and which were assembled by smaller nano particles. The average size was 120 nm, while the shape was regular and the particle size was homogeneous. Under the excitation of 980 nm, the as-prepared particles could emit blue (438 and 486 nm), green (523 and 539 nm) and red (650 nm) light simultaneously. It can be seen from the color coordinates figure (CIE) that when doping concentration ratio of Tm3+ and E3+ increased from 0 to 2, the whole emitting light color of samples movedto green region. While the ratio was 1 : 1, pseudo white light was obtained. As the ratio changed from 2 to 7, the luminous color was moved to red region. PMID- 24159846 TI - [Emission spectrum temperature sensitivity of Mg4FGeO6 : mn induced by laser]. AB - In order to develop a new sort of thermally sensitive phosphor coating, the emission spectrum thermally sensitivity of Mg4FGeO6 : Mn induced by laser was studied. The spectrum measurement system with heating function was set up, and the emission spectrum of Mg4FGeO6 : Mn at various temperatures were measured. Absorption spectrum was measured, and the mechanism of formation of the structure of double peak was analyzed with the perturbation theory of crystal lattice. The group of peaks around 630 nm is represented by the transitions 4F"2 to 4A2, whereas the group of peaks around 660 nm is due to the transitions 4F'2 to 4A2. The occupancy of both excited states 4F'2 and 4F"2 is in thermal equilibrium. Thus increasing temperature causes the intensity of the emission in the group around 630 nm to increase at the expense of the emission intensity of the group around 660 nm. The various spectral regions in emission differ with temperature, which could be used to support the intensity-ratio measurement method. The intensity-ratio change curve as a function of temperature was fitted, which shows that the range of temperature measurement is between room temperature and 800 K. PMID- 24159847 TI - [Application of terahertz technology in medical testing and diagnosis]. AB - Terahertz science and technology is increasingly emphasized in science and industry, and has progressed significantly in recent years. There is an important aspect of attention in the application of terahertz technology to medicine. The overview of the terahertz characters, terahertz spectroscopy and terahertz imaging technology is introduced. This paper focuses on reviewing the use of and research progress in terahertz spectroscopy and terahertz imaging technology in medical testing and diagnosis. Furthermore, the problems to be solved and development directions of terahertz spectroscopy and terahertz imaging technology are discussed. PMID- 24159848 TI - [Study on the response to the soil moisture polarized spectrum under visible-near infrared band]. AB - Moisture is one of the important parameters in soil polarized spectrum. It has great significance in soil remote sensing band selection and image interpretation; it also provides the information for soil investigation and analysis on physical and chemical properties. In the present paper we tested and analyzed the soil polarized spectrum with different moisture in 350-2 500 nm wavelength range to study on the relationship between soil polarized spectral data and moisture, to determine the spectral response and changes in soil moisture, to establish models between spectral data and soil moisture and select the best forecast model. The results show that the accuracy of the polarized derivative spectra model is higher than the polarized spectral model and absorbance model. All the models showed a water content threshold, and found that it is a certain regularity that critical value of soil moisture in different polarization is near 30%. PMID- 24159849 TI - [Multiple scattering of visible and infrared light by sea fog over wind driving rough sea surface]. AB - The present paper is concerned with computing the multiple scattering characteristics of a sea fog-sea surface couple system within this context. The single scattering characteristics of sea fog were studied by Mie theory, and the multiple scattering of sunlight by single sea fog layer was studied by radiative transfer theory. The reflection function of a statistically rough ocean surface was obtained using the standard Kirchhoff formulation, with shadowing effects taken into account. The reflection properties of the combined sea fog and ocean surface were obtained employing the adding method, and the results indicated that the reflected light intensity of sea fog increased with the sea background. PMID- 24159850 TI - [Low carbon number fatty acid content prediction based on near-infrared spectroscopy]. AB - The rapid prediction of the low-carbon fatty acids (C < or = 14) content in grease samples was achieved by a mathematical model established by near infrared spectroscopy combined with support vector machine regression (SVR). In the present project, near-infrared spectrometer SupNIR-5700 was used to collect near infrared spectra of 58 samples; partial least square (PLS) was applied to remove the strange samples, and principal component analysis (PCA) was conducted on the measurements; radial basis function (RBF) kernel function was selected to establish a regression model supporting vector machine, and then detailed analysis and discussions were conducted concerning their spectral preprocessing and parameters optimization methods. Experimental results showed that by applying particle swarm optimization (PSO) the model demonstrated improved performance, stronger generalization ability, better prediction accuracy and robustness. In the second pretreatment method after PSO, when the optimization parameters are: C = 2.085, gamma = 22.20, the prediction set and calibration set correlation coefficient (gamma) reached 0.998 0 and 0.925 8, respectively; and root mean square errors (MSE) were 0.000 4 and 0.014 3, respectively. Research results proved that the method based on near infrared spectroscopy and PSO-SVR for accurate and fast prediction of the low-carbon fatty acid content in vegetable oil is feasible. PMID- 24159851 TI - [Application of kernel orthogonal projection to latent structure discriminant analysis in the discrimination of adulterated milk]. AB - Based on the method of kernet Orthogonal Projection to Latent Structure Discriminant Analysis, discrimination models for adulterated milk were established in the present paper. Forty adulterated milk samples with melamine (0.01-3 g x L(-1)) and 40 adulterated milk samples with urea (1-20 g x L(-1)) were prepared, respectively. Then the near-infrared absorption spectra of all samples were measured. The spectra in the range of 4 200-4 800 cm(-1) were selected to construct the KOPLS-DA models for milk adulterated with melamine, milk adulterated with urea and milk adulterated with both melamine and urea. The results showed that, compared with PLS-DA and OPLS-DA models, KOPLS-DA model had better discriminant ability for the adulterated milk, and its classification accuracy rate (CAR) for milk adulterated with melamine, milk adulterated with urea and milk adulterated with both melamine and urea were 95%, 100% and 97.5%, respectively. PMID- 24159852 TI - [IR spectrum characteristics and significance of Luodian jade from Guizhou]. AB - In the present paper we selected some typical samples from Luodian jade to perform FTIR test in order to study the vibration attribution of crystals structure. The results confirm that the main mineral composition of Luodian jade is tremolite. Not only has it been not reported in other IR study on natural nephrite that the absorption bands at wave numbers between 840 and 860 cm(-1) caused by residual diopside exist in Luodian jade with the process of tremolite rock transformed to nephrite, but is also the biggest difference between the Luodian jade and other nephrite. The results reveal important mineralogy evidence of metamorphism of Luodian jade, and on the other hand, it also shows that there is a certain difference in the process of nephrite change between Luodian jade and other natural nephrite. Moreover, it further suggests that Luodian jade is a kind of new genetic nephrite ore. PMID- 24159853 TI - [Use of visible and near infrared reflectance spectroscopy to identify the cashmere and wool]. AB - The wool and cashmere samples (n = 130) from different areas of Gansu province were identified by visible and near-infrared reflectance spectroscopy (Vis/NIRs). The result shows that principal component-mahalanobis distance pattern can identify the wool and cashmere, and the boundary between two categories was clear; The calibration set samples were used to establish calibration qualitative model using PCR combined with the best pretreatment of the spectra and math, including multivariate scattering correction (MSC), first derivative, eight for the best principal component factor, one for uncertainty factor, this calibration model of the predicted was the best, and the result of the external validation was correct completely. Results from this experiment indicate that Vis/NIRs can be utilized to identify the wool and cashmere. PMID- 24159854 TI - [Characterization of processing batch for preparation of radix scutellariae based on dependent component analysis and infrared spectrometry]. AB - Dependent component analysis (DCA) was applied to directly estimate source spectral profiles from IR spectra of synthetic mixtures and characterize processing batch for preparation of radix scutellariae. The results show that DCA can estimate information of dependent components (DCs) from the measured infrared spectral (IR) signal obtained during the processing batch for preparation of radix scutellariae, and the estimated information of DCs is corresponding to the IR features of the active components of scutelliare; by inspection of the change trends of the estimated DCs, the endpoint of the processing batch was determined as 55 min. The proposed approach provides a novel way for process analysis and endpoint determination of procedure for preparation of scutellariae. PMID- 24159855 TI - [Application of wavenumber-linear scaling to the calculated Raman frequencies of polyenes and carotenoids]. AB - Raman spectra of two typical carotenoids (beta-carotene and lutein) and some short (n = 2-5) polyenes were calculated using density functional theory. The wavenumber-linear scaling (WLS) and other frequency scaling methods were used to calibrate the calculated frequencies. It was found that the most commonly used uniform scaling (UFS) method can only calibrate several individual frequencies perfectly, and the systematic result of this method is not very good. The fitting parameters obtained by the WLS method are upsilon(obs)/upsilon(calc)) = 0.999 9 0.000 027 4upsilon(calc) and upsilon(obs)/upsilon(calc)= 0.993 8-0.000 024 8upsilon(calc) for short polyenes and carotenoids, respectively. The calibration results of the WLS method are much better than the UFS method. This result suggests that the WLS method can be used for the frequency scaling of the molecules as large as carotenoids. The similar fitting parameters for short polyenes and carotenoids indicate that the fitting parameters obtained by WLS for short polyenes can be used for calibrating the calculated vibrational frequencies of carotenoids. This presents a new frequency scaling method for vibrational spectroscopic analysis of carotenoids. PMID- 24159856 TI - [Strain in GaN epi-layer grown by hydride vapor phase epitaxy]. AB - In the present paper, strain in GaN epitaxial layer grown by hydride vapor phase epitaxy (HVPE) was investigated by means of high-resolution X-ray diffraction (HRXRD), Raman spectra and photoluminescence (PL) measurements. Both the biaxial in-plane and out-of-plane strains (of the order of -10(-4) and 10(-4), respectively) and the hydrostatic strain component (of the order of -10(-5)) were extracted from HRXRD measurements. These values agreed well with the ones computed from the blue-shift of E2 Raman mode and the near-band-edge PL peak. The results showed that strains in GaN layer were superposed by the biaxial strain and hydrostatic strain. PMID- 24159857 TI - [The analysis and identification of fritillaria cirrhosa by Raman spectra]. AB - Laser Raman spectrum technology was used to distinguish fritillaria cirrhosa from its adulterants rapidly and accurately. The study is based on that different traditional Chinese medicine contains different chemical compositions, and the differences could be displayed in Raman spectra. The Raman spectra of fritillaria cirrhosas shows that several characteristic strong peaks could be found at 442, 480, 863, 941, 1 083, 1 129, 1 342, 1 463 and 2 910 cm(-1), and a few obvious peaks appear at 111, 302, 360, 409, 527, 579, 618, 718, 767, 1 052, 1 083, 1 207 and 1 261 cm(-1). According to the Raman spectra, a Raman fingerprint of fritillaria cirrhosa was set up, which could be used to distinguish its adulterants. This analysis could be used in identifying fritillaria cirrhosa rapidly, accurately and nondestructively. PMID- 24159859 TI - [Study of interaction of umbelliferone with three aromatic amino acids by fluorescence spectroscopy]. AB - The interaction between umbelliferone (UMB) with tryptophan (Trp), tyrosine (Tyr) and phenylalanine (Phe) was studied by using fluorescence (FS) and ultraviolet (UV) spectroscopy. The results show that UMB can strongly quench the fluorescence of the three aromatic amino acids with the maximum quenching wavelengths at 347, 303 and 282 nm, respectively. Data analyses based on the Stern-Volmer curve and the UV spectroscopy show that static quenching occurred through the formation of the complexes of UMB with each aromatic amino acid in a molar ratio of 1 : 1. The binding constant K(c) of UMB with Trp, Tyr and Phe is 2.993 x 10(6), 7.858 x 10(4) and 1.186 x 10(3) L x mol(-1) (298.15 K) and 2.702 x 10(4), 1.063 x 10(5) and 8.352 x 10(3) L x mol(-1) (310.15 K), respectively. The thermodynamic parameters indicate that UMB has a strong interaction with the three aromatic amino acids. Hydrogen bond and Van der Waals force may play a major role in the reaction of UMB with Trp, whereas hydrophobic interaction should be responsible for the binding of UMB with Tyr and Phe. In addition, the dipole-dipole interaction may be another factor in the reactions between UMB and the three aromatic aminoacids. PMID- 24159860 TI - [Characterizing composition and transformation of dissolved organic matter in subsurface wastewater infiltration system]. AB - In the present study, the soil column with radius of 30 cm and height of 200 cm was used to simulate a subsurface wastewater infiltration system. Under the hydraulic loading of 4 cm x d(-1), composition and transformation of dissolved organic matter (DOM) from different depths were analyzed in a subsurface wastewater infiltration system for treatment of septic tank effluent using three dimensional excitation emission matrix fluorescence spectroscopy (3D-EEM) with regional integration analysis (FRI). The results indicate that: (1) from different depth, the composition of DOM was also different; influent with the depth of 0.5 m was mainly composed of protein-like substances, and that at other depths was mainly composed of humic- and fulvic-like substances. (2) DOM stability gradually increased and part of the nonbiodegradable organic matter can be removed during organic pollutants degradation process. (3) Not only the organic pollutants concentration was reduced effectively, but also the stability of the DOM improved in subsurface wastewater infiltration system. PMID- 24159861 TI - [Studies on thermal denaturation of peanut allergen Ara h1 and its interaction with reducing sugars]. AB - The thermal denaturation of peanut allergen Ara h1, its interaction with reducing sugars and the corresponding changes in allergenicity were investigated by circular dichroism (CD), fluorescence and ELISA method comprehensively. The experimental results indicate that the secondary structure of Ara h1 changes significantly along with decreasing alpha-helical structure and its allergenicity with the temperature higher than 85 degrees C, and that both xylose and fructose can stabilize Ara h1 protein structure through interacting with Ara h1 protein and decrease its allergenicity obviously. This study should be helpful to the further understanding of sensitization mechanism of food allergy and be useful for the guidance on reasonable manufacturing of peanut foods. PMID- 24159862 TI - [Super-low-frequency spectrum analysis for buried faults in coalfield]. AB - Based on the super-low-frequency (SLF) electromagnetic detection technology, the advanced detection for the buried fault in the coalfield is still at the exploratory stage, while the technology has a strong practical significance for production and design of the coal mine. Firstly, in this paper, the SLF electromagnetic detection signals were collected in study area. Spectrum analysis of SLF signal by wavelet transform can remove high-frequency noise. Secondly, the profile of the measuring line across the fault was analyzed and interpreted geologically. Accordingly SLF spectrum characteristics of the buried fault could be researched. Finally, combined with the geological and seismic data, the characteristics and distribution of fault structures can be verified in the mining area. The results show that: the buried fault could be detected quickly and effectively by SLF electromagnetic detection Hence, SLF electromagnetic detection technology is an effective method for buried fault detection. PMID- 24159863 TI - [Study on the co-adsorption mechanism of Pb (II) and chlorpyrifos on arid loess in northwestern China]. AB - The co-adsorption characteristics of Pb(II) and chlorpyrifos on arid loess were investigated with batch adsorption procedures, and the co-adsorption mechanism was studied with approaches of SEM, FT-IR, XRD and theoretical analysis. The experimental results indicated that the adsorption process of Pb(II) and chlorpyrifos on loess fit better the Langmuir isotherm, the maximum adsorption capacity of q(m) is 12.5 and 0.64 mg x g(-1) for Pb(II) and chlorpyrifos on loess, respectively, and the reaction could be illustrated with pseudo-second order kinetic equation. The SEM micrograph of loess surface varies little after the adsorption process of Pb(II) and chlorpyrifos, and certain wave peaks of FTIR spectra red-shift, disappears or intensity-decrease, with the XRD pattern and theoretical analysis, the adsorption mechanism is described as follows: the adsorption of Pb (II) on arid loess is the chemical-effect of coordination complexation and Van der Waals force; the physical-adsorption on chlorpyrifos involves the interception function, hydrogen bonds and Van der Waals force, and chemical adsorption effect to some extent. The organic matter in arid loess plays an important role in Pb(II) and chlorpyrifos adsorption. PMID- 24159864 TI - [Effects of water stress on red-edge parameters and yield in wheat cropping]. AB - The objective of the present paper is to study the influence of water stress on wheat spectrum red edge parameters by using field wheat spectrum data obtained from water stress experiment. Firstly, the authors analyzed the influence of water stress on wheat spectrum reflectance. Then the authors got the wheat red edge position and red edge peak through calculating wheat spectrum first-order differential and analyzed the influence of water stress on wheat red edge parameters. Finally the authors discussed the relationship between red peak and wheat yield. The results showed that the wheat red edge position shows "red shift" at the beginning of the wheat growth period and "blue shift" at the later period of the wheat growth period under the water stress experiment. Also, the red edge peak of the wheat showed that red edge peak increased with the water stress sharpening at the beginning of the wheat growth period, and then the red edge peak reduced with the water stress sharpening. The wheat red edge peak presented positive correlation with the wheat yield before the elongation period, and exhibited negative correlation after that period. PMID- 24159865 TI - [Spectral properties, photodynamic anticancer activity and the interaction with albumin of silicon phthalocyanine axially modified by pyrimidine derivatives]. AB - Photophysical photochemical properties, in vitro photodynamic anticancer activity and interaction with albumin of a new axially modified silicon phthalocyanine, i. e. di (2-amino-6-trifluoromethyl-4-pyrimidinyloxy) silicon phthalocyanine (SiPcF), were studied in the present paper. The Q band maximum absorption of SiPcF located at 686 nm with the molar absorption coefficient of 2.3 x 10(5) mol( 1) * L * cm(-1). The fluorescence emission of SiPcF peaked at 694 nm with a fluorescence quantum yield of 0.46. Its singlet oxygen quantum yield produced by photosensitization is 0.38, suggesting that SiPcF is an effective 1O2 photosensitizer. There is strong interaction between SiPcF and bovine serum albumin (BSA). The binding constant is 4.33 x 10(5) mol X L(-1) and the number of binding sites is 1. In vitro experiments show that SiPcF had a high photodynamic anticancer activity against human hepatoma cells HepG2 with an IC50 value down to 5 x 10(-7) mol X L(-1). PMID- 24159866 TI - [Research on methane concentration monitoring system based on electro-optical modulation interference]. AB - Gas monitoring for methane concentration has been applied in many areas, while the vast majority of methods were based on the chemical reaction. There is a low security and poor stability shortcomings. In contrast, it is of high stability and strong anti-interference ability to monitor methane concentration using optical interferometry for quantitative analysis. As the system static interference limits the spectrcum resolution, we designed the electro-optical modulation interference system to further improve the detection accuracy for methane concentration. In the interferometer system, a variable refractive index crystal LiNbO3 was used for electro-optical modulation, and the static optical path length scan range was increased to improve the spectrum resolution. Both sides of the crystal were loaded with opposite phase modulated signal, so that it does not change the improved spectrum resolution interferometer size. By derivation of refractive index modulation as a function of optical path difference, the simulation found that the resolution was increased by nearly an order of magnitude than interference system spectrum resolution of the same size. The experiments used the SGT-3-type acousto-optical modulator and the 1 650 nm infrared lasers to detect different concentrations of methane gas. The experimental results show that the method is better than the traditional pyroelectric method in terms of accuracy and stability, and more suitable for application in the mine complex environment. PMID- 24159867 TI - [Study of spatial interpolation of soil Cd contents in sewage irrigated area based on soil spectral information assistance]. AB - To acquire the accuracy distribution information of soil heavy metal, improving interpolation precision is very important for agricultural safety production and soil environment protection. In the present study, the spatial variation and Cokriging interpolation of soil Cd was studied in a sewage irrigation area. Fifty two soil samples were collected to measure the contents of soil total Cd (TCd), available Cd (ACd), pH, organic matter (OM), iron oxide (Fe2 O3) and soil reflection spectrum. Through correlation analysis, it was found that TCd and ACd had a significant correlation with soil first-order differential spectrum ( 0.585** at 759 nm and -0.551** at 719 nm, respectively), which were much higher than the correlation coefficients between soil Cd contents and other environmental variables (pH, OM and Fe2O3). The spatial patterns of soil Cd were predicted by Cokriging which used soil first-order differential spectrum as covariate. Compared with the Kriging, the root-mean-square error decreased by 8.22% for TCd and 20.09% for ACd, respectively; the correlation coefficients between the predicted values and measured values increased by 27.45% for TCd and by 53.13% for ACd, respectively. Meanwhile, the prediction accuracy improved by Cokriging with soil spectrum as covariate was still higher than by Cokriging with soil environment variables (OM and Fe2O3). Therefore, it was found that Cokriging was a more accurate interpolation method which could provide more precise distribution information of soil heavy metal. At the same time, soil reflection spectrum was shown to be more economic, time-saving and easier to acquire than these usual environment variables, which indicated that soil spectrum information is more suited as a covariate used in Cokriging. PMID- 24159868 TI - [Study on the enhanced spectrum quantitative analysis of SDBS induced by beta cyclodextrin]. AB - A novel enhanced ultraviolet absorption spectrometry method was developed for the quantitative analysis of SDBS induced by beta-cyclodextrin(beta-CD) with strong interferences. The ultraviolet absorption spectra of SDBS indicated that the presence of beta-CD could result in the enhancement of absorption intensities of SDBS. A good linearity was obtained between the UV-absorption intensity of the system and the concentration of SDBS. The results indicated that the determination precision and the determination ranges of SDBS could be greatly improved by beta-CD. The effect of several common interfering substances (SDS, OP 10, HPAM) on the determination of SDBS could be significantly reduced in beta-CD aqueous solution. Therefore, the maximum errors of the determined SDBS were less than 2.0% under multifactor interferences, and the precision of the method was also as high as 10(-2) - 10(-3) mg x L(-1). The stable inclusion of beta-CD and SDBS could be automatically formed in water with molar ratio of 1 : 1. The stability constant of the inclusion, K(a), was 87 and the standard Gibbs function of molar reaction, delta(gamma)G(m)(see symbol) (298 K), was -11.064 kJ x mol( 1). FTIR analysis exhibited that SDBS could be induced by beta-CD since the phenyl group in SDBS molecule could exist stably in the cavity of beta-CD and form the inclusion. PMID- 24159869 TI - [Study on early detection of gray mold on tomato leaves using hyperspectral imaging technique]. AB - The present paper put forward the technology route for feature images extraction of grey mold sick on tomato leaves based on SIMCA--combination image extraction based on MLR-grey mold sick information extraction based on minimum distance method. Firstly, through the 680-740 nm band's variance image and the discrimination power parameter, the feature band images was found, then the feature bands information was used as the input of MLR analysis, and under the 0.5 accuracy threshold value, 99% accuracy was obtained, which showed the discrimination power of the features bands for grey mold sick tomato leaf detection, and using the MLR regression coefficient to extract a band combination image, and through the minimum distance method, tomato grey mold sick information was found. The result shows that the proposed method has a very good prediction ability and greatly reduces the hyperspectral data processing time. PMID- 24159870 TI - [The noise filtering and baseline correction for harmonic spectrum based on wavelet transform]. AB - The problem of noise and baseline drift is a hot topic in infrared spectral harmonic detection system. This paper presents a new algorithm based on wavelet transform Mallet decomposition to solve the problem of eliminating a variety of complex noise and baseline drift in the harmonic detection. In the algorithm, the appropriate wavelet function and decomposition level were selected to decomposed the noise, baseline drift and useful signal in the harmonic curve into different frequency bands. the bands' information was analysed and a detecting band was set, then the information in useful frequency was reserved by zeroing method of treatment and the coefficient of the threshold. We can just use once transform and reconstruction to remove interference noise and baseline from double-harmonic signal by applying the wavelet transform technique to the harmonic detection spectrum pretreatment. Experiments show that the wavelet transform method can be used to different harmonic detection systems and has universal applicability. PMID- 24159871 TI - [Research on spectral characteristics of the water content of snow in the northern slope of Tianshan Mountain during snow melt]. AB - The research on water content of snow has the real meaning of the flow of runoff and flood in Spring. Our team got the original data from ASD and Snow Folk, meanwhile these data were anglicized and handled under the help of SPSS19.0 and Excel. The result shows that there are several valleys for the absorbing in visible and near-infrared region in the curve of spectrum characteristics; the spectrum characteristics and the water content of surface snow are negative correlated, and this kind of relation will change with the increase in wavelength, and there lies three minimum values of correlation in the visible and near infrared region. The prediction model wasconstructed, which lies in the visible light band, the result is positive, the model in the band of 350 nm has high-precision, reaching 75.9%, and there is high fitting degree of the predicted and measured values, while in the near infrared, the model constructed in the band of 1 204 nm holds the highest accuracy. PMID- 24159872 TI - [Study of the effect of surface reflectance on atmospheric CO2 retrieval and ratio spectrometry]. AB - Retrieving atmospheric CO2 concentration from space-based infrared measurements is an ill-posed problem, and the uncertainty of ground properties is an important impacting factor. For the requirement of high precision retrieval of atmospheric CO2, the effects of surface reflectance must be corrected. Thus a surface reflectance correction method is proposed. In this correction method, the selection of non-CO2 absorption (off-line) channel is an important part, so several different types of off-line channels were compared and analyzed. We finally found that averaging all data of multi-channels as off-line channel is the best way, in which the retrieval precision is highest and dispersion is lowest, because the advantage is that averaging many data can reduce random error. The effects of surface reflectance on CO2 retrieval decreased significantly after correction using ratio spectrometry combined with the selected off-line channel, and CO2 retrieval precision improved greatly. PMID- 24159873 TI - [Using in-situ reflectance to monitor the chlorophyll concentration in the surface layer of tidal flat]. AB - An optical monitoring method is proposed for the rapid, non destructive measurements of chlorophyll concentration (Chl-a) in the surface sediments of emerged tidal flat, and it can be further applied in remote sensing work. Hyperspectral reflectance of intertidal sediments were measured in day time at the tidal flats of the Sishili Bay, the Northern Yellow Sea, and surface sediments (3 mm) were sampled for the in-door measurements of Chl-a. On the basis of the reflectance at 650, 675 and 700 nm, the indices of normalized difference index of microbenthos (NDI-MPB) and trough depth (T-depth) were proposed for the measurements of microphytobenthos biomass. T-depth can be used to remove the linear background spectral noises and indicate the existence of microphytobenthos; Good linear relationship was observed between NDI-MPB and Chl a content in sediments (2.22-49.36 mg x m(-2), r > 0.99), which may be used to monitor the biomass of microphy to benthos. PMID- 24159874 TI - [Classification of hyperspectral imagery based on ant colony compositely optimizing SVM in spatial and spectral features]. AB - A novel classification algorithm of hyperspectral imagery based on ant colony compositely optimizing support vector machine in spatial and spectral features was proposed. Two types of virtual ants searched for the bands combination with the maximum class separation distance and heterogeneous samples in spatial and spectral features alternately. The optimal characteristic bands were extracted, and bands redundancy of hyperspectral imagery decreased. The heterogeneous samples were eliminated form the training samples, and the distribution of samples was optimized in feature space. The hyperspectral imagery and training samples which had been optimized were used in classification algorithm of support vector machine, so that the class separation distance was extended and the accuracy of classification was improved. Experimental results demonstrate that the proposed algorithm, which acquires an overall accuracy 95.45% and Kappa coefficient 0.925 2, can obtain greater accuracy than traditional hyperspectral image classification algorithms. PMID- 24159875 TI - [The impact of load density differences on land subsidence based on build-up index and PS-InSAR technology]. AB - The excessive mining for underground water is the main reason inducing the land subsidence in Beijing, while, increasing of load brought by the urban construction aggravate the local land subsidence in a certain degree. As an international metropolis, the problems of land subsidence that caused by urban construction are becoming increasingly highlights, so revealing the relationship between regional load increase and the response of land subsidence also becomes one of the key problems in the land subsidence research field. In order to analyze the relationship between the load changes in construction and the land subsidence quantitatively, the present study selected the TM remote sensing image covering Beijing plain and used Erdas Modeler tool to invert the index based on building site (IBI), acquired the spatial and temporal change information in research area further; Based on results monitored by PS-InSAR (permanent scatterer interferometry) and IBI index method, and combined with the GIS spatial analysis method in the view of pixels in different scales, this paper analyzes the correlation between typical area load change and land subsidence, The conclusions show that there is a positive correlation between the density of load and the homogeneity of subsidence, especially in area which has a high sedimentation rate. Owing to such characteristics as the complexity and hysteretic nature of soil and geological structure, it is not obvious that the land subsidence caused by the increase of load in a short period. But with the increasing of local land load made by high density buildings and additional settlement of each monomer building superposed with each other, regional land subsidence is still a question that cannot be ignored and needs long-term systematic research and discussion. PMID- 24159876 TI - [Estimation of chlorophyll content in apple tree canopy based on hyperspectral parameters]. AB - The hyperspectral reflectance of apple tree canopy during spring shoots stopping growth period was measured using ASD FieldSpec3 field spectrometer. Original spectral data were processed in deviation forms, and significant spectrum parameters correlated with chlorophyll content were found out with correlation analysis. The best vegetation indices were chosen and the apple canopy chlorophyll content estimation model was established by analyzing vegetation index of two-band combination in the sensitive region 400-1 350 nm. The result showed that (1) The sensitive band region of apple canopy chlorophyll content is 400-1 350 nm. (2) The vegetation index CCI(D(794)/D(763)) can commendably estimate the apple canopy chlorophyll content. (3) The model with CCI(D(794)/D(763)) as the independent variables was determined to be the best for chlorophyll content prediction of apple tree canopy. Therefore, using hyperspectral technology can estimate apple canopy chlorophyll content more rapidly and accurately, and provides a theoretical basis for rapid apple tree canopy nutrition diagnosis and growth monitoring. PMID- 24159878 TI - [Indirect determination of Cr(III) and Cr(VI) in milks by hydride generation fluorescence spectrometry]. AB - In the medium of 3 mol x L(-1) hydrochloric acid, Cr(VI) oxidized As(III) to be As(V), the As(III) content, which was left over, was determined by hydride generation-fluorescence spectrometry, giving that it was inversely proportional to Cr(VI) content. Based on the same principle and combined with potassium permanganate oxidation of Cr(III) to be Cr(VI), the Cr(III) was, therefore, determined. The sample digestion procedures and co-existing ions which might have interference were investigated. The instrumental operation parameters, reaction acidity and other influence factors were studied. Under optimum operation conditions, a good linear relationship was obtained in the range of 4.0-20 microg x L(-1) Cr. The detection limit of the method was 2.5 microg x L(-1). When the method was applied to milk analysis, a relative standard deviation (RSD, n = 6) of 1.6%-2.7% was found. The recovery was 96.5%-104.2%. PMID- 24159877 TI - [Analysis of the mineral elements of Lactuca sativa under the condition of different spectral components]. AB - Mineral elements absorption and content of Lactuca sativa under different spectral component conditions were studied by ICP-AES technology. The results showed that: (1) For Lactuca sativa, the average proportion for Ca : Mg : K : Na : P was 5.5 : 2.5 : 2.3 : 1.5 : 1.0, the average proportion for Fe : Mn : Zn : Cu : B was 25.9 : 5.9 : 2.8 : 1.1 : 1.0; (2) The absorptions for K, P, Ca, Mg and B are the largest under the LED treatment R/B = 1 : 2.75, red light from fluorescent lamps and LED can both promote the absorptions of Fe and Cu; (3)The LED treatments exhibiting relatively higher content of mineral elements are R/B = 1 : 2.75 and R/W = 1 : 1 while higher dry matter accumulations are R/B = 1 : 2.75 and B/W = 1 : 1. PMID- 24159879 TI - [Determination of heavy metals in artificial soil on railway rock-cut slopes by microwave digestion-AAS]. AB - The purpose of this paper is as follows: (1) Optimizing the parameters of microwave digestion-atomic absorption spectroscopy (AAS) and establishing method for the determination of heavy metals in artificial soils. (2) Evaluating heavy metal pollution conditions in artificial soil samples from railway rock-cut slopes. The results showed that the mixture of HNO3-H2O2-HF was found to have the best digestion efficiency; under the optimized conditions, the recoveries of the method ranged from 95% to 105%; the measurement precision and the relative deviation were less than 4% and 5%, respectively; the concentrations of Cd, Pb and Zn were significantly higher in the artificial soil on railway rock-cut slope than in the control soil, and they were 4.7, 1.3 and 1.2 times as much as the control soil, respectively; compared to the contents of Cr, Cu and Fe in control soils, there was no significant difference. This research will provide a reliable method for determining metal elements in artificial soils on rock-cut slopes and a theoretical basis for the management of the railway rock-cut slopes. PMID- 24159880 TI - [Synthesis of crosslinked polymer containing beta-cyclodextrin and its adsorption for Pb2+ and Zn2+ studied by AAS]. AB - Crosslinked copolymer(AA/beta-CD-AA/ABE) containing beta-cyclodextrin was synthesized by microwave heating with acylation, allyl-biphenyl-ether(ABE), crylic acid(AA) as monomer and N, N-methylenebisacrylamide (MBA) as cross-linking agent, and characterized by means of FTIR. The adsorption of Pb2+ and Zn2+ on the synthesized copolymer and the factors (adsorption time, pH and temperature) which affect the adsorption capacity were investigated by atomic absorption spectrometry (AAS) as the detection means. The results show that the optimum experimental conditions of adsorption: 35 degrees C, 2 h and pH 2-3, adsorbance Q for Pb2+ reached maximum 29.5 mg x g(-1); 30 degrees C, 3 h and pH 3-4, adsorbance Q for Zn2+ reached maximum 43.7 mg x g(-1); the adsorption equilibriums for Pb2+ and Zn2+ fit the Freundlich on the whole. PMID- 24159881 TI - [Application of confocal technology based on polycapillary X-ray lens in measuring thickness]. AB - A confocal micro X-ray fluorescence thickness gauge based on a polycapillary focusing X-ray lens, a polycapillary parallel X-ray lens and a laboratory X-ray source was designed in order to analyze nondestructively the thickness of thin film and cladding material. The performances of this confocal thickness gauge were studied. Two Ni films with a thickness of about 25 and 15 microm respectively were measured. The relative errors corresponding to them were 3.5% and 7.1%, respectively. The thickness uniformity of a Ni films with a thickness of about 10 microm was analyzed. This confocal technology for measuring the thickness was both spatially resolved and elemental sensitive, and therefore, it could be used to measure the thickness of the multilayer sample and analyze the thickness uniformity of the sample. This confocal thickness gauge had potential applications in analyzing the thickness of sample. PMID- 24159882 TI - [Study on high-temperature phase change of tobermorite]. AB - In the present paper, the high-temperature phase change of pure tobermorite was investigated by TGA/DSC, X-ray diffraction and infrared spectroscopy (IR) respectively. The DSC results showed that four interlayer water molecules were lost when they were heated at 300 degrees C. As the temperature increased to 724 degrees C, Si-O-H bonds were cleaved and dehydroxylation occurred. The XRD results showed that many diffraction peaks o f tobermorite disappeared and the crystal structure was broken and collapsed. Then tobermorite tends to be disordered and amorphous. When the calcination temperature increased to 861 degrees C, the disordered structure recombined to wollastonite, and the crystal structure became ordered and stable. Finally, the structure completely transformed to 2M-wollastonite at 1 000 degrees C. It should include the process of high-temperature phase change of tobermorite: tobermorite --> dehydration tobermorite --> dehydroxylation tobermorite --> wollastonite. PMID- 24159883 TI - [Study on the effect of target thickness on output spectrum in transmission anode micro X-ray tube by MC method]. AB - The transmission anode micro X-ray tube is a key component of energy dispersive X ray Fluorescence Analysis (EDXRFA) as exciting source. So in EDXRFA we hope to get the primary X-ray spectrum which is simply distributed. In the present paper, the authors used the Monte Carlo (MC) method to study the spectrum character of the transmission anode micro X-ray tube with different thickness of target. We cut the spectrum into high energy (5keV-50keV) part and low energy (< 5 keV) part and compared them to each other. The result showed that the flux of high energy part is big and the flux of low energy part is small when the electron energy is 50 keV and the target is 4 microm thick Ag. This is better for EDXRFA. PMID- 24159884 TI - [The characteristics of microstructure and chemical compositions of K-feldspar, sphene and zircon with zoning structure]. AB - K-feldspar, sphene and zircon in quartz monzonite from Shahewan, south Qinling, showing strong zoning structure. Characteristics of microstructure and chemical compositions of K-feldspar, sphene and zircon with zoning structure were investigated using advanced instruments of electron probe micro analyses equipped with wavelength dispersive spectrometer (EPM-WDS), scanning electron microscopy with energy dispersive spectrometer (SEM-EDS) and laser ablation--inductively coupled plasma--mass spectrometry (LA-ICP-MS). Our study suggests that K+ could be substituted by small amounts of Na+, Ca2+, Ba2+, Fe2+ and Ce3+. Ca2+ in sphene could be replaced by V3+, Ce3+, Ba2+ and Ti4+ could be substituted by both Fe2+ and Al3+. Zircon contains trace elements like Fe, Th, U, Nb, Ta, Y, Hf, Yb and Pb. Concentration of Si, Al, K, Ca, Na, Mg and Ba in K-feldspar ranked from high to low, among which the contents of K and Na are negatively correlated, the lighter part of BSE images featuring K-feldspar is attributed to comparably higher Ba content, additionally, Si and K contents are elevated while Na content decreased rimward. Ca, Si, Ti, Ba, V, Ce, Al and Fe concentration listed downward, among which higher iron content corresponds to brighter portion of BSE images. Element concentration of zircon could be ranked from high to low as Zr, Si, Nd, Ce, Hf, U, Pb and Th, in which Hf and Zr exhibit negatively correlated. Zr concentration increased while Hf, U and Th concentration decreased from core to rim. PMID- 24159885 TI - [Research on the content prediction model for the determination of nickel in soil by portable energy dispersive X-ray fluorescence analyzer]. AB - The present paper discusses the influence of matrix effect on measurement results when portable energy dispersive X-ray fluorescence analyzer is used for the determination of Ni in soil. Based on the scattered X-ray intensity of WL(alpha) emitted from the X-ray tube on the sample, a correction method was proposed, and it combines with the correction of absorption element, which can effectively overcome the matrix effect. The correlation coefficient of the content prediction model based on this method is 0.999 and the residual standard deviation is 2.541. The average relative error is 3.90 when the content prediction model is used to measure the content of Ni in the national standard soil samples, so the results coincide well with standard values, and the precision is high. PMID- 24159886 TI - [Research on the composition characteristics of imitated Longquan celadon in Jingdezhen and Longquan celadon]. AB - Longquan celadon not only has been loved widely by the domestic and international ceramic lovers, but also imitated by the kiln workers from different places. Among all of the imitated celadons, the most representative products appeared in Ming and Qing dynasties. This paper used EDXRF to test 38 pieces of Longquan celadon of Song, Yuan and Ming dynasty and imitated Longquan celadon in Jingdezhen of Ming dynasty, combined with firing temperature in order to analyze the different composition characteristics of the bodies and the glaze, evolution rule and formation reasons of these samples in the two different places from the views of time and space. It will be contributed to realising the evolution development, mutual communication and influence of the southern celadon and also provide a scientific basis to get the exact information of the celadon including its time and place of origin and so on. PMID- 24159887 TI - [The study of M dwarf spectral classification]. AB - As the most common stars in the galaxy, M dwarfs can be used to trace the structure and evolution of the Milky Way. Besides, investigating M dwarfs is important for searching for habitability of extrasolar planets orbiting M dwarfs. Spectral classification of M dwarfs is a fundamental work. The authors used DR7 M dwarf sample of SLOAN to extract important features from the range of 600-900 nm by random forest method. Compared to the features used in Hammer Code, the authors added three new indices. Our test showed that the improved Hammer with new indices is more accurate. Our method has been applied to classify M dwarf spectra of LAMOST. PMID- 24159888 TI - [An abnormal characteristic line mining method of celestial spectrum based on attribute weight and w(k)-distance]. AB - Outlier mining is one of the effective methods to find the abnormal celestial spectrum data, and is also one of effective ways to discover the special and unknown celestial bodies. In the present paper, an abnormal characteristic line mining method of celestial spectrum is presented based on the attribute weight and w(k)-distance by using the idea of information entropy. Based on it, an abnormal characteristic line mining system of celestial spectrum was designed and implemented. Firstly, attribute weight of characteristic line was determined by using the idea of information entropy, so that important degree was effectively reflected for each characteristic line. Secondly, massive characteristic line data set of celestial spectrum was reduced by utilizing pruning technique based on neighborhood radius, so that candidate set of abnormal characteristic line was obtained by deleting data objects in which there may not be abnormal characteristic lines. Thirdly, w(k)-distance sum was computed according to the deviation between the data objects in the candidate set, and the objects whose w(k)-distance sum value ranks the first top n were regarded as abnormal characteristic line data objects. In the end, the experimental and the system's running results validated the effectiveness and feasibility of the method by using the SDSS star spectral data set. PMID- 24159889 TI - [Automatic recognition of M-star spectral subtype based on fractal coding]. AB - According to the local fractal feature in an astronomical spectrum, the data in the spectrum were coded in three bands 400-510, 600-700 and 780-900 nm. In the present paper, using the position of the matching data block and the minimum matching error, the fractal coding method was used to recognize the subtypes of astronomical spectra for the first time. The experimental results show that the fractal coding method has certain noise immunity and cannot be affected by the calibration error and the effective curves of LAMOST. The fractal method can effectively recognize the subtype of M stars of LAMOST and SDSS. PMID- 24159890 TI - [The realization of moving mirror scanning in FTIR spectrometer using completely digital control method]. AB - In view of the complexity of the conventional control of scanning mirror based on a digital-analog hybrid design, this paper focuses on a concise and efficient control method around the completely digital signal. The quadrate-encoder pulses A and B generated by the scanning mirror were sent into CPLD pins where an algorithm on position control and velocity control had been built. As a result, the CPLD will generate two PWM signals. These two signals are regenerated by a digital power chip to drive the voice of motor bundled with the moving mirror. Experiments validated that the stability of velocity of moving mirror is better than 97.2% and the method can improve the SNR of the measured spectrum and guarantee the accuracy of spectral qualitative and quantitative analyses. PMID- 24159891 TI - [Correction method for infrared spectral emissivity measurement system based on integrating sphere reflectometer]. AB - In view of the influence of non-ideal reference standard on spectral emissivity measurement, by analyzing the principle of infrared emissivity measurement system based on integrating sphere reflectometer, a calibration method suitable for measuring spectral emissivity system using the reflection measurement was proposed. By fitting a spectral reflectance curve of the reference standard sample to the given reflectance data, the correction coefficient of measurement system was computed. Then the output voltage curve of reference standard sample was corrected by this coefficient. The system error caused by the imperfection of reference standard was eliminated. The correction method was applied to the spectral emissivity measurement system based on integrating sphere reflectometer. The results measured by the corrected system and the results measured by energy comparison measurement were compared to verify the feasibility and effectivity of this correction method in improving the accuracy of spectral emissivity measurement. PMID- 24159892 TI - [Sub-field imaging spectrometer design based on Offner structure]. AB - To satisfy imaging spectrometers's miniaturization, lightweight and large field requirements in space application, the current optical design of imaging spectrometer with Offner structure was analyzed, and an simple method to design imaging spectrometer with concave grating based on current ways was given. Using the method offered, the sub-field imaging spectrometer with 400 km altitude, 0.4 1.0 microm wavelength range, 5 F-number of 720 mm focal length and 4.3 degrees total field was designed. Optical fiber was used to transfer the image in telescope's focal plane to three slits arranged in the same plane so as to achieve subfield. The CCD detector with 1 024 x 1 024 and 18 microm x 18 microm was used to receive the image of the three slits after dispersing. Using ZEMAX software optimization and tolerance analysis, the system can satisfy 5 nm spectrum resolution and 5 m field resolution, and the MTF is over 0.62 with 28 lp x mm(-1). The field of the system is almost 3 times that of similar instruments used in space probe. PMID- 24159893 TI - [The coding correction of slit diffraction in Hadamard transform spectrometer]. AB - According to the principles of Hadamard transform spectrometer and the slit diffraction characteristics, the influence of spectrometer entrance slit diffraction of Hadamard transform spectrometer on the measurement result was analyzed, for the diffraction case, the Hadamard transform spectrometer instrument structure matrix was studied, and the Hadamard transform spectrometer encoding/decoding method was established. The analysis of incident spectral verified the correctness of the coding/ decoding. This method is very important for the high precision measurement of Hadamard transform spectrometer. PMID- 24159894 TI - [Central wavelength shift analysis between laboratory and field spectral calibrations of grating based imaging spectrometer]. AB - Spectral calibration must be carried out in order to determine its central wavelength and half-wave band width of each pixel before the usage of imaging spectrometer. But it was found out that these parameters vary as environment changes. The present paper studies the effect based on test field data. The authors analyzed the optical structure and compared the working environmental parameters. Then a theoretical model is established and the influences of vibration, distortion and temperature parameters are evaluated. The theoretical model and the caculation results are in good consistency, which testifies the theoretical model. This research will shed some light on the high accuracy spectral calibration of the grating based imaging spectrometer and its manufacture. PMID- 24159895 TI - [Study on the advanced Schwarzschild imaging spectrometer with high resolution in broadband]. AB - The Schwarzschild optical structure was studied for the application of imaging spectrometer. The perfect astigmatism-corrected condition was obtained based on the analysis of the astigmatism of the Schwarzschild structure. The structure was advanced in the paper. The Schwarzschild imaging spectrum system is composed of two Schwarzschild structures, which are the collimating mirror-convex mirror and the convex mirror-focusing mirror. The calculation was given to present the parameters of the imaging spectrum system. An example of the imaging spectrum system in the waveband of 340-500 nm was designed and proved our design theory. The solution of the initial optimum structure was designed by our theory and simulated. A system with NA 1.25, of which the modulation transfer functions (MTF) of all fields of view are more than 0.58 in the waveband in the required Nyquist frequency (20 lp x mm(-1)), is presented in the paper. The form of the design structure can be changed as C-T system, Ebert-Fastie system and Offner system. The result also certificated that the optical system theory can be applied to the small scale imaging spectrometer with high resolution and spectral broadband. PMID- 24159896 TI - [Research on the transmittance spectrum of wedge thin film filter with oblique incidence]. AB - Angle-tuned thin film filter is widely used in the DWDM system for its broad tunable wavelength range and high rectangular degree. The transmissivity and the half bandwidth is greatly influenced not only by the incident angle, but also by the wedge angle of the non-paralleled thin film filter. In the present paper, the influences of the wedge angle on the transmissivity and the half bandwidth were detailedly analyzed. The proper wedge angle and the orientation can greatly improve the characteristics of the transmittance spectrum. The angle-tuned thin film filter with 0.8 degrees wedge angle was also fabricated. The experimental results show that keeping the wedge angle with the same orientation to the incident angle will worsen the transmissivity and the rectangular degree of the transmittance spectrum. However, keeping the wedge angle orientation reverse to the incident angle will greatly enhance the transmissivity and the rectangular degree of the filter and its tunable wavelength range will broaden by 10 nm. PMID- 24159897 TI - [Design of a compact structure interferometer]. AB - A novel interferometer system based on the combinations of cube-corner reflectors and fixed plane mirrors was designed, the moving mirror drive system was designed and analysed, and its governor PID algorithm was used to ensure that the movement of the moving mirror is collimated, uniform and smooth. The parameters of the optical system of the interferometer and the optical devices were described. Finally, after validation of the experiment, it was indicated that the wave number accuracy, resolution, signal to noise ratio and other key indicators can meet the needs of practical application. PMID- 24159898 TI - [Design and development of trace Cr(VI) sensor]. AB - Hexavalent chromium detection in medicine capsules is generally analyzed in the laboratory, it is difficult to meet the demand for field detection, and to address this problem, a sensor which can be used for on-site detection of trace amounts of hexavalent chromium was designed. It mainly includes chemically sensitive materials, optical sensing module and signal processing module, the chemical sensitive materials is to achieve the conversion of the hexavalent chromium concentration signal, the optical sensing module is to complete a stable output of the laser light source, and the signal processing module is to complete a photoelectric conversion of the weak fluorescence signal, signal amplification, and data processing and displaying. With using the indigenously developed photoelectric acquisition, conversion and signal processing system to complete the rapid detection of trace amounts of hexavalent chromium, so the miniaturization of testing instruments and on-site detection were achieved. Experimental results show that: the sensor detection results have a good linear relationship when the hexavalent chromium concentration is 10-500 microg x L(-1), the linear equation is Y = 1.542 47 x X-2.353 47, and the linearity is 0.998 62, the detection limit reaches 10 microg x L(-1), the sensor response time is about 90 seconds, 5 capsule samples were selected to do the contrast detection, and the results show that the sensor quantitative detection data is reliable, which meets trace hexavalent low cost, fast and field detection demands. PMID- 24159899 TI - The free radical theory of aging is dead. Long live the damage theory! AB - The free radical theory of aging posits that aging is caused by accumulation of damage inflicted by reactive oxygen species (ROS). Although this concept has been very useful in defining the contribution of oxidative damage to the aging process, an increasing number of studies contradict it. The idea that oxidative damage represents only one of many causes of aging also has limitations, as it does not explain causal relationships and inevitability of damage accumulation. Here, it is discussed that infidelity, heterogeneity, and imperfectness of each and every biological process may be responsible for the inevitable accumulation of by-products and other damage forms. Although ROS are prototypical by-products, their contribution to aging is governed by the metabolic organization of the cell, its protective systems, and genotype. These factors are controlled by natural selection and, like dietary and genetic interventions that extend lifespan, change the composition of cumulative damage and the rates of accumulation of its various forms. Oxidative damage, like other specific damage types viewed in isolation or in combination, does not represent the cause of aging. Instead, biological imperfectness, which leads to inevitable accumulation of damage in the form of mildly deleterious molecular species, may help define the true root of aging. Free radical and other specialized damage theories served their purpose in the understanding of the aging process, but in the current form they limit further progress in this area. PMID- 24159900 TI - Composite molecular assemblies: nanoscale structural control and spectroelectrochemical diversity. AB - The controlled deposition of metal complexes from solution on inorganic surfaces offers access to functional materials that otherwise would be elusive. For such surface-confined interfaces to form, specific assembly sequences are often used. We show here that varying the assembly sequence of two well-defined and iso structural osmium and ruthenium polypyridyl complexes results in interfaces with strikingly different spectroelectrochemical properties. Successive deposition of redox-active layers of osmium and ruthenium polypyridyl complexes, leads to self propagating molecular assemblies (SPMAs) with distinct internal interfaces and individually addressable components. In contrast, the clear separation of these interfaces upon sequential deposition of these two complexes, results in charge trapping or electrochemical communication between the metal centers, as a function of layer thickness and applied assembly sequence. The SPMAs were characterized using a variety of techniques, including: UV-vis spectroscopy, spectroscopic ellipsometry, electrochemistry, synchrotron X-ray reflectivity, angle-resolved X-ray photoelectron spectroscopy, and spectroelectrochemistry. The combined data demonstrate that the sequence-dependent assembly is a decisive factor that influences and provides the material properties that are difficult to obtain otherwise. PMID- 24159901 TI - Total synthesis of thaxtomin A and its stereoisomers and findings of their biological activities. AB - The first and facile total synthesis of thaxtomin A and its three stereoisomers has been achieved. The synthetic approach involves intramolecular nucleophilic cyclization of an amide toward a ketoamide group to produce a C hydroxydiketopiperazine scaffold. The most amazing discovery was that each of the four stereoisomers of TA exhibits different phytotoxic, fungicidal, and antiviral activities. PMID- 24159902 TI - Substance abuse journal: new beginnings. PMID- 24159903 TI - INCASE: accomplishments and challenges. PMID- 24159904 TI - Team-based learning exercise efficiently teaches brief intervention skills to medicine residents. AB - BACKGROUND: Evaluations of substance use screening and brief intervention (SBI) curricula typically focus on learner attitudes and knowledge, although effects on clinical skills are of greater interest and utility. Moreover, these curricula often require large amounts of training time and teaching resources. This study examined whether a 3-hour SBI curriculum for internal medicine residents utilizing a team-based learning (TBL) format is effective for SBI skills as measured by a standardized patient (SP) assessment. METHODS: A waitlist controlled design was employed. RESULTS: Twenty-four postgraduate year 2 (PGY-2) and PGY-3 residents participated in a SP assessment prior to the TBL session (waitlist control group) and 32 participated in a SP assessment after the TBL session (intervention group). The intervention residents demonstrated better brief intervention skills than waitlist control residents, but there were no differences between the groups in screening and assessment skills. Residents receiving the TBL curriculum prior to the SP assessment reported increased confidence in all SBI skills. CONCLUSION: Findings indicate that a brief educational intervention can improve brief intervention skills. However, more intensive education may be needed to improve substance use screening and assessment. PMID- 24159905 TI - Teaching and assessing residents' skills in managing heroin addiction with objective structured clinical examinations (OSCEs). AB - BACKGROUND: Heroin-abusing patients present a significant challenge. Objective Structured Clinical Examinations (OSCEs) allow evaluation of residents' clinical skills. The objective of this study was to examine residents' OSCE performance assessing and managing heroin abuse. METHODS: Evaluation and comparison of heroin specific communication, assessment, and management skills in a 5-station postgraduate year 3 (PGY3) substance abuse OSCE. Faculty used a 4-point Likert scale to assess residents' skills; standardized patients provided written comments. RESULTS: Two hundred sixty-five internal and family medicine residents in an urban university hospital participated over 5 years. In the heroin station, residents' skills were better (P < .001 for both comparisons) in communication (mean overall score: 316 +/- 0.51) than in either assessment (mean overall score: 2.66 +/- 0.60) or management (mean overall score: 2.50 +/- 0.73). The mean score for assessing specific high-risk behaviors was lower than the mean overall assessment score (222 +/- 1.01 vs. 2.74 +/- .59; P < .0001), and the mean score for recommending appropriate harm reduction management strategies was lower than the mean overall management score (2.39 +/- .89 vs. 2.54 +/- .74; P < .005). Standardized patients' comments reflected similar weaknessess in residents' skills. CONCLUSIONS: Assessment and management of heroin abuse were more challenging for residents than general communication. Additional training is required for residents to assess and counsel patients about high-risk behaviors. PMID- 24159906 TI - Stigmatization of substance use disorders among internal medicine residents. AB - BACKGROUND: Evidence suggests that some physicians harbor negative attitudes towards patients with substance use disorders (SUDs). The study sought to (1) measure internal medicine residents' attitudes towards patients with SUDs and other conditions; (2) determine whether demographic factors influence regard for patients with SUDs; and (3) assess the efficacy of a 10-hour addiction medicine course for improving attitudes among a subset of residents. METHODS: A prospective cohort study of 128 internal medicine residents at an academic medical center in New York City. Scores from the validated Medical Condition Regard Scale (MCRS) were used to assess attitude towards patients with alcoholism, dependence on narcotic pain medication, heartburn, and pneumonia. Demographic variables included gender, postgraduate training year, and prior addiction education. RESULTS: Mean baseline MCRS scores were lower (less regard) for patients with alcoholism (41.4) and dependence on narcotic pain medication (35.3) than for patients with pneumonia (54.5) and heartburn (48.9) (P < .0001). Scores did not differ based upon gender, prior hours of addiction education, or year of training. After the course, MCRS scores marginally increased for patients with alcoholism (mean increased by 0.16, P = .04 [95% confidence interval, CI: 0.004-0.324]) and dependence on narcotic pain medication (mean increased by 0.09, P = .10 [95% CI: 0.02-0.22]). CONCLUSIONS: Internal medicine residents demonstrate less regard for patients with SUDs. Participation in a course in addiction medicine was associated with modest attitude improvement; however, other efforts may be necessary to ensure that patients with potentially stigmatized conditions receive optimal care. PMID- 24159907 TI - Internal medicine residents' training in substance use disorders: a survey of the quality of instruction and residents' self-perceived preparedness to diagnose and treat addiction. AB - BACKGROUND: Resident physicians are the direct care providers for many patients with addiction. This study assesses residents' self-perceived preparedness to diagnose and treat addiction, measures residents' perceptions of the quality of addictions instruction, and evaluates basic knowledge of addictions. METHODS: A survey was e-mailed to 184 internal medicine residents at Massachusetts General Hospital in May 2012. RESULTS: Responses were obtained from 55% of residents. Residents estimated that 26% of inpatients they cared for met criteria for a substance use disorder (SUD). Twenty-five percent of residents felt unprepared to diagnose and 62% felt unprepared to treat addiction. Only 13% felt very prepared to diagnose addiction. No residents felt very prepared to treat addiction. Preparedness to diagnose or treat addiction did not differ significantly across postgraduate year (PGY) level. Fifty-five percent rated the overall instruction in addictions as poor or fair. Seventy-two percent of residents rated the quality of addictions training as poor or fair in the outpatient clinical setting, and 56% in the inpatient setting. No resident answered all 6 knowledge questions correctly. Slightly more than half correctly identified the mechanism of buprenorphine and 19% correctly answered a question about naltrexone. Nine percent of residents responded that someone had expressed concern about the respondent's substance use. CONCLUSIONS: Despite providing care for a substantial population with addiction, the majority of internal medicine residents in this study feel unprepared to treat SUDs. More than half rate the quality of addictions instruction as fair or poor. Structured and comprehensive addictions curriculum and faculty development are needed to address the deficiencies of the current training system. PMID- 24159908 TI - Prevalence and sociodemographic correlates of lifetime substance use among a rural and diverse sample of adolescents. AB - BACKGROUND: Data are limited regarding the prevalence of substance use among adolescents in rural and ethnically diverse communities. This study examined rates and sociodemographic correlates of lifetime substance use among adolescents in Mississippi, a rural state that is the poorest in the country (21.3% poverty rate) and has the largest proportion of African Americans per capita (36.3%). METHODS: Participants in this cross-sectional study were 6349 adolescents (6th through 12th grade) who reported on lifetime tobacco, alcohol, marijuana, cocaine, inhalant, hallucinogen, and methamphetamine use. RESULTS: Lifetime smoking (10.2% to 44.5%), alcohol (23.2% to 72.0%), and marijuana use (7.9% to 39.2%) increased steadily when comparing students in 6th to 12th grade. Substances with more serious abuse potential (cocaine [6.7% to 11.1%], inhalants [12.2% to 17.9%], hallucinogens [4.4% to 12.1%], and methamphetamine [3.0% to 6.7%]) displayed more modest increases across grade. Adolescents who classified their race/ethnicity as "Other" (i.e., not white, black/African American, Asian, or Hispanic/Latino/Latina) demonstrated more than 2-fold increased likelihood of methamphetamine use (odds ratio [OR] = 2.42), and increased risk for use of any illicit substance (OR = 1.49). In general, males demonstrated an increased risk for use across substances (OR = 1.15-1.94), and higher income was associated with a decreased likelihood of illicit substance use (OR = 0.51-0.67). Living in a more populated area was associated with an increased likelihood of alcohol (OR = 1.43), marijuana (OR = 2.11), and cocaine use (OR = 2.06), and use of any illicit substance (OR = 1.54). CONCLUSIONS: Mississippi adolescents reported higher rates of lifetime cocaine, inhalant, hallucinogen, and methamphetamine use across all grade levels compared with national surveys. Male gender, low income, and residence in more populated areas were associated with increased use of several substances. Findings demonstrate the need for prevention and intervention programs targeting impoverished rural and ethnically diverse communities. PMID- 24159909 TI - Sociodemographic factors associated with tobacco smoking among intermediate and secondary school students in Jazan Region of Saudi Arabia. AB - BACKGROUND: The objectives of this study were to (i) determine the prevalence of and characteristics associated with tobacco smoking; (ii) identify the factors associated with tobacco smoking; and (iii) evaluate the association between tobacco smoking and khat chewing among intermediate and secondary school students in Jazan Region, Saudi Arabia. METHODS: A cross-sectional study was conducted with a representative sample (N = 4100) of intermediate and secondary school students in Jazan Region. The data were collected using a pretested modified version of the global youth tobacco survey questionnaire. RESULTS: A total of 3923 students from 72 intermediate and secondary schools for males and females in Jazan Region, Saudi Arabia, were included in this study. The ever having smoked prevalence was 17.3%, and the current smoking prevalence was 10.7%. The most important independent predictors of smoking were academic performance (odds ratio [OR]: 5.32), having friends who used khat (OR: 3.23), and having friends who used tobacco (OR: 2.88). CONCLUSIONS: Understanding the factors and predictors associated with tobacco use are crucial to identifying high-risk groups to design tobacco prevention and control programs. For the first time, a strong and statistically significant association was identified between tobacco smoking and khat chewing among intermediate and secondary school students in Jazan Region. Because the use of khat is increasingly spreading outside of its traditional areas to Europe and America, this finding may have an important impact on tobacco control efforts internationally. PMID- 24159911 TI - Self-forgiveness, shame, and guilt in recovery from drug and alcohol problems. AB - BACKGROUND: People with drug and/or alcohol problems often experience feelings of shame and guilt, which have been associated with poorer recovery. Self forgiveness has the potential to reduce these negative experiences. METHODS: The current study tested theorized mediators (acceptance, conciliatory behavior, empathy) of the relationships between shame and guilt with self-forgiveness. A cross-sectional sample of 133 individuals (74.4% male) receiving residential treatment for substance abuse completed self-report measures of shame, guilt, self-forgiveness, and the mediators. RESULTS: Consistent with previous research, guilt had a positive association with self-forgiveness, whereas shame was negatively associated with self-forgiveness. Acceptance mediated the guilt and self-forgiveness relationship and had an indirect effect on the shame and self forgiveness relationship. CONCLUSIONS: These findings emphasize the importance of targeting acceptance when trying to reduce the effects of shame and guilt on self forgiveness. PMID- 24159912 TI - Association of prescription drug misuse with risky motor vehicle behaviors among low-income young women. AB - BACKGROUND: The purpose of this study was to examine the association between prescription drug misuse and risky motor vehicle behaviors among 16-24-year-old women. METHODS: A survey was conducted on misuse of 4 classes of prescription drugs (pain relievers, tranquilizers, stimulants, and sedatives) and past-month risky motor vehicle behaviors among these women during 2008-2010. RESULTS: Overall, 47.7% (1408/2952) of women reported risky motor vehicle behavior(s) in the past month. Misuse of 1 or more of the 4 classes was 30.1% (lifetime), 15.0% (past year), and 6.7% (past month). Misuse of 1 or more of these prescription drug classes was associated with risky motor vehicle behaviors in their lifetime (odds ratio [OR]: 1.83, 95% confidence interval [CI]: 1.54-2.18), past year (OR: 2.25, 95% CI: 1.80-2.83), and past month (OR: 2.70, 95% CI: 1.94-3.78). CONCLUSIONS: The current finding that misuse of 1 or more of the 4 prescription drug classes, irrespective of when this last occurred, is associated with risky motor vehicle behaviors may help formulate awareness programs. PMID- 24159913 TI - Necrosis of the intranasal structures and soft palate as a result of heroin snorting: a case series. AB - BACKGROUND: The link between nasal inhalation of cocaine and nasal and palatal necrosis is well documented. In contrast, few data are available concerning nasal mucosa necrosis related to heroin snorting. The authors report here the retrospective analysis of 24 cases of orofacial lesions in patients with nasal heroin usage, collected between 2006 and 2012. CASES: The cases concern 17 males and 7 females (median age 29.5 (range: 24-42)) with chronic consumption of intranasal heroin (from 2 months to more than 10 years). Six patients had a history of cocaine abuse. The median daily amount of heroin consumption was 5 g (range: 0.5-10). The complications were nasal perforation (11 cases), nasal ulceration or erythema (5 cases), nasal septum necrosis (5 cases), pharyngeal ulceration (3 cases), and palate damages (5 cases). The most common clinical signs and symptoms were nasal pain, purulent sputum, dysphagia, and rhinitis. Maintenance therapy with methadone (19 cases) or buprenorphine (3 cases) was initiated. In 8 cases, the injury improved. DISCUSSION: The potential of heroin to induce destructive orofacial lesions should be considered when nasal damages are observed in patients with drug abuse. A multidisciplinary approach seems to be the most effective means of managing such patients. PMID- 24159910 TI - Why would khat chewers quit? An in-depth, qualitative study on Saudi Khat quitters. AB - BACKGROUND: Khat chewing, which has many adverse health and social consequences, is highly prevalent and socially accepted in the Jazan region of the Kingdom of Saudi Arabia. METHODS: A qualitative study was conducted with 47 adult male former khat users regarding their khat initiation, continuance, and cessation, the amounts of khat they had used, and the health and social consequences of their use and cessation of use. RESULTS: Participants noted a desire to show maturity, ease of availability of khat, and peer pressure as reasons for initiating khat chewing. Many noted long leisure times with little to do as a reason for continuing use. Negative consequences of khat use were seen in economic, health, familial, and sexual areas of their lives. After quitting khat use, participants saw improvements in all of these areas. CONCLUSIONS: A comprehensive community development program (CCDP) tackling, among other issues, the normalization of khat use, substantial leisure times with few positive activities, and misinformation about the "benefits" of khat use, as well as developing peer and family training programs to help prevent or stop khat use, would be useful to reduce khat chewing in this community. PMID- 24159914 TI - State-specific liquor excise taxes and retail prices in 8 US states, 2012. AB - The authors investigated the relationship between state excise taxes and liquor prices in 8 states, using 2012 data for 45 brands. The authors made 6042 price observations among 177 liquor stores with online prices. Using a hierarchical model, the authors examined the relationship between excise taxes and product prices. State excise taxes were significantly related to liquor prices, with an estimated pass-through rate of 0.93. The proportion of price accounted for by excise taxes averaged 7.0%. The authors find that excise taxes do increase the price of alcohol, but states are not taking advantage of this opportunity to reduce alcohol-related morbidity and mortality. PMID- 24159916 TI - Comparative proteomics of peanut gynophore development under dark and mechanical stimulation. AB - Peanut (Arachis hypogaea. L) is an important leguminous crop and source of proteins and lipids. It has attracted widespread attention of researchers due to its unique growth habit of geocarpy, which is regulated by geotropism, negative phototropism, and haptotropism. However, the protein expression pattern and molecular regulatory mechanism underlying the physiological processes of peanut remain unknown. In this study, the peanut gynophores under five treatment conditions were used for proteomic analysis, including aerial growth of the gynophores, the gynophores penetrated into the soil, as well as aerial growth of the gynophores under mechanical stimulation, dark, and mechanical stimulation combined with dark. The analysis of protein abundances in peanut gynophores under these conditions were conducted using comparative proteomic approaches. A total of 27 differentially expressed proteins were identified and further classified into nine biological functional groups of stress and defense, carbohydrate and energy metabolism, metabolism, photosynthesis, cell structure, signaling, transcription, protein folding and degradation, and function unknown. By searching gene functions against peanut database, 10 genes with similar annotations were selected as corresponding changed proteins, and their variation trends in gynophores under such growth conditions were further verified using quantitative real-time PCR. Overall, the investigation will benefit to enrich our understanding of the internal mechanisms of peanut gynophore development and lay a foundation for breeding and improving crop varieties and qualities. PMID- 24159917 TI - Gastrointestinal stromal tumors: a case-only analysis of single nucleotide polymorphisms and somatic mutations. AB - BACKGROUND: Gastrointestinal stromal tumors are rare soft tissue sarcomas that typically develop from mesenchymal cells with acquired gain-in-function mutations in KIT or PDGFRA oncogenes. These somatic mutations have been well-characterized, but little is known about inherited genetic risk factors. Given evidence that certain susceptibility loci and carcinogens are associated with characteristic mutations in other cancers, we hypothesized that these signature KIT or PDGFRA mutations may be similarly fundamental to understanding gastrointestinal stromal tumor etiology. Therefore, we examined associations between 522 single nucleotide polymorphisms and seven KIT or PDGFRA tumor mutations types. Candidate pathways included dioxin response, toxin metabolism, matrix metalloproteinase production, and immune and inflammatory response. METHODS: We estimated odds ratios and 95% confidence intervals for associations between each candidate SNP and tumor mutation type in 279 individuals from a clinical trial of adjuvant imatinib mesylate. We used sequence kernel association tests to look for pathway-level associations. RESULTS: One variant, rs1716 on ITGAE, was significantly associated with KIT exon 11 non-codon 557-8 deletions (odds ratio = 2.86, 95% confidence interval: 1.71-4.78) after adjustment for multiple comparisons. Other noteworthy associations included rs3024498 (IL10) and rs1050783 (F13A1) with PDGFRA mutations, rs2071888 (TAPBP) with wild type tumors and several matrix metalloproteinase SNPs with KIT exon 11 codon 557-558 deletions. Several pathways were strongly associated with somatic mutations in PDGFRA, including defense response (p = 0.005) and negative regulation of immune response (p = 0.01). CONCLUSIONS: This exploratory analysis offers novel insights into gastrointestinal stromal tumor etiology and provides a starting point for future studies of genetic and environmental risk factors for the disease. PMID- 24159918 TI - Increased risk of gastric adenocarcinoma after treatment of primary gastric diffuse large B-cell lymphoma. AB - BACKGROUND: There have been sporadic reports about synchronous as well as metachronous gastric adenocarcinoma and primary gastric lymphoma. Many reports have dealt with metachronous gastric adenocarcinoma in mucosa-associated lymphoid tissue lymphoma of stomach. But to our knowledge, there have been no reports that document the increased incidence of metachronous gastric adenocarcinoma in patients with gastric diffuse large B-cell lymphoma. This retrospective study was conducted to estimate the incidence of metachronous gastric adenocarcinoma after primary gastric lymphoma treatment, especially in diffuse large B-cell lymphoma. METHODS: The retrospective cohort study of 139 primary gastric lymphoma patients treated with radiotherapy at our hospital. Mean observation period was 61.5 months (range: 3.7-124.6 months). Patients profile, characteristics of primary gastric lymphoma and metachronous gastric adenocarcinoma were retrieved from medical records. The risk of metachronous gastric adenocarcinoma was compared with the risk of gastric adenocarcinoma in Japanese population. RESULTS: There were 10 (7.2%) metachronous gastric adenocarcinoma patients after treatment of primary gastric lymphomas. It was quite high risk compared with the risk of gastric carcinoma in Japanese population of 54.7/100,000. Seven patients of 10 were diffuse large B-cell lymphoma and other 3 patients were mixed type of diffuse large B-cell lymphoma and mucosa associated lymphoid tissue lymphoma. Four patients of 10 metachronous gastric adenocarcinomas were signet-ring cell carcinoma and two patients died of gastric adenocarcinoma. Metachronous gastric adenocarcinoma may have a more malignant potential than sporadic gastric adenocarcinoma. Old age, Helicobacter pylori infection and gastric mucosal change of chronic gastritis and intestinal metaplasia were possible risk factors for metachronous gastric adenocarcinoma. CONCLUSION: There was an increased risk of gastric adenocarcinoma after treatment of primary gastric lymphoma, especially of diffuse large B-cell lymphoma. PMID- 24159919 TI - Conformation-based restrictions and scaffold replacements in the design of hepatitis C virus polymerase inhibitors: discovery of deleobuvir (BI 207127). AB - Conformational restrictions of flexible torsion angles were used to guide the identification of new chemotypes of HCV NS5B inhibitors. Sites for rigidification were based on an acquired conformational understanding of compound binding requirements and the roles of substituents in the free and bound states. Chemical bioisosteres of amide bonds were explored to improve cell-based potency. Examples are shown, including the design concept that led to the discovery of the phase III clinical candidate deleobuvir (BI 207127). The structure-based strategies employed have general utility in drug design. PMID- 24159920 TI - Mental health consequences of disasters. AB - We present in this review the current state of disaster mental health research. In particular, we provide an overview of research on the presentation, burden, correlates, and treatment of mental disorders following disasters. We also describe challenges to studying the mental health consequences of disasters and discuss the limitations in current methodologies. Finally, we offer directions for future disaster mental health research. PMID- 24159921 TI - Top-down and bottom-up approaches to health care quality: the impacts of regulation and report cards. AB - The high cost of the US health care system does not buy uniformly high quality of care. Concern about low quality has prompted two major types of public policy responses: regulation, a top-down approach, and report cards, a bottom-up approach. Each can result in either functional provider responses, which increase quality, or dysfunctional responses, which may lower quality. What do we know about the impacts of these two policy approaches to quality? To answer this question, we review the extant literature on regulation and report cards. We find evidence of both functional and dysfunctional effects. In addition, we identify the areas in which additional research would most likely be valuable. PMID- 24159922 TI - Assessment of right heart dilatation with magnetic resonance imaging and multidetector computed tomography angiography: spectrum of disease findings. AB - Right heart chamber enlargement can be caused by a diverse and heterogeneous group of conditions with highly varied clinical symptoms and signs. An appreciation of the pathophysiology, causes, and imaging features of right heart enlargement is paramount in recognizing and potentially ameliorating the development of right heart dysfunction or adverse cardiac events. Chest x-ray and transthoracic echocardiography have traditionally been, and still are, the mainstay in initial evaluation of right heart dilatation; however, recent advances in both multidetector computed tomography and cardiovascular magnetic resonance imaging now permit a comprehensive assessment of the causes and consequences of right heart dilatation. PMID- 24159923 TI - Imaging of coronary artery bypass grafts by computed tomography coronary angiography. AB - In recent years, computed tomography coronary angiography is commonly performed as a follow-up examination after coronary artery bypass graft surgery. Coronary grafts owing to their minimal motion are well visualized by computed tomography coronary angiography, allowing radiologists to assess their patency noninvasively with very high diagnostic accuracy. The purpose of this pictorial essay is to provide an excellent overview of the anatomy and findings concerning coronary artery bypass grafts. PMID- 24159924 TI - Pediatric spinal neoplasia: a practical imaging overview of intramedullary, intradural, and osseous tumors. AB - Imaging of the pediatric spine can be a daunting task for pediatric radiologists, neuroradiologists, and musculoskeletal imagers alike. This is in large part consequent to multiple differential considerations that are frequently specific to this patient population. Though a definitive diagnosis is not always possible through imaging, determining an appropriate anatomical compartment facilitates a more focused differential list, and therefore provides value to the treating providers. This is typically achieved with magnetic resonance imaging and computed tomography. The purpose of this paper is to equip the radiologist with a useful approach to the imaging of, and creating a practical differential for tumors of the pediatric spine. This includes intramedullary, intradural, and osseous pathology. We focus on the most commonly encountered lesions in each of the above compartments. We discuss less common lesions where appropriate owing to their incidence in the adult spine or pediatric extraspinal locations, and are often included in imaging reports or tumor board discussions. As such, this review offers the radiologist a reasonable and reproducible framework for imaging and diagnosing the vast majority of lesions encountered in the pediatric spine. PMID- 24159925 TI - Renal and urologic disorders in antiretroviral-treated patients with HIV infection or AIDS: spectrum of cross-sectional imaging findings. AB - In the aging human immunodeficiency virus (HIV)-infected population with improved immune function under antiretroviral treatment, many different opportunistic disorders may be encountered, along with rare presentations or complicated forms of common diseases. Renal and urologic abnormalities observed in the setting of HIV infection or acquired immunodeficiency syndrome are reviewed with their imaging appearances, including renal dysfunction, urolithiasis, urinary tract infections and related complications, genitourinary tuberculosis, vascular lesions, urogenital tumors, and bladder abnormalities, with emphasis on characterization. In HIV-positive patients, early cross-sectional imaging is warranted to detect uncommon disorders and complications, with the aim to preserve renal function. PMID- 24159926 TI - Electrochemical post-treatment of infinite coordination polymers: an effective route to preparation of Pd nanoparticles supported onto carbon nanotubes with enhanced electrocatalytic activity toward ethanol oxidation. AB - This study describes an effective method to prepare highly dispersed palladium nanoparticles supported onto single-walled carbon nanotubes (SWNTs) with high electrocatalytic activity toward the oxidation of ethanol. This method is essentially based on electrochemical post-treatment of Pd-based infinite coordination polymer (ICP). The Pd-based ICP is synthesized through the coordination reaction between Zn(2+) and metallo-Schiff base (MSB) to form Zn-MSB Zn (ZMZ) ICP that precipitates from ethyl ether. The as-formed Zn-MSB-Zn ICP is then subjected to an ion-exchange reaction with Pd(2+) to obtain the Zn-MSB-Pd (ZMP) ICP. To prepare Pd/SWNT nanocomposite, the ZMP ICP is mixed into the SWNT dispersion in N-dimethylformamide (DMF) to form a homogeneous dispersion that is then drop-coated onto a glassy carbon (GC) electrode. Electrochemical post treatment of ZMP ICP to form Pd/SWNT nanocomposite is thus performed by polarizing the coated electrode at -0.2 V for 600 s in 0.5 M H2SO4. The results obtained with scanning electron microscopy (SEM) and transmission electron microscopy (TEM) reveal that the resulting Pd nanoparticles are highly dispersed onto SWNTs and the particles size are small and narrowly distributed (2.12 +/- 0.32 nm). X-ray photoelectron spectroscopy (XPS) analysis shows that, after the electrochemical post-treatment, no detectable ZMP ICP precursors are left on the surface of SWNTs. The electrocatalytic activity of the as-formed Pd/SWNT nanocomposite toward ethanol oxidation is investigated by cyclic voltammetry and chronoamperometry. The results show that the Pd/SWNT nanocomposite prepared here shows a more negative potential and higher mass catalytic activity, as well as higher stability for the oxidation of ethanol than the commercial Pd/C catalyst. This work demonstrates a novel approach to the formation of ultrasmall and highly dispersed Pd/SWNT nanocomposite with enhanced electrocatalytic activity toward ethanol oxidation. PMID- 24159927 TI - LARP1 predict the prognosis for early-stage and AFP-normal hepatocellular carcinoma. AB - BACKGROUND: The La-related protein 1 (LARP1) has been found to be a RNA binding protein and was related to spermatogenesis, embryogenesis and cell-cycle progression. The aim of this study was to investigate the prognostic value of LARP1 in hepatocellular carcinoma (HCC). METHODS: LARP1 expression was examined in 15 HCC cell lines and 272 clinical specimens using real-time PCR, immunohistochemistry (IHC) and western blot analysis (WB). LARP1 expression was also studied in 6 paired HCC lesions and the adjacent non-cancerous tissue samples. Statistical analyses were applied to derive association between LARP1 expression scores and clinical characters as well as patient survival. RESULTS: mRNA and protein levels of LARP1 were higher in HCC cell lines and HCC lesions than in normal liver epithelial cells and the paired adjacent noncancerous tissues. LARP1 expression was correlated to survival time, vital status, tumor size and Child-Pugh score. Overall survival analysis showed HCC patients with high LARP1 expression level had lower survival rate (P<0.01). Importantly, this correlation remained significant in patients with early-stage HCC or with normal serum AFP level. CONCLUSIONS: LARP1 protein may represent a promising biomarker for predicting the prognosis of HCC, including in early-stage and AFP-normal patients. PMID- 24159928 TI - Memory performance in older adults before and after temporal lobectomy for pharmacoresistant epilepsy. AB - Little is known about the effects of epilepsy surgery on memory in older adults. The purpose of this study was to determine if older adults exhibit greater memory decline than younger adults after anterior temporal lobectomy (ATL). Patients 55 years and older at time of surgery (23 left, 14 right ATL, range 55-66 years) were compared to patients age 25-35 years (44 left, 33 right ATL) to assess differences in preoperative to postoperative change in WMS-III index scores. Repeated-measures ANOVAs and ANCOVAs revealed that older patients did not demonstrate greater decline than younger patients across any of the memory indices. Rather, in the left ATL group, older patients showed less decline than younger patients on the Auditory Delayed Memory Index. Similarly, in the right ATL group, older patients showed less decline than younger patients on the Visual Delayed Memory Index. These patterns were also apparent in frequency of individual change. Results provide preliminary evidence that older adults who are good candidates for ATL are not at greater risk for memory decline when measured at 7 months postoperatively. PMID- 24159929 TI - Diels-Alder reactions of graphene: computational predictions of products and sites of reaction. AB - The cycloaddition reactions and noncovalent pi interactions of 2,3 dimethoxybutadiene (DMBD), 9-methylanthracene (MeA), tetracyanoethylene (TCNE), and maleic anhydride (MA) with graphene models have been investigated using density functional theory (DFT) calculations. Reaction enthalpies have been obtained to assess the reactivity and selectivity of covalent and noncovalent functionalization. Results indicate that graphene edges may be functionalized by the four reagents through cycloaddition reactions, while the interior regions cannot react. Noncovalent complexation is much more favorable than cycloaddition reactions on interior bonds of graphene. The relative reactivities of different sites in graphene are related to loss of aromaticity and can be predicted using Huckel molecular orbital (HMO) localization energy calculations. PMID- 24159930 TI - New colorimetric screening assays for the directed evolution of fungal laccases to improve the conversion of plant biomass. AB - BACKGROUND: Fungal laccases are multicopper oxidases with huge applicability in different sectors. Here, we describe the development of a set of high-throughput colorimetric assays for screening laccase libraries in directed evolution studies. RESULTS: Firstly, we designed three colorimetric assays based on the oxidation of sinapic acid, acetosyringone and syringaldehyde with lambdamax of 512, 520 and 370 nm, respectively. These syringyl-type phenolic compounds are released during the degradation of lignocellulose and can act as laccase redox mediators. The oxidation of the three compounds by low and high-redox potential laccases evolved in Saccharomyces cerevisiae produced quantifiable and linear responses, with detection limits around 1 mU/mL and CV values below 16%. The phenolic substrates were also suitable for pre-screening mutant libraries on solid phase format. Intense colored-halos were developed around the yeast colonies secreting laccase. Furthermore, the oxidation of violuric acid to its iminoxyl radical (lambdamax of 515 nm and CV below 15%) was devised as reporter assay for laccase redox potential during the screening of mutant libraries from high-redox potential laccases. Finally, we developed three dye-decolorizing assays based on the enzymatic oxidation of Methyl Orange (470 nm), Evans Blue (605 nm) and Remazol Brilliant Blue (640 nm) giving up to 40% decolorization yields and CV values below 18%. The assays were reliable for direct measurement of laccase activity or to indirectly explore the oxidation of mediators that do not render colored products (but promote dye decolorization). Every single assay reported in this work was tested by exploring mutant libraries created by error prone PCR of fungal laccases secreted by yeast. CONCLUSIONS: The high-throughput screening methods reported in this work could be useful for engineering laccases for different purposes. The assays based on the oxidation of syringyl-compounds might be valuable tools for tailoring laccases precisely enhanced to aid biomass conversion processes. The violuric assay might be useful to preserve the redox potential of laccase whilst evolving towards new functions. The dye-decolorizing assays are useful for engineering ad hoc laccases for detoxification of textile wastewaters, or as indirect assays to explore laccase activity on other natural mediators. PMID- 24160168 TI - Sharing the British National Health Service around the world: a self-interested perspective. AB - As the UK reiterates its commitment to protecting and growing its development aid budget amidst an adverse economic environment for the UK and Europe, we discuss the potential to use the country's National Health Service (NHS) model as a vehicle for promoting the country's economic as well as global health diplomacy and development priorities, through a coordinated cross-government plan of action. With the country's Prime Minister serving as a co-chair of the UN post 2015 development agenda panel,a this is a unique opportunity for the UK to put forward its health system architecture as a highly applicable and well-tested model for providing access to efficient and cost-effective care, with minimal financial hardship. Arguably, such a model tailored to the needs of specific countries could consequently lead to commercial opportunities for UK plc. in areas such as consulting, training, education and healthcare products. Finally, this approach would be consistent with the current thinking on the evolving role of UK aid, especially in the case of emerging powers such as India, where the focus has shifted from aid to investment in technical assistance and cooperation as a means of boosting bilateral business and trade. PMID- 24159931 TI - True lemurs...true species - species delimitation using multiple data sources in the brown lemur complex. AB - BACKGROUND: Species are the fundamental units in evolutionary biology. However, defining them as evolutionary independent lineages requires integration of several independent sources of information in order to develop robust hypotheses for taxonomic classification. Here, we exemplarily propose an integrative framework for species delimitation in the "brown lemur complex" (BLC) of Madagascar, which consists of seven allopatric populations of the genus Eulemur (Primates: Lemuridae), which were sampled extensively across northern, eastern and western Madagascar to collect fecal samples for DNA extraction as well as recordings of vocalizations. Our data base was extended by including museum specimens with reliable identification and locality information for skull shape and pelage color analysis. RESULTS: Between-group analyses of principal components revealed significant heterogeneity in skull shape, pelage color variation and loud calls across all seven populations. Furthermore, post-hoc statistical tests between pairs of populations revealed considerable discordance among different data sets for different dyads. Despite a high degree of incomplete lineage sorting among nuclear loci, significant exclusive ancestry was found for all populations, except for E. cinereiceps, based on one mitochondrial and three nuclear genetic loci. CONCLUSIONS: Using several independent lines of evidence, our results confirm the species status of the members of the BLC under the general lineage concept of species. More generally, the present analyses demonstrate the importance and value of integrating different kinds of data in delimiting recently evolved radiations. PMID- 24160169 TI - Prevalence of Dermanyssus gallinae (Mesostigmata: Dermanyssidae) in industrial poultry farms in North-East Tunisia. AB - Dermanyssus gallinae (Mesostigmata: Dermanyssidae), a mite of poultry, represents the most important ecotoparasite of egg-laying poultry in several countries. We estimated the prevalence of D. gallinae infestation in 38 industrial poultry farms (28 egg-laying and 10 reproductive hen farms) in the governorate of Nabeul (North-East Tunisia). Traps were placed in two locations of each farm during 24 h in August. The overall prevalence at the farms was estimated to be 34%. A total number of 329 D. gallinae were collected, giving an intensity of 0.0028 and an abundance of 0.0015. Infestation intensity and abundance were significantly higher in egg production farms than reproductive farms. There was no correlation between the intensity of infestation and temperature. An exponential correlation was observed between the birds' age and infestation intensity. We recommend a systematic survey of poultry farms during the whole breeding period. Prompt treatment is recommended to avoid the exponential increase of mite population. PMID- 24160170 TI - Avian malaria prevalence and mosquito abundance in the Western Cape, South Africa. AB - BACKGROUND: The close relationship between vector-borne diseases and their environment is well documented, especially for diseases with water-dependent vectors such as avian malaria. Mosquitoes are the primary vectors of avian malaria and also the definitive hosts in the disease life cycle. Factors pertinent to mosquito ecology are likely to be influential to observed infection patterns; such factors include rainfall, season, temperature, and water quality. METHODS: The influence of mosquito abundance and occurrence on the prevalence of Plasmodium spp. in the Ploceidae family (weavers) was examined, taking into account factors with an indirect influence upon mosquito ecology. Mosquitoes and weaver blood samples were simultaneously collected in the Western Cape, South Africa over a two-year period, and patterns of vector abundance and infection prevalence were compared. Dissolved oxygen, pH, temperature and salinity measurements were taken at 20 permanent waterbodies. Rainfall during this period was also quantified using remotely sensed data from up to 6 months prior to sampling months. RESULTS: Sixteen wetlands had weavers infected with avian malaria. More than half of the mosquitoes caught were trapped at one site; when this site was excluded, the number of mosquitoes trapped did not vary significantly between sites. The majority of mosquitoes collected belonged to the predominant vector species group for avian malaria (Culex culex species complex). Seasonal variation occurred in infection and mosquito prevalence, water pH and water temperature, with greater variability observed in summer than in winter. There was a significant correlation of infection prevalence with rainfall two months prior to sampling months. Mosquito prevalence patterns across the landscape also showed a close relationship to patterns of rainfall. Contrary to predictions, a pattern of asynchronous co-variation occurred between mosquito prevalence and infection prevalence. CONCLUSION: Overall, salinity, rainfall, and mosquito prevalence and season were the most influential vector-related factors on infection prevalence. After comparison with related studies, the tentative conclusion drawn was that patterns of asynchronous variation between malaria prevalence and mosquito abundance were concurrent with those reported in lag response patterns. PMID- 24160171 TI - Associations between the purchase of healthy and fast foods and restrictions to food access: a cross-sectional study in Melbourne, Australia. AB - OBJECTIVE: To examine the associations between financial, physical and transport conditions that may restrict food access (which we define as food security indicators) and the purchase of fast foods and nutritious staples such as bread and milk. DESIGN: Multilevel logistic and multinomial regression analysis of cross-sectional survey data to assess associations between the three indicators of food insecurity and household food shopping adjusted for sociodemographic and socio-economic variables. SETTING: Random selection of households (n 3995) from fifty Census Collector Districts in Melbourne, Australia, in 2003. SUBJECTS: The main food shoppers in each household (n 2564). RESULTS: After adjustment for confounders, analysis showed that a greater likelihood of purchasing chain-brand fast food on a weekly basis compared with never was associated with running out of money to buy food (OR = 1.59; 95 % CI 1.08, 2.34) and reporting difficulties lifting groceries (OR = 1.77; 95 % CI 1.23, 2.54). Respondents without regular access to a car to do food shopping were less likely to purchase bread types considered more nutritious than white bread (OR = 0.75; 95 % CI 0.59, 0.95) and milk types considered more nutritious than full-cream milk (OR = 0.62; 95 % CI 0.47, 0.81). The food insecurity indicators were not associated with the purchasing of fruits, vegetables or non-chain fast food. CONCLUSIONS: Householders experiencing financial and physical barriers were more likely to frequently purchase chain fast foods while limited access to a car resulted in a lower likelihood that the nutritious options were purchased for two core food items (bread and milk). Policies and interventions that improve financial access to food and lessen the effect of physical limitations to carrying groceries may reduce the purchasing of fast foods. Further research is required on food sourcing and dietary quality among those with food access restrictions. PMID- 24160174 TI - New perspectives of valproic acid in clinical practice. AB - INTRODUCTION: Valproic acid (VPA) has been used in clinical practice as an anticonvulsant for more than four decades. Its pharmacokinetics and toxicity are thus well documented. VPA is also a potent class-selective histone deacetylase (HDAC) inhibitor at nontoxic therapeutic concentrations. New areas of application for VPA are currently opening up in clinical practice. AREAS COVERED: The authors discuss VPA and how it may serve as an effective drug for cancer therapy. This is due to its ability to induce differentiation of a number of cancer cells in vitro and also to decrease tumor growth and metastases in animal models. The authors highlight how the utilization of VPA as an HDAC inhibitor is not limited to a single-agent therapy. Early clinical studies have also revealed promising potency of VPA in combination treatment with classic anticancer drugs. The authors do this by summarizing the published results and providing insight into the potential future developments for this field. EXPERT OPINION: VPA was shown to restore or improve responsiveness of tumors to conventional therapeutic agents, to enhance the efficacy of adenoviral gene therapy, to sensitize TRAIL-resistant tumor cells to apoptosis, and to enhance radiosensitivity of tumor cells. Drawbacks in VPA medical applications include its teratogenicity and complexity of its effects. PMID- 24160176 TI - Protein engineering for directed immobilization. AB - Much effort has been put into the optimization of the functional activity of proteins. For biosensors this protein functional optimization will increase the biosensor's sensitivity and/or selectivity. However, the strategy chosen for the immobilization of the proteins to the sensor surface might be equally important for the development of sensor surfaces that are optimally biologically active. Several studies published in recent years show that the oriented immobilization of the bioactive molecules improves the sensor's properties. In this review, we discuss the state of the art of the different protein immobilization strategies that are commonly used today with a special focus on biosensor applications. These strategies include nonspecific immobilization techniques either by physical adsorption, by covalent coupling, or by specific immobilization via site specifically introduced tags or bio-orthogonal chemistry. The different tags and bio-orthogonal chemistry available and the techniques to site-specifically introduce these groups in proteins are also discussed. PMID- 24160175 TI - Histone deacetylase-3 interacts with ataxin-7 and is altered in a spinocerebellar ataxia type 7 mouse model. AB - Spinocerebellar ataxia type 7 (SCA7) is caused by a toxic polyglutamine (polyQ) expansion in the N-terminus of the protein ataxin-7. Ataxin-7 has a known function in the histone acetylase complex, Spt/Ada/Gcn5 acetylase (STAGA) chromatin-remodeling complex. We hypothesized that some histone deacetylase (HDAC) family members would impact the posttranslational modification of normal and expanded ataxin-7 and possibly modulate ataxin-7 function or neurotoxicity associated with the polyQ expansion. Interestingly, when we coexpressed each HDAC family member in the presence of ataxin-7 we found that HDAC3 increased the posttranslational modification of normal and expanded ataxin-7. Specifically, HDAC3 stabilized ataxin-7 and increased modification of the protein. Further, HDAC3 physically interacts with ataxin-7. The physical interaction of HDAC3 with normal and polyQ-expanded ataxin-7 affects the toxicity in a polyQ-dependent manner. We detect robust HDAC3 expression in neurons and glia in the cerebellum and an increase in the levels of HDAC3 in SCA7 mice. Consistent with this we found altered lysine acetylation levels and deacetylase activity in the brains of SCA7 transgenic mice. This study implicates HDAC3 and ataxin-7 interaction as a target for therapeutic intervention in SCA7, adding to a growing list of neurodegenerative diseases that may be treated by HDAC inhibitors. PMID- 24160177 TI - Knockdown of autophagy-related protein 5, ATG5, decreases oxidative stress and has an opposing effect on camptothecin-induced cytotoxicity in osteosarcoma cells. AB - BACKGROUND: Autophagy induction can increase or decrease anticancer drug efficacy. Anticancer drug-induced autophagy induction is poorly characterized in osteosarcoma (OS). In this study, we investigated the impact of autophagy inhibition on camptothecin (CPT)-induced cytotoxicity in OS. METHODS: Autophagy inhibited DLM8 and K7M3 metastatic murine OS cell lines were generated by infection with lentiviral shRNA directed against the essential autophagy protein ATG5. Knockdown of ATG5 protein expression and inhibition of autophagy was confirmed by immunoblot of ATG5 and LC3II proteins, respectively. Metabolic activity was determined by MTT assay and cell viability was determined by trypan blue exclusion. Acridine orange staining and immunoblotting for LC3II protein expression were used to determine autophagy induction. Oxidative stress was assessed by staining cells with HE and DCFH-DA followed by flow cytometry analysis. Mitochondrial membrane potential was determined by staining cells with TMRE followed by flow cytometry analysis. Immunoblotting was used to detect caspase activation, Parp cleavage and p53 phosphorylation. RESULTS: Autophagy inhibition caused a greater deficit in metabolic activity and cell growth in K7M3 cells compared to DLM8 cells. K7M3 cells exhibited higher basal autophagy levels than DLM8 cells and non-transformed murine MCT3 osteoblasts. Autophagy inhibition did not affect CPT-induced DNA damage. Autophagy inhibition decreased CPT-induced cell death in DLM8 cells while increasing CPT-induced cell death in K7M3 cells. Autophagy inhibition reduced CPT-induced mitochondrial damage and CPT-induced caspase activation in DLM8 cells. Buthionine sulfoximine (BSO)-induced cell death was greater in autophagy-competent DLM8 cells and was reversed by antioxidant pretreatment. Camptothecin-induced and BSO-induced autophagy induction was also reversed by antioxidant pretreatment. Significantly, autophagy inhibition not only reduced CPT-induced oxidative stress but also reduced basal oxidative stress. CONCLUSIONS: The results of this study indicate that autophagy inhibition can have an opposing effect on CPT-induced cytotoxicity within OS. The cytoprotective mechanism of autophagy inhibition observed in DLM8 cells involves reduced CPT-induced oxidative stress and not reduced DNA damage. Our results also reveal the novel finding that knockdown of ATG5 protein reduces both basal oxidative stress and drug-induced oxidative stress. PMID- 24160178 TI - Gene expression analysis in allergology: the prediction of Hymenoptera venom allergy severity and treatment efficacy. AB - Insect venom allergy (IVA) may result in the most severe systemic reactions seen in allergology. The only potentially curative treatment option is venom immunotherapy (VIT) over 3 to 5 years. This treatment is effective in more than 90% of subjects but no reliable predictors of VIT effectiveness exist. Sting challenge with a living insect can be performed to assess the effectiveness of VIT: the predictive value of sting challenge can be highly sensitive in patients with honeybee venom allergy whereas in yellow jacket allergy, a negative result can be reliable if the challenge has been repeated at least 3 times.The analysis of gene expression may be a step towards personalized venom immunotherapy assessing the effectiveness of treatment, the minimal required time for VIT and the persistence of long term tolerance induced by the treatment. Recent studies have enabled construction of a predictive model that could potentially be used in clinical practice to assess the efficacy of insect venom immunotherapy. A set of 69 genes that may be responsible for long-term protection was identified. Further analysis of the previously identified 6 transcripts make up the 18 gene predictive peripheral blood showed differences in patients treated with IVA. Further studies are needed to investigate the usefulness of gene expression analysis and other markers in the prediction of VIT effectiveness. PMID- 24160179 TI - Evolution of cardiac and renal impairment detected by high-field cardiovascular magnetic resonance in mice with renal artery stenosis. AB - BACKGROUND: Renal artery stenosis (RAS) promotes hypertension and cardiac dysfunction. The 2-kidney, 1-clip mouse model in many ways resembles RAS in humans and is amenable for genetic manipulation, but difficult to evaluate noninvasively. We hypothesized that cardiovascular magnetic resonance (CMR) is capable of detecting progressive cardiac and renal dysfunction in mice with RAS and monitoring the progression of the disease longitudinally. METHODS: RAS was induced at baseline in eighteen mice by constricting the renal artery. Nine additional animals served as normal controls. CMR scans (16.4 T) were performed in all mice one week before and 2 and 4 weeks after baseline. Renal volumes and hemodynamics were assessed using 3D fast imaging with steady-state precession and arterial spin labelling, and cardiac function using CMR cine. Renal hypoxia was investigated using blood oxygen-level dependent (BOLD) MR. RESULTS: Two weeks after surgery, mean arterial pressure was elevated in RAS mice. The stenotic kidney (STK) showed atrophy, while the contra-lateral kidney (CLK) showed hypertrophy. Renal blood flow (RBF) and cortical oxygenation level declined in the STK but remained unchanged in CLK. Moreover, cardiac end-diastolic and stroke volumes decreased and myocardial mass increased. At 4 weeks, STK RBF remained declined and the STK cortex and medulla showed development of hypoxia. Additionally, BOLD detected a mild hypoxia in CLK cortex. Cardiac end-diastolic and stroke volumes remained reduced and left ventricular hypertrophy worsened. Left ventricular filling velocities (E/A) indicated progression of cardiac dysfunction towards restrictive filling. CONCLUSIONS: CMR detected longitudinal progression of cardiac and renal dysfunction in 2K, 1C mice. These observations support the use of high-field CMR to obtain useful information regarding chronic cardiac and renal dysfunction in small animals. PMID- 24160180 TI - Codon usage patterns in Chinese bayberry (Myrica rubra) based on RNA-Seq data. AB - BACKGROUND: Codon usage analysis has been a classical topic for decades and has significances for studies of evolution, mRNA translation, and new gene discovery, etc. While the codon usage varies among different members of the plant kingdom, indicating the necessity for species-specific study, this work has mostly been limited to model organisms. Recently, the development of deep sequencing, especial RNA-Seq, has made it possible to carry out studies in non-model species. RESULT: RNA-Seq data of Chinese bayberry was analyzed to investigate the bias of codon usage and codon pairs. High frequency codons (AGG, GCU, AAG and GAU), as well as low frequency ones (NCG and NUA codons) were identified, and 397 high frequency codon pairs were observed. Meanwhile, 26 preferred and 141 avoided neighboring codon pairs were also identified, which showed more significant bias than the same pairs with one or more intervening codons. Codon patterns were also analyzed at the plant kingdom, organism and gene levels. Changes during plant evolution were evident using RSCU (relative synonymous codon usage), which was even more significant than GC3s (GC content of 3rd synonymous codons). Nine GO categories were differentially and independently influenced by CAI (codon adaptation index) or GC3s, especially in 'Molecular function' category. Within a gene, the average CAI increased from 0.720 to 0.785 in the first 50 codons, and then more slowly thereafter. Furthermore, the preferred as well as avoided codons at the position just following the start codon AUG were identified and discussed in relation to the key positions in Kozak sequences. CONCLUSION: A comprehensive codon usage Table and number of high-frequency codon pairs were established. Bias in codon usage as well as in neighboring codon pairs was observed, and the significance of this in avoiding DNA mutation, increasing protein production and regulating protein synthesis rate was proposed. Codon usage patterns at three levels were revealed and the significance in plant evolution analysis, gene function classification, and protein translation start site predication were discussed. This work promotes the study of codon biology, and provides some reference for analysis and comprehensive application of RNA-Seq data from other non-model species. PMID- 24160182 TI - Analysis of human resources for health strategies and policies in 5 countries in Sub-Saharan Africa, in response to GFATM and PEPFAR-funded HIV-activities. AB - BACKGROUND: Global Health Initiatives (GHIs), aiming at reducing the impact of specific diseases such as Human Immunodeficiency Virus (HIV), have flourished since 2000. Amongst these, PEPFAR and GFATM have provided a substantial amount of funding to countries affected by HIV, predominantly for delivery of antiretroviral therapy (ARV) and prevention strategies. Since the need for additional human resources for health (HRH) was not initially considered by GHIs, countries, to allow ARV scale-up, implemented short-term HRH strategies, adapted to GHI-funding conditionality. Such strategies differed from one country to another and slowly evolved to long-term HRH policies. The processes and content of HRH policy shifts in 5 countries in Sub-Saharan Africa were examined. METHODS: A multi-country study was conducted from 2007 to 2011 in 5 countries (Angola, Burundi, Lesotho, Mozambique and South Africa), to assess the impact of GHIs on the health system, using a mixed methods design. This paper focuses on the impact of GFATM and PEPFAR on HRH policies. Qualitative data consisted of semi structured interviews undertaken at national and sub-national levels and analysis of secondary data from national reports. Data were analysed in order to extract countries' responses to HRH challenges posed by implementation of HIV-related activities. Common themes across the 5 countries were selected and compared in light of each country context. RESULTS: In all countries successful ARV roll-out was observed, despite HRH shortages. This was a result of mostly short-term emergency response by GHI-funded Non-Governmental Organizations (NGOs) and to a lesser extent by governments, consisting of using and increasing available HRH for HIV tasks. As challenges and limits of short-term HRH strategies were revealed and HIV became a chronic disease, the 5 countries slowly implemented mid to long-term HRH strategies, such as formalisation of pilot initiatives, increase in HRH production and mitigation of internal migration of HRH, sometimes in collaboration with GHIs. CONCLUSION: Sustainable HRH strengthening is a complex process, depending mostly on HRH production and retention factors, these factors being country-specific. GHIs could assist in these strategies, provided that they are flexible enough to incorporate country-specific needs in terms of funding, that they coordinate at global-level and minimise conditionality for countries. PMID- 24160181 TI - Structural insights into Resveratrol's antagonist and partial agonist actions on estrogen receptor alpha. AB - BACKGROUND: Resveratrol, a naturally occurring stilbene, has been categorized as a phytoestrogen due to its ability to compete with natural estrogens for binding to estrogen receptor alpha (ERalpha) and modulate the biological responses exerted by the receptor. Biological effects of resveratrol (RES) on estrogen receptor alpha (ERalpha) remain highly controversial, since both estrogenic and anti-estrogenic properties were observed. RESULTS: Here, we provide insight into the structural basis of the agonist/antagonist effects of RES on ERalpha ligand binding domain (LBD). Using atomistic simulation, we found that RES bound ERalpha monomer in antagonist conformation, where Helix 12 moves away from the ligand pocket and orients into the co-activator binding groove of LBD, is more stable than RES bound ERalpha in agonist conformation, where Helix 12 lays over the ligand binding pocket. Upon dimerization, the agonistic conformation of RES ERalpha dimer becomes more stable compared to the corresponding monomer but still remains less stable compared to the corresponding dimer in antagonist conformation. Interestingly, while the binding pocket and the binding contacts of RES to ERalpha are similar to those of pure agonist diethylstilbestrol (DES), the binding energy is much less and the hydrogen bonding contacts also differ providing clues for the partial agonistic character of RES on ERalpha. CONCLUSIONS: Our Molecular Dynamics simulation of RES-ERalpha structures with agonist and antagonist orientations of Helix 12 suggests RES action is more similar to Selective Estrogen Receptor Modulator (SERM) opening up the importance of cellular environment and active roles of co-regulator proteins in a given system. Our study reveals that potential co-activators must compete with the Helix 12 and displace it away from the activator binding groove to enhance the agonistic activity. PMID- 24160183 TI - The use of the rapid osmotic fragility test as an additional test to diagnose canine immune-mediated haemolytic anaemia. AB - BACKGROUND: Diagnosing canine immune-mediated haemolytic anaemia (IMHA) is often challenging because all currently available tests have their limitations. Dogs with IMHA often have an increased erythrocyte osmotic fragility (OF), a characteristic that is sometimes used in the diagnosis of IMHA. Since the classic osmotic fragility test (COFT) is time-consuming and requires specialized equipment, an easy and less labour-intensive rapid osmotic fragility test (ROFT) has been used in some countries, but its diagnostic value has not yet been investigated.This study aimed to evaluate erythrocyte osmotic fragility in dogs with and without IMHA, to compare results of the classic (COFT) and rapid (ROFT) test and to assess the value of the ROFT as diagnostic test for canine IMHA.Nineteen dogs with IMHA (group 1a), 21 anaemic dogs without IMHA (group 1b), 8 dogs with microcytosis (group 2), 13 hyperlipemic dogs (group 3), 10 dogs with lymphoma (group 4), 8 dogs with an infection (group 5) and 13 healthy dogs (group 6) were included.In all dogs, blood smear examination, in-saline auto agglutination test, Coombs' test, COFT and ROFT were performed. In the COFT, OF5, OF50 and OF90 were defined as the NaCl concentrations at which respectively 5, 50 and 90% of erythrocytes were haemolysed. RESULTS: Compared with healthy dogs, OF5 and OF50 were significantly higher in group 1a (P < 0.001) and OF5 was significantly higher in group 3 (P = 0.0266). The ROFT was positive in 17 dogs with IMHA, 10 hyperlipemic dogs, one anaemic dog without IMHA and one healthy dog. CONCLUSIONS: Osmotic fragility was increased in the majority of dogs with IMHA and in dogs with hyperlipidemia, but not in dogs with microcytosis, lymphoma or an infection. Although more detailed information was obtained about the osmotic fragility by using the COFT, the COFT and ROFT gave similar results. The ROFT does not require specialized equipment, is rapid and easy to perform and can be used easily in daily practice. Although, the ROFT cannot replace other diagnostic tests, it may be a valuable additional tool to diagnose canine IMHA. PMID- 24160184 TI - Oral language supports early literacy: a pilot cluster randomized trial in disadvantaged schools. AB - This study examined the impact of teacher professional development aimed at improving the capacity of primary teachers in disadvantaged schools to strengthen children's expressive and receptive oral language skills and early literacy success in the first 2 years of school. Fourteen low-SES schools in Victoria, Australia were randomly allocated to a research (n = 8) or control arm (n = 6), resulting in an initial sample of 1254 students, (n = 602 in research arm and n = 652 in control arm). The intervention comprised 6 days of teacher and principal professional development (delivered by language and literacy experts), school based continuing contact with the research team and completion by one staff member of each research school of a postgraduate unit on early language and literacy. Schools in the control arm received standard teaching according to state auspiced curriculum guidelines. Full data were available on 979 students at follow-up (time 2). Students in the research arm performed significantly better on Test of Language Development: Primary (Fourth Edition) sub-tests (p <= .002) and the Reading Progress Test (F = 10.4(1); p = .001) than students in the control arm at time 2. Narrative scores were not significantly different at time 2, although students in research schools showed greater gains. Findings provide "proof of concept" for this approach, and are discussed with respect to implications for teacher professional development and pre-service education concerning the psycholinguistic competencies that underpin the transition to literacy. PMID- 24160185 TI - The effects of radiation on angiogenesis. AB - The average human body contains tens of thousands of miles of vessels that permeate every tissue down to the microscopic level. This makes the human vasculature a prime target for an agent like radiation that originates from a source and passes through the body. Exposure to radiation released during nuclear accidents and explosions, or during cancer radiotherapy, is well known to cause vascular pathologies because of the ionizing effects of electromagnetic radiations (photons) such as gamma rays. There is however, another type of less well-known radiation - charged ion particles, and these atoms stripped of electrons, have different physical properties to the photons of electromagnetic radiation. They are either found in space or created on earth by particle collider facilities, and are of significant recent interest due to their enhanced effectiveness and increasing use in cancer radiotherapy, as well as a health risk to the growing number of people spending time in the space environment. Although there is to date, relatively few studies on the effects of charged particles on the vascular system, a very different picture of the biological effects of these particles compared to photons is beginning to emerge. These under researched biological effects of ion particles have a large impact on the health consequences of exposure. In this short review, we will discuss the effects of charged particles on an important biological process of the vascular system, angiogenesis, which creates and maintains the vasculature and is highly important in tumor vasculogenesis. PMID- 24160186 TI - Documenting malaria case management coverage in Zambia: a systems effectiveness approach. AB - BACKGROUND: National malaria control programmes and their partners must document progress associated with investments in malaria control. While documentation has been achieved through population-based surveys for most interventions, measuring changes in malaria case management has been challenging because the increasing use of diagnostic tests reduces the denominator of febrile children who should receive anti-malarial treatment. Thus the widely used indicator, "proportion of children under five with fever in the last two weeks who received anti-malarial treatment according to national policy within 24 hours from onset of fever" is no longer relevant. METHODS: An alternative sequence of indicators using a systems effectiveness approach was examined using data from nationally representative surveys in Zambia: the 2012 population-based Malaria Indictor Survey (MIS) and the 2011 Health Facility Survey (HFS). The MIS measured fever treatment-seeking behaviour among 972 children under five years (CU5) and 1,848 people age five years and above. The HFS assessed management of 435 CU5 and 429 people age five and above with fever/history of fever seeking care at 149 health facilities. Consultation observation and exit interviews measured use of diagnostic tests, artemisinin combination therapy (ACT) prescription, and patient comprehension of prescribed regimens. RESULTS: Systems effectiveness for malaria case management among CU5 was estimated as follows: [100% ACT efficacy] x [55% fever treatment seeking from an appropriate provider (MIS)] x [71% malaria blood testing (HFS)] x [86% ACT prescription for positive cases (HFS)] x [73% patient comprehension of prescribed ACT drug regimens (HFS)] = 25%. Systems effectiveness for malaria case management among people age five and above was estimated at 15%. CONCLUSIONS: Tracking progress in malaria case management coverage can no longer rely solely on population-based surveys; the way forward likely entails household surveys to track trends in fever treatment-seeking behaviour, and facility/provider data to track appropriate management of febrile patients. Applying health facility and population-based data to the systems effectiveness framework provides a cogent and feasible approach to documenting malaria case management coverage and identifying gaps to direct program action. In Zambia, this approach identified treatment-seeking behaviour as the largest contributor to reduction in systems effectiveness for malaria case management. PMID- 24160188 TI - [Another year the journal Nutricion Hospitalaria increases its contents, visibility and impact]. PMID- 24160187 TI - Meta-analysis confirms association between TNFA-G238A variant and JIA, and between PTPN22-C1858T variant and oligoarticular, RF-polyarticular and RF positive polyarticular JIA. AB - BACKGROUND: Although more than 100 non-HLA variants have been tested for associations with juvenile idiopathic arthritis (JIA) in candidate gene studies, only a few have been replicated. We sought to replicate reported associations of single nucleotide polymorphisms (SNPs) in the PTPN22, TNFA and MIF genes in a well-characterized cohort of children with JIA. METHODS: We genotyped and analyzed 4 SNPs in 3 genes: PTPN22 C1858T (rs2476601), TNFA G-308A, G-238A (rs1800629, rs361525) and MIF G-173C (rs755622) in 647 JIA cases and 751 healthy controls. We tested for association between each variant and JIA as well as JIA subtypes. We adjusted for multiple testing using permutation procedures. We also performed a meta-analysis that combined our results with published results from JIA association studies. RESULTS: While the PTPN22 variant showed only modest association with JIA (OR = 1.29, p = 0.0309), it demonstrated a stronger association with the RF-positive polyarticular JIA subtype (OR = 2.12, p = 0.0041). The MIF variant was not associated with the JIA as a whole or with any subtype. The TNFA-238A variant was associated with JIA as a whole (OR 0.66, p = 0.0265), and demonstrated a stronger association with oligoarticular JIA (OR 0.33, p = 0.0006) that was significant after correction for multiple testing. TNFA-308A was not associated with JIA, but was nominally associated with systemic JIA (OR = 0.33, p = 0.0089) and enthesitis-related JIA (OR = 0.40, p = 0.0144). Meta-analyses confirmed significant associations between JIA and PTPN22 (OR 1.44, p <0.0001) and TNFA-238A (OR 0.69, p < 0.0086) variants. Subtype meta-analyses of the PTPN22 variant revealed associations between RF-positive, RF-negative, and oligoarticular JIA, that remained significant after multiple hypothesis correction (p < 0.0005, p = 0.0007, and p < 0.0005, respectively). CONCLUSIONS: We have confirmed associations between JIA and PTPN22 and TNFA G-308A. By performing subtype analyses, we discovered a statistically-significant association between the TNFA-238A variant and oligoarticular JIA. Our meta analyses confirm the associations between TNFA-238A and JIA, and show that PTPN22 C1858T is associated with JIA as well as with RF-positive, RF-negative and oligoarticular JIA. PMID- 24160189 TI - Whole-body vibration training as complement to programs aimed at weight loss. AB - INTRODUCTION: Whole-body vibration training (WBVT) has been shown to be an extremely useful tool for increasing muscle mass, bone tissue, muscle power, flexibility, and strength, among others. However, to date, there are few studies on the effects of WBVT on energy metabolism and whether this tool could be able to enhance weight loss in addition to a nutritional plan and/or exercise. OBJECTIVE: The aim of this review is to analyse the most recent studies on vibration training in order to determine whether this method constitutes a reliable complement to programs aimed at weight loss. METHODS: An updated literature search was conducted using PubMed, SciELO and SPORTDiscus. In addition, a detailed search was also performed from references given in selected studies. RESULTS: WBVT appears to be associated with three pathways involved in weight loss: inhibition of adipogenesis and reduction of fat mass, increased energy expenditure, and increase in muscle mass. After analysing the literature, none of the results for the proposed pathways are consistent, and indeed are often contradictory. CONCLUSION: Further in-depth research is required on this subject. However, WBVT would appear to be a safe method, and may possibly yield benefits, mainly as regards muscle mass, which in turn might promote weight loss when combined with a nutritional plan and a traditional exercise program. PMID- 24160190 TI - [Systematic review about dental caries in children and adolescents with obesity and/or overweight]. AB - INTRODUCTION: Obesity and overweight (O/OW) in children have reached epidemic character and both are a risk factor for chronic serious health problems. This study was perfomed in order to research the relationship between O/OW and dental caries. MATERIAL AND METHODS: [corrected] A SR was conducted between 2007-2011 in tertiary information sources (Trip, Cochrane and NGC), secondary (PubMed, IME, MEDES IBECS) and primary (reference checks). INCLUSION CRITERIA: Patients (children 0-18 years), risk factor (O/OW) and outcomes (primary: caries, secondary: other oral pathology). DATA COLLECTED: Author, year, country, type of study, patient age, cases (with O/OW) and controls (body mass index-BMI-normal or low), comorbidities, socioeconomic status, prevalence of caries and other results in oral health. RESULTS: Forty-seven documents were located, 37 of them met the criteria of the RS, temporarily distributed in 2007 (6 articles), 2008 (6), 2009 (5), 2010 (11) and 2011 (9). They presented a very wide degree of heterogeneity (in patients, intervention, primary outcome and type of design), which does not allow to apply quantitative synthesis of data (meta-analysis). Studies are conflicting regarding the relationship between BMI and frequency of dental caries (DMFT, dmft). CONCLUSIONS: Systematic review allows dentists and pediatricians to know the relationship between O/OW and dental caries. PMID- 24160191 TI - Dairy products consumption versus type 2 diabetes prevention and treatment; a review of recent findings from human studies. AB - INTRODUCTION: It has been claimed that the appropriate consumption of dairy products can be beneficial for the prevention and treatment of type 2 diabetes mellitus (T2DM). OBJECTIVE: The objective of this review is to critically analyze the main scientific evidence about this topic. METHODS: MEDLINE, PubMEd, Science Direct, SCIELO and LILACS were searched for studies published over the past 12 years exploring the effects of the consumption of dairy products or its components (calcium, vitamin D and magnesium) on T2DM. RESULTS AND DISCUSSION: Epidemiological studies indicate that consumption of at least three servings of low-fat dairy products per day as a part of a healthy diet is crucial to reduce the risk of developing T2DM. The majority of the analyzed intervention studies reported beneficial effects of increased calcium and vitamin D ingestion on insulin sensitivity improvement and T2DM prevention. CONCLUSIONS: Although the impact of dairy consumption to treat T2DM needs further investigation, the consumption of low-fat dairy products may be an important strategy to prevent and control T2DM. PMID- 24160192 TI - [Selenium and health; reference values and current status of Spanish population]. AB - Selenium (Se) has gone, in a few years, from being considered only a toxic element to attribute it remarkable benefits for the human health: from antioxidant and hormonal regulations of thyroid functions to established anti carcinogen effects. The Se is an essential microelement for humans and livestock, but not for plants, which extract it from soil incidentally. Therefore the population Se status of a area ultimately depends on its presence in soil. In the last two decades have shown that the individual Se requirements are higher than the values referenced given for Official Organism, and that should be considered not only the direct effects of deficiency, but adequate to achieve optimal health through maximize/ optimize the Se-proteins. In Spain, the few studies on healthy people show low Se levels in blood. This fact is corroborated by the low Se concentration on the main food groups. The cereals, more specifically wheat and derivative products, is one of main groups that provide greater Se contribution to the diet. However, the wheat Se concentrations in Spain are low, partly explaining the low blood levels found in the Spanish population. It would need to involve the National Public Organizations to increase the number of studies of this subject, in order to elucidate the extent of Se deficiencies in Spanish population and to evaluate possible solutions. PMID- 24160193 TI - Green juice as a protector against reactive species in rats. AB - INTRODUCTION: Green juice is popularly known for introducing antioxidants, improving intestinal function and reducing weight gain. OBJECTIVES: In the present study we determine the antioxidant effect of green juice comparing it with orange juice. METHODS: Rats were divided into three experimental groups and submitted to supplementation for 15 days: the (GJ) group received green juice, the (OJ) group received orange juice and the control group received water. We evaluated the antioxidant activity and total phenolic content of green and orange juices, as well as rat weight gain. We also investigated some oxidative stress parameters, namely thiobarbituric acid-reactive substances (TBARS), superoxide dismutase and catalase in rat cerebral cortex. RESULTS AND DISCUSSION: Results showed that GJ had significantly less weight gain than the control group. With respect to antioxidant activity screening, the remaining percentage of DPPH at dilutions 1:10, 1:100 and 1:1000 of green juice was 22.8%, 58% and 78%, and orange juice, at the same dilutions, was 5.6%, 5.6% and 77.2%, respectively. The ability of juices to reduce the ABTS radical was 3.5 mmol trolox/L for green juice and 5.2 mmol trolox/L for orange juice. Additionally, the green juice did not present any difference in total phenolic acid content when compared to orange juice. TBARS were reduced in GJ and OJ. Besides, GJ supplementation decreased catalase activity. In conclusion, our data showed that green juice reduced weight gain, lipoperoxidation and catalase activity, suggesting that this supplementation may have a protective effect against reactive species. PMID- 24160194 TI - [Multiple emulsions; bioactive compounds and functional foods]. AB - The continued appearance of scientific evidence about the role of diet and/or its components in health and wellness, has favored the emergence of functional foods which currently constitute one of the chief factors driving the development of new products. The application of multiple emulsions opens new possibilities in the design and development of functional foods. Multiple emulsions can be used as an intermediate product (food ingredient) into technological strategies normally used in the optimization of the presence of bioactive compounds in healthy and functional foods. This paper presents a summary of the types, characteristics and formation of multiple emulsions, possible location of bioactive compounds and their potential application in the design and preparation of healthy and functional foods. Such applications are manifested particularly relevant in relation to quantitative and qualitative aspects of lipid material (reduced fat/calories and optimization of fatty acid profile), encapsulation of bioactive compounds mainly hydrophilic and sodium reduction. This strategy offers interesting possibilities regarding masking flavours and improving sensory characteristics of foods. PMID- 24160195 TI - Nori- and sea spaghetti- but not wakame-restructured pork decrease the hypercholesterolemic and liver proapototic short-term effects of high-dietary cholesterol consumption. AB - Restructured pork (RP) enriched in Seaweeds are potential functional foods. The antiapoptotic and hypocholesterolemic effects of consuming cholesterol enriched diets containing Wakame-RP (CW), Nori-RP (CN) and Sea Spaghetti (CS) were tested in a 1-wk study. Groups of six rats per group were fed a mix of 85% AIN-93M rodent-diet containing cholesterol and cholic acid as a cholesterol rising agent plus 15% RP containing alga. These diets were compared to control-RP diets enriched or not in cholesterol (CC and C, respectively). After 1-wk, cholesterol feeding significantly increased liver apoptosis markers which were significantly reduced by CS (cellular cycle DNA, caspase-3, and cytochrome c), CN (caspase-3 and cytochrome c) and CW (caspase-3) diets. CN and CS diets significantly blocked the cholesterolaemic rising effect observed in the CC group but no protective effect was observed in the CW group. Differences in seaweed composition added to RP appear responsible for blocking or not the proapoptotic and hypercholesterolemic effects of high cholesterol-RP consumption; thus, any generalization on seaweed effects or food containing seaweeds must be avoided. Although present results are worthy, future studies are demanded to ascertain the utility of consuming algal-RP as part of usual diets. PMID- 24160196 TI - [Food insecurity among elderly people in 15 districts of the Great Santiago area; an unresolved issue]. AB - INTRODUCTION: To experience food insecurity determines negative consequences regarding nutrition, health and general wellness among older adults and their families. In Chile it practically doesn't exist any information related to it, despite this matter represents a major public health issue in other countries in the region. OBJECTIVES: To determine the prevalence of food insecurity and it's relation with socio-demographic, economic and nutritional factors among older adults residing in medium-low and low-income status districts, in the Great Santiago area. MATERIALS AND METHODS: A cross-sectional observational study in 344 older adults, between 65 and 74 year-old; a socioeconomic, demographic, nutritional and food-insecurity survey at the homes (HFIAS). A prevalence of food insecurity and it relation with the independent variables was determined, by means of multi-variety logistic regression models. RESULTS: The 40.4% of the sample presented food insecurity (95% IC 35.2-45.6%), predominantly of the mild type, with a higher proportion of women, at the limit of the statistic significance. The probability of perceiving food insecurity was significantly associated to low family income (OR 4.2 IC 2.1-8.6), with a greater number of members in the home (OR 2.4), malnutrition by deficit and/or excess (OR 2.0), not to be the owner of the house (OR 2.0), and low individual income (OR 1.8). CONCLUSIONS: There exists a high prevalence of food insecurity among this population, which is associated with socio-demographic, economic and nutritional status. The food security represents an important public health and nutritional issue in the country, which needs to be investigated further. PMID- 24160197 TI - [Study on the nutritional risk of autonomous non-institutionalized adult elder people]. AB - OBJECTIVES: To assess the nutritional status of autonomous, non institutionalized, elder adults in social centers by means of the MNA scale and to analyze their distribution according to socio-demographical variables: gender, age, civil status, living with other people, educational level, and rural/urban setting. METHODS: Cross-sectional study performed in 660 autonomous, non institutionalized elder adults in social center of the province of Valencia. The subjects were assessed at 12 social centers selected though stratified sample sets. The inclusion criteria were: being 65 years of older, living at home, having functional autonomy, residing for more than one year in the province of Valencia, attending periodically the social center, and willing to participate. The MNA scale was used for nutritional assessment. RESULTS: Of the 660 included subjects, 48.33% were males and 51.6% females; the mean age was 74.3 +/- 6.57 years. 23.3% of the participants were at risk for malnutrition. The prevalence of malnutrition odds ratio was higher in: females as compared to men (OR = 1.43), subjects >= 85 years as compared to the 65-69 years group (OR = 2.27), widowed subjects as compared to those with a stable companion (OR = 1.82) and people with the lowest educational level as compared to those with some educational level (OR = 1.73). CONCLUSIONS: The prevalence of malnutrition risk in autonomous, non institutionalized elder adults at social centers of the province of Valencia reaches one out of four people, being higher in widowed subjects (mostly elder women living alone) and in uneducated people. PMID- 24160198 TI - Algorithm for the early diagnosis of vitamin B12 deficiency in elderly people. AB - BACKGROUND: The elderly population is particularly at risk for developing vitamin B12-deficiency. Serum cobalamin does not necessarily reflect a normal B12 status. The determination of methylmalonic acid is not available in all laboratories. Issues of sensitivity for holotranscobalamin and the low specificity of total homocysteine limit their utility. The aim of the present study is to establish a diagnostic algorithm by using a combination of these markers in place of a single measurement. METHODS: We compared the diagnostic efficiency of these markers for detection of vitamin B12 deficiency in a population (n = 218) of institutionalized elderly (median age 80 years). Biochemical, haematological and morphological data were used to categorize people with or without vitamin B12 deficiency. RESULTS: In receiver operating curves characteristics for detection on vitamin B12 deficiency using single measurements, serum folate has the greatest area under the curve (0.87) and homocysteine the lowest (0.67). The best specificity was observed for erythrocyte folate and methylmalonic acid (100% for both) but their sensitivity was very low (17% and 53%, respectively). The highest sensitivity was observed for homocysteine (81%) and serum folate (74%). When we combined these markers, starting with serum and erythrocyte folate, followed by holotranscobalamin and ending by methylmalonic acid measurements, the overall sensitivity and specificity of the algorithm were 100% and 90%, respectively. CONCLUSION: The proposed algorithm, which combines erythrocyte folate, serum folate, holotranscobalamin and methylmalonic acid, but eliminate B12 and tHcy measurements, is a useful alternative for vitamin B12 deficiency screening in an elderly institutionalized cohort. PMID- 24160199 TI - [Influence of the social context on the body image perception of women undergoing breast cancer surgery]. AB - In Western cultures, female breasts are strongly related to the world of sexuality and physical attractiveness, although this can vary according to the social context. OBJECTIVE: To determine the influence of social context on the body image perception of women undergoing breast cancer surgery. MATERIAL AND METHOD: An observational, descriptive and cross-sectional study was performed. Study settings were the State Oncology Center of the ISSEMyM (Social Security Institute of the State of Mexico and its Municipalities) in Toluca (Mexico) and San Cecilio University Hospital in Granada (Spain). The study sample comprised 72 mastectomized females, 30 from Mexico and 42 from Spain. Data were gathered on their socio-demographic variables, self-reported personal and family clinical histories, and scores on the validated Hopwood Body Image Scale (BIS). RESULTS: In the Spanish group of mastectomized women, 67.7% were in active employment compared with 43.3% of the Mexican group, a significant difference (p < 0.05). Body image perception was superior in women connected to the world of work and with a higher educational level. The women in a more developed social context had a significantly (p < 0.05) better body image perception. CONCLUSIONS: The social context of masectomized women affects their body image perception, which is influenced by their occupation and educational level. PMID- 24160200 TI - [Nutritional status of patients with cancer of oral cavity]. AB - INTRODUCTION: Cancer of the oral cavity ranks twelfth worldwide. This type of cancer is usually managed surgically followed by radiotherapy, which may be indicated alone or with chemotherapy; this type of therapies have significant functional side effects on the nutritional status of the patient. OBJECTIVE: The aim of this work is to know the impact of the different treatments on the nutritional status of patients with cancer of the oral cavity treated at the National Cancer Institute for the period comprised between 2009 and 2011. MATERIAL AND METHODS: A descriptive and retrospective study was carried out. Ninety-nine patients with cancer of the oral cavity were included. The following variables were recorded: gender, age, type of treatment (surgery, chemotherapy, radiotherapy), most important complications secondary to treatment, weight loss, body mass index (BMI) and albumin. RESULTS AND DISCUSSION: The prevalence of cancer of the oral cavity was greater in women (58.6%); the mean age was 61.22 years. Complications secondary to the therapy were xerostomia (20%) followed by odynophagia and mucositis (19%), the relationship between weight loss and symptoms was observed in 54% of the patient due to the type of feeding before, during and after the treatment, with a preponderance of the use of mush. CONCLUSION: Weight loss due to complications of the medical treatment was observed, affecting the nutritional status; therefore continuous monitoring is important in order to improve the success of a multidisciplinary approach. PMID- 24160201 TI - Clinical effects of a w3 enhanced powdered nutritional formula in postsurgical ambulatory head and neck cancer patients. AB - BACKGROUND: Patients with head and neck cancer undergoing surgery have a high risk of nutritional complications. OBJECTIVE: The aim of our study was to investigate the influence of an oral w3 enriched immunoenhanced powdered formula in nutritional and biochemical parameters in postsurgical ambulatory patients with head and neck tumor. DESIGN: A population of 33 ambulatory postsurgical patients with oral and laryngeal cancer was enrolled. At Hospital discharge postsurgical head and neck cancer patients were asked to consume two units per day of a w3 enriched immunoenhanced powdered formula for a twelve week period. RESULTS: The mean age was 61.3 +/- 9.1 years (6 female/27 males). Duration of supplementation was 95.9 +/- 21.1 days. A significant increase of albumin and transferrin levels was observed, in total group and in patients undergoing radiotherapy and without it. No differences were detected in weight and other anthropometric parameters in total group and in patients with radiotherapy during the protocol. Nevertheless, patients without radiotherapy showed a significant improvement of BMI; weight, fat free mass and fat mass. CONCLUSIONS: At dose used, an omega 3 enriched powdered formula improved seric protein levels in ambulatory postoperative head and neck cancer patients. Improvement of weight, fat mass and fat free mass was observed in patients whom not received radiotherapy during the follow up. PMID- 24160202 TI - Excessive adiposity and sedentary lifestyles are prevalent in cancer patients; a pilot study. AB - Cancer aetiology is multifactorial; risk factors comprise obesity, central adiposity, physical inactivity and excessive/ deficient intake of foods and/or nutrients with procarcinogenic/ protective effects. We aim to analyze the pattern of nutritional status, food intake and physical activity in a cohort of cancer patients. This pilot crosssectional study was conducted in 64 outpatients referred for Radiotherapy. Nutritional parameters evaluated: BMI, waist circumference, body composition by tetrapolar bioimpedance (Xitron(r)). Usual food intake was collected with a short food frequency questionnaire and physical activity was assessed with Jacksons' questionnaire. Overweight/obesity and excessive body fat mass prevalence was of 53% and 61%, respectively. Central obesity, which indicates moderate/high cardio-metabolic risk, was found in 78% of patients. Food frequency analysis showed a poor intake in vegetables and a high intake in meat and carbohydrates. Physical inactivity was prevalent. This pilot study in cancer patients, showed a high prevalence of overweight/obesity, excessive fat mass and central obesity, simultaneously with sedentary lifestyles and an inadequate diet, poor in protective foods and excessive in deleterious ones. Thus, these patients exhibit a high risk pattern for cancer development and for a poorer prognosis. The implementation of measures to promote balanced and protective diets and to encourage physical activity practice is urgently needed. PMID- 24160203 TI - The influence of body composition on quality of life of patients with breast cancer. AB - INTRODUCTION: Unwanted changes in body composition, as well as their impact on these people's quality of life, have been little investigated in patients with breast cancer. OBJECTIVE: [corrected] To assess the role of body composition on quality of life and the impact of chemotherapy on both, in women with breast cancer. METHODS: It was assessed prospectively women with breast cancer in a cohort of patients undergoing chemotherapy. Body composition was estimated through bioelectrical impedance. The quality of life was evaluated using the World Health Organization quality of life questionnaire. RESULTS: This study assessed 70 women, 77 and 73% of those were initially overweight and had excess of body fat, respectively. There was a significant increase in fat-free mass (p > 0.001), body mass index (p = 0.03) and weight (p = 0.02) while quality of life stayed the same during the study. Moreover, women with excess of body fat showed a significantly lower initial general health score, compared to those with normal body fat (p = 0.02). CONCLUSIONS: Chemotherapy proved to be a potential inducer in the weight gain in this population. We highlight the importance of further investigation about the impact of body fat accumulation on those women's quality of life. PMID- 24160204 TI - [Nutritional risk factors in patients with head and neck cancer in oncology care center Michoacan state]. AB - The head and neck cancer in Michoacan, Mexico, ranks as the third most common cancer and accounts for 12% of deaths. The increase in malnutrition in a patient with this disease has been associated with increased mortality. MATERIAL AND METHODS: We studied prospectively 30 patients of both sexes, aged 18 years with head and neck cancer in the Cancer Care Center of Michoacan. In the evaluation period since August 2010 to August 2011. Formats were used VGS-Oncology (Subjective Global Assessment), NRS 2002 (Nutritional risk screen) and Guss (Gugging Swallowing Screen), through which nutritional risk was determined, and established the swallowing capacity of the study population. RESULTS: In our study, 53.3% of the population had moderate malnutrition according to the VGS Oncology, 33% weight loss record. The NRS 2002 show that 43.3% is at risk of malnutrition. The degree of dysphagia is shown more often in older patients, cancer type and stage of illness. CONCLUSIONS: Nutritional risk scales relate directly proportional to tumor location and stage, as well, there are other different oncological factors involved in the patient's nutritional deterioration. Therefore it is of vital importance to have a nutritionist as part of the multidisciplinary team, to detect the nutritional risk and to be able to handle it in an opportune way. PMID- 24160205 TI - Acute physiological response to indoor cycling with and without hydration; case and self-control study. AB - INTRODUCTION: Oral rehydration drinks help maintain physical capacity and hydration during exercise. OBJECTIVE: Evaluate, in a case and self-control study, the effectiveness of three hydration and exercise protocols on work capacity and physical and psychosomatic stress during indoor cycling (InC). METHODS: 14 middle aged eutrophic men participated in three controlled randomly and not sequentially hydration (~278 mL 6/c 15 min) and exercise (InC/90 min) protocols: No liquids, plain water, or sports drinks (SD). The response variables were: Body temperature (BT), heart rate (HR), and mean blood pressure (MBP). The covariables: Distance traveled (DT), ergometer resistance (R), body fat (BF), difference in body weight between tests (rBW), and age of the participants. The differences between protocols were evaluated using GLM Repeated Measures, the independence of associations by multiple linear regression. RESULTS: In non-liquids, the subjects showed higher BT, HR, and MBP than when they drank plain water or SD (p < 0.01). Work capacity was the same in the three hydration protocols. BT was the most sensitive variable detected by the hydration status of the subjects. 34%, 99%, and 21% of the associated variance to HR, MBP, and BT was explained by DT + BT, BT + BF, and DeltaBW + age + R + DT + BF, respectively. CONCLUSIONS: Liquid intake with or without electrolytes does not affect work capacity, and they are equally effective as hydration sources during =?90 min of InC at strong and very strong intensities. Body temperature is the most sensitive variable detected by the subject's hydration status during exercise. PMID- 24160206 TI - [Validation of aseptic technique of parenteral nutrition compounding in a pharmacy service according to USP Chapter 797]. AB - INTRODUCTION: During the process of parenteral nutrition preparation, aseptic techniques by nursing staff must be guaranteed. Chapter 797 of the United States Pharmacopeia classifies the risk levels of sterile compounding and defines the requirements that must be followed throughout the compounding. OBJECTIVE: To describe the development of an aseptic technique validation procedure for nurses who compound parenteral nutrition at the compounding area Pharmacy Service according to Chapter 797 United States Pharmacopeia guidelines. MATERIAL AND METHODS: Chapter 797 United States Pharmacopeia was reviewed and parenteral nutritions were classified as medium risk level compounded sterile preparations. RESULTS: We adapted the United States Pharmacopeia guidelines for medium risk level compounded sterile preparations and we performed a procedure of aseptic technique validation for parenteral nutrition compounding. CONCLUSIONS: The aseptic technique validation procedure allows the validation of aseptic management quality of nursing staff. The procedure has been incorporated into practice and is performed monthly by the nursing staff in the nutrition area. PMID- 24160207 TI - [Management of parenteral nutrition in intensive care units in Spain]. AB - INTRODUCTION AND OBJECTIVES: some relevant aspects related to parenteral nutrition in the Spanish ICUs are still unclear. These aspects include: caloric and protein intake, total volume, glycemic control, the type of lipid emulsion used or the comparison of different formulations. Our objective is to know the clinical practice patterns of artificial nutrition therapeutics, particularly of parenteral nutrition in the Spanish ICUs. MATERIAL AND METHODS: twelve representative ICU's participated in a nutrition survey from January to March 2012. The survey was divided in two sections: A) Management of artificial nutritional support in critically ill patients and B) Assessment of a new parenteral nutrition formulation adapted to critically ill patients. The following information was collected: percentage of patients receiving artificial nutrition; availability of enteral formulations; types of lipid emulsions; calories, amino acids and lipids supplied; addition of glutamine, vitamins and trace elements; management of volume and hyperglycemia; and comparative data between patients receiving the new formulation vs. standard formulations: glycemic control, assessment of hepatic function and infectious complications as well as the intake of total calories, proteins, volume and insulin supplied. RESULTS: The average number of hospital beds and ICU beds is 780 and 25 respectively; the average number of patients admitted in the ICU is 950 per year. 49% were medical patients, 31% surgical patients and 20% trauma patients. 59.75% of patients required artificial nutrition (AN), of which, 58.7% required enteral nutrition (EN), 16% total parenteral nutrition (TPN); and 25.3% suplementary parenteral nutrition (SPN). When EN was contraindicated, 83.3% of patients were started on early TPN (24 hours) and if EN was not sufficient, 66.7% were started on SPN within 48 hours. Regarding prescribers usual practice, 50% tried to reduce volume of PN and 100% of them had an insulin infusion protocol. 39% of prescribers recommended high-protein, low-volume and low-glucose TPN; 42% prescribe TPN with SMOF (soybean, MCT, olive and fish oil); and 33% with OOBE (olive oil based emulsion) as lipid emulsion. 92% added glutamine. 60% considered that the new formulation may be indicated for sepsis, trauma, burn patients and MOF (multiple organ failure) and the 30% would use it as a routine therapy at the time of admission. 40% considered that insulin requirements were reduced; 50% claimed better volume management and 60% highlighted the protein/volume ratio. Attending to patient outcome, patients receiving the specific formulation have less affected hepatic function, higher protein intake and lower volume infusion but no significant differences were observed and they required less insulin dosage (p = 0.07). CONCLUSIONS: In the twelve ICUs included in the survey, the clinical practice patterns related to parenteral nutrition management are adapted to the guidelines of scientific societies such as the Spanish Society of Intensive Care Medicine and Coronary Units (SEMICYUC), the Spanish Society of Parenteral and Enteral Nutrition (SENPE) and the European Society for Clinical Nutrition and Metabolism (ESPEN). The new formulations designed for critically ill patients may be indicated for these conditions. PMID- 24160208 TI - [Impact of an intervention on diet and physical activity on obesity prevalence in schoolchildren]. AB - In Chile childhood obesity is a growing public health problem. Intervention programs within schools have shown variable results, with better impacts when multiple aspects are involved and included the entire educational community. The objective of the study was to evaluate the effect on the nutritional status of children in intervention schools within 2 years of duration (Healthy Living Program). The sample included 2,527 students first through fourth grade of 3 counties of Santiago. The students were intervened and followed for a period of two years in their food and nutrition habits, physical activity and self-care practices, by a team of nutritionists and physical education teachers. Weight and height were measured at start of program, end of the first and second years of intervention, under standardized conditions and calculated the Z score of BMI and nutritional status according to the WHO reference 2007. At the end of the second year 1,453 children were reassessed. There was a significant decrease in BMI Z score in obese children (-0.3 SD) and obesity decreased from 21.8% to 18.4% at the end of the intervention. 75% of schoolchildren obese and 60.5% overweight decreased their BMI Z score, reduction that was greater in men and students in the upper grades. 51.9% of normal weight children increased their BMI Z-score age, although most less than 0.5 SD. The intervention in education, nutrition and physical activity among schoolchildren in three communes of Greater Santiago was effective in reducing the prevalence of obesity (-3.4 percentage points). The big challenge is to find mechanisms to give continuity to the program and evaluate long-term effects. PMID- 24160209 TI - [The association between dietary macronutrients intake and obesity among children and adolescents; a case-control study]. AB - INTRODUCTION: The high prevalence of obesity among Spanish children and adolescents has become an important public health problem. OBJECTIVE: To assess the association between dietary macronutrient intake and obesity in a case control study of children and adolescents (aged 5.5 to 18.8) from Navarra. METHODS: Cases were 178 obese children (body mass index > 97th percentile), from Navarra. Controls were individually matched by sex and age. Anthropometric data were collected by trained personal using standardized procedures. Personal interviews were performed to collect previously validated semiquantitative food frequency questionnaires (FFQs). From these FFQs we calculated the intake of macronutrients (carbohydrates, proteins and fats) and types of fatty acids. Energy-adjusted macronutrient intake was divided into quintiles. Conditional logistic regression was used and confounder factors were taken into account. RESULTS: The macronutrient composition of the diet was similar between cases and controls, except for polyunsaturated fatty acids (PUFA) intake, which was significantly inversely associated with obesity (p for trend < 0.01), with adjusted odds ratio = 0.34 (95% CI: 0.15 to 0.77) for the fifth versus the first quintile. CONCLUSIONS: An inverse and significant association between PUFA intake and obesity was found in this case-control study. PMID- 24160210 TI - Effectiveness of cognitive-behavioral therapy in morbidity obese candidates for bariatric surgery with and without binge eating disorder. AB - AIMS: To analyze changes in the general and specific psychopathology of morbidly obese bariatric surgery (BS) candidates after cognitive behavioral therapy (CBT) and assess differences between patients with and without binge eating disorder (BED) and between patients with obesity grades III and IV, studying their influence on weight loss. METHODS: 110 consecutive morbidly obese BS candidates [77 females; aged 41 +/- 9 yrs; body mass index 49.1 +/- 9.0 kg/m2] entered a three-month CBT program (12 two-hour sessions) before BS. Participants were assessed with general and specific psychopathology tests pre- and post-CBT. Data were analyzed according to the degree of obesity and presence/ absence of BED. RESULTS: At baseline, BED patients were more anxious and depressive with lower self-esteem and quality of life versus non-BED patients (p < 0.05) and were more concerned with food, weight and figure, felt greater hunger, fear and guilt, and were more influenced by contextual cues (p < 0.005). Post-CBT, these differences in self-esteem, depression, and eating disorders disappeared due to significant improvements in BED patients. No difference between OIII and OIV groups was found in any psychopathology test pre- or post-CBT. Multivariate analysis demonstrated that CBT was effective to treat psychological comorbidity regardless of the presence/ absence of BED or degree of obesity. At 1 yr post-CBT, weight loss versus baseline (before CTT) was > 10% in 61%, with no intergroup differences. CONCLUSIONS: CBT is effective to treat psychological comorbidity in BS candidates, regardless of the presence of BED and degree of obesity. PMID- 24160211 TI - [Predictor variables for low adherence to a lifestyle modification program of overweight treatment in primary health care]. AB - OBJECTIVES: To identify predictive variables of low adherence to a pilot Lifestyle Modification Program (LMP) for overweight and obesity treatment in primary health care (PC ). MATERIAL AND METHODS: Sixty subjects with BMI > 27 kg/m(2) were recruited. Health professionals directed the program in a group structure and biweekly, based on nutrition education with individualized dietary guidelines, promotion of physical activity and motivational support. A validated questionnaire on lifestyle habits for overweight and obesity subjects was used to identify variables related with program adherence and anthropometric variables were measured before and 6 months after intervention. Low adherence was considered when patients attended to less than 80% of visits. RESULTS: Twenty seven subjects (45%) presented high adherence to the program. The variables associated to low adherence were related to baseline with IMC >= 35 kg/m(2) (p < 0.05); ex smoker period <= 4 months (p < 0.01); high caloric diet (p < 0.01) and scarce physical activity (p < 0.05). At 6 months the subjects who finalized the program presented a significant decrease of weight (86.0 +/- 15.6 vs 79.2 +/- 13.4 kg; p < 0,001); fat mass percentage (41,6 +/- 4,6 vs 38.8 +/- 5,4%; p < 0.001), blood glucose (108 +/- 45.48 vs 94.38 +/- 11.97 mg/dl; p < 0.01). It also improved caloric diet profile, above all decreasing the percentage of fat (39.6 +/- 4.8 vs 35.5 +/- 5.6%; p < 0.01). CONCLUSION: Have recently left smoking, obesity degree two or higher, a high caloric diet and scarce physical activity were basal variables identified as predictive of a low adhesion to a LMP for the treatment of overweight and obesity in primary health care. We do not consider this pilot experience as satisfactory and other new strategies are under development. PMID- 24160212 TI - Maternal age as risk factor of prematurity in Spain; Mediterranean area. AB - BACKGROUND: Maternal age is a preponderant variable in the epidemiological analysis of the premature birth. Studies show that in the extreme ages of the maternal life there is a risk of premature birth that generates a high rate of neonatal morbidity. OBJECTIVES: [corrected] Determine the effect on the extreme ages of women residents in the province of Alicante on the total of the premature births. METHOD: An explanatory, retrospective case-control study was conducted during the period from January 1st, 2008 to December 31st, 2011. The study was based on the revision of the newborn registers from the Neonatal Screening Center of the province of Alicante. All the preterm were included, this means between 22 & 36 complete weeks of pregnancy (5,295 out of 78,391 newborn which represents 6.75% of prematurity), and a random sample of the deliveries with 37 weeks or more of pregnancy (control group). The age of the mother was studied as independent variable and the prematurity as dependent variable. RESULTS: Clearly shows an increased risk of prematurity among teenage mothers compared to the age group nearest to them, which is confirmed by a squared Chi test which gives a significantly different distribution (p < 0,0001) and an OD for very preterm of 2,41 (1,51-3,24) and of preterm of 1,71 (1,32-2,19). This probability is also higher among mothers over 40 years old with an OD of 1,86 (1,39-2,48) and 1,66 (1,44-1,91) for very preterm newborns and preterm newborns respectively. DISCUSSION: The results clearly manifest that teenagers and older pregnant mothers are at higher prematurity and low birth weight risk, therefore imposes the need to trace educational interventions to minimize this problem from the results in this research. PMID- 24160213 TI - [Correspondence between the fatty acids in healthy children serum and in membrane phospholipids]. AB - INTRODUCTION: The diet is important in the supply of fatty acids in humans, especially those of the n-3 and n-6 families by its essentiality and related physiological function. It is important to have reference values in accessible biological samples: serum and erythrocyte membranes, in order to alleviate potential shortfalls. The objective is quantifying fatty acids present in these samples from C6 to C26. MATERIAL AND METHODS: the determinations of the fatty acids of 30 healthy children in serum and its corresponding membrane phospholipids from blood cells by lipid extraction, methylation, separation and quantification in gas chromatography with detection of masses have been. It is comparing the values obtained in each serum and its partner of cell membranes. RESULTS AND DISCUSSION: It is have obtained normal values in healthy children. The C16, which represent a quarter of all fatty acids, it is in the same proportion in both samples, in the rest of fatty acids, there is no clear correspondence between both values. In the n-6 family, the C18:2n6 is higher in serum against the C20:4n6 which is in the phospholipids. In the same way between the n-3 family, the C20:5n3 is higher in serum and the C22:6n3 is in membrane phospholipids. These values are cause of different processes, recent nutritional contribution to serum and with long-term implications and metabolic values in the phospholipids of membranes. PMID- 24160214 TI - Lifestyle, quality of life, nutritional status and headache in school-age children. AB - BACKGROUND: Headache has been described as a factor with significant negative impact on the quality of life of school-aged children with a high risk of developing in chronic and persistent form in adulthood. Among other headache associated triggers or aggravating factors, lifestyle and obesity has been investigated, but results are still conflicting. OBJECTIVE: To evaluate the prevalence of headache in school-aged children and its relationship to anthropometric characteristics, lifestyle, and quality of life. METHODS: A cross sectional study was conducted in six schools located in two cities in southern Brazil, involving 750 students aged 7 to 14 years. Information was collected on sociodemographic characteristics, clinical variables (presence of headache and menarche), anthropometric data, lifestyle, and quality of life. RESULTS: A total of 185 (24.7%) students reported having headache crises in the last 3 months. Among students aged 10 to 14 years, presence of headache was associated with female sex, affecting 32.2% of girls vs. 23.3% of boys (p = 0.042, chi-square test). Anthropometric parameters (data on overweight/obesity) were consistent with national prevalence rates, and there was no association between Body Mass Index (BMI) and headache. Regarding lifestyle, 2.0% of students reported smoking and 1.6% consuming alcohol occasionally, and neither was associated with headache. Quality of life, especially aspects of social life, appeared to be affected by the presence of headache. CONCLUSION: This study found a high prevalence of headache in school-aged children, which was associated with female students aged 10-14 years and quality of life. PMID- 24160215 TI - Somatotype and intellectual ability (Raven Progressive Matrices Test) in Chilean school-age children. AB - OBJECTIVES: The aim of this study was to determine the relationship between somatotype and intellectual ability (IA) in 11-12 and 15-16 year-old students (n = 1,015) in the Chile's Metropolitan Region from a representative sample of 33 educational establishments chosen at random. METHODS: The Heath-Carter somatotype and the IA assessed through the Raven Progressive Matrices Test were measured. RESULTS: The endomorph was observed in 59% of the students; 28% had a mesomorph and 13% ectomorph. The IA was distributed in: 11.2% Grade I, 26.8% Grade II, 41% Grade III, 17.6% Grade IV and 3.2% Grade V. A positive and significant correlation of IA with the endomorphic component (r = 0.074, p = 0.02) was found in the total sample and only in females (r = 0.109, p = 0.02); at the same time, a positive and significant correlation with the ectomorph component was also observed (r = 0.067, p < 0.05). CONCLUSIONS: This suggests that other variables would influence more strongly the IA for which further research is needed to quantitate this multifactorial problem. PMID- 24160216 TI - Students of dietetics & nutrition; a high risk group for eating disorders? AB - INTRODUCTION: Changes in eating behaviour of university students are common and widely studied. Although the risk of developing eating disorders seems to be obvious among nutrition students, there is a lack of research in this field. This study aimed to: determine the risk of developing eating disorders in Dietetics and Nutrition (DN) students, through the comparison of eating behaviours, food habits, nutritional status, body composition and physical activity with those of other college students (from health and non-health degrees). METHODS: Cross sectional and comparative study. The sample included 189 female students, aged 18 to 25 years (20.3 +/- 2.0), from two Portuguese public universities. All students were measured (weight, height, % fat mass and waist circumference) and answered four validated questionnaires to assess eating behaviour, food patterns and physical activity. RESULTS: There was a low risk of eating disorders development among these students (4.2%). No significant differences between students from DN, health and nonhealth degrees concerning eating behaviour, nutritional status and body composition were found, contrasting with differences in some food habits and physical activity (p < 0.05). CONCLUSIONS: Despite the low risk of eating disorders among DN students, a large percentage of them had body weight concerns. DN students had the highest percentages of normal weight, no cardio-metabolic risk according to waist circumference and normal fat mass. DN students had the healthiest food habits and they also practiced moderate and intense physical activity in a high percentage, suggesting a possible positive influence of more knowledge on food and health. Results suggested the importance of more research in college students in order to identify the need for intervention and improve their lifestyle. PMID- 24160217 TI - [Impact of a brief educational intervention about nutrition and healthy lifestyles to school students given by a healthcare provider]. AB - INTRODUCTION: Obesity is an important health concern worldwide. Spain has one of the highest pediatric obesity rates among European countries, and they are increasing, which mandates the development of innovative strategies aimed at reverting this trend and decreasing the health problems related to obesity and the considerable waste of resources foreseen for the upcoming years. OBJECTIVES: To determine if an educational intervention from a health professional would yield an additional benefit in the acquisition of knowledge on nutrition. A second objective was to determine the prevalence of weight excess as well as the lifestyle habits in a sample of school students. MATERIAL AND METHODS: Analytical, interventional, random, longitudinal, pilot study in a sample of 107 students aged 9-15 years. The weight, height, adherence to the Mediterranean diet, level of physical activity and sedentarism, and knowledge on feeding and healthy lifestyles were estimated through a questionnaire. In an intervention group (54 students) a short educational intervention was carried out by a health professional. Two months later, the knowledge on diet and lifestyle habits was reassessed in all the students. RESULTS: After the educational intervention, the students in the intervention group had better knowledge regarding feeding and healthy lifestyles than the control students, and this difference was statistically significant. CONCLUSIONS: the additional educational activities on healthy lifestyles within the scholar program given by a health professional may represent an additional benefit to the strategies aimed at decreasing pediatric obesity in our setting. PMID- 24160218 TI - [Efficacy of zinc on lineal growth on Latin American children younger than 5; systematic review]. AB - BACKGROUND: In most Latin American countries, the prevalence of micronutrient deficiencies, growth stunting, morbidity and mortality are highly present in children. Single micronutrient deficiencies such as zinc have been associated to growth retardation. The purpose of this study was to conduct a systematic review of randomized control trials that examined the association between zinc supplementation and children s growth in Latin America. METHODOLOGY: An electronic literature search was conducted with the keywords "Micronutrients supplementation and growth" in the PubMed databases, of RCT, published from January 2005 to April 2013. There were 279 RCT found assessing the effect of zinc supplementation on linear growth; 34 were conducted in Latin American countries, of which five met the inclusion criteria. A study referred by other authors was also included. RESULTS: Six studies were analyzed. The studies were conducted in Brazil, Cuba, Peru, Ecuador, and Guatemala. None of the studies analyzed observed the positive effect of zinc on lineal growth. CONCLUSIONS: The conducted review suggests that zinc supplementation has not a significant effect on linear growth; however, zinc supplementation might be beneficial over lineal growth to zinc deficient children, if other deficient nutrients are added. PMID- 24160219 TI - Metabolic syndrome components can predict C reactive protein concentration in adolescents. AB - BACKGROUND: Metabolic syndrome (MS) is suggested to be associated with a low grade inflammation state, but the relationship between inflammation biomarkers and the components of metabolic syndrome in adolescents are still lacking. OBJECTIVE: To investigate the association between C-reactive protein (CRP) serum concentrations and metabolic syndrome components in adolescents. METHODS: A cross sectional population based study was conducted. Anthropometric, biochemical and clinical data were collected from 524 adolescents (11-15 years old) randomly sampled from school population of Alegre city, Espirito Santo, Brazil. Data were analyzed by STATA version 9.0. RESULTS: Adolescents with higher values for BMI (p = 0.001) and higher body fat percentage (p = 0.003) had higher CRP concentrations than those with lower BMI and body fat percentage. CRP concentrations was directly correlated with BMI (r = 0.17, p = 0.0001), waist circumference (r = 0.15, p = 0.0005), HDL-c (r = 0.13, p = 0.003), fasting insulin (r = 0.12, p = 0.003) and systolic blood pressure (r = 0.11, p with = 0.01). In the multiple linear regression analysis BMI (r = 0.05, p = 0.002), fasting glucose (r = -0.01, p = 0.003) and HDL-c (r = 0.017, p < 0.001) were associated to CRP concentrations after adjusting for the other components of MS. CONCLUSION: The association found between individual components of MS and CRP concentrations suggests that inflammation might be an early event in the development of metabolic disorders in adolescents. PMID- 24160220 TI - [Subclinical atheroesclerosis and metabolic syndrome in children]. AB - INTRODUCTION: Metabolic syndrome (MS) in children has been associated to subclinical atherosclerosis as estimated by carotid intima-media thickness (CIMT). OBJECTIVES: We aim to ascertain the influence of MS, insulin resistance (IR) and nutritional status on CIMT. Percentiles with an increased risk of CIMT were also explored. METHODS: A cross-sectional study of 447 children attending public schools in Santiago, Chile, was performed during years 2009-2011. This sample was selected considering the presence of one or more MS component and IR. Anthropometry and BP were assessed. A blood sample for determination of glycemia, insulinemia and lipids was taken. CIMT was assessed using high resolution ultrasonography with automated software. Pearson correlation, Student's t-test, Chisquared test, and stepwise logistic regression were computed. RESULTS: Mean age was 11.5 +/- 1.0 years old (range 10- 14); 59% girls; 93% pubertal; 72% excess weight; 24% MS; and 15% IR. Mean values of MS components in children with CIMT >= percentile 75 versus < percentile 75 had differences for systolic BP or diastolic BP >= percentile 90 (BP >= percentile 90) and high density lipoproteins cholesterol <= 40 mg/dL (CHDL <= 40 mg/dL). The logistic regression for CIMT >= percentile 75 only selected BP >= percentile 90 and CHDL <= 40 mg/dL. The logistic regression for CIMT >= percentile 90 did not select independent variables. CONCLUSIONS: In this group of children BP >= percentile 90 and CHDL <= 40 mg/dL values were associated to CIMT >= percentile 75. Influences of IR and nutritional status on CIMT were not found. PMID- 24160221 TI - Variability of formulas to assess insulin sensitivity and their association with the Matsuda index. AB - OBJECTIVE: To assess the individual variability of HOMA and QUICKI indexes for the assessment of insulin resistance, using three fasting blood samples obtained within 30 minutes. RESEARCH METHODS & PROCEDURES: Data from 80 participants aged 41.5 +/- 15 years (26 females), who underwent an oral glucose tolerance test to calculate Matsuda index, were used. Every participant had three fasting blood samples obtained within 30 minutes and four blood samples obtained at 30, 60, 90 and 120 minutes after a 75 g oral glucose load. Insulin and glucose were measured in each sample. HOMA and QUICKI indexes were calculated using the nine possible combinations of the three fasting blood samples. Matsuda index was calculated with all samples obtained. RESULTS: Median values of HOMA-IR, HOMA-beta, QUICKI and Matsuda indexes were 1.9, 117.9, 0.35 and 3.71 arbitrary units, respectively. The individual variation coefficients of HOMA-IR, HOMA-beta and QUICKI were 11.8 (7.8-18.9), 15 (10.2-22.9) and 1.8 (8.8-21.9) % respectively. When compared with Matsuda index, the R squared values of HOMA-IR, HOMA-beta and QUICKI were 0.46, 0.2 and 0.71, respectively. CONCLUSIONS: Among fasting indexes for insulin resistance, QUICKI had the lower variation coefficient and the higher correlation with Matsuda index. PMID- 24160222 TI - C-peptide levels predict type 2 diabetes remission after bariatric surgery. AB - BACKGROUND: C-peptide (Cp) serves as a surrogate of pancreatic beta-cell reserve. This study evaluates the clinical significance of basal Cp as a predictor of type 2 diabetes (T2D) remission after bariatric surgery (BS). RESEARCH DESIGN AND METHODS: Retrospective study of 22 patients with BMI > 35 kg/m2 and T2D who underwent BS. Evaluation of anthropometric and glucose metabolism parameters before BS and at one-year follow-up. Analysis of patients with T2D remission (HbA1c < 6%, fasting glucose (FG) < 100 mg/dl, absence of pharmacologic treatment) and preoperative characteristics associated (logistic binary regression model). ROC curve to estimate an optimal Cp value to predict T2D remission. RESULTS: Preoperativeley (mean +/- SD): age 53.3 +/- 9.4 years, BMI 42.9 +/- 6.8 kg/m2, T2D duration 6.9 +/- 5.2 years, FG 159.6 +/- 56.6 mg/dL, HbA1c 7.5 +/- 1.1%, Cp 4.0 +/- 2.0 (median 3.8, range 0.1-8.9) ng/mL. At one year follow-up, remission of T2D in 12 cases (54.5%). Preoperative Cp correlated with 12-month HbA1c (r = -0.519, p = 0.013). Preoperative Cp was higher in those who achieved remission: 5.0 +/- 1.7 vs 3.0 +/- 1.7 ng/ml, p = 0,013. A Cp concentration > 3.75 ng/mL provided a clinically useful cut-off for prediction of T2D remission. T2D remission rates were different according to median preoperative Cp: 27.3% if Cp < 3.8 ng/mL and 81.7% if Cp > 3.8 ng/mL (p = 0.010). CONCLUSIONS: Patients with elevated preoperative Cp levels achieve higher rates of T2D remission one year after BS. A Cp concentration > 3.75 ng/mL seems clinically useful. PMID- 24160223 TI - [A short-term training program reduced acute phase proteins in premenopausal women with metabolic syndrome]. AB - INTRODUCTION: It is accepted low grade systemic inflammation plays a key role in metabolic syndrome. Further, several studies have reported it may be considered a therapeutic target. Accordingly, this study was conducted to ascertain the impact of a short-term aerobic training program on acute phase proteins in women with metabolic syndrome. MATERIAL AND METHODS: A total of 135 adult women (38.4 +/- 3.3 years) with metabolic syndrome volunteered for this study. Participants assigned to the intervention group underwent a 12-week aerobic training program, 3 sessions/week. The main part of each exercise sessions was performed in a treadmill at moderate intensity (60- 75%HRmax; increasing 5% each 3 weeks) for 25 40 minutes (increasing 5 minutes each 3 weeks). Physical fitness was determined by a continuous maximal incremental test. Further, fat mass percentage and indices of obesity were assessed. Plasmatic levels of C reactive protein (CRP-us) and fibrinogen were determined by nephelometry and HPLC respectively. This protocol was approved by an Institutional Ethics Committee. RESULTS: Aerobic training improved physical fitness and reduced both fat mass percentage and indices of obesity. Compared with baseline, it also reduced significantly plasmatic levels of CRP-us (4.90 +/- 0.7 vs. 3.77 +/- 0.4 mg/l; p = 0.017) and fibrinogen (3.88 +/- 0.4 vs. 3.36 +/- 0.2 g/l; p = 0.025). Further, a moderate correlation was found between CRP-us and waist circumference (r = 0.66; p = 0.008). No significant changes were found in controls. CONCLUSION: A short-term, aerobic training program reduced acute phase proteins in young women with metabolic syndrome. Further, long-term, well-conducted studies are still required to determine whether correction of this low-grade inflammation improves clinical outcomes of women with metabolic syndrome. PMID- 24160224 TI - [Associated factors to insulin values in a population-based study in adolescents]. AB - OBJECTIVES: To identify factors that correlate with insulin values and to examine its independent associations among adolescents. METHODS: A cross-sectional population-based study was conducted among adolescents aged 12-16,9 years old. A multi-stage stratified cluster random sampling method was employed. Anthropometric measurements and nutritional survey were performed, and fasting blood samples for insulin were obtained. STATISTICS: Multiple lineal regression. RESULTS: 379 adolescents were included. Mean age was 14.08 +/- 1.30 years. Factors associated with higher fasting insulin levels were puberty [beta 4.55 (95% IC 0.42-8.69)], abdominal obesity [beta 6.11 (95% IC 3.93-8.29)] and to be born small for gestational age (SGA) [beta 7.45 (95% IC 2.47-12.44)]. It was observed a negative association between the regular intake of olive oil at home and insulin values [beta -4.14 (95% IC -7.31- -0.98)]. CONCLUSIONS: Abdominal obesity and SGA were factors associated with higher fasting insulin values. In contrast, the regular intake of olive oil at home was an independent protective factor. PMID- 24160225 TI - Nutritional assessment in hepatic cirrhosis; clinical, anthropometric, biochemical and hematological parameters. AB - INTRODUCTION: Since malnutrition is common in patients with hepatic cirrhosis (HC) is necessary to investigate the interference of the pathophysiological changes of liver in the methods of diagnosis of the nutritional status. OBJECTIVE: To evaluate the frequency of malnutrition among patients with HC outpatients, using different assessment methods of the nutritional state. METHODS: Nutritional state was determined by subjective global assessment (SGA); body mass index (BMI); percentage of ideal body weight (%BW); triceps skinfold thickness (%TST), mid-arm circumference (%MAC) and of the ideal mid-arm muscle circumference (%MAMC); serum albumin (ALB) and total lymphocyte count (TLC). RESULTS: Seventy-eight patients were evaluated, 56.4% were male and mean age were 53.0 +/- 7.7 years. The HC etiology was alcoholic in 56.4% of the cases. According to the classification of Child-Pugh, 48.7% were A, 26.9% were B and 24.4% were C. Variable degrees of malnutrition were diagnosed in 61.5% (SGA), 16.7% (BMI), 17.9% (%BW), 93.6% (%TST), 62.8% (%MAC) and 38.5% (%MAMC) of the patients. The levels of ALB and TLC were compatible with malnutrition diagnosis in 43.6% and 69.2% of the patients, respectively. The frequency of diagnosis of malnutrition increased according to the severity of HC and it also increased in patients with alcoholic etiology. A greater depletion of adipose tissue in women and of muscular tissue in men was demonstrated. CONCLUSIONS: The diagnostic frequency of malnutrition in ambulatory-treated patients varies according to the nutritional evaluation method used. The prevalence of malnutrition is greater in the more advanced stages of HC and in alcoholic etiology. PMID- 24160226 TI - [Software for performing a global phenotypic and genotypic nutritional assessment]. AB - BACKGROUND: The nutritional assessment of a patient needs the simultaneous managing a extensive information and a great number of databases, as both aspects of the process of nutrition and the clinical situation of the patient are analyzed. The introduction of computers in the nutritional area constitutes an extraordinary advance in the administration of nutrition information, providing a complete assessment of nutritional aspects in a quick and easy way. OBJECTIVE: To develop a computer program that can be used as a tool for assessing the nutritional status of the patient, the education of clinical staff, for epidemiological studies and for educational purposes. DESIGN: Based on a computer program which assists the health specialist to perform a full nutritional evaluation of the patient, through the registration and assessment of the phenotypic and genotypic features. The application provides nutritional prognosis based on anthropometric and biochemical parameters, images of states of malnutrition, questionnaires to characterize diseases, diagnostic criteria, identification of alleles associated with the development of specific metabolic illnesses and questionnaires of quality of life, for a custom actuation. The program includes, as part of the nutritional assessment of the patient, food intake analysis, design of diets and promotion of physical activity, introducing food frequency questionnaires, dietary recalls, healthy eating indexes, model diets, fitness tests, and recommendations, recalls and questionnaires of physical activity. RESULT: A computer program performed under Java Swing, using SQLite database and some external libraries such as JfreeChart for plotting graphs. This brand new designed software is composed of five blocks categorized into ten modules named: Patients, Anthropometry, Clinical History, Biochemistry, Dietary History, Diagnostic (with genetic make up), Quality of life, Physical activity, Energy expenditure and Diets. Each module has a specific function which evaluates a different aspect of the nutritional status of the patient. CONCLUSIONS: UNyDIET is a global computer program, customized and upgradeable, easy to use and versatile, aimed to health specialists, medical staff, dietitians, nutritionists, scientists and educators. This tool can be used as a working instrument in programs promoting health, nutritional and clinical assessments as well as in the evaluation of health care quality, in epidemiological studies, in nutrition intervention programs and teaching. PMID- 24160227 TI - [Validation of self-reported weight and height university population and factors associated with differences between self reported and measured antropometrics]. AB - INTRODUCTION: Obesity is an important public health problem related to a higher risk of death from chronic degenerative diseases such as diabetes, cardiovascular diseases and several types of cancer. In epidemiological studies of big sample size, only self-reported weight and height can be collected for feasibility reasons and body mass index (BMI) estimates may be questioned. OBJECTIVES: In this study we compare self-reported and measured weight, height and BMI in a mostly young population of university students, and explore factors associated with discrepancies between self-reported and measured data. METHODS: In the period 2006-2012, 628 University students (476 women) from health sciences subject gave consent to participate in this study. Self-reported weight and height were collected by questionnaire and compared with weight and height measured afterward in health exams wearing light clothes and using standardized protocols. The validity of self-reported anthropometric estimates was explored by correlation coefficients and sensitivity, specificity, predictive values and kappa to detect measured overweight/obesity (BMI >= 25 kg/m2). Multiple linear regression was used to explore the factors related to the discrepancies between self-reported and measured data. RESULTS: The mean of self-reported weight, height and BMI was 62.5 kg, 167.6 cm and 22.1 kg/m2 and the mean of measured data was 62.6 kg, 167.4 cm y 22.2 kg/m2 respectively. Correlations between self reported and measured data were r = 0.97 for weight, 0.96 for height and 0.95 for BMI. The sensitivity to detect overweight (IMC >= 25 kg/m2) using self-reported data was 81.0%, the specificity was 98.5%, the predictive value was 90.6% and the kappa index was 0.75. The discrepancy between measured and self-reported weight, height and BMI was associated with a higher age, and a higher sleeping time was also associated to discrepancies in self-reported and measured height. CONCLUSIONS: Despite the self-reported weight and BMI may underestimate the true weight and BMI, and self-reported height overestimate, the validity of self reported anthropometric measures is adequate to use be used in epidemiological studies among young people with a high educational level. PMID- 24160228 TI - Predictive ability of the anthropometric and body composition indicators for detecting changes in inflammatory biomarkers. AB - INTRODUCTION: Obesity has been considered a chronic subclinical inflammation. High sensitivity C-reactive protein (hs-CRP) and fibrinogen are increasingly associated with cardiovascular risk. OBJECTIVES: To evaluate the ability of anthropometric and body composition indicators in discriminating higher levels of hs-CRP and fibrinogen. METHODS: 130 men (20-59 years) were assessed, having measurement of weight, height, waist circumference (WC), hip and thigh circumferences, sagittal abdominal diameter (SAD), coronal diameter (CD) and body composition. Conicity index, waist/height ratio, body mass index, waist/hip ratio, waist/thigh ratio and sagittal index were calculated. It was considered as the cutoff point for hs-CRP values >= 0.12 mg/dL and for fibrinogen the 50th percentile of the evaluated sample. RESULTS: Sagittal index (r = 0.280), waist/thigh ratio (r = 0.233) and waist/height ratio (r = 0.233) showed the best correlation with hs-CRP (p < 0.01). Conicity index (r = 0.305) and waist/height ratio (r = 0.279) showed the best correlation with fibrinogen (p < 0.01). In ROC analysis, the SAD (0.698 +/- 0.049) and the conicity index (0.658 +/- 0.048) had greater ability to discriminate cardiovascular risk through higher levels of hs CRP and fibrinogen, respectively (p < 0.01). The cutoff points of 30 cm, 89.9 cm and 20.5 cm were the ones that reached largest sum between sensitivity and specificity values for the CD, WC and SAD, respectively. CONCLUSIONS: The SAD and the conicity index demonstrated a greater ability to detect higher levels of hs CRP and fibrinogen, respectively, in apparently healthy adult men. PMID- 24160229 TI - Preliminary nutritional assessment of the Ecuadorian diet based on a 24-h food recall survey in Ecuador. AB - INTRODUCTION: Ecuador is a country with limited nutritional information, with exception of some general studies supported by Food Agriculture Organization (FAO). AIMS: To carry out a nutritional assessment of the Ecuadorian diet and determine the percentage of contribution to the intake of different nutrients according to the order of the meal (breakfast, morning snack, lunch, afternoon snack, and dinner snack) and Dietary Reference Intake (DRI). METHODS: For that purpose a pilot survey based on 24-h food recall method was carried out in three specific regions in Ecuador and collected information was processed, analyzed statistically and compared with DRIs established for Latin-American population. RESULTS: The study found significant differences for energy and certain vitamins in men and women in addition to determining that the highest energy contribution was obtained in lunch, followed by the afternoon snack and breakfast. Intermediate meals (morning snack, afternoon snack and dinner snack) contributed significantly less in the daily diet in comparison with other types of meal. Furthermore, it was observed that analyzed intakes did not meet the DRI for Carbohydrates, some vitamins (Thiamin, Pantothenic, Biotin, Folate Vitamin D and Vitamin E) and minerals (Ca, K, Cu, Mn, I and Fe). The Na intakes were quite above the DRI and Tolerable Upper Limit given by USDA, indicating a Public Health problem in relation with this electrolyte. CONCLUSIONS: The present pilot survey can be considered as a starting point to get insight into the Ecuadorian diet. This will allow to determine consumption patterns affecting population welfare and to evidence attendant positive and adverse effects. PMID- 24160230 TI - [Vitamin D intake in a representative sample of Spanish population aged 7-16 years. Differences in the contribution and in the food sources of the vitamin according to age]. AB - BACKGROUND: Vitamin D can play an important role in maintaining bone health and in the prevention of some diseases. Few foods are a natural source of vitamin D and these are not normally consumed, being the most common oily fish and yolk. AIM: To analyze the intake and sources of vitamin D in schoolchildren aged 7-16 years. METHODS: A representative sample of the Spanish population aged 7-16 years (n = 1,976) selected from ten Spanish provinces was studied. Dietary data were obtained by using a 3-day food record. The body weight and height were measured. RESULTS AND DISCUSSION: Mean vitamin D intake (1.63 (0.96-3.35) MUg/day) was lower than the recommended intake (RI) in 85.4% of study participants and it was influenced by age (OR = 0.935; IC: 0.889-0.983; p < 0.01). The main sources of vitamin D were eggs (27.7%), followed by cereals (25.8%), fish (20.9%) and dairy products (12.7%). Additionally, it has been found that vitamin D RI can be adequately covered the greater the consumption of fish is (r = 0.734; p < 0.001). Thereby, an increase of one fish serving decreased a 72.5% the odds of not covering vitamin D RI. CONCLUSIONS: Vitamin D intake is lower than the recommended intake in a high percentage of the participants. Having into account that the contribution of vitamin D is mainly determined by fish, an increase in the consumption of this food group would be desirable. Young children merit special attention. PMID- 24160231 TI - Effects of supplementation of antioxidant vitamins and lipid peroxidation in critically ill patients. AB - INTRODUCTION: Critical patients present systemic inflammatory process that can be followed by decrease in plasma concentrations of antioxidant vitamins. OBJECTIVE: [corrected] The aim of this study was to evaluate the effect of the supplementation of antioxidant vitamins in critical patients and their relation with lipid peroxidation. METHODS: 23 patients went on a standard diet (G1) and 11 went on a diet with daily supplementation of 10,000 IU of vitamin A, 400 mg of vitamin E and 600 mg of vitamin C (G2). The APACHE II score was made. Serum concentrations of retinol, beta-carotene, vitamins C and E, malondialdehyde (MDA) and C-reactive protein was measured before (T0) and on the 8th day after the beginning of the nutritional therapy (T1). The groups had been monitored on T0, T1 and T2, (at discharges or death) on the following parameters: mechanical ventilation; hospitalization days; mortality; infection incidence. RESULTS: Serum concentrations of MDA and vitamin E were significantly lower in G2 after intervention and strong tendency to increase vitamin C. There were not significant differences between the groups regarding the clinical parameters. CONCLUSIONS: The doses of vitamin A, C and E that were indicated were effective for the current lipid peroxidation reduction. PMID- 24160232 TI - [Eating habits and attitudes towards change in Spanish university students and workers]. AB - INTRODUCTION: Universities and workplaces are important targets for the promotion of the nutritional interventions in adult population. OBJECTIVES: The aim of this study was to assess the dietary habits and attitudes towards change in workers and university students from different academic fields. METHODS: The study data came from a cross-sectional study of a Spanish University population of 1,429 participants. We analyzed the dietary habits and the attitudes toward dietary change. RESULTS: The mean age of workers and students was 37 and 23 years, respectively. Both groups reported eating four meals per day. Among students, the consumption of vegetables, wine, fish and nuts was less frequent whereas carbonated beverages, commercial bakery, fast food and red meat was higher. On the other hand, overall dietary pattern of science students was healthier than other students. Although no significant differences were found between students and workers in attitudes towards change, 32% of employees and 39% of students said they were seriously considering changing them. CONCLUSIONS: The dietary pattern was healthier among workers than among students, particularly those participants that studied social sciences degrees. They constituted the most vulnerable segment of the university population from a nutritional point of view. About a third of workers and students considered changing their habits. PMID- 24160233 TI - Comprehensive quality evaluation of Chishao by HPLC. AB - OBJECTIVE: The purpose of this paper is to comprehensively evaluate the quality of Chishao. METHODS: In the experiment of this paper, the fingerprint spectrums of Chishao in all locations are established by RP-HPLC and the model of principle component analysis with the RP-HPLC peak areas is established. RESULTS: The quality of Chishao in the northern part of China or that made of Paeonia lactiflora is better than that of these in others or that made of other species. The quality of Chishao comes from P. veitchii is in the middle class and is better than those that comes from P. obovata, P. mairei and P. anomala. The results are consistent with traditional views of the quality of this plant. These results indicates that principal component analysis (PCA) can be used as an effective and economic method to evaluate the quality of Chishao, and may be extended to other Chinese medicinal plants. CONCLUSIONS: Due to the complex basis of the efficacy of Traditional Chinese Medicine (TCM), the method such as PCA of several chemical components appears to be a more appropriate method for the quality evaluation of TCM in contrast to the determination of a single or few chemicals. PMID- 24160234 TI - Conicity index as a contributor marker of inflammation in haemodialysis patients. AB - INTRODUCTION: Abdominal fat mass is an important risk factor of inflammation in the general population as it is in haemodialysis (HD) patients. The aim of this study was to investigate the association of adiposity using the conicity index (Ci) with nutritional-inflammatory markers and to analyse whether these factors were related with the clinical outcome in HD patients. METHODS: A cross-sectional study in 80 HD patients (men, 65%; aged 68.2 +/- 14.2) was carried out. Abdominal fat deposition was evaluated by Ci median with regard to baseline inflammatory, anthropomorphic, and nutritional markers. Linear regression analysis was applied to identify whether serum C-reactive protein (CRP), as an inflammatory biomarker, was an independent predictor of Ci in HD patients. RESULTS: Mean Ci was significantly greater in men (p = 0.001). Significant positive correlations were observed between Ci and serum triglycerides (r = 0.23; p < 0.05) and Ln of serum CRP (r = 0.27; p < 0.01). A significantly higher median Ci (men >= 1.39 and women >= 1.33) was observed in inflammated overweight patients by multivariate analysis (p < 0.05). Serum CRP, as an inflammatory biomarker, was a significant predictor (p = 0.021) of Ci, but its predictive value disappeared after median Ci adjustment of linear regression analysis. CONCLUSION: Abdominal fat mass, measured by Ci, appears directly linked to inflammation in dialysis. Results support the hypothesis that inflammation in HD patients has pleiotropic effects depending on abdominal body adiposity. PMID- 24160235 TI - [Integration of a software for hospital nutritional support prescription and the electronic medical record]. AB - INTRODUCTION: The prescription of parenteral nutrition is a medical procedure that should be properly documented and that requires adequate communication between physicians, pharmacists and nurses. Prescription may be made by orders and paper forms or with software applications, in which case their integration with the rest of the hospital information systems may be difficult. We present our experience with a software for prescribing artificial nutrition integrated with the electronic medical record. METHODS: In order to develop a software application for artificial nutrition prescription, meetings between the Clinical Nutrition Unit and the Computing Service staff were held, which set the needs of the clinical services and features that should have the application. DESCRIPTION OF THE SOFTWARE: The software allows the prescription of parenteral nutrition component by component or using predesigned templates, generates alerts if extreme value of components or possible physical- chemical incompatibility, imports and stores the results of the labs of patients and records the composition of parenteral nutrition formula in the electronic medical record, among other features. DISCUSSION: Our experience shows that collaboration between clinical services and hospital Computing permits to develop useful applications for the clinical teams and that can be integrated with other hospital software. PMID- 24160236 TI - Validity and reliability of the Dietary Sodium Restriction Questionnaire (DSRQ). AB - INTRODUCTION: The Dietary Sodium Restriction Questionnaire (DSRQ) was designed to assess attitudes and behaviors of patients with heart failure (HF) related to following a low-sodium diet. Recently, it has been translated and culturally adapted for use in Brazil. However, further validation of the instrument is required before it can be used in the management of patients with HF in Brazil. OBJECTIVE: To test the reliability and validity of the Brazilian version of the DSRQ. METHODS: Face and content validity were assessed by a panel of experts. Construct validity was tested using exploratory and confirmatory factor analysis. Reliability was tested using Cronbach's alpha to assess the internal consistency of the instrument. RESULTS: A total of 206 systolic HF outpatients were assessed (mean age, 60.4 +/- 11.9 years). Face and content validity analysis showed equivalence between the Brazilian version and the original instrument. In the exploratory factor analysis, the principal component analysis (PCA) yielded four factors with eigenvalues greater than 1. Three models were tested in the confirmatory factor analysis, and the three-factor model resulting from the PCA showed the best fit, accounting for 49% of the variance. Alpha values obtained for the attitude/subjective norm, perceived behavioral control, and dependent behavior subscales were 0.71, 0.67, and 0.79, respectively. CONCLUSIONS: Our results suggest that the final validated Brazilian version of the DSRQ is a valid and reliable tool for measuring attitudes and behaviors related to following a low-sodium diet in Brazilian patients with HF. PMID- 24160237 TI - Prolonged fasting with fluid therapy is related to poorer outcomes in medical patients. AB - BACKGROUND AND OBJECTIVE: An inadequate fluid therapy can worsen the outcomes of surgical patients, but there are no data in medical patients. The aim of this study was to determine the adequacy of fluid therapy in hospitalised patients of medical wards, and its influence on outcomes. METHODS: Cross-sectional study including nil-per-os patients admitted in medical wards of the Complejo Asistencial Universitario de Leon. The administered fluid therapy was compared with the standardised requirements. Nutritional status was evaluated with Subjective Global Assessment. Fasting was considered inappropriate if it lasted > 7 days in well-nourished, and >5 days in malnourished patients if nutritional support had not been provided. RESULTS: Fluid therapy lasted 4 (IQR = 2) days, and fasting was inadequately maintained in 27% of patients. Fluid requirements were correctly fulfilled, but patients received an excess of sodium (+58.4%) and chloride (+62.2%), and potassium administration was insufficient (-35.1%). Glucose supply was 68.8 (29.2) g/d, and 99% received < 130 g/d. Patients with an inadequate duration of fasting had a longer hospital stay after adjusting for sex, age, nutritional status, infused volume, electrolytes, glucose and diseases. Only malnutrition predicted mortality during hospitalisation (OR 10.5; 95%CI 1.3 to 83.2), when multivariate analysis was performed. CONCLUSIONS: Fasting medical patients receive an inadequate supply of glucose and electrolytes. Prolonged fluid therapy and malnutrition may worsen the outcomes of these patients, independently of other conditions like age or diseases. PMID- 24160238 TI - [Effect of refeeding on the body composition of females with restrictive anorexia nervosa; anthropometry versus bioelectrical impedance]. AB - OBJECTIVE: To assess the body composition in a group of malnourished patients with anorexia nervosa as compared to healthy controls, before and after nutritional support, by means of anthropometry and bioimpedance. METHODS: Prospective observational study. Complete anthropometry was performed as well as bioimpedance analysis in 12 women (24.5 years) with restrictive anorexia nervosa at hospital admission and weekly thereafter during re-feeding. The control group was formed by 24 healthy women (21 years). The Student's t test, the Mann-Whitney U test, the Student's t test for repeated measurements, and the Wilcoxon's test were applied. The level of agreement between anthropometry and BIA was calculated by the interclass correlation coefficient and the Bland-Altman s test. RESULTS: The patients had significant improvements in all indexes of body composition throughout their hospital staying although their values at discharge still were lower than those of the control subjects. The average weight gain was 5.22 kg (SD: 1.42), of which 51.4% was fat mass, preferentially centrally distributed. In the control subjects, the BIA equation that correlated the best with anthropometrics was Sun s equation (CCI = 0.896); in the patients, the level of agreement was weaker, both at hospital admission and at hospital discharge. CONCLUSIONS: Re-feeding produces weight gain, essentially at the expense of fat mass, which is centrally distributed; the nutritional status is not reestablished. The level of agreement between anthropometry and bioimpedance for studying body composition is acceptable, especially in healthy subjects. In those cases with severe changes in body composition and/or water balance, anthropometry is recommended when vectorial BIA or some other gold standard method are not available for the analysis of body composition. PMID- 24160239 TI - Diet choice in weight-restored patients with eating disorders; progressive autonomy process by nutritional education. AB - INTRODUCTION: Human eating behaviour is regulated by multiple factors. Anorexia nervosa patients show a restrictive eating pattern while bulimia nervosa patients present bingeing-purging episodes. Although treatments are specially successful in the normalization of body composition, maladaptive eating behaviours tend to persist being a risk factor for relapse and recurrence. OBJECTIVES: The aim of this work was to assess the quality of the nutritional choice of eating disorders patients after a year of nutritional education and to assess improvements in choice capacity. METHODS: Thirty-one outpatients of an eating disorders unit planned a menu after body composition normalization and repeated this plan each three months during a one-year programme of nutritional education. RESULTS: Patients improved the time spent on the assignment (p < 0.01), Body Mass Index (p < 0.01), their body fat mass (p < 0.01) and the content of energy (p < 0.05), carbohydrates (p < 0.01) and polyunsaturated fatty acids (p < 0.05) in their chosen menus. No differences were found on proteins, total fat or fat profile, vitamins or minerals. 12.9% and 3.2% of the patients chose their menu according to the recommendations of caloric and lipid profile, respectively, after a year of nutritional education. DISCUSSION: Although patients improved energy and carbohydrates content of the menus they tended to reduce caloric and fat food choices, which could lead to relapse and recurrence. Specific nutritional education programmes along with the mandatory psychological and psychiatric treatment may be effective. CONCLUSIONS: One year of nutritional education combined with psychological and psychiatric treatment improved those factors usually involved in relapse and recurrence, thus contributing to a proper outcome. PMID- 24160240 TI - Study on the mortality in Ecuador related to dietary factors. AB - Diet is an important factor related to the development of numerous diseases. In developing countries like Ecuador, this aspect is not considered as priority however, the study of the incidence of certain diet-related diseases could help to assess consumption habits of a country from a Public Health perspective and support national nutrition policies and programs. The objective the present study is to investigate the mortality rate of certain diet-related diseases in Ecuador and its possible relationship with Ecuadorian consumption habits. For that, mortality rates (2001-2008) associated with five different disease groups related to dietary factors (cancer of colon, cerebrovascular diseases, cardiovascular diseases, diabetes mellitus and liver diseases) were collected, analyzed and compared to consumption patterns in Ecuador. According to results, Ecuador has a low level of cancer of colon in comparison with developed countries (e.g. Spain). The group with the highest number of deaths corresponded to cardiovascular diseases followed by cerebrovascular diseases. The mortality study per province revealed that Amazonian provinces showed few deaths in relation to other provinces in Ecuador. This could be due to different factors including fails in the disease surveillance information systems, environmental factors and consumption patterns. In this sense, further investigation on native products consumption such as "chontaduro" might help to find valuable foods contributing to healthier Ecuadorian diet. These results, though preliminary, evidence that a major effort should be made by national and international organisations to collect data on consumption patterns and nutritional aspects of the Ecuadorian population in order to better support the development of effective food security and nutrition policies. PMID- 24160241 TI - [Mediterranean and Western dietary patterns in adult population of a Mediterranean area; a cluster analysis]. AB - OBJECTIVE: To identify dietary patterns among participants in a representative nutritional survey in the Valencia Community, and to analyze the association with socio-demographic characteristics and lifestyles. METHODS: Data for this study were from 1803 participants (973 women) in the Nutrition and Health Survey conducted in 1994 on a representative sample of adult population of Valencia Community. Diet was assessed by a validated food frequency questionnaire. Foods intakes were adjusted for 1,000 calories and grouped in 26 groups. Cluster analysis was used to identify dietary patterns using standardized values of the variables (z-scores). RESULTS: Three dietary patterns were identified and labeled as follows: the Prudent pattern (57.2%), characterized by a low-medium intake of most food of groups; the Mediterranean pattern (29.1%) characterized by high intake of fruits, vegetables, fish, poultry, cheese, and legumes; and the Western pattern (13.7%) characterized by high intake of meat and processed meats, high fat content foods, sweets and sugar, beverages, and alcoholic beverages. The Mediterranean pattern obtained higher scores for known diet quality index defined a priori. Using the Mediterranean pattern as reference, Western pattern included significantly more young people, higher number of men and smokers, and the Prudent pattern higher number of men, lower physical activity and lower alcohol consumption. CONCLUSION: Three dietary patterns were identified among participants in the Nutrition Survey of Valencia conducted in the mid-1990S: Prudent, Mediterranean and Western. The Prudent pattern was the most prevalent; the Mediterranean pattern was associated with healthier lifestyles and behaviors; and the Western pattern, the less prevalent although more frequently followed by youth, men and smokers. Further Nutrition Surveys should be carried out to make nutritional surveillance and analyze health effects of these observed patterns. PMID- 24160242 TI - [Association of consumption of carbonated beverages and decalcification in woman on reproductive and non-reproductive age of Mexico City]. AB - INTRODUCTION AND OBJECTIVE: There is not enough information about carbonated beverages (CB) consumption in Mexican women and its association with bone mineral density (BMD). The objective was to identify the association of CB consumption with BMD in two groups of Mexican women. METHODS: Transversal study with 328 women in reproductive age (WRA) and not reproductive (WNRA) with diet and anthropometric evaluation and BMD. RESULTS: Mean age of 18.7 years in WRA and 47 in WNRA. Energy adequacy percentage was lower in WNRA (98 +/- 28% vs 144 +/- 55) (p = 0.001), calcium intake was < 700 mg/day in women with osteopenia of both groups and median consumption of CB was higher in WRA, with 200 mL/day (0-462) vs 0 (0-250) in WNRA (p = 0.001), WRA with osteopenia drank 500 mL/day (253-750) of CB vs 100 (0-200) in who had not (p = 0.001). Anthropometric parameters were higher in WNRA (p =?0.002) and femoral neck BMD was lower (1.031 +/- 0.14 vs 1.107 +/- 0.10) (p = 0.001) and higher in L2-L4 (1.114 +/- 0.13 vs 1.003 +/- 0.09) (p = 0.001) in WRA. Variables associated with risk of osteopenia: drink CB (OR 11.186, p = 0.001), consuming < 700 mg of calcium (OR 5.774, p = 0.001) and dinner no milk (OR 1.942, p = 0.042). CONCLUSIONS: To drink CB increases risk of osteopenia in both groups, WRA drink more CB than WNRA and they will have high probability of fractures younger. PMID- 24160243 TI - The intake effects of Cyssus sicyoides drink on body mass, glycemia and femur parameters in male rats. AB - BACKGROUND: The Cissus sicyoides, popularly called insulin plant, the drink is widely used in folk medicine to control glycemia. However, there are not enough datas about the effect of Cissus sicyoides on bone physiology. Thus, the goal was evaluate the glycemia and femur parameters in male rats. MATERIAL AND METHODS: Wistar male rats with 12 weeks were divided control group (C) and treated with 5% of Cissus sicyoides (CS). After 42 days of treatment the groups were sacrificed and the body mass (g), glycemia, body organs and femur parameters were assessed. RESULTS: In the last week the CS group showed significantly lower body mass and lower glycemia. After 42 days the CS showed heart and liver mass were significantly lower. In regard to bone paramaters, the mass and BMD of femur were significantly lower in CS group. CONCLUSIONS: Despite the Cissus sicyoides drink decrease the glycemia, nevertheless it intake does not seem unfavorable for bone parameters. PMID- 24160244 TI - [Utility of Nutricion Hospitalaria in Latin America]. PMID- 24160245 TI - LPA, HGF, and EGF utilize distinct combinations of signaling pathways to promote migration and invasion of MDA-MB-231 breast carcinoma cells. AB - BACKGROUND: Various pathways impinge on the actin-myosin pathway to facilitate cell migration and invasion including members of the Rho family of small GTPases and MAPK. However, the signaling components that are considered important for these processes vary substantially within the literature with certain pathways being favored. These distinctions in signaling pathways utilized are often attributed to differences in cell type or physiological conditions; however, these attributes have not been systematically assessed. METHODS: To address this question, we analyzed the migration and invasion of MDA-MB-231 breast carcinoma cell line in response to various stimuli including lysophosphatidic acid (LPA), hepatocyte growth factor (HGF) and epidermal growth factor (EGF) and determined the involvement of select signaling pathways that impact myosin light chain phosphorylation. RESULTS: LPA, a potent stimulator of the Rho-ROCK pathway, surprisingly did not require the Rho-ROCK pathway to stimulate migration but instead utilized Rac and MAPK. In contrast, LPA-stimulated invasion required Rho, Rac, and MAPK. Of these three major pathways, EGF-stimulated MDA-MB-231 migration and invasion required Rho; however, Rac was essential only for invasion and MAPK was dispensable for migration. HGF signaling, interestingly, utilized the same pathways for migration and invasion, requiring Rho but not Rac signaling. Notably, the dependency of HGF-stimulated migration and invasion as well as EGF stimulated invasion on MAPK was subject to the inhibitors used. As expected, myosin light chain kinase (MLCK), a convergence point for MAPK and Rho family GTPase signaling, was required for all six conditions. CONCLUSIONS: These observations suggest that, while multiple signaling pathways contribute to cancer cell motility, not all pathways operate under all conditions. Thus, our study highlights the plasticity of cancer cells to adapt to multiple migratory cues. PMID- 24160248 TI - Skin repair properties of d-Limonene and perillyl alcohol in murine models. AB - The orange-peel derived terpene d-Limonene, probably through its metabolite, perillyl alcohol (POH), has been reported to have tissue-repair properties. Two murine models of respectively 12-O-Tetradecanoylphorbol-13-Acetate (TPA)-induced dermatitis and mechanical skin lesion were used here to assess the efficacy of d Limonene or POH applied topically. Macroscopic and microscopic evaluation of skin lesions was performed as well as that of P-selectin expression, together with measurements of serum concentrations of IL-1beta, IL-6 and TNF-alpha in the first model. Healing and angiogenesis around the scar were examined in the second model. Because differences in angiogenesis were noted, the effect of both d Limonene and POH was further tested on an in vitro model of endothelial microtubules formation. Both d-Limonene and POH reduced the severity and extension of TPA-induced skin lesions with significantly lowered macroscopic and microscopic scores (p<0.04 in both cases). Moreover, the expression of P-selectin induced by TPA was abrogated by POH and significantly lower serum concentrations of IL-6 and TNF-alpha were observed in d-Limonene- and POH-treated mice (p<0.04 and 0.03). In the second model, tissue regeneration was improved, especially by POH, and was clearly associated with reduced neovascularization. This surprising anti-angiogenic effect was confirmed in the matrigel model of endothelial microtubules formation. These studies show that d-Limonene and POH demonstrate significant anti-inflammatory effects in murine dermal inflammation and wound healing. The decreased systemic cytokine production as well as a consistent inhibition of endothelial P-selectin expression and neo-vascularization induced by these terpenic compounds contribute to their healing effects on the epidermal barrier. PMID- 24160246 TI - IQuaD dental trial; improving the quality of dentistry: a multicentre randomised controlled trial comparing oral hygiene advice and periodontal instrumentation for the prevention and management of periodontal disease in dentate adults attending dental primary care. AB - BACKGROUND: Periodontal disease is the most common oral disease affecting adults, and although it is largely preventable it remains the major cause of poor oral health worldwide. Accumulation of microbial dental plaque is the primary aetiological factor for both periodontal disease and caries. Effective self-care (tooth brushing and interdental aids) for plaque control and removal of risk factors such as calculus, which can only be removed by periodontal instrumentation (PI), are considered necessary to prevent and treat periodontal disease thereby maintaining periodontal health. Despite evidence of an association between sustained, good oral hygiene and a low incidence of periodontal disease and caries in adults there is a lack of strong and reliable evidence to inform clinicians of the relative effectiveness (if any) of different types of Oral Hygiene Advice (OHA). The evidence to inform clinicians of the effectiveness and optimal frequency of PI is also mixed. There is therefore an urgent need to assess the relative effectiveness of OHA and PI in a robust, sufficiently powered randomised controlled trial (RCT) in primary dental care. METHODS/DESIGN: This is a 5 year multi-centre, randomised, open trial with blinded outcome evaluation based in dental primary care in Scotland and the North East of England. Practitioners will recruit 1860 adult patients, with periodontal health, gingivitis or moderate periodontitis (Basic Periodontal Examination Score 0-3). Dental practices will be cluster randomised to provide routine OHA or Personalised OHA. To test the effects of PI each individual patient participant will be randomised to one of three groups: no PI, 6 monthly PI (current practice), or 12 monthly PI.Baseline measures and outcome data (during a three year follow-up) will be assessed through clinical examination, patient questionnaires and NHS databases.The primary outcome measures at 3 year follow up are gingival inflammation/bleeding on probing at the gingival margin; oral hygiene self-efficacy and net benefits. DISCUSSION: IQuaD will provide evidence for the most clinically-effective and cost-effective approach to managing periodontal disease in dentate adults in Primary Care. This will support general dental practitioners and patients in treatment decision making. TRIAL REGISTRATION: Protocol ID: ISRCTN56465715. PMID- 24160249 TI - Processed foods available in the Pacific Islands. AB - BACKGROUND: There is an increasing reliance on processed foods globally, yet food composition tables include minimal information on their nutrient content. The Pacific Islands share common trade links and are heavily reliant on imported foods. The objective was to develop a dataset for the Pacific Islands on nutrient composition of processed foods sold and their sources. METHODS: Information on the food labels, including country of origin, nutrient content and promotional claims were recorded into a standardised dataset. Data were cleaned, converted to per 100 g data as needed and then checked for anomalies and recording errors. SETTING: Five representative countries were selected for data collection, based on their trading patterns: Fiji, Guam, Nauru, New Caledonia, and Samoa. Data were collected in the capitals, in larger stores which import their own foods. SUBJECTS: Processed foods in stores. RESULTS: The data from 6041 foods and drinks were recorded. Fifty four countries of origin were identified, with the main provider of food for each Pacific Island country being that with which it was most strongly linked politically. Nutrient data were not provided for 6% of the foods, imported from various countries. Inaccurate labels were found on 132 products. Over one-quarter of the foods included some nutrient or health-related claims. CONCLUSIONS: The globalisation of the food supply is having considerable impacts on diets in the Pacific Islands. While nutrient labels can be informative for consumers looking for healthier options, difficulties still exist with poor labelling and interpretation can be challenging. PMID- 24160250 TI - Multimorbidity's research challenges and priorities from a clinical perspective: the case of 'Mr Curran'. AB - Older patients, suffering from numerous diseases and taking multiple medications are the rule rather than the exception in primary care. A manifold of medical conditions are often associated with poor outcomes, and their multiple medications raise additional risks of polypharmacy. Such patients account for most healthcare expenditures. Effective approaches are needed to manage such complex patients in primary care. This paper describes the results of a scoping exercise, including a two-day workshop with 17 professionals from six countries, experienced in general practice and primary care research as well as epidemiology, clinical pharmacology, gerontology and methodology. This was followed by a consensus process investigating the challenges and core questions for multimorbidity research in primary care from a clinical perspective and presents examples of the best research practice. Current approaches in measuring and clustering multimorbidity inform policy-makers and researchers, but research is needed to provide support in clinical decision making. Multimorbidity presents a complexity of conditions leading to individual patient's needs and demanding complex processes in clinical decision making. The identification of patterns presupposes the development of strategies on how to manage multimorbidity and polypharmacy. Interventions have to be complex and multifaceted, and their evaluation poses numerous methodological challenges in study design, outcome measurement and analysis. Overall, it can be seen that complexity is a main underlying theme. Moreover, flexible study designs, outcome parameters and evaluation strategies are needed to account for this complexity. PMID- 24160252 TI - Development of a nutritionally balanced pizza as a functional meal designed to meet published dietary guidelines. AB - OBJECTIVE: To develop a worked example of product reformulation of a very popular 'junk food' to meet nutritional guidelines for public health in a ready meal. DESIGN: Indicative survey of popular Margherita pizzas, followed by product reformulation, applying dietary guidelines to generate a single-item pizza meal containing 30 % daily amounts of energy and all nutrients. An iterative process was used; first to optimize nutrient balance by adjusting the proportions of bread base, tomato-based sauce and mozzarella topping, then adding ingredients to provide specific nutrients and consumer tasting. SETTING: Urban areas of contrasting socio-economic status. SUBJECTS: Untrained unselected adults (n 49) and children (n 63), assessing pizza at tasting stations. RESULTS: Most commercial pizzas provide insufficient information to assess all nutrients and traditional Margherita pizza ingredients provide insufficient Fe, Zn, iodine, and vitamins C and B12. Energy content of the portions currently sold as standard range from 837 to 2351 kJ (200 to 562 kcal), and most exceed 30 % Guideline Daily Amounts for saturated fat and Na when a 2510 kJ (600 kcal) notional meal is considered. The 'nutritionally balanced pizza' provides the required energy for a single-item meal (2510 kJ/600 kcal), with all nutrients within recommended ranges: Na (473 mg, ~45 % below recommended level), saturated fat (<11 % energy) and dietary fibre (13.7 g). Most adults (77 %) and children (81 %) rated it 'as good as' or 'better than' their usual choice. CONCLUSIONS: Nutritional guidelines to reduce chronic diseases can be applied to reformulate 'junk food' ready meals, to improve public health through a health-by-stealth approach without requiring change in eating habits. PMID- 24160251 TI - Disrupting rhythms in Plasmodium chabaudi: costs accrue quickly and independently of how infections are initiated. AB - BACKGROUND: In the blood, the synchronous malaria parasite, Plasmodium chabaudi, exhibits a cell-cycle rhythm of approximately 24 hours in which transitions between developmental stages occur at particular times of day in the rodent host. Previous experiments reveal that when the timing of the parasite's cell-cycle rhythm is perturbed relative to the circadian rhythm of the host, parasites suffer a (~50%) reduction in asexual stages and gametocytes. Why it matters for parasites to have developmental schedules in synchronization with the host's rhythm is unknown. The experiment presented here investigates this issue by: (a) validating that the performance of P. chabaudi is negatively affected by mismatch to the host circadian rhythm; (b) testing whether the effect of mismatch depends on the route of infection or the developmental stage of inoculated parasites; and, (c) examining whether the costs of mismatch are due to challenges encountered upon initial infection and/or due to ongoing circadian host processes operating during infection. METHODS: The experiment simultaneously perturbed the time of day infections were initiated, the stage of parasite inoculated, and the route of infection. The performance of parasites during the growth phase of infections was compared across the cross-factored treatment groups (i e, all combinations of treatments were represented). RESULTS: The data show that mismatch to host rhythms is costly for parasites, reveal that this phenomenon does not depend on the developmental stage of parasites nor the route of infection, and suggest that processes operating at the initial stages of infection are responsible for the costs of mismatch. Furthermore, mismatched parasites are less virulent, in that they cause less anaemia to their hosts. CONCLUSION: It is beneficial for parasites to be in synchronization with their host's rhythm, regardless of the route of infection or the parasite stage inoculated. Given that arrested cell-cycle development (quiescence) is implicated in tolerance to drugs, understanding how parasite schedules are established and maintained in the blood is important. PMID- 24160253 TI - Design and synthesis of P1-P3 macrocyclic tertiary-alcohol-comprising HIV-1 protease inhibitors. AB - To study P1-P3 macrocyclizations of previously reported tertiary-alcohol comprising HIV-1 protease inhibitors (PIs), three new 14- and 15-member macrocyclic PIs were designed, synthesized by ring-closing metathesis, and evaluated alongside with 10 novel linear PIs. Cocrystallized complexes of the macrocyclic PIs and the HIV-1 protease are presented, analyzed, and discussed. The macrocyclic structures exhibited higher activities than the linear precursors with Ki and EC50 values down to 3.1 nM and 0.37 MUM, respectively. PMID- 24160254 TI - PAX9 polymorphisms and susceptibility with sporadic tooth agenesis in Turkish populations: a case-control study. AB - BACKGROUND: Hypodontia, the congenital absence of one or a few teeth is one of the most common alterations of the human dentition. Familial hypodontia is caused by mutations in PAX9, Msx1 and Axin2 genes. Limited numbers of studies are present to show etiological factors beyond this anomaly in Turkish community belonging to Caucasian racial family. The purpose of this study is to investigate the relationships between the two different single nucleotide polymorphisms that are G-1031A and T-912C with hypodontia in Caucasians. 200 individuals having hypodontia and 114 normal individuals having all 32 teeth present were selected for the study. Blood samples were collected from each individual and DNA was extracted. To determine the polymorphisms, PCR-RFLP method was used. RESULTS: The outcomes suggest that the individuals having AC haplotype carry less risk in having hypodontia compared with the rest of the haplotype groups (OR = 3.88; CI = 95%; p = 0.001). The ratio of GT haplotype is less in the hypodontia group meaning that the GT carriers are in risk group in terms of hypodontia risk. CONCLUSION: These results indicate that polymorphisms in the promoter region of PAX9 gene may have an influence on the transcriptional factors and activity of this gene and are associated with hypodontia in Caucasian individuals. PMID- 24160255 TI - Automated design of bacterial genome sequences. AB - BACKGROUND: Organisms have evolved ways of regulating transcription to better adapt to varying environments. Could the current functional genomics data and models support the possibility of engineering a genome with completely rearranged gene organization while the cell maintains its behavior under environmental challenges? How would we proceed to design a full nucleotide sequence for such genomes? RESULTS: As a first step towards answering such questions, recent work showed that it is possible to design alternative transcriptomic models showing the same behavior under environmental variations than the wild-type model. A second step would require providing evidence that it is possible to provide a nucleotide sequence for a genome encoding such transcriptional model. We used computational design techniques to design a rewired global transcriptional regulation of Escherichia coli, yet showing a similar transcriptomic response than the wild-type. Afterwards, we "compiled" the transcriptional networks into nucleotide sequences to obtain the final genome sequence. Our computational evolution procedure ensures that we can maintain the genotype-phenotype mapping during the rewiring of the regulatory network. We found that it is theoretically possible to reorganize E. coli genome into 86% fewer regulated operons. Such refactored genomes are constituted by operons that contain sets of genes sharing around the 60% of their biological functions and, if evolved under highly variable environmental conditions, have regulatory networks, which turn out to respond more than 20% faster to multiple external perturbations. CONCLUSIONS: This work provides the first algorithm for producing a genome sequence encoding a rewired transcriptional regulation with wild-type behavior under alternative environments. PMID- 24160256 TI - Dynamic assessment of word learning skills of pre-school children with primary language impairment. AB - Dynamic assessment has been shown to have considerable theoretical and clinical significance in the assessment of socially disadvantaged and culturally and linguistically diverse children. In this study it is used to enhance assessment of pre-school children with primary language impairment. The purpose of the study was to determine whether a dynamic assessment (DA) has the potential to enhance the predictive capacity of a static measure of receptive vocabulary in pre-school children. Forty pre-school children were assessed using the static British Picture Vocabulary Scale (BPVS), a DA of word learning potential and an assessment of non-verbal cognitive ability. Thirty-seven children were followed up 6 months later and re-assessed using the BPVS. Although the predictive capacity of the static measure was found to be substantial, the DA increased this significantly especially for children with static scores below the 25th centile. The DA of children's word learning has the potential to add value to the static assessment of the child with low language skills, to predict subsequent receptive vocabulary skills and to increase the chance of correctly identifying children in need of ongoing support. PMID- 24160257 TI - The identification of a novel splicing mutation in C1qB in a Japanese family with C1q deficiency: a case report. AB - C1q deficiency is a rare disease that is associated with a high probability of developing systemic lupus erythematosus. We report a 4-year-old Japanese girl who presented with fever, facial erythema, joint pain, and oral ulceration. Complement deficiencies were suspected because of her persistent hypocomplementemia and normal levels of the complement proteins C3 and C4. We identified a novel homozygous splicing mutation in the C1qB gene, c.187 + 1G > T, which is the first mutation to be confirmed in a Japanese individual. Because treatment with steroids and immunosuppressive drugs was not effective, we commenced use of fresh frozen plasma to provide C1q supplements. Currently, the patient remains almost asymptomatic, and we are attempting to control the drug dosage and administration intervals of fresh frozen plasma. PMID- 24160258 TI - The role of in vitro methods as alternatives to animals in toxicity testing. AB - INTRODUCTION: It is accepted that animal testing should be reduced, refined or replaced as far as it is practicably possible. There are also a wide variety of in vitro models, which are used as screening studies and mechanistic investigations. The ability of an in vitro assay to be reliable, biomedically, is essential in pharmaceutical development. Furthermore, it is necessary that cells used in in vitro testing mimic the phenotype of cells within the human target tissue. AREAS COVERED: The focus of this review article is to identify the key points of in vitro assays. In doing so, the authors take into account the chemical agents that are assessed and the integrated in vitro testing strategies. EXPERT OPINION: There is a transfer of toxicological data from primary in vivo animal studies to in vitro assays. The key element for designing an integrated in vitro testing strategy is summarized as follows: exposure modeling of chemical agents for in vitro testing; data gathering, sharing and read-across for testing a class of chemical; a battery of tests to assemble a broad spectrum of data on different mechanisms of action to predict toxic effects; and applicability of the test and the integrated in vitro testing strategies and flexibility to adjust the integrated in vitro testing strategies to test substance. While these methods will be invaluable if effective, more studies must be done to ensure reliability and suitability of these tests for humans. PMID- 24160260 TI - Asymmetric access to the smallest enolate intermediate via organocatalytic activation of acetic ester. AB - An NHC-catalyzed activation of acetic esters to afford enolate intermediates is disclosed. The catalytically generated triazolium enolate intermediates serve as two-carbon nucleophiles that undergo highly enantioselective reactions with enones and alpha,beta-unsaturated imines to give alpha-unsubstituted delta lactones and lactams, respectively. PMID- 24160259 TI - Standardization of whole blood immune phenotype monitoring for clinical trials: panels and methods from the ONE study. AB - BACKGROUND: Immune monitoring by flow cytometry is a fast and highly informative way of studying the effects of novel therapeutics aimed at reducing transplant rejection or treating autoimmune diseases. The ONE Study consortium has recently initiated a series of clinical trials aimed at using different cell therapies to promote tolerance to renal allografts. To compare the effectiveness of different cell therapies, the consortium developed a robust immune monitoring strategy, including procedures for whole blood (WB) leukocyte subset profiling by flow cytometry. METHODS: Six leukocyte profiling panels computing 7- to 9-surface marker antigens for monitoring the major leukocyte subsets as well as characteristics of T cell, B cell, and dendritic cell (DC) subsets were designed. The precision and variability of these panels were estimated. The assay was standardized within eight international laboratories using Flow-Set Pro beads for mean fluorescence intensity target definition and the flow cytometer setup procedure. Standardization was demonstrated by performing inter-site comparisons. RESULTS: Optimized methods for sample collection, storage, preparation, and analysis were established, including protocols for gating target subsets. WB specimen age testing demonstrated that staining must be performed within 4 hours of sample collection to keep variability low, meaning less than or equal to 10% for the majority of defined leukocyte subsets. Inter-site comparisons between all participating centers testing shipped normal WB revealed good precision, with a variability of 0.05% to 30% between sites. Intra-assay analyses revealed a variability of 0.05% to 20% for the majority of subpopulations. This was dependent on the frequency of the particular subset, with smaller subsets showing higher variability. The intra-assay variability performance defined limits of quantitation (LoQ) for subsets, which will be the basis for assessing statistically significant differences achieved by the different cell therapies. CONCLUSIONS: Local performance and central analysis of the ONE Study flow cytometry panel yields acceptable variability in a standardized assay at multiple international sites. These panels and procedures with WB allow unmanipulated analysis of changes in absolute cell numbers of leukocyte subsets in single- or multicenter clinical trials. Accordingly, we propose the ONE Study panel may be adopted as a standardized method for monitoring patients in clinical trials enrolling transplant patients, particularly trials of novel tolerance promoting therapies, to facilitate fair and meaningful comparisons between trials. PMID- 24160262 TI - GPs' experiences with out-of-hours GP cooperatives: a survey study from the Netherlands. AB - BACKGROUND: Out-of-hours primary care has been provided by general practitioner (GP) cooperatives since the year 2000 in the Netherlands. Early studies in countries with similar organizational structures showed positive GP experiences. However, nowadays it is said that GPs experience a high workload at the cooperative and that they outsource a considerable part of their shifts. OBJECTIVES: To examine positive and negative experiences of GPs providing out-of hours primary care, and the frequency and reasons for outsourcing shifts. METHODS: A cross-sectional observational survey among 688 GPs connected to six GP cooperatives in the Netherlands, using a web-based questionnaire. RESULTS: The response was 55% (n = 378). The main reasons for working in GP cooperatives were to retain registration as GP (79%) and remain experienced in acute care (74%). GPs considered the peak hours (81%) and the high number of patients (73%) as the most negative aspects. Most GPs chose to provide the out-of-hours shifts themselves: 85% outsourced maximally 25% of their shifts. The percentage of outsourced shifts increased with age. Main reasons for outsourcing were the desire to have more private time (76%); the high workload in daytime practice (71%); and less the workload during out-of-hours (46%). CONCLUSION: GPs are motivated to work in out-of-hours GP cooperatives, and they outsource few shifts. GPs consider the peak load and the large number of (non-urgent) help requests as the most negative aspects. To motivate and involve GPs for 7 * 24-h primary care, it is important to set limits on their workload. PMID- 24160263 TI - Enhancement of SERS background through charge transfer resonances on single crystal gold surfaces of various orientations. AB - Surface-enhanced Raman scattering (SERS) spectra are accompanied by broad background emission, which limits improvements in the signal-to-noise ratio. Despite the close correlation between the background generation and the SERS enhancement, the chemical origin of the background emission has remained somewhat mysterious. In this work, SERS spectra of organic monolayers are systematically measured on an atomically defined single crystalline gold surface of various orientations, which specifically define metal-molecule chemical interactions. The use of sphere-plane type plasmonic nanogap structures on a well-defined surface enables us to evaluate the contribution of charge transfer resonances to SERS enhancement. The present results not only reveal that charge transfer resonance at metal-molecule interfaces increases the intensity of plasmon-mediated broadband emission but also provide us a consistent view about electronic structures of metal-molecule interfaces. PMID- 24160264 TI - Clinical significance in self-rated HRQoL among survivors after childhood cancer demonstrated by anchor-based thresholds. AB - BACKGROUND: There is a need to establish clinically relevant thresholds (anchors) for identification of differences in health-related quality of life (HRQoL) and thereby provide stronger evidence regarding the HRQoL of childhood cancer survivors. AIM: To investigate HRQoL in childhood cancer survivors with a standardised instrument and to establish thresholds for clinically significant differences by using qualitative interviews as anchors. An additional aim was to investigate survivors' HRQoL in relation to an age-matched comparison group without cancer experience. MATERIAL AND METHODS: Self-rated HRQoL (KIDSCREEN-27) was assessed in a national cohort of survivors (n = 63, aged 12-22) and a comparison group (n = 257, aged 11-23). Findings from qualitative interview data were also used (n = 61); three subgroups ("Feeling like anyone else"; "Feeling almost like others"; "Feeling different") were identified based on survivors own perception of influence on daily life. Effect size calculations based on means from the KIDSCREEN-27 dimensions were performed using the subgroups as anchors to indicate clinical importance. Furthermore, standard multiple regression analyses were performed. Results. Effect sizes between the subgroups "Feeling like anyone else" and "Feeling almost like others" and the group "Feeling different" were large for all dimensions (1.04-2.07). The multiple regression models showed that being a survivor was significantly associated with one of the dimensions, School Environment, where survivors scored higher HRQoL. Furthermore, female sex and older age (17-23 years) significantly contributed to lower self-rated HRQoL. Conclusion. In clinical practice the KIDSCREEN-27 could be a useful screening tool to identify survivors of childhood cancer in need of extra support, using KIDSCREEN dimension mean values of 45 or less as thresholds. Larger scale studies are recommended to identify and test thresholds with regard to different age groups and time since diagnosis. PMID- 24160265 TI - An integrated strategy for efficient vector construction and multi-gene expression in Plasmodium falciparum. AB - BACKGROUND: The construction of plasmid vectors for transgene expression in the malaria parasite, Plasmodium falciparum, presents major technical hurdles. Traditional molecular cloning by restriction and ligation often yields deletions and re-arrangements when assembling low-complexity (A + T)-rich parasite DNA. Furthermore, the use of large 5'- and 3'- untranslated regions of DNA sequence (UTRs) to drive transgene transcription limits the number of expression cassettes that can be incorporated into plasmid vectors. METHODS: To address these challenges, two high fidelity cloning strategies, namely yeast homologous recombination and the Gibson assembly method, were evaluated for constructing P. falciparum vectors. Additionally, some general rules for reliably using the viral 2A-like peptide to express multiple proteins from a single expression cassette while preserving their proper trafficking to various subcellular compartments were assessed. RESULTS: Yeast homologous recombination and Gibson assembly were found to be effective strategies for successfully constructing P. falciparum plasmid vectors. Using these cloning methods, a validated family of expression vectors that provide a flexible starting point for user-specific applications was created. These vectors are also compatible with traditional cloning by restriction and ligation, and contain useful combinations of commonly used features for enhancing plasmid segregation and site-specific integration in P. falciparum. Additionally, application of a 2A-like peptide for the synthesis of multiple proteins from a single expression cassette, and some rules for combinatorially directing proteins to discrete subcellular compartments were established. CONCLUSIONS: A set of freely available, sequence-verified and functionally validated parts that offer greater flexibility for constructing P. falciparum vectors having expanded expression capacity is provided. PMID- 24160267 TI - Cu(OTf)2-mediated fluorination of aryltrifluoroborates with potassium fluoride. AB - This Communication describes the Cu(OTf)2-mediated fluorination of aryltrifluoroborates with KF. The reaction proceeds under mild conditions (at 60 degrees C over 20 h) and shows a broad substrate scope and functional group tolerance. The Cu is proposed to play two separate roles in this transformation: (1) as a mediator for the aryl-F coupling and (2) as an oxidant for accessing a proposed Cu(III)(aryl)(F) intermediate. PMID- 24160266 TI - Nuclear-encoded mitochondrial MTO1 and MRPL41 are regulated in an opposite epigenetic mode based on estrogen receptor status in breast cancer. AB - BACKGROUND: MTO1 and MRPL41 are nuclear-encoded mitochondrial genes encoding a mitochondrial tRNA-modifying enzyme and a mitochondrial ribosomal protein, respectively. Although both genes have been known to have potential roles in cancer, little is known about their molecular regulatory mechanism, particularly from an epigenetic approach. In this study, we aimed to address their epigenetic regulation through the estrogen receptor (ER) in breast cancer. METHODS: Digital differential display (DDD) was conducted to identify mammary gland-specific gene candidates including MTO1 and MRPL41. Promoter CpG methylation and expression in breast cancer cell lines and tissues were examined by methylation-specific PCR and real time RT-PCR. Effect of estradiol (E2), tamoxifen, and trichostatin A (TSA) on gene expression was examined in ER + and ER- breast cancer cell lines. Chromatin immunoprecipitation and luciferase reporter assay were performed to identify binding and influencing of the ER to the promoters. RESULTS: Examination of both cancer tissues and cell lines revealed that the two genes showed an opposite expression pattern according to ER status; higher expression of MTO1 and MRPL41 in ER- and ER+ cancer types, respectively, and their expression levels were inversely correlated with promoter methylation. Tamoxifen, E2, and TSA upregulated MTO1 expression only in ER+ cells with no significant changes in ER- cells. However, these chemicals upregulated MRPL41 expression only in ER- cells without significant changes in ER+ cells, except for tamoxifen that induced downregulation. Chromatin immunoprecipitation and luciferase reporter assay identified binding and influencing of the ER to the promoters and the binding profiles were differentially regulated in ER+ and ER- cells. CONCLUSIONS: These results indicate that different epigenetic status including promoter methylation and different responses through the ER are involved in the differential expression of MTO1 and MRPL41 in breast cancer. PMID- 24160268 TI - "Would a man smell a rose then throw it away?" Jordanian men's perspectives on women's breast cancer and breast health. AB - BACKGROUND: Breast cancer is the most common malignancy afflicting women, and the most common cancer overall in Jordan. A woman's decision to go for screening is influenced by her social support network. This study aims to explore Jordanian men's individual and contextual perspectives on women's breast cancer and their own role in the breast health of the females within their families. METHODS: An explorative qualitative design was used to purposively recruit 24 married men aged 27 to 65 years (median 43 years) from four governorates in Jordan. Data in the form of interviews transcriptions was subjected to qualitative content analysis. RESULTS: Three themes were identified: a) Supporting one's wife; b) Marital needs and obligations; c) Constrained by a culture of destiny and shame. The first theme was built on men's feelings of responsibility for the family's health and well-being, their experiences of encouraging their wives to seek health care and their providing counselling and instrumental support. The second theme emerged from men's views about other men's rejection of a wife inflicted by breast cancer, their own perceptions of diminished femininity due to mastectomy and their own concerns about protecting the family from the hereditary risk of breast cancer. The third theme was seen in men's perception of breast cancer as an inevitable act of God that is far away from one's own family, in associating breast cancer with improper behaviour and in their readiness to face the culture of Eib (shame). CONCLUSIONS: Jordanian men perceive themselves as having a vital role in supporting, guiding and encouraging their wives to follow breast cancer early detection recommendations. Breast health awareness campaigns could involve husbands to capitalize on family support. PMID- 24160269 TI - Controversies in dermatology: part V. PMID- 24160270 TI - Skin cancer screening and primary prevention: facts and controversies. AB - Skin cancer is both common and responsible for significant morbidity and mortality. Opportunities for both primary and secondary prevention are available to both dermatologists and non-dermatologists. Counseling selected patients about ultraviolet avoidance and proper use of sunscreens is recommended. Due to technical and financial barriers, no study has conclusively confirmed the benefits of skin cancer screening. Both dermatologists and non-dermatologists often do not perform total body skin examinations during clinical encounters, despite high acceptance rates by patients. Many non-dermatologists would benefit from additional education pertaining to the diagnosis of cutaneous malignancy. Teledermatology may have a role in areas with poor access to dermatologists. There are ample opportunities for more to be learned in the future. PMID- 24160271 TI - The light and the dark of dermatoscopy in the early diagnosis of melanoma: facts and controversies. AB - Early diagnosis remains the best method to reduce melanoma and non-melanoma skin cancer-related mortality and morbidity. Dermatoscopy was first introduced at the end of the last century, and besides the strict criticism that it initially received, the majority of the scientific community presently considers it revolutionary in the field of melanocytic lesion diagnostics. Cumulative evidence provides definite data that dermatoscopy improves the clinicians' diagnostic accuracy for melanoma compared with other clinical diagnostic approaches. There remain some barriers for its use such as lack of training, lack of time, and lack of reimbursement, as well as persisting skepticism about its true utility. In the current contribution, we focus on false beliefs and facts concerning dermatoscopy in the early diagnosis of melanoma and shed some light on some of the remaining "dark sides" of this issue. PMID- 24160272 TI - The role of nutrition in dermatologic diseases: facts and controversies. AB - Many dermatologic diseases are chronic with no definitive cure. For some diseases, the etiology is not completely understood, with treatment being difficult and associated with side effects. In such cases, patients may try alternative treatments to prevent onset, reduce symptom severity, or prevent reoccurrence of a disease. Dietary modification, through supplementation and exclusion, is an extremely popular treatment modality for patients with dermatologic conditions. It is, therefore, important for dermatologists to be aware of the growing body of literature pertaining to nutrition and skin disease to appropriately inform patients on benefits and harms of specific dietary interventions. We address the role of nutrition in psoriasis, atopic dermatitis, urticaria, and bullous diseases and specific dietary modifications as an adjunct or alternative to conventional therapy. PMID- 24160273 TI - Aging skin: the role of diet: facts and controversies. AB - The role of diet in aging skin is highly controversial with limited available scientific data. There are recommended daily allowances for vitamins and other essential nutrients necessary for the maintenance of health, but these allowances were arrived at by consensus rather than science. These nutritional allowances are set at the minimum required for health, providing little advice as to the optimal nutritional intake for a given age. We now know that the requirements set for vitamin D intake were too low and not properly age adjusted. This contribution examines the role of nutrition, glycation, and oxidation in skin aging. PMID- 24160274 TI - Psychological factors in skin diseases: stress and skin: facts and controversies. AB - Psychological stress (PS) has long been related to many common skin diseases and conditions, thought to be the cause of their onset or aggravation. Although clinical experience is often in concordance with this notion, apparently scientific proof can sometimes be challenging rather than straight forward. Although many data have been published, it appears that not enough good statistical evidence exists to support them. The difficulty in validating beyond a doubt the stress-skin interactions has rendered some skepticism among physicians. The gap between clinical expertise and problematic clinical research data has led scientists to bypass the need to tackle the question directly by searching the evidence in basic science. PMID- 24160276 TI - Will nonablative rejuvenation replace ablative lasers? Facts and controversies. AB - Since the early 1980s, the field of skin rejuvenation has evolved rapidly. Traditional ablative resurfacing with carbon dioxide and Er:YAG lasers offered dramatic improvement of the skin tone and texture, but prolonged postoperative period and an increased risk for side effects and complications were unacceptable for the majority of patients. It prompted the development of nonablative lasers and non-laser systems, which stimulate dermal neocollagenesis without epidermal disruption, and therefore, produce less adverse effects with little or no healing time. Recently, fractional nonablative and ablative lasers have been introduced, employing a completely new concept of fractional photothermolysis, which ensures high efficacy and fewer risks. Ablative laser resurfacing still remains the gold standard for treating advanced and severe photoaging providing excellent results in experienced hands. Alternatively, ablative fractional resurfacing can be used, with the results, which are comparable to fully ablative lasers with better standard of safety. Nonablative resurfacing is ideal for patients under the age of 50 years with minimal facial sagging, and for those who are unwilling to undergo expensive and demanding ablative procedures. It can be concluded that the key of therapeutic success is in proper patient selection, setting appropriate expectations and combining different rejuvenation technologies with other therapeutic modalities, such as botulinum toxin and fillers. PMID- 24160275 TI - Solar keratoses: photodynamic therapy, cryotherapy, 5-fluorouracil, imiquimod, diclofenac, or what? Facts and controversies. AB - Actinic keratosis is a common dermatologic condition that may regress, remain stable, or progress to squamous cell carcinoma. Some question whether all actinic keratoses should be routinely treated, whereas others contend that the unpredictable natural history of this disease necessitates treatment to prevent malignant transformation. Available treatments include photodynamic therapy, cryotherapy, 5-fluorouracil, imiquimod, and diclofenac. Each of these options has its advantages and disadvantages, although they all have a place in the management of actinic keratosis. An overview of these treatment modalities is presented, as are the controversies surrounding the treatment of actinic keratosis. PMID- 24160277 TI - Cellulite: advances in treatment: facts and controversies. AB - Cellulite is traditionally considered a highly prevalent aesthetic condition in women. From a clinical standpoint, it is characterized by a cottage-cheese-like appearance of the skin, which can be most commonly found in certain areas of the body (eg, thighs, buttocks, and legs). Although cellulite is generally asymptomatic, the more severe stages can be accompanied by the appearance of painful nodules and increased local temperature, which are suggestive of an inflammatory reaction occurring in the dermis and in the underlying subcutaneous adipose tissue. Whether cellulite is a real disease or only a disturbing aesthetic issue is still a matter of controversy. This debate notwithstanding, it seems clear from market trends that there is considerable commercial interest in developing effective strategies aimed at reducing the cottage-cheese-like appearance of cellulite areas. Quite disturbingly, the majority of treatment attempts to date have been conducted in an empirical manner and without the application of rigorous scientific methodology. This is likely due--at least in part--to the lack of major, evidence-based pathophysiological insights into the nature of this condition. More stringent regulatory control is needed over commercial products aiming at improving the appearance of cellulite. PMID- 24160278 TI - Dermal fillers: facts and controversies. AB - Dermal fillers have been used for decades in soft tissue augmentation. Currently, filler implementation is among the most common minimally invasive procedures for rejuvenation and body sculpturing. There is a broad variety of filler materials and products. Despite immense experience, a number of controversies in this topic exist. Some of these controversies are addressed in this review, for example, who should perform filler injections, the difference between permanent and nonpermanent fillers, the off-label use of liquid silicone, and the role of pain reduction. Implementation of guidelines and restriction of filler use by trained physicians can improve safety for patients. PMID- 24160279 TI - Facial skin rejuvenation: ablative laser resurfacing, chemical peels, or photodynamic therapy? Facts and controversies. AB - Patients and cosmetic surgeons continue to develop innovative devices and techniques in search of the elusive fountain of youth. Our efforts in the past decade can be distilled to three primary approaches: refinement of existing technologies (ablative lasers); refinement of tried-and-true techniques (chemical peeling); and innovative use of new technologies (photorejuvenation). In this contribution, the authors discuss how these three approaches are used to achieve facial skin rejuvenation. Specifically, the authors compare and contrast the clinical benefits and disadvantages of the ablative fractionated and unfractionated carbon dioxide resurfacing lasers, medium-depth and deep chemical peeling, and the combination of photodynamic therapy with intense-pulsed light. PMID- 24160280 TI - Isomorphic phenomenon of Koebner: facts and controversies. AB - Heinrich Koebner (1838-1904) presented in a meeting in 1872 and reported in 1877 the emergence of psoriatic lesions following trauma to healthy skin areas of patients with psoriasis. Since then, the Koebner phenomenon has been the subject of research, as it offers a unique opportunity in the investigation of the disease, especially in experimental studies, when this dermatosis may be observed in all its phases. Establishing the differences between Koebner, Wolf, Renbok, reverse Koebner, pseudo-Koebner phenomena, and pathergy is sometimes unclear. We review the various aspects of the Koebner phenomenon's clinical description and presentation, pathophysiology, histopathology, reverse phenomenon, therapeutic treatments, and prevention. PMID- 24160281 TI - Anti-aging cosmetics: facts and controversies. AB - The authors review ageing in its extrinsic and intrinsic mechanisms, as well as the therapies available for improving its effects, and present some of the facts and controversies related to anti-aging cosmetics. PMID- 24160282 TI - Disorders of hair growth and the pilosebaceous unit: facts and controversies. AB - We discuss three controversial situations related to disorders of hair growth and the pilosebaceous unit: alopecia areata incognita, pseudopelade of Brocq, and the association of psoriasis and alopecia. PMID- 24160283 TI - Kickbacks, stark violations, client billing, and joint ventures: facts and controversies. AB - Many current business trends in the field of dermatopathology deserve ethical scrutiny. An important point to consider in these analyses is that which is legal is not necessarily ethical. We examine the topics of client billing, contractual joint ventures, and health information technology donations, including both the legal implications as pertaining to the Stark Law and Anti-Kickback Statute, and the ethical ramifications of these practices. PMID- 24160284 TI - Conundrum: who should care for the dermatologic needs of the medicaid patient? Facts and controversies. AB - With the impending implementation of Obamacare in the context of a depressed American economy; an unsustainable national deficit and debt; and increasing personal dependency upon government largesse, a perfect storm is developing in the United States. This perfect storm is embodied by the paradox that an expanding population of Title XIX insured patients is increasingly dependent upon a diminishing number of American dermatologists to provide essential dermatologic care. In this context, we discuss whose responsibility it is to care for the dermatologic needs of Title XIX patients. PMID- 24160285 TI - Brand name versus generic drugs: the ethical quandary in caring for our sophisticated patients while trying to reduce health-care costs: facts and controversies. AB - Medical ethics are the values and guidelines that govern decisions made in medical practice. Four prima facie moral principles can serve as a framework to help physicians analyze problems and make ethical decisions: (1) respect for autonomy, (2) beneficence, (3) non-maleficence, and (4) justice. With the cost of health care rising, all parties involved in the delivery of health care need to work to reduce costs, while continuing to provide quality care to our patients. One mechanism to reduce costs is to increase utilization of generic medications in daily practice, but there are many ethical issues inherent in utilizing brand name versus generic medications in dermatology. PMID- 24160286 TI - Employing an aesthetician in a dermatology practice: facts and controversies. AB - Employment of aestheticians in dermatology offices is becoming an everyday occurrence, as the dermatology patients' demand for cosmetic services taxes the availability of limited resources. Proponents of the practice state that aestheticians can help meet patients' expectations, while allowing dermatologists to focus their practice on the medical needs of patients. Opponents believe employment of fee-for-service aesthetic technicians compromises our ethical duties to our patients and diminishes the stature of dermatology as a profession. PMID- 24160287 TI - Influence of treatments on prognosis for vulvar lichen sclerosus: facts and controversies. AB - Lichen sclerosus (LS) is an inflammatory dermatosis with a predilection for the anogential skin. Vulvar LS can be a debilitating disease, causing pruritus and pain, and it carries the potential for atrophy, scarring, and significant functional impairment. Recently, many advances have been made regarding the etiology and natural history of the disease process; however, much debate still exists regarding the most advantageous medical and surgical management of this disorder. In an effort to provide a comprehensive review on current vulvar LS literature, the following three controversies will be discussed: (1) optimal disease treatment, (2) theories behind LS's oncogenicity and treatments for minimizing malignancy, and (3) the value of surgical treatment for LS. Ultra potent topical corticosteroids (TCSs) are the first-line treatment for vulvar LS, while topical calcineurin inhibitors (TCIs) remain second-line agents for patients for whom TCS treatment resulted in incomplete resolution of symptoms or adverse events. Due to the relapsing nature of the disease, long-term maintenance therapy is often required. In addition, recent advances have contributed to the understanding of the association between LS and squamous cell carcinoma (SCC). While the exact mechanism responsible for LS-associated SCC is not known, immune dysregulation and inflammation may play an important role; therefore, successful treatment of LS should be directed towards alleviation of symptoms and reversal of the underlying histopathologic changes. Patients with LS-associated malignancy, as well as patients who need correction of functionally restrictive, scarring processes, can successfully undergo surgical intervention with tissue conservation. PMID- 24160288 TI - Barrier-repair prescription moisturizers: do we really need them? Facts and controversies. AB - There is now scientific evidence of genetically driven skin-barrier anomalies in atopic patients. These barrier anomalies facilitate sustained antigen ingress through the defective barrier, which can bring about a Th2-dominant response. It enhances the transepidermal water loss, resulting in dry skin and leading to the release of preformed proinflammatory cytokines and to a cascade of events ending up in inflammation. PMID- 24160289 TI - Non-melanoma skin cancers: photodynamic therapy, cryotherapy, 5-fluorouracil, imiquimod, diclofenac, or what? Facts and controversies. AB - Surgical modalities-excision, Mohs micrographic surgery, and electrodesiccation with curettage-are the preferred treatments for nonmelanoma skin cancer (NMSC). When used within guidelines, they have cure rates greater than 90%. Despite this, many other treatments have been studied and utilized for NMSC. We present a comprehensive review of the literature on these topical treatments. Photodynamic therapy (PDT) is administered under numerous and significantly varied regimens, and there are a wide range of cure rates reported. Even with aggressive regimens, PDT is not as effective as surgery is, and it is not a first-line therapy for NMSC. The cryotherapy regimen aggressive enough to adequately treat NMSC carries adverse effects and cosmetic outcomes poor enough to negate its usefulness. Topical 5-fluorouracil and imiquimod are efficacious and safe for the treatment of superficial basal cell carcinoma (BCC) but not other BCC subtypes or squamous cell carcinoma. They are self-administered twice daily for several weeks; therefore, patient and tumor selection are vital to ensuring adherence. There are currently insufficient data to support the use of topical diclofenac and ingenol mebutate for NMSC. PMID- 24160290 TI - Why we should let "evidence-based medicine" rest in peace. AB - Evidence-based medicine is a redundant term to the extent that doctors have always claimed they practiced medicine on the basis of evidence. They have, however, disagreed about what exactly constitutes legitimate evidence and how to synthesize the totality of evidence in a way that supports clinical action. Despite claims to the contrary, little progress has been made in solving this hard problem in any sort of formal way. The reification of randomized clinical trials (RCTs) and the tight linkage of such evidence to the development of clinical guidelines have led to error. In part, this relates to statistical and funding issues, but it also reflects the fact that the clinical events that comprise RCTs are not isomorphic with most clinical practice. Two possible and partial solutions are proposed: (1) to test empirically in new patient populations whether guidelines have the desired effects and (2) to accept that a distributed ecosystem of opinion rather than a hierarchical or consensus model of truth might better underwrite good clinical practice. PMID- 24160292 TI - Hepatic cell lines for drug hepatotoxicity testing: limitations and strategies to upgrade their metabolic competence by gene engineering. AB - One key issue in the pharmaceutical development of new compounds is knowledge on metabolism, the enzymes involved and the potential hepatotoxicity of a drug. Primary cultured hepatocytes are a valuable in vitro model for drug metabolism studies. However, human hepatocytes show phenotypic instability and have restricted accessibility and high batch-to-batch functional variability, which seriously complicates their use in routine testing. Therefore, several liver derived cell models have been developed for drug metabolism and hepatotoxicity screening to circumvent these drawbacks. Hepatoma cell lines offer important advantages, availability, an unlimited life span and a stable phenotype, thus rendering them suitable models for such studies. However, currently available human hepatoma cell lines are not a good alternative to cultured hepatocytes as they show very limited expression for most drug-metabolising enzymes. Other approaches have been developed to generate immortalised hepatic cells with metabolic competence (use of plasmids encoding immortalising genes to transform human hepatocytes, cell lines obtained from transgenic animals, hepatocytomes or hydrid cells). Recombinant models heterologously expressing cytochrome P450 enzymes in hepatoma cells have also been generated, and are widely used in drug metabolism and toxicity evaluations. In recent years, new approaches to up regulate the expression of drug-biotransformation enzymes in human cell lines (i.e., transfection with the expression vectors encoding key hepatic transcription factors) have also been investigated. This paper reviews the features of liver-derived cell lines, their suitability for drug metabolism and hepatotoxicity studies, and the state-of-the-art strategies pursued to generate metabolically competent hepatic cell lines. PMID- 24160291 TI - The impact of the genome-wide supported variant in the cyclin M2 gene on gray matter morphology in schizophrenia. AB - BACKGROUND: Genome-wide significant associations of schizophrenia with eight SNPs in the CNNM2, MIR137, PCGEM1, TRIM26, CSMD1, MMP16, NT5C2 and CCDC68 genes have been identified in a recent mega-analysis of genome-wide association studies. To date, the role of these SNPs on gray matter (GM) volumes remains unclear. METHODS: After performing quality control for minor-allele frequency > 5% using a JPT HapMap sample and our sample, a genotyping call rate > 95% and Hardy-Weinberg equilibrium testing (p > 0.01), five of eight SNPs were eligible for analysis. We used a comprehensive voxel-based morphometry (VBM) technique to investigate the effects of these five SNPs on GM volumes between major-allele homozygotes and minor-allele carriers in Japanese patients with schizophrenia (n = 173) and healthy subjects (n = 449). RESULTS: The rs7914558 risk variant at CNNM2 was associated with voxel-based GM volumes in the bilateral inferior frontal gyri (right T = 4.96, p = 0.0088, left T = 4.66, p = 0.031). These peak voxels, which were affected by the variant, existed in the orbital region of the inferior frontal gyri. Individuals with the risk G/G genotype of rs7914558 had smaller GM volumes in the bilateral inferior frontal gyri than carriers of the non-risk A allele. Although several effects of the genotype and the genotype-diagnosis interaction of other SNPs on GM volumes were observed in the exploratory VBM analyses, these effects did not remain after the FWE-correction for multiple tests (p > 0.05). CONCLUSIONS: Our findings suggest that the genetic variant in the CNNM2 gene could be implicated in the pathogenesis of schizophrenia through the GM volumetric vulnerability of the orbital regions in the inferior frontal gyri. PMID- 24160293 TI - Drug metabolism and transport under hypoxia. AB - Tumour progression is characterized by a rapid cell growth accompanied by changes in the microenvironment, largely due to hypoxia. The angiogenic switch involves changes in the expression of genes that play key roles in tumour progression, invasion, metastasis and therapeutic response, contributing to tumour aggressiveness. The effect of hypoxia on the cellular concentrations of drug metabolizing enzymes and transporters is much less understood. A brief summary of the signaling mechanisms triggered by hypoxia is presented, followed by a review of the known effects of hypoxia on drug metabolism and transport. Most of the studies available have focused on Cytochromes P450 and ATP-binding cassette transporters, while influx transporters of the SLC family have been less investigated. Given its potential to contribute both to the understanding of the pathogenesis of disease and to the optimization of therapeutics, it is rather surprising that this area of research is still underdeveloped. An increasing number of studies focusing on this subject are bound to provide key information for drug development and optimization of therapeutics. PMID- 24160295 TI - Vitamin D: preventive and therapeutic potential in Parkinson's disease. AB - Vitamin D is one of the important nuclear steroid transcription regulators that controls transcriptions of a large number of genes. Vitamin D supplement is commonly recommended for the elderly to prevent bone diseases. Amounting new evidence has indicated that vitamin D plays a crucial role in brain development, brain function regulation and neuroprotection. Parkinson's disease (PD) is a degenerative disorder commonly seen in the elderly, characterized by movement disorders including tremor, akinesia, and loss of postural reflexes. The motor symptoms largely result from the continued death of dopaminergic neurons in the substantia nigra, despite use of current therapeutic interventions. The cause and mechanism of neuron death is currently unknown. Vitamin D deficiency is common in patients with PD suggesting its preventive and therapeutic potential. Vitamin D may exert protective and neurotropic effects directly at cellular level, e.g. protection of dopamine system, and/or by regulating gene expression. This review summarizes the epidemiological, genetic and translational evidence implicating vitamin D as a candidate for prevention and treatment for PD. PMID- 24160296 TI - Butyrate and colorectal cancer: the role of butyrate transport. AB - Colorectal cancer (CRC) is one of the most common solid tumors worldwide. A diet rich in dietary fiber is associated with a reduction in its risk. Butyrate (BT) is one of the main end products of anaerobic bacterial fermentation of dietary fiber in the human colon. This short-chain fatty acid is an important metabolic substrate in normal colonic epithelial cells and has important homeostatic functions at this level, including the ability to prevent/inhibit carcinogenesis. BT is transported into colonic epithelial cells by two specific carrier-mediated transport systems, the monocarboxylate transporter 1 (MCT1) and the sodium coupled monocarboxylate transporter 1 (SMCT1). In normal colonic epithelial cells, BT is the main energy source for normal colonocytes and it is effluxed by BCRP. Colonic epithelial tumoral cells show a reduction in BT uptake (through a reduction in MCT1 and SMCT1 protein expression), an increase in the rate of glucose uptake and glycolysis becomes their primary energy source. BT presents an anticarcinogenic effect (induction of cell differentiation and apoptosis and inhibition of cell proliferation) but has an apparent opposing effect upon growth of normal colonocytes (the "BT paradox"). Because the cellular effects of BT (e.g. inhibition of histone deacetylases) are dependent on its intracellular concentration, knowledge on the mechanisms involved in BT membrane transport and its regulation seem particularly relevant in the context of the physiological and pharmacological benefits of this compound. This review discusses the mechanisms of BT transport and integrates this knowledge with the effects of BT in tumoral and normal colonocytes. PMID- 24160294 TI - Cellular targets and mechanisms in the cytotoxic action of non-biodegradable engineered nanoparticles. AB - The use of nanoparticles (NPs) has improved the quality of many industrial, pharmaceutical, and medical products. Increased surface reactivity, a major reason for the positive effects of NPs, may, on the other hand, also cause adverse biological effects. Almost all non-biodegradable NPs cause cytotoxic effects but employ quite different modes of action. The relation of biodegradable or loaded NPs to cytotoxic mechanism is more difficult to identify because effects may by caused by the particles or degradation products thereof. This review introduces problems of NPs in conventional cytotoxicity testing (changes of particle parameters in biological fluids, cellular dose, cell line and assay selection). Generation of reactive oxygen and nitrogen species by NPs and of metal ions due to dissolution of the NPs is discussed as a cause for cytotoxicity. The effects of NPs on plasma membrane, mitochondria, lysosomes, nucleus, and intracellular proteins as cellular targets for cytotoxicity are summarized. The comparison of the numerous studies on the mechanism of cellular effects shows that, although some common targets have been identified, other effects are unique for particular NPs or groups of NPs. While titanium dioxide NPs appear to act mainly by generation of reactive oxygen and nitrogen species, biological effects of silver and iron oxide are caused by both reactive species and free metal ions. NPs lacking heavy metals, such as carbon nanotubes and polystyrene particles, interfere with cell metabolism mainly by binding to macromolecules. PMID- 24160297 TI - Synthesis and evaluation of multi-target-directed ligands against Alzheimer's disease based on the fusion of donepezil and ebselen. AB - A novel series of compounds obtained by fusing the cholinesterase inhibitor donepezil and the antioxidant ebselen were designed as multi-target-directed ligands against Alzheimer's disease. An in vitro assay showed that some of these molecules did not exhibit highly potent cholinesterase inhibitory activity but did have various other ebselen-related pharmacological effects. Among the molecules, compound 7d, one of the most potent acetylcholinesterase inhibitors (IC50 values of 0.042 MUM for Electrophorus electricus acetylcholinesterase and 0.097 MUM for human acetylcholinesterase), was found to be a strong butyrylcholinesterase inhibitor (IC50 = 1.586 MUM), to possess rapid H2O2 and peroxynitrite scavenging activity and glutathione peroxidase-like activity (nu0 = 123.5 MUM min(-1)), and to be a substrate of mammalian TrxR. A toxicity test in mice showed no acute toxicity at doses of up to 2000 mg/kg. According to an in vitro blood-brain barrier model, 7d is able to penetrate the central nervous system. PMID- 24160298 TI - C-5 palsy after cervical laminoplasty with instrumented posterior fusion. AB - OBJECT: Postoperative C-5 palsy is known as a common complication after cervical laminoplasty. The authors of this article have encountered postoperative C-5 palsy more often when laminoplasty was combined with instrumented posterior spinal fusion than when it was performed alone. The purpose of this clinical study was to examine the incidence of fifth cervical nerve root palsy (C-5 palsy) and surgical results in patients with cervical myelopathy who had undergone laminoplasty with or without instrumented spinal fusion. METHODS: The authors retrospectively studied patients with cervical myelopathy who had undergone laminoplasty with or without instrumented posterior spinal fusion. RESULTS: Clinical data on 58 patients were evaluated and analyzed. Preoperative diagnoses were cervical spondylotic myelopathy or ossification of the posterior longitudinal ligament of the cervical spine. Twenty-four patients with spondylolisthesis or kyphosis underwent laminoplasty combined with posterior spinal fusion using instrumented lateral mass fixation (fusion group), while the remaining 34 patients underwent laminoplasty without posterior spinal fusion (no fusion group). In the fusion group, C-5 palsy developed in 6 patients; in the no fusion group, it occurred in only 1 patient. There was a significant difference in the rate of this complication between the 2 groups. In the fusion group, local kyphosis and spondylolisthesis level were reduced at the fusion level, and all patients with C-5 palsy underwent C4-5 spinal fusion. CONCLUSIONS: The incidence of postoperative C-5 palsy is significantly higher after laminoplasty when it is combined with spinal fusion. Correction of kyphosis and spondylolisthesis using posterior instrumentation may be a risk factor for iatrogenic intervertebral foraminal stenosis leading to C-5 palsy. PMID- 24160299 TI - Dr. Samuel Stover: promoting health and participation through leadership in spinal cord injury medicine. PMID- 24160300 TI - Diagnostic accuracy studies in mild traumatic brain injury: a systematic review and descriptive analysis of published evidence. AB - OBJECTIVES: To synthesize evidence and report findings from a systematic search and descriptive analysis of peer-reviewed published evidence of the accuracy of tests used for diagnosing mild traumatic brain injury (mTBI). The article also summarizes points of concurrence and divergence regarding case definitions of mTBI identified during the review. TYPE: Systematic review and descriptive analysis of published evidence. LITERATURE SURVEY: A search of PubMed, PsychInfo, and the Cochrane Library for peer-reviewed publications between 1990 and July 6, 2011, identified 1218 abstracts; 277 articles were identified for full review, and 13 articles met the criteria for evaluation. METHODOLOGY: Manuscript inclusion criteria were (1) reported sensitivity (Se) and specificity (Sp), or reported data were sufficient to compute Se and Sp; (2) >1 participant in the study; (3) at least 80% of the study cohort was >=18 years of age; and (4) written in English. Articles describing clinical practice guidelines, opinions, theories, or clinical protocols were excluded. Seven investigators independently evaluated each article according to the Standards for Reporting of Diagnostic Accuracy (STARD) criteria. SYNTHESIS: Findings indicate that all 13 studies involved civilian noncombat populations. In 7 studies, authors examined acute mTBI, and in 4 studies, historical remote mTBI was examined. In the 13 studies, Se ranged from 13%-92% and Sp ranged from 72%-99%, but confidence in these findings is problematic because the STARD review indicates opportunities for bias in each study. CONCLUSIONS: Findings indicate that no well-defined definition or clinical diagnostic criteria exist for mTBI and that diagnostic accuracy is currently insufficient for discriminating between mTBI and co-occurring mental health conditions for acute and historic mTBI. Findings highlight the need for research examining the diagnostic accuracy for acute and historic mTBI. PMID- 24160302 TI - Management of a patient with slow recovery from a mild traumatic brain injury. PMID- 24160301 TI - Balancing burdens and benefits: ethical issues of off-label prescription pharmaceutical use. PMID- 24160303 TI - Inadequate calcium intake is highly prevalent in Korean children and adolescents: the Korea National Health and Nutrition Examination Survey (KNHANES) 2007-2010. AB - OBJECTIVE: The present study aimed to assess the adequacy of Ca intake and major food sources of Ca in Korean children and adolescents. DESIGN: A cross-sectional study. SETTING: Data from the Korean National Health and Nutrition Examination Survey (KNHANES) 2007-2010. We analysed the daily Ca intake, major food sources of Ca and the prevalence of inadequate Ca intake in the study population. Ca intake was categorized as inadequate when the participant's daily Ca intake was less than the Estimated Average Requirement. Subject The study population consisted of 7233 children and adolescents (3973 boys, 3260 girls; aged 1-18 years). RESULTS: Mean Ca intake was 510.2 mg/d in boys and 431.7 mg/d in girls. Overall, 75.0 % of adolescents (boys 71.6 %, girls 79.1 %) had inadequate Ca intake. The prevalence of inadequate Ca intake increased significantly from toddlers (45-55 %) to adolescents (78-86 %) in both genders. The highest ranked food sources for Ca were dairy products (35.0 %), followed by vegetables (17.3 %), grains (11.3 %) and seafood (9.9 %). Ca intake from dairy products decreased significantly from 57 % in toddlers to 30 % in adolescents, while Ca intakes from other foods increased with age. CONCLUSIONS: Inadequate Ca intake is highly prevalent and increased with age in Korean children and adolescents. It should be emphasized to encourage children and adolescents to eat more Ca-rich products to meet their Ca needs. PMID- 24160304 TI - The slower the better? Does the speaker's speech rate influence children's performance on a language comprehension test? AB - The aim of this study was to examine the effects of speech rate on children's performance on a widely used language comprehension test, the Test for Reception of Grammar, version 2 (TROG'2), and to explore how test performance interacts with task difficulty and with the child's working memory capacity. Participants were 102 typically-developing Swedish-speaking children randomly assigned to one of the three conditions; the TROG'2 sentences spoken by a speech-language pathologist with slow, normal or fast speech rate. Results showed that the fast speech rate had a negative effect on the TROG'2 scores and that slow rate was more beneficial in general. However, for more difficult tasks the beneficial effect of slow speech was only pronounced for children with better scores on a working memory task. The interpretation is that slow speech is particularly helpful when children do not yet fully master a task but are just about to grasp it. These results emphasize the necessity of careful considerations of the role dynamic aspects of examiner's speech might play in test administration and favour digitalized procedures in standardized language comprehension assessment. PMID- 24160305 TI - Systematic design methodology for robust genetic transistors based on I/O specifications via promoter-RBS libraries. AB - BACKGROUND: Synthetic genetic transistors are vital for signal amplification and switching in genetic circuits. However, it is still problematic to efficiently select the adequate promoters, Ribosome Binding Sides (RBSs) and inducer concentrations to construct a genetic transistor with the desired linear amplification or switching in the Input/Output (I/O) characteristics for practical applications. RESULTS: Three kinds of promoter-RBS libraries, i.e., a constitutive promoter-RBS library, a repressor-regulated promoter-RBS library and an activator-regulated promoter-RBS library, are constructed for systematic genetic circuit design using the identified kinetic strengths of their promoter RBS components.According to the dynamic model of genetic transistors, a design methodology for genetic transistors via a Genetic Algorithm (GA)-based searching algorithm is developed to search for a set of promoter-RBS components and adequate concentrations of inducers to achieve the prescribed I/O characteristics of a genetic transistor. Furthermore, according to design specifications for different types of genetic transistors, a look-up table is built for genetic transistor design, from which we could easily select an adequate set of promoter RBS components and adequate concentrations of external inducers for a specific genetic transistor. CONCLUSION: This systematic design method will reduce the time spent using trial-and-error methods in the experimental procedure for a genetic transistor with a desired I/O characteristic. We demonstrate the applicability of our design methodology to genetic transistors that have desirable linear amplification or switching by employing promoter-RBS library searching. PMID- 24160306 TI - Construction of a reference genetic linkage map for carnation (Dianthus caryophyllus L.). AB - BACKGROUND: Genetic linkage maps are important tools for many genetic applications including mapping of quantitative trait loci (QTLs), identifying DNA markers for fingerprinting, and map-based gene cloning. Carnation (Dianthus caryophyllus L.) is an important ornamental flower worldwide. We previously reported a random amplified polymorphic DNA (RAPD)-based genetic linkage map derived from Dianthus capitatus ssp. andrezejowskianus and a simple sequence repeat (SSR)-based genetic linkage map constructed using data from intraspecific F2 populations; however, the number of markers was insufficient, and so the number of linkage groups (LGs) did not coincide with the number of chromosomes (x = 15). Therefore, we aimed to produce a high-density genetic map to improve its usefulness for breeding purposes and genetic research. RESULTS: We improved the SSR-based genetic linkage map using SSR markers derived from a genomic library, expression sequence tags, and RNA-seq data. Linkage analysis revealed that 412 SSR loci (including 234 newly developed SSR loci) could be mapped to 17 linkage groups (LGs) covering 969.6 cM. Comparison of five minor LGs covering less than 50 cM with LGs in our previous RAPD-based genetic map suggested that four LGs could be integrated into two LGs by anchoring common SSR loci. Consequently, the number of LGs corresponded to the number of chromosomes (x = 15). We added 192 new SSRs, eight RAPD, and two sequence-tagged site loci to refine the RAPD-based genetic linkage map, which comprised 15 LGs consisting of 348 loci covering 978.3 cM. The two maps had 125 SSR loci in common, and most of the positions of markers were conserved between them. We identified 635 loci in carnation using the two linkage maps. We also mapped QTLs for two traits (bacterial wilt resistance and anthocyanin pigmentation in the flower) and a phenotypic locus for flower-type by analyzing previously reported genotype and phenotype data. CONCLUSIONS: The improved genetic linkage maps and SSR markers developed in this study will serve as reference genetic linkage maps for members of the genus Dianthus, including carnation, and will be useful for mapping QTLs associated with various traits, and for improving carnation breeding programs. PMID- 24160307 TI - Effects of rehydration and food consumption on salivary flow, pH and buffering capacity in young adult volunteers during ergometer exercise. AB - BACKGROUND: The aim of this study was to investigate the influences of rehydration and food consumption on salivary flow, pH, and buffering capacity during bicycle ergometer exercise in participants. METHODS: Ten healthy volunteers exercised on a bicycle ergometer at 80% of their maximal heart rate. These sessions lasted for two periods of 20 min separated by 5-min rest intervals. Volunteers were subjected to one of the following conditions: (1) no water (mineral water) or food consumption, (2) only water for rehydration, (3) water and food consumption, (4) a sports drink only for rehydration, and (5) rehydration with a sports drink and food. Statistical significance was assessed using one-way analysis of variance and Dunnett's test (p < 0.05). RESULTS: The salivary pH decreased significantly during and after exercise in conditions 4 and 5. The salivary buffering capacity decreased significantly during exercise and/or after the exercise in conditions 1, 3, 4, and 5. CONCLUSIONS: The results showed that salivary pH and buffering capacity decreased greatly depending on the combination of a sports drink and food. PMID- 24160308 TI - Stereoselective synthesis of sialylated tumor-associated glycosylamino acids. AB - Suitably protected sialyl T(N) and 2,6-sialyl T tumor-associated carbohydrate antigen-derived amino acids have been prepared stereoselectively using an oxazolidinone-derived sialoside donor. These glycosylamino acids can be employed directly in the solid-phase synthesis of glycopeptides, as demonstrated by the efficient preparation of tumor-associated MUC1 glycopeptide fragments. PMID- 24160309 TI - Growing burden of diabetes in sub-saharan Africa: contribution of pesticides ? AB - The diabetes burden is growing in Sub-Saharan Africa (SSA). The low overall access to health care has been documented to contribute to the high diabetes related mortality. Due to economic, demographic, epidemiological and nutrition transitions in SSA, the growing prevalence of diabetes appears to be related to obesogenic lifestyles and the intergenerational impact of malnutrition in women of childbearing age. Both overnutrition and undernutrition have been associated with the development of diabetes and other chronic diseases. Africans are also suspected of being genetically predisposed to diabetes. According to existing data in developed countries, exposure to pesticides, particularly organochlorines and metabolites, is associated with a higher risk of developing type 2 diabetes and its comorbidities. In African countries, pesticide exposure levels often appear much higher than in developed countries. Furthermore, undernutrition, which is still highly prevalent in SSA, could increase susceptibility to the adverse effects of organic pollutants. Therefore, the growing and inadequate use of pesticides may well represent an additional risk factor for diabetes in SSA. Additionally, high exposure to pesticides in African infants in utero and during the perinatal period may increase the intergenerational risk of developing diabetes in SSA. PMID- 24160310 TI - Invited commentary. PMID- 24160311 TI - Current efficacy of open and endovascular interventions for advanced superficial femoral artery occlusive disease. AB - BACKGROUND: There has been a marked paradigm shift in the treatment of symptomatic femoro-popliteal disease with a shift from open to endoluminal therapy. The consequence of this shift in therapy is poorly described. The aim of this study is to examine the clinical efficacy of this shift in treatment strategies. METHODS: A database of patients undergoing open (OPEN) and endoluminal (ENDO) intervention for TASC II C and D femoro-popliteal lesions between 1990 and 2010 was retrospectively queried. Kaplan-Meier survival analyses were performed to assess time-dependent outcomes. Factor analyses were performed using a multivariant Cox proportional hazard model for time-dependent variables. RESULTS: A total of 2593 limbs underwent either OPEN or ENDO treatment for symptomatic and anatomically advanced femoro-popliteal disease over a 20-year period. There was a two-fold rise in endovascular interventions between the first and second decade. In the first decade, 80% of the interventions were OPEN, while in the second decade, 61% of the interventions were ENDO. There were equivalent comorbidities in both groups, and survival was also equivalent. Endoluminal therapy was more commonly performed on claudicants. Thirty-day mortality was equivalent, but major morbidity was higher in OPEN compared with ENDO. Cumulative patency was equivalent in both groups with a similar reintervention rate. In contrast, clinical efficacy (freedom from recurrent symptoms, maintenance of ambulation, and avoidance of major amputation) was significantly higher in the OPEN group (P = .002). The presence of critical limb ischemia, diabetes, end stage renal disease, and poor tibial runoff were predictors of poor anatomic and functional outcomes in both groups. CONCLUSIONS: There has been a marked shift in treatment modality for advanced femoro-popliteal disease with a lowering of the symptomatic threshold for intervention over 2 decades, likely spurred by the ease of endoluminal interventions. Although peri-procedural and anatomic outcomes for both procedures are equivalent, it appears that open surgery carries a superior long-term clinical efficacy. This superiority is negatively influenced by poor preoperative ambulation status, high modified Cardiac Risk Score, worse presenting symptoms, the occurrence of major adverse cardiovascular events, poor tibial runoff, the absence of hemodynamic success, and occlusion of the original bypass. PMID- 24160312 TI - Discussion. PMID- 24160313 TI - A rare pathognomonic sign of extracranial vertebral dissection. PMID- 24160315 TI - Forearm large hematoma following transulnar artery cardiac catheterization. PMID- 24160314 TI - Isolated interrupted aortic arch in an adult male. PMID- 24160316 TI - Are we unique? PMID- 24160317 TI - Regarding "Race as a predictor of morbidity, mortality, and neurologic events after carotid endarterectomy". PMID- 24160318 TI - Reply: To PMID 23375438. PMID- 24160320 TI - The assessment for living with aphasia: reliability and construct validity. AB - The Assessment for Living with Aphasia (ALA) is a pictographic, self-report measure of aphasia-related quality-of-life. Research was undertaken to assess test-re-test reliability, construct validity, and the ability to discriminate aphasia severity. The ALA was administered to 101 participants with aphasia on two occasions. Test-re-test reliability was evaluated using intra-class correlations and internal consistency using Cronbach's alpha. Three reference measures were administered to assess construct validity. A focus group reported on ease of administration and face validity. Analysis identified 15 out of 52 rated items for elimination. For the remaining items, test-re-test reliability was excellent for the total score (ICC = .86) and moderate-to-strong for a priori domains adapted from the WHO ICF (.68-.83). Internal consistency was acceptable to-high. Significant correlations were observed between the ALA and reference tests (SAQOL-39, .72; p < .001; VASES, .62, p = .03; BOSS CAPD, -.69; p = .008). The language impairment domain discriminated between all aphasia severity groups, while mild aphasia was different from moderate and severe aphasia in participation and total scores. The ALA was reportedly easy to administer and captured key aspects of the experience of living with aphasia. Results suggest acceptable test-re-test reliability, internal consistency and construct validity of the ALA. PMID- 24160319 TI - A potential source for cellulolytic enzyme discovery and environmental aspects revealed through metagenomics of Brazilian mangroves. AB - The mangroves are among the most productive and biologically important environments. The possible presence of cellulolytic enzymes and microorganisms useful for biomass degradation as well as taxonomic and functional aspects of two Brazilian mangroves were evaluated using cultivation and metagenomic approaches. From a total of 296 microorganisms with visual differences in colony morphology and growth (including bacteria, yeast and filamentous fungus), 179 (60.5%) and 117 (39.5%) were isolated from the Rio de Janeiro (RJ) and Bahia (BA) samples, respectively. RJ metagenome showed the higher number of microbial isolates, which is consistent with its most conserved state and higher diversity. The metagenomic sequencing data showed similar predominant bacterial phyla in the BA and RJ mangroves with an abundance of Proteobacteria (57.8% and 44.6%), Firmicutes (11% and 12.3%) and Actinobacteria (8.4% and 7.5%). A higher number of enzymes involved in the degradation of polycyclic aromatic compounds were found in the BA mangrove. Specific sequences involved in the cellulolytic degradation, belonging to cellulases, hemicellulases, carbohydrate binding domains, dockerins and cohesins were identified, and it was possible to isolate cultivable fungi and bacteria related to biomass decomposition and with potential applications for the production of biofuels. These results showed that the mangroves possess all fundamental molecular tools required for building the cellulosome, which is required for the efficient degradation of cellulose material and sugar release. PMID- 24160321 TI - Weight gain in the first two years of life, asthma and atopy: the SCAALA cohort study. AB - OBJECTIVE: To evaluate the association between weight gain in the first two years of life and the occurrence of wheezing, asthma, serum IgE, skin reactivity and pulmonary function. DESIGN: Cohort study. SETTING: The metropolitan region of Salvador, Bahia, Brazil. SUBJECTS: The association was studied between 1997 and 2005 in 669 children up to 11 years of age. Data were collected on asthma and risk factors, both current factors and those present in the first years of life. Weight gain was considered fast when the Z-score was >0.67. Poisson regression was used in the multivariate statistical analysis. RESULTS: Wheezing was reported in 25.6 % of the children. Weight gain was considered fast (Z-score >0.67) in 29.6 % of the children and slow (Z-score <-0.67) in 13.9 %. Children in the slow weight gain group had 36 % fewer symptoms of asthma (prevalence ratio = 0.65; 95 % CI 0.42, 0.99). CONCLUSIONS: Slower weight gain in the early years of life may constitute a protective factor against symptoms of asthma. The relevance of this finding for public health is not yet certain, since it is known that children with slow and fast weight gain may be more likely to develop adverse health consequences related to both these situations. PMID- 24160322 TI - Sparing of the dystrophin-deficient cranial sartorius muscle is associated with classical and novel hypertrophy pathways in GRMD dogs. AB - Both Duchenne and golden retriever muscular dystrophy (GRMD) are caused by dystrophin deficiency. The Duchenne muscular dystrophy sartorius muscle and orthologous GRMD cranial sartorius (CS) are relatively spared/hypertrophied. We completed hierarchical clustering studies to define molecular mechanisms contributing to this differential involvement and their role in the GRMD phenotype. GRMD dogs with larger CS muscles had more severe deficits, suggesting that selective hypertrophy could be detrimental. Serial biopsies from the hypertrophied CS and other atrophied muscles were studied in a subset of these dogs. Myostatin showed an age-dependent decrease and an inverse correlation with the degree of GRMD CS hypertrophy. Regulators of myostatin at the protein (AKT1) and miRNA (miR-539 and miR-208b targeting myostatin mRNA) levels were altered in GRMD CS, consistent with down-regulation of myostatin signaling, CS hypertrophy, and functional rescue of this muscle. mRNA and proteomic profiling was used to identify additional candidate genes associated with CS hypertrophy. The top ranked network included alpha-dystroglycan and like acetylglucosaminyltransferase. Proteomics demonstrated increases in myotrophin and spectrin that could promote hypertrophy and cytoskeletal stability, respectively. Our results suggest that multiple pathways, including decreased myostatin and up-regulated miRNAs, alpha-dystroglycan/like acetylglucosaminyltransferase, spectrin, and myotrophin, contribute to hypertrophy and functional sparing of the CS. These data also underscore the muscle-specific responses to dystrophin deficiency and the potential deleterious effects of differential muscle involvement. PMID- 24160323 TI - Treatment with anti-gremlin 1 antibody ameliorates chronic hypoxia/SU5416-induced pulmonary arterial hypertension in mice. AB - The expression of the bone morphogenetic protein antagonist, Gremlin 1, was recently shown to be increased in the lungs of pulmonary arterial hypertension patients, and in response to hypoxia. Gremlin 1 released from the vascular endothelium may inhibit endogenous bone morphogenetic protein signaling and contribute to the development of pulmonary arterial hypertension. Here, we investigate the impact of Gremlin 1 inhibition in disease after exposure to chronic hypoxia/SU5416 in mice. We investigated the effects of an anti-Gremlin 1 monoclonal antibody in the chronic hypoxia/SU5416 murine model of pulmonary arterial hypertension. Chronic hypoxic/SU5416 exposure of mice induced upregulation of Gremlin 1 mRNA in lung and right ventricle tissue compared with normoxic controls. Prophylactic treatment with an anti-Gremlin 1 neutralizing mAb reduced the hypoxic/SU5416-dependent increase in pulmonary vascular remodeling and right ventricular hypertrophy. Importantly, therapeutic treatment with an anti-Gremlin 1 antibody also reduced pulmonary vascular remodeling and right ventricular hypertrophy indicating a role for Gremlin 1 in the progression of the disease. We conclude that Gremlin 1 plays a role in the development and progression of pulmonary arterial hypertension in the murine hypoxia/SU5416 model, and that Gremlin 1 is a potential therapeutic target for pulmonary arterial hypertension. PMID- 24160324 TI - Islet transplantation and insulin administration relieve long-term complications and rescue the residual endogenous pancreatic beta cells. AB - Islet transplantation is a poorly investigated long-term strategy for insulin replacement and for treatment of complications in patients with diabetes. We investigated whether islet transplantation and insulin treatment can relieve diabetic neuropathy and rescue the residual endogenous pancreatic beta cells. We used a multimodal approach, with five groups of Sprague-Dawley rats studied for 8 months: control rats, diabetic rats, insulin-treated diabetic rats with moderate or mild hyperglycemia, and diabetic rats transplanted with microencapsulated islets. Islet transplantation normalized glycemia and increased body and muscle weight; it was also effective in reducing proteinuria and altered liver function. Transplantation significantly improved tail nerve conduction velocity, Na(+)-K(+) ATPase activity, and morphological alterations in the sciatic nerve as evidenced by decrease in g-ratio; it also restored thermal and ameliorated mechanical nociceptive thresholds. Morphometric analysis of pancreas indicated a significant beta-cell volume increase in transplanted rats, compared with mildly and moderately hyperglycemic rats. Thus, allogeneic islet transplantation had a positive systemic effect in diabetic rats and induced regression of the established neuropathy and restitution of the typical characteristics of the islets. These findings strongly reinforce the need for improving glycemic control, not only to reverse established diabetic complications but also to improve beta-cell status in diabetic pancreas. PMID- 24160325 TI - CNS inflammation and bone marrow neuropathy in type 1 diabetes. AB - By using pseudorabies virus expressing green fluorescence protein, we found that efferent bone marrow-neural connections trace to sympathetic centers of the central nervous system in normal mice. However, this was markedly reduced in type 1 diabetes, suggesting a significant loss of bone marrow innervation. This loss of innervation was associated with a change in hematopoiesis toward generation of more monocytes and an altered diurnal release of monocytes in rodents and patients with type 1 diabetes. In the hypothalamus and granular insular cortex of mice with type 1 diabetes, bone marrow-derived microglia/macrophages were activated and found at a greater density than in controls. Infiltration of CD45(+)/CCR2(+)/GR-1(+)/Iba-1(+) bone marrow-derived monocytes into the hypothalamus could be mitigated by treatment with minocycline, an anti inflammatory agent capable of crossing the blood-brain barrier. Our studies suggest that targeting central inflammation may facilitate management of microvascular complications. PMID- 24160327 TI - Enantio-, diastereo-, and regioselective iridium-catalyzed asymmetric allylic alkylation of acyclic beta-ketoesters. AB - The first regio-, diastereo-, and enantioselective allylic alkylation of acyclic beta-ketoesters to form vicinal tertiary and all-carbon quaternary stereocenters is reported. Critical to the successful development of this method was the employment of iridium catalysis in concert with N-aryl-phosphoramidite ligands. Broad functional group tolerance is observed at the keto-, ester-, and alpha positions of the nucleophile. Various transformations demonstrating the utility of this method for rapidly accessing complex enantioenriched compounds are reported. PMID- 24160326 TI - Continuous exposure to chrysotile asbestos can cause transformation of human mesothelial cells via HMGB1 and TNF-alpha signaling. AB - Malignant mesothelioma is strongly associated with asbestos exposure. Among asbestos fibers, crocidolite is considered the most and chrysotile the least oncogenic. Chrysotile accounts for more than 90% of the asbestos used worldwide, but its capacity to induce malignant mesothelioma is still debated. We found that chrysotile and crocidolite exposures have similar effects on human mesothelial cells. Morphological and molecular alterations suggestive of epithelial mesenchymal transition, such as E-cadherin down-regulation and beta-catenin phosphorylation followed by nuclear translocation, were induced by both chrysotile and crocidolite. Gene expression profiling revealed high-mobility group box-1 protein (HMGB1) as a key regulator of the transcriptional alterations induced by both types of asbestos. Crocidolite and chrysotile induced differential expression of 438 out of 28,869 genes interrogated by oligonucleotide microarrays. Out of these 438 genes, 57 were associated with inflammatory and immune response and cancer, and 14 were HMGB1 targeted genes. Crocidolite-induced gene alterations were sustained, whereas chrysotile-induced gene alterations returned to background levels within 5 weeks. Similarly, HMGB1 release in vivo progressively increased for 10 or more weeks after crocidolite exposure, but returned to background levels within 8 weeks after chrysotile exposure. Continuous administration of chrysotile was required for sustained high serum levels of HMGB1. These data support the hypothesis that differences in biopersistence influence the biological activities of these two asbestos fibers. PMID- 24160328 TI - Prognostic effect of preoperative serum estradiol level in postmenopausal breast cancer. AB - BACKGROUND: The prognostic role of serum estrogen level in breast cancer patients is unclear. We investigated the prognostic importance of preoperative serum estradiol (E2) level in postmenopausal women according to their estrogen receptor (ER) status. METHODS: The medical records of 313 postmenopausal breast cancer patients who underwent surgery between 2006 and 2008 at a single institution were retrospectively evaluated. Patients who received neoadjuvant chemotherapy, synchronous bilateral breast cancer, or those with metastasis at diagnosis were excluded. Serum E2 and follicular stimulating hormone (FSH) levels were measured by radioimmunoassay and immunoradiometric assay, respectively, within 3 months prior to surgery. After a median follow-up of 52.0 months (11-77 months), 21 women were found to have metastatic disease. RESULTS: The overall, median E2 level was 13.0 pg/ml, and was slightly higher in ER-positive than ER-negative (p=0.69). The mean serum E2 level was significantly higher in patients with metastasis (17.41 +/- 8.34 pg/ml) than in those without metastasis (13.54 +/- 7.58 pg/ml) (p=0.02). Kaplan-Meier analysis using a cut-off of 13 pg/ml showed that, ER negative (p=0.02) but not ER positive (p>0.05) patients with higher E2 level showed significantly poorer metastasis-free survival. Multivariate analysis showed that, the high E2 level of ER negative tumors was an independent negative prognostic factor for metastasis- free survival (HR, 3.32; 95% CI, 1.05 to 10.51; p=0.04). CONCLUSIONS: Higher preoperative serum E2 level had a negative prognostic effect in postmenopausal women with breast cancer, especially in the ER-negative subgroup. PMID- 24160330 TI - Family history tools for primary care are not ready yet to be implemented. A systematic review. AB - BACKGROUND: Taking the family history helps the doctor in estimating the probability of disease in individual patients. However, significant barriers to obtaining adequate family history information remain. Tools overcoming these barriers might support family physicians in this task. OBJECTIVE: To review systematically the characteristics of existing family history tools and discuss their potential use in primary care. METHODS: Studies were identified through searches of PubMed, Embase and Cinahl from 1 January 2002 until May 2012. All authors independently screened studies and included original research papers on family history tools of which assessment had been performed or was planned. We reviewed diseases for which family history information was collected, study setting, tool design, type of family history collection, presence of risk assessment and recommendations for management, and assessment (categorized as either validity or benefit). RESULTS: Eighteen family history tools were identified: six generic, two on cardiovascular disease and ten on cancer. The six generic tools were partly tested in primary care (3x), are mainly computerized (4x), rarely include management recommendations for the physician (1x) and were partly validated against a reference standard (genetic counsellor) (3x, plus one planned). Of the five specific tools studied in primary care, none was validated. No family history tool allows electronic transfer of family history information to electronic medical record systems. Use of a family history tool improved identification of patients at risk for disease. CONCLUSION: Several promising family history tools for primary care have been developed but large-scale implementation cannot be advised yet, based on available validation studies. PMID- 24160331 TI - Do practice nurses have the knowledge to provide diabetes self-management education? AB - Abstract Purpose: Practice nurses are ideally positioned to provide key aspects of self-management education to a large majority of people with diabetes within a primary care setting. However, practice nurses have seldom had comprehensive training in this field and consequently their role may have limitations. A study was designed to determine the diabetes related knowledge levels of practice nurses in a regional/rural setting in Australia. Methods: A cross-sectional study was undertaken using a questionnaire to identify the knowledge of practice nurses. A convenience sample of PNs (N = 52) was drawn from a Division of General Practice in a regional/rural area of NSW. Data was collected using a 14 item knowledge survey from the National Association of Diabetes Centres (NADC). Results: Twenty nine PNs (55%) responded to the survey; primarily the participants were registered nurses (89.6%), only one had completed a postgraduate qualification in diabetes, although 76% had recently completed one or more short courses in diabetes management. Pathophysiology related knowledge was strong (M= 88%) as was knowledge concerning blood glucose monitoring (87%). Less strong was dietary knowledge (79.5%), although one particular question relating to sources of carbohydrate contributed to the lower score. The weakest knowledge area was medication management, with PNs scoring a mean score of only 54%. Conclusion: These findings suggest that PNs have deficits in the knowledge required for DSME and therefore, this must be addressed through targeting continuing professional development. PMID- 24160332 TI - Evaluation of the content variation of anthraquinone glycosides in rhubarb by UPLC-PDA. AB - BACKGROUND: Rhubarb is an important Chinese medicinal herb with a long history of over 2000 years and has been commonly used as a laxative. It is the radix and rhizome of Rheum officinale Baill., R. palmatum L. and R. tanguticum Maxim, all of which are mainly distributed in a broad region in the Tibetan plateau. Anthraquinone glycosides are a series of major active ingredients found in all three species. They are key intermediates in the anthraquinone secondary metabolism and the sennnoside biosynthesis. The variation of the anthraquinone glycoside content in rhubarb in response to specific factors remains an attractive topic. RESULTS: A simple and sensitive Ultra Performance Liquid Chromatography with Photo-Diode Array (UPLC-PDA) detector was developed for the simultaneous determination of six anthraquinone glycosides in rhubarb, i.e., aloeemodin-8-O-glucoside, rhein-8-O-glucoside, chrysophanol-1-O-glucoside, emodin 1-O-glucoside, chrysophanol-8-O-glucoside, emodin-8-O-glucoside. Twenty-seven batches from three species were submitted to the multi-component analysis. The results showed that the anthraquinone glycoside content varied significantly even within the same species. The results showed that the anthraquinone glycoside content varied significantly within the same species but not between different species. The PCA and content analysis results confirmed that the plant species has no obvious effect on the content variation. Neither was any significant correlation observed between the anthraquinone glycoside content and the geographic distribution of the rhubarb. Through correlational analysis, altitude was found to be the main factor that affects the anthraquinone glycoside content in rhubarb. Rhubarb grown at higher altitude has higher anthraquinone glycoside content. CONCLUSIONS: This work provides a rapid, sensitive and accurate UPLC-PDA method for the simultaneous determination of six anthraquinone glycosides in rhubarb. The anthraquinone glycoside content varied significantly within the same species. The relationship of the anthraquinone glycoside content with plant species, geographic distribution and altitude were studied using correlational analysis, principal component analysis and spatial autocorrelation analysis through SPSS and ArcGIS. Plant species and geographic distribution were found not to affect the content of the six anthraquinone glycosides in rhubarb. The variations in the anthraquinone glycoside content were primarily due to the different altitude where the plant was grown. PMID- 24160333 TI - The M-OVIN study: does switching treatment to FSH and / or IUI lead to higher pregnancy rates in a subset of women with world health organization type II anovulation not conceiving after six ovulatory cycles with clomiphene citrate - a randomised controlled trial. AB - BACKGROUND: Clomiphene citrate (CC) is first line treatment in women with World Health Organization (WHO) type II anovulation and polycystic ovary syndrome (PCOS). Whereas 60% to 85% of these women will ovulate on CC, only about one half will have conceived after six cycles. If women do not conceive, treatment can be continued with gonadotropins or intra-uterine insemination (IUI). At present, it is unclear for how many cycles ovulation induction with CC should be repeated, and when to switch to ovulation induction with gonadotropins and/or IUI. METHODS/DESIGN: We started a multicenter randomised controlled trial in the Netherlands comparing six cycles of CC plus intercourse or six cycles of gonadotrophins plus intercourse or six cycles of CC plus IUI or six cycles of gonadotrophins plus IUI.Women with WHO type II anovulation who ovulate but did not conceive after six ovulatory cycles of CC with a maximum of 150 mg daily for five days will be included.Our primary outcome is birth of a healthy child resulting from a pregnancy that was established in the first eight months after randomisation. Secondary outcomes are clinical pregnancy, miscarriage, multiple pregnancy and treatment costs. The analysis will be performed according to the intention to treat principle. Two comparisons will be made, one in which CC is compared to gonadotrophins and one in which the addition of IUI is compared to ovulation induction only. Assuming a live birth rate of 40% after CC, 55% after addition of IUI and 55% after ovulation induction with gonadotrophins, with an alpha of 5% and a power of 80%, we need to recruit 200 women per arm (800 women in total).An independent Data and Safety Monitoring Committee has criticized the data of the first 150 women and concluded that a sample size re-estimation should be performed after including 320 patients (i.e. 80 per arm). DISCUSSION: The trial will provide evidence on the most effective, safest and most cost effective treatment in women with WHO type II anovulation who do not conceive after six ovulatory cycles with CC with a maximum of 150 mg daily for five days. This evidence could imply the need for changing our guidelines, which may cause a shift in large practice variation to evidence based primary treatment for these women. TRIAL REGISTRATION NUMBER: Netherlands Trial register NTR1449. PMID- 24160334 TI - A new piece in the puzzle of the novel avian-origin influenza A (H7N9) virus. AB - Using phylogenetic analysis on newly available sequences, we characterize A/chicken/Jiangsu/RD5/2013(H10N9) as currently closest precursor strain for the NA segment in the novel avian-origin H7N9 virus responsible for an outbreak in China. We also show that the internal segments of this precursor strain are closely related to those of the presumed precursor for the HA segment, A/duck/Zhejiang/12/2011(H7N3), which indicates that the sources of both HA and NA donors for the reassortant virus are of regional and not migratory-bird origin and highlights the role of chicken already in the early reassortment events. PMID- 24160336 TI - Malaria control in South Sudan, 2006-2013: strategies, progress and challenges. AB - BACKGROUND: South Sudan has borne the brunt of years of chronic warfare and probably has the highest malaria burden in sub-Saharan Africa. However, effective malaria control in post-conflict settings is hampered by a multiplicity of challenges. This manuscript reports on the strategies, progress and challenges of malaria control in South Sudan and serves as an example epitome for programmes operating in similar environments and provides a window for leveraging resources. CASE DESCRIPTION: To evaluate progress and challenges of the national malaria control programme an in-depth appraisal was undertaken according to the World Health Organization standard procedures for malaria programme performance review. Methodical analysis of published and unpublished documents on malaria control in South Sudan was conducted. To ensure completeness, findings of internal thematic desk assessments were triangulated in the field and updated by external review teams. DISCUSSION AND EVALUATION: South Sudan has strived to make progress in implementing the WHO recommended malaria control interventions as set out in the 2006-2013 National Malaria Strategic Plan. The country has faced enormous programmatic constraints including infrastructure, human and financial resource and a weak health system compounded by an increasing number of refugees, returnees and internally displaced people. The findings present a platform on which to tailor an evidence-based 2014-2018 national malaria strategic plan for the country and a unique opportunity for providing a model for countries in a post-conflict situation. CONCLUSIONS: The prospects for effective malaria control and elimination are huge in South Sudan. Nevertheless, strengthened coordination, infrastructure and human resource capacity, monitoring and evaluation are required. To achieve all this, allocation of adequate local funding would be critical. PMID- 24160335 TI - Cost-effectiveness of telaprevir in combination with pegylated interferon alpha and ribavirin in previously untreated chronic hepatitis C genotype 1 patients. AB - BACKGROUND: Telaprevir (T, TVR) is a direct-acting antiviral (DAA) used for the treatment of genotype 1 chronic hepatitis C virus (HCV) infection. The sustained virological response (SVR) rates, i.e., undetectable HCV RNA levels 24 weeks after the end of treatment, is what differentiate treatments. This analysis evaluated the cost-effectiveness of TVR combined with pegylated interferon (Peg IFN) alfa-2a plus ribavirin (RBV), with Peg-IFN and RBV (PR) alone or with boceprevir (B, BOC) plus Peg-IFN alfa-2b and RBV, in naive patients. METHODS: A Markov cohort model of chronic HCV disease progression reflected the pathway of naive patients initiating anti-HCV therapy. SVR rates were derived from a mixed treatment comparison including results from Phase II and III trials of TVR and BOC, and trials comparing both PR regimens. SVR has significant impact on survival, quality-of-life, and costs. Incremental cost per life year (LY) gained and quality-adjusted-life-year (QALY) gained were computed at lifetime, adopting the (National Health Service) NHS perspective. Cost and health outcomes were discounted at 3.5%. Uncertainty was assessed using deterministic and probabilistic sensitivity analyses. Sub-group analyses were also performed by interleukin (IL)-28B genotype and fibrosis stage. RESULTS: Higher costs and improved outcomes were associated with T/PR relative to PR alone, resulting in an ICER of L12,733 per QALY gained. T/PR retained a significant SVR advantage over PR alone and was cost-effective regardless of IL-28B genotype and fibrosis stages. T/PR regimen 'dominated' B/PR, generating 0.2 additional QALYs and reducing lifetime cost by L2758. Sensitivity analyses consistently resulted in ICERs less than L30,000/QALY for the T/PR regimen over PR alone. LIMITATIONS: No head-to-head trial provides direct evidence of better efficacy of T/PR vs B/PR. CONCLUSION: The introduction of TVR-based therapy for genotype 1 HCV patients is cost-effective for naive patients at the L30,000 willingness-to-pay threshold, regardless of IL-28B genotype or fibrosis stage. PMID- 24160337 TI - Photoconductivities in monocrystalline layered V2O5 nanowires grown by physical vapor deposition. AB - Photoconductivities of monocrystalline vanadium pentoxide (V2O5) nanowires (NWs) with layered orthorhombic structure grown by physical vapor deposition (PVD) have been investigated from the points of view of device and material. Optimal responsivity and gain for single-NW photodetector are at 7,900 A W-1 and 30,000, respectively. Intrinsic photoconduction (PC) efficiency (i.e., normalized gain) of the PVD-grown V2O5 NWs is two orders of magnitude higher than that of the V2O5 counterpart prepared by hydrothermal approach. In addition, bulk and surface controlled PC mechanisms have been observed respectively by above- and below bandgap excitations. The coexistence of hole trapping and oxygen sensitization effects in this layered V2O5 nanostructure is proposed, which is different from conventional metal oxide systems, such as ZnO, SnO2, TiO2, and WO3. PMID- 24160338 TI - [Efficacy of standard antiviral therapy retreatment following interferon treatment failure in chronic hepatitis C patients]. AB - OBJECTIVE: To investigate the therapeutic efficacy of standard antiviral therapy applied after interferon (IFN) treatment failure in patients with chronic hepatitis C (CHC). METHODS: CHC patients who completed a 48-week course of IFN therapy (pegylated (Peg)-IFNa-2a at 180 mug, qw, ih with or without ribavirin (RBV) at 15 mg/kg/w) in our hospital between January 2009 and June 2012 but who showed no response (at week 48) or who relapsed (at week 72) were enrolled in the study. Prior to initiating the 48-week course of retreatment therapy (Peg-IFNa-2a plus RBV as above), the hepatitis C virus (HCV) genotype was detected and the viral load measured (baseline) by PCR of HCV RNA. Each patient's response to therapy was classified as follows: baseline vs. week 4 (rapid virological response, RVR), vs. weeks 12 and 24 (early virological response, EVR), vs. week 48 (end of treatment virological response, ETVR) and vs. week 72 (sustained virological response, SVR). RESULTS: Of the total 235 cases administered retreatment therapy, 60.0% (n = 140) achieved RVR, 77.4% (n = 182) achieved EVR, 83.8% (n = 197) achieved ETVR, 68.0% (n = 68%) achieved SVR, and 15.7% (n = 37) relapsed. Stratification analysis of recurrence (n = 158) and non-responsive (n = 77) sub-groups showed that the recurrence group experienced significantly higher rates of RVR, EVR, ETVR and SVR, but a significantly lower rate of relapse. Stratification analysis of genotype 1b carrier (n = 206) and non-1b carrier (n = 29) sub-groups showed that the 1b carriers had significantly lower rates of RVR, EVR, ETVR and SVR, but a significantly higher rate of relapse. Finally, the patients who achieved RVR (vs. non RVR, n = 95) and EVR (vs. non-EVR, n = 53) showed higher rates of SVR and ETVR. CONCLUSION: CHC patients who fail to respond to the initial course of standard IFN-based therapy may achieve SVR upon retreatment, especially those infected with the HCV genotype 1b. PMID- 24160339 TI - [Hepatitis B virus-mediated effects on host expression of the proprotein convertase Furin]. AB - OBJECTIVE: To study the effects of hepatitis B virus (HBV) infection on the expression of Furin, an important proprotein convertase, in liver cells to provide insights towards its potential as a therapeutic target for improved antiviral efficacy. METHODS: Furin expression was measured in human liver specimens (infected tissues from patients with chronic HBV hepatitis vs. normal tissues from healthy donors) and in hepatoma cell lines (HBV-infected HepG2.2.15 cells vs. uninfected parental cell lines HepG2) using quantitative real-time RT PCR (for mRNA), western blotting and immunohistochemistry (for protein). RESULTS: Compared to the uninfected tissues and cells, the HBV-infected tissue and cells showed down-regulated expression of furin at both the mRNA and protein levels. In particular, the HepG2.2.15 cells showed -50% less furin mRNA expression than the HepG2 cells and the difference was statistically significant (P less than 0.05). CONCLUSION: HBV may suppress the host cell's expression of furin, possibly to benefit its survival and replication in the host cell. PMID- 24160340 TI - [Effects of Ling Qi Juan Gan capsule drug-containing serum on PDGF-induced proliferation and JAK/STAT signaling of HSC-T6 cells]. AB - OBJECTIVE: To analyze the effects of Ling Qi Juan Gan capsule drug-containing serum at different concentrations on the platelet-derived growth factor (PDGF) induced proliferative capabilities of and JAK2 and p-STAT3 protein expression in hepatic stellate cells (HSC) using an in vitro system. METHODS: Twenty-five Sprague-Dawley rats were randomly divided into five equal groups for intragastric administration of physiological saline (10 ml/kg; group A), Fufang Biejia Ruangan tablet solution (1.5 g/kg; group B), or Ling Qi Juan Gan capsule solution at low dose (2.125 g/kg; group C1), mid dose (4.25 g/kg; group C2), or high dose (8.5 g/kg; group C3). The post-administration serum isolated from each rat (200 ml/L) was used to treat the HSC-T6 cell line following induction by PDGF (10 ng/ml). At 24, 48 and 72 h post-exposure, the cells' proliferation was measured using the Cell Counting Kit-8 (CCK-8) colorimetric assay. In addition, at 24 h post exposure the expression of JAK2 and p-STAT3 was measured by western blotting (expressed as grey scale intensity). Multiple group comparison of repeated measures data was made by one-way ANOVA with Student-Newman-Keuls post hoc test. RESULTS: Compared to group A, groups C2 and C3 had significantly higher inhibited proliferation at all post-exposure time points examined (24 h: A = 1.550 +/- 0.065, C2 = 1.335 +/- 0.106, C3 = 1.241 +/- 0.205; 48 h: A = 1.311 +/- 0.650, C2 = 1.090 +/- 0.106, C3 = 0.909 +/- 0.191; 72 h: A = 1.039 +/- 0.103, C2 = 0.719 +/ 0.116, C3 = 0.641 +/- 0.110, F = 36.292, all P less than 0.05); in contrast, compared to group A, group C1 showed no inhibition of proliferation at 24 h (1.522 +/- 0.128, P = 0.717) but showed significantly higher inhibition of proliferation at 48 h and 72 h (1.153 +/- 0.183 and 0.753 +/- 0.210, respectively, F = 36.292, P less than 0.05). Compared with group A, all Ling Qi Juan Gan capsule-containing serum-treated groups showed significantly lower expression of both JAK2 (A = 1.605 +/- 0.024 vs. C1 = 1.170 +/- 0.042, C2 = 0.842 +/- 0.036, C3 = 0.555 +/- 0.036, F = 43.091) and p-STAT3 (A = 1.401 +/- 0.030 vs. C1 = 1.229 +/- 0.025, C2 = 0.668 +/- 0.034, C3 = 0.630 +/- 0.026, F = 78.426, all P less than 0.01). CONCLUSION: Ling Qi Juan Gan capsule drug-containing serum can inhibit the proliferation of HSC-T6 cells in a dose-dependent manner and cause an overall decrease in the expression of JAK2 and p-STAT3 in activated HSC, thereby leading to a suppression of the JAK/STAT signal transduction pathway. PMID- 24160341 TI - [Therapeutic effects of Fuzhenghuayu decoction in a CCl4-induced liver cirrhosis rat model and on hepatic stellate cell activation]. AB - OBJECTIVE: To evaluate the influence of Fuzhenghuayu decoction on fibrotic liver tissue and activated hepatic stellate cells (HSCs) using a carbon tetrachloride (CCl4)-induced liver cirrhosis rat model system. METHODS: Sixty-four Sprague Dawley rats were randomly divided into the following groups: normal (non-model, non-drug intervention), CCl4 liver fibrosis model, and CCl4 liver fibrosis model Fuzhenghuayu drug intervention at low dose (0.75 g/kg/d) and high dose (1.5 g/kg/d). The drug intervention was administered via oral-gastric irrigation once daily for 6 times per week over a 6-week period. Four rats from each group were sacrificed at the end of week 2, 4, and 6 for serum and liver tissue collection. Liver fibrosis was evaluated by histology, and expression of a-smooth muscle actin (a-SMA) was determined by immunohistochemistry. Liver function was assessed by measuring levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), and total bilirubin (TBil). Between-group comparisons were made by completely random design and ANOVA with Bonferroni correction. RESULTS: At the end of weeks 2, 4 and 6, all four groups showed significantly different levels of ALT, AST, and TBil; in addition, the model group and drug intervention groups had significantly higher levels of ALT, AST, and TBil than the control group, the drug intervention groups showed significantly lower levels of ALT, AST, and TBil than the model group (P less than 0.01 or less than 0.05), and the differences between the low dose and high dose groups reached statistical significance (P less than 0.01 or less than 0.05). At the end of weeks 2, 4 and 6, the model group and drug intervention groups had significantly higher area ratio of liver fibrosis than the normal group (F = model: 18.68, low dose: 49.95, high dose: 82.44, P less than 0.01), but the two drug intervention groups had significantly less area ratio of liver fibrosis than the model group (P less than 0.05) and the high dose group showed the most robust decrease. In addition, the model group and drug intervention groups showed higher expression of a-SMA than the normal group (F = model: 18.68, low dose: 49.95, high dose: 82.44, P less than 0.01), but two drug intervention groups had significantly less a-SMA than the model group (F = model: 46.32, low dose: 40.30, high dose: 58.42, P less than 0.05) and the high dose group showed the most robust decrease. CONCLUSION: The Fuzhenghuayu decoction reduces the numbers of activated HSCs, thereby leading to down regulated a-SMA expression and reduced degree of liver fibrosis; these effects may represent the mechanism by which this drug suppresses hepatic fibrosis. PMID- 24160342 TI - [Role of the IGF-1/PI3K pathway and the molecular mechanism of Fuzhenghuayu therapy in a spontaneous recovery rat model of liver fibrosis]. AB - OBJECTIVE: To determine the role of IGF-1/PI3K pathway and investigate the molecular mechanism of Fuzhenghuayu (FZHY) therapy in a spontaneous recovery rat model of liver fibrosis. METHODS: The liver fibrosis model was induced in male Wistar rats by administering 8 weeks of twice weekly CCL4 intraperitoneal injections without (untreated model) or with once daily FZHY (treated model). Normal, untreated rats served as the control group. At weeks 4, 6 and 8 (fibrosis) and 10, 12 and 14 (spontaneous recovery) after modeling initiation, effects on protein (a-SMA, IGF-1, PI3K) and mRNA (IGF-1, PI3K) expression levels were evaluated by immunohistochemistry and RT-PCR, respectively. Serum markers of liver function (alanine aminotransferase (ALT) and aspartate aminotransferase (AST)) and liver cell damage (alkaline hydrolysis, HYP) were measured. Histology was performed to assess the degree of inflammation and fibrosis (Ishak scoring system). RESULTS: In the untreated model group, progression of liver fibrosis (weeks 4, 6 and 8) was accompanied by gradual increases in inflammation, necrosis, serum ALT and AST, and hepatic expression of a-SMA protein and IGF-1 and PI3K protein and mRNA; however, during the spontaneous recovery period (weeks 10, 12 and 14) the IGF-1 and PI3K protein and mRNA levels rapidly decreased and the HYP level, Ishak score, and a-SMA hepatic expression also decreased. The FZHY treated model group showed significantly lower fibrosis-related up-regulation of IGF-1 and PI3K protein and mRNA expression, HYP level, Ishak score, and a-SMA hepatic expression at each time point (vs. untreated model group). CONCLUSION: The IGF-1/PI3K pathway may contribute to progression of liver fibrosis. The mechanism by which FZHY prevents liver fibrosis in a rat model may involve blocking of the IGF/PI3K pathway and inhibiting HSC activation. PMID- 24160343 TI - [Relationship between metastasis or recurrence of hepatocellular carcinoma and hepatitis B virus DNA or double mutation at 1762/1764 in the basic core promoter]. AB - OBJECTIVE: To study the relationship between metastasis or recurrence of hepatocellular carcinoma (HCC) and hepatitis B virus (HBV) DNA load or the presence of double mutation at 1762/1764 in the basic core promoter (BCP). METHODS: One-hundred-and-fifty-seven patients with HCC were included in the study. Events of tumor metastasis or recurrence were recorded during 120 weeks of clinical follow-up after treatment by surgery or transarterial chemoembolization (TACE). The 1-year follow-up included monthly alpha fetoprotein (AFP) measurement and abdominal ultrasonography (US), as well as helical computed tomographic (CT) scan performed every 3 months. Follow-up beyond 1-year (surveillance) included AFP measurement and abdominal US every 2 months and helical CT scan every 6 months. Suspected metastasis or recurrence was investigated by hepatic angiography and confirmed according to the combined imaging findings. Serum HBV DNA level was measured by real-time PCR. HBV genotypes were determined by PCR restriction fragment length polymorphism analysis. RESULTS: Of the 157 HCC cases 110 experienced tumor metastasis or recurrence; the cumulative probability of post-treatment HCC metastasis or recurrence was 4 (2.55%) at week 12, 14 (8.92%) at week 24, 28 (17.83%) at week 48, 64 (40.76%) at week 72, 92 (58.60%) at week 96, and 110 (70.06%) at week 120. Multivariate analysis indicated that both the BCP 1762/1764 double mutations and HBV DNA levels were risk factors for HCC recurrence or metastasis. In particular, the incidence of HCC recurrence or metastasis increased with baseline serum HBV DNA levels in a dose-response manner, ranging from 8/19 (42.1%) for less than 3 log10 copies/ml HBV DNA to 35/61 (57.3%) for 3-5 log10 copies/ml and 67/77 (87.0%) for more than 5 log10 copies/ml. After adjusting for potential confounders, serum HBV DNA level remained independently associated with HCC metastasis or recurrence. HCC recurrence or metastasis occurred in 22/43 (51.2%) of patients without BCP 1762/1764 mutations and 88/114 (77.2%) of patients with BCP 1762/1764 mutations. The adjusted odds ratio for patients infected with BCP 1762/1764 double mutation HBV, compared with those infected with non-BCP 1762/1764 mutation HBV, was 5.264 (95% CI: 1.436-12.574, P less than 0.05). CONCLUSION: Infection with HBV carrying the BCP 1762/1764 double mutation and presence of high HBV DNA load are independent risk factors for developing HCC metastasis or recurrence after surgery or TACE. PMID- 24160344 TI - [Hepatocellular carcinoma and angiogenesis imaging using synchrotron radiation]. AB - OBJECTIVE: To investigate the potential utility of microangiography with synchrotron radiation to detect murine hepatocellular carcinoma (HCC) angiogenesis using an ex vivo model system. METHODS: An HCC xenograft model was established by implanting HCCLM3 cells into male mice livers (n = 6). Twenty eight days later, three of the mice were randomly selected for barium sulfate infusion into the liver and tumor via the inferior vena cava followed by ligation of the arteries, veins and common bile duct; the remaining three mice were left untreated and served as controls. All mice were sacrificed to collect livers for analysis using the BL13W beamline X-ray imager (Shanghai Synchrotron Radiation Facility, China). In addition, the tumor vasculature was evaluated by immunostaining of formalin-fixed tissues for CD31, CD34, and F8. RESULTS: High resolution images of tumor angiogenesis were acquired and image analysis indicated that the normal blood vessels had been displaced by the fast growing tumors. Abundant and tortuous tumor angiogenesis in the tumor periphery area and sparse angiogenesis inside the tumor were also visualized clearly. These features were similar to the immunohistological results. The smallest tumor vessels visualized were approximately 20 mum in diameter. CONCLUSION: Microangiography with synchrotron radiation using barium sulfate as contrast agent is a viable imaging strategy for tumor angiogenesis. PMID- 24160345 TI - [Expression of CD90/EpCAM/CD24 in hepatocellular carcinoma cell lines at various stages of differentiation]. AB - OBJECTIVE: To confirm the malignant phenotype of hepatocarcinoma cell (HCC) lines at various stages of differentiation (MHCC97L, MHCC97H and HCCLM3) and to explore their expression levels of cancer stem cell (CSC) markers. METHODS: The invasive and proliferative properties of each HCC line were assessed by transwell assay and the Cell Counting Kit-8 (CCK-8) colorimetric assay. Sensitivity to chemotherapy was assessed by treatment with oxaliplatin and determination of the half inhibitory concentration (IC50). The expression of CD90, EpCAM and CD24 was measured by flow cytometry. RESULTS: The number of cells that migrated through the invasion assay membrane were significantly different between the three HCC lines: HCCLM3 (30.57 +/- 8.95) more than MHCC97H (21.33 +/- 4.17) more than HCC97L (9.33 +/- 3.85), P less than 0.01. The IC50 was significantly different between the three HCC lines: HCCLM3 (36.57 +/- 6.95) mumol/L more than MHCC97H (26.35+/-3.88) mumol/L more than MHCC97L (17.68 +/- 3.25) mumol/L. The CSC marker with the highest expression on all three HCC lines was CD90 (HCCLM3: 0.92% +/- 0.21%, MHCC97H: 1.98% +/- 0.23%, and MHCC97L: 2.55% +/- 0.34%), followed by EpCAM (2.11% +/- 0.32%, 3.23% +/- 0.18%, and 4.38% +/-0.49%, respectively), and CD24 as the lowest (0.68% +/- 0.37%, 1.22% +/- 0.26%, and 1.36% +/- 0.24%, respectively). CONCLUSION: Higher expression of CSC markers on HCC lines is associated with a stronger invasive ability and higher sensitivity to chemotherapy. PMID- 24160346 TI - [Therapeutic efficacy of endoscopic variceal ligation to treat gastric varices: a study of 63 consecutive cases]. AB - OBJECTIVE: To investigate the therapeutic efficacy of endoscopic variceal ligation (EVL) for treating various types of gastric varices (GV) by reviewing patient cases in order to identify the influencing factors of EVL-related recurrence and rebleeding. METHODS: The medical records of 101 GV cases treated by EVL in our department between January 2008 and October 2012 were retrospectively reviewed. The cases were grouped according to GV type: type 1 (GOV1, n = 63), type 2 (GOV2, n = 18), GOV1 coexisting with GOV2 (n = 11), isolated GOV1 (IGV1, n = 9), and GOV2 (IGV2, n = 0). Data from follow-up examinations (range: 1.5 - 48.0 months, average: 14.9 +/- 9.1 months) were extracted for analysis and included early (less than 72 h after EVL) and late (72 h to 6 weeks after EVL) rebleeding and recurrence. In addition, data from computed tomography (CT) or CT angiography (CTA), performed in 32 of the patients, were extracted to determine the influence of supplying veins, gastrorenal or splenorenal shunts, and portal vein and/or splenic vein diameters on GV recurrence. Data analysis was carried out by ANOVA, Chi-square, Fisher's exact or rank-sum tests, as appropriate. Kaplan-Meier analysis was used to evaluate the time of first recurrent bleeding, and the log-rank test was used to compare between-group differences. RESULTS: GOV2 and IGV1 varices were more severe than the varices of GOV1 (GOV2 and GOV1: u = -2.960; IGV1 and GOV1: u = 2.871; both P less than 0.05). GOV1 had a significantly lower recurrence rate than all other GV types (x2 = 7.054, P less than 0.05). The CT and CTA data indicated that all GV were supplied by left gastric veins, while 83.3% of IGV1 had blood supplementation by left gastric veins and short gastric or posterior gastric veins, and 100% of IGV1 had gastrorenal or splenorenal shunts. Approximately one-half of the total GV cases (56.3%, 18/32) had gastrorenal or splenorenal shunts, and this parameter was correlated with portal vein diameter (t = -2.766, P less than 0.05). The presence of gastrorenal or splenorenal shunts was correlated with both recurrence and rebleeding (P less than 0.05). CONCLUSION: EVL can effectively control bleeding and prevent rebleeding for GV; although, the best therapeutic efficacy and lowest rate of recurrence was achieved in GOV1 cases. The presence of gastrorenal or splenorenal shunts increases the risk of GV recurrence. PMID- 24160347 TI - [Clinical characteristics of the adaptive phenomenon of antituberculosis drug induced liver injury]. AB - OBJECTIVE: To investigate the clinical characteristics of the adaptation phenomenon occurring in antituberculosis drug-induced liver injury. METHODS: Our department's clinical records were searched using the standardized diagnostic criteria and monitoring programs parameters of drug-induced liver injury to identify cases with the adaptation phenomenon. The 32 identified cases were classified according to whether or not the drug was discontinued after development of the drug-induced liver injury: withdrawal group (n = 11) and continuing group (n = 21). The types of patients with adaptation phenomenon were assessed to determine the relationship between liver injury and development time, and between the severity grade of liver injury (determined by biomarker expression) and symptoms. RESULTS: All of the 32 cases of drug-induced liver injury with the adaptation phenomenon were classified as the hepatocellular injury type. The average overall incubation period was 16.59+/-13.05 days (range: 6-60 days), while that of the continuing group was 17.05 +/-13.71 days (6-60 days) and that of the withdrawal group was 16.46+/-12.09 days (6-43 days). The average overall time for peak transaminase levels to decrease to the normal range was 11.34 +/-5.97 days (6-30 days), while that of the continuing group was 11.20+/-5.92 days (6-30 days) and that of the withdrawal group was 11.91/-6.20 days (7-30 days). Thirty of the overall patients showed grade 1 degree of liver injury and only two showed grade 2. CONCLUSION: The clinical characteristics of the adaptation phenomenon include a transient increase in biochemical indicators of the antituberculosis drug-induced liver injury. It is important to understand the clinical variations in the adaptation phenomenon to formulate feasible and appropriate programs for monitoring and prevention. PMID- 24160349 TI - [New oral anticoagulants (NOACs): happy or not happy?]. PMID- 24160348 TI - [Lung expression of tissue factor mRNA and its significance in a rat model of hepatopulmonary syndrome]. AB - OBJECTIVE: To determine the lung expression of tissue factor (TF) mRNA in hepatopulmonary syndrome (HPS) using a rat model system and to investigate the potential significance of its differential expression. METHODS: Forty male Sprague-Dawley rats were used to establish models of cirrhosis (n = 20) and HPS (n = 20). Blood gas analysis was used to investigate the effects of each model on pulmonary function. Effects on the expression of TF mRNA in lung were determined by qRT-PCR and on lung pathology by histological analysis. RESULTS: The HPS rats showed significantly lower PaO2 than the cirrhosis rats (58.20 +/- 3.19 mmHg vs. 85.00 +/- 2.53 mmHg, P less than 0.05) but significantly higher TF mRNA expression in lung (0.77 +/- 0.22 vs. 0.33 +/- 0.14, P less than 0.05). TF mRNA expression was negatively correlated with the value of PaO2 (r = -0.565, P less than 0.05). The lungs of the cirrhosis rats showed widened alveolar intervals, diversified sizes of alveolar spaces, reduced lung capacity, inflammatory cell infiltration, and hyperemia in the pulmonary vessels. The lungs of the HPS rats showed all of the same changes but also with accumulated macrophages and micro thrombosis in the pulmonary vessels. Among the HPS rats, those with micro thrombosis in pulmonary vessels showed a greater increase in TF mRNA expression than those without (0.68 +/- 0.17 vs. 0.40 +/- 0.12, P less than 0.05). CONCLUSION: The expression of TF mRNA in lung of hepatopulmonary syndrome model rats was elevated and might increase the incidence of thromboembolism in the lung. PMID- 24160350 TI - Synthesis and evaluation of a (18)F-labeled diarylpyrazole glycoconjugate for the imaging of NTS1-positive tumors. AB - Aiming to image NTS1 overexpressing tumors, the diarylpyrazole glycoconjugate 8, derived from the potent NTS1 antagonist SR142948A, was synthesized taking advantage of the palladium-catalyzed aminocarbonylation reaction. The glycoconjugate 8 displayed excellent affinity and selectivity toward NTS1. Radiosynthesis proceeded straightforwardly, obtaining [(18)F]8 with excellent stability and highly beneficial biodistribution in vivo as demonstrated by PET imaging in HT29 tumor-bearing nude mice. Thus, the tracer [(18)F]8 represents a highly promising candidate for PET imaging of NTS1-positive tumors. PMID- 24160352 TI - The head of the pancreas: another unusual site of coccidioidomycosis. AB - BACKGROUND: The lung is the most common site of coccidioidomycosis, with extrapulmonary sites of infection being described rarely. To date, the pancreas has not been reported as an isolated site of coccidioidomycosis. METHODS: Case report and literature review. CASE REPORT: Computed tomography (CT)-guided biopsy and gram staining of the pancreatic lesion of an immunocompetent patient without known risk factors revealed coccidioidomycosis of the head of the pancreas without malignant neoplasm or atypia. Serologic tests yielded positive titers for antibodies to Coccidioides lmmitis. The patient responded to treatment with fluconazole, as evidenced by regression of her pancreatic lesion by CT and negative serologic test results for Coccidioides upon completion of treatment. CONCLUSIONS: Solid masses in the head of the pancreas encountered in surgical practice are challenging in terms of both surgical technique and diagnosis. Although malignant disease remains a high possibility in the differential diagnosis of such masses, and must always be considered until proved to be absent, non-malignant etiologies should also be considered. In a number of patients with benign lesions of the pancreatic head, unnecessary surgical exploration and resection is avoidable. Although they are rare, several fungal infections of the pancreas have been reported in the literature. The unusual case of coccidioidomycosis of the pancreatic head presented here adds to the list of uncommon causes of pancreatic lesions. Surgeons and physicians managing patients in areas in which coccidioidomycosis is endemic should be aware of this rare entity. PMID- 24160351 TI - High-throughput sequencing of small RNA transcriptomes reveals critical biological features targeted by microRNAs in cell models used for squamous cell cancer research. AB - BACKGROUND: The implication of post-transcriptional regulation by microRNAs in molecular mechanisms underlying cancer disease is well documented. However, their interference at the cellular level is not fully explored. Functional in vitro studies are fundamental for the comprehension of their role; nevertheless results are highly dependable on the adopted cellular model. Next generation small RNA transcriptomic sequencing data of a tumor cell line and keratinocytes derived from primary culture was generated in order to characterize the microRNA content of these systems, thus helping in their understanding. Both constitute cell models for functional studies of microRNAs in head and neck squamous cell carcinoma (HNSCC), a smoking-related cancer. Known microRNAs were quantified and analyzed in the context of gene regulation. New microRNAs were investigated using similarity and structural search, ab initio classification, and prediction of the location of mature microRNAs within would-be precursor sequences. Results were compared with small RNA transcriptomic sequences from HNSCC samples in order to access the applicability of these cell models for cancer phenotype comprehension and for novel molecule discovery. RESULTS: Ten miRNAs represented over 70% of the mature molecules present in each of the cell types. The most expressed molecules were miR-21, miR-24 and miR-205, Accordingly; miR-21 and miR-205 have been previously shown to play a role in epithelial cell biology. Although miR-21 has been implicated in cancer development, and evaluated as a biomarker in HNSCC progression, no significant expression differences were seen between cell types. We demonstrate that differentially expressed mature miRNAs target cell differentiation and apoptosis related biological processes, indicating that they might represent, with acceptable accuracy, the genetic context from which they derive. Most miRNAs identified in the cancer cell line and in keratinocytes were present in tumor samples and cancer-free samples, respectively, with miR-21, miR 24 and miR-205 still among the most prevalent molecules at all instances. Thirteen miRNA-like structures, containing reads identified by the deep sequencing, were predicted from putative miRNA precursor sequences. Strong evidences suggest that one of them could be a new miRNA. This molecule was mostly expressed in the tumor cell line and HNSCC samples indicating a possible biological function in cancer. CONCLUSIONS: Critical biological features of cells must be fully understood before they can be chosen as models for functional studies. Expression levels of miRNAs relate to cell type and tissue context. This study provides insights on miRNA content of two cell models used for cancer research. Pathways commonly deregulated in HNSCC might be targeted by most expressed and also by differentially expressed miRNAs. Results indicate that the use of cell models for cancer research demands careful assessment of underlying molecular characteristics for proper data interpretation. Additionally, one new miRNA-like molecule with a potential role in cancer was identified in the cell lines and clinical samples. PMID- 24160353 TI - Drug repositioning from bench to bedside: tumour remission by the antihelmintic drug mebendazole in refractory metastatic colon cancer. PMID- 24160354 TI - Remarkable catalytic property of nanoporous gold on activation of diborons for direct diboration of alkynes. AB - A novel catalytic property of nanoporous gold for activation of bis(pinacolato)diboron has been reported that allows the direct diboration of alkynes to proceed sufficiently in a heterogeneous process. The experimental results revealed that the nanoporous gold catalyst is able to cleave the B-B bond of bis(pinacolato)diboron without using any additives. PMID- 24160355 TI - Intravitreal injections and diabetic macular edema: actual and new therapeutic options. AB - The management of diabetic macular edema (DME) has been revolutionized in recent years. Focal and focal/ grid laser photocoagulation have been the mainstay of treatment for DME for much time. However, nowadays, there is growing evidence that intravitreal VEGF-inhibitors (combined or not with laser photocoagulation) provide better visual outcome in patients with diabetic retinopathy. Hence, anti VEGF injections are considered the new gold standard to treat diabetic macular edema and eyes with a reduced visual function. Further studies assessing different treatment regimens are underway to define better clinical care pathways. PMID- 24160356 TI - Status of stem cell based clinical trials in the treatment for diabetes. AB - Rapidly increasing number of diabetic patients across the world is a great challenge to the current therapeutic approach. Although the traditional method of rendering exogenous insulin is an established method of treatment, it is not sufficient and often causes lethal hypoglycemia. There is also a good amount of success with whole organ transplantation or Islet cells' transplantation. But this technique is limited with regards the availability of donors. Currently, many clinicians and researchers are involved in clinical studies using various different stem cells from embryonic as well as adult sources for the treatment of diabetes. In this review we have tried to discuss the results of various clinical trials using stem cells. We have also tried to look at various stem cell types and the routes of injections that are currently being followed world wide. PMID- 24160357 TI - Type 2 diabetes mellitus and Invokana: an FDA approved drug. AB - Diabetes Mellitus is a chronic metabolic disease affecting wide range of people across the globe. In India the rate of subjects being suffered from diabetes is continuously increasing. So, the development of drugs for its effective treatment is essential. Thereby, various attempts have been made to discover newer drugs, to reduce the rate of anti diabetic occurrence. Anti-diabetic drugs were found to treat diabetes mellitus by lowering glucose levels in the blood. Both the use antidiabetic drugs as well as the changes in lifestyle and proper diet can significantly affect the severity of diabetes mellitus and also reduces the symptoms and occurrence of the disease. Researches in the past few years on diabetes mellitus showed that this disease is spreading at a very faster rate, thereby; various attempts have been made to treat it efficaciously. Development and approval of antidiabetic drugs is quite necessary. There are different classes of anti-diabetic drugs reported to treat diabetes. The objective of the present review is to explore Invokana as a newly approved antidiabetic drug for the effective treatment of type 2 diabetes. This review focuses mainly on the various aspects of diabetes mellitus and its treatment perspectives. From the various clinical studies done on Invokana, it was concluded that and Invokana was found to be very effective for the efficacious therapy of diabetes mellitus. PMID- 24160358 TI - Pedometer-based walking interventions for free-living adults with type 2 diabetes: a systematic review. AB - Physical activity (PA) is prescribed as an important method of treatment for type 2 diabetes (T2DM), but is neglected in a majority of patients. Walking is an appropriate and safe form of PA which improves glucose utilization in inactive people diagnosed with T2DM. Pedometers have been successfully used to motivate and track progress in many types of walking programs, but there is no current review of their effectiveness compared to other methods to increase PA in people with T2DM. A systematic literature review was performed using MEDLINE, CINAHL, SPORTDiscus, ERIC, and Academic Search Premier to determine the effectiveness of pedometer-based walking interventions at increasing PA in free-living adults with T2DM. Ten studies from 2004 to 2011 were included. All studies were randomized controlled trials except for one quasi-experimental design. Interventions lasted from 6 weeks to 6 months and only 2 studies showed significant improvements in blood glucose control following the intervention. Nine of the ten interventions were able to produce an increase in PA using a pedometer and/or other methods. Pedometers are effective means of increasing PA among T2DM patients in the short term while several other intervention methods beyond normal treatment are also successful. Future research should include longer intervention durations, low cost methods, larger sample sizes, and dietary intervention components to further understand successful intervention techniques for patients with T2DM. PMID- 24160359 TI - Breastfeeding throughout pregnancy in Turkish women. AB - INTRODUCTION: Around the world, as well as in Turkey, women breastfeed their infants as long as possible. There is, however, a strong cultural taboo against continuing breastfeeding while having a new pregnancy. The aim of this study was to evaluate the outcome of pregnancies occurring during the lactation period and to determine whether lactation throughout the pregnancy had any adverse effects. This is the first study in Turkey to provide data on the association between the practice of lactation throughout pregnancy and outcome. SUBJECTS AND METHODS: One hundred sixty-five multiparous women with singleton pregnancies who were >= 18 years of age, breastfeeding the previous child, and did not have systemic disease were included. Forty-five of the 165 pregnant women continued lactating, whereas 120 did not. We compared weight gain during pregnancy, hemoglobin level alterations, pregnancy complications, neonatal weight, and Apgar scores between the two groups. RESULTS: Lactating pregnant women gained less weight than the nonlactating group, and the decreased level of hemoglobin during pregnancy was significant in the lactating group. Between the two groups, there was no statistically significant difference in hyperemesis gravidarum, threatened abortion, preeclampsia, premature labor and birth, neonatal weight, or Apgar scores. CONCLUSIONS: Breastfeeding during pregnancy is not harmful, and health professionals should not advise weaning if overlapping occurs and should observe mother, infant, and fetus closely for negative effects, and if a negative effect occurs they should take precautions. PMID- 24160360 TI - Concentrations of immunoglobulin A, interleukin-6, and tumor necrosis factor in breastmilk of adolescent and adult mothers in Quito, Ecuador: a cohort study. PMID- 24160361 TI - Surface microanalysis and chemical imaging of early dentin remineralization. AB - This study reports physical and chemical changes that occur at early dentin remineralization stages. Extracted human third molars were sectioned to obtain dentin discs. After polishing the dentin surfaces, three groups were established: (1) untreated dentin (UD), (2) 37% phosphoric acid application for 15 s (partially demineralized dentin-PDD), and (3) 10% phosphoric acid for 12 h at 25 degrees C (totally demineralized dentin-TDD). Five different remineralizing solutions were used: chlorhexidine (CHX), artificial saliva (AS), phosphate solution (PS), ZnCl2, and ZnO. Wettability (contact angle), zeta potential and Raman spectroscopy analysis were determined on dentin surfaces. Demineralization of dentin resulted in a higher contact angle. Wettability decreased after immersion in all solutions. zeta potential analysis showed dissimilar performance ranging from -6.21 mV (TDD + AS) up to 3.02 mV (PDD + PS). Raman analysis showed an increase in mineral components after immersing the dentin specimens, in terms of crystallinity, mineral content, and concentration. This confirmed the optimal incorporation and deposition of mineral on dentin collagen. Organic content reflected scarce changes, except in TDD that appeared partially denatured. Pyridinium, as an expression of cross-linking, appeared in all spectra except in specimens immersed in PS. PMID- 24160362 TI - Transient anterior subcapsular vacuolar change of the crystalline lens in patients after posterior chamber phakic intraocular lens implantation. AB - BACKGROUND: We present two cases of transient vacuolar changes in the anterior subcapsular space of the crystalline lens in patients after posterior chamber phakic intraocular lens implantation. CASE PRESENTATION: Implantable collamer lenses (ICL) were implanted in healthy myopic patients. Vacuolar changes developed just after the irrigating procedure through the narrow space between the ICL and the crystalline lens. Slit-lamp examinations and spectral domain optical coherence tomography showed bleb-like lesions in the anterior subcapsular space of one eye in each case, though the lesions gradually improved without visual deterioration. Consequently, the lesions turned into a few anterior subcapsular small faint opacities. CONCLUSION: Direct irrigation of the narrow space confined by the ICL and the crystalline lens is at risk for the development of vacuolar changes in the crystalline lens. The observed spontaneous reversal indicates that surgeons should not rush to surgical intervention but rather opt for close follow over several weeks. PMID- 24160363 TI - Silver-mediated oxidative C-H/P-H functionalization: an efficient route for the synthesis of benzo[b]phosphole oxides. AB - A Ag-mediated C-H/P-H functionalization reaction of arylphosphine oxides with internal alkynes was described for the direct preparation of benzo[b]phosphole oxides with a high yield. An unusual aryl migration on the P-atom derived from a C-P bond cleavage and a new C-P bond formation was also observed and demonstrated to proceed via the radical process. PMID- 24160364 TI - Why do patients discontinue antidepressant therapy early? A qualitative study. AB - BACKGROUND: Current guidelines for antidepressant prescribing are that treatment should be continued following the resolution of symptoms: six months after a first episode and for at least two years for those with previous episodes. Despite this, sub-optimal treatment duration still predominates. Patients have negative and positive views on antidepressants, which change throughout their treatment journey. OBJECTIVES: To explore views and experiences of patients recently initiated on antidepressants (within six months), and to consider the influences on early discontinuation. METHODS: A qualitative interview study was used in four general practices in the North East of Scotland. A purposive sample of primary care patients, newly initiated on antidepressants, was interviewed to explore views and experiences with antidepressant therapy. Interviews were audio recorded and transcribed verbatim. Thematic analysis was conducted using a consensus coding frame developed by two researchers. RESULTS: Twenty-nine patients participated. Three main factors influencing discontinuation were identified: ownership, knowledge and support. The treatment journey was characterized by four important time points where health care intervention may be helpful. CONCLUSION: Health care professionals would benefit from exploring patient knowledge and views on depression and antidepressants at an early stage in treatment. Patients would welcome active involvement in treatment decision making, the provision of information and ongoing support. PMID- 24160368 TI - A school based study of psychological disturbance in children following the Omagh bomb. AB - OBJECTIVE: To assess the extent and nature of psychiatric morbidity among children (aged 8 to 13 years) 15 months after a car bomb explosion in the town of Omagh, Northern Ireland. METHOD: A survey was conducted of 1945 school children attending 13 schools in the Omagh district. Questionnaires included demographic details, measures of exposure, the Horowitz Impact of Events Scale, the Birleson Self-Rating Depression Scale, and the Spence Children's Anxiety Scale. RESULTS: Children directly exposed to the bomb reported higher levels of probable PTSD (70%), and psychological distress than those not exposed. Direct exposure was more closely associated with an increase in PTSD symptoms than in general psychiatric distress. Significant predictors of increased IES scores included being male, witnessing people injured and reporting a perceived life threat but when co-morbid anxiety and depression are included as potential predictors anxiety remains the only significant predictor of PTSD scores. CONCLUSIONS: School-based studies are a potentially valuable means of screening and assessing for PTSD in children after large-scale tragedies. Assessment should consider type of exposure, perceived life threat and other co-morbid anxiety as risk factors for PTSD. PMID- 24160369 TI - beta-Sitosterol induces G1 arrest and causes depolarization of mitochondrial membrane potential in breast carcinoma MDA-MB-231 cells. AB - BACKGROUNDS: It is suggested that dietary phytosterols, such as beta-sitosterol (ST), have cancer chemopreventive effects; however, studies are limited to support such claims. Here, we evaluated the efficacy of ST on three different human cancer cell lines including skin epidermoid carcinoma A431 cells, lung epithelial carcinoma A549 cells and breast adenocarcinoma MDA-MB-231. METHODS: Cell growth assay, cell cycle analysis, FACS, JC-1 staining, annexin V staining and immunoblotting were used to study the efficacy of ST on cancer cells. RESULTS: ST (30-90 MUM) treatments for 48 h and 72 h did not show any significant effect on cell growth and death in A431 cells. Whereas similar ST treatments moderately inhibited the growth of A549 cells by up to 13% (p <= 0.05) in 48 h and 14% (p <= 0.05-0.0001) in 72 h. In MDA-MB-231 cells, ST caused a significant dose-dependent cell growth inhibition by 31- 63% (p <= 0.0001) in 48 h and 40-50% (p <= 0.0001) in 72 h. While exploring the molecular changes associated with strong ST efficacy in breast cancer cells, we observed that ST induced cell cycle arrest as well as cell death. ST caused G0/G1 cell cycle arrest which was accompanied by a decrease in CDK4 and cyclin D1, and an increase in p21/Cip1and p27/Kip1 protein levels. Further, cell death effect of ST was associated with induction of apoptosis. ST also caused the depolarization of mitochondrial membrane potential and increased Bax/Bcl-2 protein ratio. CONCLUSIONS: These results suggest prominent in vitro anti-proliferative and pro-apoptotic effects of ST in MDA-MB-231 cells. This study provides valuable insight into the chemopreventive efficacy and associated molecular alterations of ST in breast cancer cells whereas it had only moderate efficacy on lung cancer cells and did not show any considerable effect on skin cancer cells. These findings would form the basis for further studies to understand the mechanisms and assess the potential utility of ST as a cancer chemopreventive agent against breast cancer. PMID- 24160370 TI - Coupling of HPLC with electrospray ionization mass spectrometry for studying the aging of ultrasmall multifunctional gadolinium-based silica nanoparticles. AB - Sub-5 nm multimodal nanoparticles have great potential for theranostic applications due to their easy renal elimination combined with complementary imaging properties and therapeutic facilities. Their potential clinical use requires the full characterization of not only the nanoparticle but also all its possible degradation products. We have recently proposed new ultrasmall gadolinium-based nanoparticles for multimodal imaging and radiosensitization. The aim of this article is to describe an analytical tool to characterize degradation products in a highly diluted medium. We demonstrate that HPLC coupled to electrospray ionization mass spectrometry (ESI-MS) can be used in order to determine precisely the composition of nanoparticles and their degradation fragments during aging. PMID- 24160373 TI - Compressibility of porous TiO2 nanoparticle coating on paperboard. AB - Compressibility of liquid flame spray-deposited porous TiO2 nanoparticle coating was studied on paperboard samples using a traditional calendering technique in which the paperboard is compressed between a metal and polymer roll. Surface superhydrophobicity is lost due to a smoothening effect when the number of successive calendering cycles is increased. Field emission scanning electron microscope surface and cross-sectional images support the atomic force microscope roughness analysis that shows a significant compressibility of the deposited TiO2 nanoparticle coating with decrease in the surface roughness and nanoscale porosity under external pressure. PACS: 61.46.-w; 68.08.Bc; 81.07.-b. PMID- 24160372 TI - Algorithm for automatic analysis of electro-oculographic data. AB - BACKGROUND: Large amounts of electro-oculographic (EOG) data, recorded during electroencephalographic (EEG) measurements, go underutilized. We present an automatic, auto-calibrating algorithm that allows efficient analysis of such data sets. METHODS: The auto-calibration is based on automatic threshold value estimation. Amplitude threshold values for saccades and blinks are determined based on features in the recorded signal. The performance of the developed algorithm was tested by analyzing 4854 saccades and 213 blinks recorded in two different conditions: a task where the eye movements were controlled (saccade task) and a task with free viewing (multitask). The results were compared with results from a video-oculography (VOG) device and manually scored blinks. RESULTS: The algorithm achieved 93% detection sensitivity for blinks with 4% false positive rate. The detection sensitivity for horizontal saccades was between 98% and 100%, and for oblique saccades between 95% and 100%. The classification sensitivity for horizontal and large oblique saccades (10 deg) was larger than 89%, and for vertical saccades larger than 82%. The duration and peak velocities of the detected horizontal saccades were similar to those in the literature. In the multitask measurement the detection sensitivity for saccades was 97% with a 6% false positive rate. CONCLUSION: The developed algorithm enables reliable analysis of EOG data recorded both during EEG and as a separate metrics. PMID- 24160371 TI - A process for Decision-making after Pilot and feasibility Trials (ADePT): development following a feasibility study of a complex intervention for pelvic organ prolapse. AB - BACKGROUND: Current Medical Research Council (MRC) guidance on complex interventions advocates pilot trials and feasibility studies as part of a phased approach to the development, testing, and evaluation of healthcare interventions. In this paper we discuss the results of a recent feasibility study and pilot trial for a randomized controlled trial (RCT) of pelvic floor muscle training for prolapse (ClinicalTrials.gov: NCT01136889). The ways in which researchers decide to respond to the results of feasibility work may have significant repercussions for both the nature and degree of tension between internal and external validity in a definitive trial. METHODS: We used methodological issues to classify and analyze the problems that arose in the feasibility study. Four centers participated with the aim of randomizing 50 women. Women were eligible if they had prolapse of any type, of stage I to IV, and had a pessary successfully fitted. Postal questionnaires were administered at baseline, 6 months, and 7 months post-randomization. After identifying problems arising within the pilot study we then sought to locate potential solutions that might minimize the trade off between a subsequent explanatory versus pragmatic trial. RESULTS: The feasibility study pointed to significant potential problems in relation to participant recruitment, features of the intervention, acceptability of the intervention to participants, and outcome measurement. Finding minimal evidence to support our decision-making regarding the transition from feasibility work to a trial, we developed a systematic process (A process for Decision-making after Pilot and feasibility Trials (ADePT)) which we subsequently used as a guide. The process sought to: 1) encourage the systematic identification and appraisal of problems and potential solutions; 2) improve the transparency of decision-making processes; and 3) reveal the tensions that exist between pragmatic and explanatory choices. CONCLUSIONS: We have developed a process that may aid researchers in their attempt to identify the most appropriate solutions to problems identified within future pilot and feasibility RCTs. The process includes three key steps: a decision about the type of problem, the identification of all solutions (whether addressed within the intervention, trial design or clinical context), and a systematic appraisal of these solutions. PMID- 24160374 TI - Does generic entry lower the prices paid for pharmaceuticals in Australia? A comparison before and after the introduction of the mandatory price-reduction policy. AB - OBJECTIVE: We investigated the relationship between the number of generic medicines and pharmaceutical prices over time in Australia. METHODS: A dataset was utilised containing 76 items for 4 years (2003-2007) on the national subsidy scheme - the Pharmaceutical Benefits Scheme (PBS) - for which a generic brand is available. The PBS price was used as the dependent variable, and the number of generics available the key explanatory variable. The ordinary least-squares estimator was adopted for estimation. In the robustness analysis, an instrumental variables method was used to account for potential endogeneity. RESULTS: Results suggested that the effect of increased generic medicine sellers on reducing the prices paid for generics is marginal but statistically significant. CONCLUSIONS: It is suggested that structural changes to the way generic prices are determined needs to be reconsidered by the Australian government if the policy aim of using increased 'competition' to lower prices is to be maximised. PMID- 24160375 TI - Forfeited hepatogenesis program and increased embryonic stem cell traits in young hepatocellular carcinoma (HCC) comparing to elderly HCC. AB - BACKGROUND: Hepatocellular carcinoma (HCC) in young subjects is rare but more devastating. We hypothesize that genes and etiological pathways are unique to young HCC (yHCC; <= 40 years old at diagnosis) patients. We therefore compared the gene expression profiles between yHCCs and HCCs from elderly patients. RESULTS: All 44 young HCCs (<= 40 years old at the diagnosis; 23 cases in the training set while another 21 in the validation cohort) were positive for serum hepatitis B surface antigen (HBsAg), but negative for antibodies to hepatitis C virus (anti-HCV). All 48 elderly (>40 years old; 38 in the training set while another 10 in the validation cohort) HCC patients enrolled were also serum HBsAg positive and anti-HCV negative. Comparative genomics analysis was further performed for elucidating enriched or suppressed biological activities in different HCC subtypes.The yHCC group showed more macroscopic venous invasions (60.9% vs. 10.5%, p < 0.001), fewer associated cirrhosis (17.4% vs. 63.2%, p < 0.001), and distinct profiles of expressed genes, especially those related to DNA replication and repair. yHCCs possessed increased embryonic stem cell (ESC) traits and were more dedifferentiated. A 309-gene signature was obtained from two training cohorts and validated in another independent data set. The ILF3 ESC gene, which was previously reported in poorly differentiated breast cancers and bladder carcinomas, was also present in yHCCs. Genes associated with HCC suppression, including AR and ADRA1A, were less abundant in yHCCs. ESC genes were also more enriched in advanced HCCs from elderly patients. CONCLUSION: This study revealed the molecular makeup of yHCC and the link between ESC traits and HCC subtypes. Findings in elderly tumors, therefore, cannot be simply extrapolated to young patients, and yHCC should be treated differently. PMID- 24160377 TI - How are we doing? Not as well as we think. PMID- 24160376 TI - Synthesis and biological evaluation of aryloxazole derivatives as antimitotic and vascular-disrupting agents for cancer therapy. AB - A series of aryloxazole, thiazole, and isoxazole derivatives was synthesized as vascular-targeting anticancer agents. Antiproliferative activity and tumor vascular-disrupting activity of all of the synthesized compounds were tested in vitro using various human cancer cell lines and HUVECs (human umbilical vein endothelial cells). Several compounds with an arylpiperazinyl oxazole core showed excellent cytotoxicity and metabolic stability in vitro. Among this series, two representative compounds (6-48 and 6-51) were selected and tested for the evaluation of anticancer effects in vivo using tumor-bearing mice. Compound 6-48 effectively reduced tumor growth (42.3% reduction in size) at the dose of 100 mg/kg. We believe that compound 6-48 will serve as a good lead compound for antimitotic and vascular-disrupting agents; further investigation to improve the in vivo efficacy of this series is underway. PMID- 24160378 TI - Safety-basket suture for management of malpositioned posterior chamber intraocular lens. AB - The safety-basket suture technique is used during surgical management of a malpositioned or subluxated posterior chamber intraocular lens (IOL) in post vitrectomy eyes. The purpose of the safety suture is to prevent posterior dislocation of the IOL during repositioning. The technique has been used in 32 cases to date with no occurrence of IOL posterior luxation. The only complication was transient vitreous hemorrhage in 2 eyes. This technique provides increased safety in the management of malpositioned IOLs and can be used for secondary IOL implantation by suture or intrascleral fixation. PMID- 24160379 TI - Rock 'n' roll phacoemulsification technique: noncracking and nonchopping approach. AB - The rock 'n' roll phaco technique we describe does not require nucleus chopping or cracking. In this easy-to-learn technique, the lens nucleus is fragmented from both sides, which seems to be an advantage in very soft nuclei. PMID- 24160380 TI - Intraocular lens prediction accuracy after corneal refractive surgery using K values from 3 devices. AB - PURPOSE: To compare results of intraocular lens (IOL) power calculation methods using different keratometry (K) values after myopic refractive surgery. SETTING: Seoul St. Mary's Hospital, Seoul, South Korea. DESIGN: Evaluation of diagnostic test or technology. METHODS: The IOL power of patients who had cataract surgery after refractive surgery was calculated using the SRK/T formula with true net power (TNP) and the equivalent K using the Pentacam Scheimpflug system. The simulated K, 2.0 mm zone of total mean power (TMP 2.0 mm) maps, and 4.0 mm zone of total optical power (TOP 4.0 mm) maps were calculated using the Orbscan II scanning-slit topographer and keratometer of the IOLMaster partial coherence interferometer (PCI). The IOL power was also calculated with the Haigis-L method with the corneal radius using the PCI system. The PCI axial length was used with all methods. RESULTS: The prediction error and absolute prediction error measured with the Haigis-L, TNP, TMP 2.0 mm, and TOP 4.0 mm were significantly lower than the equivalent K, simulated K, and PCI K (P<.05). The percentages of correct refraction predictions within +/- 0.50 diopter (D), +/- 1.00 D, and +/- 2.00 D in the Haigis-L method were the highest (64.5%, 80.6%, and 100%, respectively) of all methods. CONCLUSIONS: The Haigis-L using corneal radius with the PCI measurement was the most predictable method for IOL calculation after corneal refractive laser surgery in patients without a clinical history. The TMP 2.0 mm in the scanning-slit topographer and the TNP in the Scheimpflug system may also be relatively predictable keratometric values for IOL calculation. PMID- 24160381 TI - Comparison of visual function after bilateral implantation of inferior sector shaped near-addition and diffractive-refractive multifocal IOLs. AB - PURPOSE: To compare visual function after bilateral implantation of multifocal Lentis Mplus LS-312 (Group A) or Acrysof Restor SN6AD1 (Group B) intraocular lenses (IOLs). SETTING: Ophthalmology Unit, Centro Hospitalar e Universitario de Coimbra, and Visual Neuroscience Laboratory, IBILI, Faculty of Medicine, University of Coimbra, Coimbra, Portugal. DESIGN: Comparative case series. METHODS: Patients between 49 years and 76 years had bilateral cataract surgery with multifocal IOL implantation. Patients were evaluated preoperatively and 3 months postoperatively for distance, intermediate, and near visual acuities; static photopic and mesopic contrast sensitivity; and visual acuity under a glare source using the Metrovision contrast sensitivity platform. Color vision was evaluated with the Cambridge Colour Test. RESULTS: Group A comprised 56 eyes and Group B, 44 eyes. Visual and refractive results were comparable between the 2 groups. Photopic contrast sensitivity was significantly better in Group B at intermediate (2.2 cycles per degree [cpd] and 3.4 cpd) and high (7.1 cpd and 23.6 cpd) spatial frequencies. Under low mesopic conditions (0.08 candelas/m(2)), differences were significant at 1.1 cpd and 2.2 cpd spatial frequencies. There were no differences in visual acuity under a glare source or in color vision. CONCLUSIONS: Both IOLs provided good distance, intermediate, and near visual acuities. Visual acuity under a glare source and color vision were similar in the 2 groups. However, photopic and low mesopic contrast sensitivities were better in Group B, particularly for intermediate spatial frequencies, which are important for night driving. PMID- 24160382 TI - Efficacy and safety of intracameral triamcinolone acetonide to control postoperative inflammation after phacotrabeculectomy. AB - PURPOSE: To evaluate the efficacy and safety of intracameral triamcinolone acetonide in phacotrabeculectomy. SETTING: Beijing Shijitan Hospital, Capital University of Medical Sciences, Beijing, China. DESIGN: Prospective randomized controlled trial. METHODS: Patients having combined trabeculectomy and cataract surgery were enrolled from March 2010 through January 2012. The patients were randomly divided into 4 groups. At the conclusion of the surgery, Group A received intracameral triamcinolone acetonide 0.5 mg, Group B received triamcinolone acetonide 1.0 mg, Group C received triamcinolone acetonide 2.0 mg. Group D was the control group and did not receive triamcinolone acetonide. All patients had a conventional 2-side trabeculectomy and phacoemulsification with foldable posterior chamber intraocular lens implantation. Visual acuity and clinical indexes of anterior segment inflammation were assessed 1, 7, 14, and 28 days postoperatively. RESULTS: One hundred twenty-six eyes of 126 patients with a mean age of 64.09 years +/- 8.22 (SD) were enrolled. The eyes treated with triamcinolone acetonide had better visual acuity and less anterior chamber inflammation than the control eyes. Intracameral triamcinolone acetonide was highly effective in controlling postoperative inflammation in phacotrabeculectomy, and triamcinolone acetonide 1.0 mg provided the best postoperative result. CONCLUSION: Intracameral injection of triamcinolone acetonide in phacotrabeculectomy resulted in a significant reduction in aqueous inflammation and improvement in visual acuity. PMID- 24160383 TI - Efficacy of surgical simulator training versus traditional wet-lab training on operating room performance of ophthalmology residents during the capsulorhexis in cataract surgery. AB - PURPOSE: To compare the operating room performance of ophthalmology residents trained by traditional wet-lab versus surgical simulation on the continuous curvilinear capsulorhexis (CCC) portion of cataract surgery. SETTING: Academic tertiary referral center. DESIGN: Prospective randomized study. METHODS: Residents who chose to participate and provided informed consent were randomized to preoperative CCC training in the wet lab or on a simulator. Residents completed pre-practice demographic questionnaires including habits of daily living. After completion of their preoperative training (wet lab versus simulator), residents performed their first CCC of the clinical rotation under the direct supervision of an attending physician as part of their standard training at the facility. Residents then completed satisfaction questionnaires regarding their preoperative training. Two attending surgeons reviewed and graded each video of operating room performance. The mean score between the 2 attending physicians was used as the individual performance score for each of the 12 performance criteria. The overall score was calculated as the sum of these 12 individual performance scores (standardized). RESULTS: Ten residents trained in the wet lab and 11 on the simulator. There was no significant difference in overall score between the 2 groups (P=.608). There was no significant difference in any individual score except time (wet-lab group faster than simulator group) (P=.038). CONCLUSIONS: Preoperative simulator training prepared residents for the operating room as effectively as the wet lab. The time to pass the simulator curriculum was predictive of the time and overall performance in the operating room. FINANCIAL DISCLOSURE: No author has a financial or proprietary interest in any material or method mentioned. PMID- 24160385 TI - Perineural infiltrates in Pseudomonas keratitis. AB - We describe 2 cases of contact lens-related microbial keratitis caused by infection with Pseudomonas aeruginosa in which perineural infiltrates were observed at presentation. In both cases, examination by confocal microscopy was negative for Acanthamoeba cysts but bacterial cultures and microscopy of corneal scrapings were positive for P aeruginosa. Both cases responded rapidly to treatment with topical levofloxacin with no significant long-term sequelae. These observations indicate that perineural infiltrates may occur in Pseudomonas keratitis without underlying Acanthamoeba infection and are, therefore, not pathognomonic of Acanthamoeba infection. PMID- 24160384 TI - Femtosecond laser-assisted cataract surgery. AB - Femtosecond laser-assisted cataract surgery provides surgeons an exciting new option to potentially improve patient outcomes and safety. Over the past 2 years, 4 unique laser platforms have been introduced into the marketplace. The introduction of this new technology has been accompanied by a host of new clinical, logistical, and financial challenges for surgeons. This article describes the evolution of femtosecond laser technology for use in cataract surgery. It reviews the available laser platforms and discusses the necessary modifications in cataract surgery technique and the logistics of incorporating a femtosecond laser into one's practice. PMID- 24160386 TI - Corneal heat scar caused by photodynamic therapy performed through an implanted corneal inlay. AB - A 60-year-old man had a combination of laser in situ keratomileusis and Kamra corneal inlay implantation to correct presbyopia. Although the outcome was favorable postoperatively, central serous chorioretinopathy was observed in the left eye along with a decrease in the uncorrected (UDVA) and corrected (CDVA) distance visual acuities and the corrected near visual acuity (CNVA). Photodynamic therapy (PDT) was later performed in a university hospital. After PDT, the patient experienced a decline in the visual acuity and came to our clinic a month after the PDT. Degeneration and a scar were observed at the location of the inlay due to the heat and burning. Flattening of the corneal topography was also observed where the corneal scar was located, along with a significant decrease in CDVA in the left eye. Prior to any surgery in which the corneal inlay is an impediment, surgeons should take advantage of the reversibility of the Kamra inlay by explanting the inlay. PMID- 24160387 TI - Preparation of intracameral antibiotics for injection. PMID- 24160388 TI - Haptic placement of posterior chamber intraocular lens in fibrin glue-assisted intrascleral fixation. PMID- 24160389 TI - Cataract surgical problem: November consultation #1. PMID- 24160390 TI - November consultation #2. PMID- 24160391 TI - November consultation #3. PMID- 24160392 TI - November consultation #4. PMID- 24160393 TI - November consultation #6. PMID- 24160394 TI - November consultation #5. PMID- 24160395 TI - November consultation #7. PMID- 24160396 TI - November consultation #8. PMID- 24160397 TI - November consultation #9. PMID- 24160398 TI - On retrochop technique. PMID- 24160399 TI - Reply: To PMID 23688870. PMID- 24160400 TI - Reply: To PMID 23489917. PMID- 24160401 TI - Diehl-Miller nomogram for intraocular lens power calculation. PMID- 24160402 TI - Terminology and referencing of astigmatic vector analysis. PMID- 24160403 TI - Reply: To PMID 23608569. PMID- 24160404 TI - Highly diastereoselective synthesis of 1-carbamoyl-4-aminoindoloazepinone derivatives via the Ugi reaction. AB - A one-pot procedure for the highly diastereoselective synthesis of 1-carbamoyl-4 amino-1,2,4,5-tetrahydroindolo[2,3-c]azepin-3-one derivatives is described. Using 2-formyl-L-tryptophan as a bifunctional building block, a catalyst-free Ugi-three component reaction (Ugi-3CR) was developed to present trisubstituted indoloazepinones in good yields and excellent diastereomeric excess. PMID- 24160406 TI - Ultrasound-guided capsular distension in adhesive capsulitis: the hyaluronic acid or the local anesthetic? PMID- 24160405 TI - Design, methodology and baseline data of a school-based cohort study in Central China: the Anyang Childhood Eye Study. AB - PURPOSE: To report the design, methods and baseline data of the Anyang Childhood Eye Study (ACES), aiming to determine the prevalence, incidence and risk factors of myopia and other ocular diseases in children in central China. METHODS: The ACES was a school-based cohort study conducted in Anyang city. Students have been examined and will be followed-up annually for 3-5 years. Ocular examinations included visual acuity, identification of amblyopia and strabismus, ocular biometry, optical coherence tomography, retinal photography, cycloplegic autorefraction, accommodative response, peripheral refraction, visual perception and so on. A questionnaire survey was performed to collect risk factors for myopia including near work, outdoor activity, parental myopia, birth history, habits of wearing spectacles and reading, living habits, food habits and so on. RESULTS: Of 3112 grade 1 and 2363 grade 7 students eligible for the ACES, 2893 (93.0%) and 2267 (95.9%) participated in the study, with a mean age of 7.1 years (range 5.7-9.3 years) and 12.7 years (range 10.0-15.9 years), and proportions of male to be 57.8% and 50.0%, respectively. The prevalence rates of myopia, high myopia, emmetropia and hyperopia were 3.9%, 0.1%, 72.9% and 23.3% in grade 1, and 67.3%, 2.7%, 31.4% and 1.2% in grade 7, respectively. Similar data were found in the children confined in 6-year-old and 12-year-old ages. CONCLUSIONS: The ACES is the first large-scale cohort study in China with baseline response rates over 90%. Continuous documentation of changes and risk factors of refractive errors in these cohorts would provide new insights into myopia control in school-aged children. PMID- 24160407 TI - The authors respond. PMID- 24160408 TI - On the influence of DC electric fields on the aerosol assisted chemical vapor deposition growth of photoactive titanium dioxide thin films. AB - Titanium dioxide thin films were deposited on fluorine doped tin oxide glass substrate from the electric field assisted aerosol chemical vapor deposition (EACVD) reaction of titanium isopropoxide (TTIP, Ti(OC3H7)4) in toluene on glass substrates at a temperature of 450 degrees C. DC electric fields were generated by applying a potential difference between the electrodes of the transparent coated oxide coated glass substrates during the deposition. The deposited films were characterized using scanning electron microscopy, X-ray diffraction, atomic force microscopy, Raman spectroscopy, and UV-vis spectroscopy. The photoactivity and hydrophilicity of the deposited films were also analyzed using a dye-ink test and water-contact angle measurements. The characterization work revealed that the incorporation of DC electric fields produced significant reproducible changes in the film microstructure, preferred crystallographic orientation, roughness, and film thickness. Photocatalytic activity was calculated from the half-time (t1/2) or time taken to degrade 50% of the initial resazurin dye concentration. A large improvement in photocatalytic activity was observed for films deposited using an electric field with a strong orientation in the (004) direction (t1/2 17 min) as compared to a film deposited with no electric field (t1/2 40 min). PMID- 24160409 TI - A unique collaboration to advance strain imaging. PMID- 24160410 TI - The yellow legal pad adventure: volunteering for ASE. PMID- 24160411 TI - Travel grants for scientific sessions mean better care for patients back home for 2013 vascular recipients. PMID- 24160412 TI - The effects of alpha-lipoic acid on MMP-2 and MMP-9 activities in a rat renal ischemia and re-perfusion model. AB - Matrix metalloproteinases (MMPs) are enzymes that are responsible for degradation of extracellular matrix (ECM); they are involved in the pathogenesis of ischemia re-perfusion (I-R) injury. We investigated the possible preventive effect of alpha-lipoic acid (LA) in a renal I-R injury model in rats by assessing its reducing effect on the expression and activation of MMP-2 and MMP-9 induced by I R. Rats were assigned to four groups: control, sham-operated, I-R (saline, i.p.) and I-R+ LA (100 mg/kg, i.p.). After a right nephrectomy, I-R was induced by clamping the left renal pedicle for 1 h, followed by 6 h re-perfusion. In the sham group, a right nephrectomy was performed and left renal pedicles were dissected without clamping and the entire left kidney was excised after 6 h. LA pretreatment was started 30 min prior to induction of ischemia. Injury to tubules was evaluated using light and electron microscopy. The expressions of MMP-2 and MMP-9 were determined by immunohistochemistry and their activities were analyzed by gelatin zymography. Serum creatinine was measured using a quantitative kit based on the Jaffe colorimetric technique. Malondialdehyde (MDA) and glutathione (GSH) were analyzed using high performance liquid chromatography. Tissue inhibitor of metalloproteinase (TIMP)-2 and TIMP-1 were assessed using enzyme linked immunosorbent assay (ELISA). I-R caused tubular dilatation and brush border loss. LA decreased both renal dysfunction and abnormal levels of MDA and GSH during I-R. Moreover, LA decreased significantly both MMP-2 and MMP-9 expressions and activations during I-R. TIMP-1 and TIMP-2 levels were increased significantly by LA administration. LA modulated increased MMP-2 and MMP-9 activities and decreased TIMP-1 and TIMP-2 levels during renal I-R. PMID- 24160413 TI - Con A conjugated to Europium(III) cryptate as a new histological tool for prostate cancer investigation using confocal microscopy. AB - Lectins are carbohydrate recognition proteins that can be used as probes to reveal the glycosylation state of cells. They frequently have been used for diagnostic and prognostic cancer studies. For fluorescence based analysis, lectins commonly are conjugated to fluorescein isothiocyanate (Con A-FITC); however, this molecule loses its fluorescence quickly. We conjugated Europium cryptate to Con A (Con A-cryp-Eu) for use as a histochemical luminescent probe to recognize glucose/mannose residues in benign prostatic hyperplasia and prostatic carcinoma tissues, and used confocal microscopy instead of commercial Con A-FITC. Tissues were treated with Evans blue to suppress intrinsic tissue fluorescence before incubation with Con A-cryp-Eu or Con A-FITC. Con A-cryp-Eu exhibited hemagglutinating activity. Con A-cryp-Eu showed the same binding pattern as Con A FITC in prostate stroma and gland cells. Staining was strong in benign prostate hyperplasia and prostate carcinoma tissues. Con A-cryp-Eu probe stained glucose/mannose residues in prostatic carcinoma more intensely than Con A-FITC. Furthermore, staining with Con A-cryp-Eu showed greater fluorescence intensity than Con A-FITC and the emission of Con A-cryp-Eu was more stable than the Con A FITC for seven days under the same storage conditions. Maintenance of the luminescent properties and the binding pattern of Con A-cryp-Eu favor its use as an auxiliary histochemistry probe for prostatic tissue studies. PMID- 24160414 TI - The effects of oxytocin on social reward learning in humans. AB - It has been hypothesised that the mechanisms modulating social affiliation are regulated by reward circuitry. Oxytocin, previously shown to support affiliative behaviour and the processing of socio-emotional stimuli, is expressed in areas of the brain involved in reward and motivation. However, limited data are available that test if oxytocin is directly involved in reward learning, or whether oxytocin can modulate the effect of emotion on reward learning. In a double blind, randomised, placebo-controlled, within-group study design, 24 typical male volunteers were administered 24 IU of oxytocin or placebo and subsequently completed an affective reward learning task. Oxytocin selectively reduced performance of learning rewards, but not losses, from happy faces. The mechanism by which oxytocin may be exerting this effect is discussed in terms of whether oxytocin is affecting identity recognition via affecting the salience of happy faces. We conclude that oxytocin detrimentally affects learning rewards from happy faces in certain contexts. PMID- 24160415 TI - Advances in silkworm studies accelerated by the genome sequencing of Bombyx mori. AB - Significant progress has been achieved in silkworm (Bombyx mori) research since the last review on this insect was published in this journal in 2005. In this article, we review the new and exciting progress and discoveries that have been made in B. mori during the past 10 years, which include the construction of a fine genome sequence and a genetic variation map, the evolution of genomes, the advent of functional genomics, the genetic basis of silk production, metamorphic development, immune response, and the advances in genetic manipulation. These advances, which were accelerated by the genome sequencing project, have promoted B. mori as a model organism not only for lepidopterans but also for general biology. PMID- 24160416 TI - Systematics, phylogeny, and evolution of orb-weaving spiders. AB - The orb-weaving spiders (Orbiculariae) comprise more than 25% of the approximately 44,000 known living spider species and produce a remarkable variety of webs. The wheel-shaped orb web is primitive to this clade, but most Orbiculariae make webs hardly recognizable as orbs. Orb-weavers date at least to the Jurassic. With no evidence for convergence of the orb web, the monophyly of the two typical orb web taxa, the cribellate Deinopoidea and ecribellate Araneoidea, remains problematic, supported only weakly by molecular studies. The sister group of the Orbiculariae also remains elusive. Despite more than 15 years of phylogenetic scrutiny, a fully resolved cladogram of the Orbiculariae families is not yet possible. More comprehensive taxon sampling, comparative morphology, and new molecular markers are required for a better understanding of orb-weaver evolution. PMID- 24160418 TI - Evolutionary interaction networks of insect pathogenic fungi. AB - Lineages of insect pathogenic fungi are concentrated in three major clades: Hypocreales (several genera), Entomophthoromycota (orders Entomophthorales and Neozygitales), and Onygenales (genus Ascosphaera). Our review focuses on aspects of the evolutionary biology of these fungi that have remained underemphasized in previous reviews. To ensure integration with the better-known domains of insect pathology research, we followed a conceptual framework formulated by Tinbergen, asking complementary questions on mechanism, ontogeny, phylogeny, and adaptation. We aim to provide an introduction to the merits of evolutionary approaches for readers with a background in invertebrate pathology research and to make the insect pathogenic fungi more accessible as model systems for evolutionary biologists. We identify a number of questions in which fundamental research can offer novel insights into the evolutionary forces that have shaped host specialization and life-history traits such as spore number and size, somatic growth rate, toxin production, and interactions with host immune systems. PMID- 24160417 TI - Using semifield studies to examine the effects of pesticides on mobile terrestrial invertebrates. AB - Many farmers rely on regular pesticide applications to avoid losses from arthropod pests and the diseases they vector. However, widespread and injudicious use of pesticides is detrimental to the environment, poses a health risk, and undermines biocontrol services. Researchers are increasingly required to develop techniques to quantify the trade-offs and risks associated with pesticides. Laboratory studies, though useful for assessing short-term impacts (e.g., mortality), cannot detect longer-term or indirect effects that can potentially be assessed using semifield studies. Here we review the range and scope of studies that have used semifield methods for regulatory testing and risk assessment of pesticides and for understanding the community-level effects of pesticide use in agricultural landscapes. We include studies on target and nontarget species, with an emphasis on quantifying effects when the target species is highly mobile. We suggest improvements in the design and analysis of semifield studies to more effectively assess effects on highly mobile species. PMID- 24160419 TI - Sexual selection in complex environments. AB - Sexual selection has resulted in some of the most captivating features of insects, including flashy colors, bizarre structures, and complex pheromones. These features evolve in dynamic environments, where conditions can change rapidly over space and time. However, only recently has ecological complexity been embraced by theory and practice in sexual selection. We review replicated selection studies as well as studies on variation in the agents of selection to delineate gaps in current knowledge and clarify exciting new directions for research. Existing work suggests that fluctuations in sexual selection may be extremely common, though work on the ecological factors influencing these fluctuations is scarce. We suggest that deeper ecological perspectives on sexual selection may alter some of the fundamental assumptions of sexual selection theory and rapidly lead to new discoveries. PMID- 24160421 TI - Insect speciation rules: unifying concepts in speciation research. AB - The study of speciation is concerned with understanding the connection between causes of divergent evolution and the origin and maintenance of barriers to gene exchange between incipient species. Although the field has historically focused either on examples of recent divergence and its causes or on the genetic basis of reproductive isolation between already divergent species, current efforts seek to unify these two approaches. Here we integrate these perspectives through a discussion of recent progress in several insect speciation model systems. We focus on the evolution of speciation phenotypes in each system (i.e., those phenotypes causally involved in reducing gene flow between incipient species), drawing an explicit connection between cause and effect (process and pattern). We emphasize emerging insights into the genomic architecture of speciation as well as timely areas for future research. PMID- 24160420 TI - Neural and hormonal control of postecdysial behaviors in insects. AB - The shedding of the old exoskeleton that occurs in insects at the end of a molt (a process called ecdysis) is typically followed by the expansion and tanning of a new one. At the adult molt, these postecdysial processes include expansion and hardening of the wings. Here we describe recent advances in understanding the neural and hormonal control of wing expansion and hardening, focusing on work using Drosophila melanogaster in which genetic manipulations have permitted detailed investigation of postecdysial processes and their modulation by sensory input. To place this work in context, we briefly review recent progress in understanding the neuroendocrine regulation of ecdysis, which appears to be largely conserved across insect species. Investigations into the neuroendocrine networks that regulate ecdysial and postecdysial behaviors provide insights into how stereotyped, yet environmentally responsive, sequences are generated and how they develop and evolve. PMID- 24160422 TI - Model systems, taxonomic bias, and sexual selection: beyond Drosophila. AB - Although model systems are useful in entomology, allowing generalizations based on a few well-known species, they also have drawbacks. It can be difficult to know how far to generalize from information in a few species: Are all flies like Drosophila? The use of model systems is particularly problematic in studying sexual selection, where variability among taxa is key to the evolution of different behaviors. A bias toward the use of a few insect species, particularly from the genus Drosophila, is evident in the sexual selection and sexual conflict literature over the past several decades, although the diversity of study organisms has increased more recently. As the number of model systems used to study sexual conflict increased, support for the idea that sexual interactions resulted in harm to females decreased. Future work should choose model systems thoughtfully, combining well-known species with those that can add to the variation that allows us to make more meaningful generalizations. PMID- 24160423 TI - Traumatic insemination in terrestrial arthropods. AB - Traumatic insemination is a bizarre form of mating practiced by some invertebrates in which males use hypodermic genitalia to penetrate their partner's body wall during copulation, frequently bypassing the female genital tract and ejaculating into their blood system. The requirements for traumatic insemination to evolve are stringent, yet surprisingly it has arisen multiple times within invertebrates. In terrestrial arthropods traumatic insemination is most prevalent in the true bug infraorder Cimicomorpha, where it has evolved independently at least three times. Traumatic insemination is thought to occur in the Strepsiptera and has recently been recorded in fruit fly and spider lineages. We review the putative selective pressures that may have led to the evolution of traumatic insemination across these lineages, as well as the pressures that continue to drive divergence in male and female reproductive morphology and behavior. Traumatic insemination mechanisms and attributes are compared across independent lineages. PMID- 24160424 TI - Organization and functional roles of the central complex in the insect brain. AB - The central complex is a group of modular neuropils across the midline of the insect brain. Hallmarks of its anatomical organization are discrete layers, an organization into arrays of 16 slices along the right-left axis, and precise inter-hemispheric connections via chiasmata. The central complex is connected most prominently with the adjacent lateral complex and the superior protocerebrum. Its developmental appearance corresponds with the appearance of compound eyes and walking legs. Distinct dopaminergic neurons control various forms of arousal. Electrophysiological studies provide evidence for roles in polarized light vision, sky compass orientation, and integration of spatial information for locomotor control. Behavioral studies on mutant and transgenic flies indicate roles in spatial representation of visual cues, spatial visual memory, directional control of walking and flight, and place learning. The data suggest that spatial azimuthal directions (i.e., where) are represented in the slices, and cue information (i.e., what) are represented in different layers of the central complex. PMID- 24160425 TI - Response of native insect communities to invasive plants. AB - Invasive plants can disrupt a range of trophic interactions in native communities. As a novel resource they can affect the performance of native insect herbivores and their natural enemies such as parasitoids and predators, and this can lead to host shifts of these herbivores and natural enemies. Through the release of volatile compounds, and by changing the chemical complexity of the habitat, invasive plants can also affect the behavior of native insects such as herbivores, parasitoids, and pollinators. Studies that compare insects on related native and invasive plants in invaded habitats show that the abundance of insect herbivores is often lower on invasive plants, but that damage levels are similar. The impact of invasive plants on the population dynamics of resident insect species has been rarely examined, but invasive plants can influence the spatial and temporal dynamics of native insect (meta)populations and communities, ultimately leading to changes at the landscape level. PMID- 24160426 TI - Molecular mechanisms of phase change in locusts. AB - Phase change in locusts is an ideal model for studying the genetic architectures and regulatory mechanisms associated with phenotypic plasticity. The recent development of genomic and metabolomic tools and resources has furthered our understanding of the molecular basis of phase change in locusts. Thousands of phase-related genes and metabolites have been highlighted using large-scale expressed sequence tags, microarrays, high-throughput transcriptomic sequences, or metabolomic approaches. However, only several key factors, including genes, metabolites, and pathways, have a critical role in phase transition in locusts. For example, CSP (chemosensory protein) and takeout genes, the dopamine pathway, protein kinase A, and carnitines were found to be involved in the regulation of behavioral phase change and gram-negative bacteria-binding proteins in prophylaxical disease resistance of gregarious locusts. Epigenetic mechanisms including small noncoding RNAs and DNA methylation have been implicated. We review these new advances in the molecular basis of phase change in locusts and present some challenges that need to be addressed. PMID- 24160427 TI - Mosquito diapause. AB - Diapause, a dominant feature in the life history of many mosquito species, offers a mechanism for bridging unfavorable seasons in both temperate and tropical environments and serves to synchronize development within populations, thus directly affecting disease transmission cycles. The trait appears to have evolved independently numerous times within the Culicidae, as exemplified by the diverse developmental stages of diapause in closely related species. Its impact is pervasive, not only influencing the arrested stage, but also frequently altering physiological processes both before and after diapause. How the diapause response can be molded evolutionarily is critical for understanding potential range expansions of native and newly introduced species. The study of hormonal regulation of mosquito diapause has focused primarily on adult diapause, with little current information available on larval diapause or the intriguing maternal effects that regulate egg diapause. Recent quantitative trait locus, transcriptome, and RNA interference studies hold promise for interpreting the complex suite of genes that subserve the diapause phenotype. PMID- 24160428 TI - Interactions between insect herbivores and plant mating systems. AB - Self-pollination is common in plants, and limited seed and pollen dispersal can create localized inbreeding even within outcrossing plants. Consequently, insects regularly encounter inbred plants in nature. Because inbreeding results in elevated homozygosity, greater expression of recessive alleles, and subsequent phenotypic changes in inbred plants, inbreeding may alter plant-insect interactions. Recent research has found that plant inbreeding alters resistance and tolerance to herbivores, alters the attraction and susceptibility of plants to insects that vector plant pathogens, and alters visitation rates of insect pollinators. These results suggest that interactions with insects can increase or decrease inbreeding depression (the loss of fitness due to self-fertilization) and subsequently alter the evolution of selfing within plant populations. Future work needs to focus on the mechanisms underlying genetic variation in the effects of inbreeding on plant-insect interactions and the consequences of altered plant insect interactions on the evolution of plant defense and plant mating systems. PMID- 24160429 TI - Behavioral assays for studies of host plant choice and adaptation in herbivorous insects. AB - The association of insect herbivores with their host plants is influenced by behaviors governing acceptance of those plants for feeding and oviposition. Behavioral changes accompany and may even precede host range expansion. Characterization and quantification of specific behaviors often form the basis of studies on host plant adaptation and chemical ecology. Behavioral assays of insects are usually designed to measure attraction for feeding or oviposition in relation to their host plants or specific chemistry. We review behavioral assays of insect herbivores with host plants or the volatiles they emit, with special consideration given to design, analysis, and interpretation to maximize ecological relevance. A toolkit of robust assays can help address fundamental issues at the intersection of ecology and evolution, such as the underpinnings of plant-insect interactions and the identification of genes involved in host race formation. PMID- 24160430 TI - Biology and management of psocids infesting stored products. AB - Previously regarded as minor nuisance pests, psocids belonging to the genus Liposcelis now pose a major problem for the effective protection of stored products worldwide. Here we examine the apparent biological and operational reasons behind this phenomenon and why conventional pest management seems to be failing. We investigate what is known about the biology, behavior, and population dynamics of major pest species to ascertain their strengths, and perhaps find weaknesses, as a basis for a rational pest management strategy. We outline the contribution of molecular techniques to clarifying species identification and understanding genetic diversity. We discuss progress in sampling and trapping and our comprehension of spatial distribution of these pests as a foundation for developing management strategies. The effectiveness of various chemical treatments and the availability and potential of nonchemical control methods are critically examined. Finally, we identify research gaps and suggest future directions for research. PMID- 24160431 TI - Chemical ecology of bumble bees. AB - Bumble bees are of major importance, ecologically and economically as pollinators in cool and temperate biomes and as model organisms for scientific research. Chemical signals and cues have been shown to play an outstanding role in intraspecific and interspecific communication systems within and outside of a bumble bee colony. In the present review we compile and critically assess the literature on the chemical ecology of bumble bees, including cuckoo bumble bees. The development of new and more sensitive analytical tools and improvements in sociogenetic methods significantly enhanced our knowledge about chemical compounds that mediate the regulation of reproduction in the social phase of colony development, about the interactions between host bumble bees and their social parasites, about pheromones involved in mating behavior, as well as about the importance of signals, cues and context-dependent learning in foraging behavior. Our review intends to stimulate new studies on the many unresolved questions concerning the chemical ecology of these fascinating insects. PMID- 24160432 TI - Death Valley, Drosophila, and the Devonian toolkit. AB - Most experiments on the flight behavior of Drosophila melanogaster have been performed within confined laboratory chambers, yet the natural history of these animals involves dispersal that takes place on a much larger spatial scale. Thirty years ago, a group of population geneticists performed a series of mark and-recapture experiments on Drosophila flies, which demonstrated that even cosmopolitan species are capable of covering 10 km of open desert, probably in just a few hours and without the possibility of feeding along the way. In this review I revisit these fascinating and informative experiments and attempt to explain how-from takeoff to landing-the flies might have made these journeys based on our current knowledge of flight behavior. This exercise provides insight into how animals generate long behavioral sequences using sensory-motor modules that may have an ancient evolutionary origin. PMID- 24160433 TI - Freshwater biodiversity and aquatic insect diversification. AB - Inland waters cover less than 1% of Earth's surface but harbor more than 6% of all insect species: Nearly 100,000 species from 12 orders spend one or more life stages in freshwater. Little is known about how this remarkable diversity arose, although allopatric speciation and ecological adaptation are thought to be primary mechanisms. Freshwater habitats are highly susceptible to environmental change and exhibit marked ecological gradients. Standing waters appear to harbor more dispersive species than running waters, but there is little understanding of how this fundamental ecological difference has affected diversification. In contrast to the lack of evolutionary studies, the ecology and habitat preferences of aquatic insects have been intensively studied, in part because of their widespread use as bioindicators. The combination of phylogenetics with the extensive ecological data provides a promising avenue for future research, making aquatic insects highly suitable models for the study of ecological diversification. PMID- 24160434 TI - Genetic control of mosquitoes. AB - Genetics can potentially provide new, species-specific, environmentally friendly methods for mosquito control. Genetic control strategies aim either to suppress target populations or to introduce a harm-reducing novel trait. Different approaches differ considerably in their properties, especially between self limiting strategies, where the modification has limited persistence, and self sustaining strategies, which are intended to persist indefinitely in the target population and may invade other populations. Several methods with different molecular biology are under development and the first field trials have been completed successfully. PMID- 24160435 TI - Insect mitochondrial genomics: implications for evolution and phylogeny. AB - The mitochondrial (mt) genome is, to date, the most extensively studied genomic system in insects, outnumbering nuclear genomes tenfold and representing all orders versus very few. Phylogenomic analysis methods have been tested extensively, identifying compositional bias and rate variation, both within and between lineages, as the principal issues confronting accurate analyses. Major studies at both inter- and intraordinal levels have contributed to our understanding of phylogenetic relationships within many groups. Genome rearrangements are an additional data type for defining relationships, with rearrangement synapomorphies identified across multiple orders and at many different taxonomic levels. Hymenoptera and Psocodea have greatly elevated rates of rearrangement offering both opportunities and pitfalls for identifying rearrangement synapomorphies in each group. Finally, insects are model systems for studying aberrant mt genomes, including truncated tRNAs and multichromosomal genomes. Greater integration of nuclear and mt genomic studies is necessary to further our understanding of insect genomic evolution. PMID- 24160436 TI - Theoretical investigations on CaO ions: vibronic states and photoelectron spectroscopy. AB - The low-lying electronic states, X(2)Pi and A(2)Sigma(+) of CaO(+) and X(2)Sigma(+) and A(2)Pi of CaO(-), have been determined at the MRCI+Q level of theory with the aug-cc-pV5Z(O) and cc-pCV5Z(Ca) basis sets. The two states of CaO(+) are close within <0.1 eV and coupled via spin-orbit effect. The X(2)Sigma(+) and A(2)Pi states of CaO(-) are energetically separated by <1 eV such that the first excited state is close to the electronic ground state of neutral CaO and unstable with respect to electron detachment. Using the potential energy curves and the spin-orbit coupling terms, the vibronic energy levels of these ions have been determined. The ionization energy and the electron affinity of CaO are calculated at 6.79 and 0.79 eV, respectively. The photoelectron spectra of CaO(-) and CaO have also been simulated. PMID- 24160437 TI - Intimate Partner Violence and Women's Health and Wellbeing: Impacts, risk factors and responses. AB - Abstract Women have approximately a one in four chance of experiencing intimate partner violence (IPV). Those who do are at increased risk of developing physical and mental health problems including traumatic brain injury, chronic pain, gastrointestinal disorders, depression, post-traumatic stress disorder, and substance-related disorders. Nurses, in whatever situation they work, are therefore highly likely to encounter women who are victims of IPV. This paper explores the prevalence of physical and mental health issues for women with an experience of IPV. Factors that influence a woman's experience of IPV such as culture, remaining in an abusive relationship, and childhood sexual abuse as a risk factor of IPV are also examined. Recommended responses for women with an experience of IPV are discussed. PMID- 24160438 TI - Lipid nanocarriers and molecular targets for malaria chemotherapy. AB - Malaria is the most serious tropical disease of humankind and a cause of much debilitation and morbidity throughout the world especially in endemic areas like India and Africa. The development of drug resistance may be due to insufficient drug concentration in presence of high parasite load. In addition, the present pharmaceutical dosage forms are ineffective thereby necessitating the development of novel dosage forms which are effective, safe and affordable to underprivileged population of the developing world. The rapid advancement of nanotechnology has raised the possibility of using lipid nanocarriers that interact within biological environment for treatment of infectious diseases. Thus, lipid based nano-delivery systems offer a platform to formulate old and toxic antimalarial drugs thereby modifying their pharmacokinetic profile, biodistribution and targetability. Further, there is a need to develop new chemotherapy based approaches for inhibiting the parasite-specific metabolic pathways. The present review highlights the advances in lipid nanocarriers and putative molecular targets for antimalarial chemotherapy. PMID- 24160439 TI - Cell therapies for IBD: what works? AB - The inflammatory response in patients with inflammatory bowel disease is a complex self-amplifying process with multiple cellular and molecular pathways controlling activation and shut-off of the process. Available therapeutic interventions with drugs that have a very selective action, such as anti-tumor necrosis factor antibodies, or broader effects such as corticosteroids still leave a significant proportion of patients with Crohn's disease and ulcerative colitis insufficiently treated. Cellular therapies are emerging as promising new approaches to treat inflammatory bowel diseases and in particular Crohn's disease. Experimental and clinical data are the origin of the increasing utilization of cell therapies for severe immune-mediated diseases including inflammatory bowel disease. The types of cell therapies for these diseases can be divided into two different areas: hematopoietic stem cell therapies, and selected/conditioned immune cell therapy, the latter including mesenchymal stem cells and T-regulatory cells-based therapies. PMID- 24160440 TI - Scale-up and evaluation of high solid ionic liquid pretreatment and enzymatic hydrolysis of switchgrass. AB - BACKGROUND: Ionic liquid (IL) pretreatment is receiving significant attention as a potential process that enables fractionation of lignocellulosic biomass and produces high yields of fermentable sugars suitable for the production of renewable fuels. However, successful optimization and scale up of IL pretreatment involves challenges, such as high solids loading, biomass handling and transfer, washing of pretreated solids and formation of inhibitors, which are not addressed during the development stages at the small scale in a laboratory environment. As a first in the research community, the Joint BioEnergy Institute, in collaboration with the Advanced Biofuels Process Demonstration Unit, a Department of Energy funded facility that supports academic and industrial entities in scaling their novel biofuels enabling technologies, have performed benchmark studies to identify key challenges associated with IL pretreatment using 1-ethyl 3-methylimidazolium acetate and subsequent enzymatic saccharification beyond bench scale. RESULTS: Using switchgrass as the model feedstock, we have successfully executed 600-fold, relative to the bench scale (6 L vs 0.01 L), scale-up of IL pretreatment at 15% (w/w) biomass loading. Results show that IL pretreatment at 15% biomass generates a product containing 87.5% of glucan, 42.6% of xylan and only 22.8% of lignin relative to the starting material. The pretreated biomass is efficiently converted into monosaccharides during subsequent enzymatic hydrolysis at 10% loading over a 150-fold scale of operations (1.5 L vs 0.01 L) with 99.8% fermentable sugar conversion. The yield of glucose and xylose in the liquid streams were 94.8% and 62.2%, respectively, and the hydrolysate generated contains high titers of fermentable sugars (62.1 g/L of glucose and 5.4 g/L cellobiose). The overall glucan and xylan balance from pretreatment and saccharification were 95.0% and 77.1%, respectively. Enzymatic inhibition by [C2mim][OAc] at high solids loadings requires further process optimization to obtain higher yields of fermentable sugars. CONCLUSION: Results from this initial scale up evaluation indicate that the IL-based conversion technology can be effectively scaled to larger operations and the current study establishes the first scaling parameters for this conversion pathway but several issues must be addressed before a commercially viable technology can be realized, most notably reduction in water consumption and efficient IL recycle. PMID- 24160441 TI - The independent association of anxiety with non-cardiac chest pain. AB - Non-cardiac chest pain (NCCP) is common in clinical cardiology. Anxiety is an important factor in NCCP because of its role in the neurobehavioural processes of pain regulation. It is not well established that which specific anxiety symptoms are disproportionately elevated in NCCP and whether the association between anxiety and NCCP is independent of personality factors. Participants with NCCP (N = 46; mean age 44.9 +/- 14.7; 67% women) were evaluated for anxiety (Spielberger State-Trait Anxiety Inventory[STAI]), clinical measures and personality factors (negative affectivity and social inhibition measured by the Type D inventory). Item analysis was conducted for each of the anxiety symptoms. A healthy reference group was used for comparison purposes (N = 1233; mean age 55.2 +/- 14.3; 50% women). Results showed that NCCP was associated with elevated anxiety levels (STAI >= 45) compared to the reference group (OR = 3.27, 95% CI = 1.68-6.36; p < .001). Item analyses revealed that all anxiety symptoms were associated with NCCP (median rho = .125, range .08-.18), particularly worry, tension and feeling frightened. Associations between anxiety and NCCP remained significant when adjusting for demographic, clinical and personality factors (OR = 2.52; 95% CI = 1.17-5.40). It is concluded that anxiety is strongly associated with NCCP. This association is not limited to physical anxiety symptoms and is independent of personality factors. PMID- 24160443 TI - H2 formation on interstellar grains. PMID- 24160446 TI - A cascade cross-coupling hydrogen evolution reaction by visible light catalysis. AB - Cross-dehydrogenative-coupling reaction has long been recognized as a powerful tool to form a C-C bond directly from two different C-H bonds. Most current processes are performed by making use of stoichiometric amounts of oxidizing agents. We describe here a new type of reaction, namely cross-coupling hydrogen evolution (CCHE), with no use of any sacrificial oxidants, and only hydrogen (H2) is generated as a side product. By combining eosin Y and a graphene-supported RuO2 nanocomposite (G-RuO2) as a photosensitizer and a catalyst, the desired cross-coupling products and H2 are achieved in quantitative yields under visible light irradiation at room temperature. PMID- 24160447 TI - A critical review of vaginal birth rates after a primary Caesarean in Queensland hospitals. AB - INTRODUCTION: For women with a lower uterine incision without indication for repeat Caesarean section (CS), vaginal birth for their next pregnancy is a safe option. Although these women should be encouraged to consider vaginal birth after a Caesarean section (VBAC) it is not consistently supported in practice. There is relatively little information on the extent to which maternal preference, birthing decisions and outcomes match best available evidence. AIM: To describe current VBAC rates for women in Queensland, Australia and compare this to safe, achievable VBAC rates reported in national and international studies. METHOD: Perinatal data from 2004 to 2011 were reviewed to determine current VBAC rates following a primary CS for women birthing in Queensland. These were compared with VBAC rates reported in the literature. RESULTS: Queensland has a high overall CS rate and high repeat CS rate compared with the national average. In 2010, Queensland VBAC rates for next birth following primary CS were 14% (range 13-21% public sector, 7-11% private hospitals). This is substantially lower than achievable Australian rates of 24% and international rates. CONCLUSION: Low VBAC rates reflect low numbers of women commencing labour in a pregnancy subsequent to a primary CS. There is unexplained variation in VBAC rates between maternity facilities. Clinical reviews to support evidence-based practice are warranted. PMID- 24160448 TI - Measurement of the 13C/12C of atmospheric CH4 using near-infrared (NIR) cavity ring-down spectroscopy. AB - A near-infrared (NIR) continuous-wave-cavity ring-down spectrometry (CW-CRDS) device was developed with the goal of measuring seasonal changes in the isotopic composition of atmospheric CH4 on Earth and eventually on Mars. The system consisted of three distributed feedback laser diodes (DFB-LDs), two of which were tuned to the absorption line peaks of (12)CH4 and (13)CH4 at 6046.954 cm(-1) and 6049.121 cm(-1), respectively, and a third that measured the baseline at 6050.766 cm(-1). The multiple laser design improved the long-term stability of the system and increased the data acquisition rate. The acquisition frequency was further increased by utilizing a semiconductor optical amplifier (SOA) to initiate cavity ring-down events. The high repetition rate combined with the superhigh reflectivity mirrors yielded precise isotopic measurements in this NIR region, even though the line strengths of CH4 in this region are 200 times weaker than those of the strongest mid-IR absorption bands. The current system has a detection limit of 1.9 * 10(-12) cm(-1), corresponding to 10 pptv of CH4 at 100 Torr. For ambient air samples that contained 1.9 ppmv CH4, the delta(13)C of the CH4 was determined to be -48.7 +/- 1.70/00 (1sigma). PMID- 24160442 TI - Cardiovascular disease risk reduction in rural China: a clustered randomized controlled trial in Zhejiang. AB - BACKGROUND: Cardiovascular disease (CVD) is a major cause of death in China. Despite government efforts, the majority of hypertensive and diabetic patients in China do not receive proper treatment. Reducing CVD events requires long-term care that is proactive, patient-centred, community-based, and sustainable. We have designed a package of interventions for patients at high risk of CVD to be implemented by family doctors based in township hospitals (providers of primary care) in rural Zhejiang, China. This trial aims to determine whether the systematic CVD risk reduction package results in reduced CVD events among patients at risk of CVD compared with usual care, and whether the package is cost effective and suitable for routine implementation and scale-up. METHODS/DESIGN: This is a prospective, open-label, cluster randomized controlled trial (RCT) with blinded data analysis. The trial will randomize 67 township hospitals with 31,708 participants in three counties in Zhejiang Province. Participants will be identified from existing health records and will comprise adults aged 50 to 74 years, with a calculated 10-year CVD risk of 20% or higher, or diabetes. In the intervention arm, participants will receive a package of interventions including: 1) healthy lifestyle counseling (smoking cessation, and salt, oil, and alcohol reduction); 2) prescription of a combination of drugs (antihypertensives, aspirin, and statin); and 3) adherence support for drug compliance and healthy lifestyle change. In the control arm, participants will receive usual care for hypertension and diabetes management at individual clinicians' discretion. The primary outcome is the incidence of severe CVD events over 24 months of follow up. All CVD events will be defined according to the World Health Organization (WHO) monitoring of trends and determinants in cardiovascular disease (MONICA) definitions, diagnosed at the county hospital or higher level, and reported by the Zhejiang surveillance system. Secondary outcomes include: mean systolic and diastolic blood pressure, blood glucose, serum total cholesterol (TC), and adherence to appointments, and drugs and lifestyle changes. DISCUSSION: This trial focuses on risk reduction of CVD rather than specific diseases. It is not designed to compare therapeutic and healthy lifestyle interventions, but rather their combined effects in primary care settings. Through the trial, we intend to understand the effectiveness of the comprehensive CVD reduction package in routine practice. We also intend to understand the barriers and facilitators to implementing the package, and thus to advise on policy and practice change. TRIAL REGISTRATION: Current Controlled Trials: ISRCTN58988083. PMID- 24160444 TI - Integrated transcriptomics and metabolomics decipher differences in the resistance of pedunculate oak to the herbivore Tortrix viridana L. AB - BACKGROUND: The interaction between insect pests and their host plants is a never ending race of evolutionary adaption. Plants have developed an armament against insect herbivore attacks, and attackers continuously learn how to address it. Using a combined transcriptomic and metabolomic approach, we investigated the molecular and biochemical differences between Quercus robur L. trees that resisted (defined as resistant oak type) or were susceptible (defined as susceptible oak type) to infestation by the major oak pest, Tortrix viridana L. RESULTS: Next generation RNA sequencing revealed hundreds of genes that exhibited constitutive and/or inducible differential expression in the resistant oak compared to the susceptible oak. Distinct differences were found in the transcript levels and the metabolic content with regard to tannins, flavonoids, and terpenoids, which are compounds involved in the defence against insect pests. The results of our transcriptomic and metabolomic analyses are in agreement with those of a previous study in which we showed that female moths prefer susceptible oaks due to their specific profile of herbivore-induced volatiles. These data therefore define two oak genotypes that clearly differ on the transcriptomic and metabolomic levels, as reflected by their specific defensive compound profiles. CONCLUSIONS: We conclude that the resistant oak type seem to prefer a strategy of constitutive defence responses in contrast to more induced defence responses of the susceptible oaks triggered by feeding. These results pave the way for the development of biomarkers for an early determination of potentially green oak leaf roller-resistant genotypes in natural pedunculate oak populations in Europe. PMID- 24160449 TI - Asthma incidence in children growing up close to traffic: a registry-based birth cohort. AB - BACKGROUND: Recent reviews conclude an association between traffic-related pollution and incidence of asthma in children, but not all studies agree. Studies have almost exclusively relied on parental-reported symptoms or parental-reported diagnoses of asthma and wheeze. Our aim was to investigate if traffic exposure is associated with higher incidence of early onset asthma, using registry-based outcome data. METHODS: We investigated a birth cohort in southern Sweden, consisting of N = 26,128 children with outcome and exposure data (born July 2005 2010). Of these children, N = 7898 had additional covariate information. The cohort was followed to the end of 2011.Traffic intensity, and dispersion-modeled concentrations of NOX (100*100 m grid), at residential addresses, were linked with registry data on dispensed asthma medication (the Swedish Prescribed Drug Register), and hospital and primary health care diagnoses of bronchiolitis, obstructive bronchitis and asthma (The Scania Health Care Register).Covariate information was obtained from questionnaires distributed to parents at Child Health Care-centre visits, eight months after birth. Cox proportional hazards regression was used for the statistical analyses. RESULTS: Living in close proximity to a road with >=8640 cars/day (compared to 0-8640 cars/day), was not associated with higher incidence of first purchase of inhaled beta2-agonist (adjusted hazard ratio (adj.HR) = 0.9, 95% CI: 0.8-1.0); third year purchase of inhaled beta2-agonist (adj.HR = 0.7, 95% CI: 0.6-0.9); bronchiolitis (adj.HR = 0.7, 95% CI: 0.6-0.9), obstructive bronchitis (adj.HR = 1.0, 95% CI: 0.9-1.2), or asthma (adj.HR = 0.7, 95% CI: 0.6- 0.9). Similar results were found for inhaled corticosteroids, and in relation to NOX. CONCLUSIONS: Traffic-related exposure was not associated with higher incidence of asthma medication, or diagnoses of asthma, bronchiolitis, or obstructive bronchitis, in children 0-6 years in southern Sweden. This may depend on the low levels of traffic pollution in the area, mainly well below the WHO-guideline for NO2. PMID- 24160450 TI - Expression of iron-related proteins in the duodenum is up-regulated in patients with chronic inflammatory disorders. AB - Mechanisms responsible for derangements in Fe homeostasis in chronic inflammatory conditions are not entirely clear. The aim of the present study was to test the hypothesis that inflammation affects the expression of Fe-related proteins in the duodenum and monocytes of patients with chronic inflammatory disorders, thus contributing to dysregulated Fe homeostasis. Duodenal mucosal samples and peripheral blood monocytes obtained from patients with chronic inflammatory disorders, namely ulcerative colitis (UC), Crohn's disease (CD) and rheumatoid arthritis, were used for gene and protein expression studies. Hb levels were significantly lower and serum C-reactive protein levels were significantly higher in patients in the disease groups. The gene expression of several Fe-related proteins in the duodenum was significantly up-regulated in patients with UC and CD. In patients with UC, the protein expression of divalent metal transporter 1 and ferroportin, which are involved in the absorption of dietary non-haem Fe, was also found to be significantly higher in the duodenal mucosa. The gene expression of the duodenal proteins of interest correlated positively with one another and negatively with Hb. In patients with UC, the gene expression of Fe-related proteins in monocytes was found to be unaffected. In a separate group of patients with UC, serum hepcidin levels were found to be significantly lower than those in the control group. In conclusion, the expression of Fe-related proteins was up regulated in the duodenum of patients with chronic inflammatory conditions in the present study. The effects appeared to be secondary to anaemia and the consequent erythropoietic drive. PMID- 24160452 TI - Optimised laser microdissection of the human ocular surface epithelial regions for microarray studies. AB - BACKGROUND: The most important challenge of performing insitu transcriptional profiling of the human ocular surface epithelial regions is obtaining samples in sufficient amounts, without contamination from adjacent tissue, as the region of interest is microscopic and closely apposed to other tissues regions. We have effectively collected ocular surface (OS) epithelial tissue samples from the Limbal Epithelial Crypt (LEC), limbus, cornea and conjunctiva of post-mortem cadaver eyes with laser microdissection (LMD) technique for gene expression studies with spotted oligonucleotide microarrays and Gene 1.0 ST arrays. METHODS: Human donor eyes (4 pairs for spotted oligonucleotide microarrays, 3 pairs for Gene 1.0 ST arrays) consented for research were included in this study with due ethical approval of the Nottingham Research Ethics Committee. Eye retrieval was performed within 36 hours of post-mortem period. The dissected corneoscleral buttons were immersed in OCT media and frozen in liquid nitrogen and stored at 80 degrees C till further use. Microscopic tissue sections of interest were taken on PALM slides and stained with Toluidine Blue for laser microdissection with PALM microbeam systems. Optimisation of the laser microdissection technique was crucial for efficient and cost effective sample collection. RESULTS: The starting concentration of RNA as stipulated by the protocol of microarray platforms was taken as the cut-off concentration of RNA samples in our studies. The area of LMD tissue processed for spotted oligonucleotide microarray study ranged from 86,253 MUm2 in LEC to 392,887 MUm2 in LEC stroma. The RNA concentration of the LMD samples ranged from 22 to 92 pg/MUl. The recommended starting concentration of the RNA samples used for Gene 1.0 ST arrays was 6 ng/5 MUl. To achieve the desired RNA concentration the area of ocular surface epithelial tissue sample processed for the Gene 1.0 ST array experiments was approximately 100,0000 MUm2 to 130,0000 MUm2. RNA concentration of these samples ranged from 10.88 ng/12 MUl to 25.8 ng/12 MUl, with the RNA integrity numbers (RIN) for these samples from 3.3 to 7.9. RNA samples with RIN values below 2, that had failed to amplify satisfactorily were discarded. CONCLUSIONS: The optimised protocol for sample collection and laser microdissection improved the RNA yield of the in situ ocular surface epithelial regions for effective microarray studies on spotted oligonucleotide and affymetrix platforms. PMID- 24160454 TI - Troponin testing: end of an era? PMID- 24160453 TI - Possible modulation of FAS and PTP-1B signaling in ameliorative potential of Bombax ceiba against high fat diet induced obesity. AB - BACKGROUND: Bombax ceiba Linn., commonly called as Semal, is used in various gastro-intestinal disturbances. It contains Lupeol which inhibits PTP-1B, adipogenesis, TG synthesis and accumulation of lipids in adipocytes and adipokines whereas the flavonoids isolated from B. ceiba has FAS inhibitory activity. The present study was aimed to investigate ameliorative potential of Bombax ceiba to experimental obesity in Wistar rats, and its possible mechanism of action. METHODS: Male Wistar albino rats weighing 180-220 g were employed in present study. Experimental obesity was induced by feeding high fat diet for 10 weeks. Methanolic extract of B. ceiba extract 100, 200 and 400 mg/kg and Gemfibrozil 50 mg/kg as standard drug were given orally from 7th to 10th week. RESULTS: Induction with HFD for 10 weeks caused significant (p < 0.05) increase in % body wt, BMI, LEE indices; serum glucose, triglyceride, LDL, VLDL, cholesterol, free fatty acid, ALT, AST; tissue TBARS, nitrate/nitrite levels; different fat pads and relative liver weight; and significant decrease in food intake (g and kcal), serum HDL and tissue glutathione levels in HFD control rats. Treatment with B. ceiba extract and Gemfibrozil significantly attenuated these HFD induced changes, as compared to HFD control. The effect of B. ceiba 200 and 400 mg/kg was more pronounced in comparison to Gemfibrozil. CONCLUSION: On the basis of results obtained, it may be concluded that the methanolic extract of stem bark of Bombax ceiba has significant ameliorative potential against HFD induced obesity in rats, possibly through modulation of FAS and PTP-1B signaling due to the presence of flavonoids and lupeol. PMID- 24160455 TI - Reference ranges for cardiac troponin in the era of high sensitivity assays. PMID- 24160456 TI - Nivetetracyclates A and B: novel compounds isolated from Streptomyces niveus. AB - A high-throughput screening of a microbial natural product library led to the discovery of two novel compounds named nivetetracyclates A and B (1 and 2), which were produced by Streptomyces niveus designated as LS2151. The backbone of the compounds contains a hydrotetracyclate not previously reported from a natural source. The structures of the compounds were elucidated by spectroscopic methods. The nivetetracyclates exhibited activity against human HeLa cells. PMID- 24160458 TI - PEG-g-chitosan thermosensitive hydrogel for implant drug delivery: cytotoxicity, in vivo degradation and drug release. AB - Thermosensitive hydrogels based on chitosan are of great interests for injectable implant drug delivery. The poly(ethylene glycol)-grafted-chitosan (PEG-g-CS) hydrogel was reported as a potential thermosensitive system. The objective of the present study is to evaluate the cytotoxicity, in vivo degradation and drug release of PEG-g-CS hydrogel. Cytotoxicity was evaluated using L929 murine fibrosarcoma cell line. Degradation and drug release in vivo were investigated by subcutaneous injection of the hydrogel into Sprague-Dawley rats. PEG-g-CS polymer exhibits no significant cytotoxicity when its concentration is less than 3 mg mL( 1). After being implanted, PEG-g-CS hydrogel maintains its integrity for two weeks and collapses, merging into the tissue, in the third week. It causes moderate inflammatory response but no fibrous encapsulation around the hydrogel is found. The hydrogel presents a three-week sustained release of cyclosporine A with no significant burst release in vitro and produces the effective drug concentration in blood for more than five weeks in vivo, performing almost the same bioavailability to chitosan/glycerophosphate hydrogel. Further modifications of PEG-g-CS hydrogel might be necessary to modulate the degradation and to mitigate the fluctuations in blood drug concentration. PMID- 24160457 TI - Interaction of phenanthrene and potassium uptake by wheat roots: a mechanistic model. AB - BACKGROUND: Polycyclic aromatic hydrocarbons (PAHs) are potentially carcinogenic, mutagenic and toxic to both human and non-human organisms. Dietary intake of PAHs is a dominant route of exposure for the general population where food crops are a major source of dietary PAHs. Over 20% of main food crops contain PAHs that exceed the control limits in China. However, the mechanisms on PAH accumulation in crops are not well understood. RESULTS: Here we report the physiological mechanism of potassium (K+)-stimulated uptake of phenanthrene (PHE, a model PAH) in wheat. PHE uptake is stimulated by the external K+. The addition of blockers (tetraethlyammonium and barium) for K+ channels does not suppress the process, suggesting that K+ channels are not involved. The introduction of PHE and K+ elicits a much greater depolarization in root cell membrane potential than that of either PHE or K+. K+ activates the plasma membrane proton (H+)-ATPase in a K+ dependent manner. The pattern is quite similar to that in PHE uptake in the presence of K+. The external medium pH treated with PHE and K+ is higher than that with K+, and lower than that with PHE, indicating that H+ pump involves in the interaction between PHE and K+ uptake. CONCLUSIONS: Therefore, it is concluded that a K+ influx/H+ efflux reaction is coupled with the transport of PHE into wheat root cells. Our results provide a novel insight into the PHE uptake by crop roots. PMID- 24160459 TI - Depression among patients with end-stage renal disease in hemodialysis. AB - Depression is frequent in end-stage renal disease (ESRD) and predicts mortality in dialysis patients. The aim of this study was to investigate the occurrence of depression among patients on hemodialysis. We conducted an observational cross sectional study at two hemodialysis centres in the metropolitan area of Fortaleza, Ceara, Brazil, between September and October 2010. The occurrence of depression was evaluated according to Beck Depression Inventory II. Among 148 patients interviewed, the mean age was 46 +/- 13 years and 54% were male. The average time on dialysis was 5.3 +/- 5.2 years. Depression was found in 101 (68.2%) cases. Depression was classified as mild (49.5%), moderate (41.5%) and severe (9%). Only 15.5% had prior depression diagnosis. Follow-up with Psychologist was being done in only 32.4% of cases. Patients with depression had a higher frequency of antidepressant use (20.7% vs. 4.2%, p=.01) and benzodiazepines (33.6% vs. 8.5%, p=.001). Among patients using antidepressant, improvement of symptoms was reported by 81.6%. Depression is one potentially modifiable risk factor in ESRD. The investigation and multidisciplinary approach of depression should be part of routine evaluation of patients on dialysis. PMID- 24160460 TI - Abstracts of the 21st International Conference on Oral and Maxillofacial Surgery, Barcelona, Spain. PMID- 24160465 TI - One night of sleep is insufficient to achieve sleep-to-forget emotional decontextualisation processes. AB - Neutral memories unbind from their emotional acquisition context when sleep is allowed the night after learning and testing takes place after two additional nights of sleep. However, mood-dependent memory (MDM) effects are not abolished after a restricted sleep episode mostly featuring non rapid-eye-movement (NREM) or rapid-eye-movement (REM) sleep. Here, we tested whether (1) one night of sleep featuring several NREM-REM sleep cycles is sufficient to suppress MDM effects and (2) a neutral mood is a sufficiently contrasting state to induce MDM effects, i.e. interfere with the recall of information learned in happy or sad states. Results disclosed MDM effects both in the post-learning sleep and wake conditions, with better recall in congruent than incongruent emotional contexts. Our findings suggest that the emotional unbinding needs several consecutive nights of sleep to be complete, and that even subtle mood changes are sufficient to produce MDM effects. PMID- 24160466 TI - Delusional belief flexibility and informal caregiving relationships in psychosis: a potential cognitive route for the protective effect of social support. AB - Aims. For people with psychosis, contact with informal caregivers is an important source of social support, associated with recovery, and with better outcomes following individual cognitive therapy (CBTp). In this study, we tested whether increased flexibility in delusional thinking, an established predictor of positive outcome following CBTp, was a possible mechanism underlying this effect. Methods. 219 participants with delusions (mean age 38 years; 71% male; 75% White) were grouped according to the presence of a caregiver (37% with a caregiver) and caregiver level of expressed emotion (High/Low EE, 64% Low). Delusional belief flexibility was compared between groups, controlling for interpersonal functioning, severity of psychotic symptoms, and other hypothesised outcome predictors. Results. Participants with caregivers were nearly three times more likely than those without to show flexibility (OR = 2.7, 95% CI 1.5 to 5.0, p = 0.001), and five times more likely if the caregiving relationship was Low EE (OR = 5.0, 95% CI 2.0-13.0, p = 0.001). ORs remained consistent irrespective of controlling for interpersonal functioning and other predictors of outcome. Conclusions. This is the first evidence that having supportive caregiving relationships is associated with a specific cognitive attribute in people with psychosis, suggesting a potential cognitive mechanism by which outcomes following CBTp, and perhaps more generally, are improved by social support. PMID- 24160468 TI - Narrative spaces between intractability outside the clinic. AB - In this essay, the author reflects on her experience conducting field research outside an abortion clinic amid volatile protests and counterprotests. She identifies moments of convergence in the oppositional groups' narrative explanations for participating in the weekly protests, and contemplates the possibilities for dialogue in these sorts of intractable conflicts. She concludes with reflections on communication scholars' roles in engaging with polarizing health narratives. PMID- 24160467 TI - Assessment of inflammatory resilience in healthy subjects using dietary lipid and glucose challenges. AB - BACKGROUND: Resilience or the ability of our body to cope with daily-life challenges has been proposed as a new definition of health, with restoration of homeostasis as target resultant of various physiological stress responses. Challenge models may thus be a sensitive measure to study the body's health. The objective of this study was to select a dietary challenge model for the assessment of inflammatory resilience. Meals are a challenge to metabolic homeostasis and are suggested to affect inflammatory pathways, yet data in literature are limited and inconsistent. METHOD: The kinetic responses of three different dietary challenges and a water control challenge were assessed on various metabolic and inflammatory markers in 14 healthy males and females using a full cross-over study design. The dietary challenges included glucose (75 g glucose in 300 ml water), lipids (200 ml whipping cream) and a mix of glucose and lipids (same amounts as above), respectively. Blood samples were collected at baseline and at 0.5, 1, 2, 4, 6, 8 and 10 h after consumption of the treatment products. Inflammation (IFNgamma, IL-1beta, IL-6, IL-8, IL-10, IL-12p70, TNF alpha CRP, ICAM-1, VCAM-1, SAA, E-selectin, P-selectin, thrombomodulin, leukocytes, neutrophils, lymphocytes) and clinical (e.g. glucose, insulin, triglycerides) markers as well as gene expression in blood cells and plasma oxylipin profiles were measured. RESULTS: All three dietary challenges induced changes related to metabolic control such as increases in glucose and insulin after the glucose challenge and increases in triglycerides after the lipid challenge. In addition, differences between the challenges were observed for precursor oxylipins and some downstream metabolites including DiHETrE's and HODE's. However, none of the dietary challenges induced an acute inflammatory response, except for a modest increase in circulating leukocyte numbers after the glucose and mix challenges. Furthermore, subtle, yet statistically significant increases in vascular inflammatory markers (sICAM-1 and sVCAM-1) were found after the mix challenge, when compared to the water control challenge. CONCLUSIONS: This study shows that dietary glucose and lipid challenges did not induce a strong acute inflammatory response in healthy subjects, as quantified by an accurate and broad panel of parameters. PMID- 24160470 TI - Anti-mouse CD52 monoclonal antibody ameliorates iron-deficient anaemia in IL-10 knockout mice. AB - Approximately 50 % of patients with inflammatory bowel disease (IBD) suffer from anaemia, with Fe deficiency being the most common cause. CD52 monoclonal antibody (mAb) targets the cell surface CD52 and is effective in depleting lymphocytes through cytolytic effects in vivo. The aim of the present study was to investigate the therapeutic effect of anti-mouse CD52 mAb on Fe-deficient anaemia in IBD. IL-10 knockout mice (IL-10- / -) of 12 weeks with established colitis were treated with anti-mouse CD52 mAb once per week for 2 weeks. Severity of colitis, blood T lymphocytes, blood Hb, haematocrit, plasma erythropoietin (EPO), serum Fe concentration, transferrin saturation, splenic Fe stores, expression of liver hepcidin mRNA, Western blotting of the phosphorylated form of Smad1/5/8 and total Smad1 were measured at the end of the experiment. IL-10- / - mice treated with CD52 mAb showed a reduction in the percentage of CD4+ and CD4+CD45+ T cells in blood and weight loss typically associated with colonic inflammation, serum levels of EPO, the expression of liver hepcidin mRNA and total Smad1 protein, while they showed an increase in Hb concentrations, haematocrit, levels of serum Fe, transferrin saturation and splenic Fe stores. The present results indicated that anti-CD52 therapy may ameliorate Fe-deficient anaemia by reducing colonic inflammation. These findings may open novel horizons in the treatment of patients with IBD by resetting of immunological homeostasis in the gut by depleting the activated T cells in the gut mucosa. PMID- 24160469 TI - Small molecule antagonist of the bone morphogenetic protein type I receptors suppresses growth and expression of Id1 and Id3 in lung cancer cells expressing Oct4 or nestin. AB - BACKGROUND: Bone morphogenetic proteins (BMP) are embryonic morphogens that are aberrantly expressed in lung cancer. BMPs mediate cell fate decisions and self renewal of stem cells, through transcription regulation of inhibitor of differentiation protein/DNA binding proteins (Id1-3). Inhibition of BMP signaling decreases growth and induces cell death of lung cancer cells lines by downregulating the expression of Id proteins. It is not known whether the BMP signaling cascade regulates growth and the expression of Id proteins of lung cancer cells expressing the stem cell markers Oct4 and/or nestin. METHODS: Lung cancer cells expressing Oct4 or nestin were isolated from lung cancer cell lines by stably transfecting the Oct4 promoter or nestin promoter expression vectors that induce expression of the green fluorescent protein reporter. RESULTS: Our studies suggest that lung cancer cells expressing Oct4 or nestin are different cell populations. Microarray and quantitative RT-PCR demonstrated that the expression of specific stem cell markers were different between isolated Oct4 and nestin cells. Both the Oct4 and nestin populations were more tumorigenic than controls but histologically they were quite different. The isolated Oct4 and nestin cells also responded differently to inhibition of BMP signaling. Blockade of BMP signaling with the BMP receptor antagonist DMH2 caused significant growth inhibition of both the Oct4 and nestin cell populations but only increased cell death in the nestin population. DMH2 also induced the expression of nestin in the Oct4 population but not in the nestin cells. We also show that BMP signaling is an important regulator of Id1 and Id3 in both the Oct4 and nestin cell populations. Furthermore, we show that NeuN is frequently expressed in NSCLC and provide evidence suggesting that Oct4 cells give rise to cancer cells expressing nestin and/or NeuN. CONCLUSION: These studies show that although biologically different, BMP signaling is growth promoting in cancer cells expressing Oct4 or nestin. Inhibition of BMP signaling decreases expression of Id proteins and suppresses growth of cancer cells expressing Oct4 or Nestin. Small molecule antagonists of the BMP type I receptors represent potential novel drugs to target the population of cancer cells expressing stem cell markers. PMID- 24160471 TI - Identification of genomic functional hotspots with copy number alteration in liver cancer. AB - Copy number alterations (CNAs) can be observed in most of cancer patients. Several oncogenes and tumor suppressor genes with CNAs have been identified in different kinds of tumor. However, the systematic survey of CNA-affected functions is still lack. By employing systems biology approaches, instead of examining individual genes, we directly identified the functional hotspots on human genome. A total of 838 hotspots on human genome with 540 enriched Gene Ontology functions were identified. Seventy-six aCGH array data of hepatocellular carcinoma (HCC) tumors were employed in this study. A total of 150 regions which putatively affected by CNAs and the encoded functions were identified. Our results indicate that two immune related hotspots had copy number alterations in most of patients. In addition, our data implied that these immune-related regions might be involved in HCC oncogenesis. Also, we identified 39 hotspots of which copy number status were associated with patient survival. Our data implied that copy number alterations of the regions may contribute in the dysregulation of the encoded functions. These results further demonstrated that our method enables researchers to survey biological functions of CNAs and to construct regulation hypothesis at pathway and functional levels. PMID- 24160473 TI - True petroclival meningiomas: results of surgical management. AB - OBJECT: The relentless natural progression of petroclival meningiomas mandates their treatment. The management of these tumors, however, is challenging. Among the issues debated are goals of treatment, outcomes, and quality of life, appropriate extent of surgical removal, the role of skull base approaches, and the efficacy of combined decompressive surgery and radiosurgery. The authors report on the outcome in a series of patients treated with the goal of total removal. METHODS: The authors conducted a retrospective analysis of 64 cases of petroclival meningiomas operated on by the senior author (O.A.) from 1988 to 2012, strictly defined as those originating medial to the fifth cranial nerve on the upper two-thirds of the clivus. The patients' average age was 49 years; the average tumor size (maximum diameter) was 35.48 +/- 10.09 mm (with 59 tumors > 20 mm), and cavernous sinus extension was present in 39 patients. The mean duration of follow-up was 71.57 months (range 4-276 months). RESULTS: In 42 patients, the operative reports allowed the grading of resection. Grade I resection (tumor, dura, and bone) was achieved in 17 patients (40.4%); there was no recurrence in this group (p = 0.0045). Grade II (tumor, dura) was achieved in 15 patients (36%). There was a statistically significant difference in the rate of recurrence with respect to resection grade (Grades I and II vs other grades, p = 0.0052). In all patients, tumor removal was classified based on postoperative contrast enhanced MRI, and gross-total resection (GTR) was considered to be achieved if there was no enhancement present; on this basis, GTR was achieved in 41 (64%) of 64 patients, with a significantly lower recurrence rate in these patients than in the group with residual enhancement (p = 0.00348). One patient died from pulmonary embolism after discharge. The mean Karnofsky Performance Status (KPS) score was 85.31 preoperatively (median 90) and improved on follow-up to 88, with 30 patients (47%) having an improved KPS score on follow-up. Three patients suffered a permanent deficit that significantly affected their KPS. Cerebrospinal fluid leak occurred in 8 patients (12.5%), with 2 of them requiring exploration. Eighty-nine percent of the patients had cranial nerve deficits on presentation; of the 54 patients with more than 2 months of follow-up, 21 (32.8%) had persisting cranial nerve deficits. The overall odds of permanent cranial nerve deficit of treated petroclival meningioma was 6.2%. There was no difference with respect to immediate postoperative cranial nerve deficit in patients who had GTR compared with those who had subtotal resection. CONCLUSIONS: Total removal (Grade I or II resection) of petroclival meningiomas is achievable in 76.4% of cases and is facilitated by the use of skull base approaches, with good outcome and functional status. In cases in which circumstances prevent total removal, residual tumors can be followed until progression is evident, at which point further intervention can be planned. PMID- 24160472 TI - Stromal cell-derived factor-1 promoted angiogenesis and inflammatory cell infiltration in aneurysm walls. AB - OBJECT: A small percentage of cerebral aneurysms rupture, but when they do, the effects are devastating. Current management of unruptured aneurysms consists of surgery, endovascular treatment, or watchful waiting. If the biology of how aneurysms grow and rupture were better known, a novel drug could be developed to prevent unruptured aneurysms from rupturing. Ruptured cerebral aneurysms are characterized by inflammation-mediated wall remodeling. The authors studied the role of stromal cell-derived factor-1 (SDF-1) in inflammation-mediated wall remodeling in cerebral aneurysms. METHODS: Human aneurysms, murine carotid artery aneurysms, and murine intracranial aneurysms were studied using immunohistochemistry. Flow cytometry analysis was performed on blood from mice developing carotid or intracranial aneurysms. The effect of SDF-1 on endothelial cells and macrophages was studied by chemotaxis cell migration assay and capillary tube formation assay. Anti-SDF-1 blocking antibody was given to mice and compared with control (vehicle)-administered mice for its effects on the walls of carotid aneurysms and the development of intracranial aneurysms. RESULTS: Human aneurysms, murine carotid aneurysms, and murine intracranial aneurysms all expressed SDF-1, and mice with developing carotid or intracranial aneurysms had increased progenitor cells expressing CXCR4, the receptor for SDF-1 (p < 0.01 and p < 0.001, respectively). Human aneurysms and murine carotid aneurysms had endothelial cells, macrophages, and capillaries in the walls of the aneurysms, and the presence of capillaries in the walls of human aneurysms was associated with the presence of macrophages (p = 0.01). Stromal cell-derived factor-1 promoted endothelial cell and macrophage migration (p < 0.01 for each), and promoted capillary tube formation (p < 0.001). When mice were given anti-SDF 1 blocking antibody, there was a significant reduction in endothelial cells (p < 0.05), capillaries (p < 0.05), and cell proliferation (p < 0.05) in the aneurysm wall. Mice given anti-SDF-1 blocking antibody developed significantly fewer intracranial aneurysms (33% vs 89% in mice given control immunoglobulin G, respectively; p < 0.05). CONCLUSIONS: These data suggest SDF-1 is associated with angiogenesis and inflammatory cell migration and proliferation in the walls of aneurysms, and may have a role in the development of intracranial aneurysms. PMID- 24160474 TI - Repeat digital subtraction angiography after a negative baseline assessment in nonperimesencephalic subarachnoid hemorrhage: a pooled data meta-analysis. AB - OBJECT: A repeat digital subtraction angiography (DSA) study of the cranial vasculature is routinely performed in patients with diffuse nonperimesencephalic subarachnoid hemorrhage (SAH) after negative baseline CT angiography (CTA) and DSA studies. However, DSA carries a low but substantial risk of neurological complications. Therefore, the authors evaluated the added value of repeat DSA in patients with initial angiographically negative diffuse nonperimesencephalic SAH. METHODS: A systematic review of the contemporary literature was performed according to the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) statement. Studies from January 2000 onward were reviewed since imaging modalities have much improved over the last decade. A pooled analysis was conducted to identify the detection rate of repeat DSA. In addition, the diagnostic yield of repeat DSAs in a prospectively maintained single-center series of 1051 consecutive patients with SAH was added to the analysis. RESULTS: An initial search of the literature yielded 179 studies, 8 of which met the selection criteria. Another 45 patients from the authors' institution were included in the study, providing 368 patients eligible for the pooled analysis. In 37 patients (10.0%, 95% CI 7.4%-13.6%) an aneurysm was detected on repeat DSA. The timing of the repeat DSA varied from 1 to 6 weeks after the initial DSA. The use of 3D techniques was poorly described among these studies, and no direct comparisons between CTA and DSA were made. CONCLUSIONS: Repeat DSA is still warranted in patients with a diffuse nonperimesencephalic SAH and negative initial assessment. However, the exact timing of the repeat DSA is subject to debate. PMID- 24160475 TI - Photobiomodulation inside the brain: a novel method of applying near-infrared light intracranially and its impact on dopaminergic cell survival in MPTP-treated mice. AB - OBJECT: Previous experimental studies have documented the neuroprotection of damaged or diseased cells after applying, from outside the brain, near-infrared light (NIr) to the brain by using external light-emitting diodes (LEDs) or laser devices. In the present study, the authors describe an effective and reliable surgical method of applying to the brain, from inside the brain, NIr to the brain. They developed a novel internal surgical device that delivers the NIr to brain regions very close to target damaged or diseased cells. They suggest that this device will be useful in applying NIr within the large human brain, particularly if the target cells have a very deep location. METHODS: An optical fiber linked to an LED or laser device was surgically implanted into the lateral ventricle of BALB/c mice or Sprague-Dawley rats. The authors explored the feasibility of the internal device, measured the NIr signal through living tissue, looked for evidence of toxicity at doses higher than those required for neuroprotection, and confirmed the neuroprotective effect of NIr on dopaminergic cells in the substantia nigra pars compacta (SNc) in an acute 1-methyl-4-phenyl 1,2,3,6-tetrahydropyridine (MPTP) model of Parkinson disease in mice. RESULTS: The device was stable in freely moving animals, and the NIr filled the cranial cavity. Measurements showed that the NIr intensity declined as distance from the source increased across the brain (65% per mm) but was detectable up to 10 mm away. At neuroprotective (0.16 mW) and much higher (67 mW) intensities, the NIr caused no observable behavioral deficits, nor was there evidence of tissue necrosis at the fiber tip, where radiation was most intense. Finally, the intracranially delivered NIr protected SNc cells against MPTP insult; there were consistently more dopaminergic cells in MPTP-treated mice irradiated with NIr than in those that were not irradiated. CONCLUSIONS: In summary, the authors showed that NIr can be applied intracranially, does not have toxic side effects, and is neuroprotective. PMID- 24160476 TI - Morphological and clinical risk factors for posterior communicating artery aneurysm rupture. AB - OBJECT: Recent studies have shown that posterior circulation aneurysms, specifically posterior communicating artery (PCoA) aneurysms, are more likely to rupture than other aneurysms. To date, few studies have investigated the factors contributing to PCoA aneurysm rupture. The authors aimed to identify morphological and clinical characteristics predisposing to PCoA aneurysm rupture. METHODS: The authors retrospectively reviewed 134 consecutive patients with PCoA aneurysms managed at their facility between July 2003 and December 2012. The authors divided patients into groups of those with aneurysmal rupture (n = 39) and without aneurysmal rupture (n = 95) and compared morphological and clinical characteristics. Morphological characteristics were mainly evaluated by 3D CT angiography and included diameter of arteries (anterior cerebral artery, middle cerebral artery, and internal carotid artery), size of the aneurysm, dome-to-neck ratio, neck direction of the aneurysmal dome around the PCoA (medial, lateral, superior, inferior, and posterior), aneurysm bleb formation, whether the PCoA was fetal type, and the existence of other intracranial unruptured aneurysm(s). RESULTS: Patients with ruptured PCoA aneurysms were significantly younger (a higher proportion were < 60 years of age) and a significantly higher proportion of patients with ruptured PCoA aneurysms showed a lateral direction of the aneurysmal dome around the PCoA, had bleb formation, and the aneurysm was > 7 mm in diameter and/or the dome-to-neck ratio was > 2.0. Multivariate logistic regression analysis showed age < 60 years (OR 4.3, p = 0.011), history of hypertension (OR 5.1, p = 0.008), lateral direction of the aneurysmal dome around the PCoA (OR 6.7, p = 0.0001), and bleb formation (OR 11, p < 0.0001) to be significantly associated with PCoA aneurysm rupture. CONCLUSIONS: The present results demonstrated that lateral projection of a PCoA aneurysm may be related to rupture. PMID- 24160477 TI - Smooth-muscle progenitor cells isolated from patients with moyamoya disease: novel experimental cell model. AB - OBJECT: Moyamoya disease (MMD) is a cerebrovascular occlusive disease affecting bilateral internal carotid termini. Smooth-muscle cells are one of the major cell types involved in this disease process. The characteristics of circulating smooth muscle progenitor cells (SPCs) in MMD are poorly understood. The authors purified SPCs from the peripheral blood of patients with MMD and sought to identify differentially expressed genes (DEGs) in SPCs from these patients. METHODS: The authors cultured and isolated SPCs from the peripheral blood of patients with MMD (n = 25) and healthy control volunteers (n = 22). After confirmation of the cellular phenotype, RNA was extracted from the cells and DEGs were identified using a commercially available gene chip. Real-time quantitative reverse transcription polymerase chain reaction was performed to confirm the putative pathogenetic DEGs. RESULTS: The SPC-type outgrowth cells in patients with MMD invariably showed a hill-and-valley appearance under microscopic examination, and demonstrated high alpha-smooth muscle actin, myosin heavy chain, and calponin expression (96.5% +/- 2.1%, 42.8% +/- 18.6%, and 87.1% +/- 8.2%, respectively), and minimal CD31 expression (less than 1%) on fluorescence-activated cell sorter analysis. The SPCs in the MMD group tended to make more irregularly arranged and thickened tubules on the tube formation assay. In the SPCs from patients with MMD, 286 genes (124 upregulated and 162 downregulated) were differentially expressed; they were related to cell adhesion, cell migration, immune response, and vascular development. CONCLUSIONS: With adequate culture conditions, SPCs could be established from the peripheral blood of patients with MMD. These cells showed specific DEGs compared with healthy control volunteers. This study provides a novel experimental cell model for further research of MMD. PMID- 24160478 TI - Large intracranial metastatic tumors treated by Gamma Knife surgery: outcomes and prognostic factors. AB - OBJECT: The use of radiosurgery has been well accepted for treating small to medium-size metastatic brain tumors (MBTs). However, its utility in treating large MBTs remains uncertain due to potentially unfavorable effects such as progressive perifocal brain edema and neurological deterioration. In this retrospective study the authors evaluated the local tumor control rate and analyzed possible factors affecting tumor and brain edema response. METHODS: The authors defined a large brain metastasis as one with a measurement of 3 cm or more in at least one of the 3 cardinal planes (coronal, axial, or sagittal). A consecutive series of 109 patients with 119 large intracranial metastatic lesions were treated with Gamma Knife surgery (GKS) between October 2000 and December 2012; the median tumor volume was 16.8 cm(3) (range 6.0-74.8 cm(3)). The pre-GKS Karnofsky Performance Status (KPS) score for these patients ranged from 70 to 100. The most common tumors of origin were non-small cell lung cancers (29.4% of cases in this series). Thirty-six patients (33.0%) had previously undergone a craniotomy (1-3 times) for tumor resection. Forty-three patients (39.4%) underwent whole-brain radiotherapy (WBRT) before GKS. Patients were treated with GKS and followed clinically and radiographically at 2- to 3-month intervals thereafter. RESULTS: The median duration of imaging follow-up after GKS for patients with large MBTs in this series was 6.3 months. In the first follow-up MRI studies (performed within 3 months after GKS), 77 lesions (64.7%) had regressed, 24 (20.2%) were stable, and 18 (15.1%) were found to have grown. Peritumoral brain edema as defined on T2-weighted MRI sequences had decreased in 79 lesions (66.4%), was stable in 21 (17.6%), but had progressed in 19 (16.0%). In the group of patients who survived longer than 6 months (76 patients with 77 MBTs), 88.3% of the MBTs (68 of 77 lesions) had regressed or remained stable at the most recent imaging follow-up, and 89.6% (69 of 77 lesions) showed regression of perifocal brain edema volume or stable condition. The median duration of survival after GKS was 8.3 months for patients with large MBTs. Patients with small cell lung cancer and no previous WBRT had a significantly higher tumor control rate as well as better brain edema relief. Patients with a single metastasis, better KPS scores, and no previous radiosurgery or WBRT were more likely to decrease corticosteroid use after GKS. On the other hand, higher pre GKS KPS score was the only factor that showed a statistically significant association with longer survival. CONCLUSIONS: Treating large MBTs using either microsurgery or radiosurgery is a challenge for neurosurgeons. In selected patients with large brain metastases, radiosurgery offered a reasonable local tumor control rate and favorable functional preservation. Exacerbation of underlying edema was rare in this case series. Far more commonly, edema and steroid use were lessened after radiosurgery. Radiosurgery appears to be a reasonable option for some patients with large MBTs. PMID- 24160480 TI - Aneurysm wall inflammation. PMID- 24160479 TI - The accuracy of predicting survival in individual patients with cancer. AB - OBJECT: Estimating survival time in cancer patients is crucial for clinicians, patients, families, and payers. To provide appropriate and cost-effective care, various data sources are used to provide rational, reliable, and reproducible estimates. The accuracy of such estimates is unknown. METHODS: The authors prospectively estimated survival in 150 consecutive cancer patients (median age 62 years) with brain metastases undergoing radiosurgery. They recorded cancer type, number of brain metastases, neurological presentation, extracranial disease status, Karnofsky Performance Scale score, Recursive Partitioning Analysis class, prior whole-brain radiotherapy, and synchronous or metachronous presentation. Finally, the authors asked 18 medical, radiation, or surgical oncologists to predict survival from the time of treatment. RESULTS: The actual median patient survival was 10.3 months (95% CI 6.4-14). The median physician-predicted survival was 9.7 months (neurosurgeons = 11.8 months, radiation oncologists = 11.0 months, and medical oncologist = 7.2 months). For patients who died before 10 months, both neurosurgeons and radiation oncologists generally predicted survivals that were more optimistic and medical oncologists that were less so, although no group could accurately predict survivors alive at 14 months. All physicians had individual patient survival predictions that were incorrect by as much as 12-18 months, and 14 of 18 physicians had individual predictions that were in error by more than 18 months. Of the 2700 predictions, 1226 (45%) were off by more than 6 months and 488 (18%) were off by more than 12 months. CONCLUSIONS: Although crucial, predicting the survival of cancer patients is difficult. In this study all physicians were unable to accurately predict longer-term survivors. Despite valuable clinical data and predictive scoring techniques, brain and systemic management often led to patient survivals well beyond estimated survivals. PMID- 24160481 TI - Determinants of quality of life in patients with skull base chordoma. AB - OBJECT: Skull base chordomas can be managed by surgical intervention and adjuvant radiotherapy. As survival for this disease increases, identification of determinants of quality of life becomes an important focus for guiding comprehensive patient care. In this study the authors sought to measure functional outcome and quality of life in patients with skull base chordomas and to identify determinants of quality of life in these patients. METHODS: The authors carried out an internet-based cross-sectional survey, collecting detailed data for 83 individual patients. Demographic and clinical variables were evaluated. Functional outcomes were determined by Karnofsky Performance Scale (KPS) and Glasgow Outcome Scale Extended (GOSE), quality of life was measured using the 36-Item Short Form Health Survey (SF-36), and depression was assessed using Patient Health Questions-9 (PHQ-9) instrument. Caregiver burden was assessed using the Zarit Burden Interview (ZBI). Univariate and multivariate analysis was performed to identify determinants of the physical and mental components of the SF-36. RESULTS: Patients with skull base chordomas who have undergone surgery and/or radiation treatment had a median KPS score of 90 (range 10-100, IQR 10) and a median GOSE score of 8 (range 2-8, IQR 3). The mean SF-36 Physical Component Summary score (+/- SD) was 43.6 +/- 11.8, the mean Mental Component Summary score was 44.2 +/- 12.6, and both were significantly lower than norms for the general US population (p < 0.001). The median PHQ-9 score was 5 (range 0-27, IQR 8). A PHQ-9 score of 10 or greater, indicating moderate to severe depression, was observed in 29% of patients. The median ZBI score was 12 (range 0-27, IQR 11), indicating a low burden. Neurological deficit, use of pain medication, and requirement for corticosteroids were found to be associated with worse SF-36 Physical Component Summary score, while higher levels of depression (higher PHQ-9 score) correlated with worse SF-36 Mental Component Summary score. CONCLUSIONS: Patients with skull base chordomas have a lower quality of life than the general US population. The most significant determinants of quality of life in the posttreatment phase in this patient population were neurological deficits (sensory deficit and bowel/bladder dysfunction), pain medication use, corticosteroid use, and levels of depression as scored by PHQ-9. PMID- 24160482 TI - Stereotactic radiosurgery for arteriovenous malformations of the cerebellum. AB - OBJECT: Arteriovenous malformations (AVMs) of the posterior fossa have an aggressive natural history and propensity for hemorrhage. Although the cerebellum accounts for the majority of the posterior fossa volume, there is a paucity of stereotactic radiosurgery (SRS) outcome data for AVMs of this region. The authors sought to evaluate the long-term outcomes and risks of cerebellar AVM radiosurgery. METHODS: This single-institution retrospective analysis reviewed the authors' experience with Gamma Knife surgery during the period 1987-2007. During this time 64 patients (median age 47 years, range 8-75 years) underwent SRS for a cerebellar AVM. Forty-seven patients (73%) presented with an intracranial hemorrhage. The median target volume was 3.85 cm(3) (range 0.2-12.5 cm(3)), and the median marginal dose was 21 Gy (range 15-25 Gy). RESULTS: Arteriovenous malformation obliteration was confirmed by MRI or angiography in 40 patients at a median follow-up of 73 months (range 4-255 months). The actuarial rates of total obliteration were 53% at 3 years, 69% at 4 years, and 76% at 5 and 10 years. Elevated obliteration rates were statistically higher in patients who underwent AVM SRS without prior embolization (p = 0.005). A smaller AVM volume was also associated with a higher rate of obliteration (p = 0.03). Four patients (6%) sustained a hemorrhage during the latency period and 3 died. The cumulative rates of AVM hemorrhage after SRS were 6% at 1, 5, and 10 years. This correlated with an overall annual hemorrhage rate of 2.0% during the latency interval. One patient experienced a hemorrhage 9 years after confirmed MRI and angiographic obliteration. A permanent neurological deficit due to adverse radiation effects developed in 1 patient (1.6%) and temporary complications were seen in 2 additional patients (3.1%). CONCLUSIONS: Stereotactic radiosurgery proved to be most effective for patients with smaller and previously nonembolized cerebellar malformations. Hemorrhage during the latency period occurred at a rate of 2.0% per year until obliteration occurred. PMID- 24160484 TI - Pyrolysis of coals and biomass: analysis of thermal breakdown and its products. PMID- 24160483 TI - Sustaining Transfers through Affordable Research Translation (START): study protocol to assess knowledge translation interventions in continuing care settings. AB - BACKGROUND: Bridging the research-practice gap is an important research focus in continuing care facilities, because the population of older adults (aged 65 years and over) requiring continuing care services is the fastest growing demographic among countries in the Organisation for Economic Co-operation and Development (OECD). Unlicensed practitioners, known as health care aides, provide the majority of care for residents living in continuing care facilities. However, little research examines how to sustain health care aide behavior change following initial adoption of current research evidence. METHODS/DESIGN: We will conduct a phase III, multicentre, cluster randomized controlled trial (RCT) using a stratified 2 * 2 additive factorial design, including an embedded process evaluation, in 24 supportive living facilities within the health zone of Edmonton, AB, Canada. We will determine which combination of frequency and intensity of reminders most effectively sustains the completion of the sit-to stand activity by health care aides with residents. Frequency refers to how often a reminder is implemented; intensity refers to whether a reminder is social or paper-based. We will compare monthly reminders with reminders implemented every 3 months, and we will compare low intensity, paper-based reminders and high intensity reminders provided by a health care aide peer.Using interviews, questionnaires, and observations, Sustaining Transfers through Affordable Research Translation (START) will evaluate the processes that inhibit or promote the mobility innovation's sustainability among health care aides in daily practice. We will examine how the reminders are implemented and perceived by health care aides and licensed practical nurses, as well as how health care aides providing peer reminders are identified, received by their peers, and supported by their supervisors. DISCUSSION: START will connect up-to-date innovation research with the practice of health care aides providing direct care to a growing population of older Albertans. The project's reach extends to both supportive living and long-term care settings. Furthermore, START has the potential to introduce and sustain a broad range of innovations in various care areas, such as dementia care, wound care, and pain management - domains where the uptake and sustainability of innovations also encounter significant challenges. By identifying the optimal frequency and intensity of knowledge translation interventions, we hope to enable continuing care organizations to efficiently integrate care innovations into the day-to-day care of residents. TRIAL REGISTRATION: ClinicalTrials.gov, NCT01746459. PMID- 24160485 TI - Cost effectiveness of pilot self-assessment sites in community care services in England. AB - OBJECTIVE: Self-assessment has been advocated in community care but little is known of its cost effectiveness in practice. We evaluated cost effectiveness of pilot self-assessment approaches. METHODS: Data were collected from 13 pilot projects in England, selected by central government, between October 2006 and November 2007. These were located within preventative services for people with low-level needs, occupational therapy, or assessment and care management. Cost effectiveness, over usual care, was assessed by incremental cost-effectiveness ratios (ICERs), in British pounds per unit gain in assessment satisfaction. A public-sector perspective was adopted; the provider costs of the agencies taking part. RESULTS: At 2006-07 prices, including start-up and on-going costs, only three pilots demonstrated cost effectiveness. Two pilots in assessment and care management had ICERs of L3810 and L755 per satisfaction gained, well below a benchmark from a trial of usual assessment of L18296 per satisfaction gained. When extrapolating uptake to numbers accessing assessments over 1 year, one occupational therapy pilot, of L123/satisfaction gained, also fell below this benchmark in sensitivity analysis. There was less evidence for preventative services. CONCLUSIONS AND IMPLICATIONS: Most pilot projects were not cost effective. However, self assessment is potentially cost effective in assessment and care management and occupational therapy services. Better quality cost data from pilot sites would have permitted more detailed analysis. Measuring downstream effects in terms of users' well being from receipt of self-assessment would also be beneficial. PMID- 24160487 TI - What makes y family pols potential candidates for molecular targeted therapies and novel biotechnological applications. AB - Nature has evolved DNA polymerases (Pols) with different replication fidelity with the purpose of maintaining and faithfully propagating the genetic information. Besides the four classical Pols (Pol alpha, delta, epsilon, gamma), mammalian cells contain at least twelve specialized Pols whose functions have been discovered recently and are still not completely elucidated. Among them, Pols belonging to the Y family contribute to cell survival by promoting DNA damage tolerance. They are primarily involved in the translesion synthesis (TLS) pathway, incorporating dNTPs in an error-free or error-prone manner, depending on the nature of the DNA lesion. From an evolutionary point of view, their high mutagenic potential seems to guarantee the proper flexibility of vital importance for both adaptation to a changeable environment and evolution of the species. These Pols are subjected to a complex network of regulation, since their uncontrolled access to DNA might promote mutagenesis and neoplastic transformation. Altered expression of Y family is a hallmark of several tumor types. In recent years, the unique structure and properties of Y family Pols have been exploited to design molecules that selectively interfere with the Pol of interest with minimal effect on normal cells. In addition, their distinctive properties have been applied to innovative techniques, such as compartmentalized self-replication (CSR), short-patch CSR, phage display and molecular breeding. These approaches are based on mutant Pols provided with novel and ameliorated features and find applications in various fields, from biotechnology to diagnostics, paleontology and forensic analysis. PMID- 24160490 TI - Communication: The ionization spectroscopy of mixed carboxylic acid dimers. AB - We report mass analyzed threshold ionization spectroscopy of supersonically cooled gas phase carboxylic complexes with 9-hydroxy-9-fluorenecarboxylic acid (9HFCA), an analog of glycolic acid. The vibrationally resolved cation spectrum for the 9HFCA complex with formic acid allows accurate determination of its ionization potential (IP), 64,374 +/- 8 cm(-1). This is 545 cm(-1) smaller than the IP of 9HFCA monomer. The IPs of 9HFCA complexes with acetic acid and benzoic acid shift by -1133 cm(-1) and -1438 cm(-1), respectively. Density functional calculations confirm that Cs symmetry is maintained upon ionization of the 9HFCA monomer and its acid complexes, in contrast to the drastic geometric rearrangement attending ionization in complexes of 9-fluorene carboxylic acid. We suggest that the marginal geometry changes and small IP shifts are primarily due to the collective interactions among one intramolecular and two intermolecular hydrogen bonds in the dimer. PMID- 24160489 TI - Perspective: Coulomb fluids--weak coupling, strong coupling, in between and beyond. AB - We present a personal view on the current state of statistical mechanics of Coulomb fluids with special emphasis on the interactions between macromolecular surfaces, concentrating on the weak and the strong coupling limits. Both are introduced for a (primitive) counterion-only system in the presence of macroscopic, uniformly charged boundaries, where they can be derived systematically. Later we show how this formalism can be generalized to the cases with additional characteristic length scales that introduce new coupling parameters into the problem. These cases most notably include asymmetric ionic mixtures with mono- and multivalent ions that couple differently to charged surfaces, ions with internal charge (multipolar) structure and finite static polarizability, where weak and strong coupling limits can be constructed by analogy with the counterion-only case and lead to important new insights into their properties that cannot be derived by any other means. PMID- 24160491 TI - Communication: A tractable design for a thermal transistor. AB - We propose a conceptual design for a logic device that is the thermal analog of a transistor. It has fixed hot (emitter) and cold (collector) temperatures, and a gate controls the heat current. Thermal logic could be applied for thermal digital computing, enhance energy conservation, facilitate thermal rheostats, and enable the transport of phononic data. We demonstrate such a device using molecular dynamics simulations that consider thermal transport across hot and cold solid Si regions that seal water within them. Changes in the hot side, or emitter, heat current are linear with respect to varying gate temperature but the corresponding variation in the collector current is nonlinear. This nonlinear variation in collector current defines the ON and OFF states of the device. In its OFF state, the thermal conductivity of the device is positive. In the ON state, however, more heat is extracted through the cold terminal than is provided at the hot terminal due to the intervention of the base terminal. This makes it possible to alter the transport factor by varying the gate conditions. When the device is ON, the transport factor is greater than unity, i.e., more heat is rejected at the collector than is supplied to the emitter. PMID- 24160492 TI - Communication: Predictive partial linearized path integral simulation of condensed phase electron transfer dynamics. AB - A partial linearized path integral approach is used to calculate the condensed phase electron transfer (ET) rate by directly evaluating the flux-flux/flux-side quantum time correlation functions. We demonstrate for a simple ET model that this approach can reliably capture the transition between non-adiabatic and adiabatic regimes as the electronic coupling is varied, while other commonly used semi-classical methods are less accurate over the broad range of electronic couplings considered. Further, we show that the approach reliably recovers the Marcus turnover as a function of thermodynamic driving force, giving highly accurate rates over four orders of magnitude from the normal to the inverted regimes. We also demonstrate that the approach yields accurate rate estimates over five orders of magnitude of inverse temperature. Finally, the approach outlined here accurately captures the electronic coherence in the flux-flux correlation function that is responsible for the decreased rate in the inverted regime. PMID- 24160493 TI - Communication: H-atom reactivity as a function of temperature in solid parahydrogen: The H + N2O reaction. AB - We present low temperature kinetic measurements for the H + N2O association reaction in solid parahydrogen (pH2) at liquid helium temperatures (1-5 K). We synthesize (15)N2(18)O doped pH2 solids via rapid vapor deposition onto an optical substrate attached to the cold tip of a liquid helium bath cryostat. We then subject the solids to short duration 193 nm irradiations to generate H-atoms produced as byproducts of the in situ N2O photodissociation, and monitor the subsequent reaction kinetics using rapid scan FTIR. For reactions initiated in solid pH2 at 4.3 K we observe little to no reaction; however, if we then slowly reduce the temperature of the solid we observe an abrupt onset to the H + N2O -> cis-HNNO reaction at temperatures below 2.4 K. This abrupt change in the reaction kinetics is fully reversible as the temperature of the solid pH2 is repeatedly cycled. We speculate that the observed non-Arrhenius behavior (negative activation energy) is related to the stability of the pre-reactive complex between the H-atom and (15)N2(18)O reagents. PMID- 24160494 TI - Molecular density functional theory of water describing hydrophobicity at short and long length scales. AB - We present an extension of our recently introduced molecular density functional theory of water [G. Jeanmairet et al., J. Phys. Chem. Lett. 4, 619 (2013)] to the solvation of hydrophobic solutes of various sizes, going from angstroms to nanometers. The theory is based on the quadratic expansion of the excess free energy in terms of two classical density fields: the particle density and the multipolar polarization density. Its implementation requires as input a molecular model of water and three measurable bulk properties, namely, the structure factor and the k-dependent longitudinal and transverse dielectric susceptibilities. The fine three-dimensional water structure around small hydrophobic molecules is found to be well reproduced. In contrast, the computed solvation free-energies appear overestimated and do not exhibit the correct qualitative behavior when the hydrophobic solute is grown in size. These shortcomings are corrected, in the spirit of the Lum-Chandler-Weeks theory, by complementing the functional with a truncated hard-sphere functional acting beyond quadratic order in density, and making the resulting functional compatible with the Van-der-Waals theory of liquid-vapor coexistence at long range. Compared to available molecular simulations, the approach yields reasonable solvation structure and free energy of hard or soft spheres of increasing size, with a correct qualitative transition from a volume-driven to a surface-driven regime at the nanometer scale. PMID- 24160495 TI - Hybrid approach combining dissipative particle dynamics and finite-difference diffusion model: simulation of reactive polymer coupling and interfacial polymerization. AB - A novel hybrid approach combining dissipative particle dynamics (DPD) and finite difference (FD) solution of partial differential equations is proposed to simulate complex reaction-diffusion phenomena in heterogeneous systems. DPD is used for the detailed molecular modeling of mass transfer, chemical reactions, and phase separation near the liquid/liquid interface, while FD approach is applied to describe the large-scale diffusion of reactants outside the reaction zone. A smooth, self-consistent procedure of matching the solute concentration is performed in the buffer region between the DPD and FD domains. The new model is tested on a simple model system admitting an analytical solution for the diffusion controlled regime and then applied to simulate practically important heterogeneous processes of (i) reactive coupling between immiscible end functionalized polymers and (ii) interfacial polymerization of two monomers dissolved in immiscible solvents. The results obtained due to extending the space and time scales accessible to modeling provide new insights into the kinetics and mechanism of those processes and demonstrate high robustness and accuracy of the novel technique. PMID- 24160496 TI - State-averaged Monte Carlo configuration interaction applied to electronically excited states. AB - We introduce state-averaging into the method of Monte Carlo configuration interaction (SA-MCCI) to allow the stable and efficient calculation of excited states. We show that excited potential curves for H3, including a crossing with the ground state, can be accurately reproduced using a small fraction of the full configuration interaction (FCI) space. A recently introduced error measure for potential curves [J. P. Coe and M. J. Paterson, J. Chem. Phys. 137, 204108 (2012)] is also shown to be a fair approach when considering potential curves for multiple states. We demonstrate that potential curves for LiF using SA-MCCI agree well with the FCI results and the avoided crossing occurs correctly. The seam of conical intersections for CH2 found by Yarkony [J. Chem. Phys. 104, 2932 (1996)] is used as a test for SA-MCCI and we compare potential curves from SA-MCCI with FCI results for this system for the first three triplet states. We then demonstrate the improvement from using SA-MCCI on the dipole of the 2 (1)A1 state of carbon monoxide. We then look at vertical excitations for small organic molecules up to the size of butadiene where the SA-MCCI energies and oscillator strengths are compared with CASPT2 values [M. Schreiber, M. R. Silva-Junior, S. P. A. Sauer, and W. Thiel, J. Chem. Phys. 128, 134110 (2008)]. We finally see if the SA-MCCI results for these excitation energies can be improved by using MCCIPT2 with approximate natural orbitals when the PT2 space is not onerously large. PMID- 24160488 TI - Molecular diagnosis in autoimmune skin blistering conditions. AB - Blister formation in skin and mucous membranes results from a loss of cell-cell or cell-matrix adhesion and is a common outcome of pathological events in a variety of conditions, including autoimmune and genetic diseases, viral and bacterial infections, or injury by physical and chemical factors. Autoantibodies against structural components maintaining cell-cell and cell-matrix adhesion induce tissue damage in autoimmune blistering diseases. Detection of these autoantibodies either tissue-bound or circulating in serum is essential to diagnose the autoimmune nature of disease. Various immunofluorescence methods as well as molecular immunoassays, including enzyme-linked immunosorbent assay and immunoblotting, belong to the modern diagnostic algorithms for these disorders. There is still a considerable need to increase awareness of the rare autoimmune blistering diseases, which often show a severe, chronic-relapsing course, among physicians and the public. This review article describes the immunopathological features of autoimmune bullous diseases and the molecular immunoassays currently available for their diagnosis and monitoring. PMID- 24160497 TI - A multi-state fragment charge difference approach for diabatic states in electron transfer: extension and automation. AB - The electron transfer (ET) rate prediction requires the electronic coupling values. The Generalized Mulliken-Hush (GMH) and Fragment Charge Difference (FCD) schemes have been useful approaches to calculate ET coupling from an excited state calculation. In their typical form, both methods use two eigenstates in forming the target charge-localized diabatic states. For problems involve three or four states, a direct generalization is possible, but it is necessary to pick and assign the locally excited or charge-transfer states involved. In this work, we generalize the 3-state scheme for a multi-state FCD without the need of manual pick or assignment for the states. In this scheme, the diabatic states are obtained separately in the charge-transfer or neutral excited subspaces, defined by their eigenvalues in the fragment charge-difference matrix. In each subspace, the Hamiltonians are diagonalized, and there exist off-diagonal Hamiltonian matrix elements between different subspaces, particularly the charge-transfer and neutral excited diabatic states. The ET coupling values are obtained as the corresponding off-diagonal Hamiltonian matrix elements. A similar multi-state GMH scheme can also be developed. We test the new multi-state schemes for the performance in systems that have been studied using more than two states with FCD or GMH. We found that the multi-state approach yields much better charge localized states in these systems. We further test for the dependence on the number of state included in the calculation of ET couplings. The final coupling values are converged when the number of state included is increased. In one system where experimental value is available, the multi-state FCD coupling value agrees better with the previous experimental result. We found that the multi state GMH and FCD are useful when the original two-state approach fails. PMID- 24160498 TI - The extended Koopmans' theorem for orbital-optimized methods: accurate computation of ionization potentials. AB - The extended Koopmans' theorem (EKT) provides a straightforward way to compute ionization potentials (IPs) from any level of theory, in principle. However, for non-variational methods, such as Moller-Plesset perturbation and coupled-cluster theories, the EKT computations can only be performed as by-products of analytic gradients as the relaxed generalized Fock matrix (GFM) and one- and two-particle density matrices (OPDM and TPDM, respectively) are required [J. Cioslowski, P. Piskorz, and G. Liu, J. Chem. Phys. 107, 6804 (1997)]. However, for the orbital optimized methods both the GFM and OPDM are readily available and symmetric, as opposed to the standard post Hartree-Fock (HF) methods. Further, the orbital optimized methods solve the N-representability problem, which may arise when the relaxed particle density matrices are employed for the standard methods, by disregarding the orbital Z-vector contributions for the OPDM. Moreover, for challenging chemical systems, where spin or spatial symmetry-breaking problems are observed, the abnormal orbital response contributions arising from the numerical instabilities in the HF molecular orbital Hessian can be avoided by the orbital-optimization. Hence, it appears that the orbital-optimized methods are the most natural choice for the study of the EKT. In this research, the EKT for the orbital-optimized methods, such as orbital-optimized second- and third-order Moller-Plesset perturbation [U. Bozkaya, J. Chem. Phys. 135, 224103 (2011)] and coupled-electron pair theories [OCEPA(0)] [U. Bozkaya and C. D. Sherrill, J. Chem. Phys. 139, 054104 (2013)], are presented. The presented methods are applied to IPs of the second- and third-row atoms, and closed- and open-shell molecules. Performances of the orbital-optimized methods are compared with those of the counterpart standard methods. Especially, results of the OCEPA(0) method (with the aug-cc-pVTZ basis set) for the lowest IPs of the considered atoms and closed shell molecules are substantially accurate, the corresponding mean absolute errors are 0.11 and 0.15 eV, respectively. PMID- 24160499 TI - Analytic evaluation of the dipole Hessian matrix in coupled-cluster theory. AB - The general theory required for the calculation of analytic third energy derivatives at the coupled-cluster level of theory is presented and connected to preceding special formulations for hyperpolarizabilities and polarizability gradients. Based on our theory, we have implemented a scheme for calculating the dipole Hessian matrix in a fully analytical manner within the coupled-cluster singles and doubles approximation. The dipole Hessian matrix is the second geometrical derivative of the dipole moment and thus a third derivative of the energy. It plays a crucial role in IR spectroscopy when taking into account anharmonic effects and is also essential for computing vibrational corrections to dipole moments. The superior accuracy of the analytic evaluation of third energy derivatives as compared to numerical differentiation schemes is demonstrated in some pilot calculations. PMID- 24160500 TI - Proper and improper zero energy modes in Hartree-Fock theory and their relevance for symmetry breaking and restoration. AB - We study the spectra of the molecular orbital Hessian (stability matrix) and random-phase approximation (RPA) Hamiltonian of broken-symmetry Hartree-Fock solutions, focusing on zero eigenvalue modes. After all negative eigenvalues are removed from the Hessian by following their eigenvectors downhill, one is left with only positive and zero eigenvalues. Zero modes correspond to orbital rotations with no restoring force. These rotations determine states in the Goldstone manifold, which originates from a spontaneously broken continuous symmetry in the wave function. Zero modes can be classified as improper or proper according to their different mathematical and physical properties. Improper modes arise from symmetry breaking and their restoration always lowers the energy. Proper modes, on the other hand, correspond to degeneracies of the wave function, and their symmetry restoration does not necessarily lower the energy. We discuss how the RPA Hamiltonian distinguishes between proper and improper modes by doubling the number of zero eigenvalues associated with the latter. Proper modes in the Hessian always appear in pairs which do not double in RPA. We present several pedagogical cases exemplifying the above statements. The relevance of these results for projected Hartree-Fock methods is also addressed. PMID- 24160501 TI - Nonstatistical dynamics on potentials exhibiting reaction path bifurcations and valley-ridge inflection points. AB - We study reaction dynamics on a model potential energy surface exhibiting post transition state bifurcation in the vicinity of a valley ridge inflection (VRI) point. We compute fractional yields of products reached after the VRI region is traversed, both with and without dissipation. It is found that apparently minor variations in the potential lead to significant changes in the reaction dynamics. Moreover, when dissipative effects are incorporated, the product ratio depends in a complicated and highly non-monotonic fashion on the dissipation parameter. Dynamics in the vicinity of the VRI point itself play essentially no role in determining the product ratio, except in the highly dissipative regime. PMID- 24160502 TI - Dynamical second-order Bethe-Salpeter equation kernel: a method for electronic excitation beyond the adiabatic approximation. AB - We present a dynamical second-order kernel for the Bethe-Salpeter equation to calculate electronic excitation energies. The derivation takes explicitly the functional derivative of the exact second-order self energy with respect to the one-particle Green's function. It includes naturally a frequency dependence, going beyond the adiabatic approximation. Perturbative calculations under the Tamm-Dancoff approximation, using the configuration interaction singles (CIS) eigenvectors, reveal an appreciable improvement over CIS, time-dependent Hartree Fock, and adiabatic time-dependent density functional theory results. The perturbative results also compare well with equation-of-motion coupled-cluster and experimental results. PMID- 24160503 TI - Model-free simulation approach to molecular diffusion tensors. AB - In the present work, we propose a simple model-free approach for the computation of molecular diffusion tensors from molecular dynamics trajectories. The method uses a rigid body trajectory of the molecule under consideration, which is constructed a posteriori by an accumulation of quaternion-based superposition fits of consecutive conformations. From the rigid body trajectory, we compute the translational and angular velocities of the molecule and by integration of the latter also the corresponding angular trajectory. All quantities can be referred to the laboratory frame and a molecule-fixed frame. The 6 * 6 diffusion tensor is computed from the asymptotic slope of the tensorial mean square displacement and, for comparison, also from the Kubo integral of the velocity correlation tensor. The method is illustrated for two simple model systems - a water molecule and a lysozyme molecule in bulk water. We give estimations of the statistical accuracy of the calculations. PMID- 24160504 TI - Direct measurements of collisional Raman line broadening in the S-branch transitions of acetylene (C2H2). AB - We report direct measurements of the self- and N2-broadened Raman S-branch linewidths of acetylene (C2H2), obtained by employing time-resolved picosecond rotational coherent anti-Stokes Raman scattering spectroscopy. Using broadband 115-ps pump and Stokes pulses (~135 cm(-1) bandwidth) and a spectrally narrowed 90-ps probe pulse (~0.2 cm(-1) bandwidth), Raman-coherence lifetimes are measured at room temperature for the S-branch (DeltaJ = +2) transitions associated with rotational quantum number J = 3-25. These directly measured Raman-coherence lifetimes, when converted to collisional linewidth broadening coefficients, differ from the previously reported broadening coefficients extracted from theoretical calculations by 6%-35% for self-broadening for C2H2 and by up to 60% for N2-broadened C2H2. PMID- 24160505 TI - Stationary flow conditions in pulsed supersonic beams. AB - We describe a generally applicable method for the experimental determination of stationary flow conditions in pulsed supersonic beams, utilizing time-resolved electron induced fluorescence measurements of high pressure jet expansions of helium. The detection of ultraviolet photons from electronically excited helium emitted very close to the nozzle exit images the valve opening behavior-with the decided advantage that a photon signal is not affected by beam-skimmer and beam residual gas interactions; it thus allows to conclusively determine those operation parameters of a pulsed valve that yield complete opening. The studies reveal that a "flat-top" signal, indicating constant density and commonly considered as experimental criterion for continuous flow, is insufficient. Moreover, translational temperature and mean terminal flow velocity turn out to be significantly more sensitive in testing for the equivalent behavior of a continuous nozzle source. Based on the widely distributed Even-Lavie valve we demonstrate that, in principle, it is possible to achieve quasi-continuous flow conditions even with fast-acting valves; however, the two prerequisites are a minimum pulse duration that is much longer than standard practice and previous estimates, and a suitable tagging of the appropriate beam segment. PMID- 24160506 TI - Perturbation facilitated two-color four-wave-mixing spectroscopy of C3. AB - Perturbation-facilitated two-color resonant four-wave-mixing spectroscopy is realized to access the (dark) triplet manifold of the C3 molecule from the singlet X(1)Sigmag (+) ground state. The inherent nonlinear signal dependence and coherence of the technique result in a favorable detection of the excited triplet states of interest. The observation of a newly found (3)Deltau electronic state is achieved by a two-step excitation via "gate-way" levels (i.e., singlet-triplet mixed levels). Additionally, by fixing the probe laser on a transition exhibiting mainly triplet-triplet character and scanning the pump laser, we demonstrate an effective spin-filtering in a four-wave mixing measurement where only transitions to the perturber (3)Sigmau(-) state appear exclusively in an otherwise congested spectral range of the Comet band. Ab initio calculations of excited triplet states complement our analysis with the electronic assignment of the observed resonances. PMID- 24160507 TI - Electronic transitions in liquid amides studied by using attenuated total reflection far-ultraviolet spectroscopy and quantum chemical calculations. AB - Attenuated total reflection far-ultraviolet (ATR-FUV) spectra in the 140-260 nm region were measured for several types of liquid amides (formamide, FA; N methylformamide, NMF; N-methylacetamide, NMA; N,N-dimethylformamide, NdMF; and N,N-dimethylacetamide, NdMA) to investigate their electronic transitions in the FUV region. The spectra were compared with the corresponding gas-phase spectra to examine the shift in the major absorption band in the 180-200 nm region going from the gas phase to the liquid phase, and it was found that the peak shift was dependent on the particular amide. FA and NMF, which exhibit intermolecular C=O[ellipsis...H-N hydrogen bonding, show a large shift of ~0.60 eV to lower energy; however, NMA, which also exhibits hydrogen bonding, shows only a small shift. In NdMF and NdMA, C=O groups seem to be coupled, which results in a small peak shift. Two types of quantum chemical calculations, time-dependent density functional theory (TD-DFT) and symmetry-adapted-cluster configuration interaction (SAC-CI) method, were performed to elucidate the origin of the shifts and the band assignments. The shift estimated by the monomer and dimer models with TD-DFT reproduced well the observed shift from the gas phase to the liquid phase. This suggests that the intermolecular hydrogen-bonding interaction significantly affects the magnitude of the shift. The many-body effects were also considered using the larger cluster models (trimer to pentamer). The energy shift calculated using SAC-CI with the monomer and the state-specific polarizable continuum model was also accurate, indicating that the nonlinear polarization effect appears to be important. As for the band assignments, it was found that though the major band can be mainly attributed to the pi-pi* transition, several types of Rydberg transitions also exist in its vicinity and mixing of orbitals with the same symmetry occurs. The number and type of Rydberg transitions in the spectra depend upon the type of amide molecules. The valence-Rydberg coupling of the pi-pi* transition is more significant than n-pi* transition, which also holds in the pure liquid phase. PMID- 24160508 TI - Topology of conical/surface intersections among five low-lying electronic states of CO2: multireference configuration interaction calculations. AB - Multi-reference configuration interaction with single and double excitation method has been utilized to calculate the potential energy surfaces of the five low-lying electronic states (1)A1, (1)A2, (3)A2, (1)B2, and (3)B2 of carbon dioxide molecule. Topology of intersections among these five states has been fully analyzed and is associated with double-well potential energy structure for every electronic state. The analytical potential energy surfaces based on the reproducing kernel Hilbert space method have been utilized for illustrating topology of surface crossings. Double surface seam lines between (1)A1 and (3)B2 states have been found inside which the (3)B2 state is always lower in potential energy than the (1)A1 state, and thus it leads to an angle bias collision dynamics. Several conical/surface intersections among these five low-lying states have been found to enrich dissociation pathways, and predissociation can even prefer bent-geometry channels. Especially, the dissociation of O((3)P) + CO can take place through the intersection between (3)B2 and (1)B2 states, and the intersection between (3)A2 and (1)B2 states. PMID- 24160509 TI - Mode-specific tunneling using the Qim path: theory and an application to full dimensional malonaldehyde. AB - We present a theory of mode-specific tunneling that makes use of the general tunneling path along the imaginary-frequency normal mode of the saddle point, Qim, and the associated relaxed potential, V(Qim) [Y. Wang and J. M. Bowman, J. Chem. Phys. 129, 121103 (2008)]. The novel aspect of the theory is the projection of the normal modes of a minimum onto the Qim path and the determination of turning points on V(Qim). From that projection, the change in tunneling upon mode excitation can be calculated. If the projection is zero, no enhancement of tunneling is predicted. In that case vibrationally adiabatic (VA) theory could apply. However, if the projection is large then VA theory is not applicable. The approach is applied to mode-specific tunneling in full-dimensional malonaldehyde, using an accurate full-dimensional potential energy surface. Results are in semi quantitative agreement with experiment for modes that show large enhancement of the tunneling, relative to the ground state tunneling splitting. For the six out of-plane modes, which have zero projection on the planar Qim path, VA theory does apply, and results from that theory agree qualitatively and even semi quantitatively with experiment. We also verify the failure of simple VA theory for modes that show large enhancement of tunneling. PMID- 24160510 TI - High resolution spectroscopy of HCl-water clusters: IR bands of undissociated and dissociated clusters revisited. AB - We report a detailed study on the IR spectroscopy of HCl-water complexes in superfluid helium nanodroplets in the frequency range from 2660 to 2675 cm(-1). We have recorded spectra of HCl-H2(16)O as well as of HCl-H2(18)O complexes and compared these results with theoretical predictions. In addition, we have carried out mass-selective intensity measurements as a function of partial pressure of HCl as well as of H2(18)O (pick-up curves). The results support a scenario where the IR-absorption in this part of the spectrum contains contributions from undissociated as well as from dissociated clusters with Cl(-)(H2O)3(H3O)(+) being the smallest dissociated complex. These findings are corroborated by additional electric field measurements yielding the orientation of the vibrational transition moment with respect to the permanent dipole moment. As a result we are able to assign a broad absorption band starting at 2675 cm(-1) to dissociated HCl water clusters (HCl)1(H2O)n with n >= 4. The two narrow absorption lines at 2667.9 cm(-1) and 2670 cm(-1) are assigned to an undissociated cluster, in agreement with previous studies. PMID- 24160511 TI - Accurate ab initio-based adiabatic global potential energy surface for the 2(2)A" state of NH2 by extrapolation to the complete basis set limit. AB - A full three-dimensional global potential energy surface is reported first time for the title system, which is important for the photodissociation processes. It is obtained using double many-body expansion theory and an extensive set of accurate ab initio energies extrapolated to the complete basis set limit. Such a work can be recommended for dynamics studies of the N((2)D) + H2 reaction, a reliable theoretical treatment of the photodissociation dynamics and as building blocks for constructing the double many-body expansion potential energy surface of larger nitrogen/hydrogen containing systems. In turn, a preliminary theoretical study of the reaction N((2)D)+H2(X(1)Sigmag (+))(nu=0,j=0) >NH(a(1)Delta)+H((2)S) has been carried out with the method of quasi-classical trajectory on the new potential energy surface. Integral cross sections and thermal rate constants have been calculated, providing perhaps the most reliable estimate of the integral cross sections and the rate constants known thus far for such a reaction. PMID- 24160512 TI - Corresponding states principle and van der Waals potentials of Zn2, Cd2, and Hg2. AB - Based on the assumptions that the corresponding states principle is valid for the group 12 dimers and that the interaction potentials of these dimers can be described by the Tang-Toennies potential model, a set of correlation relations between the spectroscopic constants of these dimers are derived. Some recently measured spectroscopic constants satisfy these relations quite well, but older experimental data do not. These recent spectroscopic constants and the newly available dispersion coefficients are used to construct the entire van der Waals potentials of Zn2, Cd2, and Hg2. There are indications that the ground state Hg2 potential predicted by the present study is possibly the most accurate to date. No unequivocal conclusion can be made for Zn2 and Cd2 potentials. Compared with the recent experiments, the present Zn2 bond length is eight percent too small, and the present Cd2 bond length is eight percent too large. However, both Zn2 and Cd2 bond lengths predicted by the present study are in good agreement with the quantum Monte Carlo results. PMID- 24160513 TI - Theoretical study on reaction mechanism and kinetics of HNCS with CN. AB - We presented a theoretical study on the detailed reaction mechanism and kinetics of the CN radical with the HNCS molecule. The barrierless minimum energy path and the most favorable entrance channel have been determined by constructing a two dimensional potential energy surface of the C atom of CN attacking the HNCS molecule. The reaction of the C atom attacking the S atom was finally identified as the dominant entrance channel based on the rate constants' results calculated with the canonical variational transition state theory. The master equation method was employed to calculate the products' branching ratios, the overall rate constant, and the pressure dependence of the title reaction. The B3LYP/6 311+G(2d,p) method was employed for all the geometrical optimizations and a multi level extrapolation method based on the CCSD(T) and MP2(FC) energies was employed for further energy refinements. PMID- 24160514 TI - The high-resolution infrared spectrum of DC4H from 450 to 1100 cm-1: overtone, combination, and hot bands. AB - The high-resolution infrared spectrum of monodeuterated diacetylene has been recorded in the 450-1100 cm(-1) spectral region by Fourier transform infrared spectroscopy. Seven new bands have been identified: the nu3 fundamental (C-C stretch), and the nu8 + nu9, nu7 + nu8, 2nu7, 2nu8, nu8 + nu9 - nu9, and nu6 + nu9 - nu9 combination, overtone, and hot bands. The assigned transitions, together with those previously reported for the fundamental bands [F. Tamassia, L. Bizzocchi, C. Degli Esposti, L. Dore, M. Di Lauro, L. Fusina, M. Villa, and E. Cane, Astron. Astrophys. 549, A38 (2013)], form a comprehensive data set which comprises more than 2500 ro-vibrational transitions, and involves all singly and most doubly excited vibrational states of DC4H lying below 1000 cm(-1). Rotational and vibrational l-type resonance effects among the sub-levels of excited bending states were considered in the analysis, which also included a careful treatment of the various anharmonic interactions coupling many vibrational states lying above 600 cm(-1). Reliable and unambiguous spectroscopic parameters were obtained for each investigated state, including the rotational and centrifugal distortion constants Bv and Dv, the l-type doubling parameter qt, the anharmonicity constants xL(89), xL(69), and the vibrational l-type terms r89, r69 for the v8 = v9 = 1 and v6 = v9 = 1 bend-bend combination states. PMID- 24160515 TI - An ab initio study of the electronic structure of boron arsenide, BAs. AB - The completely unexplored BAs diatomic has been thoroughly studied by high level multireference variational ab initio methods. Potential energy curves for 42 molecular states dissociating to the first four asymptotic channels and covering an energy range of 5.8 eV have been constructed revealing an interesting morphology and a rich spectroscopy. The ground state is of (3)Pi symmetry while its first excited (1)Sigma(+) state lies ~8 kcal/mol higher. A general feature of the potential curves is the presence of avoided crossings that challenge the validity of the Born Oppenheimer approximation. PMID- 24160516 TI - Six-dimensional and seven-dimensional quantum dynamics study of the OH + CH4 -> H2O + CH3 reaction. AB - The reaction dynamics of hydroxyl radical with methane has been investigated using time-dependent wave packet approach within reduced six- and seven dimensional models. Initial state-selected total reaction probabilities and integral cross sections for the hydrogen abstraction reaction have been computed on the empirical potential energy surface developed by Espinosa-Garcia et al. [J. Chem. Phys. 112, 5731 (2000)]. Excitations of the CH stretching mode and/or the CH3 umbrella mode enhance the reaction. They are, however, both less efficient than translational energy in promoting the reaction, at least at low collision energies. Also, we studied the accuracy of two approximations: centrifugal sudden (CS) and J-shifting (JS), in the calculations of the integral cross sections by a comparison to coupled-channel (CC) calculations. The integral cross sections obtained indicated that the CS approximation works well over the whole energy range studied, and the JS approximation gives accurate cross sections at low collision energies, while noticeably overestimates them at relatively high collision energies. In addition, the OH radical acts as a good spectator as it has a negligible effect on the reaction. PMID- 24160517 TI - On-the-fly semiclassical study of internal conversion rates of formaldehyde. AB - Internal conversion is an inherently quantum mechanical process. To date, "ab initio" computation of internal conversion rates was limited to harmonic based approximations. These are questionable since the typical transition to the ground electronic state occurs at energies which are far from the harmonic limit. It is thus of interest to study the applicability of the Semiclassical Initial Value Representation (SCIVR) approach which is in principle amenable to "on the fly" studies even with "many" degrees of freedom. In this work we apply the Herman Kluk-SCIVR methodology to compute the internal conversion rates for formaldehyde for a variety of initial vibronic states. The SCIVR computation gives reasonable agreement with experiment, while the harmonic approximation typically gives rates that are too high. PMID- 24160518 TI - Impact of proton transfer phenomena on the electronic structure of model Schiff bases: an AIM/NBO/ELF study. AB - Understanding of the electronic structure evolution due to a proton dynamics is a key issue in biochemistry and material science. This paper reports on density functional theory calculations of Schiff bases containing short, strong intramolecular hydrogen bonds where the bridged proton is located: (i) at the donor site, (ii) strongly delocalized, and (iii) at the acceptor site. The mobility of the bridged proton and its influence on the molecular structure and properties of the chosen Schiff base derivatives have been investigated on the basis of Atoms in Molecules, Natural Bond Orbitals, and Electron Localization Function theories. It has been observed that the extent of the bridged proton delocalization is strongly modified by the steric and inductive effects present in the studied compounds introduced by various substituents. It has been shown that: (i) potential energy profiles for the proton motion are extremely dependent on the substitution of the aromatic ring, (ii) the topology of the free electron pairs present at the donor/acceptor site, as well as their electron populations, are affected qualitatively by the bridged proton position, (iii) the distortion of the molecular structure due to the bridged proton dynamics includes the atomic charge fluctuations, which are in some cases non-monotonic, and (iv) topology of the ELF recognizes events of proton detachment from the donor and attachment to the acceptor. The quantitative and qualitative results shed light onto molecular consequences of the proton transfer phenomena. PMID- 24160519 TI - Non-Born-Oppenheimer molecular dynamics of the spin-forbidden reaction O(3P) + CO(X(1)Sigma+) -> CO2(X(1)Sigmag(+)). AB - The lowest-energy singlet (1 (1)A') and two lowest-energy triplet (1 (3)A' and 1 (3)A") electronic states of CO2 are characterized using dynamically weighted multireference configuration interaction (dw-MRCI+Q) electronic structure theory calculations extrapolated to the complete basis set (CBS) limit. Global analytic representations of the dw-MRCI+Q/CBS singlet and triplet surfaces and of their CASSCF/aug-cc-pVQZ spin-orbit coupling surfaces are obtained via the interpolated moving least squares (IMLS) semiautomated surface fitting method. The spin forbidden kinetics of the title reaction is calculated using the coupled IMLS surfaces and coherent switches with decay of mixing non-Born-Oppenheimer molecular dynamics. The calculated spin-forbidden association rate coefficient (corresponding to the high pressure limit of the rate coefficient) is 7-35 times larger at 1000-5000 K than the rate coefficient used in many detailed chemical models of combustion. A dynamical analysis of the multistate trajectories is presented. The trajectory calculations reveal direct (nonstatistical) and indirect (statistical) spin-forbidden reaction mechanisms and may be used to test the suitability of transition-state-theory-like statistical methods for spin forbidden kinetics. Specifically, we consider the appropriateness of the "double passage" approximation, of assuming statistical distributions of seam crossings, and of applications of the unified statistical model for spin-forbidden reactions. PMID- 24160520 TI - Light-induced conical intersections in polyatomic molecules: general theory, strategies of exploitation, and application. AB - When the carrier frequency of a laser pulse fits to the energy difference between two electronic states of a molecule, the potential energy surfaces of these states dressed by the field become energetically close and the states can couple strongly to each other. Recently, it has been predicted that for diatomic molecules these surfaces may exhibit a conical intersection induced by the laser light in the space of the nuclear internal and external coordinates. Here, we report a general theory of the light-induced conical intersections emerging in polyatomic molecules where additional internal degrees of freedom are involved in the dynamics. Freely rotating and also fixed-in-space arbitrary polyatomic molecules exposed to differently polarized optical laser pulses of resonant carrier frequency are considered. Detailed analysis of the theory shows how the light-induced conical intersections can be controlled by molecular orientation and by the carrier frequency, polarization, strength, and duration of the laser pulse. This opens the possibility to also control the ensuing non-adiabatic dynamics. Different strategies of exploitation of the light-induced conical intersections are proposed. The present theory is exemplified by utilizing the light-induced conical intersections to control photodissociation of the second electronically excited state S2 of the fixed-in-space cis-methyl nitrite CH3ONO. PMID- 24160521 TI - The test-particle induced inhomogeneous direct correlation functions and extensions of Widom's theorem: impacts on the incremental chemical potentials and high-order correlation functions. AB - We develop the potential distributions of several test particles to obtain a hierarchy of the nonuniform singlet direct correlation functions (s-DCFs). These correlation functions are interpreted as the segmental chemical potentials or works of insertion of successive test particles in a classical fluid. The development has several interesting consequences: (i) it extends the Widom particle insertion formula to higher-order theorems, the first member gives the chemical potential as in the original theorem, the second member gives the incremental energy for dimer formation, with higher members giving the energies for forming trimers, tetramers, etc. (ii) The second and third order s-DCFs can be related to the cavity distribution functions y((2)) and y((3)) in the liquid state theory. Thus we can express the triplet cavity function y((3)) in terms of these s-DCFs in an exact form. This enables us to calculate, as an illustration of the above theoretical developments, the numerical values of the s-DCFs via Monte Carlo (MC) simulation data on hard spheres. We use these data to critically analyze the commonly used approximations, the Kirkwood superposition (KSA) and the linear approximation (LA) for triplet correlation functions. An improved rule over KSA and LA is proposed for triplet hard spheres in the rolling-contact configurations. (iii) The s-DCFs are naturally suited for analyzing the chain incremental Ansatz or hypothesis in the calculation of the chemical potentials of polymeric chain molecules. The first few segments of a polymer chain have been shown from extensive Monte Carlo simulations to not obey this Ansatz. By examining the insertion energies of successive segments through the s-DCFs, we are able to quantitatively decipher the decay of the segmental chemical potentials for at least the first three segments. Comparison with MC data on 4 mer and 8-mer hard-sphere fluids shows commensurate behavior with the s-DCFs. In addition, an analytical density functional theory is derived, through the potential distribution theorem, for obtaining these nonuniform direct correlation functions. PMID- 24160522 TI - Distinct dynamical and structural properties of a core-softened fluid when confined between fluctuating and fixed walls. AB - Molecular dynamics simulations were used to study the structural and dynamical properties of a water-like core-softened fluid under confinement when the confining media is rigid or fluctuating. The fluid is modeled using a two-length scale potential that reproduces, in the bulk, the anomalous behavior observed in water. We perform simulations in the NVT ensemble for fixed flat walls and in the NpT ensemble using a fluctuating wall control of pressure to study how the fluid behavior is affected by fixed and non-fixed walls. Our results indicate that the dynamical and structural properties of the fluid are strongly affected by the wall mobility. PMID- 24160523 TI - Thermodynamic properties of supercritical n-m Lennard-Jones fluids and isochoric and isobaric heat capacity maxima and minima. AB - Molecular dynamics simulations are reported for the thermodynamic properties of n m Lennard-Jones fluids, where n = 10 and 12, and m = 5 and 6. Results are reported for the thermal expansion coefficient, isothermal and adiabatic compressibilities, isobaric and isochoric heat capacities, Joule-Thomson coefficient, and speed of sound at supercritical conditions covering a wide range of fluid densities. The thermodynamic criteria for maxima/minima in the isochoric and isobaric heat capacities are identified and the simulation results are also compared with calculations from Lennard-Jones equations of state. The Johnson et al. [Mol. Phys. 78, 591 (1993)] equation of state can be used to reproduce all heat capacity phenomena reported [T. M. Yigzawe and R. J. Sadus, J. Chem. Phys. 138, 194502 (2013)] from molecular dynamics simulations for the 12-6 Lennard Jones potential. Significantly, these calculations and molecular dynamics results for other n-m Lennard-Jones potentials support the existence of Cp minima at supercritical conditions. The values of n and m also have a significant influence on many other thermodynamic properties. PMID- 24160524 TI - Accurate statistical associating fluid theory for chain molecules formed from Mie segments. AB - A highly accurate equation of state (EOS) for chain molecules formed from spherical segments interacting through Mie potentials (i.e., a generalized Lennard-Jones form with variable repulsive and attractive exponents) is presented. The quality of the theoretical description of the vapour-liquid equilibria (coexistence densities and vapour pressures) and the second-derivative thermophysical properties (heat capacities, isobaric thermal expansivities, and speed of sound) are critically assessed by comparison with molecular simulation and with experimental data of representative real substances. Our new EOS represents a notable improvement with respect to previous versions of the statistical associating fluid theory for variable range interactions (SAFT-VR) of the generic Mie form. The approach makes rigorous use of the Barker and Henderson high-temperature perturbation expansion up to third order in the free energy of the monomer Mie system. The radial distribution function of the reference monomer fluid, which is a prerequisite for the representation of the properties of the fluid of Mie chains within a Wertheim first-order thermodynamic perturbation theory (TPT1), is calculated from a second-order expansion. The resulting SAFT-VR Mie EOS can now be applied to molecular fluids characterized by a broad range of interactions spanning from soft to very repulsive and short-ranged Mie potentials. A good representation of the corresponding molecular-simulation data is achieved for model monomer and chain fluids. When applied to the particular case of the ubiquitous Lennard-Jones potential, our rigorous description of the thermodynamic properties is of equivalent quality to that obtained with the empirical EOSs for LJ monomer (EOS of Johnson et al.) and LJ chain (soft-SAFT) fluids. A key feature of our reformulated SAFT-VR approach is the greatly enhanced accuracy in the near-critical region for chain molecules. This attribute, combined with the accurate modeling of second-derivative properties, allows for a much improved global representation of the thermodynamic properties and fluid-phase equilibria of pure fluids and their mixtures. PMID- 24160525 TI - Determining the phase diagram of water from direct coexistence simulations: the phase diagram of the TIP4P/2005 model revisited. AB - Direct coexistence simulations between the fluid and solid phases are performed for several ices. For ices Ih and VII it has already been shown that the methodology is successful and the melting point is in agreement with that obtained from free energy calculations. In this work the methodology is applied to ices II, III, V, and VI. The lengths of the direct coexistence runs for the high pressure polymorphs are not too long and last less than 20 ns for all ices except for ice II where longer runs (of about 150 ns) are needed. For ices II, V, and VI the results obtained are completely consistent with those obtained from free energy calculations. However, for ice III it is found that the melting point from direct coexistence simulations is higher than that obtained from free energy calculations, the difference being greater than the statistical error. Since ice III presents partial proton orientational disorder, the departure is attributed to differences in the partial proton order in the water model with respect to that found in the experiment. The phase diagram of the TIP4P/2005 model is recalculated using the melting points obtained from direct coexistence simulations. The new phase diagram is similar to the previous one except for the coexistence lines where ice III is involved. The range of stability of ice III on the p-T plot of the phase diagram increases significantly. It is seen that the model qualitatively describes the phase diagram of water. In this work it is shown that the complete phase diagram of water including ices Ih, II, III, V, VI, VII, and the fluid phase can be obtained from direct coexistence simulations without the need of free energy calculations. PMID- 24160526 TI - Unified interatomic potential and energy barrier distributions for amorphous oxides. AB - Amorphous tantala, titania, and hafnia are important oxides for biomedical implants, optics, and gate insulators. Understanding the effects of oxide doping is crucial to optimize performance in these applications. However, no molecular dynamics potentials have been created to date that combine these and other oxides that would allow computational analyses of doping-dependent structural and mechanical properties. We report a novel set of computationally efficient, two body potentials modeling van der Waals and covalent interactions that reproduce the structural and elastic properties of both pure and doped amorphous oxides. In addition, we demonstrate that the potential accurately produces energy barrier distributions for pure and doped samples. The distributions can be directly compared to experiment and used to calculate physical quantities such as internal friction to understand how doping affects material properties. Future analyses using these potentials will be of great value to determine optimal doping concentrations and material combinations for myriad material science applications. PMID- 24160527 TI - Evidence and characterization of dynamic heterogeneity in binary mixtures of phosphoric acid and benzimidazole. AB - We report here anomalous diffusions of components in mixtures of monomer of polybenzimidazole, i.e., 2-phenyl-1H,1'H-5,5'-bibenzo[d]imidazole (BI) and phosphoric acid (PA) from molecular dynamics simulations. We have observed initial drop and further increase in self-diffusion constant for both monomer molecule (BI) and PA with gradual increase in PA concentration. The origin of such anomalous diffusion is identified in this work, which happens to be the presence of dynamic heterogeneity in each component of the binary mixture. We characterized microscopic picture of dynamical heterogeneity by finding correlation between dynamical heterogeneity and structural arrangement among the components of the binary system. Different types of H-bonding arrangements in the BI-PA systems at different concentration of PA are observed. The stability of the H-bonded network consisting of different types of H-bonds between BI and PA in the system has been studied by calculating the lifetime of various H-bonds. The results indicate that there are fast and slow moving PA molecules in the mixtures because of coexistence of different types of hydrogen bonds among the components of the mixture. PMID- 24160528 TI - On the accuracy of van der Waals inclusive density-functional theory exchange correlation functionals for ice at ambient and high pressures. AB - Density-functional theory (DFT) has been widely used to study water and ice for at least 20 years. However, the reliability of different DFT exchange-correlation (xc) functionals for water remains a matter of considerable debate. This is particularly true in light of the recent development of DFT based methods that account for van der Waals (vdW) dispersion forces. Here, we report a detailed study with several xc functionals (semi-local, hybrid, and vdW inclusive approaches) on ice Ih and six proton ordered phases of ice. Consistent with our previous study [B. Santra, J. Klimes, D. Alfe, A. Tkatchenko, B. Slater, A. Michaelides, R. Car, and M. Scheffler, Phys. Rev. Lett. 107, 185701 (2011)] which showed that vdW forces become increasingly important at high pressures, we find here that all vdW inclusive methods considered improve the relative energies and transition pressures of the high-pressure ice phases compared to those obtained with semi-local or hybrid xc functionals. However, we also find that significant discrepancies between experiment and the vdW inclusive approaches remain in the cohesive properties of the various phases, causing certain phases to be absent from the phase diagram. Therefore, room for improvement in the description of water at ambient and high pressures remains and we suggest that because of the stern test the high pressure ice phases pose they should be used in future benchmark studies of simulation methods for water. PMID- 24160529 TI - Self-diffusion of carbon dioxide in samaria/alumina aerogel catalyst using high field NMR diffusometry. AB - Pulsed field gradient (PFG) NMR was used to investigate the self-diffusion of carbon dioxide in alumina stabilized samaria aerogel catalyst, a promising porous catalyst for gas-phase reactions featuring high porosity and high surface area. For diffusion studies, the catalyst was prepared in two sample packing types, macroscopic monoliths (i.e., macroscopic cylindrical particles) and powder beds with particle sizes around 200 MUm that are considered for catalytic applications. Studies of diffusion in these samples revealed how macroscopic packing influences the catalyst transport properties. Application of a high magnetic field of 17.6 T in the reported PFG NMR studies enabled diffusion measurements for relatively low carbon dioxide densities in the catalyst samples corresponding to a gas loading pressure of around 0.1 atm. As a result, it was possible to perform diffusion measurements for a large range of carbon dioxide loading pressures between 0.1 and 10 atm. The measured carbon dioxide diffusivities in the beds of catalyst particles are interpreted in the context of a simple diffusion-mediated exchange model previously used for zeolites and other porous materials. PMID- 24160530 TI - Structural, electronic, and optical properties of hybrid silicene and graphene nanocomposite. AB - Structural, electronic, and optical properties of hybrid silicene and graphene (S/G) nanocomposite are examined with density functional theory calculations. It turns out that weak van der Waals interactions dominate between silicene and graphene with their intrinsic electronic properties preserved. Interestingly, interlayer interactions in hybrid S/G nanocomposite induce tunable p-type and n type doping of silicene and graphene, respectively, showing their doping carrier concentrations can be modulated by their interfacial spacing. PMID- 24160531 TI - AA stacking, tribological and electronic properties of double-layer graphene with krypton spacer. AB - Structural, energetic, and tribological characteristics of double-layer graphene with commensurate and incommensurate krypton spacers of nearly monolayer coverage are studied within the van der Waals-corrected density functional theory. It is shown that when the spacer is in the commensurate phase, the graphene layers have the AA stacking. For this phase, the barriers to relative in-plane translational and rotational motion and the shear mode frequency of the graphene layers are calculated. For the incommensurate phase, both of the barriers are found to be negligibly small. A considerable change of tunneling conductance between the graphene layers separated by the commensurate krypton spacer at their relative subangstrom displacement is revealed by the use of the Bardeen method. The possibility of nanoelectromechanical systems based on the studied tribological and electronic properties of the considered heterostructures is discussed. PMID- 24160532 TI - Critical behaviour of the Ising ferromagnet confined in quasi-cylindrical pores: a Monte Carlo study. AB - The critical behaviour of the Ising ferromagnet confined in pores of radius R and length L is studied by means of Monte Carlo computer simulations. Quasi cylindrical pores are obtained by replicating n-times a triangular lattice disc of radius R, where L = na and a is the spacing between consecutive replications. So, spins placed at the surface of the pores have less nearest-neighbours (NN) as compared to 8 NN for spins in the bulk. These "missing neighbour" effects undergone by surface spins cause a strong suppression of surface ordering, leading to an ordinary surface transition. Also, the effect propagates into the bulk for small tubes (R <= 12) and the effective critical temperature of the pores is shifted towards lower values than in the bulk case. By applying the standard finite-size scaling theory, subsequently supported by numerical data, we concluded that data collapse of relevant observables, e.g., magnetization (m), susceptibility, specific heat, etc., can only be observed by comparing simulation results obtained by keeping the aspect ratio C = R/L constant. Also, by extrapolating "effective" R-dependent critical temperatures to the thermodynamic limit (R -> infinity, C fixed), we obtained T(C)(infinity) = 6.208(4). As suggested by finite-size scaling arguments, the magnetization is measured at the critical point scales according to [|m|]Tc R(beta/nu) is proportional to [R/L](1/2), where beta and nu are the standard exponents for the order parameter and the correlation length, respectively. Furthermore, it is shown that close to criticality the axial correlation length decreases exponentially with the distance. That result is the signature of the formation of (randomly distributed) alternating domains of different magnetization, which can be directly observed by means of snapshot configurations, whose typical length (xi) is given by the characteristic length of the exponential decay of correlations. Moreover, we show that at criticality xi = 0.43(2)R. PMID- 24160533 TI - Electron-induced chemistry of methyl chloride caged within amorphous solid water. AB - The interaction of low energy electrons (1.0-25 eV) with methyl-chloride (CD3Cl) molecules, caged within Amorphous Solid Water (ASW) films, 10-120 monolayer (ML) thick, has been studied on top of a Ru(0001) substrate under Ultra High Vacuum (UHV) conditions. While exposing the ASW film to 3 eV electrons a static electric field up to 8 * 10(8) V/m is developed inside the ASW film due to the accumulation of trapped electrons that produce a plate capacitor voltage of exactly 3 V. At the same time while the electrons continuously strike the ASW surface, they are transmitted through the ASW film at currents of ca. 3 * 10(-7) A. These electrons transiently attach to the caged CD3Cl molecules leading to C Cl bond scission via Dissociative Electron Attachment (DEA) process. The electron induced dissociation cross sections and product formation rate constants at 3.0 eV incident electrons at ASW film thicknesses of 10 ML and 40 ML were derived from model simulations supported by Thermal Programmed Desorption (TPD) experimental data. For 3.0 eV electrons the CD3Cl dissociation cross section is 3.5 * 10(-16) cm(2), regardless of ASW film thickness. TPD measurements reveal that the primary product is deuterated methane (D3CH) and the minor one is deuterated ethane (C2D6). PMID- 24160534 TI - Single molecule magnets with protective ligand shells on gold and titanium dioxide surfaces: in situ electrospray deposition and x-ray absorption spectroscopy. AB - Two single molecule magnets based on the dodecamanganese (III, IV) cluster with either benzoate or terphenyl-4-carboxylate ligands, have been studied on the Au(111) and rutile TiO2(110) surfaces. We have used in situ electrospray deposition to produce a series of surface coverages from a fraction of a monolayer to multilayer films in both cases. X-ray absorption spectroscopy measured at the Mn L-edge (Mn 2p) has been used to study the effect of adsorption on the oxidation states of the manganese atoms in the core. In the case of the benzoate-functionalised complex reduction of the manganese metal centres is observed due to the interaction of the manganese core with the underlying surface. In the case of terphenyl-4-carboxylate, the presence of this much larger ligand prevents the magnetic core from interacting with either the gold or the titanium dioxide surfaces and the characteristic Mn(3+) and Mn(4+) oxidation states necessary for magnetic behaviour are preserved. PMID- 24160535 TI - Multivalent ion effects on electrostatic stability of virus-like nano-shells. AB - Electrostatic properties and stability of charged virus-like nano-shells are examined in ionic solutions with monovalent and multivalent ions. A theoretical model based on a thin charged spherical shell and multivalent ions within the "dressed multivalent ion" approximation, yielding their distribution across the shell and the corresponding electrostatic (osmotic) pressure acting on the shell, is compared with extensive implicit Monte-Carlo simulations. It is found to be accurate for positive or low negative surface charge densities of the shell and for sufficiently high (low) monovalent (multivalent) salt concentrations. Phase diagrams involving electrostatic pressure exhibit positive and negative values, corresponding to an outward and an inward facing force on the shell, respectively. This provides an explanation for the high sensitivity of viral shell stability and self-assembly of viral capsid shells on the ionic environment. PMID- 24160536 TI - Dynamical coupling and negative differential resistance from interactions across the molecule-electrode interface in molecular junctions. AB - Negative differential resistance - a decrease in current with increasing bias voltage - is a counter-intuitive effect that is observed in various molecular junctions. Here, we present a novel mechanism that may be responsible for such an effect, based on strong Coulomb interaction between electrons in the molecule and electrons on the atoms closest to the molecule. The Coulomb interaction induces electron-hole binding across the molecule-electrode interface, resulting in a renormalized and enhanced molecule-electrode coupling. Using a self-consistent non-equilibrium Green's function approach, we show that the effective coupling is non-monotonic in bias voltage, leading to negative differential resistance. The model is in accord with recent experimental observations that showed a correlation between the negative differential resistance and the coupling strength. We provide detailed suggestions for experimental tests which may help to shed light on the origin of the negative differential resistance. Finally, we demonstrate that the interface Coulomb interaction affects not only the I-V curves but also the thermoelectric properties of molecular junctions. PMID- 24160537 TI - Pin-wheel hexagons: a model for anthraquinone ordering on Cu(111). AB - The 4-state model of anthraquinone molecules ordering in a pin-wheel large-pore honeycomb phase on Cu(111) is proposed and solved by Monte Carlo simulation. The model is defined on a rescaled triangular lattice with the lattice constant a being equal to intermolecular distance in the honeycomb phase. The pin-wheel triangle formations are obtained taking into account the elongated shape of the molecules and anisotropic interactions for main two attractive short range (double and single dimeric) H-bond interactions. The long-range intermolecular interactions, corresponding to repulsive dipole-dipole forces, are assumed to be isotropic. Also, a very small (compared to short-range forces) isotropic attractive long-range interaction at the "characteristic" distance of a pore diameter is employed, and its effect carefully studied. This interaction is crucial for a formation of closed porous ordered systems, pin-wheel hexagons in particular. If each side of a pin-wheel hexagon is formed of n parallel molecules, the distance of this characteristic interaction is a?(3n(2)+1). The phase diagrams including different pin-wheel hexagon phases and a variety of other ordered structures are obtained. By changing the distance of characteristic interaction, different ordering routes into the experimental pin-wheel honeycomb phase are explored. The results obtained imply that classical explanation of the origin of the pin-wheel honeycomb phase in terms of some balance of attractive and repulsive forces cannot be totally discounted yet. PMID- 24160538 TI - Phase separation of binary nonadditive hard sphere fluid mixture confined in random porous media. AB - I analyze the fluid-fluid phase separation of nonadditive hard sphere fluid mixture absorbed in random porous media. An equation of state is derived by using the perturbation theory to this complex system with quenched disorders. The results of this theory are in good agreement with those obtained from semi-grand canonical ensemble Monte Carlo simulations. The contact value of the fluid-fluid radial distribution functions of the reference which is the key point of the perturbation process is derived as well, the comparison against Monte Carlo simulations shows that it has an excellent accuracy. PMID- 24160539 TI - Theoretical studies of the passivants' effect on the Si(x)Ge(1-x) nanowires: composition profiles, diameter, shape, and electronic properties. AB - Theoretically, we have performed a systematic investigation on the passivants' effect on the geometrical and electronic properties of Si(x)Ge(1-x) nanowires. First-principles calculations revealed that, in the nanowires passivated by fluorine (F)/chlorine (Cl)/hydrogen (H) atoms, Si atoms preferred to segregate towards the surface due to the stronger Si-X bonds than that of Ge-X bonds (X = F, Cl, H). The energy barriers of X atoms' desorption is higher than that of the Si/Ge atoms' exchanging, inducing a feasible and strong surface segregation of Si atoms at proper temperature. Considering the Si/Ge interactions and mixing entropy, the composition profiles of Si/Ge distributions are obtained by minimizing the Gibbs free energy, which indicates the outmost layer of surface should be mostly occupied by Si. With total Si surface segregation, the diameter and shape of most stable Si(x)Ge(1-x) nanowires are found to be determined by the composition x and the passivants' chemical potential. In addition, charge distribution of near-gap levels can be modulated through the surface passivants. Our finding provides a practical avenue to tune the electronic properties of Si(x)Ge(1-x) nanowires, by modulating the morphologies of nanowires with the composition control of Si/Ge and the chemical potential of passivants. PMID- 24160540 TI - Quantum irreversible decoherence behaviour in open quantum systems with few degrees of freedom: application to 1H NMR reversion experiments in nematic liquid crystals. AB - An experimental study of NMR spin decoherence in nematic liquid crystals is presented. Decoherence dynamics can be put in evidence by means of refocusing experiments of the dipolar interactions. The experimental technique used in this work is based on the MREV8 pulse sequence. The aim of the work is to detect the main features of the irreversible quantum decoherence in liquid crystals, on the basis of the theory presented by the authors recently. The focus is laid on experimentally probing the eigen-selection process in the intermediate time scale, between quantum interference of a closed system and thermalization, as a signature of the quantum spin decoherence of the open quantum system, as well as on quantifying the effects of non-idealities as possible sources of signal decays which could mask the intrinsic decoherence. In order to contrast experiment and theory, the theory was adapted to obtain the decoherence function corresponding to the MREV8 reversion experiments. Non-idealities of the experimental setting, like external field inhomogeneity, pulse misadjustments, and the presence of non reverted spin interaction terms are analysed in detail within this framework, and their effects on the observed signal decay are numerically estimated. It is found that though all these non-idealities could in principle affect the evolution of the spin dynamics, their influence can be mitigated and they do not present the characteristic behaviour of the irreversible spin decoherence. As unique characteristic of decoherence, the experimental results clearly show the occurrence of eigen-selectivity in the intermediate timescale, in complete agreement with the theoretical predictions. We conclude that the eigen-selection effect is the fingerprint of decoherence associated with a quantum open spin system in liquid crystals. Besides, these features of the results account for the quasi-equilibrium states of the spin system, which were observed previously in these mesophases, and lead to conclude that the quasi-equilibrium is a definite stage of the spin dynamics during its evolution towards equilibrium. PMID- 24160541 TI - High-functionality star-branched macromolecules: polymer size and virial coefficients. AB - We perform high-statistics Monte Carlo simulations of a lattice model to compute the radius of gyration Rg, the center-to-end distance, the monomer distribution, and the second and third virial coefficients of star polymers for a wide range of functionalities f, 6 <= f <= 120. We consider systems with a large number L of monomers per arm (100 is approximately < L is approximately < 1000 for f <= 40 and 100 is approximately < L is approximately < 400 for f = 80, 120), which allows us to determine accurately all quantities in the scaling regime. Results are extrapolated to determine the behavior of the different quantities in the limit f -> infinity. Structural results are finally compared with the predictions of the Daoud-Cotton model. It turns out that the blob picture of a star polymer is essentially correct up to the corona radius Rc, which depends on f and which varies from 0.7Rg for f = 6 to 1.0Rg for f = 40. The outer region (r > Rc), in which the monomer distribution decays exponentially, shrinks as f increases, but it does not disappear in the scaling regime even in the limit f -> infinity. We also consider the Daoud-Cotton scaling relation Rg (2)~f(1-nu)L(2nu), which is found to hold only for f >> 100. PMID- 24160542 TI - Mixtures of functionalized colloids on substrates. AB - Patchy particles are a class of colloids with functionalized surfaces. Through surface functionalization, the strength and directionality of the colloidal interactions are tunable allowing control over coordination of the particle. Exquisite equilibrium phase diagrams of mixtures of coordination two and three have been reported. However, the kinetics of self-organization and the feasibility of the predicted structures are still largely unexplored. Here, we study the irreversible aggregation of these mixtures on a substrate, for different fractions of two-patch particles. Two mechanisms of mass transport are compared: diffusion and advection. In the diffusive case, an optimal fraction is found that maximizes the density of the aggregate. By contrast, for advective transport, the density decreases monotonically with the fraction of two-patch colloids, in line with the behavior of the liquid density on the spinodal of the equilibrium phase diagram. PMID- 24160543 TI - Intermediate range order and structure in colloidal dispersions with competing interactions. AB - Colloidal dispersions with a short-range attraction and long-range repulsion can exhibit an intriguing intermediate range order, manifested in scattering experiments as a low-q peak in the structure factor. Monte Carlo simulations are performed on fluids that exhibit intermediate range order to explicitly determine its connection to a possible state of microphase separation, equilibrium clustering. This is accomplished by decomposing the structure factor into cluster cluster, monomer-monomer, and cross-correlations that cannot be extracted from experimental scattering patterns. Our simulation results indicate that the intermediate range order arises from either monomeric or cluster species, depending on solution conditions, and reflects the presence of a preferred length scale that is not trivially related to the interparticle potential. Further, criteria are established to define monomer, cluster, and percolated states in these systems that facilitate further studies. Combining scattering techniques with simulations provides an effective method for identifying clustered states in complex fluids. PMID- 24160544 TI - Probing energy transfer events in the light harvesting complex 2 (LH2) of Rhodobacter sphaeroides with two-dimensional spectroscopy. AB - Excitation energy transfer events in the photosynthetic light harvesting complex 2 (LH2) of Rhodobacter sphaeroides are investigated with polarization controlled two-dimensional electronic spectroscopy. A spectrally broadened pulse allows simultaneous measurement of the energy transfer within and between the two absorption bands at 800 nm and 850 nm. The phased all-parallel polarization two dimensional spectra resolve the initial events of energy transfer by separating the intra-band and inter-band relaxation processes across the two-dimensional map. The internal dynamics of the 800 nm region of the spectra are resolved as a cross peak that grows in on an ultrafast time scale, reflecting energy transfer between higher lying excitations of the B850 chromophores into the B800 states. We utilize a polarization sequence designed to highlight the initial excited state dynamics which uncovers an ultrafast transfer component between the two bands that was not observed in the all-parallel polarization data. We attribute the ultrafast transfer component to energy transfer from higher energy exciton states to lower energy states of the strongly coupled B850 chromophores. Connecting the spectroscopic signature to the molecular structure, we reveal multiple relaxation pathways including a cyclic transfer of energy between the two rings of the complex. PMID- 24160545 TI - Sequence dependent free energy profiles of localized B- to A-form transition of DNA in water. AB - DNA carries an inherent polymorphism, which surfaces under various external conditions. While B-form remains predominant under normal physiological conditions for most of the DNA sequences, low humidity and increased ion concentration cause B- to A-form transition. Certain proteins and molecules also sometimes cause local deformation of the DNA to the specific A-form. Previous experimental and computational studies focused on the overall B- to A-form transition. Here for the first time we investigated thermodynamics and mechanism of B- to A-form transition in water for various DNA sequences at a local dinucleotide base pair level. We introduced a new reaction coordinate Zp', based on the unique order parameter Zp, to drive B- to A-form transition locally and thereby calculate free energy profiles for the same for all the ten different dinucleotide steps embedded in a twelve base pair DNA. Results show that the trend of "A" and "B" philicity observed in experiment is preserved even at this local dinucleotide level, indicating its localized origin. Higher free energy cost obtained here is attributed to the cost of creating B/A junctions along with formation of B->A transition at dimer level. We find that while water energetically stabilizes A-form for all the ten different dinucleotide steps to various extents, entropy acts against it. Therefore, we find that the stability of B-form DNA in water is entropic in origin. Mechanism of the conversion appears to be triggered by Slide; however, backbone parameters change concertedly. PMID- 24160546 TI - The network of stabilizing contacts in proteins studied by coevolutionary data. AB - The primary structure of proteins, that is their sequence, represents one of the most abundant sets of experimental data concerning biomolecules. The study of correlations in families of co-evolving proteins by means of an inverse Ising model approach allows to obtain information on their native conformation. Following up on a recent development along this line, we optimize the algorithm to calculate effective energies between the residues, validating the approach both back-calculating interaction energies in a model system, and predicting the free energies associated to mutations in real systems. Making use of these effective energies, we study the network of interactions which stabilizes the native conformation of some well-studied proteins, showing that it displays different properties than the associated contact network. PMID- 24160550 TI - Lumbar puncture-related cerebrospinal fluid leakage on magnetic resonance myelography: is it a clinically significant finding? AB - BACKGROUND: Post-dural puncture headache (PDPH) due to excessive cerebrospinal fluid (CSF) leakage is a well-known complication of lumbar puncture. Although various factors, especially the type of spinal needle, have been demonstrated to be associated with PDPH, the clinical implications of CSF leakage detected on magnetic resonance myelography (MRM) images remain unclear. The objective of this case-control study was to evaluate the association between radiologically visualized CSF leakage and PDPH. METHODS: Clinical data including patients' age and gender, types of spinal needle, duration of bed rest, interval between lumbar puncture procedures and MRM studies, and incidence of PDPH were compared between patients who were radiologically-positive and -negative for CSF leakage. RESULTS: Of the 22 patients with definite CSF leakage on MRM images, most were asymptomatic (86%, 19/22). The remaining three patients, who were suffering from PDPH, only complained of headaches and were treated conservatively. In a review of patients' clinical data, there were no significant differences in any parameter including the incidence of PDPH between the 22 patients who were radiologically-positive for CSF leakage and the 31 radiologically-negative patients. CONCLUSION: The significance of radiologically visualized CSF leakage should not be overestimated, as most such incidents are not associated with PDPH and do not require any treatment. PMID- 24160552 TI - Geno- and cytotoxicity of propyl gallate food additive. AB - Synthetic phenolic food additives, such as propyl 3,4,5-trihydroxybenzoate (propyl galate; PG), have been used as an antioxidant in the food industry to prevent oils from spoiling. Their toxicity is one of the challengeable issues resulting from the widespread usage of them in food-related industrials. In this study, we investigated the anticell proliferation effects of PG on A549 lung cancer cells. The result showed that PG dose and time dependently decreased the growth of A549 cells with an half-maximal inhibitory concentration of approximately 1 * 10(-3) and 5 * 10(-4)M of PG at 48 and 72 hours, respectively. In addition, DNA strand breaks have been observed through the comet assay technique. Also, morphology of 4',6-diamidino-2-phenylindole (DAPI)-stained cells showed an obvious fragmentation in the chromatin and DNA rings within the nucleus of PG-treated cells, and, finally, flow cytometry analyses of the cells confirmed DAPI staining assay and determined early and late apoptosis in treated cells. PMID- 24160553 TI - Sensitization of visible and NIR emitting lanthanide(III) ions in noncentrosymmetric complexes of hexafluoroacetylacetone and unsubstituted monodentate pyrazole. AB - A series of highly volatile eight-coordinate air and moisture stable lanthanide complexes of the type [Ln(hfaa)3(L)2] (Ln = Pr (1), Nd (2), Eu (3), Gd (4), Tb (5), Dy (6), Ho (7), Er (8), Tm (9), and Yb (10); hfaa = anion of hexafluoroacetylacetone and L = pyrazole) have been synthesized and characterized by elemental analysis, IR, ESI-MS(+), and NMR studies. Single-crystal X-ray structures have been determined for the Eu(III) and Dy(III) complexes. These complexes crystallize in the monoclinic space group P2(1)/c. The lanthanide ion in each of these complexes is eight-coordinate with six oxygen atoms from three hfaa and two N-atoms from two pyrazole units, forming a coordination polyhedron best describable as a distorted square antiprism. The NMR spectra reveal that both the pyrazole units remain attached to the metal in solution and the beta diketonate and pyrazole protons are shifted in opposite directions in the case of paramagnetic complexes. The lanthanide-induced chemical shifts are dipolar in nature. The hypersensitive transitions of Nd(III), Ho(III), and Er(III) are sensitive to the environment (solvent), which is reflected by the oscillator strength and band shape of these transitions. The band shape due to the hypersensitive transition of Nd(III) in noncoordinating chloroform and dichloromethane is similar to those of the typical eight-coordinate Nd(III) beta diketonate complexes. The quantum yield and lifetime of Pr(III), Eu(III), Tb(III), Dy(III), and Tm(III) in visible and Pr(III), Nd(III), Dy(III), Ho(III), Er(III) Tm(III), and Yb(III) in the NIR region are sizable. The environment around these metal ions is asymmetric, which leads to increased radiative rates and luminescence efficiencies. The quantum yield of the complexes reveal that ligand-to-metal energy transfer follows the order Eu(III) > Tb(III) ? Pr(III) > Dy(III) > Tm(III). Both ligands (hfaa and pyrazole) are good sensitizers for all the visible and NIR emitters effectively, except for Tb(III), Dy(III), and Tm(III), where pyrazole gave a negative effect (e.g., energy back-transfer) that is due to poor intramolecular energy transfer match. The good luminescent properties make these NIR-luminescent complexes to have potential application in optical communication, telecommunications, and fluoroimmunoassays. PMID- 24160551 TI - Polygonum cuspidatum inhibits pancreatic lipase activity and adipogenesis via attenuation of lipid accumulation. AB - BACKGROUND: Obesity causes metabolic disease and is a serious health problem around the world. Polygonum cuspidatum (POCU1b) has been used clinically for the treatment of constipation, gallstones, hepatitis, and inflammation in East Asian countries. The principal aim of this study was to investigate for the first time whether the extract of Polygonum cuspidatum (POCU) biologically affects adipogenesis in 3 T3-L1 preadipocytes. METHODS: Fractions (n-hexan, ethyl acetate, n-butanol, and water) of POCU ethanol extract were evaluated in vitro for their inhibitory activities on pancreatic lipase. Of the fractions, the n butanol of POCU ethanol extract (POCU1b) was examined anti-obesity activity in 3 T3-L1 preadipocytes. To examine the inhibitory effect of POCU1b on adipogenesis, 3 T3-L1 preadipocytes were treated every the other day with POCU1b at various concentrations (0 ~ 25 MUg/mL) for twelve days. Oil-red O staining and triglyceride content assay were performed to determine the lipid accumulation. The expression of mRNA and proteins associated lipid accumulation was measured using RT-PCR and Western blotting analysis. We also examined the effect of POCU1b on level of phosphorylated AMP-activated protein kinase (pAMPK) in 3 T3-L1 preadipocytes with POCU1b at various concentrations during adipocyte differentiation. RESULTS: POCU1b exhibited the most pronounced inhibitory effects on pancreatic lipase activity. We found that POCU1b inhibited adipocyte differentiation in 3 T3-L1 preadipocytes in a dose-dependent manner, as evidenced by the reduced formation of lipid droplets and decreased glycerol-3-phosphate dehydrogenase (GPDH) activity. We also showed that the expression levels of adipocyte differentiation-related protein (ADRP) and perilipin (a protein that coats lipid droplets in adipocytes) were both reduced after POCU1b treatment. Peroxisome proliferator-activated receptor-gamma (PPAR-gamma) and CCAAT/enhancer binding protein-alpha (C/EBP-alpha) proteins, both major adipogenic transcription factors, were markedly reduced by POCU1b. Moreover, ADRP, perilipin, C/EBP-alpha, and PPAR-gamma mRNA levels were also reduced by POCU1b. Levels of phosphorylated AMP-activated protein kinase (pAMPK) were elevated after POCU1b treatment (5, 10, and 25) in a dose-dependent manner. CONCLUSIONS: Taken together, these results suggest that the anti-obesity effects of POCU1b involve the inhibition of pancreatic lipase activity and adipogenesis via the down-regulation of lipid accumulation. PMID- 24160554 TI - Vitamin D status of children with severe early childhood caries: a case-control study. AB - BACKGROUND: Severe Early Childhood Caries (S-ECC) affects the health and well being of young children. There is limited research in this area, though evidence suggests that children with S-ECC are at an increased risk of malnutrition. The purpose of this study was to determine the association between vitamin D (25(OH)D) levels and S-ECC. METHODS: This case-control study was conducted from 2009 to 2011 in the city of Winnipeg, Manitoba, Canada. 144 preschool children with S-ECC were recruited from a local health centre on the day of their slated dental surgery under general anesthetic. 122 caries-free controls were recruited from the community. Children underwent a blood draw for vitamin D (25(OH)D), calcium, parathyroid hormone, and albumin levels. Parents completed an interviewed questionnaire assessing the child's nutritional habits, oral health, and family demographics. Analyses included descriptive and bivariate statistics as well as multiple and logistic regression. A p value <= 0.05 was significant. RESULTS: The mean age of participants was 40.8 +/- 14.1 months. Children with S ECC had significantly lower mean 25(OH)D (68.9 +/- 28.0 nmol/L vs. 82.9 +/- 31.1, p < 0.001), calcium (p < 0.001), and albumin (p < 0.001) levels, and significantly higher parathyroid hormone (p < 0.001) levels than those caries free. Children with S-ECC were significantly more likely to have vitamin D levels below recognized thresholds for optimal and adequate status (i.e. < 75 and < 50 nmol/L, respectively). Multiple regression analysis revealed that S-ECC, infrequent milk consumption, and winter season were significantly associated with lower 25(OH)D concentrations. Low 25(OH)D levels, low household income, and poorer ratings of the child's general health were significantly associated with S ECC on logistic regression. CONCLUSION: Children with S-ECC appear to have relatively poor nutritional health compared to caries-free controls, and were significantly more likely to have low vitamin D, calcium, and albumin concentrations and elevated PTH levels. PMID- 24160555 TI - Plexiform fibromyxoma: report of two pediatric cases and review of the literature. AB - Plexiform fibromyxoma is a distinctive mesenchymal neoplasm usually arising in the gastric antrum. We report 2 cases of this entity in pediatric patients, including the first case arising in the esophagus. The patients were a 16-year old female who presented with chest pain and was found on computed tomographic scan to have a midesophageal mass at the level of the carina, and an 11-year-old female with a gastric mass. Both patients underwent surgical resection of their tumors, which histologically exhibited a plexiform growth pattern with multiple nodules in the muscularis propria and infiltrative borders. The nodules were composed of a rich myxoid stroma with bland uniform spindle cells, no mitoses or necrosis, and delicate blood vessels in the background. Immunohistochemical studies demonstrated that the tumor cells were immunoreactive with smooth muscle actin and not reactive with S-100, CD34, desmin, and c-kit (CD117). We report the first case of plexiform fibromyxoma originating in the esophagus, emphasize its occurrence in pediatric patients, and review the related literature. PMID- 24160556 TI - Comment on: Clinical benefits of ezetimibe: absence of proof is just that. PMID- 24160557 TI - Computer-assisted structure identification (CASI)--an automated platform for high throughput identification of small molecules by two-dimensional gas chromatography coupled to mass spectrometry. AB - Compound identification is widely recognized as a major bottleneck for modern metabolomic approaches and high-throughput nontargeted characterization of complex matrices. To tackle this challenge, an automated platform entitled computer-assisted structure identification (CASI) was designed and developed in order to accelerate and standardize the identification of compound structures. In the first step of the process, CASI automatically searches mass spectral libraries for matches using a NIST MS Search algorithm, which proposes structural candidates for experimental spectra from two-dimensional gas chromatography with time-of-flight mass spectrometry (GC * GC-TOF-MS) measurements, each with an associated match factor. Next, quantitative structure-property relationship (QSPR) models implemented in CASI predict three specific parameters to enhance the confidence for correct compound identification, which were Kovats Index (KI) for the first dimension (1D) separation, relative retention time for the second dimension separation (2DrelRT) and boiling point (BP). In order to reduce the impact of chromatographic variability on the second dimension retention time, a concept based upon hypothetical reference points from linear regressions of a deuterated n-alkanes reference system was introduced, providing a more stable relative retention time measurement. Predicted values for KI and 2DrelRT were calculated and matched with experimentally derived values. Boiling points derived from 1D separations were matched with predicted boiling points, calculated from the chemical structures of the candidates. As a last step, CASI combines the NIST MS Search match factors (NIST MF) with up to three predicted parameter matches from the QSPR models to generate a combined CASI Score representing the measure of confidence for the identification. Threshold values were applied to the CASI Scores assigned to proposed structures, which improved the accuracy for the classification of true/false positives and true/false negatives. Results for the identification of compounds have been validated, and it has been demonstrated that identification using CASI is more accurate than using NIST MS Search alone. CASI is an easily accessible web-interfaced software platform which represents an innovative, high-throughput system that allows fast and accurate identification of constituents in complex matrices, such as those requiring 2D separation techniques. PMID- 24160558 TI - Novel controlled drug delivery system for multiple drugs based on electrospun nanofibers containing nanomicelles. AB - This research described a novel composite electrospun nanofibers, which were consisted of MPEG-b-PLA micelles, chitosan, and PEO, realizing controlled release of both hydrophobic and hydrophilic drugs. 5-FU and Cefradine used as model drugs were successfully loaded in the nanofibers. The in vitro studies showed there was a low initial burst release of 5-FU from micelles-loaded nanofibers, and the final release proportion was about 91.4% after continually releasing for 109 h. In vitro cytotoxicity studies revealed that 5-FU-loaded nanofibers restrained HepG-2 cells efficiently, and the cell viability was 45.9% after three days of cultivation in solutions containing micelles-loaded nanofibers with 21.6 MUg 5 FU. All results suggested that micelles-loaded nanofibers with two kinds of drugs can be used as an effective controlled drug delivery vehicle and may have a bright future in cancer chemotherapy or clinical treatments. PMID- 24160560 TI - Using cognitive and affective illustrations to enhance older adults' website satisfaction and recall of online cancer-related information. AB - This study examined the effect of adding cognitive and affective illustrations to online health information (vs. text only) on older adults' website satisfaction and recall of cancer-related information. Results of an online experiment among younger and older adults showed that illustrations increased satisfaction with attractiveness of the website. Younger adults were significantly more satisfied with the comprehensibility of the website than older adults, whereas older adults were more satisfied with perceived emotional support from the website than younger adults. Being more emotionally satisfied with the website led to greater recall of information for older adults, but not for younger adults. Illustrations can be used to enhance older adults' website satisfaction and consequently recall of online cancer-related information. PMID- 24160561 TI - Radical migration-addition of N-tert-butanesulfinyl imines with organozinc reagents. AB - A novel migration-addition sequence was discovered for the reaction of enantioenriched N-tert-butanesulfinyl iminoacetate 1a with functionalized benzylzinc bromide reagents, producing tert-leucine derivatives in excellent diastereoselectivity (dr 98:2). The absolute configurations of two new chiral centers were unambiguously assigned by chemical transformations and X-ray crystallography. In addition, the regio- and diastereoselectivities of this novel reaction were both explained through the key N-sulfinamine intermediate M6 generated by the tert-butyl radical attack on the imine. Computational analysis of this reaction process, which was performed at the B3LYP/6 311++G(3df,2p)//B3LYP/6-31G*-LANL2DZ level, also supported our proposed two-stage mechanism. PMID- 24160559 TI - Dietary N-nitroso compounds and risk of colorectal cancer: a case-control study in Newfoundland and Labrador and Ontario, Canada. AB - Several N-nitroso compounds (NOC) have been shown to be carcinogenic in a variety of laboratory animals, but evidence of their carcinogenicity in humans is lacking. We aimed to examine the association between NOC intake and colorectal cancer (CRC) risk and possible effect modification by vitamins C and E and protein in a large case-control study carried out in Newfoundland and Labrador and Ontario, Canada. A total of 1760 case patients with pathologically confirmed adenocarcinoma and 2481 population controls were asked to complete a self administered FFQ to evaluate their dietary intakes 1 year before diagnosis (for cases) or interview (for controls). Adjusted OR and 95 % CI were calculated across the quintiles of NOC (measured by N-nitrosodimethylamine (NDMA)) intake and relevant food items using unconditional logistic regression. NDMA intake was found to be associated with a higher risk of CRC (highest v. lowest quintiles: OR 1.42, 95 % CI 1.03, 1.96; P for trend = 0.005), specifically for rectal carcinoma (OR 1.61, 95 % CI 1.11, 2.35; P for trend = 0.01). CRC risk also increased with the consumption of NDMA-containing meats when the highest tertile was compared with the lowest tertile (OR 1.47, 95 % CI 1.03, 2.10; P for trend = 0.20). There was evidence of effect modification between dietary vitamin E and NDMA. Individuals with high NDMA and low vitamin E intakes had a significantly increased risk than those with both low NDMA and low vitamin E intakes (OR 3.01, 95 % CI 1.43, 6.51; P for interaction = 0.017). The present results support the hypothesis that NOC intake may be positively associated with CRC risk in humans. Vitamin E, which inhibits nitrosation, could modify the effect of NDMA on CRC risk. PMID- 24160562 TI - Hypolipidemic effect of gypenosides in experimentally induced hypercholesterolemic rats. AB - BACKGROUND: To investigate the anti-hyperlipidemic effect of gynosaponins (GPs) in hyperlipidemic rats induced by high lipid diet. METHODS: Animal model of hyperlipidemia was established by high-fat and high-cholesterol diet. Rats were randomly divided into 6 groups, except the normal and model groups, rats in GPs groups were daily administered intragastrically with GPs (50, 100, and 200 mg/kg), and rats in simvastatin group were daily administered intragastrically with simvastatin (10 mg/kg). It was measured that the contents of glutathione peroxidase (GSH-Px), superoxide dismutase (SOD), catalase (CAT), malondialdehyde (MDA), total cholesterol (TC), triglyceride (TG), high-density lipoprotein cholesterol (HDL-C) and low-density lipoprotein-cholesterol (LDL-C) in the serum, TG and TC in the liver during this experiment, respectively. The left lobe of liver was observed by histopathological staining, and the immunohistochemical staining was used to observe the effects on the effect of GPs on liver functions. RESULTS: Compared with the model group, GPs groups could remarkably decrease the content of lipids, GSH-Px, SOD, CAT and MDA in the serum and TC and TG in the liver of the hyperlipidemic rats. The pathomorphological results of hepatic tissue showed that fatty degeneration and inflammatory reaction of GPs groups were lightened compared with the model group. CONCLUSIONS: The results show that GPs has good effects on the treatment of hyperlipidemia induced by high lipid diet in rats. The possible anti-hyperlipidemia mechanism maybe those GPs can regulate the disorder of lipid metabolism as well as ameliorate hepatic function. PMID- 24160565 TI - Which placebo to cure depression? A thought-provoking network meta-analysis. AB - BACKGROUND: Antidepressants are often considered to be mere placebos despite the fact that meta-analyses are able to rank them. It follows that it should also be possible to rank different placebos, which are all made of sucrose. To explore this issue, which is rather more epistemological than clinical, we designed an unusual meta-analysis to investigate whether the effects of placebo in one situation are different from the effects of placebo in another situation. METHODS: Published and unpublished studies were searched for by three reviewers on Medline, the Cochrane Library, Embase, clinicaltrials.gov, Current Controlled Trial, in bibliographies, and by mailing key organizations. The following studies in first-line treatment for major depressive disorder were considered to construct an "evidence network": 1) randomized controlled trials (RCTs) versus placebo on fluoxetine, venlafaxine and 2) fluoxetine versus venlafaxine head-to head RCTs.Two network meta-analyses were run to indirectly compare response and remission rates among three different placebos: 1) fluoxetine placebo, 2) venlafaxine placebo, and 3) venlafaxine/fluoxetine placebo (that is, placebo compared to both venlafaxine and fluoxetine). Publication biases were assessed using funnel plots and statistically tested. RESULTS: The three placebos were not significantly different in terms of response or remission. The antidepressant agents were significantly more efficacious than the placebos, and venlafaxine was more efficacious than fluoxetine. The funnel plots, however, showed a major publication bias. CONCLUSION: The presence of significant levels of publication bias indicates that we cannot even be certain of the conclusion that sucrose equals sucrose in trials of major depressive disorder. This result should remind clinicians to step back to take a more objective view when interpreting a scientific result. It is of crucial importance for their practice, far more so than ranking antidepressant efficacy. PMID- 24160566 TI - General practitioners' knowledge of whiplash guidelines improved with online education. AB - OBJECTIVE: The primary objective of this study was to evaluate the effect of an online education program used to implement the Australian (New South Wales) whiplash guidelines with general practitioners (GP). The secondary aim was to identify factors associated with learning. METHODS: An online educational and evaluation activity was developed to reflect the key messages for GP from the Australian whiplash guidelines. The educational activity was hosted on the Royal Australian College of General Practitioners' website (www.gplearning.com.au) for a period of 3 years. Participants were recruited through advertisement and media releases. Participants completed a baseline evaluation of their knowledge, participated in the interactive educational activity and completed a post knowledge questionnaire. The primary outcome was change in professional knowledge, predictors of learning were computed using linear regression. RESULTS: Two hundred and fifteen GP participated. Knowledge significantly improved between baseline and post-knowledge questionnaire scores (P < 0.00001). A total of 57.2% of participants improved their knowledge by more than 20%, indicating a large effect. Low baseline knowledge predicted learning, accounting for 71% of the variance. CONCLUSIONS: Online education of GP significantly improved their knowledge in relation to guidelines for whiplash. Those with low baseline knowledge improved their knowledge the most, suggesting that implementation strategies should be targeted at this group. PMID- 24160567 TI - Novel method using hybrid markers: development of an approach for pulmonary measurement of multi-walled carbon nanotubes. AB - BACKGROUND: Multi-walled carbon nanotubes (MWCNT)s are suspected to induce pulmonary and pleural cancers due to their asbestos-like configurations. Therefore, accurate measurement of inhaled nanotubes in target organs is crucial for assessing cancer risk. Conventionally, nanotubes are measured after combustion at high temperature for conversion into CO2; however, the sensitivity is poor and the method lacks versatility. We have therefore developed a novel approach using hybrid markers for nanotube analysis, featuring high sensitivity and the capacity to conduct repeated analyses. The method involves adsorption of markers to nanotubes, followed by their desorption and assessment by means of high performance liquid chromatography (HPLC). METHODS: Recovery of MWCNT from rat lungs was conducted, and pulmonary MWCNT amounts were determined using rats intratracheally-exposed to MWCNT aerosol at 5 mg/m3 for 6 hours/day. RESULTS: The correlation coefficient for the calibration curve of MWCNT weight and the HPLC area was 0.9991. Consequently, the lower quantitation limit yielded was 0.2 MUg. The recovery was 92-98% at approximately 0.4-2.0 MUg demonstrating that MWCNTs in the lung could be measured accurately and precisely. CONCLUSIONS: We have developed a novel method using a hybrid marker approach for nanotube analysis, featuring very high sensitivity and the capacity to conduct repeated analyses. We further confirmed correlations between the amounts of nanotubes and markers and pulmonary nanotube measurement demonstrated that trace amounts could be detected with values closely relating to the administered dose, verifying that the method is sensitive and precise. PMID- 24160568 TI - Effects of aqueous leaf extract of Asystasia gangetica on the blood pressure and heart rate in male spontaneously hypertensive Wistar rats. AB - BACKGROUND: Asystasia gangentica (A. gangetica) belongs to the family Acanthaceae. It is used to treat hypertension, rheumatism, asthma, diabetes mellitus, and as an anthelmintic in South Africa, India, Cameroun, Nigeria, and Kenya respectively. It has also been reported to inhibit the angiotensin I converting enzyme (ACE) in-vitro. Therefore, the aim of this study is to investigate the in-vivo effect of aqueous leaf extract (ALE) of A. gangetica on the blood pressure (BP) and heart rate (HR) in anaesthetized male spontaneously hypertensive rats (SHR); and to elucidate possible mechanism(s) by which it acts. METHODS: The ALE of A. gangetica (10-400 mg/kg), angiotensin I human acetate salt hydrate (ANG I, 3.1-100 MUg/kg) and angiotensin II human (ANG II, 3.1-50 MUg/kg) were administered intravenously. The BP and HR were measured via a pressure transducer connecting the femoral artery to a Powerlab and a computer for recording. RESULTS: A. gangetica significantly (p<0.05), and dose-dependently reduced the systolic, diastolic, and mean arterial BP. The significant (p<0.05) reductions in HR were not dose-dependent. Both ANG I and ANG II increased the BP dose-dependently. Co-infusion of A. gangetica (200 mg/kg) with either ANG I or ANG II significantly (p<0.05) suppressed the hypertensive effect of both ANG I and ANG II respectively, and was associated with reductions in HR. CONCLUSIONS: A. gangetica ALE reduced BP and HR in the SHR. The reduction in BP may be a result of actions of the ALE on the ACE, the ANG II receptors and the heart rate. PMID- 24160569 TI - Preparation and characterization of Simvastatin solid dispersion using skimmed milk. AB - Simvastatin has low aqueous solubility resulting in low oral bioavailability (5%) and thus presents a challenge in formulating a suitable dosage form. To improve the aqueous solubility, a solid dispersion formulation of Simvastatin was prepared by lyophilization utilizing skimmed milk as a carrier. Six different formulations were prepared with varying ratios of drug and carrier and the corresponding physical mixtures were also prepared. The improvement of amorphous state through solid dispersion was confirmed by differential scanning calorimetry and X-ray diffraction studies. The optimum drug-to-carrier ratio of 1:9 enhanced solubility nearly 30-fold as compared to pure drug. In-vitro drug release studies exhibited a cumulative release of 86.69% as compared to 25.19% for the pure drug. Additionally, scanning electron microscopy studies suggested the conversion of crystalline Simvastatin to an amorphous form. In a Triton-induced hyperlipidemia model, a 3-fold increase in the lipid lowering potential was obtained with the reformulated drug as compared to pure drug. These results suggest that solid dispersion of Simvastatin using skimmed milk as carrier is a promising approach for oral delivery of Simvastatin. PMID- 24160570 TI - The relationship between mitral annular systolic velocity and ejection fraction in patients with preserved global systolic function of the left ventricle. AB - BACKGROUND: The aim of the study was to investigate the relationship between the ejection fraction (EF) and the mitral annular systolic velocity (Sm) in patients with preserved left ventricular systolic function (EF>55%). The study task was to evaluate whether the assessment of Sm(avg) can be used as an alternative to the Simpson's method in assessment of the EF. The expected benefit was that Sm could be used to predict EF, when EF is difficult to assess due to poor image quality (IQ). METHOD: Sm was obtained by spectral pulse wave Tissue Doppler Imaging (pwTDI) from the lateral and septal sites of the mitral annulus (MA) and an averaged value was calculated - Sm(avg). EF was assessed using Simpson's rule. Participants were divided into controls (n=70), hypertensive (HTN, n=56), HTN with diastolic dysfunction (HTN/DD, n=65), HTN with diabetes mellitus (HTN/DM, n=52) and HTN with DD and DM (HTN/DD/DM, n=65). RESULTS: Sm(avg) showed strong correlation with EF (r=0.978; p<0.0001). There were no significant differences between the correlation coefficients between the subgroups and the controls. The mathematical model that the study recommended to assess the EF is: EF=45.0 + 2 * Sm(avg). CONCLUSION: The assessment of Sm(avg) could be used as an alternative to EF. This approach may be useful especially when the IQ is poor. The method maintains high accuracy and reproducibility in prediction of the EF. PMID- 24160572 TI - Humor in print health advertisements: enhanced attention, privileged recognition, and persuasiveness of preventive messages. AB - This study tested the effect of humor in one particular type of print advertisement: the preventive health ads for three topics (alcohol, tobacco, obesity). Previous research using commercial ads demonstrated that individuals' attention is spontaneously attracted by humor, leading to a memory advantage for humorous information over nonhumorous information. Two experiments investigated whether the positive effect of humor can occur with preventive health ads. In Experiment 1, participants observed humorous and nonhumorous health ads while their viewing times were recorded. In Experiment 2, to compare humorous and nonhumorous ads, the memory of health messages was assessed through a recognition task and a convincing score was collected. The results confirmed that, compared to nonhumorous health ads, those using humor received prolonged attention, were judged more convincing, and their messages were better recognized. Overall, these findings suggest that humor can be of use in preventive health communication. PMID- 24160571 TI - Prevalence of smoking among secondary school male students in Jeddah, Saudi Arabia: a survey study. AB - BACKGROUND: This study was conducted to examine the prevalence of smoking and the smoking habits among male secondary school students in Jeddah, Kingdom of Saudi Arabia and to assess their knowledge and attitudes towards smoking. METHODS: A cross-sectional study was conducted in Jeddah, using a two-stage cluster sample that randomly selected four schools from 85 public secondary schools for males. Data were obtained through a self-administered questionnaire containing questions on personal background, smoking behavior, knowledge, and behavior and attitudes towards smoking. A total of 695 students responded to the questionnaires with an 87.4% response rate. RESULTS: The age range of this student sample was 16-22 years. Two hundred fifty-eight (37%) of the study group were current smokers. The most common reasons given for smoking were personal choice (50.8%) and the peer pressure from smoker friends (32.8%). Many students researched the smoking hazards (68.1%), but only 47.6% knew about the bad effects of passive smoking. Two thirds of the smoking students wanted to quit smoking (63.2%), especially if suitable help was available, and 75.1% tried to quit. A third of the smoking students (36.8%) found it difficult to stop smoking in no-smoking areas. CONCLUSION: A well-planned integrated antismoking campaign is urgently required, especially among students and teachers. Our study revealed that smoking prevalence was high, which will lead to future high smoking-related health problems if proper preventive measures are not taken accordingly. PMID- 24160573 TI - Cholesteryl ester transfer protein rs1532624 gene polymorphism is associated with reduced response to statin therapy. AB - The aim of the study was to determine the allele and genotype frequencies of rs1532624 SNP of the cholesteryl ester transfer protein gene (CETP) among 116 Jordanian patients taking statins, and to study the impact of the genotypes on response to statin therapy. The study was approved by the Institutional review Board (IRB) of The Jordan University Hospital. An informed consent was signed by every participant. A single fragment encoding a 307 bp sequence of the CETP gene, including the SNP of interest at position 14645 in intron 7, was amplified using a polymerase chain reaction (PCR) technique directly from whole blood. The PCR product was then subjected to DNA sequencing. The frequencies of the genotypes of the homozygous minor allele (AA), the homozygous major allele (CC), and the heterozygous allele (CA) were 0.121, 0.405, and 0.474, respectively. The minor allele (A) frequency was 0.358. The frequencies did not deviate from Hardy Weinberg equilibrium. The lipid profile before the start of statin therapy was similar for all genotypes regarding total cholesterol (TC), low density lipoprotein cholesterol (LDL-C), and triglycerides, while high density lipoprotein cholesterol (HDL-C) was significantly higher in the AA genotype. The AA genotype was also associated with significantly lower CETP activity than the other genotypes. The response to statin therapy was less in the AA genotype than the other genotypes for TC and LDL-C. In conclusion, the homozygous minor allele subjects have higher base line HDL-C, and lower CETP activity than the other genotypes (CA and CC). They also have less reduction in TC and LDL-C after statin therapy. PMID- 24160574 TI - Antihypertensive therapy: from 2003 to 2013 and beyond. PMID- 24160575 TI - Are we there yet? Closing the gender gap in coronary heart disease recognition, management and outcomes. PMID- 24160576 TI - The role of environment and epigenetics in hypertension. PMID- 24160578 TI - Coronary microvascular dysfunction in women: an overview of diagnostic strategies. AB - Coronary microvascular dysfunction (CMD) also known as syndrome X, is characterized by typical anginal symptoms, evidence of myocardial ischemia on non invasive testing and normal to minimal coronary disease on coronary angiography. It has a female preponderance and has been detected in up to 50% of women presenting with chest pain symptoms. Definitive diagnosis of CMD is critical as recent evidence suggests that women with this condition are at increased risk of cardiovascular events in the future. Invasive coronary reactivity testing on coronary angiography is considered to be the 'gold standard' for diagnosis of CMD. Non-invasive imaging techniques such as PET and cardiac magnetic resonance hold promise for detection of CMD in the future. PMID- 24160580 TI - Dividing line between quantum and classical trajectories in a measurement problem: Bohmian time constant. AB - This Letter proposes an answer to a challenge posed by Bell on the lack of clarity in regards to the dividing line between the quantum and classical regimes in a measurement problem. To this end, a generalized logarithmic nonlinear Schrodinger equation is proposed to describe the time evolution of a quantum dissipative system under continuous measurement. Within the Bohmian mechanics framework, a solution to this equation reveals a novel result: it displays a time constant that should represent the dividing line between the quantum and classical trajectories. It is shown that continuous measurements and damping not only disturb the particle but compel the system to converge in time to a Newtonian regime. While the width of the wave packet may reach a stationary regime, its quantum trajectories converge exponentially in time to classical trajectories. In particular, it is shown that damping tends to suppress further quantum effects on a time scale shorter than the relaxation time of the system. If the initial wave packet width is taken to be equal to 2.8*10(-15) m (the approximate size of an electron), the Bohmian time constant is found to have an upper limit, i.e., tau(Bmax)=10(-26) s. PMID- 24160579 TI - Acute aortic dissection in women: challenges and opportunities. AB - Acute aortic dissection (AAD) is a severe and potentially fatal disease which requires rapid diagnosis and appropriate treatment in order to improve survival. The variable and sometimes non-specific presentation of this rare condition makes it a continued diagnostic challenge for even the best of clinicians. Multiple clinical factors have been studied for their role in increasing the risk of AAD. While the complete pathophysiology of the condition is not known, contemporary research has shed light on many important factors that might lead to the development of aortic aneurysms and AAD. Despite continued research in this area, there is scant research looking at gender-related differences in the epidemiology, presentation, treatment and outcomes of patients with AAD. This review first revisits lessons about gender-related differences seen in various cardiovascular diseases, and then critically examines the data on gender-related differences in AAD diagnosis, management and outcomes. A summary of the pathophysiology and possible reasons for gender-specific differences in the development of aneurysms and dissections is also provided. PMID- 24160581 TI - Rabi oscillations between atomic and molecular condensates driven with coherent one-color photoassociation. AB - We demonstrate coherent one-color photoassociation of a Bose-Einstein condensate, which results in Rabi oscillations between atomic and molecular condensates. We attain atom-molecule Rabi frequencies that are comparable to decoherence rates by driving photoassociation of atoms in an ^{88}Sr condensate to a weakly bound level of the metastable 1S0+3P1 molecular potential, which has a long lifetime and a large Franck-Condon overlap integral with the ground scattering state. Transient shifts and broadenings of the excitation spectrum are clearly seen at short times, and they create an asymmetric excitation profile that only displays Rabi oscillations for blue detuning from resonance. PMID- 24160582 TI - Algebraic versus Exponential Decoherence in Dissipative Many-Particle Systems. AB - The interplay between dissipation and internal interactions in quantum many-body systems gives rise to a wealth of novel phenomena. Here we investigate spin-1/2 chains with uniform local couplings to a Markovian environment using the time dependent density matrix renormalization group. For the open XXZ model, we discover that the decoherence time diverges in the thermodynamic limit. The coherence decay is then algebraic instead of exponential. This is due to a vanishing gap in the spectrum of the corresponding Liouville superoperator and can be explained on the basis of a perturbative treatment. In contrast, decoherence in the open transverse-field Ising model is found to be always exponential. In this case, the internal interactions can both facilitate and impede the environment-induced decoherence. PMID- 24160583 TI - Tying knots in light fields. AB - We construct analytically, a new family of null solutions to Maxwell's equations in free space whose field lines encode all torus knots and links. The evolution of these null fields, analogous to a compressible flow along the Poynting vector that is shear free, preserves the topology of the knots and links. Our approach combines the construction of null fields with complex polynomials on S3. We examine and illustrate the geometry and evolution of the solutions, making manifest the structure of nested knotted tori filled by the field lines. PMID- 24160584 TI - Linear optical quantum computing in a single spatial mode. AB - We present a scheme for linear optical quantum computing using time-bin-encoded qubits in a single spatial mode. We show methods for single-qubit operations and heralded controlled-phase (cphase) gates, providing a sufficient set of operations for universal quantum computing with the Knill-Laflamme-Milburn [Nature (London) 409, 46 (2001)] scheme. Our protocol is suited to currently available photonic devices and ideally allows arbitrary numbers of qubits to be encoded in the same spatial mode, demonstrating the potential for time-frequency modes to dramatically increase the quantum information capacity of fixed spatial resources. As a test of our scheme, we demonstrate the first entirely single spatial mode implementation of a two-qubit quantum gate and show its operation with an average fidelity of 0.84+/-0.07. PMID- 24160585 TI - Bosonic Mott insulator with Meissner currents. AB - We introduce a generic bosonic model exemplifying that (spin) Meissner currents can persist in insulating phases of matter. We consider two species of interacting bosons on a lattice. Our model exhibits separation of charge (total density) and spin (relative density): the charge sector is gapped in a bosonic Mott insulator phase with total density one, while the spin sector remains superfluid due to interspecies conversion. Coupling the spin sector to the gauge fields yields a spin Meissner effect reflecting the long-range spin superfluid coherence. We investigate the resulting phase diagram and describe other possible spin phases of matter in the Mott regime possessing chiral currents as well as a spin-density wave phase. The model presented here is realizable in Josephson junction arrays and in cold atom experiments. PMID- 24160586 TI - Formation and coalescence of cosmological supermassive-black-hole binaries in supermassive-star collapse. AB - We study the collapse of rapidly rotating supermassive stars that may have formed in the early Universe. By self-consistently simulating the dynamics from the onset of collapse using three-dimensional general-relativistic hydrodynamics with fully dynamical spacetime evolution, we show that seed perturbations in the progenitor can lead to the formation of a system of two high-spin supermassive black holes, which inspiral and merge under the emission of powerful gravitational radiation that could be observed at redshifts z is approximately equal or > to 10 with the DECIGO or Big Bang Observer gravitational-wave observatories, assuming supermassive stars in the mass range 10(4)-10(6)M[symbol: see text]. The remnant is rapidly spinning with dimensionless spin a*=0.9. The surrounding accretion disk contains ~10% of the initial mass. PMID- 24160587 TI - Equivalence principle and bound kinetic energy. AB - We consider the role of the internal kinetic energy of bound systems of matter in tests of the Einstein equivalence principle. Using the gravitational sector of the standard model extension, we show that stringent limits on equivalence principle violations in antimatter can be indirectly obtained from tests using bound systems of normal matter. We estimate the bound kinetic energy of nucleons in a range of light atomic species using Green's function Monte Carlo calculations, and for heavier species using a Woods-Saxon model. We survey the sensitivities of existing and planned experimental tests of the equivalence principle, and report new constraints at the level of between a few parts in 10(6) and parts in 10(8) on violations of the equivalence principle for matter and antimatter. PMID- 24160588 TI - Excess astrophysical photons from a 0.1-1 keV cosmic axion background. AB - Primordial decays of string theory moduli at z~10(12) naturally generate a dark radiation cosmic axion background with 0.1-1 keV energies. This cosmic axion background can be detected through axion-photon conversion in astrophysical magnetic fields to give quasithermal excesses in the extreme ultraviolet and soft x-ray bands. Substantial and observable luminosities may be generated even for axion-photon couplings <<10(-11) GeV(-1). We propose that axion-photon conversion may explain the observed excess emission of soft x rays from galaxy clusters, and may also contribute to the diffuse unresolved cosmic x-ray background. We list a number of correlated predictions of the scenario. PMID- 24160589 TI - Baryogenesis and dark matter through a Higgs asymmetry. AB - In addition to explaining the masses of elementary particles, the Higgs boson may have far-reaching implications for the generation of the matter content in the Universe. For instance, the Higgs boson plays a key role in two main theories of baryogenesis, namely, electroweak baryogenesis and leptogenesis. In this Letter, we propose a new cosmological scenario where the Higgs chemical potential mediates asymmetries between visible and dark matter sectors, either generating a baryon asymmetry from a dark matter asymmetry or vice versa. We illustrate this mechanism with a simple model with two new fermions coupled to the Higgs boson and discuss the associated signatures. PMID- 24160591 TI - Limits on exotic long-range spin-spin interactions of electrons. AB - We surrounded a rotating torsion pendulum containing 9.8*10(22) polarized electrons by 2 or 4 stationary sources, each with a net spin of 6.0*10(24) polarized electrons. Multiple source configurations gave sensitivity to hypothetical dipole-dipole, spin-dot-spin, and spin-cross-spin exchange interactions mediated by bosons with masses up to 20 MUeV. For bosons with masses <=0.1 MUeV our null results for the dipole-dipole, spin-dot-spin, and spin-cross spin forces imply 1sigma upper limits on (g(P)(e))(2)/(hc), (g(A)(e))(2)/(hc) and (g(V)(e)g(A)(e))/(hc) of 2.2*10(-16), 3.8*10(-40), and 1.2*10(-28), respectively. We also constrain, for the first time, any possible linear combination of static spin-spin interactions. In this case our upper limits relax to 5.6*10(-16), 9.8*10(-40), and 1.2*10(-28), respectively. PMID- 24160597 TI - Nuclear fluxes in diatomic molecules deduced from pump-probe spectra with spatiotemporal resolutions down to 5 pm and 200 asec. AB - When molecules move, their nuclei flow. The corresponding quantum observable, i.e., the nuclear flux density, was introduced by Schrodinger in 1926, but until now, it has not been measured. Here the first experimental results are deduced from high-resolution pump-probe measurements of the time-dependent nuclear densities in a vibrating diatomic molecule or molecular ion. The nuclear densities are converted to flux densities by means of the continuity equation. The flux densities are much more sensitive to time-dependent quantum effects than the densities. Applications to the sodium molecule and the deuterium molecular ion unravel four new effects; e.g., at the turns from bond stretch to compression, the flux of the nuclei exhibits multiple changes of directions, from small to large bond lengths, a phenomenon that we call the "quantum accordion." PMID- 24160595 TI - Critical Landau velocity in helium nanodroplets. AB - The best-known property of superfluid helium is the vanishing viscosity that objects experience while moving through the liquid with speeds below the so called critical Landau velocity. This critical velocity is generally considered a macroscopic property as it is related to the collective excitations of the helium atoms in the liquid. In the present work we determine to what extent this concept can still be applied to nanometer-scale, finite size helium systems. To this end, atoms and molecules embedded in helium nanodroplets of various sizes are accelerated out of the droplets by means of optical excitation, and the speed distributions of the ejected particles are determined. The measurements reveal the existence of a critical velocity in these systems, even for nanodroplets consisting of only a thousand helium atoms. Accompanying theoretical simulations based on a time-dependent density functional description of the helium confirm and further elucidate this experimental finding. PMID- 24160594 TI - N-representability in noncollinear spin-polarized density-functional theory. AB - The N-representability problem for noncollinear spin-polarized densities was left open in the pioneering work of von Barth and Hedin [J. Phys. C 5, 1629 (1972)] setting up the Kohn-Sham density-functional theory for magnetic compounds. In this Letter, we demonstrate that, contrarily to the nonpolarized case, the sets of pure and mixed state N-representable densities are different in general. We provide a simple characterization of the latter by means of easily checkable necessary and sufficient conditions on the components rho(alphabeta)(r) of the spin-polarized density. PMID- 24160596 TI - Retardation effects and the Born-Oppenheimer approximation: theory of tunneling ionization of molecules revisited. AB - We show that retardation in adjusting an electronic state to an instantaneous internuclear configuration caused by the finiteness of the electron's velocity breaks the validity of the Born-Oppenheimer (BO) approximation at large electron nuclei distances. This applies even to the ground state. As a result, the BO approximation in the theory of tunneling ionization of molecules breaks down at sufficiently weak fields. We also show that to account for nuclear motion the weak-field asymptotic expansion for the tunneling ionization rate must be restructured. The predictions for the rate using the BO approximation and the asymptotic expansion are compared with numerical results for a one-dimensional three-body system modeling a diatomic molecule, with both electronic and nuclear motions treated exactly. PMID- 24160599 TI - Coherent ultrafast measurement of time-bin encoded photons. AB - Time-bin encoding is a robust form of optical quantum information, especially for transmission in optical fibers. To readout the information, the separation of the time bins must be larger than the detector time resolution, typically on the order of nanoseconds for photon counters. In the present work, we demonstrate a technique using a nonlinear interaction between chirped entangled time-bin photons and shaped laser pulses to perform projective measurements on arbitrary time-bin states with picosecond-scale separations. We demonstrate a tomographically complete set of time-bin qubit projective measurements and show the fidelity of operations is sufficiently high to violate the Clauser-Horne Shimony-Holt-Bell inequality by more than 6 standard deviations. PMID- 24160598 TI - Implementation of an impedance-matched Lambda system by dressed-state engineering. AB - In one-dimensional optical setups, light-matter interaction is drastically enhanced by the interference between the incident and scattered fields. Particularly, in the impedance-matched Lambda-type three-level systems, a single photon deterministically induces the Raman transition and switches the electronic state of the system. Here, we show that such a Lambda system can be implemented by using dressed states of a driven superconducting qubit and a resonator. The input microwave photons are perfectly absorbed and are down-converted into other frequency modes in the same waveguide. The proposed setup is applicable to the detection of single microwave photons and the swapping of the photon and matter qubits. PMID- 24160593 TI - Isomers in 128Pd and 126Pd: evidence for a robust shell closure at the neutron magic number 82 in exotic palladium isotopes. AB - The level structures of the very neutron-rich nuclei 128Pd and 126Pd have been investigated for the first time. In the r-process waiting-point nucleus 128Pd, a new isomer with a half-life of 5.8(8) MUs is proposed to have a spin and parity of 8(+) and is associated with a maximally aligned configuration arising from the g(9/2) proton subshell with seniority upsilon=2. For 126Pd, two new isomers have been identified with half-lives of 0.33(4) and 0.44(3) MUs. The yrast 2(+) energy is much higher in 128Pd than in 126Pd, while the level sequence below the 8(+) isomer in 128Pd is similar to that in the N=82 isotone 130Cd. The electric quadrupole transition that depopulates the 8(+) isomer in 128Pd is more hindered than the corresponding transition in 130Cd, as expected in the seniority scheme for a semimagic, spherical nucleus. These experimental findings indicate that the shell closure at the neutron number N=82 is fairly robust in the neutron-rich Pd isotopes. PMID- 24160600 TI - Optical vortex generation from molecular chromophore arrays. AB - The generation of light endowed with orbital angular momentum, frequently termed optical vortex light, is commonly achieved by passing a conventional beam through suitably constructed optical elements. This Letter shows that the necessary phase structure for vortex propagation can be directly produced through the creation of twisted light from the vacuum. The mechanism is based on optical emission from a family of chromophore nanoarrays that satisfy specific geometric and symmetry constraints. Each such array can support pairs of electronically delocalized doubly degenerate excitons whose azimuthal phase progression is responsible for the helical wave front of the emitted radiation. The exciton symmetry dictates the maximum magnitude of topological charge; detailed analysis secures the conditions necessary to deliver optical vortices of arbitrary order. PMID- 24160601 TI - Dynamic beam steering from a subwavelength slit by selective excitation of guided modes. AB - Dynamic control of the direction of radiation of the light emanating from a subwavelength slit carved out of a thin metal film is experimentally demonstrated. This is achieved by selective excitation of the individual guided modes in the slit by setting the phase of three coherent laser beams. By changing the voltage across a piezoelement, we obtain unprecedented directional steering, without relying on any mechanical alignment of optical elements. The angular range over which this maximum can be swept is determined by the intensity setting of one of the incident beams. Through simulations, we show that this method can also be applied to steer the radiation from a square hole in two independent directions. Our method can be applied to create a directional nanoemitter which can selectively address one or more detectors, or as an optical switch in photonic circuits. PMID- 24160603 TI - Sound and light from fractures in scintillators. AB - Prompted by intriguing events observed in certain particle-physics searches for rare events, we study light and acoustic emission simultaneously in some inorganic scintillators subject to mechanical stress. We observe mechanoluminescence in Bi4Ge3O12, CdWO4, and ZnWO4, in various mechanical configurations at room temperature and ambient pressure. We analyze the temporal and amplitude correlations between the light emission and the acoustic emission during fracture. A novel application of the precise energy calibration of Bi4Ge3O12 provided by radioactive sources allows us to deduce that the fraction of elastic energy converted to light is at least 3*10(-5). PMID- 24160602 TI - Measuring large optical transmission matrices of disordered media. AB - We report a measurement of the large optical transmission matrix (TM) of a complex turbid medium. The TM is acquired using polarization-sensitive, full field interferometric microscopy equipped with a rotating galvanometer mirror. It is represented with respect to input and output bases of optical modes, which correspond to plane wave components of the respective illumination and transmitted waves. The modes are sampled so finely in angular spectrum space that their number exceeds the total number of resolvable modes for the illuminated area of the sample. As such, we investigate the singular value spectrum of the TM in order to detect evidence of open transmission channels, predicted by random matrix theory. Our results comport with theoretical expectations, given the experimental limitations of the system. We consider the impact of these limitations on the usefulness of transmission matrices in optical measurements. PMID- 24160604 TI - Viscous control of peeling an elastic sheet by bending and pulling. AB - Propagation of a viscous fluid beneath an elastic sheet is controlled by local dynamics at the peeling front, in close analogy with the capillary-driven spreading of drops over a precursor film. Here we identify propagation laws for a generic elastic peeling problem in the distinct limits of peeling by bending and peeling by pulling, and apply our results to the radial spread of a fluid blister over a thin prewetting film. For the case of small deformations relative to the sheet thickness, peeling is driven by bending, leading to radial growth as t(7/22). Experimental results reproduce both the spreading behavior and the bending wave at the front. For large deformations relative to the sheet thickness, stretching of the blister cap and the consequent tension can drive peeling either by bending or by pulling at the front, both leading to radial growth as t(3/8). In this regime, detailed predictions give excellent agreement and explanation of previous experimental measurements of spread in the pulling regime in an elastic Hele-Shaw cell. PMID- 24160590 TI - Measurement of the CP asymmetry in B(+)->K(+)MU(+)MU(-) decays. AB - A measurement of the CP asymmetry in B(+)->K(+)MU(+)MU(-) decays is presented using pp collision data, corresponding to an integrated luminosity of 1.0 fb(-1), recorded by the LHCb experiment during 2011 at a center-of-mass energy of 7 TeV. The measurement is performed in seven bins of MU(+)MU(-) invariant mass squared in the range 0.05J/psiK(+) decay as a control mode. Averaged over all the bins, the CP asymmetry is found to be A(CP)=0.000+/-0.033 (stat)+/-0.005 (syst)+/-0.007 (J/psiK), where the third uncertainty is due to the CP asymmetry of the control mode. This is consistent with the standard model prediction. PMID- 24160605 TI - Nonlinear stabilization of tokamak microturbulence by fast ions. AB - Nonlinear electromagnetic stabilization by suprathermal pressure gradients found in specific regimes is shown to be a key factor in reducing tokamak microturbulence, augmenting significantly the thermal pressure electromagnetic stabilization. Based on nonlinear gyrokinetic simulations investigating a set of ion heat transport experiments on the JET tokamak, described by Mantica et al. [Phys. Rev. Lett. 107, 135004 (2011)], this result explains the experimentally observed ion heat flux and stiffness reduction. These findings are expected to improve the extrapolation of advanced tokamak scenarios to reactor relevant regimes. PMID- 24160606 TI - Magnetoplasmons in rotating dusty plasmas. AB - A rotating dusty plasma apparatus was constructed to provide the possibility of experimental emulation of extremely high magnetic fields by means of the Coriolis force, observable in a corotating measurement frame. We present collective excitation spectra for different rotation rates with a magnetic induction equivalent of up to 3200 T. We identify the onset of magnetoplasmon-equivalent mode dispersion in the rotating macroscopic two-dimensional single-layer dusty plasma. The experimental results are supported by molecular dynamics simulations of 2D magnetized Yukawa systems. PMID- 24160607 TI - K-shell photoabsorption edge of strongly coupled matter driven by laser-converted radiation. AB - The first observation of the K-shell photoabsorption edge of strongly coupled matter with an ion-ion coupling parameter of about 65 generated by intense x-ray radiation-driven shocks is reported. The soft x-ray radiation generated by laser interaction with a "dog bone" high-Z hohlraum is used to ablate two thick CH layers, which cover a KCl sample, to create symmetrical inward shocks. While the two shocks impact at the central KCl sample, a highly compressed KCl is obtained with a density of 3-5 times solid density and a temperature of about 2-4 eV. The photoabsorption spectra of chlorine near the K-shell edge are measured with a crystal spectrometer using a short x-ray backlighter. The redshift of the K edge up to 11.7 eV and broadening of 15.2 eV are obtained for the maximum compression. A comparison of the measured redshifts and broadenings with dense plasma calculations are made, and it indicates potential improvements in the theoretical description. PMID- 24160609 TI - Rotating instability in low-temperature magnetized plasmas. AB - The formation of a rotating instability associated with an ionization front ("rotating spoke") and driven by a cross-field current in a cylindrical magnetized plasma is shown and explained for the first time on the basis of a fully kinetic simulation. The rotating spoke is a strong double layer (electrostatic sheath) moving towards the higher potential region at a velocity close to the critical ionization velocity, a concept proposed by Alfven in the context of the formation of the solar system. The mechanisms of cross-field electron transport induced by this instability are analyzed. PMID- 24160608 TI - Two-pulse ionization injection into quasilinear laser wakefields. AB - We describe a scheme for controlling electron injection into the quasilinear wakefield driven by a guided drive pulse via ionization of a dopant species by a collinear injection laser pulse with a short Rayleigh range. The scheme is analyzed by particle-in-cell simulations which show controlled injection and acceleration of electrons to an energy of 370 MeV, a relative energy spread of 2%, and a normalized transverse emittance of 2.0 MUm. PMID- 24160610 TI - Feshbach resonance without a closed-channel bound state. AB - The physics of Feshbach resonance is analyzed using an analytic expression for the s-wave scattering phase shift and the scattering length a which we derive within a two-channel tight-binding model. Employing a unified treatment of bound states and resonances in terms of the Jost function, it is shown that, for strong interchannel coupling, Feshbach resonance can occur even when the closed channel does not have a bound state. This may extend the range of ultracold atomic systems that can be manipulated by Feshbach resonance. The dependence of the sign of a on the coupling strength in the unitary limit is elucidated. As a by product, analytic expressions are derived for the background scattering length, the external magnetic field at which resonance occurs, and the energy shift epsilon-epsilon(B), where epsilon is the scattering energy and epsilon(B) is the bound-state energy in the closed channel (when there is one). PMID- 24160611 TI - Amorphization driven by defect-induced mechanical instability. AB - Using ab initio molecular dynamics simulations, we perform a comparative study of the defect accumulation process in silicon carbide (SiC) and zirconium carbide (ZrC). Interestingly, we find that the fcc Si sublattice in SiC spontaneously and gradually collapses following the continuous introduction of C Frenkel pairs (FPs). Above a critical amorphization dose of ~0.33 displacements per atom (dpa), the pair correlation function exhibits no long-range order. In contrast, the fcc Zr sublattice in ZrC remains structurally stable against C sublattice displacements up to the highest dose of 1.0 dpa considered. Consequently, ZrC cannot be amorphized by the accumulation of C FPs. We propose defect-induced mechanical instability as the key mechanism driving the amorphization of SiC under electron irradiation. PMID- 24160612 TI - Universal medium-range order of amorphous metal oxides. AB - We propose that the structure of amorphous metal oxides can be regarded as a dual dense-random-packing structure, which is a superposition of the dense random packing of metal atoms and that of oxygen atoms. Our ab initio molecular dynamics simulations show that the medium-range order of amorphous HfO2, ZrO2, TiO2, In2O3, Ga2O3, Al2O3, and Cu2O is characterized by the pentagonal-bipyramid arrangement of metal atoms and that of oxygen atoms, and prove the validity of our dual-random-sphere-packing model. In other words, we find that the pentagonal medium-range order is universal independent of type of metal oxide. PMID- 24160613 TI - Signatures of a pressure-induced topological quantum phase transition in BiTeI. AB - We report the observation of two signatures of a pressure-induced topological quantum phase transition in the polar semiconductor BiTeI using x-ray powder diffraction and infrared spectroscopy. The x-ray data confirm that BiTeI remains in its ambient-pressure structure up to 8 GPa. The lattice parameter ratio c/a shows a minimum between 2.0-2.9 GPa, indicating an enhanced c-axis bonding through p(z) band crossing as expected during the transition. Over the same pressure range, the infrared spectra reveal a maximum in the optical spectral weight of the charge carriers, reflecting the closing and reopening of the semiconducting band gap. Both of these features are characteristics of a topological quantum phase transition and are consistent with a recent theoretical proposal. PMID- 24160614 TI - Synthesis-dependent atomic surface structures of oxide nanoparticles. AB - Using SrTiO3 nanocuboids as a model system, we show with aberration-corrected high resolution electron microscopy at sub-A resolution that surface relaxations or reconstructions are present on the nanocuboids, depending on the synthetic process. Oleic acid synthesis, acetic acid synthesis, and microwave-assisted acetic acid synthesis result in a SrO termination, TiO2-rich reconstruction, and mixed termination, respectively. The experimental atomic positions are in better agreement with density functional theory calculations using an exact-exchange corrected PBEsol functional than the Perdew-Burke-Ernzerhof (PBE) functional. PMID- 24160615 TI - Transverse spin-gradient functional for noncollinear spin-density-functional theory. AB - We present a novel functional for spin-density-functional theory aiming at the description of noncollinear magnetic structures. The construction of the functional employs the spin-spiral-wave state of the uniform electron gas as reference system. We show that the functional depends on transverse gradients of the spin magnetization; i.e., in contrast with the widely used local spin density approximation, the functional is sensitive to local changes of the direction of the spin magnetization. As a consequence the exchange-correlation magnetic field is not parallel to the spin magnetization and a local spin torque is present in the ground state of the Kohn-Sham system. As a proof of principle, we apply the functional to a Chromium monolayer in the noncollinear 120 degrees -Neel state. PMID- 24160616 TI - Interface-induced topological insulator transition in GaAs/Ge/GaAs quantum wells. AB - We demonstrate theoretically that interface engineering can drive germanium, one of the most commonly used semiconductors, into a topological insulating phase. Utilizing giant electric fields generated by charge accumulation at GaAs/Ge/GaAs opposite semiconductor interfaces and band folding, the new design can reduce the sizable gap in Ge and induce large spin-orbit interaction, which leads to a topological insulator transition. Our work provides a new method to realize topological insulators in commonly used semiconductors and suggests a promising approach to integrate it in well-developed semiconductor electronic devices. PMID- 24160617 TI - Structural transition in atomic chains driven by transient doping. AB - A reversible structural transition is observed on Si(553)-Au by scanning tunneling microscopy, triggered by electrons injected from the tip into the surface. The periodicity of atomic chains near the step edges changes from the 1*3 ground state to a 1*2 excited state with increasing tunneling current. The threshold current for this transition is reduced at lower temperatures. In conjunction with first-principles density-functional calculations it is shown that the 1*2 phase is created by temporary doping of the atom chains. Random telegraph fluctuations between two levels of the tunneling current provide direct access to the dynamics of the phase transition, revealing lifetimes in the millisecond range. PMID- 24160618 TI - Stripe antiferromagnetic spin fluctuations in SrCo2As2. AB - Inelastic neutron scattering measurements of paramagnetic SrCo2As2 at T=5 K reveal antiferromagnetic (AFM) spin fluctuations that are peaked at a wave vector of Q(AFM)=(1/2,1/2,1) and possess a large energy scale. These stripe spin fluctuations are similar to those found in AFe2As2 compounds, where spin-density wave AFM is driven by Fermi surface nesting between electron and hole pockets separated by Q(AFM). SrCo2As2 has a more complex Fermi surface and band-structure calculations indicate a potential instability toward either a ferromagnetic or stripe AFM ground state. The results suggest that stripe AFM magnetism is a general feature of both iron and cobalt-based arsenides and the search for spin fluctuation-induced unconventional superconductivity should be expanded to include cobalt-based compounds. PMID- 24160619 TI - Discovery of a superhard iron tetraboride superconductor. AB - Single crystals of novel orthorhombic (space group Pnnm) iron tetraboride FeB4 were synthesized at pressures above 8 GPa and high temperatures. Magnetic susceptibility and heat capacity measurements demonstrate bulk superconductivity below 2.9 K. The putative isotope effect on the superconducting critical temperature and the analysis of specific heat data indicate that the superconductivity in FeB4 is likely phonon mediated, which is rare for Fe-based superconductors. The discovered iron tetraboride is highly incompressible and has the nanoindentation hardness of 62(5) GPa; thus, it opens a new class of highly desirable materials combining advanced mechanical properties and superconductivity. PMID- 24160620 TI - Formation of gapless Fermi arcs and fingerprints of order in the pseudogap state of cuprate superconductors. AB - We use angle-resolved photoemission spectroscopy and a new quantitative approach based on the partial density of states to study properties of seemingly disconnected portions of the Fermi surface (FS) that are present in the pseudogap state of cuprates called Fermi arcs. We find that the normal state FS collapses very abruptly into Fermi arcs at the pseudogap temperature (T*). Surprisingly, the length of the Fermi arcs remains constant over an extended temperature range between T* and T(pair), consistent with the presence of an ordered state below T*. These arcs collapse again at the temperature below which pair formation occurs (T(pair)) either to a point or a very short arc, whose length is limited by our experimental resolution. The tips of the arcs span between points defining a set of wave vectors in momentum space, which are the fingerprints of the ordered state that causes the pseudogap. PMID- 24160621 TI - Singularity of the London penetration depth at quantum critical points in superconductors. AB - We present a general theory of the singularity in the London penetration depth at symmetry-breaking and topological quantum critical points within a superconducting phase. While the critical exponents and ratios of amplitudes on the two sides of the transition are universal, an overall sign depends upon the interplay between the critical theory and the underlying Fermi surface. We determine these features for critical points to spin density wave and nematic ordering, and for a topological transition between a superconductor with Z2 fractionalization and a conventional superconductor. We note implications for recent measurements of the London penetration depth in BaFe2(As(1-x)P(x))2 [K. Hashimoto et al., Science 336, 1554 (2012)]. PMID- 24160623 TI - Orbital order and Hund's rule frustration in Kondo lattices. AB - We analyze a microscopic origin of the Kondo effect-assisted orbital order in heavy-fermion materials. By studying the periodic two-orbital Anderson model with two local electrons, we show that frustration of Hund's rule coupling due to the Kondo effect leads to an incommensurate spiral orbital and magnetic order, which exists only inside the Kondo screened (heavy-electron) phase. This spiral state can be observed in neutron and resonant x-ray scattering measurements in U- and Pr-based heavy-fermion compounds, and realized in cold atomic gases, e.g., fermionic 173Yb. PMID- 24160622 TI - Emergent spin excitations in a Bethe lattice at percolation. AB - We study the spin-1/2 quantum Heisenberg antiferromagnet on a Bethe lattice diluted to the percolation threshold. Dilution creates areas of even or odd sublattice imbalance resulting in "dangling spins" [L. Wang and A. W. Sandvik, Phys. Rev. Lett. 97, 117204 (2006); Phys. Rev. B 81, 054417 (2010)]. These collectively act as "emergent" spin-1/2 degrees of freedom and are responsible for the creation of a set of low-lying "quasidegenerate states." Using density matrix renormalization group calculations, we detect the presence and location of these emergent spins. We find an effective Hamiltonian of these emergent spins, with Heisenberg interactions that decay exponentially with the distance between them. PMID- 24160624 TI - Theory of a competitive spin liquid state for weak Mott insulators on the triangular lattice. AB - We propose a novel quantum spin liquid state that can explain many of the intriguing experimental properties of the low-temperature phase of the organic spin liquid candidate materials kappa-(BEDT-TTF)2Cu2(CN)3 and EtMe3Sb[Pd(dmit)2]2. This state of paired fermionic spinons preserves all symmetries of the system, and it has a gapless excitation spectrum with quadratic bands that touch at momentum k[over ->]=0. This quadratic band touching is protected by symmetries. Using variational Monte Carlo techniques, we show that this state has highly competitive energy in the triangular lattice Heisenberg model supplemented with a realistically large ring-exchange term. PMID- 24160625 TI - Spin excitations of individual Fe atoms on Pt(111): impact of the site-dependent giant substrate polarization. AB - We demonstrate using inelastic scanning tunneling spectroscopy and simulations based on density functional theory that the amplitude and sign of the magnetic anisotropy energy for a single Fe atom adsorbed onto the Pt(111) surface can be manipulated by modifying the adatom binding site. Since the magnitude of the measured anisotropy is remarkably small, up to an order of magnitude smaller than previously reported, electron-hole excitations are weak and thus the spin excitation exhibits long lived precessional lifetimes compared to the values found for the same adatom on noble metal surfaces. PMID- 24160626 TI - Elemental topological insulator with tunable Fermi level: strained alpha-Sn on InSb(001). AB - We report on the epitaxial fabrication and electronic properties of a topological phase in strained alpha-Sn on InSb. The topological surface state forms in the presence of an unusual band order not based on direct spin-orbit coupling, as shown in density functional and GW slab-layer calculations. Angle-resolved photoemission including spin detection probes experimentally how the topological spin-polarized state emerges from the second bulk valence band. Moreover, we demonstrate the precise control of the Fermi level by dopants. PMID- 24160627 TI - First-principles method of propagation of tightly bound excitons: verifying the exciton band structure of LiF with inelastic x-ray scattering. AB - We propose a simple first-principles method to describe the propagation of tightly bound excitons. By viewing the exciton as a composite object (an effective Frenkel exciton in Wannier orbitals), we define an exciton kinetic kernel to encapsulate the exciton propagation and decay for all binding energies. Applied to prototypical LiF, our approach produces three exciton bands, which we verified quantitatively via inelastic x-ray scattering. The proposed real-space picture is computationally inexpensive and thus enables study of the full exciton dynamics, even in the presence of surfaces and impurity scattering. It also provides an intuitive understanding to facilitate practical exciton engineering in semiconductors, strongly correlated oxides, and their nanostructures. PMID- 24160628 TI - Proposed Rabi-Kondo correlated state in a laser-driven semiconductor quantum dot. AB - Spin exchange between a single-electron charged quantum dot and itinerant electrons leads to an emergence of Kondo correlations. When the quantum dot is driven resonantly by weak laser light, the resulting emission spectrum allows for a direct probe of these correlations. In the opposite limit of vanishing exchange interaction and strong laser drive, the quantum dot exhibits coherent oscillations between the single-spin and optically excited states. Here, we show that the interplay between strong exchange and nonperturbative laser coupling leads to the formation of a new nonequilibrium quantum-correlated state, characterized by the emergence of a laser-induced secondary spin screening cloud, and examine the implications for the emission spectrum. PMID- 24160629 TI - Hyperfine splitting and room-temperature ferromagnetism of Ni at multimegabar pressure. AB - Magnetic and elastic properties of Ni metal have been studied up to 260 GPa by nuclear forward scattering of synchrotron radiation with the 67.4 keV Mossbauer transition of 61Ni. The observed magnetic hyperfine splitting confirms the ferromagnetic state of Ni up to 260 GPa, the highest pressure where magnetism in any material has been observed so far. Ab initio calculations reveal that the pressure evolution of the hyperfine field, which features a maximum in the range of 100 to 225 GPa, is a relativistic effect. The Debye energy obtained from the Lamb-Mossbauer factor increases from 33 meV at ambient pressure to 60 meV at 100 GPa. The change of this energy over volume compression is well described by a Gruneisen parameter of 2.09. PMID- 24160630 TI - Antiphase synchronization in a flagellar-dominance mutant of Chlamydomonas. AB - Groups of beating flagella or cilia often synchronize so that neighboring filaments have identical frequencies and phases. A prime example is provided by the unicellular biflagellate Chlamydomonas reinhardtii, which typically displays synchronous in-phase beating in a low-Reynolds number version of breaststroke swimming. We report the discovery that ptx1, a flagellar-dominance mutant of C. reinhardtii, can exhibit synchronization in precise antiphase, as in the freestyle swimming stroke. High-speed imaging shows that ptx1 flagella switch stochastically between in-phase and antiphase states, and that the latter has a distinct waveform and significantly higher frequency, both of which are strikingly similar to those found during phase slips that stochastically interrupt in-phase beating of the wild-type. Possible mechanisms underlying these observations are discussed. PMID- 24160632 TI - Comment on "Probing phase fluctuations in a 2D Degenerate Bose gas by free expansion". PMID- 24160631 TI - Periodic migration in a physical model of cells on micropatterns. AB - We extend a model for the morphology and dynamics of a crawling eukaryotic cell to describe cells on micropatterned substrates. This model couples cell morphology, adhesion, and cytoskeletal flow in response to active stresses induced by actin and myosin. We propose that protrusive stresses are only generated where the cell adheres, leading to the cell's effective confinement to the pattern. Consistent with experimental results, simulated cells exhibit a broad range of behaviors, including steady motion, turning, bipedal motion, and periodic migration, in which the cell crawls persistently in one direction before reversing periodically. We show that periodic motion emerges naturally from the coupling of cell polarization to cell shape by reducing the model to a simplified one-dimensional form that can be understood analytically. PMID- 24160633 TI - Choi et al. Reply. PMID- 24160634 TI - Multivariate reference technique for quantitative analysis of fiber-optic tissue Raman spectroscopy. AB - We report a novel method making use of multivariate reference signals of fused silica and sapphire Raman signals generated from a ball-lens fiber-optic Raman probe for quantitative analysis of in vivo tissue Raman measurements in real time. Partial least-squares (PLS) regression modeling is applied to extract the characteristic internal reference Raman signals (e.g., shoulder of the prominent fused silica boson peak (~130 cm(-1)); distinct sapphire ball-lens peaks (380, 417, 646, and 751 cm(-1))) from the ball-lens fiber-optic Raman probe for quantitative analysis of fiber-optic Raman spectroscopy. To evaluate the analytical value of this novel multivariate reference technique, a rapid Raman spectroscopy system coupled with a ball-lens fiber-optic Raman probe is used for in vivo oral tissue Raman measurements (n = 25 subjects) under 785 nm laser excitation powers ranging from 5 to 65 mW. An accurate linear relationship (R(2) = 0.981) with a root-mean-square error of cross validation (RMSECV) of 2.5 mW can be obtained for predicting the laser excitation power changes based on a leave one-subject-out cross-validation, which is superior to the normal univariate reference method (RMSE = 6.2 mW). A root-mean-square error of prediction (RMSEP) of 2.4 mW (R(2) = 0.985) can also be achieved for laser power prediction in real time when we applied the multivariate method independently on the five new subjects (n = 166 spectra). We further apply the multivariate reference technique for quantitative analysis of gelatin tissue phantoms that gives rise to an RMSEP of ~2.0% (R(2) = 0.998) independent of laser excitation power variations. This work demonstrates that multivariate reference technique can be advantageously used to monitor and correct the variations of laser excitation power and fiber coupling efficiency in situ for standardizing the tissue Raman intensity to realize quantitative analysis of tissue Raman measurements in vivo, which is particularly appealing in challenging Raman endoscopic applications. PMID- 24160635 TI - Morphological and molecular analyses of larval taeniid species in small mammals from contrasting habitats in Denmark. AB - Taeniid infections in intermediate hosts manifest themselves as extraintestinal larval stages which, in early development, lack species-specific characteristics. The inability to distinguish infections of zoonotic importance such as Echinococcus multilocularis from other taeniid infections that have mainly veterinary significance stimulated the development of species-specific molecular diagnostics. In this study, the prevalence of taeniid infections in potential intermediate hosts was evaluated using both morphological diagnosis and a newly described multiplex polymerase chain reaction (PCR) for species determination. Small mammals (N= 719) were trapped in three different types of habitats in north east Zealand, Denmark. The sensitivity of the multiplex PCR (90.5%) exceeded that of morphological examination (57.9%) for identifying 95 taeniid infections. The use of the multiplex PCR resulted in higher prevalence rates due to improved detection of immature liver infections with Hydatigera taeniaeformis and Versteria mustelae, but did not affect the observed prevalence rates of peritoneal metacestodes of Taenia polyacantha. The prevalence of taeniid infections showed a significant difference according to habitat type, potentially identifying a 'sylvatic' transmission and an 'urban' transmission, with marked variation among different taeniid species. Versteria mustelae and T. polyacantha were more prevalent in rural forests, while infections with H. taeniaeformis were dominant in urban parks/forests and in residential and farm gardens. The multiplex PCR facilitated a better utilization of wildlife samples by yielding a higher number of definitive diagnoses of ambiguous taeniid infections in liver lesions, allowing for more accurate epidemiological data and, hence, a more accurate risk assessment. PMID- 24160638 TI - Correspondence between Gentile oscillators and N-annulenes. AB - The cyclic hydrocarbon polyenes with the general formula CNHN are called N annulenes. In this paper, we discover that Gentile oscillators and N-annulenes in the Huckel approximation have the same energy spectra determined by the contact points of a regular polygon inscribed on a circle. This correspondence is derived from the symmetry of a C(n + 1) rotational group and dihedral group DihN. On the basis of their energy spectra, we further demonstrate that these two kinds of systems have the same partition functions and, thus, the same thermodynamics properties. N-annulenes can, therefore, be viewed as the natural realization of Gentile systems. PMID- 24160637 TI - Astrocytes acquire resistance to iron-dependent oxidative stress upon proinflammatory activation. AB - BACKGROUND: Astrocytes respond to local insults within the brain and the spinal cord with important changes in their phenotype. This process, overall known as "activation", is observed upon proinflammatory stimulation and leads astrocytes to acquire either a detrimental phenotype, thereby contributing to the neurodegenerative process, or a protective phenotype, thus supporting neuronal survival. Within the mechanisms responsible for inflammatory neurodegeneration, oxidative stress plays a major role and has recently been recognized to be heavily influenced by changes in cytosolic iron levels. In this work, we investigated how activation affects the competence of astrocytes to handle iron overload and the ensuing oxidative stress. METHODS: Cultures of pure cortical astrocytes were preincubated with proinflammatory cytokines (interleukin-1beta and tumor necrosis factor alpha) or conditioned medium from lipopolysaccharide activated microglia to promote activation and then exposed to a protocol of iron overload. RESULTS: We demonstrate that activated astrocytes display an efficient protection against iron-mediated oxidative stress and cell death. Based on this evidence, we performed a comprehensive biochemical and molecular analysis, including a transcriptomic approach, to identify the molecular basis of this resistance. CONCLUSIONS: We propose the protective phenotype acquired after activation not to involve the most common astrocytic antioxidant pathway, based on the Nrf2 transcription factor, but to result from a complex change in the expression and activity of several genes involved in the control of cellular redox state. PMID- 24160652 TI - A call to improve the health and healthcare of Latino children. PMID- 24160653 TI - 50 Years ago in The Journal of Pediatrics: The nature and origin of fluid in the fetal lamb lung. PMID- 24160654 TI - 50 Years ago in The Journal of Pediatrics: Hypoglycemia, growth retardation, and probable isolated growth hormone deficiency in a 1-year-old child. PMID- 24160655 TI - 50 years ago in The Journal of Pediatrics: Hepatic coma in childhood. PMID- 24160656 TI - 50 Years ago in The Journal of Pediatrics: cigarettes, school children, and lung cancer. PMID- 24160657 TI - 50 years ago in The Journal of Pediatrics: the Cornelia de Lange syndrome. PMID- 24160658 TI - 50 years ago in The Journal of Pediatrics: The development of children with congenital hypothyroidism. A note on early, temporary replacement therapy for 2 goitrous infants. PMID- 24160659 TI - A single application of dimeticone is superior to two applications of permethrin in ridding head lice. PMID- 24160660 TI - Adenotonsillectomy in childhood obstructive sleep apnea syndrome improves polysomnographic measures of breathing and sleep, but not attention and executive function. PMID- 24160661 TI - A lower oxygen-saturation target decreases retinopathy of prematurity but increases mortality in premature infants. PMID- 24160662 TI - Respiratory syncytial virus infection is linked to recurrent wheezing in healthy premature infants. PMID- 24160663 TI - On-demand, not scheduled, nebulization (epinephrine or saline) improves important clinical outcomes in hospitalized infants with bronchiolitis. PMID- 24160664 TI - Welcome to the fourth issue of the year. PMID- 24160666 TI - Successful treatment of hemorrhagic congenital intracranial immature teratoma with neoadjuvant chemotherapy and surgery. AB - Congenital intracranial immature teratomas carry a dismal prognosis, and the usefulness of chemotherapy for these tumors has not been elucidated. The authors report on the successful management of a case of congenital intracranial immature teratoma by using neoadjuvant chemotherapy and surgery after the failure of an initial attempt at resection. The patient was an infant who had begun vomiting frequently at the age of 12 days and had been admitted to a hospital at the age of 18 days with continued vomiting, increased head circumference, and disturbance of consciousness. A CT scan of the brain revealed a large mass in his posterior fossa and hydrocephalus. Surgery was performed on an emergent basis, but only minor tumor resection could be performed due to massive intraoperative hemorrhage. The histopathological diagnosis was immature teratoma. Postoperatively, the infant was in critical condition due to severe postoperative complications, and when he was transferred to the authors' institution 43 days after birth, his respiratory condition was still unstable because of lower cranial nerve palsy. Chemotherapy with carboplatin and etoposide resulted in moderate shrinkage of the tumor. Further chemotherapy led to improvement in the patient's general condition and weight gain, which allowed for a second attempt at resection. During this second surgery, which was performed when the child was 8 months of age, after 8 courses of chemotherapy, the tumor was completely resected with little bleeding. Histological findings from the second operation were consistent with mature teratoma. This case indicates that upfront chemotherapy may be effective for the initial management of such cases. Although the objective response to the treatment was modest, chemotherapy reduced the hemorrhagic nature of the tumor, facilitated improvement of the patient's general condition, and allowed for successful resection. PMID- 24160668 TI - Angiography-negative primary angiitis of the central nervous system in childhood. AB - Childhood primary angiitis of the CNS is a recently characterized, potentially reversible disease process. A favorable outcome requires early diagnosis and appropriate treatment. The histological findings of childhood primary angiitis of the CNS are characterized by a lymphocytic, nongranulomatous vasculitis. This disorder can lead to neurological deficits, seizures, and strokes. Laboratory and radiographic investigation are part of the evaluation, but are often nonspecific. Conventional angiography can fail to show any abnormality, and biopsy may ultimately be required for diagnosis. Although there can be significant rates of morbidity and mortality if untreated, patients who receive appropriate therapy can experience excellent outcomes, and in many cases will demonstrate near complete or total clinical and radiographic resolution. The case of a previously healthy 13-year-old girl with new-onset generalized tonic-clonic seizures is presented, with a review of the literature. PMID- 24160667 TI - Sturge-Weber syndrome with spontaneous intracerebral hemorrhage in childhood. AB - A girl aged 2 years 10 months suddenly went into a deep coma and demonstrated left hemiplegia. At birth, she had exhibited a left-sided facial port-wine stain typical of Sturge-Weber syndrome (SWS) and involving the V1 and V2 distributions of the trigeminal nerve. Computed tomography showed a right thalamic hemorrhage with acute hydrocephalus. Magnetic resonance imaging with Gd enhancement 8 months before the hemorrhage had shown a patent superior sagittal sinus (SSS) and deep venous system. Magnetic resonance imaging and MR angiography studies 2 months before the hemorrhage had revealed obstruction of the SSS and right internal cerebral vein (ICV). Given that a digital subtraction angiography study obtained after the hemorrhage did not show the SSS or right ICV, the authors assumed that impaired drainage was present in the deep venous system at that stage. The authors speculated that the patient's venous drainage pattern underwent compensatory changes because of the occluded SSS and deep venous collectors, shifting outflow through other cortical venous channels to nonoccluded dural sinuses. Sudden congestion (nearly total to total obstruction) of the ICV may have caused the thalamic hemorrhage in this case, which is the first reported instance of pediatric SWS with intracerebral hemorrhage and no other vascular lesion. Findings suggested that the appearance of major venous sinus occlusion in a child with SWS could be a warning sign of hemorrhage. PMID- 24160670 TI - An in vitro study on the risk of non-allergic type-I like hypersensitivity to Momordica charantia. AB - BACKGROUND: Momordica charantia (MC) is a tropical plant that is extensively used in folk medicine. However, the knowledge about side effects of this plant is relatively little according to knowledge about its therapeutic effects. The aim of this study is to reveal the effects of non-allergic type-I like hypersensitivity to MC by an experiment which was designed in vitro. METHODS: In the present study, the expression of CD63 and CD203c on peripheral blood basophils against different dilutions of MC extracts was measured using flow cytometry and compared with one another. In addition to this, intra-assay CV's of testing extracts were calculated for precision on reproducibility of test results. RESULTS: It was observed that the fruit extract of MC at 1/100 and 1/1000 dilutions significantly increased active basophils compared to same extract at 1/10000 dilution. CONCLUSIONS: In conclusion, Momordica charantia may elicit a non-allergic type-I like hypersensitivity reaction in especially susceptible individuals. PMID- 24160669 TI - Impact of APOE gene polymorphisms on the lipid profile in an Algerian population. AB - BACKGROUND: The importance of apolipoprotein E (APOE) in lipid and lipoprotein metabolism is well established. However, the impact of APOE polymorphisms has never been investigated in an Algerian population. This study assessed, for the fist time, the relationships between three APOE polymorphisms (epsilon, rs439401, rs4420638) and plasma lipid concentrations in a general population sample from Algeria. METHODS: The association analysis was performed in the ISOR study, a representative sample of the population living in Oran (787 subjects aged between 30 and 64). Polymorphisms were considered both individually and as haplotypes. RESULTS: In the ISOR sample, APOE epsilon4 allele carriers had higher plasma triglyceride (p=0.0002), total cholesterol (p=0.009) and LDL-cholesterol (p=0.003) levels than epsilon3 allele carriers. No significant associations were detected for the rs4420638 and rs439401 SNPs. Linkage disequilibrium and haplotype analyses confirmed the respectively deleterious and protective impacts of the epsilon4 and epsilon2 alleles on LDL-cholesterol levels and showed that the G allele of the rs4420638 polymorphism may exert a protective effect on LDL cholesterol levels in subjects bearing the APOE epsilon 4 allele. CONCLUSION: Our results showed that (i) the APOE epsilon polymorphism has the expected impact on the plasma lipid profile and (ii) the rs4420638 G allele may counterbalance the deleterious effect of the epsilon4 allele on LDL-cholesterol levels in an Algerian population. PMID- 24160671 TI - Fluorescent sensor based on BINOL for recognition of cysteine, homocysteine, and glutathione. AB - A new and simple fluorescent sensor based on unmodified BINOL was developed. The fluorescence of BINOL could be turned off with high selectivity toward Cu(II) among 27 metal ions. Meanwhile, it was found that BINOL was oxidized to dibenzo[a,kl]xanthen-1-ol (A) by Cu(NO3)2. A new peak appeared at ~482 nm upon addition of thiol-containing cysteine (Cys), homocysteine (Hcy), and glutathione (GSH). Thus, a cascade recognition of Cu(II) and Cys, Hcy, and GSH are well presented. PMID- 24160672 TI - The demise of the Liverpool Care Pathway? A cautionary tale for palliative care. PMID- 24160673 TI - Quantifying under-reporting of pathology tests in Medical Benefits Schedule claims data. AB - OBJECTIVE: We investigated the completeness of recording of pathology tests in Australian Medical Benefits Schedule (MBS) claims data, using the example of the prostate-specific antigen (PSA) test. With some exceptions, MBS claims data records only the three most expensive pathology items in an episode of care, and this practice ('episode coning') means that pathology tests can be under recorded. METHODS: The analysis used MBS data for male participants in the 45 and Up Study. The number and cost of items in each episode of care were used to determine whether an episode contained a PSA screening test (Item 66655), or could have lacked a record of this item because of episode coning. RESULTS: MBS data for 1070392 episodes involving a request for a pathology test for 118074 men were analysed. Of these episodes, 11% contained a request for a PSA test; a further 7.5% may have been missing a PSA request that was not recorded because of episode coning. CONCLUSIONS: It is important to consider under-reporting of pathology tests as a result of episode coning when interpreting MBS claims data. Episode coning creates uncertainty about whether a person has received any given pathology test. The extent of this uncertainty can be estimated by determining the proportion of episodes in which the test may have been performed but was not recorded due to episode coning. PMID- 24160674 TI - A feasibility study of short message service text messaging as a surveillance tool for alcohol consumption and vehicle for interventions in university students. AB - BACKGROUND: Practitioners who come into contact with the intoxicated, such as those in unscheduled care, often have limited resources to provide structured interventions. There is therefore a need for cost-effective alcohol interventions requiring minimal input. This study assesses the barriers, acceptability and validity of text messaging to collect daily alcohol consumption data and explores the feasibility of a text-delivered intervention in an exploratory randomised controlled trial. METHODS: Study I. Participants (n = 82) completed the initial online screening survey and those eligible were asked each day, for 157 days via text message, to reply with the number of alcohol units consumed the previous day. Analyses compared standard measures of hazardous consumption with self report alcohol use. Attrition and sampling biases were examined. Study I included secondary exploratory analyses using data from 70 participants to determine associations between events (including Christmas and other celebratory occasions) and consumption. Study I further included the thematic analysis of semi structured interview data and assessed the feasibility of and barriers to surveillance and interventions delivered through text messaging. Developing findings from Study I, Study II developed an exploratory randomised control trial that delivered a single message on monthly alcohol expenditure in order to assess effect size and test generalisability. RESULTS: Self-report alcohol consumption data was significantly associated with FAST and AUDIT scores. Attrition from the study was not associated with greater alcohol use. Greater alcohol use was observed on Fridays, Saturdays and Wednesdays as were notable celebratory events. Interview data indicated that text messaging was acceptable to participants and preferred over email and web-based methods. The exploratory randomised controlled trial suggested that a simple text delivered intervention might be effective in eliciting a reduction in alcohol consumption in a future trial. CONCLUSIONS: The ubiquity of mobile telephones and the acceptability of text messaging suggests that this approach can be developed as a surveillance tool to collect high frequency consumption data to identify periods of vulnerability and that it can offer a platform through which targeted interventions can be delivered. PMID- 24160675 TI - Regenerative medicine approach to reconstruction of the equine upper airway. AB - Airway obstruction is a common cause of poor performance in horses. Structural abnormalities (insufficient length, rigidity) can be a cause for the obstruction. Currently, there are a few effective clinical options for reconstruction of the equine larynx. A regenerative medicine approach to reconstruction may provide the capability to stabilize laryngeal structures and to encourage restoration of site appropriate, functional, and host-derived tissue. The purpose of this study was the histopathological evaluation of (1) decellularization of equine (horse) laryngeal cartilages (epiglottis and arytenoids); (2) the host response to decellularized laryngeal cartilages implanted subcutaneously in a donkey model as a test of biocompatibility; and (3) the use of decellularized laryngeal cartilages in a clinically relevant pilot study in the horse larynx. Equine laryngeal cartilages were found to be sufficiently decellularized and were subsequently implanted subcutaneously in donkeys to test biocompatibility. After 4 weeks, the implanted cartilage was harvested. In the subcutaneous model, the samples did not elicit a rejection or foreign body type reaction and were judged suitable for implantation in a clinically relevant equine model. Implants were placed in the upper airway (arytenoids and epiglottis) of one horse. At 4 weeks, the implants were observed to remodel rapidly and were replaced by dense connective tissue with signs of new hyaline cartilage formation in the arytenoids and by connective tissue containing glandular structures and an epithelial covering in the epiglottis. The results of the present study demonstrate the feasibility of a scaffold-based regenerative medicine approach to reconstruction of the equine upper airway; however, further studies investigating long-term integration, formation of new cartilage, and mechanical properties are needed. PMID- 24160677 TI - Factors associated with family-centered involvement in family practice--a cross sectional multivariate analysis. AB - The importance of a family-centered approach in family practice has been emphasized. Knowledge about factors associated with higher family-centered involvement seems beneficial to stimulate its realization. German office-based family physicians completed a questionnaire addressing several aspects of family centered care. Logistic regression was used to identify associations with the involvement overall and in different domains: routine inquiry and documentation of family-related information, family orientation regarding diagnosis and treatment, family-oriented dialogues, family conferences, and case-related collaboration with marriage and family therapists. We found significant associations between physicians' family-centered involvement and expected patient receptiveness, perceived impact of the family's influence on health, self perceived psychosocial family-care competences (overall and concerning concepts for family orientation, psychosocial intervention in family conferences, and the communication of the idea of family counseling), advanced training in psychosocial primary care (PPC), personal acquaintance with family therapists (regarding case-related collaboration), and rural office environment. Increased emphasis on the family's influence on health in medical education and training, the provision of concepts for a family-centered perspective, and versatile skills for psychosocial intervention and inquiry of patient preferences, as well as the strengthening of networking between family physicians and family therapists, might promote the family-centered approach in family practice. PMID- 24160676 TI - Enantioselective degradation and enantiomerization of indoxacarb in soil. AB - In this study, the enantioselective degradation and enantiomerizaton of indoxacarb were investigated in two soils under nonsterilized and sterilized conditions using a chiral OD-RH column on a reversed-phase HPLC. Under nonsterilized conditions, the degradation of indoxacarb in two soils was enantioselective. In acidic soil, the half-lives of R-(-)- and S-(+)-indoxacarb were 10.43 and 14.00 days, respectively. Acidic soil was preferential to the degradation of R-(-)-indoxacarb. In alkaline soil, the half-lives of R-(-)- and S (+)-indoxacarb were 12.14 and 4.88 days, respectively. S-(+)-Indoxacarb was preferentially degraded. Under sterilized conditions, approximately 5-10% of the initial concentration degraded after 75 days of incubation in acidic soil, whereas in alkaline soil, approximately half of the initial concentration degraded due to chemical hydrolysis under alkaline conditions. Enantiomerization was also discovered in acidic and alkaline soils. The results showed that mutual transformation existed between two enantiomers and that S-(+)-indoxacarb had a significantly higher inversion rate to R-(-)-indoxacarb than its antipode. PMID- 24160678 TI - Mercury-cadmium-telluride waveguides--a novel strategy for on-chip mid-infrared sensors. AB - We report the first planar waveguides made from mercury-cadmium-telluride (MCT)-a material to date exclusively used for mid-infrared (MIR) detector elements serving as on-chip MIR evanescent field transducers in combination with tunable quantum cascade lasers (tQCLs) emitting in the spectral regime of 5.78-6.35 MUm. This novel MIR sensing approach utilizes structured MCT chips fabricated via molecular beam epitaxy (MBE) as waveguide enabling sensing via evanescent field absorption spectroscopy, as demonstrated by the detection of 1 nL of acetone. Complementary finite difference time domain (FDTD) simulations fit well with the experimentally obtained data and predict an improvement of the limit of detection by at least 2 orders of magnitude upon implementation of thinner MCT waveguides. With the first demonstration of chemical sensing using on-chip MCT waveguides, monolithically fabricated IR sensing systems directly interfacing the waveguide with the MCT detector element may be envisaged. PMID- 24160680 TI - Sleep apnea headache and headaches with sleep apnea: the importance of being secondary. PMID- 24160679 TI - Google Scholar as replacement for systematic literature searches: good relative recall and precision are not enough. AB - BACKGROUND: Recent research indicates a high recall in Google Scholar searches for systematic reviews. These reports raised high expectations of Google Scholar as a unified and easy to use search interface. However, studies on the coverage of Google Scholar rarely used the search interface in a realistic approach but instead merely checked for the existence of gold standard references. In addition, the severe limitations of the Google Search interface must be taken into consideration when comparing with professional literature retrieval tools.The objectives of this work are to measure the relative recall and precision of searches with Google Scholar under conditions which are derived from structured search procedures conventional in scientific literature retrieval; and to provide an overview of current advantages and disadvantages of the Google Scholar search interface in scientific literature retrieval. METHODS: General and MEDLINE-specific search strategies were retrieved from 14 Cochrane systematic reviews. Cochrane systematic review search strategies were translated to Google Scholar search expression as good as possible under consideration of the original search semantics. The references of the included studies from the Cochrane reviews were checked for their inclusion in the result sets of the Google Scholar searches. Relative recall and precision were calculated. RESULTS: We investigated Cochrane reviews with a number of included references between 11 and 70 with a total of 396 references. The Google Scholar searches resulted in sets between 4,320 and 67,800 and a total of 291,190 hits. The relative recall of the Google Scholar searches had a minimum of 76.2% and a maximum of 100% (7 searches). The precision of the Google Scholar searches had a minimum of 0.05% and a maximum of 0.92%. The overall relative recall for all searches was 92.9%, the overall precision was 0.13%. CONCLUSION: The reported relative recall must be interpreted with care. It is a quality indicator of Google Scholar confined to an experimental setting which is unavailable in systematic retrieval due to the severe limitations of the Google Scholar search interface. Currently, Google Scholar does not provide necessary elements for systematic scientific literature retrieval such as tools for incremental query optimization, export of a large number of references, a visual search builder or a history function. Google Scholar is not ready as a professional searching tool for tasks where structured retrieval methodology is necessary. PMID- 24160681 TI - Subcutaneous infusions of apomorphine: a reappraisal of its therapeutic efficacy in advanced Parkinson's disease. AB - Subcutaneous infusion of apomorphine is a useful treatment for motor and nonmotor complications in Parkinson's disease patients and improves the patient's quality of life. An adequate selection of suitable candidates is crucial for obtaining the best results with this therapy. Parkinsonian patients with severe biphasic dyskinesias, demented or having experienced serious neuropsychiatric side effects with other dopamine agonists should not be offered this treatment. The therapeutic effect of continuous apomorphine infusion is reviewed and practical recommendations on its use are provided. PMID- 24160682 TI - Unraveling the mechanisms underlying postural instability in Parkinson's disease using dynamic posturography. AB - Postural instability, one of the cardinal symptoms of Parkinson's disease (PD), has devastating consequences for affected patients. Better strategies to prevent falls are needed, but this calls for an improved understanding of the complex mechanisms underlying postural instability. We must also improve our ability to timely identify patients at risk of falling. Dynamic posturography is a promising avenue to achieve these goals. The latest moveable platforms can deliver 'real life' balance perturbations, permitting study of everyday fall circumstances. Dynamic posturography studies have shown that PD patients have fundamental problems in scaling their postural responses in accordance with the need of the actual balance task at hand. On-going studies evaluate the predictive ability of impaired posturography performance for daily life falls. We also review recent work aimed at exploring balance correcting steps in PD, and the presumed interaction between startle pathways and postural responses. PMID- 24160686 TI - Synthesis and coordinative layer-by-layer deposition of pyridine-functionalized gold nanoparticles and tetralactam macrocycles on silicon substrates. AB - Coordination chemistry was applied to deposit pyridine-functionalized gold nanoparticles on silicon substrates. The particles were synthesized through the Brust/Schiffrin route with a subsequent ligand exchange reaction yielding well defined particles of two different sizes. Multilayer deposition was carried out on a pyridine-terminated SAM, anchored on a hydroxyl-terminated silicon surface. Analogously, Hunter/Vogtle-type tetralactam macrocycle multilayers were deposited as well as mixed layers containing both either in an alternating sequence or as a macrocycle multilayer with a terminating nanoparticle layer. These composite layers were examined with respect to their ability to bind squaraine axles in the macrocycle cavities. The amount of guest bound is higher for the composite layer with alternating macrocycles and nanoparticles. PMID- 24160683 TI - Immunogenicity and tumorigenicity of pluripotent stem cells and their derivatives: genetic and epigenetic perspectives. AB - One aim of stem cell-based therapy is to utilize pluripotent stem cells (PSCs) as a supplementary source of cells to repair or replace tissues or organs that have ceased to function due to severe tissue damage. However, PSC-based therapy requires extensive research to ascertain if PSC derivatives are functional without the risk of tumorigenicity, and also do not engender severe immune rejection that threatens graft survival and function. Recently, the suitability of induced pluripotent stem cells applied for patient-tailored cell therapy has been questioned since the discovery of several genetic and epigenetic aberrations during the reprogramming process. Hence, it is crucial to understand the effect of these abnormalities on the immunogenicity and survival of PSC grafts. As induced PSC-based therapy represents a hallmark for the potential solution to prevent and arrest immune rejection, this review also summarizes several up-to date key findings in the field. PMID- 24160687 TI - Recruitment and retention of rural nursing students: a retrospective study. AB - INTRODUCTION: The shortage of registered nurses is an issue globally, but particularly in rural and remote areas. Previous research in medicine suggests that recruiting students from rural backgrounds is an effective strategy to enhance the supply of rural healthcare providers. This strategy has not been widely adopted or evaluated in nursing. The purpose of this study was to compare rural and urban nursing students in relation to application, admission, and retention/graduation trends at a metropolitan state university in the Pacific Northwest area of the USA. METHODS: A retrospective longitudinal descriptive design was used, analyzing existing data from 2005 to 2010. The sample included 1283 applicants, accepted students, and graduates. Rural-urban classification was made using rural urban commuting area (RUCA) codes based on high school zip codes, identifying 356 (28%) rural and 927 (72%) urban individuals. The data were analyzed quantitatively, assessing demographic characteristics along with application, admission and retention/graduation rates. RESULTS: The analysis indicated no significant differences between the rural and urban samples in relation to age, gender, parents' level of education, income, or retention rates. The acceptance rate for rural students (66.3%) was significantly lower than for urban students (73.1%) (p=0.015). When rural subgroups (isolated, small rural and large rural) were examined, the isolated group (n=61) had the highest acceptance rate of any rural or urban group (75%). This group was the least ethnically diverse (95% Caucasian), was the least likely to be first-generation college (22%), had the highest percentage of females (85%) and had the highest entering grade point average (3.65 on a four-point scale). In contrast, the subgroup including individuals from large rural communities (n=182) had the lowest acceptance rate (64%), the lowest retention rate 85%, the lowest entering grade point average (3.42), and the highest percentage of first-generation college individuals (50.9%). CONCLUSIONS: The findings suggest that students from rural backgrounds achieve similar levels of success in nursing education, despite lower acceptance rates, when compared with urban students. Addressing issues related to lower acceptance rates for rural nursing students, including targeted recruitment and support efforts with students interested in pursuing nursing at the junior and senior high school levels, may be indicated. Further research is indicated to explore differences among rural subgroups in relation to preparation for and achievement in nursing education. Greater research attention is also needed to assess if nursing students from rural backgrounds tend to practice in rural areas more than students from urban backgrounds, similar to previous research in medicine. Because students tend to practice near their place of education, nursing education programs may need to consider locating outside of large urban areas to promote rural practice. Inclusion of rural content and clinical experiences within nursing curricula is also recommended. PMID- 24160688 TI - Copper shell networks in polymer composites for efficient thermal conduction. AB - Thermal management of polymeric composites is a crucial issue to determine the performance and reliability of the devices. Here, we report a straightforward route to prepare polymeric composites with Cu thin film networks. Taking advantage of the fluidity of polymer melt and the ductile properties of Cu films, the polymeric composites were created by the Cu metallization of PS bead and the hot press molding of Cu-plated PS beads. The unique three-dimensional Cu shell networks in the PS matrix demonstrated isotropic and ideal conductive performance at even extremely low Cu contents. In contrast to the conventional simple melt mixed Cu beads/PS composites at the same concentration of 23.0 vol %, the PS composites with Cu shell networks indeed revealed 60 times larger thermal conductivity and 8 orders of magnitude larger electrical conductivity. Our strategy offers a straightforward and high-throughput route for the isotropic thermal and electrical conductive composites. PMID- 24160689 TI - Accurate determination of the deformation of the benzene ring upon substitution: equilibrium structures of benzonitrile and phenylacetylene. AB - Accurate equilibrium, re, structures of the monosubstituted benzene molecules benzonitrile, C6H5CN, and phenylacetylene, C6H5CCH, have been determined using two different, to some extent complementary techniques. The semiexperimental, r(e)(SE), structural parameters are the result of a least-squares fit to equilibrium rotational constants derived from experimental effective ground-state rotational constants and rovibrational corrections based principally on an ab initio cubic force field. The composite ab initio Born-Oppenheimer, r(e)(BO), structural parameters are obtained from frozen-core and all-electron MP2 and the CCSD(T) geometry optimizations using Gaussian basis sets up to quintuple-zeta quality. The DFT(B3LYP) method, with two different Gaussian basis sets, 6-31G* and 6-311+G(3df,2pd), was used to calculate the cubic force field employed during the r(e)(SE) structure determination. With the 6-31G* basis set, the error of the rovibrational correction is to a large extent random, whereas with the 6 311+G(3df,2pd) basis set it is mainly systematic. As shown here, systematic errors do not have a significant effect on the accuracy of the derived structure; the quality of the structural fit, however, is sensitive to the true accuracy of the ground-state rotational constants. An even more important general conclusion of this study is that the addition of extra rotational constants from multisubstituted species does not seem to improve the accuracy of the r(e)(SE) structures, quite in contrast to the highly desirable availability of data corresponding to all singly substituted species. PMID- 24160690 TI - Is Opisthorchis viverrini an avian liver fluke? AB - Recently, in the Journal of Helminthology (May 2013), Dao et al. reported that Opisthorchis viverrini-like flukes were found in the bile duct of domestic ducks in Vietnam. They stated that this is the first record of Opisthorchis sp. in birds in Vietnam. However, three Opisthorchis species--O. cheelis, O. longissimus and O. parageminus--in birds in Vietnam were described by Le in 2000. Amongst these, O. parageminus was first reported, by Oshmarin in 1970, as a new Opisthorchis species found in domestic ducks (Anas platyrhynchos) in Vietnam. Morphologially O. viverrini-like flukes described by Dao et al. are much more similar to O. parageminus than to O. viverrini. The phylogenetic trees of internal transcribed spacer 2 (ITS2) and cytochrome oxidase 1 (CO1) gene sequences also showed that the O. viverrini-like liver flukes from domestic ducks were closer to O. lobatus than to O. viverrini. Therefore, O. viverrini-like liver flukes reported by Dao et al. (2013) are most likely to be O. parageminus. PMID- 24160691 TI - Differences in the mean amplitude of glycemic excursions calculated by two automated methods. PMID- 24160692 TI - Knowledge of safe motherhood among women in rural communities in northern Nigeria: implications for maternal mortality reduction. AB - BACKGROUND: Most developed countries have made considerable progress in addressing maternal mortality, but it appears that countries with high maternal mortality burdens like Nigeria have made little progress in improving maternal health outcomes despite emphasis by the Millennium Development Goals (MDGs). Knowledge about safe motherhood practices could help reduce pregnancy related health risks. This study examines knowledge of safe motherhood among women in selected rural communities in northern Nigeria. METHODS: This was a cross sectional study carried out in two states (Kaduna and Kano States) within northern Nigeria. Pretested, interviewer-administered questionnaires were applied by female data collectors to 540 randomly selected women who had recently delivered within the study site. Chi-square tests were used to determine possible association between variables during bivariate analysis. Variables significant in the bivariate analysis were subsequently entered into a multivariate logistic regression analysis. The degree of association was estimated by odds ratio (OR) and 95% confidence interval (CI) between knowledge of maternal danger signs and independent socio-demographic as well as obstetric history variables which indicated significance at p < 0.05. RESULTS: Over 90% of respondents in both states showed poor knowledge of the benefits of health facility delivery by a skilled birth attendant. More than 80% of respondents in both states displayed poor knowledge of the benefits of ANC visits. More than half of the respondents across both states had poor knowledge of maternal danger signs. According to multivariate regression analysis, ever attending school by a respondent increased the likelihood of knowing maternal danger signs by threefold (OR 2.63, 95% CI: 1.2-5.8) among respondents in Kaduna State. While attendance at ANC visits during most recent pregnancy increased the likelihood of knowing maternal danger signs by twofold among respondents in Kano State (OR 2.05, 95% CI: 1.1-3.9) and threefold among respondents in Kaduna State (OR 3.33, 95% CI: 1.6-7.2). CONCLUSION: This study found generally poor knowledge about safe motherhood practices among female respondents within selected rural communities in northern Nigeria. Knowledge of safe pregnancy practices among some women in rural communities is strongly associated with attendance at ANC visits, being employed or acquiring some level of education. Increasing knowledge about safe motherhood practices should translate into safer pregnancy outcomes and subsequently lead to lower maternal mortality across the developing world. PMID- 24160693 TI - Systems approach to neurodegenerative disease biomarker discovery. AB - Biomarkers are essential for performing early diagnosis, monitoring neurodegenerative disease progression, gauging responses to therapies, and stratifying neurodegenerative diseases into their different subtypes. A wide range of molecular markers are under investigation in tissues and biofluids as well as through imaging; moreover, many are prominent proteins present in cerebrospinal fluid. However, in more frequently and easily collected fluids such as plasma, these proteins show only a modest correlation with disease and thus lack the necessary sensitivity or specificity for clinical use. High-throughput and quantitative proteomic technologies and systems-driven approaches to biofluid analysis are now being utilized in the search for better biomarkers. Biomarker discovery involves many critical steps including study design, sample preparation, protein and peptide separation and identification, and bioinformatics and data integration issues that must be carefully controlled before independent confirmation and validation. In this review, we summarize current proteomic and nucleic acid technologies involved in the discovery of biomarkers of neurodegenerative diseases, particularly Alzheimer's, Parkinson's, Huntington's, and prion diseases. PMID- 24160696 TI - Role of hepatic efflux transporters in regulating systemic and hepatocyte exposure to xenobiotics. AB - Hepatic efflux transporters include numerous well-known and emerging proteins localized to the canalicular or basolateral membrane of the hepatocyte that are responsible for the excretion of drugs into the bile or blood, respectively. Altered function of hepatic efflux transporters due to drug-drug interactions, genetic variation, and/or disease states may lead to changes in xenobiotic exposure in the hepatocyte and/or systemic circulation. This review focuses on transport proteins involved in the hepatocellular efflux of drugs and metabolites, discusses mechanisms of altered transporter function as well as the interplay between multiple transport pathways, and highlights the importance of considering intracellular unbound concentrations of transporter substrates and/or inhibitors. Methods to evaluate hepatic efflux transport and predict the effects of impaired transporter function on systemic and hepatocyte exposure are discussed, and the sandwich-cultured hepatocyte model to evaluate comprehensively the role of hepatic efflux in the hepatobiliary disposition of xenobiotics is characterized. PMID- 24160695 TI - Pharmaceutical and toxicological properties of engineered nanomaterials for drug delivery. AB - Novel engineered nanomaterials (ENMs) are being developed to enhance therapy. The physicochemical properties of ENMs can be manipulated to control/direct biodistribution and target delivery, but these alterations also have implications for toxicity. It is well known that size plays a significant role in determining ENM effects since simply nanosizing a safe bulk material can render it toxic. However, charge, shape, rigidity, and surface modifications also have a significant influence on the biodistribution and toxicity of nanoscale drug delivery systems (NDDSs). In this review, NDDSs are considered in terms of platform technologies, materials, and physical properties that impart their pharmaceutical and toxicological effects. Moving forward, the development of safe and effective nanomedicines requires standardized protocols for determining the physical characteristics of ENMs as well as assessing their potential long-term toxicity. When such protocols are established, the remarkable promise of nanomedicine to improve the diagnosis and treatment of human disease can be fulfilled. PMID- 24160694 TI - GABAA receptor subtypes: Therapeutic potential in Down syndrome, affective disorders, schizophrenia, and autism. AB - The gamma-aminobutyric acid (GABA) system plays a pivotal role in orchestrating the synchronicity of local networks and the functional coupling of different brain regions. Here we review the impact of the GABAA receptor subtypes on cognitive and emotional behavior, paying particular attention to five disease states: cognitive dysfunction and Down syndrome, anxiety disorders, depression, schizophrenia, and autism. Through the bidirectional modulation of tonic inhibition, alpha5-subunit-containing GABAA receptors permit the bidirectional modulation of cognitive processes, and a partial inverse agonist acting at the alpha5-subunit-containing GABAA receptor is in a clinical trial in individuals with Down syndrome. With regard to anxiety disorders, the viability of nonsedative anxiolytics based on the modulation of alpha2- and alpha3-subunit containing GABAA receptors has been established in clinical proof-of-concept trials. Regarding the remaining three disease states, the GABA hypothesis of depression offers new options for antidepressant drug development; cognitive symptoms in schizophrenia are attributed to a cortical GABAergic deficit, and dysfunctional GABAergic inhibition is increasingly understood to contribute to the pathophysiology of autism spectrum disorders. PMID- 24160698 TI - Targeting protein-protein interaction by small molecules. AB - Protein-protein interactions (PPIs) are critical regulatory events in physiology and pathology, and they represent an important target space for pharmacological intervention. However, targeting PPIs with small molecules is challenging owing to the large surface area involved in protein-protein binding and the lack of obvious small-molecule-binding pockets at many protein-protein interfaces. Nonetheless, successful examples of small-molecule modulators of PPIs have been growing in recent years. This article reviews some of the recent advances in the discovery of small-molecule regulators of PPIs that involve key oncogenic proteins. Our discussion focuses on the three key modes of action for these small molecule modulators: orthosteric inhibition, allosteric regulation, and interfacial binding/stabilization. Understanding the opportunities and challenges of these diverse mechanisms will help guide future efforts in developing small molecule modulators against PPIs. PMID- 24160697 TI - Understanding and modulating mammalian-microbial communication for improved human health. AB - The fact that the bacteria in the human gastrointestinal (GI) tract play a symbiotic role was noted as early as 1885, well before we began to manage microbial infections using antibiotics. However, even with the first antimicrobial compounds used in humans, the sulfa drugs, microbes were recognized to be critically involved in the biotransformation of these therapeutics. Thus, the roles played by the microbiota in physiology and in the management of human health have long been appreciated. Detailed examinations of GI symbiotic bacteria that started in the early 2000s and the first phases of the Human Microbiome Project that were completed in 2012 have ushered in an exciting period of granularity with respect to the ecology, genetics, and chemistry of the mammalian microbial axes of communication. Here we review aspects of the biochemical pathways at play between commensal GI bacteria and several mammalian systems, including both local-epithelia and nonlocal responses impacting inflammation, immunology, metabolism, and neurobiology. Finally, we discuss how the microbial biotransformation of therapeutic compounds, such as anticancer or nonsteroidal anti-inflammatory drugs, can be modulated to reduce toxicity and potentially improve therapeutic efficacy. PMID- 24160702 TI - Free fatty acid (FFA) and hydroxy carboxylic acid (HCA) receptors. AB - Saturated and unsaturated free fatty acids (FFAs), as well as hydroxy carboxylic acids (HCAs) such as lactate and ketone bodies, are carriers of metabolic energy, precursors of biological mediators, and components of biological structures. However, they are also able to exert cellular effects through G protein-coupled receptors named FFA1-FFA4 and HCA1-HCA3. Work during the past decade has shown that these receptors are widely expressed in the human body and regulate the metabolic, endocrine, immune and other systems to maintain homeostasis under changing dietary conditions. The development of genetic mouse models and the generation of synthetic ligands of individual FFA and HCA receptors have been instrumental in identifying cellular and biological functions of these receptors. These studies have produced strong evidence that several FFA and HCA receptors can be targets for the prevention and treatment of various diseases, including type 2 diabetes mellitus, obesity, and inflammation. PMID- 24160701 TI - Fetal and perinatal exposure to drugs and chemicals: novel biomarkers of risk. AB - Pregnant women are almost always excluded from randomized controlled clinical trials, as the risks to the fetus posed by most new chemical entities or approved drugs cannot be sufficiently ruled out. Hence, a major scientific challenge in this field is to discover and validate alternative tools that will fill the knowledge gap created by the lack of participation in gold-standard randomized trials. This review focuses on novel tools that allow estimation of fetal risks after exposure to therapeutic agents, such as placental perfusion studies, biomarkers of fetal exposure, and novel epidemiological and pharmacogenetic tools, all of which have been tested successfully in recent years. PMID- 24160703 TI - Targeting PCSK9 for hypercholesterolemia. AB - Dyslipidemias are a predominant risk factor for cardiovascular disease. Biological and genetic research has led to the identification of several genes and proteins that may be pharmacologically targeted to improve lipoprotein profiles and possibly cardiovascular outcomes in patients with dyslipidemia. The observation that proprotein convertase subtilisin/kexin type 9 (PCSK9) regulates the levels of circulating low-density lipoprotein C (LDL-C) by enhancing the degradation of the hepatic low-density lipoprotein receptor (LDLR) prompted the search for drugs that inhibit PCSK9 activity. Several approaches to inhibiting PCSK9 activity have been proposed; these involve inhibitory antibodies, small molecules, and gene silencing. To date, the most promising and advanced approach relates to monoclonal antibodies, which can decrease LDL cholesterol by 65-70%, even as an add-on therapy to a maximal dose of a statin. Phase III studies and large, event-driven clinical trials are ongoing and will fully address the viability and role of these drugs in clinical practice. PMID- 24160699 TI - Small-molecule allosteric activators of sirtuins. AB - The mammalian sirtuins (SIRT1-7) are NAD(+)-dependent lysine deacylases that play central roles in cell survival, inflammation, energy metabolism, and aging. Members of this family of enzymes are considered promising pharmaceutical targets for the treatment of age-related diseases including cancer, type 2 diabetes, inflammatory disorders, and Alzheimer's disease. SIRT1-activating compounds (STACs), which have been identified from a variety of chemical classes, provide health benefits in animal disease models. Recent data point to a common mechanism of allosteric activation by natural and synthetic STACs that involves the binding of STACs to a conserved N-terminal domain in SIRT1. Compared with polyphenols such as resveratrol, the synthetic STACs show greater potency, solubility, and target selectivity. Although considerable progress has been made regarding SIRT1 allosteric activation, key questions remain, including how the molecular contacts facilitate SIRT1 activation, whether other sirtuin family members will be amenable to activation, and whether STACs will ultimately prove safe and efficacious in humans. PMID- 24160704 TI - Learning to program the liver. AB - Half a century ago, people were learning to program computers. Similarly, we have been trying to learn how to program the liver to protect us from chemicals. We have given various chemicals that activate transcription factors such as the nuclear receptors: These ligand-activated nuclear receptors enter the nucleus of liver cells (hepatocytes) and bind to their specific motifs in DNA to increase the transcription of various genes that protect against chemical-induced injury. Several examples from our laboratory are given to demonstrate this detoxification process: (a) a steroid chemical that increases the expression of a hepatic transporter to enhance the elimination of other chemicals and thus decrease their toxicity, (b) a metal that decreases its own toxicity by increasing the production of a protein to which it binds, and (c) an herbal chemical that activates a transcription factor that serves as a sensor of oxidative stress and electrophiles to protect against cytotoxicity by increasing the expression of numerous antioxidant proteins. In addition, at the present time, we are investigating which bile acids that are synthesized in the liver and altered by bacteria in the intestine may be used to alter the programming of the liver, as well as how the liver reprograms itself after birth in the transition from a hematopoietic organ to one that decreases the toxicity of chemicals. PMID- 24160705 TI - G protein-coupled receptors revisited: therapeutic applications inspired by synthetic biology. AB - G protein-coupled receptors (GPCRs) mediate the majority of cellular responses to hormones and neurotransmitters within the human body. They have much potential in the emerging field of synthetic biology, which is the rational, systematic design of biological systems with desired functionality. The responsiveness of GPCRs to a plethora of endogenous and exogenous ligands and stimuli make them ideal sensory receptor modules of synthetic gene networks. Such networks can activate target gene expression in response to a specific stimulus. Additionally, because GPCRs are important pharmacological targets of various human diseases, genes encoding their protein/peptide ligands can also be incorporated as target genes of the response output elements of synthetic gene networks. This review aims to critically examine the potential role of GPCRs in constructing therapeutic synthetic gene networks and to discuss various challenges in utilizing GPCRs for synthetic biology applications. PMID- 24160706 TI - Cause and consequence of cancer/testis antigen activation in cancer. AB - Tumor cells frequently exhibit widespread epigenetic aberrations that significantly alter the repertoire of expressed proteins. In particular, it has been known for nearly 25 years that tumors frequently reactivate genes whose expression is typically restricted to germ cells. These gene products are classified as cancer/testis antigens (CTAs) owing to their biased expression pattern and their immunogenicity in cancer patients. While these genes have been pursued as targets for anticancer vaccines, whether these reactivated testis proteins have roles in supporting tumorigenic features is less studied. Recent evidence now indicates that these proteins can be directly employed by the tumor cell regulatory environment to support cell-autonomous behaviors. Here, we review the history of the CTA field and present recent findings indicating that CTAs can play functional roles in supporting tumorigenesis. PMID- 24160700 TI - Chronopharmacology: new insights and therapeutic implications. AB - Most facets of mammalian physiology and behavior vary according to time of day, thanks to endogenous circadian clocks. Therefore, it is not surprising that many aspects of pharmacology and toxicology also oscillate according to the same 24-h clocks. Daily oscillations in abundance of proteins necessary for either drug absorption or metabolism result in circadian pharmacokinetics, and oscillations in the physiological systems targeted by these drugs result in circadian pharmacodynamics. These clocks are present in most cells of the body, organized in a hierarchical fashion. Interestingly, some aspects of physiology and behavior are controlled directly via a "master clock" in the suprachiasmatic nuclei of the hypothalamus, whereas others are controlled by "slave" oscillators in separate brain regions or body tissues. Recent research shows that these clocks can respond to different cues and thereby show different phase relationships. Therefore, full prediction of chronopharmacology in pathological contexts will likely require a systems biology approach that considers chronointeractions among different clock-regulated systems. PMID- 24160707 TI - Recent progress in the development of histone deacetylase inhibitors as anti cancer agents. AB - Histone deacetylases (HDACs) regulate the expression and activity of many proteins in both cancer initiation and cancer progression. HDACs are now recognized as promising targets for anticancer agent development. HDAC inhibitors (HDACIs) are emerging as promising anticancer drugs which possess tumor-selective cytotoxicity. HDACIs could promote growth arrest, differentiation, and apoptosis of cancer cells, with minimal effects on normal tissue. Research of HDACIs is now becoming an interesting field. HDACIs comprise structurally diverse anticancer agents and have been widely used in the clinic. This review describes recent progress in the development of HDACIs, especially focusing on the design strategies, novel chemical structures, biological properties and structure activity relationships (SARs) of HDACIs. We hope it will be helpful for medicinal chemists who are interested in the discovery of anticancer agents. PMID- 24160708 TI - Developments of polo-like kinase 1 (Plk1) inhibitors as anti-cancer agents. AB - Polo-like kinases (Plks) are a family of serine/threonine kinases with a highly conserved N-terminal Ser/Thr kinase catalytic domain and a C-terminal region that play crucial roles in cell cycle progression. Plk1, playing a key role in multiple steps of mitotic progression, is the most studied member of the family. It is overexpressed in a wide spectrum of cancer types and is a promising target in oncology. Most of Plk1 inhibitors competitively bind to the ATP-binding site, which is characterized with unique features. Other inhibitors target regions outside the ATP pocket. In this review some pre-clinical or clinical Plk1 inhibitors are reported, focusing on SAR studies and biological activities, including the kinase activity, in vitro and in vivo anti-tumor efficacy. Those studies exhibited the inhibitors' significant therapeutic effects. Moreover, combination therapies of these Plk1 inhibitors with other anticancer drugs resulted with synergistic effects. PMID- 24160709 TI - Chalcone and curcumin derivatives: a way ahead for malarial treatment. AB - Malaria has been a major cause of morbidity and mortality in developing countries, particularly in Sub-Saharan Africa and South Asia. The global malaria situation is increasingly being challenging owing to lack of credible malaria vaccine and the emergence of drug resistance to most of the available antimalarials. They demand search for novel generation of drugs. Versatility and flexibility for structural modification of natural and synthetic analogues of curcumin and chalcone have been explored extensively for designing new antimalarial agent. Recent advances to our knowledge of parasite biology as well as the availability of the genome sequence, have opened up new vista in the firmament of antimalarial drug designing for identifying novel molecular targets. Curcumin and chalcones has been reported to exert anti-malarial effect by binding directly to numerous signaling molecules, such as histone acetyltransferase, histone deacetylase, sarco (endo) plasmic reticulum Ca(2+)-ATPase, cysteine proteases etc. This review highlights insights the more recent antimalarial activities of these compounds, their mechanisms of action, molecular targets and relevant structureactivity relationship studies. Natural lead compounds like chalcone and curcumin have shown good and optimal binding to many enzymes present in parasite and can be explored as molecular targets for in silico studies to develop new, affordable and effective antimalarial drugs. With no credible malaria vaccine in sight, there is an imperative need to develop new drugs with different mechanisms of action to help preclude issues of cross-resistance. PMID- 24160710 TI - Haloperidol cytotoxicity and its relation to oxidative stress. AB - Haloperidol (HP) is used for the symptomatic treatment of psychosis, manic phases, hyperactivity, aggressiveness, and acute delirium. Long-term use leads to various adverse side effects, especially to severe impairment of extrapyramidal nerve tracts and in particular, altered QT interval and increased incidence of arrhytmias. It is believed that cytotoxicity of HP and its metabolites is responsible for both neurotoxicity and cardiotoxicity. Extrapyramidal and cardiac adverse side effects may be explained by the HP-induced oxidative stress, as implicated by many studies. HP was reported to induce lipid peroxidation with subsequent membrane changes, responsible for cell death. Vice versa, cells resistant to oxidative stress are also resistant to the toxic effects of HP. Similarly, high percentage of patients suffering from extrapyramidal symptoms treated by vitamin E and other lipid-soluble antioxidants demonstrates diminishing of these adverse side effects. HP's ability to induce oxidative stress by multi-modal action (increased metabolism of dopamine, decrease of glutathione content, induction of NF-kappaB transcription factor, and inhibition of complex I of respiratory chain) has been established just recently. This review brings summarizing view on the cytotoxicity of haloperidol and involvement of reactive oxygen species and oxidative stress HP-induced cytotoxicity. PMID- 24160711 TI - Acute myocardial infarction due to coronary artery embolus associated with atrial fibrillation. AB - Coronary artery embolus is a rare and potentially under- recognised cause of acute myocardial infarction. We describe the case of an 80-year-old woman presenting with an acute coronary syndrome secondary to coronary artery embolus associated with atrial fibrillation, which was successfully treated with the use of a thrombectomy aspiration catheter. PMID- 24160712 TI - Percutaneous bail-out treatment of vein graft rupture with a polytetrafluoroethylene-covered stent. AB - Vessel perforation is an undesirable and life-threatening complication during vein graft angioplasty. We report on a case of vein graft rupture during angioplasty, which was successfully managed with deployment of a polytetrafluoroethylene-covered stent. PMID- 24160713 TI - Modulation of benzo[a]pyrene-induced toxic effects in Japanese medaka (Oryzias latipes) by 2,2',4,4'-tetrabromodiphenyl ether. AB - Because polycyclic aromatic hydrocarbons (PAHs) and polybrominated diphenylethers (PBDEs) are ubiquitous and coexist in the environment and in wildlife, there are potential interactions between them that could cause toxic effects. In this study, the modulating effects of 2,2',4,4'-tetrabromodiphenyl ether (BDE47) and benzo[a]pyrene (BaP)-induced reproductive and developmental toxic effects in Japanese medaka (Oryzias latipes) were investigated by exposing adult Japanese medaka to BaP alone, BDE47 alone, and coexposing them with both BaP and BDE47 at different concentrations, respectively. Exposure to BaP alone significantly suppressed fecundity and egg protein content and markedly induced skeletal deformation in F1 generation eleutheroembryos. BDE47 significantly recovered reproductive functions, fecundity, and egg protein content, suppressed by BaP when the concentration of BDE47 increased to 0.44 MUg/L. Such effects can be at least partly explained by the decreased BaP levels in the coexposure groups and the accompanying increase in the circulating level of 17beta-estradiol in female medaka fish. The prevalence of skeletal deformations markedly increased to 19.3 +/- 2.4% and 16.0 +/- 1.6% in fish coexposed to BaP and BDE47 at 0.44 and 2.58 MUg/L compared with that of fish exposed to 1.21 MUg/L BaP alone (9.7 +/- 1.7%), and the impacts on male medaka fish in the coexposure groups would be the crucial reason leading to these effects. Considering that the measured water concentrations of BaP and BDE47 in the present study were comparable with those reported in rivers and harbors, BaP and BDE47 contamination in the real world would have a significant level of interactive effects on wild fish. PMID- 24160714 TI - The effectiveness of an aged care specific leadership and management program on workforce, work environment, and care quality outcomes: design of a cluster randomised controlled trial. AB - BACKGROUND: A plethora of observational evidence exists concerning the impact of management and leadership on workforce, work environment, and care quality. Yet, no randomised controlled trial has been conducted to test the effectiveness of leadership and management interventions in aged care. An innovative aged care clinical leadership program (Clinical Leadership in Aged Care--CLiAC) was developed to improve managers' leadership capacities to support the delivery of quality care in Australia. This paper describes the study design of the cluster randomised controlled trial testing the effectiveness of the program. METHODS: Twenty-four residential and community aged care sites were recruited as managers at each site agreed in writing to participate in the study and ensure that leaders allocated to the control arm would not be offered the intervention program. Sites undergoing major managerial or structural changes were excluded. The 24 sites were randomly allocated to receive the CLiAC program (intervention) or usual care (control), stratified by type (residential vs. community, six each for each arm). Treatment allocation was masked to assessors and staff of all participating sites. The objective is to establish the effectiveness of the CLiAC program in improving work environment, workforce retention, as well as care safety and quality, when compared to usual care. The primary outcomes are measures of work environment, care quality and safety, and staff turnover rates. Secondary outcomes include manager leadership capacity, staff absenteeism, intention to leave, stress levels, and job satisfaction. Differences between intervention and control groups will be analysed by researchers blinded to treatment allocation using linear regression of individual results adjusted for stratification and clustering by site (primary analysis), and additionally for baseline values and potential confounders (secondary analysis). Outcomes measured at the site level will be compared by cluster-level analysis. The overall costs and benefits of the program will also be assessed. DISCUSSION: The outcomes of the trial have the potential to inform actions to enhance leadership and management capabilities of the aged care workforce, address pressing issues about workforce shortages, and increase the quality of aged care services. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry (ACTRN12611001070921). PMID- 24160715 TI - Practices of receptive and insertive anal sex among transgender women in relation to partner types, sociocultural factors, and background variables. AB - It is urgent to develop efficacious HIV prevention programs to curb the reported extremely high HIV prevalence and incidence among transgender women (male-to female transgender persons) who reside in large cities in the USA. This study aimed to describe unprotected receptive anal sex (URAS) and unprotected insertive anal sex (UIAS) among high-risk transgender women in relation to partner types, psychosocial factors, and background variables. Based on purposive sampling from the targeted communities and AIDS service organizations in San Francisco and Oakland, a total of 573 transgender women who had a history of sex work were recruited and individually interviewed using a structured survey questionnaire. Significant correlates with URAS with primary, casual, and commercial sex partners were found (e.g., needs for social support, frequency of social support received, exposure to transphobia, self-esteem, economic pressure, norms toward practicing healthy behaviors, and self-efficacy toward practicing safe sex). Multiple logistic regression analyses revealed that transgender women who had engaged in URAS with commercial partners were more likely to have higher levels of transphobia or lower levels of the norms or self-efficacy to practice safe sex. Among the participants who did not have vaginoplasty (preoperative transgender women), 16.4% had engaged in insertive anal sex (IAS) with commercial partners in the past 30 days. The participants who were HIV positive and had engaged in IAS were more likely to be African-American or Caucasians, coinfected with sexually transmitted infections, or identified themselves as homosexual. Practices of IAS among transgender women have not been thoroughly investigated in relation to sexual and gender identity. UIAS with homosexual and bisexual men in addition to URAS may be a cause for high HIV incidence among transgender women. An HIV prevention intervention study must be developed and evaluated, which aims to reduce HIV-positive and -negative transgender women's URAS and UIAS. PMID- 24160716 TI - Knowledge and attitudes towards hepatitis C and injecting drug use among mental health support workers of a community managed organisation. AB - OBJECTIVES: People with mental illness are at significantly higher risk of acquiring hepatitis C virus (HCV) compared with the general population. This study assessed knowledge of and attitudes towards people with HCV and people who inject drugs (PWID) among support workers of clients with mental illness. METHODS: Support workers from a community managed organisation (CMO) in Australia were recruited to complete an online cross-sectional survey. The survey collected data about their knowledge of HCV and attitudes towards PWID and people with HCV. RESULTS: Valid responses were received from 117 support workers. Although HCV knowledge was moderate, there were significant knowledge gaps around transmission and treatment of HCV. Higher HCV knowledge was significantly associated with more positive attitudes towards PWID, but not with attitudes towards people with HCV. Participants had more positive attitudes towards people with HCV than towards PWID. Additionally, those with more positive attitudes towards HCV tended to also have more positive attitudes towards PWID. CONCLUSIONS: Given that people with mental illness are at higher risk of acquiring HCV, these results point to the need for education targeted at support workers of clients with mental illness to increase HCV knowledge and promote positive attitudes towards PWID and people with HCV. PMID- 24160717 TI - Quality of life for patients diagnosed with diabetic foot. PMID- 24160718 TI - Ankle arthroscopy in a hanging position combined with hindfoot endoscopy for the treatment of concurrent anterior and posterior impingement syndrome of the ankle. AB - The purpose of the present study was to evaluate the results of arthroscopic and endoscopic treatment of concurrent anterior and posterior ankle impingement with the patient in a prone position. From May 2009 to September 2010, 22 patients with simultaneously combined anterior and posterior ankle impingements underwent ankle arthroscopy in a prone position. Noninvasive ankle distraction was achieved by hanging the affected ankle on a shoulder-holding traction frame, followed by hindfoot endoscopy. The mean age at surgery was 22.6 (range 20 to 46) years. The mean follow-up duration was 15.4 (range 12 to 29) months. The American Orthopaedic Foot and Ankle Society scores and Foot Function Index were checked preoperatively and at the final follow-up visit. The mean American Orthopaedic Foot and Ankle Society score increased from 62.6 preoperatively to 86.0 at the final follow-up visit (p < .05). The Foot Function Index improved from 45.8 to 17.2 (p < .05). Of the 22 patients, 18 were very satisfied or satisfied with the results, 2 rated their results as fair, and 2 were dissatisfied. No complications related to ankle distraction in a hanging position occurred. Ankle arthroscopy with the patient in a prone position with the ankle hung on a shoulder-holding traction frame combined with hindfoot endoscopy provided a useful method for treating anterior and posterior ankle impingement that does not require changing the patient's position from supine to prone. PMID- 24160719 TI - Computed tomography review of tarsal canal anatomy with reference to the fitting of sinus tarsi implants in the tarsal canal. AB - Sinus tarsi implants are used in the treatment of symptomatic hyperpronating flexible flatfeet in children. Although some implants are inserted only into the sinus tarsi, others occupy both the sinus tarsi and the tarsal canal. The stem that is anchored in the tarsal canal depends on interference fit for the initial resistance to slippage. The first part of this computed tomography anatomic study in children was aimed at finding and measuring the dimensions in the narrowest point in the canal that provided the interference fit. The second part of the study assessed the possibility of the implant being loaded with axial body weight in the tarsal canal. All foot computed tomography scans performed consecutively at Birmingham Children's Hospital from January 2008 to December 2011 were reviewed to assess the tarsal canal dimensions on the sagittal views. A total of 52 scans fulfilled the inclusion criteria. The average age was 12.7 years. The narrowest mean anteroposterior diameter of the canal was 7.3 +/- 1.12 (range 5.2 to 10.0) mm. The narrowest mean superoinferior diameter was 9.2 +/- 1.32 (range 6.3 to 12.7) mm. A total of 50 patients had the narrowest dimension in the anteroposterior plane. A positive linear correlation was found between the anteroposterior diameter and the superoinferior distance (r = 0.51, p < .01). We have concluded that the stem of an arthroereisis implant extending into the tarsal canal is unlikely to be constantly bearing body weight, because it obtains an interference grip in the anteroposterior direction in almost all patients and not in the superoinferior line of axial body weight. PMID- 24160720 TI - Efficacy of magnetic resonance imaging in diagnosing diabetic foot osteomyelitis in the presence of ischemia. AB - Magnetic resonance imaging (MRI) has been recognized as the most accurate imaging modality for the detection of diabetic foot osteomyelitis. However, how accurately MRI displays the extent of diabetic foot osteomyelitis in the presence of ischemia is still unclear. We retrospectively compared the preoperative MRI findings with the results of histopathologic examinations of resected bones and studied the efficacy of MRI in the diagnosis of diabetic foot osteomyelitis of different etiologies. A total 104 bones from 18 foot ulcers in 16 diabetic patients (10 men and 6 women; age range 42 to 84 years) treated by surgical intervention from 2008 to 2012 was examined. In 8 neuropathic ulcers, 29 bones were accurately diagnosed in detail using MRI, even those with severe soft tissue infection. Of 75 bones in 10 ischemic ulcers, only 7 bones evaluated by MRI after revascularization were diagnosed accurately; the other 68 could not be diagnosed because of unclear or equivocal MRI findings. On histopathologic examination, all the bones were found to be infected through the bone cortex by the surrounding infected soft tissue, not directly by articulation. Overall, preoperative MRI is effective in the diagnosis of neuropathic ulcers, but less so of ischemic ones. PMID- 24160721 TI - Registry data trends of total ankle replacement use. AB - Joint arthroplasty registry data are meaningful when evaluating the outcomes of total joint replacement, because they provide unbiased objective information regarding survivorship and incidence of use. Critical evaluation of the registry data information will benefit the surgeon, patient, and industry. However, the implementation and acceptance of registry data for total ankle replacement has lagged behind that of hip and knee implant arthroplasty. Currently, several countries have national joint arthroplasty registries, with only some procuring information for total ankle replacement. We performed an electronic search to identify publications and worldwide registry databanks with pertinent information specific to total ankle replacement to determine the type of prostheses used and usage trends over time. We identified worldwide registry data from 33 countries, with details pertinent to total ankle replacement identified in only 6 countries. The obtained information was arbitrarily stratified into 3 distinct periods: 2000 to 2006, 2007 to 2010, and 2011. Within these study periods, the data from 13 total ankle replacement systems involving 3,980 ankles were identified. The vast majority (97%) of the reported ankle replacements were 3-component, mobile bearing, uncemented prostheses. Three usage trends were identified: initial robust embracement followed by abrupt disuse, minimal use, and initial embracement followed by sustained growth in implantation. Before the widespread acceptance of new total ankle replacements, the United States should scrutinize and learn from the international registry data and develop its own national joint registry that would include total ankle replacement. Caution against the adoption of newly released prostheses, especially those without readily available revision components, is recommended. PMID- 24160722 TI - Intra-articular plica causing ankle impingement in a young handball player: a case report. AB - Ankle sprains are common injuries that respond well to rehabilitation. In the case of persisting symptoms, the differential diagnosis should include osteochondral defects, tendon injury, mechanical instability, and ankle impingement. In the present case report, we describe a 16-year-old male handball player who presented with persisting pain and locking in the right ankle 3 years after having sustained multiple minor inversion trauma. The clinical examination and conventional radiography showed no abnormalities. On magnetic resonance imaging, a flake fracture at the anteromedial talar dome and/or loose body was assumed. Arthroscopic examination revealed an intra-articular plica originating from an osteochondral fossa at the anteromedial tibial plafond. The plica was debrided. Retrospectively, the arthroscopic findings matched the radiographs and magnetic resonance images. The postoperative protocol consisted of early mobilization. At 6 weeks of follow-up, the patient had no pain and had returned to his sports activities. The present case report illustrates, to the best of our knowledge, the first case of ankle impingement due to a, most likely congenital, intra-articular plica arising from an osteochondral fossa at the anteromedial tibial plafond. This rare clinical condition can be diagnosed with magnetic resonance imaging. Arthroscopic debridement will effectively relieve the symptoms. PMID- 24160723 TI - An alternative method of fixation of calcaneal tuberosity fractures using the Tightrope((r)) technique. AB - Calcaneal tuberosity fractures account for 1% to 3% of all calcaneal fractures. These fractures are frequently seen in the osteoporotic or diabetic elderly population. The patient's comorbidities, coupled with the usually osteoporotic bone, make fixing this fracture pattern a challenge. Numerous surgical techniques have been advocated for this fracture, including the standard lag screw fixation, tension band wiring, suture anchors, and direct suture repair. Whichever method is used, the construct must resist the massive pull of the gastrocnemius-soleus complex. We have described a method of fixing the avulsed calcaneal tuberosity using the TightRope((r)) ankle syndesmosis fixation device (Arthrex((r)), Naples, FL), which offers the advantages of allowing a robust and reliable fixation of a small or comminuted fragment. It is particularly advantageous in osteoporotic bone because of concern regarding the use of standard lag screw fixation, and it also may eliminate complications associated with retained hardware. PMID- 24160724 TI - Modified Blair tibiotalar arthrodesis for post-traumatic avascular necrosis of the talus: a case report. AB - Surgical treatment of post-traumatic avascular necrosis of the talus coupled with collapse often results in limited treatment options. Of those options, the Blair tibiotalar arthrodesis has been beneficial in preserving limb length and subtalar motion. The complications associated with Blair tibiotalar arthrodesis have led to modifications to improve stability and functional outcomes with rigid internal fixation. We present the case of a 29-year-old female with a history of an open fracture dislocation of the talus 10 years previously, with subsequent development of avascular necrosis of the talus. The purpose of the present case report was to describe the surgical approach and use of an anterior compression plate to augment the modified Blair tibiotalar arthrodesis. PMID- 24160725 TI - The effect of clustering on lot quality assurance sampling: a probabilistic model to calculate sample sizes for quality assessments. AB - BACKGROUND: Traditional Lot Quality Assurance Sampling (LQAS) designs assume observations are collected using simple random sampling. Alternatively, randomly sampling clusters of observations and then individuals within clusters reduces costs but decreases the precision of the classifications. In this paper, we develop a general framework for designing the cluster(C)-LQAS system and illustrate the method with the design of data quality assessments for the community health worker program in Rwanda. RESULTS: To determine sample size and decision rules for C-LQAS, we use the beta-binomial distribution to account for inflated risk of errors introduced by sampling clusters at the first stage. We present general theory and code for sample size calculations.The C-LQAS sample sizes provided in this paper constrain misclassification risks below user specified limits. Multiple C-LQAS systems meet the specified risk requirements, but numerous considerations, including per-cluster versus per-individual sampling costs, help identify optimal systems for distinct applications. CONCLUSIONS: We show the utility of C-LQAS for data quality assessments, but the method generalizes to numerous applications. This paper provides the necessary technical detail and supplemental code to support the design of C-LQAS for specific programs. PMID- 24160726 TI - A facile in situ synthesis route for CuInS(2) quantum-dots/In(2)S(3) co sensitized photoanodes with high photoelectric performance. AB - CuInS2 quantum-dot sensitized TiO2 photoanodes with In2S3 buffer layer were in situ prepared via chemical bath deposition of In2S3, where the Cd-free In2S3 layer then reacted with TiO2/CuxS which employed a facile SILAR process to deposit CuxS quantum dots on TiO2 film, followed by a covering process with ZnS layer. Polysulfide electrolyte and Cu2S on FTO glass counter electrode were used to provide higher photovoltaic performance of the constructed devices. The characteristics of the quantum dots sensitized solar cells were studied in more detail by optical measurements, photocurrent-voltage performance measurements, and impedance spectroscopy. On the basis of optimal CuxS SILAR cycles, the best photovoltaic performance with power conversion efficiency (eta) of 1.62% (Jsc = 6.49 mA cm(-2), Voc = 0.50 V, FF = 0.50) under full one-sun illumination was achieved by using Cu2S counter electrode. Cu2S-FTO electrode exhibits superior electrocatalytic ability for the polysulfide redox reactions relative to that of Pt-FTO electrode. PMID- 24160727 TI - Ocular decompression retinopathy: a review. AB - Ocular decompression retinopathy (ODR) presents as retinal hemorrhages following acute lowering of the intraocular pressure (IOP). We review 32 articles published from 1992 to 2011 and address the pathogenesis, clinical features, management, and outcomes of ODR. ODR is defined as a multifocal hemorrhagic retinopathy that results from acute lowering of IOP and is not explained by another process. Hemorrhages occur in all retinal layers, and most patients are asymptomatic. The mean drop in IOP in ODR is 33.2 +/- 15.8 mm Hg (range, 4-57 mm Hg). Eighty-two percent are diagnosed by the first postoperative day, all within 2 weeks. ODR resolved in a mean of 13 +/- 12.4 weeks (range, 2-72 weeks). Vitrectomy was required for vitreous and subhyaloid hemorrhage in 14% of cases. Visual outcomes are generally good, with 85% of eyes returning to baseline vision. Although ODR infrequently results in significant ocular morbidity, gradual reduction in IOP might prevent this complication. PMID- 24160728 TI - Management of post-photorefractive keratectomy pain. AB - Photorefractive keratectomy (PRK) is a refractive procedure gaining popularity that eliminates the risk of ectasia and flap complications that can occur after laser in situ keratomileusis. Post-operative discomfort is a major drawback after PRK and thus the management of pain and discomfort following PRK is of great importance. We summarize corneal pain pathways and summarize current approaches to pain management after PRK. PMID- 24160729 TI - Idiopathic macular telangiectasia type 2 (idiopathic juxtafoveolar retinal telangiectasis type 2A, Mac Tel 2). AB - Macular telangiectasia type 2-also known as idiopathic perifoveal telangiectasia and juxtafoveolar retinal telangiectasis type 2A or Mac Tel 2-is an acquired bilateral neurodegenerative macular disease that usually manifests itself during the fourth to sixth decades of life and is characterized by minimal dilatation of the parafoveal capillaries with graying of the retinal area involved, a lack of lipid exudation, right-angled retinal venules, refractile deposits in the superficial retina, hyperplasia of the retinal pigment epithelium, foveal atrophy, and subretinal neovascularization (SRNV). Optical coherence tomography images typically demonstrate intraretinal hyporeflective spaces that are usually not related to retinal thickening or fluorescein leakage. The typical fluorescein angiographic finding is a deep intraretinal hyperfluorescent leakage in the temporal parafoveal area. With time the leakage may involve the whole parafovea, but does not extend to the center of the fovea. Long-term prognosis for central vision is variable and depends on the development of SRNV or macular atrophy. Pathogenesis remains unclear, but Muller cells and macular pigment appear to play a central role. Currently there is no known treatment for the underlying cause of this condition, but treatment of the SRNV may be beneficial. PMID- 24160730 TI - Treatment of cystic macular lesions in hereditary retinal dystrophies. AB - Cystic macular lesions frequently contribute to impaired visual acuity in hereditary retinal dystrophies. Their pathogenesis varies and is not entirely understood. Carbonic anhydrase inhibitors have proven to be potentially efficacious, although not in all cases. We discuss the various factors and mechanisms implicated in the etiology of cystic macular lesions (anatomical abnormalities, impairment of the blood-retinal barrier, tangential vitreous traction, and mutations in retinoschin, etc.) and the various treatments that have been proposed. PMID- 24160731 TI - Iron, zinc, and copper in retinal physiology and disease. AB - The essential trace metals iron, zinc, and copper play important roles both in retinal physiology and disease. They are involved in various retinal functions such as phototransduction, the visual cycle, and the process of neurotransmission, being tightly bound to proteins and other molecules to regulate their structure and/or function or as unbound free metal ions. Elevated levels of "free" or loosely bound metal ions can exert toxic effects, and in order to maintain homeostatic levels to protect retinal cells from their toxicity, appropriate mechanisms exist such as metal transporters, chaperones, and the presence of certain storage molecules that tightly bind metals to form nontoxic products. The pathways to maintain homeostatic levels of metals are closely interlinked, with various metabolic pathways directly and/or indirectly affecting their concentrations, compartmentalization, and oxidation/reduction states. Retinal deficiency or excess of these metals can result from systemic depletion and/or overload or from mutations in genes involved in maintaining retinal metal homeostasis, and this is associated with retinal dysfunction and pathology. Iron accumulation in the retina, a characteristic of aging, may be involved in the pathogenesis of retinal diseases such as age-related macular degeneration (AMD). Zinc deficiency is associated with poor dark adaptation. Zinc levels in the human retina and RPE decrease with age in AMD. Copper deficiency is associated with optic neuropathy, but retinal function is maintained. The changes in iron and zinc homeostasis in AMD have led to the speculation that iron chelation and/or zinc supplements may help in its treatment. PMID- 24160733 TI - Ethnic and gender specific life expectancies of the Singapore population, 1965 to 2009 - converging, or diverging? AB - BACKGROUND: The increase in life expectancy and the persistence of expectancy gaps between different social groups in the 20th century are well-described in Western developed countries, but less well documented in the newly industrialised countries of Asia. Singapore, a multiethnic island-state, has undergone a demographic and epidemiologic transition concomitant with economic development. We evaluate secular trends and differences in life expectancy by ethnicity and gender in Singapore, from independence to the present. METHODS: Period abridged life tables were constructed to derive the life expectancy of the Singapore population from 1965 to 2009 using data from the Department of Statistics and the Registry of Births and Deaths, Singapore. RESULTS: All 3 of Singapore's main ethnic groups, and both genders, experienced an increase in life expectancy at birth and at 65 years from 1965 to 2009, though at substantially different rates. Although there has been a convergence in life expectancy between Indians and Chinese, the (substantial) gap between Malays and the other two ethnic groups has remained. Females continued to have a higher life expectancy at birth and at 65 years than males throughout this period, with no evidence of convergence. CONCLUSIONS: Ethnic and gender differences in life expectancy persist in Singapore despite its rapid economic development. Targeted chronic disease prevention measures and health promotion activities focusing on people of Malay ethnicity and the male community may be needed to remedy this inequality. PMID- 24160734 TI - How do nucleophiles accelerate the reactions of dialkylstannylene acetals? The effects of adding fluoride to dialkoxydi-n-butylstannanes. AB - Dialkylstannylene acetals are organotin intermediates widely used to facilitate regioselective monofunctionalization of diols or polyols by electrophiles. Alkylation is both the slowest and the most useful reaction of these intermediates, and this reaction is markedly accelerated by the addition of nucleophiles to the reaction media, usually cesium fluoride in dimethylformamide (DMF) or tetrabutylammonium iodide or bromide in toluene. The regioselectivity may be influenced by aggregation of the dialkylstannylene acetals into dimers and higher oligomers, and by the addition of these nucleophiles. The stabilities and the geometries of the species potentially involved in these processes were examined by using theoretical chemistry methods with di-n-butyldialkoxytin derivatives as examples and fluoride as the nucleophile. Geometry optimizations were performed at B3LYP/6-31G(d,p) level, and single point energies obtained at the MP2/6-311G(2d,p) level with diffuse functions added for fluorine. The LANL2DZdp basis set with diffuse and polarization functions and its effective core potential were used to describe tin. The addition of fluoride to monomeric di-n-butyldialkoxytin derivatives to give fluoridated monomers is predicted to be strongly exothermic, by 187 to 209 kJ/mol, depending on the alkoxyl group. The fluoridated monomers are calculated to react with monomers exothermically to give monofluoridated dimers, except for the di-t-butoxy derivative. Dimer formation on average is about 20 kJ mol(-1) more exothermic than for the nonfluoridated monomers alone. Monofluoridated monomers strongly prefer to exist as monomers because the difluoridated dimers are estimated to be 209 to 278 kJ mol(-1) less stable at 298 K. PMID- 24160732 TI - Prenatal determinants of optic nerve hypoplasia: review of suggested correlates and future focus. AB - Optic nerve hypoplasia (ONH), a congenital malformation characterized by an underdeveloped optic nerve, is a seemingly epidemic cause of childhood blindness and visual impairment with associated lifelong morbidity. Although the prenatal determinants of ONH are unknown, early case reports have led to a longstanding speculation that risky health behaviors (e.g., prenatal use of recreational drugs, alcohol) are a likely culprit. There has yet to be a systematic review of the epidemiology of ONH to assess the common prenatal features that may help focus research efforts in the identification of likely prenatal correlates. A review of the past 50 years of epidemiologic research was conducted to examine the prenatal features linked with ONH and provide direction for future research. There are select prominent prenatal features associated with ONH: young maternal age and primiparity. Commonly implicated prenatal exposures (recreational or pharmaceutical drugs, viral infection, etc.) were rare or uncommon in large cohort studies of ONH and therefore unlikely to be major contributors to ONH. Familial cases and gene mutations are rare. The preponderance of young mothers and primiparity among cases of ONH is striking, although the significance is unclear. Recent research suggests a potential role for prenatal nutrition, weight gain, and factors of deprivation. With the rapidly increasing prevalence of ONH, future research should focus on investigating the relevance of young maternal age and primiparity and exploring the recently suggested etiologic correlates in epidemic clusters of ONH. PMID- 24160735 TI - Antagonistic effect of alkaloids and saponins on bioactivity in the quinine tree (Rauvolfia caffra sond.): further evidence to support biotechnology in traditional medicinal plants. AB - BACKGROUND: The Quinine tree (Rauvolfia caffra) is used as a medicinal plant among traditional communities in many countries to manage tumors and other diseases associated with oxidative stress. To validate indigenous knowledge and possibly position this herb for technology uptake and utilization, we established the level of antioxidant activity in R. caffra, and probed for the presence of associated phytochemicals. METHODS: Antioxidant activity was determined on 1,1 diphenyl-2-picrylhydrazyl (DPPH) while major phytochemicals were identified by multiple tests on methanol fractions. RESULTS: R. caffra showed promise as a cure, with antioxidant activity comparable to the commercially used drug quercetin (R. caffra = 79.7% +/-1.9; quercetin = 82.6% +/- 2.0). However, we found two phytochemicals with possible antagonistic effect: co-occurrence of alkaloids and saponins significantly reduced antioxidant activity (alkaloids only = 63%; alkaloids plus saponins = 15%; steroids, terpenoids and cardiac glycosides = 82%), thus alkaloids and saponins should be exclusive to each other in drug formulations. CONCLUSIONS: Antagonistic relationship among phytochemicals would affect the efficacy of crude extracts as used in traditional medicine. Unlike in herbal medicine, use of modern biotechnology in extraction, purification and design of optimal combinations will ensure efficient drug formulations with optimum bioactivity and minimum toxicity. Metabolic pathway engineering under a controlled environment may optimize availability of desired compounds. PMID- 24160736 TI - Release rates of liposomal contents are controlled by kosmotropes and chaotropes. AB - Contents release from redox-responsive liposomes is anion-specific. Liposomal contents release is initiated by the contact of apposed liposome bilayers having in their outer leaflet 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine (DOPE), whose presence is due to the redox-stimulated removal of a quinone propionic acid protecting group (Q) from Q-DOPE lipids. Contents release occurs upon the phase transition of DOPE from its lamellar liquid-crystalline phase (Lalpha) to its hexagonal-II inverted micelle (HII) phase. Contents release is slower in the presence of weakly hydrated chaotropic anions versus highly hydrated kosmotropic anions and is attributed to ion accumulation near the zwitterionic DOPE headgroups, in turn altering the headgroup hydration, as indicated by the Lalpha > HII phase transition temperature, TH, for DOPE. The results are significant, not only for mechanistic aspects of liposome contents release in DOPE-based systems but also for drug delivery applications wherein exist at drug targeting sites variations in the type and concentration of ions and neutral species. PMID- 24160738 TI - Atomic structure and special reactivity toward methanol oxidation of vanadia nanoclusters on TiO2(110). AB - We have grown highly controlled VOx nanoclusters on rutile TiO2(110). The combination of photoemission and photoelectron diffraction techniques based on synchrotron radiation with DFT calculations has allowed identifying these nanostructures as exotic V4O6 nanoclusters, which hold vanadyl groups, even if vanadium oxidation state is formally +3. Our theoretical investigation also indicates that on the surface of titania, vanadia mononuclear species, with oxidation states ranging from +2 to +4, can be strongly stabilized by aggregation into tetramers that are characterized by a charge transfer to the titania substrate and a consequent decrease of the electron density in the vanadium 3d levels. We then performed temperature programmed desorption experiments using methanol as probe molecule to understand the impact of these unusual electronic and structural properties on the chemical reactivity, obtaining that the V4O6 nanoclusters can selectively convert methanol to formaldehyde at an unprecedented low temperature (300 K). PMID- 24160737 TI - Photocatalytic degradation of water contaminants in multiple photoreactors and evaluation of reaction kinetic constants independent of photon absorption, irradiance, reactor geometry, and hydrodynamics. AB - The literature on photocatalytic oxidation of water pollutants often reports reaction kinetic constants, which cannot be unraveled from photoreactor type and experimental conditions. This study addresses this challenging aspect by presenting a general and simple methodology for the evaluation of fundamental "intrinsic" reaction kinetic constants of photocatalytic degradation of water contaminants, which are independent of photoreactor type, catalyst concentration, irradiance levels, and hydrodynamics. The degradation of the model contaminant, oxalic acid (OA) on titanium dioxide (TiO2) aqueous suspensions, was monitored in two annular photoreactors (PR1 and PR2). The photoreactors with significantly different geometries were operated under different hydrodynamic regimes (turbulent batch mode and laminar flow-through recirculation mode), optical thicknesses, catalyst and OA concentrations, and photon irradiances. The local volumetric rate of photon absorption (LVRPA) was evaluated by the six-flux radiation absorption-scattering model (SFM). The SFM was further combined with a comprehensive kinetic model for the adsorption and photodecomposition of OA on TiO2 to determine local reaction rates and, after integration over the reactor volume, the intrinsic reaction kinetic constants. The model could determine the oxidation of OA in both PR1 and PR2 under a wide range of experimental conditions. This study demonstrates a more meaningful way for determining reaction kinetic constants of photocatalytic degradation of water contaminants. PMID- 24160742 TI - Ethical considerations in end-of-life deactivation of durable mechanical circulatory support devices. PMID- 24160741 TI - Patient safety incidents in hospice care: observations from interdisciplinary case conferences. AB - BACKGROUND: In the home hospice environment, issues arise every day presenting challenges to the safety, care, and quality of the dying experience. The literature pertaining to the safety challenges in this environment is limited. AIM: The study explored two research questions; 1) What types of patient safety incidents occur in the home hospice setting? 2) How many of these incidents are recognized by the hospice staff and/or the patient or caregiver as a patient safety incident? DESIGN AND METHODS: Video-recordings of hospice interdisciplinary team case conferences were reviewed and coded for patient safety incidents. Patient safety incidents were defined as any event or circumstance that could have resulted or did result in unnecessary harm to the patient or caregiver, or that could have resulted or did result in a negative impact on the quality of the dying experience for the patient. Codes for categories of patient safety incidents were based on the International Classification for Patient Safety. SETTING/PARTICIPANTS: The setting for the study included two rural hospice programs in one Midwestern state in the United States. One hospice team had two separately functioning teams, the second hospice had three teams. RESULTS: 54 video-recordings were reviewed and coded. Patient safety incidents were identified that involved issues in clinical process, medications, falls, family or caregiving, procedural problems, documentation, psychosocial issues, administrative challenges and accidents. CONCLUSION: This study distinguishes categories of patient safety events that occur in home hospice care. Although the scope and definition of potential patient safety incidents in hospice is unique, the events observed in this study are similar to those observed with in other settings. This study identifies an operating definition and a potential classification for further research on patient safety incidents in hospice. Further research and consensus building of the definition of patient safety incidents and patient safety incidents in this setting is recommended. PMID- 24160743 TI - Hungry bone syndrome: persistent hypocalcemia related to osteoblastic bone metastases of prostate cancer. PMID- 24160744 TI - See the Seal? Understanding Restrained Eaters' Responses to Nutritional Messages on Food Packaging. AB - Food packaging in general and packaging incorporating health messages in particular have been active areas of inquiry, receiving attention from policymakers and food manufacturers alike. This study explores the effects of package seals and claims on perceived product healthfulness as a function of dietary restraint status. A laboratory experiment using realistic three dimensional packaging shows that for restrained eaters (i.e., those who try to restrict their food intake), nutrition claims on "healthy" products and nutrition seals on "unhealthy" products are effective at enhancing perceptions of product healthfulness. Unrestrained eaters, in contrast, are largely unaffected by nutrition seals and claims. These results provide insights into restrained eaters' purchase motivations, as well as guidance for policymakers seeking to regulate the use of seals and claims. PMID- 24160745 TI - Why are the prevalence and diversity of helminths in the endemic Pyrenean brook newt Calotriton asper (Amphibia, Salamandridae) so low? AB - A cornerstone in parasitology is why some species or populations are more parasitized than others. Here we examine the influence of host characteristics and habitat on parasite prevalence. We studied the helminths parasitizing the Pyrenean brook newt Calotriton asper (n= 167), paying special attention to the relationship between parasites and ecological factors such as habitat, sex, ontogeny, body size and age of the host. We detected two species of parasites, Megalobatrachonema terdentatum (Nematoda: Kathlaniidae) and Brachycoelium salamandrae (Trematoda: Brachycoeliidae), with a prevalence of 5.99% and 1.2%, respectively. Marginally significant differences were found in the prevalence between sexes, with females being more parasitized than males. The present results show significant differences in the body length of paedomorphic and metamorphic individuals, the former being smaller. Nevertheless, no significant correlations between parasite prevalence and either newt body length, ontogenetic stage or age were found. In comparison with other Salamandridae living in ponds, prevalence and diversity values were low. This may be due to a long hibernation period, the species' lotic habitat and its reophilous lifestyle, which probably do not allow for a high parasite load. PMID- 24160746 TI - In vivo anti-inflammatory properties of aerial parts of Nasturtium officinale. AB - CONTEXT: Nasturtium officinale R. Br. (watercress) has long been used in Iranian folk medicine to treat hypertension, hyperglycemia, and renal colic. Moreover, anticancer, antioxidant, and hepatoprotective properties of N. officinale have been reported. OBJECTIVE: In this study, anti-inflammatory activity of the hydro alcoholic extract from aerial parts of N. officinale was investigated. MATERIALS AND METHODS: Oral administration of the hydro-alcoholic extract of N. officinale (250, 500 and 750 mg kg(-1)) was investigated on two well-characterized animal models of inflammation, including carrageenan- or formalin-induced paw edema in rats. Then, the topical anti-inflammatory effect of N. officinale (2 and 5 mg/ear) was studied on 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced mouse ear edema. Finally, biopsy of the paw or ear was performed for pathological evaluation. RESULTS: Acute toxicity tests of N. officinale in rats established an oral LD50 of >5 g kg(-1). The extract of watercress (250, 500 and 750 mg kg(-1)) significantly inhibited carrageenan-induced paw edema 1, 2, 3 and 4 h after carrageenan challenge (p < 0.001). The extract (500 mg kg(-1)) also showed considerable activity against formalin-evoked paw edema over a period of 24 h (p < 0.001). Furthermore, topical application of N. officinale (5 mg/ear) reduced TPA-induced ear edema (p < 0.05). Histopathologically, the extract decreased swelling and the tissue damage induced by carrageenan or TPA. DISCUSSION AND CONCLUSION: Our findings indicate potent anti-inflammatory activity of N. officinale in systemic and topical application and propose its potential as an anti-inflammatory agent for treatment of inflammatory conditions. PMID- 24160747 TI - Comparative effectiveness and acceptability of home-based and clinic-based sampling methods for sexually transmissible infections screening in females aged 14-50 years: a systematic review and meta-analysis. AB - BACKGROUND: Home-based sampling is a strategy to enhance uptake of sexually transmissible infection (STI) screening. This review aimed to compare the screening uptake levels of home-based self-sampling and clinic-based specimen collection for STIs (chlamydia (Chlamydia trachomatis), gonorrhoea (Neisseria gonorrhoeae) and trichomoniasis) in females aged 14-50 years. Acceptability and effect on specimen quality were determined. METHODS: Sixteen electronic databases were searched from inception to September 2012. Randomised controlled trials (RCTs) comparing the uptake levels of home-based self-sampling and clinic-based sampling for chlamydia, gonorrhoea and trichomoniasis in females aged 14-50 years were eligible for inclusion. The risk of bias in the trials was assessed. Risk ratios (RRs) for dichotomous outcomes were meta-analysed. RESULTS: Of 3065 papers, six studies with seven RCTs contributed to the final review. Compared with clinic-based methods, home-based screening increased uptake significantly (P=0.001-0.05) in five trials and was substantiated in a meta-analysis (RR: 1.55; 95% confidence interval: 1.30-1.85; P=0.00001) of two trials. In three trials, a significant preference for home-based testing (P=0.001-0.05) was expressed. No significant difference was observed in specimen quality. Sampling was rated as easy by a significantly higher number of women (P=0.01) in the clinic group in one trial. CONCLUSIONS: The review provides evidence that home-based testing results in greater uptake of STI screening in females (14-50 years) than clinic based testing without compromising quality in the developed world. Home collection strategies should be added to clinic-based screening programs to enhance uptake. PMID- 24160592 TI - Measurement of the azimuthal angle dependence of inclusive jet yields in Pb+Pb collisions at ?(sNN)=2.76 TeV with the ATLAS detector. AB - Measurements of the variation of inclusive jet suppression as a function of relative azimuthal angle, Deltaphi, with respect to the elliptic event plane provide insight into the path-length dependence of jet quenching. ATLAS has measured the Deltaphi dependence of jet yields in 0.14 nb(-1) of ?(s(NN))=2.76 TeV Pb+Pb collisions at the LHC for jet transverse momenta p(T)>45 GeV in different collision centrality bins using an underlying event subtraction procedure that accounts for elliptic flow. The variation of the jet yield with Deltaphi was characterized by the parameter, v(2)(jet), and the ratio of out-of plane (Deltaphi~pi/2) to in-plane (Deltaphi~0) yields. Nonzero v(2)(jet) values were measured in all centrality bins for p(T)<160 GeV. The jet yields are observed to vary by as much as 20% between in-plane and out-of-plane directions. PMID- 24160748 TI - Nucleic acid structure: a continuing tradition. PMID- 24160750 TI - Personalizing and targeting therapy for COPD: the role of molecular and clinical biomarkers. AB - Chronic obstructive pulmonary disease (COPD) is a heterogeneous disease characterized by persistent airflow limitation. It is the third leading cause of death worldwide, and there are currently no curative strategies for this disease. Many factors contribute to COPD susceptibility, progression and exacerbations. These include cigarette smoking, environmental and occupational pollutants, respiratory infections and comorbidities. As the clinical phenotypes of COPD are so variable, it has been difficult to devise an individualized treatment plan for patients with this complex chronic disease. This review will highlight how potential clinical, inflammatory, genomic and epigenomic biomarkers for COPD could be used to personalize treatment, leading to improved disease management and prevention for our patients. PMID- 24160751 TI - Citric acid mediates the iron absorption from low molecular weight human milk fractions. AB - Previously, we have demonstrated increased iron absorption from low molecular weight (LMW) human milk whey fractions. In the present study, we investigated the effect of heat denaturation, zinc (a competitor of iron), duodenal cytochrome b (DcytB) antibody neutralization and citrate lyase treatment on LMW human milk fraction (>5 kDa referred as 5kF) induced ferric iron reduction, solubilization, and uptake in Caco-2 cells. Heat denaturation and zinc inhibited the 5kF fraction induced ferric iron reduction. In contrast, zinc but not heat denaturation abrogated the ferric iron solubilization activity. Despite inhibition of ferric iron reduction, iron uptake in Caco-2 cells was similar from both native and heat denatured 5kF fractions. However, iron uptake was higher from native compared to heat denatured 5kF fractions in the cells preincubated with the DcytB antibody. Citrate lyase treatment inhibited the ferric iron reduction, solubilization, and uptake in Caco-2 cells. These findings demonstrate that citric acid present in human milk solubilizes the ferric iron which could be reduced by other heat labile components leading to increased uptake in intestinal cells. PMID- 24160752 TI - A comparison of fully automated methods of data analysis and computer assisted heuristic methods in an electrode kinetic study of the pathologically variable [Fe(CN)6](3-/4-) process by AC voltammetry. AB - Fully automated and computer assisted heuristic data analysis approaches have been applied to a series of AC voltammetric experiments undertaken on the [Fe(CN)6](3-/4-) process at a glassy carbon electrode in 3 M KCl aqueous electrolyte. The recovered parameters in all forms of data analysis encompass E(0) (reversible potential), k(0) (heterogeneous charge transfer rate constant at E(0)), alpha (charge transfer coefficient), Ru (uncompensated resistance), and Cdl (double layer capacitance). The automated method of analysis employed time domain optimization and Bayesian statistics. This and all other methods assumed the Butler-Volmer model applies for electron transfer kinetics, planar diffusion for mass transport, Ohm's Law for Ru, and a potential-independent Cdl model. Heuristic approaches utilize combinations of Fourier Transform filtering, sensitivity analysis, and simplex-based forms of optimization applied to resolved AC harmonics and rely on experimenter experience to assist in experiment-theory comparisons. Remarkable consistency of parameter evaluation was achieved, although the fully automated time domain method provided consistently higher alpha values than those based on frequency domain data analysis. The origin of this difference is that the implemented fully automated method requires a perfect model for the double layer capacitance. In contrast, the importance of imperfections in the double layer model is minimized when analysis is performed in the frequency domain. Substantial variation in k(0) values was found by analysis of the 10 data sets for this highly surface-sensitive pathologically variable [Fe(CN)6](3-/4-) process, but remarkably, all fit the quasi-reversible model satisfactorily. PMID- 24160749 TI - Association of the MLXIPL/TBL2 rs17145738 SNP and serum lipid levels in the Guangxi Mulao and Han populations. AB - BACKGROUND: The rs17145738 single nucleotide polymorphism (SNP) near MLX interacting protein-like/transducin (beta)-like 2 (MLXIPL/TBL2) loci is associated with serum lipid levels, but the results are inconsistent in diverse ethnic/racial groups. The current study was to investigate the association of MLXIPL/TBL2 rs17145738 SNP and several environmental factors with serum lipid profiles in the Guangxi Mulao and Han populations. METHODS: A total of 649 subjects of Mulao nationality and 712 participants of Han nationality aged 16-84 years were randomly selected from our previous stratified randomized samples. Genotyping was performed by polymerase chain reaction and restriction fragment length polymorphism combined with gel electrophoresis, and then confirmed by direct sequencing. RESULTS: Serum apolipoprotein (Apo) B levels were higher in Mulao than in Han (P < 0.001). There were no significant differences in the genotypic and allelic frequencies of the MLXIPL/TBL2 rs17145738 SNP between the two ethnic groups or between males and females. The T allele carriers had higher triglyceride (TG) and ApoB levels in Mulao, and higher total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-C) levels in Han than the T allele non carriers (P < 0.05 for all). Subgroup analyses showed that the T allele carriers had higher ApoB levels in both Mulao and Han females than the T allele non carriers, but the T allele carriers had lower ApoB levels in Han males than the T allele non-carriers (P < 0.05, respectively). The T allele carriers in Han had higher TC, high-density lipoprotein cholesterol (HDL-C) levels and ApoA1/ApoB ratio and lower TG levels in males, and higher LDL-C levels and lower ApoA1/ApoB ratio in females than the T allele non-carriers (P < 0.05 for all). Serum TC levels in the combined population of the two ethnic groups and in Han, and HDL-C levels in Han males were correlated with genotypes (P < 0.05 for all). Serum lipid parameters were also correlated with several environmental factors (P < 0.05-0.01). CONCLUSIONS: The association of MLXIPL/TBL2 rs17145738 SNP and serum lipid profiles is different between the Mulao and Han populations. There is a sex specific association in the both ethnic groups. PMID- 24160753 TI - Relationship between longest utterances and later MLU in late talkers. AB - The task of developing prognoses for late-talking children has long been a challenge for speech-language pathologists, developmental psychologists, and pediatricians. Improved predictors would help to assess long-term risk and determine appropriate intervention services. The present study evaluated children's length of longest utterances (LLU) as a predictor of mean length of utterance (MLU) one year later. Relationships between LLU at 30 months, MLU at 30 months and MLU at 42 months were examined in 43 late talkers (LT) and 33 age matched children whose language was typically developing (TD). LLU was a significant predictor of MLU at 42 months with particularly strong correlations within the LT group. Similar results were obtained when controlling for language sample size, which was positively related to LLU. For the LT group, a regression model combining 30-month LLU and MLU was better at predicting 42-month MLU than 30-month MLU alone. The results are discussed in terms of frequency distributions of utterance lengths within language samples. PMID- 24160754 TI - Sensory epithelia of the fish inner ear in 3D: studied with high-resolution contrast enhanced microCT. AB - INTRODUCTION: While a number of studies have illustrated and analyzed 3D models of inner ears in higher vertebrates, inner ears in fishes have rarely been investigated in 3D, especially with regard to the sensory epithelia of the end organs, the maculae. It has been suggested that the 3D curvature of these maculae may also play an important role in hearing abilities in fishes. We therefore set out to develop a fast and reliable approach for detailed 3D visualization of whole inner ears as well as maculae. RESULTS: High-resolution microCT imaging of black mollies Poecilia sp. (Poeciliidae, Teleostei) and Steatocranus tinanti (Cichlidae, Teleostei) stained with phosphotungstic acid (PTA) resulted in good tissue contrast, enabling us to perform a reliable 3D reconstruction of all three sensory maculae of the inner ears. Comparison with maculae that have been 3D reconstructed based on histological serial sections and phalloidin-stained maculae showed high congruence in overall shape of the maculae studied here. CONCLUSIONS: PTA staining and subsequent high-resolution contrast enhanced microCT imaging is a powerful method to obtain 3D models of fish inner ears and maculae in a fast and more reliable manner. Future studies investigating functional morphology, phylogenetic potential of inner ear features, or evolution of hearing and inner ear specialization in fishes may benefit from the use of 3D models of inner ears and maculae. PMID- 24160755 TI - Vibration-reducing gloves: transmissibility at the palm of the hand in three orthogonal directions. AB - Vibration-reducing (VR) gloves are commonly used as a means to help control exposures to hand-transmitted vibrations generated by powered hand tools. The objective of this study was to characterise the vibration transmissibility spectra and frequency-weighted vibration transmissibility of VR gloves at the palm of the hand in three orthogonal directions. Seven adult males participated in the evaluation of seven glove models using a three-dimensional hand-arm vibration test system. Three levels of hand coupling force were applied in the experiment. This study found that, in general, VR gloves are most effective at reducing vibrations transmitted to the palm along the forearm direction. Gloves that are found to be superior at reducing vibrations in the forearm direction may not be more effective in the other directions when compared with other VR gloves. This casts doubts on the validity of the standardised glove screening test. Practitioner Summary: This study used human subjects to measure three-dimensional vibration transmissibility of vibration-reducing gloves at the palm and identified their vibration attenuation characteristics. This study found the gloves to be most effective at reducing vibrations along the forearm direction. These gloves did not effectively attenuate vibration along the handle axial direction. PMID- 24160757 TI - Exogenous cannabinoids as substrates, inhibitors, and inducers of human drug metabolizing enzymes: a systematic review. AB - Exogenous cannabinoids are structurally and pharmacologically diverse compounds that are widely used. The purpose of this systematic review is to summarize the data characterizing the potential for these compounds to act as substrates, inhibitors, or inducers of human drug metabolizing enzymes, with the aim of clarifying the significance of these properties in clinical care and drug interactions. In vitro data were identified that characterize cytochrome P-450 (CYP-450) enzymes as potential significant contributors to the primary metabolism of several exogenous cannabinoids: tetrahydrocannabinol (THC; CYPs 2C9, 3A4); cannabidiol (CBD; CYPs 2C19, 3A4); cannabinol (CBN; CYPs 2C9, 3A4); JWH-018 (CYPs 1A2, 2C9); and AM2201 (CYPs 1A2, 2C9). CYP-450 enzymes may also contribute to the secondary metabolism of THC, and UDP-glucuronosyltransferases have been identified as capable of catalyzing both primary (CBD, CBN) and secondary (THC, JWH-018, JWH-073) cannabinoid metabolism. Clinical pharmacogenetic data further support CYP2C9 as a significant contributor to THC metabolism, and a pharmacokinetic interaction study using ketoconazole with oromucosal cannabis extract further supports CYP3A4 as a significant metabolic pathway for THC and CBD. However, the absence of interaction between CBD from oromucosal cannabis extract with omeprazole suggests a less significant role of CYP2C19 in CBD metabolism. Studies of THC, CBD, and CBN inhibition and induction of major human CYP-450 isoforms generally reflect a low risk of clinically significant drug interactions with most use, but specific human data are lacking. Smoked cannabis herb (marijuana) likely induces CYP1A2 mediated theophylline metabolism, although the role of cannabinoids specifically in eliciting this effect is questionable. PMID- 24160758 TI - Making change last: applying the NHS institute for innovation and improvement sustainability model to healthcare improvement. AB - The implementation of evidence-based treatments to deliver high-quality care is essential to meet the healthcare demands of aging populations. However, the sustainable application of recommended practice is difficult to achieve and variable outcomes well recognised. The NHS Institute for Innovation and Improvement Sustainability Model (SM) was designed to help healthcare teams recognise determinants of sustainability and take action to embed new practice in routine care. This article describes a formative evaluation of the application of the SM by the National Institute for Health Research Collaboration for Leadership in Applied Health Research and Care for Northwest London (CLAHRC NWL). Data from project teams' responses to the SM and formal reviews was used to assess acceptability of the SM and the extent to which it prompted teams to take action. Projects were classified as 'engaged,' 'partially engaged' and 'non-engaged.' Quarterly survey feedback data was used to explore reasons for variation in engagement. Score patterns were compared against formal review data and a 'diversity of opinion' measure was derived to assess response variance over time. Of the 19 teams, six were categorized as 'engaged,' six 'partially engaged,' and seven as 'non-engaged.' Twelve teams found the model acceptable to some extent. Diversity of opinion reduced over time. A minority of teams used the SM consistently to take action to promote sustainability but for the majority SM use was sporadic. Feedback from some team members indicates difficulty in understanding and applying the model and negative views regarding its usefulness. The SM is an important attempt to enable teams to systematically consider determinants of sustainability, provide timely data to assess progress, and prompt action to create conditions for sustained practice. Tools such as these need to be tested in healthcare settings to assess strengths and weaknesses and findings disseminated to aid development. This study indicates the SM provides a potentially useful approach to measuring teams' views on the likelihood of sustainability and prompting action. Securing engagement of teams with the SM was challenging and redesign of elements may need to be considered. Capacity building and facilitation appears necessary for teams to effectively deploy the SM. PMID- 24160756 TI - Pigment epithelium-derived factor reduces apoptosis and pro-inflammatory cytokine gene expression in a murine model of focal retinal degeneration. AB - AMD (age-related macular degeneration) is a neurodegenerative disease causing irreversible central blindness in the elderly. Apoptosis and inflammation play important roles in AMD pathogenesis. PEDF (pigment epithelium-derived factor) is a potent neurotrophic and anti-inflammatory glycoprotein that protects the retinal neurons and photoreceptors against cell death caused by pathological insults. We studied the effects of PEDF on focal retinal lesions in DKO rd8 (Ccl2(-/-)/Cx3cr1(-/-) on C57BL/6N [Crb1(rd8)]) mice, a model for progressive, focal rd (retinal degeneration). First, we found a significant decrease in PEDF transcript expression in DKO rd8 mouse retina and RPE (retinal pigment epithelium) than WT (wild-type, C57BL/6N). Next, cultured DKO rd8 RPE cells secreted lower levels of PEDF protein in the media than WT. Then the right eyes of DKO rd8 mice were injected intravitreously with recombinant human PEDF protein (1 MUg), followed by a subconjunctival injection of PEDF (3 MUg) 4 weeks later. The untreated left eyes served as controls. The effect of PEDF was assessed by fundoscopy, ocular histopathology and A2E {[2,6-dimethyl-8-(2,6,6-trimethyl-1 cyclohexen-1-yl)-1E,3E,5E,7E-octatetra-enyl]-1-(2-hydroxyethyl)-4-[4-methyl 6(2,6,6-trimethyl-1-cyclohexen-1-yl) 1E,3E,5E,7E-hexatrienyl]-pyridinium} levels, as well as apoptotic and inflammatory molecules. The PEDF-treated eyes showed slower progression or attenuation of the focal retinal lesions, fewer and/or smaller photoreceptor and RPE degeneration, and significantly lower A2E, relative to the untreated eyes. In addition, lower expression of apoptotic and inflammatory molecules were detected in the PEDF-treated than untreated eyes. Our results establish that PEDF potently stabilizes photoreceptor degeneration via suppression of both apoptotic and inflammatory pathways. The multiple beneficial effects of PEDF represent a novel approach for potential AMD treatment. PMID- 24160759 TI - The condensation of water on adsorbed viruses. AB - The wetting and dewetting behavior of biological nanostructures and to a greater degree single molecules is not well-known even though their contact with water is the basis for all biology. Here, we show that environmental electron microscopy (EM) can be applied as a means of imaging the condensation of water onto viruses. We captured the formation of submicrometer water droplets and filaments on single viral particles by environmental EM and by environmental transmission EM. The condensate structures are compatible with capillary condensation between adsorbed virus particles and with known droplet shapes on patterned surfaces. Our results confirm that such droplets exist down to <50 nm. The viruses preserved their shape after a condensation/evaporation cycle as expected from their stability in air and water. Moreover we developed procedures that overcome problems of beam damage and of resolving structures with a low atomic number. PMID- 24160760 TI - High-field EPR on membrane proteins - crossing the gap to NMR. AB - In this review on advanced EPR spectroscopy, which addresses both the EPR and NMR communities, considerable emphasis is put on delineating the complementarity of NMR and EPR concerning the measurement of molecular interactions in large biomolecules. From these interactions, detailed information can be revealed on structure and dynamics of macromolecules embedded in solution- or solid-state environments. New developments in pulsed microwave and sweepable cryomagnet technology as well as ultrafast electronics for signal data handling and processing have pushed to new horizons the limits of EPR spectroscopy and its multifrequency extensions concerning the sensitivity of detection, the selectivity with respect to interactions, and the resolution in frequency and time domains. One of the most important advances has been the extension of EPR to high magnetic fields and microwave frequencies, very much in analogy to what happens in NMR. This is exemplified by referring to ongoing efforts for signal enhancement in both NMR and EPR double-resonance techniques by exploiting dynamic nuclear or electron spin polarization via unpaired electron spins and their electron-nuclear or electron-electron interactions. Signal and resolution enhancements are particularly spectacular for double-resonance techniques such as ENDOR and PELDOR at high magnetic fields. They provide greatly improved orientational selection for disordered samples that approaches single-crystal resolution at canonical g-tensor orientations - even for molecules with small g anisotropies. Exchange of experience between the EPR and NMR communities allows for handling polarization and resolution improvement strategies in an optimal manner. Consequently, a dramatic improvement of EPR detection sensitivity could be achieved, even for short-lived paramagnetic reaction intermediates. Unique structural and dynamic information is thus revealed that can hardly be obtained by any other analytical techniques. Micromolar quantities of sample molecules have become sufficient to characterize stable and transient reaction intermediates of complex molecular systems - offering highly interesting applications for chemists, biochemists and molecular biologists. In three case studies, representative examples of advanced EPR spectroscopy are reviewed: (I) High-field PELDOR and ENDOR structure determination of cation-anion radical pairs in reaction centers from photosynthetic purple bacteria and cyanobacteria (Photosystem I); (II) High-field ENDOR and ELDOR-detected NMR spectroscopy on the oxygen-evolving complex of Photosystem II; and (III) High-field electron dipolar spectroscopy on nitroxide spin-labelled bacteriorhodopsin for structure-function studies. An extended conclusion with an outlook to further developments and applications is also presented. PMID- 24160762 TI - Identifying and understanding barriers to sexually transmissible infection testing among young people. AB - BACKGROUND: To counter the disproportionate impact of sexually transmissible infections (STIs) among young people and encourage higher levels of STI testing, it is necessary to identify the factors that influence STI testing. METHODS: A mixed-methods study incorporating a cross-sectional quantitative survey and qualitative analysis of individual interviews was conducted in England. Some 275 university students aged 17-25 years completed an online questionnaire. Interviews were conducted with a purposively selected sample of eight men and women. RESULTS: Multivariate analysis of quantitative data revealed that injunctive norms (i.e. a desire to comply with others' wishes for testing), descriptive norms (i.e. perceptions of others' behaviour) and shame related to STIs predicted past testing behaviour. Intention to undergo testing was predicted by greater perceived susceptibility, past testing, stronger injunctive norms and greater willingness to disclose sexual histories. Qualitative analysis of interview data confirmed the importance of perceived susceptibility, normative beliefs, stigma and shame, and perceived ease of testing. CONCLUSIONS: To increase STI testing among young people, there is a need to promote pro-testing norms, address low perceived susceptibility and make testing easier. PMID- 24160761 TI - Sensitivity and resolution enhancement of oriented solid-state NMR: application to membrane proteins. AB - Oriented solid-state NMR (O-ssNMR) spectroscopy is a major technique for the high resolution analysis of the structure and topology of transmembrane proteins in native-like environments. Unlike magic angle spinning (MAS) techniques, O-ssNMR spectroscopy requires membrane protein preparations that are uniformly oriented (mechanically or magnetically) so that anisotropic NMR parameters, such as dipolar and chemical shift interactions, can be measured to determine structure and orientation of membrane proteins in lipid bilayers. Traditional sample preparations involving mechanically aligned lipids often result in short relaxation times which broaden the (15)N resonances and encumber the manipulation of nuclear spin coherences. The introduction of lipid bicelles as membrane mimicking systems has changed this scenario, and the more favorable relaxation properties of membrane protein (15)N and (13)C resonances make it possible to develop new, more elaborate pulse sequences for higher spectral resolution and sensitivity. Here, we describe our recent progress in the optimization of O-ssNMR pulse sequences. We explain the theory behind these experiments, demonstrate their application to small and medium size proteins, and describe the technical details for setting up these new experiments on the new generation of NMR spectrometers. PMID- 24160763 TI - Porous titania nanosheet/nanoparticle hybrids as photoanodes for dye-sensitized solar cells. AB - Porous titania nanohybrids (NHs) were successfully prepared by hybridizing the exfoliated titania nanosheets with anatase TiO2 nanoparticles. Various characterizations revealed that the titania NHs as photoanodes play a trifunctional role (light harvesting, dye adsorption, and electron transfer) in improving the efficiency (eta) of the dye-sensitized solar cells. The optimized photoanode consisting layered NHs demonstrated a high overall conversion efficiency of 10.1%, remarkably enhanced by 29.5% compared to that (7.8%) obtained from the benchmark P25 nanoparticles under the same testing conditions. PMID- 24160764 TI - Response to manuscript 'Is Opisthorchis viverrini an avian liver fluke?'. PMID- 24160765 TI - Degradation of 2,5-dihydroxy-1,4-benzoquinone by hydrogen peroxide under moderately alkaline conditions resembling pulp bleaching: a combined kinetic and computational study. AB - 2,5-Dihydroxy-1,4-benzoquinone (DHBQ) is one of the key chromophores occurring in all types of aged cellulosics. This study investigates the mechanism of H2O2 degradation of DHBQ under conditions relevant to pulp bleaching (3.0% H2O2, NaOH, pH 10), to obtain insights useful for improved pulp processing. DHBQ is degraded quantitatively into malonic acid with an activation energy (E(a)) of 16.1 kcal/mol and activation entropy (Delta(?)S degrees ) of ~28 cal/mol.K. Higher concentrations of sodium cations increase the reaction rate. Theoretical computations indicate the formation of an intermediate I(O) having an O-O bridge between C-2 and C-5 of the 1,4-cyclohexadione structure. I(O) undergoes O-O homolysis to form a biradical Bt, which is fragmented into malonate anions. The calculated E(a) (17.8 kcal/mol) agrees well with the experimental one. Coordination of Na(+) to I(O) and Bt decreases their energies and enhances the O O homolysis rate, which is consistent with the acceleration by sodium cation and the negative Delta(?)S degrees . The homolysis of I(O) is much favored over that of the neutral counterpart, with the unpaired electrons of Bt being stabilized by the geminal anionic oxygen. This difference in the stability of the intermediates translates into significant variations in the reaction rate and the product distribution between pH 10 and neutral/acidic conditions. PMID- 24160766 TI - The story of anybody, somebody, nobody and everybody. PMID- 24160767 TI - A new constant memory recursion for hidden Markov models. AB - We develop the recursion for hidden Markov (HM) models proposed by Bartolucci and Besag (2002), and we show how it may be used to implement an estimation algorithm for these models that requires an amount of memory not depending on the length of the observed series of data. This recursion allows us to obtain the conditional distribution of the latent state at every occasion, given the previous state and the observed data. With respect to the estimation algorithm based on the well known Baum-Welch recursions, which requires an amount of memory that increases with the sample size, the proposed algorithm also has the advantage of not requiring dummy renormalizations to avoid numerical problems. Moreover, it directly allows us to perform global decoding of the latent sequence of states, without the need of a Viterbi method and with a consistent reduction of the memory requirement with respect to the latter. The proposed approach is compared, in terms of computing time and memory requirement, with the algorithm based on the Baum-Welch recursions and with the so-called linear memory algorithm of Churbanov and Winters-Hilt. The comparison is also based on a series of simulations involving an HM model for continuous time-series data. PMID- 24160768 TI - A phenolic ester from Aglaia loheri leaves reveals cytotoxicity towards sensitive and multidrug-resistant cancer cells. AB - BACKGROUND: Bioactivity-guided fractionation of extracts of Aglaia loheri Blanco (Meliaceae) yielded a cytotoxic isolate, termed Maldi 531.2[M + H]+. This phenolic ester was further investigated for its in vitro cytotoxicity toward human CCRF-CEM leukemia cells and their multi-drug resistant (MDR) subline, CEM/ADR5000. The intrinsic mitochondrial membrane potential (DeltaPsim) and induction of apoptosis by this isolate were evaluated. METHODS: Chromatography techniques, mass spectrometry and proton NMR were employed to isolate Maldi 531.2[M + H]+. XTT cell proliferation and viability assay was used for cytotoxic test, and JC-1[5',5',6,6',-tetrachloro-1,1',3,3'-tetraethylbenzimidazoyl carbocyanine iodide was used to assess DeltaPsim and initiation of apoptosis; Annexin V/FITC-PI staining was employed to analyse apoptosis. RESULTS: Maldi 531.2[M + H]+ was cytotoxic towards both CCRF-CEM and CEM/ADR5000 cells with IC50 values of 0.02 and 0.03 MUM, respectively. The mitochondrial membrane potential (DeltaPsim) of MDR cells was significantly reduced in a dose-dependent manner leading to apoptosis as detected by flow cytometric Annexin V-FITC/ PI staining. CONCLUSION: Maldi 531.2[M + H]+ may be a potential anti-cancer drug candidate whose mode of action include reduction of the mitochondrial membrane potential and induction of apoptosis. PMID- 24160769 TI - Dose to organs at risk in the upper abdomen in patients treated with extended fields by helical tomotherapy: a dosimetric and clinical preliminary study. AB - BACKGROUND: The aim of this work was to determine the technical feasibility and safety of extended-field radiotherapy (EF), performed by Helical TomoTherapy, in patients with positive pelvic and/or para-aortic nodes. Dosimetric data were collected and acute and sub-acute toxicities of the upper abdominal organs at risk (OAR) were evaluated. METHODS: Twenty-nine patients suitable for EF irradiation for local disease and/or nodal disease in the pelvic or para-aortic area were treated. The prescription dose was 50.4/54 Gy (1.7-1.8 Gy/fraction) for prophylactic lymph nodes (N-) and 60-70.5 Gy (2-2.35 Gy/fraction) for clinically evident gross disease (N+). Modulation factor (MF), pitch and field width (FW) were chosen to optimize dose distribution and treatment duration. Dose values of PTVs and OAR were analysed. The length of the treatment field, the N + and N- volumes, and treatment duration were reported. To evaluate the safety of treatment, haematological, hepatic, renal and pancreatic functions were assessed before, during and after treatment. The median follow-up time was 17.6 months (range: 6-22 months). RESULTS: The treatment was well tolerated and all patients but one completed treatment without interruption. Four of the 29 patients experienced G3 haematological acute toxicity (13.8%), but no patient experienced sub-acute grade G3 toxicity. Ten patients experienced G1 and three G2 acute gastrointestinal toxicity (nausea). No sub-acute gastrointestinal or renal toxicity was observed. Only one (3.7%) patient had a persistent slight increase of pancreatic enzymes and two (7.4%) patients a slight increase of hepatic enzymes six months after radiotherapy (G1 toxicity). CONCLUSIONS: With our treatment design and dose regimen, we found that EF treatment by TomoTherapy could be safely and effectively delivered with minimal acute and sub-acute toxicities in the upper abdomen area. PMID- 24160770 TI - A multistage volumetric bar chart chip for visualized quantification of DNA. AB - Nucleic acid detection is critical in disease diagnosis as well as in the environmental assays of harmful bacteria or viruses and forensic applications. Current methods for visualized quantification of DNA require costly and sophisticated instruments. Here, we report a multistage propelled volumetric bar chart chip (MV-Chip) for multiplexing and quantitative detection of DNA. Because of its "rocket-like" propelling reaction, the predeposited platinum films could perform cascade amplification and detect as low as 20 pM DNA targets after three stages of platinum-catalyzed propulsion. The resulting ink bar charts can be directly read out by the naked eye, and the signal shows little interference from serum. Single-nucleotide polymorphism and multiplex DNA detection were carried out to demonstrate this powerful application. PMID- 24160771 TI - Triply resonant sum frequency spectroscopy: combining advantages of resonance Raman and 2D-IR. AB - This article describes the new multidimensional spectroscopy technique triply resonant sum frequency spectroscopy, a four-wave mixing technique sharing advantages of both 2D-IR and resonance Raman experiments. In this technique, lasers with three independent frequencies interact coherently within a sample and generate an output frequency at their triple summation. The output intensity depends on coupled electronic and vibrational resonances in the sample. We use an organic dye as a model system to demonstrate fully resonant, fully coherent multidimensional spectroscopy using two independently tunable mid-infrared vibrational interactions and one visible electronic interaction. When the pulses are time ordered, the method has a single coherence pathway, eliminating interference between pathways. Fundamental vibrational transitions appear on one axis and overtones and combinations bands on the other, allowing anharmonicities of the modes to be determined easily and conveying molecular coupling information. The experiments demonstrate coupling between seven vibrational ring modes and an electronic state, the resolution of a Fermi resonance, detection of low concentrations, elimination of excitation pulse scattering and fluorescence, background suppression of solvent and co-solutes, and observation of coherence dephasing dynamics. The electronic resonance enhancements used in this methodology are similar to the enhancements responsible for resonance Raman spectroscopy and can be considered resonance 2D-IR spectroscopy. PMID- 24160772 TI - Performance of Cockcroft-Gault, MDRD, and CKD-EPI in estimating prevalence of renal function and predicting survival in the oldest old. AB - BACKGROUND: The question for prevalence estimation and validation of the various eGFRs in old age is still under debate. To assess renal function with increasing age, we estimated mean eGFR, in subjects aged 20-85 years. Furthermore, we assessed prevalence of eGFR in a population-based sample of 85 year olds and investigated the performance of these eGFRs in predicting mortality in the oldest old. METHODS: Renal function with increasing age was assessed in subjects aged 20 85 years from the Bronovo Study Cohort. We estimated prevalences of eGFRs and mortality risks in a population-based study of persons aged 85 years and older, the Leiden 85-plus Study. The GFRs were estimated by three different formulas. RESULTS: After the age of 70 years, the C-G tended to give relatively lower eGFRs. An eGFR < 60 was found in 90% of the subjects aged 85 years as calculated by C-G, in 55% of the subjects using MDRD and in 68% of the 85 year old subjects as calculated by CKD-EPI. When renal function was <30 ml/min/1.73 m2, an increased mortality risk was observed by C-G (HR 1.9 (95% CI 1.1-3.3)), by MDRD (HR 3.5 (95% CI 1.8-6.7)), whereas by CKD-EPI significance was not reached (HR 2.4 (95% CI 0.9-6.4)). CONCLUSIONS: Our study demonstrates that in subjects above age 70, C-G gives lower estimates of renal function when compared to MDRD and CKD EPI. Furthermore, prevalence of renal dysfunction (CKD stage 1-3) at age 85 years was highest for C-G (90%), lowest for MDRD (55%), and 68% for CKD-EPI. Moreover, we found that in subjects aged 85 years MDRD predicted mortality best. PMID- 24160773 TI - The ability of retention, drug release and rheological properties of nanogel bioadhesives based on cellulose derivatives. AB - The rheological and drug release behavior of biopolymer nanocomposite gels based on the cellulose derivatives, formulated as the bioadhesive drug delivery platforms, were investigated. The bioadhesive gel is composed of the microcrystalline cellulose, sodium carboxymethyl cellulose and phosphate buffered saline (pH = 7.4 at 20 degrees C) as the dissolution and release medium. The reinforcing nanofillers such as MMT-clay, fumed porous silica and porous starch were used as additives in the nanogel bioadhesive. The constant steady state viscosities of this nanogels upon incorporation of various nanofillers into the systems is the sign of structural stability. Hence, this system is suitable for use in the controlled drug delivery systems in contact with the biological tissues. Based on the rheological measurements, the shear flow properties (i.e. zero shear viscosity and yield stress) were influenced by the concentration of polymers and nanoparticles. The results indicate that the nonlinear rheological data are fitted properly by the Giesekus model. Furthermore, the results showed that the nonlinear viscoelastic parameters (lambda and alpha) are highly affected by the biogel and nanoparticles concentrations. Finally, the drug release was measured, and the results indicated that the biopolymer-clay nanocomposites have appropriate release pattern as the release is better controlled compared to the other nanogel formulations. PMID- 24160774 TI - Postpartum anxiety and comorbid depression in a population-based sample of women. AB - BACKGROUND: Population-based estimates of prevalence of anxiety and comorbid depression are lacking. Therefore, we estimated the prevalence and risk factors for postpartum anxiety and comorbid depressive symptoms in a population-based sample of women. METHODS: Using multinomial logistic regression, we examined the prevalence and risk factors for postpartum anxiety and depressive symptoms using 2009-2010 data from the Illinois and Maryland Pregnancy Risk Assessment Monitoring System, a population-based survey of mothers who gave birth to live infants. Survey participants are asked validated screening questions on anxiety and depressive symptoms. RESULTS: Among 4451 postpartum women, 18.0% reported postpartum anxiety symptoms, of whom 35% reported postpartum depressive symptoms (6.3% overall). In the multivariable model, higher numbers of stressors during pregnancy (adjusted odds ratio [aOR] range: 1.3-9.7) and delivering an infant at <=27 weeks gestation (aOR range: 2.0-5.7) were associated with postpartum anxiety and postpartum depressive symptoms, experienced individually or together. Smoking throughout pregnancy was associated with postpartum anxiety symptoms only (aOR=2.3) and comorbid anxiety and depressive symptoms (aOR=2.9). CONCLUSIONS: Given the possible adverse effects of postpartum anxiety and comorbid depression on maternal health and infant development, clinicians should be aware of the substantial prevalence, comorbidity, and risk factors for both conditions and facilitate identification, referral, and/or treatment. PMID- 24160776 TI - Persistent organic pollutants and transthyretin-bound thyroxin in plasma of Inuit women of childbearing age. AB - The Inuit population of Nunavik (Northern Quebec, Canada) is highly exposed to persistent organic pollutants (POPs) through their traditional diet. Some POPs, i.e., hydroxylated metabolites of polychlorinated biphenyls (OH-PCBs), pentachlorophenol (PCP), and perfluorooctane sulfonate (PFOS), compete with thyroxin (T4) for binding sites on transthyretin (TTR), a T4 transport protein found in plasma and cerebrospinal fluid. We tested the hypothesis that these TTR binding compounds decrease circulating concentrations of T4 bound to TTR (T4-TTR) in Inuit women of reproductive age. We measured the concentration of T4-TTR in plasma samples obtained from 120 Inuit women (18-39 years old) by combining native-polyacrylamide gel electrophoresis and liquid chromatography-tandem mass spectrometry (LC-MS/MS) techniques. Total T4, TTR, and thyroxin-binding globulin (TBG) concentrations were also determined, while POPs levels had been previously measured. The mean T4-TTR concentration was 8.4 nmol/L (SD = 2.4) with values ranging from 2.9 to 14.4 nmol/L. Linear regression analysis revealed that TTR, TBG, and total T4 concentrations were significant predictors (p < 0.002) of T4 TTR levels (total adjusted R-squared = 0.26, p < 0.0001) but not levels of OH PCBs, chlorophenols, or PFOS. Our results suggest that circulating levels of these TTR-binding compounds in Inuit women of childbearing age are not high enough to affect TTR-mediated thyroid hormone transport. The possibility of increased delivery of these compounds to the developing brain requires further investigation. PMID- 24160775 TI - Serum retinol binding protein 4 is negatively related to beta cell function in Chinese women with non-alcoholic fatty liver disease: a cross-sectional study. AB - BACKGROUND: To observe the relationship between serum retinol binding protein 4(RBP4) and beta cell function in Chinese subjects with non-alcoholic fatty liver disease (NAFLD) and without known diabetes. METHODS: 106 patients diagnosed as fatty liver by ultrasonography (M/F: 61/45; aged 47.44 +/- 14.16 years) were enrolled in our current cross-sectional study. Subjects with known diabetes, chronic virus hepatitis and excessive alcohol consumption were excluded. Serum RBP4 was detected by ELISA and validated by quantitative Western blotting. beta cell function were assessed by HOMA in all subjects and by hyperglycemic clamp in 17 normal glucose tolerance subjects (M = 6, F = 11). RESULTS: The levels of serum RBP4 in men were higher than that in women (55.96 +/- 11.14 vs 45.87 +/- 10.31 MUg/ml, p < 0.001). Pearson's correlation analysis demonstrated that in women, serum RBP4 levels were significantly associated with fasting blood glucose (FBG), HOMA-beta, and increment of first phase insulin secretion (1PH), but not associated with age, BMI, waist circumference, WHR, systolic (SBP) and diastolic blood pressure (DBP), TC, TG, HDL-c, LDL-c, 2 h blood glucose, HOMA-IR, ALT, AST, gamma-GT, hepatic fat content (HFC), and insulin sensitivity index (ISI). However, in men, serum RBP4 levels were significantly associated with HDL-c, ALT, AST, but not associated with any other parameters as mentioned above. A stepwise multiple linear regression analysis demonstrated that in women, HOMA-IR and RBP4 were significantly associated with HOMA-beta, while in men, HOMA-IR and BMI were significantly variables associated with HOMA-beta. CONCLUSIONS: Serum RBP4, secreted mainly by liver and adipose tissue, may involve in the pathogenesis of beta cell dysfunction in Chinese women patients with NAFLD. PMID- 24160777 TI - Fluorescent artificial enzyme-linked immunoassay system based on Pd/C nanocatalyst and fluorescent chemodosimeter. AB - Artificial enzyme mimics have recently attracted considerable interest because they possess many advantages compared with natural enzymes, such as low cost of preparation and high stability. Herein, we present a novel fluorescent artificial enzyme-linked immunoassay strategy by utilizing Pd/C nanocatalyst as the enzyme mimic and bis-allyloxycarbonyl rhodamine 110 (BI-Rho 110) as the substrate, and the amplification procedure is based on the palladium-catalyzed Tsuji-Trost reaction. Pd/C nanocatalyst with the average size of 150 nm was prepared by the impregnation-reduction method, and high resolution transmission electron microscopy (HRTEM), X-ray diffraction (XRD), and X-ray photoelectron spectroscopy (XPS) analyses reveal that Pd clusters with an average size of about 1 nm are dispersed uniformly on each carbon nanosphere's surface. Kinetic studies show that this reaction follows Michaelis-Menten kinetics and the fluorescence intensity is proportional to the concentration of Pd/C nanocatalyst under certain conditions. The turnover number of Pd/C nanocatalyst reaches up to 3.3 * 10(7) (h(-1)). The analytical performance of this system in detecting hCG shows that after a 24 h incubation the sensitivity limit can reach 0.1 ng/mL and the dynamic linear working range is 1-10 ng/mL. Our findings pave the way to use Pd-catalyzed reaction for design and development of novel analytical methods. PMID- 24160778 TI - Non-pollen particulates in honey and sugar. AB - A total of 19 honey samples, mostly from Germany but also from France, Italy, Spain and Mexico, were analysed for non-pollen particulates. Only coloured fibres and fragments were quantified. Transparent fibres, considered to be cellulosic because they could be stained with fuchsin, were not quantified. Coloured material was found in all the samples investigated. Fibre counts ranged from 40/kg to 660/kg of honey, with a mean value of 166 +/- 147/kg of honey, whereas fragments were considerably less abundant (0-38/kg of honey; mean 9 +/- 9/kg of honey). Sources are tentatively identified as environmental, that is particles having been transported by the bees into the hive, or having been introduced during honey processing or both. In addition, five commercial sugars were analysed. In all the refined samples, transparent and coloured fibres (mean 217 +/- 123/kg of sugar) and fragments (32 +/- 7/kg of sugar) were found. Unrefined cane sugar had 560 fibres and 540 fragments per kilogram of honey. In addition, in both honey and sugar samples, granular non-pollen material was observed. PMID- 24160779 TI - Predictors of early postoperative outcomes in 375 consecutive hepatectomies: a single-institution experience. AB - Although the safety of hepatic resection has improved, it is still a highly morbid procedure. A retrospective cohort of 375 patients undergoing hepatectomy (2004 to 2012) was done. All procedures were performed by a single surgeon at a tertiary center. To help identify trends over time, two subgroups were identified: Group 1 (n = 195 from October 2004 to December 2010) and Group 2 (n = 180 from January 2011 to November 2012). The two study groups had similar patient characteristics except there were more patients with cirrhosis in Group 2 (10 vs 17%, P = 0.04). A similar number of major hepatectomies was noted. Median estimated blood loss was 400 mL versus 300 mL (P = 0.04) in Group 2. Overall complications were more common in Group 1 (54 vs 45%). Fewer Grade 3 or greater Clavien complications (22 vs 13%, P = 0.04) and fewer hospital readmissions were noted in Group 2 (20 vs 8%, P = 0.002). Morbidity was associated with worse Eastern Cooperative Oncology Group (ECOG) performance status, age older than 60 years, and open surgery. Grade 3 or greater Clavien complications were also associated with age older than 60 years, higher American Society of Anesthesiologists class, and worse ECOG status and median estimated blood less greater than 400 mL. Higher Model for End-stage Liver Disease score and advanced ECOG status were correlated with mortality. Outcomes of hepatic resection improved time despite more complex patient characteristics and an equal number of major hepatectomies being performed. However, worse ECOG performance status was a major predictor of postoperative complications and increased mortality. PMID- 24160780 TI - Minimally invasive resection of benign gastric tumors in challenging locations: prepyloric region or gastroesophageal junction. AB - Benign gastric tumors in a prepyloric location or within 3 cm adjacent of the gastroesophageal junction (GEJ) are often challenging to resect using minimally invasive surgical techniques. The aim of this study was to examine the outcomes of patients who underwent minimally invasive enucleation or resection of benign gastric tumors at these difficult locations. The charts of patients undergoing minimally invasive resection of benign-appearing submucosal gastric tumors between June 2001 and December 2012 were reviewed. Data on tumor size and location, type of minimally invasive surgical resection, perioperative complications, 90-day mortality, pathology, and recurrence were collected. A total of 70 consecutive patients underwent laparoscopic resection of benign appearing submucosal gastric tumors; there were 24 patients with lesions close to the GEJ and nine patients with lesions close to the prepyloric region. All lesions were successfully resected laparoscopically. For prepyloric tumors, surgical approaches included enucleation (n = 1), wedge resection (n = 2), and distal gastrectomy with reconstruction (n = 6). For tumors close to the GEJ, surgical approaches included enucleation (n = 16), wedge resection (n = 3), and esophagogastrectomy (n = 5). Complications in this series of 33 patients included late strictures requiring endoscopic dilation in three patients who underwent esophagogastrectomy. The 90-day mortality rate was zero. There were no recurrences over a mean follow-up of 15 months (range, 1 to 86 months). Minimally invasive enucleation or formal anatomic resection of submucosal tumors located adjacent to the GEJ or at the prepyloric region is safe and carries a low risk for tumor recurrence. Submucosal gastric lesions adjacent to the GEJ are amenable to laparoscopic enucleation or wedge resection unless they extend proximally into the esophagus. Prepyloric lesions often require formal anatomic resection with reconstruction. PMID- 24160781 TI - Acute care surgery in heart transplant recipients. AB - Orthotopic heart transplantation (OHT) is the optimal treatment for end-stage heart failure. We reviewed our institutional experience between 2008 and 2012 with acute care surgery (ACS) consultations and procedures within 1 year of OHT in recipients bridged to transplantation with medical therapy (MT, n = 169), including intravenous inotropes, and ventricular assist devices (VADs, n = 74). In total, 28 consultations were required in 21 patients (9%) and 16 procedures were performed in 11 patients (5%). The interval from transplantation to consultation was shorter for the MT group (50 vs 82 days; P = 0.015), whereas the interval from consultation to operation was longer (5 vs 1 day; P = 0.03). Patients undergoing MT were more likely to require consultation for abdominal problems (88 vs 27%; P = 0.004). All but one of the seven ischemic/inflammatory abdominal problems occurred in the MT group. Complications occurred after five ACS procedures (31%) in two patients undergoing MT and three patients undergoing VAD. Mortality was 24 per cent with five deaths occurring within 30 days of ACS consultation and/or operation. In summary, this is one of the largest series of ACS problems in patients undergoing OHT bridged to transplant with MT or VAD. With similar incidence in MT and VAD groups, ACS consultations and operations are infrequent with high mortality and morbidity. PMID- 24160782 TI - Postmastectomy reconstruction is associated with improved survival in patients with invasive breast cancer: a single-institution study. AB - Breast reconstruction after mastectomy positively affects psychosocial well being; however, the influence of reconstruction on cancer outcomes is unknown. The objective of our study was to compare survival in reconstructed versus nonreconstructed patients after mastectomy. All consecutive female patients diagnosed with invasive breast cancer and treated with mastectomy between 2002 and 2011 were identified from our single-institution database. All cancer operations were performed by two surgeons. Survival was calculated using the Kaplan-Meier method and compared using the log-rank test. To identify the effect of reconstruction on survival, a multivariate Cox regression analysis was performed. Of 474 patients treated, 340 (71.7%) underwent breast reconstruction. At a mean follow-up 3.3 years, reconstructed patients had a longer 5-year survival (91 vs 74%, P < 0.001). After controlling for age, race, payer source, cancer stage, triple negative status, and receipt of radiation or chemotherapy, reconstructed patients maintained a survival advantage over nonreconstructed patients (hazard ratio, 0.47; 95% confidence interval, 0.25 to 0.88; P = 0.02). Patients with breast cancer who undergo reconstruction have longer survival than nonreconstructed patients. The explanation for this finding may be related to improved psychosocial qualities of life versus possible antitumorigenic effects of implants. PMID- 24160783 TI - Emergency department thoracotomy: too little, too much, or too late. AB - Emergency department thoracotomy (EDT) is a dramatic lifesaving procedure demanding timely surgical intervention, technical expertise, and coordinated resuscitation efforts. Inappropriate use is costly and futile. All patients admitted to a Level II trauma center who underwent EDT from January 2003 to July 2012 were studied. The primary end point was appropriateness of EDT. Secondary end points were staff exposure, survival, and return to normal function. Eighty seven patients including 59 patients with penetrating wounds had a mean loss of vital signs (LOV) 11.6 +/-10.6 minutes and Injury Severity Score (ISS) of 45.8 +/ 16.1, whereas 28 blunt injury patients had a mean LOV of 10.4 +/- 11.5 minutes and ISS of 50.4 +/- 19.4. Mortality was 81 per cent (48 of 59) in penetrating injury and 93 per cent (26 of 28) in blunt injury patients, respectively (odds ratio [OR] 2.99; P 0.21). Fifty-five EDTs were indicated with 10 survivors (18.2%) and 32 not indicated with three survivors (9.4%). Surgeons adhered to guidelines more compared with ED physicians (OR, 4.9; P = 0.03) whose patients were more likely to die (OR, 3.52; P = 0.124). Survivors (11 of 13 [84.6%]) were discharged home without significant long-term neurologic disability. EDT is lifesaving when performed for penetrating injury by experienced surgeons following established guidelines but futile in blunt injury or when performed by nonsurgeons regardless of mechanism. PMID- 24160784 TI - Efficacy of contemporary medical management for asymptomatic carotid artery stenosis. AB - In the Asymptomatic Carotid Artery Stenosis trial (1995), medical management was defined as aspirin in addition to adequate control of comorbidities. Since then, medical management of asymptomatic carotid artery stenosis (CAS) has progressed to include broader use of statins. Our purpose was to review the effect of contemporary medical management on stroke prevention. A retrospective review of the Kaiser Permanente, Southern California medical group database was performed. All patients with a diagnosis of asymptomatic CAS by International Classification of Diseases, 9th Revision codes from 2007 to 2011 were identified. Intervention for stroke prevention was the criteria for exclusion. Medications used were evaluated as was the rate of stroke. Asymptomatic CAS was noted in 7255 patients. Of these, 158 (2.2%) sustained a stroke within a mean follow-up of 37 months. Patients who were taking a statin had a statistically significant lower risk of stroke (1.6 vs 3.9%). The data support that contemporary medical management of asymptomatic CAS has decreased the incidence of stroke in comparison to previously published data. The use of statins was protective against the development of stroke. Future prospective randomized trials are needed to evaluate the efficacy of carotid intervention versus current medical management. PMID- 24160785 TI - Outcome of abdominal wall hernia repair with PermacolTM biologic mesh. AB - The use of biologic mesh in abdominal wall operations has gained popularity despite a paucity of outcome data. We aimed to review the experience of a large healthcare organization with PermacolTM. A retrospective study was conducted of patients who underwent abdominal hernia repair with PermacolTM in 14 Southern California hospitals. One hundred ninety-five patients were analyzed over a 4 year period. Operations included ventral/incisional hernia repairs, ostomy closures, parastomal hernia repairs, and inguinal hernia repairs. In 50 per cent of the patients, PermacolTM was used to reinforce a primary fascial repair and in 50 per cent as a fascial bridge. The overall complication rate was 39.5 per cent. The complication rate was higher in patients with infected versus clean wounds, body mass index (BMI) 40 kg/m(2) or greater versus BMI less than 40 kg/m(2), in patients with prior mesh repair, and when mesh was used as a fascial bridge. With a mean follow-up of 2.1 years, morbid obesity was associated with a higher recurrence. To date this is the largest study on the use of PermacolTM in abdominal wall hernia repair. In our patient population undergoing heterogeneous operations with a majority of wounds as Class II or higher, use of PermacolTM did not eliminate wound morbidity or prevent recurrence, especially in morbidly obese patients. PMID- 24160786 TI - Exploring potential use of internet, E-mail, and instant text messaging to promote breast health and mammogram use among immigrant Hispanic women in Los Angeles County. AB - Breast cancer is now the leading cause of death in Hispanic women (HW). Internet, e-mail, and instant text messaging may be cost-effective in educating HW about breast health and in reducing breast cancer mortality. We surveyed 905 HW women attending a free health fair about their technology use, acculturation, insurance status, mammography use, and breast cancer knowledge. Data were analyzed by t test or chi(2) tests. Mean age was 51.9 +/- 14.2 years (range, 18 to 88 years). Ninety-two per cent were foreign-born. Most had completed some high school (39%) or elementary (38%) education. Most (62%) were uninsured. The majority spoke (67%) and read (66%) only Spanish. Only 60 per cent of HW older than 40 years had a recent mammogram. HW older than 40 years who had not had a recent mammogram were younger (mean 54.9 +/- 10.8 vs 58 +/- 10.4 years) and less likely to have health insurance (25 vs 44%; P < 0.001). Most HW never use the Internet (58%) or e-mail (64%). However, 70 per cent have mobile phones (66% older than 40 years), and 65 per cent use text messaging daily (58% older than 40 years, P = 0.001). In fact, 45 per cent wish to receive a mammogram reminder by text. Text messaging may be an inexpensive way to promote breast health and screening mammography use among uninsured HW. PMID- 24160787 TI - Seatbelt sign as an indication for four-vessel computed tomography angiogram of the neck to diagnose blunt carotid artery and other cervical vascular injuries. AB - Computed tomography angiography (CTA) of the neck has become the most common modality for diagnosing blunt carotid artery injury (BCAI). The protocol at our institution includes CTA on trauma patients with a seatbelt sign. The purpose of this study is to evaluate whether a solitary seatbelt sign is an indication for CTA of the neck to diagnose BCAI. We conducted a retrospective review of patients from 2000 to 2010 who received CTAs as a result of a seatbelt sign performed at our Level I trauma center. Four hundred eighteen patients received CTAs based on the presence of a seatbelt sign. Two hundred twenty-six had skeletal injuries, obvious soft tissue injuries, and/or positive findings on imaging, including 11 positive vascular findings with two BCAIs found. Patients with noncarotid vascular injuries on CTA had a higher Injury Severity Score than patients with solitary seatbelt signs (11.4 +/- 7.6 vs 3.4 +/- 4.2, P < 0.01). The correlation between seatbelt sign and positive finding on CTA was weak (r = 0.007). Patients with vascular findings on CTA also had obvious hard/soft tissue injuries and/or positive findings on standard trauma imaging. This suggests that a protocol for CTA of the neck for patients with a seatbelt sign can be reserved for those with associated injuries on physical examination and/or findings on standard trauma imaging. PMID- 24160788 TI - Polyp on ultrasound: now what? The association between gallbladder polyps and cancer. AB - The association between gallbladder polyps (GBP) and gallbladder cancer (GBC) is unclear. We sought to determine the association between preoperative diagnosis of GBP on imaging and GBC. A retrospective review of patients over 9 years was conducted using International Classification of Diseases, 9th Revision codes for GBP and GBC who underwent cholecystectomy at our institution. Demographics, imaging findings, and pathology results were recorded. A total of 2416 patients underwent cholecystectomy during the study period. Twenty-seven had an operation for GBP either as a result of concern for size or symptoms. Polyp sizes were categorized as less than 1 cm, 1 to 2 cm, or 2 cm or greater. Twenty-four patients in this group (88.9%) had no evidence of high-grade dysplasia or cancer and all of these benign polyps were 2 cm or less on imaging. One patient with a 2.4-cm polyp had high-grade dysplasia, and two patients with polyps over 3 cm had adenocarcinoma. During the same period, 20 patients had an operation for GBC with two patients common to the polyp group. The group of patients with noncancerous polyps was significantly younger than the cancer group (polyps and no polyps). The cancer group was more likely to be symptomatic. Therefore, polyps over 2 cm should be removed given the risk of high-grade dysplasia and cancer above this size. Polyps less than 2 cm were not associated with high-grade dysplasia or cancer and thus surgery may not be required. Intermediate- and small-sized polyps can be monitored with serial ultrasound, especially in younger, asymptomatic patients in whom the risk of malignancy is low. PMID- 24160789 TI - Paget's disease of the nipple with parenchymal ductal carcinoma in situ is associated with worse prognosis than Paget's disease alone. AB - Paget's disease of the nipple is often found in conjunction with underlying ductal carcinoma in situ (DCIS). In isolation, Paget's disease of the nipple, like DCIS, confers an excellent prognosis for survival. Our objective was to determine if Paget's disease identified with synchronous parenchymal DCIS has as favorable an outcome as Paget's disease alone. We analyzed a prospectively maintained pathology database and medical records to identify all patients diagnosed with Paget's disease of the nipple between June 1996 and December 2011. Overall survival was analyzed using Kaplan-Maier statistics and Cox proportional hazards modeling. Seventy-four patients were identified with Paget's disease: five (6%) with isolated Paget's of the nipple, 22 (30%) associated with parenchymal DCIS, and 47 (64%) associated with invasive cancer (+/- DCIS). Unexpectedly, patients with Paget's disease and DCIS had a worse prognosis than those with Paget's disease alone. Survival correlated with pathologic stage at diagnosis. Among the 16 deaths, median survival was 2.8 years (range, 0.1 to 15.2 years). Median follow-up for the entire cohort was 4.2 years (range, 0.1 to 15.2 years). Thus, Paget's disease with parenchymal DCIS may confer worse survival than isolated Paget's disease of the nipple, suggesting the difficulty of identifying invasive carcinoma within a background of DCIS. PMID- 24160790 TI - Can the need for colectomy after computed tomography-guided percutaneous drainage for diverticular abscess be predicted? AB - The primary aim of this study was to define predictors of computed tomography (CT)-guided percutaneous abscess drainage treatment failure in complicated diverticulitis. A 10-year retrospective analysis of inpatients seen in surgical consultation for diverticular abscess management subsequently referred for CT guided percutaneous drainage (PD) was conducted. The clinical courses of patients undergoing a technically successful PD were categorized into three groups: 1) no colectomy; 2) elective colectomy; and 3) nonelective colectomy. Forty study patients were identified. Thirteen (33%) of the 40 patients required a nonelective colectomy, 20 patients (50%) underwent elective resection, and seven patients (18%) have been managed nonoperatively with no recurrent diverticulitis for a median of 46.8 months (range, 3.2 to 84.3 months). Forward logistic regression identified the presence of immunosuppression or renal insufficiency (creatinine 1.5 mg/dL or greater) as factors independently associated with failure of PD and need for nonelective colectomy. No clinical, laboratory, or radiologic variables were predictive of long-term nonoperative success. Although PD allows for the resolution of intra-abdominal sepsis for most cases of diverticulitis complicated by an abscess, a substantial proportion progress to nonelective colectomy, emphasizing the need for clinical vigilance in follow-up. PMID- 24160791 TI - Initial outcomes of laparoscopic paraesophageal hiatal hernia repair with mesh. AB - The use of mesh in laparoscopic paraesophageal hiatal hernia repair (LHR) may reduce the risk of late hernia recurrence. The aim of this study was to evaluate initial outcomes and recurrence rate of 92 patients who underwent LHR reinforced with a synthetic bioabsorbable mesh. Surgical approaches included LHR and Nissen fundoplication (n = 64), LHR without fundoplication (n = 10), reoperative LHR (n = 9), LHR with a bariatric operation (n = 6), and emergent LHR (n = 3). The mean length of hospital stay was 2 +/- 3 days (range, 1 to 30 days). There were no conversions to open laparotomy and no intraoperative complications. One of 92 patients (1.1%) required intensive care unit stay. The 90-day mortality was zero. Minor complications occurred in 3.3 per cent, major complications in 2.2 per cent, and late complications in 5.5 per cent of patients. There were no perforations or early hernia recurrence. The 30-day reoperation rate was 1.1 per cent. For patients with available 1-year follow-up, the overall recurrence rate was 18.5 per cent with a mean follow-up of 30 months (range, 12 to 51 months). LHR repair with mesh is associated with low perioperative morbidity and no mortality. The use of bioabsorbable mesh appears to be safe with no early hiatal hernia recurrence or late mesh erosion. Longer follow-up is needed to determine the long-term rate of hernia recurrence associated with LHR with mesh. PMID- 24160792 TI - The unequal distribution of parathyroid neoplasms in male patients. AB - There is a known lesser incidence of primary hyperparathyroidism and parathyroid neoplasms in male patients. Any difference in the anatomic distribution between males and females has not been documented. Review of our institutional experience with 125 pathologically confirmed parathyroid adenomas (119) or carcinomas (six) from 2000 through 2012 was conducted. The anatomic location was identified from operative records and the distributions between males and females were compared. Ninety-two females with parathyroid neoplasms had equal anatomic distributions between left and right sides and no significant difference between superior and inferior locations (P = 0.381). In marked contrast, tumors in 33 male patients had a significant predilection for the right side (67%, P = 0.016) and inferior position (85%, P = 0.033) and most notably the right inferior position (64%, P = 0.026). For the group as a whole, inferior adenomas were significantly more common (70%, P = 0.044). All patients had postoperative normalization of serum calcium levels. Late biochemical recurrence was noted in two patients. This is the first operatively confirmed delineation of the anatomic distributions of parathyroid neoplasms in separate sexes. Based on the unexpected findings of this study, we recommend the right inferior cervical region be explored first in males with suspected parathyroid tumors of indeterminate location. PMID- 24160793 TI - Colorectal surgery in kidney transplant recipients: a decade of trends and outcomes in the United States. AB - There is paucity of data evaluating the trends and outcomes of colorectal surgery (CRS) in kidney transplant recipients (KTRs). Using the Nationwide Inpatient Sample 2001 to 2010, a retrospective review of CRS performed in KTRs was performed. Trends, demographics, indications, and outcomes were examined for elective and emergent cases and compared with the general population (GP) on multivariate logistic regression. A total of 2616 KTRs underwent CRS, 50 per cent of which were done emergently. KTRs developed colon and rectal cancer at a younger age and had significantly higher incidence of comorbidities compared with the GP. Diverticular disease was the most common indication for surgery (48%) followed by cancer (30.6%). Compared with the GP, KTRs had higher rates of mortality (6.29 vs 3.64%), wound complications (8.02 vs 5.37%), and acute renal failure (ARF) (17.14 vs 7.10%) (all P < 0.05). No difference was seen in the incidence of anastomotic leak. On multivariate analysis, KTRs had higher associated odds of ARF (odds ratio, 2.02; P < 0.001), whereas the odds of mortality, wound, and anastomotic complications were similar to the GP. Emergency surgery in KTRs was associated with worse outcomes compared with the elective setting. KTRs undergoing CRS have unique characteristics that are different than the GP. They are at an increased risk of complications, especially acute renal failure. PMID- 24160794 TI - Morbidity of diverting ileostomy for rectal cancer: analysis of the American College of Surgeons National Surgical Quality Improvement Program. AB - There is controversy regarding the potential benefits of diverting ileostomy after low anterior resection (LAR). This study aims to examine the morbidity associated with diverting ileostomy in rectal cancer. A retrospective review of LAR cases was performed using the American College of Surgeons National Surgical Quality Improvement Program (2005 to 2011). Patients who underwent LAR with and without diversion were selected. Demographics, intraoperative events, and postoperative complications were reviewed. Among the 6337 cases sampled, 991 (16%) received a diverting ileostomy. Patients who were diverted were younger (60 vs 63 years), predominantly male (64 vs 53%), and more likely to have received pre-operative radiation (39 vs 12%). There was no significant difference in steroid use, weight loss, or intraoperative transfusion. Postoperatively, there was no significant difference in length of stay, rate of septic complications, wound infections, and mortality. The rate of reoperation was lower in the diverted group (4.5 vs 6.9%). Diversion was associated with a higher risk adjusted rate of acute renal failure (OR 2.4; 95% CI (1.2, 4.6); P < 0.05). The use of diverting ileostomy reduces the rate of reoperation but is associated with an increased risk of acute renal insufficiency. These findings emphasize the need for refinement of patient selection and close follow-up to limit morbidity. PMID- 24160795 TI - Introspection into institutional database allows for focused quality improvement plan in cardiac surgery: example for a new global healthcare system. AB - Reducing readmission rates is vital to improving quality of care and reducing healthcare costs. In accordance with the Patient Protection and Affordable Care Act, Medicare will cut payments to hospitals with high 30-day readmission rates. We retrospectively reviewed an institutional database to identify risk factors predisposing adult cardiac surgery patients to rehospitalization within 30 days of discharge. Of 2302 adult cardiac surgery patients within the study period from 2008 to 2011, a total of 218 patients (9.5%) were readmitted within 30 days. Factors found to be significant predictors of readmission were nonwhite race (P = 0.003), government health insurance (P = 0.02), ejection fraction less than 40 per cent (P = 0.001), chronic lung disease (P < 0.001), and hospital length of stay greater than 7 days (P = 0.02). Patients undergoing aortic and mitral valve operations had an increased risk of readmission compared with other cardiac operations (P < 0.001). The most common reasons for rehospitalization were pneumonia and other respiratory complications (n = 27 [12.4%]). Recognition of risk factors is crucial to reducing readmissions and improving patient care. Our data suggest that optimizing cardiopulmonary status in patients with comorbidities such as heart failure and chronic obstructive pulmonary disease, increasing directed pneumonia prophylaxis, patient education tailored to specific patient social needs, earlier patient follow-up, and better communication between inpatient and outpatient physicians may reduce readmission rates. PMID- 24160796 TI - Validation of revised American Joint Committee on Cancer staging for gallbladder cancer based on a single institution experience. AB - Gallbladder cancer is a rare malignancy, which often goes undiagnosed until advanced stages of disease and is associated with poor prognosis. The only potentially curative treatment is surgical resection. This retrospective study aims to investigate the validity of the revised 7th edition American Joint Committee on Cancer staging criteria and determine prognostic factors. Forty-two patients with confirmed gallbladder cancer who underwent attempted curative resection from 1999 to 2012 at the University of California, Irvine Medical Center were reviewed. Survival probability was determined using the Kaplan-Meier method. Ten patients underwent laparoscopy, were deemed unresectable, and no further surgical intervention was performed. R0 surgical resection, which included radical portal lymphadenectomy, liver segment IVb/V resection, with or without bile duct resection, was performed in the remaining 32 patients. N2 nodes were resected if positive on frozen section. Overall survival probability for Stage I to II patients was 100 per cent. Overall survival probability for Stage III patients was 80 per cent (95% confidence interval [CI], 61 to 99%) and 39.3 per cent (95% CI, 28 to 78%) for Stage IV patients. This study demonstrates that 7th edition clinical stage, T stage, and liver involvement are statistically significant predictors of prognosis. These data also demonstrate a benefit to extended resection in patients even with Stage III and IV disease. PMID- 24160797 TI - Evaluation of heparin prophylaxis protocol on deep venous thrombosis and pulmonary embolism in traumatic brain injury. AB - There is currently no accepted standard for deep venous thrombosis (DVT) and pulmonary embolism (PE) prophylaxis in patients with traumatic brain injury (TBI). The objective of our study was to evaluate the effects of implementing a subcutaneous heparin prophylaxis protocol for patients with TBI that began in our hospital as of June 2009. In our retrospective cohort study, we examined 3812 TBI records between January 2007 and December 2011. A significant reduction in the risk of DVT/PE development was not demonstrated by comparing DVT and PE incidences before and after protocol implementation. A clear trend between heparin use and DVT occurrence could not be determined from a review of TBI records after June 2009. The use of heparin after initiation of our protocol among operative TBI cases without intracranial hemorrhage (ICH) based on admission head computed tomography was 58 per cent. ICH complication from heparin prophylaxis was 10.6 per cent for patients with TBI with ICH on admission (five of 47 cases) compared with 0.7 per cent for those without ICH on admission (four of 535 cases). PMID- 24160798 TI - Choledochoduodenostomy as the biliary-enteric bypass of choice for benign and malignant distal common bile duct strictures. AB - Choledochoduodenostomy (including hepaticoduodenostomy) for common bile duct (CBD) strictures has been underused because of concerns regarding postoperative duodenal fistula and cholangitis attending the so-called "sump syndrome." An institutional retrospective review of 55 consecutive choledochoduodenostomy procedures for CBD strictures from 1995 to 2011 was performed to examine its suitability as the biliary-enteric bypass procedure of choice. There were 30 male (55%) and 25 female (45%) patients with a mean age of 49 years (range, 13 to 73 years). Thirty-seven (67%) patients had benign CBD strictures and 18 (33%) had unresectable periampullary adenocarcinomas. Forty-nine (89%) underwent choledochoduodenostomy and six (11%) underwent hepaticoduodenostomy. There were no 30-day postoperative deaths, anastomotic leaks, or intra-abdominal abscesses. Five patients (9%) sustained Clavien Grade III or IV complications. Over a mean long-term follow-up of 29 months (range, 1 to 162 months), there was one anastomotic stricture successfully managed by endoscopic dilation and temporary stenting. Liver function tests in all other patients returned to and remained within normal limits. We conclude that choledochoduodenostomy is the preferred biliary-enteric bypass for both benign and malignant distal CBD strictures because of its ease, safety, and durability. Persistent fears of duodenal fistula and the "sump syndrome" are not warranted by the empiric data and should be abandoned. PMID- 24160799 TI - Predictive risk factors of early postoperative enteric fistula in colon and rectal surgery. AB - Early postoperative enteric fistula (PEF) is a complication associated with a high rate of morbidity and mortality in colon and rectal surgery. We evaluated the effect of patient characteristics, comorbidities, pathology, resection type, surgical technique, lysis of adhesions, and admission type on the rate of PEF in colorectal surgery. Using the National Inpatient Sample database, we examined the clinical data of patients who underwent colon and rectal resection from 2009 to 2010. A total of 646,414 patients underwent colorectal resection during this period. Overall, the rate of PEF was 0.37 per cent (2407 patients). Using multivariate regression analysis, Crohn's disease (adjusted odds ratio [AOR], 4.68), lysis of abdominal adhesions (AOR, 4.25), open procedure (AOR, 3.18), and transverse colectomy (AOR, 2.13) significantly impacted the risk of PEF. Although teaching hospitals (AOR, 1.69), obesity (AOR, 1.40), male gender (AOR, 1.30), emergent surgery (AOR, 1.27), age older than 65 years (AOR, 1.24), and diabetes mellitus (AOR, 1.21) also had statistically significant impact on rates of PEF, these were less clinically significant than the other factors. The presence of Crohn's disease and lysis of abdominal adhesions are strongly associated with the development of PEF after colorectal surgery. Laparoscopic surgery was associated with a lower rate of PEF; further studies would be needed to evaluate the importance of this finding. PMID- 24160800 TI - Outcomes of vascular resection in pancreaticoduodenectomy: single-surgeon experience. AB - Extension of pancreatic adenocarcinoma into adjacent vasculature often necessitates resection of the portal vein (PV) and/or superior mesenteric vein (SMV) during pancreaticoduodenectomy (PD). The vein is reconstructed primarily by end-to-end anastomosis of vein remnants or venoplasty or by use of autologous or synthetic vein grafts. The objective of this study was to review outcomes in patients undergoing PD for pancreatic adenocarcinoma, specifically comparing the short- and long-term outcomes between the patients undergoing vascular resection and those undergoing standard PD. All patients undergoing PD for pancreatic adenocarcinoma by a single surgeon between 2007 and 2012 were reviewed. Of the 61 patients identified, 18 patients underwent vascular resection of the PV (four patients), SMV (10 patients), or both (four patients). The remaining 43 patients had standard PD. Demographic, perioperative, pathological, and long-term outcomes data were collected and both vascular and standard groups were compared. Both groups had similar demographics. The vascular group had significantly longer operative times (529 vs 406 minutes; P < 0.01) with a trend to greater estimated blood loss (0.64 vs 0.53 L; P = 0.06). Pathological analysis showed no difference between the two groups with regard to lymph node status/ratio and rate of R0 resection (94 vs 91%; P = 0.57); however, the size of the tumor was significantly greater in the vascular group (4.2 vs 3 cm; P < 0.01). Short-term outcomes were similar in the vascular group and standard group, respectively, with no difference in pancreatic fistula rate (6 vs 7%; P = 1.0), transfusion rate (44 vs 35%; P = 0.57), and median length of stay (8 vs 7 days; P = 0.10), and there was no 30-day mortality in either group. Based on Kaplan-Meier methods, the median recurrence-free survival was 18 versus 23 months (P = 0.37) in the vascular and standard groups, respectively, and the overall survival was almost identical in both groups, each with a median of 31 months (P = 0.91). In our experience, mesenteric and PV resection during PD was performed safely and without compromise of short- or longer-term outcomes. It can be performed safely and patients have no significant difference in perioperative outcomes or overall survival. PMID- 24160801 TI - Incidence and survival patterns of rare anal canal neoplasms using the surveillance epidemiology and end results registry. AB - Small cell, neuroendocrine tumors, and melanoma of the anus are rare. Limited data exist on the incidence and management for these rare tumors. A large, prospective, population-based database was used to determine incidence and survival patterns of rare anal neoplasms. The Surveillance, Epidemiology and End Results registry was queried to identify patients diagnosed with anal canal neoplasms. Incidence and survival patterns were evaluated with respect to age, sex, race, histology, stage, and therapy. We identified 7078 cases of anal canal neoplasms: melanoma (n = 149), neuroendocrine (n = 61), and small cell neuroendocrine (n = 26). Squamous cell carcinoma (SCC) (n = 6842) served as the comparison group. Anal melanoma (AM) demonstrated the lowest survival rate at 2.5 per cent. Neuroendocrine tumors (NETs) demonstrated similar survival as SCC (10 year survival for regional disease of 25 and 22.3%, respectively). Ten-year survival of small cell NETs resembled AM (5.3 vs 2.5%). Age 60 years or older, sex, black race, stage, and surgery were independent predictors of survival. This study presents the largest patient series of rare anal neoplasms. NETs of the anal canal demonstrate similar survival patterns to SCC, whereas small cell NETs more closely resemble AM. Accurate histologic diagnosis is vital to determine treatment and surgical management because survival patterns can differ among rare anal neoplasms. PMID- 24160802 TI - Early adoption of robotic pulmonary lobectomy: feasibility and initial outcomes. AB - Despite the published benefits of minimally invasive video-assisted thoracoscopic surgery (VATS) for lobectomy, the majority of lobectomies in the United States continue to be performed through a thoracotomy. The low adoption rate of VATS has been attributed to its technical challenges and ergonomic inefficiencies. Robotic surgery has been proposed as an alternative minimally invasive technique that allows the replication of open lobectomy with wristed instruments and three dimensional vision. Our aim was to analyze the transition from open to robotic lobectomy at our hospital where there had been no significant VATS lobectomy experience. We analyzed 88 open and 43 robotic lobectomies that met criteria for inclusion. Operative times were significantly longer with the robotic group but decreased with experience. The resection time of the latter half of the robotic cases decreased to within 20 minutes of the open cases. There were no conversions in the robotic cases to either VATS or open. Robotic lobectomy was associated with faster postoperative recovery with a 60 per cent decrease in length of stay. Complications were uncommon and there were no deaths in the robotic group. We conclude that the transition from open to robotic lobectomy can be achieved safely with excellent postoperative outcomes. This new technique is a viable alternative to VATS lobectomy. PMID- 24160804 TI - The association between high-risk behavior and central nervous system injuries: analysis of traffic-related fatalities in a large coroner's series. AB - High-risk behaviors leading to traffic fatalities are often a result of severe traumatic brain and spine injuries. The objective of the study was to analyze patterns of behavior in drivers and motorcyclists that are associated with central nervous system (CNS)-related prehospital deaths that may serve as a basis for future prevention initiatives. Our study group comprised 514 fatalities with severe CNS injuries documented at autopsy. The majority (n = 491) was the result of motor vehicle collisions (MVCs). In this group, male drivers predominated and the majority, 80 per cent, wore seatbelts. Toxicology analysis revealed 53 per cent of drivers with a mean concentration of ethanol above the legal limit. Texting while driving comprised 45 per cent of the study group. Less than 5 per cent of the fatalities were the result of road or weather conditions. In the motorcycle group (n = 23), 100 per cent of the victims were unhelmeted. We report a large autopsy series of CNS-related deaths with analysis of behavioral factors associated with the fatalities. Substance abuse and distracted driving are dominant patterns of high-risk behavior in MVCs and not wearing a motorcycle helmet is deadly for victims of motorcycle crashes. PMID- 24160803 TI - Timing of redebridement after initial source control impacts survival in necrotizing soft tissue infection. AB - Necrotizing soft tissue infections (NSTIs) are associated with a high mortality rate. There is a lack of literature examining outcomes in NSTI when surgical redebridements are performed in early versus delayed intervals. We hypothesized that early redebridement is associated with improved survival. Patients with NSTIs were prospectively enrolled between January 2006 and December 2011. Patient demographics, comorbidities, primary infection site, laboratory values, tissue cultures, time to surgery, and time between subsequent debridements were obtained. Two study groups with divergent redebridement protocols were observed: a short interval redebridement (SIRD) and an extended interval redebridement (EIRD). Univariate and multivariate statistics were performed. The primary outcome evaluated was in-hospital mortality. Sixty-four patients (46 SIRD, 18 EIRD) were included in the analysis. The two groups had comparable demographics. Polymicrobial NSTI was noted in 61 per cent of patients with Staphylococcus species being the predominant causative organism (59%). Multivariate analysis showed the EIRD protocol to be associated with a significantly increased incidence of acute kidney injury (adjusted odds ratio, 4.9 [1.1 to 22.5]; P = 0.04) and worse overall survival (hazard ratio, 10.6 [2.1 to 53.9]; P = 0.004). Delayed redebridement after initial source control in NSTIs results in worse survival and an increased incidence of acute kidney injury. Further studies to identify the optimal time interval for redebridement are warranted. PMID- 24160805 TI - Computed tomography blush and splenic injury: does it always require angioembolization? AB - The implication of splenic contrast blush on computed tomography (CT) in blunt trauma patients and whether it is an indication for angioembolization (AE) remains controversial. Our objective was to determine whether CT blush and its subsequent treatment have any impact on outcomes in blunt trauma patients with low-grade splenic injuries. A retrospective review identified adult patients with splenic injury (American Association for the Surgery of Trauma grades 1 to 3) from blunt abdominal trauma who were evaluated with a CT scan over a 3.5-year period at a Level I trauma center. Patient groups analyzed included: observation patients with no CT blush (n = 110), observation patients with CT blush (n = 18), and AE patients with CT blush (n = 22). Patients with CT blush who were observed did not demonstrate significantly worse outcomes compared with the patients with no CT blush. Additionally, patients with CT blush who underwent AE did not show any significant improvement in outcomes compared with patients who were observed with CT blush. Our study suggests that CT blush does not predict worse outcomes for blunt trauma patients with low-grade splenic injury who underwent observation. Furthermore, AE does not seem to provide any advantage to this subset of patients. PMID- 24160806 TI - Acute hemodilution is safe in patients with comorbid illness undergoing partial hepatectomy. AB - Despite increased use of acute hemodilution (AH) to reduce perioperative blood transfusion in patients undergoing partial hepatectomy, there is a lack of data on safety in those with comorbid medical illness. We performed a retrospective review of 96 patients undergoing partial hepatectomy with AH and low central venous pressure (CVP) anesthesia. The cohort was compared with 63 patients undergoing partial hepatectomy using standard anesthetic management (SA) and low CVP anesthesia. All were American Society of Anesthesiologists physical status 3 or 4. 58 per cent were baseline hypertensive on medication. Hepatic resection was predominantly performed for metastatic colorectal (41%) and primary hepatic (32%) cancer. Forty per cent underwent major hepatectomy. The mean volume of blood removed for AH was 497 mL (range, 0 to 1 L). Most achieved low CVP (AH 90% vs SA 84%, P = 0.3). Blood loss was lower with AH (mean 480 mL vs 904 mL, P < 0.001). Blood transfusion rate was 74 per cent lower with AH (P < 0.001). There was no difference in cardiac, respiratory, renal, or overall complications with AH compared with SA. Acute hemodilution is well tolerated by patients with comorbid illness undergoing partial hepatectomy, favoring ongoing use and further study. PMID- 24160807 TI - A unique use of intraoperative digital specimen radiography in the treatment of primary hyperparathyroidism. AB - Intraoperative evaluation of primary parathyroid specimens historically has been difficult. Frozen section diagnosis is not reliable and time-consuming. A visible rim of compressed normal parathyroid tissue is seen histologically surrounding a parathyroid adenoma and absent in parathyroid hyperplasia. Adjuncts such as radionuclide scanning and intraoperative parathyroid hormone levels help but are indirect methods of evaluation. Intraoperative digital specimen radiography (IDSR) of specimens is a novel technique that was compared with frozen section analysis. The study spanned a 12-month period. Thirty-six patients with primary hyperparathyroidism met eligibility criteria. Resected parathyroid specimens were evaluated with the Bioptics PiXarray100 digital radiograph system and pathologic evaluation. Thirty-nine specimens were evaluated with IDSR, reflecting three patients with multiple glands excised. Thirty patients were pathologically found to have adenomas (83%) and six were hyperplasia (17%). Twenty-seven of 30 adenoma specimens had an IDSR visible rim of compressed tissue (sensitivity 90%) and no hyperplasia specimens had an IDSR visible rim (specificity 100%). Fisher's exact test was significant (P = 0.000). Frozen section correctly diagnosed adenoma in only 16 of 30 specimens (sensitivity 53%). IDSR of parathyroid specimens is a powerful modality in the real-time differentiation of parathyroid adenomas from hyperplasia (sensitivity 90%). This technique is noninferior to the current "gold standard," frozen section (sensitivity 53%). We propose IDSR evaluation of all parathyroid surgical specimens for the immediate diagnosis of adenoma versus hyperplasia. PMID- 24160808 TI - Predictors of mortality and limb loss in necrotizing soft tissue infections. AB - Necrotizing soft tissue infections (NSTIs) require prompt diagnosis and treatment. Early identification of patients at greatest risk of limb amputation and death may help in targeting aggressive medical and surgical management. The aim of this study was to assess predictors of limb loss and mortality in patients with NSTI based on admission variables. We performed a retrospective review of two hospitals that care for a large volume of patients with NSTI. Univariate and multivariable analyses were used to determine the association of admission biochemical markers to limb loss and mortality. Of 174 patients with NSTI, there were 19 deaths (10.9%) and 42 required amputations (24.1%). Multivariable logistic regression analysis revealed that only arterial lactate was predictive for both mortality (odds ratio [OR], 1.5; 95% confidence interval [CI], 1.1 to 2.0; P = 0.009) and limb loss (OR, 1.3; 95% CI, 1.0 to 1.7; P = 0.02). In patients with a suspected NSTI, an arterial lactate should be ordered early on to guide aggressive therapeutic interventions and to provide information with regard to long-term outcomes of amputation and death that is needed for early discussion with the patient and family. PMID- 24160809 TI - Oversedation in postoperative patients requiring ventilator support greater than 48 hours: a 4-year National Surgical Quality Improvement Program-driven project. AB - Prolonged mechanical ventilation of postoperative patients can contribute to an increase in morbidity. Every effort should be made to wean patients from the ventilator after surgery. Oversedation may prevent successful extubation. Cases identified by the National Surgical Quality Improvement Program (NSQIP) for Huntington Hospital were reviewed. Oversedation, days on the ventilator, type and duration of sedation, and cost were studied. Data were collected from the NSQIP database and patient charts. Oversedation was determined by the Richmond Agitation Sedation Score (RASS) of each patient. The hospital pharmacy provided data on propofol. Forty-three (35%) patients were oversedated. Propofol was used in 111 (90%) cases with an average use of 4.8 days. Propofol was used greater than 48 hours in 77 (62%) cases. After identifying inconsistent nurse documentation of sedation, corrective actions helped decrease oversedation, average number of days on the ventilator, number of days on propofol, hospital expenditure on propofol, and number of patients on the ventilator greater than 48 hours. Oversedation contributed to prolonged mechanical ventilation. Standardization of RASS and physician sedation order sheets contributed to improving our NSQIP rating. Sedation use decreased and fewer patients spent less time on the ventilator. NSQIP is an effective tool to identify issues with quality in surgical patients. PMID- 24160810 TI - When it is not a Spigelian hernia: abdominal cutaneous nerve entrapment syndrome. AB - Abdominal wall pain at the linea semilunaris is classically the result of a Spigelian hernia. If no hernia is detected, these patients may be left with chronic pain without a diagnosis or treatment. A retrospective review was performed of patients presenting with abdominal wall pain at the linea semilunaris between 2009 and 2012. Of the 14 patients, three (21%) were diagnosed with a Spigelian hernia confirmed by imaging. The remaining patients were eventually diagnosed with abdominal cutaneous nerve entrapment syndrome (ACNES). The average delay in diagnosis was 4 years with patients with ACNES suffering twice as long with chronic pain. Patients with a Spigelian hernia and ACNES had different demographics and presenting complaints. Physical examination findings were nondiagnostic. Of the patients with ACNES, five (50%) had resolution of pain with serial nerve blocks alone; another five proceeded to surgical neurectomy with resolution of their pain. Thus, to prevent delay in diagnosis and treatment, patients with chronic abdominal wall pain at the linea semilunaris should first be ruled out for Spigelian hernia. Then, they should be evaluated and treated for ACNES. PMID- 24160811 TI - Surgical management of advanced adrenocortical carcinoma: a 21-year population based analysis. AB - Adrenocortical carcinoma (ACC) is a rare endocrine malignancy with a dismal prognosis. When diagnosed in advanced stages of the disease, the outcomes of surgical resection are not well understood. The objective of this study is to determine the impact of surgery in patients with advanced ACC. Using the Surveillance, Epidemiology and End Results database, we identified patients diagnosed with Stage III and IV ACC between 1988 and 2009. A total of 320 patients with Stage III and IV disease were included in our analysis. In patients treated with surgical resection, the Stage III 1- and 5-year survival rates were 77 and 40 per cent, respectively, whereas the Stage IV 1- and 5-year survival rates were 54 and 27.6 per cent, respectively. Patients treated without surgery had poor survival at 1 year for both Stage III (13%) and Stage IV (16%) (P < 0.01 compared with the surgical groups). Lymph node dissection was performed in 26 per cent of the patients with advanced ACC and was associated with improved survival in univariate analysis of Stage IV patients. Overall, our results indicate that favorable survival outcomes can be achieved even in patients with Stage III and IV disease and surgery should be considered in patients with advanced ACC. PMID- 24160812 TI - Rate of re-excision after breast-conserving surgery for invasive lobular carcinoma. AB - Invasive lobular carcinoma (ILC) accounts for approximately 5 to 20 per cent of all breast cancers and is often multicentric. Despite pre- and intraoperative assessments to achieve negative margins, ILC is reported to be associated with higher rates of positive margin. This cross-sectional study examined patients with breast cancer treated at our institution from 2000 to 2010. The objective was to investigate the rate of re-excision resulting from positive or close margin (1 mm or less) in patients who underwent breast-conserving surgery (BCS) for ILC compared with invasive ductal carcinoma (IDC) and ductal carcinoma in situ (DCIS). Of the 836 patients treated, 416 patients underwent BCS. The rate of re-excision after BCS for ILC was 35.1 versus 17.7 per cent for IDC and 20.0 per cent for DCIS (P = 0.04). Re-excisions were more often performed for positive margin in patients with ILC (11 of 37 [29.7%]) versus IDC (36 of 334 [10.8%]) and DCIS (five of 45 [11.1%];(P = 0.004). In this single-institution review, BCS for ILC had significantly higher rates of re-excision as a result of positive margins when compared with IDC and DCIS. Tumor size greater than 2 cm and lymph node involvement were identified as factors associated with positive surgical margin in ILC. The higher possibility of positive margins and the need for additional procedures should be discussed with patients undergoing BCS for ILC. PMID- 24160813 TI - A case study template to support experimental design in Augmentative and Alternative Communication and Assistive Technology. AB - PURPOSE: The field of Augmentative and Alternative Communication/Assistive Technology (AAC/AT) has an extensive literature of non-experimental case descriptions. This limits the generalisation of findings. The current study aimed to develop a template to contribute to single case experimental design specifically for the field of enquiry. METHOD: A qualitative case study methodology was adopted to construct and evaluate the content and structure of the case study template. Participants represented relevant stakeholder groups. Data were collected through template evaluations and focus groups. Data were analysed using Framework Analysis. RESULTS: Across stakeholder groups, results produced a consensus on AAC/AT terminology, content and detail that may usefully inform single case experimental design. CONCLUSIONS: This is a complex area of rehabilitation that can best support its service users and service commissioners by using tools that facilitate collaborative working. The findings suggest that it is possible to produce a data collection tool that is acceptable to all stakeholder perspectives. PMID- 24160815 TI - The emergence of H7N9 viruses: a chance to redefine correlates of protection for influenza virus vaccines. PMID- 24160817 TI - Signal-peptide-mediated translocation is regulated by a p97-AIRAPL complex. AB - Protein homoeostasis is a fundamental requirement for all living cells in order to survive in a dynamic surrounding. Proper levels of AIRAPL (arsenite-inducible RNA-associated protein-like protein) (ZFAND2B) are required in order to maintain cellular folding capacity in metazoans, and functional impairment of AIRAPL results in acceleration of aging and protein aggregation. However, the cellular roles of AIRAPL in this process are not known. In the present paper, we report that AIRAPL binds and forms a complex with p97 [VCP (valosin-containing protein)/Cdc48], Ubxd8 (ubiquitin regulatory X domain 8), Npl4-Ufd1, Derlin-1 and Bag6 on the ER (endoplasmic reticulum) membrane. In spite of the fact that AIRAPL complex partners are involved in the ERAD (ER-associated degradation) process, AIRAPL knockdown does not show any impairment in ERAD substrate degradation. However, translocation into the ER of a subset of ERAD- and non-ERAD-secreted proteins are regulated by AIRAPL. The ability to regulate translocation by the p97-AIRAPL complex is entirely dependent on the proteins' signal peptide. Our results demonstrate a p97 complex regulating translocation into the ER in a signal-peptide-dependent manner. PMID- 24160818 TI - Connection between thermodynamics and dynamics of simple fluids in highly attractive pores. AB - Using molecular simulations, we investigate the structural and diffusive dynamics properties of a model fluid in highly absorptive cylindrical pores. At subcritical temperatures, self-diffusivity displays three distinct regimes as a function of average pore density rho: (1) a decrease in self-diffusivity with increasing rho at low rho, (2) constant self-diffusivity with respect to varying rho at moderate density, and (3) a decrease in self-diffusivity with increasing rho at high density. These regimes are closely linked to the thermodynamic properties of the fluid in the pore, specifically, the adsorption isotherm, isosteric heat of adsorption, and the density profile. We show that these three diffusivity regimes qualitatively correspond to three distinct adsorption regimes: monolayer formation, multilayer adsorption, and pore filling, respectively. In addition, we find that the self-diffusivity is a universal function of the local film density in the monolayer formation regime at subcritical temperatures. The results of this work suggest a potential means to estimate the self-diffusivity over a broad pressure range using a limited number of experiments. PMID- 24160816 TI - Formulation of curcumin delivery with functionalized single-walled carbon nanotubes: characteristics and anticancer effects in vitro. AB - CONTEXT: Single-walled carbon nanotubes (SWCNTs), an important class of artificial nanomaterials with unique physicochemical properties, were used as novel carriers of curcumin. OBJECTIVE: Formulation and evaluation of curcumin loaded SWCNTs systems for utilizing the curcumin's anticancer potential by circumventing conventional limitations of extremely low aqueous solubility and instability under physiological conditions, and combining SWCNTs photothermal therapy enabled by the strong optical absorbance of SWCNTs in the 0.8-1.4 MUm resulting in excessive local heating. METHODS: After functionalized SWCNTs were confirmed, they were conjugated with curcumin (SWCNT-Cur). Subsequently, the formulation was analyzed for size, zeta-potential and morphology. And the solubility, stability and release of curcumin were assessed using spectrofluorometer, and the solid state of the curcumin was determined using X ray diffraction and UV spectroscopy. Furthermore, in PC-3 cells, photothermal response was further determined by irradiating laser after the antitumor effect of SWCNT-Cur was evaluated. RESULTS AND DISCUSSION: SWCNTs were functionalized, and subsequent SWCNT-Cur conjugates were found to possess an average size of 170.4 nm, a zeta potential of -12.5 mV and to significantly enhance the solubility and stability of curcumin, overcoming the barriers to adequate curcumin delivery. Moreover, curcumin in SWCNT-Cur was in an amorphous form and could be rapidly released. In PC-3 cells, improved inhibition efficacy was achieved by SWCNT-Cur compared with native curcumin. Meanwhile, the SWCNTs in SWCNT-Cur served not only as scaffolds but also as thermal ablation agents, further inhibiting PC-3 cell growth. CONCLUSION: SWCNT-Cur assemblies may provide a promising delivery system for curcumin for use in cancer therapy. PMID- 24160819 TI - Bringing transparency to physician-industry relationships: what the Physician Payment Sunshine Act will mean for interventional radiologists. PMID- 24160820 TI - Requirements for training in interventional radiology. PMID- 24160821 TI - Yttrium-90 radioembolization as a bridge to liver transplantation: a single institution experience. AB - PURPOSE: To evaluate our experience with the use of yttrium-90 ((90)Y) radioembolization in maintaining potential candidacy and, in some instances, downstaging hepatocellular carcinoma (HCC) that does not meet Milan criteria for liver transplantation. MATERIALS AND METHODS: A retrospective review of 20 consecutive patients with HCC who were listed to receive a liver transplant and were treated with (90)Y radioembolization as a sole modality for locoregional "bridge" therapy was performed. Demographics, radiographic and pathologic response, survival, and recurrences were examined. RESULTS: Twenty-two (90)Y treatments were performed in 20 patients before transplantation. Median time from first treatment to transplantation was 3.5 months. HCC in 14 patients met the Milan criteria at the time of the first (90)Y treatment, and HCC in six did not. All cases that originally met the Milan criteria remained within the criteria before transplantation, and two of six patients whose disease did not meet the criteria (33%) had their disease successfully downstaged to meet the criteria. Overall, nine patients (45%) had complete or partial radiologic response to (90)Y radioembolization according to modified Response Evaluation Criteria In Solid Tumors. Complete necrosis of tumor with no evidence of viable tumor on pathologic examination was observed in five patients (36%) whose disease met the Milan criteria. CONCLUSIONS: Particularly in regions with long wait list times, (90)Y treatment is effective in maintaining tumor size in potential liver transplantation candidates with HCC. In addition, it can also be considered as a downstaging therapy in select patients before transplantation. PMID- 24160822 TI - A rare anomaly of the middle colic artery. PMID- 24160823 TI - Hospital-admitting privileges in interventional radiology: how IR should reposition itself in the wake of one hospital's policy change. PMID- 24160824 TI - Still so far to go. PMID- 24160825 TI - Vena Tech LGM filter retrieval 16 years after implantation: piecemeal removal by intentional mechanical fracture. AB - A 48-year-old man presented with symptomatic inferior vena cava (IVC) occlusion from a chronically thrombosed and embedded Vena Tech LGM filter resulting in exercise intolerance from diminished cardiac preload and postthrombotic syndrome from chronic venous insufficiency. The patient was treated using a new PRIME technique--Piecemeal Removal by Intentional MEchanical fracture--to achieve successful filter retrieval 16 years after implantation. Removal of the obstructing filter permitted endovascular IVC recanalization with restoration of venous outflow and alleviation of venous obstructive symptoms. Cardiac preload was restored, allowing the patient to resume long-distance running, and he successfully completed a half-marathon 3 months after treatment. PMID- 24160826 TI - Pseudoaneurysm of the inferior vena cava after filter removal. PMID- 24160827 TI - Combined sling and grasping forceps technique for embedded inferior vena cava filter retrieval. PMID- 24160828 TI - Prophylactic embolization of the gastroduodenal and right gastric arteries is not routinely necessary before radioembolization with glass microspheres. PMID- 24160829 TI - Unexpected ischemic complication after proximal coil embolization of a replaced left hepatic artery before yttrium-90 radioembolization. PMID- 24160830 TI - Hybrid treatment of isolated dissection of the superior mesenteric artery. PMID- 24160831 TI - Fluoroscopy-guided hepaticoneojejunostomy in recurrent anastomotic stricture after repeated surgical hepaticojejunostomy. PMID- 24160832 TI - Postlaparotomy retrograde navigation of an obstructed ileal conduit to relieve urinary sepsis. PMID- 24160833 TI - Radiofrequency ablation of a rare case of an intraosseous hibernoma causing therapy-refractory pain. PMID- 24160834 TI - Radiofrequency ablation of an unusual vertebral body osteoid osteoma contiguous with the intervertebral disc. PMID- 24160835 TI - Solitary intercostal arterial trunk: second case report. PMID- 24160836 TI - Internal mammary artery-to-pulmonary artery and vein fistula acquired after video assisted thoracoscopic surgery and pleurodesis. PMID- 24160837 TI - Congenital inferior mesenteric arteriovenous malformation presenting with ischemic colitis: endovascular treatment. PMID- 24160838 TI - Point-of-care tests for sexually transmissible infections: what do 'end users' want? AB - BACKGROUND: Clinicians and developers identify sensitivity as an important quality in a point-of-care test (POCT) for sexually transmissible infections (STIs). Little information exists regarding what patients want for STI POCTs. METHODS: A qualitative study, encompassing five focus groups among attendees of STI and adolescent health centres in Baltimore, Maryland, and Cincinnati, Ohio, were conducted between March 2008 and April 2009. Discussion topics included advantages and disadvantages of having a POCT, perceived barriers to using POCTs in the clinic setting and at home, priorities for the development of new POCTs for STIs, and envisioned characteristics of an ideal POCT. All discussions were recorded and transcribed. A qualitative content analysis was performed to examine frequencies or patterns of recurring codes, which were regrouped and indexed to identify salient themes. RESULTS: Patients attending STI and adolescent outpatient clinics are in favour of diagnostic tests that are rapid, easy to read and simple to use. Home testing options for POCTs were acceptable and provided better confidentiality, privacy and convenience, but clinic-based POCTs were also acceptable because they offer definitive results and ensure immediate treatment. Barriers to home POCTs centred on cost and the ability to read and perform the test correctly at home. Opinions did not differ by patient ethnicity, except that Hispanic participants questioned the reliability of home test results, wanted high sensitivity and desired bilingual instructions. CONCLUSIONS: Patients attending STI and adolescent medical centres are in favour of STI POCTs if they are affordable, rapid, easy to read and simple to use. PMID- 24160839 TI - The distribution of word matches between Markovian sequences with periodic boundary conditions. AB - Word match counts have traditionally been proposed as an alignment-free measure of similarity for biological sequences. The D(2) statistic, which simply counts the number of exact word matches between two sequences, is a useful test bed for developing rigorous mathematical results, which can then be extended to more biologically useful measures. The distributional properties of the D(2) statistic under the null hypothesis of identically and independently distributed letters have been studied extensively, but no comprehensive study of the D(2) distribution for biologically more realistic higher-order Markovian sequences exists. Here we derive exact formulas for the mean and variance of the D(2) statistic for Markovian sequences of any order, and demonstrate through Monte Carlo simulations that the entire distribution is accurately characterized by a Polya-Aeppli distribution for sequence lengths of biological interest. The approach is novel in that Markovian dependency is defined for sequences with periodic boundary conditions, and this enables exact analytic formulas for the mean and variance to be derived. We also carry out a preliminary comparison between the approximate D(2) distribution computed with the theoretical mean and variance under a Markovian hypothesis and an empirical D(2) distribution from the human genome. PMID- 24160840 TI - Polyprodrug amphiphiles: hierarchical assemblies for shape-regulated cellular internalization, trafficking, and drug delivery. AB - Solution self-assembly of block copolymers (BCPs) typically generates spheres, rods, and vesicles. The reproducible bottom-up fabrication of stable planar nanostructures remains elusive due to their tendency to bend into closed bilayers. This morphological vacancy renders the study of shape effects on BCP nanocarrier-cell interactions incomplete. Furthermore, the fabrication of single BCP assemblies with built-in drug delivery functions and geometry-optimized performance remains a major challenge. We demonstrate that PEG-b-PCPTM polyprodrug amphiphiles, where PEG is poly(ethylene glycol) and PCPTM is polymerized block of reduction-cleavable camptothecin (CPT) prodrug monomer, with >50 wt % CPT loading content can self-assemble into four types of uniform nanostructures including spheres, large compound vesicles, smooth disks, and unprecedented staggered lamellae with spiked periphery. Staggered lamellae outperform the other three nanostructure types, exhibiting extended blood circulation duration, the fastest cellular uptake, and unique internalization pathways. We also explore shape-modulated CPT release kinetics, nanostructure degradation, and in vitro cytotoxicities. The controlled hierarchical organization of polyprodrug amphiphiles and shape-tunable biological performance opens up new horizons for exploring next-generation BCP-based drug delivery systems with improved efficacy. PMID- 24160841 TI - High-performance dispenser printed MA p-type Bi(0.5)Sb(1.5)Te(3) flexible thermoelectric generators for powering wireless sensor networks. AB - This work presents a novel method to synthesize p-type composite thermoelectric materials to print scalable thermoelectric generator (TEG) devices in a cost effective way. A maximum ZT of 0.2 was achieved for mechanically alloyed (MA) p type Bi0.5Sb1.5Te3 (8 wt % extra Te additive)-epoxy composite films cured at 250 degrees C. A 50% increase in Seebeck coefficient as a result of adding 8 wt % extra Te in stoichiometric Bi0.5Sb1.5Te3 contributed to the increase in ZT. To demonstrate cost-effective and scalable manufacturing, we fabricated a sixty element thermoelectric generator prototype with 5.0 mm * 600 MUm * 120 MUm printed dimensions on a custom designed polyimide substrate with thick metal contacts. The prototype TEG device produced a power output of 20.5 MUW at 0.15 mA and 130 mV for a temperature difference of 20 K resulting in a device areal power density of 152 MUW/cm(2). This power is sufficient for low power applications such as wireless sensor network (WSN) devices. PMID- 24160842 TI - Preparation and characterization of thermochemiluminescent acridine-containing 1,2-dioxetanes as promising ultrasensitive labels in bioanalysis. AB - Thermochemiluminescence is the luminescence process in which a thermodynamically unstable molecule decomposes with light emission when heated above a threshold temperature. We recently reported the thermochemiluminescence properties of an acridine-containing 1,2-dioxetane, which emits at relatively low temperatures (i.e., below 100 degrees C). Herein, we explored the effect of the introduction of methyl substituents in the acridine system. The methyl group did not determine an excessive destabilization of 1,2-dioxetane ring nor significantly affect the general physical properties of the molecule. Monosubstituted methyl derivatives and a series of derivatives bearing several combinations of two, three, and four methyl groups were prepared. The rate of formation of 1,2-dioxetane derivatives 1b-k strongly depended on the methyl substitution pattern. All members of this library of mono-, di-, tri-, and tetramethyl-substituted derivatives were characterized in terms of photophysical and thermochemiluminescence properties. The introduction of methyl groups into the acridine ring caused a marked decrease in the activation energy of the thermochemiluminescent reaction. Tri- and tetramethyl-substituted acridones had the highest fluorescence quantum yields, in the range 0.48-0.52, and the corresponding 1,2-dioxetanes 1h and 1j showed in thermochemiluminescence imaging experiments limit of detection values more than ten times lower with respect to the unsubstituted derivative. PMID- 24160843 TI - Features of complementary and alternative medicine use by patients with coronary artery disease in Beijing: a cross-sectional study. AB - BACKGROUND: Complementary and alternative medicine (CAM) is commonly used in China for the management of coronary artery disease (CAD). However, few studies have been conducted to investigate the prevalence, perceived effectiveness, types, and reasons of CAM use in patients diagnosed with CAD. METHODS: A cross sectional study design was adopted. Questionnaires were distributed at the outpatient cardiac clinics of four tertiary-level teaching general hospitals in Beijing. Quantitative data were analyzed using Student's t-test. Categorical data were analyzed using chi-square test. Logistic regression was employed to explore factors associated with the use of CAM as well as CAM use features in Chinese medicine (CM) hospitals when significant differences were found upon comparisons. RESULTS: From May to July, 2009, a total of 600 questionnaires were distributed, and 546 patients with a diagnosis of CAD responded with valid values and were included in the present study. CAM was used by 69.1% of the patients with CAD; the majority (75.9%) of these CAM users believes that CAM is effective. "Few side effects" (49.6%) was the main reason of CAM use; whereas "doubt of effect" (61.5%) was the main reason for non-use. Patent herbal medicine (90.7%) was the most commonly used CAM type. Compared with non-CAM users, CAM users tended to be older (p < 0.01), have a longer disease duration (p = 0.02) and better current health status. In addition, CAM users had significant lower odds for emergency admission and hospitalization within the past one year. Patients with CAD from CM and WM hospitals differ in CAM use frequency, types, perceived effectiveness, as well as reasons for CAM use or non-CAM use. CONCLUSION: The present study suggested a group of significant factors which could influence the use of CAM in patients with CAD. CAM use patterns differ in patients from CM and WM hospitals. PMID- 24160844 TI - Posterior regeneration in Isodiametra pulchra (Acoela, Acoelomorpha). AB - INTRODUCTION: Regeneration is a widespread phenomenon in the animal kingdom, but the capacity to restore damaged or missing tissue varies greatly between different phyla and even within the same phylum. However, the distantly related Acoelomorpha and Platyhelminthes share a strikingly similar stem-cell system and regenerative capacity. Therefore, comparing the underlying mechanisms in these two phyla paves the way for an increased understanding of the evolution of this developmental process.To date, Isodiametra pulchra is the most promising candidate as a model for the Acoelomorpha, as it reproduces steadily under laboratory conditions and is amenable to various techniques, including the silencing of gene expression by RNAi. In order to provide an essential framework for future studies, we report the succession of regeneration events via the use of cytochemical, histological and microscopy techniques, and specify the total number of cells in adult individuals. RESULTS: Isodiametra pulchra is not capable of regenerating a new head, but completely restores all posterior structures within 10 days. Following amputation, the wound closes via the contraction of local muscle fibres and an extension of the dorsal epidermis. Subsequently, stem cells and differentiating cells invade the wound area and form a loosely delimited blastema. After two days, the posterior end is re-patterned with the male (and occasionally the female) genital primordium being apparent. Successively, these primordia differentiate into complete copulatory organs. The size of the body and also of the male and female copulatory organs, as well as the distance between the copulatory organs, progressively increase and by nine days copulation is possible. Adult individuals with an average length of 670 MUm consist of approximately 8100 cells. CONCLUSION: Isodiametra pulchra regenerates through a combination of morphallactic and epimorphic processes. Existing structures are "re-modelled" and provide a framework onto which newly differentiating cells are added. Growth proceeds through the intercalary addition of structures, mirroring the embryonic and post-embryonic development of various organ systems. The suitability of Isodiametra pulchra for laboratory techniques, the fact that its transcriptome and genome data will soon be available, as well as its small size and low number of cells, make it a prime candidate subject for research into the cellular mechanisms that underlie regeneration in acoelomorphs. PMID- 24160845 TI - Mandarin-speaking three-year-olds' demonstration of productive knowledge of syntax: evidence from syntactic productivity and structural priming with the SVO ba alternation. AB - Two studies investigated syntactic productivity in three-year-old Mandarin speakers' use of verbs in the SVO and SbaOV constructions. In Study 1, children were taught novel verbs in one construction and assessed for their production in the other construction. Children produced verbs taught in the ba constructions in SVO utterances, but showed order effects when producing verbs taught in SVO constructions in ba utterances. In Study 2, children described animated scenes either with structural priming (i.e., after hearing verbs in SVO or ba constructions). Children demonstrated structural priming, producing more SVO and ba utterances, respectively, directly after hearing verbs in these constructions. These results indicate that Mandarin speaking three-year-olds demonstrate productive knowledge of both SVO and SbaOV constructions. Their ability to override the predominant input frequency of SVO runs counter to a purely usage based account of early acquisition of grammar. PMID- 24160846 TI - A label-free silicon quantum dots-based photoluminescence sensor for ultrasensitive detection of pesticides. AB - Sensitive, rapid, and simple detection methods for the screening of extensively used organophosphorus pesticides and highly toxic nerve agents are in urgent demand. A novel label-free silicon quantum dots (SiQDs)-based sensor was designed for ultrasensitive detection of pesticides. This sensing strategy involves the reaction of acetylcholine chloride (ACh) with acetylcholinesterase (AChE) to form choline that is in turn catalytically oxidized by choline oxidase (ChOx) to produce betaine and H2O2 which can quench the photoluminescence (PL) of SiQDs. Upon the addition of pesticides, the activity of AChE is inhibited, leading to the decrease of the generated H2O2, and hence the PL of SiQDs increases. By measuring the increase in SiQDs PL, the inhibition efficiency of pesticide to AChE activity was evaluated. It was found that the inhibition efficiency was linearly dependent on the logarithm of the pesticides concentration. Consequently, pesticides, such as carbaryl, parathion, diazinon, and phorate, were determined with the SiQDs PL sensing method. The lowest detectable concentrations for carbaryl, parathion, diazinon, and phorate reached 7.25 * 10( 9), 3.25 * 10(-8), 6.76 * 10(-8), and 1.9 * 10(-7) g/L, respectively, which were much lower than those previously reported. The detecting results of pesticide residues in food samples via this method agree well with those from high performance liquid chromatography. The simple strategy reported here should be suitable for on-site pesticides detection, especially in combination with other portable platforms. PMID- 24160848 TI - Transmission of t(11;14)-positive cells by allogeneic stem cell transplant: 10 year journey to mantle cell lymphoma. PMID- 24160847 TI - Medical decision analysis for first-line therapy of chronic myeloid leukemia. AB - Several tyrosine kinase inhibitors (TKIs) are approved for the treatment of chronic myeloid leukemia (CML). Our goal was to develop a clinical decision analytic model for evaluation of the long-term effectiveness of different therapy regimens. We developed a Markov cohort model with a lifelong time horizon for first-line treatment with imatinib, dasatinib or nilotinib. Seven strategies including combinations of TKIs, chemotherapy and stem cell transplant were evaluated. The model was parameterized using published trial data, the Austrian CML registry and practice patterns estimated by experts. Health outcomes evaluated were life-years (LYs) and quality-adjusted LYs (QALYs). Based on our decision analysis, dasatinib following nilotinib failure was the most effective treatment in terms of LYs (19.8 LYs) and QALYs (16.1 QALYs). Sensitivity analyses showed that the ranking of strategies was mostly influenced by the duration of first- and second-line therapies. Our results may support decision-making regarding the sequential application of TKIs. PMID- 24160849 TI - Large B-cell lymphomas in adolescents and young adults in comparison to adult patients: a matched-control analysis in 55 patients. AB - The aim of our study was to assess whether large B-cell lymphoma (LBCL) in adolescents and young adults (AYA) should be considered as a clinocopathological entity, and to evaluate the prognostic value of age. Fifty-five patients aged > 15-30 years were fully matched to 365 adult patients aged 31-65 years. We found a high incidence of primary mediastinal thymic LBCL subtype (33% vs. 5%), while histological transformation was rare (2% vs. 14%). LBCL in AYA presented with a bulky mediastinal mass (51% vs. 21%), and the lactate dehydrogenase (LDH) value was significantly higher (73% vs. 54%). The complete response rate to chemotherapy was similar in the two groups. Five-year overall survival (OS) and event-free survival (EFS) of AYA were 73% and 68%, respectively. The matched control analysis showed no difference for either OS or EFS. LBCL in AYA presents with some critical features which differ from those of older adults. However, the outcome is equivalent to that observed in older patients. PMID- 24160851 TI - Hypoxia-related gene expression profile in childhood acute lymphoblastic leukemia: prognostic implications. AB - A cellular hypoxic condition is a key event in several human cancers, but knowledge about its role in childhood acute lymphoblastic leukemia (ALL) is very limited. In the present study, the gene expression profile of hypoxia-related genes (HIF1A, CA9, VEGF and SCL2A1) was evaluated in bone marrow samples of 113 pediatric patients. HIF1A mRNA up-regulation was significantly associated with higher 5-year event-free survival rates in patients with B-ALL as well as in the overall ALL population in both univariate and multivariate analysis (p = 0.023 and p = 0.041, respectively). In gene expression analysis, low oxygen levels promoted HIF1A activation in a time-dependent manner, in both ALL cell lines. In vitro cytotoxic assays suggested an initial trend toward hypoxia-related resistance in the first 24 h, but evaluation at later time points (48-72 h) clearly showed that there was no relevant difference in drug response when comparing hypoxic and normal oxygen level conditions. Modulation of mRNA expression of several hypoxia-related genes was also observed after hypoxic exposure in a cell specific manner, suggesting that HIF1A mRNA expression could play a different role in specific subtypes of leukemia. Despite the remaining questions regarding hypoxia-mediated mechanisms, these findings could be helpful to provide new insights into the role of hypoxia in childhood ALL. PMID- 24160850 TI - Arsenic trioxide in front-line therapy of acute promyelocytic leukemia (C9710): prognostic significance of FLT3 mutations and complex karyotype. AB - The addition of arsenic trioxide (ATO) to frontline therapy of acute promyelocytic leukemia (APL) has been shown to result in significant improvements in disease-free survival (DFS). FLT3 mutations are frequently observed in APL, but its prognostic significance remains unclear. We analyzed 245 newly diagnosed adult patients with APL treated on intergroup trial C9710 and evaluated previously defined biological and prognostic factors and their relationship to FLT3 mutations and to additional karyotypic abnormalities. FLT3 mutations were found in 48% of patients, including 31% with an internal tandem duplication (FLT3 ITD), 14% with a point mutation (FLT3-D835) and 2% with both mutations. The FLT3 ITD mutant level was uniformly low, < 0.5. Neither FLT3 mutation had an impact on remission rate, induction death rate, DFS or overall survival (OS). The addition of ATO consolidation improved outcomes regardless of FLT3 mutation type or level, initial white blood cell count, PML-RARA isoform type or transcript level. The presence of a complex karyotype was strongly associated with an inferior OS independently of post-remission treatment. In conclusion, the addition of ATO to frontline therapy overcomes the impact of previously described adverse prognostic factors including FLT3 mutations. However, complex karyotype is strongly associated with an inferior OS despite ATO therapy. PMID- 24160853 TI - To be or not to be in a cavity: the hydrated electron dilemma. AB - The hydrated electron-the species that results from the addition of a single excess electron to liquid water-has been the focus of much interest both because of its role in radiation chemistry and other chemical reactions, and because it provides for a deceptively simple system that can serve as a means to confront the predictions of quantum molecular dynamics simulations with experiment. Despite all this interest, there is still considerable debate over the molecular structure of the hydrated electron: does it occupy a cavity, have a significant number of interior water molecules, or have a structure somewhere in between? The reason for all this debate is that different computer simulations have produced each of these different structures, yet the predicted properties for these different structures are still in reasonable agreement with experiment. In this Feature Article, we explore the reasons underlying why different structures are produced when different pseudopotentials are used in quantum simulations of the hydrated electron. We also show that essentially all the different models for the hydrated electron, including those from fully ab initio calculations, have relatively little direct overlap of the electron's wave function with the nearby water molecules. Thus, a non-cavity hydrated electron is better thought of as an "inverse plum pudding" model, with interior waters that locally expel the surrounding electron's charge density. Finally, we also explore the agreement between different hydrated electron models and certain key experiments, such as resonance Raman spectroscopy and the temperature dependence and degree of homogeneous broadening of the optical absorption spectrum, in order to distinguish between the different simulated structures. Taken together, we conclude that the hydrated electron likely has a significant number of interior water molecules. PMID- 24160852 TI - A short questionnaire for the assessment of quality of life in patients with chronic obstructive pulmonary disease: psychometric properties of VQ11. AB - BACKGROUND: There is a need for a validated short instrument that can be used in routine practice to quantify potential short-term change in Health-Related Quality of Life (HRQoL) in patients with chronic obstructive pulmonary disease (COPD). Our aim is to determine the validity and reliability of the VQ11 questionnaire dedicated to the routine assessment of HRQoL. METHODS: 181 COPD patients (40-85 yrs, I to IV GOLD stages) completed the VQ11, and several tests. One week later, 49 of these patients completed the VQ11 again. RESULTS: Confirmatory factor analysis supported the two-level hierarchical structure of the VQ11 with 11 items covering three components and HRQoL at a higher level. The VQ11 showed good internal consistency and good reproducibility (r = 0.88). Concurrent validity showed significant correlations between VQ11 total scores and St George's Respiratory Questionnaire-C (r = 0.70), Short Form-36 (r = -0.66 for the physical component and -0.63 for the mental component). We obtained significant correlations with MRC Dyspnea Grades (r = 0.59), the Hospital Anxiety and Depression Scale total score (r = 0.62), and the BODE index (r = 0.53). CONCLUSION: The VQ11 has good measurement properties and provides a valid and reliable measure of COPD-specific HRQoL. It is ready for use in routine practice. CLINICAL REGISTRATION: The study was approved by the University of Montpellier 1 Ethics Committee and the Regional Ethics Committee (authorization number: A00332 53). PMID- 24160854 TI - Prevalence of hearing loss in patients with late-onset Pompe disease: Audiological and otological consequences. AB - OBJECTIVE: The metabolic disorder Pompe disease mainly affects the skeletal muscle in adults. The hearing impairment due to stapedius muscle involvement in adult patients is not known. DESIGN: The frequency, severity, and type of hearing impairment was characterized prospectively using pure-tone audiometry, tympanometry, stapedial reflexes, otoacoustic emissions, and brainstem-evoked response audiometry in adult patients on enzyme replacement therapy for genetically confirmed Pompe disease. STUDY SAMPLE: 11 adult patients (median age: 47 years, range: 22-71). RESULTS: Four patients complained about subjective hearing disturbances. Using World Health Organization definition of hearing impairment, abnormal hearing thresholds resulting in mild hearing loss were found in 36% of patients. Compared to normative data (ISO 7029), the hearing threshold was below the median in all but three ears. Stapedial reflexes could not be elicited ipsilateral in 18% and contralateral in 36%. Auditory brainstem responses showed no retrocochlear pathology. CONCLUSIONS: The prevalence of hearing loss slightly exceeded the normative data of the general population. Consistent with previous studies the hearing impairment was usually mild. The percentage of pathological stapedial reflexes exceeded that of matched control subjects and suggests a selective involvement of the stapedius muscle, potentially as a sequela of Pompe disease. PMID- 24160856 TI - An examination of social support influences on participation for older adults with chronic health conditions. AB - Social support can improve participation in everyday activities among older adults with chronic health conditions, but the specific types of support that are needed are unclear. PURPOSE: This study examined the types of social support that most strongly predict participation in everyday activities. METHOD: Two hundred and twenty-seven participants completed a self-administered cross-sectional survey. The sample included adults aged 60 years or more with arthritis, diabetes, chronic obstructive pulmonary disease and/or heart disease. Participation was defined as satisfaction with participation in 11 life areas. Social support was defined as availability of tangible, affectionate, emotional/informational and positive social interaction support. RESULTS: Multiple regression analyses showed that participants who perceived greater tangible support and positive social interaction support had higher satisfaction with participation than participants with lower levels of these types of support. CONCLUSIONS: Targeting and developing tangible and social interaction support may help to facilitate satisfaction with participation for older adults with chronic conditions. Creating networks for companionship appears equally as important as providing support for daily living needs. Implications for Rehabilitation Varying types of social support can improve participation in older adults with chronic health conditions. Tangible support and positive social interaction support are the strongest predictors of participation. Creating networks for companionship may be equally as important as providing support for daily living needs. PMID- 24160857 TI - Efficacy of leisure intervention groups in rehabilitation of people with an acquired brain injury. AB - PURPOSE: To determine whether participation in a week-long residential leisure intervention program targeting individuals with an acquired brain injury (ABI) improved the leisure satisfaction, self-esteem and quality of life (QOL) of participants. The program included leisure awareness, leisure resources, social interaction skills and leisure activity skills. METHOD: Using a pre- and post intervention design leisure satisfaction, self-esteem and QOL were assessed prior to, immediately following and at three months post program. Data were analyzed using Wilcoxon signed-rank tests. RESULTS: Participants were eight men and four women aged between 19 and 49 years who were recent clients of a rural Brain Injury Rehabilitation Service. The majority (7/12) had acquired their ABI more than two years previously, and for most (10/12) the cause was trauma. Program participants showed clinically important and statistically significant improvements in leisure satisfaction (p = 0.002), self-esteem (p = 0.03) and QOL (p = 0.02 to 0.008 for four domains of the World Health Organisation Quality of Life - Bref scale) three months post program. CONCLUSION: Adults with an ABI participating in leisure education programs can experience improvements in leisure satisfaction, self-esteem and QOL following the program. The findings suggest that active leisure intervention programs should be included in the ongoing rehabilitative care of adults with an ABI. Implications for Rehabilitation Leisure participation, leisure satisfaction and social integration can be seriously compromised following an acquired brain injury (ABI). Engagement in leisure activities has positive effects on physical and mental health and is increasingly recognised as an important determinant of quality of life (QOL) for people with ABI. Participation in a short-term intensive leisure intervention program can improve leisure satisfaction, self-esteem and QOL. Active leisure intervention programs should be included in the ongoing rehabilitation and reintegration of adults with ABI. PMID- 24160855 TI - Walking activity patterns in youth with cerebral palsy and youth developing typically. AB - PURPOSE: To describe daily walking stride rate patterns of young children with cerebral palsy (CP) as compared to a typically developing youth (TDY) cohort relative to age and functional level. METHOD: A cross-sectional comparison cohort study compared 209 youth with CP with 368 TDY aged 2-13 years. Youth with CP had Gross Motor Function Classification System (GMFCS) levels I-III with 60% bilateral involvement and 79% spastic. Five days of StepWatch data were averaged and classified into low, moderate and high stride rates. Group differences were examined by t-test and analysis of variance. RESULTS: Children with CP walk significantly less each day than TDY (F = 245, p <= 0.001) and differ by GMFCS (F = 1.51, p < 0.001). TDY walk a similar number of strides in low and moderate stride rates each day while youth with CP do not. TDY attained high stride rates (>60 strides/min) for 8 min/d with levels I-III at 4.0, 3.2 and 0.53 min/d, respectively. CONCLUSIONS: The relative relationship of walking intensity levels within total daily stride activity differs for youth with CP as compared to TDY. The influence of functional walking ability on walking stride activity levels and intensity does not appear to differ significantly across age groups. IMPLICATIONS FOR REHABILITATION: Limitation in the ability to attain moderate stride-rate intensity, regardless of total number of strides taken each day for ambulatory youth with CP, is a potential area of focus for intervention. Understanding of stride activity levels and intensity in youth with CP may be employed to focus rehabilitation strategies to enhance habitual walking activity. Community-based stride rate data has potential as an effectiveness outcome for rehabilitation strategies focused on walking (i.e. orthopedic surgery, orthoses and injections therapies). PMID- 24160858 TI - Important aspects of participation and participation restrictions in people with a mild intellectual disability. AB - PURPOSE: This study explored a possibility to assess the concepts of participation and participation restrictions in the International Classification of Functioning, Disability and Health (ICF) by combining self-ratings of the perceived importance with the actual performance of different everyday activities in people with a mild intellectual disability. METHOD: Structured interviews regarding 68 items from the ICF activity/participation domain were conducted (n = 69). The items were ranked by perceived importance, performance and by combined measures. Furthermore, the measures were related to a single question about subjective general well-being. RESULTS: Rankings of performance highlighted about the same items as "important participation", while rankings of low performance addressed quite different items compared with "important participation restriction". Significant correlations were found between subjective general well being and high performance (r = 0.56), high performance/high importance (important participation) (r = 0.56), low performance (r = -0.56) and low performance/high importance (important participation restriction; r = -0.55). CONCLUSIONS: The results support the clinical relevance of the ICF and the studied selection of 68 items. Although performance only may sometimes be a relevant aspect, knowledge about the relationship between the perceived importance and the actual performance is essential for clinical interventions and for research aiming to understand specific needs regarding participation. IMPLICATIONS FOR REHABILITATION: The concepts of participation and participation restriction are highly relevant in people with a mild intellectual disability. Self-rated performance might be sufficient to assess participation at a group level. In clinical practices, the relationship between the perceived importance and the actual performance of an activity is essential to assess. PMID- 24160859 TI - Sex and gender reporting in sexual health: implications for authors. PMID- 24160860 TI - The disposition of oxytetracycline to feathers after poultry treatment. AB - In the combat against bacterial resistance, there is a clear need to check the use of antibiotics in animal husbandry, including poultry breeding. The use of chicken feathers as a tool for the detection of use of antibiotics was investigated. An extraction method for the analysis of oxytetracycline (OTC) from feathers was developed and was tested by using incurred feathers obtained from a controlled animal treatment study. The use of McIlvain-ethylenediaminetetraacetic acid buffer only in combination with acetone gave the highest extraction yield, indicating the need of an organic solvent for feather extraction. By using the developed method, it was found that after a withdrawal time, the OTC concentration in feathers is in the mg kg-1 range, far higher than that in muscle and liver tissue. Based on the analysis of individual segments of feathers from OTC-treated chicken, evidence was found supporting the hypothesis of secretion of antibiotics through the uropygial gland and external spread over feathers by grooming behaviour. It was also found that part of the administered OTC is built into the feather rachis. Finally, we provide the first evidence that the analysis of individual segments of the rachis can be used as a tool to discriminate among different treatment strategies, for example, therapeutic versus subtherapeutic. As a result, we concluded that the analysis of feathers is an extremely valuable tool in residue analysis of antibiotics. PMID- 24160861 TI - ReactionMap: an efficient atom-mapping algorithm for chemical reactions. AB - Large databases of chemical reactions provide new data-mining opportunities and challenges. Key challenges result from the imperfect quality of the data and the fact that many of these reactions are not properly balanced or atom-mapped. Here, we describe ReactionMap, an efficient atom-mapping algorithm. Our approach uses a combination of maximum common chemical subgraph search and minimization of an assignment cost function derived empirically from training data. We use a set of over 259,000 balanced atom-mapped reactions from the SPRESI commercial database to train the system, and we validate it on random sets of 1000 and 17,996 reactions sampled from this pool. These large test sets represent a broad range of chemical reaction types, and ReactionMap correctly maps about 99% of the atoms and about 96% of the reactions, with a mean time per mapping of 2 s. Most correctly mapped reactions are mapped with high confidence. Mapping accuracy compares favorably with ChemAxon's AutoMapper, versions 5 and 6.1, and the DREAM Web tool. These approaches correctly map 60.7%, 86.5%, and 90.3% of the reactions, respectively, on the same data set. A ReactionMap server is available on the ChemDB Web portal at http://cdb.ics.uci.edu . PMID- 24160863 TI - Vaccine development costs: a review. AB - The cost of drug development is commonly cited between US$800 and US$1.8 billion. A similar statistic for vaccines is yet to be estimated, and it is unclear whether the cost of vaccines is similar to drug development. Financial and regulatory policy significantly impacts the extent and cost of pharmaceutical development, and as such it is important that governments should be informed about the costs of developing vaccines. The purpose of this paper is to review the concept of drug and vaccine R&D costs, to review the associated literature and to relate these findings to the area of vaccine industry's financial and regulatory policy. PMID- 24160864 TI - Thermoresponsive fluconazole gels for topical delivery: rheological and mechanical properties, in vitro drug release and anti-fungal efficacy. AB - The aim of this study was to develop thermosensitive gels using poloxamers for topical delivery of fluconazole (FLZ). Eight different formulations containing 1% FLZ in poloxamer and a particular co-solvent (propylene glycol (PG) or Transcutol P) of various concentrations were prepared. The gels were characterized for transition temperatures, rheological and mechanical properties. FLZ permeability and antifungal effect of the gels were also evaluated. Except for one formulation, all gels exhibited thermosensitive property, i.e. transformed from Newtonian (liquid-like) behavior at 20 degrees C to non-Newtonian (gel-like) behavior at 37 degrees C. Transcutol-P increased the transition temperature of the formulations, while the opposite effect was observed for PG. At 37 degrees C, formulations with high poloxamer concentrations (17%) resulted in high viscosity, compressibility and hardness. Formulations containing 17% poloxamer and 20% Transcutol-P and 10% PG, respectively, exhibited high adhesiveness. No significant differences in the in vitro antifungal activity of FLZ were observed among the formulations suggesting that the gel vehicles did not influence the biological effect of FLZ. FLZ permeability decreased with increasing poloxamer concentration. Formulations containing 17% poloxamer and 20% Transcutol-P and 10% PG seemed to be promising in situ gelling systems for the topical delivery of FLZ. PMID- 24160865 TI - Effects of PEGylation on the binding interaction of magainin 2 and tachyplesin I with lipid bilayer surface. AB - Poly(ethylene glycol) (PEG)-grafted magainin 2 and tachyplesin I were simulated with lipid bilayers. In the simulations of PEGylated magainin 2 and tachyplesin I in water, both peptides are wrapped by PEG chains. The alpha-helical structure of PEGylated magainin 2 is broken in water, while the beta-sheet of PEGylated tachyplesin I keeps stable, similar to the structural behavior of unPEGylated peptides, in agreement with experiments. Simulations of PEGylated peptides with lipid bilayers show that PEG chains block the electrostatic interaction between cationic residues of peptides and anionic phosphates of lipids, leading to the less binding of the peptide to the bilayer surface, which is observed more significantly for magainin 2 than for tachyplesin I. Since the random-coiled magainin 2 can be more completely covered by PEGs than does the beta-sheet tachyplesin I, the PEGylation effect on the decreased binding is larger for magainin 2, showing the dependence of PEGylation on the peptide structure. These simulation findings qualitatively support the experimental observation of the different extents of the reduced membrane-permeabilizing activity for PEGylated magainin 2 and tachyplesin I. PMID- 24160866 TI - Ovarian Sertoli-Leydig cell tumors: MRI findings and pathological correlation. AB - BACKGROUND: To investigate the magnetic resonance imaging (MRI) characteristics of ovarian Sertoli-Leydig cell tumors (SLCT). METHODS: The clinical, MRI and pathological findings of five cases of SLCT were reviewed retrospectively. MRI appearances of tumors including laterality, shape and size, architecture, wall, septa and vegetation, signal intensity and contrast-enhancement pattern were evaluated and correlated with pathological findings. RESULTS: Two tumors were solid which appeared as low signal intensity on T1-weighted imaging (T1WI) and moderate on T2-weighted imaging (T2WI) with multiple small cysts in one of them. The remaining three SLCT were multilocular cystic with the irregularly thickened wall and septa, and with solid area and mural nodules in one of them. The cystic components had the same signal intensity as urine. All the solid components were intensely enhanced after administration of contrast medium. All five tumors were pathologically intermediate differentiation and at FIGO stage I. CONCLUSIONS: SLCT demonstrate variable MRI morphological appearances. However, the irregularly thickened wall and septa, the moderate T2WI signal intensity and obvious enhancement in the solid components are three MRI features. PMID- 24160862 TI - Future directions in idiopathic pulmonary fibrosis research. An NHLBI workshop report. AB - The median survival of patients with idiopathic pulmonary fibrosis (IPF) continues to be approximately 3 years from the time of diagnosis, underscoring the lack of effective medical therapies for this disease. In the United States alone, approximately 40,000 patients die of this disease annually. In November 2012, the NHLBI held a workshop aimed at coordinating research efforts and accelerating the development of IPF therapies. Basic, translational, and clinical researchers gathered with representatives from the NHLBI, patient advocacy groups, pharmaceutical companies, and the U.S. Food and Drug Administration to review the current state of IPF research and identify priority areas, opportunities for collaborations, and directions for future research. The workshop was organized into groups that were tasked with assessing and making recommendations to promote progress in one of the following six critical areas of research: (1) biology of alveolar epithelial injury and aberrant repair; (2) role of extracellular matrix; (3) preclinical modeling; (4) role of inflammation and immunity; (5) genetic, epigenetic, and environmental determinants; (6) translation of discoveries into diagnostics and therapeutics. The workshop recommendations provide a basis for directing future research and strategic planning by scientific, professional, and patient communities and the NHLBI. PMID- 24160867 TI - Effect of tai chi on musculoskeletal health-related fitness and self-reported physical health changes in low income, multiple ethnicity mid to older adults. AB - BACKGROUND: Tai Chi (TC) has proven to be effective at improving musculoskeletal fitness by increasing upper and lower body strength, low back flexibility and overall physical health. The objectives of this study were to examine changes in musculoskeletal health-related fitness and self-reported physical health after a 16 week TC program in a low income multiple ethnicity mid to older adult population. METHODS: Two hundred and nine ethnically diverse mid to older community dwelling Canadian adults residing in low income neighbourhoods were enrolled in a 16 week Yang style TC program. Body Mass Index and select musculoskeletal fitness measures including upper and lower body strength, low back flexibility and self-reported physical health measured by SF 36 were collected pre and post the TC program. Determinants of health such as age, sex, marital status, education, income, ethnicity of origin, multi-morbidity conditions, weekly physical activity, previous TC experience as well as program adherence were examined as possible musculoskeletal health-related fitness change predictors. RESULTS: Using paired sample t-tests significant improvements were found in both upper and lower body strength, low back flexibility, and the SF 36 physical health scores (p < 0.05). Based on multiple linear regression analyses, no common health determinants explained a significant portion of the variation in percent changes of the musculoskeletal fitness and SF 36 measures. CONCLUSIONS: These results reveal that TC has the potential of having a beneficial influence on musculoskeletal health-related fitness and self-reported physical health in a mid to older low socioeconomic, ethnically diverse sample. PMID- 24160868 TI - An analysis of respiratory induced kidney motion on four-dimensional computed tomography and its implications for stereotactic kidney radiotherapy. AB - BACKGROUND AND PURPOSE: Stereotactic ablative body radiotherapy (SABR) is an emerging treatment modality for primary renal cell carcinoma. To account for respiratory-induced target motion, an internal target volume (ITV) concept is often used in treatment planning of SABR. The purpose of this study is to assess patterns of kidney motion and investigate potential surrogates of kidney displacement with the view of ITV verification during treatment. MATERIAL AND METHODS: Datasets from 71 consecutive patients with free breathing four dimensional computed tomography (4DCT) planning scans were included in this study. The displacement of the left and right hemi-diaphragm, liver dome and abdominal wall were measured and tested for correlation with the displacement of the both kidneys and patient breathing frequency. RESULTS: Nine patients were excluded due to severe banding artifact. Of 62 evaluable patients, the median age was 68 years, with 41 male patients and 21 female patients. The mean (range) of the maximum, minimum and average breathing frequency throughout the 4DCTs were 20.1 (11-38), 15.1 (9-24) and 17.3 (9-27.5) breaths per minute, respectively. The mean (interquartile range) displacement of the left and right kidneys was 0.74 cm (0.45-0.98 cm) and 0.75 cm (0.49-0.97) respectively. The amplitude of liver-dome motion was correlated with right kidney displacement (r=0.52, p<0.001), but not with left kidney displacement (p=0.796). There was a statistically significant correlation between the magnitude of right kidney displacement and that of abdominal displacement (r=0.36, p=0.004), but not the left kidney (r=0.24, p=0.056). Hemi-diaphragm displacements were correlated with kidney displacements respectively, with a weaker correlation for the left kidney/left diaphragm (r=0.45, [95% CI 0.22 to 0.63], p=<0.001) than for the right kidney/right diaphragm (r=0.57, [95% CI 0.37 to 0.72], p=<0.001). CONCLUSIONS: For the majority of patients, maximal left and right kidney displacement is subcentimeter in magnitude. The magnitude of kidney motion cannot be reliably estimated from the diaphragmatic, liver dome or abdominal wall surrogates. One explanation may be that the kidneys are not uniformly in contact with the surrogates investigated in this study. Further investigation is required before surrogates of kidney displacement are used for clinical SABR delivery. PMID- 24160869 TI - The Integrated Behavioural Model for Water, Sanitation, and Hygiene: a systematic review of behavioural models and a framework for designing and evaluating behaviour change interventions in infrastructure-restricted settings. AB - BACKGROUND: Promotion and provision of low-cost technologies that enable improved water, sanitation, and hygiene (WASH) practices are seen as viable solutions for reducing high rates of morbidity and mortality due to enteric illnesses in low income countries. A number of theoretical models, explanatory frameworks, and decision-making models have emerged which attempt to guide behaviour change interventions related to WASH. The design and evaluation of such interventions would benefit from a synthesis of this body of theory informing WASH behaviour change and maintenance. METHODS: We completed a systematic review of existing models and frameworks through a search of related articles available in PubMed and in the grey literature. Information on the organization of behavioural determinants was extracted from the references that fulfilled the selection criteria and synthesized. Results from this synthesis were combined with other relevant literature, and from feedback through concurrent formative and pilot research conducted in the context of two cluster-randomized trials on the efficacy of WASH behaviour change interventions to inform the development of a framework to guide the development and evaluation of WASH interventions: the Integrated Behavioural Model for Water, Sanitation, and Hygiene (IBM-WASH). RESULTS: We identified 15 WASH-specific theoretical models, behaviour change frameworks, or programmatic models, of which 9 addressed our review questions. Existing models under-represented the potential role of technology in influencing behavioural outcomes, focused on individual-level behavioural determinants, and had largely ignored the role of the physical and natural environment. IBM-WASH attempts to correct this by acknowledging three dimensions (Contextual Factors, Psychosocial Factors, and Technology Factors) that operate on five-levels (structural, community, household, individual, and habitual). CONCLUSIONS: A number of WASH-specific models and frameworks exist, yet with some limitations. The IBM-WASH model aims to provide both a conceptual and practical tool for improving our understanding and evaluation of the multi-level multi-dimensional factors that influence water, sanitation, and hygiene practices in infrastructure constrained settings. We outline future applications of our proposed model as well as future research priorities needed to advance our understanding of the sustained adoption of water, sanitation, and hygiene technologies and practices. PMID- 24160873 TI - A review on the applications of portable near-infrared spectrometers in the agro food industry. AB - Industry has created the need for a cost-effective and nondestructive quality control analysis system. This requirement has increased interest in near-infrared (NIR) spectroscopy, leading to the development and marketing of handheld devices that enable new applications that can be implemented in situ. Portable NIR spectrometers are powerful instruments offering several advantages for nondestructive, online, or in situ analysis: small size, low cost, robustness, simplicity of analysis, sample user interface, portability, and ergonomic design. Several studies of on-site NIR applications are presented: characterization of internal and external parameters of fruits and vegetables; conservation state and fat content of meat and fish; distinguishing among and quality evaluation of beverages and dairy products; protein content of cereals; evaluation of grape ripeness in vineyards; and soil analysis. Chemometrics is an essential part of NIR spectroscopy manipulation because wavelength-dependent scattering effects, instrumental noise, ambient effects, and other sources of variability may complicate the spectra. As a consequence, it is difficult to assign specific absorption bands to specific functional groups. To achieve useful and meaningful results, multivariate statistical techniques (essentially involving regression techniques coupled with spectral preprocessing) are therefore required to extract the information hidden in the spectra. This work reviews the evolution of the use of portable near-infrared spectrometers in the agro-food industry. PMID- 24160874 TI - A novel classification method for multispectral imaging combined with portable Raman spectroscopy for the analysis of a painting by Vincent Van Gogh. AB - In this work, a novel combination of portable micro-Raman spectroscopy and semi automatic methods of data treatment are proposed for the classification and mapping of visible multispectral imaging data for the analysis of a painting on paper by Vincent Van Gogh. Analysis of multispectral imaging data with the sequential maximum-angle convex cone (SMACC) and spectral angle mapper (SAM) algorithms differentiated the surface into areas on the basis of the presence of pigment mixtures. Complementary analytical information was obtained through portable Raman spectroscopy was performed on a few selected points of the painting, allowing for the determination of Van Gogh's palette and the mapping of pigment mixtures on the painting's surface; the number of mixtures employed is varied and at least two different blues are present. The results obtained were integrated with the information from prior ultraviolet (UV)-induced luminescence analysis performed on the same painting to better understand the materials used by the artist. The mathematical treatment of multispectral data using the proposed methods could be extended to the analysis of other painted surfaces. PMID- 24160871 TI - High-resolution analytical electron microscopy reveals cell culture media-induced changes to the chemistry of silver nanowires. AB - There is a growing concern about the potential adverse effects on human health upon exposure to engineered silver nanomaterials (particles, wires, and plates). However, the majority of studies testing the toxicity of silver nanomaterials have examined nominally "as-synthesized" materials without considering the fate of the materials in biologically relevant fluids. Here, in-house silver nanowires (AgNWs) were prepared by a modified polyol process and were incubated in three cell culture media (DMEM, RPMI-1640, and DCCM-1) to examine the impact of AgNW medium interactions on the physicochemical properties of the AgNWs. High resolution analytical transmission electron microscopy revealed that Ag2S crystals form on the surface of AgNWs within 1 h of incubation in DCCM-1. In contrast, the incubation of AgNWs in RPMI-1640 or DMEM did not lead to sulfidation. When the DCCM-1 cell culture medium was separated into its small molecule solutes and salts and protein components, the AgNWs were found to sulfidize in the fraction containing small molecule solutes and salts but not in the fraction containing the protein component of the media. Further investigation showed the AgNWs did not readily sulfidize in the presence of isolated sulfur containing amino acids or proteins, such as cysteine or bovine serum albumin (BSA). The results demonstrate that the AgNWs can be transformed by the media before and during the incubation with cells, and therefore, the effects of cell culture media must be considered in the analysis of toxicity assays. Appropriate media and material controls must be in place to allow accurate predictions about the toxicity and, ultimately, the health risk of this commercially relevant class of nanomaterial. PMID- 24160875 TI - Enhancement of laser-induced breakdown spectroscopy (LIBS) Detection limit using a low-pressure and short-pulse laser-induced plasma process. AB - Laser-induced breakdown spectroscopy (LIBS) technology is an appealing technique compared with many other types of elemental analysis because of the fast response, high sensitivity, real-time, and noncontact features. One of the challenging targets of LIBS is the enhancement of the detection limit. In this study, the detection limit of gas-phase LIBS analysis has been improved by controlling the pressure and laser pulse width. In order to verify this method, low-pressure gas plasma was induced using nanosecond and picosecond lasers. The method was applied to the detection of Hg. The emission intensity ratio of the Hg atom to NO (IHg/INO) was analyzed to evaluate the LIBS detection limit because the NO emission (interference signal) was formed during the plasma generation and cooling process of N2 and O2 in the air. It was demonstrated that the enhancement of IHg/INO arose by decreasing the pressure to a few kilopascals, and the IHg/INO of the picosecond breakdown was always much higher than that of the nanosecond breakdown at low buffer gas pressure. Enhancement of IHg/INO increased more than 10 times at 700 Pa using picosecond laser with 35 ps pulse width. The detection limit was enhanced to 0.03 ppm (parts per million). We also saw that the spectra from the center and edge parts of plasma showed different features. Comparing the central spectra with the edge spectra, IHg/INO of the edge spectra was higher than that of the central spectra using the picosecond laser breakdown process. PMID- 24160876 TI - Characterization of silver halide fiber optics and hollow silica waveguides for use in the construction of a mid-infrared attenuated total reflection fourier transform infrared (ATR FT-IR) spectroscopy probe. AB - Advances in fiber optic materials have allowed for the construction of fibers and waveguides capable of transmitting infrared radiation. An investigation of the transmission characteristics associated with two commonly used types of infrared transmitting fibers/waveguides for prospective use in a fiber/waveguide-coupled attenuated total internal reflection (ATR) probe was performed. Characterization of silver halide polycrystalline fiber optics and hollow silica waveguides was done on the basis of the transmission of infrared light using a conventional fiber optic coupling accessory and an infrared microscope. Using the fiber optic coupling accessory, the average percent transmission for three silver halide fibers was 18.1 +/- 6.1% relative to a benchtop reflection accessory. The average transmission for two hollow waveguides (HWGs) using the coupling accessory was 8.0 +/- 0.3%. (Uncertainties in the relative percent transmission represent the standard deviations.) Reduced transmission observed for the HWGs was attributed to the high numerical aperture of the coupling accessory. Characterization of the fibers/waveguides using a zinc selenide lens objective on an infrared microscope indicated 24.1 +/- 7.2% of the initial light input into the silver halide fibers was transmitted. Percent transmission obtained for the HWGs was 98.7 +/- 0.1%. Increased transmission using the HWGs resulted from the absence or minimization of insertion and scattering losses due to the hollow air core and a better matched numerical aperture. The effect of bending on the transmission characteristics of the fibers/waveguides was also investigated. Significant deviations in the transmission of infrared light by the solid-core silver halide fibers were observed for various bending angles. Percent transmission greater than 98% was consistently observed for the HWGs at the bending angles. The combined benefits of high percent transmission, reproducible instrument responses, and increased bending tolerance indicated HWGs should be preferred in the construction of a fiber/waveguide-coupled ATR probe. PMID- 24160877 TI - Detection of harmful residues in honey using terahertz time-domain spectroscopy. AB - Terahertz time-domain spectroscopy (THz-TDS) has been applied for the detection and discrimination of harmful chemical residues in honey. Three antibiotics (sulfapyridine, sulfathiazole, and tetracycline) and two acaricides (coumaphos and amitraz) were characterized in the THz frequency regime between 0.5 THz and 6.0 THz. All chemical substances present distinct absorption peaks. THz transmission measurements of honey mixtures with antibiotics have been performed, revealing that antibiotic residues are traceable in highly absorptive food products, such as honey, at concentrations down to 1% weight percentage, thanks to their THz fingerprints. Moreover, multiple antibiotics were identified in their mixture with honey, pointing out the potential of the technique to be used in the near future as a fast, real-time technique for detecting and discriminating multi-residues strictly related to food safety issues. PMID- 24160878 TI - A fluorescent nanoprobe based on graphene oxide fluorescence resonance energy transfer for the rapid determination of oncoprotein vascular endothelial growth factor (VEGF). AB - Oncoprotein vascular endothelial growth factor (VEGF) is one of the most critical growth factors that regulates tumor growth and division. The vascular endothelial growth factor (VEGF) is also an important biomarker for different diseases and clinical disorders. Herein, we propose a graphene oxide (GO) fluorescence resonance energy transfer (FRET)-based aptasensor for rapid, sensitive, and selective detection of VEGF in homogeneous solution. The fluorescent dye-labeled anti-VEGF aptamer is adsorbed on the surface of GO via pi-pi interaction between the flat planar GO sheets and the ring structures in the nucleobases, which results in the fluorescence quenching of the dye due to the highly effective FRET from the dye to GO. Upon recognition and binding with the target VEGF, it specifically forms a VEGF/aptamer complex and then release from the GO surface, leading to the restoration of fluorescence signal of the dye. This GO-based sensing platform exhibits high sensitivity and specificity toward VEGF versus other proteins, with the detection limits corresponding to 2.5*10(-10) M. The sensitivity of this new type of aptamer-based assay is at least one order of magnitude higher than that of conventional homogeneous optical assays. Moreover, the application of this nanosensor for human serum sample analysis is also demonstrated. The GO/aptamer-based assay approach holds great promise as a general platform for detection of a variety of target molecules. PMID- 24160879 TI - Line selection and parameter optimization for trace analysis of uranium in glass matrices by laser-induced breakdown spectroscopy (LIBS). AB - Laser-induced breakdown spectroscopy (LIBS) has been evaluated for the determination of uranium in real-world samples such as uraninite. NIST Standard Reference Materials were used to evaluate the spectral interferences on detection of uranium. The study addresses the detection limit of LIBS for several uranium lines and their relationship to non-uranium lines, with emphasis on spectral interferences. The data are discussed in the context of optimizing the choice of emission lines for both qualitative and quantitative analyses from a complex spectrum of uranium in the presence of other elements. Temporally resolved spectral emission intensities, line width, and line shifts were characterized to demonstrate the parameter influence on these measurements. The measured uranium line width demonstrates that LIBS acquired with moderately high spectral resolution (e.g., by a 1.25 m spectrometer with a 2400 grooves/mm grating) can be utilized for isotope shift measurements in air at atmospheric pressure with single to tens of parts per million (ppm) level detection limits, as long as an appropriate transition is chosen for analysis. PMID- 24160880 TI - A comparative study of pressure-dependent emission characteristics in different gas plasmas induced by nanosecond and picosecond neodymium-doped yttrium aluminum garnet (Nd:YAG) lasers. AB - An experimental study has been performed on the pressure-dependent plasma emission intensities in Ar, He, and N2 surrounding gases with the plasma induced by either nanosecond (ns) or picosecond (ps) yttrium aluminum garnet laser. The study focused on emission lines of light elements such as H, C, O, and a moderately heavy element of Ca from an agate target. The result shows widely different pressure effects among the different emission lines, which further vary with the surrounding gases used and also with the different ablation laser employed. It was found that most of the maximum emission intensities can be achieved in Ar gas plasma generated by ps laser at low gas pressure of around 5 Torr. This experimental condition is particularly useful for spectrochemical analysis of light elements such as H, C, and O, which are known to suffer from intensity diminution at higher gas pressures. Further measurements of the spatial distribution and time profiles of the emission intensities of H I 656.2 nm and Ca II 396.8 nm reveal the similar role of shock wave excitation for the emission in both ns and ps laser-induced plasmas, while an additional early spike is observed in the plasma generated by the ps laser. The suggested preference of Ar surrounding gas and ps laser was further demonstrated by outperforming the ns laser in their applications to depth profiling of the H emission intensity and offering the prospect for the development of three-dimensional analysis of a light element such as H and C. PMID- 24160881 TI - Non-destructive determination of ethylene vinyl acetate cross-linking in photovoltaic (PV) modules by Raman spectroscopy. AB - Vibrational spectroscopy was found to be a suitable method for the determination of the degree of cross-linking of ethylene vinyl acetate (EVA) polymers. Spectral changes in the Raman spectra of EVA with increasing lamination time (which equals increasing degree of cross-linking) were mainly detected in the CH vibrational regions, namely, in the relative intensities of the characteristic CH3 and CH2 bands. These spectral regions were chosen for a chemometric evaluation where a calibration was performed with the Raman spectra of reference EVA samples and the results obtained from corresponding thermal analysis (differential scanning calorimetry) and Soxhlet extraction data. These datasets were subsequently used to non-destructively determine the progress of cross-linking in EVA foils, embedded in various mini-modules by Raman microscopy. Thus, we could show that Raman spectroscopy is a highly interesting method for quality control in the production of photovoltaic (PV) modules. However, this approach is valid only for a given grade of EVA, meaning a demand for a new calibration when changing the supplier or the type of EVA used. In addition, the applicability of infrared spectroscopy for the determination of the degree of cross-linking was tested. A good correlation of the decrease in intensity of the characteristic cross-linker infrared bands with increasing progress of the cross-linking was found, as determined by reference methods. However, this analytical method requires taking samples of the EVA foils and is, thus, unsuitable for the non-destructive determination of the degree of cross-linking of the EVA encapsulated within a PV module. PMID- 24160882 TI - Mapping of leaf water content using near-infrared hyperspectral imaging. AB - In this study, near-infrared hyperspectral imaging was applied to predict the water content of golden pothos (Epipremnum aureum) leaves, after which partial least squares regression (PLSR) analysis was performed to predict their averaged water content. The resulting predictive model was then applied to each single pixel spectra in order to construct a water content image that could be used to evaluate the model's applicability to the single-pixel spectra through partial least squares score comparisons between the averaged spectra used for calibration and the single-pixel spectra. In the next phase, it was determined that a rebuilt PLSR predictive model based on the averaged spectra of an applicable pixel showed higher prediction accuracy than that of the original model. This study provides effective information about the limitations of prediction mapping and the optimization of pixel selections for better calibrations. PMID- 24160883 TI - Investigation on the adsorption of alkoxysilanes on stainless steel. AB - Alkoxysilanes, and mainly trialkoxysilanes, have been widely used as coupling agents on metallic surfaces. They are of interest mainly because they form a water-stable covalent bond with a surface composed of hydroxides. The grafting of these molecules should also give rise to the formation of a siloxane network at the substrate's surface. However, only a few studies examine stainless steel substrate, such as AISI 316L, for which the main difficulty is the low surface reactivity. In order to improve the silane anchoring, a prehydrolysis of the alkoxysilane was performed to transform the methoxy groups into silanol groups. This reaction happened in an aqueous medium and at a controlled pH, which impacted the prehydrolysis efficiency. Curing followed this step, which allows the grafting of the alkoxysilane on stainless steel's surface. Polarization modulation infrared reflection absorption spectroscopy (PM-IRRAS) was performed in order to identify the grafting of the silane molecules. Tests were made to compare the grafting of alkoxysilanes as a function of their functional groups and their prehydrolysis conditions. PM-IRRAS coupled with atomic force microscopy allowed the observation of the grafting of the studied alkoxysilanes. The nature of the remaining functional group (its ability to react with polymer, for example) of the alkoxysilane plays a major role in this process, since its chemical nature influences the grafting mechanism. PMID- 24160884 TI - Design and characterization of hybrid morphology nanoarrays as plasmonic Raman probes for antimicrobial detection. AB - Advances in nanofabrication have allowed the production of new and more reproducible substrates for the Raman detection of trace antimicrobials in water. The superior substrate uniformity combined with the ability to control surface morphology represents a significant step forward in the design of substrates with improved enhancement factors and trace-detection capabilities. The work presented herein successfully combines electron-beam lithography (EBL) and reactive ion etching (RIE) protocols for the construction, testing, and validation of plasmonic hybrid morphology nanoarrays for the detection of arsenic antimicrobials in water. The fabricated substrates consist of 2500 MUm(2) Ag coated silicon dioxide (SiO2)/Si pillar nanoarrays of alternating hexagonal and elliptical features. Control of simple fabrication parameters such as inter particle spacing (gap) and its orientation relative to the laser polarization vector (parallel or orthogonal) result in over a tenfold improvement in the apparent Raman response under optimized conditions. At a 633 nm excitation frequency, the best substrate performance was observed on parallel-oriented features with a 200 nm gap, with over one order of magnitude increase in the apparent surface-enhanced Raman scattering (SERS) signal relative to standard silver-polydimethylsiloxane (Ag-PDMS) nanocomposites. Monitoring of the characteristic As-C stretching band at 594 cm(-1) allowed the detection of arsenic antimicrobials in water well within the parts per million range. Calculated surface-enhancement factors (SEF) for this substrate, employing 532, 785, and 633 nm excitation wavelengths, was within five, six, and seven orders of magnitude, respectively. The effect of substrate morphology and nanofabrication process on the Raman enhancement factor is presented. PMID- 24160885 TI - Quantitative assessment of hydrocarbon contamination in soil using reflectance spectroscopy: a "multipath" approach. AB - Petroleum hydrocarbons are contaminants of great significance. The commonly used analytic method for assessing total petroleum hydrocarbons (TPH) in soil samples is based on extraction with 1,1,2-Trichlorotrifluoroethane (Freon 113), a substance prohibited to use by the Environmental Protection Agency. During the past 20 years, a new quantitative methodology that uses the reflected radiation of solids has been widely adopted. By using this approach, the reflectance radiation across the visible, near infrared-shortwave infrared region (400-2500 nm) is modeled against constituents determined using traditional analytic chemistry methods and then used to predict unknown samples. This technology is environmentally friendly and permits rapid and cost-effective measurements of large numbers of samples. Thus, this method dramatically reduces chemical analytical costs and secondary pollution, enabling a new dimension of environmental monitoring. In this study we adapted this approach and developed effective steps in which hydrocarbon contamination in soils can be determined rapidly, accurately, and cost effectively solely from reflectance spectroscopy. Artificial contaminated samples were analyzed chemically and spectrally to form a database of five soils contaminated with three types of petroleum hydrocarbons (PHCs), creating 15 datasets of 48 samples each at contamination levels of 50 5000 wt% ppm (parts per million). A brute force preprocessing approach was used by combining eight different preprocessing techniques with all possible datasets, resulting in 120 different mutations for each dataset. The brute force was done based on an innovative computing system developed for this study. A new parameter for evaluating model performance scoring (MPS) is proposed based on a combination of several common statistical parameters. The effect of dividing the data into training validation and test sets on modeling accuracy is also discussed. The results of this study clearly show that predicting TPH levels at low concentrations in selected soils at high precision levels is viable. Dividing a dataset into training, validation, and test groups affects the modeling process, and different preprocessing methods, alone or in combination, need to be selected based on soil type and PHC type. MPS was found to be a better parameter for selecting the best performing model than ratio of prediction to deviation, yielding models with the same performance but less complicated and more stable. The use of the "all possibilities" system proved to be mandatory for efficient optimal modeling of reflectance spectroscopy data. PMID- 24160886 TI - Agricultural case studies of classification accuracy, spectral resolution, and model over-fitting. AB - This paper describes the relationship between spectral resolution and classification accuracy in analyses of hyperspectral imaging data acquired from crop leaves. The main scope is to discuss and reduce the risk of model over fitting. Over-fitting of a classification model occurs when too many and/or irrelevant model terms are included (i.e., a large number of spectral bands), and it may lead to low robustness/repeatability when the classification model is applied to independent validation data. We outline a simple way to quantify the level of model over-fitting by comparing the observed classification accuracies with those obtained from explanatory random data. Hyperspectral imaging data were acquired from two crop-insect pest systems: (1) potato psyllid (Bactericera cockerelli) infestations of individual bell pepper plants (Capsicum annuum) with the acquisition of hyperspectral imaging data under controlled-light conditions (data set 1), and (2) sugarcane borer (Diatraea saccharalis) infestations of individual maize plants (Zea mays) with the acquisition of hyperspectral imaging data from the same plants under two markedly different image-acquisition conditions (data sets 2a and b). For each data set, reflectance data were analyzed based on seven spectral resolutions by dividing 160 spectral bands from 405 to 907 nm into 4, 16, 32, 40, 53, 80, or 160 bands. In the two data sets, similar classification results were obtained with spectral resolutions ranging from 3.1 to 12.6 nm. Thus, the size of the initial input data could be reduced fourfold with only a negligible loss of classification accuracy. In the analysis of data set 1, several validation approaches all demonstrated consistently that insect-induced stress could be accurately detected and that therefore there was little indication of model over-fitting. In the analyses of data set 2, inconsistent validation results were obtained and the observed classification accuracy (81.06%) was only a few percentage points above that obtained using random data (66.7-77.4%). Thus, our analysis highlights a potential risk of model over-fitting and emphasizes the importance of testing for this important aspect as part of developing reliable and robust classification models. PMID- 24160887 TI - Atmospheric compensation in Fourier transform infrared (FT-IR) spectra of clinical samples. AB - A new method is proposed for the elimination of the spectral contribution of two atmospheric gases (CO2 and H2O) in Fourier transform infrared (FT-IR) spectra of clinical samples. The algorithm is based on the measurement of reference spectra of H2O followed by an automatic calculation of the spectral contribution of the above-mentioned gases to the sample spectra. Then this contribution is compensated by spectral subtraction. Attenuated total reflectance FT-IR spectra of serum and urine samples in the presence of atmospheric gases were corrected and compared with spectra obtained with an N2 purge. Visual inspection of the spectra as well as calculated noise levels confirmed that the method compensated for the contribution of CO2 and H2O to serum and urine spectra to a great extent. As compared with the correction performed by a commercial software package, the proposed method clearly improved the correction of CO2 and provided similar results for H2O compensation. Correlation values between corrected spectra and those obtained under N2-purged conditions in the fingerprint region were higher than 0.995, and noise values in regions where samples did not absorb confirmed the suitability of the correction. The proposed method is fast, easy, and extensible to other gaseous interferences, devices, and acquisition conditions. PMID- 24160888 TI - A novel approach for a functional group to predict protein in undigested residue and protein digestibility by mid-infrared spectroscopy. AB - To evaluate nutrient digestibility, we propose the novel approach of functional group digestibility (FGD). The FGD was based on the absorbance of specific Fourier transform infrared (FT-IR) peaks and the ratio of an inorganic indigestible marker in diet and digesta, without calibration. For application, samples of diet and digesta of wheat with predetermined crude protein (CP) digestibility were scanned on an FT-IR spectrometer equipped with a single reflection attenuated total reflection (ATR) attachment. The FGD in the amide I region (1689-1631 cm (-1)) of digesta spectra was strongly related (R(2) = 0.99) with CP digestibility. The measured diet CP digestibility ranged from 60.4 to 87.8% with a standard error of prediction of 1.09%. In conclusion, instead of predictions based on calibrations, FGD can be calculated directly from spectra, provided the ratio of marker in diet and undigested residue is known, and then accurately predicts nutrient digestibility. PMID- 24160889 TI - Universal binding behavior for ionic alkyl surfactants with oppositely charged polyelectrolytes. AB - Oppositely charged polyelectrolyte-surfactant mixtures are ubiquitous in biology and the basis of numerous consumer healthcare products. Despite their broad use, however, a rational approach to their formulation remains challenging because of the complicated association mechanisms. Through compilation and analysis of literature reports and our own research, we have developed a semiempirical correlation of the binding strength of surfactants to polyelectrolytes in salt free mixtures as a function of the polyion linear charge density and the surfactant hydrophobicity. We have found that the cooperative binding strength increases as the square of the polyelectrolyte's linear charge density and in proportion to the surfactant's hydrophobicity, such that a quantitative relationship holds across a broad range of polyelectrolytes. Deviations from the correlation reveal the role of system-specific interactions not considered in the analysis. This engineering relationship aids in the rational design of oppositely charged polyelectrolyte-surfactant formulations for consumer products and biomedicines by enabling the prediction of binding strengths in polyelectrolyte surfactant mixtures based on mesoscale parameters determined from the chemical composition. PMID- 24160890 TI - Michael addition-aromatization reaction of dienylimines bearing a leaving group and its application to the preparation of thiol-selective labeling reagents capable of forming strong carbon-sulfur bonds. AB - The reaction of a dienylimine with thiols was found to proceed smoothly to afford the corresponding indolines bearing aromatic carbon-sulfur bonds as a result of a Michael addition-aromatization sequence. Furthermore, this reaction was applied to the development of fluorogenic dienylimines that could be used as thiol selective fluorescent labeling reagents. PMID- 24160891 TI - Escherichia coli with two linear chromosomes. AB - A number of attempts have been made to simplify the synthesis of whole chromosomes to generate artificial microorganisms. However, the sheer size of the average bacterial genome makes the task virtually impracticable. A major limitation is the maximum assembly DNA size imposed by the current available technologies. We propose to fragment the bacterial chromosome into autonomous replicating units so that (i) each episome becomes small enough to be assembled in its entirety within an assembly host and (ii) the complete episome set should be able to generate a viable cell. In this work, we used the telN/tos system of bacteriophage N1 to show that the circular genome of Escherichia coli can be split into two linear chromosomes that complement each other to produce viable cells. PMID- 24160892 TI - Autonomic care platform for optimizing query performance. AB - BACKGROUND: As the amount of information in electronic health care systems increases, data operations get more complicated and time-consuming. Intensive Care platforms require a timely processing of data retrievals to guarantee the continuous display of recent data of patients. Physicians and nurses rely on this data for their decision making. Manual optimization of query executions has become difficult to handle due to the increased amount of queries across multiple sources. Hence, a more automated management is necessary to increase the performance of database queries. The autonomic computing paradigm promises an approach in which the system adapts itself and acts as self-managing entity, thereby limiting human interventions and taking actions. Despite the usage of autonomic control loops in network and software systems, this approach has not been applied so far for health information systems. METHODS: We extend the COSARA architecture, an infection surveillance and antibiotic management service platform for the Intensive Care Unit (ICU), with self-managed components to increase the performance of data retrievals. We used real-life ICU COSARA queries to analyse slow performance and measure the impact of optimizations. Each day more than 2 million COSARA queries are executed. Three control loops, which monitor the executions and take action, have been proposed: reactive, deliberative and reflective control loops. We focus on improvements of the execution time of microbiology queries directly related to the visual displays of patients' data on the bedside screens. RESULTS: The results show that autonomic control loops are beneficial for the optimizations in the data executions in the ICU. The application of reactive control loop results in a reduction of 8.61% of the average execution time of microbiology results. The combined application of the reactive and deliberative control loop results in an average query time reduction of 10.92% and the combination of reactive, deliberative and reflective control loops provides a reduction of 13.04%. CONCLUSIONS: We found that by controlled reduction of queries' executions the performance for the end-user can be improved. The implementation of autonomic control loops in an existing health platform, COSARA, has a positive effect on the timely data visualization for the physician and nurse. PMID- 24160893 TI - A cohort study in university students: investigation of risk factors for cytomegalovirus infection. AB - Little is known about the main routes of human cytomegalovirus (HCMV) transmission in young adult populations. This study investigated risk factors for HCMV transmission in young adults attending university over a 3-year period. Blood samples were tested for HCMV specific viral capsid antigen IgG by enzyme immunoassay. Being born in a developing country and having lived in Africa were associated with HCMV seropositivity at study onset. No risk factors were associated with HCMV seroconversion over the 3-year follow-up. In contrast to previous reports, sexual activity was not associated with HCMV seroprevalence or seroconversion. PMID- 24160894 TI - Survey of causative agents for acute respiratory infections among patients in Khartoum-State, Sudan, 2010-2011. AB - BACKGROUND: This study was carried out to determine causative agents of acute respiratory illness of patients in Khartoum State, Sudan. METHODS: Four hundred patients experiencing respiratory infections within January-March 2010 and January-March 2011 were admitted at Khartoum Hospital and had their throat swab samples subjected to multiplex real-time RT-PCR to detect influenza viruses (including subtypes) and other viral agents. Isolation, nucleotide sequence and phylogenetic analysis on some influenza viruses based on the HA gene were done. RESULTS: Out of 400 patients, 66 were found to have influenza viruses (35, 27, 2, and 2 with types A, B, C, and A and B co-infections, respectively). Influenza viruses were detected in 28, 33 and 5 patients in the age groups <1, 1-10, and 11 30 years old, respectively but none in the 31-50 years old group. Out of 334 patients negative for influenza viruses, 27, 14, and 2 were positive for human respiratory syncytial virus, rhinovirus and adenovirus, respectively. Phylogenetic tree on influenza A (H1N1) pdm09 subtype shows that Sudan strains belong to the same clade and are related to those strains from several countries such as USA, Japan, Italy, United Kingdom, Germany, Russia, Greece, Denmark, Taiwan, Turkey and Kenya. Seasonal A H3 subtypes have close similarity to strains from Singapore, Brazil, Canada, Denmark, USA and Nicaragua. For influenza B, Sudan strains belong to two different clades, and just like influenza A (H1N1) pdm09 and A H3 subtypes, seem to be part of worldwide endemic population (Kenya, USA, Brazil, Russia, Taiwan and Singapore). CONCLUSIONS: In Sudan, the existence of respiratory viruses in patients with acute respiratory infection was confirmed and characterized for the first time by using molecular techniques. PMID- 24160895 TI - Fluidity enhancement: a critical factor for performance of liposomal transdermal drug delivery system. AB - Liposomes are well known lipid carriers for drug delivery of bioactive molecules encapsulated inside their membrane. Liposomes as skin drug delivery systems were initially promoted primarily for localized effects with minimal systemic delivery. Subsequently, a novel vesicular system, transferosomes was reported for transdermal delivery with efficiency similar to subcutaneous injection. The multiple bilayered organizations of lipids applied in these vesicles structure are somewhat similar to complex nature of stratum corneal intercellular lipids domains. The incorporation of novel agents into these lipid vesicles results in the loss of entrapped markers but it is similar to fluidization of stratum corneum lipids on treatment with a penetration enhancer. This approach generated the utility of penetration enhancers/fluidizing agents in lipids vesicular systems for skin delivery. For the transdermal and topical applications of liposomes, fluidity of bilayer lipid membrane is rate limiting which governs the permeation. This article critically reviews the relevance of using different types of vesicles as a model for skin in permeation enhancement studies. This study has also been designed to encompass all enhancement measurements and analytical tools for characterization of permeability in liposomal vesicular system. PMID- 24160896 TI - Estimating error rates in bioactivity databases. AB - Bioactivity databases are routinely used in drug discovery to look-up and, using prediction tools, to predict potential targets for small molecules. These databases are typically manually curated from patents and scientific articles. Apart from errors in the source document, the human factor can cause errors during the extraction process. These errors can lead to wrong decisions in the early drug discovery process. In the current work, we have compared bioactivity data from three large databases (ChEMBL, Liceptor, and WOMBAT) who have curated data from the same source documents. As a result, we are able to report error rate estimates for individual activity parameters and individual bioactivity databases. Small molecule structures have the greatest estimated error rate followed by target, activity value, and activity type. This order is also reflected in supplier-specific error rate estimates. The results are also useful in identifying data points for recuration. We hope the results will lead to a more widespread awareness among scientists on the frequencies and types of errors in bioactivity data. PMID- 24160897 TI - Expressivity of hearing loss in cases with Usher syndrome type IIA. AB - OBJECTIVE: The purpose of this study was to compare the genotype/phenotype relationship between siblings with identical USH2A pathologic mutations and the consequent audiologic phenotypes, in particular degree of hearing loss (HL). Decade audiograms were also compared among two groups of affected subjects with different mutations of USH2A. DESIGN: DNA samples from patients with Usher syndrome type II were analysed. The audiological features of patients and affected siblings with USH2A mutations were also examined to identify genotype phenotype correlations. STUDY SAMPLE: Genetic and audiometric examinations were performed in 18 subjects from nine families with Usher syndrome type IIA. RESULTS: Three different USH2A mutations were identified in the affected subjects. Both similarities and differences of the auditory phenotype were seen in families with several affected siblings. A variable degree of hearing loss, ranging from mild to profound, was observed among affected subjects. No significant differences in hearing thresholds were found the group of affected subjects with different pathological mutations. CONCLUSIONS: Our results indicate that mutations in the USH2A gene and the resulting phenotype are probably modulated by other variables, such as modifying genes, epigenetics or environmental factors which may be of importance for better understanding the etiology of Usher syndrome. PMID- 24160899 TI - Impacts of social networking sites on patient care in the emergency department. AB - The use of Facebook is ubiquitous among both patients and physicians. Often Facebook intrudes into medical practice, thereby highlighting its potential to be either a positive or negative factor in a patient's medical care. Despite being a "hot topic" in the medical literature, very few real world examples exist of physicians actually using information obtained from Facebook to reach a diagnosis or otherwise affect patient care. We present a case involving a 13-year-old girl who posted photographs and captions on Facebook demonstrating suicidal ideation. The patient's parents were alerted to the girl's statements in her Facebook profile and brought her to the emergency department. The girl's statements and photographs, as reported by her parents, were used by an emergency physician to make a diagnosis of suicidal risk and to disposition of the patient to an inpatient psychiatric ward. We discuss the potential diagnostic utility of information posted on Facebook and briefly discuss the ethical questions surrounding this situation. PMID- 24160900 TI - Barriers to using text message appointment reminders in an HIV clinic. AB - INTRODUCTION: Failure to attend medical appointments among persons living with human immunodeficiency virus (HIV) has been associated with poor health outcomes. Text message appointment reminders are a novel tool to potentially improve appointment attendance, but the feasibility of this tool among persons living with HIV in the United States is unknown. SUBJECTS AND METHODS: We conducted a randomized, controlled trial of text message reminders in a large HIV clinic. Patients who declined enrollment were asked for reasons for declining. For all patients randomized, demographic and clinical data were collected from medical records. RESULTS: Of 94 patients screened for the study, 42 (45%) did not elect to participate; the most common reason for declining participation was the lack of either a cell phone or text messaging service. Cost, comfort with text messaging, and privacy were other major barriers to study enrollment. Among the 25 subjects randomized to receive text messages, 6 (24%) had their phones disconnected prior to the appointment reminder date. Ultimately, there were no differences in clinic attendance rates between the group that received text reminders versus the group that did not (72% versus 81%, p=0.42) in an intention to-treat analysis. CONCLUSIONS: Although text message reminders may be successful in certain groups of patients, barriers must be addressed before they are used as a universal approach to improve clinic attendance. PMID- 24160901 TI - The impact of "modern telecommunication" in palliative care--the views of the professionals. AB - BACKGROUND: Specialized palliative care teams are typically based in larger hospitals, from where home visits, telephone consultations, and support are given directly to patients and relatives, but also to professionals working on the frontline. One of the challenges is the long distances to the patients' homes. Modern telecommunication may help overcome this, but little is known about the perceived advantages and barriers to palliative care. This study analyzed the views on modern telecommunication from specialized palliative care professionals' perspective. MATERIALS AND METHODS: This descriptive study is based on four semistructured group interviews where 17 health professionals from three different palliative care teams in the Central Denmark Region were interviewed from November 2009 to March 2010. RESULTS: We found that face-to-face communication is essential. The participants perceived a potentially added communicative value in visual telecommunication but would never let it replace face-to-face communication. Ethical and practical concerns were expressed on the implementation of "modern telecommunication" and in particular strong reservations against permanent telemonitoring in the patient's home. CONCLUSIONS: Our study underlines the necessity of face-to-face contact in optimal palliative care and that home visits were favored. The participants were generally positive toward telecommunication, although reservations and prerequisites were voiced. PMID- 24160898 TI - Prognostic value of isocitrate dehydrogenase 1, O6-methylguanine-DNA methyltransferase promoter methylation, and 1p19q co-deletion in Japanese malignant glioma patients. AB - BACKGROUND: To determine the prognostic value of isocitrate dehydrogenase 1 (IDH1) mutation, O6-methylguanine-DNA methyltransferase (MGMT) promoter methylation, and 1p/19q co-deletion in Japanese patients with malignant gliomas. METHODS: We studied 267 malignant gliomas, which included 171 glioblastomas (GBMs), 40 anaplastic astrocytomas (AAs), 30 anaplastic oligodendrogliomas (AOs), and 26 anaplastic oligoastrocytomas (AOAs). These malignant gliomas were divided into 2 groups (Group 1: GBM + AA, Group 2: AO + AOA) according to the presence of the oligodendroglioma component. We examined IDH1 mutation and MGMT promoter methylation in each group by direct sequencing and methylation-specific PCR, respectively. We further examined 1p/19q co-deletion in Group 2 by fluorescence in situ hybridization. Survival between groups was compared by Kaplan-Meier analysis. RESULTS: In Group 1, patients with IDH1 mutations exhibited a significantly longer survival time than patients with wild-type IDH1. However, no significant difference was observed in Group 2, although patients with IDH1 mutations tended to show prolonged survival. For both Group 1 and Group 2, patients with MGMT methylation survived longer than those without this methylation. Further, patients with 1p/19q co-deletion showed significantly better outcome in Group 2. CONCLUSIONS: Our study confirms the utility of IDH1 mutations and MGMT methylation in predicting the prognosis of Group 1 patients (GBM + AA) and demonstrated that IDH1 mutations may serve as a more reliable prognostic factor for such patients. We also showed that MGMT methylation and 1p/19q co-deletion rather than IDH1 mutations were prognostic factors for Group 2 patients (AOA + AO). Our study suggests that patients survive longer if they have IDH1 mutations and undergo total resection. Further, irrespective of MGMT promoter methylation status, the prognosis of glioma patients can be improved if total resection is performed. Moreover, our study includes the largest number of Japanese patients with malignant gliomas that has been analyzed for these three markers. We believe that our findings will increase the awareness of oncologists in Japan of the value of these markers for predicting prognosis and designing appropriate therapeutic strategies for treating this highly fatal disease. PMID- 24160904 TI - Effect of pulsed Nd:YAG laser in the treatment of neuropathic foot ulcers in children with spina bifida: a randomized controlled study. AB - OBJECTIVE: This study assessed the effects of pulsed Nd:YAG laser treatment of neuropathic foot ulcers in children with spina bifida. BACKGROUND DATA: Children with spina bifida face increased risk for developing neuropathic foot ulcers. METHODS: In a randomized controlled trial, 39 children and adolescents (ages 6-15 years) with spina bifida and stage III neuropathic foot ulcers were randomly assigned to the laser group or the placebo laser group. The former received pulsed Nd:YAG laser treatments (i.e., total energy of 300-350 J during three sessions/week) plus standard wound care, and the latter received sham laser treatments plus standard wound care. Wound size and wound appearance were assessed for all patients at the beginning of the treatment, after 5 weeks, and after 10 weeks. RESULTS: The decrease in wound surface area at 5 and 10 weeks post- treatment was significantly greater in the laser group (i.e., 2.44 +/- 0.33 and 0.29 +/- 0.25 cm(2), respectively) than in the placebo group (i.e., 3.81 +/- 0.18 and 3.24 +/- 0.44 cm(2), respectively). Also, the decrease in the total score for the Pressure Sore Status Tool (PSST) at 5 and 10 weeks post-treatment was significantly different for the laser group (i.e., 32.76 +/- 2.30 and 17.52 +/- 1.66, respectively) than for the placebo group (i.e., 46.50 +/- 2.12 and 38.11 +/- 3.17, respectively). CONCLUSIONS: Treatment with pulsed neodymium:yttrium aluminum garnet (Nd:YAG) laser combined with standard wound care decreases wound size and improves wound appearance for stage III neuropathic foot ulcers in children with spina bifida. PMID- 24160902 TI - Brain delivery of proteins via their fatty acid and block copolymer modifications. AB - It is well known that hydrophobic small molecules penetrate cell membranes better than hydrophilic molecules. Amphiphilic molecules that dissolve both in lipid and aqueous phases are best suited for membrane transport. Transport of biomacromolecules across physiological barriers, e.g. the blood-brain barrier, is greatly complicated by the unique structure and function of such barriers. Two decades ago we adopted a simple philosophy that to increase protein delivery to the brain one needs to modify this protein with hydrophobic moieties. With this general idea we began modifying proteins (antibodies, enzymes, hormones, etc.) with either hydrophobic fatty acid residues or amphiphilic block copolymer moieties, such as poy(ethylene oxide)-poly(propylene oxide)-poly(ethylene oxide) (pluronics or poloxamers) and more recently, poly(2-oxasolines). This simple approach has resulted in impressive successes in CNS drug delivery. We present a retrospective overview of these works initiated in the Soviet Union in 1980s, and then continued in the United States and other countries. Notably some of the early findings were later corroborated by brain pharmacokinetic data. Industrial development of several drug candidates employing these strategies has followed. Overall modification by hydrophobic fatty acids residues or amphiphilic block copolymers represents a promising and relatively safe strategy to deliver proteins to the brain. PMID- 24160903 TI - Spacer length impacts the efficacy of targeted docetaxel conjugates in prostate specific membrane antigen expressing prostate cancer. AB - Combination of targeted delivery and controlled release is a powerful technique for cancer treatment. In this paper, we describe the design, synthesis, structure validation and biological properties of targeted and non-targeted N-(2 hydroxypropyl)methacrylamide (HPMA) copolymer-docetaxel conjugates. Docetaxel (DTX) was conjugated to HPMA copolymer via a tetrapeptide spacer (-GFLG-). 3-(1,3 dicarboxypropyl)-ureido]pentanedioic acid (DUPA) was used as the targeting moiety to actively deliver DTX for treatment of Prostate-Specific Membrane Antigen (PSMA) expressing prostate cancer. Short and long spacer DUPA monomers were prepared, and four HPMA copolymer--DTX conjugates (non-targeted, two targeted with short spacer of different molecular weight and targeted with long spacer) were prepared via Reversible Addition-Fragmentation Chain Transfer (RAFT) copolymerization. Following confirmation of PSMA expression on C4-2 cell line, the DTX conjugates' in vitro cytotoxicity was tested against C4-2 tumor cells and their anticancer efficacies were assessed in nude mice bearing s.c. human prostate adenocarcinoma C4-2 xenografts. The in vivo results show that the spacer length between targeting moieties and HPMA copolymer backbone can significantly affect the treatment efficacy of DTX conjugates against C4-2 tumor bearing nu/nu mice. Moreover, histological analysis indicated that the DUPA-targeted DTX conjugate with longer spacer had no toxicity in major organs of treated mice. PMID- 24160906 TI - An official American Thoracic Society research statement: comparative effectiveness research in pulmonary, critical care, and sleep medicine. AB - BACKGROUND: Comparative effectiveness research (CER) is intended to inform decision making in clinical practice, and is central to patient-centered outcomes research (PCOR). PURPOSE: To summarize key aspects of CER definitions and provide examples highlighting the complementary nature of efficacy and CER studies in pulmonary, critical care, and sleep medicine. METHODS: An ad hoc working group of the American Thoracic Society with experience in clinical trials, health services research, quality improvement, and behavioral sciences in pulmonary, critical care, and sleep medicine was convened. The group used an iterative consensus process, including a review by American Thoracic Society committees and assemblies. RESULTS: The traditional efficacy paradigm relies on clinical trials with high internal validity to evaluate interventions in narrowly defined populations and in research settings. Efficacy studies address the question, "Can it work in optimal conditions?" The CER paradigm employs a wide range of study designs to understand the effects of interventions in clinical settings. CER studies address the question, "Does it work in practice?" The results of efficacy and CER studies may or may not agree. CER incorporates many attributes of outcomes research and health services research, while placing greater emphasis on meeting the expressed needs of nonresearcher stakeholders (e.g., patients, clinicians, and others). CONCLUSIONS: CER complements traditional efficacy research by placing greater emphasis on the effects of interventions in practice, and developing evidence to address the needs of the many stakeholders involved in health care decisions. Stakeholder engagement is an important component of CER. PMID- 24160907 TI - Reviewing progress: 7 year trends in characteristics of adults and children enrolled at HIV care and treatment clinics in the United Republic of Tanzania. AB - BACKGROUND: To evaluate the on-going scale-up of HIV programs, we assessed trends in patient characteristics at enrolment and ART initiation over 7 years of implementation. METHODS: Data were from Optimal Models, a prospective open cohort study of HIV-infected (HIV+) adults (>=15 years) and children (<15 years) enrolled from January 2005 to December 2011 at 44 HIV clinics in 3 regions of mainland Tanzania (Kagera, Kigoma, Pwani) and Zanzibar. Comparative statistics for trends in characteristics of patients enrolled in 2005-2007, 2008-2009 and 2010-2011 were examined. RESULTS: Overall 62,801 HIV + patients were enrolled: 58,102(92.5%) adults, (66.5% female); 4,699(7.5%) children.Among adults, pregnant women enrolment increased: 6.8%, 2005-2007; 12.1%, 2008-2009; 17.2%, 2010-2011; as did entry into care from prevention of mother-to-child HIV transmission (PMTCT) programs: 6.6%, 2005-2007; 9.5%, 2008-2009; 12.6%, 2010-2011. WHO stage IV at enrolment declined: 27.1%, 2005-2007; 20.2%, 2008-2009; 11.1% 2010-2011. Of the 42.5% and 29.5% with CD4+ data at enrolment and ART initiation respectively, median CD4+ count increased: 210 cells/MUL, 2005-2007; 262 cells/MUL, 2008-2009; 266 cells/MUL 2010-2011; but median CD4+ at ART initiation did not change (148 cells/MUL overall). Stavudine initiation declined: 84.9%, 2005-2007; 43.1%, 2008 2009; 19.7%, 2010-2011.Among children, median age (years) at enrolment decreased from 6.1(IQR:2.7-10.0) in 2005-2007 to 4.8(IQR:1.9-8.6) in 2008-2009, and 4.1(IQR:1.5-8.1) in 2010-2011 and children <24 months increased from 18.5% to 26.1% and 31.5% respectively. Entry from PMTCT was 7.0%, 2005-2007; 10.7%, 2008 2009; 15.0%, 2010-2011. WHO stage IV at enrolment declined from 22.9%, 2005-2007, to 18.3%, 2008-2009 to 13.9%, 2010-2011. Proportion initiating stavudine was 39.8% 2005-2007; 39.5%, 2008-2009; 26.1%, 2010-2011. Median age at ART initiation also declined significantly. CONCLUSIONS: Over time, the proportion of pregnant women and of adults and children enrolled from PMTCT programs increased. There was a decline in adults and children with advanced HIV disease at enrolment and initiation of stavudine. Pediatric age at enrolment and ART initiation declined. Results suggest HIV program maturation from an emergency response. PMID- 24160909 TI - Refraining from pre-hospital advanced airway management: a prospective observational study of critical decision making in an anaesthesiologist-staffed pre-hospital critical care service. AB - INTRODUCTION: We report prospectively recorded observational data from consecutive cases in which the attending pre-hospital critical care anaesthesiologist considered performing pre-hospital advanced airway management but decided to withhold such interventions. MATERIALS AND METHODS: Anaesthesiologists from eight pre-hospital critical care teams in the Central Denmark Region (a mixed rural and urban region with 1.27 million inhabitants) registered data from February 1st 2011 to October 31st 2012. Included were patients of all ages for whom pre-hospital advanced airway management were considered but not performed. The main objectives were to investigate (1) the pre hospital critical care anaesthesiologists' reasons for considering performing pre hospital advanced airway management in this group of patients (2) the pre hospital critical care anaesthesiologists' reasons for not performing pre hospital advanced airway management (3) the methods used to treat these patients (4) the incidence of complications related to pre-hospital advanced airway management not being performed. RESULTS: We registered data from 1081 cases in which the pre-hospital critical care anaesthesiologists' considered performing pre-hospital advanced airway management. The anaesthesiologists decided to withhold pre-hospital advanced airway management in 32.1% of these cases (n = 347). In 75.1% of these cases (n = 257) pre-hospital advanced airway management were withheld because of the patient's condition and in 30.8% (n = 107) because of patient co-morbidity. The most frequently used alternative treatment was bag mask ventilation, used in 82.7% of the cases (n = 287). Immediate complications related to the decision of not performing pre-hospital advanced airway management occurred in 0.6% of the cases (n = 2). CONCLUSION: We have illustrated the complexity of the critical decision-making associated with pre-hospital advanced airway management. This study is the first to identify the most common reasons why pre-hospital critical care anaesthesiologists sometimes choose to abstain from pre-hospital advanced airway management as well as the alternative treatment methods used. PMID- 24160908 TI - Development of streptavidin-based nanocomplex for siRNA delivery. AB - In our previous study, we have identified a PCBP2 siRNA that exhibits antifibrotic activity in rat hepatic stellate cells (HSCs) by inhibition of alphaCP2, a protein responsible for stabilization of the collagen alpha1 (I) mRNA in alcoholic liver fibrosis. This study aims to develop a streptavidin-based nanocomplex that can efficiently deliver the PCBP2 siRNA to HSCs. Biotin-siRNA and biotin-cholesterol were mixed with streptavidin to form the streptavidin biotin complex, which was further condensed electrostatically with positively charged protamine to form the final multicomponent siRNA nanocomplex in the size range of 150-250 nm. The siRNA nanocomplex does not induce cytotoxicity in rat HSCs as compared to commercially available transfection agents. The cellular uptake efficiency of the siRNA nanocomplex is higher in rat HSCs than other cell lines, such as Caco-2 and PC-3, indicating that receptor-mediated endocytosis mainly contributes to the cellular uptake of the siRNA nanocomplex. The siRNA nanocomplex exhibits more than 85% silencing effect on the PCBP2 mRNA in HSCs. Stability study indicates that the nanocomplex can efficiently protect siRNA from degradation in the serum. The streptavidin-based multicomponent siRNA nanocomplex provides a promising strategy to deliver the PCBP2 siRNA to HSCs. Moreover, the nanocomplex can be used as a platform for other diseases by changing the siRNA sequence and targeting ligand. PMID- 24160910 TI - Radiation-induced liver disease after stereotactic body radiotherapy for small hepatocellular carcinoma: clinical and dose-volumetric parameters. AB - BACKGROUND: To investigate the clinical and dose-volumetric parameters that predict the risk of radiation-induced liver disease (RILD) for patients with small, unresectable hepatocellular carcinoma (HCC) treated with stereotactic body radiotherapy (SBRT). METHODS: Between March 2007 and December 2009, 92 patients with HCC treated with SBRT were reviewed for RILD within 3 months of completing treatment. RILD was evaluated according to the Common Terminology Criteria for Adverse Events, version 3.0. A dose of 10-20 Gy (median, 15 Gy) per fraction was given over 3-4 consecutive days for a total dose of 30-60 Gy (median, 45 Gy). The following clinical and dose-volumetric parameters were examined: age, gender, Child-Pugh class, presence of hepatitis B virus, gross tumor volume, normal liver volume, radiation dose, fraction size, mean dose to the normal liver, and normal liver volumes receiving from < 5 Gy to < 60 Gy (in increments of 5 Gy). RESULTS: Seventeen (18.5%) of the 92 patients developed grade 2 or worse RILD after SBRT (49 patients in grade 1, 11 in grade 2, and 6 in >= grade 3). On univariate analysis, Child-Pugh class was identified as a significant clinical parameter, while normal liver volume and normal liver volumes receiving from < 15 Gy to < 60 Gy were the significant dose-volumetric parameters. Upon multivariate analysis, only Child-Pugh class was a significant parameter for predicting grade 2 or worse RILD. CONCLUSIONS: The Child-Pugh B cirrhosis was found to have a significantly greater susceptibility to the development of grade 2 or worse RILD after SBRT in patients with small, unresectable HCC. Additional efforts aimed at testing other models to predict the risk of RILD in a large series of HCC patients treated with SBRT are needed. PMID- 24160912 TI - A review on different modes and methods for yielding a pentose sugar: xylitol. AB - Xylitol, a five-carbon polyalcohol, holds a substantial place in the cure and prevention of a number of diseases. The foremost reason for its lesser usage in day-to-day practice is its cost. The method employed on large scale production of this polyol, i.e. chemical reduction, uses extensive machinery and expensive chemicals thus increasing the basic cost of the sugar. Yield of xylitol by other methods including fermentation and enzymatic production is far less than chemical reduction. We did a literature analysis and briefed out the various experiments carried out till date and concluded on the required studies for improving its production and lowering down its cost. PMID- 24160911 TI - Cardiopulmonary involvement in Puumala hantavirus infection. AB - BACKGROUND: Hantavirus infections cause potentially life-threatening disease in humans world-wide. Infections with American hantaviruses may lead to hantavirus pulmonary syndrome characterised by severe cardiopulmonary distress with high mortality. Pulmonary involvement in European Puumala hantavirus (PUUV) infection has been reported, whereas knowledge of potential cardiac manifestations is limited. We aimed to comprehensively investigate cardiopulmonary involvement in patients with PUUV-infection. METHODS: Twenty-seven hospitalised patients with PUUV-infection were examined with lung function tests, chest high-resolution CT (HRCT), echocardiography including speckle tracking strain rate analysis, ECG and measurements of cardiac biomarkers N-terminal pro-B-type natriuretic peptide (NT ProBNP) and troponin T. Patients were re-evaluated after 3 months. Twenty-five age and sex-matched volunteers acted as controls for echocardiography data. RESULTS: Two-thirds of the patients experienced respiratory symptoms as dry cough or dyspnoea. Gas diffusing capacity was impaired in most patients, significantly improving at follow-up but still subnormal in 38%. HRCT showed thoracic effusions or pulmonary oedema in 46% of the patients. Compared to controls, the main echocardiographic findings in patients during the acute phase were significantly higher pulmonary vascular resistance, higher systolic pulmonary artery pressure, lower left ventricular ejection fraction and impaired left atrial myocardial motion. Pathological ECG, atrial fibrillation or T-wave changes, was demonstrated in 26% of patients. NT-ProBNP concentrations were markedly increased and were inversely associated with gas diffusing capacity but positively correlated to pulmonary vascular resistance. Furthermore, patients experiencing impaired general condition at follow-up had significantly lower gas diffusing capacity and higher pulmonary vascular resistance, compared to those feeling fully recovered. CONCLUSIONS: In a majority of patients with PUUV-infection, both cardiac and pulmonary involvement was demonstrated with implications on patients' recovery. The results demonstrate vascular leakage in the lungs that most likely is responsible for impaired gas diffusing capacity and increased pulmonary vascular resistance with secondary pulmonary hypertension and right heart distress. Interestingly, NT-ProBNP was markedly elevated even in the absence of overt ventricular heart failure. The method of simultaneous investigations of important cardiac and respiratory measurements improves the interpretation of the underlying pathophysiologic mechanisms. PMID- 24160913 TI - Turning Russian specialized microbial culture collections into resource centers for biotechnology. AB - Specialized nonmedical microbial culture collections contain unique bioresources that could be useful for biotechnology companies. Cooperation between collections and companies has suffered from shortcomings in infrastructure and legislation, hindering access to holdings. These challenges may be overcome by the transformation of collections into national bioresource centers and integration into international microbial resource networks. PMID- 24160914 TI - InterVA versus Spectrum: how comparable are they in estimating AIDS mortality patterns in Nairobi's informal settlements? AB - BACKGROUND: The Spectrum computer package is used to generate national AIDS mortality estimates in settings where vital registration systems are lacking. Similarly, InterVA-4 (the latest version of the InterVA programme) is used to estimate cause-of-mortality data in countries where cause-specific mortality data are not available. OBJECTIVE: This study aims to compare trends in adult AIDS related mortality estimated by Spectrum with trends from the InterVA-4 programme applied to data from a Health and Demographic Surveillance System (HDSS) in Nairobi, Kenya. DESIGN: A Spectrum model was generated for the city of Nairobi based on HIV prevalence data for Nairobi and national antiretroviral therapy coverage, underlying mortality, and migration assumptions. We then used data, generated through verbal autopsies, on 1,799 deaths that occurred in the HDSS area from 2003 to 2010 among adults aged 15-59. These data were then entered into InterVA-4 to estimate causes of death using probabilistic modelling. Estimates of AIDS-related mortality rates and all-cause mortality rates from Spectrum and InterVA-4 were compared and presented as annualised trends. RESULTS: Spectrum estimated that HIV prevalence in Nairobi was 7%, while the HDSS site measured 12% in 2010. Despite this difference, Spectrum estimated higher levels of AIDS related mortality. Between 2003 and 2010, the proportion of AIDS-related mortality in Nairobi decreased from 63 to 40% according to Spectrum and from 25 to 16% according to InterVA. The net AIDS-related mortality in Spectrum was closer to the combined mortality rates when AIDS and tuberculosis (TB) deaths were included for InterVA-4. CONCLUSION: Overall trends in AIDS-related deaths from both methods were similar, although the values were closer when TB deaths were included in InterVA. InterVA-4 might not accurately differentiate between TB and AIDS deaths. PMID- 24160917 TI - Conformational modifications of gB from herpes simplex virus type 1 analyzed by synthetic peptides. AB - Entry of enveloped viruses requires fusion of viral and cellular membranes, driven by conformational changes of viral glycoproteins. The crystallized trimeric glycoprotein gB of herpes simplex virus has been described as a postfusion conformation, and several studies prove that like other class III fusion proteins, gB undergoes a pH-dependent switch between the pre- and postfusion conformations. Using several biophysical techniques, we show that peptides corresponding to the long helix of the gB postfusion structure interfere with the membrane fusion event, likely hampering the conformational rearrangements from the pre- to the postfusion structures. Those peptides represent good candidates for further design of peptidomimetic antagonists capable of blocking the fusion process. PMID- 24160916 TI - Guidelines adherence in the treatment of patients with newly diagnosed type 2 diabetes: a historical cohort comparing the use of metformin in Quebec pre and post-Canadian Diabetes Association guidelines. AB - BACKGROUND: Given the high prevalence of diabetes, guidelines are updated frequently to reflect optimal treatment recommendations. Our study aims to measure the response of primary care physicians to changes in choice of initial therapy for patients with type 2 diabetes in relationship to a change in Canadian Diabetes Association (CDA) Guidelines in 2008. We also assessed patients' and physicians' factors which may affect this change. METHODS: Historical cohort study of primary care physicians' participating in an electronic medical record research network in Quebec, Canada. 111 primary care physicians and 1279 newly treated patients with diabetes with a prescription of an oral hypoglycemic agent (OHA) between January 20 2003 and December 29 2011 were included. Multivariate GEE logistic regression was used to estimate the impact of guideline change on treatment choice controlling for patients' and physicians' characteristics. RESULTS: After the new CDA guidelines, there was an increase in incident use of metformin from 89.7% to 94.6% (OR 1.86, 95% CI 1.20-2.90) with an accompanying reduction in the use of thiazolidinediones (OR 0.21, 95% CI 0.08-0.55), and reduction in the initiation of sulfonylureas (OR 0.78, 95% CI 0.43-1.09). Physicians' attitudes to evidence-based practice did not significantly modify response to a change in guidelines recommendations. However, older patients and those with renal failure were less likely to receive metformin. CONCLUSIONS: Metformin initiation in newly diagnosed diabetes patients has increased post 2008 CDA guidelines. However, due to the nature of the study design, we can not determine whether the observed change in metformin prescribing was causally related to the change in the guideline. PMID- 24160915 TI - Improving quality in population surveys of headache prevalence, burden and cost: key methodological considerations. AB - Population-based studies of headache disorders are important. They inform needs assessment and underpin service policy for a set of disorders that are a public health priority. On the one hand, our knowledge of the global burden of headache is incomplete, with major geographical gaps; on the other, methodological differences and variable quality are notable among published studies of headache prevalence, burden and cost. The purpose here was to start the process of developing standardized and better methodology in these studies. An expert consensus group was assembled to identify the key methodological issues, and areas where studies might fail. Members had competence and practical experience in headache epidemiology or epidemiology in general, and were drawn from all WHO world regions. We reviewed the relevant literature, and supplemented the knowledge gathered from this exercise with experience gained from recent Global Campaign population-based studies, not all yet published. We extracted methodological themes and identified issues within them that were of key importance. We found wide variations in methodology. The themes within which methodological shortcomings had adverse impact on quality were the following: study design; selection and/or definition of population of interest; sampling and bias avoidance; sample size estimation; access to selected subjects (managing and reporting non-participation); case definition (including diagnosis and timeframe); case ascertainment (including diagnostic validation of questionnaires); burden estimation; reporting (methods and results). These are discussed. PMID- 24160918 TI - Polybrominated diphenyl ether (PBDE) accumulation by earthworms (Eisenia fetida) exposed to biosolids-, polyurethane foam microparticle-, and Penta-BDE-amended soils. AB - Polybrominated diphenyl ether (PBDE) flame retardants have been used in consumer polymers at up to percent levels. While long viewed as biologically inaccessible therein, PBDEs may become bioaccessible following volatilization or polymer deterioration. PBDEs may then enter soils via polymer fragmentation or following land application of sewage sludge-derived biosolids. Studies of direct PBDE uptake from these materials by soil organisms are scarce. We thus exposed earthworms ( Eisenia fetida ) to artificial soil amended with a Class B anaerobically digested biosolid (ADB), an exceptional quality composted biosolid (CB), PBDE-containing polyurethane foam (PUF) microparticles, and Penta-BDE spiked artificial soil (SAS). Worms accumulated mg/kg (lipid) ?Penta-PBDE burdens from all substrates. Biota-soil accumulation factors (BSAFs) for worms exposed to ADB- and CB-amended soils were comparable after 28 d. BSAFs generally decreased with increasing congener KOW and substrate dosage. Biosolids-associated PBDE bioavailability was lower than spiked PBDEs. BSAFs for worms exposed to PUF microparticles ranged from 3.9 to 33.4, with ?Penta-PBDE tissue burdens reaching 3740 mg/kg lipid. Congener accumulation patterns were similar in worms and polyethylene passive sampling devices immersed in ADB-amended soil coincident with exposed worms. However, passive sampler accumulation factors were lower than BSAFs. Our results demonstrate that PBDEs may accumulate in organisms ingesting soils containing biosolids or waste plastics. Such organisms may then transfer their burdens to predators or translocate them from the site of application/disposal. PMID- 24160920 TI - Statin-fibrate combination therapy is safe and effective in normalizing lipid profile and in keeping cardiovascular event rates low. PMID- 24160919 TI - Kinetic solvent isotope effect in human P450 CYP17A1-mediated androgen formation: evidence for a reactive peroxoanion intermediate. AB - Human steroid hormone biosynthesis is the result of a complex series of chemical transformations operating on cholesterol, with key steps mediated by members of the cytochrome P450 superfamily. In the formation of the male hormone dehydroepiandrosterone, pregnenolone is first hydroxylated by P450 CYP17A1 at the 17-carbon, followed a second round of catalysis by the same enzyme that cleaves the C17-C20 bond, releasing acetic acid and the 17-keto product. In order to explore the mechanism of this C-C "lyase" activity, we investigated the kinetic isotope effect on the steady-state turnover of Nanodisc-incorporated CYP17A1. Our experiments revealed the expected small positive (~1.3) isotope effect for the hydroxylase chemistry. However, a surprising result was the large inverse isotope effect (~0.39) observed for the C-C bond cleavage activity. These results strongly suggest that the P450 reactive intermediate involved in this latter step is an iron-bound ferric peroxoanion. PMID- 24160922 TI - Management of gastrointestinal emergencies. PMID- 24160921 TI - Yeast oligo-mediated genome engineering (YOGE). AB - High-frequency oligonucleotide-directed recombination engineering (recombineering) has enabled rapid modification of several prokaryotic genomes to date. Here, we present a method for oligonucleotide-mediated recombineering in the model eukaryote and industrial production host Saccharomyces cerevisiae , which we call yeast oligo-mediated genome engineering (YOGE). Through a combination of overexpression and knockouts of relevant genes and optimization of transformation and oligonucleotide designs, we achieve high gene-modification frequencies at levels that only require screening of dozens of cells. We demonstrate the robustness of our approach in three divergent yeast strains, including those involved in industrial production of biobased chemicals. Furthermore, YOGE can be iteratively executed via cycling to generate genomic libraries up to 10 (5) individuals at each round for diversity generation. YOGE cycling alone or in combination with phenotypic selections or endonuclease-based negative genotypic selections can be used to generate modified alleles easily in yeast populations with high frequencies. PMID- 24160923 TI - Acute upper gastrointestinal bleeding (UGIB) - initial evaluation and management. AB - Acute upper gastrointestinal bleeding (UGIB) is the most common reason that the 'on-call' gastroenterologist is consulted. Despite the diagnostic and therapeutic capabilities of upper endoscopy, there is still significant associated morbidity and mortality in patients experiencing acute UGIB, thus this is a true GI emergency. Acute UGIB is divided into non-variceal and variceal causes. The most common type of acute UGIB is 'non-variceal' and includes diagnoses such as peptic ulcer (gastric and duodenal), gastroduodenal erosions, Mallory-Weiss tears, erosive oesophagitis, arterio-venous malformations, Dieulafoy's lesion, and upper GI tract tumours and malignancies. This article focuses exclusively on initial management strategies for acute upper GI bleeding. We discuss up to date and evidence-based strategies for patient risk stratification, initial patient management prior to endoscopy, potential causes of UGIB, role of proton pump inhibitors, prokinetic agents, prophylactic antibiotics, vasoactive pharmacotherapies, and timing of endoscopy. PMID- 24160924 TI - Management of GI emergencies: peptic ulcer acute bleeding. AB - Peptic ulcer bleeding is a common medical emergency. Management of acute ulcer bleeding requires prompt assessment for risk stratification, evaluation for early endoscopy, initiation of pharmacotherapy and treatment of co-morbid diseases. Tremendous advances in endoscopic technique and pharmacotherapy in the past few decades have reduced recurrent bleeding, the need for surgery and mortality of the disease. Strategies to minimize recurrence have been defined for various types of peptic ulcers. This article reviews the current management of acute peptic ulcer bleeding. PMID- 24160925 TI - Variceal and other portal hypertension related bleeding. AB - Variceal bleeding is one of the commonest and most severe complications of liver cirrhosis. Even with the current best medical care, mortality from variceal bleeding is still around 20%. When cirrhosis is diagnosed, varices are present in about 30-40% of compensated patients and in 60% of those who present with ascites. Once varices have been diagnosed, the overall incidence of variceal bleeding is in the order of 25% at two years. Variceal size is the most useful predictor for variceal bleeding, other predictors are severity of liver dysfunction (Child-Pugh classification) and the presence of red wale marks on the variceal wall. The current consensus is that every cirrhotic patient should be endoscopically screened for varices at the time of diagnosis to detect those requiring prophylactic treatment. Non-selective beta-adrenergic blockers (NSBB) and endoscopic band ligation (EBL) have been shown effective in the prevention of first variceal bleeding. The current recommendation for treating acute variceal bleeding is to start vasoactive drug therapy early (ideally during the transferral or to arrival to hospital, even if active bleeding is only suspected) and performing EBL. Once bleeding is controlled, combination therapy with NSBB + EBL should be used to prevent rebleeding. In patients at high risk of treatment failure despite of using this approach, an early covered-TIPS within 72 h (ideally 24 h) should be considered. Data on management of gastric variceal bleeding is limited. No clear recommendation for primary prophylaxis can be done. In acute cardiofundal variceal bleeding, vasoactive agents together with cyanoacrylate (CA) injection seem to be the treatment of choice. Further CA injections and/or NSBB may be used to prevent rebleeding. TIPS or Balloon occluded retrograde transvenous obliteration when TIPS is contraindicated may be used as a rescue therapy. PMID- 24160926 TI - Non-hemorrhagic acute complications associated with cirrhosis and portal hypertension. AB - Timely recognition and management of acute complications of cirrhosis is of significant importance in order to reduce morbidity and mortality, especially in the hospitalized patient. In this review, we present a practical approach to the identification and management of non-hemorrhagic acute complications of cirrhosis, specifically bacterial infections, acute kidney injury, and acute exacerbation of hepatic encephalopathy, focusing on patient stratification. PMID- 24160927 TI - Foreign bodies and caustic lesions. AB - Foreign body ingestions, food bolus impactions, and caustic agent injuries are frequent but specific situations. Although most foreign bodies will naturally pass through the digestive tract, practitioners should recognize specific situations were endoscopic management is required. In such cases, timing and adequate equipment are critical. Endoscopic treatment is successful in about 95% of patients. Severe complications (including oesophageal perforations) are rare. Underlying diseases (including eosinophilic oesophagitis) must be investigated after food bolus impaction. Accidental or suicidal ingestion of corrosive agents may result in severe upper gastrointestinal tract injuries requiring a multidisciplinary approach including gastroenterologists, surgeons, otorhynolaryngologists, anaesthesiologists and psychiatrists. Treatment includes conservative management of patients with mild injuries, while patients with severe injuries undergo emergency surgical exploration. At distance of the ingestion episode, oesophageal reconstruction is required in patients who underwent oesophageal resection and in patients who developed oesophageal strictures that failed dilatation. PMID- 24160928 TI - Acute GI obstruction. AB - Acute gastrointestinal obstruction occurs when the normal flow of intestinal contents is interrupted. The blockage can occur at any level throughout the gastrointestinal tract. The clinical symptoms depend on the level and extent of obstruction. Various benign and malignant processes can produce acute gastrointestinal obstruction, which often represents a medical emergency because of the potential for bowel ischemia leading to perforation and peritonitis. Early recognition and appropriate treatment are thus essential. The typical clinical symptoms associated with obstruction include nausea, vomiting, dysphagia, abdominal pain and failure to pass bowel movements. Abdominal distention, tympany due to an air-filled stomach and high-pitched bowel sounds suggest the diagnosis. The diagnostic process involves imaging including radiography, ultrasonography, contrast fluoroscopy and computer tomography in less certain cases. In patients with uncomplicated obstruction, management is conservative, including fluid resuscitation, electrolyte replacement, intestinal decompression and bowel rest. In many cases, endoscopy may aid in both the diagnostic process and in therapy. Endoscopy can be used for bowel decompression, dilation of strictures or placement of self-expandable metal stents to restore the luminal flow either as a final treatment or to allow for a delay until elective surgical therapy. When gastrointestinal obstruction results in ischemia, perforation or peritonitis, emergency surgery is required. PMID- 24160929 TI - Gastro-intestinal vascular emergencies. AB - Gastro-Intestinal Vascular Emergencies include all digestive ischaemic injuries related to acute or chronic vascular and/or haemodynamic diseases. Gastro intestinal ischaemic injuries can be occlusive or non-occlusive, arterial or venous, localized or generalized, superficial or transmural and share the risks of infarction, organ failure and death. The diagnosis must be suspected, at the initial presentation of any sudden, continuous and unusual abdominal pain, contrasting with normal physical examination. Risk factors are often unknown at presentation and no biomarker is currently available. The diagnosis is confirmed by abdominal computed tomography angiography identifying intestinal ischaemic injury, either with vascular occlusion or in a context of low flow. Recent knowledge in the pathophysiology of acute mesenteric ischaemia, clinical experience and existing recommendations have generated a multimodal and multidisciplinary management strategy. Based on the gastro-intestinal viability around a simple algorithm, and coordinated by gastroenterologists, the dual aim is to avoid large intestinal resections and death. PMID- 24160931 TI - Acute biliary conditions. AB - Acute biliary complications may result from several medical conditions such as gallstone pancreatitis, acute cholangitis, acute cholecystitis, bile leak, liver abscess and hepatic trauma. Gallstones are the most common cause of acute pancreatitis. About 25% of theses patients will develop clinically severe acute pancreatitis, usually due to necrotizing pancreatitis. Choledocholithiasis, malignant and benign biliary strictures, and stent dysfunction may cause partial or complete obstruction and infection in the biliary tract with acute cholangitis. Bile leaks are most commonly associated with hepatobiliary surgeries or invasive procedures such as open or laparoscopic cholecystectomy, hepatic resection, hepatic transplantation, liver biopsy, and percutaneous transhepatic cholangiography. Endoscopic retrograde cholangiopancreatography (ERCP) and endoscopic ultrasound (EUS) may have an essential role in the management of these complications. PMID- 24160930 TI - Early management of acute pancreatitis. AB - Acute pancreatitis is the most common gastro-intestinal indication for acute hospitalization and its incidence continues to rise. In severe pancreatitis, morbidity and mortality remains high and is mainly driven by organ failure and infectious complications. Early management strategies should aim to prevent or treat organ failure and to reduce infectious complications. This review addresses the management of acute pancreatitis in the first hours to days after onset of symptoms, including fluid therapy, nutrition and endoscopic retrograde cholangiography. This review also discusses the recently revised Atlanta classification which provides new uniform terminology, thereby facilitating communication regarding severity and complications of pancreatitis. PMID- 24160933 TI - Fulminant colitis. AB - Fulminant colitis is an ill-defined entity that is usually viewed as the most severe form of uncomplicated acute colitis. It usually occurs in the course of ulcerative colitis and infectious colitis, but can also be seen in other forms of colitis. Every patient with clinical criteria for severe or fulminant colitis should be approached in a systematic way, based on two premises - intense medical treatment and early surgery in non-responders. PMID- 24160932 TI - Acute liver failure. AB - Untreated acute liver failure (ALF) has a poor outcome and so rapid diagnosis and management is vital if the patient is to survive. ALF has such profound and widespread physiological consequences that whenever possible, patients with ALF should be managed in an intensive care unit. Management is to support the physiology and treat the underlying cause. Advice should be sought from a centre capable of performing liver transplantation. Should recovery seem unlikely, liver transplantation is a viable treatment option in some cases. PMID- 24160935 TI - Paediatric GI emergencies. AB - Paediatric GI emergencies constitute a wide range of gut pathologies ranging from those that are common, easily diagnosed and treated to conditions that are rarer, often more severe and challenging to manage. Among a myriad of ordinary clinical symptoms and signs physicians have to identify the child with a serious, life threatening pathology and initiate the appropriate diagnostic and therapeutic pathway. The aim of the review is to present and discuss a selection of key paediatric GI emergencies that provide challenges in diagnosis and treatment. These conditions are classified by their presentation or pathogenesis and include inflammatory conditions, those presenting with GI obstruction or haemorrhage and the ingestion of foreign bodies or caustic substances. The most recent advances regarding the management of these entities are discussed along with key areas of clinical practice and future research. PMID- 24160934 TI - Emergencies after endoscopic procedures. AB - Endoscopy adverse events (AEs), or complications, are a rising concern on the quality of endoscopic care, given the technical advances and the crescent complexity of therapeutic procedures, over the entire gastrointestinal and bilio pancreatic tract. In a small percentage, not established, there can be real emergency conditions, as perforation, severe bleeding, embolization or infection. Distinct variables interfere in its occurrence, although, the awareness of the operator for their potential, early recognition, and local organized facilities for immediate handling, makes all the difference in the subsequent outcome. This review outlines general AEs' frequencies, important predisposing factors and putative prophylactic measures for specific procedures (from conventional endoscopy to endoscopic cholangio-pancreatography and ultrasonography), with comprehensive approaches to the management of emergent bleeding and perforation. PMID- 24160936 TI - Health systems organization for emergency care. AB - The increasing number of acute and severe digestive diseases presenting to hospital emergency departments, mainly related with an ageing population, demands an appropriate answer from health systems organization, taking into account the escalating pressure on cost reduction. However, patients expect and deserve a response that is appropriate, effective, efficient and safe. The huge variety of variables which can influence the evolution of such cases warranting intensive monitoring, and the coordination and optimization of a range of human and technical resources involved in the care of these high-risk patients, requires their admission in hospital units with conveniently equipped facilities, as is done for heart attack and stroke patients. Little information of gastroenterology emergencies as a function of structure, processes and outcome is available at the organizational level. Surveys that have been conducted in different countries just assess local treatment outcome and question the organizational structure and existing resources but its impact on the outcome is not clear. Most studies address the problem of upper gastrointestinal bleeding and the out-of-hours endoscopy services in the hospital setting. The demands placed on emergency (part of the overall continuum of care) are obvious, as are the needs for the efficient use of resources and processes to improve the quality of care, meaning data must cover the full care cycle. Gastrointestinal emergencies, namely gastrointestinal bleeding, must be incorporated into the overall emergency response as is done for heart attack and stroke. This chapter aims to provide a review of current literature/evidence on organizational health system models towards a better management of gastroenterology emergencies and proposes a research agenda. PMID- 24160938 TI - Transcatheter aortic valve replacement: game-changing innovation for patients with aortic stenosis. AB - Transcatheter aortic valve replacement (TAVR) is an emerging technology for the management of patients with severe aortic stenosis (AS). First reported in 2002, TAVR has made remarkable progress in the past decade with completion of major randomized clinical trials, multiple observational registries, and evolution of several new devices. This article is a brief introductory overview of the TAVR procedure, devices, trials and registries, and newer developments in the field. PMID- 24160940 TI - Anti-B cell antibody therapies for inflammatory rheumatic diseases. AB - Several monoclonal antibodies targeting B cells have been tested as therapeutics for inflammatory rheumatic diseases. We review important observations from randomized clinical trials regarding the efficacy and safety of anti-B cell antibody-based therapies for rheumatoid arthritis, systemic lupus erythematosus, antineutrophil cytoplasmic antibody-associated vasculitis, polymyositis/dermatomyositis, and primary Sjogren's syndrome. For some anti-B cell agents, clinical benefits have been convincingly demonstrated, while other B cell-targeted therapies failed to improve outcomes when added to standard-of-care treatment or were associated with increased rates of adverse events. Although the risk-benefit balance seems to be acceptable for currently licensed anti-B cell agents, additional studies are required to fully assess the safety of treatment regimens involving prolonged interference with B cell counts and functions in rheumatic disorders. Future studies should also evaluate how to maintain disease control by means of conventional and/or biologic immunosuppressants after remission-induction with anti-B cell antibodies. PMID- 24160939 TI - Reducing hospital readmission rates: current strategies and future directions. AB - New financial penalties for institutions with high readmission rates have intensified efforts to reduce rehospitalization. Several interventions that involve multiple components (e.g., patient needs assessment, medication reconciliation, patient education, arranging timely outpatient appointments, and providing telephone follow-up) have successfully reduced readmission rates for patients discharged to home. The effect of interventions on readmission rates is related to the number of components implemented; single-component interventions are unlikely to reduce readmissions significantly. For patients discharged to postacute care facilities, multicomponent interventions have reduced readmissions through enhanced communication, medication safety, advanced care planning, and enhanced training to manage medical conditions that commonly precipitate readmission. To help hospitals direct resources and services to patients with greater likelihood of readmission, risk-stratification methods are available. Future work should better define the roles of home-based services, information technology, mental health care, caregiver support, community partnerships, and new transitional care personnel. PMID- 24160941 TI - New cost-effective treatment strategies for acute emergency situations. AB - In an era of ever-increasing healthcare costs, new treatments must not only improve outcomes and quality of care but also be cost-effective. This is most challenging for emergency and critical care. Bigger and better has been the mantra of Western medical care for decades, leading to costlier but not necessarily better care. Recent advances focused on new implementation processes for evidence-based best practices such as checklists and bundles have transformed medical care. We outline recent advances in medical practice that have positively affected both the quality of care and its cost-effectiveness. Future medical care must be smarter and more effective if we are to meet the increasing demands of an aging patient population in the context of ever more limited resources. PMID- 24160942 TI - Uniformity and diversity of response properties of neurons in the primary visual cortex: selectivity for orientation, direction of motion, and stimulus size from center to far periphery. AB - Although the primary visual cortex (V1) is one of the most extensively studied areas of the primate brain, very little is known about how the far periphery of visual space is represented in this area. We characterized the physiological response properties of V1 neurons in anaesthetized marmoset monkeys, using high contrast drifting gratings. Comparisons were made between cells with receptive fields located in three regions of V1, defined by eccentricity: central (3-5 degrees ), near peripheral (5-15 degrees ), and far peripheral (>50 degrees ). We found that orientation selectivity of individual cells was similar from the center to the far periphery. Nonetheless, the proportion of orientation-selective neurons was higher in central visual field representation than in the peripheral representations. In addition, there were similar proportions of cells representing all orientations, with the exception of the representation of the far periphery, where we detected a bias favoring near-horizontal orientations. The proportions of direction-selective cells were similar throughout V1. When the center/surround organization of the receptive fields was tested with gratings with varying diameters, we found that the population of neurons that was suppressed by large gratings was smaller in the far periphery, although the strength of suppression in these cells tended to be stronger. In addition, the ratio between the diameters of the excitatory centers and suppressive surrounds was similar across the entire visual field. These results suggest that, superimposed on the broad uniformity of V1, there are subtle physiological differences, which indicate that spatial information is processed differently in the central versus far peripheral visual fields. PMID- 24160943 TI - Profile of hepatitis B virus resistance mutations against nucleoside/nucleotide analogue treatment in Chinese patients with chronic hepatitis B. AB - AIM: Antiviral drug-resistant HBV mutants are complex and currently partly understood. This study was performed to analyze the profile of hepatitis B virus (HBV) resistance mutations against nucleos(t)ide analogues (NAs) in patients with chronic hepatitis B (CHB). METHODS: This was a population-based cross-sectional study. Serum samples of 179 patients with virological breakthrough undergoing different NAs treatment were obtained between January 2008 and December 2012. The HBV reverse transcriptase region was sequenced and the following NAs-resistant changes including rtL80, rtI169, rtV173, rtL180, rtA181, rtT184, rtA194, rtS202, rtM204, rtN236 and rtM250 were analyzed. RESULTS: In this cohort, 21.2% (38/179) were genotypes B and 78.8% (141/179) were genotypes C; and 89.4% (160/179) of them detected NAs-resistant mutations. The prevalence of HBV mutations at rtM204 was 93.0% (106/114) in patients with lamivudine (LAM) or telbivudine (LdT)-based therapies, and that of rtN236 mutations was 76.1% (35/46) in patients with adefovir dipivoxil (ADV)-based therapies. Among LAM/LdT based therapies, HBV rtM204I was significantly associated with HBV rtL80I/V mutations [rtM204I+rtL80I/V (50.0%, 32/64) vs. rtM204V+rtL80I/V (27.3%,9/33), P=0.032]; while the HBV rtM204V mutations was significantly associated with HBV rtL180M mutations [rtM204V+rtL180M (100%, 33/33) vs. rtM204I+rtL180M (60.9%, 39/64), P<0.001]. Additionally, HBV rtA181 mutations were observed in 19.3% (22/114) of patients with LAM/LdT-based therapy and 23.9% (11/46) of patients with ADV-based therapy. CONCLUSIONS: Majority of virological breakthrough is associated with NAs resistant HBV, and the mutation patterns of NAs-resistant HBV are complicated in real clinical practice. PMID- 24160945 TI - Surface-bound norbornylogous bridges as molecular rulers for investigating interfacial electrochemistry and as single molecule switches. AB - Electron transfer (ET) reactions through molecules attached to surfaces, whether they are through single molecules or ensembles, are the subject of much research in molecular electronics, bioelectronics, and electrochemistry. Therefore, understanding the factors that govern ET is of high importance. The availability of rigid hydrocarbon molecular scaffolds possessing well-defined configurations and lengths that can be systematically varied is crucial to the development of such devices. In this Account, we demonstrate how suitably functionalized norbornylogous (NB) systems can provide important insights into interfacial ET processes and electrical conduction through single molecules. To this end, we created NB bridges with vic-trans-bismethylenethiol groups at one end so they can assemble on gold electrodes and redox species at the distal ends. With these in hand, we then formed mixed self-assembled monolayers (SAMs) containing a small proportion of the NB bridges diluted with alkanethiols. As such, the NB bridges served as molecular rulers for probing the environment above the surface defined by the diluent species. Using this construct, we were able to measure the interfacial potential distribution above the diluent surface, and track how variation in the ionic distribution in the electrical double layer impacts ET kinetics. Using the same construct, but with a redox molecule that remains neutral in both oxidized and reduced states, we could explore the impact of the chemical environment near a surface on ET processes. These results are important, because with conventional surface constructs, ET occurs across this interfacial region. Such knowledge is therefore relevant to the design of molecular systems at surfaces involving ET. With a second family of molecules, we investigated aspects of single-molecule electrical conduction using NB bridges bearing vic trans-bismethylenethiol groups at both ends of the bridge. This gave us insights into distance-dependent electron transport through single molecules and introduced a method of boosting the conductance of saturated molecules by incorporating aromatic moieties in their backbone. These partially conjugated NB molecules represent a new class of molecular wires with far greater stability than conventional completely conjugated molecular wires. Of particular note was our demonstration of a single molecule switch, using a NB bridge containing an embedded anthraquinone redox group, the switching mechanism being via electrochemically controlled quantum interference. PMID- 24160946 TI - [Recent development presented in gastroenterology]. PMID- 24160944 TI - High-dose stereotactic body radiotherapy correlates increased local control and overall survival in patients with inoperable hepatocellular carcinoma. AB - BACKGROUND: Recent studies using stereotactic body radiotherapy (SBRT) for hepatocellular carcinoma (HCC) have reported high tumor response and local control. However, the optimal SBRT dose remains unknown, and it is still not clear whether a dose response relationship for local control (LC) and overall survival (OS) exist or not. We performed this study to determine whether a dose response relationship for LC and OS is observed in SBRT for inoperable HCC. METHODS: Between 2003 and 2011, 108 patients with HCC were treated with SBRT. All patients were unsuitable for surgery or local ablation and had incomplete response to transarterial chemoembolization. Eighty-two patients with a longest tumor diameter (LD) less than or equal to 7.0 cm who were treated with 3-fraction SBRT and were analyzed. This cohort comprised 74 Child-Turcotte-Pugh (CTP) class A patients and 8 CTP class B7 patients. The median LD was 3.0 cm (range, 1.0-7.0 cm), and the median dose was 51 Gy (range, 33-60 Gy). RESULTS: LC and OS rates at 2 years after SBRT were 87% and 63%, respectively, with a median follow-up duration of 30 months for all patients. The 2-year LC/OS rates for patients treated with doses of > 54, 45-54, and < 45 Gy were 100/71, 78/64, and 64%/30%, respectively (p = .009/p < .001). Multivariate analysis revealed that the SBRT dose (p = .005) and Barcelona Clinic Liver Cancer stage (p = .015) were significant prognostic factors for OS. Correlation analysis revealed a positive linear relationship between the SBRT dose and LC (p = .006, R = .899)/OS (p = .002, R = .940) at 2 years. Based on the tumor-control probability model, a dose of 54.8 Gy provides 2-year LC with a 90% probability. Five patients experienced grade 3 or higher gastrointestinal toxicity, and 6 had deteriorating of CTP score by greater than or equal to 2 within 3 months of SBRT. CONCLUSIONS: This study demonstrated a dose response relationship for LC and OS with SBRT for HCC. Higher LC rates resulting from an increased dose may translate into survival benefits for patients with HCC. PMID- 24160947 TI - [Functional and motor digestive disorders]. AB - This article discusses the most interesting studies on functional and motility gastrointestinal disorders presented in Digestive Diseases Week (DDW) in 2013. New data were reported on the clinical importance of functional gastrointestinal disorders (FGID) and on how they can produce numerous disturbances such as inflammatory bowel disease. These disturbances are associated with somatic functional disease and particularly with fatigue. In addition, new data have emerged on the physiopathology of these disorders, with some studies reporting that environmental factors and events in early infancy can favor their development. Data were also presented on how bile acids can increase susceptibility to diarrhea in patients with irritable bowel syndrome (IBS) and on how the type of food intake can favor the development of symptoms. More data are available on the presence of underlying celiac disease in patients with IBS, which should prompt us to investigate this disease in our patients. Likewise, indiscriminate application of a gluten-free diet in patients with IBS has been shown not to produce a clear improvement. Regarding the physiopathology of functional dyspepsia (FD), results have been presented on how psychological factors can modify gastric accommodation and how this is in turn related to visceral hypersensitivity and gastric emptying. Regarding therapy, mirtazapine can improve symptoms and lead to weight gain in patients with severe FD and substantial weight loss. Results were presented on new drugs for IBS such as ibodutant and on old drugs with new applications such as mesalazine and ebastine. The antinociceptive effect of linaclotide is now better understood and a meta analysis has shown its effectiveness in IBS with constipation as the main symptom. In patients with constipation, pelvic floor dysynergy can be diagnosed by a simple clinical interview and rectal touch. More data are available on the efficacy of prucalopride (which has been shown to accelerate colon transit time) and data were provided on plecanatide, a potential new drug that could be useful in constipation. Finally, results were presented on the use of botulinum toxin injection in patients with spastic motility disorders of the esophagus. Also worthy of mention is a study confirming a higher frequency of esophageal cancer patients with achalasia who receive treatment. PMID- 24160948 TI - [Safety in the diagnosis and treatment of inflammatory bowel disease]. AB - The presentations at Digestive Disease Week 2013 emphasized treatment safety. Anti-tumor necrosis factor (TNF) agents and thiopurines are reasonably safe in breastfeeding and pregnancy. Several studies indicate that controlling the risk of tuberculosis when anti-TNF agents are planned presents several problems, both in the initial diagnosis of latent tuberculosis and in subsequent patient follow up, given that cases of tuberculosis continue to occur, despite recommendations. Thiopurines increase the risk of lymphoma, but there is no residual risk when these drugs are withdrawn. Despite increasing knowledge of the risks and recommendations on how to avoid them, there remain considerable shortfalls in the application of preventive measures and, more specifically, in vaccinations. Infliximab and cyclosporin produce similar results when used to treat severe outbreaks of ulcerative colitis. Thromboembolism prevention continues to be deficient, and the barriers to effective prevention concern not only physicians but can also involve nursing staff, for example. There is still a wide margin for improvement in safety. New drugs under study (vedolizumab, golimumab) have not shown any hitherto unknown signs of significant toxicity. PMID- 24160949 TI - [New advances in the treatment of inflammatory bowel disease]. AB - Several studies on conventional drugs and new treatments in inflammatory bowel disease were presented in Digestive Disease Week 2013. Various studies have compared infliximab and cyclosporin in corticosteroid-refractory ulcerative colitis in clinical practice, providing complementary information to the CYSIF clinical trial. For the first time, a clinical trial has evaluated the efficacy of adalimumab in preventing recurrence of Crohn's disease after surgery. The results of some studies suggest that thiopurines improve response to infliximab, in both Crohn disease and ulcerative colitis. Finally, several studies were presented on new drugs with new therapeutic targets, such as vedolizumab, in the treatment of inflammatory bowel disease. The preliminary results of the ASTIC trial were reported, which evaluated the safety and efficacy of bone marrow transplantation in Crohn's disease. PMID- 24160950 TI - [Follow-up of patients with inflammatory bowel disease]. AB - Multiple data were presented on inflammatory bowel disease (IBD) in Digestive Disease Week (DDW). Of particular interest to gastroenterologists were those on novel treatments and information on safety. Other data, such as those relating to disease "follow-up", were possibly of lesser interest. However, the information reported this year was, in my opinion, highly important, because it could lead to significant changes in clinical practice. Thus, results presented strongly suggest that patients with asymptomatic IBD, specifically Crohn's disease (CD), often develop complications during their clinical course. Moreover, this is especially true in patients with CD and biological signs of inflammation, despite being asymptomatic. In addition, it seems clear that the absence of symptoms does not imply an absence of inflammation. These observations indicate a dual practical message: patients should be followed-up and objectively evaluated. Multiple data were presented on how to objectively evaluate disease activity in IBD. The prognostic value and objectivity of endoscopy has been reaffirmed, specifically with new data on the only validated index, the UCEIS, in ulcerative colitis. Together with endoscopy, the role of less invasive techniques such as imaging tests (magnetic resonance enterography, computed tomography enterography and even echography, with and without contrast agent) and fecal markers has been reaffirmed in several conditions and these techniques have a certain predictive value. Finally, many studies were reported that confirm the therapeutic activity of levels of anti-TNF and its antibodies in certain conditions and with some limitations. PMID- 24160951 TI - [Helicobacter pylori-related diseases]. AB - This article summarizes the main conclusions drawn from the presentations on Helicobacter pylori at Digestive Disease Week 2013. Knowledge of this infection among the general population continues to be extremely limited. H. pylori is the main cause of "aging" of the human stomach. In developed countries, the prevalence of H. pylori infection has decreased but continues to be considerable. In most countries, clarithromycin and metronidazole resistance rates are markedly high. H. pylori eradication improves the symptoms of functional dyspepsia, but only in a minority of patients. The frequency of idiopathic peptic ulcers seems to be rising and their prognosis is worse. Most patients with gastric cancer have, or have had, prior H. pylori infection. The risk of developing preneoplastic lesions depends on the type (strain) of the microorganism. To prevent the development of gastric cancer, eradication therapy should be administered early (before the development of intestinal metaplasia). Among H. pylori-infected patients, those who receive long-term treatment with proton pump inhibitors more frequently develop preneoplastic lesions. In patients who undergo endoscopic resection of early gastric cancer, H. pylori eradication reduces the incidence of metachronous tumors. Eradication therapy induces regression of MALT lymphoma in most patients and tumoral recurrence in the long term is exceptional; eradication is a reasonable option even when H. pylori infection has not been identified in patients with MALT lymphoma. Several diagnostic innovations were presented, such as some polymerase chain reaction techniques for use in gastric biopsy specimens or gastric juice. The efficacy of triple standard therapy is clearly inadequate. The superiority of "sequential" therapy over standard triple therapy has not been definitively established. "Concomitant" therapy is more effective and is simpler than "sequential" therapy. After failure of standard triple therapy, second-line levofloxacin-based schemes for 10 days are effective and are also simpler and better tolerated than bismuth-based quadruple therapy. Levofloxacin-based triple therapy is also a promising alternative after failure of "sequential" and "concomitant" therapies. New-generation quinolones, such as moxifloxacin, could be useful as eradication therapy, especially as rescue therapy. After failure of clarithromycin-based triple therapy, followed by that of levofloxacin-based triple therapy, a bismuth-based quadruple scheme is an acceptable alternative. Even after the failure of 3 eradication therapies, a fourth empirical rescue therapy (with rifabutin) can be effective. PMID- 24160952 TI - [Esophageal diseases: gastroesophageal reflux disease, Barrett's esophagus, achalasia and eosinophilic esophagitis]. AB - Important new advances were presented in esophageal disease in Digestive Disease Week 2013. A highlight was confirmation of the high efficacy of weight loss to treat symptoms of reflux and an interesting pilot study suggesting that a simple ligature with supra- and infracardial bands could be an effective technique in esophageal reflux. If the excellent results and safety and efficacy of this technique are confirmed in the long term, it could revolutionize the management of gastroesophageal reflux disease. Also of note this year was the presentation of multiple studies validating a new technique, peroral endoscopic myotomy (POEM) for the endoscopic treatment of achalasia. This technique seems to have excellent efficacy and safety. PMID- 24160954 TI - [Colorectal cancer screening]. AB - Colorectal cancer is the paradigm of tumoral growth that is susceptible to preventive measures, especially screening. Various screening strategies with demonstrated efficacy and efficiency are currently available, notable examples being the fecal occult blood test and endoscopic tests. In addition, new modalities have appeared in the last few years that could become viable alternatives in the near future. The present article reviews the most important presentations on colorectal screening at the annual congress of the American Gastroenterological Association held in Orlando in May 2013, with special emphasis on the medium- and long-term results of strategies using the fecal occult blood test and flexible sigmoidoscopy, as well as initial experiences with the use of new biomarkers. PMID- 24160953 TI - [Update on non-variceal gastrointestinal bleeding]. AB - This article summarizes the main studies in the field of non-variceal gastrointestinal bleeding reported in the last American Congress of Gastroenterology (Digestive Disease Week) in 2013. Some of these studies have provided new knowledge and expertise in areas of uncertainty. In this context and among other findings, it has been reported that the administration of a proton pump inhibitor (PPI) prior to endoscopy or the early performance of endoscopy within 6 hours of admission in patients with upper gastrointestinal bleeding (UGIB) (or colonoscopy within 24 hours in patients with lower gastrointestinal bleeding)-does not improve the prognosis of the event. It has also been reported that oral administration of a PPI after endoscopic hemostasis may produce a similar outcome to that of intravenously administered PPI in patients with upper gastrointestinal bleeding (UGIB). In the field of endoscopic therapy, the use of radiofrequency ablation for antral vascular ectasia is of interest. Regarding UGIB and nonsteroidal antiinflammatory drugs (NSAIDs), new data confirm the risk of cardiovascular events by stopping treatment with acetylsalicylic acid (ASA) after an episode of UGIB, the increased risk of UGIB when associating gastrotoxic drugs, and the need to identify both the gastrointestinal and cardiovascular risks of each NSAID and coxib when prescribing these agents. Finally, there is evidence that both environmental and genetic factors are involved in individual susceptibility to gastrointestinal bleeding. PMID- 24160955 TI - [Genetics of colorectal cancer]. AB - Up to 5% of all cases of colorectal cancer (CRC) are due to a known hereditary syndrome. These hereditary forms often require a high degree of suspicion for their diagnosis and specific and specialized management. Moreover, a diagnosis of hereditary CRC has important consequences, not only for patients-for whom highly effective preventive measures are available-, but also for their relatives, who may be carriers of the same condition. The most significant advances in the field of hereditary CRC have been produced in the diagnosis and characterization of these syndromes and in the discovery of new causative genes. PMID- 24160956 TI - [Surveillance colonoscopy: risk of colorectal tumors]. AB - Colonoscopy is currently the technique of choice for the diagnosis of colorectal cancer (CRC), as well as for the identification and resection of precursor lesions. However, its efficacy has been questioned due to evidence that some patients receive a diagnosis of CRC after a recent "negative" colonoscopy. These post-colonoscopy cancers are also known as interval cancers and, in the last few years, there has been interest in identifying their possible causes. The studies presented this year in the congress of the American Gastroenterological Association (AGA), described in the present article, provide important information for identification of the potential causes of neoplasms detected after a recent colonoscopy and propose methods to reduce this risk. Notable among such studies are those on the prevalence of interval colorectal cancer, those aiming to improve the quality of colonoscopy with a view to increasing the detection of neoplastic lesions, such as assessments of bowel cleansing and of the adenoma detection rate, and studies that propose new alternatives in endoscopy and in colon visualization, such as the colon capsule. PMID- 24160957 TI - [Latest advances in chronic pancreatitis]. AB - This article summarizes some of the recent and clinically relevant advances in chronic pancreatitis. These advances mainly concern knowledge of the etiopathogenesis of the disease, the pharmacological treatment of pain, and knowledge of the natural history of autoimmune pancreatitis. New evidence supports the relatively low prevalence of chronic alcoholic pancreatitis, and the role of tobacco in triggering the etiopathogenic mechanisms of chronic pancreatitis is better understood. Some studies have identified certain factors that are associated with having a positive genetic test in adults with chronic idiopathic pancreatitis, which should help to select those patients who should undergo genetic studies. Antioxidant therapy has been shown to be effective in reducing pain secondary to chronic pancreatitis, although the type and optimal dose of antioxidants remains to be elucidated. Finally, the development of exocrine and endocrine pancreatic insufficiency is a very common finding during the long-term follow-up of patients with autoimmune pancreatitis. Smoking also seems to play a role in this type of pancreatitis. PMID- 24160958 TI - [Latest advances in pancreatic tumors]. AB - Pancreatic cancer (PC) continues to have a very poor prognosis. New epidemiological trials suggest that statins could play a protective role in smokers, while HbsAg-positive hepatitis B virus could be a risk factor. Endoscopic ultrasound (EUS) is the main diagnostic tool for PC, and new technologies associated with this technique have emerged, such as quantitative elastography, intravenous contrasts or, more recently, LASER confocal endomicroscopy. New markers in urine or pancreatic juice have appeared to distinguish between PC and chronic pancreatitis. The role of the "on site" cytopathologist to increase the diagnostic yield of EUS-guided pancreatic sampling is completely supported by new prospective trials and some multicenter studies have been reported that compare the standard cytologic needles with the new procore-histology needles. Regarding cystic pancreatic tumors, most studies have aimed to validate the 2012 Sendai international guidelines and to ascertain predictive factors of malignancy in cystic lesions, mainly intraductal papillary mucinous neoplasm (IPMN). The role of intracystic CEA levels in determining malignancy is challenged. From a therapeutic point of view, EUS-guided radiofrequency ablation of cystic and solid lesions has emerged as a feasible and safe procedure in specific circumstances. PMID- 24160959 TI - [Latest advances in acute pancreatitis]. AB - The present article analyzes the main presentations on acute pancreatitis (AP) in Digestive Disease Week 2013. Perfusion computed tomography allows early diagnosis of pancreatic necrosis. Neutrophil gelatinase-associated lipocalin predicts the development of acute renal failure, severe AP and death. Factors associated with greater fluid sequestration in AP are alcoholic etiology, an elevated hematocrit, and the presence of criteria of systemic inflammatory response syndrome; fluid sequestration is associated with a worse outcome. True pseudocysts (fluid collections without necrosis for more than 4 weeks) are a highly infrequent complication in AP. Patients with necrotic collections have a poor prognosis, especially if associated with infection. A meta-analysis on fluid therapy suggests that early aggressive fluid administration is associated with higher mortality and more frequent respiratory complications. According to a meta analysis, enteral nutrition initiated within 24 hours of admission improves the outcome of AP compared with later initiation of enteral nutrition. Pentoxifylline could be a promising alternative in AP; a double-blind randomized study showed that this drug reduced the length of hospital and intensive care unit stay, as well as the need for intensive care unit admission. The association of octreotide and celecoxib seems to reduce the frequency of organ damage compared with octreotide alone. Mild AP can be managed in the ambulatory setting through hospital-at-home units after a short, 24-hour admission. PMID- 24160960 TI - Treatment of chronic noninfectious uveitis in children--the trend toward tumor necrosis factor-alpha inhibition. PMID- 24160961 TI - Ocular toxoplasmosis: the treatment dilemma. PMID- 24160963 TI - Risk factors associated with the relapse of uveitis in patients with juvenile idiopathic arthritis: a preliminary report. AB - PURPOSE: To identify risk factors associated with relapse of uveitis in patients with recurrent uveitis associated with juvenile idiopathic arthritis (JIA) after treatment with immunomodulatory therapy (IMT) and durable remission of 1 year. METHODS: The medical records of 30 patients with JIA-associated uveitis who were successfully treated with IMT to a state of corticosteroid-free remission and subsequently remained in remission after discontinuation of IMT for a period of at least 1 year were retrospectively reviewed. In subsequent follow-up, some patients had relapse of uveitis, whereas others continued to be in remission. Remission was defined as <1 + cells in the anterior chamber and <1 + vitreous haze grading; relapse was defined as >= 1 + cell in the anterior chamber or >= 1 + vitreous haze grading. RESULTS: A total of 30 patients were included. Of these, 17 (56.7%) patients remained in uveitic remission, whereas 13 (43.3%) relapsed. The patients in remission received IMT earlier in the course of disease compared with patients who relapsed (median, 12 months vs 72 months; P = 0.002 [Mann Whitney test]). Patients in remission had received treatment with IMT at a younger age compared with the relapse group (median age, 7 years vs 13 years; P = 0.02 [Mann-Whitney test]). None of the other factors studied revealed a statistically significant association. CONCLUSIONS: Patients with JIA-associated uveitis who were treated with IMT earlier in the course of disease and at a younger age were associated with a lower rate of relapse of uveitis after durable remission and 1 year of quiescence, compared with similar patients who relapsed. PMID- 24160962 TI - Adalimumab therapy for refractory childhood uveitis. AB - PURPOSE: To report the results of adalimumab therapy in a cohort of children with refractory noninfectious uveitis. METHODS: The medical records of patients diagnosed with uveitis and treated with biweekly adalimumab injections for a period of at least 3 months at the University Hospital of La Paz from 2007-2012 were retrospectively reviewed. Improvement in inflammatory activity was graded according to grading schema of the Standardization of Uveitis Nomenclature Working Group. RESULTS: A total of 15 patients participated in the study (12 girls; mean patient age, 12 years). Diagnoses included juvenile idiopathic arthritis in 10 patients, idiopathic uveitis in 4, and familial juvenile systemic granulomatosis or Blau syndrome in 1. Mean follow-up was 32 months (median, 36; range, 15-58 months). Improvement in inflammatory activity was initially observed in 12 (86%) of 14 children, with a mean time to achieve response of 6 weeks (median, 4; range, 1-18). Treatment was effective in 9 patients (60%), mildly effective in 2 (13%), ineffective in 2 (13%), and resulted in worsening in 2 (13%). In the juvenile idiopathic arthritis patients, response was effective in 6 cases (60%), mildly effective in 2 (20%), and ineffective in 2 (20%). Adalimumab therapy was discontinued in 4 patients. CONCLUSIONS: Adalimumab was effective in most patients in the initial control of acute inflammatory activity in children with refractory uveitis, although therapy appears to become less effective in the long term. PMID- 24160965 TI - Differentiating bilateral superior oblique paresis from sensory extorsion. AB - PURPOSE: To determine whether patients historically diagnosed with bilateral superior oblique paresis (BSOP) categorized into (1) immediate-onset and (2) gradual-onset torsional diplopia groups are also distinguishable on the basis of patterns of subjective misalignment in various directions of gaze, consistent with the gradual-onset group being caused by sensory extorsion rather than by BSOP. METHODS: The medical records of all patients diagnosed with BSOP, V-pattern esotropia, or V-pattern exotropia between 1978 and 2009 were retrospectively reviewed. Those patients with torsional diplopia were classified into immediate- or gradual-onset diplopia groups. The torsional misalignments measured by Lancaster red-green plots were compared, and the surgical outcomes were evaluated. RESULTS: Of 38 patients identified, 27 had immediate-onset and 11 gradual-onset diplopia. There was a statistically significant difference in the increase in extorsion from up- to downgaze between the immediate- versus gradual onset group (17.8 degrees versus -1.5 degrees , P < 0.001). Patients in the immediate-onset group fared significantly better with bilateral Harada-Ito procedures than with bilateral inferior oblique-weakening procedures (P = 0.02), whereas patients in the gradual-onset group fared equally well with either procedure (P = 0.72). CONCLUSIONS: Extorsion in upgaze is largely absent in patients with immediate-onset BSOP but is present in both up- and downgaze in patients with gradual-onset sensory extorsion. Lancaster red-green testing aids in distinguishing these two groups. The bilateral Harada-Ito procedure is a better procedure for true BSOP, whereas a bilateral inferior oblique-weakening procedure may be preferred for patients with sensory extorsion. PMID- 24160964 TI - Effectiveness of medial rectus advancement alone or in combination with resection or lateral rectus recession in the management of consecutive exotropia. AB - PURPOSE: To prospectively determine the long-term success of medial rectus advancement alone or in combination with other procedures in the management of consecutive exotropia. METHODS: All patients with consecutive exotropia who underwent medial rectus advancement alone or in combination with medial rectus resection or lateral rectus recession or both, performed by a single surgeon between 1999 and 2010, were included. Initially, a retrospective review was performed. Patients were then recalled and examined by a masked observer. Good results were defined as final alignment within 10(Delta) of orthotropia. RESULTS: A total of 46 patients were enrolled in the study with a mean age of 43 +/- 15.5 years (range, 14-76) and a mean exotropia of 32 +/- 18(Delta) (range, 10-90). Good results were achieved in 33 patients (72%) at a mean follow-up time of 2.5 years. Of the 21 patients returning for prospective examination, 15 (71%) had good alignment at an average follow-up of 4.2 years (range, 6.9 months to 8.6 years). Adduction deficits were improved in 30 of 33 (91%) patients at final follow-up. CONCLUSIONS: In patients with consecutive exotropia, surgery including medial rectus advancement alone or in combination with resection or lateral rectus recession or both usually is effective. PMID- 24160966 TI - Esotropia surgery in children with Down syndrome. AB - PURPOSE: To evaluate postoperative alignment in children with and without Down syndrome after surgical correction of esotropia. METHODS: The medical records of consecutive patients with Down syndrome who underwent corrective surgery for esotropia between August 1992 and July 2012 were retrospectively reviewed. Age range for eligibility was between 8 months and 17 years at surgery. The control group comprised randomly selected, age-matched patients without Down syndrome who underwent the same surgical procedure. Postoperative alignment within 10(Delta) of orthotropia at 6 months' follow-up and at the final postoperative visit was considered a successful outcome. RESULTS: A total of 17 children with Down syndrome and 27 control subjects were included. The control group and Down syndrome group did not differ significantly in either postoperative follow-up (5.2 +/- 3.2 versus 5.6 +/- 5.2 years, respectively) or magnitude of deviation before surgery (40 +/- 18.2(Delta) versus 39 +/- 12.8(Delta), respectively). Surgical success was achieved in 76% of patients with Down syndrome and in 85% of control patients at 6 months' follow-up. CONCLUSIONS: In this patient cohort, good surgical outcomes were achieved in children with esotropia and Down syndrome compared with those with esotropia but without Down syndrome using the same surgical technique. PMID- 24160967 TI - Rectus muscle plication using an adjustable suture technique. AB - PURPOSE: Rectus muscle plication is an alternative muscle-strengthening procedure to rectus muscle resection. Possible advantages of rectus muscle plication include a lower risk of "lost" muscles and anterior segment ischemia. METHODS: This was a retrospective case series describing a surgical procedure for rectus muscle plication using an adjustable suture technique that can be used on any of the four rectus muscles. RESULTS: A total of 5 adult patients underwent adjustable suture plication procedures. Of these, 2 patients required suture adjustment postoperatively. At the final follow-up visit, all the patients maintained satisfactory ocular alignment within 6(Delta) of orthotropia for horizontal deviations and 2(Delta) of orthotropia for vertical deviations. Diplopia was eliminated in all cases with preoperative diplopia. There were no postoperative complications or unexpected shifts in ocular alignment. CONCLUSIONS: Rectus muscle plication using this adjustable suture technique may serve as an alternative to rectus muscle resection and may be particularly useful in patients who are at risk for anterior segment ischemia or those in whom a shorter anesthesia time is recommended. PMID- 24160969 TI - Failure of stem cell therapy to improve visual acuity in children with optic nerve hypoplasia. AB - PURPOSE: To evaluate the effectiveness of stem cell therapy in improving visual acuity or optic nerve function in children with optic nerve hypoplasia (ONH). METHODS: Subjects with ONH aged 7-17 years who voluntarily elected to undergo stem cell therapy in China were matched with controls on age, visual acuity, and communication level. Visual acuity, optic nerve size, and sensitivity to light were assessed before stem cell therapy and twice after. Controls were evaluated on the same schedule. RESULTS: Two case-control pairs were enrolled. There were no clinically significant changes in pupillary constriction or optic nerve measurements in any participant eye. Improvement in visual acuity was noted in study participants regardless of treatment status. CONCLUSIONS: On the basis of this small sample, there is no evidence that stem cell therapy improves visual acuity in children with ONH. PMID- 24160968 TI - The effect of a temperature-sensitive poloxamer-alginate-CaCl2 mixture after strabismus surgery in a rabbit model. AB - PURPOSE: To determine the efficacy of a temperature-sensitive poloxamer-alginate mixture in reducing adhesions after strabismus surgery in a rabbit model. METHODS: The superior rectus muscle was recessed in each of 36 eyes from 18 rabbits. One randomly assigned eye in each rabbit was treated with a poloxamer alginate mixture (PA group); the other eye was treated with a subconjunctival injection of saline (control group). The adhesions between the superior rectus muscle, sclera, and conjunctiva were clinically evaluated by a masked observer at 1 day, 1 week, and 4 weeks after surgery. Inflammation was analyzed by hematoxylin and eosin staining and anti-CD11b staining. Late fibrosis was assessed by the Masson trichrome and alpha-smooth muscle actin staining. Adhesion, inflammation, and fibrosis were graded on a scale of 0-4. RESULTS: There was no significant between-group difference in the degree of adhesion at 1 day and 4 weeks after surgery. However, the degree of adhesion in the PA group was lower than that in the control group at postoperative week 1 (P < 0.05). Acute inflammation was similar between the groups (P > 0.05). At postoperative week 4, inflammatory cell infiltration was reduced in the PA group (P = 0.046). A significant between-group difference in late fibrosis at postoperative week 4 was observed through the Masson trichrome (P = 0.024) and alpha-smooth muscle actin staining (P = 0.025). CONCLUSIONS: The poloxamer-alginate mixture significantly decreased adhesion after strabismus surgery in a rabbit model. Additional studies are warranted to evaluate the use of this mixture in preventing postoperative adhesions. PMID- 24160970 TI - Utility of an open field Shack-Hartmann aberrometer for measurement of refractive error in infants and young children. AB - PURPOSE: To assess the utility of an open-field Shack-Hartmann aberrometer for measurement of refractive error without cycloplegia in infants and young children. METHOD: Data included 2698 subject encounters with Native American infants and children aged 6 months to <8 years. We attempted right eye measurements without cycloplegia using the pediatric wavefront evaluator (PeWE) on all participants while they viewed near (50 cm) and distant (2 m) fixation targets. Cycloplegic autorefraction (Rmax [Nikon Retinomax K-plus2]) measurements were obtained for children aged >= 3 years. RESULTS: The success rates of noncycloplegic PeWE measurement for near (70%) and distant targets (56%) significantly improved with age. Significant differences in mean spherical equivalent (M) across near versus distant fixation target conditions were consistent with the difference in accommodative demand. Differences in astigmatism measurements for near versus distant target conditions were not clinically significant. Noncycloplegic PeWE and cycloplegic Rmax measurements of M and astigmatism were strongly correlated. Mean noncycloplegic PeWE M was significantly more myopic or less hyperopic and astigmatism measurements tended to be greater in magnitude compared with cycloplegic Rmax. CONCLUSIONS: The PeWE tended to overestimate myopia and underestimate hyperopia when cycloplegia was not used. The PeWE is useful for measuring accommodation and astigmatism. PMID- 24160971 TI - Racial variation in optic nerve head parameters quantified in healthy newborns by handheld spectral domain optical coherence tomography. AB - PURPOSE: To characterize optic nerve head (ONH) morphology and parameters, including vertical disk diameter, vertical cup diameter, and vertical cup/disk ratio in healthy, full-term newborns using a handheld spectral domain optical coherence tomography (SD-OCT) device. METHODS: In this prospective observational case series, healthy white, black, and Hispanic full-term newborns delivered at the Duke Birthing Center between August 2010 and May 2011 underwent dilated fundus examination and SD-OCT imaging of the optic nerve in each eye. OCT parameters were calculated and compared for each group of infants. RESULTS: A total of 58 consecutive newborns of white (n = 22), black (n = 15) and Hispanic (n = 21) ethnicity were included. Mean vertical disk diameter in white, black, and Hispanic newborns was 1.29 +/- 0.15 mm (standard deviation), 1.38 +/- 0.14 mm, and 1.38 +/- 0.14 mm, respectively (white versus Hispanic, P = 0.02; white versus black, P = 0.07). Mean vertical cup diameter in white, black, and Hispanic newborns was 0.44 +/- 0.15 mm, 0.56 +/- 0.23 mm, and 0.46 +/- 0.30 mm, respectively (white versus black, P = 0.03). Mean vertical cup/disk ratio was 0.34 +/- 0.10 for white, 0.40 +/- 0.17 for black, and 0.33 +/- 0.20 for Hispanic newborns (P = 0.07 for white versus black). CONCLUSIONS: Handheld SD-OCT is an effective means of imaging the ONH in newborns. Racial differences in cup/disk ratio are present at birth. These data may serve as the beginning of a normative dataset for characterizing development of the ONH as well as for comparison to the neonatal ONH in disease states. PMID- 24160973 TI - Traumatic pediatric cataract in southern Ethiopia--results of 49 cases. AB - PURPOSE: To report the experience of two tertiary care facilities in southern Ethiopia in the treatment of traumatic pediatric cataract for a period of more than 1 year. METHODS: The medical records of consecutive traumatic pediatric cataract patients who underwent surgery at the Hawassa University and the Yirgalem University schools of medicine from July 2007 to August 2008 were retrospectively reviewed. All patients with a follow-up of at least 12 months were included. RESULTS: A total of 49 children were included. Mean patient age was 8.6 +/- 0.3 years (range, 5-15 years). Of the 49 cases, 32 (65%) were caused by blunt trauma. Average follow-up period was 15 months. Postoperative visual acuity of counting fingers or better was achieved in 43 (88%) eyes compared with 5 (10%) at presentation (P < 0.0001). Better visual acuity at presentation and blunt trauma were associated with better final visual acuity. Only blunt trauma was found by multivariate analysis to influence final visual acuity (P = 0.0001). CONCLUSIONS: Visual acuity of counting fingers or better visual can be achieved in most cases. Blunt trauma is a good independent prognostic factor for visual acuity. PMID- 24160972 TI - The possible association of attention deficit hyperactivity disorder with undiagnosed refractive errors. AB - PURPOSE: To evaluate whether attention deficit disorder (ADD) or attention deficit with hyperactivity disorder (ADHD) is associated with undiagnosed refractive errors or binocular function difficulties. METHODS: In this case control study, ADD/ADHD children diagnosed according to criteria of the Diagnostic and Statistical Manual of Mental Disorders (DSM IV-TR), along with age matched controls, were examined at the ADD clinic at the Sheba Medical Center. For children in both groups the following data were recorded: uncorrected visual acuity for distance and near, cycloplegic refraction, ocular motility, and binocular function. RESULTS: A total of 56 children (12 girls; mean subject age, 9.5 years) were included in the ADD/ADHD group. The control group comprised 66 patients (29 girls; mean subject age, 9 years). Mean uncorrected visual acuity was nearly 20/20 for distance and J1 for near in both groups. Cycloplegic spherical equivalent was +0.89 +/- 1.1 D for the control group and +0.63 +/- 0.89 D for the ADD/ADHD group (P = 0.16). Binocular function and accommodation were similar in both groups, except for a significant difference between the near point of convergence of the controls versus the ADD/ADHD group (5.3 +/- 2.3 cm versus 4.1 +/- 1.8 cm, respectively; P = 0.002). CONCLUSIONS: ADD/ADHD children had similar visual acuity at distance and near and refractive errors as normal subjects. Binocular function and accommodation were also found to be similar in both groups and thus might not contribute to ADD/ADHD. PMID- 24160974 TI - Results of a community vision-screening program using the Spot photoscreener. AB - PURPOSE: To describe the results of vision screenings performed with the Spot photoscreener in the community setting. METHODS: Low-income, predominantly Hispanic children in day care and preschool settings were screened by lay operators using the Spot photoscreener. Inclusion criteria were age 6-72 months and availability of a complete photoscreening record. Referral criteria were based on Vision Screening Committee of American Association for Pediatric Ophthalmology and Strabismus guidelines. Data were stratified by age group and analyzed for percentage of children referred for hyperopia, myopia, astigmatism, anisometropia, anisocoria, and ocular misalignment. Vision screening records were compared with comprehensive eye examination records from an optometrist or ophthalmologist to determine positive predictive value. RESULTS: Vision screening examinations were performed on 8,317 subjects from September 2011 through May 2012. The mean age of the 7,814 subjects (3953 males) meeting inclusion criteria was 44.4 months. The Spot referred 2,393 (30.6%). Of the screened population, the suspected reason for referral was astigmatism in 1,863 (23.8%), ocular misalignment in 879 (11.3%), anisometropia in 90 (1.2%), myopia in 82 (1.1%), hyperopia in 63 (0.8%), and anisocoria in 16 (0.2%). Comprehensive examination reports, including a cycloplegic refraction, were available for 300 referred children (12.5%). The reason for referral was confirmed in 55.7%, with an overall positive predictive value of 65.7%. CONCLUSIONS: The Spot photoscreener yielded a high overall referral rate. Although a high prevalence of astigmatism may be expected in this population, a high referral rate for suspected ocular misalignment led to a very high proportion of false positive referrals, suggesting that the software for this algorithm is in need of refinement. PMID- 24160975 TI - A new, removable, sliding noose for adjustable-suture strabismus surgery. AB - We describe a new removable sliding polyglactin 910 suture noose for postoperative suture adjustment following extraocular muscle surgery. No excess suture material remains after adjustment has been completed, helping to reduce discomfort, inflammation, and scarring. We have used this noose with the cul-de sac conjunctival incision in approximately 360 patients over a period of 18 months. This report details how to fashion, use, and remove the noose. PMID- 24160976 TI - Conjunctival autograft as treatment for anterior displacement and scarring of the plica semilunaris after strabismus surgery. AB - Medial conjunctival scarring and displacement of the plica toward the limbus is a rare but well-described complication of strabismus surgery, especially after multiple procedures. We report the case of a patient with this complication, treated successfully with excision and conjunctival autotransplantation. This technique has been broadly described in pterygium surgery but has not to our knowledge previously been reported in this context. PMID- 24160977 TI - Periorbital globe fixation after severe extraocular muscle injury. AB - Endoscopic sinus surgery is a popular surgical treatment for chronic sinus disease. Despite improved surgical techniques, postoperative orbital complications can occur, including extraocular muscle injury. We report the case of a 62-year-old woman who suffered from medial rectus muscle transection after transnasal endoscopic ethmoidectomy. She was successfully managed with periorbital globe fixation. PMID- 24160978 TI - Necrotizing scleritis after strabismus surgery in thyroid eye disease. AB - Surgically induced necrotizing scleritis, which can lead to potentially devastating consequences, is a rare sequela to many types of ocular surgeries. We describe a 58-year-old woman who developed necrotizing scleritis following strabismus surgery for thyroid ophthalmopathy. Tectonic corneal patch grafting resulted in a favorable outcome. PMID- 24160979 TI - Retained subretinal date palm tree thorn in a child. AB - A 3-year-old boy presented with severe eye pain and nausea after colliding with a date palm tree branch. Examination under anesthesia revealed a self-sealed corneal laceration and traumatic cataract in his left eye. Cultures were taken and the patient received prophylactic subconjunctival, intravitreal, and systemic antibiotics because of the high risk of endophthalmitis. A thorn from the same tree grew Bacillus cereus. Examination after 2 weeks of the injury revealed a subretinal foreign body (a palm tree thorn), although there were no signs of endophthalmitis or retinal detachment. The patient underwent cataract extraction and laser demarcation of the subretinal foreign body, which was not removed. He was fitted for an aphakic contact lens. With alternate patching, his best corrected visual acuity improved to 20/30. PMID- 24160980 TI - Immunoglobulin G4-related sclerosing disease with orbital inflammation in a 12 year-old girl. AB - Immunoglobulin G4-related sclerosing disease is a rare but potentially debilitating cause of orbital inflammation, with a predilection for older males. We report the case of a 12-year-old African girl with immunoglobulin G4-related sclerosing disease, including possible extraorbital involvement. Because of an escalating severity of illness leading to oculomotor nerve palsy and cavernous sinus thrombosis that was resistant to steroids, systemic immunosuppressive therapy with rituximab was used to achieve disease remission. The diagnosis was histologically confirmed with a tissue biopsy. PMID- 24160981 TI - Primary uveal melanoma in a 4-year-old black child. AB - Primary uveal melanoma is extremely rare in children and also among blacks. Uveal melanomas may be associated with various preexisting conditions, including congenital ocular melanocytosis and dysplastic nevus syndrome. We report the case of a 4-year-old black girl who presented with pronounced proptosis and no light perception secondary to a massive intraocular tumor with extrascleral extension. Biopsy of the tumor confirmed the diagnosis of primary uveal melanoma, and the patient was treated by enucleation and external beam radiation therapy. Although metastatic disease was ruled out at the time, the patient died approximately 3 months later. PMID- 24160982 TI - Presumed allograft stromal rejection after deep anterior lamellar keratoplasty in a boy presenting with interface fluid syndrome. AB - Selective anterior lamellar corneal replacement procedures have resulted in fewer allograft rejections compared with penetrating keratoplasty. Deep anterior lamellar keratoplasty offers several advantages over conventional penetrating keratoplasty, significantly reducing the lifetime endothelial rejection. We report the case of a child with a presumed immune-mediated stromal rejection after deep anterior lamellar keratoplasty who presented with interface fluid, confirmed by optical coherence tomography, that subsequently resolved after prompt topical steroid treatment. PMID- 24160983 TI - Mixed hyperpigmentation and hypopigmentation of iris and choroid in Chediak Higashi syndrome. AB - An 8-year-old Taiwanese girl presented with hyperpigmentation and scattered hypopigmentation in her irides and choroids. Her skin showed hyperpigmentation with speckled hypopigmentation over cheeks and sun-exposed areas. Medical history was remarkable for frequent infectious episodes and lower extremity bruising. A peripheral blood smear revealed large inclusion bodies in the cytoplasm of neutrophils. The patient was diagnosed with Chediak-Higashi syndrome and continues to be monitored closely. PMID- 24160984 TI - Reply: To PMID 23237752. PMID- 24160985 TI - Reply: To PMID 23352720. PMID- 24160987 TI - Evaluation of a treatment algorithm for acute traumatic osseous Bankart lesions resulting from first time dislocation of the shoulder with a two year follow-up. AB - BACKGROUND: Studies dealing with acute osseous Bankart lesions and corresponding treatment strategies are rare. The purpose of this study is to analyze the results after applying our treatment algorithm for acute glenoid rim fractures caused by first time traumatic anterior shoulder dislocations. METHODS: 25 patients were included in this retrospective case series. All patients sustained a first time shoulder dislocation caused by ski or snowboard accidents. An osseous Bankart lesion was detected in all shoulders. Operative therapy was performed in patients with osseous defects of 5% or more, otherwise conservative therapy was initiated. Primary study outcome parameter was the Rowe score. Additionally, the outer rotation deficit and operative complications were analysed. RESULTS: 12 patients showed a defect size of less than 5% and were treated conservatively. The average lesion size was 2%. For these patients, the Rowe score was excellent in 58%, good in 25%, and moderate in 17% of patients. Three patients (25%) complained about a feeling of instability. 13 patients had a lesion size of more than 5%, average 15%, and were treated operatively. The Rowe score for this group was excellent in 54%, good in 31%, and moderate results in 15% of patients. One patient (8%) complained about a feeling of instability, without recurrent dislocations. There were no statistically significant differences between both study groups (ROWE score: p = 0.98). CONCLUSIONS: Applying our treatment algorithm for acute osseous Bankart lesions consisting of a conservative strategy for small defect sizes and a surgical approach for medium sized and large defects leads to encouraging mid-term results and a low rate of recurrent instability in active patients. PMID- 24160986 TI - Refinements in brow reconstruction: synergy between plastic surgery and aesthetic medicine. AB - OBJECTIVE: The purpose of this study was the introduction in clinical practice of the combined application of traditional reconstructive surgery and intense pulsed light (IPL) for the restoration of a post-traumatic eyebrow defect. CASE: The authors present a case of surgical eyebrow reconstruction with an axial temporal hair-bearing scalp island flap. A persistent localized erythema and a marked difference in hair density in comparison with the contralateral one harmed the eventual surgical outcome. RESULTS: A combined sequential treatment with IPL achieved both hair density and skin erythema reduction, and eventually allowed for a very satisfactory result. CONCLUSIONS: Our experience demonstrated the efficacy of the integrated multidisciplinary approach involving traditional plastic reconstructive surgery and the innovative new technologies in aiming for perfection. PMID- 24160988 TI - A review of generalist and specialist community health workers for delivering adolescent health services in sub-Saharan Africa. AB - BACKGROUND: The health of adolescents is increasingly seen as an important international priority because the world's one point eight billion young people (aged 10 to 24 years) accounts for 15.5% of the global burden of disease and are disproportionately located in low- and middle-income countries (LMICs). Furthermore, an estimated 70% of premature adult deaths are attributable to unhealthy behaviors often initiated in adolescence (such as smoking, obesity, and physical inactivity). In order for health services to reach adolescents in LMICs, innovative service delivery models need to be explored and tested. This paper reviews the literature on generalist and specialist community health workers (CHWs) to assess their potential for strengthening the delivery of adolescent health services. METHODS: We reviewed the literature on CHWs using Medline (PubMed), EBSCO Global Health, and Global Health Archive. Search terms (n = 19) were sourced from various review articles and combined with subject heading 'sub Saharan Africa' to identify English language abstracts of original research articles on generalist and specialist CHWs. RESULTS: A total of 106 articles, from 1985 to 2012, and representing 24 African countries, matched our search criteria. A single study in sub-Saharan Africa used CHWs to deliver adolescent health services with promising results. Though few comprehensive evaluations of large-scale CHW programs exist, we found mixed evidence to support the use of either generalist or specialist CHW models for delivering adolescent health services. CONCLUSIONS: This review found that innovative service delivery approaches, such as those potentially offered by CHWs, for adolescents in sub Saharan Africa are lacking, CHW programs have proliferated despite the absence of high quality evaluations, rigorous studies to establish the comparative effectiveness of generalist versus specialist CHW programs are needed, and further investigation of the role of CHWs in providing adolescent health services in sub-Saharan Africa is warranted. PMID- 24160989 TI - TNF-alpha blockade is ineffective in animal models of established polycystic kidney disease. AB - BACKGROUND: Given the large medical burden of polycystic kidney disease (PKD) and recent clinical trial failures, there is a need for novel, safe and effective treatments for the disorder. METHODS: In PCK rat and PKD2(ws25/w183) mouse models, entanercept was administered once every three days at 5 or 10 mg/kg, once daily. Mozavaptan was administered as a pilot control, provided continuously via milled chow at 0.1%. Animals were assessed for measures of pharmacodynamic response, and improvements in measures of polycystic kidney disease. RESULTS: Entanercept treatment modulated inflammatory markers, but provided limited therapeutic benefit in multiple animal models of established polycystic kidney disease. Kidney weight, cyst burden and renal function markers remained unchanged following administration of etanercept at various dose levels and multiple treatment durations. CONCLUSIONS: While it remains possible that TNF-alpha inhibition may be effective in truly preventative settings, our observations suggest this pathway is less likely to exhibit therapeutic or disease-modifying efficacy following the standard clinical diagnosis of disease. PMID- 24160990 TI - Biological therapies for psoriasis. AB - INTRODUCTION: Biological therapies have revolutionized moderate-to-severe psoriasis treatment. Increased understanding of disease pathogenesis has yielded multiple therapeutic targets involving the IL-23/Th17 pathway, while current therapies continue to be monitored for long-term efficacy and safety. AREAS COVERED: This review details current understanding of psoriasis immunopathogenesis specifically related to therapeutic targets. Approved and emerging biological psoriasis therapies targeting TNF-alpha, IL-12/23p40, IL-17 and IL-23p19 are covered. Biological agent uses in special circumstances are reviewed together with the emerging debate on biosimilar therapies and their potential future role in psoriasis and other inflammatory diseases. EXPERT OPINION: Psoriasis treatment has expanded and has become more effective due to increased understanding of disease pathogenesis. However, lack of efficacy in select psoriasis patients, safety concerns and limited treatment efficacy in psoriasis variants (e.g., pustular) are areas which still need improvement. As such, pharmacogenomics will be of vital importance in future for individualized psoriasis care. Further, a better understanding of the multiple psoriasis comorbidities, especially cardiovascular disease, continues to be of significant interest in the psoriasis community. Last, the emergence of biosimilar agents has the potential to change psoriasis treatment, especially as it relates to better access for the psoriasis community worldwide. PMID- 24160991 TI - Diamide linked gamma-cyclodextrin dimers as molecular-scale delivery systems for the medicinal pigment curcumin to prostate cancer cells. AB - Diamide linked gamma-cyclodextrin (gamma-CD) dimers are proposed as molecular scale delivery agents for the anticancer agent curcumin. N,N'-Bis(6(A)-deoxy gamma-cyclodextrin-6(A)-yl)succinamide (66gammaCD2su) and N,N'-bis(6(A)-deoxy gamma-cyclodextrin-6(A)-yl)urea (66gammaCD2ur) markedly suppress the degradation of curcumin by forming a strong 1:1 cooperative binding complexes. The results presented in this study describe the potential efficacy of 66gammaCD2su and 66gammaCD2ur for intracellular curcumin delivery to cancer cells. Cellular viability assays demonstrated a dose-dependent antiproliferative effect of curcumin in human prostate cancer (PC-3) cells that was preserved by the curcumin 66gammaCD2su complex. In contrast, delivery of curcumin by 66gammaCD2ur significantly delayed the antiproliferative effect. We observed similar patterns of gene regulation in PC-3 cells for curcumin complexed with either 66gammaCD2su or 66gammaCD2ur in comparison to curcumin alone, although curcumin delivered by either 66gammaCD2su or 66gammaCD2ur induces a slightly higher up-regulation of heme oxygenase-1. Highlighting their nontoxic nature, neither 66gammaCD2su nor 66gammaCD2ur carriers alone had any measurable effect on cell proliferation or candidate gene expression in PC-3 cells. Finally, confocal fluorescence imaging and uptake studies were used to demonstrate the intracellular delivery of curcumin by 66gammaCD2su and 66gammaCD2ur. Overall, these results demonstrate effective intracellular delivery and action of curcumin when complexed with 66gammaCD2su and 66gammaCD2ur, providing further evidence of their potential applications to deliver curcumin effectively in cancer and other treatment settings. PMID- 24160993 TI - Reproducibility of measurements in tablet-assisted, PC-aided, and manual cephalometric analysis. AB - OBJECTIVE: To assess the reproducibility of cephalometric measurements performed with software for a tablet, with a program for personal computers (PCs), and manually. MATERIALS AND METHODS: The pretreatment lateral cephalograms of 20 patients that were acquired using the same digital cephalometer were collected. Tracings were performed with NemoCeph for Windows (Nemotec), with SmileCeph for iPad (Glace Software), and by hand. Landmark identification was carried out with a mouse-driven cursor using NemoCeph and with a stylus pen on the iPad screen using SmileCeph. Hand tracings were performed on printouts of the cephalograms, using a 0.3-mm 2H pencil and a protractor. Cephalometric landmarks and linear and angular measurements were recorded. All the tracings were done by the same investigator. To evaluate reproducibility, for each cephalometric measurement the agreement between the value derived from NemoCeph, that given by SmileCeph and that measured manually was assessed with the intraclass correlation coefficient (ICC). Agreement was rated as low for an ICC<=0.75, and an ICC>0.75 was considered indicative of good agreement. Also, differences in measurements between each software and manual tracing were statistically evaluated (P<.05). RESULTS: All the measurements had ICC>0.8, indicative of a high agreement among the tracing methods. Relatively lower ICCs occurred for linear measurements related to the occlusal plane and to N perpendicular to the Frankfurt plane. Differences in measurements between both software programs and hand tracing were not statistically significant for any of the cephalometric parameters. CONCLUSION: Tablet-assisted, PC-aided, and manual cephalometric tracings showed good agreement. PMID- 24160992 TI - An animal study to compare the degree of the suppressive effects on the afferent pathways of micturition between tamsulosin and sildenafil. AB - BACKGROUND: Tamsulosin, an alpha1-adrenoceptor antagonist, and sildenafil, a phosphodiesterase (PDE) inhibitor, are reported to improve lower urinary tract symptoms including overactive bladder (OAB). This study is aimed at investing the effects of tamsulosin and sildenafil and comparing the degree of the suppressive effects on the afferent pathways of micturition between them using an animal model of OAB, the spontaneously hypertensive rat (SHR). RESULTS: The cystometric parameters, the basal pressure and duration of bladder contraction, were significantly increased in the SHR group as compared with the Wistar-Kyoto (WKY) group. The intercontraction interval also significantly decreased in the SHR group. In the SHR-Tam 0.01 mg/kg group and the SHR-Sil 1 mg/kg group, however, the basal pressure and duration were significantly reduced and the intercontraction interval was significantly prolonged. Moreover, the degree of the expression of c-Fos and NGF was significantly higher in the SHR group as compared with the WKY group. But it was significantly reduced in the SHR-Tam 0.01 mg/kg group and the SHR-Sil 1 mg/kg group. Furthermore, tamsulosin had a higher degree of effect as compared with sildenafil. CONCLUSIONS: In conclusion, alpha1 adrenergic receptor antagonists and PDE-5 inhibitors may have an effect in improving the voiding functions through an inhibition of the neuronal activity in the afferent pathways of micturition. PMID- 24160994 TI - Facial development disorders due to inhibition to endochondral ossification of mandibular condyle process caused by malnutrition. AB - OBJECTIVE: To analyze the effect of protein restriction on histomorphometric parameters of bone remodeling in mandibular condyle process and its possible influence in facial development in growing rats. MATERIALS AND METHODS: Wistar rats weaned at the age of 21 days were assigned to one of the following groups: control (fed a regular hard diet ad libitum) and protein restricted (PR) (fed a hard diet lacking in protein ad libitum). The animals were euthanized on day 35 after the onset of the experiment. Mandibles were resected, fixed in 10% formalin, hemisected at the symphysis, and then radiographed in order to perform cephalometric studies of the condylar process length and the height of the lower alveolar process. Mandibles were then processed for light microscopy, and histomorphometric determinations were performed on histologic sections of the condylar process subchondral bone. RESULTS: The PR group showed a significantly lower body weight than control group at the end of the experiment. The length of the condylar process was lower in the PR group; however, the diet used in this study did not affect the height of the lower alveolar process. The histomorphometric analysis showed that the PR group exhibited a statistically significant decrease in bone formation and bone volume in condylar process subchondral bone. CONCLUSION: Protein restriction inhibits bone formation and longitudinal growth in the mandibular condylar process. This result suggest that protein restriction can alter normal facial development. PMID- 24160996 TI - Analysis of smile esthetics in American Board of Orthodontic patients. AB - OBJECTIVE: To investigate the common denominators of an esthetically pleasing smile in patients who were considered to be successfully treated upon the submission to American Board Orthodontics (ABO) clinical examination. MATERIAL AND METHODS: A total of 462 patients were examined. Ninety subjects that fulfilled the inclusion criteria were included. Standardized digital smile photographs of the subjects were rated by 30 panel members, including orthodontists, general dentists, and parents of orthodontic patients, using a numeric version of the visual analog scale. Three groups were formed using the mean esthetic score+/-standard deviation range: unattractive (n=21), average (n=47), and attractive (n=22) smiles. Eleven smile characteristics were digitally measured on the photographs and compared between the groups using one-way analysis of variance and chi2 tests. Additionally, regression analyses were used to investigate the association of the smile characteristics with the esthetic score. RESULTS: A significant difference was found between the three groups for the comparison of smile arc relationship (P<.001). When all the variables used in this study were entered in the regression analysis, a positive association was found (r=0.658; r2=0.434; P<.001). Additionally, two models were defined using stepwise regression. The first model included the smile arc (r=0.478; r2=0.228; P<.001), and the second model had both the smile arc and right gingival display/visible dentition display ratio (r =0.567; r2=0.321; P<.001). CONCLUSIONS: A harmonious smile arc relationship and less gingival display during a smile are significantly associated with smile attractiveness in patients considered successfully treated according to ABO standards. PMID- 24160995 TI - Cone-beam computed tomography for assessment of palatal displaced canine position: a methodological study. AB - OBJECTIVE: To assess the inter- and intraexaminer reliability of a measurement method for evaluation of eruption angles and position of palatal displaced canines (PDCs) with cone-beam computed tomography (CBCT) images and to test the validity of the measured angles on a dry skull. MATERIALS AND METHODS: Twenty patients (eight boys, 12 girls; age 11.4+/-1.2 years) were randomly chosen among 67 patients from a study evaluating the interceptive effect of extracting the deciduous canine in children with PDCs. In total, 60 images were analyzed, because each patient had three CBCT examinations (baseline, 6-month control, and endpoint). Two observers assessed the following measurements twice: mesioangular and sagittal angle, vertical position, canine cusp tip, and canine apex to dental arch. The validity of the angular measurements was tested against angular measurements on a dry skull using mathematical formulations. RESULTS: The inter- and intraexaminer mean differences for angular and linear measurements were all low and statistically insignificant (P>.05). The mean differences between the physical and 3D measurements were 0.5+/-0.39 mm for the sagittal angle and 0.22+/ 0.19 mm for the mesioangular angle. CONCLUSIONS: Linear and angular measurements on CBCT images are accurate and precise and can be used to assess the precise position of a PDC. PMID- 24160998 TI - A mixed quantum-classical molecular dynamics study of anti-tetrol and syn-tetrol dissolved in liquid chloroform II: infrared emission spectra, vibrational excited state lifetimes, and nonequilibrium hydrogen-bond dynamics. AB - The effect of vibrational excitation and relaxation of the hydroxyl stretch on the hydrogen-bond structure and dynamics of stereoselectively synthesized syn tetrol and anti-tetrol dissolved in deuterated chloroform are investigated via a mixed quantum-classical molecular dynamics simulation. Emphasis is placed on the changes in hydrogen-bond structure upon photoexcitation and the nonequilibrium hydrogen-bond dynamics that follows the subsequent relaxation from the excited to the ground vibrational state. The propensity to form hydrogen bonds is shown to increase upon photoexcitation of the hydroxyl stretch, thereby leading to a sizable red-shift of the infrared emission spectra relative to the corresponding absorption spectra. The vibrational excited state lifetimes are calculated within the framework of Fermi's golden rule and the harmonic-Schofield quantum correction factor, and found to be sensitive reporters of the underlying hydrogen bond structure. The energy released during the relaxation from the excited to the ground state is shown to break hydrogen bonds involving the relaxing hydroxyl. The spectral signature of this nonequilibrium relaxation process is analyzed in detail. PMID- 24160997 TI - Effects of sliding velocity on friction: an in vitro study at extremely low sliding velocity approximating orthodontic tooth movement. AB - OBJECTIVE: To evaluate the effects of sliding velocity on friction, particularly at extremely low sliding velocity approximating orthodontic tooth movement. MATERIALS AND METHODS: Stainless-steel (SS) 0.022-inch preadjusted brackets and 0.016- and 0.016*0.022-inch SS wires and superelastic nickel-titanium 0.016*0.022 inch wires were used for this test. The wire was secured in a SS preadjusted bracket with an elastomeric module. One end of the wire was pulled upward 1.5 mm at a speed of 5.0*10(-7), 1.0*10(-5), 1.0*10(-4), 1.0*10(-3), 1.0*10(-2), and 1.0*10(-1) mm/s by the micrometer. The measurements were conducted 10 times and averaged. Tukey-Kramer tests were used to compare the mean differences of each testing measurement among the different sliding velocities. RESULTS: The frictional forces tended to increase as the sliding velocity decreased. The mean frictional force for 5.0*10(-7) mm/s sliding velocity (approximating orthodontic tooth movement) was 106.8 cN in 0.016*0.022-inch SS wires, almost double the 1.0*10(-1) mm/s sliding velocity. CONCLUSION: The effects of sliding velocity cannot be ignored when we estimate frictional forces in clinical orthodontics. PMID- 24160999 TI - Health promotion for children, mothers and families: here's why we should "think about it before conception". AB - About 90,000 preterm infants or babies with birth defects are born in Italy every year, nearly 250 per day. These congenital conditions and their outcomes represent the most important burden of disease affecting the health status and the quality of life during infancy, childhood and beyond. In many cases they are fostered by the presence of maternal and/or paternal preconception risk factors whose effects can be modified by primary prevention.In the contemporary vision of maternal and child health, the traditional gap between preconception period and pregnancy is overcome through promotion of reproductive health and wellness in women, men and couples, regardless of their reproductive plans and possible future pregnancies. This paradigm should become the basic foundation to improve and protect infants', children's and adolescents' health. Useful interventions belong to four broad areas: a) promotion of women's and couples' health in general, and protection from risk of adverse events in future pregnancies (if any); b) identification and treatment of conditions that increase the risk of adverse reproductive outcomes; c) help for women (couples) planning for pregnancy; d) identification of genetic risks, and help for independent and responsible decision making.Pediatricians and neonatologists can effectively promote primary prevention in the interconception period, when parents seek consultation for their previous child, in adolescent medicine, in family health education, in socio-sanitary network, and in advocacy activities in favor of infants and children. These actions should be part of an operational framework including perinatal outreach programs, information campaigns, and focus on problems of high-risk women, children and families. PMID- 24161000 TI - Synthesis of fluorescent ring-fused 2-pyridone peptidomimetics. AB - Thiazolino fused 2-pyridone peptidomimetics are of significant biological importance due to their ability to interfere with adhesive fiber formation in uropathogenic Escherichia coli and oligomerization of amyloid fibers. We have developed an efficient synthetic route to fluorescent BODIPY analogues, with structural diversification from a key intermediate enabling introduction of C-2 substituents and late incorporation of the BODIPY moiety. A mild lithium halide mediated hydrolysis enabled preparation of peptidomimetic fluorophores with useful photophysical properties for further chemical biology applications. PMID- 24161001 TI - A highly efficient and enantioselective intramolecular Cannizzaro reaction under TOX/Cu(II) catalysis. AB - An asymmetric intramolecular Cannizzaro reaction of aryl and alkyl glyoxals with alcohols has been realized with an unprecedented high level of enantioselectivity, on the basis of a newly developed congested TOX ligand and a gradual liberation protocol of active glyoxals from glyoxal monohydrates. Preliminary results suggested a mechanism of enantioselective addition of alcohols to glyoxals contributing most to the stereoselectivity, other than by the dynamic kinetic resolution of hemiacetal intermediates. PMID- 24161002 TI - Endless fascination. AB - Each of us fortunate enough to have had a career in experimental science has a tale to tell, often one with surprising twists and turns, full of lessons that can help guide those embarking on a similar journey. At the very least, a well written recounting of a career can be entertaining. I offer my memory's version of my career in immunology and hope the readers will find it of value or at least of interest. PMID- 24161003 TI - Feasibility and effectiveness of remote, telephone-based delivery of cardiac rehabilitation. AB - OBJECTIVES: Cardiac rehabilitation (CR) provides significant benefit for persons with cardiovascular disease. However, access to CR services may be limited by driving distance, costs, need for a driver, time away from work, or being a family primary caregiver. The primary aim of the project was to test the reach (i.e., patient and provider uptake), effectiveness (safety and clinical outcomes), and implementation (time and costs) of a remote telephone-based Phase 2 CR program. A secondary aim was to compare outcomes between patients attending the remote program (home-CR) and those attending an on-site program (comparison group). SUBJECTS AND METHODS: Subjects were given a choice of the remote or face to-face program. Remote CR participants (n=48) received education and assessment during 12 weekly by telephone calls. Data were compared with those for face-to face CR program participants (n=14). Independent t tests and chi-squared tests were used for continuous and categorical variables, respectively. Repeated measures analysis of covariance models were used to assess differences in outcomes. Costs were analyzed using a cost-minimization analysis. RESULTS: Of 107 eligible patients, 45 refused participation, 5 dropped out, and 1 died unrelated to the study. Participants had a mean age of 64 (standard deviation 7.5) years. Remote CR participants were highly satisfied with their care and had a higher completion rate (89% of authorized sessions versus 73% of face-to-face). Costs for each program were comparable. There were no significant changes over time in any measured outcome between groups at 12 weeks except medication adherence, which decreased over time in both groups; face-to-face patients reported a greater decrease (p=0.05). CONCLUSIONS: This is the first study to test a remote CR program in a population of older Veterans. Many hospitals do not provide comprehensive CR services on-site; thus remote CR is a viable alternative to bring services closer to the patient. PMID- 24161004 TI - Understanding gender differences in m-health adoption: a modified theory of reasoned action model. AB - BACKGROUND: Mobile health (m-health) services are becoming increasingly popular in healthcare, but research on m-health adoption is rare. This study was designed to obtain a better understanding of m-health adoption intention. MATERIALS AND METHODS: We conducted an empirical research of a 481-respondent sample consisting of 44.7% women and 55.3% men and developed a modified theory of reasoned action (TRA) model by incorporating the nonlinearities between attitude and subjective norms and the moderating effect of gender. RESULTS: The results indicate that, based on the study population in China: (1) facilitating conditions, attitude, and subjective norms are significant predictors of m-health adoption intention; (2) the model including the nonlinearities enhances its explanatory ability; (3) males enjoy a higher level of m-health adoption intention compared with females; (4) the modified TRA model can predict men's behavior intention better than that of women; and (5) males have an Edgeworth-Pareto substitutability between attitude and subjective norms in predicting m-health adoption intention. CONCLUSIONS: Thus, we found gender differences in m-health adoption from the perspective of social psychology. PMID- 24161005 TI - Leukocytosis as a prognostic marker in the development of fetal inflammatory response syndrome. AB - OBJECTIVE: To identify and evaluate the correlation between leukocyte count in maternal blood and the risk of developing fetal inflammatory response syndrome (FIRS). PATIENTS AND METHODS: The study involved 158 infants born at 22 - 34 weeks of gestation and their mothers. Umbilical cord blood cytokines were evaluated in immunoassay tests and maternal blood was tested for the leukocyte formula. RESULTS: The period of gestation was significantly shorter in the FIRS group compared to the control group (29.5+/-3.1 vs. 32.2+/-2.4 weeks, p<0.001). Gestational age was <=30 weeks for 53.8% of the newborns in the FIRS group and 15.8% of the newborns in the control group (p<0.001). The number of leukocytes in maternal blood before and during labor was significantly higher in the FIRS group than in the control group (p=0.034 and 0.004, respectively). The study determined the correlation between the total leukocyte count in maternal blood and IL-6 concentration during labor (p=0.05) and tumor necrosis factor (TNF-alpha) concentration in umbilical cord blood before and during labor (p=0.02 and 0.007, respectively). CONCLUSION: Leukocytosis in the FIRS group was significantly higher than in the control group before and during labor. According to our data, one of the possible indicators of intrauterine infection could be the number of leukocytes in maternal blood. PMID- 24161006 TI - Problem solving with pentagons: Tsai-type quasicrystal as a structural response to chemical pressure. AB - Even after significant advances in the structural characterization of quasicrystals--phases whose diffraction patterns combine the sharp peaks normally associated with lattice periodicity and rotational symmetries antithetical to such periodicity--this new form of long-range order remains enigmatic. Here, we present DFT-chemical pressure calculations on the Tsai-type quasicrystal approximant CaCd6, which reveal how its icosahedral clusters can be traced to simple CaCu5-type (hP6) intermetallics. The results indicate that the Tsai-type clusters emerge from an atomic-size-driven transformation from planar arrangements to spherical clusters, recalling the relationship between graphene and C60. PMID- 24161007 TI - Quality of antenatal care services at public health facilities of Bahir-Dar special zone, Northwest Ethiopia. AB - BACKGROUND: Antenatal care (ANC) is one of the evidence based interventions to decrease the probability of bad health outcomes for mothers and their newborns. Effectiveness of antenatal care, however, relies on the quality of care provided during each antenatal care visit. Hence this study attempted to assess the quality of antenatal care services at public health facilities of Bahir-Dar special zone, North Western Ethiopia. METHODS: A facility based cross-sectional study employing both quantitative and qualitative methods was conducted from March to April 2010 in Bahir-Dar special zone, North Western Ethiopia. Quality of care was measured as a proportion of patients receiving recommended components of care. To measure the indicators, data was collected from 369 pregnant women who attended ANC clinics in eight public health facilities, during the data collection period. Data were collected through exit interviews with ANC attendees, observation during consultation, and in-depth interviews with health care providers. RESULTS: Pregnant mothers attending ANC clinics were found to receive only part of recommended care components. Venereal Disease Research Laboratory (VDRL) test, blood group and Rhesus factor tests were done only for 73 (19.8%) and 133 (36.0%) of the women, respectively. Moreover 236 (64.0%) of the mothers missed the opportunity of receiving iron/folic acid supplement during their ANC visit. Three hundred fifty five (96.2%) of the women received tetanus toxoid vaccine. And only 226 (61.2%) of the women had their conjunctiva checked for anemia. Lack of reagents partly explained the problems observed in the provision of recommended care components. CONCLUSION: Almost half, 175 (47.7%) of the study women were not satisfied and a large proportion of mothers are missing opportunities to receive screening (like blood pressure and weight measurements) and preventive components of antenatal care (iron/folic acid supplementation). Therefore, efforts should be targeted to avoid missed opportunities by taking quality improvement measures including the fulfillment of all necessary resources. PMID- 24161008 TI - In situ overlap and sequence synthesis during DNA assembly. AB - Modern cloning methods are independent from restriction enzyme recognition sites. However, nearly all current cloning methods still require the introduction of overlaps by PCR, which can introduce undesired mutations. Here, we investigated whether overlaps needed for DNA assembly can be synthesized in situ and we tested if the de novo synthesis of sequences can be simultaneously combined with the assembly of larger double-stranded DNA fragments. We showed in a set of 44 cloning experiments that overlaps of 20 bp needed for DNA assembly can be synthesized in situ from single-stranded oligonucleotides. Short sequences of 30 255 bp can be synthesized from single-stranded oligonucleotides concurrently with DNA assembly, and both techniques can be combined. The assembly of similar constructs by state-of-the-art techniques would have required multiple rounds of cloning or tedious sample preparations, whereas our approach is a one-step reaction. PMID- 24161010 TI - A novel application for bolus remifentanil: blunting the hemodynamic response to Mayfield skull clamp placement. AB - OBJECTIVE: Neurosurgery often requires skull immobilization with a Mayfield clamp, which often causes brief intense nociceptive stimulation, hypertension and tachycardia. Blunting this response may help prevent increased intracranial pressure, cerebral aneurysm or vascular malformation rupture, and/or myocardial stress. While various interventions have been described to blunt this response, no reports have compared administration of a propofol versus a remifentanil bolus. METHODS: We retrospectively analyzed the hemodynamic response to Mayfield placement in over 800 patients who received a prior propofol or remifentanil bolus from 2004 to 2010. RESULTS: Patients who received remifentanil experienced a 55% smaller increase in heart rate (p < 0.0001) and a 40% smaller increase in systolic blood pressure (p < 0.0001) after Mayfield placement than patients who received propofol. These data were retrospectively obtained from patients who were not randomized to receive remifentanil versus propofol, and hence these data could be subject to possible confounding. Nonetheless, these differences remained significant after multivariate analysis for possible confounding variables. CONCLUSIONS: Thus, a remifentanil bolus is more effective than a propofol bolus in blunting hemodynamic responses to Mayfield placement, and possibly for other short, intense nociceptive stimuli. PMID- 24161011 TI - Midterm outcomes of electromagnetic computer-assisted navigation in minimally invasive total knee arthroplasty. AB - BACKGROUND: A combination of two emerging technologies, computer-assisted navigation and minimally invasive surgery, in total knee arthroplasty has gained increasing interests from orthopedic surgeons around the world. To date, there has never been any midterm study for clinical and radiographic outcomes from using an electromagnetic computer-assisted navigation system. In this study, we aimed to systematically compare clinical and radiographic outcomes of minimally invasive surgery in total knee arthroplasty (MIS-TKA) performed with and without electromagnetic computer-assisted navigation at immediate and midterm follow-ups. METHODS: A total of 151 patients (160 knees) who underwent MIS-TKA were randomized to be operated with electromagnetic computer-assisted navigation (group I: 75 patients, 80 knees) or without the navigation (group II: 76 patients, 80 knees). The clinical and radiographic outcomes of immediate, 6-week postoperative follow-up and average 6.1-year follow-up were compared. RESULTS: On immediate, 6-week postoperative follow-up, clinical and radiographic outcomes did not reveal any difference between the two groups except for the fact that the operative time was longer in the navigation group. On 6.1-year follow-up, a total of 58 patients (63 knees) from group I and 58 patients (61 knees) from group II were reevaluated. There were no significant differences in clinical and radiographic loosening and in complications between the two groups. CONCLUSION: In this study, no significant differences of clinical and radiographic outcomes were found for immediate and midterm follow-ups of MIS-TKA performed with and without electromagnetic computer-assisted navigation except for the additional operating time in the navigation group. PMID- 24161013 TI - Preparing leaders in health professions education. AB - In the past 15 years, the number of Master's degree programs in Health Professions Education (MHPE) has grown from 7 to 121 programs worldwide. New MHPE programs continue to be developed each year, due to increased demand for individuals with specialized knowledge concerning how to best educate future health professionals. During the 2012 Association of Medical Education in Europe (AMEE) meeting in Lyon, France, a symposium was organized to explore the reasons for the proliferation of MHPE programs worldwide. In particular, the issues explored included the need for such programs, their outcomes in developing education leaders and scholars in HPE, and facilitators, barriers and models for initiating such programs. This paper synthesizes the discussion during this symposium. Some of the reasons for enrolling in a Master's degree program in HPE include the formal credential, knowledge of a number of theories and frameworks, new approaches to problems and ways of thinking, the mentored project, and networking and working with faculty and students. The uniqueness of being a trainee in an MHPE program is the immersion in the medical education environment and the assimilation of a new approach to scholarship and a new approach to leadership. PMID- 24161012 TI - Comprehensive profiling of Epstein-Barr virus-encoded miRNA species associated with specific latency types in tumor cells. AB - BACKGROUND: Epstein-Barr virus (EBV) is an etiological cause of many human lymphocytic and epithelial malignancies. EBV expresses different genes that are associated with three latency types. To date, as many as 44 EBV-encoded miRNA species have been found, but their comprehensive profiles in the three types of latent infection that are associated with various types of tumors are not well documented. METHODS: In the present study, we utilized poly (A)-tailed quantitative real-time RT-PCR in combination with microarray analysis to measure the relative abundances of viral miRNA species in a subset of representative lymphoid and epithelial tumor cells with various EBV latency types. RESULTS: Our findings showed that the miR-BHRF1 and miR-BART families were expressed differentially in a tissue- and latency type-dependent manner. Specifically, in nasopharyngeal carcinoma (NPC) tissues and the EBV-positive cell line C666-1, the miR-BART family accounted for more than 10% of all detected miRNAs, suggesting that these miRNAs have important roles in maintaining latent EBV infections and in driving NPC tumorigenesis. In addition, EBV miRNA-based clustering analysis clearly distinguished between the three distinct EBV latency types, and our results suggested that a switch from type I to type III latency might occur in the Daudi BL cell line. CONCLUSIONS: Our data provide a comprehensive profiling of the EBV miRNA transcriptome that is associated with specific tumor cells in the three types of latent EBV infection states. EBV miRNA species represent a cluster of non-encoding latency biomarkers that are differentially expressed in tumor cells and may help to distinguish between the different latency types. PMID- 24161015 TI - The construction of a decision tool to analyse local demand and local supply for GP care using a synthetic estimation model. AB - BACKGROUND: This study addresses the growing academic and policy interest in the appropriate provision of local healthcare services to the healthcare needs of local populations to increase health status and decrease healthcare costs. However, for most local areas information on the demand for primary care and supply is missing. The research goal is to examine the construction of a decision tool which enables healthcare planners to analyse local supply and demand in order to arrive at a better match. METHODS: National sample-based medical record data of general practitioners (GPs) were used to predict the local demand for GP care based on local populations using a synthetic estimation technique. Next, the surplus or deficit in local GP supply were calculated using the national GP registry. Subsequently, a dynamic internet tool was built to present demand, supply and the confrontation between supply and demand regarding GP care for local areas and their surroundings in the Netherlands. RESULTS: Regression analysis showed a significant relationship between sociodemographic predictors of postcode areas and GP consultation time (F [14, 269,467] = 2,852.24; P <0.001). The statistical model could estimate GP consultation time for every postcode area with >1,000 inhabitants in the Netherlands covering 97% of the total population. Confronting these estimated demand figures with the actual GP supply resulted in the average GP workload and the number of full-time equivalent (FTE) GP too much/too few for local areas to cover the demand for GP care. An estimated shortage of one FTE GP or more was prevalent in about 19% of the postcode areas with >1,000 inhabitants if the surrounding postcode areas were taken into consideration. Underserved areas were mainly found in rural regions. CONCLUSIONS: The constructed decision tool is freely accessible on the Internet and can be used as a starting point in the discussion on primary care service provision in local communities and it can make a considerable contribution to a primary care system which provides care when and where people need it. PMID- 24161014 TI - The mid-term outcome of total ankle arthroplasty and ankle fusion in rheumatoid arthritis: a systematic review. AB - BACKGROUND: While arthrodesis is the standard treatment of a severely arthritic ankle joint, total ankle arthroplasty has become a popular alternative. This review provides clinical outcomes and complications of both interventions in patients with rheumatoid arthritis. METHODS: Studies were obtained from Pubmed, Embase and Web of Science (January 1980-June 2011) and additional manual search. INCLUSION CRITERIA: original clinical study, > 5 rheumatoid arthritis (population), internal fixation arthrodesis or three-component mobile bearing prosthesis (intervention), ankle scoring system (outcome). The clinical outcome score, complication- and failure rates were extracted and the methodological quality of the studies was analysed. RESULTS: 17 observational studies of 868 citations were included. The effect size concerning total ankle arthroplasty ranged between 1.9 and 6.0, for arthrodesis the effect sizes were 4.0 and 4.7. Reoperation due to implant failure or reoperation due to non-union, was 11% and 12% for respectively total ankle arthroplasty and arthrodesis. The methodological quality of the studies was low (mean 6.4 out of a maximum of 14 points) and was lower for arthrodesis (mean 4.8) as compared to arthroplasty (mean 7.8) (p = 0.04). CONCLUSIONS: 17 observational and no (randomized) controlled clinical trials are published on the effectiveness of arthroplasty or arthrodesis of the ankle in rheumatoid arthritis. Regardless of the methodological limitations it can be concluded that both interventions show clinical improvement and in line with current literature neither procedure is superior to the other. PMID- 24161016 TI - Importance of N-terminal pro-brain natriuretic peptide in monitoring acute rheumatic carditis. AB - PURPOSE: To detect the relationship of N-terminal pro-brain natriuretic peptide levels with clinical and laboratory findings by measuring them at diagnosis, during, and after treatment in children with acute rheumatic carditis. METHOD: A total of 40 children including 20 acute rheumatic carditis patients aged between 5 and 16 years 20 healthy children as controls were included in the study. Blood was drawn from patients at diagnosis and in the first week, first month and third month after treatment in order to detect pro-brain natriuretic peptide, C reactive protein levels and erythrocyte sedimentation rates. All patients underwent echocardiography. RESULTS: The N-terminal pro-brain natriuretic peptide levels of children with acute rheumatic carditis were significantly higher than those of the control group at diagnosis and during treatment (p<0.05). Echocardiographic evaluation of acute rheumatic carditis patients revealed that the left atrium diameter continued to decrease during the study and that the mean left atrium diameters measured at diagnosis and in the first week were statistically higher than the mean left atrium diameters measured in the third month. There was significant correlation between left atrium diameters at diagnosis and in the first month and N-terminal pro-brain natriuretic peptide levels during the same periods in the patient group. CONCLUSION: Previous studies have used N-terminal pro-brain natriuretic peptide levels as a marker of enlargement of the left atrium, whereas in this study we want to emphasise its role as a marker of inflammation. This increase was significantly correlated with enlargement in the left atrium. N-terminal pro-brain natriuretic peptide levels were found to be a valuable determinant in indicating cardiac inflammation and haemodynamics. PMID- 24161017 TI - Relationship between Icodextrin use and decreased level of small low-density lipoprotein cholesterol fractioned by high-performance gel permeation chromatography. AB - BACKGROUND: Because of the absorption of glucose in peritoneal dialysis (PD) solution, PD patients show an atherogenic lipid profile, which is predictive of poor survival in PD patients. Lipoprotein subclasses consist of a continuous spectrum of particles of different sizes and densities (fraction). In this study, we investigated the lipoprotein fractions in PD patients with controlled serum low-density lipoprotein (LDL) cholesterol level, and evaluated the effects of icodextrin on lipid metabolism. METHODS: Forty-nine PD patients were enrolled in this cross-sectional study in Japan. The proportions of cholesterol levels to total cholesterol level (cholesterol proportion) in 20 lipoprotein fractions were measured using an improved method of high-performance gel permeation chromatography (HPGPC). RESULTS: Twenty-six patients used icodextrin. Although no significant differences in cholesterol levels in LDL and high-density lipoprotein (HDL) were observed between the patients using icodextrin (icodextrin group) and control groups, HPGPC showed that the icodextrin group had significantly lower cholesterol proportions in the small LDL (t-test, p=0.053) and very small LDL (p=0.019), and significantly higher cholesterol proportions in the very large HDL and large HDL than the control group (p=0.037; p=0.066, respectively). Multivariate analysis adjusted for patient characteristics and statin use showed that icodextrin use was negatively associated with the cholesterol proportions in the small LDL (p=0.037) and very small LDL (p=0.026), and positively with those in the very large HDL (p=0.040), large HDL (p=0.047), and medium HDL (p=0.009). CONCLUSIONS: HPGPC showed the relationship between icodextrin use and the cholesterol proportions in lipoprotein fractions in PD patients. These results suggest that icodextrin may improve atherogenic lipid profiles in a manner different from statin. PMID- 24161018 TI - Safety and efficacy of treatment switch to raltegravir plus tenofovir/emtricitabine or abacavir/lamivudine in patients with optimal virological control: 48-week results from a randomized pilot study (Raltegravir Switch for Toxicity or Adverse Events, RASTA Study). AB - BACKGROUND: The Raltegravir Switch for Toxicity or Adverse Events (RASTA) Study is a 2-arm randomized pilot study exploring the safety and efficacy at 48 weeks of a treatment switch to raltegravir associated with tenofovir/emtricitabine or abacavir/lamivudine in patients with regimens with optimal virological control. METHODS: Patients treated with stable protease inhibitor (PI)-, non-nucleoside reverse transcriptase inhibitor (NNRTI)-, or nucleoside reverse transcriptase inhibitor (NRTI)-based regimens, with HIV-RNA levels < 50 copies/ml for >= 3 months and a CD4 cell count > 200 cells/MUl were eligible. Enrollment of 40 patients was planned: at baseline patients were randomized 1:1 to switch to raltegravir plus tenofovir/emtricitabine (arm A) or abacavir/lamivudine (arm B). Laboratory parameters, raltegravir plasma levels, self- reported adherence, quality of life parameters, neurocognitive performance, bone composition, and body fat distribution were monitored. Virological failure was defined as HIV-RNA > 50 copies/ml on 2 consecutive determinations. RESULTS: After 48 weeks, 5/40 (12.5%) regimen discontinuations occurred: 2 were for low-level viremia virological failure (both in arm A, at weeks 24 and 48) and 3 were for adverse events (neurological disturbances and skin rash in arm B; proximal tubulopathy in arm A). Overall, a significant CD4 increase was observed at weeks 36 and 48, and a significant decrease in total cholesterol, non-high density lipoprotein cholesterol, and triglycerides was observed at each study visit. Physical health/satisfaction in therapy scores and neuropsychological performance improved. The lumbar column Z-score improved, with no modification in other bone composition and fat distribution parameters. CONCLUSIONS: The investigated switch strategy was associated with rare virological failure. Improvements in lipid levels, quality of life measures, neuropsychological performance, and bone composition suggest good tolerability of raltegravir-based regimens. PMID- 24161019 TI - Molecular target therapy for bone metastasis: starting a new era with denosumab, a RANKL inhibitor. AB - INTRODUCTION: The skeleton is generally the primary, and sometimes the only, site of metastasis in patients with advanced solid tumors. Bone metastases are the most frequent cause of cancer-related pain and the origin of severe morbidity in patients. Among the treatment options available for the prevention of skeletal related events (SREs) associated with bone metastasis, zoledronic acid, an antiresorptive treatment from the group of bisphosphonates, is currently the standard of care in this setting. AREAS COVERED: Zoledronic acid, together with denosumab (a monoclonal antibody against the receptor activator of nuclear factor kappa B ligand), is the most frequent approach for the prevention of cancer related events in skeleton. This paper reviews several trials evaluating the efficacy of denosumab in comparison with zoledronic acid in patients with solid osteotropic tumors. In this setting of skeleton-invading cancers, denosumab was demonstrated to be superior to zoledronic acid in preventing or delaying SREs. In comparison with zoledronic acid, denosumab significantly delayed the time to first SRE by 17%. EXPERT OPINION: Current research on denosumab is addressed to prove the immunomodulator effect of this agent in humans. Other avenue of research is focused on its antitumor activity observed in some Phase III trials. PMID- 24161020 TI - The free groin flap in the rat: a model for improving microsurgical skills and for microvascular perfusion studies. AB - The goal of this study was to evaluate the free groin flap in the rat transplanted to the neck as a tool for extending microsurgical skills and to assess its suitability as a model for microvascular perfusion studies following secondary venous ischaemia. An analysis of 60 consecutive groin flap transplantations was performed in male Sprague Dawley rats with special regard to anatomy and operation times (Part I, animals No. 1-60). Following flap transplantation, the animals No. 10-30 (n = 21) were used for the determination of the critical time period of a complete venous stasis of the free groin flap resulting in a total flap loss (Part II). The flaps of animals No. 31-41 (n = 11) were used for assessing the feasibility and reproducibility of intra-vital video microscopy (IVM) of the flaps (Part III). The mean total operation time decreased from 166 (+/- 26) minutes ins the first 10 animals to 126 (+/- 21) minutes and 130 (+/- 12) minutes in the latter two groups of 10 animals, respectively. After a critical period of 35 minutes of a complete artificial venous stasis a complete flap necrosis occurred. IVM detected a higher functional capillary density of the skin of the transplanted groin flaps in the animals in which the flaps were rinsed with 1 ml of Ringer's lactated solution prior to I/R. In conclusion, this model is simple and reliable. The model may be a useful tool for evaluating and comparing the effects of various anticoagulants or vasomotor drugss on microvascular perfusion in critically compromised free flaps. PMID- 24161021 TI - Not only "nurture", but also "nature", influence the outcome of zygoma repair. AB - The present study aims to elucidate the relationship between preoperative deviation patterns of fractured zygomas and treatment outcomes. Forty-five randomly selected patients with tri-pod type zygoma fractures were classified into a medial rotation group and a lateral rotation group, depending on preoperative deviation patterns. A minimum of 6 months after the operation, symmetry of the cheek was evaluated by three plastic surgeons using a VAS system. The evaluated scores were compared between the two groups. Furthermore, simulation of postoperative secondary deformity was performed by applying hypothetically defined relapse forces on CAD models produced by referring to the CT data of 20 patients. The deviation values obtained by the simulation were compared between the two groups. The results demonstrate that VAS scores were higher for the lateral rotation group than for the medial rotation group and that the deviation values were higher for the medial rotation group than for the lateral rotation group. It is concluded that treatment outcomes of zygoma fractures are affected by preoperative deviation patterns. Cases with medial rotation are likely to present poorer outcomes than those with lateral rotation. PMID- 24161022 TI - Direct access to 6/5/7/5- and 6/7/5/5-fused tetracyclic triterpenoids via divergent transannular aldol reaction of lanosterol-derived diketone. AB - In an effort to access biologically relevant chemical space, a complex natural product derived nonsymmetrical diketone was prepared as a substrate for divergent transannular aldol reactions. The use of common aldol conditions resulted in predominant syn-addition via pathway a, while the use of alumina provided access to the anti-adduct. Screening of a range of Lewis acids of varying strength unexpectedly resulted in the formation of aldol products with 6/7/5/5-fused molecular skeleton via pathway b. PMID- 24161023 TI - Nonlabeled quantitative proteomic comparison identifies differences in acid resistance between Escherichia coli O157:H7 curli production variants. AB - To understand the nature of a bacterial strain, it is necessary to be able to identify and measure the proteins expressed by the bacteria. In this research, the entire protein complements produced by Escherichia coli O157:H7 strain 43894OW and its naturally occurring curli producing variant 43894OR were compared to better understand the unique capabilities of these two closely related strains. A nonlabeled proteomic comparison was performed utilizing the spectra counting and peptide fractionation abilities of a quadrupole-time of flight analyzer mass spectrometer to identify and quantitate the proteins produced by the two strains. The process reliably identified and measured the concentration of 419 proteins from strains 43894OW and 43894OR within three separate biological replicates. From these two sets, 59 proteins were identified that were preferentially expressed in strain 43894OW compared to 43894OR and 14 proteins that were conversely preferentially expressed in 43894OR. A subset of the preferentially expressed proteins was assayed to determine whether their levels of gene transcription corresponded with the observed protein expression. From the resulting list of confirmed differentially expressed proteins, it was observed that the proteins contributing to acid survival--GadA and GadB--were overexpressed in 43894OW compared to 43894OR. The predicted enhanced acid resistance phenotype of 43894OW was confirmed by experimentation at pH 2.5. Additionally, a knockout mutation in the csgD genes of the 43894OR strain was constructed and suggested that CsgD had a repressive effect on acid survival in 43894OR. PMID- 24161024 TI - Molecular epidemiological analysis of five outbreaks associated with Salmonella enterica serovar Enteritidis between 2008 and 2010 on Jeju Island, Republic of Korea. AB - With the increasing incidence of Salmonella enterica serovar Enteritidis (SE) infections, five SE foodborne outbreaks were identified between 2008 and 2010 on Jeju Island, Republic of Korea. In this study, the genetic relatedness of isolates recovered from the five outbreaks was investigated to identify the source of foodborne SE infections. In total, 57 SE isolates from five outbreaks (17 isolates, 5 isolates, 18 isolates, 8 isolates, and 9 isolates, respectively) were used for antimicrobial susceptibility testing, pulsed-field gel electrophoresis (PFGE), and multiple-locus variable-number tandem repeat analysis (MLVA). SE isolates from 2008 and 2009 were resistant to nalidixic acid, whereas SE isolates from 2010 were resistant to five antibiotics. Of the five outbreaks, outbreaks A, B, and D had identical PFGE-XbaI and PFGE-BlnI patterns, SEGX01.003 and SEGA26.001, respectively. Outbreak C had patterns SEGX01.011 and SEGA26.005, and outbreak E had patterns SEGX01.007 and SEGA26.007. However, MLVA profiles further distinguished the SE isolates from each outbreak into patterns SEGM.014 (outbreak A), SEGM.012 (outbreak B), SEGM.008 (outbreak C), SEGM.016 (outbreak D), and SEGM.015 (outbreak E). Among these five outbreaks, three outbreaks were presumed to be caused by the clonal SE isolates depending on PFGE pattern, but the MLVA results elucidated that these were caused by different SE isolates from the different origins. Therefore, for the epidemiological investigation or surveillance of SE foodborne diseases, both PFGE and MLVA should be used together. PMID- 24161025 TI - Survival of Vibrio vulnificus genotypes in male and female serum, and production of siderophores in human serum and seawater. AB - Vibrio vulnificus is an estuarine bacterium responsible for 95% of all seafood related deaths in the United States. Several studies have demonstrated that V. vulnificus infections are enhanced when host iron availability is increased, such as occurs with chronic liver disease. Because of the gender difference seen in these infections, we examined whether there was a difference in the survival in both male and female serum by both the C (clinical) and E (environmental) genotypes of V. vulnificus. We further determined the significance of the catecholate and hydroxamate siderophores produced by this pathogen during both human infections and while in its natural estuarine environment. We found that only C-genotype strains were capable of growth in human serum, regardless of inoculum size, with growth in male and female serum being equal. We found the catecholate outer membrane receptor gene (vuuA) to be expressed significantly more than that for the hydroxamate siderophore (fhuA) when the cells were exposed to human serum, regardless of the genotype. When cells were exposed to natural seawater, fhuA showed increased expression over time, while vuuA showed decreased expression. Our data suggest that the catecholate siderophore is important during human infections, whereas the hydroxamate siderophore may be more important in the estuarine environment this pathogen inhabits. PMID- 24161026 TI - c-kit expression profile and regulatory factors during spermatogonial stem cell differentiation. AB - BACKGROUND: It has been proven that c-kit is crucial for proliferation, migration, survival and maturation of spermatogenic cells. A periodic expression of c-kit is observed from primordial germ cells (PGCs) to spermatogenetic stem cells (SSCs), However, the expression profile of c-kit during the entire spermatogenesis process is still unclear. This study aims to reveal and compare c kit expression profiles in the SSCs before and after the anticipated differentiation, as well as to examine its relationship with retinoic acid (RA) stimulation. RESULTS: We have found that there are more than 4 transcripts of c kit expressed in the cell lines and in the testes. The transcripts can be divided into short and long categories. The long transcripts include the full-length canonical c-kit transcript and the 3' end short transcript. Short transcripts include the 3.4 kb short transcript and several truncated transcripts (1.9-3.2 kb). In addition, the 3.4 kb transcript (starting from intron 9 and covering exons 10 ~ 21) is discovered to be specifically expressed in the spermatogonia. The extracellular domain of Kit is obtained in the spermatogonia stage, but the intracellular domain (50 kDa) is constantly expressed in both SSCs and spermatogonia. The c-kit expression profiles in the testis and the spermatogonial stem cell lines vary after RA stimulation. The wave-like changes of the quantitative expression pattern of c-kit (increase initially and decrease afterwards) during the induction process are similar to that of the in vivo male germ cell development process. CONCLUSIONS: There are dynamic transcription and translation changes of c-kit before and after SSCs' anticipated differentiation and most importantly, RA is a significant upstream regulatory factor for c-kit expression. PMID- 24161027 TI - In vivo screening of four phytochemicals/extracts and a fungal immunomodulatory protein against an Eimeria acervulina infection in broilers. AB - BACKGROUND: Besides the anticoccidial drug resistance problem, increasing consumer concerns about food safety and residues have propelled the quest for alternative prevention and control strategies amongst which phytotherapy has gained appeal due to a renewed interest in natural medicine. OBJECTIVE: The objective was in vivo screening of four phytochemicals/extracts and a fungal immunomodulatory protein (FIP) against an Eimeria acervulina infection in broilers. ANIMALS AND METHODS: Four phytochemicals/extracts (extract from Echinacea purpurea, betaine (BetainTM), curcumin, carvacrol (two different doses)), and a recombinant FIP from Ganoderma lucidum cloned and expressed in Escherichia coli were investigated for their anticoccidial potential. The experiment was conducted in a battery cage trial with 54 cages of eight birds each. Broilers infected with E. acervulina (a low and high infection dose of 10(4) and 10(5) sporulated oocysts, respectively) and treated with the phytochemicals/extracts or the FIP were compared with broilers treated with the anticoccidial salinomycin sodium (Sacox(r)) and with an untreated uninfected and an untreated infected control group. Coccidiosis lesion scores, body weight gains and oocyst shedding were used as parameters. RESULTS: The results showed a coccidiosis infection dose effect on the mean coccidiosis lesion scores. The phytochemicals/extracts and the FIP failed to reduce coccidiosis lesion scores and oocyst shedding, while salinomycin efficiently controlled the E. acervulina infection and enabled significantly higher body weight gains. CONCLUSION: In conclusion, the selected phytochemicals/extracts and the FIP did not reduce the lesions of an experimentally induced E. acervulina infection. PMID- 24161028 TI - Simulation of ion transport through an N-acetylneuraminic acid-inducible membrane channel: from understanding to engineering. AB - N-acetylneuraminic acid-inducible channel (NanC) is an outer membrane channel of Escherichia coli . This porin folds as a 12-stranded beta-barrel leading to a tubular shape. Electrophysiological experiments have revealed an asymmetric conductance with respect to the direction of the applied voltage and a weak anion selectivity of the channel. To this end, we performed all-atom molecular dynamics (MD) simulations to decipher the ion transport properties of the NanC channel. Concentration-dependent applied-field MD simulations recover the asymmetric conductance property and the anion selectivity of the channel in agreement with experiments. Further molecular analysis revealed the role of the asymmetric charge distribution inside the channel as the basis of the asymmetry in conductance. In addition, the particular distribution of charged residues at the inner channel walls leads to a faster permeation of Cl(-) ions compared to K(+) ions resulting in the anion selectivity of NanC. These findings are well supported by position-dependent diffusion coefficients and potential of mean force profiles derived from unbiased MD simulations. Taking one step further, we were able to engineer the NanC channel in silico by mutations leading to enhanced asymmetric conductances and anion selectivities. The E186Q mutant, for example, changes NanC into a decent molecular diode with an ionic current ratio of about 3:1 for opposite bias voltages. PMID- 24161029 TI - Beyond antimalarial stock-outs: implications of health provider compliance on out of-pocket expenditure during care-seeking for fever in South East Tanzania. AB - BACKGROUND: To better understand how stock-outs of the first line antimalarial, Artemisinin-based Combination Therapy (ACT) and other non-compliant health worker behaviour, influence household expenditures during care-seeking for fever in the Ulanga District in Tanzania. METHODS: We combined weekly ACT stock data for the period 2009-2011 from six health facilities in the Ulanga District in Tanzania, together with household data from 333 respondents on the cost of fever care seeking in Ulanga during the same time period to establish how health seeking behaviour and expenditure might vary depending on ACT availability in their nearest health facility. RESULTS: Irrespective of ACT stock-outs, more than half (58%) of respondents sought initial care in the public sector, the remainder seeking care in the private sector where expenditure was higher by 19%. Over half (54%) of respondents who went to the public sector reported incidences of non compliant behaviour by the attending health worker (e.g. charging those who were eligible for free service or referring patients to the private sector despite ACT stock), which increased household expenditure per fever episode from USD0.14 to USD1.76. ACT stock-outs were considered to be the result of non-compliant behaviour of others in the health system and increased household expenditure by 21%; however we lacked sufficient statistical power to confirm this finding. CONCLUSION: System design and governance challenges in the Tanzanian health system have resulted in numerous ACT stock-outs and frequent non-compliant public sector health worker behaviour, both of which increase out-of-pocket health expenditure. Interventions are urgently needed to ensure a stable supply of ACT in the public sector and increase health worker accountability. PMID- 24161031 TI - Is progesterone a synonym for medroxyprogesterone acetate? PMID- 24161030 TI - The protonation states of oxo-bridged Mn(IV) dimers resolved by experimental and computational Mn K pre-edge X-ray absorption spectroscopy. AB - In nature, the protonation of oxo bridges is a commonly encountered mechanism for fine-tuning chemical properties and reaction pathways. Often, however, the protonation states are difficult to establish experimentally. This is of particular importance in the oxygen evolving complex of photosystem II, where identification of the bridging oxo protonation states is one of the essential requirements toward unraveling the mechanism. In order to establish a combined experimental and theoretical protocol for the determination of protonation states, we have systematically investigated a series of Mn model complexes by Mn K pre-edge X-ray absorption spectroscopy. An ideal test case for selective bis-MU oxo-bridge protonation in a Mn dimer is represented by the system [Mn(IV)2(salpn)2(MU-OHn)2](n+). Although the three species [Mn(IV)2(salpn)2(MU O)2], [Mn(IV)2(salpn)2(MU-O)(MU-OH)](+) and [Mn(IV)2(salpn)2(MU-OH)2](2+) differ only in the protonation of the oxo bridges, they exhibit distinct differences in the pre-edge region while maintaining the same edge energy. The experimental spectra are correlated in detail to theoretically calculated spectra. A time dependent density functional theory approach for calculating the pre-edge spectra of molecules with multiple metal centers is presented, using both high spin (HS) and broken symmetry (BS) electronic structure solutions. The most intense pre edge transitions correspond to an excitation of the Mn 1s core electrons into the unoccupied orbitals of local e(g) character (d(z)(2) and d(xy) based in the chosen coordinate system). The lowest energy experimental feature is dominated by excitations of 1s-alpha electrons, and the second observed feature is primarily attributed to 1s-beta electron excitations. The observed energetic separation is due to spin polarization effects in spin-unrestricted density functional theory and models final state multiplet effects. The effects of spin polarization on the calculated Mn K pre-edge spectra, in both the HS and BS solutions, are discussed in terms of the strength of the antiferromagnetic coupling and associated changes in the covalency of Mn-O bonds. The information presented in this paper is complemented with the X-ray emission spectra of the same compounds published in an accompanying paper. Taken together, the two studies provide the foundation for a better understanding of the X-ray spectroscopic data of the oxygen evolving complex (OEC) in photosystem II. PMID- 24161032 TI - Meta-analysis of the association of HLA-DRB1 with rheumatoid arthritis in Chinese populations. AB - BACKGROUND: Individual studies have reported different results regarding the association of HLA alleles with RA in Chinese populations. This study was performed to systematically summarize results on the association of HLA-DRB1 with rheumatoid arthritis (RA) in China. METHODS: We examined the case-control studies concerned about the relationship between HLA-DRB1 and RA and differences of clinical and laboratory parameters between the HLA-DR4 (DR4)+ and DR4- in RA patients in Chinese populations. Odds ratios (ORs) and weighted mean difference (WMD) with corresponding 95% confidence intervals (CI) was used to describe the relationship. RESULTS: 22 studies with 1690 cases and 1793 controls were included. Chinese populations with RA had significantly higher frequencies of HLA DRB1*04, *0401, *0404, *0405 and *0410 than controls (ORDRB1*04 =4.19, 95% CI =3.44-5.11, p<0.00001; ORDRB1*0401 =2.53, 95% CI =1.54-4.16, p=0.0003; ORDRB1*0404 =2.28, 95% CI =1.28-4.06, p=0.005; ORDRB1*0405=3.71, 95% CI =2.52 5.45, p<0.00001; ORDRB1*0410 =2.99, 95% CI =1.25-7.14, p=0.01 respectively). As to laboratory parameters, Erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), Rheumatoid factor (RF), Anti-cyclic citrullinated peptide antibodies (Anti-CCP ) in patients with DR4+ were higher than patients with DR4- (WMD=0.26, 95% CI =0.15-0.37, p<0.00001; WMD = 0.26, 95% CI =0.12-0.41, p=0.0005; WMD = 0.44, 95% CI =0.23-0.65, p<0.00001; WMD = 0.58, 95% CI =0.24-0.91, p=0.0007 respectively). As to clinical features, there was no difference in duration of morning stiffness, number of swollen joints, number of joint tenderness, X-ray phases and joint function between the DR4+ and DR4- in RA patients. CONCLUSIONS: It was found that HLA-DRB1*04, *0401, *0404, *0405 and *0410 are risk factors for RA in Chinese populations. ESR, CRP, RF, Anti-CCP are different between the DR4+ and DR4- in RA patients in Chinese populations, while there's no difference for indexes of clinical features. PMID- 24161033 TI - Key elements of the human bocavirus type 1 (HBoV1) promoter and its trans activation by NS1 protein. AB - BACKGROUND: Human bocavirus (HBoV), a parvovirus, is suspected to be an etiologic agent of respiratory disease and gastrointestinal disease in humans. All mRNAs of HBoV1 are transcribed from a single promoter. METHODS: In this study, we constructed EGFP and luciferase reporter gene vectors under the control of the HBoV1 full promoter (nt 1-252) and its mutated variants, respectively. Fluorescence microscopy was used to observe expression activities of the EGFP. Dual-luciferase reporter vectors were employed in order to evaluate critical promoter elements and the effect of NS1 protein on promoter activity. RESULTS: The HBoV1 promoter activity was about 2.2-fold and 1.9-fold higher than that of the CMV promoter in 293 T and HeLa cells, respectively. The putative transcription factor binding region of the promoter was identified to be located between nt 96 and nt 145. Mutations introduced in the CAAT box of the HBoV1 promoter reduced promoter activity by 34%, whereas nucleotide substitutions in the TATA box had no effect on promoter activity. The HBoV1 promoter activities in 293 T and HeLa cells, in the presence of NS1 protein, were 2- to 2.5-fold higher than those in the absence of NS1 protein. CONCLUSION: The HBoV1 promoter was highly active in 293 T and HeLa cell lines, and the sequence from nt 96 to nt 145 was critical for the activity of HBoV1 promoter. The CAAT box, in contrast to the TATA-box, was important for optimum promoter activity. In addition, the transcriptional activity of this promoter could be trans-activated by the viral nonstructural protein NS1 in these cells. PMID- 24161034 TI - Introduction: Complement-mediated kidney diseases. PMID- 24161035 TI - Overview of complement activation and regulation. AB - Complement is an important component of the innate immune system that is crucial for defense from microbial infections and for clearance of immune complexes and injured cells. In normal conditions complement is tightly controlled by a number of fluid-phase and cell surface proteins to avoid injury to autologous tissues. When complement is hyperactivated, as occurs in autoimmune diseases or in subjects with dysfunctional regulatory proteins, it drives a severe inflammatory response in numerous organs. The kidney appears to be particularly vulnerable to complement-mediated inflammatory injury. Injury may derive from deposition of circulating active complement fragments in glomeruli, but complement locally produced and activated in the kidney also may have a role. Many kidney disorders have been linked to abnormal complement activation, including immune-complex mediated glomerulonephritis and rare genetic kidney diseases, but also tubulointerstitial injury associated with progressive proteinuric diseases or ischemia-reperfusion. PMID- 24161036 TI - Dense deposit disease and C3 glomerulopathy. AB - C3 glomerulopathy refers to those renal lesions characterized histologically by predominant C3 accumulation within the glomerulus, and pathogenetically by aberrant regulation of the alternative pathway of complement. Dense deposit disease is distinguished from other forms of C3 glomerulopathy by its characteristic appearance on electron microscopy. The extent to which dense deposit disease also differs from other forms of C3 glomerulopathy in terms of clinical features, natural history, and outcomes of treatment including renal transplantation is less clear. We discuss the pathophysiology of C3 glomerulopathy, with evidence for alternative pathway dysregulation obtained from affected individuals and complement factor H (Cfh)-deficient animal models. Recent linkage studies in familial C3 glomerulopathy have shown genomic rearrangements in the Cfh-related genes, for which the novel pathophysiologic concept of Cfh deregulation has been proposed. PMID- 24161038 TI - The role of complement in membranous nephropathy. AB - Membranous nephropathy (MN) describes a histopathologic pattern of injury marked by glomerular subepithelial immune deposits and collectively represents one of the most common causes of adult nephrotic syndrome. Studies in Heymann nephritis, an experimental model of MN, have established a paradigm in which these deposits locally activate complement to cause podocyte injury, culminating in cytoskeletal reorganization, loss of slit diaphragms, and proteinuria. There is much circumstantial evidence for a prominent role of complement in human MN because C3 and C5b-9 are found consistently within immune deposits. Secondary MN often shows the additional presence of C1q, implicating the classic pathway of complement activation. Primary MN, however, is IgG4-predominant and IgG4 is considered incapable of binding C1q and activating the complement pathway. Recent studies have identified the M-type phospholipase A2 receptor (PLA2R) as the major target antigen in primary MN. Early evidence hints that IgG4 anti-PLA2R autoantibodies can bind mannan-binding lectin and activate the lectin complement pathway. The identification of anti-PLA2R antibodies as likely participants in the pathogenesis of disease will allow focused investigation into the role of complement in MN. Definitive therapy for MN is immunosuppression, although future therapeutic agents that specifically target complement activation may represent an effective temporizing measure to forestall further glomerular injury. PMID- 24161040 TI - Complement in ANCA-associated vasculitis. AB - Antineutrophil cytoplasmic autoantibodies (ANCA) are the likely cause for necrotizing small-vessel vasculitis and crescentic glomerulonephritis. Unlike other forms of crescentic glomerulonephritis induced by immune complexes or anti glomerular basement membrane antibodies that have conspicuous vessel wall immunoglobulin and complement, there is a paucity, although usually not an absence, of vessel wall immunoglobulin and complement in ANCA-associated glomerulonephritis. Despite this comparatively lower level and more localized distribution of vessel wall complement, experimental and clinical observations strongly incriminate alternative complement pathway activation as critically important in the pathogenesis of ANCA disease. Experimental data in animal models and in vitro experiments has shown that primed neutrophils are activated by ANCA, which generates C5a, which engages C5a receptors on neutrophils. This attracts and in turn primes more neutrophils for activation by ANCA. In patients with ANCA disease, plasma levels of C3a, C5a, soluble C5b-9, and Bb have been reported to be higher in active disease than in remission, whereas no difference was reported in plasma C4d in active versus ANCA disease remission. Thus, experimental and clinical data support the hypothesis that ANCA-induced neutrophil activation activates the alternative complement pathway and generates C5a. C5a not only recruits additional neutrophils through chemotaxis but also primes neutrophils for activation by ANCA. This creates a self-fueling inflammatory amplification loop that results in the extremely destructive necrotizing vascular injury. PMID- 24161037 TI - Atypical hemolytic uremic syndrome. AB - Hemolytic uremic syndrome (HUS) is a triad of microangiopathic hemolytic anemia, thrombocytopenia, and acute renal failure. The atypical form of HUS is a disease characterized by complement overactivation. Inherited defects in complement genes and acquired autoantibodies against complement regulatory proteins have been described. Incomplete penetrance of mutations in all predisposing genes is reported, suggesting that a precipitating event or trigger is required to unmask the complement regulatory deficiency. The underlying genetic defect predicts the prognosis both in native kidneys and after renal transplantation. The successful trials of the complement inhibitor eculizumab in the treatment of atypical HUS will revolutionize disease management. PMID- 24161039 TI - The role of the complement system in acute kidney injury. AB - Acute kidney injury is a common and severe clinical problem. Patients who develop acute kidney injury are at increased risk of death despite supportive measures such as hemodialysis. Research in recent years has shown that tissue inflammation is central to the pathogenesis of renal injury, even after nonimmune insults such as ischemia/reperfusion and toxins. Examination of clinical samples and preclinical models has shown that activation of the complement system is a critical cause of acute kidney injury. Furthermore, complement activation within the injured kidney is a proximal trigger of many downstream inflammatory events within the renal parenchyma that exacerbate injury to the kidney. Complement activation also may account for the systemic inflammatory events that contribute to remote organ injury and patient mortality. Complement inhibitory drugs have now entered clinical use and may provide an important new therapeutic approach for patients suffering from, or at high risk of developing, acute kidney injury. PMID- 24161041 TI - Complement regulation of T-cell alloimmunity. AB - Complement proteins are generated both by the liver (systemic compartment) and by peripheral tissue-resident cells and migratory immune cells (local compartment). The immune cell-derived, alternative pathway complement components activate spontaneously, yielding local, but not systemic, production of C3a and C5a. These anaphylatoxins bind to their respective G-protein-coupled receptors, the C3a receptor and the C5a receptor, expressed on T cells and antigen-presenting cells, leading to their reciprocal activation and driving T-cell differentiation, expansion, and survival. Complement deficiency or blockade attenuates T-cell mediated autoimmunity and delays allograft rejection in mice. Increasing complement activation, achieved by genetic removal of the complement regulatory protein decay accelerating factor, enhances murine T-cell immunity and accelerates allograft rejection. Signaling through the C3a receptor and the C5a receptor reduces suppressive activity of natural regulatory T cells and the generation and stability of induced regulatory T cells. The concepts, initially generated in mice, recently were confirmed in human immune cells, supporting the need for testing of complement targeting therapies in organ transplants patients. PMID- 24161044 TI - Building a national direction for research in the prevention of mother to child transmission of HIV: results from a national prioritization initiative in Malawi. AB - BACKGROUND: In 2011, Malawi initiated an ambitious program for the prevention of maternal to child transmission (PMTCT) of HIV, called 'Option B+,' which employs a universal test and life-long treatment strategy for all pregnant women. Priority setting should take place in defining a national research agenda for evaluating Option B + rollout in Malawi. METHODS: In April 2011, a three-day workshop took place for all major stakeholders in PMTCT aiming to provide an update on current PMTCT operational research in Malawi, find consensus on key questions not yet being addressed, identify opportunities for collaboration, and develop multi-partner research proposals. RESULTS: Overall, 24 participants attended the workshop including representatives from the Ministry of Health, the National AIDS Commission and 12 multilateral, non-governmental organizations and academic partners.Three interrelated clusters emerged as priorities for research: i) pregnancy intentions and family planning needs; ii) evaluation of models of care; and iii) determinants of uptake, adherence, and retention of women for Option B+. In addition, two cross-cutting themes arose: partner involvement in PMTCT services and cost-effectiveness as a guide to priority setting. Within each cluster a coordinator was designated and a proposed plan for research and potential collaborators were discussed. The results of the workshop were presented to the national technical working groups and the National AIDS Commission. Several large-scale, collaborative proposals have been developed and funded to address the research areas defined. CONCLUSIONS: Option B + represents a significant change in PMTCT policy in Malawi and the process for evaluation of the Malawi PMTCT strategy is outlined. This workshop contributed to defining and coordinating the national agenda for research priorities. PMID- 24161043 TI - Complement-mediated cellular injury. AB - Complement activation and recruitment of inflammatory leukocytes is an important defense mechanism against bacterial infection. However, complement also can mediate cellular injury and contribute to the pathogenesis of various diseases. With the appreciation that the C5b-9 membrane attack complex can injure cells in the absence of leukocytes, a role for the terminal complement pathway in inducing cell injury and kidney disease was shown in several experimental models, including the rat passive Heymann nephritis model of human membranous nephropathy. In podocytes, sublytic C5b-9 activates a variety of downstream pathways including protein kinases, lipid metabolism, reactive oxygen species, growth factors/gene transcription, endoplasmic reticulum stress, and the ubiquitin-proteasome system, and it impacts the integrity of the cytoskeleton and slit diaphragm proteins. C5b-9 also injures other kidney cells, including mesangial, glomerular endothelial, and tubular epithelial cells, and it contributes to the pathogenesis of mesangial-proliferative glomerulonephritis, thrombotic microangiopathy, and acute kidney injury. Conversely, certain C5b-9 signals limit complement-induced injury, or promote recovery of cells. In addition to C5b-9, complement cleavage products, such as C5a and C1q, can injure kidney cells. Thus, the complement system contributes to various kidney pathologies by causing cellular damage in both an inflammation-dependent and inflammation-independent manner. PMID- 24161045 TI - Characterization of target mRNA reduction through in situ RNA hybridization in multiple organ systems following systemic antisense treatment in animals. AB - Advances in the medicinal chemistry of antisense oligonucleotide drugs have been instrumental in achieving and optimizing antisense activity in cell types other than hepatocytes, the cell type that is most sensitive to antisense effects following systemic treatment. To broadly characterize the effects of antisense drugs on target messenger RNA (mRNA) levels in different organs and cell types in animals, we have developed a sensitive RNA in situ hybridization technique using the noncoding RNA metastasis associated lung adenocarcinoma transcript 1 (MALAT1) as a surrogate target. We have used this technique to evaluate the effects of 2' O-methoxy ethyl (MOE) and constrained ethyl bicyclic nucleic acid (cEt) gapmer antisense oligonucleotides (ASOs). ASO tissue distribution was also characterized using immunohistochemical techniques, and MALAT1 mRNA reductions were confirmed by quantitative real time-polymerase chain reaction. Our findings demonstrate that systemic antisense drug administration in both mice and non-human primates resulted in marked reductions in MALAT1 RNA in many tissues and cell types other than liver including kidney, muscle, lung, adipose, adrenal gland, and peripheral nerve tissue. As expected, ASOs with cEt chemistry were more efficacious than MOE ASO in all tissues examined. PMID- 24161046 TI - [Anales de Pediatria: a new phase]. PMID- 24161042 TI - Complement regulation in renal disease models. AB - Activation of the complement system is tightly regulated by plasma and cell associated complement regulatory proteins (CRPs), such as factor H (fH), decay accelerating factor, and membrane cofactor protein. Animal models of disease have provided considerable insights into the important roles for CRPs in the kidney. Mice deficient in fH have excessive fluid phase C3 activation and inactivation, leading to deposition of inactivated C3b in glomerular capillary walls (GCW), comparable with dense deposit disease. In contrast, when fH lacks C-terminal surface targeting regions, local activation on the GCW leads to a disease reminiscent of thrombotic microangiopathy. The uniquely rodent protein, CR1 related y (Crry), has features analogous to human membrane cofactor protein. Defective Crry leads to unrestricted alternative pathway activation in the tubulointerstitium, resulting in pathologic features ranging from thrombotic microangiopathy (TMA), acute kidney injury, and tubulointerstitium nephritis. In the presence of initiators of the classic or lectin pathways, commonly in the form of immune complexes in human glomerular diseases, complement regulation is stressed, with the potential for recruitment of the spontaneously active alternative pathway. The threshold for this activation is set by CRPs; pathology is more likely when complement regulation is defective. Within the endocapillary region of the GCW, fH is key, while decay-accelerating factor and Crry are protective on mesangial cells and podocytes. Arguably, acquired alterations in these CRPs is a more common event, extending from pathologic states of cellular injury or production of inhibitory antibodies, to physiological fine tuning of the adaptive immune response. PMID- 24161047 TI - Self-management of multiple chronic conditions among African American women with asthma: a qualitative study. AB - OBJECTIVE: African American women are disproportionately burdened by asthma morbidity and mortality and may be more likely than asthma patients in general to have comorbid health conditions. This study sought to identify the self management challenges faced by African American women with asthma and comorbidities, how they prioritize their conditions and behaviors perceived as beneficial across conditions. METHODS: In-depth interviews were conducted with 25 African-American women (mean age 52 years) with persistent asthma and at least one of the following: diabetes, heart disease or arthritis. Information was elicited on women's experiences managing asthma and concurrent health conditions. The constant-comparison analytic method was used to develop and apply a coding scheme to interview transcripts. Key themes and subthemes were identified. RESULTS: Participants reported an average of 5.7 comorbidities. Fewer than half of the sample considered asthma their main health problem; these perceptions were influenced by beliefs about the relative controllability, predictability and severity of their health conditions. Participants reported ways in which comorbidities affected asthma management, including that asthma sometimes took a "backseat" to conditions considered more troublesome or worrisome. Mood problems, sometimes attributed to pain or functional limitations resulting from comorbidities, reduced motivation for self-management. Women described how asthma affected comorbidity management; e.g. by impeding recommended exercise. Some self management recommendations, such as physical activity and weight control, were seen as beneficial across conditions. CONCLUSIONS: Multiple chronic conditions that include asthma may interact to complicate self-management of each condition. Additional clinical attention and self-management support may help to reduce multimorbidity-related challenges. PMID- 24161049 TI - ClinicalTrials.gov: what the numbers don't tell us. PMID- 24161048 TI - Combined ceftazidime and amikacin resistance among Gram-negative isolates in acute-onset postoperative endophthalmitis: prevalence, antimicrobial susceptibilities, and visual acuity outcome. AB - BACKGROUND: The purpose of this study is to evaluate the prevalence, antimicrobial susceptibilities, and visual acuity outcome of acute-onset postoperative Gram-negative bacterial endophthalmitis cases resistant to both ceftazidime and amikacin seen between 2005 and 2010 at L. V. Prasad Eye Institute, a tertiary care ophthalmic Centre in South India. Medical records of all patients with Gram-negative bacterial endophthalmitis resistant to both amikacin and ceftazidime between 1 January 2005 and 31 December 2010 were reviewed in this non-comparative, consecutive, retrospective case series. Favorable outcome was defined as a best-corrected visual acuity of >=20/200. RESULTS: Sixty five (39.6%) of 164 culture-positive postoperative endophthalmitis were caused by Gram-negative organisms. Among these 65 isolates, 32 (49%; 95% confidence interval (CI) 37% to 61%) were resistant to ceftazidime, 17 (26%; 95% CI 15% to 37%) to amikacin, and 12 (18.5%; 95% CI 9% to 27%) to both ceftazidime and amikacin. Eight Pseudomonas isolates, three Enterobacter isolates, and one Haemophilus isolate were resistant to both ceftazidime and amikacin. The isolates were sensitive to fluoroquinolones (42%) and imipenem (50%). Presenting visual acuity was light perception in 10 (83.3%) cases. A final visual acuity >=20/200 was achieved in 5/12 (41.7%) of these patients. CONCLUSION: In the current study, Pseudomonas was the most common Gram-negative bacteria resistant to both amikacin and ceftazidime. The emergence of multidrug-resistant bacteria causing endophthalmitis is a matter of concern in India. Alternative antibiotics like imipenem or fluoroquinolones may be considered for the management of these resistant organisms. PMID- 24161050 TI - Multimorbidity: the new normal. PMID- 24161051 TI - Pneumonia and lung infiltrates in neutropenic patients: many stones unturned. PMID- 24161053 TI - Intrapulmonary arteriovenous anastomoses. Physiological, pathophysiological, or both? AB - Large-diameter, intrapulmonary arteriovenous anastomoses exist in human lungs. In developing fetuses, blood flows physiologically through pulmonary arteriovenous channels that appear to regress during lung maturation. Blood flow through intrapulmonary arteriovenous anastomoses is a normal occurrence during exercise or inhalation of reduced oxygen gas mixtures in most healthy humans. However, the importance of blood flow through these anastomoses to the efficiency of pulmonary gas exchange in normal and pathological states remains controversial. Newly reported three-dimensional dissections of human lung samples provide direct anatomic evidence of intrapulmonary arteriovenous anastomoses in the lungs of prematurely born infants, and suggest that these vessels contribute consequentially to the severe arterial hypoxemia experienced by infants who die of bronchopulmonary dysplasia. Surgical construction of a cavopulmonary anastomosis can also induce pathological arteriovenous shunting suggestive of a regression to the fetal state, possibly implicating an enigmatic hepatic factor in arteriovenous shunt regulation. These two observations support an important contribution of blood flow through intrapulmonary arteriovenous anastomoses to arterial hypoxemia under at least some pathological conditions. The degree to which these vessels contribute to arterial hypoxemia in other disease states where intrapulmonary shunting is present, such as hepatopulmonary syndrome, remains unknown. PMID- 24161052 TI - Cigarette smoking as a risk factor for delirium in hospitalized and intensive care unit patients. A systematic review. AB - BACKGROUND: Active smokers are prevalent in hospitalized and critically ill patients. Cigarette smoking and nicotine withdrawal may increase delirium in these populations. This systematic review aims to determine whether active cigarette smoking increases the risk for delirium in hospitalized and intensive care unit (ICU) patients. METHODS: A systematic search of English-, Spanish-, and French-language articles published from 1966 to April 2013 was performed. Studies were included if they measured cigarette smoking as a risk factor and delirium as an outcome in adult hospitalized or ICU patients. Methodologic quality of studies was assessed using both the validated Newcastle Ottawa Scale and an additional evidence-based quality rating scale. RESULTS: A total of 14 cohort studies of surgical and ICU populations were included in the review. No studies in non-ICU inpatients were identified. The incidence of delirium ranged from 9 to 52%, and the prevalence of active smokers ranged from 9 to 44%. The quality of assessment for active smoking varied widely. None of the studies used biochemical measures to determine cigarette smoke exposure. Of the six studies restricting the smoking group to active smokers only, active smoking was independently associated with delirium in one study, trended toward an association in one study, and showed a dose response in one study. Quantitative summary measures were not calculated due to study heterogeneity and missing data. CONCLUSIONS: There is currently insufficient evidence to determine if cigarette smoking is a risk factor for delirium. Future studies should consider using biochemical measures of cigarette smoke exposure to objectively quantify smoking behavior. PMID- 24161054 TI - Global health care of the critically ill in low-resource settings. AB - The care of the critically ill patient in low-resource settings is challenging because of many factors, including limitations in the existing infrastructure, lack of disposables, and low numbers of trained healthcare workers. Although cost constraints in low-resource settings have traditionally caused critical care to be relegated to a low priority, ethical issues and the potential for mitigation of the lethal effects of often reversible acute conditions, such as sepsis and traumatic hemorrhage, argue for prudent deployment of critical care resources. Given these challenges, issues that require prioritization include timely and reliable delivery of evidence-based or generally accepted interventions to acutely ill patients before the development of organ failure, context-specific adaptation and evaluation of clinical evidence, and sustained investments in quality improvement and health systems strengthening. Specific examples include fluid resuscitation algorithms for patients with sepsis and reliable, low-cost, high-flow oxygen concentrators for patients with pneumonia. The lessons from new research on clinical management and sustainable education and quality improvement approaches will likely improve the care of critically ill patients worldwide. PMID- 24161055 TI - Persistent pneumonia in an infant. Keeping an open mind. PMID- 24161056 TI - Exophytic tracheal mass. A rare presentation of Rosai-Dorfman disease. PMID- 24161057 TI - Endobronchial valve placement for a giant bulla in a patient with hypercapnic respiratory failure. PMID- 24161058 TI - Measurement of lung volumes in patients with obstructive lung disease. A matter of time (constants). PMID- 24161059 TI - Sleep rhythms. PMID- 24161060 TI - Long-term success after bilateral lung transplantation for Mounier-Kuhn syndrome: a physiological description. PMID- 24161061 TI - Airflow during forced expiration. PMID- 24161062 TI - Reply: Airflow during forced expiration. PMID- 24161063 TI - Introduction to ATS seminars: intensive care ultrasound. PMID- 24161064 TI - Intensive care ultrasound: I. Physics, equipment, and image quality. PMID- 24161065 TI - Intensive care ultrasound: II. Central vascular access and venous diagnostic ultrasound. PMID- 24161066 TI - Gordon L. Snider, M.D., 1922-2013. PMID- 24161067 TI - Expression of concern: Safety of thoracentesis and small-bore chest tube placement in patients on clopidogrel. PMID- 24161068 TI - An official American Thoracic Society workshop report: assessment and palliative management of dyspnea crisis. AB - In 2009, the American Thoracic Society (ATS) funded an assembly project, Palliative Management of Dyspnea Crisis, to focus on identification, management, and optimal resource utilization for effective palliation of acute episodes of dyspnea. We conducted a comprehensive search of the medical literature and evaluated available evidence from systematic evidence-based reviews (SEBRs) using a modified AMSTAR approach and then summarized the palliative management knowledge base for participants to use in discourse at a 2009 ATS workshop. We used an informal consensus process to develop a working definition of this novel entity and established an Ad Hoc Committee on Palliative Management of Dyspnea Crisis to further develop an official ATS document on the topic. The Ad Hoc Committee members defined dyspnea crisis as "sustained and severe resting breathing discomfort that occurs in patients with advanced, often life-limiting illness and overwhelms the patient and caregivers' ability to achieve symptom relief." Dyspnea crisis can occur suddenly and is characteristically without a reversible etiology. The workshop participants focused on dyspnea crisis management for patients in whom the goals of care are focused on palliation and for whom endotracheal intubation and mechanical ventilation are not consistent with articulated preferences. However, approaches to dyspnea crisis may also be appropriate for patients electing life-sustaining treatment. The Ad Hoc Committee developed a Workshop Report concerning assessment of dyspnea crisis; ethical and professional considerations; efficient utilization, communication, and care coordination; clinical management of dyspnea crisis; development of patient education and provider aid products; and enhancing implementation with audit and quality improvement. PMID- 24161069 TI - Tandem dienone photorearrangement-cycloaddition for the rapid generation of molecular complexity. AB - A tandem dienone photorearrangement-cycloaddition (DPC) reaction of novel cyclohexadienone substrates tethered with various 2pi and 4pi reaction partners resulted in the formation of polycyclic, bridged frameworks. In particular, use of alkynyl ether-tethered substrates led to (3 + 2) cycloaddition to afford strained alkenes which could be further elaborated by intra- and intermolecular cycloaddition chemistry to produce complex, polycyclic chemotypes. PMID- 24161070 TI - Prevalence and antimicrobial susceptibility of foodborne bacteria in wild boars (Sus scrofa) and wild deer (Cervus nippon) in Japan. AB - This study aimed to evaluate the role of wild boars and deer as reservoirs of foodborne bacteria. We investigated the prevalence and antimicrobial susceptibility of Campylobacter spp., Salmonella spp., Shiga toxin-producing Escherichia coli (STEC) O157 and O26, and Listeria monocytogenes isolated from wild boars and deer in Japan, from July through December 2010. Campylobacter spp. and Salmonella spp. were isolated from 43.8% (95% confidence interval [CI]: 35.0 52.6) and 7.4% (95% CI: 2.8-12.1) of rectal content samples of wild boars, respectively, but not from wild deer. The most common Campylobacter species was C. lanienae and C. hyointestinalis. The nine Salmonella serovars isolated were S. enterica subsp. enterica serovar Agona (three isolates), S. Narashino (two), S. Enteritidis (one), S. Havana (one), S. Infantis (one), and S. Thompson (one). Five (16%) and 6 (29%) isolates of C. lanienae and C. hyointestinalis, respectively, were resistant to enrofloxacin. STEC O157 and O26 and L. monocytogenes were isolated from 2.3% (95% CI: 0-5.0), 0.8% (95% CI: 0-2.3), and 6.1% (95% CI: 1.7-10.5) of the rectal content samples of wild deer, respectively, but not from wild boars. This first nationwide survey of the prevalence of foodborne bacteria in wild boars and wild deer in Japan suggests that consumption of meat from these animals is associated with the risk of causing infection with these bacteria in humans. Moreover, these animals are potential vehicles for distribution of antimicrobial-resistant bacteria into their habitat. The prevalence and antimicrobial susceptibility of such foodborne bacteria in these wild animals should be monitored periodically. PMID- 24161072 TI - Special series introduction: NIH EXAMINER and the assessment of executive functioning. PMID- 24161073 TI - The molecular landscape of diffuse glioma and prospects for biomarker development. AB - INTRODUCTION: High-throughput molecular profiling is transforming long-standing conceptions of diffuse gliomas, the most common primary brain tumors. Indeed, comprehensive genomic, transcriptomic and epigenomic analyses have not only provided striking mechanistic insights into the pathogenesis of diffuse gliomas but also greatly enriched the pool of potential biomarkers for prognostic and predictive patient stratification. AREAS COVERED: This article summarizes significant recent developments in the molecular characterization of diffuse gliomas, focusing on implications for biomarker development and application. In doing so, we will also address relevant high-throughput molecular profiling technologies and both the opportunities and challenges implicit in their widespread incorporation into disease management workflows. EXPERT OPINION: Although the number of validated biomarkers guiding diffuse glioma management is currently quite small, rapidly progressing molecular annotation continues to provide a steady stream of clinically relevant candidates, many of which show promise for predictive capabilities in the context of specific targeted therapeutics. Such potential now requires rigorous validation in well-designed clinical trials supported by robust molecular profiling assays operative from standard clinical material. PMID- 24161074 TI - Cost-effectiveness of antiplatelet therapy to prolong primary patency of hemodialysis graft. AB - INTRODUCTION: The Dialysis Access Consortium (DAC) study group previously reported that treatment with extended-release dipyridamole plus aspirin (DASA) resulted in a significant but clinically modest improvement in primary unassisted arteriovenous graft (AVG) patency. Utilizing DAC published data, the objective of this study is to evaluate the cost effectiveness of antiplatelet interventions aimed at preventing loss of primary AVG patency in hemodialysis (HD) patients. METHODS: We performed a cost-utility analysis, using a decision analysis tree model with a 12-month time horizon and a third party payer perspective. Interventions included DASA with and without concurrent aspirin, aspirin alone, and no prophylaxis. The modeled population was defined as adult (>= 18 years of age) end-stage renal disease (ESRD) patients who had undergone placement of a new AVG in the United States. The outcomes were costs, quality-adjusted life-years (QALY), incremental cost-effectiveness ratios, and net monetary benefit. Probabilities were based upon published studies performed by the DAC Study Group while costs of medications and procedures were drawn from public sources. Utilities of health states were derived from published reports and the Short Form 6D (SF-6D) instrument. RESULTS: Aspirin alone is the most cost effective strategy for AVG pharmacologic prophylaxis, as compared to no prophylaxis or DASA with or without concurrent aspirin. The results are robust on multiple scenario analyses using both deterministic and Monte Carlo probabilistic sensitivity analyses. Accounting for both costs and QALY, using aspirin alone to prevent AVG thrombosis can potentially reduce healthcare costs by $24,679,412 per year compared to no aspirin use, at a willingness-to-pay of $50,000/ QALY. CONCLUSIONS: Aspirin monotherapy compared favorably to other strategies based on cost per QALY. Our findings support the use of aspirin prophylaxis in HD patients with a new AVG who do not have a contraindication to aspirin. PMID- 24161075 TI - Physiology and pharmacology of the enteroendocrine hormone glucagon-like peptide 2. AB - Glucagon-like peptide-2 (GLP-2) is a 33-amino-acid proglucagon-derived peptide secreted from enteroendocrine L cells. GLP-2 circulates at low basal levels in the fasting period, and plasma levels rise rapidly after food ingestion. Renal clearance and enzymatic inactivation control the elimination of bioactive GLP-2. GLP-2 increases mesenteric blood flow and activates proabsorptive pathways in the gut, facilitating nutrient absorption. GLP-2 also enhances gut barrier function and induces proliferative and cytoprotective pathways in the small bowel. The actions of GLP-2 are transduced via a single G protein-coupled receptor (GLP-2R), expressed predominantly within the gastrointestinal tract. Disruption of GLP-2R signaling increases susceptibility to gut injury and impairs the adaptive mucosal response to refeeding. Sustained augmentation of GLP-2R signaling reduces the requirement for parenteral nutrition in human subjects with short-bowel syndrome. Hence GLP-2 integrates nutrient-derived signals to optimize mucosal integrity and energy absorption. PMID- 24161077 TI - Multiple cavernous hemangiomas of the skull with dural tail sign: a case report and literature review. AB - BACKGROUND: Primary intraosseous cavernous hemangioma is a rare bony tumor. To date, only 9 cases of multiple lesions and 2 cases with a dural tail sign have been reported. CASE PRESENTATION: Here, we present a case of multiple cavernous hemangiomas of the skull with dural tail sign in a 24-year-old man. No abnormalities were observed in the right orbit by craniography, but frontal bone destruction was unintentionally discovered. Computed tomography and magnetic resonance imaging demonstrated multiple intraosseous lesions that destroyed the surrounding bone and intracranial extension. Total resection of the two lesions and cranioplasty were performed. Histological examination confirmed the lesions as a cavernous hemangioma. CONCLUSION: Cavernous hemangioma is a rare bony tumor that should be considered in the differential diagnosis of skull tumors. Resection of all lesions should be performed on patients with multiple cavernous hemangiomas, and these patients should have regular follow-up examinations. Based on this case, and our literature review, we found that outcomes are usually very good. PMID- 24161078 TI - The eNOS 894G/T gene polymorphism and its influence on early and long-term mortality after on-pump cardiac surgery. AB - BACKGROUND: The eNOS 894G/T polymorphism (GG, GT, and TT) is associated with cardiovascular mortality and may influence cardiovascular diseases as a genetic risk factor. Moreover, this polymorphism has an impact on intraoperative hemodynamics during cardiac surgery with cardiopulmonary bypass (CPB). In this study, we analyzed the influence of this gene polymorphism on early clinical outcome in patients who underwent cardiac surgery with CPB. Also, we performed a 5-year follow-up, assessing the impact of this polymorphism on long-term mortality. METHOD: 500 patients who underwent cardiac surgery with CPB between 2006 and 2007 were included in this prospective single centre study. Genotyping for the eNOS gene polymorphism was performed by polymerase chain reaction amplification. RESULTS: Genotype distribution of 894G/T was: GG 50.2%; GT 42.2%; TT 7.8%. Cardiovascular risk factors were equally distributed between the different genotypes of the eNOS 894G/T polymorphism. No significant difference among the groups was shown regarding Euroscore, SAPS II and APACHE II. Perioperative characteristics were also not affected by the genotypes, except for the consumption of norepinephrine (p = 0.03) and amiodarone (p = 0.01) which was higher in the GT allele carrier. The early postoperative course was quite uniform across the genotypes, except for mean intensive care unit length of stay which was significantly prolonged in GT carriers (p = 0.001). The five-year follow-up was 100% complete and showed no significant differences regarding mortality between the groups. CONCLUSION: Our results show that the eNOS 894G /T polymorphism is not associated with early and late clinical outcome after cardiac surgery. Thus, this polymorphism can actually not help to identify high risk groups in the heterogeneous population of individuals who undergo cardiac surgery with CPB. PMID- 24161079 TI - Clinical microbiology of Coxiella burnetii and relevant aspects for the diagnosis and control of the zoonotic disease Q fever. AB - Coxiella burnetii is the causative agent of the zoonotic disease Q fever. Since its first recognition as a disease in the 1930s, the knowledge about the agent and the disease itself has increased. This review summarizes the current knowledge on C. burnetii and Q fever, its pathogenesis, diagnosis and control. C. burnetii is a bacterium which naturally replicates inside human or animal host cells. The clinical presentation of Q fever varies per host species. C. burnetii infection in animals is mainly asymptomatic except for pregnant ruminants in which abortions and stillbirth can occur. In humans, the disease is also mainly asymptomatic, but clinical presentations include acute and chronic Q fever and the post-Q fever fatigue syndrome. Knowledge of the pathogenesis of Q fever in animals and excretion of C. burnetii in infected animals is crucial in understanding the transmission routes and risks of human infection. Our studies indicated that infected pregnant animals only excrete C. burnetii during and after parturition, independent of abortion, and that C. burnetii phase specific serology can be a useful tool in the early detection of infection. Domestic ruminants are the main reservoir for human Q fever, which has a major public health impact when outbreaks occur. In outbreaks, epidemiological source identification can only be refined by genotypic analysis of the strains involved. To control outbreaks and Q fever in domestic ruminants, vaccination with a phase 1 vaccine is effective. Future challenges are to identify factors for virulence, host susceptibility and protection. PMID- 24161080 TI - The application of central tension plate with sharp hook in the treatment of intra-articular olecranon fracture. AB - BACKGROUND: Standard plate fixation can be used to treat intraarticular olecranon fractures with satisfactory functional recovery, but its use is accompanied by implant related complications. This retrospective study reports on the functional outcome of intraarticular olecranon fractures treated with a central tension plate with sharp hook. METHODS: A retrospective review of any patient with an olecranon fracture from August 2007 to December 2008 was conducted. Patients were considered for inclusion in the study if they were treated surgically with a central tension plate with sharp hook. Patients with pathological fractures or previous fractures of the proximal ulna were excluded. The quality of reduction was evaluated using postoperative imaging. The functional recoveries of the affected upper limbs were evaluated postoperatively at regular intervals using the Mayo Elbow Performance (MEP) score and Disability of the Arm, Shoulder and Hand questionnaire (DASH). RESULTS: Twenty six patients met the study criteria and were included in analysis. There were ten Type IIA, nine Type IIB, four Type IIIA and three Type IIIB fractures according to the Mayo classification system. Thirteen patients exhibited other concomitant fractures at the time of surgery: one patient with a coronoid fracture, two with a fracture of the radial head, and ten with fractures in other bones. Postoperative radiographic assessment revealed an anatomical or nearly anatomical reduction of all olecranon fractures treated. All olecranon fractures healed at an average of 14 weeks (range, 9 to 32 weeks). The patients were followed up for 42 months (range, 32 to 54 months). The mean DASH score was 8.5 (range, 0 to 31.7). The mean MEP score was 93.6 (range, 75 to 100). Based on the MEP score, all patients achieved good or excellent outcomes. No symptomatic plate removal was performed at the time of last follow-up. CONCLUSION: The central tension plate with sharp hook closely contours to the osteology of the proximal ulna. Treating intra-articular olecranon fracture with this new plate can achieve good to excellent functional outcome with a high union rate and a low incidence of hardware related complications. PMID- 24161076 TI - Redox-dependent anti-inflammatory signaling actions of unsaturated fatty acids. AB - Unsaturated fatty acids are metabolized to reactive products that can act as pro- or anti-inflammatory signaling mediators. Electrophilic fatty acid species, including nitro- and oxo-containing fatty acids, display salutary anti inflammatory and metabolic actions. Electrophilicity can be conferred by both enzymatic and oxidative reactions, via the homolytic addition of nitrogen dioxide to a double bond or via the formation of alpha,beta-unsaturated carbonyl and epoxide substituents. The endogenous formation of electrophilic fatty acids is significant and influenced by diet, metabolic, and inflammatory reactions. Transcriptional regulatory proteins and enzymes can sense the redox status of the surrounding environment upon electrophilic fatty acid adduction of functionally significant, nucleophilic cysteines. Through this covalent and often reversible posttranslational modification, gene expression and metabolic responses are induced. At low concentrations, the pleiotropic signaling actions that are regulated by these protein targets suggest that some classes of electrophilic lipids may be useful for treating metabolic and inflammatory diseases. PMID- 24161082 TI - The impact of different prioritisation policies on waiting times: case studies of Norway and Scotland. AB - We investigate the distributional consequences of two different waiting times initiatives, one in Norway, and one in Scotland. The primary focus of Scotland's recent waiting time reforms, introduced in 2003, and modified in 2005 and 2007, has been on reducing maximum waiting times through the imposition of high profile national targets accompanied by increases in resources. In Norway, the focus of the reform introduced in September 2004, has been on assigning patients referred to hospital a maximum waiting time based on disease severity, the expected benefit and the cost-effectiveness of the treatment. We use large, national administrative datasets from before and after each of these reforms and assign priority groups based on the maximum waiting times stipulated in medical guidelines. The analysis shows that the lowest priority patients benefited most from both reforms. This was at the cost of longer waiting times for patients that should have been given higher priority in Norway, while Scotland's high priority patients remained unaffected. PMID- 24161081 TI - Experimental and computational X-ray emission spectroscopy as a direct probe of protonation states in oxo-bridged Mn(IV) dimers relevant to redox-active metalloproteins. AB - The protonation state of oxo bridges in nature is of profound importance for a variety of enzymes, including the Mn4CaO5 cluster of photosystem II and the Mn2O2 cluster in Mn catalase. A set of dinuclear bis-MU-oxo-bridged Mn(IV) complexes in different protonation states was studied by Kbeta emission spectroscopy to form the foundation for unraveling the protonation states in the native complex. The valence-to-core regions (valence-to-core XES) of the spectra show significant changes in intensity and peak position upon protonation. DFT calculations were performed to simulate the valence-to-core XES spectra and to assign the spectral features to specific transitions. The Kbeta(2,5) peaks arise primarily from the ligand 2p to Mn 1s transitions, with a characteristic low energy shoulder appearing upon oxo-bridge protonation. The satellite Kbeta" peak provides a more direct signature of the protonation state change, since the transitions originating from the 2s orbitals of protonated and unprotonated MU-oxo bridges dominate this spectral region. The energies of the Kbeta" features differ by ~3 eV and thus are well resolved in the experimental spectra. Additionally, our work explores the chemical resolution limits of the method, namely, whether a mixed (MU-O)(MU-OH2) motif can be distinguished from a symmetric (MU-OH)2 one. The results reported here highlight the sensitivity of Kbeta valence-to-core XES to single protonation state changes of bridging ligands, and form the basis for further studies of oxo-bridged polymetallic complexes and metalloenzyme active sites. In a complementary paper, the results from X-ray absorption spectroscopy of the same Mn(IV) dimer series are discussed. PMID- 24161083 TI - Race, life course socioeconomic position, racial discrimination, depressive symptoms and self-rated health. AB - Greater levels of socioeconomic position (SEP) are generally associated with better health. However results from previous studies vary across race/ethnicity and health outcomes. Further, the majority of previous studies do not account for the effects of life course SEP on health nor the effects of racial discrimination, which could moderate the effects of SEP on health. Using data from the Coronary Artery Risk Development in Young Adults (CARDIA) study, we examined the relationship between a life course SEP measure on depressive symptoms and self-rated health. A life course SEP was constructed for each participant, using a framework that included parental education and occupation along with respondents' highest level of education and occupation. Interaction terms were created between life course SEP and racial discrimination to determine whether the association between SEP and health was moderated by experiences of racial discrimination. Analyses revealed that higher levels of life course SEP were inversely related to depressive symptoms. Greater life course SEP was positively associated with favorable self-rated health. Racial discrimination was associated with more depressive symptoms and poorer self-rated health. Analyses indicated a significant interaction between life course SEP and racial discrimination on depressive symptoms in the full sample. This suggested that for respondents with greater levels of SEP, racial discrimination was associated with reports of more depressive symptoms. Future research efforts should be made to examine whether individuals' perceptions and experiences of racial discrimination at the interpersonal and structural levels limits their ability to acquire human capital as well as their advancement in education and occupational status. PMID- 24161084 TI - Child health security in China: a survey of child health insurance coverage in diverse areas of the country. AB - China embarked on an ambitious health system reform in 2009, and pledged to achieve universal health insurance coverage by 2020. However, there are gaps in access to healthcare for some children in China. We assessed health insurance status and associated variables among children under five in twelve communities in 2010: two urban community health centers and two rural township health centers in each of three municipalities located in China's distinctly different East, Central and Western regions. Information on demographic and socio-economic variables and children's insurance status was gathered from parents or caregivers of all children enrolled in local health programs, and others recruited from the local communities. Only 62% of 1131 children assessed were insured. This figure did not vary across geographic regions, but urban children were less likely to be insured than rural children. In multivariate analysis, infants were 2.44 times more likely to be uninsured than older children and children having at least one migrant parent were 1.90 times more likely to be uninsured than those living with non-migrant parents. Low maternal education was also associated with being uninsured. Gaps in China's child health insurance coverage might be bridged if newborns are automatically covered from birth, and if insurance is extended to all urban migrant children, regardless of the family's residential registration status and size. PMID- 24161085 TI - Aboriginal Australians' experience of social capital and its relevance to health and wellbeing in urban settings. AB - Social capital has been linked to physical and mental health. While definitions of social capital vary, all include networks of social relationships and refer to the subsequent benefits and disadvantages accrued to members. Research on social capital for Aboriginal Australians has mainly focused on discrete rural and remote Aboriginal contexts with less known about the features and health and other benefits of social capital in urban settings. This paper presents findings from in-depth interviews with 153 Aboriginal people living in urban areas on their experiences of social capital. Of particular interest was how engagement in bonding and bridging networks influenced health and wellbeing. Employing Bourdieu's relational theory of capital where resources are unequally distributed and reproduced in society we found that patterns of social capital are strongly associated with economic, social and cultural position which in turn reflects the historical experiences of dispossession and disadvantage experienced by Aboriginal Australians. Social capital was also found to both reinforce and influence Aboriginal cultural identity, and had both positive and negative impacts on health and wellbeing. PMID- 24161087 TI - Efficacy of text messaging-based interventions for health promotion: a meta analysis. AB - This meta-analysis investigated the efficacy of text messaging-based health promotion interventions. Nineteen randomized controlled trials conducted in 13 countries met inclusion criteria and were coded on a variety of participant, intervention, and methodological moderators. Meta-analytic procedures were used to compute and aggregate effect sizes. The overall weighted mean effect size representing the impact of these interventions on health outcomes was d = .329 (95% CI = .274, .385; p < .001). This effect size was statistically heterogeneous (Q18 = 55.60, p < .001, I(2) = 67.62), and several variables significantly moderated the effects of interventions. Smoking cessation and physical activity interventions were more successful than interventions targeting other health outcomes. Message tailoring and personalization were significantly associated with greater intervention efficacy. No significant differences were found between text-only interventions and interventions that included texting plus other components. Interventions that used an individualized or decreasing frequency of messages over the course of the intervention were more successful than interventions that used a fixed message frequency. We discuss implications of these results for health promotion interventions that use text messaging. PMID- 24161086 TI - The effect of marriage and HIV risks on condom use acceptability in rural Malawi. AB - A large and increasing proportion of HIV transmissions in sub-Saharan Africa occur within marriage. Condom use within marriage could, therefore, be an important prevention strategy, but there is considerable debate about whether married couples would be willing to use condoms. This paper contributes to this debate by identifying key factors that affect the acceptability of condom use within marriage and actual condom use among men and women in rural Malawi, using three waves of longitudinal data from 2004, 2006 and 2008. Specifically, we focused on the effect of (1) entry into first marriage, (2) respondent's HIV status, HIV perceptions, and risk behaviors, and (3) spouse's HIV characteristics on condom use acceptability within marriage and actual condom use with a spouse or steady partner. Using fixed-effects regression, we found that getting married coincides with a pronounced attitudinal shift regarding the acceptability of condom use within marriage that cannot be explained by differences in fertility status or selection into marriage. In addition, we found that, for women, perceived HIV status of the respondent and spouse generally had greater influence than actual HIV status on the acceptability of condom use within marriage and actual condom use with a spouse or steady partner, even after HIV status is known; while actual HIV status and HIV risk behaviors are generally more important among men. Although condom use within marriage remained low, these findings suggest that attitudes about and use of condoms are susceptible to change and that both marital status and perceptions of risk are important influences on condom use. PMID- 24161088 TI - Perceived neighborhood social cohesion and stroke. AB - Research in the last three decades has shown that negative neighborhood factors such as neighborhood violence, noise, traffic, litter, low neighborhood socioeconomic status, and poor air quality increase the risk of poor health. Fewer studies have examined the potential protective effect that neighborhood factors can have on health, particularly stroke. We examined whether higher perceived neighborhood social cohesion was associated with lower stroke incidence after adjusting for traditional risk and psychological factors that have been linked with stroke risk. Prospective data from the Health and Retirement Study--a nationally representative panel study of American adults over the age of 50--were used. Analyses were conducted on a subset of 6740 adults who were stroke-free at baseline. Analyses adjusted for chronic illnesses and relevant sociodemographic, behavioral, and psychosocial factors. Over a four-year follow-up, higher perceived neighborhood social cohesion was associated with a lower risk of stroke. Each standard deviation increase in perceived neighborhood social cohesion was associated with a multivariate-adjusted odds ratio (O.R.) of 0.85 for stroke incidence (95% CI, 0.75-0.97, p < 0.05). The effect of perceived neighborhood social cohesion remained significant after adjusting for a comprehensive set of risk factors. Therefore, perceived neighborhood social cohesion plays an important role in protecting against stroke. PMID- 24161089 TI - Exploring the health consequences of majority-minority neighborhoods: minority diversity and birthweight among native-born and foreign-born blacks. AB - We examined the association between neighborhood minority diversity and infant birthweight among non-Hispanic US-born black women and foreign-born black women from Sub-Saharan Africa and the non-Spanish speaking Caribbean using 2002-2006 vital statistics birth record data from the state of New Jersey (n = 73,907). We used a standardized entropy score to measure the degree of minority diversity (i.e., non-white multiethnic racial heterogeneity) for each census tract where women lived. We distinguished between four levels of minority diversity, with the highest level representing majority-minority neighborhoods. We estimated mean birthweight for singleton births over this 5-year period using linear regression with robust standard errors to correct for clustering of mothers within census tracts. We found significant differences in mean birthweight by mother's country of origin such that infants of US-born black mothers weighed significantly less than the infants of African and Caribbean immigrants (3130 g vs. 3299 g and 3212 g; p < 0.001). Adjustments for neighborhood deprivation, residential instability, individual-level sociodemographics, maternal health behaviors and conditions, and gestational age did not reduce these origin differences. Minority diversity had a protective effect on black infant health. Women living in low and moderately diverse tracts as well as those in majority-minority neighborhoods had heavier babies (beta = 26.5, 29.8 and 61.2, respectively, p < 0.001) on average than women in the least diverse tracts. The results for majority-minority neighborhoods were robust when we controlled for neighborhood- and individual level covariates. PMID- 24161090 TI - The socioeconomic health gradient across the life cycle: what role for selective mortality and institutionalization? AB - Several studies have documented the now fairly stylized fact that health inequalities by income differ across the age distribution: in cross-sections the health gap between rich and poor tends to widen until about age 50 and then declines at higher ages. It has been suggested that selective mortality and institutionalization could be important factors driving the convergence at higher ages. We use eight waves of a health survey linked to four registries (on mortality, hospitalizations, (municipal) residence status and taxable incomes) to test this hypothesis. We construct life cycle profiles of health for birth year/gender/income groups from the health surveys (based on 128,689 observations) and exploit the registries to obtain precise estimates of individual probabilities of mortality and institutionalization using a seven year observation period for 2,521,122 individuals. We generate selection corrected health profiles using an inverse probability weighting procedure and find that attrition is indeed not random: older, poorer and unhealthier individuals are significantly more likely not to survive the next year and to be admitted to an institution. While these selection effects are very significant, they are not very large. We therefore reject the hypothesis that selective dropout is an important determinant of the differential health trajectories by income over the life course in the Netherlands. PMID- 24161091 TI - Shame as a barrier to health seeking among indigenous Huichol migrant labourers: an interpretive approach of the "violence continuum" and "authoritative knowledge". AB - This article discusses the manner in which social and historical factors impact upon indigenous conceptions of health and health-seeking behaviour, reinforcing their authoritative knowledge about birth and wellbeing. It explores how Mexican indigenous Huichol migrant labourers experience structural, everyday and symbolic violence while away working, and in their home communities. The study was based on semi-structured interviews and observations with 33 Huichol migrant labourers and 12 key informants from the community (traditional healthcare providers), health sector (medical doctors based in the highlands) and tobacco industry (farmers, tobacco union leader and pesticide sellers) during 2010-11. Findings show how the continuum of violence is experienced by these migrants as shame, timidity and humiliation, expressions of symbolic violence that have helped define their tradition of birthing alone and their feeling of entitlement to the conditional welfare payments which sustain their marginalised subsistence lifestyle. This paper proposes that there is a cyclical relationship between structural violence and authoritative knowledge as the former reinforces their adherence to a set of cultural beliefs and practices which are the basis of racial discrimination against them. PMID- 24161092 TI - The acceptability and feasibility of task-sharing for mental healthcare in low and middle income countries: a systematic review. AB - Task-sharing has frequently been proposed as a strategy to overcome human resource shortages in order to scale up mental health care. Although evidence suggests this approach is effective, to date no review has been conducted to assess its acceptability and feasibility among service users and health care practitioners. This review summarises current findings and provides evidence based recommendations to improve the success and sustainability of task-sharing approaches. All study designs were included and both qualitative and quantitative data were extracted and reviewed using a comparative thematic analysis. In total, 21 studies were included, nine of which were of strong or adequate quality and twelve of unknown quality. The review highlighted that task-sharing is not an outright solution for overcoming human resource shortages in low and middle income countries. A number of factors need to be considered in order for task sharing to be acceptable and feasible, for example the incidence of distress experienced by the task-sharing workforce, their self-perceived level of competence, the acceptance of the workforce by other health care professionals and the incentives provided to ensure workforce retention. As the main barrier to addressing these is a lack of resources, an increased investment in mental health care is essential in order to ensure that task-sharing interventions are successful and sustainable. PMID- 24161093 TI - Planning safer suburbs: do changes in the built environment influence residents' perceptions of crime risk? AB - A growing body of evidence has reiterated the negative impacts that crime and perceptions of insecurity can have on the health and wellbeing of local residents. Strategies that reduce residents' perceived crime risk may contribute to improved health outcomes; however interventions require a better understanding of the neighbourhood influences on residents perceptions of crime and safety. We examined the impact of changes in the objective built environment following relocation on changes in residents' perceived crime risk for participants in a longitudinal study of people moving to new neighbourhoods in Perth, Western Australia (n = 1159). They completed a questionnaire before moving to their new neighbourhood, and again 36 months after relocation. Individual-level objective environmental measures were generated at both time points using Geographic Information Systems, focussing on the characteristics that comprise a 'walkable neighbourhood'. Linear regression models examined the influence of objective environmental changes between the two environments on perceived crime risk, with progressive adjustment for other change variables (i.e., perceptions of the physical and social environment, reported crime). We found that increases in the proportion of land allocated to shopping/retail land-uses increased residents' perceived crime risk (beta = 11.875, p = 0.001), and this relationship remained constant, despite controlling for other influences on perceived crime risk (beta = 9.140, p = 0.004). The findings highlight an important paradox: that the neighbourhood characteristics known to enhance one outcome, such as walking, may negatively impact another. In this instance, the 'strangers' that retail destinations attract to a neighbourhood may be interpreted by locals as a threat to safety. Thus, in areas with more retail destinations, it is vital that other environmental strategies be employed to balance any negative effects that retail may have on residents' perceptions of crime risk (e.g., minimising incivilities, improved lighting and aesthetics). PMID- 24161094 TI - Neighbourhood socioeconomic status and individual lung cancer risk: evaluating long-term exposure measures and mediating mechanisms. AB - Neighbourhood socioeconomic status (SES) has been associated with numerous chronic diseases, yet little information exists on its association with lung cancer incidence. This outcome presents two key empirical challenges: a long latency period that requires study participants' residential histories and long term neighbourhood characteristics; and adequate data on many risk factors to test hypothesized mediating pathways between neighbourhood SES and lung cancer incidence. Analysing data on urban participants of a large Canadian population based lung cancer case-control study, we investigate three issues pertaining to these challenges. First, we examine whether there is an association between long term neighbourhood SES, derived from 20 years of residential histories and five national censuses, and lung cancer incidence. Second, we determine how this long term neighbourhood SES association changes when using neighbourhood SES measures based on different latency periods or at time of study entry. Third, we estimate the extent to which long-term neighbourhood SES is mediated by a range of individual-level smoking behaviours, other health behaviours, and environmental and occupational exposures. Results of hierarchical logistic regression models indicate significantly higher odds of lung cancer cases residing in the most compared to the least deprived quintile of the long-term neighbourhood SES index (OR: 1.46; 95% CI: 1.13-1.89) after adjustment for individual SES. This association remained significant (OR: 1.38; 1.01-1.88) after adjusting for smoking behaviour and other known and suspected lung cancer risk factors. Important differences were observed between long-term and study entry neighbourhood SES measures, with the latter attenuating effect estimates by over 50 percent. Smoking behaviour was the strongest partial mediating pathway of the long-term neighbourhood SES effect. This research is the first to examine the effects of long-term neighbourhood SES on lung cancer risk and more research is needed to further identify specific, modifiable pathways by which neighbourhood context may influence lung cancer risk. PMID- 24161095 TI - Spaces for smoking in a psychiatric hospital: social capital, resistance to control, and significance for 'therapeutic landscapes'. AB - This paper reports on research framed by theories of therapeutic landscapes and the ways that the social, physical and symbolic dimensions of landscapes relate to wellbeing and healing. We focus especially on the question of how attributes of therapeutic landscapes are constructed in different ways according to the variable perspectives of individuals and groups. Through an ethnographic case study in a psychiatric hospital in the North of England we explore the perceived significance for wellbeing of 'smoking spaces' (where tobacco smoking is practiced in ways that may, or may not be officially sanctioned). We interpret our findings in light of literature on how smoking spaces are linked to the socio geographical power relations that determine how smoking is organised within the hospital and how this is understood by different groups using the hospital building. We draw on qualitative research findings from discussion groups, observations, and interviews with patients, carers and staff. These focused on their views about the building design and setting of the new psychiatric hospital in relation to their wellbeing, and issues relating to smoking spaces emerged as important for many participants. Creating and managing smoking spaces as a public health measure in psychiatric hospitals is shown to be a controversial issue involving conflicting aims for health and wellbeing of patients and staff. Our findings indicate that although from a physical health perspective, smoking is detrimental, the spaces in which patients and staff smoke have social and psychological significance, providing a forum for the creation of social capital and resistance to institutional control. While the findings relate to one case study setting, the paper illustrates issues of wider relevance and contributes to an international literature concerning the tensions between perceived psychological and psychosocial benefits of smoking vs. physical harm that smoking is likely to cause. We consider the implications for hospital design and the model of care. PMID- 24161096 TI - What constitutes a health-enabling neighborhood? A grounded theory situational analysis addressing the significance of social capital and gender. AB - Variations in health between neighborhoods are well known and the conceptualization of social capital has contributed to an understanding of how contextual factors influence these differences. Studies show positive health effects from living in high social capital areas, at least for some population sub-groups. The aim of this qualitative study was to understand what constitutes a 'health-enabling' neighborhood. It follows up results from a social capital survey in northern Sweden indicating that the health effects of living in a high social capital neighborhood is gendered in favor of women. A grounded theory situational analysis of eight focus group discussions--four with men and four with women--illustrated similar and different positions on how neighborhood characteristics influence health. A neighborhood, where people say hi to each other ("hi-factor") and where support between neighbors exist, were factors perceived as positive for health by all, as was a good location, neighborhood greenness and proximity to essential arenas. Women perceived freedom from demands, feeling safe and city life as additional health enabling factors. For men freedom to do what you want, a sense of belonging, and countryside life were important. To have burdensome neighbors, physical disturbances and a densely living environment were perceived as negative for health in both groups while demands for a well styled home and feeling unsafe were perceived as negative for health among women. Neighborhood social capital, together with other elements in the living environment, has fundamental influence on people's perceived health. Our findings do not confirm that social capital is more important for women than for men but that distinctive form of social capital differ in impact. Investing in physical interventions, such as planning for meeting places, constructing attractive green areas, and making neighborhoods walking-friendly, may increase human interactions that is instrumental for social capital and is likely to have health promoting effects for all. PMID- 24161097 TI - Child marriage prevention in Amhara Region, Ethiopia: association of communication exposure and social influence with parents/guardians' knowledge and attitudes. AB - Despite increasing international attention to child marriage and its negative health and social consequences, little is known about the knowledge and beliefs of individuals who are in control of negotiating children's marriages and of the social context in which these individuals function. Using data from a 2007 cross sectional household survey and multilevel logistic regression models, this paper examined the associations of communication exposure and measures of social influence with knowledge of marriage legislation, perceptions that marriage before age 18 was "too early", and beliefs in daughters' rights to individual marriage choice among parents/guardians in Amhara Region, Ethiopia. The study found that mass media and interpersonal communication exposure were positively associated with all outcomes. The influence of communication exposure on knowledge of the legal minimum age at marriage and the perception that marriage before 18 was "too early" varied significantly across communities. Community pressure to stop child marriages and awareness of marriage law enforcement were positively associated with endorsing daughters' rights to choose their marriage age and partner. Perceived social norms regarding early marriage, normative beliefs and perceived benefits of delayed marriage were at least as important as communication exposure for endorsing daughters' rights to marriage choice. Gender and education differences were detected. The findings imply that child marriage prevention programs should diversify information channels, reinforce perceived advantages of delayed marriage, and adopt a social influence perspective. PMID- 24161098 TI - Variation in the interpretation of scientific integrity in community-based participatory health research. AB - Community-based participatory research (CBPR) has become essential in health disparities and environmental justice research; however, the scientific integrity of CBPR projects has become a concern. Some concerns, such as appropriate research training, lack of access to resources and finances, have been discussed as possibly limiting the scientific integrity of a project. Prior to understanding what threatens scientific integrity in CBPR, it is vital to understand what scientific integrity means for the professional and community investigators who are involved in CBPR. This analysis explores the interpretation of scientific integrity in CBPR among 74 professional and community research team members from of 25 CBPR projects in nine states in the southeastern United States in 2012. It describes the basic definition for scientific integrity and then explores variations in the interpretation of scientific integrity in CBPR. Variations in the interpretations were associated with team member identity as professional or community investigators. Professional investigators understood scientific integrity in CBPR as either conceptually or logistically flexible, as challenging to balance with community needs, or no different than traditional scientific integrity. Community investigators interpret other factors as important in scientific integrity, such as trust, accountability, and overall benefit to the community. This research demonstrates that the variations in the interpretation of scientific integrity in CBPR call for a new definition of scientific integrity in CBPR that takes into account the understanding and needs of all investigators. PMID- 24161099 TI - Exploring substance use normalization among adolescents: a multilevel study in 35 countries. AB - The substance use normalization thesis predicts that adolescent substance users are less likely to report substance use risk factors in high than in low prevalence countries. This study tests whether national population-level alcohol, cigarette and cannabis prevalence rates moderate the strength of the relationship between individual level social and behavioral risk factors and individual level alcohol, cigarette and cannabis use. Data from 2009/2010 Health Behaviour in School-Aged Children Study (N = 68,045, age = 15) from 35 countries was analyzed using logistic Hierarchical Linear Modeling. As expected based on low cannabis prevalence rates in all countries studied, no evidence of normalization was found for recent cannabis use. Also in line with the normalization thesis, results show that for substance use that reaches above 40% in at least some of the countries studied (drunkenness, alcohol and cigarette use), adolescents who reported use are less likely to report social and behavioral risk factors in high prevalence countries than in low prevalence countries. However, support for the normalization thesis was only partial in that results show that in models where evidence for normalization was found, there are risk factors that predict substance use to an equal degree regardless of country level prevalence rates. The current research shows that the normalization thesis is a useful framework for understanding the contextual aspects of adolescent alcohol, tobacco, and cannabis use. The study has implications for drug prevention as it suggests that selective prevention efforts may be particularly useful in low prevalence countries where screening based on risk factors may usefully identify adolescents at most risk for developing drug use problems. This approach may be less useful in high prevalence countries where screening based on risk factors is less likely to satisfactorily identify those at risk for developing drug use problems. PMID- 24161100 TI - Mothers' reading skills and child survival in Nigeria: examining the relevance of mothers' decision-making power. AB - Mothers' literacy skills are emerging as a key determinant of children's health and survival in low-income contexts, with emphasis on the cognitive and psychological agency that literacy skills provide. This work has clearly established a strong association between mothers' reading skills--a key subcomponent of broader literacy and language skills--and child mortality. However, this relatively nascent literature has not yet considered how broader social structures condition the process. In Nigeria and in sub-Saharan Africa more broadly, gender-based social inequality constrains many mothers' decision making power over children's health matters; this structural feature may condition the association between mothers' reading skills and child mortality. This paper uses data from the 2003 Nigerian Demographic and Health Survey (N = 12,076) to test the conditionality of the relationship between mothers' reading skills and child survival on mothers' decision-making power, highlighting how structural realities should factor more heavily into this individual-action oriented literature. Among Nigerian children whose mothers have decision-making power, mothers' reading skills convey a 27 percent lower risk of child mortality; however, for children whose mothers lack decision-making power, mothers' reading skills do not yield a significant survival advantage. Overall, these findings support the need for future work to further analyze how broader social structures condition the benefits of mothers' reading skills for children's health. PMID- 24161102 TI - Individual and hospital-specific factors influencing medical graduates' time to medical specialization. AB - Previous studies of gender differences in relation to medical specialization have focused more on social variables than hospital-specific factors. In a multivariate analysis with extended Cox regression, we used register data for socio-demographic variables (gender, family and having a child born during the study period) together with hospital-specific variables (the amount of supervision available, efficiency pressure and the type of teaching hospital) to study the concurrent effect of these variables on specialty qualification among all 2474 Norwegian residents who began specialization in 1999-2001. We followed the residents until 2010. A lower proportion of women qualified for a specialty in the study period (67.9% compared with 78.7% of men, p < 0.001), and they took on average six months longer than men did to complete the specialization qualification (p < 0.01). Fewer women than men entered specialties providing emergency services and those with longer working hours, and women worked shorter hours than men in all specialties. Hospital factors were significant predictors for the timely attainment of specialization: working at university hospitals (regional) or central hospitals was associated with a reduction in the time taken to complete the specialization, whereas an increased patient load and less supervision had the opposite effect. Multivariate analysis showed that the smaller proportion of women who qualified for a specialty was explained principally by childbirth and by the number of children aged under 18 years. PMID- 24161101 TI - The influence of parental monitoring and parent-adolescent communication on Bahamian adolescent risk involvement: a three-year longitudinal examination. AB - The literature suggests that parental monitoring can best be conceptualized and measured through the domains of parental knowledge, youth disclosure, parental solicitation, and parental control. Using longitudinal data on 913 grade-six Bahamian students followed over a period of three years, we examined the unique and independent roles of these domains of parental monitoring and parent adolescent communication in relation to adolescent involvement in delinquency, substance use, and sexual risk behaviors. The results obtained with mixed-effects models indicate that parental knowledge, youth disclosure, and parental control are negatively associated with both delinquency and substance use. Open parent adolescent communication was associated with decreased sexual risk behavior, whereas problematic parent-adolescent communication was associated with increased sexual risk behavior. The results obtained with path models indicate that youth disclosure is a significant longitudinal predictor of reduced adolescent delinquency and that parental control during early adolescence predicted reduced substance use in middle adolescence. The findings suggest that parental knowledge, youth disclosure and parental control differ in their impacts on substance use, delinquency and sexual risk behaviors. Problematic parent adolescent communication is consistently associated with increases in all three types of adolescent risk behaviors. Future parental monitoring interventions should focus on enhancing parents' interpersonal communication skills and emphasize the differences in and importance of the unique components of parental monitoring. PMID- 24161103 TI - Negotiating last-minute concerns in closing Korean medical encounters: the use of gaze, body and talk. AB - Although patients may raise new concerns during any time of the medical visit, the closing phase of the consultation is a critical locus for the negotiation of the topicalization of additional concerns. Using conversation analysis as the primary method of analysis, this study provides an analysis of the structure of consultation "closings" in Korean primary-care encounters and the way in which the organization of closings in this context discourages patients' presentation of additional concerns. Data are drawn from 60 videotaped primary-care encounters collected from Korea, between 2007 and 2008. The rare occasions in which last minute concerns are raised are closely analyzed to reveal that the organization of gaze and body orientation play an important role in foreclosing the presentation of additional concerns. The results contribute to our understanding of closings in the primary-care interview by investigating a non-western setting that includes an investigation of an understudied subject--that of embodied resources--and shows how these closings serve the doctor's purpose of bringing closure in the face of last-minute concerns broached by the patient. The cultural meaning of gaze in the Korean medical care context is also discussed. The findings have implications for research on nonverbal communication, cultural differences, and interactions in medical care. PMID- 24161104 TI - Healthcare provider views on the health effects of biomass fuel collection and use in rural Eastern Cape, South Africa: an ethnographic study. AB - Policymakers at global level recognise that household biomass use in developing countries has significant health consequences. However, it is unclear how local level health professionals perceive and respond to such health effects. This paper which is derived from the findings of a larger study on perceptions and responses to the harmful health effects of carrying heavy firewood loads and to smoke from cooking fires is based on a study conducted in South Africa among managers of health programmes and community nurses of Qaukeni and Mhlontlo municipalities in rural Eastern Cape. Interviews and participant observations were conducted in 2009 using ethnographic grounded theory approaches. In addition to a 10-month period of ethnographic fieldwork, ten programme managers and nurses in two villages were interviewed about health patterns in the villages that they serve, their perceptions of, and responses to the health effects of carrying heavy firewood loads, and inhalation of smoke from wood and dung cooking fires, their professional qualifications and experience, their own household energy use; and observations made as they served clinic clients. Results show that these programme managers and nurses perceive the health effects of carrying heavy loads of firewood and of cooking smoke as minor. Sometimes, nurses give women symptomatic relief for musculoskeletal pain resulting from carrying heavy loads. We posit that their perceptions are derived from customary neglect of work related health and non-communicable diseases, cultural interpretations of womanhood, limited access to relevant information, and limited interactions between health and energy sector professionals. We conclude that culturally and gender-sensitive awareness programmes are needed for local-level health professionals to effectively address health effects of biomass collection and use. This paper provides new insights into overlooked differences between globally-driven initiatives to address health effects of biomass use and local perceptions. PMID- 24161105 TI - Palladium-catalyzed oxidative coupling of aromatic primary amines and alkenes under molecular oxygen: stereoselective assembly of (Z)-enamines. AB - An efficient Pd-catalyzed oxidative coupling of aromatic primary amines and alkenes under molecular oxygen is disclosed. Under mild reaction conditions, it provides a rapid access to (Z)-enamine compounds with exceptional functional group tolerance and excellent regio- and stereoselectivity. This attractive route is of great significance due to its applicability to a wide range of aromatic primary amines, most of which could not be efficiently converted into enamines previously. Moreover, this protocol is scalable, and the resultant enamines could be conveniently transformed into a series of N-containing heterocyclics, thus illustrating its potential applications in synthetic and medicinal chemistry. PMID- 24161106 TI - Environment-responsive fluorescent nucleoside analogue probe for studying oligonucleotide dynamics in a model cell-like compartment. AB - The majority of fluorescent nucleoside analogue probes that have been used in the in vitro study of nucleic acids are not suitable for cell-based biophysical assays because they exhibit excitation maxima in the UV region and low quantum yields within oligonucleotides. Therefore, we propose that the photophysical characterization of oligonucleotides labeled with a fluorescent nucleoside analogue in reverse micelles (RM), which are good biological membrane models and UV-transparent, could provide an alternative approach to studying the properties of nucleic acids in a cell-like confined environment. In this context, we describe the photophysical properties of an environment-sensitive fluorescent uridine analogue (1), based on the 5-(benzo[b]thiophen-2-yl)pyrimidine core, in micelles and RM. The emissive nucleoside, which is polarity- and viscosity sensitive, reports the environment of the surfactant assemblies via changes in its fluorescence properties. The nucleoside analogue, incorporated into an RNA oligonucleotide and hybridized to its complementary DNA and RNA oligonucleotides, exhibits a significantly higher fluorescence intensity, lifetime, and anisotropy in RM than in aqueous buffer, which is consistent with the environment of RM. Collectively, our results demonstrate that nucleoside 1 could be utilized as a fluorescent label to study the function of nucleic acids in a model cellular milieu. PMID- 24161107 TI - Induction of robust immunity response in mice by dual-expression-system-based recombinant baculovirus expressing the capsid protein of porcine circovirus type 2. AB - BACKGROUND: Porcine circovirus type 2 (PCV2) is associated with post-weaning multisystemic wasting syndrome (PMWS), an emerging swine disease that causes progressive weight loss, dyspnea, tachypnea, anemia, jaundice, and diarrhea in piglets. Although baculovirus is an enveloped virus that infects insects in nature, it has emerged as a vaccine vector, and we used it to develop a novel candidate vaccine for a preventive or therapeutic strategy to control PCV2 infections. METHODS: Immunoblotting analysis of recombinant baculovirus and immunofluorescent staining of baculovirus-infected cells were followed using anti ORF2 monoclonal antibodies. The BALB/c mice were immunized intramuscularly with this baculovirus. The titers of antibodies were mensurated with a Cap-protein specific enzyme-linked immunosorbent assay (ELISA) and a serum neutralization assay. The IFN-gamma response in splenocytes harvested from immunized mice was measured by ELISA. Student's t-test was used to compare immune responses of different groups. RESULTS: In this study, we successfully constructed a dual expression-system-based recombinant baculovirus BV-GD-ORF2, which can display the PCV2 capsid (Cap) protein and VSV-G protein on the viral envelope and also expressing Cap protein on transduced mammalian cells, thereby functioning as both a subunit and a DNA vaccine. After infection, the Cap protein was expressed and displayed on the viral surface, as demonstrated with an indirect fluorescence assay and immunoblotting. The vaccination of mice with recombinant baculovirus BV GD-ORF2 successfully induced robust Cap-protein-specific humoral and cellular immune responses. CONCLUSIONS: Our findings collectively demonstrate that the recombinant baculovirus BV-GD-ORF2 is a potential vaccine against PCV2 infections. PMID- 24161109 TI - Molecular co-evolution of a protease and its substrate elucidated by analysis of the activity of predicted ancestral hatching enzyme. AB - BACKGROUND: Hatching enzyme is a protease that digests the egg envelope, enabling hatching of the embryo. We have comprehensively studied the molecular mechanisms of the enzyme action to its substrate egg envelope, and determined the gene/protein structure and phylogenetic relationships. Because the hatching enzyme must have evolved while maintaining its ability to digest the egg envelope, the hatching enzyme-egg envelope protein pair is a good model for studying molecular co-evolution of a protease and its substrate. RESULTS: Hatching enzymes from medaka (Oryzias latipes) and killifish (Fundulus heteroclitus) showed species-specific egg envelope digestion. We found that by introducing four medaka-type residue amino acid substitutions into recombinant killifish hatching enzyme, the mutant killifish hatching enzyme could digest medaka egg envelope. Further, we studied the participation of the cleavage site of the substrate in the species-specificity of hatching enzyme. A P2-site single amino acid substitution was responsible for the species-specificity. Estimation of the activity of the predicted ancestral enzymes towards various types of cleavage sites along with prediction of the evolutionary timing of substitutions allowed prediction of a possible evolutionary pathway, as follows: ancestral hatching enzyme, which had relatively strict substrate specificity, developed broader specificity as a result of four amino acid substitutions in the active site cleft of the enzyme. Subsequently, a single substitution occurred within the cleavage site of the substrate, and the recent feature of species-specificity was established in the hatching enzyme-egg envelope system. CONCLUSIONS: The present study clearly provides an ideal model for protease-substrate co-evolution. The evolutionary process giving rise to species-specific egg envelope digestion of hatching enzyme was initiated by amino acid substitutions in the enzyme, resulting in altered substrate specificity, which later allowed an amino acid substitution in the substrate. PMID- 24161110 TI - Man with epistaxis and dysphagia. Benign nasal polyp. PMID- 24161111 TI - Commentary. PMID- 24161108 TI - Dual gene expression cassette vectors with antibiotic selection markers for engineering in Saccharomyces cerevisiae. AB - BACKGROUND: Manipulations in Saccharomyces cerevisiae classically depend on use of auxotrophy selection markers. There are several disadvantages to this in a microbial cell factory setting: (1) auxotrophies must first be engineered in prototrophic strains, and many industrial strains are polyploid/aneuploid prototrophs (2) available strain auxotrophies must be paired with available repair plasmids (3) remaining auxotrophies must be repaired prior to development of industrial bioprocesses. Use of dominant antibiotic resistance markers can circumvent these problems. However, there are relatively few yeast antibiotic resistance marker vectors available; furthermore, available vectors contain only one expression cassette, and it is often desirable to introduce more than one gene at a time. RESULTS: To overcome these problems, eight new shuttle vectors have been developed. The plasmids are maintained in yeast under a 2 MUm ori and in E. coli by a pUC ori. They contain two yeast expression cassettes driven by either (1) the constitutive TEF1 and PGK1 promoters, or (2) the constitutive TEF1 promoter and the inducible GAL10 or HXT7 promoters. Expression strength of these promoters over a typical production time frame in glucose/galactose medium was examined, and identified the TEF1 and HXT7 promoters as preferred promoters over long term fermentations. Selection is provided by either aphA1 (conferring resistance to G418 in yeast and kanamycin/neomycin in E. coli) or ble (conferring resistance to phleomycin in both yeast and E. coli). Selection conditions for these plasmids/antibiotics in defined media were examined, and selection considerations are reviewed. In particular, medium pH has a strong effect on both G418 and phleomycin selection. CONCLUSIONS: These vectors allow manipulations in prototrophic yeast strains with expression of two gene cassettes per plasmid, and will be particularly useful for metabolic engineering applications. The vector set expands the (currently limited) selection of antibiotic marker plasmids available for use in yeast, and in addition makes available dual gene expression cassettes on individual plasmids using antibiotic selection. The resistance gene cassettes are flanked by loxP recognition sites to allow CreA-mediated marker removal and recycling, providing the potential for genomic integration of multiple genes. Guidelines for selection using G418 and phleomycin are provided. PMID- 24161112 TI - Finish line becomes front line at Boston Marathon. PMID- 24161113 TI - Measuring and explaining computed tomography use in the United States and Canada: a consideration of health economics, use versus appropriateness, and interpreting potential conflict of interest: November 2013 Annals of Emergency Medicine Journal Club. PMID- 24161114 TI - Man with dizziness and vomiting. Horner's syndrome. PMID- 24161115 TI - Details in operational definitions of length of visit and boarding variables in the National Hospital Ambulatory Medical Care Survey. PMID- 24161116 TI - In reply. PMID- 24161117 TI - NHAMCS: does it hold up to scrutiny? PMID- 24161118 TI - In reply. PMID- 24161119 TI - What are the true costs of emergency department services? PMID- 24161120 TI - Owning the cost of emergency medicine: beyond 2%. PMID- 24161121 TI - Effect of IL-12B, IL-2, TGF-beta1, and IL-4 polymorphism and expression on hepatitis B progression. AB - The hepatitis B virus (HBV) infection-induced chronic inflammation is considered to be the major etiological factor for HBV-related disease chronicity. Cytokines act as the key coordinators of the inflammatory responses involved in HBV disease pathogenesis. The present study assessed association among IL-12B(+1188), IL-2( 330), TGF-beta1(-509), and IL-4(-590) genotypes; mRNA; and protein levels with HBV-hepatocellular carcinoma (HCC) risk in India. For this, 403 subjects (153 controls, 67 inactive HBV-carriers, 62 chronic-active HBV patients, 62 HBV cirrhotics, and 59 HBV-HCC ssubjects) were enrolled in the study. The genotyping was carried by polymerase chain reaction (PCR)-restriction fragment length polymorphism (IL-12+1188A/C, IL-2-330T/G, and TGF-beta1-509C/T), and allele specific (AS)-polymerase chain reaction (IL-4-590C/T). Enzyme-linked immunosorbent assay and reverse transcriptase-polymerase chain reaction methods were used for assessing protein and the mRNA expression, respectively, of the mentioned cytokines. The study revealed that the IL-12B(+1188) CC genotype shared a significant positive association with hepatitis, among controls. While, in the case of IL-2(-330), both the TG and GG genotypes were not significantly associated with HCC risk. The TGF-beta1(-509) TT genotype acted as a potential protective factor for cirrhosis and the HCC risk, among carriers. On the contrary, the IL-4(-590) CT genotype was found to be a vital protective factor for the development of hepatitis, among carriers. Besides, IL-12B, TGF-beta1, and IL-2 seem to be majorly involved in the development of HCC, while, IL-4 might be responsible for the progression of the HBV disease till cirrhosis development. These initial findings are indicative of the vital role of genotypes and/or levels of IL-12B, IL-2, IL-4, and TGF-beta1 in HBV disease chronicity in Indian population. PMID- 24161123 TI - Prostate transglutaminase (TGase-4, TGaseP) enhances the adhesion of prostate cancer cells to extracellular matrix, the potential role of TGase-core domain. AB - BACKGROUND: Transglutaminase-4 (TGase-4), also known as the Prostate Transglutaminase, is an enzyme found to be expressed predominately in the prostate gland. The protein has been recently reported to influence the migration and invasiveness of prostate cancer cells. The present study aimed to investigate the influence of TGase-4 on cell-matrix adhesion and search for the candidate active domain[s] within the protein. METHODS: Human prostate cancer cell lines and prostate tissues were used. Plasmids that encoded different domains and full length of TGase-4 were constructed and used to generate sublines that expressed different domains. The impact of TGase-4 on in vitro cell-matrix adhesion, cell migration, growth and in vivo growth were investigated. Interactions between TGase-4 and focal adhesion complex proteins were investigated using immunoprecipitation, immunofluorescence and phosphospecific antibodies. RESULTS: TGase-4 markedly increased cell-matrix adhesion and cellular migration, and resulted in a rapid growth of prostate tumours in vivo. This effect resided in the Core-domain of the TGase-4 protein. TGase-4 was found to co-precipitate and co-localise with focal adhesion kinase (FAK) and paxillin, in cells, human prostate tissues and tumour xenografts. FAK small inhibitor was able to block the action mediated by TGase-4 and TGase-4 core domain. CONCLUSION: TGase-4 is an important regulator of cell-matrix adhesion of prostate cancer cells. This effect is predominately mediated by its core domain and requires the participation of focal adhesion complex proteins. PMID- 24161124 TI - Sustainable flow Oppenauer oxidation of secondary benzylic alcohols with a heterogeneous zirconia catalyst. AB - A flow chemistry process for the Oppenauer oxidation of benzylic secondary alcohols using partially hydrated zirconium oxide and a simple carbonyl containing oxidant such as acetone, cyclohexanone, and neopentanal is reported. The heterogeneous oxidative system could be applied to a wide range of functionalized alcohol substrates, allowing clean and fast delivery of ketone products within a few minutes between 40 and 100 degrees C. PMID- 24161127 TI - Redox regulation of transient receptor potential channels. AB - SIGNIFICANCE: Environmental and endogenous reactive species such as reactive oxygen species (ROS), reactive nitrogen species (RNS), and other electrophiles are not only known to exert toxic effects on organisms, but are also emerging as molecules that mediate cell signaling responses. However, the mechanisms underlying this cellular redox signaling by reactive species remains largely uncharacterized. RECENT ADVANCES: Ca2+-permeable cation channels encoded by the transient receptor potential (trp) gene superfamily are characterized by a wide variety of activation triggers that act from outside and inside the cell. Recent studies have revealed that multiple TRP channels sense reactive species and induce diverse physiological and pathological responses, such as cell death, chemokine production, and pain transduction. TRP channels sense reactive species either indirectly through second messengers or directly via oxidative modification of cysteine residues. In this review, we describe the activation mechanisms and biological roles of redox-sensitive TRP channels, including TRPM2, TRPM7, TRPC5, TRPV1, and TRPA1. CRITICAL ISSUES: The sensitivity of TRP channels to reactive species in vitro has been well characterized using molecular and pharmacological approaches. However, the precise activation mechanism(s) and in vivo function(s) of ROS/RNS-sensitive TRP channels remain elusive. FUTURE DIRECTIONS: Redox sensitivity of TRP channels has been shown to mediate previously unexplained biological phenomena and is involved in various pathologies. Understanding the physiological significance and activation mechanisms of TRP channel regulation by reactive species may lead to TRP channels becoming viable pharmacological targets, and modulators of these channels may offer therapeutic options for previously untreatable diseases. PMID- 24161128 TI - Solubilizing the most easily ionized molecules and generating powerful reducing agents. AB - Two very soluble compounds having W2(bicyclic guanidinate)4 paddlewheel structures show record low ionization energies (onsets at 3.4 to 3.5 eV) and very negative oxidation potentials in THF (-1.84 to -1.90 V vs Ag/AgCl). DFT computations show the correlation from the gas-phase ionization energies to the solution redox potentials and chemical behavior. These compounds are thermally stable and easy to synthesize in high yields and good purity. They are very reactive and potentially useful stoichiometric reducing agents in nonpolar, nonprotonated solvents. PMID- 24161126 TI - Roles of DUOX-mediated hydrogen peroxide in metabolism, host defense, and signaling. AB - SIGNIFICANCE: Among the NADPH oxidases, the dual oxidases, DUOX1 and DUOX2, constitute a distinct subfamily initially called thyroid oxidases, based on their high level of expression in thyroid tissue. Genetic alterations causing inherited hypothyroidism clearly demonstrate their physiological implication in thyroid hormonogenesis. However, a growing list of biological functions triggered by DUOX dependent reactive oxygen species (ROS) in highly differentiated mucosae have recently emerged. RECENT ADVANCES: A role of DUOX enzymes as ROS providers for lactoperoxidase-mediated killing of invading pathogens has been well established and a role in bacteria chemorepulsion has been proposed. Control of DUOX expression and activity by inflammatory molecules and immune receptor activation consolidates their contributions to innate immune defense of mucosal surfaces. Recent studies conducted in ancestral organisms have identified effectors of DUOX redox signaling involved in wound healing including epithelium regeneration and leukocyte recruitment. Moreover, local generation of hydrogen peroxide (H2O2) by DUOX has also been suggested to constitute a positive feedback loop to promote receptor signaling activation. CRITICAL ISSUES: A correct balance between H2O2 generation and detoxification mechanisms must be properly maintained to avoid oxidative damages. Overexpression of DUOX genes has been associated with an increasing number of chronic inflammatory diseases. Furthermore, H2O2-mediated DNA damage supports a mutagenic function promoting tumor development. FUTURE DIRECTIONS: Despite the high sequence similarity shared between DUOX1 and DUOX2, the two isoforms present distinct regulations, tissue expression and catalytic functions. The phenotypic characterization of novel DUOX/DUOXA invalidated animal models will be very useful for defining their medical importance in pathological conditions. PMID- 24161125 TI - Redox regulation of neuronal voltage-gated calcium channels. AB - SIGNIFICANCE: Voltage-gated calcium channels are ubiquitously expressed in neurons and are key regulators of cellular excitability and synaptic transmitter release. There is accumulating evidence that multiple subtypes of voltage-gated calcium channels may be regulated by oxidation and reduction. However, the redox mechanisms involved in the regulation of channel function are not well understood. RECENT ADVANCES: Several studies have established that both T-type and high-voltage-activated subtypes of voltage-gated calcium channel can be redox regulated. This article reviews different mechanisms that can be involved in redox regulation of calcium channel function and their implication in neuronal function, particularly in pain pathways and thalamic oscillation. CRITICAL ISSUES: A current critical issue in the field is to decipher precise mechanisms of calcium channel modulation via redox reactions. In this review we discuss covalent post-translational modification via oxidation of cysteine molecules and chelation of trace metals, and reactions involving nitric oxide-related molecules and free radicals. Improved understanding of the roles of redox-based reactions in regulation of voltage-gated calcium channels may lead to improved understanding of novel redox mechanisms in physiological and pathological processes. FUTURE DIRECTIONS: Identification of redox mechanisms and sites on voltage-gated calcium channel may allow development of novel and specific ion channel therapies for unmet medical needs. Thus, it may be possible to regulate the redox state of these channels in treatment of pathological process such as epilepsy and neuropathic pain. PMID- 24161129 TI - Relationship between frequency of involuntary autobiographical memories and cognitive failure. AB - Involuntary autobiographical memories are memories of personal experiences that pop into mind without a conscious attempt at their retrieval. This study investigated individual differences in the number of involuntary autobiographical memories, and explored the relationship between the frequency of occurrence in involuntary autobiographical memory and cognitive failures in everyday memory, as indexed by metamemory questionnaires. A total of 24 undergraduate students reported involuntary autobiographical memories in controlled field interviews, and completed the Everyday Memory Questionnaire and the Cognitive Failures Questionnaire. The results showed that, despite controlled conditions, considerable individual differences were observed in the number of involuntary autobiographical memories reported while walking along a prescribed route on the campus, and that reported memories were predominantly serving self function. In addition, the number of involuntary autobiographical memories was positively related to cognitive failures in everyday memory: participants who acknowledged more problems in everyday memory had a higher frequency of involuntary memories. The implications of these results are discussed in terms of the complementary function of involuntary autobiographical memory in everyday life. PMID- 24161131 TI - Advanced gastric cancer: is chemotherapy needed after surgery? PMID- 24161130 TI - Disentangling the body weight-bone mineral density association among breast cancer survivors: an examination of the independent roles of lean mass and fat mass. AB - BACKGROUND: Bone mineral density (BMD) and lean mass (LM) may both decrease in breast cancer survivors, thereby increasing risk of falls and fractures. Research is needed to determine whether lean mass (LM) and fat mass (FM) independently relate to BMD in this patient group. METHODS: The Health, Eating, Activity, and Lifestyle Study participants included 599 women, ages 29-87 years, diagnosed from 1995-1999 with stage 0-IIIA breast cancer, who underwent dual-energy X-ray absorptiometry scans approximately 6-months postdiagnosis. We calculated adjusted geometric means of total body BMD within quartiles (Q) of LM and FM. We also stratified LM-BMD associations by a fat mass index threshold that tracks with obesity (lower body fat: <= 12.9 kg/m2; higher body fat: >12.9 kg/m2) and stratified FM-BMD associations by appendicular lean mass index level corresponding with sarcopenia (non-sarcopenic: >= 5.45 kg/m2 and sarcopenic: < 5.45 kg/m2). RESULTS: Higher LM (Q4 vs. Q1) was associated with higher total body BMD overall (1.12 g/cm2 vs. 1.07 g/cm2, p-trend < 0.0001), and among survivors with lower body fat (1.13 g/cm2 vs. 1.07 g/cm2, p-trend < 0.0001) and higher body fat (1.15 g/cm2 vs. 1.08 g/cm2, p-trend = 0.004). Higher FM (Q4 vs. Q1) was associated with higher total body BMD overall (1.12 g/cm2 vs. 1.07 g/cm2, p-trend < 0.0001) and among non-sarcopenic survivors (1.15 g/cm2 vs. 1.08 g/cm2, p < 0.0001), but the association was not significant among sarcopenic survivors (1.09 g/cm2 vs. 1.04 g/cm2, p-trend = 0.18). CONCLUSION: Among breast cancer survivors, higher LM and FM were independently related to higher total body BMD. Future exercise interventions to prevent bone loss among survivors should consider the potential relevance of increasing and preserving LM. PMID- 24161133 TI - Surgery for Crohn's disease and anti-TNF agents: the changing scenario. AB - Surgery has been a mainstay of therapy for Crohn's disease for a long time, essentially as a consequence of the fairly modest efficacy of traditional medications such as immunomodulators, antibiotics and 5-ASA, especially in severe cases. However, in the past decade and half, the advent of anti-TNF agents has greatly changed the medical approach to this disease and may modify its general management as well. Here, we have reviewed the current literature on incidence of surgery, timing of surgery and postoperative recurrence of Crohn's disease before and after the advent of anti-TNF agents. In addition, we have reviewed the risk of perioperative complications in patients on anti-TNF agents before surgery. The data show that the use of these medications is changing or expecting to change shortly a number of surgical aspects of Crohn's disease management. PMID- 24161134 TI - Sphincter of Oddi dysfunction: an evidence-based review. AB - Sphincter of Oddi dysfunction is a painful syndrome that presents as recurrent episodes of right upper quadrant biliary pain, or recurrent idiopathic pancreatitis. It is a disease process that has been a subject of controversy, in part because its natural history, disease course and treatment outcomes have not been clearly defined in large controlled studies with long-term follow-up. This review is aimed at clarifying the state-of-the-art with an evidence-based summary of the current diagnostic and therapeutic approaches and modalities for sphincter of Oddi dysfunction. PMID- 24161136 TI - The biological implication of cancer stem cells in hepatocellular carcinoma: a possible target for future therapy. AB - Recent studies indicated the importance of stem cells in cancer, including in hepatocellular carcinoma. The presence of the stem cells and cancer stem cells in liver diseases is associated with the initiation, maintenance, metastasis and chemoresistance. Since hepatocellular carcinoma is a heterogeneous disease with a wide variety of prognostic types, which may limit the efficiency of standardized therapy, the understanding of the source of the cancer, alteration in important molecular signaling pathways and interaction between cancer cells and other cells types will be important in defining future, tailored treatment strategies. PMID- 24161141 TI - A common variant on chromosome 4q25 is associated with prolonged PR interval in subjects with and without atrial fibrillation. AB - Single nucleotide polymorphisms (SNPs) at chromosome 4q25 (near PITX2) are strongly associated with atrial fibrillation (AF). We assessed whether a 4q25 tagging SNP (rs2200733) is associated with PR interval duration in patients with lone and typical AF and controls. Patients with lone (n = 169) and typical (n = 269) AF enrolled in the Vanderbilt AF registry and controls (n = 1,403) derived from the Vanderbilt DNA Biobank were studied. Carriage of the rs2200733T allele (CT or TT genotype) was more common in patients with lone (39%) than typical (25%) AF or controls (21%, p <0.01 for both comparisons). In both AF cohorts, we observed an association between genotype and PR interval duration (median PR interval for CC, CT, and TT: 162, 178, and 176 ms, respectively, for lone, p = 0.038 and 166, 180, and 196 ms, respectively, for typical, p = 0.001). After adjustment for covariates, the association between T allele and PR prolongation persisted, with mean effect size of 10.9, 12.8, and 4.4 ms for patients with lone and typical AF and controls, respectively (p <0.05 for each comparison). We found that a common 4q25 AF susceptibility allele (rs2200733) is associated with PR interval prolongation in patients with lone and typical AF and controls with no AF. Given that prolonged PR interval is an established risk factor for AF, this observation, in the context of previously described functional effects of PITX2 deficiency, provides further knowledge about the pathophysiological link of 4q25 variants with AF. PMID- 24161143 TI - Uncertainty in the spatial distribution of tropical forest biomass: a comparison of pan-tropical maps. AB - BACKGROUND: Mapping the aboveground biomass of tropical forests is essential both for implementing conservation policy and reducing uncertainties in the global carbon cycle. Two medium resolution (500 m - 1000 m) pantropical maps of vegetation biomass have been recently published, and have been widely used by sub national and national-level activities in relation to Reducing Emissions from Deforestation and forest Degradation (REDD+). Both maps use similar input data layers, and are driven by the same spaceborne LiDAR dataset providing systematic forest height and canopy structure estimates, but use different ground datasets for calibration and different spatial modelling methodologies. Here, we compare these two maps to each other, to the FAO's Forest Resource Assessment (FRA) 2010 country-level data, and to a high resolution (100 m) biomass map generated for a portion of the Colombian Amazon. RESULTS: We find substantial differences between the two maps, in particular in central Amazonia, the Congo basin, the south of Papua New Guinea, the Miombo woodlands of Africa, and the dry forests and savannas of South America. There is little consistency in the direction of the difference. However, when the maps are aggregated to the country or biome scale there is greater agreement, with differences cancelling out to a certain extent. When comparing country level biomass stocks, the two maps agree with each other to a much greater extent than to the FRA 2010 estimates. In the Colombian Amazon, both pantropical maps estimate higher biomass than the independent high resolution map, but show a similar spatial distribution of this biomass. CONCLUSIONS: Biomass mapping has progressed enormously over the past decade, to the stage where we can produce globally consistent maps of aboveground biomass. We show that there are still large uncertainties in these maps, in particular in areas with little field data. However, when used at a regional scale, different maps appear to converge, suggesting we can provide reasonable stock estimates when aggregated over large regions. Therefore we believe the largest uncertainties for REDD+ activities relate to the spatial distribution of biomass and to the spatial pattern of forest cover change, rather than to total globally or nationally summed carbon density. PMID- 24161135 TI - Telomeres and telomere dynamics: relevance to cancers of the GI tract. AB - Aberrations in telomere length and telomere maintenance contribute to cancer development. In this article, we review the basic principles of telomere length in normal and tumor tissue and the presence of the two main telomere maintenance pathways as they pertain to gastrointestinal tract cancer. Peripheral blood telomeres are shorter in patients with many types of gastrointestinal tract cancers. Telomere length in tumor DNA also appears to shorten early in cancer development. Tumor telomere shortening is often accompanied by telomerase activation to protect genetically damaged DNA from normal cell senescence or apoptosis, allowing immortalized but damaged DNA to persist. Alternative lengthening of telomeres is another mechanism used by cancer to maintain telomere length in cancer cells. Telomerase and alternative lengthening of telomeres activators and inhibitors may become important chemopreventive or chemotherapeutic agents as our understanding of telomere biology, specific telomere-related phenotypes and its relationship to carcinogenesis increases. PMID- 24161142 TI - Determinants of outcome after isolated coronary artery bypass grafting in patients aged <=50 years (from the Coronary aRtery diseAse in younG adultS study). AB - This study was planned to identify the determinants of outcome after coronary artery bypass (CABG) in young patients. Data on 592 patients aged <=50 years who underwent CABG from 9 European institutions were collected retrospectively. Twenty-eight percent of patients received at least 2 arterial grafts. Clopidogrel was used at discharge in 16.2% and statins in 67.2% of patients. Freedom from major adverse cardiac and cerebrovascular events at 1, 3, and 5 years was 93.8%, 90.1%, and 85.0%; survival rate was 98.3%, 96.3%, and 94.9%; freedom from myocardial infarction was 96.3%, 95.1%, and 92.5%; and freedom from repeat revascularization was 96.3%, 95.1%, and 92.5%, respectively. Neither types of grafts nor medication at discharge had any impact on the late outcome. Age <40 years (relative risk [RR] 2.19, 95% confidence interval [CI] 1.17 to 4.11), diabetes (RR 1.71, 95% CI 1.02 to 2.88), estimated glomerular filtration rate <60 ml/min/1.73 m(2) (RR 2.44, 95% CI 1.26 to 4.72), non-ST-elevation myocardial infarction/ST-elevation myocardial infarction (RR 2.12, 95% CI 1.27 to 3.55), emergency procedure (RR 2.34, 95% CI 1.13 to 4.88), and left ventricular ejection fraction <30% (RR 3.18, 95% CI 1.41 to 7.16) were independent predictors of major adverse cardiac and cerebrovascular events. Patients with left ventricular ejection fraction <30% had a particularly poor survival rate (at 5 years 67.7% vs 96.1%; adjusted analysis RR 14.01, 95% CI 5.16 to 38.03). Poor left ventricular function, myocardial infarction, diabetes, renal failure, and age <40 years are major determinants of late outcome after CABG in young patients. In conclusion, data from this real-world registry indicate that multiple arterial grafts and statin treatment are largely underutilized in these patients. PMID- 24161144 TI - Determination of volatile thiols in lipid matrix by simultaneous derivatization/extraction and liquid chromatography-high resolution mass spectrometric analysis. Application to virgin olive oil. AB - A simple, reliable, selective and sensitive method for the determination of volatile thiols at trace levels in lipid matrices was developed. The method consisted of a single-step derivatization/extraction procedure followed by electrospray ionization-high performance liquid chromatography-high resolution mass spectrometry (ESI-HPLC-HRMS) analysis using ebselen as a derivatization agent. The analytical conditions were optimized in a lipid model system (triolein) and virgin olive oil (VOO), both spiked with seven representative volatile thiols. The method was validated and the sensitivity, precision, accuracy and selectivity were evaluated. The experimental limit of quantification (LOQ) of the tested thiols in the VOO matrix ranged from 0.05 to 0.5ng/kg. Moreover, the intra-day relative standard deviation (RSD) was in general lower than 10%, except for esters, which reached RSD values of around 13%. The inter day RDS ranged between 9.6% and 36.6%. The recovery in VOO ranged from 79% to 20% for derivatives with the highest and lowest polarity, respectively. The methodology was applied to the analysis of some VOO samples. Within this first probe sample, some of the VOO analyzed presented concentrations of 4-methoxy-2 methyl-2-butanethiol above the LOQ, ranging between 0.2 and 1.9ng/kg. The advantage of using full-scan acquisition mode when working with HRMS is that it allows the use of a non-target approach based on the fragmentation of thiol derivatives yielding a main product ion at m/z 275.9922 [C13H10ONSe](+) and that corresponded to the ebselen moiety of the derivatives. Any positive finding satisfied the identification and confirmation criteria established during the validation: retention time drift <3-fold the standard deviation of the method, mass accuracy <2ppm with real resolution >=20,000 (full width at half maximum) at the mass range of interest, and the presence of isotope ions containing (80)Se and (78)Se, respectively. PMID- 24161145 TI - Trace analysis of biocidal oligoguanidines in environmental water samples. AB - This paper demonstrates the determination of residues of biocidal oligoguanidines manufactured by polycondensation of guanidine hydrochloride and 2,2' (ethylenedioxy)bis(ethylamine) in environmental water samples. The analytes were preconcentrated from samples adjusted to pH 4 by solid-phase extraction using a mixed-mode sorbent with weak cation exchange functionalities. Elution from the sorbent was achieved by 2M hydrochloric acid in methanol. After evaporation and reconstitution in water, the extract was analyzed by reversed-phase high performance liquid chromatography combined with quadrupole/time-of-flight or triple quadrupole mass spectrometry employing electrospray ionization. A preconcentration factor of 10,000 could be achieved and detection limits were in the sub-MUgL(-1) range. This method looks promising to monitor the fate of these biocides released into the aquatic environment during different applications. PMID- 24161146 TI - Ensuring selectivity and sensitivity by timed- and ultra-selective reaction monitoring during gas chromatography-tandem mass spectrometric determination of pesticides. AB - In multiresidue analysis, as the complexity of matrix increases, matrix co extractives might co-elute and interfere with the detection of target analytes, and thereby result in false positives and erroneous quantifications. This paper aims to evaluate the combination of enhanced mass resolution and concurrent selectivity and sensitivity in analyzing a complex mixture of 341 pesticides in grape, orange, tomato, okra and spinach by gas chromatography triple quadrupole mass spectrometry (GC-MS/MS). Timed-selective reaction monitoring (t-SRM) was found advantageous over segment SRM in terms of ease of method optimization and sensitivity. The optimized t-SRM method was used to test the applicability of ultra-SRM (USRM) in filtering out co-eluting interfering matrix compounds. False detections of benfluralin, dimethoate, etc. could be avoided when mass resolution was increased from 0.7 to 0.4 and 0.2Da (full width at half maximum). Similar observations were noted for chlorobenzilate, spiromesifen, tebuconazole, etc., in grape; omethoate, bendiocarb, monocrotophos, etc. in orange; omethoate, dimethoate, ethoxyquin, atrazine, etc., in tomato; and dichlobenil, omethoate, propoxur, monocrotophos, etc., in okra. The analysis at higher mass resolution could significantly minimize matrix effects (ME), e.g., 34% at 0.7Da for spiroxamine in grape to 0.6% (0.4Da) and -44% (0.7Da) for dichlorvos in okra to 8.8% (0.1Da). A feature called "quantitation enhanced data-dependent (QED) scan feature" was found effective in targeted screening to confirm the detection of atrazine, azoxystrobin, lambda-cyhalothrin, etc. at trace quantities in incurred samples and avoid false detection of chlorpyrifos. PMID- 24161147 TI - Improved gas chromatography-flame ionization detector analytical method for the analysis of epoxy fatty acids. AB - In this study an improved method for analysis of epoxy fatty acids is reported. Data obtained from analysis of polar fatty acids has previously been presented, but due to the high number of compounds that co-elute in the polar fraction, the resultant chromatograms are complex which may lead to compromising the accuracy of the data. A three steps separation of fatty acid methyl esters (FAMEs) by solid-phase extraction (SPE) on a silica gel column to remove hydroxy fatty acid interferences was proposed. This approach is opposed to a two step separation procedure that has been often used to prevent analytical interferences caused by non-altered fatty acids. A gas chromatograph with a flame ionization detector (GC FID) equipped with a polar CP-Sil 88TM column was used. Quantification was based on the use of methyl nonadecanoate (C19:0), as an internal standard. Individual mono epoxy fatty acids were well separated without co-eluting compounds. The optimized method was finally applied to screen epoxy fatty acids in 37 fresh oil samples. Results obtained for the total epoxy fatty acids were in the range 0.03 2mgg(-1) of oil with repeatability coefficient of variation (CV) ranging from 2.8 to 9.9% for duplicate analysis showing that the results obtained are repeatable. PMID- 24161148 TI - Graphene oxide: an adsorbent for the extraction and quantification of aflatoxins in peanuts by high-performance liquid chromatography. AB - In this paper, graphene oxide (GO) was synthesized and specifically selected by centrifugation to extract four aflatoxins (B1, B2, G1, and G2) as an effective adsorbent. Then, the amount of aflatoxins was quantitatively measured by high performance liquid chromatography (HPLC). The GO was characterized by X-ray diffraction (XRD), atomic force microscopy (AFM), and ultraviolet (UV) spectrophotometer. Several parameters that could affect the extraction efficiency, including the GO amount, methanol concentration in the extraction solvent, spiked amount, extraction time, and elution cycle, were also investigated and optimized in this work. Under optimal conditions, good linear relationships were achieved with the correlation coefficient (r) ranging from 0.99217 to 0.99995. The detection limit of this method for the four aflatoxins ranged from 0.08 to 0.65ng/g. Finally, the proposed method has been successfully applied to determine aflatoxins in peanut samples. The results show that the recoveries of the four aflatoxins range from 85.1% to 100.8% with the relative standard deviations between 2.1% and 7.9%. PMID- 24161149 TI - Emerging issues in safe and sustainable mobility for older persons. PMID- 24161150 TI - A novel carboxyl-terminal protease derived from Paenibacillus lautus CHN26 exhibiting high activities at multiple sites of substrates. AB - BACKGROUND: Carboxyl-terminal protease (CtpA) plays essential functions in posttranslational protein processing in prokaryotic and eukaryotic cells. To date, only a few bacterial ctpA genes have been characterized. Here we cloned and characterized a novel CtpA. The encoding gene, ctpAp (ctpA of Paenibacillus lautus), was derived from P. lautus CHN26, a Gram-positive bacterium isolated by functional screening. Recombinant protein was obtained from protein over expression in Escherichia coli and the biochemical properties of the enzyme were investigated. RESULTS: Screening of environmental sediment samples with a skim milk-containing medium led to the isolation of a P. lautus CHN26 strain that exhibited a high proteolytic activity. A gene encoding a carboxyl-terminal protease (ctpAp) was cloned from the isolate and characterized. The deduced mature protein contains 466 aa with a calculated molecular mass of 51.94 kDa, displaying 29-38% amino acid sequence identity to characterized bacterial CtpA enzymes. CtpAp contains an unusual catalytic dyad (Ser309-Lys334) and a PDZ substrate-binding motif, characteristic for carboxyl-terminal proteases. CtpAp was expressed as a recombinant protein and characterized. The purified enzyme showed an endopeptidase activity, which effectively cleaved alpha S1- and beta- casein substrates at carboxyl-terminus as well as at multiple internal sites. Furthermore, CtpAp exhibited a high activity at room temperature and strong tolerance to conventional protease inhibitors, demonstrating that CtpAp is a novel endopeptidase. CONCLUSIONS: Our work on CtpA represents the first investigation of a member of Family II CtpA enzymes. The gene was derived from a newly isolated P. lautus CHN26 strain exhibiting a high protease activity in the skim milk assay. We have demonstrated that CtpAp is a novel endopeptidase with distinct cleavage specificities, showing a strong potential in biotechnology and industry applications. PMID- 24161152 TI - Multilocus phylogeny and cryptic diversity in Asian shrew-like moles (Uropsilus, Talpidae): implications for taxonomy and conservation. AB - BACKGROUND: The genus Uropsilus comprises a group of terrestrial, montane mammals endemic to the Hengduan and adjacent mountains. These animals are the most primitive living talpids. The taxonomy has been primarily based on cursory morphological comparisons and the evolutionary affinities are little known. To provide insight into the systematics of this group, we estimated the first multi locus phylogeny and conducted species delimitation, including taxon sampling throughout their distribution range. RESULTS: We obtained two mitochondrial genes (~1, 985 bp) and eight nuclear genes (~4, 345 bp) from 56 specimens. Ten distinct evolutionary lineages were recovered from the three recognized species, eight of which were recognized as species/putative species. Five of these putative species were found to be masquerading as the gracile shrew mole. The divergence time estimation results indicated that climate change since the last Miocene and the uplift of the Himalayas may have resulted in the diversification and speciation of Uropsilus. CONCLUSIONS: The cryptic diversity found in this study indicated that the number of species is strongly underestimated under the current taxonomy. Two synonyms of gracilis (atronates and nivatus) should be given full species status, and the taxonomic status of another three potential species should be evaluated using extensive taxon sampling, comprehensive morphological, and morphometric approaches. Consequently, the conservation status of Uropsilus spp. should also be re-evaluated, as most of the species/potential species have very limited distribution. PMID- 24161154 TI - New layered iron sulfide NaFe(1.6)S2: synthesis and characterization. AB - Na was intercalated between [Fe2S2] layers for the first time, giving a novel compound NaFe(1.6)S2. This material adopts a CaAl2Si2-type structure with ~20% iron vacancies and represents the first layered compound in a ternary Na-M-X (M = Fe, Co, Ni; X = S, Se) system. First-principles calculations reveal that phonon dynamics is an important factor for it to prefer the CaAl2Si2-type rather than the ThCr2Si2-type structure. It features a magnetic transition at 205 K and is a narrow-band-gap semiconductor. PMID- 24161153 TI - High-yield production of functional soluble single-domain antibodies in the cytoplasm of Escherichia coli. AB - BACKGROUND: For their application in the area of diagnosis and therapy, single domain antibodies (sdAbs) offer multiple advantages over conventional antibodies and fragments thereof in terms of size, stability, solubility, immunogenicity, production costs as well as tumor uptake and blood clearance. Thus, sdAbs have been identified as valuable next-generation targeting moieties for molecular imaging and drug delivery in the past years. Since these probes are much less complex than conventional antibody fragments, bacterial expression represents a facile method in order to produce sdAbs in large amounts as soluble and functional proteins. RESULTS: By the combined use of high cell density cultivation media with a genetically engineered E. coli mutant strain designed for the cytoplasmic formation of proper disulfide bonds, we achieved high level of intracellular sdAb production (up to 200 mg/L). Due to a carboxyterminal hexahistidine epitope, the soluble recombinant sdAbs could be purified by one step immobilized metal affinity chromatography to apparent homogeneity and easily radiolabeled with 99mTc within 1 h. The intradomain disulfide bridge being critical for the stability and functionality of the sdAb molecule was shown to be properly formed in ~96% of the purified proteins. In vitro binding studies confirmed the high affinity and specificity of the expressed sdAb 7C12 towards its molecular target. CONCLUSIONS: Our study demonstrates an efficient cultivation and expression strategy for the production of substantial amounts of soluble and functional sdAbs, which may be adopted for high-yield production of other more complex proteins with multiple disulfides as well. PMID- 24161157 TI - An active, general, and long-lived palladium catalyst for cross-couplings of deactivated (hetero)aryl chlorides and bromides with arylboronic acids. AB - An active, general, and long-lived palladium catalyst for Suzuki-Miyaura reactions of aryl and heteroaryl chlorides deactivated by steric hindrance, electron richness, and coordinating functional groups is reported. In reactions of arylbromide bearing two o-tert-butyl substituents, C(sp(3))-H arylation of the tert-butyl group, rather than the Suzuki-Miyaura reaction, proceeded in excellent yield. The key to the success of the reactions was the development of biphenylene substituted dicyclohexylruthenocenylphosphine (CyR-Phos) as a supporting ligand. PMID- 24161158 TI - Treatment of severe IgA nephropathy: mycophenolate mofetil/prednisone compared to cyclophosphamide/prednisone. AB - OBJECTIVE: To compare the efficacy of mycophenolate mofetil (MMF)/prednisone to cyclophosphamide (CYC)/prednisone in the treatment of severe IgA nephropathy. METHODS: Patients (n = 84) with severe IgA nephropathy received either MMF/prednisone (MMF group) or CYC/prednisone (CYC group). The MMF induction dose was 1.5 g/d for 6 months and the maintenance dose was 0.75 - 1.0 g/day for 12 months. The CYC induction dose was 0.8 - 1.0 g/month for 6 months and the maintenance dose was 0.8 - 1.0 g/3 months for 12 months. Laboratory tests, clinical remission rate and side effects were investigated. RESULTS: After 18 months of treatment, the total effective rate in the MMF group was significantly higher than that of the CYC group. Patients' 24-hour urinary protein excretion in the MMF group was lower than the CYC group. Patients' plasma albumin and total protein in the MMF group was higher than the CYC group. MMF and prednisone reduced serum lipids, while in the CYC group serum lipids remained unchanged. There was also a lower incidence of adverse effects in the MMF group (4.76%) than in the CYC group (26.2%). CONCLUSION: Combination therapy with MMF and prednisone for severe IgA nephropathy achieved a higher remission rate compared to treatment with CYC and prednisone. This therapy also reduced the 24-hour urinary protein and serum lipids while increasing plasma albumin and improving renal function. The incidence of adverse effects was significantly lower in the MMF group compared to the CYC group. *These authors have contributed equally to this work. PMID- 24161159 TI - Prescribing patterns of duloxetine in France: a prescription assessment study in real-world conditions. AB - Duloxetine is a serotonin and norepinephrine reuptake inhibitor approved in the European Union for the treatment of major depressive disorder, generalized anxiety disorder, and diabetic peripheral neuropathic pain in adults. This study aimed to assess the real-world conditions of duloxetine use in France. Between April 2009 and January 2010, 290 dispensing pharmacies, randomly selected from a nationally representative list, included 1,104 patients who presented a duloxetine prescription and consented to the study. Demographic, clinical, and prescription data were extracted from pharmacy records and requested from prescribing physicians. Of the 294 patients with full data available, the mean age (standard deviation) was 54.5 (13.5) years; 74.1% were female; and 86.7% presented with a renewal prescription. 73.5% of patients had major depressive disorder; 3.4% generalized anxiety disorder; and 3.4% diabetic peripheral neuropathic pain. Overall, 78.2% (95% CI: 73.1; 82.8) of patients received duloxetine for an EU-approved indication; 95.2% (95% CI: 92.1; 97.4) of patients had no contra-indication to duloxetine; and 99.0% (95% CI: 97.0; 99.8) received an approved dose. Combining these three criteria, the overall approved use of duloxetine was 73.7% (95% CI: 68.3; 78.7). The strengths and limitations of the study design are discussed. PMID- 24161160 TI - Lack of an effect of rilpivirine on the pharmacokinetics of ethinylestradiol and norethindrone in healthy volunteers. AB - Rilpivirine is a human immunodeficiency virus Type 1 (HIV-1) non-nucleoside reverse transcriptase inhibitor. OBJECTIVE: Rilpivirine metabolism involves cytochrome P450 3A4 (CYP3A4). This trial (ClinicalTrials. gov number: NCT00739622) evaluated the interaction between rilpivirine and ethinylestradiol/norethindrone (combination oral contraceptives), which are metabolized by multiple pathways, including CYP3A4. METHODS: During three consecutive 28-day cycles, 18 HIV-negative females received once-daily ethinylestradiol (35 MUg)/norethindrone (1 mg) (Days 1 - 21); Days 22 - 28 were pill-free. Only in Cycle 3 was once-daily rilpivirine (25 mg) co-administered (Days 1 - 15). Minimum and maximum plasma concentrations (Cmin; Cmax) and area under the plasma concentration-time curve over 24 hours (AUC24h) of ethinylestradiol/norethindrone (Day 15, Cycles 2 and 3) and rilpivirine (Day 15, Cycle 3) were evaluated. RESULTS: Rilpivirine coadministration had no effect on (least square mean ratio, 90% confidence interval) ethinylestradiol Cmin (1.09, 1.03 - 1.16) or AUC24h (1.14, 1.10 - 1.19), but increased Cmax by 17% (1.17, 1.06 - 1.30), which is unlikely to affect ethinylestradiol pharmacodynamics. Norethindrone pharmacokinetics were unaffected by rilpivirine (AUC24h: 0.89, 0.84 - 0.94; Cmin: 0.99, 0.90 - 1.08; Cmax: 0.94, 0.83 - 1.06). Steady-state rilpivirine pharmacokinetics with ethinylestradiol/norethindrone was comparable with historical data for rilpivirine alone. Rilpivirine with ethinylestradiol/norethindrone was generally well tolerated. No new safety events were identified. CONCLUSIONS: Co-administration of rilpivirine, at the therapeutic dosing regimen, with ethinylestradiol/norethindrone does not affect hormone pharmacokinetics, and is, therefore, unlikely to affect the efficacy or safety of this oral hormonal contraceptive. Rilpivirine pharmacokinetics was not affected by ethinylestradiol/norethindrone. Rilpivirine (25 mg once daily) can be co-administered with ethinylestradiol/norethindrone-based contraceptives without dose modification. PMID- 24161161 TI - Assessment of disease-drug-drug interaction between single-dose tocilizumab and oral contraceptives in women with active rheumatoid arthritis. AB - OBJECTIVES: The objective of this study was to evaluate the effect of a single intravenous dose of tocilizumab (TCZ) on pharmacokinetics (PK) of oral contraceptive (OC; norethindrone (NE) and ethinyl estradiol (EE)) and on sex hormone levels (progesterone (PG), luteinizing hormone (LH), and follicle stimulating hormone (FSH)) in subjects with active rheumatoid arthritis (RA) who were on stable doses of methotrexate. METHODS: This was an open-label, nonrandomized, multicenter, two-parallel group, one-sequence crossover study. In Group 1, Cycle 1 was a baseline cycle to determine the PK of OC and levels of sex hormones. At the start of Cycle 2, patients continued to receive OC and single TCZ dosing on Day 1. In Cycle 2, we determined the PK of OC and levels of sex hormones when OC and TCZ were combined. In Cycle 3, we determined the PK of OC and the levels of sex hormones after TCZ treatment was stopped. PK for EE and NE were analyzed serially on Day 7 when maximum TCZ effect on inflammation as indicated by C-reactiv protein (CRP) was expected. Hormone levels (PG, LH and FSH) were measured mid-cycle (cycle Days 12 - 16 and Day 21) during each cycle. Group 2 (healthy subjects) was studied to compare the levels of OC PK exposures with those in each cycle of Group 1 (RA subjects). RESULTS: Levels of PG, LH and FSH were not affected by the combination of TCZ/OC treatment in RA patients studied. No breakthrough bleeding was attributed to the initiation of TCZ treatment in subjects receiving OCs. PK exposures of EE and NE were similar between RA and healthy subjects at baseline and were not affected by single-dose TCZ. Administration of OC with or without a single dose of TCZ was well tolerated. CONCLUSIONS: Data from this study indicated that the PK and sex hormone levels were not affected in RA subjects who had active disease and were on a stable regimen of methotrexate. PMID- 24161162 TI - Impact of CYP3A and ABCB1 polymorphisms on the pharmacokinetics and pharmacodynamics of fentanyl. PMID- 24161163 TI - Data driven, predictive molecular dynamics for nanoscale flow simulations under uncertainty. AB - For over five decades, molecular dynamics (MD) simulations have helped to elucidate critical mechanisms in a broad range of physiological systems and technological innovations. MD simulations are synergetic with experiments, relying on measurements to calibrate their parameters and probing "what if scenarios" for systems that are difficult to investigate experimentally. However, in certain systems, such as nanofluidics, the results of experiments and MD simulations differ by several orders of magnitude. This discrepancy may be attributed to the spatiotemporal scales and structural information accessible by experiments and simulations. Furthermore, MD simulations rely on parameters that are often calibrated semiempirically, while the effects of their computational implementation on their predictive capabilities have only been sporadically probed. In this work, we show that experimental and MD investigations can be consolidated through a rigorous uncertainty quantification framework. We employ a Bayesian probabilistic framework for large scale MD simulations of graphitic nanostructures in aqueous environments. We assess the uncertainties in the MD predictions for quantities of interest regarding wetting behavior and hydrophobicity. We focus on three representative systems: water wetting of graphene, the aggregation of fullerenes in aqueous solution, and the water transport across carbon nanotubes. We demonstrate that the dominant mode of calibrating MD potentials in nanoscale fluid mechanics, through single values of water contact angle on graphene, leads to large uncertainties and fallible quantitative predictions. We demonstrate that the use of additional experimental data reduces uncertainty, improves the predictive accuracy of MD models, and consolidates the results of experiments and simulations. PMID- 24161164 TI - Exendin-4 and sitagliptin protect kidney from ischemia-reperfusion injury through suppressing oxidative stress and inflammatory reaction. AB - BACKGROUND: This study tested the hypothesis that exendin-4 and sitagliptin can effectively protect kidney from acute ischemia-reperfusion (IR) injury. METHODS: Adult SD-rats (n = 48) equally divided into group 1 (sham control), group 2 (IR injury), group 3 [IR + sitagliptin 600 mg/kg at post-IR 1, 24, 48 hr)], and group 4 [IR + exendin-4 10 MUm/kg at 1 hr after procedure] were sacrificed after 24 and 72 hrs (n = 6 at each time from each group) following clamping of bilateral renal pedicles for 60 minutes (groups 2-4). RESULTS: Serum creatinine level and urine protein to creatinine ratio were highest in group 2 and lowest in group 1 (all p < 0.001) without notable differences between groups 3 and 4. Kidney injury score, expressions of inflammatory biomarkers at mRNA (MMP-9, TNF-alpha, IL-1beta, PAI 1), protein (TNF-alpha, NF-kappaB and VCAM-1), and cellular (CD68+) levels in injured kidneys at 24 and 72 hr showed an identical pattern compared to that of creatinine level in all groups (all p < 0.0001). Expressions of oxidized protein, reactive oxygen species (NOX-1, NOX-2), apoptosis (Bax, caspase-3 and PARP), and DNA damage marker (gammaH2AX+) of IR kidney at 24 and 72 hrs exhibited a pattern similar to that of inflammatory mediators among all groups (all p < 0.01). Renal expression of glucagon-like peptide-1 receptor, and anti-oxidant biomarkers at cellular (GPx, GR) and protein (NQO-1, HO-1, GPx) levels at 24 and 72 hr were lowest in group 1, significantly lower in group 2 than in groups 3 and 4 (all p < 0.01). CONCLUSION: Exendin-4 and sitagliptin provided significant protection for the kidneys against acute IR injury. PMID- 24161165 TI - Enhanced silencing and stabilization of siRNA polyplexes by histidine-mediated hydrogen bonds. AB - Branched peptides containing histidines and lysines (HK) have been shown to be effective carriers for DNA and siRNA. We anticipate that elucidation of the binding mechanism of HK with siRNA will provide greater insight into the self assembly and delivery of the HK:siRNA polyplex. Non-covalent bonds between histidine residues and nucleic acids may enhance the stability of siRNA polyplexes. We first compared the polyplex biophysical properties of a branched HK with those of branched asparagine-lysine peptide (NK). Consistent with siRNA silencing experiments, gel electrophoresis demonstrated that the HK siRNA polyplex maintained its integrity with prolonged incubation in serum, whereas siRNA in complex with NK was degraded in a time-dependent manner. Isothermal titration calorimetry of various peptides binding to siRNA at pH 7.3 showed that branched polylysine, interacted with siRNA was initially endothermic, whereas branched HK exhibited an exothermic reaction at initial binding. The exothermic interaction indicates formation of non-ionic bonds between histidines and siRNA; purely electrostatic interaction is entropy-driven and endothermic. To investigate the type of non-ionic bond, we studied the protonation state of imidazole rings of a selectively (15)N labeled branched HK by heteronuclear single quantum coherence NMR. The peak of Ndelta1-H tautomers of imidazole shifted downfield (in the direction of deprotonation) by 0.5-1.0 ppm with addition of siRNA, providing direct evidence that histidines formed hydrogen bonds with siRNA at physiological pH. These results establish that histidine-rich peptides form hydrogen bonds with siRNA, thereby enhancing the stability and biological activity of the polyplex in vitro and in vivo. PMID- 24161166 TI - Promotion of airway anastomotic microvascular regeneration and alleviation of airway ischemia by deferoxamine nanoparticles. AB - Airway tissue ischemia and hypoxia in human lung transplantation is a consequence of the sacrifice of the bronchial circulation during the surgical procedure and is a major risk factor for the development of airway anastomotic complications. Augmented expression of hypoxia-inducible factor (HIF)-1alpha promotes microvascular repair and alleviates allograft ischemia and hypoxia. Deferoxamine mesylate (DFO) is an FDA-approved iron chelator which has been shown to upregulate cellular HIF-1alpha. Here, we developed a nanoparticle formulation of DFO that can be topically applied to airway transplants at the time of surgery. In a mouse orthotopic tracheal transplant (OTT) model, the DFO nanoparticle was highly effective in enhancing airway microvascular perfusion following transplantation through the production of the angiogenic factors, placental growth factor (PLGF) and stromal cell-derived factor (SDF)-1. The endothelial cells in DFO treated airways displayed higher levels of p-eNOS and Ki67, less apoptosis, and decreased production of perivascular reactive oxygen species (ROS) compared to vehicle-treated airways. In summary, a DFO formulation topically applied at the time of surgery successfully augmented airway anastomotic microvascular regeneration and the repair of alloimmune-injured microvasculature. This approach may be an effective topical transplant-conditioning therapy for preventing airway complications following clinical lung transplantation. PMID- 24161167 TI - The enhancement of bone regeneration by gene activated matrix encoding for platelet derived growth factor. AB - Gene therapy using non-viral vectors that are safe and efficient in transfecting target cells is an effective approach to overcome the shortcomings of protein delivery of growth factors. The objective of this study was to develop and test a non-viral gene delivery system for bone regeneration utilizing a collagen scaffold to deliver polyethylenimine (PEI)-plasmid DNA (pDNA) [encoding platelet derived growth factor-B (PDGF-B)] complexes. The PEI-pPDGF-B complexes were fabricated at amine (N) to phosphate (P) ratio of 10 and characterized for size, surface charge, and in vitro cytotoxicity and transfection efficacy in human bone marrow stromal cells (BMSCs). The influence of the complex-loaded collagen scaffold on cellular attachment and recruitment was evaluated in vitro using microscopy techniques. The in vivo regenerative capacity of the gene delivery system was assessed in 5 mm diameter critical-sized calvarial defects in Fisher 344 rats. The complexes were ~100 nm in size with a positive surface charge. Complexes prepared at an N/P ratio of 10 displayed low cytotoxicity as assessed by a cell viability assay. Confocal microscopy revealed significant proliferation of BMSCs on complex-loaded collagen scaffolds compared to empty scaffolds. In vivo studies showed significantly higher new bone volume/total volume (BV/TV) % in calvarial defects treated with the complex-activated scaffolds following 4 weeks of implantation (14- and 44-fold higher) when compared to empty defects or empty scaffolds, respectively. Together, these findings suggest that non-viral PDGF-B gene-activated scaffolds are effective for bone regeneration and are an attractive gene delivery system with significant potential for clinical translation. PMID- 24161168 TI - Differentiation of neuronal stem cells into motor neurons using electrospun poly L-lactic acid/gelatin scaffold. AB - Neural stem cells (NSCs) provide promising therapeutic potential for cell replacement therapy in spinal cord injury (SCI). However, high increases of cell viability and poor control of cell differentiation remain major obstacles. In this study, we have developed a non-woven material made of co-electrospun fibers of poly L-lactic acid and gelatin with a degradation rate and mechanical properties similar to peripheral nerve tissue and investigated their effect on cell survival and differentiation into motor neuronal lineages through the controlled release of retinoic acid (RA) and purmorphamine. Engineered Neural Stem-Like Cells (NSLCs) seeded on these fibers, with and without the instructive cues, differentiated into beta-III-tubulin, HB-9, Islet-1, and choactase-positive motor neurons by immunostaining, in response to the release of the biomolecules. In addition, the bioactive material not only enhanced the differentiation into motor neuronal lineages but also promoted neurite outgrowth. This study elucidated that a combination of electrospun fiber scaffolds, neural stem cells, and controlled delivery of instructive cues could lead to the development of a better strategy for peripheral nerve injury repair. PMID- 24161169 TI - The difficult case of voluntariness as autonomy in anti-love biotechnology. PMID- 24161171 TI - Anti-love biotechnologies: integrating considerations of the social. PMID- 24161170 TI - If I could just stop loving you: anti-love biotechnology and the ethics of a chemical breakup. AB - "Love hurts"-as the saying goes-and a certain amount of pain and difficulty in intimate relationships is unavoidable. Sometimes it may even be beneficial, since adversity can lead to personal growth, self-discovery, and a range of other components of a life well-lived. But other times, love can be downright dangerous. It may bind a spouse to her domestic abuser, draw an unscrupulous adult toward sexual involvement with a child, put someone under the insidious spell of a cult leader, and even inspire jealousy-fueled homicide. How might these perilous devotions be diminished? The ancients thought that treatments such as phlebotomy, exercise, or bloodletting could "cure" an individual of love. But modern neuroscience and emerging developments in psychopharmacology open up a range of possible interventions that might actually work. These developments raise profound moral questions about the potential uses-and misuses-of such anti love biotechnology. In this article, we describe a number of prospective love diminishing interventions, and offer a preliminary ethical framework for dealing with them responsibly should they arise. PMID- 24161173 TI - Anti-love biotechnology: was it not better to have loved and lost than never to have loved at all? PMID- 24161172 TI - The vice of in-principlism and the harmfulness of love. PMID- 24161174 TI - The heart outright: a comment on "if I could just stop loving you". PMID- 24161175 TI - Involuntary exposures to love-enhancing or anti-love agents. PMID- 24161176 TI - When love hurts children: controlling the feelings of minors. PMID- 24161177 TI - A Thomistic account of anti-love biotechnology. PMID- 24161178 TI - An error theory of biotechnology and the ethics of chemical breakups: it is the reasons, not the pharmaceuticals, that are important in defending against perilous love. PMID- 24161179 TI - Amantes sunt amentes: pathologizing love and the meaning of suffering. PMID- 24161180 TI - Anti-love or anti-"lifestyle": historical reflections on reparative therapies for homosexuality. PMID- 24161182 TI - Deception in human experimental and public health research on alcohol problems. PMID- 24161181 TI - The use of deception in public health behavioral intervention trials: a case study of three online alcohol trials. AB - Some public health behavioral intervention research studies involve deception. A methodological imperative to minimize bias can be in conflict with the ethical principle of informed consent. As a case study, we examine the specific forms of deception used in three online randomized controlled trials evaluating brief alcohol interventions. We elaborate our own decision making about the use of deception in these trials, and present our ongoing findings and uncertainties. We discuss the value of the approach of pragmatism for examining these kinds of ethical issues that can arise in research on public health interventions. PMID- 24161183 TI - Deceiving without debriefing: a pragmatic overreach? PMID- 24161184 TI - Deception by omission. PMID- 24161185 TI - Public health research, deception, and distrust. PMID- 24161186 TI - Methodological and inducement manipulation. PMID- 24161187 TI - Consenting in the dark: choose your own deception. PMID- 24161188 TI - Tangling the web: deception in online research. PMID- 24161189 TI - Nudging in context: response to open peer commentaries on "nudging and informed consent". PMID- 24161190 TI - Highly substituted enantioenriched cyclopentane derivatives by palladium catalyzed [3 + 2] trimethylenemethane cycloadditions with disubstituted nitroalkenes. AB - beta,beta-Disubstituted nitroalkenes readily undergo palladium-catalyzed [3 + 2] cycloaddition with trimethylenemethane to generate nitrocyclopentanes in excellent yield and enantioselectivity. The reaction provides access to heavily substituted cyclopentanes containing up to three contiguous stereocenters, and the products may be converted to both cyclopentylamines and cyclopentenones. A rare dependence of the sense of chirality of the cycloadducts was observed to be exclusively dependent on the structure of the palladium-bound trimethylenemethane intermediate. PMID- 24161194 TI - Cardiovascular risk and psoriasis: beyond the traditional risk factors. AB - Psoriasis is an autoimmune disease resulting in plaques of the skin. Similar to atherosclerosis, inflammation is integral to the initiation and propagation of plaque development. Mounting evidence has emerged demonstrating that psoriasis not only is associated with increased prevalence of cardiovascular risk factors, but also is an independent risk factor for the development of cardiovascular disease. Systemic therapies for moderate to severe psoriasis can increase the cardiovascular risk. Despite the evidence that psoriasis is an independent risk factor for cardiovascular disease, current guidelines only address managing traditional risk factors. An interdisciplinary approach is needed to find the necessary steps beyond classic risk reduction and detection of early cardiovascular disease in patients with psoriasis, as well as to develop a cardiovascular disease preventive regimen. PMID- 24161195 TI - A lesson from the Mockingbird: patient autonomy in Harper Lee's To Kill a Mockingbird. PMID- 24161192 TI - Modeling Alzheimer's disease in transgenic rats. AB - Alzheimer's disease (AD) is the most common form of dementia. At the diagnostic stage, the AD brain is characterized by the accumulation of extracellular amyloid plaques, intracellular neurofibrillary tangles and neuronal loss. Despite the large variety of therapeutic approaches, this condition remains incurable, since at the time of clinical diagnosis, the brain has already suffered irreversible and extensive damage. In recent years, it has become evident that AD starts decades prior to its clinical presentation. In this regard, transgenic animal models can shed much light on the mechanisms underlying this "pre-clinical" stage, enabling the identification and validation of new therapeutic targets. This paper summarizes the formidable efforts to create models mimicking the various aspects of AD pathology in the rat. Transgenic rat models offer distinctive advantages over mice. Rats are physiologically, genetically and morphologically closer to humans. More importantly, the rat has a well characterized, rich behavioral display. Consequently, rat models of AD should allow a more sophisticated and accurate assessment of the impact of pathology and novel therapeutics on cognitive outcomes. PMID- 24161196 TI - Two new compounds from Crataegus pinnatifida and their antithrombotic activities. AB - One new sesquiterpene, (1alpha,4abeta,8aalpha)-1-isopropanol-4a-methyl-8 methylenedecahydronaphthalene (1), with one new phenylpropanoid, threo-2-(4 hydroxy-3,5-dimethoxyphenyl)-3-(4-hydroxy-3-methoxyphenyl)-3-ethoxypropan-1-ol (2), along with four known phenylpropanoids were isolated from Crataegus pinnatifida. The structures of compounds 1 and 2 were elucidated on the basis of 1D, 2D NMR analyses, and HR-ESI-MS. The antithrombotic activity in vitro of all isolates was assayed, and only compound 1 exhibited potent antithrombotic activity by inhibiting platelet aggregation in rat plasma by 81.4% at 1 mg/ml. PMID- 24161197 TI - Slowing DNA translocation through a nanopore using a functionalized electrode. AB - Nanopores were fabricated with an integrated microscale Pd electrode coated with either a hydrogen-bonding or hydrophobic monolayer. Bare pores, or those coated with octanethiol, translocated single-stranded DNA with times of a few microseconds per base. Pores functionalized with 4(5)-(2-mercaptoethyl)-1H imidazole-2-carboxamide slowed average translocation times, calculated as the duration of the event divided by the number of bases translocated, to about 100 MUs per base at biases in the range of 50 to 80 mV. PMID- 24161198 TI - Health care for the "bottom of the pyramid". PMID- 24161200 TI - Perceptual complexity, rather than valence or arousal accounts for distracter induced overproductions of temporal durations. AB - For humans and other species, the ability to estimate the physical passage of time is of fundamental importance for perceptual, cognitive or motor functions. Despite this importance, any subjective estimation of temporal durations not only depends on the temporal dynamics of the to-be-timed stimulus or event, but also can be distorted by non-temporal perceptual, cognitive, and emotional effects. This study aimed to further explore critical stimulus characteristics modulating distracter-induced distortions in human time-reproduction. To this end, we investigated whether subjectively rated distracter dimensions of arousal and valence (related to levels of emotionality), or rather stimulus complexity, as a confounder, produce distortions in participants' reproduction of a previously trained target interval. Accuracy and precision of time-reproduction have been measured in distracter-trials, and compared to timing performance in baseline trials without any distraction. Results showed temporal overproductions in a magnitude of less than distracter duration only for complex distracters. Most importantly, arousal level and valence of distracters were not accountable for temporal distortions. Within an internal clock framework, our pattern of results can best be interpreted in the context of attention-, rather than arousal-based mechanisms of timing. PMID- 24161199 TI - Potential cancer-related role of circadian gene TIMELESS suggested by expression profiling and in vitro analyses. AB - BACKGROUND: The circadian clock and cell cycle are two global regulatory systems that have pervasive behavioral and physiological effects on eukaryotic cells, and both play a role in cancer development. Recent studies have indicated that the circadian and cell cycle regulator, TIMELESS, may serve as a molecular bridge between these two regulatory systems. METHODS: To assess the role of TIMELESS in tumorigenesis, we analyzed TIMELESS expression data from publically accessible online databases. A loss-of-function analysis was then performed using TIMELESS targeting siRNA oligos followed by a whole-genome expression microarray and network analysis. We further tested the effect of TIMELESS down-regulation on cell proliferation rates of a breast and cervical cancer cell line, as suggested by the results of our network analysis. RESULTS: TIMELESS was found to be frequently overexpressed in different tumor types compared to normal controls. Elevated expression of TIMELESS was significantly associated with more advanced tumor stage and poorer breast cancer prognosis. We identified a cancer-relevant network of transcripts with altered expression following TIMELESS knockdown which contained many genes with known functions in cancer development and progression. Furthermore, we observed that TIMELESS knockdown significantly decreased cell proliferation rate. CONCLUSIONS: Our results suggest a potential role for TIMELESS in tumorigenesis, which warrants further investigation of TIMELESS expression as a potential biomarker of cancer susceptibility and prognostic outcome. PMID- 24161202 TI - CpG oligodeoxynucleotides enhance chemosensitivity of 5-fluorouracil in HepG2 human hepatoma cells via downregulation of the antiapoptotic factors survivin and livin. AB - BACKGROUND: Recent studies indicated that a synthetic oligonucleotide containing un-methylated CpG oligodeoxynucleotides (CpG-ODN) has a potential function for cancer therapy. In this study, we evaluated the chemosensitizing effects of CpG ODN in 5-fluorouracil (5-FU)-treated HepG2 human hepatoma cells. METHODS: Cell viability assay were utilized to evaluate the direct cytotoxicity of CpG-ODN in the presence or absence of 5-FU in HepG2 cells, and apoptosis as well as cell cycle was examined by flow cytometry analysis. The mRNA expression of Bcl-2, Livin and Survivin within HepG2 cells treated with CpG-ODN and/or 5-FU were analyzed by Real Time PCR assay in vitro. RESULTS: CpG-ODN in combination with 5 FU could decrease cell viability, increase apoptosis and further induce HepG2 cells cycle arrest at S phase when compared with CpG-ODN or 5-FU. CpG-ODN or 5-FU could down-regulate the mRNA expression of Bcl-2 within HepG2 cells. The mRNA expression of Livin and Survivin decreased in cells treated with CpG-ODN alone but increased in cells treated with 5-FU alone. However, CpG-ODN in combination with 5-FU could down-regulate the mRNA expression of Livin and Survivin within HepG2 cells. CONCLUSIONS: Our finding demonstrated that CpG-ODN enhanced the chemosentivity of 5-FU in HepG2 human hepatoma cells at least in part by down regulating the expression of Livin and Survivin, leading to apoptosis and further inducing cell cycle arrest at S phase. Therefore, CpG-ODN may be a potential candidate as chemosensitizer for human hepatocellular carcinoma. PMID- 24161203 TI - Rest myocardial perfusion imaging: a valuable tool in ED. AB - BACKGROUND: Acute chest pain is a frequent cause of emergency department (ED) visits. Rest myocardial perfusion imaging (RMPI) during or immediately after an episode of chest pain can provide diagnostic and prognostic information concerning acute coronary syndromes. AIM: Our purpose was to evaluate the RMPI score in risk stratification of chest pain suspected to be of cardiac ischemic origin and negative troponin assessment. METHODS: Ninety-six patients without an ongoing myocardial infarction or a history of coronary artery disease and in whom RMPI was performed in the ED because of chest pain suspected to be related with acute myocardial ischemia were included. Follow-up was performed considering the occurrence of death, myocardial infarction, or revascularization in a 12-month period admission. RESULTS: Fourteen (14.6%) patients had events. According to survival analysis, the variables related with events were a history of angina (hazard ratio [HR], 4.5; P <= .01), an ischemic electrocardiogram (HR, 4.0; P <= .01), the abnormal RMPI (HR, 11.4; P <= .05), and the RMPI score (HR, 1.1; P <= .0001). When the variables of interest were forced into a multivariate model, the chi(2) associated with the model that includes clinical and electrocardiogram information was 16.3 (P <= .005) and in the model that also includes RMPI score, it was 23.0 (P <= .0005). CONCLUSION: In a low- to intermediate-risk group of patients with suspected acute myocardial ischemia, RMPI gives not only diagnostic information but adds prognostic value to the traditional ED risk stratification tools. PMID- 24161204 TI - Takotsubo cardiomyopathy and torsade de pointes in myasthenic crisis: be aware of QT prolongation. PMID- 24161205 TI - A novel de novo mutation of the mitochondrial tRNAlys gene mt.8340G>a associated with pure myopathy. AB - Most patients with mutations in the tRNA(lys) gene (MTTK) present with symptoms from the central nervous system (CNS). We describe a 41-year-old woman with pure myopathy associated with a novel de novo mtDNA mutation, mt.8340G>A, which was heteroplasmic in muscle (53%), blood, urine and mouth epithelial cells (<7%). No other family members, including her mother, carried the mutation. She presented with exercise intolerance from age 9, and since age 20 she experienced ptosis and reduced ocular motility. A muscle biopsy revealed ragged red fibres (10%), no COX negative fibres, and many fibres with central nuclei (30%), indicating ongoing damage and repair. The present case expands the mutational and phenotypic spectrum of diseases associated with mutations in MTTK. PMID- 24161206 TI - Assembly of a key dienic intermediate for tetrodotoxin via a Machetti-DeSarlo reaction. AB - A route to a racemic diene intermediate for the synthesis of tetrodotoxin is described. Key steps of the sequence leading to such a compound include the oxidative amidation of a phenol, a Cu(II)-catalyzed cyclocondensation of a nitroketone with an olefin (Machetti-DeSarlo reaction), and a nucleophilic fragmentation of the resulting isoxazoline. Several unusual reactions encountered in the course of this study are thoroughly discussed. PMID- 24161207 TI - Formation of dihydronaphthalenes via organocatalytic enatioselective Michael aldol cascade reactions with arylalkanes. AB - An organocatalytic highly enantioselective Michael-aldol cascade access to valuable chiral dihydronaphthalenes has been realized. Notably, the strategy via activation of nucleophilic alkyl chains by introducing nitro, chloro, or CF3 group(s) at the ortho- and/or para-position(s) on an aromatic ring renders them readily deprotonated to produce highly reactive nulecophilic species in the cascade process under mild conditions. PMID- 24161209 TI - Plasma exchange and ribavirin for rapidly progressive severe fever with thrombocytopenia syndrome. AB - Severe fever with thrombocytopenia syndrome (SFTS) is an emerging tick-borne disease caused by a novel bunyavirus. Although the increasing numbers of cases and deaths is of great concern, an effective treatment strategy for SFTS has not been established. We present the cases of two patients with rapidly progressing SFTS who were successfully treated with plasma exchange and ribavirin. PMID- 24161208 TI - Multiphasic and multifocal cryptococcal immune reconstitution inflammatory syndrome in an HIV-infected patient: interplay of infection and immunity. AB - We report a case of cryptococcal immune reconstitution inflammatory syndrome affecting the lungs, and 10 months later the cervical lymph nodes, in the absence of cryptococcal meningitis, in advanced HIV infection. Our report demonstrates the organ-specificity of the timing of the inflammatory response and illustrates the organ-specific interplay of immunity and infection in cryptococcal disease. PMID- 24161210 TI - Low-density lipoprotein as a biomarker for the mobilization of hematopoietic stem cells in peripheral blood. AB - The predictor of hematopoietic stem cells (HSCs) mobilized in peripheral blood (PB) remains unknown. We retrospectively examined the relationship between serum cholesterol level and CD34-positive cells mobilized with granulocyte stimulating factor in PB. PB- mobilized CD34-positive cells were significantly higher in patients with high titers of total cholesterol and low-density lipoprotein cholesterol (LDL-C) than in patients with normal levels (average total cholesterol, 122.94 vs. 51.03/MUL, p<0.05; average LDL-C 130.07 vs. 53.77, p<0.05). Multivariable analysis showed that LDL-C significantly influenced PB mobilized CD34-positive cells, suggesting that LDL-C may be an effective biomarker for mobilization of HSCs in PB. PMID- 24161211 TI - Alleviating the reference standard dilemma using a systematic exact mass suspect screening approach with liquid chromatography-high resolution mass spectrometry. AB - In this study, the efficiency of a suspect screening strategy using liquid chromatography-high resolution mass spectrometry (LC-HRMS) without the prior purchase of reference standards was systematically optimized and evaluated for assessing the exposure of rarely investigated pesticides and their transformation products (TPs) in 76 surface water samples. Water-soluble and readily ionizable (electrospray ionization) substances, 185 in total, were selected from a list of all insecticides and fungicides registered in Switzerland and their major TPs. Initially, a solid phase extraction-LC-HRMS method was established using 45 known, persistent, and high sales volume pesticides. Seventy percent of these target substances had limit of quantitation (LOQ) < 5 ng L(-1). This compound set was then used to develop and optimize a HRMS suspect screening method using only the exact mass as a priori information. Thresholds for blank subtraction, peak area, peak shape, signal-to-noise, and isotopic pattern were applied to automatically filter the initially picked peaks. The success rate was 70%; false negatives mainly resulted from low intense peaks. The optimized approach was applied to the remaining 140 substances. Nineteen additional substances were detected in environmental samples, two TPs for the first time in the environment. Sixteen substances were confirmed with reference standards purchased subsequently, while three TP standards could be obtained from industry or other laboratories. Overall, this screening approach was fast and very successful and can easily be expanded to other micropollutant classes for which reference standards are not readily accessible such as TPs of household chemicals. PMID- 24161213 TI - Various three-dimensional structures connected by Al-O/OH/acetate-Al bonds. AB - In the present work, significantly various structures connected by Al O/OH/acetate-Al bonds were synthesized in a versatile sol-gel route. The various bond systems result in several three-dimensional (e.g., fibrous, highly porous, and compact) macrostructures. The shared acetate and OH ions provide the fibrous character; the shared OH ions and oxygen-bridges between octahedral Al(III) ions assist in the formation of a porous network; and the oxygen-bridges between differently (octa-, tetra-, and pentahedrally) coordinated Al(III) ions characterize the compact structures. The newly developed synthesis route is a fast and low-energy consumption sol-gel technique. This method applies only two starting materials and does not adopt any basic agent or catalyst. The synthesis is fast because it does not require any time-consuming peptization; a 3-D network forms directly from the initial solution. The low energy consumption arises from the low temperature of reactions (80 degrees C) and heat treatment (400-600 degrees C). PMID- 24161212 TI - In vitro reconstitution and analysis of the 6-deoxyerythronolide B synthase. AB - Notwithstanding an extensive literature on assembly line polyketide synthases such as the 6-deoxyerythronolide B synthase (DEBS), a complete naturally occurring synthase has never been reconstituted in vitro from purified protein components. Here, we describe the fully reconstituted DEBS and quantitatively characterize some of the properties of the assembled system that have never been explored previously. The maximum turnover rate of the complete hexamodular system is 1.1 min(-1), comparable to the turnover rate of a truncated trimodular derivative (2.5 min(-1)) but slower than that of a bimodular derivative (21 min( 1)). In the presence of similar concentrations of methylmalonyl- and ethylmalonyl CoA substrates, DEBS synthesizes multiple regiospecifically modified analogues, one of which we have analyzed in detail. Our studies lay the foundation for biochemically interrogating and rationally engineering polyketide assembly lines in an unprecedented manner. PMID- 24161215 TI - Naming fluency in dyslexic and nondyslexic readers: differential effects of visual crowding in foveal, parafoveal, and peripheral vision. AB - Reading fluency is often indexed by performance on rapid automatized naming (RAN) tasks, which are known to reflect speed of access to lexical codes. We used eye tracking to investigate visual influences on naming fluency. Specifically, we examined how visual crowding affects fluency in a RAN-letters task on an item-by item basis, by systematically manipulating the interletter spacing of items, such that upcoming letters in the array were viewed in the fovea, parafovea, or periphery relative to a given fixated letter. All lexical information was kept constant. Nondyslexic readers' gaze durations were longer in foveal than in parafoveal and peripheral trials, indicating that visual crowding slows processing even for fluent readers. Dyslexics' gaze durations were longer in foveal and parafoveal trials than in peripheral trials. Our results suggest that for dyslexic readers, influences of crowding on naming speed extend to a broader visual span (to parafoveal vision) than that for nondyslexic readers, but do not extend as far as peripheral vision. The findings extend previous research by elucidating the different visual spans within which crowding operates for dyslexic and nondyslexic readers in an online fluency task. PMID- 24161214 TI - IGF-I increases markers of osteoblastic activity and reduces bone resorption via osteoprotegerin and RANK-ligand. AB - BACKGROUND: Bone is one of the major target tissues for Insulin-like Growth Factor I (IGF-I). Low doses of IGF-I were able to improve liver-associated osteopenia. In the present work, a model of partial IGF-I deficiency was used in order to provide insight into the mechanisms of the beneficial actions of IGF-I replacement therapy in bone. METHODS: Several proteins involved in osteoblastic/osteocyte and osteoclastic differentiation and activity were studied in the three experimental groups: control (CO) group (wild type mice, Igf+/+, n=10), heterozygous Igf+/- group with partial IGF-I deficiency (Hz, n=10), and heterozygous Igf+/- mice treated with IGF-I for 10 days (Hz+IGF-I, n=10). RESULTS: Data in this paper confirm that the simple partial IGF-I deficiency is responsible for osteopenia, determined by densitometry and histopathology. These findings are associated with a reduced gene expression of osteoprotegerin, sclerostin, calcitonin receptor (CTR), insulin-like growth factor binding protein 5 and RUNX2. IGF-I replacement therapy normalized CTR gene expression and reduced markers of osteoclastic activity. CONCLUSIONS: Low doses of IGF-I constituted a real replacement therapy that normalized IGF-I serum levels improving the expression of most of these proteins closely involved in bone-forming, and reducing bone resorption by mechanisms related to osteoprotegerin, RANKL and PTH receptor. PMID- 24161216 TI - An optimisation-based model for full-body upright reaching movements. AB - An optimal simulation 3D model for full-body upright reaching movements was developed using graphic-based modelling tools (SimMechanics) to generate an inverse dynamics model of the skeleton and using parameterisation methods for a sensory motor controller. The adaptive weight coefficient of the cost function based on the final motor task error (i.e. distance between end-effector and target at the end of movement) was used to correct motor task error and physiological measurements (e.g. joint power, centre of mass displacement, etc.). The output of the simulation models using various cost functions were compared to experimental data from 15 healthy participants performing full-body upright reaching movements. The proposed method can reasonably predict full-body voluntary movements in terms of final posture, joint power, and movement of the centre of mass (COM) using simple algebraic calculations of inverse dynamics and forward kinematics instead of the complicated integrals of the forward dynamics. We found that the combination of several control strategies, i.e. minimising end effector error, total joint power and body COM produced the best fit of the full body reaching task. PMID- 24161217 TI - Evidence for extraplacental sources of circulating angiogenic growth effectors in human pregnancy. AB - Pregnancy complications such as preeclampsia (PE) and intrauterine growth restriction (IUGR) are associated with reduced blood flow, contributing to placental and fetal hypoxia. Placental hypoxia is thought to cause altered production of angiogenic growth effectors (AGEs), reflected in the circulation of mother and fetus. Vascular endothelial growth factor (VEGF), placental growth factor (PlGF) and their soluble binding protein (sFlt-1) are, in turn, postulated as being causally involved in PE via induction of systemic endothelial cell dysfunction. To dissect the role of AGEs, accurate measurement is of great importance. However, the values of AGEs are highly variable, contributing to heterogeneity in their association (or lack thereof) with preeclampsia. To test the hypothesis that variability may be due to peripheral cell release of AGEs we obtained blood samples from normal healthy pregnant women (n = 90) and the cord blood of a subset of their neonates using standard serum separation and compared results obtained in parallel samples collected into reagents designed to inhibit peripheral cell activation (sodium citrate, theophylline, adenosine and dipyridamole-CTAD). AGEs were measured by ELISA. CTAD collection reduced maternal and fetal free VEGF by 83%, and 98%, respectively. Free PlGF was decreased by 29%, maternal sFlt-1 by >20% and fetal sFlt-1 by 59% in the CTAD-treated vs. serum sample (p < 0.0001). In summary blood collection techniques can profoundly alter measured concentrations of AGEs in mother and fetus. This process is highly variable, contributes to variation reported in the literature, and renders questionable the true impact of alteration in AGEs on pregnancy pathologies. PMID- 24161218 TI - Feeding dysfunction in children with single ventricle following staged palliation. AB - OBJECTIVE: To determine the prevalence of feeding dysfunction in children with single ventricle defects and identify associated risk factors. STUDY DESIGN: Patients aged 2-6 years with single ventricle physiology presenting for routine cardiology follow-up at the Children's Hospital of Wisconsin were prospectively identified. Parents of the patients completed 2 validated instruments for assessment of feeding dysfunction. Chart review was performed to retrospectively obtain demographic and diagnostic data. RESULTS: Instruments were completed for 56 patients; median age was 39 months. Overall, 28 (50%) patients had some form of feeding dysfunction. Compared with a normal reference population, patients with single ventricle had statistically significant differences in dysfunctional food manipulation (P < .001), mealtime aggression (P = .002), choking/gagging/vomiting (P < .001), resistance to eating (P < .001), and parental aversion to mealtime (P < .001). Weight and height for age z-scores were significantly lower in subjects with feeding dysfunction (-0.84 vs -0.33; P < .05 and -1.46 vs -0.56; P = .001, respectively). Multivariable analysis identified current gastrostomy tube use (P = .02) and a single parent household (P = .01) as risk factors for feeding dysfunction. CONCLUSION: Feeding dysfunction is common in children with single ventricle defects, occurring in 50% of our cohort. Feeding dysfunction is associated with worse growth measures. Current gastrostomy tube use and a single parent household were identified as independent risk factors for feeding dysfunction. PMID- 24161219 TI - Reply: To PMID 23415615. PMID- 24161220 TI - Volumetric capnography in infants with bronchopulmonary dysplasia. AB - OBJECTIVES: To assess the feasibility of using volumetric capnography in spontaneously breathing small infants and its ability to discriminate between infants with and without bronchopulmonary dysplasia (BPD). STUDY DESIGN: Lung function variables for 231 infants (102 term, 52 healthy preterm, 77 BPD), matched for post-conceptional age of 44 weeks, were collected. BPD was defined as supplemental oxygen requirement at 36 weeks post-menstrual age. Tidal breath-by breath volume capnograms were obtained by mainstream capnography. The capnographic slope of phase II (SII) and slope of phase III (SIII) were calculated and compared between study groups. The effect of BPD, tidal volume (VT), respiratory rate (RR), and prematurity on the magnitude of the slopes was assessed. RESULTS: SII was steeper in infants with BPD (100 +/- 28/L) compared with healthy preterm (88 +/- 22/L; P = .007) and term infants (79 +/- 18/L; P < .001), but this finding was attributed to differences in VT, RR, and gestational age. SIII was steeper in the BPD group (26.8 +/- 14.1/L) compared with healthy preterm (16.2 +/- 6.2/L; P < .001) and term controls (14.8 +/- 5.4/L; P < .001). BPD was a significant predictor of SIII independently of VT, RR, and gestational age. The ability of SIII to discriminate between BPD and controls was significantly higher compared with lung clearance index (area under the curve 0.83 vs 0.56; P < .001). CONCLUSIONS: Volumetric capnography may provide valuable information regarding functional lung alterations related to BPD and might be considered as an alternative to more involved lung function techniques for monitoring chronic lung disease during early infancy. PMID- 24161221 TI - Motor outcomes in children exposed to early psychosocial deprivation. AB - OBJECTIVES: To determine the effect of psychosocial deprivation early in life on motor development, assess the impact of a foster care intervention on improving motor development, and assess the association between motor and cognitive outcomes in children with a history of institutional care. STUDY DESIGN: In a randomized controlled trial, children living in Romanian institutions were randomly assigned to care as usual in the institution or placed in family centered foster care as part of the Bucharest Early Intervention Project. The average age at placement into foster care was 23 months. At age 8 years, the Bruininks-Oseretsky Test of Motor Proficiency, Second Edition, Short Form (BOT2 SF) was applied to assess the motor proficiency of children in both groups, as well as a never-institutionalized group from the Romanian community. RESULTS: Children in the never-institutionalized group did significantly better on the BOT2-SF than children who had ever been institutionalized (P < .001). There was no significant difference in performance between children in the care as usual group and the foster care group. This finding also held true for all individual items on the BOT2-SF except sit-ups. Regression analyses revealed that the between-group and within-group differences in BOT2-SF scores were largely mediated by IQ. CONCLUSION: Early deprivation had a negative effect on motor development that was not resolved by placement in foster care. This effect was predominantly mediated by IQ. This study highlights the importance of monitoring for and addressing motor delays in children with a history of institutionalization, particularly those children with low IQ. PMID- 24161222 TI - Prevalence and neonatal factors associated with autism spectrum disorders in preterm infants. AB - OBJECTIVES: To determine the prevalence of autism spectrum disorders (ASD) across gestational age, examine the risk of ASD by gestational age controlling for other risk factors, and identify potential risk factors in the neonatal intensive care unit. STUDY DESIGN: A retrospective cohort of infants born at >= 24 weeks between January 1, 2000, and December 31, 2007 at 11 Kaiser Permanente Northern California hospitals (n = 195,021). ASD cases were defined by a diagnosis made at a Kaiser Permanente ASD evaluation center, by a clinical specialist, or by a pediatrician. Cox proportional hazards regression models were used to evaluate the association between gestational age and ASD as well as potential risk factors in the neonatal intensive care unit and ASD. RESULTS: The prevalence of ASD in infants <37 weeks was 1.78% compared with 1.22% in infants born >= 37 weeks (P < .001). Compared with term infants, infants born at 24-26 weeks had an adjusted hazard ratio (HR) for a diagnosis of ASD of 2.7 (95% CI 1.5-5.0). Infants born at 27-33 weeks (adjusted HR 1.4, 95% CI 1.1-1.8) and 34-36 weeks (adjusted HR 1.3, 95% CI 1.1-1.4) were also at increased risk. High frequency ventilation and intracranial hemorrhage were associated with ASD in infants < 34 weeks. CONCLUSIONS: ASD was ~ 3 times more prevalent in infants <27 weeks compared with term infants. Each week of shorter gestation was associated with an increased risk of ASD. High frequency ventilation and intracranial hemorrhage were associated with ASD among infants <34 weeks. PMID- 24161224 TI - Effects of non-equilibrium association-dissociation processes in the dynamic electrophoretic mobility and dielectric response of realistic salt-free concentrated suspensions. AB - Electrokinetic investigations in nanoparticle suspensions in aqueous media are most often performed assuming that the liquid medium is a strong electrolyte solution with specified concentration. The role of the ions produced by the process of charging the surfaces of the particles is often neglected or, at most, the concentrations of such ions are estimated in some way and added to the concentrations of the ions in the externally prepared solution. The situation here considered is quite different: no electrolyte is dissolved in the medium, and ideally only the counterions stemming from the particle charging are assumed to be in solution. This is the case of so-called salt-free systems. With the aim of making a model for such kind of dispersions as close to real situations as possible, it was previously found to consider the unavoidable presence of H(+) and OH(-) coming from water dissociation, as well as the (almost unavoidable) ions stemming from the dissolution of atmospheric CO2. In this work, we extend such approach by considering that the chemical reactions involved in dissociation and recombination of the (weak) electrolytes in solution must not necessarily be in equilibrium conditions (equal rates of forward and backward reactions). To that aim, we calculate the frequency spectra of the electric permittivity and dynamic electrophoretic mobility of salt-free suspensions considering realistic non-equilibrium conditions, using literature values for the rate constants of the reactions. Four species are linked by such reactions, namely H(+) (from water, from the--assumed acidic--groups on the particle surfaces, and from CO2 dissolution), OH(-) (from water), HCO3(-) and H2CO3 (again from CO2). A cell model is used for the calculations, which are extended to arbitrary values of the surface charge, the particle size, and particle volume fraction, in a wide range of the field frequency omega. Both approaches predict a high frequency relaxation of the counterion condensated layer and a Maxwell-Wagner-O'Konski electric double layer relaxation at intermediate frequencies. Also, in both cases an inertial decay of the electrophoretic mobility at high omega takes place. The most significant difference between the present model and previous results based on the equilibrium hypothesis is by no means negligible: only in non-equilibrium conditions do we find a low-frequency relaxation (mostly noticed in permittivity data, while its significance is lower in dynamic mobility spectra). This new relaxation presents all the characteristic features of the concentration polarization (or alpha) dispersion. These are: i) the average electric polarization of the system increases when the relaxation frequency is surpassed, contrary to the behavior after Maxwell-Wagner type relaxations; ii) the amplitude of the relaxation increases with surface charge, reaching a sort of saturation if the charge is too high; iii) the relaxation frequency increases with volume fraction while the relaxation amplitude decreases; iv) the characteristic frequency is reduced by the increase in particle radius. All these facts confirm that the non-equilibrium approach seems to better describe the physics of the system by giving rise to a concentration polarization kind of relaxation, only possible when ions can accumulate on both sides of the particles as dictated by the field, and not as determined by equilibrium conditions in the dissociation recombination reactions involved. PMID- 24161225 TI - Emulsions with unique properties from proteins as emulsifiers. AB - Many proteins are surface active molecules and form stable emulsions. In these emulsions, the protein covered oil droplets behave as sticky droplets even when they are ionically charged. As a result of the stickiness of the droplets the emulsions have gel-like properties. The stickiness is due to the multipolar nature of the proteins in contrast to the bipolar nature of surfactants or other amphiphilic compounds that form emulsions with repulsive droplets. Stable emulsions are also formed from particles like clays to which proteins are adsorbed. These hybrid compounds form even more stable emulsions with stronger elastic properties than clays and proteins on their own. These so called pickering emulsions have paste-like properties and do not flow. The scaffolding network of the crosslinked protein bilayers on the droplets is so strong that both the water and the oil can be removed from the emulsions by freeze drying without collapse of the scaffold. The resulting sponge can be used again for the uptake of both water and oil. Emulsions which are prepared from different proteins differ mainly in their elastic properties. PMID- 24161223 TI - Electrographic seizures after convulsive status epilepticus in children and young adults: a retrospective multicenter study. AB - OBJECTIVE: To describe the prevalence, characteristics, and predictors of electrographic seizures after convulsive status epilepticus (CSE). STUDY DESIGN: This was a multicenter retrospective study in which we describe clinical and electroencephalographic (EEG) features of children (1 month to 21 years) with CSE who underwent continuous EEG monitoring. RESULTS: Ninety-eight children (53 males) with CSE (median age of 5 years) underwent subsequent continuous EEG monitoring after CSE. Electrographic seizures (with or without clinical correlate) were identified in 32 subjects (33%). Eleven subjects (34.4%) had electrographic-only seizures, 17 subjects (53.1%) had electroclinical seizures, and 4 subjects (12.5%) had an unknown clinical correlate. Of the 32 subjects with electrographic seizures, 15 subjects (46.9%) had electrographic status epilepticus. Factors associated with the occurrence of electrographic seizures after CSE were a previous diagnosis of epilepsy (P = .029) and the presence of interictal epileptiform discharges (P < .0005). The median (p25-p75) duration of stay in the pediatric intensive care unit was longer for children with electrographic seizures than for children without electrographic seizures (9.5 [3 22.5] vs 2 [2-5] days, Wilcoxon test, Z = 3.916, P = .0001). Four children (4.1%) died before leaving the hospital, and we could not identify a relationship between death and the presence or absence of electrographic seizures. CONCLUSIONS: After CSE, one-third of children who underwent EEG monitoring experienced electrographic seizures, and among these, one-third experienced entirely electrographic-only seizures. A previous diagnosis of epilepsy and the presence of interictal epileptiform discharges were risk factors for electrographic seizures. PMID- 24161226 TI - Streptococcal necrotizing myositis: a case report and clinical review. AB - BACKGROUND: Streptococcal necrotizing myositis, also known as gangrenous myositis, is a very rare and severe soft tissue infection that predominately involves skeletal muscle and, eventually, superficial fascia and surrounding tissues. The presentation is often nonspecific until the rapidly progressing clinical course becomes apparent. A high morbidity and mortality rate has been reported in the small number of cases since 1900. Despite several attempts to better define the different entities causing necrotizing myositis, no single definitive causal relationship has been defined. OBJECTIVES: A review of the literature is presented here to help clinicians distinguish those with necrotizing myositis from those with nonnecrotizing myositis when the clinician is at all confronted with the suspicion for such an infection. CASE REPORT: The case presented is that of a 48-year-old woman who had streptococcal necrotizing myositis. She died roughly 72 h after admission. After the patient's death, the clinical team sought consent for autopsy. Hospital staff made contact with family, and information was obtained from the family that the onset of the patient's symptoms was allegedly temporally related to her acquisition of a new tattoo on the right back, where the tattoo process allegedly included injection of cremated ashes of a pet dog. CONCLUSION: A high level of suspicion for necrotizing myositis must be maintained for a patient with unexplained severe muscle pain and soft tissue swelling accompanied by systemic inflammatory response syndrome. PMID- 24161227 TI - Intratympanic hemorrhage and concussion in a football offensive lineman. AB - BACKGROUND: A 26-year-old arena football lineman participating in a "bull in the ring" blocking and tackling drill was blindsided by an opposing teammate. He sustained a direct helmet-to-helmet blow to the right temporal area. OBJECTIVES: This case describes a unique mechanism of ear barotrauma (intratympanic hemorrhage) and concussion caused by helmet-to-helmet contact in American football. CASE REPORT: Initial sideline evaluation revealed mild headache, confusion, dizziness, photophobia, and tinnitus, all consistent with a concussion diagnosis. Physical examination revealed a large postauricular contusion over the right mastoid process and diffuse right intratympanic hemorrhage on examination. No hemotympanum or effusion of the middle ear was noted. Abnormalities were seen on vestibular testing and visual accommodation and convergence testing. Computed tomography and magnetic resonance imaging were performed with attention to the temporal bones and were normal. Neuropsychological testing was abnormal compared to baseline. Audiology testing was within normal limits. Diagnosis was intratympanic hemorrhage secondary to barotrauma caused by helmet-to-helmet contact, with mastoid contusion and season-ending concussion. CONCLUSIONS: The tympanic membrane (TM) is a highly vascular membrane that is very sensitive to variations of atmospheric pressure. Overpressure can enter the external auditory canal, stretching and displacing the TM medially and causing injury to the tympanic membrane secondary to barotrauma. This concussed football player was never able to return to play due to his postconcussive symptoms. He had no residual hearing or ear problems. PMID- 24161228 TI - Faculty prediction of in-training examination scores of emergency medicine residents. AB - BACKGROUND: The Emergency Medicine In-Training Examination (EMITE) is one of the only valid tools for medical knowledge assessment in current use by emergency medicine (EM) residencies. However, EMITE results return late in the academic year, providing little time to institute potential remediation. OBJECTIVE: The goal of this study was to determine the ability of EM faculty to accurately predict resident EMITE scores prior to results return. METHODS: We asked EM faculty at the study site to predict the 2012 EMITE scores of the 50 EM residents 2 weeks prior to results being available. The primary outcome was prediction accuracy, defined as the proportion of predictions within 6% of the actual score. The secondary outcome was prediction precision, defined as the mean deviation of predictions from the actual scores. We assessed several faculty background variables, including years of experience, educational leadership status, and clinical hours worked, for correlation with the two outcomes. RESULTS: Thirty-two of the 38 faculty (84.2%, 95% confidence interval [CI] 69.6-92.6) participated in the study, rendering a total of 1600 predictions for 50 residents. Mean resident EMITE score was 81.1% (95% CI 79.5-82.8%). Mean prediction accuracy for all faculty participants was 69% (95% CI 65.9-72.1%). Mean prediction precision was 5.2% (95% CI 4.9-5.5%). Education leadership status was the only background variable correlated with the primary and secondary outcomes (Spearman's rho = 0.51 and -0.53, respectively). CONCLUSION: Faculty possess only moderate accuracy at predicting resident EMITE scores. We recommend a multicenter study to evaluate the generalizability of the present results. PMID- 24161230 TI - Letter to the Editor. PMID- 24161229 TI - Perceptions of basic, advanced, and pediatric life support training in a United States medical school. AB - BACKGROUND: Basic Life Support (BLS), Advanced Cardiac Life Support (ACLS), and Pediatric Advanced Life Support (PALS) are integral parts of emergency resuscitative care. Although this training is usually reserved for residents, introducing the training in the medical student curriculum may enhance acquisition and retention of these skills. OBJECTIVES: We developed a survey to characterize the perceptions and needs of graduating medical students regarding BLS, ACLS, and PALS training. METHODS: This was a study of graduating 4th-year medical students at a U.S. medical school. The students were surveyed prior to participating in an ACLS course in March of their final year. RESULTS: Of 152 students, 109 (71.7%) completed the survey; 48.6% of students entered medical school without any prior training and 47.7% started clinics without training; 83.4% of students reported witnessing an average of 3.0 in-hospital cardiac arrests during training (range of 0-20). Overall, students rated their preparedness 2.0 (SD 1.0) for adult resuscitations and 1.7 (SD 0.9) for pediatric resuscitations on a 1-5 Likert scale, with 1 being unprepared. A total of 36.8% of students avoided participating in resuscitations due to lack of training; 98.2%, 91.7%, and 64.2% of students believe that BLS, ACLS, and PALS, respectively, should be included in the medical student curriculum. CONCLUSIONS: As per previous studies that have examined this topic, students feel unprepared to respond to cardiac arrests and resuscitations. They feel that training is needed in their curriculum and would possibly enhance perceived comfort levels and willingness to participate in resuscitations. PMID- 24161231 TI - Prevalence of oppositional defiant disorder in Spain. AB - INTRODUCTION: Oppositional defiant disorder (ODD) is characterized by a pattern of negative, defiant, disobedient and hostile behavior toward authority figures. ODD is one of the most frequent reasons for clinical consultation on mental health during childhood and adolescence. ODD has a high morbidity and dysfunction, and has important implications for the future if not treated early. OBJECTIVE: To determine the prevalence of ODD in schoolchildren aged 6-16 years in Castile and Leon (Spain). MATERIAL AND METHODS: Population study with a stratified multistage sample, and a proportional cluster design. Sample analyzed: 1,049. Cases were defined according to DSM-IV criteria. RESULTS: An overall prevalence rate of 5.6% was found (95% CI: 4.2%-7%). Male gender prevalence=6.8%; female=4.3%. Prevalence in secondary education=6.2%; primary education=5.3%. No significant differences by gender, age, grade, type of school, or demographic area were found. ODD prevalence without considering functional impairment, such as is performed in some research, would increase the prevalence to 7.4%. ODD cases have significantly worse academic outcomes (overall academic performance, reading, maths and writing), and worse classroom behavior (relationship with peers, respect for rules, organizational skills, academic tasks, and disruption of the class). CONCLUSIONS: Castile and Leon has a prevalence rate of ODD slightly higher to that observed in international publications. Depending on the distribution by age, morbidity and clinical dysfunctional impact, an early diagnosis and a preventive intervention are required for health planning. PMID- 24161232 TI - Antimicrobial resistance in intensive care units. PMID- 24161233 TI - Interventions to reduce colonisation and transmission of antimicrobial-resistant bacteria in intensive care units: an interrupted time series study and cluster randomised trial. AB - BACKGROUND: Intensive care units (ICUs) are high-risk areas for transmission of antimicrobial-resistant bacteria, but no controlled study has tested the effect of rapid screening and isolation of carriers on transmission in settings with best-standard precautions. We assessed interventions to reduce colonisation and transmission of antimicrobial-resistant bacteria in European ICUs. METHODS: We did this study in three phases at 13 ICUs. After a 6 month baseline period (phase 1), we did an interrupted time series study of universal chlorhexidine body washing combined with hand hygiene improvement for 6 months (phase 2), followed by a 12-15 month cluster randomised trial (phase 3). ICUs were randomly assigned by computer generated randomisation schedule to either conventional screening (chromogenic screening for meticillin-resistant Staphylococcus aureus [MRSA] and vancomycin-resistant enterococci [VRE]) or rapid screening (PCR testing for MRSA and VRE and chromogenic screening for highly resistant Enterobacteriaceae [HRE]); with contact precautions for identified carriers. The primary outcome was acquisition of resistant bacteria per 100 patient-days at risk, for which we calculated step changes and changes in trends after the introduction of each intervention. We assessed acquisition by microbiological surveillance and analysed it with a multilevel Poisson segmented regression model. We compared screening groups with a likelihood ratio test that combined step changes and changes to trend. This study is registered with ClinicalTrials.gov, number NCT00976638. FINDINGS: Seven ICUs were assigned to rapid screening and six to conventional screening. Mean hand hygiene compliance improved from 52% in phase 1 to 69% in phase 2, and 77% in phase 3. Median proportions of patients receiving chlorhexidine body-washing increased from 0% to 100% at the start of phase 2. For trends in acquisition of antimicrobial-resistant bacteria, weekly incidence rate ratio (IRR) was 0.976 (0.954-0.999) for phase 2 and 1.015 (0.998-1.032) for phase 3. For step changes, weekly IRR was 0.955 (0.676-1.348) for phase 2 and 0.634 (0.349-1.153) for phase 3. The decrease in trend in phase 2 was largely caused by changes in acquisition of MRSA (weekly IRR 0.925, 95% CI 0.890-0.962). Acquisition was lower in the conventional screening group than in the rapid screening group, but did not differ significantly (p=0.06). INTERPRETATION: Improved hand hygiene plus unit-wide chlorhexidine body-washing reduced acquisition of antimicrobial-resistant bacteria, particularly MRSA. In the context of a sustained high level of compliance to hand hygiene and chlorhexidine bathings, screening and isolation of carriers do not reduce acquisition rates of multidrug-resistant bacteria, whether or not screening is done with rapid testing or conventional testing. FUNDING: European Commission. PMID- 24161237 TI - Physical activity before and during pregnancy and risk of abnormal glucose tolerance among Hispanic women. AB - AIM: Women diagnosed with abnormal glucose tolerance and gestational diabetes mellitus are at increased risk for subsequent type 2 diabetes, with higher risks in Hispanic women. Studies suggest that physical activity may be associated with a reduced risk of these disorders; however, studies in Hispanic women are sparse. METHODS: We prospectively evaluated this association among 1241 Hispanic participants in Proyecto Buena Salud. The Pregnancy Physical Activity Questionnaire was used to assess pre, early, and mid pregnancy physical activity. Medical records were abstracted for pregnancy outcomes. RESULTS: A total of 175 women (14.1%) were diagnosed with abnormal glucose tolerance and 57 women (4.6%) were diagnosed with gestational diabetes. Increasing age and body mass index were strongly and positively associated with risk of gestational diabetes. We did not observe statistically significant associations between total physical activity or meeting exercise guidelines and risk. However, after adjusting for age, BMI, gestational weight gain, and other important risk factors, women in the top quartile of moderate-intensity activity in early pregnancy had a decreased risk of abnormal glucose tolerance (odds ratio=0.48, 95% Confidence Interval 0.27 0.88, Ptrend=0.03) as compared to those in the lowest quartile. Similarly, women with the highest levels of occupational activity in early pregnancy had a decreased risk of abnormal glucose tolerance (odds ratio=0.48, 95% Confidence Interval 0.28-0.85, Ptrend=0.02) as compared to women who were unemployed. CONCLUSION: In this Hispanic population, total physical activity and meeting exercise guidelines were not associated with risk. However, high levels of moderate-intensity and occupational activity were associated with risk reduction. PMID- 24161238 TI - Lethality by pneumonia and factors associated to death. AB - OBJECTIVE: To describe the case-fatality rate (CFR) and risk factors of death in children with community-acquired acute pneumonia (CAP) in a pediatric university hospital. METHOD: A longitudinal study was developed with prospective data collected from 1996 to 2011. Patients aged 1 month to 12 years were included in the study. Those who left the hospital against medical orders and those transferred to ICU or other units were excluded. Demographic and clinical etiological characteristics and the initial treatment were studied. Variables associated to death were determined by bivariate and multivariate analysis using logistic regression. RESULTS: A total of 871 patients were selected, of whom 11 were excluded; thus 860 children were included in the study. There were 26 deaths, with a CFR of 3%; in 58.7% of these, penicillin G was the initial treatment. Pneumococcus was the most common pathogen (50.4%). From 1996 to 2000, there were 24 deaths (93%), with a CFR of 5.8% (24/413). From 2001 to 2011, the age group of hospitalized patients was older (p = 0.03), and the number of deaths (p = 0.02) and the percentage of disease severity were lower (p = 0.06). Only disease severity remained associated to death in the multivariate analysis (OR = 3.2; 95%CI: 1.2-8.9; p = 0.02). CONCLUSION: When the 1996-2000 and 2001-2011 periods were compared, a significant reduction in CFR was observed in the latter, as well as a change in the clinical profile of the pediatric inpatients at the institute. These findings may be related to the improvement in the socio economical status of the population. Penicillin use did not influence CFR. PMID- 24161236 TI - A metabolomics investigation of non-genotoxic carcinogenicity in the rat. AB - Non-genotoxic carcinogens (NGCs) promote tumor growth by altering gene expression, which ultimately leads to cancer without directly causing a change in DNA sequence. As a result NGCs are not detected in mutagenesis assays. While there are proposed biomarkers of carcinogenic potential, the definitive identification of non-genotoxic carcinogens still rests with the rat and mouse long-term bioassay. Such assays are expensive and time-consuming and require a large number of animals, and their relevance to human health risk assessments is debatable. Metabolomics and lipidomics in combination with pathology and clinical chemistry were used to profile perturbations produced by 10 compounds that represented a range of rat non-genotoxic hepatocarcinogens (NGC), non-genotoxic non-hepatocarcinogens (non-NGC), and a genotoxic hepatocarcinogen. Each compound was administered at its maximum tolerated dose level for 7, 28, and 91 days to male Fisher 344 rats. Changes in liver metabolite concentration differentiated the treated groups across different time points. The most significant differences were driven by pharmacological mode of action, specifically by the peroxisome proliferator activated receptor alpha (PPAR-alpha) agonists. Despite these dominant effects, good predictions could be made when differentiating NGCs from non-NGCs. Predictive ability measured by leave one out cross validation was 87% and 77% after 28 days of dosing for NGCs and non-NGCs, respectively. Among the discriminatory metabolites we identified free fatty acids, phospholipids, and triacylglycerols, as well as precursors of eicosanoid and the products of reactive oxygen species linked to processes of inflammation, proliferation, and oxidative stress. Thus, metabolic profiling is able to identify changes due to the pharmacological mode of action of xenobiotics and contribute to early screening for non-genotoxic potential. PMID- 24161239 TI - The tensor-based model of plant growth applied to leaves of Arabidopsis thaliana: a two-dimensional computer model. AB - Plant organs grow in coordinated and continuous way. Such growth is of a tensor nature, hence there is an infinite number of different directions of growth rate in each point of the growing organ. Three mutually orthogonal directions of growth can be recognized in which growth achieves extreme values (principal directions of growth [PDGs]). Models based on the growth tensor have already been successfully applied to the root and shoot apex. This paper presents the 2D model of growth applied to the arabidopsis leaf. The model employs the growth tensor method with a non-stationary velocity field. The postulated velocity functions are confirmed by growth measurements with the aid of the replica method. PMID- 24161240 TI - Accumulation of PrLeg, a Perilla legumin protein in potato tuber results in enhanced level of sulphur-containing amino acids. AB - Potato is the fourth staple food in the world, following rice, wheat, and maize, whereas tubers contain high quality of starch, relatively high amounts of vitamin C and many other important substances. It also contains relatively good quality of protein (about 3 to 6% of the dried weight) and patatin, and 11S globulin is a major storage protein with high level of lysine. However, tuber protein contains relatively low amounts of sulphur-containing amino acids, which may result in low nutritional value. Recently, we cloned a gene encoding PrLeg polypeptide, a seed storage protein from Perilla, which contains relatively higher levels of sulphur containing amino acids. We transformed PrLeg cDNA into a potato plant to over express under the direction of the tuber-specific promoter, patatin. Most of the transgenic lines identified through PCR and RT-PCR analyses were able to accumulate high amount of prLeg transcript in their tuber tissue, while very little or no transcript that were detected in their leaf tissues. The level of methionine content was elevated up to three-fold compared to non-transgenic parental line, without any significant changes in other amino acids, suggesting that further research is required to get a deeper insight into their nutritional value. PMID- 24161241 TI - On the biology of Spiruroidea parasites of murine rodents on El Hierro (Canary Islands, Spain) with molecular characterization of Streptopharagus greenbergi Wertheim, 1993. AB - This paper reports the role of darkling beetles Pimelia laevigata costipennis and Hegeter amaroides (Tenebrionidae) as intermediate hosts of spiruroid nematodes parasites of the black rat and house mouse of El Hierro (Canary Islands). Larvae of spiruroid species were found in the two tenebrionids (18.1% in P. l. costipennis, 7.8% in H. amaroides), Streptopharagus greenbergi being predominant in both (16.1% and 7.1%, respectively), ahead of Mastophorus muris and Gongylonema type larva. The larval stages of S. greenbergi are described for the first time, and adult worms were obtained experimentally from an infected laboratory rat, allowing the identification of the species. Morphometric measurements of experimental adults match those of adults detected in naturally infected rats on the island. Molecular data for S. greenbergi, and the ITS nucleotide sequence of the genus Streptopharagus are also provided for the first time. After the isolation of S. greenbergi DNA and amplification of the ITS region, the ITS1 of this spirocercid was sequenced and deposited in the GenBank database. PMID- 24161242 TI - DNA barcoding for the identification of eight species members of the Thai Hyrcanus Group and investigation of their stenogamous behavior. AB - Eight species members of the Thai Hyrcanus Group were identified based on the intact morphology and molecular analysis (COI barcoding, 658 bp) of F1-progenies. Five iso-female lines of each species were pooled in order to establish stock colonies. A stenogamous colony of each species was investigated by making 200 and 300 newly emerged adult females and males co-habit in a 30 cm cubic cage for one week. After ovipositon, the spermathecae of females were examined for sperms. The results revealed that Anopheles argyropus, Anopheles crawfordi, Anopheles nitidus, Anopheles pursati, Anopheles sinensis, Anopheles nigerrimus, Anopheles paraliae and Anopheles peditaeniatus yielded insemination rates of 0%, 0%, 0%, 31%, 33%, 42%, 50% and 77%, respectively. Continuous selection to establish stenogamous colonies indicated that An. sinensis, An. pursati, An. nigerrimus, An. paraliae and An. peditaeniatus provided insemination rates of 33-34%, 27-31%, 42-58%, 43-57% and 61-86% in 1, 2, 5, 6 and 20 generations of passages, respectively. PMID- 24161243 TI - Spatial distribution of brood-bearing females of limnetic species of Cladocera. AB - In this study, the spatial distribution of brood-bearing females of five species of limnetic cladocerans (Daphnia cucullata, D. longispina, Bosmina coregoni, B. longirostris, Diaphanosoma brachyurum) in the deep mesotrophic lake in relation to the predation pressure of planktivorous fish (roach Rutilus rutilus, perch Perca fluviatilis, catfish Ictalurus nebulosus, white fish Coregonus albula, bleak Alburnus alburnus), and planktonic invertebrates (cyclopoids Mesocyclops leuckartii, Thermocyclops oithonoides, T. crassus, and cladoceran Leptodora kindtii) as well as some environmental variables was estimated. Most cladocerans showed apparent differences in horizontal distribution (ANOVA F=0.2-0.45, P<0.05) in the littoral zone and lack of such differences in the pelagic zone (F=0.07 0.13, P>0.05). Vertical distribution of most species, in turn, showed a clear pattern in the pelagic zone (F=0.31-0.39, P<0.05) and less regularities in the littoral zone (F=0.15-029, P>0.05). The differences in spatial distribution of non-predated and predated species suggest that predation pressure, but not predatory type, was an important factor structuring their distribution. Other factors that affected their distribution were conductivity, dissolved oxygen, TOC and macrophyte biomass; however, most of those variables better explained the distribution of brood-bearing cladocerans in the vertical than horizontal aspect. PMID- 24161244 TI - Contributions to the tooth morphology in early embryos of three species of hammerhead sharks (Elasmobranchii: Sphyrnidae) and their evolutionary implications. AB - The tooth types in the embryos of the hammerhead sharks Sphyrna tiburo, Sphyrna tudes and Eusphyra blochii are here described in labial and lingual views, and, in some cases, in additional views. The presence of cusplets was observed in the anterior teeth of S. tiburo and S. tudes, which is secondarily lost after early embryonic stages. Many aligned root foramina were detected in the sphyrnids, which, as the cusplets, are shared by many phylogenetic-related carcharhinids. Other anatomic features, related to the root and central cusp, are presented for the first time. Such characters represent the first step to compare the teeth of extant and fossil species. PMID- 24161245 TI - Chemical bioavailability in the terrestrial environment - recent advances. PMID- 24161247 TI - Effects of childhood trauma on personality in a sample of Chinese adolescents. AB - Childhood trauma is a major public health problem which has an impact on personality development, yet no studies have examined the association between exposure to trauma and personality in a sample of Chinese adolescents. Four hundred eighty-five students completed the Childhood Trauma Questionnaire-Short Form (CTQ-SF) and the Eysenck Personality Questionnaire (EPQ). The CTQ-SF cut-off scores for exposure were used to calculate the prevalence of trauma. The possible associations between specific types of trauma and the EPQ subscale scores were examined. The rates of emotional abuse (EA), physical abuse (PA), sexual abuse (SA), emotional neglect (EN), and physical neglect (PN) were 18.76%, 11.13%, 27.01%, 49.48%, and 68.66%, respectively. Individuals subjected to EA, PA, and SA had significantly higher neuroticism (EPQ-N) and psychoticism (EPQ-P) scores on the EPQ compared with those who had not experienced EA, PA, or SA (all p values<0.05). Significant positive correlations existed between CTQ-SF subscale scores for EA, SA, CTQ-SF total scores, and EPQ-N, EPQ-P scores (all p values<0.05). Significant number of subjects in this adolescent sample reported experience of childhood abuse and neglect. Exposure to childhood trauma is associated with personality development in Chinese adolescents. PMID- 24161248 TI - Ocular and optical coherence tomography-based corneal aberrometry in keratoconic eyes treated by intracorneal ring segments. AB - PURPOSE: To analyze corneal and total aberrations using custom-developed anterior segment spectral optical coherence tomography (OCT) and laser ray tracing in keratoconic eyes implanted with intracorneal ring segments (ICRS). DESIGN: Evaluation of technology. Prospective study. Case series. METHODS: Nineteen keratoconic eyes were measured before and after ICRS surgery. Anterior and posterior corneal topographic and pachymetric maps were obtained pre- and postoperatively from 3-dimensional OCT images of the anterior segment, following automatic image analysis and distortion correction. The pupil center coordinates were used as reference for estimation of corneal aberrations. Corneal aberrations were estimated by computational ray tracing on the anterior and posterior corneal surfaces. Total aberrations were measured using a custom-developed laser ray tracing aberrometer. Corneal and total aberrations were compared in 8 eyes pre- and postoperatively for 4-mm pupils. RESULTS: Total and corneal aberrations were highly correlated. Average root mean square of corneal and total high-order aberrations (HOAs) were 0.78 +/- 0.35 MUm and 0.57 +/- 0.39 MUm preoperatively, and 0.88 +/- 0.36 MUm and 0.53 +/- 0.24 MUm postoperatively (4-mm pupils). The anterior corneal surface aberrations were partially compensated by the posterior corneal surface aberrations (by 8.3% preoperatively and 4.1% postoperatively). Astigmatism was 2.03 +/- 1.11 MUm preoperatively and 1.60 +/- 0.94 MUm postoperatively. The dominant HOA aberrations both pre- and postoperatively were vertical coma (Z3(-1)), vertical trefoil (Z3(-3)), and secondary astigmatism (Z4(4)). ICRS decreased corneal astigmatism by 27% and corneal coma by 5%, but on average, the overall amount of HOA did not decrease significantly with ICRS treatment. CONCLUSIONS: OCT is a reproducible technique to evaluate corneal aberrations. OCT-based corneal aberrations and ocular aberrations show a high correspondence in keratoconic patients before and after ICRS implantation. ICRS produced a decrease in astigmatism, but on average did not produce a consistent decrease of HOAs. PMID- 24161249 TI - Visual impairment corrected via cataract surgery and 5-year survival in a prospective cohort. AB - PURPOSE: To compare mortality risk between cataract surgical patients with corrected and persistent visual impairment. DESIGN: Cohort study. METHODS: A total of 1864 consecutive patients, aged >=64 years, undergoing phacoemulsification surgery at Westmead Hospital were followed annually for 5 years postoperatively. Visual impairment status in the surgical eye was categorized as none (presenting visual acuity [VA], >=20/40), mild (VA <20/40 20/60), or moderate-severe (VA <20/60). All-cause mortality was obtained from the Australian National Death Index. RESULTS: Of 901 patients with moderate-severe visual impairment before surgery, 60.4% (n = 544), 15.5% (n = 140), and 24.1% (n = 217) had no, mild, or moderate-severe visual impairment in the surgical eye, respectively, 1 month postoperatively. Age-standardized 5-year mortality rates were nonsignificantly lower in patients with either mild (24.7%, 95% confidence interval [CI] 16.5%-32.9%) or no visual impairment (24.1%, 95% CI 19.9%-28.4%) post surgery compared to that in patients whose moderate-severe visual impairment persisted (30.6%, 95% CI 23.3%-37.9%). After adjusting for age, sex, smoking, body mass index, and individual comorbid conditions, such as hypertension, diabetes, angina, myocardial infarction, stroke, transient ischemic attack, and kidney disease, patients with no visual impairment 1 month postoperatively had a lower mortality risk (HR 0.73, 95% CI 0.52-1.01) compared to those with persistent moderate-severe visual impairment after surgery. This finding was significant (HR 0.71, 95% CI 0.51-0.99) after additional adjustment for number of medications taken (continuous variable) and number (>=3 vs <3) of comorbid conditions. CONCLUSION: Correcting moderate-severe visual impairment in older patients with phacoemulsification surgery was associated with a lower mortality risk, compared to surgical patients whose visual impairment persisted postoperatively. PMID- 24161250 TI - Laparoscopic sleeve gastrectomy for a two-and a half year old morbidly obese child - A leap into the unknown. PMID- 24161251 TI - Children and adolescents in the Psychiatric Emergency Department: a 10-year survey in Copenhagen County. AB - BACKGROUND: Knowledge on psychiatric emergencies in children and adolescents is limited. The Psychiatric Emergency Departments (PED) in Copenhagen enable the acute examination of children and adolescents 24 h a day, 7 days a week. However, very little is known about who presents to the PED, and the reason for their visit. AIM: To describe the prevalence and characteristics of presentations in PED and treatment provided. METHODS: A retrospective population based study comprising data of more than 4000 visitors presenting to PED from 2001-2010. In 2003 and 2006, two randomly chosen years, a more thorough analysis was performed, based on the individual emergency charts. Inter-rater reliability was high. RESULTS: Visits increased nearly threefold during the period. Symptom score for 2003 and 2006 revealed that more than one third of the visitors had suicidal ideation. Depressive and anxiety symptoms together with suicidal ideation rose significantly (P < 0.001). Psychoses and suicidal attempts remained unchanged. In one third of the visits, the discharge diagnosis was anxiety and stress-related disorders, followed by personality, behavioural and emotional disorders. Between 15% and 20% of the visits resulted in admission and more than 50% in referral for outpatient follow-up. CONCLUSIONS: The number of presenting psychiatric emergencies has increased over the last 10 years. Comparing symptoms from 2003 and 2006 showed a significant rise in their severity. This study highlights the need for 24-h access for acute evaluation by physicians skilled in child and adolescent psychiatry, and raises concern that the severity could increase. PMID- 24161252 TI - Bullying behaviour among Norwegian adolescents: psychiatric diagnoses and school well-being in a clinical sample. AB - BACKGROUND: Few studies have focused the association between bullying and psychiatric disorders in clinical samples. The aim of this study was to examine if bullying behaviour was associated with psychiatric disorders and school well being. METHODS: The cross-sectional study was part of a health survey at St. Olav's University Hospital. The sample consisted of 685 adolescent patients aged 13-18 years who completed an electronic questionnaire. Clinical diagnoses were collected from clinical records. RESULTS: In this clinical psychiatric sample, 19% reported being bullied often or very often, and 51% reported being bullied from time to time. Logistic regression analyses showed associations between being a victim and having a mood disorder, and between being involved in bullying behaviour and reporting lower scores on school well-being. No difference was found in bullying behaviour on gender, age and SES. CONCLUSION: The risk of being a victim was high among adolescents in this clinical sample, especially among patients with mood disorders. Any involvement in bullying behaviour was associated with reduced school well-being. PMID- 24161253 TI - A novel mutation of the SLC25A13 gene in a Chinese patient with citrin deficiency detected by target next-generation sequencing. AB - Type II citrullinaemia, also known as citrin deficiency, is an autosomal recessive metabolic disorder, which is caused by pathogenic mutations in the SLC25A13 gene on chromosome 7q21.3. One of the clinical manifestations of type II citrullinaemia is neonatal intrahepatic cholestatic hepatitis caused by citrin deficiency (NICCD, OMIM# 605814). In this study, a 5-month-old female Chinese neonate diagnosed with type II citrullinaemia was examined. The diagnosis was based on biochemical and clinical findings, including organic acid profiling using a gas chromatography mass spectrometry (GC/MS), and the patient's parents were unaffected. Approximately 14 kb of the exon sequences of the SLC25A13 and two relative genes (ASS1 and FAH) from the proband and 100 case-unrelated controls were captured by array-based capture method followed by high-throughput next-generation sequencing. Two single-nucleotide mutations were detected in the proband, including the previous reported c.1177+1G>A mutation and a novel c.754 G>A mutation in the SLC25A13 gene. Sanger sequence results showed that the patient was a compound heterozygote for the two mutations. The novel mutation (c.754 G>A), which is predicted to affect the normal structure and function of citrin, is a candidate pathogenic mutation. Target sequence capture combined with high-throughput next-generation sequencing technologies is proven to be an effective method for molecular genetic testing of type II citrullinaemia. PMID- 24161255 TI - Ultrasound assisted production of fatty acid methyl esters from transesterification of triglycerides with methanol in the presence of KOH catalyst: optimization, mechanism and kinetics. AB - Ultrasound assisted transesterification of triglycerides (TG) with methanol in the presence of KOH catalyst was investigated, where the changes in the reactants and products (diglycerides (DG), monoglycerides (MG), fatty acid methyl esters (FAME) and glycerin (GL)) concentrations were discussed to understand the reaction mechanism and kinetics under ultrasound irradiation. The optimum reaction condition for the FAME production was the concentration of KOH 1.0 wt.%, molar ratio of TG to methanol of 1:6, and irradiation time of 25 min. The rate constants during the TG transesterification with methanol into GL and FAME were estimated by a curve fitting method with simulated curves to the obtained experimental results. The rate constants of [Formula: see text] were estimated to be 0.21, 0.008, 0.23, 0.005, 0.14 and 0.001 L mol(-1)min(-1), respectively. The rate determining step for the TG transesterification with methanol into GL and FAME was the reaction of MG with methanol into GL and FAME. PMID- 24161256 TI - A simple technique to control the heat generated during light polymerization of custom impression trays. PMID- 24161254 TI - In vivo biodistribution of siRNA and cisplatin administered using CD44-targeted hyaluronic acid nanoparticles. AB - Multidrug resistance (MDR) is a significant problem in the clinical management of several cancers. Overcoming MDR generally involves multi-modal therapeutic approaches that integrate enhancement of delivery efficiency using targeted nano platforms as well as strategies that can sensitize cancer cells to drug treatments. We recently demonstrated that tandem delivery of siRNAs that downregulate anti-apoptotic genes overexpressed in cisplatin resistant tumors followed by therapeutic challenge using cisplatin loaded CD44 targeted hyaluronic acid (HA) nanoparticle (NP) induced synergistic antitumor response CD44 expressing tumors that are resistant to cisplatin. In the current study, a near infrared (NIR) dye-loaded HA NP was employed to image the whole body localization of NPs after intravenous (i.v.) injection into live mice bearing human lung tumors that were sensitive and resistant to cisplatin. In addition, we quantified the siRNA duplexes and cisplatin dose distribution in various tissues and organs using an ultra-sensitive quantitative PCR method and inductively coupled plasma mass spectrometry (ICP-MS), respectively, after i.v. injection of the payload loaded HA NPs in tumor bearing mice. Our findings demonstrate that the distribution pattern of the siRNA and cisplatin using specifically engineered CD44 targeting HA NPs correlated well with the tumor targeting capability as well as the activity and efficacy obtained with combination treatments. PMID- 24161257 TI - Effect of repair resin type and surface treatment on the repair strength of heat polymerized denture base resin. AB - STATEMENT OF PROBLEM: Acrylic resin denture fracture is common in prosthodontic practice. When fractured denture bases are repaired, recurrent fractures frequently occur at the repair surface interface or adjacent areas. PURPOSE: The purpose of this study was to evaluate the effect of different surface treatments on the flexural strength of the acrylic resin denture base repaired with heat polymerized acrylic resin, autopolymerizing resin, and light-polymerized acrylic resin. MATERIAL AND METHODS: Ninety-six specimens of heat-polymerized acrylic resin were prepared according to the American Dental Association Specification No. 12 (65.0 * 10.0 * 2.5 mm) and sectioned into halves to create a repair gap (3.0 * 10 * 2.5 mm). The sectioned specimens were divided into 3 groups according to their repair materials. The specimens from each group were divided into 4 subgroups according to their surface treatments: a control group without any surface treatment; an experimental group treated with methyl methacrylate monomer (MMA group); an experimental group treated with airborne-particle abrasion with aluminum oxide particles of 250-MUm particle size (abrasion group); and an experimental group treated with erbium:yttrium-aluminum-garnet laser (laser group). After the surface treatments, the 3 materials were placed into the repair gaps and then polymerized. After all of the specimens had been ground and polished, they were stored in distilled water at 37 degrees C for 1 week and subjected to a 3-point bend test. Data were analyzed with a 2-way analysis of variance, and the Tukey honestly significant difference test was performed to identify significant differences (alpha=.05). The effects of the surface treatments and repair resins on the surface of the denture base resin were examined with scanning electron microscopy. RESULTS: Significant differences were found among the groups in terms of repair resin type (P<.001). All surface treated specimens had higher flexural strength than controls, except the surface treated with the methyl methacrylate in the heat-polymerized group. A significant difference between the control and abrasion groups (P=.013) was found. The scanning electron microscopy observations showed that the application of surface treatments modified the surface of the denture base resin. CONCLUSIONS: The repair procedure with heat-polymerized resin exhibited significantly higher flexural strength than that of the autopolymerized and light-polymerized resins. In addition, the airborne-particle abrasion with aluminum oxide particles of 250 MUm particle size improved the flexural strength of the specimens tested. PMID- 24161258 TI - Evaluation of the mechanical properties and porcelain bond strength of cobalt chromium dental alloy fabricated by selective laser melting. AB - STATEMENT OF PROBLEM: Limited information is available regarding the microstructure and mechanical properties of dental alloy fabricated by selective laser melting (SLM). PURPOSE: The purpose of this study was to evaluate the mechanical properties of a cobalt-chromium (Co-Cr) dental alloy fabricated by SLM and to determine the correlation between its microstructure and mechanical properties and its porcelain bond strength. MATERIAL AND METHODS: Five metal specimens and 10 metal ceramic specimens were fabricated to evaluate the mechanical properties of SLM Co-Cr dental alloy (SLM alloy) with a tensile test and its porcelain bond strength with a 3-point bending test. The relevant properties of the SLM alloy were compared with those of the currently used Co-Cr dental alloy fabricated with conventional cast technology (cast alloy). The Student t test was used to compare the results of the SLM alloy and the cast alloy (alpha=.05). The microstructure of the SLM alloy was analyzed with a metallographic microscope; the metal ceramic interface of the SLM porcelain bonded alloy was studied with scanning electron microscopy, energy dispersive x ray spectroscopy, and an electron probe microanalyzer. RESULTS: Both the mean (standard deviation) yield strength (884.37 +/- 8.96 MPa) and tensile strength (1307.50 +/-10.65 MPa) of the SLM alloy were notably higher than yield strength (568.10 +/- 30.94 MPa) and tensile strength (758.73 +/- 25.85 MPa) of the currently used cast alloy, and the differences were significant (P<.05). The porcelain bond strength of the SLM alloy was 55.78 +/- 3.02 MPa, which was similar to that of the cast alloy, 54.17 +/- 4.96 MPa (P>.05). Microstructure analysis suggested that the SLM alloy had a dense and obviously orientated microstructure, which led to excellent mechanical properties. Analysis from scanning electron microscopy, energy dispersive x-ray spectroscopy, and the electron probe microanalyzer indicated that the SLM alloy had an intermediate layer with elemental interpenetration between the alloy and the porcelain, which resulted in an improved bonding interface. CONCLUSIONS: Compared with the currently used cast alloy, SLM alloy possessed improved mechanical properties and similar porcelain bond strength. PMID- 24161259 TI - Influence of corrosion on lipopolysaccharide affinity for two different titanium materials. AB - STATEMENT OF PROBLEM: Titanium is subject to corrosion in the oral cavity, which could contribute to periimplantitis. However, the effect of corrosion on the lipopolysaccharide affinity for titanium remains unknown. PURPOSE: This study evaluated the role of corrosion (in artificial saliva at pHs 3, 6.5, and 9) on the lipopolysaccharide (LPS) affinity for commercially pure titanium (cp-Ti) and Ti-6Al-4V alloy. MATERIAL AND METHODS: Seventy-two titanium disks were anodically polarized in a controlled environment (n=9). Control specimens were not corroded. Deionized water with different concentrations of LPS (1.5, 15, and 150 MUg/mL) were used to treat the disks for 24 hours to investigate LPS adherence (n=3). Then specimens were immersed in LPS-free water to evaluate LPS elution at 24, 48, and 72 hours. Data were analyzed by the 2-way, 3-way, and 3-way repeated measures ANOVA, t tests, and the Tukey honestly significant difference (HSD) tests (alpha=.05). RESULTS: A greater corrosion rate of cp-Ti and Ti-6Al-4V alloy and a higher LPS adherence to titanium surfaces (P<.05) were noted at acidic pH. The LPS affinity was higher for the Ti-6Al-4V alloy than for cp-Ti (P<.05). More LPS was eluted from titanium surfaces after a 24-hour interval. CONCLUSION: Lipopolysaccharide affinity for cp-Ti and Ti-6Al-4V alloy is influenced by the corrosion process. PMID- 24161260 TI - Fracture resistance of endodontically treated teeth restored with glass fiber posts of different lengths. AB - STATEMENT OF PROBLEM: Endodontically treated teeth are known to have reduced structural strength. Glass fiber posts may influence fracture resistance and should be evaluated. PURPOSE: The purpose of this study was to evaluate the influence of glass fiber post length on the fracture resistance of endodontically treated teeth. MATERIAL AND METHODS: Forty intact human maxillary canines were selected and divided into 4 groups, the control group consisting of teeth restored with a custom gold cast post and core, with a length of two-thirds of the root. Other groups received prefabricated glass fiber posts in different lengths: group 1/3, removal of one-third of the sealing material (5 mm); group 1/2, removal of one-half of the sealing material (7.5 mm); and group 2/3, removal of two-thirds of the sealing material (10 mm). All the posts were cemented with resin cement, and the specimens with glass fiber posts received a composite resin core. All the specimens were restored with a metal crown and submitted to a compressive load until failure occurred. The results were evaluated by 1-way ANOVA, and the all pairwise multiple comparison procedures (Tukey honestly significantly difference test) (alpha=.05). RESULTS: The ANOVA showed significant differences among the groups (P<.002). The Tukey test showed that the control group presented significantly higher resistance to static load than the other groups (control group, 634.94 N; group 1/3, 200.01 N; group 1/2, 212.17 N; and group 2/3, 236.08 N). Although teeth restored with a cast post and core supported a higher compressive load, all of them fractured in a catastrophic manner. For teeth restored with glass fiber posts, the failure occurred at the junction between the composite resin core and the root. CONCLUSION: The length of glass fiber posts did not influence fracture load, but cast post and cores that extended two-thirds of the root length had significantly greater fracture resistance than glass fiber posts. PMID- 24161261 TI - Molecular identification, morphological characterization and new insights into the ecology of larval Pseudoterranova cattani in fishes from the Argentine coast with its differentiation from the Antarctic species, P. decipiens sp. E (Nematoda: Anisakidae). AB - Larvae of the genus Pseudoterranova constitute a risk for human health when ingested through raw or undercooked fish. They can provoke pseudoterranovosis in humans, a fish-borne zoonotic disease whose pathogenicity varies with the species involved, making their correct specific identification a necessary step in the knowledge of this zoonosis. Larvae of Pseudoterranova decipiens s.l. have been reported in several fish species from off the Argentine coasts; however, there are no studies dealing with their specific identification in this region. Here, a genetic identification and morphological characterization of larval Pseudoterranova spp. from three fish species sampled from Argentine waters and from Notothenia coriiceps from Antarctic waters was carried out. Larvae were sequenced for their genetic/molecular identification, including the mitochondrial cytochrome c oxidase subunit II (mtDNA cox2), the first (ITS-1) and the second (ITS-2) internal transcribed spacers of the nuclear ribosomal DNA, and compared with all species of the P. decipiens (sensu lato) species complex (sequences available in GenBank). Further, adults of Pseudoterranova spp. from the definitive host, the southern sea lion, Otaria flavescens, from Argentine and Chilean coasts were sequenced at the same genes. The sequences obtained at the ITS-1 and ITS-2 genes from all the larvae examined from fish of Argentine waters, as well as the adult worms, matched 100% the sequences for the species P. cattani. The sequences obtained at mtDNA cox2 gene for Antarctic larvae matched 99% those available in GenBank for the sibling P. decipiens sp. E. Both MP and BI phylogenetic trees strongly supported P. cattani and P. decipiens sp. E as two distinct phylogenetic lineages and depicted the species P. decipiens sp. E as sister taxon to the remaining taxa of the P. decipiens complex. Larval morphometry was similar between specimens of P. cattani from Argentina, but significantly different from those of P. decipiens sp. E, indicating that larval forms can be distinguished based on their morphology. Pseudoterranova cattani is common and abundant in a variety of fish species from Chile, whereas few host species harbour these larvae in Argentina where they show low levels of parasitism. This pattern could arise from a combination of factors, including environmental conditions, density and dietary preferences of definitive hosts and life-cycle pathways of the parasite. Finally, this study revealed that the life cycle of P. cattani involves mainly demersal and benthic organisms, with a marked preference by large-sized benthophagous fish. PMID- 24161262 TI - Transitions from injecting to non-injecting drug use: potential protection against HCV infection. AB - Transitions from injecting to non-injecting drug use have been reported from many different areas, particularly in areas with large human immunodeficiency virus (HIV) epidemics. The extent to which such transitions actually protect against HIV and HCV has not been determined. A cross-sectional survey with HIV and hepatitis C (HCV) testing was conducted with 322 former injectors (persons who had injected illicit drugs but permanently transitioned to non-injecting use) and 801 current injectors recruited in New York City between 2007 and 2012. There were no differences in HIV prevalence, while HCV prevalence was significantly lower among former injectors compared to current injectors. Years injecting functioned as a mediating variable linking former injector status to lower HCV prevalence. Transitions have continued well beyond the reduction in the threat of AIDS to injectors in the city. New interventions to support transitions to non injecting drug use should be developed and supported by both drug treatment and syringe exchange programs. PMID- 24161263 TI - Glycan structure determinants for cation-independent mannose 6-phosphate receptor binding and cellular uptake of a recombinant protein. AB - The cation-independent mannose 6-phosphate receptor (CI-MPR) plays a critical role in intracellular transport of lysosomal enzymes as well as the uptake of recombinant proteins. To define the minimal glycan structure determinants necessary for receptor binding and cellular uptake, we synthesized a series of glycans containing mono-, di-, tri-, tetra-, and hexamannoses terminated with either one or two phosphates for conjugating to a model protein, recombinant human acid alpha-glucosidase. A high affinity interaction with the CI-MPR can be achieved for the enzyme conjugated to a dimannose glycan with a single phosphate. However, tightest binding to a CI-MPR affinity column was observed with a hexamannose structure containing two phosphates. Moreover, maximal cellular uptake and a 5-fold improvement in in vivo potency were achieved when the bisphosphorylated hexamannose glycan is conjugated to the protein by a beta linker. Nevertheless, even a monophosphorylated dimannose glycan conjugate showed stronger binding to the receptor affinity column, higher cellular uptake, and significantly greater in vivo efficacy compared to the unconjugated protein which contains a low level of high affinity glycan structure. These results demonstrate that the phosphorylated dimannose moiety appears to be the minimal structure determinant for enhanced CI-MPR binding and that the orientation of the glycan is critical for maximum receptor interaction. In summary, we have improved the understanding of the mechanism of CI-MPR binding and developed a simple alternative for CI-MPR targeting. PMID- 24161267 TI - A series of weak ferromagnets based on a chromium-acetylide-TTF type complex: correlation of the structures and magnetic properties and origin of the weak ferromagnetism. AB - The crystal structures and magnetic properties of a series of new weak ferromagnets containing a chromium-acetylide-tetrathiafulvalene (TTF) type complex, [CrCyclam(C=C-5-methyl-4'5'-ethylenedithio-TTF)2](2+) ([1](2+)), were investigated. The six new isostructural weak ferromagnets [1][BF4]2(PhF)2(MeCN), [1][ClO4]2(PhF)2(MeCN), [1][ReO4]2(PhCl)2(MeCN), [1][ClO4]2(PhBr)3, [1][ReO4]2(PhBr)3, and [1][ClO4]2(PhI)3 contain ferrimagnetic chain structures of [1](2+)infinity with different interchain distances that are dependent on the sizes of the anions and solvent molecules. Magnetic measurements of the salts revealed that the weak ferromagnetic transition temperature gradually increases from 14.5 to 26.0 K as the interchain distance decreases from 3.997(2) to 3.803(2) A, while the remanent magnetization at 2 K decreases from 0.0215 to 0.0079 MUB. The observed magnetic properties and crystal structures suggest that the weak ferromagnetism originates from the single-ion anisotropy of [1](2+), where a stronger interchain antiferromagnetic interaction not only causes a higher transition temperature but also suppresses the noncollinear canted spin alignment. PMID- 24161266 TI - A cytochrome P450 serves as an unexpected terpene cyclase during fungal meroterpenoid biosynthesis. AB - Viridicatumtoxin (1) is a tetracycline-like fungal meroterpenoid with a unique, fused spirobicyclic ring system. Puzzlingly, no dedicated terpene cyclase is found in the gene cluster identified in Penicillium aethiopicum. Cytochrome P450 enzymes VrtE and VrtK in the vrt gene cluster were shown to catalyze C5 hydroxylation and spirobicyclic ring formation, respectively. Feeding acyclic previridicatumtoxin to Saccharomyces cerevisiae expressing VrtK confirmed that VrtK is the sole enzyme required for cyclizing the geranyl moiety. Thus, VrtK is the first example of a P450 that can catalyze terpene cyclization, most likely via initial oxidation of C17 to an allylic carbocation. Quantum chemical modeling revealed a possible new tertiary carbocation intermediate E that forms after allylic carbocation formation. Intermediate E can readily undergo concerted 1,2 alkyl shift/1,3-hydride shift, either spontaneously or further aided by VrtK, followed by C7 Friedel-Crafts alkylation to afford 1. The most likely stereochemical course of the reaction was proposed on the basis of the results of our computations. PMID- 24161268 TI - Homologous desensitization of human histamine H3 receptors expressed in CHO-K1 cells. AB - Histamine H3 receptors (H3Rs) modulate the function of the nervous system at the pre- and post-synaptic levels. In this work we aimed to determine whether, as other G protein-coupled receptors (GPCRs), H3Rs desensitize in response to agonist exposure. By using CHO-K1 cells stably transfected with the human H3R (hH3R) we show that functional responses (inhibition of forskolin-induced cAMP accumulation in intact cells and stimulation of [(35)S]-GTPgammaS binding to cell membranes) were markedly reduced after agonist exposure. For cAMP accumulation assays the effect was significant at 60 min with a maximum at 90 min. Agonist exposure resulted in decreased binding sites for the radioligand [(3)H]-N-methyl histamine ([(3)H]-NMHA) to intact cells and modified the sub-cellular distribution of H3Rs, as detected by sucrose density gradients and [(3)H]-NMHA binding to cell membranes, suggesting receptor internalization. The reduction in the inhibition of forskolin-stimulated cAMP formation observed after agonist pre incubation was prevented by incubation in hypertonic medium or in ice-cold medium. Agonist-induced loss in binding sites was also prevented by hypertonic medium or incubation at 4 degrees C, but not by filipin III, indicating clathrin dependent endocytosis. Immunodetection showed that CHO-K1 cells express GPCR kinases (GRKs) 2/3, and both the GRK general inhibitor ZnCl2 and a small interfering RNA against GRK-2 reduced receptor desensitization. Taken together these results indicate that hH3Rs experience homologous desensitization upon prolonged exposure to agonists, and that this process involves the action of GRK 2 and internalization via clathrin-coated vesicles. PMID- 24161269 TI - Victoria Symptom Validity Test: cutoff scores for psychometrically defined malingering groups in a military sample. AB - The Victoria Symptom Validity Test (VSVT) is one of the least widely used tests to assess performance validity on tests of neurocognitive functioning, but a meta analysis has suggested that it is one of the more effective validity tests. The current research examined cutoffs for several different scores derived from the VSVT in an active duty military sample composed primarily of mild TBI patients. The results are consistent with previous research and provide additional evidence that much higher cutoffs scores than originally recommended for the VSVT by the developers based on binomial probability theory can produce excellent classification and diagnostic statistics when a psychometrically defined non malingering group is compared with two psychometrically defined malingering groups (Probable and Probable to Definite). The utility of the difference score between the Easy and Hard Items is supported by this research. The results also indicate that reaction times have some utility, but they are constrained by a lack of sensitivity. PMID- 24161270 TI - [Liver enzyme elevation secondary to macroenzymes: macro-GOT]. PMID- 24161271 TI - Improvement of driving skills in persons with relapsing-remitting multiple sclerosis: a pilot study. AB - OBJECTIVE: To determine the potential to improve driving-related skills using a simulator-based program in persons with relapsing-remitting multiple sclerosis (RRMS). DESIGN: Pre-post intervention. SETTING: A university driving simulator laboratory. PARTICIPANTS: Participants (N=50) with RRMS and Expanded Disability Status Scale (EDSS) scores between 1 and 7 were enrolled. Pre- and posttraining data from 36 participants (mean age +/- SD, 46+/-11y; 30 women) who received training and 6 participants (mean age +/- SD, 48+/-13y; 5 women) who did not receive training (control group) were compared. INTERVENTIONS: Five hours of driving training in a simulator. MAIN OUTCOME MEASURES: Performance on a road test at pre- and posttraining. Secondary outcome measures were performance on visual, physical, and cognitive tests. RESULTS: Overall, no significant differences were observed between the training and control groups before and after training. However, 4 of the 7 participants in the training group who failed the road test at pretraining passed posttraining, while the only participant in the control group who failed at pretraining still failed at posttraining. The training group also improved on perception of red and colored numbers, the Paced Auditory Serial Addition Test, and the dot cancellation test of the Stroke Driver Screening Assessment battery and reported less fatigue. These improvements were most pronounced among those with an EDSS score between 3 and 7. CONCLUSIONS: This pilot study demonstrates the potential of using a simulator to improve driving related visual, cognitive, and on-road skills in individuals with RRMS, particularly those with an EDSS score >3. Future randomized controlled trials with adequate power are needed to expand this field of study. PMID- 24161272 TI - Suicide mortality after spinal cord injury in the United States: injury cohorts analysis. AB - OBJECTIVES: To compare 12-year suicide-specific mortalities of 3 different injury cohorts, identify the risk factors for suicide mortality after spinal cord injury (SCI), and investigate whether suicide mortality is higher among those with SCI than in the general population. DESIGN: Retrospective cohort study. SETTING: United States hospitals (n=28) designated as SCI Model Systems. PARTICIPANTS: Participants (N=31,339) injured between January 1, 1973, and December 31, 1999. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURE: Suicide death after SCI. RESULTS: The crude annual suicide mortality rate during the first 12 years after SCI was 91 per 100,000 person-years for 1973 to 1979 injury cohort, 69 per 100,000 person-years for 1980 to 1989 injury cohort, and 46 per 100,000 person years for 1990 to 1999 injury cohort. Suicide mortality was associated with race, injury severity, and years since injury. The standardized mortality ratios for the 3 cohorts were 5.2, 3.7, and 3.0, respectively. CONCLUSIONS: Suicide mortality among those with SCI decreased over 3 injury cohorts, but it still remained 3 times higher than that of the general population. PMID- 24161273 TI - Impact of time on quality of motor control of the paretic upper limb after stroke. AB - OBJECTIVE: To establish the time course of recovery regarding smoothness of upper limb movements in the first 6 months poststroke. DESIGN: Cohort study with 3 dimensional kinematic measurements in weeks 1, 2, 3, 4, 5, 8, 12, and 26 poststroke. SETTING: Onsite 3-dimensional kinematic measurements in stroke units, rehabilitation centers, nursing homes, and patients' homes. PARTICIPANTS: Patients (N=44; 19 women, 25 men; mean age +/- SD, 58+/-12y) with a first-ever unilateral ischemic stroke and incomplete upper limb paresis (27 left sided, 17 right sided) were included. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: In each measurement, an electromagnetic motion tracker acquired hand and finger trajectories during a reach-to-grasp task. Movement duration was determined, and smoothness of hand transport and grasp aperture was quantified by normalized jerk. With the use of random coefficient analysis, the effect of progress of time on smoothness of hand transport and grasp aperture was investigated. RESULTS: During the first 5 weeks poststroke, there was a significant contribution of progress of time to reductions in movement duration and normalized jerk of hand transport and grasp aperture (P<.01). CONCLUSIONS: The present longitudinal 3 dimensional kinematic study showed that smoothness of paretic upper limb movements improves in the first 8 weeks poststroke. This improvement suggests that motor control normalizes in the first 8 weeks poststroke and can be mostly explained by spontaneous neurologic recovery that occurs typically in the first weeks poststroke. Future 3-dimensional kinematic studies should investigate whether therapies starting early after stroke can improve the quality of motor control beyond spontaneous neurologic recovery. PMID- 24161275 TI - Human apolipoprotein E4 modulates the expression of Pin1, Sirtuin 1, and Presenilin 1 in brain regions of targeted replacement apoE mice. AB - The apolipoprotein E4 (apoE4) allele is consistently associated with increased risk for Alzheimer's disease (AD). We investigated the molecular mechanism of this susceptibility by analyzing the levels of genes involved in AD pathogenesis in transgenic mice expressing human apoE3 or apoE4 isoforms. mRNA and protein levels of Pin1, Sirtuin 1 (Sirt1), Presenilin 1 (PS1), and pro-Brain-derived Neurotrophic Factor (BDNF) were analyzed in brain regions affected by neuropathological changes in AD. Pin1 mRNA was significantly higher in the hippocampus of apoE4 mice than in apoE3 controls, whereas lower expression was detected in the entorhinal and parietal cortices. Reduced Pin1 levels may increase neurofibrillary degeneration and amyloidogenic processes, while compensatory mechanisms may take place in the hippocampus to balance spatial memory deficits. Sirt1 levels were significantly reduced in the frontal cortex of apoE4 mice. Sirt1 reduction may hinder its protective role against the formation of plaques and tangles and diminish its anti-inflammatory actions. Sirt1 decrease may also play a role in apoE4-associated memory impairments. Moreover, in apoE4 mice PS1 mRNA levels were lower in the frontal cortex. Lower PS1 expression may hamper gamma-secretase function, thus affecting amyloid precursor protein processing. Pro-BDNF mRNA levels did not differ between apoE3 and apoE4 mice in any region analyzed. This study showed dysregulated expression of Pin1, Sirt1, and PS1 genes in different cerebral areas of apoE4 mice, suggesting that these changes may play a role in the mechanism of AD vulnerability. PMID- 24161274 TI - Chronic inflammatory pain prevents tolerance to the antinociceptive effect of morphine microinjected into the ventrolateral periaqueductal gray of the rat. AB - The ventrolateral periaqueductal gray (vlPAG) contributes to morphine antinociception and tolerance. Chronic inflammatory pain causes changes within the PAG that are expected to enhance morphine tolerance. This hypothesis was tested by assessing antinociception and tolerance following repeated microinjections of morphine into the vlPAG of rats with chronic inflammatory pain. Microinjection of morphine into the vlPAG reversed the allodynia caused by intraplantar administration of complete Freund's adjuvant and produced antinociception on the hot plate test. Although there was a gradual decrease in morphine antinociception with repeated testing, there was no evidence of tolerance when morphine- and saline-treated rats with hind paw inflammation were tested with cumulative doses of morphine. In contrast, repeated morphine injections into the vlPAG caused a rightward shift in the morphine dose-response curve in rats without hind paw inflammation, as would be expected with the development of tolerance. The lack of tolerance in complete Freund's adjuvant treated rats was evident whether rats were exposed to repeated behavioral testing or not (experiment 2) and whether they were treated with 4 or 8 prior microinjections of morphine into the vlPAG (experiment 3). These data demonstrate that chronic inflammatory pain does not disrupt the antinociceptive effect of microinjecting morphine into the vlPAG, but it does disrupt the development of tolerance. PERSPECTIVE: The present data show that induction of chronic inflammatory pain does not disrupt the antinociceptive effect of microinjecting morphine into the vlPAG, but it does attenuate the development of tolerance. This finding indicates that tolerance to opioids in rats with inflammatory pain is mediated by structures other than the vlPAG. PMID- 24161276 TI - Asymmetry in primary auditory cortex activity in tinnitus patients and controls. AB - Tinnitus is a bothersome phantom sound percept and its neural correlates are not yet disentangled. Previously published papers, using [(18)F]-fluoro-deoxyglucose positron emission tomography (FDG-PET), have suggested an increased metabolism in the left primary auditory cortex in tinnitus patients. This unilateral hyperactivity has been used as a target in localized treatments such as transcranial magnetic stimulation. The purpose of the current study was to test whether left-sided hyperactivity in the auditory cortex is specific to tinnitus or is a general characteristic of the auditory system unrelated to tinnitus. Therefore, FDG-PET was used to measure brain metabolism in 20 tinnitus patients and to compare their results to those in 19 control subjects without tinnitus. In contrast to our expectation, there was no hyperactivity associated with tinnitus. Nevertheless, the activity in the left primary auditory cortex was higher than in the right primary auditory cortex, but this asymmetry was present in both tinnitus patients and control subjects. In contrast, the lateralization in secondary auditory cortex was opposite, with higher activation in the right hemisphere. These data show that hemisphere asymmetries in the metabolic resting activity of the auditory cortex are present, but these are not associated with tinnitus and are a normal characteristic of the normal brain. PMID- 24161277 TI - Mechanisms underlying obesity resistance associated with high spontaneous physical activity. AB - Obesity resistance due to elevated orexin signaling is accompanied by high levels of spontaneous physical activity (SPA). The behavioral and neural mechanisms underlying this observation have not been fully worked out. We determined the contribution of hypothalamic orexin receptors (OXRs) to SPA stimulated by orexin A (OXA), whether OXA-stimulated SPA was secondary to arousal and whether voluntary wheel running led to compensations in 24-h SPA. We further tested whether orexin action on dopamine one receptors (DA1R) in the substantia nigra (SN) plays an important role in the generation of SPA. To test this, SPA response was determined in lean and obese rats with cannulae targeted toward the rostral lateral hypothalamus (rLH) or SN. Sleep/wake states were also measured in rats with rLH cannula and electroencephalogram/electromyogram radiotelemetry transmitters. SPA in lean rats was more sensitive to antagonism of the OX1R and in the early response to the orexin 2 agonist. OXA increased arousal equally in lean and obese rodents, which is discordant from the greater SPA response in lean rats. Obesity-resistant rats ran more and wheel running was directly related to 24-h SPA levels. The OX1R antagonist, SB-334867-A, and the DA1R antagonist, SCH3390, in SN more effectively reduced SPA stimulated by OXA in obesity resistant rats. These data suggest OXA-stimulated SPA is not secondary to enhanced arousal, propensity for SPA parallels inclination to run and that orexin action on dopaminergic neurons in SN may participate in the mediation of SPA and running wheel activity. PMID- 24161278 TI - Copper chelation and exogenous copper affect circadian clock phase resetting in the suprachiasmatic nucleus in vitro. AB - Light stimulates specialized retinal ganglion cells to release glutamate (Glu) onto circadian clock neurons of the suprachiasmatic nucleus (SCN). Glu resets the phase of the SCN circadian clock by activating N-methyl-d-aspartate receptors (NMDAR) causing either delays or advances in the clock phase, depending on early- or late-night stimulation, respectively. In addition, these Glu-induced phase shifts require tropomyosin receptor kinase B (TrkB) receptor activity. Previous studies show that copper (Cu) released at hippocampal synapses can inhibit NMDAR activity, and application of exogenous Cu likewise inhibits NMDAR activity. We investigated the effects of Cu in acute SCN brain slices prepared from C57BL/6Nhsd adult, male mice using treatments that decrease or increase available Cu levels in vitro and recorded neuronal activity on the following day. When bath applied for 10 min at zeitgeber time (ZT) 16 (where ZT0=lights-on in the donor animal colony), the Cu-specific chelators tetrathiomolybdate (TTM) and bathocuproine disulfonate each induce ~2.5-3-h phase delays in circadian neuronal activity rhythms, similarly to Glu-induced phase delays. Co-application of 10 MUM CuCl2, but not 10 MUM CoCl2 blocks TTM-induced phase delays. Furthermore, TTM causes phase advances when applied at ZT23. At both application times, TTM induced phase shifts are blocked by NMDA or TrkB receptor antagonists. Surprisingly, bath-application of 10 MUM Cu alone also induces phase shifts in analogous experiments at ZT16 and ZT23. Inhibiting NMDAR does not block Cu induced phase shifts. TrkB inhibition blocks Cu-induced phase delays but not phase advances. Thus, increasing and decreasing Cu availability appear to shift the SCN clock phase through different mechanisms, at least at the receptor level. We propose that Cu plays a role in the SCN circadian clock by modulating Glu signaling. PMID- 24161280 TI - Sphingolipid profiles are altered in prefrontal cortex of rats under acute hyperglycemia. AB - Diabetes type 1 is a common autoimmune disease manifesting by insulin deficiency and hyperglycemia, which can lead to dementia-like brain dysfunctions. The factors triggering the pathological processes in hyperglycemic brain remain unknown. We reported in this study that brain areas with different susceptibility to diabetes (prefrontal cortex (PFC), hippocampus, striatum and cerebellum) revealed differential alterations in ceramide (Cer) and sphingomyelin (SM) profiles in rats with streptozotocin-induced hyperglycemia. Employing gas-liquid chromatography, we found that level of total Cer increased significantly only in the PFC of diabetic animals, which also exhibited a broad spectrum of sphingolipid (SLs) changes, such as elevations of Cer-C16:0, -C18:0, -C20:0, C22:0, -C18:1, -C24:1 and SM-C16:0 and -C18:1. In opposite, only minor changes were noted in other examined structures. In addition, de novo synthesis pathway could play a role in generation of Cer containing monounsaturated fatty acids in PFC during hyperglycemia. In turn, simultaneous accumulation of Cers and their SM counterparts may suggest that overproduced Cers are converted to SMs to avoid excessive Cer-mediated cytotoxicity. We conclude that broad changes in SLs compositions in PFC induced by hyperglycemia may provoke membrane rearrangements in some cell populations, which can disturb cellular signaling and cause tissue damage. PMID- 24161279 TI - Modeling nigrostriatal degeneration in organotypic cultures, a new ex vivo model of Parkinson's disease. AB - Parkinson's disease (PD) is the second most frequent neurodegenerative disorder afflicting 2% of the population older than 65 years worldwide. Recently, brain organotypic slices have been used to model neurodegenerative disorders, including PD. They conserve brain three-dimensional architecture, synaptic connectivity and its microenvironment. This model has allowed researchers a simple and rapid method to observe cellular interactions and mechanisms. In the present study, we developed an organotypic PD model from rat brains that includes all the areas involved in the nigrostriatal pathway in a single slice preparation, without using neurotoxins to induce the dopaminergic lesion. The mechanical transection of the nigrostriatal pathway obtained during slice preparation induced PD-like histopathology. Progressive nigrostriatal degeneration was monitored combining innovative approaches, such as diffusion tensor magnetic resonance imaging (DT RMI) to follow fiber degeneration and mass spectrometry to quantify striatal dopamine content, together with bright-field and fluorescence microscopy imaging. A substantia nigra dopaminergic cell number decrease was observed by immunohistochemistry against rat tyrosine hydroxylase (TH) reaching 80% after 2 days in culture associated with a 30% decrease of striatal TH-positive fiber density, a 15% loss of striatal dopamine content quantified by mass spectrometry and a 70% reduction of nigrostriatal fiber fractional anisotropy quantified by DT RMI. In addition, a significant decline of medium spiny neuron density was observed from days 7 to 16. These sagittal organotypic slices could be used to study the early stage of PD, namely dopaminergic degeneration, and the late stage of the pathology with dopaminergic and GABAergic neuron loss. This novel model might improve the understanding of PD and may represent a promising tool to refine the evaluation of new therapeutic approaches. PMID- 24161281 TI - Neural pathway in the right hemisphere underlies verbal insight problem solving. AB - Verbal insight problem solving means to break mental sets, to select the novel semantic information and to form novel, task-related associations. Although previous studies have identified the brain regions associated with these key processes, the interaction among these regions during insight is still unclear. In the present study, we explored the functional connectivity between the key regions during solving Chinese 'chengyu' riddles by using event-related functional magnetic resonance imaging. Results showed that both insight and noninsight solutions activated the bilateral inferior frontal gyri, middle temporal gyri and hippocampi, and these regions constituted a frontal to temporal to hippocampal neural pathway. Compared with noninsight solution, insight solution had a stronger functional connectivity between the inferior frontal gyrus and middle temporal gyrus in the right hemisphere. Our study reveals the neural pathway of information processing during verbal insight problem solving, and supports the right-hemisphere advantage theory of insight. PMID- 24161282 TI - Social isolation stress reduces hippocampal long-term potentiation: effect of animal strain and involvement of glucocorticoid receptors. AB - BACKGROUND: Depressive patients show cognitive impairments that are strongly associated with cortisol levels and hippocampus functioning that interact via unknown mechanisms. In addition, a relation between depression and hippocampal synaptic plasticity was described. METHODS: In the first experiment, strain dependent effects of 72-h social isolation on long-term potentiation (LTP) in the CA1 area of the in vitro hippocampus, was determined. Extracellular field excitatory postsynaptic potentials were recorded and a brief high-frequency stimulation (100 Hz, 1s) was applied and recording resumed after the high frequency stimulation (HFS) for 30 min to determine the effect of HFS. In the second experiment we investigated the effect of 72 h of corticosterone treatment and the involvement of glucocorticoid receptors (GRs) in the effect of 72 h of social isolation on LTP in the CA1 area of hippocampus, in vitro. RESULTS: Genetic background has a major effect on the level of hippocampal LTP impairment in mice following social isolation. Data showed that the potentiation levels in socially housed (SH) A/J mice were significantly higher than the SH C57BL/6J mice (224.88 +/- 16.65, 131.56 +/- 6.25% of the baseline values, t(9)=2.648, p=0.026). However, both strains showed depressed induction of potentiation when reared in an isolated environment for 72 h, and no significant difference was recorded between the two (112.88 +/- 16.65%, and 117.91 +/- 3.23% of the baseline values, respectively, t(10)=0.618, p=0.551). Social isolation increased corticosterone levels significantly and chronic corticosterone infusion in SH phenocopied the LTP impairments observed in socially isolated mice. Infusion of the GR antagonist RU38486 rescued the LTP-impairments following social isolation. CONCLUSIONS: These findings support the notion that increased levels of stress hormone act via the GR on hippocampal functioning and that, in this way, the cognitive deficits in mood disorders may be restored. PMID- 24161283 TI - Fictive rhythmic motor patterns produced by the tail spinal cord in salamanders. AB - Most investigations into the role of the body axis in vertebrate locomotion have focused on the trunk, although in most tetrapods, the tail also plays an active role. In salamanders, the tail contributes to propulsion during swimming and to dynamic balance and maneuverability during terrestrial locomotion. The aim of the present study was to obtain information concerning the neural mechanisms that produce tail muscle contractions during locomotion in the salamander Pleurodeles waltlii. We recorded the ventral root activities in in vitro spinal cord preparations in which locomotor-like activity was induced via bath application of N-methyl-d-aspartate (20MUM) and d-serine (10MUM). Recordings showed that the tail spinal cord is capable of producing propagated waves of motor activity that alternate between the left and right sides. Lesion experiments further revealed that the tail rhythmogenic network is composed of a double chain of identical hemisegmental oscillators. Finally, using spinal cord preparations bathed in a chamber partitioned into two pools, we revealed efficient short-distance coupling between the trunk and tail networks. Together, our results demonstrate the existence of a pattern generator for rhythmic tail movements in the salamander and show that the global architecture of the tail network is similar to that previously proposed for the mid-trunk locomotor network in the salamander. Our findings further support the view that salamanders can control their trunk and tail independently during stepping movements. The relevance of our results in relation to the generation of tail muscle contractions in freely moving salamanders is discussed. PMID- 24161284 TI - Peripheral immunomodulation with ginsenoside Rg1 ameliorates neuroinflammation induced behavioral deficits in rats. AB - Neuroinflammatory disturbances have been closely associated with depression and many other neuropsychiatric diseases. Although targeting neuroinflammatory mediators with centrally acting drugs has shown certain promise, its translation is faced with several challenges especially drug delivery and safety concerns. Here, we report that neuroinflammation-induced behavioral abnormality could be effectively attenuated with immunomodulatory agents that need not to gain brain penetration. In a rat model with intracerebral lipopolysaccharide (LPS) challenge, we validated that ginsenoside Rg1 (Rg1), a well-established anti inflammatory agent, was unable to produce a direct action in the brain. Interestingly, peripherally restricted Rg1 could effectively attenuate the weight loss, anorexic- and depressive-like behavior as well as neurochemical disturbances associated with central LPS challenge. Biochemical assay of neuroimmune mediators in the periphery revealed that Rg1 could mitigate the deregulation of the hypothalamic-pituitary-adrenal axis and selectively blunt the increase in circulating interleukin-6 levels. Furthermore, these peripheral regulatory effects were accompanied by dampened microglial activation, mitigated expression of pro-inflammatory mediators and neurotoxic species in the central compartment. Taken together, our work suggested that targeting the peripheral immune system may serve as a novel therapeutic approach to neuroinflammation induced neuropsychiatric disorders. Moreover, our findings provided the rationale for employing peripherally active agents like Rg1 to combat mental disturbances. PMID- 24161286 TI - Clinical relevance of diffusion tensor imaging parameters in lumbar disco radicular conflict. AB - PURPOSE: To measure the fractional anisotropy (FA) and the mean diffusivity (MD) values of L4, L5 and S1 nerve roots using diffusion tensor imaging (DTI) and to correlate them with four different clinical patterns. PATIENTS AND METHODS: Fifty six human participants were prospectively included and divided between four groups: healthy subjects, patients with clinical symptomatic nerve root pain with and without anatomical discoradicular conflict and patients with incidental anatomical discoradicular conflict seen on magnetic resonance imaging (MRI). MRI protocol included anatomical sequences (sagittal T1- and T2-weighted, axial T2 weighted) and a 25 directions DTI sequence. FA and MD values were measured in consensus by two readers and compared between the four groups. RESULTS: Mean FA and MD values were significantly different for patients with clinically symptomatic nerve root pain (n=27) both with (n=16) (FA=0.187+/-0.015; MD=510+/ 40) and without (n=11) (FA=0.193+/-0.011; MD=490+/-30.5) anatomical discoradicular conflict compared to healthy subjects (n=29) (FA=0.221+/-0.011; MD=460.9+/-35.5) including 2 subjects with incidental anatomical discoradicular conflict (FA=0.211+/-0.013; MD=450.8+/-41.2) on MRI (P=0.003). CONCLUSION: Measurement of FA and MD values of L4, L5 and S1 nerve roots using DTI could be useful in lumbar nerve root pain assessment. Further studies with different image processing methods are needed. PMID- 24161287 TI - Medication pain management in the elderly: unique and underutilized analgesic treatment options. AB - BACKGROUND: By 2030, the US population of adults aged >=65 years will increase by >80%, and these adults will account for nearly 20% of the US population. In this population, the decline of multiple physiologic processes and diseases collectively influence treatment options. Physiologic changes, drug-drug interactions resulting from polypharmacy, and drug-disease interactions combine to make elderly patients more sensitive to the adverse events (AEs) associated with medications, all of which must be considered in drug selection. OBJECTIVE: This article focuses on select underutilized medication options for analgesia that may provide significant advantages in the elderly population above and beyond commonly prescribed conventional choices. METHODS: We performed a complete review of the literature using the search terms pain management, elderly, opioids, NSAIDs, topical NSAIDs, levorphanol, buprenorphine transdermal, and tapentadol. Databases searched included PubMed, Google Scholar, Ovid, and Athens. Package inserts were utilized for approval dates, indications, and formulations available. We looked at reviews of agents to identify important studies for consideration that searches may have missed. Pharmacology and pharmacokinetic data were taken from randomized trials focusing in this area. Pivotal Phase III trials were utilized for discussion of clinical trial experience and to summarize efficacy and AEs. For purposes of validity, only peer-reviewed literature was included. RESULTS: There were limited data that specifically outlined analgesic drug selection and highlighted safer alternatives for the elderly patient based on polypharmacy risks, end-organ deterioration, and/or drug choices that presented less risk. We focused on unique opioid alternatives: levorphanol, which offers several therapeutic advantages similar to methadone but without the pharmacokinetic and drug-interaction pitfalls associated with methadone; tapentadol, associated with significantly less gastrointestinal distress and constipation; and transdermal buprenorphine, an agonist/antagonist with less risk for the toxicities associated with conventional opioids and with compliance benefits. Topical NSAIDs are discussed as a viable therapeutic option. Specific attention to a more desirable tolerability profile, including avoidance of drug interactions, end-organ dysfunction, and gastrointestinal bleed with topical NSAID agents versus their oral counterparts is discussed, including the ability to achieve superior tissue levels for appropriately selected inflammatory conditions. CONCLUSION: It is incumbent that providers consider these options as part of an analgesic armamentarium in an effort to maximize therapeutic benefit and minimize risks in the increasing elderly patient population. PMID- 24161288 TI - Reducing the pain of microemulsion propofol injections: a double-blind, randomized study of three methods of tourniquet and lidocaine. AB - BACKGROUND: Although the new formulation of lipid-free microemulsion propofol (MP) has some advantages over the lipid emulsion, it reportedly produces more injection pain than lipid-based propofol. Intravenous lidocaine with application of a rubber tourniquet before administration of propofol is considered to be the best method for reducing injection pain; however, this technique is not perfect. OBJECTIVE: The goal of this study was to evaluate the effect of different methods of tourniquet application and lidocaine administration on MP injection pain. METHODS: This single-center, randomized controlled clinical trial was conducted in 140 patients aged 18 to 65 years. Patients were randomly divided into 4 groups (n = 35 each). Group A received MP (2 mg/kg) after lidocaine (0.6 mg/kg) with a tourniquet with arm down (venous engorgement); group B received MP after lidocaine with a tourniquet with arm up (venous gravity drainage); group C received MP with a tourniquet with arm down; and group D (control group) received MP only (with no tourniquet). In groups A and C, the tourniquet was released after MP; in group B, the tourniquet was released before MP. Injection pain was evaluated by using a verbal pain score (VPS). The bispectral index, the time from the beginning of drug injection to the loss of eyelash reflex, and time to the lowest bispectral index value were recorded. RESULTS: Group A showed significantly less incidence of pain than the control group when MP was injected. The mean VPS was significantly lower in groups A, B, and C than in group D (the control group). The VPS of group A was significantly lower than that in group B. Other observed values were not significantly different. CONCLUSIONS: We concluded that intravenous retention of lidocaine with the application of a rubber tourniquet under venous engorgement of the arm reduces the incidence and intensity of MP injection pain. CLINICAL TRIAL REGISTRY: UMIN000010725. PMID- 24161285 TI - Differential postpartum sensitivity to the anxiety-modulating effects of offspring contact is associated with innate anxiety and brainstem levels of dopamine beta-hydroxylase in female laboratory rats. AB - In female mammals, the postpartum period involves dramatic shifts in many socioemotional behaviors. This includes a suppression of anxiety-related behaviors that requires recent physical contact with offspring. Factors contributing to differences among females in their susceptibility to the anxiety modulating effect of offspring contact are unknown, but could include their innate anxiety and brain monoaminergic activity. Anxiety behavior was assessed in a large group of nulliparous female rats and the least-anxious and most-anxious tertiles were mated. Anxiety was assessed again postpartum after females were permitted or prevented from contacting their offspring 4 h before testing. Levels of dopamine beta-hydroxylase (DBH, norepinephrine synthesizing enzyme) and tryptophan hydroxylase-2 (TPH2, serotonin synthesizing enzyme) were measured in the brainstem and dorsal raphe, respectively. It was found that anxiety-related behavior in the two groups did not differ when dams were permitted contact with offspring before testing. Removal of the offspring before testing, however, differentially affected anxiety based on dams' innate anxiety. Specifically, dams reverted back to their pre-mating levels of anxiety such that offspring removal slightly increased anxiety in the most-anxious females but greatly lowered anxiety in the least-anxious females. This reduction in anxiety in the least anxious females after litter removal was associated with lower brainstem DBH. There was no relationship between females' anxiety and dorsal raphe TPH2. Thus, a primary effect of recent contact with offspring on anxiety-related behavior in postpartum rats is to shift females away from their innate anxiety to a more moderate level of responding. This effect is particularly true for females with the lowest anxiety, may be mediated by central noradrenergic systems, and has implications for their ability to attend to their offspring. PMID- 24161289 TI - Combined factor V and VIII deficiency and pregnancy--need for an early protocol based multidisciplinary management. AB - We report the medical management of a 32-year-old primigravida, after she was found to have a combined factor V (FV) and factor VIII (FVIII) deficiency during pregnancy. A routine coagulation profile performed during the 6th month of pregnancy showed a prolonged activated partial thromboplastin time (aPTT) of 78 seconds, giving a patient/control ratio of 2.29, combined with a prothrombin time (PT) of 28 seconds. An investigation of the coagulation factors showed a combined FV and FVIII deficiency of 29% and 21% respectively. The bleeding risk was considered to be high. A multidisciplinary approach permitted a specific and individualized FVIII substitution protocol. At 39 weeks of amenorrhea, the patient was admitted to the labor room. An infusion of 2000IU of FVIII was implemented over 5 minutes; soon thereafter, PT was 17 seconds, aPTT patient/control ratio had decreased to 1.9 and FV and FVIII reached 38% and 36% respectively. Six hours later, the patient delivered an infant weighing 2850g who had an Apgar score of 10. No bleeding was detected. The patient was then closely monitored for 2 hours in the recovery room. Twelve hours after administration of the first dose of FVIII, another infusion of 2000IU of FVIII was administered. This substitution treatment was continued every 12 hours in ever-decreasing doses, allowing maintenance of FVIII level >50% for 5days. At D7 post-partum, the patient was discharged uneventfully. PMID- 24161290 TI - [Hepatic portal venous gas: surgery or not surgery?]. AB - Finding hepatic portal venous gas with pneumatosis intestinalis on computed tomography (CT) represents diagnostic and therapeutic challenge. The intestinal necrosis, particularly associated with acute mesenteric ischemia, is the very first hypothesis to assess, with the underlying question of an urgent surgery. However, knowing the non-surgical causes that have been identified in the last decade seems necessary to better assess the risk-benefit ratio of emergency surgery. Among these causes, we report the case of the acute colonic pseudo obstruction, also known as Ogilvie's syndrome, whose first line treatment is medical. PMID- 24161291 TI - [Group A streptococcal meningitis: Streptococcus pneumoniae is not the only one to seep into the CSF fluid leak!]. AB - We reported a case of group A streptococcal meningitis in a patient with a CSF fluid leak. This case underlined several relevant points: (i) an unfrequent cause of bacterial meningitis; (ii) the main diagnosis to evoke when the direct examination of CSF shows Gram+ cocci with a negative pneumococcal antigen; (iii) that bacteria other than Streptococcus pneumoniae are possible in front of a meningitis associated with a CSF fluif leak. PMID- 24161292 TI - [Accidental discovery of a persistent left superior vena cava]. PMID- 24161293 TI - Tamponade a rare cause of shock in patients with pancreatitis: difficulty of diagnostic in patients with positive pressure ventilation. AB - The causes of hemodynamic instability in acute pancreatitis are numerous. Although pericardial effusion during pancreatitis is common, a cardiac tamponade is rarely reported. The diagnosis of compressive cardiac disorders (CDD) by echocardiography is easily reported when the patient is breathing spontaneously; it becomes difficult when the patient is assisted with positive pressure ventilation. PMID- 24161294 TI - [Aspirin and its danger: Reye syndrome in young adult]. AB - We describe the case of a 19-year-old male diagnosed with Reye syndrome within the context of viral pericarditis and salicylate ingestion. He presented a fatal brain oedema without liver failure. Brain biopsies obtained during a decompressive craniectomy led to the diagnosis. PMID- 24161295 TI - [Traumatic injuries of the descending thoracic aorta apart from the isthmus: diagnosis and therapeutic approach]. AB - Lesions involving the descending thoracic aorta apart from isthmus are rare and less known by anesthetists. We report the clinical course of two severely injured patients who sustained a thoracic aortic rupture in whom favorable outcome was achieved with endovascular treatment. Mechanisms, diagnosis and therapeutics aspects of these rare lesions are discussed according to literature. PMID- 24161296 TI - [Peripartum period and hemophilia carriers]. AB - Women who are carriers for hemophilia are usually considered as safe carriers. However, they can present hemorragic symptoms associated with low factor VIII or IX levels. During pregancy, factor VIII increases whereas factor IX does not. The peripartum period is at risk of increased bleeding in these women. Here are presented reports of clinical data concerning two hemophilia carriers with low factor VIII or IX (30-40%) during the peripartum period. They received remifentanil and ketamine for labor pain management because of contraindication of epidural and spinal analgesia. Delivery occured quickly but they presented immediate moderate postpartum haemorrage. They did not necessitate blood transfusion. The one with hemophilia A received desmopressin just after delivery and the other one received factor IX when she arrived in delivery room. Blood factor VIII or IX has to be assessed in these women with familial history of hemophilia and bleeding. During pregnancy, factor VIII increases and can be assessed many times during pregnancy expecting a level over 50%. Factor IX does not really increase during pregancy and hemorrage can occur. Epidural and spinal anesthesia seem to be contraindicated as far as recommandations are concerned. Coagulation factor substitution is a mean of increasing factor level before these anaesthesias and can be discussed for each case. PMID- 24161297 TI - [Alternative breathing system or simplicity does not rhythm with safety]. PMID- 24161298 TI - [Safety anesthesia in sub-Saharan Africa: Togo' experience]. PMID- 24161299 TI - Molecular phylogeny and evolutionary dynamics of influenza A nonstructural (NS) gene. AB - While the nonstructural gene (NS) of the influenza A virus plays a crucial role in viral virulence and replication, the complete understanding of its molecular phylogeny and evolutionary dynamics remains lacking. In this study, the phylogenetic analysis of 7581 NS sequences revealed ten distinct lineages within alleles A and B: three host-specific (human, classical swine and equine), two reassortment-originated (A(H1N1)pdm09 and triple reassortment swine), one transmission-originated (Eurasian swine), and two geographically isolated avian (Eurasian/Oceanian and North American) for allele A and two geographically isolated avian (Eurasian/Oceanian and North American) for allele B. The average nucleotide substitution rates of the lineages range from 1.24*10(-3) (equine) to 4.34*10(-3) (A(H1N1)pdm09) substitutions per site per year. The selection pressure analysis demonstrated that the dN/dS ratio of the NS gene in A(H1N1)pdm09 lineage was higher than its closely related triple reassortant swine, which could be attributed to the adaptation to the new host and/or intensive surveillance after the inter-species transmission from swine to human. The positive selection sites were found in all lineages except the equine lineage and mostly in the NS1 region. The positive selection sites 22, 26, 226, 227 and 230 of the human lineage are significant because these residues participate in either forming the dimerization of the two RNA binding domain (RBD) monomers or blocking the replication of host genes. Residues at position 171 provide hydrophobic interactions with hydrophobic residues at p85beta and thus induce viral cell growth. The lineages and evolutionary dynamics of influenza A NS gene obtained in this study, along with the studies of other gene segments, are expected to improve the early detection of new viruses and thus have the potential to enhance influenza surveillance. PMID- 24161300 TI - Reducing online identity disclosure using warnings. AB - In an experimental design, we tested whether written warnings can reduce the amount of identity information exposure online. A psychological attack on information privacy that has been shown to be effective in previous research was launched. This attack took advantage of the fact that people respond to certain types of requests in a relatively automatic, or mindless, fashion. The experiment manipulated the word that was used in the alert header: "warning", "caution", or "hazard". All warnings proved to be effective in reducing disclosure, but "hazard" proved to be most effective. Also warnings were more effective in reducing disclosure of driver's license numbers than email addresses. The discussion (a) provides tentative conclusions why these patterns were obtained, (b) suggests how to design warnings in cyber-environments, and (c) addresses future possibilities for research on this topic. PMID- 24161301 TI - Sarcomas of the uterine cervix: a united and multidisciplinary approach is required. PMID- 24161302 TI - Polycystic ovary syndrome: is obesity a symptom? PMID- 24161304 TI - Genetic testing: new challenges in the healthcare of women. Interview by Hannah Branch. AB - Dr Wera Hofmann is an expert in biochemistry and has over 12 years of human genetic diagnostics experience. Until 2006, she supervised a diagnostic unit for BRCA gene testing at the Interdisciplinary Center for Hereditary Breast Cancer (Max Delbruck Center, Berlin, Germany). She has also been the Managing Director of the Professional Association of German Human Geneticists, BVDH, which is a trade association. In 2008, Hofmann became a Medical Director at LifeCodexx (Konstanz, Germany), where she has worked on the development of a noninvasive prenatal diagnostic test that detects chromosomal aneuploidies in fetuses. PMID- 24161305 TI - Eribulin mesylate in breast cancer. AB - Eribulin mesylate is a synthetic analog of halichondrin B (a polyether macrolide isolated from a marine sponge). It is a nontaxane microtubule dynamics inhibitor with a novel mechanism of action. It is the first drug that has demonstrated an improvement in overall survival as a single agent compared with the physician's choice of currently available treatments in locally advanced or metastatic breast cancer, previously treated with anthracyclines and taxanes. It has shown a good manageable tolerability profile. This drug has been approved by the US FDA and by the EMA for patients with locally advanced or metastatic breast cancer who have received at least two chemotherapeutic regimens for advanced/metastatic disease. Prior therapy should have included an anthracycline and a taxane in either the adjuvant or metastatic setting unless patients were not suitable for these treatments. The aim of this article is to describe the mechanism of action, pharmacokinetics, pharmacodynamics and the most relevant clinical trials in the development of this drug. PMID- 24161306 TI - Managing depression during pregnancy. AB - Depression is a common illness during pregnancy, yet it often goes undetected and/or untreated. Untreated depression during pregnancy has been associated with increased rates of adverse maternal, obstetrical and fetal outcomes; consequently, it is crucial to manage these women effectively and adequately during this vulnerable time of their lives. The barriers to treatment include the stigma surrounding mental health and the challenges of navigating the constantly growing, and apparently conflicting, evidence regarding the safety of antidepressant use during pregnancy, as well as other concerns unique to pregnant women. In this paper, we suggest the management of women with depression during pregnancy, using evidence-based information, taking into account all of the aspects of treatment, including screening, risks of untreated depression and evaluation of the safety data regarding pharmaceutical treatments. In addition, we have designed a treatment algorithm to assist clinicians in making evidence based decisions in this highly sensitive and complex clinical field. Finally, it is important to evaluate each woman on an individual, case-by-base basis, in order to ensure the best outcome for both the mother and her baby. PMID- 24161307 TI - Treatment of premenstrual dysphoric disorder. AB - Premenstrual dysphoric disorder (PMDD) is comprised of a cluster of affective, behavioral and somatic symptoms recurring monthly during the luteal phase of the menstrual cycle. The disorder affects 3-8% of menstruating women and represents the more severe and disabling end of the spectrum of premenstrual disorders, which includes premenstrual syndrome and premenstrual aggravation of underlying affective disorder. Rigorous and specific diagnostic criteria for PMDD were specified in the Diagnostic and Statistical Manual of Mental Disorders IV (1994) and reaffirmed in the Diagnostic and Statistical Manual of Mental Disorders V (2013) and, consequently, there has been a marked increase in well-designed, placebo-controlled studies evaluating treatment modalities. Although the exact pathogenesis of PMDD is still elusive, treatment of PMDD and severe premenstrual syndrome has centered on neuromodulation via serotonin reuptake inhibitor antidepressants, and ovulation suppression utilizing various contraceptive and hormonal preparations. Unlike the approach to the treatment of depression, serotonergic antidepressants need not be given daily, but can be effective when used cyclically, only in the luteal phase or even limited to the duration of the monthly symptoms. Less, well-substantiated alternative treatments, such as calcium supplementation, agnus castus (chasteberry), Hypericum perforatum (St John's wort) and cognitive/behavioral/relaxation therapies, may be useful adjuncts in the treatment of PMDD. This review provides an overview of current information on the treatment of PMDD. PMID- 24161308 TI - Complementary and alternative medicine and mind-body therapies for treatment of irritable bowel syndrome in women. AB - Irritable bowel syndrome (IBS) is a common gastrointestinal disorder, characterized by chronic or recurrent abdominal pain with constipation, diarrhea and/or an alternation of the two, and often bloating. Complementary and alternative medicine (CAM) consists of a group of medical treatments that are not commonly considered to be a part of traditional medicine. CAM is commonly used for difficult-to-treat chronic medical conditions. Many patients choose CAM because there are only a limited number of treatments available for IBS or because they would like to have a 'natural therapy'. Mind-body therapies for IBS have proven efficacy, but have not been well accepted by patients or practitioners for treatment. This article reviews the use of CAM and mind-body therapies in IBS, with a focus on probiotics, acupuncture, herbal medicines and psychological therapies. PMID- 24161309 TI - The role of exercise in reducing the risks of gestational diabetes mellitus. AB - Gestational diabetes mellitus (GDM) is the most common medical complication of pregnancy and is particularly prevalent among obese women. Both GDM and obesity confer significant comorbidities for the mother and her offspring, including perinatal complications, excessive fetal growth and long-term risks for maternal and offspring obesity and diabetes. Exercise has well-documented health benefits and reduces peripheral insulin resistance in nonpregnant individuals, a major risk factor for the development of diabetes. Observational studies conducted in large population-based cohorts suggest that women who are the most active before pregnancy are less insulin-resistant in late pregnancy and have lower rates of GDM. This article will review the evidence supporting a role for exercise in the prevention of GDM, the management of glycemic control in women with established GDM, and the reduction of GDM-associated maternal and offspring health consequences. Wherever possible, the discussion will focus on studies carried out on obese women. However, there are many areas where strong evidence is lacking in obese populations, and it may be inferred from similar studies performed in normal weight pregnant women. PMID- 24161310 TI - Primary therapy in breast cancer: what have we learned from landmark trials? AB - Primary anticancer therapy is currently accepted as a therapeutic option for patients with early-stage breast cancer. Its objectives are to increase the chance of achieving a conservative surgery and, similar to adjuvant chemotherapy, to reduce the risk of distant recurrence. The prognostic significance of obtaining a pathological complete response has been evaluated in several randomized clinical trials and meta-analyses. Growing evidence suggests that pathological complete response may act as a valid predictor of overall survival. Of note, a significant association between pathological complete response and outcome has especially been observed in patients with HER2-positive and triple negative (hormonal receptors negative and HER2-negative) breast cancer. This review focuses on recent trials of neoadjuvant treatment with specific attention to HER2-negative disease. PMID- 24161311 TI - Unintended consequences: surgical complications in gynecologic cancer. AB - More than 91,000 women in the USA will be diagnosed with a gynecologic malignancy in 2013. Most will undergo surgery for staging, treatment or both. No therapeutic intervention is without consequence, therefore, it is imperative to understand the possible complications associated with the perioperative period before undertaking surgery. Complication rates are affected by a patient population that is increasingly older, more obese and more medically complicated. Surgical modalities consist of abdominal, vaginal, laparoscopic and robotic-assisted approaches, and also affect rates of complications. An understanding of the various approaches, patient characteristics and surgeon experience allow for individualized decision-making to minimize the complications after surgery for gynecologic cancer. PMID- 24161312 TI - Use of psychotropic medication during pregnancy and the postpartum period. AB - Women with active psychiatric disorders who become pregnant face treatment dilemmas. Although results from studies are inconsistent, small but significant, risks on birth outcomes occur with exposure to untreated disorders, as well as to psychotropic medications. Prenatal antidepressant medication exposure may increase the risk for spontaneous miscarriage, preterm birth, cardiac malformations, persistent pulmonary hypertension of the newborn and postnatal adaptation syndrome. The use of valproate is contraindicated during pregnancy due to teratogenicity and neurocognitive delay and deficits. This review of selected studies will highlight some of the current issues with the use of psychotropic medications during pregnancy and the postpartum period. PMID- 24161314 TI - Subjective cognitive complaints and mortality: does the type of complaint matter? AB - Middle-aged subjects report subjective cognitive complaints (SSCs) but whether these are meaningfully related to health remains unknown. We examined the association between SCCs, both amnestic and non-amnestic, and mortality in a middle-aged population after taking into account the role of depression. 15,510 participants (26.2% women), mean age 57.9 years in 2002, from the French GAZEL study provided data on 3 measures of SCCs: memory complaints, cognitive symptoms (forgetfulness, difficulties in recalling memories, retaining new information, mental calculation, in language, and orientation) and whether they sought medical advice for SCCs. All-cause mortality was assessed between 2002 and 2012. Over the follow-up 56.3% participants reported memory problems, 62.6% cognitive complaints, 22.3% sought medical advice and 651 died. All SCCs were strongly associated (odds ratio 2.08-6.35) with depression which was itself associated with greater mortality (HR = 1.77, 95% CI: 1.50, 2.09). In analyses adjusted for age, sex, education, marital status and depression difficulty in mental calculation (HR = 1.30, 95% CI: 1.08, 1.60) and seeking medical advice for cognitive symptoms (HR = 1.41, 95% CI: 1.18, 1.68) were significantly associated with mortality, while memory complaints did not carry increased risk (HR = 0.93, 95% CI: 0.79, 1.09). All SCCS were strongly associated with depression but not all carried excess risk of mortality. PMID- 24161315 TI - Multiplexed VeraCode bead-based serological immunoassay for colorectal cancer. AB - Colorectal cancer (CRC) is the second leading cause of cancer deaths in the US and Western world. Despite increased screening and advances in treatment, the mortality rate (ca. 50,000/year) and high national health-care burden for CRC are likely to remain high unless an effective non-invasive screening test for CRC is instituted for a large segment of the population. Blood-based protein biomarkers hold great promise for early disease diagnosis and personalized medicine; yet robust and reproducible multiplexing platforms and methodologies have lagged behind their genomic counterparts. Here, we report the development of a novel, multiplexed, hybrid immunoassay for CRC that is formatted on barcoded VeraCodeTM micro-beads, which have until now only been used for genomic assays. The method combines a sandwich immunoassay format for detection of serum protein biomarkers with an antigen assay for autoantibody detection. The serum protein biomarkers CEA and GDF15 as well as autoantibodies to the p53 tumor associated antigen (TAA) were used to exemplify the method. This multiplex biomarker panel was configured to run on Illumina's holographically barcoded VeraCodeTM micro-bead platform, which is capable of measuring hundreds of analytes simultaneously in a single well from small volumes of blood (<50 MUL) using a 96-well industry standard microtiter plate. This novel use of the VeraCodeTM micro-bead platform translates into a potentially low volume, high throughput, multiplexed assay for CRC, for the purposes of biomarker validation, as well as patient screening, diagnostics and prognostics. In an evaluation of a 186 patient sera training set (CRC and normal), we obtained a diagnostic sensitivity of 54% and a specificity of 98%. We anticipate that by expanding and refining the biomarkers in this initial panel, and performing more extensive clinical validations, such an assay could ultimately provide a basis for CRC population screening to complement the more invasive, expensive and low throughput (but highly sensitive and specific) colonoscopy. PMID- 24161316 TI - New therapeutic targets for calcific aortic valve stenosis: the lipoprotein(a) lipoprotein-associated phospholipase A2-oxidized phospholipid axis. PMID- 24161317 TI - The year in review of clinical cardiac electrophysiology. PMID- 24161318 TI - Cancer, chemotherapy, and cor pulmonale. PMID- 24161319 TI - Circulating miR-29a, among other up-regulated microRNAs, is the only biomarker for both hypertrophy and fibrosis in patients with hypertrophic cardiomyopathy. AB - OBJECTIVES: The purpose of this paper was to determine whether microRNAs (miRNAs) involved in myocardial remodeling were differentially expressed in the blood of hypertrophic cardiomyopathy (HCM) patients, and whether circulating miRNAs correlated with the degree of left ventricular hypertrophy and fibrosis. BACKGROUND: miRNAs-small, noncoding ribonucleic acids (RNAs) that regulate gene expression by inhibiting RNA translation-modulate cellular function. Myocardial miRNAs modulate processes such as cardiomyocyte (CM) hypertrophy, excitation contraction coupling, and apoptosis; non-CM-specific miRNAs regulate myocardial vascularization and fibrosis. Recently, the possibility that circulating miRNAs may be biomarkers of cardiovascular disease has been raised. METHODS: Forty-one HCM patients were characterized with conventional transthoracic echocardiography and cardiac magnetic resonance. Peripheral plasma levels of 21 miRNAs were assessed by quantitative real-time polymerase chain reaction and were compared with levels in a control group of 41 age- and sex-matched blood donors. RESULTS: Twelve miRNAs (miR-27a, -199a-5p, -26a, -145, -133a, -143, -199a-3p, -126-3p, 29a, -155, -30a, and -21) were significantly increased in HCM plasma. However, only 3 miRNAs (miR-199a-5p, -27a, and -29a) correlated with hypertrophy; more importantly, only miR-29a correlated also with fibrosis. CONCLUSIONS: Our data suggest that cardiac remodeling associated with HCM determines a significant release of miRNAs into the bloodstream: the circulating levels of both cardiac- and non-cardiac-specific miRNAs are significantly increased in the plasma of HCM patients. However, correlation with left ventricular hypertrophy parameters holds true for only a few miRNAs (i.e., miR-199a-5p, -27a, and -29a), whereas only miR 29a is significantly associated with both hypertrophy and fibrosis, identifying it as a potential biomarker for myocardial remodeling assessment in HCM. PMID- 24161320 TI - Polypill therapy, subclinical atherosclerosis, and cardiovascular events implications for the use of preventive pharmacotherapy: MESA (Multi-Ethnic Study of Atherosclerosis). AB - OBJECTIVES: This study examines whether the coronary artery calcium (CAC) score can be used to define the target population to treat with a polypill. BACKGROUND: Prior studies have suggested a single polypill to reduce cardiovascular disease (CVD) at the population level. METHODS: Participants from MESA (Multi-Ethnic Study of Atherosclerosis) were stratified using the criteria of 4 polypill studies (TIPS [The Indian Polycap Study], Poly-Iran, Wald, and the PILL [Program to Improve Life and Longevity] Collaboration). We compared coronary heart disease (CHD) and CVD event rates and calculated the 5-year number needed to treat (NNT) after stratification based on the CAC score. RESULTS: Among MESA participants eligible for TIPS, Poly-Iran, Wald, and the PILL Collaboration, CAC = 0 was observed in 58.6%, 54.5%, 38.9%, and 40.8%, respectively. The rate of CHD events among those with CAC = 0 varied from 1.2 to 1.9 events per 1,000 person-years, those with CAC scores from 1 to 100 had event rates ranging from 4.1 to 5.5, and in those with CAC scores >100 the event rate ranged from 11.6 to 13.3. The estimated 5-year NNT to prevent 1 CVD event ranged from 81-130 for patients with CAC = 0, 38-54 for those with CAC scores from 1 to 100, and 18-20 for those with CAC scores >100. CONCLUSIONS: In MESA, among individuals eligible for treatment with the polypill, the majority of CHD and CVD events occurred in those with CAC scores >100. The group with CAC = 0 had a very low event rate and a high projected NNT. The avoidance of treatment in individuals with CAC = 0 could allow for significant reductions in the population considered for treatment, with a more selective use of the polypill and, as a result, avoidance of treatment in those who are unlikely to benefit. PMID- 24161321 TI - Short- versus long-term duration of dual antiplatelet therapy in patients treated for in-stent restenosis: a PRODIGY trial substudy (Prolonging Dual Antiplatelet Treatment After Grading Stent-Induced Intimal Hyperplasia). AB - OBJECTIVES: This study sought to investigate the clinical outcome of patients treated with percutaneous coronary intervention (PCI) for in-stent restenosis (ISR) randomized to short (6 months) versus long (24 months) dual antiplatelet therapy (DAPT) regimen. BACKGROUND: It is still unclear if patients treated for ISR may benefit from a long DAPT regimen. METHODS: For the present purpose, we selected 224 patients undergoing the PCI procedure for ISR enrolled in the PRODIGY (Prolonging Dual Antiplatelet Treatment After Grading Stent-Induced Intimal Hyperplasia) trial and randomized to short (6 months) versus long (24 months) DAPT regimen. The primary objective was the cumulative incidence of death, nonfatal myocardial infarction (MI), or cerebrovascular accident at 24 months. Safety endpoints were moderate and major bleeding complications. RESULTS: Overall, 114 patients were allocated to short DAPT regimen, whereas 110 patients were allocated to long DAPT regimen. Twenty-seven patients reached the primary endpoint (19 in short DAPT regimen vs. 8 in long DAPT regimen; p = 0.02). The cumulative incidence of the primary endpoint at 24 months was 16.7% in the short DAPT regimen group compared with 7.3% in the long DAPT regimen group (p = 0.034). This is principally due to a lower occurrence of death and MI in the long DAPT regimen group as compared to the short DAPT regimen group (6.5% vs. 15.5%; p = 0.03). There was no difference in the occurrence of bleeding complications between long and short DAPT regimen. CONCLUSIONS: Our study offers preliminary evidence that patients receiving a new PCI procedure for ISR may benefit from long-term administration of aspirin plus clopidogrel. (Synergy Between Stent and Drugs to Avoid Ischemic Recurrences After Percutaneous Coronary Intervention [PRODIGY]; NCT00611286). PMID- 24161322 TI - Heart failure with preserved ejection fraction: comparison of patients with and without angina pectoris (from the Duke Databank for Cardiovascular Disease). AB - OBJECTIVES: This study investigated the characteristics and outcomes of patients with heart failure with preserved ejection fraction (HFpEF) and angina pectoris (AP). BACKGROUND: AP is a predictor of adverse events in patients with heart failure with reduced EF. The implications of AP in HFpEF are unknown. METHODS: We analyzed HFpEF patients (EF >=50%) who underwent coronary angiography at Duke University Medical Center from 2000 through 2010 with and without AP in the previous 6 weeks. Time to first event was examined using Kaplan-Meier methods for the primary endpoint of death/myocardial infarction (MI)/revascularization/stroke (i.e., major adverse cardiac events [MACE]) and secondary endpoints of death/MI/revascularization, death/MI/stroke, death/MI, death, and cardiovascular death/cardiovascular hospitalization. RESULTS: In the Duke Databank, 3,517 patients met criteria for inclusion and 1,402 (40%) had AP. Those with AP were older with more comorbidities and prior revascularization compared with non-AP patients. AP patients more often received beta-blockers, angiotensin-converting enzyme inhibitors, nitrates, and statins (all p < 0.05). In unadjusted analysis, AP patients had increased MACE and death/MI/revascularization (both p < 0.001), lower rates of death and death/MI (both p < 0.05), and similar rates of death/MI/stroke and cardiovascular death/cardiovascular hospitalization (both p > 0.1). After multivariable adjustment, those with AP remained at increased risk for MACE (hazard ratio [HR]: 1.30, 95% confidence interval [CI]: 1.17 to 1.45) and death/MI/revascularization (HR: 1.29, 95% CI: 1.15 to 1.43), but they were at similar risk for other endpoints (p > 0.06). CONCLUSIONS: AP in HFpEF patients with a history of coronary artery disease is common despite medical therapy and is independently associated with increased MACE due to revascularization with similar risk of death, MI, and hospitalization. PMID- 24161323 TI - Lipoprotein(a) for risk assessment in patients with established coronary artery disease. AB - OBJECTIVES: The purpose of this study was to assess the prognostic utility of lipoprotein(a) [Lp(a)] in individuals with coronary artery disease (CAD). BACKGROUND: Data regarding an association between Lp(a) and cardiovascular (CV) risk in secondary prevention populations are sparse. METHODS: Plasma Lp(a) was measured in 6,708 subjects with CAD from 3 studies; data were then combined with 8 previously published studies for a total of 18,978 subjects. RESULTS: Across the 3 studies, increasing levels of Lp(a) were not associated with the risk of CV events when modeled as a continuous variable (odds ratio [OR]: 1.03 per log transformed SD, 95% confidence interval [CI]: 0.96 to 1.11) or by quintile (Q5:Q1 OR: 1.05, 95% CI: 0.83 to 1.34). When data were combined with previously published studies of Lp(a) in secondary prevention, subjects with Lp(a) levels in the highest quantile were at increased risk of CV events (OR: 1.40, 95% CI: 1.15 to 1.71), but with significant between-study heterogeneity (p = 0.001). When stratified on the basis of low-density lipoprotein (LDL) cholesterol, the association between Lp(a) and CV events was significant in studies in which average LDL cholesterol was >=130 mg/dl (OR: 1.46, 95% CI: 1.23 to 1.73, p < 0.001), whereas this relationship did not achieve statistical significance for studies with an average LDL cholesterol <130 mg/dl (OR: 1.20, 95% CI: 0.90 to 1.60, p = 0.21). CONCLUSIONS: Lp(a) is significantly associated with the risk of CV events in patients with established CAD; however, there exists marked heterogeneity across trials. In particular, the prognostic value of Lp(a) in patients with low cholesterol levels remains unclear. PMID- 24161324 TI - Increased need for right ventricular support in patients with chemotherapy induced cardiomyopathy undergoing mechanical circulatory support: outcomes from the INTERMACS Registry (Interagency Registry for Mechanically Assisted Circulatory Support). AB - OBJECTIVES: The aim of this study was to investigate the use of durable mechanical circulatory support (MCS) in patients with chemotherapy-induced cardiomyopathy (CCMP) and determine their outcomes and survival in comparison to that of other patients with end-stage heart failure treated similarly. BACKGROUND: Patients with end-stage heart failure as a result of CCMP from anthracyclines are often precluded from heart transplantation because of a history of cancer. In such patients, durable MCS may offer an important chance for life prolongation. Yet, there are no data to support the use of MCS in this increasingly prevalent group of patients. METHODS: We searched 3,812 MCS patients from June 2006 through March 2011 in the INTERMACS (Interagency Registry for Mechanically Assisted Circulatory Support) database for the diagnosis of CCMP. We compared characteristics, outcomes, and survival between CCMP patients and patients with nonischemic cardiomyopathy and ischemic cardiomyopathy. RESULTS: Compared with patients with nonischemic cardiomyopathy and ischemic cardiomyopathy, patients with CCMP were overwhelmingly female (72% vs. 24% vs. 13%, p = 0.001), had MCS more often implanted as destination therapy (33% vs. 14% vs. 22%, p = 0.03), required more right ventricular assist device support (19% vs. 11% vs. 6%, p = 0.006), and had a higher risk of bleeding (p = 0001). Survival of CCMP patients was similar to that of other groups. CONCLUSIONS: CCMP patients treated with MCS have survival similar to other MCS patients despite more frequent need for right ventricular assist device support and increased bleeding risk. PMID- 24161326 TI - "De-risking" risk reduction: should coronary artery calcium scoring be the gatekeeper to preventive pharmacotherapy with the polypill? PMID- 24161325 TI - Elevated expression of lipoprotein-associated phospholipase A2 in calcific aortic valve disease: implications for valve mineralization. AB - OBJECTIVES: This study sought to document the presence and role of lipoprotein associated phospholipase A2 (Lp-PLA2) in calcific aortic valve disease (CAVD). BACKGROUND: CAVD is a chronic disorder characterized by pathological mineralization and remodeling. Studies have indicated that human CAVD tissues are infiltrated by lipids and that inflammation may play a role in the pathobiology. We hypothesized that Lp-PLA2 (encoded by the PLA2G7 gene) is expressed in CAVD and may play a role in the mineralization of valve interstitial cells. METHODS: We have documented the expression of the phospholipase A2 family of genes in aortic valves by using a transcriptomic assay. Messenger ribonucleic acid and protein expression were confirmed in aortic valves explanted from 60 patients by quantitative polymerase chain reaction and immunohistochemistry, respectively. The effect of lysophosphatidylcholine, the product of Lp-PLA2 activity, was documented on the mineralization of valve interstitial cell cultures. RESULTS: Transcriptomic analyses of CAVD and control nonmineralized aortic valves revealed that Lp-PLA2 was increased by 4.2-fold in mineralized aortic valves. Higher expression of Lp-PLA2 in stenotic aortic valves was confirmed by quantitative polymerase chain reaction, immunohistochemistry, and enzymatic Lp-PLA2 activity. The number of Lp-PLA2 transcripts correlated with several indexes of tissue remodeling. In vitro, lysophosphatidylcholine increased the expression of alkaline phosphatase, the ectonucleotide pyrophosphatase/phosphodiesterase 1 enzyme, sodium-dependent phosphate cotransporter 1 (encoded by the SLC20A1 gene), and osteopontin. We then showed that lysophosphatidylcholine-induced mineralization involved ectonucleotidase enzyme as well as apoptosis through a protein-kinase-A-dependent pathway. CONCLUSIONS: Together, these results demonstrated that Lp-PLA2 is highly expressed in CAVD, and it plays a role in the mineralization of valve interstitial cells. Further work is necessary to document whether Lp-PLA2 could be considered as a novel target in CAVD. PMID- 24161327 TI - Our preoccupation with renal artery disease in patients undergoing cardiac surgery: much ado about nothing? PMID- 24161328 TI - The impact of renal artery stenosis on outcomes after open-heart surgery. AB - OBJECTIVES: The aim of this study was to assess the impact of atherosclerotic renal artery stenosis (ARAS) on outcomes after open-heart surgery (OHS). BACKGROUND: Acute kidney injury after OHS portends significant morbidity and mortality. METHODS: Data from all adult patients undergoing OHS from January 2000 to April 2010 who underwent renal duplex ultrasound were prospectively collected. ARAS was severe (60% to 99% stenosis) if peak systolic velocity was >200 cm/s. The associations between ARAS and post-operative reduction in glomerular filtration rate (GFR), need for renal replacement therapy, length of stay, and overall short-term and long-term mortality (up to 8 years) were tested using multivariate time-to-event adjusted analysis. RESULTS: A total of 714 patients were evaluated, with a mean age of 67 +/- 12 years (63% men) and a mean GFR of 52 +/- 25.9 ml/min/1.73 m(2). A total of 206 (29%) had ARAS; of these, 79% (n = 163) had unilateral and 21% (n = 43) had bilateral ARAS. ARAS was associated with peripheral artery disease (p = 0.004) and lower high-density lipoprotein levels (p = 0.04). Patients with advanced age (p = 0.01) and descending aorta grafting (p = 0.004) had significant post-operative reductions in GFR. Adjusted models showed a nonsignificant trend between ARAS and reduction in GFR (p = 0.09). ARAS was not associated with need for renal replacement therapy (p = 0.4), longer length of stay (p = 0.7), or mortality (p = 0.7), but low pre-operative GFR was a strong predictor of long-term mortality. CONCLUSIONS: ARAS does not appear to be associated with post-operative change in GFR, need for hemodialysis, longer length of stay, or mortality in patients undergoing OHS. PMID- 24161329 TI - Percutaneous mitral valve repair with the MitraClip system for severe mitral regurgitation in patients with surgical mitral valve repair failure. PMID- 24161330 TI - Statistical uncertainty in 10-year Framingham risk of coronary heart disease and cardiovascular disease. PMID- 24161331 TI - Positron emission tomography/computed tomography for diagnosis of prosthetic valve endocarditis: suggestions to increase diagnostic accuracy. PMID- 24161332 TI - Same-day discharge after percutaneous coronary intervention: trial sequential analysis of outcomes. PMID- 24161333 TI - AMG 145, a monoclonal antibody against PCSK9, facilitates achievement of national cholesterol education program-adult treatment panel III low-density lipoprotein cholesterol goals among high-risk patients: an analysis from the LAPLACE-TIMI 57 trial (LDL-C assessment with PCSK9 monoclonal antibody inhibition combined with statin thErapy-thrombolysis in myocardial infarction 57). AB - OBJECTIVES: This study sought to define the ability of AMG 145, a monoclonal antibody directed against proprotein convertase subtilisin kexin type 9 (PCSK9), to enable subjects at high risk for major adverse cardiovascular events to achieve National Cholesterol Education Program-Adult Treatment Panel III (NCEP ATP III) parameters for low-density lipoprotein cholesterol (LDL-C) and other lipid goals. BACKGROUND: Many patients at high risk for adverse cardiovascular events are unable to achieve the NCEP-ATP III LDL-C goal of <70 mg/dl, even with high-potency statin therapy. METHODS: In 282 subjects from the LAPLACE-TIMI 57 (LDL-C Assessment with PCSK9 monoclonaL Antibody Inhibition Combined With Statin thErapy-Thrombolysis In Myocardial Infarction 57) trial at high risk according to NCEP-ATP III criteria, we compared the proportion of subjects achieving the NCEP ATP III recommended LDL-C goal of <70 mg/dl across treatment arms. Other outcomes included the triple goals of LDL-C <70 mg/dl, non-high-density lipoprotein cholesterol (HDL-C) <100 mg/dl, and apolipoprotein B (ApoB) <80 mg/dl. RESULTS: During the dosing interval, more than 90% of subjects in both of the top dose groups every 2 weeks and every 4 weeks attained this lipid target over the dosing interval, with similar success rates for the triple lipid goal. CONCLUSIONS: PCSK9 inhibition with AMG 145 enables high-risk patients to achieve established lipid goals. If this therapy demonstrates efficacy for reducing cardiovascular events with a favorable safety profile in ongoing phase 3 trials, we believe it will have major public health implications. PMID- 24161335 TI - TAVI in patients unsuitable for surgery: a prognostic benefit for all? PMID- 24161334 TI - Stratification of outcomes after transcatheter aortic valve replacement according to surgical inoperability for technical versus clinical reasons. AB - OBJECTIVES: The goal of this study was to examine the impact of reasons for surgical inoperability on outcomes in patients undergoing transcatheter aortic valve replacement (TAVR). BACKGROUND: Patients with severe aortic stenosis may be deemed inoperable due to technical or clinical reasons. The relative impact of each designation on early and late outcomes after TAVR is unclear. METHODS: Patients were studied from the inoperable arm (cohort B) of the randomized PARTNER (Placement of Aortic Transcatheter Valve) trial and the nonrandomized continued access registry. Patients were classified according to whether they were classified as technically inoperable (TI) or clinically inoperable (CLI). Reasons for TI included porcelain aorta, previous mediastinal radiation, chest wall deformity, and potential for injury to previous bypass graft on sternal re entry. Reasons for CLI were systemic factors that were deemed to make survival unlikely. RESULTS: Of the 369 patients, 23.0% were considered inoperable for technical reasons alone; the remaining were judged to be CLI. For TI, the most common cause was a porcelain aorta (42%); for CLI, it was multiple comorbidities (48%) and frailty (31%). Quality of life and 2-year mortality were significantly better among TI patients compared with CLI patients (mortality 23.3% vs. 43.8%; p < 0.001). Nonetheless, TAVR led to substantial survival benefits compared with standard therapy in both inoperable cohorts. CONCLUSIONS: Patients undergoing TAVR based solely on TI have better survival and quality of life improvements than those who are inoperable due to clinical comorbidities. Both TI and CLI TAVR have significant survival benefit in the context of standard therapy. (THE PARTNER TRIAL: Placement of AoRTic TraNscathetER Valve Trial; NCT00530894). PMID- 24161336 TI - Intrapericardial schwannoma presenting as acute coronary syndrome. PMID- 24161337 TI - A rare association of cor triatriatum sinister with congenitally corrected transposition of great arteries. PMID- 24161338 TI - Elevated lipoprotein(a) and risk of aortic valve stenosis in the general population. AB - OBJECTIVES: The purpose of this study was to determine whether elevated lipoprotein(a) levels and corresponding LPA risk genotypes (rs10455872, rs3798220, kringle IV type 2 repeat polymorphism) prospectively associate with increased risk of aortic valve stenosis (AVS). BACKGROUND: The etiologic basis of AVS is unclear. Recent data implicate an LPA genetic variant (rs10455872), associated with Lp(a) levels, in calcific AVS. METHODS: We combined data from 2 prospective general population studies, the Copenhagen City Heart Study (1991 to 2011; n = 10,803) and the Copenhagen General Population Study (2003 to 2011; n = 66,877), following up 77,680 Danish participants for as long as 20 years, during which time 454 were diagnosed with AVS. We conducted observational and genetic instrumental variable analyses in a Mendelian randomization study design. RESULTS: Elevated Lp(a) levels were associated with multivariable adjusted hazard ratios for AVS of 1.2 (95% confidence interval [CI]: 0.8 to 1.7) for 22nd to 66th percentile levels (5 to 19 mg/dl), 1.6 (95% CI: 1.1 to 2.4) for 67th to 89th percentile levels (20 to 64 mg/dl), 2.0 (95% CI: 1.2 to 3.4) for 90th to 95th percentile levels (65 to 90 mg/dl), and 2.9 (95% CI: 1.8 to 4.9) for levels greater than 95th percentile (>90 mg/dl), versus levels less than the 22nd percentile (<5 mg/dl; trend, p < 0.001). Lp(a) levels were elevated among carriers of rs10455872 and rs3798220 minor alleles, and of low number of KIV-2 repeats (trend, all p < 0.001). Combining all genotypes, instrumental variable analysis yielded a genetic relative risk for AVS of 1.6 (95% CI: 1.2 to 2.1) for a 10-fold Lp(a) increase, comparable to the observational hazard ratio of 1.4 (95% CI: 1.2 to 1.7) for a 10-fold increase in Lp(a) plasma levels. CONCLUSIONS: Elevated Lp(a) levels and corresponding genotypes were associated with increased risk of AVS in the general population, with levels >90 mg/dl predicting a threefold increased risk. PMID- 24161339 TI - Minimally invasive surgery for primary supratentorial intracerebral haemorrhage. AB - The use of minimally invasive surgery (MIS) in the treatment of primary supratentorial intracerebral haemorrhage (ICH) is controversial. This review was undertaken to combine all available evidence on this topic and to assess the efficacy of MIS compared to medical treatment or haematoma evacuation via craniotomy for patients with primary supratentorial ICH. The Cochrane Central Register of Controlled Trials, MEDLINE and EMBASE databases were searched for randomised controlled trials which compared MIS to any control treatment for intracerebral haemorrhage. Conference proceedings, reference lists and internet based clinical trial registries were searched for additional studies. Quality was assessed using the Cochrane "risk of bias" analysis tool. The methodological quality of studies was not high, with only two studies conforming to all quality standards assessed. There were 11 studies with 1717 patients. There was a significant reduction in relative risk (RR) for death at end of follow-up when MIS was compared to both medical management (RR = 0.67, 95% confidence interval 0.53-0.84) and craniotomy (RR = 0.57, 95% confidence interval 0.39-0.84) with no significant heterogeneity. Non-significant benefits were observed for the outcomes death or dependent survival (RR = 0.95, 95% confidence interval 0.91 1.00) and independent survival (RR = 1.24, 95% confidence interval 0.99-1.55). There was significant heterogeneity for both these outcomes. MIS for primary supratentorial ICH is associated with a significant reduction in the RR of death when compared to medical management and craniotomy. Other important outcomes need further evaluation. PMID- 24161340 TI - Recanalisation success is associated with good clinical outcome despite advanced age and stroke severity in patients treated with the Solitaire stentriever. AB - Intravenous recombinant tissue plasminogen activator is associated with significant recanalisation failure in the setting of large artery occlusion. Endovascular treatment by stentriever achieves improved rates of recanalisation but its impact on clinical outcomes remains unclear. We hypothesise that successful recanalisation, unattentuated by age and stroke severity, is associated with improved clinical outcomes in patients treated with the Solitaire stentriever (ev3 Endovascular, Plymouth, MN, USA). We conducted a retrospective study of 60 consecutive acute ischaemic stroke patients treated with the Solitaire stentriever. The data included demographics, vascular risk factors, ictal onset time, National Institutes of Health Stroke Scale (NIHSS) score at presentation, angiographic findings, post-procedure imaging, and clinical follow up. Recanalisation success was defined as a thrombolysis in cerebral infarction score (TICI) >= 2b. Good clinical outcome was defined as a modified Rankin Scale score (mRS) <= 2 at 3 months. Of the 60 patients, the mean age was 64.1 (standard deviation 13.4) years and 68.3% were men. Median NIHSS score at presentation was 18 (interquartile range 14-22). Successful recanalisation (TICI >= 2b) was achieved in 44 patients (73.3%). Of these 44 patients, 25 patients (56.8%) achieved mRS <= 2 at 3months. Multiple logistic regression showed significant association between recanalisation success and improved clinical outcome (p=0.019). Of all patients, four (6.7%) developed symptomatic intracranial haemorrhage. Overall mortality was 28.3%. In conclusion, the Solitaire stentriever was associated with improved recanalisation rates. We showed that successful recanalisation is associated with good clinical outcomes after adjustments for age, sex and stroke severity. PMID- 24161341 TI - Concurrent split cord malformation and teratoma: dysembryology, presentation, and treatment. AB - Split cord malformation (SCM) is a rare form of spinal dysraphism in which the spinal cord is divided in the sagittal plane, forming a double neural tube. In addition to being associated with a variety of malformations, SCM may occur with spinal cord tumors, with only exceptional cases involving teratomas. As only eight patients with a teratoma associated with SCM have been reported, their presentation characteristics and treatment are currently unclear. We review the literature of all patients with SCM with concurrent spinal teratoma, discuss the potential dysembryology, and report the first case of SCM with concurrent spinal teratoma in an elderly patient. The mean age of those with concurrent SCM and teratomas was 39.4 years, with 55.6% occurring in females. The lumbar spine was the most frequent location for teratomas (66.7%), with the Type II malformation more commonly occurring with these tumors (75%). The duration of symptoms varied widely, ranging from 1 month to 5 years, with the average duration being nearly 2 years. Back pain (87.5%) and lower extremity weakness (75%) were the most common presenting symptoms. As SCM may be associated with progressive neurological deterioration and teratomas can contain immature or malignant components, surgery should be attempted with the goal of gross total resection. Nonetheless, in patients with a concurrent tumor and spinal dysraphism, spinal teratomas should be considered in the differential diagnosis. Gross total resection of these lesions may be safely achieved even in the presence of SCM using intraoperative electrophysiologic monitoring. PMID- 24161342 TI - Secondary syphilis with oral manifestation. PMID- 24161343 TI - Coupled methyl group epimerization and reduction by polyketide synthase ketoreductase domains. Ketoreductase-catalyzed equilibrium isotope exchange. AB - Incubation of [2-(2)H]-(2S,3R)-2-methyl-3-hydroxypentanoyl-SACP ([2-(2)H]-1a) with the epimerizing ketoreductase domain EryKR1 in the presence of a catalytic amount NADP(+) (0.05 equiv) resulted in time- and cofactor-dependent washout of deuterium from 1a, as a result of equilibrium isotope exchange of transiently generated [2-(2)H]-2-methyl-3-ketopentanoyl-ACP. Incubations of [2-(2)H]-(2S,3S) 2-methyl-3-hydroxy-pentanoyl-SACP with RifKR7 and with NysKR1 also resulted in time-dependent loss of deuterium. By contrast, incubations of [2-(2)H]-(2R,3S)-2 methyl-3-hydroxypentanoyl-SACP and [2-(2)H]-(2R,3R)-2-methyl-3-hydroxypentanoyl SACP with the non-epimerizing ketoreductase domains EryKR6 and TylKR1, respectively, did not result in any significant washout of deuterium. The isotope exchange assay directly establishes that specific polyketide synthase ketoreductase domains also have an intrinsic epimerase activity, thus enabling mechanistic analysis of a key determinant of polyketide stereocomplexity. PMID- 24161344 TI - A novel synthetic analog of Militarin, MA-1 induces mitochondrial dependent apoptosis by ROS generation in human lung cancer cells. AB - A synthetic Militarin analog-1[(2R,3R,4R,5R)-1,6-bis(4-(2,4,4-trimethylpentan-2 yl)phenoxy) hexane-2,3,4,5-tetraol] is a novel derivative of constituents from Cordyceps militaris, which has been used to treat a variety of chronic diseases including inflammation, diabetes, hyperglycemia and cancers. Here, we report for the first time the synthesis of Militarin analog-1 (MA-1) and the apoptotic mechanism of MA-1 against human lung cancer cell lines. Treatment with MA-1 significantly inhibited the viability of 3 human lung cancer cell lines. The inhibition of viability and growth in MA-1-treated A549 cells with an IC50 of 5MUM were mediated through apoptosis induction, as demonstrated by an increase in DNA fragmentation, sub-G0/G1-DNA fraction, nuclear condensation, and phosphatidylserine exposure. The apoptotic cell death caused mitochondrial membrane permeabilization through regulation of expression of the Bcl-2 family proteins, leading to cytochrome c release in a time-dependent manner. Subsequently, the final stage of apoptosis, activation of caspase-9/-3 and cleavage of poly (ADP ribose) polymerase, was induced. Furthermore, A549 lung cancer cells were more responsive to MA-1 than a bronchial epithelial cell line (BEAS-2B), involving the rapid generation of reactive oxygen species (ROS), c-Jun N-terminal kinase (JNK) and p38 mitogen-activated protein kinase (MAPK) activation. The pharmacological inhibition of ROS generation and JNK/p38 MAPK exhibited attenuated DNA fragmentation in MA-1-induced apoptosis. Oral administration of MA-1 also retarded growth of A549 orthotopic xenografts. In conclusion, the present study indicates that the new synthetic derivative MA-1 triggers mitochondrial apoptosis through ROS generation and regulation of MAPKs and may be a potent therapeutic agent against human lung cancer. PMID- 24161345 TI - The interactions of azure B, a metabolite of methylene blue, with acetylcholinesterase and butyrylcholinesterase. AB - Methylene blue (MB) is reported to possess diverse pharmacological actions and is attracting increasing attention for the treatment of neurodegenerative disorders such as Alzheimer's disease. Among the pharmacological actions of MB, is the significant inhibition of acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE). These activities may, at least in part, underlie MB's beneficial effects in Alzheimer's disease. MB is metabolized to yield N-demethylated products of which azure B, the monodemethyl metabolite, is the predominant species. Azure B has been shown to be pharmacologically active and also possesses a variety of biological actions. Azure B therefore may contribute to the pharmacological profile of MB. Based on these considerations, the present study investigates the possibility that azure B may, similar to MB, act as an inhibitor of human AChE and BuChE. The results document that azure B inhibits AChE and BuChE with IC50 values of 0.486MUM and 1.99MUM, respectively. The results further show that azure B inhibits AChE and BuChE reversibly, and that the modes of inhibition are most likely competitive. Although the AChE and BuChE inhibitory activities of azure B are twofold and fivefold, respectively, less potent than those recorded for MB [IC50(AChE)=0.214MUM; IC50(BuChE)=0.389MUM] under identical conditions, azure B may be a contributor to MB's in vivo activation of the cholinergic system and beneficial effects in Alzheimer's disease. PMID- 24161347 TI - Risk of congenital malformations among offspring of mothers and fathers with celiac disease: a nationwide cohort study. AB - BACKGROUND & AIMS: Many patients with celiac disease experience malabsorption, weight loss, and anemia; undiagnosed celiac disease during pregnancy has been linked with adverse outcomes. Studies of celiac disease and congenital malformations in offspring have been underpowered. We investigated the risk of congenital malformations among the offspring of parents with celiac disease. METHODS: We performed a nationwide cohort study of data from linked health care registers in Sweden from 1973 through 2009. We collected histopathology data from 28 pathology departments in Sweden to identify individuals with celiac disease (based on the presence of villous atrophy). We estimated the risks of malformations in the offspring of mothers and fathers with and without celiac disease. Logistic regression was used to estimate adjusted prevalence odds ratios (aPORs) with 95% confidence intervals (CIs). RESULTS: Among 11,382 offspring of mothers with celiac disease, there were 672 cases (5.9%) of malformation compared with 2098 cases (5.1%) among 40,922 offspring of mothers without celiac disease. Similarly, 352 (5.9%) of 6002 offspring of fathers with celiac disease and 1009 (5.1%) of 19,600 offspring of fathers without celiac disease had a malformation. In adjusted analyses, the offspring of mothers or fathers with celiac disease had a slightly increased risk of having children with malformations (for those with mothers with celiac disease: aPOR, 1.15; 95% CI, 1.05-1.26; for those with fathers with celiac disease: aPOR, 1.14; 95% CI, 1.00-1.29). However, these excess risks decreased or vanished entirely when we restricted our data to births since 2000 (for those with mothers with celiac disease: aPOR, 1.11; and 95% CI, 0.79-1.56; for those with fathers with celiac disease: aPOR, 1.01; 95% CI, 0.81 1.26). CONCLUSIONS: In a nationwide study, we found an increased risk for malformation among the offspring of mothers or fathers with celiac disease. However, the excess risk is small; the upper limits of the CIs for malformation indicate a 29% maximum relative increase. PMID- 24161348 TI - Obstructive sleep apnea and environmental contributors for Barrett's esophagus. PMID- 24161346 TI - Diversity among Tacaribe serocomplex viruses (Family Arenaviridae) associated with the southern plains woodrat (Neotoma micropus). AB - The southern plains woodrat (Neotoma micropus) is the principal host of Catarina virus in southern Texas and a natural host of other North American Tacaribe serocomplex viruses. The objectives of this study were to increase our knowledge of the genetic diversity among Tacaribe serocomplex viruses associated with N. micropus and to define better the natural host relationships of these viruses. Pairwise comparisons of complete glycoprotein precursor gene sequences and complete nucleocapsid protein gene sequences revealed a high level of genetic diversity among Tacaribe serocomplex viruses associated with N. micropus in western Oklahoma, southern New Mexico, and northern and southern Texas. Collectively, the results of Bayesian analyses of nucleotide sequences and pairwise comparisons of amino acid sequences confirmed that the arenaviruses associated with N. micropus in Oklahoma and New Mexico should be included in the Whitewater Arroyo species complex, and indicated that that the arenaviruses associated with N. micropus in northern Texas are strains of a novel arenaviral species--tentatively named "Middle Pease River virus". Together, the results of assays for arenavirus and assays for anti-arenavirus antibody in 54 southern plains woodrats and 325 other rodents captured at 2 localities suggested that the southern plains woodrat is the principal host of Middle Pease River virus in northern Texas. PMID- 24161349 TI - Association between reduced plasma 25-hydroxy vitamin D and increased risk of cancer in patients with inflammatory bowel diseases. AB - BACKGROUND & AIMS: Vitamin D deficiency is common among patients with inflammatory bowel diseases (IBD) (Crohn's disease or ulcerative colitis). The effects of low plasma 25-hydroxy vitamin D (25[OH]D) on outcomes other than bone health are understudied in patients with IBD. We examined the association between plasma level of 25(OH)D and risk of cancers in patients with IBD. METHODS: From a multi-institutional cohort of patients with IBD, we identified those with at least 1 measurement of plasma 25(OH)D. The primary outcome was development of any cancer. We examined the association between plasma 25(OH)D and risk of specific subtypes of cancer, adjusting for potential confounders in a multivariate regression model. RESULTS: We analyzed data from 2809 patients with IBD and a median plasma level of 25(OH)D of 26 ng/mL. Nearly one-third had deficient levels of vitamin D (<20 ng/mL). During a median follow-up period of 11 years, 196 patients (7%) developed cancer, excluding nonmelanoma skin cancer (41 cases of colorectal cancer). Patients with vitamin D deficiency had an increased risk of cancer (adjusted odds ratio, 1.82; 95% confidence interval, 1.25-2.65) compared with those with sufficient levels. Each 1-ng/mL increase in plasma 25(OH)D was associated with an 8% reduction in risk of colorectal cancer (odds ratio, 0.92; 95% confidence interval, 0.88-0.96). A weaker inverse association was also identified for lung cancer. CONCLUSIONS: In a large multi-institutional IBD cohort, a low plasma level of 25(OH)D was associated with an increased risk of cancer, especially colorectal cancer. PMID- 24161350 TI - Portosplenomesenteric venous thrombosis in patients with acute pancreatitis is associated with pancreatic necrosis and usually has a benign course. AB - BACKGROUND & AIMS: Although there are some data on prevalence of portosplenomesenteric venous thrombosis (PSMVT) in patients with acute pancreatitis (AP), the progression of PSMVT in patients who have and have not received anticoagulants has not been studied systematically. We evaluated the prevalence and natural history of PSMVT in a well-defined cohort of individuals with AP. METHODS: In a retrospective study, we analyzed data from the University of Pittsburgh Medical Center on 162 patients with a sentinel attack of AP from 2003-2010. Data were collected on patient demographics, clinical presentation, etiology, clinical course, and outcomes. One hundred twenty-two patients underwent contrast-enhanced computed tomography; the scans were reviewed to identify thromboses and/or narrowing of splanchnic veins (splenic, superior mesenteric, and portal). RESULTS: PSMVT was detected in 22 patients overall (14%; 18% among patients who underwent contrast-enhanced computed tomography). Median time to detection of PSMVT was 17 days (interquartile range, 11-40 days). PSMVT formed most frequently in the splenic vein (19 of 22, 86%), followed by portal (8 of 22, 36%) and superior mesenteric (6/22, 27%) veins. Development of PSMVT was associated with presence (21 of 22, 95%), location, and extent of pancreatic necrosis. Fifty-three percent of patients (21 of 40) with necrosis developed PSMVT. Anticoagulants were administered infrequently (6 of 22, 27%) and always for indications unrelated to PSMVT. Most patients with PSMVT developed collateral veins (19 of 22, 86%), and 27% (6 of 22) were found to have varices during endoscopic evaluation, but clot resolution was infrequent (2 of 22, 9%). No patient developed complications directly related to PSMVT. CONCLUSIONS: PSMVT develops in about half of patients with necrotizing AP and is rare in the absence of necrosis. Despite infrequent administration of anticoagulants, complications directly related to PSMVT are rare. PMID- 24161351 TI - If your physician cannot help, try cannabis: how trial design may lead to hazardous conclusions. PMID- 24161353 TI - Effects of autofluorescence imaging on detection and treatment of early neoplasia in patients with Barrett's esophagus. AB - BACKGROUND & AIMS: Studies have reported that autofluorescence imaging (AFI) increases targeted detection of high-grade intraepithelial neoplasia (HGIN) and intramucosal cancer (IMC) in patients with Barrett's esophagus (BE). We analyzed data from trials to assess the clinical relevance of AFI-detected lesions. METHODS: We collected information on 371 patients with BE, along with endoscopy and histology findings, from databases of 5 prospective studies of AFI (mean age, 65 years; 305 male). We compared these data with outcomes of treatment and follow up. Study end points included the diagnostic value of AFI (proportion of surveillance patients with HGIN or IMC detected only by AFI-targeted biopsies) and value of AFI in selection of therapy (the proportion of patients for which detection of an HGIN or IMC lesion by AFI changed the treatment strategy based on white-light endoscopy or random biopsy analysis). RESULTS: Of study participants, 211 were referred for surveillance and 160 were referred for early stage neoplasia; HGIN or IMC were diagnosed in 147 patients. In 211 patients undergoing surveillance, 39 had HGIN or IMC (23 detected by white-light endoscopy, 11 detected by random biopsies, 5 detected by AFI). So, the diagnostic value of AFI was 5 (2%) of 211. In 24 patients, HGIN or IMC was diagnosed using only AFI. In 33 patients, AFI detected additional HGINs or IMCs next to lesions detected by primary white-light endoscopy. Lesions detected by AFI were treated in 57 patients: 26 patients underwent radiofrequency ablation and showed full remission of neoplasia, whereas 31 underwent endoscopic resection and 6 were found to have IMC. The value of AFI in selection of therapy was 6 (2%) of 371. CONCLUSIONS: Based on an analysis of data from clinical trials of patients with BE, detection of lesions by AFI has little effect on the diagnosis of early stage neoplasia or therapeutic decision making. AFI therefore has a limited role in routine surveillance or management of patients with BE. PMID- 24161352 TI - Development of a program to train physician extenders to perform transnasal esophagoscopy and screen for Barrett's esophagus. AB - BACKGROUND & AIMS: Screening for Barrett's esophagus (BE) and esophageal adenocarcinoma is not recommended because it was not found to be cost effective. However, physician extenders (PEs) are able to perform unsedated procedures; their involvement might reduce the costs of BE screening. We examined the feasibility of training PEs to independently perform transnasal esophagoscopy (TNE) and screen patients for BE and measured their learning curve. METHODS: Two PEs at a Veterans Affairs (VA) medical center underwent a structured didactic training program and observed nasopharyngoscopies before performing TNE under the supervision of attending endoscopists. Individual technical and cognitive components of TNE were rated on a 9-point structured scale. Learning curves were constructed using cumulative summation. Once the PEs were judged to be technically competent, each PE performed 10 independent videotaped TNEs, which were graded. RESULTS: Both PEs identified anatomic landmarks after 18 consecutive procedures. PE1 and PE2 performed satisfactory nasal intubations after 20 and 25 procedures and esophageal intubations after 29 and 35 procedures, respectively. They acquired overall competence after supervised training on 43 and 47 procedures, respectively. CONCLUSIONS: We developed a program at a VA medical center to train PEs to perform TNE to screen for BE. The PEs were able to perform TNE and recognize esophageal landmarks independently after a modest number of supervised procedures. PMID- 24161354 TI - New perspectives of vesicular monoamine transporter 2 chemical characteristics in mammals and its constant expression in type 1 diabetes rat models. AB - Vesicular monoamine transporter 2 (VMAT2) has been exploited as a biomarker of beta-cell mass in human islets. However, a current report suggested no immunoreactivity of VMAT2 in the beta cells of rat islets. To investigate the cellular localization of VMAT2 in islets further, the pancreatic tissues from monkeys and humans were compared with those of rats and mice. The study was performed using among-species comparisons and a type 1 diabetes model (T1DM) for rats by Western blotting, double-label immunofluorescence, and confocal laser scanning microscopy. We found that VMAT2-immunoreactivity (IR) was distributed peripherally in the islets of rodents, but was widely scattered throughout the islets of primates. Consistent with rodent islets, VMAT2-IR did not exist in insulin (INS)-IR cells but was abundantly present in glucagon (GLU)-IR and pancreatic polypeptide (PP)-IR cells in monkey and human islets. VMAT2-IR had no colocalization with INS-IR in any part of the rat pancreas (head, body, and tail). INS-IR cells were reduced dramatically in T1DM rat islets, but no significant alteration in the proportion of VMAT2-IR cells and GLU-IR cells was observed. Furthermore, a strong colocalization of VMAT2-IR with GLU-IR was distributed in the peripheral regions of diabetic islets. For the first time, the current study demonstrates the presence of VMAT2 in alpha cells and PP cells but not in beta cells in the islets of monkeys and humans. This study provides convinced morphologic evidence that VMAT2 is not present in beta cells. There needs to be studies for new markers for beta cell mass. PMID- 24161355 TI - Role of sex steroids and sexual dimorphism on cardiac iron metabolism in iron overload cardiomyopathy. PMID- 24161356 TI - [Assessment tools to measure burden in the informal caregiver of patients with dementia]. AB - The complexity of dementia caregiver burden concept has led to a significant number of assessment tests using various approaches. For this reason, a review of these measurementss could be useful for clinical or research purposes. OBJECTIVE: The objective of the study is to perform an updated review on the tools available, classifying them according to the burden criterion by studying their characteristics and psychometric properties, and providing those most relevant for application. METHOD: The method applied consisted of a database search Pubmed, PsycINFO, Embase and Psicodoc (1980-2012). RESULTS: A total of 31 assessment tools were selected, grouped on the basis of the burden concept evaluated: objective/subjective burden, burden from a multidimensional approach, and as distress associated with patient impairment. CONCLUSIONS: This study provides a suitable tool for using caregiver burden assessment tools accurately. A marked conclusion is the need to establish agreements in the assessment methods, in order to develop standard knowledge and application to healthcare practice. PMID- 24161357 TI - Chronic antidepressant desipramine treatment increases open field-induced brain expression and spleen production of interleukin 10 in rats. AB - In the present study, we established a role of individual differences in locomotor response to novelty or social position in modulatory effect of chronic (14 consecutive days) antidepressant drug desipramine pretreatment (10mg/kg i.p.) on acute (30 min), white and illuminated open field (OF)-induced changes in spleen anti-tumor activity of natural killer (NK) cells (chromium release assay) in parallel to the brain anti-inflammatory interleukin 10 (IL-10) and Fos expression (immunohistochemistry), splenocytic pro-inflammatory interferon gamma (IFN-gamma) and IL-10 production (ELISA), and plasma corticosterone concentration (RIA) in rats. The involvement of individual differences (high (HR) and low (LR) responders to novelty or dominants (D) and subordinates (S)) in the anti depressive responsiveness, was investigated in the desipramine treated by itself (DES) or following 7 consecutive days of OF exposure (ChS-DES) group. In the desipramine pretreated groups, OF stress decreased spleen NKCC, behavioral activity, the Con A-stimulated splenocyte IFN-gamma response and plasma corticosterone concentration whereas it increased the brain and splenocyte IL-10 response. The percentage of OF-induced IL-10/Fos(+) cells was increased in the CA1 and dentate gyrus of the hippocampus and amygdaloid nucleus, particularly in the LR-D (DES) and LR-S (ChS-DES) rats. Moreover, a decreased splenocytic ability to produce IFN-gamma and IL-10, particularly in the HR-S (DES) and LR-S (ChS-DES) rats, was noted. There were no significant differences in the OF-induced NKCC suppression between the behavioral groups. These studies emphasize that chronic desipramine pretreatment had anti-inflammatory but not immunoprotective properties against OF stress-induced neuroimmunological effects which depend on the animal's behavioral characteristics and treatment. PMID- 24161358 TI - CORM-3, a water soluble CO-releasing molecule, uncouples mitochondrial respiration via interaction with the phosphate carrier. AB - Carbon monoxide is continuously produced in small quantities in tissues and is an important signaling mediator in mammalian cells. We previously demonstrated that CO delivered to isolated rat heart mitochondria using a water-soluble CO releasing molecule (CORM-3) is able to uncouple mitochondrial respiration. The aim of this study was to explore more in depth the mechanism(s) of this uncoupling effect. We found that acceleration of mitochondrial O2 consumption and decrease in membrane potential induced by CORM-3 were associated with an increase in mitochondrial swelling. This effect was independent of the opening of the mitochondrial transition pore as cyclosporine A was unable to prevent it. Interestingly, removal of phosphate from the incubation medium suppressed the effects mediated by CORM-3. Blockade of the dicarboxylate carrier, which exchanges dicarboxylate for phosphate, decreased the effects induced by CORM-3 while direct inhibition of the phosphate carrier with N-ethylmaleimide completely abolished the effects of CORM-3. In addition, CORM-3 was able to enhance the transport of phosphate into mitochondria as evidenced by changes in mitochondrial phosphate concentration and mitochondrial swelling that evaluates the activity of the phosphate carrier in de-energized conditions. These results indicate that CORM-3 activates the phosphate carrier leading to an increase in phosphate and proton transport inside mitochondria, both of which could contribute to the non classical uncoupling effect mediated by CORM-3. The dicarboxylate carrier amplifies this effect by increasing intra-mitochondrial phosphate concentration. PMID- 24161359 TI - Photosystem II photoinhibition-repair cycle protects Photosystem I from irreversible damage. AB - Photodamage of Photosystem II (PSII) has been considered as an unavoidable and harmful reaction that decreases plant productivity. PSII, however, has an efficient and dynamically regulated repair machinery, and the PSII activity becomes inhibited only when the rate of damage exceeds the rate of repair. The speed of repair is strictly regulated according to the energetic state in the chloroplast. In contrast to PSII, Photosystem I (PSI) is very rarely damaged, but when occurring, the damage is practically irreversible. While PSII damage is linearly dependent on light intensity, PSI gets damaged only when electron flow from PSII exceeds the capacity of PSI electron acceptors to cope with the electrons. When electron flow to PSI is limited, for example in the presence of DCMU, PSI is extremely tolerant against light stress. Proton gradient (DeltapH) dependent slow-down of electron transfer from PSII to PSI, involving the PGR5 protein and the Cyt b6f complex, protects PSI from excess electrons upon sudden increase in light intensity. Here we provide evidence that in addition to the DeltapH-dependent control of electron transfer, the controlled photoinhibition of PSII is also able to protect PSI from permanent photodamage. We propose that regulation of PSII photoinhibition is the ultimate regulator of the photosynthetic electron transfer chain and provides a photoprotection mechanism against formation of reactive oxygen species and photodamage in PSI. PMID- 24161360 TI - Environmental estrogens in an urban aquatic ecosystem: I. Spatial and temporal occurrence of estrogenic activity in effluent-dominated systems. AB - The present study investigated occurrence of environmental estrogens (EEs) in waterways managed by the Metropolitan Water Reclamation District of Greater Chicago ('District') - one of the largest and most complex water districts in the United States. The objectives of the study were: (i) to document spatial and temporal occurrence of EEs in the Chicago Area Waterways (CAWs); (ii) to determine whether water reclamation plant (WRP) effluents contribute to estrogenic pollution of the receiving streams; (iii) to determine whether the mandated water quality monitoring data could be used to predict estrogenic pollution in the receiving streams; and (iv) to determine whether snow melt, storm runoff and combined sewer overflows may also be contributors of estrogenic activity to these systems. The estrogenic potency of the waterways was assessed using a cell-based reporter gene assay. The water quality data was readily available as part of the District's regular monitoring program. Our findings indicate that EEs are commonly found in the CAWs, and that WRP effluents are one of, but not the only important contributor to estrogenic activity. Mean estrogenic activities in CAWs (11ng estradiol equivalents (EEQs/L)) are well within the values reported for other urban areas and WRP effluents. The estrogenic activity exhibited significant seasonal variation with highest values noted during the spring and summer months. When comparing the mean estrogenic activity of general use waters, secondary contact waters and WRP effluents, we found that general use waters had significantly lower estrogenic activity (ca 5ng EEQ/L) than the other two matrices (ca 15 and 17ng EEQ/L respectively). Our analyses indicate that estrogenic activity of the waterways was not reliably associated with mandated water quality parameters, and that such measurements may not be useful for predicting estrogenic activity, especially so in the complex urban systems. One of the prominent findings of this study is that EEs do not follow predictable spatial patterns - many of the upstream sites in the heavily urbanized areas had levels of estrogenic activity comparable to those found in the effluents and downstream locations. Our data suggest that surface runoff and snow melt are estrogenic (0-9ng EEQ/L), and given that their estrogenic activities are similar to those of their receiving waterways (0-7ng EEQ/L), we conclude that these non-WRP sources are important contributors to estrogenic activity of the CAWs. PMID- 24161362 TI - A radical procedure of circumferential spinal cord decompression through a modified posterior approach for thoracic myelopathy caused by severely impinging anterior ossification. AB - BACKGROUND CONTEXT: Thoracic myelopathy caused by an anterior, massive ossified plaque is often progressive and responds poorly to conservative treatment. Direct removal of the compressing ossification is the optimal procedure for a spinal cord that is severely impinged anteriorly. However, both anterior and posterior decompressive manipulations have caused catastrophic iatrogenic spinal cord injuries. A comprehensive treatment method for severe thoracic myelopathy that enables a sufficient and safe decompression of the spinal cord is needed. PURPOSE: The purpose of this study is to demonstrate the efficacy, safety, and results of a one-stage circumferential decompressive procedure using a modified posterior approach in patients with severe thoracic myelopathy resulting from anterior spinal compression. STUDY DESIGN: A modified procedure of circumferential spinal cord decompression for thoracic myelopathy is described. A retrospective study was conducted to investigate the clinical outcomes of 23 sequentially treated patients. PATIENT SAMPLE: Twenty-three patients were treated sequentially with a modified procedure for circumferential spinal cord decompression for thoracic myelopathy. OUTCOME MEASURES: Outcomes were assessed using the Japanese Orthopedic Association (JOA) score, modified Frankel classification, Hirabayashi recovery rate, and a general assessment of complications. METHODS: Twenty-three patients with thoracic myelopathy caused by a massive, anterior ossified structure were treated with an extensive posterior laminectomy, anterior removal of the ossification, and interbody fusion with kyphosis-reversing stabilization through a modified posterolateral approach. The neurologic outcomes are evaluated according to the JOA and the modified Frankel classification before surgery, 2 weeks after surgery, 1 year after surgery, and at the final follow-up visit. The surgical outcomes are also described using the Hirabayashi recovery rate. Radiographs, computed tomography (CT), and magnetic resonance imaging were performed before and after surgery. A postoperative CT scan was obtained to determine the efficacy of the decompression. Operative time, intraoperative blood loss, and complications were reviewed from the medical records. In addition, a 48-year-old man who presented with severe thoracic myelopathy resulting from anterior impingement with multiple osteophytes is described as an illustrative patient. RESULTS: The sites of ossification in this series were distributed widely, from T4-T12. The anterior ossified plaques of all patients were resected completely. Five patients who had intraoperative evidence of dural ossification required resection of the ossified dura matter. The average operating time was 276 minutes. Mean intraoperative blood loss was 1,350 mL. The postoperative follow-up ranged from 2.5 to 6 years, with an average of 4.6 years. The average preoperative JOA score was 4.3+/-1.5 points, and it improved to 6.1+/ 1.9 points 2 weeks postoperatively, to 8.1+/-1.8 points 1 year postoperatively, and to 8.5+/-1.9 points at the most recent follow-up. The overall Hirabayashi recovery rate at the final examination averaged 63.6+/-22.4%. Eight patients were graded as excellent, 10 as good, 4 as fair, and 1 as unchanged. No patient was graded as deteriorated. The paralysis improved by at least 1 grade in 22 patients (95.7%). Transient deterioration of thoracic myelopathy occurred immediately after surgery in three patients (13%). Cerebrospinal fluid leakage occurred in six patients (26.1%). One patient sustained severe bilateral groin pain, three had unilateral intercostal neuralgia, and pleura tear occurred in one patient. CONCLUSION: One-stage posterior decompression, anterior extirpation of the ossification, and interbody fusion with instrumentation via a modified posterior approach is a safe and effective treatment for severe thoracic myelopathy resulting from prominent anterior impingement. This procedure is technically demanding, and the indications are limited to thoracic myelopathy caused by severe anterior impingement of various etiologies from T4-T12. PMID- 24161361 TI - Long-term follow-up of a randomized trial on 118 patients with polyarteritis nodosa or microscopic polyangiitis without poor-prognosis factors. AB - The purpose of this study was to assess the long-term outcomes of patients with polyarteritis nodosa (PAN) or microscopic polyangiitis (MPA) without Five-Factor Score (FFS)-defined poor-prognosis factors (FFS=0) and enrolled in a prospective clinical trial. Patients were followed (2005-2012) under routine clinical care in an extended study and data were recorded prospectively. Long-term survival, disease-free survival (DFS), relapses, therapeutic responses and sequelae were analyzed. Mean+/-SD follow-up was 98.2+/-41.9months. After having initially received glucocorticoids (GC) alone, according to the study protocol, 82% (97/118) patients achieved remission but 18% (21/118) required >=1 immunosuppressant(s) (IS) before 19/21 achieved remission. Two patients died before entering remission. After remission, 53% (61/116) patients relapsed 25.6+/ 27.9months after starting treatment. The 5- and 8-year overall survival rates were 93% and 86%, respectively, with no difference between PAN and MPA, and between relapsers and nonrelapsers. DFS was shorter for MPA than PAN patients (P=0.02). Throughout follow-up, 47% of patients required >=1 IS. At the last follow-up visit, 44% were still taking GC and 15% IS. The mean vasculitis damage index score was 1.9+/-1.9; the most frequent sequelae were peripheral neuropathy, hypertension and osteoporosis. For PAN or MPA patients without poor-prognosis factors at diagnosis and treated initially with GC alone, long-term survival was excellent. However, relapses remained frequent, requiring IS introduction for nearly half of the patients. To lower the frequencies of relapses and sequelae remains a challenge for FFS=0 PAN and MPA patients. PMID- 24161363 TI - Gorham disease of the lumbar spine with an abdominal aortic aneurysm: a case report. AB - BACKGROUND CONTEXT: Reports of Gorham disease of the lumbar spine complicated by abdominal aortic aneurysms are rare. PURPOSE: We herein report the case of a patient with Gorham disease of the lumber spine involving an abdominal aortic aneurysm (AAA). STUDY DESIGN: Case report. METHODS: A 49-year-old man had a 1 month history of right leg pain and severe low back pain. Plain lumbar radiography revealed an osteolytic lesion in the L4 vertebral body. Computed tomography images demonstrated the presence of an extensive osteolytic lesion in the L4 vertebral body and an AAA in front of the L4 vertebral body. RESULTS: The patient underwent mass resection, spinal reconstruction, and blood vessel prosthesis implantation. During surgery, it was found that the wall of the aorta had completely disappeared and was shielded by the tumor mass; therefore, we speculated that the mass in the lumbar spine had directly invaded the aorta. CONCLUSIONS: The patient was able to walk without right leg or low back pain 1 year after undergoing surgery. No recurrence was demonstrated in the magnetic resonance images taken 1 year and 10 months after surgery. PMID- 24161364 TI - The Morel-Lavallee lesion revisited: management in spinopelvic dissociation. AB - BACKGROUND CONTEXT: The Morel-Lavallee lesion occurs from a compression and shear force that usually separates the skin and subcutaneous tissue from the underlying muscular fascia. A dead space is created that becomes filled with blood, liquefied fat, and lymphatic fluid from the shearing of vasculature and lymphatics. If not treated appropriately, these lesions can become infected, cause tissue necrosis, or form chronic seromas. PURPOSE: To review appropriate identification and treatment of Morel-Lavallee lesions in spinopelvic dissociation patients. STUDY DESIGN: Uncontrolled case series. METHODS: Retrospective review of medical records. No funding was received in support of this study. The authors report no conflicts of interest. RESULTS: We present four cases of patients with traumatic spinopelvic dissociation. All had concomitant lumbosacral Morel-Lavallee lesions. All four trauma patients suffered traumatic spinopelvic dissociation with concomitant lumbosacral Morel-Lavallee lesions. Appropriate treatment included irrigation and debridement, drainage, antibiotics, and vacuum-assisted wound closure. CONCLUSIONS: Our series reflects an association of Morel-Lavallee lesion in spinopelvic dissociation trauma patients. Possibly, the rotatory injury that occurs at the spinopelvic junction creates a shear force to form the Morel-Lavallee lesion. When presented with a spinopelvic dissociation patient, one should be prepared to treat a Morel-Lavallee lesion. PMID- 24161365 TI - Bilateral rib-to-pelvis Eiffel Tower VEPTR construct for children with neuromuscular scoliosis: a preliminary report. AB - BACKGROUND CONTEXT: Neuromuscular scoliosis could develop at a young age and progress beyond skeletal maturity. An early spinal fusion arrests growth of the spine and thorax, risking the development of secondary thoracic insufficiency syndrome. Vertical expandable prosthetic titanium rib (VEPTR) is a fusionless technique aiming at correction of the deformity with preservation of growth potential. PURPOSE: To demonstrate the preliminary results of the use of VEPTR in an Eiffel Tower construct in children with neuromuscular scoliosis in regard to coronal and sagittal profiles, space available for the lungs (SAL), and spinal growth. The report lists the complications we faced during the follow-up of 1.33 years after the index procedure. STUDY DESIGN: A retrospective analysis of prospectively collected data of a case series. PATIENT SAMPLE: Twenty nonambulatory children (mean 8.9 years) with neuromuscular scoliosis. Their primary diagnoses were myelomeningocele in seven, cerebral palsy in three, spinal muscular atrophy in two, myopathies in three, arthrogryposis in one, and syndromic scoliosis in four patients. METHODS: All 20 patients received percutaneous rib-to-pelvis VEPTR implantation. Mean operative time was 2 hours, and mean hospital stay was 12 days. None of them needed blood transfusion. They underwent 20 primary implantations and 39 lengthenings. OUTCOME MEASURES: The patients were assessed based on physiologic measures, that is, the radiographic improvement of their scoliosis, SAL, pelvic tilt, spinal height, and sagittal and coronal decompensation. RESULTS: At the latest follow-up, thoracolumbar curvature improved significantly (65.7 degrees +/-20.5 degrees to 49.9 degrees +/-15.7 degrees ), as did lumbar curvature (61.6 degrees +/-19.5 degrees to 35 degrees +/-21.2 degrees ), thoracic (17.2+/-2.3 to 20+/-2.3 cm) and lumbar spinal height (9.9+/-1.7 to 11.9+/-1.8 cm), SAL (86.5+/-8.9 to 97+/-10), pelvic obliquity (12.5 degrees +/-8 degrees to 5.2 degrees +/- 5.2 degrees ), and the iliolumbar angle (15 degrees +/-8 degrees to 10.06 degrees +/-7.1 degrees ). Nine patients suffered complications in the form of proximal cradle migration (five), implant breakage (five), deep wound infection (three), and dislodged iliac hooks (two). CONCLUSIONS: Early results of VEPTR for neuromuscular scoliosis are encouraging. Follow-up till skeletal maturity will best determine future indications. PMID- 24161366 TI - HDR brachytherapy for the reirradiation of cervical and vaginal cancer: analysis of efficacy and dosage delivered to organs at risk. AB - OBJECTIVE: To evaluate the efficacy and toxicity of HDR brachytherapy (BT) for the reirradiation of cervical or vaginal cancer arising within a previously irradiated area with a special focus on dosage delivery to organs at risk. METHODS: Twenty consecutive patients with cervical (N = 19) or vaginal (N = 1) cancer were reirradiated with curative intent using BT with or without external beam irradiation and hyperthermia. The median biologically equivalent dose in 2 Gy fractions (EQD2), assuming alpha/beta = 10, for reirradiation was 48.8 Gy (range: 16.0-91.0 Gy), and the median cumulative EQD2 (for primary treatment and reirradiation) was 133.5 Gy (range: 96.8-164.2 Gy). The median follow-up after retreatment was 31 months (range: 6-86 months). RESULTS: The 3-year overall survival (OS) rate was 68% (95% confidence interval [CI]: 44%-91%). The 3-year disease-free survival (DFS) rate was 42% (95% CI: 19%-65%). The 3-year local control (LC) rate was 45% (95% CI: 22%-69%). For nine patients who received 3D treatment planning, the median cumulative EQD2 to 2 cm(3) of rectum was 94.4 Gy (range: 67.1-118.8 Gy) and to 2 cm(3) of bladder was 99.3 Gy (range: 70.4-122.3 Gy). Grade 3 late toxicity was observed in 3 patients (15%). An interval between primary RT and reirradiation of <= 12 months and a tumor diameter >3 cm were significant prognostic factors adversely affecting OS, DFS and LC. CONCLUSIONS: HDR BT is a valuable method for the reirradiation of cervical cancer. A cumulative EQD2 of approximately 100 Gy was safely delivered to 2 cm(3) of the bladder and the rectum. PMID- 24161367 TI - Comparison of the dietary intakes of new parents, second-time parents, and nonparents: a longitudinal cohort study. AB - The objective of this study was to examine the dietary intake profiles of first time parents, second-time parents, and couples without children; once during pregnancy, then at 6- and 12-months postpartum. This was an observational, longitudinal, cohort study. Participants were a community-based sample of 153 couples aged 25 to 40 years. Data were collected between 2007 and 2011. Dietary intake was recorded using 3-day dietary recall. Hierarchical linear modeling was used to compare the dietary intakes of groups (ie, parent, sex, and couple days) over time. Percentage of participants per group meeting recommended daily dietary guidelines was also analyzed, as were variables that influenced meeting overall recommended guidelines using a multivariate analysis of variance. First-time mothers had higher overall energy, fat, sugar, fruit, and milk intake compared with women without children, and longitudinally first-time mothers decreased their fruit intake. Second-time mothers had higher overall energy, fat, sugar, and fruit intake compared with nonparent women, and longitudinally second-time mothers increased their meat intake. First-time fathers had overall higher bread intake compared with second-time fathers and men without children, and first-time fathers consumed less sugar than second-time fathers. Longitudinally, first-time fathers increased their fiber intake. At any stage of data collection, from pregnancy to 12-months postpartum, only 2% to 16% of all mothers met recommended overall daily dietary guidelines. The only variable investigated that influenced meeting overall daily dietary guidelines at baseline was parent status. PMID- 24161368 TI - Implementation of the Nutrition Care Process and International Dietetics and Nutrition Terminology in a single-center hemodialysis unit: comparing paper vs electronic records. AB - There is little doubt surrounding the benefits of the Nutrition Care Process and International Dietetics and Nutrition Terminology (IDNT) to dietetics practice; however, evidence to support the most efficient method of incorporating these into practice is lacking. The main objective of our study was to compare the efficiency and effectiveness of an electronic and a manual paper-based system for capturing the Nutrition Care Process and IDNT in a single in-center hemodialysis unit. A cohort of 56 adult patients receiving maintenance hemodialysis were followed for 12 months. During the first 6 months, patients received the usual standard care, with documentation via a manual paper-based system. During the following 6-month period (Months 7 to 12), nutrition care was documented by an electronic system. Workload efficiency, number of IDNT codes used related to nutrition-related diagnoses, interventions, monitoring and evaluation using IDNT, nutritional status using the scored Patient-Generated Subjective Global Assessment Tool of Quality of Life were the main outcome measures. Compared with paper-based documentation of nutrition care, our study demonstrated that an electronic system improved the efficiency of total time spent by the dietitian by 13 minutes per consultation. There were also a greater number of nutrition related diagnoses resolved using the electronic system compared with the paper based documentation (P<0.001). In conclusion, the implementation of an electronic system compared with a paper-based system in a population receiving hemodialysis resulted in significant improvements in the efficiency of nutrition care and effectiveness related to patient outcomes. PMID- 24161369 TI - Effects of bolus rheology on aspiration in patients with Dysphagia. AB - Bolus manipulation is a primary treatment strategy in the management of oral pharyngeal dysphagia. The use of thickening agents to alter bolus rheology is particularly commonplace; however, the precise effects of these alterations on swallowing remain uncertain. The purpose of our study, a prospective, double blind clinical trial (Level 1b), was to investigate the effects of viscosity on aspiration. One hundred patients with dysphagia were prospectively evaluated with fluoroscopic swallow studies performed across three standardized and randomized conditions: thin liquid barium (THIN), liquid barium thickened with a starch based agent (STARCH), and liquid barium thickened with a gum-based agent (GUM). Outcome measures included the prevalence of aspiration and score on the Penetration-Aspiration Scale. A total of 23 out of 100 patients exhibited 56 episodes of aspiration. Twenty patients aspirated on THIN, 15 on STARCH, and 11 on GUM bolus conditions (P<0.05, thin vs gum). There were 28 instances of aspiration on THIN, 16 on STARCH, and 12 on GUM. Mean Penetration-Aspiration Scale score +/- standard deviation was 2.11 +/- 2.22 for THIN, 1.76 +/- 1.88 for STARCH, and 1.42 +/- 1.47 for GUM conditions, respectively (P<0.001, THIN vs GUM). A clinically significant reduction in the incidence of penetration and aspiration was observed for gum-thickened barium compared with thin liquid barium. PMID- 24161370 TI - Alveolar epithelial cells (A549) exposed at the air-liquid interface to diesel exhaust: First study in TNO's powertrain test center. AB - Air-liquid interface (ALI) exposures enable in vitro testing of mixtures of gases and particles such as diesel exhaust (DE). The main objective of this study was to investigate the feasibility of exposing human lung epithelial cells at the ALI to complete DE generated by a heavy-duty truck in the state-of-the-art TNO powertrain test center. A549 cells were exposed at the air-liquid interface to DE generated by a heavy-duty Euro III truck for 1.5h. The truck was tested at a speed of ~70kmh(-1) to simulate free-flowing traffic on a motorway. Twenty-four hours after exposure, cells were analyzed for markers of oxidative stress (GSH and HO-1), cytotoxicity (LDH and Alamar Blue assay) and inflammation (IL-8). DE exposure resulted in an increased oxidative stress response (significantly increased HO-1 levels and significantly reduced GSH/GSSH ratio), and a decreased cell viability (significantly decreased Alamar Blue levels and slightly increased LDH levels). However, the pro-inflammatory response seemed to decrease (decrease in IL-8). The results presented here demonstrate that we are able to successfully expose A549 cells at ALI to complete DE generated by a heavy-duty truck in TNO's powertrain test center and show oxidative stress and cytotoxicity responses due to DE exposure. PMID- 24161371 TI - Human in vivo database now on ACuteTox home page. PMID- 24161372 TI - Care strategy for death rattle in terminally ill cancer patients and their family members: recommendations from a cross-sectional nationwide survey of bereaved family members' perceptions. AB - CONTEXT: Bereaved family members witnessing a patient's death rattle often experience distress. However, the benefits of specific care measures aimed at decreasing death rattle-associated family distress have not yet been evaluated. OBJECTIVES: To clarify death rattle-related emotional distress levels among family members and their perceptions of the need for death rattle care improvement and explore the factors influencing both these issues. METHODS: A cross-sectional questionnaire survey of bereaved family members of cancer patients was conducted in 95 palliative care units in June 2007. RESULTS: Six hundred sixty-three questionnaires were mailed out, and 390 (61%) responses were analyzed. Among these, 181 (46%) respondents experienced death rattle. Of these, 66% reported high distress levels and 53% perceived a strong need for improved death rattle care. Factors influencing high distress levels were the gender (female) of family members, unawareness about death rattle being a natural phenomenon, and their fear and distressing interpretations of death rattle. Factors influencing perceptions of a strong need for improved care were the gender (male) of family members, severity of death rattle, death rattle associated discomfort to patients, family members' experiences of inadequate nursing care (e.g., repositioning) and insufficient consultation about suctioning, and their perception of uncomfortable smells. CONCLUSION: To decrease family-perceived distress, medical staff should alleviate patient symptoms and suffering with a comprehensive care strategy, try to decrease uncomfortable smells, and communicate with family members to address distressing interpretations and fears. PMID- 24161373 TI - Targeted gene delivery in the cricket brain, using in vivo electroporation. AB - The cricket (Gryllus bimaculatus) is a hemimetabolous insect that is emerging as a model organism for the study of neural and molecular mechanisms of behavioral traits. However, research strategies have been limited by a lack of genetic manipulation techniques that target the nervous system of the cricket. The development of a new method for efficient gene delivery into cricket brains, using in vivo electroporation, is described here. Plasmid DNA, which contained an enhanced green fluorescent protein (eGFP) gene, under the control of a G. bimaculatus actin (Gb'-act) promoter, was injected into adult cricket brains. Injection was followed by electroporation at a sufficient voltage. Expression of eGFP was observed within the brain tissue. Localized gene expression, targeted to specific regions of the brain, was also achieved using a combination of local DNA injection and fine arrangement of the electroporation electrodes. Further studies using this technique will lead to a better understanding of the neural and molecular mechanisms that underlie cricket behaviors. PMID- 24161374 TI - Apolipoprotein A5 T-1131C variant and risk for metabolic syndrome in obese adolescents. AB - BACKGROUND: Apolipoprotein A5 (APOA5) gene variants are associated with increased plasma triglycerides, a risk factor for metabolic syndrome (MS). The goal of the current study was the investigation of the distribution of T-1131C variant among obese adolescents with MS compared with healthy controls. SUBJECTS AND METHODS: The study included 150 obese adolescents (75 males and 75 females) with MS and 204 age and sex matched normal healthy controls (100 males and 104 females). The mean age of the patients was 15.47 +/- 2.54 years, ranged from 17 to 20 years. They were genotyped by polymerase chain reaction-restriction fragment length polymorphism for the mutation (T-1131C). RESULTS: The blood pressure, triglyceride and HOMA-R levels were significantly higher and HDL-C levels were significantly lower in carrier (TC+CC) compared to non-carrier (TT) MS patients. There was accumulation of -1131C allele frequency in the MS group (31.33% vs. control group 11.76%), p<0.001. The genotypes were in Hardy-Weinberg equilibrium both in the patients with metabolic syndrome and in the control subjects. Results of analysis of multiple regression models showed that the ApoA5 -1131C carriers showed an increased incidence of MS (OR=1.73, 95% CI: 1.41-2.11). CONCLUSIONS: The present study suggests that the 1131T>C polymorphism is a risk factor for the development of metabolic syndrome in obese adolescents. PMID- 24161375 TI - The use of caffeinated alcoholic beverages among underage drinkers: results of a national survey. AB - OBJECTIVE: The mixing of alcoholic beverages with caffeine has been identified as a public health problem among college students; however, little is known about the consumption of such drinks among younger adolescents. We estimated the prevalence of caffeinated alcoholic beverage (CAB) use among a wide age range of underage drinkers, examined differences in traditional (i.e. self-mixed alcoholic beverages with soda, coffee and tea) and non-traditional CAB use (pre-mixed caffeinated alcoholic beverages or self-mixed alcoholic beverages with energy drinks or energy shots) among underage drinkers by age and other demographic characteristics, and examined differences in hazardous drinking behavior between CAB and non-CAB users. METHODS: We used an existing Internet panel maintained by Knowledge Networks, Inc. to assess the use of pre-mixed and self-mixed CABs in the past 30 days among a national sample of 1031 youth drinkers age 13-20. We conducted logistic regression analyses to estimate the relationship between traditional and non-traditional CAB use and risky drinking behavior as well as adverse outcomes of drinking, while controlling for age, gender, race/ethnicity, income, and general risk-taking (seat belt use). RESULTS: The overall prevalence of CAB use in the sample of underage drinkers was 52.4% (95% confidence interval [CI], 47.4%-57.4%). CAB prevalence was 48.4% among 13-15 year-old drinkers, 45.3% among 16-18 year-old drinkers, and 58.4% among 19-20 year-old drinkers. After controlling for other variables, we found a continuum of risk with non traditional CAB use most significantly associated with binge drinking (odds ratio [OR]=6.3), fighting (OR=4.4), and alcohol-related injuries (OR=5.6). CONCLUSIONS: The problem of caffeinated alcoholic beverage use is not restricted to college aged youth. The prevalence of CAB use among underage drinkers is higher than previously thought and begins in early adolescence. Adolescents who consume CABs, and particularly non-traditional CABs, are at increased risk of adverse outcomes. PMID- 24161376 TI - Impaired cognitive functions in adult-onset primary cranial cervical dystonia. AB - BACKGROUND: Adult-onset primary dystonia is thought to be a purely motor disorder. Nevertheless, several studies provided evidence that sensory and psychiatric disturbances may contribute to the clinical spectrum of of dystonia, whereas evidence supporting cognitive impairment is still limited. METHODS: A set of neuropsychological tests was administered to non depressed, non demented patients with cranial-cervical dystonia and healthy control subjects. The test battery included n-Back Task, Wechsler Memory Scale, Trail Making Test version A and B, and Wisconsin Card Sorting Test. RESULTS: As compared with healthy control subjects of similar age, sex and socio-economic status, patients with cranial cervical dystonia showed deficit on working memory functions revealed by n-Back task, impairment of mental control and visual reproduction subtests of Wechsler memory scale, deficit on information processing speed and set-shifting capacity revealed by Trail Making Test A and B. CONCLUSION: Patients with cranial-cervical dystonia may have impairment in specific cognitive domains relative to working memory, processing speed, visual motor ability and short term memory. Probably, these deficits are not dependent on the clinical expression of dystonia but might rather reflect the cortical and subcortical changes highlighted by functional and VBM imaging studies in patients with different forms of dystonia. PMID- 24161377 TI - The impact of non-motor symptoms on the Health-Related Quality of Life of Parkinson's disease patients from Southwest China. AB - BACKGROUND: The impact of non-motor symptoms (NMS) on the Health-Related Quality of Life (HRQoL) of patients with Parkinson's disease (PD) in the Chinese population are largely unknown. OBJECTIVES: To study the impact of NMS on the HRQoL in Chinese PD patients. METHODS: A total of 693 PD patients from Southwest China were included in the study. NMS of patients were evaluated by non-motor symptoms scale (NMSS) and Parkinson's disease questionnaire-39 item version (PDQ 39) was used to evaluate the HRQoL of PD. RESULTS: The mean total score of NMSS was 37.2 +/- 33.0 and the most prevalent NMS domain was sleep/fatigue (79.8%). There was a significant strong positive correlation between total NMSS score (rs = 0.71, P < 0.01), sleep/fatigue domain (rs = 0.60, P < 0.01) and PDQ-39 SI. Mood/apathy (rs = 0.55, P < 0.01), attention/memory (rs = 0.42, P < 0.01), gastrointestinal (rs = 0.44, P < 0.01) and Miscellany domains (rs = 0.46, P < 0.01) moderately correlated with PDQ-39 SI. A strong correlation was found between PDQ-39 SI (rs = 0.71, P < 0.01), emotional well-being (rs = 0.62, P < 0.01), cognitions (rs = 0.62, P < 0.01), and the total score of NMSS. Moderate correlation was found between mobility (rs = 0.45, P < 0.01), activities of daily living (rs = 0.43, P < 0.01), stigma (rs = 0.42, P < 0.01), communication (rs = 0.47, P < 0.01), bodily discomfort (rs = 0.46, P < 0.01) and the total score of NMSS. Female, H-Y stage, UPDRS-III and NMSS total score were the potential determinants of worse HRQoL of PD patients. CONCLUSIONS: NMS have close association with various aspects of the HRQoL. Severe NMS may be related to dramatic decline of the HRQoL of PD patients. PMID- 24161378 TI - [Consensus Statement by GeSIDA/National AIDS Plan Secretariat on antiretroviral treatment in adults infected by the human immunodeficiency virus (Updated January 2013)]. AB - OBJECTIVE: This consensus document is an update of combined antiretroviral therapy (cART) guidelines for HIV-1 infected adult patients. METHODS: To formulate these recommendations a panel composed of members of the GeSIDA/National AIDS Plan Secretariat (Grupo de Estudio de Sida and the Secretaria del Plan Nacional sobre el Sida) reviewed the efficacy and safety advances in clinical trials, cohort and pharmacokinetic studies published in medical journals (PubMed and Embase) or presented in medical scientific meetings. The strength of the recommendations and the evidence which support them are based on a modification of the criteria of Infectious Diseases Society of America. RESULTS: cART is recommended in patients with symptoms of HIV infection, in pregnant women, in serodiscordant couples with high risk of transmission, in hepatitisB co-infection requiring treatment, and in HIV nephropathy. cART is recommended in asymptomatic patients if CD4 is <500cells/MUl. If CD4 are >500cells/MUl cART should be considered in the case of chronic hepatitisC, cirrhosis, high cardiovascular risk, plasma viral load >100.000 copies/ml, proportion of CD4 cells <14%, neurocognitive deficits, and in people aged >55years. The objective of cART is to achieve an undetectable viral load. The first cART should include 2 reverse transcriptase inhibitors (RTI) nucleoside analogs and a third drug (a non-analog RTI, a ritonavir boosted protease inhibitor, or an integrase inhibitor). The panel has consensually selected some drug combinations, for the first cART and specific criteria for cART in acute HIV infection, in tuberculosis and other HIV related opportunistic infections, for the women and in pregnancy, in hepatitisB or C co-infection, in HIV-2 infection, and in post-exposure prophylaxis. CONCLUSIONS: These new guidelines update previous recommendations related to first cART (when to begin and what drugs should be used), how to monitor, and what to do in case of viral failure or adverse drug reactions. cART specific criteria in comorbid patients and special situations are similarly updated. PMID- 24161379 TI - Pollution status of the Bohai Sea: an overview of the environmental quality assessment related trace metals. AB - It is well recognized that the ecosystem of the Bohai Sea is being rapidly degraded and the Sea has basically lost its function as a fishing ground. Billions of funds have been spent in slowing down, halting and finally reversing the environmental deterioration of the Bohai Sea. Although trace metals are routinely monitored, the data with high temporal resolution for a clear understanding of biogeochemical processes in the ecosystem of the Bohai Sea are insufficient, especially in the western literature. In this review, status of trace metal contamination in the Bohai Sea is assessed based on a comprehensive review of their concentrations recorded in the waters, sediments and organisms over the past decades. Studies show that metal contamination in the Bohai Sea is closely associated with the fast economic growth in the past decades. Concentrations of trace metals are high in coastal areas especially in the estuaries. Alarmingly high metal concentrations are observed in the waters, sediments and organisms from the western Bohai Bay and the northern Liaodong Bay, especially the coasts near Huludao in the northernmost area of the Bohai Sea, which is being polluted by industrial sewage from the surrounding areas. The knowledge of the speciation and fractionation of trace metals and the influence of submarine groundwater discharge on the biogeochemistry of trace metals in the Bohai Sea is far from enough and related work needs to be done urgently to get a better understanding of the influence of trace metals on the ecosystem of the Bohai Sea. A clear understanding of the trace metal pollution status of the Bohai Sea could not be achieved presently for lack of systematic cooperation in different research fields. It is quite necessary to apply the environmental and ecological modeling to the investigation of trace metals in the Bohai Sea and then provide foundations for the protection of the environment and ecosystem of the Bohai Sea. PMID- 24161380 TI - Prioritizing agricultural pesticides used in South Africa based on their environmental mobility and potential human health effects. AB - South Africa is the largest user of pesticides in sub-Saharan Africa and many studies have highlighted the occurrence of pesticides in water resources. Poor management of water treatment facilities in combination with a relatively high dependency on untreated water from boreholes and rivers creates the potential for exposure of human communities to pesticides and their associated health effects. Pesticide use, physicochemical and toxicity data was therefore used to prioritize pesticides in terms of their potential risk to human health. After eliminating pesticides used in very low quantities, four indices were used to prioritize active ingredients applied in excess of 1000 kg per annum; the quantity index (QI) which ranked pesticides in terms of the quantity of their use; the toxicity potential index (TP) which ranked pesticides according to scores derived for their potential to cause five health effects (endocrine disruption, carcinogenicity, teratogenicity, mutagenicity and neurotoxicity); hazard potential index (HP) which multiplied the TP by an exposure potential score determined by the GUS index for each pesticide (to provide an indication of environmental hazard); and weighted hazard potential (WHP), which multiplied the HP for a pesticide by the ratio of its use to the total use of all pesticides in the country. The top 25 pesticides occurring in each of these indices were identified as priority pesticides, resulting in a combined total of 69 priority pesticides. A principal component analysis identified the indices that were most important in determining why a specific pesticide was included in the final priority list. As crop specific application pesticide use data was available it was possible to identify crops to which priority pesticides were applied to. Furthermore it was possible to prioritize crops in terms of the specific pesticide applied to the crop (by expressing the WHP as a ratio of the total amount of pesticide applied to the crop to the total use of all pesticides applied in the country). This allows for an improved spatial assessment of the use of priority pesticides. The methodology applied here provides a first level of basic, important information that can be used to develop monitoring programmes, identify priority areas for management interventions and to investigate optimal mitigation strategies. PMID- 24161381 TI - Long-term exposure to high particulate matter pollution and cardiovascular mortality: a 12-year cohort study in four cities in northern China. AB - Epidemiologic studies have demonstrated that long-term exposure to relatively low levels of particulate air pollution is associated with adverse cardiovascular outcomes in Europe and North America. However, few studies have assessed the association with high level air pollutants. We aimed to assess the cardiovascular effects of long-term exposure to high level concentrations of inhalable particulate and to identify the characteristics of the Chinese population that are susceptible to the health effects. A retrospective cohort, containing 39,054 subjects from four cities in northern China, was followed for mortality of all cause and specific cardiovascular diseases from 1998 to 2009. Information on concentrations of PM10 (particulate matter<10 MUm in aerodynamic diameter) was collected from the local Environmental Monitoring Centers. The estimated exposure for the study participants was the mean concentration of PM10 over their surviving years during the cohort period. Relative risk values were obtained using Cox proportional hazards regression models after adjusting for potential confounding factors. For each 10 MUg/m(3) increase in PM10, the relative risk ratios (RRs) of all-cause mortality, cardiovascular disease mortality, ischemic heart disease mortality, heart failure disease mortality, and cerebrovascular disease mortality were 1.24 (95% CI, 1.22-1.27), 1.23 (95% CI, 1.19-1.26), 1.37 (95% CI, 1.28-1.47), 1.11(95% CI, 1.05-1.17), and 1.23(95% CI:1.18-1.28), respectively. Results from stratified analyses suggest that the effects of PM10 on cardiovascular mortality were more pronounced in males, smokers and people with a higher socioeconomic status. Long-term exposure to PM10 increases mortality from cardiovascular disease, especially from ischemic heart disease and this association seemed to be modified by other factors. Further research that focuses on exploring dose-response relationship and inter-population comparisons is warranted. PMID- 24161383 TI - Biocompatibility of functionalized boron phosphate (BPO4) nanoparticles for boron neutron capture therapy (BNCT) application. AB - Boron neutron capture therapy (BNCT) is a radiotherapy treatment based on the accumulation in the tumor of a (10)B-containing drug and subsequent irradiation with low energy neutrons, which bring about the decay of (10)B to (7)Li and an alpha particle, causing the death of the neoplastic cell. The effectiveness of BNCT is limited by the low delivery and accumulation of the used boron-containing compounds. Here we report the development and the characterization of BPO4 nanoparticles (NPs) as a novel possible alternative drug for BNCT. An extensive analysis of BPO4 NP biocompatibility was performed using both mature blood cells (erythrocytes, neutrophils and platelets) and a model of hematopoietic progenitor cells. A time- and concentration-dependent cytotoxicity study was performed on neoplastic coloncarcinoma and osteosarcoma cell lines. BPO4 functionalization with folic acid, introduced to improve the uptake by tumor cells, appeared to effectively limit the unwanted effects of NPs on the analyzed blood components. FROM THE CLINICAL EDITOR: Boron neutron capture therapy (BNCT) is a radiotherapy treatment modality based on the accumulation of a (10)B-containing drug and subsequent irradiation with low energy neutrons, inducing the decay of (10)B to (7)Li and an alpha particle, causing neoplastic cell death. This team of authors reports on a folic acid functionalized BPO4 nanoparticle with improved characteristics compared with conventional BNCT approaches, as demonstrated in tumor cell lines, and hopefully to be followed by translational human studies. PMID- 24161382 TI - Multimodal imaging enables early detection and characterization of changes in tumor permeability of brain metastases. AB - Our goal was to develop strategies to quantify the accumulation of model therapeutics in small brain metastases using multimodal imaging, in order to enhance the potential for successful treatment. Human melanoma cells were injected into the left cardiac ventricle of immunodeficient mice. Bioluminescent, MR and PET imaging were applied to evaluate the limits of detection and potential for contrast agent extravasation in small brain metastases. A pharmacokinetic model was applied to estimate vascular permeability. Bioluminescent imaging after injecting d-luciferin (molecular weight (MW) 320 D) suggested that tumor cell extravasation had already occurred at week 1, which was confirmed by histology. 7T T1w MRI at week 4 was able to detect non-leaky 100 MUm sized lesions and leaky tumors with diameters down to 200 MUm after contrast injection at week 5. PET imaging showed that (18)F-FLT (MW 244 Da) accumulated in the brain at week 4. Gadolinium-based MRI tracers (MW 559 Da and 2.066 kDa) extravasated after 5 weeks (tumor diameter 600 MUm), and the lower MW agent cleared more rapidly from the tumor (mean apparent permeabilities 2.27 * 10(-5)cm/s versus 1.12 * 10(-5)cm/s). PET imaging further demonstrated tumor permeability to (64)Cu-BSA (MW 65.55 kDa) at week 6 (tumor diameter 700 MUm). In conclusion, high field T1w MRI without contrast may improve the detection limit of small brain metastases, allowing for earlier diagnosis of patients, although the smallest lesions detected with T1w MRI were permeable only to d-luciferin and the amphipathic small molecule (18)F FLT. Different-sized MR and PET contrast agents demonstrated the gradual increase in leakiness of the blood tumor barrier during metastatic progression, which could guide clinicians in choosing tailored treatment strategies. PMID- 24161384 TI - Microfluidic fabrication of 6-methoxyethylamino numonafide-eluting magnetic microspheres. AB - Recently, 6-methoxyethylamino numonafide (MEAN) exhibited potent inhibition of hepatocellular carcinoma (HCC) cell growth and less systemic toxicity than amonafide. MEAN may serve as an ideal candidate for the treatment of HCC; however, liver-directed, selective infusion methods may be critical to maximize the MEAN dose delivered to the targeted tumors. This study describes the microfluidic fabrication of MEAN-eluting ultrasmall superparamagnetic iron oxide (USPIO) nanocluster-containing alginate microspheres (MEAN-magnetic microspheres) intended for selective transcatheter delivery to HCC. The resulting drug delivery platform was mono-disperse, microsphere sizes were readily controlled based on channel flow rates during synthesis procedures, and drug release rates from the microspheres could be readily controlled with the introduction of USPIO nanoclusters. The MR relaxivity properties of the microspheres suggest the feasibility of in vivo imaging after administration, and these microspheres exhibited potent therapeutic effects significantly inhibiting cell growth inducing apoptosis in hepatoma cells. PMID- 24161385 TI - Peri- and intra-implant bone response to microporous Ti coatings with surface modification. AB - Bone growth on and into implants exhibiting substantial surface porosity is a promising strategy in order to improve the long-term stable fixation of bone implants. However, the reliability in clinical applications remains a point of discussion. Most attention has been dedicated to the role of macroporosity, leading to the general consensus of a minimal pore size of 50-100 MUm in order to allow bone ingrowth. In this in vivo study, we assessed the feasibility of early bone ingrowth into a predominantly microporous Ti coating with an average thickness of 150 MUm and the hypothesis of improving the bone response through surface modification of the porous coating. Implants were placed in the cortical bone of rabbit tibiae for periods of 2 and 4 weeks and evaluated histologically and histomorphometrically using light microscopy and scanning electron microscopy. Bone with osteocytes encased in the mineralized matrix was found throughout the porous Ti coating up to the coating/substrate interface, highlighting that osseointegration of microporosities (<10 MUm) was achievable. The bone trabeculae interweaved with the pore struts, establishing a large contact area which might enable an improved load transfer and stronger implant/bone interface. Furthermore, there was a clear interconnection with the surrounding cortical bone, suggesting that mechanical interlocking of the coating in the host bone in the long term is possible. When surface modifications inside the porous structure further reduced the interconnective pore size to the submicrometer level, bone ingrowth was impaired. On the other hand, application of a sol-gel-derived bioactive glass-ceramic coating without altering the pore characteristics was found to significantly improve bone regeneration around the coating, while still supporting bone ingrowth. PMID- 24161387 TI - Physiological responses to spinal manipulation therapy: investigation of the relationship between electromyographic responses and peak force. AB - OBJECTIVE: It is believed that systematic modulation of spinal manipulative therapy (SMT) parameters should yield varying levels of physiological responses and eventually a range of clinical responses. However, investigation of SMT dose physiological response relationship is recent and has mostly been conducted using animal or cadaveric models. The main objective of the present study is to investigate SMT dose-physiological response relation in humans by determining how different levels of force can modify electromyographic (EMG) responses to spinal manipulation. METHODS: Twenty-six participants were subjected to 2 trials of 4 different SMT force-time profiles using a servo-controlled linear actuator motor. Normalized EMG activity of paraspinal muscles (left and right muscles at level T6 and T8) was recorded during and after SMT, and EMG values were compared across the varying levels of force. RESULTS: Increasing the level of force yielded an increase in paraspinal muscle EMG activity during the thrust phase of SMT but also in the two 250-millisecond time windows after the spinal manipulation impulse. These muscle activations quickly attenuated (500 milliseconds after spinal manipulation impulse). CONCLUSION: The study confirmed the presence of a local paraspinal EMG response after SMT and highlighted the linear relationship between the SMT peak force and paraspinal muscle activation. PMID- 24161386 TI - Effects of unilateral facet fixation and facetectomy on muscle spindle responsiveness during simulated spinal manipulation in an animal model. AB - OBJECTIVES: Manual therapy practitioners commonly assess lumbar intervertebral mobility before deciding treatment regimens. Changes in mechanoreceptor activity during the manipulative thrust are theorized to be an underlying mechanism of spinal manipulation (SM) efficacy. The objective of this study was to determine if facet fixation or facetectomy at a single lumbar level alters muscle spindle activity during 5 SM thrust durations in an animal model. METHODS: Spinal stiffness was determined using the slope of a force-displacement curve. Changes in the mean instantaneous frequency of spindle discharge were measured during simulated SM of the L6 vertebra in the same 20 afferents for laminectomy-only and 19 laminectomy and facet screw conditions; only 5 also had data for the laminectomy and facetectomy condition. Neural responses were compared across conditions and 5 thrust durations (<= 250 milliseconds) using linear-mixed models. RESULTS: Significant decreases in afferent activity between the laminectomy-only and laminectomy and facet screw conditions were seen during 75 millisecond (P < .001), 100-millisecond (P = .04), and 150-millisecond (P = .02) SM thrust durations. Significant increases in spindle activity between the laminectomy-only and laminectomy and facetectomy conditions were seen during the 75-millisecond (P < .001) and 100-millisecond (P < .001) thrust durations. CONCLUSION: Intervertebral mobility at a single segmental level alters paraspinal sensory response during clinically relevant high-velocity, low-amplitude SM thrust durations (<= 150 milliseconds). The relationship between intervertebral joint mobility and alterations of primary afferent activity during and after various manual therapy interventions may be used to help to identify patient subpopulations who respond to different types of manual therapy and better inform practitioners (eg, chiropractic and osteopathic) delivering the therapeutic intervention. PMID- 24161388 TI - Referral to massage therapy in primary health care: a survey of medical general practitioners in rural and regional New South Wales, Australia. AB - OBJECTIVES: Massage therapists are an important part of the health care setting in rural and regional Australia and are the largest complementary and alternative medicine (CAM) profession based on both practitioner numbers and use. The purpose of this study was to survey medical general practitioners (GPs) in rural and regional New South Wales, Australia, to identify their knowledge, attitudes, relationships, and patterns of referral to massage therapy in primary health care. METHODS: A 27-item questionnaire was sent to all 1486 GPs currently practicing in rural and regional Divisions of General Practice in New South Wales, Australia. The survey had 5 general areas: the GP's personal use and knowledge of massage, the GP's professional relationships with massage practice and massage practitioners, the GP's specific opinions on massage, the GP's information-seeking behavior in relation to massage, and the GP's assumptions on massage use by patients in their local areas. RESULTS: A total of 585 questionnaires were returned completed, with 49 survey questionnaires returned as "no longer at this address" (response rate of 40.7%). More than three-quarters of GPs (76.6%) referred to massage therapy at least a few times per year, with 12.5% of GPs referring at least once per week. The GP being in a nonremote location (odds ratio [OR], 14.28; 95% confidence interval [CI], 3.7-50.0), graduating from an Australian medical school (OR, 2.03; 95% CI, 1.09-3.70), perceiving a lack of other treatment options (OR, 2.64; 95% CI, 1.15-6.01), perceiving good patient access to a wide variety of medical specialists (OR, 11.1; 95% CI, 1.7-50.0), believing in the efficacy of massage therapy (OR, 2.75; 95% CI, 1.58-4.78), experiencing positive results from patients using massage therapy previously (OR, 13.95; 95% CI, 5.96-32.64), or having prescribed any CAM previously (OR, 1.83; 95% CI, 1.03-3.27) were all independently predictive of increased referral to massage therapy among the GPs in this study. CONCLUSIONS: There appears to be substantial interface between massage therapy and GPs in rural and regional Australia. There are high levels of support for massage therapies among Australian GPs, relative to other CAM professions, with low levels of opposition to the incorporation of these therapies in patient care. PMID- 24161389 TI - Concordance of upper limb neurodynamic tests with medical examination and magnetic resonance imaging in patients with cervical radiculopathy: a diagnostic cohort study. AB - OBJECTIVE: The purpose of this study was to investigate the concordance of the upper limb neurodynamic tests (ULNTs) with a chosen reference standard, consisting of medical examination and magnetic resonance imaging (MRI), in patients with cervical radiculopathy. METHODS: This diagnostic cohort study included 51 consecutive patients referred to a center for spinal surgery for clinical investigation of cervical and/or arm pain in Sweden during the period of November 2007 to February 2008. The patients were exposed to the 4 different tests of ULNT. One diagnosis based on each of the tests separately and one based on the tests combined were compared with a chosen reference standard consisting of MRI, anamnestic features, and clinical examination. RESULTS: The ULNT (1-3 used combined) had a sensitivity of 0.97 and a specificity of 0.69. The results of ULNT (1-3 used combined) corresponded in 88.2% with the reference standard. Individually, the ULNT 1 (median) showed the highest validity, and ULNT 2b (radial), the lowest. CONCLUSION: Upper limb neurodynamic test (combined) showed a substantial agreement with findings from medical examination including MRI. These results indicate the importance of ULNT (combined) to complement the clinical examination of patients with radiculopathy. PMID- 24161390 TI - The mitochondrial fatty acid synthesis (mtFASII) pathway is capable of mediating nuclear-mitochondrial cross talk through the PPAR system of transcriptional activation. AB - Mammalian cells contain two fatty acid synthesis pathways, the cytosolic FASI pathway, and the mitochondrial FASII pathway. The selection behind the conservation of the mitochondrial pathway is not completely understood, given the presence of the cytosolic FAS pathway. In this study, we show through heterologous gene reporter systems and PCR-based arrays that overexpression of MECR, the last step in the mtFASII pathway, causes modulation of gene expression through the PPAR pathway. Electromobility shift assays (EMSAs) demonstrate that overexpression of MECR causes increased binding of PPARs to DNA, while cell fractionation and imaging studies show that MECR remains localized to the mitochondria. Interestingly, knock down of the mtFASII pathway lessens the effect of MECR on this transcriptional modulation. Our data are most consistent with MECR-mediated transcriptional activation through products of the mtFASII pathway, although we cannot rule out MECR acting as a coactivator. Further investigation into the physiological relevance of this communication will be necessary to better understand some of the phenotypic consequences of deficits in this pathway observed in animal models and human disease. PMID- 24161391 TI - Two distinct WT1 mutations identified in patients and relatives with isolated nephrotic proteinuria. AB - Wilms' tumor type 1 gene (WT1) encodes a zinc-finger transcription factor that plays a key role during genitourinary development and in adult kidney. Mutations in exons 8 and 9 are associated with Denys-Drash Syndrome, whereas those occurring in the intron 9 donor splice site are associated with Frasier Syndrome. Familial cases of WT1 mutations are rare with only few cases described in the literature, whereas cases of WT1 mutations associated with isolated nephrotic proteinuria with or without focal segmental glomerular sclerosis (FSGS) are even rarer. Exons 8 and 9 of WT1 gene were analyzed in two non-related female patients and their parents. Patient 1, who presented with isolated nephrotic proteinuria and histologic pattern of FSGS, is heterozygous for the mutation c.1227+4C>T. This mutation was inherited from her mother, who had undergone kidney transplant due to FSGS. Patient 2 is heterozygous for the novel c.1178C>T transition inherited from her father. The putative effect of this nucleotide substitution on WT1 protein is p.Ser393Phe mutation located within the third zinc-finger domain. The patient and her father presented, respectively, isolated nephrotic proteinuria and chronic renal failure. These data highlight the importance of the inclusion of WT1 gene mutational analysis in patients with isolated nephrotic proteinuria, especially when similar conditions are referred to the family. PMID- 24161392 TI - Effects of the dual TP receptor antagonist and thromboxane synthase inhibitor EV 077 on human endothelial and vascular smooth muscle cells. AB - The prothrombotic mediator thromboxane A2 is derived from arachidonic acid metabolism through the cyclooxygenase and thromboxane synthase pathways, and transduces its effect through the thromboxane prostanoid (TP) receptor. The aim of this study was to determine the effect of the TP receptor antagonist and thromboxane synthase inhibitor EV-077 on inflammatory markers in human umbilical vein endothelial cells and on human coronary artery smooth muscle cell proliferation. To this end, mRNA levels of different proinflammatory mediators were studied by real time quantitative PCR, supernatants were analyzed by enzyme immune assay, and cell proliferation was assessed using WST-1. EV-077 significantly decreased mRNA levels of ICAM-1 and PTX3 after TNFalpha incubation, whereas concentrations of 6-keto PGF1alpha in supernatants of endothelial cells incubated with TNFalpha were significantly increased after EV-077 treatment. Although U46619 did not alter coronary artery smooth muscle cell proliferation, this thromboxane mimetic enhanced the proliferation induced by serum, insulin and growth factors, which was significantly inhibited by EV-077. In conclusion, EV 077 inhibited TNFalpha-induced endothelial inflammation and reduced the enhancement of smooth muscle cell proliferation induced by a thromboxane mimetic, supporting that the thromboxane pathway may be associated with early atherosclerosis in terms of endothelial dysfunction and vascular hypertrophy. PMID- 24161393 TI - Pigment epithelium-derived factor (PEDF) binds to caveolin-1 and inhibits the pro inflammatory effects of caveolin-1 in endothelial cells. AB - Pigment epithelium-derived factor (PEDF) exerts atheroprotective effects both in cell culture and animal models through its anti-oxidative and anti-inflammatory properties. Caveolin-1 (Cav), a major protein component of caveolae in endothelial cells (ECs), plays a role in the progression of atherosclerosis. However, effects of PEDF on Cav-exposed ECs remain unknown. In this study, we examined whether and how PEDF could inhibit the Cav-induced inflammatory and thrombogenic reactions in human umbilical vein ECs (HUVECs). Surface plasmon resonance revealed that PEDF bound to Cav at the dissociation constant of 7.36*10(-7) M. Further, one of the major Cav-interacting proteins in human serum was identified as PEDF by peptide mass fingerprinting analysis using BIAcore 1000 combined with matrix-assisted laser desorption/ionization time-of-flight mass spectrometry. Exogenously added Cav was taken up into the membrane fraction of HUVECs and dose-dependently increased monocyte chemoattractant protein-1 (MCP-1), vascular cell adhesion molecule-1 (VCAM-1) and plasminogen activator inhibitor-1 (PAI-1) mRNA levels, all of which were blocked by the simultaneous treatment with 10nM PEDF. Small interfering RNAs directed against Cav decreased endogenous Cav levels and suppressed gene expression of MCP-1, VCAM-1 and PAI-1 in HUVECs. This study indicates that PEDF binds to Cav and could block the inflammatory and thrombogenic reactions in Cav-exposed HUVECs. Our present study suggests that atheroprotective effects of PEDF might be partly ascribed to its Cav-interacting properties. PMID- 24161394 TI - Cationic antioxidants as a powerful tool against mitochondrial oxidative stress. AB - This review describes evidence that mitochondrial reactive oxygen species (mROS) are of great importance under many physiological and pathological conditions. The most demonstrative indications favoring this conclusion originate from recent discoveries of the in vivo effects of mitochondria-targeted antioxidants (MitoQ and SkQs). The latter compounds look promising in treating several incurable pathologies as well as aging. PMID- 24161395 TI - Sirt2 suppresses glioma cell growth through targeting NF-kappaB-miR-21 axis. AB - Sirtuins are NAD(+)-dependent deacetylases that regulate numerous cellular processes including aging, DNA repair, cell cycle, metabolism, and survival under stress conditions. The roles of sirtuin family members are widely studied in carcinogenesis. However, their roles in glioma remain unclear. Here we report that Sir2 was under expressed in human glioma tissues and cell lines. We found that Sirt2 overexpression decreased cell proliferation and colony formation capacity. In addition, Sirt2 overexpression induced cellular apoptosis via up regulating cleaved caspase 3 and Bax, and down-regulating anti-apoptotic protein Bcl-2. Sirt2 knockdown obtained opposing results. We showed that Sirt2 overexpression inhibited miR-21 expression, and Sirt2 was not sufficient to reduce cell proliferation and colony formation as well as to induce apoptosis when miR-21 was knocked down in glioma cells. Mechanically, we demonstrated that Sirt2 deacetylated p65 at K310 and blocked p65 binding to the promoter region of miR-21, thus regressing the transcription of miR-21. In summary, Sirt2 is critical in human glioma via NF-kappaB-miR-21 pathway and Sirt2 activator may serve as candidate drug for glioma therapy. PMID- 24161396 TI - Zfp296 is a novel Klf4-interacting protein and functions as a negative regulator. AB - Pluripotency and self-renewing ability of embryonic stem (ES) cells are regulated by several transcription factors, including Oct3/4, Sox2, Kruppel-like factor 4 (Klf4), and c-Myc. These transcription factors reprogram somatic cells into induced pluripotent stem (iPS) cells. Zinc finger protein (Zfp) 296 has been reported to enhance iPS cell formation. Here we found that Zfp296 interacts with Klf4. A maltose-binding protein pull-down assay demonstrated that Klf4 binds to the Zfp296 158-483 amino acid region, and that Zfp296 binds to the Klf4 DNA binding domain (DBD). A quantitative reverse transcription-polymerase chain reaction analysis revealed that expression of Zfp296 and Klf4 decreased during differentiation of E14 and ZHBTc4 ES cells. We also found that green fluorescent protein-labeled Zfp296 and Klf4 were localized to the nucleus. Because Zfp296 bound to the Klf4 DBD, we next examined the influence of Zfp296 on Klf4 DNA binding activity. A biotin DNA pull-down assay showed that Klf4 binds to the Lefty1 promoter region, and that binding activity was sustained even in the presence of Zfp296. In contrast, a reporter assay showed that the Lefty1 promoter was activated by Klf4, and that the enhanced activity was repressed by Zfp296. These findings suggest that Zfp296 is a functional regulator of Klf4 in ES cells. PMID- 24161397 TI - Risk distribution and its influence on the population targets for diabetes prevention. AB - OBJECTIVE: To quantify the influence of type 2 diabetes risk distribution on prevention benefit and apply a method to optimally identify population targets. METHODS: We used data from the 2011 Canadian Community Health Survey (N=45,040) and the validated Diabetes Population Risk Tool to calculate 10-year diabetes risk. We calculated the Gini coefficient as a measure of risk dispersion. Intervention benefit was estimated using absolute risk reduction (ARR), number needed-to-treat (NNT), and number of cases prevented. RESULTS: There is a wide variation of diabetes risk in Canada (Gini=0.48) and with an inverse relation to risk (r=-0.99). Risk dispersion is lower among individuals meeting an empirically derived risk cut-off (Gini=0.18). Targeting prevention based on a risk cut-off (10-year risk >= 16.5%) resulted in a greater number of cases prevented (340 thousand), higher ARR (7.7%) and lower NNT (13) compared to targeting individuals based on risk factor targets. CONCLUSIONS: This study provides empirical evidence to demonstrate that risk variability is an important consideration for estimating the prevention benefit. Prioritizing target populations using an empirically derived cut-off based on a multivariate risk score will result in greater benefit and efficiency compared to risk factor targets. PMID- 24161398 TI - SSP: an interval integer linear programming for de novo transcriptome assembly and isoform discovery of RNA-seq reads. AB - Recent advances in the sequencing technologies have provided a handful of RNA-seq datasets for transcriptome analysis. However, reconstruction of full-length isoforms and estimation of the expression level of transcripts with a low cost are challenging tasks. We propose a novel de novo method named SSP that incorporates interval integer linear programming to resolve alternatively spliced isoforms and reconstruct the whole transcriptome from short reads. Experimental results show that SSP is fast and precise in determining different alternatively spliced isoforms along with the estimation of reconstructed transcript abundances. The SSP software package is available at http://www.bioinf.cs.ipm.ir/software/ssp. PMID- 24161399 TI - Bone conduction in Thiel-embalmed cadaver heads. AB - INTRODUCTION: Sound can reach the inner ear via at least two different pathways: air conduction and bone conduction (BC). BC hearing is used clinically for diagnostic purposes and for BC hearing aids. Research on the motion of the human middle ear in response to BC stimulation is typically conducted using cadaver models. We evaluated middle ear motion of Thiel-embalmed whole-head specimens in terms of linearity, reproducibility, and consistency with the reported middle ear motion of living subjects, fresh cadaveric temporal bones, and whole-heads embalmed with a Non-Thiel solution of salts. METHODS: We used laser Doppler vibrometry to measure the displacement of the skull, the umbo, the cochlear promontory, the stapes, and the round window in seven ears from four human whole head specimens embalmed according to Thiel's method. The ears were stimulated with a Baha((r)) implanted behind the auricle. RESULTS: The Thiel model shows promontory velocity similar to that reported in the literature for whole-heads embalmed with a Non-Thiel solution of salts (0- to 7-dB difference). The Thiel heads' relative velocity of the stapes with respect to the promontory was similar to that of fresh cadaver temporal bones (0- to 4-dB difference). The velocity of the umbo was comparable in Thiel-embalmed heads and living subjects (0- to 10-dB difference). The skull and all middle ear elements measured responded linearly to different stimulation levels, with an average difference less than 1 dB. The variability of repeated measurements for both short- (2 h; 4 dB) and long-term (4 16 weeks; 6 dB) repetitions in the same ear, and the difference between the two ears of the same donor (approximately 10 dB) were lower than the inter-individual difference (up to 25 dB). CONCLUSION: Thiel-embalmed human whole-head specimens can be used as an alternative model for the study of human middle ear mechanics secondary to BC stimulation. At some frequencies, differences from living subjects must be considered. PMID- 24161400 TI - Brain "Globalopathies" cause mental disorders. AB - "Consciousness" "mood," "identity" and "personality" are all emergent properties from whole-brain organizations; these are typically disturbed in psychiatric disorders. This work proposes that the underlying etiopathology of mental disorders originates from disturbances to global brain dynamics, or "Globalopathies" that are divided into three major interdependent types (1) "Resting-State Networkpathies," in personality disorders, (2) "Entropiathies" in mood disorders, and (3) "Connectopathies" in psychosis and schizophrenia spectrum disorders. Novel approaches of processing signals from the brain are beginning to reveal brain organization in health and disease. For example a "small world network" has been described for optimal brain functions and breakdown of that organization might underlie relevant psychiatric manifestations. A novel diagnostic reformulation can be generated based on pathologies of whole brain organizations, such new brain related diagnostic nosology is testable and thus can be validated. Once validated Globalopathies can provide for "Global therapies" i.e., interventions that can reorganize the brain and cure psychiatric disorders. The technology for such interventions is becoming available. PMID- 24161401 TI - Modulation of microRNAs in hypertension-induced arterial remodeling through the beta1 and beta3-adrenoreceptor pathways. AB - BACKGROUND: Dysregulation of microRNAs (miRNAs) in arterial dysfunction and hypertension has not been extensively investigated yet. This project determined the effects of two anti-hypertensive beta1 adrenergic selective blockers on miRNA expression in the Dahl Salt Sensitive (DSS) hypertensive rat model. METHODS AND RESULTS: Microarray analysis showed that a set of miRNAs is differently expressed in the aorta of high salt (HS) treated rats with miR-320 increased and miR-26b and -21 decreased. All of these changes were reverted to normal by nebivolol (NEB, a beta1 selective-blocker and beta3 activator). The selective beta3 adrenoceptor antagonist S-(-)-cyanopindolol (Syc) counteracted the effect of NEB on these miRNAs. Atenolol (ATN, a pure beta1-blocker) combined with specific beta3 agonist BRL37344 restored the expression of all three miRNAs, similar to NEB, while ATN alone had only a partial effect on miR-320 expression. Computational analysis found Insulin Growth Factor-1 Receptor (IGF1R) as a putative target of miR-320, and Phosphatase and tensin homolog on chromosome ten (PTEN) as a putative target of miR-26b and -21. The targets were verified by luciferase reporter assays. Inhibition of miR-320 by an antisense inhibitor or NEB increased IGF1R expression, while miR-320 overexpression reversed the effect of NEB. Overexpression of miR-26b or -21 or NEB decreased PTEN levels, while inhibition of miR-26b or -21 attenuated the effect of NEB. HS diet induced downregulation of IGF1R and upregulation of PTEN in the aorta. NEB normalized the aberrant expression of IGF1R and PTEN and also improved the impairment of vascular AKT/eNOS signaling. Moreover, both NEB and ATN showed to have protective effects on salt-induced hypertension, oxidative stress, and vascular remodeling. NEB had a greater effect than ATN. CONCLUSIONS: Our data supports a differential miRNA expression profile in salt-induced hypertension. Manipulation of dysregulated miRNAs by beta-blockers may substantially induce alterations of gene expression and prevent arterial dysfunction and remodeling. PMID- 24161402 TI - Methane oxidation needs less stressed plants. AB - Methane oxidation rates in soil are liable to be reduced by plant stress responses to climate change. Stressed plants exude ethylene into soil, which inhibits methane oxidation when present in the soil atmosphere. Here we discuss opportunities to use 1-aminocyclopropane-1-carboxylate deaminase to manage methane oxidation by regulating plant stress responses. PMID- 24161404 TI - The effect of rTMS over the inferior parietal lobule on EEG sensorimotor reactivity differs according to self-reported traits of autism in typically developing individuals. AB - Previous research suggested that EEG markers of mirror neuron system activation may differ, in the normal population as a function of different levels of the autistic spectrum quotient; (AQ). The present study aimed at modulating the EEG sensorimotor reactivity induced by hand movement observation by means of repetitive transcranial magnetic stimulation (rTMS) applied to the inferior parietal lobule. We examined how the resulting rTMS modulation differed in relation to the self-reported autistic traits in the typically developing population. Results showed that during sham stimulation, all participants had significantly greater sensorimotor alpha reactivity (motor cortex-C electrodes) when observing hand movements compared to static hands. This sensorimotor alpha reactivity difference was reduced during active rTMS stimulation. Results also revealed that in the average AQ group at sham there was a significant increase in low beta during hand movement than static hand observation (pre-motor areas-FC electrodes) and that (like alpha over the C electrodes) this difference is abolished when active rTMS is delivered. Participants with high AQ scores showed no significant difference in low beta sensorimotor reactivity between active and sham rTMS during static hand or hand movement observation. These findings suggest that unlike sham, active rTMS over the IPL modulates the oscillatory activity of the low beta frequency of a distal area, namely the anterior sector of the sensorimotor cortex, when participants observe videos of static hand. Importantly, this modulation differs according to the degree of self-reported traits of autism in a typically developing population. PMID- 24161403 TI - R-flurbiprofen improves tau, but not Abeta pathology in a triple transgenic model of Alzheimer's disease. AB - We have previously reported that chronic ibuprofen treatment improves cognition and decreases intracellular Abeta and phosphorylated-tau levels in 3xTg-AD mice. Ibuprofen is a non-steroidal anti-inflammatory drug (NSAID) that independently of its anti-inflammatory effects has anti-amyloidogenic activity as a gamma secretase modulator (GSM) and both activities have the potential to decrease Abeta pathology. To further understand the effects of NSAIDs in 3xTg-AD mice, we treated 3xTg-AD mice with R-flurbiprofen, an enantiomer of the NSAID flurbiprofen that maintains the GSM activity but has greatly reduced anti-inflammatory activity, and analyzed its effect on cognition, Abeta, tau, and the neurochemical profile of the hippocampus. Treatment with R-flurbiprofen from 5 to 7 months of age resulted in improved cognition on the radial arm water maze (RAWM) test and decreased the level of hyperphosphorylated tau immunostained with AT8 and PHF-1 antibodies. No significant changes in the level of Abeta (using 6E10 and NU-1 antibodies) were detected. Using magnetic resonance spectroscopy (MRS) we found that R-flurbiprofen treatment decreased the elevated level of glutamine in 3xTg AD mice down to the level detected in non-transgenic mice. Glutamine levels correlated with PHF-1 immunostained hyperphosphorylated tau. We also found an inverse correlation between the concentration of glutamate and learning across all the mice in the study. Glutamine and glutamate, neurochemicals that shuttles between neurons and astrocytes to maintain glutamate homeostasis in the synapses, deserve further attention as MR markers of cognitive function. PMID- 24161405 TI - Evidence for reduced tonic levels of GABA in the hippocampus of an animal model of ADHD, the spontaneously hypertensive rat. AB - Recent studies have investigated the role of gamma-aminobutyric acid (GABA) in the behavioural symptoms of attention-deficit/hyperactivity disorder (ADHD), specifically in behavioural disinhibition. Spontaneously hypertensive rats (SHR) are widely accepted as an animal model of ADHD, displaying core symptoms of the disorder. Using an in vitro superfusion technique, we have shown that glutamate stimulated release of radio-actively labelled norepinephrine ([(3)H]NE) from prefrontal cortex and hippocampal slices is greater in SHR than in their normotensive control strain, Wistar-Kyoto rats (WKY), and/or a standard control strain, Sprague-Dawley rats (SD). In the present study, we investigated how the level of extracellular (tonic) GABA affects release of [(3)H]NE in hippocampal slices of male and female SHR, WKY and SD rats, in response to 3 glutamate stimulations (S1, S2, and S3). The hippocampal slices were prelabelled with [(3)H]NE and superfused with buffer containing 0MUM, 1MUM, 10MUM, or 100MUM GABA. Three consecutive glutamate stimulations were achieved by exposing slices to 3 pulses of glutamate (1mM), each separated by 10min. Increasing tonic levels of GABA increased basal and stimulated release of [(3)H]NE in all strains. When GABA was omitted from the superfusion buffer used to perfuse SHR hippocampal slices, but present at 100uM in the buffer used to perfuse WKY and SD hippocampal slices, glutamate-stimulated release of [(3)H]NE was similar in all three strains. In these conditions, the decrease in [(3)H]NE release from S1 to S2 and S3 was also similar in all three strains. These findings suggest that extracellular concentrations of GABA may be reduced in SHR hippocampus, in vivo, compared to WKY and SD. An underlying defect in GABA function may be at the root of the dysfunction in catecholamine transmission noted in SHR, and may underlie their ADHD-like behaviours. PMID- 24161406 TI - Potential of handheld optical coherence tomography to determine cause of infantile nystagmus in children by using foveal morphology. AB - OBJECTIVE: To investigate the feasibility of handheld (HH) ultra-high-resolution spectral-domain optical coherence tomography (SD-OCT) in young children with nystagmus, to determine its sensitivity and specificity in classifying foveal abnormalities, and to investigate its potential to determine the cause of infantile nystagmus with the use of foveal morphology. DESIGN: Prospective, case control study. PARTICIPANTS AND CONTROLS: A total of 50 patients with nystagmus and 50 healthy control subjects (mean age, 3.2 years; range, 0-8 years). METHODS: Each patient was scanned using HH SD-OCT (Bioptigen Inc., Research Triangle Park, NC) without sedation, and foveal morphology was classified into 1 of 4 categories: (1) typical foveal hypoplasia (predicting clinical diagnosis of albinism, PAX6 mutations, or isolated foveal hypoplasia); (2) atypical foveal hypoplasia (predicting achromatopsia); (3) other foveal changes (corresponding to retinal dystrophies); and (4) normal fovea (predicting idiopathic or manifest latent nystagmus). An independent interpretation of the HH SD-OCT scans by masked examiners was performed, and the sensitivity and specificity of the predicted diagnosis were calculated. MAIN OUTCOME MEASURES: The success rate of image acquisition and sensitivity and specificity of the HH SD-OCT in classifying foveal abnormalities. RESULTS: In 94% of examinations, HH SD-OCT was successful. Twenty-three patients had typical foveal hypoplasia (category 1). Of these patients, 21 were diagnosed with albinism and 2 were diagnosed with PAX6 mutations. Five patients were classified as atypical (category 2) and diagnosed with achromatopsia. Six patients had other abnormal foveal morphology (category 3) and were diagnosed with retinal dystrophy. Sixteen patients had normal foveal morphology (category 4). Of these patients, 12 were diagnosed with idiopathic nystagmus and 4 were diagnosed with manifest latent nystagmus. Sensitivities of HH SD-OCT for classifying typical or atypical foveal hypoplasia, other abnormal foveal morphology, and normal morphology were 92.8%, 86.7%, 41.1%, and 88.4%, respectively, with specificities of 91.4%, 94.8%, 97.7% and 95.1%, respectively. CONCLUSIONS: We demonstrate excellent feasibility of HH SD-OCT in the diagnosis of conditions associated with infantile nystagmus. The HH SD-OCT classification of foveal abnormalities was highly sensitive and specific. This classification was used to determine the underlying cause of infantile nystagmus. Handheld SD OCT in early childhood can facilitate focused investigations and earlier diagnosis. This is important in an era when potentially time-sensitive treatment, such as gene therapy, is imminent. PMID- 24161407 TI - Built-in bias in HCV clearance in acute HCV infection. PMID- 24161409 TI - Reply to: "Built-in bias in HCV clearance in acute HCV infection". PMID- 24161408 TI - A method for establishing allocation equity among patients with and without hepatocellular carcinoma on a common liver transplant waiting list. AB - BACKGROUND & AIMS: The current organ allocation system for liver transplantation (LT) creates an imbalance between patients with and without hepatocellular carcinoma (HCC). We describe a model designed to re-establish allocation equity among patient groups using transplant benefit as the common endpoint. METHODS: We enrolled consecutive adult patients entering the waiting list (WL group, n=2697) and undergoing LT (LT group, n=1702) during the period 2004-2009 in the North Italy Transplant program area. Independent multivariable regressions (WL and LT models) were created for patients without HCC and for those with stage T2 HCC. Monte Carlo simulation was used to create distributions of transplant benefit, and covariates such as Model for End-stage Liver Disease (MELD) and alpha fetoprotein (AFP) were combined in regression equations. These equations were then calibrated to create an "MELD equivalent" which matches HCC patients to non HCC patients having the same numerical MELD score. RESULTS: Median 5 year transplant benefit was 15.12 months (8.75-25.35) for the non-HCC patients, and 28.18 months (15.11-36.38) for the T2-HCC patients (p<0.001). Independent predictors of transplant benefit were MELD score (estimate=0.89, p<0.001) among non-HCC patients, and MELD (estimate=1.14, p<0.001) and logAFP (estimate=-0.46, p<0.001) among HCC patients. The equation "HCC-MELD"=1.27*MELD - 0.51*logAFP+4.59 calculates a numerical score for HCC patients, whereby their transplant benefit is equal to that of non-HCC patients with the same numerical value for MELD. CONCLUSIONS: We describe a method for calibrating HCC and non-HCC patients according to survival benefit, and propose that this method has the potential, if externally validated, to restore equity to the organ allocation system. PMID- 24161411 TI - Evidence of avian-like H9N2 influenza A virus among dogs in Guangxi, China. AB - We reported for the first time the isolation of H9N2 influenza virus from dogs in southern China. Genetic analysis of an isolate revealed that it was a novel genotype closely related to avian H9N2 virus. Epidemiologic studies demonstrated that the new H9N2-subtype virus was the causative agent of a disease in canine. Therefore, an appropriate countermeasure is urgently needed. PMID- 24161413 TI - Coverage and cost of a large oral cholera vaccination program in a high-risk cholera endemic urban population in Dhaka, Bangladesh. AB - A feasibility study of an oral cholera vaccine was carried out to test strategies to reach high-risk populations in urban Mirpur, Dhaka, Bangladesh. The study was cluster randomized, with three arms: vaccine, vaccine plus safe water and hand washing practice, and no intervention. High risk people of age one year and above (except pregnant woman) from the two intervention arms received two doses of the oral cholera vaccine, ShancholTM. Vaccination was conducted between 17th February and 16th April 2011, with a minimum interval of fourteen days between two doses. Interpersonal communication preceded vaccination to raise awareness amongst the target population. The number of vaccine doses used, the population vaccinated, left-out, drop out, vaccine wastage and resources required were documented. Fixed outreach site vaccination strategy was adopted as the mode of vaccine delivery. Additionally, mobile vaccination sites and mop-up activities were carried out to reach the target communities. Of the 172,754 target population, 141,839 (82%) and 123,666 (72%) received complete first and second doses of the vaccine, respectively. Dropout rate from the first to the second dose was 13%. Two complete doses were received by 123,661 participants. Vaccine coverage in children was 81%. Coverage was significantly higher in females than in males (77% vs. 66%, P<0.001). Vaccine wastage for delivering the complete doses was 1.2%. The government provided cold-chain related support at no cost to the project. Costs for two doses of vaccine per-person were US$3.93, of which US$1.63 was spent on delivery. Cost for delivering a single dose was US$0.76. We observed no serious adverse events. Mass vaccination with oral cholera vaccine is feasible for reaching high risk endemic population through the existing national immunization delivery system employed by the government. PMID- 24161412 TI - Cost minimisation analysis of fingolimod vs natalizumab as a second line of treatment for relapsing-remitting multiple sclerosis. AB - INTRODUCTION: At present, there is a lack of economic assessments of second-line treatments for relapsing-recurring multiple sclerosis. The aim of this study was to compare the efficiency between fingolimod and natalizumab in Spain. METHODS: A cost minimisation analysis model was developed for a 2-year horizon. The same relapse rate was applied to both treatment arms and the cost of resources was calculated using Spain's stipulated rates for 2012 in euros. The analysis was conducted from the perspective of Spain's national health system and an annual discount rate of 3% was applied to future costs. A sensitivity analysis was performed to validate the robustness of the model. RESULTS: Indirect comparison of fingolimod with natalizumab revealed no significant differences (hazard ratio between 0.82 and 1.07). The total direct cost, considering a 2-year analytical horizon, a 7.5% discount stipulated by Royal Decree, and a mean annual relapse rate of 0.22, was ? 40914.72 for fingolimod and ? 45890.53 for natalizumab. Of the total direct costs that were analysed, the maximum cost savings derived from prescribing fingolimod prescription was ? 4363.63, corresponding to lower administration and treatment maintenance costs. Based on the sensitivity analysis performed, fingolimod use was associated with average savings of 11% (range 3.1% 18.7%). CONCLUSIONS: Fingolimod is more efficient than natalizumab as a second line treatment option for relapsing-remitting multiple sclerosis and it generates savings for the Spanish national health system. PMID- 24161414 TI - Lifetime achievement from a brain-adrenal perspective: on the CRF-urocortin glucocorticoid balance. AB - This contribution dedicated to Wylie Vale is focused on the action of the glucocorticoid hormone aimed to counterbalance the stress response orchestrated by the corticotrophin releasing factor (CRF) and urocortin (Ucn) family of peptides. It appears that the release and action of these stress hormones themselves are subjected to intrinsic self-regulatory feedback loops that operate as checks and balances in stress adaptation. One of these feedback loops is operated by the mineralocorticoid (MR) and glucocorticoid receptors (GR) that mediate in complementary fashion the action of endogenous cortisol/corticosterone in brain circuits underlying the onset and termination of the stress response. By affecting appraisal processes MR has an important role in coordinating emotional expression and cognitive flexibility with the onset of the stress response, while GR's role is prominent in the management of behavioral and physiological adaptations during the recovery phase. Genetic variation in interaction with environmental input and experience-related factors can modulate this balance between susceptibility and recovery governed by a balanced MR:GR signaling. Thanks to the Wylie Vale School of scientists a parallel balanced regulation between the CRF/CRF-1 and Ucn/CRF-2 receptor systems is being uncovered, leading inexorably to the question: how do the CRF/Ucn and glucocorticoid systems interact in multiple brain sites to maintain homeostasis and health? PMID- 24161410 TI - Poxviruses and the evolution of host range and virulence. AB - Poxviruses as a group can infect a large number of animals. However, at the level of individual viruses, even closely related poxviruses display highly diverse host ranges and virulence. For example, variola virus, the causative agent of smallpox, is human-specific and highly virulent only to humans, whereas related cowpox viruses naturally infect a broad spectrum of animals and only cause relatively mild disease in humans. The successful replication of poxviruses depends on their effective manipulation of the host antiviral responses, at the cellular-, tissue- and species-specific levels, which constitutes a molecular basis for differences in poxvirus host range and virulence. A number of poxvirus genes have been identified that possess host range function in experimental settings, and many of these host range genes target specific antiviral host pathways. Herein, we review the biology of poxviruses with a focus on host range, zoonotic infections, virulence, genomics and host range genes as well as the current knowledge about the function of poxvirus host range factors and how their interaction with the host innate immune system contributes to poxvirus host range and virulence. We further discuss the evolution of host range and virulence in poxviruses as well as host switches and potential poxvirus threats for human and animal health. PMID- 24161415 TI - The pattern recognition molecule ficolin-1 exhibits differential binding to lymphocyte subsets, providing a novel link between innate and adaptive immunity. AB - Ficolin-1 is a soluble pattern recognition molecule synthesized by myeloid cells and capable of activating the lectin pathway of complement on the surface of pathogens. It is tethered to the membranes of monocytes and granulocytes; however, the biological significance of cell-associated ficolin-1 is unknown. Recognition of healthy host cells by a pattern recognition molecule constitutes a potential hazard to self cells and tissues, emphasizing the importance of further elucidating the reported self-recognition. In the current study we investigated the potential recognition of lymphocytes by ficolin-1 and demonstrated that CD56(dim) NK-cells and both CD4(+) and CD8(+) subsets of activated T-cells were recognized by ficolin-1. In contrast we did not detect binding of ficolin-1 to CD56(bright) NK-cells, NKT-cells, resting T-cells or B-cells. Furthermore, we showed that the protein-lymphocyte interaction occurred via the pathogen recognition domain of ficolin-1 to sialic acid on the cell surface. Thus, the differential binding of ficolin-1 to lymphocyte subsets suggests ficolin-1 as a novel link between innate and adaptive immunity. Our results provide new insight about the recognition properties of ficolin-1 and point toward additional immune modulating functions of the molecule besides its role in pathogen recognition. PMID- 24161416 TI - Abdominal cocoon syndrome: A diagnostic and therapeutic challenge. Case report. PMID- 24161417 TI - Is open surgery or endovascular therapy best to treat acute mesenteric occlusive disease? AB - A best evidence topic in vascular surgery was written according to a structured protocol. The question addressed whether endovascular treatment improved peri operative outcomes when compared to an open approach to restore arterial perfusion in acute mesenteric occlusive disease. Four hundred and ninety seven papers were identified using the reported search; of which 4 represented the best evidence to answer the question and are discussed. The evidence on this subject is limited, comprising largely of non-randomised retrospective cohort studies. The evidence suggests that endovascular treatment is associated with reduced mortality and has better short-term peri-operative outcomes, as well as longer term survival - however many endovascular cases require subsequent open surgery. There is also conflicting evidence to suggest endovascular therapy is associated with longer ICU stays. Aside from procedural complications, factors such as patient status, time delay to diagnosis and treatment may play a greater role in determining mortality rates. In summary, endovascular therapy appears to be a feasible treatment option with post-operative complications and inpatient mortality rates lower than those seen in open surgery. PMID- 24161418 TI - Predictors of intra-abdominal coagulopathic hemorrhage after living donor liver transplantation. AB - BACKGROUND: Results of preoperative conventional coagulation assays are a poor predictor of hemorrhage after liver transplantation. In this study, we evaluated the factors that are predictive of intra-abdominal coagulopathic hemorrhage after living donor liver transplantation surgery. METHODS: During the period from January 2009 to December 2012, 118 adults underwent living donor liver transplantation (LDLT) in our institution. Of those patients, 18 (15.3%) developed intra-abdominal coagulopathic hemorrhage (n = 7) or hemorrhage due to non-coagulopathic causes (n = 11) that required emergency medical, radiological, or surgical intervention within the first month after LDLT. Possible predictors of postoperative coagulopathic hemorrhage included donor-related factors, age, body mass index, MELD score, INR value, intra-operative blood transfusion, graft/recipient weight ratio, anhepatic phase, cold ischemia time, operative time, APACHE II score, onset of re-bleeding, and hemoglobin levels during rebleeding episodes. RESULTS: There were no differences in any of the variables between the two groups (coagulopathic and noncoagulopathic hemorrhage) except for cold ischemia time. We found that cold ischemia time was significantly longer in patients with postoperative coagulopathic hemorrhage (160.50 +/- 45.02 min) than in patients with hemorrhage due to non-coagulopathic causes (113.55 +/- 29.31 min; P = 0.027). CONCLUSION: Prolonged cold ischemia time is associated with postoperative intra-abdominal coagulopathic hemorrhage in patients after LDLT. It is, therefore, necessary to shorten the cold ischemia time in order to reduce the risk of postoperative intra-abdominal hemorrhage due to coagulopathic causes. PMID- 24161419 TI - Preoperative CEA and CA 19-9 are prognostic markers for survival after curative resection for ductal adenocarcinoma of the pancreas - a retrospective tumor marker prognostic study. AB - BACKGROUND: The prognosis for patients with ductal adenocarcinoma of the pancreas (PDAC) remains poor even after curative resection. Carbohydrate antigen 19-9 (CA 19-9) and the carcinoembryonic antigen (CEA) are the most widely used serum-based tumor markers for the diagnosis and follow up of pancreatic cancer. In our analysis we aim to assess the prognostic value of a combination of both tumor markers in patients with pancreatic ductal adenocarcinoma (PDAC). PATIENTS AND METHODS: Between 01/1995 and 08/2012 we performed a total of 264 pancreatic resections due to PDAC. Patients were stratified into 3 groups in regard to their preoperative tumor marker levels. Survival was compared between the groups using Kaplan Meier analysis and log rank test. Univariate subgroup analysis and multivariate analysis were performed. RESULTS: For 259 cases complete follow up could be obtained. In patients with low preoperative CEA and CA 19-9 levels (group 1 n = 91) the mean survival was 33.3 month (CI 95% 25.1-41.5). If one of the analyzed tumor markers (CEA/CA19-9) was preoperatively elevated above the cut off level (group 2 n = 106) mean survival was 28.5 month (CI 95% 22.1-35.1). 62 patients showed preoperative elevation of both, CEA and CA 19-9 (group 3); mean survival in this group was 23.9 month (CI 95% 13.9-33.9), p > 0.01. Multivariate analysis confirmed preoperative CEA/CA 19-9 level as independent prognostic factor (HR 1.299). CONCLUSION: Preoperative CEA and CA 19-9 levels correlate with patient prognosis after curative pancreatic resection due to PDAC. This is especially true for the most frequently pT 3/4 stages of PDAC. Even if CEA and CA 19-9 might not be appropriate for screening, its serum levels should therefore be determined prior to operation and taken into account when resectability or operability is doubtful. PMID- 24161420 TI - Five-year outcomes, cosmesis, and toxicity with 3-dimensional conformal external beam radiation therapy to deliver accelerated partial breast irradiation. AB - PURPOSE: To report the interim results from a study comparing the efficacy, toxicity, and cosmesis of breast-conserving treatment with accelerated partial breast irradiation (APBI) or whole breast irradiation (WBI) using 3-dimensional conformal external beam radiation therapy (3D-CRT). METHODS AND MATERIALS: 102 patients with early-stage breast cancer who underwent breast-conserving surgery were randomized to receive either WBI (n=51) or APBI (n=51). In the WBI arm, 48 Gy was delivered to the whole breast in daily fractions of 2 Gy, with or without additional 10 Gy to the tumor bed. In the APBI arm, patients received 37.5 Gy in 3.75 Gy per fraction delivered twice daily. Toxicity results were scored according to the Radiation Therapy Oncology Group Common Toxicity Criteria. Skin elasticity was measured using a dedicated device (Multi-Skin-Test-Center MC-750 B2, CKelectronic-GmbH). Cosmetic results were assessed by the physician and the patients as good/excellent, regular, or poor. RESULTS: The median follow-up time was 5 years. No local recurrences were observed. No significant differences in survival rates were found. APBI reduced acute side effects and radiation doses to healthy tissues compared with WBI (P<.01). Late skin toxicity was no worse than grade 2 in either group, without significant differences between the 2 groups. In the ipsilateral breast, the areas that received the highest doses (ie, the boost or quadrant) showed the greatest loss of elasticity. WBI resulted in a greater loss of elasticity in the high-dose area compared with APBI (P<.05). Physician assessment showed that >75% of patients in the APBI arm had excellent or good cosmesis, and these outcomes appear to be stable over time. The percentage of patients with excellent/good cosmetic results was similar in both groups. CONCLUSIONS: APBI delivered by 3D-CRT to the tumor bed for a selected group of early-stage breast cancer patients produces 5-year results similar to those achieved with conventional WBI. PMID- 24161421 TI - Is biological subtype prognostic of locoregional recurrence risk in women with pT1-2N0 breast cancer treated with mastectomy? AB - PURPOSE: To examine locoregional and distant recurrence (LRR and DR) in women with pT1-2N0 breast cancer according to approximated subtype and clinicopathologic characteristics. METHODS AND MATERIALS: Two independent datasets were pooled and analyzed. The study participants were 1994 patients with pT1-2N0M0 breast cancer, treated with mastectomy without radiation therapy. The patients were classified into 1 of 5 subtypes: luminal A (ER+ or PR+/HER 2-/grade 1-2, n=1202); luminal B (ER+ or PR+/HER 2-/grade 3, n=294); luminal HER 2 (ER+ or PR+/HER 2+, n=221); HER 2 (ER-/PR-/HER 2+, n=105) and triple-negative breast cancer (TNBC) (ER-/PR-/HER 2-, n=172). RESULTS: The median follow-up time was 4.3 years. The 5-year Kaplan-Meier (KM) LRR were 1.8% in luminal A, 3.1% in luminal B, 1.7% in luminal HER 2, 1.9% in HER 2, and 1.9% in TNBC cohorts (P=.81). The 5 year KM DR was highest among women with TNBC: 1.8% in luminal A, 5.0% in luminal B, 2.4% in luminal HER 2, 1.1% in HER 2, and 9.6% in TNBC cohorts (P<.001). Among 172 women with TNBC, the 5-year KM LRR were 1.3% with clear margins versus 12.5% with close or positive margins (P=.04). On multivariable analysis, factors that conferred higher LRR risk were tumors>2 cm, lobular histology, and close/positive surgical margins. CONCLUSIONS: The 5-year risk of LRR in our pT1-2N0 cohort treated with mastectomy was generally low, with no significant differences observed between approximated subtypes. Among the subtypes, TNBC conferred the highest risk of DR and an elevated risk of LRR in the presence of positive or close margins. Our data suggest that although subtype alone cannot be used as the sole criterion to offer postmastectomy radiation therapy, it may reasonably be considered in conjunction with other clinicopathologic factors including tumor size, histology, and margin status. Larger cohorts and longer follow-up times are needed to define which women with node-negative disease have high postmastectomy LRR risks in contemporary practice. PMID- 24161422 TI - Impact of chemotherapy on normal tissue complication probability models of acute hematologic toxicity in patients receiving pelvic intensity modulated radiation therapy. AB - PURPOSE: To determine how chemotherapy agents affect radiation dose parameters that correlate with acute hematologic toxicity (HT) in patients treated with pelvic intensity modulated radiation therapy (P-IMRT) and concurrent chemotherapy. METHODS AND MATERIALS: We assessed HT in 141 patients who received P-IMRT for anal, gynecologic, rectal, or prostate cancers, 95 of whom received concurrent chemotherapy. Patients were separated into 4 groups: mitomycin (MMC) + 5-fluorouracil (5FU, 37 of 141), platinum +/- 5FU (Cis, 32 of 141), 5FU (26 of 141), and P-IMRT alone (46 of 141). The pelvic bone was contoured as a surrogate for pelvic bone marrow (PBM) and divided into subsites: ilium, lower pelvis, and lumbosacral spine (LSS). The volumes of each region receiving 5-40 Gy were calculated. The endpoint for HT was grade >=3 (HT3+) leukopenia, neutropenia or thrombocytopenia. Normal tissue complication probability was calculated using the Lyman-Kutcher-Burman model. Logistic regression was used to analyze association between HT3+ and dosimetric parameters. RESULTS: Twenty-six patients experienced HT3+: 10 of 37 (27%) MMC, 14 of 32 (44%) Cis, 2 of 26 (8%) 5FU, and 0 of 46 P IMRT. PBM dosimetric parameters were correlated with HT3+ in the MMC group but not in the Cis group. LSS dosimetric parameters were well correlated with HT3+ in both the MMC and Cis groups. Constrained optimization (0=2 seemed lower in ACEI users than in nonusers (34% vs 46%), but this apparent difference was not statistically significant (P=.06). In multivariate analysis of all patients, ACEI use was not associated with the risk of symptomatic RP (hazard ratio [HR] = 0.66; P=.07) after adjustment for sex, smoking status, mean lung dose (MLD), and concurrent carboplatin and paclitaxel chemotherapy. Subgroup analysis showed that ACEI use did have a protective effect from RP grade >=2 among patients who received a low (<=20-Gy) MLD (P<.01) or were male (P=.04). CONCLUSIONS: A trend toward reduction in symptomatic RP among patients taking ACEIs during RT for NSCLC was not statistically significant on univariate or multivariate analyses, although certain subgroups may benefit from use (ie, male patients and those receiving low MLD). The evidence at this point is insufficient to establish whether the use of ACEIs does or does not reduce the risk of RP. PMID- 24161425 TI - The role of postmastectomy radiation therapy after neoadjuvant chemotherapy in clinical stage II-III breast cancer patients with pN0: a multicenter, retrospective study (KROG 12-05). AB - PURPOSE: The purpose of this study was to investigate the role of postmastectomy radiation therapy (PMRT) after neoadjuvant chemotherapy (NAC) in clinical stage II-III breast cancer patients with pN0. METHODS AND MATERIALS: We retrospectively identified 417 clinical stage II-III breast cancer patients who achieved an ypN0 at surgery after receiving NAC between 1998 and 2009. Of these, 151 patients underwent mastectomy after NAC. The effect of PMRT on disease-free survival (DFS), locoregional recurrence-free survival (LRRFS), and overall survival (OS) was evaluated by multivariate analysis including known prognostic factors using the Kaplan-Meier method and compared using the log-rank test and Cox proportional regression analysis. RESULTS: Of the 151 patients who underwent mastectomy, 105 (69.5%) received PMRT and 46 patients (30.5%) did not. At a median follow-up of 59 months, 5 patients (3.3%) developed LRR (8 sites of recurrence) and 14 patients (9.3%) developed distant metastasis. The 5-year DFS, LRRFS, and OS rates were 91.2, 98.1, and 93.3% with PMRT and 83.0%, 92.3%, and 89.9% without PMRT, respectively (all P values not significant). By univariate analysis, only age (<=40 vs >40 years) was significantly associated with decreased DFS (P=.027). By multivariate analysis, age (<=40 vs >40 years) and pathologic T stage (0-is vs 1 vs 2-4) were significant prognostic factors affecting DFS (hazard ratio [HR] 0.353, 95% confidence interval [CI] 0.135-0.928, P=.035; HR 2.223, 95% CI 1.074 4.604, P=.031, respectively). PMRT showed no correlation with a difference in DFS, LRRFS, or OS by multivariate analysis. CONCLUSIONS: PMRT might not be necessary for pN0 patients after NAC, regardless of clinical stage. Prospective randomized clinical trial data are needed to assess whether PMRT can be safely omitted in pN0 patients after NAC and mastectomy for clinical stage II-III breast cancer. PMID- 24161426 TI - Surgeons' knowledge and practices regarding the role of radiation therapy in breast cancer management. AB - PURPOSE: Population-based studies suggest underuse of radiation therapy, especially after mastectomy. Because radiation oncology is a referral-based specialty, knowledge and attitudes of upstream providers, specifically surgeons, may influence patients' decisions regarding radiation, including whether it is even considered. Therefore, we sought to evaluate surgeons' knowledge of pertinent risk information, their patterns of referral, and the correlates of surgeon knowledge and referral in specific breast cancer scenarios. METHODS AND MATERIALS: We surveyed a national sample of 750 surgeons, with a 67% response rate. We analyzed responses from those who had seen at least 1 breast cancer patient in the past year (n=403), using logistic regression models to identify correlates of knowledge and appropriate referral. RESULTS: Overall, 87% of respondents were general surgeons, and 64% saw >10 breast cancer patients in the previous year. In a scenario involving a 45-year-old undergoing lumpectomy, only 45% correctly estimated the risk of locoregional recurrence without radiation therapy, but 97% would refer to radiation oncology. In a patient with 2 of 20 nodes involved after mastectomy, 30% would neither refer to radiation oncology nor provide accurate information to make radiation decisions. In a patient with 4 of 20 nodes involved after mastectomy, 9% would not refer to radiation oncology. Fewer than half knew that the Oxford meta-analysis revealed a survival benefit from radiation therapy after lumpectomy (45%) or mastectomy (32%). Only 16% passed a 7-item knowledge test; female and more-experienced surgeons were more likely to pass. Factors significantly associated with appropriate referral to radiation oncology included breast cancer volume, tumor board participation, and knowledge. CONCLUSIONS: Many surgeons have inadequate knowledge regarding the role of radiation in breast cancer management, especially after mastectomy. Targeted educational interventions may improve the quality of care. PMID- 24161427 TI - High-grade glioma radiation therapy target volumes and patterns of failure obtained from magnetic resonance imaging and 18F-FDOPA positron emission tomography delineations from multiple observers. AB - PURPOSE: The objective of this study was to compare recurrent tumor locations after radiation therapy with pretreatment delineations of high-grade gliomas from magnetic resonance imaging (MRI) and 3,4-dihydroxy-6-[(18)F]fluoro-L phenylalanine ((18)F-FDOPA) positron emission tomography (PET) using contours delineated by multiple observers. METHODS AND MATERIALS: Nineteen patients with newly diagnosed high-grade gliomas underwent computed tomography (CT), gadolinium contrast-enhanced MRI, and (18)F-FDOPA PET/CT. The image sets (CT, MRI, and PET/CT) were registered, and 5 observers contoured gross tumor volumes (GTVs) using MRI and PET. Consensus contours were obtained by simultaneous truth and performance level estimation (STAPLE). Interobserver variability was quantified by the percentage of volume overlap. Recurrent tumor locations after radiation therapy were contoured by each observer using CT or MRI. Consensus recurrence contours were obtained with STAPLE. RESULTS: The mean interobserver volume overlap for PET GTVs (42% +/- 22%) and MRI GTVs (41% +/- 22%) was not significantly different (P=.67). The mean consensus volume was significantly larger for PET GTVs (58.6 +/- 52.4 cm(3)) than for MRI GTVs (30.8 +/- 26.0 cm(3), P=.003). More than 95% of the consensus recurrence volume was within the 95% isodose surface for 11 of 12 (92%) cases with recurrent tumor imaging. Ten (91%) of these cases extended beyond the PET GTV, and 9 (82%) were contained within a 2 cm margin on the MRI GTV. One recurrence (8%) was located outside the 95% isodose surface. CONCLUSIONS: High-grade glioma contours obtained with (18)F-FDOPA PET had similar interobserver agreement to volumes obtained with MRI. Although PET based consensus target volumes were larger than MRI-based volumes, treatment planning using PET-based volumes may not have yielded better treatment outcomes, given that all but 1 recurrence extended beyond the PET GTV and most were contained by a 2-cm margin on the MRI GTV. PMID- 24161428 TI - A prospective longitudinal clinical trial evaluating quality of life after breast conserving surgery and high-dose-rate interstitial brachytherapy for early-stage breast cancer. AB - PURPOSE: To prospectively examine quality of life (QOL) of patients with early stage breast cancer treated with accelerated partial breast irradiation (APBI) using high-dose-rate (HDR) interstitial brachytherapy. METHODS AND MATERIALS: Between March 2004 and December 2008, 151 patients with early stage breast cancer were enrolled in a phase 2 prospective clinical trial. Eligible patients included those with Tis-T2 tumors measuring <=3 cm excised with negative surgical margins and with no nodal involvement. Patients received 3.4 Gy twice daily to a total dose of 34 Gy. QOL was measured using European Organization for Research and Treatment of Cancer (EORTC) QLQ-C30, version 3.0, and QLQ-BR23 questionnaires. The QLQ-C30 and QLQ-BR23 questionnaires were evaluated during pretreatment and then at 6 to 8 weeks, 3 to 4 months, 6 to 8 months, and 1 and 2 years after treatment. RESULTS: The median follow-up was 55 months. Breast symptom scores remained stable in the months after treatment, and they significantly improved 6 to 8 months after treatment. Scores for emotional functioning, social functioning, and future perspective showed significant improvement 2 years after treatment. Symptomatic fat necrosis was associated with several changes in QOL, including increased pain, breast symptoms, systemic treatment side effects, dyspnea, and fatigue, as well as decreased role functioning, emotional functioning, and social functioning. CONCLUSIONS: HDR multicatheter interstitial brachytherapy was well tolerated, with no significant detrimental effect on measured QOL scales/items through 2 years of follow-up. Compared to pretreatment scores, there was improvement in breast symptoms, emotional functioning, social functioning, and future perspective 2 years after treatment. PMID- 24161429 TI - Anti-inflammatory action of hydroalcoholic extract, dichloromethane fraction and steroid alpha-spinasterol from Polygala sabulosa in LPS-induced peritonitis in mice. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Polygala sabulosa A. W. Bennett is a small herb popularly known as "timutu-pinheirinho" that is widely distributed in southern Brazil and that is used to treat disorders of the bowel and kidney and as a topical anesthetic and expectorant in folk medicine. This study was designed to investigate the anti-inflammatory properties of the hydroalcoholic extract (HEPs), CH2Cl2 fraction and the steroid alpha-spinasterol obtained from the aerial parts of Polygala sabulosa in a model of acute inflammation induced by intraperitoneal injection of bacterial lipopolysaccharide in mice. MATERIALS AND METHODS: The anti-inflammatory effect of HEPs (3-300 mg/kg, i.g.), CH2Cl2 fraction (0.003-30 mg/kg, i.g.) and steroid alpha-spinasterol (0.001-1mg/kg, i.p. or 1-10mg/kg, i.g.), were evaluated in mice subjected to the acute inflammation caused by intraperitoneal (i.p.) injection of lipopolysaccharide (LPS, 0.02 ug/kg). The anti-inflammatory activity of the HEPs, CH2Cl2 fraction and steroid were assessed by determining the total numbers of leukocytes and differential cell counts (neutrophils and mononuclear cells) and levels of pro-inflammatory (IL-1beta, TNF-alpha, IL-6) or anti-inflammatory (IL-10) cytokines in peritoneal fluid. RESULTS: The administration of HEPs (3-300 mg/kg, i.g.) completely inhibited inflammatory cell infiltration (300 mg/kg, i.g.) and it reduced TNF alpha (100-300 mg/kg) and IL-1beta (100mg/kg) levels in LPS-injected mice. Furthermore, the administration of CH2Cl2 fraction (0.003-30 mg/kg, i.g.) or alpha-spinasterol (0.001-10mg/kg, by i.p. or i.g.) significantly reduces inflammatory cell infiltration in LPS-injected mice. Moreover, dexamethasone (0.5mg/kg, i.p., used as a positive control) inhibited inflammatory cell infiltration and reduced the levels of TNF-alpha, IL-1beta and IL-6 in LPS injected mice. CONCLUSIONS: Taken together, these results provide the first experimental evidence demonstrating that HEPs have significant anti-inflammatory effects on LPS-induced inflammation. These effects appear to be, at least in part, due to the presence of alpha-spinasterol. These findings support the widespread use of Polygala sabulosa in popular medicine and demonstrate that this plant has therapeutic potential for the development of phytomedicines with anti inflammatory properties. PMID- 24161430 TI - Protective effect of Sheng-Nao-Kang decoction on focal cerebral ischemia reperfusion injury in rats. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Sheng-Nao-Kang decoction (SNK), a modified traditional Chinese medicine (TCM), has been used clinically for the treatment of acute and chronic cerebrovascular related diseases. To evaluate the protective effect of SNK on focal cerebral ischemia-reperfusion (I/R) injury in rats and investigate the underlying mechanisms. MATERIALS AND METHODS: Focal cerebral I/R injury in rats was induced by middle cerebral artery occlusion (MCAO) for 2h followed by reperfusion for 24h. Adult male Sprague-Dawley (SD) rats were randomly divided into six kinds of groups: Sham group; I/R group; SNK-treated groups at doses of 0.7 g/kg, 1.4 g/kg and 2.8 g/kg; and nimodipine (NMP)-treated group. The recoveries of neurological function in rats were estimated by neurological defect scoring and 2,3,5-triphenyltetrazolium chloride (TTC) staining after 24h reperfusion. Various biochemical indexes in serum were assayed by colorimetry, including malondialdehyde (MDA), superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), inducible nitric oxide synthase (iNOS) and total nitric oxide synthase (TNOS). Histological structures of the brain in rats were observed by hematoxylin and eosin (H&E) staining. Immunohistochemistry was performed to detect the caspase-3 protein content in rats. RESULTS: SNK administration significantly reduced the neurological defect scores and lessened the cerebral infarction volume. The treatment of SNK lowered MDA content, up regulated SOD and GSH-Px levels, down-regulated iNOS and TNOS levels in serum. Furthermore, histological examination indicated that dense neuropil and largely surviving neurons were seen in SNK-treated rats. SNK administration restrained the expression of caspase-3 positive protein significantly. CONCLUSION: The results suggest that SNK demonstrates a strong and ameliorative effect on cerebral I/R damage in rats. The protective mechanisms of SNK are associated with its properties of anti-apoptosis and anti-oxidation as well as regulation of iNOS and TNOS. PMID- 24161431 TI - Anti-inflammatory and antinociceptive effects of Chinese medicine SQ gout capsules and its modulation of pro-inflammatory cytokines focusing on gout arthritis. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Shuang-Qi gout capsule is a traditional Chinese medicine prescription, which has been used in the treatment of joint pain, inflammation and gout arthritis. This study evaluates anti-inflammatory and antinociceptive effects of Shuang-Qi gout capsule and its modulation of pro inflammatory cytokines with special reference to gout arthritis. MATERIALS AND METHODS: Anti-inflammatory effect of Shuang-Qi gout capsule was investigated bymice tail-flick response, acetic acid induced writhing response, Xylene-induced auricle inflammation and the hind paw volume of the monosodium urate (MSU) crystal induced rats with different time durations. To investigate the effects on gout arthritis, ankle joint of rats induced by MSU crystals and assessed for edema and histopathological changes. In vitro, prepared serum was incubated with urate crystal induced HUVE cells and the release of TNF-alpha and IL-1beta determined by ELISA. RESULTS: Shuang-Qi gout capsule showed significant and dose dependent anti-inflammatory effect via reducing edema and pain, throughout all the models. The high dose of Shuang-Qi gout capsule and Indomethacin significantly attenuated the edema. Histopathological results showed that high and medium dose of Shuang-Qi gout capsule and Indomethacin reduced gouty joint inflammatory features, while the high dose of Shuang-Qi gout capsule showed a better therapeutic effect. High and medium dose of Shuang-Qi gout capsule significantly reduced the release of TNF-alpha and IL-1beta (p<0.05). CONCLUSION: Shuang-Qi gout capsule can effectively inhibit the inflammation, analgesia, through the modulation of emission of pro-inflammatory cytokines and the curative effect is dose dependent. Conversely, these MSU induced in vivo and in vitro studies of Shuang-Qi gout capsule suggest that, Shuang-Qi gout capsule may be a potential agent for treatment in gouty arthritis. PMID- 24161432 TI - G15, a GPR30 antagonist, induces apoptosis and autophagy in human oral squamous carcinoma cells. AB - As GPR30 has been implicated in mediating cancer cell proliferation, this study aimed to examine the antitumor effect of the GPR30 antagonist G15 in human oral squamous cell carcinoma (OSCC). G15 induced dose-dependent cytotoxicity, apoptosis and G2/M cell cycle arrest in a panel of OSCC cells. The results showed that G15 could inhibit the growth of the oral cancer cells with IC50 value 11.2 MUM for SCC4, 15.6 MUM for SCC9, and 7.8 MUM for HSC-3, respectively. Flow cytometric analysis and Comet assay indicated that G15 suppressed the viability of SCC4 and HSC-3 cells by inducing apoptosis and G2/M arrest. In addition, G15 down regulated the expression of Akt, cell cycle-related proteins, and mitogen activated protein kinases, but increased the levels of LC3B-II and the accumulation of autophagosomes. Inhibition of autophagy by chloroquine does not affect the G15-induced apoptosis in SCC4 cells. Mechanistic evidence indicated that the antiproliferative effect was mediated through the downregulation of cdc2, cdc25c and NF-kappaB expression. Taken together, our findings suggest the potential of G15 in treating OSCC. PMID- 24161433 TI - Serum protein oxidation by diesel exhaust particles: effects on oxidative stress and inflammatory response in vitro. AB - Considerable evidence shows a key role for protein modification in the adverse effects of chemicals; however, the interaction of diesel exhaust particles (DEP) with proteins and the resulting biological activity remains unclear. DEP and carbon black (CB) suspensions with and without bovine serum albumin (BSA) were used to elucidate the biological effects of air pollutants. The DEP and CB samples were then divided into suspensions and supernatants. Two important goals of the interaction of DEP with BSA were as follows: (1) understanding BSA modification by particles and (2) investigating the effects of particles bound with BSA and the corresponding supernatants on cellular oxidative stress and inflammation. We observed significant free amino groups production was caused by DEP. Using liquid chromatography-mass spectrometry (LC-MS), we observed that BSA was significantly oxidised by DEP in the supernatants and that the peptides ETYGDMADCCEK, MPCTEDYLSLILNR and TVMENFVAFVDK, derived BSA-DEP conjugates, were also oxidised. In A549 cells, DEP-BSA suspensions and the corresponding supernatants reduced 8-hydroxy-2'-deoxyguanosine (8-OHdG) production and increased interleukin-6 (IL-6) levels when compared to DEP solutions without BSA. Our findings suggest that oxidatively modified forms of BSA caused by DEP could lead to oxidative stress and the activation of inflammation. PMID- 24161434 TI - Treatment by any other name would be more environmentally friendly. PMID- 24161435 TI - A geochemical record of environmental changes in sediments from Sishili Bay, northern Yellow Sea, China: anthropogenic influence on organic matter sources and composition over the last 100 years. AB - Total organic carbon (TOC), total nitrogen (TN), delta(13)C and delta(15)N were measured in sediment cores at three sites in Sishili Bay, China, to track the impacts of anthropogenic activities on the coastal environment over the last 100 years. The increased TOC and TN in the upper section of sediment cores indicated a eutrophic process since 1975. In comparison, the TOC and TN in the sediment core near to a scallop aquaculture area displayed a much slower increase, indicating the contribution of scallop aquaculture in mitigating eutrophication. Combined information from delta(13)C, delta(15)N and TOC:TN indicated an increased terrestrial signal, although organic matter sources in Sishili Bay featured a mixture of terrestrial and marine sources, with phytoplankton being dominant. Increased fertilizer use since 1970s contributed to the eutrophic process in Sishili Bay since 1975, and increased sewage discharge from 1990s has added to this process. PMID- 24161436 TI - [Refusal of care faced by case manager from elderly persons in complex situation: cross perspectives]. AB - PURPOSE: Case management is a new professional field in France. It is addressed to elderly persons living in community whose situation is regarded as particularly complex. Case managers have to assess needs and coordinate necessary services. One common criteria of complexity is refusal of care. The objective of this study is to compare the words of users with those of case managers about refusal of care, in order to understand its meaning, professionals' attitudes and ethical challenges. METHODS: Two researchers have cooperated on this qualitative research: the first one, anthropologist, interviewed 19 individuals, and 11 of their caregivers. The second one, geriatrician and researcher in medical ethics, lead four focus groups gathering a total of 18 case managers. RESULTS: Refusal of care often is the result of the will of preserving one's identity, compromised by illness. Individuals seek control on their life. Facing this behaviour, case managers try to secure the individual, by establishing a personal relationship that respects their choices, even if care has to be delayed. Refusal of care may sometimes disclose a desire to vanish, in front of which professionals meet their own limits. CONCLUSION: To recognise an elderly person that refuses care as a unique individual who can make choices secure his identity, and allow him to change. PMID- 24161437 TI - First report of transradial renal denervation with the dedicated radiofrequency IberisTM catheter. AB - We describe the first use of transradial access renal denervation in a patient with resistant hypertension using a dedicated radiofrequency catheter (IberisTM; Terumo Medical Corporation, Tokyo, Japan). The system includes a generator and a 4 Fr single-use radiofrequency (RF) device which has to be introduced via a 6 Fr guiding catheter. Radiofrequency energy is delivered at the tip of the catheter. The system was CE approved in March 2013. PMID- 24161439 TI - Delayed rupture of the iliac artery after percutaneous angioplasty. AB - Rupture of the iliac artery during percutaneous angioplasty is a life-threatening condition that requires prompt diagnosis and treatment to rescue the patient. Recently, percutaneous angioplasty has become an outpatient procedure, but there is no reliable guideline for observation time in the hospital after percutaneous angioplasty. We describe a 67-year-old man with bilateral lesions in the iliac artery who experienced a delayed rupture of the iliac artery 2 days after percutaneous balloon angioplasty and placement of a self-expandable stent. The patient was successfully treated by endovascular intervention with a stent graft. In our department, percutaneous angioplasty is not performed in an outpatient clinic, and all patients are admitted to the hospital and observed for at least 3 days after percutaneous angioplasty. Because our patient was in the hospital when the iliac artery ruptured, prompt diagnosis and treatment were possible. Moreover, because appropriately sized stent grafts were prepared in the hospital, timely endovascular treatment could be performed, and the patient recovered successfully. From this case, we conclude that observing patients for a sufficient time in the hospital and preparing appropriately sized stent grafts are 2 important factors for the safety of patients who undergo percutaneous angioplasty. PMID- 24161438 TI - SAMHD1 host restriction factor: a link with innate immune sensing of retrovirus infection. AB - SAMHD1 [sterile alpha motif and histidine-aspartic domain (HD) containing protein 1] is the most recent addition to a unique group of host restriction factors that limit retroviral replication at distinct stages of the viral life cycle. SAMHD1 is a deoxynucleoside triphosphate triphosphohydrolase that degrades the intracellular pool of deoxynucleoside triphosphates available during early reverse transcription. SAMHD1 activity is blocked by the Vpx accessory function present in human immunodeficiency virus type 2 and SIVsm. Mutations in SAMHD1 are associated with the autoimmune disorder Aicardi-Goutieres syndrome, thus emphasizing its role in regulation of the immune response. SAMHD1 antiretroviral activity is modulated by post-translational modifications, cell-cycle-dependent functions and cytokine-mediated changes. Innate receptors that sense retroviral DNA intermediates are the focus of intense study, and recent studies have established a link among SAMHD1 restriction, innate sensing of DNA and protective immune responses. Cell-cycle-dependent regulation of SAMHD1 by phosphorylation and the increasingly broad range of viruses inhibited by SAMHD1 further emphasize the importance of these mechanisms of host restriction. This review highlights current knowledge regarding SAMHD1 regulation and its impact on innate immune signaling and retroviral restriction. PMID- 24161440 TI - A single-institution experience: the integrated vascular surgery residency's effect on fellowship and general surgery resident case volume and diversity. AB - BACKGROUND: To determine whether the formation of an integrated vascular surgery residency (0 + 5) has negatively impacted the case volume and diversity of the vascular surgery fellows (5 + 2) and chief general surgeons at the same institution. METHODS: Operative data from the vascular integrated (0 + 5), independent (5 + 2), and general surgery residencies at a single institution were retrospectively reviewed and analyzed to determine vascular surgery case volumes from 2006-2012. National operative data (Residency Review Committee) were used for comparison of diversity and volume. Standard statistical methods were applied. RESULTS: During this period, the 5 + 2 fellows at our institution performed on average 741 (range, 554-1002) primary cases and 1091 (range, 844 1479) combined primary and secondary cases for the 2-year fellowship. Our integrated residency began in July 2007. Our fellows' primary case volumes remained relatively stable between 2006 and 2011, with a 4% increase in the number of cases, although their total (primary and secondary) case volumes fell 15%; by comparison, the equivalent national 50th percentile rates rose 16% during this time frame. Our institution's general surgery residents performed an average of 116 (range, 56-221) vascular cases individually during their 5-year residency from 2005-2011. From 2006-2011, the total case volume fell only 5%, while the national 50th percentile rate fell 24%. Across all years, however, resident and fellow volumes both continue to be above Accreditation Council for Graduate Medical Education minimum requirements, and the major vascular case volume at our institution in all groups studied remained statistically greater than or equal to the national 50th percentile of cases. Our first integrated resident to graduate finished in June 2012 with 931 total vascular cases and 249 general surgery cases for a total operative experience of 1180 cases during the 5-year residency. Finally, after an 8-year period (2003-2010) in which none of our general surgery residents pursued vascular training, 1 resident in each of the 2011, 2012, and 2013 graduating years has now done so. CONCLUSIONS: At our institution, the introduction of a 0 + 5 vascular residency has correlated with a modest drop (15%) in overall case volume for the 5 + 2 fellows, but the number of primary cases have actually increased slightly and they continue to meet or exceed Accreditation Council for Graduate Medical Education requirements and national 50th percentile rates. General surgery residents' vascular volumes, by contrast, have remained stable, and interest in vascular surgery by residents has increased. Our integrated vascular residents are projected to exceed the fellows' 50th percentile case volume and diversity targets during their residency experience. PMID- 24161441 TI - Management of non traumatic corneal perforations with cyanoacrylate tissue adhesive: The 'contact lens sandwich' technique. PMID- 24161442 TI - Metabolic stability of superoxide adducts derived from newly developed cyclic nitrone spin traps. AB - Reactive oxygen species are by-products of aerobic metabolism involved in the onset and evolution of various pathological conditions. Among them, the superoxide radical is of special interest as the origin of several damaging species such as H2O2, hydroxyl radical, or peroxynitrite (ONOO(-)). Spin trapping coupled with ESR is a method of choice to characterize these species in chemical and biological systems and the metabolic stability of the spin adducts derived from reaction of superoxide and hydroxyl radicals with nitrones is the main limit to the in vivo application of the method. Recently, new cyclic nitrones bearing a triphenylphosphonium or permethylated beta-cyclodextrin moiety have been synthesized and their spin adducts demonstrated increased stability in buffer. In this article, we studied the stability of the superoxide adducts of four new cyclic nitrones in the presence of liver subcellular fractions and biologically relevant reductants using an original setup combining a stopped-flow device and an ESR spectrometer. The kinetics of disappearance of the spin adducts were analyzed using an appropriate simulation program. Our results highlight the interest of the new spin trapping agents CD-DEPMPO and CD-DIPPMPO for specific detection of superoxide with high stability of the superoxide adducts in the presence of liver microsomes. PMID- 24161443 TI - Aldose reductase regulates miR-200a-3p/141-3p to coordinate Keap1-Nrf2, Tgfbeta1/2, and Zeb1/2 signaling in renal mesangial cells and the renal cortex of diabetic mice. AB - Aberrant regulation in oxidative stress, fibrogenesis, and the epithelial mesenchymal transition (EMT) in renal cells under hyperglycemic conditions contributes significantly to the onset and progression of diabetic nephropathy. The mechanisms underlying these hyperglycemia-induced dysregulations, however, have not been clearly elucidated. Herein, we report that aldose reductase is capable of regulating the expression of miR-200a-3p/141-3p negatively in renal mesangial cells. MiR-200a-3p/141-3p, in turn, act to target Keap1, Tgfbeta2, fibronectin, and Zeb2 directly and regulate Tgfbeta1 and Nrf2 indirectly under high-glucose conditions, resulting in profound dysregulations in Keap1-Nrf2, Tgfbeta1/2, and Zeb1/2 signaling. In vivo in streptozotocin-induced diabetic mice, we found that aldose reductase deficiency caused significant elevations in miR-200a-3p/141-3p in the renal cortex, which were accompanied by a significant downregulation of Keap1, Tgfbeta1/2, and fibronectin but significant upregulation of Nrf2. Moreover, in vivo administration of inhibitors of miR-200a-3p in diabetic animals significantly exacerbated cortical and glomerular fibrogenesis and increased urinary albumin excretion, tightly linking dysregulated miR-200a-3p with the development of diabetic nephropathy. Collectively, our results reveal a novel mechanism whereby hyperglycemia induces aldose reductase to regulate renal expression of miR-200a-3p/141-3p to coordinately control hyperglycemia-induced renal oxidative stress, fibrogenesis, and the EMT. Our novel findings also suggest that inhibition of aldose reductase and in vivo renal cortical restoration of miR-200a-3p/141-3p or their combination are very promising avenues for the development of therapeutic strategies or drugs against diabetic nephropathy. PMID- 24161444 TI - Methylated pentavalent arsenic metabolites are bifunctional inducers, as they induce cytochrome P450 1A1 and NAD(P)H:quinone oxidoreductase through AhR- and Nrf2-dependent mechanisms. AB - Activation of the aryl hydrocarbon receptor (AhR) ultimately leads to the induction of the carcinogen-activating enzyme cytochrome P450 1A1 (CYP1A1), and activation of the nuclear factor-erythroid 2 p45-related factor 2 (Nrf2) in addition to the AhR pathway induces the expression of the NADP(H):quinone oxidoreductase (NQO1). Therefore, the aim of this study was to examine the effect of As(III) pentavalent metabolites, MMA(V), DMA(V), and TMA(V), on AhR and Nrf2 activation and on the expression of their prototypical downstream targets CYP1A1 and NQO1, respectively. Our results showed that treatment of HepG2 cells with MMA(V), DMA(V), or TMA(V) in the absence and presence of 2,3,7,8 tetrachlorodibenzo-p-dioxin or sulforaphane significantly induced both CYP1A1 and NQO1 at the mRNA, protein, and catalytic activity levels. Furthermore, these metabolites increased the AhR-dependent XRE-driven and the Nrf2-dependent ARE driven luciferase reporter activities, which coincided with increased nuclear accumulation of both transcription factors. However, none of these metabolites were shown to be AhR ligands. The induction of CYP1A1 by these metabolites seems to be ligand-independent, possibly through a decrease in HSP90 protein expression levels. The metabolites also increased ROS production, which was significantly higher than that produced by As(III). Upon knockdown of AhR and Nrf2 the MMA(V)-, DMA(V)-, and TMA(V)-mediated induction of both CYP1A1 and NQO1 proteins was significantly decreased. In conclusion, this study demonstrates for the first time that methylated pentavalent arsenic metabolites are bifunctional inducers, as they increase CYP1A1 by activating the AhR/XRE signaling pathway and they increase NQO1 by activating the Nrf2/ARE signaling pathway in addition to the AhR/XRE pathway. PMID- 24161446 TI - Early life phthalate exposure and atopic disorders in children: a prospective birth cohort study. AB - The role of phthalate exposure at different stages in the immune system and atopic disorders is not well-known. This study aims to evaluate the effects of prenatal and postnatal phthalate exposures on immunoglobulin E (IgE) levels and atopic dermatitis (AD) in children by objective biomarkers. We conducted a prospective Taiwan Birth Panel cohort study with 483 mother/infant pairs. Finally, 161 urine specimens at 3rd trimester of pregnancy, 219 urine specimens from children at age 2, and 192 urine specimens at age 5 were analyzed after excluding missing data and loss to follow-up. Urine monoethyl phthalate (MEP), monobutyl phthalate (MBP), monobenzyl phthalate (MBzP), and mono-(2-ethylhexyl) phthalate (MEHP) at 3rd trimester of pregnancy and at ages 2 and 5 were measured by ultra-performance liquid chromatography coupled with tandem mass spectrometry. At ages 2 and 5, information on the development of AD and serum total IgE was collected. The association between urine phthalate metabolite levels at different stages and serum IgE and AD was evaluated by multivariate linear regression and logistic regression. Urine phthalate metabolite levels were higher at age 2 than those at pregnancy and age 5. At each period, urine MBP levels were higher than MEP, MEHP, and MBzP. MEHP levels at age 2 positively correlated with serum IgE levels (per ln-unit: beta=0.191, p=0.02). Analyses stratified by gender revealed that MEHP levels positively correlated with serum IgE levels only in boys (per ln unit: beta=0.256, p=0.03). When dividing into quartiles, urine MBzP levels at age 2 had a significant association with AD. We found no statistically significant association of other phthalate metabolites with IgE and AD. Early life phthalate exposure may increase the risk of allergic sensitization and atopic disorders. PMID- 24161445 TI - Urinary phthalate metabolite concentrations among pregnant women in Northern Puerto Rico: distribution, temporal variability, and predictors. AB - BACKGROUND: Phthalate contamination exists in the North Coast karst aquifer system in Puerto Rico. In light of potential health impacts associated with phthalate exposure, targeted action for elimination of exposure sources may be warranted, especially for sensitive populations such as pregnant women. However, information on exposure to phthalates from a variety of sources in Puerto Rico is lacking. The objective of this study was to determine concentrations and predictors of urinary phthalate biomarkers measured at multiple times during pregnancy among women living in the Northern karst area of Puerto Rico. METHODS: We recruited 139 pregnant women in Northern Puerto Rico and collected urine samples and questionnaire data at three separate visits (18 +/- 2 weeks, 22 +/- 2 weeks, and 26 +/- 2 weeks of gestation). Urine samples were analyzed for eleven phthalate metabolites: mono-2-ethylhexyl phthalate (MEHP), mono-2-ethyl-5 hydroxyhexyl phthalate, mono-2-ethyl-5-oxohexyl phthalate, mono-2-ethyl-5 carboxypentyl phthalate, mono-ethyl phthalate (MEP), mono-n-butyl phthalate, mono benzyl phthalate, mono-isobutyl phthalate, mono-3-carboxypropyl phthalate (MCPP), mono carboxyisononyl phthalate (MCNP), and mono carboxyisooctyl phthalate (MCOP). RESULTS: Detectable concentrations of phthalate metabolites among pregnant women living in Puerto Rico was prevalent, and metabolite concentrations tended to be higher than or similar to those measured in women of reproductive age from the general US population. Intraclass correlation coefficients ranged from very weak (MCNP; 0.05) to moderate (MEP; 0.44) reproducibility among all phthalate metabolites. We observed significant or suggestive positive associations between urinary phthalate metabolite concentrations and water usage/storage habits (MEP, MCNP, MCOP), use of personal care products (MEP), and consumption of certain food items (MCPP, MCNP, and MCOP). CONCLUSIONS: To our knowledge this is the first study to report concentrations, temporal variability, and predictors of phthalate biomarkers among pregnant women in Puerto Rico. Preliminary results suggest several potentially important exposure sources to phthalates in this population and future analysis from this ongoing prospective cohort will help to inform targeted approaches to reduce exposure. PMID- 24161447 TI - Potential health impacts of residential exposures to extremely low frequency magnetic fields in Europe. AB - Over the last two decades residential exposure to extremely low frequency magnetic fields (ELF MF) has been associated with childhood leukaemia relatively consistently in epidemiological studies, though causality is still under investigation. We aimed to estimate the cases of childhood leukaemia that might be attributable to exposure to ELF MF in the European Union (EU27), if the associations seen in epidemiological studies were causal. We estimated distributions of ELF MF exposure using studies identified in the existing literature. Individual distributions of exposure were integrated using a probabilistic mixture distribution approach. Exposure-response functions were estimated from the most recently published pooled analysis of epidemiological data. Probabilistic simulation was used to estimate population attributable fractions (AFP) and attributable cases of childhood leukaemia in the EU27. By assigning the literature review-based exposure distribution to all EU27 countries, we estimated the total annual number of cases of leukaemia attributable to ELF MF at between ~50 (95% CIs: -14, 132) and ~60 (95% CIs: -9, 610), depending on whether exposure-response was modelled categorically or continuously, respectively, for a non-threshold effect. This corresponds to between ~1.5% and ~2.0% of all incident cases of childhood leukaemia occurring annually in the EU27. Considerable uncertainties are due to scarce data on exposure and the choice of exposure-response model, demonstrating the importance of further research into better understanding mechanisms of the potential association between ELF MF exposure and childhood leukaemia and the need for improved monitoring of residential exposures to ELF MF in Europe. PMID- 24161448 TI - Implementation and validation of a modeling framework to assess personal exposure to black carbon. AB - Because people tend to move from one place to another during the day, their exposure to air pollution will be determined by the concentration at each location combined with the exposure encountered in transport. In order to estimate the exposure of individuals in a population more accurately, the activity-based modeling framework for Black Carbon exposure assessment, AB(2)C, was developed. An activity-based traffic model was applied to model the whereabouts of individual agents. Exposure to black carbon (BC) in different microenvironments is assessed with a land use regression model, combined with a fixed indoor/outdoor factor for exposure in indoor environments. To estimate exposure in transport, a separate model was used taking into account transport mode, timing of the trip and degree of urbanization. The modeling framework is validated using weeklong time-activity diaries and BC exposure as revealed from a personal monitoring campaign with 62 participants. For each participant in the monitoring campaign, a synthetic population of 100 model-agents per day was made up with all agents meeting similar preconditions as each real-life agent. When these model-agents pass through every stage of the modeling framework, it results in a distribution of potential exposures for each individual. The AB(2)C model estimates average personal exposure slightly more accurately compared to ambient concentrations as predicted for the home subzone; however the added value of a dynamic model lies in the potential for detecting short term peak exposures rather than modeling average exposures. The latter may bring new opportunities to epidemiologists: studying the effect of frequently repeated but short exposure peaks on long term exposure and health. PMID- 24161449 TI - A minimum 5-year follow-up of an oxidized zirconium femoral prosthesis used for total knee arthroplasty. AB - BACKGROUND: Bearing surface wear remains a potential concern amongst younger patients undergoing total knee arthroplasty (TKA). Because of the potential for lower prosthetic wear rates, oxidized zirconium is a potentially attractive bearing surface for TKA in young, active patients. This material is also well suited for patients with suspected nickel sensitivities as it has no measurable nickel content, in contrast to standard femoral bearings made of cobalt-chromium alloys. Although in vitro testing on knee wear simulators has demonstrated favorable wear characteristics of oxidized zirconium compared to traditional cobalt-chrome bearings, in vivo clinical outcome data with this novel bearing surface are sparse. METHODS: We retrospectively reviewed 109 consecutive TKAs in 82 patients at a minimum of five years postoperatively to determine prosthetic survivorship and to assess whether any adverse clinical consequences could be attributed to this bearing. Knees were evaluated with Knee Society scores, UCLA activity scores, clinical examinations, and radiographs. The mean age for this cohort was 58.7 years. RESULTS: Survivorship free of bearing related complications was 100% at a minimum of five years post-surgery. There were no revisions for loosening, osteolysis, implant failure, or deep infection. There were no knees with radiographic failure, visible wear, loosening, or osteolysis. CONCLUSION: Oxidized zirconium remains an attractive option for patients with nickel sensitivities and in those patients at risk for prosthetic wear due to young age or high activity levels. PMID- 24161450 TI - Complex regional pain syndrome: a comprehensive and critical review. AB - Complex regional pain syndrome (CRPS) is a term used to describe a variety of disorders characterized by spontaneous or stimulus-induced pain that is disproportional to the inciting event and accompanied by a myriad of autonomic and motor disturbances in highly variable combinations. There are no standards which can be applied to the diagnosis and would fulfill definitions of evidence based medicine. Indeed, there are almost as many diagnostic criteria as there are names to this disorder. The umbrella term CRPS has been subdivided into type I and type II. CRPS I is intended to encompass reflex sympathetic dystrophy and similar disorders without a nerve injury; while CRPS II occurs after damage to a peripheral nerve. There are numerous etiological pathophysiological events that have been incriminated in development of CRPS, including inflammation, autoimmune responses, abnormal cytokine production, sympathetic-sensory disorders, altered blood flow and central cortical reorganization. However, the number of studies that have included appropriate controls and have sufficient numbers of patients to allow statistical analysis with appropriate power calculations is vanishingly small. This has led to over-diagnosis and often excessive pharmacotherapy and even unnecessary surgical interventions. In this review we provide a detailed critical overview of not only the history of CRPS, but also the epidemiology, the clinical features, the pathophysiological studies, the proposed criteria, the therapy and, in particular, an emphasis that future research should apply more rigorous standards to allow a better understanding of CRPS, i.e. what it is, if it is, and when it is. PMID- 24161452 TI - C-reactive protein and cortisol in drug-naive patients with short-illness duration first episode major depressive disorder: possible role of cortisol immunomodulatory action at early stage of the disease. AB - BACKGROUND: Hypercortisolemia and low grade systemic inflammation are observed in major depressive disorder (MDD). Studies on markers of systematic inflammation and Hypothalamic-Pituitary-Adrenal (HPA) axis dysregulation in MDD produce confounded results due to heterogeneity of MDD patients related to illness stages and severity with a large proportion suffering from remitted-recurrent and treatment-resistant/chronic depression with first-episode major depression being underrepresented. This study was designed to examine whether and to what extent CRP is related to baseline cortisol concentrations in a well defined cohort of short-illness-duration first-episode, treatment-naive MDD patients. METHODS: The levels of salivary C-reactive protein (CRP) and baseline plasma cortisol concentrations were studied in this cross-sectional case-control study on 20 non late-life adult, treatment- naive MDD patients with short-illness-duration first affective episode and in 20 age- and sex-matched healthy controls. Depressed patients showed a basal score in the Hamilton Rating Scale for Depression (HAMD 17) higher than 20. RESULTS: No significant difference in CRP concentration between MDD and control groups was found. Significantly higher baseline cortisol (p=0.01) concentration was observed in MDD as compared to controls. Significant positive correlation was found between cortisol and CRP levels both in MDD subjects (r=0.57; p=0.008) and controls (r=0.61; p=0.004). LIMITATIONS: The current study is limited by its cross-sectional design and small sample size. CONCLUSION: The study supports data on elevated cortisol concentration in MDD providing no evidence for elevated CRP levels at the early stage of the disease. PMID- 24161451 TI - Interaction between genetic variants and exposure to Hurricane Katrina on post traumatic stress and post-traumatic growth: a prospective analysis of low income adults. AB - BACKGROUND: There is considerable variation in psychological reactions to natural disasters, with responses ranging from relatively mild and transitory symptoms to severe and persistent posttraumatic stress (PTS). Some survivors also report post traumatic growth (PTG), or positive psychological changes due to the experience and processing of the disaster and its aftermath. Gene-environment interaction (GxE) studies could offer new insight into the factors underlying variability in post-disaster psychological responses. However, few studies have explored GxE in a disaster context. METHODS: We examined whether ten common variants in seven genes (BDNF, CACNA1C, CRHR1, FKBP5, OXTR, RGS2, SLC6A4) modified associations between Hurricane Katrina exposure and PTS and PTG. Data were from a prospective study of 205 low-income non-Hispanic Black parents residing in New Orleans prior to and following Hurricane Katrina. RESULTS: We found a significant association (after correction) between RGS2 (rs4606; p=0.0044) and PTG, which was mainly driven by a cross-over GxE (p=0.006), rather than a main genetic effect (p=0.071). The G (minor allele) was associated with lower PTG scores for low levels of Hurricane exposure and higher PTG scores for moderate and high levels of exposure. We also found a nominally significant association between variation in FKBP5 (rs1306780, p=0.0113) and PTG, though this result did not survive correction for multiple testing. LIMITATIONS: Although the inclusion of low income non-Hispanic Black parents allowed us to examine GxE among a highly vulnerable group, our findings may not generalize to other populations or groups experiencing other natural disasters. Moreover, not all participants invited to participate in the genetic study provided saliva. CONCLUSIONS: To our knowledge, this is the first study to identify GxE in the context of post-traumatic growth. Future studies are needed to clarify the role of GxE in PTS and PTG and post disaster psychological responses, especially among vulnerable populations. PMID- 24161454 TI - In vivo intravascular biotinylation of Schistosoma bovis adult worms and proteomic analysis of tegumental surface proteins. AB - Schistosoma bovis is a blood-dwelling fluke of ruminants that lives for years inside the vasculature of their hosts. The parasite tegument covers the surface of the worms and plays a key role in the host-parasite relationship. The parasite molecules expressed at the tegument surface are potential targets for immune or drug intervention. The purpose of this work was the identification of the proteins expressed in vivo on the surface of the tegument of S. bovis adult worms. To accomplish this we used a method based on in vivo vascular perfusion of mice infected with S. bovis which allowed the labelling of the surface of the worms inside the blood vasculature. The biotinylation of parasite inside blood vessels prevents the handling of worms in vitro and hence possible damage to the tegument that could produce results that would be difficult to interpret. Trypsin digestion of biotinylated proteins and subsequent liquid chromatography and tandem mass spectrometry analysis (LC-MS/MS) resulted in the identification on the S. bovis tegument of 80 parasite proteins and 28 host proteins. The proteins identified were compared with the findings from other proteomic studies of the schistosome surface. The experimental approach used in this work is a reliable method for selective investigation of the surface of the worms and provides valuable information about the exposed protein repertoire of the tegument of S. bovis in the environmental conditions that the parasite faces inside the blood vessels. BIOLOGICAL SIGNIFICANCE: To identify the proteins expressed on the surface of the tegument of S. bovis adult worms we used a method based on in vivo vascular perfusion, with biotin, of mice infected with S. bovis which allowed the labelling of the surface of the worms inside the blood vasculature. This methodology prevents the handling of worms in vitro and hence possible damage to the tegument that could produce results that would be difficult to interpret. This work is the first in which vascular perfusion has been used to investigate, in vivo, the protein exposed by an intravascular pathogen on its surface to the host, and provides valuable information about the exposed protein repertoire of the tegument of S. bovis in the environmental conditions that the parasite faces inside the blood vessels. PMID- 24161453 TI - Triage of patients with moderate to severe heart failure: who should be referred to a heart failure center? AB - OBJECTIVES: The purpose of this study was to evaluate simple criteria for referral of patients from the general practitioner to a heart failure (HF) center. BACKGROUND: In advanced HF, the criteria for heart transplantation, left ventricular assist device, and palliative care are well known among HF specialists, but criteria for referral to an advanced HF center have not been developed for generalists. METHODS: We assessed observed and expected all-cause mortality in 10,062 patients with New York Heart Association (NYHA) functional class III to IV HF and ejection fraction <40% registered in the Swedish Heart Failure Registry between 2000 and 2013. Next, 5 pre-specified universally available risk factors were assessed as potential triggers for referral, using multivariable Cox regression: systolic blood pressure <=90 mm Hg; creatinine >=160 MUmol/l; hemoglobin <=120 g/l; no renin-angiotensin system antagonist; and no beta-blocker. RESULTS: In NYHA functional class III to IV and age groups <=65 years, 66 to 80 years, and >80 years, there were 2,247, 4,632, and 3,183 patients, with 1-year observed versus expected survivals of 90% versus 99%, 79% versus 97%, and 61% versus 89%, respectively. In the age <=80 years group, the presence of 1, 2, or 3 to 5 of these risk factors conferred an independent hazard ratio for all-cause mortality of 1.40, 2.30, and 4.07, and a 1-year survival of 79%, 60%, and 39%, respectively (p < 0.001). CONCLUSIONS: In patients <=80 years of age with NYHA functional class III to IV HF and ejection fraction <40%, mortality is predominantly related to HF or its comorbidities. Potential heart transplantation/left ventricular assist device candidacy is suggested by >=1 risk factor and potential palliative care by multiple universally available risk factors. These patients may benefit from referral to an advanced HF center. PMID- 24161455 TI - An adaptive recurrent neural-network controller using a stabilization matrix and predictive inputs to solve a tracking problem under disturbances. AB - We present a recurrent neural-network (RNN) controller designed to solve the tracking problem for control systems. We demonstrate that a major difficulty in training any RNN is the problem of exploding gradients, and we propose a solution to this in the case of tracking problems, by introducing a stabilization matrix and by using carefully constrained context units. This solution allows us to achieve consistently lower training errors, and hence allows us to more easily introduce adaptive capabilities. The resulting RNN is one that has been trained off-line to be rapidly adaptive to changing plant conditions and changing tracking targets. The case study we use is a renewable-energy generator application; that of producing an efficient controller for a three-phase grid connected converter. The controller we produce can cope with the random variation of system parameters and fluctuating grid voltages. It produces tracking control with almost instantaneous response to changing reference states, and virtually zero oscillation. This compares very favorably to the classical proportional integrator (PI) controllers, which we show produce a much slower response and settling time. In addition, the RNN we propose exhibits better learning stability and convergence properties, and can exhibit faster adaptation, than has been achieved with adaptive critic designs. PMID- 24161456 TI - Implementation of speech recognition in a community-based radiology practice: effect on report turnaround times. AB - PURPOSE: Large academic practices have reported important benefits with the implementation of speech recognition software (SRS). However, the applicability of these results has been questioned in the community hospital setting because of major differences in workflow. The aim of this study was to evaluate the impact of SRS on radiology report turnaround times (TATs) at a community-based hospital practice with no radiology training program. The secondary goal was to evaluate the impact of SRS on radiologist productivity. METHODS: SRS was implemented at a 150-bed community hospital between May 2011 and July 2011. Radiology report TATs and normalized radiologist productivity were determined during 5 months before and after SRS implementation. Median and 80th and 95th percentile report TATs were compared between the preimplementation and postimplementation periods. The trend in productivity was also assessed. RESULTS: Median and 80th and 95th percentile report TATs decreased multiple-fold between the preimplementation and postimplementation periods (median, from 24 to 1 hour; 80th percentile, from 60 to 10 hours; 95th percentile, from 165 to 33 hours; P < .0001). No significant trend in report TATs was appreciated beyond the initial implementation of the software, a sustained effect on TATs. Normalized radiologist productivity was stable throughout the study period. CONCLUSIONS: The implementation of SRS was associated with 24-fold improvement in the median radiology report TAT in a community hospital setting with no radiology trainees. Improvements were obtained without affecting normalized radiologist productivity. PMID- 24161457 TI - Strategies for incorporating radiology into early medical school curricula. AB - Clinically oriented material is being incorporated increasingly early into medical school curricula. Traditional models of incorporating radiology early on, mainly as an adjunct to pathology or anatomy instruction, are not focused on learning important aspects of clinical radiology. Medical students can be better served by an integrated curriculum that focuses on appropriate ordering of radiology studies, an intuitive understanding of imaging modalities, and understanding the patient experience. PMID- 24161458 TI - The prevalence of incidentally detected adrenal enlargement on CT. AB - AIM: To assess the prevalence and the department's detection rate of adrenocortical hyperplasia. MATERIALS AND METHODS: All computed tomography (CT) examinations of the adrenal glands between February and April 2011 were reviewed. The study excluded patients with known underlying cancer, abdominal trauma, or endocrine disease. The adrenal gland was deemed enlarged if its body was greater than 10 mm diameter, or a limb greater than 5 mm. RESULTS: There were a total of 564 eligible CT studies during this period. A total of 64 cases of incidental adrenal enlargement were found giving a prevalence of 11.3%. Only nine cases were reported in the contemporaneous CT report. CONCLUSION: The results of the present study show that incidental adrenal enlargement has a significant prevalence. It is often dismissed during reporting, and awareness needs to be raised in the radiological community. Equally, the clinical and biochemical significance needs to be assessed with endocrine correlation. PMID- 24161459 TI - MDCT of primary, locally recurrent, and metastatic duodenal gastrointestinal stromal tumours (GISTs): a single institution study of 25 patients with review of literature. AB - AIM: To describe the multidetector computed tomography (MDCT) features of primary, locally recurrent, and metastatic duodenal gastrointestinal stromal tumours (GISTs). MATERIALS AND METHODS: In this institutional review board approved, Health Insurance Portability and Accountability Act of 1996 (HIPAA) compliant, retrospective study, 25 patients [13 men, 12 women; mean age 56 years (34-74 years)] with histopathologically confirmed duodenal GISTs seen at Dana Farber Cancer Institute and Brigham and Women's Hospital from December 1999 to October 2009 were identified. The MDCT of primary tumours in six patients and follow-up imaging in all the 25 patients was reviewed by two radiologists in consensus. Electronic medical records were reviewed to document the clinical characteristics and management. RESULTS: The mean size of the primary tumour was 3.7 cm (range 2.5-5.6 cm). Three of six primary tumours were in the second and third portions of the duodenum, one in the third portion, one in the third and fourth portions, and one in the fourth portion. Three of six of the tumours were exophytic, two were both exophytic and intraluminal, and one was intramural. The tumours were well-circumscribed, round or oval masses, with few lobulations, and were either homogeneously hyper-enhancing or heterogeneously isodense at MDCT. None of the tumours had necrosis, haemorrhage, calcification, or loco regional lymphadenopathy on imaging. Sixteen of 25 (64%) patients developed metastatic disease, the most common sites being liver (14/16; 87.5%) and peritoneum (5/16; 31%). CONCLUSION: Duodenal GISTs are well-circumscribed, round or oval masses, and occur in the second through fourth portions of the duodenum, without lymphadenopathy or duodenal obstruction. Duodenal GISTS metastasize frequently to the liver and peritoneum. PMID- 24161460 TI - Psychiatric disorders and characteristics of abuse in sexually abused children and adolescents with and without intellectual disabilities. AB - The purpose of this study was to compare sexually abused children and adolescents, with and without intellectual disabilities (ID), in terms of post abuse psychiatric disorders, features of the sexual abuse, and sociodemographic characteristics. The study included sexually abused children aged 6-16 years, who were sent to three different child mental health units for forensic evaluation; there were 102 cases (69 girls and 33 boys) with ID and 154 cases (126 girls and 28 boys) without ID. Researchers retrospectively examined the files, social examination reports, and the judicial reports of the cases. It was determined that in the group with ID, sexual abuse types including penetration and contact had higher rates, they were exposed to more frequent repeated abuses, the abuses were revealed with their own reports at a later period and lower rates, and post abuse pregnancies were more frequent. It was also determined that the abuser was a familiar person and a family member at lower rates and more than one abuser was encountered more frequently, compared to the group without ID. While no difference was determined between the two groups in terms of the frequency of post-abuse post-traumatic stress disorder (PTSD) and major depressive disorder (MDD), conduct disorder (CD) was observed more frequently in the group with ID. This study emphasizes that sexual abuse, which is an important problem in individuals with ID, has different features and effects. PMID- 24161461 TI - Topics, methods and challenges in health promotion for people with intellectual disabilities: a structured review of literature. AB - People with intellectual disabilities (ID) experience substantial health inequities compared, with the general population. Many secondary conditions and lifestyle related health problems could be, prevented with adequate health promotion. The aim of this structured review is to provide insight into, the main characteristics of published health promotion intervention studies for people with ID and, in, doing so, to identify best practice and knowledge gaps. Relevant studies were identified through a, structured literature search of multiple electronic databases (PubMed, CINHAS, Scopus, PsychINFO), the search strategy covered health promotion and intellectual disabilities for available papers, published between February 2002 and 2012. In total, 25 studies were included and analyzed. Overall, studies were diverse and explored a variety of health issues. Papers included a variety of participants (in relation to level of disability) and intervention approaches. With regard to quality, many studies, failed to report how they recruited their participants, and there were substantial challenges identified, by authors in relation to recruitment, implementation of interventions, and the selection of outcome, measures used as well as the usability of measures themselves. Our findings suggest that this field, experiences methodological weaknesses and inconsistencies that make it difficult to compare and, contrast results. Theoretically driven studies that take into account the views and expectations of, participants themselves are needed, as is research that investigates the reliability and validity of, outcome measures for the ID population. Collaboration with mainstream health promotion research is, critical. PMID- 24161462 TI - Country- and age-specific optimal allocation of dengue vaccines. AB - Several dengue vaccines are under development, and some are expected to become available imminently. Concomitant with the anticipated release of these vaccines, vaccine allocation strategies for dengue-endemic countries in Southeast Asia and Latin America are currently under development. We developed a model of dengue transmission that incorporates the age-specific distributions of dengue burden corresponding to those in Thailand and Brazil, respectively, to determine vaccine allocations that minimize the incidence of dengue hemorrhagic fever, taking into account limited availability of vaccine doses in the initial phase of production. We showed that optimal vaccine allocation strategies vary significantly with the demographic burden of dengue hemorrhagic fever. Consequently, the strategy that is optimal for one country may be sub-optimal for another country. More specifically, we showed that, during the first years following introduction of a dengue vaccine, it is optimal to target children for dengue mass vaccination in Thailand, whereas young adults should be targeted in Brazil. PMID- 24161463 TI - Atrazine is primarily responsible for the toxicity of long-term exposure to a combination of atrazine and inorganic arsenic in the nigrostriatal system of the albino rat. AB - Chronic and simultaneous exposure to a variety of chemicals present in the environment is an unavoidable fact. However, given the complexity of studying chemical mixtures, most toxicological studies have focused on the effects of short-term exposure to single substances. The aim of this study was to evaluate the effects on the nigrostriatal system of the chronic, simultaneous exposure to two widely distributed substances that have been identified as potential dopaminergic system toxicants, inorganic arsenic (iAs) and atrazine (ATR). Six groups of rats were treated daily for one year with atrazine (10mg ATR/kg), inorganic arsenic (0.5 or 50mgiAs/L of drinking water), or a combination of ATR+0.5mgiAs/L or ATR+50mgiAs/L. The 50mgiAs/L group showed locomotor hypoactivity, while all treatments decreased motor coordination in contrast no effects of treatment were found on the place and response learning tasks. Regarding markers for liver and muscle damage, there were no differences between groups in creatine kinase (CK) or aspartate transaminase (AST) activities, while decreases in lactate dehydrogenase (LDH) levels were found in some exposed groups. The striatal DA content was significantly reduced in ATR, 0.5mgiAs/L, ATR+0.5mgiAs/L, and ATR+50mgiAs/L groups, in comparison to the control group. The number of mesencephalic tyrosine hydroxylase positive cells decreased in the ATR and ATR+0.5mgiAs/L groups compared to the control. In contrast, immunoreactivity to cytochrome oxidase was reduced compared to the control in all treated groups, except for the group treated with 0.5iAsmg alone. Our results indicate that ATR has deleterious effects on dopaminergic neurons and that the combination of ATR and iAs does not exacerbate these effects. PMID- 24161464 TI - The influence of nodal yield in neck dissections on lymph node ratio in head and neck cancer. AB - OBJECTIVES: Recent studies suggest that lymph node ratio (LNR) is a strong prognostic factor in head and neck cancer. This study aims to determine if the yield of harvested lymph nodes (LNs) influences the LNR. METHODS: The study included 522 head and neck cancer patients, undergoing 638 primary and salvage (selective) neck dissections between 2002 and 2012. Before 2007 the neck dissection specimens were macroscopically and microscopically examined by pathologists and after 2007 the macroscopic examination was performed by pathology technicians. For comparison of mean LN yields, univariate and multivariate analyses were performed. RESULTS: The mean number of LNs among 374 specimens examined by pathologists was 24 (range 0-89) vs. 32 (range 2-89) among 264 specimens examined by pathology technicians (P<.001). This caused the mean LNR in the non pre-treated patient group to drop from 11.4% to 8.7%. The counts of LNs per type of neck dissection were significantly different and increased with the number of levels involved. However, there was no linear relationship and the higher yields could be mostly ascribed to LNs in level V. The LNR varied from 8.1% to 18.4% among the different types of neck dissections. CONCLUSIONS: A significant increase in the number of harvested LNs, but a decrease in LNR was observed after introducing pathology technicians for macroscopic examination. A clear association between the extent of the dissection and the number of harvested LNs was observed. LNR appears to be strongly dependent on the harvesting protocol and the extent of the dissection. PMID- 24161466 TI - Processing of emotional vocalizations in bilateral inferior frontal cortex. AB - A current view proposes that the right inferior frontal cortex (IFC) is particularly responsible for attentive decoding and cognitive evaluation of emotional cues in human vocalizations. Although some studies seem to support this view, an exhaustive review of all recent imaging studies points to an important functional role of both the right and the left IFC in processing vocal emotions. Second, besides a supposed predominant role of the IFC for an attentive processing and evaluation of emotional voices in IFC, these recent studies also point to a possible role of the IFC in preattentive and implicit processing of vocal emotions. The studies specifically provide evidence that both the right and the left IFC show a similar anterior-to-posterior gradient of functional activity in response to emotional vocalizations. This bilateral IFC gradient depends both on the nature or medium of emotional vocalizations (emotional prosody versus nonverbal expressions) and on the level of attentive processing (explicit versus implicit processing), closely resembling the distribution of terminal regions of distinct auditory pathways, which provide either global or dynamic acoustic information. Here we suggest a functional distribution in which several IFC subregions process different acoustic information conveyed by emotional vocalizations. Although the rostro-ventral IFC might categorize emotional vocalizations, the caudo-dorsal IFC might be specifically sensitive to their temporal features. PMID- 24161465 TI - A European perspective on alternatives to animal testing for environmental hazard identification and risk assessment. AB - Tests with vertebrates are an integral part of environmental hazard identification and risk assessment of chemicals, plant protection products, pharmaceuticals, biocides, feed additives and effluents. These tests raise ethical and economic concerns and are considered as inappropriate for assessing all of the substances and effluents that require regulatory testing. Hence, there is a strong demand for replacement, reduction and refinement strategies and methods. However, until now alternative approaches have only rarely been used in regulatory settings. This review provides an overview on current regulations of chemicals and the requirements for animal tests in environmental hazard and risk assessment. It aims to highlight the potential areas for alternative approaches in environmental hazard identification and risk assessment. Perspectives and limitations of alternative approaches to animal tests using vertebrates in environmental toxicology, i.e. mainly fish and amphibians, are discussed. Free access to existing (proprietary) animal test data, availability of validated alternative methods and a practical implementation of conceptual approaches such as the Adverse Outcome Pathways and Integrated Testing Strategies were identified as major requirements towards the successful development and implementation of alternative approaches. Although this article focusses on European regulations, its considerations and conclusions are of global relevance. PMID- 24161467 TI - Osteogenetic changes in elongated styloid processes of Eagle syndrome patients. AB - Abnormal elongation of the styloid process, or Eagle syndrome, can be painful, and is associated with differential diagnoses including cranio-facial malformations and vasculo-neurological disturbances. The precise molecular mechanism leading to styloid process elongation is unknown. In this study, elongated styloid processes with periosteal fibrous ligament tissue were obtained from three patients with Eagle syndrome and examined by immunohistochemical methods using different antisera. In all cases, marked bony deposition was found at the apex of the styloid process. The osteogenetic proteins, such as osteonectin, osteocalcin, BMP-2, BMP-4, and RANKL were strongly positive by immunohistochemistry in both the ligament fibers and the periosteal membrane attached to the styloid process apex. Staining for protective proteins, HO-1, HSP 70, and HSP-90 was also positive. These results suggest that styloid process elongation is related to increased expression of osteogenetic and protective proteins. Therefore, we propose that Eagle syndrome results from a protective response to increased tensile stress in the ligament attached to the styloid process, which could also signal osteogenetic protein expression in the periosteal fibrous tissue. PMID- 24161468 TI - Plasmodium falciparum RuvB2 translocates in 5'-3' direction, relocalizes during schizont stage and its enzymatic activities are up regulated by RuvB3 of the same complex. AB - Two similar proteins RuvB like1 (Rvb1/Pontin) and RuvB like2 (Rvb2/Reptin) of AAA+ family of enzymes are present in yeast to human and are well known to be involved in diverse cellular activities. The human malaria parasite Plasmodium falciparum contains three different RuvB like proteins. Thus it has been of interest to explore why P. falciparum requires three RuvB like proteins and how these enzymes are biochemically regulated. In this study, we present the detailed biochemical characterization of PfRuvB2. The complex of PfRuvB3 was immunopurified and the presence of PfRuvB2 was confirmed. The in vitro interaction study shows that PfRuvB2 interacts only with PfRuvB3 but not with PfRuvB1. The recombinant as well as endogenous PfRuvB2 contains ATPase as well as weak DNA helicase activities. The presence of PfRuvB3 in the helicase reaction of PfRuvB2 increases the helicase activity significantly. Interestingly PfRuvB2/PfRuvB3 complex preferentially translocates and unwinds DNA in the 5'-3' direction. In vivo studies showed that PfRuvB2 is expressed in all the asexual intraerythrocytic developmental stages and localizes mainly in the nucleus during merozoite, ring and trophozoite stages while during schizont stage it relocalizes partially in the nucleus and partially towards cytoplasm. As PfRuvB3 is specific to intraerythrocytic mitosis so we interpret that PfPuvB3 interacts with PfRuvB2 during schizont/intraerythrocytic mitosis and acts as its modulator mainly for the appreciable helicase activity. PMID- 24161469 TI - In vitro and in vivo study of dolichyl phosphate on the efflux activity of P glycoprotein at the blood-brain barrier. AB - It has been commonly recognized that accumulated amyloid-beta (Abeta) in the brain plays a crucial role in the pathogenesis of Alzheimer's disease (AD). Since the deficiency of the P-glycoprotein (P-gp) at the blood-brain barrier (BBB) in AD may aggravate Abeta deposition and the P-gp reversal agents display lower selectivity of the action, to selectively restore activity of the efflux pump is eagerly required. This study was designed to investigate the influence of dolichyl-phosphate (dolichyl-P) on the P-gp at the BBB. The results revealed that treatment with dolichyl-P increased transendothelial transfer of Rhodamine123 (Rh123) and Abeta42 from the apical compartment to the basolateral compartment but reduced that from the basolateral compartment to the apical compartment in the co-culture of rat brain microvessel endothelial cells (rBMECs) and astrocytes, down regulated P-gp expression in rBMECs and significantly elevated content of Rh123 in rat cortex and hippocampus tissues. The present results implied that accumulated dolichyl-P in the brain may exert an important role in the depression of the P-gp at the BBB, which may suggest valuable clues to promote function of the pump at the BBB in AD. PMID- 24161470 TI - Three cases of pseudolymphoma successfully treated with amoxicillin. PMID- 24161471 TI - The innate and adaptive immunological aspects in neurodegenerative diseases. AB - Neurodegenerative diseases affect a considerable percentage of the elderly population. New therapeutic approaches are warranted, aiming to at least delay and possibly reverse disease progression. Strategies to elaborate such approaches require knowledge of specific immune system involvement in disease pathogenesis. In this review, innate and adaptive immunological aspects of neurodegenerative disorders, in particular Parkinson's disease, Alzheimer's disease, and amyotrophic lateral sclerosis (ALS), are discussed. Initiating disease factors, as well as common mechanistic pathways, are detailed and potential immunological therapeutic targets are identified. PMID- 24161472 TI - CLOVES syndrome. AB - A cohort of patients with overgrowth syndromes has been identified with congenital lipomatous overgrowth, dysregulated fat deposits, and mixed vascular malformations. The acronym CLOVES was given on a heuristic basis to stand for congenital lipomatous overgrowth (CLO), vascular malformation (V), epidermal nevi (E), and scoliosis and spinal deformities (S). These patients have upper limb anomalies with variable phenotypes. Although hand anomalies alone cannot make the diagnosis, the foot, truncal, cutaneous and spinal anomalies are particularly diagnostic. CLOVES syndrome has emerged as a distinct clinical entity diagnosed by clinical and radiographic examinations. The overgrowth pattern is now easily distinguished from other overgrowth syndromes. PMID- 24161473 TI - Grip lock injury resulting in extensor tendon pseudorupture: case report. AB - Grip lock injuries are uncommon, potentially devastating occurrences in male gymnasts performing high bar routines, and typically cause severe wrist sprains or forearm fractures. We retrospectively reviewed medical records of a 24-year old former collegiate gymnast surgically treated for complete loss of index and long finger extension (pseudorupture) after a grip lock injury. Intraoperative evaluation 3 weeks after injury revealed profound intratendinous attenuation of index and long finger extensors with adhesions in the fourth compartment. We performed tenolysis and imbrication of the affected tendons. At 12-month follow up, the patient had no pain, full digital range of motion with the wrist in neutral, but residual extensor lag with the wrist in extension. He had returned to gymnastics with some apprehension. This case broadens the known spectrum of grip lock injuries. PMID- 24161474 TI - Comparison of pregnancy rates in users of extended and cyclic combined oral contraceptive (COC) regimens in the United States: a brief report. AB - OBJECTIVE: To evaluate pregnancy rates with 84/7, 21/7, and 24/4 combined oral contraceptives (COCs). STUDY DESIGN: Data were obtained from the i3Invision Data Mart(TM) retrospective claims database. Subjects were 15 to 40 years; first prescribed COCs between January 1, 2006 and April 1, 2011; and continuously insured for >=1 year. Eighty four over seven users (84/7) were matched 1:1 to 21/7 and 24/4 users. RESULTS: One-year pregnancy rates were significantly lower with 84/7 than with 21/7 (4.4% vs. 7.3%; p<.0001) and 24/4 (4.4% vs. 6.9%, p<.0001) regimens. CONCLUSION: Preliminary results suggest fewer pregnancies with 84/7 versus 21/7 or 24/4 regimens. IMPLICATIONS: While newer COCs, including 84/7 and 24/4 regimens, potentially improve efficacy and alter bleeding profiles compared to 21/7 regimens, few data on comparative pregnancy rates with these regimens are available. In this retrospective claims analysis, real-world pregnancy rates were lower with 84/7 regimens versus 21/7 and 24/4 regimens. PMID- 24161475 TI - Understanding women's desires for contraceptive counseling at the time of first trimester surgical abortion. AB - OBJECTIVE: The objective was to investigate whether or not women presenting for a first-trimester surgical abortion want to discuss contraception on the day of their procedure. STUDY DESIGN: Between October 2012 and January 2013, an anonymous self-administered survey was distributed to women receiving first trimester surgical abortions at four northern California family planning clinics. The survey obtained demographic information about each woman and inquired about her desire for contraceptive counseling during her appointment. Results were analyzed using both univariate and multivariable regression analyses to assess trends in responses related to desire for contraceptive counseling based on demographic and other variables. RESULTS: Of the 199 respondents, 64% reported that they did not want to talk to a counselor or doctor about contraception on the day of their abortion. About half of the women (52%) who did not want to discuss contraception indicated they already knew what they wanted for pregnancy prevention. Of the 25% who reported that they did want to discuss contraception, the most important topic desired from the counseling was identification of methods that were easier to use than what they used previously. CONCLUSION: The majority of women seeking first-trimester surgical abortion may not desire additional information about contraception on the day of the procedure. IMPLICATIONS STATEMENT: This study demonstrates that a significant proportion of women may not want contraceptive counseling on the day of a planned surgical abortion. PMID- 24161477 TI - ACE levels may affect cystatin C measurements. AB - OBJECTIVE: To assess the relationship between angiotensin-converting enzyme (ACE) levels and cystatin C in a patient with the presumed diagnosis of sarcoidosis. DESIGN AND METHODS: Case report with correlation analysis between ACE levels and cystatin C concentrations while considering gold-standard nuclear medicine glomerular filtration rate (GFR) methods for the measurement of renal function. RESULTS: We observed a strong correlation between ACE levels and cystatin C concentration in 12-year old with the presumed diagnosis of sarcoidosis in the absence of renal pathology and abnormal renal function. CONCLUSION: Elevated ACE levels may cause non-specific cystatin C elevation irrespective of GFR. PMID- 24161476 TI - A one-step dipstick assay for the on-site detection of nucleic acid. AB - OBJECTIVES: We have developed a one-step nucleic acid dipstick assay (NADA) for visually detecting polymerase chain reaction (PCR) products within 3min. "One step" means that there were no additional procedures between amplification and detection. METHODS: This method was achieved through the use of asymmetric PCR and specially designed probes with appropriate melting temperature values. We initially combined one-step NADA with asymmetric capillary convective PCR (ACCPCR), an easy and rapid nucleic acid amplification technique, to construct an on-site nucleic acid diagnostic platform. RESULTS: We developed a diagnostic assay for the hepatitis B virus based on the ACCPCR-NADA platform to verify its feasibility. It exhibited an analytical sensitivity of three copies per test and a broad detection spectrum including genotype A-I. It also showed 97.9% sensitivity and 100% specificity based on the results observed using 67 serum samples with the Roche COBAS AmpliPrep/COBAS TaqMan (COBAS) system as the standard for comparison. CONCLUSION: The results provide evidence for the feasibility of using an ACCPCR-NADA platform in practical applications, especially in on-site test. PMID- 24161478 TI - Clinical evaluation of a dried blood spot method for determination of mycophenolic acid in renal transplant patients. AB - OBJECTIVES: The aim of this study is to evaluate the clinical application of dried blood spots (DBS) sampling in renal transplant patients under mycophenolic acid (MPA) immunosuppression, comparing measurements performed in paired plasma and DBS samples. DESIGN AND METHODS: 77 paired DBS and plasma samples were obtained from 19 renal transplant patients. MPA was measured in both matrices by HPLC-DAD. Estimated plasma concentrations (EPC) were calculated from DBS concentrations (DC) using the formula EPC=DC/[1-(Hct/100)], using either individual or mean hematocrit (Hct). Agreement between methods was evaluated using Passing-Bablok regression and Bland-Altman difference plots. RESULTS: MPA concentrations in DBS were in mean 60.7% of those measured in plasma. EPC calculated from DBS and patient's individual Hct presented a high correlation with blood plasma (r=0.9862), and comparable absolute values (slope 1.0563 and intercept -0.0739), being in mean 102.2% of the measured plasma concentrations. EPC can also be calculated with the mean Hct of the group of patients, with similar results. CONCLUSIONS: DBS sampling can be used for TDM of MPA in a clinical setting, employing conventional HPLC equipment, presenting similar results to plasma samples after a proper mathematical treatment. Moreover, due to its intrinsic stability and handling safety, DBS sampling can be considered a useful alternative especially in developing countries where sample logistics could be a major difficulty. PMID- 24161479 TI - Redundans nervi radix cauda equina: pathophysiology and clinical significance of an intriguing radiologic sign. PMID- 24161480 TI - Loss of PINK1 enhances neurodegeneration in a mouse model of Parkinson's disease triggered by mitochondrial stress. AB - Parkinson's disease (PD) shows a complex etiology, where both genetic and environmental factors contribute to initiation and advance of pathology. Mitochondrial dysfunction and mutation of genes implicated in mitochondria quality control are recognized contributors to etiopathology and progression of PD. Here we report the development and characterization of a genetic mouse model of PD with a combined etiology comprising: 1) induction of mitochondrial stress achieved through the expression of a mitochondrial matrix protein that accumulates in an unfolded state and 2) deletion of PINK1 gene. Using this model we address the role of PINK1 in mitochondrial quality control and disease progression. To induce mitochondrial stress specifically in catecholaminergic neurons we generated transgenic animals where the conditional expression of mitochondrial unfolded ornithine transcarbamylase (dOTC) is achieved under the tyrosine hydroxylase (Th) promoter. The mice were characterized in terms of survival, growth and motor behaviour. The characterization was followed by analysis of cell death induced in dopaminergic neurons and responsiveness to l dopa. We demonstrate that accumulation of dOTC in dopaminergic neurons causes neurodegeneration and motor behaviour impairment that illustrates a parkinsonian phenotype. This associates with l-dopa responsiveness validating the model as a model of PD. The combined transgenic model where dOTC is overexpressed in PINK1 KO background presents increased neurodegeneration as compared to dOTC transgenic in wild-type background. Moreover, this combined model does not show responsiveness to l-dopa. Our in vivo data show that loss of PINK1 accelerates neurodegenerative phenotypes induced by mitochondrial stress triggered by the expression of an unfolded protein in this organelle. PMID- 24161481 TI - Association of outcome with left ventricular parameters measured by two dimensional and three-dimensional echocardiography in patients at high cardiovascular risk. AB - BACKGROUND: Left ventricular (LV) ejection fraction (EF) measured by two dimensional echocardiographic (2DE) imaging is an important correlate of survival. Real-time three-dimensional echocardiographic (3DE) imaging has addressed some of the limitations of 2DE imaging. The aim of this study was to determine whether 3DE imaging is more predictive of outcomes than 2DE imaging. METHODS: A total of 529 patients undergoing LV assessment with 2DE and 3DE imaging in 2003 and 2004 at a tertiary referral cardiac center were studied. Patients had a high frequency of cardiovascular risk factors. Images were gathered over four cardiac cycles using a matrix-array transducer, with measurements performed offline. Follow-up (all-cause mortality or cardiac hospitalization) was obtained over 6.6 +/- 3.4 years in 455 of 486 patients with images suitable for measurement (94%). RESULTS: There were 194 events (43%), including 75 deaths (16.4%). Larger LV volumes and lower EF were associated with worse outcomes independent of age, heart failure, or end-stage renal disease. In stepwise Cox regression analyses, the associations of cardiac hospitalization and survival with clinical variables (age, chronic kidney disease, and heart failure) were augmented by 3DE EF and end-systolic volume more than by 2DE parameters. The incremental model chi(2) value with 3DE EF was 14.67 (P < .001), compared with 9.72 (P = .002) for 2DE EF. Similarly, in Cox regression analyses of mortality, the effects of clinical variables (age, advanced renal disease, and heart failure) were augmented more by 3DE EF (incremental chi(2) = 14.04, P < .0001) than 2DE EF (incremental chi(2) = 5.13, P = .024). CONCLUSIONS: In this outcome study, 3DE EF and volumes showed stronger associations with outcomes than those derived from 2DE imaging. PMID- 24161482 TI - Altered transmural contractility in postmenopausal women affected by cardiac syndrome X. AB - BACKGROUND: Cardiac syndrome X (CSX) is characterized by typical angina and abnormal exercise test results, with normal coronary arteries. Cardiovascular magnetic resonance imaging has shown subendocardial hypoperfusion in patients with CSX after adenosine. The aim of this study was to investigate the contribution of separate myocardial layers to global function under stress in women with CSX. METHODS: Twenty-two postmenopausal women with CSX were studied and compared with 20 healthy women matched for age and body mass index. All subjects underwent clinical evaluations and exercise echocardiography. Left ventricular systolic and diastolic parameters were evaluated at rest and at peak exercise. Layer-specific global longitudinal strain (GLS) and strain rate (SR) were assessed from the endocardium, midmyocardium, and epicardium using two dimensional speckle-tracking echocardiography. RESULTS: All subjects showed normal contractile function at rest and at peak exercise. Significant increases in GLS and SR in all myocardial layers were observed at peak exercise in the control group, whereas patients with CSX showed significantly lower increases in endocardial GLS and SR compared with the control group (endocardial DeltaSR, 0.17 +/- 0.19 vs 0.33 +/- 0.13 [P < .01]; endocardial DeltaGLS, 1.33 +/- 2.93 vs 6.64 +/- 2.62 [P < .001]). Moreover, significantly impaired diastolic function (DeltaE', 1.1 +/- 3.3 vs 4.0 +/- 2.03) was observed in patients with CSX. CONCLUSIONS: The results of this study show subendocardial impairment of contractile function during exercise in patients with CSX, confirming the existence of reduced myocardial perfusion reserve in patients with CSX and suggesting layer-targeted exercise echocardiography as a sensitive diagnostic tool in the assessment of suspected CSX. PMID- 24161483 TI - Mitral inflow patterns after MitraClip implantation at rest and during exercise. AB - BACKGROUND: MitraClip implantation reduces mitral regurgitation effectively but decreases mitral valve area, creating iatrogenic mitral stenosis. Evaluation with transesophageal echocardiography intraprocedurally is necessary to measure mitral regurgitation and mitral valve pressure gradient (MVPG) to determine whether it is necessary and safe to place more clips. The aim of this study was to investigate whether these intraprocedural hemodynamics represent postprocedural measurements and whether exercise is affected by the stenosis. METHODS: In this retrospective single-center study, 51 patients who underwent MitraClip implantation were included. Measurements were performed intraprocedurally using transesophageal echocardiography and postprocedurally using transthoracic echocardiography. In 23 of these patients, exercise echocardiography was performed at follow-up. RESULTS: Intraprocedural mean MVPG was 3.0 +/- 1.6 mm Hg and increased to 4.3 +/- 2.2 mm Hg postprocedurally (P < .001). During exercise, mean MVPG increased significantly compared with rest conditions (from 3.6 +/- 1.7 to 6.3 +/- 2.7 mm Hg, P < .001). Six patients had mean resting MVPGs >= 5 mm Hg at follow-up and had higher systolic pulmonary artery pressure (sPAPs) than patients with mean MVPGs < 5 mm Hg (47 +/- 7 vs 35 +/- 12 mm Hg, P = .035). Higher MVPG and sPAP did not lead to more symptoms of heart failure. Receiver operating characteristic curve analysis showed an estimated cutoff point for intraprocedural pressure half-time of 91 msec to identify patients with mitral stenosis and sPAP >= 50 mm Hg postprocedurally. CONCLUSIONS: Mean MVPG during MitraClip implantation measured by TEE underestimates the hemodynamics in daily life, of which operators should be aware when deciding on placing one or more clips. Pressure half-time seems to be the most robust parameter compared with mean and maximum MVPG and may contribute to this decision. Patients with higher mean MVPGs after MitraClip implantation have higher sPAPs at follow-up. However, more symptoms of heart failure were not detected at follow-up. PMID- 24161484 TI - ManA is regulated by RssAB signaling and promotes motility in Serratia marcescens. AB - Serratia marcescens swarms on 0.8% LB agar at 30 degrees C but not at 37 degrees C. To understand the molecular mechanism regulating Serratia swarming, transposon mutagenesis was performed to screen for mutants that swarmed at 37 degrees C. In one mutant, S. marcescens WW100, the transposon was inserted in the upstream region of manA, which encodes mannose-6-phosphate isomerase, a type I phosphomannose isomerase. The transcriptional and translational levels of manA were higher in S. marcescens WW100 than in the wild-type strain. S. marcescens WW100 produced more serrawettin W1 (biosurfactant) than the wild-type, as detected by thin-layer chromatography, to promote surface motility by reducing surface tension. Serratia swarming was previously shown to be negatively regulated by the RssA-RssB two-component system. An electrophoretic mobility shift assay (EMSA) indicated that phosphorylated RssB (the response regulator) binds upstream of the transposon insertion site and manA in S. marcescens WW100. Analysis by real-time RT-PCR (qRT-PCR) revealed that, compared to the wild-type level, manA mRNA was increased in the rssA deletion mutant. The results indicated that RssA-RssB signaling directly represses the expression of manA and that overexpression of manA increases the production of serrawettin for Serratia swarming at 37 degrees C. PMID- 24161485 TI - 5,6,7-trimethoxyflavone suppresses pro-inflammatory mediators in lipopolysaccharide-induced RAW 264.7 macrophages and protects mice from lethal endotoxin shock. AB - 5,6,7-Trimethoxyflavone (TMF), methylations of the hydroxyl groups of oroxylin A or baicalein, was found to significantly inhibit the productions of nitric oxide (NO) and prostaglandin E2 (PGE2) in lipopolysaccharide (LPS)-treated RAW 264.7 macrophages. However, no report has been issued on the anti-inflammatory potential of TMF and the underlying molecular mechanism. In the present study, we investigated the anti-inflammatory effects of TMF in LPS-induced RAW 264.7 macrophages and LPS-induced septic shock in mice. TMF dose-dependently inhibits iNOS and COX-2 at the protein, mRNA, and promoter binding levels and that these inhibitions cause attendant decreases in the productions of NO and PGE2. TMF inhibits the productions and mRNA expressions of tumor necrosis factor-alpha (TNF alpha), interleukin (IL)-1beta, and IL-6 induced by LPS. Furthermore, TMF suppress the transcriptional activity of nuclear factor-kappa B (NF-kappaB) and activator protein-1 (AP-1), and nuclear translocations of NF-kappaB, AP-1, and signal transducer and activator of transcription 1/3 (STAT1/3). Pretreatment with TMF increase the survival rate of mice with LPS-induced endotoxemia and reduced the serum levels of cytokines. Taken together, these findings suggest that TMF down-regulates the expressions of the pro-inflammatory iNOS, COX-2, TNF-alpha, IL 1beta, and IL-6 genes in macrophages by interfering with the activation of NF kappaB, AP-1, and STAT1/3. PMID- 24161487 TI - Rubus idaeus L. reverses epithelial-to-mesenchymal transition and suppresses cell invasion and protease activities by targeting ERK1/2 and FAK pathways in human lung cancer cells. AB - Epithelial to mesenchymal transition (EMT) has been considered essential for cancer metastasis, a multistep complicated process including local invasion, intravasation, extravasation, and proliferation at distant sites. Herein we provided molecular evidence associated with the antimetastatic effect of Rubus idaeus L. extracts (RIE) by showing a nearly complete inhibition on the invasion (p<0.001) of highly metastatic A549 cells via reduced activities of matrix metalloproteinase-2 (MMP-2) and urokinasetype plasminogen activator (u-PA). We performed Western blot to find that RIE could induce up-regulation of epithelial marker such as E-cadherin and alpha-catenin and inhibit the mesenchymal markers such as N-cadherin, fibronectin, snail-1, and vimentin. Selective snail-1 inhibition by snail-1-specific-siRNA also showed increased E-cadherin expression in A549 cells suggesting a possible involvement of snail-1 inhibition in RIE caused increase in E-cadherin level. RIE also inhibited p-FAK, p-paxillin and AP 1 by Western blot analysis, indicating the anti-EMT effect of RIE in human lung carcinoma. Importantly, an in vivo BALB/c nude mice xenograft model showed that RIE treatment reduced tumor growth by oral gavage, and RIE represent promising candidates for future phytochemical-based mechanistic pathway-targeted cancer prevention strategies. PMID- 24161486 TI - Effects of red ginseng on the regulation of cyclooxygenase-2 of spleen cells in whole-body gamma irradiated mice. AB - Exposure to gamma radiation causes a wide range of biological damage and alterations, including oxidative stress, inflammation and cancer. This study aimed to identify the radioprotective effect of Korean red ginseng extract (RG) against whole-body gamma-irradiation (gammaIR) in mice and the regulatory mechanisms of the radiosensitive gene in spleen, cyclooxygenase-2 (COX-2). RG was administered intraperitoneally (i.p.) or orally (p.o.) to C57BL/6 mice for five days, which were then exposed to 6.5 Gy of (137)Cs-gammaIR. Thymus and spleen were harvested after three days, and organ size and COX-2 expression of the spleen using Western blotting, were examined. gammaIR shrank both organs and RG recovered the size of thymus but not spleen. RG also significantly inhibited the increased expression of COX-2 induced by gammaIR. These results were similar following both routes of RG administration, however i.p. RG administration was more effective, thus it was used in progressive studies. In terms of COX-2 expression related intracellular factors, we found here that gammaIR activated the p38 MAPK, PI3K/Akt and HO-1 but not NF-kappaB or Nrf2. Activated p38 MAPK, PI3K/Akt and HO-1 were down-regulated by RG while the RG-induced COX-2 expression was only related to HO-1 activation. These results suggest that RG supplementation provides protective effects against radiation-induced inflammation and cancer, and its potential to be utilized in clinical trials and functional foods. PMID- 24161488 TI - Extra virgin olive oil potentiates the effects of aromatase inhibitors via glutathione depletion in estrogen receptor-positive human breast cancer (MCF-7) cells. AB - There have been numerous evidences supporting the relationship between olive oil and cancer, with most of the attention being directed toward its fat and phenolic content. The aims of this study were to investigate whether EVOO and OA could enhance the effects of aromatase inhibitors (letrozole and anastrozole) in ER positive MCF-7 cells, as well as to investigate its influence on cytochrome c release and GSH levels. It was observed that upon combination treatment, anti proliferation effects and apoptosis induction were augmented. Apoptosis was triggered via the intrinsic pathway in accordance with cytochrome c release into the cytosol based on IF-IC and ELISA observations. Intracellular GSH levels were also reduced upon EVOO/OA treatment in combination with aromatase inhibitors, and were found to be inversely correlated to cytosolic cytochrome c levels. Additionally, the estrogenic suppressive effects of letrozole and anastrozole were amplified when used in combination with EVOO/OA. Therefore, the employment of aromatase inhibitors in combination with EVOO/OA could orchestrate a reduction in intracellular estrone biosynthesis which feeds ER-positive cells, while simultaneously depleting GSH levels and increasing ROS generation, thus releasing cytochrome c and subsequent induction of apoptosis in MCF-7 cells. PMID- 24161489 TI - Influence of glucocorticosteroids on the biomechanical properties of in-vivo rabbit cornea. AB - Understanding corneal biomechanical responses during long-term glucocorticosteroids administration is important in clinical practice. The purpose of this study is to investigate the biomechanical influence of fluorometholone 0.1% eye drops on rabbit cornea. Thirty-eight Japanese white rabbits were randomly divided into three groups; a fluorometholone group, a supernatant group and a blank control group. For each rabbit in fluorometholone group, one cornea was treated with fluorometholone 0.1% eye drops four times a day for 8 weeks, while corneas of rabbits in supernatant group were treated in the same frequency with supernatant fraction centrifuged from fluorometholone 0.1% eye drops. The rabbits in the blank control group were not given any treatment. At the end of the 8 week observation period, the rabbits were euthanized and the eyes immediately enucleated and prepared for inflation testing. The experimental pressure-deformation data was used to derive the stress strain behavior of each eye using an inverse modeling procedure. Comparisons of mechanical stiffness of corneas were conducted among the three groups to determine the influence of fluorometholone. The results showed that corneal stiffness decreased as the fluorometholone administration time prolonged. Comparisons of tangent modulus indicated average stiffness reductions of 34.2% and 33.5% in the fluorometholone group compared to the supernatant and control groups, respectively, at the end of the observation period. The stiffness reduction effect of fluorometholone on the cornea should be considered in clinical management, especially when administrating it to biomechanically weakened corneas, such as after refractive surgeries and in cases of keratoconus. PMID- 24161490 TI - Dimensions of integration in interdisciplinary explanations of the origin of evolutionary novelty. AB - Many philosophers of biology have embraced a version of pluralism in response to the failure of theory reduction but overlook how concepts, methods, and explanatory resources are in fact coordinated, such as in interdisciplinary research where the aim is to integrate different strands into an articulated whole. This is observable for the origin of evolutionary novelty-a complex problem that requires a synthesis of intellectual resources from different fields to arrive at robust answers to multiple allied questions. It is an apt locus for exploring new dimensions of explanatory integration because it necessitates coordination among historical and experimental disciplines (e.g., geology and molecular biology). These coordination issues are widespread for the origin of novel morphologies observed in the Cambrian Explosion. Despite an explicit commitment to an integrated, interdisciplinary explanation, some potential disciplinary contributors are excluded. Notable among these exclusions is the physics of ontogeny. We argue that two different dimensions of integration-data and standards-have been insufficiently distinguished. This distinction accounts for why physics-based explanatory contributions to the origin of novelty have been resisted: they do not integrate certain types of data and differ in how they conceptualize the standard of uniformitarianism in historical, causal explanations. Our analysis of these different dimensions of integration contributes to the development of more adequate and integrated explanatory frameworks. PMID- 24161491 TI - Pharmacist services provided in general practice clinics: a systematic review and meta-analysis. AB - BACKGROUND: Integration of pharmacists into primary care general practice clinics has the potential to improve interdisciplinary teamwork and patient care; however this practice is not widespread. OBJECTIVE: The aim of this study was to review the effectiveness of clinical pharmacist services delivered in primary care general practice clinics. METHODS: A systematic review of English language randomized controlled trials cited in the Cochrane Central Register of Controlled Trials, MEDLINE, EMBASE and International Pharmaceutical Abstracts was conducted. Studies were included if pharmacists had a regular and ongoing relationship with the clinic; delivered an intervention aimed at optimizing prescribing for, and/or medication use by, clinic patients; and were physically present within the clinic for all or part of the intervention, or for communication with staff. The search generated 1484 articles. After removal of duplicates and screening of titles and abstracts against inclusion criteria, 131 articles remained. A total of 38 studies were included in the review and assessed for quality. Seventeen studies had common endpoints (blood pressure, glycosylated hemoglobin, cholesterol and/or Framingham risk score) and were included in meta-analyses. RESULTS: Twenty-nine of the 38 studies recruited patients with specific medical conditions, most commonly cardiovascular disease (15 studies) and/or diabetes (9 studies). The remaining 9 studies recruited patients at general risk of medication misadventure. Pharmacist interventions usually involved medication review (86.8%), with or without other activities delivered collaboratively with the general practitioner (family physician). Positive effects on primary outcomes related to medication use or clinical outcomes were reported in 19 studies, mixed effects in six studies, and no effect in 13 studies. The results of meta-analyses favored the pharmacist intervention, with significant improvements in blood pressure, glycosylated hemoglobin, cholesterol and Framingham risk score in intervention patients compared to control patients. CONCLUSIONS: Pharmacists co located in general practice clinics delivered a range of interventions, with favorable results in various areas of chronic disease management and quality use of medicines. PMID- 24161492 TI - Anti-oxidative and anti-inflammatory activities of caffeoyl hemiterpene glycosides from Spiraea prunifolia. AB - Activity guided isolation of a Spiraea prunifolia extract yielded five caffeoyl hemiterpene glycosides: 4'-(6-O-caffeoyl-beta-D-glucopyranosyl)-2'-methyl butyric acid, 1-O-caffeoyl-6-O-(4'-hydroxy-2'-methylene-butyroyl)-beta-D-glucopyranoside, 1,2-O-dicaffeoyl-6-O-(4'-hydroxy-2'-methylene-butyroyl)-beta-D-glucopyranoside, 1 O-caffeoyl-6-O-(4'-caffeoyl-2'-methylene-butyroyl)-beta-D-glucopyranoside, and 1 O-caffeoyl-6-O-(4'-caffeoyl-3'-hydroxy-2'-methylene-butyroyl)-beta-D glucopyranoside, and nine known compounds. Structures were elucidated by analysis of 1D and 2D NMR spectra and FAB-MS. To evaluate the anti-oxidative and anti inflammatory properties of all fourteen compounds, DPPH radical scavenging, NBT superoxide scavenging, and inhibition of nitric oxide production in LPS stimulated RAW264.7 cells were examined. Three of the caffeoyl hemiterpene glycosides exhibited potent anti-oxidative and anti-inflammatory activities compared with Vitamin C and l-NMMA, which were used as positive controls. PMID- 24161493 TI - Postnatal experiences and support needs of first-time mothers in Singapore: a descriptive qualitative study. AB - OBJECTIVES: to explore first-time mothers' postnatal experiences and support needs after hospital discharge in Singapore. DESIGN AND SETTING: a descriptive qualitative study was adopted in this study. Participants were recruited from a public tertiary hospital in Singapore. Semi-structured interviews were used for data collection and the interview transcripts were analysed using thematic analysis. PARTICIPANTS: a purposive sample of 13 English-speaking first-time mothers of age 21 years and above were interviewed within 7-11 days after their hospital discharge. FINDINGS: five themes emerged from the thematic analysis: (1) mixed emotions: participants experienced anxiety, labile emotions and stress over infant care; (2) breast feeding concerns: low breast milk supply and physical discomfort; (3) social support: many participants had sufficient social support from family members except their husbands; (4) cultural postnatal practice: majority of participants followed traditional postnatal practices of their culture; and (5) professional support needs: participants needed more information, access to health care services and continuity of care. CONCLUSIONS: this study highlighted the importance of providing professional postnatal care to first-time mothers after their discharge from the hospital. Future studies are needed to explore new practices that will enhance the quality of maternity health care and promote positive maternal experiences and well-being in Singapore. IMPLICATIONS FOR PRACTICE: there is a need for more innovative advertisement to promote antenatal classes and improve attendance rate. Health care providers should assist women in establishing proper breast feeding techniques. Alternative models of care in the postnatal period, such as midwifery-led care, could facilitate a more woman-centred approach. Postnatal home visits may be considered within the first week of the mothers' hospital discharge, which may be legislated by public health care policies. PMID- 24161494 TI - De novo deletion of FMN2 in a girl with mild non-syndromic intellectual disability. AB - We present the case of a child with mild non-syndromic intellectual disability in whom array genomic hybridization revealed a de novo heterozygous deletion involving only one gene, FMN2. FMN2 encodes FORMIN-2, a member of the formin homology family, which is primarily expressed in the developing and mature brain, and has an important role in cytoskeletal organization and actin nucleation. A heterozygous deletion of FMN2 along with 2 other genes has been recently reported in a boy with non-syndromic intellectual disability. This report provides further support for the important role of FMN2 in brain development and cognition. PMID- 24161495 TI - Involvement of germline DDX1-MYCN duplication in inherited nephroblastoma. AB - This report concerns a 3-year-old girl with prenatal bilateral nephroblastomatosis and a family history of nephroblastoma. This girl had a chromosome 8 pericentric inversion inherited from her father. This inversion was observed in healthy individuals of the family and was absent in other individuals suffering from embryonic kidney tumor. We then supposed that another genetic anomaly predisposed her to tumorogenesis. Additional cryptic imbalances are reported in cases of apparently balanced chromosomal rearrangements with an abnormal phenotype. Array-CGH analysis showed a 569 kb duplication at 2p24.3 including the DDX1 and MYCN genes. This duplication was inherited from the patient's father who also had a nephroblastoma. A link between germline MYCN duplication and the occurrence of other embryonic cancers such as neuroblastoma has already been described. We supposed that germline DDX1-MYCN duplication could also be involved in the apparition of nephroblastomas. PMID- 24161496 TI - Lichen planus pemphigoides possibly induced by hormone therapy. PMID- 24161497 TI - Effects of low concentrations of the antiprogestin mifepristone (RU486) in adults and embryos of zebrafish (Danio rerio): 1. Reproductive and early developmental effects. AB - Effects of synthetic progestins have recently been reported in fish, but potential effects of the synthetic antiprogestin mifepristone (MIF), also called RU486, have not been studied. The present study provides first insights into reproductive effects of MIF in zebrafish in comparison to the progesterone receptor agonist, progesterone (P4). We carried out a reproductive study using breeding groups of adult zebrafish. After a 14 day pre-exposure, zebrafish were exposed for 21 days to 5, 39, 77 ng/L MIF, 25 ng/L P4 and water and solvent controls. In addition, embryos originating from exposed adult fish were continuously exposed to 3, 15, 26 ng/L MIF, and 254 ng/L P4, respectively, for 96 h post fertilization. We found a significant U-shaped increase in egg production after exposure to 5 and 77 ng/L MIF, but no effects at 25 ng/L P4. Levels of sex steroid hormones in blood plasma of adult males (11-ketotestosterone) and females (17 beta-estradiol) were not altered. In addition to an increase of mature vitellogenic oocytes in ovaries of females exposed to MIF and P4, we observed several histopathological changes in ovaries, including post-ovulatory follicles, atretic follicles and proteinaceous fluid. Male gonads showed no or less alterations and no histopathological effects. Fertility of eggs and hatching success of embryos (F1 generation) was not affected at 3-26 ng/L MIF and 254 ng/L P4, respectively. The data lead to the conclusion that trace quantities of MIF affect reproduction of zebrafish and ovaries of female zebrafish. Effects on transcriptional changes in adult and embryonic zebrafish of this study in comparison to in vitro effects are reported in the associated report (Bluthgen et al., 2013a). PMID- 24161498 TI - Novel continuous flow technology for the development of a nanostructured aprepitant formulation with improved pharmacokinetic properties. AB - The oral bioavailability of Aprepitant is limited by poor dissolution of the compound in the gastrointestinal tract which is more prominent in the fasted state resulting in significant positive food effect. Due to the low aqueous solubility of the active substance the product development has been focused on decreasing the particle size of the active compound down to the submicron range in order to overcome this disadvantageous pharmacokinetic property. The marketed drug consisting of wet-milled nanocrystals exhibits significantly higher oral bioavailability in the fasted state and reduced food effect when compared to the unformulated compound. We have developed a novel process for the production of a nanostructured Aprepitant formulation in which the generation of the nanosized particles takes place at molecular level. The process relies on controlled continuous flow precipitation of the compound from its solution in the presence of stabilizers. The precise control of the production parameters (mixing geometry, flow rates, temperature, etc.) allows to tailor the physicochemical properties and biological performance of the active compound. We have prepared a novel nanostructured Aprepitant formulation using this method and compared its physicochemical and pharmacokinetic properties with the reference compound and the marketed nanoformula. We found that our method produces a stable amorphous solid form comprising novel nanostructured particles having a particle size of less than 100 nm with instantaneous redispersibility characteristics and improved apparent solubility and permeability. In vivo beagle dog pharmacokinetic studies showed that the novel formula exhibited greatly improved pharmacokinetic characteristics when compared to the reference compound, while serum blood concentrations for the nanostructured formula and the wet-milled formula were similar. The marked food effect observed for the reference compound was practically eliminated by our formulation method. These results indicate that the novel continuous flow precipitation technology is a suitable tool to prepare nanostructured formulations with similar, or even superior in vitro and in vivo characteristics when compared to the industrial standard milling technology. PMID- 24161499 TI - Editorial comment. PMID- 24161500 TI - Reply by authors. PMID- 24161501 TI - Chitosan-DNA complexes: charge inversion and DNA condensation. AB - The design of biocompatible polyelectrolyte complexes is a promising strategy for in vivo delivery of biologically active macromolecules. Particularly, the condensation of DNA by polycations received considerable attention for its potential in gene delivery applications, where the development of safe and effective non-viral vectors remains a central challenge. Among polymeric polycations, Chitosan has recently emerged as a very interesting material for these applications. In this study, we compare the observed aggregation behavior of Chitosan-DNA complexes with the predictions of existing models for the complexation of oppositely charged polyelectrolytes. By using different and complementary microscopy approaches (AFM, FESEM and TEM), light scattering and electrophoretic mobility techniques, we characterized the structures of the complexes formed at different charge ratios and Chitosan molecular weight. In good agreement with theoretical predictions, a reentrant condensation, accompanied by charge inversion, is clearly observed as the polycation/DNA charge ratio is increased. In fact, the aggregates reach their maximum size in correspondence of a value of the charge ratio where their measured net charge inverts its sign. This value does not correspond to the stoichiometric 1:1 charge ratio, but is inversely correlated with the polycation length. Distinctive "tadpole-like" aggregates are observed in excess polycation, while only globular aggregates are found in excess DNA. Close to the isoelectric point, elongated fiber-like structures appear. Within the framework of the models discussed, different apparently uncorrelated observations reported in the literature find a systematic interpretation. These results suggest that these models are useful tools to guide the design of new and more efficient polycation-based vectors for a more effective delivery of genetic material. PMID- 24161502 TI - Synthesis and characterization of biocatalytic gamma-Fe2O3@SiO2 particles as recoverable bioreactors. AB - In this work, we present a suitable methodology to produce magnetically recoverable bioreactors based on enzymes, which are covalently attached on the surface of iron oxide@silica nanoparticles. In order to produce this system, iron oxide clusters with a mean diameter of 68 nm were covered with silica. This strategy yields spherical gamma-Fe2O3@SiO2 cluster@shell nanoparticles with a mean diameter of 200 nm which present magnetic responsiveness and enhanced stability. The surface of these nanoparticles was modified into two steps with the aim to obtain carboxylic functional groups, which were activated to react with the enzyme glucose oxidase (GOx) that was thus immobilized on the surface of the nanoparticles. The objective of this chemistry at the nanoparticles interface is to produce magnetic-responsive bioreactors. The enzymatic activity was evaluated by using the recoverable bioreactors as part of an amperometric biosensor. These measurements allowed determining the stability, catalytic activity and the amount of enzyme immobilized on the surface of the nanoparticles. Furthermore, the functionalized nanoparticles can be recovered by applying an external magnetic field, which allows them to be employed in chemical processes where the recovery of the biocatalyst is important. PMID- 24161503 TI - Preparation of lotus-leaf-like structured blood compatible poly(epsilon caprolactone)-block-poly(L-lactic acid) copolymer film surfaces. AB - Lotus-leaf-like structured poly(epsilon-caprolactone)-block-poly(L-lactic acid) copolymer (PCL-b-PLLA) films cast using the solvent-nonsolvent casting method. PCL-b-PLLA was synthesized by the well-known copolymerization process, and was confirmed by (1)H NMR analysis. The molecular weight of the synthesized PCL-b PLLA was measured by gel permeation chromatography (GPC). The number-average (Mn), weight-average (Mw) molecular weights and polydispersity (Mw/Mn) were 3.9*10(4), 5.1*10(4), and 1.3, respectively. PCL-b-PLLA films were cast in vacuum conditions with various nonsolvent ratios. Tetrahydrofuran (THF) was used as solvent and ethanol was used as nonsolvent. Surface hydrophobicity was confirmed by the water contact angle. The water contact angle was increased from 90.9 degrees +/-4.2 degrees to 130.2 degrees +/-3.6 degrees . Water contact angle was found to be influenced by surface topography. The prepared film surfaces were characterized by scanning electron microscopy (SEM). Changes in crystalline property were characterized by X-ray diffraction (XRD). Platelet adhesion tests of the modified PCL-b-PLLA film surfaces were evaluated by platelet-rich plasma (PRP) and whole blood. Cell adhesive behavior on the modified film surfaces was evaluated by fibroblast cell culture. The prepared lotus-leaf-like structured film surfaces exhibited reduced platelet adhesion and an increased fibroblast cell proliferation ratio. PMID- 24161504 TI - Carbopol gel containing chitosan-egg albumin nanoparticles for transdermal aceclofenac delivery. AB - In the present work, various aceclofenac-loaded chitosan-egg albumin nanoparticles were prepared through heat coagulation method. These aceclofenac loaded nanoparticles were characterized by FE-SEM, FTIR, DSC and P-XRD analyses. The in vitro drug release from nanoparticles showed sustained drug release over 8h. Aceclofenac-loaded nanoparticles (prepared using 200mg chitosan, 500 mg egg albumin and 2% (w/v) NaTPP) showed highest drug entrapment (96.32+/-1.52%), 352.90 nm average particle diameter and -22.10 mV zeta potential, which was used for further preparation of Carbopol 940 gel for transdermal application. The prepared gel exhibited sustained ex vivo permeation of aceclofenac over 8h through excised mouse skin. The in vivo anti-inflammatory activity in carrageenean-induced rats demonstrated comparative higher inhibition of swelling of rat paw edema by the prepared gel compared with that of the marketed aceclofenac gel over 4 h. PMID- 24161505 TI - Studies on surface coating of phospholipid vesicles with a non-ionic polymer. AB - Liposomes coated with polymers may have a great potential in drug delivery. In this study, adsorption of the non-ionic hydroxyethyl cellulose (HEC) onto non charged phospholipid vesicles was investigated. Both unmodified and hydrophobically modified (HM) HEC were included in the study. Possible interactions between the liposomes and the polymers were determined by changes in the size and the size distribution. Rheo-SALS measurements were carried out to verify the successfulness of the coating process. The stability was investigated by zeta potential measurements, UV-analysis and HPTLC. Mixing unmodified HEC (Mw 90,000 and 300,000) with the liposomes yielded no increase in the particle size. HM-HEC, however, was adsorbed onto both the fluid phase egg-PC liposomes and the gel phase DPPC liposomes. The Rheo-SALS measurements confirmed the successful coating of the liposomes. Complete coating resulted in increased chemical stability of the dispersion and in addition prevented aggregation. This study has shown that the non-ionic HM-HEC can be used to form polymer coated liposomes with neutral surface charge for enhanced stability. PMID- 24161506 TI - Interaction of O-acylated chitosans with biomembrane models: probing the effects from hydrophobic interactions and hydrogen bonding. AB - One of the major challenges in establishing the mechanisms responsible for the chitosan action in biomedical applications lies in the determination of the molecular-level interactions with the cell membrane. In this study, we probed hydrophobic interactions and H-bonding in experiments with O,O'-diacetylchitosan (DACT) and O,O'-dipropionylchitosan (DPPCT) incorporated into monolayers of distinct phospholipids, the zwitterionic dipalmitoyl phosphatidyl choline (DPPC), and the negatively charged dipalmitoyl phosphatidyl glycerol (DPPG) and dimyristoyl phosphatidic acid (DMPA). The importance of hydrophobic interactions was confirmed with the larger effects observed for DACT and DPPCT than for parent chitosan (Chi), particularly for the more hydrophobic DPPCT. Such larger effects were noted in surface pressure isotherms and elasticity of the monolayers. Since H-bonding is hampered for the chitosan derivatives, which have part of their hydroxyl groups shielded by O-acylation, these effects indicate that H-bonding does not play an important role in the chitosan-membrane interactions. Using polarization-modulated infrared reflection absorption (PM-IRRAS) spectroscopy, we found that the chitosan derivatives were incorporated into the hydrophobic chain of the phospholipids, even at high surface pressures comparable to those in a real cell membrane. Taken together, these results indicate that the chitosan derivatives containing hydrophobic moieties would probably be more efficient than parent chitosan as antimicrobial agents, where interaction with the cell membrane is crucial. PMID- 24161507 TI - Plasma treated polyethylene terephthalate/polypropylene films assembled with chitosan and various preservatives for antimicrobial food packaging. AB - In this study, polyethylene terephthalate/polypropylene (PET/PP) films were treated via atmospheric pressure plasma, assembled with chitosan and various preservatives and applied for antimicrobial food packaging. Surface properties of these obtained films were studied by contact angle measurement, atomic force microscopy (ATM), X-ray photoelectron spectroscopy (XPS), Fourier transformed infrared spectroscopy (FT-IR) and dynamic laser scattering (DLS). The above results showed that the surface hydrophilicity and roughness of the films increased after the plasma treatment. Besides, chitosan and the preservatives were successfully assembled onto the surface of the films. In addition, the antimicrobial activities of the films against three kinds of microorganisms (Staphylococcus aureus, Bacillus subtilis and Escherichia coli) were investigated and the results indicated that the inhibition ratios against B. subtilis and E. coli reached almost 100% while the inhibition ratios against S. aureus were lower than 85%. Moreover, the accumulative release profiles of the antimicrobial substances migrating from the assembled films into the release solutions revealed that their release speed increased with the increment of temperature and acidity, but decreased with enhancing the ionic strength regulated by sodium chloride or with lowering the ionic mobility regulated by sucrose. PMID- 24161508 TI - Aspartic acid incorporated monolithic columns for affinity glycoprotein purification. AB - Novel aspartic acid incorporated monolithic columns were prepared to efficiently affinity purify immunoglobulin G (IgG) from human plasma. The monolithic columns were synthesised in a stainless steel HPLC column (20 cm * 5 mm id) by in situ bulk polymerisation of N-methacryloyl-L-aspartic acid (MAAsp), a polymerisable derivative of L-aspartic acid, and 2-hydroxyethyl methacrylate (HEMA). Monolithic columns [poly(2-hydroxyethyl methacrylate-N-methacryloyl-L-aspartic acid) (PHEMAsp)] were characterised by swelling studies, Fourier transform infrared spectroscopy (FTIR) and scanning electron microscopy (SEM). The monolithic columns were used for IgG adsorption/desorption from aqueous solutions and human plasma. The IgG adsorption depended on the buffer type, and the maximum IgG adsorption from aqueous solution in phosphate buffer was 0.085 mg/g at pH 6.0. The monolithic columns allowed for one-step IgG purification with a negligible capacity decrease after ten adsorption-desorption cycles. PMID- 24161510 TI - A paucity of data, not robust scientific evidence: a response to Johnston and Foreyt. PMID- 24161511 TI - Proteomic analysis at the subcellular level for host targets against influenza A virus (H1N1). AB - Influenza viruses (IVs) trigger a series of intracellular signaling events and induce complex cellular responses from the infected host cell. Accumulating evidence suggests that host cell proteins play an essential role in viral propagation and represent novel antiviral therapeutic targets. Subcellular proteomic technology provides a method for understanding regional differences at the protein level. The present study, which utilized subcellular proteomic technology, aimed to identify host cell proteins involved in influenza virus (HIN1) infection. Two-dimensional gel electrophoresis (2-DE) combined with mass spectrum (MS) was performed on protein extracts from the nuclei, cytoplasm, and mitochondria of infected and control human lung epithelial cells (A549). In total, 112 differentially expressed protein molecules were identified; 80 protein spots were successfully validated using MS. The differential expression of ISG15, MIF, PDCD5, and UCHL1 was confirmed by western blot. Furthermore, antisense oligodeoxyribonucleotide (ODN) targeting ISG15, MIF, PDCD5, and UCHL1 significantly mitigated HIN1 propagation, cytopathic effects, vRNA by RT-qPCR, and rescued cell viability in A549 cells. Taken together, the differentially expressed proteins identified in this study might provide novel targets for anti influenza drug development. PMID- 24161509 TI - The role of TDP1 and APTX in mitochondrial DNA repair. AB - In recent years, our knowledge surrounding mammalian mitochondrial DNA (mtDNA) damage and repair has increased significantly. Greater insights into the factors that govern mtDNA repair are being elucidated, thus contributing to an increase in our understanding year on year. In this short review two enzymes, tyrosyl-DNA phosphodiesterase 1 (TDP1) and aprataxin (APTX), involved in mitochondrial single strand break repair (SSBR) are discussed. The background into the identification of these enzymes in mtDNA repair is communicated with further deliberation into some of the specifics relating to the import of these enzymes into the mitochondrion. With the discovery of these enzymes in mitochondria comes the probability that other mechanisms underlying mtDNA repair are yet to be fully understood, suggesting there is much left to discover when shaping our understanding of this relatively undefined subject. PMID- 24161512 TI - Nuclear import and export inhibitors alter capsid protein distribution in mammalian cells and reduce Venezuelan Equine Encephalitis Virus replication. AB - Targeting host responses to invading viruses has been the focus of recent antiviral research. Venezuelan Equine Encephalitis Virus (VEEV) is able to modulate host transcription and block nuclear trafficking at least partially due to its capsid protein forming a complex with the host proteins importin alpha/beta1 and CRM1. We hypothesized that disrupting the interaction of capsid with importin alpha/beta1 or the interaction of capsid with CRM1 would alter capsid localization, thereby lowering viral titers in vitro. siRNA mediated knockdown of importin alpha, importin beta1, and CRM1 altered capsid localization, confirming their role in modulating capsid trafficking. Mifepristone and ivermectin, inhibitors of importin alpha/beta-mediated import, were able to reduce nuclear-associated capsid, while leptomycin B, a potent CRM1 inhibitor, confined capsid to the nucleus. In addition to altering the level and distribution of capsid, the three inhibitors were able to reduce viral titers in a relevant mammalian cell line with varying degrees of efficacy. The inhibitors were also able to reduce the cytopathic effects associated with VEEV infection, hinting that nuclear import inhibitors may be protecting cells from apoptosis in addition to disrupting the function of an essential viral protein. Our results confirm that VEEV uses host importins and exportins during part of its life cycle. Further, it suggests that temporarily targeting host proteins that are hijacked for use by viruses is a viable antiviral therapy. PMID- 24161513 TI - Attenuated pain response of obese mice (B6.Cg-lep(ob)) is affected by aging and leptin but not sex. AB - Genetically obese mice (B6.Cg-lep(ob)) manifest decreased responses to noxious thermal stimuli (hotplate test) suggesting endogenous analgesia (Roy et al., 1981). To examine further the analgesic response of these mice, we conducted 4 experiments. Experiment 1 assessed the response of ob/ob mice to tail flick, another noxious thermal test. Tail-flick testing was performed on B6.Cg-lep(ob) mice (n=14) and B6.Cg-lep(OB/?) (n=12) across a range of temperatures. Ob/ob mice exhibited longer latencies than control mice at all temperatures tested. In Experiment 2, potential sex differences were examined. Tail-flick latencies in male and female ob/ob mice (n=6/group) did not differ. The final 2 experiments examined factors that could modulate endogenous analgesia. Experiment 3 assessed the effects of aging in ob/ob mice (n=10/group). Older mice displayed longer tail flick latencies than did younger mice. Experiment 4 examined the effect of leptin administration in the leptin-deficient ob/ob mice. Two groups (n=10/group) of ob/ob mice received osmotic pump implants filled with either leptin or vehicle, and were tail-flick tested at days 7 and 14 post-implantation. Ob/ob mice receiving leptin showed shorter latencies than did vehicle-receiving ob/ob mice. Taken together, these results support earlier reports of heightened analgesia in ob/ob mice and suggest that aging further reduces the already impaired pain response. Furthermore, leptin deficiency partially contributes to decreased pain sensation of ob/ob mice. PMID- 24161514 TI - Transmission of stress between cagemates: a study in rats. AB - The neuroendocrine responses triggered by stressors cause significant behavioral changes in animals. Considering the continuous behavioral interaction between social animals, it would be reasonable to suggest that the aforementioned behavioral changes can lead to transmission of stress between individuals. In the present study the aim is to investigate the outcomes of the behavioral interaction between stressed and unstressed animals housed together. A total of 28 adult male Wistar rats were used in the study. The animals were randomly allocated to four groups. Two of the groups were exposed to white noise stress in a period of 15days, while the other two groups remained unstressed. One of the stress exposed groups served as the stress control (SC) group and one of the non stressed groups served as the reference value (RV) group. The remaining two groups were transmission groups. Every two animals of the non-stressed transmission group (TC) have been housed with two other animals of the stress exposed transmission group (TS) during the experimental period. After the stress exposure period, six animals from each group were subjected to behavioral assessment in an elevated plus maze (EPM), and subsequently, their cortisol levels were determined. White noise exposure of animals in the SC group induced a stress response indicated by an 1.8 fold increase of plasma cortisol level compared to the RV group (2.11+/-0.43 and 1.16+/-0,02, respectively). The transmission groups (TS and TC) entered the open arms more frequently and spent more time in open arms compared to the RV group. White noise exposure caused a stress response characterized by an elevation of cortisol level in rats. The gradual decrease of cortisol level from the SC towards the RV group may be interpreted as an evidence supporting the hypothesis of stress-transmission between cagemates. The moderate stress levels of the transmission groups, but not low and high levels of the SC and RV groups, decreased the anxiety-like behavior, which indicates an inverted U-shaped relationship between stress levels and anxiolytic effectiveness. PMID- 24161515 TI - Pilocarpine-induced epilepsy in mice alters seizure thresholds and the efficacy of antiepileptic drugs in the 6-Hertz psychomotor seizure model. AB - The 6-Hz psychomotor seizure model in mice is increasingly been used as a model for differentiation of anticonvulsant activity during development of new antiepileptic drugs (AEDs). It was previously proposed as a useful model of AED resistant seizures, but more recent data have cast doubt on this proposal. The aim of the present study was to determine whether performing the 6-Hz test not in normal but epileptic mice renders the 6-Hz test more resistant to AEDs. Furthermore, thresholds for induction of 6-Hz seizures, maximal electroshock seizures (MES) and pentylenetetrazole (PTZ) seizures were compared in normal and epileptic mice, using the pilocarpine model. Epileptic mice had a significantly lower threshold for induction of 6-Hz seizures and were more susceptible to PTZ, whereas the MES threshold was not altered. Unexpectedly, 6-Hz seizures were not more resistant to AEDs in epileptic vs. nonepileptic mice, but instead showed an increased sensitivity to the anticonvulsant effects of some AEDs, particularly levetiracetam. The anticonvulsant ED50 of levetiracetam in the 6-Hz test (using a 32mA stimulus) was 17.6mg/kg in nonepileptic mice, but only 1.5mg/kg in epileptic mice. The data indicate that the complex pathophysiological and functional alterations associated with epilepsy in mice may strikingly alter the sensitivity of acutely induced seizures to an AED. PMID- 24161517 TI - [Awake craniotomy for surgical resection of a recurrent astrocytoma located in an eloquent brain area in a case of bilingualism]. PMID- 24161516 TI - Marginal and internal fit of heat pressed versus CAD/CAM fabricated all-ceramic onlays after exposure to thermo-mechanical fatigue. AB - OBJECTIVES: The aim of the study was to evaluate the marginal and internal fit of heat-pressed and CAD/CAM fabricated all-ceramic onlays before and after luting as well as after thermo-mechanical fatigue. MATERIALS AND METHODS: Seventy-two caries-free, extracted human mandibular molars were randomly divided into three groups (n=24/group). All teeth received an onlay preparation with a mesio occlusal-distal inlay cavity and an occlusal reduction of all cusps. Teeth were restored with heat-pressed IPS-e.max-Press* (IP, *Ivoclar-Vivadent) and Vita-PM9 (VP, Vita-Zahnfabrik) as well as CAD/CAM fabricated IPS-e.max-CAD* (IC, Cerec 3D/InLab/Sirona) all-ceramic materials. After cementation with a dual polymerising resin cement (VariolinkII*), all restorations were subjected to mouth-motion fatigue (98 N, 1.2 million cycles; 5 degrees C/55 degrees C). Marginal fit discrepancies were examined on epoxy replicas before and after luting as well as after fatigue at 200* magnification. Internal fit was evaluated by multiple sectioning technique. For the statistical analysis, a linear model was fitted with accounting for repeated measurements. RESULTS: Adhesive cementation of onlays resulted in significantly increased marginal gap values in all groups, whereas thermo-mechanical fatigue had no effect. Marginal gap values of all test groups were equal after fatigue exposure. Internal discrepancies of CAD/CAM fabricated restorations were significantly higher than both press manufactured onlays. CONCLUSIONS: Mean marginal gap values of the investigated onlays before and after luting as well as after fatigue were within the clinically acceptable range. Marginal fit was not affected by the investigated heat-press versus CAD/CAM fabrication technique. Press fabrication resulted in a superior internal fit of onlays as compared to the CAD/CAM technique. CLINICAL RELEVANCE: Clinical requirements of 100 MUm for marginal fit were fulfilled by the heat-press as well as by the CAD/CAM fabricated all-ceramic onlays. Superior internal fit was observed with the heat-press manufacturing method. The impact of present findings on the clinical long-term behaviour of differently fabricated all-ceramic onlays warrants further investigation. PMID- 24161518 TI - [Ultrasound-guided axillary block: anatomical variations of terminal branches of the brachial plexus in relation to the brachial artery]. AB - OBJECTIVES: To describe the distribution of the terminal branches of the brachial plexus at the axillary level and define distribution patterns after ultrasound evaluation. MATERIAL AND METHOD: Fifty volunteers underwent ultrasound bilateral axillary brachial plexus scanning exploration. Nerve distribution around the humeral artery was described and the distance between each nerve and the center of the artery was measured. The distance and relationship between the ulnar nerve and the humeral vein were also recorded. RESULTS: The median nerve was located in the anterolateral quadrant (-29+/-40 degrees ) and at a mean distance of 2.1+/ 0.9mm from the artery (85%). The ulnar nerve was found at 53+/-26 degrees and at 4.2+/-2.1mm from the artery in the anteromedial quadrant (90%), anterolateral to the vein in 46% of cases, and deep to it in 54%. The radial nerve was at 122+/-38 degrees and at 3.3+/-1.7mm from the artery in the posteromedial quadrant (86%). The musculocutaneous nerve was found at -103+/-22 degrees and 9.3+/-5.6mm from the artery in the posterolateral quadrant (90%) and in the anterolateral quadrant (-55+/-16 degrees ) at 4.8+/-2.7mm (10%). There were no differences regarding laterality, gender or overweight patients. CONCLUSIONS: Our results allow defining four different anatomical patterns, two based in the position of the musculocutaneous nerve and two based on the disposition of the ulnar nerve with respect to the humeral vein. These patterns were not related to laterality, gender or body weight. PMID- 24161519 TI - Simple and sensitive colorimetric sensors for the selective detection of Cu2+ in aqueous buffer. AB - Simple chromogenic sensor for the selective detection of Cu(2+) was described. With the addition of Cu(2+), a bathochromic shift about 82 nm was observed in the UV-VIS spectra, with the color change from colorless to bright yellow. This suggested that the coordination between receptor and Cu(2+) was formed, and the strong push-pull system occurred. The followed IR spectra indicated that Cu(2+) coordinated to the two phenolic oxygen atoms and one of two azomethines in the receptor. PMID- 24161520 TI - Early changes in the pupal transcriptome of the flesh fly Sarcophagha crassipalpis to parasitization by the ectoparasitic wasp, Nasonia vitripennis. AB - We investigated changes in the pupal transcriptome of the flesh fly Sarcophaga crassipalpis, 3 and 25 h after parasitization by the ectoparasitoid wasp, Nasonia vitripennis. These time points are prior to hatching of the wasp eggs, thus the results document host responses to venom injection, rather than feeding by the wasp larvae. Only a single gene appeared to be differentially expressed 3 h after parasitization. However, by 25 h, 128 genes were differentially expressed and expression patterns of a subsample of these genes were verified using RT-qPCR. Among the responsive genes were clusters of genes that altered the fly's metabolism, development, induced immune responses, elicited detoxification responses, and promoted programmed cell death. Envenomation thus clearly alters the metabolic landscape and developmental fate of the fly host prior to subsequent penetration of the pupal cuticle by the wasp larva. Overall, this study provides new insights into the specific action of ectoparasitoid venoms. PMID- 24161521 TI - Interface pressure in transtibial socket during ascent and descent on stairs and its effect on patient satisfaction. AB - BACKGROUND: Transtibial amputees encounter stairs and steps during their daily activities. The excessive pressure between residual limb/socket may reduce the walking capability of transtibial prosthetic users during ascent and descent on stairs. The purposes of the research were to evaluate the interface pressure between Dermo (shuttle lock) and Seal-In X5 (prosthetic valve) interface systems during stair ascent and descent, and to determine their satisfaction effects on users. METHODS: Ten amputees with unilateral transtibial amputation participated in the study. Interface pressure was recorded with F-socket transducer (9811E) during stair ascent and descent at self-selected speed. Each participant filled in a questionnaire about satisfaction and problems encountered with the use of the two interface systems. FINDINGS: The resultant mean peak pressure (kPa) was significantly lower for the Dermo interface system compared to that of the Seal In X5 interface system at the anterior, posterior and medial regions during stair ascent (63.14 vs. 80.14, 63.14 vs. 90.44, 49.21 vs. 66.04, respectively) and descent (67.11 vs. 80.41, 64.12 vs. 88.24, 47.33 vs. 65.11, respectively). Significant statistical difference existed between the two interface systems in terms of satisfaction and problems encountered (P<0.05). INTERPRETATION: The Dermo interface system caused less pressure within the prosthetic socket compared to the Seal-In X5 interface system during stair negotiation. The qualitative survey also showed that the prosthesis users experienced fewer problems and increased satisfaction with the Dermo interface system. PMID- 24161522 TI - Primary stability of unicompartmental knee arthroplasty under dynamic compression shear loading in human tibiae. AB - BACKGROUND: The objective of our study was to evaluate the impact of a single- ("implant only") versus a double-layer ("implant & bone") cementing technique on the primary stability of unicompartmental tibial plateaus under dynamic compression-shear loading conditions in human tibiae. METHODS: Twelve fresh frozen human knees of a mean donor age of 72.3 years were used to perform medial UKA under a less invasive parapatellar surgical approach. The tibiae were divided into two groups of matched pairs based on comparable trabecular bone mineral density. To assess the primary stability, a new method based on a combination of dynamic compression-shear testing, kinematic analysis of the tibial plateau migration relative to the bone and evaluation of the cement layer by CT-scans and fragments cut through the implant-cement-bone interface in the frontal plane was introduced. FINDINGS: For the "implant only" cementation technique the mean load to failure was 2600 (SD 675) N and for "implant & bone" it was 2820 (SD 915) N. Between the final load level at failure and the bone mineral density a significant correlation was found for the groups "implant only" (r(s) = 0.875) and "implant & bone" (r(s) = 0.907). INTERPRETATION: From our observations, we conclude that there is no significant difference between a single- ("implant only") and double-layer ("implant & bone") cementing technique in the effect on the primary stability of unicompartmental tibia plateaus, in terms of failure load, correlation between final load at failure and bone mineral density, migration characteristics, cement layer thickness and penetration depth. PMID- 24161524 TI - In-line monitoring of thermal degradation of PHA during melt-processing by Near Infrared spectroscopy. AB - Polyhydroxyalkanoate (PHA) biopolymer processing is often challenged by low thermal stability, meaning that the temperatures and time for which these polymers can be processed is restrictive. Considering the sensitivity of PHA to processing conditions, there is a demand for in-line monitoring of the material behaviour in the melt. This paper investigates the application of Near-Infrared (NIR) spectroscopy for monitoring the thermal degradation of PHAs during melt processing. Two types of materials were tested: two mixed culture PHAs extracted from biomass produced in laboratory and pilot scale after an acidic pre treatment, and two commercially available materials derived from pure culture production systems. Thermal degradation studies were carried out in a laboratory scale extruder with conical twin screws connected to a NIR spectrometer by a fibre optic to allow in situ monitoring. Multivariate data analysis methods were applied for assessing thermal degradation kinetics and predicted the degree of degradation as measured by (1)H NMR (proton nuclear magnetic resonance spectroscopy). The pre-treated mixed culture PHAs were found to be more thermally stable when compared with the commercial pure culture PHAs as demonstrated by NIR, (1)H NMR and GPC (gel permeation chromatography). PMID- 24161523 TI - Forward genetics defines Xylt1 as a key, conserved regulator of early chondrocyte maturation and skeletal length. AB - The long bones of the vertebrate body are built by the initial formation of a cartilage template that is later replaced by mineralized bone. The proliferation and maturation of the skeletal precursor cells (chondrocytes) within the cartilage template and their replacement by bone is a highly coordinated process which, if misregulated, can lead to a number of defects including dwarfism and other skeletal deformities. This is exemplified by the fact that abnormal bone development is one of the most common types of human birth defects. Yet, many of the factors that initiate and regulate chondrocyte maturation are not known. We identified a recessive dwarf mouse mutant (pug) from an N-ethyl-N-nitrosourea (ENU) mutagenesis screen. pug mutant skeletal elements are patterned normally during development, but display a ~20% length reduction compared to wild-type embryos. We show that the pug mutation does not lead to changes in chondrocyte proliferation but instead promotes premature maturation and early ossification, which ultimately leads to disproportionate dwarfism. Using sequence capture and high-throughput sequencing, we identified a missense mutation in the Xylosyltransferase 1 (Xylt1) gene in pug mutants. Xylosyltransferases catalyze the initial step in glycosaminoglycan (GAG) chain addition to proteoglycan core proteins, and these modifications are essential for normal proteoglycan function. We show that the pug mutation disrupts Xylt1 activity and subcellular localization, leading to a reduction in GAG chains in pug mutants. The pug mutant serves as a novel model for mammalian dwarfism and identifies a key role for proteoglycan modification in the initiation of chondrocyte maturation. PMID- 24161525 TI - Combination of paclitaxel, cisplatin, and gemcitabine (TPG) for multiple relapses or platinum-resistant germ cell tumors: long-term outcomes. AB - BACKGROUND: Rescue of patients who fail to be cured after 2 or 3 chemotherapy combinations (including high-dose chemotherapy [HDCT]) or whose disease is refractory to cisplatin is still an unmet need. We assessed the efficacy of a triple-combination chemotherapy in the salvage setting, beyond second-line regimens. PATIENTS AND METHODS: We retrospectively reviewed institutional data on consecutive patients who received paclitaxel 80 mg/m(2) intravenously (IV), cisplatin 50 mg/m(2) IV, and gemcitabine 800 mg/m(2) IV on days 1 and 8 every 3 weeks for a maximum of 8 administrations, followed by surgery. Response, survival (progression-free survival [PFS] and overall survival [OS]), and safety/toxicity outcomes were the end points. The Kaplan-Meier method was used for survival estimates, and multiple Cox regression models were used to analyze the prognostic factors. RESULTS: Seventy-five patients were treated from April 1999 to July 2011. Eight complete responses (CR, 10.7%), 29 partial responses with normal markers (PRm(-), 38.7%), and 13 cases of incomplete response/stable disease were recorded, for a major response rate (CR + PRm(-)) of 49%. Thirty-three patients (44%) underwent surgery, which was radical in 14 cases (42.4%). Two-year PFS was 14.8% (95% confidence interval [CI], 8.5%-25.8%), whereas 2-year OS was 29.5% (95% CI, 20.3%-42.7%). Five-year OS in disease-free patients (no evidence of disease) was 60.3% (95% CI, 42.2%-86.2%), and median OS between patients with and without evidence of disease was significantly different (71 [interquartile range {IQR}, 14-116] vs. 12.5 [IQR, 8-19] months with a 6-month landmark analysis; P = .0019). CONCLUSION: TPG is an effective combination, and best results were achieved if a radical clearance of residual disease could be accomplished. A randomized comparison with dose-intensified regimens is advisable. PMID- 24161526 TI - A sensitive quartz crystal microbalance assay of adenosine triphosphate via DNAzyme-activated and aptamer-based target-triggering circular amplification. AB - In this work, a simple and novel quartz crystal microbalance (QCM) assay is demonstrated to selectively and sensitively detect the adenosine triphosphate (ATP). The amplification process consists of circular nucleic acid strand displacement polymerization, aptamer recognition strategy and nanoparticle signal amplification. With the involvement of an aptamer-based complex, two amplification reaction templates and AuNP-functionalized probes, the whole circle amplification process is triggered by the target recognition of ATP. As an efficient mass amplifier, AuNP-functionalized probes are introduced to enhance the QCM signals. As a result of DNA multiple amplification, a large number of AuNP-functionalized probes are released and hybridized with the capture probes on the gold electrode. Therefore the QCM signals are significantly enhanced, reaching a detection limit of ATP as low as 1.3 nM. This strategy can be conveniently used for any aptamer-target binding events with other biological detection such as protein and small molecules. Moreover, the practical determination of ATP in cancer cells demonstrates the feasibility of this QCM approach and potential application in clinical diagnostics. PMID- 24161527 TI - [Lupus nephropathy in black patients with systemic lupus erythematosus in Senegal: 43 cases]. AB - This study sought to assess the prevalence of lupus nephropathy and to determine its clinical, histological, therapeutic and outcome profiles. PATIENTS AND METHODS: This retrospective study examined records covering a 10-year period from 1999 to 2009 at the nephrology department of the Aristide Le Dantec University Hospital Center. RESULTS: The records showed 43 patients with systemic lupus erythematosus (SLE), and 72% had lupus nephritis. The patients' mean age was 32.9 years; 40 were women and 3 men, for a sex ratio of 0.075. The lupus nephritis led to discovery of SLE in 27.9%. The mean proteinuria concentration was 2.01 g/dL. Seventeen patients had impaired renal function, and 26 had renal biopsies. It found class II nephritis in 2 patients, class IV in 10, and class V in 12. In addition, fifteen patients received combined corticosteroid + immunosuppressant treatment. Four patients died during the study period, one from SLE activity, two from complications of renal failure, and the fourth from sepsis. CONCLUSION: A larger study would be useful to assess more acurately the prevalence of various classes and severity of lupus nephropathy among blacks living in sub-Saharan Africa. PMID- 24161528 TI - [Relations between ethnicity and child malnutrition in rural Benin]. AB - Relations between ethnicity and child malnutrition in rural Benin. RATIONALE: In a therapeutic feeding center in northern Benin, we found disparities between the three main ethnic groups in the proportions of children hospitalized; undernutrition seemed more frequent and severe in the Gando than in the Bariba and the Fulani groups. This survey sought to identify risk factors for malnutrition. METHODS: We used a standardized questionnaire to interview women from these three groups, all with a child aged 5 years or younger. RESULTS: The study included 165 mothers from the three main ethnic groups, 62 of whom had weaned a child. Children from the Bariba group seemed to have access to better sanitary and nutritional conditions than those from the Gando and Fulani groups: higher quality water (from boreholes), more frequent access to latrines, higher usage of bed nets, higher likelihood of birth in a medicalized environment, early breastfeeding, and progressive and voluntary weaning. During and after weaning, children from the Fulani group received more milk-based food than the other groups. In the Fulani group, therefore, the supply of milk of animal origin may compensate for some less favorable practices related to childbirth and breastfeeding. CONCLUSION: We identified several factors, probably influenced by socioeconomic and cultural conditions, that probably affect child undernutrition. Sanitary and nutritional education programs should be conducted to target specific ethnic groups of this region. PMID- 24161529 TI - Bioactive polyhydroxylated sterols from the marine sponge Haliclona crassiloba. AB - Four new polyhydroxylated sterols, named halicrasterols A-D (1-4), together with six known analogs (5-10) were isolated from the marine sponge Haliclona crassiloba. Compounds 1 and 2 represented rare examples of steroids featuring 17(20)E-double bonds. The structures of 1-10 were elucidated by spectroscopic analysis and comparison with reported data. This is the first report of a steroid profile for this species. The antimicrobial activities of 1-10 were evaluated against a panel of bacterial and fungal strains in vitro, and compounds 4 and 9 showed moderate activity against some of the Gram-positive strains with MICs ranging from 4 to 32 MUg/mL. PMID- 24161530 TI - Graphene-based nanomaterials for drug delivery and tissue engineering. AB - Nanomaterials offer interesting physicochemical and biological properties for biomedical applications due to their small size, large surface area and ability to interface/interact with the cells/tissues. Graphene-based nanomaterials are fast emerging as "two-dimensional wonder materials" due to their unique structure and excellent mechanical, optical and electrical properties and have been exploited in electronics and other fields. Emerging trends show that their exceptional properties can be exploited for biomedical applications, especially in drug delivery and tissue engineering. This article presents a comprehensive review of various types and properties of graphene family nanomaterials. We further highlight how these properties are being exploited for drug delivery and tissue engineering applications. PMID- 24161531 TI - Obstructive sleep apnea and risk of cardiovascular disease and all-cause mortality: a meta-analysis of prospective cohort studies. AB - BACKGROUND: The association between obstructive sleep apnea (OSA) and the incidence of cardiovascular disease (CVD) has been examined in many studies. However, the findings are not entirely consistent across studies. Our goal was to evaluate the association between OSA and risk of CVD and all-cause mortality by performing a meta-analysis of prospective cohort studies. METHODS: We used generalized least squares regression models to estimate the dose-response relationship. Heterogeneity, subgroup, and sensitivity analyses and publication bias were performed. RESULTS: Twelve prospective cohort studies involving 25,760 participants were included in the meta-analysis. The overall combined relative risks for individuals with severe OSA compared with individuals with an AHI of <5 were 1.79 (95% confidence interval [CI]: 1.47 to 2.18) for CVD, 1.21 (95% CI: 0.75 to 1.96) for incident fatal and non-fatal coronary heart disease, 2.15 (95% CI: 1.42 to 3.24) for incident fatal and non-fatal stroke, and 1.92 (95% CI: 1.38 to 2.69) for deaths from all-causes. A positive association with CVD was observed for moderate OSA but not for mild OSA. The results of the dose-response relationship indicated that per 10-unit increase in the apnea-hypopnea index was associated with a 17% greater risk of CVD in the general population. CONCLUSIONS: This meta-analysis of prospective cohort studies suggests that severe OSA significantly increases CVD risk, stroke, and all-cause mortality. A positive association with CVD was observed for moderate OSA but not for mild OSA. PMID- 24161532 TI - The effect of off-pump coronary artery bypass on mortality after acute coronary syndrome: a meta-analysis. AB - BACKGROUND: Patients requiring surgical revascularisation for acute coronary syndrome (ACS) form a clinically heterogeneous group ranging from haemodynamic stability to cardiogenic shock. Whilst 'off-pump' revascularisation (OPCAB) is often considered, patient selection and operative timing remain controversial. This study aims to identify whether OPCAB may confer a mortality benefit over ONCAB in revascularisation for ACS. Secondly, we review the impact of OPCAB on completeness of revascularisation (CR) and long-term re-intervention. METHODS: A systematic literature review identified 9 studies (1 randomised controlled trial) of which 8 fulfilled criteria for meta-analysis. Outcomes for a total of 3001 patients (n=817 OPCAB, 2184 'on-pump' (ONCAB)) were meta-analysed using random effects modelling. Heterogeneity, subgroup analysis and quality scoring were assessed. Primary endpoints were 30-day and mid-term mortality. Secondary endpoints were CR, revascularisation index and re-intervention. RESULTS: OPCAB conferred comparable mortality to ONCAB at both 30-days and mid-term follow up (p=0.08 and p=0.46 respectively). OPCAB was also associated with less CR (WMD 0.60, 95% CI [-0.82, -0.38], p<0.00001) and a lower revascularisation index (WMD 0.25, 95% CI [-0.30, -0.19], p<0.00001), although no difference was observed in re-intervention rate (OR 1.33; 95% CI [0.99, 2.07], p=0.99). CONCLUSIONS: We conclude that OPCAB may be a safe and comparable alternative to ONCAB in clinically stable ACS patients requiring urgent/emergent revascularisation. However, in order to finally determine whether OPCAB may provide any more than just comparability to ONCAB in the setting of ACS, further research must clearly define selection criteria, better characterize this heterogeneous patient group and assess the effects of incomplete revascularisation on long-term outcomes. PMID- 24161533 TI - Direct AT2 receptor stimulation is athero-protective and stabilizes plaque in apolipoprotein E-deficient mice. AB - BACKGROUND: The angiotensin II type 2 receptor (AT2R) has been suggested to have an athero-protective role, however no studies have investigated the effect of direct stimulation of this receptor in atherosclerosis. Thus this study aimed to determine the effect of direct AT2R stimulation in setting of atherosclerosis, using the known AT2R agonist, CGP42112. METHODS AND RESULTS: Apolipoprotein E deficient (ApoE(-/-)) mice were fed a high fat (21%) diet for 16 weeks, with subcutaneous infusions of CGP42112 (1, 5 or 10 MUg/kg/min) administered via osmotic mini-pumps in the final 4 weeks. CGP42112 treatment at all doses significantly improved endothelial function (p<0.001) when compared to acetylcholine mediated-vasorelaxation in aorta taken from vehicle-treated ApoE(-/ ) mice. In aortic segments adjacent to those used for vascular reactivity studies, CGP42112 treatment at all doses concomitantly increased eNOS immunoreactivity and protein levels whilst superoxide (O2(-)) production was significantly (p<0.01) decreased compared to levels measured in aorta from vehicle-treated ApoE(-/-) mice. Moreover, CGP42112 (1 MUg/kg/min) treatment significantly attenuated (p<0.05) atherosclerotic lesion progression (assessed as both lipid deposits and luminal encroachment in thoracic aorta and aortic arch) and significantly increased plaque stability in the brachiocephalic artery, a region normally prone to rupture. Both the vaso- and athero-protective effects of CGP42112 (1 MUg/kg/min) were reversed with co-infusion of the AT2R antagonist, PD123319, but not the MasR antagonist, A779. CONCLUSION: For the first time we have shown that direct stimulation of the AT2R improves endothelial function, reduces atherosclerotic lesion progression and mediates plaque stability with these effects at least partly due to restoration of nitric oxide bioavailability. PMID- 24161534 TI - Coexistence of Leishmania tropica and Leishmania infantum in Sefrou province, Morocco. AB - Cutaneous leishmaniasis (CL) has been recently emerged in new foci, posing a public health problem. Increasing cases of CL have been reported during recent years in Sefrou province, a previously non-endemic area. The present study was designed for epidemiological and parasitological characterization of the disease for the first time in this area. The results of a retrospective analysis of CL cases reports, between 2000 and 2011 showed that the incidence was estimated to 463/100,000 inhabitants/year, with a total of 1242 cases were notified from 1997 to 2011. Most patients were infected in the sector El Menzel (22.81%) and Sefrou (20.51%). Other cases have been reported in the 15 other sectors, reflecting the geographical spread of the disease. The highest rate lesions were found in the age group of 9 years or less with significant differences (p-value<2.2e-16) comparing to the older age groups. The most affected lesion was localized in the face (64%). The average number of lesions per patient was 2.35 with a maximum of 5 lesions. The clinical aspects of lesions were mostly crusted. The causative agents of CL in this province were identified as the coexistence of L. tropica and L. infantum by species-specific ITS1-PCR-RFLP assay. CL remains an emergent disease in Sefrou with an incidence and a continuously geographical spread. Recent environmental changes, auspicious to vectors had probably contributed to that situation. PMID- 24161535 TI - Temperature dependence of Opisthorchis viverrini infection in first intermediate host snail, Bithynia siamensis goniomphalos. AB - Determining of the success of a parasite's infectiveness in its snail host clearly depends on environmental conditions. Temperature, one of the most influential factors impinging on metabolism of cold-blooded animals, is believed to be an important factor in parasitic infection in snails. In order to elucidate the influence of temperature, sex and size of snails on infectivity of Opisthorchis viverrini to its first intermediate host, Bithynia siamensis goniomphalos, 960 snails were divided into 2 groups by sex. Each group was subdivided by their size into small and medium sub-groups. Each snail was fed with embryonated uterine-eggs of O. viverrini at different temperatures (16-37 degrees C, 3 degrees C intervals). Dissections were carried out 1, 7, 14, 28 and 56 days thereafter and detection of O. viverrini infection was undertaken by PCR using specific primers. Infection was strongly temperature-dependent, as temperature increases of 1 degrees C resulted in increased odds of infection 5.4% (P<0.01). A temperature of 34 degrees C gave the highest rate of infection of 44.14%. We also found that the odds of infection in small sized snails was 39.8% higher relative to medium sized snails (P<0.05). Relative to day 1, the decrease in the odds of infection was detected when the day post infection was longer (P<0.01). Proportion of infection in female was not different to male significantly. PMID- 24161536 TI - Working memory in schizotypal personality disorder: fMRI activation and deactivation differences. AB - BACKGROUND: Schizotypal personality disorder (SPD) is considered a schizophrenia spectrum disorder, sharing with schizophrenia cognitive, neuropsychological, epidemiological, and biological characteristics. Working memory may be one area of shared deficit, although to date, this is only the second study to investigate working memory in SPD using fMRI. METHODS: In a block-design fMRI study, fifteen antipsychotic-naive SPD and sixteen healthy control subjects performed blocks of a 2back visual working memory task and 0back continuous performance task while undergoing whole-brain fMRI at 3T. Whole-brain analyses were performed for the 0back>rest (fixation baseline) and the 2back>0back contrasts (isolating the working memory component from the visual perception and attention component). Parameter estimates were extracted to determine whether observed differences were due to task-induced activation and/or deactivation. RESULTS: Activation differences emerged between the two groups, without differences in task performance. In the 0back task, SPD showed decreased task-induced activation of the left postcentral gyrus. In the 2back>0back contrast, HC showed greater task induced activation of the left posterior cingulate gyrus, superior temporal gyrus, insula, and middle frontal gyrus. These differences were due to SPD subjects' decreased task-induced activation in the left posterior cingulate gyrus, and task-induced deactivation in the remaining regions. CONCLUSIONS: These findings suggest that compared to HC subjects, individuals with SPD may achieve comparable working memory performance. However, differences emerge at the level of functional neural activation, attributable to different task-induced activation and deactivation patterns. Such differential recruitment of neural resources may be beneficial, contributing to SPD subjects' ability to perform these tasks comparably to HC subjects. PMID- 24161537 TI - Novel antibacterial peptides from the skin secretion of the Indian bicoloured frog Clinotarsus curtipes. AB - HPLC elution profile and MALDI TOF MS analysis of electro-stimulated skin secretion of the Indian Ranid frog Clinotarsus curtipes of the Western Ghats confirmed the presence of multiple peptides. Peptides eluted out of the C18 column at higher hydrophobic solvent region showed antibacterial activity against diverse bacterial strains, including the clinical isolates of V. cholerae and methicillin resistant Staphylococcus aureus (MRSA). Peptidomic analysis of the most potent chromatographic effluent fraction identified five novel peptide amides having sequence homology with brevinin family. These peptides are named as brevinin1CTcu1 (B1CTcu1) to brevinin1CTcu5 (B1CTcu5). Peptide B1CTcu1 is non haemolytic while the others are haemolytic in nature but all elicited potential antibacterial activity. B1CTcu5 is a twenty-one residue peptide amide having proline hinge region in the middle and the typical C-terminal intramolecular disulfide-bridged hepta peptide domain (Rana box) that is present in most of the brevinin peptides. Analysis of their killing kinetics with E. coli and S. aureus and the ability to induce membrane depolarization proved that these are two independent events. These novel multifunctional peptides play an important role to protect C. curtipes from invading pathogenic microorganisms present in the environment. PMID- 24161538 TI - Neurotensin-loaded collagen dressings reduce inflammation and improve wound healing in diabetic mice. AB - Impaired wound healing is an important clinical problem in diabetes mellitus and results in failure to completely heal diabetic foot ulcers (DFUs), which may lead to lower extremity amputations. In the present study, collagen based dressings were prepared to be applied as support for the delivery of neurotensin (NT), a neuropeptide that acts as an inflammatory modulator in wound healing. The performance of NT alone and NT-loaded collagen matrices to treat wounds in streptozotocin (STZ) diabetic induced mice was evaluated. Results showed that the prepared dressings were not-cytotoxic up to 72h after contact with macrophages (Raw 264.7) and human keratinocyte (HaCaT) cell lines. Moreover, those cells were shown to adhere to the collagen matrices without noticeable change in their morphology. NT-loaded collagen dressings induced faster healing (17% wound area reduction) in the early phases of wound healing in diabetic wounded mice. In addition, they also significantly reduced inflammatory cytokine expression namely, TNF-alpha (p<0.01) and IL-1beta (p<0.01) and decreased the inflammatory infiltrate at day 3 post-wounding (inflammatory phase). After complete healing, metalloproteinase 9 (MMP-9) is reduced in diabetic skin (p<0.05) which significantly increased fibroblast migration and collagen (collagen type I, alpha 2 (COL1A2) and collagen type III, alpha 1 (COL3A1)) expression and deposition. These results suggest that collagen-based dressings can be an effective support for NT release into diabetic wound enhancing the healing process. Nevertheless, a more prominent scar is observed in diabetic wounds treated with collagen when compared to the treatment with NT alone. PMID- 24161539 TI - Mutation of the human mitochondrial phenylalanine-tRNA synthetase causes infantile-onset epilepsy and cytochrome c oxidase deficiency. AB - Mitochondrial aminoacyl-tRNA synthetases (aaRSs) are essential enzymes in protein synthesis since they charge tRNAs with their cognate amino acids. Mutations in the genes encoding mitochondrial aaRSs have been associated with a wide spectrum of human mitochondrial diseases. Here we report the identification of pathogenic mutations (a partial genomic deletion and a highly conserved p. Asp325Tyr missense variant) in FARS2, the gene encoding mitochondrial phenylalanyl-tRNA synthetase, in a patient with early-onset epilepsy and isolated complex IV deficiency in muscle. The biochemical defect was expressed in myoblasts but not in fibroblasts and associated with decreased steady state levels of COXI and COXII protein and reduced steady state levels of the mt-tRNA(Phe) transcript. Functional analysis of the recombinant mutant p. Asp325Tyr FARS2 protein showed an inability to bind ATP and consequently undetectable aminoacylation activity using either bacterial tRNA or human mt-tRNA(Phe) as substrates. Lentiviral transduction of cells with wildtype FARS2 restored complex IV protein levels, confirming that the p.Asp325Tyr mutation is pathogenic, causing respiratory chain deficiency and neurological deficits on account of defective aminoacylation of mt tRNA(Phe). PMID- 24161541 TI - Clinical modeling--a critical analysis. AB - BACKGROUND: Modeling clinical processes (and their informational representation) is a prerequisite for optimally enabling and supporting high quality and safe care through information and communication technology and meaningful use of gathered information. OBJECTIVES: The paper investigates existing approaches to clinical modeling, thereby systematically analyzing the underlying principles, the consistency with and the integration opportunity to other existing or emerging projects, as well as the correctness of representing the reality of health and health services. METHODS: The analysis is performed using an architectural framework for modeling real-world systems. In addition, fundamental work on the representation of facts, relations, and processes in the clinical domain by ontologies is applied, thereby including the integration of advanced methodologies such as translational and system medicine. RESULTS: The paper demonstrates fundamental weaknesses and different maturity as well as evolutionary potential in the approaches considered. It offers a development process starting with the business domain and its ontologies, continuing with the Reference Model-Open Distributed Processing (RM-ODP) related conceptual models in the ICT ontology space, the information and the computational view, and concluding with the implementation details represented as engineering and technology view, respectively. CONCLUSION: The existing approaches reflect at different levels the clinical domain, put the main focus on different phases of the development process instead of first establishing the real business process representation and therefore enable quite differently and partially limitedly the domain experts' involvement. PMID- 24161542 TI - Editorial: Microbial source tracking. PMID- 24161540 TI - Advances in allergen-microarray technology for diagnosis and monitoring of allergy: the MeDALL allergen-chip. AB - Allergy diagnosis based on purified allergen molecules provides detailed information regarding the individual sensitization profile of allergic patients, allows monitoring of the development of allergic disease and of the effect of therapies on the immune response to individual allergen molecules. Allergen microarrays contain a large variety of allergen molecules and thus allow the simultaneous detection of allergic patients' antibody reactivity profiles towards each of the allergen molecules with only minute amounts of serum. In this article we summarize recent progress in the field of allergen microarray technology and introduce the MeDALL allergen-chip which has been developed for the specific and sensitive monitoring of IgE and IgG reactivity profiles towards more than 170 allergen molecules in sera collected in European birth cohorts. MeDALL is a European research program in which allergen microarray technology is used for the monitoring of the development of allergic disease in childhood, to draw a geographic map of the recognition of clinically relevant allergens in different populations and to establish reactivity profiles which are associated with and predict certain disease manifestations. We describe technical advances of the MeDALL allergen-chip regarding specificity, sensitivity and its ability to deliver test results which are close to in vivo reactivity. In addition, the usefulness and numerous advantages of allergen microarrays for allergy research, refined allergy diagnosis, monitoring of disease, of the effects of therapies, for improving the prescription of specific immunotherapy and for prevention are discussed. PMID- 24161544 TI - Unique considerations in renal replacement therapy in children: core curriculum 2014. PMID- 24161543 TI - Influence of resuspension on the fate of fecal indicator bacteria in large-scale flumes mimicking an oligotrophic river. AB - In this study, large-scale flume systems simulating an oligotrophic river were used to explore the fate and transport of the fecal indicator bacteria (FIB) Escherichia coli and enterococci following a combined sewer overflow (CSO). Specifically, the removal pattern of FIB from the water column was examined as well as deposition onto the flume bed. Finally, the impact that a sudden increase in bed shear stress has on FIB in the water column was investigated. The large scale flumes utilized in this study proved extremely useful for our investigations as they very closely approximated conditions within the Isar River (Munich, Germany). By using both natural substratum and fresh river water, as well as a flow velocity of nearly 1 m s(-1) at a water depth of roughly 0.5 m, shear stresses typical of the Isar River (9 N m(-2)) were achieved. As a result, scaling effects were appreciably reduced. In our flume system, UV inactivation played only a minimal role in overall FIB removal. Therefore, we were able to more precisely investigate other mechanisms which result in FIB removal from the water column. From the two standard FIB removal experiments following a CSO, the removal rate coefficient (k) of 0.2 h(-1) was identified for both E. coli and enterococci in the water column. An increase in the bed shear stress led to more than a 150% rise in total suspended solid (TSS) levels in the water column. These elevated TSS levels (~ 50 mg l(-1)) increased the persistence of suspended FIB in the water column by 20 h (k = 0.05 h(-1)). This indicates that higher TSS loads resulting from resuspended bed sediments can significantly expand the area that is impacted by a CSO event. At lower TSS loads (<20 mg l(-1)) deposition onto the flume bed did not contribute significantly to FIB removal from the water column. Any deposition which did occur did not result in a net accumulation of culturable FIB in the benthic biofilm. PMID- 24161545 TI - For this peripheral nerve lesion, it is best to avoid the knife. PMID- 24161546 TI - Advancement in atlantoaxial fixation. PMID- 24161547 TI - The enigma of external ventricular drain placement. PMID- 24161548 TI - Correlation of diffusion tensor magnetic resonance imaging metrics with clinical outcomes. PMID- 24161549 TI - Is macrocephaly a neural marker of a local bias in autism? AB - Previous research has suggested that the local processing bias often reported in studies of Autism Spectrum Condition may only be typical of a subgroup of individuals with autism also presenting with macrocephaly. The current study examined a group of children with autism, with and without macrocephaly, on the Children's Embedded Figures Test (CEFT), a well-established measure of local processing bias. The results demonstrated that the children with autism and macrocephaly performed significantly better on the CEFT than children with autism without macrocephaly, indicative of a local bias. These results lend support to the proposal that both macrocephaly in autism and a local processing bias may arise from the same underlying neural processes and these characteristics represent an endophenotype in a subgroup of individuals with ASC worthy of further investigation. PMID- 24161550 TI - Halo-alkalitolerant and thermostable cellulases with improved tolerance to ionic liquids and organic solvents from Paenibacillus tarimensis isolated from the Chott El Fejej, Sahara desert, Tunisia. AB - The wide number of industrial processes applying cellulases highlights the importance of discovering robust enzymes able to work under harsh conditions. In this study, carboxymethyl cellulase (CMCase) activity of Paenibacillus tarimensis was characterized. A high activity was observed in pH range 3.0-10.5 and 9 mM-5 M NaCl. In high salt buffer at 80 degrees C, >80% and >76% of relative activity was retained at 20% of the ionic liquids (ILs) [EMIM]Ac and [BMIM]Cl; while >40% was detected with 40% [BMIM]Cl. Five CMCases were detected by renaturing SDS-PAGE. Their activity was retained in presence of 1.7 up to 5 M NaCl (for CMC1) or 4.6 M KCl; 5% organic solvents or 10 mM bivalent ions, EDTA and heavy metals; under neutral and halo-alkaline conditions. These cellulases stabile and highly functional under harsh conditions are promising candidates for application in detergents, textiles, paper/pulp industry; and simultaneous ILs treatment saccharification of lignocellulose. PMID- 24161551 TI - Impact of the lignocellulosic material on fast pyrolysis yields and product quality. AB - The paper describes the fast pyrolysis conversion of lignocellulosic materials inside a bubbling fluidized bed. The impact of biopolymers distribution in the biomass feed, namely hemicelluloses, cellulose and lignin, on the yields and properties of pyrolytic bio-oils and chars was investigated. Although it is not possible to deconvoluate chemical phenomena from transfer phenomena using bubbling fluidized bed reactors, the key role of hemicelluloses in biomass feedstocks was illustrated by: (i) its influence on the production of pyrolytic water, (ii) its impact on the production of organics, apparently due to its bonding relationship with the lignin and (iii) its ability to inhibit the development of chars porosity, while the cellulose appeared to be the precursor for the microporous character of the biochars. These results are of interest for the selection of suitable feedstocks aimed at producing bio-oil and char as fuels and soil amendment, respectively. PMID- 24161552 TI - Thermogravimetric and kinetic analysis of thermal decomposition characteristics of low-lipid microalgae. AB - The thermal decomposition behavior of two microalgae, Chlorella pyrenoidosa (CP) and Spirulina platensis (SP), were investigated on a thermogravimetric analyzer under non-isothermal conditions. Iso-conversional Vyazovkin approach was used to calculate the kinetic parameters, and the universal integral method was applied to evaluate the most probable mechanisms for thermal degradation of the two feedstocks. The differential equations deduced from the models were compared with experimental data. For the range of conversion fraction investigated (20-80%), the thermal decomposition process of CP could be described by the reaction order model (F3), which can be calculated by the integral equation of G(alpha) = [(1 - alpha)(-2) - 1]/2. And the apparent activation energy was in the range of 58.85 114.5 kJ/mol. As for SP, it can be described by the reaction order model (F2), which can be calculated by the integral equation of G(alpha) = (1 - alpha)(-1) - 1, and the range of apparent activation energy was 74.35-140.1 kJ/mol. PMID- 24161553 TI - Direct membrane filtration of municipal wastewater with chemically enhanced backwash for recovery of organic matter. AB - Direct membrane filtration (DMF) of municipal wastewater using a microfiltration membrane was investigated to capture organic matter. In contrast to the expectation that membrane fouling cannot be controlled in DMF of domestic wastewater, it was possible to stably continue membrane filtration with relatively high membrane fluxes (~20 LMH) for >200 h by applying chemically enhanced backwash (CEB), whereas approximately 75% of the organic matter in wastewater could be recovered. Off-line chemical membrane cleaning could completely restore membrane permeability, indicating the possibility of a much longer operation of DMF. Selection of chemical reagents used for CEB was found to influence the amount of organic matter recovered by DMF. Based on the experimental results, feasibility of DMF was discussed by a comparison with a conventional wastewater treatment plant treating the same wastewater as studied in this study. PMID- 24161554 TI - The strengthening effect of a static magnetic field on activated sludge activity at low temperature. AB - The strengthening effects of static (homopolar and heteropolar) magnetic fields (MF) on microorganisms were compared in activated sludge degrading organic matter at low temperature. The TTC dehydrogenase activity improved substantially through external heteropolar MF intensification, and led to the highest COD removal rate of 94.9% at 5 degrees C. Phospholipid fatty acid analysis showed that C16:1omega7c, C18:1omega7c and C18:1omega9c were the essential unsaturated fatty acids in cell membrane at low temperature (4-15 degrees C), accounting for the majority of the whole unsaturated fatty acids. The MF effect increased the Gram negative bacteria content to improve the cold adaptability. Shannon-Wiener diversity analysis demonstrated the samples with heteropolar MF had a higher PLFA diversity index (1.17-1.25) than that with homopolar MF (0.89-1.13). AFM observation showed MF smoothed part of the microbial cell surface, with some remaining distinct protuberances. Heteropolar MF enhancement performance is much more effective than that of the homopolar MF with identical plate distance. PMID- 24161555 TI - Microcirculatory perfusion is preserved during off-pump but not on-pump cardiac surgery. AB - OBJECTIVE: This study investigated the perioperative course of microcirculatory perfusion in off-pump compared with on-pump surgery. Additionally, the impact of changes in systemic hemodynamics, hematocrit, and body temperature was studied. DESIGN: Prospective, nonrandomized, observational study. SETTING: Tertiary university hospital. PARTICIPANTS: Patients undergoing coronary artery bypass grafting with (n = 13) or without (n = 13) use of cardiopulmonary bypass. INTERVENTIONS: Microcirculatory measurements were obtained at 5 time points ranging from induction of anesthesia to ICU admission. MEASUREMENTS AND MAIN RESULTS: Microcirculatory recordings were performed with sublingual sidestream dark field imaging. Despite a comparable reduction in intraoperative blood pressure between groups, the perfused vessel density decreased more than 20% after onset of extracorporeal circulation but remained stable in the off-pump group. The reduction in microvascular perfusion in the on-pump group was further paralleled by decreased hematocrit and temperature. Although postbypass hematocrit levels and body temperature were restored to similar levels as in the off-pump group, the median microvascular flow index remained reduced after bypass (2.4 [2.3-2.7]) compared with baseline (2.8 [2.7-2.9]; p = 0.021). CONCLUSIONS: Microcirculatory perfusion remained unaltered throughout off-pump surgery. In contrast, microvascular perfusion declined after initiation of cardiopulmonary bypass and did not recover in the early postoperative phase. PMID- 24161556 TI - Suicide prevention on campus--what direction? PMID- 24161558 TI - Superinfection reconciles host-parasite association and cross-species transmission. AB - Parasites are either dedicated to a narrow host range, or capable of exploiting a wide host range. Understanding how host ranges are determined is very important for public health, as well as wildlife, plant, livestock and agricultural diseases. Our current understanding of host-parasite associations hinges on co evolution, which assumes evolved host preferences (host specialization) of the parasite. Despite the explanatory power of this framework, we have only a vague understanding of why many parasites routinely cross the host species' barrier. Here we introduce a simple model demonstrating how superinfection (in a heterogeneous community) can promote host-parasite association. Strikingly, the model illustrates that strong host-parasite association occurs in the absence of host specialization, while still permitting cross-species transmission. For decades, host specialization has been foundational in explaining the maintenance of distinct parasites/strains in host species. We argue that host specializations may be exaggerated, and can occur as a byproduct (not necessarily the cause) of host-parasite associations. PMID- 24161560 TI - Neurochemical mechanisms and pharmacologic strategies in managing nausea and vomiting related to cyclic vomiting syndrome and other gastrointestinal disorders. AB - Nausea and vomiting are common gastrointestinal complaints which could be triggered by stimuli in both the peripheral and central nervous systems. They may be considered as defense mechanisms when threatening toxins/agents enter the gastrointestinal tract or there is excessive retention of gastrointestinal contents due to obstruction. The pathophysiology of nausea and vomiting is complex and much still remains unknown. Therefore, treatments are restricted or ineffective in many cases. Nausea and vomiting with functional etiologies including cyclic vomiting syndrome are challenging in gastroenterology. In this article, we review potential pathways, neurochemical transmitters, and their receptors which are possibly involved in the pathophysiology of nausea and vomiting including the entity cyclic vomiting syndrome. PMID- 24161559 TI - Economic epidemiology of avian influenza on smallholder poultry farms. AB - Highly pathogenic avian influenza (HPAI) is often controlled through culling of poultry. Compensating farmers for culled chickens or ducks facilitates effective culling and control of HPAI. However, ensuing price shifts can create incentives that alter the disease dynamics of HPAI. Farmers control certain aspects of the dynamics by setting a farm size, implementing infection control measures, and determining the age at which poultry are sent to market. Their decisions can be influenced by the market price of poultry which can, in turn, be set by policy makers during an HPAI outbreak. Here, we integrate these economic considerations into an epidemiological model in which epidemiological parameters are determined by an outside agent (the farmer) to maximize profit from poultry sales. Our model exhibits a diversity of behaviors which are sensitive to (i) the ability to identify infected poultry, (ii) the average price of infected poultry, (iii) the basic reproductive number of avian influenza, (iv) the effect of culling on the market price of poultry, (v) the effect of market price on farm size, and (vi) the effect of poultry density on disease transmission. We find that under certain market and epidemiological conditions, culling can increase farm size and the total number of HPAI infections. Our model helps to inform the optimization of public health outcomes that best weigh the balance between public health risk and beneficial economic outcomes for farmers. PMID- 24161561 TI - Novel high-performance purification protocol of recombinant CNBP suitable for biochemical and biophysical characterization. AB - Cellular nucleic acid binding protein (CNBP) is a highly conserved multi-zinc knuckle protein that enhances c-MYC expression, is related to certain human muscular diseases and is required for proper rostral head development. CNBP binds to single-stranded DNA (ssDNA) and RNA and acts as nucleic acid chaperone. Despite the advances made concerning CNBP biological roles, a full knowledge about the structure-function relationship has not yet been achieved, likely due to difficulty in obtaining pure and tag-free CNBP. Here, we report a fast, simple, reproducible, and high-performance expression and purification protocol that provides recombinant tag-free CNBP from Escherichia coli cultures. We determined that tag-free CNBP binds its molecular targets with higher affinity than tagged-CNBP. Furthermore, fluorescence spectroscopy revealed the presence of a unique and conserved tryptophan, which is exposed to the solvent and involved, directly or indirectly, in nucleic acid binding. Size-exclusion HPLC revealed that CNBP forms homodimers independently of nucleic acid binding and coexist with monomers as non-interconvertible forms or in slow equilibrium. Circular dichroism spectroscopy showed that CNBP has a secondary structure dominated by random-coil and beta-sheet coincident with the sequence-predicted repetitive zinc knuckles motifs, which folding is required for CNBP structural stability and biochemical activity. CNBP structural stability increased in the presence of single-stranded nucleic acid targets similar to other unstructured nucleic acid chaperones. Altogether, data suggest that CNBP is a flexible protein with interspersed structured zinc knuckles, and acquires a more rigid structure upon nucleic acid binding. PMID- 24161562 TI - Expression, purification, and characterization of full-length bovine leukemia virus Gag protein from bacterial culture. AB - In retroviruses, the Gag protein is a precursor from which the mature proteins matrix, capsid, and nucleocapsid are derived. Gag plays an important structural role in the assembly of virions at the plasma membrane. While Gag proteins from several different retroviruses have been purified for study in vitro, there has yet to be a report of successful purification of deltaretroviral Gag. In this paper, we report the cloning, expression and purification of full-length bovine leukemia virus (BLV) Gag from Escherichia coli using a combination of polyethyleneimine precipitation, ammonium sulfate precipitation, and affinity chromatography. Experiments using size-exclusion chromatography were also performed to analyze the oligomeric state of the Gag protein in solution, and results suggest that it exists primarily as a monomer but may oligomerize into higher-order complexes to a small extent. Molecular weight estimation by comparison of elution volume to a set of protein standards supports the hypothesis that BLV Gag adopts a slightly extended conformation in solution. The results are discussed in comparison to the solution structure and assembly pathways of other retrovirus genera. PMID- 24161563 TI - Zinc supplementation protects human endostatin Fc fusion against proteolytic degradation during cell culture. AB - Endostatin is a potent anti-angiogenesis compound with efficacy in treating solid tumors and other diseases. However, its clinical application has been hampered by the susceptibility to proteolytic degradation during cell culture production. Here we describe a simple and effective strategy for stabilizing a CHO cell derived human endostatin Fc fusion. Mass spectrometry analysis of the prominent clipped species revealed that the cleavage sites are located at the N-terminal zinc binding region, which is known to be critical for the structural stability of the molecule. Accordingly, we tested the effect of zinc supplementation on stabilizing the molecule and found that micromolar concentrations of zinc chloride significantly reduced the level of clipping. The protective effect appeared to be mediated via direct interaction between zinc and endostatin, as zinc protects purified endostatin spiked into conditioned medium. Interestingly, copper which is known to have high affinity to endostatin, also prevents degradation. The method provides a robust process for manufacturing Fc endostatin. PMID- 24161564 TI - A photoelectrochemical biosensor for o-aminophenol based on assembling of CdSe and DNA on TiO2 film electrode. AB - A novel photoelectrochemical (PEC) biosensing platform was constructed by assembling CdSe quantum dots (QDs) and DNA on liquid phase deposited TiO2 (DNA CdSe/TiO2) film electrode. The transmission electron microscopy (TEM), scanning electron microscopy (SEM) and X-ray diffraction (XRD) analysis indicated that CdSe QDs were homogeneously assembled on TiO2 film. The UV-visible diffuse reflectance spectra (DRS) showed that CdSe and DNA could effectively enhance the absorption of TiO2 film to visible light. The obtained electrode showed a sensitive PEC response to o-aminophenol (OAP) under visible light irradiation. Due to the interaction between DNA and OAP, the response of OAP was improved by DNA immobilized on the sensing film. Under optimized conditions, the photocurrent was linearly proportional to OAP in the concentration range from 4.0 * 10(-7) to 2.7 * 10(-5) mol L(-1), with a detection limit (3S/N) of 8.0 * 10(-8) mol L(-1). The novel strategy could provide a fast and sensitive method for OAP determination. PMID- 24161565 TI - Label-free immunosensor based on Pd nanoplates for amperometric immunoassay of alpha-fetoprotein. AB - In this paper, Pd nanoplates were used as a kind of electrode materials for fabrication of an electrochemical immunosensor, which was applied for detection of cancer biomarker alpha-fetoprotein (AFP). Thanks to the unique structure and properties of Pd nanoplates, the antibody of AFP (Ab) was effectively immobilized onto the surface of the Pd nanoplates modified glassy carbon electrode (GCE). Moreover, the good electrochemical properties of Pd nanoplates greatly improved the electronic transmission rate and enhanced the electrochemical signal, which led to an increase of the detection sensitivity. Based on the specific antibody antigen interaction, a label-free immunosensor based on Pd nanoplates was developed for sensing of AFP. The current method allows us to detect AFP over a wide concentration range from 0.01 to 75.0 ng/mL with a detection limit of 4 pg/mL. The proposed immunosensor has been used to determine AFP in human serum with satisfactory results. PMID- 24161566 TI - Reduced collagen internalization via down-regulation of MRC2 expression by UVA irradiation and its recovery by all-trans retinoic acid. PMID- 24161568 TI - A prospective randomized trial comparing hypofractionation with conventional fractionation radiotherapy for T1-2 glottic squamous cell carcinomas: results of a Korean Radiation Oncology Group (KROG-0201) study. AB - BACKGROUND AND PURPOSE: To prospectively investigate the effect of radiotherapy fraction size on clinical outcomes in early glottic carcinoma METHODS AND MATERIALS: Patients with T1-2 glottic carcinoma were eligible for the protocol. Although 282 patients were required, the study was closed prematurely due to poor accrual with only 156 patients. Of these, 82 patients were allocated to conventional fractionation (CONV) arm (66 Gy/33 fractions for T1 and 70 Gy/35 fractions for T2), with 74 patients to hypofractionation (HYPO) arm (63 Gy/28 fractions for T1 and 67.5 Gy/30 fractions for T2). The primary objective was local progression-free survival (LPFS). RESULTS: With a median follow-up of 67 months (range, 2-122 months), the 5-year LPFS was 77.8% for CONV arm and 88.5% for HYPO arm (HR 1.55, p=0.213). No significant difference was observed in the toxicity profile between the two arms. In a subgroup exploratory analysis for T1a disease, the 5-year LPFS trended positively in HYPO arm (76.7% vs. 93.0%, HR 3.65, p=0.056). CONCLUSIONS: Given that HYPO is at least not inferior to CONV with a similar toxicity profile, the hypofractionation scheme used in this study can be offered to patients with T1-2 glottic carcinoma with potential advantages in terms of local control and a shortened overall treatment time. PMID- 24161567 TI - Induction of a chloracne phenotype in an epidermal equivalent model by 2,3,7,8 tetrachlorodibenzo-p-dioxin (TCDD) is dependent on aryl hydrocarbon receptor activation and is not reproduced by aryl hydrocarbon receptor knock down. AB - BACKGROUND: 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is a potent activator of the aryl hydrocarbon receptor (AhR) and causes chloracne in humans. The pathogenesis and role of AhR in chloracne remains incompletely understood. OBJECTIVE: To elucidate the mechanisms contributing to the development of the chloracne-like phenotype in a human epidermal equivalent model and identify potential biomarkers. METHODS: Using primary normal human epidermal keratinocytes (NHEK), we studied AhR activation by XRE-luciferase, AhR degradation and CYP1A1 induction. We treated epidermal equivalents with high affinity TCDD or two non chloracnegens: beta-naphthoflavone (beta-NF) and 2-(1'H-indole-3'-carbonyl) thiazole-4-carboxylic acid methyl ester (ITE). Using Western blotting and immunochemistry for filaggrin (FLG), involucrin (INV) and transglutaminase-1 (TGM 1), we compared the effects of the ligands on keratinocyte differentiation and development of the chloracne-like phenotype by H&E. RESULTS: In NHEKs, activation of an XRE-luciferase and CYP1A1 protein induction correlated with ligand binding affinity: TCDD>beta-NF>ITE. AhR degradation was induced by all ligands. In epidermal equivalents, TCDD induced a chloracne-like phenotype, whereas beta-NF or ITE did not. All three ligands induced involucrin and TGM-1 protein expression in epidermal equivalents whereas FLG protein expression decreased following treatment with TCDD and beta-NF. Inhibition of AhR by alpha-NF blocked TCDD induced AhR activation in NHEKs and blocked phenotypic changes in epidermal equivalents; however, AhR knock down did not reproduce the phenotype. CONCLUSION: Ligand-induced CYP1A1 and AhR degradation did not correlate with their chloracnegenic potential, indicating that neither CYP1A1 nor AhR are suitable biomarkers. Mechanistic studies showed that the TCDD-induced chloracne-like phenotype depends on AhR activation whereas AhR knock down did not appear sufficient to induce the phenotype. PMID- 24161569 TI - Estimation of heart-position variability in 3D-surface-image-guided deep inspiration breath-hold radiation therapy for left-sided breast cancer. AB - PURPOSE: To investigate the heart position variability in deep-inspiration breath hold (DIBH) radiation therapy (RT) for breast cancer when 3D surface imaging would be used for monitoring the BH depth during treatment delivery. For this purpose, surface setup data were compared with heart setup data. MATERIALS AND METHODS: Twenty patients treated with DIBH-RT after breast-conserving surgery were included. Retrospectively, heart registrations were performed for cone-beam computed tomography (CBCT) to planning CT. Further, breast-surface registrations were performed for a surface, captured concurrently with CBCT, to planning CT. The resulting setup errors were compared with linear regression analysis. Furthermore, geometric uncertainties of the heart (systematic [Sigma] and random [sigma]) were estimated relative to the surface registration. Based on these uncertainties planning organ at risk volume (PRV) margins for the heart were calculated: 1.3Sigma-0.5sigma. RESULTS: Moderate correlation between surface and heart setup errors was found: R(2)=0.64, 0.37, 0.53 in left-right (LR), cranio caudal (CC), and in anterior-posterior (AP) direction, respectively. When surface imaging would be used for monitoring, the geometric uncertainties of the heart (cm) are [Sigma=0.14, sigma=0.14]; [Sigma=0.66, sigma=0.38]; [Sigma=0.27, sigma=0.19] in LR; CC; AP. This results in PRV margins of 0.11; 0.67; 0.25 cm in LR; CC; AP. CONCLUSION: When DIBH-RT after breast-conserving surgery is guided by the breast-surface position then PRV margins should be used to take into account the heart-position variability relative to the breast-surface. PMID- 24161571 TI - Impact of medical education on knowledge and attitudes regarding the human papilloma virus and vaccination: comparison before and 6 years after the introduction of the vaccines. AB - AIM: The lifetime risk for acquiring a human papilloma virus (HPV) infection is 80% for sexually active people. High-risk HPVs are causally related to almost every case of cervical cancer, and to a subgroup of vaginal, vulvar, anal, penile and oral/oropharyngeal cancer. Low-risk HPVs are related to cutaneous, anogenital, and oral warts. Two prophylactic vaccines were launched in 2007: they were included in the national vaccination program in Belgium (2009) and in the Netherlands (2010). The objectives of the present study were to determine and compare knowledge and attitudes regarding HPV and vaccination among a study population in 2006 and in 2012. MATERIALS AND METHODS: Shortly before the introduction, and three years after the inclusion, 715 (2006) and 678 participants (2012) were questioned. Participants were categorised as into non medics, medics, or paramedics. RESULTS: In general, knowledge about HPV has increased over time (p<0.01). Well-known facts are the relationship of HPV with cervical cancer (>94% in 2006; >96% in 2012), and that an HPV infection might be asymptomatic (>95% in 2006; >99% in 2012). In 2012, versus in 2006, paramedics and non-medics (both p<0.01), were more likely to vaccinate all female teenagers. Medics were less likely to support this (p=0.001). More respondents agreed to vaccinate their daughters (p<0.01), as well as their sons (p<0.01). In 2012, when compared with 2006, less non-medics and medics (both p<0.01) and more paramedics (p=0.001) would accept a free catch-up vaccination. Arguments against catch-up vaccination reflected the belief not being at risk and doubts about the vaccines' safety. CONCLUSION: The facts that vaccination programs are regarded as being important, and that knowledge on HPV increased, do not automatically result in an increase in participation in HPV vaccination programs. To increase participation, information must be provided with arguments that cannot be misinterpreted. PMID- 24161572 TI - A relevant in vitro ELISA test in alternative to the in vivo NIH test for human rabies vaccine batch release. AB - To assess the quality of vaccine batches before release, international regulation requires the control of potency of each lot of human rabies vaccines by the in vivo NIH challenge test. Meanwhile, the 3Rs strategy for animal testing encourages the replacement of the in vivo potency test by an in vitro assay. Consequently, since more than 10 years, an ELISA method has been implemented by ANSM in parallel to the NIH test for rabies vaccines lots. It consists in the evaluation of the glycoprotein content using a monoclonal antibody recognizing the trimeric native form of the glycoprotein. This ELISA method is able 1) to monitor the consistency of production with a similar profile than the NIH; 2) to detect a low quantity of glycoprotein in vaccines and 3) to agree with the manufacturer's NIH results by declaring a non compliant batch. This ELISA which characterizes the immunogenic form of the glycoprotein formulated in vaccines seems to be relevant to replace the NIH test and is a promising candidate to be standardized by a collaborative study. PMID- 24161570 TI - Loss of Sip1 leads to migration defects and retention of ectodermal markers during lens development. AB - SIP1 encodes a DNA-binding transcription factor that regulates multiple developmental processes, as highlighted by the pleiotropic defects observed in Mowat-Wilson syndrome, which results from mutations in this gene. Further, in adults, dysregulated SIP1 expression has been implicated in both cancer and fibrotic diseases, where it functionally links TGFbeta signaling to the loss of epithelial cell characteristics and gene expression. In the ocular lens, an epithelial tissue important for vision, Sip1 is co-expressed with epithelial markers, such as E-cadherin, and is required for the complete separation of the lens vesicle from the head ectoderm during early ocular morphogenesis. However, the function of Sip1 after early lens morphogenesis is still unknown. Here, we conditionally deleted Sip1 from the developing mouse lens shortly after lens vesicle closure, leading to defects in coordinated fiber cell tip migration, defective suture formation, and cataract. Interestingly, RNA-Sequencing analysis on Sip1 knockout lenses identified 190 differentially expressed genes, all of which are distinct from previously described Sip1 target genes. Furthermore, 34% of the genes with increased expression in the Sip1 knockout lenses are normally downregulated as the lens transitions from the lens vesicle to early lens, while 49% of the genes with decreased expression in the Sip1 knockout lenses are normally upregulated during early lens development. Overall, these data imply that Sip1 plays a major role in reprogramming the lens vesicle away from a surface ectoderm cell fate towards that necessary for the development of a transparent lens and demonstrate that Sip1 regulates distinctly different sets of genes in different cellular contexts. PMID- 24161573 TI - Vaccination policies for healthcare workers in Europe. AB - Health-care workers (HCWs) are at increased risk for acquisition of vaccine preventable diseases (VPDs) and vaccination is justified in order to protect them from occupational exposure and to prevent the spread of VPDs that pose a threat to susceptible patients. Review of European vaccination policies for HCWs revealed significant differences between countries in terms of recommended vaccines, implementation frame (mandatory or recommendation), target HCW groups and health-care settings. Further, the few published studies available identified indicate significant immunity gaps among HCWs against VPDs in Europe. In order to achieve higher vaccination coverage against VPDs stronger recommendations are needed. The issue of mandatory vaccination should be considered for diseases that can be transmitted to susceptible patients (influenza, measles, mumps, rubella, hepatitis B, pertussis, varicella). The acceptance of vaccinations and of mandatory vaccinations by HCWs is a challenge and appears to be VPD-specific. PMID- 24161574 TI - Immunogenicity of a recombinant measles HIV-1 subtype C vaccine. AB - The HIV epidemic is greatest in Sub-Saharan Africa and India where HIV-1 subtype C is predominant. To control the spread of HIV in these parts of the world a preventive HIV-1 subtype C vaccine is urgently required. Here we report the immunogenicity of a candidate HIV-1 subtype C vaccine delivered by a recombinant measles vector carrying an insert encoding HIV-1 subtype C Gag, RT and Nef (MV1 F4), in MHC-typed non-human primates. HIV-1 specific cytokine secreting CD4+ and CD8+ T cell responses were detected in 15 out of 16 vaccinees. These HIV-specific T cell responses persisted in lymphoid tissues. Anti-HIV-1 antibody responses were detected in 15 out of 16 vaccinees and titres were boosted by a second immunisation carried out 84 days later. These findings support further exploration of the MV1-F4 vector as a candidate HIV-1 subtype C vaccine or as part of a wider vaccine strategy. PMID- 24161575 TI - Characterizing, typing, and naming human adenovirus type 55 in the era of whole genome data. PMID- 24161577 TI - Optimal descriptor as a translator of eclectic information into the prediction of membrane damage by means of various TiO(2) nanoparticles. AB - The increasing use of nanomaterials incorporated into consumer products leads to the need for developing approaches to establish "quantitative structure-activity relationships" (QSARs) for various nanomaterials. However, the molecular structure as rule is not available for nanomaterials at least in its classic meaning. An possible alternative of classic QSAR (based on the molecular structure) is the using of data on physicochemical features of TiO(2) nanoparticles. The damage to cellular membranes (units L(-1)) by means of various TiO(2) nanoparticles is examined as the endpoint. PMID- 24161578 TI - The release of persistent organic pollutants from a closed system dicofol production process. AB - High concentrations of polychlorinated dibenzo-p-dioxins and dibenzofurans (PCDD/Fs) have been found to be produced in chemical processes in which chlorine is a raw material. Samples of workshop air, waste water, waste acid, and the dicofol product were collected from a pesticide factory in China that uses a closed-system dicofol production process, and were analyzed for PCDD/Fs and SigmaDDTs. The SigmaDDTs concentrations were 1.88-17.53 MUg m(-3) in the workshop air samples, 4.85-456 MUg kg(-1) in the waste water and waste acid samples, and 4.74 g kg(-1) in the dicofol product. The total estimated daily intakes of SigmaDDTs for workers by inhalation in the workplace were in the range of 0.38 3.51 MUg kg(-1)bwd(-1) for moderate activities. The annual amounts of SigmaDDTs and p,p'-DDT directly released to the environment via the use of dicofol were 9,480 kg and 1,080 kg, respectively. The PCDD/F toxicity equivalent values (I TEQs) in the waste water and waste acid samples ranged from 1.5 to 122 pg I-TEQ kg(-1) and 86.3 ng I-TEQ kg(-1) in the dicofol sample. The annual amount of PCDD/Fs released to the environment was 0.17 g I-TEQ. From the PCDD/F distribution patterns, it is suggested that the major pathway for PCDD/F formation involves precursor synthesis during the production of dicofol in the closed-system process. PMID- 24161576 TI - Disruption of social bonds induces behavioral and physiological dysregulation in male and female prairie voles. AB - The social disruption of losing a partner may have particularly strong adverse effects on psychological and physiological functioning. More specifically, social stressors may play a mediating role in the association between mood disorders and cardiovascular dysfunction. This study investigated the hypothesis that the disruption of established social bonds between male and female prairie voles would produce depressive behaviors and cardiac dysregulation, coupled with endocrine and autonomic nervous system dysfunction. In Experiment 1, behaviors related to depression, cardiac function, and autonomic nervous system regulation were monitored in male prairie voles during social bonding with a female partner, social isolation from the bonded partner, and a behavioral stressor. Social isolation produced depressive behaviors, increased heart rate, heart rhythm dysregulation, and autonomic imbalance characterized by increased sympathetic and decreased parasympathetic drive to the heart. In Experiment 2, behaviors related to depression and endocrine function were measured following social bonding and social isolation in both male and female prairie voles. Social isolation produced similar levels of depressive behaviors in both sexes, as well as significant elevations of adrenocorticotropic hormone and corticosterone. These alterations in behavioral and physiological functioning provide insight into the mechanisms by which social stressors negatively influence emotional and cardiovascular health in humans. PMID- 24161579 TI - Effects of sub-lethal glyphosate concentrations on growth and photosynthetic performance of non-target species Bolboschoenus maritimus. AB - Glyphosate use has increased over the last decades for the control of invasive plant species in wetland ecosystems. Although glyphosate has been considered 'environmentally' safe, its repeated use could increase the toxicological risk derived from diffuse pollution of surface and groundwater on non-target vegetation. A glasshouse study was designed to determine the effect produced by the addition of different sub-lethal doses of glyphosate herbicides (5-30 mg L( 1)) to the nutrient solution on the growth and photosynthetic apparatus of Bolboschoenus maritimus. Although B. maritimus plants were able to grow and survive after 20 d of exposure to glyphosate, the presence of this herbicide affected their growth, through a direct interaction with the root system. Particularly, at 30 mg L(-1) glyphosate, B. maritimus showed ca. 30% of biomass decrease. The reduction in B. maritimus growth was due to a decrease in net photosynthetic rate (A), which ranged between values ca. 11.5 and 5.5 MUmol m( 2)s(-1) CO2 for the control and the highest glyphosate treatment, respectively. The response of A to glyphosate could be largely accounted for by non-stomatal limitations, since stomatal conductance was similar in all glyphosate treatments. Thus, A decrease was prompted by the negative impact of herbicide on photochemical (PSII) apparatus, the reduction in the absorption of essential nutrients, the reduction of photosynthetic pigments and possibly the reduction in Rubisco carboxilation capacity. Moreover, glyphosate excess caused photoinhibitory damage. In conclusion, in this study we have shown that herbicide water pollution could be a source of indirect phytotoxicity for B. maritimus. PMID- 24161580 TI - Cytotoxic and genotoxic effects of metal(oid)s bioactivated in rocket leaves (Eruca vesicaria subsp. sativa Miller). AB - Rocket is an important source of essential elements. However, it may also accumulate toxic elements such as metal(oids). The objectives of the present work were (i) to study the uptake of arsenic, lead, cadmium and zinc in rocket grown in contaminated soils, (ii) to establish the genotoxic and cytotoxic activities of this vegetable material, and (iii) to study the modulator role of the glucosinolate and metal contents in the genotoxic/cytotoxic activities. Lead, cadmium and zinc leaf concentrations in our study were over the concentrations allowed by the statutory limit set for metal(oid) contents in vegetables. The accessions were non genotoxic at the different concentrations studied, although one of the accessions showed the highest mutation rates doubling those of negative control. The cytotoxicity assays with HL60 human leukaemia cells showed that the tumouricide activities of rocket leaves decreased with the increasing of metal(oid) concentrations and also with the decreasing of glucosinolate concentrations in their tissues. An interaction between metal(oid)s and glucosinolate degradation products contained in rocket leaves is suggested as the main modulator agents of the biological activity of the plants grown in metal contaminated soils. PMID- 24161581 TI - Denitrification of industrial wastewater: Influence of glycerol addition on metabolic activity and community shifts in a microbial consortium. AB - The wastewater originating from explosives manufacturing plants are characterized by a high concentration of nitrates (3200mgNL(-1)), sulfates (1470mgL(-1)) and low pH (1.5) as well as the presence of organic compounds, such as nitroglycerin (1.9mgL(-1)) and nitroglycol (4.8mgL(-1)). The application of glycerol (C/N=3) at such a high concentration enabled complete removal of nitrates and did not cause the anaerobic glycerol metabolic pathway of the DNC4 consortium to activate, as confirmed by the low concentrations of 1,3-propanediol (0.16gL(-1)) and acetic acid (0.11gL(-1)) in the wastewater. Increasing the glycerol content (C/N=5) contributed to a notable increase in the concentration of both compounds: 1.12gL( 1) for acetic acid and 1.82 for 1,3-PD (1,3-propanediol). The nitrate reduction rate was at 44mgNg(-1) biomass d(-1). In order to assess the metabolic activity of the microorganisms, a method to determine the redox potential was employed. It was established, that the microorganisms can be divided into four groups, based on the determined denitrification efficiency and zero-order nitrate removal constants. The first group, involving Pseudomonas putida and Pseudomonas stutzeri, accounts for microorganisms capable of the most rapid denitrification, the second involves rapid denitrifying microbes (Citrobacter freundi and Pseudomonas alcaligenes), the third group are microorganisms exhibiting moderate denitrification ability: Achrobactrum xylosoxidans, Ochrobactrum intermedium and Stenotrophomonas maltophila, while the last group consists of slow denitrifying bacteria: Rodococcus rubber and Sphignobacterium multivorum. PMID- 24161582 TI - Associations of organochlorine pesticides and polychlorinated biphenyls in visceral vs. subcutaneous adipose tissue with type 2 diabetes and insulin resistance. AB - Background exposure to organochlorine (OC) pesticides and polychlorinated biphenyls (PCBs) has been linked to type 2 diabetes. As OC pesticides and PCBs mainly accumulate in adipose tissue and there are physiological and clinical differences between visceral adipose tissue (VAT) and subcutaneous adipose tissue (SAT), we explored if there were associations of OC pesticides and PCBs in VAT or SAT with type 2 diabetes and insulin resistance. Participants were 50 patients with or without type 2 diabetes who underwent surgery for either cancer or benign liver or gallbladder lesions. We analyzed 14 OC pesticides and 22 PCB congeners in both VAT and SAT. Insulin resistance was estimated using homeostasis model assessment (HOMA). Although concentrations of OC pesticides and PCBs were strongly correlated between VAT and SAT, absolute concentrations differed substantially between them. In particular, concentrations of all PCBs were consistently about 5-10 times higher in VAT than SAT, but these patterns were independent of diabetes status. Some OC pesticides or PCBs, such as dichlorodiphenyltrichloroethanes (DDTs), chlordanes, and PCBs with 5 or less chlorides showed significant associations with diabetes or insulin resistance. For example, when tertiles of concentration-based summary measures were used, adjusted ORs were 1.0, 2.3, and 9.0 (P trend=0.02) for DDTs in VAT and 1.0, 2.1, and 5.7 (P trend=0.08) for PCBs with 5 or less chlorides. This study generally confirmed previous findings using serum concentrations. It would be useful to study pharmacodynamics of POPs in VAT and SAT further. PMID- 24161583 TI - Characterising the individual health risk in infants exposed to organochlorine pesticides via breast milk by applying appropriate margins of safety derived from estimated daily intakes. AB - Milk secretion being an important way of elimination of organochlorine pesticides (OCPs) poses a concern due to potential risk for breastfed infants. This study aims to provide a tool for assessing such risks to infants exposed to OCPs (through accumulation in the mother's body), using calculated individual margins of safety (MoS). Selected OCPs included; p,p'-DDT, p,p'-DDD, p,p'-DDE, beta-HCH, gamma-HCH and HCB which were analysed in 28 samples of maternal milk. The highest intakes were recorded for p,p'-DDE (at 2.90 MUg kg(-1)bw d(-1)) whilst the lowest was for gamma-HCH, (at 0.019 MUg kg(-1)bwd(-1)). For the risk characterisation purposes MoSs were calculated for the compounds for which toxicological reference values (e.g. ADI, TDI) were adopted. The MoS for average ?DDT concentrations was found to be relatively low (2.82) somewhat similar to that for HCB at 7.08, and for gamma-HCH, the MoS was substantially higher at 263.1. This, however does not take into account the extremely high individual concentrations. Thus, it was decided to calculate estimated daily intake (EDI) values based on OCP levels in individual milk samples. MoS levels of <1 (meaning unacceptable risk) were noted both for HCB in one sample as well as for ?DDT in 3 samples indicating likely threats to infant's health. The lowest MoS noted for gamma-HCH equalled to 60.6, indicating that this compound was not a threat to the health of any of the breastfed infants from the study group. PMID- 24161584 TI - Injury severity in delivery-motorcycle to vehicle crashes in the Seoul metropolitan area. AB - More than 56% of motorcycles in Korea are used for the purpose of delivering parcels and food. Since such delivery requires quick service, most motorcyclists commit traffic violations while delivering, such as crossing the centerline, speeding, running a red light, and driving in the opposite direction down one-way streets. In addition, the fatality rate for motorcycle crashes is about 12% of the fatality rate for road traffic crashes, which is considered to be high, although motorcycle crashes account for only 5% of road traffic crashes in South Korea. Therefore, the objective of this study is to analyze the injury severity of vehicle-to-motorcycle crashes that have occurred during delivery. To examine the risk of different injury levels sustained under all crash types of vehicle-to motorcycle, this study applied an ordered probit model. Based on the results, this study proposes policy implications to reduce the injury severity of vehicle to-motorcycle crashes during delivery. PMID- 24161586 TI - Time trends of physical activity among Brazilian adolescents over a 7-year period. AB - PURPOSE: To evaluate time trends in physical activity among adolescents aged 10 to 19 years living in southern Brazil over a 7-year period. METHODS: Two population-based cross-sectional surveys with similar methodologies were carried out in the city of Pelotas, Brazil, in 2005 and 2012. Leisure-time and transport related physical activity were measured using a validated questionnaire. A cut off point of 300 minutes per week was used to classify adolescents as active or not. We also analyzed the two domains of physical activity (leisure time and transportation) separately. RESULTS: The prevalence of physical inactivity was 69.6% (95% CI 66.5-73.2) in 2005 and 69.9% (95% CI 66.5-72.7) in 2012. The percentage of active adolescents in leisure time also remained stable in the period (26.3% in 2005 [95% CI 23.3-29.2] vs. 28.1% in 2012 [95% CI 24.9-31.4]). Among boys, we observed an increase in the practice of some leisure-time activities-weight lifting (87%) and running (78%)-and a decline in others volleyball (61%) and basketball (56%). Among girls, the only significant difference was an increase in the practice of weight lifting (271%). The prevalence of active commuting to and from school declined from 69% (95% CI 65.6 72.4) in 2005 to 56.5% (95% CI 52.5-60.2) in 2012. CONCLUSIONS: There was a significant decline in active commuting to school among adolescents. Interventions promoting active commuting modes to school are urgently needed in Brazil. PMID- 24161585 TI - Challenging recruitment of youth with type 2 diabetes into clinical trials. AB - PURPOSE: To better understand and overcome difficulties with recruitment of adolescents with type 2 diabetes into clinical trials at three United States institutions, we reviewed recruitment and retention strategies in clinical trials of youth with various chronic conditions. We explored whether similar strategies might be applicable to pediatric patients with type 2 diabetes. METHODS: We compiled data on recruitment and retention of adolescents with type 2 diabetes at three centers (National Institutes of Health, Bethesda, Maryland; Baylor College of Medicine, Houston, Texas; and Children's National Medical Center, Washington, DC) from January 2009 to December 2011. We also conducted a thorough literature review on recruitment and retention in adolescents with chronic health conditions. RESULTS: The number of recruited patients was inadequate for timely completion of ongoing trials. Our review of recruitment strategies in adolescents included monetary and material incentives, technology-based advertising, word-of mouth referral, and continuous patient-research team contact. Cellular or Internet technology appeared promising in improving participation among youths in studies of various chronic conditions and social behaviors. CONCLUSIONS: Adolescents with type 2 diabetes are particularly difficult to engage in clinical trials. Monetary incentives and use of technology do not represent "magic bullets," but may presently be the most effective tools. Future studies should be conducted to explore motivation in this population. We speculate that (1) recruitment into interventional trials that address the main concerns of the affected youth (e.g., weight loss, body image, and stress management) combined with less tangible outcomes (e.g., blood glucose control) may be more successful; and (2) study participation and retention may be improved by accommodating patients' and caregivers' schedules, by scheduling study visits before and after working hours, and in more convenient locations than in medical facilities. PMID- 24161587 TI - Flavored-little-cigar and flavored-cigarette use among U.S. middle and high school students. AB - PURPOSE: Flavors can mask the harshness and taste of tobacco, making flavored tobacco products appealing to youth. We assessed the prevalence and correlates of flavored-little-cigar and flavored-cigarette use among U.S. middle and high school students in 2011. METHODS: Data were obtained from the 2011 National Youth Tobacco Survey, a nationally representative school-based survey of U.S. students in grades 6-12. National estimates of current flavored-little-cigar use, flavored cigarette use, and combined use of either product were calculated overall and among current smokers by respondent characteristics, including sex, race/ethnicity, school level, and grade. Additionally, intention to quit tobacco and smoking frequency were assessed by flavored product use. RESULTS: The overall prevalence of current use was 4.2% for flavored cigarettes, 3.3% for flavored little cigars, and 6.3% for either product. Among current cigar smokers, 35.9% reported using flavored little cigars, and among current cigarette smokers, 35.4% reported using flavored cigarettes. Among current cigar or cigarette smokers, 42.4% reported using flavored little cigars or flavored cigarettes. Flavored product use among current smokers was higher among non-Hispanic whites than among blacks and Hispanics, higher among high school students than middle school students, and increased with grade. Among cigar smokers, prevalence of no intention to quit tobacco was higher among flavored-little-cigar users (59.7%) than nonusers (49.3%). CONCLUSIONS: More than two fifths of U.S. middle and high school smokers report using flavored little cigars or flavored cigarettes, and disparities in the use of these products exist across subpopulations. Efforts are needed to reduce flavored tobacco product use among youth. PMID- 24161588 TI - Effects of intestinal bacteria-derived p-cresyl sulfate on Th1-type immune response in vivo and in vitro. AB - Protein fermentation by intestinal bacteria generates various compounds that are not synthesized by their hosts. An example is p-cresol, which is produced from tyrosine. Patients with chronic kidney disease (CKD) accumulate high concentrations of intestinal bacteria-derived p-cresyl sulfate (pCS), which is the major metabolite of p-cresol, in their blood, and this accumulation contributes to certain CKD-associated disorders. Immune dysfunction is a CKD associated disorder that frequently contributes to infectious diseases among CKD patients. Although some studies imply pCS as an etiological factor, the relation between pCS and immune systems is poorly understood. In the present study, we investigated the immunological effects of pCS derived from intestinal bacteria in mice. For this purpose, we fed mice a tyrosine-rich diet that causes the accumulation of pCS in their blood. The mice were shown to exhibit decreased Th1 driven 2, 4-dinitrofluorobenzene-induced contact hypersensitivity response. The concentration of pCS in blood was negatively correlated with the degree of the contact hypersensitivity response. In contrast, the T cell-dependent antibody response was not influenced by the accumulated pCS. We also examined the in vitro cytokine responses by T cells in the presence of pCS. The production of IFN-gamma was suppressed by pCS. Further, pCS decreased the percentage of IFN-gamma producing Th1 cells. Our results suggest that intestinal bacteria-derived pCS suppressesTh1-type cellular immune responses. PMID- 24161590 TI - Hepato-pancreato-biliary lesions are present in both Carney complex and McCune Albright syndrome: comments on P. Salpea and C. Stratakis. AB - One of the key messages of recent Salpea and Stratakis work is to underline the clinical similarities shared by these syndromes that could be explained by a defect in the same signaling pathway, i.e. activation of the cAMP pathway. That being said, we would like to emphasize that hepatopancreato-biliary lesions are one additional feature shared both by Carney complex and McCune Albright syndrome. PMID- 24161589 TI - Mechanisms for luteinizing hormone induction of growth hormone gene transcription in fish model: crosstalk of the cAMP/PKA pathway with MAPK-and PI3K-dependent cascades. AB - In our previous studies in grass carp pituitary cells, local production of luteinizing hormone (LH) was shown to induce growth hormone (GH) production and gene expression, which constitutes a major component of the "intrapituitary feedback loop" regulating GH secretion and synthesis via autocrine/paracrine interactions between gonadotrophs and somatotrophs in the carp pituitary. To further investigate the signaling mechanisms mediating LH action at the transcriptional level, promoter studies were performed in GH3 cells co transfected with the expression vector for carp LH receptor and luciferase expressing reporter constructs with grass carp GH promoter. In this cell model, treatment with human chorionic gonadotropin (hCG) was effective in increasing GH promoter activity and the responsive sequence was mapped to position -616 and 572 of the grass carp GH promoter. GH promoter activation induced by hCG occurred with concurrent rise in cAMP production, CREB phosphorylation, and could be inhibited by inactivation of adenylate cyclase (AC), PKA, MEK1/2, P(38) MAPK, PI3K and mTOR. AC activation, presumably via cAMP production, could mimic hCG induced CREB phosphorylation and GH promoter activity, and these stimulatory effects were also sensitive to the blockade of PKA-, MAPK- and PI3K- dependent cascades. These results, as a whole, suggest that LH receptor activation in the carp pituitary may trigger GH gene transcription through CREB phosphorylation as a result of the functional crosstalk of the cAMP/PKA pathway with MAPK-and PI3K dependent cascades. PMID- 24161591 TI - Cyclic AMP enhances progesterone action in human myometrial cells. AB - Cyclic AMP (cAMP) has been shown to promote progesterone and glucocorticoid action in a variety of cellular settings. In this study, we have used human myometrial cells to investigate whether cAMP potentiates the ability of progesterone to repress IL-1beta-driven COX-2 expression. We found that forskolin enhanced progesterone-repression of IL-1beta-driven COX-2 expression in association with delayed IL-1beta-induced nuclear phospho-p65 entry and reduced NF-kappaB binding to the COX-2 promoter. Further, forskolin enhanced the progesterone-induced expression of FKBP5 and 11betaHSD1, progesterone-driven activity of a progesterone response element (PRE) and progesterone receptor (PR) B binding to a transfected PRE. In addition, forskolin treatment increased PR-B levels and reduced the PR-A:PR-B ratio while acutely decreasing the association between PR and nuclear receptor co-repressor (NCoR) and reducing NCoR levels after 6h. These findings are of importance in situations where enhancing progesterone activity is desirable, for example in the management of endometrial cancer, the promotion of endometrial receptivity or the maintenance of myometrial quiescence during pregnancy. PMID- 24161593 TI - Prediction of 94mTc production for positron emission tomography studies using the Monte Carlo code MCNPX-2.6. AB - In this study, a Monte Carlo code was used to simulate a proton beam flux to calculate the (94m)Tc production yield from the (94)Mo(p,n)(94m)Tc reaction. An experimental yield of 3.465 GBq/MUAh was measured for 48 min of irradiation at 1MUA. An estimated value of 3.048 GBq/MUAh was calculated for the yield produced based on the MCNPX proton flux in the same situation. These results demonstrate the usefulness and precision of MCNPX as a tool to design targets for the production of PET radionuclides. The yield of isotopic impurities from the (94)Mo(p,xn)(94g, 93m, 93g)Tc reactions was also calculated by the MCNPX code. PMID- 24161592 TI - Incubation of saccharin craving and within-session changes in responding for a cue previously associated with saccharin. AB - Time-dependent increases in cue-induced sucrose seeking after forced abstinence have been described in rats with a history of sucrose self-administration, suggesting sucrose craving "incubates". In the present study, we examined whether the incubation of craving generalizes to the artificial sweetener, saccharin. Thirty-one male Long-Evans rats lever pressed for 0.3% saccharin solution 1h/day for 10 days. On either Day 1 or 30 of forced abstinence, rats responded for 1h for presentation of a tone+light cue previously presented with every saccharin delivery during self-administration training. Rats responded more during this cue reactivity test session following 30 vs. 1 day of forced abstinence ("incubation of craving"). This result is the first demonstration of the "incubation of saccharin craving" and suggests that a post-ingestive caloric consequence of self administration is not a necessary condition for the development of incubation of sucrose craving. We also examined the time course (within-session decreases) of active-lever responding during the 1-h cue-reactivity test session. Rats in the Day 30 group responded more than rats in the Day 1 group from the beginning of the test session. In addition, within-session decreases in responding were shallower in slope in the Day 30 than the Day 1 group. These results indicate that "incubation of saccharin craving" enhances the persistence of seeking behavior. PMID- 24161594 TI - Genome-scale evolution and phylodynamics of H5N1 influenza virus in China during 1996-2012. AB - Highly pathogenic avian influenza A (HPAI) H5N1 is endemic in China. It is expanding its borders over time and the associated economic and health consequences are critically important. To determine the evolutionary history and phylodynamics of HPAI H5N1, a comprehensive analysis of the demographic, adaptive and spatial dynamics of H5N1 viruses in China over almost two decades based on whole genome sequences was performed. We divided HPAI H5N1 isolates into five and seven distinct groups for HA and NA respectively, and several regionally dominant subgroups were found as well. We detected five reassortants, and our analysis suggested that the intrasubtype reassortment may resulted in enhanced virulence. Seven and eight positively selected sites were detected in HA and NA genes respectively, and the relatively higher dN/dS ratio and nucleotide substitution rate were observed in NS gene. Our BSP analysis about the effective population size increase and decrease showed similar temporal patterns to those in the epidemiological studies. Here we show that the time to most recent common ancestor (tMRCA) of earlier reassortments was dated back to 1970s. And our phylogeographic analysis indicated that the geographic spread of HPAI H5N1 accelerated the viral evolution and expanded their host ranges, prompting potential cross-species transmission. PMID- 24161595 TI - Manganese superoxide dismutase is reduced in the liver of male but not female humans and rodents with non-alcoholic fatty liver disease. AB - Non-alcoholic fatty liver disease (NAFLD) is among the most common liver diseases. Oxidative stress is one of the pathogenic mechanisms contributing to the progression of simple fatty liver to non-alcoholic steatohepatitis (NASH). Manganese superoxide dismutase (MnSOD) is a mitochondrial antioxidative enzyme and here its expression in rodent and human NAFLD has been analyzed. MnSOD is found reduced in the liver of male mice fed a high fat diet and male ob/ob mice. Female mice fed an atherogenic diet to induce NASH have MnSOD protein levels comparable to controls. In a cohort of 30 controls, 41 patients with fatty liver and 39 NASH patients, MnSOD mRNA is significantly lower in the steatotic and NASH liver. When analyzed in both genders separately reduction of MnSOD expression is only found in males. Here, MnSOD mRNA negatively correlates with steatosis grade but not with extent of fibrosis or inflammation. MnSOD is, however, not reduced in primary human hepatocytes (PHH) treated with palmitate or oleate to increase cellular triglycerides. Lipopolysaccharide, TNF, IL-6, TGFbeta and leptin which are all raised in NAFLD do not affect MnSOD in PHH. Adiponectin which attenuates oxidative stress partly by increasing MnSOD in macrophages does not induce MnSOD in PHH. In summary, current data show that hepatic MnSOD is reduced in male but not female humans and rodents with NAFLD. PMID- 24161596 TI - [Epidemiology and treatment of chronic heart failure; use of bisoprolol]. AB - The prevalence of chronic heart failure in Hungary is 1.6% in the adult population, but it occurs in 15-20% of subjects over 80 years of age. The base of treatment of heart failure is the blockade of the neuro-hormonal system, which includes the use of angiotensin converting enzyme inhibitors (angiotensin receptor blockers in case of angiotensin converting enzyme inhibitors intolerance), beta receptor blockers and mineralocorticoid receptor antagonists. Because of their negative inotropic effect, beta blockers were neglected for a long time from the treatment of heart failure. However, during the past decades several studies have demonstrated that beta blockers decrease mortality in patients with heart failure. The effectiveness of bisoprolol in reducing mortality has also also been documented in a number of studies. PMID- 24161597 TI - [Obesity and hypertension]. AB - The frequency of hypertension and obesity is gradually growing in Hungary. At present 68.5% of men and 78% of women are obese. Hypertension and obesity are the most important risk factors of morbidity and mortality from cardiovascular disease. The relationship between increased sympathetic activity and hypertension is well known. Waist circumference and body fat mass correlate significantly with sympathetic activity, in which hyperlipidemia plays also a role. The increased activity of renin-angiotensin-aldosterone system via its vascular and renal effects also contributes to an increase of blood pressure. Increased sympathetic activity with decreasing vagal tone accompanying the imbalance of the autonomous nervous system is independent and significant risk factor of cardiovascular events including sudden cardiac death. PMID- 24161598 TI - [Diagnosis of cerebral hemorrhage before the era of computed tomography]. AB - INTRODUCTION: During the past decades there has been a great progress in neuroimaging methods. Cranial computed tomography is part of the daily routine now and its use allows a fast diagnosis of parenchymal hemorrhage. However, before the availability of computed tomography the differentiation between ischemic and hemorrhagic stroke was based on patient history, physical examination, percutan angiography and cerebrospinal fluid sampling, and the clinical utility could be evaluated by autopsy of deceased patients. AIM: The authors explored the diagnostic performance of cerebrospinal fluid examination for the diagnosis of ischemic and hemorrhagic stroke. METHOD: Data of 200 deceased stroke patients were retrospectively evaluated. All patients had liquor sampling at admission and all of them had brain autopsy. RESULTS: Bloody or yellowish cerebrospinal fluid at admission had a positive predictive value of 87.5% for hemorrhagic stroke confirmed by autopsy, while clear cerebrospinal fluid had positive predictive value of 90.7% for ischemic stroke. Patients who had clear liquor, but autopsy revealed hemorrhagic stroke had higher protein level in the cerebrospinal fluid, but the difference was not statistically significant (p = 0.09). CONCLUSIONS: The results confirm the importance of pathological evaluation of the brain in cases deceased from cerebral stroke. With this article the authors wanted to salute for those who contributed to the development of the Hungarian neuropathology. In this year we remember the 110th anniversary of the birth, and the 60th anniversary of the death of professor Kalman Santha. Professor Laszlo Molnar would be 90 years old in 2013. PMID- 24161599 TI - [Metabolic differences in healthy first-degree female relatives of type 2 diabetic patients]. AB - INTRODUCTION: Today the prevalence of type 2 diabetes reached an epidemic level. It is known that type 2 diabetes could only be prevented before the manifestation, during the "prediabetic" state, urging the development of diagnostic tests to recognize the group at risk in time. AIM: The authors explored metabolic differences between healthy, normal glucose tolerant, normal insulin resistant females having first degree relatives with and without type 2 diabetes. METHOD: Healthy, normal insulin sensitive females without (n = 26) and with (n = 18) type 2 diabetic relatives were investigated. RESULTS: Healthy females with first degree diabetic relatives had lower low density lipoproteins and higher high density lipoproteins as well as higher glucose and insulin levels at the 120 min of oral glucose test as compared to those without first degree diabetic relatives. CONCLUSIONS: These results suggest that the appearance of insulin resistance is preceded by hepatic insulin resistance and impaired lipid metabolism in the symptom-free prediabetic period of genetically susceptible females. PMID- 24161600 TI - [History of the therapy of pernicious anemia]. AB - Increased blood cell regeneration in exsanguinated experimental animals treated either with liver or with aqueous liver extracts was reported by Whipple and by Jeney and Jobling, respectively. These findings stimulated Minot and Murphy to provide evidence for the efficacy of liver against anaemia in clinical studies. After oral administration of liver (45-50 g per day) for 45 patients with anaemia perniciosa improvement of the hematological status was demonstrated. Consequently, for proving the therapeutic value of liver therapy Whipple, Minot and Murphy received Nobel price in 1934. The isolation of the antianemic factor from the liver has been succeeded in 1948 and designated as vitamin B12. At the same time Lucy Wills applied yeast for the treatment of pregnant women with anemia related to undernourishment. The conclusions of this study inspired the discovery of folate. The detailed investigation of the mode of action of vitamin B12 and folate enriched our knowledge in the area of pathophysiology and extended the clinical application of these two drugs. PMID- 24161601 TI - [The Bible - a medical approach, IX. "Circumcise every male at your place ..." and List of "heary hearts"]. PMID- 24161602 TI - [To the Editors regarding Tibor Gyokeres et al., "Introduction of a quality index in a Hungarian gastroenterologic endoscopy unit"]. PMID- 24161604 TI - Morphogenesis of a unique pseudourostylid ciliate, Trichototaxis songi (Ciliophora, Urostylida). AB - Divisional morphogenesis in the freshwater spirotrichous ciliate, Trichototaxis songiChen et al., 2007, was investigated. The main morphogenetic events are characterised as follows: (1) the parental oral apparatus is completely renewed by the independently formed oral primordium in the proter; (2) the oral primordium in the opisthe is formed on the cell surface; (3) several left cirri of the midventral pairs participate in the formation of the oral primordium in the opisthe; (4) FVT-anlage I forms the leftmost pair of the bicorona; (5) the macronuclear nodules fuse into many masses rather than a single or branched mass as described in most pseudokeronopsids; and (6) usually, two marginal anlagen develop within each left marginal row separately. However, the number of left marginal anlagen is highly variable, even differing between the proter and opisthe of the same divider. The increase in the number of left marginal anlagen is by de novo generation of small anlagen to the left of the intrakinetal left marginal anlage, whereas the decrease in number is by resorption of the old marginal row(s). We posit that Trichototaxis is an intermediate form between the Pseudourostylidae and Pseudokeronopsidae as it shares morphogenetic features with both. Additionally, as in Uroleptopsis (Uroleptopsis), FVT-anlage I forms the leftmost pair of the bicorona in Trichototaxis indicating these genera may be closely related. PMID- 24161603 TI - High-resolution crystal structure of the eukaryotic HMP-P synthase (THIC) from Arabidopsis thaliana. AB - Vitamin B1 is an essential compound in all organisms acting as a cofactor in key metabolic reactions. It is formed by the condensation of two independently biosynthesized molecules referred to as the pyrimidine and thiazole moieties. In bacteria and plants, the biosynthesis of the pyrimidine moiety, 4-amino-5 hydroxymethyl-2-methylpyrimidine phosphate (HMP-P), requires a single enzyme, THIC (HMP-P synthase). The enzyme uses an iron-sulfur cluster as well as a 5' deoxyadenosyl radical as cofactors to rearrange the 5-amino-imidazole ribonucleotide (AIR) substrate to the pyrimidine ring. So far, the only structure reported is the one from the bacteria Caulobacter crescentus. In an attempt to structurally characterize an eukaryotic HMP-P synthase, we have determined the high-resolution crystal structure of THIC from Arabidopsis thaliana at 1.6 A. The structure is highly similar to its bacterial counterpart although several loop regions show significant differences with potential implications for the enzymatic properties. Furthermore, we have found a metal ion with octahedral coordination at the same location as a zinc ion in the bacterial enzyme. Our high resolution atomic model shows a metal ion with multiple coordinated water molecules in the close vicinity of the substrate binding sites and is an important step toward the full characterization of the chemical rearrangement occurring during HMP-P biosynthesis. PMID- 24161605 TI - Standardization of rehabilitation after limb salvage surgery for sarcomas improves patients' outcome. AB - BACKGROUND AND OBJECTIVE: The purpose of this study is to establish a standardized postoperative rehabilitation protocol following limb salvage surgery (LSS) in patients with primary bone sarcoma in five major anatomical locations: distal femur, proximal tibia, proximal and total femur, humerus and shoulder girdle and pelvic resections. SETTING AND DESIGN: Retrospective study. PATIENTS AND METHODS: All LSSs were performed by an orthopedic oncology surgeon, and rehabilitation of all patients was based on a devised standardized rehabilitation protocol. Patient outcomes were measured using the modified Musculoskeletal Tumor Society-International Symposium on the Limb Salvage (MSTS-ISOLS) scoring system. RESULTS: A total of 59 patients received LSS in the above mentioned locations; endoprostheses were used in 49, bone allograft in five, while no replacements were made in five patients. At a mean follow-up of 24 months, the mean modified MSTS-ISOLS score for all patients was 87% (95% CI; 0.85-0.89). The highest scores were encountered for patients with distal femur replacement: 93% (95% CI; 0.91 0.95). Seven patients had interruption of more than six weeks in their rehabilitation and had a mean score of 71% (95% CI; 0.64-0.82). CONCLUSION: The proposed rehabilitation protocol is a comprehensive, organized and applicable guideline to be used after performing LSS at the above mentioned anatomical locations. The use of standardized rehabilitation protocol resulted in improved patient functional outcome. PMID- 24161606 TI - Mesenchymal stem cells promote leukaemic cells aberrant phenotype from B-cell acute lymphoblastic leukaemia. AB - BACKGROUND AND OBJECTIVES: The role of bone marrow-mesenchymal stem cells (BM MSC) in leukaemic cell control is controversial. The purpose of this work was to evaluate BM-MSC role regarding the viability, proliferation and immunophenotype of normal B-cell precursors from control (Ct) patients and leukaemic cells from B acute lymphoblastic leukaemia (B-ALL) patients. PATIENTS AND METHODS: BM-MSC were isolated and characterised from voluntary donors. Mononuclear cells isolated from Ct and B-ALL bone marrow samples were cultured in the presence or absence of BM MSC for 7days. Cell viability was determined with LIVE/DEAD and proliferation index evaluated by CFSE labelling. Cell population immunophenotypes were characterised by estimating CD19, CD10, CD20 and CD45 antigens by flow cytometry. RESULTS: After co-culture, B-ALL cells exhibited higher viability (20-40%) as compared to just cells (3-10%). Ct and B-ALL absolute cell counts were higher in the presence of BM-MSC (Ct: 25/mm(3)cf8/mm(3), B-ALL: 15/mm(3)cf3/mm(3)). Normal B-cell subpopulations in co-culture had increased expression of CD19 and CD10 (Pre-pre B) and CD45 and CD20 antigens (Pre-B). B-ALL cells co-cultured with BM MSC showed an increase in CD19 and CD20, although the greatest increase was observed in the CD10 antigen. CONCLUSIONS: Lymphoid cell maintenance, at early stages of differentiation, was significantly promoted by BM-MSC in normal and leukaemic cells. Co-cultures also modulated the expression of antigens associated with the B-ALL asynchronous phenotype as CD10 co-expressed with CD19 and CD20. To our knowledge, this is the first time that CD10, CD19 and CD20 leukaemic antigens have been reported as being regulated by BM-MSC. PMID- 24161607 TI - Isolated and combined effects of asymmetric stance and pushing movement on the anticipatory and compensatory postural control. AB - OBJECTIVE: To investigate effects of symmetric and asymmetric stance and pushing movement on anticipatory and compensatory postural adjustments (APAs and CPAs). METHODS: Ten healthy volunteers stood symmetrically (feet parallel) or asymmetrically (one foot forward and the other backward) and pushed a handle with both hands or right or left hand. Bilateral EMG activity of the trunk and leg muscles and center of pressure (COP) displacements in the anterior-posterior (AP) and medial-lateral (ML) directions were recorded and analyzed during the APAs and CPAs. RESULTS: Isolated asymmetry of stance was associated with larger muscle activity of the backward leg while isolated asymmetry of pushing movement induced larger trunk muscle activity on the contralateral side. A combined asymmetry of stance and pushing movement resulted in the increase or decrease of the thigh muscle activity and ML COP displacement depending on whether both asymmetries were induced on the same side of the body or on opposite sides. CONCLUSIONS: Both isolated and combined asymmetries affect APAs and CPAs in pushing. Using combined asymmetry of stance and arm movement might be beneficial in performing pushing activity. SIGNIFICANCE: The outcome of the study provides a basis for studying postural control in individuals with unilateral impairment while performing daily tasks involving pushing. PMID- 24161609 TI - Enhancement and in vitro evaluation of amifostine permeation through artificial membrane (PAMPA) via ion pairing approach and mechanistic selection of its optimal counter ion. AB - This study presents the results of in vitro evaluation of a series of organic counter ions that form ion pairs with amifostine. The selected counter ions have different lipophilicity, shape and flexibility. Intrinsic octanol buffer partition coefficient and binding constant of the ion pairs were calculated using quasi-equilibrium analysis. Permeation through hydrophobic PAMPA membranes of amifostine and its ion pairs with different counter ions was studied. Three counter ions, succinic acid, benzoic acid and phthalic acid demonstrated an increase in the apparent partition coefficient of amifostine in n-octanol. These counter ions were selected for permeability experiments in PAMPA membranes and an increase of the apparent permeability value Papp (cm/s) was also observed as a function of the counter ion concentration. Phthalic acid produced 1.6-fold increase of log PAB while for benzoic acid and succinic acid the values were 1.2 and 0.75-fold respectively. PAMPA permeability of amifostine significantly increased in the presence of phthalic acid (42-fold), benzoic acid (37-fold) and succinic acid (10.5-fold). This study showed that the permeability of amifostine across a lipophilic membrane was enhanced in the presence of counter-ions resulting ion pair formation. PMID- 24161608 TI - Co-modulation of finely tuned high-gamma band activity across hemispheres in Parkinson's disease. AB - OBJECTIVE: Dopaminergic treatment of patients with Parkinson's disease can be associated with a finely tuned high-gamma (FTG) band oscillation between 60 and 90 Hz in the basal ganglia (BG) nuclei. This activity, together with suppression of excessive neural synchrony in the beta frequency band (15-30 Hz), is hypothesized to contribute to the pro-kinetic effects of dopaminergic medication. Beta activity, which high-gamma replaces, has been shown to be bilaterally coherent, but whether sub-cortical FTG activity is in some way linked across hemispheres remains unknown. METHODS: We analyse bilateral local field potential activity recorded from the subthalamic nuclei of 10 patients on dopaminergic medication while at rest, following surgery for deep brain stimulation. RESULTS: In three of these patients FTG activities were coherent across the hemispheres. Short duration (<=18 s) bilateral amplitude and frequency co-modulation were recorded in all subjects, although the two phenomena were independent in time and independent of similar episodes in other frequency bands. CONCLUSIONS: FTG co modulation can be independent of movement and of co-modulation episodes at other frequencies. SIGNIFICANCE: Relatively independent organisation of processing through amplitude and frequency modulation within different frequency bands potentially affords opportunities for functional segregation and multiplexing of processing streams within the BG. PMID- 24161610 TI - Molecular phylogenetic analysis of the Papionina using concatenation and species tree methods. AB - The Papionina is a geographically widespread subtribe of African cercopithecid monkeys whose evolutionary history is of particular interest to anthropologists. The phylogenetic relationships among arboreal mangabeys (Lophocebus), baboons (Papio), and geladas (Theropithecus) remain unresolved. Molecular phylogenetic analyses have revealed marked gene tree incongruence for these taxa, and several recent concatenated phylogenetic analyses of multilocus datasets have supported different phylogenetic hypotheses. To address this issue, we investigated the phylogeny of the Lophocebus + Papio + Theropithecus group using concatenation methods, as well as alternative methods that incorporate gene tree heterogeneity to estimate a 'species tree.' Our compiled DNA sequence dataset was ~56 kb pairs long and included 57 independent partitions. All analyses of concatenated alignments strongly supported a Lophocebus + Papio clade and a basal position for Theropithecus. The Bayesian concordance analysis supported the same phylogeny. A coalescent-based Bayesian method resulted in a very poorly resolved species tree. The topological agreement between concatenation and the Bayesian concordance analysis offers considerable support for a Lophocebus + Papio clade as the dominant relationship across the genome. However, the results of the Bayesian concordance analysis indicate that almost half the genome has an alternative history. As such, our results offer a well-supported phylogenetic hypothesis for the Papio/Lophocebus/Theropithecus trichotomy, while at the same time providing evidence for a complex evolutionary history that likely includes hybridization among lineages. PMID- 24161611 TI - Graphene-based immunoassay for human lipocalin-2. AB - We have developed a highly sensitive immunoassay using graphene nano platelets (GNPs) for the rapid detection of human lipocalin-2 (LCN2) in plasma, serum, and whole blood. It has the dynamic range, linear range, limit of detection, and analytical sensitivity of 0.6 to 5120, 80 to 2560, 0.7, and 1pg/ml, respectively. It is the most sensitive assay for the detection of LCN2, which has 80-fold higher analytical sensitivity and 3-fold lesser immunoassay duration than the commercially available sandwich enzyme-linked immunosorbent assay (ELISA) kit. The functionalization of microtiter plate (MTP) with GNPs, dispersed in 3 aminopropyltriethoxysilane (APTES), provided the increased surface area that leads to higher immobilization density of capture antibodies. Moreover, the generation of free amino groups on MTP and GNPs by APTES enables the leach-proof covalent crosslinking of anti-human LCN2 capture antibody by its carboxyl groups using 1-ethyl-3-[3-dimethylaminopropyl]carbodiimide hydrochloride (EDC) as the heterobifunctional crosslinker. The anti-LCN2 antibody-bound MTPs were highly stable given that they did not show any significant decrease in their functional activity when stored at 4 degrees C in 0.1M phosphate-buffered saline (PBS) for 8weeks. The developed immunoassay correlated well with the conventional ELISA, thereby demonstrating its high precision and potential utility for highly sensitive analyte detection in industrial and clinical settings. PMID- 24161612 TI - The best approach: homogenization or manual permeabilization of human skeletal muscle fibers for respirometry? AB - The number of studies on mitochondrial function is growing as a result of the recognition of the pivotal role of an intact mitochondrial function in numerous diseases. Measurements of oxygen consumption by the mitochondria in human skeletal muscle are used in many studies. There are several advantages of studying mitochondrial respiration in permeabilized fibers (Pfi), but the method requires a manual procedure of mechanical separation of the fiber bundles in the biopsy and chemical permeabilization of the cell membrane. This is time-consuming and subject to interpersonal variability. An alternative is to use a semiautomatic tool for preparation of a homogenate of the muscle biopsy. We investigated whether the PBI shredder is useful in preparing a muscle homogenate for measurements of mitochondrial respiratory capacity. The homogenate is compared with the Pfi preparation. Maximal respiratory capacity was significantly reduced in the homogenate compared with the Pfi from human skeletal muscle. A marked cytochrome c response was observed in the homogenate, which was not the case with the Pfi, indicating that the outer mitochondrial membrane was not intact. The mitochondria in the homogenate were more uncoupled compared with the Pfi. Manual permeabilization is an advantageous technique for preparing human skeletal muscle biopsies for respirometry. PMID- 24161614 TI - A target-triggered strand displacement reaction cycle: the design and application in adenosine triphosphate sensing. AB - A strand displacement reaction (SDR) system that runs solely on oligonucleotides has been developed for the amplification detection of adenosine triphosphate (ATP). It involves a target-induced SDR and an entropy-driven catalytic cycle of two SDRs with five oligonucleotides, denoted as substrate, fuel, catalyst, C-1, and C-2. Catalyst, released from the ATP aptamer-catalyst duplex by ATP molecule, catalyzes the SDRs to finally form the substrate-fuel duplex. All of the intermediates in the catalytic SDR processes have been identified by polyacrylamide gel electrophoresis (PAGE) analysis. The introduction of ATP into the SDR system will induce the ATP aptamer to form G-quadruplex conformation so as to release catalyst and trigger the SDR cycle. When the substrate and C-2 oligonucleotides were labeled with a carboxyfluorescein (FAM) fluorophore and a 4 ([4-(dimethylamino)phenyl]azo)benzoic acid (DABCYL) quencher, this SDR catalytic system exhibited a "turn-on" response for ATP. The condition for detecting ATP, such as Mg2+ concentration, has been optimized to afford a detection limit of 20 nM. This work provides an enzyme-free biosensing strategy and has potential application in aptamer-based biosensing. PMID- 24161615 TI - Comparison of two approaches for quantitative O-linked glycan analysis used in characterization of recombinant proteins. AB - The principal aim of this study was to demonstrate the optimization and fine tuning of quantitative and nonselective analysis of O-linked glycans released from therapeutic glycoproteins. Two approaches for quantitative release of O linked glycans were examined: ammonia-based beta-elimination and hydrazinolysis deglycosylation strategies. A significant discrepancy in deglycosylation activity was observed between the ammonia-based and hydrazinolysis procedures. Specifically, the release of O-glycans from glycoproteins was approximately 20 to 30 times more efficient with hydrazine compared with ammonia-based beta elimination reagent. In addition, the ammonia-based reagent demonstrated bias in the release of particular glycan species. A robust quantitative hydrazinolysis procedure was developed for characterization of O-glycans. The method performance parameters were evaluated. It was shown that this procedure is superior for quantitative nonselective release of O-glycans. Identity confirmation and structure elucidation of O-glycans from hydrophilic interaction chromatography (HILIC) fractions was also demonstrated using linear ion trap Fourier transform mass spectrometry (LTQ FT MS) with mass accuracy below 1ppm. PMID- 24161613 TI - Inhibition of protein carbamylation in urea solution using ammonium-containing buffers. AB - Urea solution is one of the most commonly employed protein denaturants for protease digestion in proteomic studies. However, it has long been recognized that urea solution can cause carbamylation at the N termini of proteins/peptides and at the side chain amino groups of lysine and arginine residues. Protein/peptide carbamylation blocks protease digestion and affects protein identification and quantification in mass spectrometry analysis by blocking peptide amino groups from isotopic/isobaric labeling and changing peptide charge states, retention times, and masses. In addition, protein carbamylation during sample preparation makes it difficult to study in vivo protein carbamylation. In this study, we compared the peptide carbamylation in urea solutions of different buffers and found that ammonium-containing buffers were the most effective buffers to inhibit protein carbamylation in urea solution. The possible mechanism of carbamylation inhibition by ammonium-containing buffers is discussed, and a revised procedure for the protease digestion of proteins in urea and ammonium containing buffers was developed to facilitate its application in proteomic research. PMID- 24161616 TI - Biochemical characterization of the venom of the coral snake Micrurus tener and comparative biological activities in the mouse and a reptile model. AB - The objective of this study was to identify the venom components that could play a relevant role during envenomation caused by the coral snake Micrurus tener, through its biochemical characterization as well as the analysis of its effects on a murine model. Furthermore, it aimed to evaluate crude venom, in addition to its components, for possible specificity of action on a natural prey model (Conopsis lineata). The toxicity of the crude venom (delivered subcutaneously) showed a significant difference between the Median Lethal Dose (LD50) in mice (4.4 MUg/g) and in Conopsis lineata (12.1 MUg/g) that was not observed when comparing the Median Paralyzing Dose (PD50) values (mice = 4.7 MUg/g; snakes = 4.1 MUg/g). These results are evidence that the choice of study model strongly influences the apparent effects of crude venom. Moreover, based on the observed physical signs in the animal models, it was concluded that the most important physical effect caused by the venom is flaccid paralysis, which facilitates capture and subduing of prey regardless of whether it is alive; death is a logical consequence of the lack of oxygenation. Venom fractionation using a C18 reverse phase column yielded 35 fractions from which 16.6% caused paralysis and/or death to both animal models, 21.9% caused paralysis and/or death only to C. lineata and 1.6% were murine specific. Surprisingly, the diversity of snake specific fractions did not reflect a difference between the PD50s of the crude venom in mice and snakes, making it impossible to assume some type of specificity for either of the study models. Finally, the great diversity and abundance of fractions with no observable effect in snakes or mice (42.7%) suggested that the observed lethal fractions are not the only relevant toxic fractions within the venom and emphasized the possible relevance of interaction between components to generate the syndrome caused by the venom as a whole. PMID- 24161617 TI - beta-Phenylethylamine requires the dopamine transporter to increase extracellular dopamine in Caenorhabditis elegans dopaminergic neurons. AB - beta-Phenylethylamine (betaPEA) is an endogenous amine that has been shown to increase the synaptic levels of dopamine (DA). A number of in vitro and behavioral studies suggest the dopamine transporter (DAT) plays a role in the effects generated by betaPEA, however the mechanism through which betaPEA affects DAT has not yet been elucidated. Here, we used Caenorhabditis (C.) elegans DAT (DAT-1) expressing LLC-pk1 cells and neuronal cultures to investigate whether the betaPEA-induced increase of extracellular DA required DAT-1. Our data show that betaPEA increases extracellular dopamine both in DAT-1 transfected cells and cultures of differentiated neurons. RTI-55, a cocaine homologue and DAT inhibitor, completely blocked the betaPEA-induced effect in transfected cells. However in neuronal cultures, RTI-55 only partly inhibited the increase of extracellular DA generated by betaPEA. These results suggest that betaPEA requires DAT-1 and other, not yet identified proteins, to increase extracellular DA when tested in a native system. Furthermore, our results suggest that betaPEA induced increase of extracellular DA does not require functional monoamine vesicles as genetic ablation of the C. elegans homologue vesicular monoamine transporter, cat-1, did not compromise the ability of betaPEA to increase extracellular DA. Finally, our electrophysiology data show that betaPEA caused fast-rising and self-inactivating amperometric currents in a subset of wild-type DA neurons but not in neurons isolated from dat-1 knockout animals. Taken together, these data demonstrate that in both DA neurons and heterogeneous cultures of differentiated C. elegans neurons, betaPEA releases cytoplasmic DA through DAT-1 to ultimately increase the extracellular concentration of DA. PMID- 24161618 TI - Knockout of Toll-like receptor 2 attenuates Abeta25-35-induced neurotoxicity in organotypic hippocampal slice cultures. AB - Toll-like receptors (TLRs), which have been implicated in various neuroinflammatory responses, are thought to act in defense mechanisms by inhibiting neuronal cell death in Alzheimer's disease. In this study, we evaluated the effects of TLR2 on amyloid beta peptide 25-35 (Abeta25-35)-induced neuronal cell death, synaptic dysfunction, and microglial activation in organotypic hippocampal slice cultures (OHSCs) from wild-type (WT) C57BL/6 mice and TLR2-knockout (KO) mice. In WT mice, Abeta25-35 induced beta-amyloid aggregation and surrounding TLR2 expression. And, propidium iodide (PI) uptake, which is a measure of cell death, increased in a dose-dependent manner in slices with Abeta25-35 treatment. In the Abeta25-35-treated TLR2-KO OHSCs, the PI uptake was significantly attenuated to the control level, indicating that the cells were less susceptible to Abeta25-35-induced neuronal toxicity. In the ultrastructural analysis, nuclear shrinkage, slightly swollen mitochondria, and degraded organelles were detected in the Abeta25-35-treated slices from WT mice but not in the Abeta25-35-treated slices from TLR2-KO, suggesting the resistance of TLR2-KO to Abeta25-35-induced neurotoxicity. In Abeta25-35-treated OHSCs of WT mice, the levels of phosphorylated tau were increased and the levels of synaptophysin were decreased in a dose-dependent manner, but they were not changed in OHSCs of TLR2 KO mice. In WT mice, Abeta25-35 increased total protein level and immunoreactivity of Iba-1, which was colocalized with TLR2. However, there were no significant changes in the slices of Abeta25-35-treated TLR2-KO mice. These results suggested that TLR2 may play a role in Abeta25-35-induced neuronal cell loss and synaptic dysfunction through the activation of microglia in OHSCs. PMID- 24161620 TI - Cerebrospinal fluid light and heavy neurofilaments in neuromyelitis optica. AB - BACKGROUND: Axonal injury is the correlate of disease progression in NMO and MS. Neurofilament (Nf) belongs to neuron specific intermediate filaments located in axons. Nf protein subunits are potential biomarkers in cerebrospinal fluid (CSF) for acute axonal injury. However, whether CSF NfH and NfL levels are elevated in NMO patients has remained unclear. METHODS: Nf light subunit (NfL) and Nf heavy subunit NfH in cerebrospinal fluid were measured by enzyme-linked immunosorbent assay (ELISA) in NMO (n=32), MS (n=25), and other non-inflammatory neurological disease patients (OND, n=18). RESULTS: CSF pNf-H levels were increased in the NMO patients compared with OND patients (p=0.001). CSF NfL levels in the NMO patients were also higher compared with MS patients (p=0.001), and OND patients (p=0.000001). When comparing NfL levels between MS and OND patients, there also significant differences (p=0.0003). NMO and MS patients revealed a trend to an increased disability with increased CSF NfL during relapse (NMO: p=0.006; MS: p=0.017). There is positive relationship between CSF pNf-H and disability of MS patients (p=0.041). CONCLUSIONS: CSF levels of NfL are increased in NMO patients and reflect the disease severity in NMO. PMID- 24161619 TI - Stereoselective inhibition of serotonin transporters by antimalarial compounds. AB - The serotonin (5-HT) transporter (SERT) is an integral membrane protein that functions to reuptake 5-HT released into the synapse following neurotransmission. This role serves an important regulatory mechanism in neuronal homeostasis. Previous studies have demonstrated that several clinically important antimalarial compounds inhibit serotonin (5-hydroxytryptamine, 5-HT) reuptake. In this study, we examined the details of antimalarial inhibition of 5-HT transport in both Drosophila (dSERT) and human SERT (hSERT) using electrophysiologic, biochemical and computational approaches. We found that the cinchona alkaloids quinidine and cinchonine, which have identical stereochemistry about carbons 8 and 9, exhibited the greatest inhibition of dSERT and hSERT transporter function whereas quinine and cinchonidine, enantiomers of quinidine and cinchonine, respectively, were weaker inhibitors of dSERT and hSERT. Furthermore, SERT mutations known to decrease the binding affinity of many antidepressants affected the cinchona alkaloids in a stereo-specific manner where the similar inhibitory profiles for quinine and cinchonidine (8S,9R) were distinct from quinidine and cinchonine (8R,9S). Small molecule docking studies with hSERT homology models predict that quinine and cinchonidine bind to the central 5-HT binding site (S1) whereas quinidine and cinchonine bind to the S2 site. Taken together, the data presented here support binding of cinchona alkaloids to two different sites on SERT defined by their stereochemistry which implies separate modes of transporter inhibition. Notably, the most potent antimalarial inhibitors of SERT appear to preferentially bind to the S2 site. Our findings provide important insight related to how this class of drugs can modulate the serotonergic system as well as identify compounds that may discriminate between the S1 and S2 binding sites and serve as lead compounds for novel SERT inhibitors. PMID- 24161621 TI - Differential sensitivity of p44/p42-MAPK- and PI3K/Akt-targeted neuroblastoma subtypes to arsenic trioxide. AB - PI3K/Akt and MAPK/ERK pathways are differentially activated in neuroblastoma (NB) cell types. In an effort to enhance the effectiveness of the NB treatment, we designed experiments to evaluate the effects of ATO in combination with PI3K and MEK1/2 specific inhibitors, LY29004 and U0126, respectively, in SK-N-MC and SK-N BE(2) cell lines. The results indicated that specific inhibition of PI3K and MEK1/2 significantly enhanced antiproliferative and proapoptotic effects of ATO in SK-N-BE(2), but not in SK-N-MC. Furthermore, in SK-N-BE(2), NF-kappaB activation was significantly suppressed by LY29004+ATO treatments as compared with ATO alone, indicating that inhibition of PI3K may enhance anti-neoplastic properties of ATO in I-type NB cells through suppression of NF-kappaB. Moreover, expressions of c-Myc, Bad, Bax and ATM in SK-N-BE(2) cell line were significantly increased by U0126+ATO treatment as compared to treatment with ATO alone. Expression of telomerase hTERT was almost depleted by U0126+ATO treatment. Regarding the fact that activation of PI3K and MAPK in SK-N-BE(2) is higher than in other NB subtypes, we hypothesize that growth of SK-N-BE(2) cell line is highly dependent on these pathways and inhibition of these pathways may has promise for the treatment of multi-drug resistant I-type NB cells by ATO. However, for successful strategies for the treatment of this heterogeneous tumor, other combinations approaches need to be considered to simultaneously target other NB cells. PMID- 24161622 TI - Pre-licensed driving experience and car crash involvement during the learner and restricted, licence stages of graduated driver licensing: Findings from the New Zealand drivers study. AB - OBJECTIVE: The aim of this study was to determine whether pre-licence driving experiences, that is driving before beginning the licensing process, increased or decreased crash risk as a car driver, during the learner or the restricted licence stages of the graduated driver licensing system (GDLS). METHOD: Study participants were 15-24 year old members of the New Zealand Drivers Study (NZDS) a prospective cohort study of newly licensed car drivers. The interview stages of the NZDS are linked to, the three licensing stages of the GDLS: learner, restricted and full. Baseline demographic (age, ethnicity, residential location, deprivation), personality (impulsivity, sensation seeking, aggression) and, behavioural data, (including pre-licensed driving behaviour), were obtained at the learner licence interview. Data on distance driven and crashes that occurred at the learner licence and restricted licence stages, were reported at the restricted and full licence interviews, respectively. Crash data were also obtained from police traffic crash report files and this was combined with the self-reported crash data. The analysis of the learner licence stage crashes, when only supervised driving is allowed, was based on the participants who had passed the restricted licence test and undertaken the NZDS, restricted licence interview (n=2358). The analysis of the restricted licence stage crashes, when unsupervised driving is first allowed, was based on those who had passed the full licence test and completed the full licence interview (n=1428). RESULTS: After controlling for a range of demographic, personality, behavioural variables and distance driven, Poisson regression showed that the only pre-licence driving behaviour that showed a consistent relationship with subsequent crashes was on-road car driving which was associated with an increased risk of being the driver in a car crash during the learner licence period. CONCLUSION: This research showed that pre-licensed driving did not reduce crash risk among learner or restricted licensed drivers, and in some cases (such as on-road car driving) may have increased risk. Young people should be discouraged from the illegal behaviour of driving a car on-road before licensing. PMID- 24161623 TI - Murine double minute 2 siRNA and wild-type p53 gene therapy enhances sensitivity of the SKOV3/DDP ovarian cancer cell line to cisplatin chemotherapy in vitro and in vivo. AB - SKOV3/DDP cells urgently require an efficient therapy to improve drug resistance. Here we show a critical role for cisplatin combined with gene therapy, using transfection of a p53 gene/MDM2-siRNA plasmid, in improving cisplatin sensitivity of SKOV3/DDP cells with a strong inhibition of tumor cell growth in vitro and in vivo. The effects may be associated with enhancement of intracellular platinum accumulation via decreased MDR1/P-gp and improvement of apoptotic resistance via increased P53, PUMA and NOXA expression. The combined therapy may efficiently inhibit cell invasion and migration via deceased HIF-1, VEGF, MMP-9 and MMP-2 to suppress malignant progression. These results indicate that cisplatin chemotherapy combined with targeting the MDM2/p53 axis is an attractive strategy to treat SKOV3/DDP cancer. PMID- 24161624 TI - Increase of lysosomal phospholipase A2 in aqueous humor by uveitis. AB - This study was conducted to elucidate pathophysiological roles of the lysosomal phospholipase A2 (LPLA2), a phospholipid-degrading enzyme, of the aqueous humor (AH) in uveitis using an animal model and clinical specimens. Endotoxin-induced uveitis (EIU) was induced by subcutaneous injections of lipopolysaccharide from Escherichia coli to seven-week-old male Lewis rats. Inflammation of the anterior chamber (AC) was evaluated by measurement of the protein concentration of rat AH. The LPLA2 activity in the AH, serum and cerebrospinal fluid obtained from EIU rats was detected using liposomes consisting of 1,2 dioleoylphosphatidylglycerol/N-acetylsphingosine as the substrate under acidic conditions. Immunohistochemical analysis was performed using antibodies against CD11b and LPLA2. Sixty-five human AH specimens, in which 11 eyes had a history of chronic uveitis, were collected during patient cataract surgeries and used to determine LPLA2 activity. The LPLA2 activity in rat AH was significantly increased by EIU induction, and was correlated to the extent of inflammation in the AC. By contrast, the LPLA2 activity in rat serum or cerebrospinal fluid was not influenced by EIU induction. According to the immunohistochemistry, LPLA2 was found in CD11b positive cells in the AC of the EIU rats. In the clinical specimens, the AH obtained from the patients with a history of uveitis possessed significantly higher LPLA2 activity than that from the senile patients with cataract but without other ocular diseases. These results demonstrate that the LPLA2 activity in the AH is augmented with the inflammation in the AC and suggest that the LPLA2 in the AH participates in the inflammation process in the AC. PMID- 24161625 TI - Functional brain network analysis using minimum spanning trees in Multiple Sclerosis: an MEG source-space study. AB - Cognitive dysfunction in Multiple Sclerosis (MS) is closely related to altered functional brain network topology. Conventional network analyses to compare groups are hampered by differences in network size, density and suffer from normalization problems. We therefore computed the Minimum Spanning Tree (MST), a sub-graph of the original network, to counter these problems. We hypothesize that functional network changes analysed with MSTs are important for understanding cognitive changes in MS and that changes in MST topology also represent changes in the critical backbone of the original brain networks. Here, resting-state magnetoencephalography (MEG) recordings from 21 early MS patients and 17 age-, gender-, and education-matched controls were projected onto atlas-based regions of-interest (ROIs) using beamforming. The phase lag index was applied to compute functional connectivity between regions, from which a graph and subsequently the MST was constructed. Results showed lower global integration in the alpha2 (10 13Hz) and beta (13-30Hz) bands in MS patients, whereas higher global integration was found in the theta band. Changes were most pronounced in the alpha2 band where a loss of hierarchical structure was observed, which was associated with poorer cognitive performance. Finally, the MST in MS patients as well as in healthy controls may represent the critical backbone of the original network. Together, these findings indicate that MST network analyses are able to detect network changes in MS patients, which may correspond to changes in the core of functional brain networks. Moreover, these changes, such as a loss of hierarchical structure, are related to cognitive performance in MS. PMID- 24161626 TI - Neural correlates of second-order verbal deception: a functional near-infrared spectroscopy (fNIRS) study. AB - The present study focused on neural correlates underlying second-order deception. In first-order deception, the recipient of deception is unaware of the deceiver's deceptive intention. However, during second-order deception, the recipient is fully aware of the deceiver's deceptive intention and thus the deceiver needs to use both lies and truths to deceive the recipient. Using the functional near infrared spectroscopy (fNIRS) methodology and a naturalistic interactive game, we found that second-order deception elicited significantly greater [oxy-Hb] changes in the prefrontal cortex (the right superior frontal gyrus (SFG), BA6) than the non-deceptive control condition. This finding suggests that second-order deception, like first-order deception, engages specifically the cortical regions associated with the planning of complex actions and goal processing. We also found that lying to deceive produced greater neural activities in the right middle frontal gyrus than truth-telling to deceive. This suggests that although both actions serve deceptive purposes, making a false statement contradicting the true state of affairs still requires more executive control and thus greater neural responses in the cortical regions associated with this function. In addition, we found that the successful deception produced greater neural activities in a broad area of the prefrontal frontal cortex than failure to deceive, indicating the involvement of the cortical reward system during second order deception. Further, failure of truth-telling to deceive produced greater neural responses in the right SFG than failure of lying to deceive. The present findings taken together suggest that second-order deception engages both the cortical executive and reward systems. PMID- 24161627 TI - How do we define "difficult" patients? PMID- 24161628 TI - Death happens every day. AB - I finally got to read my pile of journals that had been occupying my coffee table for the summer. I usually take a few volumes and hole up on the couch absorbing the new research that has come out. I was personally touched by Dr. Anne Katz's (2013) editorial in the July issue of the Oncology Nursing Forum titled "Scar Tissue in the Heart." It has happened before with her articles, but this time was a little more poignant than ever before. I felt like she was articulating thoughts that I have in my own head in a clearer way than I could ever express them myself. Dr. Katz, stop reading my mind. PMID- 24161629 TI - Is dyspnea management evidence-based? AB - Reviewing the articles published in the past 40 years in the Oncology Nursing Forum (ONF) can assist in the identification of trends related to lung cancer treatment and management. Fifty-eight articles or studies published in ONF during that time were specific to lung cancer. The total number of published articles increased with each decade, but no articles were identified in the 1970s. The topics were quite varied, with each of the following represented by three or more articles: symptom clusters, radiation, smoking cessation, dyspnea, nutrition, and quality of life. To better focus this review on a specific aspect of lung cancer management, dyspnea was chosen. PMID- 24161630 TI - Professional development for oncology nurses: a commitment to lifelong learning. AB - Think back to the day you graduated from your entry-level nursing program. The feelings we experienced at that time are likely universal, whether that day was one year ago or more than 40 years ago. No more tests, no more papers, no more clinical skills practice, and no more preparing the dreaded nursing care plan. School was finished. We all looked forward to passing our nursing boards and getting our first real nursing jobs. Certainly, we all had some vague idea that during our life as nurses we would, at some time, have to learn a new skill, or work with a new type of equipment; however, many of us did not seriously contemplate or acknowledge that we were embarking on a career path that expected us to be lifelong learners. Little did we know that engaging in the process of lifelong learning is not necessarily something that comes naturally; it is, in fact, a personal commitment that each of us makes to the pursuit of learning throughout our professional career. PMID- 24161631 TI - Acute pain transfusion reaction. AB - A 34-year-old woman with a diagnosis of hemophagocytic lymphohistocytosis (HLH) received a double umbilical cord blood transplantation following a myeloablative chemotherapy preparative regimen with busulfan and cyclophosphamide. HLH is a rare, potentially fatal hematologic disorder characterized by the overactivation of histocytes and T lymphocytes, leading to organ infiltration and acute illness. On day 25 post-transplantation, the patient required a platelet transfusion for a platelet count of 6,000 per ml (normal range = 150,000-450,000 per ml). The patient's blood type prior to the cord blood transplantation was B positive and, although both umbilical cord blood donors were O positive, the patient was still B positive per blood bank testing on that day. Although the recipient of an allogenic stem cell transplantation will eventually become the blood type of the donor, the time for this process to occur varies for each person. That process must be monitored by the blood bank for the purpose of cross-matching blood products to decrease hemolysis as much as possible. The patient was premedicated with the facility's standard for platelet transfusions: acetaminophen 650 mg and diphenhydramine 25 mg about 30 minutes prior to the platelet transfusion. PMID- 24161632 TI - Understanding CYP2D6 and its role in tamoxifen metabolism. AB - The gene CYP2D6 has an extremely important role in drug metabolism. "Cytochrome P450, family 2, subfamily D, polypeptide 6" is the official name of CYP2D6. The gene is located at position 13.1 on the long (q) arm of chromosome 21 and encodes a member of the cytochrome P450 superfamily of enzymes. The cytochrome P450 proteins are monooxygenases that are heavily involved in drug metabolism (Genetics Home Reference, 2013), and many drugs are activated into their biologically active compounds. Because of numerous polymorphisms, the gene also has significant person-to-person variability. To date, more than 80 distinct CYP2D6 alleles and specific types and frequencies have been associated with different ethnic groups. CYP2D6*4 is the most common variant allele in Caucasians and, in that population, has a frequency of about 25%. On the other hand, CYP2D6*10 is common in the Asian population (Stearns & Rae, 2008). PMID- 24161633 TI - Identification of tools to measure changes in musculoskeletal symptoms and physical functioning in women with breast cancer receiving aromatase inhibitors. AB - PURPOSE/OBJECTIVES: To estimate and compare responsiveness of standardized self reported measures of musculoskeletal symptoms (MSSs) and physical functioning (PF) during treatment with aromatase inhibitors (AIs). DESIGN: Prospective, longitudinal study. SETTING: Park Nicollet Institute and North Memorial Cancer Center, both in Minneapolis, MN. SAMPLE: 122 postmenopausal women with hormone receptor-positive breast cancer. METHODS: MSSs and PF were assessed before starting AIs and at one, three, and six months using six self-reported MSSs measures and two PF tests. MAIN RESEARCH VARIABLES: MSSs and PF changes from baseline to six months. FINDINGS: Using the Breast Cancer Prevention Trial Musculoskeletal Symptom (BCPT-MS) subscale, 54% of participants reported MSSs by six months. Scores from the BCPT-MS subscale and the physical function subscales of the Australian/Canadian Osteoarthritis Hand Index (AUSCAN) and Western Ontario and McMaster Osteoarthritis Index (WOMAC) were most responsive to changes over six months. CONCLUSIONS: BCPT-MS, AUSCAN, and WOMAC were the most responsive instruments for measuring AI-associated MSSs. IMPLICATIONS FOR NURSING: Assessment and management of MSSs are important aspects of oncology care because MSSs can affect functional ability and AI adherence. KNOWLEDGE TRANSLATION: The three measures with the greatest sensitivity were the BCPT-MS, AUSCAN, and WOMAC questionnaires. These measures will be useful when conducting research on change in MSSs associated with AI treatment in women with breast cancer. PMID- 24161634 TI - Spiritual growth and decline among patients with cancer. AB - PURPOSE/OBJECTIVES: To investigate spiritual transformation among patients with cancer. DESIGN: Longitudinal. SETTING: A university medical center in the midwestern United States. SAMPLE: 47 adult cancer survivors. METHODS: Patients were asked about spirituality, religious and spiritual importance, religious coping, and spiritual gain and decline at baseline as well as nine months post treatment. MAIN RESEARCH VARIABLES: Religious importance, religious coping, and spiritual gain or decline. FINDINGS: Positive religious coping at baseline predicted spiritual growth at the nine-month follow-up point. Spiritual decline was predicted by negative religious importance. A bivariate relationship existed between increased levels of negative religious coping and increased spiritual growth. CONCLUSIONS: Positive religious coping strategies may influence spiritual transformation. IMPLICATIONS FOR NURSING: Healthcare providers who support a strengths-based perspective on human functioning may be equipped to perform research on spiritual or religious interventions for patients with cancer. KNOWLEDGE TRANSLATION: Greater use of spiritual resources, even if conceptualized as negative religious coping mechanisms or initial spiritual decline, may contribute to increased levels of spiritual growth later. When acting as expert companions, healthcare providers may facilitate spiritual growth by addressing spiritual transformation, creating safe environments for exploring spirituality, becoming familiar with different religious faiths, and seeking appropriate consultation and referrals for patients. PMID- 24161635 TI - Survivorship after prostate cancer treatment: spouses' quality of life at 36 months. AB - PURPOSE/OBJECTIVES: To determine the long-term effects of prostate cancer treatment on spouse quality of life (QOL) at 36 months following treatment. DESIGN: Descriptive-exploratory; community-based study. SETTING: Telephone interviews. SAMPLE: 95 female spouses of men treated for early-stage prostate cancer. METHODS: A computer-assisted telephone interview was used to evaluate QOL among spouses of prostate cancer survivors at 36 months after initial prostate cancer treatment. MAIN RESEARCH VARIABLES: Lymphedema, demographic information, self-reported comorbid diseases or medical issues, and medication usage. FINDINGS: Spouses who had more negative appraisal of caregiving had lower sexual satisfaction, poorer cancer-specific QOL, and poorer mental QOL. Spouses who perceived bother related to the patient's sexual or hormone function reported more threatening appraisals of caregiving, less sexual satisfaction, and poorer QOL. CONCLUSIONS: Spouses continued to experience negative appraisal of caregiving, which affected QOL 36 months after their husbands' treatment for prostate cancer. Additional studies related to factors that influence spouse QOL during survivorship will help guide clinical practice. IMPLICATIONS FOR NURSING: Healthcare providers must help spouses find strategies that promote positive coping and lessen negative appraisal. Giving caregivers information early in the treatment process will help them understand what to expect over time. Supporting caregivers and helping them manage stress will enhance QOL during survivorship. KNOWLEDGE TRANSLATION: Spouses who experienced more bother related to urinary, sexual, and hormonal function experience more stress and worse QOL at 36 months post-treatment. Spouse appraisal can have a significant effect on QOL. Offering counseling to couples following treatment for prostate cancer may improve QOL by helping couples manage relationship intimacy. PMID- 24161636 TI - Barriers and facilitators to implementing cancer survivorship care plans. AB - PURPOSE/OBJECTIVES: To evaluate the process of survivorship care plan (SCP) completion and to survey oncology staff and primary care physicians (PCPs) regarding challenges of implementing SCPs. DESIGN: Descriptive pilot study. SETTING: Two facilities in Vermont, an urban academic medical center and a rural community academic cancer center. SAMPLE: 17 oncology clinical staff created SCPs, 39 PCPs completed surveys, and 58 patients (breast or colorectal cancer) participated in a telephone survey. METHODS: Using Journey Forward tools, SCPs were created and presented to patients. PCPs received the SCP with a survey assessing its usefulness and barriers to delivery. Oncology staff were interviewed to assess perceived challenges and benefits of SCPs. Qualitative and quantitative data were used to identify challenges to the development and implementation process as well as patient perceptions of the SCP visit. MAIN RESEARCH VARIABLES: SCP, healthcare provider perception of barriers to completion and implementation, and patient perception of SCP visit. FINDINGS: Oncology staff cited the time required to obtain information for SCPs as a challenge. Completing SCPs 3-6 months after treatment ended was optimal. All participants felt advanced practice professionals should complete and review SCPs with patients. The most common challenge for PCPs to implement SCP recommendations was insufficient knowledge of cancer survivor issues. Most patients found the care plan visit very useful, particularly within six months of diagnosis. CONCLUSIONS: Creation time may be a barrier to widespread SCP implementation. Cancer survivors find SCPs useful, but PCPs feel insufficient knowledge of cancer survivor issues is a barrier to providing best follow-up care. Incorporating SCPs in electronic medical records may facilitate patient identification, appropriate staff scheduling, and timely SCP creation. IMPLICATIONS FOR NURSING: Oncology nurse practitioners are well positioned to create and deliver SCPs, transitioning patients from oncology care to a PCP in a shared-care model of optimal wellness. Institution support for the time needed for SCP creation and review is imperative for sustaining this initiative. KNOWLEDGE TRANSLATION: Accessing complete medical records is an obstacle for completing SCPs. A 3-6 month window to develop and deliver SCPs may be ideal. PCPs perceive insufficient knowledge of cancer survivor issues as a barrier to providing appropriate follow-up care. PMID- 24161637 TI - Stressors relating to patient psychological health following stoma surgery: an integrated literature review. AB - PURPOSE/OBJECTIVES: To summarize empirical evidence relating to stressors that may affect patients' psychosocial health following colostomy or ileostomy surgery during hospitalization and after discharge. DATA SOURCES: An extensive search was performed on the CINAHL(r), Cochrane Library, PubMed, PsycINFO, Scopus, Science Direct, and Web of Science electronic databases. DATA SYNTHESIS: Eight articles were included with three qualitative and five quantitative research designs. Most studies were conducted in Western nations with one other in Taiwan. Following colostomy or ileostomy surgery, common stressors reported by patients during hospitalization included stoma formation, diagnosis of cancer, and preparation for self-care. After discharge, stressors that patients experienced encompassed adapting to body changes, altered sexuality, and impact on social life and activities. CONCLUSIONS: This review suggests that patients with stomas experience various stressors during hospitalization and after discharge. Additional research is needed for better understanding of patient postoperative experiences to facilitate the provision of appropriate nursing interventions to the stressors. IMPLICATIONS FOR NURSING: To help patients deal with stressors following stoma surgery, nurses may provide pre- and postoperative education regarding the treatment and recovery process and encourage patient self-care. Following discharge, nurses may provide long-term ongoing counseling and support, build social networks among patients with stomas, and implement home visit programs. KNOWLEDGE TRANSLATION: Stoma surgery negatively affects patients' physical, psychological, social, and sexual health. Postoperative education programs in clinical settings mostly focus on physical health and underemphasize psychological issues. More pre- and postoperative education programs are needed to help patients cope with stoma stressors. PMID- 24161639 TI - The Institute of Medicine report on high-quality cancer care: implications for oncology nursing. AB - PURPOSE/OBJECTIVES: To present key recommendations from a recently released Institute of Medicine (IOM) report on high-quality cancer care. DATA SOURCES: The recommendations were derived from the IOM report Delivering High-Quality Cancer Care: Charting a New Course for a System in Crisis. DATA SYNTHESIS: The authors reviewed each of the recommendations to identify implications for oncology nurses. CONCLUSIONS: Nurses will play a vital role in the future design and delivery of high-quality cancer care. IMPLICATIONS FOR NURSING: Oncology nurses should use the IOM recommendations in their settings to prepare for the delivery of oncology care amidst health system challenges, including an aging society. KNOWLEDGE TRANSLATION: The IOM recommendations identify key areas of concern to nurses. Key aspects of nursing practice, including involvement in advanced care planning, patient-centered care, and evidence-based practice, are essential for high-quality care. Oncology nurses will be centrally involved in healthcare innovations, such as rapid learning systems, and as key members of a well-trained workforce. PMID- 24161638 TI - It's the "good" cancer, so who cares? Perceived lack of support among young thyroid cancer survivors. AB - PURPOSE/OBJECTIVES: To describe the survivorship experience of young adult patients with thyroid cancer. RESEARCH APPROACH: A qualitative, descriptive study. SETTING: Four Canadian provinces, with most participants from Ontario. PARTICIPANTS: 12 young adult thyroid cancer survivors who participated in a larger study on follow-up care needs consisting of 55 young adult cancer survivors. METHODOLOGIC APPROACH: Telephone interviews were conducted with cancer survivors who were diagnosed from age 18-39 years and were 1-5 years post treatment. FINDINGS: All 12 thyroid cancer survivors discussed the feeling that their cancer experiences often were downplayed because thyroid cancer is labeled as the "good" cancer. Many said that they were not considered real patients with cancer by healthcare providers and other patients with cancer, and they were unable or unwilling to access support programs or assistance from healthcare providers. CONCLUSIONS: Cancer can have an impact on a person's life regardless of the prognosis. Being diagnosed with thyroid cancer at a young age can pose additional challenges because of the lack of available support to address needs specific to young adults. INTERPRETATION: Healthcare providers must recognize the needs of thyroid cancer survivors and encourage them to access supportive services. KNOWLEDGE TRANSLATION: Patients with thyroid cancer believe that their needs often are overlooked because of high survival rates, and they have difficulty accessing support resources and finding help. Young adults with cancer often have unique support needs. Support needs may not be the same for all young adult patients with cancer, and those needs should be recognized and addressed. PMID- 24161642 TI - Effects of tailored message education about breast cancer risk appraisal for obese Korean women. AB - PURPOSE/OBJECTIVES: To examine the effects of tailored message education about breast cancer risk in obese Korean women. DESIGN: Pretest/post-test with two comparison treatments. SETTING: Rural community settings in South Korea. SAMPLE: Non-random sample of 64 obese women. METHODS: Based on the Health Belief Model, tailored message education involved a one-session individual approach addressing cognitive, emotional, and behavioral domains. The comparison group received a one time standard education group session. Data on breast cancer risk factors and mammography findings were recorded. MAIN RESEARCH VARIABLES: Knowledge, awareness, emotional barriers, self-efficacy, and intent to screen and prevent breast cancer. FINDINGS: Compared to standard education, tailored message education showed significantly higher score changes on awareness of personal risk (F = 5.21, p < 0.05), self-efficacy for breast self-examination (BSE) (F = 5.16, p < 0.001), intent to perform BSE (F = 6.24, p < 0.05), intent to have mammography (F = 5.45, p < 0.05), and intent to prevent breast cancer with eating habits (F = 7.28, p < 0.05) and exercising (F = 12.51, p < 0.001). CONCLUSIONS: Individually tailored education effectively enhanced awareness of personal risk for breast cancer, self-efficacy for BSE, and intent to screen and prevent breast cancer. IMPLICATIONS FOR NURSING: Tailored message education targeting breast cancer and risk associated with obesity is useful in breast cancer screening education. Future studies should incorporate individualized messages on nutrition, exercise, and cultural barriers to reduce breast cancer risk in obese women. KNOWLEDGE TRANSLATION: Individual educational strategies can effectively enhance breast cancer prevention and early screening. Public and preventive education should include a focus on cultural, cognitive, and emotional domains. For obese women, a heightened awareness and self-efficacy may influence screening behaviors. PMID- 24161643 TI - Healthcare professionals' response to cachexia in advanced cancer: a qualitative study. AB - PURPOSE/OBJECTIVES: To explore healthcare professionals' experience, understanding, and perception of the needs of patients with cachexia in advanced cancer. RESEARCH APPROACH: A qualitative approach based on symbolic interactionism. SETTING: A regional cancer center in a large teaching hospital in the United Kingdom. PARTICIPANTS: 34 healthcare professionals who had experience providing care to patients with cachexia in advanced cancer. METHODOLOGIC APPROACH: Data collection consisted of two phases: focus group and semistructured interviews. Interviews were digitally recorded and transcribed verbatim for analysis. This article reports on findings from the second phase of data collection. FINDINGS: Analysis revealed that professional approaches to cachexia were influenced by three overarching and interthinking themes: knowledge, culture, and resources. Healthcare professionals commonly recognized the impact of the syndrome; however, for nonpalliative healthcare professionals, a culture of avoidance and an overreliance on the biomedical model of care had considerable influence on the management of cachexia in patients with advanced cancer. CONCLUSIONS: Cachexia management in patients with advanced cancer can be difficult and is directed by a variable combination of the influence of knowledge, culture of the clinical area, and available resources. Distinct differences exist in the management of cachexia among palliative and nonpalliative care professionals. INTERPRETATION: This study presented a multiprofessional perspective on the management of cachexia in patients with advanced cancer and revealed that cachexia is a complex and challenging syndrome that needs to be addressed from a holistic model of care. KNOWLEDGE TRANSLATION: Cachexia management in patients with advanced cancer is complex and challenging and is directed by a combination of variables. An overreliance on the biomedical model of health and illness occurs in the management of cachexia in patients with advanced cancer. Cachexia needs to be addressed from a holistic model of care to reflect the multidimensional needs of patients and their families. PMID- 24161644 TI - Development and psychometric testing of a breast cancer survivor self-efficacy scale. AB - PURPOSE/OBJECTIVES: To describe the development of a self-efficacy instrument that measures perceived ability to manage symptoms and quality-of-life problems resulting from the diagnosis and treatment of breast cancer. DESIGN: Items were developed and content validity assessed. A 14-item scale was psychometrically evaluated using internal consistency reliability and several types of construct validity. SAMPLE: 1,127 female breast cancer survivors (BCSs). METHODS: Written consents were mailed to the research office. Data were collected via mail and telephone. MAIN RESEARCH VARIABLES: Demographics, symptom bother, communication with healthcare provider, attention function, fear of recurrence, depression, marital satisfaction, fatigue, sexual functioning, trait and state anxiety, and overall well-being. FINDINGS: Data demonstrated that the breast cancer self efficacy scale (BCSES) was reliable, with an alpha coefficient of 0.89, inter item correlations ranging from 0.3-0.6, and item-total correlation coefficients ranging from 0.5-0.73. Three of 14 items were deleted because of redundancy as identified through high (> 0.7) inter-item correlations. Factor analysis revealed that the scale was unidimensional. Predictive validity was supported through testing associations between self-efficacy and theoretically supported quality-of life variables, including physical, psychological, and social dimensions, as well as overall well-being. CONCLUSIONS: The BCSES demonstrated high internal consistency reliability, unidimensionality, and excellent content and construct validity. This scale should be integrated into interventions that target self efficacy for managing symptoms in BCSs. IMPLICATIONS FOR NURSING: Nurses working with BCSs may use this tool to assess areas in which survivors might need to build confidence to adequately cope with their specific survivorship concerns. KNOWLEDGE TRANSLATION: The use of the BCSES can inform nurse researchers about the impact of an intervention on self-efficacy in the context of breast cancer survivorship, improving the ability to deliver effective interventions. The scale is brief and easy to administer. Results of this study demonstrate clear psychometric reliability and validity, suggesting that the BCSES should be put to use immediately in interventions targeting the quality of life of BCSs. PMID- 24161646 TI - Luteal-phase ovarian stimulation is feasible for producing competent oocytes in women undergoing in vitro fertilization/intracytoplasmic sperm injection treatment, with optimal pregnancy outcomes in frozen-thawed embryo transfer cycles. AB - OBJECTIVE: To explore the feasibility of luteal-phase ovarian stimulation using hMG and letrozole in terms of ovarian response and pregnancy outcome using frozen thawed embryo transfer. DESIGN: A prospective cohort study. SETTING: Academic tertiary-care medical center. PATIENT(S): Two hundred forty-two female patients undergoing IVF/intracytoplasmic sperm injection (ICSI) treatment. INTERVENTION(S): Ovarian stimulation was initiated with hMG 225 IU and letrozole 2.5 mg daily after spontaneous ovulation. Letrozole administration was stopped when the dominant follicles reached diameters of 12 mm. Ovulation was induced with a GnRH agonist 100 MUg when at least three follicles reached diameters of 18 mm or one dominant follicle reached 20 mm. The highest quality embryos were extracted and cryopreserved for later transfer. MAIN OUTCOME MEASURE(S): The primary outcome measured was the number of oocytes retrieved. Secondary outcomes were the clinical pregnancy rate, ongoing pregnancy rate, and implantation rate after frozen embryo transfer (FET) cycles. RESULT(S): Of the 242 women enrolled in the study, all participants succeeded in producing oocytes and 227 women had highest-quality embryos to cryopreserve. The average number of oocytes retrieved was 13.1, producing an average of 4.8 highest quality embryos. Moreover, no cases experienced a premature LH surge or moderate/severe ovarian hyperstimulation syndrome during the stimulation cycles. In FETs, the clinical pregnancy rate, ongoing pregnancy rate, and implantation rate were 55.46% (127/229), 48.91% (112/229), and 40.37% (174/431), respectively. Of all the pregnancies in the study, 68 resulted in live births and 44 were ongoing. CONCLUSION(S): Luteal phase ovarian stimulation is feasible for producing competent oocytes/embryos in women undergoing IVF/ICSI treatments, with optimal pregnancy outcomes in FET cycles. PMID- 24161647 TI - Scenario optimization modeling approach for design and management of biomass-to biorefinery supply chain system. AB - The aim of this study was to develop a scenario optimization model to address weather uncertainty in the Biomass Supply Chain (BSC). The modeling objective was to minimize the cost of biomass supply to biorefineries over a one-year planning period using monthly time intervals under different weather scenarios. The model is capable of making strategic, tactical and operational decisions related to BSC system. The performance of the model was demonstrated through a case study developed for Abengoa biorefinery in Kansas. Sensitivity analysis was done to demonstrate the effect of input uncertainty in yield, land rent and storage dry matter loss on the model outputs. The model results show that available harvest work hours influence major cost-related decisions in the BSC. PMID- 24161648 TI - Enhanced performance of sulfate reducing bacteria based biocathode using stainless steel mesh on activated carbon fabric electrode. AB - An anoxic biocathode was developed using sulfate-reducing bacteria (SRB) consortium on activated carbon fabric (ACF) and the effect of stainless steel (SS) mesh as additional current collector was investigated. Improved performance of biocathode was observed with SS mesh leading to nearly five folds increase in power density (from 4.79 to 23.11 mW/m(2)) and threefolds increase in current density (from 75 to 250 mA/m(2)). Enhanced redox currents and lower Tafel slopes observed from cyclic voltammograms of ACF with SS mesh indicated the positive role of uniform electron collecting points. Differential pulse voltammetry technique was employed as an additional tool to assess the redox carriers involved in bioelectrochemical reactions. SRB biocathode was also tested for reduction of volatile fatty acids (VFA) present in the fermentation effluent stream and the results indicated the possibility of integration of this system with anaerobic fermentation for efficient product recovery. PMID- 24161649 TI - Feasibility of grass co-digestion in an agricultural digester, influence on process parameters and residue composition. AB - This study investigated the potential of co-digestion of grass clippings in a typical Flemish agro-digester characterized by an input of 30% manure, 30% maize silage and 40% side streams. No significant adverse effects in the microbiological functioning of the reactors were detected when part of the maize input was replaced by 10-20% grass. However at the highest dosage of grass input, dry matter content and the viscosity of the reactor content increased substantially. These parameters could be reduced again by enzyme addition in the form of MethaPlus L100. It can be concluded that co-digestion of 20% grass in an agricultural digester would not pose any problem if dry matter content and viscosity are improved by the use of an enzyme mixture. PMID- 24161650 TI - Development of a rotating algal biofilm growth system for attached microalgae growth with in situ biomass harvest. AB - This work aimed to develop a rotating algal biofilm (RAB) cultivation system that can be widely adopted by microalgae producers for easy biomass harvest. Algal cells were grown on the surface of a material rotating between nutrient-rich liquid and CO2-rich gaseous phase. Scrapping biomass from the attached surface avoided the expensive harvest operations such as centrifugation. Among various attachment materials, cotton sheet resulted in best algal growth, durability, and cost effectiveness. A lab-scale RAB system was further optimized with harvest frequency, rotation speed, and CO2 levels. The algal biomass from the RAB system had a similar water content as that in centrifuged biomass. An open pond raceway retrofitted with a pilot-scale RAB system resulted in a much higher biomass productivity when compared to a control open pond. Collectively, the research shows that the RAB system is an efficient algal culture system for easy biomass harvest with enhanced biomass productivity. PMID- 24161651 TI - Interaction proteins of invertase and invertase inhibitor in cold-stored potato tubers suggested a protein complex underlying post-translational regulation of invertase. AB - The activity of vacuolar invertase (VI) is vital to potato cold-induced sweetening (CIS). A post-translational regulation of VI activity has been proposed which involves invertase inhibitor (VIH), but the mechanism for the interaction between VI and VIH has not been fully understood. To identify the potential partners of VI and VIH, two cDNA libraries were respectively constructed from CIS-resistant wild potato species Solanum berthaultii and CIS sensitive potato cultivar AC035-01 for the yeast two-hybrid analysis. The StvacINV1 (one of the potato VIs) and StInvInh2B (one of the potato VIHs), previously identified to be associated with potato CIS, were used as baits to screen the two libraries. Through positive selection and sequencing, 27 potential target proteins of StvacINV1 and eight of StInvInh2B were clarified. The Kunitz type protein inhibitors were captured by StvacINV1 in both libraries and the interaction between them was confirmed by bimolecular fluorescence complementation assay in tobacco cells, reinforcing a fundamental interaction between VI and VIH. Notably, a sucrose non-fermenting-1-related protein kinase 1 was captured by both the baits, suggesting that a protein complex could be necessary for fine turning of the invertase activity. The target proteins clarified in present research provide a route to elucidate the mechanism by which the VI activity can be subtly modulated. PMID- 24161652 TI - Long DNA passenger strand highly improves the activity of RNA/DNA hybrid siRNAs. AB - Small interfering RNAs (siRNAs) are potent tools in biomedical research, which can reduce the expression level of target proteins through RNAi pathway. They are composed of 19-25 bp double strand RNA (dsRNAs), therefore, stimulate dsRNAs dependent interferon responses in a non-specific manner. This problem has prevented siRNAs from being applied as new therapeautic agents. In the present paper, we tried to circumvent interferon responses using RNA/DNA hetero siRNAs (HsiRNAs) composed of RNA guide and DNA passenger strands. It was previously reported that siRNAs which were partially substituted with DNA had RNAi activity and that DNA substitution often caused the activity loss. In our results, HsiRNAs, in which the passenger strand of siRNAs were exchanged with DNA also showed much lower activity than that of parental siRNAs. Here, we found that attachment of 5' flanking sequence to DNA passenger strand improved the activity of HsiRNAs. Furthermore, the effective HsiRNAs induced much lower interferon responses than parental siRNAs. Thus, HsiRNAs with 5' flanking sequence are expected to be novel siRNA drug candidates. PMID- 24161653 TI - Impact of new sequencing technologies on studies of the human B cell repertoire. PMID- 24161654 TI - Remote control-triggering of brain autoimmune disease in the gut. AB - Converging evidence indicates that multiple sclerosis, an inflammatory demyelinating disease of the central nervous system, is caused by brain-specific, self-reactive T lymphocytes. These are normal components embedded in the human immune system throughout healthy life. Only upon activation in the periphery, the T cells assume properties that enable them to break through the vascular blood brain barrier and to invade the brain white matter. While activation has been traditionally associated with microbial infections, recently, studies of animal models revealed a critical role of the commensal gut flora as a key triggering factor. These findings may pave the way to new strategies to treat MS and other human autoimmune diseases, and commend a reevaluation of dietary approaches. PMID- 24161655 TI - Supersaturation, nucleation, and crystal growth during single- and biphasic dissolution of amorphous solid dispersions: polymer effects and implications for oral bioavailability enhancement of poorly water soluble drugs. AB - The influence of polymers on the dissolution, supersaturation, crystallization, and partitioning of poorly water soluble compounds in biphasic media was evaluated. Amorphous solid dispersions (ASDs) containing felodipine (FLD) and itraconazole (ITZ) were prepared by hot melt mixing (HMM) using various polymers. The ASDs were analyzed using powder X-ray diffraction (PXRD), differential scanning calorimetry (DSC), and HPLC. Amorphous drug conversion was confirmed using DSC and PXRD, and drug stability by HPLC. Single- and biphasic dissolution studies of the ASDs with concurrent dynamic light scattering (DLS) and polarized light microscopic (PLM) analysis of precipitated drugs were performed. HPLC revealed no HMM-induced drug degradation. Maximum partitioning into the organic phase was dependent upon the degree of supersaturation. Although the highest supersaturation of FLD was attained using Eudragit(r) EPO and AQOAT(r) AS-LF with better nucleation and crystal growth inhibition using the latter, higher partitioning of the drug into the organic phase was achieved using Pharmacoat(r) 603 and Kollidon(r) VA-64 by maintaining supersaturation below critical nucleation. Critical supersaturation for ITZ was surpassed using all of the polymers, and partitioning was dependent upon nucleation and crystal growth inhibition in the order of Pharmacoat(r) 603>Eudragit(r) L-100-55>AQOAT(r) AS-LF. HMM drug-polymer systems that prevent drug nucleation by staying below critical supersaturation are more effective for partitioning than those that achieve the highest supersaturation. PMID- 24161656 TI - 2-Dioleoyl-sn-glycero-3-phosphocholine-based nanoliposomes as an effective delivery platform for 17beta-estradiol. AB - The high loading efficiency and controlled release of hydrophobic drugs is still an unmet goal in the development of drug delivery systems. In the present study, liposomes were developed to encapsulate 17beta-estradiol (E2), which is a sex steroid shown to confer protective effects in the cardiovascular system. Egg phosphatidylcholine (EPC), 2-dioleoyl-sn-glycero-3-phosphocholine (DOPC), or 1,2 dipalmitoyl-sn-glycero-3-phosphocholine (DPPC) were used to prepare liposomes by thin film hydration and tested for their ability to load E2 with a high efficiency. DOPC-based liposomes were found to improve E2 encapsulation efficiency and loading capacity compared to those composed of EPC and DPPC. In addition, neutral liposomes, liposomes prepared with the cationic charging agent DDAB, and liposomes prepared with the anionic charging agent DMPG, were characterized with regard to their E2 encapsulation efficiency, loading capacity, particle size, zeta potential, and in vitro drug release. A human coronary artery endothelial (HCAE) cell model was used to further evaluate liposome effects on cytotoxicity and relative cellular uptake efficiency of each formulation. Results showed that DOPC liposomes composed of DDAB had the highest E2 loading capacity and improved cellular uptake compared to uncharged and DMPG-based liposomes, demonstrating the greatest potential to be used in future cardiovascular therapeutic applications. PMID- 24161661 TI - Enhanced effect of inhibition of thrombin on endothelium in murine endotoxaemia: specific inhibition of thrombocytopenia. AB - INTRODUCTION: In systemic endotoxaemia, bacterial lipopolysaccharide causes the rapid expression of tissue factor (TF) and disseminated intravascular coagulation and in animal models, anticoagulants limit pathology and promote survival. Recent studies have emphasised the importance of TF expressed by mononuclear cells for initiating thrombin generation during endotoxaemia and suggested that endothelial cell TF is of little relevance. However, the precise importance of endothelium for intravascular thrombin generation has not been established. In this study, we compared the effect of equivalent levels of hirudin tethered to either endothelium or platelets and monocytes. MATERIALS AND METHODS: CD31-Hir-Tg mice express a vesicle-targeted, membrane-tethered hirudin fusion protein on endothelium, platelets and monocytes. Bone marrow chimeras between these mice and C57BL/6 were generated The level of intravascular hirudin expressed during endotoxaemia was quantified by inhibition studies using an anti-hirudin antibody and reference to the circulating thrombin anti-thrombin complexes generated in control mice given soluble hirudin. RESULTS AND CONCLUSIONS: Antibody inhibition studies indicated that individual chimeras expressed similar levels of hirudin fusion protein on endothelium alone as on platelets and leukocytes combined and accordingly, the levels of thrombin anti-thrombin complexes and fibrinogen in each chimera were similar, indicating equivalent inhibition of thrombin generation. However, mice with hirudin on endothelium alone developed significantly less thrombocytopenia. These results suggest a hitherto unrecognized role of endothelium in thrombin-dependent platelet sequestration during endotoxaemia. The data have implications for the development of therapeutic strategies based on targeted anticoagulation to limit disseminated intravascular coagulation. PMID- 24161662 TI - Audition influences color processing in the sound-induced visual flash illusion. AB - Multisensory interactions can lead to illusory percepts, as exemplified by the sound-induced extra flash illusion (SIFI: Shams, Kamitani, & Shimojo, 2000, 2002). In this illusion, an audio-visual stimulus sequence consisting of two pulsed sounds and a light flash presented within a 100 ms time window generates the visual percept of two flashes. Here, we used colored visual stimuli to investigate whether concurrent auditory stimuli can affect the perceived features of the illusory flash. Zero, one or two pulsed sounds were presented concurrently with either a red or green flash or with two flashes of different colors (red followed by green) in rapid sequence. By querying both the number and color of the participants' visual percepts, we found that the double flash illusion is stimulus specific: i.e., two sounds paired with one red or one green flash generated the percept of two red or two green flashes, respectively. This implies that the illusory second flash is induced at a level of visual processing after perceived color has been encoded. In addition, we found that the presence of two sounds influenced the integration of color information from two successive flashes. In the absence of any sounds, a red and a green flash presented in rapid succession fused to form a single orange percept, but when accompanied by two sounds, this integrated orange percept was perceived to flash twice on a significant proportion of trials. In addition, the number of concurrent auditory stimuli modified the degree to which the successive flashes were integrated to an orange percept vs. maintained as separate red-green percepts. Overall, these findings show that concurrent auditory input can affect both the temporal and featural properties of visual percepts. PMID- 24161663 TI - How do people understand their neuropathic pain? A Q-study. AB - Neuropathic pain (NP) is not easy to understand for those with the diagnosis. Even in specialist medical services, explanation may not be given or may not be integrated with patients' existing beliefs about their conditions. We were curious about how people with NP conceptualised the problem. Web sites relevant to NP were used to recruit 79 people with NP. They were sampled using Q methodology, which requires sorting according to degree of agreement or disagreement with diverse statements about NP, derived from the widest possible range of sources. The sets of sorted statements are analysed for factors which represent shared constructions. The four factors that we found differed in important ways: (1) identification of nerve damage as cause; (2) the necessity of identifying cause; (3) the acceptability of symptomatic treatment; (4) the existence or not of psychological influences; and (5) the usefulness of psychological treatment. The meaning of these factors was extended by participants' free comments: certain viewpoints showed associations with their medical and treatment histories and with the interference of pain with daily life. Overall, a biopsychosocial model of pain was only weakly represented, and no integrated model of pain emerged across the four different accounts. There was little reference to NP having been explained when the diagnosis was made. This study highlights the need for more accessible explanations of NP within and outside medical services if people with NP are to use their understanding of NP to help them manage their pain and reduce its impact on their lives. PMID- 24161664 TI - A century after Fisher: time for a new paradigm in quantitative genetics. AB - Quantitative genetics traces its roots back through more than a century of theory, largely formed in the absence of directly observable genotype data, and has remained essentially unchanged for decades. By contrast, molecular genetics arose from direct observations and is currently undergoing rapid changes, making the amount of available data ever greater. Thus, the two disciplines are disparate both in their origins and their current states, yet they address the same fundamental question: how does the genotype affect the phenotype? The rapidly accumulating genomic data necessitate sophisticated analysis, but many of the current tools are adaptations of methods designed during the early days of quantitative genetics. We argue here that the present analysis paradigm in quantitative genetics is at its limits in regards to unraveling complex traits and it is necessary to re-evaluate the direction that genetic research is taking for the field to realize its full potential. PMID- 24161665 TI - Mismatch negativity is a stronger indicator of functional outcomes than neurocognition or theory of mind in patients with schizophrenia. AB - OBJECTIVES: Mismatch negativity (MMN) is known to be associated with neurocognition, social cognition, and functional outcomes. The present study explored the relationships of MMN with neurocognition, theory of mind, and functional outcomes in patients with schizophrenia, first-degree relatives of patients with schizophrenia, and healthy controls. METHODS: Twenty-five patients with schizophrenia, 21 first-degree relatives of patients with schizophrenia, and 29 healthy controls were recruited. We examined symptom severity, neurocognition, theory of mind, functional outcomes, and MMN. RESULTS: MMN amplitudes decreased in order of patients with schizophrenia, then first-degree relatives, then healthy controls. MMN amplitude was significantly correlated with measures of neurocognition, theory of mind, and functional outcome measurements in patients with schizophrenia. However, the most powerful correlations were those between MMN in the frontal region and measures of functional outcomes. The power and frequency of the correlations were weaker in first-degree relatives and healthy controls than in patients with schizophrenia. Hierarchical regression analysis revealed that functional outcomes (relative to measures of neurocognition and theory of mind) constituted the most powerful predictor of MMN. CONCLUSIONS: Our results suggest that MMN reflects functional outcomes more efficiently than do measures of neurocognition and theory of mind in patients with schizophrenia. PMID- 24161666 TI - Dysregulated responses to emotions among abstinent heroin users: correlation with childhood neglect and addiction severity. AB - The aim of this paper was to investigate the subjective responses of abstinent heroin users to both neutral and negative stimuli and the related hypothalamus pituitary-adrenal reactions to emotional experience in relationship to their perception of childhood adverse experiences. Thirty male abstinent heroin dependents were included in the study. Emotional responses and childhood neglect perception were measured utilizing the State-Trait Anxiety Inventory Y-1 and the Child Experience of Care and Abuse Questionnaire. Neutral and unpleasant pictures selected from the International Affective Picture System and the Self-Assessment Manikin procedure have been used to determine ratings of pleasure and arousal. These ratings were compared with normative values obtained from healthy volunteers used as control. Blood samples were collected before and after the experimental sessions to determine both adrenocorticotropic hormone and cortisol plasma levels. Basal anxiety scores, cortisol and adrenocorticotropic hormone levels were higher in abstinent heroin users than in controls. Tests showed that anxiety scores did not change in controls after the vision of neutral slides, whilst they did in abstinent heroin addicts, increasing significantly; and increased less significantly after the unpleasant task, in comparison to controls. Abstinent heroin users showed significantly higher levels of parent antipathy and childhood emotional neglect perception than controls for both the father and the mother. Plasma adrenocorticotropic hormone and cortisol levels did not significantly increase after unpleasant slide set viewing among addicted individuals, because of the significantly higher basal levels characterizing the addicted subjects in comparison with controls. Multiple regression correlation showed a significant relationship between childhood neglect perception, arousal reaction, impaired hypothalamus-pituitary-adrenal axis response and addiction severity. Early adverse experiences seem to affect the entire interaction between hyper-arousal, reduced hormonal response to stress and addiction severity. Our findings, although obtained in a small number of subjects, indicate a significant link between the perception of parental style/care/support during childhood and the ability to cope with stressful emotional stimuli in adulthood and addiction severity. PMID- 24161668 TI - Endoscopic subcutaneous approach to component separation. PMID- 24161667 TI - Integrating patient reported outcomes with clinical cancer registry data: a feasibility study of the electronic Patient-Reported Outcomes From Cancer Survivors (ePOCS) system. AB - BACKGROUND: Routine measurement of Patient Reported Outcomes (PROs) linked with clinical data across the patient pathway is increasingly important for informing future care planning. The innovative electronic Patient-reported Outcomes from Cancer Survivors (ePOCS) system was developed to integrate PROs, collected online at specified post-diagnostic time-points, with clinical and treatment data in cancer registries. OBJECTIVE: This study tested the technical and clinical feasibility of ePOCS by running the system with a sample of potentially curable breast, colorectal, and prostate cancer patients in their first 15 months post diagnosis. METHODS: Patients completed questionnaires comprising multiple Patient Reported Outcome Measures (PROMs) via ePOCS within 6 months (T1), and at 9 (T2) and 15 (T3) months, post diagnosis. Feasibility outcomes included system informatics performance, patient recruitment, retention, representativeness and questionnaire completion (response rate), patient feedback, and administration burden involved in running the system. RESULTS: ePOCS ran efficiently with few technical problems. Patient participation was 55.21% (636/1152) overall, although varied by approach mode, and was considerably higher among patients approached face-to-face (61.4%, 490/798) than by telephone (48.8%, 21/43) or letter (41.0%, 125/305). Older and less affluent patients were less likely to join (both P<.001). Most non-consenters (71.1%, 234/329) cited information technology reasons (ie, difficulty using a computer). Questionnaires were fully or partially completed by 85.1% (541/636) of invited participants at T1 (80 questions total), 70.0% (442/631) at T2 (102-108 questions), and 66.3% (414/624) at T3 (148-154 questions), and fully completed at all three time-points by 57.6% (344/597) of participants. Reminders (mainly via email) effectively prompted responses. The PROs were successfully linked with cancer registry data for 100% of patients (N=636). Participant feedback was encouraging and positive, with most patients reporting that they found ePOCS easy to use and that, if asked, they would continue using the system long-term (86.2%, 361/419). ePOCS was not administratively burdensome to run day-to-day, and patient-initiated inquiries averaged just 11 inquiries per month. CONCLUSIONS: The informatics underlying the ePOCS system demonstrated successful proof-of-concept--the system successfully linked PROs with registry data for 100% of the patients. The majority of patients were keen to engage. Participation rates are likely to improve as the Internet becomes more universally adopted. ePOCS can help overcome the challenges of routinely collecting PROs and linking with clinical data, which is integral for treatment and supportive care planning and for targeting service provision. PMID- 24161669 TI - Unroofing and grasp-and-snare techniques in the management of a large, duodenal lipoma by duodenoscope combined with a double-channel endoscope. PMID- 24161670 TI - Delineation of the TRAK binding regions of the kinesin-1 motor proteins. AB - Understanding specific cargo distribution in differentiated cells is a major challenge. Trafficking kinesin proteins (TRAKs) are kinesin adaptors. They bind the cargo binding domain of kinesin-1 motor proteins forming a link between the motor and their cargoes. To refine the TRAK1/2 binding sites within the kinesin-1 cargo domain, rationally designed C-terminal truncations of KIF5A and KIF5C were generated and their co-association with TRAK1/2 determined by quantitative co immunoprecipitations following co-expression in mammalian cells. Three contributory regions forming the TRAK2 binding site within KIF5A and KIF5C cargo binding domains were delineated. Differences were found between TRAK1/2 with respect to association with KIF5A. PMID- 24161671 TI - Checkpoint blocking antibodies in cancer immunotherapy. AB - Cancers can be recognized by the immune system, and the immune system may regulate and even eliminate tumors. The development of checkpoint blocking antibodies, such as those directed against cytotoxic T-lymphocyte antigen 4 (CTLA 4) and programmed death 1 receptor (PD-1), have demonstrated significant recent promise in the treatment of an expanding list of malignancies. While both CTLA-4 and PD-1 function as negative regulators, each plays a non-redundant role in modulating immune responses. CTLA-4 attenuates the early activation of naive and memory T cells. In contrast, PD-1 is primarily involved in modulating T cell activity in peripheral tissues via interaction with its ligands, PD-L1 and PD-L2. Unfortunately, not all patients respond to these therapies, and evaluation of biomarkers associated with clinical outcomes is ongoing. This review will examine the efficacy, toxicities, and clinical development of checkpoint blocking antibodies, including agents already approved by the US Food and Drug Administration (anti-CTLA-4, ipilimumab) or in development (anti-PD-1, PD-L1). Future studies will likely uncover new promising immunologic checkpoints to target alone or in combination with other immunotherapeutic approaches, chemotherapy, radiotherapy, and small molecules. PMID- 24161672 TI - Lipid raft-regulated IGF-1R activation antagonizes TRAIL-induced apoptosis in gastric cancer cells. AB - Gastric cancer cells are resistant to tumor necrosis factor-related apoptosis inducing ligand (TRAIL) and the resistance mechanism is not fully understood. In human gastric cancer MGC803 and BGC823 cells, TRAIL induces insulin-like growth factor-1 receptor (IGF-1R) pathway activation. Treatment with IGF-1R inhibitor OSI-906 or small interfering RNAs against IGF-1R, prevents IGF-1R pathway activation and increases TRAIL-induced apoptosis. The TRAIL-induced IGF-1R pathway activation is promoted by IGF-1R translocation into lipid rafts. Moreover, the translocation of IGF-1R into lipid rafts is regulated by Casitas B lineage lymphoma b (Cbl-b). Taken together, TRAIL-induced IGF-1R activation antagonizes TRAIL-induced apoptosis by Cbl-b-regulated distribution of IGF-1R in lipid rafts. PMID- 24161674 TI - Dimeric peptides of the C-terminal region of CXCL14 function as CXCL12 inhibitors. AB - We recently reported that CXCL14 binds to CXCR4 with high affinity and inhibits CXCL12-mediated chemotaxis. Here we found that the C-terminal 51-77 amino acid residues of CXCL14 are responsible for CXCR4 binding. A disulfide dimer peptide of CXCL14(51-77) bound to CXCR4 with comparable affinity to full length CXCL14, and exhibited CXCL12 inhibitor activity. CXCR4 was efficiently internalized upon binding of dimeric CXCL14(51-77), thereby being reduced on the cell surface. Substitution of 5 amino acid residues in combination with the use of an oxime linker for dimerization increased the solubility and chemical stability of the dimeric CXCL14(51-77). PMID- 24161673 TI - Engine out of the chassis: cell-free protein synthesis and its uses. AB - The translation machinery is the engine of life. Extracting the cytoplasmic milieu from a cell affords a lysate capable of producing proteins in concentrations reaching to tens of micromolar. Such lysates, derivable from a variety of cells, allow the facile addition and subtraction of components that are directly or indirectly related to the translation machinery and/or the over expressed protein. The flexible nature of such cell-free expression systems, when coupled with high throughput monitoring, can be especially suitable for protein engineering studies, allowing one to bypass multiple steps typically required using conventional in vivo protein expression. PMID- 24161675 TI - Nuclear and plastid markers reveal the persistence of genetic identity: a new perspective on the evolutionary history of Petunia exserta. AB - Recently divergent species that can hybridize are ideal models for investigating the genetic exchanges that can occur while preserving the species boundaries. Petunia exserta is an endemic species from a very limited and specific area that grows exclusively in rocky shelters. These shaded spots are an inhospitable habitat for all other Petunia species, including the closely related and widely distributed species P. axillaris. Individuals with intermediate morphologic characteristics have been found near the rocky shelters and were believed to be putative hybrids between P. exserta and P. axillaris, suggesting a situation where Petunia exserta is losing its genetic identity. In the current study, we analyzed the plastid intergenic spacers trnS/trnG and trnH/psbA and six nuclear CAPS markers in a large sampling design of both species to understand the evolutionary process occurring in this biological system. Bayesian clustering methods, cpDNA haplotype networks, genetic diversity statistics, and coalescence based analyses support a scenario where hybridization occurs while two genetic clusters corresponding to two species are maintained. Our results reinforce the importance of coupling differentially inherited markers with an extensive geographic sample to assess the evolutionary dynamics of recently diverged species that can hybridize. PMID- 24161676 TI - Kinetic and mechanistic characterization of the glyceraldehyde 3-phosphate dehydrogenase from Mycobacterium tuberculosis. AB - Glyceraldehyde 3-phosphate dehydrogenase (GAPDH) is a glycolytic protein responsible for the conversion of glyceraldehyde 3-phosphate (G3P), inorganic phosphate and nicotinamide adenine dinucleotide (NAD(+)) to 1,3 bisphosphoglycerate (1,3-BPG) and the reduced form of nicotinamide adenine dinucleotide (NADH). Here we report the characterization of GAPDH from Mycobacterium tuberculosis (Mtb). This enzyme exhibits a kinetic mechanism in which first NAD(+), then G3P bind to the active site resulting in the formation of a covalently bound thiohemiacetal intermediate. After oxidation of the thiohemiacetal and subsequent nucleotide exchange (NADH off, NAD(+) on), the binding of inorganic phosphate and phosphorolysis yields the product 1,3-BPG. Mutagenesis and iodoacetamide (IAM) inactivation studies reveal the conserved C158 to be responsible for nucleophilic catalysis and that the conserved H185 to act as a catalytic base. Primary, solvent and multiple kinetic isotope effects revealed that the first half-reaction is rate limiting and utilizes a step-wise mechanism for thiohemiacetal oxidation via a transient alkoxide to promote hydride transfer and thioester formation. PMID- 24161677 TI - A 6MWT index to predict O2 flow correcting exercise induced SpO2 desaturation in ILD. AB - INTRODUCTION: Ambulatory oxygen (O2) is prescribed to interstitial lung disease (ILD) patients with mild hypoxemia, breathlessness and dyspnea on exertion. Oxygen titration is generally done with the 6 minute walk test (6MWT) to determine the O2 flow preventing oxygen saturation by pulse oximetry (SpO2) from falling below 88%. His study was designed to generate a 6MWT index predicting the O2 flow allowing completion of the 6MWT without oxygen desaturation. METHODS: Oxygen titration data from a group of 66 ILD patients and 30 controls, were used to generate the algorithm determining an index (O2-GAP) predicting oxygen flow required to complete a 6MWT without desaturation below 88%. This index was validated in a group of 93 ILD patients. RESULTS: The O2-GAP index, as obtained from the derivation population, (r(2) = 0.97, p < 0.001) was shown to correctly predict the oxygen flow required to complete the 6MWT without SpO2 falling below 88% validated in the validation population (r(2) = 0.842; p < 0.001). CONCLUSIONS: The O2-GAP index appears to be a useful tool to titrate ambulatory O2 with a single 6MWT on room air in ILD patients with breathlessness and dyspnea on exertion. PMID- 24161678 TI - Development of 3,4-dihydroisoquinolin-1(2H)-one derivatives for the Positron Emission Tomography (PET) imaging of sigma2 receptors. AB - sigma2 Receptors are promising biomarkers for cancer diagnosis given the relationship between the proliferative status of tumors and their density. With the aim of contributing to the research of sigma2 receptor Positron Emission Tomography (PET) probes, we developed 2-[3-[6,7-dimethoxy-3,4-dihydroisoquinolin 2(1H)-yl]propyl]-3,4-dihydroisoquinolin-1(2H)-one (3), with optimal sigma2 pharmacological properties and appropriate lipophilicity. Hence, 3 served as the lead compound for the development of a series of dihydroisoquinolinones amenable to radiolabeling. Radiosynthesis for compound 26, which displayed the most appropriate sigma2 profile, was developed and sigma2 specific binding for the corresponding [(18)F]-26 was confirmed by in vitro autoradiography on rat brain slices. Despite the excellent in vitro properties, [(18)F]-26 could not successfully image sigma2 receptors in the rat brain in vivo, maybe because of its interaction with P-gp. Nevertheless, [(18)F]-26 may still be worthy of further investigation for the imaging of sigma2 receptors in peripheral tumors devoid of P-gp overexpression. PMID- 24161679 TI - 2-Heteroarylimino-5-arylidene-4-thiazolidinones as a new class of non-nucleoside inhibitors of HCV NS5B polymerase. AB - Hepatitis C virus (HCV) NS5B polymerase is an important and attractive target for the development of anti-HCV drugs. Here we report on the design, synthesis and evaluation of twenty-four novel allosteric inhibitors bearing the 4 thiazolidinone scaffold as inhibitors of HCV NS5B polymerase. Eleven compounds tested were found to inhibit HCV NS5B with IC50 values ranging between 19.8 and 64.9 MUM. Compound 24 was the most active of this series with an IC50 of 5.6 MUM. A number of these derivatives further exhibited strong inhibition against HCV 1b and 2a genotypes in cell based antiviral assays. Molecular docking analysis predicted that the thiazolidinone derivatives bind to the NS5B thumb pocket-II (TP-II). Our results suggest that further optimization of the thiazolidinone scaffold may be possible to yield new derivatives with improved enzyme- and cell based activity. PMID- 24161681 TI - A cryogenic receiver for EPR. AB - Cryogenic probes have significantly increased the sensitivity of NMR. Here, we present a compact EPR receiver design capable of cryogenic operation. Compared to room temperature operation, it reduces the noise by a factor of ~2.5. We discuss in detail the design and analyze the resulting noise performance. At low microwave power, the input noise density closely follows the emission of a cooled 50Omega resistor over the whole measurement range from 20K up to room temperature. To minimize the influence of the microwave source noise, we use high microwave efficiency (~1.1-1.7mTW(-1/2)) planar microresonators. Their efficient conversion of microwave power to magnetic field permits EPR measurements with very low power levels, typically ranging from a few MUW down to fractions of nW. PMID- 24161682 TI - Reduced dimensionality tailored HN(C)N experiments for facile backbone resonance assignment of proteins through unambiguous identification of sequential HSQC peaks. AB - Two novel reduced dimensionality (RD) tailored HN(C)N [S.C. Panchal, N.S. Bhavesh, R.V. Hosur, Improved 3D triple resonance experiments, HNN and HN(C)N, for HN and 15N sequential correlations in (13C, 15N) labeled proteins: application to unfolded proteins, J. Biomol. NMR 20 (2001) 135-147] experiments are proposed to facilitate the backbone resonance assignment of proteins both in terms of its accuracy and speed. These experiments - referred here as (4,3)D hNCOcaNH and (4,3)D-hNcoCANH - exploit the linear combination of backbone (15)N and (13)C'/(13)C(alpha) chemical shifts simultaneously to achieve higher peak dispersion and randomness along their respective F1 dimensions. Simply, this has been achieved by modulating the backbone (15)N(i) chemical shifts with that of (13)C' (i-1)/(13)C(alpha) (i-1) spins following the established reduced dimensionality NMR approach [T. Szyperski, D.C. Yeh, D.K. Sukumaran, H.N. Moseley, G.T. Montelione, Reduced-dimensionality NMR spectroscopy for high throughput protein resonance assignment, Proc. Natl. Acad. Sci. USA 99 (2002) 8009-8014]. Though the modification is simple it has resulted an ingenious improvement of HN(C)N both in terms of peak dispersion and easiness of establishing the sequential connectivities. The increased dispersion along F1 dimension solves two purposes here: (i) resolves the ambiguities arising because of degenerate (15)N chemical shifts and (ii) reduces the signal overlap in F2((15)N)-F3((1)H) planes (an important requisite in HN(C)N based assignment protocol for facile and unambiguous identification of sequentially connected HSQC peaks). The performance of both these experiments and the assignment protocol has been demonstrated using bovine apo Calbindin-d9k (75 aa) and urea denatured UNC60B (a 152 amino acid ADF/cofilin family protein of Caenorhabditis elegans), as representatives of folded and unfolded protein systems, respectively. PMID- 24161680 TI - Deletion of naive T cells recognizing the minor histocompatibility antigen HY with toxin-coupled peptide-MHC class I tetramers inhibits cognate CTL responses and alters immunodominance. AB - Alloreactive T-cell responses directed against minor histocompatibility (H) antigens, which arise from diverse genetic disparities between donor and recipient outside the MHC, are an important cause of rejection of MHC-matched grafts. Because clinically significant responses appear to be directed at only a few antigens, the selective deletion of naive T cells recognizing donor-specific, immunodominant minor H antigens in recipients before transplantation may be a useful tolerogenic strategy. We have previously demonstrated that peptide-MHC class I tetramers coupled to a toxin can efficiently eliminate specific TCR transgenic T cells in vivo. Here, using the minor histocompatibility antigen HY as a model, we investigated whether toxic tetramers could inhibit the subsequent priming of the two H2-D(b)-restricted, immunodominant T-cell responses by deleting precursor CTL. Immunization of female mice with male bone marrow elicited robust CTL activity against the Uty and Smcy epitopes, with Uty constituting the major response. As hypothesized, toxic tetramer administration prior to immunization increased survival of cognate peptide-pulsed cells in an in vivo CTL assay, and reduced the frequency of corresponding T cells. However, tetramer-mediated decreases in either T-cell population magnified CTL responses against the non-targeted epitope, suggesting that D(b)-Uty(+) and D(b)-Smcy(+) T cells compete for a limited common resource during priming. Toxic tetramers conceivably could be used in combination to dissect manipulate CD8(+) T-cell immunodominance hierarchies, and to prevent the induction of donor-specific, minor H antigen CTL responses in allotransplantation. PMID- 24161683 TI - Drugs, genes and the blues: pharmacogenetics of the antidepressant response from mouse to man. AB - While antidepressant drugs are beneficial to many patients, current treatments for depression remain sub-optimal. Up to half of patients with a major depressive episode fail to achieve remission with a first line antidepressant treatment. Identification of the molecular mechanisms that dictate whether a patient will successfully respond to a particular antidepressant treatment while tolerating its side-effects is not only a major challenge in biological psychiatry research but is also one that shows great promise. This review summarises data from both clinical and preclinical studies that point to a role of specific genes in the response and resistance to antidepressant therapeutics. Moreover, we discuss how such findings have increased our understanding of the mechanism of action of antidepressant drugs. Finally, we comment on how this information may potentially influence the future development of personalised medicine approaches for the treatment of depression. PMID- 24161684 TI - Isolation rearing reduces mechanical allodynia in a mouse model of chronic inflammatory pain. AB - Social isolation rearing in mice after weaning reduces pain sensitivity to acute pain, and this hypoalgesia is mediated by the descending serotonergic pain inhibitory system in which the spinal serotonin (5-HT)1A receptor is involved. However, it is not known whether isolation rearing affects pain sensitivity to neuropathic or inflammatory chronic pain. In this study, we examined the effects of isolation rearing on chronic pain induced by Freund's complete adjuvant (FCA) and partial sciatic nerve ligation using the von Frey test (to assess mechanical allodynia) and the plantar test (to assess thermal hyperalgesia). In the FCA model, isolation rearing reduced mechanical allodynia, but not thermal hyperalgesia. In contrast, isolation rearing had no effect on allodynia or hyperalgesia in the sciatic nerve ligation model. The isolation rearing-induced inhibition of allodynia was alleviated by intrathecal injection of WAY100635, a selective 5-HT1A receptor antagonist. FCA increased 5-HT turnover and decreased 5 HT1A receptor expression in the spinal cord of group-reared mice, while it did not have these effects in isolation-reared mice. These results suggest that FCA suppresses the serotonergic pain inhibitory system selectively in group-reared mice. Moreover, systemic administration of osemozotan, a selective 5-HT1A receptor agonist, inhibited FCA-induced mechanical allodynia in group-reared mice, and this effect of the drug was suppressed by intrathecal injection of WAY100635. Collectively, these findings suggest that isolation rearing selectively reduces FCA-induced mechanical allodynia in mice and that this effect is mediated by the activation of spinal 5-HT1A receptors. PMID- 24161685 TI - Repeated restraint stress alters sensitivity to the social consequences of ethanol differentially in early and late adolescent rats. AB - In rats, considerable differences in the social consequences of acute ethanol are seen across ontogeny, with adolescents being more sensitive to low dose ethanol induced social facilitation and less sensitive to the social inhibition evident at higher ethanol doses relative to adults. Stressor exposure induces social anxiety-like behavior, indexed via decreases in social preference, and alters responsiveness to the social consequences of acute ethanol by enhancing ethanol associated social facilitation and anxiolysis regardless of age. Given that substantial ontogenetic differences in the social consequences of ethanol are evident even within the adolescent period, the present study was designed to investigate whether similar stress-associated alterations in social behavior and ethanol responsiveness are evident in early and late adolescents. Juvenile-early adolescent [postnatal days (P) 24-28] and mid-late adolescent (P38-42) male and female Sprague-Dawley rats were repeatedly restrained (90 min/day) for 5 days, followed by examination of ethanol-induced (0, 0.25, 0.5, or 1.0 g/kg) alterations in social behaviors on the last day. Responsiveness to restraint stress in terms of both stress-induced behavioral alterations and stress associated changes in sensitivity to the social consequences of acute ethanol challenge differed drastically at the two ages. Repeated restraint increased anxiety-like behavior in a social context in older adolescents, whereas previously stressed young adolescent males showed substantial increases in play fighting - an effect of stress not evident in P28 females or P42 adolescents of either sex. Unexpectedly, repeated restraint eliminated sensitivity to ethanol induced social facilitation in P28 adolescent males and made their female counterparts less sensitive to this effect. In contrast, previously stressed late adolescents became sensitive to the socially facilitating and anxiolytic effects of acute ethanol. PMID- 24161686 TI - Surface patch binding and mesophase separation in biopolymeric polyelectrolyte polyampholyte solutions. AB - Surface patch binding (SPB) induced mesophase separation causing complex coacervation between biopolymers: gelatin A-gelatin B, chitosan-gelatin A, chitosan-gelatin B, and, agar-gelatin B was investigated with and without salt (I=0-0.3 M NaCl). SPB was induced by pH change and three characteristic pHs identified transitions in a turbidity plot: intermolecular interactions ensued at pHc, coacervation transition occurred at pHPhi and phase separation was noticed at pHprep. Associative interactions lead to formation of soluble complexes at pHc exclusively through SPB whereas the coacervation transition was driven by electrostatic binding (EB). Neither pHc nor pHPhi displayed discernible ionic strength (till 50 mM) or temperature dependence, but coacervate yield reduced with increase in ionic strength. Coacervation was completely suppressed beyond 50 mM NaCl. Linear combination of attractive and repulsive parts operating between a polyelectrolyte (charged rod) with a polyampholyte (dipole or point charge) was used to model the interaction potential as function of ionic strength. Relative strength of SPB vis a vis EB was used as SPB index to establish a linear relationship with zeta potential ratio of binding partners. Different phase diagrams could be constructed which clearly identified distinct interaction regimes encountered in solutions undergoing coacervation transition. PMID- 24161687 TI - Performance limitations in the tracking and regulation problem for discrete-time systems. AB - In this paper, the optimal tracking and regulation performance of discrete-time, multi-input multi-output, linear time-invariant systems is investigated. The control signal is influenced by the external disturbance, and the output feedback is subjected to an additive white Gaussian noise (AWGN) corruption. The tracking error with channel input power constraint and the output regulation with control energy constraint are adopted as the measure of tracking and regulation performance respectively, which can be obtained by searching through all stabilizing two-parameter controllers. Both results demonstrate that the performance is closely related to locations and directions of the nonminimum phase zeros, unstable poles of the plant and may be badly degraded by external disturbance and AWGN. PMID- 24161688 TI - Co-expression patterns of cocaine- and amphetamine-regulated transcript (CART) with neuropeptides in dorsal root ganglia of the pig. AB - In the present study the neuronal distribution of CART was evaluated immunohistochemically in porcine dorsal root ganglia (DRGs). In co-localization studies the co-expression patterns of CART with SP, CGRP, galanin, CALB and LENK were investigated by means of triple immunohistochemical stainings. In porcine DRGs, the expression of CART was found in approximately 5% of primary sensory neurons. The vast majority (ca. 95%) of CART-immunoreactive (IR) neurons were small and middle sized, and only 5% were categorized as large. CART-IR neurons additionally exhibiting the presence of SP/CGRP (ca. 12%), SP/CALB (ca. 12%), SP/LENK (ca. 5%) were found. The vast majority of CART-IR/CGRP-IR neurons did not display immunoreaction to SP (ca. 60%). Subclasses of CART-IR/LENK-IR/SP-negative (ca. 5%), as well as CART-IR/CALB-IR/SP-negative neurons (ca. 10%), were also visualized. In addition, CART-IR neurons with no immunoreactivities to any of the neuropeptides studied were also shown. In porcine DRGs none of the CART-IR neurons exhibited the presence of galanin. The results obtained in the study suggest that CART may functionally modulate the activity of the porcine primary sensory neurons. It is concluded that co-expression of CART with CGRP, SP, LENK and CALB in subsets of the pig L1-L6 DRGs neurons provide anatomical evidence for a CART role in pain processing. PMID- 24161689 TI - Acta Histochemica celebrates 60 years of publication (1954-2014). PMID- 24161690 TI - Actin cytoskeleton reorganization correlates with polarization of secretory vesicle and cell morphology in the degranulation of mast cell subtypes in human colon tissues. AB - Mast cells play a central role in the intestinal immune response. To investigate the relationship between degranulation, cell polarization and the reorganization of actin cytoskeleton of mast cells, we used fluorescence or gold labeling methods to identify different mast cell subtypes in human colon. The reorganization of filamentous actin was visualized and then the polarization of secretory vesicles, as well as cell surfaces, was analyzed by fluorescence microscopy and electron microscopy. Our results first showed a diversity of filamentous actin assembly or disassembly within the contacting cell membrane of different mast cell subtypes. The polarization and degranulation of secretory vesicles was not only accompanied with the assembly and disassembly of filamentous actin at the cell periphery, but also with changes of cell surface polarization. Our study provides an insight into the local membranous structures and suggested correlations of cytoskeleton arrangement with the polarization of secretory vesicles and cell surface configuration during mast cell degranulation. PMID- 24161691 TI - Galangin inhibits proliferation of hepatocellular carcinoma cells by inducing endoplasmic reticulum stress. AB - Prolonged endoplasmic reticulum (ER) stress may activate apoptotic pathways in cancer cells. It is suggested that ER stress has the potential of enhancing tumor death in cancer therapy. Galangin, a flavonol derived from Alpinia officinarum Hance, has been shown to suppress the proliferation of hepatocellular carcinoma cells (HCC). The aim of this study was to determine whether galangin was able to induce ER stress in HepG2, Hep3B and PLC/PRF/5 cells. The proliferation of HCC was tested by MTT method. Intracellular Ca(2+) levels were measured with Fluo3 AM.The proteins levels of GRP94, GRP78 and CHOP were detected by Western blot. To further understand the anti-HCC mechanism of galangin, mitogen-activated protein kinases (MAPKs) were detected. The results showed that galangin treatment induced ER stress was evidenced by increased protein levels of GRP94, GRP78 and CHOP, as well as increased free cytosolic Ca(2+) concentration. ER stress inhibitor 4-PBA and CHOP siRNA blocked significantly galangin-induced ER in all three cell lines. Further experiments showed that MAPKs involved in ER stress induced by galangin. In summary, galangin is identified as a stimulator of ER stress to suppress the proliferation of HCC, and may be used as a potential anti-cancer agent. PMID- 24161692 TI - TNFR1/TNF-alpha and mitochondria interrelated signaling pathway mediates quinocetone-induced apoptosis in HepG2 cells. AB - Quinocetone, a new quinoxaline 1, 4-dioxide derivative, has been widely used as an animal feed additive in China. This study was conducted to explore the molecular mechanisms of apoptosis induced by quinocetone in HepG2 cells. MTT assay revealed that the viability of HepG2 cells was significantly inhibited by quinocetone in a dose- and time-dependent manner. Quinocetone-induced apoptosis in HepG2 cells was characterized by cell and nuclei morphology change, cell membrane phosphatidylserine translocation, DNA fragmentation, cleavage of poly (ADP-ribose) polymerase (PARP) and a cascade activation of caspase-8, caspase-9 and caspase-3. Simultaneously, quinocetone induced HepG2 cell cycle arrest, which was supported by overexpression of p21. Cytochrome c release was caused by the mitochondrial membrane potential dissipation, a process related to quinocetone induced Bid cleavage and elevated Bax/Bcl-2 ratio. Moreover, quinocetone treatment caused the up-regulation of TNF-alpha and TNFR1 in HepG2 cells. Both soluble TNFR1 receptors and caspase inhibitors suppressed quinocetone-induced apoptosis. In addition, the protein levels of p53, p-p38 and p-JNK were increased in quinocetone-treated cells. Taken together, quinocetone induced apoptosis in HepG2 cells via activation of caspase, interaction of TNF-alpha and TNFR1 and modulation of the protein levels of Bid, Bax and Bcl-2, involving the participation of p53, p38 and JNK. PMID- 24161693 TI - A protective role of heme-regulated eIF2alpha kinase in cadmium-induced toxicity in erythroid cells. AB - Although a number of studies have demonstrated that cadmium (Cd) can incur damage to mature red cells, the potential injuries of Cd to erythroid progenitor cells have not been investigated thus far. Heme-regulated eIF2alpha kinase (Hri) is essential for translational regulation and survival of erythroid precursors in the setting of iron deficiency. Hri has been demonstrated to activate Atf4 signaling in reducing oxidative stress and in promoting erythroid differentiation during stress erythropoiesis. Here, we demonstrated that Cd significantly provoked cell death and suppressed erythroid differentiation of erythroid progenitor cells. Importantly, our results established a crucial role of Hri in ameliorating Cd-induced impairment to erythropoiesis. Upon Cd treatment, Hri eIF2alphaP-Atf4 signaling was activated to protect cells from cell death and differentiation attenuation in Wt fetal liver erythroblasts; in contrast, Hri(-/ ) erythroblasts suffered from enhanced oxidative stress, as evidenced by increased levels of reactive oxygen species (ROS) and consequentially elevated apoptosis. As for Cd administration in vivo, impaired erythropoiesis in bone marrow and dramatic extramedullary erythropoiesis in spleen were observed in Hri( /-) mice. Taken together, our combined data highlighted a crucial role of Hri in protecting survival and differentiation of erythroid progenitor cells upon Cd treatment. PMID- 24161694 TI - Quercetin modulates OTA-induced oxidative stress and redox signalling in HepG2 cells - up regulation of Nrf2 expression and down regulation of NF-kappaB and COX 2. AB - BACKGROUND: Ochratoxin A (OTA), a mycotoxin, causes extensive cell damage, affecting liver and kidney cells. OTA toxicity is fairly well characterized where oxidative stress is believed to play a role, however, the sequence of molecular events after OTA-exposure, have not been characterized in literature. Further, antidotes for alleviating the toxicity are sparsely reported. The aim of this study was to understand the sequence of some molecular mechanisms for OTA-induced toxicity and the cytoprotective effect of quercetin on OTA-induced toxicity. METHODS: Time course studies to evaluate the time of intracellular calcium release and ROS induction were carried out. The time of activation and induction of two key redox- sensitive transcription factors, NF-kappaB and Nrf-2 were determined by nuclear localization and expression respectively. The time of expression of inflammatory marker COX-2 was determined. Oxidative DNA damage by comet assay and micronucleus formation was studied. The ameliorative effect of quercetin on OTA-induced toxicity was also determined on all the above-mentioned parameters. RESULTS: OTA-induced calcium release, ROS generation and activated NF kappaB nuclear translocation and expression. Pre-treatment with quercetin ameliorated ROS and calcium release as well as NF-kappaB induction and expression. Quercetin induced Nrf-2 nuclear translocation and expression. Quercetin's anti-inflammatory property was exhibited as it down regulated COX-2. Anti-genotoxic effect of quercetin was evident in prevention of DNA damage and micronucleus formation. CONCLUSION: Quercetin modulated OTA-induced oxidative stress and redox-signaling in HepG2 cells. GENERAL SIGNIFICANCE: The results of the study demonstrate for the first time that quercetin prevents OTA-induced toxicity in HepG2 cells. PMID- 24161695 TI - Histone code of genes induced by co-treatment with a glucocorticoid hormone agonist and a p44/42 MAPK inhibitor in human small intestinal Caco-2 cells. AB - BACKGROUND: Inactivation of glucocorticoid hormones and p44/42 mitogen-activated protein kinase (MAPK) is thought to be important in small intestinal maturation and expression of genes related to intestinal differentiation and functions. METHODS: We investigated target genes induced by co-treatment for 48h with a glucocorticoid hormone agonist, dexamethasone (Dex), and a p44/42 MAPK inhibitor, PD98059 (PD), in a small intestine-like cell line (Caco-2) using microarray analysis. We also investigated whether expression changes of the target genes induced by the co-treatment are associated with histone modifications around these genes. RESULTS: Co-treatment of Caco-2 cells with Dex and PD enhanced several genes related to intestinal differentiation and functions such as SCNN1A, FXYD3, LCT and LOX. Induction of the SCNN1A gene was associated with increased presence of acetylated histone H3 and H4 and di-methylated histone H3 at lysine (K) 4 around the transcribed region of the gene, and induction of the FXYD3 gene was associated with increased presence of acetylated histones H3 and H4 from the promoter/enhancer to the transcribed region of the gene. Induction of LCT and LOX genes was associated with increased presence of acetylated histone H4 on the promoter/enhancer region of the genes. CONCLUSIONS: Histone acetylation and/or histone H3 K4 methylation around the promoter/enhancer or/and transcribed regions of target genes are associated with induction of the genes by co-treatment with Dex and PD in Caco-2 cells. GENERAL SIGNIFICANCE: The histone code is specific to each gene with respect to induction by glucocorticoid hormone and inhibition of p44/42 MAPK in Caco-2 cells. PMID- 24161696 TI - N-Linked glycan site occupancy impacts the distribution of a potassium channel in the cell body and outgrowths of neuronal-derived cells. AB - BACKGROUND: Vacancy of occupied N-glycosylation sites of glycoproteins is quite disruptive to a multicellular organism, as underlined by congenital disorders of glycosylation. Since a neuronal component is typically associated with this disease, we evaluated the impact of N-glycosylation processing of a neuronal voltage gated potassium channel, Kv3.1b, expressed in a neuronal-derived cell line, B35 neuroblastoma cells. METHODS: Total internal reflection fluorescence and differential interference contrast microscopy measurements of live B35 cells expressing wild type and glycosylation mutant Kv3.1b proteins were used to evaluate the distribution of the various forms of the Kv3.1b protein in the cell body and outgrowths. Cell adhesion assays were also employed. RESULTS: Microscopy images revealed that occupancy of both N-glycosylation sites of Kv3.1b had relatively similar amounts of Kv3.1b in the outgrowth and cell body while vacancy of one or both sites led to increased accumulation of Kv3.1b in the cell body. Further both the fully glycosylated and partially glycosylated N229Q Kv3.1b proteins formed higher density particles in outgrowths compared to cell body. Cellular assays demonstrated that the distinct spatial arrangements altered cell adhesion properties. CONCLUSIONS: Our findings provide direct evidence that occupancy of the N-glycosylation sites of Kv3.1b contributes significantly to its lateral heterogeneity in membranes of neuronal-derived cells, and in turn alters cellular properties. GENERAL SIGNIFICANCE: Our study demonstrates that N-glycans of Kv3.1b contain information regarding the association, clustering, and distribution of Kv3.1b in the cell membrane, and furthermore that decreased occupancy caused by congenital disorders of glycosylation may alter the biological activity of Kv3.1b. PMID- 24161697 TI - Resveratrol enhances chemosensitivity of doxorubicin in multidrug-resistant human breast cancer cells via increased cellular influx of doxorubicin. AB - BACKGROUND: Multidrug resistance is a major problem in the treatment of breast cancer, and a number of studies have attempted to find an efficient strategy with which to overcome it. In this study, we investigate the synergistic anticancer effects of resveratrol (RSV) and doxorubicin (Dox) against human breast cancer cell lines. METHODS: The synergistic effects of RSV on chemosensitivity were examined in Dox-resistant breast cancer (MCF-7/adr) and MDA-MB-231 cells. In vivo experiments were performed using a nude mouse xenograft model to investigate the combined sensitization effect of RSV and Dox. RESULTS AND CONCLUSION: RSV markedly enhanced Dox-induced cytotoxicity in MCF-7/adr and MDA-MB-231 cells. Treatment with a combination of RSV and Dox significantly increased the cellular accumulation of Dox by down-regulating the expression levels of ATP-binding cassette (ABC) transporter genes, MDR1, and MRP1. Further in vivo experiments in the xenograft model revealed that treatment with a combination of RSV and Dox significantly inhibited tumor volume by 60%, relative to the control group. GENERAL SIGNIFICANCE: These results suggest that treatment with a combination of RSV and Dox would be a helpful strategy for increasing the efficacy of Dox by promoting an intracellular accumulation of Dox and decreasing multi-drug resistance in human breast cancer cells. PMID- 24161698 TI - Discovery of novel differentiation markers in the early stage of chondrogenesis by glycoform-focused reverse proteomics and genomics. AB - BACKGROUND: Osteoarthritis (OA) is one of the most common chronic diseases among adults, especially the elderly, which is characterized by destruction of the articular cartilage. Despite affecting more than 100 million individuals all over the world, therapy is currently limited to treating pain, which is a principal symptom of OA. New approaches to the treatment of OA that induce regeneration and repair of cartilage are strongly needed. METHODS: To discover potent markers for chondrogenic differentiation, glycoform-focused reverse proteomics and genomics were performed on the basis of glycoblotting-based comprehensive approach. RESULTS: Expression levels of high-mannose type N-glycans were up-regulated significantly at the late stage of differentiation of the mouse chondroprogenitor cells. Among 246 glycoproteins carrying this glycotype identified by ConA affinity chromatography and LC/MS, it was demonstrated that 52% are classified as cell surface glycoproteins. Gene expression levels indicated that mRNAs for 15 glycoproteins increased distinctly in the earlier stages during differentiation compared with Type II collagen. The feasibility of mouse chondrocyte markers in human chondrogenesis model was demonstrated by testing gene expression levels of these 15 glycoproteins during differentiation in human mesenchymal stem cells. CONCLUSION: The results showed clearly an evidence of up-regulation of 5 genes, ectonucleotide pyrophosphatase/phosphodiesterase family member 1, collagen alpha 1(III) chain, collagen alpha-1(XI) chain, aquaporin-1, and netrin receptor UNC5B, in the early stages of differentiation. GENERAL SIGNIFICANCE: These cell surface 5 glycoproteins become highly sensitive differentiation markers of human chondrocytes that contribute to regenerative therapies, and development of novel therapeutic reagents. PMID- 24161700 TI - Moral rigidity in obsessive-compulsive disorder: do abnormalities in inhibitory control, cognitive flexibility and disgust play a role? AB - BACKGROUND AND OBJECTIVES: Abnormalities in cognitive control and disgust responding are well-documented in obsessive-compulsive disorder (OCD), and also interfere with flexible, outcome-driven utilitarian moral reasoning. The current study examined whether individuals with OCD differ from healthy and anxious individuals in their use of utilitarian moral reasoning, and whether abnormalities in inhibitory control, cognitive flexibility and disgust contribute to moral rigidity. METHODS: Individuals with OCD (n = 23), non-OCD anxiety (n = 21) and healthy participants (n = 24) gave forced-choice responses to three types of moral dilemmas: benign, impersonal, personal. Scores on measures of cognitive flexibility, inhibitory control and trait disgust were also examined. RESULTS: Individuals with OCD gave fewer utilitarian responses to impersonal moral dilemmas compared to healthy, but not anxious, individuals. Poorer cognitive flexibility was associated with fewer utilitarian responses to impersonal dilemmas in the OCD group. Furthermore, greater trait disgust was associated with increased utilitarian responding to personal dilemmas in the OCD group, but decreased utilitarian responding to impersonal dilemmas in the anxious group. LIMITATIONS: Although we did not find an association between inhibitory control and moral reasoning, smaller associations may be evident in a larger sample. CONCLUSION: These data indicate that individuals with OCD use more rigid moral reasoning in response to impersonal moral dilemmas compared to healthy individuals, and that this may be associated with reduced cognitive flexibility. Furthermore, these data suggest that trait disgust may exert opposing effects on moral reasoning in individuals with OCD compared to those with other forms of anxiety. PMID- 24161701 TI - Imagery rescripting as a stand-alone treatment for patients with social phobia: a case series. AB - BACKGROUND AND OBJECTIVES: The majority of patients with social phobia reports experiencing negative images, usually linked to memories of earlier aversive social experiences. Several studies have indicated that such negative self imagery appears to have a causal role in maintaining social phobia, which suggests that interventions aimed at dealing with these images could be beneficial in the treatment of social phobia. One potentially powerful approach is imagery rescripting (IR), a clinical intervention that focuses on changing the meaning and impact of unpleasant memories. In the treatment of social phobia IR was only used as part of a broader cognitive-behavioral treatment package. However, we propose that IR alone might also be an effective treatment for this anxiety disorder. The present study reports an initial evaluation of the application of IR as a stand-alone treatment for six adult outpatients presenting with social phobia. METHODS: A single case series using an A-B replication across patients design was employed. Following a no-treatment baseline period, IR was delivered weekly and patients were followed up for 3 and 6 months. RESULTS: For all patients, substantial reductions were obtained on all outcome measures at post-treatment, and gains were largely maintained at 6-months follow-up. LIMITATIONS: The generalizability of the effects of IR for social phobia is limited by the small number of patients treated by only one therapist. CONCLUSIONS: The results of this preliminary case series suggest that IR as a stand alone treatment is an apparently effective intervention in the treatment of patients with social phobia, and indicate that controlled evaluation of its efficacy might be worthwhile. PMID- 24161699 TI - Rifaximin alters intestinal bacteria and prevents stress-induced gut inflammation and visceral hyperalgesia in rats. AB - BACKGROUND & AIMS: Rifaximin is used to treat patients with functional gastrointestinal disorders, but little is known about its therapeutic mechanism. We propose that rifaximin modulates the ileal bacterial community, reduces subclinical inflammation of the intestinal mucosa, and improves gut barrier function to reduce visceral hypersensitivity. METHODS: We induced visceral hyperalgesia in rats, via chronic water avoidance or repeat restraint stressors, and investigated whether rifaximin altered the gut microbiota, prevented intestinal inflammation, and improved gut barrier function. Quantitative polymerase chain reaction (PCR) and 454 pyrosequencing were used to analyze bacterial 16S ribosomal RNA in ileal contents from the rats. Reverse transcription, immunoblot, and histologic analyses were used to evaluate levels of cytokines, the tight junction protein occludin, and mucosal inflammation, respectively. Intestinal permeability and rectal sensitivity were measured. RESULTS: Water avoidance and repeat restraint stress each led to visceral hyperalgesia, accompanied by mucosal inflammation and impaired mucosal barrier function. Oral rifaximin altered the composition of bacterial communities in the ileum (Lactobacillus species became the most abundant) and prevented mucosal inflammation, impairment to intestinal barrier function, and visceral hyperalgesia in response to chronic stress. Neomycin also changed the composition of the ileal bacterial community (Proteobacteria became the most abundant species). Neomycin did not prevent intestinal inflammation or induction of visceral hyperalgesia induced by water avoidance stress. CONCLUSIONS: Rifaximin alters the bacterial population in the ileum of rats, leading to a relative abundance of Lactobacillus. These changes prevent intestinal abnormalities and visceral hyperalgesia in response to chronic psychological stress. PMID- 24161702 TI - Pyrazole scaffold: a remarkable tool in the development of anticancer agents. AB - Pyrazole has been the topic of interest for thousands of researchers across the world because of its wide spectrum pharmacological activities. Various structural modifications of the pyrazole nucleus have been made to explore its characteristics and biological potential. The present work aims to review the use of molecular modeling in the designing of novel pyrazole analogs that may target various receptors such as protein kinase inhibitor, tyrosine kinase, Aurora-A kinase, tumor growth factor (TGF), cyclin dependent kinase (CDK) and fibroblast growth factor (FGF), which are significant for the management of cancer. An insight has been given in this article for the importance of pyrazoles in the treatment of cancer and the perspectives that they hold for future research. PMID- 24161703 TI - Esters and amides of maslinic acid trigger apoptosis in human tumor cells and alter their mode of action with respect to the substitution pattern at C-28. AB - Cancer is one of the most commonly diagnosed diseases worldwide; its mortality rate is high, and there is still a demand for the development of antitumor active drugs. Triterpenoic acids show many pharmacological effects, among them antitumor activity. One of these, maslinic acid-1 is of interest because of its antitumor profile. It is not only cytotoxic but also triggers apoptosis in various human tumor cell lines. To improve the cytotoxicity of parent 1 we set out to synthesize a series of esters and amides differing in structure and lipophilicity. These compounds were tested in a sulforhodamine B assay for cytotoxicity, and screened for their ability to induce apoptosis using an acridine orange/propidium iodide assay, DNA laddering and cell cycle experiments. Esters containing small-chain, lipophilic residues increased the cytotoxicity whereas amides as well long-chain esters led to a decrease in activity. The antitumor activity seems to be independent from the substitution pattern at position C-28 for esters and amides but alters their mode of action. PMID- 24161704 TI - Synthesis of some dihydropyrimidine-based compounds bearing pyrazoline moiety and evaluation of their antiproliferative activity. AB - Two series of 2-(3,5-diaryl-4,5-dihydropyrazol-1-yl)-1-methyl-6-oxo-4-phenyl-1,6 dihydropyrimidine-5-carbonitriles 5a-h and 4-(4-chlorophenyl)-2-(3,5-diaryl-4,5 dihydropyrazol-1-yl)-1-methyl-6-oxo-1,6-dihydropyrimidine-5-carbonitriles 6a-h were synthesized via a cyclocondensation reaction of the corresponding 2 hydrazinopyrimidines 3a,b with the appropriate 2-propen-1-ones 4a-h. The target compounds were screened for their antiproliferative activity against A 549 (lung), HT 29 (colon), MCF 7 and MDA-MB 231 (breast) cell lines. The two most susceptible cell lines were the colon (HT 29) and breast (MDA-MB 231). Generally, the 4-unsubstitutedphenylpyrimidine derivatives 5a-h were more active than their 4-chlorophenylpyrimidine analogs 6a-h. Compounds 5e and 5g, showed high activity against three of the cell lines. The most active compound 5c possessed IC50 = 1.76 MUM against A 549 cell line. PMID- 24161705 TI - Investigation of nuclease, proteolytic and antiproliferative effects of copper(II) complexes of thiophenylmethanamine derivatives. AB - Four coordinate copper(II) complexes 1, 2 and 3 of ligands based on thiophenemethylamine containing imidazole, benzimidazole and pyridine moiety have been synthesized and characterized. Complex 1 has also been crystallographically characterized. The three complexes bind to DNA non-intercalatively, though partial intercalation in the case of complex 2 cannot be ruled out. All the three complexes bring about hydroxyl radical mediated DNA cleavage in the presence of H2O2. Binding of the three copper(II) complexes to BSA lead to changes in the helicity of the protein. Among the three complexes, 2 and 3 are more effective in inhibiting the growth of cancerous MG63 cells than normal NIH3T3 cells. These two complexes promote apoptosis in MG 63 cells. PMID- 24161706 TI - Phosphorus-nitrogen compounds part 27. Syntheses, structural characterizations, antimicrobial and cytotoxic activities, and DNA interactions of new phosphazenes bearing secondary amino and pendant (4-fluorobenzyl)spiro groups. AB - A number of partly (7-9) and fully (10a-12d, Scheme 1) substituted mono(4 fluorobenzyl)spiro cyclotriphosphazenes was prepared. The structures of the compounds were determined by MS, FTIR, 1D and 2D NMR techniques. The crystal structures of 9, 11b and 12b were verified by X-ray diffraction analysis. In vitro cytotoxic activity of the phosphazenes (10a-12d) against HeLa cervical cancer cell lines was evaluated. Compound 12c was found to be the most effective, as it is a cytotoxic reagent that might activate apoptosis by altering mitochondrial membrane potential. Compounds 10b, 11b and 12b showed very good activity against yeast strains Candida tropicalis and Candida albicans. BamHI and HindIII digestion results demonstrate that the compounds (10a-12a, 10b-12b, 10d 12d), and (9, 10c-12c) bind with G/G and A/A nucleotides, respectively. PMID- 24161707 TI - Polyethylene wear particles play a role in development of osteoarthritis via detrimental effects on cartilage, meniscus, and synovium. AB - OBJECTIVE: While ultra-high molecular weight polyethylene (UHMWPE) wear particles are known to cause periprosthetic osteolysis, its interaction with other intra articular tissues in the case of partial joint arthroplasties is not well understood. We hypothesized that UHMWPE particles per se would interact with intra-articular tissue, which by acting as inflammatory reservoirs, would subsequently induce osteoarthritic (OA) changes. Our goal was to assess the inflammatory response, phagocytic activity, as well as apoptosis of intra articular cells in the presence of UHMWPE particles in vitro, and the in vivo response of those tissues after intra-articular injection of particles in a murine model. DESIGN: Three cell types were used for the in vitro study; chondrocytes, meniscal fibrochondrocytes, and synoviocytes. Each cell type was cultured with two different concentrations of UHMWPE particles. Pro-inflammatory cytokine production, phagocytosis, and apoptosis were analyzed. In vivo experiments were done by injecting two concentrations of UHMWPE particles into normal and murine OA model knee joints. RESULTS: In vitro experiments showed that UHMWPE particles increase pro-inflammatory cytokine and mediator (IL-1beta, IL-6, TNF-alpha, Nitric Oxide, and Prostaglandin E2) production, phagocytosis of particles, and apoptosis in all cell types. In vivo experiment showed degeneration of cartilage and meniscus, as well as synovitis after particle injection. CONCLUSIONS: UHMWPE wear particles per se exert detrimental effects in cartilage, synovium, and meniscus of the knee joint resulting in pro-inflammatory cytokine release, phagocytosis of particles and apoptosis. Particles induced and exacerbated OA changes in a murine model. PMID- 24161708 TI - A histological comparison of the repair tissue formed when using either Chondrogide((r)) or periosteum during autologous chondrocyte implantation. AB - OBJECTIVE: In this study, we compare the clinical and histological outcome between periosteum and Chondrogide((r)) during autologous chondrocyte implantation (ACI). METHOD: This study consisted of 88 patients having received ACI in the knee; 33 treated with Chondrogide((r)) (ACI-C) and 55 with periosteum (ACI-P). Post-operative biopsies were taken at a mean of 16.6 +/- 8 months (range 7-37 months) and 19 +/- 18.4 months (range 4-114) for ACI-C and ACI-P respectively. Histological assessment was performed using the ICRS II and OsScore scoring systems. The immunolocalisation of elastin and collagen types I and II was analysed using specific antibodies. Lysholm scores, a measure of knee function, were obtained pre- and post-operatively at the time of biopsy and annually thereafter. RESULTS: Compared with ACI-P, the repair tissue formed from patients treated with ACI-C demonstrated a significantly higher score for cellular morphology (ICRS II score), significantly better surface morphology from medial femoral condyle treated defects (ICRS II score) and a significantly higher proportion of hyaline cartilage formation (OsScore). Elastin fibres were present in both ACI-C and ACI-P samples, although their presence was very variable in quantity, distribution, orientation, thickness and length. Patients treated with ACI-C demonstrated significantly more collagen type II immunolocalisation compared with ACI-P. Both groups exhibited a significant increase in Lysholm score post-ACI. CONCLUSIONS: This study demonstrates a significantly better quality of repair tissue formed with ACI-C compared with ACI-P. Hence Chondrogide((r)) is perhaps a better alternative to periosteum during ACI. PMID- 24161709 TI - Type I Chiari malformation presenting central sleep apnea. AB - Sleep apnea is a rare but a well-known clinical feature of type I Chiari malformation. It may be obstructive or central in nature. Sleep apnea in patients with type I Chiari malformation rarely presents without accompanying neurological signs or symptoms. We here report a case of a 10-year-old girl who presented with central sleep apnea without any other neurological signs but was ultimately diagnosed with type I Chiari malformation. The patient initially showed mild improvement in symptoms after administration of an acetazolamide. Finally, posterior fossa decompression dramatically improved her respiratory status during sleep, both clinically and on polysomnography. This case suggests that type I Chiari malformation should be considered in the differential diagnoses of central apneas in children, even if there are no other neurological signs and symptoms. Furthermore, sagittal craniocervical magnetic resonance imaging may be necessary for a definitive diagnosis. PMID- 24161711 TI - Novel cassette array in a class 1 integron in clinical isolates of Acinetobacter baumannii from central Iran. AB - Antibiotic resistance in Acinetobacter baumannii is a major problem in the hospital and outbreaks caused by this organism have been reported frequently. The present study aimed at determining the antibiotic susceptibility patterns, the prevalence of different classes of integrons and the characterization of integron class 1 gene cassettes in Iranian A. baumannii isolates. A total of 63 non duplicate A. baumannii isolates were collected from clinical and environmental specimens in the Vali-Asr hospital in the central province of Iran (March to September, 2011). The antimicrobial susceptibility for 15 antibiotics which are used conventionally was determined by disk diffusion. The presence of different integron classes was investigated by PCR and the size of gene cassettes in class 1 integrons was then determined by PCR as well. Moreover, integron cassette arrays of isolates were delineated by RFLP and sequencing amplicons with different lengths. Of 63 isolates 62 (98.4%) carried a class 1 integron. The prevalence of IntI2 was 15.9% and the length of the amplicons ranged from 500 bp to 3 kb. Sequencing of integrons of class 1 revealed the presence of many resistance genes (aadA, aacA, aacC, dfrA, bla(GES) and bla(IMP)). We identified a completely new gene cassette which contained aacA7-qacF-aadA5-bla(IMP), this cassette has not been reported previously in A. baumannii. PMID- 24161710 TI - Global proteome analysis of vancomycin stress in Staphylococcus aureus. AB - Vancomycin is one of the few remaining treatment options for multi resistant Staphylococcus aureus infections. Several transcriptomics and proteomics studies have investigated the bacterium's cellular response to vancomycin, but quantitative proteomic studies have been limited in the number of proteins and restricted to certain sub-cellular compartments so far. Here, we combined the enrichment of different proteomic sub-fractions with in vivo metabolic labeling and shotgun proteomics to analyze the vancomycin induced stress response. Quantitative data for approximately 1400 proteins could be obtained, covering the majority of cytosolic as well as membrane localized proteins, cell surface associated and extracellular proteins. Besides major adaptive processes induced by limited growth of the cells due to the sublethal vancomycin exposure, specific cellular responses are seen on proteome level, e.g. the specific increase of proteins synthesizing amino acids which are essential for the peptidoglycan synthesis or the decrease of most proteins with a virulence related function. Most important, the influence on regulatory targets of the two-component system VraSR as the main regulatory system known for cell wall stress as well as for global regulons like SigB and SaeR was detected. PMID- 24161712 TI - Receptor binding and pH stability - how influenza A virus hemagglutinin affects host-specific virus infection. AB - Influenza A virus strains adopt different host specificities mainly depending on their hemagglutinin (HA) protein. Via HA, the virus binds sialic acid receptors of the host cell and, upon endocytic uptake, HA triggers fusion between the viral envelope bilayer and the endosomal membrane by a low pH-induced conformational change leading to the release of the viral genome into the host cell cytoplasm. Both functions are crucial for viral infection enabling the genesis of new progeny virus. Adaptation to different hosts in vitro was shown to require mutations within HA altering the receptor binding and/or fusion behavior of the respective virus strain. Human adapted influenza virus strains (H1N1, H3N2, H2N2) as well as recent avian influenza virus strains (H5, H7 and H9 subtypes) which gained the ability to infect humans mostly contained mutations in the receptor binding site (RBS) of HA enabling increased binding affinity of these viruses to human type (alpha-2,6 linked sialic acid) receptors. Thus, the receptor binding specificity seems to be the major requirement for successful adaptation to the human host; however, the RBS is not the only determinant of host specificity. Increased binding to a certain cell type does not always correlate with infection efficiency. Furthermore, viruses carrying mutations in the RBS often resulted in reduced viral fitness and were still unable to transmit between mammals. Recently, the pH stability of HA was reported to affect the transmissibility of influenza viruses. This review summarizes recent findings on the adaptation of influenza A viruses to the human host and related amino acid substitutions resulting in altered receptor binding specificity and/or modulated fusion pH of HA. Furthermore, the role of these properties (receptor specificity and pH stability of HA) for adaptation to and transmissibility in the human host is discussed. This article is part of a Special Issue entitled: Viral Membrane Proteins -- Channels for Cellular Networking. PMID- 24161714 TI - New horizons in pharmaceutical biotechnology by melding biology and engineering. PMID- 24161713 TI - The intersection of neighborhood racial segregation, poverty, and urbanicity and its impact on food store availability in the United States. AB - BACKGROUND: Food store availability may determine the quality of food consumed by residents. Neighborhood racial residential segregation, poverty, and urbanicity independently affect food store availability, but the interactions among them have not been studied. PURPOSE: To examine availability of supermarkets, grocery stores, and convenience stores in US census tracts according to neighborhood racial/ethnic composition, poverty, and urbanicity. METHODS: Data from 2000 US Census and 2001 InfoUSA food store data were combined and multivariate negative binomial regression models employed. RESULTS: As neighborhood poverty increased, supermarket availability decreased and grocery and convenience stores increased, regardless of race/ethnicity. At equal levels of poverty, Black census tracts had the fewest supermarkets, White tracts had the most, and integrated tracts were intermediate. Hispanic census tracts had the most grocery stores at all levels of poverty. In rural census tracts, neither racial composition nor level of poverty predicted supermarket availability. CONCLUSIONS: Neighborhood racial composition and neighborhood poverty are independently associated with food store availability. Poor predominantly Black neighborhoods face a double jeopardy with the most limited access to quality food and should be prioritized for interventions. These associations are not seen in rural areas which suggest that interventions should not be universal but developed locally. PMID- 24161716 TI - Comparacion de la Eficacia de un Dentifrico que Contiene Arginina al 1.5% y 1450ppm de Fluoruro con la de un Dentifrico que Contiene 1450ppm de Fluoruro Solamente, en el Manejo de la Caries Radicular Primaria. PMID- 24161715 TI - Activation of brain endothelial cells by interleukin-1 is regulated by the extracellular matrix after acute brain injury. AB - The extracellular matrix (ECM) of the central nervous system (CNS) is essential for normal brain function, whilst ECM remodelling is associated with cerebrovascular inflammation driven by the cytokine interleukin-1 (IL-1) after acute brain injury. The effect of ECM remodelling on endothelial activation during neuroinflammation remains unknown. Here we report that ECM remodelling in the cerebrovasculature critically regulates IL-1-induced endothelial cell activation after cerebral ischaemia; Expression levels of ECM molecules associated with the cerebrovasculature, namely fibronectin (FN) and collagen IV (Col IV), strongly increased in brain blood vessels after middle cerebral artery occlusion (MCAo) in a time-dependent manner, reaching a peak of vascular expression 48 h after MCAo. In cultures, FN and Col IV (but also laminin-1 and fibrillin-1) promoted strong attachment of the GPNT endothelial cell line and primary rat brain endothelial cells, which was markedly inhibited by RGD (Arg-Gly Asp) peptide, or specific integrin beta1, alpha4, alpha5 and alphav blockade. IL 1beta-induced activation of extracellular-regulated kinase 1/2 (ERK1/2) and nuclear factor kappaB (NFkappaB), and synthesis of cytokine-induced neutrophil chemoattractant (CINC-1) were enhanced in cells plated onto ECM molecules, and these responses were inhibited by selective integrin blockade. Finally, increased ECM expression in vessels after MCAo was found associated with vinculin clustering, increased integrin beta1 expression, and increased IL-1 receptor associated kinase-1 (IRAK-1) activity in endothelial cells and perivascular astrocytes. Therefore, our data indicate a novel function for the ECM in the regulation of cerebrovascular inflammation triggered by IL-1 during acute brain injury. PMID- 24161717 TI - Desarrollo y validacion de una nueva tecnologia, basada en arginina al 1.5%, un compuesto de calcio insoluble y fluoruro, para el uso diario en la prevencion y tratamiento de la caries dental. AB - OBJETIVO: este articulo discute brevemente la prevalencia de caries, la naturaleza multifactorial de su etiologia, el riesgo de caries y el papel y eficacia del fluoruro. Resalta tambien la investigacion sobre el metabolismo bacteriano, que ha aportado conocimientos sobre la defensa natural oral contra la caries y la base para el desarrollo de una nueva tecnologia para la prevencion diaria y el tratamiento de la caries. Por ultimo, se resume la evidencia que respalda que la tecnologia complementa y mejora la eficacia anti-caries de la crema dental con fluoruro. CONCLUSIONES: los datos globales muestran que a pesar de la exitosa introduccion del fluoruro, la caries dental es una enfermedad prevalente. La experiencia de caries depende del balance entre el consumo de azucares, la higiene oral y el uso del fluoruro. Hay tres conceptos cientificos que son fundamentales en las nuevas mediciones para detectar, tratar y monitorear la caries: (1) la caries dental es un proceso dinamico, (2) la caries dental es un proceso continuo de etapas que van desde reversible (pre-clinica) hasta irreversible (lesiones clinicamente detectables), y (3) el proceso de la caries es un balance de factores patologicos y protectores que pueden modularse para el manejo de la caries. El fluoruro funciona como factor protector al detener y revertir el proceso de la caries, pero el fluoruro no previene los factores patologicos que inician el proceso. Se ha identificado una tecnologia novedosa, basada en arginina y un compuesto insoluble de calcio, que esta dirigida a la placa dental para prevenir la iniciacion del proceso de caries al reducir los factores patologicos. Como los mecanismos de accion de la arginina y el fluoruro son altamente complementarios, se ha desarrollado un nuevo dentifrico que combina la arginina y el fluoruro, y se ha probado clinicamente que brinda una prevencion superior contra la caries. PMID- 24161718 TI - Pleural effusion hyaluronic acid as a prognostic marker in pleural malignant mesothelioma. AB - BACKGROUND: Malignant mesothelioma (MM), a primarily asbestos-induced tumour, has a poor prognosis, with over-all 5-year survival less than 5%. Tumour biomarkers are being intensely investigated in MM as aids to diagnosis and prognosis. Hyaluronic acid (HA) is produced in MM but its role in prognostication remains uncertain. MATERIALS AND METHODS: HA concentrations were determined in matching serum and pleural effusion of 96 MM patients, 26 lung cancer patients and 42 patients with benign effusions resulting from infectious, cardiac, renal, liver and rheumatoid diseases and compared to the current 'best practice' biomarker, mesothelin. Liver and kidney function were determined for each patient. Diagnostic accuracy was determined by area under the receiver operator characteristic curve (AUC) analysis following logistic regression modelling. Difference in survival between groups was determined by both log-rank test and Cox proportional hazards regression modelling. RESULTS: For effusion HA, the AUC (IQ range) was 0.89 (0.82-0.94) and for effusion mesothelin, it was 0.85 (0.78 0.90). Serum HA was not diagnostically useful. A combined measure of effusion HA, and serum and effusion mesothelin had an AUC of 0.92 (0.86-0.96), which was significantly higher than effusion mesothelin alone. Effusion HA had a biphasic distribution in MM patients, dichotomised at a concentration of 75 mg/L. The median survival of MM patients with high effusion HA was 18.0 (13.7-22.4) months, significantly longer than those with low HA effusion levels (12.6 months (8.4 16.8), p=0.004). Serum HA, and effusion and serum mesothelin were not significant prognostic indicators. CONCLUSION: This study demonstrates that a combined biomarker panel has greater diagnostic accuracy than effusion mesothelin alone, and that significant prognostic information is provided by effusion HA. PMID- 24161719 TI - Lung cancer: what are the links with oxidative stress, physical activity and nutrition. AB - Oxidative stress appears to play an essential role as a secondary messenger in the normal regulation of a variety of physiological processes, such as apoptosis, survival, and proliferative signaling pathways. Oxidative stress also plays important roles in the pathogenesis of many diseases, including aging, degenerative disease, and cancer. Among cancers, lung cancer is the leading cause of cancer in the Western world. Lung cancer is the commonest fatal cancer whose risk is dependent on the number of cigarettes smoked per day as well as the number of years smoking, some components of cigarette smoke inducing oxidative stress by transmitting or generating oxidative stress. It can be subdivided into two broad categories, small cell lung cancer and non-small-cell lung cancer, the latter is the most common type. Distinct measures of primary and secondary prevention have been investigated to reduce the risk of morbidity and mortality caused by lung cancer. Among them, it seems that physical activity and nutrition have some beneficial effects. However, physical activity can have different influences on carcinogenesis, depending on energy supply, strength and frequency of exercise loads as well as the degree of exercise-mediated oxidative stress. Micronutrient supplementation seems to have a positive impact in lung surgery, particularly as an antioxidant, even if the role of micronutrients in lung cancer remains controversial. The purpose of this review is to examine lung cancer in relation to oxidative stress, physical activity, and nutrition. PMID- 24161720 TI - Complex instability of the elbow. AB - Injuries to the elbow are commonly encountered in orthopaedic practice. They range from low energy, simple isolated fractures, to high energy complex fracture dislocations with severe ligamentous disruption. Recognising the precise pattern of injury is critical in restoring elbow function and preventing chronic instability, pain and weakness. This article discusses the important osseous and ligamentous stabilisers of the elbow joint and provides management protocols for the common patterns of complex injury encountered by the practising surgeon. PMID- 24161721 TI - The effects of intraganglionic injection of calcium/calmodulin-dependent protein kinase II inhibitors on pain-related behavior in diabetic neuropathy. AB - Calcium/calmodulin-dependent protein kinase II (CaMKII) has been implicated in the transmission of nociceptive input in diabetic neuropathy. The aim of this study was to test whether intraganglionic (i.g.) injection of CaMKII inhibitors may alleviate pain-related behavior in diabetic rats. Diabetes was induced in Sprague-Dawley rats using 55 mg/kg streptozotocin intraperitoneally. Two weeks after diabetes induction, CaMKII inhibitors myristoil-AIP and KN93 were injected directly into the right L5 dorsal root ganglion (DRG). Behavioral testing with mechanical and thermal stimuli was performed before induction of diabetes, the day preceding the injection, as well as 2 and 24h after the i.g. injection. The expression of total CaMKII and its alpha isoform in DRG neurons was analyzed using immunohistochemistry. CaMKII inhibitors attenuated pain-related behavior in a modality-specific fashion. Attenuation of nociceptive behavior was accompanied with a corresponding decrease of CaMKII alpha expression in DRG neurons on the side of injection. A significant decrease of CaMKII alpha expression was seen in small- and medium-sized neurons. In conclusion, our study provides evidence that CaMKII inhibitors are potential pharmacological agents that should be further explored for treatment of diabetic neuropathy symptoms. PMID- 24161722 TI - Development of nNOS-positive neurons in the rat sensory and sympathetic ganglia. AB - Neurochemical features in sympathetic and afferent neurons are subject to change during development. Nitric oxide (NO) plays a developmental role in the nervous system. To better understand the neuroplasticity of sympathetic and afferent neurons during postnatal ontogenesis, the distribution of neuronal NO synthase (nNOS) immunoreactivity was studied in the sympathetic para- and prevertebral, nodose ganglion (NG) and Th2 and L4 dorsal root ganglia (DRG) from female Wistar rats of different ages (newborn, 10-day-old, 20-day-old, 30-day-old, 2-month-old, 6-month-old, 1-year-old, and 3-year-old). nNOS-positive neurons were revealed in all sensory ganglia but not in sympathetic ones from birth onward. The percentage of nNOS-immunoreactive (IR) neurons increased during first 10 days of life from 41.3 to 57.6 in Th2 DRG, from 40.9 to 59.1 in L4 DRG and from 31.6 to 38.5 in NG. The percentage of nNOS-IR neurons did not change in the NG later during development and senescence. However, in Th2 and L4 DRG the proportion of nNOS-IR neurons was high in animals between 10 and 30days of life and decreased up to the second month of life. In 2-month-old rats, the percentage of nNOS-IR neurons was 52.9 in Th2 DRG and 51.3 in L4 DRG. We did not find statistically significant differences in the percentage of nNOS-IR neurons between Th2 and L4 DRG and between young and aged rats. In NG and DRG of 10-day-old and older rats, a high proportion of nNOS-IR neurons binds isolectin B4. In newborn animals, only 41.3%, 45.3% and 28.4% of nNOS neuron profiles bind to IB4 in Th2, L4 DRG and NG, respectively. In 10-day-old and older rats, the number of sensory nNOS-IR neurons binding IB4 reached more than 90% in DRG and more than 80% in NG. Only a small number of nNOS-positive cells showed immunoreactivity to calcitonin gene-related peptide, neurofilament 200, calretinin. The information provided here will also serve as a basis for future studies investigating mechanisms of the development of sensory neurons. PMID- 24161723 TI - White matter plasticity in adulthood. AB - CNS white matter is subject to a novel form of neural plasticity which has been termed "myelin plasticity". It is well established that oligodendrocyte generation and the addition of new myelin internodes continue throughout normal adulthood. These new myelin internodes maybe required for the de novo myelination of previously unmyelinated axons, myelin sheath replacement, or even myelin remodeling. Each process could alter axonal conduction velocity, but to what end? We review the changes that occur within the white matter over the lifetime, the known regulators and mediators of white matter plasticity in the mature CNS, and the physiological role this plasticity may play in CNS function. PMID- 24161724 TI - Improved efficiency and safety for EVAR with utilization of a hybrid room. AB - OBJECTIVE: Access to a hybrid endovascular suite is touted as a necessity for advanced endovascular aneurysm repair (EVAR) to improve imaging accuracy and safety. Yet there remain little data documenting this intuitive advantage of a hybrid setup versus a traditional operating room (OR) utilizing a portable fluoroscopic unit (C-arm) for imaging. We hypothesized that standard elective EVAR performed in a hybrid suite would improve procedural efficiency and accuracy, as well minimize patient exposure to both contrast and radiation. METHODS: We retrospectively reviewed a single attending surgeon's EVAR practice, which encompassed the transition to a hybrid endovascular suite (opened July 2010). Only consecutive abdominal aneurysms were included in the analysis to attempt to create a homogenous cohort. All emergent, aorto-uni-iliac (AUI), snorkel, fenestrated, or hybrid procedures were excluded. Standard variables evaluated and compared between the two study subgroups included fluoroscopy time, operative time, contrast use, stent-graft component utilization, complication rates, and short-term endoleaks. RESULTS: From January 2008 to August 2012, we performed 213 EVAR procedures for abdominal aortic aneurysms. After excluding emergent, AUI, snorkel, or hybrid procedures, we analyzed 109 routine EVARs. Fifty-eight consecutive cases were done in the OR with a C-arm until July 2010, and the last 51 cases were done in the hybrid room. Both groups were well matched in terms of demographics, aneurysm morphology, and procedural characteristics. No difference was found in terms of complication rates or operative mortality, although there was a trend towards decreased fluoroscopy time, type I/III endoleaks, and a number of additional endograft components utilized. Compared with patients repaired in the OR/C-arm, EVAR done in the hybrid room resulted in less total OR time and contrast usage (p < .05). CONCLUSIONS: Routine EVAR performed in a hybrid fixed-imaging suite affords greater efficiency and less harmful exposure of contrast and possible radiation to the patient. Accurate imaging quality and deployment is associated with less need for additional endograft components, which should lead to improved cost efficiency. Confirmation of these findings might be necessary in a randomized control trial to fully justify the capital expenditure necessary for hybrid endovascular suites. PMID- 24161725 TI - Tandem Staudinger/aza-Wittig reaction of 6-azido-6-deoxycellulose derivative. AB - The tandem Staudinger/aza-Wittig reaction of the 6-azido-6-deoxycellulose derivative (2) with triphenylphosphine and carbon disulfide afforded the corresponding 6-isothiocyanato-6-deoxycellulose derivative (3) in 47.3% yield. Compound 3 was further reacted with 4'-aminobenzo-15-crown ether to afford the crown ether-containing 6-N-thioureido-6-deoxycellulose derivative (4) in 70.0% yield. Compound 4 was also obtained in 28.7% yield from the one-pot reaction (tandem Staudinger/aza-Wittig reaction/thiocarbamoylation) of compound 2. The tandem Staudinger/aza-Wittig reaction is a useful alternative to the Huisgen reaction for the synthesis of functional cellulose derivatives from 6-azido-6 deoxycellulose derivatives. PMID- 24161726 TI - Artificial radionuclides in surface air in Finland following the Fukushima Dai ichi nuclear power plant accident. AB - We present observations of radionuclides released during the Fukushima Dai-ichi nuclear power plant accident in ambient air and in deposition made in Finland during March-May 2011. The first observed fission product was (131)I, which arrived in Finland 8-9 days after the accident. Detections of (137)Cs and (134)Cs were made 2-3 days after the first (131)I observations. The highest concentrations of fission products in Finland were observed during March 31st and April 1st. The highest observed concentrations of the following isotopes were: (131)I (10.6 +/- 0.4 mBq/m(3)), (134)Cs (0.397 +/- 0.020 mBq/m(3)), (137)Cs (0.405 +/- 0.017 mBq/m(3)), (136)Cs (28 +/- 2 MUBq/m(3)), (129)Te (129 +/- 9 MUBq/m(3)), (129m)Te (234 +/- 20 MUBq/m(3)), (132)Te (51 +/- 3 MUBq/m(3)) and (132)I (54 +/- 3 MUBq/m(3)). Generally, higher concentrations of fission product were observed in Southern Finland than in Northern Finland. The variations in the (137)Cs and (134)Cs activity concentration data suggest that three separate plumes passed over Finland with decreasing concentrations. The first plume, with highest cesium concentrations, passed over Finland during March 31st - April 2nd, the second plume during April 4th - 6th and the third and smallest one during April 10th - April 11th. Both aerosol and gaseous iodine fractions were sampled simultaneously and thus an accurate view of the behaviour of aerosol and gaseous fractions was obtained. Large variations between different fractions were observed with the gaseous fraction representing 65-98% of the total (131)I. The (134)Cs/(137)Cs ratio was determined to be 0.99 +/- 0.10, which indicates a fuel burnup of approximately 30 MWd/t. The (136)Cs/(137)Cs and (129m)Te/(132)Te ratios were used to estimate the time lapse after the accident. The differences between true time lapse and the ones deduced from the isotope ratios were from the correct time lapse to 0-3 days for (136)Cs/(137)Cs and 5 days for (129m)Te/(132)Te, respectively. Radionuclides from the Fukuhisma Dai-ichi nuclear power plant were also observed in deposition samples. In Norther Finland, the total deposition of 0.28-0.62 Bq/m(2) for (137)Cs and 0.21-0.57 Bq/m(2) for (134)Cs was determined during March-May 2011. For (131)I the deposition of 8.5 +/ 2.9 Bq/m(2) was determined at Rovaniemi from the samples from the sample collected during April 1st - 12th. PMID- 24161727 TI - Systematic review and new insights into the molecular characterization of the Candida rugosa species complex. AB - Recently, Candida rugosa was characterized as a species complex comprising four taxa: C. rugosa sensu stricto, Candida pseudorugosa, Candida neorugosa and Candida mesorugosa. Although considered relatively rare, several clusters of candidemia due to C. rugosa complex had been reported presenting mortality rates close to 70%. In this work we discuss the systematization, phenotyping and molecular methods based on internal transcribed spacer region (ITS) sequencing and proteomic analyses for species identification, as well as clinical aspects of the C. rugosa complex. We performed a Bayesian phylogenetic analysis using 72 ITS sequences representative of C. rugosa complex isolates and related species within the genus. Biochemical, morphological and MALDI-TOF MS analyses were processed with C. rugosa complex type strains and related species isolates. We described that the phylogeny showed four distinct clades inferred with high posterior probabilities, corresponding to the four species within the C. rugosa complex, excluding C. pararugosa. Biochemical and morphological aspects distinguished only C. rugosa sensu stricto but were not sufficient to accurately identify species within the rest of the complex. Protein spectrum profiles differentiated all reference strains from different species analyzed. To our knowledge, we presented the first phylogenetic analysis using a large collection of ITS sequences as well as proteomic profiles generated from isolates of the C. rugosa complex and related species that can enlighten systematics, diagnostics and clinical research fields. PMID- 24161728 TI - The MpkB MAP kinase plays a role in autolysis and conidiation of Aspergillus nidulans. AB - The mpkB gene of Aspergillus nidulans encodes a MAP kinase homologous to Fus3p of Saccharomyces cerevisiae which is involved in conjugation process. MpkB is required for completing the sexual development at the anastomosis and post karyogamy stages. The mpkB deletion strain could produce conidia under the repression condition of conidiation such as sealing and even in the submerged culture concomitant with persistent brlA expression, implying that MpkB might have a role in timely regulation of brlA expression. The submerged culture of the deletion strain showed typical autolytic phenotypes including decrease in dry cell mass (DCM), disorganization of mycelial balls, and fragmentation of hyphae. The chiB, engA and pepJ genes which are encoding cell wall hydrolytic enzymes were transcribed highly in the submerged culture. Also, we observed that the enzyme activity of chitinase and glucanase in the submerged culture of mpkB deletion strain was much higher than that of wild type. The deletion of mpkB also caused a precocious germination of conidia and reduction of spore viability. The expression of the vosA gene, a member of velvet gene family, was not observed in the mpkB deletion strain. These results suggest that MpkB should have multiple roles in germination and viability of conidia, conidiation and autolysis through regulating the expression of vosA and brlA. PMID- 24161729 TI - Disruption of the nitrogen regulatory gene AcareA in Acremonium chrysogenum leads to reduction of cephalosporin production and repression of nitrogen metabolism. AB - AcareA, encoding a homologue of the fungal nitrogen regulatory GATA zinc-finger proteins, was cloned from Acremonium chrysogenum. Gene disruption and genetic complementation revealed that AcareA was required for nitrogen metabolism and cephalosporin production. Disruption of AcareA resulted in growth defect in the medium using nitrate, uric acid and low concentration of ammonium, glutamine or urea as sole nitrogen source. Transcriptional analysis showed that the transcription of niaD/niiA was increased drastically when induced with nitrate in the wild-type and AcareA complemented strains but not in AcareA disruption mutant. Consistent with the reduction of cephalosporin production, the transcription of pcbAB, cefD2, cefEF and cefG encoding the enzymes for cephalosporin production was reduced in AcareA disruption mutant. Band shift assays showed that AcAREA bound to the promoter regions of niaD, niiA and the bidirectional promoter region of pcbAB-pcbC. Sequence analysis showed that all the AcAREA binding sites contain the consensus GATA elements. These results indicated that AcAREA plays an important role both in the regulation of nitrogen metabolism and cephalosporin production in A. chrysogenum. PMID- 24161730 TI - N-acetylglucosamine-induced white-to-opaque switching in Candida albicans is independent of the Wor2 transcription factor. AB - Candida albicans, a major opportunistic fungal pathogen of humans, can spontaneously undergo white-to-opaque switching, a prerequisite of mating. The phenotypes of white and opaque cells are heritable and bistable. The zinc-finger transcription factor Wor2 (White Opaque Regulator 2) has previously been identified as an important regulator of white-to-opaque switching. Deletion of WOR2 locks cells in the white phase when cultured on media containing glucose as the sole carbon source. In this study, we report that N-acetylglucosamine (GlcNAc) can induce white-to-opaque switching in the wor2/wor2 null mutant and stabilize the opaque phenotype of C. albicans. Moreover, overexpression of RAS1V13 (the activating form of RAS1) hypersensitizes white cells of the wor2/wor2 mutant to GlcNAc. These results suggest that Wor2 is not required for opaque cell formation at least under some culture conditions. Therefore C. albicans cells may adopt a different gene expression profile in response to GlcNAc to activate phenotypic switching. PMID- 24161731 TI - The N-terminus region of the putative C2H2 transcription factor Ada1 harbors a species-specific activation motif that regulates asexual reproduction in Fusarium verticillioides. AB - Fusarium verticillioides is an important plant pathogenic fungus causing maize ear and stalk rots. In addition, the fungus is directly associated with fumonisin contamination of food and feeds. Here, we report the functional characterization of Ada1, a putative Cys2-His2 zinc finger transcription factor with a high level of similarity to Aspergillus nidulans FlbC, which is required for the activation of the key regulator of conidiation brlA. ADA1 is predicted to encode a protein with two DNA binding motifs at the C terminus and a putative activator domain at the N terminus region. Deletion of the flbC gene in A. nidulans results in "fluffy" cotton-like colonies, with a defect in transition from vegetative growth to asexual development. In this study we show that Ada1 plays a key role in asexual development in F. verticillioides. Conidia production was significantly reduced in the knockout mutant (Deltaada1), in which aberrant conidia and conidiophores were also observed. We identified genes that are predicted to be downstream of ADA1, based on A. nidulans conidiation signaling pathway. Among them, the deletion of stuA homologue, FvSTUA, resulted in near absence of conidia production. To further investigate the functional conservation of this transcription factor, we complemented the Deltaada1 strain with A. nidulans flbC, F. verticillioides ADA1, and chimeric constructs. A. nidulans flbC failed to restore conidia production similar to the wild-type level. However, the Ada1N terminal domain, which contains a putative activator, fused to A. nidulans FlbC C terminal motif successfully complemented the Deltaada1 mutant. Taken together, Ada1 is an important transcriptional regulator of asexual development in F. verticillioides and that the N-terminus domain is critical for proper function of this transcription factor. PMID- 24161732 TI - Optimod--an automated approach for constructing and optimizing initial models for single-particle electron microscopy. AB - Single-particle cryo-electron microscopy is now well established as a technique for the structural characterization of large macromolecules and macromolecular complexes. The raw data is very noisy and consists of two-dimensional projections, from which the 3D biological object must be reconstructed. The 3D object depends upon knowledge of proper angular orientations assigned to the 2D projection images. Numerous algorithms have been developed for determining relative angular orientations between 2D images, but the transition from 2D to 3D remains challenging and can result in erroneous and conflicting results. Here we describe a general, automated procedure, called OptiMod, for reconstructing and optimizing 3D models using common-lines methodologies. OptiMod approximates orientation angles and reconstructs independent maps from 2D class averages. It then iterates the procedure, while considering each map as a raw solution that needs to be compared with other possible outcomes. We incorporate procedures for 3D alignment, clustering, and refinement to optimize each map, as well as standard scoring metrics to facilitate the selection of the optimal model. We also show that small angle tilt-pair data can be included as one of the scoring metrics to improve the selection of the optimal initial model, and also to provide a validation check. The overall approach is demonstrated using two experimental cryo-EM data sets--the 80S ribosome that represents a relatively straightforward case for ab initio reconstruction, and the Tf-TfR complex that represents a challenging case in that it has previously been shown to provide multiple equally plausible solutions to the initial model problem. PMID- 24161734 TI - Role of self-avoidance in neuronal wiring. PMID- 24161733 TI - Bayesian analysis of individual electron microscopy images: towards structures of dynamic and heterogeneous biomolecular assemblies. AB - We develop a method to extract structural information from electron microscopy (EM) images of dynamic and heterogeneous molecular assemblies. To overcome the challenge of disorder in the imaged structures, we analyze each image individually, avoiding information loss through clustering or averaging. The Bayesian inference of EM (BioEM) method uses a likelihood-based probabilistic measure to quantify the consistency between each EM image and given structural models. The likelihood function accounts for uncertainties in the molecular position and orientation, variations in the relative intensities and noise in the experimental images. The BioEM formalism is physically intuitive and mathematically simple. We show that for experimental GroEL images, BioEM correctly identifies structures according to the functional state. The top-ranked structure is the corresponding X-ray crystal structure, followed by an EM structure generated previously from a superset of the EM images used here. To analyze EM images of highly flexible molecules, we propose an ensemble refinement procedure, and validate it with synthetic EM maps of the ESCRT-I-II supercomplex. Both the size of the ensemble and its structural members are identified correctly. BioEM offers an alternative to 3D-reconstruction methods, extracting accurate population distributions for highly flexible structures and their assemblies. We discuss limitations of the method, and possible applications beyond ensemble refinement, including the cross-validation and unbiased post assessment of model structures, and the structural characterization of systems where traditional approaches fail. Overall, our results suggest that the BioEM framework can be used to analyze EM images of both ordered and disordered molecular systems. PMID- 24161735 TI - The effects of low vitamin D on coronary artery disease. AB - PURPOSE: Coronary Artery Disease (CAD) remains a major cause of morbidity and mortality in the world. Low vitamin D status has been shown to be associated with increased risk of developing cardiovascular disease, hypertension and obesity. We planned to research the association between low vitamin D status and the severity of CAD. PROCEDURES: A total of 348 consecutive patients undergoing coronary angiography for evaluation of CAD were included in this study. 25-Hydroxyvitamin D [25(OH)D] was measured by chemiluminescence assay. CAD severity was assessed by using the SYNTAX scores. The data presented are the mean levels/values and standard deviation. FINDINGS: The serum 25(OH)D level of CAD patients was 18.2 +/ 10.6 ng/ml. The SYNTAX scores were 27.8 +/- 8.5. In a multivariate linear regression analysis (adjusted for age, high-sensitivity C-reactive protein, SYNTAX score, parathyroid hormone, body mass index, haemoglobin and creatinine), the serum 25(OH)D level showed a negative correlation with SYNTAX score and high sensitivity C-reactive protein (hsCRP) level. Logistic regression analysis identified 25(OH)D as an independent factor related to high SYNTAX scores. Patients whose vitamin D levels were in the lowest 25(OH)D category (<20 ng/ml) were more often in the high SYNTAX scores group, with their incidence about two fold higher than those in the highest 25(OH)D category (>30 ng/ml). CONCLUSION: Low vitamin D is associated with the severity of coronary artery stenosis. PMID- 24161736 TI - Human serum activates CIDEB-mediated lipid droplet enlargement in hepatoma cells. AB - Human hepatocytes constitutively express the lipid droplet (LD) associated protein cell death-inducing DFFA-like effector B (CIDEB). CIDEB mediates LD fusion, as well as very-low-density lipoprotein (VLDL) maturation. However, there are limited cell culture models readily available to study CIDEB's role in these biological processes, as hepatoma cell lines express negligible levels of CIDEB. Recent work has highlighted the ability of human serum to differentiate hepatoma cells. Herein, we demonstrate that culturing Huh7.5 cells in media supplemented with human serum activates CIDEB expression. This activation occurs through the induced expression of PGC-1alpha, a positive transcriptional regulator of CIDEB. Coherent anti-Stokes Raman scattering (CARS) microscopy revealed a correlation between CIDEB levels and LD size in human serum treated Huh7.5 cells. Human serum treatment also resulted in a rapid decrease in the levels of adipose differentiation-related protein (ADRP). Furthermore, individual overexpression of CIDEB was sufficient to down-regulate ADRP protein levels. siRNA knockdown of CIDEB revealed that the human serum mediated increase in LD size was CIDEB dependent. Overall, our work highlights CIDEB's role in LD fusion, and presents a new model system to study the PGC-1alpha/CIDEB pathway's role in LD dynamics and the VLDL pathway. PMID- 24161738 TI - Astrocytes express functional TRPV2 ion channels. AB - Thermosensitive transient receptor potential (thermo TRP) channels are important for sensory transduction. Among them, TRPV2 has an interesting characteristic of being activated by very high temperature (>52 degrees C). In addition to the heat sensor function, TRPV2 also acts as a mechanosensor, an osomosensor and a lipid sensor. It has been reported that TRPV2 is expressed in heart, intestine, pancreas and sensory nerves. In the central nervous system, neuronal TRPV2 expression was reported, however, glial expression and the precise roles of TRPV2 have not been determined. To explore the functional expression of TRPV2 in astrocytes, the expression was determined by histological and physiological methods. Interestingly, TRPV2 expression was detected in plasma membrane of astrocytes, and the astrocytic TRPV2 was activated by very high temperature (>50 degrees C) consistent with the reported characteristic. We revealed that the astrocytic TRPV2 was also activated by lysophosphatidylcholine, a known endogenous lipid ligand for TRPV2, suggesting that astrocytic TRPV2 might regulate neuronal activities in response to lipid metabolism. Thus, for the first time we revealed that TRPV2 is functionally expressed in astrocytes in addition to neurons. PMID- 24161737 TI - Unfolding protein response signaling is involved in development, maintenance, and regression of the corpus luteum during the bovine estrous cycle. AB - The corpus luteum (CL) is a transient endocrine organ. Development, maintenance, and regression of CL are effectively controlled by dynamic changes in gene expression. However, it is unknown what types of gene are affected during the CL life span of the estrous cycle in bovine. Here, we determined whether unfolded protein response (UPR) signaling via eIF2alpha/ATF4/GADD34, p90ATF6/p50ATF6, and IRE1/XBP1, which is a cellular stress response associated with the endoplasmic reticulum (ER), is involved in the bovine CL life span. Our results indicated that expression of Grp78/Bip, the master UPR regulator, was increased during the maintenance stage and rapidly decreased at the regression stage. Additionally, UPR signaling pathways genes were found to be involved in luteal phase progression during the estrous cycle. Our findings suggested that Grp78/Bip, ATF6, and XBP1 act as ER chaperones for initiating CL development and maintaining the CL. In addition, we investigated whether ER stress-mediated apoptosis is occurred through three UPR signaling pathways in CL regression stage. Interestingly, pIRE1 and CHOP were found to be involved in both the adaptive response and ER stress-mediated apoptosis. During the CL regression stage, increased expression of pJNK and CHOP, two components of ER stress-mediated apoptotic cascades, occurred before increased level of cleaved caspase 3 were observed. The present investigation was performed to identify a functional link between UPR signaling and CL life span during the bovine estrous cycle. Taken together, results from this study demonstrated that UPR protein/gene expression levels were different at various stages of the bovine CL life span. Variations in the expression of these protein/genes may play important roles in luteal stage progression during the estrous cycle. PMID- 24161739 TI - A new anti-angiogenic small molecule, G0811, inhibits angiogenesis via targeting hypoxia inducible factor (HIF)-1alpha signal transduction. AB - Regulation of hypoxia inducible factor (HIF)-1alpha stabilization, which in turn contributes to adaptation of tumor cells to hypoxia has been highlighted as a promising therapeutic target in angiogenesis-related diseases. We have identified a new small molecule, G0811, as a potent angiogenesis inhibitor that targets HIF 1alpha signal transduction. G0811 suppressed HIF-1alpha stability in cancer cells and inhibited in vitro and in vivo angiogenesis, as validated by tube formation, chemoinvasion, and chorioallantoic membrane (CAM) assays. In addition, G0811 effectively decreased the expression of vascular endothelial growth factor (VEGF), which is one of target genes of HIF-1alpha. However, G0811 did not exhibit anti-proliferative activities or toxicity in human umbilical vein endothelial cells (HUVECs) at effective doses. These results demonstrate that G0811 could be a new angiogenesis inhibitor that acts by targeting HIF-1alpha signal transduction pathway. PMID- 24161740 TI - What patient characteristics guide nurses' clinical judgement on pressure ulcer risk? A mixed methods study. AB - BACKGROUND: Nurses' clinical judgement plays a vital role in pressure ulcer risk assessment, but evidence is lacking which patient characteristics are important for nurses' perception of patients' risk exposure. OBJECTIVES: To explore which patient characteristics nurses employ when assessing pressure ulcer risk without use of a risk assessment scale. DESIGN: Mixed methods design triangulating observational data from the control group of a quasi-experimental trial and data from semi-structured interviews with nurses. SETTING: Two traumatological wards at a university hospital. PARTICIPANTS: Quantitative data: A consecutive sample of 106 patients matching the eligibility criteria (age >= 18 years, no pressure ulcers category >= 2 at admission and >= 5 days expected length of stay). Qualitative data: A purposive sample of 16 nurses. METHODS: Quantitative data: Predictor variables for pressure ulcer risk were measured by study assistants at the bedside each second day. Concurrently, nurses documented their clinical judgement on patients' pressure ulcer risk by means of a 4-step global judgement scale. Bivariate correlations between predictor variables and nurses' risk estimates were established. Qualitative data: In interviews, nurses were asked to assess fictitious patients' pressure ulcer risk and to justify their risk estimates. Patient characteristics perceived as relevant for nurses' judements were thematically clustered. Triangulation: Firstly, predictors of nurses' risk estimates identified in bivariate analysis were cross-mapped with interview findings. Secondly, three models to predict nurses' risk estimates underwent multiple linear regression analysis. RESULTS: Nurses consider multiple patient characteristics for pressure ulcer risk assessment, but regard some conditions more important than others. Triangulation showed that these are measures reflecting patients' exposure to pressure or overall care dependency. Qualitative data furthermore indicate that nurses are likely to trade off risk-enhancing conditions against conditions perceived to be protective. Here, patients' mental capabilities like willingness to engage in one owns care seem to be particularly important. Due to missing information on these variables in the quantitative data, they could not be incorporated into triangulation. CONCLUSIONS: Nurses' clinical judgement draws on well-known aetiological factors, and tends to expand conditions covered by risk assessment scales. Patients' care dependency and self care abilities seem to be core concepts for nurses' risk assessment. PMID- 24161741 TI - Substrate specificity of human matriptase-2. AB - Human matriptase-2 is an enzyme that belongs to the family of type II transmembrane serine proteases. So far there is a limited knowledge regarding its specificity and protein substrate(s). One of the identified natural substrates is hemojuvelin, a protein involved in the control of iron homeostasis. In this work, we describe the synthesis and evaluation of internal quenched substrates using a combinatorial approach. The iterative deconvolution of two libraries to define the specificity of matriptase-2 yielded to the identification of the substrate ABZ-Ile-Arg-Ala-Arg-Ser-Ala-Gly-Tyr(3-NO2)-NH2 with a k(cat)/K(m) value of 4.5 * 10(5) M(-1) * s(-1), i.e. the highest specificity constant reported so far for matriptase-2. PMID- 24161742 TI - Role of sediment characteristics on natural radiation level of the Vaigai river sediment, Tamilnadu, India. AB - The sediment characteristics such as granulometric contents (sand, silt and clay), organic matter, magnetic susceptibility (low and high frequency) and weight percentage of magnetic minerals and the natural radionuclide ((238)U, (232)Th and (40)K) contents have been analyzed for the sediment samples of Vaigai river with an aim of evaluating the radiation hazard nature and assessing characterization of sediment. Granulometric analysis confirmed that the sand is major content. The organic matter content is ranged from 0.30 to 8.62% and comparison shows that the present river has high organic content. The magnetic measurement results indicated that the sites S16, S18 and S25 may be affected anthropogenically. Frequency dependence magnetic susceptibility is calculated to know the contribution of grains to magnetic susceptibility. Average of activity concentrations (except (40)K) and all calculated radiological parameters are within the recommended level. Multivariate statistical analyses (Pearson correlation, cluster and factor analysis) dictated that the role of sediment characteristics on the level of radioactivity in the river sediments. The content of organic matter and clay, and magnetic parameters are positively correlated with important radioactive variables. The measurement of organic matter and magnetic susceptibility in various granulometric contents show some higher values in silt and clay fractions. Radioactivity level was also measured for the samples (after removing silt and clay fractions from bulk samples) and the results show decrease in radioactive variables. The present study stated that the lower grain sized fractions have the ability to absorb the contents such as organic content and magnetic minerals as cations on their surface and raise the level of radioactivity. Percentage of decrease in the natural radionuclides of (238)U, (232)Th, (40)K and absorbed dose rate of the samples (after removing the silt and clay fractions from bulk samples) to the bulk samples are 13.59, 33.37, 20.52 and 26.13% respectively. Thus, it is concluded that the radiation effect does not pose to the public those who are using these sediments. PMID- 24161743 TI - A novel use of the caesium-137 technique to estimate human interference and historical water level in a Mediterranean Temporary Pond. AB - The sustainability of, and the effects of human pressures on, Omalos Mediterranean Temporary Pond (MTP), Chanea, Greece was assessed. The (137)Cs technique was used to identify alleged anthropogenic interference (excavation) in the studied area. It was found that about one third of the ponds bed surface material had been removed and disposed of on the northeast edge, confirming unplanned excavations that took place in the MTP area some years ago. Nonetheless, five years after the excavation, the MTP's ecosystem (flora and fauna) had recovered, which indicates that these small ecosystems are resilient to direct human pressures, like excavations. Moreover, with the (137)Cs technique it was possible to identify the historical water level of Omalos MTP, when the fallout from the Chernobyl accident reached this area, in May of 1986. Therefore, the (137)Cs technique can be useful in the identification of the historical water level of small MTPs and other ephemeral water bodies. Applications include the verification and validation of hydrological models. PMID- 24161744 TI - Th17 response to Dermatophagoides pteronyssinus is related to late-phase airway and systemic inflammation in allergic asthma. AB - BACKGROUND: Th17 cells may play a role in the development of late-phase allergen induced airway and systemic inflammation in allergic asthma, although the mechanisms involved remain to be elucidated. METHODS: A total of 36 subjects were enrolled into the study: 15 allergic asthma patients with early asthmatic reaction (n=7) or dual asthmatic reaction (n=8) developed to inhaled D. pteronyssinus, 13 patients with allergic rhinitis, and 8 healthy subjects. Peripheral blood and induced sputum were collected 24h before as well as 7h and 24h after a bronchial challenge with D. pteronyssinus. Th17 cells were analyzed by FACS; IL-17 levels were determined by ELISA. RESULTS: At baseline, the percentage of peripheral blood Th17 cells and serum and sputum IL-17 levels were significantly higher in all groups of studied patients compared with those of healthy subjects. After the bronchial challenge, there was a significant increase in the percentage of peripheral blood Th17 cells and in serum and sputum IL-17 levels in rhinitis and asthma patients compared with their baseline values, particularly in allergic asthma patients with the dual asthmatic reaction. Positive correlations were found between the percentage of Th17 cells and IL-17 levels in serum (Rs=0.649; P=0.009) as well in sputum (Rs=0.583; P=0.022) in allergic asthma patients 24h after the bronchial challenge. CONCLUSIONS: The Th17 response is associated with the development of late-phase airway and systemic inflammation after the inhalation of D. pteronyssinus in patients with allergic asthma. PMID- 24161745 TI - Total glucosides of paeony inhibit the proliferation of fibroblast-like synoviocytes through the regulation of G proteins in rats with collagen-induced arthritis. AB - The aim of this study was to investigate the expression of G proteins in fibroblast-like synoviocytes (FLSs) from rats with collagen-induced arthritis (CIA) and to determine the effect of total glucosides of paeony (TGP). CIA rats were induced with chicken type II collagen (CCII) in Freund's complete adjuvant. The rats with experimental arthritis were randomly separated into five groups and then treated with TGP (25, 50, and 100mg/kg) from days 14 to 35 after immunization. The secondary inflammatory reactions were evaluated through the polyarthritis index and histopathological changes. The level of cyclic adenosine monophosphate (cAMP) was measured by radioimmunoassay. The FLS proliferation response was determined by the 3-(4,5-dimethylthiazol-2-yl)-2,5 diphenyltetrazolium bromide (MTT) assay. The toxin-catalyzed ADP-ribosylation of G proteins was performed through autoradiography. The results show that TGP (25, 50, and 100mg/kg) significantly decreased the arthritis scores of CIA rats and improved the histopathological changes. TGP inhibited the proliferation of FLSs and increased the level of cAMP. Moreover, the FLS proliferation and the level of Galphai expression were significantly increased, but the level of Galphas expression was decreased after stimulation with IL-1beta (10ng/ml) in vitro. TGP (12.5 and 62.5MUg/ml) significantly inhibited the FLS proliferation and regulated the balance between Galphai and Galphas. These results demonstrate that TGP may exert its anti-inflammatory effects through the suppression of FLS proliferation, which may be associated with its ability to regulate the balance of G proteins. Thus, TGP may have potential as a therapeutic agent for the treatment of rheumatoid arthritis. PMID- 24161747 TI - Endoplasmic reticulum stress influences bronchial asthma pathogenesis by modulating nuclear factor kappaB activation. AB - BACKGROUND: Despite many studies on endoplasmic reticulum (ER) stress in patients with various inflammatory diseases, there is scarce information on ER stress in patients with bronchial asthma. OBJECTIVE: In this study we aimed to elucidate the role of ER stress in the pathogenesis of bronchial asthma. METHODS: Using mice sensitized with ovalbumin (OVA) and LPS and challenged with OVA (OVA(LPS) OVA mice), as well as mice sensitized and challenged with OVA (OVA-OVA mice), we investigated whether ER stress is involved in the pathogenesis of bronchial asthma. Moreover, we also determined the levels of ER stress markers in blood and bronchoalveolar lavage fluid from asthmatic patients. RESULTS: The OVA(LPS)-OVA mice showed that the expression of ER stress markers and the protein levels of unfolded protein response-related markers in lung tissue were significantly increased after OVA challenge. Moreover, we found that ER stress markers in PBMCs and bronchoalveolar lavage fluid from human asthmatic patients were dramatically increased compared with those from healthy control subjects. In OVA(LPS)-OVA mice 4-phenylbutyric acid (4-PBA), a chemical chaperone, significantly reduced the increases in ER stress, nuclear translocation of nuclear factor kappaB, inflammatory cytokine levels, dendritic cell infiltration, Toll-like receptor 4 expression, airway inflammation, and bronchial hyperresponsiveness, whereas it further enhanced the increase in IL-10 levels. Additionally, the established asthmatic features of OVA-OVA mice were substantially attenuated by 4-PBA administered after completion of OVA challenge. CONCLUSION: These results indicate that ER stress might be implicated in the pathogenesis of bronchial asthma at least in part through modulation of nuclear factor kappaB activation. PMID- 24161748 TI - Childhood-to-adolescence evolution of IgE antibodies to pollens and plant foods in the BAMSE cohort. PMID- 24161749 TI - Immunodiagnosis of porcine cysticercosis: identification of candidate antigens through immunoproteomics. AB - Cysticercosis, caused by the larval stage of Taenia solium, is a zoonotic disease affecting pigs and humans that is endemic to developing countries in Latin America, Africa and South East Asia. The prevalence of infection in pigs, the intermediate host for T. solium, has been used as an indicator for monitoring disease transmission in endemic areas. However, accurate and specific diagnostic tools for porcine cysticercosis remain to be established. Using proteomic approaches and the T. solium genome sequence, seven antigens were identified as specific for porcine cysticercosis, namely, tropomyosin 2, alpha-1 tubulin, beta tubulin 2, annexin B1, small heat-shock protein, 14-3-3 protein, and cAMP dependent protein kinase. None of these proteins were cross-reactive when tested with sera from pigs infected with Ascaris spp., Cysticercus tenuicollis and hydatid cysts of Echinococcus spp. or with serum from a Taenia saginata-infected cow. Comparison with orthologues, indicated that the amino acid sequences of annexin B1 and cAMP-dependent protein kinase possessed highly specific regions, which might make them suitable candidates for development of a specific diagnostic assay for porcine cysticercosis. PMID- 24161751 TI - Post-feeding physiology in Rhodnius prolixus: the possible role of FGLamide related allatostatins. AB - Allatostatins (ASTs) are neuropeptides that were first identified as inhibitors of juvenile hormone biosynthesis by the corpora allata of some insect species. The FGLamide-related ASTs (FGLa/ASTs) belong to one of three families of insect ASTs. Previously, we showed that Rhodnius prolixus FGLa/ASTs (Rhopr-FGLa/ASTs) are present throughout the R. prolixus central nervous system and are associated with 5 dorsal unpaired median (DUM) neurons in the mesothoracic ganglionic mass. A similar set of neurons contain serotonin which is a diuretic hormone in R. prolixus. Rhopr-FGLa/ASTs inhibit both spontaneous contractions of the anterior midgut and leucokinin-1-induced hindgut contractions. Since these tissues are involved with post-feeding diuresis, these data suggest a possible role for FGLa/ASTs in events associated with feeding, and a possible interaction with serotonin. To investigate this possibility, we have examined the DUM neurons in more detail with regard to their peptide content, examined the potential release of Rhopr-FGLa/ASTs into the haemolymph following feeding, and further investigated the effects of Rhopr-FGLa/ASTs on feeding-related tissues. There are 10 DUM neurons in the abdominal neuromeres, 5 of which express serotonin-like immunoreactivity and the other 5 express FGLa/AST-like immunoreactivity. FGLa/AST like immunoreactivity is reduced in the 5 DUM neuron cell bodies and their neurohaemal sites on abdominal nerves at 3-5 h post feeding. Rhopr-FGLa/ASTs do not inhibit serotonin-stimulated anterior midgut absorption or Malpighian tubule secretion but do inhibit hindgut contractions induced by an endogenous kinin, suggesting that they may only indirectly affect post-feeding diuresis in R. prolixus. PMID- 24161750 TI - Age- and gender-associated changes in the concentrations of serum TGF-1beta, DHEA S and IGF-1 in healthy captive baboons (Papio hamadryas anubis). AB - Age-related changes in the concentration of factors like TGF-1beta, DHEA-S and IGF-1 may increase the risk of disease and illnesses in advanced life. A better understanding of these changes would aid in the development of more appropriate treatments and/or preventative care for many conditions associated with age. Due to their similar immune system and vulnerability to pathogens, baboons are an ideal model for humans. However, little research has been done examining the general effects of age in baboons. Therefore, we wanted to further examine the effects of aging in baboons by determining the age-dependent changes in serum TGF 1beta, DHEA-S and IGF-1 concentrations. Blood samples were collected during routine health checks in 113-118 captive baboons. In addition, longitudinal samples from 23 to 27 adult individuals were collected an average of 10.7years apart. Both age and gender influenced the concentrations of serum TGF-1beta and IGF-1. When both genders were analyzed together, TGF-1beta increased 16.1% as adults, compared to younger and older animals, but male and female baboons showed a slightly different temporal pattern of change. IGF-1 decreased with increasing age and males had a 30% greater concentration of IGF-1 than did females. While there was no effect of gender among our population, serum DHEA-S was negatively correlated with age, decreasing by 51.6% in the oldest animals. There were no effects of age or gender on serum IGFBP-3. In longitudinal samples collected from the same individuals, the concentrations of TGF-1beta, DHEA-S and IGF-1 were reduced with age. The results presented herein provide additional knowledge of the aging process in baboons and further validate the use of this species as an appropriate model for aging in humans. PMID- 24161752 TI - Transcription-replication collision increases recombination efficiency between plasmids. AB - It has been proposed that the stalling of the replication forks can induce homologous recombination in several organisms, and that arrested replication forks may offer nuclease targets, thereby providing a substrate for proteins involved in double-strand repair. In this article, we constructed a plasmid with the potential for transcription-replication collision (TRC), in which DNA replication and RNA transcription occur on the same DNA template simultaneously. Theoretically, transcription will impede DNA replication and increase homologous recombination. To validate this hypothesis, another plasmid was constructed that contained a homologous sequence with the exception of some mutated sites. Co transfection of these two plasmids into 293T cells resulted in increased recombination frequency. The ratio of these two plasmids also affected the recombination frequency. Moreover, we found high expression levels of RAD51, which indicated that the increase in the recombination rate was probably via the homologous recombination pathway. These results indicate that mutant genes in plasmids can be repaired by TRC-induced recombination. PMID- 24161753 TI - Three isozymes of peptidylarginine deiminase in the chicken: molecular cloning, characterization, and tissue distribution. AB - Peptidylarginine deiminase (PAD; EC 3.5.3.15) is a post-translational modification enzyme that catalyzes the conversion of protein-bound arginine to citrulline (deimination) in a calcium ion dependent manner. Although PADI genes are widely conserved among vertebrates, their function in the chicken is poorly understood. Here, we cloned and sequenced three chicken PADI cDNAs and analyzed the expression of their proteins in various tissues. Immunoblotting analysis showed that chicken PAD1 and PAD3 were present in cells of several central neuron system tissues including the retina; the chicken PAD2 protein was not detected in any tissue. We expressed recombinant chicken PADs in insect cells and characterized their enzymatic properties. The chicken PAD1 and PAD3 recombinant proteins required calcium ions as an essential cofactor for their catalytic activity. The two recombinant proteins showed similar substrate specificities toward synthetic arginine derivatives. By contrast to them, chicken PAD2 did not show any activity. We found that one of the conserved active centers in mammalian PADs had been altered in chicken PAD2; we prepared a reverse mutant but we did not detect an activity. We conclude that chicken PAD1 and PAD3 might play specific roles in the nervous system, but that chicken PAD2 might not be functional under normal physiological conditions. PMID- 24161754 TI - Overexpression of mitochondrial uncoupling protein conferred resistance to heat stress and Botrytis cinerea infection in tomato. AB - The mitochondrial uncoupling protein genes improve plant stress tolerance by minimizing oxidative damage. However, the underlying mechanism of redox homeostasis and antioxidant signaling associated with reactive oxygen species (ROS) accumulation remained poorly understood. We introduced LeUCP gene into tomato line Ailsa Craig via Agrobacterium-mediated method. Transgenic lines were confirmed for integration into the tomato genome using PCR and Southern blot hybridization. One to three copies of the transgene were integrated into the tomato nuclear genome. Transcription of LeUCP in various transgenic lines was determined using real-time PCR. Transgenic tomato overexpressing LeUCP showed higher growth rate, chlorophyll content, maximum photochemical efficiency of PSII (Fv/Fm), photochemical quenching coefficient (qP) and electron transport rate (ETR), increased contents of AsA and proline, higher AsA/DHA ratio and GalLDH activity, reduced ROS accumulation, and enhanced heat stress tolerance compared with the control plants. The transgenic tomato plants also exhibited significant increases in tolerance against the necrotrophic fungus Botrytis cinerea. Taken together, our results suggest that LeUCP may play a pivotal role in controlling a broad range of abiotic and biotic stresses in plants by increasing redox level and antioxidant capacity, elevating electron transport rate, lowering H2O2 and lipid peroxidation accumulation. PMID- 24161755 TI - Tc-cAPX, a cytosolic ascorbate peroxidase of Theobroma cacao L. engaged in the interaction with Moniliophthora perniciosa, the causing agent of witches' broom disease. AB - The level of hydrogen peroxide (H2O2) in plants signalizes the induction of several genes, including that of ascorbate peroxidase (APX-EC 1.11.1.11). APX isoenzymes play a central role in the elimination of intracellular H2O2 and contribute to plant responses to diverse stresses. During the infection process in Theobroma cacao by Moniliophthora perniciosa oxidative stress is generated and the APX action recruited from the plant. The present work aimed to characterize the T. cacao APX involved in the molecular interaction of T. cacao-M. perniciosa. The peroxidase activity was analyzed in protein extracts from cocoa plants infected by M. perniciosa and showed the induction of peroxidases like APX in resistant cocoa plants. The cytosolic protein of T. cacao (GenBank: ABR68691.2) was phylogenetically analyzed in relation to other peroxidases from the cocoa genome and eight genes encoding APX proteins with conserved domains were also analyzed. The cDNA from cytosolic APX was cloned in pET28a and the recombinant protein expressed and purified (rTc-cAPX). The secondary structure of the protein was analyzed by Circular Dichroism (CD) displaying high proportion of alpha helices when folded. The enzymatic assay shows stable activity using ascorbate and guaiacol as an electron donor for H2O2 reduction. The pH 7.5 is the optimum for enzyme activity. Chromatographic analysis suggests that rTc-cAPX is a homodimer in solution. Results indicate that the rTc-cAPX is correctly folded, stable and biochemically active. The purified rTc-cAPX presented biotechnological potential and is adequate for future structural and functional studies. PMID- 24161756 TI - Overexpression, purification and enzymatic characterization of a recombinant plastidial glucose-6-phosphate dehydrogenase from barley (Hordeum vulgare cv. Nure) roots. AB - In plant cells, the plastidial glucose 6-phosphate dehydrogenase (P2-G6PDH, EC 1.1.1.49) represents one of the most important sources of NADPH. However, previous studies revealed that both native and recombinant purified P2-G6PDHs show a great instability and a rapid loss of catalytic activity. Therefore it has been difficult to describe accurately the catalytic and physico-chemical properties of these isoforms. The plastidial G6PDH encoding sequence from barley roots (Hordeum vulgare cv. Nure), devoid of a long plastidial transit peptide, was expressed as recombinant protein in Escherichia coli, either untagged or with an N-terminal his-tag. After purification from both the soluble fraction and inclusion bodies, we have explored its kinetic parameters, as well as its sensitivity to reduction. The obtained results are consistent with values determined for other P2-G6PDHs previously purified from barley roots and from other land plants. Overall, these data shed light on the catalytic mechanism of plant P2-G6PDH, summarized in a proposed model in which the sequential mechanism is very similar to the mammalian cytosolic G6PDH. This study provides a rational basis to consider the recombinant barley root P2-G6PDH as a good model for further kinetic and structural studies. PMID- 24161757 TI - QsMYB1 expression is modulated in response to heat and drought stresses and during plant recovery in Quercus suber. AB - Cork oak is an economically important forest species showing a great tolerance to high temperatures and shortage of water. However, the mechanisms underlying this plasticity are still poorly understood. Among the stress regulators, transcription factors (TFs) are especially important since they can control a wide range of stress-inducible genes, which make them powerful targets for genetic engineering of stress tolerance. Here we evaluated the influence of increasing temperatures (up to 55 degrees C) or drought (18% field capacity, FC) on the expression profile of an R2R3-MYB transcription factor of cork oak, the QsMYB1. QsMYB1 was previously identified as being preferentially expressed in cork tissues and as having an associated alternative splicing mechanism, which results in two different transcripts (QsMYB1.1 and QsMYB1.2). Expression analysis by reverse transcription quantitative PCR (RT-qPCR) revealed that increasing temperatures led to a gradual down-regulation of QsMYB1 transcripts with more effect on QsMYB1.1 abundance. On the other hand, under drought condition, expression of QsMYB1 variants, mainly the QsMYB1.2, was transiently up-regulated shortly after the stress imposition. Recovery from each stress has also resulted in a differential response by both QsMYB1 transcripts. Several physiological and biochemical parameters (plant water status, chlorophyll fluorescence, lipid peroxidation and proline content) were determined in order to monitor the plant performance under stress and recovery. In conclusion, this report provides the first evidence that QsMYB1 TF may have a putative function in the regulatory network of cork oak response to heat and drought stresses and during plant recovery. PMID- 24161758 TI - Metabolomic analysis revealed the differential responses in two pedigrees of clam Ruditapes philippinarum towards Vibrio harveyi challenge. AB - Manila clam Ruditapes philippinarum is an important marine aquaculture shellfish. This species has several pedigrees including White, Zebra, Liangdao Red and Marine Red distributing in the coastal areas in North China. In this work, we studied the metabolic differences induced by Vibrio harveyi in hepatopancreas from White and Zebra clams using NMR-based metabolomics. Metabolic responses (e.g., amino acids, glucose, glycogen, ATP and succinate) and altered mRNA expression levels of related genes (ATP synthase, heat shock protein 90, defensin and lysozyme) suggested that V. harveyi induced clear disruption in energy metabolism and immune stresses in both White and Zebra clam hepatopancreas. However, V. harveyi caused obvious osmotic stress in Zebra clam hepatopancreas, which was not observed in V. harveyi-challenged White clams samples. In addition, V. harveyi challenge induced more severe disruption in energy metabolism and immune stress in White clams than in Zebra clams. Overall, our results indicated that the biological differences between different pedigrees of R. philippinarum should be considered in immunity studies. PMID- 24161759 TI - Activator protein-1 (AP-1) and response to pathogen infection in the Hong Kong oyster (Crassostrea hongkongensis). AB - Growing evidence suggests that the transcription factor activator protein-1 (AP 1), a downstream target of mitogen-activated protein kinase (MAPK) signaling, plays a major role in stimulating the synthesis of immune effector molecules during innate immune responses. We have characterized ChAP-1, an AP-1-like protein in Crassostrea hongkongensis that is a member of the AP-1 family of proteins. ChAP-1 is composed of 290 amino acid residues with a Jun and bZIP domain at the N- and C-termini, respectively, a structure similar to that of known Ap-1 proteins. ChAP-1 mRNA is expressed in several tissues analyzed, with highest expression in the mantle. Expression of ChAP-1 increases in response to Vibrio alginolyticus, Salmo haemolyticus or Salmo cerevisiae infection and, despite the location of GFP-tagged full-length ChAP-1 protein in the cytoplasm, ChAP-1 activates the transcription of an L8G5-luc reporter gene, and its over expression can also activate the AP-1-Luc reporter gene in HEK293T cells. PMID- 24161760 TI - Transcriptional immune response of cage-cultured Pacific bluefin tuna during infection by two Cardicola blood fluke species. AB - Infections by two blood fluke species, Cardicola orientalis and Cardicola opisthorchis, currently present the greatest disease concern for the sea-cage culture of Pacific bluefin tuna (PBT) - a species of high global economic importance and ecological concern. In this study, we aimed to rapidly, quantitatively, and differentially identify infections by these two parasite species in cultured PBT as well as identify potential host immune responses. Using real-time qPCR, we were successful in quantitatively detecting parasite specific DNA from within host blood, gill, and heart tissues; positively identifying parasitic infections 44 days earlier than microscopy methods previously employed. Both gill and heart became heavily infected by both parasite species in PBT within two months of sea-cage culture, which was only mitigated by the administration of anthelmintic praziquantel. Nevertheless, fish were observed to mount an organ specific transcriptive immune response during infection that mirrored the relative quantity of pathogenic load. In heart, significant (3-6 fold) increases in IgM, MHC2, TCRbeta, and IL-8 transcription was observed in infected fish relative to uninfected controls; whereas in the gills only IgM transcription was observed to be induced (11 fold) by infection. Interestingly, the relative quantity of IgM transcription was highly correlated to the relative abundance of C. orientalis but not C. opisthorchis DNA in the gill samples, even though this organ showed high prevalence of DNA from both parasite species. Taken together, these findings indicate that although ineffective at combating infection during primary exposure, a cellular immune response is mounted in PBT as a potential rejoinder to future Cardicola exposure, particularly against C. orientalis. Although future investigation into antibody effectiveness will be needed, this work provides valuable preliminary insight into host responsiveness to Cardicola infection as well as additional support for the need of anthelmintic treatment following primary parasite exposure during PBT culture. PMID- 24161761 TI - A novel ortholog of serum response factor (SRF) with immune defense function identified in Crassostrea hongkongensis. AB - Serum response factor (SRF) function is essential for transcriptional regulation of numerous growth-factor-inducible genes and triggers proliferation, differentiation and apoptosis of the cells. In this report, the first mollusk serum response factor like homolog gene (designated ChSRF) was identified and characterized from the Hong Kong oyster, Crassostrea hongkongensis. The full length cDNA of ChSRF was 1716 bp in length and encodes a putative protein of 434 amino acids respectively, and shares the MADS domain at the N-terminal. ChSRF is ubiquitously expressed in various tissues, with the highest expression level observed in muscle. Temporal expression of ChSRF following microbe infection shows that the expression of ChSRF in hemocytes increases from 3 to 24 h post challenge. As a target gene of SRF, beta-actin demonstrates a similar gene expression mode in constitutive tissue and pathogen infection. Furthermore, some protein profiles of ChSRF was revealed, fluorescence microscopy results show that ChSRF located in the nuclei of HeLa cells and over-expression of ChSRF activated the transcriptional activities of MAPK signal pathway in HEK293T cells. These results indicate that ChSRF maybe play an important role in signal transduction in the immunity and development response of oysters. Furthermore, we found that ChSRF could regulate the expression of beta-actin gene, which indicate that ChSRF is a muscle differentiation regulator in the oyster and it will help us to improve aquaculture production. PMID- 24161762 TI - The effect of Pediococcus acidilactici bacteria used as probiotic supplement on the growth and non-specific immune responses of green terror, Aequidens rivulatus. AB - A 56-day feeding trial was conducted on a species of ornamental fish called green terror (Aequidens rivulatus) (0.388 +/- 0.0021 g) to assess the effect of probiotic bacteria, Pediococcus acidilactici on the growth indices and innate immune response. The fish were randomly allocated into 9 oval tanks (120 l) at a density of 60 fish per tank. The experimental diets were comprised of the control (C), C complemented with fish oil (O) and the probiotic and fish oil (PA) and fed ad lib twice a day. The growth indices (specific growth rate (SGR), feed conversion ratio (FCR) and immunological indices of fish fed the diets including lysozyme activity, total immunoglobulin and alternative complement activity were measured. The Fish fed with the diet containing P. acidilactici (PA) displayed significantly (P < 0.05) higher final weight (3.25 +/- 0.065 g), weight gain (830.94 +/- 9.46%), SGR (3.53 +/- 0.02%/day) and lower FCR (1.45 +/- 0.011) compared to those of other experimental diets. Total immunoglobulin (10.05 +/- 0.12 MUg/ml), lysozyme activity (4.08 +/- 0.85 MUg/ml) and alternative complement activity (2.65 +/- 0.12 U/ml) in the serum of PA fed fish showed significant compared to other treatments (P < 0.05). The results showed positive effects of P. acidilactici as a potent probiotic on growth indices and non-specific immune system of green terror. PMID- 24161763 TI - Interleukin-8 is related to poor chemotherapeutic response and tumourigenicity in hepatocellular carcinoma. AB - AIM: Interleukin-8 (IL-8) has been suggested as a prognostic biomarker for human hepatocellular carcinoma (HCC), but its roles in HCC progression and drug resistance have not been studied. This study investigates the role and underlying mechanism of IL-8 in the chemoresistance and progressive growth of HCC. METHODS: The change of chemosensitivity and proportion of side population in hepatoma cells was examined by cell growth and flow cytometric analyses after anti-cancer treatments or knockdown of IL-8. Expression of IL-8 and ATP-binding cassette (ABC) transporters in hepatoma cells, xenograft and clinical HCC tissues was determined by Western blot and immunohistochemical analyses. Tumourigenicity of hepatoma cells was evaluated in vivo after silencing IL-8 gene. RESULTS: Treatment of hepatoma cells with anti-cancer drugs increased the production of IL 8 and its receptor, as well as the proportion of side population (SP). Exogenous IL-8 increased the SP fraction and expression of multidrug resistance-1, decreasing the drug sensitivity. Silencing of IL-8 gene decreased the ratio of SP cells and drug resistance properties. Both IL-8 and ABC transporters were highly expressed in xenograft and clinical HCC tissues, and knockdown of IL-8 significantly reduced tumour size in vivo. CONCLUSION: Anti-cancer drug-induced IL-8 secretion increased the expression of ABC transporters and SP cells, promoting the growth of HCC in vitro. Thus IL-8 may be a potential therapeutic target in the treatment of HCC. PMID- 24161764 TI - [Hereditary optic neuropathies: from clinical signs to diagnosis]. AB - Inherited optic atrophy must be considered when working up any optic nerve involvement and any systemic disease with signs of optic atrophy, even with a negative family history. There are two classical forms: dominant optic atrophy, characterized by insidious, bilateral, slowly progressive visual loss and temporal disc pallor, and Leber's optic atrophy, characterized by acute loss of central vision followed by the same event in the fellow eye within a few weeks to months, with disc hyperemia in the acute phase. Family history is critical for diagnosis. In the absence of family history, the clinician must rule out an identifiable acquired cause, i.e. toxic, inflammatory, perinatal injury, traumatic or tumoral, with orbital and brain imaging (MRI). Recessive optic atrophies are more rare and more severe and occur as part of multisystemic disorders, particularly Wolfram syndrome (diabetes mellitus, diabetes insipidus, and hearing loss). Effective treatments are limited; alcohol and smoking should be avoided. A cyclosporine trial (taken immediately upon visual loss in the first eye) is in progress in Leber's optic atrophy to prevent involvement of the fellow eye. PMID- 24161765 TI - NF-kappaB, ERK, p38 MAPK and JNK contribute to the initiation and/or maintenance of mechanical allodynia induced by tumor necrosis factor-alpha in the red nucleus. AB - Previous studies have demonstrated that tumor necrosis factor-alpha (TNF-alpha) in the red nucleus (RN) plays facilitated roles in the development of abnormal pain. Here, the roles of nuclear factor-kappa B (NF-kappaB), extracellular signal regulated kinase (ERK), p38 mitogen-activated protein kinase (MAPK) and c-Jun N terminal kinase (JNK) in TNF-alpha-evoked mechanical allodynia were investigated. Repeated microinjection of recombinant rat TNF-alpha (20 ng daily for 3 days) into the unilateral RN of normal rats induced a significant mechanical allodynia in the contralateral but not ipsilateral hind paw at the fifth day and disappeared 24h later. Re-injection of a single bolus of 20 ng TNF-alpha into the same RN reproduced this mechanical allodynia within 30 min, which was used as a pain model for further experiments. Immunohistochemistry demonstrated that NF kappaB, phospho-ERK (p-ERK) and p-p38 MAPK in the RN were significantly up regulated at 1h after TNF-alpha microinjection, the up-regulations of NF-kappaB and p-ERK but not p-p38 MAPK remained at high levels till 4h later. A significant up-regulation of p-JNK occurred at 4h (but not 1h) after TNF-alpha microinjection, which was later than those of NF-kappaB, p-ERK and p-p38 MAPK. Pre-treatment with NF-kappaB inhibitor PDTC, ERK inhibitor PD98059 or p38 MAPK inhibitor SB203580 at 30 min before TNF-alpha microinjected into the RN completely prevented TNF-alpha-evoked mechanical allodynia. Pre-treatment with JNK inhibitor SP600125 did not prevent but reversed TNF-alpha-evoked mechanical allodynia during the subsequent detection time. Post-treatment with PDTC, PD98059 or SP600125 (but not SB203580) at 4h after TNF-alpha microinjected into the RN significantly reversed TNF-alpha-evoked mechanical allodynia. These results further prove that TNF-alpha in the RN plays a crucial role in the development of abnormal pain, and the algesic effect of TNF-alpha is initiated through activating NF-kappaB, ERK and p38 MAPK. The later maintenance of TNF-alpha-evoked mechanical allodynia mainly relies on the activation of NF-kappaB, ERK and JNK, but not p38 MAPK. PMID- 24161766 TI - Effect of HSP10 on apoptosis induced by testosterone in cultured mouse ovarian granulosa cells. AB - OBJECTIVE: To investigate the effect of heat shock protein 10 (HSP10) on apoptosis induced by testosterone in granulosa cells (GCs) of mouse ovaries in order to define the possible roles of HSP10 in ovarian pathological development of polycystic ovarian syndrome (PCOS) and hyperandrogenic conditions. STUDY DESIGN: Cultured mouse ovarian GCs were treated with testosterone (10(-5) mol/l). Apoptosis was assessed using flow cytometry, and proliferation was assessed using the MTT assay. HSP10 expression in the treated GCs was detected by real-time polymerase chain reaction (PCR). HSP10 gene was downregulated in the cultured GCs by AdCMV-H1-SiRNA/HSP10 or overexpressed by AdCMV-HSP10. PD98059 [phosphorylated ERK (p-ERK) inhibitor] was used to treat GCs to induce a high apoptosis index. Critical apoptotic factors and proliferation factors, including P-ERK, Bcl-2, Bax, caspase 9, caspase 3 and Ki67, were monitored by real-time reverse transcriptase PCR (RT-PCR) and Western blot. RESULTS: Compared with the control group, the apoptosis index was higher (p<0.05) and HSP10 expression was lower (p<0.05) in the testosterone-treated groups. In the AdCMV-H1-SiRNA/HSP10-treated group, cell viability was decreased (p<0.05) and the cell cycle was arrested at G2. Expression of p-ERK, Bcl-2 and Ki67, and the Bcl-2:Bax ratio were lower, while expression of apoptotic factors, including Bax, caspase 9 and caspase 3, was higher (p<0.05). Compared with the control group, Bcl-2 expression in the GCs that overexpressed HSP10 was increased (p<0.05), while the reduction of p-ERK and Bcl-2 and the elevation of caspase 9 and caspase 3 induced by PD98059 were significantly suppressed (p<0.05). CONCLUSIONS: Hyperandrogenic conditions induced apoptosis of mouse GCs. Testosterone may have reduced HSP10 expression in GCs, leading to reduced Bcl-2 expression and increased Bax expression. PMID- 24161767 TI - Towards global reporting of every paediatric cardiac arrest. PMID- 24161768 TI - 3:1 compression to ventilation ratio versus continuous chest compression with asynchronous ventilation in a porcine model of neonatal resuscitation. AB - OBJECTIVE: In contrast to the resuscitation guidelines of children and adults, guidelines on neonatal resuscitation recommend synchronized 90 chest compressions with 30 manual inflations (3:1) per minute in newborn infants. The study aimed to determine if chest compression with asynchronous ventilation improves the recovery of bradycardic asphyxiated newborn piglets compared to 3:1 Compression:Ventilation cardiopulmonary resuscitation (CPR). INTERVENTION AND MEASUREMENTS: Term newborn piglets (n=8/group) were anesthetized, intubated, instrumented and exposed to 45-min normocapnic hypoxia followed by asphyxia. Protocolized resuscitation was initiated when heart rate decreased to 25% of baseline. Piglets were randomized to receive resuscitation with either 3:1 compressions to ventilations (3:1C:V CPR group) or chest compressions with asynchronous ventilations (CCaV) or sham. Continuous respiratory parameters (Respironics NM3((r))), cardiac output, mean systemic and pulmonary artery pressures, and regional blood flows were measured. MAIN RESULTS: Piglets in 3:1C:V CPR and CCaV CPR groups had similar time to return of spontaneous circulation, survival rates, hemodynamic and respiratory parameters during CPR. The systemic and regional hemodynamic recovery in the subsequent 4h was similar in both groups and significantly lower compared to sham-operated piglets. CONCLUSION: Newborn piglets resuscitated by CCaV had similar return of spontaneous circulation, survival, and hemodynamic recovery compared to those piglets resuscitated by 3:1 Compression:Ventilation ratio. PMID- 24161769 TI - Communication of the death of a patient in hospices and nursing homes: a qualitative study. AB - PURPOSE OF THE RESEARCH: Announcing the death of a patient to another in hospices and nursing homes (NH) requires special skills, especially when the recipient is another resident. The aim of this study is to describe how hospice and NH staff deal with the communication regarding a patient's death, if this communication is perceived as a problem, and strategies implemented. METHODS AND SAMPLE: The 55 health care workers (HCWs, 26 nurses and 29 auxiliary nurses) of two NHs and two hospices in Turin (Italy) were interviewed with a semi-structured interview exploring the residents' perception of need to receiving information on another patient's death, the experiences of having given this information in the last 6 months, and the strategies implemented. The interviews were analyzed using Colaizzi's method and researchers looked for the main themes and related subthemes. KEY RESULTS: Six themes were identified and grouped into 2 main themes: a. the choice to tell the truth or not, which may be influenced by: the patients' request for confirmation of the fate of the other resident, by patients' fear of death ("I will be next"), the relationships among the guests, and personal and group experiences; b. the need to share own feelings and the burden of deciding whether or not to inform the other residents and how to go about this. CONCLUSIONS: If a structured discussion of experiences and reflection on cases is not implemented, HCWs may limit communication to bare information, lies, and adopt behaviors of avoidance and concealment. PMID- 24161770 TI - CsTrx80, a truncated form of thioredoxin, possesses chemokine-like property and enhances the immune defense of Cynoglossus semilaevis against bacterial infection. AB - Thioredoxin (Trx) is a redox protein that plays an important role in anti oxidative stress and redox signaling. In a recent report, we observed that the Trx of tongue sole (Cynoglossus semilaevis), CsTrx1, is a reductase and an antioxidant with immunostimulatory property. In the current work, we studied the biological effect of a truncated CsTrx1, CsTrx80, which is composed of the N terminal 80 residues of CsTrx1. We found that recombinant CsTrx80 (rCsTrx80) purified from Escherichia coli exhibited no insulin disulfide reductase activity; however, unlike rCsTrx1, which showed no apparent chemotactic activity, rCsTrx80 was able to bind to the head kidney monocytes of tongue sole and caused cellular migration in a dose-dependent manner. Mutation of the two cysteine residues in the highly conserved CXXC motif had no effect on the chemotactic activity of rCsTrx80. Like rCsTrx1, rCsTrx80 induced the expression of immune relevant genes in the target cells, but the induction patterns differed from that induced by rCsTrx1. In vivo study showed that when tongue sole were administered with rCsTrx80 before being infected with a bacterial pathogen, bacterial dissemination and colonization in fish tissues were significantly reduced compared to control fish. Taken together, these results indicate for the first time that a Trx80 derived from fish Trx possesses chemotactic and immunoregulatory properties which promote host resistance against bacterial infection. PMID- 24161772 TI - Identification and characterization of Rab7 from orange-spotted grouper, Epinephelus coioides. AB - Rab7 is a small GTPase that regulates vesicular traffic from early to late endosomal stages of the endocytic pathway. During the virus-host co-evolution, host Rab7 was also exploited by virus to complete their life cycle. To date, however, the roles of fish Rab7 in virus infection remained largely unknown. Here, we cloned and characterized a Rab7 gene from grouper, Epinephelus coioides (Ec-Rab7). The full-length Ec-Rab7 cDNA was composed of 1182 bp and encoded a polypeptide of 207 amino acids which shared 99% identity with that from Anoplopoma fimbria or Oreochromis niloticus. Ec-Rab7 contained five conserved domains of Rab GTPase family including GTP-binding or GTPase regions as well as an effector site. RT-PCR analysis revealed that Ec-Rab7 ubiquitously expressed in all detected tissues and its transcript in spleen was up-regulated after challenge with Singapore grouper iridovirus (SGIV). Subcellular localization analysis revealed that Ec-Rab7 was distributed in the cytoplasm as spots and mostly colocalized with lysosomes. Notably, the ectopic expressed Ec-Rab7 partly aggregated into the viral factories in cells infected by SGIV. Furthermore, overexpression of Ec-Rab7 accelerated the occurrence of cytopathic effect (CPE) induced by SGIV infection and promoted viral gene transcription. In addition, far western blotting assay revealed that Ec-Rab7 might interact with viral proteins, including SGIV VP69 and VP101. Taken together, our data suggested that Ec-Rab7 might be potentially involved in SGIV replication. PMID- 24161771 TI - Transcriptional regulation of teleost Aicda genes. Part 1 - suppressors of promiscuous promoters. AB - In order to better understand antibody affinity maturation in fishes we sought to identify gene regulatory elements that could drive expression of activated B-cell specific fluorescent reporter transgenes in zebrafish. Specifically the promoter and several non-coding regions of the channel catfish (Ictalurus punctatus) and zebrafish (Danio rerio) were tested for transcriptional activity using a dual luciferase reporter system in transfected fish leukocytes and two mammalian cell lines that constitutively express Aicda (activation-induced cytidine deaminase). The promoters of both fish Aicda genes were as transcriptionally active as an SV40 promoter control in all cell lines tested, regardless of the cells ability to express Aicda. Coupling of a putative intron 1 enhancer or a region 10 kb upstream of the zebrafish promoter effectively silenced transcription from the fish Aicda promoter. Paradoxically these suppressor elements enhanced transcription when they were coupled to the mouse Aicda intron 1 enhancer. The results are considered in context of similar observations for Aicda transcriptional regulation in mice and in light of recent evidence that Aicda is utilized for epigenetic reprogramming of several non-lymphoid cell types. PMID- 24161773 TI - Administration of Bacillus subtilis strains in the rearing water enhances the water quality, growth performance, immune response, and resistance against Vibrio harveyi infection in juvenile white shrimp, Litopenaeus vannamei. AB - In this study, vegetative cell suspensions of two Bacillus subtilis strains, L10 and G1 in equal proportions, was administered at two different doses 10(5) (BM5) and 10(8) (BM8) CFU ml(-1) in the rearing water of shrimp (Litopenaeus vannamei) for eight weeks. Both probiotic groups showed a significant reduction of ammonia, nitrite and nitrate ions under in vitro and in vivo conditions. In comparison to untreated control group, final weight, weight gain, specific growth rate (SGR), food conversion ratio (FCR) and digestive enzymatic activity were significantly greater in the BM5 and BM8 groups. Significant differences for survival were recorded in the BM8 group as compared to the control. Eight weeks after the start of experiment, shrimp were challenged with Vibrio harveyi. Statistical analysis revealed significant differences in shrimp survival between probiotic and control groups. Cumulative mortality of the control group was 80%, whereas cumulative mortality of the shrimp that had been given probiotics was 36.7% with MB8 and 50% with MB5. Subsequently, real-time RT-PCR was employed to determine the mRNA levels of prophenoloxidase (proPO), peroxinectin (PE), lipopolysaccharide- and beta-1,3-glucan- binding protein (LGBP) and serine protein (SP). The expression of all immune-related genes studied was only significantly up-regulated in the BM5 group compared to the BM8 and control groups. These results suggest that administration of B. subtilis strains in the rearing water confers beneficial effects for shrimp aquaculture, considering water quality, growth performance, digestive enzymatic activity, immune response and disease resistance. PMID- 24161774 TI - Immunostimulation by poly-beta hydroxybutyrate-hydroxyvalerate (PHB-HV) from Bacillus thuringiensis in Oreochromis mossambicus. AB - The present study was designed to test the immunostimulatory efficacy of poly beta hydroxybutyrate-hydroxyvalerate (PHB-HV) extracted from Bacillus thuringiensis B.t.A102 on the immune system of Oreochromis mossambicus. Fish were fed with 0%, 1%, 3% or 5% PHB-HV supplemented feed and were bled at regular intervals of 5 days. The specific immune response was measured in terms of antibody response to sheep red blood cells, the nonspecific immune mechanisms were analysed in terms of serum lysozyme activity, total peroxidases activity and antiprotease activity. The overall functional immunity was tested by experimental challenge with live virulent Aeromonas hydrophila. The results revealed that all the doses of PHB-HV supplementation in feed were effective in stimulating both specific and nonspecific immune mechanisms. The bacterial challenge experiment showed that highest dose of 5% PHB-HV supplementation was more effective than 1% and 3% doses. The study concludes that PHB-HV can be used as a potential immunostimulant in finfish aquaculture. PMID- 24161775 TI - Effects of three strains of intestinal autochthonous bacteria and their extracellular products on the immune response and disease resistance of common carp, Cyprinus carpio. AB - The study isolated three strains of intestinal autochthonous bacteria Aeromonas veronii BA-1, Vibrio lentus BA-2, and Flavobacterium sasangense BA-3 from the intestinal tract of the common carp (Cyprinus carpio). To reveal the effects of these three strains of bacteria on the innate immunity of carp, the lysozyme, complement C3, total serum protein, albumin and globulin levels, respiratory burst activity, phagocytic activity by blood leucocytes and the expression of IL 1b, lysozyme-C, and TNF-alpha were examined after feeding with seven different diets for up to 28 days. Also the survival of carp against Aeromonas hydrophila was challenged for 14 days. The carp were fed seven different diets: one control, three diets supplemented with 1 * 10(8) cell g(-1) of carp intestinal bacteria BA 1 (Group D-I), BA-2 (Group D-II) and BA-3 (Group D-III), and three diets supplemented with extracellular products FA-1 (Group E-I), FA-2 (Group E-II) and FA-3 (Group E-III) which were corresponding to the strains BA-1, BA-2, and BA-3, respectively, up to 28 days. For groups D-I, D-III, E-I and E-III, the innate immune parameters of carp were significantly increased, the expression of three immune-related genes in blood was significantly up-regulated examined during 7, 14, and 21 days of feeding, and the survival rate was improved. The study indicates that the two isolated intestinal autochthonous bacteria A. veronii BA-1 and F. sasangense BA-3 could positively influence immune response and enhance disease resistance of carp against A. hydrophila infection. PMID- 24161777 TI - Hemiuroid trematode sporocysts are undetected by hemocytes of their intermediate host, the ark cockle Anadara trapezia: potential role of surface carbohydrates in successful parasitism. AB - In order to establish a successful relationship with their hosts, parasites must subvert or evade immune defences. Cockle Anadara trapezia and Sydney Rock oyster (SRO) Saccostrea glomerata live in the same location but only ark cockles are infected by sporocysts of hemiuroid trematode. This provides an opportunity to explore differing interactions between the parasite and the immune system of susceptible and refractive hosts. Rapid migration and encapsulation of sporocysts was observed by SRO hemocytes but not by cockle hemocytes. This migration/encapsulation was inhibited by N-acetylglucosamine or N acetylgalactosamine but not by the other sugars, implicating specific surface carbohydrates in immune detection. Effector responses of hemocytes were investigated in vitro in terms of production of reactive oxygen production (ROS). Hemocytes of both species strongly reacted to Zymosan, but only SRO hemocytes responded to live sporocysts. Neither species' hemocytes produced ROS in the presence of dead/fixed sporocysts, and there was no suppression of Zymosan induced respiratory burst by sporocysts. This suggests that immune escape is mediated by avoiding encapsulation, perhaps through molecular mimicry. Membrane shaving with proteases indicated that sporocyst surface proteins are not a key factors in hemocytic detection. Surface carbohydrates of SRO and cockle hemocytes and of sporocysts were profiled with a panel of biotinylated lectins. This revealed substantial differences between cockle and SRO hemocytes, but greater similarity between cockle hemocytes and sporocysts. Results suggest that surface carbohydrates play an integral role in hemocyte immunorecognition and that surface carbohydrate molecular mimicry is a potential strategy for immune evasion in cockles by hemiuroid trematode sporocysts. PMID- 24161776 TI - Dietary synbiotic application modulates Atlantic salmon (Salmo salar) intestinal microbial communities and intestinal immunity. AB - A feeding trial was conducted to determine the effect of dietary administration of Pediococcus acidilactici MA18/5M and short chain fructooligosaccharides (scFOS) on Atlantic salmon (Salmo salar L.) intestinal health. Salmon (initial average weight 250 g) were allocated into triplicate sea pens and were fed either a control diet (commercial diet: 45% protein, 20% lipid) or a synbiotic treatment diet (control diet + P. acidilactici at 3.5 g kg(-1) and 7 g kg(-1) scFOS) for 63 days. At the end of this period, fish were sampled for intestinal microbiology, intestinal histology and the expression of selected immune-related genes (IL1beta, TNFalpha, IL8, TLR3 and MX-1) in the intestine. Compared to the control fish, the total bacterial levels were significantly lower in the anterior mucosa, posterior mucosa and posterior digesta of the synbiotic fed fish. qPCR revealed good recovery (log 6 bacteria g(-1)) of the probiotic in the intestinal digesta of the synbiotic fed fish and PCR-DGGE revealed that the number of OTUs, as well as the microbial community diversity and richness were significantly higher in the anterior digesta of the synbiotic fed fish than the control. Compared to the control fed fish, the mucosal fold (villi) length and the infiltration of epithelial leucocytes were significantly higher in the anterior and posterior intestine, respectively, in the synbiotic group. Real-time PCR demonstrated that all of the genes investigated were significantly up-regulated in the anterior and posterior intestine of the synbiotic fed salmon, compared to the control group. At the systemic level, serum lysozyme activity was significantly higher in the synbiotic fed fish and growth performance, feed utilisation and biometric measurements (condition factor, gutted weight and gut loss) were not affected. Together these results suggest that the synbiotic modulation of the gut microbiota has a protective action on the intestinal mucosal cells, improving morphology and stimulating the innate immune response without negatively affecting growth performance or feed utilization of farmed Atlantic salmon. PMID- 24161778 TI - Immunostimulatory activity of sulfated galactans isolated from the red seaweed Gracilaria fisheri and development of resistance against white spot syndrome virus (WSSV) in shrimp. AB - Sulfated galactans (SG) were isolated from the red seaweed Gracilaria fisheri (G. fisheri). Chemical analysis revealed SG contains sulfate (12.7%) and total carbohydrate (42.2%) with an estimated molecular mass of 100 kDa. Structure analysis by NMR and FT-IR spectroscopy revealed that SG is a complex structure with a linear backbone of alternating 3-linked beta-D-galactopyranose and 4 linked 3,6-anhydrogalactose units with partial 6-O-methylate-beta-D galactopyranose and with sulfation occurring on C4 of D-galactopyranose and C6 of L-galactopyranose units. SG treatment enhanced immune parameters including total haemocytes, phenoloxidase activity, superoxide anions and superoxide dismutase in shrimp Penaeus monodon. Shrimp fed with Artemia salina enriched with SG (100 and 200 MUg ml(-1)) and inoculated with white spot syndrome virus (WSSV) showed a significantly lower mortality rate and lower viral VP 28 amplification and expression than control. The results suggest that SG from G. fisheri exhibits immune stimulatory and antiviral activities that could protect P. monodon from WSSV infection. PMID- 24161779 TI - Grey matter abnormalities in untreated hyperthyroidism: a voxel-based morphometry study using the DARTEL approach. AB - OBJECTIVE: Hyperthyroidism is frequently associated with pronounced neuropsychiatric symptoms such as impulsiveness, irritability, poor concentration, and memory impairments. Functional neuroimaging has revealed changes in cerebral metabolism in hyperthyroidism, but regional changes in cortical morphology associated with specific neurological deficits have not been studied so far. To investigate the pathophysiology underlying hyperthyroid associated neural dysfunction, we compared grey matter volume (GMV) between adult hyperthyroid patients and matched healthy controls using voxel-based morphometry (VBM). MATERIALS AND METHODS: High resolution 3D T1-weighted images were acquired by 3T MRI from 51 hyperthyroid patients and 51 controls. VBM analysis was performed using SPM8. Correlations between regional GMV and both serum free thyroid hormone (TH) concentrations and disease duration were assessed by multiple regression analysis. RESULTS: Compared to controls, GM volumes in the bilateral hippocampus, parahippocampal gyrus, calcarine, lingual gyrus, and left temporal pole were lower and bilateral supplementary motor area GMV higher in hyperthyroid patients. Serum free triiodothyronine (FT3) concentration was negatively correlated with the normalized regional volume (NRV) of the left parahippocampal gyrus and serum free thyroxine (FT4) concentration negatively correlated with the NRV of the left hippocampus and right parahippocampal gyrus. Disease duration was negatively correlated with the NRV of the left hippocampus, bilateral parahippocampal gyrus, and left temporal pole. CONCLUSION: Hyperthyroid patients exhibited reduced GMV in regions associated with memory, attention, emotion, vision, and motor planning. Negative correlations between GMV and both free TH and disease duration suggest that chronic TH elevation induces abnormalities in the adult cortex. PMID- 24161780 TI - Incremental clinical value of ultrasound in men with mammographically confirmed gynecomastia. AB - PURPOSE: To determine whether ultrasound is of any value in male patients presenting with focal symptoms who have classic features of gynecomastia but no concerning findings on mammography. MATERIALS AND METHODS: Over a 3-year period, all male patients who underwent mammographic evaluation were identified in this retrospective study. Patients with a mammographic diagnosis of gynecomastia and subsequent breast ultrasound at a large tertiary academic medical center comprised the study cohort. Men whose ultrasound diagnosis differed from the initial mammographic evaluation were analyzed for both additional benign findings as well as findings that warranted biopsy. RESULTS: A total of 353 mammograms were obtained from 327 unique patients (ages 18-95, mean 51 years). Of all mammographic examinations, gynecomastia was the sole finding in 73% (259). In those 259 studies, 85% were further evaluated with ultrasound, in which 6 (2.7%) showed additional benign findings, and 4 (1.8%) showed suspicious findings for which biopsy was recommended. No malignancies were detected in those patients. Furthermore, no malignancies were detected in patients whose mammogram revealed only normal fatty parenchyma or only gynecomastia. In all cases of cancer, mammography revealed visible masses. CONCLUSION: Judicious use of breast ultrasound in men improves outcome. Our data suggest that targeted ultrasound is of limited value in symptomatic male patients where mammography is negative or reveals only gynecomastia and leads to unnecessary benign biopsies in these patients. When mammography reveals concerning findings, ultrasound adds positively to clinical management. PMID- 24161781 TI - Image-guided radiofrequency ablation of hepatocellular carcinoma (HCC): is MR guidance more effective than CT guidance? AB - OBJECTIVES: The purpose of the study was to retrospectively compare technique effectiveness of computed tomography (CT)-guided versus magnetic resonance (MR) guided radiofrequency (RF) ablation of hepatocellular carcinoma (HCC). MATERIALS AND METHODS: In 35 consecutive patients 53 CT-guided (n=29) or MR-guided (n=24) ablation procedures were performed in the treatment of 56 (CT: 29; MR: 27) HCC. The entire ablation procedure was performed at a multislice CT-scanner or an interventional 0.2-Tesla MR-scanner. Assessment of treatment response was based on dynamic MR imaging at 1.5Tesla. The mean follow-up was 22.9 months. Primary technique effectiveness was assessed 4 months after ablation therapy. Secondary technique effectiveness was assessed 4 months after a facultative second ablation procedure. Primary and secondary technique effectiveness of CT-guided and MR guided RF ablation was compared by using Chi-Square (likelihood ratio) test. RESULTS: Primary technique effectiveness after a single session was achieved in 26/27 (96.3%) HCC after MR-guided RF ablation and 23/29 (79.3%) HCC after CT guided RF ablation (Chi-Square: p=0.04). Secondary technique effectiveness was achieved in 26/27 (96.3%) HCC after MR-guided RF ablation and in 26/29 (89.7%) HCC after CT-guided RF ablation (Chi-Square: p=0.32). A local tumor progression was detected in 8/52 (15.4%) tumors after initial technique effectiveness. Major complications were detected after 3/53 (5.7%) ablation procedures. CONCLUSIONS: CT-guided and MR-guided RF ablations are locally effective therapies in the treatment of HCC. Due to a higher rate of primary technique effectiveness MR guided RF ablation may reduce the number of required sessions for complete tumor treatment. PMID- 24161782 TI - Diffusion weighted magnetic resonance imaging of kidneys in children with vesicoureteral reflux. AB - PURPOSE: The apparent diffusion coefficient (ADC) which obtain from diffusion weighted magnetic resonance imaging (DWI), is a quantitative parameter representing the renal function and parenchymal damage in some renal disorders. The primary aim of this study was to investigate whether renal tissue alterations associated with vesicoureteral reflux (VUR) can be displayed by DWI. The secondary aim was to assess how ADC values change with age in kidneys with and without VUR. MATERIALS AND METHODS: This prospective study included 46 patients (8 boys, 38 girls; mean age 7.3 +/- 4.2; range 1-15 years) with VUR and 54 control subjects (21 boys, 33 girls; mean age 7.7 +/- 5.2; range 1-17 years). All subjects underwent DWI of the kidneys using b value of 600s/mm(2) in addition to MR urography. The ADC values of 71 kidneys with VUR were compared with those of 81 kidneys without VUR. RESULTS: The mean ADC values were (1.93 +/- 0.36)*10( 3)mm(2)/s, (1.97 +/- 0.24)* 10(-3)mm(2)/s, (1.83 +/- 0.37)* 10(-3)mm(2)/s, (1.98 +/- 0.20)*10(-3)mm(2)/s and (2.08 +/- 0.42)* 10(-3)mm(2)/s in normal kidneys, and in those with grade 1, grade 2, grade 3 and grade 4 VUR, respectively. There was no significant difference in ADC values between kidneys with and without VUR. There was a significant positive correlation between the age and ADC values both in kidneys with and without VUR (r=0.79, p<0.001 and r=0.82; p<0.001, respectively). CONCLUSION: DWI does not reveal probable parenchymal alterations in reflux nephropathy. ADC values increase with age during childhood not only in normal kidneys but also in kidneys with VUR. PMID- 24161783 TI - Vertebral split fractures: technical feasibility of percutaneous vertebroplasty. AB - OBJECTIVE: The treatment of vertebral split fractures remains controversial, consisting of either corset or internal fixation. The aim of this study was to evaluate the technical feasibility of CT- and fluoroscopy-guided percutaneous vertebroplasty in the treatment of vertebral split fractures. MATERIALS AND METHODS: Institutional review board approval and informed consent were obtained for this study. Sixty-two consecutive adult patients who had post-traumatic vertebral split fractures (A2 according to the AO classification) without neurological symptoms were prospectively treated by percutaneous vertebroplasty. All these procedures were performed by an interventional radiologist under computed tomography (CT) and fluoroscopy guidance by using only local anaesthesia. Postoperative outcome was assessed using the visual analogue scale (VAS) and Oswestry disability index (ODI) scores. RESULTS: Vertebroplasty was performed on thoracic and lumbar vertebrae, creating a cement bridge between the displaced fragment and the rest of the vertebral body. Seven discal cement leakages (11%) were observed, without occurrence of adjacent vertebral compression fractures. The mean VAS measurements +/- standard deviation (SD) significantly decreased from 7.9 +/- 1.5 preoperatively to 3.3 +/- 2.1 at 1 day, 2.2 +/- 2.0 at 1 month, and 1.8 +/- 1.4 at 6 months (P<0.001). The mean ODI scores +/- SD had also a significant improvement: 62.3 +/- 17.2 preoperatively and 15.1 +/- 6.0 at the 6-month follow-up (P<0.001). CONCLUSION: This study suggests that type A2 vertebral fractures could be successfully treated by CT- and fluoroscopy-guided percutaneous vertebroplasty. PMID- 24161785 TI - Novel compound PS-101 exhibits selective inhibition in non-small-cell lung cancer cell by blocking the EGFR-driven antiapoptotic pathway. AB - This study investigated the anticancer effect of a novel compound PS-101 in human lung cancer cells. By phenotype screening, PS-101 exhibited highly selective inhibition in EGFR-overexpressed non-small cell lung cancer cells NCI-H460 and A549 while displaying no obvious toxicity to normal hepatic cell HL-7702, lung fibroblast cell WI-38, liver cancer cell BEL-7404 and gastric cancer cell MCG 803. A combination of cell viability assay, immunoblotting, and RNA interference revealed that PS-101 induced EGFR-dependent inhibition selectivity. Further studies showed that PS-101 caused cell cycle arrest at G1 phase, changed cell size, induced apoptosis and led to cell death by increasing the proportion of sub G1 cells. Molecular mechanism studies suggested that blocking the EGFR-driven antiapoptotic pathway is essential for PS-101-induced apoptosis. The contribution of blocking the EGFR-driven antiapoptotic pathway was verified through examines abundance of likely candidate proteins and RNA interference. The root cause for increase in BAD and decrease in Bcl-2 which altogether initiated caspase dependent apoptosis were predominantly due to down-regulation the expression of EGFR after PS-101 treatment. PS-101 strongly down-regulated the EGFR expression to trigger proapototic protein BAD increase and antiproapototic protein Bcl-2 decrease, which altogether actived effector caspase-3/9 to initiate cell apoptisis. Taken together, these results suggest that PS-101 may be a potential candidate for cancer therapy against human lung cancer. PMID- 24161784 TI - Ligand modulation of a dinuclear platinum compound leads to mechanistic differences in cell cycle progression and arrest. AB - Despite similar structures and DNA binding profiles, two recently synthesized dinuclear platinum compounds are shown to elicit highly divergent effects on cell cycle progression. In colorectal HCT116 cells, BBR3610 shows a classical G2/M arrest with initial accumulation in S phase, but the derivative compound BBR3610 DACH, formed by introduction of the 1,2-diaminocyclohexane (DACH) as carrier ligand, results in severe G1/S as well as G2/M phase arrest, with nearly complete S phase depletion. The origin of this unique effect was studied. Cellular interstrand crosslinking as assayed by comet analysis was similar for both compounds, confirming previous in vitro results obtained on plasmid DNA. Immunoblotting revealed a stabilization of p53 and concomitant transient increases in p21 and p27 proteins after treatment with BBR3610-DACH. Cell viability assays and cytometric analysis of p53 and p21 null cells indicated that BBR3610-DACH-induced cell cycle arrest was p21-dependent and partially p53 dependent. However, an increase in the levels of cyclin E was observed with steady state levels of CDK2 and Cdc25A, suggesting that the G1 block occurs downstream of CDK/cyclin complex formation. The G2/M block was corroborated with decreased levels of cyclin A and cyclin B1. Surprisingly, BBR3610-DACH-induced G1 block was independent of ATM and ATR. Finally, both compounds induced apoptosis, with BBR3610-DACH showing a robust PARP-1 cleavage that was not associated with caspase-3/7 cleavage. In summary, BBR3610-DACH is a DNA binding platinum agent with unique inhibitory effects on cell cycle progression that could be further developed as a chemotherapeutic agent complementary to cisplatin and oxaliplatin. PMID- 24161786 TI - Different efficacy of adenosine and NECA derivatives at the human A3 adenosine receptor: insight into the receptor activation switch. AB - A3 Adenosine receptors are promising drug targets for a number of diseases and intense efforts are dedicated to develop selective agonists and antagonists of these receptors. A series of adenosine derivatives with 2-(ar)-alkynyl chains, with high affinity and different degrees of selectivity for human A3 adenosine receptors was tested for the ability to inhibit forskolin-stimulated adenylyl cyclase. All these derivatives are partial agonists at A3 adenosine receptors; their efficacy is not significantly modified by the introduction of small alkyl substituents in the N(6)-position. In contrast, the adenosine-5'-N-ethyluronamide (NECA) analogs of 2-(ar)-alkynyladenosine derivatives are full A3 agonists. Molecular modeling analyses were performed considering both the conformational behavior of the ligands and the impact of 2- and 5'-substituents on ligand-target interaction. The results suggest an explanation for the different agonistic behavior of adenosine and NECA derivatives, respectively. A sub-pocket of the binding site was analyzed as a crucial interaction domain for receptor activation. PMID- 24161787 TI - Andrographolide downregulates the v-Src and Bcr-Abl oncoproteins and induces Hsp90 cleavage in the ROS-dependent suppression of cancer malignancy. AB - Andrographolide is a diterpenoid compound isolated from Andrographis paniculata that exhibits anticancer activity. We previously reported that andrographolide suppressed v-Src-mediated cellular transformation by promoting the degradation of Src. In the present study, we demonstrated the involvement of Hsp90 in the andrographolide-mediated inhibition of Src oncogenic activity. Using a proteomics approach, a cleavage fragment of Hsp90alpha was identified in andrographolide treated cells. The concentration- and time-dependent induction of Hsp90 cleavage that accompanied the reduction in Src was validated in RK3E cells transformed with either v-Src or a human truncated c-Src variant and treated with andrographolide. In cancer cells, the induction of Hsp90 cleavage by andrographolide and its structural derivatives correlated well with decreased Src levels, the suppression of transformation, and the induction of apoptosis. Moreover, the andrographolide-induced Hsp90 cleavage, Src degradation, inhibition of transformation, and induction of apoptosis were abolished by a ROS inhibitor, N-acetyl-cysteine. Notably, Hsp90 cleavage, decreased levels of Bcr-Abl (another known Hsp90 client protein), and the induction of apoptosis were also observed in human K562 leukemia cells treated with andrographolide or its active derivatives. Together, we demonstrated a novel mechanism by which andrographolide suppressed cancer malignancy that involved inhibiting Hsp90 function and reducing the levels of Hsp90 client proteins. Our results broaden the molecular basis of andrographolide-mediated anticancer activity. PMID- 24161788 TI - A microchip for quantitative analysis of CNS axon growth under localized biomolecular treatments. AB - Growth capability of neurons is an essential factor in axon regeneration. To better understand how microenvironments influence axon growth, methods that allow spatial control of cellular microenvironments and easy quantification of axon growth are critically needed. Here, we present a microchip capable of physically guiding the growth directions of axons while providing physical and fluidic isolation from neuronal somata/dendrites that enables localized biomolecular treatments and linear axon growth. The microchip allows axons to grow in straight lines inside the axon compartments even after the isolation; therefore, significantly facilitating the axon length quantification process. We further developed an image processing algorithm that automatically quantifies axon growth. The effect of localized extracellular matrix components and brain-derived neurotropic factor treatments on axon growth was investigated. Results show that biomolecules may have substantially different effects on axon growth depending on where they act. For example, while chondroitin sulfate proteoglycan causes axon retraction when added to the axons, it promotes axon growth when applied to the somata. The newly developed microchip overcomes limitations of conventional axon growth research methods that lack localized control of biomolecular environments and are often performed at a significantly lower cell density for only a short period of time due to difficulty in monitoring of axonal growth. This microchip may serve as a powerful tool for investigating factors that promote axon growth and regeneration. PMID- 24161789 TI - National Health and Nutrition Examination Survey whole-body dual-energy X-ray absorptiometry reference data for GE Lunar systems. AB - The National Health and Nutrition Examination Survey (NHANES 1999-2004) includes adult and pediatric comparisons for total body bone and body composition results. Because dual-energy x-ray absorptiometry (DXA) measurements from different manufacturers are not standardized, NHANES reference values currently are applicable only to a single make and model of Hologic DXA system. The purpose of this study was to derive body composition reference curves for GE Healthcare Lunar DXA systems. Published values from the NHANES 1999-2004 survey were acquired from the Centers for Disease Control and Prevention website. Using previously reported cross-calibration equations between Hologic and GE-Lunar, we converted the total body and regional bone and soft-tissue measurements from NHANES 1999-2004 to GE-Lunar values. The LMS (LmsChartMaker Pro Version 3.5) curve fitting method was used to generate GE-Lunar reference curves. Separate curves were generated for each sex and ethnicity. The reference curves were also divided into pediatric (<=20 years old) and adult (>20 years old) groups. Adult reference curves were derived as a function of age. Additional relationships of pediatric DXA values were derived as a function of height, lean mass, and bone area. Robustness was tested between Hologic and GE-Lunar Z-score values. The NHANES 1999-2004 survey included a sample of 20,672 participants' (9630 female) DXA scans. A total of 8056 participants were younger than 20 yr and were included in the pediatric reference data set. Participants enrolled in the study who weighed more than 136 kg (over scanner table limit) were excluded. The average Z scores comparing the new GE-Lunar reference curves are close to zero, and the standard deviation of the Z-scores are close to one for all variables. As expected, all measurements on the GE-Lunar reference curves for participants younger than 20 yr increase monotonically with age. In the adult population, most of the curves are constant at younger age and drop moderately as age increases. We have presented NHANES reference curves applicable to DXA whole-body scans acquired on GE Healthcare Lunar systems by age, sex and ethnicity. Users of GE Healthcare GE-Lunar DXA systems can now benefit from the large body composition reference data set collected in the NHANES 1999-2004 study. PMID- 24161790 TI - Morphometric vertebral assessments via the use of dual X-ray absorptiometry for the evaluation of radiographic damage in ankylosing spondylitis: a pilot study. AB - We performed a pilot study to compare vertebral fracture assessments (VFA) and lateral X-rays in terms of inter- and intraobserver reliability and degree of correlation for the detection of syndesmophytes in ankylosing spondylitis (AS). We recruited 19 patients with AS and recent lumbar or cervical lateral X-rays with at least one syndesmophyte. Each patient underwent dual-energy X-ray absorptiometry with measurement of bone mineral density and dorso-lumbar VFA. Intra- and interreader reliability for VFA and X-rays were measured using 2 independent, blinded observers and Cohen's kappa values. An adapted modified Stoke Ankylosing Spondylitis Spinal Score (amSASSS) was generated with each method, and these 2 values correlated. For X-rays, intraobserver and interobserver agreement were 94.3% (kappa = 0.83) and 98.6% (kappa = 0.96), respectively; for VFA, corresponding values were 92.8% (kappa = 0.79) and 93.8% (kappa = 0.82). Overall agreement between the 2 techniques was 88.6% (kappa = 0.72). The Pearson correlation coefficient for the 2 methods was 0.95 for the modified Stoke Ankylosing Spondylitis Spinal Score . Per dual-energy X-ray absorptiometry-generated bone mineral density, >50% of patients were osteopenic and 10% osteoporotic. In terms of reproducibility and correlation with X-rays, performing a VFA appears to be a candidate for assessing radiographic damage in AS, thought further research is necessary to justify this indication. PMID- 24161791 TI - Pelvic periprosthetic bone mineral density measurement around cemented vs cementless acetabular prostheses. AB - We compared the short-term precision of pelvic periprosthetic bone mineral density (BMD) measurement around a cementless acetabular prosthesis (n = 29) vs a cemented all-polyethylene acetabular prosthesis (n = 19) in patients after total hip arthroplasty. Two dual-energy x-ray absorptiometry scans of the pelvis were made on the same day in each subject with subject repositioning between scans and analyzed independently with a 4-region of interest model. Precision was expressed as coefficient of variation (CV%). The measured BMD around the cemented prostheses was greater than the cementless prostheses p < 0.004, all analyses). The net CV for pelvic BMD measurements around the cementless prosthesis was 1.9% vs 3.6% around the cemented prosthesis (F-test p < 0.001). The CVs of individual regions of interest was between 2.8% and 4.8% for the cementless prosthesis vs 4.4% to 8.4% for the cemented prosthesis (F-test; p < 0.05, all comparisons). Prospective studies would require 57 subjects to detect a 10% change in net pelvic BMD around a cementless prosthesis and 122 to detect a similar change around a cemented prosthesis with 90% power and with an alpha error of 0.05. In conclusion, the precision of pelvic BMD measurements made around cementless prostheses are better vs those for cemented prostheses. Dual-energy x-ray absorptiometry studies of cemented prosthesis require approximately double the number of subjects vs cementless prostheses to achieve a similar level of power. PMID- 24161792 TI - The time windows of the sense of agency. AB - The sense of agency depends on some internal cues that derive from action control, as well as external cues like contextual information and prior information (degree of contingency between an action and is effect). We assessed whether external agency cues are combined with internal agency cues to affect the sense of agency. In two experiments participants performed a movement (button press) that elicited, after a varying delay, an effect (ball appearing on a screen), and reported their sense of agency over the effect (full, partial or no agency) while internal cues (premotor information) and external cues (contextual and prior information) were manipulated. We assessed the effect of agency cues on the delays at which the sense of agency varied. The delays were increased with premotor signals but were decreased with contextual information. These findings favour a model of integration of internal and external agency cues over time. PMID- 24161794 TI - Thyme to touch: infants possess strategies that protect them from dangers posed by plants. AB - Plants have been central to human life as sources of food and raw materials for artifact construction over evolutionary time. But plants also have chemical and physical defenses (such as harmful toxins and thorns) that provide protection from herbivores. The presence of these defenses has shaped the behavioral strategies of non-human animals. Here we report evidence that human infants possess strategies that would serve to protect them from dangers posed by plants. Across two experiments, infants as young as eight months exhibit greater reluctance to manually explore plants compared to other entities. These results expand the growing literature showing that infants are sensitive to certain ancestrally recurrent dangers, and provide a basis for further exploration. PMID- 24161793 TI - Assessment of the role in protection and pathogenesis of the Chlamydia muridarum V-type ATP synthase subunit A (AtpA) (TC0582). AB - A novel Chlamydia muridarum antigen (TC0582) was used to vaccinate BALB/c mice. Mice were also immunized with other components of the ATP synthase complex (TC0580, TC0581, and TC0584), or with the major outer membrane protein (MOMP). TC0582 was also formulated in combination with TC0580, TC0581 or MOMP. TC0582 alone, or in combination with the other antigens, elicited strong Chlamydia specific humoral and cellular immune responses. Vaccinated animals were challenged intranasally and the course of the infection was followed for 10 days. Based on percentage change in body weight, lung weight, and number of Chlamydia inclusion forming units recovered from the lungs, mice immunized with TC0582, TC0581 or MOMP, as single antigens, showed significant protection. Mice immunized with combinations of two antigens were also protected but the level of protection was not additive. TC0582 has sequence homology with the eukaryotic ATP synthase subunit A (AtpA). Therefore, to determine if immunization with TC0582, or with Chlamydia, elicited antibodies that cross-reacted with the mouse AtpA, the two proteins were printed on a microarray. Sera from mice immunized with TC0582 and/or live Chlamydia, strongly reacted with TC0582 but did not recognize the mouse AtpA. In conclusion, TC0582 may be considered as a Chlamydia vaccine candidate. PMID- 24161795 TI - Semi-automatic segmentation and detection of aorta dissection wall in MDCT angiography. AB - Aorta dissection is a serious vascular disease produced by a rupture of the tunica intima of the vessel wall that can be lethal to the patient. The related diagnosis is strongly based on images, where the multi-detector CT is the most generally used modality. We aim at developing a semi-automatic segmentation tool for aorta dissections, which will isolate the dissection (or flap) from the rest of the vascular structure. The proposed method is based on different stages, the first one being the semi-automatic extraction of the aorta centerline and its main branches, allowing an subsequent automatic segmentation of the outer wall of the aorta, based on a geodesic level set framework. This segmentation is then followed by an extraction the center of the dissected wall as a 3D mesh using an original algorithm based on the zero crossing of two vector fields. Our method has been applied to five datasets from three patients with chronic aortic dissection. The comparison with manually segmented dissections shows an average absolute distance value of about half a voxel. We believe that the proposed method, which tries to solve a problem that has attracted little attention to the medical image processing community, provides a new and interesting tool to isolate the intimal flap that can provide very useful information to the clinician. PMID- 24161796 TI - Expressing the joint moments of drop jumps and sidestep cutting in different reference frames--does it matter? AB - Joint moments help us understand joint loading and muscle function during movement. However, the interpretation depends on the choice of reference frame, but the different reference frames have not been compared in dynamic, high-impact sporting movements. We have compared the magnitude and the resulting ranking of hip and knee joint moments expressed in the laboratory coordinate system, the local system of the distal segment and projected or decomposed to the Joint Coordinate System (JCS) axes. Hip and knee joint moments of drop jumps and sidestep cutting in 70 elite female handball players were calculated based on recordings from an eight-camera 240 Hz system and two force platforms and expressed with the four methods. The greatest variations in magnitude between conditions were seen for drop jump hip internal rotation (range: 0.31-0.71 Nm/kg) and sidestep cutting knee flexion (2.87-3.39 Nm/kg) and hip internal rotation (0.87-2.36 Nm/kg) and knee internal rotation (0.10-0.40 Nm/kg) moments. The rank correlations were highest between conditions for flexion moments (0.88-1.00) and sidestep cutting abduction moments (0.71-0.98). The rank correlations ranged from 0.64 to 0.73 for drop jump knee abduction moments and between -0.17 and 0.67 for hip and knee internal rotation moments. Expression of joint moments in different reference systems affects the magnitude and ranking of athletes. This lack of consistency may complicate the comparison and combination of results. Projection to the JCS is the only method where joint moments correspond to muscle and ligament loading. More widespread adoption of this convention could facilitate comparison of studies and ease the interpretation of results. PMID- 24161797 TI - Compliant bipedal model with the center of pressure excursion associated with oscillatory behavior of the center of mass reproduces the human gait dynamics. AB - Although the compliant bipedal model could reproduce qualitative ground reaction force (GRF) of human walking, the model with a fixed pivot showed overestimations in stance leg rotation and the ratio of horizontal to vertical GRF. The human walking data showed a continuous forward progression of the center of pressure (CoP) during the stance phase and the suspension of the CoP near the forefoot before the onset of step transition. To better describe human gait dynamics with a minimal expense of model complexity, we proposed a compliant bipedal model with the accelerated pivot which associated the CoP excursion with the oscillatory behavior of the center of mass (CoM) with the existing simulation parameter and leg stiffness. Owing to the pivot acceleration defined to emulate human CoP profile, the arrival of the CoP at the limit of the stance foot over the single stance duration initiated the step-to-step transition. The proposed model showed an improved match of walking data. As the forward motion of CoM during single stance was partly accounted by forward pivot translation, the previously overestimated rotation of the stance leg was reduced and the corresponding horizontal GRF became closer to human data. The walking solutions of the model ranged over higher speed ranges (~1.7 m/s) than those of the fixed pivoted compliant bipedal model (~1.5m/s) and exhibited other gait parameters, such as touchdown angle, step length and step frequency, comparable to the experimental observations. The good matches between the model and experimental GRF data imply that the continuous pivot acceleration associated with CoM oscillatory behavior could serve as a useful framework of bipedal model. PMID- 24161798 TI - Vancomycin-resistant enterococci colonization does not increase mortality in end stage kidney failure: a case-control study. AB - BACKGROUND: Vancomycin-resistant enterococci (VRE) colonization is a frequent occurrence in patients with renal failure. Understanding the impact of VRE colonization on this group of patients has considerable clinical applicability. AIM: To understand whether VRE colonization in renal patients has an impact on number of admissions to hospital, length of stay, and mortality. METHODS: A retrospective case-control study of renal dialysis patients was performed between 2000 and 2010. Cases were 134 VRE-colonized patients requiring renal replacement therapy and matched controls were 137 non-colonized patients with the same baseline characteristics. Matched cases and controls were analysed for differences in number of admissions, length of stay, and mortality. FINDINGS: There was no difference in mortality between colonized and non-colonized patients (hazard ratio: 1.14; 95% confidence interval: 0.78-1.69; P = 0.49). Length of stay for colonized patients was 7.29 days compared with 4.14 days (P < 0.001). The number of admissions for VRE-colonized patients was not significantly different compared with controls (9.34 vs 8.33, P = 0.78). CONCLUSION: VRE colonization did not increase mortality in renal patients but did contribute to increased length of stay. PMID- 24161799 TI - New quantification methods for carotid intra-plaque neovascularization using contrast-enhanced ultrasound. AB - As carotid intra-plaque neovascularization (IPN) is linked to progressive atherosclerotic disease and plaque vulnerability, its accurate quantification might allow early detection of plaque vulnerability. We therefore developed several new quantitative methods for analyzing IPN perfusion and structure. From our analyses, we derived six quantitative parameters-IPN surface area (IPNSA), IPN surface ratio (IPNSR), plaque mean intensity, plaque-to-lumen enhancement ratio, mean plaque contrast percentage and number of micro-vessels (MVN)-and compared these with visual grading of IPN by two independent physicians. A total of 45 carotid arteries with symptomatic stenosis in 23 patients were analyzed. IPNSA (correlation r = 0.719), IPNSR (r = 0.538) and MVN (r = 0.484) were found to be significantly correlated with visual scoring (p < 0.01). IPNSA was the best match to visual scoring. These results indicate that IPNSA, IPNSR and MVN may have the potential to replace qualitative visual scoring and to measure the degree of carotid IPN. PMID- 24161800 TI - Attention orienting and inhibitory control across the different mood states in bipolar disorder: an emotional antisaccade task. AB - An antisaccade experiment, using happy, sad, and neutral faces, was conducted to examine the effect of mood-congruent information on inhibitory control (antisaccade task) and attentional orienting (prosaccade task) during the different episodes of bipolar disorder (BD) - manic (n=22), depressive (n=25), and euthymic (n=24). A group of 28 healthy controls was also included. Results revealed that symptomatic patients committed more antisaccade errors than healthy individuals, especially with mood-congruent faces. The manic group committed more antisaccade errors in response to happy faces, while the depressed group tended to commit more antisaccade errors in response to sad faces. Additionally, antisaccade latencies were slower in BD patients than in healthy individuals, whereas prosaccade latencies were slower in symptomatic patients. Taken together, these findings revealed the following: (a) slow inhibitory control in BD patients, regardless of their episode (i.e., a trait), and (b) impaired inhibitory control restricted to symptomatic patients (i.e., a state). PMID- 24161801 TI - Understanding the reward system functioning in anorexia nervosa: crucial role of physical activity. AB - Hyperactivity is a potential neurobiological marker and a core psychopathological trait in anorexia nervosa (AN). We investigated the processing of hyperactivity related information in fifteen AN patients, 15 athletes and 15 non-athletes to examine if they represent disorder-related reward information using eye tracking. We assessed the extent of individually performed physical activity, mood, trait reward sensitivity and serum leptin levels. Results revealed a pronounced bias in overall attentional engagement toward stimuli associated with physical activity in patients and athletes as compared to non-athletes. In patients, relevant correlations were found: trait reward sensitivity and attentional orienting were strongly correlated and amount of physical activity correlated with attentional orienting and engagement. Compared to non-athletes, patients and athletes rated exercise stimuli as more pleasant. Findings suggest that exercise-related stimuli are perceived as rewarding by AN patients. Positive motivational valence of physical activity might contribute to disorder development and maintenance. PMID- 24161802 TI - Relationship between nitrogen concentration, light, and Zostera marina habitat quality and survival in southeastern Massachusetts estuaries. AB - The relationship of eelgrass survival and habitat quality to water column nitrogen level, phytoplankton biomass, particulate matter, bottom light intensity, and light attenuation was quantified at 70 sites within 19 Massachusetts estuaries through 4 growing seasons (2007-2009, 2011). Sites included a range of eelgrass habitat quality, from stable productive eelgrass beds, to degraded beds, to areas that have lost all eelgrass coverage. Survival of transplanted eelgrass culms was used as a bio-indicator of habitat quality. Habitat quality based upon both changes in stability of eelgrass coverage and transplant survival was positively related to light intensity and percent transmittance. Transplant survival was consistent with habitat designations based upon long-term changes in eelgrass coverage, with lowest light coinciding with areas that lost eelgrass in earlier decades. Bottom light declined in proportion to increases in total nitrogen levels, phytoplankton biomass, and water column particulates determined from long-term water quality data. Field surveys indicated that eelgrass survival required bottom light >=100 MUE/m(2)/s and healthy eelgrass existed where tidally-averaged total nitrogen was less than 0.34 mg/L, equivalent to a mid-ebb tide water-column total nitrogen of <0.37 mg/L. Traditional sampling of water column nitrogen at mid-ebb tide was found to slightly overestimate the average nitrogen level over a complete tidal cycle. However, since long-term, ebb-tide and tidally-averaged total nitrogen are correlated, it is possible to use the monitoring average to guide management until tidally-averaged TN becomes available. Nitrogen thresholds that support eelgrass communities provide a fundamental tool for managing this habitat and for selection of transplant sites aimed at accelerating restoration of this resource under increasing nitrogen loading of the coastal zone. PMID- 24161803 TI - A review of binders used in cemented paste tailings for underground and surface disposal practices. AB - Increased public awareness of environmental issues coupled with increasingly stringent environmental regulations pertaining to the disposal of sulphidic mine waste necessitates the mining industry to adopt more competent and efficient approaches to manage acid rock drainage. Cemented paste tailings (CPT) is an innovative form of amalgamated material currently available to the mining industry in developed countries. It is made usually from mill tailings mingled with a small amount of binder (customarily Portland cement) and water. The high cost associated with production and haulage of ordinary Portland cement and its alleged average performance as a sole binder in the long term (due to vulnerability to internal sulphate attack) have prompted users to appraise less expensive and technically efficient substitutes for mine tailings paste formulations. Generally, these binders include but are not limited to sulphate resistant cements, and/or as a partial replacement for Portland cement by artificial pozzolans, natural pozzolans, calcium sulphate substances and sodium silicates. The approach to designing environmentally efficient CPT is to ensure long-term stability and effective control over environmental contaminants through the use of composite binder systems with enhanced engineering properties to cater for inherit deficiencies in the individual constituents. The alkaline pore solution created by high free calcium rich cement kiln dust (CKD) (byproduct of cement manufacturing) is capable of disintegrating the solid glassy network of artificial pozzolans to produce reactive silicate and aluminate species when attacked by (OH(-)) ions. The augmented pozzolanic reactivity of CKD-slag and CKD fly ash systems may produce resilient CPT. Since cemented paste comprising mine tailings and binders is a relatively new technology, a review of the binding materials used in such formulations and their performance evaluation in mechanical fill behaviour was considered pertinent in the study. PMID- 24161805 TI - Energy saving membrane treatment of high organic load industrial effluents: from lab to pilot scale. AB - In this study, a nanofiltration unit was implemented at an industrial site, for the treatment of industrial wastewater generated during rubber tubing extrusion. The aim was to reduce the energy input required, while assuring a final effluent quality that meets the requirements of environmental legislation. In a first stage, two membrane process treatments, ultrafiltration and nanofiltration, were evaluated at laboratory scale in order to assess the rejection of pollutants and maximise permeate throughput. Permeate generated from nanofiltration using either an NF90 or an NF270 membrane were shown to meet the effluent discharge requirements (<2000 mg COD/l). The less restrictive membrane, NF270, was chosen for study in a pilot plant at the industrial site, due to its higher membrane permeability. The pilot nanofiltration unit was integrated into the treatment plant operation aiming at optimising the process in terms of the efficiency of pollutant removal with minimal energy input. A feasibility study was performed for this case-study and it was concluded that the energy expenditure of the new process represents only 62% of the current energy consumption of the treatment plant. The proposed solution in this work may be retrofitted to full scale wastewater treatment processes, and may be applicable to industries that employ similar manufacturing processes, and face similar difficulties. PMID- 24161804 TI - Evaluating Ireland's IBIA as an approach to improving the quality and effectiveness of biodiversity impact assessment. AB - The assessment of potential impacts of plans, programmes and projects on biodiversity is required under various legislative remits (including the European Union's Habitats, Strategic Environmental Assessment and Environmental Impact Assessment Directives). The objective of such assessments is to ensure that potential negative impacts on both protected nature conservation sites and species and wider biodiversity are efficiently identified in a timely manner, quantified and subsequently avoided or mitigated, while enhancing positive effects. The procedural requirements of these legal obligations vary and, as a result, differing methodological steps, data gathering and analysis methods, and impact assessment techniques are commonly applied under each individual process, often leading to uncoordinated assessment efforts and results (in terms, for example, of scope, scale and assessment detail). In order to address these issues and improve current practice, an Integrated Biodiversity Impact Assessment (IBIA) methodology has been developed in Ireland with the overall aim of providing a holistic and systematic approach to biodiversity impact assessment. The IBIA framework seeks to ensure that relevant procedures are effectively integrated, time and resource efficiencies are optimised, and unnecessary duplication avoided. Particular emphasis is given to compliance with legal requirements, integration and communication of scientific knowledge, spatial assessment and biodiversity data considerations, and integration of biodiversity aspects with a variety of other concerns during the plan-making process. This paper presents the IBIA methodology and critically examines current key issues in biodiversity impact assessment that can be potentially addressed through IBIA, as well as remaining challenges. In addition, and in order to support the examination of the anticipated benefits of using this new methodological framework (such as biodiversity-inclusive planning through improved communication and coordinated assessment), two contrasting case studies are used, one pre-dating the development of IBIA and a second where elements of IBIA have been implemented. PMID- 24161806 TI - Feasibility and interest of the anammox process as treatment alternative for anaerobic digester supernatants in manure processing--an overview. AB - Completely autotrophic nitrogen removal (ANR) is based on the combination of partial nitritation (PN) and anaerobic ammonium oxidation (anammox). It is a promising alternative for the subsequent treatment of biogas digester supernatants in livestock manure processing and nitrogen surplus scenarios. However, as no full-scale experiences in the treatment of manure digestates by ANR have been published to date, future field studies addressing treatment of this kind of effluent would be of great interest. Some topics to be considered in these studies would be coupling anaerobic digestion and ANR, analysis of the factors that affect the process, comparing reactor configurations, microbial ecology, gas emissions, and achieving robust performance. This paper provides an overview of published studies on ANR. Specific issues related to the applicability of the process for treating manure digestates are discussed. The energy requirements of ANR are compared with those of other technological alternatives aimed at recovering nitrogen from digester supernatants. The results of the assessment were shown to depend on the composition of the supernatant. In this regard, the PN-anammox process was shown to be more competitive than other alternatives particularly at concentrations of up to 2 kg NH4(+)-N m(-3). PMID- 24161807 TI - Will climate change drive alien invasive plants into areas of high protection value? An improved model-based regional assessment to prioritise the management of invasions. AB - Species distribution models (SDMs) studies suggest that, without control measures, the distribution of many alien invasive plant species (AIS) will increase under climate and land-use changes. Due to limited resources and large areas colonised by invaders, management and monitoring resources must be prioritised. Choices depend on the conservation value of the invaded areas and can be guided by SDM predictions. Here, we use a hierarchical SDM framework, complemented by connectivity analysis of AIS distributions, to evaluate current and future conflicts between AIS and high conservation value areas. We illustrate the framework with three Australian wattle (Acacia) species and patterns of conservation value in Northern Portugal. Results show that protected areas will likely suffer higher pressure from all three Acacia species under future climatic conditions. Due to this higher predicted conflict in protected areas, management might be prioritised for Acacia dealbata and Acacia melanoxylon. Connectivity of AIS suitable areas inside protected areas is currently lower than across the full study area, but this would change under future environmental conditions. Coupled SDM and connectivity analysis can support resource prioritisation for anticipation and monitoring of AIS impacts. However, further tests of this framework over a wide range of regions and organisms are still required before wide application. PMID- 24161809 TI - Enteroendocrine secretion of gut hormones in diabetes, obesity and after bariatric surgery. AB - Gastric bypass surgery is associated with a major weight loss and often causes remission in patients with type 2 diabetes. Surgery is also associated with dramatic increases in the secretion of the gut hormones, glucagon-like peptide-1 (GLP-1) and peptide YY (PYY), both of which regulate appetite and food intake, while GLP-1 in addition functions as an incretin hormone, stimulating insulin secretion. It has been possible to probe the role of GLP-1 for the diabetes resolution after gastric bypass using a GLP-1 receptor antagonist, and it is clear that the enhanced beta cell sensitivity to glucose which underlies the enhanced insulin secretion in the patients after the operation depends critically on the increased GLP-1 secretion. Both hormones seem to contribute importantly to the reduction in food intake after bypass and, therefore, to the weight loss. Currently, there are no data to indicate that decreased secretion of the hormones is involved in the pathogenesis of obesity and/or diabetes, but impaired secretion generally observed in obesity (and hence also in diabetes) may contribute to the development. Because of these effects receptor agonists for both hormones are currently being developed for the treatment of obesity and diabetes. PMID- 24161808 TI - MNE software for processing MEG and EEG data. AB - Magnetoencephalography and electroencephalography (M/EEG) measure the weak electromagnetic signals originating from neural currents in the brain. Using these signals to characterize and locate brain activity is a challenging task, as evidenced by several decades of methodological contributions. MNE, whose name stems from its capability to compute cortically-constrained minimum-norm current estimates from M/EEG data, is a software package that provides comprehensive analysis tools and workflows including preprocessing, source estimation, time frequency analysis, statistical analysis, and several methods to estimate functional connectivity between distributed brain regions. The present paper gives detailed information about the MNE package and describes typical use cases while also warning about potential caveats in analysis. The MNE package is a collaborative effort of multiple institutes striving to implement and share best methods and to facilitate distribution of analysis pipelines to advance reproducibility of research. Full documentation is available at http://martinos.org/mne. PMID- 24161810 TI - The effect of an inflammatory bowel disease nurse position on service delivery. AB - Inflammatory bowel disease (IBD) management is increasingly concentrated in units with expertise in the condition leading to substantial improvement in outcomes. Such units often employ nurses with a specialised interest in IBD with enhancements in care reflecting in part the promotion of more efficient use of medical and hospital services by this role. However, the relative contributions of nurse specialist input, and the effect of medical staff with a sub-speciality interest in IBD are unclear although this has major implications for funding. Determining the value of IBD nurses by assessing the direct impact of an IBD nurse on reducing admissions and outpatient attendances has immediate cost benefits, but the long-term sustainability of these savings has not been previously investigated. We therefore assessed the effect of an IBD nurse on patient outcomes in a tertiary hospital IBD Unit where the position has been established for 8years by measuring the number of occasions of service (OOS) and outcomes of all interactions between the nurse and patients in a tertiary hospital IBD Unit over a 12-month period. There were 4920 OOS recorded involving 566 patients. IBD nurse intervention led to avoidance of 27 hospital admissions (representing a saving of 171 occupied bed days), 32 Emergency Department presentations and 163 outpatient reviews. After deducting salary and on-costs related to the IBD nurse there was a net direct saving to the hospital of AUD $136,535. IBD nurse positions provide sustained direct cost reductions to health services via reducing hospital attendances. This is additional to benefits that accrue through better patient knowledge, earlier presentation and increased compliance. PMID- 24161812 TI - Vero/CHOK1, a novel mixture of cell lines that is optimal for the rescue of influenza A vaccine seeds. AB - Seasonal and pandemic influenza vaccine manufacturing is challenged with a tight production schedule. Reverse genetics constitutes a rapid method for creating viruses. Vero and CHOK1 cells were found to be an appropriate cell mixture for the generation of influenza reassortants by reverse genetics under the constraints of vaccine production, such as the use of regulatory-compliant cells and culture media devoid of components of animal origin. In addition, no further amplification in cell or egg substrates was required, thus reducing the time needed to obtain reassortant seed virus. In parallel, the cloning step was shown to be dramatically improved, permitting the rapid vRNA expression of influenza viruses. In addition, nucleoporation of the cells was conducted to more efficiently target the nucleus and avoid the use of chemical reagents containing proteins of animal origin. In conclusion, the reverse genetics system for influenza A viruses reported in this study was shown to be rapid, simple to perform and totally animal component-free to best comply with the requirements of health authorities for the production of a vaccine seed. PMID- 24161811 TI - Development of a real time polymerase chain reaction assay for equine encephalosis virus. AB - Equine encephalosis virus (EEV) is the cause of equine encephalosis. The disease is similar to mild forms of African horse sickness (AHS) and the two diseases are easily confused. Laboratory identification and serotyping of EEV is based on viral isolation in BHK-21 cells and a viral plaque inhibition neutralisation test. These procedures are time-consuming and therefore a more rapid diagnostic assay for EEV that can distinguish EEV from African horse sickness virus (AHSV) infections was developed. The S7 (VP7) gene from 38 EEV isolates representing all seven serotypes was amplified and sequenced. A conserved region at the 5' end of the gene was identified and used to design group-specific EEV primers and a TaqMan((r)) MGBTM hydrolysis probe. The efficiency of the EEV real-time RT-PCR assay was 81%. The assay was specific, as it did not detect any of the nine serotypes of AHSV, nor 24 serotypes of bluetongue virus (BTV) and sensitive, with a 95% limit of detection of 10(2.9) TCID50/ml blood (95% confidence interval: 10(2.7) to 10(3.3)). The real-time format was selected because of its convenience, sensitivity and ability to produce results rapidly. PMID- 24161813 TI - Detection of potato mop-top virus in soils and potato tubers using bait-plant bioassay, ELISA and RT-PCR. AB - The hilly region of Northwest of Pakistan is leading seed potato producing areas of the country. Soil and plant samples were collected from the region and tested for PMTV using both conventional and molecular techniques. The bait plants exhibited PMTV-characteristic v-shaped yellow leaf markings in Nicotiana debneyi plants grown in putative viruliferious soils from 20/26 locations. The results were confirmed by back inoculation of sap from both roots and leaves of bait plant on indicator hosts (N. debneyi, Nicotiana benthamiana). The root samples of bait plants grown in soils of 25 locations and leaves of 24 locations reproduced systemic infection on indicator hosts upon back inoculation. The virus was identified in bait plants grown in soils from 25/26 locations using double antibody sandwich-enzyme linked immunosorbent assay (DAS)-ELISA and reverse transcription and polymerase chain reaction (RT-PCR) methods. The products of the 566bp were amplified from coat protein region of PMTV RNA 3 in both root and leaf samples of baited plants. The virus was detected in 10 potato cultivars commercially grown in the region using DAS-ELISA and RT-PCR. The virus was also detected in zoospores of Spongospora subterranea derived from the peels of selected scabby tubers using triple antibody sandwich (TAS)-ELISA. The results indicate that a bait plant bioassay, infectivity assay, ELISA and RT-PCR can detect PMTV in roots and leaves of baited plants, field samples, zoospores of S. subterranea and tubers of 10 potato cultivars commercially grown in the region. PMID- 24161814 TI - Production of cocktail of polyclonal antibodies using bacterial expressed recombinant protein for multiple virus detection. AB - Cocktail of polyclonal antibodies (PAb) were produced that will help in multiple virus detection and overcome the limitation of individual virus purification, protein expression and purification as well as immunization in multiple rabbits. A dual fusion construct was developed using conserved coat protein (CP) sequences of Cucumber mosaic virus (CMV) and Papaya ringspot virus (PRSV) in an expression vector, pET-28a(+). The fusion protein (~40kDa) was expressed in Escherichia coli and purified. Likewise, a triple fusion construct was developed by fusing conserved CP sequences of CMV and PRSV with conserved nucleocapsid protein (N) sequence of Groundnut bud necrosis virus (GBNV) and expressed as a fusion protein (~50kDa) in pET-28a(+). PAb made separately to each of these three viruses recognized the double and triple fusion proteins in Western blot indicating retention of desired epitopes for binding with target antibodies. The fusion proteins (~40kDa and ~50kDa) were used to produce cocktail of PAb by immunizing rabbits, which simultaneously detected natural infection of CMV and PRSV or CMV, PRSV and GBNV in Cucurbitaceous, Solanaceous and other hosts in DAC-ELISA. This is the first report on production of a cocktail of PAb to recombinant fusion protein of two or three distinct viruses. PMID- 24161815 TI - Evaluation of a rabies ELISA as an alternative method to seroneutralisation tests in the context of international trade of domestic carnivores. AB - For several years, international movements with pets have greatly increased. Most countries have relaxed their quarantine measures and adopted a scheme combining vaccination of pets against rabies followed by a serological test to check the efficacy of vaccination. This new scheme has been strongly supported by the OIE, WHO and the European Commission to facilitate the free movement of people and pets around the world. Currently, only two reference methods are recognised and prescribed (the FAVN test and the RFFIT) to measure rabies antibody levels in serum samples for international trade. They are reliable and valuable methods of assessing the efficacy of rabies vaccination but they are time-consuming and require well-trained people and specialised laboratory facilities. A few years ago, an ELISA (PlateliaTM Rabies II kit ad usum Veterinarium) was developed for domestic carnivores and wildlife. To our knowledge, this ELISA is the only one certified and prescribed by the OIE. Following its marketing, one task of the EURL for rabies serology was to evaluate the performance of laboratories using this new kit. The results revealed that 26% of the participants, which were already approved laboratories for rabies serology, failed the inter-laboratory trial. Such unsatisfactory results have never been observed during any of the previous proficiency tests organised annually since 2000 by the EURL for rabies serology using reference methods. More investigations were undertaken through internal and collaborative studies to assess the performance of this newly marketed ELISA kit. The results of the internal study revealed that even with a specificity of 100%, the sensitivity evaluated on 593 samples of domestic carnivores came to 78.2%. An issue regarding the underestimation of serum titres was also revealed during the study. The results of a collaborative study involving 23 international laboratories reinforced the preliminary conclusions regarding lack of sensitivity. Indeed, only 5 laboratories out of the 23 obtained satisfactory results. We therefore suggest adopting a threshold of 0.3 EU/mL instead of 0.5 EU/mL to increase the sensitivity of the test. PMID- 24161816 TI - Comparison of a commercial dengue IgM capture ELISA with dengue antigen focus reduction microneutralization test and the Centers for Disease Control dengue IgM capture-ELISA. AB - Dengue (DENV) infection is caused by an arbovirus that is a member of the family Flaviviridae, genus Flavivirus. The diagnosis of acute dengue infection using clinical signs and symptoms can be difficult since the manifestations cannot be readily differentiated from other infections. Therefore the diagnosis of acute dengue infection depends upon laboratory assays. Dengue virus ELISAs have been designed for the detection of IgM and IgG antibodies in addition to nonstructural 1 (NS1) antigens. The InBios IgM Dengue ELISA was compared to the Antigen Focus Reduction Microneutralization Test (FRMUNT90) and Centers for Disease Control Dengue IgM Capture-ELISA (CDC MAC-ELISA). The calculated sensitivity, specificity and agreement of the InBios ELISA compared to FRMUNT90 and CDC MAC-ELISA was 88.7% (C.I. 81.4-93.7), 93.1% (C.I. 89.1-95.8) and 91.5% (C.I. 86.3-95.0), respectively. In summary the InBios IgM Dengue ELISA sensitivity and specificity is comparable to other commercially available IgM Capture-ELISAs. PMID- 24161817 TI - Biochemical alterations induced by oral subchronic exposure to fipronil, fluoride and their combination in buffalo calves. AB - The effects of various pesticides and minerals on biochemical parameters have been explored in different species, but hardly any data exist regarding the combined toxicological effect of pesticides and minerals on these parameters in animals. The present study investigated the effects of fipronil and fluoride co exposure on biochemical parameters in buffalo calves. Twenty-four healthy male buffalo calves divided into four groups were treated for 98 consecutive days. Group I, receiving no treatment served as the control. Animals of groups II and III were orally administered with fipronil @ 0.5mg/kg/day and sodium fluoride (NaF) @ 6.67 mg/kg/day, respectively, for 98 days. An additional group IV was co administered fipronil and NaF at the same dosages as groups II and III. Administration of fipronil alone produced mild toxic signs, significant elevation in plasma proteins, blood glucose, blood urea nitrogen (BUN) and significant decline in the plasma cholesterol levels. NaF exposure produced toxic signs specifically of muscle weakness and brown and black discoloration of teeth. Significant elevation was seen in whole blood cholinesterase, BUN and creatinine levels. However, it produced significant decline in blood glucose, cholesterol and plasma protein levels. Combined exposure to fipronil and sodium fluoride produced toxic signs with greater intensity while biochemical alterations produced were similar to those that were produced by their individual exposures. PMID- 24161818 TI - Tissue-specific bioconcentration of the synthetic steroid hormone medroxyprogesterone acetate in the common carp (Cyprinus carpio). AB - The steroid hormone medroxyprogesterone acetate (MPA), commonly used in oral and injectable contraceptives, has been detected in surface and wastewaters near urban and agricultural areas in several rivers of the world. The objectives of this study were to examine the accumulative potential and tissue distribution of MPA in fish. A freshwater species, the common carp (Cyprinus carpio), was exposed to 100 MUg/L of MPA for a 7-day period followed by a depuration phase in which fish were maintained in dechlorinated tap water for an additional 7 days. Tissues (muscle, brain, plasma, and liver) were sampled during the uptake (days 1, 3, and 7) and depuration (day 14) phases of the experiment. Tissue-specific bioconcentration factors (BCF) ranged from 4.3 to 37.8 and uptake was greatest in the liver>brain>plasma and lowest in the muscle. From a regulatory standpoint, MPA shows little tendency to bioaccumulate in fish. PMID- 24161819 TI - Reconsidering the effects of tannin on seed dispersal by rodents: evidence from enclosure and field experiments with artificial seeds. AB - The question of how tannin affects feeding and hoarding preferences of rodents still remains poorly understood, in part, because it is difficult to control for other seed traits when considering the sole effect of tannin. Here, we constructed a series of artificial 'seeds' with different tannin levels, made from wheat flour, peanut powder and hydrolysable tannins, to determine the direct effects of tannin on both feeding and hoarding preferences. We first presented 'seeds' to individual rodents of two species (Tamias sibiricus and Apodemus peninsulae) confined in semi-natural enclosures and then monitored patterns of seed dispersal and consumption by free-ranging animals in a temperate forest in the Xiaoxing'an Mountains, Heilongjiang Province of China. Our results showed that small rodents displayed a significant preference for low-tannin 'seeds' for both consumption and caching in both captive and field experiments. Moreover, our two-year study consistently showed that tannin concentration was significantly and negatively correlated with the number of cached 'seeds' at both the individual and population levels. Seed size, compared with tannin concentrations, appeared to have little effect on dispersal distances and the number of 'seeds' cached. Low-tannin 'seeds' tended to be dispersed greater distances by rodents in the field than those with higher levels of tannin. These results failed to support those of previous reports indicating that acorns containing higher tannins are more likely to be cached by food hoarding animals. PMID- 24161821 TI - The first tissue-engineered airway transplantation: 5-year follow-up results. AB - BACKGROUND: In 2008, the first transplantation of a tissue-engineered trachea in a human being was done to replace an end-staged left main bronchus with malacia in a 30-year-old woman. We report 5 year follow-up results. METHODS: The patient was followed up approximately every 3 months with multidetector CT scan and bronchoscopic assessment. We obtained mucosal biopsy samples every 6 months for histological, immunohistochemical, and electron microscopy assessment. We also assessed quality of life, respiratory function, cough reflex test, and production and specificity of recipient antibodies against donor human leucocyte antigen. FINDINGS: By 12 months after transplantation, a progressive cicatricial stenosis had developed in the native trachea close to the tissue-engineered trachea anastomosis, which needed repeated endoluminal stenting. However, the tissue engineered trachea itself remained open over its entire length, well vascularised, completely re-cellularised with respiratory epithelium, and had normal ciliary function and mucus clearance. Lung function and cough reflex were normal. No stem-cell-related teratoma formed and no anti-donor antibodies developed. Aside from intermittent bronchoscopic interventions, the patient had a normal social and working life. INTERPRETATION: These clinical results provide evidence that a tissue-engineering strategy including decellularisation of a human trachea, autologous epithelial and stem-cell culture and differentiation, and cell-scaffold seeding with a bioreactor is safe and promising. FUNDING: European Commission, Knut and Alice Wallenberg Foundation, Swedish Research Council, ALF Medicine. PMID- 24161822 TI - The end of the beginning for tissue engineering. PMID- 24161823 TI - Stem-cell transplantation for chronic granulomatous disease. PMID- 24161820 TI - Reduced-intensity conditioning and HLA-matched haemopoietic stem-cell transplantation in patients with chronic granulomatous disease: a prospective multicentre study. AB - BACKGROUND: In chronic granulomatous disease allogeneic haemopoietic stem-cell transplantation (HSCT) in adolescents and young adults and patients with high risk disease is complicated by graft-failure, graft-versus-host disease (GVHD), and transplant-related mortality. We examined the effect of a reduced-intensity conditioning regimen designed to enhance myeloid engraftment and reduce organ toxicity in these patients. METHODS: This prospective study was done at 16 centres in ten countries worldwide. Patients aged 0-40 years with chronic granulomatous disease were assessed and enrolled at the discretion of individual centres. Reduced-intensity conditioning consisted of high-dose fludarabine (30 mg/m(2) [infants <9 kg 1.2 mg/kg]; one dose per day on days -8 to -3), serotherapy (anti-thymocyte globulin [10 mg/kg, one dose per day on days -4 to 1; or thymoglobuline 2.5 mg/kg, one dose per day on days -5 to -3]; or low-dose alemtuzumab [<1 mg/kg on days -8 to -6]), and low-dose (50-72% of myeloablative dose) or targeted busulfan administration (recommended cumulative area under the curve: 45-65 mg/L * h). Busulfan was administered mainly intravenously and exceptionally orally from days -5 to -3. Intravenous busulfan was dosed according to weight-based recommendations and was administered in most centres (ten) twice daily over 4 h. Unmanipulated bone marrow or peripheral blood stem cells from HLA matched related-donors or HLA-9/10 or HLA-10/10 matched unrelated-donors were infused. The primary endpoints were overall survival and event-free survival (EFS), probabilities of overall survival and EFS at 2 years, incidence of acute and chronic GVHD, achievement of at least 90% myeloid donor chimerism, and incidence of graft failure after at least 6 months of follow-up. FINDINGS: 56 patients (median age 12.7 years; IQR 6.8-17.3) with chronic granulomatous disease were enrolled from June 15, 2003, to Dec 15, 2012. 42 patients (75%) had high risk features (ie, intractable infections and autoinflammation), 25 (45%) were adolescents and young adults (age 14-39 years). 21 HLA-matched related-donor and 35 HLA-matched unrelated-donor transplants were done. Median time to engraftment was 19 days (IQR 16-22) for neutrophils and 21 days (IQR 16-25) for platelets. At median follow-up of 21 months (IQR 13-35) overall survival was 93% (52 of 56) and EFS was 89% (50 of 56). The 2-year probability of overall survival was 96% (95% CI 86.46-99.09) and of EFS was 91% (79.78-96.17). Graft-failure occurred in 5% (three of 56) of patients. The cumulative incidence of acute GVHD of grade III-IV was 4% (two of 56) and of chronic graft-versus-host disease was 7% (four of 56). Stable (>=90%) myeloid donor chimerism was documented in 52 (93%) surviving patients. INTERPRETATION: This reduced-intensity conditioning regimen is safe and efficacious in high-risk patients with chronic granulomatous disease. FUNDING: None. PMID- 24161824 TI - Prolyl carboxypeptidase mRNA expression in the mouse brain. AB - Prolyl carboxypeptidase (PRCP), a serine protease, is widely expressed in the body including liver, lung, kidney and brain, with a variety of known substrates such as plasma prekallikrein, bradykinin, angiotensins II and III, and alpha-MSH, suggesting its role in the processing of tissue-specific substrates. In the brain, PRCP has been shown to inactivate hypothalamic alpha-MSH, thus modulating melanocortin signaling in the control of energy metabolism. While its expression pattern has been reported in the hypothalamus, little is known on the distribution of PRCP throughout the mouse brain. This study was undertaken to determine PRCP expression in the mouse brain. Radioactive in situ hybridization was performed to determine endogenous PRCP mRNA expression. In addition, using a gene-trap mouse model for PRCP deletion, X-gal staining was performed to further determine PRCP distribution. Results from both approaches showed that PRCP gene is broadly expressed in the brain. PMID- 24161825 TI - Leptin enhances the invasive ability of glioma stem-like cells depending on leptin receptor expression. AB - Glioma stem-like cells have been demonstrated to have highly invasive activity, which is the major cause of glioma recurrence after therapy. Leptin plays a role in glioma invasion, however, whether and how leptin contributes to the biological properties of glioma stem-like cells, such as invasion, remains to be explored. In the current study, we aimed to explore the role of leptin during glioma stem like cells invasion as well as the signaling pathway. We found that glioma stem like cells exhibited high invasive potential, especially in the presence of leptin, Ob-R coexpressed with CD133 in glioma stem-like cells was showed to be responsible for leptin mediated invasion of glioma stem-like cells. Our results indicated that leptin served as a key intermediary linking the accumulation of excess adipokine to the invasion of glioma stem-like cells, which may be a novel therapeutic target for suppressing tumor invasion and recurrence. PMID- 24161826 TI - Features and timing of the response of single neurons to novelty in the substantia nigra. AB - Substantia nigra neurons are known to play a key role in normal cognitive processes and disease states. While animal models and neuroimaging studies link dopamine neurons to novelty detection, this has not been demonstrated electrophysiologically in humans. We used single neuron extracellular recordings in awake human subjects undergoing surgery for Parkinson disease to characterize the features and timing of this response in the substantia nigra. We recorded 49 neurons in the substantia nigra. Using an auditory oddball task, we showed that they fired more rapidly following novel sounds than repetitive tones. The response was biphasic with peaks at approximately 250 ms, comparable to that described in primate studies, and a second peak at 500 ms. This response was primarily driven by slower firing neurons as firing rate was inversely correlated to novelty response. Our data provide human validation of the purported role of dopamine neurons in novelty detection and suggest modifications to proposed models of novelty detection circuitry. PMID- 24161827 TI - Multiple effects of copper on NMDA receptor currents. AB - Copper (Cu) is an essential metal present in the human brain and released from synaptic vesicles following neuronal depolarization. Cu is known to reduce the NMDA receptor (NR) current with IC50~20 uM. We have studied the effect of Cu on the NR current in cultured neonatal rat cerebellum granule cells (CGC) and in transiently transfected HEK293 cells (HEK), expressing either GluN1/GLUN2A or GluN1/GluN2B receptors. In CGCs, Cu causes a potentiation of the NR current at concentrations <30 uM (EC50=4.6 uM) and a block at higher concentrations (IC50=24 uM). In Fura2 loaded CGCs, Cu (<=30 uM) caused an increase of NMDA-driven calcium influx. This facilitating effect was prevented by pre-treatment with the reducing agent DTT. Cu also caused an increase of the NR current in GluN1/GluN2A receptors (EC50=2 uM) and a block at higher concentrations (IC50=26 uM). Both facilitation and inhibition were independent of voltage. The effect of Cu was quantitatively similar in GluN1/GluN2B receptors, which were potentiated by 10 uM and inhibited by 100 uM Cu. Potentiation was absent in mutants deleted of their entire amino terminal domain (ATD) of the protein, suggesting an involvement of this region in the interaction. These results indicate that Cu can facilitate the NR current at lower concentrations than those required for blocking it; this effect can have consequences on the activity of the metal at synaptic and extrasynaptic sites. PMID- 24161828 TI - Intrinsic organization of the suprachiasmatic nucleus in the capuchin monkey. AB - The suprachiasmatic nucleus (SCN), which is the main circadian biological clock in mammals, is composed of multiple cells that function individually as independent oscillators to express the self-sustained mRNA and protein rhythms of the so-called clock genes. Knowledge regarding the presence and localization of the proteins and neuroactive substances of the SCN are essential for understanding this nucleus and for its successful manipulation. Although there have been advances in the investigation of the intrinsic organization of the SCN in rodents, little information is available in diurnal species, especially in primates. This study, which explores the pattern of expression and localization of PER2 protein in the SCN of capuchin monkey, evaluates aspects of the circadian system that are common to both primates and rodents. Here, we showed that PER2 protein immunoreactivity is higher during the light phase. Additionally, the complex organization of cells that express vasopressin, vasoactive intestinal polypeptide, neuron-specific nuclear protein, calbindin and calretinin in the SCN, as demonstrated by their immunoreactivity, reveals an intricate network that may be related to the similarities and differences reported between rodents and primates in the literature. PMID- 24161829 TI - Brain potentials to inflected adjectives: beyond storage and decomposition. AB - This study uses event-related brain potentials (ERPs) to investigate the temporal sequencing of structural (grammatical) and lexical (semantic) properties of complex words during language comprehension. Morphologically complex words do not only consist of stems and affixes (e.g., 'feel'+'-s'), but affixes also contain grammatical structure, viz. feature bundles specifying their morpho-syntactic functions (e.g., -s= [3rd person, singular, present tense]). We examined inflected adjectives of German, which consist of an unaltered stem plus a portmanteau affix encoding case, number and gender. The same group of 24 adult native speakers was tested in two cross-modal ERP priming experiments separately studying effects of lexical-semantic relatedness and related affixes. The results of these experiments revealed clearly distinct brain potentials. Prime-target overlap with respect to morpho-syntactic features was associated with a reduced positivity, whereas lexical-level priming led to a reduced negativity. The former was most pronounced between 200 and 300 ms and the latter in a later time window, between 300 and 400 ms. We interpret the reduced early positivity as reflecting ease of grammatical processing effort in case of primed (relative to unprimed) morpho-syntactic features and the reduced negativity as signaling facilitation in lexical retrieval for primed (compared to unprimed) words. Our ERP results indicate that grammatical information becomes available earlier than semantic information providing support for structure-first models of language processing. PMID- 24161830 TI - Filtering and ranking techniques for automated selection of high-quality 16S rRNA gene sequences. AB - StrainInfo has augmented its type strain and species/subspecies passports with a recommendation for a high-quality 16S rRNA gene sequence available from the public sequence databases. These recommendations are generated by an automated pipeline that collects all candidate 16S rRNA gene sequences for a prokaryotic type strain, filters out low-quality sequences and retains a high-quality sequence from the remaining pool. Due to thorough automation, recommendations can be renewed daily using the latest updates of the public sequence databases and the latest species descriptions. We discuss the quality criteria constructed to filter and rank available 16S rRNA gene sequences, and show how a partially ordered set (poset) ranking algorithm can be applied to solve the multi-criteria ranking problem of selecting the best candidate sequence. The proof of concept of the recommender system is validated by comparing the results of automated selection with an expert selection made in the All-Species Living Tree Project. Based on these validation results, the pipeline may reliably be applied for non type strains and developed further for the automated selection of housekeeping genes. PMID- 24161832 TI - A nuclear DNA based phylogeny of endemic sand dune ants of the genus Mycetophylax (Emery, 1913): how morphology is reflected in molecular data. AB - Molecular methods have substantially advanced our knowledge about ant systematics in the past few years. Here, we infer the molecular phylogeny of sand dune ants of the genus Mycetophylax, Emery 1913 (Formicidae: Myrmicinae: Attini) using 730 base pairs of DNA sequences of the two nuclear genes longwave rhodopsin and wingless. Our analyses indicate that Mycetophylax is monophyletic, as suggested by its morphological characters. M. morschi, previously considered a species of Cyphomyrmex due to a scrobe-like impressed area on the head, forms a well supported cluster with the two other species of Mycetophylax, M. conformis and M. simplex. Our analysis yields the first comprehensive phylogeny of Mycetophylax based on molecular data and includes specimens from localities within a wide distributional range as well as all species belonging to the genus following the recent taxonomic revision. PMID- 24161831 TI - Characterization of olfactory receptor neurons for pheromone candidate and plant volatile compounds in the clover root weevil, Sitona lepidus. AB - Antennal olfactory receptor neurons (ORNs) for pheromone and plant volatile compounds were identified and characterized in male and female clover root weevil, Sitona lepidus (Gyllenhal), using the single sensillum recording technique with five pheromone-related compounds, and 40 host and non-host plant volatile compounds. Overall, seven different types of olfactory sensilla containing specialized ORNs were identified in each sex of S. lepidus. Among them, three different types of sensilla in the males and two types in the females housed ORNs specialized for pheromone-related compounds. The ORNs in males were specialized for 4-methyl-3,5-heptanedione or one or more of four stereoisomers of 5-hydroxy-4-methyl-3-heptanone. In contrast, female sensilla did not contain ORNs sensitive to 4-methyl-3,5-heptanedione while they contained ORNs sensitive to and specialized for the stereoisomers of (4S,5S)-5-hydroxy-4-methyl-3-heptanone. In addition to the pheromone-related ORNs, four types of olfactory sensilla contained ORNs responsive to plant volatile compounds in male S. lepidus, and five types in females. Most of the ORNs identified in S. lepidus showed a high degree of specificity to specific volatile compounds although some of the active compounds showed overlapping response spectra in the ORNs across different types of sensilla. The most active plant volatile compounds were the four green leaf volatile compounds, (E)-2-hexenol, (Z)-2-hexenol, (Z)-3-hexenol and (E)-2 hexenal, and isomers of two monoterpenols, (+/-)-linalool and (+/-)-alpha terpineol, all eliciting strong responses from relatively large numbers of ORNs in male and female S. lepidus. Our study indicates that S. lepidus has a set of highly sensitive and selective ORNs for pheromone and plant volatile compounds. Further work is needed to elucidate the behavioral implications of these findings. PMID- 24161833 TI - Synthesis, DNA-binding abilities and anticancer activities of triazole pyrrolo[2,1-c][1,4]benzodiazepines hybrid scaffolds. AB - We synthesized a new series of PBD-hybrid derivatives having tethered triazoles and investigated for their cytotoxicity. The studies indicated that cis-olefin compounds induce higher cytotoxicity with increase in the G1 cell cycle phase compared with the trans-compounds. Quantitative RT-PCR assay indicated that compounds (16a-d) induced G1 phase arrest through down-regulation of cyclin D1 and up-regulation of p21, p27, and p53 mRNA expressions. Compounds 16a-d induced A375 early apoptosis as detected by flow cytometry after double-staining with annexin V and propidium iodide. Moreover, the Western blot analysis showed that A375 treated by compounds (16a-d) resulted in decreased levels of Bcl-2 and Bcl xL, increased levels of Bax and Bad, and caspase/PARP degradation to identify apoptotic cells. PMID- 24161834 TI - The discovery of the benzazepine class of histamine H3 receptor antagonists. AB - This Letter describes the discovery of a novel series of H3 receptor antagonists. The initial medicinal chemistry strategy focused on deconstructing and simplifying an early screening hit which rapidly led to the discovery of a novel series of H3 receptor antagonists based on the benzazepine core. Employing an H3 driven pharmacodynamic model, the series was then further optimised through to a lead compound that showed robust in vivo functional activity and possessed overall excellent developability properties. PMID- 24161835 TI - Polyribosome and ribonucleoprotein complex redistribution of mRNA induced by GnRH involves both EIF2AK3 and MAPK signaling. AB - The neuropeptide gonadotropin-releasing hormone stimulates synthesis and secretion of the glycoprotein gonadotropic hormones and activates the unfolded protein response, which causes a transient reduction of endoplasmic reticulum associated mRNA translation. Hormone-treated cell extracts were fractionated to resolve mRNA in active polyribosomes from mRNA in inactive complexes. Quantitative real-time PCR and expression array analysis were used to determine hormone-induced redistribution of mRNAs between fractions and individual mRNAs were found to be redistributed differentially. Among the affected mRNAs relevant to gonadotropin synthesis, the luteinizing hormone subunit genes Lhb and Cga were enriched in the ribonucleoprotein pool. The MAP kinase phosphatase Dusp1 was enriched in the polyribosome pool. Enrichment of Dusp1 mRNA in the polyribosome pool was independent of the unfolded protein response, sensitive to ERK inhibition, and dependent on the 3'untranslated region. The results show that GnRH exerts translational control to modulate physiologically relevant gene expression through two distinct signaling pathways. PMID- 24161837 TI - Are short-term late-generation antibiotics equivalent to standard penicillin therapy in the resolution of symptoms in acute strep throat in children? PMID- 24161838 TI - Temporization of penetrating abdominal-pelvic trauma with manual external aortic compression: a novel case report. AB - A young civilian man experienced multiple gunshots to the lower abdomen, pelvis, and thigh. These were not amenable to direct compression by a single rescuer. This report outlines the first case in the peer-reviewed literature of manual external aortic compression after severe trauma. This technique successfully temporized external bleeding for more than 10 minutes and restored consciousness to the moribund victim. Subsequently, external bleeding could not be temporized by a second smaller rescuer, or during ambulance transfer. Therefore, we also gained insights about the possible limits of bimanual compression and when alternates, such as pneumatic devices, may be required. Research is needed to test our presumption that successful bimanual compression requires larger-weight rescuers, smaller-weight victims, and a hard surface. It is therefore unclear whether manual external aortic compression is achievable by most rescuers or for most victims. However, it offers an immediate and equipment-free life-sustaining strategy when there are limited alternatives. PMID- 24161839 TI - Identifying emergency-sensitive conditions for the calculation of an emergency care inhospital standardized mortality ratio. AB - STUDY OBJECTIVE: Hospital standardized mortality ratios are used for hospital performance assessment. As a first step to develop a ratio variant sensitive to the outcome of patients admitted from the emergency department (ED), we identified International Classification of Diseases, 10th Revision, Canada diagnosis groups in which high-quality ED care would be expected to reduce inhospital mortality (emergency-sensitive conditions). METHODS: To identify emergency-sensitive conditions, we assembled a multidisciplinary panel of emergency care providers and managers (n=14). Using a modified RAND/University of California, Los Angeles Appropriateness Method, 3 rounds of independent ratings including a teleconference were conducted from May to October 2012. Panelists serially rated diagnosis groups included in the Canadian hospital standardized mortality ratio (n=72) according to the extent ED management influences mortality. RESULTS: The panel rated ED care as potentially reducing patient mortality for 37 diagnosis groups (eg, sepsis) and morbidity for 43 diagnosis groups (eg, atrial fibrillation) and rated timely ED care as critical for 40 diagnosis groups (eg, stroke). Panelists also identified 47 diagnosis groups (eg, asthma) not included in the Canadian hospital standardized mortality ratio in which mortality could potentially be decreased by ED care. CONCLUSION: We identified 37 diagnosis groups representing emergency-sensitive conditions that will enable the calculation of a hospital standardized mortality ratio relevant to emergency care. PMID- 24161836 TI - EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs: 2013 update. AB - In this article, the 2010 European League against Rheumatism (EULAR) recommendations for the management of rheumatoid arthritis (RA) with synthetic and biological disease-modifying antirheumatic drugs (sDMARDs and bDMARDs, respectively) have been updated. The 2013 update has been developed by an international task force, which based its decisions mostly on evidence from three systematic literature reviews (one each on sDMARDs, including glucocorticoids, bDMARDs and safety aspects of DMARD therapy); treatment strategies were also covered by the searches. The evidence presented was discussed and summarised by the experts in the course of a consensus finding and voting process. Levels of evidence and grades of recommendations were derived and levels of agreement (strengths of recommendations) were determined. Fourteen recommendations were developed (instead of 15 in 2010). Some of the 2010 recommendations were deleted, and others were amended or split. The recommendations cover general aspects, such as attainment of remission or low disease activity using a treat-to-target approach, and the need for shared decision-making between rheumatologists and patients. The more specific items relate to starting DMARD therapy using a conventional sDMARD (csDMARD) strategy in combination with glucocorticoids, followed by the addition of a bDMARD or another csDMARD strategy (after stratification by presence or absence of adverse risk factors) if the treatment target is not reached within 6 months (or improvement not seen at 3 months). Tumour necrosis factor inhibitors (adalimumab, certolizumab pegol, etanercept, golimumab, infliximab, biosimilars), abatacept, tocilizumab and, under certain circumstances, rituximab are essentially considered to have similar efficacy and safety. If the first bDMARD strategy fails, any other bDMARD may be used. The recommendations also address tofacitinib as a targeted sDMARD (tsDMARD), which is recommended, where licensed, after use of at least one bDMARD. Biosimilars are also addressed. These recommendations are intended to inform rheumatologists, patients, national rheumatology societies and other stakeholders about EULAR's most recent consensus on the management of RA with sDMARDs, glucocorticoids and bDMARDs. They are based on evidence and expert opinion and intended to improve outcome in patients with RA. PMID- 24161841 TI - Primary arthroscopic synovectomy for pigmented villo-nodular synovitis of the knee: recurrence rate and functional outcomes after a mean follow-up of seven years. AB - BACKGROUND: Pigmented villo-nodular synovitis (PVNS) is an uncommon proliferative condition of the synovial membrane that chiefly affects the knee. Arthroscopic synovectomy may carry lower morbidity rates but higher recurrence rates than open synovectomy. Here, our objective was to evaluate recurrence rates and functional outcomes after primary arthroscopic synovectomy for PVNS of the knee. HYPOTHESIS: Primary arthroscopic synovectomy preserves knee function while producing low recurrence and complication rates. MATERIALS AND METHODS: We retrospectively included consecutive patients with histologically documented PVNS managed with primary arthroscopic synovectomy at two centres between 1998 and 2011. Twenty three patients, 13 men and 10 women with a mean age of 41 +/- 12 years, were reviewed including 16 patients with nodular and 7 with diffuse form of this disease. Patients with localized disease underwent partial synovectomy and those with diffuse disease complete synovectomy followed by chemical synovectomy of any residual lesions. The primary outcome measure was recurrence. Secondary outcome measures were the Tegner-Lysholm and Ogilvie-Harris scores. RESULTS: Follow-up data were obtained after a mean of 7 +/- 4 years in 21 patients (14 with nodular and 7 with diffuse disease), of whom 2 had recurrences, after 2 and 5 years, respectively. At last follow-up, neither patient had any evidence of recurrence. The mean Tegner-Lysholm score was significantly improved (from 68 +/- 10 to 90 +/ 8, P=0.0004) and the mean Ogilvie-Harris score indicated excellent function (11 +/- 1). DISCUSSION: Primary arthroscopic synovectomy ensures satisfactory control of PVNS while preserving knee function. A full recovery remains possible even in patients with diffuse disease. In the event of a recurrence, open synovectomy can be performed. PMID- 24161840 TI - Emergency physicians' perspectives on their use of health information exchange. AB - STUDY OBJECTIVE: We explore what emergency physicians with access to health information exchange have to say about it and strive to better understand the factors affecting their use of it. METHODS: A qualitative study using grounded theory principles was conducted in 4 urban emergency departments that had health information exchange access for 4 years. Data were collected with unstructured interviews from 15 emergency physicians. RESULTS: Emergency physicians reported that a number of factors affected their use of health information exchange, but the most prevalent was that it was not user friendly and disrupted workflow. Five major themes emerged: variations in using health information exchange and its access, influencing clinical decisions, balancing challenges and barriers, recognizing benefits and success factors, and justifying not using health information exchange. The themes supported a theoretical interpretation that the process of using health information exchange is more complex than balancing challenges or barriers against benefits, but also how they justify not using it when making clinical decisions. We found that health information exchange systems need to be transformed to meet the needs of emergency physicians and incorporated into their workflow if it is going to be successful. The emergency physicians also identified needed improvements that would increase the frequency of health information exchange use. CONCLUSION: The emergency physicians reported that health information exchange disrupted their workflow and was less than desirable to use. The health information exchange systems need to adapt to the needs of the end user to be both useful and useable for emergency physicians. PMID- 24161843 TI - Reprint of: In-vitro model systems for the study of human embryo-endometrium interactions. AB - Implantation requires highly orchestrated interactions between the developing embryo and maternal endometrium. The association between abnormal implantation and reproductive failure is evident, both in normal pregnancy and in assisted reproduction patients. Failure of implantation is the pregnancy rate-limiting step in assisted reproduction, but, as yet, empirical interventions have largely failed to address this problem. Better understanding of the mechanisms underlying human embryo-endometrium signalling is a prerequisite for the further improvement of assisted reproduction outcomes and the development of effective interventions to prevent early pregnancy loss. Studying human embryo implantation is challenging since in-vivo experiments are impractical and unethical, and studies in animal models do not always translate well to humans. However, in recent years in-vitro models have been shown to provide a promising way forward. This review discusses the principal models used to study early human embryo development and initial stages of implantation in vitro. While each model has limitations, exploiting these models will improve understanding of the molecular mechanisms and embryo-endometrium cross-talk at the early implantation site. They provide valuable tools to study early embryo development and pathophysiology of reproductive disorders and have revealed novel disease mechanisms such as the role of epigenetic modifications in recurrent miscarriage. PMID- 24161842 TI - ERK1/2 regulates hepatocyte Trib1 in response to mitochondrial dysfunction. AB - The TRIB1 locus (8q24.13) is a novel locus identified and replicated by several genome-wide association studies for associations with plasma triglycerides, apolipoprotein B and coronary artery disease. The TRIB1 protein product, tribbles like protein 1 (Trib1), regulates MAPK activity. MAP kinases transduce a large variety of external signals, leading to a wide range of cellular responses, including growth, differentiation, inflammation and apoptosis. Importantly, Trib1 has been shown to regulate hepatic lipogenesis and very low density lipoprotein production. Despite the relevance of hepatocyte Trib1 to lipid metabolism and atherosclerosis, little is known about the mechanisms regulating Trib1 itself. Here, we identify the mitochondria axis as a regulator of Trib1. Treatment of HepG2 cells with a short pulse of a low oligomycin concentration led to a potent and prolonged increase in the Trib1 mRNA, an effect that was shared with other mitochondria stressors. HuH7 cells as well murine hepatocytes were also responsive albeit to a weaker extent. The upregulation appeared largely independent of reactive oxygen species generation or metabolic stress and was mainly under transcriptional control, with ERK1/2 playing an important regulating role in the process. While the presence of the Trib1 protein could be inferred, attempts to correlate the increased mRNA to changes in protein level were unsuccessful due to the lack of recognizable Trib1 signal. Our data enrich the current paradigm of Trib1 as an activator of the MAPK pathway by uncovering a role for MAPK in regulating Trib1. PMID- 24161844 TI - Vibrational spectra and theoretical calculations (dimerization, UV-Vis, multinuclear NMR and pes analyses) of 3,4-dimethylbenzamide and 3,4,5 trihydroxybenzamide. AB - The FT-IR and FT-Raman spectra of 3,4-dimethyl benzamide (DMBA) and 3,4,5 trihydroxy benzamide (THBA) have been measured in the regions 400-4000 and 50 3500 cm(-1), respectively. Utilizing the observed FT-IR and FT-Raman data, a complete vibrational assignment and analysis of the fundamental modes of the title compounds were carried out. The vibrational frequencies which were determined experimentally are compared with those theoretical frequencies from force field calculation based on B3LYP/6-311++G(d,p) methods. Stability of the compound arising from hyperconjugative interactions and charge delocalization have been analyzed using natural bond orbital analysis. UV-Vis analysis of the title compounds has also been done using TD-DFT method. The (1)H and (13)C nuclear magnetic resonance (NMR) chemical shifts of the compounds were calculated by the gauge independent atomic orbital (GIAO) method and compared with experimental results. HOMO-LUMO and MEP analyses have been done for the title compounds. PMID- 24161845 TI - [Ineffective sexuality pattern in an adolescent: nursing approach in primary health care]. AB - Adolescent is a phase of continual physiological, psychological and social adaptation. It is during this time that young people tend to have their first sexual experiences. Sexual dysfunctions are characterized by important clinical changes in sexual desire and/or by psycho-physiological changes in the sexual response cycle. Premature ejaculation is one of the most frequent sexual dysfunction amongst men, with a higher prevalence in the younger population compared to other populations. The clinical case is presented of a 17 year-old male who experienced difficulties during his sexual relations. It is discussed whether his condition was a sexual dysfunction or ineffective sexual pattern. The care plan which was developed in nursing consultation was described for ineffective sexual pattern; the pending nursing treatment incorporated activities recommended by scientific evidence. Finally, the role of primary health care nursing professionals is pointed out in the detection and approach of sexual problems in adolescents. PMID- 24161846 TI - [Social and organizational innovation to tackle the challenge of integrated care of the chronically ill]. AB - The increase in life expectancy, coupled with other factors, has led to an increase in the prevalence of chronic diseases and multiple morbidity. This has led to the need to develop new health and social care models, which will allow managing these efficiently and in a sustainable manner. In particular, there seems to be consensus on the need to move towards integrated, patient-centered, and more proactive care. Thus, in recent years, chronic care models have been developed at international, national and regional level, as well as introducing strategies to tackle the challenge of chronic illness. However, the implementation of actions facilitating the change towards this new model of care does not seem to be an easy task. This paper presents some of the strategic lines and initiatives carried out by the Department of Health of the Basque Government. These actions can be described within a social and organizational innovation framework, as a means for effective implementation of interventions and strategies that shape the model required for the improved care of chronic illnesses within a universal and tax-funded health system. PMID- 24161847 TI - A combined DTI and structural MRI study in medicated-naive chronic schizophrenia. AB - Disconnection in white matter (WM) pathway and alterations in gray matter (GM) structure have been hypothesized as pathogenesis in schizophrenia. However, the relationship between the abnormal WM integrity and the alteration of GM in anatomically connected areas remains uncertain. Moreover, the potential influence of antipsychotic medication on WM anisotropy and cortical morphology was not excluded in previous studies. In this study, a total number of 34 subjects were enrolled, including 17 medicated-naive chronic schizophrenia patients and 17 healthy controls. Tract-based spatial statistics (TBSS) were applied to investigate the level of WM integrity. The FreeSurfer surface-based analysis was used to determine GM volume, cortical thickness and the surface area of GM regions which corresponded to abnormal WM fiber tracts. We observed that patients possessed lower fractional anisotropy (FA) values in the left inferior fronto occipital fasciculus (IFOF) and left inferior longitudinal fasciculus (ILF), along with smaller GM volume and cortical thinning in temporal lobe than the healthy controls, which reflected the underlying WM and GM disruption that contributed to the disease. In the patient population, the lower connectivity of ILF and IFOF was positively associated with cortical thickness in left lateral orbitofrontal cortex, superior temporal gyrus and lingual gyrus in males, and positively correlated with GM volume in left lateral orbitofrontal cortex in females. On the other hand, it was negatively correlated with cortical area of middle temporal gyrus in males and temporal pole in females respectively, but not when genders were combined. These findings suggested that abnormal WM integrity and anatomical correspondence of GM alterations in schizophrenia were interdependent on gender-separated analysis in patients with schizophrenia. Moreover, combining TBSS and FreeSurfer might be a useful method to provide significant insight into interacting processes related to WM fiber tracts and GM changes in schizophrenia. PMID- 24161848 TI - Regulation of cell polarity in the cartilage growth plate and perichondrium of metacarpal elements by HOXD13 and WNT5A. AB - The morphology of bones is genetically determined, but the molecular mechanisms that control shape, size and the overall gestalt of bones remain unclear. We previously showed that metacarpals in the synpolydactyly homolog (spdh) mouse, which carries a mutation in Hoxd13 similar to the human condition synpolydactyly (SPD), were transformed to carpal-like bones with cuboid shape that lack cortical bone and a perichondrium and are surrounded by a joint surface. Here we provide evidence that spdh metacarpal growth plates have a defect in cell polarization with a random instead of linear orientation. In parallel prospective perichondral cells failed to adopt the characteristic flattened cell shape. We observed a similar cell polarity defect in metacarpals of Wnt5a(-/-) mice. Wnt5a and the closely related Wnt5b were downregulated in spdh handplates, and HOXD13 induced expression of both genes in vitro. Concomitant we observed mislocalization of core planar cell polarity (PCP) components DVL2 and PRICKLE1 in spdh metacarpals indicating a defect in the WNT/PCP pathway. Conversely the WNT/beta-CATENIN pathway, a hallmark of joint cells lining carpal bones, was upregulated in the perichondral region. Finally, providing spdh limb explant cultures with cells expressing either HOXD13 or WNT5A led to a non-cell autonomous partial rescue of cell polarity the perichondral region and restored the expression of perichondral markers. This study provides a so far unrecognized link between HOX proteins and cell polarity in the perichondrium and the growth plate, a failure of which leads to transformation of metacarpals to carpal-like structures. PMID- 24161849 TI - Zebrafish Dynamin is required for maintenance of enveloping layer integrity and the progression of epiboly. AB - Epiboly, the first morphogenetic cell movement that occurs in the zebrafish embryo, is the process by which the blastoderm thins and spreads to engulf the yolk cell. This process requires the concerted actions of the deep cells, the enveloping layer (EVL) and the extra-embryonic yolk syncytial layer (YSL). The EVL is mechanically coupled to the YSL which acts as an epiboly motor, generating the force necessary to draw the blastoderm towards the vegetal pole though actomyosin flow and contraction of the actomyosin ring. However, it has been proposed that the endocytic removal of yolk cell membrane just ahead of the advancing blastoderm may also play a role. To assess the contribution of yolk cell endocytosis in driving epiboly movements, we used a combination of drug- and dominant-negative-based approaches to inhibit Dynamin, a large GTPase with a well characterized role in vesicle scission. We show that Dynamin-dependent endocytosis in the yolk cell is dispensable for epiboly of the blastoderm. However, global inhibition of Dynamin function revealed that Dynamin plays a fundamental role within the blastoderm during epiboly, where it maintains epithelial integrity and the transmission of tension across the EVL. The epithelial defects were associated with disrupted tight junctions and a striking reduction of cortically localized phosphorylated ezrin/radixin/moesin (P-ERM), key regulators of epithelial integrity in other systems. Furthermore, we show that Dynamin maintains EVL and promotes epiboly progression by antagonizing Rho A activity. PMID- 24161850 TI - Lasing the DNA fragments through beta-diketimine framed Knoevenagel condensed Cu(II) and Zn(II) complexes--an in vitro and in vivo approach. AB - The syntheses, structures and spectroscopic properties of Cu(II) and Zn(II) complexes having Knoevenagel condensate beta-diketimine Schiff base ligands have been investigated in this paper. Characterization of these complexes was carried out using FTIR, NMR, UV-Vis, elemental analysis, mass and EPR techniques. Absorption titration, electrochemical analyses and viscosity measurements have also been carried out to determine the mode of binding. The shift in DeltaEp, E1/2 and Ipc values explores the interaction of CT DNA with the above metal complexes. Interaction of ligands and their complexes with DNA revealed an intercalative mode of binding between them. Antimicrobial studies showed an effective antimicrobial activity of the metal ions after coordination with the ligands. The antioxidant properties of the Schiff base ligands and their complexes were evaluated in a series of in vitro tests by using 1,1-diphenyl-2 picrylhydrazyl (DPPH) and H2O2 free radical scavengers. In vivo and in vitro antitumor functions of the complexes against Ehrlich ascites carcinoma tumor model have also been investigated. All the results support that beta-diketone derived Knoevenagel condensate Schiff base complexes may act as novel antitumor drugs and suggest that their potent cell life inhibition may contribute to their anti-cancer efficacy. PMID- 24161851 TI - A highly selective quinoline-based fluorescent sensor for Zn(II). AB - A quinoline-based simple receptor (bis(2-quinolinylmethyl)benzylamine = 1) as a Zn(2+) selective fluorescent chemosensor showed a large fluorescent enhancement with a blue shift in the presence of Zn(2+) which is attributed to a chelation enhanced fluorescence (CHEF) effect with inhibition of a photoinduced electron transfer (PET) process of 1. In particular, this receptor could clearly distinguish Zn(2+) from Cd(2+). The binding mode of 1 and Zn(2+) was found to be a 1:1 and confirmed by Job plot, (1)H NMR titration and ESI-mass spectrometry analysis. PMID- 24161852 TI - A phosphorescent rhenium emitter with minimal fluorescent component induced by heavy atom: synthetic procedure, molecular structure, photophysical feature and optoelectronic application. AB - In this paper, a Br-containing diamine ligand of 2-(4-bromophenyl)-5-(pyridin-2 yl)-1,3,4-oxadiazole (referred to as BrPO) and its corresponding Re(I) complex of Re(CO)3(BrPO)Br are synthesized and studied in detail, including molecular structure, photophysical feature, thermal stability and electrochemical property. Experimental data suggest that Re(CO)3(BrPO)Br takes a octahedral coordination environment, and the pi-pi attraction between BrPO ligands makes complex molecules take a highly-ordered arrangement. Re(CO)3(BrPO)Br is found to be a yellow emitter peaking at 565 nm with emission yield of 0.11 and excited state lifetime of 4.21 MUs. The emission comes from triplet excited state of ML&LLCT, where ML&LLCT means metal-to-ligand-charge-transfer and ligand-to-ligand-charge transfer as suggested by theoretical calculation. The fluorescent component in the emissive center is minimized by the heavy-atom turbulence effect. Re(CO)3(BrPO)Br owns a high thermal decomposition of 280 degrees C, with HOMO of 5.45eV and LUMO of -3.12 eV. The optimal electroluminescent device using Re(CO)3(BrPO)Br as the emitting dopant gives a maximum brightness of 5906 cd/m(2) and a maximum current efficiency of 5.6 cd/A. PMID- 24161853 TI - Study on the interaction between histidine-capped Au nanoclusters and bovine serum albumin with spectroscopic techniques. AB - The understanding of the protein-nanoclusters interaction has significant implications for biological applications of nanoclusters (NCs). In this manuscript, the interaction of histidine-capped Au nanoclusters (NCs) with bovine serum albumin (BSA) has been investigated by fluorescence, UV-vis, circular dichroism (CD) and Raman spectroscopic techniques under simulative physiological conditions. The results showed that the fluorescence of BSA was quenched by Au NCs. The quenching mechanism was discussed to be a dynamic quenching style, which was proved by the fluorescence spectra and UV-vis absorption spectra. According to modified Stern-Volmer equations at different temperatures, corresponding thermodynamic parameters, DeltaH(theta), DeltaS(theta) and DeltaG(theta) were observed to be 35.97 kJ mol(-1), 199.53 J mol(-1) K(-1) and -23.49 kJ mol(-1), respectively. The hydrophobic force played a key role in the interaction process. Further results from the CD spectra and Raman spectra demonstrated that the alpha helical content in BSA was reduced upon interaction with Au NCs which induced a partial protein destabilization. This study contributes to a better understanding of the biology toxicity of Au NCs to biomolecular, which is very essential for the development of safe and functional Au NCs. PMID- 24161854 TI - The example of calix[4]pyrrole derivative containing Bodipy unit: fluorometric and colorimetric sensor for F- ion. AB - A novel chemosensor based on calix[4]pyrrole derivative modified by Bodipy unit has been synthesized, and its complexes with various anions were investigated. The results show that the receptors can selectively recognize biologically important fluoride ions. The binding affinity for fluoride ions was investigated by naked-eye color change, absorption, emission, proton nuclear magnetic resonance spectroscopy. The addition of fluoride ions to an acetonitrile solution of chemosensor can result in an obvious color change (brownish yellow color to straw yellow). The stoichiometries between the receptor and fluoride were determined from the molar ratio plots using the UV-visible spectra, which showed evident 1:1. The proton nuclear magnetic resonance spectral data supported the fluoride anion recognition with the disappearance of the amino proton peaks. PMID- 24161855 TI - "Naked-eye" colorimetric and "turn-on" fluorometric chemosensors for reversible Hg2+ detection. AB - Two new Hg(2+)-colorimetric and fluorescent sensors based on 2-[3-(2 aminoethylsulfanyl) propylsulfanyl]ethanamine covalently bound to one and two units of rhodamine-6G moieties, 1 and 2, were synthesised, and their sensing behaviors toward metal ions were investigated by UV/Vis and fluorescence spectroscopy. Upon the addition of Hg(2+), the sensors exhibited highly sensitive "turn-on" fluorescence enhancement as well as a color change from colorless to pink, which was readily noticeable for naked eye detection. Especially, 1 exhibited the reversible behavior and revealed a very high selectivity in the presence of competitive ions, particularly Cu(2+), Ag(+), Pb(2+), Ca(2+), Cd(2+), Co(2+), Fe(2+), Mn(2+), Na(+), Ni(2+), K(+), Ba(2+), Li(+) and Zn(2+), with a low detection limit of 1.7 ppb toward Hg(2+). PMID- 24161856 TI - A proline-based aminophenol ligand: synthesis, iron complexation, magnetic, electronic and redox investigation. AB - A new proline-based aminophenol ligand was synthesized by a convenient procedure. The ligand was characterized by (1)H NMR, (13)C NMR and IR spectroscopies, elemental analysis and optical activity measurements. Mononuclear iron(III) complex (FeL(Pro)) of this ligand was synthesized and characterized by IR, UV vis, ESI-MS, magnetic susceptibility studies and cyclic voltammetry techniques. The equilibrium formation constant of FeL(Pro) and the pure UV-vis spectral profile of the complex was determined by multivariate hard modeling method. The molecular structure of FeL(Pro) determined by ESI-MS consist of two aminophenolate ligands. The variation of magnetic susceptibility with temperature indicates paramagnetic iron(III) in the monomeric complex. FeL(Pro) complex undergo metal-centered reduction, and ligand-centered oxidation. PMID- 24161857 TI - A novel solid fluorescence method for the fast determination of quercetin in biological samples based on the quercetin-Al(III) complex imprinted polymer. AB - In this work, a novel solid fluorescence method was proposed and applied to the fast determination of quercetin in urine and onion skin samples by using metal coordination imprinted polymer membrane, which was regarded as a recognition element. The quercetin-Al(III) imprinted polymer was immobilized in the microporous polypropylene fiber membrane via consecutive in situ polymerization. The CIP membrane had the porous, loose and layer upon layer structure. The CIP membrane was characterized by electron microscope photographs, infrared spectra, thermogravimetric analysis and solvent-resistant investigation. The extraction conditions including extraction solvent, extraction time, desorption solvent were optimized. Compared with MIP and NIP membrane, CIP membrane had been proved to be peculiar selective for quercetin even in presence of the structurally similar compounds such as kaempferol, rutin, naringenin and alpinetin. The CIP membrane was characteristic of high selectivity, stable and sensitive response to quercetin in polar environment. Under the optimum condition, there was a linear relationship between the state fluorescent response and the concentration of quercetin. The linear calibration range was over 0.02 mg L(-1)-0.80 mg L(-1) with a detection limit of 5 MUg L(-1). The method was characteristic of flexible and good repeatability with relative standard deviation (RSD) of 4.1%. The proposed method was also successfully applied for the determination of quercetin in urine and onion skin samples without complicated pretreatment. The recoveries were 84.0 112.4% and RSDs varied from 1.5% to 6.8%. The results obtained by the proposed method agreed well with those obtained by HPLC method. PMID- 24161858 TI - Performance of fruit extract of Melastoma malabathricum L. as sensitizer in DSSCs. AB - Dye-sensitized solar cells (DSSCs) with fruit extracts, of Melastoma malabathricum L. as sensitizer, were fabricated. The fruit dye was extracted in two different solvents; de-ionized water (MMD) and ethanol (MME). The dye was subjected to UV-Vis and DSC studies. UV-Vis studies show absorption of light for a wider range of wavelength for MMD as compared to MME. Both MMD and MME were found to be stable till 121 degrees C, as shown by DSC studies, beyond which MME showed unstable behavior. FTIR spectra of MMD and MME along with dye adsorbed TiO2 were recorded. MMD showed better adsorption with TiO2 than with MME. Voc, Jsc and efficiencies of the MMD sensitized solar cells were obtained in the ranges 420-430 mV, 1.25-1.50 mA cm(-2) and 1.11-1.37% respectively, while for MME sensitized solar cells they were in the ranges 370-380 mV, 0.63-0.87 mA cm(-2) and 0.41-0.72% respectively. Preliminary investigation on stability of DSSCs which were fabricated using both the extracts revealed sharp drop in efficiency of DSSC with MME in comparison to DSSC with MMD as sensitizer. PMID- 24161859 TI - Spectroscopic investigation and optical characterization of Eu3+ ions in K-Nb-Si glasses. AB - This paper reports on the effect of concentration of Eu(3+) ions in K2O-Nb2O5 SiO2-Eu2O3 (KNbSiEu) glasses prepared by the melt quenching technique. By using the Judd-Ofelt (JO) theory, the intensity parameters Omegalambda (lambda=2, 4, 6) have been determined from the absorption and emission spectra of Eu(3+) ions under different constraints. The radiative properties of some of the excited states of Eu(3+) ions have been calculated. The decay curves of (5)D0 level exhibited single exponential for all the Eu(3+) ions concentrations. From these results, it is suggested that the strong red emission at 616 nm corresponding to the (5)D0->(7)F2 transition could be used for the development of optical display devices. PMID- 24161860 TI - Fluorescence enhancement of europium(III) perchlorate by benzoic acid on bis(benzylsulfinyl)methane complex and its binding characteristics with the bovine serum albumin (BSA). AB - A novel ligand with double sulfinyl groups, bis(benzylsulfinyl)methane L, was synthesized by a new method. Its novel ternary complex, EuL2.5?L'.(ClO4)2?5H2O, has been synthesized [using L as the first ligand, and benzoic acid L' as the second ligand], and characterized by elemental analysis, molar conductivity, coordination titration analysis, FTIR, TG-DSC, (1)H NMR and UV-vis. In order to study the effect of the second ligand on the fluorescence properties of rare earth sulfoxide complex, a novel binary complex EuL2.5.(ClO4)3.3H2O has been synthesized. Photoluminescent measurement showed that the first ligand L could efficiently transfer the energy to Eu(3+) ions in the complex. Furthermore, the detailed luminescence analyses on the rare earth complexes indicated that the ternary Eu (III) complex manifested stronger fluorescence intensities, longer lifetimes, and higher fluorescence quantum efficiencies than the binary Eu (III) materials. After introducing the second ligand L', the fluorescence emission intensities and fluorescence lifetimes of the ternary complex enhanced more obviously than the binary complex. This illustrated that the presence of both the first ligand L and the second ligand L' could sensitize fluorescence intensities of Eu (III) ions. The fluorescence spectra, fluorescence lifetime and phosphorescence spectra were also discussed. To explore the potential biological value of Eu (III) complexes, the binding interaction among Eu (III) complexes and bovine serum albumin (BSA) was studied by fluorescence spectrum. The result indicated that the reaction between Eu (III) complexes and BSA was a static quenching procedure. The binding site number, n, of 0.60 and 0.78, and binding constant, Ka, of 0.499 and 4.46 were calculated according to the double logarithm regression equation, respectively for EuL2.5?L'?(ClO4)2?5H2O and EuL2.5?(ClO4)3?3H2O systems. PMID- 24161861 TI - Rapid approach to analyze biochemical variation in rat organs by ATR FTIR spectroscopy. AB - ATR FTIR spectra were collected from rat tissue homogenates (myocardium, brain, liver, lung, intestine, and kidney) to analyze their biochemical content. Based on the second derivative of an average spectral profile it was possible to assign bands e.g. to triglycerides and cholesterol esters, proteins, phosphate macromolecules (DNA, RNA, phospholipids, phosphorylated proteins) and others (glycogen, lactate). Peaks in the region of 1600-1700 cm(-1) related to amide I mode revealed the secondary structure of proteins. The collected spectra do not characterize morphological structure of the investigated tissues but show their different composition. The comparison of spectral information gathered from FTIR spectra of the homogenates and those obtained previously from FTIR imaging of the tissue sections implicates that the presented here approach can be successfully employed in the investigations of biochemical variation in animal tissues. Moreover, it can be used in the pharmacological and pharmacokinetic studies to correlate the overall biochemical status of the tissue with the pathological changes it has undergone. PMID- 24161862 TI - A vibrational spectroscopic study of the silicate mineral ardennite-(As). AB - We have used a combination of scanning electron microscopy with EDX and vibrational spectroscopy to study the mineral ardennite-(As). The mineral ardennite-(As) of accepted formula Mn4(2+)(Al,Mg)6(Si3O10)(SiO4)2(AsO4,VO4)(OH)6 is a silicate mineral which may contain arsenate and/or vanadates anions. Because of the oxyanions present, the mineral lends itself to analysis by Raman and infrared spectroscopy. Qualitative chemical analysis shows a homogeneous phase, composed by Si, Mn, Al and As. Ca and V were also observed in partial substitution for Mn and As. Raman bands at 1197, 1225, 1287 and 1394 cm(-1) are assigned to SiO stretching vibrations. The strong Raman bands at 779 and 877 cm( 1) are assigned to the AsO4(3-) antisymmetric and symmetric stretching vibrations. The Raman band at 352 cm(-1) is assigned to the nu2 symmetric bending vibration. The series of Raman bands between 414 and 471 cm(-1)are assigned to the nu4 out of plane bending modes of the AsO4(3-) units. Intense Raman bands observed at 301 and 314 cm(-1) are attributed to the MnO stretching and bending vibrations. Raman bands at 3041, 3149, 3211 and 3298 cm(-1) are attributed to the stretching vibrations of OH units. There is vibrational spectroscopic evidence for the presence of water adsorbed on the ardennite-(As) surfaces. PMID- 24161864 TI - Spectra investigation on surface characteristics of graphene oxide nanosheets treated with tartaric, malic and oxalic acids. AB - The surface characteristics of graphene oxide nanosheets (GO) treated respectively with tartaric acid, malic acid and oxalic acid, have been investigated by mainly using optical spectroscopic methods including Fourier transform infrared spectroscopy (FT-IR), Ultraviolet-visible (UV-Vis) absorption and Raman spectroscopy. Additionally, the electrochemical property of the products has also been studied. The data revealed that oxygen-containing groups such as OH, COOH and CO on the GO surface have been almost removed and thus reduced graphene oxide nanosheets (RGN) were obtained. Interestingly, the number of sp(2) domains of RGN increases as treated by tartaric acid112%). FBN1-positive patients carrying a non missense mutation more often had LV dilatation than missense mutation carriers (14/74 versus 5/75; p<0.05). Finally, FBN1-negative MFS patients significantly more often demonstrated LV dilatation than FBN1-positive patients (10/33 versus 19/149; p<0.05). It is concluded that LV dilatation in MFS patients is more often seen in patients with a non-missense mutation and in those patients without an FBN1 mutation. Therefore physicians should be aware of the possibility of LV dilatation in these patients even in the absence of valvular pathology. PMID- 24161887 TI - Laparoendoscopic single-site radical hysterectomy with pelvic lymphadenectomy: initial multi-institutional experience for treatment of invasive cervical cancer. AB - STUDY OBJECTIVE: To describe the feasibility, safety, and outcomes of women with stage I cervical cancer treated with laparoendoscopic single-site surgery radical hysterectomy (LESS-RH). DESIGN: A retrospective descriptive study (Canadian Task Force classification III). SETTING: Multiple academic teaching hospitals. PATIENTS: Women with Federation Internationale de Gynecologie et d'Obstetrique FIGO stage IA1 to IB1 cervical cancer. INTERVENTIONS: LESS-RH as the primary therapy for cervical cancer performed by a gynecologic oncologist with expertise in LESS. A multichannel, single-port access device; a flexible-tipped 5-mm laparoscope; and a multifunctional instrument were used in all cases. Clinicopathologic, surgical, and perioperative outcomes were analyzed. MEASUREMENTS AND MAIN RESULTS: Twenty-two women were identified in whom a LESS-RH was attempted; 20 (91%) successfully underwent the procedure, including 19 in whom pelvic lymphadenectomy (PLND) was completed. Of the 2 converted procedures, 1 patient underwent 2-port laparoscopy secondary to truncal obesity, and 1 patient underwent conversion to laparotomy secondary to external iliac vein laceration during PLND. The median age and body mass index were 46 years and 23.3 kg/m(2), respectively. The median number of pelvic lymph nodes removed was 22. One patient experienced an intraoperative complication, and no patient required reoperation. The margins of excision were negative. One patient with 2 positive pelvic nodes and 1 patient with microscopic parametrial disease received adjuvant chemosensitized radiation; 3 additional patients received adjuvant radiation therapy secondary to an intermediate risk for recurrence. After a median follow up of 11 months, no recurrences were detected. CONCLUSION: LESS-RH/PLND is feasible and safe for select patients with stage I cervical cancer. Larger studies are needed to confirm whether the increased technical difficulty of this procedure justifies its use in routine gynecologic oncology practice. PMID- 24161888 TI - Fear extinction can be made state-dependent on peripheral epinephrine: role of norepinephrine in the nucleus tractus solitarius. AB - We investigate whether the extinction of inhibitory avoidance (IA) learning can be subjected to endogenous state-dependence with systemic injections of epinephrine (E), and whether endogenous norepinephrine (NE) and the nucleus tractus solitarius (NTS)->locus coeruleus->hippocampus/amygdala (HIPP/BLA) pathway participate in this. Rats trained in IA were submitted to two sessions of extinction 24 h apart: In the first, the animals were submitted to a training session of extinction, and in the second they were tested for the retention of extinction. Saline or E were given i.p. immediately after the extinction training (post-extinction training injections) and/or 6 min before the extinction test (pre-extinction test). Post-extinction training E (50 or 100 MUg/kg) induced a poor retrieval of extinction in the test session of this task unless an additional E injection (50 MUg/kg) was given prior to the extinction test. This suggested state-dependence. Muscimol (0.01 MUg/side) microinfused into the NTS prior to the extinction test session blocked E-induced state-dependence. Norepinephrine (NE, 1 MUg/side) infused bilaterally into NTS restores the extinction impairment caused by post-extinction training i.p. E. In animals with bilateral NTS blockade induced by muscimol, NE (1 MUg/side) given prior to the extinction test into the CA1 region of the dorsal hippocampus or into the basolateral amygdala restored the normal extinction levels that had been impaired by muscimol. These results suggest a role for the NTS->locus coeruleus->HIPP/BLA pathway in the retrieval of extinction, as it has been shown to have in the consolidation of inhibitory avoidance and of object recognition learning. PMID- 24161883 TI - Genetic variants in selenoprotein P plasma 1 gene (SEPP1) are associated with fasting insulin and first phase insulin response in Hispanics. AB - CONTEXT: Insulin resistance is not fully explained on a molecular level, though several genes and proteins have been tied to this defect. Knockdowns of the SEPP1 gene, which encodes the selenoprotein P (SeP) protein, have been shown to increase insulin sensitivity in mice. SeP is a liver-derived plasma protein and a major supplier of selenium, which is a proposed insulin mimetic and antidiabetic agent. OBJECTIVE: SEPP1 single nucleotide polymorphisms (SNPs) were selected for analysis with glucometabolic measures. PARTICIPANTS AND MEASURES: The study included1424 Hispanics from families in the Insulin Resistance Atherosclerosis Family Study (IRASFS). Additionally, the multi-ethnic Insulin Resistance Atherosclerosis Study was used. A frequently sampled intravenous glucose tolerance test was used to obtain precise measures of acute insulin response (AIR) and the insulin sensitivity index (SI). DESIGN: 21 SEPP1 SNPs (tagging SNPs (n=12) from HapMap, 4 coding variants and 6 SNPs in the promoter region) were genotyped and analyzed for association. RESULTS: Two highly correlated (r(2)=1) SNPs showed association with AIR (rs28919926; Cys368Arg; p=0.0028 and rs146125471; Ile293Met; p=0.0026) while rs16872779 (intronic) was associated with fasting insulin levels (p=0.0097). In the smaller IRAS Hispanic cohort, few of the associations seen in the IRASFS were replicated, but meta-analysis of IRASFS and all 3 IRAS cohorts (N=2446) supported association of rs28919926 and rs146125471 with AIR (p=0.013 and 0.0047, respectively) as well as rs7579 with SI (p=0.047). CONCLUSIONS: Overall, these results in a human sample are consistent with the literature suggesting a role for SEPP1 in insulin resistance. PMID- 24161889 TI - Glycerol rhizotomy via a retrosigmoid approach as an alternative treatment for trigeminal neuralgia. AB - OBJECTIVES: Trigeminal neuralgia is a sensory nerve disorder characterized by lancinating pain and treated most commonly with carbamazepine, rhizotomy treatment, or open surgical management with microvascular decompression. We describe a novel technique to complement surgical treatment for trigeminal neuralgia via direct injection of the trigeminal nerve with glycerin in the cisternal portion of the nerve. PATIENTS AND METHODS: We performed a retrospective analysis of patients who received standard microvascular decompression and injection of glycerin to the inferior third of the cisternal portion of the nerve anterior to the root entry zone with lack of a compressive vessel on MRI as the primary indication. Fourteen patients were identified and demographic information, post-operative course and complications were recorded. RESULTS: There were eleven females and three males with an average age at time of surgery of 54.8 years. 100% of patients reported that their trigeminal pain was significantly improved following surgical intervention. Four out of fourteen patients reported a 50-80% decrease from the pre-surgery baseline pain at one month and three month follow up. One patient developed a CSF leak, and no surgical site infections or motor deficits were observed. CONCLUSION: Intra operative glycerin rhizotomy in conjunction with microvascular decompression can be used to safely treat patients suffering from trigeminal neuralgia. PMID- 24161890 TI - The role of alpha-2 adrenoceptor subtype in the antiallodynic effect of intraplantar dexmedetomidine in a rat spinal nerve ligation model. AB - The purpose of this study was to examine the effects of intraplantar dexmedetomidine to relieve neuropathic pain and determine the role of peripheral alpha2-adrenoceptors. Neuropathic pain was induced by ligating the L5 and L6 spinal nerves in male Sprague-Dawley rats, and mechanical allodynia was assessed using von Frey filaments. Several antagonists were injected into the hindpaws to evaluate the mechanisms of action of dexmedetomidine, a nonselective alpha2 adrenoceptor antagonist yohimbine, an alpha2A-adrenoceptor antagonist BRL 44408, an alpha2B-adrenoceptor antagonist ARC 239, and a alpha2C-adrenoceptor antagonist JP 1302. The expression of alpha2A-adrenoceptor, alpha2B-adrenoceptor, and alpha2C-adrenoceptor genes in the lumbar segment of the spinal cord and the plantar skin of the nerve-injured leg was detected by reverse transcription polymerase chain reaction. Ipsilateral intraplantar injection of dexmedetomidine produced dose-dependent antiallodynia. Ipsilateral, but not contraleral, intraplantar injection of yohimbine reversed the antinociception of dexmedetomidine. Intraplantar BRL 44408, ARC 239, and JP 1302 reversed the antinociception of dexmedetomidine. The expression levels of alpha2-adrenoceptor genes in the lumbar spinal cord did not differ between rats with neuropathic pain and naive rats. The expression levels of alpha2B-adrenoceptor and alpha2C adrenoceptor genes of plantar skin were upregulated significantly in the model group, whereas alpha2A-adrenoceptor expression was unchanged. These results suggest that intraplantar injection of dexmedetomidine produced an antiallodynic effect in spinal nerve ligation-induced neuropathic pain. All three types of peripheral alpha2A, alpha2B, and alpha2C-adrenoceptors were involved in the antiallodynic mechanism of dexmedetomidine. PMID- 24161891 TI - 8-(Furan-2-yl)-3-phenethylthiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidine-2(3H) thione as novel, selective and potent adenosine A(2A) receptor antagonist. AB - Antagonism of the human A2A receptor has been implicated to alleviate the symptoms associated with Parkinson's disease. The present finding reveals the potential of PTTP (8-(furan-2-yl)-3-phenethylthiazolo[1,2,4]triazolo[1,5 c]pyrimidine-2(3H)-thione) as novel and potent A2AR antagonist. In radioligand binding assay, PTTP showed significantly high binding affinity (Ki 6.3 nM) and selectivity with A2AR (A1R/A2AR=4603) which was comparable to the results of docking analysis (Ki=1.6 nM, DeltaG=-14.52 Kcal/mol). PTTP antagonized (0.46 pmol/ml) the effect of NECA-induced increase in cAMP concentration (0.65 pmol/ml) better than SCH58261 (0.55 pmol/ml) in HEK293T cells. Haloperidol and NECA induced mice pre-treated with PTTP at 10mg/kg showed attenuation in catalepsy and akinesia without significant neurotoxicity in rotarod test at 20mg/kg. Essentially, novel compound demonstrated remarkable potential as A2AR antagonist in the therapy of PD. PMID- 24161892 TI - Acai (Euterpe oleraceae Mart.) berry extract exerts neuroprotective effects against beta-amyloid exposure in vitro. AB - The native South American palm acai berry (Euterpe oleraceae Mart.) has high polyphenolic and antioxidant levels. This study examined whether acai berry extract afforded protection against beta-amyloid (Abeta)-mediated loss of cell viability and oxidative stress associated with anti-fibrillar effects. PC12 cells were exposed to either Abeta1-42, Abeta25-35 or tert butyl hydroperoxide (t-BHP), alone or in the presence of acai extract (0.5-50MUg/ml). Thioflavin T (ThT) binding assay and transmission electron microscopy were used to determine effects of acai extract on Abeta1-42 fibril morphology and compared to acai phenolics gallic acid, cyanidin rutinoside and cyanidin glucoside. Exposure to Abeta1-42, Abeta25-35 or t-BHP decreased PC12 cell viability. Pretreatment with acai extract significantly improved cell viability following Abeta1-42 exposure, however Abeta25-35 or t-BHP-mediated viability loss was unaltered. Acai extract inhibited ThT fluorescence and disrupted Abeta1-42 fibril and aggregate morphology. In comparison with other phenolics, acai was most effective at inhibiting Abeta1-42 aggregation. Inhibition of beta-amyloid aggregation may underlie a neuroprotective effect of acai. PMID- 24161893 TI - Intra-cerebellar microinjection of histamine enhances memory consolidation of inhibitory avoidance learning in mice via H2 receptors. AB - Studies have demonstrated the relationship between the histaminergic system and the cerebellum, and we intend to investigate the role of the cerebellar histaminergic system on memory consolidation. This study investigated the effect of intra-cerebellar microinjection of histamine on memory retention of inhibitory avoidance in mice, and the role of H1 and H2 receptors in it. The cerebellar vermis of male mice were implanted with guide cannulae, and after three days of recovery, the inhibitory avoidance test was performed. Immediately after a training session, animals received a microinjection of histaminergic drugs: in the experiment 1, saline (SAL) or histamine (HA 0.54, 1.36, 2.72 or 4.07 nmol); experiment 2, SAL or 1.36 nmol HA 5 min after a pretreatment with 0.16 nmol chlorpheniramine (CPA) or SAL; and experiment 3, SAL or 1.36 nmol HA 5 min after a pretreatment with 2.85 nmol ranitidine (RA) or SAL. Twenty-four hours later, a retention test was performed. The data were analyzed using one-way analysis of variance (ANOVA) and Duncan's tests. In experiment 1, animals microinjected with 1.36 nmol HA showed a higher latency to cross to the dark compartment compared to controls and to 2.72 and 4.07 nmol HA groups. In experiment 2, the combined infusions revealed difference between control (SAL+SAL) and SAL+HA and CPA+HA; while in the experiment 3 the analysis indicated differences in retention latency between mice injected with SAL+SAL and SAL+HA. The groups that received the H2 antagonist RA did not show difference compared to control. These results indicate that 1.36 nmol HA enhances memory consolidation of inhibitory avoidance learning in mice and that the pretreatment with H2 antagonist RA was able to prevent this effect. PMID- 24161895 TI - Age-related deterioration of cortical responses to slow FM sounds in the auditory belt region of adult C57BL/6 mice. AB - To compare age-related deterioration of neural responses in each subfield of the auditory cortex in C57BL/6 mice, we evaluated amplitudes of tonal responses in young (5-11 weeks old) and adult (16-23 weeks old) groups using transcranial flavoprotein fluorescence imaging. Cortical responses to 20-kHz amplitude modulated (AM) sounds, which were mainly found in the anterior auditory field (AAF) and the primary auditory cortex (AI) of the core region, were not markedly different between the two groups. In contrast, cortical responses to direction reversal of slow frequency-modulated (FM) sounds, which were mainly found in the ultrasonic field (UF), were significantly disrupted in the adult group compared with those in the young group. To investigate the mechanisms underlying such age related deterioration, biotinylated dextran amine (BDA) was injected into UF. The number of retrograde labeled neurons in the dorsal division of the medial geniculate body (MGd) was markedly reduced in the adult group compared with that in the young group. These results strongly suggest that cortical responses to FM direction reversal in UF of adult C57BL/6 mice are mainly deteriorated by loss of non-lemniscal thalamic inputs from MGd to UF due to aging. PMID- 24161894 TI - GAB2 polymorphism rs2373115 confers susceptibility to sporadic Alzheimer's disease. AB - It has been reported that a single nucleotide polymorphism (SNP), rs2373115, in the GRB-associated binding protein 2 (GAB2) gene was associated with late-onset AD in Caucasians. Subsequently, other researchers have attempted to validate this finding in different ethnic populations. However, these findings have produced both negative and positive results. To derive a more precise estimation for whether GAB2 polymorphism rs2373115 is associated with sporadic Alzheimer's disease (SAD), we performed the present meta-analysis. Databases including PubMed, AlzGene, China National Knowledge Infrastructure (CNKI) and Wan Fang were searched to find relevant studies. Odds ratios (ORs) with 95% confidence intervals (CIs) were used to assess the strength of association. All analyses were calculated using STATA Version 11.0 and RevMan (v.5.1) software. Ten total case-control studies were included. The statistical results showed that GAB2 SNP rs2373115 is significantly associated with an increased risk for SAD, and the subgroup analysis showed that SNP rs2373115 may only be associated with an increased risk for SAD risk in Caucasians but not in Asians. Furthermore, in APOE E4 carriers or noncarriers, those with rs2373115 genotype GG did not have a significantly higher risk for SAD compared with those with genotype GT and TT (APOE E4 carriers: OR=1.20, 95% CI=0.92-1.56, P=0.178; APOE E4 noncarriers: OR=1.08, 95% CI=0.97-1.20, P=0.157) in the present study. The current meta analysis further supports previous findings that the GAB2 gene may be associated with SAD risk. PMID- 24161897 TI - Differential recovery of bacterial and archaeal 16S rRNA genes from ruminal digesta in response to glycerol as cryoprotectant. AB - Bacteria and archaea in frozen (-20 degrees C) ruminal digesta were analysed by qPCR and cloning/sequencing of 16S rRNA genes. Samples frozen with and without glycerol as cryoprotectant indicated a major loss of Bacteroidetes in unprotected samples, resulting in higher proportions of Firmicutes. Archaeal numbers and diversity were unaffected. PMID- 24161896 TI - [Potentially inappropriate prescriptions in the ambulatory treatment of elderly patients]. AB - INTRODUCTION: The aim of this study was to establish the percentage of potentially inappropriate prescriptions, according to STOPP/START criteria, in the ambulatory treatments of patients over 65 years admitted to an internal medicine unit, and to identify the most common prescription errors. MATERIAL AND METHODS: A prospective, observational study was performed between October and December 2012. The variable recorded were,age, gender, Charlson comorbidity index, reason for hospitalisation and pharmacological ambulatory treatment. RESULTS: Data from 131 patients were collected (Mean age: 80.2 years; 58.8% male, mean Charlson comorbidity index: 2; mean number of medications per patient: 8.6). Main reasons for hospitalisation: decompensated heart failure, respiratory infection, exacerbated COPD, urinary tract infection, pneumonia, and unintended weight loss. There were 121 potentially inappropriate prescriptions detected in 73 patients (55.7%). The most common STOPP criteria were therapeutic duplicities. The most common START criteria were the omission of statins and antiplatelets in primary prevention for cardiovascular risk in patients with diabetes mellitus and at least one cardiovascular risk factor. CONCLUSIONS: The percentage of patients with inappropriate prescriptions was similar to those obtained in similar studies. Over 50% of elderly patients had at least one inappropriate prescription. This warrants a joint search for errors by excess and by default in the prescription of medications, with the aim of performing a more complete evaluation of prescription practice and to achieve optimization of therapy in elderly patients, especially the most fragile. PMID- 24161898 TI - Targeted gene deletion in Aspergillus fumigatus using microbial machinery and a recyclable marker. AB - The emerging invasive fungal pathogen Aspergillus fumigatus causes very serious infections among immunocompromised patient populations. While the genome of this pathogen has been sequenced, a major barrier to better understanding the complex biology of this eukaryotic organism is a lack of tools for efficient genetic manipulation. To improve upon this, we have generated a new gene deletion system for A. fumigatus using yeast recombinational cloning and Agrobacterium tumefaciens mediated transformation (ATMT) employing a recyclable marker system. This system reduced the time for generating a gene deletion strain in our hands by two-thirds (12 weeks to 3 weeks) using minimal human labor, and we demonstrate that it can be used to efficiently generate multiple gene deletions within a single strain. PMID- 24161899 TI - Organs: tradable, but not necessarily inheritable. PMID- 24161900 TI - Long-term oncological results after 400 skin-sparing mastectomies. AB - OBJECTIVE OF THE STUDY: Skin-sparing mastectomies (SSM) have gained acceptance among teams performing immediate breast reconstruction because this technique provides the best cosmetic outcome. Nevertheless, in France, concerns have been raised that limited skin excision during mastectomy could result in an increased risk of local recurrence especially in invasive breast cancer; many surgeons continue to have reservations regarding the oncologic safety of this operation. This is a retrospective, long-term follow-up study of 400 patients operated and followed by two oncoplastic surgeons. PATIENTS AND METHODS: A total of 400 patients with breast cancer underwent SSM with immediate breast reconstruction from January 1, 1992 to December 31, 2002. The American Joint Committee on Cancer pathological staging was Stage 0 (41.5%), Stage I (33.25%), Stage II (16%), Stage III (7.5%), while 1.75% were non-stageable. RESULTS: With a mean follow-up period of 88 months (range: 13-215 months), the locoregional recurrence rate was 3.5%, the rate of distant metastases was 13.5%, and 83% of patients have remained free of recurrent disease. CONCLUSION: This study provides encouraging results suggesting that skin-sparing mastectomy is a safe and reliable option for the management of selected cases of women with invasive or in situ breast cancer. PMID- 24161901 TI - With regard to the article "Adjustable gastric banding, sleeve gastrectomy or gastric bypass. Can evidence-based medicine help us to choose?" Letter to the editor. PMID- 24161902 TI - Procedures for the biochemical enrichment and proteomic analysis of the cytoskeletome. AB - The cell cytoskeleton is composed of microtubules, intermediate filaments, and actin that provide a rigid support structure important for cell shape. However, it is also a dynamic signaling scaffold that receives and transmits complex mechanosensing stimuli that regulate normal physiological and aberrant pathophysiological processes. Studying cytoskeletal functions in the cytoskeleton's native state is inherently difficult due to its rigid and insoluble nature. This has severely limited detailed proteomic analyses of the complex protein networks that regulate the cytoskeleton. Here, we describe a purification method that enriches for the cytoskeleton and its associated proteins in their native state that is also compatible with current mass spectrometry-based protein detection methods. This method can be used for biochemical, fluorescence, and large-scale proteomic analyses of numerous cell types. Using this approach, 2346 proteins were identified in the cytoskeletal fraction of purified mouse embryonic fibroblasts, of which 635 proteins were either known cytoskeleton proteins or cytoskeleton-interacting proteins. Functional annotation and network analyses using the Ingenuity Knowledge Database of the cytoskeletome revealed important nodes of interconnectivity surrounding well-established regulators of the actin cytoskeleton and focal adhesion complexes. This improved cytoskeleton purification method will aid our understanding of how the cytoskeleton controls normal and diseased cell functions. PMID- 24161903 TI - Abnormal mitral valve chorda. PMID- 24161905 TI - Remote ischemic conditioning. From organs/tissues to organs. PMID- 24161904 TI - No-reflow: is the "great challenge" getting smaller? PMID- 24161907 TI - Current status of medical treatment for abdominal aortic aneurysm. AB - Although cardiovascular disease is widely recognized as the leading cause of death, a lesser known fact is that aortic aneurysm is the 15th leading cause of death over the age of 65 years in the USA. The golden standard of the treatments are invasive interventions either with open surgical repair (OS) or endovascular aneurysm repair (EVAR). The concept of medical treatment is to prevent abdominal aortic aneurysm (AAA) from rupture and avoid surgical treatment by preventing aneurysm enlargement or even reducing aneurysm size. Matrix metalloproteinases (MMP) are structurally related metalloendopeptidases that can degrade the extracellular matrix and is thought to play important roles in AAA. There are many proposed pharmacological treatments including: beta-blockers, angiotensin converting enzyme inhibitor (ACE inhibitors), angiotensin-receptor blocker (ARB), statins, macrolides and, doxycycline, an inhibitor of the MMP. The latter is a potential promising drug as medical treatment for AAA and the Non-invasive Treatment of Abdominal Aortic Aneurysm Clinical Trial (N-TA(3)CT) is currently ongoing in the USA. Here, the pathophysiology and potential medical therapy for AAA will be reviewed. PMID- 24161906 TI - Loss of angiotensin-converting enzyme 2 exacerbates myocardial injury via activation of the CTGF-fractalkine signaling pathway. AB - BACKGROUND: Angiotensin-converting enzyme 2 (ACE2) has been implicated in human heart failure, but the mechanism remains elusive. We hypothesized that ACE2 deficiency would exacerbate angiotensin (Ang) II-mediated myocardial injury. METHODS AND RESULTS: 10-week-old ACE2 knockout (ACE2KO) and wild-type mice received by mini-osmotic pump either AngII (1.5 mg.kg(-1).day(-1)) or saline for 2 weeks. ACE2 deficiency triggered greater increases in the expression of connective tissue growth factor (CTGF), fractalkine (FKN) and phosphorylated ERK1/2 in AngII-treated ACE2KO hearts. These changes were associated with greater activation of matrix metalloproteinase (MMP) 2, MMP9 and MT1-MMP and exacerbation of myocardial injury and dysfunction. In cultured cardiofibroblasts, exposure to AngII (100 nmol/L) for 30 min resulted in marked increases in superoxide production and expression of CTGF, FKN and phosphorylated ERK1/2, which were strikingly prevented by recombinant human ACE2 (rhACE2; 1mg/ml) and the CTGF neutralizing antibody (5 MUg/ml), but were aggravated by ACE2 inhibitor DX600 (0.5 MUmol/L). These protective effects of rhACE2 were eradicated by the Ang-(1 7) antagonist A779 (1 MUmol/L). More intriguingly, rhACE2 treatment significantly abolished AngII-mediated increases in MMP2, MMP9 and MT1-MMP in cardiofibroblasts. CONCLUSIONS: Loss of ACE2 exacerbates AngII-mediated inflammation, myocardial injury and dysfunction in ACE2-deficient hearts via activation of the CTGF-FKN-ERK and MMP signaling. ACE2 gene may represent a potential candidate to prevent and treat myocardial injury and heart diseases. PMID- 24161908 TI - Mitochondrial oxidative stress is the Achille's heel of melanoma cells resistant to Braf-mutant inhibitor. AB - Vemurafenib/PLX4032, a selective inhibitor of mutant BRAFV600E, constitutes a paradigm shift in melanoma therapy. Unfortunately, acquired resistance, which unavoidably occurs, represents one major limitation to clinical responses. Recent studies have highlighted that vemurafenib activated oxidative metabolism in BRAFV600E melanomas expressing PGC1alpha. However, the oxidative state of melanoma resistant to BRAF inhibitors is unknown. We established representative in vitro and in vivo models of human melanoma resistant to vemurafenib including primary specimens derived from melanoma patients. Firstly, our study reveals that vemurafenib increased mitochondrial respiration and ROS production in BRAFV600E melanoma cell lines regardless the expression of PGC1alpha. Secondly, melanoma cells that have acquired resistance to vemurafenib displayed intrinsically high rates of mitochondrial respiration associated with elevated mitochondrial oxidative stress irrespective of the presence of vemurafenib. Thirdly, the elevated ROS level rendered vemurafenib-resistant melanoma cells prone to cell death induced by pro-oxidants including the clinical trial drug, elesclomol. Based on these observations, we propose that the mitochondrial oxidative signature of resistant melanoma constitutes a novel opportunity to overcome resistance to BRAF inhibition. PMID- 24161910 TI - The role of pulmonary vascular contractile protein expression in pulmonary arterial hypertension. AB - Pulmonary arterial hypertension (PAH) is associated with refractory vasoconstriction and impaired NO-mediated vasodilatation of the pulmonary vasculature. Vascular tone is regulated by light chain (LC) phosphorylation of both nonmuscle (NM) and smooth muscle (SM) myosins, which are determined by the activities of MLC kinase and MLC phosphatase. Further, NO mediated vasodilatation requires the expression of a leucine zipper positive (LZ+) isoform of the myosin targeting subunit (MYPT1) of MLC phosphatase. The objective of this study was to define contractile protein expression in the pulmonary arterial vasculature and vascular reactivity in PAH. In severe PAH, compared to controls, relative LZ+MYPT1 expression was decreased (100 +/- 14% vs. 60 +/- 6%, p<0.05, n=7-8), and NM myosin expression was increased (1 5 +/- 4% vs. 53 +/- 5% of total myosin, p<0.05, n=4-6). These changes in contractile protein expression should alter vascular reactivity; following activation with Ang II, force activation and relaxation were slowed, and sustained force was increased. Further, the sensitivity to ACh-mediated relaxation was reduced. These results demonstrate that changes in the pulmonary arterial SM contractile protein expression may participate in the molecular mechanism producing both the resting vasoconstriction and the decreased sensitivity to NO-mediated vasodilatation associated with PAH. PMID- 24161912 TI - Antiarrhythmic properties of some 1,4-disubstituted piperazine derivatives with alpha1-adrenoceptor affinities. AB - A series of 1,4-disubstituted piperazine derivatives with alpha1-adrenolytic properties was evaluated for antiarrhythmic, electrocardiographic and antioxidant activity in vitro and in vivo. Most of them displayed strong antiarrhythmic activity in the adrenaline induced model of arrhythmia and in the rat coronary artery ligation-reperfusion model. Their antiarrhythmic effect is mainly related to alpha1-adrenolytic properties. Among them one compound showed characteristics similar to quinidine in different arrhythmia models as well as electrocardiogram (ECG) studies which suggests that it possesses not only alpha1-adrenoceptor blocking properties but also affinity for cardiac Na(+) and K(+) channels, similar to class IA antiarrhythmic agents. Two other compounds revealed some antioxidant effects. Another compound (MH-79) is particularly promising since it displayed a strong antiarrhythmic effect without the influence on ECG record. PMID- 24161913 TI - Effects of WIN 55,212-2 mesylate on the anticonvulsant action of lamotrigine, oxcarbazepine, pregabalin and topiramate against maximal electroshock-induced seizures in mice. AB - The aim of this study was to determine the effect of WIN 55,212-2 mesylate (WIN - a non-selective cannabinoid CB1 and CB2 receptor agonist) on the protective action of four second-generation antiepileptic drugs (lamotrigine, oxcarbazepine, pregabalin and topiramate) in the mouse maximal electroshock seizure model. Tonic hind limb extension (seizure activity) was evoked in adult male albino Swiss mice by a current (sine-wave, 25 mA, 500 V, 50 Hz, 0.2s stimulus duration) delivered via auricular electrodes. Drug-related adverse effects were ascertained by use of the chimney test (evaluating motor performance), the step-through passive avoidance task (assessing long-term memory) and the grip-strength test (evaluating skeletal muscular strength). Total brain concentrations of antiepileptic drugs were measured by high-pressure liquid chromatography to ascertain any pharmacokinetic contribution to the observed antiseizure effect. Results indicate that WIN (5mg/kg, i.p.) significantly enhanced the anticonvulsant action of lamotrigine (P<0.05), pregabalin (P<0.001) and topiramate (P<0.05), but not that of oxcarbazepine in the maximal electroshock induced tonic seizure test in mice. Furthermore, none of the investigated combinations of WIN with antiepileptic drugs were associated with any concurrent adverse effects with regards to motor performance, long-term memory or muscular strength. Pharmacokinetic characterization revealed that WIN had no impact on total brain concentrations of lamotrigine, oxcarbazepine, pregabalin and topiramate in mice. These preclinical data would suggest that WIN in combination with lamotrigine, pregabalin and topiramate is associated with beneficial anticonvulsant pharmacodynamic interactions in the maximal electroshock-induced tonic seizure test. PMID- 24161914 TI - Antifibrotic effect of atorvastatin on paraquat-induced pulmonary fibrosis: role of PPARgamma receptors. AB - This study was carried out to highlight the role of PPARgamma in the paraquat (PQ)-induced pulmonary fibrosis. Forty-two male Wistar rats were exposed either against saline as a control group or PQ (3.5mg/kg, i.p.) as test groups. The test groups were nominated as PQ (PQ-exposed non-treated animals), pioglitazone (PGT, 10mg/kg, orally), atorvastatin (STN, 10mg/kg, orally), PGT+STN, PGT+GW9662 (1mg/kg, i.p.) and STN+GW9662 (1mg/kg). Atorvastatin but not PGT was able to reverse significantly (P<0.05) the PQ-increased ratio of lung to body weight. STN was successfully able to recover the PQ-reduced antioxidant potency and the GW9662 administration resulted in antagonizing the protective effect of both PGT and STN. Although both PGT and STN were able to reduce the hydrxoproline content of the lungs, GW9662, however, could reverse only STN-related effect. Histochemical studies revealed that PQ exposure resulted in a remarkable increase of fibroblasts and collagen fibers in the interstitial tissue and around vessels and bronchioles, which was improved by the STN administration. Only STN-received animals showed the down-regulation of the TGF-beta1 expression and GW9662 was able to antagonize this down-regulation. Co-administration of PGT and STN could not exert any synergistic protective effect. These data suggest that the PQ induced pulmonary fibrosis could be more effectively reversed by STN rather than PGT. Moreover, STN-induced protective effects might attribute to the regulation of TGF-beta1 expression, which is antagonized by PPARgamma antagonist, suggesting that STN may improve the PQ-induced damages via PPARgamma. PMID- 24161909 TI - Japanese encephalitis: the virus and vaccines. AB - Japanese encephalitis (JE) is an infectious disease of the central nervous system caused by Japanese encephalitis virus (JEV), a zoonotic mosquito-borne flavivirus. JEV is prevalent in much of Asia and the Western Pacific, with over 4 billion people living at risk of infection. In the absence of antiviral intervention, vaccination is the only strategy to develop long-term sustainable protection against JEV infection. Over the past half-century, a mouse brain derived inactivated vaccine has been used internationally for active immunization. To date, however, JEV is still a clinically important, emerging, and re-emerging human pathogen of global significance. In recent years, production of the mouse brain-derived vaccine has been discontinued, but 3 new cell culture-derived vaccines are available in various parts of the world. Here we review current aspects of JEV biology, summarize the 4 types of JEV vaccine, and discuss the potential of an infectious JEV cDNA technology for future vaccine development. PMID- 24161911 TI - The C-terminus of the long AKAP13 isoform (AKAP-Lbc) is critical for development of compensatory cardiac hypertrophy. AB - The objective of this study was to determine the role of A-Kinase Anchoring Protein (AKAP)-Lbc in the development of heart failure, by investigating AKAP-Lbc protein kinase D1 (PKD1) signaling in vivo in cardiac hypertrophy. Using a gene trap mouse expressing a truncated version of AKAP-Lbc (due to disruption of the endogenous AKAP-Lbc gene), that abolishes PKD1 interaction with AKAP-Lbc (AKAP Lbc-DeltaPKD), we studied two mouse models of pathological hypertrophy: i) angiotensin (AT-II) and phenylephrine (PE) infusion and ii) transverse aortic constriction (TAC)-induced pressure overload. Our results indicate that AKAP-Lbc DeltaPKD mice exhibit an accelerated progression to cardiac dysfunction in response to AT-II/PE treatment and TAC. AKAP-Lbc-DeltaPKD mice display attenuated compensatory cardiac hypertrophy, increased collagen deposition and apoptosis, compared to wild-type (WT) control littermates. Mechanistically, reduced levels of PKD1 activation are observed in AKAP-Lbc-DeltaPKD mice compared to WT mice, resulting in diminished phosphorylation of histone deacetylase 5 (HDAC5) and decreased hypertrophic gene expression. This is consistent with a reduced compensatory hypertrophy phenotype leading to progression of heart failure in AKAP-Lbc-DeltaPKD mice. Overall, our data demonstrates a critical in vivo role for AKAP-Lbc-PKD1 signaling in the development of compensatory hypertrophy to enhance cardiac performance in response to TAC-induced pressure overload and neurohumoral stimulation by AT-II/PE treatment. PMID- 24161915 TI - Protective effect of cryptotanshinone on lipopolysaccharide-induced acute lung injury in mice. AB - Crytotanshinone (CTN), one of the main constituents of tanshinones, has been reported to exhibit anti-tumor, anti-inflammatory and other important therapeutic activities. The aim of this study was to investigate the potential therapeutic effects of CTN on murine model of lipopolysaccharide (LPS)-induced acute lung injury (ALI). Male BALB/c mice were pretreated with dexamethasone or CTN 1h before intranasal instillation of LPS. Seven hours after LPS administration, the myeloperoxidase (MPO) in lung tissues, lung wet/dry weight ratio and inflammatory cells in the bronchoalveolar lavage fluid (BALF) were determined. The effects of CTN on pro-inflammatory cytokines and signaling pathways were analyzed by enzyme linked immunosorbent assay (ELISA) and Western blot. The results showed that CTN significantly inhibited LPS induced increases of macrophages and neutrophils infiltration of lung tissues, as well as markedly attenuated MPO activity. Furthermore, CTN significantly reduced the wet/dry weight ratio of lungs and the concentrations of TNF-alpha, IL-6 and IL-1beta in BALF. Compared with LPS group, lung histopathologic changes were less pronounced in the CTN pretreated mice. Additionally, western blotting showed that CTN efficiently inhibited the phosphorylation of IkappaB-alpha, p65 NF-kappaB and the expression of TLR4. Taken together, our results suggest that the anti-inflammatory effects of CTN against LPS-induced acute lung injury may be due to its ability to inhibit TLR4 mediated NF-kappaB signaling pathways. CTN may be a promising potential therapeutic reagent for ALI treatment. PMID- 24161916 TI - Similar activity of mecamylamine stereoisomers in vitro and in vivo. AB - A previous characterization of mecamylamine stereoisomers using nicotinic acetylcholine receptors expressed in Xenopus oocytes revealed only small differences between the activity of the R and S forms of mecamylamine. However, that work was limited in the breadth of receptor subtypes tested, especially in regard to the discrimination of high and low sensitivity receptors, which differ in the ratios of alpha and beta subunits. We report new data using subunit concatamers, which produce uniform populations of high-sensitivity or low sensitivity receptors, as well as alpha2, alpha5, and alpha6-containing receptors, which were not studied previously. Consistent with previous studies, we found that beta4-containing receptors were most sensitive to mecamylamine and that the IC50 values for the inhibition of net charge were lower than for inhibition of peak currents. No large differences were seen between the activities of the mecamylamine isomers. Additionally, a previously reported potentiation of high-sensitivity alpha4beta2 receptors by S-mecamylamine could not be reproduced in the oocyte system, even with mutants that had greatly reduced sensitivity to mecamylamine inhibition or when the selective agonist TC 2559 was used. In vivo studies suggested that the R-isomer might be somewhat more potent than the S isomer at blocking CNS effects of nicotine. Although the potency difference was no more than a factor of two, it is consistent with lower LD50 estimates previously reported for the R isomer. Our results significantly extend knowledge of the nicotinic acetylcholine receptor activity profile of mecamylamine and support the hypothesis that these effects are not strongly stereoisomer selective. PMID- 24161918 TI - Complete genome sequence of Pseudomonas sp. strain VLB120 a solvent tolerant, styrene degrading bacterium, isolated from forest soil. AB - Pseudomonas sp. VLB120 was isolated in Stuttgart, Germany, as a styrene degrading organism. The complete genome sequence includes genomic information of solvent tolerance mechanisms, metabolic pathways for various organic compounds, and the megaplasmid pSTY. PMID- 24161917 TI - A cell sorting protocol for selecting high-producing sub-populations of Sf9 and High FiveTM cells. AB - Insect cell lines such as Sf9 and High FiveTM have been widely used to produce recombinant proteins mostly by the lytic baculovirus vector system. We have recently established an expression platform in Sf9 cells using a fluorescence based recombinase mediated cassette exchange (RMCE) strategy which has similar development timelines but avoids baculovirus infection. To expedite cell engineering efforts, a robust fluorescence-activated cell sorting (FACS) protocol optimized for insect cells was developed here. The standard sorting conditions used for mammalian cells proved to be unsuitable, resulting in post-sorting viabilities below 10% for both cell lines. We found that the extreme sensitivity to the shear stress displayed by Sf9 and High FiveTM cells was the limiting factor, and using Pluronic F-68 in the cell suspension could increase post sorting viabilities in a dose dependent manner. The newly developed protocol was then used to sort stable populations of both cell lines tagged with a DsRed expressing cassette. Before sorting, the average fluorescence intensity of the Sf9 cell population was 3-fold higher than that of the High FiveTM cell population. By enriching with the 10% strongest DsRed-fluorescent cells, the productivity of both cell populations could be successfully improved. The established sorting protocol potentiates the use of RMCE technology for recombinant protein production in insect cells. PMID- 24161919 TI - Evaluation of heterologous promoters for genetic analysis of Actinoplanes teichomyceticus--Producer of teicoplanin, drug of last defense. AB - Actinoplanes teichomyceticus is the only known producer of the valuable glycopeptide antibiotic teicoplanin. Random mutagenesis and selection were extensively applied to teicoplanin producers, while the gene engineering methods were not used, because of the paucity of genetic tools for A. teichomyceticus. Particularly, availability of promoters of different strength that are functional in Actinoplanes would be very useful for overexpression of beneficial genes. Here we report the use of a glucuronidase reporter system (gusA) for studying transcriptional activity in A. teichomyceticus and describe the behavior of a set of heterologous promoters in this strain. We reveal several elements that exceed in their strength the well-established Streptomyces promoter ermEp, underscoring the utility of the gusA reporter for Actinoplanes sp. Remarkable overproduction of teicoplanin was achieved by constructing strains carrying additional copies of the regulatory gene tcp28 under the control of one of the two most active promoters, moeE5p and actp, discovered in this study. PMID- 24161920 TI - D-xylose detection in Escherichia coli by a xylose binding protein-dependent response. AB - A gene circuit for the controlled expression of a marker gene and for the assay of xylose concentration in Escherichia coli has been designed and tested. The xylF coding sequence for the xylose binding protein (XBP) was cloned in pT7T318U downstream from the promoter for xylanase A from B. subtilis (Pbsu), together with the GFP coding sequence (gfp) under the control of the xylF promoter, forming the pT7T3-GFP-XBP construct. GFP fluorescence in Escherichia coli JW3538 1 xylF-transformed with pT7T3-GFP-XBP was approximately 1.4 * higher after 520 min growth in the presence of 5mM xylose than in cells transformed with pT7T3 GFP. Under saturating xylose concentration, flow cytometry analysis showed that all cells resulted in homogeneous populations, and the population with XBP showed a fluorescence greater than that without XBP. Activity of the xylF promoter in cells transformed with pT7T3-GFP-XBP was ~ 40% higher than with the pT7T3-GFP. No response was observed with arabinose and ribose, showing that the expression effects were specific for xylose, demonstrating the potential use of the gene circuit as a biosensor. PMID- 24161921 TI - Overproduction of geraniol by enhanced precursor supply in Saccharomyces cerevisiae. AB - Monoterpene geraniol, a compound obtained from aromatic plants, has wide applications. In this study, geraniol was synthesized in Saccharomyces cerevisiae through the introduction of geraniol synthase. To increase geraniol production, the mevalonate pathway in S. cerevisiae was genetically manipulated to enhance the supply of geranyl diphosphate, a substrate used for the biosynthesis of geraniol. Identification and optimization of the key regulatory points in the mevalonate pathway in S. cerevisiae increased geraniol production to 36.04 mg L( 1). The results obtained revealed that the IDI1-encoded isopentenyl diphosphate isomerase is a rate-limiting enzyme in the biosynthesis of geraniol in S. cerevisiae, and overexpression of MAF1, a negative regulator in tRNA biosynthesis, is another effective method to increase geraniol production in S. cerevisiae. PMID- 24161922 TI - HCMV infection of humanized mice after transplantation of G-CSF-mobilized peripheral blood stem cells from HCMV-seropositive donors. AB - Human cytomegalovirus (HCMV) infection, including primary infection resulting from transmission from a seropositive donor to a seronegative recipient (D(+)/R( )), remains a significant problem in the setting of peripheral blood stem cell transplantation (PBSCT). The lack of a suitable animal model for studying HCMV transmission after PBSCT is a major barrier to understanding this process and, consequently, developing novel interventions to prevent HCMV infection. Our previous work demonstrated that human CD34(+) progenitor cell-engrafted NOD-scid IL2Rgammac(null) (NSG) mice support latent HCMV infection after direct inoculation and reactivation after treatment with granulocyte colony-stimulating factor. To more accurately recapitulate HCMV infection in the D(+)/R(-) PBSCT setting, granulocyte colony-stimulating factor-mobilized peripheral blood stem cells from seropositive donors were used to engraft NSG mice. All recipient mice demonstrated evidence of HCMV infection in liver, spleen, and bone marrow. These findings validate the NSG mouse model for studying HCMV transmission during PBSCT. PMID- 24161924 TI - Rejection of leukemic cells requires antigen-specific T cells with high functional avidity. AB - In a context where injection of antigen (Ag)-specific T cells probably represents the future of leukemia immunotherapy, identification of optimal target Ags is crucial. We therefore sought to discover a reliable marker for selection of the most potent Ags. To this end, (1) we immunized mice against 8 individual Ags: 4 minor histocompatibility Ags (miHAs) and 4 leukemia-associated Ags (LAAs) that were overexpressed on leukemic relative to normal thymocytes; (2) we assessed their ability to reject EL4 leukemic cells; and (3) we correlated the properties of our Ags (and their cognate T cells) with their ability to induce protective antileukemic responses. Overall, individual miHAs instigated more potent antileukemic responses than LAAs. Three features had no influence on the ability of primed T cells to reject leukemic cells: (1) MHC-peptide affinity; (2) the stability of MHC-peptide complexes; and (3) epitope density at the surface of leukemic cells, as assessed using mass spectrometry. The cardinal feature of successful Ags is that they were recognized by high-avidity CD8 T cells that proliferated extensively in vivo. Our work suggests that in vitro evaluation of functional avidity represents the best criterion for selection of Ags, which should be prioritized in clinical trials of leukemia immunotherapy. PMID- 24161923 TI - Reduced-intensity hematopoietic cell transplantation for patients with primary myelofibrosis: a cohort analysis from the center for international blood and marrow transplant research. AB - We evaluated outcomes and associated prognostic factors in 233 patients undergoing allogeneic hematopoietic cell transplantation (HCT) for primary myelofibrosis (MF) using reduced-intensity conditioning (RIC). The median age at RIC HCT was 55 yr. Donors were a matched sibling donor (MSD) in 34% of RIC HCTs, an HLA well-matched unrelated donor (URD) in 45%, and a partially matched/mismatched URD in 21%. Risk stratification according to the Dynamic International Prognostic Scoring System (DIPSS) was 12% low, 49% intermediate-1, 37% intermediate-2, and 1% high. The probability of survival at 5 yr was 47% (95% confidence interval [CI], 40% to 53%). In a multivariate analysis, donor type was the sole independent factor associated with survival. Adjusted probabilities of survival at 5-yr were 56% (95% CI, 44% to 67%) for MSD, 48% (95% CI, 37% to 58%) for well-matched URD, and 34% (95% CI, 21% to 47%) for partially matched/mismatched URD (P = .002). The relative risk (RR) for NRM was 3.92 (P = .006) for well-matched URD and 9.37 (P < .0001) for partially matched/mismatched URD. Trends toward increased NRM (RR, 1.7; P = .07) and inferior survival (RR, 1.37; P = .10) were observed in DIPSS intermediate-2/high-risk patients compared with DIPSS low/intermediate-1 risk patients. Our data indicate that RIC HCT is a potentially curative option for patients with MF, and that donor type is the most important factor influencing survival in these patients. PMID- 24161925 TI - [Contribution of the chromogenic medium CHROMagar((r))Candida in mycological diagnosis of yeasts]. AB - The incidence of invasive candidiasis has increased dramatically over the last decades due to a larger number of patients at risk. The diagnosis remains difficult as the clinical presentation is not specific and the biological diagnosis usually takes several days to become positive. We propose in this work through a prospective study to evaluate the contribution of a chromogenic medium CHROMagar((r)) (Becton-Dickinson) in the mycological diagnosis of Candida. We selected 680 samples from patients hospitalized in the intensive care unit for epidemiological surveillance over a period of 11 weeks. We treated samples by culture on Sabouraud and on CHROMagar((r)). The species identification was performed by chlamydosporulation test and carbohydrate assimilation tests. We found that the CHROMagar((r))Candida evaluated in our work was a valuable tool in the primary culture in differentiating the most frequently isolated yeast species and in better detection of mixed cultures. PMID- 24161926 TI - Dictyostelium, a microbial model for brain disease. AB - BACKGROUND: Most neurodegenerative diseases are associated with mitochondrial dysfunction. In humans, mutations in mitochondrial genes result in a range of phenotypic outcomes which do not correlate well with the underlying genetic cause. Other neurodegenerative diseases are caused by mutations that affect the function and trafficking of lysosomes, endosomes and autophagosomes. Many of the complexities of these human diseases can be avoided by studying them in the simple eukaryotic model Dictyostelium discoideum. SCOPE OF REVIEW: This review describes research using Dictyostelium to study cytopathological pathways underlying a variety of neurodegenerative diseases including mitochondrial, lysosomal and vesicle trafficking disorders. MAJOR CONCLUSIONS: Generalised mitochondrial respiratory deficiencies in Dictyostelium produce a consistent pattern of defective phenotypes that are caused by chronic activation of a cellular energy sensor AMPK (AMP-activated protein kinase) and not ATP deficiency per se. Surprisingly, when individual subunits of Complex I are knocked out, both AMPK-dependent and AMPK-independent, subunit-specific phenotypes are observed. Many nonmitochondrial proteins associated with neurological disorders have homologues in Dictyostelium and are associated with the function and trafficking of lysosomes and endosomes. Conversely, some genes associated with neurodegenerative disorders do not have homologues in Dictyostelium and this provides a unique avenue for studying these mutated proteins in the absence of endogeneous protein. GENERAL SIGNIFICANCE: Using the Dictyostelium model we have gained insights into the sublethal cytopathological pathways whose dysregulation contributes to phenotypic outcomes in neurodegenerative disease. This work is beginning to distinguish correlation, cause and effect in the complex network of cross talk between the various organelles involved. This article is part of a Special Issue entitled Frontiers of Mitochondrial Research. PMID- 24161928 TI - Human or monitor feedback to improve mask ventilation during simulated neonatal cardiopulmonary resuscitation. AB - OBJECTIVE: To investigate if external chest compressions (ECC) increase mask leak, and if human or technical feedback improves mask ventilation during simulated neonatal cardiopulmonary resuscitation (CPR). STUDY DESIGN: In this observational study, 32 participants delivered positive pressure ventilation (PPV) to a modified, leak-free manikin via facemask. Mask leak, tidal volume (VT), positive end expiratory pressure (PEEP) and respiratory rate (RR) were measured with a respiratory function monitor (RFM). Participants had to perform four studies. In the first study, participants performed PPV alone as baseline. Thereafter, three studies were performed in random order. In the PPV+ECC+manometer group, participants had to observe the manometer while the RFM was covered; in the PPV+ECC+RFM group, the RFM was used while the manometer was covered; and in the PPV+ECC+verbal feedback group, the RFM and manometer were covered while a team leader viewed the RFM and provided verbal feedback to the participants. RESULTS: Median (IQR) mask leak of all studies was 15% (5-47%). Comparing the studies, PPV+ECC+RFM and PPV+ECC+verbal feedback had significantly less mask leak than PPV+ECC+manometer. Mean (SD) VT of all studies was 9.5+/-3.5 mL. Comparing all studies, PPV+ECC+RFM had a significantly higher VT than PPV and PPV+ECC+manometer. As well, PPV+ECC+verbal feedback had a significantly higher VT than PPV. PEEP and RR were within our target, mean (SD) PEEP was 6+/-2 cmH2O and RR was 36+/-13/min. CONCLUSIONS: During simulated neonatal CPR, ECCs did not influence mask leak, and a RFM and verbal feedback were helpful methods to reduce mask leak and increase VT significantly. PMID- 24161927 TI - Modelling biochemical features of mitochondrial neuropathology. AB - BACKGROUND: The neuropathology of mitochondrial disease is well characterised. However, pathophysiological mechanisms at the level of biochemistry and cell biology are less clear. Progress in this area has been hampered by the limited accessibility of neurologically relevant material for analysis. SCOPE OF REVIEW: Here we discuss the recent development of a variety of model systems that have greatly extended our capacity to understand the biochemical features associated with mitochondrial neuropathology. These include animal and cell based models, with mutations in both nuclear and mitochondrial DNA encoded genes, which aim to recapitulate the neuropathology and cellular biochemistry of mitochondrial diseases. MAJOR CONCLUSIONS: Analysis of neurological tissue and cells from these models suggests that although there is no unifying mode of pathogenesis, dysfunction of the oxidative phosphorylation (OXPHOS) system is often central. This can be associated with altered reactive oxygen species (ROS) generation, disruption of the mitochondrial membrane potential (DeltaPsim) and inadequate ATP synthesis. Thus, other cellular processes such as calcium (Ca(2+)) homeostasis, cellular signaling and mitochondrial morphology could be altered, ultimately compromising viability of neuronal cells. GENERAL SIGNIFICANCE: Mechanisms of neuronal dysfunction in mitochondrial disease are only just beginning to be characterised, are system dependent and complex, and not merely driven by energy deficiency. The diversity of pathogenic mechanisms emphasises the need for characterisation in a wide range of models, as different therapeutic strategies are likely to be needed for different diseases. This article is part of a Special Issue entitled Frontiers of Mitochondrial Research. PMID- 24161929 TI - Heart field origin of great vessel precursors relies on nkx2.5-mediated vasculogenesis. AB - The pharyngeal arch arteries (PAAs) are transient embryonic blood vessels that make indispensable contributions to the carotid arteries and great vessels of the heart, including the aorta and pulmonary arteries. During embryogenesis, the PAAs appear in a craniocaudal sequence to connect pre-existing segments of the primitive circulation after de novo vasculogenic assembly from angioblast precursors. Despite the unique spatiotemporal characteristics of PAA development, the embryonic origins of PAA angioblasts and the genetic factors regulating their emergence remain unknown. Here, we identify the embryonic source of PAA endothelium as nkx2.5(+) progenitors in lateral plate mesoderm long considered to adopt cell fates within the heart exclusively. Further, we report that PAA endothelial differentiation relies on Nkx2.5, a canonical cardiac transcription factor not previously implicated in blood vessel formation. Together, these studies reveal the heart field origin of PAA endothelium and attribute a new vasculogenic function to the cardiac transcription factor Nkx2.5 during great vessel precursor development. PMID- 24161930 TI - Sin1 phosphorylation impairs mTORC2 complex integrity and inhibits downstream Akt signalling to suppress tumorigenesis. AB - The mechanistic target of rapamycin (mTOR) functions as a critical regulator of cellular growth and metabolism by forming multi-component, yet functionally distinct complexes mTORC1 and mTORC2. Although mTORC2 has been implicated in mTORC1 activation, little is known about how mTORC2 is regulated. Here we report that phosphorylation of Sin1 at Thr 86 and Thr 398 suppresses mTORC2 kinase activity by dissociating Sin1 from mTORC2. Importantly, Sin1 phosphorylation, triggered by S6K or Akt, in a cellular context-dependent manner, inhibits not only insulin- or IGF-1-mediated, but also PDGF- or EGF-induced Akt phosphorylation by mTORC2, demonstrating a negative regulation of mTORC2 independent of IRS-1 and Grb10. Finally, a cancer-patient-derived Sin1-R81T mutation impairs Sin1 phosphorylation, leading to hyper-activation of mTORC2 by bypassing this negative regulation. Together, our results reveal a Sin1 phosphorylation-dependent mTORC2 regulation, providing a potential molecular mechanism by which mutations in the mTORC1-S6K-Sin1 signalling axis might cause aberrant hyper-activation of the mTORC2-Akt pathway, which facilitates tumorigenesis. PMID- 24161931 TI - Nfat and miR-25 cooperate to reactivate the transcription factor Hand2 in heart failure. AB - Although aberrant reactivation of embryonic gene programs is intricately linked to pathological heart disease, the transcription factors driving these gene programs remain ill-defined. Here we report that increased calcineurin/Nfat signalling and decreased miR-25 expression integrate to re-express the basic helix-loop-helix (bHLH) transcription factor dHAND (also known as Hand2) in the diseased human and mouse myocardium. In line, mutant mice overexpressing Hand2 in otherwise healthy heart muscle cells developed a phenotype of pathological hypertrophy. Conversely, conditional gene-targeted Hand2 mice demonstrated a marked resistance to pressure-overload-induced hypertrophy, fibrosis, ventricular dysfunction and induction of a fetal gene program. Furthermore, in vivo inhibition of miR-25 by a specific antagomir evoked spontaneous cardiac dysfunction and sensitized the murine myocardium to heart failure in a Hand2 dependent manner. Our results reveal that signalling cascades integrate with microRNAs to induce the expression of the bHLH transcription factor Hand2 in the postnatal mammalian myocardium with impact on embryonic gene programs in heart failure. PMID- 24161932 TI - GTP regulates the microtubule nucleation activity of gamma-tubulin. AB - Both subunits of alphabeta-tubulin that comprise the core components of microtubules bind GTP. GTP binding to alpha-tubulin has a structural role, whereas beta-tubulin binds and hydrolyses GTP to regulate microtubule dynamics. gamma-tubulin, another member of the tubulin superfamily that seeds microtubule nucleation at microtubule-organizing centres, also binds GTP; however, the importance of this association remains elusive. To address the role of GTP binding to gamma-tubulin, we systematically mutagenized the GTP contact residues in the yeast gamma-tubulin Tub4. Tub4(GTP)-mutant proteins that exhibited greatly reduced GTP affinity still assembled into the small gamma-tubulin complex. However, tub4(GTP) mutants were no longer viable, and had defects in interaction between gamma-tubulin and alphabeta-tubulin, decreased microtubule nucleation and defects in microtubule organization. In vitro and in vivo data show that only gamma-tubulin loaded with GTP nucleates microtubules. Our results suggest that GTP recruitment to gamma-tubulin enhances its interaction with alphabeta-tubulin similarly to GTP recruitment to beta-tubulin. PMID- 24161935 TI - Anaesthesia and orphan disease: a 26-year-old patient with achondroplasia. PMID- 24161933 TI - Determinants of robustness in spindle assembly checkpoint signalling. AB - The spindle assembly checkpoint is a conserved signalling pathway that protects genome integrity. Given its central importance, this checkpoint should withstand stochastic fluctuations and environmental perturbations, but the extent of and mechanisms underlying its robustness remain unknown. We probed spindle assembly checkpoint signalling by modulating checkpoint protein abundance and nutrient conditions in fission yeast. For core checkpoint proteins, a mere 20% reduction can suffice to impair signalling, revealing a surprising fragility. Quantification of protein abundance in single cells showed little variability (noise) of critical proteins, explaining why the checkpoint normally functions reliably. Checkpoint-mediated stoichiometric inhibition of the anaphase activator Cdc20 (Slp1 in Schizosaccharomyces pombe) can account for the tolerance towards small fluctuations in protein abundance and explains our observation that some perturbations lead to non-genetic variation in the checkpoint response. Our work highlights low gene expression noise as an important determinant of reliable checkpoint signalling. PMID- 24161934 TI - TGF-beta2 dictates disseminated tumour cell fate in target organs through TGF beta-RIII and p38alpha/beta signalling. AB - In patients, non-proliferative disseminated tumour cells (DTCs) can persist in the bone marrow (BM) while other organs (such as lung) present growing metastasis. This suggested that the BM might be a metastasis 'restrictive soil' by encoding dormancy-inducing cues in DTCs. Here we show in a head and neck squamous cell carcinoma (HNSCC) model that strong and specific transforming growth factor-beta2 (TGF-beta2) signalling in the BM activates the MAPK p38alpha/beta, inducing an (ERK/p38)(low) signalling ratio. This results in induction of DEC2/SHARP1 and p27, downregulation of cyclin-dependent kinase 4 (CDK4) and dormancy of malignant DTCs. TGF-beta2-induced dormancy required TGF beta receptor-I (TGF-beta-RI), TGF-beta-RIII and SMAD1/5 activation to induce p27. In lungs, a metastasis 'permissive soil' with low TGF-beta2 levels, DTC dormancy was short-lived and followed by metastatic growth. Importantly, systemic inhibition of TGF-beta-RI or p38alpha/beta activities awakened dormant DTCs, fuelling multi-organ metastasis. Our work reveals a 'seed and soil' mechanism where TGF-beta2 and TGF-beta-RIII signalling through p38alpha/beta regulates DTC dormancy and defines restrictive (BM) and permissive (lung) microenvironments for HNSCC metastasis. PMID- 24161936 TI - Hepatopulmonary syndrome: the anaesthetic considerations. AB - Hepatopulmonary syndrome (HPS) is a pulmonary complication observed in patients with chronic liver disease and/or portal hypertension, attributable to an intrapulmonary vascular dilatation that induces severe hypoxaemia. Considering the favourable long-term survival of HPS patients as well as the reversal of the syndrome with a functional liver graft, HPS is now an indication for orthotopic liver transplantation (OLT). Consequently, blood gas analysis and imaging techniques should be performed when cirrhotic patients present with shortness of breath as well as when OLT candidates are placed on the transplant waiting list. If the arterial partial pressure of oxygen (PaO2) is more than 10.7 kPa when breathing room air, HPS can be excluded and no other investigation is needed. When the PaO2 when breathing room air is 10.7 kPa or less, contrast-enhanced echocardiography should be performed to exclude pulmonary vascular dilatation. Lung function tests may also help detect additional pulmonary diseases that can contribute to impaired oxygenation. When contrast-enhanced echocardiography is negative, HPS is excluded and no follow-up is needed. When contrast-enhanced echocardiography is positive and PaO2 less than 8 kPa, patients should obtain a severity score that provides them with a reasonable probability of being transplanted within 3 months. In mild-to-moderate HPS (PaO2 8 to 10.6 kPa), periodic follow-up is recommended every 3 months to detect any further deterioration in PaO2. Although no intraoperative deaths have been directly attributed to HPS, oxygenation may worsen immediately following OLT due to volume overload and postoperative infections. Mechanical ventilation is often prolonged with an extended stay in the ICU. A high postoperative mortality (mostly within 6 months) is observed in this group of patients in comparison to non-HPS patients. However, the recovery of an adequate PaO2 within 12 months after OLT explains the similar outcome of HPS and non-HPS patients following OLT over a longer time period. PMID- 24161938 TI - Simple laccase-based biosensor for formetanate hydrochloride quantification in fruits. AB - This work describes the development of an electrochemical enzymatic biosensor for quantification of the pesticide formetanate hydrochloride (FMT). It is based on a gold electrode modified with electrodeposited gold nanoparticles and laccase. The principle behind its development relies on FMT's capacity to inhibit the laccase catalytic reaction that occurs in the presence of phenolic substrates. The optimum values for the relevant experimental variables such as gold nanoparticles electrochemical deposition (at -0.2V for 100s), laccase immobilization (via glutaraldehyde cross-linking), laccase concentration (12.4mg/mL), substrate selection and concentration (5.83*10(-5)M of aminophenol), pH (5.0), buffer (Britton-Robinson), and square-wave voltammetric parameters were determined. The developed biosensor was successfully applied to FMT determination in mango and grapes. The attained limit of detection was 9.5*10(-8)+/-9.5*10(-10)M (0.02+/ 2.6*10(-4)mg/kg on a fresh fruit weight basis). Recoveries for the five tested spiking levels ranged from 95.5+/-2.9 (grapes) to 108.6+/-2.5% (mango). The results indicated that the proposed device presents suitable characteristics in terms of sensitivity (20.58+/-0.49A/MUM), linearity (9.43*10(-7) to 1.13*10( 5)M), accuracy, repeatability (RSD of 1.4%), reproducibility (RSD of 1.8%) and stability (19days) for testing of compliance with established maximum residue limits of FMT in fruits and vegetables. PMID- 24161937 TI - Safety of an Escherichia coli-expressed bivalent human papillomavirus (types 16 and 18) L1 virus-like particle vaccine: an open-label phase I clinical trial. AB - An Escherichia coli-expressed recombinant bivalent human papillomavirus (types 16 and 18) vaccine candidate has been shown to be safe and immunogenic in preclinical trials. The safety of this vaccine was analyzed in an open-label phase I clinical trial in Jiangsu province, China. Thirty-eight healthy women from 18 to 55 y of age were enrolled and vaccinated at 0, 1, and 6 mo. Adverse events that occurred within 30 d after each injection and serious adverse events that occurred throughout the study were recorded. In addition, blood parameters were tested before and after each injection. All but one woman received all 3 doses. Thirty-two (84.2%) of the participants reported adverse events, all adverse events of which were mild, of short duration and resolved spontaneously. No serious adverse events occurred during the study. Changes in blood parameters after each injection were random, mild, and not clinically significant. These preliminary results show that a new Escherichia coli-expressed recombinant HPV 16/18 bivalent vaccine is well tolerated in healthy women and support further immunogenicity and efficacy studies for this HPV vaccine candidate. PMID- 24161940 TI - Identification and characterization of two new types of bacterial L-serine dehydratases and assessment of the function of the ACT domain. AB - Two new types of bacterial Fe-S L-serine dehydratases have been identified. These join two previously recognized enzyme types, for a total of four, that are distinguished on the basis of domain arrangement and amino acid sequence. A Type 3 enzyme from Amphibacillus xylanus (axLSD) and a Type 4 enzyme from Heliscomenobacter hydrossis (hhLSD) were cloned, expressed, purified, and characterized. Like the Type 1 enzyme from Bacillus subtilis (bsLSD), axLSD required a monovalent cation, preferably potassium, for activity. However, the hhLSD was without activity even after reconstitution of the iron-sulfur center by a process that successfully restored activity to oxygen-inactivated axLSD. This and other characteristics suggest that this Type 4 protein may be a pseudoenzyme. The oxygen sensitivity of axLSD was greater than other L-serine dehydratases so far studied and suggested that there may be significant conformational differences among the four types resulting in widely different solvent accessibility of the Fe-S clusters in these enzymes. The role of the ACT domain in these enzymes was explored by deleting it from bsLSD. Although there was an effect on the kinetic parameters, this domain was not responsible for the cation requirement nor did its removal have a significant effect on oxygen sensitivity. PMID- 24161939 TI - Effectiveness of the influenza vaccine at preventing hospitalization due to acute exacerbation of cardiopulmonary disease in Korea from 2011 to 2012. AB - There is a lack of targeted studies to validate the effectiveness of influenza vaccination on the reduction in influenza-related hospitalizations among patients with co-morbidities. In this study, we estimate the effectiveness of influenza vaccination on preventing hospitalizations in persons with cardiopulmonary disease and establish an evidence base for recommendations on influenza vaccination in this population. During the influenza epidemic in 2011-2012, we performed a multicenter, retrospective case-control study. Cases were patients hospitalized due to acute exacerbation of asthma, COPD, ischemic heart disease (IHD), and congestive heart failure (CHF). Controls were selected from outpatients who visited study hospitals but who were not hospitalized. Cases and controls were matched 1:1 based on age, gender, and date of hospital visit. Conditional logistic regression analyses were used to determine the effectiveness of vaccination. Between 25 December 2011 and 5 May 2012, 828 of each hospitalized and control subjects were identified. The influenza vaccination rate of the hospitalized and non-hospitalized patients was 54.2% and 60.4%, respectively (P = 0.006). The overall vaccine effectiveness for preventing hospitalization was 33.7% (95% confidence interval [CI] 14.0-49.0%; P = 0.002). Conditional logistic regression analysis showed that influenza vaccination significantly reduced the risk of hospitalization, especially due to acute exacerbation of IHD and CHF, in patients aged 65 y and older. The estimated vaccine effectiveness in these patients was 56.0% (95% CI 32.1-71.4%, P = 0.002). Influenza vaccination was associated with a reduction in the risk of hospitalization due to acute exacerbation of cardiopulmonary disease. We recommend the vaccine be given primarily to patients with underlying cardiovascular disease, particularly those 65 y of age and older. PMID- 24161941 TI - Heme oxygenation and the widening paradigm of heme degradation. AB - Heme degradation through the action of heme oxygenase (HO) is unusual in that it utilizes heme as both a substrate and cofactor for its own degradation. HO catalyzes the oxygen-dependent degradation of heme to biliverdin with the release of CO and "free" iron. The characterization of HO enzymes from humans to bacteria reveals a similar overall structural fold that contributes to the unique reaction manifold. The heme oxygenases share a similar heme-dependent activation of O2 to the ferric hydroperoxide as that of the cytochrome P450s and peroxidases. However, whereas the P450s promote cleavage of the ferric hydroperoxide OO bond to the oxoferryl species the HOs stabilize the ferric hydroperoxide promoting hydroxylation at the heme edge. The alternate reaction pathway in HO is achieved through the conformational flexibility and extensive hydrogen bond network within the heme binding site priming the heme for hydroxylation. Until recently it was believed that all heme degrading enzymes converted heme to biliverdin and iron, with the release of carbon monoxide (CO). However, the recent discovery of the bacterial IsdG-like heme degrading proteins of Staphylococcus aureus, Bacillus anthracis and Mycobacterium tuberculosis has expanded the reaction manifold of heme oxidation. Characterization of the heme degradation products in the IsdG like reaction suggests a mechanism distinct from the classical HOs. In the following review we will discuss the structure-function of the canonical HOs as it relates to the emerging alternate reaction manifold of the IsdG-like proteins. PMID- 24161942 TI - Kinetic isotope effects as a probe of hydrogen transfers to and from common enzymatic cofactors. AB - Enzymes use a number of common cofactors as sources of hydrogen to drive biological processes, but the physics of the hydrogen transfers to and from these cofactors is not fully understood. Researchers study the mechanistically important contributions from quantum tunneling and enzyme dynamics and connect those processes to the catalytic power of enzymes that use these cofactors. Here we describe some progress that has been made in studying these reactions, particularly through the use of kinetic isotope effects (KIEs). We first discuss the general theoretical framework necessary to interpret experimental KIEs, and then describe practical uses for KIEs in the context of two case studies. The first example is alcohol dehydrogenase, which uses a nicotinamide cofactor to catalyze a hydride transfer, and the second example is thymidylate synthase, which uses a folate cofactor to catalyze both a hydride and a proton transfer. PMID- 24161943 TI - 14-3-3epsilon and NAV2 interact to regulate neurite outgrowth and axon elongation. AB - Neuron navigator 2 (NAV2) is required for all-trans retinoic acid (atRA) to induce neurite outgrowth in human neuroblastoma cells. Further, ectopic overexpression of full-length human NAV2 rescues an axonal elongation defect in the Caenorhabditis elegans unc-53 (NAV2 ortholog) mutant. Using a region of NAV2 that independently associates with the cytoskeleton as bait in a yeast-two-hybrid screen, 14-3-3epsilon was identified as a novel NAV2 interacting partner. Amino acids 761-960 of NAV2 are sufficient to confer a positive interaction with 14-3 3epsilon as evidenced by a two-hybrid screen and co-immunoprecipitation assay. Knockdown of 14-3-3epsilon leads to a decrease in atRA-mediated neurite outgrowth, similar to the elongation defects observed when NAV2 is depleted or mutated. Likewise, posterior lateral microtubule (PLM) defects in C. elegans fed unc-53 RNAi are similar to those fed ftt-2 (14-3-3 homolog) RNAi. The discovery of an interaction between NAV2 and 14-3-3epsilon could provide insight into the mechanism by which NAV2 participates in promoting cell migration and neuronal elongation. PMID- 24161944 TI - CBS domains: Ligand binding sites and conformational variability. AB - Cystathionine beta-synthase (CBS) domains or CBS motifs are conserved structural domains that are present in thousands of non functionally-related proteins from all kingdoms of life. Their importance is underlined by the range of hereditary diseases associated with mutations in their amino acid sequence. CBS motifs associate in pairs referred to as Bateman modules. In contrast with initial assumptions, it is now well documented that CBS motifs and/or Bateman modules may suffer conformational changes upon binding of adenosine derivatives, metal ions or nucleic acids. The degree and direction of these structural changes depend on the type of ligand, the intrinsic features of the binding sites and the association manner of the Bateman modules. This review aims to provide a summary of the current knowledge on the structural basis of ligand recognition and on the structural effects caused by these ligands in CBS domain containing proteins. PMID- 24161945 TI - Hydrosilylation kinetics of silicon nanocrystals. AB - Hydrosilylation kinetics of hydride-capped silicon nanocrystals with 1-decene are reported for the first time. In a side-by-side comparison, it is found that microwave heating has no evident acceleration effect on the hydrosilylation rate relative to conventional thermal heating. PMID- 24161947 TI - Fusiforma themisticola n. gen., n. sp., a new genus and species of apostome ciliate infecting the hyperiid amphipod Themisto libellula in the Canadian Beaufort Sea (Arctic Ocean), and establishment of the Pseudocolliniidae (Ciliophora, Apostomatia). AB - A novel parasitic ciliate Fusiforma themisticola n. gen., n. sp. was discovered infecting 4.4% of the hyperiid amphipod Themisto libellula. Ciliates were isolated from a formaldehyde-fixed whole amphipod and the DNA was extracted for amplification of the small subunit (SSU) rRNA gene. Sequence and phylogenetic analyses showed unambiguously that this ciliate is an apostome and about 2% divergent from the krill-infesting apostome species assigned to the genus Pseudocollinia. Protargol silver impregnation showed a highly unusual infraciliature for an apostome. There are typically 8 (6-9) bipolar somatic kineties covering the banana-shaped body. The anterior end of the oral cavity begins about 1/3 of the body length from the anterior end and is composed of an inpocketing that is lined on its anterior and left wall with an oral field of densely packed ciliated kinetosomes. Stomatogenesis begins with some dedifferentiation of the parental oral field and elongation of its paroral and oral kineties. A new oral field develops midventrally and the paroral and oral kineties break to form the oral apparatus of the opisthe, which completes development by additional kinetosomal proliferation and migration of the paroral. This morphology is novel among apostomes and justifies the establishment of a new genus and species. PMID- 24161948 TI - Effects of electrical pulse polarity shape on intra cochlear neural responses in humans: triphasic pulses with cathodic second phase. AB - Charge balanced pulses are used in modern cochlear implants to avoid direct current (DC) stimulation that may damage neural tissues. In this context the effect of electrical pulse shape and polarity is still a matter of debate and the most effective pulse shape needs to be determined (Bahmer et al., 2010a; Undurraga et al., 2010; Wieringen et al., 2008; Macherey et al., 2008). Therefore, we conducted electrophysiological measurements, namely electrical compound action potentials (ECAPs) to assess response strength elicited by various pulse shapes and polarities in five cochlear implant recipients (SonataTI100/PulsarCI100 devices, MED-EL Innsbruck). ECAP response strength depending on pulse shape was compared with individual psychophysical thresholds. Results indicated the weakest response amplitude and highest thresholds for symmetric triphasic pulse shapes (with cathodic second phase), and the strongest response amplitude and lowest thresholds for biphasic pulses with anodic first phase. Biphasic pulses with cathodic first phase generated intermediate response amplitude and thresholds. PMID- 24161946 TI - Niche-based screening identifies small-molecule inhibitors of leukemia stem cells. AB - Efforts to develop more effective therapies for acute leukemia may benefit from high-throughput screening systems that reflect the complex physiology of the disease, including leukemia stem cells (LSCs) and supportive interactions with the bone marrow microenvironment. The therapeutic targeting of LSCs is challenging because LSCs are highly similar to normal hematopoietic stem and progenitor cells (HSPCs) and are protected by stromal cells in vivo. We screened 14,718 compounds in a leukemia-stroma co-culture system for inhibition of cobblestone formation, a cellular behavior associated with stem-cell function. Among those compounds that inhibited malignant cells but spared HSPCs was the cholesterol-lowering drug lovastatin. Lovastatin showed anti-LSC activity in vitro and in an in vivo bone marrow transplantation model. Mechanistic studies demonstrated that the effect was on target, via inhibition of HMG-CoA reductase. These results illustrate the power of merging physiologically relevant models with high-throughput screening. PMID- 24161949 TI - Connect the dots: a rare case of spontaneous haemopneumothorax. PMID- 24161951 TI - Cross-talk between diverse serine integrases. AB - Phage-encoded serine integrases are large serine recombinases that mediate integrative and excisive site-specific recombination of temperate phage genomes. They are well suited for use in heterologous systems and for synthetic genetic circuits as the attP and attB attachment sites are small (<50 bp), there are no host factor or DNA supercoiling requirements, and they are strongly directional, doing only excisive recombination in the presence of a recombination directionality factor. Combining different recombinases that function independently and without cross-talk to construct complex synthetic circuits is desirable, and several different serine integrases are available. However, we show here that these functions are not reliably predictable, and we describe a pair of serine integrases encoded by mycobacteriophages Bxz2 and Peaches with unusual and unpredictable specificities. The integrases share only 59% amino acid sequence identity and the attP sites have fewer than 50% shared bases, but they use the same attB site and there is non-reciprocal cross-talk between the two systems. The DNA binding specificities do not result from differences in specific DNA contacts but from the constraints imposed by the configuration of the component half-sites within each of the attachment site DNAs. PMID- 24161950 TI - Exploration of alternate catalytic mechanisms and optimization strategies for retroaldolase design. AB - Designed retroaldolases have utilized a nucleophilic lysine to promote carbon carbon bond cleavage of beta-hydroxy-ketones via a covalent Schiff base intermediate. Previous computational designs have incorporated a water molecule to facilitate formation and breakdown of the carbinolamine intermediate to give the Schiff base and to function as a general acid/base. Here we investigate an alternative active-site design in which the catalytic water molecule was replaced by the side chain of a glutamic acid. Five out of seven designs expressed solubly and exhibited catalytic efficiencies similar to previously designed retroaldolases for the conversion of 4-hydroxy-4-(6-methoxy-2-naphthyl)-2 butanone to 6-methoxy-2-naphthaldehyde and acetone. After one round of site directed saturation mutagenesis, improved variants of the two best designs, RA114 and RA117, exhibited among the highest kcat (>10(-3)s(-1)) and kcat/KM (11-25M( 1)s(-1)) values observed for retroaldolase designs prior to comprehensive directed evolution. In both cases, the >10(5)-fold rate accelerations that were achieved are within 1-3 orders of magnitude of the rate enhancements reported for the best catalysts for related reactions, including catalytic antibodies (kcat/kuncat=10(6) to 10(8)) and an extensively evolved computational design (kcat/kuncat>10(7)). The catalytic sites, revealed by X-ray structures of optimized versions of the two active designs, are in close agreement with the design models except for the catalytic lysine in RA114. We further improved the variants by computational remodeling of the loops and yeast display selection for reactivity of the catalytic lysine with a diketone probe, obtaining an additional order of magnitude enhancement in activity with both approaches. PMID- 24161952 TI - Structural analysis and optimization of the covalent association between SpyCatcher and a peptide Tag. AB - Peptide tagging is a key strategy for observing and isolating proteins. However, the interactions of proteins with peptides are nearly all rapidly reversible. Proteins tagged with the peptide SpyTag form an irreversible covalent bond to the SpyCatcher protein via a spontaneous isopeptide linkage, thereby offering a genetically encoded way to create peptide interactions that resist force and harsh conditions. Here, we determined the crystal structure of the reconstituted covalent complex of SpyTag and SpyCatcher at 2.1A resolution. The structure showed the expected reformation of the beta-sandwich domain seen in the parental streptococcal adhesin, but flanking sequences at both N- and C-termini of SpyCatcher were disordered. In addition, only 10 out of 13 amino acids of the SpyTag peptide were observed to interact with SpyCatcher, pointing to specific contacts important for rapid split protein reconstitution. Based on these structural insights, we expressed a range of SpyCatcher variants and identified a minimized SpyCatcher, 32 residues shorter, that maintained rapid reaction with SpyTag. Together, these results give insight into split protein beta-strand complementation and enhance a distinct approach to ultrastable molecular interaction. PMID- 24161954 TI - B-Raf mutation: a key player in molecular biology of cancer. AB - B-Raf is one of the more commonly mutated proto-oncogenes implicated in the development of cancers. In this review, we consider the mechanisms and clinical impacts of B-Raf mutations in cancer and discuss the implications for the patient in melanoma, thyroid cancer and colorectal cancer, where B-Raf mutations are particularly common. PMID- 24161955 TI - Changes in the pathogenesis of alcohol-induced liver disease -- preclinical studies. AB - Excessive alcohol consumption presents considerable health risks in humans. A variety of morphologic and functional changes contribute to hepatic injury produced by heavy drinking. The present review summarizes the current knowledge of alcohol-induced liver disease and describes preclinical experimental approaches used to understand alcoholic liver disease (ALD), with a particular emphasis on impaired protein and lipid trafficking, disruption of proteolysis and autophagy, alterations in methionine metabolism and perturbations in metabolic signaling that cause dysfunctional gene expression and the eventual formation of aggresomal Mallory-Denk bodies (MDB) in liver cells. These changes eventually lead to some of the more severe hepatic impairments, including alcoholic hepatitis and fibrosis. Moreover the misuse of alcohol contributes to immune dysfunction and inadequate immune response to viral infections. PMID- 24161953 TI - The oligomeric state of the active Vps4 AAA ATPase. AB - The cellular ESCRT (endosomal sorting complexes required for transport) pathway drives membrane constriction toward the cytosol and effects membrane fission during cytokinesis, endosomal sorting, and the release of many enveloped viruses, including the human immunodeficiency virus. A component of this pathway, the AAA ATPase Vps4, provides energy for pathway progression. Although it is established that Vps4 functions as an oligomer, subunit stoichiometry and other fundamental features of the functional enzyme are unclear. Here, we report that although some mutant Vps4 proteins form dodecameric assemblies, active wild-type Saccharomyces cerevisiae and Sulfolobus solfataricus Vps4 enzymes can form hexamers in the presence of ATP and ADP, as assayed by size-exclusion chromatography and equilibrium analytical ultracentrifugation. The Vta1p activator binds hexameric yeast Vps4p without changing the oligomeric state of Vps4p, implying that the active Vta1p-Vps4p complex also contains a single hexameric ring. Additionally, we report crystal structures of two different archaeal Vps4 homologs, whose structures and lattice interactions suggest a conserved mode of oligomerization. Disruption of the proposed hexamerization interface by mutagenesis abolished the ATPase activity of archaeal Vps4 proteins and blocked Vps4p function in S. cerevisiae. These data challenge the prevailing model that active Vps4 is a double-ring dodecamer, and argue that, like other type I AAA ATPases, Vps4 functions as a single ring with six subunits. PMID- 24161956 TI - Impact of tissue processing, archiving and enrichment techniques on DNA methylation yield in rectal carcinoma. AB - BACKGROUND: Formalin fixation, duration of tissue storage and tissue enrichment techniques can affect DNA methylation yield but these effects have not been quantitatively measured. The aim is to investigate the relative impact of these conditions on DNA methylation in rectal cancer. METHODS: 10 rectal cancers with matched undissected fresh frozen tissues, laser capture microdissected (LCM) formalin-fixed paraffin-embedded (FFPE) tissues, manual macrodissected FFPE tissues, adjacent normal mucosa and stromal tissues were analysed for APC and LINE-1 methylation using bisulphite pyrosequencing. RESULTS: FFPE cancer tissues, which had been stored for at least 4 years showed similar APC and LINE-1 methylation changes to matched fresh frozen cancer tissues. Laser capture microdissection did not increase the degree of methylation detected compared to manual macrodissection. Analysis of stromal tissues showed that they had undergone significant methylation changes compared to adjacent macroscopically normal mucosa, but not to the same extent as cancer tissues. CONCLUSION: Reliable DNA methylation results can be obtained from FFPE rectal cancer tissues, which have been in long-term storage. Because only minor differences in methylation between macrodissected and LCM cancer tissues were found, our results do not support the routine use of LCM to enrich for cancer cells for DNA methylation studies. PMID- 24161958 TI - MicroRNAs as novel biological targets for detection and regulation. AB - MicroRNAs are being considered as a novel type of bio-markers and potential therapeutic targets for various diseases. Diverse chemical tools are being developed for the detection or regulation of microRNAs with bio-medical implications. Chemical probes have been developed for use in combination with in situ signal amplification strategies to realize sensitive detection of microRNAs of low abundance. Regulation of microRNAs aberrantly expressed in tumours represents a new approach to cancer chemotherapy. Synthetic oligonucleotides including antisense oligonucleotides and microRNA mimics have been successfully delivered into cells or tissues to inhibit or enhance the function of specific endogenous microRNAs. Small-molecule modifiers of microRNAs that modify the expression or function of endogenous microRNAs are emerging not only as useful probes to explore microRNA-involved regulatory networks, but also as potential therapeutic reagents. In this tutorial review, we discuss the strategies developed by chemists in recent years for microRNA detection and regulation, with a focus on the potential of these chemical tools in microRNA-related biomedical applications. PMID- 24161959 TI - Molecular mimicry and original biochemical strategies for the biogenesis of a Legionella pneumophila replicative niche in phagocytic cells. AB - Legionella pneumophila is a paradigm of highly adapted intravacuolar pathogens that acquired the rare ability to replicate within a phagocytic cell. Here, we review recent progress about the role of Type 4 secretion system effectors involved in the biogenesis of the replicative niche, the Legionella containing vacuole. PMID- 24161960 TI - Escherichia coli K1 induces pterin production for enhanced expression of Fcgamma receptor I to invade RAW 264.7 macrophages. AB - Macrophages serve as permissive niches for Escherichia coli (E. coli) K1 to attain high grade bacteremia in the pathogenesis of meningitis in neonates. Although pterin levels are a diagnostic marker for immune activation, the role of macrophages in pterin production and in the establishment of meningitis is unknown. Here, we demonstrate that macrophages infected with E. coli K1 produce both neopterin and biopterin through increased expression of GTP-cyclohydrolase 1 (GCH1). Of note, increased production of biopterin enhances the expression of Fc gamma receptor I (CD64), which in turn, aided the entry of E. coli K1 in macrophages while increased neopterin suppresses reactive oxygen species (ROS), thereby aiding bacterial survival. Inhibition of GCH1 by 2, 4-Diamino-6 hydroxypyrimidine (DAHP) prevented the E. coli K1 induced expression of CD64 in macrophages in vitro and the development of bacteremia in a newborn mouse model of meningitis. These studies suggest that targeting GCH1 could be therapeutic strategy for preventing neonatal meningitis by E. coli K1. PMID- 24161961 TI - SERS spectroscopic approach to study doxorubicin complexes with Fe(2+) ions and drug release from SPION-based nanocarriers. AB - The aim of this work is to present a surface-enhanced Raman scattering (SERS) spectroscopic approach to study complexes of a frequently used antineoplastic agent, doxorubicin (DOX), with ferrous ions, at sub-micromolar concentrations in aqueous solution. The SERS bands of DOX were assigned according to critical analysis of literature. Prior to the complexation study, the spectral changes related to the drug orientation on the silver surface and to its protonation state were highlighted. The SERS spectra of DOX-Fe(2+) complexes showed several features distinguishing them from the free drug, protonated or not on the phenolic part of its chromophore. The lowest detectable content of the DOX-iron complex in the presence of free DOX was estimated to be 5-10%. This property is particularly interesting from the analytical point of view, since it allows for study of drug-iron interactions upon the drug loading on and release from magnetic drug carriers based on superparamagnetic iron oxide nanoparticles (SPIONs), stabilized with citrate ions or coated with polyethylene glycol (PEG) polymer. Our SERS data indicate that the drug loaded on magnetic nanocarriers as DOX-iron chelate was mainly released in the free DOX form. These results demonstrate the strength of the SERS approach for the study of DOX-iron interactions in relation to delivery issues and drug action mechanisms. PMID- 24161963 TI - Impaired left ventricular mechanics in nonalcoholic fatty liver disease: a speckle-tracking echocardiography study. AB - BACKGROUND: Nonalcoholic fatty liver disease (NAFLD) encompasses a disease spectrum ranging from simple steatosis to nonalcoholic steatohepatitis (NASH). We aimed to evaluate left ventricular (LV) systolic function using two-dimensional speckle-tracking echocardiography (2D-STE) in patients with NAFLD and to investigate whether any changes exist among the subgroups of NAFLD. MATERIALS AND METHODS: We included 55 NAFLD patients and 21 healthy controls. The diagnosis of NAFLD was made on the basis of liver biopsy. After the patients were categorized into groups according to their histopathological analysis (simple steatosis, borderline NASH, and definitive NASH), all patients underwent echocardiography. In the 2D-STE analysis of the LV global longitudinal strain (G-LS), strain rate in systole (G-SRsys), strain rate in early diastole (G-SRearly), and strain rate in late diastole (G-SRlate) values were obtained. RESULTS: G-LS and G-SRsys values were lower in the NAFLD group. Although there was a significant difference in the G-LS between controls and simple steatosis, borderline NASH, and definitive NASH, no significant differences were found between NAFLD groups. To investigate whether impaired LV systolic dysfunction, determined using 2D-STE, is the consequence of NAFLD components, we included a subgroup. A total of 11 patients with NAFLD who were normotensive, nondiabetic, nonobese, and had a normal lipid profile and low homeostasis model assessment of insulin resistance (HOMA-IR) values were included. Echocardiographic abnormalities in systolic function were not different between this subgroup of NAFLD and healthy individuals. CONCLUSION: Patients with NAFLD and its subgroups have evidence of subclinical myocardial dysfunction in relation to the presence of insulin resistance. 2D-STE could not be used for differentiation of the NAFLD subgroups. PMID- 24161962 TI - Diagnosis, surveillance, and treatment strategies for familial adenomatous polyposis: rationale and update. AB - Familial adenomatous polyposis is characterized by the development of multiple (>100) colorectal adenomas throughout the colorectum. This disorder can be caused by a germline mutation in the adenomatous polyposis coli gene and can be diagnosed either clinically or genetically. After diagnosis with the condition, patients should undergo prophylactic proctocolectomy with a neoreservoir, usually an ileoanal pouch, at an appropriate time. Individuals with a family history of this disease who have not been diagnosed should be advised to attend genetic counseling and to enroll in appropriate clinical and genetic surveillance programs. Recent progress in endoscopic technology, including high-resolution endoscopy, capsule endoscopy, and double-balloon endoscopy, has made possible more detailed and wide-ranging investigation of the gastrointestinal tract. Although there has been limited evidence, further studies on these new endoscopic technologies might alter the surveillance strategies for familial adenomatous polyposis. PMID- 24161964 TI - Implantation of tetrapod-shaped granular artificial bones or beta-tricalcium phosphate granules in a canine large bone-defect model. AB - We investigated biodegradability and new bone formation after implantation of tetrapod-shaped granular artificial bone (Tetrabone(r)) or beta-tricalcium phosphate granules (beta-TCP) in experimental critical-size defects in dogs, which were created through medial and lateral femoral condyles. The defect was packed with Tetrabone(r) (Tetrabone group) or beta-TCP (beta-TCP group) or received no implant (control group). Computed tomography (CT) was performed at 0, 4 and 8 weeks after implantation. Micro-CT and histological analysis were conducted to measure the non-osseous tissue rate and the area and distribution of new bone tissue in the defect at 8 weeks after implantation. On CT, beta-TCP was gradually resorbed, while Tetrabone(r) showed minimal resorption at 8 weeks after implantation. On micro-CT, non-osseous tissue rate of the control group was significantly higher compared with the beta-TCP and Tetrabone groups (P<0.01), and that of the beta-TCP group was significantly higher compared with the Tetrabone group (P<0.05). On histology, area of new bone tissue of the beta-TCP group was significantly greater than those of the Tetrabone and control groups (P<0.05), and new bone distribution of the Tetrabone group was significantly greater than those of the beta-TCP and control groups (P<0.05). These results indicate differences in biodegradability and connectivity of intergranule pore structure between study samples. In conclusion, Tetrabone(r) may be superior for the repair of large bone defects in dogs. PMID- 24161965 TI - The regulation of the expression of ABCG2 gene through mitogen-activated protein kinase pathways in canine lymphoid tumor cell lines. AB - Treatments for canine lymphoma often fail, because tumor cells acquire multidrug resistance (MDR). MDR can develop through several mechanisms, among which the overexpression of drug transporters in tumor cells is a well-studied mechanism. ATP-binding cassette sub-family G member 2 (ABCG2) belongs to the ABC transporters, that are representative drug efflux pumps associated with MDR in human tumor cells. However, the regulation of ABCG2 gene expression in canine tumors is not well understood. The purpose of the present study was to reveal the regulatory mechanism of ABCG2 gene expression in 4 canine lymphoid tumor cell lines, GL-1, CLBL-1, UL-1 and Ema. Treatment with phorbol 12-myristate 13-acetate (PMA), the protein kinase C (PKC) activator, stimulated MAPK/ERK pathway in GL-1, UL-1 and Ema cells and JNK pathway in UL-1 and Ema cells. When GL-1 and UL-1 cells were treated with PMA and the MAPK/ERK kinase inhibitor U0126, ABCG2 gene expression levels were elevated above those in untreated cells. Similarly, ABCG2 gene expression increased above control levels in UL-1 and Ema cells treated with PMA and the JNK inhibitor SP600125. However, ABCG2 gene expression was unaffected by U0126 exposure in CLBL-1 cells, in which activation of MAPK/ERK pathway was observed in non-treated cells. These results suggested that MAPK/ERK and JNK pathways downregulate ABCG2 gene expression, which is upregulated by unidentified but possibly PKC-dependent pathways, in several types of canine lymphoid tumor cells. PMID- 24161966 TI - Real-time PCR genotyping assay for GM2 gangliosidosis variant 0 in toy poodles and the mutant allele frequency in Japan. AB - GM2 gangliosidosis variant 0 (Sandhoff disease, SD) is a fatal, progressive neurodegenerative lysosomal storage disease caused by mutations of the HEXB gene. In canine SD, a pathogenic mutation (c.283delG) of the canine HEXB gene has been identified in toy poodles. In the present study, a TaqMan probe-based real-time PCR genotyping assay was developed and evaluated for rapid and large-scale genotyping and screening for this mutation. Furthermore, a genotyping survey was carried out in a population of toy poodles in Japan to determine the current mutant allele frequency. The real-time PCR assay clearly showed all genotypes of canine SD. The assay was suitable for large-scale survey as well as diagnosis, because of its high throughput and rapidity. The genotyping survey demonstrated a carrier frequency of 0.2%, suggesting that the current mutant allele frequency is low in Japan. However, there may be population stratification in different places, because of the founder effect by some carriers. Therefore, this new assay will be useful for the prevention and control of SD in toy poodles. PMID- 24161967 TI - The way you say it. PMID- 24161968 TI - The author file: Jeff Dangl. PMID- 24161969 TI - Points of significance: error bars. PMID- 24161970 TI - Stem cells: The developing human brain--modeled in a dish. PMID- 24161971 TI - Molecular engineering: Antibodies, made to order. PMID- 24161972 TI - Molecular biology: A tool belt for GFP. PMID- 24161982 TI - Cell biology: Self-destruct sequences. PMID- 24161973 TI - Biochemistry: Constructing complicated carbohydrates. PMID- 24161983 TI - Gene expression: Studying function at the genome scale. PMID- 24161984 TI - Synthetic biology: Engineering off the beaten pathway. PMID- 24161986 TI - Retraction: Marker-independent identification of glioma-initiating cells. PMID- 24161989 TI - Characterizing the laulimalide-peloruside binding site using site-directed mutagenesis of TUB2 in S. cerevisiae. AB - Baker's yeast, Saccharomyces cerevisiae, has significant sequence conservation with a core subset of mammalian proteins and can serve as a model for disease processes. The aim of this study was to determine whether yeast could be used as a model system to identify new agents that interact with the laulimalide peloruside binding site on beta-tubulin. Agents that bind to this site cause stabilization of microtubules and interfere with cell division. Based on the location of the proposed laulimalide-peloruside binding site and of previously identified mutations shown to cause resistance in mammalian cells, we made the corresponding mutations in yeast and tested whether they conferred resistance to laulimalide and peloruside. Mutations A296T and R306H, which cause 6-fold and 40 fold increased resistance in human 1A9 ovarian carcinoma cells, respectively, also led to resistance in yeast to these compounds. Similarly, other mutations led to resistance or, in one case, increased sensitivity. Thus, we conclude that yeast is an appropriate model to screen for small molecule drugs that may be efficacious in cancer therapy in humans through the newly characterised laulimalide-peloruside binding site. PMID- 24161985 TI - A reversible gene trap collection empowers haploid genetics in human cells. AB - Knockout collections are invaluable tools for studying model organisms such as yeast. However, there are no large-scale knockout collections of human cells. Using gene-trap mutagenesis in near-haploid human cells, we established a platform to generate and isolate individual 'gene-trapped cells' and used it to prepare a collection of human cell lines carrying single gene-trap insertions. In most cases, the insertion can be reversed. This growing library covers 3,396 genes, one-third of the expressed genome, is DNA-barcoded and allows systematic screens for a wide variety of cellular phenotypes. We examined cellular responses to TNF-alpha, TGF-beta, IFN-gamma and TNF-related apoptosis-inducing ligand (TRAIL), to illustrate the value of this unique collection of isogenic human cell lines. PMID- 24161990 TI - Apoptosis-like death in Leishmania donovani promastigotes induced by eugenol-rich oil of Syzygium aromaticum. AB - Leishmaniasis consists of a complex spectrum of infectious diseases with worldwide distribution of which visceral leishmaniasis or kala-azar caused by Leishmania donovani is the most devastating. In the absence of vaccines, chemotherapy remains the mainstay for the control of leishmaniasis. The drugs of choice are expensive and associated with multiple adverse side effects. Because of these limitations, the development of new antileishmanial compounds is imperative and plants offer prospects in this regard. The present work was conducted to study the antileishmanial potential of oil from Syzygium aromaticum flower buds (clove). The S. aromaticum oil was characterized by gas chromatography and GC-MS and eugenol as well as eugenyl acetate were found to be the most abundant compounds, composing 59.75 % and 29.24 %, respectively of the oil. Our findings have shown that eugenol-rich essential oil from S. aromaticum (EROSA) possesses significant activity against L. donovani, with 50 % inhibitory concentration of 21 +/- 0.16 ug ml(-1) and 15.24 +/- 0.14 ug ml(-1), respectively, against promastigotes and intracellular amastigotes. Alterations in cellular morphology and growth reversibility assay substantiated the leishmanicidal activity of EROSA. The leishmanicidal effect was mediated via apoptosis as confirmed by externalization of phosphatidylserine, DNA nicking by TdT-mediated dUTP nick-end labelling (TUNEL) assay, dyskinetoplastidy, cell cycle arrest at sub-G0-G1 phase, loss of mitochondrial membrane potential and reactive oxygen species generation. EROSA presented no adverse cytotoxic effects against murine macrophages even at 200 ug ml(-1). Our studies authenticate the promising antileishmanial activity of EROSA, which is mediated by programmed cell death, and, accordingly, EROSA may be a source of novel agents for the treatment of leishmaniasis. PMID- 24161991 TI - CDK6 and p16INK4A in lymphoid malignancies. PMID- 24161992 TI - Quantum mechanical which-way experiment with an internal degree of freedom. AB - For a particle travelling through an interferometer, the trade-off between the available which-way information and the interference visibility provides a lucid manifestation of the quantum mechanical wave-particle duality. Here we analyse this relation for a particle possessing an internal degree of freedom such as spin. We quantify the trade-off with a general inequality that paints an unexpectedly intricate picture of wave-particle duality when internal states are involved. Strikingly, in some instances which-way information becomes erased by introducing classical uncertainty in the internal degree of freedom. Furthermore, even imperfect interference visibility measured for a suitable set of spin preparations can be sufficient to infer absence of which-way information. General results are illustrated with a proof-of-principle single-photon experiment. PMID- 24161993 TI - Structural insights into the interaction of platinum-based inhibitors with the Alzheimer's disease amyloid-beta peptide. AB - Extended X-ray absorption fine structure spectroscopy, mass spectrometry, dynamic light scattering and density functional theory are combined to derive structural models for the interaction of neurotoxicity-ablating platinum-based compounds with the amyloid-beta peptide. PMID- 24161994 TI - Da-Huang-Fu-Zi-Tang attenuates liver injury in rats with severe acute pancreatitis. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Da-Huang-Fu-Zi-Tang (DHFZT) is a famous traditional Chinese prescription with strong anti-inflammatory effects. Our previous work found that DHFZT could act against pancreatic injury in rats with severe acute pancreatitis (SAP) via inhibiting the Janus kinase 2/signal transducers and activators of transcription 3 (JAK2/STAT3) signaling pathway in pancreatic tissues. AIM OF THE STUDY: To investigate the therapeutic effects of DHFZT on liver injury in SAP rats, and the effects on JAK2/STAT3 signaling in liver tissue and Kupffer cells (KCs). MATERIALS AND METHODS: Fifty SD male rats were randomly divided into five groups: sham operation group (SO), SAP model group, DHFZT treatment groups (12, 24, and 48 mg/kg body weight). The model of SAP was constructed by injecting sodium taurocholate (3.5%) into pancreatic and biliary ducts. One hour before constructing the model, DHFZT was perfused into the stomach. All rats were sacrificed after 24h following the operation; livers were examined with hematoxylin and eosin staining. The protein expression of pJAK2 and pSTAT3 in liver tissue was detected by immunohistochemical staining. The activity of ALT, IL-6 and TNF-alpha in serum was detected. KCs of each group were isolated. After culture for 4h, the protein expression of JAK2, pJAK2, STAT3 and pSTAT3, the mRNA expression of IL-6 and TNF-alpha in KCs were examined. RESULTS: Sodium taurocholate induced liver injury concomitant with increased expression of pJAK2 and pSTAT3 in liver tissue and KCs. Pretreatment with DHFZT significantly attenuated liver injury induced by SAP, and concurrently, effectively lowered the serum ALT level. Furthermore, our studies showed that DHFZT obviously decreased the expression of pJAK2 and pSTAT3 in liver tissue and KCs. CONCLUSIONS: DHFZT could ameliorate liver injury in rats with SAP. PMID- 24161995 TI - Acupuncture treatment for hypertension: a case study. AB - This report describes the regular use of acupuncture treatments for a patient with hypertension who could not tolerate the side effects of the antihypertensive agents. The patient received 60 acupuncture treatments in the course of 12 weeks, during which time his overall wellbeing improved, his blood pressure reduced and the side effects of antihypertensive drugs were removed. Although acupuncture plus the drug appeared to have a substantial synergistic effect that was weakened when the drug was discontinued, acupuncture may still play a role in the management of hypertension, especially for patients who cannot tolerate the side effects of antihypertensive agents. PMID- 24161996 TI - Effects of electroacupuncture on bone mineral density, oestradiol level and osteoprotegerin ligand expression in ovariectomised rabbits. AB - OBJECTIVES: To investigate the effects of electroacupuncture (EA) on the oestradiol level, bone mineral density and osteoprotegerin ligand (OPGL) expression, and to explore whether EA might be a complementary method to prevent and treat osteoporosis. METHODS: A total of 21 New Zealand rabbits were randomly divided into three groups: a normal control (NC) group undergoing no surgery or EA; an ovariectomised (OVX) group, in which rabbits were ovariectomised but did not receive EA; an EA group, in which rabbits were ovariectomised and treated with EA. Acupuncture was applied at ST35, BL20 and BL23 points bilaterally. EA (10 Hz, 2 mA) was applied bilaterally at BL20 and BL23 for 30 min a day for 14 days. After 14 days, all animals were killed. OPGL expression level was determined by immunohistochemistry. Blood serum levels of oestradiol were measured by ELISA and bone mineral density was detected by dual-energy x-ray absorptiometry. RESULTS: After ovariectomy, the bone mineral density and oestradiol level decreased significantly in the OVX group compared with the NC group (p=0.001), whereas the OPGL expression level increased. After EA, the bone mineral density and oestradiol level increased compared with the OVX group (p=0.049 and p=0.012, respectively). The OPGL level OPGL level in the EA group was lower than that in the OVX group (p=0.022). CONCLUSIONS: EA restored bone mineral density towards normal and was associated with increased plasma oestradiol level and reduced OPGL expression in an ovariectomised rabbit model of osteoporosis. PMID- 24161997 TI - The economic burden of genetic tests for the infertile male: a pilot algorithm to improve test predictive value. AB - PURPOSE: We developed a model to optimize genetic testing in infertile men with nonobstructive azoospermia and severe oligospermia. We also assessed the optimal cutoff value of the predicted probability of advising genetic testing and evaluated the direct cost saving of using the model. MATERIALS AND METHODS: We retrospectively reviewed the records of infertile men who underwent Y microdeletion and karyotype testing at our fertility center from 2006 to 2012. Semen parameters, testicular volume, testosterone, luteinizing hormone, follicular stimulating hormone and varicocele were assessed as potential predictors of genetic disorders. We fitted logistic regression to all predictors and selected a nomogram based on the concordance index and calibration. We calculated the cost saving of using the model. RESULTS: Of 325 patients 278 fulfilled study inclusion criteria, including 27 with an abnormal karyotype, 11 with a Y microdeletion and 1 with each condition. We developed a nomogram using sperm concentration and motility, testicular volume and serum testosterone level. The nomogram concordance index was 0.738. The optimal cutoff value was 13.8% with 0.788 sensitivity, 0.590 specificity, 0.245 positive predictive value and 0.943 negative predictive value. Testing men above the 13.8% cutoff resulted in a direct 45% cost saving. However, 15.4% of genetic anomalies were missed, including 2 Y microdeletions. CONCLUSIONS: Using common clinical and laboratory parameters our nomogram detects 84.6% of genetic anomalies. Nomogram use resulted in a 45% direct cost saving but carries the risk of missing pertinent genetic abnormalities. PMID- 24161998 TI - Bone mineral density and response to treatment in men younger than 50 years with testosterone deficiency and sexual dysfunction or infertility. AB - PURPOSE: Testosterone deficiency is a known risk factor for osteopenia and osteoporosis in older men. Less is known about the impact of testosterone deficiency on bone mineral density in younger men. MATERIALS AND METHODS: We retrospectively reviewed the charts at an andrology/infertility clinic and identified 399 men younger than 50 years who underwent baseline dual energy x-ray absorptiometry and had total testosterone less than 350 ng/dl or free testosterone less than 1.5 ng/dl. Additional analysis was done in a subgroup of 75 men (18.8%) in whom dual energy x-ray absorptiometry was repeated after treatment at a mean +/- SD of 30.4 +/- 16.2 months. The determination of osteoporosis or osteopenia was based on T-scores (osteopenia less than -1.0 and osteoporosis less than -2.5) of the lumbar spine and left hip. RESULTS: Of all 399 men 141 (35.3%) had bone mineral density consistent with osteopenia at the lumbar spine (137) and/or the total hip (19). In 11 men (2.75%) bone mineral density was consistent with osteoporosis at the lumbar spine. On multivariate analysis higher body mass index was independently associated with increased bone mineral density at the spine (p <0.0001) as well as the hip (p <0.001). Testosterone treatment in 43 men increased spine bone mineral density (p <0.001). Significant decreases in spine bone mineral density developed in 21 men treated with clomiphene citrate or anastrazole (p = 0.003). No significant change was noted in hip bone mineral density for any treatment. CONCLUSIONS: More than a third of men younger than 50 years with testosterone deficiency and infertility or sexual dysfunction had decreased bone mineral density. Testosterone treatment increased bone mineral density while estrogen modulators such as clomiphene citrate or aromatase inhibitors decreased bone mineral density. These results suggest that dual energy x-ray absorptiometry may be warranted in young men with testosterone deficiency. PMID- 24161999 TI - 'Enter at your own risk': a multimethod study of air quality and biological measures in Canadian waterpipe cafes. AB - BACKGROUND: Tobacco and non-tobacco-based waterpipe smoking has increased exponentially in many countries in recent decades, particularly among youth and young adults. Although tobacco smoking is banned in many indoor public places, waterpipe smoking, ostensibly non-tobacco, continues in Ontario and other jurisdictions where only tobacco smoking is prohibited. This study assessed air quality and exposure in waterpipe cafes using multiple methods and markers. METHODS: Indoor (n=12) and outdoor (n=5) air quality was assessed in Toronto, Canada waterpipe cafes from 30 August to 11 October 2012. Real-time measurements of air nicotine, fine particulate matter less than 2.5 microns in diameter (PM2.5) and ambient carbon monoxide (CO) were collected in 2 h sessions. Levels of CO in breath were collected in non-smoking field staff before entering and upon leaving venues. Observations of occupant behaviour, environmental changes and venue characteristics were also recorded. RESULTS: In indoor venues, mean values were 1419 ug/m(3) for PM2.5, 17.7 ppm for ambient CO, and 3.3 ug/m(3) for air nicotine. Levels increased with increasing number of active waterpipes. On outdoor patios, mean values were 80.5 ug/m(3) for PM2.5, 0.5 ppm for ambient CO, and 0.6 ug/m(3) for air nicotine. Air quality levels in indoor waterpipe cafes are hazardous for human health. Outdoor waterpipe cafes showed less harmful particulate levels than indoors, but mean PM2.5 levels (80.5 ug/m(3)) were still 'poor'. CONCLUSIONS: Staff and patrons of waterpipe cafes are exposed to air quality levels considered hazardous to human health. Results support eliminating waterpipe smoking in hospitality venues indoors and out. PMID- 24162000 TI - Nucleation, stability and current-induced motion of isolated magnetic skyrmions in nanostructures. AB - Magnetic skyrmions are topologically stable spin configurations, which usually originate from chiral interactions known as Dzyaloshinskii-Moriya interactions. Skyrmion lattices were initially observed in bulk non-centrosymmetric crystals, but have more recently been noted in ultrathin films, where their existence is explained by interfacial Dzyaloshinskii-Moriya interactions induced by the proximity to an adjacent layer with strong spin-orbit coupling. Skyrmions are promising candidates as information carriers for future information-processing devices due to their small size (down to a few nanometres) and to the very small current densities needed to displace skyrmion lattices. However, any practical application will probably require the creation, manipulation and detection of isolated skyrmions in magnetic thin-film nanostructures. Here, we demonstrate by numerical investigations that an isolated skyrmion can be a stable configuration in a nanostructure, can be locally nucleated by injection of spin-polarized current, and can be displaced by current-induced spin torques, even in the presence of large defects. PMID- 24162002 TI - Multilineage potential and proteomic profiling of human dental stem cells derived from a single donor. AB - Dental tissues provide an alternative autologous source of mesenchymal stem cells (MSCs) for regenerative medicine. In this study, we isolated human dental MSCs of follicle, pulp and papilla tissue from a single donor tooth after impacted third molar extraction by excluding the individual differences. We then compared the morphology, proliferation rate, expression of MSC-specific and pluripotency markers, and in vitro differentiation ability into osteoblasts, adipocytes, chondrocytes and functional hepatocyte-like cells (HLCs). Finally, we analyzed the protein expression profiles of undifferentiated dental MSCs using 2DE coupled with MALDI-TOF-MS. Three types of dental MSCs largely shared similar morphology, proliferation potential, expression of surface markers and pluripotent transcription factors, and differentiation ability into osteoblasts, adipocytes, and chondrocytes. Upon hepatogenic induction, all MSCs were transdifferentiated into functional HLCs, and acquired hepatocyte functions by showing their ability for glycogen storage and urea production. Based on the proteome profiling results, we identified nineteen proteins either found commonly or differentially expressed among the three types of dental MSCs. In conclusion, three kinds of dental MSCs from a single donor tooth possessed largely similar cellular properties and multilineage potential. Further, these dental MSCs had similar proteomic profiles, suggesting their interchangeable applications for basic research and call therapy. PMID- 24162001 TI - Highly efficient gate-tunable photocurrent generation in vertical heterostructures of layered materials. AB - Layered materials of graphene and MoS2, for example, have recently emerged as an exciting material system for future electronics and optoelectronics. Vertical integration of layered materials can enable the design of novel electronic and photonic devices. Here, we report highly efficient photocurrent generation from vertical heterostructures of layered materials. We show that vertically stacked graphene-MoS2-graphene and graphene-MoS2-metal junctions can be created with a broad junction area for efficient photon harvesting. The weak electrostatic screening effect of graphene allows the integration of single or dual gates under and/or above the vertical heterostructure to tune the band slope and photocurrent generation. We demonstrate that the amplitude and polarity of the photocurrent in the gated vertical heterostructures can be readily modulated by the electric field of an external gate to achieve a maximum external quantum efficiency of 55% and internal quantum efficiency up to 85%. Our study establishes a method to control photocarrier generation, separation and transport processes using an external electric field. PMID- 24162003 TI - Dimethyl phenyl piperazine iodide (DMPP) induces glioma regression by inhibiting angiogenesis. AB - 1,1-Dimethyl-4-phenyl piperazine iodide (DMPP) is a synthetic nicotinic acetylcholine receptor (nAChR) agonist that could reduce airway inflammation. In this study, we demonstrated that DMPP could dramatically inhibit glioma size maintained on the chick embryonic chorioallantoic membrane (CAM). We first performed MTT and BrdU incorporation experiments on U87 glioma cells in vitro to understand the mechanism involved. We established that DMPP did not significantly affect U87 cell proliferation and survival. We speculated that DMPP directly caused the tumor to regress by affecting the vasculature in and around the implanted tumor on our chick CAM model. Hence, we conducted detailed analysis of DMPP's inhibitory effects on angiogenesis. Three vasculogenesis and angiogenesis in vivo models were used in the study which included (1) early chick blood islands formation, (2) chick yolk-sac membrane (YSW) and (3) CAM models. The results revealed that DMPP directly suppressed all developmental stages involved in vasculogenesis and angiogenesis - possibly by acting through Ang-1 and HIF 2alpha signaling. In sum, our results show that DMPP could induce glioma regression grown on CAM by inhibiting vasculogenesis and angiogenesis. PMID- 24162004 TI - Becker muscular dystrophy-like myopathy regarded as so-called "fatty muscular dystrophy" in a pig: a case report and its diagnostic method. AB - We describe a case of human Becker muscular dystrophy (BMD)-like myopathy that was characterized by the declined stainability of dystrophin at sarcolemma in a pig and the immunostaining for dystrophin on the formalin-fixed, paraffin embedded (FFPE) tissue. The present case was found in a meat inspection center. The pig looked appeared healthy at the ante-mortem inspection. Muscular abnormalities were detected after carcass dressing as pale, discolored skeletal muscles with prominent fat infiltrations and considered so-called "fatty muscular dystrophy". Microscopic examination revealed following characteristics: diffused fat infiltration into the skeletal muscle and degeneration and regeneration of the remaining skeletal muscle fibers. Any lesions that were suspected of neurogenic atrophy, traumatic muscular degeneration, glycogen storage disease or other porcine muscular disorders were not observed. The immunostaining for dystrophin was conducted and confirmed to be applicable on FFPE porcine muscular tissues and revealed diminished stainability of dystrophin at the sarcolemma in the present case. Based on the histological observations and immunostaining results, the present case was diagnosed with BMD-like myopathy associated with dystrophin abnormality in a pig. Although the genetic properties were not clear, the present BMD-like myopathy implied the occurrence of dystrophinopathy in pigs. To the best of our knowledge, this is the first report of a natural case of myopathy associated with dystrophin abnormalities in a pig. PMID- 24162005 TI - Quintuple-modality (SERS-MRI-CT-TPL-PTT) plasmonic nanoprobe for theranostics. AB - A unique quintuple-modality theranostic nanoprobe (QMT) is developed with gold nanostars for surface-enhanced Raman scattering (SERS), magnetic resonance imaging (MRI), computed tomography (CT), two-photon luminescence (TPL) imaging and photothermal therapy (PTT). The synthesized gold nanostars were tagged with a SERS reporter and linked with an MRI contrast agent Gd(3+). In vitro experiments demonstrated the developed QMT nanoprobe to be a potential theranostic agent for future biomedical applications. PMID- 24162007 TI - What is the value of growth hormone therapy in Prader Willi syndrome? AB - Prader Willi syndrome (PWS) is a genetic condition caused by loss of the paternal copy of a region of imprinted genes on chromosome 15. There is severe muscular hypotonia in the neonatal period, with the onset of hyperphagia and food-seeking behaviour in childhood. All individuals with PWS have developmental delay. Without careful control of food intake and the food environment, individuals with PWS become morbidly obese and are likely to die as young adults from the complications of obesity. The aims of growth hormone (GH) treatment in PWS are distinct from the use of GH in other conditions-although GH does increase final height in PWS, the main benefits of treatment are improved body composition and better exercise capacity, which can help with the aim of preventing obesity. GH trials in PWS have demonstrated improved muscle bulk, reduced fat mass and increased levels of physical activity. GH has also been demonstrated to improve attainment of developmental and cognitive milestones in children with PWS. GH treatment appears to change respiratory status in PWS, possibly because of growth of lymphoid tissue at the start of treatment. Respiratory assessment is recommended prior to, and just after starting GH treatment. Ideal age for starting GH is not clear, although there has been a trend towards starting at younger ages. It may be that GH treatment in childhood confers benefits into adult life. There are less data to support continuing GH treatment into adult life. PMID- 24162006 TI - Management of Kawasaki disease. AB - Kawasaki disease (KD) is an acute self-limiting inflammatory disorder, associated with vasculitis, affecting predominantly medium-sized arteries, particularly the coronary arteries. In developed countries KD is the commonest cause of acquired heart disease in childhood. The aetiology of KD remains unknown, and it is currently believed that one or more as yet unidentified infectious agents induce an intense inflammatory host response in genetically susceptible individuals. Genetic studies have identified several susceptibility genes for KD and its sequelae in different ethnic populations, including FCGR2A, CD40, ITPKC, FAM167A BLK and CASP3, as well as genes influencing response to intravenous immunoglobulin (IVIG) and aneurysm formation such as FCGR3B, and transforming growth factor (TGF) beta pathway genes. IVIG and aspirin are effective therapeutically, but recent clinical trials and meta-analyses have demonstrated that the addition of corticosteroids to IVIG is beneficial for the prevention of coronary artery aneurysms (CAA) in severe cases with highest risk of IVIG resistance. Outside of Japan, however, clinical scores to predict IVIG resistance perform suboptimally. Furthermore, the evidence base does not provide clear guidance on which corticosteroid regimen is most effective. Other therapies, including anti-TNFalpha, could also have a role for IVIG-resistant KD. Irrespective of these caveats, it is clear that therapy that reduces inflammation in acute KD, improves outcome. This paper summarises recent advances in the understanding of KD pathogenesis and therapeutics, and provides an approach for managing KD patients in the UK in the light of these advances. PMID- 24162009 TI - Disproportionate disadvantage of the young: Britain, the Unicef report on child well-being, and political choices. PMID- 24162008 TI - Inhaled corticosteroid and children's growth. PMID- 24162010 TI - The expansion and functional diversification of the mammalian ribonuclease a superfamily epitomizes the efficiency of multigene families at generating biological novelty. AB - The ribonuclease (RNase) A superfamily is a vertebrate-specific gene family. Because of a massive expansion that occurred during the early mammalian evolution, extant mammals in general have much more RNase genes than nonmammalian vertebrates. Mammalian RNases have been associated with diverse physiological functions including digestion, cytotoxicity, angiogenesis, male reproduction, and host defense. However, it is still uncertain when their expansion occurred and how a wide array of functions arose during their evolution. To answer these questions, we generate a compendium of all RNase genes identified in 20 complete mammalian genomes including the platypus, Ornithorhynchus anatinus. Using this, we delineate 13 ancient RNase gene lineages that arose before the divergence between the monotreme and the other mammals (~220 Ma). These 13 ancient gene lineages are differentially retained in the 20 mammals, and the rate of protein sequence evolution is highly variable among them, which suggest that they have undergone extensive functional diversification. In addition, we identify 22 episodes of recent expansion of RNase genes, many of which have signatures of adaptive functional differentiation. Exemplifying this, bursts of gene duplication occurred for the RNase1, RNase4, and RNase5 genes of the little brown bat (Myotis lucifugus), which might have contributed to the species' effective defense against heavier pathogen loads caused by its communal roosting behavior. Our study illustrates how host-defense systems can generate new functions efficiently by employing a multigene family, which is crucial for a host organism to adapt to its ever-changing pathogen environment. PMID- 24162012 TI - Tunable catalytic activities and selectivities of metal ion doped TiO2 nanoparticles--oxidation of organic compounds. AB - A series of metal ion doped TiO2 nanoparticles (M-TiO2, M = Cr(3+), Mn(2+), Fe(3+), V(5+), Zn(2+), Ni(2+), Ag(+), Cu(2+) and Co(2+)) were prepared by a facile co-precipitation approach and characterized by means of ICP-AES, N2 adsorption-desorption isotherms, XRD, TEM and HRTEM. Their catalytic performance was investigated via the oxidation of organic compounds. The variation of metal ion species and doping contents allowed tuning the catalytic properties of the M TiO2. Among them, the catalyst Cu-10 displayed excellent activity (97.5%) in the oxidation of styrene and the selectivity of benzaldehyde was as high as 99.4%. Surprisingly, the product distribution of styrene oxidation experienced a reverse trend over the Co-TiO2 catalysts with different doping amounts of cobalt ions: Co 10 was in favor of forming benzaldehyde (80.2% selectivity), in contrast with Co 15, which produced styrene oxide as the dominant product (84.7% selectivity). The M-TiO2 catalysts also showed catalytic activities for the oxidation of benzyl alcohol and toluene to generate chlorine-free benzaldehyde in excellent selectivities (>99%). PMID- 24162011 TI - Apparent variation in Neanderthal admixture among African populations is consistent with gene flow from Non-African populations. AB - Recent studies have found evidence of introgression from Neanderthals into modern humans outside of sub-Saharan Africa. Given the geographic range of Neanderthals, the findings have been interpreted as evidence of gene exchange between Neanderthals and modern humans descended from the Out-of-Africa (OOA) migration. Here, we examine an alternative interpretation in which the introgression occurred earlier within Africa, between ancestors or relatives of Neanderthals and a subset of African modern humans who were the ancestors of those involved in the OOA migration. Under the alternative model, if the population structure among present-day Africans predates the OOA migration, we might find some African populations show a signal of Neanderthal introgression whereas others do not. To test this alternative model, we compiled a whole-genome data set including 38 sub Saharan Africans from eight populations and 25 non-African individuals from five populations. We assessed differences in the amount of Neanderthal-like single nucleotide polymorphism alleles among these populations and observed up to 1.5% difference in the number of Neanderthal-like alleles among African populations. Further analyses suggest that these differences are likely due to recent non African admixture in these populations. After accounting for recent non-African admixture, our results do not support the alternative model of older (e.g., >100 kya) admixture between modern humans and Neanderthal-like hominids within Africa. PMID- 24162013 TI - Effects of heat waves on mortality: effect modification and confounding by air pollutants. AB - BACKGROUND: Heat waves and air pollution are both associated with increased mortality. Their joint effects are less well understood. METHODS: We explored the role of air pollution in modifying the effects of heat waves on mortality, within the EuroHEAT project. Daily mortality, meteorologic, and air pollution data from nine European cities for the years 1990-2004 were assembled. We defined heat waves by taking both intensity and duration into account. The city-specific effects of heat wave episodes were estimated using generalized estimating equation models, adjusting for potential confounders with and without inclusion of air pollutants (particles, ozone, nitrogen dioxide, sulphur dioxide, carbon monoxide). To investigate effect modification, we introduced an interaction term between heat waves and each single pollutant in the models. Random effects meta analysis was used to summarize the city-specific results. RESULTS: The increase in the number of daily deaths during heat wave episodes was 54% higher on high ozone days compared with low, among people age 75-84 years. The heat wave effect on high PM10 days was increased by 36% and 106% in the 75-84 year and 85+ year age groups, respectively. A similar pattern was observed for effects on cardiovascular mortality. Effect modification was less evident for respiratory mortality, although the heat wave effect itself was greater for this cause of death. The heat wave effect was smaller (15-30%) after adjustment for ozone or PM10. CONCLUSIONS: The heat wave effect on mortality was larger during high ozone or high PM10 days. When assessing the effect of heat waves on mortality, lack of adjustment for ozone and especially PM10 overestimates effect parameters. This bias has implications for public health policy. PMID- 24162014 TI - Keeping the engine clean: a mitophagy task for cellular physiology. PMID- 24162016 TI - 1,4-oxazine. AB - The fundamental heterocyclic compound 1,4-oxazine has been generated using FVP. It is the first parent heterocycle among all the possible isomeric oxazines, thiazines and their heavier atom analogues to be characterised spectroscopically, and is shown to exist in solution entirely as the 4H-isomer. X-ray structure determination of the N-Boc precursor shows significant deviations from theoretically predicted geometric parameters. PMID- 24162015 TI - Alterations of immune response of Non-Small Cell Lung Cancer with Azacytidine. AB - Innovative therapies are needed for advanced Non-Small Cell Lung Cancer (NSCLC). We have undertaken a genomics based, hypothesis driving, approach to query an emerging potential that epigenetic therapy may sensitize to immune checkpoint therapy targeting PD-L1/PD-1 interaction. NSCLC cell lines were treated with the DNA hypomethylating agent azacytidine (AZA - Vidaza) and genes and pathways altered were mapped by genome-wide expression and DNA methylation analyses. AZA induced pathways were analyzed in The Cancer Genome Atlas (TCGA) project by mapping the derived gene signatures in hundreds of lung adeno (LUAD) and squamous cell carcinoma (LUSC) samples. AZA up-regulates genes and pathways related to both innate and adaptive immunity and genes related to immune evasion in a several NSCLC lines. DNA hypermethylation and low expression of IRF7, an interferon transcription factor, tracks with this signature particularly in LUSC. In concert with these events, AZA up-regulates PD-L1 transcripts and protein, a key ligand-mediator of immune tolerance. Analysis of TCGA samples demonstrates that a significant proportion of primary NSCLC have low expression of AZA-induced immune genes, including PD-L1. We hypothesize that epigenetic therapy combined with blockade of immune checkpoints - in particular the PD-1/PD-L1 pathway - may augment response of NSCLC by shifting the balance between immune activation and immune inhibition, particularly in a subset of NSCLC with low expression of these pathways. Our studies define a biomarker strategy for response in a recently initiated trial to examine the potential of epigenetic therapy to sensitize patients with NSCLC to PD-1 immune checkpoint blockade. PMID- 24162017 TI - ortho-Selective nucleophilic addition of amines to 3-borylbenzynes: synthesis of multisubstituted anilines by the triple role of the boryl group. AB - Nucleophilic addition of amines to 3-[(dan)boryl]benzynes (dan = 1,8 diaminonaphthalene) generated by a fluoride ion proceeded with high ortho selectivity to give 2-borylaniline derivatives, under conditions that are tolerant to various functional groups. The (dan)boryl group of the adduct was hydrolyzed into a boronic acid under acidic conditions, which could further serve for various C-C, C-O, C-N, and C-H bond-formation reactions. The overall process provides a promising entry for preparing multisubstituted aniline derivatives. PMID- 24162019 TI - Nanodiamond decorated liposomes as highly biocompatible delivery vehicles and a comparison with carbon nanotubes and graphene oxide. AB - Studying interactions between nano-carbons and lipid membranes is important for multiplexed drug delivery, device fabrication and for understanding toxicity. Herein, we report that nanodiamond (ND, sp(3) carbon) forms a complex with highly biocompatible zwitterionic liposomes based on hydrogen bonding, which is confirmed by pH-dependent and urea-dependent assays. Despite such weak interaction, the complex is highly stable. Comparisons were made with two sp(2) carbons: nanoscale graphene oxide (NGO) and carbon nanotubes (CNTs), where CNT adsorption is the weakest. Adsorption of the nano-carbons does not induce liposome leakage or affect lipid phase transition temperature. Therefore, the potential toxicity of nano-carbons is unlikely to be related to direct membrane damage. ND facilitates cellular uptake of liposomes and co-delivery of negatively charged calcein and positively charged doxorubicin has been demonstrated. ND has the lowest toxicity, while CNTs and NGO are slightly more toxic. The effect of introducing fusogenic lipids and cholesterol was further studied to understand the effect of lipid formulation. PMID- 24162020 TI - Synthesis of silver nanocubes with controlled size using water-soluble poly(amic acid) salt as the intermediate via a novel ion-exchange self-assembly technique. AB - Here, we report for the first time on the successful fabrication of monodispersed silver nanocubes with regular shape and controlled size in the solid phase via a novel ion-exchange self-assembly technique by using water-soluble poly(amic acid) salt as the intermediate and silver nitrate as the metal precursor. By simply altering the annealing times at high temperature, the size of the silver nanocubes could be finely tuned in the range of 90-160 nm in the present case. Further attempts with different metal salts show that the present method is also feasible for other metal species and might be universal. PMID- 24162018 TI - Wnt secretion is required to maintain high levels of Wnt activity in colon cancer cells. AB - Aberrant regulation of the Wnt/beta-catenin pathway has an important role during the onset and progression of colorectal cancer, with over 90% of cases of sporadic colon cancer featuring mutations in APC or beta-catenin. However, it has remained a point of controversy whether these mutations are sufficient to activate the pathway or require additional upstream signals. Here we show that colorectal tumours express elevated levels of Wnt3 and Evi/Wls/GPR177. We found that in colon cancer cells, even in the presence of mutations in APC or beta catenin, downstream signalling remains responsive to Wnt ligands and receptor proximal signalling. Furthermore, we demonstrate that truncated APC proteins bind beta-catenin and key components of the destruction complex. These results indicate that cells with mutations in APC or beta-catenin depend on Wnt ligands and their secretion for a sufficient level of beta-catenin signalling, which potentially opens new avenues for therapeutic interventions by targeting Wnt secretion via Evi/Wls. PMID- 24162021 TI - Contribution of TRPA1 as a downstream signal of proteinase-activated receptor-2 to pancreatic pain. AB - We examined if TRPA1, like TRPV1, contributes to pancreatic nociceptor excitation following proteinase-activated receptor-2 (PAR2) stimulation and to pancreatitis related pain in mice. A PAR2-activating peptide, infused into the pancreatic duct, caused spinal Fos expression, which was prevented by AP18, a TRPA1 inhibitor. Repeated administration of cerulein caused referred hyperalgesia accompanying pancreatitis, which was reversed by SB366791, a TRPV1 inhibitor, but not AP18. AP18, administered in combination with a subeffective dose of SB366791, significantly suppressed the referred hyperalgesia. Our findings suggest that TRPA1, like TRPV1, mediates PAR2-triggered pancreatic nociception and that TRPA1 in collaboration with TRPV1 latently contributes to pancreatitis-related pain. PMID- 24162022 TI - Oligomycin, an F1Fo-ATPase inhibitor, protects against ischemic acute kidney injury in male but not in female rats. AB - We investigated the effects of oligomycin, an F1Fo-ATPase inhibitor, on ischemic acute kidney injury in male and female rats. Ischemic acute kidney injury was induced by clamping the left renal artery and vein for 45 or 60 min followed by reperfusion, 2 weeks after contralateral nephrectomy. Renal dysfunction and histological renal damage were observed 1 day after reperfusion in both male and female rats, although these renal injuries were more marked in male rats than in female rats. Intravenous bolus injection of oligomycin (0.5 mg/kg) 5 min before ischemia markedly attenuated the ischemia/reperfusion-induced renal injury in male rats. However, oligomycin did not show the protective effect in female rats subjected to ischemia/reperfusion-induced renal injury. Pre-ischemic treatment with oligomycin suppressed partly but significantly ischemia-induced renal ATP depletion only in male rats. These results indicate that oligomycin prevents the onset of ischemic acute kidney injury in male but not in female rats, and the effect is accompanied by suppression of the ATP depletion only in the male rat kidney during ischemia, thereby suggesting that the ATP hydrolysis pathway by mitochondrial F1Fo-ATPase induces a sex difference in ischemic acute kidney injury. PMID- 24162023 TI - K-685, a TRPV1 antagonist, blocks PKC-sensitized TRPV1 activation and improves the inflammatory pain in a rat complete Freund's adjuvant model. AB - Transient receptor potential vanilloid 1 (TRPV1) is a Ca(2+)-permeable non selective cation channel that transmits pain signals. TRPV1 is activated by multiple stimuli such as capsaicin, acid, and heat. During inflammation, TRPV1 is reported to be sensitized by protein kinase C (PKC) in dorsal root ganglia (DRG) neurons, which leads to reduction in the threshold of the temperature for TRPV1 activation to body temperature. This sensitization is considered to contribute to chronic inflammatory pain. In a previous study, we discovered orally active 5,5 diarylpentadienamide TRPV1 antagonists. To examine the effects of our TRPV1 antagonists on PKC-sensitized TRPV1, we developed an in vitro assay system to monitor the TRPV1 sensitization by PKC. In this assay system, our TRPV1 antagonists, such as (2E,4Z)-N-[(3R)-3-hydroxy-2-oxo-1,2,3,4-tetrahydro-5 quinolyl]-5-(4-isopropoxyphenyl)-5-(4-trifluoromethylphenyl)-2,4-pentadienamide (K-685), inhibited the activation of TRPV1 sensitized by PKC. The potentiation of heat-induced inward currents by PKC was seen in rat DRG neurons, and K-685 attenuated these currents. Furthermore, K-685 reversed the thermal hyperalgesia and mechanical allodynia in a rat complete Freund's adjuvant-induced inflammatory pain model. These results therefore suggest that K-685 has a strong potential as a new analgesic drug for the treatment of inflammatory pain. PMID- 24162024 TI - Na+/Ca2+ exchanger 1/2 double-heterozygote knockout mice display increased nitric oxide component and altered colonic motility. AB - The Na+/Ca2+ exchanger (NCX) is a plasma membrane transporter involved in regulating intracellular Ca2+ concentrations. NCX is critical for Ca2+ regulation in cardiac muscle, vascular smooth muscle, and nerve fibers. To determine the role of NCX1 and NCX2 in gastrointestinal tissues, we examined electric field stimulation (EFS)-induced responses in the longitudinal smooth muscle of the distal colon in NCX1 and NCX2 double-heterozygote knockoutmice (Double HET). We found that the amplitudes of EFS-induced relaxation that persisted during EFS were greater in Double HET than in wild-type mice (WT). Under the non-adrenergic, non-cholinergic (NANC) condition, EFS-induced relaxation in Double HET was similar in amplitude to that of WT. In the experiments in which l-NNA was added under NANC conditions following the EFS, the magnitudes of EFS-induced relaxation were smaller in Double HET than those in WT. In addition, an NCX inhibitor, SN-6, enhanced EFS-induced relaxation but did not affect EFS-induced relaxation under NANC condition, as in Double HET. Moreover, the magnitudes of relaxation induced by NOR-1, which generates NO, were greater in Double HET compared with WT. Similarly, SN-6 potentiated the magnitudes of NOR-1-induced relaxation. In this study, we demonstrate that NCX regulate colonic motility by altering the sensitivity of the inhibitory component. PMID- 24162025 TI - Test-retest paradigm of the forced swimming test in female mice is not valid for predicting antidepressant-like activity: participation of acetylcholine and sigma 1 receptors. AB - The forced swimming test (FST) in mice is widely used to predict the antidepressant activity of a drug, but information describing the immobility of female mice is limited. We investigated whether a prior swimming experience affects the immobility duration in a second FST in female mice and whether the test-retest paradigm is a valid screening tool for antidepressants. Female ICR mice were exposed to the FST using two experimental paradigms: a single FST and a double FST in which mice had experienced FST once 24 h prior to the second trail. The initial FST experience reliably prolonged immobility duration in the second FST. The antidepressants imipramine and paroxetine significantly reduced immobility duration in the single FST, but not in the double FST. Scopolamine and the sigma-1 (sigma1) antagonist NE-100 administered before the second trial significantly prevented the prolongation of immobility. Neither a 5-HT1A nor a 5 HT2A receptor agonist affected immobility duration. We suggest that the test retest paradigm in female mice is not adequate for predicting antidepressant-like activity of a drug; the prolongation of immobility in the double FST is modulated through acetylcholine and sigma1 receptors. PMID- 24162028 TI - [Do we have a good blood supply?]. PMID- 24162026 TI - Targeting lipid biosynthesis and salvage in apicomplexan parasites for improved chemotherapies. AB - Apicomplexa are some of the most widespread and poorly controlled pathogens in the world. The metabolism of lipids in these parasites, which include Plasmodium spp., Toxoplasma gondii and Cryptosporidium spp., is essential for the production of infectious progeny and pathogen persistence in their mammalian hosts. Metabolic maps of apicomplexan lipid syntheses reveal auxotrophies for many lipid species, which force these parasites to meet their high demand for lipids through networks of both synthesis and scavenging. Here, I review the unique lipid biosynthetic enzymes and lipid transporter systems of Apicomplexa, focusing on isoprenoids, sphingolipids and cholesterol, and highlight promising chemotherapeutic targets in the lipid synthetic and salvage pathways. PMID- 24162029 TI - [Data for epidemiological research on ageing in Germany. Opportunities and limitations of existing datasets: results of the second workshop of the working group Epidemiology of Ageing within the German Society for Epidemiology (DGEpi)]. AB - Due to the increasing proportion of older people in the general population epidemiologists are interested in identifying which factors determine healthy ageing. For this reason within the German Society for Epidemiology we founded the working group 'Epidemiology of Ageing' in 2011. The working group organised a workshop to present useful datasets on ageing in Germany for epidemiological research. Those presented included: Study of Health in Pomerania (SHIP) The German Ageing Survey (DEAS) Surveys from the Robert Koch Institute: German Health Interview and Examination Survey for Adults (DEGS) and the German Health Update (GEDA) The German Socio-Economic Panel Study (SOEP) Cooperative Health Research in the Region of Augsburg (KORA-Age) Survey of Health, Ageing and Retirement in Europe (SHARE) Germany Claims data from statutory health insurance agencies Presentations contained a brief description of the datasets, methodologies, age related themes, their strengths and limitations as well as their availability for secondary analysis. All presented datasets can be used for longitudinal analyses and are available to the scientific community. PMID- 24162027 TI - Past, present and future: 30 years of HIV research. AB - This year marks the thirtieth anniversary of the publication of the study that first reported the isolation of HIV-1. In this Timeline article, we provide a historical perspective of some of the major milestones in HIV science, highlighting how translational research has affected treatment and prevention of HIV. Finally, we discuss some of the current research directions and the scientific challenges ahead, in particular in the search for a cure for HIV. PMID- 24162031 TI - Conveying science: original studies versus case reports. PMID- 24162033 TI - The association between anti-plasminogen antibodies and disease activity in ANCA associated vasculitis. AB - OBJECTIVE: Previous studies have shown that in patients with ANCA-associated vasculitis (AAV), anti-plasminogen antibodies were associated with reduced renal function and the presence of fibrinoid necrosis and cellular crescents in renal histology. The purpose of the current study was to investigate whether anti plasminogen antibodies are associated with the systemic disease activity of AAV. METHODS: One hundred and four Chinese patients with AAV were recruited. Anti plasminogen antibodies were detected in sequential serum samples at initial onset and remission of the disease. Associations of anti-plasminogen antibodies with clinicopathological parameters were analysed. RESULTS: The prevalence of anti plasminogen antibodies was significantly higher in AAV patients than in healthy controls (19/104 vs 0/50, chi(2) = 8.8, P = 0.003). The prevalence of anti plasminogen antibodies was significantly higher in the active stage of AAV than in remission (19/104 vs 1/48, chi(2) = 7.5, P = 0.013). The level of anti plasminogen antibodies (expressed as a percentage of the positive controls) correlated with the ESR (r = 0.207, P = 0.042), serum creatinine (r = 0.302, P = 0.002), d-dimer (r = 0.273, P = 0.009) and the percentage of glomeruli with crescents in renal specimens (r = 0.393, P = 0.004). The level of Birmingham vasculitis activity scores and the prevalence of arthralgia and gastrointestinal involvement in patients with anti-plasminogen antibodies were significantly higher than in patients without anti-plasminogen antibodies [22.5 (s.d. 5.63) vs. 19.4 (s.d. 4.66), P = 0.015; 63.2% vs. 25.8%, P = 0.002; 57.9% vs. 21.1%, P = 0.001, respectively]. CONCLUSION: Circulating anti-plasminogen antibodies were associated with systemic disease activity and renal disease activity of AAV. PMID- 24162034 TI - Interpretation of the Juvenile Arthritis Disease Activity Score: responsiveness, clinically important differences and levels of disease activity in prospective cohorts of patients with juvenile idiopathic arthritis. AB - OBJECTIVES: The objectives of this study were to assess 27-joint Juvenile Arthritis Disease Activity Score (JADAS-27) responsiveness, JADAS-27 changes corresponding to clinically important differences and cut-off scores for low and high disease activity in a large prospective JIA cohort. METHODS: JADAS-27 responsiveness, using effect size and standardized response mean (SRM), and changes in the JADAS-27 corresponding to clinically important differences were determined for clinical improvement (ACRpedi30) and worsening (flare). To assess whether various degrees of change in the JADAS-27 could be used to demonstrate improvement or worsening in individual patients, diagnostic parameters were computed for cut-off score changes. Finally, cut-off scores for low and high disease activity and their diagnostic parameters were determined. RESULTS: In 228 patients with 529 consecutive visits, ACRpedi30 was detected in 109 and flare in 111 visits. Regarding responsiveness, the effect size was 0.93 and SRM was 1.26 for clinical improvement, while for clinical worsening the effect size was 0.65 and SRM was 0.60. Changes in the JADAS-27 corresponding to clinically important difference were -5.5 for improvement and +1.7 for worsening. Cut-off score changes in the JADAS-27 had 65-90% sensitivity and 67-86% specificity for improvement, and 31-64% sensitivity and 89-97% specificity for worsening. The JADAS-27 cut-off score for low disease activity was <=2.7 with 76% sensitivity and 62% specificity, and the cut-off score for high disease activity was >=6 with 77% sensitivity and 77% specificity. CONCLUSION: The JADAS-27 had moderate to good responsiveness and was changed by clinically important differences. The JADAS-27 cut-off scores differentiated between low and high disease activity. These JADAS-27 interpretations could be potentially applicable in clinical care and trials. PMID- 24162032 TI - Increased effectiveness of early therapy with anti-tumor necrosis factor-alpha vs an immunomodulator in children with Crohn's disease. AB - BACKGROUND & AIMS: Standard therapy for children newly diagnosed with Crohn's disease (CD) includes early administration of immunomodulators after initial treatment with corticosteroids. We compared the effectiveness of early (<=3 mo after diagnosis) treatment with an anti-tumor necrosis factor (TNF)alpha with that of an immunomodulator in attaining clinical remission and facilitating growth of pediatric patients. METHODS: We analyzed data from the RISK study, an observational research program that enrolled patients younger than age 17 diagnosed with inflammatory (nonpenetrating, nonstricturing) CD from 2008 through 2012 at 28 pediatric gastroenterology centers in North America. Patients were managed by physician dictate. From 552 children (median age, 11.8 y; 61% male; 63% with pediatric CD activity index scores >30; and median C-reactive protein level 5.6-fold the upper limit of normal), we used propensity score methodology to identify 68 triads of patients matched for baseline characteristics who were treated with early anti-TNFalpha therapy, early immunomodulator, or no early immunotherapy. We evaluated relationships among therapies, corticosteroid and surgery-free remission (pediatric CD activity index scores, <=10), and growth at 1 year for 204 children. Treatment after 3 months was a covariate. RESULTS: Early treatment with anti-TNFalpha was superior to early treatment with an immunomodulator (85.3% vs 60.3% in remission; relative risk, 1.41; 95% confidence interval [CI], 1.14-1.75; P = .0017), whereas early immunomodulator therapy was no different than no early immunotherapy (60.3% vs 54.4% in remission; relative risk, 1.11; 95% CI, 0.83-1.48; P = .49) in achieving remission at 1 year. Accounting for therapy after 3 months, early treatment with anti-TNFalpha remained superior to early treatment with an immunomodulator (relative risk, 1.51; 95% CI, 1.20-1.89; P = .0004), whereas early immunomodulator therapy was no different than no early immunotherapy (relative risk, 1.00; 95% CI, 0.75-1.34; P = .99). The mean height z-score increased compared with baseline only in the early anti-TNFalpha group. CONCLUSIONS: In children newly diagnosed with comparably severe CD, early monotherapy with anti-TNFalpha produced better overall clinical and growth outcomes at 1 year than early monotherapy with an immunomodulator. Further data will be required to best identify children most likely to benefit from early treatment with anti-TNFalpha therapy. PMID- 24162035 TI - Maternal concentrations of persistent organochlorine pollutants and the risk of asthma in offspring: results from a prospective cohort with 20 years of follow up. AB - BACKGROUND: Previous findings suggest that developmental exposures to persistent organochlorine pollutants (POPs) may be detrimental for the development of the immune system in the offspring. Whether these suspected immunoregulatory effects persist beyond early childhood remains unclear. OBJECTIVES: The objective of this study was to evaluate the association between maternal serum concentrations of POPs and the risk of asthma in offspring after 20 years of follow-up. METHODS: A birth cohort with 965 women was formed in 1988-1989 in Aarhus, Denmark. Concentrations of six polychlorinated biphenyls (PCBs) (congeners 118, 138, 153, 156, 170, 180), hexachlorobenzene (HCB), and dichlorodiphenyldichloroethylene (p,p'-DDE) were quantified in maternal serum (n=872) collected in gestation week 30. Information about offspring use of asthma medications was obtained from the Danish Registry of Medicinal Product Statistics. RESULTS: Maternal serum concentrations of HCB and dioxin-like PCB-118 were positively associated with offspring asthma medication use after 20 years of follow-up (p for trend<0.05). Compared with subjects in the first tertile of maternal concentration, those in the third tertile of PCB-118 had an adjusted hazard ratio (HR) of 1.90 (95% CI: 1.12, 3.23). For HCB the HR for the third versus the first tertile of maternal concentration was 1.92 (95% CI: 1.15, 3.21). Weak positive associations were also estimated for PCB-156 and the non-dioxin-like PCBs (PCBs 138, 153, 170, 180). No associations were found for p,p'-DDE. CONCLUSIONS: Maternal concentrations of PCB 118 and HCB were associated with increased risk of asthma in offspring followed through 20 years of age. PMID- 24162036 TI - Isolated vestibular nuclear infarction: report of two cases and review of the literature. AB - Cerebral infarction presenting with isolated vertigo remains a diagnostic challenge. To define the clinical characteristics of unilateral infarctions restricted to the vestibular nuclei, two patients with isolated unilateral vestibular nuclear infarction had bedside and laboratory evaluation of the ocular motor and vestibular function, including video-oculography, bithermal caloric irrigation, the head impulse test (HIT) using magnetic scleral coils, and cervical and ocular vestibular-evoked myogenic potentials (VEMPs). We also reviewed the literature on isolated vertigo from lesions restricted to the vestibular nuclei, and analyzed the clinical features of seven additional patients. Both patients showed spontaneous torsional-horizontal nystagmus that beat away from the lesion side, and direction-changing gaze-evoked nystagmus. Recording of HIT using a magnetic search coil system documented decreased gains of the vestibular-ocular reflex for the horizontal and posterior semicircular canals on both sides, but more for the ipsilesional canals. Bithermal caloric tests showed ipsilesional canal paresis in both patients. Cervical and ocular VEMPs showed decreased or absent responses during stimulation of the ipsilesional ear. Initial MRIs including diffusion-weighted images were normal or equivocal, but follow-up imaging disclosed a circumscribed acute infarction in the area of the vestibular nuclei. Infarctions restricted to the vestibular nuclei may present with isolated vertigo with features of both peripheral and central vestibulopathies. Central signs should be sought even in patients with spontaneous horizontal-torsional nystagmus and positive HIT. In patients with combined peripheral and central vestibulopathy, a vestibular nuclear lesion should be considered especially when hearing is preserved. PMID- 24162037 TI - Immune cell subtyping in the cerebrospinal fluid of patients with neurological diseases. AB - The analysis of cerebrospinal fluid (CSF) with the assessment of CSF cell counts and proteins is an important method in the diagnostic workup of neurological diseases. As an addition to this standard approach, we here present data on the distribution of CSF immune cell subsets in common neurological diseases, and provide reference values along with cases of rare neurological diseases. CD4+ and CD8+ T cells, the CD4/CD8 ratio, B cells, plasmablasts, monocytes and NK cells in the CSF of 319 patients with inflammatory or non-inflammatory neurological diseases were analysed by seven-color flow cytometry. Diagnoses included headache, idiopathic intracranial hypertension, Guillain-Barre syndrome, multiple sclerosis, Lyme neuroborreliosis, bacterial and viral meningitis, human immunodeficiency virus (HIV) infection, stroke, and CNS malignancies, among others. T cells were the predominant population in the CSF with CD4+ T cells being more prevalent than CD8+ T cells. Mostly in HIV patients, and under other conditions of immunosuppression, CD4+ and CD8+ T cells were significantly altered and the CD4/CD8 ratio reduced. B cells and plasmablasts could hardly be detected in non-inflammatory diseases but were consistently elevated in inflammatory diseases. Monocytes were reduced in neuroinflammation and showed a negative correlation with B cells. NK cells were slightly elevated in neuroinflammation. Both monocytes and NK cells were slightly elevated in CNS malignancies. The analysis of immune cell subsets in the CSF adds valuable information to clinicians and is a promising tool for the differential diagnosis of neurological diseases. PMID- 24162038 TI - Mapping the differences in care for 5,000 spinal muscular atrophy patients, a survey of 24 national registries in North America, Australasia and Europe. AB - Spinal muscular atrophy (SMA) is an autosomal recessive genetic disorder characterised by the degeneration of motor neurons and progressive muscle weakness. It is caused by homozygous deletions in the survival motor neuron gene on chromosome 5. SMA shows a wide range of clinical severity, with SMA type I patients often dying before 2 years of age, whereas type III patients experience less severe clinical manifestations and can have a normal life span. Here, we describe the design, setup and utilisation of the TREAT-NMD national SMA patient registries characterised by a small, but fully standardised set of registry items and by genetic confirmation in all patients. We analyse a selection of clinical items from the SMA registries in order to provide a snapshot of the clinical data stratified by SMA subtype, and compare these results with published recommendations on standards of care. Our study included 5,068 SMA patients in 25 countries. A total of 615 patients were ventilated, either invasively (178) or non-invasively (437), 439 received tube feeding and 455 had had scoliosis surgery. Some of these interventions were not available to patients in all countries, but differences were also noted among high-income countries with comparable wealth and health care systems. This study provides the basis for further research, such as quality of life in ventilated SMA patients, and will inform clinical trial planning. PMID- 24162039 TI - Impact of cerebro-spinal fluid biomarkers of Alzheimer's disease in clinical practice: a multicentric study. AB - CSF biomarkers of Alzheimer's disease are well validated in clinical research; however, their pragmatic utility in daily practice is still unappreciated. These biomarkers are used in routine practice according to Health Authority Recommendations. In 604 consecutive patients explored for cognitive disorders, questionnaires were prospectively proposed and filled. Before and after CSF biomarker results, clinicians provided a diagnosis and an estimate of their diagnostic confidence. Analysis has compared the frequency of diagnosis before and after CSF biomarker results using the net reclassification improvement (NRI) method. We have evaluated external validity comparing with data of French Bank National of AD (BNA). A total of 561 patients [Alzheimer's disease (AD), n = 253; non-AD, n = 308] were included (mean age, 68.6 years; women, 52 %). Clinically suspected diagnosis and CSF results were concordant in 65.2 % of cases. When clinical hypothesis and biological results were discordant, a reclassification occurred in favour of CSF biomarkers results in 76.9 %. The NRI was 39.5 %. In addition, the results show a statistically significant improvement in clinician confidence for their diagnosis. In comparison with BNA data, patients were younger and more frequently diagnosed with AD. Clinicians tend to heavily rely on the CSF AD biomarkers results and are more confident in their diagnoses using CSF AD biomarkers. Thus, these biomarkers appear as a key tool in clinical practice. PMID- 24162040 TI - Altered GABAergic system in the living brain of a patient with spinocerebellar ataxia type 8. PMID- 24162041 TI - A theoretical study of the photochemistry of indigo in its neutral and dianionic (leucoindigo) forms. AB - A thorough analysis of the single and double proton transfer and the internal rotations of neutral indigo and its dianionic leucoindigo form has been performed for the ground and first singlet excited electronic states using, respectively, DFT and TDDFT state-of-the-art methods. Our theoretical analysis discloses that the diketo isomer is the most stable one in the ground state of indigo but not in leucoindigo where the dienol minimum is more stable. Single and double proton transfer processes are not energetically favored in the ground electronic state but a single proton transfer gives a more stable tautomer in the excited electronic state of indigo whereas a double proton transfer is energetically favorable in the excited state of leucoindigo. The internal rotations are not thermodynamically allowed except for the keto-enol tautomer where a full rotation of the inter-ring C-C bond leads to another stable keto-enol structure. A preliminary analysis of the plausible conical intersections for both indigo and leucoindigo allows the discussion of the likely deactivation paths that will follow light irradiation. Our results point to a very different photochemistry of the two molecules. For indigo the proton transfer can only take place through tunneling so the main deactivation path would involve a conical intersection accessed directly upon internal rotation of the keto-keto tautomer. For leucoindigo a richer photochemistry is expected as the single and double proton transfer processes are energetically open. The more favorable path involves single proton transfer followed by a trans to cis isomerization and a second proton transfer. This process competes on equal grounds with several non radiative decays through conical intersections. All these results are in agreement with the experimental facts known to date. PMID- 24162042 TI - 2013 Founder's Award - Janet A. Johnson. PMID- 24162043 TI - 2013 Health Physics Society Honor Roll - Robert D. (Rob) Forrest. PMID- 24162044 TI - 2013 Health Physics Society Honor Roll - George J. Vargo, Jr. PMID- 24162045 TI - 2013 Health Physics Society Honor Roll - Thomas E. Widner. PMID- 24162046 TI - 2013 Elda E. Anderson Award - Peter F. Caracappa. PMID- 24162047 TI - 2013 William A. McAdams Outstanding Service Award - Kent Lambert. PMID- 24162048 TI - 2013 Geoffrey G. Eichholz Outstanding Science Teacher Award - Brenda Angus. PMID- 24162054 TI - A numerical survey of motion-induced electric fields experienced by MRI operators. AB - This paper deals with the electric field generated inside the bodies of people moving in proximity to magnetic resonance scanners. Different types of scanners (tubular and open) and various kinds of movements (translation, rotation, and revolution) are analyzed, considering the homogeneous human model proposed in some technical Standards. The computations are performed through the Boundary Element Method, adopting a reference frame attached to the body, which significantly reduces the computational burden. The induced electric fields are evaluated in terms of both spatial distributions and local time evolutions. The possibility of limiting the study to the head without affecting the accuracy of the results is also investigated. Finally, a first attempt to quantify the transient effect of charge separation is proposed. PMID- 24162055 TI - Development of a Voxel-based Chinese reference female phantom from color photographs for radiation dosimetry applications. AB - The objective of this study was to develop a Voxel-based Chinese Reference female Phantom (VCRP-woman) from high-resolution color photographs acquired from an adult female cadaver. Forty-six organs/tissues, including all radiosensitive organs/tissues specified in the 2007 recommendations of the International Commission on Radiological Protection (ICRP), were either segmented manually or subjected to semi-automatic segmentation as seen in color photographs of the unadjusted female. A C++ program was developed to adjust the masses of the organs/tissues to values applicable to the Chinese Reference adult female. The resulting VCRP-woman consists of more than 106 million voxels, each with dimensions of 1.03 mm * 1.03 mm * 1.95 mm. Organ absorbed dose and effective dose conversion coefficients for monoenergetic photons from 0.015-10 MeV were calculated for several reference irradiation geometries (anterior-posterior, posterior-anterior, left-lateral, rotational, and isotropic) by Monte Carlo radiation transport. The results for the VCRP-woman were compared to those of the original (or unadjusted) female voxel phantom as well as the ICRP Publication 110 adult reference female computational phantom. PMID- 24162056 TI - Frequency and collective dose of medical procedures in Kenya. AB - The first comprehensive national survey on frequency and radiation dose imparted to the population from radiological procedures was carried out in Kenya and reported here. This survey involved assessment of frequency, typical patient radiation exposure, and collective effective dose from general radiography, fluoroscopy, interventional procedures (IPs), mammography, and computed tomography. About 300 x-ray facilities across the country were invited to participate in the survey, and a 31% response was recorded. The individual and collective radiation burdens of more than 62 types of pediatric and adult radiological examinations were quantified using effective and collective dose. The average effective dose for each radiological examination was assessed from the x-ray efficiency performance tests and patient data from over 30 representative radiological facilities. The results found indicated that over 3 million x-ray procedures were performed in 2011, resulting in an annual collective effective dose of 2,157 person-Sv and an annual effective dose per capita of 0.05 mSv. The most frequent examinations were general radiography (94%), computed tomography (3.3%), and fluoroscopy (2.5%). Although the contribution of computed tomography was small in terms of frequency, this procedure accounted for 36% of the effective dose per capita. General radiography was the most frequent type of examination with a contribution of 55% of the effective dose per capita. PMID- 24162057 TI - How to estimate multislice CT effective dose more correctly. AB - The purpose of this paper is to provide data concerning differences in multislice CT effective dose estimation when using various methods and techniques, determine the reasons for these differences, and submit proposals for improving the estimation accuracy. All the experiments (chest and head exam settings) were conducted using 64-slice CT scanners from various manufacturers. Effective dose estimates have been obtained on the basis of the conventional dose-length product method, absorbed dose distribution curves, and using anthropomorphic phantoms with thermoluminescent dosimeters as a model method. Using the conventional dose length product method leads to underestimation of effective doses (approximately 16 and 19% for head and chest studies, respectively, on average for all scanners) due to partly neglecting scattered in-patient radiation. Additional differences in dose estimates occur when using the "new" ICRP 103 instead of the "old" ICRP 60 Publication recommendations (13% for chest and 23% for head studies on average). It seems reasonable to calibrate scanners with weighted CT dose index values taking into account complete scattered radiation effects. Dose conversion factors for different studies and patient age must be recalculated in conformity with ICRP Publication 103 recommendations. With implementation of the presented proposals, the discrepancy in effective dose evaluation will not exceed a few percent as compared to anthropomorphic phantom measurements. PMID- 24162059 TI - Rapid estimation of inhaled particle size for internal dose during nuclear emergency medicine. AB - Information on particle size is one of the important factors for internal dose estimation at accidents with airborne radioactive materials. An autoradiography method has been investigated as a technique for the sizing of alpha-emitting particles. Concerning nuclear emergency medicine, the waiting time for dose estimation is limited. For determining the shortest estimation time, the exposure time of autoradiography was examined using PuO2 particles captured on HEPA filters. In this study, the effective counting efficiency of tracks produced by alpha particles was evaluated to be 0.31 by a numerical simulation. The minimum exposure time for PuO2 with aerodynamic diameter of 5 MUm was found to be only 10 min. When any star-like alpha particle track was not detected after 6 h of exposure, even if the sample had significant radioactivity, the aerodynamic diameter was assumed to be less than 1 MUm. When the radioactivity of PuO2 particles detected by autoradiography within 1 h was dominant of total activity, the aerodynamic diameter would be estimated to be over 5 MUm. These results indicate that the precise dose estimation is useful for the decision of medical treatment. PMID- 24162058 TI - Assessment of biodosimetry methods for a mass-casualty radiological incident: medical response and management considerations. AB - Following a mass-casualty nuclear disaster, effective medical triage has the potential to save tens of thousands of lives. In order to best use the available scarce resources, there is an urgent need for biodosimetry tools to determine an individual's radiation dose. Initial triage for radiation exposure will include location during the incident, symptoms, and physical examination. Stepwise triage will include point of care assessment of less than or greater than 2 Gy, followed by secondary assessment, possibly with high throughput screening, to further define an individual's dose. Given the multisystem nature of radiation injury, it is unlikely that any single biodosimetry assay can be used as a standalone tool to meet the surge in capacity with the timeliness and accuracy needed. As part of the national preparedness and planning for a nuclear or radiological incident, the authors reviewed the primary literature to determine the capabilities and limitations of a number of biodosimetry assays currently available or under development for use in the initial and secondary triage of patients. Understanding the requirements from a response standpoint and the capability and logistics for the various assays will help inform future biodosimetry technology development and acquisition. Factors considered include: type of sample required, dose detection limit, time interval when the assay is feasible biologically, time for sample preparation and analysis, ease of use, logistical requirements, potential throughput, point-of-care capability, and the ability to support patient diagnosis and treatment within a therapeutically relevant time point. PMID- 24162060 TI - Wi-Fi and health: review of current status of research. AB - This review summarizes the current state of research on possible health effects of Wi-Fi (a commercial name for IEEE 802.11-compliant wireless networking). In response to public concerns about health effects of Wi-Fi and wireless networks and calls by government agencies for research on possible health and safety issues with the technology, a considerable amount of technology-specific research has been completed. A series of high quality engineering studies have provided a good, but not complete, understanding of the levels of radiofrequency (RF) exposure to individuals from Wi-Fi. The limited number of technology-specific bioeffects studies done to date are very mixed in terms of quality and outcome. Unequivocally, the RF exposures from Wi-Fi and wireless networks are far below U.S. and international exposure limits for RF energy. While several studies report biological effects due to Wi-Fi-type exposures, technical limitations prevent drawing conclusions from them about possible health risks of the technology. The review concludes with suggestions for future research on the topic. PMID- 24162065 TI - Trinuclear heterometallic Cu(II)-Mn(II) complexes of a salen type Schiff base ligand: anion dependent variation of phenoxido bridging angles and magnetic coupling. AB - Five new trinuclear heterometallic Cu(II)-Mn(II) complexes [(CuL)2Mn(O2CPh)2] (1), [(CuL)2Mn(N3)2] (2), [(CuL)2Mn(NCO)2] (3), [(CuL)2Mn(NO3)2] (4) and [(CuL)2Mn(Sal)2].CH2Cl2 (5) have been synthesized with the di-Schiff base ligand H2L (where H2L = N,N'-bis(salicylidene)-1,3-propanediamine and Sal = salicylate). These complexes with different anionic co-ligands have been synthesized to attain a large variation in phenoxido bridging angles and to investigate its consequence on magnetic properties. Single crystal X-ray diffraction analyses reveal that complexes 1, 2, 4 and 5 are linear, whereas 3 has an angular geometry. Variable temperature magnetic susceptibility measurements suggest that all five complexes possess an overall antiferromagnetic interaction between Cu(II) and Mn(II) ions, which results in a final ferrimagnetic ground state with spin 3/2 in the Cu(II) Mn(II)-Cu(II) trinuclear structure. The weakest antiferromagnetic interaction (J(Cu-Mn) = -7.0 cm(-1)) is observed for 2 having the lowest value of the Cu-O-Mn angle (92.0 degrees ), while the strongest antiferromagnetic interaction (J(Cu Mn) = -26.5 cm(-1)) is observed for 3 having the largest Cu-O-Mn angle (101.4 degrees ). Complexes 1, 4 and 5 show average Cu-O-Mn angles of 98.2 degrees , 97.6 degrees and 97.7 degrees , respectively, that lead to intermediate antiferromagnetic interactions (J(Cu-Mn) = -9.6, -9.7, -9.3 cm(-1) respectively). PMID- 24162066 TI - A theoretical study on 1,5-diazido-3-nitrazapentane (DANP) and 1,7-diazido-2,4,6 trinitrazaheptane (DATNH): molecular and crystal structures, thermodynamic and detonation properties, and pyrolysis mechanism. AB - 1,5-Diazido-3-nitrazapentane (DANP) and 1,7-diazido-2,4,6-trinitrazaheptane (DATNH) are two energetic plasticizers. To better understand them, a detailed theoretical investigation was carried out using density functional theory and molecular mechanics methods. The crystal structures, spectra, thermodynamic properties, heats of formation, detonation velocity, detonation pressure, specific impulse and thermal stability were estimated. Possible initiation steps of pyrolysis were discussed by considering the bond breaking of N-NO2, C-N3, and N-N2 (via hydrogen transfer) for both compounds and the cyclization of the adjacent nitro and azido groups for DATNH. Results show that the rupture of N-NO2 and N-N2 (via hydrogen transfer) may happen simultaneously as the initial step of pyrolysis. Both crystals have P-1 symmetry as was observed experimentally. DANP has higher stability than DATNH, while DATNH has better detonation performance than DANP. In addition, DANP has a lower while DATNH has a higher specific impulse than RDX, which shows their prospects as propellant components. PMID- 24162064 TI - Mutagenesis and phenotyping resources in zebrafish for studying development and human disease. AB - The zebrafish (Danio rerio) is an important model organism for studying development and human disease. The zebrafish has an excellent reference genome and the functions of hundreds of genes have been tested using both forward and reverse genetic approaches. Recent years have seen an increasing number of large scale mutagenesis projects and the number of mutants or gene knockouts in zebrafish has increased rapidly, including for the first time conditional knockout technologies. In addition, targeted mutagenesis techniques such as zinc finger nucleases, transcription activator-like effector nucleases and clustered regularly interspaced short sequences (CRISPR) or CRISPR-associated (Cas), have all been shown to effectively target zebrafish genes as well as the first reported germline homologous recombination, further expanding the utility and power of zebrafish genetics. Given this explosion of mutagenesis resources, it is now possible to perform systematic, high-throughput phenotype analysis of all zebrafish gene knockouts. PMID- 24162067 TI - A DFT study on the thermal cracking of JP-10. AB - Density functional theory (DFT) calculations have been carried out to investigate the thermal cracking pathways of JP-10, a high energy density hydrocarbon fuel. Thermal cracking mechanisms are proposed, as supported by our previous experimental results (Xing et al. in Ind Eng Chem Res 47:10034-10040, 2008). Using DFT calculations, the potential energy profiles of the possible thermal cracking pathways for all of the diradicals obtained from homolytic C-C bond cleavage of JP-10 were derived and are presented here. The products of the different thermal cracking pathways are in good agreement with our previous experimental observations. PMID- 24162068 TI - Cooperativity between fluorine-centered halogen bonds: investigation of substituent effects. AB - This article analyzes the substitution effects on cooperativity between fluorin centered halogen bonds in NCF . . . NCF . . . NCX and CNF . . . CNF . . . CNX complexes, where X = H, F, Cl, CN, OH, and NH2. These effects are investigated theoretically in terms of geometric and energetic features of the complexes, which are computed by ab initio methods. The topological analysis, based on the quantum theory of atoms in molecules (QTAIM), is used to characterize the interactions and analyze their enhancement with varying electron density at bond critical points. It is found that the complexes with electron-donating groups exhibit a strong cooperativity, while a much weaker cooperativity occurs in the NCF . . . NCF . . . NCCN and CNF . . . CNF . . . CNCN trimers. An excellent correlation is found between the cooperative energy in the ternary complexes and the calculated three-body interaction energies. The energy decomposition analysis (EDA) indicates that the electrostatic and dispersion effects play a main role in the cooperativity of fluorine-centered halogen bonding. PMID- 24162069 TI - The reciprocal roles of PARK2 and mitofusins in mitophagy and mitochondrial spheroid formation. AB - Mitochondrial homeostasis is critical to cellular homeostasis, and mitophagy is an important mechanism to eliminate mitochondria that are superfluous or damaged. Multiple events can be involved in the recognition of mitochondria by the phagophore, and the key one is the priming of the mitochondria with specific molecular signatures. PARK2/Parkin is an E3 ligase that can be recruited to depolarized mitochondria and is required for mitophagy caused by respiration uncoupling. PARK2 induces ubiquitination of mitochondrial outer membrane proteins, which are subsequently degraded by the proteasome. Why these PARK2 mediated priming events are necessary for mitophagy to occur is not clear. We propose that they are needed to prevent a default pathway that would be inhibitory to mitophagy. In the default pathway depolarized and fragmented mitochondria undergo a dramatic three-dimensional conformational change to become mitochondrial spheroids. This transformation requires mitofusins; however, PARK2 inhibits this process by causing mitofusin ubiquitination and degradation. The spherical transformation may prevent recognition of the damaged mitochondria by the autophagosome, and PARK2 ensures that no such transformation occurs in order to promote mitophagy. Whether the formed mitochondrial spheroids functionally represent an alternative mitigation to mitophagy or an adverse consequence in the absence of PARK2 has yet to be determined. PMID- 24162070 TI - Retention in continuous two-dimensional thermal field-flow fractionation: comparison of experimental results with theory. AB - A theoretical and experimental study of continuous two-dimensional thermal field flow fractionation (2D-ThFFF) is presented. Separation takes place in radial flow between two closely spaced discs, one of which is heated and the other cooled in order to maintain a temperature gradient across the channel. The cooled disc, which serves as the accumulation wall, is rotated relative to the other to create a shear component to the fluid flow. Under the influence of the thermal gradient and flow components, the sample components spiral outwards along different paths to the outer rim of the channel to be collected. The general principle of operation is described and an approximate theoretical model formulated for predicting the outlet position for the path of each sample component. The influence of the principal operational parameters, such as radial and angular flow rates and thermal gradient, on the deflection angle of the sample trajectory is investigated. Fractionation is demonstrated for polystyrene polymer standards in a binary solvent consisting of cyclohexane and ethylbenzene. Experimental results are compared with theoretical predictions. PMID- 24162071 TI - CGmCGCG is a versatile substrate with which to evaluate Tet protein activity. AB - Tet family proteins have the ability to convert 5-methylcytosine (mC) to 5 hydroxymethylcytosine, and further to 5-formylcytosine and 5-carboxycytosine. We found that CGmCGCG can be the substrate of Tet protein, and observed iterative oxidation of mC by HPLC analysis. We also demonstrated that Tet protein favours single-stranded DNA over double-stranded DNA. PMID- 24162073 TI - Self-assembled growth of multi-layer graphene on planar and nano-structured substrates and its field emission properties. AB - Vertical multi-layer graphenes (MLGs) have been synthesized without a catalyst on planar and nano-structured substrates by using microwave plasma enhanced chemical vapor deposition. The growth of MLGs on non-carbon substrates is quite different from that on carbon-based substrates. It starts with a pre-deposition of a carbon buffer layer to achieve a homo-epitaxial growth. The nucleation and growth of MLGs was found to be strongly influenced by the surface geometry and topography of substrates. Planar substrates suitable for atom diffusion are favorable for growing large-scale MLGs, and defect-rich substrates are beneficial for quick MLG nucleation and thus the growth of densely distributed MLGs. The field emission properties of MLGs grown on planar and nano-structured substrates were studied and are found to be strongly dependent on the nature of substrates. Substrates having good conductivity and large aspect ratios such as carbon nanotubes (CNTs) have good field emission properties. The best field emission properties of MLG/CNT composites with optimal shapes were observed with a low turn-on electric field of 0.93 V MUm(-1), a threshold field of 1.56 V MUm(-1), a maximum emission current density of 60.72 mA cm(-2), and excellent stability. PMID- 24162072 TI - Low-dose pegylated interferon-alpha2a plus ribavirin therapy for elderly and/or cirrhotic patients with HCV genotype-1b and high viral load. AB - BACKGROUND: Pegylated interferon (PEG-IFN) plus ribavirin therapy is still recommended for elderly and/or cirrhotic patients. This study examined whether sustained virological response (SVR) to low-dose PEG-IFN-alpha2a plus ribavirin therapy for elderly and/or cirrhotic patients could be predicted based on viral reduction within 2 weeks after therapy initiation or interleukin IL-(28B) polymorphism and viral mutations. METHODS: Participants comprised 115 elderly (>=65 years) and/or cirrhotic patients with genotype-1b and high viral load. Reduced doses of PEG-IFN-alpha2a (90 MUg/kg/week) and ribavirin (400-800 mg/day) were administered for 48-72 weeks based on virological response of each patient. RESULTS: SVR was achieved in 34% (39/115), and treatment was discontinued in 15% (17/115). Univariate analysis identified age, alpha-fetoprotein, fibrosis marker, interferon sensitivity-determining region (ISDR), IL-28B polymorphism and level of viral reduction within 2 weeks as factors contributing significantly to SVR. However, no significant differences were noted in core amino acid substitutions. Multivariate analysis identified age, hyaluronic acid, ISDR and viral reduction as factors independently associated with SVR. Positive predictive value (PPV) and negative predictive value (NPV) of SVR based on the level of viral reduction at 2 weeks (cutoff level, 1.7 log IU/ml) were 83% and 84%, respectively. The PPV of SVR based on IL-28B major and ISDR mutant was 70%, and the NPV of SVR based on IL 28B minor and wild-type ISDR was 89%. CONCLUSIONS: Evaluations of viral reduction at 2 weeks or both IL-28B and ISDR are useful to predict SVR to low-dose PEG-IFN alpha2a plus ribavirin therapy for elderly and/or cirrhotic patients. PMID- 24162074 TI - Factoring 51 and 85 with 8 qubits. AB - We construct simplified quantum circuits for Shor's order-finding algorithm for composites N given by products of the Fermat primes 3, 5, 17, 257, and 65537. Such composites, including the previously studied case of 15, as well as 51, 85, 771, 1285, 4369, ... have the simplifying property that the order of a modulo N for every base a coprime to N is a power of 2, significantly reducing the usual phase estimation precision requirement. Prime factorization of 51 and 85 can be demonstrated with only 8 qubits and a modular exponentiation circuit consisting of no more than four CNOT gates. PMID- 24162076 TI - Differential expression of liver fluke beta-tubulin isotypes at selected life cycle stages. AB - We have shown that Fasciola hepatica expresses at least six beta-tubulins in the adult stage of its life cycle, designated F.hep-beta-tub1-6 (Ryan et al., 2008). Here we show that different complements of tubulin isotypes are expressed in different tissues and at different life cycle stages; this information may inform the search for novel anthelmintics. The predominant (as judged by quantitative PCR) isotype transcribed at the adult stage was F.hep-beta-tub1 and immunolocalisation studies revealed that this isotype occurred mainly in mature spermatozoa and vitelline follicles. Quantitative PCR indicated that changes occurred in the transcription levels of beta-tubulin isotypes at certain life cycle stages and may be of importance in the efficacy of benzimidazole-based anthelmintic drugs, but there were no significant differences between the triclabendazole-susceptible Leon isolate and the triclabendazole-resistant Oberon isolate in the transcription levels of each of the isotypes. When three well characterised isolates with differing susceptibilities to triclabendazole were compared, only one amino acid change resulting from a homozygous coding sequence difference (Gly269Ser) in isotype 4 was observed. However, this change was not predicted to alter the overall structure of the protein. In conclusion, these findings indicate that there is tissue-specific expression of tubulin isotypes in the liver fluke but the development of resistance to triclabendazole is not associated with changes in its presumed target molecule. PMID- 24162077 TI - A novel hook-shaped enhancement on contrast-enhanced sagittal magnetic resonance image in acute Sheehan's syndrome: a case report. AB - We report characteristic magnetic resonance (MR) image findings in a case of Sheehan's syndrome. A 37-year-old woman experienced complications of retained placenta and massive bleeding (3600 g) during delivery of a full-term baby. A pituitary function test demonstrated panhypopituitarism. MR image of the pituitary gland on postpartum day 10 revealed swelling of the anterior lobe. A hook-shaped enhancement was demonstrated on a sagittal image. The pituitary stalk, majority of the marginal zone of the anterior lobe, the anterior lobe just in front of the posterior lobe, and posterior lobe were well enhanced. In contrast, the central portion and the superior margin, just in front of the stalk insertion of the anterior lobe, were not enhanced. Anatomically, blood supply to these unenhanced portions of the anterior lobe was via the hypophyseal long portal vein and trabecular artery, which are tributaries of the superior hypophyseal artery that originate far from the internal carotid artery. Based on clinical history and MR image findings, the patient was diagnosed with Sheehan's syndrome and treated with hydrocortisone and levothyroxine. Follow-up MR image revealed marked atrophy of the anterior lobe. The characteristic hook-shaped enhancement in Sheehan's syndrome well reflected the vulnerability to massive bleeding based on the complex pituitary vasculature, which has not been reported previously. MR image with contrast enhancement is useful in the diagnosis of the acute phase of Sheehan's syndrome and in evaluating infarction of the anterior lobe. PMID- 24162078 TI - Collective hydrogen-bond dynamics dictates the electronic structure of aqueous I3(-). AB - The molecular and electronic structures of aqueous I3(-) and I(-) ions have been investigated through ab initio molecular dynamics (MD) simulations and photoelectron (PE) spectroscopy of the iodine 4d core levels. Against the background of the theoretical simulations, data from our I4d PE measurements are shown to contain evidence of coupled solute-solvent dynamics. The MD simulations reveal large amplitude fluctuations in the I-I distances, which couple to the collective rearrangement of the hydrogen bonding network around the I3(-) ion. Due to the high polarizability of the I3(-) ion, the asymmetric I-I vibration reaches partially dissociated configurations, for which the electronic structure resembles that of I2 + I(-). The charge localization in the I3(-) ion is found to be moderated by hydrogen-bonding. As seen in the PE spectrum, these soft molecular vibrations are important for the electronic properties of the I3(-) ion in solution and may play an important role in its electrochemical function. PMID- 24162075 TI - Molecular systematics of pinniped hookworms (Nematoda: Uncinaria): species delimitation, host associations and host-induced morphometric variation. AB - Hookworms of the genus Uncinaria have been widely reported from juvenile pinnipeds, however investigations of their systematics has been limited, with only two species described, Uncinaria lucasi from northern fur seals (Callorhinus ursinus) and Uncinaria hamiltoni from South American sea lions (Otaria flavescens). Hookworms were sampled from these hosts and seven additional species including Steller sea lions (Eumetopias jubatus), California sea lions (Zalophus californianus), South American fur seals (Arctocephalus australis), Australian fur seals (Arctocephalus pusillus), New Zealand sea lions (Phocarctos hookeri), southern elephant seals (Mirounga leonina), and the Mediterranean monk seal (Monachus monachus). One hundred and thirteen individual hookworms, including an outgroup species, were sequenced for four genes representing two loci (nuclear ribosomal DNA and mitochondrial DNA). Phylogenetic analyses of these sequences recovered seven independent evolutionary lineages or species, including the described species and five undescribed species. The molecular evidence shows that U. lucasi parasitises both C. ursinus and E. jubatus, whereas U. hamiltoni parasitises O. flavescens and A. australis. The five undescribed hookworm species were each associated with single host species (Z. californianus, A. pusillus, P. hookeri, M. leonina and M. monachus). For parasites of otarids, patterns of Uncinaria host-sharing and phylogenetic relationships had a strong biogeographic component with separate clades of parasites from northern versus southern hemisphere hosts. Comparison of phylogenies for these hookworms and their hosts suggests that the association of U. lucasi with northern fur seals results from a host-switch from Steller sea lions. Morphometric data for U. lucasi shows marked host-associated size differences for both sexes, with U. lucasi individuals from E. jubatus significantly larger. This result suggests that adult growth of U. lucasi is reduced within the host species representing the more recent host parasite association. Intraspecific host-induced size differences are inconsistent with the exclusive use of morphometrics to delimit and diagnose species of Uncinaria from pinnipeds. PMID- 24162080 TI - Simulation of non-Abelian gauge theories with optical lattices. AB - Many phenomena occurring in strongly correlated quantum systems still await conclusive explanations. The absence of isolated free quarks in nature is an example. It is attributed to quark confinement, whose origin is not yet understood. The phase diagram for nuclear matter at general temperatures and densities, studied in heavy-ion collisions, is not settled. Finally, we have no definitive theory of high-temperature superconductivity. Though we have theories that could underlie such physics, we lack the tools to determine the experimental consequences of these theories. Quantum simulators may provide such tools. Here we show how to engineer quantum simulators of non-Abelian lattice gauge theories. The systems we consider have several applications: they can be used to mimic quark confinement or to study dimer and valence-bond states (which may be relevant for high-temperature superconductors). PMID- 24162079 TI - Primary health care experiences of hispanics with serious mental illness: a mixed methods study. AB - This mixed-methods study examines the primary health care experiences of Hispanic patients with serious mental illness. Forty patients were recruited from an outpatient mental health clinic. Participants reported a combination of perceived discrimination and stigmatization when receiving medical care. They rated the quality of chronic illness care as poor and reported low levels of self-efficacy and patient activation. These indicators were positively associated with how patients viewed their relationships with primary care providers. A grounded model was developed to describe the structural, social, and interpersonal processes that shaped participants' primary care experiences. PMID- 24162081 TI - Efficacy of extended release quetiapine fumarate monotherapy in elderly patients with major depressive disorder: secondary analyses in subgroups of patients according to baseline anxiety, sleep disturbance, and pain levels. AB - This study evaluated extended release quetiapine fumarate (quetiapine XR) monotherapy in elderly patients with major depressive disorder (MDD) according to baseline levels of anxiety, sleep disturbance, and pain. Post-hoc analyses of data from an 11-week (9-week randomized-treatment, 2-week post-treatment phase), double-blind, placebo-controlled study of quetiapine XR (50-300 mg/day) monotherapy in elderly (>=66 years) patients (n=338) with MDD were carried out. Outcomes included randomization to week 9 change in Montgomery Asberg Depression Rating Scale (MADRS) score and week 9 response (>=50% MADRS score reduction) rates. Post-hoc analyses were carried out to assess subgroups of patients with MDD according to baseline levels in terms of the following: higher or lower anxiety (Hamilton Rating Scale for Anxiety total score>=20 or < 20, respectively); high or low sleep disturbance [Hamilton Rating Scale for Depression sleep disturbance factor (items 4+5+6) score>=5 or <5, respectively]; and pain visual analog scale total score 40 mm or higher or less than 40 mm. At week 9, quetiapine XR reduced the MADRS total score compared with placebo in the higher anxiety (least squares mean change -17.8 vs. -8.5; P<0.001) and lower anxiety (-14.8 vs. -8.8; P<0.001) subgroups. MADRS total score was also reduced with quetiapine XR compared with placebo in the high (-17.6 vs. -8.7; P<0.001) and low (-14.4 vs. -9.2; P<0.001) sleep disturbance subgroups, as well as in the pain visual analog scale subgroups [>=40 mm (-16.6 vs. -8.9; P<0.001) and <40 mm (-15.7 vs. -8.7; P<0.001)]. Quetiapine XR response rates were higher than those of placebo in all subgroups analyzed. In this study, quetiapine XR (50-300 mg/day) monotherapy was shown to be effective against depressive symptoms in elderly patients with MDD, irrespective of baseline levels of anxiety, sleep disturbance, and pain. PMID- 24162083 TI - MpigE, a gene involved in pigment biosynthesis in Monascus ruber M7. AB - Monascus pigments (MPs) have been used as food colorants for several centuries in Asian countries. However, MP biosynthesis pathway is still a controversy, and only few related genes have been reported. In this study, the function of MpigE, a gene involved in MP biosynthesis in Monascus ruber M7, was analyzed. The results revealed that the disruption, complementation, and overexpression of MpigE in M. ruber M7 had very little effects on the growth and phenotypes except MPs. The MpigE deletion strain (?MpigE) just yielded four kinds of yellow MPs and very little red pigments, while the wild-type strain M. ruber M7 produced a MP complex mixture including three (orange, red, and yellow) categories of MP compounds. Two of the four yellow MPs produced by ?MpigE were the same as those yielded by M. ruber M7. The MpigE complementation strain (?MpigE::MpigE) recovered the ability to generate orange and red MPs as M. ruber M7. The MP types produced by the MpigE overexpression strain (M7::PtrpC-MpigE) were consistent with those of M. ruber M7, while the color value was about 1.3-fold as that of M. ruber M7 (3,129 U/g red kojic). For the production of citrinin, the disruption of MpigE almost had no influence on the strain, whereas the overexpression of MpigE made citrinin decrease drastically in YES fermentation. This work will make a contribution to the study on the biosynthesis pathway of MPs in M. ruber. PMID- 24162084 TI - Comparative proteome profiling of host-pathogen interactions: insights into the adaptation mechanisms of Francisella tularensis in the host cell environment. AB - The intracellular pathogens have the unique capacity to sense the host cell environment and to respond to it by alteration in gene expression and protein synthesis. Proteomic analysis of bacteria exposed directly to the host cell milieu might thus greatly contribute to the elucidation of processes leading to bacterial adaptation and proliferation inside the host cell. Here we have performed a global proteome analysis of a virulent Francisella tularensis subsp. holarctica strain during its intracellular cycle within the macrophage-like murine cell line J774.2 using the metabolic pulse-labeling of bacterial proteins with (35)S-methionine and (35)S-cysteine in various periods of infection. The two dimensional gel analysis revealed macrophage-induced bacterial proteome changes in which 64 identified proteins were differentially expressed in comparison to controls grown in tissue culture medium. Nevertheless, activation of macrophages with interferon gamma before in vitro infection decreased the number of detected alterations in protein levels. Thus, these proteomic data indicate the F. tularensis ability to adapt to the intracellular hostile environment that is, however, diminished by prior interferon gamma treatment of host cells. PMID- 24162085 TI - Carbon dioxide utilisation of Dunaliella tertiolecta for carbon bio-mitigation in a semicontinuous photobioreactor. AB - Bio-fixation of carbon dioxide (CO2) by microalgae has been recognised as an attractive approach to offset anthropogenic emissions. Biological carbon mitigation is the process whereby autotrophic organisms, such as microalgae, convert CO2 into organic carbon and O2 through photosynthesis; this process through respiration produces biomass. In this study Dunaliella tertiolecta was cultivated in a semicontinuous culture to investigate the carbon mitigation rate of the system. The algae were produced in 1.2-L Roux bottles with a working volume of 1 L while semicontinuous production commenced on day 4 of cultivation when the carbon mitigation rate was found to be at a maximum for D. tertiolecta. The reduction in CO2 between input and output gases was monitored to predict carbon fixation rates while biomass production and microalgal carbon content are used to calculate the actual carbon mitigation potential of D. tertiolecta. A renewal rate of 45 % of flask volume was utilised to maintain the culture in exponential growth with an average daily productivity of 0.07 g L(-1) day(-1). The results showed that 0.74 g L(-1) of biomass could be achieved after 7 days of semicontinuous production while a total carbon mitigation of 0.37 g L(-1) was achieved. This represented an increase of 0.18 g L(-1) in carbon mitigation rate compared to batch production of D. tertiolecta over the same cultivation period. PMID- 24162086 TI - Medium chain length polyhydroxyalkanoate (mcl-PHA) production from volatile fatty acids derived from the anaerobic digestion of grass. AB - A two step biological process for the conversion of grass biomass to the biodegradable polymer medium chain length polyhydroxyalkanoate (mcl-PHA) was achieved through the use of anaerobic and aerobic microbial processes. Anaerobic digestion (mixed culture) of ensiled grass was achieved with a recirculated leach bed bioreactor resulting in the production of a leachate, containing 15.3 g/l of volatile fatty acids (VFAs) ranging from acetic to valeric acid with butyric acid predominating (12.8 g/l). The VFA mixture was concentrated to 732.5 g/l with a 93.3 % yield of butyric acid (643.9 g/l). Three individual Pseudomonas putida strains, KT2440, CA-3 and GO16 (single pure cultures), differed in their ability to grow and accumulate PHA from VFAs. P. putida CA-3 achieved the highest biomass and PHA on average with individual fatty acids, exhibited the greatest tolerance to higher concentrations of butyric acid (up to 40 mM) compared to the other strains and exhibited a maximum growth rate (MUMAX = 0.45 h-1). Based on these observations P. putida CA-3 was chosen as the test strain with the concentrated VFA mixture derived from the AD leachate. P. putida CA-3 achieved 1.56 g of biomass/l and accumulated 39 % of the cell dry weight as PHA (nitrogen limitation) in shake flasks. The PHA was composed predominantly of 3 hydroxydecanoic acid (>65 mol%). PMID- 24162087 TI - Kinetic and thermodynamic analysis of Candida antarctica lipase B-catalyzed alcoholytic resolution of (R,S)-beta-butyrolactone in organic solvents. AB - Optically pure (R)-beta-butyrolactone as an important chiral building block in the syntheses of various biologically active compounds and biodegradable polymers was prepared from (R,S)-beta-butyrolactone through kinetic resolution. Candida antarctica lipase B (CALB) with a high enantiomeric ratio of 198 enantioselectively catalyzed the ring opening of the racemate with methanol in methyl tert-butyl ether at 45 degrees C and yielded the remaining (R)-beta butyrolactone. A detailed kinetic analysis indicated that methanol and (R)- and (S)-methyl ester all acted as competitive inhibitors for the enzyme. Comparisons of the theoretical and experimental conversions for both enantiomers were further made and elucidated. The thermodynamic analysis implied the enantiomer discrimination for the transition states of both enantiomers to be entropy-driven in the temperature range investigated. Moreover, preliminary results from the lipase reusability, feed-batch operation, and remaining substrate recovery were addressed. PMID- 24162088 TI - Changes in physical activity and heart rate variability in chronic neck-shoulder pain: monitoring during work and leisure time. AB - OBJECTIVES: Neck-shoulder pain (NSP) is a common work-related musculoskeletal disorder with unclear mechanisms. Changes in physical activity and autonomic nervous system regulation may be involved in the pathogenesis of chronic NSP. The aim of the current study was to investigate autonomic regulation in relation to physical activity and perceived symptoms during work and leisure time among workers with chronic NSP (n = 29) as compared to a healthy control group (CON, n = 27). METHODS: Physical activity was objectively monitored for 7 days using accelerometry. Beat-to-beat heart rate was collected continuously for 72 h, with simultaneous momentary ratings of pain, stress, and fatigue. Duration of sitting/lying, standing and walking, number of steps, and energy expenditure were used as measures of physical activity. Heart rate variability (HRV) indices were extracted in time and frequency domains as reflecting autonomic regulation. Data were divided into work hours, leisure time, and sleep. RESULTS: The NSP group rated higher levels of stress and fatigue at work and leisure, and reduced sleep quality as compared to CON. Elevated heart rate and reduced HRV were found in NSP compared with CON, especially during sleep. The NSP group demonstrated a different pattern of physical activity than CON, with a lower activity level in leisure time. Higher physical activity was associated with increased HRV in both groups. CONCLUSION: Changes in HRV reflected an autonomic imbalance in workers with chronic musculoskeletal pain. This can be explained by reduced physical activity in leisure time. Intervention studies aimed at increasing physical activity may shed further light on the association between autonomic regulation and physical activity in work-related NSP. PMID- 24162090 TI - Guiana dolphins (Sotalia guianensis) as marine ecosystem sentinels: ecotoxicology and emerging diseases. AB - Guiana dolphins (Sotalia guianensis) are small cetaceans that inhabit coastal regions down to a 50 m depth. As a coastally distributed species, they are exposed to a variety of human-induced risks that include passive fishing nets, persistent environmental pollution, and emerging diseases. As a top predatorS. guianensis occupies an important ecological niche in marine ecosystems. However, this niche also exposes this dolphin to extensive biomagnification of marine contaminants that may accumulate and be stored throughout their life of about 30 years.In this paper, we have compiled available data on the Guiana dolphin as regards its exposure to chemical pollutants, pathogenic microbes, infectious diseases, and injuries caused by interactions with passive fishing gears. Our analysis of the data shows that Guiana dolphins are particularly sensitive to environmental changes.Although the major mortal threat to dolphins results from contact with fishing other human-related activities in coastal zones also pose risks and need more attention.Such human-related risks include the presence of persistent toxicants in the marine environment, such as PCBs and PBDEs. Residues of these chemicals have been detected in Guiana dolphin's tissues at similar or higher levels that exist in cetaceans from other known polluted areas. Another risk encountered by this species is the non lethal injuries caused by fishing gear. Several incidents of this sort have occurred along the Brazilian coast with this species. When injuries are produced by interaction with fishing gear, the dorsal fin is the part of the dolphin anatomy that is more affected, commonly causing severe laceration or even total loss.The Guiana dolphins also face risks from infectious diseases. The major ones thus far identified include giardiasis, lobomycosis, toxoplasmosis, skin and skeletal lesions. Many bacterial pathogens from the family Aeromonadaceae and Vibrionaceae have been isolated from Guiana dolphins. Several helminth species have also been observed to affectS. guianensis. These results suggest a vulnerability of this species to environmental disturbances. Moreover, there is some evidence that the effects of some infectious diseases may be enhanced from stress caused by habitat impairment. For example, certain diseases and pathogenic organisms in S.guianensis may be associated with the high levels of endocrine-disruptor contaminants(e.g., PCBs; DDTs; PBDEs) that have been detected in marine waters.Although the data available on S. guianensis is growing, most of the work has been focused on a small portion of the species total area of distribution. Most studies,to date, have been carried out in the Southern region of the distribution, and in north eastern Brazil. Few studies have been conducted in the northern region of the South America or in Central America. Therefore, future studies should be conducted that address the heterogeneity of this species total distribution.The biology and ecology of the Guiana dolphin renders this species potentially useful as a sentinel species for detecting environmental changes, such as chemical and biological pollution. Research about this dolphin is encouraged as a way to assess what coastal environmental changes have occurred and to continue evaluating the health status of this vulnerable species in a changing environment. PMID- 24162091 TI - Predicted no-effect concentration and risk assessment for 17-[beta]-estradiol in waters of China. AB - Contamination of the aquatic environment by EDCs has received considerable attention from scientists, government officials, and the public. E2, one of the EDCs with high estrogenic effect, has the potential to cause multiple endocrine disrupting effects, even at small concentrations. In the present review, the toxicity of E2 to aquatic organisms was reviewed. Results of published studies show that, for aquatic species, reproductive effects were the most sensitive endpoint for E2 exposure.Although the risks posed by EDCs have caused much attention, the research on the WQC 'for EDCs is still at the initial stage. It has been suggested in several reports that the PNEC can be regarded as the most appropriate reference value for developing WQC for the EDCs. The SSD method was applied to derive PNECs that were based on reproductive effects endpoints. In the present review, 31 NOECs, based on reproductive effect endpoints for different species, were selected to construct the curve. ThePNEC value was determined to be 0.73 ng E2/L, which could protect the biodiversity of aquatic ecosystems. Moreover, 6 NOECs for multigeneration species were also analyzed in anticipation of sensitivity comparison between the Fa and the F1 generations.When multiple generations of aquatic species were exposed to concentrations no greater than 100 ng E2/L, nearly 71.4% of the F 1 generation individuals were more sensitive to the effects of E2 than those of the Fa generation. This result indicated that different generations of the same species may respond differently to EDCs exposure.Individuals of the F 1 generation were slightly more sensitive than those of the Fa generation,in general. Therefore, protecting the F1 generation of aquatic organisms is particularly important when WQC values for the EDCs are established.Considering the toxic effects of EDCs on reproduction, long-term toxic effects(viz., full-life cycle study and the most sensitive life stage) should be used in settingWQC. Unfortunately, the NOECs of E2 for multigeneration species did not meet the requirement of PNEC derivation for protecting the Fl generation. Therefore, further research results are needed on the Fl generation of aquatic species to provide more insight into what constitutes adequate protection for aquatics lives. In the present review, the PNEC values derived in the study were compared to thePNEC values developed by others, and the results showed that they were highly consistent. In addition, we also compared the PNEC value for E2 to the PNEC value for EE2, a similar estrogen, and the result was also highly consistent when their EEFs were considered. These comparisons affirmed that the method we used for deriving the PNEC value of E2 was reasonable and the PNEC values we derived were acceptable for protecting aquatic organisms. By comparing the PNEC values we calculated to actual E2 concentrations in the natural water environment, we found that E2 in surface waters may pose high risks in many countries, especially China, Japan, the USA, Great Britain, and Italy. PMID- 24162092 TI - Adverse effects of bisphenol A on male reproductive function. AB - BPA is a ubiquitous environmental contaminant, resulting mainly from manufacturing,use or disposal of plastics of which it is a component, and the degradation of industrial plastic-related wastes. Growing evidence from research on laboratory animals, wildlife, and humans supports the view that BPA produces an endocrine disrupting effect and adversely affects male reproductive function. To better understand the adverse effects caused by exposure to BPA, we performed an up-to-date literature review on the topic, with particular emphasis on in utero exposure, and associated effects on spermatogenesis, steroidogenesis, and accessory organs.BPA studies on experimental animals show that effects are generally more detrimental during in utero exposure, a critical developmental stage for the embryo. BPA has been found to produce several defects in the embryo, such as feminization of male fetuses, atrophy of the testes and epididymides, increased prostate size, shortening of AGD, disruption of BTB, and alteration of adult sperm parameters (e.g.,sperm count, motility, and density). BPA also affects embryo thyroid development.During the postnatal and pubertal periods and adulthood, BPA affects the hypothalamic-pituitary-testicular axis by modulating hormone (e.g., LH and FSH,androgen and estrogen) synthesis, expression and function of respective receptors(ER, AR). These effects alter sperm parameters. BPA also induces oxidative stress in the testis and epididymis, by inhibiting antioxidant enzymes and stimulating lipid peroxidation. This suggests that employing antioxidants may be a promising strategy to relieve BPA-induced disturbances.Epidemiological studies have also provided data indicating that BPA alters male reproductive function in humans. These investigations revealed that men occupationally exposed to BPA had high blood/urinary BPA levels, and abnormal semen parameters. BPA-exposed men also showed reduced libido and erectile ejaculatory difficulties; moreover, the overall BPA effects on male reproduction appear to be more harmful if exposure occurs in utero. The regulation of BPA and BPA-related products should be reinforced, particularly where exposure during the fetal period can occur. The current TDI for BPA is proposed as 25 and 50 1-1g/kg bwt/day (European Food Safety Authority and Health Canada, respectively). Based on the evidence available, we believe that a TDI value of 5 1-1g/kg bwt/day is more appropriate (the endpoint is modulation of rat testicular function). Certain BPA derivatives are being considered as alternatives to BPA. However, certain of these related products display adverse effects that are similar to those of BPA. These effects should be carefully considered before using them as final alternatives to BPA in plastic production. PMID- 24162089 TI - Oral administration of angiotensin-(1-7) ameliorates type 2 diabetes in rats. AB - Diabetes mellitus type 2 (DM2) is a disease with increasing importance in modern societies and insufficient treatment options. Pharmacological stimulation of insulin signaling, which is blunted in DM2, is a promising approach to treat this disease. It has been shown that activation of the angiotensin (Ang)-(1-7)/Mas axis of the renin-angiotensin system leads to an improved glucose uptake. In this study, we intended to evaluate, whether this effect could be exploited therapeutically. We first confirmed that Ang-(1-7) improves insulin signaling and glucose uptake in vitro in cultured cardiomyocytes. We then evaluated the therapeutic effect of a newly developed hydro-xypropyl-beta-cyclodextrin-based Ang-(1-7) nano-formulation in a novel transgenic rat model of inducible insulin resistance and DM2. The chronic administration of this compound prevented the marked elevation in blood glucose levels in these rats at a dose of 30 MUg/kg, reversed the established hyperglycemic state at a dose of 100 MUg/kg, and resulted in improved insulin sensitivity, reduced plasma insulin and decreased diabetic nephropathy. In conclusion, an oral Ang-(1-7) formulation reverses hyperglycemia and its consequences in an animal model of DM2 and represents a novel therapeutic option for the treatment of DM2 and other cardio-metabolic diseases. KEY MESSAGE: A novel rat model with inducible diabetes can be used to evaluate new therapies. Angiotensin-(1-7) is effective in an oral formulation packaged in cyclodextrine. Angiotensin-(1-7) is a promising antidiabetic drug. PMID- 24162093 TI - Biochar: an effective amendment for remediating contaminated soil. AB - Biochar is a carbon-rich material derived from incomplete combustion of biomass.Applying biochar as an amendment to treat contaminated soils is receiving increasing attention, and is a promising way to improve soil quality. Heavy metals are persistent and are not environmentally biodegradable. However, they can be stabilized in soil by adding biochar. Moreover, biochar is considered to be a predominant sorptive agent for organic pollutants, having a removal efficiency of about 1 order of magnitude higher than does soil/sediment organic matter or their precursor substances alone.When trying to stabilize organic and inorganic pollutants in soil, several features of biochar' s sorption capacity should be considered, viz., the nature of the pollutants to be remediated, how the biochar is prepared, and the complexity of the soil systemin which biochar may be used. In addition, a significant portion of the biochar or some of its components that are used to remediate soils do change over time through abiotic oxidation and microbial decomposition. This change process is commonly referred to as "aging:" Biochar "aging" in nature is inevitable, and aged biochar exhibits an effect that is totally different than non-aged biochar on stabilizing heavy metals and organic contaminants in soils.Studies that have been performed to date on the use of biochar to remediate contaminated soil are insufficient to allow its use for wide-scale field application.Therefore, considerable new data are necessary to expand both our understanding of how biochar performs in the field, and where it can be best used in the future for soil remediation. For example, how biochar and soil biota (microbial and faunal communities)interact in soils is still poorly understood. Moreover, studies are needed on how to best remove new species of heavy metals, and on how biochar aging affects sorption capacity are also needed. PMID- 24162094 TI - Fusarial toxins: secondary metabolites of Fusarium fungi. AB - Exposure to mycotoxins occurs worldwide, even though there are geographic and climatic differences in the amounts produced and occurrence of these substances.Mycotoxins are secondary chemical metabolites of different fungi. They are natural contaminants of cereals, so their presence is often inevitable. Among many genera that produce mycotoxins, Fusarium fungi are the most widespread in cereal-growing areas of the planet. Fusarium fungi produce a diversity of mycotoxin types, whose distributions are also diverse. What is produced and where it is produced is influenced primarily by environmental conditions, and crop production and storage methods. The amount of toxin produced depends on physical (viz., moisture, relative humidity, temperature, and mechanical damage), chemical (viz., carbon dioxide,oxygen, composition of substrate, insecticides and fungicides), and biological factors (viz., plant variety, stress, insects, spore load, etc.). Moisture and temperature have a major influence on mold growth rate and mycotoxin production.Among the most toxic and prevalent fusaria) toxins are the following: zearalenone,fumonisins, moniliformin and trichothecenes (T-2/HT-2 toxin, deoxynivalenol,diacetoxyscirpenol, nivalenol). Zearalenone (ZEA; ZON, F-2 toxin) isaphy to estrogenic compound, primarily a field contaminant, which exhibits estrogenic activity and has been implicated in numerous mycotoxicoses of farm animals,especially pigs. Recently, evidence suggests that ZEA has potential to stimulate the growth of human breast cancer cells. Fumonisins are also cancer promoting metabolites,of which Fumonisin 8 I (FBI) is the most important. Moniliformin (MON) isalso highly toxic to both animals and humans. Trichothecenes are classified as gastrointestinal toxins, dermatotoxins, immunotoxins, hematotoxins, and gene toxins.T-2 and HT-2 toxin, and diacetoxyscirpenol (DAS, anguidine) are the most toxic mycotoxins among the trichothecene group. Deoxynivalenol (DON, vomitoxin) and nivalenol although less toxic are important because they frequently occur at levels high enough to cause adverse effects.The presence of mycotoxins in the animal diet can produce significant production losses. Any considerable presence of mycotoxins, in major dietary components,confirms the need to adopt a continuous prevention and control program. Such programs are usually based on several common approaches to minimize mycotoxin contamination in the food chain. Major strategies include preventing fungal growth and therefore mycotoxin formation, reducing or eliminating mycotoxins from contaminated feedstuffs, or diverting contaminated products to low risk uses. Because of the complexity of their chemical structures, mycotoxins also present a major analytical challenge. They are also found in a vast array of feed matrices. Analysis is essential for determining the extent of mycotoxin contamination, for risk analysis, confirming the diagnosis of a mycotoxicosis and for monitoring mycotoxin mitigation strategies.For the future, adequately controlling the mycotoxin problem in the livestock economy will depend on implementing appropriate agricultural management policies,as well as augmenting production and storage systems and analysis methods.Only such policies offer the opportunity to bring solid and long-lasting economical results to the livestock industry that is afflicted with the mycotoxin problem. PMID- 24162095 TI - Fungi contamination of drinking water. AB - Aquatic fungi commonly infest various aqueous environments and play potentially crucial roles in nutrient and carbon cycling. Aquatic fungi also interact with other organisms to influence food web dynamics. In recent decades, numerous studies have been conducted to address the problem of microorganism contamination of water. The major concern has been potential effects on human health from exposure to certain bacteria, viruses, and protozoa that inhabit water and the microbial metabolites,pigments, and odors which are produced in the water, and their effects on human health and animals. Fungi are potentially important contaminants because they produce certain toxic metabolites that can cause severe health hazards to humans and animals. Despite the potential hazard posed by fungi, relatively few studies on them as contaminants have been reported for some countries.A wide variety of fungi species have been isolated from drinking water, and some of them are known to be strongly allergenic and to cause skin irritation, or immunosuppression in immunocompromised individuals (e.g., AIDS, cancer, or organ transplant patients). Mycotoxins are naturally produced as secondary metabolites by some fungi species, and exposure of humans or animals to them can cause health problems. Such exposure is likely to occur from dietary intake of either food,water or beverages made with water. However, mycotoxins, as residues in water,may be aerosolized when showering or when being sprayed for various purposes and then be subject to inhalation. Mycotoxins, or at least some of them, are regarded to be carcinogenic. There is also some concern that toxic mycotoxins or other secondary metabolites of fungi could be used by terrorists as a biochemical weapon by adding amounts of them to drinking water or non drinking water. Therefore, actions to prevent mycotoxin contaminated water from affecting either humans or animals are important and are needed. Water treatment plants may serve to partially accomplish this, by first filtering the water and finally by adding disinfection treatments adequate to remove or mitigate fungi or their toxic metabolites. PMID- 24162096 TI - Phase stability of a garnet-type lithium ion conductor Li7La3Zr2O12. AB - The phase stability of Li7La3Zr2O12 (LLZ) was investigated using high temperature X-ray diffraction (HT-XRD). An Al-free tetragonal LLZ phase transformed into a non-quenchable cubic phase around 650 degrees C. The phase transformation process between the tetragonal phase and the new cubic phase showed perfect reversibility. The thermal analysis showed a pair of endothermic and exothermic peaks around 640 degrees C that is in good agreement with the phase transformation process observed in the HT-XRD study. The non-quenchable high temperature cubic phase showed high ionic conductivity with extraordinarily low activation energy (0.117 eV). The tetragonal phase showed another phase transformation to a low temperature (LT) cubic phase around 150-200 degrees C in air by absorbing CO2 into the structure. The preferred temperature for the CO2 absorption process was around 200 degrees C and the absorbed CO2 was extracted once the temperature reached 450 degrees C or above resulting in the phase transformation back to the tetragonal phase. On the other hand the high temperature (HT) cubic phase which shows high ionic conductivity was stabilized by Al substitution. A Li-poor LLZ containing impurity phases such as La2Zr2O7 and La2O3 effectively reacted with gamma-Al2O3 resulting in the formation of a pure Al-stabilized cubic LLZ, while the stoichiometric LLZ took a much longer time to complete the Al-substitution. The result suggested that the formation of Li vacancies is the primary step in the formation of the Al-stabilized cubic phase. PMID- 24162097 TI - Sensitive electrochemical immunoassay of metallothionein-3 based on K3[Fe(CN)6] as a redox-active signal and C-dots/Nafion film for antibody immobilization. AB - The fabrication of a facile, sensitive, and versatile immunosensor for the quantification of metallothionein-3 (MT-3) is proposed in this work. The K3[Fe(CN)6]-chitosan-glutaraldehyde (K-CS-GA) conjugate prepared from K3[Fe(CN)6], chitosan and glutaraldehyde was employed as the redox-active signal source. Carbon nanodots (C-dots) were coupled with Nafion to form the nanocomposite architecture layer to carry antibodies (Abs). C-dots enhanced the electrochemical response of the proposed immunosensor to improve the detection sensitivity. The fabrication steps of the immunosensor were characterized using differential pulse voltammetry (DPV) and cyclic voltammetry (CV). Antigen determination was achieved via the decreased current response of the K3[Fe(CN)6] caused by the insulated coupled antigen. The detected signals were proportional to the logarithm of the concentrations of MT-3 ranging from 5 pg mL(-1) to 20 ng mL(-1) with a detection limit of 2.5 pg mL(-1) in PBS. The proposed immunosensor showed high sensitivity, good selectivity and reproducibility. Furthermore, detection results using real serum samples showed the immunosensor's potential applications in clinical diagnostics. PMID- 24162098 TI - Delayed emergence of HIV-1 variants resistant to 4'-ethynyl-2-fluoro-2' deoxyadenosine: comparative sequential passage study with lamivudine, tenofovir, emtricitabine and BMS-986001. AB - BACKGROUND: 4'-Ethynyl-2-fluoro-2'-deoxyadenosine (EFdA) contains an ethynyl moiety and the 3'-hydroxyl and exerts highly potent activity against various HIV type-1 (HIV-1) strains including multi-drug-resistant variants. METHODS: Comparative selection passages against EFdA, lamivudine (3TC), tenofovir disoproxil fumarate (TDF), emtricitabine (FTC) or BMS-986001 (Ed4T) were conducted using a mixture of 11 highly multi-drug-resistant clinical HIV-1 isolates (HIV11MIX) as a starting virus population. RESULTS: Before selection, HIV11MIX was sensitive to EFdA with a 50% inhibitory concentration (IC50) of 0.032 MUM, less susceptible to TDF and Ed4T with IC50s of 0.57 and 2.6 MUM, respectively, and highly resistant to 3TC and FTC with IC50s>10 MUM. IC50s of TDF against HIV11MIX exposed to EFdA and TDF for 17 (HIV11MIX(EFdA-P17)) and 14 (HIV11MIX(TDF-P14)) passages were 8 and >10 MUM, respectively, while EFdA remained active against HIV11MIX(EFdA-P17) and HIV11MIX(TDF-P14) with IC50s of 0.15 and 0.1 MUM, respectively. Both selected variants were highly resistant against zidovudine, 3TC, Ed4T and FTC (IC50 values >10 MUM). CONCLUSIONS: The present data demonstrate that HIV11MIX developed resistance more rapidly against 3TC, FTC, TDF and Ed4T than against EFdA and that EFdA remained substantially active against TDF- and EFdA-selected variants. Thus, EFdA has a favourable resistance profile and represents a potentially promising new-generation nucleoside reverse transcriptase inhibitor. PMID- 24162101 TI - The big five personality traits: psychological entities or statistical constructs? AB - The present study employed multivariate genetic item-level analyses to examine the ontology and the genetic and environmental etiology of the Big Five personality dimensions, as measured by the NEO Five Factor Inventory (NEO-FFI) [Costa and McCrae, Revised NEO personality inventory (NEO PI-R) and NEO five factor inventory (NEO-FFI) professional manual, 1992; Hoekstra et al., NEO personality questionnaires NEO-PI-R, NEO-FFI: manual, 1996]. Common and independent pathway model comparison was used to test whether the five personality dimensions fully mediate the genetic and environmental effects on the items, as would be expected under the realist interpretation of the Big Five. In addition, the dimensionalities of the latent genetic and environmental structures were examined. Item scores of a population-based sample of 7,900 adult twins (including 2,805 complete twin pairs; 1,528 MZ and 1,277 DZ) on the Dutch version of the NEO-FFI were analyzed. Although both the genetic and the environmental covariance components display a 5-factor structure, applications of common and independent pathway modeling showed that they do not comply with the collinearity constraints entailed in the common pathway model. Implications for the substantive interpretation of the Big Five are discussed. PMID- 24162102 TI - Applications of nanomaterials in mass spectrometry analysis. AB - Mass spectrometry (MS) based analyses have received intense research interest in a series of rapidly developing disciplines. Although current MS techniques have enjoyed great successes, several key challenges still remain in practical applications, especially for the detection of biomolecules in biological systems. The use of nanomaterials in MS based analysis provides a promising approach due to their unique physical and chemical properties. In this review, nanomaterials with different compositions and nanostructures employed in MS applications are summarised and classified by their functions. Such an integrated and wide reaching review will provide a comprehensive handbook to researchers with various backgrounds working in this exciting interdisciplinary area. PMID- 24162103 TI - Synthesis and anionophoric activities of dimeric polyamine-sterol conjugates: the impact of rigid vs. flexible linkers. AB - Two dimeric spermine-choloyl conjugates were synthesized and found to be capable of promoting the transport of anions across egg-yolk L-alpha-phosphatidylcholine based liposomal membranes, via an anion-exchange mechanism and with moderate selectivity with respect to monoanionic ions. A Hill analysis indicated that these two conjugates exhibited similar aggregation behaviors. However, the conjugate bearing a rigid p-bis(aminomethyl)benzene moiety functioned more efficiently than the analogue having a flexible putrescine linker. PMID- 24162104 TI - Cumulative human impacts on marine predators. AB - Stressors associated with human activities interact in complex ways to affect marine ecosystems, yet we lack spatially explicit assessments of cumulative impacts on ecologically and economically key components such as marine predators. Here we develop a metric of cumulative utilization and impact (CUI) on marine predators by combining electronic tracking data of eight protected predator species (n=685 individuals) in the California Current Ecosystem with data on 24 anthropogenic stressors. We show significant variation in CUI with some of the highest impacts within US National Marine Sanctuaries. High variation in underlying species and cumulative impact distributions means that neither alone is sufficient for effective spatial management. Instead, comprehensive management approaches accounting for both cumulative human impacts and trade-offs among multiple stressors must be applied in planning the use of marine resources. PMID- 24162105 TI - Impact of social punishment on cooperative behavior in complex networks. AB - Social punishment is a mechanism by which cooperative individuals spend part of their resources to penalize defectors. In this paper, we study the evolution of cooperation in 2-person evolutionary games on networks when a mechanism for social punishment is introduced. Specifically, we introduce a new kind of role, punisher, which is aimed at reducing the earnings of defectors by applying to them a social fee. Results from numerical simulations show that different equilibria allowing the three strategies to coexist are possible as well as that social punishment further enhance the robustness of cooperation. Our results are confirmed for different network topologies and two evolutionary games. In addition, we analyze the microscopic mechanisms that give rise to the observed macroscopic behaviors in both homogeneous and heterogeneous networks. Our conclusions might provide additional insights for understanding the roots of cooperation in social systems. PMID- 24162106 TI - Opportunity costs and financial incentives for Hispanic youth participating in a family-based HIV and substance use preventive intervention. AB - This paper presents results from a pilot study of the synergies between the opportunity costs incurred by research participants, participant compensation, and program attendance in a family-based substance use and HIV preventive intervention for Hispanic adolescents in Miami-Dade County, Florida. To estimate parent/caretaker cost per session and cost for the duration of the intervention, we administered the Caretaker Drug Abuse Treatment Cost Analysis Program to a random sample of 34 families who participated in a recent clinical trial of Familias Unidas. The total opportunity cost per parent/caretaker was under $40 per group session, under $30 per family session, and just over $570 for the duration of the intervention. Participants were compensated between $40 and $50 per session and attended more than 79% of family and group sessions. Parents and caretakers incurred a cost of approximately $30-40 per intervention session for which they were adequately compensated. Attendance was very good overall for this group (>79%) and significantly higher than attendance in a comparable uncompensated study group from another recent Familias Unidas trial that targeted similar youth. Findings suggest that incentives should be considered important for future implementations of Familias Unidas and similar family-based interventions that target minority and low-SES populations. PMID- 24162107 TI - HER-2/neu vaccine-primed autologous T-cell infusions for the treatment of advanced stage HER-2/neu expressing cancers. AB - This phase I study evaluated the feasibility of expanding HER-2/neu (HER2) vaccine-primed peripheral blood T-cells ex vivo and assessed the safety of T-cell infusions. Eight patients with HER2(+) treatment refractory metastatic cancers were enrolled. T-cells could be expanded to predefined parameters in seven patients (88%). Ninety-two percent of adverse events were grade 1 or 2. Three of seven patients developed infusion-related inflammatory reactions at their disease sites. HER2-specific T-cells significantly increased in vivo compared to pre infusion levels (p = 0.010) and persisted in 4/6 patients (66%) over 70 days after the first infusion. Partial clinical responses were observed in 43% of patients. Levels of T-regulatory cells in peripheral blood prior to infusion (p < 0.001), the level of HER2-specific T-cells in vivo (p = 0.030), and development of diverse clonal T-cell populations (p < 0.001) were associated with response. The generation of HER2 vaccine-primed autologous T-cells for therapeutic infusion is feasible and well tolerated. This approach provides a foundation for the application of T-cell therapy to additional solid tumor types. PMID- 24162109 TI - "Sarcoidosis Americana-route Europa". PMID- 24162108 TI - Elotuzumab directly enhances NK cell cytotoxicity against myeloma via CS1 ligation: evidence for augmented NK cell function complementing ADCC. AB - Elotuzumab is a monoclonal antibody in development for multiple myeloma (MM) that targets CS1, a cell surface glycoprotein expressed on MM cells. In preclinical models, elotuzumab exerts anti-MM efficacy via natural killer (NK)-cell-mediated antibody-dependent cellular cytotoxicity (ADCC). CS1 is also expressed at lower levels on NK cells where it acts as an activating receptor. We hypothesized that elotuzumab may have additional mechanisms of action via ligation of CS1 on NK cells that complement ADCC activity. Herein, we show that elotuzumab appears to induce activation of NK cells by binding to NK cell CS1 which promotes cytotoxicity against CS1(+) MM cells but not against autologous CS1(+) NK cells. Elotuzumab may also promote CS1-CS1 interactions between NK cells and CS1(+) target cells to enhance cytotoxicity in a manner independent of ADCC. NK cell activation appears dependent on differential expression of the signaling intermediary EAT-2 which is present in NK cells but absent in primary, human MM cells. Taken together, these data suggest elotuzumab may enhance NK cell function directly and confer anti-MM efficacy by means beyond ADCC alone. PMID- 24162110 TI - Pleural manometry: ready for prime time. PMID- 24162111 TI - Infections associated with tunnelled indwelling pleural catheters in patients undergoing chemotherapy. AB - BACKGROUND: Malignant pleural effusions are common complications of advanced malignancies and are associated with significant morbidity and reduced survival. Tunnelled indwelling pleural catheters (TIPCs) are implantable devices used for palliation of symptomatic malignant pleural effusions. Although complication rates are overall low, their use in the setting of concurrent chemotherapy has not been carefully reviewed. We report our experience with infectious complications directly attributable to TIPCs (pleural or local soft tissue infections) in those patients receiving concurrent chemotherapy. METHODS: We conducted a retrospective analysis of patients who underwent TIPC placement for malignant pleural effusion in a 6-year period from November 2005 to March 2011. We reviewed the incidence of infection in these patients receiving catheter placement and attempted to determine whether chemotherapy was associated with an increased infectious risk. RESULTS: A total of 262 TIPC procedures, performed in 243 patients, were included in the study. Out of 262, 173 (66%) TIPC were in the chemotherapy group and 89 TIPC were in the nonchemotherapy group. Infections developed in 16 of the 262 TIPC placements (6.1%). The rate of complications in the chemotherapy group was 9 of the 173 TIPCs (5.2%) compared with 7 of the 89 TIPCs (7.9%) in the other group, a difference that was not statistically different (P=0.4). CONCLUSIONS: The overall risk of infection in TIPC is low. Patients undergoing chemotherapy while the TIPC is in place do not seem to have an increased risk of infection, and therefore chemotherapy should not necessarily be viewed as a contraindication to TIPC insertion. PMID- 24162112 TI - Transforming growth factor-beta1 rise in pleural fluid after tunneled pleural catheter placement: pilot study. AB - BACKGROUND: Transforming growth factor-beta1 (TGF-beta1) plays a major role in pleural fibrosis and chemical pleurodesis. Approximately 50% of patients with tunneled pleural catheters (TPCs) for malignant pleural effusions (MPEs) will have autopleurodesis. Pleural TGF-beta1 levels have never been measured in the setting of TPC drainage and may predict autopleurodesis. METHODS: Pleural fluid was collected prospectively in subjects with MPE and planned TPC insertion. Pleural fluid was collected at time 0 (T0, thoracentecis before TPC placement), time 1 (T1, TPC insertion), and time 2 (T2, 2 wk after TPC insertion). The MPE levels of TGF-beta1, vascular endothelial growth factor, and plasminogen activator inhibitor-1 were measured using ELISA. Lactate dehydrogenase levels were also measured at T0. Patients were followed up for autopleurodesis and TPC removal. RESULTS: Nineteen samples were collected from 9 patients with MPE who underwent TPC placement. Three patients died before the study completion. The median level of TGF-beta1 of 1243 pg/mL (range, 620 to 4547 pg/mL) at T1 in 6 patients showed a statistically significant rise to 2857 pg/mL (range, 2120 to 7160 pg/mL) after TPC placement (P=0.004, R=0.898). There was no statistically significant increase in TGF-beta1 levels from T0 to T1. There was a linear relationship between TGF-beta1 and lactate dehydrogenase at T0 (R=0.635). Plasminogen activator inhibitor-1 levels increased from T1 to T2, but was not statistically significant. There was no significant rise in vascular endothelial growth factor from T1 to T2. CONCLUSIONS: TPC insertion results in an independent increase in TGF-beta1 levels in MPE. PMID- 24162113 TI - Utility of bronchoscopy in pulmonary Langerhans cell histiocytosis. AB - BACKGROUND: Pulmonary Langerhans cell histiocytosis (PLCH) is an uncommon form of interstitial lung disease and is usually smoking-related when seen in adults. There are relatively little data regarding the utility of bronchoscopic lung biopsy for this disorder. METHODS: A computer-assisted search was carried out to identify patients with PLCH seen at Mayo Clinic Rochester, MN from 1997 to 2012 and who underwent bronchoscopy with lung biopsy. Approval was obtained from the Mayo Foundation Institutional Review Board before beginning the study. Medical records of these patients were reviewed to extract data with regard to demographic and clinical features, imaging studies, and biopsy results. RESULTS: Thirty-eight patients with PLCH underwent diagnostic bronchoscopy with biopsies. Their median age was 39.5 years (range, 21 to 66 y) and included 24 women. Thirty two patients (84%) were current smokers at the time of the diagnosis, 5 were ex smokers (13%), and 1 was a never-smoker (3%). The diagnosis of PLCH required the presence of typical histopathologic features on surgical or bronchoscopic lung biopsy, >5% CD1a-positive cells in the bronchoalveolar lavage (BAL), and/or biopsy of an extrapulmonary site in the presence of clinical and chest computed tomographic findings compatible with the diagnosis. Bronchoscopic biopsy yielded diagnostic specimens that allowed the diagnosis of PLCH in 19 patients (50%). CD1a immunostaining of BAL cells had been performed in 8 patients and demonstrated >= 5% CD1a-positive BAL cells in 3 additional patients (8%). CONCLUSIONS: We conclude that bronchoscopic lung biopsy is useful in the diagnosis of PLCH and should be the initial method of obtaining diagnostic specimens. PMID- 24162114 TI - Foreign body aspiration in adults and in children: advantages and consequences of a dedicated protocol in our 30-year experience. AB - BACKGROUND: Foreign body (FB) inhalation is a potentially life-threatening emergency also in clinically stable patients as the situation could worsen at any moment. There is varying opinion regarding the urgency for removal of inhaled FBs, and there are no guidelines in the literature. The aim of our study was to present our experience with FB aspiration in children and adults from 1993, when we introduced our Thoracic Endoscopy Service with the availability "on call" of a bronchologist 24 hours a day, 7 days a week, defining a dedicated protocol together with our anaesthesiologists for prompt intervention in this situation. METHODS: We consulted our database and examined the records of all patients undergoing bronchoscopy for suspected FB aspiration from 1993 onwards; our previous experience of 11 children and 14 adults with FBs from 1981 to 1992 was also included to compare the results obtained. RESULTS: In this period, we removed 159 FBs (in 70 children and 89 adults) and performed 23 negative bronchoscopies in children and 6 in adults for suspected aspiration. All FBs were removed successfully. We were able to intervene immediately also in critical situations: in 60/70 children within 24 hours of admission to hospital, in 44 of these 60 on the actual day of admission, thus avoiding a potentially dangerous delay between aspiration and removal. We had no complications, and no patients needed surgery. CONCLUSIONS: We conclude that an efficient organization involving a dedicated protocol of intervention, trained staff available 24 hours a day, 7 days a week, appropriate setting, and the right instrumentation enabled us to tackle this important emergency. PMID- 24162115 TI - Percutaneous dilational tracheostomy in patients receiving antiplatelet therapy: is it safe? AB - Antiplatelet agents have become a mainstay therapy for vascular diseases; yet, it increases the risk of bleeding. The latter has a potential to impact the safety of invasive procedures. A retrospective chart review of patients undergoing percutaneous dilational tracheostomy (PDT) at each of the 2 institutions was performed to determine the bleeding risk for patients on antiplatelet therapy who underwent PDT. Out of the 246 patients who underwent PDT over the study period, 20 qualified for the study group. All were being treated with clopidogrel. A control group of 137 patients was created. No major bleeding occurred in either of the group. Minor bleeding occurred in 1 study patient (5%) and in 5 (3.6%) of the control patients (P=0.85). The data support the performance of PDT without stopping clopidogrel if there was a clear and ongoing indication for the antiplatelet agent. PMID- 24162116 TI - Ulcerative tracheobronchitis due to Aspergillus. AB - Aspergillus ulcerative tracheobronchitis is a life-threatening form of invasive aspergillosis and is seldom seen in patients without underlying an immunocompromised state. Bronchoscopists must be familiar with this entity and consider Aspergillus ulcerative tracheobronchitis whenever mucosal erosions are seen, especially when unconventional risk factors such as intensive care unit admission and short-term glucocorticoid therapy are present. We present a case of invasive Aspergillus causing widespread ulcerative tracheobronchitis in a 39-year old man with an asthma exacerbation requiring intensive care unit admission. PMID- 24162117 TI - Endobronchial cryotherapy for a mycetoma. AB - Mycetoma is defined as a fungus ball that fills a preexisting lung cavity, most frequently being of tuberculous or sarcoid etiology. The most frequently isolated fungus is the species of Aspergillus, but other fungi such as Fusarium or Zygomycetes can also be present. Most patients lack symptoms. However, presentation may also be with hemoptysis, which can be massive and life threatening. We describe the case of a 50-year-old man with a history of prior pulmonary tuberculosis, with recurrent episodes of cough and hemoptysis. He was diagnosed to have mycetoma in the left upper lobe cavity. The mycetoma was extracted through bronchoscopy under general anesthesia using a cryoprobe. Treatment was completed with amphotericin B instilled in the cavity and the patient was placed on oral itraconazole. This is the first case report to date in which cryotherapy was used to remove a mycetoma. PMID- 24162118 TI - Serial lobar lung lavage in pulmonary alveolar proteinosis. AB - Pulmonary alveolar proteinosis (PAP) is a rare disease with worldwide distribution and an estimated incidence of 0.36 cases per million. We report a case of a PAP coexisting with Pneumocystis jiroveci pneumonia and Mycobacterium tuberculosis infection. The patient was treated with serial lobar lung lavages, GM-CSF, cotrimoxazole, and antituberculosis drugs. His PaO2 on room air improved from 45.7 to 63.8 torr and pulmonary functions normalized (FVC 81.2%, FEV1 95.3%, FEV1/FVC 91.8). A high-resolution computed tomography scan of the thorax showed clearing of both lower lobes. Whole-lung lavage is used in the treatment of PAP, but it may worsen the hypoxemia and lead to hemodynamic instability during the procedure. To the best of our knowledge, there are no reports of bronchoscopic serial lobar lung lavages in cases of PAP performed in India. This method can be performed in bronchoscopic suites having general anesthesia facilities without the requirement of special gadgets. PMID- 24162119 TI - Mediastinal abscess after endobronchial ultrasound-guided transbronchial needle aspiration: a case report and literature review. AB - Endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) is a minimally invasive technique that allows lung cancer nodal staging and biopsy of parabronchial and paratracheal tissue. Its simplicity, high diagnostic yield, ability to diagnose both benign and malignant conditions, and exceedingly low complication rate has resulted in rapid widespread adoption by surgeons and physicians. EBUS-TBNA-related complications, however, do occur and need to be considered when assessing the risk-benefit profile of performing the procedure, and if the patient represents with unexpected symptoms after the procedure. We describe a 64-year-old woman who presented with a mediastinal abscess 5 days after EBUS-TBNA. This case demonstrates the importance of considering EBUS-TBNA related complications to guide relevant imaging decisions and antibiotic choices. We review the published literature regarding infective complications of EBUS-TBNA and propose possible pathophysiologies. These complications are likely to increase in frequency as the technique is more widely adopted. PMID- 24162120 TI - Intussusception technique of intrabronchial silicone stents: description of technique and a case report. AB - Respiratory tract infection with human papillomavirus has been associated with major airway complications, including tracheal stenosis. We report a case of recurrent respiratory papillomatosis infection complicated with iatrogenic airway fire injury causing airway stenosis. This was treated with reconstruction and a silicone Y stent placement. Three years after the stent placement, the patient presented with wheezing and shortness of breath. Bronchoscopy revealed tracheal narrowing proximal to the tracheal limb of the Y stent. The stenosis was treated with a stent intussusception technique with satisfactory results. PMID- 24162122 TI - Transpulmonary artery needle aspiration of hilar masses with endobronchial ultrasound: a necessary evil. AB - The safety with regard to bleeding complications of endobronchial ultrasound transbronchial needle aspiration (EBUS-TBNA) of hilar and mediastinal lymphadenopathy has been well established. The real-time visualization of targeted and surrounding structures allows the operator to avoid puncturing even small vessels. However, on occasions, the only way to reach the target is by traversing vessels. We report 2 cases of right hilar masses that were successfully diagnosed with EBUS-TBNA performed by traversing the pulmonary artery without any complications. We suggest that transpulmonary artery needle aspiration can be safely conducted but should be performed only by experienced operators and should be reserved as a last resort for making a diagnosis. PMID- 24162121 TI - Pleuroscopic punch biopsy using insulated-tip diathermic knife-2 for the diagnosis of desmoplastic malignant mesothelioma. AB - Desmoplastic malignant mesothelioma (DMM) is a rare subtype of malignant pleural mesothelioma (MPM) and is often difficult to distinguish from pleural fibrosis and reactive mesothelial hyperplasia, especially if the biopsy samples are small. We performed full-thickness pleural biopsy on a lesion suspected to be DMM using an insulated-tip diathermic knife-2 (IT knife-2) during flex-rigid pleuroscopy. IT knife-2 is a novel electrosurgical device for endoscopic submucosal dissection in the early gastrointestinal cancer. It consists of a needle knife with 3 short blades at the distal end attached to an insulated ceramic tip. A 54-year-old man presenting with chest wall mass and thickened pleura, in whom a computed tomography-guided percutaneous needle aspiration had remained negative, underwent flex-rigid pleuroscopy for definitive diagnosis. While applying electric current, we used the IT knife-2 to incise the pleura in a circular shape just above the endothoracic fascia. The incised pleura was removed by forceps and examined pathologically. The microscopic examination was compatible with DMM. We discovered that pleuroscopic punch biopsy using IT knife-2 can diagnose DMM. Use of IT knife-2 during flex-rigid pleuroscopy can obtain sufficient samples from densely thickened pleura, which is difficult to diagnose with small biopsies. PMID- 24162123 TI - Successful removal of a distally located foreign body using a guide sheath. AB - This report presents the case of successful removal of a distally located foreign body using a guide sheath (GS). A 78-year-old man was brought for x-ray examination after a dental treatment at a local clinic. A dental instrument, a diamond bur, was missing after the treatment. The chest x-ray revealed a needle like instrument located in the peripheral right middle lobe. The distally located foreign body was removed with a flexible bronchoscope using a curette and a biopsy forceps placed through a GS. This is the first report of use of a GS to remove a foreign body. PMID- 24162124 TI - Simple and economical management of a prolonged air leak. AB - Prolonged air leak has been described in many pulmonary diseases but remains one of the common complications of pulmonary resections. Although, the management of prolonged air leaks related to broncho-pleural or alveolo-pleural fistulae traditionally requires surgical repair. In recent years, bronchoscopic approaches have drawn attention because of their conservative nature. We report a case of prolonged air leak after a pulmonary wedge resection that was treated with a simple and economical endobronchial method. PMID- 24162125 TI - The latest generation in flexible bronchoscopes: a description and evaluation. AB - BACKGROUND: Since the introduction of the flexible bronchoscope over 50 years ago, bronchoscopists have seen vast improvement in the technology available for diagnostics and therapeutics in the bronchoscopy laboratory. We set forth to evaluate the latest evolution in flexible bronchoscopes with features designed to improve imaging and airway navigation. METHODS: The BF-Q190, BF-H190, and/or BF 1TH190 bronchoscopes were evaluated prospectively in 105 patients undergoing bronchoscopy from November 2010 to August 2011 at 2 tertiary care centers in the United States. Data collected from each procedure included method of insertion, airway images, and therapeutic interventions. At the completion of the study, 10 bronchoscopists were surveyed using a 7-point Likert scale to identify the perceived benefits of the design. RESULTS: Insertion methods included nasal, oral, laryngeal mask airway or endotracheal tube, and tracheostomy. Procedures performed included bronchoalveolar lavage, endobronchial biopsy or brushing, transbronchial biopsy, transbronchial needle aspiration or injection, peripheral navigation, and large airway therapeutic interventions. Survey of bronchoscopists revealed that when compared with current bronchoscopes, the features rated as having the most significant impact on functionality are the 210-degree tip angulation (average 2.4/3) and rotational capability of the insertion tube (average 2.4/3). CONCLUSIONS: The new-generation flexible bronchoscope offers improvement in image quality, magnification options, unique insertion tube rotation, and an increased 210-degree distal tip angulation over currently available flexible bronchoscopes. The bronchoscopes are an overall improvement to the current generation of bronchoscopes. The increased tip angulation and novel rotating insertion tube add the most to improvement in functionality. PMID- 24162127 TI - Cardiac wall mass identified by endobronchial ultrasonography. PMID- 24162126 TI - Removal of an endobronchial foreign body using an ultrathin flexible bronchoscope and a novel suction system. PMID- 24162128 TI - Endobronchial tumor embolism. PMID- 24162129 TI - Is it time for conventional TBNA to die? PMID- 24162131 TI - Anomalous Debye-like dielectric relaxation of water in micro-sized confined polymeric systems. AB - While it is well known that spatial confinement on a nm scale affects the molecular dynamics of water resulting in a hindered dipolar reorientation, question of whether these effects could result at length scales larger than these, i.e., in confined regions of the order of MUm or more, is still under debate. Here we use dielectric relaxation spectroscopy techniques to study the relaxation orientation dynamics of water entrapped in different polymeric matrices with pore sizes of the order of 100 MUm, analyzing the frequency relaxation behaviour of the dielectric response. Our results show that, contrary to what has been generally thought, even in confinements which are not particularly high such as those realized here, regions typically hundred micrometers in size can affect the water structure, inducing a water phase with properties different from those of bulk water. In particular, we observe a dielectric dispersion centered in the range 10(5)-10(7) Hz, in between the one characteristic of ice (8.3 kHz at T = 0 degrees C) and the one of bulk water (19.2 GHz at T = 25 degrees C). The analysis of the dependence on temperature of the relaxation time of this unexpected contribution rules out the possibility that it can be attributed to an interfacial polarization (Maxwell-Wagner effect) and suggests a dipolar Debye-like origin due to a slow-down of the hydrogen bonded network orientational polarization. Also at these scales, the confinement alters the structure of water, leading to a hindered reorientation. These properties imply that water confined within these polymeric porous matrices is more ordered than bulk water. These findings may be important in order to understand biological processes in cells and in different biological compartments, where water is physiologically confined. PMID- 24162130 TI - A mathematical model for carbon dioxide elimination: an insight for tuning mechanical ventilation. AB - PURPOSE: The aim is to provide better understanding of carbon dioxide (CO2) elimination during ventilation for both the healthy and atelectatic condition, derived in a pressure-controlled mode. Therefore, we present a theoretical analysis of CO2 elimination of healthy and diseased lungs. METHODS: Based on a single-compartment model, CO2 elimination is mathematically modeled and its contours were plotted as a function of temporal settings and driving pressure. The model was validated within some level of tolerance on an average of 4.9% using porcine dynamics. RESULTS: CO2 elimination is affected by various factors, including driving pressure, temporal variables from mechanical ventilator settings, lung mechanics and metabolic rate. CONCLUSION: During respiratory care, CO2 elimination is a key parameter for bedside monitoring, especially for patients with pulmonary disease. This parameter provides valuable insight into the status of an atelectatic lung and of cardiopulmonary pathophysiology. Therefore, control of CO2 elimination should be based on the fine tuning of the driving pressure and temporal ventilator settings. However, for critical condition of hypercapnia, airway resistance during inspiration and expiration should be additionally measured to determine the optimal percent inspiratory time (%TI) to maximize CO2 elimination for treating patients with hypercapnia. PMID- 24162132 TI - Re: BMP-2 augmented fusion in the low-risk, healthy subjects: a confirmation of effectiveness and harms highlights the need for study in high risk patients. PMID- 24162133 TI - Detection and characterization of silver nanoparticles and dissolved species of silver in culture medium and cells by AsFlFFF-UV-Vis-ICPMS: application to nanotoxicity tests. AB - A methodology based on Asymmetric Flow Field-Flow Fractionation (AsFlFFF) coupled with UV-Vis absorption spectrometry and ICP mass spectrometry (ICPMS) has been developed and applied to the study of silver nanoparticles (AgNPs) and dissolved species of silver in culture media and cells used in cytotoxicity tests. The effect of a nano-silver based product (protein stabilized silver nanoparticles ca. 15 nm average diameter) on human hepatoma (HepG2) cell viability has been studied. UV-Vis absorption spectrometry provided information about the nature (organic vs. nanoparticle) of the eluted species, whereas the silver was monitored by ICPMS. A shift towards larger hydrodynamic diameters was observed in the AgNPs after a 24 hour incubation period in the culture medium, which suggests a "protein corona" effect. Silver(I) associated with proteins present in the culture medium has also been detected, as a consequence of the oxidation process experimented by the AgNPs. However, the Ag(I) released into the culture medium did not justify the toxicity levels observed. AgNPs associated with the cultured HepG2 cells were also identified by AsFlFFF, after applying a solubilisation process based on the use of tetramethylammonium hydroxide (TMAH) and Triton X 100. These results have been confirmed by transmission electronic microscopy (TEM) analysis of the fractions collected from the AsFlFFF. The effect of AgNPs on HepG2 cells has been compared to that caused by silver(I) as AgNO3 under the same conditions. The determination of the total content of silver in the cells confirms that a much larger mass of silver as AgNPs with respect to AgNO3 (16 to 1) is needed to observe a similar toxicity. PMID- 24162134 TI - Intra-abdominal giant infected seroma following laparoscopic inguinal hernia repair. AB - Seroma formation following open or laparoscopic mesh repair of inguinal hernia is common, albeit with no impact on recovery. One of the possible complication from such a seroma is infection. A patient presented with such an infective complication 6 years following a total extra peritoneal (TEP) repair of bilateral inguinal hernia. This report gives an account of its management. PMID- 24162135 TI - A reevaluation of the anatomy of the jaw-closing system in the extant coelacanth Latimeria chalumnae. AB - The coelacanth Latimeria is the only extant representative of the Actinistia, a group of sarcopterygian fishes that originated in the Devonian. Moreover, it is the only extant vertebrate in which the neurocranium is divided into an anterior and a posterior portion that articulate by means of an intracranial joint. This joint is thought to be highly mobile, allowing an elevation of the anterior portion of the skull during prey capture. Here we provide a new description of the skull and jaw-closing system in Latimeria chalumnae in order to better understand its skull mechanics during prey capture. Based on a dissection and the CT scanning of an adult coelacanth, we provide a detailed description of the musculature and ligaments of the jaw system. We show that the m. adductor mandibulae is more complex than previously reported. We demonstrate that the basicranial muscle inserts more anteriorly than has been described previously, which has implications for its function. Moreover, the anterior insertion of the basicranial muscle does not correspond to the posterior tip of the tooth plate covering the parasphenoid, questioning previous inferences made on fossil coelacanths and other sarcopterygian fishes. Strong ligaments connect the anterior and the posterior portions of the skull at the level of the intracranial joint, as well as the notochord and the catazygals. These observations suggest that the intracranial joint is likely to be less mobile than previously thought and that its role during feeding merits to be reexamined. PMID- 24162136 TI - Overexpression of NgAUREO1, the gene coding for aurechrome 1 from Nannochloropsis gaditana, into Saccharomyces cerevisiae leads to a 1.6-fold increase in lipid accumulation. AB - Aureochrome-1 (AUREO1) is a transcription factor that is induced by blue light and controls branching of Vaucheria frigida. We have cloned the gene, NgAUREO1, coding for AUREO1 from Nannochloropsis gaditana, and report that the lipid content in recombinant Saccharomyces cerevisiae was 1.6-fold more than in wild type S. cerevisiae (6.3 % lipid increased to 10 %). Over-expression of AUREO1 in S. cerevisiae up-regulated the expression of acetyl-CoA carboxylase and acyl CoA:diacylglycerol acyl-transferase but down-regulated the expression of long chain-acyl CoA synthetase. This enhanced the accumulation of lipid. This study highlights a novel function of AUREO1 and allows a better understanding of the regulation mechanism of fatty acid metabolism. PMID- 24162137 TI - Development of motorized plasma lithography for cell patterning. AB - The micropatterning of cells, which restricts the adhesive regions on the substrate and thus controls cell geometry, is used to study mechanobiology related cell functions. Plasma lithography is a means of providing such patterns and uses a spatially-selective plasma treatment. Conventional plasma lithography employs a positionally-fixed mask with which the geometry of the patterns is determined and thus is not suited for producing on-demand geometries of patterns. To overcome this, we have manufactured a new device with a motorized mask mounted in a vacuum chamber of a plasma generator, which we designate motorized plasma lithography. Our pilot tests indicate that various pattern geometries can be obtained with the control of a shielding mask during plasma treatment. Our approach can thus omit the laborious process of preparing photolithographically microfabricated masks required for the conventional plasma lithography. PMID- 24162138 TI - Single-stage laparoscopic common bile duct exploration and cholecystectomy versus two-stage endoscopic stone extraction followed by laparoscopic cholecystectomy for patients with concomitant gallbladder stones and common bile duct stones: a randomized controlled trial. AB - BACKGROUND: The ideal method for managing concomitant gallbladder stones and common bile duct (CBD) stones is debatable. The currently preferred method is two stage endoscopic stone extraction followed by laparoscopic cholecystectomy (LC). This prospective randomized trial compared the success and cost effectiveness of single- and two-stage management of patients with concomitant gallbladder and CBD stones. METHODS: Consecutive patients with concomitant gallbladder and CBD stones were randomized to either single-stage laparoscopic CBD exploration and cholecystectomy (group 1) or endoscopic retrograde cholangiopancreatography (ERCP) for endoscopic extraction of CBD stones followed by LC (group 2). Success was defined as complete clearance of CBD and cholecystectomy by the intended method. Cost effectiveness was measured using the incremental cost-effectiveness ratio. Intention-to-treat analysis was performed to compare outcomes. RESULTS: From February 2009 to October 2012, 168 patients were randomized: 84 to the single-stage procedure (group 1) and 84 to the two-stage procedure (group 2). Both groups were matched with regard to demographic and clinical parameters. The success rates of laparoscopic CBD exploration and ERCP for clearance of CBD were similar (91.7 vs. 88.1 %). The overall success rate also was comparable: 88.1 % in group 1 and 79.8 % in group 2 (p = 0.20). Direct choledochotomy was performed in 83 of the 84 patients. The mean operative time was significantly longer in group 1 (135.7 +/- 36.6 vs. 72.4 +/- 27.6 min; p <= 0.001), but the overall hospital stay was significantly shorter (4.6 +/- 2.4 vs. 5.3 +/- 6.2 days; p = 0.03). Group 2 had a significantly greater number of procedures per patient (p < 0.001) and a higher cost (p = 0.002). The two groups did not differ significantly in terms of postoperative wound infection rates or major complications. CONCLUSIONS: Single- and two-stage management for uncomplicated concomitant gallbladder and CBD stones had similar success and complication rates, but the single-stage strategy was better in terms of shorter hospital stay, need for fewer procedures, and cost effectiveness. PMID- 24162139 TI - Laparoscopic versus open elective repair of primary umbilical hernias: short-term outcomes from the American College of Surgeons National Surgery Quality Improvement Program. AB - BACKGROUND: Approximately 175,000 umbilical hernia repairs are performed annually in the US. Controversy exists regarding the optimal approach for the elective repair of primary umbilical hernias. OBJECTIVE: The objective of this study was to compare 30-day outcomes of elective primary open (OHR) and laparoscopic (LHR) umbilical hernia repairs, using a prospectively collected dataset. METHODS: We performed a retrospective cohort study using the American College of Surgeons National Surgery Quality Improvement Program Participant Use Files during 2009 and 2010. Current Procedural Terminology and post-operative International Classification of Diseases, Ninth Revision diagnostic codes were used to identify primary umbilical hernia repairs. Primary outcomes included composite endpoints of 30-day mortality, and major and overall complications. Univariate analyses and multivariate logistic regression were performed controlling for relevant patient characteristics. Secondary outcomes included operative time and hospital length of stay (LOS). RESULTS: Overall, 14,652 patients were identified-13,109 (89.5 %) OHR and 1543 (10.5 %) LHR. Univariate analyses of primary outcomes demonstrated similar 30-day morbidity and mortality between groups. In our multivariate model, however, after controlling for body mass index, gender, American Society of Anesthesiologists class, and chronic obstructive pulmonary disease, the odds ratio (OR) for overall complications favored LHR (OR 0.60; p = 0.01). This difference was driven primarily by the reduced wound complication rate in the LHR group [OR 0.41 (0.20, 0.78); p = 0.005]. LHR was associated with significantly longer operative time [57.7 min (SD 32.6) vs. 38.3 min (SD 22.9); p < 0.001], longer LOS [0.29 days (SD 0.68) vs. 0.17 days (SD 1.47); p = 0.001], and an increased rate of respiratory (0.52 vs. 0.10 %; p < 0.001) and cardiac (0.26 vs. 0.05 %; p = 0.005) complications. CONCLUSIONS: This study identified potential decreased total and wound morbidity associated with LHR for elective primary umbilical hernia repairs at the expense of increased operative time, LOS, and respiratory and cardiac complications. These results should be considered within the context of a retrospective study with its inherent risks of bias and limitations. PMID- 24162142 TI - Facile hydrothermal synthesis of TiO2-Bi2WO6 hollow superstructures with excellent photocatalysis and recycle properties. AB - One-dimensional mesoporous TiO2-Bi2WO6 hollow superstructures are prepared using a hydrothermal method and their photocatalysis and recycle properties are investigated. Experimental results indicate that anatase TiO2 nanoparticles are coupled with hierarchical Bi2WO6 hollow tubes on their surfaces. The TiO2-Bi2WO6 structure has a mesoporous wall and the pores in the wall are on average 21 nm. The hierarchical TiO2-Bi2WO6 heterostructures exhibit the highest photocatalytic activity in comparison with P25, pure Bi2WO6 hollow tube and mechanical mixture of Bi2WO6 tube and TiO2 nanoparticle in the degradation of rhodamine B (RhB) under simulated sunlight irradiation. The as-prepared TiO2-Bi2WO6 heterostructures can be easily recycled through sedimentation and they retains their high photocatalytic activity during the cycling use in the simulated sunlight-driving photodegradation process of RhB. The prepared mesoporous TiO2 Bi2WO6 with hollow superstructure is therefore a promising candidate material for water decontamination use. PMID- 24162141 TI - Not all anti-reflux treatment failures are due to persistence of abnormal esophageal acid exposure. PMID- 24162140 TI - A material cost-minimization analysis for hernia repairs and minor procedures during a surgical mission in the Dominican Republic. AB - INTRODUCTION: Expenditures on material supplies and medications constitute the greatest per capita costs for surgical missions. We hypothesized that supply acquisition at non-profit organization (NPO) costs would lead to significant cost savings compared with supply acquisition at US academic institution costs from the provider perspective for hernia repairs and minor procedures during a surgical mission in the Dominican Republic. METHODS: Items acquired for a surgical mission were uniquely QR-coded for accurate consumption accounting. Both NPO and US academic institution unit costs were associated with each item in an electronic inventory system. Medication doses were recorded and QR codes for consumed items were scanned into a record for each sampled procedure. Mean material costs and cost-savings +/- SDs were calculated in US dollars for each procedure type. Cost-minimization analyses between the NPO and the US academic institution platforms for each procedure type ensued using a two-tailed Wilcoxon matched-pairs test with alpha = 0.05. Item utilization analyses generated lists of most frequently used materials by procedure type. RESULTS: The mean cost savings of supply acquisition at NPO costs for each procedure type were as follows: $482.86 +/- $683.79 for unilateral inguinal hernia repair (n = 13); $332.46 +/- $184.09 for bilateral inguinal hernia repair (n = 3); $127.26 +/- $13.18 for hydrocelectomy (n = 9); $232.92 +/- $56.49 for femoral hernia repair (n = 3); $120.90 +/- $30.51 for umbilical hernia repair (n = 8); $36.59 +/- $17.76 for minor procedures (n = 26); and $120.66 +/- $14.61 for pediatric inguinal hernia repair (n = 7). CONCLUSION: Supply acquisition at NPO costs leads to significant cost-savings compared with supply acquisition at US academic institution costs from the provider perspective for inguinal hernia repair, hydrocelectomy, umbilical hernia repair, minor procedures, and pediatric inguinal hernia repair during a surgical mission in the Dominican Republic. Item utilization analysis can generate minimum-necessary material lists for each procedure type to reproduce cost-savings for subsequent missions. PMID- 24162143 TI - Synthesis and structure of large difluoromethylene containing alicycles by ring closing metathesis (RCM). AB - Cyclotetra- and cyclohexa-decane ring systems were prepared with CF2 groups spaced 1,4- and 1,6- for tetradecanes together with 1,5- and 1,6- for hexadecanes. These alicyclic systems were assembled by ring closing metathesis reactions of long terminal diolefins. Ring cyclisation by RCM was promoted by the introduction of the dithiane motif, using a sulfur compatible metathesis catalyst. This gave rise to macrocyclic E-cycloalkanes, which were hydrogenated also using a sulfur compatible catalyst. Finally the dithianes emerged as appropriate precursor motifs for the introduction of difluoromethylene groups. X Ray structures revealed that the resultant rings have the CF2 groups located only at corner positions and that these groups dictated the overall macrocyclic ring conformations. PMID- 24162145 TI - Occupational burnout and severe injuries: an eight-year prospective cohort study among Finnish forest industry workers. AB - OBJECTIVES: Burnout is a psychological consequence of prolonged work stress. Studies have shown that it is related to physical and mental disorders. The safety outcomes of burnout have been studied to a lesser extent and only in the work context. This study explored the effect of burnout on future severe injuries regardless of their context. METHODS: A total of 10,062 forest industry employees (77% men, 63% manual workers) without previous injuries participated in 1996 or 2000 in the "Still Working" study examining the work-related antecedents of health and mortality. Burnout was assessed using the Maslach Burnout Inventory General Survey. Injuries leading to death or hospitalization were regarded as severe. We extracted such injuries from independent national registers. The relationship between burnout and new injuries was analyzed using Cox proportional regression. The analyses were adjusted for age, sex, marital status, and occupational status. RESULTS: There were 788 new injuries over eight years. Injuries were more common among male and manual workers. After adjustments, each one-unit increase in the burnout score was related to a 9% increase in the risk of injury (95% confidence interval: 1.2-1.17). Experiencing symptoms at least monthly was related to a 1.18-fold adjusted injury risk (95% CI: 1.2-1.36). Of the subscales of burnout, exhaustion and cynicism but not lack of professional efficacy predicted injuries after adjustments. CONCLUSIONS: In addition to mental and physical disorders, burnout predicts severe injuries. Developing work conditions and optimizing workload may enhance safety and decrease health expenses related to all injuries. PMID- 24162144 TI - Attomolar DNA detection with chiral nanorod assemblies. AB - Nanoscale plasmonic assemblies display exceptionally strong chiral optical activity. So far, their structural design was primarily driven by challenges related to metamaterials whose practical applications are remote. Here we demonstrate that gold nanorods assembled by the polymerase chain reaction into DNA-bridged chiral systems have promising analytical applications. The chiroplasmonic activity of side-by-side assembled patterns is attributed to a 7-9 degree twist between the nanorod axes. This results in a strong polarization rotation that matches theoretical expectations. The amplitude of the bisignate 'wave' in the circular dichroism spectra of side-by-side assemblies demonstrates excellent linearity with the amount of target DNA. The limit of detection for DNA using side-by-side assemblies is as low as 3.7 aM. This chiroplasmonic method may be particularly useful for biological analytes larger than 2-5 nm which are difficult to detect by methods based on plasmon coupling and 'hot spots'. Circular polarization increases for inter-nanorod gaps between 2 and 20 nm when plasmonic coupling rapidly decreases. Reaching the attomolar limit of detection for simple and reliable bioanalysis of oligonucleotides may have a crucial role in DNA biomarker detection for early diagnostics of different diseases, forensics and environmental monitoring. PMID- 24162146 TI - A prospective study of factors associated with risk of turnover among care workers in group homes for elderly individuals with dementia. AB - OBJECTIVES: A prospective study was conducted to assess factors associated with risk of turnover among care workers in group homes (GHs) for elderly individuals with dementia. METHODS: In January, 2010, 51 out of 238 GHs in Sapporo City responded to our request for participation in a survey. During February and March of 2010, 438 out of 700 care workers (62.6%) in the GHs returned a completed questionnaire to us. They were followed up with until March of 2012, and 395 subjects (90.1%) responded to our survey, which was conducted twice. Over the course of 2 years, 91 subjects left their jobs. Cox's proportional hazards model was used for analysis, adjusting for gender and age. RESULTS: Less provision of social support by supervisors, colleagues, family or friends was significantly associated with increased risk of turnover. Financial aids for off-the-job training was marginally significantly associated with reduced risk of turnover. Longer duration of working for frail elderly care was significantly associated with decreased risk of turnover. Habitual smoking was significantly associated with increased risk of turnover. CONCLUSIONS: Social support in the workplace may be important to reduce the risk of turnover in care workers at GHs. Further prospective studies are required in other areas in Japan. PMID- 24162147 TI - A comparison of hand-arm vibration syndrome between Malaysian and Japanese workers. AB - OBJECTIVES: The aim of this study was to investigate the clinical characteristics of HAVS in a tropical environment in comparison with a temperate environment. METHODS: We conducted a series medical examinations among the forestry, construction and automobile industry workers in Malaysia adopting the compulsory medical examination procedure used by Wakayama Medical University for Japanese vibratory tools workers. We matched the duration of vibration exposure and compared our results against the Japanese workers. We also compared the results of the Malaysian tree fellers against a group of symptomatic Japanese tree fellers diagnosed with HAVS. RESULTS: Malaysian subjects reported a similar prevalence of finger tingling, numbness and dullness (Malaysian=25.0%, Japanese=21.5%, p=0.444) but had a lower finger skin temperature (FST) and higher vibrotactile perception threshold (VPT) values as compared with the Japanese workers. No white finger was reported in Malaysian subjects. The FST and VPT of the Malaysian tree fellers were at least as bad as the Japanese tree fellers despite a shorter duration (mean difference=20.12 years, 95%CI=14.50, 25.40) of vibration exposure. CONCLUSIONS: Although the vascular disorder does not manifest clinically in the tropical environment, the severity of HAVS can be as bad as in the temperate environment with predominantly neurological disorder. Hence, it is essential to formulate national legislation for the control of the occupational vibration exposure. PMID- 24162148 TI - Bedtime and sleep duration in relation to depressive symptoms among Japanese workers. AB - OBJECTIVES: While bedtime may influence circadian rhythms, potentially leading to depression, epidemiological data on this issue are limited. We cross-section-ally investigated the association between bedtime and depressive symptoms in Japanese workers, taking sleep duration into consideration. METHODS: The participants were 1,197 workers who participated in a health survey during a periodic checkup and had no history of psychiatric disease. Depressive symptoms were assessed using the Center for Epidemiologic Studies Depression (CES-D) scale. Usual bedtime and wake time were inquired about using a self-administered questionnaire, and sleep duration was calculated based on the difference between these two values. Multiple logistic regression was used to estimate the odds ratio of depressive symptoms for bedtime or sleep duration categories. RESULTS: Short sleep duration (<6 hours) was significantly associated with an increased prevalence of depressive symptoms. Late bedtime was also significantly associated with an increased prevalence of depressive symptoms (CES-D score of L19); the multi variable-adjusted odds ratio of depressive symptoms for a bedtime of 1:00 or later versus 23:00 to 23:59 was 1.90 (95% confidence interval, 1.16-3.12). After additional adjustment for sleep duration, however, the association was largely attenuated (odds ratio, 1.17; 95% confidence interval, 0.66-2.06). CONCLUSIONS: Late bedtime was associated with increased prevalence of depressive symptoms, but this association could be largely accounted for by short sleep duration. Avoiding a late bedtime and obtaining a sufficient sleep duration may prevent depressive mood among workers. PMID- 24162149 TI - Characteristics of particulate matter generated while handling municipal household waste. AB - OBJECTIVES: This study was conducted to assess the size characteristics of particulate matter (PM) generated during waste collection and sorting, and to assess the effect of the type of waste-handling activity on levels of coarse and fine PM. METHODS: A portable aerosol spectrometer calibrated to 1.2 //min was used to monitor PM generated during four types of waste-handling activities. The types of PM measured included inhalable particulate matter (IPM), PM10, respirable particulate matter (RPM), PM2.5 and PM1. Twenty-eight data sets with 3,071 subsets recorded every 6 sec were categorized according to occupational and environmen!tal classifications, including type of waste-handling activity. An ANOVA was used to compare PM levels characterized by size. Significant variables with p-values <0.25 were included in a multiple regression model for predicting levels of each PM. RESULTS: The average levels of PM10 and PM2.5 greatly exceeded the air-quality levels enforced by the Korean Ministry of the Environment. The highest PM2.5 fine-particle levels monitored were during waste-transfer work, while the highest IPM and PM10 coarse-particle levels monitored were during waste sorting work. The type of waste-collection activity was the only factor that significantly affected both PM25 and IPM, accounting for 36% (p=0.0034) and 40% (p=0.0049), respectively, of the observed variations. None of the factors affected PM10 or RPM levels. CONCLUSIONS: Waste-collection and Waste-transfer work may be associated with the generation of high levels of fine PM, which can be influenced by environ Workmental conditions such as traffic levels and the type of waste transport vehicle. PMID- 24162150 TI - Patient-level improvements in pain and activities of daily living after total knee arthroplasty. AB - OBJECTIVE: To study patient-level improvements in pain and limitations of key activities of daily living (ADLs) after primary or revision total knee arthroplasty (TKA). METHODS: We analysed prospectively collected data from the Mayo Clinic Total Joint Registry for improvements in index knee pain severity and limitations in three key ADLs (walking, climbing stairs and rising from a chair) from pre-operative to 2 and 5 years post-TKA. RESULTS: The primary TKA cohort consisted of 7229 responders pre-operatively, 7139 at 2 years and 4234 at 5 years post-operatively. The revision TKA cohort consisted of 1206 responders pre operatively, 1533 at 2 years and 881 at 5 years post-operatively. In the primary TKA cohort, important pain reduction to mild or no knee pain at 2 years was reported by 92% with moderate pre-operative pain and 93% with severe pre operative pain; respective proportions were 91% and 91% at 5 years follow-up. For revision TKA, respective proportions were 71% and 66% at 2 years and 68% and 74% at 5 years. Three per cent with no/mild pre-operative overall limitation and 19% with moderate/severe pre-operative overall limitation had moderate/severe overall activity limitation 2 years post-operatively; at 5 years the respective proportions were 4% and 22%. Respective proportions for revision TKA were up to 3% and 32% at 2 years and 4% and 34% at 5 years. CONCLUSION: Our study provides comprehensive data for patient-level improvements in pain and key ADLs. These data can be used to inform patients pre-operatively of expected outcomes, based on pre-operative status, which may further help patients set realistic goals for improvements after TKA. PMID- 24162151 TI - Systemic involvement in primary Sjogren's syndrome evaluated by the EULAR-SS disease activity index: analysis of 921 Spanish patients (GEAS-SS Registry). AB - OBJECTIVE: To evaluate systemic involvement in primary SS in a large cohort of Spanish patients using the EULAR-SS disease activity index (ESSDAI) definitions. METHODS: Systemic involvement was characterized using ESSDAI definitions for the 10 clinical domains (constitutional, lymphadenopathy, glandular, articular, cutaneous, pulmonary, renal, peripheral nervous system, central nervous system and muscular). ESSDAI scores at diagnosis, during follow-up and cumulated at the last visit were calculated. RESULTS: The cohort consisted of 921 patients. After a mean follow-up of 75 months, 77 (8%) patients still had an ESSDAI score of zero at the last visit. Organ by organ, the percentage of patients who developed activity during the follow-up (ESSDAI score >= 1 at any time) ranged between 1.4% and 56%, with articular, pulmonary and peripheral neurological involvement being the most common. Logistic multivariate regression analysis showed the following features at diagnosis and had the closest association with systemic activity (statistically significant independent variables in at least two domains): cryoglobulinaemia in five domains; anaemia, lymphopenia and low C3 levels in three domains each and age <35 years in two domains. Sicca features, ANA and RF at diagnosis were not associated with a higher cumulated activity score in any clinical domain. CONCLUSION: Primary SS is undeniably a systemic disease, with the joints, lungs, skin and peripheral nerves being the most frequently involved organs. Cytopenias, hypocomplementaemia and cryoglobulinaemia at diagnosis strongly correlated with higher cumulated ESSDAI scores in the clinical domains. Clinically the ESSDAI provides a reliable picture of systemic involvement in primary SS. PMID- 24162152 TI - Therapeutic strategy using extracorporeal life support, including appropriate indication, management, limitation and timing of switch to ventricular assist device in patients with acute myocardial infarction. AB - The appropriate indication for, management of and limitations to extracorporeal life support (ECLS) and the timing of a switch to a ventricular assist device (VAD) remain controversial issues in patients with acute myocardial infarction (AMI) complicated with cardiogenic shock or cardiopulmonary arrest. To evaluate and discuss these issues, we studied patients with AMI treated with ECLS and compared deceased and discharged patients. Thirty-eight patients with AMI who needed ECLS [35 men (92.1 %), aged 59.9 +/- 13.5 years] were enrolled in this study. Of these 38 patients, 34 subsequently underwent percutaneous coronary intervention (PCI), and four subsequently received coronary artery bypass grafting (CABG). Fourteen patients (36.8 %) were discharged from the hospital. The outcome was not favorable for those patients with deteriorating low output syndrome (LOS) and the development of leg ischemia, hemolysis and multiple organ failure during ECLS. Levels of creatine kinase, creatine kinase-MB (CK-MB), lactate dehydrogenase, serum creatinine (Cr) and amylase after the patient had been put on ECLS and fluctuation of the cardiac index, blood pressure, arterial blood gas analysis and CK-MB and Cr levels during ECLS were indicators to switch from the ECLS to VAD. In the case of patients with no complication associated with ECLS, 4.6-5.6 days after initiation of ECLS was assumed to be the threshold to decide whether to switch from ECLS to VAD. Patients with AMI who suddenly developed refractory pulseless ventricular tachycardia or ventricular fibrillation without deteriorating LOS and who underwent successful PCI or CABG, and who prevented the complications associated with ECLS, showed a high probability of recovering with ECLS. PMID- 24162153 TI - Major QTLs reduce the deleterious effects of high temperature on rice amylose content by increasing splicing efficiency of Wx pre-mRNA. AB - KEY MESSAGE: We discovered four QTLs that maintain proper rice amylose content at high temperature by increasing the splicing efficiency of Wx gene. Amylose content mainly controlled by Wx gene is a key physicochemical property for eating and cooking quality in rice. During the grain filling stage, high temperature can harm rice grain quality by significantly reducing the amylose content in many rice varieties. Here, we provide genetic evidences between Wx gene expression and rice amylose content at high temperature, and identified several quantitative trait loci (QTLs) in this pathway. We performed a genome-wide survey on a set of chromosome segment substitution lines (CSSLs) which carried chromosomal segments from the heat resistant indica 9311 in the heat-sensitive japonica Nipponbare background. Four QTLs, qHAC4, qHAC8a, qHAC8b and qHAC10, which can reduce the deleterious effects of amylose content at high temperature, were identified and mapped to chromosome 4, 8, 8 and 10, respectively. The major QTL qHAC8a, with the highest LOD score of 6.196, was physically mapped to a small chromosome segment (~300 kb). The CSSLs carrying the qHAC8a, qHAC8b and/or qHAC4 from 9311 have the high pre-mRNA splicing efficiency of Wx gene and likely lead to stable amylose content at high temperature. Thus, increasing pre-mRNA processing efficiency of Wx gene could be an important regulation mechanism for maintaining stable amylose content in rice seeds at high temperature. In addition, our results provide a theoretical basis for breeding heat-stable grain in rice. PMID- 24162154 TI - Yield stability of hybrids versus lines in wheat, barley, and triticale. AB - KEY MESSAGE: We present experimental data for wheat, barley, and triticale suggesting that hybrids manifest on average higher yield stability than inbred lines. Yield stability is assumed to be higher for hybrids than for inbred lines, but experimental data proving this hypothesis is scarce for autogamous cereals. We used multi-location grain yield trials and compared the yield stability of hybrids versus lines for wheat (Triticum aestivum L.), barley (Hordeum vulgare L.), and triticale (*Triticosecale Wittmack). Our study comprised three phenotypic data sets of 1,749 wheat, 96 barley, and 130 triticale genotypes, which were evaluated for grain yield in up to five contrasting locations. Yield stability of the group of hybrids was compared with that of the group of inbred lines estimating the stability variance. For all three crops we observed a significantly (P < 0.05) higher yield stability of hybrids compared to lines. The enhanced yield stability of hybrids as compared to lines represents a major step forward, facilitating coping with the increasing abiotic stress expected from the predicted climate change. PMID- 24162155 TI - Digital templating in total knee and hip replacement: an analysis of planning accuracy. AB - PURPOSE: The aim of this study was to determine how well pre-operative size selection for total knee and hip arthroplasties based on the digital imaging with and without additional referencing correlated with the size actually implanted. METHODS: Size selection planning of total knee arthroplasty by digital templating was documented in 46 cases with reference ball (group A) and in 48 cases without ball (group B). In addition, prospective analysis of pre-operative planning was conducted for 52 acetabular components with reference ball (group C) and 69 without ball (group D) as well as stem planning in 38 cases with ball (group E) and 54 cases without ball (group F). The data were analysed and compared with the size of the final component selected during surgery. RESULTS: The correlation between planned and implanted size for total knee arthroplasty in group A resulted in femoral anteroposterior (AP) r = 0.8622 and lateral r = 0.8333 and in group B AP r = 0.4552 and lateral r = 0.6950. Tibial in group A was AP r = 0.9030 and lateral r = 0.9074 and in group B AP r = 0.7000 and lateral r = 0.6376. For the acetabular components, the results in group C were r = 0.5998 and group D r = 0.6923. For stems, group E was r = 0.5306 and group F r = 0.5786. No correlation between BMI and the difference between planned and implanted size was found in any of the groups. CONCLUSION: In the case of total hip arthroplasty there was a relatively low correlation between planned and implanted sizes with or without reference ball. For total knee arthroplasties the already high precision of size planning was further improved by the additional referencing with a reference ball. PMID- 24162156 TI - Are the claims made in orthopaedic print advertisements valid? AB - PURPOSE: Advertisements are commonplace in orthopaedic journals and may influence the readership with claims of clinical and scientific fact. Since the last assessment of the claims made in orthopaedic print advertisements ten years ago, there have been legislative changes and media scrutiny which have shaped this practice. The purpose of this study is to re-evaluate these claims. METHODS: Fifty claims from 50 advertisements were chosen randomly from six highly respected peer-reviewed orthopaedic journals (published July-December 2011). The evidence supporting each claim was assessed and validated by three orthopaedic surgeons. The assessors, blinded to product and company, rated the evidence and answered the following questions: Does the evidence as presented support the claim made in the advertisement and what is the quality of that evidence? Is the claim supported by enough evidence to influence your own clinical practice? RESULTS: Twenty-eight claims cited evidence from published literature, four from public presentations, 11 from manufacturer "data held on file" and seven had no supporting evidence. Only 12 claims were considered to have high-quality evidence and only 11 were considered well supported. A strong correlation was seen between the quality of evidence and strength of support (Spearman r = 0.945, p < 0.0001). The average ICC between the assessors' ratings was strong (r = 0.85) giving validity to the results. CONCLUSION: Orthopaedic surgeons must remain sceptical about the claims made in print advertisements. High-quality evidence is required by orthopaedic surgeons to influence clinical practice and this evidence should be sought by manufacturers wishing to market a successful product. PMID- 24162157 TI - Genomic profiling of histological special types of breast cancer. AB - Histological special types of breast cancer have distinctive morphological features and account for up to 25 % of all invasive breast cancers. We sought to determine whether at the genomic level, histological special types of breast cancer are distinct from grade- and estrogen receptor (ER)-matched invasive carcinomas of no special type (IC-NSTs), and to define genes whose expression correlates with gene copy number in histological special types of breast cancer. We characterized 59 breast cancers of ten histological special types using array based comparative genomic hybridization (aCGH). Hierarchical clustering revealed that the patterns of gene copy number aberrations segregated with ER-status and histological grade, and that samples from each of the breast cancer histological special types preferentially clustered together. We confirmed the patterns of gene copy number aberrations previously reported for lobular, micropapillary, metaplastic, and mucinous carcinomas. On the other hand, metaplastic and medullary carcinomas were found to have genomic profiles similar to those of grade- and ER-matched IC-NSTs. The genomic aberrations observed in invasive carcinomas with osteoclast-like stromal giant cells support its classification as IC-NST variant. Integrative aCGH and gene expression analysis led to the identification of 145 transcripts that were significantly overexpressed when amplified in histological special types of breast cancer. Our results illustrate that together with histological grade and ER-status, histological type is also associated with the patterns and complexity of gene copy number aberrations in breast cancer, with adenoid cystic and mucinous carcinomas being examples of ER negative and ER-positive breast cancers with distinctive repertoires of gene copy number aberrations. PMID- 24162159 TI - A low-cost multichannel wireless neural stimulation system for freely roaming animals. AB - OBJECTIVES: Electrical stimulation of nerve tissue and recording of neural activity are the basis of many therapies and neural prostheses. Conventional stimulation systems have a number of practical limitations, especially in experiments involving freely roaming subjects. Our main objective was to develop a modular, versatile and inexpensive multichannel wireless system able to overcome some of these constraints. APPROACH: We have designed and implemented a new multichannel wireless neural stimulator based on commercial components. The system is small (2 cm * 4 cm * 0.5 cm) and light in weight (9 g) which allows it to be easily carried in a small backpack. To test and validate the performance and reliability of the whole system we conducted several bench tests and in vivo experiments. MAIN RESULTS: The performance and accuracy of the stimulator were comparable to commercial threaded systems. Stimulation sequences can be constructed on-the-fly with 251 selectable current levels (from 0 to 250 uA) with 1 uA step resolution. The pulse widths and intervals can be as long as 65 ms in 2 us time resolution. The system covers approximately 10 m of transmission range in a regular laboratory environment and 100 m in free space (line of sight). Furthermore it provides great flexibility for experiments since it allows full control of the stimulator and the stimulation parameters in real time. When there is no stimulation, the device automatically goes into low-power sleep mode to preserve battery power. SIGNIFICANCE: We introduce the design of a powerful multichannel wireless stimulator assembled from commercial components. Key features of the system are their reliability, robustness and small size. The system has a flexible design that can be modified straightforwardly to tailor it to any specific experimental need. Furthermore it can be effortlessly adapted for use with any kind of multielectrode arrays. PMID- 24162158 TI - Characterization of cell lines derived from breast cancers and normal mammary tissues for the study of the intrinsic molecular subtypes. AB - Five molecular subtypes (luminal A, luminal B, HER2-enriched, basal-like, and claudin-low) with clinical implications exist in breast cancer. Here, we evaluated the molecular and phenotypic relationships of (1) a large in vitro panel of human breast cancer cell lines (BCCLs), human mammary fibroblasts (HMFs), and human mammary epithelial cells (HMECs); (2) in vivo breast tumors; (3) normal breast cell subpopulations; (4) human embryonic stem cells (hESCs); and (5) bone marrow-derived mesenchymal stem cells (hMSC). First, by integrating genomic data of 337 breast tumor samples with 93 cell lines we were able to identify all the intrinsic tumor subtypes in the cell lines, except for luminal A. Secondly, we observed that the cell lines recapitulate the differentiation hierarchy detected in the normal mammary gland, with claudin-low BCCLs and HMFs cells showing a stromal phenotype, HMECs showing a mammary stem cell/bipotent progenitor phenotype, basal-like cells showing a luminal progenitor phenotype, and luminal B cell lines showing a mature luminal phenotype. Thirdly, we identified basal-like and highly migratory claudin-low subpopulations of cells within a subset of triple-negative BCCLs (SUM149PT, HCC1143, and HCC38). Interestingly, both subpopulations within SUM149PT were enriched for tumor initiating cells, but the basal-like subpopulation grew tumors faster than the claudin-low subpopulation. Finally, claudin-low BCCLs resembled the phenotype of hMSCs, whereas hESCs cells showed an epithelial phenotype without basal or luminal differentiation. The results presented here help to improve our understanding of the wide range of breast cancer cell line models through the appropriate pairing of cell lines with relevant in vivo tumor and normal cell counterparts. PMID- 24162161 TI - Trust-based prayer expectancies and health among older Mexican Americans. AB - This study assesses the health-related effects of trust-based prayer expectancies, which reflect the belief that God answers prayers at the right time and in the best way. The following relationships are evaluated in our conceptual model: (1) older Mexican Americans who attend worship services more often tend to develop a closer relationship with God; (2) people who feel close to God will be more likely to develop trust-based prayer expectancies; (3) people who endorse trust-based prayer expectancies will have greater feelings of self-esteem; and (4) higher self-esteem is associated with better self-rated health. The data support each of these relationships. PMID- 24162160 TI - SERPINB3 is associated with longer survival in transgenic mice. AB - The physiological roles of the protease inhibitor SERPINB3 (SB3) are still largely unknown. The study was addressed to assess the biological effects of this serpin in vivo using a SB3 transgenic mouse model. Two colonies of mice (123 transgenic for SB3 and 148 C57BL/6J controls) have been studied. Transgenic (TG) mice showed longer survival than controls and the difference was more remarkable in males than in females (18.5% vs 12.7% life span increase). In TG mice decreased IL-6 in serum and lower p66shc in the liver were observed. In addition, TG males showed higher expression of mTOR in the liver. Liver histology showed age-dependent increase of steatosis and decrease of glycogen storage in both groups and none of the animals developed neoplastic lesions. In conclusion, the gain in life span observed in SB3-transgenic mice could be determined by multiple mechanisms, including the decrease of circulating IL-6 and the modulation of ageing genes in the liver. PMID- 24162163 TI - Single-channel electrophysiology of cell-free expressed ion channels by direct incorporation in lipid bilayers. AB - Single-channel electrophysiology with lipid bilayer systems requires ion channel expression, purification from cell culture, and reconstitution in proteoliposomes for delivery to a planar bilayer. Here we demonstrate that single-channel current measurements of the potassium channels KcsA and hERGS5-S6 can be obtained by direct insertion in interdroplet lipid bilayers from microliters of a cell-free expression medium. PMID- 24162162 TI - Cost-effective PKHD1 genetic testing for autosomal recessive polycystic kidney disease. AB - BACKGROUND: Genetic diagnosis of autosomal recessive polycystic kidney disease (ARPKD) is challenging due to the length and allelic heterogeneity of the PKHD1 gene. Mutations appear to be clustered at specific exons, depending on the geographic origin of the patient. We aimed to identify the PKHD1 exons most likely mutated in Spanish ARPKD patients. METHODS: Mutation analysis was performed in 50 ARPKD probands and nine ARPKD-suspicious patients by sequencing PKHD1 exons arranged by their reported mutation frequency. Haplotypes containing the most frequent mutations were analyzed. Other PKD genes (HNF1B, PKD1, PKD2) were sequenced in PKHD1-negative cases. RESULTS: Thirty-six different mutations (concentrated in 24 PKHD1 exons) were detected, giving a mutation detection rate of 86%. The screening of five exons (58, 32, 34, 36, 37) yielded a 54% chance of detecting one mutation; the screening of nine additional exons (3, 9, 39, 61, 5, 22, 26, 41, 57) increased the chance to 76%. The c.9689delA mutation was present in 17 (34%) patients, all of whom shared the same haplotype. Two HNF1B mutations and one PKD1 variant were detected in negative cases. CONCLUSIONS: Establishing a PKHD1 exon mutation profile in a specific population and starting the analysis with the most likely mutated exons might significantly enhance the efficacy of genetic testing in ARPKD. Analysis of other PKD genes might be considered, especially in suspicious cases. PMID- 24162164 TI - Population splitting, trapping, and non-ergodicity in heterogeneous diffusion processes. AB - We consider diffusion processes with a spatially varying diffusivity giving rise to anomalous diffusion. Such heterogeneous diffusion processes are analysed for the cases of exponential, power-law, and logarithmic dependencies of the diffusion coefficient on the particle position. Combining analytical approaches with stochastic simulations, we show that the functional form of the space dependent diffusion coefficient and the initial conditions of the diffusing particles are vital for their statistical and ergodic properties. In all three cases a weak ergodicity breaking between the time and ensemble averaged mean squared displacements is observed. We also demonstrate a population splitting of the time averaged traces into fast and slow diffusers for the case of exponential variation of the diffusivity as well as a particle trapping in the case of the logarithmic diffusivity. Our analysis is complemented by the quantitative study of the space coverage, the diffusive spreading of the probability density, as well as the survival probability. PMID- 24162165 TI - PI3K-GSK3 signalling regulates mammalian axon regeneration by inducing the expression of Smad1. AB - In contrast to neurons in the central nervous system, mature neurons in the mammalian peripheral nervous system (PNS) can regenerate axons after injury, in part, by enhancing intrinsic growth competence. However, the signalling pathways that enhance the growth potential and induce spontaneous axon regeneration remain poorly understood. Here we reveal that phosphatidylinositol 3-kinase (PI3K) signalling is activated in response to peripheral axotomy and that PI3K pathway is required for sensory axon regeneration. Moreover, we show that glycogen synthase kinase 3 (GSK3), rather than mammalian target of rapamycin, mediates PI3K-dependent augmentation of the growth potential in the PNS. Furthermore, we show that PI3K-GSK3 signal is conveyed by the induction of a transcription factor Smad1 and that acute depletion of Smad1 in adult mice prevents axon regeneration in vivo. Together, these results suggest PI3K-GSK3-Smad1 signalling as a central module for promoting sensory axon regeneration in the mammalian nervous system. PMID- 24162166 TI - Systematic review with meta-analysis of prospective randomized trials comparing minimally invasive video-assisted thyroidectomy (MIVAT) and conventional thyroidectomy (CT). AB - BACKGROUND: Minimally invasive video-assisted thyroidectomy (MIVAT) has gained acceptance among surgeons as its feasibility has been well documented. The aim of this systematic review with meta-analysis has been to assess and validate the safety and feasibility of MIVAT when compared to conventional thyroidectomy (CT) and to verify other potential benefits and drawbacks. METHODS: A literature search for prospective randomized trials comparing MIVAT and CT was performed. Trials were reviewed for the primary outcome measures: overall morbidity, recurrent laryngeal nerve palsy, postoperative hypocalcemia, and postoperative hematoma; and for the secondary outcome measures: operative time, conversion to standard procedure, intraoperative blood loss, intraoperative drain insertion, nodule size and thyroid weight, postoperative pain evaluation, length of hospital stay, patient satisfactory score, and cosmetics results. Standardized mean difference (SMD) was calculated for continuous variables and odds ratio for qualitative variables. RESULTS: Nine prospective randomized studies comparing MIVAT and CT were analyzed. Overall, 581 patients were randomized to either MIVAT (289, 49.7 %) or CT (292, 50.3 %). The primary outcome measures of MIVAT were comparable with those of CT without statistically significant difference. Patients who underwent MIVAT experienced significantly less pain than those operated on conventionally during the whole postoperative period. Patient satisfactory score significantly favored MIVAT (9.0 vs. 6.8, SMD = -3.388, 95 % CI = -5.720 to -1.057). Operative time was significantly longer in MIVAT (75.2 vs. 59.2 min, SMD = 1.246, 95 % CI = 0.227-2.266). CONCLUSIONS: MIVAT is a safe and feasible alternative for the removal of small-volume benign thyroid disease and low-risk papillary thyroid carcinomas showing better cosmetics results and less postoperative pain but significantly longer operative time when compared to CT. New multicenter randomized studies are needed to evaluate the technique in more complex circumstances such as intermediate-risk thyroid cancer, lymph node removal, thyroiditis, and Graves' disease. PMID- 24162167 TI - Implications of Medicare's review of gastroenterology endoscopy codes. PMID- 24162168 TI - Decompression of acute left-sided malignant colorectal obstruction: comparing transanal drainage tube with metallic stent. AB - BACKGROUND AND AIM: Acute left-sided colorectal malignant obstruction is a life threatening condition and need emergent treatment. Many nonsurgical treatments to palliate obstruction have been developed in clinics. The aim of this study was to evaluate the clinical effects of transanal drainage tube (TDT) and metallic stent for the decompression of acute left-sided malignant colorectal obstruction. MATERIALS AND METHODS: Twenty-nine patients with acute left-sided malignant colorectal obstruction were enrolled in this study from January 2005 to December 2010, they were randomly divided into TDT group (13 patients) and metallic stent group (16 patients). RESULTS: There were 13 cases in TDT group (male:female=8:5, age from 65 to 80 y, mean age was 72.6+/-4.7 y). The sites of lesions were located in the rectum of 3 patients, sigmoid colon of 7 patients, and descending colon of 3 patients. TDT was successfully inserted in 11 cases (84.6%). Among the 11 patients, 1-stage operation with sufficient lymph node dissection was performed in 8 cases after adequate lavage without complications. One case underwent emergent Hartmann operation because of colonic tumor perforation 3 days after ileus tube decompression. Two cases were discharged without surgery after relief of symptom. There were 16 cases in the metallic stent group (male:female=10:6 age from 48 to 86 y, mean age was 73.3+/-8.5 y). The sites of the lesions were located in the rectum of 4 patients, sigmoid colon of 6 patients, and descending colon of 6 patients. Successful stent placement was achieved in 13 cases (81.3%) with no severe complications. Among the 13 patients, 1-stage operation with sufficient lymph node dissection was performed in 7 cases and 6 cases refused to underwent surgery with stent as the definitive palliative treatment. The price of a TDT is only one third of an expandable metallic stent. CONCLUSIONS: Both TDT and metallic stent can achieve preoperative colonic lavage for 1-stage operation for patients with acute left-sided malignant colorectal obstruction with no increase in complications. PMID- 24162169 TI - The differences in colonic mucosal microbiota between normal individual and colon cancer patients by polymerase chain reaction-denaturing gradient gel electrophoresis. AB - OBJECTIVE: The aim of this study was to analyze the differences in the intestinal composition between normal individuals and colon cancer patients. METHODS: To establish the criteria for screening a normal individual for colon cancer, human colonic biopsies were obtained at routine colonoscopy. For patients with colon cancer, samples were obtained from cancerous regions. For normal individuals, colonic biopsies were taken from 3 sites of large intestine (descending, transverse, and ascending colon). Thereafter, a comparison of the microbiota structure by polymerase chain reaction-denaturing gradient gel electrophoresis (PCR-DGGE) was carried out. At last, bacterial species were identified by sequencing special bands from DGGE gels and comparing data with sequence databases. RESULT: With PCR-DGGE, we have discovered that the diversity and richness of the bacterial community from colon cancer patient's colonic mucosa were lower than that of the normal individual's sample. Then, a special DGGE band was found in the colon cancer patients. After sequencing, we confirmed that it had a high level of similarity with bacteroides. CONCLUSIONS: Colon cancers are closely related with the alteration of intestinal flora such as the reduction of biodiversity and richness of the bacterial community. Furthermore, the increase in proportion of bacteroides may be directly associated with colon cancer. PMID- 24162170 TI - Prevalence of hepatitis-B viral markers in patients with inflammatory bowel disease in a hepatitis-B-endemic area: inadequate protective antibody levels in young patients. AB - BACKGROUND: There are few data regarding the prevalence of hepatitis-B virus (HBV) markers in inflammatory bowel disease (IBD) patients in Korea, which is a hepatitis-B-endemic area. The aim of this study was to assess the prevalence of HBV markers in IBD patients in comparison with controls. METHODS: We enrolled 513 IBD patients [241 Crohn's disease (CD) and 272 ulcerative colitis (UC)] whose hepatitis-B surface antigen and anti-HBs levels were evaluated. Anti-HBc was assayed in 357 patients. These markers were compared with those of 1020 sex matched and age-matched controls. RESULTS: Prevalence of hepatitis-B surface antigen in IBD patients was 3.7% and there was no significant difference between groups (CD 4.1%, UC 3.3%, control 4.4%, P=0.713). The frequency of effective vaccination against HBV (positive anti-HBs, without anti-HBc) was lower in IBD patients less than 30 years old compared with the same-aged controls (CD 43.3%, UC 48.5%, control 61.9%, P=0.002), whereas there was no difference between groups in subjects more than 30 years old. One third of IBD patients were at risk of susceptibility to HBV infection (nonimmune), particularly those less than 30 years old, compared with controls of the same age (CD 43.3%, UC 36.4%, control 21%, P<0.001). In IBD patients, multivariate analysis identified that age less than 30 years was an independent risk factor for nonimmune status. CONCLUSIONS: IBD was not a risk factor for HBV infection even in endemic areas. However, many young IBD patients were susceptible to HBV infection. It is crucial to screen for HBV immunity and to implement a meticulous vaccination strategy for young Korean IBD patients. PMID- 24162171 TI - Bacterial translocation contributes to cachexia and its possible pathway in patients with colon cancer. AB - GOALS AND BACKGROUND: There is increasing evidence that bacterial translocation (BT) might contribute to the occurrence and development of cancer cachexia, but the detailed mechanism remains unknown. Thus, we undertook further investigations into the association of BT with cancer cachexia and the possible pathway. STUDY: The colon cancer patients enrolled in this study were divided into cachectic and noncachectic. BT was analyzed by polymerase chain reaction and bacterial culture. Intestinal epithelial T-cell subsets and NK cells were evaluated using flow cytometry. Western blotting and immunofluorescence were used to check tight junction (TJ) proteins in intestinal epithelium. Fluorescence in situ hybridization and immunohistochemistry were used to detect the translocated bacteria and endotoxin. RESULTS: Compared with noncachectic patients, cachectic patients had a significantly higher BT ratio (P<0.001). We observed the translocated bacteria in the intestinal mucus layer associated with lower levels of T-cell subsets and NK cells in the intestinal epithelium in BT-positive patients (P<0.05). Endotoxin was detected within the small intestinal wall and the concentration of endotoxin decreased from the mucosal side to serosal side gradually in these patients. These were associated with an altered composition of TJs. CONCLUSIONS: This study suggests that BT may contribute to colon cancer in cachectic patients, and TJ could be the gateway to the possible pathway of BT. PMID- 24162172 TI - Sequence analysis by iterated maps, a review. AB - Among alignment-free methods, Iterated Maps (IMs) are on a particular extreme: they are also scale free (order free). The use of IMs for sequence analysis is also distinct from other alignment-free methodologies in being rooted in statistical mechanics instead of computational linguistics. Both of these roots go back over two decades to the use of fractal geometry in the characterization of phase-space representations. The time series analysis origin of the field is betrayed by the title of the manuscript that started this alignment-free subdomain in 1990, 'Chaos Game Representation'. The clash between the analysis of sequences as continuous series and the better established use of Markovian approaches to discrete series was almost immediate, with a defining critique published in same journal 2 years later. The rest of that decade would go by before the scale-free nature of the IM space was uncovered. The ensuing decade saw this scalability generalized for non-genomic alphabets as well as an interest in its use for graphic representation of biological sequences. Finally, in the past couple of years, in step with the emergence of BigData and MapReduce as a new computational paradigm, there is a surprising third act in the IM story. Multiple reports have described gains in computational efficiency of multiple orders of magnitude over more conventional sequence analysis methodologies. The stage appears to be now set for a recasting of IMs with a central role in processing nextgen sequencing results. PMID- 24162174 TI - A dominant homolytic O-Cl bond cleavage with low-spin triplet-state Fe(IV)=O formed is revealed in the mechanism of heme-dependent chlorite dismutase. AB - Chlorite dismutase (Cld) is a heme-dependent enzyme that catalyzes the decomposition of toxic chlorite (ClO2(-)) into innocuous chloride and O2. In this paper, using the hybrid B3LYP density functional theory (DFT) method including dispersion interactions, the Cld reaction mechanism has been studied with a chemical model constructed on the X-ray crystal structure. The calculations indicate that the reaction proceeds along a stepwise pathway in the doublet state, i.e. a homolytic O-Cl bond cleavage of the substrate leading to an O Fe(heme) species and a ClO radical, followed by a rebinding O-O bond formation between them. The O-Fe(heme) species is demonstrated to be a low-spin triplet state Fe(IV)=O diradicaloid. A low-spin singlet-state Fe(IV)=O is much less stable than the former, with an energy difference of 9.2 kcal mol(-1). The O-Cl bond cleavage is rate-limiting with a barrier of 10.6 kcal mol(-1), in good agreement with the experimental reaction rate of 2.0 * 10(5) s(-1). Furthermore, a heterolytic O-Cl bond dissociation in the initial step is shown to be unreachable, which ensures the high efficiency of the Cld enzyme by avoiding the generation of chlorate byproduct observed in the reactions of synthetic Fe porphyrins. Also, the pathways in the quartet and sextet states are unfavorable for the Cld reaction. The present results reveal a detailed mechanism III (defined in the text) including an interesting di-radical intermediate composed of a low-spin triplet-state Fe(IV)=O and a ClO radical. Compared to a competitive heterolytic Cl-O cleavage in synthetic Fe porphyrins, the revelation of the domination of homolysis in Cld indicates not only the high efficiency of enzyme, but also the sensitivity of a heme and the significance of the enzymatic active site surroundings (the His170 and Arg183 residues in the present case), which gives more insights into heme chemistry. PMID- 24162173 TI - A primer to frequent itemset mining for bioinformatics. AB - Over the past two decades, pattern mining techniques have become an integral part of many bioinformatics solutions. Frequent itemset mining is a popular group of pattern mining techniques designed to identify elements that frequently co-occur. An archetypical example is the identification of products that often end up together in the same shopping basket in supermarket transactions. A number of algorithms have been developed to address variations of this computationally non trivial problem. Frequent itemset mining techniques are able to efficiently capture the characteristics of (complex) data and succinctly summarize it. Owing to these and other interesting properties, these techniques have proven their value in biological data analysis. Nevertheless, information about the bioinformatics applications of these techniques remains scattered. In this primer, we introduce frequent itemset mining and their derived association rules for life scientists. We give an overview of various algorithms, and illustrate how they can be used in several real-life bioinformatics application domains. We end with a discussion of the future potential and open challenges for frequent itemset mining in the life sciences. PMID- 24162176 TI - Carbon fiber-ZnO nanowire hybrid structures for flexible and adaptable strain sensors. AB - We report the flexible piezotronic strain sensors fabricated using carbon fiber ZnO nanowire hybrid structures by a novel and reliable method. The I-V characteristic of the sensor shows high sensitivity to external strain due to the change in Schottky barrier height (SBH), which has a linear relationship with strain. This fabricated strain sensor has a quick, real-time current response under both static and dynamic mechanical loads. The change in SBH resulted from the strain-induced piezoelectric potential is investigated by band gap theory. In this work we develop a new feasible method to fabricate a flexible strain sensor within the fabric adapted to textile structures, able to measure their strain. PMID- 24162177 TI - Entropy production in oscillatory processes during photosynthesis. AB - The flow of matter and heat and the rate of enzymatic reactions are examined using two models of photosynthesis that exhibit sustained and damped oscillatory dynamics, with the objective of calculating the rate of entropy generation and studying the effects of temperature and kinetic constants on the thermodynamic efficiency of photosynthesis. The global coefficient of heat transfer and the direct and inverse constants of the formation reaction of the RuBisCO-CO2 complex were used as control parameters. Results show that when the system moves from isothermal to non-isothermal conditions, the transition from a steady state to oscillations facilitates an increase in the energy efficiency of the process. The simulations were carried out for two photosynthetic models in a system on a chloroplast reactor scale. PMID- 24162178 TI - A Moroccan patient with Vogt-Koyanagi-Harada syndrome and bilateral Adie's pupils. PMID- 24162179 TI - Identification and visualization of stimulus-specific transcriptional activity in cardiac hypertrophy in mice. AB - Identification of specific signaling pathways for cardiac hypertrophy in living animals is challenging because no methods have been established to directly observe sequential molecular signaling events at the transcriptional level during pathogenesis. Here, our aim was to develop a useful method for monitoring the specific signaling pathways involved in the development of cardiac hypertrophy in vivo. Expression profiling of the left ventricle by microarray was performed in 2 different mouse models of cardiac hypertrophy: mechanical pressure overload by transverse aortic constriction (TAC) and neurohumoral activation by angiotensin II (Ang II) infusion. To annotate the information on transcription factor-binding sites, we collected promoter sequences and identified significantly frequent transcription factor-binding sites in the promoter regions of coregulated genes from both models (P < 0.05, binomial probability). Finally, we injected a firefly luciferase vector plasmid containing each transcription factor-binding site into the left ventricle in both models. In the TAC and Ang II models, we selected 379 and 12 upregulated genes, respectively. Twenty binding sites for transcription factors, including activator protein 4, were identified in the TAC model, and 4 sites for transcription factors, including ecotropic viral integration 1, were identified in the Ang II model. GATA-binding sites were noted in both models of cardiac hypertrophy. Using the firefly luciferase reporter, we demonstrated the enhancement of transcriptional activity during the progression of cardiac hypertrophy using in vivo imaging in live mice. These results suggested that our approach was useful for the identification of unique transcription factors that characterize different models of cardiac hypertrophy in vivo. PMID- 24162180 TI - New inflammatory predictors for non-valvular atrial fibrillation: echocardiographic epicardial fat thickness and neutrophil to lymphocyte ratio. AB - The objective of this study was to investigate the relationship of echocardiographic epicardial fat thickness (EFT) and neutrophil to lymphocyte ratio (NLR) with different types of non-valvular atrial fibrillation (AF) in a clinical setting. A total of 197 consecutive patients were enrolled in the study. Seventy-one patients had paroxysmal non-valvular AF, 63 patients had persistent/permanent non-valvular AF, and 63 patients had sinus rhythm (control group). EFT was measured with echocardiography, while NLR was measured by dividing neutrophil count by lymphocyte count. EFT was significantly higher in patients with paroxysmal non-valvular AF compared with those in the sinus rhythm group (6.6 +/- 0.7 vs. 5.0 +/- 0.9 mm, p < 0.001). Persistent/permanent non valvular AF patients had a significantly larger EFT compared with those with paroxysmal AF (8.3 +/- 1.1 vs. 6.6 +/- 0.7 mm, p < 0.001). EFT had a significant relationship with paroxysmal non-valvular AF (odds ratio 4.672, 95 % CI 2.329 9.371, p < 0.001) and persistent/permanent non-valvular AF (OR 24.276, 95% CI 9.285-63.474, p < 0.001). NLR was significantly higher in those with paroxysmal non-valvular AF compared with those in the sinus rhythm group (2.5 +/- 0.6 vs. 1.8 +/- 0.4, p < 0.001). Persistent/permanent non-valvular AF patients had a significantly larger NLR when compared with paroxysmal non-valvular AF patients (3.4 +/- 0.6, vs. 2.5 +/- 0.6, p < 0.001). NLR (>2.1) had a significant relationship with non-valvular AF (OR 11.313, 95% CI 3.025-42.306, b 2.426, p < 0.001). EFT and NLR are highly associated with types of non-valvular AF independent of traditional risk factors. EFT measured by echocardiography and NLR appears to be related to the duration and severity of AF. PMID- 24162181 TI - Responses of tree-ring growth and crop yield to drought indices in the Shanxi province, North China. AB - In this paper, we analyze the relationships among the tree-ring chronology, meteorological drought (precipitation), agricultural drought (Palmer Drought Severity Index PDSI), hydrological drought (runoff), and agricultural data in the Shanxi province of North China. Correlation analyses indicate that the tree-ring chronology is significantly correlated with all of the drought indices during the main growing season from March to July. Sign test analyses further indicate that the tree-ring chronology shows variation similar to that of the drought indices in both high and low frequencies. Comparisons of the years with narrow tree rings to the severe droughts reflected in all three indices from 1957 to 2008 reveal that the radial growth of the trees in the study region can accurately record the severe drought for which all three indices were in agreement (1972, 1999, 2000, and 2001). Comparisons with the dryness/wetness index indicate that tree-ring growth can properly record the severe droughts in the history. Correlation analyses among agricultural data, tree-ring chronology, and drought indices indicate that the per-unit yield of summer crops is relatively well correlated with the agricultural drought, as indicated by the PDSI. The PDSI is the climatic factor that significantly influences both tree growth and per-unit yield of summer crops in the study region. These results indicate that the PDSI and tree ring chronology have the potential to be used to monitor and predict the yield of summer crops. Tree-ring chronology is an important tool for drought research and for wider applications in agricultural and hydrological research. PMID- 24162182 TI - Anterior decompression with single segmental spinal interbody fusion for Denis type B thoracolumbar burst fracture: a midterm follow-up study. AB - PURPOSE: Our goal was to observe the midterm results of a case series of Denis type B thoracolumbar burst fracture treated with anterior decompression with single segmental spinal Interbody fusion. METHODS: Twenty patients with Denis type B thoracolumbar burst fractures underwent anterior decompression with single segmental spinal Interbody fusion. They underwent clinical and radiologic follow up for at least three years after the surgery. RESULTS: The mean follow-up period lasted 57 months. To the last follow-up, there were no cases of internal fixation loosening, failure and other complications. Titanium mesh or interbody bone grafts were in good position. Spinal kyphosis was not observed. Interbody fusion was achieved for all cases. The average fusion time was 4.5 months. Based on visual analogue scale (VAS) pain scores, percentage of vertebral body height loss and Cobb angle, the difference was statistically significant between the preoperative period and postoperative one year or final follow-up (P < 0.05). Results at postoperative one year and final follow-up were better than the preoperative period. However, the difference was not significant between postoperative one year and final follow-up (P > 0.05). CONCLUSIONS: Good midterm results on clinical and radiologic evaluation of anterior decompression with single segmental spinal Interbody fusion for suitable patients with Denis type B thoracolumbar burst fracture can be achieved. The incident rate of relative complications is low. PMID- 24162183 TI - Prospective links between ethnic socialization, ethnic and American identity, and well-being among Asian-American adolescents. AB - Ethnic socialization and ethnic identity have been related to positive outcomes, but little research has examined these associations longitudinally. This three wave study prospectively linked socialization messages at Time 1, ethnic identity and American identity at Time 2, and self-esteem and depressive symptoms at Time 3 in 147 (58% female; 25% first-generation) Asian-American adolescents. The results indicated positive links between cultural socialization messages and ethnic and American identity, though the latter association was significant only for females. Ethnic identity was positively related to self-esteem, and mediated the positive effect of cultural socialization on self-esteem. The promotion of mistrust was positively linked to self-esteem and negatively related to ethnic identity, though this latter association was significant for foreign-born youth only. Our findings highlight the importance of elucidating prospective links in identity development, and examining gender and generational differences within them. PMID- 24162184 TI - 3,3'-Diindolylmethane inhibits lipopolysaccharide-induced microglial hyperactivation and attenuates brain inflammation. AB - Recent studies have revealed that microglial hyperactivation and neuroinflammation are implicated in development and progression of neurodegenerative diseases. In this study, we examined the beneficial effects of 3,3'-diindolylmethane (DIM) and indole-3-carbinol (I3C), dietary components found in cruciferous vegetables, on brain inflammation. DIM, a major metabolite of I3C, suppressed lipopolysaccharide (LPS)-induced expression of inducible nitric oxide synthase and cyclooxygenase-2 in BV-2 microglia, but I3C did not. DIM, but not I3C, attenuated DNA-binding activity of nuclear factor-kappaB (NF-kappaB) and phosphorylation of inhibitor of kappaB, suggesting that DIM might inhibit microglial hyperactivation by attenuating inflammatory transcription factor NF kappaB. In addition, DIM, but not I3C, protected primary cortical neurons from inflammatory toxicity induced by the conditioned media from LPS-stimulated BV-2 microglia, indicating that DIM might attenuate microglial hyperactivation mediated neuronal death. In an in vivo model of neuroinflammation, DIM suppressed LPS-induced brain inflammation in mouse hippocampus, as determined by the number of Iba-1-positive cells and the mRNA expression of F4/80. Taken together, these results suggest that DIM may have beneficial potential against brain inflammation and neurodegenerative diseases through the negative regulation of the NF-kappaB signal pathway in microglia. PMID- 24162185 TI - A real-time, non-invasive, micro-optrode technique for detecting seed viability by using oxygen influx. AB - Quantifying seed viability is required for seed bank maintenance. The classical methods for detecting seed viability are time consuming and frequently cause seed damage and unwanted germination. We have established a novel micro-optrode technique (MOT) to measure seed viability in a quick and non-invasive manner by measuring the oxygen influxes of intact seeds, approximately 10 seconds to screen one seed. Here, we used soybean, wheat, and oilseed rape as models to test our method. After 3-hour imbibition, oxygen influxes were recorded in real-time with the total measurement taking less than 5 minutes. The results indicated a significantly positive correlation between oxygen influxes and viability in all 3 seed types. We also established a linear equation between oxygen influxes and seed viability for each seed type. For measurements, seeds were kept in the early imbibition stage without germination. Thus, MOT is a reliable, quick, and low cost seed viability detecting technique. PMID- 24162187 TI - Variation Ontology for annotation of variation effects and mechanisms. AB - Ontology organizes and formally conceptualizes information in a knowledge domain with a controlled vocabulary having defined terms and relationships between them. Several ontologies have been used to annotate numerous databases in biology and medicine. Due to their unambiguous nature, ontological annotations facilitate systematic description and data organization, data integration and mining, and pattern recognition and statistics, as well as development of analysis and prediction tools. The Variation Ontology (VariO) was developed to allow the annotation of effects, consequences, and mechanisms of DNA, RNA, and protein variations. Variation types are systematically organized, and a detailed description of effects and mechanisms is possible. VariO is for annotating the variant, not the normal-state features or properties, and requires a reference (e.g., reference sequence, reference-state property, activity, etc.) compared to which the changes are indicated. VariO is versatile and can be used for variations ranging from genomic multiplications to single nucleotide or amino acid changes, whether of genetic or nongenetic origin. VariO annotations are position-specific and can be used for variations in any organism. PMID- 24162186 TI - System identification of the nonlinear dynamics in the thalamocortical circuit in response to patterned thalamic microstimulation in vivo. AB - OBJECTIVE: Nonlinear system identification approaches were used to develop a dynamical model of the network level response to patterns of microstimulation in vivo. APPROACH: The thalamocortical circuit of the rodent vibrissa pathway was the model system, with voltage sensitive dye imaging capturing the cortical response to patterns of stimulation delivered from a single electrode in the ventral posteromedial thalamus. The results of simple paired stimulus experiments formed the basis for the development of a phenomenological model explicitly containing nonlinear elements observed experimentally. The phenomenological model was fit using datasets obtained with impulse train inputs, Poisson-distributed in time and uniformly varying in amplitude. MAIN RESULTS: The phenomenological model explained 58% of the variance in the cortical response to out of sample patterns of thalamic microstimulation. Furthermore, while fit on trial-averaged data, the phenomenological model reproduced single trial response properties when simulated with noise added into the system during stimulus presentation. The simulations indicate that the single trial response properties were dependent on the relative sensitivity of the static nonlinearities in the two stages of the model, and ultimately suggest that electrical stimulation activates local circuitry through linear recruitment, but that this activity propagates in a highly nonlinear fashion to downstream targets. SIGNIFICANCE: The development of nonlinear dynamical models of neural circuitry will guide information delivery for sensory prosthesis applications, and more generally reveal properties of population coding within neural circuits. PMID- 24162188 TI - Improved exome prioritization of disease genes through cross-species phenotype comparison. AB - Numerous new disease-gene associations have been identified by whole-exome sequencing studies in the last few years. However, many cases remain unsolved due to the sheer number of candidate variants remaining after common filtering strategies such as removing low quality and common variants and those deemed unlikely to be pathogenic. The observation that each of our genomes contains about 100 genuine loss-of-function variants makes identification of the causative mutation problematic when using these strategies alone. We propose using the wealth of genotype to phenotype data that already exists from model organism studies to assess the potential impact of these exome variants. Here, we introduce PHenotypic Interpretation of Variants in Exomes (PHIVE), an algorithm that integrates the calculation of phenotype similarity between human diseases and genetically modified mouse models with evaluation of the variants according to allele frequency, pathogenicity, and mode of inheritance approaches in our Exomiser tool. Large-scale validation of PHIVE analysis using 100,000 exomes containing known mutations demonstrated a substantial improvement (up to 54.1 fold) over purely variant-based (frequency and pathogenicity) methods with the correct gene recalled as the top hit in up to 83% of samples, corresponding to an area under the ROC curve of >95%. We conclude that incorporation of phenotype data can play a vital role in translational bioinformatics and propose that exome sequencing projects should systematically capture clinical phenotypes to take advantage of the strategy presented here. PMID- 24162189 TI - ARF triggers senescence in Brca2-deficient cells by altering the spectrum of p53 transcriptional targets. AB - ARF is a tumour suppressor activated by oncogenic stress, which stabilizes p53. Although p53 is a key component of the response to DNA damage, a similar function for ARF has not been ascribed. Here we show that primary mouse and human cells lacking the tumour suppressor BRCA2 accumulate DNA damage, which triggers checkpoint signalling and ARF activation. Furthermore, senescence induced by Brca2 deletion in primary mouse and human cells is reversed by the loss of ARF, a phenotype recapitulated in cells lacking RAD51. Surprisingly, ARF is not necessary for p53 accumulation per se but for altering the spectrum of genes activated by this transcription factor. Specifically, ARF enables p53 transcription of Dusp4 and Dusp7, which encode a pair of phosphatases known to inactivate the MAP kinases ERK1/2. Our results ascribe a previously unanticipated function to the ARF tumour suppressor in genome integrity, controlled by replicative stress and ATM/ATR-dependent checkpoint responses. PMID- 24162190 TI - The tuning of metal enhanced fluorescence for sensing applications. AB - Stable coinage metal nanoparticles (NPs) have been synthesized individually in an aqueous alkaline solution from the corresponding metal salts as precursors using the condensation product (CP) of salicylaldehyde and triethylenetetramine as a reagent. Silver and gold NPs are obtained with and without light illumination but UV irradiation is essential for Cu(0)NP formation. During nanoparticle formation the CP is oxidized to OCP which eventually becomes a fluorophore and also a stabilizer for the in situ produced NPs. It has been observed that silver and gold particle formation kinetics is accelerated by UV exposure. Thus the ease of evolution of coinage metal NP formation relates to their nobility. The as prepared OCP solutions containing coinage metals exhibit a fluorescence contrast behaviour (fluorescence enhancement by Cu and Ag; quenching by AuNP) due to the match and mismatch of wave vectors. The electric field evident from the FDTD simulation abreast of the scattering cross section of the NPs governed from Mie theory as a consequence of surface plasmon coupled emission (SPCE), near field electromagnetic intensity enhancement and lightening rod effect concentrating the electric field around the fluorophore are responsible for the Cu and AgNPs stimulated fluorescence. Again, lossy surface waves are anticipated for efficient quenching by the AuNPs. The most unprecedented observation is 'Turn On' fluorescence which is reported here as a result of the substitution of Au(0) or Cu(0) by Ag(0). Finally, the preferential fluorescence enhancement helps the selective detection of Ag(i) and Cu(ii) well below the US Environmental Protection Agency (EPA) permissible level by tuning the experimental conditions. PMID- 24162191 TI - Genetic variation in natural populations of the cereal cyst nematode (Heterodera avenae Woll.) submitted to resistant and susceptible cultivars of cereals. AB - The purpose of the present work was to study the genetic characteristics of cereal cyst nematode (Heterodera avenae) populations re-established after the long-term use of resistant oat cultivars in field conditions. Population features were analyzed through fitness components and variation in enzymatic polymorphism (esterase and malate dehydrogenase loci). The longest (6 year) use of the same resistance genes (oat cv Panema) at high frequency (Rotation IB) led to the selection of a resistance-breaking pathotype and to a decrease in viability which suggested either a founder effect or a lower reproductive potential for the new pathotype. Analysis of esterase allelic frequencies led to the conclusions that: (1) the genetic constitution of this pathotype was different from the reference population maintained on the susceptible host (oat cv Peniarth), and (2) that the esterase locus may develop a disequilibrium linkage with loci involved in virulence Nematodes overcoming the resistance of cv Panema did not differ from H. avenae species following RFLPs in ribosomal DNA . Random mating was recorded at the whole-field level but not always at the single-plant level, suggesting that cultivation practices such as annual ploughing could play a major role in homogenizing subpopulations developed in the vicinity of a plant. These phenomena showed that the long-term use of highly effective resistance could provok marked genetic modifications in populations. These risks should be taken into account when deciding strategies for optimal use of resistance genes in nematode management programs. PMID- 24162192 TI - Genetic validity of RAPD markers at the intra- and inter-specific level in wild Brassica species with n=9. AB - The sequence homology of co-migrating RAPD markers within a genus, across species, and among populations of a species was investigated. DNA was isolated from ten wild Brassica species with n=9 and the RAPD patterns were established using three random primers. Five RAPD markers which appeared to be characteristic for the n=9 species (genus level), four markers which appeared to be species specific, and one population-specific marker were isolated from agarose gels and hybridized to the RAPD profiles of the ten Brassica species. Two RAPD markers were cloned for comparison with gel-isolated RAPD fragment probes in hybridization experiments. Non-specific and background hybridization, occurring when gel-isolated fragments were used as probes, disappeared when cloned fragments were used. A total of 250 RAPD-marker hybridizations were scored according to visual presence or absence in a gel lane. All except three markers hybridized as expected, resulting in an error rate of 1.2%. The deviating results included a lack of hybridization although a band was visible in the gel, a length polymorphism for one marker, and a dual hybridization signal for two single-band markers. PMID- 24162193 TI - Genetic relationships between growth characters in Salix viminalis grown in Sweden. AB - From an eight by eight factorial crossing with Salix viminalis, 40 of the 64 families obtained were selected for further analysis. Fourteen seedplants from each of these 40 families were planted in two pairs of contrasting environments: sand and clay soil, and low and high nutrient supply. The material in the soil contrast was harvested after 1, 4 and 6 years of growth. The material in the nutrient contrast was harvested each year for 3 years and analysed after the first and the third harvests. The correlation between number of shoots and weight in the clay environment changed from being negative in the first harvests to positive at the last harvest, compared with the sand environment where this correlation was positive in all years. In the nutrient contrast this correlation was positive at the last harvest in the high nutrient environment, but no correlation could be detected in the low nutrient environment. The differences in correlations between environments may be due to a different allocation of nutrients in the plants, depending on whether the plant is under stress or not. The data suggests that the genetic relationship between growth components is the same over age and environments when the plants are grown without stress. PMID- 24162194 TI - Molecular phylogeny of Dipterocarpaceae in Southeast Asia using RFLP of PCR amplified chloroplast genes. AB - Dipterocarpaceae is the dominant family of Southeast Asia's climax tropical rain forest region, and it contains the region's most important commercial timber species. A molecular phylogeny of the Dipterocarpaceae subfamily Dipterocapoideae was constructed using restriction fragment length polymorphisms of polymerase chain reaction-amplified specific genes in chloroplast DNA. A total of 141 site changes were detected among ten genera and 30 species in 11 different genes: rbcL, psbA, psbD, rpoB, rpoC, petB, atpH, 16S, psaA, petA and trnK. Phylogenetic trees constructed by Wanger parsimony and neighbor-joining methods, using Upuna as the outgroup, displayed five monophytelic groups that included Upuna: HopeaShorea-Parashorea-Neobalanocarpus; Dryobalanops; Dipterocarpus; Anisoptera Vatica-Cotylelobium; and Upuna. The phylogenetic trees clearly separate species with two different base chromosome numbers: the first group is x=7, and the other is x=11. The x=7 group is thought to be in a synapomorphic character state. Parashorea lucida is a sister to most Shorea species. Neobalanocarpus heimii and Hopea from a clade of a sister to two Shorea species, and Cotylelobium and Vatica are closely related species. Our conclusions agree with a phylogeny derived from wood anatomy data analysis, and with Symington's and Ashton's taxonomic classifications. PMID- 24162195 TI - Use of the additive main effects and multiplicative interaction model in QTL mapping for adaptation in barley. AB - The additive main effects and multiplicative interaction (AMMI) model has emerged as a powerful analytical tool for genotype x environment studies. The objective of the present study was to assess its value in quantitative trait locus (QTL) mapping. This was done through the analysis of a large two-way table of genotype by-environment data of barley (Hordeum vulgare L.) grain yields, where the genotypes constituted a genetic population suitable for mapping studies. Grain yield data of 150 doubled haploid lines derived from the 'Steptoe' x 'Morex' cross, and the two parental lines, were taken by the North American Barley Genome Mapping Project (NABGMP) at 16 environments throughout the barley production areas of the USA and Canada. Four regions of the genome were responsible for most of the differential genotypic expression across environments. They accounted for approximately 50% of the genotypic main effect and 30% of the genotype x environment interaction (GE) sums of squares. The magnitude and sign of AMMI scores for genotypes and sites facilitate inferences about specific interactions. The parallel use of classification (cluster analysis of environments) and ordination (principal component analysis of GE matrix) techniques allowed most of the variation present in the genotype x environment matrix to be summarized in just a few dimensions, specifically four QTLs showing differential adaptation to four clusters of environments. Thus, AMMI genotypic scores, when the genotypes constituted a population suitable for QTL mapping, could provide an adequate way of resolving the magnitude and nature of QTL x environment interactions. PMID- 24162196 TI - Chromosomal location of a gene suppressing powdery mildew resistance genes Pm8 and Pm17 in common wheat (Triticum aestivum L. em. Thell.). AB - The chromosomal location of a suppressor for the powdery mildew resistance genes Pm8 and Pm17 was determined by a monosomic set of the wheat cultivar Caribo. This cultivar carries a suppressor gene inhibiting the expression of Pm8 in cv Disponent and of Pm17 in line Helami-105. In disease resistance assessments, monosomic F1 hybrids (2n=41) of Caribo x Disponent and Caribo x Helami-105 lacking chromosome 7D were resistant, whereas monosomic F1 hybrids involving the other 20 chromosomes, as well as disomic F1 hybrids (2n=42) of all cross combinations, were susceptible revealing that the suppressor gene for Pm8 and Pm17 is localized on chromosome 7D. It is suggested that genotypes without the suppressor gene be used for the exploitation of genes Pm8 and Pm17 in enhancing powdery mildew resistance in common wheat. PMID- 24162197 TI - Construction of a molecular linkage map in coffee. AB - A linkage map for coffee (Coffea canephora P.) totalling 1402 cM has been developed on the basis of a population of doubled haploids. Both RFLP markers and PCR-based markers (RAPD) were used to construct 15 linkage groups. Coffee genomic and cDNA clones provided the source of the probes. In total, 47 RFLP and 100 RAPD loci have been placed on the linkage map. A rather low DNA polymorphism rate (18% for RFLP markers and 29% for RAPD primers) was detected. Only 81% of RAPD markers and 85% of RFLP markers fit an expected 1?1 ratio (P<0.01). The availability of a molecular linkage map has many implications for the future development of the genetics and breeding of this commercially important crop species. PMID- 24162198 TI - RFLP mapping of three new loci for resistance genes to powdery mildew (Erysiphe graminis f. sp. hordei) in barley. AB - Three new major, race-specific, resistance genes to powdery mildew (Erysiphe graminis f. sp. hordei) were identified in three barley lines, 'RS42-6*O', 'RS137 28*E', and 'HSY-78*A', derived from crosses with wild barley (Hordeum vulgare ssp. spontaneum). The resistance gene origining from wild barley in line 'RS42 6*O', showed a recessive mode of inheritance, whereas the other wild barley genes were (semi)-dominant. RFLP mapping of these three genes was performed in segregating F2 populations. The recessive gene in line 'RS42-6*O', was localized on barley chromosome 1S (7HS), while the (semi)-dominant genes in lines 'RS137 28*E', and 'HSY-78*A', were localized on chromosomes 1L (7HL) and 7L (5HL), respectively. Closely linked RFLP clones mapped at distances between 2.6cM and 5.3 cM. Hitherto, specific loci for powdery mildew resistance in barley had not been located on these chromosomes. Furthermore, tests for linkage to the unlocalized resistance gene Mlp revealed free segregation. Therefore, these genes represent new loci and new designations are suggested: mlt ('RS42-6*O'), Mlf ('RS137-28*E'), and Mlj ('HSY-78*A'). Comparisons with mapped QTLs for mildew resistance were made and are discussed in the context of homoeology among the genomes of barley (H-vulgare), wheat (Triticum aestivum), and rye (Secale cereale). Duplications of RFLP bands detected in the neighbourhood of Mlf and mlt might indicate an evolutionary interrelationship to the Mla locus for mildew resistance. PMID- 24162199 TI - A genetic map of melon (Cucumis melo L.) with RFLP, RAPD, isozyme, disease resistance and morphological markers. AB - One hundred and ten markers were analysed for linkage in 218 F2 plants derived from two divergent cultivars ('Vedrantais' and 'Songwhan Charmi') of Cucumis melo (L.). Thirty-four RFLPs, 64 RAPDs, one isozyme, four disease resistance markers and one morphological marker were used to construct a genetic map spanning 14 linkage groups covering 1390 cM of the melon genome. RAPD and RFLP markers detected similar polymorphism levels. RFLPs were largely due to base substitutions rather than insertion/deletions. Twelve percent of markers showed distorted segregation. Phenotypic markers consisted of two resistance genes against Fusarium wilt (Fom-1 and Fom-2), one gene (nsv) controlling the resistance to melon necrotic spot virus, one gene (Vat) conferring resistance to Aphis gossypii, and a recessive gene for carpel numbers (3 vs 5 carpels: p). PMID- 24162201 TI - Methods for multiple-marker mapping of quantitative trait loci in half-sib populations. AB - In this paper we consider the detection of individual loci controlling quantitative traits of interest (quantitative trait loci or QTLs) in the large half-sib family structure found in some species. Two simple approaches using multiple markers are proposed, one using least squares and the other maximum likelihood. These methods are intended to provide a relatively fast screening of the entire genome to pinpoint regions of interest for further investigation. They are compared with a more traditional single-marker least-squares approach. The use of multiple markers is shown to increase power and has the advantage of providing an estimate for the location of the QTL. The maximum-likelihood and the least-squares approaches using multiple markers give similar power and estimates for the QTL location, although the likelihood approach also provides estimates of the QTL effect and sire heterozygote frequency. A number of assumptions have been made in order to make the likelihood calculations feasible, however, and computationally it is still more demanding than the least-squares approach. The least-squares approach using multiple markers provides a fast method that can easily be extended to include additional effects. PMID- 24162200 TI - RAPD and RFLP mapping of the bacterial blight resistance gene xa-13 in rice. AB - Bacterial blight (BB) caused by Xanthomonas oryzae pv oryzae (Xoo) is one of the most serious diseases of rice. The recessive gene xa-13 confers resistance to Philippine race 6 of Xoo. To tag xa-13 with molecular markers, RAPD analysis was conducted with the combined use of near-isogenic lines and bulked segregant analysis. From the survey of 260 arbitrary 10-nucleotide primers, one primer (OPAC05) was detected to amplify specifically a 0.9-kb band from the DNA of susceptible plants. The distance between the RAPD marker OPAC05-900 and xa-13 was estimated to be 5.3 cM. The RAPD marker was then mapped on chromosome 8 using a mapping population of doubled haploid lines derived from the cross of IR64/Azucena. The linkage between RFLP markers and the RAPD marker was analyzed using an F2 population of 135 plants derived from a cross between a near-isogenic line for xa-13, IR66699-5-5-4-2, and IR24. No recombinants were found between RZ28 and CDO116 and their distance from xa-13 was estimated to be 4.8 cM. RG136 was located at 3.7 cM on the other side of xa-13. The mapping of xa-13 with closely linked DNA markers provides the basis for marker-aided selection for rice improvement. PMID- 24162202 TI - RFLP mapping of the barley homeotic mutant lax-a. AB - The lax-a homeotic mutant of barley has flowers in which lodicules are replaced by stamens (giving five stamens per flower). RFLP mapping of an F2 population from a Bonus lax-a (1) x H. spontaneum cross showed that the mutation was on the short arm of chromosome 7(5H), closely linked to the centromere. An additional F2 population was used to show that the lax-a mutation gave the five-stamen phenotype in all flowers of 6-rowed spikes and that hoods were elevated and reduced in size in lax-a/Hooded double-mutant plants. PMID- 24162203 TI - Detection and analysis of QTLs based on RAPD markers for polygenic resistance to Plasmodiophora brassicae Woron in Brassica oleracea L. AB - Resistance to Plasmodiophora brassicae Woron, the causal fungus of clubroot, was examined in an F2 population of a cross between a clubroot-resistant kale (Brassica oleracea L. var. acephala) and a susceptible cauliflower (Brassica oleracea L. var. botrytis). QTL detection was performed with RAPD markers. Two resistance notations, carried out at different times after inoculation, were used. Three markers were associated with these two notations and three were specifically linked to only one notation. QTL analysis suggests the existence of at least two genetic mechanisms implicated in the resistance phenomenon. PMID- 24162204 TI - Random amplified polymorphic DNA (RAPD) markers reveal genetic homogeneity in the endangered Himalayan species Meconopsis paniculata and M. simplicifolia. AB - Random amplified polymorphic DNA (RAPD) marker-based analysis was carried out to study the extent of genetic polymorphism between populations of the two endangered Himalayan poppy species, Meconopsis paniculata and M. Simplicifolia. Of the 90 primers tested, 38 revealed marked inter-species genetic polymorphism between individuals of the two species from geographically isolated populations. However, intra-species genetic homogeneity was also evident with respect to a number of primers both within and between populations. A comprehensive analysis incorporating data from RAPDs, DNA fingerprinting and isozyme pattern was carried out and, based on the presence or absence of bands, three matrices of similarity indices were estimated. These matrices were subsequently utilized in cluster analysis. In order to compare the three clusters generated using these three different marker systems, a Mantel matrix-correspondence test was carried out on the basis of comparisons of co-phenetic values. The overall representation of relationships by cluster analysis was similar for all three marker systems and this was substantiated by high correlations among the three analyses revealed by the Mantel matrix-correspondence test. Our results point to very low or absence of, genetic polymorphism in M. paniculata and M. simplicifolia, and are in broad agreement with our previous observations on genetic diversity of Meconopsis species which point to a genetic basis for the possible extinction of this economically important genus. PMID- 24162205 TI - Quantitative resistance to barley leaf stripe (Pyrenophora graminea) is dominated by one major locus. AB - A major gene underlying quantitative resistance of barley against Pyrenophora graminea, a seedborne pathogen causing leaf stripe, was mapped with molecular markers in a barley doubled haploid (DH) population derived from the cross 'Proctor' x 'Nudinka'. This quantitative trait locus (QTL) accounts for r (2)= 58.5% and was mapped on barley chromosome 1, tightly linked to the "naked" gene. A second resistance QTL accounting for 29.3% of the variation in the trait was identified on the P arm of barley chromosome 2. Another two minor QTLs were detected by further analysis. None of the QTLs was found in the barley chromosome 2 "Vada" region studied by Giese et al. (1993). PMID- 24162206 TI - Detecting epistatic genetic variance with a clonally replicated design: models for lowvs high-order nonallelic interaction. AB - A quantitative genetic model, that uses known family structure with clonal replicates to separate genetic variance into its additive, dominance and epistatic components, is available in the current literature. Making use of offspring testing, this model is based on the theory that components of variance from the linear model of an experimental design may be expressed in terms of expected covariances among relatives. However, if interactions between a pair of quantitative trait loci (QTLs) explain a large proportion of the total epistasis, it will seriously overestimate the additive and dominance variances but underestimate the epistatic variance. In the present paper, a new model is developed to manipulate this problem by combining parental and offspring material into the same test. Under the condition described above, the new model can provide an accurate estimate for additive x additive variances. Also, its accuracy in estimating dominance and total epistatic variances is much greater than the accuracy of the previous model. However, if there is obvious evidence showing the major contribution of high-order interactions, especially among >= 4QTLs, to the total epistasis, the previous model is more appropriate to partition the genetic variance for a quantitative trait. The re-analysis of an example from a factorial mating design in poplar shows large differences in estimating variance components between the new and previous models when two different assumptions (lowvs high-order epistatic interactions) are used. The new model will be an alternative to estimating the mode of quantitative inheritance for species, especially for longlived, predominantly outcrossing forest trees, that can be clonally replicated. PMID- 24162207 TI - Stability of quantitative traits in quinoa (Chenopodium quinoa). AB - The stability of various descriptive characters was studied over a 5-year period in 14 lines of quinoa (Chenopodium quinoa Willd.) to determine the most appropriate time in a breeding programme when selection for these characters could be performed, and which lines could serve as potential parents. Various measures of stability were employed to analyse these data, including those proposed by Francis and Kannenberg (1978) and Lin and Binns (1988), appropriately modified for the purpose of this investigation. From these results it was concluded that selection for height, inflorescence size and developmental stage could be satisfactorily performed at an early stage of the breeding programme. For saponin content, however, the measuring techniques available were too insensitive to enable a recommendation to be made. Potential parents were identified in this material for use in the development of varieties suitable for North European conditions. PMID- 24162208 TI - Identification of a YAC clone carrying the Xa-1 allele, a bacterial blight resistance gene in rice. AB - Map-based cloning methods have been applied for isolation of Xa-1, one of the bacterial blight resistance genes in rice.Xa-1 was previously mapped on chromosome 4 using molecular markers. For positional cloning of Xa-1, a high resolution genetic map was made for theXa-1 region using an F2 population of 402 plants and additional molecular markers. Three restriction fragment length polymorphism (RFLP) markers, XNpb235, XNpb264 and C600 were found to be linked tightly to Xa-1, with no recombinants, and U08 750 was mapped 1.5 cM from Xa-1. The screening of a yeast artificial chromosome (YAC) library using theseXa-1 linked RFLP markers resulted in the identification of ten contiguous YAC clones. Among these, one YAC clone, designated Y5212, with an insert of 340 kb, hybridized with all three tightly linked markers. This YAC was confirmed to possess the Xa-1 allele by mapping the Xa-1 gene between both end clones of this YAC (Y5212R and Y5212L). PMID- 24162209 TI - Cytological and molecular characterization of oat x maize partial hybrids. AB - In cereals, interspecific and intergeneric hybridizations (wide crosses) which yield karyotypically stable hybrid plants have been used as starting points to widen the genetic base of a crop and to construct stocks for genetic analysis. Also, uniparental genome elimination in karyotypically unstable hybrids has been utilized for cereal haploid production. We have crossed hexaploid oat (2n=6x=42, Avena sativa L.) and maize (2n=2x=20, Zea mays L.) and recovered 90 progenies through embryo rescue. Fifty-two plants (58%) produced from oatxmaize hybridization were oat haploids (2n=3x=21) following maize chromosome elimination. Twenty-eight plants (31%) were found to be stable partial hybrids with 1-4 maize chromosomes in addition to a haploid set of 21 oat chromosomes (2n=21+1 to 2n=21+4). Ten of the ninety plants produced were found to be apparent chromosomal chimeras, where some tissues in a given plant contained maize chromosomes while other tissues did not, or else different tissues contained a different number of maize chromosomes. DNA restriction fragment length polymorphisms (RFLPs) were used to identify the maize chromosome(s) present in the various oat-maize progenies. Maize chromosomes 2, 3, 4, 5, 6, 7, 8, and 9 were detected in partial hybrids and chromosomal chimeras. Maize chromosomes 1 and 10 were not detected in the plants analyzed to-date. Furthermore, partial self-fertility, which is common in oat haploids, was also observed in some oat maize hybrids. Upon selfing, partial hybrids with one or two maize chromosomes showed nearly complete transmission of the maize chromosome to give self-fertile maize-chromosome-addition oat plants. Fertile lines were recovered that contained an added maize chromosome or chromosome pair representing six of the ten maize chromosomes. Four independently derived disomic maize chromosome addition lines contained chromosome 4, one line carried chromosome 7, two lines had chromosome 9, one had chromosome 2, and one had chromosome 3. One maize chromosome-8 monosomic addition line was also identified. We also identified a double disomic addition line containing both maize chromosomes 4 and 7. This constitutes the first report of the production of karyotypically stable partial hybrids involving highly unrelated species from two subfamilies of the Gramineae (Pooideae - oat, and Panicoideae - maize) and the subsequent recovery of fertile oat-maize chromosome addition lines. These represent novel material for gene/ marker mapping, maize chromosome manipulation, the study of maize gene expression in oat, and the transfer of maize DNA, genes, or active transposons to oat. PMID- 24162210 TI - Ribosomal RNA genes in soybean and common bean: chromosomal organization, expression, and evolution. AB - Ribosomal RNA (5S and 45S) genes were investigated by FISH in two related legumes: soybean [Glycine max (L.) Merr.] and common bean (Phaseolis vulgaris L.). These species are both members of the same tribe (Phaseoleae), but common bean is diploid while soybean is a tetraploid which has undergone diploidization. In contrast to ploidy expectations, soybean had only one 5S and one 45S rDNA locus whereas common bean had more than two 5S rDNA loci and two 45S rDNA loci. Double hybridization experiments with differentially labelled probes indicated that the soybean 45S and 5S rDNA loci are located on different chromosomes and in their distal regions. Likewise, the common bean 45S and 5S rDNA loci were on unique chromosomes, though two of the 5S rDNA loci were on the same chromosome. FISH analysis of interphase nuclei revealed the spatial arrangement of rDNA loci and suggested expression patterns. In both species, we observed one or more 5S rDNA hybridization sites and two 45S rDNA hybridization sites associated with the nucleolar periphery. The 45S rDNA hybridization patterns frequently exhibited gene puffs as de-condensed chromatin strings within the nucleoli. The other condensed rDNA sites (both 5S and 45S) were spatially distant from the nucleolus in nucleoplasmic regions containing heterochromatin. The distribution of rDNA between the nucleoplasm and the nucleoli is consistent with differential gene expression between homologous alleles and among homoeologous loci. PMID- 24162211 TI - Inheritance of foreign genes in transgenic bean (Phaseolus vulgaris L.) co transformed via particle bombardment. AB - Exploiting the biolistic process we have generated stable transgenic bean (Phaseolus vulgaris L.) plants with unlinked and linked foreign genes. Co transformation was conducted using plasmid constructions containing a fusion of the gus and neo genes, which were co-introduced with the methionine-rich 2S albumin gene isolated from the Brazil nut and the antisense sequence of AC1, AC2, AC3 and BC1 genes from the bean golden mosaic geminivirus. The results revealed a co-transformation frequency ranging from 40% to 50% when using unlinked genes and 100% for linked genes. The introduced foreign genes were inherited in a Mendelian fashion in most of the transgenic bean lines. PCR and Southern blot hybridization confirmed the integration of the foreign genes in the plant genome. PMID- 24162212 TI - The inveterate wanderer: study of Enhancer wandering on chromosome 3 in maize. AB - The transposition of the maize transposable element Enhancer (En) had been focused on one chromosome 3 for several generations. From the a1-m(Au) allele with an autonomous En, a new En reporter allele a1-m(r)3927-1, was isolated that undergoes very infrequent and late excision events, producing one or two small spots in the aleurone. This allele is seriously impaired in its capacity to excise. Coincident with the origin of this allele, an En was located at a site close to the a1 locus. From this initial insertion site, the movement of this En was followed for three to four generations in 974 families with a higher transposition rate of this En (50% of the testcross progeny) than that found in a previous study of En transposition. This is the first case reported where a particular En was followed for more than three generations. The higher rate of wanderings of this En along the same chromosome led to the term 'vagabond' En (En (vag) ). Genetic evidence that En may transpose from a replicated donor site to an unreplicated site is provided. Speculative mechanisms on the origin of a1 m(r)3927-1 and En (vag) are discussed. PMID- 24162213 TI - Repeated DNA sequences isolated by microdissection. II. Comparative analysis in Hordeum vulgare and Triticum aestivum. AB - The genomic organization of two satellite DNA sequences, pHvMWG2314 and pHvMWG2315, of barley (Hordeum vulgare, 2n=14, HH) was studied by comparative in situ hybridization (ISH) and PCR analysis. Both sequences are members of different RsaI families. The sequence pHvMWG2314 is a new satellite element with a monomer unit of 73 bp which is moderately amplified in different grasses and occurs in interstitial clusters on D-genome chromosomes of hexaploid wheat (Triticum aestivum, 2n=42, AABBDD). The 331-bp monomer pHvMWG2315 belongs to a tandemly amplified repetitive sequence family that is present in the Poaceae and preferentially amplified in Aegilops squarrosa (2n=14, DD), H. vulgare and Agropyron elongatum. (2n=14, EE). The first described representative of this family was pAs 1 from Ae. squarrosa. Different sequences of one satellite DNA family were amplified from Ae. squarrosa, A. elongatum and H. vulgare using PCR. Characteristic differences between members of the D and H genome occurred in a variable region which is flanked by two conserved segments. The heterogeneity within this element was exploited for the cytogenetic analysis of Triticeae genomes and chromosomes. Comparative ISH with pHvMWG2315 identified individual wheat and barley chromosomes under low (75%) and high (85%) hybridization stringency in homologous and heterologous systems. We propose the designation Tas330 for the Triticeae amplified sequence (Tas) satellite family with a 330 bp average monomer length. PMID- 24162214 TI - Stability of baking quality in bread wheat using several statistical parameters. AB - Stability of quality in bread wheat was investigated for the first time with the alveograph test, a rheological test providing four technological traits. Assessment of stability was reliable because a large set of varieties (ten) were grown over a wide range of environments (14). Varieties and environments were representative of French agricultural practices. A procedure to evaluate stability of quality is proposed. Stability was measured by ecovalence, which was then modelled to determine response to environments for each genotype. A joint regression model was compared to a biadditive model with two multiplicative terms. The regression model explained a very much smaller part of ecovalence than the biadditive model. The latter made it possible to pool cultivars for genotypexenvironment interactions and to characterize varieties for their responsiveness to environments. Two check varieties for stability and instability were identified. PMID- 24162215 TI - Genes determining leucine aminopeptidase and mildew resistance from the ornamental apple, 'White Angel'. AB - Mildew resistance in the ornamental apple 'White Angel' was found to be determined by complementary genes. The gene R w was found to be necessary for the expression of resistance controlled by the resistance gene Pl w . The close linkage between the isoenzyme gene, Lap-2, for leucine aminopeptidase and P1 w was confirmed. The efficiency of Lap-2 as a marker in screening for mildew resistance is limited, as it cannot account for susceptible plants with the r w r w P1 w p1 w genotype. It has, however, an important role to play in combining resistance genes from different sources. The genotypes of 'White Angel' (R w r w , Pl w pl w , Lap-2an), 'Jester' (R w r w , p1 w p w , Lap-2an) 'Katja' (R w r w ,p1 w p1 w , Lap-2an) and 'Gloster 69' (r w r w , p1 w p1 w , Lap-2an) were determined. It also appeared that R w might influence Lap-2 activity in young seedlings. PMID- 24162216 TI - Somatic hybrid plants between the forage legumes Medicago sativa L. and Medicago arborea L. AB - Interspecific somatic hybrid plants were obtained by symmetrical electrofusion of mesophyll protoplasts of Medicago sativa with callus protoplasts of Medicago arborea. Somatic hybrid calli were picked manually from semi-solid culture medium after they were identified by their dual color in fluorescent light. Twelve putative hybrid calli were selected and one of them regenerated plants. The morphogenesis of the somatic hybrid calli was induced by the synthetic growth regulator 1,2 benzisoxazole-3-acetic acid. Somatic hybrid plants showed intensive genome rearrangements, as evidenced by isozyme and RFLP analysis. The morphology of somatic hybrid plants was in general intermediate between the parents. The production of hybrids by protoplast fusion between sexually incompatible Medicago species is related to the in vitro respon siveness of the parental protoplasts. The possibility of using somatic hybrid plants in alfalfa breeding is discussed. PMID- 24162217 TI - Multiple methods for the identification of polymorphic simple sequence repeats (SSRs) in sorghum [Sorghum bicolor (L.) Moench]. AB - Simple sequence repeats (SSRs), also known as microsatellites, are highly variable DNA sequences that can be used as markers for the genetic analysis of plants. Three approaches were followed for the development of PCR primers for the amplification of DNA fragments containing SSRs from sorghum [Sorghum bicolor (L.) Moench]: a search for sorghum SSRs in public DNA databases; the use of SSR specific primers developed in the Poaceae species maize (Zea mays L.) and seashore paspalum grass (Paspalum vaginatum Swartz); and the screening of sorghum genomic libraries by hybridization with SSR oligonucleotides. A total of 49 sorghum SSR-specific PCR primer pairs (two designed from GenBank SSR-containing sequences and 47 from the sequences of genomic clones) were screened on a panel of 17 sorghum and one maize accession. Ten primer pairs from paspalum and 90 from maize were also screened for polymorphism in sorghum. Length polymorphisms among amplification products were detected with 15 of these primer pairs, yielding diversity values ranging from 0.2 to 0.8 with an average diversity of 0.56. These primer pairs are now available for use as markers in crop improvement and conservation efforts. PMID- 24162218 TI - Molecular selection in apple for resistance to scab caused by Venturia inaequalis. AB - Large-scale marker-assisted selection requires highly reproducible, consistent and simple markers. The use of genetic markers is important in woody plant breeding in general, and in apple in particular, because of the high level of heterozygosity present in Malus species. We present here the transformation of two RAPD markers, which we found previously to be linked to the major scab resistance gene Vf, into more reliable and reproducible markers that can be applied directly to apple breeding. We give an example of how the use of such markers can speed up selection for the introduction of scab resistance genes into the same plant, reducing labour and avoiding time-consuming test crosses. We discuss the nature and relationship of the scab resistance gene Vf to the one present in Nova Easygro, thought to be Vr. PMID- 24162220 TI - Do molecular markers reflect patterns of differentiation in adaptive traits of conifers? AB - We have examined patterns of variation of several kinds of molecular markers (isozymes, RFLPs of ribosomal DNA and anonymous low-copy number DNA, RAPDs and microsatellites) and an adaptive trait [date of bud set in Scots pine (Pinus sylvestris L.)]. The study included Finnish Scots pine populations (from latitude 60 degrees N to 70 degrees N) which experience a steep climatic gradient. Common garden experiments show that these populations are adapted to the location of their origin and genetically differentiated in adaptive quantitative traits, e.g. the date of bud set in first-year seedlings. In the northernmost population, bud set took place about 21 days earlier than in the southernmost population. Of the total variation in bud set, 36.4% was found among the populations. All molecular markers showed high levels of within-population variation, while differentiation among populations was low. Among all the studied markers, microsatellites were the most variable (He=0.77). Differences between populations were small, GST was less than 0.02. Our study suggests that molecular markers may be poor predictors of the population differentiation of quantitative traits in Scots pine, as exemplified here by bud-set date. PMID- 24162221 TI - Identification of co-dominant RAPD markers tightly linked to fruit skin color in apple. AB - A simple genetic basis for the red/yellow skincolor polymorphism in apple was verified using DNA markers. Bulked segregant analysis identified one 10-base oligomer that generated different fragments in each of the bulks. After testing the primer in four populations, two fragments were found to be associated with red skin color and another two fragments associated with yellow skin color. Three of the fragments (1160, 1180, and 1230 bp) were partly sequenced and found to share high sequence homology, suggesting these were generated from the same locus. A pair of universal primers were designed to amplify the fragments. In the 'Rome Beauty' x 'White Angel' population, two fragments were associated with red skin color; one fragment designated as A(1) (1160 bp) was from 'Rome Beauty' and another fragment (A(2), 1180 bp) was from 'White Angel'. Progeny possessing both fragments, or either one, had red fruit. Both parents displayed an alternate fragment, a(1) (1230 bp), associated with yellowskinned fruit. In three other crosses tested, only fragment A(1) co-segregated with red skin color; two fragments, a(1) and a(2) (1230 bp and 1320 bp), were associated with yellow skin color. Our results are consistent with the hypothesis that the red/yellow dimorphism is controlled by a monogenic system with the presence of the red anthocyanin pigmentation being dominant. There was no indication that other modifier genes could reverse the effect of the locus (R f ) linked to the markers. Examination of amplification products in 56 apple cultivars and advanced breeding selections demonstrated that the universal primers could be used to correctly predict fruit skin color in most cases. PMID- 24162219 TI - Theobroma cacao L.: a genetic linkage map and quantitative trait loci analysis. AB - A genetic linkage map of Theobroma cacao (cocoa) has been constructed from 131 backcross trees derived from a cross between a single tree of the variety Catongo and an F1 tree from the cross of Catongo by Pound 12. The map comprises 138 markers: 104 RAPD loci, 32 RFLP loci and two morphologic loci. Ten linkage groups were found which cover 1068 centimorgans (cM). Only six (4%) molecular-marker loci show a significant deviation from the expected 1?1 segregation ratio.The average distance between two adjacent markers is 8.3 cM. The final genome-size estimates based on two-point linkage data ranged from 1078 to 1112 cM for the cocoa genome. This backcross progeny segregates for two apparently single gene loci controlling (1) anthocyanidin synthesis (Anth) in seeds, leaves and flowers and (2) self-compatibility (Autoc). The Anth locus was found to be 25 cM from Autoc and two molecular markers co-segregate with Anth. The genetic linkage map was used to localize QTLs for early flowering, trunk diameter, jorquette height and ovule number in the BC1 generation using both single-point ANOVA and interval mapping. A minimum number of 2-4 QTLs (P<0.01) involved in the genetic expression of the traits studied was detected. Coincident map locations of a QTL for jorquette height and trunk diameter suggests the possibility of pleiotropic effects in cocoa for these traits. The combined estimated effects of the different mapped QTLs explained between 11.2% and 25.8% of the phenotypic variance observed in the BC1 population. PMID- 24162222 TI - Construction of a high-resolution genetic map and YAC-contigs in the tomato Tm-2a region. AB - With the ultimate goal of cloning the Tobacco Mosaic Virus (TMV) resistance gene Tm-2a from tomato by means of positional cloning, a high-resolution map of a 4.3 cM region surrounding the Tm-2a gene has been constructed. In total, 13 RFLP and RAPD markers were mapped in close proximity to Tm-2a using 2112 individuals from an intraspecific Lycopersicon peruvianum backcross. The closest flanking markers were separated from Tm-2a by 0.05 cM on each side. Only one marker, the cDNA clone R12, co-segregated with Tm-2a. In order to physically cover the Tm-2a region, R12 and the flanking DNA marker TG207 were used to select homologous YAC clones. To-date, two YAC-contigs spanning approximately 340 kb and 360 kb have been constructed. The data obtained from these experiments indicate that recombination around the centromere of chromosome 9 is extremely suppressed. PMID- 24162224 TI - Pairing and recombination between individual chromosomes of wheat and rye in hybrids carrying the ph1b mutation. AB - Wheat-rye chromosome associations at metaphase I studied by Naranjo and Fernandez Rueda (1991) in ph1b ABDR hybrids have been reanalysed to establish the frequency of pairing between individual chromosomes of wheat and rye. Wheat chromosomes, except for 2A and 2D, and their arms were identified by C-banding. Diagnostic C bands and other cytological markers such as telocentrics or translocations were used to identify each one of the rye chromosomes and their arms. Both the amount of telomeric C-heterochromatin and the structure of the rye chromosomes relative to wheat affected the level of wheatrye pairing. The degree to which rye chromosomes paired with their wheat homoeologues varied with each of the three wheat genomes; in most groups, the B-R association was more frequent than the A-R or D-R associations. Recombination between arms 1RL and 2RL and their homoeologues of wheat possessing a different telomeric C-banding pattern was detected and quantified at anaphase I. The frequency of recombinant chromosomes obtained supports the premise that recombination between wheat and rye chromosomes may be estimated from wheat-rye pairing. PMID- 24162223 TI - Targeted comparative genome analysis and qualitative mapping of a major partial resistance gene to the soybean cyst nematode. AB - A major partial-resistance locus to the soybean cyst nematode (Heterodera glycines Ichinohe; SCN) was identified on linkage group 'G' of soybean [Glycine max (L.) Merr.] using restriction fragment length polymorphisms (RFLPs). This locus explained 51.4% (LOD=10.35) of the total phenotypic variation in disease response in soybean Plant Introduction (PI) 209332, 52.7% (LOD=15.58) in PI 90763, 40.0% (LOD=10.50) in PI 88788, and 28.1% (LOD=6.94) in 'Peking'. Initially, the region around this major resistance locus was poorly populated with DNA markers. To increase marker density in this genomic region, first random, and later targeted, comparative mapping with RFLPs from mungbean [Vigna radiata (L.) R. Wilcz.] and common bean (Phaseolus vulgaris L.) was performed, eventually leading to one RFLP marker every 2.6 centimorgans (cM). Even with this marker density, the inability to resolve SCN disease response into discrete Mendelian categories posed a major limitation to mapping. Thus, qualitative scoring of SCN disease response was carried out in an F5?6 recombinant inbred population derived from 'Evans'xPI 209332 using a 30% disease index cut-off for resistance. Using the computer program JoinMap, an integrated map of the region of interest was created, placing the SCN resistance locus 4.6 cM from RFLP marker B53 and 2.8 cM from Bng30. This study demonstrates how a combination of molecularmapping strategies, including comparative genome analysis, join mapping, and qualitative scoring of a quantitative trait, potentially provide the necessary tools for high-resolution mapping around a quantitative-trait locus. PMID- 24162225 TI - Relatedness measured by oligonucleotide probe DNA fingerprints and an estimate of the mating system of Sea Lavender (Limonium carolinianum). AB - Using DNA fingerprint markers within species and populations of wild plants requires information on the relationship between fingerprint similarity and relatedness. We identified a hypervariable marker based on oliog(GATA)4 hybridization of DpnII-cut genomic DNA from Sea Lavender (Limonium carolinianum). Banding patterns were somatically stable and highly variable among unrelated individuals. Band molecular-weight sizing errors (as a percent of band molecular weight) were estimated at 0.44%+/-0.003 within gels and 0.76%+/-0.964 between gels. Band sizing errors defined a 99% confidence bin of +/-0.95% (1.90% total) of molecular weight. Band-sharing estimates were based on this bin size and on variance estimates that compensate for non-independent comparisons. Band-sharing among nine unrelated individuals (theta) was 0.198+/-0.O11. Experimental pollinations designed to produce selfed, fulland half-sib progeny groups led to five selfed progeny groups and no outcrossed progeny (mean band-sharing, ovS=0.468+/-0.074). A linear regression between band-sharing (S) and relatedness (r) assuming 17% inbreeding was r=0.006+0.914*S (R(2)=0.973) and established the maximum amount of inbreeding. ovS(0.392+/-0.022) estimated from wild pollinated seeds from four maternal families was intermediate to unrelated individuals and experimental selfed progeny, giving evidence for mixed mating in wild plants. More extensive plant pedigrees with known levels of inbreeding will be needed to measure variation in the relationship between S and r among populations and families. PMID- 24162226 TI - Molecular mapping of the ge (s) gene controlling the super-giant embryo character in rice (Oryza sativa L.). AB - The giant-embryo character is useful for quality improvement in rice. Three alleles controlling embryo size have been reported at the ge locus. Based on trisomic analysis, this locus is known to reside on chromosome 7. The objective of the present study was to identify linkage between molecular markers and the ge (s) gene using an existing molecular map of rice and an F2 population derived from Hwacheongbyeo-ge (s) (super-giant embryo)/Milyang 23. The bulked-segregant method was used to screen 38 RFLPs and two microsatellite markers from rice chromosome 7. RZ395 and CDO497 flanked the ge (s) gene, at 2.4 cM and 3.4 cM, respectively. The two microsatellite markers, RM18 and RM10, were linked with ge (s) at 7.7 cM and 9.6 cM, respectively. The availability of molecular markers will facilitate selection of this grain character in a breeding program and provide the foundation for map-based gene isolation. PMID- 24162227 TI - Marker-based estimates of identity by descent and alikeness in state among maize inbreds. AB - Molecular markers are useful for determining relationships and similarity among inbreds, especially if the proportion of marker loci with alleles common to inbreds i and j is partitioned into: (1) the probability that marker alleles are identical by descent (Mfij); and (2) the conditional probability that marker alleles are alike in state, given that they are not identical by descent (theta ij). Our objectives were to: develop a method, based on tabular analysis of restriction fragment length polymorphism marker data, for estimating Mfij, theta ij, and the parental contribution to inbred progeny; validate the accuracy of the method with a simulated data set; and compare the pedigree-based coefficient of coancestry (fij) and Mfij among a set of maize (Zea mays L.) inbreds. Banding patterns for 73 probeenzyme combinations were determined among 13 inbreds. Iterative estimation of Mfij, theta ij, and the parental contribution to progeny was performed with procedures similar to a tabular analysis of pedigree data. Deviations of Mfij from pedigree-based fij ranged from 0.002 to 0.288, indicating large effects of selection and/or drift during inbreeding for some inbreds. Differences between marker-based estimates and expected values of parental contribution to inbred progeny were as large as 0.205. Results for a simulated set of inbreds indicated that tabular analysis of marker data provides more accurate estimates of Mfij and theta ij than other methods described in the literature. Tabular analysis requires the availability of marker data for all the progenitors of each inbred. When marker data are not available for the parents of a given inbred, Mfij and theta ij may still be calculated if parental contributions to the inbred are assumed equal to their expectations. PMID- 24162228 TI - Donor chromosome elimination and organelle composition of asymmetric somatic hybrid plants between an interspecific tomato hybrid and eggplant. AB - Morphology, the extent of elimination of donor chromosomes and the organelle composition of highly asymmetric somatic hybrid plants between a interspecific tomato hybrid Lycopersicon esculentum x L. pennellii (EP) as donor and a Solarium melongena, eggplant (E), recipient, were studied. Morphologically, the somatic hybrids most resemble eggplant but, due to polyploidy, growth is slower relative to both fusion parents. The somatic hybrids produce flowers that are characterized by abnormal styles, stigmas and by anthers which do not produce pollen. Limited amounts of donor EP genomic DNA were found in the three somatic hybrid plants (H18-1, H18-2 and H18-3), by dot-blot hybridization with probe pTHG2, equivalent to 6.23,5.41, and 5.95% EP, respectively. These percentages translated to the presence of 3.59, 2.90 and 3.19 average-size EP chromosomes in plants H1 8-1,-2 and-3, respectively. RFLP determination of L. esculentum- and L. pennellii-specific chromosomes revealed that only fragments of eight to ten out of the 24 EP chromosomes (EP has 12 L. esculentum and 12 L. pennellii chromosomes) are present in the asymmetric somatic hybrid plants. Loci of L. esculentum and L. pennellii were evenly represented in plants H18-1, -2, and -3: four to five from L. esculentum and four to five from L. pennellii. All somatic hybrid plants retained locus TG22, chromosome 4, from both EP species. Although the regeneration of plants, H18-1, -2 and-3 was from one callus, loci TG31 and TG79 of L. esculentum chromosome 2 and L. pennellii chromosome 9, respectively, were missing in hybrid plant H18-1. The three somatic hybrid plants all had chloroplast DNA fragments specific for S. melongena. The mitochondrial genome (mtDNA) in the asymmetric somatic hybrids showed predominantly the pattern of eggplant; however, some eggplant-specific polymorphic bands were not present in the three plants. PMID- 24162229 TI - Variation of starch granule proteins and chromosome mapping of their coding genes in common wheat. AB - Starch granule proteins (SGPs) of common wheat (Triticum aestivum L.) were analyzed by two electrophoretic techniques: sodium dodecyl sulphate polyacrylamide-gel electrophoresis (SDS-PAGE) and two-dimensional electrophoresis (2D-PAGE). These analyses identified three kinds of SGPs which were tentatively designated SGP-1, SGP-2 and SGP-3. SDS-PAGE resolved the products of three homoeologous genes for SGP-1 into three protein fractions, SGP-A1, -B1 and -D1. While SDS-PAGE resolved SGP-3 into one fraction, 2D-PAGE separated it into three protein fractions encoded by homoeologous genes Sgp-A3, B3 and -D3. SGP-2 was detected as one protein by SDS-PAGE and was present as one protein on 2D-PAGE. Aneuploid (nullisomic-tetrasomic and ditelosomic) analyses in the cultivar Chinese Spring showed that the genes for two SGPs (SGP-1 and -3) were located on the short arms of group-7 chromosomes. The results obtained from deletion lines for chromosome arms 7AS, 7BS and 7DS suggested that the gene order along the arms is 'centromere-Sgp-1-Sgp-3-Wx'. An electrophoretic survey of wheat germ plasm identified a few cultivars lacking one of the proteins SGP-A1, -B1, -D1, SGP-A3 and -B3. The null alleles Sgp-A1b, Sgp-B1b and Sgp-D1b will be useful for the production of a variant wheat lacking SGP-1. PMID- 24162230 TI - Mapping loci controlling the concentrations of erucic and linolenic acids in seed oil of Brassica napus L. AB - The quality of plant oil is determined by its component fatty acids. Relatively high levels of linolenic acid reduce the oxidative stability of the oil, and high levels of erucic acid in the diet have been associated with health problems. Thus, oilseed Brassica napus cultivars with low linolenic and low erucic acid contents are highly desirable for edible oil production. In order to identify genes controlling the levels of erucic and linolenic acids, we analyzed the oil composition of 99 F1-derived doubled haploid lines from a cross between cv 'Major' (high levels of erucic and linolenic acids) and cv 'Stellar' (low levels of both fatty acids). A molecular marker linkage map of 199 loci for this population was used to identify quantitative trait loci (QTL) controlling oil composition. We identified two regions that accounted for nearly all of the phenotypic variation in erucic acid concentration and one region that accounted for 47% of the variation in linolenic acid concentration. The QTL associated with linolenic acid concentration mapped near a RFLP locus detected by a cDNA clone encoding an omega-3 desaturase, suggesting that the low linolenic acid content of 'Stellar' may be due to a mutation in this gene. PMID- 24162231 TI - Genetic steady-state under BLUP selection for an infinite and homogeneous population with discrete generations. AB - A matrix derivation is proposed to analytically calculate the asymptotic genetic variance-covariance matrix under BLUP selection according to the initial genetic parameters in a large population with discrete generations. The asymptotic genetic evolution of a homogeneous population with discrete generations is calculated for a selection operating on an index including all information (pedigree and records) from a non-inbred and unselected base population (BLUP selection) or on an index restricted to records of a few ancestral generations. Under the first hypothesis, the prediction error variance of the selection index is independent of selection and is calculated from the genetic parameters of the base population. Under the second hypothesis, the prediction error variance depends on selection. Furthermore, records of several generations of ancestors of the candidates for selection must be used to maintain a constant prediction error variance over time. The number of ancestral generations needed depends on the population structure and on the occurrence of fixed effects. Without fixed effects to estimate, accounting for two generations of ancestors is sufficient to estimate the asymptotic prediction error variance. The amassing of information from an unselected base population proves to be important in order not to overestimate the asymptotic genetic gains and not to underestimate the asymptotic genetic variances. PMID- 24162232 TI - Linkage mapping of prolamin and isozyme genes on the 1S(l) chromosome of Aegilops longissima. AB - The storage proteins and isozymes of two accessions of Aegilops longissima, and the F2 progeny from the cross between them, were analyzed. Six loci were identified on the 1S(l) chromosome: Glu-S (l) 1 (coding for HMW subunits of glutenin), Gpi-S (l) 1 (coding for a Gpi isozyme), Glu-S (l) 3 (coding for LMW subunits of glutenin), Gli-S (l) 1 (coding for gliadins) and two, so far, not described new loci Gli-S (l) 4 and Gli-S (l) 5. The Gli-S (l) 4 locus codes for a omega-gliadin and the Gli-S (l) 5 codes for a gliadin with mobility in the beta region. The genetical distances found between the six loci allowed the establishment of the following gene order on the 1S(l) chromosome: Glu-S (l) 1 centromere -Gpi-S (l) 1 - Gli-S (l) 4 - Gli-S (l) 3 - Gli-S (l) 1 -Gli-S (l) 5. PMID- 24162233 TI - Myosin light chain kinase controls voltage-dependent calcium channels in vascular smooth muscle. AB - The Ca(2+)-dependent kinase myosin light chain kinase (MLCK) is the activator of smooth muscle contraction. In addition, it has been reported to be involved in Ca(2+) channel regulation in cultured cells, and we previously showed that the MLCK inhibitor ML-7 decreases arginine vasopressin (AVP)-induced Ca(2+) influx in rat aorta. This study was designed to investigate whether MLCK is involved in Ca(2+) regulation in resistance artery smooth muscle cell, which plays a major role in the control of blood pressure. As ML compounds were shown to have off target effects, MLCK was downregulated by transfection with a small interfering RNA targeting MLCK (MLCK-siRNA) in rat small resistance mesenteric artery (RMA) and in the rat embryonic aortic cell line A7r5. Noradrenaline-induced contraction and Ca(2+) signal were significantly depressed in MLCK-siRNA compared to scramble siRNA-transfected RMA. Contraction and Ca(2+) signal induced by high KCl and voltage-activated Ca(2+) current were also significantly decreased in MLCK-siRNA transfected RMA, suggesting that MLCK depletion modifies voltage-operated Ca(2+) channels. KCl- and AVP-induced Ca(2+) signals and voltage-activated Ca(2+) current were decreased in MLCK-depleted A7r5 cells. Eventually, real-time quantitative PCR analysis indicated that in A7r5, MLCK controlled mRNA expression of CaV1.2 (L-type) and CaV3.1 (T-type) voltage-dependent Ca(2+) channels. Our results suggest that MLCK controls the transcription of voltage-dependent Ca(2+) channels in vascular smooth muscle cells. PMID- 24162236 TI - The formation of carbamate ions in interstellar ice analogues. AB - Carbon dioxide and ammonia are two of the most abundant species in astrophysical media, where they can react in the solid phase under certain conditions. This contribution presents a study of this reaction both in the presence of water and for anhydrous samples. It is shown that after deposition at 15 K, the reaction can start by warming the deposit, and the process continues on up to a temperature of 220 K. Reaction products are studied using infrared spectroscopy and mass spectrometry. For anhydrous samples, a 2 : 1 stoichiometry mixture of NH3 : CO2 gives the highest yield of products. The reaction is favored when a small amount of water is present, which enables ammonia and carbon dioxide molecules to collide within the pores and channels of the amorphous water solid. Large concentration of water, on the other hand, hampers such collisions. The main reaction product is found to be ammonium carbamate, but also carbamic acid is formed, and, in the presence of water, ammonium bicarbonate is produced as well. Theoretical calculations are carried out to provide the basis for the assignment of the spectra. Some of the experiments presented in this contribution consist of the generation of a compact water ice matrix where the carbamate and ammonium ions are embedded. If such a system was found in astrophysical media, it is shown that the ammonium ion could not be detected, whereas two infrared features of the carbamate ion in the 1040 to 1115 cm(-1) (9 to 9.6 MUm) region could enable the observation of this species. PMID- 24162235 TI - Mitochondrial Ca(2+) uniporter (MCU)-dependent and MCU-independent Ca(2+) channels coexist in the inner mitochondrial membrane. AB - A protein referred to as CCDC109A and then renamed to mitochondrial calcium uniporter (MCU) has recently been shown to accomplish mitochondrial Ca(2+) uptake in different cell types. In this study, we investigated whole-mitoplast inward cation currents and single Ca(2+) channel activities in mitoplasts prepared from stable MCU knockdown HeLa cells using the patch-clamp technique. In whole mitoplast configuration, diminution of MCU considerably reduced inward Ca(2+) and Na(+) currents. This was accompanied by a decrease in occurrence of single channel activity of the intermediate conductance mitochondrial Ca(2+) current (i MCC). However, ablation of MCU yielded a compensatory 2.3-fold elevation in the occurrence of the extra large conductance mitochondrial Ca(2+) current (xl-MCC), while the occurrence of bursting currents (b-MCC) remained unaltered. These data reveal i-MCC as MCU-dependent current while xl-MCC and b-MCC seem to be rather MCU-independent, thus, pointing to the engagement of at least two molecularly distinct mitochondrial Ca(2+) channels. PMID- 24162234 TI - TMEM16A knockdown abrogates two different Ca(2+)-activated Cl (-) currents and contractility of smooth muscle in rat mesenteric small arteries. AB - The presence of Ca(2+)-activated Cl(-) channels (CaCCs) in vascular smooth muscle cells (SMCs) is well established. Their molecular identity is, however, elusive. Two distinct Ca(2+)-activated Cl(-) currents (I Cl(Ca)) were previously characterized in SMCs. We have shown that the cGMP-dependent I Cl(Ca) depends on bestrophin expression, while the "classical" I Cl(Ca) is not. Downregulation of bestrophins did not affect arterial contraction but inhibited the rhythmic contractions, vasomotion. In this study, we have used in vivo siRNA transfection of rat mesenteric small arteries to investigate the role of a putative CaCC, TMEM16A. Isometric force, [Ca(2+)]i, and SMC membrane potential were measured in isolated arterial segments. I Cl(Ca) and GTPgammaS-induced nonselective cation current were measured in isolated SMCs. Downregulation of TMEM16A resulted in inhibition of both the cGMP-dependent I Cl(Ca) and the "classical" I Cl(Ca) in SMCs. TMEM16A downregulation also reduced expression of bestrophins. TMEM16A downregulation suppressed vasomotion both in vivo and in vitro. Downregulation of TMEM16A reduced agonist (noradrenaline and vasopressin) and K(+)-induced contractions. In accordance with the depolarizing role of CaCCs, TMEM16A downregulation suppressed agonist-induced depolarization and elevation in [Ca(2+)]i. Surprisingly, K(+)-induced depolarization was unchanged but Ca(2+) entry was reduced. We suggested that this is due to reduced expression of the L type Ca(2+) channels, as observed at the mRNA level. Thus, the importance of TMEM16A for contraction is, at least in part, independent from membrane potential. This study demonstrates the significance of TMEM16A for two SMCs I Cl(Ca) and vascular function and suggests an interaction between TMEM16A and L type Ca(2+) channels. PMID- 24162237 TI - Nucleic acid and protein extraction from electropermeabilized E. coli cells on a microfluidic chip. AB - Due to the extensive use of nucleic acid and protein analysis of bacterial samples, there is a need for simple and rapid extraction protocols for both plasmid DNA and RNA molecules as well as reporter proteins like the green fluorescent protein (GFP). In this report, an electropermeability technique has been developed which is based on exposing E. coli cells to low voltages to allow extraction of nucleic acids and proteins. The flow-through electropermeability chip used consists of a microfluidic channel with integrated gold electrodes that promote cell envelope channel formation at low applied voltages. This will allow small biomolecules with diameters less than 30 A to rapidly diffuse from the permeabilized cells to the surrounding solution. By controlling the applied voltage, partial and transient to complete cell opening can be obtained. By using DC voltages below 0.5 V, cell lysis can be avoided and the transiently formed pores can be closed again and the cells survive. This method has been used to extract RNA and GFP molecules under conditions of electropermeability. Plasmid DNA could be recovered when the applied voltage was increased to 2 V, thus causing complete cell lysis. PMID- 24162238 TI - Metastasis to the choroid plexus from thyroid cancer: case report. AB - Thyroid cancer is not a common primary cancer causing intracranial metastasis. Here we report a 74-year-old woman with magnetic resonance imaging (MRI) demonstrating a 4 cm round, heterogeneously enhancing mass in the trigone of the right lateral ventricle. Systemic screening by computed tomography (CT) examination detected a 20 mm nodule with calcification in the thyroid, multiple well circumscribed nodules in bilateral lung filed, and a bone metastasis to the right dorsal rib. Cerebral angiography demonstrated a hypervascular mass fed from anterior and posterior choroidal arteries. Tumor biopsy via parietal transcortical approach confirmed a thyroid carcinoma metastasis to the choroid plexus. Of the 33 reported cases of choroid plexus metastasis, 14 (42%) are from kidney and 3 (9%) from thyroid cancer, which appears to be overrepresented considering their prevalence among all brain metastasis. There may be seed-and soil relationship between thyroid cancer and choroid plexus. PMID- 24162239 TI - Skull parosteal lipoma with reactive hyperostosis: a case report. AB - A 50-year-old female presented with more than 20-year history of a large subcutaneous mass in the left parieto-occipital portion. Magnetic resonance (MR) imaging revealed the lipomatous mass to show a high signal intensity in both T1- and T2-weighted images. A part of the lipomatous lesion progressed into the underlying hyperostosis and skull. The preoperative diagnosis was skull invasion of a well-differentiated liposarcoma. The tumor was removed completely, including the underlying hyperostosis and skull. Microscopy confirmed a lipoma without any lipoblasts, which was firmly attached to the reactive hyperostosis, and islands of lipoma were involved in the underlying hyperostosis and skull cortex. A pathological diagnosis of parosteal lipoma with reactive hyperostosis was made. Long-term progression of parosteal lipoma may cause to involve the underlying hyperostosis and skull, and led to the diagnosis of invasion of a malignant tumor on MR imaging. PMID- 24162240 TI - Acquired pial and dural arteriovenous fistulae following superior sagittal sinus thrombosis in patients with protein S deficiency: a report of two cases. AB - Two patients with protein S deficiency with acquired multiple pial and dural arteriovenous fistulae (AVFs) following superior sagittal sinus (SSS) thrombosis are reported. Case 1 is a 38-year-old male with protein S deficiency who developed generalized seizure due to SSS thrombosis. Local fibrinolysis was achieved in the acute stage. His 10-month follow-up angiogram revealed an asymptomatic acquired dural AVF arising from the middle meningeal artery and the anterior cerebral artery with drainage to the thrombosed cortical vein in the right frontal lobe. Furthermore, his 2-year follow-up angiogram revealed a de novo pial AVF from the middle cerebral artery in the Sylvian fissure with drainage to the cortical vein initially thrombosed. However, this asymptomatic pial AVF caused bleeding in the ipsilateral cerebral hemisphere 12 years after onset, whereas the dural AVF spontaneously disappeared. Surgical disconnection was successfully performed to eliminate the source of hemorrhage. Case 2 is a 50 year-old male with a past history of SSS thrombosis with protein S deficiency who developed pulsatile tinnitus and generalized seizure. His angiogram showed a cortical dural AVF in the left parietal lobe and a sporadic dural AVF involving the right sigmoid sinus. The parietal lesion was eliminated by transarterial embolization followed by craniotomy. However, a de novo pial AVF emerged from the middle cerebral artery adjacent to the previously treated lesion. Of four cortical AVFs in two patients, thrombosis of cortical veins caused by protein S deficiency might play an important role in their formation. Long-term follow-up is required because this peculiar disorder has an unusual clinical course. PMID- 24162241 TI - Mechanisms of tumor development and anti-angiogenic therapy in glioblastoma multiforme. AB - Despite advances in surgical and medical therapy, glioblastoma multiforme (GBM) remains a fatal disease. There has been no significant increase in survival for patients with this disease over the last 20 years. Tumor vasculature formation and glioma cell invasion along the white matter tracts both play a pivotal role in glioma development. Angiogenesis and invasion are the major factors believed to be responsible for treatment resistance in tumors, and a better understanding of the glioma invasion and angiogenesis mechanisms will lead to the development of potential new treatments. In this review, we focus on the molecular characteristics of angiogenesis and invasion in human malignant glioma. We discuss bevacizumab and cilengitide, which are used to inhibit angiogenesis in GBM. PMID- 24162242 TI - Correlation of middle cerebral artery tortuosity with successful recanalization using the Merci retrieval system with or without adjunctive treatments. AB - The Merci retrieval system is a useful modality for the recanalization of acute cerebral artery occlusion. However, it remains unclear whether the tortuosity of the middle cerebral artery (MCA) plays a role in successful recanalization. In this study, we investigated the association between the shape of the horizontal MCA segment (M1) and successful recanalization using the Merci retrieval system with or without adjunctive treatments. Twenty-three patients with M1 occlusion underwent thrombectomy using the Merci retrieval system with or without adjunctive treatments between July 2010 and July 2012. The anteroposterior view of final angiograms was used to measure the M1 curve angles. M1 with a curve angle measuring < 100 degrees was defined as arch-type M1, whereas that with a curve angle measuring >= 100 degrees was defined as straight-type M1. Angiographic findings were evaluated on the basis of the thrombolysis in cerebral infarction grade; grade 2B or 3 corresponds to successful recanalization. Eight patients had arch-type M1 and 15 patients had straight-type M1. Successful recanalization was achieved in 2 patients (25%) with arch-type M1 and 12 patients (80%) with straight-type M1 (p = 0.023). The mean M1 curve angle was significantly greater in the 14 patients in whom successful recanalization was achieved than in the 9 patients in whom it was not achieved (129 +/- 21 degrees vs. 93 +/- 29 degrees , p = 0.002). Arch-type M1 was an independent predictive factor of unsuccessful recanalization (odds ratio, 0.045; 95% confidence interval, 0.03-0.696). A tortuous M1 was associated with unsuccessful recanalization by the Merci retrieval system, even when adjunctive treatments were used. PMID- 24162243 TI - Differential gene expression in relation to the clinical characteristics of human brain arteriovenous malformations. AB - Arteriovenous malformations (AVMs) of the central nervous system are considered as congenital disorders. They are composed of abnormally developed dilated arteries and veins and are characterized microscopically by the absence of a capillary network. We previously reported DNA fragmentation and increased expression of apoptosis-related factors in AVM lesions. In this article, we used microarray analysis to examine differential gene expression in relation to clinical manifestations in 11 AVM samples from Japanese patients. We categorized the genes with altered expression into four groups: death-related, neuron related, inflammation-related, and other. The death-related differentially expressed genes were MMP9, LIF, SOD2, BCL2A1, MMP12, and HSPA6. The neuron related genes were NPY, S100A9, NeuroD2, S100Abeta, CAMK2A, SYNPR, CHRM2, and CAMKV. The inflammation-related genes were PTX3, IL8, IL6, CXCL10, GBP1, CHRM3, CXCL1, IL1R2, CCL18, and CCL13. In addition, we compared gene expression in those with or without clinical characteristics including deep drainer, embolization, and high-flow nidus. We identified a small number of genes. Using these microarray data we are able to generate and test new hypotheses to explore AVM pathophysiology. Microarray analysis is a useful technique to study clinical specimens from patients with brain vascular malformations. PMID- 24162244 TI - Advantages of dose-dense methotrexate protocol for primary central nervous system lymphoma: comparison of two different protocols at a single institution. AB - The efficacy and toxicity of high-dose methotrexate (HD-MTX)-based chemotherapy were retrospectively reviewed in patients with primary central nervous system lymphoma (PCNSL). All immunocompetent patients with histologically or radiographically diagnosed PCNSL treated between 2006 and 2012 at Niigata University Hospital were enrolled. Thirty-eight patients with a diagnosis of PCNSL were treated with one of two regimens during different time periods. During the first period, from 2006 to 2009, three 3-week cycles of MPV (MTX + procarbazine + vincristine) were administered (MPV3 group). In the second period, from 2010 to 2012, five 2-week cycles of MTX were administered (MTX5 group). High dose cytarabine was used in both groups following HD-MTX-based chemotherapy. Whole-brain radiotherapy was used for patients who did not attain a complete response (CR) based on magnetic resonance images. In the MPV3 group, 20 out of 23 patients (87%) completed the planned treatment. The CR rate after chemotherapy was 30%, and 57% after radiation therapy. Thirteen out of 15 patients (87%) in the MTX5 group completed the planned treatment. The CR rates after chemotherapy and radiation therapy were 53% and 93%, respectively. Renal dysfunction was assessed by measuring creatinine clearance rates, which were very similar in both groups. In terms of hematologic toxicity and other adverse reactions, there was no significant difference between the two groups. In conclusion, dose-dense MTX chemotherapy improved outcome with acceptable toxicity compared with the treatment schedule for three cycles of MPV treatment. PMID- 24162245 TI - Commendable developments in deceased organ donation and transplantation in Iran. PMID- 24162246 TI - Concomitant proton pump inhibitors with mycophenolate mofetil and the risk of rejection in kidney transplant recipients. AB - BACKGROUND: Recent pharmacokinetic studies have demonstrated that proton pump inhibitors (PPI) reduce exposure of mycophenolic acid. However, the clinical significance of this drug-drug interaction on transplantation outcomes has not been determined. METHODS: This was a retrospective cohort study in kidney transplant recipients who were prescribed rabbit antithymocyte globulin, calcineurin inhibitor, mycophenolate mofetil, and steroids. We evaluated the impact of PPI use on the 1-year rates of biopsy-proven acute rejection (BPAR). RESULTS: Two hundred thirteen patients who were prescribed PPI were compared with 384 patients who were on standard acid-suppressive therapy with ranitidine. BPAR occurred in similar rates in both groups (15% vs. 12%; P=0.31). In a multivariable analysis, black race was associated with a higher risk of rejection (risk ratio [RR], 2.38; 95% confidence interval [CI], 1.41-4.03). While controlling for rejection risk factors, PPI exposure was associated with an increased risk of rejection in black patients (RR, 1.93; 95% CI, 1.18-3.16) but not in non-black patients (RR, 0.54; 95% CI, 0.19-1.49). At 1 year, BPAR type, BPAR grade, patient and graft survival, graft function, and time to BPAR were not associated with PPI exposure. CONCLUSION: In this retrospective study, PPI use in the first transplant year was associated with an increased risk for BPAR in black patients but not in non-black patients. It is possible that a reduction in mycophenolic acid exposure contributed to the increased risk. PMID- 24162248 TI - Immunosuppression regimen and the risk of acute rejection in HIV-infected kidney transplant recipients. AB - BACKGROUND: Kidney transplantation (KT) is the treatment for end-stage renal disease in appropriate HIV-positive individuals. However, acute rejection (AR) rates are over twice those of HIV-negative recipients. METHODS: To better understand optimal immunosuppression for HIV-positive KT recipients, we studied associations between immunosuppression regimen, AR at 1 year, and survival in 516 HIV-positive and 93,027 HIV-negative adult kidney-only recipients using Scientific Registry of Transplant Recipients data from 2003 to 2011. RESULTS: Consistent with previous reports, HIV-positive patients had twofold higher risk of AR (adjusted relative risk [aRR], 1.77; 95% confidence interval [CI], 1.45 2.2; P<0.001) than their HIV-negative counterparts as well as a higher risk of graft loss (adjusted hazard ratio, 1.51; 95% CI, 1.18-1.94; P=0.001), but these differences were not seen among patients receiving antithymocyte globulin (ATG) induction (aRR for AR, 1.16; 95% CI, 0.41-3.35, P=0.77; adjusted hazard ratio for graft loss, 1.54; 95% CI, 0.73-3.25; P=0.26). Furthermore, HIV-positive patients receiving ATG induction had a 2.6-fold lower risk of AR (aRR, 0.39; 95% CI, 0.18 0.87; P=0.02) than those receiving no antibody induction. Conversely, HIV positive patients receiving sirolimus-based therapy had a 2.2-fold higher risk of AR (aRR, 2.15; 95% CI, 1.20-3.86; P=0.01) than those receiving calcineurin inhibitor-based regimens. CONCLUSION: These findings support a role for ATG induction, and caution against the use of sirolimus-based maintenance therapy, in HIV-positive individuals undergoing KT. PMID- 24162249 TI - Uremic toxin development in living kidney donors: a longitudinal study. AB - BACKGROUND: Emerging evidence suggests that uremic toxins, in particular indoxyl sulfate (IS) and p-cresyl sulfate (PCS), may be involved in the pathogenesis of cardiovascular disease. Despite a significant increase in IS and PCS in patients with established kidney damage, the effect of a nephrectomy in non-chronic kidney disease patients is not yet known. METHODS: Forty-two living kidney donors (Caucasian; 76% female [n=32]; 53 +/- 10 years) were enrolled in an observational cohort study and followed up annually for 2 years (before nephrectomy, 1 and 2 years after nephrectomy). At each time point, patients underwent measurements of serum total and free IS and PCS (using ultrahigh-performance liquid chromatography), carotid intima-media thickness (a measure of arterial stiffness), brachial artery reactivity (both flow-mediated dilatation and sublingual glycerol trinitrate, markers of endothelial dysfunction), kidney function by Chronic Kidney Disease Epidemiology Collaboration creatinine-cystatin C, and urate and high-sensitivity C-reactive protein using standard laboratory techniques. RESULTS: Kidney function decreased by 30% after nephrectomy (absolute change estimated glomerular filtration rate 28 +/- 6.9 and 27 +/- 7.6 mL/min/1.73 m at 1 and 2 years, respectively), and the concentration of toxin levels increased by 44% to 100%, which remained elevated at 2 years after nephrectomy (all P<0.001). Both toxins were associated with carotid intima-media thickness, brachial artery reactivity-glycerol trinitrate, serum urate, and C-reactive protein levels (all P<0.03). Further, IS and urate were found to be independent predictors of change in kidney function, from baseline at 2 years after nephrectomy (both P<0.03). CONCLUSION: This study demonstrated significant and sustained increases in nephrovascular toxins, IS and PCS, after nephrectomy. Levels of both toxins were associated with clinically relevant markers of cardiovascular and renal risk, warranting further research in this area. PMID- 24162250 TI - Increased negative impact of donor HLA-specific together with non-HLA-specific antibodies on graft outcome. AB - BACKGROUND: De novo donor HLA-specific (dnDSA) and non-HLA antibodies including antiangiotensin type 1 receptor antibodies (AT1R-abs) have been associated with antibody-mediated rejection (AMR) and decreased graft survival as well as cellular-mediated rejection (CMR) and early onset of microvasculopathy in heart transplantation. The aim of our study was to determine the impact of anti-AT1R-ab and anti-donor HLA-specific antibody (DSA) on clinical outcomes. METHODS: Pretransplant and posttransplant sera from 200 recipients transplanted between May 2007 and August 2011 were tested for DSA (Luminex-based single antigen bead assay) and AT1R-ab (enzyme-linked immunosorbent assay). Two cutoff levels (>= 17 and >= 12 units) were used to define high and intermediate binding of AT1R-ab. Clinical parameters examined were 5-year AMR/CMR (>= grade 2), coronary artery vasculopathy, and survival. RESULTS: At 2 years after transplant, freedom from AMR and/or CMR was 95.4% for those with no DSA (n=175), 66.9% for those with dnDSA (n=19), and 25% for those with DSA at transplant (n=6) (P<0.0001). Neither >= 17 nor >= 12 units of pretransplant levels indicated a significant difference in freedom from AMR and/or CMR. When both dnDSA and AT1R-ab >= 17 or >= 12 units were considered, freedom from AMR and/or CMR decreased to 50% and 45% (P<0.0001), respectively. Coronary artery vasculopathy and survival were not significantly impacted. CONCLUSIONS: These results show the increased negative impact of dnDSA and AT1R-ab on freedom from AMR and/or CMR and an increased hazard ratio when both parameters are considered. Both HLA- and non-HLA-specific antibodies seem to impact graft outcome in heart transplantation. PMID- 24162251 TI - Extended spectrum beta-lactamase-producing Enterobacteriaceae infection in heart and lung transplant recipients and in mechanical circulatory support recipients. AB - BACKGROUND: Extended spectrum beta-lactamase (ESBL)-producing gram-negative bacilli are increasingly reported in patients with a variety of risk factors including prior cephalosporin and antibiotic usage, prolonged hospitalizations, existence of comorbid conditions, and critical illness. METHODS: Retrospective review of infections caused by ESBL-producing Enterobacteriaceae was performed in heart transplant (HTx), lung transplant (LTx), and mechanical circulatory support (MCS) device recipients at a large transplant center. RESULTS: Among 1065 patients transplanted/implanted, the incidence of ESBL-related infections (bacteremia, urinary tract infections, pneumonia, central venous catheter associated infection, and wound infections) in HTx, LTx, and MCS device recipients was reported at 2.2%, 5.5%, and 10.7%, respectively, caused by ESBL producing Klebsiella pneumoniae, Escherichia coli, Klebsiella oxytoca, and Citrobacter freundii. CONCLUSIONS: Early detection and adequate duration of therapy for ESBL-producing Enterobacteriaceae in solid organ transplants and MCS device recipients are essential in successful patient outcomes including prevention of recurrent infection. PMID- 24162253 TI - En bloc kidneys transplanted from infant donors less than 5 kg into pediatric recipients. AB - BACKGROUND: Given the shortage of donor kidneys, the use of grafts from deceased infant donors is a potential approach to expand the donor pool. Four infant en bloc kidney transplants in pediatric recipients were reported, performed between 2012 and 2013 in the center. METHODS: The en bloc graft was implanted extraperitoneally in the right iliac fossa. The distal end of the donor aorta was anastomosed end-to-end to the internal iliac artery, while the donor vena cava was anastomosed (end-to-side) to the external iliac vein. Both ureters were anastomosed individually to the bladder, with the exception of one case in which a donor bladder patch was anastomosed to the bladder. After the operation, the recipients received basiliximab as induction therapy followed by tacrolimus and mycophenolic acid for immunosuppression. Prophylactic anticoagulation was used postoperatively. RESULTS: Recipients included two girls and two boys with age ranging from 4.6 to 11.6 years. Donor age ranged from 33 to 56 days with weight ranging from 2.5 to 5.0 kg. After a follow-up of 2 to 14 months, patient and graft survivals were 100% and 75%, respectively. Complications included delayed graft function in one patient, urine leak in one, and anticoagulation-related hemorrhage in one. One graft was lost early from vascular thrombosis. The remaining three recipients had excellent graft function with median serum creatinine of 1.1 mg/dL (range, 0.8-1.3 mg/dL) at last follow-up. CONCLUSIONS: Promising outcomes can be obtained from en bloc transplantation from infant donors. The use of this donor population for pediatric recipients should be encouraged. PMID- 24162254 TI - Influence of anemia on patient and graft survival after renal transplantation: results from the French DIVAT cohort. AB - BACKGROUND AND OBJECTIVES: Contradictory results are reported concerning the influence of anemia on patient and graft survival after renal transplantation. Assuming that level of renal function and anemia are strongly correlated, posttransplantation anemia (PTA) may have a different impact depending on the stage of chronic kidney disease (CKD). METHODS: This study is a retrospective multicenter analysis using the DIVAT French database. The prevalence, risk factors, and influence of 12-month PTA (World Health Organization's definition) on patient and graft survival were analyzed according to CKD stage (Modification of Diet in Renal Disease equation). RESULTS: The prevalence of 12-month PTA in our cohort of 4217 patients was 41.1%. Multivariate analysis demonstrated that worse renal function, donor age, period of transplantation, induction therapy, and mTOR inhibitors were significant risk factors for PTA. Posttransplantation anemia was a significant risk factor for all-cause mortality in CKD stages 1 to 2T (hazard ratio, 2.39; 95% confidence interval, 1.99-4.40) and 3T (hazard ratio, 1.52; 95% confidence interval, 1.08-2.15) and for cardiovascular mortality only on CKD stages 1T and 2T. In renal transplant recipients with CKD stages 4 to 5T, patient and graft survival were similar in patients with versus without anemia. Graft survival was not influenced by PTA, whatever the CKD stage. CONCLUSIONS: Posttransplantation anemia is associated with decreased patient survival only in CKD stages 1T, 2T, and 3T. Posttransplantation anemia has no influence on graft survival regardless of CKD stage. PMID- 24162255 TI - Evidence supporting a 1,2-dioxetanone as an intermediate in the benzofuran-2(3H) one chemiluminescence. AB - The mechanism of the chemiluminescent reaction of ethyl (5-fluoro-2-oxo-2,3 dihydrobenzofuran-3-yl) carbamate (a 2-coumaranone derivative) with a base and molecular oxygen was investigated. New evidence from the reaction kinetics and absorption/emission profiles was obtained, supporting the existence of a 1,2 dioxetanone as an intermediate: (i) its characteristic activation parameters (DeltaH(?) = 7.2 +/- 0.1 kcal mol(-1); DeltaS(?) = -45 +/- 5 cal K(-1) mol(-1)) indicating a high degree of thermal instability and (ii) its bimolecular decomposition rate constant for the reaction with perylene. The newly developed methodology has been shown to be suitable for determining the reactivity of such thermally unstable peroxides, which are very difficult to prepare and isolate, using this alternative approach of in situ generation of a 1,2-dioxetanone. PMID- 24162256 TI - Staphylococcus aureus genomic pattern and atopic dermatitis: may factors other than superantigens be involved? AB - The purpose of this investigation was to compare the genotypic profiles of Staphylococcus aureus isolated from atopic dermatitis (AD) patients and from control subjects, and to study the relationship between clinical severity, immune response, and genomic pattern of S. aureus isolated from AD patients. We selected 32 patients with AD and S. aureus skin colonization and 31 atopic controls with no history of AD who where asymptomatic carriers of S. aureus. Microarray-based genotyping was performed on S. aureus isolates. In AD patients, clinical severity was assessed using the Scoring Atopic Dermatitis index and total IgE levels and staphylococcal superantigen-specific IgE levels (SEA, SEB, SEC, TSST1) were determined. The genes lukE, lukD, splA, splB, ssl8, and sasG were more frequent in isolates from AD patients. CC30 was more common in isolates from atopic controls than in AD patients. There was a correlation between total IgE and clinical severity, but an association between clinical severity, immune response, and the presence of S. aureus superantigen genes, including enterotoxin genes, could not be demonstrated. Finally, a correlation was found between AD severity and other S. aureus genes, such as sasG and scn. S. aureus factors besides superantigens could be related to the worsening and onset of AD. PMID- 24162257 TI - PITX2 and non-canonical Wnt pathway interaction in metastatic prostate cancer. AB - The non-canonical Wnt pathway, a regulator of cellular motility and morphology, is increasingly implicated in cancer metastasis. In a quantitative PCR array analysis of 84 Wnt pathway associated genes, both non-canonical and canonical pathways were activated in primary and metastatic tumors relative to normal prostate. Expression of the Wnt target gene PITX2 in a prostate cancer (PCa) bone metastasis was strikingly elevated over normal prostate (over 2,000-fold) and primary prostate cancer (over 200-fold). The elevation of PITX2 protein was also evident on tissue microarrays, with strong PITX2 immunostaining in PCa skeletal and, to a lesser degree, soft tissue metastases. PITX2 is associated with cell migration during normal tissue morphogenesis. In our studies, overexpression of individual PITX2A/B/C isoforms stimulated PC-3 PCa cell motility, with the PITX2A isoform imparting a specific motility advantage in the presence of non-canonical Wnt5a stimulation. Furthermore, PITX2 specific shRNA inhibited PC-3 cell migration toward bone cell derived chemoattractant. These experimental results support a pivotal role of PITX2A and non-canonical Wnt signaling in enhancement of PCa cell motility, suggest PITX2 involvement in homing of PCa to the skeleton, and are consistent with a role for PITX2 in PCa metastasis to soft and bone tissues. Our findings, which significantly expand previous evidence that PITX2 is associated with risk of PCa biochemical recurrence, indicate that variation in PITX2 expression accompanies and may promote prostate tumor progression and metastasis. PMID- 24162259 TI - Diffusion tensor imaging in traumatic optic tract syndrome. PMID- 24162258 TI - Retinal nerve fiber layer thickness, brain atrophy, and disability in multiple sclerosis patients. AB - OBJECTIVE: To study the relationship between retinal nerve fiber layer (RNFL) thickness and brain atrophy using magnetic resonance imaging (MRI) with bicaudate ratio (BCR) in patients with multiple sclerosis (MS) with different levels of disease severity. We also assessed whether RNFL thickness correlated with Expanded Disability Status Scale (EDSS) score. METHODS: The participants consisted of 88 patients with MS and 59 age- and sex-matched healthy control subjects. Eleven patients had clinically isolated syndrome (CIS), 68 patients had relapsing-remitting MS (RR-MS), and 9 patients had secondary progressive MS. Patients and controls were evaluated using optical coherence tomography (OCT, Cirrus) and scanning laser polarimetry with variable corneal compensation (GDx VCC). Patients underwent the same brain MRI scanning protocol. Disability was evaluated according to the EDSS. The BCR was calculated by dividing the minimum intercaudate distance by brain width along the same level. RESULTS: The BCR was higher in patients with MS (0.12 +/- 0.03) than in controls (0.08 +/- 0.009) (P < 0.001). OCT average RNFL thickness in patients with MS was significantly lower (84.51 +/- 14.27 MUm) than in control subjects (98.44 +/- 6.83 MUm). BCR was correlated with OCT average RNFL thickness (r = -0.48, P = 0.002) in patients with MS without optic neuritis. Significant correlations were found between average RNFL thickness and EDSS (r = -0.43, P = 0.003). Additionally, there were correlations between BCR with GDx parameters in patients with MS without optic neuritis. CONCLUSIONS: This study shows that RNFL thickness correlates with BCR and with MS subtypes. Additionally, our study indicates that OCT is better suited for MS assessment than GDx. We conclude that the damage of retinal axons appears related to brain damage in patients with MS. PMID- 24162260 TI - Delaying skeletal-related events in a randomized phase 3 study of denosumab versus zoledronic acid in patients with advanced cancer: an analysis of data from patients with solid tumors. AB - PURPOSE: Bone complications of metastatic disease, including skeletal-related events (SREs), impair patients' functioning and quality of life. In a randomized, phase 3 trial of 1,776 patients with metastases from solid tumors (except breast or prostate) or multiple myeloma, denosumab was non-inferior to zoledronic acid (ZA) in delaying or preventing SREs. This ad hoc analysis reports outcomes in the subgroup of 1,597 patients with solid tumors, excluding patients with multiple myeloma. METHODS: Patients received monthly subcutaneous denosumab 120 mg or intravenous ZA 4 mg, adjusted for creatinine clearance, with calcium and vitamin D supplementation recommended. Endpoints included times to first on-study SRE, first-and-subsequent SREs, and pain worsening. RESULTS: Denosumab significantly delayed time to first on-study SRE compared with ZA (HR, 0.81; 95 % CI, 0.68 0.96) and time to first-and-subsequent SREs (RR, 0.85; 95 % CI, 0.72-1.00). Denosumab also significantly delayed time to development of moderate or severe pain (HR, 0.81; 95 % CI, 0.66-1.00), pain worsening (HR, 0.83; 95 % CI, 0.71 0.97), and worsening pain interference in patients with no/mild baseline pain (HR, 0.77; 95 % CI, 0.61-0.96). Adverse event rates were 96 % in both groups. Grade 3 or 4 hypocalcemia, mostly without clinical sequelae, was more frequent in denosumab-treated patients (denosumab 4 %, ZA 2 %). Osteonecrosis of the jaw occurred infrequently (denosumab 0.8 %, ZA 1.1 %). CONCLUSIONS: Denosumab was more effective in delaying or preventing SREs in patients with bone metastases from solid tumors and also prevented pain progression compared to ZA in this ad hoc analysis. PMID- 24162262 TI - Immunohistochemical expression of ERalpha, ERbeta, and TFF1 in type I and II ovarian tumors. AB - Surface epithelial tumors of the ovary are no longer considered as a single disease but are divided into types I and II on the basis of their molecular features, cell of origin, and their behavior. A possible direct action of gonadal steroids on ovarian carcinogenesis has been suggested. The current information about the possible role of TFF1 in ovarian tumors,, together with its relationship to the estrogen receptor (ER) status, is insufficient. The aim of this study was to investigate ERalpha, ERbeta, and TFF1 expression in type I and II ovarian tumors and their correlation with clinicopathologic parameters of each type. The present study was carried out on 97 ovarian tumors [20 benign, 15 borderline, and 62 malignant (36 type I and 26 type II tumors)]. ERalpha expression was significantly in favor of type II tumors (P=0.04), whereas high TFF1 expression was significantly in favor of type I tumors (P=0.02). ERalpha and ERbeta showed a significant positive correlation in benign cases (P=0.004) and in type I tumors (P=0.006), but not in type II tumors. In type I tumors, the expression of ERalpha was correlated with serous carcinoma (P=0.002) and bilaterality (P=0.05), whereas TFF1 was correlated with mucinous carcinoma (P=0.02), unilaterality (P=0.04), early FIGO staging (P=0.01), and a low mitotic count (P=0.03). A high ERbeta:ERalpha H score ratio was associated with advanced FIGO staging in both type I (P=0.05) and type II tumors (P=0.009). The difference in the expression of ERalpha and TFF1 between type I and II tumors may be indicative of the difference in their origin and molecular pathway. The ERbeta:ERalpha ratio is more important in determining the net result of ER effects than the evaluation of each receptor separately, and the high ratio may promote progression to advanced stage in type I and II ovarian tumors. High TFF1 expression in ovarian mucinous carcinoma may indicate that their mucinous differentiation is toward an intestinal type rather than an endocervical type. TFF1 expression in ovarian tumors seems to occur independent of the status of the ER. PMID- 24162261 TI - Automated objective determination of percentage of malignant nuclei for mutation testing. AB - Detection of DNA mutations in tumor tissue can be a critical companion diagnostic test before prescription of a targeted therapy. Each method for detection of these mutations is associated with an analytic sensitivity that is a function of the percentage of tumor cells present in the specimen. Currently, tumor cell percentage is visually estimated resulting in an ordinal and highly variant result for a biologically continuous variable. We proposed that this aspect of DNA mutation testing could be standardized by developing a computer algorithm capable of accurately determining the percentage of malignant nuclei in an image of a hematoxylin and eosin-stained tissue. Using inForm software, we developed an algorithm, to calculate the percentage of malignant cells in histologic specimens of colon adenocarcinoma. A criterion standard was established by manually counting malignant and benign nuclei. Three pathologists also estimated the percentage of malignant nuclei in each image. Algorithm #9 had a median deviation from the criterion standard of 5.4% on the training set and 6.2% on the validation set. Compared with pathologist estimation, Algorithm #9 showed a similar ability to determine percentage of malignant nuclei. This method represents a potential future tool to assist in determining the percent of malignant nuclei present in a tissue section. Further validation of this algorithm or an improved algorithm may have value to more accurately assess percentage of malignant cells for companion diagnostic mutation testing. PMID- 24162263 TI - Whole-slide, quadruple immunofluorescence labeling of routinely processed paraffin sections. AB - Whole-slide images (WSI) have acquired a stable place in diagnostic histopathology and immunohistochemistry. Immunofluorescence (IF) techniques hold a limited and selective role in diagnostics (eg, renal and cutaneous pathology) and so far remain excluded from the digital pathology evolution, with notable exceptions, such as quantitative immunopathology. We explored the ability of a commercial fluorescent slide scanner to provide 4-color IF WSI from routinely processed tissues. With minor modifications and a careful match between filters and fluorochromes, we show that 4-color IF WSI can be obtained from routine material with negligible autofluorescence, good sensitivity, and diagnostic power. PMID- 24162265 TI - The pattern of expression and role of triiodothyronine (T3) receptors and type I 5'-deiodinase in breast carcinomas, benign breast diseases, lactational change, and normal breast epithelium. AB - AIM: : To study the pattern of expression of triiodothyronine (T3) receptors and type I 5'-deiodinase in various breast pathologies comparing malignant and nonmalignant epithelia that include lactational change. METHODS AND RESULTS: A retrospective study was performed on formalin-fixed, paraffin-embedded archival material from 146 cases of carcinomas, normal breast tissue, breast tissue showing lactational change, and benign breast lesions. Archive tissue blocks were selected and sections were cut for immunohistochemistry to study the expression of thyroid hormone receptor alpha-1 (THR-alpha1) in the cytoplasm and nuclei of cells in tissues under study. Thick sections were cut for type I 5'-deiodinase evaluation using reverse transcriptional PCR.THR-alpha1 showed no nuclear expression in the carcinoma group. Combined nuclear and cytoplasmic expression was seen in 47.6%, 63.4%, 64.3%, and 58.3% in the benign, fibrocystic, fibroadenoma, and lactational change groups, respectively, compared with only 17.4% of cases in the carcinoma group. This suggests deregulation of the thyroid hormone in breast cancer. Theories for the possible role of thyroid hormone in the pathogenesis of breast cancer are discussed.Type I 5'-deiodinase was not shown to be differentially expressed in malignant versus nonmalignant groups. CONCLUSIONS: Our study revealed substantial reduction in the protein expression profile of THRs in malignant versus nonmalignant mammary epithelium suggesting a possible role in breast cancer development. The presence of THRs in mammary epithelium seems to be protective against the development of breast cancer. This could serve as a potential prognostic and therapeutic target for breast cancer. PMID- 24162264 TI - The characteristics of breast cancer subtypes: implications for treatment guidelines and individualized treatment strategies in China. AB - This study aimed at investigating the characteristics of invasive breast cancer among molecular subtypes. Patients with invasive breast cancer, with complete information on the expressions of estrogen receptor, progesterone receptor, and human epidermal growth factor receptor-2 (HER2), were recruited. chi tests and an unconditional logistic regression model were used for statistical analysis. The percentages of luminal A, luminal B, HER2/neu, and triple-negative subtypes were 54.2% (1639/3021), 14.0% (422/3021), 8.9% (269/3021), and 22.9% (691/3021), respectively. Differences among molecular subtypes (P<0.05) in tumor size, stage, pathologic type, and lymph node status were observed. The HER2/neu, luminal B, and triple-negative subtypes were more aggressive compared with the luminal A subtype in tumor stage, lymph node status, or pathologic type (P<0.05), when the findings were adjusted for age. Molecular subtypes were distributed differently between both age groups and regional groups on the basis of the socioeconomic status (P<0.05). In conclusion, luminal A and triple-negative subtypes were the 2 main subtypes of invasive breast cancer in China. The variations of molecular subtypes in pathology, age, and regional distribution may give some suggestions for updating treatment guidelines and individualized treatment strategies in China. PMID- 24162266 TI - Ancillary diagnostic techniques in the evaluation of adult epithelial renal neoplasms: indications, caveats, and pitfalls. AB - The role played currently by the different ancillary diagnostic techniques in the diagnosis of adult epithelial renal tumors continues to be debated. It has also become clear that in some instances light microscopic appearance alone cannot be used to classify these neoplasms into specific categories with the degree of precision required for therapeutic purposes. Renal cell carcinoma (RCC) subtypes may share common histologic characteristics but exhibit different biological behavior and response to therapy which clearly indicates the crucial role that advanced pathologic speciation plays in the current assessment of these neoplasms. Although immunohistochemistry is widely used for the purpose of categorizing renal tumors because of its widespread availability, the immunoprofiles of the various types of renal neoplasms overlap significantly, making definitive diagnostic determinations difficult and challenging at times. This manuscript will address how ancillary diagnostic techniques can be incorporated into the routine evaluation of neoplastic renal masses to improve classification. Both cytology and surgical specimens will be addressed, as fine needle aspiration (FNA) is being used with preference in many cases in the diagnosis of renal masses. Surgical and cytopathologists must intelligently select the ancillary diagnostic technique/s that will provide the information needed to solve the differential diagnosis under consideration in a given case. However, in some cases >1 of these techniques should be used to make an accurate diagnosis with the aim of arriving at an unequivocal diagnosis. The identification of specific signaling pathways that are defective in certain types of renal neoplasms has made possible the design of target-specific therapies that are directed towards the aberrant pathways associated with the defective proteins found in these tumors. This makes the exact classification of these neoplasms and the detection of these aberrant proteins targeted for treatment an absolute requirement for the application of these molecular-based therapeutic interventions. The role that the pathologic assessment plays in the classification of renal tumors becomes more important than ever to take advantage of this and similar new molecular-oriented therapies. PMID- 24162267 TI - The microvascular anatomy of the talus: a plastination study on the influence of total ankle replacement. AB - PURPOSE: The purpose of our study was to systematize the arterial supply of the talus and characterize the vessel damage occurring in the talus after total ankle replacement. Previous studies exist using vascular injection to visualize the topic [Giebel et al. (Surg Radiol Anat 19:231-235, 1997); Mulfinger and Trueta (J Bone Joint Surg Br 52:160-167, 1970); Peterson et al. (Acta Orthop Scand 46:1026 1034, 1975); Peterson and Goldie (Acta Orthop Scand 45:260-270, 1974)]. The vascularization of the talus has previously been described by various authors [Aquino et al. (J Foot Surg 25:188-193, 1986); Haliburton et al. (J Bone Joint Surg Am 40:1115-1120, 1958); Mulfinger and Trueta (1970); Peterson et al. (1975); Wildenauer (Z Orthop Ihre Grenzgeb 113:730, 1975)]. The plastination method provides excellent intraosseous view of the arterial system and offers a helpful method to demonstrate the influence of the Scandinavian Total Ankle Replacement (STAR) on the blood vessels. METHODS: In a first step, the nutritive foramina were analyzed on 20 macerated cadaver feet. After this, the articular surface was measured with a print using Optosil. The next step was the visualization of the vascularization of the talus using the plastination method. After vascular injection, a STAR was implanted in two specimens and a plastination was done. RESULTS: The highest amount and density of nutritive foramina were found in the sulcus tali. Using the imprint technique for the examined tali, we found a mean area covered by cartilage of 56.9% in comparison to the total surface. The deep fin of STAR has the potential to eliminate important blood vessels of the talus. CONCLUSION: The plastination methods were useful methods to analyze the arterial supply of the talus. In our study, the STAR showed a dominant influence on the vascularization of the talus. The fin appeared to be too long. A design modification with a short fin could provide the arterial supply, but should be tested biomechanically. PMID- 24162268 TI - Is pneumosinus dilatans an osteogenic disease that mimics the formation of a paranasal sinus? AB - PURPOSE: Pneumosinus dilatans is a disease that produces an abnormal expansion of a paranasal sinus cavity, which contains only air and is lined by normal mucosa, and whose bony walls are displaced outwardly to cause facial embossing or intracranial, orbital or ethmoidal encroachment. Objective was to evaluate the hypothesis that pneumosinus dilatans is primarily an osteogenic disease. METHODS: A detailed clinical history of three consecutive patients with pneumosinus dilatans was taken. Each patient also underwent computed tomography (CT), fluorine-deoxyglucose positron emission tomography-CT (FDG PET-CT), fluorine 18 labeled sodium fluoride PET-CT (NaF PET-CT), and bone pathology. RESULTS: The FDG PET-CT and pathology confirmed that the mucosa inside the pneumosinus dilatans was normal and devoid of inflammatory cell infiltrate. Significant uptake of (18)F-NaF on PET-CT images correlated well with bone pathology, showing intense and diffuse bone remodeling. At a 1-year follow-up, following a frontotomy for case #1 and a middle antrostomy for case #2, there was a marked resolution of the patients' clinical symptoms and deformities, new bone formation on the walls, stabilization of the new sinus shape and volume, and persistence of significant uptake of (18)F-NaF. CONCLUSIONS: Pneumosinus dilatans is a rare disease. Its diagnosis is based on CT scan images. This study has shown that (18)F-NaF PET-CT and bone pathology are useful modalities for the positive diagnosis of difficult cases. Pneumosinus dilatans appears to be an osteogenic disease. Further research is needed to investigate a possible link between mechanisms involved in paranasal sinus formation and those involved in pneumosinus dilatans. PMID- 24162269 TI - Enhanced near-infrared photocatalysis of NaYF4:Yb, Tm/CdS/TiO2 composites. AB - The previous works by our group (Chem. Commun., 2010, 46, 2304-2306; ACS Catal., 2013, 3, 405-412; Phys. Chem. Chem. Phys., 2013, 15, 14681-14688) have reported the near-infrared-driven photocatalysis of broadband semiconductor TiO2 or ZnO that was combined with upconverting luminescence particles to form a core-shell structure. However, the photocatalytic efficiency is low for this new type of photocatalysts. In this work, NaYF4:Yb,Tm/CdS/TiO2 composites for NIR photocatalysis were prepared by linking CdS and TiO2 nanocrystals on the NaYF4:Yb,Tm microcrystal surfaces. CdS and TiO2 were well interacted to form a heterojunction structure. The energy transfer between NaYF4:Yb,Tm and the semiconductors CdS and TiO2 was investigated by steady-state and dynamic fluorescence spectroscopy. The photocatalytic activities of the as-prepared composites were evaluated by the degradation of methylene blue in aqueous solution upon NIR irradiation. Significantly, it was found that the united adhesions of CdS and TiO2 on the NaYF4:Yb,Tm particle surfaces showed much higher catalytic activities than the individual adhesion of CdS or TiO2 on the NaYF4:Yb,Tm surfaces. This was attributed mainly to the effective separation of the photogenerated electron-hole pairs due to the charge transfer across the CdS TiO2 interface driven by the band potential difference between them. The presented composite structure of upconverting luminescence materials coupled with narrow/wide semiconductor heterojunctions provides a new model for improved NIR photocatalysis. PMID- 24162271 TI - Mesenchymal stem cells and granulomas in Crohn's disease and intestinal tuberculosis: the way forward. PMID- 24162270 TI - Intercellular adhesion molecular-1, Fas, and Fas ligand as diagnostic biomarkers for acute allograft rejection of pancreaticoduodenal transplantation in pigs. AB - BACKGROUND: The early diagnosis of pancreas allograft dysfunction is crucial for the management and long-term survival of transplanted pancreases. We investigated whether intercellular adhesion molecular-1 (ICAM-1), Fas, and Fas ligand (FasL) can be used as novel biomarkers of acute pancreaticoduodenal allograft dysfunction in pigs. METHODS: Forty outbred landraces were randomly divided into three groups. In the control group (8 pigs), a sham operation was performed but no drugs were administered. In groups 1 and 2 (8 pairs each), pancreaticoduodenal transplantation was performed, with the latter administered immunosuppressive drugs and the former not administered drugs. The expression of ICAM-1, Fas, and FasL mRNA in the peripheral vein blood was assessed by flow cytometry and RT-PCR, pre-transplant and on days 1, 3, 5, and 7 after transplantation. Simultaneously, the levels of glucose, insulin, and glucagon in the serum of the recipients were evaluated. The allograft pancreas tissue was obtained to assess the pathological damage and the expression of Fas and FasL by immunohistochemistry. RESULTS: On the first 7 days after transplantation, ICAM-1, Fas, and FasL mRNA expression in the blood leukocytes of the recipient increased significantly in groups 1 and 2 compared with the control group (P < 0.01). However, the levels in group 2 were significantly lower than those in group 1 (P < 0.05). Interestingly, the FasL expression increased but the Fas expression decreased gradually in the graft pancreas tissue during the first week after transplantation in both groups 1 and 2 compared with the control group (P < 0.05). The levels of serous glucose, insulin, and glucagon in groups 1 and 2 obviously changed on day 1 after transplantation but returned to normal on day 2. The recipient's pancreas pathological sections did not exhibit any rejection changes on days 1 and 3 after transplantation but showed rejection damage on days 5 and 7. CONCLUSION: ICAM-1, Fas, and FasL were found to be sensitive biomarkers of acute pancreas allograft dysfunction after pancreaticoduodenal transplantation in pigs, and their monitoring could be used to evaluate the effectiveness of the immunosuppression therapy. PMID- 24162272 TI - Appropriateness of laboratory testing in inflammatory bowel disease inpatients: an opportunity to reduce unnecessary healthcare costs. PMID- 24162273 TI - New roles of serotonin and tachykinins in intestinal mucositis? PMID- 24162275 TI - Oxidation and ignition of aluminum nanomaterials. AB - The oxidation and ignition of aluminum nanoparticles with a mean diameter of 150 nm are investigated with the help of simultaneous thermal analysis, X-ray powder diffraction, energy dispersive X-ray spectra analysis (EDS) and scanning and transmission electron microscopy at heating rates of 2-30 K min(-1). A unique early ignition reaction is observed when the heating rate is >=8 K min(-1) and there is a co-existence of various polymorphs of alumina (gamma-, delta-, theta-, and alpha-Al2O3) below the melting temperature of aluminum nanoparticles. It is proposed that such an early ignition reaction is due to a combined effect of solid phase transformation of the alumina shell and the early melting of the aluminum core, and is responsible for the co-existence of various polymorphs of alumina at the low temperature. The ignition temperature increases approximately with the increase of the heating rate. Regardless of the heating rate, the oxidation scenario can be described by a three-stage reaction with the main reaction occurring before the melting of aluminum nanoparticles. PMID- 24162274 TI - Effective tuberculosis and hepatitis screening prior to anti-TNF-alpha therapy: are we there yet? PMID- 24162276 TI - Empathy in palliative care: is it possible to understand another person? PMID- 24162278 TI - Role of the nurse practitioner in providing palliative care in long-term care homes. AB - AIM: The purpose of this study, which was part of a large national case study of nurse practitioner (NP) integration in long-term care (LTC), was to explore the NP role in providing palliative care in LTC. METHODS: Using a qualitative descriptive design, data was collected from five LTC homes across Canada using 35 focus groups and 25 individual interviews. In total, 143 individuals working in LTC participated, including 9 physicians, 20 licensed nurses, 15 personal support workers, 19 managers, 10 registered nurse team managers or leaders, 31 allied health care providers, 4 NPs, 14 residents, and 21 family members. The data was coded and analysed using thematic analysis. FINDINGS: NPs provide palliative care for residents and their family members, collaborate with other health-care providers by providing consultation and education to optimise palliative care practices, work within the organisation to build capacity and help others learn about the NP role in palliative care to better integrate it within the team, and improve system outcomes such as accessibility of care and number of hospital visits. CONCLUSIONS: NPs contribute to palliative care in LTC settings through multifaceted collaborative processes that ultimately promote the experience of a positive death for residents, their family members, and formal caregivers. PMID- 24162279 TI - Family members' perceptions and expectations of the use of syringe drivers: a South African study. AB - AIM: This study aimed to explore and gain insight into the perceptions and expectations of family members of terminally ill patients pertaining to the use of syringe drivers. BACKGROUND: There is a lack of research regarding the use of syringe drivers in Africa and, more specifically, South Africa. However, syringe drivers have been in use for around two decades in some South African settings. Some family members' ambivalence about the use of syringe drivers and the lack of research prompted this study. METHOD: A qualitative exploratory research design was used. Data was collected using semi-structured interviews, diaries, observation, and documentation. Thematic analysis and coding were used to analyse the data. RESULTS: Four main themes were identified: the rationale for the need for the syringe driver, positive perceptions pertaining to the use of the syringe driver, negative perceptions, and concerns/anxieties. The study also highlighted the challenges of drug addiction in some households when caring for terminally ill patients. CONCLUSION: The need for more continuous education and written information and support for immediate and extended family members was evident. PMID- 24162280 TI - Parents' perspectives on the deaths of their children in two Brazilian paediatric intensive care units. AB - OBJECTIVES: To evaluate the quality of care offered to terminally ill children and their families in the last days of life in two Brazilian Paediatric Intensive Care Units (PICUs) from the parents' perspectives. METHODS: This was a qualitative, exploratory study. Parents of a child who had died in one of the PICUs 6-12 months previously were invited to take part in two interviews: a private meeting with the PICU assistant physician who cared for their child, to discuss and review any outstanding issues related to the diagnosis, treatment, and prognosis, and a recorded interview with a researcher who was not involved in the child's treatment. Data from the interviews with the researcher were posteriorly grouped in categories according to recurrent terms. RESULTS: Six categories emerged, three of which are reported here. The quality of communication was low; the medical staff frequently used technical terms, limiting understanding. Parental participation in the decision-making process was scarce; decisions were based on the medical perspective. Finally, families reported uncompassionate attitudes from the medical staff and excessive technology in the final moments surrounding the child's death, although nurses were highly involved with palliative care measures and demonstrated sympathetic and supportive postures. CONCLUSION: The interviews uncovered deficiencies in the care provided to parents in the PICUs, indicating a need for changes in practice. PMID- 24162281 TI - Validation of the Japanese version of the Fatigue Barriers Scale (JFBS). AB - BACKGROUND: The Fatigue Barriers Scale (FBS) is an instrument to identify patient derived barriers to fatigue management. OBJECTIVE: To assess the reliability and validity of the Japanese version of the FBS (JFBS). METHODS: Participants were 112 cancer patients. Reliability was determined through internal consistency using Cronbach's alpha coefficient and through test-retest reliability using Spearman's intra-class correlation coefficient (ICC). Construct, convergent, criterion-referenced, and concurrent validities were assessed. The Cancer Fatigue Scale (CFS), Patient Fatigue Knowledge Tool (PFKT), and Kessler 6-item distress scale (K6) were used for comparisons. RESULTS: Cronbach's alpha coefficients were 0.74, 0.78, 0.72, and 0.54 for the JFBS total and for each subscale, respectively. All ICCs exceeded 0.65 (P<0.05). The JFBS had a weak negative correlation with the PFKT and a positive correlation with the CFS. The K6 scores showed weak positive correlations with the JFBS total and fatalism subscale scores. CONCLUSIONS: The JFBS can be used to measure fatigue barriers in Japanese people with cancer. PMID- 24162282 TI - General nurses' experiences of end-of-life care in the acute hospital setting: a literature review. AB - Approximately 90% of the UK population spend some time in hospital in their final year of life, and more than half of the population die in hospital. This review aims to explore the experiences of general nurses when providing end-of-life care to patients in the acute hospital setting. Nine studies were identified through a literature search, and each was then analysed and evaluated until themes emerged. Six themes were drawn from the literature: lack of education and knowledge, lack of time with patients, barriers arising in the culture of the health-care setting, communication barriers, symptom management, and nurses' personal issues. The themes cause concern about the quality of end-of-life care being provided in the acute care setting. The literature appears to be consistent in the view that terminally ill patients are best cared for in specialised care settings, such as palliative care units and hospices. However, increasing demands on health services will result in greater numbers of dying patients being admitted to the acute hospital setting. It is therefore paramount that general nurses' educational needs are met to ensure they develop clinical competence to provide high-quality holistic end-of-life care. PMID- 24162284 TI - Genetics of virulence in Leptosphaeria maculans (Desm.) Ces. et De Not., the cause of blackleg in rapeseed (Brassica napus L.). AB - The genetic basis of virulence of 24 isolates of L. maculans collected from various sites throughout south-eastern and south-western Australia were studied using five clone-lines of B. napus. The experimental design allowed the estimation of the environmental and genetic components of variance using a standard analysis of variance. Virulence of these isolates (as measured by the percentage of stem girdling, %G) on the clonelines NCII and Tap was found to be most likely controlled by a small number of genes; the broad-sense heritabilities were 79.7% and 67.5% for virulence on NCII and Tap, respectively. The significance of these results in relation to the potential of L. maculans in adapting to new resistant B. napus cultivars is discussed. PMID- 24162285 TI - QTL analysis of potato tuberization. AB - Quantitative trait loci (QTLs) affecting tuberization were detected in reciprocal backcrosses between Solanum tuberosum and S. berthaultii. Linkage analyses were performed between traits and RFLP alleles segregating from both the hybrid and the recurrent parent using a set of framework markers from the potato map. Eleven distinct loci on seven chromosomes were associated with variation in tuberization. Most of the loci had small effects, but a QTL explaining 27% of the variance was found on chromosome 5. More QTLs were detected while following alleles segregating from the recurrent S. tuberosum parent used to make the backcross than were detected by following alleles segregating from the hybrid parent. More than half of the alleles favoring tuberization were at least partly dominant. Tuberization was favored by an allele from S. berthaultii at 3 of the 5 QTLs detected by segregation from the hybrid parent. The additive effects of the QTLs for tuberization explained up to 53% of the phenotypic variance, and inclusion of epistatic effects increased this figure to 60%. The most common form of epistasis was that in which presence of an allele at each of 2 loci favoring tuberization was no more effective than the presence of a favorable allele at 1 of the 2 loci. The QTLs detected for tuberization traits are discussed in relationship to those previously detected for trichome-mediated insect resistance derived from the unadapted wild species. PMID- 24162286 TI - QTL analysis of potato tuber dormancy. AB - The potential loss of chemical sprout inhibitors because of public concern over the use of pesticides underscores the desirability of breeding for long dormancy of potato (Solanum tuberosum L.) tubers. Quantitative trait locus (QTL) analyses were performed in reciprocal backcrosses between S. tuberosum and S. berthaultii toward defining the complexity of dormancy. S. berthaultii is a wild Bolivian species characterized by a short-day requirement for tuberization, long tuber dormancy, and resistance to several insect pests. RFLP alleles segregating from the recurrent parents as well as from the interspecific hybrid were monitored in two segregating progenies. We detected QTLs on nine chromosomes that affected tuber dormancy, either alone or through epistatic interactions. Alleles from the wild parent promoted dormancy, with the largest effect at a QTL on chromosome 2. Long dormancy appeared to be recessive in the backcross to S. berthaultii (BCB). In BCB the additive effects of dormancy QTLs accounted for 48% of the measured phenotypic variance, and adding epistatic effects to the model explained only 4% more. In contrast, additive effects explained only 16% of the variance in the backcross to S. tuberosum (BCT), and an additional 24% was explained by the inclusion of epistatic effects. In BCB variation at all QTLs detected was associated with RFLP alleles segregating from the hybrid parent; in BCT all QTLs except for two found through epistasis were detected through RFLP alleles segregating from the recurrent parent. At least three dormancy QTLs mapped to markers previously found to be associated with tuberization in these crosses. PMID- 24162287 TI - Molecular and biological studies on male-sterile cytoplasm in the Cruciferae. III. Distribution of Ogura-type cytoplasm among Japanese wild radishes and Asian radish cultivars. AB - The distribution of Ogura male-sterile cytoplasm among Japanese wild radish populations and Asian cultivated radishes was studied by means of polymerase chain reaction (PCR)-aided assays using mitochondrial atp6 and orf138 loci as molecular markers. Three separate PCR experiments were performed to amplify the target sequences in normal-type atp6, Ogura-type atp6, and Ogura-specific orf138, and the cytoplasm of each plant was classified as either normal or Ogura. Among 217 wild radish plants, 93 had both Ogura-type atp6 and orf138 (or its modified form), whereas 124 had normal-type atp6. Of the 93 plants with Ogura-type cytoplasm, only a single plant showed male sterility. A complete linkage between Ogura-type atp6 and orf138 loci was found in Japanese wild radishes, confirming our findings that Ogura-type cytoplasm is distributed widely among Japanese wild radish populations. A modified form of orf138 (orf138-S) was identified in a few wild radish populations in a limited area of Japan, and the nucleotide sequence of the orf138-S revealed a 39-bp deletion shared in common with 'Kosena' male sterile cytoplasm. Among the 44 Asian cultivars analyzed, 40 were determined to have normal cytoplasm since all 4 plants tested in each cultivar showed the same PCR amplification profiles as that of 'Uchiki-Gensuke', a reference cultivar with normal cytoplasm. The plants with Ogura-type cytoplasm (or its modified form) were found in 1, 1, and 2 cultivars from Tibet, Japan, and Taiwan, respectively. Except for 1 cultivar from Taiwan, those with Ogura-type cytoplasm included a few plants having male sterility. The multiple and independent introduction of Ogura type cytoplasm from the wild radish in Asia into these cultivars is suggested. PMID- 24162288 TI - Structure and inheritance of ribosomal DNA variants in cultivated and wild hop, Humulus lupulus L. AB - Genetic variation was assessed among cultivated and wild hop, Humulus lupulus, by restriction fragment length polymorphisms (RFLPs) of the ribosomal RNA genes (rDNA). Two rDNA length variants of 10.3 and 9.3 kbp represented by three phenotypes designated A, B and C were detected with XhoI. Restriction-site mapping showed that hop rDNA is structurally similar to those of most higher plants. A high level of homogeneity existed in rDNA repeat lengths among the diverse hop genotypes. Generally, phenotype A was predominant in wild and cultivated European and Asian genotypes; phenotype B in North American cultivars; while phenotype C was present only in native North American hop, providing a potential molecular marker for the identification of this germ plasm. The rDNA data provided genetic evidence for the separation of native and cultivated American genotypes and supports the hypothesis that North American hop cultivars are of hybrid origin from European and native American genotypes. The segregation of rDNA phenotypes in four F1 families suggests that a single locus with two co dominant alleles controls genetic variability for rDNA variants in hop. PMID- 24162289 TI - Genomic factors controlling the lethality exhibited in the hybrid between Nicotiana suaveolens Lehm. and N. tabacum L. AB - Interspecific hybrid plants between Nicotiana suaveolens and N. tabacum exhibit lethal symptoms at the seedling stage and cannot grow to maturity. In this investigation, an attempt was made to clarify the genomic factors responsible for this lethality. N. suaveolens was crossed to N. sylvestris (genomic constitution: SS) and N. tomentosiformis (TT), these latter two species being the progenitors of N. tabacum (SSTT). From the cross N. suaveolens x N. tomentosiformis, many seedlings were obtained through ovule culture, and these subsequently grew to maturity without exhibiting any lethality. In the reciprocal crossing between N. sauvelons and N. sylvestris, only a few hybrid seedlings were obtained through ovlue culture and all died after unfolding their cotyledons when cultured at 28 degrees C. This lethality could be avoided by culturing the ovules at 36 degrees C. These features of hybrid lethality resembled those observed in the interspecific hybrid between N. suaveolens and N. tabacum. These findings suggest that the S genome in N. tabacum is responsible for the lethality exhibited in the hybrid between N. suaveolens and N. tabacum. PMID- 24162290 TI - Inheritance and molecular variations of PCR-SSCP fragments in pedunculate oak (Quercus robur L.). AB - Single-strand conformaiton polymorphism (SSCP) profiles of six PCR-amplified fragments (250-800 bp) were analyzed in three full-sib families of pedunculate oak (Quercus robur L.) and their parents. Among the six fragments, four were polymorphic and one exhibited complex patterns that were not changed by varying the SSCP conditions. The number of bands for the analyzed fragments varied between two and four among individuals regardless of fragment size. As shown by segregation data, the variation in the number of bands between trees could only be attributed to the allelic composition (homozygotes vs heterozygotes): a genotype that exhibited two bands was presumptively homozygous, wheras a genotype exhibiting three or four bands was heterozygous. Mendelian proportions were observed in all crosses for each polymorphic fragment. In one cross, we could clearly identify a null allele due to a possible mutation at a primer site. Single-base mutations and short insertion-deletions were shown to be the molecular causes of the SSCP polymorphism observed between different alleles. The use of SSCP as a technique to identify co-dominant markers of PCR fragments (up to 800 bp) is recommended for gene diversity studies or for gene mapping. PMID- 24162291 TI - Somaclonal variation of the mitochondrial ATPase subunit 6 gene region in regenerated triticale shoots and full-grown plants. AB - Comparative hybridization analyses of total DNA from fertile and cytoplasmic male sterile (CMS) triticale plants which had been regenerated from embryogenic callus cultures revealed the organization and variation of the mitochondrial atp6 gene region. In order to compare different developmental phases, we analysed mitochondrial DNA (mtDNA) from both the shoots and full-grown regenerants. Somaclonal variants were identified on the basis of differences in the mtDNA from fertile and CMS triticale. Several shoots as well as all of the full-grown plants analysed showed somaclonal variation. This phenomenon could be traced back to having primarily orginated from the influence of the nuclear background, which give rise to a stoichiometric increase in a rye-specific orf25 gene copy, and a tissue culture-induced combination of fertile and CMS-specific mtDNA organization of the atp6 gene area. The latter event is probably caused by the homologous recombination of repetitive sequences that may be accompanied by selective amplifications. PMID- 24162292 TI - The effect of combining scald resistance genes on disease levels, yield and quality traits in barley. AB - Pairwise combinations of genes for resistance to scald in barley were developed using linked isozyme markers to test whether such combinations conferred improved resistance to the pathogen, Rhynchosporium secalis. The resistance genes originally derived from Hordeum vulgare ssp. spontaneum. The combinations were bred into an essentially similar genetic background because the scald susceptible, Australian barley cultivar 'Clipper' was the recurrent backcross parent in their ancestry. In field tests of the recombinants over 2 years, disease levels were lower in three of six doubly resistant lines than in backcross lines carrying a single resistance gene, which in turn were less diseased than either 'Clipper' or recombinants that lacked the marked resistance genes. All resistant lines significantly outyielded 'Clipper' but did not themselves differ significantly. Lines resistant to scald had significantly higher grain size and grain weight. Gains for malt yield of about 1 % were detected in the higher disease environment. Resistance was not accompanied by any obvious "cost" in terms of yield or quality. Protection against scald is therefore a significant requirement for new malting barley cultivars in scald prone areas. PMID- 24162293 TI - Use of random amplified polymorphic DNA (RAPD) markers in the study of the parasitic weed Orobanche. AB - Despite the tremendous economic impact of broomrapes (Orobanche spp.) on agriculture in many countries little is known of the pattern of genetic variation within this group of parasitic weeds. The present paper describes the use of RAPD markers for the study of five Orobanche species in agricultural fields in Israel. Pronounced genetic differentiation was found between the species, and RAPD markers were raised for the identification of each of them. Southern hybridization patterns of RAPD products of the various species were used to confirm the interpretation. The same markers were valid both for broomrapes collected in agricultural fields and for those collected in natural habitats. The validity of the markers found for O. cumana and O. crenata was confirmed on plants of the same species that were collected in Spain. Parsimony analysis of 86 RAPD characters produced a tree that clearly distinguishes between the five studied Orobanche species, separates the two Orobanche species belonging to sect. Trionychon from those belonging to sect. Osproleon, and supports the separation of O. cumana from O. cernua and of O. aegyptiaca from O. ramosa. PMID- 24162294 TI - Introduction of a gene from fertility restored radish (Raphanus sativus) into Brassica napus by fusion of X-irradiated protoplasts from a radish restorer line and iodacetoamide-treated protoplasts from a cytoplasmic male-sterile cybrid of B. napus. AB - To establish a cytoplasmic male-sterile/restored fertility (cms-Rf) system for F1 seed production in Brassica napus, we transferred a gene from fertillity restored radish to B. napus by protoplast fusion. X-irradiated protoplasts, isolated from shoots of Raphanus sativus cv Kosena (Rf line), were fused with iodoacetamide treated protoplasts of a B. napus cms cybrid. Among 300 regenerated plants, six were male-fertile. The fertile plants were characterized for petal color, chromosome number and the percentage of viable pollen grains. Three fertile plants had aneuploid chromosome numbers and white or cream petals, which is a dominant marker in radish. Of these three plants, one which had 2n = 47 chromosomes and white petals was used for further backcrosses. After two backcrosses, chromosome number and petal color became identical to that of B. napus. No female sterility was observed in the BC3 generations. PMID- 24162295 TI - Genetic causes of heterosis in juvenile aspen:a quantitative comparison across intra- and inter-specific hybrids. AB - The genetic causes of heterosis in tree growth were investigated by a comparative genetic analysis of intra- and inter-specific crosses derived from Populus tremuloides and P. tremula. A new analytical method was developed to estimate the effective number of loci affecting a quantitative trait and the magnitudes of their additive and dominant effects across loci. The method combines the assumption of multiple alleles, as frequently found in outcrossing species, and the family structure analysis at different hierarchical levels. During the first 3 years of growth, interspecific hybrids displayed strong heterosis in stem growth, especially volume index, over intraspecific hybrids. By a series of joint analyses on the combining ability and the genetic component, we found that F1 heterosis might be due to overdominant interaction between two alleles, one from the P. tremuloides parent and the other from the P. tremula parent, at the same loci. This inference was derived from the finding that heterozygotes, newly formed through species combination, showed much greater growth than the heterozygotes from intraspecifc crosses at a reference locus. Heterosis in aspen growth appeared to be under multi-genic control, with a slightly larger number of loci for stem diameter and volume (9-10) than for height (6-8). For traits with non-significant heterosis, such as stem allometry and internode number and length, the number of underlying loci seemed to be much fewer (3-4). While additive effects appeared to influence seedling traits collectively across loci, a few major dominant loci had much larger effects on stem growth. PMID- 24162296 TI - Amplified fragment length polymorphism (AFLP) in soybean: species diversity, inheritance, and near-isogenic line analysis. AB - Amplified fragment length polymorphism (AFLP) analysis is a PCR-based technique capable of detecting more than 50 independent loci in a single PCR reaction. The objectives of the present study were to: (1) assess the extent of AFLP variation in cultivated (Gycine max L. Merr.) and wild soybean (G. soja Siebold & Zucc.), (2) determine genetic relationships among soybean accessions using AFLP data, and (3) evaluate the usefulness of AFLPs as genetic markers. Fifteen AFLP primer pairs detected a total of 759 AFLP fragments in a sample of 23 accessions of wild and cultivated soybean, with an average of 51 fragments produced per primer pair per accession. Two-hundred and seventy four fragments (36% of the total observed) were polymorphic, among which 127 (17%) were polymorphic in G. max and 237 (31%) were polymorphic in G. soja. F2 segregation analysis of six AFLP fragments indicated that they segregate as stable Mendelian loci. The number of polymorphic loci detected per AFLP primer pair in a sample of 23 accessions ranged from 9 to 27. The AFLP phenotypic diversity values were greater in wild than in cultivated soybean. Cluster and principal component analyses using AFLP data clearly separated G. max and G. soja accessions. Within the G. max group, adapted soybean cultivars were tightly clustered, illustrating the relatively low genetic diversity present in cultivated soybean. AFLP analysis of four soybean near isogenic lines (NILs) identified three AFLP markers putatively linked to a virus resistance gene from two sources. The capacity of AFLP analysis to detect thousands of independent genetic loci with minimal cost and time requirements makes them an ideal marker for a wide array of genetic investigations. PMID- 24162297 TI - A comparison of methods for the estimation of genetic diversity in strawberry cultivars. AB - RAPD markers were used to examine the genetic relatedness of eight strawberry cultivars released from four breeding programmes around the world. Ten random primers successfully amplified DNA fragments from each cultivar and specific fingerprints were generated from the molecular marker data. The cultivars were traced back to founding clones and the relationships between the cultivars were examined from both the molecular and the pedigree data. PMID- 24162298 TI - Visual characterization of recombination at FRT-gusA loci in transgenic tobacco mediated by constitutive expression of the native FLP recombinase. AB - FLP/FRT-mediated site-specific recombination was studied with a recombination reporter gene system which allows visualization of beta-glucuronidase (GUS) expression after site-specific excisional activation of a silent gusA gene. This system was used for characterization of the functional activity of the Saccharomyces cerevisiae native FLP recombinase driven by the cauliflower mosaic virus (CaMV) 35s promoter [linked to the tobacco mosaic virus (TMV) omega translational leader] in mediating site-specific recombination of chromosomal FRT sites in tobacco FLP x FRT-reporter hybrids. Six hybrids were generated from crosses of lines containing either a stably integrated recombination-reporter or a FLP-expression construct. The activated gusA phenotype was specific to hybrid progenies and was not observed in either parental plants or their selfed progenies. Recombination efficiency in whole seedlings was estimated by the percent of radioactivity on a Southern blot which was incorporated into the recombined DNA product. Estimated efficiency mean values for the six crosses ranged from 5.2 to 52.0%. Histochemical analysis in hybrid plants visualized GUS activity with variable chimeric patterns and intensities. Recombination efficiency and GUS expression varied both among and within crosses, while higher recombination efficiency coincided with larger and more intense patterns of GUS activity. These data suggest that recombination is induced randomly during somatic developmental stages and that the pattern and intensity generated in a given plant are affected by factors imposing varibility not only between but also within crosses. Additionally, while recombination in a population of FLP/FRT hybrids may occur in all plants, recombination efficiency may still be low in any given plant. The activity of the native, as compared to a modified, FLP (Kilby et al. 1995) in the activation of transgenic traits in tobacco is discussed. PMID- 24162299 TI - The morphology, cytology, and C-banded karyotypes of Brassica campestris, B. oleracea, and B. napus plants regenerated from protoplasts. AB - The behaviour of Brassica campestris (2n=20, AA), B. oleracea (2n=18, CC), and B. napus (2n=38, AACC) were studied during a tissue-culturing process. Hypocotyl protoplasts were cultivated into calli from which new plants were regenerated. The regenerated plants were compared, and mitotic root-tip cells were C-banded and karyotyped. A majority of the plants were tetraploid. The meioses were studied in the PMCs. A number of abberations were observed, mainly due to faulty spindle function. There was a difference between the three species in that B. campestris performed the most poorly with many fewer regenerated plants. These plants were more morphologically disturbed and had more problems during pollen production than B. oleracea and B. napus plants. PMID- 24162300 TI - RFLP mapping in barely of a dominant gene conferring resistance to scald (Rhynchosporium secalis). AB - A progeny consisting of 52 anther-derived doubled haploid barley lines from a F1 between the winter cultivars 'Igri' (susceptible) and 'Triton' (resistant) was tested for resistance to Rhynchosporium secalis. A dominant gene was detected and tagged by a series of cosegregating RFLP markers located in the proximal portion of the long arm of chromosome 3, close to the centromere. One of the cosegregating RFLP markers, cMWG680, was converted into a codominant sequence tagged site marker. Polymerase chain reaction analysis with this marker of a series of accessions carrying known resistance genes provided evidence that scald resistance in cv 'Triton' is due to the presence of the Rh gene. PMID- 24162301 TI - Inheritance and linkage of isozymes in sweet cherry (Prunus avium L.). AB - Eight polymorphic isozyme loci, 6PGD, G6PD, MDH, PGM, SKDH, FDP, GOT and IDH, in sweet cherry where found to be in one linkage group, with a ninth isozyme locus, GPI, being in another linkage group on a different chromosome. Isozymes were also linked to the incompatibility S locus and this explained the disturbed segregation ratios observed in the first generation from controlled hybridisations between different sweet cherry cultivars. Analysis revealed close linkage between the isozyme and S loci. The results supported a pre-existing theory that the S gene in cherry consists of three linked segments each coding for a different function. Progeny derived from selfing of Stella, the self fertile cherry cultivar, also showed disturbed segregation ratios and an absence of homozygotes for the isozyme loci assayed. This demonstrated that codominant inheritance of the S alleles had not been effected by the self-fertile mutation. PMID- 24162302 TI - Linkage mapping of quantitative trait loci controlling seed weight in pea (Pisum sativum L.). AB - Quantitative trait loci (QTLs) affecting seed weight in pea (Pisum sativum L.) were mapped using two populations, a field-grown F2 progeny of a cross between two cultivated types ('Primo' and 'OSU442-15') and glasshouse-grown single-seed descent recombinant inbred lines (RILs) from a wide cross between a P. sativum ssp. sativum line ('Slow') and a P. sativum ssp. humile accession ('JI1794'). Linkage maps for these crosses consisted of 199 and 235 markers, respectively. QTLs for seed weight in the 'Primo' x 'OSU442-15' cross were identified by interval mapping, bulked segregant analysis, and selective genotyping. Four QTLs were identified in this cross, demonstrating linkage to four intervals on three linkage groups. QTLs for seed weight in the 'JI1794' x 'Slow' cross were identified by single-marker analyses. Linkage were demonstrated to four intervals on three linkage groups plus three unlinked loci. In the two crosses, only one common genomic region was identified as containing seed-weight QTLs. Seed-weight QTLs mapped to the same region of linkage group III in both crosses. Conserved linkage relationships were demonstrated for pea, mungbean (Vigna radiata L.), and cowpea (V. unguiculata L.) genomic regions containing seed-weight QTLs by mapping RFLP loci from the Vigna maps in the 'Primo' x 'OSU442-15' and 'JI1794' x 'Slow' crosses. PMID- 24162303 TI - Segregation distortion of isozyme loci in cherimoya (Annona cherimola Mill). AB - The allelic segregation of 13 isozyme loci in hand-fertilized heterozygous cherimoya trees (Annona cherimola Mill.) has been studied. We analyzed 63 locus x progeny combinations and found non-Mendelian segregation in 12 cases. The sequential Bonferroni method revealed only eight cases of non-Mendelian segregation; these have been investigated with several chi-square tests to discover what processes were involved. Gametic selection appears to be the main contributor, although zygotic selection seems also to play a part. PMID- 24162304 TI - Quantitative genetic dissection of complex traits in a QTL-mapping pedigree. AB - This paper summarizes and modifies quantitative genetic analyses on a pedigree used to map genetic factors (i.e., QTLs) underlying a complex trait. The total genetic variance can be exactly estimated based on the F2 family derived from two homozygous parents for alternative alleles at all QTLs of interest. The parents, F1 hybrids, and two backcrosses are combined to each parent, and the total number of QTLs and the number of dominant QTLs are estimated under the assumptions of gene association with the two parents, equal gene effect, no linkage, and no epistasis among QTLs. Further relaxation for each of the assumptions are made in detail. The biometric estimator for the QTL number and action mode averaged over the entire genome could provide some basic and complementary information to QTL mapping designed to detect the effect and location of specific genetic factors. PMID- 24162305 TI - Inheritance and genetic mapping of self-incompatibility in Coffea canephora Pierre. AB - Cross-compatibility behaviour of doubled haploid (DH) and hybrid genotypes of Coffea camphora was established using both phenotypic bioassay and in situ seed set examination. The availability of DHs provided the opportunity of working with genetically homogenous pollen and female parents. The aniline blue fluorescence (ABF) method was applied to detect callose accumulation in pollen and pistil. Clear cross-compatibility/incompatibility situations were observed and confirmed by in situ seed-set analysis. Cross-compatibility analysis of hybrid combinations involving different DHs corroborated the crossing behaviour observed at the DH level. Expression of the self-incompatibility system did not appear to be affected by the low vigour of the DH. The crossing-behaviour distribution observed within DHs derived from clone IF200 confirmed that self-incompatibility in C. canephora is a gametophytic self-incompatibility system controlled by a single locus (S-locus). Reduced seed-set developments following incompatible crosses may indicate the occurrence of pseudo-incompatibility. Molecular marker linkage analysis showed that the S-locus is associated with an RFLP marker on linkage group 9. The availability of a linked DNA marker should facilitate the genetic analysis of self-incompatibility in relation to coffee breeding programmes. PMID- 24162306 TI - Development of PCR markers linked to resistance to wheat streak mosaic virus in wheat. AB - Wheat streak mosaic virus (WSMV), vectored by the wheat curl mite (Acer tulipae), is an important disease of wheat (Triticum aestivum L.) in the North American Great Plains. Resistant varieties have not been developed for two primary reasons. First, useful sources of resistance have not been available, and second, field screening for virus resistance is laborious and beyond the scope of most breeding programs. The first problem may have been overcome by the development of resistance to both the mite and the virus by the introgression of resistance genes from wild relatives of wheat. To help address the second problem, we have developed polymerase chain reaction (PCR) markers linked to the WSMV resistance gene Wsm1. Wsm1 is contained on a translocated segment from Agropyron intermedium. One sequence-tagged-site (STS) primer set (WG232) and one RAPD marker were found to be linked to the translocation containing Wsm1. The diagnostic RAPD band was cloned and sequenced to allow the design of specific PCR primers. The PCR primers should be useful for transferring Wsm1 into locally adapted cultivars. PMID- 24162307 TI - Regression analysis of yield stability is strongly affected by companion test varieties and locations - examples from a study of Nordic barley lines. AB - The suitability of regression analysis for studying the phenotypic stability of grain yield was investigated using a collection of 220 Nordic barley lines. Linear regression explained 26-52% of the genotype x environment (GE) interactions in different groupings of the material. The regression coefficient, b i , measures the yield response of the i-th genotype to improved environmental conditions. Deviations from regression, S di (2) , have been used to estimate Tai's stability parameter, lambda i , which is a measure of the phenotypic yield stability in the agronomic sense. Repeatability of b i , lambda i , and grain yield was studied by means of correlations between estimates obtained in each experimental year. Yield had the highest repeatability, with correlations between years ranging from 0.57 to 0.85. In this study, regression coefficients and lambda i -values were not repeatable, i.e. genotypes reacted differentially to the yearly climatic variations. Six-rowed (6r) barleys had higher responsiveness, but lower mean yields, than two-rowed (2r) barleys. This is partly due to the history of selection of 6r-barleys, which mainly originate from regions with low potential yield levels, i.e. Finland and Norway. In general, responsiveness and stability were not correlated with yield. The highest-yielding lines had b i ~1. The response pattern of the different types of barleys used in this study show that responsiveness can be changed by recombination. PMID- 24162308 TI - Electromagnetic interference from lasers and intense light sources in the treatment of patients with artificial pacemakers and other implantable cardiac devices. AB - Measurements of the electric and magnetic field strengths surrounding six laser systems and one intense pulsed light system were carried out. The results were compared to exposure limits published by cardiac device manufacturers to assess the risk of electromagnetic interference to implantable cardiac devices such as pacemakers or implantable cardioverter defibrillators. The majority of lasers assessed in this study were found to produce electric and magnetic field strengths below the published exposure limits for cardiac devices. However, the low-frequency electric field and static magnetic field of both the CO2 laser and the ruby laser were found to exceed these limits. Ensuring that a small separation is maintained at all times between the laser unit and any patient with a pacemaker or implantable cardioverter defibrillator appears to be a sensible expedient in avoiding overexposure of an implantable cardiac device to electromagnetic interference. Due to the single-shot fast discharge nature of the intense pulsed light system, changes in electromagnetic field strength were too fast for some of the measuring equipment used in this study to register accurate readings during operation. PMID- 24162309 TI - Pushing the glass transition towards random close packing using self-propelled hard spheres. AB - Although the concept of random close packing with an almost universal packing fraction of approximately 0.64 for hard spheres was introduced more than half a century ago, there are still ongoing debates. The main difficulty in searching the densest packing is that states with packing fractions beyond the glass transition at approximately 0.58 are inherently non-equilibrium systems, where the dynamics slows down with a structural relaxation time diverging with density; hence, the random close packing is inaccessible. Here we perform simulations of self-propelled hard spheres, and we find that with increasing activity the relaxation dynamics can be sped up by orders of magnitude. The glass transition shifts to higher packing fractions upon increasing the activity, allowing the study of sphere packings with fluid-like dynamics at packing fractions close to RCP. Our study opens new possibilities of investigating dense packings and the glass transition in systems of hard particles. PMID- 24162310 TI - Cohort profile: the Fangshan Cohort Study of cardiovascular epidemiology in Beijing, China. AB - BACKGROUND: Urbanizing rural areas in China face a rapidly growing cardiovascular disease burden. Epidemiologic studies and effective preventive strategies are urgently needed. METHODS: The Fangshan Cohort Study is a prospective study that began in 2008 and targets local residents aged 40 years or older living in 3 towns in the Fangshan district of Beijing. The baseline examination included a questionnaire on medical history, health knowledge, and behaviors related to cardiovascular disease, as well as physical and blood biochemical examinations. The questionnaire survey will be readministered every 2 years. A system for surveillance of mortality and morbidity of cardiovascular disease is under development. RESULTS: A total of 20 115 adults (6710 men and 13 405 women) were investigated at baseline (participation rate = 84.5%). The data indicate that overweight/obesity is a serious public health issue in Fangshan: average body mass index was 25.4 kg/m(2) among men and 26.5 kg/m(2) among women, and the prevalences of overweight and obesity were 43.6% and 10.3% among men and 47.0% and 17.7% among women. CONCLUSIONS: The Fangshan Cohort Study will provide data on cardiovascular risk factors and disease profile, which will assist in developing appropriate prevention and control strategies for cardiovascular disease in rural Chinese communities. PMID- 24162311 TI - Dose-response relationship between serum gamma-glutamyltransferase and arterial stiffness in Korean adults: the Namwon Study. AB - BACKGROUND: The results of epidemiologic studies of the association between serum gamma-glutamyltransferase (GGT) and brachial-ankle pulse wave velocity (baPWV) have been inconsistent. We examined the association between serum GGT and arterial stiffness in a general population of Korean adults. METHODS: The study population consisted of 6314 community-dwelling Koreans who participated in the baseline survey of the Namwon Study. We analyzed sex-specific association between serum GGT and arterial stiffness, as measured by baPWV. RESULTS: There was a significant progressive increase in age-adjusted mean baPWV across quartiles of GGT in both sexes. In fully adjusted analysis, as compared with the lowest quartile, the odds ratios (95% CI) for high baPWV (ie, sex-specific fifth quintile) were 1.51 (1.03-2.23), 1.82 (1.22-2.72), and 2.80 (1.79-4.40) among men (P-trend <0.001), and 1.11 (0.81-1.52), 1.29 (0.94-1.76), and 1.47 (1.04-2.08) among women (P-trend <0.001), for the second, third, and fourth quartiles of GGT, respectively. CONCLUSIONS: This population-based study examined the dose-response relationship between GGT and arterial stiffness as measured by baPWV in both sexes. The association between GGT and arterial stiffness was stronger among men. Additional longitudinal studies are needed to examine the relationship between GGT and arterial stiffness and clarify the mechanism underlying the association. PMID- 24162312 TI - Adaptation of novel H7N9 influenza A virus to human receptors. AB - The emergence of the novel H7N9 influenza A virus (IAV) has caused global concerns about the ability of this virus to spread between humans. Analysis of the receptor-binding properties of this virus using a recombinant protein approach in combination with fetuin-binding, glycan array and human tissue binding assays demonstrates increased binding of H7 to both alpha2-6 and alpha2-8 sialosides as well as reduced binding to alpha2-3-linked SIAs compared to a closely related avian H7N9 virus from 2008. These differences could be attributed to substitutions Q226L and G186V. Analysis of the enzymatic activity of the neuraminidase N9 protein indicated a reduced sialidase activity, consistent with the reduced binding of H7 to alpha2-3 sialosides. However, the novel H7N9 virus still preferred binding to alpha2-3- over alpha2-6-linked SIAs and was not able to efficiently bind to epithelial cells of human trachea in contrast to seasonal IAV, consistent with its limited human-to-human transmission. PMID- 24162315 TI - New insights into mechanisms of acute myocardial infarction: a journey of 100 years. PMID- 24162314 TI - A re-interpretation of the rate of tension redevelopment (k(TR)) in active muscle. AB - A slackening to zero tension by large length release (~20%) and a restretch of active muscle fibres cause a fall and a redevelopment in tension. According to the model of Brenner (Proc Natl Acad Sci USA 85(9):3265-3269, 1988), the rate constant of tension redevelopment (k TR) is the sum of attachment and detachment rate constants, hence is limited by the fast reaction. Here we propose a model in which, after restretch, cross-bridges cycle many times by stretching series elastic elements, hence k(TR) is limited by a slow reaction. To set up this model, we made an assumption that the stepping rate (v) decreases linearly with tension (F), which is consistent with the Fenn effect. The distance traveled by a cross-bridge stretches series elastic elements with stiffness sigma. With these assumptions, we set up a first order differential equation, which results in an exponential time course with the rate constant k(TR) = sigmaeta(0)nu(0)(1 - lambda)/F(1), where lambda = nu(1)/nu(0), eta = step size, the subscript 0 indicates unloaded condition, and the subscript 1 indicate isometric condition. We demonstrate that the ATP hydrolysis rate (=[myosin head]/nu(0)) is proportionate to k(TR) as the ambient temperature is changed, and that the published data fit to this relationship well if lambda = 0.28. We conclude that k(TR) is limited by the cross-bridge turnover rate; hence it represents the rate constant of the slowest reaction of the cross-bridge cycle, i.e. the ADP isomerization step before ADP is released. PMID- 24162316 TI - Pharmacogenetics and its relevance to clinical practice. PMID- 24162313 TI - Myosin phosphorylation and force potentiation in skeletal muscle: evidence from animal models. AB - The contractile performance of mammalian fast twitch skeletal muscle is history dependent. The effect of previous or ongoing contractile activity to potentiate force, i.e. increase isometric twitch force, is a fundamental property of fast skeletal muscle. The precise manifestation of force potentiation is dependent upon a variety of factors with two general types being identified; staircase potentiation referring to the progressive increase in isometric twitch force observed during low frequency stimulation while posttetanic potentiation refers to the step-like increase in isometric twitch force observed following a brief higher frequency (i.e. tetanic) stimulation. Classic studies established that the magnitude and duration of potentiation depends on a number of factors including muscle fiber type, species, temperature, sarcomere length and stimulation paradigm. In addition to isometric twitch force, more recent work has shown that potentiation also influences dynamic (i.e. concentric and/or isotonic) force, work and power at a range of stimulus frequencies in situ or in vitro, an effect that may translate to enhanced physiological function in vivo. Early studies performed on both intact and permeabilized models established that the primary mechanism for this modulation of performance was phosphorylation of myosin, a modification that increased the Ca(2+) sensitivity of contraction. More recent work from a variety of muscle models indicates, however, the presence of a secondary mechanism for potentiation that may involve altered Ca(2+) handling. The primary purpose of this review is to highlight these recent findings relative to the physiological utility of force potentiation in vivo. PMID- 24162317 TI - Coronary artery calcification across ethnic groups in Singapore. AB - INTRODUCTION: In Singapore, the age-standardised event rates of myocardial infarction (MI) are 2- and 3-fold higher for Malays and Indians respectively compared to the Chinese. The objectives of this study were to determine the prevalence and quantity of coronary artery calcification (CAC) and non-calcified plaques across these 3 ethnic groups. MATERIALS AND METHODS: This was a retrospective descriptive study. We identified 1041 patients (810 Chinese, 139 Malays, 92 Indians) without previous history of cardiovascular disease who underwent cardiac computed tomography for atypical chest pain evaluation. A cardiologist, who was blinded to the patients' clinical demographics, reviewed all scans. We retrospectively analysed all their case records. RESULTS: Overall, Malays were most likely to be active smokers (P = 0.02), Indians had the highest prevalence of diabetes mellitus (P = 0.01) and Chinese had the highest mean age (P <0.0001). The overall prevalence of patients with non-calcified plaques as the only manifestation of sub-clinical coronary artery disease was 2.1%. There was no significant difference in the prevalence of CAC, mean CAC score or prevalence of non-calcified plaques among the 3 ethnic groups. Active smoking, age and hypertension were independent predictors of CAC. Non-calcified plaques were positively associated with male gender, age, dyslipidaemia and diabetes mellitus. CONCLUSION: The higher MI rates in Malays and Indians in Singapore cannot be explained by any difference in CAC or non-calcified plaque. More research with prospective follow-up of larger patient populations is necessary to establish if ethnic-specific calibration of CAC measures is needed to adjust for differences among ethnic groups. PMID- 24162318 TI - Effect of location of out-of-hospital cardiac arrest on survival outcomes. AB - INTRODUCTION: This study aims to study how the effect of the location of patient collapses from cardiac arrest, in the residential and non-residential areas within Singapore, relates to certain survival outcomes. MATERIALS AND METHODS: A retrospective cohort study of data were done from the Cardiac Arrest and Resuscitation Epidemiology (CARE) project. Out-of- hospital cardiac arrest (OHCA) data from October 2001 to October 2004 (CARE) were used. All patients with OHCA as confirmed by the absence of a pulse, unresponsiveness and apnoea were included. All events had occurred in Singapore. Analysis was performed and expressed in terms of the odds ratio (OR) and the corresponding 95% confidence interval (CI). RESULTS: A total of 2375 cases were used for this analysis. Outcomes for OHCA in residential areas were poorer than in non-residential areas 1638 (68.9%) patients collapsed in residential areas, and 14 (0.9%) survived to discharge. This was significantly less than the 2.7% of patients who survived after collapsing in a non-residential area (OR 0.31 [0.16 - 0.62]). Multivariate logistic regression analysis showed that location alone had no independent effect on survival (adjusted OR 1.13 [0.32 - 4.05]); instead, underlying factors such as bystander CPR (OR 3.67 [1.13 - 11.97]) and initial shockable rhythms (OR 6.78 [1.95 - 23.53]) gave rise to better outcomes. CONCLUSION: Efforts to improve survival from OHCA in residential areas should include increasing CPR by family members, and reducing ambulance response times. PMID- 24162319 TI - Recognition and treatment of out-of-hospital cardiac arrests by non-emergency ambulance services in Singapore. AB - INTRODUCTION: Prompt recognition of cardiac arrest and initiation of cardiopulmonary resuscitation (CPR) and defibrillation is necessary for good outcomes from out-of-hospital cardiac arrest (OHCA). This study aims to describe the recognition and treatment of OHCA in patients conveyed by non-emergency ambulance services (EAS) in Singapore. MATERIALS AND METHODS: This is a multi centre, retrospective chart review, of cases presenting to public emergency departments (EDs), conveyed by non-EAS and found to be in cardiac arrest upon ED arrival. The study was from October 2002 to August 2009. The following variables were examined: ability to recognise cardiac arrest, whether CPR was carried out by the ambulance crew and whether an automated external defibrillator (AED) was applied. RESULTS: Eighty-six patients were conveyed by non-EAS and found to be in cardiac arrest upon ED arrival. Mean age was 63 years (SD 21.8), 70.9% were males. A total of 53.5% of arrests occurred in the ambulance while 70.9% were found to be asystolic upon ED arrival. Seven patients had a known terminal illness. Survival to discharge was 3.5%. Cardiac arrest went unrecognised by the ambulance crew in 38 patients (44.2%). CPR was performed in 35 patients (40.7%) of the 86 patients and AED was applied in only 10 patients (11.6%). CONCLUSION: We found inadequate recognition and delayed initiation of treatment for OHCA. Possible reasons include a lack of training in patient monitoring and detection of cardiac arrest, lack of CPR training, lack of confidence in performing CPR, lack of AEDs on ambulances and lack of training in their use. PMID- 24162320 TI - Hypertension management and lifestyle changes following screening for hypertension in an Asian low socioeconomic status community: a prospective study. AB - INTRODUCTION: This study investigated the effect of an access-enhanced intervention on hypertension screening and management, as well as on health behaviours among newly diagnosed hypertensives, in a multi-ethnic low socioeconomic status (SES) community. Factors associated with hypertension screening, treatment, and control in the community were also determined. MATERIALS AND METHODS: The study involved all residents aged >=40 years in 2 public rental housing precincts (low SES), between 2009 and 2011, who were followed-up prospectively for 1 year after a 6-month community-based intervention comprising a 3-month access-enhanced screening component and a 3-month follow-up (outreach) component. Blood pressure was measured at baseline and follow-up. Multivariate Cox regression determined predictors of hypertension management at follow-up. RESULTS: The follow-up rate was 80.9% (467/577). At baseline, 60.4% (282/467) were hypertensive; 53.5% (151/282) were untreated; 54.2% (71/131) uncontrolled. One year later, postintervention, 51.6% (78/151) of untreated hypertensives were treated; combined with treated hypertensives previously uncontrolled, 53.0% (79/149) achieved control. Older age independently predicted treatment (adjusted relative risk, aRR = 1.98, CI, 1.08 to 3.65); majority ethnicity (aRR = 1.76, CI, 1.05 to 2.96), employment (aRR = 1.85, CI, 1.26 to 2.80) and newly treated hypertension (aRR=1.52, CI, 1.01 to 2.32) predicted control. A total of 52.4% (97/185) were irregularly screened at baseline; at follow-up 61.9% (60/97) were regularly screened. Cost and misperceptions were common barriers to screening and treatment. Newly diagnosed hypertensives were also less likely to go for additional cardiovascular screening (aRR = 0.54, CI, 0.29 to 0.99). CONCLUSION: An access-enhanced intervention had some success in improving hypertension management within low SES communities; however, it was less successful in improving cardiovascular risk management, especially in encouraging lifestyle changes and additional cardiovascular screening amongst newly diagnosed hypertensives. PMID- 24162322 TI - Freezing the biological clock: a viable fertility preservation option for young Singapore women? AB - In March 2012, an article in The Straits Times entitled 'Freezing eggs could reverse falling birth rate' suggested that employing the latest oocyte cryopreservation techniques could both foster individual women's reproductive autonomy and impact Singapore's fertility rate, which in recent years has consistently been among the world's lowest. The article cited both local and international fertility specialists' approval of elective oocyte cryopreservation for young women wishing to protect their reproductive potential against ageing and as a potential antidote to the contemporary 'delay and defer' model of family building. Later in 2012, the Ministry of Health announced a review of oocyte cryopreservation policy taking into account related medical, scientific and ethical issues, while the Singapore College of Obstetricians and Gynaecologists endorsed oocyte cryopreservation as an "important, safe and efficient technology". This paper outlines and analyses the arguments and empirical evidence used both to support and oppose offering elective oocyte cryopreservation as a routine fertility service, before concluding that this remains unjustifiable on the basis of insufficient evidence of its clinical efficacy and safety as regards either pregnancy rates or birth outcomes. If it is to be made available at all for these reasons in Singapore, it should be subjected to rigorous clinic-specific evaluation in accordance with accepted clinical and ethical norms. PMID- 24162321 TI - Home-based advance care programme is effective in reducing hospitalisations of advanced heart failure patients: a clinical and healthcare cost study. AB - INTRODUCTION: In end-stage heart failure (HF) that is not eligible for mechanical assist device or heart transplant, palliative care serves to maximise symptom control and quality of life. We sought to evaluate the impact of home-based advance care programme (ACP) on healthcare utilisation in end-stage HF patients. MATERIALS AND METHODS: Prospectively collected registry data on all end-stage HF recruited into ACP between July 2008 and July 2010 were analysed. Chart reviews were conducted on HF database and hospital electronic records. Phone interview and home visit details by ACP team were extracted to complete data entry. HF and all-cause hospitalisations 1 year before, and any time after ACP inception were defined as events. For the latter analysis, follow-up duration adjustment to event episodes was performed to account for death less than a year. RESULTS: Forty-four patients (mean age 79 years, 39% men) were followed up for 15+/-8 months. Fifty-seven percent had diabetes, 80% ischaemic heart disease, and 60% chronic kidney disease. All reported functional class III/IV at enrolment. Mean serum sodium was 136+/-6 mmol/L, and creatinine 186+/-126 mmol/L. Thirty (68%) died within the programme. Mean time to death was 5.5 months. Mean all-cause and HF hospitalisations were 3.6 and 2.0 per patient before enrolment, but improved to 1.0 and 0.6 respectively after ACP. Thirty-six (71%) patients had fewer HF hospitalisations. When only those who survived more than a year were considered (n = 14), 10 (71%) and 9 (64%) experienced reduced HF (mean: 1.4 episodes per patient) and all-cause hospitalisations (mean: 2.2 episodes per patient) respectively. CONCLUSION: Home-based advance care programme is potentially effective in reducing healthcare utilisation of end-stage HF patients, primarily by reducing HF rehospitalisations, and in probably saving costs as well. PMID- 24162323 TI - Acute coronary syndrome: is it the primary event or a secondary phenomenon? PMID- 24162324 TI - Trends amongst implantable cardioverter defibrillator patients in a tertiary cardiac centre in Singapore from 2002 to 2011. PMID- 24162325 TI - Dengue fever outbreak: prevention possible. PMID- 24162326 TI - Re: Dengue fever outbreak: prevention possible (author's reply). PMID- 24162327 TI - Cardiogenic shock post-percutaneous coronary intervention for myocardial infarction. PMID- 24162328 TI - Geometric characterization of optimal electrode designs for improved droplet charging and actuation. AB - Droplet charging characteristics depending on the geometry of charging electrodes have been investigated experimentally and numerically. In the experiments, two contrasting electrode systems are examined: pin-pin versus planar-planar types. To confirm the different charging behaviours on each electrode, an asymmetric system of a pin-planar type has also been examined. From the experimental and numerical results, it has been found that the droplet charge can be significantly increased (more than four times) with pin type electrodes compared with planar ones due to the increase in surface charge density by the intensification of the electric field around the charging electrode. Moreover, as the system scale becomes smaller, the superior charging effect becomes greater. Through comprehensive numerical studies on the effects of the cross-sectional area and length of a charging electrode, we have found the optimal geometric design of an electrode for droplet charging and actuation. The implications for basic understanding of the charging phenomenon and electrode design of microfluidic systems are discussed. PMID- 24162330 TI - Bridging the gap in concussion knowledge. PMID- 24162332 TI - Hydroxylamine-doping effect on the Tg of 160 K for water confined in silica-gel nanopores. AB - The glass transition behavior of hydroxylamine (HA) aqueous solutions in bulk and confined in silica-gel nanopores with average width of 1.1 nm was studied by means of differential scanning calorimetry measurements and adiabatic calorimetry. The glass transition temperature (Tg) of the confined solution with high HA mole-fraction (xHA) was essentially the same as the value of the bulk. This suggests that the nano-size confinement affects the Tg of HA aqueous solution little. Meanwhile, the bulk solution with xHA < 0.3 revealed partial crystallization on cooling and, on the other hand, the confined solution with the same xHA did not crystallize. The Tg of the xHA = 0.076 confined solution was 174 K which is higher than the value of 160 K for pure water confined in the same silica-gel pores. This demonstrates that HA doping leads to no abrupt Tg decrease, unlike doping of all the other second components reported so far, suggesting that HA is set neatly in a hydrogen-bond network formed by water molecules. We discuss the xHA dependence of Tg for the HA aqueous solutions from a viewpoint related to peculiar phase-behavior of pure water. Considering that the xHA = 0.076 aqueous solution revealed no anomaly compared with pure water, it was recognized as corresponding to the high-temperature phase of pure water. PMID- 24162331 TI - Surgical outcomes for 131 cases of carcinosarcoma of the hepatobiliary tract. AB - Carcinosarcoma of the hepatobiliary tract is highly aggressive and has a poor prognosis even after curative resection. The purpose of this study was to collate and analyze published data to clarify the surgical outcome of carcinosarcoma of the hepatobiliary tract and the relationships between potential prognostic factors and survival after surgery. We surveyed worldwide literature from 1970 to 2012 and obtained clinicopathological data for 131 patients who had undergone surgical resection for carcinosarcoma of the hepatobiliary tract, including one patient from our clinic. The relationships between potential prognostic factors and survival rates were examined using the Kaplan-Meier method and the log-rank test. The overall 1-, 3-, and 5-year survival rates for patients with carcinosarcoma of the hepatobiliary tract after surgery were 44.0, 29.3, and 27.0 %, respectively. In univariate analyses, age and gender were not significant prognostic factors; however, advanced stage according to the classification of the Union for International Cancer Control in resected specimens was significantly associated with a shorter survival time after surgery. Although carcinosarcoma of the hepatobiliary tract remains a rare disease worldwide, its poor prognosis, even after curative resection, demands further epidemiological and pathological study that could lead to the development of new management strategies. PMID- 24162334 TI - Silicon nanowires nanogenerator based on the piezoelectricity of alpha-quartz. AB - Silicon nanowires are important semiconductor with core/shell structure. In this work, the piezoelectric material alpha-quartz was grown in the interface of silicon nanowires by thermal treatment at 600 degrees C for 0.5 h. These nanowires were employed as starting materials to fabricate piezoelectric nanogenerators, which could convert kinetic energy into electrical one, exhibiting an output voltage of 36.5 V and a response current of 1.4 MUA under a free-falling object of 300 g at a height of 30 cm. PMID- 24162333 TI - Younger patients with chronic myeloid leukemia do well in spite of poor prognostic indicators: results from the randomized CML study IV. AB - Since the advent of tyrosine kinase inhibitors, the impact of age on outcome of chronic myeloid leukemia (CML) patients has changed. We therefore analyzed patients from the randomized CML study IV to investigate disease manifestations and outcome in different age groups. One thousand five hundred twenty-four patients with BCR-ABL-positive chronic phase CML were divided into four age groups: (1) 16-29 years, n = 120; (2) 30-44 years, n = 383; (3) 45-59 years, n = 495; and (4) >=60 years, n = 526. Group 1 (adolescents and young adults (AYAs)) presented with more aggressive disease features (larger spleen size, more frequent symptoms of organomegaly, higher white blood count, higher percentage of peripheral blasts and lower hemoglobin levels) than the other age groups. In addition, a higher rate of patients with BCR-ABL transcript levels >10 % on the international scale (IS) at 3 months was observed. After a median observation time of 67.5 months, no inferior survival and no differences in cytogenetic and molecular remissions or progression rates were observed. We conclude that AYAs show more aggressive features and poor prognostic indicators possibly indicating differences in disease biology. This, however, does not affect outcome. PMID- 24162335 TI - Physiological, biochemical and molecular responses in four Prunus rootstocks submitted to drought stress. AB - An understanding of the mechanisms that determine plant response to reduced water availability is essential to improve water-use efficiency (WUE) of stone fruit crops. The physiological, biochemical and molecular drought responses of four Prunus rootstocks (GF 677, Cadaman, ROOTPAC 20 and ROOTPAC((r)) R) budded with 'Catherina' peach cultivar were studied. Trees were grown in 15-l containers and subjected to a progressive water stress for 26 days, monitoring soil moisture content by time domain reflectometry. Photosynthetic and gas exchange parameters were determined. Root and leaf soluble sugars and proline content were also measured. At the end of the experiment, stressed plants showed lower net photosynthesis rate, stomatal conductance and transpiration rate, and higher intrinsic leaf WUE (AN/gs). Soluble sugars and proline concentration changes were observed, in both root and leaf tissues, especially in an advanced state of stress. The accumulation of proline in roots and leaves with drought stress was related to the decrease in osmotic potential and increase in WUE, whereas the accumulation of sorbitol in leaves, raffinose in roots and proline in both tissues was related only to the increase in the WUE. Owing to the putative role of raffinose and proline as antioxidants and their low concentration, they could be ameliorating deleterious effects of drought-induced oxidative stress by protecting membranes and enzymes rather than acting as active osmolytes. Higher expression of P5SC gene in roots was also consistent with proline accumulation in the tolerant genotype GF 677. These results indicate that accumulation of sorbitol, raffinose and proline in different tissues and/or the increase in P5SC expression could be used as markers of drought tolerance in peach cultivars grafted on Prunus rootstocks. PMID- 24162337 TI - Synthesis and structural characterization of 14-vertex germa-, stanna-, and plumba-carboranes. AB - This article reports the synthesis and structures of several 14-vertex germa-, stanna-, and plumba-carboranes of the MC2B11 system. The reaction of GeCl2.dioxane, SnCl2 or Pb(OAc)2 with [8,9-(CH2)3-8,9-C2B11H11][Na2] in THF gave, after recrystallization from bidentate ligands such as bipyridine, 4,4'-dimethyl 2,2'-bipyridine, phenantroline and 1,2-bis(diphenylphosphino)ethane (dppe), eight 14-vertex p-block metallacarboranes 2,3-(CH2)3-1-(2',2''-bipyridine)-1,2,3 GeC2B11H11 (1), 2,3-(CH2)3-1-(4',4''-dimethyl-bipyridine)-1,2,3-GeC2B11H11 (2), 2,3-(CH2)3-1-(1',10'-phenantroline)-1,2,3-GeC2B11H11 (3), 2,3-(CH2)3-1-(2',2'' bipyridine)-1,2,3-SnC2B11H11 (4), 2,3-(CH2)3-1-(4',4''-dimethyl-bipyridine)-1,2,3 SnC2B11H11 (5), 2,3-(CH2)3-1-(1',10'-phenantroline)-1,2,3-SnC2B11H11 (6), 2,3 (CH2)3-1-(dppe)-1,2,3-SnC2B11H11 (7) and 2,3-(CH2)3-1-(2',2''-bipyridine)-1,2,3 PbC2B11H11 (8) in high isolated yields. Single-crystal X-ray analyses reveal that they adopt a distorted-bicapped-hexagonal antiprism geometry, in which the p block metal atom slips away from the above center of the C2B4 bonding face towards the boron side, leading to an eta(4) bonding mode. The results suggest that [nido-8,9-(CH2)3-8,9-C2B11H11](2-) is a redox inactive species and a good pi ligand for transition metals and p-block elements. PMID- 24162336 TI - An elevation of resting metabolic rate with declining health in nonagenarians may be associated with decreased muscle mass and function in women and men, respectively. AB - Previously, we showed that FI34, a frailty index based on 34 health and function ability variables, is heritable and a reliable phenotypic indicator of healthy aging. We have now examined the relationship between major components of energy expenditure and the FI34 in participants of the Louisiana Healthy Aging Study. Resting metabolic rate was associated with FI34, even after adjustment for fat free mass, fat mass, age, sex, thyroid hormones, and insulin-like growth factor 1 levels, in multiple regression analyses. In contrast, there was no association between total daily energy expenditure and FI34. Circulating creatine phosphokinase, a clinical marker of muscle damage, was also significantly associated with FI34. However, these associations of resting metabolic rate with FI34 were restricted to the oldest old (>=90 years) and absent in younger age groups. In oldest old men, the association of FI34 with creatine phosphokinase persisted, whereas in the oldest old women, only the association with resting metabolic rate pertained with the appearance of an effect of body size and composition. These results point toward an increasing metabolic burden for the maintenance of homeodynamics as health declines in nonagenarians, and this has implications for contraction of metabolic reserve that may potentially accelerate the path to disability. PMID- 24162338 TI - Molecular-cytogenetic characterization of a higher plant centromere/kinetochore complex. AB - The centromeric region of a telocentric field bean chromosome that resulted from centric fission of the metacentric satellite chromosome was microdissected. The DNA of this region was amplified and biotinylated by degenerate oligonucleotide primed polymerase chain reaction (DOP-PCR)/linker-adapter PCR. After fluorescence in situ hybridization (FISH) the entire chromosome complement of Vicia faba was labelled by these probes except for the nucleolus organizing region (NOR) and the interstitial heterochromatin, the chromosomes of V. sativa and V. narbonensis were only slightly labelled by the same probes. Dense uniform labelling was also observed when a probe amplified from a clearly delimited microdissected centromeric region of a mutant of Tradescantia paludosa was hybridized to T. paludosa chromosomes. Even after six cycles of subtractive hybridization between DNA fragments amplified from centromeric and acentric regions no sequences specifically located at the field bean centromeres were found among the remaining DNA. A mouse antiserum was produced which detected nuclear proteins of 33 kDa and 68 kDa; these were predominantly located at V. faba kinetochores during mitotic metaphase. DNA amplified from the chromatin fraction adsorbed by this serum out of the sonicated total mitotic chromatin also did not cause specific labelling of primary constrictions. From these results we conclude: (1) either centromere specific DNA sequences are not very conserved among higher plants and are - at least in species with large genomes - intermingled with complex dispersed repetitive sequences that prevent the purification of the former, or (2) (some of) the dispersed repeats themselves specify the primary constrictions by stereophysical parameters rather than by their base sequence. PMID- 24162339 TI - A detailed linkage map around an apple scab resistance gene demonstrates that two disease resistance classes both carry the V f gene. AB - A detailed genetic map has been constructed in apple (Malus x domestica Borkh.) in the region of the v f gene. This gene confers resistance to the apple scab fungus Venturia inaequalis (Cooke) Wint. Linkage data on four RAPD (random amplified polymorphic DNA) markers and the isoenzyme marker PGM-1, previously reported to be linked to the v f gene, are integrated using two populations segregating for resistance to apple scab. Two new RAPD markers linked to v f (identified by bulked segregant analysis) and a third marker previously reported as being present in several cultivars containing v f are also placed on the map. The map around v f now contains eight genetic markers spread over approximately 28 cM, with markers on both sides of the resistance gene. The study indicates that RAPD markers in the region of crab apple DNA introgressed with resistance are often transportable between apple clones carrying resistance from the same source. Analysis of co-segregation of the resistance classes 3A (weakly resistant) and 3B (weakly susceptible) with the linked set of genetic markers demonstrates that progeny of both classes carry the resistance gene. PMID- 24162340 TI - Estimation of the position and effect of a lethal factor locus on a molecular marker linkage map. AB - In the mapping of DNA markers the distortion of segregation of marker genotypes is often observed, which may be caused by a lethal factor acting in filial generations derived from distant crosses. A method is presented for estimating the recombination values between a lethal factor locus and neighboring molecular markers, and the relative viability or fertilization ability of gametes or zygotes affected by the lethal factor in an F2 population using the maximum likelihood method and the expectation conditional maximization (ECM) algorithm. Three selection models of gamete or zygote were considered, and the most likely one was determined by goodness of fit of the observed frequency of the phenotypes to the expected ones under the models. The method was applied to segregation data of molecular markers of an F2 population consisting of 144 individuals derived from a cross between an Indica and a Japonica rice variety. The presence of a lethal factor locus (L) located on chromosome III that caused partial gametic selection in both the male and female sides was suggested. The locus L was tightly linked to RFLP marker number 23 of the RFLP linkage map of Saito et al. (1991a), and the fertilization chance of a male or female gamete possessing the lethal factor was, on average, 41.5% of that of the normal gamete. PMID- 24162341 TI - Both epistatic and additive effects of QTLs are involved in polygenic induced resistance to disease: a case study, the interaction pepper - Phytophthora capsici Leonian. AB - To study the resistance of pepper to Phytophthora capsici, we analyzed 94 doubled haploid (DH) lines derived from the intraspecific F1 hybrid obtained from a cross between Perennial, an Indian pungent resistant line, and Yolo Wonder, an American bell-pepper susceptible line, with 119 DNA markers. Four different criteria were used to evaluate the resistance, corresponding to different steps or mechanisms of the host-pathogen interaction: root-rot index, receptivity, inducibility and stability. Three distinct ANOVA models between DNA marker genotypes and the four disease criteria identified 13 genomic regions, distributed across several linkage groups or unlinked markers, affecting the resistance of pepper to P. capsici. Some QTLs were criterion specific, whereas others affect several criteria, so that the four resistance criteria were controlled by different combinations of QTLs. The QTLs were very different in their quantitative effect (R(2) values), including major QTLs which explained 41-55% of the phenotypic variance, intermediate QTLs with additive or/and epistatic action (17-28% of the variance explained) and minor QTLs. Favourable alleles of some minor QTLs were carried in the susceptible parent. The total phenotypic variation accounted for by QTLs reached up to 90% for receptivity, with an important part due to epistasis effects between QTLs (with or without additive effects). The relative impact of resistance QTLs in disease response is discussed. PMID- 24162342 TI - Specific molecular marker of the genes controlling linolenic acid content in rapeseed. AB - In rapeseed, which is an agronomically important oilseed, variation in the linolenic acid content of the oil has been obtained through chemical mutagenesis treatment. Conventional breeding of this quantitative trait, however requires specific molecular markers. By means of biochemical experiments, we have established that the induced variation in linolenic acid content is associated with the fad3 gene encoding the microsomal Delta(15) desaturase. Using a pair of primers specific to this gene and a doubled haploid progeny derived from a low linolenic x high linolenic acid F1hybrid, we have identified a polymorphism of the fad3 alleles between the low- and the high-linolenic acid genotypes. The structure exon/intron of the fad3 DNA sequence seems to be very similar to that of the Arabidopsis fad3 gene. The choice of the primer pair allows specific amplification of one of the two rapeseed fad3 genes. The value and contribution of specific markers to conventional plant breeding is discussed. PMID- 24162343 TI - Use of field observations to characterise genotypic flowering responses to photoperiod and temperature: a soyabean exemplar. AB - Thirty-nine accessions of soyabean [Glycine max (L.) Merrill] and 1 of wild annual soyabean (Glycine soja L.) were sown at two sites in Taiwan in 1989 and 1990 and on six occasions during 1990 at one site in Queensland, Australia. On two of the occasions in Australia additional treatments extended natural daylengths by 0.5 h and 2 h. The number of days from sowing for the first flower to appear on 50% of the plants in each treatment was recorded (f), and from these values the rate of progress towards flowering (1/f) was related to temperature and photoperiod. In photoperiod-insensitive accessions it was confirmed that the rate is linearly related to temperature at least up to about 29 degrees C. In photoperiod-sensitive genotypes this is also the case in shorter daylengths but when the critical photoperiod (P c) is exceeded flowering is delayed. This delay increases with photoperiod until a ceiling photoperiod (P ce) is reached. Between P c and P ce, 1/f is linearly related to both temperature (positive) and photoperiod (negative), but in photoperiods longer than P ce there is no further response to either factor. The resulting triple-intersecting-plane response surface can be defined by six genetically-determined coefficients, the values of which are environment-independent but predict time to flower in any environment, and thus quantify the genotype x environment interaction. By this means the field data were used to characterise the photothermal responses of all 40 accessions. The outcome of this characterisation in conjunction with an analysis of the world wide range of photothermal environments in which soyabean crops are grown lead to the following conclusions: (1) photoperiod-insensitivity is essential in soyabean crops in temperate latitudes, but such genotypes flower too rapidly for satisfactory yields in the tropics; (2) photoperiod-sensitivity appears to be essential to delay flowering sufficiently to allow adequate biomass accumulation in the warm climates of the tropics; (3) contrary to a widely held view, some degree of photoperiod-sensitivity is also needed in the tropics if crop-duration homeostasis is required where there is variation in sowing dates (this is achieved through a photoperiod-controlled delay in flowering which counteracts the seasonal increase in temperature that is correlated with increase in day length); and (4) a greater degree of photoperiod-sensitivity is necessary to provide maturity-date homeostasis for variable sowing dates - a valuable attribute in regions of uncertain rainfall. Since the triple-intersecting-plane response model used here also applies to other species, the use of field data to characterise the photothermal responses of other crops is discussed briefly. PMID- 24162344 TI - Identification of polymorphic, conserved simple sequence repeats (SSRs) in cultivated Brassica species. AB - The application of simple sequence repeat (SSR) genotyping for the characterization of genetic variation in crop plants has been hindered by ready access to useful primer pairs and potentially limited conservation of the repeat sequences among related species. In this phase of work, we report on the identification and characterization of SSRs that are conserved in Brassica napus L. (rapeseed) and its putative progenitors, B. oleracea L. (cabbage, and related vegetable types) and B. rapa (vegetable and oil types). Approximately 140 clones from a size-fractionated genomic library of B. napus were sequenced, and primer pairs were designed for 21 dinucleotide SSRs. Seventeen primer pairs amplified products in the three species and, among these, 13 detected variation between and within species. Unlike findings on SSR information content in human, no relationship could be established between the number of tandem repeats within the target sequence and heterozygosity. All primer pairs have been designed to work under identical amplification conditions; therefore, single-reaction, multiplex polymerase chain reaction (PCR) with these SSRs is possible. Once moderate numbers of primer pairs are accessible to the user community, SSR genotyping may provide a useful method for the characterization, conservation, and utilization of agricultural crop diversity. PMID- 24162345 TI - Identification of quantitative trait loci controlling resistance to gray leaf spot disease in maize. AB - Breeding maize for gray leaf spot (GLS) resistance has been hindered by the quantitative nature of the inheritance of GLS resistance and by the limitations of selection under less than optimumal disease pressure. In order to identify the quantitative trait loci (QTLs) controlling GLS resistance, a cross was made between B73 (susceptible) and Va14 (resistant) to generate a large F2 population. Six GLS disease assessments were made throughout the disease season for over 1000 F2 plants in 1989, and for 600 F2-derived F3 lines replicated in two blocks in 1990. RFLP analysis for78 marker loci representing all ten maize chromosomes was conducted in 239 F2 individuals including those with the extreme GLS disease phenotypes. The GLS disease scores of the three field evaluations, each averaged over six ratings, were separately used for the interval mapping in order to determine the consistency of the QTL effects. The heavy GLS disease pressure, meticulous disease ratings, and large population size of this study afforded us the sensitivity for detecting QTL effects. QTLs located on three chromosomes (1, 4, and 8) had large effects on GLS resistance, each explaining 35.0-56.0%, 8.8 14.3%, and 7.7-11.0% of the variance, respectively. These three QTL effects were remarkably consistent across three disease evaluations over 2 years and two generations. Smaller QTL effects were also found on chromosomes 2 and 5, but the chromosome-5 effect might be a false positive because it was not repeatable even in the same location. The chromosome-1 QTLs had the largest effect or highest R(2) reported for any quantitative trait to-date. Except for the chromosome-4 gene, which was from the susceptible parent B73, the resistance alleles at all QTL were derived from Va14. The resistance QTLs on chromosomes 1 and 2 appear to have additive effects, but those on chromosomes 4 and 8 are dominant and recessive, respectively. Significant interaction between the QTLs on chromosomes 1 and 4 was detected in all three evaluations. Cumulatively, the four QTLs identified in this study explained 44, 60, and 68% of the variance in F2, and in F3 replications 1 and 2, respectively. PMID- 24162346 TI - A genetic linkage map of papaya based on randomly amplified polymorphic DNA markers. AB - A genetic linkage map of papaya (Carica papaya L.) was constructed using randomly amplified polymorphic DNA (RAPD) markers and a F2 population derived from a University of Hawaii UH breeding line 356 x 'Sunrise' cross. A total of 596 10 mer primers were screened, and 96 polymorphisms were detected. At LOD 4.0, 62 of these markers mapped to 11 linkage groups comprising 999.3 cM. About 80% of the markers conformed to expected Mendelian segregation ratios. We have mapped the locus that determines sex to a 14-cM region flanked by RAPD markers. The results demonstrate the usefulness of RAPD markers for developing a basic genetic linkage map in papaya. PMID- 24162347 TI - The regulatory role of vernalization in the expression of low-temperature-induced genes in wheat and rye. AB - Low temperature is one of the primary stresses limiting the growth and productivity of wheat (Triticum aestivum L.) and rye (Secale cereale L.). Winter cereals low-temperature-acclimate when exposed to temperatures colder than 10 degrees C. However, they gradually lose their ability to tolerate below-freezing temperatures when they are maintained for long periods of time in the optimum range for low-temperature acclimation. The overwinter decline in low-temperature response has been attributed to an inability of cereals to maintain low temperature-tolerance genes in an up-regulated state once vernalization saturation has been achieved. In the present study, the low-temperature-induced Wcs120 gene family was used to investigate the relationship between low temperature gene expression and vernalization response at the molecular level in wheat and rye. The level and duration of gene expression determined the degree of low-temperature tolerance, and the vernalization genes were identified as the key factor responsible for the duration of expression of low-temperature-induced genes. Spring-habit cultivars that did not have a vernalization response were unable to maintain low-temperature-induced genes in an up-regulated condition when exposed to 4 degrees C. Consequently, they were unable to achieve the same levels of low-temperature tolerance as winter-habit cultivars. A close association between the point of vernalization saturation and the start of a decline in the Wcs120 gene-family mRNA level and protein accumulation in plants maintained at 4 degrees C indicated that vernalization genes have a regulatory influence over low-temperature gene expression in winter cereals. PMID- 24162348 TI - Development of pre-isogenic lines for rice blast-resistance by marker-aided selection from a recombinant inbred population. AB - To increase the available set of near-isogenic lines (NILs) for blast-resistance in rice, we have developed a general method for establishing NILs from populations of fixed recombinants that have been used for gene mapping. We demonstrated the application of this method by the selection of lines carrying genes from the rice cultivar Moroberekan. Moroberekan is a West African japonica cultivar that is considered to have durable resistance to rice blast. Multiple genes from Moroberekan conferring complete and partial resistance to blast have previously been mapped using a recombinant inbred (RI) population derived from a cross between Moroberekan and the highly and broadly susceptible indica cultivar CO39. To analyze individual blast-resistance genes, it is desirable to transfer them individually into a susceptible genetic background. This RI population, and the associated data sets on blast reaction and restriction fragment length polymorphism (RFLP) genotypes, were used for selection of lines likely to carry individual blast-resistance genes and a minimum number of chromosomal segments from Moroberekan. Because skewed segregation in the RI population favored CO39 (indica) alleles, resistant lines carrying 8.7-17.5% of Moroberekan alleles (the proportion expected after two or three backcrosses) could be selected. We chose three RI lines carrying different complete resistance genes to blast and two RI lines carrying partial resistance genes to blast as potential parents for the development of NILs. These lines were subjected to genetic analysis, which allowed clarification of some issues that could not be resolved during the initial gene-mapping study. PMID- 24162349 TI - Heritability estimates for callus growth and regeneration in desmodium. AB - The F2 and F3 generations of two crosses (6123*13083 and 6123*144, with 6123 the regenerating parent) were evaluated for callus growth and regeneration capacity. Based on joint scaling tests and variance partitioning, neither callus growth nor regeneration fitted a simple additive-dominant genetic model. Heritability estimates obtained from parent-offspring regression analyses ranged from 0.65 to 0.77 for callus growth and from 0.19 to 0.46 for regeneration, with the range in both influenced by the cross and numerical scale employed. Members of two F3 families exhibited much more vigorous and prolific regeneration than the regenerating parental genotype. Because many individuals in the segregating generations showed no evidence of regeneration, population distributions for this trait were severely truncated, or censored. Regression-order analysis was used to estimate means and variances of these censored populations. The association between poor callus growth and high regeneration capacity observed in the parental lines was absent from the F2 and F3 generations, indicating that no association between callus growth and regeneration was present. PMID- 24162350 TI - Molecular-marker analysis of seed-weight: genomic locations, gene action, and evidence for orthologous evolution among three legume species. AB - The objectives of this study were to use molecular markers to: (1) identify quantitative trait loci (QTL) controlling seed-weight in soybean, (2) characterize the genetic basis of seed-weight expression, and (3) determine whether soybean shares orthologous seed-weight genes with cowpea and/or mung bean. An F2 population was developed between a large-seeded Glycine max breeding line and a small-seeded G. soja plant introduction. DNA samples from 150 F2 individuals were analyzed with 91 polymorphic genetic markers, including RFLPs, RAPDs and SSRs. Seed-weight was analyzed by randomly sampling 100 seeds from each of 150 greenhouse-grown F2 individuals, and their 150 F2?3 lines, from a replicated field trial. Markers associated with seed-weight were identified using the computer program MapMaker-QTL and a one-way analysis of variance. Three and five markers were significantly associated with seed-weight variation (P<0.01) in the F2 and F2?3 generations, respectively. Tests for digenic epistasis revealed three significant interactions in both generations. In a combined analysis, these markers and interactions explained 50 and 60% of the phenotypic variation for seed-weight in the F2 and F2?3 generations, respectively. Comparison of our results in soybean (Glycine) with those previously reported in cowpea and mung bean (Vigna) indicated that soybean and cowpea share an orthologous seed-weight gene. In both species, a genomic region significantly associated with seed-weight spanned the same RFLP markers in the same linkage order. A significant digenic interaction involving this genomic region was conserved in all three species. These results suggest that the exploitation of "comparative QTL mapping" is an invaluable tool for quantitative geneticists working with poorly characterized plant systems. PMID- 24162351 TI - Linkage between RFLP markers and genes affecting kernel hardness in wheat. AB - A molecular-marker linkage map of wheat (Triticum aestivum L. em. Thell) provides a powerful tool for identifying genomic regions influencing breadmaking quality. A variance analysis for kernel hardness was conducted using 114 recombinant inbred lines (F7) from a cross between a synthetic and a cultivated wheat. The major gene involved in kernel hardness, ha (hard), known to be on chromosome arm 5DS, was found to be closely linked with the locus Xmta9 corresponding to the gene of puroindoline-a. This locus explained around 63% of the phenotypic variability but there was no evidence that puroindoline-a is the product of Ha (soft). Four additional regions located on chromosomes 2A, 2D, 5B, and 6D were shown to have single-factor effects on hardness, while three others situated on chromosomes 5A, 6D and 7A had interaction effects. Positive alleles were contributed by both parents. A three-marker model explains about 75% of the variation for this trait. PMID- 24162352 TI - Inter- and intraspecific polymorphism at chloroplast SSR loci and the inheritance of plastids in Pinus radiata D. Don. AB - DNA sequence analysis of chloroplast genomes has revealed many short nucleotide repeats analogous to nuclear microsatellites, or simple sequence repeats (SSRs). We designed PCR primers flanking five of these regions identified in the chloroplast sequence from Pinus thunbergii and tested them for amplification in Pinus radiata, P. elliotii, P. taeda, P. strobus, Pseudotsuga menziesii, Cupressus macrocarpa, four New Zealand native conifer species (Podocarpus totara, Podocarpus hallii, Podocarpus nivalis, Agathis australis), and four angiosperms (Vitex lucens, Nestegis cunninghamii, Actinidia chinensis, and Arabidopsis thaliana). A PCR product in the expected size range was amplified from all species and interspecific polymorphism was detected at all five loci. Intraspecific polymorphism was detected in P. radiata with four of the five primer pairs. One of these polymorphic chloroplast SSR (cpSSR) was then used to determine the inheritance of chloroplasts in 206 progeny from four control pollinated, full-sibling P. radiata families. Approximately 99% of the progeny had the cpSSR variant of the pollen parent indicating that in Pinus radiata, like most other conifers, chloroplasts are typically inherited from the paternal parent. These results suggest that polymorphic chloroplast SSRs will be a valuable tool for studying chloroplast diversity, cyto-nuclear disequilibrium, and plastid inheritance in a range of species, and for the analysis of gene flow via pollen and paternity in species with paternal transmission of chloroplasts. PMID- 24162353 TI - Origin and diversity of North American hard spring wheats. AB - Genetic diversity is an important safeguard against crop vulnerability to biotic and abiotic stresses. Coefficient-of-parentage (COP) values of 248 North American hard spring wheat (Triticum aestivum L. em. Thell) cultivars released from 1901 to 1991 were used to estimate the genetic similarity of cultivars. COP values were used: to (1) quantify germ plasm sources and their contributions to the North American hard spring wheat gene pool; (2) measure changes in genetic diversity through time; and (3) identify major groupings of related cultivars. Landraces and local cultivars that contributed to the formation of the gene pool were: spring wheat (64%), winter wheat (16%), T. turgidum var. durum L. (10%), and T. turgidum var. emmer L. (8%). 'Fife', 'Hard Red Calcutta', and 'Turkey Red' accounted for 18%, 13%, and 8%, respectively, of the hard spring wheat origins. 'Era' and 'Butte' in the US, and 'Neepawa' and 'HY 320' in Canada, were the most commonly used named parents of cultivars released from 1981 to 1991. Both Canada and US had the greatest level of similarity among new cultivar releases in the 1930s (Canada: r=0.39, US: r=0.34). Genetic similarity in the US declined to r=0.14 in the 1940s and remained relatively constant thereafter. Similarity among released Canadian cultivars remained relatively high until the 1970s when the introduction of new market classes resulted in a 50% reduction in genetic similarity to approximately the same level of similarity found in the US. Cluster analysis was used to group cultivars released after 1941 into 13 clusters of similar genotypes. The cultivar clusters may have value for the stratified sampling of spring wheat germ plasm or in identifying diverse germ plasm for intermating. PMID- 24162354 TI - Relationships among tetraploid wheat (Triticum turgidum L.) landrace populations revealed by isozyme markers and agronomic traits. AB - Diversity and relationships among ten tetraploid wheat landrace populations, collected from different localities in the central highlands of Ethiopia, were studied using isozyme markers and agronomic traits. This type of analysis in crop species is fundamental for designing optimal germ plasm collection, management practices and for developing an index for parental selection. The populations differed in allelic frequencies. Gene-diversity estimates showed that the populations encompass an appreciable amount of variation. However, differentiation between them was low, as was also confirmed by the presence of gene flow. Much of the diversity (85%), was attributable to the within-population level. The genetic distances were mostly small with the exception of those between a few pairs of populations. Thus, the relationships discerned among the populations were more of a similarity nature which could be ascribed to sharing a common ancestral population and/or adaptation to similar climatic conditions. The pattern of genetic divergence appeared to be independent of geographic distance. Considerable divergence in the agronomic traits was observed for certain populations. Cluster analyses of the isozyme and agronomic data produced different patterns and memberships of groupings. This lack of agreement could be ascribed to the different forces of evolution acting on isozyme markers and agronomic traits since agronomic traits, are the prime target of artificial selection. The clustering based on agronomic traits resulted in grouping together populations with similar agronomic performance. The results of this study suggest that taking more samples within a locality or population would be a better approach to capture the range of variation in the landrace populations of the central highlands of Ethiopia. PMID- 24162355 TI - Comparison of RAPD and RFLP markers for mapping F2 generations in maize (Zea mays L.). AB - The F2 generations from two maize crosses were used to compare the ability of RAPD and RFLP marker systems to create a genetic linkage map. Both RFLPs and RAPDs were shown to provide Mendelian-type markers. Most of the RFLPs (80%) could be placed with a good level of certainty (LOD>4) on the genetic linkage map. However, because of their dominant nature, only between 37% and 59% of the RAPDs could be placed with such a LOD score. The use of combined data from RFLPs and RAPDs increases the level of information provided by RAPDs and allows the creation of a combined RFLP/RAPD genetic linkage map. Thus, the RAPD technique was found to be a powerful method to provide improved probes coverage on a previously created RFLP map and to locate markers linked to chromosomal regions of interest. PMID- 24162356 TI - Microsatellites as DNA markers in Sitka spruce. AB - Nine microsatellite loci were found by screening a genomic DNA library of Sitka spruce (Picea sitchensis) with the four oligonucleotide probes (TG), (CAC), (GATA) and (AT). Pairs of flanking primers were generated for seven microsatellites. Five primer pairs were used to screen up to 58 Sitka spruce clones. The five loci SStg3a, SStg4, SStg4a, SStg4c and SSgataS were found to have 15, 13, 4, 3 and 6 different length alleles respectively, and in using a combination of them almost all 58 Sitka spruce genotypes could be identified. The five primer pairs were successful in amplifying DNA from two other spruce species (Picea albutilia and Picea smithiana), while only one primer pair could amplify DNA from the pine species, Pinus sylvestris and Pinus latifolia. The inheritance of microsatellites in Sitka spruce was co-dominant Mendelian. PMID- 24162357 TI - Evaluation of barley chromosome-3 yield QTLs in a backcross F2 population using STS-PCR. AB - Chromosome 3 displayed the two largest yield QTLs in a previous study of 150 doubled haploid lines derived from a cross of Steptoe and Morex barley varieties. Low-copy number RFLP markers, detected using Southern analysis, are excellent tools for generating robust linkage maps as demonstrated by the Steptoe and Morex map produced by the North American Barley Genome Mapping Project (SM NABGMP). However, this technique can be cumbersome when applied to practically oriented plant breeding programs. In the present report, we demonstrate the conversion of RFLPs to more practically useful PCR-based markers that are co-dominant and allelic to the barley chromosome-3 RFLP markers from which they derive. We have used these sequence-tagged-site (STS) PCR markers to evaluate the putative yield QTL components of the Steptoe chromosome 3 in a Morex backcross population. Headshattering, plant lodging, and yield measurements are reported from five replicated field experiments conducted under diverse growing conditions in Montana. Our study detected significant effects for all three traits in a chromosomal region that evidently corresponds to the larger of the two previously reported chromosome-3 QTLs. However, we failed to detect any yield or other effects which might be coincidental to the second largest yield QTL. The genetic effects of the yield QTL identified in our first backcross breeding population show similar magnitude, environmental interactions, and association with lodging and headshattering QTLs observed in the SM NABGMP experiments. Our study elucidates complex environmental conditioning for headshattering and plant lodging which probably underlie the variable yield effects observed under different growing conditions. PMID- 24162358 TI - Inheritance and restriction fragment length polymorphism of chloroplast DNA in the genus Coffea L. AB - CpDNA variation among 52 tree samples belonging to 25 different taxa of Coffea and two species of Psilanthus was assessed by RFLP analysis on both the total chloroplast genome and the atpB-rbcL intergenic region. Twelve variable characters were distinguished allowing the identification of 12 different plastomes. The low sequence divergence observed might suggest that Coffea is a young genus. The results were in contradiction with the present classification into two genera. Additionally, cpDNA inheritance was studied in interspecific hybrids between C. arabica and C. canephora, and in an intraspecific progeny of C. canephora, using PCR-based markers. Both studies showed exclusively maternal inheritance of cpDNA. PMID- 24162359 TI - The effects of mating design on introgression between chromosomally divergent sunflower species. AB - Population genetic theory suggests that mating designs employing one or more generations of sib-crossing or selfing prior to backcrossing are more effective than backcrossing alone for moving alleles across linkage groups where effective recombination rates are low (e.g., chromosomally divergent linkages). To test this hypothesis, we analyzed the effects of chromosomal structural differences and mating designs on the frequency and genomic distribution of introgressed markers using the domesticated sunflower, Helianthus annuus, and one of its wild relatives, H. petiolaris, as the experimental system. We surveyed 170 progeny, representing the end products of three different mating designs (design I, P-F1 BC1-BC2-F2-F3; design II, P-F1-F2-BC1-BC2-F3; and design III, P-F1-F2-F3-BC1 BC2), for 197 parental RAPD markers of known genomic location. Comparison of observed patterns of introgression with expectations based on simulations of unrestricted introgression revealed that much of the genome was protected from introgression regardless of mating design or chromosomal structural differences. Although the simulations indicated that all markers should introgress into multiple individuals in each of the three mating designs, 20 of 58 (34%) markers from collinear linkage groups, and 112 of 139 (81%) markers from rearranged linkage groups did not introgress. In addition, the average size of introgressed fragments (12.2 cM) was less than half that predicted by theoretical models (26 33 cM). Both of these observations are consistent with strong selection against introgressed linkage blocks, particularly in chromosomally divergent linkages. Nonetheless, mating designs II and III, which employed one and two generations of sib-mating, respectively, prior to backcrossing, were significantly more effective at moving alleles across both collinear and rearranged linkages than mating design I, in which the backcross generations preceded sib-mating. Thus, breeding strategies that include sib-crossing, in combination with backcrossing, should significantly increase the effectiveness of gene transfer across complex genic or chromosomal sterility barriers. PMID- 24162360 TI - Chromosomal locations of genes that control major RNA-degrading activities in common wheat (Triticum aestivum L.). AB - Seventeen RNA-degrading enzymes of common wheat, with apparent molecular masses from 42.2 kDa to 16.3 kDa, were observed by the RNA-SDS-PAGE assay. To determine their chromosome locations, all chromosome arms of common wheat except 4BS were assayed in their null condition by using a set of ditelosomic or nullitetrasomic lines of the cultivar Chinese Spring. Our results showed that only one chromosome location each was identified for the 22.8-kDa and the 21.2-kDa enzymes, as well as for the 21.6 kDa enzyme, and they are on chromosome arms 2AS and 2DS, respectively. Loci controlling the 20.1 kDa activity were on chromosome arms 2AL, 4BS, 4DS and 6BS. The locus or loci coding for the gene(s) of the 42.2-kDa, 40.9 kDa and 39.2-kDa enzymes were probably ocated on chromosome arm 5AS, and their expression, in agreement with most other RNA-degrading enzyme activities were stimulated when chromosome arm 5AL was missing, indicating a inhibiting locus on 5AL. Our data suggested that the 31.9-kDa, 30.6-kDa and 29.6-kDa enzymes were possibly products of a common precursor which might be coded by a gene(s) on chromosome arm 6BS, and that the processing is co-regulated by loci on chromosome arms 2BS, 3DS, 6AL, 6BL and 7BS. The remaining of the enzyme activities were consistently found in all of the lines tested, and thus are presumably encoded by multiple loci. The only other possibility is that, their loci may be on chromosome arm 4BS which we have not assayed in its null condition. PMID- 24162361 TI - In situ growth of lamellar ZnTiO3 nanosheets on TiO2 tubular array with enhanced photocatalytic activity. AB - We report a self-sacrificed in situ growth design toward preparation of ZnTiO3 TiO2 heterojunction structure. Highly reactive zinc oxide colloidal particles derived by laser ablation in liquids can react with TiO2 nanotubes to form a lamellar ZnTiO3 nanosheet structure in a hydrothermal-treatment process. Such hybrid structural product was characterized by X-ray diffraction, scanning and transmission electron microscopy, UV-vis diffuse reflection spectroscopy and X ray photoelectron spectroscopy. The enhanced photocatalytic activity of the hybrid structure toward degradation of methyl orange (MO) and pentachlorophenol (PCP) molecules was demonstrated and compared with single phase TiO2, as a result of the efficient separation of light excited electrons and holes at the hetero interfaces in the two semiconductors. PMID- 24162362 TI - Deposition and organisation of cell wall polymers during maturation of poplar tension wood by FTIR microspectroscopy. AB - To advance our understanding of the formation of tension wood, we investigated the macromolecular arrangement in cell walls by Fourier transform infrared microspectroscopy (FTIR) during maturation of tension wood in poplar (Populus tremula x P. alba, clone INRA 717-1B4). The relation between changes in composition and the deposition of the G-layer in tension wood was analysed. Polarised FTIR measurements indicated that in tension wood, already before G layer formation, a more ordered structure of carbohydrates at an angle more parallel to the fibre axis exists. This was clearly different from the behaviour of opposite wood. With the formation of the S2 layer in opposite wood and the G layer in tension wood, the orientation signals from the amorphous carbohydrates like hemicelluloses and pectins were different between opposite wood and tension wood. For tension wood, the orientation for these bands remains the same all along the cell wall maturation process, probably reflecting a continued deposition of xyloglucan or xylan, with an orientation different to that in the S2 wall throughout the whole process. In tension wood, the lignin was more highly oriented in the S2 layer than in opposite wood. PMID- 24162363 TI - Trends in heart failure mortality in Poland between 1980 and 2010. AB - INTRODUCTION: Data regarding standardized trends in mortality from heart failure (HF) in the general population are limited. OBJECTIVES: The aim of the study was to evaluate trends in HF mortality in Poland in the years 1980-2010. PATIENTS AND METHODS: An analysis of a database of mortality records from 1980-2010 based on National Statistics was performed. Mortality trends for HF by age and sex were analyzed by polynomial or linear regression. RESULTS: Total crude numbers of HF deaths in 1980 were 21,519 and 23,008 for women and men, respectively, whereas, in 2010, there were 23,304 and 19,558. There was a significant change in mortality trends for HF, from a decline during the first phase of the study to an increase during the most recent years, 2005-2010 (P <0.005 for changes of trends for both sexes). The lowest value reached in 2005 constituted 47% and 41% of the baseline for women and men, respectively. These ratios increased to 59% and 52% in 2010. Stratification by age and sex brought similar results, with the exception of the youngest groups, which showed initial increases in the rates for the years 1980-1985. CONCLUSIONS: There was a significant decline in the rates of HF mortality in the Polish population for both men and women, showing a maximal reduction of about 50% around 2005. However, between 2005 and 2010, a significant increase in the rates of HF mortality was observed (crude difference equaled 12% for women and 11% for men). It is unknown whether this is a temporary or permanent trend, and the issue requires further investigation. PMID- 24162364 TI - Controlled functionalization of graphene oxide with sodium azide. AB - We present the first example of azide functionalization on the surface of graphene oxide (GO), which preserves thermally unstable groups in GO through the mild reaction with sodium azide in solids. Experimental evidence, by (15)N solid state NMR and other spectroscopic methods, indicates the substitution of organosulfate with azide anions as the reaction mechanism. PMID- 24162365 TI - Gitelman's syndrome with vomiting manifested by severe metabolic alkalosis and progressive renal insufficiency. AB - Gitelman's syndrome is an autosomal recessive salt-losing tubulopathy showing hypokalemic hypomagnesemic hypocalciuria with metabolic alkalosis and hyperreninemic hyperaldosteronism. This syndrome is caused by mutations in the SLC12A3 gene that encodes sodium-chloride cotransporter expressed at the apical membrane of renal distal convoluted tubule. Symptoms and renal outcomes of Gitelman's syndrome are, in general, mild and benign, and renal insufficiency from Gitelman's syndrome associated with long-standing hypokalemia and volume depletion is extremely rare. Herein, we report a 27-year-old male patient with Gitelman's syndrome who manifested renal failure, hypokalemia, severe metabolic alkalosis and altered mentality. About one year ago, the patient had been transferred to Seoul National University Hospital, because of unsolved hypokalemia, and was diagnosed as Gitelman's syndrome by clinical features and genetic analysis of the SLC12A3 gene. The patient carries a missense mutation at one allele of SLC12A3 gene (c.781C>T, p.Arg261Cys). His mother is also heterozygous for the same mutation and she had a history of hypokalemia. On this admission, the patient had recurrent bouts of vomiting induced by psychiatric eating disorder and showed severe volume depletion with hypotension, azotemia and metabolic alkalosis. Intense hydration therapy and emergency hemodialysis transiently improved his fluid-electrolyte imbalance and renal function. However, renal dysfunction progressively deteriorated despite the medical treatment. Our findings suggest that even in Gitelman's syndrome, constant monitoring for volume status and other comorbid conditions should be employed to prevent progressive renal injury. PMID- 24162366 TI - Active impedance metasurface with full 360 degrees reflection phase tuning. AB - Impedance metasurface is composed of electrical small scatters in two dimensional plane, of which the surface impedance can be designed to produce desired reflection phase. Tunable reflection phase can be achieved by incorporating active element into the scatters, but the tuning range of the reflection phase is limited. In this paper, an active impedance metasurface with full 360 degrees reflection phase control is presented to remove the phase tuning deficiency in conventional approach. The unit cell of the metasurface is a multiple resonance structure with two resonance poles and one resonance zero, capable of providing 360 degrees reflection phase variation and active tuning within a finite frequency band. Linear reflection phase tuning can also be obtained. Theoretical analysis and simulation are presented and validated by experiment at microwave frequency. The proposed approach can be applied to many cases where fine and full phase tuning is needed, such as beam steering in reflectarray antennas. PMID- 24162368 TI - Deoxygenation alters bacterial diversity and community composition in the ocean's largest oxygen minimum zone. AB - Oceanic oxygen minimum zones (OMZs) have a central role in biogeochemical cycles and are expanding as a consequence of climate change, yet how deoxygenation will affect the microbial communities that control these cycles is unclear. Here we sample across dissolved oxygen gradients in the oceans' largest OMZ and show that bacterial richness displays a unimodal pattern with decreasing dissolved oxygen, reaching maximum values on the edge of the OMZ and decreasing within it. Rare groups on the OMZ margin are abundant at lower dissolved oxygen concentrations, including sulphur-cycling Chromatiales, for which 16S rRNA was amplified from extracted RNA. Microbial species distribution models accurately replicate community patterns based on multivariate environmental data, demonstrate likely changes in distributions and diversity in the eastern tropical North Pacific Ocean, and highlight the sensitivity of key bacterial groups to deoxygenation. Through these mechanisms, OMZ expansion may alter microbial composition, competition, diversity and function, all of which have implications for biogeochemical cycling in OMZs. PMID- 24162369 TI - On the effects of the dispersant Corexit 9500(c) during the degradation process of n-alkanes and PAHs in marine sediments. AB - In many coastal countries, oil spill contingency plans include several alternatives for removal of the spilled oil from the ocean. Frequently, these plans include dispersants. Because this process applies chemical substances that may add toxicity to oil that already contains toxic compounds, it is, at times, a controversial method to fight oil pollution. Additionally, local conditions may result in particular complications. We investigated the possible effects of the dispersant Corexit 9500(c) under conditions similar to those of subtropical oceans. We used fuel oil #6+ diesel as the test mixture. Under certain conditions, at least part of the dispersed oil may reach the sediment, particularly if the dispersant is applied in coastal waters. Nine experimental units were used in this experiment. Similar conditions of water temperature, salinity, air fluxes into the experimental units, and hydrocarbon concentrations in sediments were used. Two treatments and one control, each one with three replicates, were carried out. We concentrated our investigation on sediment, although measurements of water were also taken. Our results suggest that once the oil has penetrated the sediment, no significant differences exist between oil that contains dispersant and oil without dispersant. Noticeable degradation of aliphatic hydrocarbons occurred mainly in the low molecular weight aliphatic hydrocarbons and not in the others. Apparently, degradation of aromatics was easier than that of alkanes. However, some differences were noticed for the degradation of PAHs in the sediment, suggesting a faster degradation under particular conditions in aerobic environments such as under this experiment. PMID- 24162370 TI - Allium cepa L. as a bioindicator to measure cytotoxicity of surface water of the Quatorze River, located in Francisco Beltrao, Parana, Brazil. AB - Due to an increase in water consumption in the industrial sector and within the Brazilian population, surface water that receives wastewater from industries, domestic sewage, agricultural industries, and sewage treatment stations can pollute water bodies when not properly treated. The water quality has been linked to catchment characteristics and intensity of agricultural activities. Thus, the aim of this study was to monitor the cytotoxic potential of the water of the Quatorze River, located in the town of Francisco Beltrao, Parana, Brazil, along its route in the rural area, using the root meristematic cells of Allium cepa L. as a bioindicator. The results showed that the water at points 2, 3, and 4 were not cytotoxic because the rates of A. cepa cell division were unaltered. Point 1 had presented a mitotic index that was statistically larger than the negative control, indicating that this water contained substances with mitogenic capacity, as demonstrated by elevated values in chemical oxygen demand (COD) and biochemical oxygen demand (BOD). However, the mitotic index values decreased along the route of the river (point 1 to point 4), possibly indicating a mechanism of self-purification, despite having received other sources of pollution. Thus, the results of this study show that the water of the Quatorze River should undergo periodic environmental monitoring at different times of the year, including cytotoxicity analysis, to evaluate the principal sources of contamination to maintain the quality of the river water and, consequently, to maintain human health and equilibrium of the entire ecosystem. PMID- 24162371 TI - Mid-infrared spectroscopic assessment of nanotoxicity in gram-negative vs. gram positive bacteria. AB - Nanoparticles appear to induce toxic effects through a variety of mechanisms including generation of reactive oxygen species (ROS), physical contact with the cell membrane and indirect catalysis due to remnants from manufacture. The development and subsequent increasing usage of nanomaterials has highlighted a growing need to characterize and assess the toxicity of nanoparticles, particularly those that may have detrimental health effects such as carbon-based nanomaterials (CBNs). Due to interactions of nanoparticles with some reagents, many traditional toxicity tests are unsuitable for use with CBNs. Infrared (IR) spectroscopy is a non-destructive, high throughput technique, which is unhindered by such problems. We explored the application of IR spectroscopy to investigate the effects of CBNs on Gram-negative (Pseudomonas fluorescens) and Gram-positive (Mycobacterium vanbaalenii PYR-1) bacteria. Two types of IR spectroscopy were compared: attenuated total reflection Fourier-transform infrared (ATR-FTIR) and synchrotron radiation-based FTIR (SR-FTIR) spectroscopy. This showed that Gram positive and Gram-negative bacteria exhibit differing alterations when exposed to CBNs. Gram-positive bacteria appear more resistant to these agents and this may be due to the protection afforded by their more sturdy cell wall. Markers of exposure also vary according to Gram status; Amide II was consistently altered in Gram-negative bacteria and carbohydrate altered in Gram-positive bacteria. ATR FTIR and SR-FTIR spectroscopy could both be applied to extract biochemical alterations induced by each CBN that were consistent across the two bacterial species; these may represent potential biomarkers of nanoparticle-induced alterations. Vibrational spectroscopy approaches may provide a novel means of fingerprinting the effects of CBNs in target cells. PMID- 24162372 TI - Measurements of computed tomography dose index for clinical scans. AB - Dose assessment in computed tomography is nowadays based on indicators such as the weighted computed tomography dose index (CTDIw) and the volume-weighted computed tomography dose index (CTDIvol), both measured only on single-axial scans. The aim of this study is to extend the set of CT protocols suitable in CTDIvol,w evaluation and therefore to perform measurements directly on clinical CT scans. With this purpose, the present work follows the methodology proposed by the American Association of Physicists in Medicine in the Report No. 111 and focuses on the central cumulative dose DL(0), which predicts CTDIvol,w values for scan length equal to 100 mm. All measurements performed with ion chamber and gafchromic films suggest that it is possible to achieve accurate CTDIvol,w values without selecting single-axial scans tailored to dosimetry. Therefore, it is not always necessary to split dosimetric and clinical CT scanner set-up. PMID- 24162373 TI - Monitoring of the neutron production at the Wendelstein 7-X stellarator. AB - The stellarator Wendelstein 7-X (W7-X), presently under construction at the Max Planck-Institute for Plasma Physics in Greifswald, will be equipped with a set of neutron monitors to measure the total annual neutron emission for official documentation and to provide information for plasma diagnostics purposes. The authors performed MCNP calculations to design and optimise the moderator geometry of the monitors to exhibit a nearly energy-independent response as well as particular angular responses for one central and two peripheral monitors. The monitors were designed with up to five neutron detector tubes with different sensitivity to thermal neutrons to cover the expected neutron emission rates of W7-X from 10(11) s(-1) to 10(16) s(-1). A prerequisite for the determination of the neutron emission produced by a D-D plasma is an in-situ calibration of the neutron monitors. Such a procedure requires a MCNP simulation of the entire geometry of the W7-X stellarator. In a first benchmark experiment during the assembly phase of W7-X, the validity of the W7-X MCNP model was tested. PMID- 24162374 TI - Comparison of radiation dose to operator between transradial and transfemoral coronary angiography with optimised radiation protection: a phantom study. AB - A growing concern in applying radial access in cardiac catheterisation is the increased operator radiation exposure. This study used an anthropomorphic phantom to simulate transradial and transfemoral coronary angiography with optimised radiation protection conditions. Operator radiation exposure was measured with thermoluminescent dosemeters at predefined locations. Compared with the femoral route, the radial route was associated with a dose decrease of 15 % at the operator's chest level with optimised radiation shielding. However, radiation exposure to the operator's hand remained significantly higher when applying radial access even with collective protective equipment used (by a factor of 2). Furthermore, the efficiency of operator radiation protection was found to be dependent on the tube incidence. Awareness should be raised about the significant increase of radiation exposure to operators' hands in transradial coronary angiography. Protection to reduce the dose level to the hands is necessary and should be further improved. PMID- 24162375 TI - Intercomparison of Monte Carlo radiation transport codes to model TEPC response in low-energy neutron and gamma-ray fields. AB - Tissue-equivalent proportional counters (TEPC) can potentially be used as a portable and personal dosemeter in mixed neutron and gamma-ray fields, but what hinders this use is their typically large physical size. To formulate compact TEPC designs, the use of a Monte Carlo transport code is necessary to predict the performance of compact designs in these fields. To perform this modelling, three candidate codes were assessed: MCNPX 2.7.E, FLUKA 2011.2 and PHITS 2.24. In each code, benchmark simulations were performed involving the irradiation of a 5-in. TEPC with monoenergetic neutron fields and a 4-in. wall-less TEPC with monoenergetic gamma-ray fields. The frequency and dose mean lineal energies and dose distributions calculated from each code were compared with experimentally determined data. For the neutron benchmark simulations, PHITS produces data closest to the experimental values and for the gamma-ray benchmark simulations, FLUKA yields data closest to the experimentally determined quantities. PMID- 24162376 TI - The mechanical activation of mTOR signaling: an emerging role for late endosome/lysosomal targeting. AB - It is well recognized that mechanical signals play a critical role in the regulation of skeletal muscle mass, and the maintenance of muscle mass is essential for mobility, disease prevention and quality of life. Furthermore, over the last 15 years it has become established that signaling through a protein kinase called the mammalian (or mechanistic) target of rapamycin (mTOR) is essential for mechanically-induced changes in protein synthesis and muscle mass, however, the mechanism(s) via which mechanical stimuli regulate mTOR signaling have not been defined. Nonetheless, advancements are being made, and an emerging body of evidence suggests that the late endosome/lysosomal (LEL) system might play a key role in this process. Therefore, the purpose of this review is to summarize this body of evidence. Specifically, we will first explain why the Ras homologue enriched in brain (Rheb) and phosphatidic acid (PA) are considered to be direct activators of mTOR signaling. We will then describe the process of endocytosis and its involvement in the formation of LEL structures, as well as the evidence which indicates that mTOR and its direct activators (Rheb and PA) are all enriched at the LEL. Finally, we will summarize the evidence that has implicated the LEL in the regulation of mTOR by various growth regulatory inputs such as amino acids, growth factors and mechanical stimuli. PMID- 24162377 TI - Toll-like receptor signaling regulates cisplatin-induced mechanical allodynia in mice. AB - PURPOSE: Cisplatin-treated mice develop a persistent pain state and a condition wherein otherwise innocuous tactile stimuli evoke pain behavior, e.g., tactile allodynia. The allodynia is associated with an up-regulation of activation transcription factor 3 (ATF3) in the dorsal root ganglia (DRG), a factor, which is activated by Toll-like receptors (TLRs). Accordingly, we sought to examine the role of the TLR signaling cascade on allodynia, weight, and changes in DRG ATF3 in cisplatin-treated mice. METHODS: Cisplatin (2.3 mg/kg/day * 6 injections every other day) or vehicle was administered to male wild-type (WT) C57BL/6, Tlr3 (-/ ), Tlr4 (-/-), Myd88 (-/-), Trif (lps2) and Myd88/Trif (lps2) mice. We examined allodynia and body weight at intervals over 30 days, when we measured DRG ATF3 by immunostaining. RESULTS: (1) WT cisplatin-treated mice showed tactile allodynia from day 3 through day 30. (2) The Myd88/Trif (lps2) mice did not show allodynia. (3) In Tlr3 (-/-), Tlr4 (-/-), and Myd88 (-/-) mice, withdrawal thresholds were elevated toward normal versus WT cisplatin-treated mice, but remained decreased as compared to vehicle mice. (4) In Trif (lps2) mice, cisplatin allodynia showed a delayed onset, but persisted. (5) In Tlr3 (-/-), Tlr4 (-/-), Myd88 (-/-), and Myd88/Trif (lps2) mice, the increase in DRG ATF3 was abolished. (6) Weight loss occurred during cisplatin administration, which was exacerbated in mutant as compared to WT mice. CONCLUSIONS: Cisplatin evoked a persistent allodynia and DRG ATF3 expression in WT mice, but these effects were reduced in mice with TLR signaling deficiency. TLR signaling may thus be involved in the mechanisms leading to the cisplatin polyneuropathy. PMID- 24162379 TI - Pharmacokinetics of high-dose simvastatin in refractory and relapsed chronic lymphocytic leukemia patients. AB - PURPOSE: To evaluate the pharmacokinetics of simvastatin at the maximum tolerated dose (MTD) of 7.5 mg/kg, twice daily, in the context of a pilot trial enrolling patients with recurrent and refractory chronic lymphocytic leukemia. METHODS: Patients received simvastatin orally at MTD for 7 days during a 21-day cycle for 6 cycles. Blood samples were collected during cycle 1. Simvastatin lactone and carboxylate concentrations were measured in plasma and peripheral blood mononuclear cells (PBMCs) using a validated HPLC-MS/MS assay. RESULTS: Patients accrued to this study showed high variability in their exposure to simvastatin. Exposure was dose proportional (AUC and C max) as compared to those receiving standard hyperlipidemia therapy. Peak plasma concentrations ranged from 0.08 to 2.2 and from 0.03 to 0.6 MUM for simvastatin lactone and carboxylate, respectively. CONCLUSION: Our study shows that when simvastatin is administered at its MTD, only low micro-molar concentrations are achieved in plasma and PBMCs, which is consistent with the results observed in previous studies with lovastatin, but far lower than the concentrations required for anticancer effects in vitro. However, whether simvastatin at its MTD can confer therapeutic benefits to patients still remains to be determined. PMID- 24162378 TI - Mechanisms of action of tasquinimod on the tumour microenvironment. AB - Tasquinimod is a small molecule with pleiotropic effects on the tumour microenvironment. Tasquinimod inhibits the growth and metastasis of tumour cells in vitro and in vivo. It targets the tumour microenvironment, enhancing the host immune response and inhibiting the angiogenic response. Tasquinimod influences infiltrating myeloid cells in the tumour milieu shifting the balance towards a less immunosuppressive phenotype. Myeloid-derived suppressor cells and tumour associated macrophages are major components of the immunosuppressive microenvironment and as a result promote tumour growth and favour angiogenesis and metastasis formation. Growing evidence indicates that tasquinimod targets these myeloid cells and modulates local tumour immunity by blocking the interaction between the multifunctional protein S100A9 and its ligands receptor of advanced glycation end products and Toll-like receptor 4. Its anti-angiogenic effects are achieved at least in part through these effects on regulatory myeloid cells and also potentially through inactivating histone deacetylase-4 and reducing expression of hypoxia-inducible factor 1-controlled genes. The aim is to comprehensively review the mode of action of tasquinimod as a novel oral anti cancer agent. Based on its unique combination of effects, tasquinimod is a novel agent with clinical therapeutic potential in various solid tumours, both alone and as part of rational combination therapy. PMID- 24162380 TI - Randomized double-blinded, placebo-controlled phase II trial of simvastatin and gemcitabine in advanced pancreatic cancer patients. AB - BACKGROUND: Statins have potential antineoplastic properties via arrest of cell cycle progression and induction of apoptosis. A previous study demonstrated in vitro and in vivo antineoplastic synergism between statins and gemcitabine. The present randomized, double-blinded, phase II trial compared the efficacy and safety of gemcitabine plus simvastatin (GS) with those of gemcitabine plus placebo (GP) in patients with locally advanced and metastatic pancreatic cancer. METHODS: Patients were randomly assigned to receive a 3-week regimen with GS (gemcitabine 1,000 mg/m(2) on days 1, 8, and 15 plus simvastatin 40 mg once daily) or GP (gemcitabine 1,000 mg/m(2) on days 1, 8, and 15 plus placebo). The primary end point was time to progression (TTP). RESULTS: Between December 2008 and April 2012, 114 patients were enrolled. The median TTP was not significantly different between the two arms, being 2.4 months (95 % CI 0.7-4.1 months) and 3.6 months (95 % CI 3.1-4.1 months) in the GS and GP arms, respectively (P = 0.903). The overall disease control rate was 39.7 % (95 % CI 12.2-33.8 %) and 57.1 % (95 % CI 19.8-44.2 %) in the GS and GP arms, respectively (P = 0.09). The 1-year expected survival rates were similar (27.7 and 31.7 % in the GS and GP arms, respectively; P = 0.654). Occurrence of grade 3 or 4 adverse events was similar in both arms, and no patients had rhabdomyolysis. CONCLUSIONS: Adding low-dose simvastatin to gemcitabine in advanced pancreatic cancer does not provide clinical benefit, although it also does not result in increased toxicity. Given the emerging role of statins in overcoming resistance to anti-EGFR treatment, further studies are justified to evaluate the efficacy and safety of combined simvastatin and anti-EGFR agents, such as erlotinib or cetuximab, plus gemcitabine for treating advanced pancreatic cancer. PMID- 24162381 TI - Enhanced efficacy of postoperative adjuvant chemotherapy in advanced gastric cancer: results from a phase 3 randomized trial (AMC0101). AB - PURPOSE: To improve the efficacy of adjuvant chemotherapy with mitomycin-C and fluoropyrimidine (Mf) in gastric cancer, we designed a new regimen (iceMFP) and investigated in a phase III study. METHODS: We randomly assigned 640 patients with resectable and macroscopically recognizable serosa-invading gastric cancer to Mf or iceMFP group during operation. The Mf consisted of intravenous mitomycin C (20 mg/m(2)) at 3-6 weeks after surgery and oral doxifluridine (460-600 mg/m(2)/day) starting 4 weeks after the administration of mitomycin-C and continuing for 3 months. The iceMFP consisted of intraoperative intraperitoneal cisplatin (100 mg), intravenous mitomycin-C (15 mg/m(2)) on postoperative day 1, followed by oral doxifluridine for 12 months, and six monthly intravenous cisplatin (60 mg/m(2)). The primary endpoint was 3-year recurrence-free survival (RFS). RESULTS: A total of 521 patients (258 in Mf, 263 in iceMFP) were eligible for analysis after excluding patients with stage I disease, distant metastasis, or R1 resection. With a median follow-up of 3.5 years, the iceMFP group had a higher RFS (hazard ratio [HR] 0.70; 95 % confidence interval [CI] 0.54-0.90; p = 0.006; 3-year RFS 60 % vs. 50 %) and overall survival (HR 0.71; 95 % CI 0.53 0.95; p = 0.02; 3-year overall survival, 71 vs. 60 %) compared with the Mf group. This was confirmed at extension analysis after a median 6.6 years of follow-up. Both regimens were well tolerated with no differences in surgical complications. CONCLUSION: The efficacy of adjuvant Mf was significantly improved by the additional therapeutic strategies of iceMFP. Considering negative results of AMC0201, these suggest that early initiation of chemotherapy and/or intraperitoneal cisplatin played a distinct role in the improved efficacy. PMID- 24162383 TI - Structure of the clean Gd5Ge4(010) surface. AB - We have characterized the (010) surface of Gd5Ge4 using scanning tunneling microscopy (STM) and x-ray photoelectron spectroscopy. Data from different samples have the following features in common: (1) the surface composition equals the bulk composition to within 5 at.%, both after ion etching and after annealing at temperatures of 400-1200 K; and (2) the surface exhibits terraces of two types. The height of the steps between similar terraces corresponds well to the separation between equivalent layers along the <010> direction in the bulk structure. Density functional theory (DFT) shows that the surface energy of the (0001) plane of hexagonal close-packed Gd is lower than that of the (111) plane of diamond-type Ge, suggesting that surfaces of Gd5Ge4 (for comparable density) should be rich in Gd. Indeed, DFT shows that among the bulk terminations of Gd5Ge4, a pure Ge termination is not favored. Each of the three remaining terminations (two pure Gd and one mixed, Gd-Ge) has its minimum surface energy in a different range of the possible Gd chemical potentials, indicating that different terminations may be stable under different conditions. DFT shows that the heights of the steps between dissimilar terraces, measured in STM, are consistent with the two pure Gd terminations. PMID- 24162382 TI - Roadmap to eliminate gastric cancer with Helicobacter pylori eradication and consecutive surveillance in Japan. AB - In Japan, the annual number of deaths from gastric cancer is approximately 50,000 and there has been no change over the last 50 years. So far, all efforts have been directed toward improving the detection of early gastric cancer by barium X ray and endoscopy, since early cancer has a good prognosis, resulting in Japan having the best diagnostic capability for early gastric cancer worldwide. The 5 year survival rate of gastric cancer patients exceeds 60 % in Japan and is much higher than that in Europe and the US (20 %) because of this superior diagnosis of early gastric cancer. In February 2013, national health insurance coverage for Helicobacter pylori eradication therapy to treat H. pylori-associated chronic gastritis became available in Japan. H. pylori-associated gastritis leads to development of gastric and duodenal ulcers and gastric polyps. Therefore, providing treatment for gastritis is likely to substantially decrease the prevalence of both gastric and duodenal ulcers and polyps. Because treatment for H. pylori-associated gastritis, which leads to atrophic gastritis and gastric cancer, is now covered by health insurance in Japan, a strategy to eliminate gastric cancer-related deaths by taking advantage of this innovation was planned. According to this strategy, patients with gastritis will be investigated for H. pylori infection and those who are positive will receive eradication therapy followed by periodic surveillance. If this strategy is implemented, deaths from gastric cancer in Japan will decrease dramatically after 10-20 years. PMID- 24162384 TI - Immunohistochemical markers in fibrohistiocytic lesions: factor XIIIa, CD34, S 100 and p75. AB - BACKGROUND: The distinction between dermatofibroma (DF), dermatofibrosarcoma protuberans (DFSP), and other benign and malignant cutaneous spindle cell lesions frequently requires immunohistochemical staining. CD34 and factor XIIIa are the most commonly used immunostains; however, they may exhibit aberrant expression and introduce the potential for misdiagnosis. There is some data supporting that p75 and S100A6 may be additional helpful immunohistochemical markers. METHODS: We undertook a large case series examining the use of CD34 and factor XIIIa as well as p75 and S100A6 in DF, cellular DF, DFSP, indeterminate fibrohistiocytic lesion, and scar. RESULTS: As expected, CD34 stained DFSP, although it was usually negative in DF. Factor XIIIa was generally positive in DF and negative in DFSP. There were exceptions in both cases of DF and DFSP. S100A6 was routinely negative in all entities studied. P75 was negative in all cases except DFSP, approximately half of which showed weak and/or patchy positivity. CONCLUSIONS: We conclude that to date, CD34 and factor XIIIa remain the most reliable immunohistochemical markers for DF and DFSP. PMID- 24162385 TI - Expression of follicular helper T-cell markers in primary cutaneous T-cell lymphoma. AB - The follicular helper T cells (TFH) seemed to be expressed in several subsets of T-cell lymphomas. However, their expression in cutaneous T-cell lymphomas (CTCLs) has been rarely described. We investigated the clinical features, histopathological morphology, and expression of TFH markers in CTCLs. Forty-nine patients (24 men and 25 women) diagnosed with CTCL were examined, 25 patients with mycosis fungoides (MF) and 24 with other CTCLs. Immunohistochemical staining for CD10, Bcl-6, inducible costimulator, CXCL13, and PD-1 were performed. Relation between PD-1 and clinical course in MF was evaluated. PD-1 was detected in 21 of 25 (84.0%) MF cases and in 11 of 24 (45.8%) other CTCL cases. Bcl-6, CXCL13, inducible costimulator, and CD10 were occasionally expressed in most T cell lymphomas, including MF. The staining for PD-1 was negative in all the MF cases with large-cell transformation. No correlation was observed between disease course and PD-1 expression rate in the MF cases. In conclusion, among the TFH markers, PD-1 was most frequently expressed in CTCL. PD-1 was expressed in most MF. PD-1 expression rates were significantly higher in MF than in other CTCLs. PMID- 24162386 TI - Fullerene modified C3N4 composites with enhanced photocatalytic activity under visible light irradiation. AB - Fullerene modified C3N4 (C60/C3N4) composites with efficient photocatalytic activity under visible light irradiation were fabricated by a simple adsorption approach. The as-prepared C60/C3N4 composites were characterized by X-ray diffraction (XRD), scanning electron microscopy (SEM), high-resolution transmission electron microscopy (HRTEM), X-ray photoelectron spectroscopy (XPS), UV-vis diffuse reflectance absorption spectra (DRS), Fourier transform infrared spectroscopy (FTIR) and photoluminescence spectra (PL). The photocatalytic degradation of rhodamine B (RhB) by the C60/C3N4 composites was investigated and optimized, suggesting that the optimal amount of C60 in the composites was 1 wt%. The significantly enhanced photocatalytic activity could be attributed to the efficient separation of photogenerated electrons and holes in the C60/C3N4 composites. A possible mechanism of C60/C3N4 composites as photocatalysts was proposed. PMID- 24162387 TI - Survival prolongation after treatment failure of first-line chemotherapy in patients with advanced gastric cancer: combined analysis of the Japan Clinical Oncology group trials JCOG9205 and JCOG9912. AB - BACKGROUND: Two randomized phase III trials of first-line chemotherapy for advanced gastric cancer (JCOG9205 and JCOG9912) conducted by the Japan Clinical Oncology Group used 5-fluorouracil continuous infusion (5-FUci) as the control arm. New active agents (e.g., S-1, irinotecan, and taxanes) were introduced as second-line chemotherapy in the late 1990s after JCOG9205. This combined analysis evaluated whether patients in the 5-FUci arm of JCOG9912 exhibited better survival after adjusting for baseline factors and also investigated the cause of survival prolongation. PATIENTS AND METHODS: The subjects were patients assigned to the 5-FUci arms who met the eligibility criteria of both JCOG9205 and JCOG9912. Overall survival (OS), time to treatment failure (TTF), and survival after treatment failure in the first-line chemotherapy (OS-TTF) were compared after adjusting baseline characteristics using the Cox proportional hazard model. Second-line chemotherapy details were also reviewed. RESULTS: The combined analysis included 89 and 230 patients in JCOG9205 and JCOG9912, respectively. After adjusting baseline characteristics, TTF was similar between groups (HR 0.95; 95 % CI, 0.73-1.26). However, both OS (HR, 0.74; 95 % CI, 0.56-0.99) and OS TTF (HR, 0.76; 95 % CI, 0.57-1.01) were longer in JCOG9912. More patients in JCOG9912 received second-line chemotherapy (83 vs. 52 %) with new drugs (77 vs. 10 %) than in JCOG9205. OS-TTF was substantially prolonged in patients who received second-line chemotherapy (HR, 0.66; 95 % CI, 0.46-0.95). CONCLUSION: OS and OS-TTF were longer in JCOG9912 than JCOG9205. Second-line chemotherapy with new drugs is a potential reason for the observed prolongation of survival. PMID- 24162388 TI - Peripartum cardiomyopathy and familial dilated Cardiomyopathy: a tale of two cases. AB - Peripartum cardiomyopathy (PPCM) is a form of pregnancyrelated heart failure that is associated with considerable morbidity and mortality. Most patients present with acute postpartal heart failure that otherwise resembles the clinical presentation of dilated cardiomyopathy (DCM). There is increasing recognition that PPCM may be due to genetic factors in a significant proportion of cases. There is evidence that at least 7% of cases of PPCM may be part of the spectrum of familial DCM. We report on two cases of PPCM, with relatives demonstrating familial DCM, both patients displaying autosomal dominant patterns of inheritance, and showing severe cardiomyopathy among proband and affected relatives. Family screening for familial DCM should be indicated in all cases of unexplained PPCM. PMID- 24162389 TI - Practice with anxiety improves performance, but only when anxious: evidence for the specificity of practice hypothesis. AB - We investigated for the first time whether the principles of specificity could be extended to the psychological construct of anxiety and whether any benefits of practicing with anxiety are dependent on the amount of exposure and timing of that exposure in relation to where in learning the exposure occurs. In Experiment 1, novices practiced a discrete golf-putting task in one of four groups: all practice trials under anxiety (anxiety), non-anxiety (control), or a combination of these two (i.e., the first half of practice under anxiety before changing to non-anxiety conditions, anxiety-control, or the reverse of this, control anxiety). Following acquisition, all groups were transferred to an anxiety condition. Results revealed a significant acquisition-to-transfer decrement in performance between acquisition and transfer for the control group only. In Experiment 2, novices practiced a complex rock climbing task in one of the four groups detailed above, before being transferred to both a high-anxiety condition and a low-anxiety condition (the ordering of these was counterbalanced across participants). Performance in anxiety transfer was greater following practice with anxiety compared to practice without anxiety. However, these benefits were influenced by the timing of anxiety exposure since performance was greatest when exposure to anxiety occurred in the latter half of acquisition. In the low anxiety transfer test, performance was lowest for those who had practiced with anxiety only, thus providing support for the specificity of practice hypothesis. Results demonstrate that the specificity of learning principle can be extended to include the psychological construct of anxiety. Furthermore, the specificity advantage appears dependent on its timing in the learning process. PMID- 24162390 TI - RFLP loci associated with soybean seed protein and oil content across populations and locations. AB - Molecular markers provide the opportunity to identify marker-quantitative trait locus (QTL) associations in different environments and populations. Two soybean [Glycine max (L.) Merr.] populations, 'Young' x PI 416 937 and PI 97100 x 'Coker 237', were evaluated with restriction fragment length polymorphism (RFLP) markers to identify additional QTLs related to seed protein and oil. For the Young x PI 416937 population, 120 F4-derived lines were secored for segregation at 155 RFLP loci. The F4-derived lines and two parents were grown at Plains, G.a., and Windblow and Plymouth, N.C. in 1994, and evaluated for seed protein and oil. For the PI 97100 x Coker 237 population, 111 F2-derived lines were evaluated for segregation at 153 RFLP loci. Phenotypic data for seed protein and oil were obtained in two different locations (Athens, G.a., and Blackville, S.C.) in 1994. Based on single-factor analysis of variance (ANOVA) for the Young x PI 416937 population, five of seven independent markers associated with seed protein, and all four independent markers associated with seed oil in the combined analysis over locations were detected at all three locations. For the PI 97 100 x Coker 237 population, both single-factor ANOVA and interval mapping were used to detect QTLs. Using single-factor ANOVA, three of four independent markers for seed protein and two of three independent markers for seed oil were detected at both locations. In both populations, singlefactor ANOVA, revealed the consistency of QTLs across locations, which might be due to the high heritability and the relatively few QTLs with large effects conditioning these traits. However, interval mapping of the PI 97100 x Coker 237 population indicated that QTLs identified at Athens for seed protein and oil were different from those at Blackville. This might result from the power of QTL mapping being dependent on the level of saturation of the genetic map. Increased seed protein was associated with decreased seed oil in the PI 97100 x Coker 237 population (r = -0.61). There were various common markers (P[Symbol: see text]0.05) on linkage groups (LG) E, G,H,K, and UNK2 identified for both seed protein and oil. One QTL on LG E was associated with seed protein in both populations. The other QTLs for protein and oil were population specific. PMID- 24162391 TI - A genetic linkage map of azuki bean constructed with molecular and morphological markers using an interspecific population (Vigna angularis x V. nakashimae). AB - A genetic linkage map of azuki bean (Vigna angularis) was constructed with molecular and morphological markers using an F2 population of an interspecific cross between azuki bean and its wild relative, V. nakashimae. In total, 132 markers (108 RAPD, 19 RFLP and five morphological markers) were mapped in 14 linkage groups covering 1250 cM; ten remained unlinked. The clusters of markers showing distorted segregation were found in linkage groups 2, 8 and 12. By comparing the azuki linkage map with those of mungbean and cowpea, using 20 RFLP common markers, some sets of the markers were found to belong to the same linkage groups of the respective maps, indicating that these linkage blocks are conserved among the three Vigna species. This map provides a tool for markerassisted selection and for studies of genome organization in Vigna species. PMID- 24162392 TI - Interspecific hybridization of cultivated rice, Oryza sativa L. with the wild rice, O. minuta Presl. AB - Crosses were made between four varieties ('Mahsuri', 'Setanjung", 'MR84" and 'MR103") of Oryza sativa L. (2n=24, AA) and one accession of O. minuta (2n= 8, BBCC). The seed set obtained ranged between 9.5% and 25.1% depending on the rice variety used. By rescuing 14-day-old embryos and culturing them on 25%-strength MS medium we obtained a total of 414 F1 hybrids. The F1s were vigorous, tillered profusely, were perennial and male-sterile. The hybrids were triploid (ABC) with 36 chromosomes and showed irregular meiosis. The average frequency and range of chromosome associations at metaphase I or early anaphase I pollen mother cells of F1 plants were 29.31(16-36) Is +3.32(0-10) IIs+0.016(0-1) IIIs+0.002(0-1) IVs. Upon backcrossing the original triploid hybrids and colchicine-treated hybrids to their respective recurrent parents, and further embryo rescue, 17 backcross-1 (BC1) plants were obtained. Of all the crosses using MR84, no BC1 plant was obtained even after pollinating 13 894 spikelets of the triploid hybrid. The BC1s were similar in appearence to the F1s and were male-sterile, their chromosome number ranged from 44 to 48. By backcrossing these BC1s and nurturing them through embryo rescue, we obtained 32 BC2 plants. Of these, however, only 18 plants grew vigorously. One of these plants has 24 chromosomes and the other 17 have chromosome numbers ranging between 30 and 37. The 24-chromosome plant was morphologically similar to the O. sativa parent and was partially fertile with a pollen and spikelet fertility of 58.8% and 12.5% respectively. All of the F1 and BC1 plants were found to be resistant to five Malaysian isolates (XO66, XO99, XO100, XO257 and XO319) of Xanthomonas campestris pv oryzae. Amongst the BC2s, the reaction varied from resistant to moderately susceptible. The 24-chromosome BC2 plant was resistant to the four isolates and moderately resistant to isolate XO100 to which the O. sativa parent was susceptible. PMID- 24162393 TI - CMV protecton in transgenic cucumber plants with an introduced CMV-O cp gene. AB - We introduced the CMV-O coat-protein gene into cucumber plants, using a Ti Agrobacterium-mediated transformation system, with the aim of producing cucumber plants with CMV resistance. The RNA transcripts from the CaMV 35s-cp gene could be detected in the leaves of the R0 transgenic cucumber plants, as well as in the epicotyls containing two cotyledons of transgenic progeny plants, by Northern blot analysis; but the presence of coat protein originating from the CaMV 35s-cp gene could not be detected in the cotyledons or leaves of R0 and transgenic progeny plants by Westernblot analysis. The progenies of a cross between cv "Sharp 1" and transgenic plants (pure line "1021") possessing the cp gene displayed strong resistance to inoculation of the CMV-Y strain, although both the control cv "Sharp 1" and segregated cp (-) plants displayed many spotted disease symptons on their leaves 5-6 days after CMV-Y inoculation on the cotyledons. The control "1021" had a slight tolerance toward CMV-Y inoculation. The transgenic cucumber plants displayed the absence of resistance to ZYMV. However, transgenic plants showed a reduced degree of disease symptom development following a double inoculation of CMV and ZYMV. The CMV resistance of the present transgenic cucumber plants seems to be due to the synergism of the slight CMV tolerance in the pure line "1021" and the protection against CMV afforded by the introduction of the CMV cp gene. This leads to the possibility of producing cucumber plants with the agronomic characteristics of very strong CMV resistance by the combination of genotypes of cucumbers and the CMV cp gene. The transgenic plants possessing the cp gene should thus be useful as a genetic source for producing cucumber plants with the agronomic characteristic of CMV resistance. PMID- 24162394 TI - Molecular characterization of Haynaldia villosa chromatin in wheat lines carrying resistance to wheat curl mite colonization. AB - Wheat-Haynaldia villosa (L.) Schur, hybrid lines were tested as potential sources of resistance to colonization by the wheat curl mite, the vector of wheat streak mosaic virus. Two lines, Add 6V-1 and Sub 6V-1, were found to be mite-resistant. Fluorescence in situ hybridization using total genomic DNA, from H. villosa in the presence of unlabelled wheat DNA, confirmed that Add 6V-1 is a disomic wheat H. villosa chromosome addition line. Sub 6V-1 turned out to be a homoeologous wheat-H. villosa chromosome translocation line rather than a substitution. The translocation in Sub 6V-1 occurred between a wheat chromosome and a chromosome from H. villosa through Robertsonian fusion of misdivided centromeres. Only the short arm of the group 6 chromosome of H. villosa was involved in the genetic control of mite resistance, a conclusion based on the genomic in situ hybridization signal and specific DNA fragments obtained by polymerase chain reaction. PMID- 24162395 TI - Heteroplasmy of the chloroplast genome of Medicago sativa L. cv 'Regen S'' confirmed by sequence analysis. AB - The heteroplasmy of chloroplast DNA (cpDNA) observed in Medicago sativa L., which involves the presence (type B) or absence (type A) of an Xba I restriction site, was examined using closed fragments covering the variable XbaI site from type-A and type-B cpDNA. The 6.2-kb PstI fragment of DNA from type-A cpDNA (-XbaI) and from type-B cpDNA (+XbaI) was cloned into pUC19 plasmids. EcoRI fragments bearing the variable XbaI site from the type-A and type-B 6.2-kb PstI fragments were subcloned into pUC19. DNA sequences of both types of the 696-bp EcoRI fragments were determined and computer-assisted analysis of the sequence data carried out. Type-A cpDNA was found to differ from type-B cpDNA by 1 base, a G to T conversion, which results in a non-recognition site for XbaI in the type-A cpDNA. The sequence difference was in a non-coding region. Cloning and sequencing of the fragments verified the individual identity of the type-A and type-B cpDNA. PMID- 24162396 TI - Detection of putative quantitative trait loci in line crosses under infinitesimal genetic models. AB - Quantitative trait locus (QTL) mapping studies often employ segregating generations derived from a cross between genetically divergent inbred lines. In the analysis of such data it is customary to fit a single QTL and use a null hypothesis which assumes that the genomic region under study contributes no genetic variance. To explore the situation in which multiple linked genes contribute to the genetic variance, we simulated an F2-mapping experiment in which the genetic difference between the two original inbred strains was caused by a large number of loci, each having equal effect on the quantitative trait. QTLs were either in coupling, dispersion or repulsion phase in the base population of inbred lines, with the expected F2 genetic variance explained by the QTLs being equivalent in the three models. Where QTLs were in coupling phase, one inbred line was fixed for all plus alleles, and the other line was fixed for minus alleles. Where QTLs were in dispersion phase, they were assumed to be randomly fixed for one or other allele (as if the inbred lines had evolved from a common ancestor by random drift). Where QTLs were in repulsion phase alleles within an inbred line were alternating plus and minus at adjacent loci, and alternative alleles were fixed in the two inbred lines. In all these genetic models a standard interval mapping test statistic used to determine whether there is a QTL of large effect segregating in the population was inflated on average. Furthermore, the use of a threshold for QTL detection derived under the assumption that no QTLs were segregating would often lead to spurious conclusions regards the presence of genes of large effects (i.e. type I errors). The employment of an alternative model for the analysis, including linked markers as cofactors in the analysis of a single interval, reduced the problem of type I error rate, although test statistics were still inflated relative to the case of no QTLs. It is argued that in practice one should take into account the difference between the strains or the genetic variance in the F2 population when setting significance thresholds. In addition, tests designed to probe the adequacy of a single-QTL model or of an alternative infinitesimal coupling model are described. Such tests should be applied in QTL mapping studies to help dissect the true nature of genetic variation. PMID- 24162397 TI - Wide hybridization between Brazilian soybean cultivars and wild perennial relatives. AB - Employing a different culture strategy, we obtained a greatly improved frequency of embryo rescue in intersubgeneric soybean hybrids. Successful crosses were obtained in 31 different genotype combinations between nine Brazilian soybean lines as the female parents and 12 accessions from Glycine canescens, G. microphylla, G. tabacina and G. tomentella. The hybrid pod retention rate dropped to about 10% during the first 8 days after pollination and stayed largely unchanged up to the 20th day. Immature harvested seeds fell into three size groups: Group 1, smaller than 1.3 mm (mostly empty seed coats); Group 2, 1.9-5.0 mm; Group 3, larger than 5 mm (from selfing). A total of 90 putative hybrid embryos were rescued using a highly enriched B5 medium to nourish the newly dissected embryos. The growing embryos were then placed in a high osmotic, modified B5 medium to induce maturation and dormancy. Schenk and Hildebrandt medium was used to germinate the dormant, partially dehydrated, physiologically mature embryos. Approximately 37% of the rescued embryos developed into plantlets in vitro, and approximately 8% grew into mature plants in the greenhouse. Morphological, cytological and isoenzyme patterns confirmed the hybrid status of all seven mature plants, all of which were generated using G. tomentella G 9943 as the paternal parent. It was observed that all soybean lines crossed with G 9943 were capable of producing mature hybrid plants. There was no correlation between the initial size of Group 2 seeds and plant survival rate. The hybrids were cloned by grafting and treated with colchicine. One of the treated plants displayed chromosome doubling. PMID- 24162398 TI - Inheritance of resistance to potato viruses Y and A in progeny obtained from potato cultivars containing gene Ry:evidence for a new gene for extreme resistance to PVA. AB - Extreme resistance in cultivated potato (Solanum tuberosum) to potato viruses Y and A (PVY and PVA) conditioned by the presence of Ry genes introduced from Solanum stoloniferum was described by Cockerham (1970). Cockerham detailed a number of genes which controlled a variety of reactions, including extreme resistance to both viruses (i.e. little or no visible reaction of plants and no viral replication following graft and manual inoculation) controlled by gene Ry sto. In the present study, cvs 'Pirola' and 'Barbara', which contain a Ry gene, were found to have extreme resistance to PVY isolates from the ordinary (PVY degrees ), veinal necrosis (PVY(N)) and potato tuber necrotic ringspot (PVY(NTN)) subgroups, and PVA. The inheritance of this phenotype was examined in seedling progenies obtained by crossing 'Barbara' and 'Pirola' with susceptible cultivars. Segregation data for resistance to PVY and PVA in a progeny involving cv 'Pirola' best fitted a genetical model of one gene controlling extreme resistance to both PVY and PVA, although the possibility that there are two genes, each controlling resistance to one virus but closely linked, cannot be excluded. Segregation data from progenies involving cv 'Barbara' best fitted a genetical model in which there are two independent genes, one controlling extreme resistance to PVA and PVY and a second gene controlling extreme resistance to PVA but not to PVY. This previously unrecognised gene conferring extreme resistance to PVA only, should be given the notation Ra in keeping with nomenclature used for other resistance genes. PMID- 24162399 TI - Genome size in wild Pisum species. AB - Genome size was measured in 75 samples of the wild pea species Pisum abyssinicum, P. elatius, P. fulvum and P. humile by ethidium-bromide (EB) flow cytometry (internal standard: Triticum monococcum) and Feulgen densitometry (internal standard: Pisum sativum 'Kleine Rheinlanderin'). Total variation of EB-DNA between samples covered 97.7% to 114.9% of the P. sativum value, and Feulgen DNA values were strongly correlated with EB-DNA values (r=0.9317, P < 0.001). Only P. fulvum was homogeneous in genome size (108.9% of P. sativum). Wide variation was observed between samples in P. abyssinicum (100.9-109.7%), P. elatius (97.7 114.9%) and P. humile (98.3-111.1% of P. sativum). In view of the world-wide genome size constancy in P. sativum, the present data are interpreted to show that the pea taxa with variable genome size are genetically inhomogeneous and that the current classification is not sufficient to describe the biological species groups adequately. PMID- 24162400 TI - Phylogenetic analysis of restriction-site variation in wild and cultivated Amaranthus species (Amaranthaceae). AB - Amaranthus includes approximately 60 species, of which three are cultivated as a grain source. Many wild Amaranthus species possess agriculturally desirable traits such as drought and salt tolerance, and pathogen resistance. We examined relationships among wild and cultivated Amaranthus species based upon restriction site variation in two chloroplast DNA regions and in a nuclear DNA region. The chloroplast regions consisted of (1) an intergenic spacer in transfer RNA genes and (2) the ribulose-1,5-bisphosphate carboxylase gene with a flanking open reading frame. The nuclear region was the internal transcribed spacers ITS-1 and ITS-2 flanking the 5.8S gene in the ribosomal DNA. These regions were amplified by the polymerase chain reaction and digested with a total of 38 restriction endonucleases. We detected 11 potentially informative restriction-site mutations and seven length-polymorphisms among the 28 Amaranthus species. Parsimony analysis was used to find the shortest tree for each separate data set (chloroplast, nuclear, and length) and for two combined matrices (chloroplast/nuclear and all data sets). Overall, there was a low level of variation which generated poorly resolved trees among the 28 species. Congruence analyses revealed that the chloroplast and nuclear data sets were congruent with each other but not to the length data set. The congruence of the chloroplast and nuclear data sets suggested that cytoplasmic gene flow may not be a confounding factor in our analyses. The phylogeny also suggested that drought tolerance evolved independently several times. The molecular phylogeny provides a basis for selection of species pairs for crop development. PMID- 24162401 TI - Identification of AFLP molecular markers for resistance against Melampsora larici populina in Populus. AB - We have identified AFLP markers tightly linked to the locus conferring resistance to the leaf rust Melampsora larici-populina in Populus. The study was carried out using a hybrid progeny derived from an inter-specific, controlled cross between a resistant Populus deltoides female and a susceptible P. nigra male. The segregation ratio of resistant to susceptible plants suggested that a single, dominant locus defined this resistance. This locus, which we have designated Melampsora resistance (Mer), confers resistance against E1, E2, and E3, three different races of Melampsora larici-populina. In order to identify molecular markers linked to the Mer locus we decided to combine two different techniques: (1) the high-density marker technology, AFLP, which allows the analysis of thousands of markers in a relatively short time, and (2) the Bulked Segregant Analysis (BSA), a method which facilitates the identification of markers that are tightly linked to the locus of interest. We analyzed approximately 11,500 selectively amplified DNA fragments using 144 primer combinations and identified three markers tightly linked to the Mer locus. The markers can be useful in current breeding programs and are the basis for future cloning of the resistance gene. PMID- 24162402 TI - Variability and genetics of tolerance for aluminum toxicity in rice (Oryza sativa L.). AB - A study was undertaken to investigate the variability among lowland rice cultivars and the mode of gene action of aluminum (Al) toxicity tolerance in rice. Pregerminated seeds were grown in a nutrient solution containing 30 ppm Al and in normal nutrient solution, and relative root length (RRL) was determined at the 14-day-old stage to characterize genotypes for tolerance. Sixty-two traditional rice cultivars grown on lowland acid sulfate soil areas of Asia and West Africa were tested. Tolerant varieties 'Azucena', 'IRAT104', and 'Moroberekan', moderately sensitive 'IR29' and 'IR43', and sensitive 'IR45' and 'IR1552' were used to investigate the genetics of tolerance by diallel analysis. Of the 62 cultivars tested, only 3 were found to be sensitive to A l toxicity. Among the tolerant cultivars identified, 11 ('Siyam Kuning', 'Gudabang Putih', 'Siyam', 'Lemo', 'Khao Daeng', 'Siyamhalus', 'Bjm-12', 'Ketan', 'Seribu Gantang', 'Bayer Raden Rati', and 'Padi Kanji') were found to possess higher levels of tolerance than the improved tolerant upland cultivar 'IRAT104'. Diallel analysis revealed that high RRL is governed by both additive and dominance effects with a preponderance of additive effects. The trait exhibited partial dominance, and one group of genes was detected. Heritability was high, and environmenal effects were low. Findings suggest that when breeding for A1 toxicity tolerance, selection can be made in early generations. The pedigree method of breeding would be suitable. Combining ability analysis revealed the importance of both general combining ability (GCA) and specific combining ability (SCA) in the genetics of A1 toxicity tolerance in rice. GCA was more prevalent than SCA. Tolerant parens 'Azucena', 'IRAT104', and 'Moroberekan' were the best general combiners. The presence of reciprocal effects among crosses suggested the proper choice of parents in hybridization programs. Results indicated that 'Azucena', 'IRAT 104', and 'Moroberekan' should be used as the female in crosses for A1 toxicity tolerance. PMID- 24162403 TI - Inhibitory activities against heterologous alpha-amylases and in vitro allergenic reactivity of Einkorn wheats. AB - Salt extracts from seeds of 36 lines of Einkorn wheats were analyzed for their inhibitory activity towards two insect (Tenebrio molitor, Coleoptera, and Ephestia kuehniella, Lepidoptera) and one mammalian (human salivary) alpha amylases. Whereas all ten T. monococcum accessions tested were active towards the lepidopteran enzyme, they had no effect on the coleopteran or the mammalian ones. More variability was found among the 21 lines of T. boeticum analyzed, although none of them inhibited human alpha-amylase. The five accessions of T. urartu showed even greater diversity. Among all Einkorn accessions tested, only two urartu lines affected the three alpha-amylases. These lines displayed inhibition patterns similar to those of T. aestivum and T. turgidum cultivars. Since several breadwheat alpha-amylase inhibitors are major allergens associated with baker's asthma, we also studied the in vitro allergenic activity of salt extracts from the Einkorn wheats under study. No significant differences in IgE-binding were found between these accessions and theT. aestivum or T. turgidum cultivars. Furthermore, putative allergens with molecular sizes in the range of 20-60 kDa were detected in these Einkorn wheats. PMID- 24162404 TI - AFLP analysis of the diversity and phylogeny of Lens and its comparison with RAPD analysis. AB - AFLP and RAPD marker techniques have been used to evaluate and study the diversity and phylogeny of 54 lentil accessions representing six populations of cultivated lentil and its wild relatives. Four AFLP primer combinations revealed 23, 25, 52 and 48 AFLPs respectively, which were used to partition variation within and among Lens taxa. The results of AFLP analysis is compared to previous RAPD analysis of the same material. The two methods provide similar conclusions as far as the phylogeny of Lens is concerned. The AFLP technique detected a much higher level of polymorphyism than the RAPD analysis. The use of 148 AFLPs arising from four primer combinations was able to discriminate between genotypes which could not be distinguished using 88 RAPDs. The level of variation detected within the cultivated lentil with AFLP analysis indicates that it may be a more efficient marker technology than RAPD analysis for the construction of genetic linkage maps between carefully chosen cultivated lentil accessions. PMID- 24162405 TI - Does the genome of Corylus avellana L. contain sequences homologous to the self incompatibility gene of Brassica? AB - Self-incompatibility is a genetic mechanism enforcing cross-pollination in plants. Hazelnut (Corylus avellana L.) expresses the sporophytic type of self incompatibility, for which the molecular genetic basis is characterized only in Brassica. The hypothesis that the hazelnut genome contains homologs of Brassica self-incompatibility genes was tested. The S-locus glycoprotein gene (SLG) and the kinase-encoding domain of the S-receptor kinase (SRK) gene of B. oleracea L. were used to probe blots of genomic DNA from six genotypes of hazelnut. Weak hybridization with the SLG probe was detected for all hazelnut genotypes tested; however, no hybridization was detected with PCR-generated probes corresponding to two conserved regions of the SLG gene. One of these PCR probes included the region of SLG encoding the 11 invariant cysteine residues that are an important structural feature of all S-family genes. The present evidence suggests that hazelnut DNA hybridizing to SLG differs significantly from the Brassica gene, and that the S-genes cloned from Brassica will not be useful for exploring self incompatibility in hazelnut. PMID- 24162406 TI - Salt tolerance in Lycopersicon species. IV. Efficiency of marker-assisted selection for salt tolerance improvement. AB - The usefulness of marker-assisted selection (MAS) to develop salt-tolerant breeding lines from a F2 derived from L. esculentum x L. pimpinellifolium has been studied. Interval mapping methodology of quantitative trait locus (QTL) analysis was used to locate more precisely previously detected salt tolerance QTLs. A new QTL for total fruit weight under salinity (TW) near TG24 was detected. Most of the detected QTLs [3 for TW, 5 for fruit number, (FN) and 4 for fruit weight (FW)] had low R (2) values, except the FW QTL in the TG180-TG48 interval, which explains 36.6% of the total variance. Dominant and overdominant effects were detected at the QTLs for TW, whereas gene effects at the QTLs for FJV and FW ranged from additive to partial dominance. Phenotypic selection of F2 familes and marker-assisted selection of F3 families were carried out. Yield under salinity decreased in the F2 generation. F3 means were similar to those of the F1 as a consequence of phentoypic selection. The most important selection response for every trait was obtained from the F3 to F4 where MAS was applied. While F3 variation was mainly due to the within-family component, in the F4 the FN and FW between-family component was larger than the within-family one, indicating an efficient compartmentalization and fixation of QTLs into the F4 families. Comparison of the yield of these families under control versus saline conditions showed that fruit weight is a key trait to success in tomato salt tolerance improvement using wild Lycopersicon germplasm. The QTLs we have detected under salinity seem to be also working under control conditions, although the interaction family x treatment was significant for TW, thereby explaining the fact that the selected families responded differently to salinity. PMID- 24162407 TI - Characterization of nematode resistance genes in the section Procumbentes genus Beta: response to two populations of Heterodera schachtii. AB - Three species of the section Procumbentes genus Beta, nine monosomic additions, and five translocation lines were tested for resistance to two Heterodera schachtii populations. Nematode population 129-v (129-virulent) was selected for virulence to resistance gene(s) transferred from chromosome 1 of Beta procumbens to the diploid resistant sugar beet KWS-NR1. This population is considered to be a pathotype. The unselected sib population 129-av (129-avirulent) was reared continuously on fodder rape, Brassica napus cv Velox. Monosomic additions with chromosome 1 from the three species of the section Procumbentes were susceptible to population 129-v, regardless of the origin of the alien chromosome. Translocations with a gene(s) for resistance from chromosome 7 of B. procumbens and B. webbiana were also susceptible to the pathotype. However, a monosomic addition with chromosome 7 of B. webbiana was resistant to population 129-v. The three wild beets of the section Procumbentes, Beta procumbens, Beta webbiana and Beta patellaris, also were highly resistant to the two populations. The results indicate the existence of just two different major genes for resistance to H. schachtii in the entire Procumbentes section. PMID- 24162408 TI - Linkage mapping of '25-kDa globulin' genes on homoeologous group-1 chromosomes of bread and durum wheat. AB - Acid polyacrylamide-gel electrophoresis (A-PAGE) of ethanol-soluble proteins from the endosperm of bread and durum wheats reveals some bands encoded by genes on the homoeologous group-1 chromosomes with higher mobility than the alpha gliadins. The isolation of these proteins showed that they were the previously described '25-kDa globulins' encoded by genes at the Glo-A1, Glo-B1, and Glo-D1 loci. The variability found among a collection of 51 bread and 81 durum wheats was very low: two allelic variants at Glo-A1 and no variants at Glo-B1 in each of the two species, and two allelic variants at Glo-D1 in bread wheat. Inheritance studies of '25-kDa globulin' genes on group-1 chromosomes of bread and durum wheat were carried out on the F2 progeny from four crosses, two in bread wheat and two in durum wheat. The linkage mapping of the 1A '25-kDa globulin' genes of bread wheat was done based on four prolamin loci: Glu-A1, Glu-A3, Gli-A1 and Gli A3. The percentages of recombination and the distances found allowed a re evaluation of the linkage map of endosperm protein loci on this chromosome. The Glo-A1 locus was found to be located at the distal end of the short arm of 1A chromosome, at a distance of 5.23+/-1.99 cM from Gli-A1, 6.85+/-2.22 cM from Glu A3, 22.64+/-3.62 cM from Gli-A1, and at a recombination percentage of 49.30+/ 4.40 from Glu-A1. A similar distance between Gli-A1 and Glo-A1 (4.82+/-1.75 and 6.66+/-2.26 cM) was found in durum wheat. The distance between Gli-D1 and Glo-D1 on chromosome 1D was 2.86+/-1.39 cM. PMID- 24162409 TI - Comparison of crossability, RAPD, SDS-PAGE and morphological markers for revealing genetic relationships within and among Lens species. AB - The phylogenetic relationships among (sub)-species in the genus Lens have been reviewed based on recent published reports. There was both a substantial level of agreement and disagreement between reports based on different analytical procedures and different plant germ plasms. Lens culinaris ssp. orientalis appeared as the wild progenitor of the cultivated lentils. A gene flow from L. odemensis and L. ervoides during lentil crop evolution was suggested. Morphological characters (quantitative and qualitative) showed a different taxonomic pattern in the genus Lens. The use of nuclear and biochemical markers (RFLPs, RAPDs, seed-protein electrophoresis) appeared to be the most consistent and reliable methods for determining genetic relationships. It is suggested that these techniques be used in combination for taxonomic analysis of the genus Lens. PMID- 24162410 TI - Intra-individual heterogeneity of rDNA allows the distinction between two closely related species in the Genus Helianthus. AB - The Ribosomal DNAs of Helianthus annuus and H. argophyllus were analysed. Total DNA from single individuals of six cultivated lines, one wild ecotype ofH. annuus, and three ecotypes of H. argophyllus, were digested with various restriction enzymes. Hybridisation of Southern blots with sunflower ribosomal probes containing most of the interspacer regions (R3) or the 25 s coding region (R2) reveals different patterns from those expected: while no difference between H. annuus and H. argophyllus had been observed in previous rDNA RFLP analysis, our study clearly distinguished the two species on the basis of two different patterns when using R3 and BamHI, BstYI, or EcoRI/BamHI. Furthermore, the sum of the fragment weights of the BamHI restriction patterns was much greater than that of the rDNA entire unit-weight space. The co-existence of different rDNA units within single individuals is proposed as a model to explain these results. Four rDNA units were distinguished, which differed in their state of methylation and by the presence of mutations at two BamRI restriction sites. H. annuus individuals displayed two types of rDNA units while H. argophyllus individuals displayed four types. PMID- 24162411 TI - The fate of ribosomal genes in three interspecific somatic hybrids of Medicago sativa: three different outcomes including the rapid amplification of new spacer length variants. AB - We have characterized the genetic consequences of somatic hybridization within the ribosomal DNA (rDNA) of three interspecific hybrids, each involving M. sativa as one of the parents. Restriction-fragment-length-polymorphisms (RFLPs) of rDNA spacers and fluorescent-in-situ-hybridization (FISH) of an 18S-gene probe to mitotic chromosomes were used to compare parental and hybrid species. The M. sativa-coerulea hybrid retained all six parental nucleolar-organizing regions (NORs) and all parental RFLPs representing a complete integration of rDNA. The M. sativa-arborea hybrid retained five of six parental NORs while losing half of the arborea-specific RFLPs, indicating that simple chromosome loss of one arborea NOR accounted for the RFLP losses. Dramatic alterations occurred within the M. sativa falcata hybrid where five of six parental NORs were retained and new rDNA RFLPs were created and amplified differentially among somaclonal-variant plants. The molecular basis of the new RFLPs involved increased numbers of a 340-bp subrepeating element within the rDNA intergenic spacer (IGS), suggesting that recurrent cycles of unequal recombination occurred at high frequency within the rDNA in somatic lineages. PMID- 24162412 TI - A new protoplast culture system in Daucus carota L. and its applications for mutant selection and transformation. AB - Petiole protoplasts from in vitro-grown carrot plants are a very good alternative to traditionally obtained protoplasts from suspension cultures. High plating and regeneration efficiencies were obtained in most of the breeding lines that were tested. The embedding of the protoplasts in alginate was crucial for initiating cell division and further development. Several streptomycin resistant and chlorophyll-deficient plant lines were selected for using the petiole protoplast system. Maternally inherited streptomycin resistance was demonstrated by sexual crosses. Protoplast fusion of several chlorophyll-deficient lines did not result in complementation, indicating the cytoplasmic nature of the mutations. Petiole protoplasts were used for direct transformation with plasmid DNA pNUNV containing NPTII as a selectable marker. High transformation frequencies (up to 1%) were obtained after PEG treatment of the protoplasts. Kanamycin resistance was shown to be inherited as a single dominant nuclear trait. PMID- 24162413 TI - Physical mapping of translocation breakpoints in a set of wheat-Aegilops umbellulata recombinant lines using in situ hybridization. AB - Aegilops umbellulata Zhuk. carries genes at Glu-U1 loci that code for a pair of high-molecular-weight glutenin subunits not found in common wheat, Triticum aestivum. Wheat-Ae. umbellulata recombinant lines were produced with the aim of transferring genes coding for glutenin subunits from Ae. umbellulata into wheat with minimal flanking material. We used fluorescent genomic in situ hybridization to evaluate the extent of recombination and to map physically the translocation breakpoints on 11 wheat-Ae. umbellulata recombinant lines. In situ hybridization was able to identify alien material in wheat and showed breakpoints not only near the centromeres but also along chromosome arms. To characterize and identify chromosomes further, including deletions along the 1U chromosome, we used simultaneous multiple target in situ hybridization to localize a tandemly repeated DNA sequence (pSc119.2) and the 18S-25S and 5S rRNA genes. One line contained an Ae. umbellulata telocentric chromosome and another two had different terminal deletions, mostly with some wheat chromosome rearrangements. Although from six independent original crosses, the other eight lines included only two types of intercalary wheat-Ae. umbellulata recombination events. Five occurred at the 5S rRNA genes on the short arm of the Ae. umbellulata chromosome with a distal wheat-origin segment, and three breakpoints were proximal to the centromere in the long arm, so most of the long arm was of Ae. umbellulata origin. The results allow characterization of recombination events in the context of the karyotype. They also facilitate the design of crossing programmes to generate lines where smaller Ae. umbellulata chromosome segments are transferred to wheat with the potential to improve bread-making quality by incorporating novel glutenin subunits without undesirable linked genes. PMID- 24162414 TI - STS-PCR markers appropriate for wheat-barley introgression. AB - Introgression of chromosomal segments across large taxonomic distances has long been an objective of scientists interested in understanding the relationships between genes and their effect on phenotype. Barley and wheat represent cultivated members of the Triticeae with different zones of adaptation, different responses to pathogens, and different end-use characteristics. Introduction of small, well-characterized chromosomal segments among grass relatives presents an opportunity to both better understand how genes perform in novel genomic environments and to learn more about the evolutionary novelties which differentiate related species. Since the distribution of the wheat-barley addition lines, the potential power and value of a comprehensive series of wheat/barley translocation lines has been widely appreciated. A scarcity of easy touse markers which unambiguously distinguish barley loci from their wheat homologues has limited the ability of scientists to identify the relatively rare inter-chromosomal recombination events which are the necessary antecedents of these lines. Since the single most critical pathogen affecting U.S. wheat producers is Karnal bunt (Tilletia indica) and since barley carries a gene conferring immunity, molecular markers may prove practically and immediately important. In this report we describe a series of 135 barley-specific markers amplified by 115 primer sets developed from sequences from previously mapped restriction fragment length polymorphism (RFLP) markers. These easily distinguish the cognate barley products from their wheat counterparts and should find ready use in the identification of lines which contain wheat/barley translocation events. PMID- 24162415 TI - Alignment of the conserved C genomes of Brassica oleracea and Brassica napus. AB - A population of 169 microspore-derived doubled-haploid lines was produced from a highly polymorphic Brassica oleracea cross. A dense genetic linkage map of B. oleracea was then developed based on the segregation of 303 RFLP-defined loci. It is hoped that these lines will be used by other geneticists to facilitate the construction of a unified genetic map of B. oleracea. When the B. oleracea map was compared to one ofB. napus (Parkin et al. 1995), based on the same RFLP probes (Sharpe et al. 1995), good collinearity between the C-genome linkage groups of the two species was observed. PMID- 24162416 TI - Early-flowering Scots pines through tissue culture for accelerating tree breeding. AB - Scots pine plantlets were produced via tissue culture using cotyledons excised from germinated embryos as explants. The optimum tissue culture conditions were: 1/2GDbasal medium gelled with agar-Gelrite during shoot formation and with agar during rooting, inclusion of 5.0MUM benzylaminopurine (BAP) and 0.05 MUM naphthaleneacetic acid (NAA) for 2 weeks for shoot induction, and repeated 2.7 MUM NAA pulses of 1 week for rooting. Micropropagation success was genotype dependent. Average multiplication rates varied among experiments from 3 to 15 shoots per embryo. The maximum shoot production from a single embryo was 35. Rooting was the most difficult phase in the propagation process. Most of the plantlets had a plagiotrophic and highly branched growth habit when growing in the greenhouse. Some individuals produced megasporangiate strobili at the age of 3 years and microsporangiate strobili with viable pollen at the age of 4 years. Early-flowering clones and the ability to conserve seedlings from which cotyledons have been cultured give new possibilities for accelerated tree breeding. PMID- 24162417 TI - Genetic dissection of height in maritime pine seedlings raised under accelerated growth conditions. AB - Random Amplified Polymorphic DNAs (RAPDs) were used to investigate quantitative trait loci (QTL) for traits related to height growth on 126 F2 seedlings of maritime pine (Pinuspinaster Ait). The haploid megagametophyte was used to determine the maternal genotype of each F2 individual. The seedlings were raised for 2 years in a greenhouse under accelerated growth conditions consisting of intense fertilization combined with continuous light treatments. Total height was measured at different developmental stages, and height growth components were measured after the second growth period. QTLs were identified for each trait. For total height, QTLs of different developmental stages were located on distinct linkage groups. However, rather than a complete temporal change in QTL expression, our results showed that maturation may induce a progressive shift of the genetic control of height growth. This may provide an explanation for a low juvenile-mature phenotypic correlation previously reported for height. Height growth components related to the initiation (controlled by the apical meristem) and elongation of shoot cycles (controlled by the subapical meristem) were mapped to different chromosomes, suggesting that the activity of these meristems is controlled by separate genetic mechanisms. PMID- 24162418 TI - Molecular mapping of genes for resistance to rice blast (Pyricularia grisea Sacc.). AB - Two dominant genes conferring complete resistance to specific isolates of the rice blast fungus, Pyricularia grisea Sacc., were located on the molecular map of rice in this study. Pi-l(t) is a blast resistance gene derived from the cultivar 'LAC23'. Its map location was determined using a pair of nearly isogenic lines (NILs) and a B6F3 segregating population from which the isoline was derived. RFLP analysis showed that Pi-l(t) is located near the end of chromosome 11, linked to RZ536 at a distance of 14.0+/-4.5 centiMorgans (cM). A second gene, derived from the cultivar 'Apura', was mapped using a rice doubled-haploid (DH) population. This gene was located on chromosome 12, flanked by RG457 and RG869, at a distance of 13.5+-4.3 cM and 17.7+-4.5 cM, respectively. The newly mapped gene on chromosome 12 may be allelic or closely linked toPi-ta. (=Pi-4(t)), a gene derived from Tetep that was previously reported to be linked to RG869 at a distance of 15.4+/-4.7 cM. The usefulness of markers linked to blast resistance genes will be discussed in the context of breeding for durable blast resistance. PMID- 24162419 TI - Evidence for a low level of genomic specificity of sequence-tagged-sites in Stylosanthes. AB - Genome-specific DNA markers are of great value in many applications. Recent work on different plants and animal species indicated that PCR- (polymerase chain reaction) based genetic marker systems using specific primers are highly genome specific. To test the genome specificity of sequence-tagged-sites (STSs) as genetic markers in Stylosanthes, 20 pairs of primers were generated. Fifteen were from randomly selected single-copy Pstl genomic clones, and the other five were from two known gene sequences. These primer pairs were analysed against a set of 24 genotypes representing 12 different Stylosanthes species. Thirteen of these primer pairs amplified successfully. Overall, there was a low level of genome specificity, suggesting a low degree of genomic divergence within this group of Stylosanthes species. Of the 312 entries (24 genotypes by 13 primer pairs), PCR amplifications were unsuccessful (little or no products) in only 16 cases. The number of banding patterns detected by each of these primer pairs varied from 2 to 12 with an average pair-wise polymorphism of 44.3%. The level of intraspecific variation detected on normal agarose gels was only 3.8%. Further evidence that diploid S. hamata and diploid S. humilis are progenitors of tetraploid S. hamata and that S. viscosa is a progenitor of S. scabra, was obtained. PMID- 24162420 TI - Development of simple sequence repeat DNA markers and their integration into a barley linkage map. AB - Simple sequence repeats (SSRs), or microsatellites, are a new class of PCR-based DNA markers for genetic mapping. The objectives of the present study were to develop SSR markers for barley and to integrate them into an existing barley linkage map. DNA sequences containing SSRs were isolated from a barley genomic library and from public databases. It is estimated that the barley genome contains one (GA)n repeat every 330 kb and one (CA)n repeat every 620 kb. A total of 45 SSRs were identified and mapped to seven barley chromosomes using doubled haploid lines and/or wheat-barley addition-line assays. Segregation analysis for 39 of these SSRs identified 40 loci. These 40 markers were placed on a barley linkage map with respect to 160 restriction fragment length polymorphism (RFLP) and other markers. The results of this study demonstrate the value of SSRs as markers in genetic studies and breeding research in barley. PMID- 24162421 TI - A genome-wide search for wild-species alleles that increase horticultural yield of processing tomatoes. AB - To identify QTLs associated with horticultural yield it is necessary to conduct replicated plot trials of the tested genotypes. The first step in the utilization of an introgression-line (IL) population of Lycopersicon pennellii in a processing-tomato variety (M82) for mapping such QTLs was to screen 51 ILs in a non-replicated plot trial. The results of this survey were compared to those obtained in a replicated trial of the same genotypes grown as single plants at wide spacing. Fruit characteristics were similar between the two stands, but yield was generally different. Eight lines that outperformed the control in the plot survey were subjected to detailed analysis in the following year. The effects of these introgressions, measured on single plants, were reproducible relative to the previous year's results. In a replicated plot trial of these ILs and their hybrids involving two genetic backgrounds, the product of yield and total soluble solids (horticultural yield) in seven of the eight hybrids was 7 13% higher than that of their nearly isogenic controls. The results revealed a consistent trend in the interaction between introgression effects and genetic background. Combining the two introgressions with the largest contribution to horticultural yield in plots resulted in a 20% increase relative to the control in the third year. This research highlights the potential of wild germ plasm for yield improvement and the ability of nearly isogenic populations to achieve this goal. PMID- 24162422 TI - Variants within the 5'-flanking regions of bovine milk-protein-encoding genes. III. Genes encoding the Ca-sensitive caseins alphas1, alpha s2 and beta. AB - The 5'-flanking regions of the Ca-sensitive casein-encoding gene family were analysed for DNA variants by automated DNA sequencing of 13 cows belonging to seven breeds. About 1 kbp of each 5'-flanking region, including non-coding exon I, was amplified by PCR and sequenced bidirectionally. A total number of 34 variable sites (17 for the alpha s1, 10 for the alpha s2, and 7 for the beta casein encoding gene) was identified. Variants were computer-analysed for location in putative regulatory sites in order to predict potential influences on gene expression. PMID- 24162423 TI - Identification of resistance to Meloidogyne javanica in the Lycopersicon peruvianum complex. AB - Clones of Lycopersicon peruvianum PI 2704352R2, PI 270435-3MH and PI 126443-1MH expressed novel resistance to three Mi-avirulent M. javanica isolates in greenhouse experiments. Clones from PI 126443-1MH were resistant to the three M. javanica isolates at 25 degrees C. The three isolates were able to reproduce on one embryorescue hybrid of PI 126443-1MH, but not on three L. peruvianum-L. esculentum bridge-line hybrids of PI 1264431MH when screened at 25 degrees C (Mi expressed temperature). Clones of PI 270435-2R2 and all its hybrids with susceptible genotypes were resistant to the three M. javanica isolates at 25 degrees C. The bridge-line hybrid EPP-2xPI 2704352R2 was susceptible to M. javanica isolate 811 at 32 degrees C, whereas PI 270435-2R2 and all other hybrids of PI 27043 5-2R2 crossed with susceptible genotypes were resistant at 32 degrees C. At 32 degrees C, one F2 progeny of PI 126443-IMHxEPP-1, and three test-cross progenies of PI 1264409MHx[PI 270435-3MHxPI 126443-1MH], and reciprocal test cross progenies of [PI 270435-3MHxPI 2704352R2]xPI 126440-9MH, each segregated into resistant: susceptible (R?S) ratios close to 3?1. The results from the F2 progeny indicated that heat-stable resistance to Mi-avirulent M. javanica in PI 126443 -1MH is conferred by a single dominant gene. The results from the test crosses indicated that this gene in PI 126443-1MH is different from the resistance gene in PI 270435-3MH. The resistance gene in PI 270435-3MH was also shown to differ from the resistance factor in PI 270435-2R2. The expression of differential susceptibility and resistance to M. javanica and M. incognita in individual plants of the bridge-line hybrid, embryo-rescue hybrid, F2, and test crosses indicated that at least some genes governing resistance to M. javanica differ from the genes conferring resistance to M. incognita. A new source of heat stable resistance to M. javanica was identified in Lycopersicon chilense. PMID- 24162424 TI - The effect of genome and sex on recombination rates in Pennisetum species. AB - The effects of homoeology and sex on recombination frequency were studied in crosses between cultivated pearl millet, Pennisetum glaucum, and two wild subspecies, P. violaceum and P. mollissimum. For the two wild x cultivated crosses, reciprocal three-way crosses were made between the F1 hybrid and an inbred line (Tift 23DB1). The three-way cross populations were mapped to produce a female map of each wide cross (where the F1 was the female) and a male map (where the F1 was the male). Total genetic map lengths of the two inter subspecies crosses were broadly similar and around 85 % of a comparable intervarietal map. In the P. glaucumxP. mollissimum crosses, the map was further shortened by a large (40 cM) inversion in linkage group 1. Comparison of the recovered recombinants from male and female meiocytes showed an overall trend for the genetic maps to be longer in the male (~10%) in both inter-subspecific crosses; however, analysis of individual linkage intervals showed no significant differences. Gametophytic selection was prevalent, and sometimes extreme, for example 12?1 in favour of 'wild' alleles in the P. glaucumxP. mollissimum male recombinant population. One of the loci which determines panicle type in cultivated pearl millet and wild relatives, H, was mapped 9 cM from Xpsm812 on linkage group 7 in the P. violaceum cross. PMID- 24162425 TI - Analysis of molecular markers associated with powdery mildew resistance genes in peach (Prunus persica (L.) Batsch)xPrunus davidiana hybrids. AB - A progeny of 77 hybrids issued from a cross between two heterozygous Prunus, peach [P. persica (L.) Batsch] (variety 'Summergrand') and a related species, P. davidiana (clone 1908), was analysed for powdery mildew resistance in five independent experiments. This population was also analysed for its genotype with isoenzyme and RAPD markers in order to map the genes responsible for resistance. A genetic linkage map was generated for each parent. The 'Summergrand' linkage map is composed of only four linkage groups including 15 RAPD markers and covering 83.1 centiMorgans (cM) of the peach nuclear genome, whereas the P. davidiana linkage map contains 84 RAPD markers and one isoenzyme assigned to ten linkage groups and covering 536 cM. Significant associations between molecular markers and powdery mildew resistance were found in each parent. For P. davidiana, one major QTL with a very strong effect and five other QTLs with minor effects were located in different linkage groups. For 'Summergrand', three QTLs for powdery mildew resistance, with minor effects, were also detected. Consequently, evidence is given here that the powdery mildew resistance of P. davidiana clone 1908 and P. persica variety 'Summergrand' is not a monogenic character but is controlled by at least one major gene and several minor genes. PMID- 24162426 TI - Utility of RAPD markers in identifying genetic linkages to genes of economic interest in peach. AB - The identification of molecular markers linked to economically important traits for use in crop improvement is very important in long-lived perennial species. Three-hundred-and-sixty RAPD primers were used with bulked segregant analysis to identify markers linked to loci of specific interest in peach [(Prunus persica) L. Batch] and peach x almond [(Prunus dulcis) Batch] crosses. The traits analyzed included flesh color, adhesion, and texture; pollen fertility; plant stature; and three isozyme loci. The Mendelian behavior of the RAPD loci was established, and RAPD markers were mapped relative to the loci controlling flesh color, adhesion, and texture, and the isozyme loci Mdh-1, 6Pgd-2 and Aat-1, as well as the existing RFLP genetic linkage map constructed previously using a peach x almond F2 population. This technique has facilitated rapid identification of RAPD and RFLP markers that are linked to the traits under study. Loci controlling these traits mapped predominantly to linkage groups 2 and 3 of the peach genetic linkage map. Linkages to genes with both dominant and co-dominant alleles were identified, but linkages to dominant genes were more difficult to find. In several crosses, RAPD marker bands proved to be allelic. One co-dominant RAPD formed a heteroduplex band in heterozygous individuals and in mixtures of alternate homozygotes. The Mendelian behavior of the RAPD loci studied was established and the results suggest that RAPD markers will be useful for plant improvement in peach. PMID- 24162427 TI - Sex influence on recombination frequency in Secale cereale L. AB - The variation in recombination frequency (rf) is important to plant breeders since their major objective is to obtain favorable recombinants of linked genes. One source of variation in rf is sex. Sex differences for recombination frequencies were studied in four of the seven chromosomes of Secale cereale L. cv 'Ailes' using isozyme and storage protein loci and were determined on the basis of reciprocal crosses between heterozygous plants of cv. 'Ailes' and homozygous plants of the inbred line 'Riodeva'. The differences were found to be strongly segmentspecific. In some cases the level of crossing-over in male and female meiosis was about the same (between Pgm1 and Ndh1 loci on chromosome arm 4RS). However, for most of the chromosome segments in 1R, 3RL and 6RL the male rf was significantly higher than the female rf. Different hypotheses about the mechanisms of plant sex differences for recombination are discussed. PMID- 24162428 TI - The genetics of blackleg [Leptosphaeria maculans (Desm.) Ces, et De Not.] resistance in rapeseed (Brassica napus L.) : I. Adult-plant resistance in F2 and first-backcross populations. AB - The genetic control of adult-plant blackleg [Leptosphaeria maculans (Desm.) Ces. et De Not.] resistance in rapeseed (Brassica napus L.) was studied in the F2 and first-backcross populations of the cross "Maluka" (blackleg-resistant) x "Niklas" (highly susceptible). A L. maculans isolate possessing high levels of host specificity (MB2) was used in all inoculations. Resistance/susceptibility was evaluated using three separate measures of crown-canker size, i.e. the percentage of crown girdled (%G), external lesion length (E) and internal lesion area (%II). Disease severity scores for the F2 and first-backcross populations based on E and %II gave discontinuous distributions, indicating major-gene control for these measures of resistance; but those for %G were continuous, indicating quantitative genetic control for this measure. Chi-square tests performed on the (poorly defined) resistance classes, based on E, in the F2 and first-backcross populations indicated the likelihood for resistance being governed by a single, incompletely dominant major gene. Although the distributions of the F2 and first backcross populations, based on%II, were clearly discontinuous, the observed segregation ratios for resistance and susceptibility did not fit any of the numerous Mendelian ratios which were considered. Differences in inheritance of resistance according to the assessment method and blackleg isolate used, were discussed. PMID- 24162429 TI - The genetics of blackleg [Leptosphaeria maculans (Desm.) Ces. et De Not.] resistance in rapeseed (Brassica napus L.) : II. Seedling and adult-plant resistance as quantitative traits. AB - Inheritance studies of seedling and adult-plant resistance to blackleg [Leptosphaeria maculans (Desm.) Ces. et De Not.] in rapeseed (Brassica napus L.) were conducted using 49 families derived by intercrosses between 14 randomly chosen F2 plants from the cross cv "Maluka"(resistant) cv "Niklas" (susceptible), conforming to the North Carolina mating design II (NCM-II). Four concurrent experiments were performed, where plants from each family were: (I) Spray inoculated with a 10(5) pycnidiospores/ml suspension 10 days after germination and assessed 2-weeks later for cotyledon-lesion development, (II) As for (I), but assessed 12 weeks after inoculation for crown-canker development, (III) Wound inoculated on the stems at growth stage 2.4-2.5 on the Harper and Berkenkamp scale and assessed for crown-canker development 5 weeks after inoculation, and (IV) Spray inoculated at growth stage 2.3-2.4 with a 10(5) pycnidiospores/ml suspension and assessed for crown-canker development nine weeks after inoculation. A L. maculans isolate possessing high levels of host specificity (MB2) was used in all inoculations. Seedling resistance was evaluated using a 0-5 cotyledon-lesion severity scale. Adult-plant resistance/susceptibility was evaluated using three separate measures of crown-canker size, i.e. the percentage of crown girdled (%G), external lesion length (E) and internal lesion area (%II). Quantitative genetic analysis of blackleg resistance using the NCM-II design revealed significant non-additive genetic variances for all measures of disease severity, in all four experiments, indicating the presence of strong dominance/epistasis at loci controlling blackleg resistance. The resistance to crown-canker development, after wound-inoculation of the stem, was found to possess the highest ratio of additive to non-additive genetic variance. Crown canker development in mature plants of the NCM-II population was not related to the degree of cotyledon-lesion development at the seedling stage, indicating the limited value of the cotyledon test in screening for adult-plant blackleg resistance. The implications of these findings to breeding for resistance to blackleg in rapeseed are discussed. PMID- 24162430 TI - Relationships between Meloidogyne incognita resistance genes in Lycopersicon peruvianum differentiated by heat sensitivity and nematode virulence. AB - Resistance to Meloidogyne incognita (Kofoid and White) Chitwood in clones of Lycopersicon peruvianum (L.) Mill. PI 126443-1MH, 270435-2R2 and 2704353MH, their F1, a field-produced F2, and their test-cross (TC1) populations, was evaluated based on egg masses and eggs produced on root systems. Reactions to M. incognita isolates differing in virulence to gene Mi were determined at 25 degrees C (Mi expressed) and 32 degrees C (Mi not expressed). PI 126443-1MH, 270435-2R2, 270435 3MH, and their F1 progenies were resistant to Mi-virulent and Mi-avirulent isolates. At 32 degrees C with a Mi-avirulent isolate and at 25 degrees C with a Mi-virulent isolate, four TC1 generations segregated into resistant: susceptible (R?S) ratios close to 3?1. These results indicated resistance to Mi-(a)virulent M. incognita isolates is conferred by different non-allelic dominant genes in PI 126443-1MH, 270435-2R2 and 270435-3MH. The F2 progeny of PI 126443-1MH x EPP-1, challenged with Mi-avirulent M. incognita at 32 degrees C and with Mi-virulent M. incognita at both 25 degrees C and 32 degrees C, segregated with a ratio of 3?1 (R?S), indicating expression of a single dominant resistance gene in PI 126443 1MH in each case. In dual screenings on clones of the same individual plants from the TC1 and F2 segregating populations, some individual plants were susceptible at 32 degrees C to a Mi-avirulent isolate but resistant to the Mi-virulent isolate, and vice versa, suggesting that different but linked genes confer heat stable resistance to Mi-avirulent M. incognita and resistance to Mi-virulent M. incognita. We propose the symbol Mi-5 for the gene in PI 126443 clone 1MH and the symbol Mi-6 for the gene in PI 270435 clone 3MH which both confer resistance to Mi-avirulent M. incognita isolates at high temperature. We propose the symbol Mi 7 for the gene in PI 270435 clone 3MH and the symbol Mi-8 for the gene in PI 270435 clone 2R2 that both confer resistance to the Mi-virulent M. incognita isolate 557R at moderate (25 degrees C) temperature. The novel resistance genes are linked and reside in a genomic region in each parental clone that is independent from the Mi locus. PMID- 24162431 TI - Differentiation of Meloidogyne incognita and M. arenaria novel resistance phenotypes in Lycopersicon peruvianum and derived bridge-lines. AB - Lycopersicon peruvianum PI 270435 clone 2R2 and PI 126443 clone 1MH were crossed reciprocally with three L. esculentum-L. peruvianum bridge-lines. The incongruity barrier between the two plant species was overcome; F1 progeny were obtained from crosses between four parental combinations without embryo-rescue culture. Hybridity was confirmed by leaf and flower morphology and by the production of nematode-resistant F1 progeny on homozygous susceptible parents. Clones of the five F1 bridgeline hybrids were highly resistant to Mi-avirulent root-knot nematode (Meloidogyne incognita) at both 25 degrees C and 30 degrees C soil temperatures. However, only clones from PI 270435-3MH and PI 126443-1MH, and hybrids from PI 126443-1MH, were resistant to Mi-virulent M. incognita isolates at high soil temperature. Clones and hybrids from PI 270435-2R2 were not resistant to two Mi-virulent M. incognita isolates at high soil temperature. A source of heat-stable resistance was identified in bridge-line EPP-2, and was found to be derived from L. peruvianum LA 1708. Accessions of the L. peruvianum 'Maranon races', LA 1708 and LA 2172, and bridge-line EPP-2, segregated for heat stable resistance to Mi-avirulent M. incognita, but were susceptible to Mi virulent M. incognita isolates. Clone LA 1708-I conferred heat-stable resistance to M. arenaria isolate W, which is virulent to heat-stable resistance genes in L. peruvianum PI 270435-2R2, PI 270435-3MH, and PI 126443-1MH. Clone LA 1708-I has a distinct heat-stable factor for resistance to Mi-avirulent M. arenaria isolate W, for which the gene symbol Mi-4 is proposed. A Mi-virulent M. arenaria isolate Le Grau du Roi was virulent on all Lycopersicon spp. accessions tested, including those with novel resistance genes. PMID- 24162432 TI - A comparative study of the mitochondrial genome organization in in vitro cultures of diploid, tetraploid, and hexaploid Triticum species. AB - Southern-blot hybridizations of total DNA to mitochondrial DNA (mtDNA) probes were used to investigate the extent of mtDNA variability in cultures derived from immature embryos of diploid (Triticum monococcum, genomic formula: AA, T. tauschii, genomic formula: DD), allotetraploid (T. durum cv "Creso", genomic formula: AABB), and allohexaploid (T. aestivum, genomic formula: AABBDD) wheat species. Similar distinct changes in mtDNA organization were observed in in vitro cultures of the derived tetraploid and the hexaploid species with related genomes. The tetraploid and hexaploid species share the B genome and mtDNA variability in in vitro culture is known to be under nuclear control. These results suggest that a study of B genome diploids and other polyploid combinations would now shed light on whether or not mtDNA variability in tissue cultures is under B-genome control. PMID- 24162433 TI - Genetic analysis of the accumulation of COR14 proteins in wild (Hordeum spontaneum) and cultivated (Hordeum vulgare) barley. AB - The cold-regulated (COR14) protein of 14 kDa is a polypeptide accumulated under low-temperature conditions in the chloroplasts of barley leaves. In H. vulgare the COR14 antibody cross-reacts with two proteins, with a slightly different relative molecular weight around the marker of 14.4 kDa, referred to as COR14a and COR14b (high and low relative molecular weight, respectively). In a collection of H. spontaneum genotypes a clear polymorphism was found for the corresponding COR proteins. While some accessions showed the same COR pattern as cultivated barley, in 38 out of 61 accessions examined the COR14 antibody cross reacted with an additional coldregulated protein with a relative molecular weight of about 24 kDa (COR24). The accumulation of COR24 was often associated with the absence of COR14b; the relationship between the COR14b/COR24 polymorphism and the adaptation of H. spontaneum to different environments is discussed. By studying COR14 accumulation in cultivated barley we have found that the threshold induction-temperature of COR14a is associated with the loci controlling winter hardiness. This association was demonstrated by using either a set of 30 cultivars of different origin, or two sets of frost-tolerant and frost-sensitive F1 doubled-haploid lines derived from the cross Dicktoo (winter type) x Morex (spring type). These results suggest that the threshold induction-temperature of COR14a can be a potential biochemical marker for the identification of superior frostresistant barley genotypes. PMID- 24162434 TI - Repetitive, genome-specific probes in wheat (Triticum aestivum L. em Thell) amplified with minisatellite core sequences. AB - The detection and analysis of DNA polymorphisms in crops is an essential component of marker-assisted selection and cultivar identification in plant breeding. We have explored the direct amplification of minisatellite DNA by PCR (DAMD-PCR) as a means for generating DNA probes that are useful for detecting DNA polymorphisms and DNA fingerprinting in wheat. This technique was facilitated by high-stringency PCR with known plant and animal minisatellite core sequences as primers on wheat genomic DNA. The products of DAMD-PCR from Triticum aestivum, T. durum, T. monococcum, T. speltoides and T. tauschii showed a high degree of polymorphism and the various genomes could be identified. Cloning of the DAMD-PCR products and subsequent Southern hybridization frequently revealed polymorphic probes showing a good degree of genome specificity. In addition, polymorphic, single locus, and moderately dispersed PCR products were cloned that may have a potential for DNA fingerprinting. Our experiments were limited primarily to diploid wheats and the results indicated that DAMD-PCR may isolate genome specific probes from wild diploid wheat species that could be used to monitor genome introgression into hexaploid wheat. PMID- 24162435 TI - Repeatability and heritability of divergent recombination frequencies in the Iowa Stiff Stalk Synthetic (Zea mays L.). AB - Variability in recombination frequency was reported in the Iowa Stiff Stalk Synthetic. The objectives of the present research were to verify the differences in recombination frequency among individuals in the Iowa Stiff Stalk Synthetic maize population and to determine if the recombination frequency differences persisted among the S1 progeny. Testcrosses to measure male recombination frequency on three chromosomes (4, su1-c2; 5, a2-bt1-pr1; 9, sh1-bz1-wx1) were repeated for eight S0 individuals. Recombination frequencies were repeatably divergent among those individuals which were selected based on high or low recombination frequencies on specific chromosomes. Individuals which had been selected for long and short total map distances across the three chromosome regions produced repeatably divergent recombination frequencies only at the su1 c2 region. The recombination frequencies of the S1 lines, derived from the S0 individuals which had the most divergent recombination frequencies on a single chromosome, were significantly different. The broadsense heritability estimates derived from the regression of six S1 lines on six S0 individuals ranged from 0.69 to 0.20 for the five chromosome regions. We conclude that genetic differences for recombination frequency exist in this population and that modification by selection should be possible. PMID- 24162436 TI - The maize two-dimensional gel protein database: towards an integrated genome analysis program. AB - This paper describes the first maize database of proteins separated by two dimensional electrophoresis. Fifty-six coleoptile proteins and 18 leaf proteins from two maize lines were partially microsequenced. Thirty-six proteins (49%) displayed high similarity with database proteins. Nine of these proteins, representing five different functions, had never been described in maize. No conclusive function could be found for 45 polypeptides (61% of the microsequenced proteins). In addition, an alternative identification method, based on amino acid analysis, allowed candidates to be proposed for 17 proteins out of 44 additional proteins analyzed in the coleoptiles. These results are stored in a database which also includes, when available, genetic information about the chromosomal location of structural genes and regulatory factors of proteins. This database is being used in the context of a project on the genetic mapping of the expressed genome in maize. PMID- 24162437 TI - Genetics of aliphatic glucosinolates. IV. Side-chain modification in Brassica oleracea. AB - The biochemical and genetical relationship between aliphatic glucosinolates which have methylthioalkyl, methylsulphinylalkyl and alkenyl side chains has not been resolved by biochemical studies. In this study, two hypothetical models are tested by the genetic analysis of a backcross population between Brassica drepanensis and B. atlantica. The results support one of the models in which 3 methylthiopropyl glucosinolate is sequentially converted to 3 methylsulphinylpropyl, and then to 2-propenyl glucosinolate, by the action of dominant alleles at two loci. RFLP mapping positioned both loci on the same linkage group homologous to the B. napus N19 linkage group. The implication of the results for the genetic manipulation of glucosinolates in Brassica to improve flavour and nutritional properties, and in order to investigate plant-insect interactions, is discussed. PMID- 24162438 TI - ICH discussion on pharmacokinetics and toxicokinetics and contributors. PMID- 24162439 TI - Simulated swelling during low-temperature N2 adsorption in polymers of intrinsic microporosity. AB - Polymers of intrinsic microporosity (PIMs) are a promising alternative in gas separation applications; however, their industrial applicability is greatly reduced by their susceptibility toward sorption-induced plasticization. In this study, the effects of swelling during nitrogen adsorption isotherms at 77 K for five PIMs (PIM-1, PIM-1c, PIM-SBF, PIM-SBF-Me, and sPIM-1) were examined through predictive molecular simulations. The structural changes and adsorptive implications of swelling each PIM from 0 to 15% were analyzed by generating swollen "snapshots" of the PIM during the swelling process by means of an effective swelling procedure. The size of the free volume elements increased with the simulated swelling percentage, while the closely packed polymer chains remained associated. By comparing the simulated swollen and available experimental isotherms, this investigation shows that the amount of swelling observed during low-temperature nitrogen adsorption is strongly correlated with the interaction strength of the polymer matrix. Therefore, this study provides further support that PIMs should be designed with functionalities to increase the associative interactions of adjacent polymer chains while simultaneously prohibiting efficient packing to construct a gas separation membrane with limited low-temperature N2 swelling and high free volumes. PMID- 24162440 TI - Demonstration of surface transport in a hybrid Bi2Se3/Bi2Te3 heterostructure. AB - In spite of much work on topological insulators (TIs), systematic experiments for TI/TI heterostructures remain absent. We grow a high quality heterostructure containing single quintuple layer (QL) of Bi2Se3 on 19 QLs of Bi2Te3 and compare its transport properties with 20 QLs Bi2Se3 and 20 QLs Bi2Te3. All three films are grown on insulating sapphire (0001) substrates by molecular beam epitaxy (MBE). In situ angle-resolved photoemission spectroscopy (ARPES) provides direct evidence that the surface state of 1 QL Bi2Se3/19 QLs Bi2Te3 heterostructure is similar to the surface state of the 20 QLs Bi2Se3 and different with that of the 20 QLs Bi2Te3. In ex situ transport measurements, the observed linear magnetoresistance (MR) and weak antilocalization (WAL) of the hybrid heterostructure are similar to that of the pure Bi2Se3 film and not the Bi2Te3 film. This suggests that the single Bi2Se3 layer on top of 19 QLs Bi2Te3 dominates its transport properties. PMID- 24162441 TI - Young Adults' Provision of Support to Middle-Aged Parents. AB - OBJECTIVES: Middle-aged adults often provide support to aging parents, but researchers know little about support that young adults provide middle-aged parents. This study examined support that young adults provide parents and explanations for that support from both offspring's and parents' perspectives. METHOD: Young adults (n = 515, mean age = 22.34) and their parents (n = 364, mean age = 50.09) from the Family Exchanges Study reported support that offspring provide parents. Participants also reported parental personal problems, parental disability status, relationship quality, and support that parents provide offspring. RESULTS: Offspring provided parents with emotional support and listening more often than other forms of support. Offspring reported providing more frequent support than parents reported receiving. We examined factors associated with support using multilevel models. Both offspring and parents reported more frequent support provided to parents when they had higher quality relationships and when parents gave more frequent support to offspring. Offspring (but not parents) reported providing more frequent support to parents when parents were disabled. DISCUSSION: Findings are consistent with solidarity theory, which suggests that high-quality relationships may explain support. The concept of self-enhancement and generativity in middle-aged parents may explain the intergenerational differences in the association between parental disability and support. PMID- 24162443 TI - Patient satisfaction with nursing after surgery due to cervical or lumbar discopathy. AB - BACKGROUND: Relationships between patient satisfaction with nursing and patient clinical data have not been fully resolved in a Polish sample. Our objectives were to determine clinical factors associated with patient satisfaction with nursing and investigate differences between patients treated surgically for cervical or lumbar discopathy and degenerative changes. MATERIAL AND METHODS: This prospective and cross-sectional study included 63 consecutively selected patients treated surgically for lumbar discopathy and degenerative spine disease and 41 patients undergoing surgery for cervical discopathy and degenerative spine disease from 1st June 2009 to 31st September 2010 in the Department of Neurosurgery and Neurotraumatology of Poznan University of Medical Sciences. In the first stage of this study, socio-demographic data, medical history, and clinical patient characteristics were collected. A minimum 12-month follow-up formed the second part. Nineteen patients with lumbar discopathy were excluded because they were unable to answer the questionnaire. Finally, 44 consecutively selected patients treated surgically for lumbar discopathy and 41 patients undergoing surgery due to cervical discopathy were evaluated with the Polish version of the Newcastle Satisfaction with Nursing Scale (NSNS-PL). RESULTS: In patients with cervical and lumbar discopathy, the average Experiences of Nursing Care Subscale (ENCS) scores were 82.0 (SD 15.1) and 79.0 (SD 13.5), respectively, whereas the average Satisfaction with Nursing Care Subscale (SNCS) scores were 75.6 (SD 18.1) and 74.4 (SD 16.8), respectively. The study groups did not differ in regards to NSNS subscales. Associations between ENCS and SNCS scores were confirmed in both patient groups (rS=.73, p<0.001 and rS=.73, p<0.001, respectively). CONCLUSIONS: Our study highlights the importance of assessing the association between patient characteristics and patient perception of quality of nursing care. Satisfaction with treatment outcome and conviction about undergoing the same treatment affected experiences and satisfaction with nursing in the cervical group only. PMID- 24162444 TI - Microsurgical treatment of meningeal malignant melanoma accompanied by nevus of Ota: two case reports and a literature review. PMID- 24162445 TI - Optical nonlinearities in non-peripherally substituted pyridyloxy phthalocyanines: a combined effect of symmetry, ring-strain and demetallation. AB - The optical nonlinearities of six non-peripherally-substituted pyridyloxy phthalocyanines have been studied at 532 nm using a nanosecond Z-scan technique in a dimethyl sulphoxide solution. Ring-strain effects and the absence of a metal center were found to greatly reduce the inherent high nonlinearities expected of some of these phthalocyanine complexes. Of the six molecules investigated, 1(4),8(11),15(18),22(25)-tetrakis-(2-pyridyloxy)phthalocyaninato lead(II) 3, 1(4),8(11),15(18),22(25)-tetrakis-(2-pyridyloxy)phthalocyanine 5, and 1(4),8(11),15(18),22(25)-tetrakis-(4-pyridyloxy)phthalocyanine 6 were found to exhibit negligible nonlinear optical behavior, due to either the absence of asymmetry or central metal and/or the presence of a ring-strain effect. A two photon absorption process was found to be the major contributor to the observed reverse saturable absorption (RSA) in 1(4),8(11),15(18),22(25)-tetrakis-(4 pyridyloxy)phthalocyaninato lead(II) 4, 1(4)-mono-(2-pyridyloxy)phthalocyaninato lead(II) 7, and 1(4)-mono-(4-pyridyloxy)phthalocyaninato lead(II) 8, with large two-photon absorption cross-section, high hyperpolarizability and high third order susceptibility values in the range of 4.53 * 10(-43)-5.33 * 10(-42) cm(4) s per photon, 1.61 * 10(-28)-1.89 * 10(-27) esu and 9.73 * 10(-12)-7.05 * 10(-11) esu respectively. PMID- 24162447 TI - Ab initio molecular dynamics simulations of threshold displacement energies in SrTiO3. AB - Ab initio molecular dynamics simulations have been carried out to study low energy recoil events in SrTiO3. The threshold displacement energies are shown to be strongly dependent on both the orientation and the corresponding atomic arrangement. The minimum threshold displacement energies are 13 eV for an O recoil along the <100> O-O chain, 25 eV for a Sr recoil along the <100> Sr-Sr chain and 38 eV for a Ti recoil along the <110> Ti-Ti chain. The weighted average threshold displacement energies along the primary crystallographic directions are 35.7, 53.5 and >64.9 eV for O, Sr and Ti, respectively. The interstitial configurations produced by the recoil events are <100> and <111> split interstitials for O and Sr, respectively, together with a Ti interstitial occupying a distorted bridge position between two Sr sites. It is found that the recoil events in SrTiO3 are partial-charge transfer assisted processes, and the partial-charge transfer plays an important role in these recoil events. PMID- 24162446 TI - Enhanced biodegradation of methyl tert-butyl-ether by a microbial consortium. AB - The widespread use of Methyl tert-butyl-ether (MTBE) as a gasoline additive has resulted in a higher detection rate of MTBE in groundwater systems. Therefore, the researchers show more concern about the bioremediation of MTBE-impacted aquifers. In this paper, a MTBE-direct-degrading bacterial consortium was enriched (named RS1) and further studied. In order to identify the microbial community of the consortium, 17 and 12 different single strains were isolated from nutrient medium and MSM media (with MTBE as the sole carbon source), respectively. 16S rDNA-based phylogenetic analysis revealed that these diverse bacteria belonged to 14 genera, in which Pseudomonas was dominant. Several strains which can grow with MTBE as the sole carbon and energy source were also identified, such as M1, related to MTBE-degrading Arthrobacter sp. ATCC27778. Furthermore, the appropriate addition of certain single strain in consortium RS1 (M1:RS1 = 1:2) facilitates MTBE degradation by increasing the quantity of efficient MTBE-degrading bacteria. This work will provide microbial source and theoretical fundament for further bioremediation of MTBE-contaminated aquifers, which has applied potential and environmental importance. PMID- 24162448 TI - A randomized controlled trial of diet and physical activity in BRCA mutation carriers. AB - High serum levels of insulin-like growth factor I (IGF-I) are associated with an increased risk of sporadic breast cancer (BC). Furthermore, insulin and markers of insulin resistance, such as abdominal obesity, high blood glucose, high serum testosterone and metabolic syndrome, may affect both BC incidence and prognosis. We hypothesized that all these factors might be relevant also for hereditary BC, due to a deleterious mutation of BRCA genes. Epidemiological observation suggested that weight, energy intake (usually associated with higher bio availability of growth factors) and physical activity may be relevant in BRCA mutation carriers. Mechanistic studies hypothesized a functional interaction between BRCA genes and the IGF-I system. We have provided some evidence that high serum levels of IGF-I are associated with a significantly increased penetrance. We are recruiting a larger cohort of BRCA mutation carriers in order to test potential modulators of penetrance and prognosis. Within this cohort, we have planned a randomized controlled trial to test whether moderate calorie and protein restriction, together with physical activity, decrease IGF-I. Eligible study subjects are women with or without BC, aged 18-70, with a proven deleterious BRCA mutation, and without metastases. All the women will receive recommendations for the dietary prevention of cancer. The women will be then randomized into an active life-style intervention group and into a control group that will receive only the baseline recommendations. We expect to significantly reduce IGF-I in the intervention group. This trial and the subsequent cohort follow-up might open up primary prevention options for genetic BC. PMID- 24162450 TI - Preoperative morphological analysis by transesophageal echocardiography and predictive value of plasma landiolol concentration during systolic anterior motion mitral valve repair : a report of three cases. AB - We report three cases with systolic anterior motion (SAM) after mitral valve plasty. Preoperative mitral valve morphology is a risk factor for SAM. The morphological characteristics of SAM have been revealed in several studies. We found a small distance between coaptation and the interventricular septum in all cases, and cases 2, and 3 had a low AL/PL ratio, whereas case 3 had a large PML, which was revealed by transesophageal echocardiography. With the use of 3D transesophageal echocardiography, when mitral valve prolapse was investigated, in all three cases, it was easy to specify lesions. The issue for the future is 3D analysis when SAM is occurring. PMID- 24162449 TI - Nitrous oxide and perioperative outcomes. AB - There is emerging evidence related to the effects of nitrous oxide on important perioperative patient outcomes. Proposed mechanisms include metabolic effects linked to elevated homocysteine levels and endothelial dysfunction, inhibition of deoxyribonucleic acid and protein formation, and depression of chemotactic migration by monocytes. Newer large studies point to possible risks associated with the use of nitrous oxide, although data are often equivocal and inconclusive. Cardiovascular outcomes such as stroke or myocardial infarction were shown to be unchanged in previous studies, but the more recent Evaluation of Nitrous Oxide in the Gas Mixture for Anesthesia I trial shows possible associations between nitrous oxide and increased cardiovascular and pulmonary complications. There are also possible effects on postoperative wound infections and neuropsychological function, although the multifactorial nature of these complications should be considered. Teratogenicity linked to nitrous oxide use has not been firmly established. The use of nitrous oxide for routine anesthetic care may be associated with significant costs if complications such as nausea, vomiting, and wound infections are taken into consideration. Overall, definitive data regarding the effect of nitrous oxide on major perioperative outcomes are lacking. There are ongoing prospective studies that may further elucidate its role. The use of nitrous oxide in daily practice should be individualized to each patient's medical conditions and risk factors. PMID- 24162451 TI - Dynamic motion analysis of dart throwers motion visualized through computerized tomography and calculation of the axis of rotation. AB - We used a dynamic three-dimensional (3D) mapping method to model the wrist in dynamic unrestricted dart throwers motion in three men and four women. With the aid of precision landmark identification, a 3D coordinate system was applied to the distal radius and the movement of the carpus was described. Subsequently, with dynamic 3D reconstructions and freedom to position the camera viewpoint anywhere in space, we observed the motion pathways of all carpal bones in dart throwers motion and calculated its axis of rotation. This was calculated to lie in 27 degrees of anteversion from the coronal plane and 44 degrees of varus angulation relative to the transverse plane. This technique is a safe and a feasible carpal imaging method to gain key information for decision making in future hand surgical and rehabilitative practices. PMID- 24162452 TI - The growth factors involved in flexor tendon repair and adhesion formation. AB - Flexor tendon injuries remain a significant clinical problem, owing to the formation of adhesions or tendon rupture. A number of strategies have been tried to improve outcomes, but as yet none are routinely used in clinical practice. Understanding the role that growth factors play in tendon repair should enable a more targeted approach to be developed to improve the results of flexor tendon repair. This review describes the main growth factors in tendon wound healing, and the role they play in both repair and adhesion formation. PMID- 24162453 TI - The search for the ideal tendon repair in zone 2: strand number, anchor points and suture thickness. AB - This review article examines the mechanical factors involved in tendon repair by sutures. The repair strength, repair stiffness and gap resistance can be increased by increasing the number of core strands and anchor points, by increased anchor point efficiency and the use of peripheral sutures, and by using thicker sutures. In the future, laboratory tests could be standardized to a specific animal model and to a defined cyclic motion programme. Clinical studies support the use of multi-strand core and peripheral sutures, but two-strand core sutures are not adequate to ensure consistently good clinical results. Training surgeons in complex tendon repair techniques is essential. PMID- 24162454 TI - Arthroscopically assisted osteosynthesis for osteochondral fracture of the triquetrum. PMID- 24162455 TI - Symptomatic bilateral bipartite lunate: a case report. PMID- 24162457 TI - Intraneural angioleiomyoma of the median nerve at the wrist. PMID- 24162456 TI - A reliable surgical treatment for digital mucous cysts. AB - There is no clear consensus about the best operative technique for the treatment of digital mucous cysts. We carried out a retrospective review of all patients who underwent excision of a digital mucous cyst using a local advancement skin flap over a 10-year period. A total of 69 patients were included and were reviewed at an average of 38 months (minimum 6 months) post-operatively. No patients were lost to follow-up. There was only one case of cyst recurrence. Of these 67 patients were happy with the scar and 63 patients said they would have the procedure again; 36 patients had a pre-operative nail deformity and 21 reported that the deformity grew out after the procedure. PMID- 24162458 TI - Metamaterial fibres for subdiffraction imaging and focusing at terahertz frequencies over optically long distances. AB - Using conventional materials, the resolution of focusing and imaging devices is limited by diffraction to about half the wavelength of light, as high spatial frequencies do not propagate in isotropic materials. Wire array metamaterials, because of their extreme anisotropy, can beat this limit; however, focusing with these has only been demonstrated up to microwave frequencies and using propagation over a few wavelengths only. Here we show that the principle can be scaled to frequencies orders of magnitudes higher and to considerably longer propagation lengths. We demonstrate imaging through straight and tapered wire arrays operating in the terahertz spectrum, with unprecedented propagation of near field information over hundreds of wavelengths and focusing down to 1/28 of the wavelength with a net increase in power density. Applications could include in vivo terahertz-endoscopes with resolution compatible with imaging individual cells. PMID- 24162459 TI - Effects of surface charges of graphene oxide on neuronal outgrowth and branching. AB - Graphene oxides with different surface charges were fabricated from carboxylated graphene oxide by chemical modification with amino- (-NH2), poly-m-aminobenzene sulfonic acid- (-NH2/-SO3H), or methoxyl- (-OCH3) terminated functional groups. The chemically functionalized graphene oxides and the carboxylated graphene oxide were characterized by infrared spectroscopy, X-ray photoelectron spectroscopy, UV Vis spectrometry, zeta potential measurements, field emission scanning electron microscopy, and contact angle analyses. Subsequently, the resulting graphene oxides were used as substrates for culturing primary rat hippocampal neurons to investigate neurite outgrowth and branching. The morphological features of neurons that directly reflect their potential capability in synaptic transmission were characterized. The results demonstrate that the chemical properties of graphene oxide can be systematically modified by attaching different functional groups that confer known characteristics to the substrate. By manipulating the charge carried by the functionalized graphene oxides, the outgrowth and branching of neuronal processes can be controlled. Compared with neutral, zwitterionic, or negatively charged graphene oxides, positively charged graphene oxide was found to be more beneficial for neurite outgrowth and branching. The ability to chemically modify graphene oxide to control neurite outgrowth could be implemented clinically, especially in cases wherein long-term presence of outgrowth modulation is necessary. PMID- 24162460 TI - Bimodal mesoporous titanium dioxide anatase films templated by a block polymer and an ionic liquid: influence of the porosity on the permeability. AB - In the present paper, we report the synthesis of bimodal mesoporous anatase TiO2 films by the EISA (Evaporation-Induced Self-Assembly) method using sol-gel chemistry combining two porogen agents, a low molecular weight ionic template and a neutral block copolymer. The surfactant template (C16mimCl) generates non oriented worm-like pores (8 to 10 nm) which connect the regularly packed ellipsoidal mesopores (15 to 20 nm diameter) formed by an amphiphilic block copolymer of the type poly(isobutylene)-b-poly(ethylene oxide) (PIB-PEO). The surfactant template can also significantly influence the size and packing of the ellipsoidal mesopores. The mesostructural organization and mesoporosity of the films are studied by Environmental Ellipsometry-Porosimetry (EEP), Grazing Incidence Small-Angle X-ray Scattering (GISAXS) and electron microscopy techniques. Electrochemical characterization is performed to study the permeability of the films to liquid solutions, using two types of probe moieties (K3Fe(III)(CN)6 and Ru(bpy)3(2+)) by the wall-jet technique. An optimum ratio of C16mimCl/PIB-PEO provides anatase films with a continuous bimodal mesopore structure, possessing a permeability up to two times higher than that of the mesoporous films templated by PIB-PEO only (with partially isolated mesopores). When C16mimCl is used in large quantities, up to 20% weight vs. PIB-PEO, large overall porous volume and surface area are obtained, but the mesostructure is increasingly disrupted, leading to a severe loss of permeability of the bimodal films. A dye-sensitized solar cell set-up is used with anatase films as the photoelectrode. The photosensitizer loading and the total energy conversion efficiency of the solar cells using the mesoporous films templated by an optimal ratio of the two porogen agents C16mimCl and PIB-PEO can be substantially increased in comparison with the solar cells using mesoporous films templated by PIB-PEO only. PMID- 24162461 TI - Pharyngeal function and breathing pattern during partial neuromuscular block in the elderly: effects on airway protection. AB - BACKGROUND: Intact pharyngeal function and coordination of breathing and swallowing are essential for airway protection and to avoid respiratory complications. Postoperative pulmonary complications caused by residual effects of neuromuscular-blocking agents occur more frequently in the elderly. Moreover, elderly have altered pharyngeal function which is associated with increased risk of aspiration. The purpose of this study was to evaluate effects of partial neuromuscular block on pharyngeal function, coordination of breathing and swallowing, and airway protection in individuals older than 65 yr. METHODS: Pharyngeal function and coordination of breathing and swallowing were assessed by manometry and videoradiography in 17 volunteers, mean age 73.5 yr. After control recordings, rocuronium was administered to obtain steady-state train-of-four ratios of 0.70 and 0.80 followed by spontaneous recovery to greater than 0.90. RESULTS: Pharyngeal dysfunction increased significantly at train-of-four ratios 0.70 and 0.80 to 67 and 71%, respectively, compared with 37% at control recordings, and swallowing showed a more severe degree of dysfunction during partial neuromuscular block. After recovery to train-of-four ratio of greater than 0.90, pharyngeal dysfunction was not significantly different from the control state. Resting pressure in the upper esophageal sphincter was lower at all levels of partial neuromuscular block compared with control recordings. The authors were unable to demonstrate impaired coordination of breathing and swallowing. CONCLUSION: Partial neuromuscular block in healthy elderly individuals causes an increased incidence of pharyngeal dysfunction from 37 to 71%, with impaired ability to protect the airway; however, the authors were unable to detect an effect of partial neuromuscular block on coordination of breathing and swallowing. PMID- 24162462 TI - A phase I, dose-escalation trial evaluating the safety and efficacy of emulsified isoflurane in healthy human volunteers. AB - BACKGROUND: This first-in-human volunteer phase I clinical trial aimed to evaluate the safety, tolerability, and anesthesia efficacy of emulsified isoflurane (EI), an intravenously injectable formulation of isoflurane. METHODS: Seventy-eight healthy volunteers were recruited in this open-label, single-bolus, dose-escalation, phase I trial and were allocated into 16 cohorts. Each volunteer received a single bolus injection of EI. The dose started with 0.3 mg/kg (for isoflurane) and was planned to end with 64.6 mg/kg. Postdose vital signs, physical examination, laboratory tests, chest radiograph, 12-lead electrocardiogram, and development of any adverse event were closely monitored as safety measurements. Effectiveness in producing sedation/anesthesia was assessed by Modified Observer's Assessment of Alertness/Sedation and Bispectral Index. RESULTS: The dose escalation ended as planned. The most common adverse events associated with EI were injection pain (77 of 78, 98.7%) and transient tachycardia (22 of 78, 25.6%). Only at high doses (>=38.3 mg/kg) did EI cause transient hypotension (5 of 78, 6.4%) or apnea (11 of 78, 14.1%), but all the affected volunteers recovered uneventfully. Fast onset of unconsciousness (typically 40 s after injection) was developed in all volunteers receiving doses of 22.6 mg/kg or greater. Waking-up time and depression in Modified Observer's Assessment of Alertness/Sedation correlated well with EI dose. None of the postdose tests revealed any abnormal result. CONCLUSIONS: EI is safe for intravenous injection in human volunteers in the dose range of 0.3 to 64.6 mg/kg. At doses of 22.6 mg/kg or higher, EI produced rapid onset of unconsciousness in all volunteers followed by fast, predictable, and complete recovery. PMID- 24162463 TI - High-mobility group box 1 protein initiates postoperative cognitive decline by engaging bone marrow-derived macrophages. AB - BACKGROUND: Aseptic trauma engages the innate immune response to trigger a neuroinflammatory reaction that results in postoperative cognitive decline. The authors sought to determine whether high-mobility group box 1 protein (HMGB1), an ubiquitous nucleosomal protein, initiates this process through activation and trafficking of circulating bone marrow-derived macrophages to the brain. METHODS: The effects of HMGB1 on memory (using trace fear conditioning) were tested in adult C57BL/6J male mice; separate cohorts were tested after bone marrow-derived macrophages were depleted by clodrolip. The effect of anti-HMGB1 neutralizing antibody on the inflammatory and behavioral responses to tibial surgery were investigated. RESULTS: A single injection of HMGB1 caused memory decline, as evidenced by a decrease in freezing time (52 +/- 11% vs. 39 +/- 5%; n = 16-17); memory decline was prevented when bone marrow-derived macrophages were depleted (39 +/- 5% vs. 50 +/- 9%; n = 17). Disabling HMGB1 with a blocking monoclonal antibody, before surgery, reduced postoperative memory decline (52 +/- 11% vs. 29 +/- 5%; n = 15-16); also, hippocampal expression of monocyte chemotactic protein 1 was prevented by the neutralizing antibody (n = 6). Neither the systemic nor the hippocampal inflammatory responses to surgery occurred in mice pretreated with anti-HMGB1 neutralizing antibody (n = 6). CONCLUSION: Postoperative neuroinflammation and cognitive decline can be prevented by abrogating the effects of HMGB1. Following the earlier characterization of the resolution of surgery-induced memory decline, the mechanisms of its initiation are now described. Together, these data may be used to preoperatively test the risk to surgical patients for the development of exaggerated and prolonged postoperative memory decline that is reflected in delirium and postoperative cognitive dysfunction, respectively. PMID- 24162464 TI - Inferring therapeutic targets from heterogeneous data: HKDC1 is a novel potential therapeutic target for cancer. AB - MOTIVATION: The discovery of therapeutic targets is important for cancer treatment. Although dozens of targets have been used in cancer therapies, cancer remains a serious disease with a high mortality rate. Owing to the expansion of cancer-related data, we now have the opportunity to infer therapeutic targets using computational biology methods. RESULTS: Here, we describe a method, termed anticancer activity enrichment analysis, used to determine genes that could be used as therapeutic targets. The results show that these genes have high likelihoods of being developed into clinical targets (>60%). Combined with gene expression data, we predicted 50 candidate targets for lung cancer, of which 19 of the top 20 genes are targeted by approved drugs or drugs used in clinical trials. A hexokinase family member, hexokinase domain-containing protein 1 (HKDC1), is the only one of the top 20 genes that has not been targeted by either an approved drug or one being used in clinical trials. Further investigations indicate that HKDC1 is a novel potential therapeutic target for lung cancer. CONCLUSION: We developed a protocol to identify potential therapeutic targets from heterogeneous data. We suggest that HKDC1 is a novel potential therapeutic target for lung cancer. CONTACT: huangjf@mail.kiz.ac.cn SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 24162465 TI - Protter: interactive protein feature visualization and integration with experimental proteomic data. AB - SUMMARY: The ability to integrate and visualize experimental proteomic evidence in the context of rich protein feature annotations represents an unmet need of the proteomics community. Here we present Protter, a web-based tool that supports interactive protein data analysis and hypothesis generation by visualizing both annotated sequence features and experimental proteomic data in the context of protein topology. Protter supports numerous proteomic file formats and automatically integrates a variety of reference protein annotation sources, which can be readily extended via modular plug-ins. A built-in export function produces publication-quality customized protein illustrations, also for large datasets. Visualizations of surfaceome datasets show the specific utility of Protter for the integrated visual analysis of membrane proteins and peptide selection for targeted proteomics. AVAILABILITY AND IMPLEMENTATION: The Protter web application is available at http://wlab.ethz.ch/protter. Source code and installation instructions are available at http://ulo.github.io/Protter/. CONTACT: wbernd@ethz.ch SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 24162466 TI - A pathway-based data integration framework for prediction of disease progression. AB - MOTIVATION: Within medical research there is an increasing trend toward deriving multiple types of data from the same individual. The most effective prognostic prediction methods should use all available data, as this maximizes the amount of information used. In this article, we consider a variety of learning strategies to boost prediction performance based on the use of all available data. IMPLEMENTATION: We consider data integration via the use of multiple kernel learning supervised learning methods. We propose a scheme in which feature selection by statistical score is performed separately per data type and by pathway membership. We further consider the introduction of a confidence measure for the class assignment, both to remove some ambiguously labeled datapoints from the training data and to implement a cautious classifier that only makes predictions when the associated confidence is high. RESULTS: We use the METABRIC dataset for breast cancer, with prediction of survival at 2000 days from diagnosis. Predictive accuracy is improved by using kernels that exclusively use those genes, as features, which are known members of particular pathways. We show that yet further improvements can be made by using a range of additional kernels based on clinical covariates such as Estrogen Receptor (ER) status. Using this range of measures to improve prediction performance, we show that the test accuracy on new instances is nearly 80%, though predictions are only made on 69.2% of the patient cohort. AVAILABILITY: https://github.com/jseoane/FSMKL CONTACT: J.Seoane@bristol.ac.uk SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 24162467 TI - Identification of important regressor groups, subgroups and individuals via regularization methods: application to gut microbiome data. AB - MOTIVATION: Gut microbiota can be classified at multiple taxonomy levels. Strategies to use changes in microbiota composition to effect health improvements require knowing at which taxonomy level interventions should be aimed. Identifying these important levels is difficult, however, because most statistical methods only consider when the microbiota are classified at one taxonomy level, not multiple. RESULTS: Using L1 and L2 regularizations, we developed a new variable selection method that identifies important features at multiple taxonomy levels. The regularization parameters are chosen by a new, data adaptive, repeated cross-validation approach, which performed well. In simulation studies, our method outperformed competing methods: it more often selected significant variables, and had small false discovery rates and acceptable false positive rates. Applying our method to gut microbiota data, we found which taxonomic levels were most altered by specific interventions or physiological status. AVAILABILITY: The new approach is implemented in an R package, which is freely available from the corresponding author. CONTACT: tpgarcia@srph.tamhsc.edu SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 24162468 TI - Anatomical entity mention recognition at literature scale. AB - MOTIVATION: Anatomical entities ranging from subcellular structures to organ systems are central to biomedical science, and mentions of these entities are essential to understanding the scientific literature. Despite extensive efforts to automatically analyze various aspects of biomedical text, there have been only few studies focusing on anatomical entities, and no dedicated methods for learning to automatically recognize anatomical entity mentions in free-form text have been introduced. RESULTS: We present AnatomyTagger, a machine learning-based system for anatomical entity mention recognition. The system incorporates a broad array of approaches proposed to benefit tagging, including the use of Unified Medical Language System (UMLS)- and Open Biomedical Ontologies (OBO)-based lexical resources, word representations induced from unlabeled text, statistical truecasing and non-local features. We train and evaluate the system on a newly introduced corpus that substantially extends on previously available resources, and apply the resulting tagger to automatically annotate the entire open access scientific domain literature. The resulting analyses have been applied to extend services provided by the Europe PubMed Central literature database. AVAILABILITY AND IMPLEMENTATION: All tools and resources introduced in this work are available from http://nactem.ac.uk/anatomytagger. CONTACT: sophia.ananiadou@manchester.ac.uk SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 24162469 TI - Inorganic nanoparticle multilayers using photo-crosslinking layer-by-layer assembly and their applications in nonvolatile memory devices. AB - We introduce a general and facile method for the preparation of organic/inorganic nanoparticle (NP) nanocomposite multilayer films that allows vertical growth of various NP layers (i.e., metal or transition metal oxide NPs) in a densely packed structure. Our approach is based on the successive photo-crosslinking layer-by layer (LbL) assembly between hydrophobic ligands onto a NP surface and photoinitiator (PI) molecules. Therefore, our approach requires neither the additional surface modification needed for well-defined NPs synthesized in organic media nor the deposition step that inserts a polymer layer bridge between adjacent inorganic NP layers in the preparation of traditional LbL-assembled NP films. We also demonstrate that photo-crosslinking LbL-assembled (metal oxide NP)n films could be used as a nonvolatile memory layer without a high-temperature thermal treatment, unlike conventional vacuum-deposition- or sol-gel-derived memory devices, which require thermal treatments at temperatures greater than 200 degrees C. This robust method could open a facile route for the design of functional NP-based electronic devices. PMID- 24162470 TI - Cystatin C, CRP, log TG/HDLc and metabolic syndrome are associated with microalbuminuria in hypertension. AB - BACKGROUND: In patients with systemic hypertension, microalbuminuria is a marker of endothelial damage and is associated with an increased risk for cardiovascular disease. OBJECTIVE: To determine the factors that may lead to the occurrence of microalbuminuria in hypertensive patients with serum creatinine lower than 1.5 mg/dL. METHODS: This cross-sectional study included 133 Brazilians with essential hypertension followed up at a hypertension outpatient clinic. Those with serum creatinine higher than 1.5 mg/dL, as well as those with diabetes mellitus, were excluded. Systolic and diastolic blood pressures were measured, and body mass index (BMI) and GFR estimated by using the CKD-EPI formula were calculated. The serum levels of the following were assessed: CysC, creatinine, total cholesterol, HDL cholesterol, LDL cholesterol, triglycerides, C-reactive protein (CRP) and fasting glucose. Microalbuminuria was determined in 24-hour urine. Hypertensive patients were classified according to the presence of one or more criteria for metabolic syndrome. RESULTS: In a multiple regression analysis, the serum levels of CysC and CRP, the atherogenic index log TG/HDLc and the presence of three or more criteria for metabolic syndrome were positively correlated with microalbuminuria (r2: 0.277, p < 0.05). CONCLUSION: CysC, CRP, log TG/HDLc, and the presence of three or more criteria for metabolic syndrome, regardless of serum creatinine, were associated with microalbuminuria, an early marker of kidney damage and cardiovascular risk in patients with essential hypertension. PMID- 24162471 TI - Atrial fibrillation ablation by use of electroanatomical mapping: efficacy and recurrence factors. AB - BACKGROUND: Radiofrequency catheter ablation guided by electroanatomical mapping is currently an important therapeutic option for the treatment of atrial fibrillation. The complexity of the procedure, the several techniques used and the diversity of the patients hinder the reproduction of the results and the indication for the procedure. OBJECTIVE: To evaluate the efficacy and factors associated with recurrence of atrial fibrillation. METHODS: Prospective cohort study with consecutive patients submitted to atrial fibrillation ablation treatment guided by electroanatomical mapping. The inclusion criteria were as follows: minimum age of 18 years; presence of paroxysmal, persistent or long standing persistent AF; AF recording on an electrocardiogram, exercise testing or Holter monitoring (duration longer than 15 minutes); presence of symptoms associated with AF episodes; AF refractoriness to, at least, two antiarrhythmic drugs, one of which being amiodarone, or impossibility to use antiarrhythmic drugs. RESULTS: The study included 95 patients (age 55 +/- 12 years, 84% men, mean CHADS2 = 0.8) who underwent 102 procedures with a median follow-up of 13.4 months. The recurrence-free rate after the procedure was 75.5% after 12 months. Atrial fibrillation recurred as follows: 26.9% of patients with paroxysmal and persistent atrial fibrillation; 45.8% of patients with long-standing persistent atrial fibrillation (p = 0.04). Of the analyzed variables, the increased size of the left atrium has proven to be an independent predictor of atrial fibrillation recurrence after the procedure (HR = 2.58; 95% CI: 1.26-4.89). Complications occurred in 4.9% of the procedures. CONCLUSION: Atrial fibrillation ablation guided by electroanatomical mapping has shown good efficacy. The increase in left atrium size was associated with atrial fibrillation recurrence. PMID- 24162472 TI - Clinical significance of histological features of thrombi in patients with myocardial infarction. AB - BACKGROUND: Percutaneous Coronary Intervention (PCI) is the most common strategy for the treatment of Acute ST segment elevation Myocardia Infarction (STEMI), and thromboaspiration has been increasingly utilized for removal of occlusive thrombi. OBJECTIVES: To analyze the influence of histopathological features of coronary thrombi in clinical outcomes of patients with STEMI, and the association of these variables with clinical, angiographic, and laboratory features and medications used in hospitalization. METHODS: Prospective cohort study. All patients were monitored during hospitalization and thirty days after the event. Aspirated thrombi were preserved in formalin and subsequently stained with hematoxylin-eosin and embedded in paraffin. Thrombi were classified as recent and old. The primary outcome was the occurrence of major cardiovascular events within thirty days. RESULTS: During the study period, 1,149 patients were evaluated with STEMI, and 331 patients underwent thrombi aspiration, leaving 199 patients available for analysis. It was identified recent thrombi in 116 patients (58%) and old thrombi in 83 patients (42%). Recent thrombi have greater infiltration of red blood cells than old thrombi (p = 0.02), but there were no statistically significant differences between other clinical, angiographic, laboratory, and histopathological features and medications in both group of patients. The rates of clinical outcomes were similar in both groups. CONCLUSIONS: Recent thrombi were identified in 58% of patients with STEMI and it was observed an association with infiltration of red blood cells. There was no association between histopathological features of thrombi and clinical variables and cardiovascular outcomes. PMID- 24162473 TI - Identification and dynamics of polyglycine II nanocrystals in Argiope trifasciata flagelliform silk. AB - Spider silks combine a significant number of desirable characteristics in one material, including large tensile strength and strain at breaking, biocompatibility, and the possibility of tailoring their properties. Major ampullate gland silk (MAS) is the most studied silk and their properties are explained by a double lattice of hydrogen bonds and elastomeric protein chains linked to polyalanine beta-nanocrystals. However, many basic details regarding the relationship between composition, microstructure and properties in silks are still lacking. Here we show that this relationship can be traced in flagelliform silk (Flag) spun by Argiope trifasciata spiders after identifying a phase consisting of polyglycine II nanocrystals. The presence of this phase is consistent with the dominant presence of the -GGX- and -GPG- motifs in its sequence. In contrast to the passive role assigned to polyalanine nanocrystals in MAS, polyglycine II nanocrystals can undergo growing/collapse processes that contribute to increase toughness and justify the ability of Flag to supercontract. PMID- 24162474 TI - Molecular markers associated with seed weight in two soybean populations. AB - Seed weight (SW) is a component of soybean, Glycine max (L.) Merr., seed yield, as well as an important trait for food-type soybeans. Two soybean populations, 120 F4-derived lines of 'Young'xPI416937 (Pop1) and 111 F2-derived lines of PI97100x'Coker 237' (Pop2), were mapped with RFLP makers to identify quantitative trait loci (QTLs) conditioning SW across environments and populations. The genetic map of Pop1 consisted of 155 loci covering 973 cM, whereas Pop2 involved 153 loci and covered 1600 cM of map distance. For Pop1, the phenotypic data were collected from Plains, GA., Windblow, N.C., and Plymouth, N.C., in 1994. For Pop2, data were collected from Athens, GA., in 1994 and 1995, and Blackville, S.C., in 1995. Based on single-factor analysis of variance (ANOVA), seven and nine independent loci were associated with SW in Pop1 and Pop2, respectively. Together the loci explained 73% of the variability in SW in Pop1 and 74% in Pop2. Transgressive segregation occurred among the progeny in both populations. The marker loci associated with SW were highly consistent across environments and years. Two QTLs on linkage group (LG) F and K were located at similar genomic regions in both populations. The high consistency of QTLs across environments indicates that effective marker-assisted selection is feasible for soybean SW. PMID- 24162475 TI - Molecular-mapping analysis in Brassica napus using isozyme, RAPD and RFLP markers on a doubled-haploid progeny. AB - We have undertaken the construction of a Brassica napus genetic map with isozyme (4%), RFLP (26.5%) and RAPD (68%) markers on a 152 lines of a doubled-haploid population. The map covers 1765 cM and comprises 254 markers including three PCR specific markers and a morphological marker. They are assembled into 19 linkage groups, covering approximatively 71% of the rapeseed genome. Thirty five percent of the studied markers did not segregate according to the expected Mendelian ratio and tended to cluster in eight specific linkage groups. In this paper, the structure of the genetic map is described and the existence of non-Mendelian segregations in linkage analysis as well as the origins of the observed distortions, are discussed. The mapped RFLP loci corresponded to the cDNAs already used to construct B. napus maps. The first results of intraspecific comparative mapping are presented. PMID- 24162476 TI - Construction of Brassica B genome synteny groups based on chromosomes extracted from three different sources by phenotypic, isozyme and molecular markers. AB - The three B genomes of Brassica contained in B. nigra, B. carinata and B. juncea were dissected by addition in B. napus. Using phenotypic, isozyme and molecular markers we characterized 8 alien B-genome chromosomes from B. nigra and B. carinata and 7 from B. juncea by constructing synteney groups. The alien chromosomes of the three different sources showed extensive intragenomic recombinations that were detected by the presence of the same loci in more than one synteny group but flanked by different markers. In addition, intergenomic recombinations were observed. These were evident in euploid AACC plants of the rapeseed phenotype derived from the addition lines carrying a few markers from the B genome due to translocations and recombinations between non-homoeologous chromosomes. The high plasticity of the Brassica genomes may have been an powerful factor in directing their evolution by hybridization and amphiploidy. PMID- 24162477 TI - Molecular verification and characterization of BYDV-resistant germ plasms derived from hybrids of wheat with Thinopyrum ponticum and Th. intermedium. AB - Twenty-five partial amphiploids (2n=8x=56), which were derived from hybrids of wheat (Triticum aestivum L.) with either Thinopyrum ponticum (Podpera) Liu & Wang, Th. intermedium (Host) Barkworth & D. Dewey, or Th. junceum (L.) A. Love, were assayed for resistance to BYDV serotype PAV by slot-blot hybridization with viral cDNA of a partial coat protein gene. Three immune lines were found among seven partial amphiploids involving Th. ponticum. Seven highly resistant lines were found in ten partial amphiploids involving Th. intermedium. None of eight partial amphiploids or 13 addition lines of Chinese Spring - Th. junceum were resistant to BYDV. Genomic in situ hybridization demonstrated that all of the resistant partial amphiploids, except TAF46, carried an alien genome most closely related to St, whether it was derived from Th. ponticum or Th. intermedium. The two partial amphiploids carrying an intact E genome of Th. ponticum are very susceptible to BYDV-PAV. In TAF46, which contains three pairs of St- and four pairs of E-genome chromo somes, the gene for BYDV resistance has been located to a modified 7 St chromosome in the addition line L1. This indicates that BYDV resistance in perennial polyploid parents, i.e., Th. ponticum and Th. intermedium, of these partial amphiploids is probably controlled by a gene(s) located on the St-genome chromosome(s). PMID- 24162478 TI - Pollen markers for gene-centromere mapping in diploid potato. AB - The utility of two pollen genetic markers for estimating the extent of meiotic recombination between the centromere and a marker gene was tested in 2n pollen of diploid potato clones. One of these markers was the distal locus amylose-free (amf) on chromosome 8 and the other was the isozyme locus alcohol dehydrogenase (Adh-1) on chromosome 4. In the case of the amf locus, the gene-centromere distance was estimated in a normal synaptic and a desynaptic genotype. In both cases the genetic analysis was confined to: (1) a direct estimation of the phenotypic (blue vs red) segregation ratios in FDR (first-division restitution) 2n pollen and (2) a classification of the 4 x progeny from 4x (nulliplex amf) x 2x (Amf/amf) crosses into duplex, simplex and nulliplex classes. The recombination frequency between the centromere and the amf locus in the normal synaptic genotype B92-7015-4 corresponded to a gene-centromere distance of 48.8 cM, whereas this distance amounted to 13.3 cM in the desynaptic genotype RS93 8025-1. Hence desynapsis reduced crossing-over by 73%. The observed genetic distance of 48.8 cM in the normal synaptic clone, B92-7015-4, is the highest gene centromere distance reported so far in potato and this could be explained on the assumption of absolute chiasma interference. For the Adh-1 locus, it was found that heterozygous 2n pollen grains could be detected in pollen samples of the diploid clones, because of the occurrence of a heterodimeric band of the isozyme. Unlike the amf locus, the genecentromere distance for the Adh-1 locus was estimated only on the basis of the duplex, simplex and nulliplex classes in the progenies from 4x (nulliplex Adh-1 (2) )x B92-7015-4 (Adh-1 (1) /Adh-1 (2) )crosses and was found to be 19.4 cM. Because the accurate positions of centromeres in relation to other loci are not available in the existing genetic maps of potato, which are saturated with molecular markers, halftetrad analysis is a promising additional approach to the basic genetics of this crop. PMID- 24162479 TI - Identification and molecular characterization of a large insertion within the repetitive domain of a high-molecular-weight glutenin subunit gene from hexaploid wheat. AB - High-molecular-weight (HMW) glutenin subunits are a particular class of wheat endosperm proteins containing a large repetitive domain flanked by two short N- and C-terminal non-repetitive regions. Deletions and insertions within the central repetitive domain has been suggested to be mainly responsible for the length variations observed for this class of proteins. Nucleotide sequence comparison of a number of HMW glutenin genes allowed the identification of small insertions or deletions within the repetitive domain. However, only indirect evidence has been produced which suggests the occurrence of substantial insertions or deletions within this region when a large variation in molecular size is present between different HMW glutenin subunits. This paper represents the first report on the molecular characterization of an unusually large insertion within the repetitive domain of a functional HMW glutenin gene. This gene is located at the Glu-D1 locus of a hexaploid wheat genotype and contains an insertion of 561 base pairs that codes for 187 amino acids corresponding to the repetitive domain of a HMW glutenin subunit encoded at the same locus. The precise location of the insertion has been identified and the molecular processes underlying such mutational events are discussed. PMID- 24162480 TI - A storage-protein marker associated with the suppressor of Pm8 for powdery mildew resistance in wheat. AB - A suppressor of resistance to powdery mildew conferred by Pm8 showed complete association with the presence of a storage-protein marker resolved by electrophoresis on SDS-PAGE gels. This marker was identified as the product of the gliadin allele Gli-A1a. The mildewresponse phenotypes of wheats possessing the 1BL.1RS translocation were completely predictable from electrophoretograms. The suppressor, designated SuPm8, was located on chromosome 1AS. It was specific in its suppression of Pm8, and did not affect the rye-derived resistance phenotypes of wheat lines with Pm17, also located in 1RS, or of lines with Pm7. PMID- 24162481 TI - Reducing the tetraploid non-nodulating alfalfa (Medicago sativa) MnNC-1008(NN) germ plasm to the diploid level. AB - MnNC-1008(NN) (referred to as MN-1008) is a tetraploid alfalfa mutant with two recessive genes (nn 1 and nn 2 )conditioning the non-nodulating trait. The tetraploid level (2n=4x=32) of this Medicago sativa germ plasm was reduced to the diploid (2n=2x=16) level using the 4x-2x genetic cross originally described as a workable method for the induction of haploidy in alfalfa by T. E. Bingham. In our experiments more than 7000 emasculated flowers of a single non-nodulating MN-1008 mutant alfalfa plant with purple petals were cross-pollinated with pollen from a single, diploid, yellow-flowered alfalfa plant. Mature seeds from these crosses were collected and germinated, after which the plants were subjected to morphological and cytogenetic analyses as well as to DNA fingerprinting. Out of 26 viable progeny, 6 were hybrid plants, 19 proved to be self-mated derivatives of MN-1008, while one descendant turned out to be a diploid (2n=2x=16), purple flowered, non-nodulating plant denoted as M. sativa DN-1008. This diploid, non nodulating alfalfa plant can serve as starting material to facilitate the comprehensive morphological, physiological and genetic analysis (gene mapping and cloning) of nodulation in order to learn more about the biology of the symbiotic root nodule development. To produce diploid, nodulating hybrid F1 plants, DN-1008 was crossed with a diploid, yellow-flowered M. sativa ssp. quasifalcata plant. An F2 population segregating the nn 1 and nn 2 genes in a diploid manner, in which the genetic analysis is more simple than in a tetraploid population, can be established by self-mating of the F1 plants. PMID- 24162482 TI - Dosage effects of the three Wx genes on amylose synthesis in wheat endosperm. AB - Amylose synthesis in wheat endosperm is mainly controlled by the granule-bound starch synthase of about 60 kDa, the so-called waxy (Wx) protein. The Wx proteins are the product of the Wx genes at a triplicate set of single-copy homoeoloci located on chromosomes 7A (Wx-A1), 4A (Wx-B1) and 7D (Wx-D1). Using 'Chinese Spring' and its aneuploid lines, including nullisomic-tetrasomics, tetrasomics, ditelosomics and deletion stocks, together with single-chromosome substitution lines for these chromosomes, the effects of varying the dosage of whole chromosomes and chromosome arms, as well as the effects of null alleles, upon amylose synthesis were investigated. Nullisomic 4A and the deletion of chromosome segments carrying the Wx-B1 gene reduced the amylose content by more than 3%. A reasonable agreement was found in the substitution lines. This confirms that the absence of the Wx-B1 gene, or else substitution of this gene by its null allele, has the most striking effect on decreasing amylose synthesis. The removal of chromosomes carrying either the Wx-A1 or the Wx-D1 gene reduces the amylose content by less than 2%. A similar reduction was revealed by substitution of these two genes by the null alleles. Double dosages of chromosomes 7A, 4A and 7D did not increase amylose content, while the tetrasomic chromosomes produced more of the respective Wx proteins. This suggests that a certain level of Wx gene activity or of the Wx proteins led to the maximum amount of amylose. PMID- 24162483 TI - Microsatellite DNA markers for rice chromosomes. AB - We found 369 complete microsatellites, of which (CGG/GCC)n was the most frequent, in 11 798 rice sequences in the database. Of these microsatellites, 35 out of 45 could be successfully converted into microsatellite DNA markers using sequence information in their flanking regions. Thus, the time and labor used to develop new microsatellite DNA markers could be saved by using these published sequences. Twenty eight polymorphic markers between Asominori (japonica) and IR24 (indica) have been correctly mapped on the rice genome and microsatellites appear to be randomly distributed in the rice chromosomes. Integration of these markers with the published microsatellite DNA markers showed that about 35% of the rice chromosomes were covered by the 56 microsatellite DNA markers. These microsatellites were hypervariable and were easily to assay by PCR; they were distributed to all chromosomes and therefore, one can easily select plants carrying desired chromosome regions using these microsatellite DNA markers. Thus, microsatellite maps should aid the development of new breeds of rice saving time, labor, and money. PMID- 24162484 TI - Allele-specific amplification of polymorphic sites for the detection of powdery mildew resistance loci in cereals. AB - Primers for the polymerase chain reaction (PCR) were tailored to selectively amplify RFLP marker alleles associated with resistance and susceptibility for powdery mildew in cereals. The differentiation between marker alleles for susceptible and resistant genotypes is based on the discrimination of a single nucleotide by using allele-specific oligonucleotides as PCR primers. The PCR assays developed are diagnostic for RFLP alleles at the loci MWG097 in the barley genome and Whs350 in the wheat genome. The first marker locus is closely linked to MlLa resistance in barley, while the latter is linked to Pm2 resistance locus in wheat. PCR analysis of 31 barley and 30 wheat cultivars, with some exceptions, verified the presence or absence of the resistance loci investigated. These rapid PCR-based approaches are proposed as an efficient alternative to conventional procedures for selecting powdery mildew-resistant genotypes in breeding programs. PMID- 24162485 TI - Genetic analysis using trans-dominant linked markers in an F2 family. AB - Trans-dominant linked markers pairs (trans referring to the repulsion linkage phase) provide a model for inferring the F2 progeny genotype based upon both the conditional probabilities of F2 genotypes, given the F2 phenotype, and prior information on marker arrangement. Prior information of marker arrangement can be readily obtained from a linkage analysis performed on marker segregation data in a family resulting by crossing the F1 individual to a "tester" parent or else can be obtained directly from the gametes of the F1, or from recombinant inbred lines. We showed that a trans-dominant linked marker (TDLM) pair can be recoded as a "co-dominant megalocus" when the recombination fraction, r1, for apair of TDLMs is less than 0.05. We obtained a maximum-likelihood estimator (MLE) of the recombination frequency, r2, between a TDLM pair and a co-dominant marker in an F2 family using the EM algorithm. The MLE was biased. Mean bias increased as r1 and r2 increased, and decreased as sample size increased. The information content for r2 was compared to the information content of dominant and co-dominant markers segregating in an F2 family. It was almost identical with two co-dominant markers when r1<=0.01 and r2>=0.05. For larger values of r1, (0.05<=r1<=0.15) a TDLM pair provided 75%-66% of the information content of two co-dominant markers. Although dominant markers can be converted to co-dominant markers by a laborious process of cloning, sequencing, and PCR, TDLM pairs could easily substitute for co-dominant markers in order to detect quantitative trait loci (QTLs) and estimate gene action in an F2 family. PMID- 24162486 TI - Estimating major gene effects with partial information using Gibbs sampling. AB - A method for estimating major gene effects using Gibbs sampling to infer genotype of individuals with unknown values, was compared with a standard mixed-model analysis. The purpose of this study was to evaluate the effect of including information of individuals with unknown genotypes on the estimates and their error variances (Ve) of the single-gene effects. When genotypes were known for all the individuals, results using the Gibbs method (GS) were similar to those obtained with the mixed model (MM). In the absence of selection, when information from individuals with unknown genotypes was included, GS yielded unbiased estimates of the major gene effects while reducing the Ve associated with them. This reduction in Ve depended on the gene frequency and mode of action of the major locus. For the additive effect, the reduction in Ve ranged from 29 to 69% of the total reduction which would have been obtained if all individuals had had a known genotype. Similarly the reduction in Ve found for the dominance effect ranged from 12 to 58%. Estimates using GS generally had small detectable biases when the polygenic heritability used in the analysis was inflated or estimated simultaneously. However, the benefit of using information from individuals with unknown genotypes was still maintained when comparing the mean square error of the estimates using either GS or MM when genotypes are only known for a subset of the population. When the population has been under selection, the use of Gibbs sampling to incorporate information of individuals without genotypes reduced substantially the bias and mean square error found for MM analysis on partial data. Nevertheless, there was some bias detected using Gibbs sampling. The gene frequency of the major gene in the base population was also well estimated despite its change over generations due to selection. PMID- 24162487 TI - Testcross additive and dominance effects in best linear unbiased prediction of maize single-cross performance. AB - Best linear unbiased prediction (BLUP) has been found to be useful in maize (Zea mays L.) breeding. The advantage of including both testcross additive and dominance effects (Intralocus Model) in BLUP, rather than only testcross additive effects (Additive Model), has not been clearly demonstrated. The objective of this study was to compare the usefulness of Intralocus and Additive Models for BLUP of maize single-cross performance. Multilocation data from 1990 to 1995 were obtained from the hybrid testing program of Limagrain Genetics. Grain yield, moisture, stalk lodging, and root lodging of untested single crosses were predicted from (1) the performance of tested single crosses and (2) known genetic relationships among the parental inbreds. Correlations between predicted and observed performance were obtained with a delete-one cross-validation procedure. For the Intralocus Model, the correlations ranged from 0.50 to 0.66 for yield, 0.88 to 0.94 for moisture, 0.47 to 0.69 for stalk lodging, and 0.31 to 0.45 for root lodging. The BLUP procedure was consistently more effective with the Intralocus Model than with the Additive Model. When the Additive Model was used instead of the Intralocus Model, the reductions in the correlation were largest for root lodging (0.06-0.35), smallest for moisture (0.00-0.02), and intermediate for yield (0.02-0.06) and stalk lodging (0.02-0.08). The ratio of dominance variance (v D) to total genetic variance (v G) was highest for root lodging (0.47) and lowest for moisture (0.10). The Additive Model may be used if prior information indicates that VD for a given trait has little contribution to VG. Otherwise, the continued use of the Intralocus Model for BLUP of single-cross performance is recommended. PMID- 24162488 TI - Comparative analysis of genetic diversity in pea assessed by RFLP- and PCR-based methods. AB - DNA-based molecular-marker techniques have been proven powerful in genetic diversity estimations. Among them, RFLP was the first and is still the most commonly used in the estimation of genetic diversity of eukaryotic species. The recently developed PCR-based multiple-loci marker techniques, which include RAPD, AFLP, Microsatellite-AFLP and inter-SSR PCR, are playing increasingly important roles in this type of research. Despite the wide application of these techniques, no direct comparison of these methods in the estimation of genetic diversity has been carried out. Here we report a direct comparison of DNA-based RFLP with various PCR-based techniques regarding their informativeness and applicability for genetic diversity analysis. Among ten pea genotypes studied, all the PCR based methods were much more informative than cDNA-RFLP. Genetic diversity trees were derived from each marker technique, and compared using Mantel's test. By this criterion, all trees derived from the various molecular marker techniques, except for the tree derived from inter-SSR PCR, were significantly correlated, suggesting that these PCR-based techniques could replace RFLP in the estimation of genetic diversity. On the basis of this result, AFLP analysis was applied to assess the genetic diversity of a sample of accessions representing the various species and subspecies within the genus Pisum. PMID- 24162490 TI - Markers for selection of the rice Xa21 disease resistance gene. AB - Six molecular markers were mapped to a 7.4-cM region of rice chromosome 11 containing the Xa21 gene, which confers resistance to the pathogen Xanthomonas oryzae pv oryzae. Three markers, RG103, 248 and 818, co-segregated with Xa21 in a population of 1141 plants. Multiple copies of all marker loci were present within the region that was introgressed from Oryza longistaminata into O. sativa. The marker loci were cloned and primers were designed that defined sequence-tagged sites. Physical mapping of the three tightly linked central markers revealed that RG103, the marker that hybridizes to the Xa21 gene, resides on a separate DNA fragment from the other two markers. PMID- 24162489 TI - A molecular linkage map of rye. AB - A genetic map of six chromosomes of rye, (all of the rye chromosomes except for 2R), was constructed using 77 RFLP and 12 RAPD markers. The map was developed using an F2 population of 54 plants from a cross between two inbred lines. A rye genomic library was constructed as a source of clones for RFLP mapping. Comparisons were made between the rye map and other rye and wheat maps by including additional probes previously mapped in those species. These comparisons allowed (1) chromosome arm orientation to the linkage groups to be given, (2) the corroboration of several evolutionary translocations between rye chromosomes and homoeologous chromosomes of wheat; (3) an increase in the number of available markers for target regions of rye that show colinearity with wheat. Inconsistencies in the location of markers between the wheat and rye maps were mostly detected by multi-copy probes. PMID- 24162491 TI - A new family of dispersed repeats from Brassica nigra: characterization and localization. AB - The 459-bp HindIII (pBN-4) and the 1732-bp Eco RI (pBNE8) fragments from the Brassica nigra genome were cloned and shown to be members of a dispersed repeat family. Of the three major diploid Brassica species, the repeat pBN-4 was found to be highly specific for the B. nigra genome. The family also hybridized to Sinapis arvensis showing that B. nigra had a closer relationship with the S. arvensis genome than with B. oleracea or B. campestris. The clone pBNE8 showed homology to a number of tRNA species indicating that this family of repeats may have originated from a tRNA sequence. The species-specific 459-bp repeat pBN-4 was localized on the B. nigra chromosomes using monosomic addition lines. In addition to the localization of pBN-4, the chromosomal distribution of two other species-specific repeats, pBN34 and pBNBH35 (reported earlier), was studied. The dispersed repeats pBN-4 and pBNBH35 were found to be present on all of the chromosomes, whereas the tandem repeat pBN34 was localized on two chromosomes. PMID- 24162492 TI - Genetic mapping of new morphological, isozyme and RAPD markers in Vicia faba L. using trisomics. AB - Thirteen F2 families of faba bean (Vicia faba L.), descended from plants trisomic for chromosomes 3, 4, 5 and 6, have been analyzed for morphological, isozyme and RAPD markers. This allowed the establishment of linkage relationships among these markers as well as the assignment of some markers and/or linkage groups to their respective chromosomes. The linkage analysis of partially overlapping sets of informative genetic markers for the data pooled from 13 F2 families has revealed 48 linkage groups, six of which have been precisely assigned to specific chromosomes. A statistical procedure to analyze the data of joint segregation analysis in families derived from trisomic plants has been developed. PMID- 24162493 TI - Synaptic behaviour of the tetraploid wheat Triticum timopheevii. AB - Triticum timopheevii (2n=4x=A(t)A(t)GG) is an allotetraploid wheat which shows a diploid-like behaviour at metaphase-I. The synaptic process was analyzed in fully traced spread nuclei at mid-zygotene, late-zygotene and pachytene. The length and type of synaptonemal complexes, as well as the number of bivalent and multivalent associations, were determined in each nucleus. A high number of bivalents per nucleus was detected at all three stages. Nuclei at pachytene showed a lower frequency of multivalents than did zygotene nuclei, which suggests the existence of a pairing correction mechanism. At metaphase-I only homologous bivalents and, rarely, one pair of univalents were observed. Similarities between the diploidization mechanism of T. timopheevii and that of allohexaploid wheat, controlled by chromosome 5B, are discussed. PMID- 24162494 TI - Aroma in rice: genetic analysis of a quantitative trait. AB - A new approach was developed which succeeded in tagging for the first time a major gene and two QTLs controlling grain aroma in rice. It involved a combination of two techniques, quantification of volatile compounds in the cooking water by gas chromatography, and molecular marker mapping. Four types of molecular marker were used (RFLPs, RAPDs, STSs, isozymes). Evaluation and mapping were performed on a doubled haploid line population which (1) conferred a precise character evaluation by enabling the analysis of large quantities of grains per genotype and (2) made possible the comparison of gas chromatography results and sensitive tests. The population size (135 lines) provided a good mapping precision. Several markers on chromosome 8 were found to be closely linked to a major gene controlling the presence of 2-acetyl-1-pyrroline (AcPy), the main compound of rice aroma. Moreover, our results showed that AcPy concentration in plants is regulated by at least two chromosomal regions. Estimations of recombination fractions on chromosome 8 were corrected for strong segregation distortion. This study confirms that AcPy is the major component of aroma. Use of the markers linked to AcPy major gene and QTLs for marker-assisted selection by successive backcrosses may be envisaged. PMID- 24162495 TI - The pattern of zygotene and pachytene pairing in allotetraploid Aegilops species sharing the U genome. AB - Allotetraploid Aegilops species sharing the U genome, Ae. columnaris (UUMM), Ae. ovata (UUMM), Ae. triaristata (UUMM), Ae. triuncialis (UUCC) and Ae. variabilis (UUSS), regularly form bivalents at metaphase I of meiosis. The pattern of zygotene and pachytene pairing was analyzed by whole-mount surface-spreading of synaptonemal complexes under the electron microscope. The data indicated that at the zygotene stage the chromosomes were almost exclusively associated as bivalents; only a few multivalents (7%) were observed. These observations are discussed in relation to mechanisms of diploidization of polyploid meiosis. PMID- 24162496 TI - Joint mapping of quantitative trait loci using F2 populations. AB - In this paper, the theory of joint mapping of quantitative trait loci is extended to F2 populations. Two independent regression equations, related to the additive and dominance effects respectively, are derived. Therefore, there are three alternative strategies for mapping QTLs, called additive-based mapping (ABM), dominance-based mapping (DBM) and additive-dominance-based mapping (ADBM). Simulation results have shown that ADBM is the most appropriate in most situations. PMID- 24162497 TI - A Monte Carlo method for Bayesian analysis of linkage between single markers and quantitative trait loci. I. Methodology. AB - A Bayesian approach to the statistical mapping of Quantitative Trait Loci (QTLs) using single markers was implemented via Markov Chain Monte Carlo (MCMC) algorithms for parameter estimation and hypothesis testing. Parameter estimators were marginal posterior means computed using a Gibbs sampler with data augmentation. Variables sampled included the augmented data (marker-QTL genotypes, polygenic effects), an indicator variable for linkage, and the parameters (allele frequency, QTL substitution effect, recombination rate, polygenic and residual variances). Several MCMC algorithms were derived for computing Bayesian tests of linkage, which consisted of the marginal posterior probability of linkage and the marginal likelihood of the QTL variance associated with the marker. PMID- 24162498 TI - A Monte Carlo method for Bayesian analysis of linkage between single markers and quantitative trait loci. II. A simulation study. AB - A Bayesian approach to the statistical mapping of Quantitative Trait Loci (QTLs) using single markers was implemented via Markov Chain Monte Carlo (MCMC) algorithms for parameter estimation and hypothesis testing. Parameters were estimated by marginal posterior means computed with a Gibbs sampler with data augmentation. Variables sampled included the augmented data (marker-QTL genotypes, polygenic effects), the event of linkage or nonlinkage, and the parameters (allele frequencies, QTL substitution effect, recombination rate, polygenic and residual variances). The analysis was evaluated empirically via application to simulated granddaughter designs consisting of 2000 sons, 20 related sires and their ancestors. Results obtained in this study and preliminary work on multiple linked markers and multiple QTLs support the usefulness of the Bayesian method for the statistical mapping of QTLs. PMID- 24162499 TI - The pattern of zygotene and pachytene pairing in allotetraploid Aegilops species sharing the D genome. AB - Chromosome pairing behaviour of the allotetraploid Aegilops species sharing the D genome, Ae. crassa (DDMM), Ae. cylindrica (DDCC) and Ae. ventricosa (DDNN), was analyzed by electron microscopy in surfacespread prophase-I nuclei. Synaptonemal complex analysis at zygotene and pachytene revealed that synapsis in the allotetraploids was mostly between homologous chromosomes, although a few multivalents were also formed. Only homologous bivalents were observed at metaphase-I. It is concluded that the mechanism controlling bivalent formation in these species acts mainly at zygotene by restricting pairing to homologous chromosomes, but also acts at pachytene by preventing chiasma formation in homoeologous associations. These observations are discussed in relation to mechanisms of diploidization of polyploid meiosis. PMID- 24162500 TI - Engineering of interstitial foreign chromosome segments containing the K(+)/Na (+) selectivity gene Kna1 by sequential homoeologous recombination in durum wheat. AB - Targeted homoeologous recombination mediated by the absence of the Ph1 locus is currently the most efficient technique by which foreign genes can be introgressed into polyploid wheat species. Because intra-arm homoeologous double cross-overs are rare, introgressed foreign genes are usually on terminal foreign chromosome segments. Since the minimum length of such a segment is determined by the position of a gene in the chromosome, large chromosome segments with undesirable genetic effects are often introgressed. Introgression of foreign genes on short interstitial segments based on two cycles of homoeologous recombination is described here. The utility of the technique is demonstrated by the introgression of the Kna1 locus, which controls K(+)/Na(+) selectivity in T. aesivum L., on short interstitial segments of chromosome 4D into chromosome 4B of Triticum turgidum L. The level of recombination in a homoeologous segment is not significantly affected by a juxtaposed proximal homologous segment in the absence of the Ph1 locus. PMID- 24162501 TI - Selective DMSO-induced conformational changes in proteins from Raman optical activity. AB - The function of a protein is determined by its structure, which is intrinsically related to its solvent environment. Based on this paradigm, there has been a great deal of interest in the role that non-aqueous solvents play in regulating protein structure, with some debate in the literature regarding dimethyl sulfoxide (DMSO). Thus, in this work we have used Raman and Raman optical activity (ROA) spectroscopies to investigate conclusively the changes induced by DMSO in the secondary structure of an array of proteins including human serum albumin (highly alpha-helical), bovine alpha-lactalbumin (mainly alpha-helical), bovine ribonuclease A (containing both alpha-helix and beta-sheet), bovine beta lactoglobulin (mainly beta-sheet), and bovine alpha-casein (disordered). Our results clearly demonstrate that 100% DMSO solutions destabilize alpha-helices completely, converting them into the poly(L-proline) II (PPII) helix conformation. However, low concentrations of DMSO (10% v/v) were found to have little effect on the structure of even the most helical protein, human serum albumin. In the case of alpha-casein, the natively unfolded protein rich in PPII helix was converted into a further disordered structure when dissolved in pure DMSO. By contrast, beta-sheets remained mostly unaffected regardless of DMSO concentration. While providing new insights into protein structure in organic solvents, this work reinforces the capability of vibrational optical activity to assess conformations of biomolecules in conditions not accessible to other techniques, such as X-ray crystallography and NMR. PMID- 24162502 TI - Prognostic predictors and spread patterns in adult ovarian granulosa cell tumors: a multicenter long-term follow-up study of 108 patients. AB - PURPOSE: To identify prognostic predictors and spread patterns in adult ovarian granulosa cell tumors (OGCTs). METHODS: Available retrospective data of 108 OGCT patients managed at three centers between January 1, 1991 and December 31, 2010 were abstracted and analyzed. RESULTS: Stage distributions at diagnosis for stage I, II and III OGCT were 84.3, 5.4, and 9.3 %, respectively. Optimal cytoreduction with no macroscopically visible disease was achieved in 99/108 (91.6 %) patients. The median disease-free interval to first recurrence was 61 months. The overall 5 and 10-year survival rates were 93.3 and 90.9 %, respectively. Disease recurred in 18 (16.6 %) patients, and 8 (7.4 %) patients died of their disease. The first recurrence sites included the pelvic peritoneum (n = 10), liver/liver-capsule (n = 5), rectosigmoid colon (n = 4), retroperitoneal lymph nodes (n = 3), omentum (n = 3), small bowel mesenterium (n = 2), and vaginal cuff (n = 2). Multiple-site recurrence was observed in 9/18 (50 %) patients. Secondary cytoreduction requiring extensive surgery was performed in 14 patients with an optimality rate of 71.4 %. The remaining four patients received only chemotherapy. Multivisceral approaches, including pelvic peritonectomy (n = 9; 64.2 %), rectosigmoid resection (n = 3; 21.4 %), and segmental liver capsule resection (n = 2; 14.2 %) were performed more frequently during the secondary surgery. Definitive retroperitoneal lymph node metastasis rates at the initial and recurrent settings were 5.1 % (3/58) and 21.4 % (3/14), respectively. Both stage and residual tumor status were significantly associated with recurrence in univariate and multivariate analyses. CONCLUSIONS: Stage and residual tumor status are predictors of recurrence. Pelvic peritoneal, nodal and hepatic involvement, and multiple-site spread patterns requiring extensive cytoreductive surgery are likely associated with recurrence of OGCTs. PMID- 24162503 TI - Self-stopping effects of lithium penetration into silicon nanowires. AB - Using first-principles molecular dynamics simulations, we demonstrate that the penetration of lithium atoms into a silicon nanowire (SiNW) self-stops once a metallic amorphous Li-Si shell forms. This explains the extended life of crystalline Si cores in SiNW battery electrodes observed in experiments. Metallic Li-Si shells grasp Li atoms and prohibit them from directly segregating through interstitial channels toward the crystalline center of SiNWs. Meanwhile, high pressure develops on the core as it shrinks, due to the expansion and tension in the amorphous shell, which eventually frustrate the step-forward amorphization. We also elucidate the reasons why H-passivated SiNWs are not suitable for studies of lithiation processes. PMID- 24162504 TI - Assessing the expenditure distribution of animal health surveillance: the case of Great Britain. AB - Animal health surveillance in Great Britain (GB) is conducted through public and private initiatives, yet there is no consolidated information on these activities and their outcomes. We developed an inventory of livestock health surveillance programmes in GB to identify gaps in resource use and potential synergies that could be exploited. The inventory contained details of 36 livestock surveillance activities active in 2011. Data were collected by questionnaire and interviews. Livestock health surveillance funding was found to be unevenly distributed between species: the vast majority (approximately 94 per cent) was spent on cattle diseases (tuberculosis surveillance accounted for most of this expenditure), with 2 per cent on pigs, 2 per cent on sheep/goats, 1 per cent on poultry, and 1 per cent on antimicrobial resistance surveillance across all species. Consequently, surveillance efforts in GB appears heavily skewed towards regions with high cattle densities, particularly high-prevalence tuberculosis areas such as the southwest. The contribution of private schemes to surveillance funding was hard to quantify due to limited access to data, but was estimated to be about 10 per cent. There is scope to better understand the benefits of surveillance, enhance data sharing, clarify costs and identify who pays and who gains. Health surveillance should be considered within the sharing of responsibilities for disease control. PMID- 24162505 TI - The effects of subarachnoid administration of hyperbaric solutions of bupivacaine or ropivacaine in xylazine-sedated calves undergoing surgery. AB - The aim of this study was to compare the effects of subarachnoid administration of hyperbaric solutions of bupivacaine or ropivacaine in xylazine-sedated calves undergoing surgery. Subarachnoid anaesthesia was performed with either 20 mg of hyperbaric bupivacaine (bupivacaine group (BG), n=10) or 30 mg of hyperbaric ropivacaine (ropivacaine group (RG), n=10) into the lumbar dural space of 20 calves in a randomised, prospective clinical trial. Systolic (SBP), diastolic (DBP) and mean (MBP) blood pressure, heart rate (HR), respiratory rate, rectal temperature were recorded after sedation (time 0), and up to 120 minutes after injection. Onset, duration and magnitude of sensory block (scale 1-4) were determined using the pin-prick test throughout surgery. Data were analysed using analysis of variance and non-parametric tests (P<0.05). Bodyweight, age, duration of surgery, SBP, DBP, MBP, HR were not significantly different between groups. Onset of anaesthesia (mean+/-sd; BG, 5+/-1 minutes; RG, 7+/-1 minutes) and duration of anaesthesia (mean+/-sd; BG, 153+/-32 minutes; RG, 86+/-12 minutes) were significantly different between groups. Analgesic scores were significantly higher than baseline from 5 to 120 min, and from 7 to 85 min in BG and RG, respectively. Subarachnoid administration of hyperbaric solutions of bupivacaine produced faster onset and longer duration of anaesthesia than ropivacaine. PMID- 24162506 TI - Factors affecting the accuracy of pregnancy scanning in ewes. AB - The objective was to evaluate the accuracy of pregnancy scanning by transabdominal ultrasonography and affecting factors. Altogether 44,783 ewes were registered (2008-2010), 39,724 diagnosed as pregnant and subsequently lambed. The ewes, 0.5-14 years old, were divided into 4 age and 6 breed groups and analysed. The accuracy (per cent; number of scanned fetuses/number of born lambs) decreased with increasing number of fetuses (P < 0.001). Overall accuracy was 90.3 per cent, highest (93.7 per cent) in ewes carrying one fetus, 91.9 per cent, 82.4 per cent, and 74.9 per cent in ewes with 2, 3 and >=4 fetuses at scanning, respectively. Finnsheep ewes with highest number of lambs showed lowest accuracy (P < 0.001). Analyses of a more complete sub set of data (n = 23,396), showed that number of fetuses diagnosed, breed, age of ewe, operator and time in gestation, significantly affected the accuracy. Accuracy decreased with age of ewe (P < 0.001) and was 71.8 per cent, 91.6 per cent and 89.3 per cent for scanning at <40, 40-80 and 81-100 days of gestation, respectively (P < 0.001). In general, the numbers of fetuses were overestimated at scanning and increased gradually with number of fetuses diagnosed. In conclusion, the accuracy was affected by several factors, which should be considered when interpreting/implementing the results, especially in breeds with high fecundity. PMID- 24162507 TI - Keel fracture assessment of laying hens by palpation: inter-observer reliability and accuracy. AB - The objective of this study was to assess the interobserver reliability (agreement) and accuracy of keel palpation for the purpose of detecting old fractures in an end-of-lay flock of commercial laying hens. The low level of invasiveness and the relative speed at which this evaluation can be carried out lends itself well to use in a welfare audit, but only if the results are reliable and accurate from various assessors. The palpation technique first described by Wilkins and others (2004) was used to manually palpate for keel fractures. The technique was modified in that only keel fractures were considered. Eight assessors with varying laying hen experience palpated 100 live ISA Brown hens that had been in lay for 49 weeks. The hens were then euthanased and examined by dissection to establish whether there had been a keel fracture present (yes/no). The accuracy for individual assessors ranged from 87.1 to 96.8 per cent, with a mean of 91.8 per cent among all eight assessors. The interobserver reliability among all eight assessors was moderate (kappa=0.44). Accuracy and kappa values were 84.8 per cent and 0.41 for the first 50 hens, and 99.5 per cent and 0.47 for the last 50 hens, respectively, indicating that there was increased accuracy and agreement as the assessors became more experienced at palpation. This level of agreement, and the high level of accuracy, would make this technique an acceptable measure of keel fracture prevalence in a welfare audit. PMID- 24162508 TI - Optogenetics and synaptic plasticity. AB - The intricate and complex interaction between different populations of neurons in the brain has imposed limits on our ability to gain detailed understanding of synaptic transmission and its integration when employing classical electrophysiological approaches. Indeed, electrical field stimulation delivered via traditional microelectrodes does not permit the targeted, precise and selective control of neuronal activity amongst a varied population of neurons and their inputs (eg, cholinergic, dopaminergic or glutamatergic neurons). Recently established optogenetic techniques overcome these limitations allowing precise control of the target neuron populations, which is essential for the elucidation of the neural substrates underlying complex animal behaviors. Indeed, by introducing light-activated channels (ie, microbial opsin genes) into specific neuronal populations, optogenetics enables non-invasive optical control of specific neurons with milliseconds precision. These approaches can readily be applied to freely behaving live animals. Recently there is increased interests in utilizing optogenetics tools to understand synaptic plasticity and learning/memory. Here, we summarize recent progress in applying optogenetics in in the study of synaptic plasticity. PMID- 24162509 TI - Fathers as supporters for improved exclusive breastfeeding in Viet Nam. AB - To determine the extent of exclusive breastfeeding practices among mothers of 4 and 6 month old infants whose fathers received breastfeeding education materials and counseling services. A quasi-experimental design was used. At the baseline, 251 and 241 couples were recruited into the intervention and control sites respectively. Fathers in the intervention area received breastfeeding education materials, counseling services at commune health centers and household visits. In the control site, where mothers routinely receive services on antenatal and postpartum care, fathers did not receive any intervention services on promoting breastfeeding. Primary indicators were exclusive breastfeeding at 4 and 6 months. At 6 months of age, based on 24-hour recall, 16.0% (38/238) of mothers in the intervention group were exclusively breastfeeding their children, compared to 3.9% (10/230) of those mothers in the control group (p < 0.001). Significant differences were found based on last-week recall (8.8% in the intervention group vs. 1.3% in the control group, p < 0.001) and since-birth recall (6.7% in the intervention group vs. 0.9% in the control group, p < 0.01). At 4 months of age, based on since birth recall, the breastfeeding proportion was significantly higher in the intervention group than in control group (20.6% in the intervention group vs. 11.3% in the control group, p < 0.01). An intervention targeting fathers might be effective in increasing exclusive breastfeeding practices at 4 and 6 months. To improve exclusive breastfeeding, health care staff working in maternal and child health units, should consider integrating fathers with services delivered to mothers and children. PMID- 24162511 TI - Activation of carbon dioxide and carbon disulfide by a scandium N-heterocyclic carbene complex. AB - A Sc NHC complex readily activates three equivalents of CO2 showing 'Frustrated Lewis Pair' type reactivity with each metal-carbene bond, but whilst CS2 is also activated by the labile carbenes, no metal involvement is observed. PMID- 24162510 TI - Maternal mortality and accessibility to health services by means of transit network estimated traveled distances. AB - This study analyzed the relationship between maternal mortality and variables related to the use of health services (especially residence-hospital traveled distances estimated through transit networks). Deaths were identified for Rio de Janeiro and adjacent cities, from 2000 to 2002, and were matched by age and socio economic level to birth admissions without maternal deaths (1 case to 3 controls). The variables used were: type of hospital (general * specialized maternity services), number of hospital beds, nature of hospital ownership (public * private-associated), main admission diagnostic, residence-hospital distance, age, income, and education. Distances were estimated by a geographic information system, and were based on most probable itineraries through the urban transit networks. The probability of death was estimated by conditional logistic regression models. 226 maternal deaths were studied, and another 10 were excluded due to incompleteness of information. The ROC area for the final model was 0.89 [95% CI (0.87-0.92)]. This model retained statistical significance for the variables admission diagnostic, type of hospital and residence-hospital distance. The death odds ratio for women who traveled 5-10 km (reference category: <5 km) was 3.84 [95% CI (1.96-7.55)]. The traveled distance measured through transit networks was an important risk factor for death in the studied population. PMID- 24162512 TI - Topological superfluids with finite-momentum pairing and Majorana fermions. AB - Majorana fermions (MFs), quantum particles that are their own antiparticles, are not only of fundamental importance in elementary particle physics and dark matter, but also building blocks for fault-tolerant quantum computation. Recently MFs have been intensively studied in solid state and cold atomic systems. These studies are generally based on superconducting pairing with zero total momentum. On the other hand, finite total momentum Cooper pairings, known as Fulde-Ferrell (FF) Larkin-Ovchinnikov (LO) states, were widely studied in many branches of physics. However, whether FF and LO superconductors can support MFs has not been explored. Here we show that MFs can exist in certain types of gapped FF states, yielding a new quantum matter: topological FF superfluids/superconductors. We demonstrate the existence of such topological FF superfluids and the associated MFs using spin-orbit-coupled degenerate Fermi gases and derive their parameter regions. The implementation of topological FF superconductors in semiconductor/superconductor heterostructures is also discussed. PMID- 24162513 TI - 2-Aminoethylphosphonate utilization by the cold-adapted Geomyces pannorum P11 strain. AB - Cold-adapted strain of Geomyces pannorum P11 was found to mineralize of phosphorus-carbon bond-containing compound--2-aminoethylphosphonic acid (2-AEP, ciliatine). The biodegradation process proceeded in the phosphate-independent manner. Ciliatine-metabolizing enzymes' activity was detectable in cell-free extracts prepared from psychrophilic G. pannorum pregrown on 4 mM 2-AEP. Phosphonoacetaldehyde hydrolase (phosphonatase) activity in a partially purified extract was demonstrated at 10 degrees C. PMID- 24162515 TI - Molecular analysis for art, archaeometry and conservation. PMID- 24162514 TI - Clinical and imaging findings in children with non-syndromic lambdoid synostosis. AB - True unilateral lambdoid synostosis is a very rare type of craniosynostosis. Patients present with unilateral posterior plagiocephaly. The differentiation between frequent, simple positional (deformational) posterior plagiocephaly and lambdoid synostosis is not easy and to date subject of controversy. Accurate and early diagnosis is important, because treatment is different. Simple positional plagiocephaly responds to conservative treatment, but craniosynostosis may require neurosurgical intervention. We analyzed clinical presentation of five patients in whom non-syndromic lambdoid synostosis was confirmed by CT imaging, in one additionally by high-resolution ultrasound, and finally neurosurgical intervention. However, clinical inspection alone did not reliably identify infants with lambdoid synostosis. CONCLUSION: Diagnosis of lambdoid synostosis is not always possible based on clinical inspection alone. To confirm the diagnosis imaging is recommended. There is evidence that high-resolution ultrasound can be used first-line in the future. PMID- 24162516 TI - Evidence for corticostriatal dysfunction during cognitive skill learning in adolescent siblings of patients with childhood-onset schizophrenia. AB - Patients with schizophrenia perform poorly on cognitive skill learning tasks. This study is the first to investigate the neural basis of impairment in cognitive skill learning in first-degree adolescent relatives of patients with schizophrenia. We used functional magnetic resonance imaging to compare activation in 16 adolescent siblings of patients with childhood-onset schizophrenia (COS) and 45 adolescent controls to determine whether impaired cognitive skill learning in individuals with genetic risk for schizophrenia was associated with specific patterns of neural activation. The siblings of patients with COS were severely impaired on the Weather Prediction Task (WPT) and showed a relative deactivation in frontal regions and in the striatum after extensive training on the WPT compared with controls. These differences were not accounted for by performance differences in the 2 groups. The results suggest that corticostriatal dysfunction may be part of the liability for schizophrenia. PMID- 24162518 TI - Dynamics of the cell-cycle network under genome-rewiring perturbations. AB - The cell-cycle progression is regulated by a specific network enabling its ordered dynamics. Recent experiments supported by computational models have shown that a core of genes ensures this robust cycle dynamics. However, much less is known about the direct interaction of the cell-cycle regulators with genes outside of the cell-cycle network, in particular those of the metabolic system. Following our recent experimental work, we present here a model focusing on the dynamics of the cell-cycle core network under rewiring perturbations. Rewiring is achieved by placing an essential metabolic gene exclusively under the regulation of a cell-cycle's promoter, forcing the cell-cycle network to function under a multitasking challenging condition; operating in parallel the cell-cycle progression and a metabolic essential gene. Our model relies on simple rate equations that capture the dynamics of the relevant protein-DNA and protein protein interactions, while making a clear distinction between these two different types of processes. In particular, we treat the cell-cycle transcription factors as limited 'resources' and focus on the redistribution of resources in the network during its dynamics. This elucidates the sensitivity of its various nodes to rewiring interactions. The basic model produces the correct cycle dynamics for a wide range of parameters. The simplicity of the model enables us to study the interface between the cell-cycle regulation and other cellular processes. Rewiring a promoter of the network to regulate a foreign gene, forces a multitasking regulatory load. The higher the load on the promoter, the longer is the cell-cycle period. Moreover, in agreement with our experimental results, the model shows that different nodes of the network exhibit variable susceptibilities to the rewiring perturbations. Our model suggests that the topology of the cell-cycle core network ensures its plasticity and flexible interface with other cellular processes, without a need for an optimal setting of the kinetic parameters. PMID- 24162517 TI - Mood instability and psychosis: analyses of British national survey data. AB - BACKGROUND: We used British national survey data to test specific hypotheses that mood instability (1) is associated with psychosis and individual psychotic phenomena, (2) predicts the later emergence of auditory hallucinations and paranoid ideation, and (3) mediates the link between child sexual abuse and psychosis. METHODS: We analyzed data from the 2000 and 2007 UK national surveys of psychiatric morbidity (N = 8580 and 7403, respectively). The 2000 survey included an 18-month follow-up of a subsample (N = 2406). Mood instability was assessed from the Structured Clinical Interview for DSM-IV Axis II (SCID-II) questionnaire. Our dependent variables comprised auditory hallucinations, paranoid ideation, the presence of psychosis overall, and a 15-item paranoia scale. RESULTS: Mood instability was strongly associated in cross-sectional analyses with psychosis (2000: OR: 7.5; 95% CI: I 4.1-13.8; 2007: OR: 21.4; CI: 9.7-41.2), paranoid ideation (2000: OR: 4.7; CI: 4.1-5.4; 2007: OR: 5.7; CI: 4.9 6.7), auditory hallucinations (2000: OR: 3.4; CI: 2.6-4.4; 2007: OR 3.5; CI: 2.7 4.7), and paranoia total score (2000: Coefficient: 3.6; CI: 3.3-3.9), remaining so after adjustment for current mood state. Baseline mood instability significantly predicted 18-month inceptions of paranoid ideation (OR: 2.3; CI: 1.6-3.3) and of auditory hallucinations (OR: 2.6; CI: 1.5-4.4). Finally, it mediated a third of the total association of child sexual abuse with psychosis and persecutory ideation and a quarter of that with auditory hallucinations. CONCLUSIONS: Mood instability is a prominent feature of psychotic experience and may have a role in its genesis. Targeting mood instability could lead to innovative treatments for psychosis. PMID- 24162519 TI - The evolution of degenerative marrow (Modic) changes in the cervical spine in neck pain patients. AB - PURPOSE: To evaluate the natural course of end plate marrow (Modic) changes (MC) in the cervical spine on MRI scans of patients with neck pain. A few longitudinal studies have assessed the development of MC over time in the lumbar spine but only two recent studies evaluated MC in the cervical spine in asymptomatic volunteers and those with whiplash. Thus, this study now reports on the natural course of MC in the cervical spine in symptomatic patients. METHODS: From the cervical MRI scans of 426 neck pain patients (mean age 61.2 years), 64 patients had follow-up MRI studies. The prevalence and types of MC were retrospectively assessed on the follow-up scans and compared to the original MRI findings. RESULTS: With an average of 2.5 years between the two MRI scans, the prevalence of MC type 1 (MC1) noted at baseline (7.4% or 19 motion segments) slightly increased (8.2% or 21 segments) but the prevalence of MC2 (14.5% or 37 segments) increased considerably (22.3% or 57 segments). In addition, 14 new MC1 segments and 8 new MC2 segments were noted. Twelve segments with MC1 at baseline converted to MC2 at follow-up. No conversion from MC2 to MC1 or reverting to a normal image was observed. CONCLUSIONS: MC in the cervical spine are a dynamic phenomenon similar to the lumbar spine. PMID- 24162520 TI - Hemivertebrae resection for unbalanced multiple hemivertebrae: is it worth it? AB - PURPOSE: To assess the correction effect of hemivertebra resection for unbalanced multiple hemivertebrae by measuring corresponding parameters in both coronal and sagittal planes on series posteroanterior and lateral radiographs and report the related complications. METHODS: Twelve children with unbalanced multiple hemivertebrae were operated on by hemivertebra resection through a combined anterior and posterior approach or a posterior-only procedure. Mean age at time of surgery was 9.8 years (range 2-14 years). They were retrospectively studied with a mean follow-up of 48.7 months (range 30-60 months). RESULTS: The mean Cobb angle of the main curve was 65.3 degrees (range 45 degrees -92 degrees ) before surgery and 13.8 degrees (range 4 degrees -30 degrees ) at the last follow-up. The correction rate was 80.0% (range 65.5-92.4 %). The compensatory cranial curve was corrected from 25.8 degrees (range 5 degrees -53 degrees ) to 11.7 degrees (range 0 degrees -34 degrees ) with a correction rate of 65.9% (range 33.3-100%), and the compensatory caudal curve was corrected from 32.4 degrees (range 17 degrees -57 degrees ) to 7.1 degrees (range 0 degrees -20 degrees ) with a correction rate of 81.4% (range 53.1-100%). The angle of segmental kyphosis was 41.3 degrees (range 12 degrees -76 degrees ) before surgery and 17.0 degrees (range -12 degrees to 45 degrees ) at the final follow-up. The coronal imbalance was -1.0 cm (range -3.5 to 3 cm) before surgery and 0.0 cm (range -1.0 to 1.5 cm) at the most recent follow-up. The sagittal imbalance was 0.9 cm (range -3.2 to 3 cm) before surgery and 0.6 cm (range -3.0 to 3.5 cm) at the most recent follow up. Complications including pedicle fractures, and pseudarthrosis were found in two patients (20 %). CONCLUSIONS: In the patients with unbalanced multiple hemivertebrae, hemivertebra resection allows for excellent correction in both the coronal and sagittal planes, and great care should be taken to reduce the rate of complications. PMID- 24162521 TI - Spinopelvic balance: new biomechanical insights with clinical implications for Parkinson's disease. AB - PURPOSE: The aim of this study was to describe the disease-related sagittal balance changes in relation to the sacropelvic morphology of PD patients with different durations of disease. METHODS: Thirty-one consecutive Parkinson's disease patients (26 males, 5 females; age 55-83 years) participated in the cross sectional study. The clinical assessment included: Hoehn Yahr score; plumb line distance from the spinous process of C7, kyphosis apex, spinous process of L3 and S1. Lumbar lordosis (LL), thoracic kyphosis (TK), spinosacral angle, spinopelvic angle, spinal tilt, pelvic incidence, sacral slope (SS) and pelvic tilt were radiographically assessed. RESULTS: Radiographic spinopelvic angles appeared normal, but many patients presented variations from normality. In particular, pelvic tilt increased and SS decreased; spinosacral and spinopelvic angles were greatly reduced compared to healthy people, and spinal tilt increased. Unlike TK, LL was well correlated with most of the parameters. CONCLUSIONS: Sagittal balance evaluation provides new valuable insights for biomechanical understanding of PD patients. Specific spinal parameters (spinosacral, spinopelvic and spinal tilt angles), and their clinical correlation, as well as pelvic parameters like pelvic tilt and sacral slope, appear particularly interesting for their clinical implications in terms of spinal deformities correction in PD population. PMID- 24162522 TI - Core-shell Zn2GeO4 nanorods and their size-dependent photoluminescence properties. AB - Size-tunable crystalline core-crystalline shell Zn2GeO4 nanorods were synthesized via a facile hydrothermal reaction. High purity Zn2GeO4 nanorods were obtained at pH = 7. The length of Zn2GeO4 nanorods (L = 50-100 nm) can be controlled through a one-step process, while micro-sized nanorods with an aspect ratio of the length to the diameter of 10 were yielded in a two-step process. The single crystalline nature of Zn2GeO4 nanorods with a core-shell structure was verified by high resolution transmission electron microscopy (HRTEM) and selected area electron diffraction (SAED) measurements. The Raman study revealed that there is no oxygen defect in Zn2GeO4 nanocrystals, suggesting that photoluminescence emission of Zn2GeO4 can be attributed to the presence of the interstitial Zn defect in Zn2GeO4 nanocrystals. As the diameter of nanorods decreased, the excitation and emission peaks appeared to be redshifted due to the quantum size effect. PMID- 24162523 TI - Lipophilicity of amine neurotransmitter precursors, metabolites and related drugs estimated on various TLC plates. AB - The retention behavior for a series of amine neurotransmitters, their precursors, metabolites and structurally related drugs has been investigated in reversed phase thin-layer chromatography using RP-18, RP-8, RP-2, CN and Diol stationary phases and mixtures of phosphate buffer and methanol as mobile phase. According to the computed lipophilicity of the neutral form of the investigated compounds, the most lipophilic compound is dobutamine (log P(N) = 3.78), while the less lipophilic is norepinephrine (log P(N) = -0.14). The experimental results also show dobutamine as the most lipophilic compound in the case of RP-18 and CN stationary phases (RM0(RP-18) = 1.58 and RM(CN) = 1.21), while RP-8 indicates norepinephrine as the less lipophilic one (RM0(RP8) = -0.70). Both the theoretical computation and the experimental data revealed that only one ionic form of the compounds prevails in the used chromatographic conditions. In addition, the evaluation of the experimental results showed that a similar chromatographic behavior could be assumed in the case of RP-18, RP-8 and CN stationary phases. Moreover, the mRM (mean of the RM values) and PC1/RM (scores of the first principal component) experimental lipophilicity indices showed a high correlation with the computed lipophilicity indices. PMID- 24162524 TI - Evolution of topological defects in two-dimensional quenched colloidal systems. AB - We investigated the evolution of topological defects in two-dimensional (2D) quenched colloidal systems using topological current theory. As a singularity of topological currents in order parameter fields, a topological defect is associated with three cases of solutions of zero points: the isolation solution, the limit point, and the bifurcation point. At the limit point, the defects represent a generation or annihilation process, and the number of defects satisfies a power law time-dependent scaling behaviour N d ? t (-1) . At the bifurcation point, a merging or splitting process appears and N d ? t (-2) . These properties are in agreement with the results from Brownian dynamics simulations of the quenching processes in 2D colloidal systems with a Yukawa pair interaction. PMID- 24162525 TI - Unbinding transition from fluid membranes with associated polymers. AB - We consider two neighboring fluid membranes that are associated with long flexible polymers (proteins or other macromolecules). We are interested in two physical systems consisting of i) two adjacent membranes with end-grafted (or adsorbed) polymers (system I), or ii) two membranes confining a polymer solution (system II). In addition to the pure interactions between membranes, the presence of polymers gives rise to new induced mediated interactions, which are repulsive, for system I, and attractive, for system II. In fact, repulsive induced interactions are caused by the excluded-volume forces between grafted polymers, while attractive ones, by entropy loss, due to free motion of polymers between membranes. The main goal is a quantitative study of the unbinding transition thermodynamics that is drastically affected by the associated polymers. For system I, the repulsive polymer-mediated force delays this transition that can happen at low temperature. To investigate the unbinding phenomenon, we first present an exact mathematical analysis of the total potential that is the sum of the primitive and induced potentials. This mathematical study enables us to classify the total interaction potentials, in terms of all parameters of the problem. Second, use is made of the standard variational method to calculate the first moments of the membrane separation. Special attention is paid to the determination of the unbinding temperature. In particular, we discuss its dependence on the extra parameters related to the associated polymers, which are the surface coverage and the polymer layer thickness on each membrane (for system I) or the polymer density and the gyration radius of coils (for system II). Third, we compute the disjoining pressure upon membrane separation. Finally, we emphasize that the presence of polymers may be a mechanism to delay or to accentuate the appearance of the unbinding transition between fluid membranes. PMID- 24162526 TI - In memoriam: William H. Daughaday, MD, 1918-2013. PMID- 24162527 TI - Editorial: Molecular endocrinology articles in the spotlight for November 2013. PMID- 24162529 TI - Competition as a source of errors in RAPD analysis. AB - We have used artificial 1?1 DNA mixtures of all pairwise combinations of four doubled haploid Brassica napus lines to test the ability of RAPDs to function as reliable dominant genetic markers. In situations where a specific RAPD band is present in one homozygous line but absent in the other, the band is expected in the artificial heterozygote, i.e. in the 1?1 DNA mixture. In 84 of all 613 heterozygous situations analysed, the expected band failed to amplify in the RAPD reaction. Thus, RAPD markers will lead to an erroneous genetic interpretation in 14% of all cases. In contrast, the formation of non-parental heteroduplex bands was found at a frequency of only 0.2%. Analysis of 1? 1 mixtures using (1) a different set of optimized reaction conditions and (2) a material with low genomic complexity (Bacillus cereus) gave identical results. Serial dilutions of one genome into another, in steps of 10%, showed that all of the polymorphic bands decreased in intensity as a linear function of their respective proportion in the mixture. In dilutions with water no differences in band intensity were detected. Thus, competition occurs in the amplification of all RAPD fragments and is a major source of genotyping errors in RAPD analysis. PMID- 24162530 TI - Estimation of the contribution of quantitative trait loci (QTL) to the variance of a quantitative trait by means of genetic markers. AB - The estimation of the contribution of an individual quantitative trait locus (QTL) to the variance of a quantitative trait is considered in the framework of an analysis of variance (ANOVA). ANOVA mean squares expectations which are appropriate to the specific case of QTL mapping experiments are derived. These expectations allow the specificities associated with the limited number of genotypes at a given locus to be taken into account. Discrepancies with classical expectations are particularly important for two-class experiments (backcross, recombinant inbred lines, doubled haploid populations) and F2 populations. The result allows us firstly to reconsider the power of experiments (i.e. the probability of detecting a QTL with a given contribution to the variance of the trait). It illustrates that the use of classical formulae for mean squares expectations leads to a strong underestimation of the power of the experiments. Secondly, from the observed mean squares it is possible to estimate directly the variance associated with a locus and the fraction of the total variance associated to this locus (r l (2) ). When compared to other methods, the values estimated using this method are unbiased. Considering unbiased estimators increases in importance when (1) the experimental size is limited; (2) the number of genotypes at the locus of interest is large; and (3) the fraction of the variation associated with this locus is small. Finally, specific mean squares expectations allows us to propose a simple analytical method by which to estimate the confidence interval of r l (2) . This point is particularly important since results indicate that 95% confidence intervals for r l (2) can be rather wide:2 23% for a 10% estimate and 8-34% for a 20% estimate if 100 individuals are considered. PMID- 24162531 TI - PCR-based fingerprinting using AFLPs as a tool for studying genetic relationships in Lactuca spp. AB - AFLP markers were evaluated for determining the phylogenetic relationships Lactuca spp. Genetic distances based on AFLP data were estimated for 44 morphologically diverse lines of cultivated L. sativa and 13 accessions of the wild species L. serriola, L. saligna, L. virosa, L. perennis, and L. indica. The same genotypes were analyzed as in a previous study that had utilized RFLP markers. The phenetic tree based on AFLP data was consistent with known taxonomic relationships and similar to a tree developed with RFLP data. The genetic distance matrices derived from AFLP and RFLP data were compared using least squares regression analysis and, for the cultivar data, by principal component analysis. There was also a positive linear relationship between distance estimates based on AFLP data and kinship coefficients calculated from pedigree data. AFLPs represent reliable PCR-based markers for studies of genetic relationships at a variety of taxonomic levels. PMID- 24162532 TI - Comparative mapping of QTLs for agronomic traits of rice across environments using a doubled haploid population. AB - We report here the RFLP mapping of quantitative triat loci (QTLs) that affect some important agronomic traits in cultivated rice. An anther culturederived doubled haploid (DH) population was established from a cross between an indica and a japonica rice variety. On the basis of this population a molecular linkage map comprising 137 markers was constructed that covered the rice genome at intervals of 14.8cM on average. Interval mapping of the linkage map was used to locate QTLs for such important agronomic traits as heading date, plant height, number of spikelets per panicle, number of grains Per panicle, 1000-grain weight and percentage of seed set. Evidence of genotype-byenvironment interaction was found by comparing QTL maps of the same population grown in three diverse environments. A total of 22 QTLs for six agronomic traits were detected that were significant in at least one environment, but only 7 were significant in all three environments, 7 were significant in two environments and 8 could only be detected in a single environment. However, QTL-by-environment interaction was traitdependent. QTLs for spikelets and grains per panicle were common across environments, while traits like heading date and plant height were more sensitive to environment. PMID- 24162533 TI - Molecular marker heterozygosity and hybrid performance in indica and japonica rice. AB - An essential assumption underlying markerbased prediction of hybrid performance is a strong linear correlation between molecular marker heterozygosity and hybrid performance or heterosis. This study was intended to investigate the extent of the correlations between molecular marker heterozygosity and hybrid performance in crosses involving two sets of rice materials, 9 indica and 11 japonica varieties. These materials represent a broad spectrum of the cultivated rice gene pool including landraces, primitive cultivars, historically important cultivars, modern elite cultivars and parents of superior hybrids. Varieties within each set were intermated in all possible nonreciprocal pairs resulting in 36 crosses in the indica set and 55 in the japonica set. The F1s and their parents, 111 entries in total, were examined for performance of seven traits in a replicated field trial. The parents were surveyed for polymorphisms using 96 RFLP and ten SSR markers selected at regular intervals from a published molecular marker linkage map. Molecular marker genotypes of the F1 hybrids were deduced from the parental genotypes. The analysis showed that, with very few exceptions, correlations in the indica dataset were higher than in that of their japonica counterparts. Among the seven traits analyzed, plant height showed the highest correlation between heterozygosity and hybrid performance and heteorsis in both indica and japonica datasets. Correlations were low to intermediate between hybrid performance and heterozygosity (both general and specific) in yield and yield component traits in both indica and japonica sets, and also low to intermediate between specific heterozygosity and heterosis in the indica set, whereas very little correlation was detected between heterosis and heterozygosity (either general or specific) in the japonica set. In comparison to the results from our previous studies, we concluded that the relationship between molecular marker heterozygosity and heterosis is variable, depending on the genetic materials used in the study, the diversity of rice germplasms and the complexity of the genetic basis of heterosis. PMID- 24162534 TI - Inter- and intra-genomic homology of the Brassica genomes: implications for their origin and evolution. AB - In order to determine the homologous regions shared by the cultivated Brassica genomes, linkage maps of the diploid cultivated B. rapa (A genome, n = 10), B. nigra (B genome, n = 8) and B. oleracea (C genome, n = 9), were compared. We found intergenomic conserved regions but with extensitve reordering among the genomes. Eighteen linkage groups from all three species could be associated on the basis of homologous segments based on at least three common markers. Intragenomic homologous conservation was also observed for some of the chromosomes of the A, B and C genomes. A possible chromosome phylogenetic pathway based on an ancestral genome of at least five, and no more than seven chromosomes, was drawn from the chromosomal inter-relationships observed. These results demonstrate that extensive duplication and rearrangement have been involved in the formation of the Brassica genomes from a smaller ancestral genome. PMID- 24162535 TI - Expression of the C3-C 4 intermediate character in somatic hybrids between Brassica napus and the C3-C 4 species Moricandia arvensis. AB - The wild crucifer Moricandia arvensis is a potential source of alien genes for the genetic improvement of related Brassica crops. In particular M. arvensis has a C3-C4 intermediate photosynthetic mechanism which results in enhanced recapture of photorespired CO2 and may increase plant water-use efficiency. In order to transfer this trait into Brassica napus, somatic hybridisations were made between leaf mesophyll protoplasts from cultured M. arvensis shoot tips and hypocotyl protoplasts from three Brassica napus cultivars, 'Ariana', 'Cobra' and 'Westar'. A total of 23 plants were recovered from fusion experiments and established in the greenhouse. A wide range of chromosome numbers were observed among the regenerated plants, including some apparent mixoploids. Thirteen of the regenerated plants were identified as nuclear hybrids between B. napus and M. arvensis on the basis of isozyme analysis. The phenotypes of these hybrids were typically rather B. napus-like, but much variability was observed, including variation in flower colour, leaf shape and colour, leaf waxiness, fertility and plant vigour. CO2 compensation point measurements on the regenerated plants demonstrated that 3 of the hybrids express the M. arvensis C3-C4 intermediate character at the physiological level. Semi-thin sections through leaf tissues of these 3 plants revealed the presence of a Kranz-like leaf anatomy characteristic of M. arvensis but not found in B. napus. This is the first report of the expression of this potentially important agronomic trait, transferred from Moricandia, in M. arvensis x B. napus hybrids. PMID- 24162536 TI - Production of intertribal somatic hybrids between Brassica napus L. and Lesquerella fendleri (Gray) Wats. AB - Intertribal Brassica napus (+) Lesquerella fendleri hybrids have been produced by polyethylene glycol-induced fusions of B. napus hypocotyl and L. fendleri mesophyll protoplasts. Two series of experiments were performed. In the first, symmetric fusion experiments, protoplasts from the two materials were fused without any pretreatments. In the second, asymmetric fusion experiments, X-ray irradiation at doses of 180 and 200 Gy were used to limit the transfer of the L. fendleri genome to the hybrids. X-ray irradiation of L. fendleri mesophyll protoplasts did not suppress the proliferation rate and callus formation of the fusion products but did significantly decrease growth and differentiation of non fused L. fendleri protoplasts. In total, 128 regenerated plants were identified as intertribal somatic hybrids on the basis of morphological criteria. Nuclear DNA analysis performed on 80 plants, using species specific sequences, demonstrated that 33 plants from the symmetric fusions and 43 plants from the asymmetric fusions were hybrids. Chloroplast and mitochondrial DNA analysis revealed a biased segregation that favoured B. napus organelles in the hybrids from the symmetric fusion experiments. The bias was even stronger in the hybrids from the asymmetric fusion experiments where no hybrids with L. fendleri organelles were found. X-ray irradiation of L. fendleri protoplasts increased the possibility of obtaining mature somatic hybrid plants with improved fertility. Five plants from the symmetric and 24 plants from the asymmetric fusion experiments were established in the greenhouse. From the symmetric fusions 2 plants could be fertilised and set seeds after cross-pollination with B. napus. From the asymmetric fusions 9 plants could be selfed as well as fertilised when backcrossed with B. napus. Chromosome analysis was performed on all of the plants but 1 that were transferred to the greenhouse. Three plants from the symmetric fusions contained 50 chromosomes, which corresponded to the sum of the parental genomes. From the asymmetric fusions, 11 hybrids contained 38 chromosomes. Among the other asymmetric hybrids, plants with 50 chromosomes and with chromosome numbers higher than the sum of the parental chromosomes were found. When different root squashes of the same plant were analysed, a total of 6 plants were found that had different chromosome numbers. PMID- 24162537 TI - Soybean pedigree analysis using map-based molecular markers: recombination during cultivar development. AB - An analysis of the genome structure of soybean cultivars was conducted to determine if cultivars are composed of large regions of chromosomes inherited intact from one parent (indicative of minimal recombination) or if the chromosomes are a mixture of one parent's DNA interspersed with the DNA from the other parent (indicative of maximal recombination). Twenty-one single-cross derived and 5 single-backcross-derived soybean cultivars and their immediate parents (47 genotypes) were analyzed at 89 RFLP loci to determine the minimal number and distribution of recombination events detected. Cultivars derived from single-cross and single-backcross breeding programs showed an average of 5.2 and 8.0 recombination events per cultivar, respectively. A homogeneity Chi-square test based upon a Poisson distribution of recombination events across 13 linkage groups indicated that the number of recombinations observed among linkage groups was random for the single-cross cultivars, but not for the single-backcross derived cultivars. A twotailed t-test demonstrated that for some linkage groups, the number of recombinations per map unit exceeded the confidence interval developed from a t-distribution of recombinations standardized for map unit distance. Paired t-tests of the number of recombinations observed between linkage group ends and the mid-portion of the linkage groups indicated that during the development of the cultivars analyzed in this study more recombinations were associated with the ends of linkage groups than with the middle region. Detailed analysis of each linkage group revealed that large portions of linkage groups D, F, and G were inherited intact from one parent in several cultivars. A portion of linkage group G, in contrast, showed more recombination events than expected, based on genetic distance. These analyses suggest that breeders may have selected against recombination events where agronomically favorable combinations of alleles are present in one parent, and for recombination in areas where agronomically favorable combinations of alleles are not present in either parent. PMID- 24162538 TI - The effects of selective genotyping on estimates of proportion of recombination between linked quantitative trait loci. AB - Selective genotyping is the marker assay of only the more extreme phenotypes for a quantitative trait and is intended to increase the efficiency of quantitative trait loci (QTL) mapping. We show that selective genotyping can bias estimates of the recombination frequency between linked QTLs - upwardly when QTLs are in repulsion phase, and downwardly when QTLs are in coupling phase. We examined these biases under simple models involving two QTLs segregating in a backcross or F2 population, using both analytical models and computer simulations. We found that bias is a function of the proportion selected, the magnitude of QTL effects, distance between QTLs and the dominance of QTLs. Selective genotyping thus may decrease the power of mapping multiple linked QTLs and bias the construction of a marker map. We suggest a large proportion than previously suggested (50%) or the entire population be genotyped if linked QTLs of large effects (explain > 10% phenotypic variance) are evident. New models need to be developed to explicitly incorporate selection into QTL map construction. PMID- 24162539 TI - Doubled haploids of wheat from wheat x maize crosses:genotypic influence, fertility and inheritance of the 1BL-1RS chromosome. AB - The wheat x maize cross as a technique for haploid induction in wheat was evaluated in a replicated block design comprising 18 wheat F1 hybrids and five Zea mays L. parents. Haploid plants were regenerated at an average of 9.1 (4.4 14.7) plants per 100 florets processed. Genotypic differences for haploid production efficiency were recorded for both wheat and Zea mays L. Interaction between parents was significant for number of plants/100 florets. All 610 of the 1,703 regenerated plantlets that were analyzed by flow cytometry were haploid. At maturity, 70% (60-81 %) of the colchicinetreated haploid plants were fertile, but the frequency of fertile and sterile plants was not consistent over the wheat hybrids from which they were derived. Flow cytometry performed using the first tiller which arose following colchicine treatment enabled prediction of fertility. The 1BL-1RS chromosome was found at the expected ratios in the F2 and in the haploid progenies produced through the wheat x maize cross but deviated from the 1?1 ratio in the haploid progenies produced by anther culture. PMID- 24162540 TI - Heterozygosity and hybrid performance in larch. AB - Random Amplified Polymorphic DNAs (RAPD) were used for estimating genetic distances between 12 European larches (Larix decidua) and 12 Japanese larches (L. kaempferi) that were the parents in a factorial mating design. One hundred and eleven fragments were used for establishing genetic distances based on Jaccard's coefficient between parents. Thirteen fragments differentiated the larch species. The genetic distance between individuals of the same species (D J =0.39 in the Japanese larch and 0.45 in the European larch) was lower than the genetic distance between species (D J =0.72). A UPGMA dendrogram based on genetic distances clearly clustered each larch species, confirming the speciation at a molecular level. Correlations between genetic distances of the parents and performances of the hybrid families were established for various quantitative traits. Significant values were found for growth characters and branch insertion angle, which suggested an effect of general heterozygosity level on hybrid traits. These correlations also evolved with tree age: the maximal correlation was noticed on 6-year-old trees for height. The lack of correlation between parental genetic distances and hybrid performances for the other quantitative traits suggested that these characters were controlled by fewer genes. The results of this study show that crosses between genetically distant parents produce hybrids with excellent growth performances; this represents a potential selection criterion of the genitors. PMID- 24162541 TI - Length polymorphism and homologies of microsatellites in several Cucurbitaceae species. AB - The objectives of this research were to assess (1) the degree of Simple Sequence Repeats (SSR) DNA length polymorphism in melon (Cucumis melo L.) and other species within the Cucurbitaceae family and (2) the possibility of utilizing SSRs flanking primers from single species to other genera or species of Cucurbitaceae. Five melon (CT/GA) n SSRs were isolated from a genomic library. Two cucumber (Cucumis sativus L.) SSRs were detected through a search of DNA sequence databases, one contained a (CT)8 repeat, the other a (AT)13 repeat. The seven SSRs were used to test a diverse sample of Cucurbitaceae, including 8 melon, 11 cucumber, 5 squash, 1 pumpkin, and 3 watermelon genotypes. Five of the seven SSRs detected length polymorphism among the 8 melon genotypes. PCR amplification revealed between three and five length variants (alleles) for each SSR locus, with gene diversity values ranging from 0.53 to 0.75. Codominant segregation of the alleles among F2 progeny was demonstrated for each of the five SSR loci. Four of the seven SSRs detected polymorphism among the 11 cucumber genotypes, with gene diversity values ranging between 0.18 and 0.64. Primers specific to SSRs of C. melo and C. sativus also amplified DNA extracted from genotypes belonging to other genera of the Cucurbitaceae family. PMID- 24162542 TI - Chromosome substitutions of Triticum timopheevii in common wheat and some observations on the evolution of polyploid wheat species. AB - Whether the two tetraploid wheat species, the well known Triticum turgidum L. (macaroni wheat, AABB genomes) and the obscure T. timopheevii Zhuk. (A(t)A(t)GG), have monophyletic or diphyletic origin from the same or different diploid species presents an interesting evolutionary problem. Moreover, T. timopheevii and its wild form T. araraticum are an important genetic resource for macaroni and bread wheat improvement. To study these objectives, the substitution and genetic compensation abilities of individual T. timopheevii chromosomes for missing chromosomes of T. aestivum 'Chinese Spring' (AABBDD) were analyzed. 'Chinese Spring' aneuploids (nullisomic-tetrasomics) were crossed with a T. timopheevii x Aegilops tauschii amphiploid to isolate T. timopheevii chromosomes in a monosomic condition. The F1 hybrids were backcrossed one to four times to Chinese Spring aneuploids without selection for the T. timopheevii chromosome of interest. While spontaneous substitutions involving all A(t)- and G-genome chromosomes were identified, the targeted T. timopheevii chromosome was not always recovered. Lines with spontaneous substitutions from T. timopheevii were chosen for further backcrossing. Six T. timopheevii chromosome substitutions were isolated: 6A(t) (6A), 2G (2B), 3G (3B), 4G (4B), 5G (5B) and 6G (6B). The substitution lines had normal morphology and fertility. The 6A(t) of T. timopheevii was involved in a translocation with chromosome 1G, resulting in the transfer of the group-1 gliadin locus to 6A(t). Chromosome 2G substituted for 2B at a frequency higher than expected and may carry putative homoeoalleles of gametocidal genes present on group-2 chromosomes of several alien species. Our data indicate a common origin for tetraploid wheat species, but from separate hybridization events because of the presence of a different spectrum of intergenomic translocations. PMID- 24162543 TI - An approximation to the likelihood for a pedigree with loops. AB - This paper presents a new approximation to the likelihood for a pedigree with loops, based on cutting all loops and extending the pedigree at the cuts. An opimum loop-cutting strategy and an iterative extension technique are presented. The likelihood for a pedigree with loops is then approximated by the conditional likelihood for the entire cut-extended pedigree given the extended part. The approximate likelihoods are compared with the exact likelihoods obtained using the program MENDEL for several small pedigrees with loops. The approximation is efficient for large pedigrees with complex loops in terms of computing speed and memory requirements. PMID- 24162544 TI - Components of resistance of leaf rust (Melamspora laricii epitea Kleb./Melampsora ribesii-viminalis Kleb.) in Salix viminalis L. AB - Selection on partial resistance components, namely latent period, development rate of uredia and number and size of uredia, has been suggested as a means to achieve durable resistance. Three experiments were carried out in growth chambers to assess the impact of environmental and genetic factors on these components in the Salix-Melampsora host-pathogen system. They confirmed the environmental ability of the Melampsora-Salicaceae relationship and provided no definite answer on the possibility of attaining durable resistance through selection on partial resistance components. On the one hand, there is a large amount of heritable variation among clones for most components; on the other hand, all components were extremely sensitive to environmental conditions and isolates, making the development of standard selection methods difficult. PMID- 24162545 TI - A method to determine the mean pollen dispersal of individual plants growing within a large pollen source. AB - Pollen dispersal has been recently focused on as a major issue in the risk assessment of transgenic crop plants. The shape of the pollen dispersal of individual plants is hard to determine since a very large number of plants must be monitored in order to track rare longdistance dispersal events. Conversely, studies using large plots as a pollen source provide a pollen distribution that depends on the shape of the source plot. We report here on a method based on the use of Fourier transforms by which the pollen dispersal of a single, average individual can be obtained from data using large plots as pollen sources, thus allowing the estimation of the probability of long-distance dispersal for single plants. This method is subsequently implemented on simulated data to test its susceptibility to random noise and edge effects. Its conditions of application and value for use in ecological studies, in particular risk assessment of the deliberate release of transgenic plants, are discussed. PMID- 24162546 TI - Genetic diversity in the orange subfamily Aurantioideae. II. Genetic relationships among genera and species. AB - Genetic relationships were studied by means of ten isoenzymatic systems, at the genus and species level, using two distances and four methods of aggregation in a germplasm collection of 198 cultivars and accessions of 54 species belonging to Citrus and 13 related genera. The most consistent results were obtained by the chord distance and the neighbor-joining clustering method. Citrus species were distributed in two main groups: the orange-mandarin group and the lime lemon citron-pummelo group. The species C. halimii and C. tachibana are not included in these groups. Mandarin species fall into three main subgroups: one includes C. sinensis; the second, C. aurantium, the third, small-fruit species. The citron, the pummelo and the ancient lemon subgroups form a cluster to which the species belonging to subgenus Papeda and the cultivated limes, lemons and bergamots are related. Microcitrus spp, to which Severinia buxifolia and Atalantia ceylanica seem to be related, cluster with the lime lemon-citron-pummelo group while Fortunella is close to the orange-mandarin group. Poncirus trifoliata, the most important species for citrus rootstock improvement is located far from Citrus but connected to it through Fortunella spp. A broad distribution of species has been found that should be taken into account to sample new genotypes in the search of desired characters in order to fully and efficiently use genetic resources for citrus improvement. PMID- 24162547 TI - The effect of index selection on allele frequencies and future genetic gains when traits are correlated. AB - The application of the selection index in the case of an additive two-trait model in which the genetic effect on each trait is determined by a finite number of loci is examined. Simulation results indicate that the direction of change in the frequency of favourable alleles is not necessarily in the positive direction at all loci when index selection is used as the basis for truncation selection. When the genetic correlation was positive (or favourable with respect to the economic weights), there was little difference (<5%) in genetic gain over 20 generations and no difference in the direction of change in allele frequencies or genetic correlation whether or not updated values for the genetic (co)variances were used in constructing the selection index. However, when the genetic correlation was negative or unfavourable, the effect of using genetic parameters which were not updated had unexpected effects on the allele frequencies and genetic correlation and reduced the genetic gain by a greater amount (< 12%). PMID- 24162549 TI - The effect of diet on ontogenic development of the digestive tract in juvenile reared long snout seahorse Hippocampus guttulatus. AB - Ontogenetic development of the digestive tract and associated organs in long snout seahorse Hippocampus guttulatus juveniles was morphologically and histologically examined from the time of release from the male's pouch until 72 h after the first meal. When released from the male's pouch, juvenile seahorses are small adult replicates. This means that unlike other teleost fish larvae, the first developmental phase has already taken place, and juveniles are morphologically prepared and able to feed on live prey immediately following parturition. At this stage, the buccopharynx, oesophagus, and intestine already appear to be fully developed. The intestine is divided into the midgut and hindgut by an intestinal valve, and intestinal villi are visible in the midgut. When fed with DHA-Selco((r)) enriched Artemia, H. guttulatus juveniles developed a severe condition of overinflation of the gas bladder. The continuous overinflation of the gas bladder forced air into the gut (48 h after the first meal), resulting in overinflation of both the gut and the gas bladder (72 h after the first meal), and death occurred within 120 h after the first meal. When fed natural copepods, H. guttulatus juveniles continued a normal feeding activity with no signs of intestinal disorders, and the gas bladder and intestine maintained their normal shape. This is the first study to positively associate gas bladder overinflation of juvenile seahorses with nutritionally unbalanced diets, and not to gas supersaturation alone. It is therefore necessary to develop more adequate feed and/or enrichment products to improve the survival of juvenile seahorses in captivity. PMID- 24162548 TI - Switching molecular orientation of individual fullerene at room temperature. AB - Reversible molecular switches with molecular orientation as the information carrier have been achieved on individual fullerene molecules adsorbed on Si (111) surface at room temperature. Scanning tunneling microscopy imaging directly demonstrates that the orientation of individual fullerene with an adsorption geometry of 5-6 bond is rotated by integral times as 30 degree after a pulse bias is applied between the STM tip and the molecule. Dependences of the molecular rotation probability on the voltage and the process of applied bias reveal that the rotation of a fullerene molecule takes place in two successive steps: the bonding between the fullerene and the Si surface is firstly weakened via electronic excitation and then low energy electron bombardment causes the molecule to rotate by certain degree. PMID- 24162550 TI - Is gestational weight gain associated with diet quality during pregnancy? AB - The gestational weight gain (GWG) guidelines of the Institute of Medicine (IOM) aim to optimize birth outcomes and reduce pregnancy complications. The GWG guidelines are set based on the prepregnancy weight status and optimal weight gain at different trimesters of pregnancy. Dietary references intakes (DRIs) of the IOM are set for each trimester of pregnancy for energy intake and other essential nutrients by age groups (<= 18, 19-30, 31-51 years). The DRIs, however, do not take into account the differing energy and nutrient requirements of women with different prepregnancy weights. In this cross-sectional study, we tested the hypothesis that diet quality during pregnancy is associated with adequate GWG at different stages of pregnancy. Diet quality during pregnancy was assessed from a 24-h recall measured by the healthy eating index of 2005 (HEI-2005). Both GWG and diet quality data were from 490 pregnant women aged 16-43 years included in National Health and Nutrition Examination Survey 2003-2006, a program of studies designed to assess the health and nutritional status of adults and children in the US, during which pregnant women were oversampled. Logistic regression models adjusted for age, trimester of gestation, race/ethnicity, education level, marital status, family poverty income ratio, daily supplement use, physical activity, and prepregnancy BMI were used to investigate if HEI-2005 is a determinant of GWG status at different trimesters of pregnancy. We found that HEI 2005 scores were not determinants of adequate GWG, although inadequate intake of total vegetables (OR 3.8, CI 1.1-13.2, p = 0.03) and oils were associated with excessive GWG (OR 2.8, CI 1.2-6.4, p = 0.02) when covariates were controlled. Although adequate GWG was not associated with diet quality as measured by HEI 2005 during pregnancy in this study, comprehensive prenatal counseling is still important to reduce adverse birth outcomes. PMID- 24162553 TI - Topological Fulde-Ferrell-Larkin-Ovchinnikov states in spin-orbit-coupled Fermi gases. AB - Pairing in an attractively interacting two-component Fermi gas in the absence of time-reversal symmetry or inversion symmetry may give rise to exotic superfluid states. Notable examples range from the Fulde-Ferrell-Larkin-Ovchinnikov state with a finite centre-of-mass momentum in a polarized Fermi gas to the topological superfluid (TSF) state in a two-dimensional (2D) Fermi gas under Rashba spin orbit coupling and an out-of-plane Zeeman field. Here we show that a TSF state with a single-component nonzero centre-of-mass momentum, called a topological Fulde-Ferrell (tFF) state, can be stabilized in a 2D Fermi gas with Rashba spin orbit coupling and both in-plane and out-of-plane Zeeman fields. The tFF state features a non-trivial Berry phase, along with unique properties that may be detected using existing experimental techniques. PMID- 24162552 TI - Predictors of maternal encouragement to diet: a moderated mediation analysis. AB - Maternal encouragement to diet has been linked to child disordered eating, overweight and obesity, and negative psychosocial outcomes. A limited amount of research has examined variables that may contribute to maternal encouragement to diet. The current study examined the relationship between child BMI, parent BMI, maternal concern about child weight status, and maternal encouragement to diet. 80 youths, aged 8-17, and their mothers were administered questionnaires to assess maternal weight concern and child perception of maternal encouragement to diet. Data were analyzed using a bootstrapped moderated mediation model. Higher child BMI predicted increased maternal weight concern, which in turn was related to increased encouragement to diet. Mothers of overweight and obese youth were more likely to be concerned about their child's weight if mothers themselves were overweight or obese. Overweight or obese girls (but not boys) with an overweight or obese mother were more likely to be encouraged to diet. The model accounted for 48% of the variance in maternal encouragement to diet. Results indicate a potential mechanism by which encouragement to diet occurs and highlight the relevance of maternal weight and child gender in the prediction of encouragement to diet. PMID- 24162554 TI - Difficulties in immunofixation analysis: a concordance study on the IFM 2007-02 trial. PMID- 24162551 TI - Pandemic influenza A (H1N1) in non-vaccinated, pregnant women in Spain (2009 2010). AB - The aim of this study was to investigate the main characteristics of non vaccinated pregnant women who were hospitalised for influenza A (H1N1) pdm09 pandemic versus pregnant women hospitalised for non-influenza-related reasons in Spain, and to characterise the clinical presentation of the disease in this population to facilitate early diagnosis and future action programmes. Understanding influenza infection during pregnancy is important as pregnant women are a high-risk population for increased morbidity from influenza infection. We investigated the socio-demographic and clinical features of 51 non-vaccinated, pregnant women infected with the pandemic influenza A (H1N1) virus in Spain (cases) and compared them to 114 controls (non-vaccinated and non-infected pregnant women) aged 15-44 years. Substantial and significant odd ratios (ORs) for pandemic influenza A (H1N1) were found for the pregnant women who were obese compared with controls (body mass index > 30) (OR 3.03; 95% confidence intervals 1.13-8.11). The more prevalent symptoms observed in pandemic influenza-infected pregnant women were high temperature, cough (82.4%), malaise (80.5%), myalgia (56.1%), and headaches (54.9%). Our results suggest that the initial symptoms and risk factors for infection of pregnant women with the influenza A (H1N1) pdm09 virus are similar to the symptoms and risk factors for seasonal influenza, which make early diagnosis difficult, and reinforces the need to identify and protect high-risk groups. PMID- 24162555 TI - CoO-carbon nanofiber networks prepared by electrospinning as binder-free anode materials for lithium-ion batteries with enhanced properties. AB - CoOx-carbon nanofiber networks were prepared from cobalt(ii) acetate and polyacrylonitrile by an electrospinning method followed by thermal treatment. The XPS results demonstrated that the cobalt compound in CoOx-carbon obtained at 650 degrees C was CoO rather than Co or Co3O4. The CoO nanoparticles with diameters of about 8 nm were homogeneously distributed in the matrix of the nanofibers with diameters of 200 nm. As binder-free anodes for lithium-ion batteries, the discharge capacities of such CoO-carbon (CoO-C) composite nanofiber networks increased with the pyrolysis and annealing temperature, and the highest value was 633 mA h g(-1) after 52 cycles at a current density of 0.1 A g(-1) when the CoO-C was obtained at 650 degrees C. In addition, the rate capacities of the CoO-C obtained at 650 degrees C were found to be higher than that of the sample annealed at a lower temperature and pure carbon nanofiber networks annealed at 650 degrees C. The improved properties of CoO-C nanofiber networks were ascribed to nanofibers as the framework to keep the structural stability, and favorable mass and charge transport. The present study may provide a new strategy for the synthesis of binder-free anodes for lithium-ion batteries with excellent properties. PMID- 24162557 TI - On the structure and ambiphilicity of a sulfonyl substituted alpha-chloro lithium base. AB - An alpha-chloro lithium base stabilised by a sulfonyl and thiophosphinoyl moiety was selectively prepared by lithiation of its protonated precursor and oxidation of the corresponding dilithio methandiide. The carbenoid-like compound was found to be remarkably stable even at room temperature and thus allowed for its spectroscopic characterisation in solution and in the solid state. Its ambiphilic nature was tested and compared with typical carbenoids both experimentally and by computational methods. The electronic stabilisation results in its thermal stability but considerably reduces the ambiphilic character limiting the reactivity patterns generally observed for lithium carbenoids. PMID- 24162556 TI - Exercise training improves heart rate variability after methamphetamine dependency. AB - PURPOSE: Heart rate variability (HRV) reflects a healthy autonomic nervous system and is increased with physical training. Methamphetamine dependence (MD) causes autonomic dysfunction and diminished HRV. We compared recently abstinent methamphetamine-dependent participants with age-matched, drug-free controls (DF) and also investigated whether HRV can be improved with exercise training in the methamphetamine-dependent participants. METHODS: In 50 participants (MD = 28; DF = 22), resting heart rate (HR; R-R intervals) was recorded over 5 min while seated using a monitor affixed to a chest strap. Previously reported time domain (SDNN, RMSSD, pNN50) and frequency domain (LFnu, HFnu, LF/HF) parameters of HRV were calculated with customized software. MD were randomized to thrice-weekly exercise training (ME = 14) or equal attention without training (MC = 14) over 8 wk. Groups were compared using paired and unpaired t-tests. Statistical significance was set at P <= 0.05. RESULTS: Participant characteristics were matched between groups (mean +/- SD): age = 33 +/- 6 yr; body mass = 82.7 +/- 12 kg, body mass index = 26.8 +/- 4.1 kg.min. Compared with DF, the MD group had significantly higher resting HR (P < 0.05), LFnu, and LF/HF (P < 0.001) as well as lower SDNN, RMSSD, pNN50, and HFnu (all P < 0.001). At randomization, HRV indices were similar between ME and MC groups. However, after training, the ME group significantly (all P < 0.001) increased SDNN (+14.7 +/- 2.0 ms, +34%), RMSSD (+19.6 +/- 4.2 ms, +63%), pNN50 (+22.6% +/- 2.7%, +173%), HFnu (+14.2 +/- 1.9, +60%), and decreased HR (-5.2 +/- 1.1 bpm, -7%), LFnu (-9.6 +/- 1.5, -16%), and LF/HF (-0.7 +/- 0.3, -19%). These measures did not change from baseline in the MC group. CONCLUSIONS: HRV, based on several conventional indices, was diminished in recently abstinent, methamphetamine-dependent individuals. Moreover, physical training yielded a marked increase in HRV, representing increased vagal modulation or improved autonomic balance. PMID- 24162558 TI - Electrooxidation of methanol in an alkaline fuel cell: determination of the nature of the initial adsorbate. AB - It is essential to correctly determine the nature of the initial adsorbate in order to calculate the pathway for any given reaction. Recent literature provides conflicting information on the first step in the methanol decomposition pathway. This work sets out to establish what role the solution and the surface have to play in the initial adsorption-deprotonation process. Density functional theory (DFT) calculations, in combination with a cluster-continuum model approach are used to resolve the nature of the adsorbing species. We show that methanol is the dominant species in solution over methoxide, and also has a smaller barrier to adsorption. The nature of the surface species is revealed to be a methanol-OH complex. PMID- 24162559 TI - High-resolution linkage map for two honeybee chromosomes: the hotspot quest. AB - Meiotic recombination is a fundamental process ensuring proper disjunction of homologous chromosomes and allele shuffling in successive generations. In many species, this cellular mechanism occurs heterogeneously along chromosomes and mostly concentrates in tiny fragments called recombination hotspots. Specific DNA motifs have been shown to initiate recombination in these hotspots in mammals, fission yeast and drosophila. The aim of this study was to check whether recombination also occurs in a heterogeneous fashion in the highly recombinogenic honeybee genome and whether this heterogeneity can be connected with specific DNA motifs. We completed a previous picture drawn from a routine genetic map built with an average resolution of 93 kb. We focused on the two smallest honeybee chromosomes to increase the resolution and even zoomed at very high resolution (3.6 kb) on a fragment of 300 kb. Recombination rates measured in these fragments were placed in relation with occurrence of 30 previously described motifs through a Poisson regression model. A selection procedure suitable for correlated variables was applied to keep significant motifs. These fine and ultra-fine mappings show that recombination rate is significantly heterogeneous although poorly contrasted between high and low recombination rate, contrarily to most model species. We show that recombination rate is probably associated with the DNA methylation state. Moreover, three motifs (CGCA, GCCGC and CCAAT) are good candidates of signals promoting recombination. Their influence is however moderate, doubling at most the recombination rate. This discovery extends the way to recombination dissection in insects. PMID- 24162560 TI - Identification of appropriate reference genes for normalizing transcript expression by quantitative real-time PCR in Litsea cubeba. AB - Quantitative real-time PCR has emerged as a highly sensitive and widely used method for detection of gene expression profiles, via which accurate detection depends on reliable normalization. Since no single control is appropriate for all experimental treatments, it is generally advocated to select suitable internal controls prior to use for normalization. This study reported the evaluation of the expression stability of twelve potential reference genes in different tissue/organs and six fruit developmental stages of Litsea cubeba in order to screen the superior internal reference genes for data normalization. Two softwares-geNorm, and NormFinder-were used to identify stability of these candidate genes. The cycle threshold difference and coefficient of variance were also calculated to evaluate the expression stability of candidate genes. F-BOX, EF1alpha, UBC, and TUA were selected as the most stable reference genes across 11 sample pools. F-BOX, EF1alpha, and EIF4alpha exhibited the highest expression stability in different tissue/organs and different fruit developmental stages. Besides, a combination of two stable reference genes would be sufficient for gene expression normalization in different fruit developmental stages. In addition, the relative expression profiles of DXS and DXR were evaluated by EF1alpha, UBC, and SAMDC. The results further validated the reliability of stable reference genes and also highlighted the importance of selecting suitable internal controls for L. cubeba. These reference genes will be of great importance for transcript normalization in future gene expression studies on L. cubeba. PMID- 24162561 TI - Discriminative motif analysis of high-throughput dataset. AB - MOTIVATION: High-throughput ChIP-seq studies typically identify thousands of peaks for a single transcription factor (TF). It is common for traditional motif discovery tools to predict motifs that are statistically significant against a naive background distribution but are of questionable biological relevance. RESULTS: We describe a simple yet effective algorithm for discovering differential motifs between two sequence datasets that is effective in eliminating systematic biases and scalable to large datasets. Tested on 207 ENCODE ChIP-seq datasets, our method identifies correct motifs in 78% of the datasets with known motifs, demonstrating improvement in both accuracy and efficiency compared with DREME, another state-of-art discriminative motif discovery tool. More interestingly, on the remaining more challenging datasets, we identify common technical or biological factors that compromise the motif search results and use advanced features of our tool to control for these factors. We also present case studies demonstrating the ability of our method to detect single base pair differences in DNA specificity of two similar TFs. Lastly, we demonstrate discovery of key TF motifs involved in tissue specification by examination of high-throughput DNase accessibility data. AVAILABILITY: The motifRG package is publically available via the bioconductor repository. CONTACT: yzizhen@fhcrc.org SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 24162562 TI - Finding the right path: Baldwin "rules for ring closure" and stereoelectronic control of cyclizations. AB - Truly important scientific breakthroughs often come from catching the glimpses of order in chaos and distilling a large body of disjointed data into a clear set of simple concepts. Even more impressive is when the new conceptual framework is created with some of the keystones still missing. Such bold predictions, i.e. Mendeleev's eka-silicon, challenge and inspire, serving as powerful catalysts for scientific growth. The rules for ring closure formulated by Sir Jack Baldwin in 1976 constitute one of such bold intellectual advances. Baldwin developed a classification system that brought order to the chaos of possible cyclization patterns and suggested a set of rules to define the favourable modes of ring closure. Where sufficient data was lacking, particularly for the cyclizations of alkynes, Baldwin made testable predictions that challenged theoretical and experimental chemists. These guidelines have become the common starting point in the design of new cyclization reactions and catalyzed the development of modern stereoelectronic concepts. PMID- 24162563 TI - Non-systemic juvenile idiopathic arthritis outcome after reaching clinical remission with anti-TNF-alpha therapy: a clinical practice observational study of patients who discontinued treatment. AB - TNF-alpha-blocking agents (anti-TNF) used in juvenile idiopathic arthritis (JIA) are well established; however, time to withdraw is unclear. Neither prolonged nor tapering treatment seems to influence risk of relapse. Our aim was to assess relapse percentage after anti-TNF withdrawal of our non-systemic JIA patients after reaching clinical remission. A retrospective review of our non-systemic JIA patients in whom anti-TNF had been withdrawn due to inactive disease was achieved, between December 2000 and November 2011. We analyzed percentages of relapse according to JIA categories and antinuclear antibodies (ANA) positivity. n = 18 patients were included. Eighty-two percentage of patients relapsed after treatment withdrawal, and mean time to relapse was 3.04 months (SD 2.03). The percentage of relapse after anti-TNF discontinuation in the main JIA category was 88 % of negative rheumatoid factor polyarticular JIA and 80 % of persistent oligoarticular JIA. We did not find significant statistical differences according to ANA positivity (9 of 14 were ANA positive), and mean time to relapse (days) was 85.0 (SD 69.4) for ANA-positive versus 102.4 (SD 47.7) for ANA-negative patients (p = NS). Relapse percentage following anti-TNF discontinuation was high (82 %) and occurred within the first 3 months after it. No relationship regarding JIA subtype and ANA positivity was found. PMID- 24162564 TI - Association between prothrombin gene polymorphisms and hereditary thrombophilia in Xinjiang Kazakhs population. AB - To assess the association between polymorphisms of prothrombin gene and hereditary thrombophilia in Xinjiang Kazakhs population. Through cross-sectional investigation, permanent Kazakh population of Ili Kazakh Autonomous Prefecture was selected as the study object to measure their antithrombin III (AT-III), protein C, protein S activity and activated C protein resistance value, thus defining the situation of the crowd's hereditary thrombophilia. Sequenom Massarray detection technology was used to conduct a genotype test of the six sites selected by the case and control groups. Haploview software was used to perform linkage disequilibrium analysis of the six sites, and the impact of the interaction between genetic variations and environment on hereditary thrombophilia was researched by the use of sum model. A total of 1005 Kazakh volunteers participated in the test (332 men and 673 women), average age (41.13 +/- 11.50) years; the prevalence of hereditary thrombophilia in Xinjiang Kazakh population was 31.0%, and the prevalence of AT-III deficiency, protein C deficiency, protein S deficiency and activated protein C resistance was 16.4, 14.9, 20.6 and 7.8%, respectively. The difference in allele frequency of the hereditary thrombophilia patient group at rs3136447 and rs5896 sites was statistically significant (P = 0.0483 and P = 0.0302, respectively). rs5896 and rs2070852 had high linkage disequilibrium (r = 0.99), and constituted a single domain block 1. The rs3136447 and the rs5896 polymorphisms located in the region of the prothrombin gene may be associated with hereditary thrombophilia in the Xinjiang Kazakhs population. There is additive interactive effect of rs5896 polymorphism (CT + TT) and smoke on hereditary thrombophilia. PMID- 24162565 TI - Osmoadaptation strategy of the most halophilic fungus, Wallemia ichthyophaga, growing optimally at salinities above 15% NaCl. AB - Wallemia ichthyophaga is a fungus from the ancient basidiomycetous genus Wallemia (Wallemiales, Wallemiomycetes) that grows only at salinities between 10% (wt/vol) NaCl and saturated NaCl solution. This obligate halophily is unique among fungi. The main goal of this study was to determine the optimal salinity range for growth of the halophilic W. ichthyophaga and to unravel its osmoadaptation strategy. Our results showed that growth on solid growth media was extremely slow and resulted in small colonies. On the other hand, in the liquid batch cultures, the specific growth rates of W. ichthyophaga were higher, and the biomass production increased with increasing salinities. The optimum salinity range for growth of W. ichthyophaga was between 15 and 20% (wt/vol) NaCl. At 10% NaCl, the biomass production and the growth rate were by far the lowest among all tested salinities. Furthermore, the cell wall content in the dry biomass was extremely high at salinities above 10%. Our results also showed that glycerol was the major osmotically regulated solute, since its accumulation increased with salinity and was diminished by hypo-osmotic shock. Besides glycerol, smaller amounts of arabitol and trace amounts of mannitol were also detected. In addition, W. ichthyophaga maintained relatively small intracellular amounts of potassium and sodium at constant salinities, but during hyperosmotic shock, the amounts of both cations increased significantly. Given our results and the recent availability of the genome sequence, W. ichthyophaga should become well established as a novel model organism for studies of halophily in eukaryotes. PMID- 24162566 TI - Temporal variability of the bioaerosol background at a subway station: concentration level, size distribution, and diversity of airborne bacteria. AB - Naturally occurring bioaerosol environments may present a challenge to biological detection-identification-monitoring (BIODIM) systems aiming at rapid and reliable warning of bioterrorism incidents. One way to improve the operational performance of BIODIM systems is to increase our understanding of relevant bioaerosol backgrounds. Subway stations are enclosed public environments which may be regarded as potential bioterrorism targets. This study provides novel information concerning the temporal variability of the concentration level, size distribution, and diversity of airborne bacteria in a Norwegian subway station. Three different air samplers were used during a 72-h sampling campaign in February 2011. The results suggested that the airborne bacterial environment was stable between days and seasons, while the intraday variability was found to be substantial, although often following a consistent diurnal pattern. The bacterial levels ranged from not detected to 10(3) CFU m(-3) and generally showed increased levels during the daytime compared to the nighttime levels, as well as during rush hours compared to non-rush hours. The airborne bacterial levels showed rapid temporal variation (up to 270-fold) on some occasions, both consistent and inconsistent with the diurnal profile. Airborne bacterium-containing particles were distributed between different sizes for particles of >1.1 MUm, although ~50% were between 1.1 and 3.3 MUm. Anthropogenic activities (mainly passengers) were demonstrated as major sources of airborne bacteria and predominantly contributed 1.1- to 3.3-MUm bacterium-containing particles. Our findings contribute to the development of realistic testing and evaluation schemes for BIODIM equipment by providing information that may be used to simulate operational bioaerosol backgrounds during controlled aerosol chamber-based challenge tests with biological threat agents. PMID- 24162567 TI - Detection of extended-spectrum beta-lactamase (ESBL)-producing Escherichia coli on flies at poultry farms. AB - In the Netherlands, extended-spectrum beta-lactamase (ESBL)-producing Escherichia coli bacteria are highly prevalent in poultry, and chicken meat has been implicated as a source of ESBL-producing E. coli present in the human population. The current study describes the isolation of ESBL-producing E. coli from house flies and blow flies caught at two poultry farms, offering a potential alternative route of transmission of ESBL-producing E. coli from poultry to humans. Overall, 87 flies were analyzed in 19 pools. ESBL-producing E. coli bacteria were detected in two fly pools (10.5%): a pool of three blow flies from a broiler farm and a pool of eight house flies from a laying-hen farm. From each positive fly pool, six isolates were characterized and compared with isolates obtained from manure (n = 53) sampled at both farms and rinse water (n = 10) from the broiler farm. Among six fly isolates from the broiler farm, four different types were detected with respect to phylogenetic group, sequence type (ST), and ESBL genotype: A0/ST3519/SHV-12, A1/ST10/SHV-12, A1/ST58/SHV-12, and B1/ST448/CTX M-1. These types, as well as six additional types, were also present in manure and/or rinse water at the same farm. At the laying-hen farm, all fly and manure isolates were identical, carrying blaTEM-52 in an A1/ST48 genetic background. The data imply that flies acquire ESBL-producing E. coli at poultry farms, warranting further evaluation of the contribution of flies to dissemination of ESBL producing E. coli in the community. PMID- 24162568 TI - CRISPRs: molecular signatures used for pathogen subtyping. AB - Rapid and accurate strain identification is paramount in the battle against microbial outbreaks, and several subtyping approaches have been developed. One such method uses clustered regular interspaced short palindromic repeats (CRISPRs), DNA repeat elements that are present in approximately half of all bacteria. Though their signature function is as an adaptive immune system against invading DNA such as bacteriophages and plasmids, CRISPRs also provide an excellent framework for pathogen tracking and evolutionary studies. Analysis of the spacer DNA sequences that reside between the repeats has been tremendously useful for bacterial subtyping during molecular epidemiological investigations. Subtyping, or strain identification, using CRISPRs has been employed in diverse Gram-positive and Gram-negative bacteria, including Mycobacterium tuberculosis, Salmonella enterica, and the plant pathogen Erwinia amylovora. This review discusses the several ways in which CRISPR sequences are exploited for subtyping. This includes the well-established spoligotyping methodologies that have been used for 2 decades to type Mycobacterium species, as well as in-depth consideration of newer, higher-throughput CRISPR-based protocols. PMID- 24162569 TI - Molecular investigation and phylogeny of Anaplasma spp. in Mediterranean ruminants reveal the presence of neutrophil-tropic strains closely related to A. platys. AB - Few data are available on the prevalence and molecular typing of species belonging to the genus Anaplasma in Mediterranean ruminants. In this study, PCR analysis and sequencing of both 16S rRNA and groEL genes were combined to investigate the presence, prevalence, and molecular traits of Anaplasma spp. in ruminants sampled on the Island of Sardinia, chosen as a subtropical representative area. The results demonstrate a high prevalence of Anaplasma spp. in ruminants, with animals infected by at least four of six Anaplasma species (Anaplasma marginale, A. bovis, A. ovis, and A. phagocytophilum). Moreover, ruminants host a number of neutrophil-tropic strains genetically closely related to the canine pathogen A. platys. The high Anaplasma spp. prevalence and the identification of as-yet-unclassified neutrophil-tropic strains raise concerns about the specificity of serological tests routinely used in ruminants and provide additional background for reconstructing the evolutionary history of species genetically related to A. phagocytophilum. PMID- 24162571 TI - Glycine betaine as a direct substrate for methanogens (Methanococcoides spp.). AB - Nine marine methanogenic Methanococcoides strains, including the type strains of Methanococcoides methylutens, M. burtonii, and M. alaskense, were tested for the utilization of N-methylated glycines. Three strains (NM1, PM2, and MKM1) used glycine betaine (N,N,N-trimethylglycine) as a substrate for methanogenesis, partially demethylating it to N,N-dimethylglycine, whereas none of the strains used N,N-dimethylglycine or sarcosine (N-methylglycine). Growth rates and growth yields per mole of substrate with glycine betaine (3.96 g [dry weight] per mol) were similar to those with trimethylamine (4.11 g [dry weight] per mol). However, as glycine betaine is only partially demethylated, the yield per methyl group was significantly higher than with trimethylamine. If glycine betaine and trimethylamine are provided together, trimethylamine is demethylated to dimethyl- and methylamine with limited glycine betaine utilization. After trimethylamine is depleted, dimethylamine and glycine betaine are consumed rapidly, before methylamine. Glycine betaine extends the range of substrates that can be directly utilized by some methanogens, allowing them to gain energy from the substrate without the need for syntrophic partners. PMID- 24162573 TI - Selman A. Waksman, winner of the 1952 Nobel Prize for physiology or medicine. AB - The history of the discovery and development of streptomycin is reviewed here from the personal standpoint of a member of Dr. Selman Waksman's antibiotic screening research team. The team approach of eight individuals illustrates how the gradual enhancement of the screening methodology was developed. I illustrate three study periods with key aspects in the development of streptomycin which led to a Nobel Prize being granted to Professor Waksman. One item not previously emphasized is the employment of a submerged culture technique for large-scale production of streptomycin, thus enabling rapid animal testing and human clinical trials with Mycobacterium tuberculosis. Another is that purified streptomycin was shown by Dr. Waksman to be distinctly different from the substances called natural products, which are no longer patentable in the United States; therefore, streptomycin was found to be patentable. A third item not previously emphasized is his emphasis on the screening of actinomycetes, including the newly named Streptomyces genus. All of these factors contributed to the success of streptomycin in the treatment of tuberculosis. In combination, their successes led to Dr. Waksman's department becoming a new pharmacological research area, specializing in drug discovery. These unique accomplishments all burnish the prior rationales used by the Karolinska Institute in granting Dr. Waksman alone the 1952 Nobel Prize for Physiology or Medicine. PMID- 24162574 TI - Primer modification improves rapid and sensitive in vitro and field-deployable assays for detection of high plains virus variants. AB - A high consequence pathogen, High plains virus (HPV) causes considerable damage to wheat if the crop is infected during early stages of development. Methods for the early, accurate, and sensitive detection of HPV in plant tissues are needed for the management of disease outbreaks and reservoir hosts. In this study, the effectiveness of five methods-real-time SYBR green and TaqMan reverse transcription-quantitative PCR (RT-qPCR), endpoint RT-PCR, RT-helicase dependent amplification (RT-HDA) and the Razor Ex BioDetection System (Razor Ex)-for the broad-range detection of HPV variants was evaluated. Specific PCR primer sets and probes were designed to target the HPV nucleoprotein gene. Primer set HPV6F and HPV4R, which amplifies a product of 96 bp, was validated in silico against published sequences and in vitro against an inclusivity panel of infected plant samples and an exclusivity panel of near-neighbor viruses. The primers were modified by adding a customized 22 nucleotide long tail at the 5' terminus, raising the primers' melting temperature (Tm; ca. 10 degrees C) to make them compatible with RT-HDA (required optimal Tm = 68 degrees C), in which the use of primers lacking such tails gave no amplification. All of the methods allowed the detection of as little as 1 fg of either plasmid DNA carrying the target gene sequence or of infected plant samples. The described in vitro and in-field assays are accurate, rapid, sensitive, and useful for pathogen detection and disease diagnosis, microbial quantification, and certification and breeding programs, as well as for biosecurity and microbial forensics applications. PMID- 24162572 TI - Predominant Acidilobus-like populations from geothermal environments in yellowstone national park exhibit similar metabolic potential in different hypoxic microbial communities. AB - High-temperature (>70 degrees C) ecosystems in Yellowstone National Park (YNP) provide an unparalleled opportunity to study chemotrophic archaea and their role in microbial community structure and function under highly constrained geochemical conditions. Acidilobus spp. (order Desulfurococcales) comprise one of the dominant phylotypes in hypoxic geothermal sulfur sediment and Fe(III)-oxide environments along with members of the Thermoproteales and Sulfolobales. Consequently, the primary goals of the current study were to analyze and compare replicate de novo sequence assemblies of Acidilobus-like populations from four different mildly acidic (pH 3.3 to 6.1) high-temperature (72 degrees C to 82 degrees C) environments and to identify metabolic pathways and/or protein encoding genes that provide a detailed foundation of the potential functional role of these populations in situ. De novo assemblies of the highly similar Acidilobus-like populations (>99% 16S rRNA gene identity) represent near-complete consensus genomes based on an inventory of single-copy genes, deduced metabolic potential, and assembly statistics generated across sites. Functional analysis of coding sequences and confirmation of gene transcription by Acidilobus-like populations provide evidence that they are primarily chemoorganoheterotrophs, generating acetyl coenzyme A (acetyl-CoA) via the degradation of carbohydrates, lipids, and proteins, and auxotrophic with respect to several external vitamins, cofactors, and metabolites. No obvious pathways or protein-encoding genes responsible for the dissimilatory reduction of sulfur were identified. The presence of a formate dehydrogenase (Fdh) and other protein-encoding genes involved in mixed-acid fermentation supports the hypothesis that Acidilobus spp. function as degraders of complex organic constituents in high-temperature, mildly acidic, hypoxic geothermal systems. PMID- 24162576 TI - Monitoring rates and heterogeneity of high-pressure germination of bacillus spores by phase-contrast microscopy of individual spores. AB - Germination of Bacillus spores with a high pressure (HP) of ~150 MPa is via activation of spores' germinant receptors (GRs). The HP germination of multiple individual Bacillus subtilis spores in a diamond anvil cell (DAC) was monitored with phase-contrast microscopy. Major conclusions were that (i) >95% of wild-type spores germinated in 40 min in a DAC at ~150 MPa and 37 degrees C but individual spores' germination kinetics were heterogeneous; (ii) individual spores' HP germination kinetic parameters were similar to those of nutrient-triggered germination with a variable lag time (Tlag) prior to a period of the rapid release (DeltaTrelease) of the spores' dipicolinic acid in a 1:1 chelate with Ca(2+) (CaDPA); (iii) spore germination at 50 MPa had longer average Tlag values than that at ~150 MPa, but the DeltaTrelease values at the two pressures were identical and HPs of <10 MPa did not induce germination; (iv) B. subtilis spores that lacked the cortex-lytic enzyme CwlJ and that were germinated with an HP of 150 MPa exhibited average DeltaTrelease values ~15-fold longer than those for wild-type spores, but the two types of spores exhibited similar average Tlag values; and (v) the germination of wild-type spores given a >=30-s 140-MPa HP pulse followed by a constant pressure of 1 MPa was the same as that of spores exposed to a constant pressure of 140 MPa that was continued for >=35 min; (vi) however, after short 150-MPa HP pulses and incubation at 0.1 MPa (ambient pressure), spore germination stopped 5 to 10 min after the HP was released. These results suggest that an HP of ~150 MPa for <=30 s is sufficient to fully activate spores' GRs, which remain activated at 1 MPa but can deactivate at ambient pressure. PMID- 24162570 TI - Response of free-living nitrogen-fixing microorganisms to land use change in the Amazon rainforest. AB - The Amazon rainforest, the largest equatorial forest in the world, is being cleared for pasture and agricultural use at alarming rates. Tropical deforestation is known to cause alterations in microbial communities at taxonomic and phylogenetic levels, but it is unclear whether microbial functional groups are altered. We asked whether free-living nitrogen-fixing microorganisms (diazotrophs) respond to deforestation in the Amazon rainforest, using analysis of the marker gene nifH. Clone libraries were generated from soil samples collected from a primary forest, a 5-year-old pasture originally converted from primary forest, and a secondary forest established after pasture abandonment. Although diazotroph richness did not significantly change among the three plots, diazotroph community composition was altered with forest-to-pasture conversion, and phylogenetic similarity was higher among pasture communities than among those in forests. There was also 10-fold increase in nifH gene abundance following conversion from primary forest to pasture. Three environmental factors were associated with the observed changes: soil acidity, total N concentration, and C/N ratio. Our results suggest a partial restoration to initial levels of abundance and community structure of diazotrophs following pasture abandonment, with primary and secondary forests sharing similar communities. We postulate that the response of diazotrophs to land use change is a direct consequence of changes in plant communities, particularly the higher N demand of pasture plant communities for supporting aboveground plant growth. PMID- 24162575 TI - The cold-induced two-component system CBO0366/CBO0365 regulates metabolic pathways with novel roles in group I Clostridium botulinum ATCC 3502 cold tolerance. AB - The two-component system CBO0366/CBO0365 was recently demonstrated to have a role in cold tolerance of group I Clostridium botulinum ATCC 3502. The mechanisms under its control, ultimately resulting in increased sensitivity to low temperature, are unknown. A transcriptomic analysis with DNA microarrays was performed to identify the differences in global gene expression patterns of the wild-type ATCC 3502 and a derivative mutant with insertionally inactivated cbo0365 at 37 and 15 degrees C. Altogether, 150 or 141 chromosomal coding sequences (CDSs) were found to be differently expressed in the cbo0365 mutant at 37 or 15 degrees C, respectively, and thus considered to be under the direct or indirect transcriptional control of the response regulator CBO0365. Of the differentially expressed CDSs, expression of 141 CDSs was similarly affected at both temperatures investigated, suggesting that the putative CBO0365 regulon was practically not affected by temperature. The regulon involved genes related to acetone-butanol-ethanol (ABE) fermentation, motility, arsenic resistance, and phosphate uptake and transport. Deteriorated growth at 17 degrees C was observed for mutants with disrupted ABE fermentation pathway components (crt, bcd, bdh, and ctfA), arsenic detoxifying machinery components (arsC and arsR), or phosphate uptake mechanism components (phoT), suggesting roles for these mechanisms in cold tolerance of group I C. botulinum. Electrophoretic mobility shift assays showed recombinant CBO0365 to bind to the promoter regions of crt, arsR, and phoT, as well as to the promoter region of its own operon, suggesting direct DNA-binding transcriptional activation or repression as a means for CBO0365 in regulating these operons. The results provide insight to the mechanisms group I C. botulinum utilizes in coping with cold. PMID- 24162577 TI - Metatranscriptomic analyses of plankton communities inhabiting surface and subpycnocline waters of the Chesapeake Bay during oxic-anoxic-oxic transitions. AB - We used metatranscriptomics to study the gene transcription patterns of microbial plankton (0.2 to 64 MUm) at a mesohaline station in the Chesapeake Bay under transitions from oxic to anoxic waters in spring and from anoxic to oxic waters in autumn. Samples were collected from surface (i.e., above pycnocline) waters (3 m) and from waters beneath the pycnocline (16 to 22 m) in both 2010 and 2011. Metatranscriptome profiles based on function and potential phylogeny were different between 2010 and 2011 and strongly variable in 2011. This difference in variability corresponded with a highly variable ratio of eukaryotic to bacterial sequences (0.3 to 5.5), reflecting transient algal blooms in 2011 that were absent in 2010. The similarity between metatranscriptomes changed at a lower rate during the transition from oxic to anoxic waters than after the return to oxic conditions. Transcripts related to photosynthesis and low-affinity cytochrome oxidases were significantly higher in shallow than in deep waters, while in deep water genes involved in anaerobic metabolism, particularly sulfate reduction, succinyl coenzyme A (succinyl-CoA)-to-propionyl-CoA conversion, and menaquinone synthesis, were enriched relative to in shallow waters. Expected transitions in metabolism between oxic and anoxic deep waters were reflected in elevated levels of anaerobic respiratory reductases and utilization of propenediol and acetoin. The percentage of archaeal transcripts increased in both years in late summer (from 0.1 to 4.4% of all transcripts in 2010 and from 0.1 to 6.2% in 2011). Denitrification-related genes were expressed in a predicted pattern during the oxic-anoxic transition. Overall, our data suggest that Chesapeake Bay microbial assemblages express gene suites differently in shallow and deep waters and that differences in deep waters reflect variable redox states. PMID- 24162578 TI - A distinct model of synergism between a processive endocellulase (TfCel9A) and an exocellulase (TfCel48A) from Thermobifida fusca. AB - Lignocellulosic biomass is digested in nature by the synergistic activities of enzymes with complementary properties, and understanding synergistic interactions will improve the efficiency of industrial biomass use for sustainable fuels and chemicals. Cel9A and Cel48A from a model bacterium, Thermobifida fusca (TfCel9A and TfCel48A, respectively), are two cellulases with different properties and have previously been shown to synergize well with each other. TfCel9A is a processive endocellulase with relatively high activity on crystalline cellulose. TfCel48A is a reducing end-directed exocellulase with very low activity on crystalline cellulose. Neither enzyme fits its respective role in the classical synergism model of enzymatic cellulose digestion. Using the results of time course, endpoint, and sequential addition activity assays, we propose a model of synergistic cooperation between the two cellulases. TfCel9A is most effective on fresh bacterial cellulose with a presumably uniform surface at the molecular level. Its processive activity likely erodes the surface and thus reduces its own activity. TfCel48A is able to hydrolyze the TfCel9A-modified substrate efficiently and replenish the uniform surface required by TfCel9A, creating a feedback mechanism. The model of synergistic interactions is comparable to an earlier proposed model for Trichoderma reesei Cel7A and Cel7B, but the roles of endo- and exocellulases are reversed, a finding which suggests that bacteria and fungi may have evolved different approaches to efficient biomass degradation. PMID- 24162579 TI - Critical assessment of glyco- and phospholipid separation by using silica chromatography. AB - Phospholipid-derived fatty acids (PLFAs) are commonly used to characterize microbial communities in situ and the phylogenetic positions of newly isolated microorganisms. PLFAs are obtained through separation of phospholipids from glycolipids and neutral lipids using silica column chromatography. We evaluated the performance of this separation method for the first time using direct detection of intact polar lipids (IPLs) with high-performance liquid chromatography-mass spectrometry (HPLC-MS). We show that under either standard or modified conditions, the phospholipid fraction contains not only phospholipids but also other lipid classes such as glycolipids, betaine lipids, and sulfoquinovosyldiacylglycerols. Thus, commonly reported PLFA compositions likely are not derived purely from phospholipids and perhaps may not be representative of fatty acids present in living microbes. PMID- 24162580 TI - Diversity of Rickettsiales in the microbiome of the lone star tick, Amblyomma americanum. AB - Ticks are important vectors for many emerging pathogens. However, they are also infected with many symbionts and commensals, often competing for the same niches. In this paper, we characterize the microbiome of Amblyomma americanum (Acari: Ixodidae), the lone star tick, in order to better understand the evolutionary relationships between pathogens and nonpathogens. Multitag pyrosequencing of prokaryotic 16S rRNA genes (16S rRNA) was performed on 20 lone star ticks (including males, females, and nymphs). Pyrosequencing of the rickettsial sca0 gene (also known as ompA or rompA) was performed on six ticks. Female ticks had less diverse microbiomes than males and nymphs, with greater population densities of Rickettsiales. The most common members of Rickettsiales were "Candidatus Rickettsia amblyommii" and "Candidatus Midichloria mitochondrii." "Ca. Rickettsia amblyommii" was 2.6-fold more common in females than males, and there was no sequence diversity in the sca0 gene. These results are consistent with a predominantly vertical transmission pattern for "Ca. Rickettsia amblyommii." PMID- 24162581 TI - Answer to first reply to "Delayed surgery in displaced paediatric supracondylar fractures: a safe approach? Results from a large UK tertiary paediatric trauma centre". PMID- 24162582 TI - Antegrade intramedullary nailing for fifth metacarpal neck fractures: a systematic review and meta-analysis. AB - PURPOSE: We investigated the outcomes of the antegrade intramedullary nailing (AIMN) compared to other surgical modalities in the treatment for fifth metacarpal neck fractures via a systematic review. METHODS: Pain, functional scores, grip strength, total active motion (TAM), the range of motion (ROM) of the fifth metacarpal joint, complications and patient satisfaction were set to be the primary outcomes. The data were evaluated using a modified version of the Cochrane Collaboration tool. RESULTS: We identified four studies, comprising 163 participants, which met the inclusion criteria. Meta-analyses showed that (a) AIMN demonstrated significantly better results in relation to GS at 12 months (p < 0.0001), TAM (p = 0.01) and ROM of the fifth finger (p = 0.0001); (b) AIMN technique yielded significantly lesser residual angulation at the site of fracture (p = 0.05); (c) AIMN significantly demonstrated fewer complications (p = 0.05); (d) there was a trend for better pain scores when using AIMN. CONCLUSIONS: Though the amount of evidence was derived from just four small sample-sized studies, our findings suggested that the AIMN technique could have some advantages over the use of plates or other types of pinning in the treatment for the fifth metacarpal neck fractures. We highlighted the need for a standardization of the outcomes and their corresponding units related to this specific type of fracture. Editors and reviewers should incite authors to provide the standard deviation values for the reported means. LEVEL OF EVIDENCE: Therapeutic II. PMID- 24162583 TI - Influencing factors of functional result and bone union in tibiotalocalcaneal arthrodesis with intramedullary locking nail: a retrospective series of 30 cases. AB - BACKGROUND: Initially considered as an established salvage procedure for tibiotalocalcaneal arthrodesis (TTCA), intramedullary nailing indications have expanded as evidenced in recent literature. We have tried to identify factors influencing functional result and bone union. METHODS: In a retrospective study, 30 patients were treated by a TTCA between January 2006 and November 2011. Indications, operative technique, bone fusion, X-rays and functional result [American Foot and Ankle Society (AOFAS) and short-form health survey (SF-36) scores] before and after surgery were registered and analyzed. RESULTS: Thirty cases of TTCA were included. The patient's average age was 52 (range 24-90). Union rate was 86% for the tibiotalar joint and 74% for the subtalar joint with an average follow-up of 25.4 months (8-67). The mean AOFAS' score significantly improved (from 37 to 59) as the SF-36' score. Global complication rate was about 56%. It has not been possible to identify factors significantly influencing bone fusion or functional results. All septic cases achieved fusion without any septic resurgence. CONCLUSION: Retrograde intramedullary nailing in TTCA is an effective technique, which allows good clinical results even in case of septic history of the patient. Fusion rate and functional results were not significantly influenced by any of the factors examined in this study. PMID- 24162584 TI - The reinforcement of a C2 laminar screw by a C2 laminar hook as an anchor of occipito-C2 fusion. AB - Although a C1-C2 transarticular screw (TAS) or a C2 pedicle screw (PS) is the most rigid anchor for C2, each entails the risk of vertebral artery injury. Although a C2 laminar screw (LS) is often used as an alternative anchor in such cases, its anchoring strength may be inadequate. We introduce a technical tip, in which a C2 LS is reinforced by a C2 infralaminar hook without extending the fusion range. Six patients, for whom a unilateral TAS or C2 PS was risky or impossible, were treated with O-C2 fusion using this technique. The post operative course of each patient was uneventful. Bone union was achieved in all patients, except one who died of indifferent disease before the confirmation of bone union by computed tomography. This method would be a safe and non-technical demanding option when the placement of a TAS or PS is risky or impossible. PMID- 24162585 TI - Adult-onset deletion of Pten increases islet mass and beta cell proliferation in mice. AB - AIMS/HYPOTHESIS: Adult beta cells have a diminished ability to proliferate. Phosphatase and tensin homologue (PTEN) is a lipid phosphatase that antagonises the function of the mitogenic phosphatidylinositol 3-kinase (PI3K) pathway. The objective of this study was to understand the role of PTEN and PI3K signalling in the maintenance of beta cells postnatally. METHODS: We developed a Pten (lox/lox); Rosa26 (lacZ); RIP-CreER (+) model that permitted us to induce Pten deletion by treatment with tamoxifen in mature animals. We evaluated islet mass and function as well as beta cell proliferation in 3- and 12-month-old mice treated with tamoxifen (Pten deleted) vs mice treated with vehicle (Pten control). RESULTS: Deletion of Pten in juvenile (3-month-old) beta cells significantly induced their proliferation and increased islet mass. The expansion of islet mass occurred concomitantly with the enhanced ability of the Pten deleted mice to maintain euglycaemia in response to streptozotocin treatment. In older mice (>12 months of age), deletion of Pten similarly increased islet mass and beta cell proliferation. This novel finding suggests that PTEN-regulated mechanisms may override the age-onset diminished ability of beta cells to respond to mitogenic stimulation. We also found that proteins regulating G1/S cell-cycle transition, such as cyclin D1, cyclin D2, p27 and p16, were altered when PTEN was lost, suggesting that they may play a role in PTEN/PI3K-regulated beta cell proliferation in adult tissue. CONCLUSIONS/INTERPRETATION: The signals regulated by the PTEN/PI3K pathway are important for postnatal maintenance of beta cells and regulation of their proliferation in adult tissues. PMID- 24162586 TI - Association between maternal folate concentrations during pregnancy and insulin resistance in Indian children. AB - AIMS/HYPOTHESIS: In an Indian birth cohort, higher maternal homocysteine concentration in pregnancy was associated with lower birthweight of the offspring. Lower maternal vitamin B12 and higher folate concentrations were associated with higher offspring insulin resistance. Disordered one-carbon metabolism during early development may increase later metabolic risk. We explored these associations in another birth cohort in India at three age points. METHODS: We measured plasma vitamin B12, folate and homocysteine concentrations at 30 +/- 2 weeks' gestation in 654 women who delivered at one hospital. Neonatal anthropometry was recorded, and the children's glucose and insulin concentrations were measured at 5, 9.5 and 13.5 years of age. Insulin resistance was estimated using HOMA of insulin resistance (HOMA-IR). RESULTS: Maternal homocysteine concentrations were inversely associated with all neonatal anthropometric measurements (p < 0.05), and positively associated with glucose concentrations in the children at 5 (30 min; p = 0.007) and 9.5 years of age (120 min; p = 0.02). Higher maternal folate concentrations were associated with higher HOMA-IR in the children at 9.5 (p = 0.03) and 13.5 years of age (p = 0.03). Maternal vitamin B12 concentrations were unrelated to offspring outcomes. CONCLUSIONS/INTERPRETATION: Maternal vitamin B12 status did not predict insulin resistance in our cohort. However, associations of maternal homocysteine and folate concentrations with birth size, and with childhood insulin resistance and glycaemia in the offspring, suggest a role for nutritionally driven disturbances in one-carbon metabolism in fetal programming of diabetes. PMID- 24162588 TI - Localization precision of stochastic optical localization nanoscopy using single frames. AB - The Cramer-Rao lower bound (CRLB) on localization precision of unbiased estimators is analyzed for stochastic optical localization nanoscopy that localizes emitters frame by frame independently. It is found that the CRLB is a function of the mean number of detected photons per emitter, signal to Poisson noise ratio, signal to Gaussian noise ratio, point spread function (PSF), pixel size, and relationship of emitter locations. With a slight and practical approximation, effect of Gaussian noise is equivalent to increasing the mean photon count of Poisson noise by a number equal to the variance of Gaussian noise. Numerical examples demonstrate that the CRLB of emitters located on a curve increase fast as the distance of adjacent emitters increases. The mean CRLB of randomly uniformly distributed emitters in both two-dimensional and three dimensional imaging increases exponentially fast as the emitter density increases. The effects of PSF, standard deviation of PSF, mean number of detected photons per emitter, signal to noise ratio, axial thickness, and pixel size on the CRLB are also numerically investigated. The analytical and numerical results provide a guideline for the design of location estimators and a benchmark for the achievable localization precision of stochastic optical localization nanoscopy. PMID- 24162589 TI - A new eigenfunction spatial analysis describing population genetic structure. AB - Several methods of spatial analyses have been proposed to infer the relative importance of evolutionary processes on genetic population structure. Here we show how a new eigenfunction spatial analysis can be used to model spatial patterns in genetic data. Considering a sample of n local populations, the method starts by modeling the response variable (allele frequencies or phenotypic variation) against the eigenvectors sequentially extracted from a geographic distance matrix (n * n). The relationship between the coefficient of determination (R(2)) of the models and the cumulative eigenvalues, which we named the spatial signal-representation (SSR) curve, can be more efficient than Moran's I correlograms in describing different patterns. The SSR curve was also applied to simulated data (under distinct scenarios of population differentiation) and to analyze spatial patterns in alleles from microsatellite data for 25 local populations of Dipteryx alata, a tree species endemic to the Brazilian Cerrado. The SSR curves are consistent with previous phylogeographical patterns of the species, revealing combined effects of isolation-by-distance and range expansion. Our analyses demonstrate that the SSR curve is a useful exploratory tool for describing spatial patterns of genetic variability and for selecting spatial eigenvectors for models aiming to explain spatial responses to environmental variables and landscape features. PMID- 24162587 TI - Glyoxalase-1 overexpression reduces endothelial dysfunction and attenuates early renal impairment in a rat model of diabetes. AB - AIMS/HYPOTHESIS: In diabetes, advanced glycation end-products (AGEs) and the AGE precursor methylglyoxal (MGO) are associated with endothelial dysfunction and the development of microvascular complications. In this study we used a rat model of diabetes, in which rats transgenically overexpressed the MGO-detoxifying enzyme glyoxalase-I (GLO-I), to determine the impact of intracellular glycation on vascular function and the development of early renal changes in diabetes. METHODS: Wild-type and Glo1-overexpressing rats were rendered diabetic for a period of 24 weeks by intravenous injection of streptozotocin. Mesenteric arteries were isolated to study ex vivo vascular reactivity with a wire myograph and kidneys were processed for histological examination. Glycation was determined by mass spectrometry and immunohistochemistry. Markers for inflammation, endothelium dysfunction and renal dysfunction were measured with ELISA-based techniques. RESULTS: Diabetes-induced formation of AGEs in mesenteric arteries and endothelial dysfunction were reduced by Glo1 overexpression. Despite the absence of advanced nephrotic lesions, early markers of renal dysfunction (i.e. increased glomerular volume, decreased podocyte number and diabetes-induced elevation of urinary markers albumin, osteopontin, kidney-inflammation-molecule-1 and nephrin) were attenuated by Glo1 overexpression. In line with this, downregulation of Glo1 in cultured endothelial cells resulted in increased expression of inflammation and endothelium dysfunction markers. In fully differentiated cultured podocytes incubation with MGO resulted in apoptosis. CONCLUSIONS/INTERPRETATION: This study shows that effective regulation of the GLO I enzyme is important in the prevention of vascular intracellular glycation, endothelial dysfunction and early renal impairment in experimental diabetes. Modulating the GLO-I pathway therefore may provide a novel approach to prevent vascular complications in diabetes. PMID- 24162590 TI - Fatty acid ethyl ester synthase inhibition ameliorates ethanol-induced Ca2+ dependent mitochondrial dysfunction and acute pancreatitis. AB - OBJECTIVE: Non-oxidative metabolism of ethanol (NOME) produces fatty acid ethyl esters (FAEEs) via carboxylester lipase (CEL) and other enzyme action implicated in mitochondrial injury and acute pancreatitis (AP). This study investigated the relative importance of oxidative and non-oxidative pathways in mitochondrial dysfunction, pancreatic damage and development of alcoholic AP, and whether deleterious effects of NOME are preventable. DESIGN: Intracellular calcium ([Ca(2+)](C)), NAD(P)H, mitochondrial membrane potential and activation of apoptotic and necrotic cell death pathways were examined in isolated pancreatic acinar cells in response to ethanol and/or palmitoleic acid (POA) in the presence or absence of 4-methylpyrazole (4-MP) to inhibit oxidative metabolism. A novel in vivo model of alcoholic AP induced by intraperitoneal administration of ethanol and POA was developed to assess the effects of manipulating alcohol metabolism. RESULTS: Inhibition of OME with 4-MP converted predominantly transient [Ca(2+)](C) rises induced by low ethanol/POA combination to sustained elevations, with concurrent mitochondrial depolarisation, fall of NAD(P)H and cellular necrosis in vitro. All effects were prevented by 3-benzyl-6-chloro-2-pyrone (3 BCP), a CEL inhibitor. 3-BCP also significantly inhibited rises of pancreatic FAEE in vivo and ameliorated acute pancreatic damage and inflammation induced by administration of ethanol and POA to mice. CONCLUSIONS: A combination of low ethanol and fatty acid that did not exert deleterious effects per se became toxic when oxidative metabolism was inhibited. The in vitro and in vivo damage was markedly inhibited by blockade of CEL, indicating the potential for development of specific therapy for treatment of alcoholic AP via inhibition of FAEE generation. PMID- 24162592 TI - Oral antiviral therapy for hepatitis B: the case of besifovir, a new kid on the block with a long way to go. PMID- 24162593 TI - HBsAg seroclearance after nucleoside analogue therapy in patients with chronic hepatitis B: clinical outcomes and durability. AB - OBJECTIVE: Little is known about the long-term clinical outcome and durability of HBsAg seroclearance following nucleos(t)ide analogue (NUC) therapy in patients with chronic hepatitis B (CHB). DESIGN: During a median follow-up period of 6 years (33 567 patient-years) of 5409 CHB patients who were initially treated with lamivudine or entecavir, a total of 110 achieved HBsAg seroclearance (0.33% annual seroclearance rate) and were included in this study. RESULTS: Baseline alanine aminotransferase (ALT) level >5 times of upper limit of normal was associated with higher probability of HBsAg seroclearance (HR 1.80, p<0.01), while HBeAg positivity (HR 0.46, p<0.01), high HBV DNA level (log(10) IU/mL; HR 0.61, p<0.01), and cirrhosis (HR 0.48, p<0.01) were inversely associated with the probability of HBsAg seroclearance by multivariable analysis. During follow-up for 287 patient-years after HBsAg seroclearance, only two patients with baseline cirrhosis developed hepatocellular carcinoma (HCC) or died (0.7% annual risk), which was of a significantly lower rate compared with propensity score-matched patients without HBsAg seroclearance (HR 0.09, p<0.01). HBsAg reversion and/or HBV DNA reversion occurred in 18 patients, most of which were transient with extremely low serum levels of HBsAg (0.05-1.00 IU/mL) and HBV DNA (17-1818 IU/mL). None required retreatment. The cumulative probability of anti-HBs seroconversion (detection of anti-HBs) at 4 years was 67.4% by Kaplan-Meier analysis. Selection for lamivudine-resistance HBV mutants during treatment was not associated with composite reversion (p=0.66). CONCLUSIONS: HBsAg seroclearance achieved after NUC treatment was associated with favourable clinical outcomes and was durable in most cases during long-term follow-up. PMID- 24162594 TI - Naphtho[1,2-b]furan-4,5-dione inhibits MDA-MB-231 cell migration and invasion by suppressing Src-mediated signaling pathways. AB - Naphtho[1,2-b]furan-4,5-dione (NFD), a bioactive component of Avicennia marina, has been demonstrated to display anti-cancer activity. Breast cancer is a highly malignant carcinoma and most deaths of breast cancer are caused by metastasis. In this study, we showed that NFD blocked migration and invasion of MDA-MB-231 breast cancer cells without affecting apoptosis or growth arrest. NFD caused significant block of Src kinase activity in MDA-MB-231 cells. Moreover, NFD treatment was correlated with reduced phosphorylation of FAK at Tyr 576/577, 861 and 925 sites, p130(Cas) at Tyr 410, and paxillin at Tyr 118. NFD also suppressed the activation of phosphatidylinositol 3-kinase/Akt. Consistent with inhibition of these signaling pathways and invasion, NFD reduced the expression of matrix metalloproteinase-9. Furthermore, Src antagonist PP2 caused a significant decrease in the phosphorylation of FAK, p130(Cas), paxillin, and PI3K/Akt. Our findings provide evidences that NFD inhibits Src-mediated signaling pathways involved in controlling breast cancer migration and invasion, suggesting that it has a therapeutic potential in breast cancer treatment. PMID- 24162595 TI - [Mechanism of bone mass regulation by mechanical stress]. AB - Osteocytes establish an extensive intercellular and extracellular communication system via gap junction-coupled cell processes and canaliculi, through which cell processes pass throughout bone, and the communication system is extended to osteoblasts on the bone surface. The lacunocanalicular network formed by osteocytes is thought to be an ideal mechanosensory system and suitable for mechanotransduction, by which mechanical energy is converted into electrical and/or biochemical signals. The function of osteocytes cannot be estimated based on the events caused by osteocyte death, because apoptotic osteocytes are not phagocytosed, undergo secondary necrosis, and trigger a process of repair to replace the damaged bone. The analysis of the mice, in which both intercellular and extracellular communication systems are disturbed, shows that the osteocyte network mildly inhibits bone formation and mildly stimulates bone resorption in physiological condition. In unloaded condition, the functions of the osteocyte network are augmented, and it strongly inhibits bone formation and strongly stimulates bone resorption, at least in part, through the induction of Sost in osteocytes and Rankl in osteoblasts. PMID- 24162596 TI - [Endoplasmic reticulum stress response in osteogenesis]. AB - Various cellular conditions such as synthesis of abundant proteins, expressions of mutant proteins and oxidative stress lead to accumulation of unfolded or misfolded proteins in the endoplasmic reticulum (ER) lumen. This type of stress is called ER stress. The excessive ER stress causes cellular damages followed by apoptosis. When ER stress occurs, cells are activated ER stress response (unfolded protein response) to avoid cellular damages. Recently, it has been clear that ER stress response plays crucial roles not only in cell survival after ER stress but also in regulating various cellular functions and tissue formations. In particular, ER stress and ER stress response regulate protein quality control, secretory protein production, and smooth secretion of proteins in the cells such as osteoblasts which synthesize and secrete enormous matrix proteins. PMID- 24162597 TI - [Role of mitochondria in osteoclast function]. AB - Mitochondria, membrane-enclosed structures found in most eukaryotic cells, generate most of the cell's supply of ATP, used as a source of chemical energy. In addition to supplying cellular energy, mitochondria are involved in signaling, cellular differentiation, cell death, and the aging process. Osteoclasts, highly differentiated bone-resorbing cells of hematopoietic origin, have two conflicting tendencies : a lower capacity to survive and a higher capacity to execute energy consuming activities such as bone resorption. We here highlight the role of mitochondria in osteoclast function. Recent studies have revealed that ATP depletion following Tfam (mitochondrial transcription factor A) deficiency leads to increased bone-resorbing activity despite accelerated apoptosis, and the release of endogenous ATP negatively regulates osteoclast function through an autocrine/paracrine feedback loop. These findings provide evidence for a previously unknown mechanism by which mitochondria regulate the inverse correlation between osteoclast survival and bone resorption. PMID- 24162598 TI - [Modulation of transcriptional regulation during bone and cartilage development and their disease]. AB - Genetic and biochemical studies have identified transcription factors critical and specific for bone and cartilage development. More recent studies revealed the molecular mechanisms how these transcription factors regulate bone and cartilage development. Especially, we appreciate recent advances in molecular function of the complex assembled by these transcription factors and epigenetic regulation of them. Aging, inflammation, biological stress, and disorder of endocrine system induce several bone and/or cartilage diseases by affecting the transcriptional and epigenetic regulation. In this review, we would like to describe the transcriptional and epigenetic regulation during developmental and pathological stages. In addition, we discuss possible application of these information in regeneration of bone and cartilage. PMID- 24162599 TI - [Stress and cell communication between bone cells]. AB - Bone is constantly renewed by the balanced action of bone formation and bone resorption both of which mainly occur at the bone surface. This restructuring process called "bone remodeling" is important not only for normal bone mass and strength, but also for mineral homeostasis. Bone remodeling is stringently regulated by communication between bone component cells such as osteoclasts, osteoblasts and osteocytes. An imbalance of this process is often linked to various bone diseases. During bone remodeling, resorption by osteoclasts precedes bone formation by osteoblasts. Based on the osteocyte location within the bone matrix and the cellular morphology, it is proposed that osteocytes potentially contribute to the controls of bone remodeling as well as sensing mechanical stress. PMID- 24162600 TI - [Bone diseases caused by impaired glucose and lipid metabolism]. AB - The number of patients with lifestyle-related diseases is rapidly increasing in Japan. Metabolic syndrome caused by abdominal fat accumulation induces diabetes mellitus, dyslipidemia, and hypertension, resulting in an increase in cardiovascular diseases. On the other hand, recent studies have shown that the lifestyle-related diseases are risk factors of osteoporotic fractures. Although it remains still unclear how metabolic disorders affect bone tissue, oxidative stress and/or glycation stress might directly have negative impacts on bone tissue and increase the risk of fractures. In this review, we describe the association of diabetes mellitus and dyslipidemia with the fracture risk through oxidative stress and glycation stress. PMID- 24162601 TI - [Regulation of intracellular signal pathways via sensor proteins by oxidative stress]. AB - It has been known that reactive oxygen species (ROS) control the enzymatic and transcriptional activity of proteins via direct modification of cysteine residues. Hence, oxidation of cysteine thiol could be a vital modulator of signal transduction pathways. These findings indicate that some proteins serve as the sensor proteins highly sensitive to ROS. In this review, I show the relationship between intracellular ROS sensor and the regulation of protein function via oxidation. PMID- 24162602 TI - [Regulation of bone metabolisms by estrogen/estrogen receptors signaling]. AB - Postmenopausal osteoporosis is caused by estrogen deficiency. The precise mechanism was unclear how estrogen maintains bone mass and how estrogen deficiency alters bone metabolism. However, the progress of generation and analyses of estrogen receptoralpha (ERalpha) conditional knockout mice have revealed the pathophysiology of postmenopausal osteoporosis. Here we introduce recent reports related to the estrogen/ERalpha mediated direct and indirect regulations in bone metabolism. PMID- 24162603 TI - [Dynamics of bone resorption analyzed by intravital imaging]. AB - By using conventional methods such as histological analysis, many osteoclasts can be observed in the site of bone destruction. However, how the bone-resorptive functions of mature osteoclasts are controlled in vivo remains unclear. To answer this question, we have originally developed an advanced imaging system for visualizing living bone tissues with intravital multiphoton microscopy. Using this system, we succeeded in visualizing bone resorption of mature osteoclasts in living bone. Here we show the latest data and also discuss the further application of intravital bone imaging. This approach would be quite useful for evaluating novel anti-bone-resorptive drugs in vivo . PMID- 24162604 TI - [Collagen abnormalities and endoplasmic reticulum stress in bone and cartilage]. AB - There are many steps in the post-translational modification of collagen molecules. When abnormality occurs in some step, the unfolded collagen molecules are accumulated in the endoplasmic reticulum (ER) , leading to ER stress. ER stress also occurs downstream of the defective modification of collagen in bone and cartilage. ER stress-induced apoptosis or ER stress response without inducing apoptosis may be associated with the pathogenesis of genetic collagen disorders in bone and cartilage. PMID- 24162605 TI - [Cartilage regeneration using cell reprogramming technologies]. AB - Injuries to articular cartilage do not heal spontaneously, and when left untreated, result in the diffuse degeneration of cartilage. Autologous chondrocyte transplantation has been performed to treat focal articular cartilage defects, but the repaired tissue includes fibrous tissue. Healing with hyaline cartilage has been difficult to achieve. The generation of induced pluripotent stem (iPS) cells has enabled us to rejuvenate somatic cells and provide them with pluripotency. This technology may contribute to producing hyaline cartilage. In addition, fibroblasts can be converted toward chondrogenic cells by directed reprogramming technology. Research aimed at the realization of cartilage regeneration using cell reprogramming technologies is underway. PMID- 24162606 TI - Do natural rubber latex condoms pose a risk to aquatic systems? AB - The presence and potential adverse effects of plastic-polymers in the environment are receiving increasing attention in the popular and scientific press. However, quantifying emissions, exposure and effects of these materials remains a challenge. This paper describes the application of a questionnaire survey to quantify emissions of condom material from the domestic household to the sewage waste stream. Condoms are an important mainstay for birth control and the reduction of sexually transmitted infections. Survey participants were estimated to flush condoms down the toilet 2.96% of the time, and emissions were calculated as 0.99 mg of condom material per person per day. Using information on screening efficiencies at sewage treatment plants, the questionnaire data was combined with a GIS-based water quality model (LF2000-WQX) to predicted environmental concentrations (PEC) in a UK river basin catchment. Annual average PECs of condom material were 0.08-0.2 MUg L(-1), under the model scenario used. To put these PECs into context, rubber latex condom material was degraded in outdoor microcosms. This resulted in the formation of a complex mixture of substances including chemical degradation products and particles in the nano range. The direct effects of the degradation mixture were investigated using two freshwater organisms with different life cycle traits, the water column crustacean Daphnia magna and the sediment-dwelling larval of Chironomus riparius. Ecotoxicity tests investigated both acute and chronic endpoints and were shown to exhibit no toxic effects. This precluded the derivation of a genuine no-effect concentration. Hence, the results suggest that limited risk to invertebrates is associated with latex condom degradation products to the organisms tested. Future studies should extend this risk framework to assess risks of condoms to other taxonomic groups as well as the risks of other polymer materials. PMID- 24162607 TI - Significance of measurable cardiac troponin by high-sensitivity assays in patients with chronic stable heart failure. AB - Biological markers released into the bloodstream by the injured cardiac myocytes have contributed over the years to the diagnosis of acute myocardial infarction. Recent evidence suggests that the measurement of even minute amounts of circulating cardiac contractile proteins may be useful in the clinical assessment of patients with heart failure. Here, we briefly discuss the clinical significance of troponin measurement in chronic heart failure, in light of the availability of a new generation of highly sensitive immunoassays that are changing our understanding and interpretation of this syndrome. PMID- 24162608 TI - Antibiotic treatment of Pseudomonas aeruginosa biofilms stimulates expression of the magnesium transporter gene mgtE. AB - Pseudomonas aeruginosa is a Gram-negative opportunistic pathogen with the capacity to cause serious disease, including chronic biofilm infections in the lungs of cystic fibrosis (CF) patients. These infections are treated with high concentrations of antibiotics. Virulence modulation is an important tool utilized by P. aeruginosa to propagate infection and biofilm formation in the CF airway. Many different virulence modulatory pathways and proteins have been identified, including the magnesium transporter protein MgtE. We have recently found that isogenic deletion of mgtE leads to increased cytotoxicity through effects on the type III secretion system. To explore the role of the CF lung environment in MgtE activity, we investigated mgtE transcriptional regulation following antibiotic treatment. Utilizing quantitative real-time-PCR, we have demonstrated an increase in mgtE transcript levels following antibiotic treatment with most of the 12 antibiotics tested. To begin to determine the regulatory network governing mgtE expression, we screened a transposon-mutant library of P. aeruginosa to look for mutants with potentially altered mgtE activity, using cytotoxicity as a readout. In this screen, we observed that AlgR, which regulates production of the biofilm polysaccharide alginate, alters MgtE-mediated cytotoxicity. This cross-talk between MgtE and AlgR suggests that AlgR is involved in linking external inducing signals (e.g. antibiotics) to mgtE transcription and downstream virulence and biofilm activities. Analysing such interactions may lead to a better understanding of how the CF lung environment shapes P. aeruginosa biofilm infections. PMID- 24162609 TI - Functional and immunological evaluation of two novel proteins of Leptospira spp. AB - This work shows the production and characterization of two novel putative lipoproteins encoded by the genes LIC10645 and LIC10731 identified in the genome sequences of Leptospira interrogans. In silico conservation analysis indicated that the proteins are well conserved among pathogenic leptospiral serovars and species. Recombinant proteins were obtained in Escherichia coli BL21(DE3) Star pLysS strain, purified by metal-affinity chromatography, and used for characterization and immunological evaluations. Recombinant proteins were capable of eliciting a combination of humoral and cellular immune responses in animal models, and could be recognized by antibodies present in human serum samples. The recombinant proteins Lsa44 and Lsa45 were able to bind laminin, and were named Lsa44 and Lsa45 for leptospiral surface adhesins of 44 and 45 kDa, respectively. The attachment to laminin was dose-responsive with KD values of 108.21 and 250.38 nM for Lsa44 and Lsa45, respectively. Moreover, these proteins interact with plasminogen (PLG) with KD values of 53.56 and 36.80 nM, respectively. PLG bound to the recombinant proteins could be converted to plasmin (PLA) in the presence of an activator. Cellular localization assays suggested that the Lsa44 and Lsa45 were surface-exposed. These are versatile proteins capable of interacting with laminin and PLG/PLA, and hence could mediate bacterial adhesion and contribute to tissue penetration. PMID- 24162610 TI - Short-term sonic-hedgehog gene therapy to mitigate myelosuppression in highly irradiated monkeys: hype or reality? AB - The protection of hematopoietic stem and progenitor cells and their environment is required for recovery from radiation-induced (RI) myelosuppression. To achieve this goal, we propose a new gene therapy strategy based on local and short-term synthesis and expression of Sonic hedgehog morphogene (Shh) at the niche level. We investigated the hematopoietic response of 8 Gy gamma-irradiated monkeys to a single intra-osseous injection of multipotent mesenchymal stem cells (adipocyte derived stem cells/ASC) transduced with a Shh pIRES2 plasmid (3+/-0.4 * 10(6) cells/kg on day (D) 2; n=4). Control animals were injected with mock-ASCs (n=4). Two controls died from radiation toxicity on D19 and D196, whereas all Shh-ASC treated monkeys fully recovered. Thrombocytopenia (4.75+/-1.8 days versus 10+/ 2.2 days, platelet count <20 * 10(9)/L), neutropenia (14.2 +/-1 days versus 17.7 +/-2.6 days, ANC count<0.5 * 10(9)/L) and anemia (15.5 +/-3.6 days versus 50.7 +/ 31 days, Hb less than 10 g/dL) duration were reduced in Shh-ASC animals. Areas under the curve of platelets (P<0.05), ANCs (P=0.06) and RBC/Hb between D0 and D30 were higher in Shh-ASC injected animals. Globally this study suggests that Shh may represent a new factor to counteract RI-myelosuppression. PMID- 24162611 TI - Survey of CMV management in pediatric allogeneic HSCT programs, on behalf of the inborn errors, infectious diseases and pediatric diseases working parties of EBMT. AB - Human CMV infection is a frequent complication after HSC in children with remarkable morbidity and mortality. Antiviral drugs are relatively efficient but have numerous side effects. They are used as prophylactic, pre-emptive or therapeutic medicines. It is still a matter of debate which option is the best strategy. No uniform procedure has emerged regarding these three options, and new immunologic tools have raised more questions for physicians. To assess the current practice in the management of CMV infection, we sent a questionnaire to the EBMT centers performing hematopoietic SCT (HSCT) in children. Fifty-six out of 196 responded to the questionnaire (28.5%). Quantitative PCR was the most common monitoring tool (44/56). Only 4/56 centers use the pp65 antigenemia alone. All centers used pre-emptive strategy (56/56). 21/56 centers also used prophylactic measures, 13/21 after analysis of donor/receptor serologic status. Ganciclovir was the most common first-line agent for CMV disease (55/56). The most common dose and duration for induction treatment were 5 mg/kg bid (47/55) for 14 days (20/55). There is no uniform procedure for researching resistance strain, antiviral second-line therapy or cell therapy. A harmonization process should enable sound prospective trials to improve prevention, control and cure of CMV disease in children and adolescents. PMID- 24162612 TI - Acute GVHD prophylaxis with standard-dose, micro-dose or no MTX after fludarabine/melphalan conditioning. AB - MTX is a standard component of acute GVHD prophylaxis. However, its use can be limited by toxicity. On the basis of disease risk, we prospectively assigned 132 consecutive patients from January 2005 to February 2011 undergoing first allogeneic hematopoietic cell transplant after conditioning with fludarabine and melphalan to acute GVHD prophylaxis with tacrolimus/MTX (TAC/MTX, N=22), TAC/micro-dose MTX/mycophenolate mofetil (TAC/MUMTX/MMF, N=78) or TAC/MMF (TAC/MMF, N=32), to optimize acute GVHD prevention and decrease mortality. The median (range) follow-up was 24 (0.8-60) months. The median patient ages (range) were 37 (23-63), 56 (20-68) and 54 (22-68) years (P<0.0001) for TAC/MTX, TAC/MUMTX/MMF and TAC/MMF, respectively. The 100-day cumulative incidences of grade III-IV acute GVHD were 19, 23 and 49% (P=0.015), respectively. The cumulative incidences of severe chronic GVHD at 1 year were 38, 29 and 79% (P<0.001), respectively. Regimen-related toxicities were not significantly different among the three prophylaxis regimens. PFS and OS were equivalent between the TAC/MTX and TAC/MUMTX/MMF arms despite significantly older patients in the latter arm, and both had superior PFS and OS than the TAC/MMF arm. Acute GVHD prophylaxis with TAC/MUMTX/MMF is as effective as TAC/MTX and superior to TAC/MMF. PMID- 24162591 TI - Risk of new or recurrent cancer under immunosuppressive therapy in patients with IBD and previous cancer. AB - OBJECTIVE: To explore the risk of new or recurrent cancer among patients with IBD and previous cancer, exposed or not to immunosuppressants. DESIGN: Among the 17 047 patients of the CESAME prospective observational cohort who were enrolled from May 2004 to June 2005, and followed-up until December 2007, we identified 405 patients with cancer diagnosed previous to study entry. We calculated the rates of incident cancer in patients with or without previous cancer, and we assessed by survival analysis and nested case-control study the impact of immunosuppressants on the risk of incident new or recurrent cancer in patients with previous cancer. RESULTS: The rate of incident cancer was 21.1/1000 patient years (PY) and 6.1/1000 PY in patients with and without previous cancer, respectively. The multivariate-adjusted HR of incident cancer between patients with and without previous cancer was 1.9 (95% CI 1.2 to 3.0, p=0.003). Among patients with previous cancer, the rates of new and recurrent cancers were, respectively, 13.2/1000 PY and 6.0/1000 PY in the 312 patients who were not taking immunosuppressant at the time of study entry, and 23.1/1000 PY and 3.9/1000 PY in the 93 patients treated with immunosuppressants at study entry. There was no significant association between the exposure to immunosuppressants and the risk of new or recurrent cancer. CONCLUSIONS: Patients with IBD with a history of cancer are at increased risk of developing any (new or recurrent) cancer, with a predominant incidence of new cancers. Treatment with immunosuppressants has no overall major impact per se on this risk. PMID- 24162614 TI - Perceptions of Male Circumcision among Married Couples in Rural Malawi. AB - Voluntary medical male circumcision (VMMC) is being suggested as an essential HIV prevention strategy in high-prevalence areas. These analyses reflect data collected from 360 married couples, 50% of which included a circumcised husband and the other 50% uncircumcised, in rural Malawi. Regardless of their circumcision status, men were more likely to perceive that being circumcised was less painful than having a tooth pulled, giving birth, and having malaria. Men reported having the same sexual pleasure regardless of the circumcision status, while women were 2.0 times more likely to report greater sexual pleasure with a circumcised partner. Participants identified the medical benefits of VMMC and highlighted the potential personal benefits of VMMC. As VMMC has become a promising method of HIV prevention, this study revealed opportunities for intervention development to increase rates of VMMC among men. PMID- 24162613 TI - Favorable impact of pre-transplant ATG on outcomes of reduced-intensity hematopoietic cell transplants from partially mismatched unrelated donors. AB - Reduced-intensity conditioning (RIC) permits allogeneic hematopoietic progenitor cell transplantation in patients who would not be considered candidates for transplantation using a myeloablative preparative regimen because of age, comorbidities or prior therapy. In the setting of myeloablative transplantation, use of antithymocyte globulin (ATG) can reduce the risk of GVHD without negatively affecting transplant outcomes; however, limited data exist on the impact of ATG in the setting of RIC, particularly when there is HLA-mismatch. We performed a retrospective analysis of 85 patients who received unrelated donor transplants at our institution for hematologic malignancies following conditioning with fludarabine and melphalan (FluMel), with or without rabbit ATG (6 mg/kg). ATG was targeted to patients receiving HLA-mismatched grafts. With a median follow-up of 36 months, those receiving ATG and a mismatched graft had similar rates of acute and chronic GVHD, relapse, and similar OS compared with those receiving HLA-matched grafts without ATG. In a multivariate analysis, HLA mismatched donor was not associated with a decrement in OS. We conclude that this intermediate dose of ATG is effective in preventing severe GVHD in the setting of HLA-mismatch, without undue compromise of the graft versus tumor effects on which RIC transplants depend. PMID- 24162615 TI - Welfare Homes for Patients Living with HIV/AIDS in Andalusia. AB - AIMS: To study the AIDS welfare homes (AWHs) in Andalusia, assess their resources and the services provided, and describe the characteristics of their residents. PATIENTS AND METHODS: Cross-sectional, observational study; an interview questionnaire technique was used with the managers and the residents of the AWHs. RESULTS: A total of 7 AWHs and 96 residents were included; 32% of the staff were health care workers and 45.5% volunteers. The occupancy rate was 86% (2007) and 96% (2008). Residents' characteristics: mean age 45.6 years, 73% male, 92% with at least 1 AIDS-defining disease, median Karnofsky index 60 (50-80), and median Barthel index 80 (40-100). Half the residents had physical sequelae and 31% mental sequelae. CONCLUSION: The AWHs perform an important role in the care of certain types of patients with HIV infection. They require human and material resources to be able to tackle the immense difficulties associated with this group of patients. PMID- 24162616 TI - Outcomes of a Postexposure Prophylaxis Program at the Korle-Bu Teaching Hospital in Ghana: A Retrospective Cohort Study. AB - The risk for occupational exposure to HIV is a serious public health problem that is well characterized in the developed world, but less so in the developing countries such as Ghana. This study was undertaken to examine the characteristics of occupational exposure to HIV and the utilization of a risk assessment system (RAS)-based postexposure prophylaxis (PEP) among health care workers (HCWs) and health care students (HCSs) in the Korle-Bu Teaching Hospital (KBTH). During the study period (January 2005-December 2010), a total of 260 and 35 exposures were reported by HCWs and HCSs, respectively. Ward attendants reported the highest incidence rate of 6.46 of 100 person-years (P-Y). The incidence of high-risk exposures was 0.33 of 100 P-Y (n = 65); 60.0% occurred during a procedure of disposing of a needle and 24.6% during a cannula insertion. A total of 289 of the 295 individuals were administered PEP, of which 181 (62.6%) completed the 6-month follow-up testing schedule and none sero-converted. This shows that with a good RAS in place, it is possible to deploy an effective PEP program in a typical African teaching hospital like the KBTH in Accra, Ghana. PMID- 24162617 TI - HIV-associated thromboembolic phenomenon due to protein C deficiency. AB - HIV-infected individuals are at a high risk of developing arterial and venous thromboembolism. Opportunistic infections, protease inhibitors, low CD4 count, antiphospholipid antibodies, protein S, and protein C deficiencies are some important risk factors associated with it. However, thromboembolic phenomenon due to protein C deficiency has been rarely reported. We report a case of a 12-year old girl with facial palsy due to middle cerebral artery infarct because of HIV infection and associated protein C deficiency. PMID- 24162619 TI - Are pediatric brain tumors on the rise in the USA? Significant incidence and survival findings from the SEER database analysis. AB - INTRODUCTION: Central nervous system tumors are the second most common form of cancer in children between the ages of 1 and 19 years. We aimed to provide the most recent data on the incidence and survival of these tumors in the USA and to assess the literature. METHODS: Frequency, rates, and survival sessions were calculated using the November 2008 submission for the US Surveillance Epidemiology and End Results Program. Data were collected and analyzed for children and adolescents aged 1 to 19 years with primary brain tumors. RESULTS: We found that the incidence rate of all pediatric brain tumors has been on a gradual but steady increase from 1973 to 2008 (p < 0.001). The average annual increase was 1.37 %. Our survival analysis of the individual tumors revealed that the 5-year overall survival for children diagnosed between 1974 and 1978 with medulloblastoma was 43.7 %. However, this increased to 62.8 % for children diagnosed between 1999 and 2003. A similar survival trend was also observed when all the other pediatric brain cancer histologies were collectively analyzed (p < 0.001). CONCLUSIONS: From our study, we can conclude that contrary to previous reports indicating a plateau in the incidence rates of pediatric brain tumors since the mid-1980s, there has been an increase from 1973 to 2008. Potential causes include environmental carcinogens, but more research is needed to investigate the factors behind this sustained rise in incidence over the years. PMID- 24162618 TI - Pediatric intracranial arachnoid cysts: comparative effectiveness of surgical treatment options. AB - PURPOSE: A variety of surgical approaches for the treatment of pediatric intracranial arachnoid cysts exist. In an effort to identify the optimal surgical treatment for this disorder, we developed a decision analytic model to evaluate outcomes of four surgical approaches in children. These included open craniotomy for cyst excision, open craniotomy for cyst fenestration, endoscopic cyst fenestration, and cystoperitoneal shunting. METHODS: Pooled data were used to create evidence tables, from which we calculated incidence, relative risks, and summary outcomes in quality-adjusted life years (QALYs) for the four surgical treatments. Our study incorporated data up to 5 years postsurgery. RESULTS: We analyzed 1,324 cases from 36 case series. There were no significant differences in outcome among the four surgical strategies. The QALYs (maximum of 5) for surgical approaches resulted in a range from 4.79 (for open craniotomy and excision) to 4.92 (for endoscopic fenestration). CONCLUSIONS: Overall quality of life is comparable between patients undergoing open craniotomy for cyst excision or fenestration, endoscopic fenestration, and cystoperitoneal shunting up to 5 years after surgery. While each approach offers unique advantages and disadvantages, an individualized treatment strategy should be employed in the setting of surgical outcome equipoise. PMID- 24162620 TI - Flowering cycles of woody bamboos native to southern South America. AB - Neotropical woody bamboos range from northern Mexico to southern Argentina and Chile. The most interesting aspect of bamboo biology is their flowering habit. The species that are the most intriguing are those that manifest a cyclic pattern of gregarious flowering after long vegetative periods. The flowering cycle has been described in very few species. The goal was to identify mass flowering events of woody bamboo species native to Argentina and neighboring areas, and to estimate the flowering cycle of each species. Sixteen species were surveyed: Chusquea culeou, C. deficiens, C. lorentziana, C. montana, C. quila, C. ramosissima, C. tenella, C. valdiviensis; Colanthelia rhizantha; Guadua chacoensis, G. paraguayana, G. trinii; Merostachys clausenii, M. multiramea, Rhipidocladum neumannii and R. racemiflorum. To reconstruct flowering dates, information from literature and herbarium collections was consulted and more than 990 records were gathered. Flowering cycles were estimated by recording the intervals between reported flowering events. Evidence of regular flowering cycles of ca. 30 years was found for most of the species considered. There is a remarkable concentration of flowering cycles about multiples of 15-16 years. Flowering synchrony among different species of woody bamboos was recorded for the first time in South America. PMID- 24162622 TI - The effects of rest breaks, work shift start time, and sleep on the onset of severe injury among workers in the People's Republic of China. AB - OBJECTIVE: The aim of the present study was to investigate the effects of the duration and timing of rest breaks on traumatic injury risk across a shift in a relatively large sample of hospitalized workers with severe work-related hand injury in the People's Republic of China (PRC). METHODS: Hospitalized workers from multiple industries with severe work-related traumatic hand injury were recruited from 11 hospitals in three industrially-developed cities in the PRC: Ningbo, Liuzhou, and Wuxi. Cox regression was used to compare time into the work shift of injury across categories of rest breaks, while evaluating several potential covariates including age, gender, work hours, work start time and duration, injury day and time, duration and quality of last sleep, alertness/sleepiness, job control, and several transient work-related factors. Effect modification by work shift start time was also evaluated. RESULTS: With four days of injury, 703 hospitalized workers completed a face-to-face interview. After adjusting for significant covariates, workers with rest breaks of 1-30, 31 60, and >60 minutes were able to work significantly (P<0.001) longer into their work shift without an injury (>5 hours) then those with no rest break. A significant interaction was also observed between rest break status and start time of the work shift. CONCLUSION: The results of this study suggest that rest breaks of any duration have a significant effect on delaying the onset of a work related injury, which is modified by the time of day in which a shift begins. PMID- 24162623 TI - Paediatric and adolescent elevated conjunctival lesions in the plical area: lymphoma or reactive lymphoid hyperplasia? AB - OBJECTIVE: To report clinical, histopathological and molecular features of 'salmon patch'-like conjunctival lesions in paediatric and adolescent patients, and discuss management of these patients and outcome. METHODS: Patients who presented between 2000 and 2011 with a conjunctival 'salmon-patch'-like lesion in the plical area, were identified by chart review. Clinical parameters, demographic characteristics and details of ophthalmic imaging were collected, and the effect of treatment examined. RESULTS: Eleven patients aged 6-21 years, presented with an elevated pink conjunctival mass in the plical area of one or both eyes. Nine patients underwent an excisional biopsy that histopathologically disclosed extranodal marginal zone B cell lymphoma of mucosa-associated lymphoid tissue (also termed 'MALT lymphoma') in two cases and reactive lymphoid hyperplasia (RLH) in seven cases. Molecular diagnosis showed polyclonal B cells in six patients, monoclonal B cells in two patients, and a questionable status in one patient. Systemic examination disclosed localised ocular adnexal disease in the patients with MALT lymphoma, and none had either local or systemic recurrence during follow-up. Two other patients were treated with antiallergic medication with resolution of the lesion, and were therefore diagnosed clinically with RLH. CONCLUSIONS: It is clinically difficult to differentiate between conjunctival RLH and MALT lymphoma in the paediatric and adolescent population. Both lesions are rare in this age group, particularly MALT lymphoma. Molecular analysis of excised lesions does not always correlate with histopathology. A short treatment course with antiallergic drops may sometimes assist diagnosis without compromising the patients due to the indolent nature of lymphoma in that area. PMID- 24162624 TI - [Tumor Conference I]. PMID- 24162625 TI - [Tumor conference II]. PMID- 24162621 TI - Association analysis of 9,560 prostate cancer cases from the International Consortium of Prostate Cancer Genetics confirms the role of reported prostate cancer associated SNPs for familial disease. AB - Previous GWAS studies have reported significant associations between various common SNPs and prostate cancer risk using cases unselected for family history. How these variants influence risk in familial prostate cancer is not well studied. Here, we analyzed 25 previously reported SNPs across 14 loci from prior prostate cancer GWAS. The International Consortium for Prostate Cancer Genetics (ICPCG) previously validated some of these using a family-based association method (FBAT). However, this approach suffered reduced power due to the conditional statistics implemented in FBAT. Here, we use a case-control design with an empirical analysis strategy to analyze the ICPCG resource for association between these 25 SNPs and familial prostate cancer risk. Fourteen sites contributed 12,506 samples (9,560 prostate cancer cases, 3,368 with aggressive disease, and 2,946 controls from 2,283 pedigrees). We performed association analysis with Genie software which accounts for relationships. We analyzed all familial prostate cancer cases and the subset of aggressive cases. For the familial prostate cancer phenotype, 20 of the 25 SNPs were at least nominally associated with prostate cancer and 16 remained significant after multiple testing correction (p <= 1E (-3)) occurring on chromosomal bands 6q25, 7p15, 8q24, 10q11, 11q13, 17q12, 17q24, and Xp11. For aggressive disease, 16 of the SNPs had at least nominal evidence and 8 were statistically significant including 2p15. The results indicate that the majority of common, low-risk alleles identified in GWAS studies for all prostate cancer also contribute risk for familial prostate cancer, and that some may contribute risk to aggressive disease. PMID- 24162626 TI - Ethnicity and access to prescription medicines. PMID- 24162627 TI - Pacific people's health in New Zealand. PMID- 24162628 TI - Variation in the use of medicines by ethnicity during 2006/07 in New Zealand: a preliminary analysis. AB - AIM: To describe variations in dispensing of specific medication groups by ethnicity in New Zealand, adjusting for health need. METHOD: Preliminary linkage of dispensings of prescription medicines in 2006/07 to age/disease burden proxies of health need for Maori, Pacific peoples (Pasifika)--who are mostly of Samoan, Tongan, Niuean, or Cook Islands descent--in New Zealand, and non-Maori/non Pasifika. These disease burden proxies combine differences in prevalence, age, morbidity, and mortality. Variations were disaggregated by patients being first dispensed medicines ('access') versus subsequent dispensings ('persistence'). RESULTS: Initially, overall age-adjusted incidence of 'scripts' (prescriptions dispensed) to Maori was similar to that of non-Maori. There were differences in therapeutic coverage between Maori and Pasifika, for example greater use of asthma medicines in Maori. However, further adjustments linking with disease burden showed marked variance for a number of diseases. Differences in dispensing included areas of high health need such as heart disease, infections, diabetes, mental health and respiratory disease. Maori had 19-37% lower dispensings overall than non-Maori, with a net difference of nearly 1 million scripts. Maori were both less likely to access medicines, and then after first dispensing had fewer subsequent scripts. Patterns for Pasifika appeared similar, although needs adjusted analysis is awaited for this population. CONCLUSIONS: Once adjusting for need, there was variable but sizeable differences in medicines dispensed to Maori compared with non-Maori, and likely differences for Pasifika populations. There are however important limitations to this preliminary analysis. Crude and age standardised metrics may be poor predictors of needs-adjusted gaps in medicines use. In this analysis, solely age-standardised rates tended to underestimate differences once adjusting for burden of disease; future analyses of prescribing patterns should consider better adjusting for disease burden. PMID- 24162629 TI - Ethnicity and rectal cancer management in New Zealand. AB - AIM: Research shows survival disparities between Maori and non-Maori colon cancer patients, with comorbidity and cancer care being major contributing factors. We studied rectal cancer management and survival in a cohort of Maori and non-Maori patients with a newly diagnosed rectal cancer. METHODS: 194 Maori and non-Maori patients diagnosed with rectal cancer between 2006 and 2008 were identified from the New Zealand Cancer Registry. Medical records were reviewed and patients compared on presentation, patient and tumour characteristics, and receipt and timing of treatment. Cox regression models were fitted to compare cancer-specific survival. RESULTS: Compared to non-Maori patients, Maori patients were younger (mean age at diagnosis 63.5 and 69.2 for Maori and Non-Maori respectively; p<0.001) and had higher prevalence of comorbidity. Stage, grade and tumour size distributions were similar. Almost all stage I-III patients (97%) underwent definitive surgery, with no difference between Maori and non-Maori. Maori patients waited longer for referral to medical oncologists (40 days vs. 33 days; p=0.03). Results suggested Maori patients with stage IV disease may be less likely than non-Maori to be referred to palliative care (13% vs. 40%; p=0.07). The hazard ratio for cancer-specific death for Maori compared with non-Maori patients was 1.24 (95% CI 0.65-2.35). CONCLUSION: The findings suggest both similarities and some differences in treatment and outcomes between Maori and non Maori rectal cancer patients, but firm conclusions are limited by small sample size. PMID- 24162630 TI - Maori nurses and smoking: what do we know? AB - AIM: A research partnership between NZNO, Whakauae Research, and Taupua Waiora aimed to determine Maori registered and student nurses' smoking behaviours and attitudes to smoking cessation. METHODS: We analysed a national web-based survey that explored the behaviours and views of 410 NZNO Maori nurses, student nurses and other health workers using descriptive statistical analysis. RESULTS: Findings confirm a smoking prevalence rate of 21.5% for all respondents--32% for Maori nursing students and 20% for Maori nurses. Of smokers, 75% of nurses smoke fewer than 10 cigarettes per day, 84% smoked outside their homes, and almost 20% indicated they were considering quitting within the next month. Most nurses who had attempted to, or had, quit did not use the range of smoking cessation interventions available. Maori nurses see the value in smoking cessation for improving their own and other's health, although many did not necessarily see themselves as effective in supporting Maori with smoking prevention and cessation. CONCLUSION: Prevalence rates for smoking among Maori registered nurses was lower than previous research and many of those still smoking indicate a strong intention to quit. Quit attempts in this occupation group could be better informed by evidence. Increasing the number of Maori nurses who are smoke-free will have the added benefit of increasing the efficacy of cessation interventions with patients and whanau (extended families). PMID- 24162631 TI - Increasing primary antibiotic resistance and ethnic differences in eradication rates of Helicobacter pylori infection in New Zealand--a new look at an old enemy. AB - AIMS: To determine the current prevalence, primary antibiotic resistance and eradication rate with standard triple therapy of Helicobacter pylori (H. pylori) infection in South Auckland, New Zealand (NZ). METHODS: Consecutive patients undergoing gastroscopy in 2012 were prospectively enrolled. The prevalence of primary H. pylori infection was determined from all Campylobacter-like organism (CLO) tests performed. Antibiotic susceptibility testing was performed for a range of relevant antibiotics and the success of eradication therapy was determined by stool antigen clearance. RESULTS: The prevalence of H. pylori infection by ethnic group; European (7.7%), Maori (34.8%), Pacific People (31.3%) and Orientals (23.8%). Metronidazole resistance was found in 49.3% of isolates, clarithromycin resistance in 16.4%, and moxifloxacin resistance in 9.5%. No isolates were resistant to tetracycline. Clarithromycin resistance (greater than and equal to 15%) was prevalent among Maori, Pacific People and Orientals. Metronidazole resistance has increased significantly from 32.7% in 1999 to 49.3% in 2012 (p=0.011), and clarithromycin resistance from 7% in 1999 to 16.4% in 2012 (p=0.021). The eradication rate (intention to treat) with standard omeprazole, amoxicillin and clarithromycin (OAC) therapy in ethnic groups where clarithromycin resistance was <15% was 85.7% versus 64.9% in groups where clarithromycin resistance was greater than and equal to 15% (p=0.024). CONCLUSION: H. pylori infection is very common among certain ethnic groups living in South Auckland. Resistance to clarithromycin and metronidazole have increased significantly among treatment naive patients compared to historical NZ data. Ethnic groups with clarithromycin resistance of greater than and equal to 15% were associated with lower eradication rates with OAC therapy. This suggests a need to review the current NZ H. pylori eradication guidelines to accommodate ethnic differences in the response to first-line regimens. PMID- 24162632 TI - Timely delivery of hip fracture care: a Middlemore Hospital audit. AB - INTRODUCTION: New Zealand (NZ) hospitals lack a centralised audit process to evaluate hip fracture care whereas UK hospitals audit hip fracture care in relation to best practice guidelines. This study sought to evaluate multiple factors in hip fracture care at Middlemore Hospital (MMH). Comparisons were made with an audit from MMH in 2008 and a multicentre UK audit. METHOD: A retrospective audit of patients with hip fractures was carried out at MMH between January and June 2012. RESULTS: 120 patient charts were reviewed. In 2012, 14.2% of patients were admitted from ED within the guideline recommended period of four hours compared to 5.6% of patients in 2008. 72.5% received operative management within the guideline suggested period of 48 hours in comparison to 51% in 2008. Lack of available theatre space accounted for 51% of delays in 2008. CONCLUSION: There have been considerable improvements to timely delivery of hip fracture care at MMH between 2008 and 2012. However, there are ongoing delays to ward admission and operative management at our institution resulting in care that falls beyond the times recommended by international guidelines. The lack of available theatre space remains a major cause of delayed surgery. We advocate the development of a multicentre audit in NZ hospitals. PMID- 24162633 TI - Retrospective analysis on timeframes of referral, diagnosis and treatment of patients with endometrial carcinomas in Dunedin Hospital, 2008-2011. AB - AIM: To quantify time taken for patients diagnosed and treated for endometrial cancer in Dunedin Hospital in context of Ministry of Health New Zealand (MoHNZ) best practice indicators for cancer diagnosis and treatment, and to identify factors which could potentially cause delays if present. METHOD: Retrospective audit was carried out based on patients discussed at a Gynaecology-Oncology Multi Disciplinary Meeting (GOMDM) at Dunedin Hospital during 2008-2011 for primary endometrial cancer. Median time taken between referral dates, first specialist appointment, date of histological diagnosis, staging scan, date when patients were waitlisted for surgery, and date of first treatment were calculated. Possible factors which could contribute to delay if present were identified and further explored. RESULT: 44 eligible patients were identified. Compared to MoHNZ recommendations delays were present from initial referral to first treatment (93 days actual timeframe vs. 62 days recommended timeframe) and some delays present from initial referral to first specialist assessment (21 days vs. 14 days), with only 20% and 32% of patients being seen and treated within the best practice timeframes respectively. Patients were treated within the recommended time once they were wait-listed for first definitive treatment (19 days vs. 31 days) with 75% of patients being treated within the recommended timeframe. Waiting time for hysteroscopy and dilatation and curettage was seen to contribute towards considerably longer delays in diagnosis and treatment of endometrial cancers. Other potential factors contributing to delay identified were patients not attending clinic appointments and difficulty in obtaining a conclusive histological sample through pipelle biopsy at the initial clinic visit. CONCLUSION: Currently the practice in Dunedin Hospital does not meet the planned MoHNZ standards, and significant changes in practice and reallocation of resource will be required to meet the MOH standards for women with endometrial cancer. Training of General Practitioners in pipelle biopsy, better patient education about post-menopausal bleeding, reducing the time taken for radiological scans, and expediting referrals to the first specialist appointment and hysteroscopy for patients with high suspicion, could reduce delays. PMID- 24162634 TI - Pacific students undertaking the first year of health sciences at the University of Otago, and factors associated with academic performance. AB - AIM: To describe Pacific students in the first year of health sciences at tertiary level, their academic performance, and factors associated with academic outcomes. METHOD: Routinely collected data for students who enrolled in the Health Sciences First Year (HSFY) programme at the University of Otago between 2007 and 2011, including their school National Certificate in Educational Achievement (NCEA) results were obtained in anonymous form. Descriptive statistics were calculated and regression analyses were undertaken using SAS v9.2 software. RESULTS: A small but increasing number of Pacific students are enrolling in health sciences at tertiary level. Pacific students had poorer performance compared to non-Pacific students in both NCEA and the HSFY programme. Factors associated with academic performance were gender, NCEA results, school decile, accommodation type, ethnicity, international status and disability. CONCLUSION: Pacific students are under-represented in health sciences and would benefit from better preparation from school. Pacific solutions are required to improve academic outcomes over and above mainstream policy solutions. Tertiary institutions need to engage prospective students earlier to ensure they are well informed of requirements, and are appropriately prepared for study at the tertiary level. PMID- 24162635 TI - Why a shared care record is an official medical record. AB - The literature describes three categories of health records: the Official Medical Records held by healthcare providers, Personal Health Records owned by patients, and--a possible in between case--the Shared Care Record. New complications and challenges arise with electronic storage of this latter class of record; for instance, an electronic shared care record may have multiple authors, which presents challenges regarding the roles and responsibilities for record-keeping. This article discusses the definitions and implementations of official medical records, personal health records and shared care records. We also consider the case of a New Zealand pilot of developing and implementing a shared care record in the National Shared Care Planning Programme. The nature and purpose of an official medical record remains the same whether in paper or electronic form. We maintain that a shared care record is an official medical record; it is not a personal health record that is owned and controlled by patients, although it is able to be viewed and interacted with by patients. A shared care record needs to meet the same criteria for medico-legal and ethical duties in the delivery of shared care as pertain to any official medical record. PMID- 24162636 TI - Rothia mucilaginosa: a rare cause of peritoneal dialysis-related peritonitis. AB - We report a peritoneal dialysis-related peritonitis infection with Rothia mucilaginosa (R. mucilaginosa), a Gram-positive germ belonging to the normal flora of the human oral cavity. Successful treatment was achieved by intraperitoneal administration of cephazolin. This case report illustrates the potential virulence of R. mucilaginosa in patients on peritoneal dialysis. We propose to routinely perform specific staining and prolonged culturing techniques for unusual germs such as R. mucilaginosa in patients with peritoneal dialysis related peritonitis. PMID- 24162637 TI - Medical image. Amelanotic conjunctival melanoma. PMID- 24162638 TI - Is public meningococcal C vaccination the preferred value for money at cost neutral? PMID- 24162639 TI - A hundred dollars a minute. PMID- 24162640 TI - Medication safety and quality improvement in PGY1 teaching. PMID- 24162641 TI - Beating the blues--the association between fruit and vegetable intake and improved mood. PMID- 24162642 TI - Vitamin C supplementation and kidney stone risk. PMID- 24162643 TI - Updating New Zealand's national smokefree law to reduce anomalies and improve health protection. PMID- 24162644 TI - Persisting mobile phone use while driving and possible solutions for New Zealand. PMID- 24162645 TI - A chiroptical switch based on supramolecular chirality transfer through alkyl chain entanglement and dynamic covalent bonding. AB - Chirality transfer is an interesting phenomenon in Nature, which represents an important step to understand the evolution of chiral bias and the amplification of the chirality. In this paper, we report the chirality transfer via the entanglement of the alkyl chains between chiral gelator molecules and achiral amphiphilic Schiff base. We have found that although an achiral Schiff base amphiphile could not form organogels in any kind of organic solvents, it formed co-organogels when mixed with a chiral gelator molecule. Interestingly, the chirality of the gelator molecules was transferred to the Schiff base chromophore in the mixed co-gels and there was a maximum mixing ratio for the chirality transfer. Furthermore, the supramolecular chirality was also produced based on a dynamic covalent chemistry of an imine formed by the reaction between an aldehyde and an amine. Such a covalent bond of imine was formed reversibly depending on the pH variation. When the covalent bond was formed the chirality transfer occurred, when it was destroyed, the transfer stopped. Thus, a supramolecular chiroptical switch is obtained based on supramolecular chirality transfer and dynamic covalent chemistry. PMID- 24162646 TI - Investigating river pollution flowing into Dianchi Lake using a combination of GC MS analysis and toxicological tests. AB - Due to the presence of various harmful compounds in polluted water, toxicological tests should be combined to evaluate whether a body of water is polluted. The water quality of four rivers flowing into Dianchi Lake, which is well known for its heavy and lasting pollution, was investigated in this study using a combination of GC-MS analysis and cytotoxicity and mutagenicity tests. GC-MS analysis showed that the rivers investigated contained a variety of chemicals and suggested that severe water pollution existed. In addition, the water obtained from the four rivers induced acute cytotoxicity in CHO cells and dose-dependent mutagenicity in four Salmonella typhimurium strains (TA97, TA98, TA100 and TA102). The integration of GC-MS analysis and short-term in vitro toxicological tests might be a valuable approach that can be used to monitor the health hazards that may result from water pollution. PMID- 24162647 TI - Effect of chronic sublethal exposure of major heavy metals on filtration rate, sex ratio, and gonad development of a bivalve species. AB - The chronic toxic effects of major heavy metals including copper (Cu), zinc (Zn), lead (Pb), and cadmium (Cd) on the filtration rate (FR), sex ratio, and gonad development of immature blood clams, Tegillarca granosa, were investigated. The FRs were significantly inhibited by Cu, Pb and Cd, with rates generally decreasing with both increasing metal concentrations and exposure time. EC50 values for FR after 28 days of exposure were 12.9, 12.7 and 14.4 MUg/L for Cu, Pb and Cd, respectively. Zn exposure had no effect on FR. Sex ratios were significantly altered from controls in favor of an increased proportion of males at metal concentrations of >= 14.2, >= 86 and >= 110 MUg/L for Cu, Pb and Cd, respectively; and at >= 1.68 mg/L for Zn. The gonado-somatic index was significantly reduced in clams at all metal exposures, except for the lowest concentration of Cu (7.1 MUg/L). PMID- 24162648 TI - Modular structure of a robust microporous MOF based on Cu2 paddle-wheels with high CO2 selectivity. AB - The synthesis of a new MOF with Cu2 paddle-wheels connected to glutarate and 1,3 bis(4-pyridyl)propane linkers has been explored. Experimental gas adsorption measurements reveal that the MOF is essentially non-porous to methane whereas it presents a type III isotherm upon CO2 adsorption, leading to high capacity and outstanding CO2 selectivity. PMID- 24162649 TI - Protein O-glucosylation in Lactobacillus buchneri. AB - Based on the previous demonstration of surface (S-) layer protein glycosylation in Lactobacillus buchneri 41021/251 and because of general advantages of lactic acid bacteria for applied research, protein glycosylation in this bacterial species was investigated in detail. The cell surface of L. buchneri CD034 is completely covered with an oblique 2D crystalline array (lattice parameters, a = 5.9 nm; b = 6.2 nm; gamma ~ 77 degrees ) formed by self-assembly of the S-layer protein SlpB. Biochemical and mass spectrometric analyses revealed that SlpB is the most abundant protein and that it is O-glycosylated at four serine residues within the sequence S(152)-A-S(154)-S(155)-A-S(157) with, on average, seven Glc(alpha1-6) residues, each. Subcellular fractionation of strain CD034 indicated a sequential order of SlpB export and glucosylation as evidenced by lack of glucosylation of cytosolic SlpB. Protein glycosylation analysis was extended to strain L. buchneri NRRL B-30929 where an analogous glucosylation scenario could be detected, with the S-layer glycoprotein SlpN containing an O-glycosylation motif identical to that of SlpB. This corroborates previous data on S-layer protein glucosylation of strain 41021/251 and let us propose a species-wide S layer protein O-glucosylation in L. buchneri targeted at the sequence motif S-A-S S-A-S. Search of the L. buchneri genomes for the said glucosylation motif revealed one further ORF, encoding the putative glycosyl-hydrolase LbGH25B and LbGH25N in L. buchneri CD034 and NRRL B-30929, respectively, for which we have indications of a glycosylation comparable to that of the S-layer proteins. These findings demonstrate the presence of a distinct protein O-glucosylation system in Gram-positive and beneficial microbes. PMID- 24162650 TI - Direction selectivity is computed by active dendritic integration in retinal ganglion cells. AB - Active dendritic integration is thought to enrich the computational power of central neurons. However, a direct role of active dendritic processing in the execution of defined neuronal computations in intact neural networks has not been established. Here we used multi-site electrophysiological recording techniques to demonstrate that active dendritic integration underlies the computation of direction selectivity in rabbit retinal ganglion cells. Direction-selective retinal ganglion cells fire action potentials in response to visual image movement in a preferred direction. Dendritic recordings revealed that preferred direction moving-light stimuli led to dendritic spike generation in terminal dendrites, which were further integrated and amplified as they spread through the dendritic arbor to the axon to drive action potential output. In contrast, when light bars moved in a null direction, synaptic inhibition vetoed neuronal output by directly inhibiting terminal dendritic spike initiation. Active dendritic integration therefore underlies a physiologically engaged circuit-based computation in the retina. PMID- 24162651 TI - Cerebellar Purkinje cell activity drives motor learning. AB - The climbing fiber input to the cerebellar cortex is thought to provide instructive signals that drive the induction of motor skill learning. We found that optogenetic activation of Purkinje cells, the sole output neurons of the cerebellar cortex, can also drive motor learning in mice. This dual control over the induction of learning by climbing fibers and Purkinje cells can expand the learning capacity of motor circuits. PMID- 24162652 TI - The microglial sensome revealed by direct RNA sequencing. AB - Microglia, the principal neuroimmune sentinels of the brain, continuously sense changes in their environment and respond to invading pathogens, toxins and cellular debris. Microglia exhibit plasticity and can assume neurotoxic or neuroprotective priming states that determine their responses to danger. We used direct RNA sequencing, without amplification or cDNA synthesis, to determine the quantitative transcriptomes of microglia of healthy adult and aged mice. We validated our findings using fluorescence dual in situ hybridization, unbiased proteomic analysis and quantitative PCR. We found that microglia have a distinct transcriptomic signature and express a unique cluster of transcripts encoding proteins for sensing endogenous ligands and microbes that we refer to as the sensome. With aging, sensome transcripts for endogenous ligand recognition were downregulated, whereas those involved in microbe recognition and host defense were upregulated. In addition, aging was associated with an overall increase in the expression of microglial genes involved in neuroprotection. PMID- 24162653 TI - EZH2-mediated H3K27 trimethylation mediates neurodegeneration in ataxia telangiectasia. AB - The symptoms of ataxia-telangiectasia (A-T) include a progressive neurodegeneration caused by ATM protein deficiency. We previously found that nuclear accumulation of histone deacetylase-4, HDAC4, contributes to this degeneration; we now report that increased trimethylation of histone H3 on Lys27 (H3K27me3) mediated by polycomb repressive complex 2 (PRC2) is also important in the A-T phenotype. Enhancer of zeste homolog 2 (EZH2), a core catalytic component of PRC2, is a new ATM kinase target, and ATM-mediated phosphorylation of EZH2 on Ser734 reduces protein stability. Thus, PRC2 formation is elevated along with H3K27me3 in ATM deficiency. Chromatin immunoprecipitation and sequencing showed an increase in H3K27me3 'marks' and a dramatic shift in their location. The change of H3K27me3 chromatin-binding pattern is directly related to cell cycle reentry and cell death of ATM-deficient neurons. Lentiviral knockdown of EZH2 rescued Purkinje cell degeneration and behavioral abnormalities in Atm(-/-) mice, demonstrating that EZH2 hyperactivity is another key factor in A-T neurodegeneration. PMID- 24162654 TI - Fast modulation of visual perception by basal forebrain cholinergic neurons. AB - The basal forebrain provides the primary source of cholinergic input to the cortex, and it has a crucial function in promoting wakefulness and arousal. However, whether rapid changes in basal forebrain neuron spiking in awake animals can dynamically influence sensory perception is unclear. Here we show that basal forebrain cholinergic neurons rapidly regulate cortical activity and visual perception in awake, behaving mice. Optogenetic activation of the cholinergic neurons or their V1 axon terminals improved performance of a visual discrimination task on a trial-by-trial basis. In V1, basal forebrain activation enhanced visual responses and desynchronized neuronal spiking; these changes could partly account for the behavioral improvement. Conversely, optogenetic basal forebrain inactivation decreased behavioral performance, synchronized cortical activity and impaired visual responses, indicating the importance of cholinergic activity in normal visual processing. These results underscore the causal role of basal forebrain cholinergic neurons in fast, bidirectional modulation of cortical processing and sensory perception. PMID- 24162655 TI - TGF-beta signaling regulates neuronal C1q expression and developmental synaptic refinement. AB - Immune molecules, including complement proteins C1q and C3, have emerged as critical mediators of synaptic refinement and plasticity. Complement localizes to synapses and refines the developing visual system through C3-dependent microglial phagocytosis of synapses. Retinal ganglion cells (RGCs) express C1q, the initiating protein of the classical complement cascade, during retinogeniculate refinement; however, the signals controlling C1q expression and function remain elusive. Previous work implicated an astrocyte-derived factor in regulating neuronal C1q expression. Here we identify retinal transforming growth factor (TGF)-beta as a key regulator of neuronal C1q expression and synaptic pruning in the developing visual system. Mice lacking TGF-beta receptor II (TGFbetaRII) in retinal neurons had reduced C1q expression in RGCs and reduced synaptic localization of complement, and phenocopied refinement defects observed in complement-deficient mice, including reduced eye-specific segregation and microglial engulfment of RGC inputs. These data implicate TGF-beta in regulating neuronal C1q expression to initiate complement- and microglia-mediated synaptic pruning. PMID- 24162656 TI - Opposite actions of alcohol on tonic GABA(A) receptor currents mediated by nNOS and PKC activity. AB - The molecular mechanisms that mediate genetic variability in response to alcohol are unclear. We found that alcohol had opposite actions (enhancement or suppression) on GABA(A) receptor (GABA(A)R) inhibition in granule cells from the cerebellum of behaviorally sensitive, low alcohol-consuming Sprague-Dawley rats and DBA/2 mice and behaviorally insensitive, high alcohol-consuming C57BL/6 mice, respectively. The effect of alcohol on granule cell GABA(A)R inhibition was determined by a balance between two opposing effects: enhanced presynaptic vesicular release of GABA via alcohol inhibition of nitric oxide synthase (NOS) and a direct suppression of the activity of postsynaptic GABA(A)Rs. The balance of these two processes was determined by differential expression of neuronal NOS (nNOS) and postsynaptic PKC activity, both of which varied across the rodent genotypes. These findings identify opposing molecular processes that differentially control the magnitude and polarity of GABA(A)R responses to alcohol across rodent genotypes. PMID- 24162657 TI - One-step synthesis of carbon nanosheets converted from a polycyclic compound and their direct use as transparent electrodes of ITO-free organic solar cells. AB - Through a catalyst- and transfer-free process, we fabricated indium tin oxide (ITO)-free organic solar cells (OSCs) using a carbon nanosheet (CNS) with properties similar to graphene. The morphological and electrical properties of the CNS derived from a polymer of intrinsic microporosity-1 (PIM-1), which is mainly composed of several aromatic hydrocarbons and cycloalkanes, can be easily controlled by adjusting the polymer concentration. The CNSs, which are prepared by simple spin-coating and heat-treatment on a quartz substrate, are directly used as the electrodes of ITO-free OSCs, showing a high efficiency of approximately 1.922% under 100 mW cm(-2) illumination and air mass 1.5 G conditions. This catalyst- and transfer-free approach is highly desirable for electrodes in organic electronics. PMID- 24162658 TI - Bendless modulates JNK-mediated cell death and migration in Drosophila. AB - The TNF-JNK pathway is a highly conserved signaling pathway that regulates a wide spectrum of biological processes including cell death and migration. To further delineate this pathway, we carried out a genetic screen for dominant modifiers of the cell death phenotype triggered by ectopic expression of Eiger (Egr), the Drosophila TNF ortholog. Here we show that Bendless (Ben), an E2 ubiquitin conjugating enzyme, modulates Egr-induced JNK activation and cell death through dTRAF2. Furthermore, Ben physically interacts with dTRAF2 and regulates Egr induced dTRAF2 polyubiquitination. Finally, Ben is required for JNK-dependent tumor progression, cell migration, oxidative stress resistance and longevity. Our results indicate that Ben constitutes an essential component of the evolutionarily conserved TNF-JNK pathway that modulates cell death and invasion, tumor progression, stress response and lifespan in metazoans. PMID- 24162659 TI - The rheostat in the membrane: BCL-2 family proteins and apoptosis. AB - Apoptosis, a mechanism for programmed cell death, has key roles in human health and disease. Many signals for cellular life and death are regulated by the BCL-2 family proteins and converge at mitochondria, where cell fate is ultimately decided. The BCL-2 family includes both pro-life (e.g. BCL-XL) and pro-death (e.g. BAX, BAK) proteins. Previously, it was thought that a balance between these opposing proteins, like a simple 'rheostat', could control the sensitivity of cells to apoptotic stresses. Later, this rheostat concept had to be extended, when it became clear that BCL-2 family proteins regulate each other through a complex network of bimolecular interactions, some transient and some relatively stable. Now, studies have shown that the apoptotic circuitry is even more sophisticated, in that BCL-2 family interactions are spatially dynamic, even in nonapoptotic cells. For example, BAX and BCL-XL can shuttle between the cytoplasm and the mitochondrial outer membrane (MOM). Upstream signaling pathways can regulate the cytoplasmic-MOM equilibrium of BAX and thereby adjust the sensitivity of cells to apoptotic stimuli. Thus, we can view the MOM as the central locale of a dynamic life-death rheostat. BAX invariably forms extensive homo-oligomers after activation in membranes. However, recent studies, showing that activated BAX monomers determine the kinetics of MOM permeabilization (MOMP), perturb the lipid bilayer and form nanometer size pores, pose questions about the role of the oligomerization. Other lingering questions concern the molecular mechanisms of BAX redistribution between MOM and cytoplasm and the details of BAX/BAK-membrane assemblies. Future studies need to delineate how BCL 2 family proteins regulate MOMP, in concert with auxiliary MOM proteins, in a dynamic membrane environment. Technologies aimed at elucidating the structure and function of the full-length proteins in membranes are needed to illuminate some of these critical issues. PMID- 24162661 TI - The diversity of zinc-finger genes on human chromosome 19 provides an evolutionary mechanism for defense against inherited endogenous retroviruses. AB - Endogenous retroviruses (ERVs) are remnants of ancient retroviral infections of the germ line that can remain capable of replication within the host genome. In the soma, DNA methylation and repressive chromatin keep the majority of this parasitic DNA transcriptionally silent. However, it is unclear how the host organism adapts to recognize and silence novel invading retroviruses that enter the germ line. Krueppel-Associated Box (KRAB)-associated protein 1 (KAP1) is a transcriptional regulatory factor that drives the epigenetic repression of many different loci in mammalian genomes. Here, we use published experimental data to provide evidence that human KAP1 is recruited to endogenous retroviral DNA by KRAB-containing zinc-finger transcription factors (TFs). Many of these zinc finger genes exist in clusters associated with human chromosome 19. We demonstrate that these clusters are located at hotspots for copy number variation (CNV), generating a large and continuing diversity of zinc-finger TFs with new generations. These zinc-finger genes possess a wide variety of DNA binding affinities, but their role as transcriptional repressors is conserved. We also perform a computational study of the different ERVs that invaded the human genome during primate evolution. We find candidate zinc-finger repressors that arise in the genome for each ERV family that enters the genomes of primates. In particular, we show that those repressors that gained their binding affinity to retrovirus sequences at the same time as their targets invaded the human lineage are preferentially located on chromosome 19 (P-value: 3 * 10(-3)). PMID- 24162660 TI - Building blocks of the apoptotic pore: how Bax and Bak are activated and oligomerize during apoptosis. AB - The central role of the Bcl-2 family in regulating apoptotic cell death was first identified in the 1980s. Since then, significant in-roads have been made in identifying the multiple members of this family, characterizing their form and function and understanding how their interactions determine whether a cell lives or dies. In this review we focus on the recent progress made in characterizing the proapoptotic Bcl-2 family members, Bax and Bak. This progress has resolved longstanding controversies, but has also challenged established theories in the apoptosis field. We will discuss different models of how these two proteins become activated and different 'modes' by which they are inhibited by other Bcl-2 family members. We will also discuss novel conformation changes leading to Bak and Bax oligomerization and speculate how these oligomers might permeabilize the mitochondrial outer membrane. PMID- 24162662 TI - Epidermal Snail expression drives skin cancer initiation and progression through enhanced cytoprotection, epidermal stem/progenitor cell expansion and enhanced metastatic potential. AB - Expression of the EMT-inducing transcription factor Snail is enhanced in different human cancers. To investigate the in vivo role of Snail during progression of epithelial cancer, we used a mouse model with skin-specific overexpression of Snail. Snail transgenic mice spontaneously developed distinct histological subtypes of skin cancer, such as basal cell carcinoma, squamous cell carcinoma and sebaceous gland carcinoma. Development of sebaceous gland carcinomas strongly correlated with the direct and complete repression of Blimp 1, a central regulator of sebocyte homeostasis. Snail expression in keratinocyte stem cells significantly promotes their proliferation associated with an activated FoxM1 gene expression signature, resulting in a larger pool of Mts24 marked progenitor cells. Furthermore, primary keratinocytes expressing Snail showed increased survival and strong resistance to genotoxic stress. Snail expression in a skin-specific p53-null background resulted in accelerated formation of spontaneous tumours and enhanced metastasis. Our data demonstrate that in vivo expression of Snail results in de novo epithelial carcinogenesis by allowing enhanced survival, expansion of the cancer stem cell pool with accumulated DNA damage, a block in terminal differentiation and increased proliferation rates of tumour-initiating cells. PMID- 24162665 TI - Effects of pretreatment on the denaturation and fragmentation of genomic DNA for DNA hybridization. AB - DNA hybridization is an important step for a number of bioassays such as fluorescence in situ hybridization, microarrays, as well as the NanoGene assay. Denaturation and fragmentation of genomic DNA are two critical pretreatments for DNA hybridization. However, no thorough and systematic characterization on denaturation and fragmentation has been carried out for the NanoGene assay so far. In this study, we investigated the denaturation and fragmentation of the bacterial gDNA with physical treatments (i.e., heating and sonication) and chemical treatments (i.e., dimethyl sulfoxide). First of all, a simple approach for indicating the denaturation fraction was developed based on the absorbance difference (i.e., hyperchromic effect) between the double-stranded DNA and single stranded DNA fragments. Then the denaturation capabilities of the treatments to the gDNA were elucidated, followed by the examination of the possible renaturation over time. The fragmentation of the gDNA by each treatment was also investigated. Based on denaturation efficiency, minimum renaturation tendency, and fragmentation, the sonication method was found to be the best among the six methods. We further demonstrated that the sonication method produced the best result among the treatments examined for the DNA hybridization in the NanoGene assay. PMID- 24162663 TI - beta-arrestin protects neurons by mediating endogenous opioid arrest of inflammatory microglia. AB - Microglial activation worsens neuronal loss and contributes to progressive neurological diseases like Parkinson's disease (PD). This inflammatory progression is countered by dynorphin (Dyn), the endogenous ligand of the kappa opioid receptor (KOR). We show that microglial beta-arrestin mediates the ability of Dyn/KOR to limit endotoxin-elicited production of pro-inflammatory effectors and cytokines, subsequently protecting neurons from inflammation-induced neurotoxicity. Agonist-activated KOR enhances the interaction of beta-arrestin2 with transforming growth factor-beta-activated kinase 1 (TAK1)-binding protein 1 (TAB1), disrupting TAK1-TAB1 mediated pro-inflammatory gene expression. We reveal a new physiological role for beta-arrestin in neuroprotection via receptor internalization-triggered blockade of signal effectors of microglial inflammatory neurotoxicity. This result offers novel drug targets in the convergent KOR/beta arrestin2 and inflammatory pathways for treating microglial inflammatory neuropathologies like PD. PMID- 24162666 TI - Color error in the digital camera image capture process. AB - The color error in images taken by digital cameras is evaluated with respect to its sensitivity to the image capture conditions. A parametric study was conducted to investigate the dependence of image color error on camera technology, illumination spectra, and lighting uniformity. The measurement conditions were selected to simulate the variation that might be expected in typical telemedicine situations. Substantial color errors were observed, depending on the measurement conditions. Several image post-processing methods were also investigated for their effectiveness in reducing the color errors. The results of this study quantify the level of color error that may occur in the digital camera image capture process, and provide guidance for improving the color accuracy through appropriate changes in that process and in post-processing. PMID- 24162664 TI - Phylogenetic distinction of iNOS and IDO function in mesenchymal stem cell mediated immunosuppression in mammalian species. AB - Mammalian mesenchymal stem cells (MSCs) have been shown to be strongly immunosuppressive in both animal disease models and human clinical trials. We have reported that the key molecule mediating immunosuppression by MSCs is species dependent: indoleamine 2,3-dioxygenase (IDO) in human and inducible nitric oxide synthase (iNOS) in mouse. In the present study, we isolated MSCs from several mammalian species, each of a different genus, and investigated the involvement of IDO and iNOS during MSC-mediated immunosuppression. The characterization of MSCs from different species was by adherence to tissue culture plastic, morphology, specific marker expression, and differentiation potential. On the basis of the inducibility of IDO and iNOS by inflammatory cytokines in MSCs, the tested mammalian species fall into two distinct groups: IDO utilizers and iNOS utilizers. MSCs from monkey, pig, and human employ IDO to suppress immune responses, whereas MSCs from mouse, rat, rabbit, and hamster utilize iNOS. Interestingly, based on the limited number of species tested, the iNOS-utilizing species all belong to the phylogenetic clade, Glires. Although the evolutionary significance of this divergence is not known, we believe that this study provides critical guidance for choosing appropriate animal models for preclinical studies of MSCs. PMID- 24162667 TI - Level set segmentation of breast masses in contrast-enhanced dedicated breast CT and evaluation of stopping criteria. AB - Dedicated breast CT (bCT) produces high-resolution 3D tomographic images of the breast, fully resolving fibroglandular tissue structures within the breast and allowing for breast lesion detection and assessment in 3D. In order to enable quantitative analysis, such as volumetrics, automated lesion segmentation on bCT is highly desirable. In addition, accurate output from CAD (computer-aided detection/diagnosis) methods depends on sufficient segmentation of lesions. Thus, in this study, we present a 3D lesion segmentation method for breast masses in contrast-enhanced bCT images. The segmentation algorithm follows a two-step approach. First, 3D radial-gradient index segmentation is used to obtain a crude initial contour, which is then refined by a 3D level set-based active contour algorithm. The data set included contrast-enhanced bCT images from 33 patients containing 38 masses (25 malignant, 13 benign). The mass centers served as input to the algorithm. In this study, three criteria for stopping the contour evolution were compared, based on (1) the change of region volume, (2) the average intensity in the segmented region increase at each iteration, and (3) the rate of change of the average intensity inside and outside the segmented region. Lesion segmentation was evaluated by computing the overlap ratio between computer segmentations and manually drawn lesion outlines. For each lesion, the overlap ratio was averaged across coronal, sagittal, and axial planes. The average overlap ratios for the three stopping criteria ranged from 0.66 to 0.68 (dice coefficient of 0.80 to 0.81), indicating that the proposed segmentation procedure is promising for use in quantitative dedicated bCT analyses. PMID- 24162668 TI - An historical perspective on "The world-wide distribution of allele frequencies at the human dopamine D4 receptor locus". AB - Human population genetics is a completely different science today compared to two decades ago, at least at the empiric level. Our paper [Chang (Hum Genet 98:91 101, 1996a)] demonstrated that three different alleles were common when one considered many populations although other low frequency alleles occurred. Because previous work had been largely done on European subjects, our findings involved 36 distinct populations and showed that East Asian populations had nearly lost the 7-repeat allele, and that Native American populations had the highest frequencies of that allele globally, was a significant early empiric demonstration of the potential magnitude of population variation at important genes. There are thousands of loci tested on many of the same populations and the gene frequency pattern seen for the DRD4 7-repeat allele is seen at other loci, arguing that this pattern commonly reflects the pattern of divergence of populations and accumulated random genetic drift. PMID- 24162669 TI - Regulatory T cells use "Itch" to control asthma. AB - Regulatory T cells (Tregs) control type 2 T helper cell-mediated (Th2-mediated) lung inflammation, but the molecular mechanisms by which Tregs execute this activity remain elusive. In this issue of the JCI, Jin et al. reveal that Itch, a HECT-type E3 ubiquitin ligase in Tregs, plays a specific role in restraining Th2 cell responses. This finding has important implications for understanding the pathogenesis of allergy and asthma. PMID- 24162670 TI - Oncogenic rearrangements driving ionizing radiation-associated human cancer. AB - The Chernobyl nuclear disaster has caused a remarkable increase in radiation induced papillary thyroid carcinoma in children and young adults. In this issue of the JCI, Ricarte-Filho and colleagues demonstrate that chromosomal rearrangements are the oncogenic "drivers" in most post-Chernobyl carcinomas and that they often lead to unscheduled activation of the MAPK signaling pathway. These findings represent a major step forward in our understanding of radiation induced carcinogenesis and suggest various hypotheses about the mechanisms underlying the formation and selection of gene rearrangements during cancer cell evolution. PMID- 24162671 TI - Antifibrotic vitamin D analogs. AB - Chronic kidney disease is associated with progressive kidney fibrosis, which disrupts normal kidney function. There is a great need for treatments to reduce renal fibrosis. In this issue of the JCI, Ito and colleagues report the development of synthetic ligands of the vitamin D receptor that target the TGF beta-SMAD signaling pathway, which is known to regulate fibrosis-associated gene expression, without inducing VDR-associated genes. These ligands ameliorated renal fibrosis in two different mouse models. This study justifies further investigation of these and related compounds for treatment of humans with chronic kidney disease or other diseases characterized by fibrosis. PMID- 24162672 TI - Osteocyte-induced angiogenesis via VEGF-MAPK-dependent pathways in endothelial cells. AB - Recently, it has been suggested osteocytes control the activities of bone formation (osteoblasts) and resorption (osteoclast), indicating their important regulatory role in bone remodelling. However, to date, the role of osteocytes in controlling bone vascularisation remains unknown. Our aim was to investigate the interaction between endothelial cells and osteocytes and to explore the possible molecular mechanisms during angiogenesis. To model osteocyte/endothelial cell interactions, we co-cultured osteocyte cell line (MLOY4) with endothelial cell line (HUVECs). Co-cultures were performed in 1:1 mixture of osteocytes and endothelial cells or by using the conditioned media (CM) transfer method. Real time cell migration of HUVECs was measured with the transwell migration assay and xCELLigence system. Expression levels of angiogenesis-related genes were measured by quantitative real-time polymerase chain reaction (qRT-PCR). The effect of vascular endothelial growth factor (VEGF) and mitogen-activated phosphorylated kinase (MAPK) signaling were monitored by western blotting using relevant antibodies and inhibitors. During the bone formation, it was noted that osteocyte dendritic processes were closely connected to the blood vessels. The CM generated from MLOY4 cells-activated proliferation, migration, tube-like structure formation, and upregulation of angiogenic genes in endothelial cells suggesting that secretory factor(s) from osteocytes could be responsible for angiogenesis. Furthermore, we identified that VEGF secreted from MLOY4-activated VEGFR2-MAPK ERK-signaling pathways in HUVECs. Inhibiting VEGF and/or MAPK-ERK pathways abrogated osteocyte-mediated angiogenesis in HUVEC cells. Our data suggest an important role of osteocytes in regulating angiogenesis. PMID- 24162673 TI - Inhibition of miR-92b suppresses nonsmall cell lung cancer cells growth and motility by targeting RECK. AB - microRNAs play critical roles in the progression and metastasis of nonsmall cell lung cancer (NSCLC). miR-92b acts as an oncogene in some malignancies; however, its role in NSCLC remains poorly understood. Here, we found that miR-92b was significantly increased in human NSCLC tissues and cell lines. Inhibition of miR 92b remarkably suppressed cell proliferation, migration, and invasion of NSCLC cells. Reversion-inducing-cysteine-rich protein with kazal motifs (RECK) was identified to be a target of miR-92b. Expression of miR-92b was negatively correlated with RECK in NSCLC tissues. Collectively, miR-92b might promote NSCLC cell growth and motility partially by inhibiting RECK. PMID- 24162674 TI - Developing a new, national approach to surveillance for ventilator-associated events*. AB - OBJECTIVE: To develop and implement an objective, reliable approach to surveillance for ventilator-associated events in adult patients. DESIGN: The Centers for Disease Control and Prevention (CDC) convened a Ventilator-Associated Pneumonia (VAP) Surveillance Definition Working Group in September 2011. Working Group members included representatives of stakeholder societies and organizations and federal partners. MAIN RESULTS: The Working Group finalized a three-tier, adult surveillance definition algorithm for ventilator-associated events. The algorithm uses objective, readily available data elements and can identify a broad range of conditions and complications occurring in mechanically ventilated adult patients, including but not limited to VAP. The first tier definition, ventilator-associated condition (VAC), identifies patients with a period of sustained respiratory deterioration following a sustained period of stability or improvement on the ventilator, defined by changes in the daily minimum fraction of inspired oxygen or positive end-expiratory pressure. The second tier definition, infection-related ventilator-associated complication (IVAC), requires that patients with VAC also have an abnormal temperature or white blood cell count, and be started on a new antimicrobial agent. The third tier definitions, possible and probable VAP, require that patients with IVAC also have laboratory and/or microbiological evidence of respiratory infection. CONCLUSIONS: Ventilator associated events surveillance was implemented in January 2013 in the CDC's National Healthcare Safety Network. Modifications to improve surveillance may be made as additional data become available and users gain experience with the new definitions. PMID- 24162675 TI - Updated approach for the assessment of ventilator-associated pneumonia. PMID- 24162676 TI - Routine intra-aortic balloon pump support in high-risk cardiac surgery patients: is it time to throw away the pump?*. PMID- 24162677 TI - Low diastolic blood pressure as best predictor of mortality in cardiogenic shock*. PMID- 24162678 TI - Say no to old blood*. PMID- 24162679 TI - Measuring lung volume during high-frequency oscillatory ventilation in neonates ready for prime time?*. PMID- 24162680 TI - Artificial colloids: whither go we now?*. PMID- 24162681 TI - Apoptosis or necrosis in acetaminophen-induced acute liver failure? New insights from mechanistic biomarkers*. PMID- 24162682 TI - Dosing of continuous renal replacement therapy in critically ill patients with acute kidney injury: how low should we go?*. PMID- 24162683 TI - Position, positive end-expiratory pressure, and obstructive obesity*. PMID- 24162684 TI - Translating knowledge into practice in critical care settings*. PMID- 24162685 TI - Visualization of fibrinogen-dependent thrombus formation*. PMID- 24162686 TI - A little fat every day keeps the doctor away*. PMID- 24162687 TI - The lethal duo of hypoxemia and ischemia: not only for the brain but also for the gut*. PMID- 24162688 TI - Candidemia in ICU patients with sepsis. PMID- 24162689 TI - 2B or not 2B for selective decontamination of the digestive tract in the surviving sepsis campaign guidelines. PMID- 24162690 TI - The authors reply. PMID- 24162691 TI - Does iodinated radiocontrast material pose an appreciable risk for kidney injury in the critically ill? PMID- 24162692 TI - The authors reply. PMID- 24162693 TI - Should transient physiologic effects following lipid administration be attributed to a cellular signaling mechanism without cellular data? PMID- 24162694 TI - The authors reply. PMID- 24162695 TI - Milrinone: some (medicolegal) thoughts beyond contractility, lusitropy, and cardiac output. PMID- 24162696 TI - The authors reply. PMID- 24162697 TI - Influence of oxygenation and ventilation on outcome after cardiac arrest in children. PMID- 24162698 TI - The authors reply. PMID- 24162699 TI - Predictors of intraventricular extension of intracerebral hemorrhage confounded by antithrombotic medication exposure. PMID- 24162700 TI - The authors reply. PMID- 24162701 TI - The association between disease severity and copying prevalence. PMID- 24162702 TI - The authors reply. PMID- 24162703 TI - Selenium for sepsis: what have we learned so far? PMID- 24162704 TI - Proton pump inhibitors in patients with end-stage liver disease. PMID- 24162705 TI - The authors reply. PMID- 24162706 TI - [Roles of enteric microbial composition and metabolism in health and diseases]. AB - A complex microbiota colonizes mucosal layers in different regions of the human gut. In the healthy state, the microbial communities provide nutrients and energy to the host via fermentation of non-digestible dietary components in the large intestine. In contrast, they can play roles in inflammation and infection, including gastrointestinal diseases and metabolic syndrome such as obesity. However, because of the complexity of the microbial community, the functional connections between the enteric microbiota and metabolism are less well understood. Nevertheless, major progress has been made in defining dominant bacterial species, community profiles, and systemic characteristics that produce stable microbiota beneficial to health, and in identifying their roles in enteric metabolism. Through studies in both mice and humans, we are recently in a better position to understand what effect the enteric microbiota has on the metabolism by improving energy yield from food and modulating dietary components. Achieving better knowledge of this information may provide insights into new possibilities that reconstitution of enteric microbiota via diet can provide the maintenance of healthy state and therapeutic/preventive strategies against metabolic syndrome such as obesity. This review focuses on enteric microbial composition and metabolism on healthy and diseased states. PMID- 24162707 TI - Is there a difference in the prevalence of gastroesophageal reflux disease between peritoneal dialysis and hemodialysis patients? AB - BACKGROUND/AIMS: Gastroesophageal reflux disease (GERD) is a common upper gastrointestinal disorder in patients with chronic kidney disease (CKD). However, little is known about the prevalence of GERD in dialysis patients. The aim of the present study was to investigate the difference in the prevalence of GERD in peritoneal dialysis and hemodialysis patients. METHODS: From July 2010 to August 2011, peritoneal dialysis patients (n=30) and hemodialysis patients (n=38) were enrolled. The prevalences of GERD were assessed at a single center with endoscopic findings and interviews using a questionnaire. Also, risk factors of GERD were evaluated. RESULTS: The prevalences of GERD in peritoneal dialysis and hemodialysis patients were 33.3% and 39.5% (p=0.748), respectively. The prevalences of erosive reflux esophagitis (ERD) in peritoneal dialysis and hemodialysis patients were 16.7% and 23.7% (p=0.477), respectively. The prevalences of nonerosive reflux disease (NERD) in peritoneal dialysis and hemodialysis patients were 16.7% and 13.2% (p=0.685), respectively. The prevalences of GERD, ERD and NERD were higher than those of the general population. The risk factor for GERD was age in hemodialysis patients. CONCLUSIONS: The prevalence of GERD in dialysis patients was higher than that in the general population. However, there was no significant difference between peritoneal dialysis and hemodialysis patients. PMID- 24162708 TI - [Predictive factors of response to medical therapy in Crohn's disease patients with intestinal obstruction]. AB - BACKGROUND/AIMS: Crohn's disease is a chronic inflammatory bowel disease. Stricture is a very important indication for surgical intervention as strictures can lead to intestinal obstruction. Strictures can be divided into inflammatory and fibrous strictures. Intestinal obstruction due to inflammatory stricture is expected to be resolved with medical treatment. However, factors that can predict the response to medical treatments are unknown. In the present study, we aimed to identify the factors that can predict the response to medical treatments in Crohn's disease patients with intestinal obstruction. METHODS: Data were collected by retrospectively reviewing the medical records of patients with Crohn's disease who visited the emergency department at Samsung Medical Center in Seoul from January 1, 2000 to December 31, 2010 because of intestinal obstruction. Based on the response to medical treatments, we classified the patients as responders and non-responders and compared the clinical, biochemical, and radiological findings of the two groups. RESULTS: A total of 39 patients were enrolled. Twenty-nine patients responded to medical treatments whereas 10 patients did not. Significant differences were observed between the two groups in terms of vomiting and duration of disease before the development of obstruction. CONCLUSIONS: Patients who responded to the medical treatments exhibited a higher incidence of vomiting and longer duration of disease before the development of obstruction. However, further prospective studies are needed to identify the factors that can predict the response to medical treatments. PMID- 24162709 TI - [Advanced neoplasm detection and its associated factors in colonoscopic surveillance of endoscopically resected early colorectal cancer]. AB - BACKGROUND/AIMS: Early colon cancer can be effectively diagnosed and treated by colonoscopy, and surveillance colonoscopy is necessary to detect precursor lesions or new early colon cancer. We analyzed the surveillance results of patients with endoscopically resected early colon cancer to evaluate the detection rate of advanced neoplasia and its associated factors. METHODS: We conducted a retrospective study at Soonchunhyang University Seoul Hospital, from May 2003 to December 2011. Patients who underwent endoscopic resection for early colon cancer, showed mucosal and submucosal invasion on histopathologic examination, and received surveillance colonoscopy at least once were enrolled in the current study. Patients who underwent operation and those who were lost during surveillance period were excluded. RESULTS: Among a total of 305 patients diagnosed with early colon cancer, 211 patients met our inclusion criteria. Of these patients, 15 (7.1%) advanced neoplasias were detected at first colonoscopy. One hundred ninety-eight patients (93.8%) underwent surveillance colonoscopy within one year and 14 (7.0%) advanced neoplasias were detected in this group of patients. When patients with and without advanced neoplasia at first surveillance colonoscopy performed within one year were compared, inadequate bowel preparation (OR, 18.237; 95% CI, 3.741-88.895; p<0.001) and three or more colon polyps (OR, 9.479; 95% CI, 1.103-81.452; p=0.040) were significant risk factors for detecting advanced neoplasia. CONCLUSIONS: Considering the high detection rate of advanced neoplasia at first surveillance colonoscopy in patients with endoscopically resected early colon cancer, surveillance interval should be within one year, especially when the bowel preparation has been inadequate and three or more colon polyps have been detected. PMID- 24162711 TI - [Endoscopic submucosal dissection of a leiomyoma originating from the muscularis propria of upper esophagus]. AB - The technique of endoscopic submucosal dissection is occasionally used for resection of myogenic tumors originating from muscularis mucosa or muscularis propria of stomach and esophagus. However, endoscopic treatments for esophageal myogenic tumors >2 cm have rarely been reported. Herein, we report a case of large leiomyoma originating from muscularis propria in the upper esophagus. A 59 year-old woman presented with dysphagia. Esophagoscopy and endoscopic ultrasonography revealed an esophageal subepithelial tumor which measured 25 * 20 mm in size, originated from muscularis propria, and was located at 20 cm from the central incisors. The tumor was successfully removed by endoscopic submucosal dissection and there were no complications after en bloc resection. Pathologic examination was compatible with leiomyoma. PMID- 24162710 TI - Primary tumor maximum standardized uptake value measured on 18F fluorodeoxyglucose positron emission tomography-computed tomography is a prognostic value for survival in bile duct and gallbladder cancer. AB - BACKGROUND/AIMS: Few studies have assessed the prognostic value of the primary tumor maximum standardized uptake value (SUV max) measured by 2-[(18)F]-fluoro-2 deoxy-D-glucose PET-CT for patients with bile duct and gallbladder cancer. METHODS: A retrospective analysis of 61 patients with confirmed bile duct and gallbladder cancer who underwent FDG PET-CT in Kangbuk Samsung Medical Center (Seoul, Korea) from April 2008 to April 2011. Prognostic significance of SUV max and other clinicopathological variables was assessed. RESULTS: Twenty-three patients were diagnosed as common bile duct cancer, 17 as hilar bile duct cancer, 12 as intrahepatic bile duct cancer, and nine as gallbladder cancer. In univariate analysis, diagnosis of intrahepatic cholangiocarcinoma and gallbladder cancer, mass forming type, poorly differentiated cell type, nonsurgical treatment, advanced American Joint Committee on Cancer (AJCC) staging and primary tumor SUV max were significant predictors of poor overall survival. In multivariate analysis adjusted for age and sex, primary tumor SUV max (hazard ratio [HR], 4.526; 95% CI, 1.813-11.299), advanced AJCC staging (HR, 4.843; 95% CI, 1.760-13.328), and nonsurgical treatment (HR, 6.029; 95% CI, 1.989-18.271) were independently associated with poor overall survival. CONCLUSIONS: Primary tumor SUV max measured by FDG PET-CT is an independent and significant prognostic factor for overall survival in bile duct and gallbladder cancer. PMID- 24162712 TI - [Cytomegalovirus jejunitis diagnosed with single-balloon enteroscopy]. AB - Cytomegalovirus (CMV) infections are usually diagnosed in immunocompromised patients. A 74-year-old male without any significant medical history visited our center because of abdominal pain and diarrhea which began about a month ago. Abdominal computed tomography revealed segmental enhanced bowel wall thickening on jejunum and single-balloon enteroscopy showed multiple geographic shaped ulcerations covered with exudates on proximal jejunum. Biopsy samples taken during endoscopic examination demonstrated necrotic fibrinopurulent tissue debris and benign ulcer. Nested-PCR analysis of CMV DNA from jejunal tissue was positive. The patient was finally diagnosed with CMV jejunitis and was treated by intravenous ganciclovir for 14 days after which, abdominal pain and diarrhea improved. Our case shows that CMV jejunitis can occur in an immunocompetent adult as multiple jejunal ulcers which can be diagnosed using a single-balloon enteroscope. PMID- 24162713 TI - [A case of Crohn's disease accompanied by Peutz-Jeghers syndrome]. AB - Peutz-Jeghers syndrome is an autosomal dominant inherited disorder characterized by multiple gastrointestinal hamartomatous polyps and mucocutaneous pigmentation. Peutz-Jeghers syndrome has an incidence of approximately 1 in 25,000 to 300,000 births. Crohn's disease is a chronic inflammatory bowel disease that typically manifests as regional enteritis with its incidence ranging from 3.1 to 14.6 cases per 100,000 person-years in North America. Herein, we report a case of a 30-year old male patient who had both Peutz-Jeghers syndrome and Crohn's disease. We believe that this is the first case in Korea and the second report in the English literatures on Peutz-Jeghers syndrome coincidentally accompanied by Crohn's disease. PMID- 24162714 TI - [A case of pleomorphic liposarcoma in a patient with Crohn's disease taking azathioprine]. AB - Azathioprine is frequently used for the treatment of inflammatory bowel diseases (IBD) such as Crohn's disease and ulcerative colitis. Lymphomas, squamous cell carcinomas, and undifferentiated pleomorphic sarcomas have been reported among patients receiving azathioprine therapy. Herein, we report a case of pleomorphic liposarcoma of chest wall which occurred in a 44-year-old man with Crohn's disease taking azathioprine. He was diagnosed with Crohn's disease 3 years ago after suffering from abdominal pain and hematochezia for 12 years. He had been taking 50 mg of azathioprine per day for 23 months when he visited the thoracic and cardiovascular surgery clinic due to right chest palpable mass that had rapidly grown during the past 2 months. Excisional biopsy was performed and the mass was diagnosed as pleomorphic liposarcoma. Therefore, he underwent radical excision of the right chest wall mass, which measured 11.0 * 6.5 cm in size. He is scheduled to receive radiation therapy and chemotherapy. PMID- 24162717 TI - Intra-articular adhesions following hip arthroscopy: a risk factor analysis. AB - PURPOSE: The purpose of this study was to evaluate possible risk factors for symptomatic adhesions after hip arthroscopy. METHODS: Data were analysed from hip arthroscopies performed between 2005 and 2009. Only primary hip arthroscopies were included. Data collected included demographics, primary treatment, rehabilitation, revision surgery, and presence of adhesions at revision. RESULTS: One thousand two hundred and sixty-four hips in patients 18 years or older underwent primary hip arthroscopy during the defined period. Eight underwent revision hip arthroscopy by a different surgeon. Patients under 30 years of age were 5.9 times more likely to be in the adhesion group [95 % CI 3.1-11.5]. Patients who underwent microfracture were 3.1 times less likely to have adhesions compared to patients who did not [95 % CI 1.1-8.2]. Patients who did not receive circumduction therapy were 4.1 times more likely to have adhesions compared to those who performed circumduction exercises [95 % CI 1.25-11.0]. CONCLUSION: Risk factors for adhesions following hip arthroscopy identified were age under 30, modified Harris Hip score under 50, no microfracture performed, and rehabilitation without circumduction. PMID- 24162716 TI - Simultaneous zinc-finger nuclease editing of the HIV coreceptors ccr5 and cxcr4 protects CD4+ T cells from HIV-1 infection. AB - HIV-1 entry into CD4(+) T cells requires binding of the virus to CD4 followed by engagement of either the C-C chemokine receptor 5 (CCR5) or C-X-C chemokine receptor 4 (CXCR4) coreceptor. Pharmacologic blockade or genetic inactivation of either coreceptor protects cells from infection by viruses that exclusively use the targeted coreceptor. We have used zinc-finger nucleases to drive the simultaneous genetic modification of both ccr5 and cxcr4 in primary human CD4(+) T cells. These gene-modified cells proliferated normally and were resistant to both CCR5- and CXCR4-using HIV-1 in vitro. When introduced into a humanized mouse model of HIV-1 infection, these coreceptor negative cells engraft and traffic normally, and are protected from infection with CCR5- and CXCR4-using HIV-1 strains. These data suggest that simultaneous disruption of the HIV coreceptors may provide a useful approach for the long-term, drug-free treatment of established HIV-1 infections. PMID- 24162718 TI - Prevention of non-contact anterior cruciate ligament injuries in sports. Part II: systematic review of the effectiveness of prevention programmes in male athletes. AB - PURPOSE: To synthesize the results of systematic literature review focused on the effectiveness of anterior cruciate ligament (ACL) injury prevention programmes in male athletes. METHODS: All abstracts and articles of potential interest identified through the systematic literature search were reviewed in detail to determine on inclusion status. Information regarding prevention programmes to reduce ACL injuries or to modify risk factors for ACL injuries in male athletes was systematically extracted and included intervention and study design, characteristics of participants, sport and level of competition, characteristics of prevention programmes, results, and conclusions. All studies were evaluated for methodological quality to assess the risk of bias. RESULTS: The principal findings of this systematic review are as follows: (1) most of the studies applied prevention programmes that utilized risk factors as outcomes of interest as opposed to ACL injury incidence (5 and 2 studies, respectively); (2) the effectiveness of prevention programmes to reduce ACL injuries in male athletes is equivocal (1 in favour, 1 against) and only refers to soccer players; (3) the effectiveness of prevention programmes to modify risk factors for ACL injuries in male athletes is controversial (2 in favour, 3 against) and outcome data are limited to cutting manoeuvres. CONCLUSION: Data regarding the effectiveness of prevention programmes to reduce ACL injuries or to modify risk factors for ACL injuries in male athletes are scarce and not conclusive. Future research to better determine the most effective approaches to optimize the effectiveness of prevention programmes targeted to reduce ACL injuries in male athletes is warranted. PMID- 24162719 TI - Loading conditions of the knee: what does it mean? PMID- 24162715 TI - Recommendations for self-monitoring in pediatric diabetes: a consensus statement by the ISPED. AB - A panel of experts of the Italian Society of Pediatric Endocrinology and Diabetology comprehensively discussed and approved the Italian recommendations regarding self-monitoring of blood glucose, continuous glucose monitoring and other measures of glycemic control in children and adolescents with type 1 diabetes. After an extensive review of the literature, we took these issues into account: self-monitoring blood glucose, continuous glucose monitoring, glycemic variability, glycosuria, ketonuria, ketonemia, glycated hemoglobin, fructosamine and glycated albumin, logbook, data downloading, lancing devices, carbohydrate counting, and glycemic measurements at school. We concluded that clinical guidelines on self-management should be developed in every country with faithful adaptation to local languages and taking into account specific contexts and local peculiarities, without any substantial modifications to the international recommendations. We believe that the National Health Service should provide all necessary resources to ensure self-monitoring of blood glucose and possibly continuous glucose monitoring of all children and adolescents with type 1 diabetes, according to the standards of care provided by these recommendations and internationally. PMID- 24162720 TI - Abdominoperineal pull-through resection with delayed coloanal anastomosis as treatment option for complex recto-urinary fistulas. PMID- 24162721 TI - Optoelectronic properties of graphene thin films deposited by a Langmuir-Blodgett assembly. AB - Large area thin films of few-layered unfunctionalized graphene platelets are developed with fine control over the thickness. The thin films are obtained by a Langmuir-Blodgett assembly at the interface of graphene solution in N-methyl-2 pyrrolidone (NMP) and water, and their optoelectronic properties and conduction mechanism are investigated in relation to lateral flake size and thin film thickness. The electrical conductivity and carrier mobility are affected by the flake size (200 nm to 1 MUm) and by the packing of the nanostructure platelet network. General effective medium theory is used to explain the thickness dependent conductivity and to determine the percolation threshold film thickness which was found to be about 10 nm (at a volume fraction of ~39%) for a Langmuir Blodgett film of an average platelet lateral size of 170 +/- 40 nm. The electronic behaviour of the material shows more similarities with polycrystalline turbostratic graphite than thin films of reduced graphene oxide, carbon nanotubes, or disordered conducting polymers. While in these systems the conduction mechanism is often dominated by the presence of an energy barrier between conductive and non-conductive regions in the network, in the exfoliated graphene networks the conduction mechanism can be explained by the simple two band model which is characteristic of polycrystalline graphite. PMID- 24162722 TI - Truncation of a mannanase from Trichoderma harzianum improves its enzymatic properties and expression efficiency in Trichoderma reesei. AB - To obtain high expression efficiency of a mannanase gene, ThMan5A, cloned from Trichoderma harzianum MGQ2, both the full-length gene and a truncated gene (ThMan5ADeltaCBM) that contains only the catalytic domain, were expressed in Trichoderma reesei QM9414 using the strong constitutive promoter of the gene encoding pyruvate decarboxylase (pdc), and purified to homogeneity, respectively. We found that truncation of the gene improved its expression efficiency as well as the enzymatic properties of the encoded protein. The recombinant strain expressing ThMan5ADeltaCBM produced 2,460 +/- 45.1 U/ml of mannanase activity in the culture supernatant; 2.3-fold higher than when expressing the full-length ThMan5A gene. In addition, the truncated mannanase had superior thermostability compared with the full-length enzyme and retained 100 % of its activity after incubation at 60 degrees C for 48 h. Our results clearly show that the truncated ThMan5A enzyme exhibited improved characteristics both in expression efficiency and in its thermal stability. These characteristics suggest that ThMan5ADeltaCBM has potential applications in the food, feed, paper, and pulp industries. PMID- 24162723 TI - Surface functional groups of carbon nanotubes to manipulate capacitive behaviors. AB - The covalent functionalization of carbon nanotubes (CNTs) is a basic but important chemistry that can modify their physicochemical properties, resolve their poor dispersion capability, and improve their capacitance to enable their use as high-energy supercapacitors. However, the relationship between functional groups on the CNT surface and their capacitive characteristics has not yet been explored. Here, we demonstrate the influence of carboxylic, sulfonic, and amine groups tethered to CNTs (Cf-CNTs, Sf-CNTs, and Nf-CNTs, respectively) on capacitor performance in an organic electrolyte. The Cf-CNTs show the highest specific capacitance of 129.4 F g(-1), four-fold greater than 31.2 F g(-1) of pristine CNTs, but they reveal the lowest rate capability of 57%. In contrast, the Sf- and Nf-CNTs exhibit specific capacitances of 70.9 F g(-1) and 83.6 F g( 1), two-fold greater than that of pristine CNTs, along with a good rate capability greater than 80%. Despite their pseudocapacitive nature, all functionalized CNTs show a cyclic stability of more than 80% after 500 cycles due to the electrochemical stability of the functional groups. As demonstrated by spectroscopic analysis, the supercapacitive behaviors of the functionalized CNTs originate from specific interactions between functional groups and lithium ions and the alteration of the electronic structure arising from covalent functionalization. PMID- 24162725 TI - Endonuclease-G and the pathways to dopaminergic neurodegeneration: a question of location? PMID- 24162724 TI - Listeria phospholipases subvert host autophagic defenses by stalling pre autophagosomal structures. AB - Listeria can escape host autophagy defense pathways through mechanisms that remain poorly understood. We show here that in epithelial cells, Listeriolysin (LLO)-dependent cytosolic escape of Listeria triggered a transient amino-acid starvation host response characterized by GCN2 phosphorylation, ATF3 induction and mTOR inhibition, the latter favouring a pro-autophagic cellular environment. Surprisingly, rapid recovery of mTOR signalling was neither sufficient nor necessary for Listeria avoidance of autophagic targeting. Instead, we observed that Listeria phospholipases PlcA and PlcB reduced autophagic flux and phosphatidylinositol 3-phosphate (PI3P) levels, causing pre-autophagosomal structure stalling and preventing efficient targeting of cytosolic bacteria. In co-infection experiments, wild-type Listeria protected PlcA/B-deficient bacteria from autophagy-mediated clearance. Thus, our results uncover a critical role for Listeria phospholipases C in the inhibition of autophagic flux, favouring bacterial escape from host autophagic defense. PMID- 24162726 TI - Protection by natural IgG: a sweet partnership with soluble lectins does the trick! PMID- 24162727 TI - Elevated expression of prostaglandin E2 synthetic pathway in skeletal muscle of prior polio patients. AB - OBJECTIVE: The aim of this study was to investigate signs of inflammation in muscle of patients with prior polio, since the main symptoms in these patients are muscle pain, weakness and fatigue. In the context of pain and inflammation, the prostaglandin E2 pathway is of interest. Prostaglandin E2 has many biological actions and is a mediator of inflammation and pain. PATIENTS AND METHODS: Skeletal muscle biopsies from 8 patients with prior polio and post-polio symptoms, presenting with pain and muscular weakness, and from 6 healthy controls were studied. Immunohistochemistry, conventional microscopy, and computerized image analysis were performed. RESULTS: There was statistically significant higher expression of enzymes of the prostaglandin E2 synthetic pathway, in muscle from patients, compared with controls. Expression of prostaglandin enzymes was mainly in scattered cells and blood vessels, and may indicate an inflammatory process of the muscle, which could be secondary to systemic inflammation. CONCLUSION: This data may indicate an inflammatory process in muscle of prior polio patients. Up-regulation of the prostaglandin E2 pathway reveals a potential background to the pain experienced by these patients, and may provide opportunities for directed pharmacological and physical therapies, which could lead to better outcomes of rehabilitation interventions. PMID- 24162728 TI - Effects of herbal infusions, tea and carbonated beverages on alcohol dehydrogenase and aldehyde dehydrogenase activity. AB - Various alcoholic beverages containing different concentrations of ethanol are widely consumed, and excessive alcohol consumption may result in serious health problems. The consumption of alcoholic beverages is often accompanied by non alcoholic beverages, such as herbal infusions, tea and carbonated beverages to relieve drunk symptoms. The aim of this study was to supply new information on the effects of these beverages on alcohol metabolism for nutritionists and the general public, in order to reduce problems associated with excessive alcohol consumption. The effects of 57 kinds of herbal infusions, tea and carbonated beverages on alcohol dehydrogenase and aldehyde dehydrogenase activity were evaluated. Generally, the effects of these beverages on alcohol dehydrogenase and aldehyde dehydrogenase activity are very different. The results suggested that some beverages should not be drank after excessive alcohol consumption, and several beverages may be potential dietary supplements for the prevention and treatment of problems related to excessive alcohol consumption. PMID- 24162730 TI - Subtypes of hypertension and risk of stroke in rural Chinese adults. AB - BACKGROUND: Hypertension is a definitive risk factor for stroke. We examined the associations between hypertension subtypes and stroke incidence in rural Chinese adults. METHODS: We conducted a prospective study in a sample of 38,949 rural Chinese adults aged >=35 years and free from stroke at baseline. The subtypes of hypertension were defined as isolated systolic hypertension (ISH), isolated diastolic hypertension (IDH), systolic and diastolic hypertension (SDH), and managed hypertension (MHT). The relative risks of stroke with the subtypes of hypertension, compared with normotensive subjects, were estimated using the Cox model after adjusting for age, sex, and other confounders. RESULTS: The prevalence of hypertension was as follows: SDH = 18.6%, ISH = 10.2%, IDH = 5.8%, and MHT = 0.4%. During a total of 168,023 person-years of follow-up, 858 subjects developed stroke. The incidence rate per 100,000 person-years of overall first ever stroke was 510.6. The SDH group was at the highest risk of stroke among all the hypertensive subjects. The hazard ratio was 2.13 (95% confidence interval (CI) = 1.78-2.55) for all stroke, 2.74 (95% CI = 2.08-3.60) for hemorrhagic stroke, and 1.92 (95% CI = 1.50-2.45) for ischemic stroke. CONCLUSIONS: SDH patients warrant the most attention for prevent of stroke. However, ISH and IDH are also independent predictors of stroke. The risk factors for stroke, especially hypertension, were not controlled in the rural population we studied. More aggressive efforts to control the risk factors for stroke in rural areas are needed. PMID- 24162729 TI - Cardiac function in renovascular hypertensive patients with and without renal dysfunction. AB - BACKGROUND: Hypertension impairs left ventricular (LV) diastolic and systolic function, which might be aggravated by inflammation or neurohumoral activation. We hypothesized that LV diastolic dysfunction is more common in patients with renovascular hypertension (RVHT) compared with essential hypertension (EHT). METHODS: Hypertensive patients who underwent both renal imaging to exclude RVHT and cardiac echocardiography within a 3-year period were identified retrospectively. Patients with significant renovascular disease were included in the RVHT group (n = 75); those without significant renovascular disease were included in the EHT group (n = 69). Cardiac function and structure were compared. RESULTS: Baseline renal function was preserved (serum creatinine <= 2mg/dl) in EHT patients and impaired (serum creatinine > 2mg/dl) in only 9 RVHT patients. RVHT patients had higher systolic blood pressure, E/e' ratio, and greater prevalence of concentric hypertrophy but lower estimated glomerular-filtration rate (eGFR) compared with EHT patients. Increased prevalence of LV diastolic dysfunction remained statistically significant in patients with RVHT after multivariable adjustment for age, sex, blood pressure, eGFR, diabetes, smoking, and statin use, with a relative risk (95% CI) for abnormal E/e' of 1.70 (95% confidence interval = 1.05-2.90; P = 0.03) compared with EHT. RVHT patients with severe renal dysfunction showed greater impairments in cardiac systolic and diastolic function compared with those in EHT patients or preserved renal function RVHT patients. CONCLUSIONS: Among hypertensive patients undergoing echocardiography, cardiac structure and diastolic function are impaired in RVHT patients compared with EHT patients and remain different after adjustment for multiple significant covariables. When associated with significant renal dysfunction, RVHT aggravates LV hypertrophy and both systolic and diastolic dysfunction. Hence, identification of RVHT and renal dysfunction warrants development of targeted management strategies. PMID- 24162731 TI - Prioritization of themes and research questions for health outcomes in natural disasters, humanitarian crises or other major healthcare emergencies. AB - People making decisions about interventions, actions and strategies for natural disasters, humanitarian crises and other major healthcare emergencies need access to reliable evidence to help ensure that the choices they make are likely to do more good than harm. However, there are many gaps in this evidence base in a wide range of areas. This paper reports a priority setting exercise that was coordinated by Evidence Aid to identify thirty priorities for up-to-date systematic reviews of the effects of interventions, actions and strategies on health outcomes, which would be particularly relevant to those involved in disaster risk reduction, planning response and recovery at an international level. It builds from an ongoing needs assessment that had identified a couple of hundred relevant research questions, which were grouped under 43 themes. Ten of these themes were prioritized by an online survey and the questions attached to these themes were then discussed at a face-to-face meeting, leading to the generation of a list of 30 top priority questions which is presented in this paper. We recognize that a different group of people might have come to different priorities but regard this as an important starting point, and the extensive efforts that were made to be inclusive in gathering opinions should help ensure their wide relevance. PMID- 24162732 TI - Enhancement of PbS quantum dot-sensitized photocurrents using plasmonic gold nanoparticles. AB - For improvement of the conversion efficiency of solar cells, it is important to make effective use of near-infrared light, which accounts for about 40% of sunlight energy. Although solar cells based on quantum dots (QDs) such as PbS have been studied for the use of near-infrared light, their photoabsorption is not necessarily sufficient. In this study, we coupled PbS QD-sensitized solar cells with plasmonic Au nanoparticles (NPs) as light-harvesting antennae. As a result, the photocurrents of the cells were enhanced in the visible and near infrared regions (500-1200 nm) due to interparticle plasmon coupling of spherical Au NPs. The maximum enhancement factor was 6. We also found that the optimum QD NP spacing is shorter and that the maximum enhancement factor is higher when smaller QDs are used. These results suggest that a negative effect, quenching via energy transfer from QD to NP, is less significant for smaller PbS QDs. PMID- 24162733 TI - Matching of Soulmates: coevolution of snoRNAs and their targets. AB - Ribosomal and small nuclear RNAs (snRNAs) comprise numerous modified nucleotides. The modification patterns are retained during evolution, making it even possible to project them from yeast onto human. The stringent conservation of modification sites and the slow evolution of rRNAs and snRNAs contradicts the rapid evolution of small nucleolar RNA (snoRNA) sequences. To explain this discrepancy, we investigated the coevolution of snoRNAs and their targeted sites throughout vertebrates. To measure and evaluate the conservation of RNA-RNA interactions, we defined the interaction conservation index (ICI). It combines the quality of individual interaction with the scope of its conservation in a set of species and serves as an efficient measure to evaluate the conservation of the interaction of snoRNA and target. We show that functions of homologous snoRNAs are evolutionarily stable, thus, members of the same snoRNA family guide equivalent modifications. The conservation of snoRNA sequences is high at target binding regions while the remaining sequence varies significantly. In addition to elucidating principles of correlated evolution, we were able, with the help of the ICI measure, to assign functions to previously orphan snoRNAs and to associate snoRNAs as partners to known chemical modifications unassigned to a given snoRNA. Furthermore, we used predictions of snoRNA functions in conjunction with sequence conservation to identify distant homologies. Because of the high overall entropy of snoRNA sequences, such relationships are hard to detect by means of sequence homology search methods alone. PMID- 24162734 TI - Diversity of microbial growth strategies in a limited-nutrient world. PMID- 24162735 TI - Orthologous mammalian APOBEC3A cytidine deaminases hypermutate nuclear DNA. AB - The human APOBEC3 gene cluster locus encodes polynucleotide cytidine deaminases. Although many act as viral restriction factors through mutation of single stranded DNA, recent reports have shown that human APOBEC3A was capable of efficiently hypermutating nuclear DNA and inducing DNA breaks in genomic DNA. In addition, the enzyme was unique in efficiently deaminating 5-methylcytidine in single-stranded DNA. To appreciate the evolutionary relevance of these activities, we analyzed A3A-related enzymes from the rhesus and tamarin monkey, horse, sheep, dog, and panda. All proved to be orthologous to the human enzyme in all these activities revealing strong conservation more than 148 My. Hence, their singular role in DNA catabolism is a well-established mechanism probably outweighing any deleterious or pathological roles such as genomic instability and cancer formation. PMID- 24162736 TI - Genomic analyses identify distinct patterns of selection in domesticated pigs and Tibetan wild boars. AB - We report the sequencing at 131* coverage, de novo assembly and analyses of the genome of a female Tibetan wild boar. We also resequenced the whole genomes of 30 Tibetan wild boars from six major distributed locations and 18 geographically related pigs in China. We characterized genetic diversity, population structure and patterns of evolution. We searched for genomic regions under selection, which includes genes that are involved in hypoxia, olfaction, energy metabolism and drug response. Comparing the genome of Tibetan wild boar with those of neighboring Chinese domestic pigs further showed the impact of thousands of years of artificial selection and different signatures of selection in wild boar and domestic pig. We also report genetic adaptations in Tibetan wild boar that are associated with high altitudes and characterize the genetic basis of increased salivation in domestic pig. PMID- 24162738 TI - New loci associated with chronic hepatitis B virus infection in Han Chinese. AB - Chronic hepatitis B virus (HBV) infection is a challenging global health problem. To identify genetic loci involved in chronic HBV infection, we designed a three phase genome-wide association study in Han Chinese populations. The discovery phase included 951 HBV carriers (cases) and 937 individuals who had naturally cleared HBV infection (controls) and was followed by independent replications with a total of 2,248 cases and 3,051 controls and additional replications with 1,982 HBV carriers and 2,622 controls from the general population. We identified two new loci associated with chronic HBV infection: rs3130542 at 6p21.33 (near HLA-C, odds ratio (OR) = 1.33, P = 9.49 * 10(-14)) and rs4821116 at 22q11.21 (in UBE2L3, OR = 0.82, P = 1.71 * 10(-12)). Additionally, we replicated the previously identified associations of HLA-DP and HLA-DQ variants at 6p21.32 with chronic HBV infection. These findings highlight the importance of HLA-C and UBE2L3 in the clearance of HBV infection in addition to HLA-DP and HLA-DQ. PMID- 24162741 TI - Trifluoromethyl ketones: properties, preparation, and application. AB - Trifluoromethyl ketones (TFMKs) are exceedingly valuable synthetic targets in their own right and as synthons in the construction of fluorinated pharmacons. This Feature Article provides an overview of the properties of TFMKs, an in-depth discussion of the methods available for their synthesis, and two illustrative examples of their application as key intermediates in medicinal chemistry. PMID- 24162740 TI - Vitamin C modulates TET1 function during somatic cell reprogramming. AB - Vitamin C, a micronutrient known for its anti-scurvy activity in humans, promotes the generation of induced pluripotent stem cells (iPSCs) through the activity of histone demethylating dioxygenases. TET hydroxylases are also dioxygenases implicated in active DNA demethylation. Here we report that TET1 either positively or negatively regulates somatic cell reprogramming depending on the absence or presence of vitamin C. TET1 deficiency enhances reprogramming, and its overexpression impairs reprogramming in the context of vitamin C by modulating the obligatory mesenchymal-to-epithelial transition (MET). In the absence of vitamin C, TET1 promotes somatic cell reprogramming independent of MET. Consistently, TET1 regulates 5-hydroxymethylcytosine (5hmC) formation at loci critical for MET in a vitamin C-dependent fashion. Our findings suggest that vitamin C has a vital role in determining the biological outcome of TET1 function at the cellular level. Given its benefit to human health, vitamin C should be investigated further for its role in epigenetic regulation. PMID- 24162739 TI - Distinct H3F3A and H3F3B driver mutations define chondroblastoma and giant cell tumor of bone. AB - It is recognized that some mutated cancer genes contribute to the development of many cancer types, whereas others are cancer type specific. For genes that are mutated in multiple cancer classes, mutations are usually similar in the different affected cancer types. Here, however, we report exquisite tumor type specificity for different histone H3.3 driver alterations. In 73 of 77 cases of chondroblastoma (95%), we found p.Lys36Met alterations predominantly encoded in H3F3B, which is one of two genes for histone H3.3. In contrast, in 92% (49/53) of giant cell tumors of bone, we found histone H3.3 alterations exclusively in H3F3A, leading to p.Gly34Trp or, in one case, p.Gly34Leu alterations. The mutations were restricted to the stromal cell population and were not detected in osteoclasts or their precursors. In the context of previously reported H3F3A mutations encoding p.Lys27Met and p.Gly34Arg or p.Gly34Val alterations in childhood brain tumors, a remarkable picture of tumor type specificity for histone H3.3 driver alterations emerges, indicating that histone H3.3 residues, mutations and genes have distinct functions. PMID- 24162743 TI - MiR-200a impairs glioma cell growth, migration, and invasion by targeting SIM2-s. AB - Recently, single-minded homolog 2-short form (SIM2-s) was reported to be related to tumor development and progression and to be elevated in many human cancer cells. In this study, we investigated the factors that contribute to the regulation of SIM2-s expression in gliomas. The results showed that SIM2-s was elevated in gliomas. In addition, inhibition of SIM2-s reduced glioma cell growth, migration, and invasion. Next, we demonstrated that SIM2-s is a functional target of miR-200a. Further, miR-200a is downregulated in human glioma and inhibition of miR-200a caused upregulation of SIM2-s in T98G cells and promoted their motility. Finally, blockage of miR-200a expression in a mouse model of human glioma resulted in significant promotion of tumor growth. These findings suggest that miR-200a could serve as a therapeutic tool for glioma. PMID- 24162745 TI - Health disparities in human papillomavirus vaccine coverage: trends analysis from the National Immunization Survey-Teen, 2008-2011. AB - Adolescent uptake of human papillomavirus (HPV) vaccine remains low. We evaluated HPV vaccine uptake patterns over 2008-2011 by race/ethnicity, poverty status, and the combination of race/ethnicity and poverty status, utilizing National Immunization Survey-Teen data. Minority and below-poverty adolescents consistently had higher series initiation than white and above-poverty adolescents. PMID- 24162744 TI - Implementing a strategy for monitoring inpatient antimicrobial use among hospitals in the United States. AB - The Centers for Disease Control and Prevention is pursuing 3 distinct, complementary efforts focused on providing data for action, including facility level use metrics for benchmarking across comparable patient care settings, national estimates of usage patterns using sentinel surveillance sites, and limited assessments using proprietary data. PMID- 24162742 TI - Age-related differences in the automatic processing of single letters: implications for selective attention. AB - Older adults exhibit diminished ability to inhibit the processing of visual stimuli that are supposed to be ignored. The extent to which age-related changes in early visual processing contribute to impairments in selective attention remains to be determined. Here, 103 adults, 18-85 years of age, completed a color selective attention task in which they were asked to attend to a specified color and respond to designated target letters. An optimal approach would be to initially filter according to color and then process letter forms in the attend color to identify targets. An asymmetric N170 ERP component (larger amplitude over left posterior hemisphere sites) was used as a marker of the early automatic processing of letter forms. Young and middle-aged adults did not generate an asymmetric N170 component. In contrast, young-old and old-old adults produced a larger N170 over the left hemisphere. Furthermore, older adults generated a larger N170 to letter than nonletter stimuli over the left, but not right hemisphere. More asymmetric N170 responses predicted greater allocation of late selection resources to target letters in the ignore color, as indexed by P3b amplitude. These results suggest that unlike their younger counterparts, older adults automatically process stimuli as letters early in the selection process, when it would be more efficient to attend to color only. The inability to ignore letters early in the processing stream helps explain the age-related increase in subsequent processing of target letter forms presented in the ignore color. PMID- 24162746 TI - Sleepwalking, violence and desire in the middle ages. AB - This study discusses the phenomenon of medieval sleepwalking as a disorder of body and soul. In the thirteenth and early fourteenth centuries, medical and natural philosophical writers began to identify the category of the sleepwalker with unusual precision: the most common example of the disorder involved an aristocrat who rose, armed himself, and mounted his horse, all the while imagining that he was fighting enemies or hunting deer. Explanations for this extraordinary behaviour involved the physiology of sleep and the functioning of the brain. In particular, theorists believed that the imagination, a storehouse of images located towards the front of the brain, took control because reason and sensation had been disabled during sleep. As a consequence, daytime fears and traumas could come to the fore for some sleepers, causing them to act and react in their sleep in ways they could not, or were not willing to do, in their waking, rational state. As such, medieval medical writers viewed sleepwalking as a dangerous, disordered state which called into question the Aristotelian divide between waking and sleeping as well as the categories of reason, sensation and voluntary motion. PMID- 24162747 TI - Topographic, corneal wavefront, and refractive outcomes 2 years after collagen crosslinking for progressive keratoconus. AB - PURPOSE: The aim was to report the corneal higher-order aberrations (HOA), the topographic metrics, and the visual and refractive outcomes 2 years after performing collagen crosslinking (CXL) for progressive keratoconus. The correlation among corneal HOAs, topographic metrics, and visual acuity changes was also investigated. METHODS: This is a prospective case series involving 42 eyes from 32 patients with progressive keratoconus treated with CXL. The main outcomes measured at baseline and 6, 12, and 24 months after treatment were uncorrected distance visual acuity (UDVA), corrected distance visual acuity (CDVA), refractive changes, topographic data, and corneal aberrations. RESULTS: Two years after CXL treatment, the UDVA (P < 0.001), CDVA (P < 0.001), and spherical equivalent (P = 0.048) improved significantly. The corneal topographic data revealed significant decreases in apical keratometry (P < 0.001), differential keratometry (P = 0.031), and central keratometry (P = 0.003) compared with the baseline measurements. Aberration analyses revealed a significant reduction in coma (P = 0.016), trefoil (P = 0.018), secondary astigmatism (P < 0.001), quatrefoil (P = 0.031), secondary coma (P < 0.001), and secondary trefoil (P = 0.001). Corneal HOA (except quatrefoil) demonstrated a significant correlation with postoperative CDVA; the highest correlations were for coma (rho = 0.703, P < 0.001), secondary astigmatism (rho = 0.519, P = 0.001), and total HOA (rho = 0.487, P = 0.001). However, the corneal HOA changes were not statistically associated with improved visual acuity. After treatment, the reduction in apical keratometry was the only variable that correlated with the improvement in the CDVA (rho = 0.319, P = 0.042). CONCLUSIONS: After 2 years, CXL was found to be effective in improving the UDVA, CDVA, topographic metrics, and most corneal HOAs in eyes with progressive keratoconus. A significant reduction was observed in apical keratometry, and this reduction directly correlated with an improvement in visual acuity. PMID- 24162749 TI - Cultivation and characterization of limbal epithelial stem cells on contact lenses with a feeder layer: toward the treatment of limbal stem cell deficiency. AB - PURPOSE: Limbal epithelial sheets are used to promote corneal surface reconstruction after the detection of limbal epithelial stem cell deficiency. The aim of this study was to evaluate a novel combination of limbal stem cells (LSCs) maintained on contact lenses (CLs) in the presence of a 3T3 feeder cell layer regarding preservation of stem cell phenotype and the potential use for future in vivo transplantation. METHODS: Limbal epithelial cells were isolated from rabbit cornea and cultured with 3T3 cells on CLs. The preservation of LSC phenotype was determined using p63alpha and ABCG2 immunostaining, whereas epithelial differentiation was evaluated using CK3 and CK19. The colony-forming assay was used to determine the percentage of LSCs in cultures. Finally, CLs seeded with PKH26-labeled LSCs were transferred to rabbit eyes after performing a surgical keratectomy, and the transition and phenotype of labeled cells on the corneal surface were evaluated in whole-mount corneas. RESULTS: Proliferation of individual limbal cells was observed on CLs with a 3T3 feeder cell layer, showing holoclone formation and retention of viable stem or progenitor cell phenotype. Finally, a higher transition of cultivated cells after a dual sequential CL transplantation to the ocular surface was observed, showing the preservation of the LSC phenotype in the corneal surface. CONCLUSIONS: Limbal cells cultivated on a CL carrier overlaying a 3T3 feeder layer are mitotically active and retain the LSC phenotype. This novel technique of using CLs as a carrier offers an easily manipulable and nonimmunogenic method for transferring LSCs for ocular surface reconstruction in patients with limbal epithelial stem cell deficiency. PMID- 24162748 TI - Post-DSAEK optical changes: a comprehensive prospective analysis on the role of ocular wavefront aberrations, haze, and corneal thickness. AB - PURPOSE: The aim was to assess the visual impact of ocular wavefront aberrations, corneal thickness, and corneal light scatter prospectively after performing a Descemet stripping automated endothelial keratoplasty (DSAEK) in humans. METHODS: Data were obtained prospectively from 20 eyes preoperatively and at 1, 3, 6, and 12 months post-DSAEK. At each visit, the best spectacle-corrected visual acuity and visual acuity with glare (brightness acuity testing) were recorded, and ocular wavefront measurements and corneal optical coherence tomography (OCT) were performed. The magnitude and the sign of individual Zernike terms [higher-order aberrations (HOAs)] were determined. Epithelial, host stromal, donor stromal, and total corneal thicknesses were quantified. The brightness and intensity profiles of OCT images were generated to quantify light scatter in the whole cornea, subepithelial region, anterior and posterior host stroma, interface, and donor stroma. RESULTS: The mean best spectacle-corrected visual acuity and glare disability at low light levels improved from 1 to 12 months post-DSAEK. All corneal thicknesses and ocular lower-order aberrations and HOAs were found to be stable from 1 to 12 months, whereas total corneal, host stromal, and interface brightness intensities decreased significantly over the same period. A repeated measures analysis of variance performed across the follow-up period revealed that the change in scatter, but not the change in the HOAs, could account for the variability occurring in the acuity from 1 to 12 months post-DSAEK. CONCLUSIONS: Although ocular HOAs and scatter are both elevated over normal values post-DSAEK, our results demonstrate that the improvements in visual performance occurring over the first year post-DSAEK are associated with decreasing light scatter. In contrast, there were no significant changes in the ocular HOAs during this time. Because corneal light scatter decreased between 1 and 12 months despite there being stable corneal thicknesses over the same period, we conclude that factors that induced light scatter, other than tissue thickness or swelling (corneal edema), significantly impacted the visual improvements that occurred over time post-DSAEK. A better understanding of the cellular and extracellular matrix changes of the subepithelial region and interface, incurred by the surgical creation of a lamellar host-graft interface, and the subsequent healing of these tissues, is warranted. PMID- 24162750 TI - Limbal stem cell-sparing lamellar keratoplasty for the management of advanced keratoglobus. AB - PURPOSE: To describe the technique and outcomes of limbal stem cell-sparing lamellar keratoplasty (LSCS-LKP) for the management of advanced keratoglobus (KGB). METHODS: In a sequential interventional case series from March 2010 to December 2012, 8 eyes of 6 patients with advanced KGB underwent an LSCS-LKP. Three patients had isolated KGB, 2 were affected with the Ehlers-Danlos syndrome, and the other subject had osteogenesis imperfecta. Epithelial healing, anatomical results (corneal thickness and keratometry), and visual outcomes were evaluated after this intervention. RESULTS: Three of the 6 patients were male. Complete epithelial healing occurred in 7 eyes during 2 weeks. Refractory persistent epithelial defect and graft melting occurred in 1 eye. Corneal thickness increased and central keratometry decreased after the LSCS-LKP was performed in all the patients. The patients were followed up for at least 6 months. Visual acuity improved in all eyes except 1. CONCLUSIONS: LSCS-LKP is an effective procedure for preserving ocular integrity and for improving visual acuity in patients with advanced KGB. Early surgical intervention can be considered before the occurrence of vision-threatening traumatic corneal rupture. PMID- 24162737 TI - Meta-analysis of 74,046 individuals identifies 11 new susceptibility loci for Alzheimer's disease. AB - Eleven susceptibility loci for late-onset Alzheimer's disease (LOAD) were identified by previous studies; however, a large portion of the genetic risk for this disease remains unexplained. We conducted a large, two-stage meta-analysis of genome-wide association studies (GWAS) in individuals of European ancestry. In stage 1, we used genotyped and imputed data (7,055,881 SNPs) to perform meta analysis on 4 previously published GWAS data sets consisting of 17,008 Alzheimer's disease cases and 37,154 controls. In stage 2, 11,632 SNPs were genotyped and tested for association in an independent set of 8,572 Alzheimer's disease cases and 11,312 controls. In addition to the APOE locus (encoding apolipoprotein E), 19 loci reached genome-wide significance (P < 5 * 10(-8)) in the combined stage 1 and stage 2 analysis, of which 11 are newly associated with Alzheimer's disease. PMID- 24162751 TI - Endothelial damage with two DSAEK insertion techniques performed by a novice corneal surgeon in residency training: a comparative analysis. AB - PURPOSE: The aim was to determine which of 2 commonly used nonfold donor insertion techniques was advantageous for initial Descemet stripping automated endothelial keratoplasty (DSAEK) cases. METHODS: This involved an ex vivo, prospective comparative case series of 20 randomized DSAEK lenticule insertions. DSAEK insertions were performed by a single novice corneal surgeon (PGY4 resident) in human cadaver eyes. Ten grafts were inserted using a Sheet glide (Surgical Glide; Beaver-Visitec International Inc, Waltham, MA) and 10 were inserted using an inserter device (EndoSerter; Ocular Systems Inc, Winston-Salem, NC). The grafts were explanted, stained with trypan blue and alizarin red S, and photographed for comparison with 5 control grafts. Endothelial damage was quantitatively evaluated using Adobe Photoshop 10.0 CS3 software (Adobe Systems, San Jose, CA). RESULTS: Endothelial cell loss (ECL) was 7.10% +/- 2.27% in controls, 12.31% +/- 4.74% in the inserter group, and 13.31% +/- 5.46% in the Sheet glide group (P = 0.07). Early cases (cases 1-5) had a greater ECL compared with what later cases had (cases 6-10) for the Sheet glide group. This difference was significant for the Sheet glide group (40.42% reduction for cases 6-10, P = 0.04) but not for the EndoSerter group (32.5% reduction for cases 6-10, P = 0.11). CONCLUSIONS: Quantitative analysis revealed no statistically significant difference in the ECL between the 2 methods. With surgeon experience, there was a trend toward less ECL using both methods but especially with the Sheet glide. A novice corneal surgeon may effectively use either of these nonfold methods for initial cases. The cadaver eye model described may be a potentially useful wet laboratory tool for novice surgeons to practice DSAEK lenticule insertion. PMID- 24162752 TI - Reply: To PMID 23377751. PMID- 24162753 TI - Combined tissue excision and corneal tuck for the surgical treatment of extremely advanced pellucid marginal corneal degeneration. AB - Pellucid marginal corneal degeneration (PMCD) is managed surgically in the advanced stages of the disease, but extreme thinning extending over a very wide area in most of the corneal circumference represents a true surgical challenge that makes conventional approaches unsuitable. Here, we present the results of a new procedure (partial excision of the corneal ectasia and tuck of the residual thinned corneal lips left behind) performed in 3 eyes of 2 patients with extremely advanced PMCD, judged unsuitable for undergoing conventional surgical approaches. Preoperatively, uncorrected visual acuity was limited to the perception of hand motion in 1 eye, which presented with hydrops, and to finger counting at 1 m in the other 2 eyes. With a follow-up of 3 to 4 years, a complete, stable resolution of the ectasia was seen in all cases. As early as 1 year postoperatively, the best spectacle-corrected visual acuity was 20/30 to 20/50 with no subsequent substantial changes. Partial excision of the ectasia and tucking was found to work successfully at achieving both a new corneal shape compatible with visual rehabilitation and restoring peripheral corneal thickness in advanced cases of PMCD that were unsuitable for conventional surgery. PMID- 24162754 TI - Self-assembling colloidal system for the ocular administration of cyclosporine A. AB - PURPOSE: In this study, we developed a self-assembling micellar system to deliver cyclosporine A (CsA) in an aqueous solution to the cornea. METHODS: Two nonionic surfactants of the poly(ethylene glycol)-fatty alcohol ether type (Sympatens AS and Sympatens ACS) were characterized in terms of micelle size, shape, and charge, and their encapsulation efficiency for CsA. In an in situ single dose bioavailability study, the corneal CsA levels were determined in an enucleated porcine eye model. A commercial formulation and a 2% CsA olive oil solution served as references. RESULTS: Both surfactants formed spherical micelles with a size of 9 to 12 nm in water. A concentration as low as 0.3% (wt/vol) Sympatens AS was sufficient to entrap therapeutic levels of at least 0.1% (wt/vol) CsA. In the porcine in situ model, exceptionally high drug levels in the cornea were obtained for the micellar CsA solution (1557 +/- 407 ngCsA/gcornea). They were significantly higher than those of Restasis (545 +/- 137 ngCsA/gcornea) or the olive oil solution (452 +/- 142 ngCsA/gcornea). CONCLUSIONS: In conclusion, we have shown a promising simple and efficient approach for the application of CsA in an aqueous solution to the cornea to treat inflammatory corneal diseases. PMID- 24162755 TI - Technical tips for intersphincteric resection: how to take out the rectum. AB - Intersphincteric resection (ISR) is an ideal technique that preserves the anus, regardless of whether the internal anal sphincter is removed. However, it is difficult to dissect the anterior wall of the rectum from the adjacent organs. We herein describe a safe and useful ISR technique which draws out the rectum through the anus. The intersphincteric space (ISS) between the internal and external anal sphincter muscles was first transabdominally dissected. Next, the transanal dissection was advanced into the ISS bilaterally from the posterior side without dissecting the anterior wall of the anal canal, and the sigmoid colon and rectum were drawn out through the anus. Dissection between the anterior wall of the rectum and prostate/vagina could be easily performed under direct vision. This technique enables the dissection without any risk of a positive surgical margin or unexpected bleeding, and avoids injury to adjacent organs. This technique seems to be a safe and useful dissection technique for approaching the anterior wall of the anal canal. PMID- 24162756 TI - Prevalence of and risk factors for violent disciplinary practices at home in Viet Nam. AB - Data on parenting practices and the use of violence in child rearing remain scarce worldwide, hindering prevention efforts. This study examines disciplinary methods used on children at home in Viet Nam. It is based on data collected from 2010 to 2011 through the fourth round of the Multiple Indicator Cluster Survey (MICS4)-a household survey program supported by the United Nations Children's Fund (UNICEF) that focuses on women and children in low- and middle-income countries. Respondents in the survey were asked 11 questions relating to disciplinary measures used in the preceding month on one randomly selected child (2-14 years old) in each household. A final question about attitudes probed adults' views on the need for physical punishment in child rearing. Univariate and multivariate analyses were conducted to estimate the prevalence of violent and nonviolent forms of discipline, and to identify risk factors associated with violent punishment. Results showed that three in four children in Viet Nam are disciplined through violent means. The exposure of Vietnamese children to violent forms of discipline was significantly associated with varied characteristics of both children and their caregivers. Moreover, the use of violent disciplinary practices on children was strongly associated with positive attitudes toward corporal punishment. Risk factors for violent child discipline identified in this study can inform future interventions to promote positive practices and to protect Vietnamese children against violence in the home. PMID- 24162757 TI - G.R.I.T.S.: the southern subculture of violence and homicide offenses by girls raised in the South. AB - The southern subculture of violence is a theoretical perspective that has been examined by numerous scholars in an attempt to explain the high rates of violence in the Southern United States. Research over the past several decades has converged on a few explanations for this violence, including a culture of honor, a frontier mentality, and a presence of evangelical Protestantism. The primary focus of this research has been on either male offending or race disaggregated offending. The influence of the southern subculture of violence on female offending has only recently come to the forefront and has concentrated on relatively recent time periods (1990s to present). The present study examines the effect of southern culture on female-perpetrated homicides in the 1970s, a time when female offending was on the rise. Utilizing a southern subculture of violence index, our county-level negative binomial regression analysis finds that in counties with more Southern-born residents and a higher presence of evangelical Protestantism, female homicide offending is higher. Implications of these results and avenues for future research are discussed. PMID- 24162758 TI - Residential PTSD treatment for female veterans with military sexual trauma: does a history of childhood sexual abuse influence outcome? AB - This study examined whether a history of childhood sexual abuse (CSA) influenced treatment outcome among female veterans with an index trauma of military sexual trauma (MST) receiving residential treatment for posttraumatic stress disorder (PTSD). One hundred and ten female veterans, 61 with a history of CSA and 49 without, were compared on pre-treatment demographic and symptom measures, as well as treatment outcome, which were assessed with the Clinician-Administered PTSD Scale (CAPS), PTSD Checklist-Stressor Specific Version (PCL-S), and Depression Inventory-Second edition (BDI-II). Veterans received cognitive processing therapy (CPT) as the primary trauma-focused treatment. Study findings showed that these two groups did not significantly differ on pre-treatment variables or treatment outcome. Results suggest that CPT delivered in a residential treatment program was effective for female veterans with PTSD related to MST, with and without a history of CSA. PMID- 24162759 TI - Transgenerational functions of small RNA pathways in controlling gene expression in C. elegans. AB - RNA silencing processes use exogenous or endogenous RNA molecules to specifically and robustly regulate gene expression. In C. elegans, initial mechanistic descriptions of the different silencing processes focused on posttranscriptional regulation. In this review, we discuss recent work showing that, in this model organism, RNA silencing also controls the transcription of target genes by inducing heterochromatin formation. Specifically, it has been shown that ribonucleoprotein complexes containing small RNAs, either processed from exogenous dsRNA or synthesized from the genome itself, and proteins of the Argonaute family, mediate the deposition of repressive histone marks at the targeted loci. Interestingly, the accumulation of repressive marks is required for the inheritance of the silencing effect and the establishment of an epigenetic memory that discriminates self- from non-self-RNAs. PMID- 24162760 TI - Healing of human Achilles tendon ruptures: radiodensity reflects mechanical properties. AB - PURPOSE: This study tests the idea of using radiodensity from computed tomography to quantitatively evaluate the healing of ruptured Achilles tendons. METHODS: The radiodensity of the healing tendons in sixty-five patients who were treated for Achilles tendon rupture was measured. The hypothesis was that density would correlate with an estimate for e-modulus, derived from strain, measured by radiostereometry with different mechanical loadings. RESULTS: Radiodensity 7 weeks after injury was decreased to 67 % (SD 11) of the contralateral, uninjured tendon. There was no improvement in radiodensity from 7 to 19 weeks, whereas at 1 year, it had increased to 106 % (SD 7). Only 2 of 52 measured values at 1 year were lower than the highest value at 19 weeks, i.e. there was minimal overlap. The variation in radiodensity could explain 80 % of the variation in e-modulus, but radiodensity correlated only weakly with e-modulus at each time point separately. At 1 year, both radiodensity and e-modulus correlated with functional results, although weakly. CONCLUSIONS: From 19 weeks onwards, radiodensity appears to reflect mechanical properties of the tendon and might to some extent predict the final outcome. Radiodensity at 7 weeks is difficult to interpret, probably because it reflects both callus and damaged tissues. PMID- 24162761 TI - Long-term biomechanical outcomes after Achilles tendon ruptures. AB - PURPOSE: The ideal treatment for Achilles tendon ruptures is still unknown. Biomechanical were correlated to radiological and clinical parameters to study outcomes. METHODS: In this retrospective, assessor-blinded multi-centre cohort study, 52 patients with unilateral Achilles tendon rupture were assessed, each at least 3 years after injury. Patients underwent open surgery, percutaneous surgery or non-surgical treatment of Achilles tendon rupture. Both legs underwent plantar pressure distribution and isokinetic measures. Demographic parameters, maximum calf circumference (MCC) and clinical scores (American Orthopaedic Foot and Ankle Society, Achilles tendon rupture score, Hannover) were also evaluated. Complications were not assessed. RESULTS: Peak plantar flexion torque (PPFT) was significantly weaker on the treated side compared to the untreated leg [80.4 +/- 29.7 Nm (mean +/- SD) vs. 92.1 +/- 27.4 Nm, p < 0.0001]. PPFT and push-off force (POFF) were not different between treatment groups nor was there a leg difference in POFF alone. There was only a weak correlation of clinical scores and PPFT or POFF, respectively. MCC correlated significantly with both PPFT (R (2) = 0.21, p = 0.01) and POFF (R (2) = 0.29, p < 0.0001). POFF appeared to be a predictor of PPFT (R (2) = 0.31, p < 0.0001). Open surgery outperformed non-surgical treatment in terms of centre-of-pressure line (p = 0.007), torque per muscle volume (p = 0.04) and relative POFF per body weight (p = 0.02) and relative in side comparison (p = 0.03). CONCLUSIONS: Clinical scores do not predict biomechanical outcomes. Clinically measured MCC is a good predictor of PPFT and POFF and can easily be used in clinical practice. Relative POFF in side comparison as well as per body weight favours surgical treatment. PMID- 24162762 TI - Increased cartilage volume after injection of hyaluronic acid in osteoarthritis knee patients who underwent high tibial osteotomy. AB - PURPOSE: High tibial osteotomy (HTO) is a surgical procedure used to correct abnormal mechanical loading of the knee joint; additionally, intra-articular hyaluronic acid injections have been shown to restore the viscoelastic properties of synovial fluid and balance abnormal biochemical processes. It was hypothesized that combining HTO with intra-articular hyaluronic acid injections would have benefit to improve the cartilage volume of knee joints. METHODS: Forty patients with medial compartment knee osteoarthritis (OA) were randomly placed into 1 of 2 groups. The study group (n = 20) received 2 cycles (at 6-month intervals) of 5 weekly intra-articular hyaluronic acid injections after HTO operation. The control group (n = 20) did not receive any intra-articular injections after HTO surgery. Cartilage volume (primary outcome) was assessed by magnetic resonance imaging (MRI) pre-operatively and 1 year post-operatively. Treatment efficacy (secondary outcomes) was evaluated with the Western Ontario and McMaster Universities OA Index (WOMAC) and by the comparison of the total rescue medication (paracetamol/diclofenac) used (weeks 6, 12, 24, 48). RESULTS: MRI studies showed a significant increase in total cartilage volume (p = 0.033), lateral femoral cartilage volume (p = 0.044) and lateral tibial cartilage volume (p = 0.027) in the study group. Cartilage volume loss was detected at the lateral tibial plateau in the control group. There were significant improvements after surgery in both groups for all subscales of WOMAC scores (p < 0.001) compared to the baseline. However, no difference was found between the two groups. The study group had significantly lower amounts of diclofenac consumption (p = 0.017). CONCLUSION: Based on the findings of the present study, intra-articular hyaluronic acid injections may be beneficial for increasing total cartilage volume and preventing the loss of lateral tibiofemoral joint cartilage after HTO. LEVEL OF EVIDENCE: Therapeutic study, Level I. PMID- 24162763 TI - Factors affecting refractive outcome after cataract surgery in patients with a history of acute primary angle closure. AB - PURPOSE: This study was conducted to evaluate the influence of preoperative or intraoperative factors on the refractive outcome after cataract surgery in patients with a history of acute primary angle closure (APAC). METHODS: Eyes were divided into two groups: those with stable refractive outcome and those with unstable refractive outcome at 8 weeks after uneventful cataract surgery. Univariate and multivariate regression analyses were performed to investigate factors associated with the postoperative refractive outcome. RESULTS: Fifty three eyes of 53 patients with a history of APAC (21 eyes with stable refractive outcome, 32 eyes with unstable refractive outcome) were enrolled. In the univariate regression analysis, longer duration of APAC [odds ratio (OR) 1.328; 95 % confidence interval (CI) 1.137-1.552; P = 0.001] and poor preoperative best corrected visual acuity (OR 4.648; 95 % CI 1.071-20.168; P = 0.040) were associated with unstable refractive outcome after cataract surgery in patients with a history of APAC. In the multivariate regression analysis, the duration of APAC was the only independent factor predicting refractive outcome after cataract surgery in patients with a history of APAC (OR 1.317; 95 % CI 1.113-1.558; P = 0.001). CONCLUSIONS: Normalization of elevated intraocular pressure as soon as possible after APAC onset is recommended to obtain a stable refractive outcome after cataract surgery in patients with a history of APAC. PMID- 24162764 TI - Superior canal dehiscence syndrome: clinical manifestations and radiologic correlations. AB - The objective of this study is to describe the superior canal dehiscence syndrome (SCDS) and its vestibule-cochlear manifestations, while analyzing dehiscence size, audiogram and vestibular-evoked myogenic potential (VEMP) changes following dehiscence obliteration. We conducted a prospective study in a tertiary referral center. All Patients diagnosed and surgically treated for SCDS were operated through a middle fossa craniotomy (MFC). Clinical and radiological data were collected. The main outcome measures were Air-bone gaps, Pure-tone average (PTA), speech discrimination scores (SDS) and VEMP thresholds and were correlated to dehiscence size. 28 patients were included in this study with a mean dehiscence size of 4.68 mm. Phonophobia and imbalance were the most debilitating cochlear and vestibular symptoms, respectively. At 2 months postoperatively, low-frequency air-bone gaps showed a statistically significant improvement (p < 0.001). SDS and PTA did not show any statistically significant changes 2 months postoperatively (p = 0.282 and p = 0.295, respectively). VEMP threshold differences between operated and contralateral ears were statistically significant preoperatively (p < 0.001) and non-significant 2 months postoperatively (p = 0.173). Dehiscence size only showed a statistically significant correlation with preoperative total cochlear symptoms, while remaining insignificant with all other variables measured. Air-bone gaps, VEMP and computerized tomography remain essential tools in diagnosing and following SCDS. Dehiscence size is an independent factor in the analysis of SCDS, with cochlear symptomatology being associated to dehiscence sizes. Finally, it is shown that overall symptomatology, audiometric results and VEMP thresholds return to normal values post-obliteration, confirming the continuing success of the MFC approach for SCDS obliteration. PMID- 24162765 TI - The value of the acoustic voice quality index as a measure of dysphonia severity in subjects speaking different languages. AB - The Acoustic Voice Quality Index (AVQI) is a relatively new clinical method to quantify dysphonia severity. Since it partially relies on continuous speech, its performance may vary with voice-related phonetic differences and thus across languages. The present investigation therefore assessed the AVQI's performance in English, Dutch, German, and French. Fifty subjects were recorded reading sentences in the four languages, as well as producing a sustained vowel. These recordings were later edited to calculate the AVQI. The samples were also perceptually rated on overall dysphonia severity by three experienced voice clinicians. The AVQI's cross-linguistic concurrent validity and diagnostic precision were assessed. The results support earlier data, and confirm good cross linguistic validity and diagnostic accuracy. Although no statistical differences were observed between languages, the AVQI performed better in English and German and less well in French. These results validate the AVQI as a potentially robust and objective dysphonia severity measure across languages. PMID- 24162766 TI - Facial features and hyoid bone position in preschool children with obstructive sleep apnea syndrome. AB - The aim of the study was to evaluate facial features and hyoid bone position in children with obstructive sleep apnea syndrome (OSAS) by cephalometric radiography. A prospective cross-sectional study was conducted in a tertiary referral hospital. Twenty-nine children in the 3-6 year age bracket were evaluated: 14 children with OSAS and 15 nasal-breathing children. All children underwent otorhinolaryngologic examination, and those with OSAS also underwent in laboratory polysomnography for diagnostic confirmation. The children were then submitted to orthodontic evaluation and cephalometry. Lateral cephalometric radiographs from children with OSAS were compared to those of nasal-breathing children. We found no differences between the two groups regarding the linear and angular measurements of the face. However, the children with OSAS presented, already at the preschool age, with an inferiorly positioned hyoid bone, thus increasing the pharyngeal area. In children with OSAS, the hyoid bone appears to be in a significantly inferior position at an early age. Our findings provide evidence that there is a relationship between the position of the hyoid bone and OSAS in children, which could contribute to the persistence of OSAS into adulthood. PMID- 24162767 TI - Intracranial complications of chronic otitis media. AB - The objective of this study was to review our experience on intracranial complications (ICC) secondary to chronic otitis media (COM), and to investigate its clinical characteristics and treatment approaches. From January 1996 to December 2012, 17 patients with ICC secondary to COM were identified and included in this study, and were analyzed retrospectively. 13 out of these 17 cases (76.4 %) have cholesteatoma. The most common intracranial complication is brain abscesses (52.9 %), followed by meningitis (29.4 %), perisinus abscess (11.7 %), and epidural abscess (6 %). All patients underwent emergency mastoidectomy within the first 24 h after clear diagnosis. 7 patients underwent brain abscess drainage or abscess excision at the time of ear surgery. The mortality rates are 0 %. No recurrence was found in the 24-month follow-up period. Cholesteatoma was strongly associated with ICC. An early diagnosis and active surgical intervention in collaboration with proper antibiotic treatment is the key to cure. PMID- 24162768 TI - Diffusion-weighted MRI in diagnosing thyroid cartilage invasion in laryngeal carcinoma. AB - The diagnosis of thyroid cartilage invasion in patients presenting with laryngeal carcinoma is essential for pre-therapeutic staging. Compared to CT, diffusion weighted magnetic resonance imaging (MRI) has a similar ability to define the interface between fat and tumor, but is superior for assessing muscle and cartilage invasion. Diffusion-weighted MRI may be indicated if there are equivocal findings in the CT, including possible cartilage invasion. The aim of this study is to assess the validity of diffusion-weighted MRI in predicting inner and outer thyroid cartilage laminae invasion in patients with laryngeal carcinoma. A prospective study was carried out between August 2011 and May 2013. The study included 26 patients. Twenty-three patients underwent total laryngectomy and three patients underwent partial laryngectomy. Histopathology reports of resected specimens and pre-operative staging were blind to the consultant radiologist who reviewed the scans to comment on thyroid cartilage invasion with special emphasis on inner and outer lamina invasion by conventional MRI criteria, contrast enhancement and DWI. The sensitivity, specificity, efficiency (correct classification rate), and positive and negative predictive values of MRI for identification of inner thyroid lamina invasion were: 93, 82, 88, 88 and 90 % respectively, while those of outer thyroid lamina invasion were: 85, 85, 85, 85 and 85 %, respectively. Diffusion-weighted MRI showed high validity and precision in detecting inner and outer thyroid lamina invasion. This can have an important impact on the decision making for management of laryngeal carcinoma. PMID- 24162769 TI - Diagnostic value and clinical significance of stress hormones in patients with tinnitus. AB - Tinnitus has been found to be modulated by stress and is also closely related to the emotional state and the limbic system. In the present study, we evaluated the diagnostic and clinical values of several stress hormones in a large number of tinnitus patients. This study included 344 patients with sensorineural tinnitus and 87 normal controls. A questionnaire about tinnitus was administered to the participants, and blood levels of norepinephrine (NE), epinephrine (Epi), a metabolite of serotonin (5-hydroxyindoleacetic acid, 5-HIAA) and cortisol were compared between groups. In results, the mean values of Beck's depression inventory (BDI), Brief Encounter Psychosocial Instrument (BEPSI), NE, and 5-HIAA levels were higher in the tinnitus group, although there was no statistical significance. But, the proportion of participants with elevated 5-HIAA was significantly higher in the tinnitus group (21.8 vs. 8.0 %, P < 0.05), and the 5 HIAA level significantly correlated with the duration of tinnitus, NE and cortisol. Elevated stress-related hormones, as well as hearing loss, BDI, and BEPSI were the most related factors with tinnitus in multiple regression test with age adjustment. However, levels of stress-related hormones did not correlate with subjective measures including BDI, BEPSI and severity of tinnitus. In conclusion, blood stress hormones seemed to have some diagnostic and clinical value in patients with tinnitus, and serotonin is supposed to be the most important hormone in tinnitus. Further studies about the values of stress and stress hormones in tinnitus patients may lead to new approaches regarding diagnosis and clinical management of the disease. PMID- 24162770 TI - Lacrimal sac dacryolith (76 cases): a predictive factor for successful endonasal dacryocystorhinostomy? AB - To evaluate whether the presence of dacryolith is a predictive factor for successful dacryocystorhinostomy. The success rate of endonasal dacryocystorhinostomy (EDCR) performed to relieve obstruction of the nasolacrimal duct was evaluated according to the presence of dacryolithiasis. The surgical results of patients with (group I) and without dacryoliths (group II) were analysed and compared 1-year post surgery. A total of 771 EDCRs performed from 1994 to 2010 were evaluated. Dacryolith was found in 76/771 procedures (9.9%). Complete improvement was achieved significantly more frequently in group I (76/76; 100.0%) than in group II (633/695; 91.1%; p < 0.001). EDCRs were performed significantly more frequently in people aged 31-50-years, the average age of the group I was 41.1 years (range 18-72 years), of the group II 53.3 years (range 3 months-86 years; p < 0.001). There was no significant difference in the female-to-male ratio in the two groups. The presence of dacryoliths is a predictive factor for successful endonasal dacryocystorhinostomy. PMID- 24162771 TI - Fallopian canal dehiscence at pediatric cholesteatoma surgery. AB - The objectives of the study were to investigate the characteristics of ears with dehiscence of the fallopian canal at the time of cholesteatoma surgery and the relationship between dehiscence and age, and to consider the reasons why the fallopian canal tends to be preserved in pediatric patients. This study included 37 ears with cholesteatoma in pediatric patients (mean age 9.2 years, age range 4 14 years) and 273 ears with cholesteatoma in non-pediatric patients (mean age 45 years, age range 15-84 years). Patients were treated between January 2006 and April 2012. All patients had undergone prior tympanoplasty under general anesthesia at our institution. Facial canal dehiscence was evaluated by inspection and through palpation by blunt picking after the pathological tissues had been removed. The size of fallopian canal dehiscence was not investigated in this study. The frequency of dehiscence of the fallopian canal according to the type of cholesteatoma and coexisting pathological conditions, including destruction of the stapes, presence of a labyrinthine fistula, and dural exposure, were compared between the pediatric and non-pediatric groups. The frequency of dehiscence in cases with destruction of the stapes was also compared between the pediatric and non-pediatric groups. Dehiscence of the fallopian canal occurred in 6 of 37 ears (16.8 %) in the pediatric group and 91 of 273 ears (33.3 %) in the non-pediatric group (p < 0.05). In congenital cholesteatoma, the frequency of dehiscence was lower in the pediatric group than in the non pediatric group (p < 0.05). However, in other types of cholesteatoma there was no statistically difference between the two types of cholesteatoma. The frequency of the destruction of the stapes was higher in the pediatric group than in the non pediatric group (43.2 vs. 16.5 %, p < 0.001). In patients with severe destruction of the stapes, the fallopian canal was preserved more frequently in the pediatric group than in the non-pediatric group (p < 0.05). The frequency of dehiscence of the fallopian canal at the time of cholesteatoma surgery was lower in the ears of pediatric patients than in the ears of non-pediatric patients. This is probably due to the difference in types of cholesteatoma between the two groups and other unknown mechanisms. PMID- 24162772 TI - Medical tourism is a profitable source of income for the NHS, study finds. PMID- 24162773 TI - Tuning the 3D plasmon field of nanohole arrays. AB - Modern photonics is being revolutionized through the use of nanostructured plasmonic materials, which confine light to sub-diffraction limit resolution providing universal, sensitive, and simple transducers for molecular sensors. Understanding the mechanisms by which light interacts with plasmonic crystals is essential for developing application-focussed devices. The strong influence of grating coupling on electromagnetic field distribution, frequency and degeneracy of plasmon bands has now been characterized using hexagonal nanohole arrays. An equation for nanohole arrays was derived to demonstrate the strong influence of incidence and rotation angle on optical properties of 2D plasmonic crystals such as nanohole arrays. Consequently, we report experimental data that are in strong agreement with finite difference time-domain (FDTD) simulations that clearly demonstrate the influence of the grating coupling conditions on the optical properties (such as plasmon degeneracy and bandwidth), and on the distribution of the plasmon field around nanohole arrays (including tuneable penetration depths and highly localized fields). The tuneable 3D plasmon field allowed for controlled sensing properties and by increasing the angle of incidence to 30 degrees, the resonance wavelength was tuned from 1000 to 600 nm, and the sensitivity was enhanced by nearly 300% for a protein assay using surface plasmon resonance (SPR) and by 40% with surface-enhanced Raman scattering (SERS) sensors. PMID- 24162774 TI - The HIV-1 envelope protein gp120 impairs B cell proliferation by inducing TGF beta1 production and FcRL4 expression. AB - The humoral immune response after acute infection with HIV-1 is delayed and ineffective. The HIV-1 envelope protein gp120 binds to and signals through integrin alpha4beta7 on T cells. We found that gp120 also bound to and signaled through alpha4beta7 on naive B cells, which resulted in an abortive proliferative response. In primary B cells, signaling by gp120 through alpha4beta7 resulted in increased expression of the immunosuppressive cytokine TGF-beta1 and FcRL4, an inhibitory receptor expressed on B cells. Coculture of B cells with HIV-1 infected autologous CD4(+) T cells also increased the expression of FcRL4 by B cells. Our findings indicated that in addition to mediating chronic activation of the immune system, viral proteins contributed directly to HIV-1-associated B cell dysfunction. Our studies identify a mechanism whereby the virus may subvert the early HIV-1-specific humoral immune response. PMID- 24162775 TI - Transcriptional downregulation of S1pr1 is required for the establishment of resident memory CD8+ T cells. AB - Cell-mediated immunity critically depends on the localization of lymphocytes at sites of infection. While some memory T cells recirculate, a distinct lineage (resident memory T cells (T(RM) cells)) are embedded in nonlymphoid tissues (NLTs) and mediate potent protective immunity. However, the defining transcriptional basis for the establishment of T(RM) cells is unknown. We found that CD8(+) T(RM) cells lacked expression of the transcription factor KLF2 and its target gene S1pr1 (which encodes S1P1, a receptor for sphingosine 1 phosphate). Forced expression of S1P1 prevented the establishment of T(RM) cells. Cytokines that induced a T(RM) cell phenotype (including transforming growth factor-beta (TGF-beta), interleukin 33 (IL-33) and tumor-necrosis factor) elicited downregulation of KLF2 expression in a pathway dependent on phosphatidylinositol-3-OH kinase (PI(3)K) and the kinase Akt, which suggested environmental regulation. Hence, regulation of KLF2 and S1P1 provides a switch that dictates whether CD8(+) T cells commit to recirculating or tissue-resident memory populations. PMID- 24162776 TI - The developmental pathway for CD103(+)CD8+ tissue-resident memory T cells of skin. AB - Tissue-resident memory T cells (T(RM) cells) provide superior protection against infection in extralymphoid tissues. Here we found that CD103(+)CD8(+) T(RM) cells developed in the skin from epithelium-infiltrating precursor cells that lacked expression of the effector-cell marker KLRG1. A combination of entry into the epithelium plus local signaling by interleukin 15 (IL-15) and transforming growth factor-beta (TGF-beta) was required for the formation of these long-lived memory cells. Notably, differentiation into T(RM) cells resulted in the progressive acquisition of a unique transcriptional profile that differed from that of circulating memory cells and other types of T cells that permanently reside in skin epithelium. We provide a comprehensive molecular framework for the local differentiation of a distinct peripheral population of memory cells that forms a first-line immunological defense system in barrier tissues. PMID- 24162777 TI - Serial dilution via surface energy trap-assisted magnetic droplet manipulation. AB - This paper demonstrates a facile method of generating precise serial dilutions in the form of droplets on an open surface platform. The method relies on the use of surface energy traps (SETs), etched areas of high surface energy on a Teflon coated glass substrate, to assist in the magnetic manipulation of droplets to meter and dispense liquid of defined volumes for the preparation of serial dilutions. The volume of the dispensed liquid can be precisely controlled by the size of the SETs, facilitating generation of concentration profiles of high linearity. We have applied this approach to the generation of serial dilutions of antibiotics for anti-microbial susceptibility testing (AST). PMID- 24162779 TI - Grape seed proanthocyanidin extract protects against carrageenan-induced lung inflammation in mice through reduction of pro-inflammatory markers and chemokine expressions. AB - Proanthocyanidins are the most abundant phenolic compounds and have been reported to exert anti-inflammatory actions. The aim of this study was to investigate the effects of grape seed proanthocyanidin extract (GSPE) in a mouse model of carrageenan-induced pleurisy. Following the induction of pleurisy using lambda carrageenan (Cg, 1 %), GSPE (25, 50 and 100 mg/kg) was administered per-oral (p.o.), and the glucocorticoid-induced tumour necrosis factor receptor (GITR), IL 17A expressing cells and other markers, such as cytokines (Th1/Th2 and Th17), were studied. We evaluate the effects of GSPE on the mRNA expression of pro inflammatory and anti-inflammatory mediators. The results illustrated that the cell numbers of IL-17A and GITR expressing cells and the cytokine levels in Th1/Th17 cells were markedly increased in the Cg-group, whereas the cytokines produced by Th2 cells were significantly decreased in the same group. Treatment with GSPE reversed these effects. Histological examinations revealed anti inflammatory effects of GSPE. PMID- 24162781 TI - Transcriptome generation and analysis from spleen of Indian catfish, Clarias batrachus (Linnaeus, 1758) through normalized cDNA library. AB - Catfishes are commercially important fish for both the fisheries and aquaculture industry. Clarias batrachus, an Indian catfish species is economically important owing to its high demand. A normalized cDNA library was constructed from spleen of the Indian catfish to identify genes associated with immune function. One thousand nine hundred thirty seven ESTs were submitted to the GenBank with an average read length of approximately 700 bp. Clustering analysis of ESTs yielded 1,698 unique sequences, including 184 contigs and 1,514 singletons. Significant homology to known genes was found by homology searches against data in GenBank in 576 (34 %) ESTs, including similarity to functionally annotated unigenes for 158 ESTs. Additionally, 433 ESTs revealed similarity to unigenes and ESTs in the dbEST but the remaining 658 EST sequences (39 %) did not match any sequence in GenBank. Of a total of 1,698 ESTs generated, 65 ESTs were found to be associated with immune functions. Gene Ontology and KEGG pathway analyses of C. batrachus ESTs collectively revealed a preponderance of immune relevant pathways apart from the presence of pathways involved in protein processing, localization, folding and protein degradation. This study constitutes first EST analysis of lymphoid organ in aquaculturally important Indian catfish species and could pave the way for further research of immune-related genes and functional genomics in this catfish. PMID- 24162780 TI - Beyond toll-like receptors: Porphyromonas gingivalis induces IL-6, IL-8, and VCAM 1 expression through NOD-mediated NF-kappaB and ERK signaling pathways in periodontal fibroblasts. AB - To investigate whether oligomerization domains (NODs) are involved in Porphyromonas gingivalis-induced interleukin (IL)-6, IL-8, and vascular cell adhesion molecule (VCAM)-1 expression beyond Toll-like receptors (TLRs), we investigated the role of NOD1/2 in P. gingivalis-induced IL-6, IL-8, and VCAM-1 expression in human gingival fibroblasts (hGFs) and periodontal ligament cells (hPDLCs). The mechanism was explored by activation and silence of NODs, electrophoretic mobility shift assay (EMSA), and pathway blockade assays. Results showed that P. gingivalis could induce NOD1, NOD2, IL-6, IL-8, and VCAM-1 expression in hGFs and hPDLs at mRNA and protein levels. Activation of NOD1/2 by agonists could clearly upregulate the expression of these genes, while silence of NOD1/2 could remarkably attenuate them. EMSA and blockade of NF-kappaB and extracellular-signal-regulated kinase (ERK)1/2 pathway assays also verified that the two pathways were involved in NOD1/2-mediated IL-6, IL-8, and VCAM-1 expression. In conclusion, our findings demonstrated that P. gingivalis induced IL-6, IL-8, and VCAM-1 expression in hGFs and hPDLCs through NOD1/2-mediated NF kappaB and ERK1/2 signaling pathways beyond TLRs. PMID- 24162782 TI - Evaluating push-pull dye efficiency using TD-DFT and charge transfer indices. AB - The performances of different functionals in the prediction of Charge Transfer excitations (CT) have been assessed, both in terms of quantitative agreement with experimental absorption data and on the basis of a recently developed density based diagnostic index, for a family of 18 recently synthesized push-pull compounds, containing 4-5-dicyannoimidazole (DCI) as an acceptor moiety, six different bridges and three different donor groups. The index used also allows obtaining an estimate of the charge transferred upon excitation (qCT) and of the spatial extent associated with a given electronic transition (DCT). From the computed values of these indices an estimate of the transition energy considering a purely electrostatic model (wCT) can be computed and compared to that expected for an ideal CT between the donor and the acceptor, thus enabling us to estimate the efficiency of the CT transition for the different push-pull systems. PMID- 24162783 TI - Design and synthesis of amide derivatives as S-adenosyl-L-homocysteine hydrolase inhibitors. AB - In this study, a series of amide derivatives were synthesized and evaluated for their S-adenosyl-L-homocysteine hydrolase (SAHase) inhibitory activities. The results demonstrated that most of compounds displayed potent SAHase inhibitory activities. Interestingly, compounds 11 and 14 exhibited more potent inhibitory effects than the aristeromycin, one of the most potent SAHase inhibitors known so far. Compounds 12, 13, 15 and 17 exhibited a moderate effect (IC50<10.0 uM). The structure-activity relationship found that compounds with substituted indazole-5 yl group at Ar position and ethylamino group at the side chain showed better SAHase inhibitory activities. PMID- 24162784 TI - The clear and present potential of health IT. PMID- 24162785 TI - Location and contribution of individual beta-glucosidase from Neurospora crassa to total beta-glucosidase activity. AB - This study investigated the cellular location and the contribution of individual beta-glucosidase (BGL) to total BGL activity in Neurospora crassa. Among the seven bgl genes, bgl3, bgl5, and bgl7 were transcribed at basal levels, whereas bgl1, bgl2, bgl4, and bgl6 were significantly up-regulated when the wild-type strain was induced with cellulose (Avicel). BGL1 and BGL4 were found to be contributors to intracellular BGL activity, whereas the activities of BGL2 and BGL6 were mainly extracellular. Sextuple bgl deletion strains expressing one of the three basally transcribed bgls did not produce any detectable BGL activity when they were grown on Avicel. BGL6 is the major contributor to overall BGL activity, and most of its activity resides cell-bound. The sextuple bgl deletion strain containing only bgl6 utilized cellobiose at a rate similar to that of the wild type, while the strain with only bgl6 deleted utilized cellobiose much slower than that of the wild type. PMID- 24162787 TI - Distinct frequencies and mutation spectrums of genetic thrombophilia in Korea in comparison with other Asian countries both in patients with thromboembolism and in the general population. AB - Hereditary natural anticoagulant deficiencies are the major cause of genetic thrombophilia in Asia. Given the growing acknowledgment of the risk of venous thromboembolism in Asian populations, we investigated the frequency and mutation spectrums of natural anticoagulant deficiency in Korea. The group of patients consisted of consecutive patients with venous thromboembolism screened for thrombophilia. Genetic tests were performed on suspicion of natural anticoagulant deficiency. For the population group, >3,000 individuals were screened from routine check-ups, and those with a low level (<1(st) percentile) of natural anticoagulant underwent genetic tests. Mutations were detected by direct sequencing of PROC, PROS1, and SERPINC1, followed by additional multiplex ligation-dependent probe amplification for PROS1 and SERPINC1 for dosage mutations. Among 500 patients screened, 127 were suspected of having a natural anticoagulant deficiency, and this was genetically confirmed in 71: protein C deficiency in 36 (50.7%), antithrombin deficiency in 21 (29.6%), and protein S deficiency in 14 (19.7%). Among 3,129 individuals from the population who were screened, the frequency of natural anticoagulant deficiency was ~1.0%: antithrombin deficiency 0.49%, protein C deficiency 0.35%, and protein S deficiency 0.16%. Two PROC mutations causing type I protein C deficiency were prevalent (Arg211Trp and Met406Ile in patients and Arg211Trp in the population). Two SERPINC1 mutations causing type II antithrombin deficiency, Arg79Cys and Ser158Pro, were prevalent in the population group. This is the first study on the genetic epidemiology of natural anticoagulant deficiencies in Korea. The results demonstrated that the frequencies and spectrum of mutations underlying genetic thrombophilia in Korea are different not only from those in Caucasians but also those in other Asian populations. PMID- 24162786 TI - Aminobisphosphonates prevent the inhibitory effects exerted by lymph node stromal cells on anti-tumor Vdelta 2 T lymphocytes in non-Hodgkin lymphomas. AB - In this study, we analyzed the influence of mesenchymal stromal cells derived from lymph nodes of non-Hodgkin's lymphomas, on effector functions and differentiation of Vdelta (delta)2 T lymphocytes. We show that: i) lymph-node mesenchymal stromal cells of non-Hodgkin's lymphoma inhibit NKG2D-mediated lymphoid cell killing, but not rituximab-induced antibody-dependent cell-mediated cytotoxicity, exerted by Vdelta2 T lymphocytes; ii) pre-treatment of mesenchymal stromal cells with the aminobisphosphonates pamidronate or zoledronate can rescue lymphoma cell killing via NKG2D; iii) this is due to inhibition of transforming growth factor-beta and increase in interleukin-15 production by mesenchymal stromal cells; iv) aminobisphosphonate-treated mesenchymal stromal cells drive Vdelta2 T-lymphocyte differentiation into effector memory T cells, expressing the Thelper1 cytokines tumor necrosis factor-alpha and interferon-gamma. In non Hodgkin's lymphoma lymph nodes, Vdelta2 T cells were mostly naive; upon co culture with autologous lymph-node mesenchymal stromal cells exposed to zoledronate, the percentage of terminal differentiated effector memory Vdelta2 T lymphocytes increased. In all non-Hodgkin's lymphomas, low or undetectable transcription of Thelper1 cytokines was found. In diffused large B-cell lymphomas and in a group of follicular lymphoma, transcription of transforming growth factor beta and interleukin-10 was enhanced compared to non-neoplastic lymph nodes. Thus, in non-Hodgkin lymphomas mesenchymal stromal cells interfere with Vdelta2 T-lymphocyte cytolytic function and differentiation to Thelper1 and/or effector memory cells, depending on the prominent in situ cytokine milieu. Aminobisphosphonates, acting on lymph-node mesenchymal stromal cells, can push the balance towards Thelper1/effector memory and rescue the recognition and killing of lymphoma cells through NKG2D, sparing rituximab-induced antibody dependent cell-mediated cytotoxicity. PMID- 24162788 TI - Early lesions of follicular lymphoma: a genetic perspective. AB - The pathogenesis of follicular lymphoma is a multi-hit process progressing over many years through the accumulation of numerous genetic alterations. Besides the hallmark t(14;18), it is still unclear which other oncogenic hits contribute to the early steps of transformation and in which precursor stages these occur. To address this issue, we performed high-resolution comparative genomic hybridization microarrays on laser-capture micro-dissected cases of follicular lymphoma in situ (n=4), partial involvement by follicular lymphoma (n=4), and duodenal follicular lymphoma (n=4), assumed to represent, potentially, the earliest stages in the evolution of follicular lymphoma. Cases of reactive follicular hyperplasia (n=2), uninvolved areas from follicular lymphoma in situ lymph nodes, follicular lymphoma grade 1-2 (n=5) and follicular lymphoma grade 3A (n=5) were used as controls. Surprisingly, alterations involving several relevant (onco)genes were found in all entities, but at significantly lower proportions than in overt follicular lymphoma. While the number of alterations clearly assigns all these entities as precursors, the pattern of partial involvement by follicular lymphoma alterations was quantitatively and qualitatively closer to that of follicular lymphoma, indicating significant selective pressure in line with its faster rate of progression. Among the most notable alterations, we observed and validated deletions of 1p36 and gains of the 7p and 12q chromosomes and related oncogenes, which include some of the most recurrent oncogenic alterations in overt follicular lymphoma (TNFRSF14, EZH2, MLL2). By further delineating distinctive and hierarchical molecular and genetic features of early follicular lymphoma entities, our analysis underlines the importance of applying appropriate criteria for the differential diagnosis. It also provides a first set of candidates likely to be involved in the cascade of hits that pave the path of the various progression phases to follicular lymphoma development. PMID- 24162789 TI - Autologous stem cell transplantation after conditioning with yttrium-90 ibritumomab tiuxetan plus BEAM in refractory non-Hodgkin diffuse large B-cell lymphoma: results of a prospective, multicenter, phase II clinical trial. AB - Lymphoma patients with persistent disease undergoing autologous transplantation have a very poor prognosis in the rituximab era. The addition of radioimmunotherapy to the conditioning regimen may improve the outcome for these patients. In a prospective, phase 2 study, we evaluated the safety and efficacy of the addition of (90)Y-ibritumomab tiuxetan to the conditioning chemotherapy in patients with refractory diffuse large B-cell lymphoma. Thirty patients with induction failure (primary refractory; n=18) or refractory to salvage immunochemotherapy at relapse (n=12) were included in the study. The median age of the patients was 53 years (range, 25-67). All patients were given (90)Y ibritumomab tiuxetan at a fixed dose of 0.4 mCi/kg (maximum dose 32 mCi) 14 days prior to the preparative chemotherapy regimen. Histological examination showed that 22 patients had de novo diffuse large B-cell lymphoma and eight had transformed diffuse large B-cell lymphoma. All patients had persistent disease at the time of transplantation, with 25 patients considered to be chemorefractory. The median time to neutrophil recovery (>500 white blood cells/MUL) was 11 days (range, 9-21), while the median time to platelet recovery (>20,000 platelets/MUL) was 13 days (range, 11-35). The overall response rate at day +100 was 70% (95% CI, 53.6-86.4) with 60% (95% CI, 42.5-77.5) of patients obtaining a complete response. After a median follow-up of 31 months for alive patients (range, 16 54), the estimated 3-year overall and progression-free survival rates are 63% (95% CI, 48-82) and 61% (95% CI, 45-80), respectively. We conclude that autologous transplantation with conditioning including (90)Y-ibritumomab tiuxetan is safe and results in a very high response rate with promising survival in this group of patients with refractory diffuse large B-cell lymphoma with a very poor prognosis. Study registered at European Union Drug Regulating Authorities Clinical Trials (EudraCT) N. 2007-003198-22. PMID- 24162790 TI - Treosulfan-based conditioning regimen for children and adolescents with hemophagocytic lymphohistiocytosis. AB - In hematopoietic stem cell transplantation for hemophagocytic lymphohistiocytosis, high transplant-related mortality after busulfan-based myeloablative regimens has been observed. Conditioning regimens with reduced toxicity based on melphalan or treosulfan are promising alternatives. We retrospectively analyzed hematopoietic stem cell transplantations in 19 hemophagocytic lymphohistiocytosis patients after conditioning with fludarabine, treosulfan, alemtuzumab, with or without thiotepa. Overall and disease-free survivals were 100% (follow up 7-31 months). Two patients required second transplant (1 after haploidentical transplantation). In 6 patients, overall donor chimerism dropped below 75% and prompted donor lymphocyte infusions. Administration of donor lymphocytes or second transplantation were significantly more frequent after transplantation from a human leukocyte antigen mismatched (9/10) versus matched (10/10) donor (P=0.018). The toxicity profile was favorable, with one veno-occlusive disease, one grade 3 graft-versus-host disease after donor lymphocyte infusion, and 2 severe viral infections (1 influenza, 1 Epstein Barr virus). In conclusion, the treosulfan-based regimen in hemophagocytic lymphohistiocytosis is effective with low toxicity and gives excellent overall and disease-free survival rates. In the future, the incidence of mixed chimerism, particularly after human leukocyte antigen mismatched donor transplants, needs to be addressed. PMID- 24162791 TI - Comparison of horse and rabbit antithymocyte globulin in immunosuppressive therapy for refractory cytopenia of childhood. AB - Refractory cytopenia of childhood is the most common subtype of myelodysplastic syndrome in children. In this study, we compared the outcome of immunosuppressive therapy using horse antithymocyte globulin (n=46) with that using rabbit antithymocyte globulin (n=49) in 95 patients with refractory cytopenia of childhood and hypocellular bone marrow. The response rate at 6 months was 74% for horse antithymocyte globulin and 53% for rabbit antithymocyte globulin (P=0.04). The inferior response in the rabbit antithymocyte globulin group resulted in lower 4-year transplantation-free (69% versus 46%; P=0.003) and failure-free (58% versus 48%; P=0.04) survival rates in this group compared with those in the horse antithymocyte globulin group. However, because of successful second-line hematopoietic stem cell transplantation, overall survival was comparable between groups (91% versus 85%; P=ns). The cumulative incidence of relapse (15% versus 9%; P=ns) and clonal evolution (12% versus 4%; P=ns) at 4 years was comparable between groups. Our results suggest that the outcome of immunosuppressive therapy with rabbit antithymocyte globulin is inferior to that of horse antithymocyte globulin. Although immunosuppressive therapy is an effective therapy in selected patients with refractory cytopenia of childhood, the long-term risk of relapse or clonal evolution remains. (ClinicalTrial.gov identifiers: NCT00662090). PMID- 24162793 TI - Critical resources for hospital surge capacity: an expert consensus panel. AB - BACKGROUND: Hospital surge capacity (HSC) is dependent on the ability to increase or conserve resources. The hospital surge model put forth by the Agency for Healthcare Research and Quality (AHRQ) estimates the resources needed by hospitals to treat casualties resulting from 13 national planning scenarios. However, emergency planners need to know which hospital resource are most critical in order to develop a more accurate plan for HSC in the event of a disaster. OBJECTIVE: To identify critical hospital resources required in four specific catastrophic scenarios; namely, pandemic influenza, radiation, explosive, and nerve gas. METHODS: We convened an expert consensus panel comprised of 23 participants representing health providers (i.e., nurses and physicians), administrators, emergency planners, and specialists. Four disaster scenarios were examined by the panel. Participants were divided into 4 groups of five or six members, each of which were assigned two of four scenarios. They were asked to consider 132 hospital patient care resources- extracted from the AHRQ's hospital surge model- in order to identify the ones that would be critical in their opinion to patient care. The definition for a critical hospital resource was the following: absence of the resource is likely to have a major impact on patient outcomes, i.e., high likelihood of untoward event, possibly death. For items with any disagreement in ranking, we conducted a facilitated discussion (modified Delphi technique) until consensus was reached, which was defined as more than 50% agreement. Intraclass Correlation Coefficients (ICC) were calculated for each scenario, and across all scenarios as a measure of participant agreement on critical resources. For the critical resources common to all scenarios, Kruskal-Wallis test was performed to measure the distribution of scores across all scenarios. RESULTS: Of the 132 hospital resources, 25 were considered critical for all four scenarios by more than 50% of the participants. The number of hospital resources considered to be critical by consensus varied from one scenario to another; 58 for the pandemic influenza scenario, 51 for radiation exposure, 41 for explosives, and 35 for nerve gas scenario. Intravenous crystalloid solution was the only resource ranked by all participants as critical across all scenarios. The agreement in ranking was strong in nerve agent and pandemic influenza (ICC= 0.7 in both), and moderate in explosives (ICC= 0.6) and radiation (ICC= 0.5). CONCLUSION: In four disaster scenarios, namely, radiation, pandemic influenza, explosives, and nerve gas scenarios; supply of as few as 25 common resources may be considered critical to hospital surge capacity. The absence of any these resources may compromise patient care. More studies are needed to identify critical hospital resources in other disaster scenarios. PMID- 24162792 TI - The gene signature in CCAAT-enhancer-binding protein alpha dysfunctional acute myeloid leukemia predicts responsiveness to histone deacetylase inhibitors. AB - C/EPBalpha proteins, encoded by the CCAAT-enhancer-binding protein alpha gene, play a crucial role in granulocytic development, and defects in this transcription factor have been reported in acute myeloid leukemia. Here, we defined the C/EBPalpha signature characterized by a set of genes up-regulated upon C/EBPalpha activation. We analyzed expression of the C/EBPalpha signature in a cohort of 525 patients with acute myeloid leukemia and identified a subset characterized by low expression of this signature. We referred to this group of patients as the C/EBPalpha dysfunctional subset. Remarkably, a large percentage of samples harboring C/EBPalpha biallelic mutations clustered within this subset. We hypothesize that re-activation of the C/EBPalpha signature in the C/EBPalpha dysfunctional subset could have therapeutic potential. In search for small molecules able to reverse the low expression of the C/EBPalpha signature we applied the connectivity map. This analysis predicted positive connectivity between the C/EBPalpha activation signature and histone deacetylase inhibitors. We showed that these inhibitors reactivate expression of the C/EBPalpha signature and promote granulocytic differentiation of primary samples from the C/EBPalpha dysfunctional subset harboring biallelic C/EBPalpha mutations. Altogether, our study identifies histone deacetylase inhibitors as potential candidates for the treatment of certain leukemias characterized by down-regulation of the C/EBPalpha signature. PMID- 24162794 TI - An unprecedented Co(II) cuboctahedron as the secondary building unit in a Co based metal-organic framework. AB - A cubic metal-organic framework with an unprecedented octanuclear secondary building unit (SBU) was isolated. The obtained SBU is composed of 8 Co(II) ions at each vertex, 6 MU4-OH groups at each face, and 12 cpt(-) ligands framing the metal core. The cuboctahedra arrange in a ubt framework topology, eliciting a highly symmetrical MOF structure. Magnetic measurements as well as DFT calculations on this crystalline MOF reveal intramolecular antiferromagnetic coupling between Co(II) ions in the octanuclear SBU. PMID- 24162795 TI - Effects of gait training using a robotic constraint (Lokomat(r)) on gait kinematics and kinetics in chronic stroke patients. AB - OBJECTIVE: To evaluate the effects of a 20-min gait training session using the Lokomat(r) combined with a negative kinematic constraint on the non-paretic limb and a positive kinematic constraint on the paretic limb, on peak knee flexion and other biomechanical parameters in chronic hemiparetic subjects. DESIGN: Preliminary study, before-after design. SUBJECTS: Fifteen hemiparetic subjects. METHODS: Subjects were evaluated using 3-dimensional gait analysis before, immediately after the end of the training, and after a 20-min rest period. The positive constraint increased the range of motion of the paretic limb (hip and knee), while the negative constraint reduced the range of motion of the non paretic limb (hip and knee). RESULTS: Peak knee flexion and other, kinematic, kinetic and spatiotemporal, parameters were significantly improved following the training session. These positive effects occurred predominantly in the paretic limb. Moreover, there was no worsening of biomechanical parameters of the non paretic limb despite the use of negative constraint on this limb. These effects persisted for at least 20 min following the end of the gait training session. CONCLUSION: This type of training may be effective to improve gait in hemiparetic patients. A larger investigation of the training programme is justified. PMID- 24162796 TI - Evidence for metaplasticity in the human visual cortex. AB - The threshold and direction of excitability changes induced by low- and high frequency repetitive transcranial magnetic stimulation (rTMS) in the primary motor cortex can be effectively reverted by a preceding session of transcranial direct current stimulation (tDCS), a phenomenon referred to as "metaplasticity". Here, we used a combined tDCS-rTMS protocol and visual evoked potentials (VEPs) in healthy subjects to provide direct electrophysiological evidence for metaplasticity in the human visual cortex. Specifically, we evaluated changes in VEPs at two different contrasts (90 and 20 %) before and at different time points after the application of anodal or cathodal tDCS to occipital cortex (i.e., priming), followed by an additional conditioning with low- or high-frequency rTMS. Anodal tDCS increased the amplitude of VEPs and this effect was paradoxically reverted by applying high-frequency (5 Hz), conventionally excitatory rTMS (p < 0.0001). Similarly, cathodal tDCS led to a decrease in VEPs amplitude, which was reverted by a subsequent application of conventionally inhibitory, 1 Hz rTMS (p < 0.0001). Similar changes were observed for both the N1 and P1 component of the VEP. There were no significant changes in resting motor threshold values (p > 0.5), confirming the spatial selectivity of our conditioning protocol. Our findings show that preconditioning primary visual area excitability with tDCS can modulate the direction and strength of plasticity induced by subsequent application of 1 or 5 Hz rTMS. These data indicate the presence of mechanisms of metaplasticity that keep synaptic strengths within a functional dynamic range in the human visual cortex. PMID- 24162797 TI - The absence of zoonotic agents in invasive bullfrogs (Lithobates catesbeianus) in Belgium and The Netherlands. AB - Exotic invasive bullfrogs (Lithobates catesbeianus) are considered to exert a considerable negative impact on native amphibian communities. This can be due to competition and predation, but they are also a notorious source of the infectious diseases chytridiomycosis and ranavirosis, affecting amphibian populations globally. Little is known regarding their carriage of other microbial agents that might be transferred to humans or other animals. In this study we determined the occurrence of the amphibian pathogens Ranavirus and Batrachochytrium dendrobatidis and of the zoonotic agents Coxiella burnetii, Neospora caninum, Leptospira sp., Toxoplasma gondii, Mycoplasma sp., Campylobacter sp., Salmonella sp. and extended-spectrum beta-lactamase producing Escherichia coli in 164 bullfrogs from three populations in Belgium and The Netherlands. Although B. dendrobatidis was present at a high prevalence of 63%, mean infection loads were low with an average of 10.9 genomic equivalents (SD 35.5), confirming the role of bullfrogs as B. dendrobatidis carriers, but questioning their role as primary reservoirs for B. dendrobatidis transmission to native amphibian communities. All tested samples were negative for the other infectious agents examined. These results suggest a limited role of bullfrogs as carrier of these pathogens. PMID- 24162799 TI - AAV1.NT-3 gene therapy for charcot-marie-tooth neuropathy. AB - Charcot-Marie-Tooth (CMT) neuropathies represent a heterogeneous group of peripheral nerve disorders affecting 1 in 2,500 persons. One variant, CMT1A, is a primary Schwann cell (SC) disorder, and represents the single most common variant. In previous studies, we showed that neurotrophin-3 (NT-3) improved the trembler(J) (Tr(J)) mouse and also showed efficacy in CMT1A patients. Long-term treatment with NT-3 was not possible related to its short half-life and lack of availability. This led to considerations of NT-3 gene therapy via adenoassociated virus (AAV) delivery to muscle, acting as secretory organ for widespread distribution of this neurotrophic agent. In the Tr(J) model of demyelinating CMT, rAAV1.NT-3 therapy resulted in measurable NT-3 secretion levels in blood sufficient to provide improvement in motor function, histopathology, and electrophysiology of peripheral nerves. Furthermore, we showed that the compound muscle action potential amplitude can be used as surrogate for functional improvement and established the therapeutic dose and a preferential muscle specific promoter to achieve sustained NT-3 levels. These studies of intramuscular (i.m.) delivery of rAAV1.NT-3 serve as a template for future CMT1A clinical trials with a potential to extend treatment to other nerve diseases with impaired nerve regeneration. PMID- 24162798 TI - A review of foodborne bacterial and parasitic zoonoses in Vietnam. AB - Vietnam has experienced unprecedented economic and social development in recent years, and the livestock sector is undergoing significant transformations. Although food animal production is still dominated by small-scale 'backyard' enterprises with mixed crop-livestock or livestock-aquatic systems, there is a trend towards more intensive and vertically integrated operations. Changes in animal production, processing and distribution networks for meat and animal products, and the shift from wet markets to supermarkets will undoubtedly impact food safety risks in Vietnam in unforeseen and complex ways. Here, we review the available published literature on bacterial and parasitic foodborne zoonoses (FBZ) in Vietnam. We report on clinical disease burden and pathogen prevalence in animal reservoirs for a number of important FBZ, and outline opportunities for future research. PMID- 24162800 TI - Therapeutic targets in major psychiatric disorders revisited. PMID- 24162801 TI - Role of serotonin 1A receptors in the median raphe nucleus on the behavioral consequences of forced swim stress. AB - Despite the intense research on the neurobiology of stress, the role of serotonin (5-HT)1A receptors still remains to be elucidated. In the hippocampus, post synaptic 5-HT1A receptors activation induces anxiolytic effects in animals previously exposed to stressful situations. However, little is known about somatodendritic 5-HT1A receptors in the median raphe nucleus (MRN). Therefore, the aim of this study was to investigate the role of 5-HT1A receptors located in the MRN in rats exposed to forced swim stress. After recovering from surgery, rats were forced to swim for 15 min in a cylinder. Intra-MRN injections of saline, 8-OH-DPAT (3 nmol/0.2 uL) and/or WAY-100635 (0.3 nmol/0.2 uL) were performed immediately before or after pre-exposure or 24 h later (immediately before test). Non-stressed rats received the same treatment 24 h or 10 min before test. Our data showed that 8-OH-DPAT increased latency to display immobility while decreasing time spent immobile in almost all experimental conditions. These effects were not prevented by previous treatment with WAY-100635. No effects of different treatments were described in non-stressed animals. Taken together, our data suggest that in addition to activation of 5-HT1A, 5-HT7 receptors may also be involved in the behavioural consequences of exposure to swim stress. PMID- 24162802 TI - Bio-inspired antireflective hetero-nanojunctions with enhanced photoactivity. AB - A bio-inspired antireflective hetero-nanojunction structure has been fabricated by the hydrothermal growth of ZnO nanorods on silicon micro-pyramids. It has been shown that this structure suppresses light reflection more effectively resulting in a high photocurrent response and good charge separation simultaneously. The strategy provides a means to enhance solar energy conversion. PMID- 24162803 TI - Diamino protic ionic liquids for CO2 capture. AB - A series of multifunctional protic ionic liquids (PILs), some of which are based on a combination of primary and tertiary amines in the same moiety coupled with a carboxylic acid, have been synthesised and employed for CO2 capture, yielding absorption capacities comparable to standard absorbents. In contrast to traditional amine absorbers, CO2 was found to desorb at lower temperatures and hence could result in a significant reduction in both the energy required to strip the absorber of CO2 and the thermally activated degradation mechanisms, which in traditional absorbers result in the loss of absorber and the production of toxic compounds. The lower basicity of the amine sites resultant from PIL formation decreases the binding energy of the CO2 to the absorber. The weaker basicity is also evidenced by lower pH of the PIL CO2 absorbers, which reduces common corrosion problems associated with traditional amine absorbers. PMID- 24162804 TI - It is amazing what you can see if you look. PMID- 24162805 TI - Alteration of the endometrial EGF profile as a potential mechanism connecting the alterations in the ovarian steroid hormone profile to embryonic loss in repeat breeders and high-producing cows. AB - Poor reproductive efficiency is a worldwide problem that has affected the dairy industry during the last several decades. In an attempt to explain the changes in reproductive physiology caused by high milk production, a model of elevated steroid metabolism in lactating dairy cows has been proposed. A slow increase in levels and low peak levels of estradiol (E2) and progesterone (P4) characterize endocrine changes in high producing cows. Similar changes have been reported in the repeat breeder cows. The abnormal changes in E2 and P4 concentrations of these cows may cause an improper uterine environment due to disturbed expression of growth factors and cytokines in the endometrium. This review focuses on the alteration in epidermal growth factor (EGF) profile in the endometrium during the estrous cycle. The normal cow has two peaks of EGF concentrations on days 2-4 and 13-14. Low concentrations of EGF on these days distinguished both high-producing and repeat breeder cows from normal cows. Alteration of the EGF profile could be found in 70 and 40% of the repeat breeder and high-producing cows, respectively. Treatment with a high dose of estradiol benzoate and an intravaginal progesterone releasing device restored the normal EGF profile in about 70% of the affected cows. The cows having a normal EGF profile after treatment showed a higher pregnancy rate than the cows with the altered profile. Further studies to understand the etiology of the alteration in the EGF profile are needed to develop another treatment option and preventive management for this problem. PMID- 24162807 TI - Roles of cohesin and condensin in chromosome dynamics during mammalian meiosis. AB - Meiosis is a key step for sexual reproduction in which chromosome number is halved by two successive meiotic divisions after a single round of DNA replication. In the first meiotic division (meiosis I), homologous chromosomes pair, synapse, and recombine with their partners in prophase I. As a result, homologous chromosomes are physically connected until metaphase I and then segregated from each other at the onset of anaphase I. In the subsequent second meiotic division (meiosis II), sister chromatids are segregated. Chromosomal abnormality arising during meiosis is one of the major causes of birth defects and congenital disorders in mammals including human and domestic animals. Hence understanding of the mechanism underlying these unique chromosome behavior in meiosis is of great importance. This review focuses on the roles of cohesin and condensin, and their regulation in chromosome dynamics during mammalian meiosis. PMID- 24162808 TI - Saving genetic resources of native pigs in Occidental and Oriental countries - practical examples of the characterization and utilization of native pigs in Hungary and Laos. AB - Worldwide, only a few "fatty" pig breeds exist with different and/or regional utilization. Using the Hungarian Mangalica, which almost went extinct in Europe and the Lao Moo Lat pig, which still has a large population in South-East Asia as exemples, we wanted to demonstrate that indigenous (fatty) pig breeds may represent both national value and tremendous economic potential. Since these less prolific and less productive breeds cannot contribute to mass production, new market roles and methods should be established for them in the premium segment of pork trading. Thus their preservation and propagation needs the comprehensive collaboration of commercial, governmental actors and researchers. Briefly summarizing the history, we report the current results of reproductive physiology research. The commercial renaissance of Mangalica pigs is indebted to the enthusiastic efforts of basic scientists, pig breeding experts and dedicated Mangalica producers. Scientific achievements were applied to practical breeding and production of delicious pork and processed products, which ultimately made the economic success in the Mangalica sector possible. Both, research on and utilization of endangered (pig) breeds maintain not only breed diversities, but also may improve the livelihood of farmers worldwide. PMID- 24162809 TI - Health-related quality of life and cognitive functioning in long-term anaplastic oligodendroglioma and oligoastrocytoma survivors. AB - Overall survival of patients with anaplastic oligodendroglial tumors has been improved due to the addition of procarbazine, lomustine and vincristine (PCV) chemotherapy to radiotherapy (RT), especially in 1p/19q-codeleted tumors. With improved survival, quality of survival becomes pivotal. We evaluated cognitive functioning and health-related quality of life (HRQOL) in a cohort of long-term anaplastic oligodendroglioma survivors. Thirty-two out of 37 long-term survivors included in European Organisation for Research and Treatment of Cancer (EORTC) study 26951 in the Netherlands and France participated. Cognition was assessed using neuropsychological tests for 6 domains, and HRQOL with the EORTC Quality of Life Questionnaire (EORTC QLQ-C30) and Brain Cancer Module (EORTC QLQ-BN20). Fatigue and mood were evaluated. Results were compared to healthy controls and to patients' own HRQOL 2.5 years following initial treatment. At the time of assessment, median survival for the patients was 147 months, 27 were still progression-free since initial treatment. Of progression-free patients, 26% were not, and 30% were severely cognitively impaired; 41% were employed and 81% could live independently. Patients' HRQOL was worse compared to controls, but similar to 2.5 years after initial treatment. Initial treatment (RT versus RT + PCV) was not correlated with cognition or HRQOL. In conclusion, cognitive functioning in long-term anaplastic oligodendroglioma survivors is variable. However, most patients function independently. In progression-free patients, HRQOL is relatively stable during the disease course. In this small sample, no effect of the addition of PCV on cognition or HRQOL was identified. PMID- 24162806 TI - Roles of intracellular cyclic AMP signal transduction in the capacitation and subsequent hyperactivation of mouse and boar spermatozoa. AB - It is not until accomplishment of a variety of molecular changes during the transit through the female reproductive tract that mammalian spermatozoa are capable of exhibiting highly activated motility with asymmetric whiplash beating of the flagella (hyperactivation) and undergoing acrosomal exocytosis in the head (acrosome reaction). These molecular changes of the spermatozoa are collectively termed capacitation and promoted by bicarbonate, calcium and cholesterol acceptors. Such capacitation-promoting factors can stimulate intracellular cyclic AMP (cAMP) signal transduction in the spermatozoa. Meanwhile, hyperactivation and the acrosome reaction are essential to sperm fertilization with oocytes and are apparently triggered by a sufficient increase of intracellular Ca2+ in the sperm flagellum and head, respectively. Thus, it is necessary to investigate the relationship between cAMP signal transduction and calcium signaling cascades in the spermatozoa for the purpose of understanding the molecular basis of capacitation. In this review, I cover updated insights regarding intracellular cAMP signal transduction, the acrosome reaction and flagellar motility in mammalian spermatozoa and then account for possible roles of intracellular cAMP signal transduction in the capacitation and subsequent hyperactivation of mouse and boar spermatozoa. PMID- 24162810 TI - Chemoradiation for anaplastic oligodendrogliomas: clinical outcomes and prognostic value of molecular markers. AB - Combination of procarbazine, lomustine and vincristine (PCV) with radiation therapy (RT) has been associated with longer survival in patients with anaplastic oligodendroglioma (AO) and anaplastic oligoastrocytoma (AOA), especially in those with chromosome 1p/19q codeletion. We report a multicenter retrospective study of 84 consecutive adult patients with AO and AOA treated with RT plus concomitant and adjuvant temozolomide (TMZ) between February 2004 and January 2011. Correlations between chromosome 1p/19q codeletion, isocitrate dehydrogenase1 (IDH1) mutation, and O-6-methylguanine-DNA methyltransferase (MGMT) promoter methylation with survival outcomes have been analyzed. For all 84 patients the median overall survival (OS) and progression-free survival rates were 55.6 and 45.2 months, respectively. Grade 3 or 4 hematological toxicity occurred in 17 % of patients. Chromosome 1p/19q codeletion was detected in 57 %, IDH1 mutation in 63 %, and MGMT promoter methylation in 74 % of evaluable patients. In multivariate analysis the presence of chromosome 1p/19q codeletion was associated with significant survival benefit (median OS 34 months in noncodeleted tumors and not reached in codeleted tumors; HR 0.16, 95 % CI 0.03-0.45; P = 0.005). IDH1 mutation was also of prognostic significance for longer survival (P = 0.001; HR 0.20, 95 % 0.06-0.41), whereas MGMT promoter methylation was only of borderline significance. The study indicates that RT with concomitant and adjuvant TMZ is a relatively safe treatment associated with longer survival in patients with 1p/19q codeleted and IDH1 mutated tumors. Results from ongoing randomized studies will be essential to clarify if RT plus TMZ may provide survival as good as or better than RT combined with PCV for patients with AO and AOA. PMID- 24162811 TI - Enhanced imine synthesis in water: from surfactant-mediated catalysis to host guest mechanisms. AB - An environment-responsive and fluorogenic reaction is reported and used as a model system to demonstrate experimentally three mechanisms of enhanced imine synthesis in water using either surfactants (below and above their CMC) or double stranded DNA (acting as a reaction host). PMID- 24162813 TI - Differential regulation of myeloid leukemias by the bone marrow microenvironment. AB - Like their normal hematopoietic stem cell counterparts, leukemia stem cells (LSCs) in chronic myelogenous leukemia (CML) and acute myeloid leukemia (AML) are presumed to reside in specific niches in the bone marrow microenvironment (BMM) and may be the cause of relapse following chemotherapy. Targeting the niche is a new strategy to eliminate persistent and drug-resistant LSCs. CD44 (refs. 3,4) and interleukin-6 (ref. 5) have been implicated previously in the LSC niche. Transforming growth factor-beta1 (TGF-beta1) is released during bone remodeling and plays a part in maintenance of CML LSCs, but a role for TGF-beta1 from the BMM has not been defined. Here, we show that alteration of the BMM by osteoblastic cell-specific activation of the parathyroid hormone (PTH) receptor attenuates BCR-ABL1 oncogene-induced CML-like myeloproliferative neoplasia (MPN) but enhances MLL-AF9 oncogene-induced AML in mouse transplantation models, possibly through opposing effects of increased TGF-beta1 on the respective LSCs. PTH treatment caused a 15-fold decrease in LSCs in wild-type mice with CML-like MPN and reduced engraftment of immune-deficient mice with primary human CML cells. These results demonstrate that LSC niches in CML and AML are distinct and suggest that modulation of the BMM by PTH may be a feasible strategy to reduce LSCs, a prerequisite for the cure of CML. PMID- 24162816 TI - Smartphone quantifies Salmonella from paper microfluidics. AB - Smartphone-based optical detection is a potentially easy-to-use, handheld, true point-of-care diagnostic tool for the early and rapid detection of pathogens. Paper microfluidics is a low-cost, field-deployable, and easy-to-use alternative to conventional microfluidic devices. Most paper-based microfluidic assays typically utilize dyes or enzyme-substrate binding, while bacterial detection on paper microfluidics is rare. We demonstrate a novel application of smartphone based detection of Salmonella on paper microfluidics. Each paper microfluidic channel was pre-loaded with anti-Salmonella Typhimurium and anti-Escherichia coli conjugated submicroparticles. Dipping the paper microfluidic device into the Salmonella solutions led to the antibody-conjugated particles that were still confined within the paper fibers to immunoagglutinate. The extent of immunoagglutination was quantified by evaluating Mie scattering from the digital images taken at an optimized angle and distance with a smartphone. A smartphone application was designed and programmed to allow the user to position the smartphone at an optimized angle and distance from the paper microfluidic device, and a simple image processing algorithm was implemented to calculate and display the bacterial concentration on the smartphone. The detection limit was single cell-level and the total assay time was less than one minute. PMID- 24162817 TI - Multi-residue method for the determination of 57 persistent organic pollutants in human milk and colostrum using a QuEChERS-based extraction procedure. AB - Human breast milk represents the best choice for the nutrition of infants. However, in addition to containing beneficial nutrients and antibodies, it can also be considered the best indicator of infant exposure to contaminants. We developed a multi-residue method using a modified QuEChERS (quick, easy, cheap, effective, rugged, and safe) procedure and capillary gas chromatography-triple quadrupole mass spectrometry for the determination of 57 persistent organic pollutants, including 23 organochlorine pesticides, 18 polychlorinated biphenyl (PCB) congeners, and 16 polycyclic aromatic hydrocarbons in human milk and colostrum samples. We have used primary secondary amine in the clean-up step as it gave a more efficient separation of the analytes from fat and superior removal of the co-extracted substances compared with gel permeation chromatography. No significant matrix effect was observed for the tested pollutants, and therefore matrix-matched calibration was not necessary. The average recoveries from spiked samples were in the range of 74.8-113.0 %. The precision was satisfactory, with relative standard deviations below 16 %, while values of 0.1-0.4 MUg L(-1) were established as the limit of quantification for all the target analytes (0.05 and 100 MUg L(-1)). The method was successfully applied to the analysis of 18 human colostrum and 23 mature milk samples. All the samples tested were positive for at least nine different residues, with some samples containing up to 24 contaminants. Remarkably, the contaminants hexachlorobenzene, p,p'-DDE, PCB 138, PCB 180, phenanthrene, fluoranthene, and pyrene were present in 100 % of the colostrum and mature milk samples analyzed. PMID- 24162819 TI - Deposition of JWH-018, JWH-073 and their metabolites in hair and effect of hair pigmentation. AB - Analysis of drugs in hair is often used as a routine method to obtain detailed information about drug ingestion. However, few studies have been conducted on deposition of synthetic cannabinoids and metabolites in hair. The first purpose of this study was to establish and validate an analytical method for detection of JWH-018, JWH-073, and their metabolites in hair, by use of UHPLC-MS-MS, for forensic application. The second purpose was to investigate the distribution of synthetic cannabinoids metabolites in hair and the effect of hair pigmentation, by use of an animal model. For this, JWH-073 was chosen as a representative synthetic cannabinoid. Finally, the developed method was applied to hair samples from 18 individuals suspected of synthetic cannabinoids use. JWH-018, JWH-073, and their metabolites were extracted from hair with methanol. The extract was then filtered and analyzed by UHPLC-MS-MS with an electrospray ion source in positive-ionization mode. Validation proved the method was selective, sensitive, accurate, and precise, with acceptable linearity within the calibration ranges. No significant variations were observed when different sources of both human and rat hair were used. The animal study demonstrated that JWH-073 N-COOH M was the major metabolite of JWH-073 in rat hair, and hair pigmentation did not have a significant effect on incorporation of JWH-073 and its metabolites into hair. In the analysis of 18 authentic hair samples, only JWH-018, JWH-018 N-5-OH M, and JWH-073 were detected, with wide variation in concentrations. PMID- 24162820 TI - NIR Raman spectra of whole human blood: effects of laser-induced and in vitro hemoglobin denaturation. AB - Care must be exercised in the use of Raman spectroscopy for the identification of blood in forensic applications. The Raman spectra of dried whole human blood excited at 785 nm are shown to be exclusively due to oxyhemoglobin or related hemoglobin denaturation products. Raman spectra of whole blood are reported as a function of the incident 785-nm-laser power, and features attributable to heme aggregates are observed for fluences on the order of 10(4) W/cm(2) and signal collection times of 20 s. In particular, the formation of this local-heating induced heme aggregate product is indicated by a redshifting of several heme porphyrin ring vibrational bands, the appearance of a large broad band at 1,248 cm(-1), the disappearance of the Fe-O2 stretching and bending bands, and the observation of a large overlapping fluorescence band. This denaturation product is also observed in the low-power-excitation Raman spectrum of older ambient-air exposed bloodstains (2 weeks or more). The Raman spectrum of methemoglobin whole blood excited at 785 nm is reported, and increasing amounts of this natural denaturation product can also be identified in Raman spectra of dried whole blood particularly when the blood has been stored prior to drying. These results indicate that to use 785-nm-excitation Raman spectra as an identification method for forensic applications to maximum effect, incident laser powers need to be kept low to eliminate variable amounts of heme aggregate spectral components contributing to the signal and the natural aging process of hemoglobin denaturation needs to be accounted for. This also suggests that there is a potential opportunity for 785-nm-excitation Raman spectra to be a sensitive indicator of the age of dried bloodstains at crime scenes. PMID- 24162821 TI - Increased sensitivity of lateral flow immunoassay for ochratoxin A through silver enhancement. AB - Silver nucleation on gold has been exploited for signal amplification and has found application in several qualitative and quantitative bio-sensing techniques, thanks to the simplicity of the method and the high sensitivity achieved. Very recently, this technique has been tentatively applied to improve the performance of gold-based immunoassays. In this work, the exploitation of the signal amplification due to silver deposition on gold nanoparticles has been first applied to a competitive lateral flow immunoassay (LFIA). The signal enhancement due to silver allowed us to strongly reduce the amount of the competitor and of specific antibodies employed to build an LF device for measuring ochratoxin A (OTA), thus permitting the attainment of a highly sensitive assessment of OTA contamination, with a sensitivity gain of more than 10-fold compared to the gold based LFIA that used the same immunoreagents and to all previously reported LFIA for measuring OTA. In addition, a less sensitive "quantitative" LFIA could be established, by suitably tuning competitor and antibody amounts, which was characterized by reproducible and accurate OTA determinations (RSD% 6-12%, recovery% 82-117%). The quantitative system allowed a reliable OTA quantification in wines and grape musts at the microgram per liter level requested by the European legislation, as demonstrated by a highly results obtained through the quantitative silver-enhanced LFIA and a reference HPLC-FLD on 30 samples. PMID- 24162822 TI - In-vivo evaluation of the permeability of the blood-brain barrier to arsenicals, molybdate, and methylmercury by use of online microdialysis-packed minicolumn inductively coupled plasma mass spectrometry. AB - To study the permeability of the blood-brain barrier (BBB) to arsenates, arsenite, monomethylarsonic acid (MMA), dimethylarsinic acid (DMA), molybdate, and methylmercury, and the transfer behavior of these species, we constructed an automatic online analytical system comprising a microdialysis sampling device, a minicolumn packed with nonfunctionalized poly(vinyl chloride) beads, and an inductively coupled plasma mass spectrometer for continuous in-vivo measurement of their dynamic variation in the extracellular space of the brains of living rats. By using ion-polymer interactions as a novel working mechanism for sample pretreatment of volume-limited microdialysate, we simplified the operating procedure of conventional solid-phase extraction and reduced the contribution to the blank of the chemicals used. After optimizing this hyphenated system, we measured its performance by analysis of NIST standard reference materials 1640a (trace elements in natural water) and 2672a (trace elements in human urine) and by in-vivo monitoring of the dynamic variation of the compounds tested in the extracellular fluid (ECF) of rat brain. We found that intraperitoneal administration led to observable BBB permeability of arsenates, arsenite, DMA, MMA, and molybdate. Nevertheless, the limited sensitivity of the system and the size of microdialysis samples meant that detection of MeHg in ECF remained problematic, even when we administered a dose of 20 mg MeHg kg(-1) body weight. On the basis of these practical demonstrations, we suggest that our analytical system could be used not only for dynamic monitoring of the transfer kinetics of the four arsenicals and molybdate in the rat brain but also to describe associated neurotoxicity in terms of exposure to toxic metals and their species. PMID- 24162823 TI - Embedded passivated-electrode insulator-based dielectrophoresis (EpiDEP). AB - Here, we introduce a new technique called embedded passivated-electrode insulator based dielectrophoresis (EpiDEP) for preconcentration, separation, or enrichment of bioparticles, including living cells. This new method combines traditional electrode-based DEP and insulator-based DEP with the objective of enhancing the electric field strength and capture efficiency within the microfluidic channel while alleviating direct contact between the electrode and the fluid. The EpiDEP chip contains embedded electrodes within the microfluidic channel covered by a thin passivation layer of only 4 MUm. The channel was designed with two nonaligned vertical columns of insulated microposts (200 MUm diameter, 50 MUm spacing) located between the electrodes (600 MUm wide, 600 MUm horizontal spacing) to generate nonuniform electric field lines to concentrate cells while maintaining steady flow in the channel. The performance of the chip was demonstrated using Gram-negative (Escherichia coli) and Gram-positive (Staphylococcus aureus) bacterial pathogens in aqueous media. Trapping efficiencies of 100% were obtained for both pathogens at an applied AC voltage of 50 V peak-to-peak and flow rates as high as 10 MUl/min. PMID- 24162815 TI - Oncogenic and drug-sensitive NTRK1 rearrangements in lung cancer. AB - We identified new gene fusions in patients with lung cancer harboring the kinase domain of the NTRK1 gene that encodes the high-affinity nerve growth factor receptor (TRKA protein). Both the MPRIP-NTRK1 and CD74-NTRK1 fusions lead to constitutive TRKA kinase activity and are oncogenic. Treatment of cells expressing NTRK1 fusions with inhibitors of TRKA kinase activity inhibited autophosphorylation of TRKA and cell growth. Tumor samples from 3 of 91 patients with lung cancer (3.3%) without known oncogenic alterations assayed by next generation sequencing or fluorescence in situ hybridization demonstrated evidence of NTRK1 gene fusions. PMID- 24162824 TI - Omalizumab induced remission of idiopathic anaphylaxis in a patient suffering from indolent systemic mastocytosis. PMID- 24162825 TI - Screening effective short interfering RNA/short hairpin RNA for inhibition of human astrovirus ORF2 gene expression in cultured cells. AB - In this study, we have evaluated four different 21-nt duplexes of small interfering RNA (siRNA-469, siRNA-852, siRNA-1802 and siRNA-1806) that specifically target the ORF2 gene of human astrovirus (HAstV) in inhibiting HAstV capsid protein expression in transfected BHK-21 cells. Furthermore, fluorescence analysis, real-time quantitative PCR (RT-qPCR) and western blot assays showed that pGPU6/GFP/Neo-shRNA inhibits ORF2 gene expression in Caco2 cells. The results indicate that siRNA/shRNA-469 and siRNA/shRNA-1802 can interfere with capsid protein expression in cell culture, and this provides a powerful tool for the study of HAstV gene functions and the biological properties of the capsid protein. PMID- 24162814 TI - Loss of immune escape mutations during persistent HCV infection in pregnancy enhances replication of vertically transmitted viruses. AB - Globally, about 1% of pregnant women are persistently infected with the hepatitis C virus (HCV). Mother-to-child transmission of HCV occurs in 3-5% of pregnancies and accounts for most new childhood infections. HCV-specific CD8(+) cytotoxic T lymphocytes (CTLs) are vital in the clearance of acute HCV infections, but in the 60-80% of infections that persist, these cells become functionally exhausted or select for mutant viruses that escape T cell recognition. Increased HCV replication during pregnancy suggests that maternofetal immune tolerance mechanisms may further impair HCV-specific CTLs, limiting their selective pressure on persistent viruses. To assess this possibility, we characterized circulating viral quasispecies during and after consecutive pregnancies in two women. This revealed a loss of some escape mutations in HLA class I epitopes during pregnancy that was associated with emergence of more fit viruses. CTL selective pressure was reimposed after childbirth, at which point escape mutations in these epitopes again predominated in the quasispecies and viral load dropped sharply. Importantly, the viruses transmitted perinatally were those with enhanced fitness due to reversion of escape mutations. Our findings indicate that the immunoregulatory changes of pregnancy reduce CTL selective pressure on HCV class I epitopes, thereby facilitating vertical transmission of viruses with optimized replicative fitness. PMID- 24162826 TI - Effect of age on the pathogenesis of DHV-1 in Pekin ducks and on the innate immune responses of ducks to infection. AB - Duck hepatitis virus (DHV) affects 1-week-old but not 3-week-old ducks, and it causes a more severe disease in the younger ducks. These differences may be partially due to the host response to DHV infection. In order to understand this difference, we characterized the pathobiology of and innate immune response to DHV infection in 1-day-old (1D) and 3-week-old (3 W) ducks. Viral RNA was detected in duck livers at 24, 36 and 72 h after inoculation with DHV at a dose of 10(3) LD50. Virus-induced pathology ranged from no clinical signs to severe disease and death, and it was more severe in the 1D ducks. Infection with DHV induced up-regulation of gene expression of Toll-like receptor (TLR)-7, TLR3, retinoic-acid-inducible gene I (RIG-I), melanoma differentiation-associated gene 5 (MDA-5), interleukin (IL)-6, interferon (IFN)-alpha, interferon-induced transmembrane protein 1 (IFITM1), interferon-stimulated gene 12 (ISG12), and 2' 5' oligoadenylate synthetase-like gene (OASL) in the livers of 3 W ducks. Of these, IL-6, OASL and ISG12 mRNA levels were more than 100-fold higher in infected 3 W ducks than in mock-infected ducks of the same age. These genes were induced much less in infected 1D ducklings. We present evidence that a lower level of viral replication in the hepatocytes of 3 W ducks, whose basal level of cytokines is higher than that in 1D ducklings, may be related to the strong innate immunity induced. From our data, we conclude that duck age plays an important role in the pathogenicity of and innate immune responses to DHV. PMID- 24162827 TI - PTEN status mediates 2ME2 anti-tumor efficacy in preclinical glioblastoma models: role of HIF1alpha suppression. AB - Glioblastoma (GBM) is the most common brain cancer and is highly lethal in both adults and children. 2-methoxyestradiol (2ME2) is a microtubule inhibitor that potently inhibits HIF1alpha, GBM angiogenesis and tumor growth in preclinical models. In patients, 2ME2 exhibits low toxicity and promising but inconsistent efficacy. Given its preclinical potency and its tolerability in patients, we sought to determine whether 2ME2 therapy could be enhanced by addressing resistance via combination therapy, and with biomarkers to identify responsive glioma subgroups. We demonstrate that the PTEN-PI3K axis regulates HIF1alpha in glioma models. We utilized isogenic-pairs of glioma cell lines, deficient in PTEN or stably reconstituted with PTEN, to determine the role of PTEN in 2ME2 sensitivity in vitro and in vivo. Chou-Talalay synergy studies reveal significant synergy when a pan-PI3K inhibitor is combined with 2ME2. This synergistic activity was correlated with a synergistic suppression of HIF1alpha accumulation under hypoxic conditions in glioma models. In vivo, 2ME2 markedly inhibited tumor induced angiogenesis and significantly reduced tumor growth only in a PTEN reconstituted GBM models in both subcutaneous and orthotopic intracranial mouse models. Collectively, these results: (1) suggest that PTEN status predicts sensitivity to 2ME2 and (2) justify exploration of 2ME2 combined with pan-PI3K inhibitors for the treatment of this intractable brain cancer. PMID- 24162828 TI - Methylation-specific multiplex ligation-dependent probe amplification and its impact on clinical findings in medulloblastoma. AB - Gain of (proto-)oncogenes and loss or promoter hypermethylation of tumor suppressor genes (TSGs) play essential roles in tumorigenesis. Methylation specific multiplex ligation-dependent probe amplification (MS-MLPA) allows simultaneous detection of both these alterations. MS-MLPA was performed on 20 medulloblastoma samples (n = 12 cryoconserved; n = 8 formalin-fixed paraffin embedded, FFPE) in order to screen for copy number changes in 77 unselected TSGs and (proto-)oncogenes as well as for promoter hypermethylation in a subset of 33 TSGs. In all specimens, determination of promoter methylation status was possible, whereas robust data concerning copy number changes could be obtained on cryopreserved material only. We found a median of 1.5 deletions and 6.5 amplifications in the 12 cryopreserved medulloblastoma and a median of 5 promoter hypermethylation per tumor. Frequent copy number changes included amplification of ASC on 16p12 (5/12) and amplification of several adjacent genes on 17q (3/12) including IGFBP4. Hypermethylation of MSH6 on 2p16 was found in 16 samples. MS MLPA findings were also correlated with clinical and histological characteristics. The number of promoter hypermethylation was significantly associated with presence of necrosis (p = 0.004). Tumors which recurred within 1 year were more likely to show amplification of the GATA5 gene (p = 0.038), while hypermethylation of CASP8 was associated with a lower tumor recurrence rate (p = 0.036). There was also a trend towards a correlation between total number of aberrations and CSF dissemination (p = 0.055). Our findings confirm frequent presence of certain aberrations and reveal novel candidates for improving prognosis based on genetic and epigenetic tumor features. A medulloblastoma specific MS-MLPA probe set seems a potentially valuable tool for further investigations on larger sample series. PMID- 24162829 TI - 18beta-glycyrrhetinic acid induces apoptosis in pituitary adenoma cells via ROS/MAPKs-mediated pathway. AB - The purpose of the present study was to evaluate the anti-tumor effects of 18beta glycyrrhetinic acid (GA), a natural compound extracted from liquorice, against pituitary adenoma and its underlying mechanisms in cultured cells and mouse model of xenografted tumor. GA induced cellular damage in rat pituitary adenoma-derived MMQ and GH3 cells, manifested as reduced cell viability, increased lactate dehydrogenase release, elevated intracellular reactive oxygen species (ROS) and Ca(2+) concentration. GA also caused G0/G1 phase arrest, increased apoptosis rate and increased mitochondrial membrane permeabilization by suppressing the mitochondrial membrane potential and down-regulating a ratio of B cell lymphoma 2 (Bcl-2) and Bax. GA activated calcium/calmodulin-dependent protein kinase II (CaMKII), c-Jun N-terminal kinase (JNK) and P38; but these activating effects were attenuated by pretreatment with N-acetyl-L-cysteine, a ROS inhibitor. Pretreatment with KN93, a CaMKII inhibitor, also abolished the GA activation of JNK and P38. GA remarkably inhibited growth of pituitary adenoma grafted on nude mice. These results suggest that the anti-pituitary adenoma effect of GA is associated with its apoptotic actions by activating mitochondria-mediated ROS/mitogen-activated protein kinase pathways in particular CaMKII that may serve a linkage between ROS accumulation and the activation of JNK and P38. This study provides experimental evidence in the support of further developing GA as a chemotherapeutic agent for pituitary adenoma. PMID- 24162830 TI - Heterogeneous visible light photocatalysis for selective organic transformations. AB - The future development of chemistry entails environmentally friendly and energy sustainable alternatives for organic transformations. Visible light photocatalysis can address these challenges, as reflected by recent intensive scientific endeavours to this end. This review covers state-of-the-art accomplishments in visible-light-induced selective organic transformations by heterogeneous photocatalysis. The discussion comprises three sections based on the photocatalyst type: metal oxides such as TiO2, Nb2O5 and ZnO; plasmonic photocatalysts like nanostructured Au, Ag or Cu supported on metal oxides; and polymeric graphitic carbon nitride. Finally, recent strides in bridging the gap between photocatalysis and other areas of catalysis will be highlighted with the aim of overcoming the existing limitations of photocatalysis by developing more creative synthetic methodologies. PMID- 24162831 TI - Intra pulmonary migration of a Kirschner wire after glenohumeral fixation. PMID- 24162832 TI - Impact of local ablation on interconnected channels within ventricular scar: mechanistic implications for substrate modification. AB - BACKGROUND: The extent to which channels within scar are interconnected is not known. The objective of the study was to evaluate the impact of local ablation of late potentials (LPs) on adjacent and remote areas of slow conduction with simultaneous multipolar mapping. METHODS AND RESULTS: Analysis was performed on consecutive patients referred for ablation of scar-mediated ventricular tachycardia with double ventricular access. Ablation was performed targeting the earliest of LPs visualized on the multipolar catheter, and the impact on later LPs was recorded. In 21 patients, a multipolar catheter placed within scar visualized spatially distinct LPs. Among 39 radiofrequency applications, ablation at earlier LPs had an effect on neighboring and remote LPs in 31 (80%), with delay in 8 (21%), partial elimination in 9 (23%), and complete elimination in 14 (36%). The mean distance where an ablation impact was detected was 17.6+/-14.7 mm (range, 2-50 mm). Among all patients, 9.7+/-7.8 radiofrequency applications were delivered to homogenize the targeted scar region with a mean number of 23+/-12 LPs targeted. CONCLUSIONS: Ablation can eliminate neighboring and remote areas of slow conduction, suggesting that channels within scar are frequently interconnected. This is the first mechanistic demonstration to show that ablation can modify electrical activity in regions of scar outside of the known radius of an radiofrequency lesion. The targeting of relatively earlier LPs can expedite scar homogenization without the need for extensive ablation of all LPs. PMID- 24162833 TI - Prognostic role of subsequent atrial tachycardias occurring during ablation of persistent atrial fibrillation: a prospective randomized trial. AB - BACKGROUND: The role of subsequent atrial tachycardias (AT) in the context of persistent atrial fibrillation (AF) remains undetermined. This study evaluated the prognostic role of subsequent ATs for arrhythmia recurrences after catheter ablation of persistent AF. METHODS AND RESULTS: A total of 110 patients with persistent AF (63+/-9 years; 22 women; 61 long-lasting persistent AF) underwent pulmonary vein isolation followed by electrogram-guided ablation. After AF terminated to AT, patients were separated by the randomization protocol to receive either direct cardioversion (group A) or further ablation of subsequent ATs to sinus rhythm (group B). After a mean follow-up of 20.1+/-13.3 months after the first procedure, significantly more group B patients were in sinus rhythm as compared with patients in group A (30 [57%] versus 18 [34%]; P=0.02). Moreover, recurrences of AF were significantly less frequent of group B than in group A patients (10 [19%] versus 26 [49%]; P=0.001). After the last procedure (follow up, 34.0+/-6.4 months), significantly more group B patients were free of AF as compared with patients of group A (49 [92%] versus 39 [74%]; P=0.01). The proportion of AT recurrences did not differ between the 2 groups after the first and final procedures. The strongest predictor for an arrhythmia-free survival after a single procedure was randomization to the procedural end point of termination to sinus rhythm by elimination of subsequent ATs (P=0.004). CONCLUSIONS: Catheter ablation of subsequent ATs increases freedom from AF but not AT, suggesting a contributing role of subsequent ATs in the mechanisms of persistent AF. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01896570. PMID- 24162834 TI - Synthesis and Study the Effect of Donor-Acceptor Substituent on Fluorescence Behavior of Thieno[3, 2-c]pyridine Derivatives. AB - 4-Hetero-1-yl-2-bromothieno[3,2-c]pyridines 3(a-d) were synthesized by the reaction of 2-bromo-4-chlorothieno[3,2-c]pyridine (1) and cyclic amine 2(a-d), which on Suzuki coupling with substituted boronic acids 4(a-f) exclusively converted to corresponding 4-hetero -1-yl-2-arylthieno[3,2-c]pyridine 5(a-x) in good yields. The effect of donor-acceptor substituent on absorption emission properties and fluorescent quantum yield of new thienopyridine derivatives 5(a-x) were studied. PMID- 24162836 TI - Quality control of iodine-131-labeled metaiodobenzylguanidine. AB - AIM/OBJECTIVES/BACKGROUND: Iodine-131-m-iodobenzylguanidine ([(131)I]mIBG) is used worldwide for the diagnosis and therapy of neuroendocrine tumors, particularly adrenal medullae tumors. After the synthesis and preparation of a radioiodinated MIBG drug formulation, quality control testing to determine its radiochemical purity (RCP) should be performed. European Pharmacopoeia 8.0 requires that the quality control include a test for RCP for the determination of [(131)I]mIBG. Previously reported procedures using reversed-phase conditions require long retention times. Our system enables the separation of [(131)I]mIBG within a few minutes. The aim of this work was to carry out RCP testing for [(131)I]mIBG without any type of sample pretreatment. METHODS: RCP testing for ([(131)I]mIBG has been carried out using high-performance liquid chromatography and thin-layer chromatography methods. RESULTS: A simple and rapid reversed-phase isocratic system enables the HPLC investigation of RCP testing for [(131)I]mIBG used for therapy within a few minutes. CONCLUSIONS: From the point of view of radiation protection, this method is safer, especially for therapeutic amounts of [(131)I]mIBG. PMID- 24162835 TI - Unsymmetrically Substituted Nickel Triazatetra-Benzcorrole and Phthalocynanine Complexes: Conjugation to Quantum Dots and Applications as Fluorescent "Turn ON" Sensors. AB - We report on the design and application of fluorescent nanoprobes based on the covalent linking of L-glutathione-capped CdSe@ZnS quantum dots (QDs) to newly synthesized unsymmetrically substituted nickel mercaptosuccinic acid triazatetra benzcorrole (3) and phthalocyanine (4) complexes. Fluorescence quenching of the QDs occurred on conjugation to complexes 3 or 4. The nanoprobes were selectively screened in the presence of different cations and Hg(2+) showed excellent affinity in "turning ON" the fluorescence of the nanoprobes. Experimental results showed that the sensitivity of QDs-4 towards Hg(2+) was much higher than that of QDs-3 nanoprobe. The mechanism of reaction has been elucidated based on the ability of Hg(2+) to coordinate with the sulphur atom of the Ni complex ring and apparently "turn ON" the fluorescence of the linked QDs. PMID- 24162837 TI - Production, quality control, biodistribution assessment and preliminary dose evaluation of (177)Lu-PDTMP as a possible bone palliative agent. AB - OBJECTIVES: In this study, production, quality control, and biodistribution studies of a newly developed therapeutic compound have been presented and are followed by dosimetric evaluation for use in humans based on biodistribution data in wild-type rats. MATERIALS AND METHODS: The Lu-1,2-propylene di-amino tetramethylenephosphonic acid (Lu-PDTMP) complex was prepared successfully using synthesized PDTMP ligand and LuCl3. LuCl3 was obtained by thermal neutron irradiation (4*10 n/cm/s) of enriched Lu2O3 samples. The radiochemical purity of Lu-PDTMP was checked by instant thin-layer chromatography. Stability studies of the complex in the final preparation and in the presence of human serum were performed for up to 72 h. The biodistribution of Lu-PDTMP and LuCl3 in wild-type rats was checked in animal tissues for up to 7 days. The absorbed dose of each human organ was calculated by means of the medical internal radiation dose method. RESULTS: Lu was produced with a specific activity of 100-110 GBq/mg. Lu PDTMP was prepared with high radiochemical purity of greater than 99% and specific activity of 278 GBq/mmol. The complex demonstrated significant stability at room temperature. The agent demonstrated major accumulation in the bone tissue and a high target/nontarget uptake ratio. Dosimetric results showed that all tissues receive an insignificant absorbed dose in comparison with bone tissue. CONCLUSION: The results showed that Lu-PDTMP has considerably better properties compared with clinically used bone-seeking radiopharmaceuticals and therefore can be a good candidate for bone pain palliative therapy in skeletal metastases; however, further biological studies in other mammals are still needed. PMID- 24162838 TI - Enrolment in community-based health insurance schemes in rural Bihar and Uttar Pradesh, India. AB - This article assesses insurance uptake in three community-based health insurance (CBHI) schemes located in rural parts of two of India's poorest states and offered through women's self-help groups (SHGs). We examine what drives uptake, the degree of inclusive practices of the schemes and the influence of health status on enrolment. The most important finding is that a household's socio economic status does not appear to substantially inhibit uptake. In some cases scheduled caste/scheduled tribe households are more likely to enrol. Second, households with greater financial liabilities find insurance more attractive. Third, access to the national hospital insurance scheme Rashtriya Swasthya Bima Yojana does not dampen CBHI uptake, suggesting that the potential for greater development of insurance markets and products beyond existing ones would respond to a need. Fourth, recent episodes of illness and self-assessed health status do not influence uptake. Fifth, insurance coverage is prioritized within households, with the household head, the spouse of the household head and both male and female children of the household head, more likely to be insured as compared with other relatives. Sixth, offering insurance through women's SHGs appears to mitigate concerns about the inclusiveness and sustainability of CBHI schemes. Given the pan-Indian spread of SHGs, offering insurance through such groups offers the potential to scale-up CBHI. PMID- 24162839 TI - A teleconsultation network improves the efficacy of anti-VEGF therapy in retinal diseases. AB - We investigated the care of patients with age-related macular degeneration (AMD) managed via a physician-to-physician teleconsultation network for ophthalmology. Eleven groups of ophthalmologists took part in the study. The groups were located in 10 cities across Italy. Each group was based on a Retina Centre located at a university or hospital, with one or two expert ophthalmologists (20 expert ophthalmologists in total). In each region containing a Retina Centre, 6-10 general ophthalmologists (94 ophthalmologists in total) referred patients via the network for a period of three months between June 2011 and December 2012. An automatic grading system quantified the risk of disease progression, and a remote booking system allowed the referring ophthalmologist to make appointments directly with the appropriate Retina Centre. There were 360 network patients and 318 control patients (consecutive patients undergoing usual care during the previous three months). The time delay before therapy was significantly shorter in the network patients (mean 5.5 days) compared with the usual care patients (mean 28.7 days; P < 0.0001). There was a significant improvement in visual acuity in the network patients after treatment (first visit = 0.29 logMAR; after treatment = 0.22 logMAR; P < 0.05). In contrast, there was no improvement in the usual care patients (first visit = 0.29 logMAR; after treatment = 0.27 logMAR; P > 0.05). The telemedicine network allows regional ophthalmologists to quantify the risk of disease progression, and to send patients to a Retina Centre quickly and easily, when required. PMID- 24162840 TI - Resection of residual disease after isolated limb infusion (ILI) is equivalent to a complete response after ILI-alone in advanced extremity melanoma. AB - BACKGROUND: Isolated limb infusion (ILI) is a limb-preserving treatment for in transit extremity melanoma. The benefit of resecting residual disease after ILI is unclear. METHODS: A multi-institutional experience was analyzed comparing patients who underwent ILI plus resection of residual disease (ILI + RES) versus ILI-alone. RESULTS: A total of 176 patients were included, 154 with ILI-alone and 22 with ILI + RES. There were no differences between the groups with respect to gender, age, extremity affected, or time from diagnosis to ILI. All surgical resections were performed as an outpatient procedure, separate from the ILI. Within the ILI + RES group, 15 (68%) had a partial response (PR), 2 (9%) stable disease (SD), and 5 (23%) progressive disease (PD). The ILI-alone group had 52 (34%) CR, 30 (19%) PR, 15 (10%) SD, and 46 (30%) PD. Eleven (7%) ILI-alone patients did not have 3-month response available for review. Evaluating overall survival (OS) from date of ILI, the ILI-alone group had a median OS of 30.9 months, whereas the ILI + RES group had not reached median OS, p = 0.304. Although the ILI + RES group had a slightly longer disease-free survival (DFS) compared to those with a CR after ILI-alone (12.4 vs. 9.6), this was not statistically significant, p = 0.978. Within the ILI + RES group, those with an initial PR after ILI had improved DFS versus those with SD or PD after ILI, p < 0.0001. CONCLUSIONS: Resection of residual disease after ILI offers a DFS and OS similar to those who have a CR after ILI-alone. It may offer a treatment strategy that benefits patients undergoing ILI. PMID- 24162843 TI - The anti-overactive bladder activity of KW-7158 is mediated by blocking equilibrative nucleoside transporter-1. AB - KW-7158 is a novel therapeutic candidate for treating overactive bladder (OAB) with a unique mode of action: suppression of sensory afferent nerves. However, the molecular target of this compound remains unknown. We herein report the identification of the KW-7158 target to be equilibrative nucleoside transporter-1 (ENT1). A membrane protein expression library of ca. 7000 genes was expressed in a dorsal root ganglion cell line, which we had previously generated, and subjected to screening for binding with a fluorescent derivative that retains high binding activity to the target. The screening revealed that only cells transfected with an ENT1 expression vector exhibited significant binding. We next performed [(3)H]KW-7158 binding experiments and an adenosine influx assay and found that KW-7158 binds to and inhibits ENT1. To further demonstrate the pharmacological relevance, we evaluated other known ENT1 inhibitors (nitrobenzylthioinosine, dipyridamole, draflazine) in an in vitro bladder strip contraction assay and the rat spinal cord injury OAB model. We found that all of the inhibitors exhibited anti-OAB activities, of which the potencies were comparable to that of adenosine influx inhibition in vitro. These studies demonstrated that the pharmacological target of KW-7158 is ENT1, at least in the rat OAB model. Our results will aid understanding of the precise mechanism of action of this drug and may also shed new light on the use of the adenosine pathway for the treatment of OAB. PMID- 24162844 TI - Multipole plasmon resonances in self-assembled metal hollow-nanospheres. AB - Recently, multipole plasmonic mode resonances in metal hollow structures, such as dipole, quadrupole, and octupole modes, have been widely investigated by researchers with the aim for potential applications in bio-sensing, fluorescence, nanolasers or nonlinear nano-photonics. Here, in this work, the multipole plasmon resonances in self-assembled metal hollow-nanospheres (HNSs) are theoretically and experimentally demonstrated and the hot spots originating from the higher order mode plasmonic resonance and interparticle coupling effect are proposed to be used for Raman scattering enhancements. Dipole, quadrupole, octupole and hexadecapole mode plasmonic resonances were clearly resolved in the extinction spectra of these Ag HNS arrays showing good agreement with the theoretical simulation results. Strong regular hot spots were obtained around the surface and in the gaps of the Ag HNSs through the higher order mode plasmonic resonances and corresponding interparticle coupling effect between the HNSs. Maximum local field intensity was accomplished by optimizing the size of as well as the coupling distance between the HNSs and then it was applied to SERS sensing. Raman mapping also demonstrated these self-assembled plasmonic cavity arrays to be a stable and uniform SERS-active substrate. PMID- 24162845 TI - The nuclear receptor Rev-erbalpha controls circadian thermogenic plasticity. AB - Circadian oscillation of body temperature is a basic, evolutionarily conserved feature of mammalian biology. In addition, homeostatic pathways allow organisms to protect their core temperatures in response to cold exposure. However, the mechanism responsible for coordinating daily body temperature rhythm and adaptability to environmental challenges is unknown. Here we show that the nuclear receptor Rev-erbalpha (also known as Nr1d1), a powerful transcriptional repressor, links circadian and thermogenic networks through the regulation of brown adipose tissue (BAT) function. Mice exposed to cold fare considerably better at 05:00 (Zeitgeber time 22) when Rev-erbalpha is barely expressed than at 17:00 (Zeitgeber time 10) when Rev-erbalpha is abundant. Deletion of Rev-erbalpha markedly improves cold tolerance at 17:00, indicating that overcoming Rev erbalpha-dependent repression is a fundamental feature of the thermogenic response to cold. Physiological induction of uncoupling protein 1 (Ucp1) by cold temperatures is preceded by rapid downregulation of Rev-erbalpha in BAT. Rev erbalpha represses Ucp1 in a brown-adipose-cell-autonomous manner and BAT Ucp1 levels are high in Rev-erbalpha-null mice, even at thermoneutrality. Genetic loss of Rev-erbalpha also abolishes normal rhythms of body temperature and BAT activity. Thus, Rev-erbalpha acts as a thermogenic focal point required for establishing and maintaining body temperature rhythm in a manner that is adaptable to environmental demands. PMID- 24162842 TI - The role of primary cilia in the development and disease of the retina. AB - The normal development and function of photoreceptors is essential for eye health and visual acuity in vertebrates. Mutations in genes encoding proteins involved in photoreceptor development and function are associated with a suite of inherited retinal dystrophies, often as part of complex multi-organ syndromic conditions. In this review, we focus on the role of the photoreceptor outer segment, a highly modified and specialized primary cilium, in retinal health and disease. We discuss the many defects in the structure and function of the photoreceptor primary cilium that can cause a class of inherited conditions known as ciliopathies, often characterized by retinal dystrophy and degeneration, and highlight the recent insights into disease mechanisms. PMID- 24162846 TI - A directional switch of integrin signalling and a new anti-thrombotic strategy. AB - Integrins have a critical role in thrombosis and haemostasis. Antagonists of the platelet integrin alphaIIbbeta3 are potent anti-thrombotic drugs, but also have the life-threatening adverse effect of causing bleeding. It is therefore desirable to develop new antagonists that do not cause bleeding. Integrins transmit signals bidirectionally. Inside-out signalling activates integrins through a talin-dependent mechanism. Integrin ligation mediates thrombus formation and outside-in signalling, which requires Galpha13 and greatly expands thrombi. Here we show that Galpha13 and talin bind to mutually exclusive but distinct sites within the integrin beta3 cytoplasmic domain in opposing waves. The first talin-binding wave mediates inside-out signalling and also ligand induced integrin activation, but is not required for outside-in signalling. Integrin ligation induces transient talin dissociation and Galpha13 binding to an EXE motif (in which X denotes any residue), which selectively mediates outside-in signalling and platelet spreading. The second talin-binding wave is associated with clot retraction. An EXE-motif-based inhibitor of Galpha13-integrin interaction selectively abolishes outside-in signalling without affecting integrin ligation, and suppresses occlusive arterial thrombosis without affecting bleeding time. Thus, we have discovered a new mechanism for the directional switch of integrin signalling and, on the basis of this mechanism, designed a potent new anti-thrombotic drug that does not cause bleeding. PMID- 24162847 TI - Structural basis for the modular recognition of single-stranded RNA by PPR proteins. AB - Pentatricopeptide repeat (PPR) proteins represent a large family of sequence specific RNA-binding proteins that are involved in multiple aspects of RNA metabolism. PPR proteins, which are found in exceptionally large numbers in the mitochondria and chloroplasts of terrestrial plants, recognize single-stranded RNA (ssRNA) in a modular fashion. The maize chloroplast protein PPR10 binds to two similar RNA sequences from the ATPI-ATPH and PSAJ-RPL33 intergenic regions, referred to as ATPH and PSAJ, respectively. By protecting the target RNA elements from 5' or 3' exonucleases, PPR10 defines the corresponding 5' and 3' messenger RNA termini. Despite rigorous functional characterizations, the structural basis of sequence-specific ssRNA recognition by PPR proteins remains to be elucidated. Here we report the crystal structures of PPR10 in RNA-free and RNA-bound states at resolutions of 2.85 and 2.45 A, respectively. In the absence of RNA binding, the nineteen repeats of PPR10 are assembled into a right-handed superhelical spiral. PPR10 forms an antiparallel, intertwined homodimer and exhibits considerable conformational changes upon binding to its target ssRNA, an 18 nucleotide PSAJ element. Six nucleotides of PSAJ are specifically recognized by six corresponding PPR10 repeats following the predicted code. The molecular basis for the specific and modular recognition of RNA bases A, G and U is revealed. The structural elucidation of RNA recognition by PPR proteins provides an important framework for potential biotechnological applications of PPR proteins in RNA related research areas. PMID- 24162849 TI - Potential for spin-based information processing in a thin-film molecular semiconductor. AB - Organic semiconductors are studied intensively for applications in electronics and optics, and even spin-based information technology, or spintronics. Fundamental quantities in spintronics are the population relaxation time (T1) and the phase memory time (T2): T1 measures the lifetime of a classical bit, in this case embodied by a spin oriented either parallel or antiparallel to an external magnetic field, and T2 measures the corresponding lifetime of a quantum bit, encoded in the phase of the quantum state. Here we establish that these times are surprisingly long for a common, low-cost and chemically modifiable organic semiconductor, the blue pigment copper phthalocyanine, in easily processed thin film form of the type used for device fabrication. At 5 K, a temperature reachable using inexpensive closed-cycle refrigerators, T1 and T2 are respectively 59 ms and 2.6 MUs, and at 80 K, which is just above the boiling point of liquid nitrogen, they are respectively 10 MUs and 1 MUs, demonstrating that the performance of thin-film copper phthalocyanine is superior to that of single-molecule magnets over the same temperature range. T2 is more than two orders of magnitude greater than the duration of the spin manipulation pulses, which suggests that copper phthalocyanine holds promise for quantum information processing, and the long T1 indicates possibilities for medium-term storage of classical bits in all-organic devices on plastic substrates. PMID- 24162848 TI - High-resolution Xist binding maps reveal two-step spreading during X-chromosome inactivation. AB - The Xist long noncoding RNA (lncRNA) is essential for X-chromosome inactivation (XCI), the process by which mammals compensate for unequal numbers of sex chromosomes. During XCI, Xist coats the future inactive X chromosome (Xi) and recruits Polycomb repressive complex 2 (PRC2) to the X-inactivation centre (Xic). How Xist spreads silencing on a 150-megabases scale is unclear. Here we generate high-resolution maps of Xist binding on the X chromosome across a developmental time course using CHART-seq. In female cells undergoing XCI de novo, Xist follows a two-step mechanism, initially targeting gene-rich islands before spreading to intervening gene-poor domains. Xist is depleted from genes that escape XCI but may concentrate near escapee boundaries. Xist binding is linearly proportional to PRC2 density and H3 lysine 27 trimethylation (H3K27me3), indicating co-migration of Xist and PRC2. Interestingly, when Xist is acutely stripped off from the Xi in post-XCI cells, Xist recovers quickly within both gene-rich and gene-poor domains on a timescale of hours instead of days, indicating a previously primed Xi chromatin state. We conclude that Xist spreading takes distinct stage-specific forms. During initial establishment, Xist follows a two-step mechanism, but during maintenance, Xist spreads rapidly to both gene-rich and gene-poor regions. PMID- 24162850 TI - Dendritic spikes enhance stimulus selectivity in cortical neurons in vivo. AB - Neuronal dendrites are electrically excitable: they can generate regenerative events such as dendritic spikes in response to sufficiently strong synaptic input. Although such events have been observed in many neuronal types, it is not well understood how active dendrites contribute to the tuning of neuronal output in vivo. Here we show that dendritic spikes increase the selectivity of neuronal responses to the orientation of a visual stimulus (orientation tuning). We performed direct patch-clamp recordings from the dendrites of pyramidal neurons in the primary visual cortex of lightly anaesthetized and awake mice, during sensory processing. Visual stimulation triggered regenerative local dendritic spikes that were distinct from back-propagating action potentials. These events were orientation tuned and were suppressed by either hyperpolarization of membrane potential or intracellular blockade of NMDA (N-methyl-d-aspartate) receptors. Both of these manipulations also decreased the selectivity of subthreshold orientation tuning measured at the soma, thus linking dendritic regenerative events to somatic orientation tuning. Together, our results suggest that dendritic spikes that are triggered by visual input contribute to a fundamental cortical computation: enhancing orientation selectivity in the visual cortex. Thus, dendritic excitability is an essential component of behaviourally relevant computations in neurons. PMID- 24162851 TI - Flavin-mediated dual oxidation controls an enzymatic Favorskii-type rearrangement. AB - Flavoproteins catalyse a diversity of fundamental redox reactions and are one of the most studied enzyme families. As monooxygenases, they are universally thought to control oxygenation by means of a peroxyflavin species that transfers a single atom of molecular oxygen to an organic substrate. Here we report that the bacterial flavoenzyme EncM catalyses the peroxyflavin-independent oxygenation dehydrogenation dual oxidation of a highly reactive poly(beta-carbonyl). The crystal structure of EncM with bound substrate mimics and isotope labelling studies reveal previously unknown flavin redox biochemistry. We show that EncM maintains an unexpected stable flavin-oxygenating species, proposed to be a flavin-N5-oxide, to promote substrate oxidation and trigger a rare Favorskii-type rearrangement that is central to the biosynthesis of the antibiotic enterocin. This work provides new insight into the fine-tuning of the flavin cofactor in offsetting the innate reactivity of a polyketide substrate to direct its efficient electrocyclization. PMID- 24162853 TI - A novel 5-bp deletion mutation in AAGAB gene in a Chinese family with punctate palmoplantar keratoderma. PMID- 24162852 TI - Structure of LIMP-2 provides functional insights with implications for SR-BI and CD36. AB - Members of the CD36 superfamily of scavenger receptor proteins are important regulators of lipid metabolism and innate immunity. They recognize normal and modified lipoproteins, as well as pathogen-associated molecular patterns. The family consists of three members: SR-BI (which delivers cholesterol to the liver and steroidogenic organs and is a co-receptor for hepatitis C virus), LIMP 2/LGP85 (which mediates lysosomal delivery of beta-glucocerebrosidase and serves as a receptor for enterovirus 71 and coxsackieviruses) and CD36 (a fatty-acid transporter and receptor for phagocytosis of effete cells and Plasmodium-infected erythrocytes). Notably, CD36 is also a receptor for modified lipoproteins and beta-amyloid, and has been implicated in the pathogenesis of atherosclerosis and of Alzheimer's disease. Despite their prominent roles in health and disease, understanding the function and abnormalities of the CD36 family members has been hampered by the paucity of information about their structure. Here we determine the crystal structure of LIMP-2 and infer, by homology modelling, the structure of SR-BI and CD36. LIMP-2 shows a helical bundle where beta-glucocerebrosidase binds, and where ligands are most likely to bind to SR-BI and CD36. Remarkably, the crystal structure also shows the existence of a large cavity that traverses the entire length of the molecule. Mutagenesis of SR-BI indicates that the cavity serves as a tunnel through which cholesterol(esters) are delivered from the bound lipoprotein to the outer leaflet of the plasma membrane. We provide evidence supporting a model whereby lipidic constituents of the ligands attached to the receptor surface are handed off to the membrane through the tunnel, accounting for the selective lipid transfer characteristic of SR-BI and CD36. PMID- 24162854 TI - Does CMV infection impact the virulence of Enterococcus faecalis? PMID- 24162855 TI - Wnt and planar cell polarity signaling in cystic renal disease. AB - Cystic kidney diseases can cause end stage renal disease, affecting millions of individuals worldwide. They may arise early or later in life, are characterized by a spectrum of symptoms and can be caused by diverse genetic defects. The primary cilium, a microtubule-based organelle that can serve as a signaling antenna, has been demonstrated to have a significant role in ensuring correct kidney development and function. In the kidney, one of the signaling pathways that requires the cilium for normal development is Wnt signaling. In this review, the roles of primary cilia in relation to canonical and non-canonical Wnt/PCP signaling in cystic renal disease are described. The evidence of the associations between cilia, Wnt signaling and cystic renal disease is discussed and the significance of planar cell polarity-related mechanisms in cystic kidney disease is presented. Although defective Wnt signaling is not the only cause of renal disease, research is increasingly highlighting its importance, encouraging the development of Wnt-associated diagnostic and prognostic tools for cystic renal disease. PMID- 24162856 TI - Pre-test data and lessons learned from a group research project examining changes in physical activity behavior following construction of a rails-to-trails facility. AB - Built environments in rural settings may provide greater challenges than those in urban settings due to physical characteristics inherent to low-density population areas. Multiuse recreational trails, such as those that repurpose abandoned railroad lines, may provide a physical activity resource that is well suited to rural areas. However, the direct impact of trail availability on physical activity behavior is not generally known because it is unclear whether activity reported in most trail research represents increases in physical activity or displacement of activity in individuals who previously exercised in other locations. This research, initiated by a group of students in a graduate seminar, represents to our knowledge, the first instance in which PA was assessed prior to the availability of an entirely new rails-to-trails facility. The research was implemented using a nonequivalent dependent variable design to counter the lack of a control group; the nonequivalent dependent variable chosen was weekly servings of fruit and vegetables. Participants responding to intercept interviews classified days of activity during the prior week as mild, moderate or vigorous. Baseline results for 244 participants suggested generally low levels of activity prior to trail availability; number of reported days of activity decreased with described intensity. We also discuss several issues encountered in planning and implementing this group project including those related to data collection, variable levels of commitment among student members, and inconsistent project management, and offer potential solutions to these concerns. PMID- 24162857 TI - Predictors of never being screened for cervical cancer by metropolitan area. AB - Previous studies have shown an association between cervical cancer screening and racial/ethnic minority status, no usual source of care, and lower socioeconomic status. This study describes the demographics and health beliefs of women who report never being screened for cervical cancer by area of residence. Data from the 2010 Behavioral Risk Factor Surveillance System were used to study women aged 21-65 years who reported never being screened for cervical cancer. Multivariate logistic regression modeling was used to calculate predicted marginals to examine associations between never being screened and demographic characteristics and health belief model (HBM) constructs by metropolitan statistical area (MSA). After adjusting for all demographics and HBM constructs, prevalence of never being screened was higher for the following women: non-Hispanic Asians/Native Hawaiians/Pacific Islanders (16.5 %, 95 % CI = 13.7 %, 19.8 %) who live in MSAs; those with only a high school diploma who live in MSAs (5.5 %, 95 % CI = 4.7 %, 6.5 %); those living in non-MSAs who reported "fair or poor" general health (4.1 %, 95 % CI = 3.1 %, 5.4 %); and those living in either MSAs and non-MSAs unable to see a doctor within the past 12 months because of cost (MSA: 4.4 %, 95 % CI = 4.0 %, 4.8 %; non-MSA: 3.4 %, 95 % CI = 2.9 %, 3.9 %). The Affordable Care Act will expand access to insurance coverage for cervical cancer screening, without cost sharing for millions of women, essentially eliminating insurance costs as a barrier. Future interventions for women who have never been screened should focus on promoting the importance of screening and reaching non-Hispanic Asians/Native Hawaiians/Pacific Islanders who live in MSAs. PMID- 24162858 TI - Self-doped polypyrrole with ionizable sodium sulfonate as a renewable cathode material for sodium ion batteries. AB - A Na-host cathode is developed by grafting the polypyrrole chains with ionizable sodium sulfonate. Due to the immobile p-doping of organic anions, the self-doped polymer can act as a Na-host for reversible Na insertion-extraction reaction, thus offering a low cost and renewable organic cathode for Na ion battery applications. PMID- 24162859 TI - Accuracy of computational cerebral aneurysm hemodynamics using patient-specific endovascular measurements. AB - Computational hemodynamic simulations of cerebral aneurysms have traditionally relied on stereotypical boundary conditions (such as blood flow velocity and blood pressure) derived from published values as patient-specific measurements are unavailable or difficult to collect. However, controversy persists over the necessity of incorporating such patient-specific conditions into computational analyses. We perform simulations using both endovascularly-derived patient specific and typical literature-derived inflow and outflow boundary conditions. Detailed three-dimensional anatomical models of the cerebral vasculature are developed from rotational angiography data, and blood flow velocity and pressure are measured in situ by a dual-sensor pressure and velocity endovascular guidewire at multiple peri-aneurysmal locations in 10 unruptured cerebral aneurysms. These measurements are used to define inflow and outflow boundary conditions for computational hemodynamic models of the aneurysms. The additional in situ measurements which are not prescribed in the simulation are then used to assess the accuracy of the simulated flow velocity and pressure drop. Simulated velocities using patient-specific boundary conditions show good agreement with the guidewire measurements at measurement locations inside the domain, with no bias in the agreement and a random scatter of ~25%. Simulated velocities using the simplified, literature-derived values show a systematic bias and over predicted velocity by ~30% with a random scatter of ~40%. Computational hemodynamics using endovascularly measured patient-specific boundary conditions have the potential to improve treatment predictions as they provide more accurate and precise results of the aneurysmal hemodynamics than those based on commonly accepted reference values for boundary conditions. PMID- 24162860 TI - Laterality of quiet standing in old and young. AB - "Quiet standing" is standing without intended movement. To the naked eye, a person "quiet standing" on a rigid surface of support is stationary. In the laboratory quiet standing is indexed by behavior (at the millimeter scale) of the center of pressure (COP), the point location of the vertical ground reaction force vector (GRF). We asked whether quiet standing is lateralized and whether the COP dynamics of the right and left legs differ. In answer, we reexamined a previous quiet standing experiment (Kinsella-Shaw et al. in J Mot Behav 38:251 264, 2006) that used dual, side-by-side, force plates to investigate effects of age and embedding environment. All participants, old (M age = 72.2 +/- 4.90 years) and young (M age = 22.8 +/- 0.83 years), were right handed and right footed. Cross-recurrence quantification of the anterior-posterior and mediolateral coordinates of each COP revealed that, independent of age, and with no right GRF bias, right-leg coordination was (1) more dynamically stable and less noisy than left-leg coordination and (2) more responsive to changes in degree of visible structure. The results are considered in the context of theories of laterality inclusive of lateralized differences in postural dynamics. PMID- 24162861 TI - The ability of people with Parkinson's disease to modify dual-task performance in response to instructions during simple and complex walking tasks. AB - Gait impairments are a common and consequential motor symptom in Parkinson's disease (PD). A cognitive strategy that incorporates instructions to concentrate on specific parameters of walking is an effective approach to gait rehabilitation for persons with PD during single-task and simple dual-task walking conditions. This study examined the ability to modify dual-task walking in response to instructions during a complex walking task in people with PD compared to healthy older adults (HOA). Eleven people with PD and twelve HOA performed a cognitive task while walking with either a usual base or a narrow base of support. Dual task walking and cognitive task performance were characterized under two conditions-when participants were instructed focus on walking and when they were instructed to focus on the cognitive task. During both usual base and narrow base walking, instructions affected cognitive task response latency, with slower performance when instructed to focus on walking compared to the cognitive task. Regardless of task or instructions, cognitive task performance was slower in participants with PD compared to HOA. During usual base walking, instructions influenced gait speed for both people with PD and HOA, with faster gait speed when instructed to focus on walking compared to the cognitive task. In contrast, during the narrow base walking, instructions affected gait speed only for HOA, but not for people with PD. This suggests that among people with PD the ability to modify walking in response to instructions depends on the complexity of the walking task. PMID- 24162862 TI - Influence of removal of invisible fixation on the saccadic and manual gap effect. AB - Saccadic and manual reactions to a peripherally presented target are facilitated by removing a central fixation stimulus shortly before a target onset (the gap effect). The present study examined the effects of removal of a visible and invisible fixation point on the saccadic gap effect and the manual gap effect. Participants were required to fixate a central fixation point and respond to a peripherally presented target as quickly and accurately as possible by making a saccade (Experiment 1) or pressing a corresponding key (Experiment 2). The fixation point was dichoptically presented, and visibility was manipulated by using binocular rivalry and continuous flash suppression technique. In both saccade and key-press tasks, removing the visible fixation strongly quickened the responses. Furthermore, the invisible fixation, which remained on the display but suppressed, significantly delayed the saccadic response. Contrarily, the invisible fixation had no effect on the manual task. These results indicate that partially different processes mediate the saccadic gap effect and the manual gap effect. In particular, unconscious processes might modulate an oculomotor specific component of the saccadic gap effect, presumably via subcortical mechanisms. PMID- 24162863 TI - Eyes wide open: enhanced pupil dilation when selectively studying important information. AB - Remembering important information is imperative for efficient memory performance, but it is unclear how we encode important information. The current experiment evaluated two non-exclusive hypotheses for how learners selectively encode important information at the expense of less important information (differential resource allocation and information reduction). To evaluate these hypotheses, we measured changes in learners' pupil diameter and fixation durations while participants performed a selectivity task that involved studying lists consisting of words associated with different point values. Participants were instructed to maximize their score on a free recall task that they completed after studying each list. Participants' pupils dilated more when studying high-valued than low valued words, and these changes were associated with better memory for high valued words. However, participants fixated equally on words regardless of their value, which is inconsistent with the information reduction hypothesis. Participants also increased their memory selectivity across lists, but changes in pupil diameter and differences in fixations could not account for this increased selectivity. The results suggest that learners allocate attention differently to items as a function of their value, and that multiple processes and operations contribute to value-directed remembering. PMID- 24162864 TI - Grasping with the eyes of your hands: hapsis and vision modulate hand preference. AB - Right-hand preference has been demonstrated for visually guided reaching and grasping. Grasping, however, requires the integration of both visual and haptic cues. To what extent does vision influence hand preference for grasping? Is there a hand preference for haptically guided grasping? Two experiments were designed to address these questions. In Experiment 1, individuals were tested in a reaching-to-grasp task with vision (sighted condition) and with hapsis (blindfolded condition). Participants were asked to put together 3D models using building blocks scattered on a tabletop. The models were simple, composed of ten blocks of three different shapes. Starting condition (Vision-First or Hapsis First) was counterbalanced among participants. Right-hand preference was greater in visually guided grasping but only in the Vision-First group. Participants who initially built the models while blindfolded (Hapsis-First group) used their right hand significantly less for the visually guided portion of the task. To investigate whether grasping using hapsis modifies subsequent hand preference, participants received an additional haptic experience in a follow-up experiment. While blindfolded, participants manipulated the blocks in a container for 5 min prior to the task. This additional experience did not affect right-hand use on visually guided grasping but had a robust effect on haptically guided grasping. Together, the results demonstrate first that hand preference for grasping is influenced by both vision and hapsis, and second, they highlight how flexible this preference could be when modulated by hapsis. PMID- 24162865 TI - Perception of relative throw-ability. AB - Bingham et al. (J Exp Psychol Hum Percept Perform 15(3):507-528, 1989) showed that skilled throwers can perceive optimal objects for throwing to a maximum distance. Zhu and Bingham (J Exp Psychol Hum Percept Perform 34(4):929, 2008, 36(4):862-875, 2010) replicated this finding and then showed that felt heaviness is used to perceive this affordance (see also Zhu and Bingham in Evol Hum Behav 32(4):288-293, 2011; Zhu et al. in Exp Brain Res 224(2):221-231, 2013). Throwers pick the best weight for spherical projectiles in each graspable size. Bingham et al. (J Exp Psychol Hum Percept Perform 15(3):507-528, 1989) speculated that relative throw-ability might be perceptible. This would mean that the ordering of distances achieved by maximum effort throws of different objects could be judged. This affordance property is not the same as optimal throw-ability, because it requires all projectiles to be evaluated relative to one another with respect to ordinally scaled distances, not just a discrete optimum. We now used a magnitude estimation task to test this hypothesis, comparing the resultant ordering with that exhibited by distances of throws in previous studies. The findings show that participants were able to perform the perceptual task. However, discrimination among objects of different weight within a size was better than between sizes. The implications of these results for understanding of the information used to perform this task are discussed. PMID- 24162866 TI - An apparent contradiction: increasing variability to achieve greater precision? AB - To understand the relationship between variability of foot placement in the frontal plane and stability of gait patterns, we explored how constraining mediolateral foot placement during walking affects the structure of kinematic variance in the lower-limb configuration space during the swing phase of gait. Ten young subjects walked under three conditions: (1) unconstrained (normal walking), (2) constrained (walking overground with visual guides for foot placement to achieve the measured unconstrained step width) and, (3) beam (walking on elevated beams spaced to achieve the measured unconstrained step width). The uncontrolled manifold analysis of the joint configuration variance was used to quantify two variance components, one that did not affect the mediolateral trajectory of the foot in the frontal plane ("good variance") and one that affected this trajectory ("bad variance"). Based on recent studies, we hypothesized that across conditions (1) the index of the synergy stabilizing the mediolateral trajectory of the foot (the normalized difference between the "good variance" and "bad variance") would systematically increase and (2) the changes in the synergy index would be associated with a disproportionate increase in the "good variance." Both hypotheses were confirmed. We conclude that an increase in the "good variance" component of the joint configuration variance may be an effective method of ensuring high stability of gait patterns during conditions requiring increased control of foot placement, particularly if a postural threat is present. Ultimately, designing interventions that encourage a larger amount of "good variance" may be a promising method of improving stability of gait patterns in populations such as older adults and neurological patients. PMID- 24162867 TI - Resilience. PMID- 24162868 TI - Flow-focusing regimes for accelerated production of monodisperse drug-loadable microbubbles toward clinical-scale applications. AB - Ultrasound imaging often calls for the injection of contrast agents, micron-sized bubbles which echo strongly in blood and help distinguish vascularized tissue. Such microbubbles are also being augmented for targeted drug delivery and gene therapy, by the addition of surface receptors and therapeutic payloads. Unfortunately, conventional production methods yield a polydisperse population, whose nonuniform resonance and drug-loading are less than ideal. An alternative technique, microfluidic flow-focusing, is able to produce highly monodisperse microbubbles with stabilizing lipid membranes and drug-carrying oil layers. However, the published 1 kHz production rate for these uniform drug bubbles is very low compared to conventional methods, and must be improved before clinical use can be practical. In this study, flow-focusing production of oil-layered lipid microbubbles was tested up to 300 kHz, with coalescence suppressed by high lipid concentrations or inclusion of Pluronic F68 surfactant in the lipid solution. The transition between geometry-controlled and dripping production regimes was analysed, and production scaling was found to be continuous, with a power trend of exponent ~5/12 similar to literature. Unlike prior studies with this trend, however, scaling curves here were found to be pressure-dependent, particularly at lower pressure-flow equilibria (e.g. <15 psi). Adjustments in oil flow rate were observed to have a similar effect, akin to a pressure change of 1 3 psi. This analysis and characterization of high-speed dual-layer bubble generation will enable more-predictive production control, at rates practical for in vivo or clinical use. PMID- 24162870 TI - Comparison of once and twice daily radiotherapy for limited stage small-cell lung cancer. AB - PURPOSE: This study was designed to review outcomes of once- (QD) versus twice daily (BID) radiotherapy (RT) for limited stage small-cell lung cancer (L-SCLC) treated at Dana-Farber Cancer Institute/Brigham and Women's Hospital. METHODS: We reviewed records for all patients with L-SCLC treated with radical chemoradiotherapy at our institution between January 2005 and December 2010. Differences in patient, tumor, and treatment characteristics were assessed by Student's t test and Fisher exact test. Outcomes were compared using Kaplan-Meier estimates and Cox proportional hazards regression. RESULTS: Twenty patients received QD RT to a median dose of 61.2 Gy, and 26 patients received BID RT to a dose of 45 Gy. Median follow-up was 2.8 years. Overall survival (OS) was similar in both groups. 5-year locoregional control (LC) for all patients was 67 %: 80 % for the QD group and 57 % for the BID group (log-rank, P = 0.16). Grade 2 or higher dermatitis and pneumonitis were significantly higher in the QD group (15 vs. 0 %, P = 0.0014 and 13 vs. 4 %, P = 0.048, respectively), whereas Grade 2 or higher esophagitis trended higher in the BID group (44 vs. 24 %, P = 0.076). CONCLUSIONS: Although there were no differences in OS with QD versus BID RT, there was a trend toward increased LC in the QD group. Dermatitis and pneumonitis were more common for QD RT, and esophagitis was somewhat more common for BID RT. Possible differences in toxicities depending on RT regimen may be worth further investigation, until results from CALGB 30610 become available. PMID- 24162869 TI - Super-resolution localization microscopy with photoactivatable fluorescent marker proteins. AB - Fluorescent proteins (FPs) have become popular imaging tools because of their high specificity, minimal invasive labeling and allowing visualization of proteins and structures inside living organisms. FPs are genetically encoded and expressed in living cells, therefore, labeling involves minimal effort in comparison to approaches involving synthetic dyes. Photoactivatable FPs (paFPs) comprise a subclass of FPs that can change their absorption/emission properties such as brightness and color upon irradiation. This methodology has found a broad range of applications in the life sciences, especially in localization-based super-resolution microscopy of cells, tissues and even entire organisms. In this review, we discuss recent developments and applications of paFPs in super resolution localization imaging. PMID- 24162872 TI - Project DyAdd: implicit learning in adult dyslexia and ADHD. AB - In this study of the project DyAdd, implicit learning was investigated through two paradigms in adults (18-55 years) with dyslexia (n = 36) or with attention deficit/hyperactivity disorder (ADHD, n = 22) and in controls (n = 35). In the serial reaction time (SRT) task, there were no group differences in learning. However, those with ADHD exhibited faster RTs compared to other groups. In the artificial grammar learning (AGL) task, the groups did not differ from each other in their learning (i.e., grammaticality accuracy or similarity choices). Further, all three groups were sensitive to fragment overlap between learning and test phase items (i.e., similarity choices were above chance). Grammaticality performance of control participants was above chance, but that of participants with dyslexia and participants with ADHD failed to differ from chance, indicating impaired grammaticality learning in these groups. While the main indices of AGL performance, grammaticality accuracy and similarity choices did not correlate with the neuropsychological variables that reflected dyslexia-related (phonological processing, reading, spelling, arithmetic) or ADHD-related characteristics (executive functions, attention), or intelligence, the explicit knowledge for the AGL grammar (i.e., ability to freely generate grammatical strings) correlated positively with the variables of phonological processing and reading. Further, SRT reaction times correlated positively with full scale intelligence quotient (FIQ). We conclude that, in AGL, learning difficulties of the underlying rule structure (as measured by grammaticality) are associated with dyslexia and ADHD. However, learning in AGL is not related to the defining neuropsychological features of dyslexia or ADHD. Instead, the resulting explicit knowledge relates to characteristics of dyslexia. PMID- 24162871 TI - Interleukin-10 promoter 1082/-819/-592 polymorphisms are associated with asthma susceptibility in Asians and atopic asthma: a meta-analysis. AB - BACKGROUND: Although interleukin-10 (IL-10) is a potent inhibitor of allergic diseases, the association between promoter -1082/-819/-592 polymorphisms and asthma susceptibility remains inconclusive. We sought to determine if IL-10 promoter -1082/-819/-592 polymorphisms contribute to asthma susceptibility and are associated with phenotypes of atopic asthma. METHODS: Systematic computerized searches were performed. Pooled odds ratios (ORs) and 95 % confidence intervals (CIs) were estimated by using random-effect and fixed-effect models, based on between-study heterogeneity. Subgroup analyses were performed according to age, ethnicity, and atopy. Publication bias was detected by funnel plot using Egger's test. RESULTS: A total of 4,716 asthmatic patients and 5,093 controls were included. The asthma susceptibility correlated significantly with IL-10 promoter gene -1082 polymorphism [OR (95 % CI) 1.26 (1.02, 1.55) for AA vs. AG + GG] and 592 polymorphism [OR (95 % CI) 1.12 (1.07, 1.34) for AC + AA vs. CC] (both P < 0.05), but not with -819 polymorphism (P > 0.05). Subgroup analyzes suggested that the AA versus AG + GG genotype of -1082A/G polymorphism and AC + AA versus CC genotype of -592A/C polymorphism contributed significantly to increased asthma susceptibility in adults [OR (95 % CI) 1.39 (1.03, 1.87) for -1082A/G and 1.53 (1.25, 1.87) for -592A/C polymorphism]. The Asian population [OR (95 % CI) 1.35 (1.1, 1.7) for -1082A/G and 1.4 (1.12, 1.64) for -592A/C polymorphism] and subjects with atopic asthma [OR (95 % CI) 1.49 (1.18, 1.88) for -1082A/G and 1.23 (1.01, 1.48) for -592A/C polymorphism] also had an increased susceptibility of asthma. No publication bias was detected. CONCLUSIONS: IL-10 promoter -1028A/G, 592A/C polymorphisms and their haplotypes, but not -819T/C polymorphism, correlate with asthma susceptibility. PMID- 24162873 TI - Genetic analyses of early-expressed reproduction traits of Boran and their crosses with Holstein Friesian and Jersey in Central Highlands of Ethiopia. AB - The study was conducted to assess early-expressed reproductive traits of Boran cattle and their crosses with Jersey and Holstein Friesian (HF). The traits studied were age at first services (AFS), number of services for first conception, age at first calving (AFC), first dry period (FDP), first calving interval (FCI), and first service period (FSP). Genetic group and period of birth/calving had a significant (p < 0.05) effect on reproductive traits. The Boran cattle were inferior to HF or Jersey crosses. First crosses (F 1) for Jersey and Boran (50 % Jersey: 50 % Boran) showed a significantly (p < 0.05) younger AFS (by 7.25 months) and AFC (by 10.75 months), had shorter FCI (by 63.27 days), FDP (by 61.13 days), and FSP (by 60.3 days), and needed less (by 0.35) numbers of services per first conception as compared to the Boran cattle. The F 1 for Jersey and Boran (50 % Jersey: 50 % Boran) crosses showed better performance than the F 1 for HF and Boran (50 % HF: 50 % Boran). Heritability values for AFS and AFC were the highest and were estimated at 0.51 +/- 0.10 and 0.49 +/- 0.13, respectively, and lowest heritability was recorded for FDP (0.02 +/- 020) and FSP (0.10 +/- 0.29). The genetic correlation was highest (0.10 +/- 0.20) between AFS and AFC and was lowest (-0.01 +/- 0.66) between FCI and FSP. The breed additive for Jersey was only significant (p < 0.01) for AFS and AFC. The crossing of HF with Boran cattle has desirably reduced 9.16 +/- 2.88 months in AFS; the corresponding reduction in AFS was 3.49 +/- 3.59 months by crossing with Jersey. The performance comparisons and genetic and crossbreeding parameters indicated that crossbreeding of Boran with HF or Jersey can improve reproductive performance. PMID- 24162874 TI - The influence of fluorine in asymmetric catalysis. AB - All domains of chemistry are increasingly impacted by organofluorine molecules, often favorably. In asymmetric synthesis of fluorinated compounds, significant achievements are the result of extensive research efforts toward appropriate experimental conditions rather than of the rationalization of fluorine effects. Most of the time, the influence of fluorine is inspected retrospectively. When elaborating a synthetic plan, the question should not be only when and how to introduce fluorine but also how to use the effects of fluorine for a desirable result. The subtle effects of fluorine atom(s) on the course of asymmetric reactions are outlined in this tutorial review. We present some selected examples of asymmetric reactions that involve fluorinated components either as reactants, catalysts, solvents or additives, and a comparative study of the stereochemical outcomes with reactions carried out in the presence of non-fluorinated analogues. PMID- 24162880 TI - A typical case of paraneoplastic pemphigus without detection of malignancy: effectiveness of plasma exchange. PMID- 24162875 TI - Measuring health-related quality of life in high-grade glioma patients at the end of life using a proxy-reported retrospective questionnaire. AB - To develop, validate, and report on the use of a retrospective proxy-reported questionnaire measuring health-related quality of life (HRQoL) in the end-of-life (EOL) phase of high-grade glioma (HGG) patients. Items relevant for the defined construct were selected using existing questionnaires, topics identified as important in literature, and expert opinion (experienced neuro-oncologists and EOL experts). Psychometric properties, content validity and internal consistency, were determined and the questionnaire was subsequently adapted. Proxy-reported HRQoL data of HGG patients in the EOL, including changes over time, were analyzed. Twenty-nine items were selected covering seven domains; physical comfort, physical and cognitive functioning, psychological, social and spiritual well-being, and overall quality of life. Relatives of 83 deceased HGG patients completed the questionnaire. Content validity was assessed to be adequate. Internal consistency in the domains varied from reasonable to good. Two items were excluded due to poor psychometric properties. Symptom burden increased (p < 0.01), except for nausea (p = 0.058), as death approached. Cognitive, physical and psychological functioning deteriorated over time (all p < 0.01). Acceptance of disease seemed to increase slightly towards death, but this was not significant (p = 0.058). Participating in social activities and family life was rated as poor (<= 50), whereas received support from their social environment and dying with dignity were rated as good (>50). Overall quality of life was rated as poor, mean (SD) of 29 (26). Measuring HRQoL at the EOL of HGG patients with a retrospective, proxy-reported questionnaire was feasible, yielding a validated instrument. HRQoL was reported as poor and deteriorated as death approached. PMID- 24162881 TI - Organic semiconductors: Healing contact. PMID- 24162882 TI - Trap healing and ultralow-noise Hall effect at the surface of organic semiconductors. AB - Fundamental studies of intrinsic charge transport properties of organic semiconductors are often hindered by charge traps associated with static disorder present even in optimized single-crystal devices. Here, we report a method of surface functionalization using an inert non-conjugated polymer, perfluoropolyether (PFPE), deposited at the surface of organic molecular crystals, which results in accumulation of mobile holes and a 'trap healing' effect at the crystal/PFPE interface. As a consequence, a remarkable ultralow noise, trp-free conduction regime characterized by intrinsic mobility and transport anisotropy emerges in organic single crystals, and Hall effect measurements with an unprecedented signal-to-noise ratio are demonstrated. This general method to convert trap-dominated organic semiconductors to intrinsic systems may enable the determination of intrinsic transport parameters with high accuracy and make Hall effect measurements in molecular crystals ubiquitous. PMID- 24162883 TI - Landau theory of topological defects in multiferroic hexagonal manganites. AB - Topological defects in ordered states with spontaneously broken symmetry often have unusual physical properties, such as fractional electric charge or a quantized magnetic field flux, originating from their non-trivial topology. Coupled topological defects in systems with several coexisting orders give rise to unconventional functionalities, such as the electric-field control of magnetization in multiferroics resulting from the coupling between the ferroelectric and ferromagnetic domain walls. Hexagonal manganites provide an extra degree of freedom: in these materials, both ferroelectricity and magnetism are coupled to an additional, non-ferroelectric structural order parameter. Here we present a theoretical study of topological defects in hexagonal manganites based on Landau theory with parameters determined from first-principles calculations. We explain the observed flip of electric polarization at the boundaries of structural domains, the origin of the observed discrete vortices, and the clamping between ferroelectric and antiferromagnetic domain walls. We show that structural vortices induce magnetic ones and that, consistent with a recent experimental report, ferroelectric domain walls can carry a magnetic moment. PMID- 24162885 TI - The role of US in the evaluation of clinically suspected ulnar collateral ligament injuries of the thumb: spectrum of findings and differential diagnosis. AB - Injury to the ulnar collateral ligament (UCL) complex of the thumb is a common traumatic lesion that requires prompt imaging evaluation for adequate treatment. In this article, we review the role of ultrasound in diagnosis and illustrate the spectrum of both static and dynamic findings related to the UCL injuries. We also describe a number of alternative diagnoses in the vicinity of the first metacarpophalangeal joint that may present clinically as pseudoligamentous lesions in a trauma setting. PMID- 24162884 TI - The influence of parental nativity, neighborhood disadvantage and the built environment on physical activity behaviors in Latino youth. AB - Little evidence exists examining if parental nativity, neighborhood disadvantage and built environment features are associated with physical activity behaviors in Latino youth. We used a representative sample of Latino youth (n = 616) living in New Jersey to examine parental nativity associations with active transport to school, active use of sidewalks, use of local neighborhood parks, and use of neighborhood physical activity facilities. We estimated prevalence ratios (PR) that accounted for the complex survey design. Latino youth with foreign-born parents were generally more active than their US-born peers, and those with parents in the US 10 years or less were more likely to engage in active transport to school (PR = 1.51, 95% CI 1.04-2.21), after adjusting for census-based neighborhood disadvantage, self-reported neighborhood measures, and geocoded distance to school. Parental nativity status should be considered in policies or interventions designed to increase physical activity among Latino youth. PMID- 24162888 TI - PET-dependent fluorescence sensing of enzyme reactions using the large and tunable pKa shift of aliphatic amines. AB - A fluorescence sensing system exploiting the large and finely tunable pKa shift of aliphatic amines was developed. The amine-containing fluorescent probes with distinct pKa values in a wide pH range were successfully applied to detect a variety of enzyme reactions with a large and real-time fluorescence enhancement. PMID- 24162889 TI - Outcomes of dialytic modalities in a large incident registry cohort from Eastern Europe: the Romanian Renal Registry. AB - BACKGROUND: Studies comparing survival in hemodialysis (HD) or peritoneal dialysis (PD) patients reported controversial results, mainly during the first 2 years of treatment. Moreover, there is a significant geographic variation in the use of these modalities. We aimed to compare the survival of HD and PD patients using data from the Romanian Renal Registry. METHODS: In an intention-to-treat analysis using Kaplan-Meier and Cox proportional hazard (CPH) models, survival was compared between 8,252 incident HD patients and 1,000 incident PD patients treated between 2008 and 2011. The patients were followed from the dialysis initiation and stratified by modality on day 90. The time on dialysis was separated into four periods (3-12, 12-24, 24-36 and >36 months), and outcome comparisons were made. RESULTS: Mean survival time was 46.3 (44.9-47.6) months in PD group and 45.8 (45.3-46.3) months in HD group (p = 0.9, log-rank test). In the multivariate CPH models, age, diabetes-associated kidney disease (DM), primary renal disease and center size significantly influenced survival. In the first year of therapy, the mortality was higher in HD than in PD patients (HR = 1.34 (1.12-1.60), p = 0.001), while in the second and third year, HD patients survived better (HR = 0.69 (0.53-0.89), p = 0.005); HR = 0.56 (0.41-0.78), p = 0.001) and after 36 months, the survival difference was not statistically significant (HR = 0.63 (0.34-1.13), p = 0.1), respectively. CONCLUSIONS: Despite the survival advantage for PD patients during the first year and that of HD in the next 2 years of dialysis, the overall survival in HD and PD patients was similar and was influenced by age, DM and center size. PMID- 24162886 TI - Nuclear imaging modalities for cardiac amyloidosis. AB - Amyloidosis is a heterogeneous group of diseases characterized by localized or systemic deposition of insoluble extracellular fibrillary proteins in organs and tissues. Several types of amyloid can infiltrate the heart resulting in a restrictive cardiomyopathy, heart failure, and atrial and ventricular arrhythmias. Scintigraphy is a noninvasive method that may facilitate early diagnosis, distinguish various forms of cardiac amyloid, and may be useful in following disease burden. The amyloid-specific tracers presented in this article have been used with planar imaging and/or single-photon emission computed tomography. To date, there are no approved cardiac amyloid tracers although investigational tracers are currently under examination. This article serves to review the current nuclear imaging modalities available in the detection of cardiac amyloid. PMID- 24162891 TI - Size of quorum sensing communities. AB - Ensembles of bacteria are able to coordinate their phenotypic behavior in accordance with the size, density, and growth state of the ensemble. This is achieved through production and exchange of diffusible signal molecules in a cell cell regulatory system termed quorum sensing. In the generic quorum sensor a positive feedback in the production of signal molecules defines the conditions at which the collective behavior switches on. In spite of its conceptual simplicity, a proper measure of biofilm colony "size" appears to be lacking. We establish that the cell density multiplied by a geometric factor which incorporates the boundary conditions constitutes an appropriate size measure. The geometric factor is the square of the radius for a spherical colony or a hemisphere attached to a reflecting surface. If surrounded by a rapidly exchanged medium, the geometric factor is divided by three. For a disk-shaped biofilm the geometric factor is the horizontal dimension multiplied by the height, and the square of the height of the biofilm if there is significant flow above the biofilm. A remarkably simple factorized expression for the size is obtained, which separates the all-or-none ignition caused by the positive feedback from the smoother activation outside the switching region. PMID- 24162890 TI - A systematic review and meta-analysis of new onset hypertension after extracorporeal shock wave lithotripsy. AB - OBJECTIVE: Previous studies on the association between extracorporeal shock wave lithotripsy (SWL) and new onset hypertension have only illustrated contradictory results. In order to illustrate the association between SWL and new onset hypertension, a meta-analysis of case-control and cohort studies was conducted. METHODS: Relevant literature was searched using PubMed, EMBASE, and the Cochrane Central Search Library. A meta-analysis of the association between SWL and new onset hypertension was performed. Studies were pooled, and summary relative risk was calculated. Subgroup analyses were also conducted. RESULTS: Eleven studies were eligible for our analysis. No statistical significance was detected between SWL and new onset hypertension (RR = 1.06, 95 % CI 0.83-1.35). No association was observed when stratified analyses were performed on age, gender, study design, bilateral SWL, and different machines. CONCLUSION: Our analysis indicated that no association was found between SWL and the development of hypertension. PMID- 24162892 TI - Prevalence of presbyopia and spectacle coverage in an African population in Durban, South Africa. AB - PURPOSE: To assess the prevalence of near vision impairment caused by uncorrected presbyopia and to determine the spectacle coverage for presbyopia in Durban, KwaZulu Natal, South Africa. METHODS: A cross-sectional community-based survey was conducted to determine the prevalence of presbyopia in Durban. Eighteen clusters were randomly selected from the suburbs of Durban--Inanda, Ntuzuma, and KwaMashu. Adults over 35 years of age were enumerated through a door-to-door method using aged-based sampling. Respondents were interviewed and then underwent standardized clinical eye examinations. Spectacle coverage was determined. Applying multivariate logistic regressions, the strengths of association of presbyopia and spectacle coverage with the participants' demographic profile were determined. RESULTS: A total of 2764 participants were enumerated while 1939 (70.2%) were examined with a median age of 52 years (interquartile range 45, 60). The prevalence of presbyopia was 77.0% (95% confidence interval [CI] 74.3% 79.2%), significantly higher in those 50-64 years old (OR 10.2, 95% CI 5.3-19.6) and 65-79 years old (OR 10.7, 95% CI 3.2-35.6) and significantly lower in those who had secondary and higher education (p < 0.05). The spectacle coverage for presbyopia was 4.84% (95% CI 3.35%-6.33%), significantly higher in those who were 65-79 years old (OR 4.4, 95% CI 1.5-12.9) and 50-64 years old (OR 2.6, 95% CI 1.1 6.1). CONCLUSIONS: This study indicated that there is a high prevalence of presbyopia in the study area, with low spectacle coverage, and therefore suggests that uncorrected presbyopia is a major public health concern. The findings of this study may help in making recommendations for strategic planning for eye health intervention efforts. PMID- 24162893 TI - A new portable digital meniscometer. AB - PURPOSE: The aims of this study were (i) to develop a new portable slit-lamp mounted digital meniscometer (PDM) and (ii) to test its accuracy and repeatability compared to the existing Yokoi et al. videomeniscometer (VM). METHODS: We developed a novel application for an iPod or iPhone, which created an illuminated target of parallel black and white bands. This was used as a portable device with which to perform reflective meniscometry. The medians of three consecutive measurements on five glass capillaries (internal radii, 0.100 to 0.505 mm) were compared between VM and PDM at two different sessions. Also, the central lower tear meniscus radius (TMR) in 20 normal subjects (10 males and 10 females; mean [SD] age, 32.3 [9.3] years) was measured using both techniques. Correlations between the instruments were analyzed using the Pearson coefficient. Differences between sessions and instruments were analyzed using Bland-Altman plots, coefficient of repeatability, and paired t-tests. RESULTS: The PDM and VM were accurate in vitro (95% confidence interval [CI] of difference: PDM -0.0134 to +0.0074 mm, p = 0.468; VM -0.0282 to + 0.0226 mm; p = 0.775) and reproducible between sessions (95% coefficient of repeatability, 0.019 and 0.018, respectively). The mean difference between the PDM and VM in vitro was 0.0002 mm (95% CI, -0.0252 to + 0.0256; p = 0.984). In human subjects, mean (SD) TMR measured with the PDM (0.34 [0.10] mm) and VM (0.36 [0.11] mm) was significantly correlated (r = 0.940; p < 0.001), and there was no statistically significant difference between the measured TMR of the instruments (p = 0.124). CONCLUSIONS: This new slit-lamp mounted digital meniscometer produces accurate and reliable measurements and provides similar values for tear meniscus radius, in human studies, to the existing VM. The instrument is suitable for use in both research and clinical practice. PMID- 24162894 TI - Pacific acuity test: testability, validity, and interobserver reliability. AB - PURPOSE: The Pacific Acuity Test (PAT) is a new vanishing optotype test designed to measure recognition visual acuities in preverbal children using a face and opposing oval figure in a forced-choice preferential looking format. This study evaluates the testability, validity, and interobserver reliability of the PAT. METHODS: Fifty-two subjects, aged 6 to 36 months, were tested by a primary observer to determine both recognition and resolution visual acuities using the PAT. Subjects were also tested using the Cardiff Acuity Test (CAT) to provide comparative resolution acuities. Two additional observers independently evaluated video-recorded subject responses for testability and interobserver reliability analysis. An independent grader determined acuity thresholds from each observer's observations, and a logistic regression model was used for additional analysis of acuity thresholds, validity, and testability. RESULTS: Forty-seven of 52 subjects completed testing to obtain visual acuities with the PAT. Sixty-nine percent of subjects followed the desired forced-choice strategy to yield recognition acuities with the PAT. Testability for children younger than 18 months was 44%, whereas 96% of children 18 months and older responded to the recognition testing format. Testability for resolution acuity was 92% and 98% for the PAT and CAT, respectively. The mean difference between PAT recognition and CAT resolution acuity thresholds (PAT-CAT) was +0.11 logMAR (0.15 SD, p < 0.001). The observers were in agreement as determined by intraclass correlation coefficients of 0.90 for both PAT recognition and the CAT. CONCLUSIONS: High testability and valid recognition acuity measures were achieved using the PAT with children by approximately 18 months of age. The recognition acuities obtained with the PAT were higher, particularly for younger subjects, than comparative resolution acuities found with both the PAT and CAT. Interobserver reliability of observers was the same between the PAT and the CAT. PMID- 24162895 TI - Myopia screening: combining visual acuity and noncycloplegic autorefraction. AB - PURPOSE: To explore the effectiveness of combining uncorrected visual acuity (UCVA) and noncycloplegic autorefraction (NCAR) for large-scale myopia screening in schoolchildren with a high prevalence of myopia. METHODS: A total of 1687 children aged between 6 and 12 years, from five primary schools in the Baoshan district of Shanghai participated in the study. We measured UCVA and autorefraction before and after cycloplegia by a Topcon KR-8800. We drew receiver operating characteristic curves to achieve the best cutoff points and their corresponding sensitivities and specificities for the UCVA and NCAR, respectively. We then combined the UCVA and NCAR in serial order to explore the optimal criterion and its effectiveness. A specificity of 90% was set to compare the sensitivities among the three tests. The children were divided into three age groups (aged 6 to 7, 8 to 10, 11 to 12 years) to further examine this new method. RESULTS: A total of 1639 children with an average age of 9.35 (SD, 1.6) years were finally included, among which 428 (26.11%) children were diagnosed as being myopic (spherical equivalent refraction (SER) less than or equal to -0.5 diopters [D]). For the UCVA, the cutoff point is 0.2 logarithm of the minimum angle of resolution (20/32), with a sensitivity and specificity of 63.6% and 94.0%, respectively. For NCAR, the cutoff point is SER less than or equal to -0.75 D, with a sensitivity and specificity of 88.6% and 86.1%, respectively. When UCVA is combined with NCAR, the best cutoff point is UCVA less than or equal to 0 logarithm of the minimum angle of resolution (20/20) and SER less than or equal to -0.75 D, with a sensitivity and specificity of 84.4% and 90.5%, respectively. At a specificity of 90%, the sensitivities are 63.55%, 78.50%, and 84.35%, respectively, for UCVA, NCAR, and the combination test. In all age groups, the combination test had the highest sensitivities among the three tests. CONCLUSIONS: In a population with a high prevalence of myopia, combining the UCVA and NCAR in serial order achieved higher sensitivity than either of the two tests alone, when specificity was set at 90%. PMID- 24162896 TI - The "double-layer sign": in vivo imaging of polypoidal choroidal vasculopathy. AB - PURPOSE: Polypoidal choroidal vasculopathy (PCV), a disease of the choroidal vascular network, presents clinically with polyp-like reddish orange lesions, as well as retinal pigment epithelial (RPE) and/or neurosensory retinal detachments. Optical coherence tomography (OCT) is a useful diagnostic tool that provides cross-sectional and volumetric imaging of posterior segment microstructure. Typical OCT findings in PCV may reveal a classic hyperreflectivity in the choroidal layers known as the "double-layer" sign. This sign is indicative of an abnormal choroidal vascular network. Indocyanine green angiography is also useful for the diagnosis of PCV and clearly identifies the polyp-like lesions arising from the choroidal vasculature. CASE REPORT: A 53-year-old African American woman presented with complaints of gradually decreasing vision in the left eye (OS). Clinical examination revealed moderately reduced acuity OS with a small central scotoma found on Amsler grid testing. Dilated fundus examination revealed a hemorrhagic RPE detachment with suspicion of a choroidal neovascular membrane in the foveal region of the OS. Exudative leakage appeared circumferentially around the macula OS. Optical coherence tomography of the OS also revealed two highly reflective layers: one at the level of the RPE and another beneath the RPE ("double-layer" sign). The patient was referred to a retina subspecialist for angiography and treatment consideration. CONCLUSIONS: It is important to distinguish PCV from other variants of choroidal neovascularization. The polyp like lesions found in the PCV are a unique and classic characteristic. Proper diagnostic workup includes stereoscopic posterior fundus evaluation and imaging studies, including OCT and indocyanine green angiography. PMID- 24162897 TI - The effect of blur on the perception of up. AB - PURPOSE: Knowing one's orientation relative to the environment is important for many aspects of vision including object recognition, action planning, and balance. Here we assess how inadequate optical correction for typical refractive errors might influence this. We measured the effect of blur on the perception of orientation as measured by the subjective visual vertical (SVV) and the perceptual upright (PU). METHODS: The SVV and the PU were determined using a tilted line (was the line tilted left or right of vertical?) and the Oriented CHAracter Recognition Test (OCHART; was a character a "p" or a "d"?), respectively, in the presence of tilted visual backgrounds that were blurred using Gaussian blur with a radius of from 0 to 91 arc min. This is approximately equivalent to between 0 and 13 diopters of refractive error. RESULTS: Blur reduced the influence of vision on both the SVV and PU by one just noticeable difference (84%) when vision was blurred by 11 to 13 arc min. That is, visual cues to self-orientation remain effective until vision is degraded to about 20/240 - roughly equivalent of taking off a pair of 2 diopter prescription glasses. CONCLUSIONS: This reduction in the effectiveness of vision for determining orientation has important implications for the visually impaired and the elderly. Attempting tasks that require balance in the presence of uncorrected refractive errors may be more hazardous than expected. The effect of not optically correcting peripheral vision may also be consequential owing to the role of the far periphery in balance control. PMID- 24162899 TI - Introduction to asthma and phenotyping. AB - Asthma is an inflammatory disorder characterized by airway obstruction, airway hyperresponsiveness, and airway inflammation, all of which are variable among patients and variable in time within any specific patient. Understanding the mechanism that underlies this observed variability, and using that understanding to advance the science of asthma and the care of asthmatic patients, is an essential purpose of developing phenotypes. Clinical phenotypes have been used for decades, but overlap each other, and do not map cleanly to either pathophysiologic mechanism or with therapeutic response. Molecular phenotyping, although as yet only partially developed, offers the promise of dissecting the mechanistic underpinnings of the variability of asthma and of providing predictive therapeutics for the benefit of patients with this common and troubling disease. PMID- 24162900 TI - Epidemiology of asthma: prevalence and burden of disease. AB - While clinical guidelines clearly define mechanisms for asthma diagnosis based upon history, lung function testing, symptoms, and physical examination, surveillance for asthma is much less straightforward. Epidemiologists have long debated the best means of assessing the scope and burden of asthma, seeking to reduce the potential for confounding introduced by differential means of diagnosis and even slight differences in surveillance questions, both of which can bias surveillance results such that we over- or undercount cases. This chapter will provide an overview of asthma epidemiology in the USA and internationally, as well as review of the data and findings from the major surveillance systems, a discussion of a networked approach to the science and evaluation of therapeutic treatments using the exemplar of the Inner-City Asthma Network, and assessment of public health implications. PMID- 24162901 TI - Heterogeneity of asthma in society. AB - There has been an increased interest in studying other factors that affect asthma pathogenesis and cause heterogeneity in prevalence and incidence of asthma. The reason there are such varied expression patterns of disease in asthmatics is because of multiple variables that affect the pathogenesis of asthma. As an exemplar of an epidemiologic variable, we will discuss geographical location, obesity and vitamin D status of the individual, and their effects on asthma burden in humans. There is varying data regarding the prevalence or severity of asthma in urban versus rural setting which is likely related to the difference of the populations studied, complexity of causal variables involved, and local geographic factors. In addition to cross-sectional and cohort studies in humans, animal models and studies have established a link between asthma and obesity by investigating the mechanisms affecting both disease processes. The complicated interrelationship between obesity and asthma is an active area of epidemiological and experimental research with new insights being discovered at a rapid pace. Finally, vitamin D, an important immunomodulator thought to be important in pathogenesis of asthma, has both mechanistic and therapeutic implications in treatment of asthma. The influences of these factors on the clinical expression of asthma are discussed below. PMID- 24162898 TI - Impact of atrial fibrillation on exercise capacity in heart failure with preserved ejection fraction: a RELAX trial ancillary study. AB - BACKGROUND: Atrial fibrillation (AF) is common among patients with heart failure and preserved ejection fraction (HFpEF), but its clinical profile and impact on exercise capacity remain unclear. RELAX (Phosphodiesterase-5 Inhibition to Improve Clinical Status and Exercise Capacity in HFpEF) was a multicenter randomized trial testing the impact of sildenafil on peak VO2 in stable outpatients with chronic HFpEF. We sought to compare clinical features and exercise capacity among patients with HFpEF who were in sinus rhythm (SR) or AF. METHODS AND RESULTS: RELAX enrolled 216 patients with HFpEF, of whom 79 (37%) were in AF, 124 (57%) in SR, and 13 in other rhythms. Participants underwent baseline cardiopulmonary exercise testing, echocardiogram, biomarker assessment, and rhythm status assessment before randomization. Patients with AF were older than those in SR but had similar symptom severity, comorbidities, and renal function. beta-blocker use and chronotropic indices were also similar. Despite comparable left ventricular size and mass, AF was associated with worse systolic (lower EF, stroke volume, and cardiac index) and diastolic (shorter deceleration time and larger left atria) function compared with SR. Pulmonary artery systolic pressure was higher in AF. Patients with AF had higher N-terminal pro-B-type natriuretic peptide, aldosterone, endothelin-1, troponin I, and C-telopeptide for type I collagen levels, suggesting more severe neurohumoral activation, myocyte necrosis, and fibrosis. Peak VO2 was lower in AF, even after adjustment for age, sex, and chronotropic response, and VE/VCO2 was higher. CONCLUSIONS: AF identifies an HFpEF cohort with more advanced disease and significantly reduced exercise capacity. These data suggest that evaluation of the impact of different rate or rhythm control strategies on exercise tolerance in patients with HFpEF and AF is warranted. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00763867. PMID- 24162902 TI - Inhaled environmental allergens and toxicants as determinants of the asthma phenotype. AB - The driving environmental factors behind the development of the asthma phenotype remain incompletely studied and understood. Here, we present an overview of inhaled allergic/atopic and mainly nonallergic/nonatopic or toxicant shapers of the asthma phenotype, which are present in both the indoor and outdoor environment around us. The inhaled allergic/atopic factors include fungus, mold, animal dander, cockroach, dust mites, and pollen; these allergic triggers and shapers of the asthma phenotype are considered in the context of their ability to drive the immunologic IgE response and potentially induce interactions between the innate and adaptive immune responses, with special emphasis on the NADPH dependent reactive oxygen-species-associated mechanism of pollen-associated allergy induction. The inhaled nonallergic/nonatopic, toxicant factors include gaseous and volatile agents, such as sulfur dioxide, ozone, acrolein, and butadiene, as well as particulate agents, such as rubber tire breakdown particles, and diesel exhaust particles. These toxicants are reviewed in terms of their relevant chemical characteristics and hazard potential, ability to induce airway dysfunction, and potential for driving the asthma phenotype. Special emphasis is placed on their interactive nature with other triggers and drivers, with regard to driving the asthma phenotype. Overall, both allergic and nonallergic environmental factors can interact to acutely exacerbate the asthma phenotype; some may also promote its development over prolonged periods of untreated exposure, or possibly indirectly through effects on the genome. Further therapeutic considerations should be given to these environmental factors when determining the best course of personalized medicine for individuals with asthma. PMID- 24162903 TI - Current clinical diagnostic tests for asthma. AB - Asthma involves variable airflow obstruction in both large and small airways. The physiological consequences of obstruction include increased airway resistance and decreased expiratory flow rates, which lead to air trapping and dynamic hyperinflation. This chapter reviews current methods for pulmonary function testing to detect these physiological changes for both diagnosis and monitoring. PMID- 24162905 TI - Community-based interventions in asthma. AB - Community and public health interventions provide potentially powerful means of decreasing morbidity, hospitalizations, emergency room visits, and mortality from asthma. This chapter thus provides an overview of community-based interventions, which have been demonstrated to be effective-and/or ineffective-in reducing the burden of disease, including development of asthma coalitions, interventions for both provider and patient education, environmental controls to reduce exposure to asthma triggers, and institutional policy and systems change. Perhaps most important is the demonstrated effect of integrated, comprehensive approaches to asthma management and control. A multidisciplinary approach spanning T1 through T4 translational research, coupled with public health activities is promising and has already demonstrated success in reducing the burden of disease. PMID- 24162904 TI - Management of asthma: the current US and European guidelines. AB - Asthma management guidelines aim to improve the implementation of current knowledge into daily clinical practice by establishing a consensus of scientific practices for the management of asthma. Initial guidelines were based on consensus of expert opinion in order to employ a severity-based classification system as a guide to treatment. However, advances in asthma research led to the development of evidence-based guidelines and a major paradigm shift to control based asthma management. Control-based management is central to the published guidelines developed by The National Heart, Lung, and Blood Institute (NHLBI), The Global Initiative for Asthma (GINA), and The British Thoracic Society (BTS), each one using the same volume of evidence but emphasizing aspects particular to their specific patient populations and socioeconomic needs. This chapter summarizes the evolution of these guidelines and summarizes the key points and evidence used in the recommendations for the assessment, monitoring, and management of asthma in all ages, with particular emphasis on the NHLBI guidelines. PMID- 24162906 TI - Heterogeneity of response to therapy. AB - As noted in prior chapters, US national and international guidelines provide a consistent approach to initial management of asthma, based on easily observed physical and physiologic findings, and a detailed history. From those data, a rational initial therapeutic regimen can be prescribed. In many cases, such therapy results in near complete control of asthma symptoms, restoration of normal lung physiology, and elimination of exacerbations. In fact, such improvement is frequent enough that therapeutic responsiveness to asthma treatments was thought to be nearly universal. However, it is not uncommon for patients to return with incomplete, or even trivial improvement in these clinical metrics of control (Langmack and Martin Curr Opin Pulm Med 16:13-18, 2010). In this chapter, we review the current literature on the variability of response to commonly used therapeutic agents in asthma. PMID- 24162907 TI - Introduction to genetics and genomics in asthma: genetics of asthma. AB - While asthma is a heterogeneous disease, a strong genetic basis has been firmly established. Rather than being a single disease entity, asthma consists of related, overlapping syndromes [Barnes (Proc Am Thor Soc 8:143-148, 2011)] including three general domains: variable airway obstruction, airway hyper responsiveness, and airway inflammation with a considerable proportion, but not all, of asthma being IgE-mediated further adding to its heterogeneity. This chapter reviews the approaches to the elucidation of genetics of asthma from the early evidence of familial clustering to the current state of knowledge with genome-wide approaches. The conclusion is that research efforts have led to a tremendous repository of genetic determinants of asthma, most of which fall into the above phenotypic domains of the syndrome. We now look to future integrative approaches of genetics, genomics (Chap. 10), and epigenetics (Chap. 11) to better understand the causal mechanism through which, these genetic loci act in manifesting asthma. PMID- 24162908 TI - Gene expression profiling in asthma. PMID- 24162909 TI - Asthma epigenetics. AB - Asthma is the most common chronic disease of childhood, and a growing body of evidence indicates that epigenetic variations may mediate the effects of environmental exposures on the development and natural history of asthma. Epigenetics is the study of mitotically or meiotically heritable changes in gene expression that occur without directly altering the DNA sequence. DNA methylation, histone modifications and microRNAs are major epigenetic variations in humans that are currently being investigated for asthma etiology and natural history. DNA methylation results from addition of a methyl group to the 5 position of a cytosine ring and occurs almost exclusively on a cytosine in a CpG dinucleotide. Histone modifications involve posttranslational modifications such as acetylation, methylation, phosphorylation and ubiquitination on the tails of core histones. MicroRNAs are short ~22 nucleotide long, non-coding, single stranded RNAs that binds to complementary sequences in the target mRNAs, usually resulting in gene silencing. While many studies have documented relationships of environmental exposures that have been implicated in asthma etiology with epigenetic alterations, to date, few studies have directly linked epigenetic variations with asthma development. There are several methodological challenges in studying the epigenetics of asthma. In this chapter, the influence of epigenetic variations on asthma pathophysiology, methodological concerns in conducting epigenetic research and future direction of asthma epigenetics research are discussed. PMID- 24162910 TI - Overview. AB - Although broadly defined in the literature, for the purpose of this section, we define systems biology as the description of the dynamic genomic, proteomic, and metabolomic processes integrated into a functional model of the cell, organelle, or tissue that is capable of accurately tracking the biological system's response to environmental perturbations. The goal of this section is to complete the tripartite description of asthma systems biology, initiated by the previous section (Section II: Genetics and Genomics of Asthma), by reviewing the recent literature-the types and methods of sample collection, processing, analysis, and instrumentation-of metabolomic and proteomic investigations, including functional proteomic studies of the asthma innate immune response and glucocorticoid (GC) receptor signaling with reference to GC resistance in severe asthma. PMID- 24162911 TI - Metabolomics in asthma. AB - Asthma and airway inflammation are responses to infectious stimuli and the mechanisms of how they are mediated, whether by the innate or adaptive immune response systems, are complex and results in a broad spectrum of possible metabolic products. In principle, a syndrome such as asthma should have a characteristic temporal-spatial metabolic signature indicative of its current state and the constituents that caused it. Generally, the term metabolomics refers to the quantitative analysis of sets of small compounds from biological samples with molecular masses less than 1 kDa so unambiguous identification can be difficult and usually requires sophisticated instrumentation. The practical success of clinical metabolomics will largely hinge on a few key issues such as the ability to capture a readily available biofluid that can be analyzed to identify metabolite biomarkers with the required sensitivity and specificity in a cost-effective manner in a clinical setting. In this chapter, we review the current state of the metabolomics of asthma and airway inflammation with a focus on the different methods and instrumentation being used for the discovery of biomarkers in research and their future translation into the clinic as diagnostic aids for the choice of patient-specific therapies. PMID- 24162912 TI - Proteomic analysis of the asthmatic airway. AB - Proteomic investigations in general utilize varied technologies for sample preparation, separations, quantification, protein identification, and biological rationalization. Their applications range from pure discovery and mechanistic studies to biomarker discovery/verification/validation. In each specific case, the analytical strategy to be implemented is tailored to the type of sample that serves as the target of the investigations. Proteomic investigations take into consideration sample complexity, the cellular heterogeneity (particularly from tissues), the potential dynamic range of the protein and peptide abundance within the sample, the likelihood of posttranslational modifications (PTM), and other important factors that might influence the final output of the study. We describe the sample types typically used for proteomic investigations into the biology of asthma and review the most recent related publications with special attention to those that deal with the unique airway samples such as bronchoalveolar lavage fluids (BALF), epithelial lining fluid and cells (ELF), induced sputum (IS), and exhaled breath condensate (EBC). Finally, we describe the newest proteomics approaches to sample preparation of the unique airway samples, BALF and IS. PMID- 24162913 TI - Measurement of the innate immune response in the airway. AB - Asthma is an idiopathic disease associated with episodic inflammation and reversible airway obstruction that is triggered by environmental agents. Allergic and infectious agents trigger asthmatic exacerbations through the innate immune response (IIR). The IIR is activated by sentinel cells in the airways to elaborate inflammatory cytokines and protective mucosal interferons whose actions are designed to limit the spread of the organism, as well as to activate the adaptive immune response. We address the structure of the IIR pathway in sentinel cells of the airway and describe observations on its dysregulation. The IIR is triggered in a cell-type specific manner by germline-encoded pathogen recognition receptors (PPRs) including plasma membrane Toll-like receptors (TLRs) and the cytoplasmic Retinoic Acid-inducible Gene (RIG)-I-like RNA helicases, and protein kinase R (PKR). Although their mechanisms of intracellular signaling differ, both pathways converge on a small group of transcriptional effectors, nuclear factor kappaB (NF-kappaB), IFN regulatory factor (IRF), and signal transducer and activator of transcription (STAT). We describe several distinct techniques to quantitate the IIR including assays based on quantitative real-time PCR (Q-RT PCR) of NF-kappaB and IRF3-regulated genes, multiplex bead-based analysis of secreted proteins/cytokines and more recent developments in targeted, quantitative selected reaction monitoring (SRM)-mass spectrometry (MS). Application of these methods for quantitation of the IIR will further our understanding of the role of the IIR in asthma and its contribution to disease heterogeneity. PMID- 24162914 TI - Functional proteomics for the characterization of impaired cellular responses to glucocorticoids in asthma. AB - In chronic airway inflammatory disorders, such as asthma, glucocorticoid (GC) insensitivity is a challenging clinical problem associated with life-threatening disease progression and the potential development of serious side effects. The mechanism of steroid resistance in asthma remains unclear and may be multifactorial. Excluding noncompliance with GC treatment, abnormal steroid pharmacokinetics, and rare genetic defects in the glucocorticoid receptor (GR), the majority of GC insensitivity in asthma can be attributed to secondary defects related to GR function. Airway inflammatory cells obtained from patients with GC resistant asthma show a number of abnormalities in cell immune responses to GC, which suggests that there is a causative defect in GR signaling in GC-resistant cells that could be further elucidated by a functional and molecular proteomics approach. Since T cells, eosinophils, and monocytes play a major role in the pathogenesis of airway inflammation, most of the work published to date has focused on these cell types as the primary therapeutic targets in GC-insensitive asthma. We herein review several distinct techniques for the assessment of (1) the cellular response to GCs including the effect of GCs on cell viability, adhesion, and mediator release; (2) the functionality of GC receptors, including phosphorylation of the GR, nuclear translocation, and binding activities; and (3) the characterization of proteins differentially expressed in steroid-resistant cells by comparative 2DE-gel electrophoresis-based techniques and mass spectrometry. These comprehensive approaches are expected to reveal novel candidates for biomarkers of steroid insensitivity, which may lead to the development of effective therapeutic interventions for patients with chronic steroid-resistant asthma. PMID- 24162915 TI - Analysis and predictive modeling of asthma phenotypes. AB - Molecular classification using robust biochemical measurements provides a level of diagnostic precision that is unattainable using indirect phenotypic measurements. Multidimensional measurements of proteins, genes, or metabolites (analytes) can identify subtle differences in the pathophysiology of patients with asthma in a way that is not otherwise possible using physiological or clinical assessments. We overview a method for relating biochemical analyte measurements to generate predictive models of discrete (categorical) clinical outcomes, a process referred to as "supervised classification." We consider problems inherent in wide (small n and large p) high-dimensional data, including the curse of dimensionality, collinearity and lack of information content. We suggest methods for reducing the data to the most informative features. We describe different approaches for phenotypic modeling, using logistic regression, classification and regression trees, random forest and nonparametric regression spline modeling. We provide guidance on post hoc model evaluation and methods to evaluate model performance using ROC curves and generalized additive models. The application of validated predictive models for outcome prediction will significantly impact the clinical management of asthma. PMID- 24162916 TI - The role of visual analytics in asthma phenotyping and biomarker discovery. AB - The exponential growth of biomedical data related to diseases such as asthma far exceeds our cognitive abilities to comprehend it for tasks such as biomarker discovery, pathway identification, and molecular-based phenotyping. This chapter discusses the cognitive and task-based reasons for why methods from visual analytics can help in analyzing such large and complex asthma data, and demonstrates how one such approach called network visualization and analysis can be used to reveal important translational insights related to asthma. The demonstration of the method helps to identify the strengths and limitations of network analysis, in addition to areas for future research that can enhance the use of networks to analyze vast and complex biomedical datasets related to diseases such as asthma. PMID- 24162917 TI - Central nervous system influences in asthma. AB - Asthma is a biomedical disorder whose presentation can be markedly influenced by neurological and psychological factors. This chapter describes several approaches that provide insight into the role of psychological factors and brain function in asthma. These include the study of placebo responses and recent explorations using functional neuroimaging during the onset of asthma symptoms. Although the specific mechanisms involved remain uncertain, we are gaining an appreciation for some of the neurocircuitry that is involved. The insula and ACC may modulate inflammatory processes by their influence on neuroendocrine responses to stress, including highly studied effects on the HPA axis and its physiologic responses. However much we have recently learned, it is clear that further study of this topic is critical to fully explicate the role of the brain in asthma. PMID- 24162918 TI - Asthma, culture, and cultural analysis: continuing challenges. AB - Recent research indicates that asthma is more complicated than already recognized, requiring a multilateral approach of study in order to better understand its many facets. Apart from being a health problem, asthma is seen as a knowledge problem, and as we argue here, a cultural problem. Employing cultural analysis we outline ways to challenge conventional ideas and practices about asthma by considering how culture shapes asthma experience, diagnosis, management, research, and politics. Finally, we discuss the value of viewing asthma through multiple lenses, and how such "explanatory pluralism" advances transdisciplinary approaches to asthma. PMID- 24162919 TI - Conclusions and future directions. PMID- 24162920 TI - The origin of the genetic code: matter of metabolism or physicochemical determinism? PMID- 24162922 TI - Medical treatment of hypertension in patients with heart failure with preserved ejection fraction. AB - Heart failure with preserved ejection fraction (HFPEF) has become an increasingly common problem, accounting for as many as half of all diagnoses of heart failure. Hypertension has been shown to be a major risk factor for the development of HPEF, and the treatment of hypertension is key to both preventing the development of HFPEF as well as mitigating its impact on our health care system. While numerous studies have looked at using various classes of antihypertensive medications to treat HFPEF, there are still no well validated treatment strategies which have shown a significant mortality benefit. As a result, when choosing an antihypertensive medication to treat or prevent HFPEF, it is important to tailor the choice of antihypertensive medication to an individual patient's specific symptoms and comorbidities. PMID- 24162921 TI - Deep sequencing of viral genomes provides insight into the evolution and pathogenesis of varicella zoster virus and its vaccine in humans. AB - Immunization with the vOka vaccine prevents varicella (chickenpox) in children and susceptible adults. The vOka vaccine strain comprises a mixture of genotypes and, despite attenuation, causes rashes in small numbers of recipients. Like wild type virus, the vaccine establishes latency in neuronal tissue and can later reactivate to cause Herpes zoster (shingles). Using hybridization-based methodologies, we have purified and sequenced vOka directly from skin lesions. We show that alleles present in the vaccine can be recovered from the lesions and demonstrate the presence of a severe bottleneck between inoculation and lesion formation. Genotypes in any one lesion appear to be descended from one to three vaccine-genotypes with a low frequency of novel mutations. No single vOka haplotype and no novel mutations are consistently present in rashes, indicating that neither new mutations nor recombination with wild type are critical to the evolution of vOka rashes. Instead, alleles arising from attenuation (i.e., not derived from free-living virus) are present at lower frequencies in rash genotypes. We identify 11 loci at which the ancestral allele is selected for in vOka rash formation and show genotypes in rashes that have reactivated from latency cannot be distinguished from rashes occurring immediately after inoculation. We conclude that the vOka vaccine, although heterogeneous, has not evolved to form rashes through positive selection in the mode of a quasispecies, but rather alleles that were essentially neutral during the vaccine production have been selected against in the human subjects, allowing us to identify key loci for rash formation. PMID- 24162923 TI - A superfolding Spinach2 reveals the dynamic nature of trinucleotide repeat containing RNA. AB - Imaging RNA in living cells is a challenging problem in cell biology. One strategy for genetically encoding fluorescent RNAs is to express them as fusions with Spinach, an 'RNA mimic of GFP'. We found that Spinach was dimmer than expected when used to tag constructs in living cells owing to a combination of thermal instability and a propensity for misfolding. Using systematic mutagenesis, we generated Spinach2 that overcomes these issues and can be used to image diverse RNAs. Using Spinach2, we detailed the dynamics of the CGG trinucleotide repeat-containing 'toxic RNA' associated with Fragile X-associated tremor/ataxia syndrome, and show that these RNAs form nuclear foci with unexpected morphological plasticity that is regulated by the cell cycle and by small molecules. Together, these data demonstrate that Spinach2 exhibits improved versatility for fluorescently labeling RNAs in living cells. PMID- 24162924 TI - Mapping differential interactomes by affinity purification coupled with data independent mass spectrometry acquisition. AB - Characterizing changes in protein-protein interactions associated with sequence variants (e.g., disease-associated mutations or splice forms) or following exposure to drugs, growth factors or hormones is critical to understanding how protein complexes are built, localized and regulated. Affinity purification (AP) coupled with mass spectrometry permits the analysis of protein interactions under near-physiological conditions, yet monitoring interaction changes requires the development of a robust and sensitive quantitative approach, especially for large scale studies in which cost and time are major considerations. We have coupled AP to data-independent mass spectrometric acquisition (sequential window acquisition of all theoretical spectra, SWATH) and implemented an automated data extraction and statistical analysis pipeline to score modulated interactions. We used AP SWATH to characterize changes in protein-protein interactions imparted by the HSP90 inhibitor NVP-AUY922 or melanoma-associated mutations in the human kinase CDK4. We show that AP-SWATH is a robust label-free approach to characterize such changes and propose a scalable pipeline for systems biology studies. PMID- 24162925 TI - Quantifying protein interaction dynamics by SWATH mass spectrometry: application to the 14-3-3 system. AB - Protein complexes and protein interaction networks are essential mediators of most biological functions. Complexes supporting transient functions such as signal transduction processes are frequently subject to dynamic remodeling. Currently, the majority of studies on the composition of protein complexes are carried out by affinity purification and mass spectrometry (AP-MS) and present a static view of the system. For a better understanding of inherently dynamic biological processes, methods to reliably quantify temporal changes of protein interaction networks are essential. Here we used affinity purification combined with sequential window acquisition of all theoretical spectra (AP-SWATH) mass spectrometry to study the dynamics of the 14-3-3beta scaffold protein interactome after stimulation of the insulin-PI3K-AKT pathway. The consistent and reproducible quantification of 1,967 proteins across all stimulation time points provided insights into the 14-3-3beta interactome and its dynamic changes following IGF1 stimulation. We therefore establish AP-SWATH as a tool to quantify dynamic changes in protein-complex interaction networks. PMID- 24162926 TI - How to freak a Black & Mild: a multi-study analysis of YouTube videos illustrating cigar product modification. AB - Cigar smoking is increasingly common among adolescents who perceive cigars as less harmful than cigarettes. This perception of reduced harm is especially true for cigars that are user-modified by removing the tobacco binder through a process called 'freaking'. Little is known about 'freaking' and this multi-study, mixed-methods analysis sought to understand better the rationale and prevailing beliefs about this smoking practice using YouTube videos. In Study 1, we conducted a descriptive content analysis on the characteristics of 26 randomly sampled cigar product modification (CPM) videos posted during 2006-10. In Study 2, a thematic analysis was performed on the transcripts of commentary associated with each video to characterize viewers' comments about video content. Study 1 results revealed that 90% of videos illustrated a four-step CPM technique: 'Loosening the tobacco'; 'Dumping the tobacco'; 'Removing the cigar binder' and 'Repacking the tobacco'. Four themes related to the purpose of CPM were also derived from video content: 'Easier to smoke' (54%), 'Beliefs in reduction of health risks' (31%), 'Changing the burn rate' (15%) and 'Taste enhancement' (12%). Study 2 results concerning the content characteristics of video comments were categorized into three themes: 'Disseminating information/answering questions' (81%), 'Seeking advice/asking questions' (69%) and 'Learning cigar modification techniques' (35%). Favorable comments were more common (81%) compared to unfavorable (58%) and comment content suggested low-risk perceptions and poor understanding of smoking harms. These findings highlight a novel means for youth to access information concerning CPM that may have important implications for tobacco control policy and prevention. PMID- 24162927 TI - Electrocardiographic predictors of response to cardiac resynchronization therapy in patients with intraventricular conduction delay. AB - BACKGROUND: Little is known about predictors of response to cardiac resynchronization therapy (CRT) in patients with intraventricular conduction delay (IVCD). The purpose of this study was to investigate the benefits of CRT and significant variables on surface electrocardiogram (ECG) to predict response to CRT in those patients. METHODS AND RESULTS: Among the cohort of 152 CRT patients, 40 patients with IVCD were evaluated. Sixteen patients (40%) were responders. At baseline, responders had a wider QRS duration (158+/-18 vs. 144+/ 18ms, P=0.02) and a higher frequency of left axis deviation (LADEV; 75% vs. 29%, P=0.004) compared with non-responders. After CRT, greater shortening of QRS duration (DeltaQRS; 26+/-24 vs. 7+/-24ms, P=0.02), axis shift from LADEV to right axis deviation (RADEV; 69% vs. 13%, P<0.001), and both rightward forces in lead I and anterior forces in V1 (56% vs. 13%, P=0.003) were found more frequently in responders. Multivariable logistic regression analysis showed that LADEV at baseline, or DeltaQRS and axis shift from LADEV to RADEV after CRT were independent predictors of response to CRT. CONCLUSIONS: Patients with IVCD may not respond to CRT, but LADEV at baseline and reversal of ventricular activation after CRT on surface ECG could be important to predict response to CRT. PMID- 24162928 TI - Neoatherosclerosis and mural thrombus detection after sirolimus-eluting stent implantation. AB - BACKGROUND: Although both optical coherence tomography (OCT) and angioscopy are robust tools for detecting intrastent thrombi and neoatherosclerosis in vivo, whether OCT findings are comparable with angioscopy findings remains unclear. METHODS AND RESULTS: 22 patients presenting with de novo lesions underwent 26 sirolimus-eluting stent (SES) implantations, with follow-up OCT and angioscopy at 10 months post-implantation for segmental assessment of the proximal, mid-, and distal SES segments (66 segments). The mean signal intensity index (signal intensity of the neointima/signal intensity of fibrous intimal hyperplasia) was quantified for angioscopically detected in-stent yellow and white segments. The detection rate for red thrombi was numerically higher with angioscopy than with OCT (17% vs. 9%; P=0.053). Angioscopically detected in-stent yellow segments were categorized into 3 OCT patterns: "high-attenuation tissue covering struts" (OCT defined neoatherosclerosis), "high-attenuation tissue underneath struts," and "low-attenuation and low-intensity tissue covering struts"; further, macrophage like appearance was most frequently observed with OCT-defined neoatherosclerosis (56%, 6.3%, and 0%, respectively, P<0.001). The mean signal intensity index of neoatherosclerosis was significantly lower than that of angioscopically detected in-stent white segments (0.929 vs. 0.997, P=0.004). CONCLUSIONS: Current OCT based definitions for thrombus detection may underestimate the presence of subclinical red thrombi. Qualitative and quantitative OCT assessments of the neointima may enhance the detection of neoatherosclerosis over SES in vivo. PMID- 24162929 TI - Adherence to medication for chronic disorders during pregnancy: results from a multinational study. AB - BACKGROUND: For a variety of chronic disorders, low medication adherence during pregnancy may jeopardize maternal as well as foetal health. Little is known about how closely pregnant women follow their chronic pharmacotherapy regimens. OBJECTIVE: To explore the level of adherence to medication for a variety of chronic disorders, namely cardiovascular, rheumatic and bowel disorders, diabetes and epilepsy, during pregnancy and to identify determinants of low adherence during pregnancy. SETTING: This multinational, cross-sectional, internet-based study was undertaken in 18 countries in Europe, North America and Australia. Data originating from some South American countries were also collected. METHODS: The study period lasted from 1-October-2011 to 29-February-2012. By using an anonymous on-line questionnaire we collected information about maternal demographics, chronic disorders and related medication use during pregnancy, and women's pregnancy-specific beliefs about medication. Main outcome measure Adherence to medication during pregnancy via the 8-item Morisky Medication Adherence Scale (MMAS-8). RESULTS: A total of 210 pregnant women reported chronic medication use during pregnancy and filled in the MMAS-8. Overall, 36.2 % had low medication adherence. On the basis of the MMAS-8, the rates of low adherence were 55.6 % for medication for rheumatic disorders, 40.0 % for epilepsy, 36.1 % for bowel disorders, 32.9 % for cardiovascular disorders, and 17.1 % for diabetes. A lack of folic acid use, having previous children, and individual pregnancy specific beliefs about medication were significant determinants of low medication adherence during pregnancy. CONCLUSION: Many pregnant women had low adherence to their chronic pharmacotherapy regimens during pregnancy. Women's beliefs about medication were a central factor determining low adherence. PMID- 24162930 TI - Treatment beliefs, illness perceptions, and non-adherence to antiretroviral therapy in an ethnically diverse patient population. AB - BACKGROUND: Ethnic diversity is increasingly encountered in the HIV-infected population in North America, and it is unknown if beliefs surrounding illness and treatment vary among different ethnic groups. OBJECTIVE: Our objectives were to determine whether self-reported adherence, illness perceptions and treatment beliefs regarding HIV differ based on ethnicity. SETTING: This study was conducted during outpatient HIV clinic visits between March 1, 2010 and April 30, 2010 at two hospital-based clinics in Edmonton, AB, Canada. METHODS: A cross sectional sample of 65 patients on antiretroviral therapy (34 Caucasian, 23 Aboriginal, and 8 from other ethnic groups) attending hospital-based clinics completed a self-administered survey; medical records were reviewed for demographic and treatment information. MAIN OUTCOME MEASURE: An ANOVA with covariates was performed to measure variation of beliefs and adherence between ethnic groups. RESULTS: Mean self-reported adherence in the past week and past month was high (96 %) and the majority of patients (78.5 %) had a viral load <40 copies/mL. Patients had high perceived necessity scores and a low degree of perceived concern with antiretroviral therapy. In our study, treatment beliefs, illness perceptions, and self-reported adherence did not vary between ethnicities (p > 0.05). CONCLUSION: Treatment beliefs, illness perceptions, and adherence appear to be largely similar in English-speaking patients with diverse ethnic backgrounds who have been on treatment for at least 3 months. Strong supports may overcome any cultural differences in treatment beliefs that were expected at the outset. PMID- 24162931 TI - Poly(ADP-ribosyl)ation in regulation of chromatin structure and the DNA damage response. AB - Poly(ADP-ribose) (PAR) is a post-translational modification of proteins and is synthesised by PAR polymerases (PARPs), which have long been associated with the coordination of the cellular response to DNA damage, amongst other processes. Binding of some PARPs such as PARP1 to broken DNA induces a substantial wave of PARylation, which results in significant re-structuring of the chromatin microenvironment through modification of chromatin-associated proteins and recruitment of chromatin-modifying proteins. Similarly, other DNA damage response proteins are recruited to the damaged sites via PAR-specific binding modules, and in this way, PAR mediates not only local chromatin architecture but also DNA repair. Here, we discuss the expanding role of PAR in the DNA damage response, with particular focus on chromatin regulation. PMID- 24162932 TI - Changes in the expression of the glutamate transporter EAAT3/EAAC1 in health and disease. AB - Excitatory amino acid transporters (EAATs) are high-affinity Na(+)-dependent carriers of major importance in maintaining glutamate homeostasis in the central nervous system. EAAT3, the human counterpart of the rodent excitatory amino acid carrier 1 (EAAC1), is encoded by the SLC1A1 gene. EAAT3/EAAC1 is ubiquitously expressed in the brain, mostly in neurons but also in other cell types, such as oligodendrocyte precursors. While most of the glutamate released in the synapses is taken up by the "glial-type" EAATs, EAAT2 (GLT-1 in rodents) and EAAT1 (GLAST), the functional role of EAAT3/EAAC1 is related to the subtle regulation of glutamatergic transmission. Moreover, because it can also transport cysteine, EAAT3/EAAC1 is believed to be important for the synthesis of intracellular glutathione and subsequent protection from oxidative stress. In contrast to other EAATs, EAAT3/EAAC1 is mostly intracellular, and several mechanisms have been described for the rapid regulation of the membrane trafficking of the transporter. Moreover, the carrier interacts with several proteins, and this interaction modulates transport activity. Much less is known about the slow regulatory mechanisms acting on the expression of the transporter, although several recent reports have identified changes in EAAT3/EAAC1 protein level and activity related to modulation of its expression at the gene level. Moreover, EAAT3/EAAC1 expression is altered in pathological conditions, such as hypoxia/ischemia, multiple sclerosis, schizophrenia, and epilepsy. This review summarizes these results and provides an overall picture of changes in EAAT3/EAAC1 expression in health and disease. PMID- 24162935 TI - WITHDRAWN: Hydromorphone for acute and chronic pain. PMID- 24162936 TI - In situ forming, characterization, and transduction of nanowire memristors. AB - We report the nanorobotic in situ formation and characterization of memristors based on individual copper oxide nanowires (CuO NWs) and their potential applications as nanosensors with memory function (memristic sensors or "memsensors"). A series of in situ techniques for the experimental investigations of memristors are developed including nanorobotic manipulation, electro-beam based forming, and electron energy loss spectroscopy (EELS) enabled correlation of transport properties and dopant distribution. All experimental investigations are performed inside a transmission electron microscope (TEM). The initial CuO NW memristors are formed by localized electron-beam irradiation to generate oxygen vacancies as dopants. Current-voltage properties show distinctive hysteresis characteristics of memristors. The mechanism of such memristic behavior is explained with an oxygen vacancy migration model. The presence and migration of the oxygen vacancies is identified with EELS. Investigations also reveal that the memristic behavior can be influenced by the deformation of the nanowire, showing that the nanowire memristor can serve as a deformation/force memorable sensor. The CuO NW-based memristors will enrich the binary transition oxide family but hold a simpler and more compact design than the conventional thin-film version. With these advantages, the CuO NW-based memristors will not only facilitate their applications in nanoelectronics but play a unique role in micro-/nano electromechanical systems (MEMS/NEMS) as well. PMID- 24162934 TI - The buzz on caffeine in invertebrates: effects on behavior and molecular mechanisms. AB - A number of recent studies from as diverse fields as plant-pollinator interactions, analyses of caffeine as an environmental pollutant, and the ability of caffeine to provide protection against neurodegenerative diseases have generated interest in understanding the actions of caffeine in invertebrates. This review summarizes what is currently known about the effects of caffeine on behavior and its molecular mechanisms in invertebrates. Caffeine appears to have similar effects on locomotion and sleep in both invertebrates and mammals. Furthermore, as in mammals, caffeine appears to have complex effects on learning and memory. However, the underlying mechanisms for these effects may differ between invertebrates and vertebrates. While caffeine's ability to cause release of intracellular calcium stores via ryanodine receptors and its actions as a phosphodiesterase inhibitor have been clearly established in invertebrates, its ability to interact with invertebrate adenosine receptors remains an important open question. Initial studies in insects and mollusks suggest an interaction between caffeine and the dopamine signaling pathway; more work needs to be done to understand the mechanisms by which caffeine influences signaling via biogenic amines. As of yet, little is known about whether other actions of caffeine in vertebrates, such as its effects on GABAA and glycine receptors, are conserved. Furthermore, the pharmacokinetics of caffeine remains to be elucidated. Overall behavioral responses to caffeine appear to be conserved amongst organisms; however, we are just beginning to understand the mechanisms underlying its effects across animal phyla. PMID- 24162933 TI - Neutrophil uptake of nitrogen-bisphosphonates leads to the suppression of human peripheral blood gammadelta T cells. AB - Nitrogen-bisphosphonates (n-BP), such as zoledronate, are the main class of drugs used for the prevention of osteoporotic fractures and the management of cancer associated bone disease. However, long-term or high-dose use has been associated with certain adverse drug effects, such as osteonecrosis of the jaw and the loss of peripheral of blood Vgamma9Vdelta2 T cells, which appear to be linked to drug induced immune dysfunction. In this report we show that neutrophils present in human peripheral blood readily take up zoledronate, and this phenomenon is associated with the potent immune suppression of human peripheral blood Vgamma9Vdelta2 T cells. Furthermore, we found this zoledronate-mediated inhibition by neutrophils could be overcome to fully reconstitute Vgamma9Vdelta2 T cell proliferation by concomitantly targeting neutrophil-derived hydrogen peroxide, serine proteases, and arginase I activity. These findings will enable the development of targeted strategies to mitigate some of the adverse effects of n-BP treatment on immune homeostasis and to improve the success of immunotherapy trials based on harnessing the anticancer potential of peripheral blood gammadelta T cells in the context of n-BP treatment. PMID- 24162938 TI - Value of composite reference standards in diagnostic research. PMID- 24162939 TI - Mortality indicators used to rank hospital performance. PMID- 24162940 TI - Ibuprofen, paracetamol, and steam for patients with respiratory tract infections in primary care: pragmatic randomised factorial trial. AB - OBJECTIVE: To assess strategies for advice on analgesia and steam inhalation for respiratory tract infections. DESIGN: Open pragmatic parallel group factorial randomised controlled trial. SETTING: Primary care in United Kingdom. PARTICIPANTS: Patients aged >= 3 with acute respiratory tract infections. INTERVENTION: 889 patients were randomised with computer generated random numbers in pre-prepared sealed numbered envelopes to components of advice or comparator advice: advice on analgesia (take paracetamol, ibuprofen, or both), dosing of analgesia (take as required v regularly), and steam inhalation (no inhalation v steam inhalation). OUTCOMES: Primary: mean symptom severity on days 2-4; symptoms rated 0 (no problem) to 7 (as bad as it can be). Secondary: temperature, antibiotic use, reconsultations. RESULTS: Neither advice on dosing nor on steam inhalation was significantly associated with changes in outcomes. Compared with paracetamol, symptom severity was little different with ibuprofen (adjusted difference 0.04, 95% confidence interval -0.11 to 0.19) or the combination of ibuprofen and paracetamol (0.11, -0.04 to 0.26). There was no evidence for selective benefit with ibuprofen among most subgroups defined before analysis (presence of otalgia; previous duration of symptoms; temperature >37.5 degrees C; severe symptoms), but there was evidence of reduced symptoms severity benefit in the subgroup with chest infections (ibuprofen -0.40, -0.78 to -0.01; combination -0.47; -0.84 to -0.10), equivalent to almost one in two symptoms rated as a slight rather than a moderately bad problem. Children might also benefit from treatment with ibuprofen (ibuprofen: -0.47, -0.76 to -0.18; combination: -0.04, -0.31 to 0.23). Reconsultations with new/unresolved symptoms or complications were documented in 12% of those advised to take paracetamol, 20% of those advised to take ibuprofen (adjusted risk ratio 1.67, 1.12 to 2.38), and 17% of those advised to take the combination (1.49, 0.98 to 2.18). Mild thermal injury with steam was documented for four patients (2%) who returned full diaries, but no reconsultations with scalding were documented. CONCLUSION: Overall advice to use steam inhalation, or ibuprofen rather than paracetamol, does not help control symptoms in patients with acute respiratory tract infections and must be balanced against the possible progression of symptoms during the next month for a minority of patients. Advice to use ibuprofen might help short term control of symptoms in those with chest infections and in children. TRIAL REGISTRATION: ISRCTN 38551726. PMID- 24162941 TI - Abnormal liver function tests in pregnancy. PMID- 24162942 TI - Clinical effectiveness of a manual based coping strategy programme (START, STrAtegies for RelaTives) in promoting the mental health of carers of family members with dementia: pragmatic randomised controlled trial. AB - OBJECTIVE: To assess whether a manual based coping strategy compared with treatment as usual reduces depression and anxiety symptoms in carers of family members with dementia. DESIGN: Randomised, parallel group, superiority trial. SETTING: Three mental health community services and one neurological outpatient dementia service in London and Essex, UK. PARTICIPANTS: 260 carers of family members with dementia. INTERVENTION: A manual based coping intervention comprising eight sessions and delivered by supervised psychology graduates to carers of family members with dementia. The programme consisted of psychoeducation about dementia, carers' stress, and where to get emotional support; understanding behaviours of the family member being cared for, and behavioural management techniques; changing unhelpful thoughts; promoting acceptance; assertive communication; relaxation; planning for the future; increasing pleasant activities; and maintaining skills learnt. Carers practised these techniques at home, using the manual and relaxation CDs. MAIN OUTCOME MEASURES: Affective symptoms (hospital anxiety and depression total score) at four and eight months. Secondary outcomes were depression and anxiety caseness on the hospital anxiety and depression scale; quality of life of both the carer (health status questionnaire, mental health) and the recipient of care (quality of life-Alzheimer's disease); and potentially abusive behaviour by the carer towards the recipient of care (modified conflict tactics scale). RESULTS: 260 carers were recruited; 173 were randomised to the intervention and 87 to treatment as usual. Mean total scores on the hospital anxiety and depression scale were lower in the intervention group than in the treatment as usual group over the eight month evaluation period: adjusted difference in means -1.80 points (95% confidence interval -3.29 to -0.31; P=0.02) and absolute difference in means -2.0 points. Carers in the intervention group were less likely to have case level depression (odds ratio 0.24, 95% confidence interval 0.07 to 0.76) and there was a non-significant trend towards reduced case level anxiety (0.30, 0.08 to 1.05). Carers' quality of life was higher in the intervention group (difference in means 4.09, 95% confidence interval 0.34 to 7.83) but not for the recipient of care (difference in means 0.59, -0.72 to 1.89). Carers in the intervention group reported less abusive behaviour towards the recipient of care compared with those in the treatment as usual group (odds ratio 0.47, 95% confidence interval 0.18 to 1.23), although this was not significant. CONCLUSIONS: A manual based coping strategy was effective in reducing affective symptoms and case level depression in carers of family members with dementia. The carers' quality of life also improved. TRIAL REGISTRATION: Current Controlled Trials ISCTRN70017938. PMID- 24162944 TI - Overdiagnosis: when good intentions meet vested interests--an essay by Iona Heath. PMID- 24162943 TI - Cost effectiveness of a manual based coping strategy programme in promoting the mental health of family carers of people with dementia (the START (STrAtegies for RelaTives) study): a pragmatic randomised controlled trial. AB - OBJECTIVE: To assess whether the START (STrAtegies for RelatTives) intervention added to treatment as usual is cost effective compared with usual treatment alone. DESIGN: Cost effectiveness analysis nested within a pragmatic randomised controlled trial. SETTING: Three mental health and one neurological outpatient dementia service in London and Essex, UK. PARTICIPANTS: Family carers of people with dementia. INTERVENTION: Eight session, manual based, coping intervention delivered by supervised psychology graduates to family carers of people with dementia added to usual treatment, compared with usual treatment alone. PRIMARY OUTCOME MEASURES: Costs measured from a health and social care perspective were analysed alongside the Hospital Anxiety and Depression Scale total score (HADS-T) of affective symptoms and quality adjusted life years (QALYs) in cost effectiveness analyses over eight months from baseline. RESULTS: Of the 260 participants recruited to the study, 173 were randomised to the START intervention, and 87 to usual treatment alone. Mean HADS-T scores were lower in the intervention group than the usual treatment group over the 8 month evaluation period (mean difference -1.79 (95% CI -3.32 to -0.33)), indicating better outcomes associated with the START intervention. There was a small improvement in health related quality of life as measured by QALYs (0.03 (-0.01 to 0.08)). Costs were no different between the intervention and usual treatment groups (L252 (-28 to 565) higher for START group). The cost effectiveness calculations suggested that START had a greater than 99% chance of being cost effective compared with usual treatment alone at a willingness to pay threshold of L30,000 per QALY gained, and a high probability of cost effectiveness on the HADS-T measure. CONCLUSIONS: The manual based coping intervention START, when added to treatment as usual, was cost effective compared with treatment as usual alone by reference to both outcome measures (affective symptoms for family carers, and carer based QALYs). TRIAL REGISTRATION: ISCTRN 70017938. PMID- 24162945 TI - NHS Direct will close down in March next year. PMID- 24162946 TI - Effects of food deprivation on the hypothalamic feeding-regulating peptides gene expressions in serotonin depleted rats. AB - We examined the effects of serotonin (5-HT) depletion induced by peripheral injection of 5-HT synthesis inhibitor p-chlorophenylalanine (PCPA) on the expression of feeding-regulating peptides expressions by using in situ hybridization histochemistry in adult male Wistar rats. PCPA pretreatment had no significant effect on basal levels of oxytocin, corticotropin-releasing hormone (CRH), thyrotropin-releasing hormone (TRH), pro-opiomelanocortin (POMC), cocaine and amphetamine-regulated transcript (CART), neuropeptide-Y (NPY), agouti-related protein (AgRP), melanin-concentrating hormone (MCH) or orexin in the hypothalamus. Food deprivation for 48 h caused a significant decrease in CRH, TRH, POMC, and CART, and a significant increase in NPY, AgRP and MCH. After PCPA treatment, POMC and CART did not decrease despite food deprivation. NPY was significantly increased by food deprivation with PCPA, but was attenuated compared to food deprivation without PCPA. These results suggest that the serotonergic system in the hypothalamus may be involved in the gene expression of POMC, CART, and NPY related to feeding behavior. PMID- 24162948 TI - Pathogenic variants screening in five non-obstructive azoospermia-associated genes. AB - Non-obstructive azoospermia (NOA) is one of the most severe forms of male infertility and a recent, genome-wide association study (GWAS) has identified four risk loci associated with NOA. However, a large portion of the heritability of NOA has not been well explained by GWAS. By hypothesizing that rare, low frequency and common genetic variants might point toward a causal relation between candidate genes and NOA, we performed a two-stage study including deep exon sequencing in 96 NOA cases and 96 healthy controls and a replication study in a larger population containing 522 NOA cases and 484 healthy controls. In the solexa sequencing stage, a total of two rare mutations (chr20. 1902132 and chr20. 1902301 in SIRPA), four common mutations (rs1048055 and rs2281807 in SIRPG, rs11046992 and rs146039840 in SOX5) were identified by using next generation sequencing (NGS). In the validation stage, subjects in the NOA group had a significantly decreased frequency of the heterozygous GA genotype in SIRPA (4.23%, 22 out of 520) than that in the control group (8.60%, 41 out of 477) [odds ratios (OR) 0.47, 95% confidence intervals (CI) 0.28-0.80] (P = 6.00 * 10( 3)). The rs1048055 in SIRPG was associated with a significantly increased risk of spermatogenic impairment, compared with the CC genotype (OR 3.93, 95% CI 1.59 9.70) (P = 3.00 * 10(-3)). Our study provides evidence of independent NOA risk alleles driven by variants in the protein-coding sequence of two of the genes (SIRPA and SIRPG) discovered by GWAS. Further investigation in larger populations and functional characterizations are needed to validate our findings. PMID- 24162949 TI - Comparative analysis of flavonoids and polar metabolites from hairy roots of Scutellaria baicalensis and Scutellaria lateriflora. AB - Baicalin, baicalein, and wogonin were accumulated in hairy roots derived from Scutellaria lateriflora and Scutellaria baicalensis. The levels of baicalein and baicalin were 6.8 and 5.0 times higher, respectively, in S. baicalensis than in S. lateriflora. A total of 47 metabolites were detected and identified in Scutellaria species by GC-TOF MS. The metabolites from the two species were subjected to principal component analysis (PCA) to evaluate differences. PCA fully distinguished between the two species. The results showed that individual phenolic acids and phenylalanine, precursors for the phenylpropanoid biosynthetic pathway, were higher in S. baicalensis than in S. lateriflora. This GC-TOF MS based metabolic profiling approach was a viable alternative method to differentiate metabolic profiles between species. PMID- 24162950 TI - A new antibacterial amino phenyl pyrrolidone derivative from a novel marine gliding bacterium Rapidithrix thailandica. AB - A recently described marine gliding bacterium Rapidithrix thailandica strain TISTR 1741 was isolated from biofilm specimen collected from the Andaman Sea in Thailand. Four liters fermentation broth of R. thailandica TISTR 1741 cultivated in VY/2 medium were extracted with methanol to yield a novel amino phenyl pyrrolidone derivative compound (1) with antibacterial activities. The chemical structure and physico-chemical properties of 1 were investigated by spectrometry techniques. Compound 1 exhibited selective inhibition against vancomycin resistant Enterococcus faecalis (VRE) with the MIC of 5.97 mM. PMID- 24162951 TI - Effect of octanal on the mycelial growth of Penicillium italicum and P. digitatum. AB - The present study investigated the antifungal activity of octanal against Penicillium italicum and P. digitatum. Results showed that octanal exhibited strong antifungal activity against the test pathogens in a dose-dependent manner. Scanning electron microscopy observation revealed that octanal obviously altered the morphology of P. italicum and P. digitatum hyphae by causing the loss of cytoplasm and distortion of mycelia. A rapid increase in the membrane permeability of P. italicum and P. digitatum was observed after treated with octanal at minimum inhibitory concentration or minimum fungicidal concentration, evidenced by the release of cell constituents, the extracellular conductivity and the extracellular potential of hydrogen. In addition, octanal apparently induced a decrease in total lipid contents of P. italicum and P. digitatum cells. These results suggested that the antifungal activity of octanal against P. italicum and P. digitatum can be attributed to the disruption of the cell membrane integrity and the leakage of cell components. PMID- 24162952 TI - Computed tomography-based novel prediction model for the stone-free rate of ureteroscopic lithotripsy. AB - The purpose of this study was to evaluate whether computed tomography (CT) parameters can predict the success of ureteroscopic lithotripsy (URSL) and establish a model for predicting the success rates of a single URSL procedure for the treatment of a single ureteral stone. We retrospectively reviewed the records of 237 patients who underwent URSL for ureteral stones diagnosed by CT between January 2009 and June 2012. Stone-free status was defined as the absence of stones or residual stone fragments <2 mm by ureteroscopy and plain abdominal radiography. We analyzed the correlations between the outcome of URSL and the patients' sex, age, height, body weight, body mass index, and history of ureteral stone. Stone factors such as the diameter (D), stone height (H), volumetric stone burden (VSB; D(2) * H * 5 mm * pi * 1/6), estimated stone location (ESL; number of axial cut images between the stone and uretero-vesical junction), tissue rim sign (RS; 0-3), perinephric edema (0-3), hydronephrosis (0-3), and Hounsfield unit (HU) were also analyzed. We then developed a model to predict the probability of successful URSL by applying a logistic model to our data. The success rate of URSL was 85.7% (203/237). Univariate analysis found that stone diameter, length, VSB, ESL, HU and RS significantly affected the stone-free rate. Multivariate analysis indicated that stone diameter, ESL and RS independently influenced the stone-free rate. The logistic model indicated that success rates = 1/[1 + exp{-6.146 + 0.071(D) + 0.153(ESL) + 1.534(RS)}] with an area under the receiver operating characteristic curve of 0.825. Stone diameter, ESL, and RS were independent predictors of the outcome of a single URSL for a single ureteral stone. PMID- 24162954 TI - Comparison of shock wave lithotripsy, flexible ureterorenoscopy and percutaneous nephrolithotripsy on moderate size renal pelvis stones. AB - To compare success and complication rates of shock wave lithotripsy (SWL), flexible ureterorenoscopy (F-URS) and percutaneous nephrolithotripsy (PNL) according to modified clavien grading system of renal pelvis stones between 1 and 2 cm. The results of 149 patients were evaluated retrospectively. Patients were divided into three groups as 52 for SWL, 47 for F-URS and 50 for PNL. Complications were evaluated by modified Clavien grading system. In the first group, stone-free rates after a mean of 2, 6 sessions was 86 % (45/52). In Group 2, this ratio was 91.4 % (43/47), and in Group 3, it was 98 % (49/50). The success rate in Group 3 was significantly higher than other groups. Complication rates for Group 1, 2 and 3 were 7.6 % (4/52), 6.3 % (3/47) and 12 % (6/50), respectively. Although PNL was the most successful technique compared with other techniques, complications were also higher in this group. Even though PNL is the most successful, it should be performed for selected patient groups and indications should be carefully evaluated. PMID- 24162953 TI - Increased crystal-cell interaction in vitro under co-culture of renal tubular cells and adipocytes by in vitro co-culture paracrine systems simulating metabolic syndrome. AB - We established an experimental co-culture system for renal tubular cells and adipocytes to investigate kidney stone formation mechanisms under metabolic syndrome (MetS) conditions and examined the interaction between these cells morphologically and genetically. M-1s and 3T3-L1s were cultured individually (control, CON), with 24-h culture media from each cell type added to the other cell type (replacement, RP) in 2-layer co-culture dishes for 24 h (transwell, TW). M-1s were then exposed to calcium oxalate monohydrate (COM) crystals, and attached (14)C-labeled COM crystals were quantified. Expression of kidney stone- and adipocyte-related genes was analyzed. The radioactivity of adherent COM crystals significantly increased in TW and was relatively higher in RP compared to CON. M-1s demonstrated significant upregulation of adiponectin (Adipoq) in RP and secreted phosphoprotein 1 (Spp1) in TW compared to CON before COM crystal exposure, and significant downregulation of Spp1 in TW and upregulation of tumor necrosis factor (Tnf), interleukin 6 (Il-6), and chemokine (C-C motif) ligand 2 (Ccl2) compared to CON after COM crystal exposure. 3T3-L1s showed significant upregulation of Spp1, Adipoq, Tnf-alpha, and Ccl2 compared to CON. Enzyme-linked immunosorbent assays of co-culture medium revealed significantly increased TNF alpha in TW. Our results highlight the potential for paracrine interactions between renal tubular cells and adipocytes and suggest that MetS conditions may lead to kidney stone formation. PMID- 24162955 TI - A bioprobe based on aggregation induced emission (AIE) for cell membrane tracking. AB - A new organic dye (FD-9) derived from 1,8-naphthalimide is synthesized and shows significant aggregation induced emission (AIE) characteristics. The FD-9 dye presents excellent photostability and low toxicity, which can specifically track a cell membrane for 4 days. PMID- 24162956 TI - Soap and water: not good for the lungs?*. PMID- 24162957 TI - The parsimonious pediatric index of mortality*. PMID- 24162958 TI - Broken barriers, biomarkers, and blocking antibodies-endothelial activation in sepsis*: no snowflake in an avalanche ever feels responsible. -Voltaire/Francois Marie Arouet (1694-1778). PMID- 24162959 TI - Pediatric sepsis-light at the end of the tunnel?*. PMID- 24162960 TI - Treating cerebral edema in diabetic ketoacidosis: caveats in extrapolating from traumatic brain injury*. PMID- 24162961 TI - Thyroid hormone supplementation following pediatric cardiac surgery: all "routes" lead to rome!*. PMID- 24162962 TI - Timing is everything: whether and when to use continuous electroencephalograms in abusive head trauma comes into focus. PMID- 24162963 TI - Patient-ventilator asynchrony during noninvasive pressure support ventilation and neurally adjusted ventilatory assist in infants and children*. PMID- 24162964 TI - The nose knows what it wants: high-flow nasal cannula versus nasopharyngeal continuous positive airway pressure*. PMID- 24162965 TI - Mechanical ventilation in children with acute respiratory distress syndrome: a huge gap between what we know and our practice!*. PMID- 24162966 TI - Selecting the best mortality risk scoring systems in a PICU: a difficult decision. PMID- 24162967 TI - The authors reply. PMID- 24162968 TI - Duration of gastrointestinal colonization by extended-spectrum beta-lactamase producing enterobacteriaceae acquired by infants in the neonatal ICU. PMID- 24162969 TI - The authors reply. PMID- 24162975 TI - Predictive binding geometry of ligands to DNA minor groove: isohelicity and hydrogen-bonding pattern. AB - The interaction of drugs and dyes with nucleic acids, particularly when binding to DNA minor groove occurs, has increasing importance in biomedical sciences. This is due to the resulting biological activity and to the possibility of recognizing AT and GC base pairs. In such cases, DNA binding can be predicted if appropriate helical and hydrogen-bonding parameters are deduced from DNA models, and a simplified geometrical rule in the form of a stencil is then applied on computer-drawn molecules of interest. Relevant structure parameter values for minor groove binders are the length (4.6 < L < 5.4 A) and angle (152 < sigma < 156.5 degrees ) between three consecutive units, measured at the level of hydrogen donor or acceptor groups. Application of the stencil shows that predictive methods can aid in the design of new compounds, by checking the possible binding of isohelical sequence-specific ligands along the DNA minor groove. PMID- 24162974 TI - Fruit and vegetable consumption and sports participation among UK Youth. AB - OBJECTIVES: UK guidelines for youth recommend daily physical activity and five portions of fruit and vegetables per day. This study examined the prevalence and clustering of meeting recommendations among 10- to 15-year old. METHODS: Data for 3,914 youth, from the first wave of Understanding Society: the UK Household Longitudinal Study, were analysed. Clustering was assessed using the observed/expected ratio method. RESULTS: A minority of youth met both recommendations, and these behaviours were clustered. The odds of meeting both recommendations were lower for older youth and for Pakistani and Bangladeshi youth; boys in lower income households were less likely to meet both recommendations. CONCLUSIONS: Most youth met neither recommendation and the behaviours clustered with variations by ethnicity and socioeconomic conditions. PMID- 24162976 TI - Using microchip gel electrophoresis to probe DNA-drug binding interactions. AB - Binding of small molecules with DNA plays an important role in many biological functions such as DNA replication, repair, and transcription. These interactions also offer enormous potential as targets for diagnostics and therapeutics, leading to intense interest in development of methods to probe the underlying binding events. In this chapter, we present a new approach to investigate the structural changes that accompany binding of DNA and small molecules. Instead of relying on conventional yet delicate single-molecule imaging methods, we show how a single microchip gel electrophoresis experiment incorporating both constant electric field and on-off actuation over a specific frequency range enables fundamental structural parameters (e.g., contour and persistence lengths) to be simultaneously determined. The microchip format offers an attractive combination of simplicity and scale-up potential that makes it amenable for high-throughput screening. PMID- 24162977 TI - Identifying different types of chromatin using Giemsa staining. AB - Mixtures of polychrome methylene blue-eosin Y (i.e., Giemsa stain) are widely used in biological staining. They induce a striking purple coloration of chromatin DNA (the Romanowsky-Giemsa effect), which contrasts with the blue stained RNA-containing cytoplasm and nucleoli. After specific prestaining treatments that induce chromatin disorganization (giving banded or harlequin chromosomes), Giemsa staining produces a differential coloration, with C- and G bands appearing in purple whereas remaining chromosome regions are blue. Unsubstituted (TT) and bromo-substituted (BT) DNAs also appear purple and blue, respectively. The same occurs in the case of BT and BB chromatids.In addition to discussing the use of Giemsa stain as a suitable method to reveal specific features of chromosome structure, some molecular processes and models are also described to explain Giemsa staining mechanisms of chromatin. PMID- 24162971 TI - Photosynthesis-related quantities for education and modeling. AB - A quantitative understanding of the photosynthetic machinery depends largely on quantities, such as concentrations, sizes, absorption wavelengths, redox potentials, and rate constants. The present contribution is a collection of numbers and quantities related mainly to photosynthesis in higher plants. All numbers are taken directly from a literature or database source and the corresponding reference is provided. The numerical values, presented in this paper, provide ranges of values, obtained in specific experiments for specific organisms. However, the presented numbers can be useful for understanding the principles of structure and function of photosynthetic machinery and for guidance of future research. PMID- 24162978 TI - Analysis of DNA damage and repair by comet fluorescence in situ hybridization (Comet-FISH). AB - A useful tool in the detection of overall and region-specific DNA damage is the Comet-FISH technique. This method combines two well-established methods, the Comet assay (single cell gel electrophoresis), which makes it possible to detect and quantify DNA damage at the single cell level, and FISH (fluorescence in situ hybridization), a technique that allows the specific detection of selected DNA sequences. The influence of specific substances such as water pollutants or food ingredients on individual cells can be measured with the alkaline version of the Comet assay, which involves the embedding of cells in agarose on microscopic slides, lysis of cells, and separation of DNA via electrophoresis. In damaged cells a "comet tail" is formed by fractured DNA migrating from the nucleus (head of the comet) in the electric field.The damaged DNA (DNA strand breaks) correlates with the percentage of DNA in the tail. In combination with the FISH method, DNA damage or repair capacity in single cells can be measured using labelled probes, which hybridize to specific DNA sequences of interest. This protocol exemplarily provides a description of the Comet-FISH technique for the detection of DNA damage using hydrogen peroxide as a genotoxic model substance. PMID- 24162979 TI - Alkaline nuclear dispersion assays for the determination of DNA damage at the single cell level. AB - Over the past three decades the development of methods for visualizing at the cell level the extent of DNA breakage significantly contributed to genotoxicity testing: their availability greatly improved the knowledge in the field of genetic toxicology. These procedures are based on the separation and visualization of DNA fragments resulting from cleavage of nuclear DNA. The separation process can be obtained either electrically (comet assay, linear migration of DNA fragments) or chemically (alkaline dispersion assays, radial diffusion of DNA fragments). Once separated and stained, intact and fragmented DNA can be observed with fluorescence or light microscope. Appropriate computer assisted image analysis allows quantitative determination of the extent of DNA breakage. These procedures have been proven to be sensitive, flexible, and reliable, and, as compared to former methods, they are simpler, are less time and money consuming, and have the unique capability of detecting DNA damage at the single cell level. This last feature has the additional advantage of allowing the identification of cellular subpopulations characterized by different sensitivity to the damaging agent. The fast halo assay (FHA) is currently the simplest and quickest nuclear dispersion assay; recent modifications of FHA have further improved the assay and pave the way to a full exploitation of its analytical potential. In this chapter the development, procedures, applications, and limits of these dispersion assays, with a particular focus on FHA, will be illustrated. PMID- 24162980 TI - Polarization microscopy of extended chromatin fibers. AB - Analysis of the formation of extended chromatin fibers (ECFs) in response to the action of gravity following lysis by hypertonic and detergent solutions is a useful technical procedure relevant for studies of the positioning of particular DNA signals on chromatin filaments. Additionally, if toluidine blue molecules are allowed to bind electrostatically to available DNA phosphates on ECFs, the birefringence brightness generated in these filaments, as observed by polarization microscopy, facilitates the description of the frequency of ECF formation and extension of the chromatin filaments generated. Thus, different patterns of DNA-nuclear matrix protein associations related to varying transcriptional activities and chromatin organization in isolated cells can be assessed. A technique for producing ECFs in different isolated cell types under variable physiological and/or pathological conditions is detailed in this chapter. PMID- 24162981 TI - DNA labeling in vivo: quantification of epidermal stem cell chromatin content in whole mouse hair follicles using Fiji image processing software. AB - DNA labeling in vivo using nucleoside analogues is a current experimental approach to determine cell proliferation rates in cell cultures and tissues. It has also been successfully used to localize adult stem cell niches through the identification of nucleoside label-retaining cells (LRC) in long-term experiments. A major hindrance of this methodology relies on the selection of adequate procedures to quantify the nucleoside analogue content from image data files. Here we propose a simple procedure using Fiji image processing software to accurately calculate nucleoside analogue retaining chromatin/total chromatin (LRC/DAPI) signal ratios in the well-known mouse hair follicle stem cell niche. PMID- 24162982 TI - A historical overview of bromo-substituted DNA and sister chromatid differentiation. AB - The thymidine analogue 5-bromo-2'-deoxyuridine (BrdU) has been widely used to make sister chromatid differentiation (SCD) evident in metaphase chromosomes of cells grown for two cycles in BrdU and, thus, containing varying amounts of the thymidine analogue. A direct consequence was the possibility of making sister chromatid exchange (SCE) evident without using autoradiographic procedures. The latter phenomenon was first discovered in 1953, and its frequency is considered a reliable marker of pathological cell situations, as well as an indicator of mutagenic compounds. Several experimental procedures were found which produced SCD, such as the use of fluorochromes like 33258 Hoechst or acridine orange, whose observation under fluorescence microscopy was directly recorded by photos or stained with Giemsa to make chromosome preparations permanent. Other treatments followed by Giemsa staining required the use of saline hot solutions, acid solutions, nuclease attack and specific monoclonal antibodies. Basically two molecular mechanisms were invoked to explain the different affinity of Giemsa stain for differential BrdU-substituted chromatid DNA. The first implied debromination of chromatid DNA, whose occurrence would be greater in chromatids containing an amount of BrdU greater than that present in sister chromatids. The second mechanism, although not denying the importance of DNA debromination, postulated that chromatin structural organization, in terms of DNA-protein and/or protein-protein DNA interaction, is responsible for SCD production. PMID- 24162983 TI - Image analysis of chromatin remodelling. AB - Chromatin packaging plays a significant role in regulating gene transcription. Study of the higher-order packing states of chromatin by image analysis at the light microscope level, especially when validated by methods of molecular biology, immunochemistry, and/or immunocytochemistry, enabled the detection of changes involved in the processes associated with or preceding alterations in transcriptional activities. Here, we recommend and describe the use of relatively simple methods for staining and detecting chromatin remodelling by image analysis. PMID- 24162984 TI - FISH methods in cytogenetic studies. AB - This chapter describes the various methods derived from the protocol of standard fluorescent in situ hybridization (FISH) that are used in human, animal, plant, and microbial studies. These powerful techniques allow us to detect and physically map on interphase nuclei, chromatin fibers, or metaphase chromosomes probes derived from single-copy genes to repetitive DNA sequences. Other variants of the technique enable the co-localization of genes and the overall comparison of the genome among individuals of the same species or of different taxa. A further variant detects and localizes bacteria on tissues and cells. Overall, this offers a remarkable multiplicity of possible applications ranging from strict physical mapping, to clinical and evolutionary studies, making it a powerful and informative complement to other molecular, functional, or genomic approaches. PMID- 24162985 TI - Ultrastructural and immunofluorescent methods for the study of the XY body as a biomarker. AB - Structural and immunohistochemical methods have been extremely useful for the characterization of the XY body (the structure formed by the XY pair during meiotic prophase) in Man and in other mammals. These methods are widely used at the present time for the detection of abnormalities leading to human infertility. The basic ultrastructural methods are spreading of pachytene spermatocytes, thin sectioning techniques with or without 3-D reconstructions, and the monitoring of all specimens with semi-thin sections. Immunofluorescent techniques also use spreading of meiotic cells for the analysis of the XY body, and they can be combined with the fluorescence in situ hybridization (FISH) technique, in the so called immuno-FISH. Epitope retrieval techniques are also used. PMID- 24162986 TI - Atomic force microscopy for analyzing metaphase chromosomes: comparison of AFM images with fluorescence labeling images of banding patterns. AB - The combined use of fluorescence microscopy with atomic force microscopy (AFM) has been introduced to analyze the replication-banding patterns of human chromosomes. Human lymphocytes synchronized with excess thymidine are treated with 5-ethynyl-2'-deoxyuridine (EdU) during the late S phase. EdU-labeled DNA is detected in metaphase chromosomes using Alexa Fluor 488((r)) azide, through the 1,3-dipolar cycloaddition reaction of organic azides with the terminal acetylene group of EdU. Chromosomes with EdU incorporated during the late S phase show a banding pattern similar to the G-banding pattern of normal human chromosomes. The comparison between the fluorescence and AFM image of the same chromosome indicates the presence of ridges and grooves in the chromatid arms, which correspond to G-positive and G-negative bands, respectively. This technique of EdU-labeled replication bands combined with AFM is useful to analyze the structure of chromosomes in relation to the banding pattern. PMID- 24162987 TI - Selective detection of phagocytic phase of apoptosis in fixed tissue sections. AB - Degradation of apoptotic cells is finalized during the phagocytic waste management phase of apoptosis. This eliminates genetic material present in dying cells which often contain pathological, viral, or cancerous DNA. In the waste management phase, chromatin of apoptotic cells is engulfed and digested by professional phagocytes or surrounding tissue cells. This process is critical for the efficient completion of apoptosis and its detection is necessary in research on cancer and autoimmune diseases where clearance of dying cells plays the central role. Here we present a rapid and simple fluorescence technique for visualization of phagocytic cells participating in waste management. The detailed step-by-step protocol is provided. The approach works in fixed tissue sections and labels all types of active phagocytic cells which engulf and digest apoptotic chromatin. PMID- 24162988 TI - Selective transport of cationized fluorescent topoisomerase into nuclei of live cells for DNA damage studies. AB - The targeted delivery of fluorescently labeled, DNA-modifying proteins into cellular nuclei permits investigation of DNA damage and chromatin function in living cells. Commercially available protein delivery vectors cannot provide selective intranuclear transportation and primarily unload their cargo in the cytoplasm. Here we describe a simple approach for specific intranuclear transportation of vaccinia topoisomerase protein based on its cationization. The delivered protein can be observed and monitored by fluorescence microscopy. The technique is cost-efficient and time-saving. It can be useful in live cell studies. PMID- 24162989 TI - Visualization and interpretation of eukaryotic DNA replication intermediates in vivo by electron microscopy. AB - The detailed understanding of the DNA replication process requires structural insight. The combination of psoralen cross-linking and electron microscopy has been extensively exploited to reveal the fine architecture of in vivo DNA replication intermediates. This approach proved instrumental to uncover the basic mechanisms of DNA duplication, as well as the perturbation of this process by various forms of replication stress. The replication structures are stabilized in vivo (by psoralen cross-linking) prior to extraction and enrichment procedures, allowing their visualization at the transmission electron microscope. This chapter outlines the procedures required to visualize and interpret in vivo replication intermediates of genomic DNA, extracted from budding yeast, Xenopus egg extracts, or cultured mammalian cells. PMID- 24162990 TI - Combined bidimensional electrophoresis and electron microscopy to study specific plasmid DNA replication intermediates in human cells. AB - Replication interference by specific chromosomal sequences-such as trinucleotide repeats-plays a causative, though undefined role in the aetiology of human disease, especially neurodegenerative syndromes. However, studies on these mechanisms in human cells have been hampered by poorly defined replication origins on genomic DNA. Simian Virus 40 (SV40)-based plasmids were useful in the past to overcome these experimental limits, but have been rarely amenable for the most complex and revealing molecular biology approaches to study in vivo DNA replication interference. This chapter describes a new, safe, SV40-based episomal system that replicates with very high efficiency in human cells and allows isolation of in vivo replication intermediates with high yield and purity. We describe how to use this experimental system to run preparative agarose 2D-gel and to extract specific replication intermediates to visualize by electron microscopy. PMID- 24162991 TI - Standard DNA methylation analysis in mouse epidermis: bisulfite sequencing, methylation-specific PCR, and 5-methyl-cytosine (5mC) immunological detection. AB - In mammals, methylation of cytosine C-5 position is a major heritable epigenetic mark on the DNA molecule. Maintenance of proper DNA methylation patterns is a key process during embryo development and in the maintenance of adult tissue homeostasis. The use of experimental procedures based on the chemical modification of cytosine by sodium bisulfite and the development of antibodies recognizing 5mC have essentially contributed to our knowledge on DNA methylation dynamics in normal and disease states. Here we describe standard procedures for bisulfite sequencing, methylation-specific PCR, and 5mC immunodetection using mouse skin and the hair follicle stem cell niche as model tissues. PMID- 24162992 TI - Methyl-combing: single-molecule analysis of DNA methylation on stretched DNA fibers. AB - The methyl-combing technique combines the dynamic molecular combing method with the detection of DNA modifications. The assay allows the single-molecule analysis of epigenetic marks on regularly stretched DNA fibers, at the megabase scale with kilobase resolution. The protocol presented in this chapter is based on proof-of principle experiments where the single-molecule detection of DNA methylation has been performed on unmethylated and in vitro methylated lambda phage DNA. PMID- 24162993 TI - Investigating 5-hydroxymethylcytosine (5hmC): the state of the art. AB - The discovery of 5-hydroxymethylcytosine (5hmC) as an abundant base in mammalian genomes has excited the field of epigenetics, and stimulated an intense period of research activity aimed at decoding its biological significance. However, initial research efforts were hampered by a lack of assays capable of specifically detecting 5hmC. Consequently, the last 3 years have seen the development of a plethora of new techniques designed to detect both global levels and locus specific profiles of 5hmC in mammalian genomes. This research effort has culminated in the recent publication of two complementary techniques for quantitative, base-resolution mapping of 5hmC in mammalian genomes, the first true mammalian hydroxymethylomes. Here, we review the techniques currently available to researchers studying 5hmC, discuss their advantages and disadvantages, and explore the technical hurdles which remain to be overcome. PMID- 24162994 TI - Hydroxymethylated DNA immunoprecipitation (hmeDIP). AB - 5-hydroxymethylcytosine (5hmC) was recently identified as an abundant epigenetic mark in mammals. Subsequent research has implicated 5hmC in normal mammalian development and disease pathogenesis in humans. Many of the techniques commonly used to assay for canonical 5-methylcytosine (5mC) cannot distinguish between 5hmC and 5mC. The development of antibodies specific to 5hmC has allowed for specific enrichment of DNA fragments containing 5hmC. Hydroxymethylated DNA immunoprecipitation (hmeDIP) has become an invaluable tool for determining both locus-specific and genome-wide profiles of 5hmC in mammalian DNA. Here, we describe the use of hmeDIP to characterize the relative abundance of 5hmC at loci in mammalian DNA. PMID- 24162995 TI - Microscale thermophoresis for the assessment of nuclear protein-binding affinities. AB - The rapid advance in our knowledge of cellular regulatory mechanisms, including those involving chromatin-based processes, stems in part from the development of biophysical techniques such as fluorescence spectroscopy, surface plasmon resonance (SPR), and isothermal titration calorimetry (ITC). Despite their widespread utility, each of these techniques has its pros and cons, and new techniques are still required. Here we describe the application of microscale thermophoresis (MST), a novel technique based on thermophoresis, to characterize the binding between histone peptides and a histone chaperone protein, in free solution, with high sensitivity and low sample consumption. PMID- 24162996 TI - Analysis of histone posttranslational modifications from nucleolus-associated chromatin by mass spectrometry. AB - Chromatin is unevenly distributed within the eukaryote nucleus and it contributes to the formation of morphologically and functionally distinct substructures, called chromatin domains and nuclear bodies. Here we describe an approach to assess specific chromatin features, the histone posttranslational modifications (PTMs), of the largest nuclear sub-compartment, the nucleolus. In this chapter, methods for the isolation of nucleolus-associated chromatin from native or formaldehyde-fixed cells and the effect of experimental procedures on the outcome of mass spectrometry analysis of histone PTMs are compared. PMID- 24162997 TI - Salt-urea, sulfopropyl-sepharose, and covalent chromatography methods for histone isolation and fractionation. AB - The histones are essential basic proteins intimately involved in most DNA templated processes. Thus, their purification and fractionation for analysis and their use for in vitro chromatin transactions are of fundamental importance for understanding their role in chromatin structure and regulation of DNA functions. Here are described three new protocols for histone isolation from undisturbed whole cells. They avoid the conventional non-denaturing cell lysis, which affects the native posttranslational modifications of histones, and the cumbersome use of reverse-phase high-performance liquid chromatography. The three methodologies are shorter than the conventionally used protocols. The salt-urea method exploits the stability of the cell nucleus in salt solutions containing 8 M urea, whereas the cell cytoplasm and the majority of nuclear components, except H3/H4, are washed away. This protocol yields highly purified H3/H4 in a few minutes without the use of chromatography steps. The acid extraction-sulfopropyl (SP)-Sepharose protocol uses acidic solution for direct extraction of histones from undisturbed cells. Following extraction, the solution is neutralized with Tris-HCl, and run through a SP column. H2A/H2B are eluted from the SP-Sepharose at 0.8 M NaCl, with H3/H4 subsequently eluted at 2 M NaCl. This procedure yields highly purified H2A/H2B and H3/H4. Finally, covalent chromatography on thiopropyl-Sepharose (TPS) allows the separation of H3 from H4, by covalently binding H3 through its unique cysteine residue to the resin; H4 is recovered in the flow-through and wash fractions, and H3 is eluted with dithiothreitol. PMID- 24162998 TI - Chromatin immunoprecipitation. AB - Chromatin plays important functions in regulating many biological processes, including DNA transcription, replication, and repair. The use of chromatin immunoprecipitation (ChIP) assays has contributed enormously to identify interactions between DNA and a wide range of nuclear proteins including histones and their different posttranslational modifications as well as a variety of transcription factors. ChIP assays have been successfully used to map histone modifications and histone variants, as well as binding of transcription factors and chromatin-modifying complexes in both, specific candidate loci and the entire genome. In this chapter, we provide a brief review of the variations in ChIP assays and a detailed explanation of the basic standard ChIP protocol. PMID- 24162999 TI - Analysis of chromatin composition of repetitive sequences: the ChIP-Chop assay. AB - Chromatin immunoprecipitation (ChIP) is a powerful method that allows to probe specific protein-DNA interactions in vivo and to estimate the occupancy of proteins at specific sites of the genome. However, the traditional ChIP assay is not able to distinguish whether repeats that share identical sequences display a different composition of associated factors and, consequently, different functions. The ChIP-chop method provides a useful application to analyze the interaction of proteins with repetitive sequences based on their CpG methylation content. The detailed ChIP-chop protocol that serves to determine the chromatin composition of active and silent ribosomal RNA (rRNA) genes, repeats that share identical sequences but display distinct functions and chromatin compositions, is reported here. PMID- 24163000 TI - Purification of specific chromatin domains from single-copy gene loci in Saccharomyces cerevisiae. AB - Most methods currently available for the analysis of chromatin in vivo rely on a priori knowledge of putative chromatin components or their posttranslational modification state. The isolation of defined native chromosomal regions provides an attractive alternative to obtain a largely unbiased molecular description of chromatin. Here, we describe a strategy combining site-specific recombination at the chromosome with an efficient tandem affinity purification protocol to isolate a single-copy gene locus from the yeast Saccharomyces cerevisiae. The method allows robust enrichment of a targeted chromatin domain, making it amenable to compositional, structural, and biochemical analyses. This technique appears to be suitable to obtain a detailed description of chromatin composition and specific posttranslational histone modification state at virtually any genomic locus in yeast. PMID- 24163001 TI - Deep sequencing of small chromatin-associated RNA: isolation and library preparation. AB - Chromatin-associated RNA (caRNA) is a newly identified class of RNA molecules stably associated with chromatin, maintaining the higher order structure of euchromatic regions in an accessible form (Schubert et al., Mol Cell, doi:10.1016/j.molcel.2012.08.021, 2012). This section provides a detailed protocol describing the isolation of small caRNA from Drosophila cells and preparation of libraries suited for stranded small (20-200 bp) RNA deep sequencing on the Illumina platform. PMID- 24163002 TI - Deep sequencing of small chromatin-associated RNA: bioinformatic analysis. AB - Chromatin-associated RNA (caRNA) is a newly identified class of RNA stably linked to chromatin and responsible for maintaining the higher order structure of euchromatic regions in an accessible form (Schubert et al., Mol Cell 48, 434 - 444, 2012). This section provides a pipeline of bioinformatic analysis for this specific type of RNA-Seq. It can be run locally by combining several scripts or be carried out on the Galaxy platform (Giardine et al., Genome Res 15:1451-1455, 2005). PMID- 24163003 TI - Coordinating chiral ionic liquids. AB - A practical synthesis of novel coordinating chiral ionic liquids with an amino alcohol structural motif was developed starting from commercially available amino alcohols. These basic chiral ionic liquids could be successfully applied as catalysts in the asymmetric alkylation of aldehydes and gave high enantioselectivities of up to 91% ee. PMID- 24163004 TI - A novel single-tailed fusiform Sulfolobus virus STSV2 infecting model Sulfolobus species. AB - A newly isolated single-tailed fusiform virus, Sulfolobus tengchongensis spindle shaped virus STSV2, from Hamazui, China, is characterised. It contains a double stranded modified DNA genome of 76,107 bp and is enveloped by a lipid membrane structure. Virions exhibit a single coat protein that forms oligomers when isolated. STSV2 is related to the single-tailed fusiform virus STSV1 and, more distantly, to the two-tailed bicaudavirus ATV. The virus can be stably cultured over long periods in laboratory strains of Sulfolobus and no evidence was found for cell lysis under different stress conditions. Therefore, it constitutes an excellent model virus for archaeal virus-host studies. PMID- 24163005 TI - The adenosine transporter, ENT1, in cardiomyocytes is sensitive to inhibition by ethanol in a kinase-dependent manner: implications for ethanol-dependent cardioprotection and nucleoside analog drug cytotoxicity. AB - The adenosine transporter 1 (ENT1) transports nucleosides, such as adenosine, and cytotoxic nucleoside analog drugs. ENT1 is well established to play a role in adenosinergic signaling in the cardiovascular system by modulating adenosine levels. Moderate ethanol consumption is cardioprotective and underlying mechanisms of action are not clear although adenosinergic signaling has been implicated. Here, we show that ethanol (5-200 mM) significantly reduces ENT1 dependent [(3)H] 2-chloroadenosine uptake (by up to 27 %) in the cardiomyocyte cell line, HL-1. Inhibition or absence of ENT1 is known to be cardioprotective, suggesting that the interaction of ethanol with ENT1 may promote adenosinergic cardioprotective pathways in the cardiovasculature.Ethanol sensitivity of adenosine uptake is altered by pharmacological activation of PKA and PKC. Primary cardiomyocytes from PKCepsilon-null mice have significantly greater sensitivity to inhibition (by approximately 37 %) of adenosine uptake by ethanol than controls. These data suggest that the presence of ethanol may compromise ENT1 dependent nucleoside analog drug cytotoxicity, and indeed, ethanol (5 mM) reduces the cytotoxic effects of gemcitabine (2 nM), an anti-cancer drug, in the human cancer cell line, HTB2. Thus, the pharmacological inhibition of ENT1 by ethanol may contribute to ethanol-dependent cardioprotection but compromise gemcitabine cytotoxicity. PMID- 24163007 TI - Carrier screening for inherited haemoglobin disorders among secondary school students and young adults in Latium, Italy. AB - To reduce the incidence of beta-thalassaemia major and other severe haemoglobin related disorders by the early identification of healthy carriers, the Centro Studi Microcitemie Roma has been organising since 1975 a prevention programme in Latium, an Italian central region. This programme entails two different types of carrier screening on a voluntary basis: a universal screening offered to secondary school students and a screening offered to young adults. In 36 years of scholastic screening (from 1975 until 2011), 1,466,100 students have been examined and 26,786 (1.8 %) carriers of non-alpha thalassaemia have been identified. In the extra-scholastic screening, 388,690 adult subjects (including the carriers' relatives) have been examined and a total of 38,457 (9.9 %) carriers of non-alpha thalassaemia have been detected. These results demonstrate that the precocious identification of healthy carriers allowed the identification of at-risk couples and reduced to zero the birth of affected babies in the Latium native population. This programme does not involve huge resources and is relatively inexpensive and, as such, it is essential to be offered to the total Latium scholastic and extra-scholastic population, which is epidemiologically changing due to migratory fluxes from countries in which haemoglobin disorders are common. PMID- 24163006 TI - Natural compounds with P2X7 receptor-modulating properties. AB - The adenosine 5'-triphosphate (ATP)-gated P2X7 receptor is a membrane-bound, non selective cation channel, expressed in a variety of cell types. The P2X7 senses high extracellular ATP concentrations and seems to be implicated in a wide range of cellular functions as well as pathophysiological processes, including immune responses and inflammation, release of gliotransmitters and cytokines, cancer cell growth or development of neurodegenerative diseases. In the present study, we identified natural compounds and analogues that can block or sensitize the ATP (1 mM)-induced Ca(2+) response using a HEK293 cell line stably expressing human P2X7 and fluorometric imaging plate reader technology. For instance, teniposide potently blocked the human P2X7 at sub-miromolar concentrations, but not human P2X4 or rat P2X2. A marked block of ATP-induced Ca(2+) entry and Yo-Pro-1 uptake was also observed in human A375 melanoma cells and mouse microglial cells, both expressing P2X7. On the other hand, agelasine (AGL) and garcinolic acid (GA) facilitated the P2X7 response to ATP in all three cell populations. GA also enhanced the YO-PRO-1 uptake, whereas AGL did not affect the ATP-stimulated intracellular accumulation of this dye. According to the pathophysiological role of P2X7 in various diseases, selective modulators may have potential for further development, e.g. as neuroprotective or antineoplastic drugs. PMID- 24163008 TI - The LH2 complexes are assembled in the cells of purple sulfur bacterium Ectothiorhodospira haloalkaliphila with inhibition of carotenoid biosynthesis. AB - The effect of the inhibitor of carotenoid (Car) biosynthesis, diphenylamine (DPA), on the cells of the purple sulfur bacterium Ectothiorhodospira (Ect.) haloalkaliphila has been studied. There occurs an inhibition of the biosynthesis of colored Cars (>=99 %) at 71 MUM DPA. Considering "empty" Car pockets (Moskalenko and Makhneva 2012) the content of Cars in the DPA-treated samples is first calculated more correctly. The total content of the colored Cars in the sample at 71 MUM DPA does not exceed 1 % of the wild type. In the DPA-treated cells (membranes) a complete set of pigment-protein complexes is retained. The LH2 complex at 71 MUM DPA is isolated, which is identical to the LH2 complex of the wild type in near IR absorption spectra. This suggests that the principles for assembling this LH2 complex in vivo in the absence of colored Cars remain the same. These results are in full agreement with the data obtained earlier for Allochromatium (Alc.) minutissimum (Moskalenko and Makhneva 2012). They are as follows: (1) DPA almost entirely inhibits the biosynthesis of the colored Cars in Ect. haloalkaliphila cells. (2) In the DPA-treated samples non-colored Cars are detected at 53.25 MUM DPA (as traces) and at 71 MUM DPA. (3) DPA may affect both phytoene synthase (at <=71 MUM DPA) and phytoene desaturase (at >=53.25 MUM DPA). (4) The assembly of LH2 complex does occur without any colored Cars. PMID- 24163009 TI - Genetic polymorphism of SMAD5 is associated with Kawasaki disease. AB - Mothers against decapentaplegic homolog (SMAD) proteins are intracellular mediators of members of the transforming growth factor-beta (TGF-beta) superfamily, which are activated by bone morphogenetic proteins (BMPs). On activation, SMAD5 forms heterometric SMAD complexes, which are translated to the nucleus where they regulate gene transcription. TGF-beta induces T cell activation and cardiovascular disease, two important features of Kawasaki disease (KD), whereas BMP is associated with coronary artery disease. In this study, we hypothesized that single nucleotide polymorphisms (SNPs) of SMAD5 may be associated with KD and coronary arterial lesions (CALs). Genotyping for 15 SNPs of the SMAD5 gene (rs3764941, rs10085013, rs6596284, rs7356756, rs13179769, rs13166063, rs1109158, rs4585442, rs4146185, rs12719481, rs6865297, rs3206634, rs6871224, rs1057898, and rs7031) was performed by direct sequencing of 105 KD patients and 303 healthy adult controls. We also compared the allele frequencies between a CAL group (n = 31) and a normal coronary group (n = 74). Results showed that among the 15 SNPs, rs3206634 was significantly associated with KD in a recessive model (odds ratio = 2.31, p = 0.019), whereas there was no association between any of the 15 SNPs and CALs. These findings may be used as a risk factors development of KD or for future generations of therapeutic treatments for KD. PMID- 24163010 TI - Serum hyaluronic acid concentration in Fontan circulation: correlation with hepatic function and portal vein hemodynamics. AB - Although liver fibrosis causes significant morbidity in the late postoperative period of the Fontan procedure, the diagnostic value of hyaluronic acid (HA), a serum marker of liver fibrosis, has not been established in Fontan patients. The purpose of this study was to determine whether increased serum HA concentration in Fontan patients is associated with an increase in inspiratory-to-expiratory flow rate ratio (Qin/Qex) of the portal vein (PV), which is indicative of liver fibrosis. We retrospectively studied 28 consecutive patients with Fontan circulation who underwent cardiac catheterisation for various indications. The median age at examination was 5.5 years (range 2.2-5.6). The median HA concentration was 17.7 ng mL(-1) (range 10.0-82.1), which was used to divide our 28 patients into two groups. Patients in the high-HA group had significantly greater Qin/Qex of the PV than those in the low-HA group (1.25 +/- 0.12 vs. 1.12 +/- 0.11, p < 0.05). Platelet counts were significantly lower in the high-HA group (216 +/- 74 vs. 294 +/- 104 * 10(9) L(-1), p < 0.05). No significant difference was found in inferior vena caval pressure. In conclusion, increase of HA concentration in Fontan patients accompanies the change in PV hemodynamics peculiar to liver cirrhosis and might be an early indicator of liver fibrosis. PMID- 24163011 TI - Pediatric pulmonary arterial hypertension. AB - Pulmonary arterial hypertension (PAH) can cause morbidity and mortality in children. Although adult and pediatric PAH share many similarities, many differences have been found in children. Thus, a new classification for pediatric pulmonary hypertensive vascular disease has been proposed. Both child and adult gene mutation carriers with PAH tend to have worse prognoses. Pediatric patients present with better preserved functional class, and parents should pay high attention to any children with unexplained shortness of breath, fatigue or syncope, as symptoms of PAH in children are often misleading. Right heart catheterization is necessary for diagnosis. Although there are few medications approved for pediatric PAH and evidence-based treatment algorithms for children are still lacking, the survival of pediatric patients has been improved significantly since targeted therapies approved for adults were introduced to pediatric patients. PAH in children is unique, and further studies are needed to have a better understanding of it. PMID- 24163012 TI - Ethics and policy of medical brain drain: a review. AB - Health-worker migration, commonly called "medical brain drain", refers to the mass migration of trained and skilled health professionals (doctors, nurses, midwives) from low-income to high-income countries. This is currently leaving a significant number of poor countries, particularly in sub-Saharan Africa, with critical staff shortages in the healthcare sector. A broad consensus exists that, where medical brain drain exacerbates such shortages, it is unethical, and this review presents the main arguments underpinning this view. Notwithstanding the general agreement, which policies are justifiable on ethical grounds to tackle brain drain and how best to go about implementing them remains controversial. The review offers a discussion of the specific ethical issues that have to be taken into account when deciding which policy measures to prioritise and suggests a strategy of policy implementation to address medical brain drain as a matter of urgency. PMID- 24163014 TI - The final unadorned tris(azolyl)borate: finishing what Trofimenko started in 1966. AB - The final addition to the tris(azolyl)borate ligand family, tris(1,2,3 triazolyl)borate, has been synthesized. The sodium salt of the ligand forms a complex polymeric structure where both N2 and N3 bind to crystallographically independent sodium ions. Depending on the divalent transition metal, tris(1,2,3 triazolyl)borate forms either molecular homoleptic complexes or coordination polymers. PMID- 24163013 TI - Protrusion of the tongue in burned bodies as a vital sign? PMID- 24163015 TI - Structure and spectral characteristics of diquat-cucurbituril complexes from density functional theory. AB - Electronic structure, (1)H NMR and infrared spectra of diquat (6,7 dihydrodipyrido[1,2-b:1',2'-e] pyrazine-5,8-diium or DQ(2+)) encapsulated by cucurbit[n]uril (n = 7,8) hosts are obtained using the density functional theory. Theoretical calculations have shown that both CB[7] or CB[8] host possesses strong affinity toward DQ(2+) compared to its reduced cation or neutral species. Calculated (1)H NMR spectra reveal that Halpha protons on bi-pyridinium rings of DQ(2+)@CB[8] complex are de-shielded owing to C=O?H interactions. On the other hand aromatic (Hbeta and Hdelta) of DQ(2+) within the CB[8] cavity exhibit significant shielding. The complexation of CB[8] with DQ(2+) splits the carbonyl stretching vibration (1788 cm(-1)) into two distinct vibrations which correspond to 1765 cm(-1) arising from hydrogen bonded carbonyls and the 1792 cm(-1) band from non-interacting ones. Further, the CN stretching vibration in DQ(2+) exhibits a frequency blue-shift of 6 cm(-1) on its encapsulation within the CB[8] cavity. The direction of frequency shift has been explained on the basis of natural bond orbital analyses. PMID- 24163016 TI - Making better doctors: a survey of premedical interns working as health coaches. AB - We operate a decision support program in a medical center in San Francisco. In this program, postbaccalaureate, premedical interns deliver decision and communication, aids to patients. We asked whether working in this program helped these premedical interns develop key physician competencies. To measure physician competencies, we adopted the standards of the Accreditation Committee on Graduate Medical Education (ACGME), which accredits residency programs in the USA. The ACGME competencies are patient care, medical knowledge, practice-based learning, interpersonal and communication skills, professionalism, and systems-based practice. We developed a survey for our program alumni to rate themselves on a scale from 0 (none) to 100 (perfect) on each competency, before and after their time in our program. The survey also solicited free-text comments regarding each competency. In June 2012, we e-mailed all 47 alumni a link to our online survey and then analyzed responses received by July 15, 2012. We visually explored the distributions of ratings and compared medians. We selected the most specific and concrete comments from the qualitative responses. Respondents (21/47 or 45%) reported that their participation in Decision Services increased their competencies across the board. Qualitative comments suggest that this is because students accompanied patients on their clinic journeys (seeing multiple facets of the systems of care) while also actively facilitating patient physician communication. Providing decision support can improve self-ratings of crucial physician competencies. Educators should consider deploying premedical and medical students as decision support coaches to increase competencies through experiential learning. PMID- 24163017 TI - Ethnic differences in breast cancer prevention information-seeking among rural women: will provider mobile messages work? AB - Although growing research supports cancer survivor information-seeking, little is known about breast cancer prevention information-seeking among women. The purpose of the study was to examine differences in breast cancer risk factor knowledge, information sources, and desired mobile messages among Hispanic and non-Hispanic rural women. Women were recruited to complete a survey at an imaging center during a mammography screening visit. A total of 156 women (mean age = 61, SD = 12.07) completed the survey. Breast cancer risk factor knowledge was significantly higher for non-Hispanic women compared to Hispanic women (p = .035). Television, magazines, and Internet were the most frequent information sources. Providers were the most frequent interpersonal information source. Nearly 87 % used cell phones and 47 % used texting. Hispanic women were more likely to desire breast cancer prevention cell voice messages (p < .001) and text messages (p = .001) compared to non-Hispanic women. No significant differences were found for text appointment reminders by ethnicity. Health educators and clinicians must promote mobile messages for Hispanics and non-Hispanics for mammography adherence, breast cancer prevention education, and best practices to manage screening appointments. PMID- 24163018 TI - Asymmetric Mannich reactions of imidazo[2,1-b]thiazole-derived nucleophiles with (S(S))-N-tert-butanesulfinyl (3,3,3)-trifluoroacetaldimine. AB - Asymmetric Mannich reactions of imidazo[2,1-b]thiazole-derived nucleophiles with (SS)-N-tert-butanesulfinyl (3,3,3)-trifluoroacetaldimine were found to proceed with reasonably good yields (55%-79%) and exceptionally high stereoselectivity (>99 : 1 dr). This method presents a general approach for the preparation of a new type of biologically relevant compounds containing pharmacophoric imidazo[2,1 b]thiazole and (trifluoro)ethylamine groups. PMID- 24163019 TI - Radiosynthesis of [124I]iodometomidate and biological evaluation using small animal PET. AB - PURPOSE: The application of radiolabelled inhibitors of cytochrome P450 enzymes is a novel approach for molecular imaging of adrenocortical masses to detect adrenal tumours. One potential tracer is radiolabelled iodometomidate (IMTO) with a common option for scintigraphic diagnosis and therapeutic applications. The aim of this study was to radiolabel iodometomidate with the positron-emitting radionuclide iodine-124 ((124)I) for the investigation of the biological behaviour and pharmacokinetics with positron emission tomography (PET). PROCEDURES: [(124)I]IMTO has been synthesized by oxidative radioiodo destannylation, purified via semi-preparative HPLC and formulated in acetate buffered saline, which contained ascorbic acid and ethanol to avoid radiolytic decomposition. Biological evaluation was performed in rats which received 5.5 +/- 0.7 MBq [(124)I]IMTO in vivo. The radioactivity distribution (n = 3) has been dynamically imaged from 0-120 min after intravenous (i.v.) injection by small animal PET. Regions of interest have been defined manually in the reconstructed PET images, and the activity concentration was expressed as percent injected dose per gram tissue (%ID/g). RESULTS: [(124)I]IMTO was prepared with a radiochemical yield of 83 +/- 5 % (n = 3) and a radiochemical purity of >97 %. The final formulation of [(124)I]IMTO was stable for up to 48 h at room temperature. Two hours after i.v. administration in rats, radioactivity concentration in the adrenal glands were 2.1 +/- 0.3 %ID/g, which was sufficient to achieve highest contrast adrenal PET images. CONCLUSIONS: In the present study, the biological characteristics of radioiodinated metomidate were evaluated. [(124)I]IMTO appears as an attractive PET tracer for imaging of adrenals. PMID- 24163020 TI - Validation of fluorescence molecular tomography/micro-CT multimodal imaging in vivo in rats. AB - PURPOSE: Rats are important preclinical models for studying breast cancer metastasis and bone pathologies. In these research areas, fluorescence molecular tomography (FMT) is commonly applied for quantitative three-dimensional (3D) imaging in mice. However, uncertainties due to strong depth dependency of FMT signal and spatial resolution require a validation study in rats. PROCEDURE: FMT performance in rats was assessed based on co-registered FMT/micro-computed tomography (micro-CT) reconstructed volumes obtained from optical phantoms and from models relevant for tumor imaging, bone remodeling and biodistribution analysis of nanoparticles. RESULTS: FMT reconstructions within 20-mm-thick optical phantoms were accurate (95 +/- 11 % recovery), precise (CV <= 8 %) and linear (R(2) > 0.9788) over a range of 78-2,500 nM of the near infrared fluorescent agent VivoTag 750 (VT(750)). In vivo, implanted defined fluorescent targets yielded a recovery of 105 +/- 5 % and successfully co-registered with micro-CT delineated structures. Additionally, using the bone-targeting imaging agent Osteosense 750, regions of neo bone formation identified by FMT could be mapped to the region of epiphyseal growth plates observed in micro-CT images. Finally, as a proof of concept, to monitor nanoparticulate drug pharmacokinetics in rat subjects the accumulation/clearance of VT(750)-albumin conjugate in/from the liver was followed at 11 different time points over a period of 2 weeks by FMT/micro-CT. CONCLUSIONS: FMT imaging has been validated in optical phantoms as well as in 160 g rats, and sequential FMT/micro-CT imaging can be considered as a useful tool for preclinical research in rats. PMID- 24163021 TI - Artemisinin-based combination therapy for treating uncomplicated Plasmodium vivax malaria. AB - BACKGROUND: Plasmodium vivax is an important cause of malaria in many parts of Asia and South America, and parasite resistance to the standard treatment (chloroquine) is now high in some parts of Oceania. This review aims to assess the current treatment options in the light of increasing chloroquine resistance. OBJECTIVES: To compare artemisinin-based combination therapies (ACTs) with alternative antimalarial regimens for treating acute uncomplicated P. vivax malaria. SEARCH METHODS: We searched the Cochrane Infectious Disease Group Specialized Register; the Cochrane Central Register of Controlled Trials (CENTRAL); MEDLINE; EMBASE; LILACS; and the metaRegister of Controlled Trials (mRCT) up to 28 March 2013 using "vivax" and "arte* OR dihydroarte*" as search terms. SELECTION CRITERIA: Randomized controlled trials comparing ACTs versus standard therapy, or comparing alternative ACTs, in adults and children with uncomplicated P. vivax malaria. DATA COLLECTION AND ANALYSIS: Two authors independently assessed trials for eligibility and risk of bias, and extracted data. We used recurrent parasitaemia prior to day 28 as a proxy for effective treatment of the blood stage parasite, and compared drug treatments using risk ratios (RR) and 95% confidence intervals (CIs). We used trials following patients for longer than 28 days to assess the duration of the post-treatment prophylactic effect of ACTs. We assessed the quality of the evidence using the GRADE approach. MAIN RESULTS: We included 14 trials, that enrolled 2592 participants, and were all conducted in Asia and Oceania between 2002 and 2011. ACTs versus chloroquine: ACTs clear parasites from the peripheral blood quicker than chloroquine monotherapy (parasitaemia after 24 hours of treatment: RR 0.42, 95% CI 0.36 to 0.50, four trials, 1652 participants, high quality evidence).In settings where chloroquine remains effective, ACTs are as effective as chloroquine at preventing recurrent parasitaemias before day 28 (RR 0.58, 95% CI 0.18 to 1.90, five trials, 1622 participants, high quality evidence). In four of these trials, recurrent parasitaemias before day 28 were very low following treatment with both chloroquine and ACTs. The fifth trial, from Thailand in 2011, found increased recurrent parasitaemias following treatment with chloroquine (9%), while they remained low following ACT (2%) (RR 0.25, 95% CI 0.09 to 0.66, one trial, 437 participants).ACT combinations with long half-lives probably also provide a longer prophylactic effect after treatment, with significantly fewer recurrent parasitaemias between day 28 and day 42 or day 63 (RR 0.57, 95% CI 0.40 to 0.82, three trials, 1066 participants, moderate quality evidence). One trial, from Cambodia, Thailand, India and Indonesia, gave additional primaquine to both treatment groups to reduce the risk of spontaneous relapses. Recurrent parasitaemias after day 28 were lower than seen in the trials that did not give primaquine, but the ACT still appeared to have an advantage (RR 0.27, 95% CI 0.08 to 0.94, one trial, 376 participants, low quality evidence). ACTs versus alternative ACTs: In high transmission settings, dihydroartemisinin-piperaquine is probably superior to artemether-lumefantrine, artesunate plus sulphadoxine pyrimethamine and artesunate plus amodiaquine at preventing recurrent parasitaemias before day 28 (RR 0.20, 95% CI 0.08 to 0.49, three trials, 334 participants, moderate quality evidence).Dihydroartemisinin-piperaquine may also have an improved post-treatment prophylactic effect lasting for up to six weeks, and this effect may be present even when primaquine is also given to achieve radical cure (RR 0.21, 95% CI 0.10 to 0.46, two trials, 179 participants, low quality evidence).The data available from low transmission settings is too limited to reliably assess the relative effectiveness of ACTs. AUTHORS' CONCLUSIONS: ACTs appear at least equivalent to chloroquine at effectively treating the blood stage of P. vivax infection. Even in areas where chloroquine remains effective, this finding may allow for simplified protocols for treating all forms of malaria with ACTs. In areas where chloroquine no longer cures the infection, ACTs offer an effective alternative.Dihydroartemisinin-piperaquine is the most studied ACT. It may provide a longer period of post-treatment prophylaxis than artemether-lumefantrine or artesunate plus amodiaquine. This effect may be clinically important in high transmission settings whether primaquine is also given or not. PMID- 24163022 TI - Advances in Infectious Encephalitis: Etiologies, Outcomes, and Potential Links with Anti-NMDAR Encephalitis. AB - Encephalitis results in substantial morbidity and mortality and is a challenging syndrome for clinicians to manage. The clinical presentation is heterogeneous, there is a broad range of causative agents, and specific treatments for many etiologies are lacking. Over the past decade, a number of novel infectious and autoimmune etiologies of encephalitis have been identified. Despite such advances, however, up to 50 % of encephalitis cases typically remain without an identified etiology. Moreover, few new vaccines and therapies have been developed. Here, we discuss recent advances in encephalitis, with specific focus on several areas: (1) the changing demographics of West Nile virus in the United States and the implications for vaccine development, (2) challenges in the diagnosis of herpesviral infections in immunocompromised individuals, (3) the identification of a potential link between herpes simplex encephalitis and anti NMDA receptor encephalitis, and (4) the delineation of prognostic factors related to outcome in individuals with encephalitis. PMID- 24163023 TI - Special issue dedication: David Ian Gibson. PMID- 24163024 TI - Pseudangularia gonzalezi n. sp. and Gibsonilepis swifti (Singh, 1952) n. g., n. comb. (Cestoda, Dilepididae) from the House Swift, Apus affinis (J.E. Gray) (Aves, Apodiformes) from Franceville, Republic of Gabon. AB - Nine specimens of Apus affinis (J.E. Gray) were studied at Franceville, Haut Ogooue Province, Republic of Gabon, for the presence of helminth parasites. Two cestode species of the family Dilepididae were recorded. Pseudangularia gonzalezi n. sp. is distinguished from the most similar species P. europaea Georgiev & Murai, 1993 by having elliptical cirrus-sac, longer vagina, longer rostellar sheath and greater diameter of suckers. An identification key to the species of the genus Pseudangularia Burt, 1938 is proposed. The present study is the first record of the genus Pseudangularia in the Afrotropical Region. Our study confirms that, in dilepidids with vaginal sclerites from swifts, breaking off the cirrus after copulation is a frequent phenomenon. The genus Gibsonilepis n. g. is erected as monotypic for Vitta swifti Singh, 1952 (originally described from the same host species in India) and Gibsonilepis swifti n. comb. is proposed. Gibsonilepis n. g. is distinguished from Vitta Burt, 1938 by its highly elongate rostellum, rostellar sheath much bigger than rostellum, relatively small rostellar hooks possessing strongly developed guard, disc-shaped suckers with weak peripheral musculature and flat or convex central part, long and well expressed neck, highly lobed two-winged ovary (lobes rounded) and presence of a band consisting of rows of spine-like microtriches along posterior margin of each proglottis. This is the first record of G. swifti in the Afrotropical Region. The separation of G. swifti from the genus Vitta (parasites of swallows) suggests that, contrary to previous opinions, no dilepidid genera are shared by Apodidae (swifts) and Hirundinidae (swallows). PMID- 24163025 TI - Synopsis of the species of Thelohanellus Kudo, 1933 (Myxozoa: Myxosporea: Bivalvulida). AB - A synopsis of the species of Thelohanellus Kudo, 1933 (Myxozoa: Myxosporea: Myxobolidae) is presented. It includes a total of 108 nominal species. For each species, the most relevant morphological and morphometric characteristics are provided, together with data on the type-host and locality, the site of infection within the host and the original references. PMID- 24163026 TI - Two new species of Chrysomelobia Regenfuss, 1968 (Acariformes: Podapolipidae) from Paropsis charybdis Stal (Coleoptera: Chrysomelidae). AB - Two new species of Chrysomelobia Regenfuss, 1968, C. alleni n. sp. and C. intrusus n. sp., are described from Tasmanian specimens of the eucalyptus leaf beetle Paropsis charybdis Stal. This beetle is now known to host three species of Chrysomelobia, the other being Chrysomelobia pagurus Seeman, 2008, which is recorded from Tasmania for the first time. Thus, the three species of Paropsis Olivier known to have podapolipid mites each have three mite species from three separate lineages of Chrysomelobia. Collections of P. charybdis in New Zealand (n = 150), where it is an invasive pest species, failed to locate any infested beetles, suggesting that these populations were established by uninfested beetles. The prospect of using these mites as biocontrol agents is discussed. PMID- 24163027 TI - Two new species of mazocraeid monogeneans from Clupanodon punctatus (Temminck & Schlegel) (Clupeiformes: Clupeidae) found in Daya Bay, South China Sea, with the proposal of Chelimazocraes n. g. AB - Chelimazocraes liaoi n. g., n. sp. and Chelimazocraes ascidiformis n. sp. (Monogenea: Mazocraeidae) are described from the gills of Clupanodon punctatus (Temminck & Schlegel) in Daya Bay (South China Sea). The new genus is characterised by the following features: (i) the haptor is distinctly separated from the body proper, and the arrangement of the clamps is bilaterally symmetrical but longitudinally heteromorphic; (ii) the anterior three pairs of clamps are of the mazocraeid-type, whereas the fourth pair is of a non-mazocraeid type with three sclerites; (iii) all three pairs of clamps are similar in shape but their size gradually becomes smaller from the anterior to the posterior; (iv) the inner spines of the copulatory organ have a similar shape; and (v) the testes are numerous and arranged longitudinally posterior to the ovary. The two new species are easily distinguished from other members of the Mazocraeidae by the unique structure of the fourth pair of clamps; however, there are some noticeable differences between the two species. The major differences are as follows: (i) the body of C. liaoi n. sp. is significantly larger than that of C. ascidiformis n. sp.; (ii) the anterior three pairs of clamps consist of different sclerites in the two species; and (iii) the copulatory organ has one pair of outer spines and 15-16 pieces of inner spines in C. liaoi n. sp. (vs two pairs of outer spines and 22-26 pieces of inner spines in C. ascidiformis n. sp.). PMID- 24163028 TI - Gyrodactylus laevisoides n. sp. (Monogenea: Gyrodactylidae) infecting northern redbelly dace Phoxinus eos Cope (Cyprinidae) from Nova Scotia, Canada. AB - Gyrodactylus laevisoides n. sp. is described from the gill rakers of red belly dace, Phoxinus eos Cope (Cyprinidae), from Nova Scotia, Canada. Gyrodactylus laevisoides n. sp. is the second species of Gyrodactylus Nordmann, 1832 described from this host and is characterised by weakly curving hamuli, a small ventral bar lacking anterolateral processes, stout dorsal bar, small marginal hooks with sickles larger proximally than distally and having a small circular process on the heel, a MCO with spines arranged in two arched rows, and lack of obvious excretory bladders. The new species most closely resembles Gyrodactylus laevis Malmberg, 1957, a Eurasian species whose principle host is Phoxinus phoxinus (L.). The two species are separated by Gyrodactylus laevisoides n. sp. having less divergent and longer hamulus root and marginal hook sickle toe with a steeper continuous angle and heel that is less prominent. The morphological description is supplemented with sequences of the 18S gene (449 bp, including the V4 region) and of the ITS region (821 bp). Gyrodactylus sedelnikowi Gvosdev, 1950 infecting Barbatula barbatula (L.) and Gyrodactylus neili Leblanc, Hansen, Burt & Cone, 2006 infecting Esox niger Lesueur are the most genetically similar species on GenBank for the 18S rRNA gene and ITS regions respectively (c.96% and c.92%). Gyrodactylus laevisoides n. sp. belongs to Malmberg's subgenus Gyrodactylus (Gyrodactylus) and phylogenetic analysis of the ITS region groups this species with other members of the subgenus. The phylogeny has two main clades, one comprised of Eurasian species and the other of North American species, specifically Gyrodactylus laevisoides n. sp. and Gyrodactylus neili. It is suspected that this lineage, which is seemingly underrepresented in North America, likely colonised the new world with an ancestral species of Phoxinus via the Bering land connection around the time of the Pliocene. PMID- 24163029 TI - Description of Goussia kuehae n. sp. (Apicomplexa: Eimeriidae) infecting the Asian seabass, Lates calcarifer (Bloch) (Perciformes: Latidae), cultured in Malaysian fish farms. AB - Culturing fishes in marine cages is a rapidly developing area of marine aquaculture. The Asian seabass Lates calcarifer (Bloch) is a fast growing good quality fish that is readily cultured in intensive systems in the South Asian region and in Malaysia in particular. Although several papers have been published to date on viral, bacterial, parasitic and fungal organisms causing diseases in the Asian seabass, the occurrence of a coccidian infection in this species has only recently been recorded. We collected sporulated and unsporulated oocysts of a new species of Goussia Labbe, 1986, from the mucus covering the epithelium of the intestine of L. calcarifer. This paper provides a description of Goussia kuehae n. sp. Sporulated oocysts of this species are ellipsoidal, 37-40 MUm in length and 28-30 MUm in width. The ellipsoidal sporocysts are relatively small, 15.2-17 * 5.7-8 MUm, and located loosely in the oocyst. There are residual bodies both in the oocysts and the sporocysts. Goussia kuehae n. sp. differs from all known species of Goussia in the large size of the oocysts and in having two types of oocyst residuum. PMID- 24163030 TI - Parasitic copepods from two species of commercial fishes collected off Iraq, with description of Hatschekia shari n. sp. AB - Two species of parasitic copepods, including one new species, are described based on specimens collected from off Basrah, Iraq (Arabian Gulf). Hatschekia shari n. sp. (Siphonostomatoida: Hatschekiidae) was found from the gill filaments of the spangled emperor Lethrinus nebulosus (Forsskal) (Perciformes: Lethrinidae). The new species is characterised by the following characters in the female: a rectangular cephalothorax with dorsal frame composed of two short and one long bifid longitudinal bars, connecting to one short and one long latitudinal bars; elongate, cylindrical trunk without posterolateral processes or lobes; absence of parabasal papillae; and antennae bearing middle segments without narrow median part and with terminal claws without basal conical processes. Bactrochondria formosana Ho, Lin & Liu, 2011 (Cyclopoida: Chondracanthidae) was found on the gill filaments of the largescale tonguesole Cynoglossus arel (Bloch & Schneider) (Pleuronectiformes: Cynoglossidae). Close comparison of the specimens of B. formosana collected from off Iraq with the original description revealed some differences in elements and ornamentations on the body and appendages. Our finding of B. formosana represents not only a new record from the Indian Ocean but also from a new host. PMID- 24163031 TI - [Jewish physicians' licenses revoked 75 years ago by the Nazi legislature]. PMID- 24163033 TI - Commercial herds likely to be needed for TB vaccine field trial. PMID- 24163036 TI - More vigilance needed for variant swine influenza virus. PMID- 24163039 TI - Welsh Government fast tracks legislation on fly grazing. PMID- 24163040 TI - Call for more veterinary involvement in badger vaccination projects. PMID- 24163043 TI - Taking a history on veterinary education. AB - In this article, another in the series marking 125 years of Veterinary Record, Andrew Gardiner and Susan Rhind consider some common themes in the history of veterinary education. They look at how veterinary teaching and education have evolved over time and discuss what may happen in years to come. PMID- 24163044 TI - Which journal should I submit to? PMID- 24163045 TI - Graduate employment survey: going behind the figures. AB - The preliminary results of a recent RCVS/IES survey have raised concerns about the employment of new graduates. But are these concerns justified? asks Peter Brown. PMID- 24163047 TI - Veterinary representation on the animals in science committee. PMID- 24163046 TI - Chicken astrovirus detected in hatchability problems associated with 'white chicks'. PMID- 24163048 TI - Costs of current antihypertensive therapy in Switzerland: an economic evaluation of 3,489 patients in primary care. AB - QUESTION UNDER STUDY: Due to greater life expectancy, costs of medication have increased within the last decade. This investigation assesses health care expenditures needed to manage the current state of blood pressure (BP) control in Switzerland. OBJECTIVES: a) average day therapy costs (DTC) of substances, b) actual DTC of currently prescribed antihypertensive therapy, c) monetary differences of treatment regimens within different BP-groups and different high risk patients, d) estimated compliance-related financial loss/annum and adjusted costs/annum. Single-pill-combinations appear to be useful to increase patient's compliance, to reduce side effects and to bring more patients to their blood pressure goal. METHODS: Costs were identified based on data from the Swiss department of health. We calculated DTC for each patient using prices of the largest available tablet box. RESULTS: The average antihypertensive therapy in Switzerland currently costs CHF 1.198 +/- 0.732 per day. On average beta blockers were the cheapest substances, followed by angiotensin converting enzyme inhibitors (ARBs), calcium channel blockers and diuretics. The widest price ranges were observed within the class of ARBs. Most expensive were patients with impaired renal function. Throughout all stages, single-pill-combinations appeared to be significantly cheaper than dual-free-combinations. Stage-II-hypertension yielded the highest costs for dual free combination drug use. The actual costs for all patients observed in this analysis added up to CHF 1,525,962. Based on a compliance model, only treatment amounting to CHF 921,353 is expected to be actually taken. CONCLUSION: A disproportionately high healthcare cost is expected due to compliance reasons. The prescription of mono-therapies appears to be a major cost factor, thus, the use of single-pill-combination therapy can be considered as a suitable approach to saving costs throughout all BP- stages. PMID- 24163050 TI - Patient enrollment onto clinical trials: the role of physician knowledge. AB - Sixty-six attending physicians at academic medical centers completed a 43 question self-assessment evaluating communication skills, comfort with clinical trial enrollment, and knowledge of patient-related barriers to enrollment on clinical trials. Responses and demographic information were analyzed for trends and for association with estimated trial enrollment. Physician-described enrollment of patients onto trials varied widely, with estimated enrollment varying from less than 5 patients to well over 125 enrolled during the previous year. Participants perceived themselves to have excellent communication skills and were comfortable with the trial enrollment process, though did not consistently identify patient-related barriers to enrollment. Physician knowledge of clinical trials currently enrolling within their field was associated with increased patient enrollment on study (p = 0.03). Academic physicians expressed confidence in their skills related to clinical trial enrollment despite less than ideal reported enrollment. Knowledge of clinical trials currently enrolling within a physician's specialty was associated with estimated patient enrollment, and may represent a correctable barrier to trial enrollment. PMID- 24163051 TI - Antibiotics for preventing meningococcal infections. AB - BACKGROUND: Meningococcal disease is a contagious bacterial infection caused by Neisseria meningitidis (N. meningitidis). Household contacts have the highest risk of contracting the disease during the first week of a case being detected. Prophylaxis is considered for close contacts of people with a meningococcal infection and populations with known high carriage rates. OBJECTIVES: To study the effectiveness, adverse events and development of drug resistance of different antibiotics as prophylactic treatment regimens for meningococcal infection. SEARCH METHODS: We searched CENTRAL 2013, Issue 6, MEDLINE (January 1966 to June week 1, 2013), EMBASE (1980 to June 2013) and LILACS (1982 to June 2013). SELECTION CRITERIA: Randomised controlled trials (RCTs) or quasi-RCTs addressing the effectiveness of different antibiotics for: (a) prophylaxis against meningococcal disease; (b) eradication of N. meningitidis. DATA COLLECTION AND ANALYSIS: Two review authors independently appraised the quality and extracted data from the included trials. We analysed dichotomous data by calculating the risk ratio (RR) and 95% confidence interval (CI) for each trial. MAIN RESULTS: No new trials were found for inclusion in this update. We included 24 studies; 19 including 2531 randomised participants and five including 4354 cluster-randomised participants. There were no cases of meningococcal disease during follow-up in the trials, thus effectiveness regarding prevention of future disease cannot be directly assessed.Mortality that was reported in one study was not related to meningococcal disease or treatment. Ciprofloxacin (RR 0.04; 95% CI 0.01 to 0.12), rifampin (rifampicin) (RR 0.17; 95% CI 0.13 to 0.24), minocycline (RR 0.28; 95% CI 0.21 to 0.37) and penicillin (RR 0.47; 95% CI 0.24 to 0.94) proved effective at eradicating N. meningitidis one week after treatment when compared with placebo. Rifampin (RR 0.20; 95% CI 0.14 to 0.29), ciprofloxacin (RR 0.03; 95% CI 0.00 to 0.42) and penicillin (RR 0.63; 95% CI 0.51 to 0.79) still proved effective at one to two weeks. Rifampin was effective compared to placebo up to four weeks after treatment but resistant isolates were seen following prophylactic treatment. No trials evaluated ceftriaxone against placebo but rifampin was less effective than ceftriaxone after one to two weeks of follow-up (RR 5.93; 95% CI 1.22 to 28.68). Mild adverse events associated with treatment were observed. AUTHORS' CONCLUSIONS: Using rifampin during an outbreak may lead to the circulation of resistant isolates. Use of ciprofloxacin, ceftriaxone or penicillin should be considered. All four agents were effective for up to two weeks follow-up, though more trials comparing the effectiveness of these agents for eradicating N. meningitidis would provide important insights. PMID- 24163049 TI - The rs1333049 polymorphism on locus 9p21.3 and extreme longevity in Spanish and Japanese cohorts. AB - The rs1333049 (G/C) polymorphism located on chromosome 9p21.3 is a candidate to influence extreme longevity owing to its association with age-related diseases, notably coronary artery disease (CAD). We compared allele/genotype distributions of rs1333049 in cases (centenarians) and controls (younger adults, without (healthy) or with CAD) in two independent cohorts: Spanish (centenarians: n = 152, 128 women, 100-111 years; healthy controls: n = 343, 212 women, age <50 years; CAD controls: n = 98, 32 women, age <=65 years) and Japanese (centenarians: n = 742, 623 women, 100-115 years; healthy controls: n = 920, 511 women, < 60 years; CAD controls: n = 395, 45 women, age <=65 years). The frequency of the "risk" C-allele tended to be lower in Spanish centenarians (47.0 %) than in their healthy (52.9 %, P = 0.088) or CAD controls (55.1 %, P = 0.078), and significant differences were found in genotype distributions (P = 0.034 and P = 0.045), with a higher frequency of the GG genotype in cases than in both healthy and CAD controls as well as a lower proportion of the CG genotype compared with healthy controls. In the Japanese cohort, the main finding was that the frequency of the C-allele did not differ between centenarians (46.4 %) and healthy controls (47.3 %, P = 0.602), but it was significantly lower in the former than in CAD controls (57.2 %, P < 0.001). Although more research is needed, the present and recent pioneer findings (Rejuvenation Res 13:23-26, 2010) suggest that the rs1333049 polymorphism could be among the genetic contributors to exceptional longevity in Southern European populations, albeit this association does not exist in the healthy (CAD-free) Japanese population. PMID- 24163053 TI - New paradigms in thrombosis: novel mediators and biomarkers platelet RNA transfer. AB - Platelets, anucleated cells with a central role in hemostasis and inflammation, contain messenger RNAs and microRNAs of unknown functionality and clinical relevance. Historically, platelet RNA was viewed as merely a remnant of platelet biogenesis; however, several studies now refute this assumption. Studies have shown that platelets can actively translate RNA to protein and that specific RNA profiles correlate with select human clinical phenotypes. These studies support a more fluid role for platelet RNA in platelet function and disease development. Our lab and others have recently studied the platelet's unique ability to transfer RNA to recipient cells and the effect this transfer has on the recipient cells' functions. This transfer may represent a previously unknown form of vascular cell communication and modulation. Unlike the well-characterized thrombotic properties of platelets, the nature and purpose of platelet RNA transfer has not been determined, partly due to limitations in techniques used to manipulate platelet RNA profiles. Defining the mechanism of RNA transfer and its role in the vascular system will allow for the better understanding of how platelets function in both their traditional thrombotic role and non-traditional functions, potentially having widespread implications in several fields. PMID- 24163052 TI - Headaches related to rheumatologic disease. AB - Headaches are a common, but under-recognized and understudied symptom in the context of the rheumatic diseases. They can result from intracranial pathology, such as parenchymal and meningeal inflammation, thrombosis, space-occupying lesions, and more. Inflammation, irritation, or degeneration of anatomically related structures such as the eyes, neck, and sinuses can equally cause headaches. In addition, patients with rheumatologic disorders have the same tendencies as the general population to develop primary headaches. While the latter are benign in nature, and generally require only symptomatic relief, the former type of headaches may signal disease manifestation, progression, or complication. Thus, familiarity with common and uncommon headache syndromes related to rheumatologic disorders as well as with their possible underlying disease processes and mechanisms is important. This will help to successfully develop an effective approach toward the evaluation of patients presenting with headaches in a rheumatologic context, and, ultimately, diagnose and treat potentially severe underlying disease. PMID- 24163054 TI - A novel hollow and perforated flexible wire allows the safe and effective local application of thrombolytic therapy in a mouse model of deep vein thrombosis. AB - We tested the feasibility of local thrombolytic therapy via a novel hollow flexible and perforated wire in a mouse model of deep vein thrombosis. Inferior vena cava (IVC) thrombosis was induced by vessel wall exposure to ferric chloride after laparotomy in anesthetized C57Bl/6 mice. Thrombus formation was visualized by intravital microscopy of rhodamine-labeled platelets and leukocytes. A nitinol hypotube coronary wire with perforated tip was inserted via a 0.8 * 40 mm canula into the IVC lumen distal to the site of ferric chloride exposure. Either tissue plasminogen activator (tPA, alteplase) or saline (control) was administered via the platinum wire distal to the thrombus, avoiding mechanical fragmentation. Thrombus size was assessed by immunohistochemistry (platelet CD41 staining). Intravital microscopy of the IVC demonstrated platelet-containing thrombus growth starting 1 min after ferric chloride exposure. Alteplase administration resulted in significant thrombus size reduction within 10-20 min observed by intravital microscopy and confirmed by histological assessment of IVC cross-sections. Saline treated mice (n = 4) demonstrated near total IVC occlusion with thrombotic material (84 +/- 8% of cross-sectional area in serial sections), whereas alteplase-treated mice showed a dose-dependent decrease of thrombotic area [56 +/ 5% with 1.5, 39 +/- 4 % with 15 and 21 +/- 6% with 150 mg/kg, respectively (n = 4)]. We demonstrate that a flexible hollow and perforated wire enables the successful application of thrombolytic therapy to IVC thrombi in mice without vessel wall perforation. Flexible wire-based thrombolytic therapy appears to be a safe and reliable method for thrombus dissolution even in fragile small veins and may become a promising strategy for targeted therapy of small vessel thrombosis. PMID- 24163055 TI - Effects of ankle joint position and submaximal muscle contraction intensity on soleus H-reflex modulation in young and older adults. AB - This study investigated the effects of ankle joint position and submaximal contraction intensity on soleus (SOL) H-reflex modulation. Twenty young (25.1 +/- 4.8 years) and 20 older adults (74.2 +/- 5.1 years) performed plantar flexions during 10%, 30% and 50% maximal voluntary contractions (MVC) and at ankle positions of neutral (0 degrees ), plantar flexion (20 degrees ) and dorsiflexion (-20 degrees ) in a sitting position. The SOL H-reflex gain in older adults was relatively lower than that in young adults during 10%, 30% and 50% MVC. The SOL H reflex gain was significantly affected by the intensity of plantar flexion in the respective ankle joint position in both age groups. The latency of H-reflex was prolonged in older adults and was ankle joint dependent in young adults. Young adults demonstrated a shorter duration of the H-reflex response than that of older adults. The results indicated that there were age-related changes in the SOL H-reflex during the ankle plantar flexors activities. PMID- 24163056 TI - Antihypertensive treatment - navigating between cost, compliance and complications. PMID- 24163057 TI - Primaquine for preventing relapse in people with Plasmodium vivax malaria treated with chloroquine. AB - BACKGROUND: Plasmodium vivax infections are an important contributor to the malaria burden worldwide. The World Health Organization recommends a 14-day course of primaquine (0.25 mg/kg/day, giving an adult dose of 15 mg/day) to eradicate the liver stage of the parasite and prevent relapse of the disease. Many people find a 14-day primaquine regimen difficult to complete, and there is a potential risk of haemolytic anaemia in people with glucose-6-phosphate dehydrogenase enzyme (G6PD) deficiency. This review evaluates primaquine in P. vivax, particularly alternatives to the standard 14-day course. OBJECTIVES: To compare alternative primaquine regimens to the recommended 14-day regimen for preventing relapses (radical cure) in people with P. vivax malaria treated for blood stage infection with chloroquine. We also summarize trials comparing primaquine to no primaquine that led to the recommendation for the 14-day regimen. SEARCH METHODS: We searched the Cochrane Infectious Diseases Group's Specialized Register, CENTRAL (The Cochrane Library), MEDLINE, EMBASE and LILACS up to 8 October 2013. We checked conference proceedings, trial registries and reference lists and contacted researchers and pharmaceutical companies for eligible studies. SELECTION CRITERIA: Randomized controlled trials (RCTs) and quasi-RCTs comparing various primaquine dosing regimens with the standard primaquine regimen (15 mg/day for 14 days), or with no primaquine, in people with vivax malaria treated for blood stage infection with chloroquine. DATA COLLECTION AND ANALYSIS: We independently assessed trial eligibility, trial quality, and extracted data. We calculated risk ratios (RR) with 95% confidence intervals (CI) for dichotomous data, and used the random-effects model in meta-analyses if there was significant heterogeneity. We assessed the overall quality of the evidence using the GRADE approach. MAIN RESULTS: We included 15 trials (two cluster-RCTs) of 4377 adult and child participants. Most trials excluded people with G6PD deficiency. Trials compared various regimens of primaquine with the standard primaquine regimen, or with placebo or no treatment. All trials treated blood stage infection with chloroquine. Alternative primaquine regimens compared to 14 day primaquineRelapse rates were higher over six months with the five-day primaquine regimen than the standard 14-day regimen (RR 10.05, 95% CI 2.82 to 35.86; two trials, 186 participants, moderate quality evidence). Similarly, relapse over six months was higher with three days of primaquine than the standard 14-day regimen (RR 3.18, 95% CI 2.1 to 4.81; two trials, 262 participants, moderate quality evidence; six months follow-up); and with primaquine for seven days followed up over two months, compared to 14-day primaquine (RR 2.24, 95% CI 1.24 to 4.03; one trial, 126 participants, low quality evidence).Relapse with once-weekly supervised primaquine for eight weeks was little different over nine months follow-up compared to 14-day self administered primaquine in one small study (RR 2.97, 95% CI 0.34 to 25.87; one trial, 129 participants, very low quality evidence). Primaquine regimens compared to no primaquineThe number of people that relapsed was similar between people given five days of primaquine or given placebo or no primaquine (four trials, 2213 participants, high quality evidence; follow-up six to 15 months); but lower with 14 days of primaquine (RR 0.6; 95% CI 0.48 to 0.75; ten trials, 1740 participants, high quality evidence; follow-up seven weeks to 15 months).No serious adverse events were reported. Treatment-limiting adverse events were rare and non-serious adverse events were mild and transient. Trial authors reported that people tolerated the drugs.We did not find trials comparing higher dose primaquine regimens (0.5 mg/kg/day or more) for five days or more with the 14-day regimen. AUTHORS' CONCLUSIONS: The analysis confirms the current World Health Organization recommendation for 14-day primaquine (15 mg/day) to prevent relapse of vivax malaria. Shorter primaquine regimens at the same daily dose are associated with higher relapse rates. The comparative effects with weekly primaquine are promising, but require further trials to establish equivalence or non-inferiority compared to the 14-day regimen in high malaria transmission settings. PMID- 24163058 TI - A randomized clinical trial of nerve block to manage end-stage pancreatic cancerous pain. AB - Pain control is the most difficult puzzle in patients with terminal pancreatic cancerous pain. Many methods in clinical practice fail in 20 ~ 50% of patients. The present study aims to explore the effect of nerve block on patients with end stage pancreatic cancerous pain. In this study, 100 subjects with end-stage pancreatic cancerous pain were enrolled and randomly assigned into two groups: 68 in nerve block group (N) and 32 in sham group (S). One group was treated with nerve block and the other group with sham procedure as controls. The pain score (by visual analog scale (VAS)), pain duration, reduction of other analgesic medications, and quality of life (with questionnaire QLQ) were evaluated before and 3 months after interventions. Comparisons were performed between before and after intervention in nerve block group and sham group. The results indicated that compared with sham group, the subjects in nerve block group had significant reduction with pain score, pain duration, and other analgesic medications, as well as improvement of quality of life (P < 0.05, respectively). In conclusion, nerve block is an effective method for treating patients with end-stage pancreatic cancerous pain. PMID- 24163060 TI - Emerging psychological treatments in the field of eating disorders. AB - Few treatments for eating disorders have established a base of empirical support, and those that have are still limited by high dropout rates and low abstinence rates. Thus, there is a critical need for innovative eating disorder treatments to fill this gap. The past decade has seen a surge in the development of novel treatments that address eating pathology. This review provides an overview of the emerging psychological treatments for eating disorders, including descriptions of the therapeutic rationales, treatment techniques, and research support. The review will cover face-to-face interventions that are provided in the context of individual or group psychotherapy. Treatments included in this review were organized into the following six categories based on their underlying therapeutic rationales: (1) cognition-focused approaches, (2) emotion regulation approaches, (3) exposure-based approaches, (4) motivational enhancement, (5) integrative approaches, and (6) family- and couple-based interventions. PMID- 24163059 TI - Hepatic somatostatin receptor 2 expression during premalignant stages of hepatocellular carcinoma. AB - Growth and antigrowth hormones were occasionally investigated in hepatocarcinoma. Somatostatin regulates cell proliferation and inhibits the secretion of many growth factors engaged to tumors through a group of receptors, including somatostatin receptor type 2 (SSTR2). Caspase-3 is a transcription factor which is elevated in liver cancers. The most commonly approved marker for liver cancer is alpha fetoprotein (AFP), although it has no more than 65% sensitivity and specificity. Hepatocarcinoma is also mediated by oxidative stress. Four groups of mice were used in this work: a control group and another three groups (Gp 2, 3, and 4) used for induction of HCC with a single subnecrotic dose of diethylnitrosamine (DENA). Gp 2 was sacrificed on the last day after 8 weeks, Gp 3 after 16 weeks, and Gp 4 after 24 weeks. Both liver tissue SSR2 protein and mRNA, liver AFP, and caspase-3 mRNA expression, concomitant to tissue malondialdehyde (MDA), were significantly elevated with depressed reduced glutathione (GSH). The change was much more prominent and stage dependent for SSR2. These effects were supported by graded histological abnormalities. The study encourages the use of liver tissue SSR2 protein and mRNA as a reliable tumor marker for liver cancer rather than AFP which is always misleading during silent stages of hepatocarcinogenesis. PMID- 24163061 TI - Fundus autofluorescence and colour fundus imaging compared during telemedicine screening in patients with diabetes. AB - We investigated the use of fundus autofluorescence (FAF) imaging in screening the eyes of patients with diabetes. Images were obtained from 50 patients with type 2 diabetes undergoing telemedicine screening with colour fundus imaging. The colour and FAF images were obtained with a 15.1 megapixel non-mydriatic retinal camera. Colour and FAF images were compared for pathology seen in nonproliferative and proliferative diabetic retinopathy (NPDR and PDR, respectively). A qualitative assessment was made of the ease of detecting early retinopathy changes and the extent of existing retinopathy. The mean age of the patients was 47 years, most were male (82%) and most were African American (68%). Their mean visual acuity was 20/45 and their mean intraocular pressure was 14.3 mm Hg. Thirty-eight eyes (76%) did not show any diabetic retinopathy changes on colour or FAF imaging. Seven patients (14%) met the criteria for NPDR and five (10%) for severe NPDR or PDR. The most common findings were microaneurysms, hard exudates and intra retinal haemorrhages (IRH) (n = 6 for each). IRH, microaneurysms and chorioretinal scars were more easily visible on FAF images. Hard exudates, pre retinal haemorrhage and fibrosis, macular oedema and Hollenhorst plaque were easier to identify on colour photographs. The value of FAF imaging as a complementary technique to colour fundus imaging in detecting diabetic retinopathy during ocular screening warrants further investigation. PMID- 24163063 TI - The future of health care communication and promotion. PMID- 24163062 TI - A prospective study of mobile phones for dermatology in a clinical setting. AB - We evaluated the accuracy of diagnoses made from pictures taken with the built-in cameras of mobile phones in a 'real-life' clinical setting. A total of 263 patients took part, who photographed their own lesions where possible, and provided clinical information via a questionnaire. After the teledermatology procedure, each patient was examined face-to-face and a gold standard diagnosis was made. The telemedicine data and pictures were diagnosed by 15 dermatologists. The 299 cases contained 1-22 clinical images each (median 3). Nine dermatologists finished all the cases and the remaining six completed some of them, thus providing 2893 decisions. Overall, 61% of all cases were rated as possible to diagnose and of those, 80% were correct in comparison with the face-to-face diagnosis. Image quality was evaluated and the median was 5 on a 10-point scale. There was a significant correlation between the correct diagnosis and the quality of the photographs taken (P < 0.001). In nearly two-thirds of all cases, a teledermatology diagnosis was possible; however, there was insufficient information to make a telemedicine diagnosis in about one-third of the cases. If applied carefully, mobile phones could be a powerful tool for people to optimize their health care status. PMID- 24163064 TI - Pathology of second-generation everolimus-eluting stents versus first-generation sirolimus- and paclitaxel-eluting stents in humans. AB - BACKGROUND: Clinical trials have demonstrated that the second-generation cobalt chromium everolimus-eluting stent (CoCr-EES) is superior to the first-generation paclitaxel-eluting stent (PES) and is noninferior or superior to the sirolimus eluting stent (SES) in terms of safety and efficacy. It remains unclear whether vascular responses to CoCr-EES are different from those to SES and PES because the pathology of CoCr-EES has not been described in humans. METHODS AND RESULTS: A total of 204 lesions (SES=73; PES=85; CoCr-EES=46) from 149 autopsy cases with duration of implantation >30 days and <=3 years were pathologically analyzed, and comparison of vascular responses was corrected for duration of implantation. The observed frequency of late and very late stent thrombosis was less in CoCr-EES (4%) versus SES (21%; P=0.029) and PES (26%; P=0.008). Neointimal thickness was comparable among the groups, whereas the percentage of uncovered struts was strikingly lower in CoCr-EES (median=2.6%) versus SES (18.0%; P<0.0005) and PES (18.7%; P<0.0005). CoCr-EES showed a lower inflammation score (with no hypersensitivity) and less fibrin deposition versus SES and PES. The observed frequency of neoatherosclerosis, however, did not differ significantly among the groups (CoCr-EES=29%; SES=35%; PES=19%). CoCr-EES had the least frequency of stent fracture (CoCr-EES=13%; SES=40%; PES=19%; P=0.007 for CoCr-EES versus SES), whereas fracture-related restenosis or thrombosis was comparable among the groups (CoCr-EES=6.5%; SES=5.5%; PES=1.2%). CONCLUSIONS: CoCr-EES demonstrated greater strut coverage with less inflammation, less fibrin deposition, and less late and very late stent thrombosis compared with SES and PES in human autopsy analysis. Nevertheless, the observed frequencies of neoatherosclerosis and fracture-related adverse pathological events were comparable in these devices, indicating that careful long-term follow-up remains important even after CoCr-EES placement. PMID- 24163065 TI - Vascular progenitors from cord blood-derived induced pluripotent stem cells possess augmented capacity for regenerating ischemic retinal vasculature. AB - BACKGROUND: The generation of vascular progenitors (VPs) from human induced pluripotent stem cells (hiPSCs) has great potential for treating vascular disorders such as ischemic retinopathies. However, long-term in vivo engraftment of hiPSC-derived VPs into the retina has not yet been reported. This goal may be limited by the low differentiation yield, greater senescence, and poor proliferation of hiPSC-derived vascular cells. To evaluate the potential of hiPSCs for treating ischemic retinopathies, we generated VPs from a repertoire of viral-integrated and nonintegrated fibroblast and cord blood (CB)-derived hiPSC lines and tested their capacity for homing and engrafting into murine retina in an ischemia-reperfusion model. METHODS AND RESULTS: VPs from human embryonic stem cells and hiPSCs were generated with an optimized vascular differentiation system. Fluorescence-activated cell sorting purification of human embryoid body cells differentially expressing endothelial/pericytic markers identified a CD31(+)CD146(+) VP population with high vascular potency. Episomal CB-induced pluripotent stem cells (iPSCs) generated these VPs with higher efficiencies than fibroblast-iPSC. Moreover, in contrast to fibroblast-iPSC-VPs, CB-iPSC-VPs maintained expression signatures more comparable to human embryonic stem cell VPs, expressed higher levels of immature vascular markers, demonstrated less culture senescence and sensitivity to DNA damage, and possessed fewer transmitted reprogramming errors. Luciferase transgene-marked VPs from human embryonic stem cells, CB-iPSCs, and fibroblast-iPSCs were injected systemically or directly into the vitreous of retinal ischemia-reperfusion-injured adult nonobese diabetic severe combined immunodeficient mice. Only human embryonic stem cell- and CB-iPSC derived VPs reliably homed and engrafted into injured retinal capillaries, with incorporation into damaged vessels for up to 45 days. CONCLUSIONS: VPs generated from CB-iPSCs possessed augmented capacity to home, integrate into, and repair damaged retinal vasculature. PMID- 24163067 TI - Electromagnetic interference with implantable cardioverter-defibrillators at power frequency: an in vivo study. AB - BACKGROUND: The number of implantable cardioverter-defibrillators (ICDs) for the prevention of sudden cardiac death is continuing to increase. Given the technological complexity of ICDs, it is of critical importance to identify and control possible harmful electromagnetic interferences between various sources of electromagnetic fields and ICDs in daily life and occupational environments. METHODS AND RESULTS: Interference thresholds of 110 ICD patients (1-, 2-, and 3 chamber ICDs) were evaluated in a specifically developed test site. Patients were exposed to single and combined electric and magnetic 50-Hz fields with strengths of up to 30 kV.m-1 and 2.55 mT. Tests were conducted considering worst-case conditions, including maximum sensitivity of the device or full inspiration. With devices being programmed to nominal sensitivity, ICDs remained unaffected in 91 patients (83%). Five of 110 devices (5%) showed transient loss of accurate right ventricular sensing, whereas 14 of 31 (45%) of the 2- and 3-chamber devices displayed impaired right atrial sensing. No interference was detected in 71 patients (65%) within the tested limits with programming to maximum sensitivity, whereas 20 of 110 subjects (18%) exhibited right ventricular disturbances and 19 of 31 (61%) subjects exhibited right atrial disturbances. CONCLUSIONS: Extremely low-frequency daily-life electromagnetic fields do not disturb sensing capabilities of ICDs. However, strong 50-Hz electromagnetic fields, present in certain occupational environments, may cause inappropriate sensing, potentially leading to false detection of atrial/ventricular arrhythmic events. When the right atrial/right ventricular interferences are compared, the atrial lead is more susceptible to electromagnetic fields. CLINICAL TRIAL REGISTRATION URL: http://clinicaltrials.gov/ct2/show/NCT01626261. Unique identifier: NCT01626261. PMID- 24163068 TI - Derivation and validation of a risk standardization model for benchmarking hospital performance for health-related quality of life outcomes after acute myocardial infarction. AB - BACKGROUND: Before outcomes-based measures of quality can be used to compare and improve care, they must be risk-standardized to account for variations in patient characteristics. Despite the importance of health-related quality of life (HRQL) outcomes among patients with acute myocardial infarction (AMI), no risk standardized models have been developed. METHODS AND RESULTS: We assessed disease specific HRQL using the Seattle Angina Questionnaire at baseline and 1 year later in 2693 unselected AMI patients from 24 hospitals enrolled in the Translational Research Investigating Underlying disparities in acute Myocardial infarction Patients' Health status (TRIUMPH) registry. Using 57 candidate sociodemographic, economic, and clinical variables present on admission, we developed a parsimonious, hierarchical linear regression model to predict HRQL. Eleven variables were independently associated with poor HRQL after AMI, including younger age, previous coronary artery bypass graft surgery, depressive symptoms, and financial difficulties (R(2)=20%). The model demonstrated excellent internal calibration and reasonable calibration in an independent sample of 1890 AMI patients in a separate registry, although the model slightly overpredicted HRQL scores in the higher deciles. Among the 24 TRIUMPH hospitals, 1-year unadjusted HRQL scores ranged from 67-89. After risk-standardization, HRQL score variability narrowed substantially (range=79-83), and the group of hospital performance (bottom 20%/middle 60%/top 20%) changed in 14 of the 24 hospitals (58% reclassification with risk-standardization). CONCLUSIONS: In this predictive model for HRQL after AMI, we identified risk factors, including economic and psychological characteristics, associated with HRQL outcomes. Adjusting for these factors substantially altered the rankings of hospitals as compared with unadjusted comparisons. Using this model to compare risk-standardized HRQL outcomes across hospitals may identify processes of care that maximize this important patient-centered outcome. PMID- 24163069 TI - Subclavian artery cannulation provides superior outcomes in patients with acute type-A dissection: long-term results of 290 consecutive patients. AB - OBJECTIVES: The short-term results of subclavian artery cannulation (SC) for acute type-A dissection repair have been reported to be superior in regard to mortality and neurological outcomes when compared to femoral cannulation (FC). This study evaluates the long-term results of subclavian artery cannulation versus femoral cannulation for repair of acute type-A dissection with particular regard to neurological deficits, mortality and the need for re-operations. METHODS: From 1992-2005, 346 patients underwent surgical repair of acute type-A dissection of which 290 patients survived the operation. SC was performed in 114 patients and FC in 176 patients. Follow-up (FU) was completed in 89.5% (n = 259) and the medium FU-period was 42 months (SC) and 69 months (FC). Endpoints were persistence of neurological-deficits, mortality, major complications and necessity for re-operations. RESULTS: Overall survival and disease-free survival at 5 years were significantly higher in the SC group (83% vs. 71%; p = 0.022 and 74% vs. 61%; p = 0.044). Freedom of re-operation also appeared to be higher in the SC group (89% vs. 79%; p = 0.125). During the follow-up period, 28 patients (11/114 vs. 17/176; p = 0.58) suffered from neurological deficits of which 16 patients had permanent neurological-deficits at the 5 year follow-up. Of these patients, significantly more belonged to the FC group indicating an improved neurological-outcome for the SC group (3/11 vs. 13/17; p = 0.019). CONCLUSIONS: This study demonstrates excellent long-term outcomes after emergency surgery for acute type-A dissection. Subclavian artery perfusion represents an excellent approach to repair acute type-A dissection. Beside a significantly reduced long term mortality, this technique provides an improved neurological outcome and a higher disease-free survival-rate. PMID- 24163066 TI - Proinflammatory endothelial activation detected by molecular imaging in obese nonhuman primates coincides with onset of insulin resistance and progressively increases with duration of insulin resistance. AB - BACKGROUND: Inflammation and insulin resistance (IR) are associated processes that potentiate risk for cardiovascular disease in obesity. The temporal relation between IR and inflammation is not completely characterized. We hypothesized that endothelial cell adhesion molecule expression in large arteries is an early event that coincides with diet-induced obesity and IR in primates. METHODS AND RESULTS: Ten adult male rhesus macaques were studied at baseline and every 4 to 6 months on a high-fat diet for 2 years. Truncal fat, carotid intima-media thickness, plasma inflammatory biomarkers, and carotid P-selectin and vascular cell adhesion molecule-1 expression by contrast-enhanced ultrasound molecular imaging were assessed. Intravenous glucose tolerance test was performed at baseline and at 4 and 18 months. A high-fat diet produced a rapid increase (P<0.01) in weight, truncal fat, and degree of IR indicated by the insulin area under the curve and glucose disappearance rate on intravenous glucose tolerance test, all of which worsened minimally thereafter. Molecular imaging detected a progressive increase in endothelial cell adhesion molecule expression over time (5- to 7-fold greater than control agent signal at 2 years; P<0.01). Changes in intima-media thickness were not detected until 2 years and, although there was a trend toward an increase in plasma markers of inflammation (monocyte chemotactic protein-1, C reactive protein), the pattern of increase varied considerably over time. CONCLUSIONS: In primates with diet-induced obesity, endothelial inflammatory activation is an early event that occurs coincident with the development of IR and long before any measurable change in carotid intima-media thickness. Endothelial activation is related more to the duration rather than to the severity of IR and is not mirrored by changes in plasma biomarkers. PMID- 24163070 TI - Interventions for the treatment of Paget's disease of the vulva. AB - BACKGROUND: Extra-mammary Paget's disease is a rare form of superficial skin cancer. The most common site of involvement is the vulva. It is seen mainly in postmenopausal white women. Paget's disease of the vulva often spreads in an occult fashion, with margins extending beyond the apparent edges of the lesion. There is a range of interventions from surgical to non-invasive techniques or treatments. The challenges of interventions are to remove or treat disease that may not be visible, without overtreatment and with minimisation of morbidity from radical surgery. There is little consensus regarding treatment. Surgery, by default, is the most common treatment, but it is challenging to excise the disease adequately, and recurrence is common, leading to repeated operations, and destruction of anatomy. Alternative treatments of photodynamic therapy, laser therapy, radiotherapy, topical treatments or even chemotherapy have been mooted, and it is important to evaluate the available evidence. It is essential to assess whether newer cell-specific treatments, such as photodynamic therapy and imiquimod, can reduce the need for radical surgery. OBJECTIVES: To evaluate the benefits and harms of different treatment modalities for the management of Paget's disease of the vulva. SEARCH METHODS: We searched the Cochrane Gynaecological Cancer Group Trials Register, the Cochrane Register of Controlled Trials (CENTRAL), MEDLINE and EMBASE up to September 2013. We also searched registers of clinical trials, abstracts of scientific meetings and reference lists of review articles and contacted experts in the field. SELECTION CRITERIA: We searched for randomised controlled trials (RCTs) and well-designed non randomised studies that compared different interventions in women with Paget's disease of the vulva, DATA COLLECTION AND ANALYSIS: Two review authors independently assessed whether potentially relevant studies met the inclusion criteria. We found no trials and, therefore, no data were analysed. MAIN RESULTS: The search strategy identified 635 unique references. We found 31 references (which reported on 30 studies) in full text after inspection of titles and abstracts, but we excluded them all as they did not meet the inclusion criteria. However, we have included a comprehensive narrative account of studies where we identified an analysis of more than 10 women, as this forms the only evidence base in this rare disease. Surgery continues to be the mainstay of treatment in the current literature, with other treatments limited to case reports or treatment of inoperable or recurrent disease. AUTHORS' CONCLUSIONS: We found no reliable evidence to inform decisions about different interventions for women with Paget's disease of the vulva. Ideally, a multicentre RCT of reasonable size is needed. In particular, evidence regarding the increasing use of imiquimod would be helpful to women and clinicians alike. Well-designed non-randomised studies, that use multivariate analysis to adjust for baseline imbalances, as well as other key methodological strengths, are also lacking. PMID- 24163072 TI - Temporal changes in integrin-mediated cardiomyocyte adhesion secondary to chronic cardiac volume overload in rats. AB - Previous studies have established integrins as cell surface receptors that mediate cardiomyocyte-extracellular matrix (ECM) attachments. This study sought to determine the contributions of the myocardial beta1- and beta3-integrin subunits to ventricular dilatation and coronary flow regulation using a blood perfused isolated heart preparation. Furthermore, cardiomyocyte adhesion to collagen types I and IV, fibronectin, and laminin with and without a beta1 integrin subunit neutralizing antibody was assessed during the course of remodeling secondary to a sustained cardiac volume overload, including the onset of heart failure. Isolated cardiomyocytes were obtained during the initial, compensated, and decompensated phases of remodeling resulting from an aortocaval fistula created in 8-wk-old male Sprague-Dawley rats. Blocking the beta1-integrin subunit in isolated normal hearts produced ventricular dilatation, whereas this was not the case when the beta3-subunit was blocked. Substantial reductions in cardiomyocyte adhesion coincided with the previously documented development of ventricular dilatation and decreased contractility postfistula, with the beta1 integrin contribution to adhesion ranging from 28% to 73% over the course of remodeling being essentially substrate independent. In contrast, both integrin subunits were found to be involved in regulating coronary vascular resistance. It is concluded that marked reductions in integrin-mediated cardiomyocyte adhesion to the ECM play a significant role in the progression of adverse myocardial remodeling that leads to heart failure. Furthermore, although both the beta1- and beta3-integrin subunits were involved in regulating coronary vascular resistance, only inhibition of beta1-integrin-mediated adhesion resulted in ventricular dilatation of the normal heart. PMID- 24163071 TI - Postprandial VLDL lipolysis products increase monocyte adhesion and lipid droplet formation via activation of ERK2 and NFkappaB. AB - Postprandial lipemia is characterized by a transient increase in circulating triglyceride-rich lipoproteins such as very low-density lipoprotein (VLDL) and has been shown to activate monocytes in vivo. Lipolysis of VLDL releases remnant particles, phospholipids, monoglycerides, diglycerides, and fatty acids in close proximity to endothelial cells and monocytes. We hypothesized that postprandial VLDL lipolysis products could activate and recruit monocytes by increasing monocyte expression of proinflammatory cytokines and adhesion molecules, and that such activation is related to the development of lipid droplets. Freshly isolated human monocytes were treated with VLDL lipolysis products (2.28 mmol/l triglycerides + 2 U/ml lipoprotein lipase), and monocyte adhesion to a primed endothelial monolayer was observed using a parallel plate flow chamber coupled with a CCD camera. Treated monocytes showed more rolling and adhesion than controls, and an increase in transmigration between endothelial cells. The increased adhesive events were related to elevated expression of key integrin complexes including Mac-1 [alpha(m)-integrin (CD11b)/beta2-integrin (CD18)], CR4 [alpha(x)-integrin (CD11c)/CD18] and VLA-4 [alpha4-integrin (CD49d)/beta1 integrin (CD29)] on treated monocytes. Treatment of peripheral blood mononuclear cells (PBMCs) and THP-1 monocytes with VLDL lipolysis products increased expression of TNFalpha, IL-1beta, and IL-8 over controls, with concurrent activation of NFkB and AP-1. NFkappaB and AP-1-induced cytokine and integrin expression was dependent on ERK and Akt phosphorylation. Additionally, fatty acids from VLDL lipolysis products induced ERK2-dependent lipid droplet formation in monocytes, suggesting a link to inflammatory signaling pathways. These results provide novel mechanisms for postprandial monocyte activation by VLDL lipolysis products, suggesting new pathways and biomarkers for chronic, intermittent vascular injury. PMID- 24163073 TI - Role of macrophage PPARgamma in experimental hypertension. AB - Targeted disruption of the Alox15 gene makes mice resistant to angiotensin II-, DOCA/salt-, and N(omega)-nitro-L-arginine methyl ester (L-NAME)-induced experimental hypertension. Macrophages, a primary source of Alox15, are facilitating this resistance, but the underlying mechanism is not known. Because Alox15 metabolites are peroxisome proliferator-activated receptor (PPAR)gamma agonists, we hypothesized that activation of macrophage PPARgamma is the key step in Alox15 mediation of hypertension. Thioglycollate, used for macrophage elicitation, selectively upregulated PPARgamma and its target gene CD36 in peritoneal macrophages of both wild-type (WT) and Alox15(-/-) mice. Moreover, thioglycollate-injected Alox15(-/-) mice became hypertensive upon L-NAME treatment. A similar hypertensive effect was observed with adoptive transfer of thioglycollate-elicited Alox15(-/-) macrophages into Alox15(-/-) recipient mice. The role of PPARgamma was further specified by using the selective PPARgamma antagonist GW9662. WT mice treated with 50 MUg/kg daily dose of GW9662 for 12 days became resistant to L-NAME-induced hypertension. The PPARgamma antagonist treatment also prevented L-NAME-induced hypertension in thioglycollate-injected Alox15(-/-) mice, indicating a PPARgamma-mediated effect in macrophage elicitation and the resultant hypertension. These results indicate a regulatory role for macrophage-localized PPARgamma in L-NAME-induced experimental hypertension. PMID- 24163074 TI - Cyclosporin A in left ventricular remodeling after myocardial infarction. AB - Recent studies suggest that an increase in apoptosis within the myocardium may be a contributing factor for the progression of late adverse left ventricular (LV) remodeling following myocardial infarction (MI). Given that apoptosis is often triggered by induction of the mitochondrial permeability transition (MPT) pore, the goal of this study was to evaluate the therapeutic efficacy of cyclosporin A (CsA), an MPT blocker, to prevent cells from undergoing apoptosis and consequently attenuate late LV remodeling post-MI. MI was induced in C57BL/6 mice and then randomized to either vehicle or CsA groups. Beginning 48 h after surgery after infarction had already occurred, mice were gavaged with CsA (2 mg/kg) or vehicle once daily. LV end-diastolic volume and LV ejection fraction were assessed by echocardiography before MI induction and terminally at either 7 days (n = 7) or 28 days (n = 8) post-MI. LV end-diastolic volume increased and LV ejection fraction decreased in all MI groups with no difference between the CsA treated and untreated groups. After vehicle and CsA, areas of necrosis were present at 7 and 28 days post-MI with no difference between treatment groups. Caspase-3 activity and terminal deoxynucleotidyl transferase dUTP-mediated nick end labeling in distal nonnecrotic LV both increased after MI but were lower in CsA-treated mice compared with vehicle (P < 0.05). In conclusion, CsA decreased apoptosis occurring late after MI, confirming involvement of a CsA-sensitive MPT in the cell death. However, CsA-mediated reduction in apoptosis in non-MI myocardium was not beneficial against late pump dysfunction occurring during post MI remodeling. PMID- 24163076 TI - Pathogenesis of pulmonary hypertension: a case for caveolin-1 and cell membrane integrity. AB - Pulmonary hypertension (PH) is a progressive disease with a high morbidity and mortality rate. Despite important advances in the field, the precise mechanisms leading to PH are not yet understood. Main features of PH are loss of vasodilatory response, the activation of proliferative and antiapoptotic pathways leading to pulmonary vascular remodeling and obstruction, elevated pressure and right ventricular hypertrophy, resulting in right ventricular failure and death. Experimental studies suggest that endothelial dysfunction may be the key underlying feature in PH. Caveolin-1, a major protein constituent of caveolae, interacts with several signaling molecules including the ones implicated in PH and modulates them. Disruption and progressive loss of endothelial caveolin-1 with reciprocal activation of proliferative pathways occur before the onset of PH, and the rescue of caveolin-1 inhibits proliferative pathways and attenuates PH. Extensive endothelial damage/loss occurs during the progression of the disease with subsequent enhanced expression of caveolin-1 in smooth muscle cells. This caveolin-1 in smooth muscle cells switches from being an antiproliferative factor to a proproliferative one and participates in cell proliferation and cell migration, possibly leading to irreversible PH. In contrast, the disruption of endothelial caveolin-1 is not observed in the hypoxia-induced PH, a reversible form of PH. However, proliferative pathways are activated in this model, indicating caveolin-1 dysfunction. Thus disruption or dysfunction of endothelial caveolin-1 leads to PH, and the status of caveolin-1 may determine the reversibility versus irreversibility of PH. This article reviews the role of caveolin-1 and cell membrane integrity in the pathogenesis and progression of PH. PMID- 24163075 TI - Toll-like receptors and damage-associated molecular patterns: novel links between inflammation and hypertension. AB - Low-grade systemic inflammation is a common manifestation of hypertension; however, the exact mechanisms that initiate this pathophysiological response, thereby contributing to further increases in blood pressure, are not well understood. Aberrant vascular inflammation and reactivity via activation of the innate immune system may be the first step in the pathogenesis of hypertension. One of the functions of the innate immune system is to recognize and respond to danger. Danger signals can arise from not only pathogenic stimuli but also endogenous molecules released following cell injury and/or death [damage associated molecular patterns (DAMPs)]. In the short-term, activation of the innate immune system is beneficial in the vasculature by providing cytoprotective mechanisms and facilitating tissue repair following injury or infection. However, sustained or excessive immune system activation, such as in autoimmune diseases, may be deleterious and can lead to maladaptive, irreversible changes to vascular structure and function. An initial source of DAMPs that enter the circulation to activate the innate immune system could arise from modest elevations in peripheral vascular resistance. These stimuli could subsequently lead to ischemic or pressure-induced events aggravating further cell injury and/or death, providing more DAMPs for innate immune system activation. This review will address and critically evaluate the current literature on the role of the innate immune system in hypertension pathogenesis. The role of Toll-like receptor activation on somatic cells of the vasculature in response to the release of DAMPs and the consequences of this activation on inflammation, vasoreactivity, and vascular remodeling will be specifically discussed. PMID- 24163078 TI - Increased inducibility of ventricular tachycardia and decreased heart rate variability in a mouse model for type 1 diabetes: effect of pravastatin. AB - Although a reduction in the high-frequency (HF) component of heart rate variability (HRV) is a major complication of diabetes and a risk factor for sudden death, its relationship to ventricular tachycardia (VT) is unknown. We developed a mouse model for the study of VT and its relationship to changes in HRV in the Akita type 1 diabetic mouse. Programmed ventricular stimulation of anesthetized mice demonstrated that Akita mice were more inducible for VT compared with wild-type mice: 78.6% versus 28.6% (P = 0.007). Optical mapping of perfused hearts demonstrated multifocal breakthroughs that occasionally gave rise to short-lived rotors consistent with focal initiation and maintenance of VT. Treatment of Akita mice with pravastatin, which had been previously shown clinically to decrease ventricular ectopy and to increase HRV, decreased the inducibility of VT: 36.8% compared with 75.0% with placebo treatment (P = 0.022). The HF fraction of HRV was reduced in Akita mice (48.6 +/- 5.2% vs. 70.9 +/- 4.8% in wild-type mice, P = 0.005) and was increased compared with placebo treatment in pravastatin-treated mice. Pretreatment of Akita mice with the muscarinic agonist carbamylcholine or the beta-adrenergic receptor blocker propranolol decreased the inducibility of VT (P = 0.001). In conclusion, the increased inducibility of focally initiated VT and reduced HF fraction in Akita mice were partially reversed by both pravastatin treatment and pharmacologic reversal of parasympathetic dysfunction. In this new animal model for the study of the pathogenesis of VT in type 1 diabetes, pravastatin may play a role in the prevention of VT by attenuating parasympathetic dysfunction. PMID- 24163077 TI - Neurovascular signaling in the brain and the pathological consequences of hypertension. AB - The execution and maintenance of all brain functions are dependent on a continuous flow of blood to meet the metabolic needs of the tissue. To ensure the delivery of resources required for neural processing and the maintenance of neural homeostasis, the cerebral vasculature is elaborately and extensively regulated by signaling from neurons, glia, interneurons, and perivascular nerves. Hypertension is associated with impaired neurovascular regulation of the cerebral circulation and culminates in neurodegeneration and cognitive dysfunction. Here, we review the physiological processes of neurovascular signaling in the brain and discuss mechanisms of hypertensive neurovascular dysfunction. PMID- 24163079 TI - QT/RR curvatures in healthy subjects: sex differences and covariates. AB - Data of a large clinical study were used to investigate how much are the QT/RR patterns in healthy subjects curved and whether these curvatures differ between women and men. Daytime drug-free 12-lead Holter recordings were repeated 4 times in each of 176 female healthy subjects and 176 male healthy subjects aged 32.7 +/ 9.1 yr. In each of the subjects, up to 1,440 carefully verified QT interval measurements were obtained with QT/RR hysteresis-corrected RR intervals. Individual subject data were used to fit the following regression equation: QT = chi + (delta/gamma)(1 - RR(gamma)) + epsilon, where QT and RR are QT and RR measurements (in s), chi is regression intercept, delta is the QT/RR slope, gamma is the QT/RR curvature and provides the lowest regression residual, and epsilon represents normally distributed zero-centered errors. The bootstrap technique showed the intrasubject reproducibility of QT/RR slopes and curvatures. In women and men, QT/RR curvatures were 0.544 +/- 0.661 and 0.797 +/- 0.706, respectively (P = 0.0006). The corresponding QT/RR slopes were 0.158 +/- 0.030 and 0.139 +/- 0.023, respectively (P < 0.0001). QT/RR curvatures were related to QT/RR slopes but not to individually corrected mean QTc intervals or individual QT/RR hysteresis profiles. The individual heart rate correction formula derived from the curvilinear regression provided a significantly lower intrasubject variability of QTc interval than individual optimisation of linear or log-linear QT/RR heart rate corrections. The QT/RR curvature can be reliable measured and expressed numerically. The corresponding heart rate correction formula provides more compact data than the previously proposed approaches. There are substantial sex differences in QT/RR patterns. Women have a QT/RR pattern that is not only steeper than men but also more curved. PMID- 24163080 TI - Effects of exercise training on SFO-mediated sympathoexcitation during chronic heart failure. AB - Exercise training (ExT) has been shown to reduce sympathetic drive during heart failure (HF). The subfornical organ (SFO) is involved in the neural control of sympathetic drive. We hypothesized that an activated SFO contributes to enhanced sympathetic activity in HF. We also postulated that ExT would reduce the activation of the SFO and its contribution to the sympathetic drive during HF. Sprague-Dawley rats were subjected to coronary artery ligation to induce HF. Rats were assigned to ExT for 3-4 wk. Rats with HF had a 2.5-fold increase in FosB positive cells in the SFO compared with sham-operated rats, and this was normalized by ExT. Microinjection of ANG II (100 pmol) into the SFO resulted in a greater increase in renal sympathetic nerve activity (RSNA), blood pressure, and heart rate in the HF group than in the sham-operated group. These responses were normalized after ExT (change in RSNA: 23 +/- 3% vs. 8 +/- 2%). ExT also abolished the decrease in RSNA in HF rats after the microinjection of losartan (200 pmol) into the SFO (-21 +/- 4% vs. -2 +/- 3%). Finally, there was elevated mRNA (5 fold) and protein expression (43%) of ANG II type 1 receptors in the SFO of rats with HF, which were reversed after ExT. These data suggest that the enhanced activity of the SFO by elevated tonic ANG II contributes to the enhanced sympathoexcitation exhibited in HF. The decrease in ANG II type 1 receptor expression in the SFO by ExT may be responsible for reversing the neuronal activation in the SFO and SFO-mediated sympathoexcitation in rats with HF. PMID- 24163081 TI - Exaggerated exercise pressor reflex in adults with moderately elevated systolic blood pressure: role of purinergic receptors. AB - The neurocirculatory responses to exercise are exaggerated in hypertension, increasing cardiovascular risk, yet the mechanisms remain incompletely understood. The aim of this study was to examine the in vitro effectiveness of pyridoxal-5-phosphate as a purinergic (P2) receptor antagonist in isolated murine dorsal root ganglia (DRG) neurons and the in vivo contribution of P2 receptors to the neurocirculatory responses to exercise in older adults with moderately elevated systolic blood pressure (BP). In vitro, pyridoxal-5-phosphate attenuated the ATP-induced increases in [Ca(2+)](i) (73 +/- 15 vs. 11 +/- 3 nM; P < 0.05). In vivo, muscle sympathetic nerve activity (MSNA; peroneal microneurography) and arterial BP (Finometer) were assessed during exercise pressor reflex activation (static handgrip followed by postexercise ischemia; PEI) during a control trial (normal saline) and localized P2 receptor blockade (pyridoxal-5-phosphate). Compared with normotensive adults (63 +/- 2 yr, 117 +/- 2/70 +/- 2 mmHg), adults with moderately elevated systolic BP (65 +/- 1 yr, 138 +/- 5/79 +/- 3 mmHg) demonstrated greater increases in MSNA and BP during handgrip and PEI. Compared with the control trial, local antagonism of P2 receptors during PEI partially attenuated MSNA (39 +/- 4 vs. 34 +/- 5 bursts/min; P < 0.05) in adults with moderately elevated systolic BP. In conclusion, these data demonstrate pyridoxal 5-phosphate is an effective P2 receptor antagonist in isolated DRG neurons, which are of particular relevance to the exercise pressor reflex. Furthermore, these findings indicate that exercise pressor reflex function is exaggerated in older adults with moderately elevated systolic BP and further suggest a modest role of purinergic receptors in evoking the abnormally large reflex-mediated increases in sympathetic activity during exercise in this clinical population. PMID- 24163082 TI - Efficacy and safety between temozolomide alone and temozolomide-based double therapy for malignant melanoma: a meta-analysis. AB - Temozolomide (TMZ) has received much attention, notably in the treatment of malignant glioma and malignant melanoma. The objective of this study was to compare the clinical efficacy and safety of TMZ alone and TMZ-based combination drug therapy in patients with melanoma. Using "temozolomide" as a keyword combined with "melanoma" and "randomized controlled trials" as Medical Subject Headings, the following electronic databases were searched: the Cochrane library, MEDLINE, EBSCO, EMBASE, Ovid, cNKI, and cBMDisc. The evaluating indicators were overall response rate (ORR), 1-year survival rate, and several of the most frequent adverse events. Five randomized controlled trials met our criteria and were included in the meta-analysis, with a total of 703 participants (309 patients received TMZ alone, and 394 patients received combined regimens). The meta-analysis showed that the ORR for TMZ-based drug therapy was higher than TMZ alone [relative risk (RR) = 1.44; 95% confidence interval (CI), 1.06-1.95], but the 1-year survival rate was not significantly different between the two groups (RR = 1.13; 95% CI, 0.92-1.40). These results suggested that the impact of these increased response rates was not translated into a survival benefit. Moreover, we found no difference in the incidence of adverse events analyzed. The currently available evidence showed that the TMZ-combination therapy may moderately improve the response rate, but there was no corresponding increased toxicity. Future large-scale, high-quality, placebo-controlled, double-blind trials are needed. PMID- 24163083 TI - The polymorphism of EGFR 142285G > A exerts no risk effect on breast cancer. AB - The association between the epidermal growth factor receptor (EGFR) 142285G > A polymorphism and the susceptibility to breast cancer is unclear. We conducted a meta-analysis of all published studies to estimate the association of EGFR 142285G > A polymorphism and breast cancer risk. Systematic computerized searching of the PubMed, Web of Science, and Wanfang databases was performed for relevant publications. Overall, there were three eligible case-control studies with 1,360 cases and 1,522 controls included into our study. The pooled ORs showed that the EGFR 142285G > A variant genotypes did not increase or decrease the risk of breast cancer under the following gene models: A vs. G, OR = 1.07, 95% CI 0.96-1.19, P OR = 0.240; AA vs. GG, OR = 1.14, 95% CI 0.91-1.42, P OR = 0.239; GA vs. GG, OR = 0.99, 95% CI 0.83-1.17, P OR = 0.892; GA + AA vs. GG, OR = 1.03, 95% CI 0.87-1.21, P OR = 0.727; AA vs. GG + GA, OR = 1.17, 95% CI 0.97 1.42, P OR = 0.096. The between-study heterogeneity was not significant among all studies. The current meta-analysis showed no evidence for significant association between EGFR 142285G > A polymorphism and breast cancer risk. Subsequent studies with large sample size are needed for further elucidation. PMID- 24163084 TI - Expression and clinical significance of STIP1 in papillary thyroid carcinoma. AB - The aim of this study was to detect stress-induced phosphoprotein 1 (STIP1) expression in papillary thyroid carcinoma (PTC) and to analyze its association with prognosis of PTC patients. Immunohistochemistry was performed to detect the expression of STIP1 in 113 PTC tissues and paired adjacent noncancerous tissues. The chi2 test was used to analyze the relationship between STIP1 expression and clinicopathological characteristics. Survival curves were plotted by the Kaplan Meier method and compared using the log-rank test. Survival data was evaluated using univariate and multivariate Cox regression analysis. We identified abnormally elevated expression of STIP1 protein in PTC tissues compared to paired adjacent noncancerous tissues. Clinicopathological analysis showed that STIP1 expression was significantly correlated with tumor size (P = 0.017), lymph node metastasis (P = 0.007), and TNM stage (P = 0.026). Patients with higher STIP1 expression had shorter overall survival time, whereas those with lower STIP1 expression had longer survival time. Multivariate analysis suggested that STIP1 expression might be an independent prognostic indicator (P < 0.05) for the survival of patients with PTC. In conclusion, our findings provide evidences that positive expression of STIP1 in PTC may be important in the acquisition of an aggressive phenotype, and it is an independent biomarker for poor prognosis of patients with PTC. PMID- 24163086 TI - South Asian hospitals that lack DNAR orders deny patients holistic care. PMID- 24163087 TI - "First do no harm" revisited. PMID- 24163085 TI - MACC1 is involved in the regulation of proliferation, colony formation, invasion ability, cell cycle distribution, apoptosis and tumorigenicity by altering Akt signaling pathway in human osteosarcoma. AB - There is mounting evidence that metastasis-associated in colon cancer-1 (MACC1) plays pivotal roles in development and progression of many tumors, particularly in osteosarcoma (OS). However, its precise roles and molecular mechanisms remain to be delineated in OS. In the current study, we found that the levels of MACC1 mRNA and protein in four OS cell lines (MG-63, HOS, SaOS-2 and U2OS) were significantly higher than that in hFOB1.19 osteoblast (P < 0.05). The vector pcDNA-MACC1 contributed to the increase of MACC1 level in MG-63 cells, whereas MACC1 siRNA evoked the decrease of MACC1 level in U2OS cells. In addition, MACC1 downregualtion caused the inhibition of cell proliferation in vitro, colony formation, invasion and tumor growth in vivo, arrested cell cycle in G0/G1 phase and induced cell apoptosis in U2OS cells, and reversed effects were observed in MG-63 cells by MACC1 upregulation. Most notably, MACC1 depletion markedly inactivated Akt signaling pathway in U2OS cells, conversely, MACC1 upregulation evidently activated Akt signaling pathway in MG-63 cells. Collectively, our data presented herein suggest that biological implications triggered by MACC1 may be tightly associated with the status of Akt signaling pathway in OS. PMID- 24163088 TI - MPs reject government's preferred candidate to chair Monitor. PMID- 24163090 TI - Proponents of coordinated care should focus on quality improvement, not cutting costs, conference hears. PMID- 24163089 TI - Changed guidance on payment for study participants puts them at higher risk of harm, group says. PMID- 24163091 TI - England's health regulator screens hospitals to identify which to inspect first. PMID- 24163092 TI - Recurrent varicella following steroids and fingolimod in a Multiple Sclerosis patient. PMID- 24163093 TI - Intraarticular analgesia versus epidural plus femoral nerve block after TKA: a randomized, double-blind trial. AB - BACKGROUND: Pain management after TKA remains challenging and the efficacy of continuously infused intraarticular anesthetics remains a controversial topic. QUESTIONS/PURPOSES: We compared the side effect profile, analgesic efficacy, and functional recovery between patients receiving a continuous intraarticular infusion of ropivacaine and patients receiving an epidural plus femoral nerve block (FNB) after TKA. METHODS: Ninety-four patients undergoing unilateral TKA were prospectively randomized to receive a spinal-epidural analgesic infusion plus a single-injection FNB or a spinal anesthetic plus a continuous postoperative intraarticular infusion of 0.2% ropivacaine. All patients were blinded to their treatment with placebo saline catheters. Blinded coinvestigators collected data concerning side effect profiles (nausea, hypotension), analgesic efficacy (VAS pain scores, narcotic usage), and functional recovery (timed up and go test, quadriceps strength, WOMAC scores, Knee Society scores, early postoperative ambulatory ability, in-hospital falls). All complications and adverse events were recorded. RESULTS: The frequency of nausea and hypertension was not different between the study groups. During the first 12 and 24 postoperative hours, the mean maximum VAS pain scores were higher in the ropivacaine group than in the epidural group (first 12 hours: 3.93 versus 1.14, respectively, p < 0.0001; 12-24 hours: 3.52 versus 1.93, respectively, p = 0.008). After 24 hours, pain scores were similar between groups. Narcotic consumption was significantly higher in the ropivacaine group on the day of surgery, but overall in-hospital narcotic usage was similar between groups. There were no clinically important differences in functional recovery between groups at any time point, but patients in the epidural group were more likely to have knee buckling (32.7% versus 6.7%, p = 0.002) and delayed ambulation (16.3% versus 0.0%, p = 0.006) than patients in the ropivacaine group, though not in-hospital falls. No infections occurred in either group, and the frequency of complications was not different between groups. CONCLUSIONS: A continuous intraarticular infusion of ropivacaine can be recommended as a safe, effective alternative to epidural analgesia plus single-injection FNB after TKA. Improved analgesic efficacy in the group that received epidural analgesia plus single-injection FNB must be weighed against the disadvantage of a higher likelihood of knee buckling and delayed ambulation with that treatment approach. LEVEL OF EVIDENCE: Level I, therapeutic study. See Instructions for Authors for a complete description of levels of evidence. PMID- 24163094 TI - Long-term results and bone remodeling after THA with a short, metaphyseal-fitting anatomic cementless stem. AB - BACKGROUND: Long-term results of standard total hip arthroplasty (THA) in young patients were not optimal. There are a number of reported disadvantages to longer cementless stems in THA including thigh pain and proximal stress shielding. However, it is unknown whether a short, metaphyseal-fitting anatomic stem without diaphyseal fixation, which represents a possible alternative, will maintain fixation over the longer term. QUESTION/PURPOSES: We therefore evaluated long term (1) clinical results using validated scoring instruments; (2) osseointegration and bone remodeling; (3) complications; and (4) rates of revision and osteolysis in patients younger than 65 years who underwent THA with a short, metaphyseal-fitting anatomic cementless stem. METHODS: We reviewed 500 patients (630 hips) younger than 65 years (mean age at surgery, 52.7 years) who underwent THA with the Immediate Postoperative Stability stem (IPS; DePuy, Leeds, UK) by one surgeon (Y-HK) from January 1995 to March 2002. Demographic data, Harris hip score, WOMAC score, UCLA activity score, and radiographic data were recorded. All patients underwent dual-energy x-ray absorptiometry scanning of the acetabulum and proximal femur at 2 weeks after the operation and at final followup to determine stress shielding. Thigh pain was specifically investigated and scored by patients on a visual analog scale. Other complications were recorded. We determined component survival rates at 15 years using revision and aseptic loosening as end points. Minimum followup was 11 years (mean, 15.8 years; range, 11-18 years). RESULTS: The clinical and functional results improved significantly for the Harris hip score, WOMAC, and UCLA activity scores (p < 0.001). At latest followup, mean Harris hip, WOMAC, and UCLA activity scores were 94 (range, 71-100), 15 (range, 5-29), and 7.9 (range, 6-9) points, respectively. All hips had osseous integration of the acetabular and femoral components. No patients had thigh pain. Four hips (0.6%) had deep infection and four (0.6%) had a recurrent dislocation. No patients had Grade 3 stress shielding. Fifteen-year survival rates were 98.7% (95% confidence interval [CI], 0.95-1.00) for the acetabular component and 99.4% (95% CI, 0.97-1.00) for the femoral component with revision as the end point and 100% (95% CI, 0.98-1.00) for both components with aseptic loosening as the end point. CONCLUSIONS: The short, metaphyseal-fitting anatomic cementless femoral stem provided stable fixation without relying on diaphyseal fixation in younger patients, suggesting metaphyseal fitting alone is sufficient in young patients who have good bone quality. Because we observed no thigh pain and little stress shielding in our patients, modifying the distal stem design as is done with this implant might be advantageous, but this would need to be determined in future comparative studies. LEVEL OF EVIDENCE: Level IV, therapeutic study. See Instructions for Authors for a complete description of levels of evidence. PMID- 24163095 TI - Perception of effort changes following an isometric fatiguing exercise of elbow flexors. AB - The way psychometric and neurophysiological measurements of fatigue are connected is not well understood. Thus, the time course of perceived effort changes due to fatigue, as well as the peripheral and central neurophysiological changes accompanying fatigue, were evaluated. Twelve healthy participants (35 +/- 9 years old) undertook 10 min intermittent isometric fatiguing exercise of elbow flexors at 50% of maximum voluntary contraction (MVC). Perceived effort ratings, using the 0-10 numeric rating scale (NRS), were recorded at midrange of MVC. Single pulse TMS of the left motor cortex and electrical stimulation over the biceps muscle was used for the assessment of voluntary activation and peripheral fatigue. The fatiguing exercise caused a 44% reduction in the MVC (p < .001) accompanied by an 18% nonsignificant reduction of the biceps MEP amplitude. The resting twitch force decreased (p < .001) while the superimposed twitches increased (p < .001) causing a decrease (19%) of the voluntary activation (p < .001). The perceived effort ratings increased by 1 point at 30%, by 2 points at 50% MVC respectively on the NRS (p < .001) and were accompanied by an increase in mean biceps EMG. A substantial role of the perceived effort in the voluntary motor control system was revealed. PMID- 24163096 TI - Changes in renal function over time in patients with cardiac resynchronisation therapy. AB - QUESTION UNDER STUDY: Cardiac resynchronisation therapy (CRT) with defibrillator back-up (CRT-D) is widely used in selected patients with moderate/severe heart failure. Renal failure is common in these patients. Data on the impact of CRT on renal function are controversial and limited by short follow-up. The aim of this study was to describe changes in glomerular filtration rate (GFR) from baseline compared with 1 and 2 years after CRT implantation. METHODS: A total of 284 CRT-D patients with creatinine levels at baseline and after 1 year were identified in two prospective registries. In 149 patients, levels after 2 years were available. GFR in ml/min/1.73 m2 was estimated with the Modification Diet in Renal Disease equation and patients stratified into GFR stages 1 to 4. RESULTS: The population was predominantly male (75%), mean (+/- standard deviation) age was 61 +/- 7 years and ejection fraction 24% +/- 8 %. GFR was 63 +/- 24 ml/min/1.73 m2 at implantation and 60 +/- 24 ml/min/1.73 m2 after 1 year (p = 0.26). At the 2-year follow-up, GFR had decreased from 60 +/- 21 to 56 +/- 21 ml/min/1.73 m2 (p = 0.04). Mean GFR decreased in stages 1 and 2, remained stable in stage 3 and improved in stage 4 patients. After 2 years, GFR had decreased >=10 ml/min/1.73 m2 in 42%, but improved in only 15% (p = 0.04). CONCLUSIONS: Overall, mean GFR in CRT-D patients decreases at 1 and 2 years after implantation, depending in part on the initial degree of renal function. However, the chance of further substantial deterioration (>=10 ml/min/1.73 m2) is considerable. PMID- 24163097 TI - Strategies to improve adherence and acceptability of hormonal methods of contraception. AB - BACKGROUND: Worldwide, hormonal contraceptives are among the most popular reversible contraceptives. Despite their high theoretical effectiveness, typical use results in much lower effectiveness. In large part, this disparity reflects difficulties in adherence to the contraceptive regimen and low rates for long term continuation. OBJECTIVES: The intent was to determine the effectiveness of ancillary counseling techniques to improve adherence to, and continuation of, hormonal methods of contraception. SEARCH METHODS: Through August 2013, we searched computerized databases for randomized controlled trials (RCTs) comparing client-provider interventions with standard family planning counseling. Sources included CENTRAL, MEDLINE, EMBASE, POPLINE, ClinicalTrials.gov and ICTRP. Earlier searches also included LILACS, PsycINFO, Dissertation Abstracts, African Index Medicus, and IMEMR. SELECTION CRITERIA: We included RCTs of an intensive counseling technique or other client-provider intervention compared to routine family planning counseling. Interventions included group motivation; structured, peer, or multi-component counseling; and intensive reminders of appointments or next dosing. Outcome measures were discontinuation, reasons for discontinuation, number of missed pills or on-time injections, and pregnancy. DATA COLLECTION AND ANALYSIS: One author evaluated the titles and abstracts from the searches to determine eligibility. Two authors extracted data from the included studies. We calculated the Mantel-Haenszel odds ratio (OR) for dichotomous outcomes. For continuous variables, the mean difference (MD) was computed; RevMan uses the inverse variance approach. For all analyses, 95% confidence intervals (CI) were also computed. Since the studies identified differed in both interventions and outcome measures, we did not conduct a meta-analysis. MAIN RESULTS: Nine RCTs met our inclusion criteria. Five involved direct counseling; of those, two also provided multiple contacts by telephone. Four other trials provided intensive reminders, two of which also provided health education information. Three trials showed some benefit of the experimental intervention. In a counseling intervention, women who received repeated structured information about the injectable depot medroxyprogesterone acetate (DMPA) were less likely to discontinue the method by 12 months (OR 0.27; 95% CI 0.16 to 0.44) than women who had routine counseling. The intervention group was also less likely to discontinue due to menstrual disturbances (OR 0.20; 95% CI 0.11 to 0.37). Another trial showed a group with special counseling plus phone calls was more likely than the special-counseling group to report consistent use of oral contraceptives (OC) at 3 months (OR 1.41; 95% CI 1.06 to 1.87), though not at 12 months. The group with only special counseling did not differ significantly from those with standard care for any outcome. The third trial compared daily text-message reminders about OCs plus health information versus standard care. Women in the text-message group were more likely than the standard-care group to continue OC use by six months (OR 1.54; 95% CI 1.14 to 2.10). The text-message group was also more likely to avoid an interruption in OC use longer than seven days (OR 1.53; 95% CI 1.13 to 2.07). AUTHORS' CONCLUSIONS: Only three trials showed some benefit of strategies to improve adherence and continuation. However, several had small sample sizes and six had high losses to follow up. The overall quality of evidence was considered moderate. The intervention type and intensity varied greatly across the studies. A combination of intensive counseling and multiple contacts and reminders may be needed to improve adherence and acceptability of contraceptive use. High-quality RCTs with adequate power and well-designed interventions could help identify ways to improve adherence to, and continuation of, hormonal contraceptive methods. PMID- 24163098 TI - SMMRNA: a database of small molecule modulators of RNA. AB - We have developed SMMRNA, an interactive database, available at http://www.smmrna.org, with special focus on small molecule ligands targeting RNA. Currently, SMMRNA consists of ~770 unique ligands along with structural images of RNA molecules. Each ligand in the SMMRNA contains information such as Kd, Ki, IC50, DeltaTm, molecular weight (MW), hydrogen donor and acceptor count, XlogP, number of rotatable bonds, number of aromatic rings and 2D and 3D structures. These parameters can be explored using text search, advanced search, substructure and similarity-based analysis tools that are embedded in SMMRNA. A structure editor is provided for 3D visualization of ligands. Advance analysis can be performed using substructure and OpenBabel-based chemical similarity fingerprints. Upload facility for both RNA and ligands is also provided. The physicochemical properties of the ligands were further examined using OpenBabel descriptors, hierarchical clustering, binning partition and multidimensional scaling. We have also generated a 3D conformation database of ligands to support the structure and ligand-based screening. SMMRNA provides comprehensive resource for further design, development and refinement of small molecule modulators for selective targeting of RNA molecules. PMID- 24163099 TI - The human oncoprotein MDM2 induces replication stress eliciting early intra-S phase checkpoint response and inhibition of DNA replication origin firing. AB - Conventional paradigm ascribes the cell proliferative function of the human oncoprotein mouse double minute2 (MDM2) primarily to its ability to degrade p53. Here we report that in the absence of p53, MDM2 induces replication stress eliciting an early S-phase checkpoint response to inhibit further firing of DNA replication origins. Partially synchronized lung cells cultured from p53-/-:MDM2 transgenic mice enter S phase and induce S-phase checkpoint response earlier than lung cells from p53-/- mice and inhibit firing of DNA replication origins. MDM2 activates chk1 phosphorylation, elevates mixed lineage lymphoma histone methyl transferase levels and promotes checkpoint-dependent tri-methylation of histone H3 at lysine 4, known to prevent firing of late replication origins at the early S phase. In the absence of p53, a condition that disables inhibition of cyclin A expression by MDM2, MDM2 increases expression of cyclin D2 and A and hastens S phase entry of cells. Consistently, inhibition of cyclin-dependent kinases, known to activate DNA replication origins during firing, inhibits MDM2-mediated induction of chk1 phosphorylation indicating the requirement of this activity in MDM2-mediated chk1 phosphorylation. Our data reveal a novel pathway, defended by the intra-S-phase checkpoint, by which MDM2 induces unscheduled origin firing and accelerates S-phase entry of cells in the absence of p53. PMID- 24163100 TI - uORFdb--a comprehensive literature database on eukaryotic uORF biology. AB - Approximately half of all human transcripts contain at least one upstream translational initiation site that precedes the main coding sequence (CDS) and gives rise to an upstream open reading frame (uORF). We generated uORFdb, publicly available at http://cbdm.mdc-berlin.de/tools/uorfdb, to serve as a comprehensive literature database on eukaryotic uORF biology. Upstream ORFs affect downstream translation by interfering with the unrestrained progression of ribosomes across the transcript leader sequence. Although the first uORF-related translational activity was observed >30 years ago, and an increasing number of studies link defective uORF-mediated translational control to the development of human diseases, the features that determine uORF-mediated regulation of downstream translation are not well understood. The uORFdb was manually curated from all uORF-related literature listed at the PubMed database. It categorizes individual publications by a variety of denominators including taxon, gene and type of study. Furthermore, the database can be filtered for multiple structural and functional uORF-related properties to allow convenient and targeted access to the complex field of eukaryotic uORF biology. PMID- 24163101 TI - Genome-wide reorganization of histone H2AX toward particular fragile sites on cell activation. AB - gammaH2AX formation by phosphorylation of the histone variant H2AX is the key process in the repair of DNA lesions including those arising at fragile sites under replication stress. Here we demonstrate that H2AX is dynamically reorganized to preoccupy gammaH2AX hotspots on increased replication stress by activated cell proliferation and that H2AX is enriched in aphidicolin-induced replisome stalling sites in cycling cells. Interestingly, H2AX enrichment was particularly found in genomic regions that replicate in early S phase. High transcription activity, a hallmark of early replicating fragile sites, was a determinant of H2AX localization. Subtelomeric H2AX enrichment was also attributable to early replication and high gene density. In contrast, late replicating and infrequently transcribed regions, including common fragile sites and heterochromatin, lacked H2AX enrichment. In particular, heterochromatin was inaccessible to H2AX incorporation, maybe partly explaining the cause of mutation accumulation in cancer heterochromatin. Meanwhile, H2AX in actively dividing cells was intimately colocalized with INO80. INO80 silencing reduced H2AX levels, particularly at the INO80-enriched sites. Our findings suggest that active DNA replication is accompanied with the specific localization of H2AX and INO80 for efficient damage repair or replication-fork stabilization in actively transcribed regions. PMID- 24163102 TI - Detection of G-quadruplex DNA in mammalian cells. AB - It has been proposed that guanine-rich DNA forms four-stranded structures in vivo called G-quadruplexes or G4 DNA. G4 DNA has been implicated in several biological processes, but tools to study G4 DNA structures in cells are limited. Here we report the development of novel murine monoclonal antibodies specific for different G4 DNA structures. We show that one of these antibodies designated 1H6 exhibits strong nuclear staining in most human and murine cells. Staining intensity increased on treatment of cells with agents that stabilize G4 DNA and, strikingly, cells deficient in FANCJ, a G4 DNA-specific helicase, showed stronger nuclear staining than controls. Our data strongly support the existence of G4 DNA structures in mammalian cells and indicate that the abundance of such structures is increased in the absence of FANCJ. We conclude that monoclonal antibody 1H6 is a valuable tool for further studies on the role of G4 DNA in cell and molecular biology. PMID- 24163103 TI - Structural determinants of human APOBEC3A enzymatic and nucleic acid binding properties. AB - Human APOBEC3A (A3A) is a single-domain cytidine deaminase that converts deoxycytidine residues to deoxyuridine in single-stranded DNA (ssDNA). It inhibits a wide range of viruses and endogenous retroelements such as LINE-1, but it can also edit genomic DNA, which may play a role in carcinogenesis. Here, we extend our recent findings on the NMR structure of A3A and report structural, biochemical and cell-based mutagenesis studies to further characterize A3A's deaminase and nucleic acid binding activities. We find that A3A binds ssRNA, but the RNA and DNA binding interfaces differ and no deamination of ssRNA is detected. Surprisingly, with only one exception (G105A), alanine substitution mutants with changes in residues affected by specific ssDNA binding retain deaminase activity. Furthermore, A3A binds and deaminates ssDNA in a length dependent manner. Using catalytically active and inactive A3A mutants, we show that the determinants of A3A deaminase activity and anti-LINE-1 activity are not the same. Finally, we demonstrate A3A's potential to mutate genomic DNA during transient strand separation and show that this process could be counteracted by ssDNA binding proteins. Taken together, our studies provide new insights into the molecular properties of A3A and its role in multiple cellular and antiviral functions. PMID- 24163104 TI - REST mediates androgen receptor actions on gene repression and predicts early recurrence of prostate cancer. AB - The androgen receptor (AR) is a key regulator of prostate tumorgenesis through actions that are not fully understood. We identified the repressor element (RE)-1 silencing transcription factor (REST) as a mediator of AR actions on gene repression. Chromatin immunoprecipitation showed that AR binds chromatin regions containing well-characterized cis-elements known to mediate REST transcriptional repression, while cell imaging studies confirmed that REST and AR closely co localize in vivo. Androgen-induced gene repression also involves modulation of REST protein turnover through actions on the ubiquitin ligase beta-TRCP. Androgen deprivation or AR blockage with inhibitor MDV3100 (Enzalutamide) leads to neuroendocrine (NE) differentiation, a phenomenon that is mimicked by REST inactivation. Gene expression profiling revealed that REST not only acts to repress neuronal genes but also genes involved in cell cycle progression, including Aurora Kinase A, that has previously been implicated in the growth of NE-like castration-resistant tumors. The analysis of prostate cancer tissue microarrays revealed that tumors with reduced expression of REST have higher probability of early recurrence, independently of their Gleason score. The demonstration that REST modulates AR actions in prostate epithelia and that REST expression is negatively correlated with disease recurrence after prostatectomy, invite a deeper characterization of its role in prostate carcinogenesis. PMID- 24163105 TI - PolymiRTS Database 3.0: linking polymorphisms in microRNAs and their target sites with human diseases and biological pathways. AB - Polymorphisms in microRNAs (miRNAs) and their target sites (PolymiRTS) are known to disrupt miRNA function, leading to the development of disease and variation in physiological and behavioral phenotypes. Here, we describe recent updates to the PolymiRTS database (http://compbio.uthsc.edu/miRSNP), an integrated platform for analyzing the functional impact of genetic polymorphisms in miRNA seed regions and miRNA target sites. Recent advances in genomic technologies have made it possible to identify miRNA-mRNA binding sites from direct mapping experiments such as CLASH (cross linking, ligation and sequencing of hybrids). We have integrated data from CLASH experiments in the PolymiRTS database to provide more complete and accurate miRNA-mRNA interactions. Other significant new features include (i) small insertions and deletions in miRNA seed regions and miRNA target sites, (ii) TargetScan context + score differences for assessing the impact of polymorphic miRNA-mRNA interactions and (iii) biological pathways. The browse and search pages of PolymiRTS allow users to explore the relations between the PolymiRTSs and gene expression traits, physiological and behavioral phenotypes, human diseases and biological pathways. PMID- 24163106 TI - Stochastic reaction-diffusion processes with embedded lower-dimensional structures. AB - Small copy numbers of many molecular species in biological cells require stochastic models of the chemical reactions between the molecules and their motion. Important reactions often take place on one-dimensional structures embedded in three dimensions with molecules migrating between the dimensions. Examples of polymer structures in cells are DNA, microtubules, and actin filaments. An algorithm for simulation of such systems is developed at a mesoscopic level of approximation. An arbitrarily shaped polymer is coupled to a background Cartesian mesh in three dimensions. The realization of the system is made with a stochastic simulation algorithm in the spirit of Gillespie. The method is applied to model problems for verification and two more detailed models of transcription factor interaction with the DNA. PMID- 24163108 TI - The safety and efficacy of magnetic nano-iron hyperthermia therapy on rat brain glioma. AB - Gliomas are a group of heterogeneous primary central nervous system tumors arising from glial cells. These tumors are associated with high morbidity and mortality. New opportunities for the development of effective therapies for malignant gliomas are urgently needed. Magnetic nano-particles can heat up tumor tissues and induce the killing of cancer cells. However, the in vivo action of magnetic nano-iron hyperthermia on brain gliomas has not been widely investigated. The safety, efficacy, and suitable dose of hyperthermia therapy remain unknown. We successfully established a rat model of brain glioma by injecting C6 glioma cells into the right caudate nuclei of rats. Fixed doses (2.5, 5, or 10 mg) of magnetic nano-iron were then injected into the tumors of tumor-bearing rats. The survival time of tumor-bearing rats was subsequently observed, and imaging studies were conducted on the brain tumors. Of the 80 rats that underwent C6 glioma cell implantation, 70 exhibited decreased mobility and appetite, and wasting. Establishment of this brain glioma model was confirmed to be successful by magnetic resonance imaging. After injection of different doses of magnetic nano-iron, the survival times of the different dose groups of tumor bearing rats were not significantly different. However, the tumor size exhibited a significant decrease with magnetic nano-iron hyperthermia therapy. Injection of various doses of magnetic nano-iron was safe in tumor-bearing rats. The effective doses were 2.5 and 5 mg. Magnetic nano-iron hyperthermia significantly shrank the brain gliomas in tumor-bearing rats. PMID- 24163109 TI - Optimization of extraction and purification of arctiin from Fructus arctii and its protection against glucose-induced rat aortic endothelial cell injury. AB - To develop an efficient method for extracting and purifying the active ingredient, arctiin, from Fructus arctii and to investigate the protective effect of arctiin against glucose-induced rat aortic endothelial cell (RAEC) injury was investigated. Using a L9 (34) orthogonal array and two-step column chromatography (with AB-8 macroporous resin) arctiin extraction was optimized using a reflux method with 70% ethanol. The RAECs were then treated with different concentrations of arctiin (1, 10, or 100 MUg/ml). The effects of arctiin on cell viability in a high glucose medium, malondialdehyde (MDA) levels, and lactate dehydrogenase were measured using commercially available assays. After extraction, the purity of arctiin reached 95.7%. In rats, arctiin was shown to stimulate the proliferation of RAECs in a high glucose medium in a dose-dependent manner. Exposure of RAECs to high glucose resulted in a significant increase in MDA and release of lactate dehydrogenase. This was accompanied by significant increase in nitric oxide release and expression of antiendothelial nitric oxide synthase. This technique resulted in relatively pure arctiin extraction. Furthermore, the results from this study suggest that arctiin could potentially function as a protector against vascular endothelial cell injury and further investigation is warranted. PMID- 24163110 TI - Medical care of type 2 diabetes mellitus in light of international and national recommendations: a retrospective analysis. AB - QUESTION UNDER STUDY: Type 2 diabetes mellitus (T2Dm) is a chronic disease with great economic impact. In 2009, the Swiss Society for Endocrinology and Diabetes (SSED) published recommendations for treatment of T2Dm. In Switzerland, few data are currently available on metabolic control and physician compliance with treatment guidelines. We aimed to investigate clinical care in T2Dm in the year after the publication of SSED recommendations. METHODS: We retrospectively studied the charts of all patients with T2Dm admitted to our general internal medicine clinic during 2009. Metabolic control was judged from glycated haemoglobin A1c (HbA1c) levels. Antidiabetic therapy was analysed, and frequencies of screening for end-organ damage were investigated. A group with newly diagnosed T2Dm was analysed separately from patients with known T2Dm upon admission. RESULTS: In patients with known T2Dm, the mean (+/- standard deviation) HbA1c level was 7.66% +/- 1.73%. Only 44% of patients showed HbA1c levels at the target of <=7%. Prior to admission and at discharge, 56% and 55% of patients, respectively, were treated with metformin. Among patients with HbA1c >8.5%, the proportion of those treated with insulin increased from 49% upon admission to 76% at discharge. Only half the patients received a lifestyle intervention in the year prior to admission or during hospital stay. Screening for diabetic retinopathy and nephropathy was performed in approximately one-third and two-thirds of patients, respectively. CONCLUSIONS: In the majority of unselected T2Dm patients admitted to our hospital, metabolic control was suboptimal. Implementation of treatment recommendations by both general practitioners and hospitals should be improved. PMID- 24163107 TI - Embryonic stem cell-specific signature in cervical cancer. AB - The wide range of invasive and noninvasive lesion phenotypes associated with high risk human papillomavirus (HR-HPV) infection in cervical cancer (CC) indicates that not only the virus but also specific cervical epithelial cells in the transformation zone (TZ), such as stem cells (SCs), play an important part in the development of cervical neoplasia. In this review, we focused in an expression signature that is specific to embryonic SCs and to poorly differentiated cervical malignant tumors and we hypothesize that this expression signature may play an important role to promote cell growth, survival, colony formation, lack of adhesion, as well as cell invasion and migration in CC. PMID- 24163111 TI - A direct comparison of short-term audiomotor and visuomotor memory. AB - Audiomotor and visuomotor short-term memory are required for an important variety of skilled movements but have not been compared in a direct manner previously. Audiomotor memory capacity might be greater to accommodate auditory goals that are less directly related to movement outcome than for visually guided tasks. Subjects produced continuous isometric force with the right index finger under auditory and visual feedback. During the first 10 s of each trial, subjects received continuous auditory or visual feedback. For the following 15 s, feedback was removed but the force had to be maintained accurately. An internal effort condition was included to test memory capacity in the same manner but without external feedback. Similar decay times of ~5-6 s were found for vision and audition but the decay time for internal effort was ~4 s. External feedback thus provides an advantage in maintaining a force level after feedback removal, but may not exclude some contribution from a sense of effort. Short-term memory capacity appears longer than certain previous reports but there may not be strong distinctions in capacity across different sensory modalities, at least for isometric force. PMID- 24163112 TI - Behavioral interventions for improving condom use for dual protection. AB - BACKGROUND: Unprotected sex is a major risk factor for disease, disability, and mortality in many areas of the world due to the prevalence and incidence of sexually transmitted infections (STI) including HIV. The male condom is one of the oldest contraceptive methods and the earliest method for preventing the spread of HIV. When used correctly and consistently, condoms can provide dual protection, i.e., against both pregnancy and HIV/STI. OBJECTIVES: We examined comparative studies of behavioral interventions for improving condom use. We were interested in identifying interventions associated with effective condom use as measured with biological assessments, which can provide objective evidence of protection. SEARCH METHODS: Through September 2013, we searched computerized databases for comparative studies of behavioral interventions for improving condom use: MEDLINE, POPLINE, CENTRAL, EMBASE, LILACS, OpenGrey, COPAC, ClinicalTrials.gov, and ICTRP. We wrote to investigators for missing data. SELECTION CRITERIA: Studies could be either randomized or nonrandomized. They examined a behavioral intervention for improving condom use. The comparison could be another behavioral intervention, usual care, or no intervention. The experimental intervention had an educational or counseling component to encourage or improve condom use. It addressed preventing pregnancy as well as the transmission of HIV/STI. The focus could be on male or female condoms and targeted to individuals, couples, or communities. Potential participants included heterosexual women and heterosexual men.Studies had to provide data from test results or records on a biological outcome: pregnancy, HIV/STI, or presence of semen as assessed with a biological marker, e.g., prostate-specific antigen. We did not include self-reported data on protected or unprotected sex, due to the limitations of recall and social desirability bias. Outcomes were measured at least three months after the behavioral intervention started. DATA COLLECTION AND ANALYSIS: Two authors evaluated abstracts for eligibility and extracted data from included studies. For the dichotomous outcomes, the Mantel-Haenszel odds ratio (OR) with 95% CI was calculated using a fixed-effect model. Cluster randomized trials used various methods of accounting for the clustering, such as multilevel modeling. Most reports did not provide information to calculate the effective sample size. Therefore, we presented the results as reported by the investigators. No meta-analysis was conducted due to differences in interventions and outcome measures. MAIN RESULTS: Seven studies met our eligibility criteria. All were randomized controlled trials; six assigned clusters and one randomized individuals. Sample sizes for the cluster-randomized trials ranged from 2157 to 15,614; the number of clusters ranged from 18 to 70. Four trials took place in African countries, two in the USA, and one in England. Three were based mainly in schools, two were in community settings, one took place during military training, and one was clinic-based.Five studies provided data on pregnancy, either from pregnancy tests or national records of abortions and live births. Four trials assessed the incidence or prevalence of HIV and HSV-2. Three trials examined other STI. The trials showed or reported no significant difference between study groups for pregnancy or HIV, but favorable effects were evident for some STI. Two showed a lower incidence of HSV-2 for the behavioral-intervention group compared to the usual-care group, with reported adjusted rate ratios (ARR) of 0.65 (95% CI 0.43 to 0.97) and 0.67 (95% CI 0.47 to 0.97), while HIV did not differ significantly. One also reported lower syphilis incidence and gonorrhea prevalence for the behavioral intervention plus STI management compared to the usual-care group. The reported ARR were 0.58 (95% CI 0.35 to 0.96) and 0.28 (95% CI 0.11 to 0.70), respectively. Another study reported a negative effect on gonorrhea for young women in the intervention group versus the control group (ARR 1.93; 95% CI 1.01 to 3.71). The difference occurred among those with only one year of the intervention. AUTHORS' CONCLUSIONS: We found few studies and little clinical evidence of effectiveness for interventions promoting condom use for dual protection. We did not find favorable results for pregnancy or HIV, and only found some for other STI. The overall quality of evidence was moderate to low; losses to follow up were high. Effective interventions for improving condom use are needed to prevent pregnancy and HIV/STI transmission. Interventions should be feasible for resource-limited settings and tested using valid and reliable outcome measures. PMID- 24163113 TI - Dipeptidyl peptidase-4 inhibition in patients with type 2 diabetes treated with saxagliptin, sitagliptin, or vildagliptin. AB - INTRODUCTION: Saxagliptin, sitagliptin, and vildagliptin are dipeptidyl peptidase 4 (DPP-4) inhibitors widely approved for use in patients with type 2 diabetes. Using a crossover design, the present study compared trough levels of DPP-4 inhibition provided by these agents in a single cohort of patients with type 2 diabetes. METHODS: This was a randomized, placebo-controlled, open-label, five period crossover study. Eligible patients were 18-65 years of age, either treatment-naive or off prior antihyperglycemic agent therapy for at least 6 or 12 weeks (depending on the prior therapy), and had glycated hemoglobin (HbA1C) >=6.5% and <=10.0%. In separate study periods, patients received 5 mg saxagliptin q.d. (saxa-5), 100 mg sitagliptin q.d. (sita-100), 50 mg vildagliptin q.d. (vilda 50-q.d.), 50 mg vildagliptin b.i.d. (vilda-50-b.i.d.), or placebo for 5 days. The primary endpoint was trough %DPP-4 inhibition, derived by comparing DPP-4 activity 24 h after the Day-5 morning dose with predose activity in the same period and analyzed using a linear mixed-effects model with fixed-effects terms for treatment and period. RESULTS: Mean (range) baseline HbA1C was 7.4% (6.4 9.0%; N = 22). Least-squares (LS) mean trough %DPP-4 inhibition was 73.5%, 91.7%, 28.9%, 90.6%, and 3.5% after saxa-5, sita-100, vilda-50-q.d., vilda-50-b.i.d., and placebo, respectively. In patients treated with sita-100, the LS-mean difference in trough %DPP-4 inhibition was 18.2% greater than with saxa-5 (p < 0.001), 62.9% greater than with vilda-50-q.d. (p < 0.001), 1.1% greater than with vilda-50-b.i.d. (p = 0.128), and 87.8% greater than with placebo (p < 0.001). Mean %DPP-4 inhibition was nearly maximal at 12 h postdose regardless of active treatment. Thus, these between-group comparisons at trough primarily reflected differences in duration of action. Adverse events reported during the study were transient and mild or moderate in intensity. CONCLUSION: Once daily treatment with sitagliptin provided trough DPP-4 inhibition significantly greater than saxagliptin or vildagliptin administered once daily, and similar to that provided by vildagliptin administered twice daily. PMID- 24163115 TI - Anxiety score and radial artery vasospasm. PMID- 24163114 TI - Modeling the autism spectrum disorder phenotype. AB - Autism Spectrum Disorder (ASD) is highly heritable, and although there has been active research in an attempt to discover the genetic factors underlying ASD, diagnosis still depends heavily on behavioral assessments. Recently, several large-scale initiatives, including those of the Autism Consortium, have contributed to the collection of extensive information from families affected by ASD. Our goal was to develop an ontology that can be used 1) to provide improved access to the data collected by those who study ASD and other neurodevelopmental disorders, and 2) to assess and compare the characteristics of the instruments that are used in the assessment of ASD. We analyzed two dozen instruments used to assess ASD, studying the nature of the questions asked and items assessed, the method of delivery, and the overall scope of the content. These data together with the extensive literature on ASD contributed to our iterative development of an ASD phenotype ontology. The final ontology comprises 283 concepts distributed across three high-level classes, 'Personal Traits', 'Social Competence', and 'Medical History'. The ontology is fully integrated with the Autism Consortium database, allowing researchers to pose ontology-based questions. The ontology also allows researchers to assess the degree of overlap among a set of candidate instruments according to several objective criteria. The ASD phenotype ontology has promise for use in research settings where extensive phenotypic data have been collected, allowing a concept-based approach to identifying behavioral features of importance and for correlating these with genotypic data. PMID- 24163117 TI - Uric acid and coronary collateral circulation: to be or not to be? PMID- 24163116 TI - Effect of atorvastatin on low-density lipoprotein subpopulations and comparison between indicators of plasma atherogenicity: a pilot study. AB - Treatment with statins to achieve target low-density lipoprotein cholesterol (LDL C) levels is still associated with residual risk. Lipoprotein subfraction evaluation can provide additional information regarding atherogenicity in these individuals. Patients (n = 40) with hypercholesterolemia (29 females, mean age 63 years), without previous hypolipemic treatment, were treated with atorvastatin 40 mg/d for 3 months. Atorvastatin significantly reduced total cholesterol (6.7 +/- 1.0 vs 4.6 +/- 1.3 mmol/L, P < .001), LDL-C (4.3 +/- 1.0 vs 2.6 +/- 0.9 mmol/L, P < .001), triglycerides (1.8 +/- 0.9 vs 1.5 +/- 1.00 mmol/L, P < .05), small-dense LDL (sdLDL) fraction 3 to 7 (0.22 +/- 0.37 vs 0.09 +/- 0.16 mmol/L, P < .001), and apolipoprotein B (apoB; 1.0 +/- 0.2 vs 0.74 +/- 0.2 g/L, P < .001). There was a negative correlation of atherogenic index of plasma (AIP) with buoyant LDL-1 and LDL-2 (r = -.35; P < .05) and positive with sdLDL-3 to sdLDL-7 (r = .52, P < .001). Administration of atorvastatin 40 mg/d in patients with hypercholesterolemia caused a shift in sdLDL subfractions to large, buoyant subfractions. The AIP better correlated with sdLDL than apoB levels. PMID- 24163118 TI - gamma-Glutamyl transferase activity and the burden of coronary atherosclerosis in patients with ST-segment elevation myocardial infarction. AB - The relationship between extent, severity, and complexity of coronary artery disease (CAD) in patients with ST-segment elevation myocardial infarction (STEMI) and serum gamma-glutamyl transferase (GGT) activity has not been adequately studied. We evaluated the relationship between GGT activity and the burden of CAD as assessed by SYNTAX score (SXscore) in patients with STEMI. A total of 243 patients (age 67.1 +/- 8.6, 77.4% male) with STEMI were divided into 2 groups. Low- and high-SXscore groups were defined as SXscore <22 and >=22, respectively. Admission GGT activities were similar between low- and high-SXscore groups (32 +/ 17 vs 33 +/- 18; P = .625), and there was no significant correlation between GGT activity and SXscore. Although there was an association between high SXscore and major adverse cardiovascular events, as expected, our results did not demonstrate any relationship between admission GGT activities and complexity and extent of the coronary lesions in patients with STEMI. PMID- 24163119 TI - Treat-to-target low-density lipoprotein cholesterol: time to debate a too simple and dogmatic paradigm. PMID- 24163120 TI - Comparision of effects of rosuvastatin versus atorvastatin treatment on plasma levels of asymmetric dimethylarginine in patients with hyperlipidemia having coronary artery disease. AB - Elevated plasma levels of asymmetric dimethylarginine (ADMA) are prevalent in patients with hypercholesterolemia and coronary artery disease. A total of 83 patients with hypercholesterolemia and angiographically documented mild coronary artery stenosis were randomized to rosuvastatin treatment (20 mg) or atorvastatin treatment (40 mg) once daily for 6 weeks after a 4-week dietary lead-in phase. Both statins decreased total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), and triglyceride levels effectively. Only rosuvastatin increased high-density lipoprotein cholesterol (HDL-C) levels. Both rosuvastatin and atorvastatin decreased plasma ADMA levels; rosuvastatin had a significantly greater effect. The reduction in ADMA levels were correlated with the reduction in TC and LDL-C levels as well as LDL-C-HDL-C ratio. Treatment with rosuvastatin or atorvastatin in patients with hyperlipidemia with mild coronary artery stenosis may lead to a decrease in ADMA levels, which may contribute to improved endothelial function. PMID- 24163121 TI - Effect of remote ischemic preconditioning in the elderly patients with coronary artery disease with diabetes mellitus undergoing elective drug-eluting stent implantation. AB - There is conflicting evidence regarding the effectiveness of remote ischemic preconditioning (RIPC) in patients undergoing elective percutaneous coronary intervention (PCI). Therefore, we prospectively enrolled elderly patients with coronary heart disease (CHD) with diabetes mellitus (DM) undergoing elective drug eluting stent (DES) implantation. They were randomized to receive RIPC within 2 hours before PCI (n = 102) or not (controls, n = 98). Baseline clinical characteristics were similar between the 2 groups. Despite a trend toward decline, the median high-sensitivity cardiac troponin I (hscTnI) level (P = .256) and the incidence of myocardial infarction (MI) type 4a (P = .106) in the RIPC group 16 hours after PCI procedure was not significantly different from the control group. The RIPC could attenuate the release of a myocardial biomarker but failed to show a significant effect on hscTnI level or MI type 4a incidence after PCI procedure in elderly patients with CHD having DM undergoing elective DES implantation. PMID- 24163122 TI - Serum concentration of uric acid associated with prehypertension among Chinese population. AB - We evaluated the association between serum uric acid (SUA) levels and prehypertension in a Chinese population. A cross-sectional study was performed during 2008 to 2010, and a total of 11199 participants without hypertension or other cardiovascular diseases (CADs), aged >=35 years, were available for analysis. After adjusting for age, alcohol consumption, smoking status, body mass index, diabetes, total cholesterol, triglycerides, serum creatinine, the odds ratios (ORs) and 95% confidence intervals (CIs) of the prehypertension from the lowest (referent) to the highest levels of SUA were 1.00 (95% CI, 0.91-1.10), 1.12 (95% CI, 1.03-1.21), 1.17 (95% CI, 1.09-1.27), and 1.25 (95% CI, 1.13-1.39; linear trend P = .002). This association persisted in subgroup analysis by gender and was also consistent with separate analysis by classification of age, smoking status, alcohol usage, overweight, and diabetes mellitus. Independent of other cardiovascular risk factors, higher SUA levels are positively associated with prehypertension in a Chinese population without hypertension and CADs. Prospective trials should evaluate interventions that lower the SUA levels. PMID- 24163123 TI - Serum bilirubin level and aortic intima-media thickness in patients without clinical manifestation of atherosclerotic cardiovascular disease. AB - We investigated the association between serum bilirubin level and thoracic aortic intima-media thickness (IMT). The study population consisted of 417 patients without coronary artery disease, who underwent transesophageal echocardiography examination for various indications. The highest aortic IMT values were observed in the bilirubinlow group compared with the bilirubinhigh group (P < .001). Serum bilirubin level was associated with high-density lipoprotein cholesterol level (r = .162, P = .001), high-sensitivity C-reactive protein (hsCRP; r = -.265, P < .001), and aortic IMT (r = -.551, P < .001) in bivariate analysis. Multivariate linear regression analysis showed that serum bilirubin level was independently and negatively associated with hsCRP (beta = -.095, P = .028) and aortic IMT (beta = -.513, P < .001). Serum bilirubin level may be an independent predictor of the extent of subclinical aortic atherosclerosis assessed by thoracic aortic IMT. PMID- 24163124 TI - Update on evidence for treatment with ranolazine in stable angina. AB - Chronic angina represents a major burden for public health systems because of its poor prognosis and its high treatment costs. Ranolazine is an emerging drug recently approved for the treatment of this disease. The main molecular mechanism underlying ranolazine-mediated beneficial effects has been identified as inhibition of the late Na+ current during the action potential, which potentially improves oxygen consumption, diastolic dysfunction and coronary blood flow. Moreover, this particular mechanism of action also confers on ranolazine a potential antiarrhythmic effect. The aim of this review is to update the evidence for ranolazine treatment in chronic angina and discuss its therapeutic perspectives based on the most recent clinical and experimental studies. PMID- 24163125 TI - Tripal v1.1: a standards-based toolkit for construction of online genetic and genomic databases. AB - Tripal is an open-source freely available toolkit for construction of online genomic and genetic databases. It aims to facilitate development of community driven biological websites by integrating the GMOD Chado database schema with Drupal, a popular website creation and content management software. Tripal provides a suite of tools for interaction with a Chado database and display of content therein. The tools are designed to be generic to support the various ways in which data may be stored in Chado. Previous releases of Tripal have supported organisms, genomic libraries, biological stocks, stock collections and genomic features, their alignments and annotations. Also, Tripal and its extension modules provided loaders for commonly used file formats such as FASTA, GFF, OBO, GAF, BLAST XML, KEGG heir files and InterProScan XML. Default generic templates were provided for common views of biological data, which could be customized using an open Application Programming Interface to change the way data are displayed. Here, we report additional tools and functionality that are part of release v1.1 of Tripal. These include (i) a new bulk loader that allows a site curator to import data stored in a custom tab delimited format; (ii) full support of every Chado table for Drupal Views (a powerful tool allowing site developers to construct novel displays and search pages); (iii) new modules including 'Feature Map', 'Genetic', 'Publication', 'Project', 'Contact' and the 'Natural Diversity' modules. Tutorials, mailing lists, download and set-up instructions, extension modules and other documentation can be found at the Tripal website located at http://tripal.info. DATABASE URL: http://tripal.info/. PMID- 24163126 TI - Sensory control of balance: a comparison of children with fetal alcohol spectrum disorders to children with typical development. AB - BACKGROUND: Inefficient central processing and integration of visual, vestibular, and somatosensory information may contribute to poor balance and diminished postural control in children with fetal alcohol spectrum disorders (FASD). OBJECTIVES: This pilot study examined sensorimotor performance and the sensory control of balance using a battery of clinical tests in combination with an experimental laboratory assessment that quantifies sensory subsystem use (i.e., sensory weighting) among a systematically diagnosed sample of children with FASD and children with typical development. METHODS: Using a case-control design, 10 children with FASD (8.0-15.9 years; 20% female) were compared to 10 age- and sex matched controls on standardized clinical measures and on kinematic outcomes from the Multimodal Balance Entrainment Response system (MuMBER), a computerized laboratory assessment whereby visual, vestibular, and somatosensory input is manipulated at different frequencies during standing balance. RESULTS: Children with FASD showed poorer sensorimotor performance across clinical outcomes with significant group differences (p < .05) on parent-reported movement behaviors (Sensory Processing Measure and Movement Assessment Battery for Children-2 Checklist) and performance on the Dynamic Gait Index. Experimental kinematic outcomes yielded statistically significant group differences (p <.10) on a small proportion of somatosensory and vestibular sensory weighting fractions and postural sway velocity in response to the manipulation of sensory input. CONCLUSIONS: Preliminary findings showed small group differences in sensorimotor and sensory weighting behaviors, specifically those that rely on the integration of vestibular sensation. Differences must be examined and replicated with a larger sample of children with FASD to understand the impact on balance control and functional sensorimotor behaviors. PMID- 24163128 TI - NF1 is a critical regulator of muscle development and metabolism. AB - There is emerging evidence for reduced muscle function in children with neurofibromatosis type 1 (NF1). We have examined three murine models featuring NF1 deficiency in muscle to study the effect on muscle function as well as any underlying pathophysiology. The Nf1(+/-) mouse exhibited no differences in overall weight, lean tissue mass, fiber size, muscle weakness as measured by grip strength or muscle atrophy-recovery with limb disuse, although this model lacks many other characteristic features of the human disease. Next, muscle-specific knockout mice (Nf1muscle(-/-)) were generated and they exhibited a failure to thrive leading to neonatal lethality. Intramyocellular lipid accumulations were observed by electron microscopy and Oil Red O staining. More mature muscle specimens lacking Nf1 expression taken from the limb-specific Nf1Prx1(-/-) conditional knockout line showed a 10-fold increase in muscle triglyceride content. Enzyme assays revealed a significant increase in the activities of oxidative metabolism enzymes in the Nf1Prx1(-/-) mice. Western analyses showed increases in the expression of fatty acid synthase and the hormone leptin, as well as decreased expression of a number of fatty acid transporters in this mouse line. These data support the hypothesis that NF1 is essential for normal muscle function and survival and are the first to suggest a direct link between NF1 and mitochondrial fatty acid metabolism. PMID- 24163129 TI - Coregulation and modulation of NFkappaB-related genes in celiac disease: uncovered aspects of gut mucosal inflammation. AB - It is known that the NFkappaB route is constitutively upregulated in celiac disease (CD), an immune-mediated disorder of the gut caused by intolerance to ingested gluten. Our aim was to scrutinize the expression patterns of several of the most biologically relevant components of the NFkappaB route in intestinal biopsies from active and treated patients and after in vitro gliadin challenge, and to assess normalization of the expression using an inhibitor of the MALT1 paracaspase. The expression of 93 NFkappaB genes was measured by RT-PCR in a set of uncultured active and treated CD and control biopsies, and in cultured biopsy series challenged with gliadin, the NFkappaB modulator, both compounds and none. Methylation of eight genes involved in NFkappaB signaling was analyzed by conventional pyrosequencing. Groups were compared and Pearson's correlation matrixes were constructed to check for coexpression and co-methylation. Our results confirm the upregulation of the NFkappaB pathway and show that constitutively altered genes usually belong to the core of the pathway and have central roles, whereas genes overexpressed only in active CD are more peripheral. Additionally, this is the first work to detect methylation level changes in celiac intestinal mucosa. Coexpression is very common in controls, whereas gliadin challenge and especially chronic inflammation present in untreated CD result in the disruption of the regulatory equilibrium. In contrast, co methylation occurs more often in active CD. Importantly, NFkappaB modulation partially restores coregulation, opening the door to future therapeutic possibilities and targets. PMID- 24163130 TI - Arap3 is dysregulated in a mouse model of hypotrichosis-lymphedema-telangiectasia and regulates lymphatic vascular development. AB - Mutations in SOX18, VEGFC and Vascular Endothelial Growth Factor 3 underlie the hereditary lymphatic disorders hypotrichosis-lymphedema-telangiectasia (HLT), Milroy-like lymphedema and Milroy disease, respectively. Genes responsible for hereditary lymphedema are key regulators of lymphatic vascular development in the embryo. To identify novel modulators of lymphangiogenesis, we used a mouse model of HLT (Ragged Opossum) and performed gene expression profiling of aberrant dermal lymphatic vessels. Expression studies and functional analysis in zebrafish and mice revealed one candidate, ArfGAP with RhoGAP domain, Ankyrin repeat and PH domain 3 (ARAP3), which is down-regulated in HLT mouse lymphatic vessels and necessary for lymphatic vascular development in mice and zebrafish. We position this known regulator of cell behaviour during migration as a mediator of the cellular response to Vegfc signalling in lymphatic endothelial cells in vitro and in vivo. Our data refine common mechanisms that are likely to contribute during both development and the pathogenesis of lymphatic vascular disorders. PMID- 24163127 TI - Genome-wide association study identifies multiple loci associated with bladder cancer risk. AB - Candidate gene and genome-wide association studies (GWAS) have identified 11 independent susceptibility loci associated with bladder cancer risk. To discover additional risk variants, we conducted a new GWAS of 2422 bladder cancer cases and 5751 controls, followed by a meta-analysis with two independently published bladder cancer GWAS, resulting in a combined analysis of 6911 cases and 11 814 controls of European descent. TaqMan genotyping of 13 promising single nucleotide polymorphisms with P < 1 * 10(-5) was pursued in a follow-up set of 801 cases and 1307 controls. Two new loci achieved genome-wide statistical significance: rs10936599 on 3q26.2 (P = 4.53 * 10(-9)) and rs907611 on 11p15.5 (P = 4.11 * 10( 8)). Two notable loci were also identified that approached genome-wide statistical significance: rs6104690 on 20p12.2 (P = 7.13 * 10(-7)) and rs4510656 on 6p22.3 (P = 6.98 * 10(-7)); these require further studies for confirmation. In conclusion, our study has identified new susceptibility alleles for bladder cancer risk that require fine-mapping and laboratory investigation, which could further understanding into the biological underpinnings of bladder carcinogenesis. PMID- 24163132 TI - Distinct roles of TRAF6 at early and late stages of muscle pathology in the mdx model of Duchenne muscular dystrophy. AB - Duchenne muscular dystrophy (DMD) is a lethal genetic disorder caused by loss of functional dystrophin protein. Accumulating evidence suggests that the deficiency of dystrophin leads to aberrant activation of many signaling pathways which contribute to disease progression. However, the proximal signaling events leading to the activation of various pathological cascades in dystrophic muscle remain less clear. TNF receptor-associated factor 6 (TRAF6) is an adaptor protein which acts as a signaling intermediate for several receptor-mediated signaling events leading to the context-dependent activation of a number of signaling pathways. TRAF6 is also an E3 ubiquitin ligase and an important regulator of autophagy. However, the role of TRAF6 in pathogenesis of DMD remains unknown. Here, we demonstrate that the levels and activity of TRAF6 are increased in skeletal muscle of mdx (a mouse model of DMD) mice. Targeted deletion of TRAF6 improves muscle strength and reduces fiber necrosis, infiltration of macrophages and the activation of proinflammatory transcription factor nuclear factor-kappa B (NF kappaB) in 7-week-old mdx mice. Ablation of TRAF6 also increases satellite cells proliferation and myofiber regeneration in young mdx mice. Intriguingly, ablation of TRAF6 exacerbates muscle injury and increases fibrosis in 9-month-old mdx mice. TRAF6 inhibition reduces the markers of autophagy and Akt signaling in dystrophic muscle of mdx mice. Collectively, our study suggests that while the inhibition of TRAF6 improves muscle structure and function in young mdx mice, its continued inhibition causes more severe myopathy at later stages of disease progression potentially through repressing autophagy. PMID- 24163131 TI - Absence of cell surface expression of human ACE leads to perinatal death. AB - Renal tubular dysgenesis (RTD) is a recessive autosomal disease characterized most often by perinatal death. It is due to the inactivation of any of the major genes of the renin-angiotensin system (RAS), one of which is the angiotensin I converting enzyme (ACE). ACE is present as a tissue-bound enzyme and circulates in plasma after its solubilization. In this report, we present the effect of different ACE mutations associated with RTD on ACE intracellular trafficking, secretion and enzymatic activity. One truncated mutant, R762X, responsible for neonatal death was found to be an enzymatically active, secreted form, not inserted in the plasma membrane. In contrast, another mutant, R1180P, was compatible with life after transient neonatal renal insufficiency. This mutant was located at the plasma membrane and rapidly secreted. These results highlight the importance of tissue-bound ACE versus circulating ACE and show that the total absence of cell surface expression of ACE is incompatible with life. In addition, two missense mutants (W594R and R828H) and two truncated mutants (Q1136X and G1145AX) were also studied. These mutants were neither inserted in the plasma membrane nor secreted. Finally, the structural implications of these ACE mutations were examined by molecular modelling, which suggested some important structural alterations such as disruption of intra-molecular non-covalent interactions (e.g. salt bridges). PMID- 24163133 TI - Sex-biased methylome and transcriptome in human prefrontal cortex. AB - Brain function and cognitive performance differ between men and women in some measures. The phenotypic variation may be partially due to sex differences in epigenomes and transcriptomes in specific brain regions [e.g. the prefrontal cortex (PFC)]. Genome-wide DNA methylation and gene expression were examined in postmortem PFC of 32 males and 14 females (all were Caucasians) using Illumina's 450K Methylation and HT-12 v4 Gene Expression BeadChips, respectively. Multiple linear regression, Pearson correlation and DAVID functional annotation analyses were applied to investigate sex-biased DNA methylation and gene expression, DNA methylation-gene expression correlation and gene ontology (GO) annotations overrepresented by differentially methylated and expressed genes. A total of 22 124 CpGs showed differential methylation between males and females (2.6 * 10(-38) <= Pnominal <= 0.05), and the P-values of 8357 CpGs withstood multiple-testing correction (q < 0.05). A total of 1489 genes showed differential expression between males and females (4.1 * 10(-36) <= Pnominal <= 0.05), and the P-values of 35 genes survived multiple-testing correction (q < 0.05). A significant correlation (Pcorrelation < 0.05) was observed between methylation levels of 585 differentially methylated CpGs (Pnominal <= 0.05) and expression levels of 188 differentially expressed host genes (Pnominal < 0.05). The GO terms enriched by these 188 genes (134 on autosomes and 54 on sex chromosomes) were assigned to 24 clusters, and 33 genes involved in the top cluster (enrichment score: 4.7) mainly participate in ribosome structure and function, RNA binding and protein translation. This study demonstrated sex-specific methylomic and transcriptomic profiles in the human PFC. Our findings suggest that sex-biased DNA methylation and gene expression could be either the cause or consequence of differential brain development between males and females. PMID- 24163134 TI - Restoration of muscle strength in dystrophic muscle by angiotensin-1-7 through inhibition of TGF-beta signalling. AB - Duchenne muscular dystrophy (DMD) is the most common inherited neuromuscular disease, and is characterized by the lack of dystrophin, muscle wasting, increased transforming growth factor (TGF)-beta Smad-dependent signalling and fibrosis. Acting via the Mas receptor, angiotensin-1-7 [Ang-(1-7)], is part of the renin-angiotensin system, with the opposite effect to that of angiotensin II. We hypothesized that the Ang-(1-7)/Mas receptor axis might protect chronically damaged tissues as in skeletal muscle of the DMD mouse model mdx. Infusion or oral administration of Ang-(1-7) in mdx mice normalized skeletal muscle architecture, decreased local fibrosis and improved muscle function in vitro and in vivo. These positive effects were mediated by the inhibition of TGF-beta Smad signalling, which in turn led to reduction of the pro-fibrotic microRNA miR-21 concomitant with a reduction in the number of TCF4 expressing fibroblasts. Mdx mice infused with Mas antagonist (A-779) and mdx deficient for the Mas receptor showed highly deteriorated muscular architecture, increased fibrosis and TGF-beta signalling with diminished muscle strength. These results suggest that this novel compound Ang-(1-7) might be used to improve quality of life and delay death in individuals with DMD and this drug should be investigated in further pre-clinical trials. PMID- 24163135 TI - Different mtDNA mutations modify tumor progression in dependence of the degree of respiratory complex I impairment. AB - Mitochondrial DNA mutations are currently investigated as modifying factors impinging on tumor growth and aggressiveness, having been found in virtually all cancer types and most commonly affecting genes encoding mitochondrial complex I (CI) subunits. However, it is still unclear whether they exert a pro- or anti tumorigenic effect. We here analyzed the impact of three homoplasmic mtDNA mutations (m.3460G>A/MT-ND1, m.3571insC/MT-ND1 and m.3243A>G/MT-TL1) on osteosarcoma progression, chosen since they induce different degrees of oxidative phosphorylation impairment. In fact, the m.3460G>A/MT-ND1 mutation caused only a reduction in CI activity, whereas the m.3571insC/MT-ND1 and the m.3243A>G/MT-TL1 mutations induced a severe structural and functional CI alteration. As a consequence, this severe CI dysfunction determined an energetic defect associated with a compensatory increase in glycolytic metabolism and AMP-activated protein kinase activation. Osteosarcoma cells carrying such marked CI impairment displayed a reduced tumorigenic potential both in vitro and in vivo, when compared with cells with mild CI dysfunction, suggesting that mtDNA mutations may display diverse impact on tumorigenic potential depending on the type and severity of the resulting oxidative phosphorylation dysfunction. The modulation of tumor growth was independent from reactive oxygen species production but correlated with hypoxia-inducible factor 1alpha stabilization, indicating that structural and functional integrity of CI and oxidative phosphorylation are required for hypoxic adaptation and tumor progression. PMID- 24163136 TI - Overexpression of metallothionein-I, a copper-regulating protein, attenuates intracellular copper dyshomeostasis and extends lifespan in a mouse model of amyotrophic lateral sclerosis caused by mutant superoxide dismutase-1. AB - Over 170 mutations in superoxide dismutase-1 (SOD1) cause familial amyotrophic lateral sclerosis (ALS), a lethal motor neuron disease. Although the molecular properties of SOD1 mutants differ considerably, we have recently shown that intracellular copper dyshomeostasis is a common pathogenic feature of different SOD1 mutants. Thus, the potentiation of endogenous copper regulation could be a therapeutic strategy. In this study, we investigated the effects of the overexpression of metallothionein-I (MT-I), a major copper-regulating protein, on the disease course of a mouse model of ALS (SOD1(G93A)). Using double transgenic techniques, we found that the overexpression of MT-I in SOD1(G93A) mice significantly extended the lifespan and slowed disease progression, but the effects on disease onset were modest. Genetically induced MT-I normalized copper dyshomeostasis in the spinal cord without influencing SOD1 enzymatic activity. The overexpression of MT-I in SOD1(G93A) mice markedly attenuated the pathological features of the mice, including the death of motor neurons, the degeneration of ventral root axons, the atrophy of skeletal muscles, and the activation of glial cells. Double transgenic mice also showed a decreased level of SOD1 aggregates within the glial cells of the spinal cord. Furthermore, the overexpression of MT-I in SOD1(G93A) mice reduced the number of spheroid-shaped astrocytes cleaved by active caspase-3. We concluded that therapeutic strategies aimed at the potentiation of copper regulation by MT-I could be of benefit in cases of ALS caused by SOD1 mutations. PMID- 24163137 TI - Psychological interventions for depression in adolescent and adult congenital heart disease. AB - BACKGROUND: Adult and adolescent congenital heart disease is increasing in prevalence as better medical care means more children are surviving to adulthood. People with chronic disease often also experience depression. There are several non-pharmacological treatments that might be effective in treating depression and improving quality of life for adults and young adults with congenital heart disease. The aim of this review was to assess the effects of treatments such as psychotherapy, cognitive behavioural therapies and talking therapies for treating depression in this population. OBJECTIVES: To update the previous review on the effects (both harms and benefits) of psychological interventions for treating depression in young adults and adults with congenital heart disease. Psychological interventions include cognitive behavioural therapy, psychotherapy, or 'talking/counselling' therapy for depression. SEARCH METHODS: We updated the searches of the Cochrane Central Register of Controlled Trials (CENTRAL) on The Cochrane Library (Issue 1, 2013), MEDLINE (OVID, 1946 to January week 4 2013), EMBASE (OVID, 1980 to 2013 week 05), PsycINFO (OVID, 1806 to January week 5 2013), the Database of Abstracts of Reviews of Effectiveness (DARE) on The Cochrane Library (Issue 1, 2013), BIOSIS (Thomson Reuters, 1969 to 21 February 2013), and CINAHL (January 1980 to February 2013) on 5 February 2013. We did not search abstracts from national and international cardiology and psychology conferences and dissertation abstracts for this update. No language restrictions were applied. SELECTION CRITERIA: Randomised controlled trials comparing psychological interventions with no intervention for people over 15 years with depression who have congenital heart disease. DATA COLLECTION AND ANALYSIS: Two review authors independently screened titles and abstracts of studies that were potentially relevant to the review. We rejected studies that were clearly ineligible. Two review authors independently assessed the abstracts or full papers for inclusion criteria. We sought further information from the authors where papers contained insufficient information to make a decision about eligibility. MAIN RESULTS: We did not identify any randomised controlled trials that met the inclusion criteria. AUTHORS' CONCLUSIONS: Depression is common in people with congenital heart disease and can exacerbate the physical consequences of the illness. There are effective pharmacological and non-pharmacological treatments for depression, but we have not been able to identify any trials showing the effectiveness of non-pharmacological treatments. A well-designed randomised controlled trial is needed to assess the effects of psychological interventions for depression in congenital heart disease. PMID- 24163138 TI - Resection of isolated renal cell carcinoma metastases of the pancreas: outcomes from the Johns Hopkins Hospital. AB - PURPOSE: This study aims to assess outcomes and characteristics associated with resection of metastatic renal cell carcinoma (mRCC) to the pancreas. MATERIALS AND METHODS: From April 1989 to July 2012, a total of 42 patients underwent resection of pancreatic mRCC at our institution. We retrospectively reviewed records from a prospectively managed database and analyzed patient demographics, comorbidities, perioperative outcomes, and overall survival. Cox proportional hazards models were used to evaluate the association between patient-specific factors and overall survival. RESULTS: The mean time from resection of the primary tumor to reoperation for pancreatic mRCC was 11.2 years (range, 0-28.0 years). In total, 17 patients underwent pancreaticoduodenectomy, 16 underwent distal pancreatectomy, and 9 underwent total pancreatectomy. Perioperative complications occurred in 18 (42.9%) patients; there were two (4.8%) perioperative mortalities. After pancreatic resection, the median follow-up was 7.0 years (0.1-23.2 years), and median survival was 5.5 years (range, 0.4-21.9). The overall 5-year survival was 51.8%. On univariate analysis, vascular invasion (hazard ratio, 5.15; p = 0.005) was significantly associated with increased risk of death. CONCLUSIONS: Pancreatic resection of mRCC can be safely achieved in the majority of cases and is associated with long-term survival. Specific pathological factors may predict which patients will benefit most from resection. PMID- 24163139 TI - Esophagogastrostomy plus gastrojejunostomy: a novel reconstruction procedure after curative resection for proximal gastric cancer. AB - OBJECTIVE: The choice of surgical strategy for patients with proximal gastric cancer remains controversial. In this study, we recommend that a new reconstruction procedure be performed following proximal gastrectomy. METHODS: We conducted a retrospective study involving 71 patients who underwent gastrectomy for proximal gastric cancer. Clinicopathological features, postoperative complications, nutritional status, and overall survival (OS) rate were compared among three different reconstruction approaches. RESULTS: There were 34 cases of proximal gastrectomy followed by esophagogastrostomy reconstruction (EG), 16 cases of total gastrectomy and Roux-en Y reconstruction (RY) and 21 cases of proximal gastrectomy followed by esophagogastrostomy plus gastrojejunostomy reconstruction (EGJ). Though the clinicopathological features, the nutritional status and OS rate were similar among the three groups of patients, the incidence of reflux esophagitis was significantly higher in the EG group (35.3%) than the RY (6.2%) and EGJ (9.6%) groups(P < 0.05). Few EGJ patients suffered from either reflux esophagitis or anastomotic stenosis. CONCLUSIONS: The EGJ reconstruction method helps to resolve the syndrome of reflux esophagitis. Our data indicates that it is a simple, safe, and effective reconstruction procedure for PGC. PMID- 24163141 TI - Amplification of steroid-mediated SP-B expression by physiological levels of caffeine. AB - Factors positively influencing surfactant homeostasis in general and surfactant protein B (SP-B) expression in particular are considered of clinical importance regarding an improvement of lung function in preterm infants. The objective of this study was to identify effects of physiological levels of caffeine on glucocorticoid-mediated SP-B expression in vitro and in vivo. Levels of SP-B and pepsinogen C were quantified by quantitative real-time RT-PCR or immunoblotting in NCI-H441 cells daily exposed to caffeine and/or dexamethasone (DEX). In vivo, SP-B expression was analyzed in bronchoalveolar lavage (BAL) of preterm sheep exposed to antenatal DEX and/or postnatal caffeine. If DEX and caffeine were continuously present, SP-B mRNA and protein levels were increased for up to 6 days after induction (P < 0.05). Additionally, caffeine enhanced SP-B mRNA expression in DEX-pretreated cells (P < 0.05). Moreover, caffeine amplified DEX induced pepsinogen C mRNA expression (P < 0.05). After short-term treatment with caffeine in vivo, only slightly higher SP-B levels could be detected in BAL of preterm sheep following antenatal DEX, combined with an increase of arterial oxygen partial pressure (P < 0.01). Our data demonstrated that the continuous presence of caffeine in vitro is able to amplify DEX-mediated SP-B expression. In contrast, short-term improvement of lung function in vivo is likely to be independent of altered SP-B transcription and translation. An impact of caffeine on release of surfactant reservoirs from lamellar bodies could, however, quickly affect SP-B content in BAL, which has to be further investigated. Our findings indicate that caffeine is able to amplify main effects of glucocorticoids that result from changes in surfactant production, maturation, and release. PMID- 24163140 TI - The anti-asthma herbal medicine ASHMI acutely inhibits airway smooth muscle contraction via prostaglandin E2 activation of EP2/EP4 receptors. AB - Our previous studies have shown that the anti-asthma traditional Chinese medicine herbal formula ASHMI (anti-asthma simplified herbal medicine intervention) inhibits acetylcholine-induced contractions of tracheal rings from ovalbumin sensitized and naive mice in a beta-adrenoceptor-independent manner. We sought to determine whether acute in vivo ASHMI administration inhibits airway hyperreactivity (AHR) in a murine model of allergic asthma and acetylcholine induced tracheal ring constriction ex vivo and to elucidate the cellular mechanisms underlying these effects. Ovalbumin-sensitized mice received a single oral ASHMI dose 2 h before intravenous acetylcholine challenge. AHR was determined by invasive airway measurements. Myography was used to determine the effects of ASHMI on acetylcholine-induced constriction of tracheal rings from asthmatic mice with or without epithelial denudation. The effect of cyclooxygenase inhibition and EP2/EP4 receptor blockade on ASHMI attenuation of acetylcholine contractions was evaluated. Tracheal cAMP and PGE2 levels were measured by ELISA. A single acute oral dose of ASHMI dramatically reduced AHR in response to acetylcholine provocation in ovalbumin-sensitized mice (P < 0.001). In ex vivo experiments, ASHMI significantly and dose-dependently reduced tracheal ring constriction to acetylcholine (P < 0.05-0.001), which was epithelium independent and associated with elevated cAMP levels. This effect was abrogated by cyclooxygenase inhibition or EP2/EP4 receptor blockade. ASHMI also inhibited contraction to high K(+) (P < 0.001). ASHMI increased tracheal ring PGE2 release in response to acetylcholine or high K(+) (P < 0.05 for both). ASHMI produced direct and acute inhibition of AHR in vivo and blocked acetylcholine-induced tracheal ring constriction via the EP2/EP4 receptor pathway, identifying the mechanism by which ASHMI is an orally active bronchoprotective agent. PMID- 24163143 TI - SerpinB1 deficiency is not associated with increased susceptibility to pulmonary emphysema in mice. AB - Chronic obstructive pulmonary disease (COPD) is characterized by emphysema and chronic bronchitis and is a leading cause of morbidity and mortality worldwide. Tobacco smoke and deficiency in alpha1-antitrypsin (AAT) are the most prominent environmental and genetic risk factors, respectively. Yet the pathogenesis of COPD is not completely elucidated. Disease progression appears to include a vicious circle driven by self-perpetuating lung inflammation, endothelial and epithelial cell death, and proteolytic degradation of extracellular matrix proteins. Like AAT, serpinB1 is a potent inhibitor of serine proteases including neutrophil elastase and cathepsin G. Because serpinB1 is expressed in myeloid and lung epithelial cells and is protective during lung infections, we investigated the role of serpinB1 in preventing age-related and cigarette smoke-induced emphysema in mice. Fifteen-month-old mice showed increased lung volume and decreased pulmonary function compared with young adult mice (3 mo old), but no differences were observed between serpinB1-deficient (KO) and wild-type (WT) mice. Chronic exposure to secondhand cigarette smoke resulted in structural emphysematous changes compared with respective control mice, but no difference in lung morphometry was observed between genotypes. Of note, the different pattern of stereological changes induced by age and cigarette smoke suggest distinct mechanisms leading to increased airway volume. Finally, expression of intracellular and extracellular protease inhibitors were differently regulated in lungs of WT and KO mice following smoke exposure; however, activity of proteases was not significantly altered. In conclusion, we showed that, although AAT and serpinB1 are similarly potent inhibitors of neutrophil proteases, serpinB1 deficiency is not associated with more severe emphysema. PMID- 24163142 TI - Tuning endothelial monolayer adhesion: a neutron reflectivity study. AB - Endothelial cells, master gatekeepers of the cardiovascular system, line its inner boundary from the heart to distant capillaries constantly exposed to blood flow. Interendothelial signaling and the monolayers adhesion to the underlying collagen-rich basal lamina are key in physiology and disease. Using neutron scattering, we report the first ever interfacial structure of endothelial monolayers under dynamic flow conditions mimicking the cardiovascular system. Endothelial adhesion (defined as the separation distance l between the basal cell membrane and solid boundary) is explained using developed interfacial potentials and intramembrane segregation of specific adhesion proteins. Our method provides a powerful tool for the biophysical study of cellular layer adhesion strength in living tissues. PMID- 24163145 TI - Idiopathic macular epiretinal membrane surgery with simultaneous internal limiting membrane peeling. The experience of the Fribourg Eye Clinic. AB - PURPOSE: To evaluate the visual and anatomical outcomes following idiopathic macular epiretinal membrane (ERM) removal. METHODS: A retrospective study of 30 eyes operated for idiopathic ERM was conducted. Pars plana vitrectomy was combined with ERM removal and indocyanine green (ICG) assisted internal limiting membrane (ILM) peeling. RESULTS: Mean preoperative best corrected visual acuity (BCVA) was 0.4 logMAR (0.4 in decimal units), whereas mean postoperative BCVA was 0.26 logMAR (0.6 in decimal units). Mean preoperative foveal thickness was 392 MUm, whereas mean postoperative foveal thickness was 305 MUm. A statistically significant difference was observed between preoperative and postoperative BCVA (p <0.001, Student's t-test). Optical coherence tomography (OCT) measurement of postoperative foveal thickness revealed a significant decrease in thickness (p <0.0001, Student's t-test), however, no correlation was observed between postoperative BCVA and postoperative foveal thickness (Pearson's correlation coefficient, r = 0.228; p = 0.22). CONCLUSIONS: Although significant visual acuity improvement and anatomical recovery was detected after idiopathic ERM removal, full restoration of foveal thickness was not achieved in the majority of cases. PMID- 24163144 TI - Could signal transducer and activator of transcription 3 be a therapeutic target in obesity-related gastrointestinal malignancy? AB - INTRODUCTION: A large body of evidence has implicated the signal transducer and activator of transcription (STAT) family and particularly the ubiquitously expressed STAT3 protein in the pathogenesis of colorectal, hepatocellular, gastric and pancreatic carcinoma. DISCUSSION: Concomitantly, an increasing body of epidemiological evidence has linked obesity and its associated pro inflammatory state with the development of gastrointestinal cancers. Visceral adipose tissue is no longer considered inert and is known to secrete a number of adipocytokines such as leptin, interleukin (IL)-6, IL-8, IL-1beta and tumour necrosis factor-alpha (TNF-alpha) into the surrounding environment. Interestingly, these adipocytokines are strongly linked with the Janus kinase (JAK)/STAT pathway of signal transduction and there is experimental evidence linking IL-1beta, IL-8 and TNF-alpha to JAK/STAT signaling in other tissues. The result is an up-regulation of a wide range of anti-apoptotic, pro-metastatic and pro-angiogenic genes and processes. This is particularly relevant for gastrointestinal malignancy as these factors have the potential to signal adjacent endothelial cells in a paracrine manner. CONCLUSION: This review examines the potential role of the STAT3 signaling pathway in the pathogenesis of obesity-related gastrointestinal malignancy and the potential therapeutic role of STAT3 blockade given its status as a signaling hub for a number of inflammatory adipocytokines. PMID- 24163147 TI - Validation of a patient decision aid for choosing between dabigatran and warfarin for atrial fibrillation. AB - BACKGROUND: Decision aids have been helpful to support patients in decision making including anticoagulation. With the introduction of new oral anticoagulants (NOACs), it will be important to assist patients and physicians in shared decision-making about NOACs and warfarin. OBJECTIVES: To validate a patient decision aid (DA) for warfarin versus dabigatran, the first NOAC approved for atrial fibrillation (AF). METHODS: Participants without AF and not taking anticoagulants were recruited for the validation exercise. The decision aid described AF, stroke, and hemorrhagic events in terms of incidence, clinical presentation, and prognosis. Warfarin and dabigatran were then compared on multiple clinical and process outcomes as outlined in the pivotal clinical trial. Our primary outcome was confidence in making a treatment decision, using a decisional conflict scale. Secondary outcomes were change in knowledge scores and ratings of clarity, helpfulness and comprehensiveness. RESULTS: 35 patients (mean age 62.7 [SD 9.68], 37.1% female) participated. After use of the decision aid, the mean total decisional conflict score was low at 18.9 (SD: 14.2). Mean knowledge score improved significantly from 4.60 (SD 1.48) to 6.42 (SD 0.80) out of a total score of 7. Only one participant (2.9%) found the decision aid difficult to understand. All 35 participants rated the DA as helpful for making a decision about anticoagulant treatment for AF. Two participants (5.7%) requested more information on adverse effects of the two drugs. CONCLUSION: Our DA to allow patients to make an informed decision with their physician regarding dabigatran versus warfarin in AF, proved understandable, comprehensive and helpful. PMID- 24163146 TI - Split-hand/foot malformation - molecular cause and implications in genetic counseling. AB - Split-hand/foot malformation (SHFM) is a congenital limb defect affecting predominantly the central rays of the autopod and occurs either as an isolated trait or part of a multiple congenital anomaly syndrome. SHFM is usually sporadic, familial forms are uncommon. The condition is clinically and genetically heterogeneous and shows mostly autosomal dominant inheritance with variable expressivity and reduced penetrance. To date, seven chromosomal loci associated with isolated SHFM have been described, i.e., SHFM1 to 6 and SHFM/SHFLD. The autosomal dominant mode of inheritance is typical for SHFM1, SHFM3, SHFM4, SHFM5. Autosomal recessive and X-linked inheritance is very uncommon and have been noted only in a few families. Most of the known SHFM loci are associated with chromosomal rearrangements that involve small deletions or duplications of the human genome. In addition, three genes, i.e., TP63, WNT10B, and DLX5 are known to carry point mutations in patients affected by SHFM. In this review, we focus on the known molecular basis of isolated SHFM. We provide clinical and molecular information about each type of abnormality as well as discuss the underlying pathways and mechanism that contribute to their development. Recent progress in the understanding of SHFM pathogenesis currently allows for the identification of causative genetic changes in about 50 % of the patients affected by this condition. Therefore, we propose a diagnostic flow chart helpful in the planning of molecular genetic tests aimed at identifying disease causing mutation. Finally, we address the issue of genetic counseling, which can be extremely difficult and challenging especially in sporadic SHFM cases. PMID- 24163148 TI - Pak3 promotes cell cycle exit and differentiation of beta-cells in the embryonic pancreas and is necessary to maintain glucose homeostasis in adult mice. AB - The transcription factor neurogenin3 (Ngn3) triggers islet cell differentiation in the developing pancreas. However, little is known about the molecular mechanisms coupling cell cycle exit and differentiation in Ngn3(+) islet progenitors. We identified a novel effector of Ngn3 endocrinogenic function, the p21 protein-activated kinase Pak3, known to control neuronal differentiation and implicated in X-linked intellectual disability in humans. We show that Pak3 expression is initiated in Ngn3(+) endocrine progenitor cells and next maintained in maturing hormone-expressing cells during pancreas development as well as in adult islet cells. In Pak3-deficient embryos, the proliferation of Ngn3(+) progenitors and beta-cells is transiently increased concomitantly with an upregulation of Ccnd1. beta-Cell differentiation is impaired at E15.5 but resumes at later stages. Pak3-deficient mice do not develop overt diabetes but are glucose intolerant under high-fat diet (HFD). In the intestine, Pak3 is expressed in enteroendocrine cells but is not necessary for their differentiation. Our results indicate that Pak3 is a novel regulator of beta-cell differentiation and function. Pak3 acts downstream of Ngn3 to promote cell cycle exit and differentiation in the embryo by a mechanism that might involve repression of Ccnd1. In the adult, Pak3 is required for the proper control of glucose homeostasis under challenging HFD. PMID- 24163149 TI - Effect of rosuvastatin on OX40L and PPAR-gamma expression in human umbilical vein endothelial cells and atherosclerotic cerebral infarction patients. AB - Atherosclerotic cerebral infarction (ACI) is characterized by extremely high fatality and disability rate. Recent studies indicate that co-stimulatory signal of tumor necrosis factor superfamily OX40/OX40L contributes to the atherosclerosis effect in ACI patients. However, it remains unclear the mechanism underlying the anti-atherosclerosis process. So this study aims to investigate the effects of rosuvastatin on the expression of OX40L, peroxisome proliferator activated receptors gamma (PPAR-gamma) in human umbilical vein endothelial cells (HUVEC), and human peripheral blood lymphocytes. Different concentration of rosuvastatin and oxidized low-density lipoprotein (OX-LDL) co-intervene HUVEC to observe the expression of OX40L and PPAR-gamma using real-time quantitative RT PCR (Q-RTPCR) and Western-blot. Furthermore, we examined the level changes of plasmic sOX40L and hs-CRP in acute atherosclerotic cerebral infarction patients. The results demonstrated that concentration-dependent and time-dependent OX-LDL remarkably stimulate the expression of OX40L and inhibit the expression of PPAR gamma in vitro. But concentration-dependent rosuvastatin can reverse the impact of OX-LDL, suggesting that rosuvastatin can prevent the expression of OX40L, and the process may be associated with mevalonate pathway. In vivo, acute atherosclerotic cerebral infarction patients taking 20 mg rosuvastatin exhibited significantly reduced expression of OX40L in peripheral blood lymphocyte, sOX40L in blood plasma, and hs-CRP compared with before treatment. Our studies identified rosuvastatin as an effective medicine in controlling atherosclerosis process in ACI by inhibiting OX40L and stimulating PPAR-gamma expression. PMID- 24163150 TI - Regulation of hypoxia-induced inflammatory responses and M1-M2 phenotype switch of primary rat microglia by sex steroids. AB - Microglia cells are the primary mediators of the CNS immune defense system and crucial for the outcome of shaping inflammatory responses. They are highly dynamic, moving constantly, and become activated by neuronal signaling under pathological conditions. They fulfill a dual role by not only regulating local neuroinflammation but also conferring neuronal protection. Gonadal steroids are known to exert anti-inflammatory effects in the CNS. Recently, we have shown that the microglial-like cell line BV-2 is hypoxia-sensitive and regulated by gonadal steroids. The present study used primary rat cerebral cortex-derived microglia to analyze whether this cell type directly perceive and respond to acute hypoxia. Second, we investigated whether 17beta-estradiol (E2) and progesterone (P) interfere with hypoxia-induced changes. Short-term hypoxia increased the expression of a subset of pro-inflammatory (TNFa, IL1b) and oxidative stress related (Hif1a) genes. The induction of TNFa and IL1b was counteracted by P. Hypoxia shifted the primary microglia to the pro-inflammatory M1 phenotype. The administration of E2 and P favored the neuroprotective M2 phenotype. Our findings extend previous data obtained with BV-2 cells and show that the primary microglia directly perceive hypoxia which increase their inflammatory activity. Both steroid hormones directly and indirectly interact with the microglia cells by reducing the inflammatory scenario and stimulating neuroprotection. PMID- 24163152 TI - Hold-over admissions: are they educational for residents? AB - PURPOSE: Since implementation of resident duty-hour restrictions, many academic medical centers utilize night-float teams to admit patients during off hours. Patients are transferred to other resident physicians the subsequent morning as "hold-over admissions." Despite the increase of hold-over admissions, there are limited data on resident perceptions of their educational value. This study investigated resident perceptions of hold-over admissions, and whether they approach hold-over admissions differently than new admissions. METHOD: Survey of internal medicine residents at an academic medical center. RESULTS: A total of 111 residents responded with a response rate of 71 %. Residents reported spending 56.2 min (standard deviation [SD] 18.9) compared to 80.0 min (SD 25.8) admitting new patients (p < 0.01). Residents reported spending significantly (p < 0.01) less time reviewing the medical record, performing histories, examining patients, devising care plans and writing orders in hold-over admissions compared to new admissions. Residents had neutral views on the educational value of hold-over admissions. Features that significantly (p < 0.01) increased the educational value of admissions included severe illness, patient complexity, and being able to write the initial patient care orders. Residents estimated 42.5 % (SD 14) of their admissions were hold-over patients. CONCLUSIONS: Residents spend less time in all aspects of admitting hold-over patients. Despite less time spent admitting hold-over patients, residents had neutral views on the educational value of such admissions. PMID- 24163151 TI - Specialties differ in which aspects of doctor communication predict overall physician ratings. AB - BACKGROUND: Effective doctor communication is critical to positive doctor-patient relationships and predicts better health outcomes. Doctor communication is the strongest predictor of patient ratings of doctors, but the most important aspects of communication may vary by specialty. OBJECTIVE: To determine the importance of five aspects of doctor communication to overall physician ratings by specialty. DESIGN: For each of 28 specialties, we calculated partial correlations of five communication items with a 0-10 overall physician rating, controlling for patient demographics. PATIENTS: Consumer Assessment of Healthcare Providers and Systems Clinician and Group (CG-CAHPS(r)) 12-month Survey data collected 2005-2009 from 58,251 adults at a 534-physician medical group. MAIN MEASURES: CG-CAHPS includes a 0 ("Worst physician possible") to 10 ("Best physician possible") overall physician rating. Five doctor communication items assess how often the physician: explains things; listens carefully; gives easy-to-understand instructions; shows respect; and spends enough time. KEY RESULTS: Physician showing respect was the most important aspect of communication for 23/28 specialties, with a mean partial correlation (0.27, ranging from 0.07 to 0.44 across specialties) that accounted for more than four times as much variance in the overall physician rating as any other communication item. Three of five communication items varied significantly across specialties in their associations with the overall rating (p < 0.05). CONCLUSIONS: All patients valued respectful treatment; the importance of other aspects of communication varied significantly by specialty. Quality improvement efforts by all specialties should emphasize physicians showing respect to patients, and each specialty should also target other aspects of communication that matter most to their patients. The results have implications for improving provider quality improvement and incentive programs and the reporting of CAHPS data to patients. Specialists make important contributions to coordinated patient care, and thus customized approaches to measurement, reporting, and quality improvement efforts are important. PMID- 24163153 TI - Should patients with a hip or femur fracture sustained abroad be repatriated for surgery? AB - OBJECTIVE: To investigate the clinical outcome of patients with hip or femur fractures sustained while travelling, depending on the place where surgery was performed (abroad or in Switzerland). METHODS: This was an ambispective cohort study of 90 patients in two groups. Outcome measures were: number and type of complications, impairment of walking ability at six months compared to the preoperative state, and chronic pain with ongoing use of analgesic medication at six months RESULTS: A total of 62 patients were transported to be operated on in Switzerland, and 28 patients received their surgery abroad. Age and gender distribution of the two groups were comparable, as was comorbidity status. A total of 64% of patients operated on abroad suffered one or more complications, as compared with 37% of patients operated on in Switzerland (p = 0.01). Logistical regression showed no evidence of an association between the variables investigated as possible confounding factors and the outcome, the place where surgery was performed (abroad or at home), was the only predictor of complications in general and of a reoperation in particular (95% confidence intervals 1.55-13.7 and 1.39-41.25, respectively). When compared with their preoperative state, 89% of patients operated on abroad reported some postoperative walking impairment, compared with 57% of patients operated on in Switzerland (p = 0.004). A total of 59% of patients operated on abroad had to use analgesic medication intermittently or regularly six months after surgery, as compared with 35% of patients operated on in Switzerland (p = 0.03). CONCLUSION: Swiss patients with hip or femoral fractures sustained while travelling in a foreign country had fewer complications and a better functional outcome if repatriated and operated on in Switzerland than if operated on abroad. The reasons for this unexpected result remain unclear. Medical, ethnic and psychological factors could well play a part. These results need further clarification and should be tested in larger studies with different pathologies. PMID- 24163154 TI - Exploring temporal dissipation of attention settings in auditory task switching. AB - Using a cued auditory task-switching variant of dichotic listening, we varied the response-cue interval (RCI) to examine temporal dissipation effects. On each trial, participants were presented with two different number words, one spoken by a female speaker and another by a male speaker (dichotic listening), that served as competing targets for a numerical judgment. The gender of the task-relevant speaker was indicated by a visual task cue prior to each trial. Experiment 1A used two different cues for each task (i.e., gender) and showed only small cue repetition benefits (same cue vs. alternate cue) but large auditory switch costs (alternate cue vs. task switch). A replication without immediate cue repetitions (Experiment 1B) showed very similar switch costs, suggesting that immediate cue repetitions play a negligible role for the size of auditory task switch costs. Moreover, switch costs were reduced when the (entirely task-irrelevant) location of the task-relevant speaker changed, relative to when it was unchanged, suggesting an episodic feature-binding component in our dichotic-listening task. Importantly, both experiments showed no effect of RCI on auditory switch costs. Because statistical power for this null effect was reasonably high across experiments (n = 50), this finding suggests that auditory attention settings do not dissipate quickly over time. PMID- 24163155 TI - Clinical correlates of fetal alcohol spectrum disorder among diagnosed individuals in a rural diagnostic clinic. AB - BACKGROUND: Diagnosis of fetal alcohol spectrum disorder (FASD) is relevant for the reduction of long term adverse sequalae. However, the diagnostic guidelines require a multidisciplinary approach which may hinder access to diagnostic and management services. Most diagnostic clinics are located in urban areas. There is less emphasis on the operations, capacities, and outcomes from rural diagnostic clinics. METHODS: Over a ten and half years of clinic operations to diagnose children and subsequently adults, all consenting adults provided answers to interviews, participated in measurements and other diagnostic procedures. Information was collected on their contact with mental health services. Comparison of the findings with those from other established clinics included variables relevant to outcome measures. RESULTS: 375 individuals were referred, assessed and diagnosed according to the existing guidelines for FASD diagnosis. Alcohol-related neurodevelopmental disorder (ARND), which was closely associated with age, was the most prevalent FASD diagnosis. One third of those diagnosed had IQ above the average range and ADHD was the most relevant clinical correlate. The diagnostic clinic was able to complete diagnosis on potentially 37.5% of likely affected individuals. CONCLUSION: FASD can be diagnosed in children and adults in a rural setting. ADHD and other mental disorders should be a focus for treatment in affected individuals especially adults. It is important to consider the impact of age on the outcome of FASD. To increase diagnostic capacity, clinic operations could be modelled similarly. PMID- 24163156 TI - The availability, functionality, and quality of mobile applications supporting medication self-management. AB - OBJECTIVE: To systematically review mobile applications currently available to patients to support outpatient medication self-management. METHODS: Three online stores were searched in March 2013 using nine distinct search terms. Applications were selected if they supported general outpatient medication self-management for adults; they were excluded if they focused on only one medication or condition, provided only a medication list or reference, only ordered refills, were written in a non-English language, or were for local pharmacy/hospital patients only. A multi-step review process was utilized by two independent reviewers to identify eligible applications. A standardized form was used to abstract data. User reviews were compiled from a subsample of applications and qualitatively coded to identify common criticisms. RESULTS: 14,893 applications were initially identified. After the multi-step review process, 424 applications were deemed eligible for inclusion by reviewers (kappa=0.85). On average, applications were rated 2.8 stars (out of 5) from 107 reviews. Almost all provided medication reminders (91.0%), half enabled patients to create a medication history or log (51.5%), and 22% could email the log to a third party. Few helped patients organize their regimen (6.2%), check for drug interactions (2.8%), or identify pills (4.0%). User reviews (N=1091) from the subsample of 26 applications revealed common criticisms, including technical malfunctions, poor compatibility with certain medications, and absence of desired features. CONCLUSIONS: Hundreds of applications exist in the marketplace to support medication self-management. However, their quality, content, and functionality are highly variable. Research is needed to determine optimal capabilities, evaluate utility, and determine clinical benefit. PMID- 24163158 TI - Directed differentiation of aged human bone marrow multipotent stem cells effectively generates dopamine neurons. AB - This study aimed to isolate aged human bone marrow multipotent stem cells (hAMSCs) with the potential for multilineage differentiation and to directly induce the cells to generate dopamine neurons, which could be used for Parkinson's disease therapy. We compared different culture methods for stem cells from aged human bone marrow and identified hAMSCs that could proliferate in vitro for at least 60 doubling times. Using RT-PCR and IHC, we found that these hAMSCs expressed pluripotent genes, such as Oct4, Sox2, and Nanog. In vitro studies also proved that hAMSCs could differentiate into three germ layer-derived cell types, such as osteogenic, chondrogenic, adipogenic, and hepatocyte-liked cells. After induction for more than 20 d in vitro with retinoic acid, basic fibroblast growth factor, and sonic hedgehog using a two-step method and withdrawal of serum, hAMSCs could differentiate into dopamine neurons at the positive ratio of 70%, which showed DA secretion function upon depolarization. In conclusion, we suggest that hAMSCs can be used as cell sources to develop medical treatments to prevent the progression of Parkinson's disease, especially in aged persons. PMID- 24163159 TI - Novel in vitro cardiovascular constructs composed of vascular-like networks and cardiomyocytes. AB - The interaction between different cardiac cells has shown to be important for critical biological properties including cell survival, proliferation, differentiation and function. The improvement of culture conditions with different cell types and to study their effects on cardiomyocyte viability and functionality is essential. For practical applications including general toxicity testing, drug development and tissue engineering it is important to study whether co-cultures have additional advantages over cardiomyocyte monoculture. Two multicellular in vitro cardiovascular constructs devoid of added biomaterial were developed in this study. In the first construct, neonatal rat cardiomyocytes (CM) were seeded on vascular-like network formed by human umbilical vein endothelial cells (HUVEC) and human adipose stromal cells (hASC). In the second construct, CMs were seeded on vascular-like network formed by HUVECs and human foreskin fibroblasts. The ability of these two vascular-like networks to support the viability and functionality of CMs was analyzed. Different culture media compositions were evaluated to support the development of optimal cardiovascular construct. Our results demonstrate that both vascular-like networks markedly improved CM viability and functionality. In the constructs, co-localization of CMs and vascular-like networks was seen. Multicellular constructs also allowed synchronized contractility of CMs. Serum-free medium supplemented with vascular endothelial growth factor and basic fibroblast growth factor was found to provide the most optimal conditions for cardiovascular construct as an entity. In conclusion, when combining a vascular-like network with CMs, the viability and functionality of CMs was markedly improved. The results suggest that the cardiovascular constructs developed provide a promising new tool for the assessment of toxicological and safety pharmacological effects of compounds in vitro. PMID- 24163160 TI - A new insect cell line from the pupal ovary of the Asian corn borer moth Ostrinia furnacalis. AB - Ovaries were removed from Ostrinia furnacalis (Guenee) pupae and were placed in a flask containing TNM-FH medium with 10% inactivated fetal bovine serum. Cell migration occurred after about 1 wk of the initiation in June 2011. The migrated cells were distributed over most of the flask and were treated with N-methyl-N' nitro-N-nitrosoguanidine (MNNG), a chemical carcinogen, after about 1 mo of initiation for 26 d. Cells were first subcultured successfully 12 d after the MNNG was removed, followed by subculturing for 30 passages. The established cell line, designated IOZCAS-Osfu-1, were analyzed by DNA fingerprinting-PCR (DAF-PCR) to confirm that it originated from O. furnacalis. PMID- 24163161 TI - Concanavalin A-mediated T cell proliferation is regulated by herpes virus entry mediator costimulatory molecule. AB - T cell activation is regulated by two distinct signals, signals one and two. Concanavalin A (ConA) is an antigen-independent mitogen and functions as signal one inducer, leading T cells to polyclonal proliferation. CD28 is known to be one of major costimulatory receptors and to provide signal two in the ConA-induced T cell proliferation. Here, we have studied the implication of other costimulatory pathways in the ConA-mediated T cell proliferation by using soluble recombinant proteins consisting of an extracellular domain of costimulatory receptors and Fc portion of human IgG. We found that T cell proliferation induced by ConA, but not PMA plus ionomycin or anti-CD3 mAb, is significantly inhibited by herpes virus entry mediator (HVEM)-Ig, even in the presence of CD28 signaling. Moreover, the high concentration of HVEM-Ig molecules almost completely suppressed ConA mediated T cell proliferation. These results suggest that HVEM might play more important roles than CD28 in ConA-mediated T cell proliferation. PMID- 24163162 TI - In vitro evaluation of the effects of human umbilical cord extracts on human fibroblasts, keratinocytes, and melanocytes. AB - Skin aging is the result of internal and external factors. So-called photoaging has been identified as the major factor in skin aging. Effects of photoaging include inhibition of fibroblast and keratinocyte proliferation as well as collagen and fibronectin expression, while activating expression of collagenases such as matrix metalloproteinase-1. Previous studies have shown that extracts or products from human placenta significantly improve skin aging and chronic wound healing. However, there are few studies of umbilical cord extracts. Therefore, this study aimed to evaluate the effects of umbilical cord extract-derived formulae on three kinds of skin cells including fibroblasts, keratinocytes, and melanocytes. We prepared 20 formulae from intracellular umbilical cord extracts, extracellular umbilical cord extracts, and umbilical cord-derived stem cell extracts, as well as five control formulae. We evaluated the effects of the 25 formulae on fibroblast and keratinocyte proliferation, and expression of collagen I, fibronectin, and matrix metalloproteinase-1 in fibroblasts and tyrosinase in melanocytes. The results showed that 7.5% formula 35 was the most effective formula for promotion of fibroblast and keratinocyte proliferation. At this concentration, formula 35 also induced collagen expression and inhibited matrix metalloproteinase-1 expression at the transcriptional level. However, this formula had no effect on tyrosinase expression in melanocytes. These results demonstrate that umbilical cord extracts can serve as an attractive source of proteins for skincare and chronic wound healing products. PMID- 24163164 TI - [Reasons for non-participation in mammography screening--a survey in Schleswig Holstein, Germany]. AB - BACKGROUND: In 2007, an organized population-based mammography screening program in Schleswig-Holstein has been implemented. According the European guideline a participation rate of 70% should be reached as a measurement of quality. In Schleswig-Holstein participation rate reached only 45% and is one of the lowest rates in Germany. The reasons are unknown. METHOD: To 20,000 women, aged 50-69, who did not participate in mammography screening after an invitation letter, a questionnaire was sent to assess reasons of non-participation and knowledge about the program. We calculated the proportion of women answering to given aspects in the questionnaire. RESULTS: The response rate was 14.8% (n = 2591). Women reported multiple reasons for non-participation. Medical reasons and personal attitude were the most frequent ones. Organizational reasons were of minor importance. 75% of women get primarily informed about the program by the invitation letter. 25% of women talked with their practitioner about the program. CONCLUSION: The low participation rate of mammography screening in Schleswig Holstein is not based on worse organization but on medical reasons or personal attitudes of the women. It seems, that information about the program and benefits and harms of mammography screening has not reached the general population. So general practitioner or gynecologists should advice women more intensively. Leaflets and pamphlets should be more disseminated. PMID- 24163163 TI - [What kind of antiplatelet treatment in acute coronary syndrome?--Intensive antiplatelet treatment only for patients with invasive strategy]. PMID- 24163166 TI - [26-year-old man with dyspnea and palpitation]. PMID- 24163165 TI - [Cutaneous manifestation of tuberculosis causing impaired healing after minor injury]. AB - HISTORY AND CLINICAL FINDINGS: After a trivial injury, a male patient from India presented with a non-healing minor injury. A necrotic lesion at the right medial ankle was evident. EXAMINATIONS: Mycobacterium tuberculosis complex was detected from tissue material both in cultures and by molecular markers. Sonography of the abdomen indicated a retroperitoneal abcess formation. DIAGNOSIS, TREATMENT AND COURSE: Cutaneous tuberculosis with involvement of the spine and an abscess of the psoas muscle was diagnosed. After initiation of antituberculotic treatment elevation of liver enzymes was noted. The initially observed skin lesion in the area of the right ankle healed quickly; however, the abscess of the psoas muscle did not. The abscess was drained by puncture. During follow up no fistula formation was observed. CONCLUSION: Tuberculosis should be considered as differential diagnosis in cases of poorly healing skin lesions caused by trauma, especially in patients from tuberculosis high incidence regions. PMID- 24163167 TI - [Antidiarrheal drugs for chronic diarrhea]. AB - Chronic diarrhea can be caused by multiple disease entities. Basic diagnostic tests are required in order to administer specific therapies whenever possible. If no specific treatment can be used, a symptomatic management should be initiated in order to prevent massive electrolyte- and water losses. Substances that can be used are loperamide, cholestyramine, bulking agents, probiotics, anticholinergic agents and in severe cases opioids. If used properly these agents can be prescribed longterm with an acceptable side effect profile. PMID- 24163168 TI - [Vasopressin receptor antagonists in therapy of congestive heart failure]. PMID- 24163169 TI - [Long-term use of proton pump inhibitors--really harmless?]. PMID- 24163170 TI - [Legal requirements on medical advertising using the example of Kinesio Taping]. PMID- 24163171 TI - Virtually numbed: immersive video gaming alters real-life experience. AB - As actors in a highly mechanized environment, we are citizens of a world populated not only by fellow humans, but also by virtual characters (avatars). Does immersive video gaming, during which the player takes on the mantle of an avatar, prompt people to adopt the coldness and rigidity associated with robotic behavior and desensitize them to real-life experience? In one study, we correlated participants' reported video-gaming behavior with their emotional rigidity (as indicated by the number of paperclips that they removed from ice cold water). In a second experiment, we manipulated immersive and nonimmersive gaming behavior and then likewise measured the extent of the participants' emotional rigidity. Both studies yielded reliable impacts, and thus suggest that immersion into a robotic viewpoint desensitizes people to real-life experiences in oneself and others. PMID- 24163172 TI - Cultural modulations of space-time compatibility effects. AB - The representation of elapsing time may require spatial attention. In certain circumstances, this spatial representation develops from left to right. This is suggested by a performance advantage in responding short with the left hand and long with the right hand (spatial-temporal association between response codes [STEARC]). The present study tests whether one possible determinant of the directionality of the STEARC effect is cultural. In particular, we investigated whether reading/writing habits can affect STEARC direction by administering a visual time judgment task to Italian participants, who were exposed to a left-to right reading/writing system, and Israeli participants, who mainly used a right to-left system. The Italian participants showed a left-to-right STEARC effect, while this effect was not present in the Israeli group. The study demonstrates that cultural habits can influence the way in which spatial attention supports the representation of time, similar to the pattern found in other nonspatial domains such as numbers. PMID- 24163173 TI - Alcohol exposure among pregnant women in sub-saharan Africa: a systematic review. AB - BACKGROUND: The prevalence of general alcohol use in many countries of sub Saharan Africa (SSA) is high. However, research examining alcohol use in among pregnant women within this population is limited. A review of the current status of research examining the prevalence of alcohol exposed pregnancies (AEP) is required to inform future research aiming to decrease this occurrence and its subsequent socio-economic complications. OBJECTIVE: The primary objective was to identify all published papers estimating prevalence and risk-factors of alcohol use among pregnant women in SSA. A secondary objective was to determine changes in alcohol use following pregnancy recognition. METHODS: PubMed/Medline, Embase, IPA, CINAHL were systematically searched using MeSH terms and keywords from inception date to March 2013. Studies from SSA reporting prevalence of alcohol use among pregnant women were included. RESULTS: Twelve studies were identified. Studies varied significantly according to design and study population. Prevalence of alcohol use during pregnancy ranged from 2.2%-87%. The most important risk factors for alcohol use included tobacco use, partner violence, urban living, and having a male partner who drank alcohol. Only three studies examined changes in alcohol use prior to and following pregnancy recognition with absolute reductions of between 9% and 15%. CONCLUSIONS: Although the burden of alcohol use during pregnancy is likely a significant problem, limited data currently exist for the majority of SSA countries. Furthermore, significant variation likely exists within various populations. Further research is required to explore alcohol use in pregnancy. Strategies to decrease AEP must be developed and implemented in standard pre-natal care. PMID- 24163174 TI - Quantitative assessment of global hepatic glycolysis in patients with cirrhosis and normal controls using 18F-FDG-PET/CT: a pilot study. AB - OBJECTIVE: To compare differences in global measures of hepatic metabolism between control subjects and subjects with cirrhosis. MATERIALS AND METHODS: FDG PET/CT scans of 33 subjects either without or with cirrhosis were analyzed retrospectively and classified as follows: group 1 includes subjects without cirrhosis or extrahepatic malignancy (1a) (n=11) and subjects without cirrhosis but with history of extrahepatic malignancy (1b) (n=10); group 2 includes subjects with cirrhosis and history of extrahepatic malignancy (n=12). Subjects with focal hepatic lesions, prior hepatic surgery, co-existing liver pathology, or who received chemotherapy or radiation therapy within the last 6 months were excluded. The hepatic volumes, hepatic mean standardized uptake value (SUVmean), and global hepatic glycolysis (GHG) were compared between groups. RESULTS: Subjects with cirrhosis showed a lower average hepatic SUVmean as compared to non cirrhotic patients (1.55+/-0.29 for group 2 versus 1.81+/-0.23 for group 1; p value=0.009) and lower average values for GHG (2238.29+/-903.60 for group 2 versus 2974.67+/-829.16 for group 1; p value=0.024). No differences were noted between the non-cirrhotic subgroups (i.e., between the groups 1a and 1b) without and with associated extrahepatic malignancy, respectively. CONCLUSIONS: We hypothesize that presence of fibrosis, reduction of active inflammation, and decreased hepatic metabolism and function are potential causes of the lower FDG uptake in cirrhotic livers. Our results also indicate that extrahepatic cancer status does not influence FDG uptake in the non-cirrhotic liver in subjects without hepatic metastases. PMID- 24163177 TI - A previously undescribed form of intraductal papillary neoplasm of the bile duct. PMID- 24163178 TI - Esophageal metallic stent fixation with dental floss: a simple method to prevent migration. PMID- 24163176 TI - Foliar abscisic acid content underlies genotypic variation in stomatal responsiveness after growth at high relative air humidity. AB - BACKGROUND AND AIMS: Stomata formed at high relative air humidity (RH) respond less to abscisic acid (ABA), an effect that varies widely between cultivars. This study tested the hypotheses that this genotypic variation in stomatal responsiveness originates from differential impairment in intermediates of the ABA signalling pathway during closure and differences in leaf ABA concentration during growth. METHODS: Stomatal anatomical features and stomatal responsiveness to desiccation, feeding with ABA, three transduction elements of its signalling pathway (H2O2, NO, Ca(2+)) and elicitors of these elements were determined in four rose cultivars grown at moderate (60 %) and high (90 %) RH. Leaf ABA concentration was assessed throughout the photoperiod and following mild desiccation (10 % leaf weight loss). KEY RESULTS: Stomatal responsiveness to desiccation and ABA feeding was little affected by high RH in two cultivars, whereas it was considerably attenuated in two other cultivars (thus termed sensitive). Leaf ABA concentration was lower in plants grown at high RH, an effect that was more pronounced in the sensitive cultivars. Mild desiccation triggered an increase in leaf ABA concentration and equalized differences between leaves grown at moderate and high RH. High RH impaired stomatal responses to all transduction elements, but cultivar differences were not observed. CONCLUSIONS: High RH resulted in decreased leaf ABA concentration during growth as a result of lack of water deficit, since desiccation induced ABA accumulation. Sensitive cultivars underwent a larger decrease in leaf ABA concentration rather than having a higher ABA concentration threshold for inducing stomatal functioning. However, cultivar differences in stomatal closure following ABA feeding were not apparent in response to H2O2 and downstream elements, indicating that signalling events prior to H2O2 generation are involved in the observed genotypic variation. PMID- 24163175 TI - Hepatic cytochrome P450s, phase II enzymes and nuclear receptors are downregulated in a Th2 environment during Schistosoma mansoni infection. AB - Inflammation and infection downregulate the activity and expression of cytochrome P450s (P450s) and other drug metabolizing enzymes (DMEs) involved in hepatic drug clearance. Schistosoma mansoni infection was reported to cause a downregulation of hepatic P450-dependent activities in mouse liver, but little is known about the specific enzymes affected or whether phase II DMEs are also affected. Here we describe the effect of murine schistosomiasis on the expression of hepatic P450s, NADPH-cytochrome P450 reductase (Cpr), phase II drug metabolizing enzymes, and nuclear receptors at 30 and 45 days postinfection (dpi). Although the hepatic expression of some of these genes was altered at 30 dpi, we observed substantial changes in the expression of the majority of P450 mRNAs and proteins measured, Cpr protein, as well as many of the UDP-glucuronosyltransferases and sulfotransferases at 45 dpi. S. mansoni infection also altered nuclear receptor expression, inducing mRNA levels at 30 dpi and depressing levels at 45 dpi. S. mansoni evoked a T helper 2 (Th2) inflammatory response at 45 dpi, as indicated by the induction of hepatic Th2 cytokine mRNAs [interleukins 4, 5, and 13], whereas the hepatic proinflammatory response was relatively weak. Thus, chronic schistosomiasis markedly and selectively alters the expression of multiple DMEs, which may be associated with Th2 cytokine release. This would represent a novel mechanism of DME regulation in disease states. These findings have important implications for drug testing in infected mice, whereas the relevance to humans with schistosomiasis needs to be determined. PMID- 24163179 TI - Successful over-the-scope clip (OTSC) treatment for severe bleeding due to anastomotic dehiscence. PMID- 24163180 TI - Recurrent intra-abdominal abscess formation due to a gastric diverticulum. PMID- 24163181 TI - Endoscopic removal of a fractured nasojejunal tube in the duodenum. PMID- 24163182 TI - Endoscopic ultrasound-guided biliary rendezvous with primary sphincteroplasty for stone extraction from an "inverse pitcher" papilla. PMID- 24163183 TI - Extensive small-bowel diverticulosis identified with the newly introduced On Demand Enteroscopy system. PMID- 24163184 TI - A large impacted pancreatic duct stone causing acute cholangitis. PMID- 24163185 TI - Identifying the neurobehavioral phenotype of fetal alcohol spectrum disorder in young children. AB - BACKGROUND: Most children with Fetal Alcohol Spectrum Disorder (FASD) do not display the typical facial changes, making the diagnosis much more challenging due to poor specificity of the brain dysfunction exhibited by these children. We have recently described and validated a behavioral phenotype of FASD using items from the Child Behavior Checklist (The Neurobehavioral Screening Test, NST). This tool has high sensitivity and specificity in separating children aged 6-13 yrs with FASD from those with ADHD and from healthy controls. OBJECTIVES: To test the validity of the NST for children aged 4-6 years in order to help facilitate diagnosis of FASD in young children. METHODS: Children referred to Motherisk for FASD diagnosis are all tested using the Child Behavior Checklist. We compared the scores of children 4-6 yrs diagnosed with FASD to those referred but not receiving a diagnosis, as well as to normal healthy control children of the same age range.ResultsOut of the 10 items of NST used at age 6-13 years, 3 are not scored in children 4-6 years of age. Using the 7 remaining items, children with FASD endorsed significantly more items (6.7+/-1.3) than healthy controls ( 2.3+/ 1.2 ), or alcohol- exposed children who were not given an FASD diagnosis (4.7+/- 1.9). Using a cut-off of 5 out of7 items, the NST had a 94% sensitivity and 96% specificity in identifying children with FASD. Nine of 19 children exposed to alcohol with whom an FASD diagnosis could not be confirmed, scored 5 or more on the NST. CONCLUSIONS: In this pilot study, the NST has shown very high sensitivity and specificity and can be used to identify children who are very likely to be diagnosed with FASD. PMID- 24163186 TI - Yoga and psychophysiological determinants of cardiovascular health: comparing yoga practitioners, runners, and sedentary individuals. AB - BACKGROUND: The evidence of cardiovascular benefits of yoga is promising, but lacks demonstrations of specificity compared to other interventions. PURPOSE: The present cross-sectional study examined cardiovascular health markers in long-term practitioners of yoga (yogis), runners, and sedentary individuals. METHODS: We compared physiological, psychological, and lifestyle variables associated with cardiovascular health across groups. RESULTS: Yogis (n = 47) and runners (n = 46) showed favorable profiles compared to sedentary individuals (n = 52) on heart rate, heart rate variability, depression, perceived stress, and cigarette smoking. Runners and male yogis showed superior aerobic fitness compared to the sedentary group. Runners reported greater social support compared to other groups. Yogis demonstrated a lower respiration rate compared to sedentary individuals and were more likely to refrain from eating meat compared to other groups. CONCLUSIONS: Yogis and runners demonstrated several cardiovascular health advantages over sedentary individuals. Our findings raise the possibility that yoga may improve aerobic fitness in men but not women. PMID- 24163187 TI - The effectiveness of gain-versus loss-framed health messages in improving oral health in Iranian secondary schools: a cluster-randomized controlled trial. AB - BACKGROUND: Adherence to oral self-care behaviors is low among adolescents. PURPOSE: This study aims to examine effects of two message framing interventions on oral self-care behaviors and health among Iranian adolescents. METHODS: Cluster-randomized controlled trial, with four schools randomly assigned to receive gain-framed, loss-framed, or no messages. Brushing/flossing, attitudes, intentions, oral health related quality of life (OHRQOL), and clinical examinations were measured at baseline, two and twenty-four weeks. Data were analyzed using multilevel modeling. RESULTS: At 2 weeks, loss-frame participants reported higher brushing and flossing rates, and more favorable attitudes and intentions to brush, compared to the other groups. At 24 weeks, loss-frame participants showed better OHRQOL, gingival health and less dental plaque compared to the other groups. Attitudes and intentions mediated intervention effects for the loss-framed group. CONCLUSIONS: Loss-framed messages were more effective than gain-framed messages in encouraging oral self-care behaviors among Iranian adolescents. These effects were mediated through attitudes and intentions. (clinicaltrials.gov number NCT01421108.). PMID- 24163188 TI - The psychosocial context impacts medication adherence after acute coronary syndrome. AB - BACKGROUND: Depression is associated with poor adherence to medications and worse prognosis in patients with acute coronary syndrome (ACS). PURPOSE: To determine whether cognitive, behavioral, and/or psychosocial vulnerabilities for depression explain the association between depression and medication adherence among ACS patients. METHODS: One hundred sixty-nine ACS patients who agreed to have their aspirin adherence measured using an electronic pill bottle for 3 months were enrolled within 1 week of hospitalization. Linear regression was used to determine whether depression vulnerabilities predicted aspirin adherence after adjustment for depressive symptoms, demographics, and comorbidity. RESULTS: Of the depression vulnerabilities, only role transitions (beta = -3.32; P = 0.02) and interpersonal conflict (beta -3.78; P = 0.03) predicted poor adherence. Depression vulnerabilities did not mediate the association between depressive symptoms and medication adherence. CONCLUSIONS: Key elements of the psychosocial context preceding the ACS including major role transitions and conflict with close contacts place ACS patients at increased risk for poor medication adherence independent of depressive symptoms. PMID- 24163189 TI - Prophylaxis of venous thromboembolism with low molecular weight heparin in bariatric surgery: a prospective, randomised pilot study evaluating two doses of parnaparin (BAFLUX Study). AB - BACKGROUND: The optimal dose of low molecular weight heparin (LMWH) to prevent venous thromboembolism (VTE) after bariatric surgery remains controversial. The aim of this multicentre, open-label, pilot study was to evaluate the efficacy and safety of two different doses of the LMWH parnaparin administered to patients undergoing bariatric surgery. METHODS: Patients were randomised to receive 4,250 IU/day (group A) or 6,400 IU/day (group B) of parnaparin s.c. for 7-11 days. Bilateral colour Doppler ultrasound of the lower limb was performed before surgery and at the end of the treatment period. The primary efficacy outcome was a composite of asymptomatic and symptomatic deep vein thrombosis, symptomatic pulmonary embolism and death from any cause during treatment. The primary safety endpoint was major and clinically relevant non-major bleeding. RESULTS: A total of 258 patients underwent randomization; 8 subjects were excluded following the safety analysis. One hundred thirty-one patients [106 females; mean age, 40.3 years (standard deviation (SD) +/-9.6); mean body mass index (BMI), 44.6 kg/m(2) (SD +/-5.4)] were assigned to group A and 119 patients [93 females; mean age, 41.5 years (SD +/-9.9); mean BMI, 44.2 kg/m(2) (SD +/-5.4)] were assigned to group B. The rate of the primary efficacy outcome was 1.5% (two cases; 95 % confidence interval (CI), 0.2-6.0%) in group A as compared with 0.8% (one case; 95% CI, 0.4-5.3%) in group B (p = ns). The composite incidence of major bleeding and clinically relevant non-major bleeding was 6.1% (eight cases; 95% CI, 2.9 12.1%) in group A and 5.0% (six cases; 95% CI, 2.1-11.1%) in group B (p = ns). CONCLUSIONS: A parnaparin dose of 4,250 IU/day seems suitable for VTE prevention in patients undergoing bariatric surgery. PMID- 24163190 TI - Endoscopic submucosal dissection using the "Clutch Cutter" for early esophageal squamous cell carcinoma. AB - BACKGROUND AND STUDY AIMS: To reduce the risk of complications related to the use of knives in endoscopic submucosal dissection (ESD), we developed the Clutch Cutter which can grasp and incise targeted tissue using electrosurgical current, similarly to a biopsy technique. The study aim was to evaluate the efficacy and safety of ESD using the Clutch Cutter for early esophageal squamous cell carcinoma. PATIENTS AND METHODS: ESD using the Clutch Cutter was performed on 32 consecutive patients with early esophageal squamous cell carcinoma. Therapeutic efficacy and safety were assessed. RESULTS: All lesions were treated easily and safely without unintended incision. En bloc resection was obtained in all patients. Histologically negative margins were obtained in 26/32 patients (81%). Endoscopic perforation due to the hood in one patient (3%), mediastinitis without endoscopic perforation in one patient (3%), and post-ESD stricture in 5 patients (16%) were observed. All were successfully managed conservatively. CONCLUSIONS: ESD using the Clutch Cutter appears to be a safe, easy, and technically efficient method for resecting early esophageal squamous cell carcinomas. PMID- 24163191 TI - The ENKI-2 water-jet system versus Dual Knife for endoscopic submucosal dissection of colorectal lesions: a randomized comparative animal study. AB - BACKGROUND AND STUDY AIMS: The ENKI-2 water-jet system for endoscopic submucosal dissection (ESD) combines submucosal saline pressure injection with dissection. The aim of this study was to compare ENKI-2 with a standard device in terms of procedure time and perforation rate during colorectal ESD. METHODS: In this randomized comparative study, 10 30-mm-diameter lesions were created in the colon and rectum of 10 healthy adult pigs. The ESD procedure time and perforation rates were recorded for the ENKI-2 system and a standard Dual Knife method. Each pig had half the lesions dissected by ENKI-2 and half dissected by Dual Knife. One experienced and one inexperienced endoscopist took part in the study. RESULTS: A total of 95 lesions were dissected (47 by ENKI-2 and 48 by Dual Knife). The experienced endoscopist was able to excise comparably sized 30-mm lesions using both techniques. The dissection time was shorter for ENKI-2 (18.9 vs. 25.6 minutes; P = 0.034) and the perforation rate was lower compared with the Dual Knife (one perforation [4 %] vs. nine perforations [36 %]; P = 0.011). The inexperienced endoscopist performed significantly larger dissections using the ENKI-2 (934 +/- 405 mm2 vs. 673 +/- 312 mm2; P = 0.021) despite pre-marking similarly sized artificial lesions. Multivariate analysis demonstrated that for all lesions the dissection time was significantly longer for lesions in the proximal colon (P = 0.001) and the distal colon (P < 0.0001) and shorter for the experienced operator (P < 0.0001). ENKI-2 shortened the dissection time, but not significantly (P = 0.093). CONCLUSIONS: In experienced hands, the ENKI-2 system shortens dissection time and reduces the perforation rate. This effect was not statistically significant for an inexperienced operator. Dissection was faster in the rectum than the colon. PMID- 24163192 TI - A pilot study of in vivo identification of pancreatic cystic neoplasms with needle-based confocal laser endomicroscopy under endosonographic guidance. AB - BACKGROUND AND STUDY AIMS: Endoscopic ultrasound (EUS) with fine-needle aspiration (FNA) of pancreatic cystic lesions (PCL) is flawed by inadequate diagnostic yield. Needle-based confocal laser endomicroscopy (nCLE) utilizes a sub-millimeter probe that is compatible with an EUS needle and enables real-time imaging with microscopic detail of PCL. The aims of the In vivo nCLE Study in the Pancreas with Endosonography of Cystic Tumors (INSPECT) pilot study were to assess both the diagnostic potential of nCLE in differentiating cyst types and the safety of the technique. PATIENTS AND METHODS: Eight referral centers performed nCLE in patients with PCL. Stage 1 defined descriptive terms for structures visualized by an off-line, unblinded consensus review. Cases were reviewed with a gastrointestinal pathologist to identify correlations between histology and nCLE. Stage 2 assessed whether the specific criteria defined in Stage 1 could identify pancreatic cystic neoplasms (PCN) including intraductal papillary mucinous neoplasms, mucinous cystic adenoma, or adenocarcinoma in an off-line blinded consensus review. RESULTS: A total of 66 patients underwent nCLE imaging and images were available for 65, 8 of which were subsequently excluded due to insufficient information for consensus reference diagnosis. The presence of epithelial villous structures based on nCLE was associated with PCN (P=0.004) and provided a sensitivity of 59%, specificity of 100%, positive predictive value of 100 %, and negative predictive value of 50%. The overall complication rate was 9% and included pancreatitis (1 mild case, 1 moderate case), transient abdominal pain (n=1), and intracystic bleeding not requiring any further measures (n=3). CONCLUSIONS: These preliminary data suggested that nCLE has a high specificity in the detection of PCN, but may be limited by a low sensitivity. The safety of nCLE requires further evaluation. PMID- 24163193 TI - Updating the management of patients with rectal neuroendocrine tumors. AB - Rectal neuroendocrine tumors (NETs) account for approximately one-third of all digestive NETs, with an increasing incidence and good overall prognosis. Although recent guidelines have been published, endoscopic techniques have expanded substantially and the most recent reports should be taken into account for clinical practice. The objectives of this report were to review the latest advances on prognosis, pre-interventional explorations, treatment-with particular focus on endoscopy-and surveillance of well-differentiated rectal NETs, excluding poorly differentiated and metastatic tumors. PMID- 24163194 TI - Intravenous sildenafil in the management of pulmonary hypertension associated with congenital diaphragmatic hernia. AB - BACKGROUND: Pulmonary artery hypertension (PAH) is a significant cause of morbidity and mortality in infants with congenital diaphragmatic hernia (CDH). The phosphodiesterase-5 inhibitor sildenafil may be beneficial as a pulmonary vasodilator in CDH. Use of oral preparations of sildenafil may be restricted by feeding delays and intolerance. This study assessed the cardiorespiratory effects of a newly available intravenous (IV) preparation of sildenafil in CDH. OBJECTIVES: The objective of the article is to assess the acute effects of IV sildenafil infusion on myocardial function, pulmonary artery pressure (PAP), and oxygenation in infants with CDH. METHODS: Retrospective case review of infants with CDH who received continuous IV sildenafil. Physiological and echocardiographic data were reviewed to obtain oxygenation index (OI), PAP, patent ductus arteriosus (PDA) flow, myocardial tissue Doppler velocities, and right ventricular output (RVO) at 48 hours presildenafil, and at 24 to 48 hours and 72 to 96 hours after commencing IV sildenafil. RESULTS: A total of nine infants received IV sildenafil at a dose of 100 to 290 MUg/kg/h after CDH repair but before enteral feeding. Pre-IV sildenafil PAP was >= systemic blood pressure in all infants, systolic and diastolic right ventricular myocardial velocities were impaired. After 72 to 96 hours of IV sildenafil, OI and Fio 2 were significantly reduced. Ratio of right-to-left to left-to-right PDA flow was > 1 pre-IV sildenafil and < 1 post-IV sildenafil. CONCLUSIONS: IV sildenafil infusion was associated with improved oxygenation. Prospective trials of IV sildenafil are required to determine effects on longer term outcome. PMID- 24163195 TI - Preformed silos versus traditional abdominal wall closure in gastroschisis: 163 infants at a single institution. AB - INTRODUCTION: The surgical management of gastroschisis (GS) is controversial. The most commonly used strategy for abdominal wall closure is surgery on day 1 of life with the aim of primary closure (PC) or construction of a surgical silo (SS) and secondary closure thereafter. The other widely used technique is application of a preformed silo (PFS) and reduction of contents over a few days before final closure. There is still a paucity of comparative outcome data. METHODS: A retrospective case note review of all infants initially treated at a single institution between October 1993 and October 2012. PFS was adopted as the technique of choice in April 2005. Infants with closed or closing GS were excluded. Data are presented as median (range). p < 0.05 were significant. RESULTS: There were 163 infants (156 complete data sets). PFSs were applied in 67 infants and PC/SS were applied in 89 infants of whom 19 infants required a SS. There was no statistical difference between gestational age (p = 0.8), birth weight (p = 0.7), time to first (p = 0.07) and full enteral feeding (p = 0.08), length of hospital stay (p = 0.17), or necrotizing enterocolitis (p = 0.4) and mortality (p = 0.4). Infants treated with PC + SS were closed on day 0 (range, 0 11 days) versus day 6 (range, 2-22 days) of life (p < 0.001). PC + SS were ventilated for day 5 (range, 1-22 days) versus day 3.5 (range, 0-20 days) days (p = 0.01). CONCLUSION: Infants treated with PFS required less ventilation than those treated by PC + SS. There was no difference in time to full feeds, length of hospital stay mortality or morbidity. PMID- 24163196 TI - Work-related injuries with child labor in Iran. AB - AIM: Accurate present-day child labor information is difficult to obtain. The aim of this study was to evaluate the characteristics of child labor patients according to worker status and identify the proportion of work-related injuries that could be prevented by protection devices. PATIENTS AND METHODS: This study was performed in one of the largest pediatric trauma center in the central part of Iran. In a prospective case series study, injured children with age less than 15 years who were consecutively admitted to the trauma center for management of their trauma were evaluated. In each patient data such as age, sex, worker status, anatomic site of injury, and costs were collected. RESULTS: In this study, a total of 127 children were evaluated. Most of the injuries (80.3%) occurred in urban areas. In most of the injured patients, the main reason of working was to help pay own family debts or supplement family income. Industrial workroom was the most common place for injury (58.2%). Falling from height or in horizontal surface was the most common mechanism of injury (44%). None of the patients had preventable device at the time of injury. Cuts (49.6%) were the most commonly reported injuries. The lengths of hospitalization were 1.23 + 0.88 days. There was no death reported in our cases. The mean of cost of hospitalization was US $29.9 +/- 20.36. CONCLUSION: Our study showed that child labor injury in the central part of Iran mainly occurred in nonagricultural sector due to falling. These injuries are nonfatal and might be prevented by protective equipment. PMID- 24163197 TI - Long-term follow-up of children with congenital diaphragmatic hernia- observations from a single institution. AB - INTRODUCTION: Congenital diaphragmatic hernia (CDH) is a complex malformation. The majority of children after CDH repair lead normal life, with good exercise tolerance. However, in some patients, long-term sequelae are observed, resulting from the primary defect and implemented treatment. MATERIAL AND METHODS: We evaluated (basing on clinical examination and review of medical records) the incidence of the most common long-term complications after surgical repair of CDH and determined their risk factors. The study group comprised 50 children operated in our department for CDH. RESULTS: The following long-term complications were seen: recurrent respiratory system infections (34%), pathological gastrointestinal reflux (30%), body mass deficiency (20%), and chest deformations (40%). Parents reported most common symptoms from the gastrointestinal tract (48%) and recurring respiratory system infections (34%). Perfusion of the ipsilateral lung was significantly lower in the group of children in whom negative prognostic factors were present: patch repair, transposition of the liver up CDH, lung hypertension in echocardiography, high-frequency oscillatory ventilation (HFOV) use, prolonged artificial ventilation. In lung scintigraphy, in 70% of patients ipsilateral lung hypoplasia was found. There was a correlation between gastroesophageal reflux (GER) and early detection of CHD in prenatal studies and the presence of polyhydramnios. Patients with GER also required longer artificial ventilation and longer hospitalization. Significant body mass deficiency (below 3rd centile) was found in 20%, correlated with patch repair and HFOV. Chest deformations were more common in children who required synthetic patch repair and artificial ventilation for longer than 10 days. CONCLUSIONS: The most common long-term complications observed in children after CDH repair are recurrent infections of the respiratory tract, lung hypoplasia, pathological GER, somatic growth abnormalities, and skeletal deformations. Children operated for CDH should be followed up regularly for many years by a multispecialty medical team. Diagnostics and/or follow-up of the above complications require detailed clinical examination, lung perfusion scintigraphy, spirometry, and 24-hour pH metry. PMID- 24163199 TI - Dupuytren contracture in the pediatric population: a systematic review. AB - Dupuytren contracture of the palm is a relatively common benign fibroproliferative disease of the palmar fascia typically affecting the adult population. There have however been several reported cases of Dupuytren contracture in children. We sought to review the literature for Dupuytren contracture and highlight the main clinical features and management of the disease in children. PMID- 24163198 TI - Pneumothoraces as a fatal complication of congenital diaphragmatic hernia in the era of gentle ventilation. AB - INTRODUCTION: Pneumothorax remains a life-threatening complication that occurs in congenital diaphragmatic hernia (CDH), even under respiratory management with gentle ventilation. The aim of this study was to evaluate the prevalence of pneumothoraces as a fatal complication during the management of CDH based on the results of a nationwide Japanese survey conducted in the era of gentle ventilation. MATERIALS AND METHODS: A retrospective cohort study was performed as part of a nationwide Japanese survey of CDH. A total of 510 neonates with isolated CDH born between 2006 and 2010 were included in this study. The patients were divided into four groups according to operative findings related to the diaphragmatic defect size and operability, which represents the disease severity: defects less than 25%, defects more than 25% but less than 75%, defects more than 75%, and a patient group that was unable to undergo surgery. The prevalence of pneumothorax and the survival rate were compared with respect to each disease severity group. Each case was evaluated to determine whether the development of a pneumothorax was the primary cause of death. RESULTS: Of the 510 neonates with isolated CDH, 69 patients developed a pneumothorax before and/or after surgical intervention. Of the 69 patients 38 patients died, and only 26 patients were discharged from the hospital without any major morbidity that requires home treatment ("intact discharge"). The prevalence of pneumothorax increased and the survival rate and intact discharge rate decreased as the severity of the disease worsened. The number of patients whose pneumothorax was presumed to be the primary cause of death also increased as the severity of the disease worsened. The survival rate of the patients with pneumothorax was significantly lower than that of the patients without pneumothorax among the groups with 25 to 75% defects and 75% or more defects. CONCLUSIONS: Pneumothoraces was found to more likely occur in neonates with CDH associated with a large defect of the diaphragm. The survival rate and intact discharge rate decreased as the severity of the disease worsened, especially among the patients who developed pneumothorax accompanied by large diaphragmatic defects. No other risk factors related to pneumothorax occurrence were found, except for the severity of the disease itself, thus suggesting that pneumothorax was associated with a lethal outcome in neonates with CDH associated with a large defect of the diaphragm. PMID- 24163200 TI - Modeling, simulation and analysis of methylation profiles from reduced representation bisulfite sequencing experiments. AB - The ENCODE project has funded the generation of a diverse collection of methylation profiles using reduced representation bisulfite sequencing (RRBS) technology, enabling the analysis of epigenetic variation on a genomic scale at single-site resolution. A standard application of RRBS experiments is in the location of differentially methylated regions (DMRs) between two sets of samples. Despite numerous publications reporting DMRs identified from RRBS datasets, there have been no formal analyses of the effects of experimental and biological factors on the performance of existing or newly developed analytical methods. These factors include variable read coverage, differing group sample sizes across genomic regions, uneven spacing between CpG dinucleotide sites, and correlation in methylation levels among sites in close proximity. To better understand the interplay among technical and biological variables in the analysis of RRBS methylation profiles, we have developed an algorithm for the generation of experimentally realistic RRBS datasets. Applying insights derived from our simulation studies, we present a novel procedure that can identify DMRs spanning as few as three CpG sites with both high sensitivity and specificity. Using RRBS data from muscle vs. non-muscle cell cultures as an example, we demonstrate that our method reveals many more DMRs that are likely to be of biological significance than previous methods. PMID- 24163201 TI - Vitamin D status 10 years after primary gastric bypass: gravely high prevalence of hypovitaminosis D and raised PTH levels. AB - BACKGROUND: The primary aim of this study was to evaluate the prevalence of vitamin D deficiency and secondary hyperparathyroidism after Roux-en-Y gastric bypass. Secondly, we have tried to assess predictors for vitamin D deficiency. METHODS: Five hundred thirty-seven patients who underwent primary Roux-en-Y gastric bypass surgery between 1993 and 2003 at the Orebro University Hospital and Uppsala University Hospital were eligible for the study. Patients were asked to provide a blood sample between November 2009 and June 2010 and to complete a questionnaire about their postoperative health status. Serum values of 25-OH vitamin D, parathyroid hormone (PTH), alkaline phosphatase (ALP) and calcium were determined. RESULTS: Follow-up was completed in 293 patients, of which 83 % were female, with an age of 49 +/- 9.9 years after a median time of 11 +/- 2.8 years. Vitamin D, PTH and albumin-corrected calcium values were 42 +/- 20.4 nmol/L, 89.1 +/- 52.7 ng/L and 2.3 +/- 0.1 mmol/L, respectively. Of all patients, 65 % were vitamin D deficient, i.e. 25-OH vitamin D <50 nmol/L, and 69 % had PTH above the upper normal reference range, i.e. >73 ng/L. Vitamin D was inversely correlated with PTH levels (p < 0.001) and positively correlated with calcium (p = 0.016). Vitamin D did not correlate with ALP. The only factor found to predict vitamin D deficiency was high preoperative body mass index (BMI) (p = 0.008), whereas gender, age, time after surgery and BMI at follow-up did not. CONCLUSIONS: Vitamin D deficiency and secondary hyperparathyroidism after Roux-en-Y gastric bypass (RYGB) were confirmed in our study because 65 % of patients had vitamin D deficiency, and 69 % had increased PTH levels more than 10 years after surgery. These data are alarming and highlight the need for improved long-term follow-up. Vitamin D deficiency does not seem to progress with time after surgery, possibly due to weight loss. Only preoperative BMI, cutoff point 43 kg/m(2), was a predictor of vitamin D deficiency at follow-up. Improved long-term follow-up of patients that undergo RYGB is needed. PMID- 24163202 TI - Mind the gap: difference between Framingham heart age and real age increases with age in HIV-positive individuals-a clinical cohort study. AB - OBJECTIVES: To measure the excess risk of cardiovascular disease (CVD) in HIV positive individuals by comparing 'heart age' with real age and to estimate associations of patients' characteristics with heart age deviation (heart age real age). DESIGN: Clinical Cohort Study. SETTING: Bristol HIV clinic, Brecon Unit at Southmead Hospital, Bristol, UK. PARTICIPANTS: 749 HIV-positive adults who attended for care between 2008 and 2011. Median age was 42 years (IQR 35-49), 67% were male and 82% were treated with antiretroviral therapy. MAIN OUTCOME MEASURES: We calculated the Framingham 10-year risk of CVD and traced back to 'heart age', the age of an individual with the same score but ideal risk factor values. We estimated the relationship between heart age deviation and real age using fractional polynomial regression. We estimated crude and mutually adjusted associations of sex, age, CD4 count, viral load/treatment status and period of starting antiretroviral therapy with heart age deviation. RESULTS: The average heart age for a male aged 45 years was 48 years for a non-smoker and 60 years for a smoker. Heart age deviation increased with real age and at younger ages was smaller for females than males, although this reversed after 48 years. Compared to patients with CD4 count <500 cells/mm(3), heart age deviation was 2.4 (95% CI 0.7 to 4.0) and 4.3 (2.3 to 6.3) years higher for those with CD4 500-749 cells/mm(3) and >=750 cells/mm(3), respectively. CONCLUSIONS: In HIV-positive individuals, the difference between heart age and real age increased with age and CD4 count and was very dependent on smoking status. Heart age could be a useful tool to communicate CVD risk to patients and the benefits of stopping smoking. PMID- 24163203 TI - Treadmill walking speed and survival prediction in men with cardiovascular disease: a 10-year follow-up study. AB - OBJECTIVE: To determine whether the walking speed maintained during a 1 km treadmill test at moderate intensity predicts survival in patients with cardiovascular disease. DESIGN: Population-based prospective study. SETTING: Outpatient secondary prevention programme in Ferrara, Italy. PARTICIPANTS: 1255 male stable cardiac patients, aged 25-85 years at baseline. MAIN OUTCOME MEASURES: Walking speed maintained during a 1 km treadmill test, measured at baseline and mortality over a median follow-up of 8.2 years. RESULTS: Among 1255 patients, 141 died, for an average annual mortality of 1.4%. Of the variables considered, the strongest predictor of all-cause mortality was walking speed (95% CI 0.45 to 0.75, p<0.0001). Based on the average speed maintained during the test, participants were subdivided into quartiles and mortality risk adjusted for confounders was calculated. Compared to the slowest quartile (average walking speed 3.4 km/h), the relative mortality risk decreased for the second, third and fourth quartiles (average walking speed 5.5 km/h), with HRs of 0.73 (95% CI 0.46 to 1.18); 0.54 (95% CI 0.31 to 0.95) and 0.20 (95% CI 0.07 to 0.56), respectively (p for trend <0.0001). Receiver operating curve analysis showed an area under the curve of 0.71 (p<0.0001) and the highest Youden index (0.35) for a walking speed of 4.0 km/h. CONCLUSIONS: The average speed maintained during a 1 km treadmill walking test is inversely related to survival in patients with cardiovascular disease and is a simple and useful tool for stratifying risk in patients undergoing secondary prevention and cardiac rehabilitation programmes. PMID- 24163205 TI - Cross-sectional survey: risk-averse French GPs use more rapid-antigen diagnostic tests in tonsillitis in children. AB - OBJECTIVES: We tested the following hypotheses: (1) risk-averse general practitioners (GPs) might use more Rapid Antigen Diagnostic Tests (RADTs) in tonsillitis in children, probably to decrease their diagnostic uncertainty regarding the aetiology of the disease (viral vs due to group A Streptococcus); and (2) GPs not using RADT might prescribe more antibiotics when they are risk averse. DESIGN, SETTING AND PARTICIPANTS: We conducted a cross-sectional survey of a nationwide French representative sample of 1093 GPs in 2012. OUTCOME MEASURES: Multivariate analyses adjusted on the four stratification variables (age, gender, location and volume of activity, ie, the number of annual consultations) were performed to identify the risk domains associated with indicators of good or poor practice. RESULTS: 69.4% of GPs were aware of national guidelines regarding tonsillitis and declared that they had taken these guidelines into account for their last paediatric tonsillitis case. 59.1% declared they used RADT in their last patient aged between 3 and 16 years presenting with tonsillitis; 29.7% of these tests were positive. Among the GPs who used RADT, 30.7% prescribed an antibiotic; 98.3% did either prescribe an antibiotic because of a positive RADT result, or did not prescribe an antibiotic in view of a negative result. Among the GPs who did not use RADT, 50.7% prescribed an antibiotic. In multivariate analyses, risk-averse GPs declared being more aware of and compliant with guidelines (OR=1.56, p<0.01), and used RADTs more often for their last patient (OR=1.30, p<0.05). Among GPs not using RADT in their last patient, risk-averse GPs prescribed more antibiotics compared with risk-tolerant doctors (OR=1.18, p<0.05). CONCLUSIONS: Individual risk attitudes influenced GPs' practices in tonsillitis, particularly the use of RADTs and antibiotic prescriptions. PMID- 24163204 TI - Loss to follow-up occurs at all stages in the diagnostic and follow-up period among HIV-infected patients in Guinea-Bissau: a 7-year retrospective cohort study. AB - OBJECTIVES: To describe loss to follow-up (LTFU) at all stages of the HIV programme. DESIGN: A retrospective cohort study. SETTING: The HIV clinic at Hospital National Simao Mendes in Bissau, Guinea-Bissau. PARTICIPANTS: A total of 4080 HIV-infected patients. OUTCOME MEASURES: Baseline characteristics, percentages and incidence rates of LTFU as well as LTFU risk factors at four different stages: immediately after HIV diagnosis (stage 1), after the first CD4 cell count and before a follow-up consultation (stage 2), after a follow-up consultation for patients not eligible for antiretroviral treatment (ART; stage 3) and LTFU among patients on ART (stage 4). RESULTS: Almost one-third of the patients were lost to the programme before the first consultation where ART initiation is decided; during the 7-year observation period, more than half of the patients had been lost to follow-up (overall incidence rate=51.1 patients lost per 100 person-years). Age below 30 years at inclusion was a risk factor for LTFU at all stages of the HIV programme. The biggest risk factors were body mass index <18.5 kg/m(2) (stage 1), male gender (stage 2), HIV-2 infection (stage 3) and CD4 cell count <200 cells/MUL (stage 4). CONCLUSIONS: In this study, LTFU constituted a major problem, and this may apply to other similar ART facilities. More than half of the patients were lost to follow-up shortly after enrolment, possibly implying a high mortality. Thus, retention should be given a high priority. PMID- 24163206 TI - Associations between antinuclear antibody staining patterns and clinical features of systemic lupus erythematosus: analysis of a regional Swedish register. AB - OBJECTIVE: Antinuclear antibody (ANA) analysis by immunofluorescence (IF) microscopy remains a diagnostic hallmark of systemic lupus erythematosus (SLE). The clinical relevance of ANA fine-specificities in SLE has been addressed repeatedly, whereas studies on IF-ANA staining patterns in relation to disease manifestations are very scarce. This study was performed to elucidate whether different staining patterns associate with distinct SLE phenotypes. DESIGN: Observational cohort study. SETTING: One university hospital rheumatology unit in Sweden. PARTICIPANTS: The study population consisted of 222 cases (89% women; 93% Caucasians), where of 178 met >=4/11 of the 1982 American College of Rheumatology (ACR-82) criteria. The remaining 20% had an SLE diagnosis based on positive IF ANA (HEp-2 cells) and >=2 typical organ manifestations at the time of diagnosis (Fries' criteria). OUTCOME MEASURES: The IF-ANA staining patterns homogenous (H ANA), speckled (S-ANA), combined homogenous and speckled (HS-ANA), centromeric (C ANA), nucleolar (N-ANA)+/-other patterns and other nuclear patterns (oANA) were related to disease manifestations and laboratory measures. Antigen-specificities were also considered regarding double-stranded DNA (Crithidia luciliae) and the following extractable nuclear antigens: Ro/SSA, La/SSB, Smith antigen (Sm), small nuclear RNP (snRNP), Scl-70 and Jo-1 (immunodiffusion and/or line-blot technique). RESULTS: 54% of the patients with SLE displayed H-ANA, 22% S-ANA, 11% HS-ANA, 9% N-ANA, 1% C-ANA, 2% oANA and 1% were never IF-ANA positive. Staining patterns among patients meeting Fries' criteria alone did not differ from those fulfilling ACR-82. H-ANA was significantly associated with the 10th criterion according to ACR-82 ('immunological disorder'). S-ANA was inversely associated with arthritis, 'immunological disorder' and signs of organ damage. CONCLUSIONS: H-ANA is the dominant IF-ANA pattern among Swedish patients with SLE, and was found to associate with 'immunological disorder' according to ACR-82. The second most common pattern, S-ANA, associated negatively with arthritis and organ damage. PMID- 24163207 TI - Effects of tanshinone on hyperandrogenism and the quality of life in women with polycystic ovary syndrome: protocol of a double-blind, placebo-controlled, randomised trial. AB - INTRODUCTION: Polycystic ovary syndrome (PCOS) is one of the most common endocrine disorders in reproductive-age women. Chinese herbal medicine has been used for the treatment of PCOS, but the evidence for its efficacy and safety is minimal. Tanshinones are a class of bioactive molecules isolated from Salvia miltiorrhiza, a commonly used herb in Traditional Chinese Medicine. This study aims to evaluate the efficacy of tanshinones on hyperandrogenism and quality of life in women with PCOS who do not attempt to conceive. METHODS AND ANALYSIS: A total of 100 patients will be recruited and randomised into the tanshinone or placebo group. Tanshinone or placebo capsules will be taken orally for 12 weeks. The primary outcome parameter will be a change in plasma testosterone. Secondary end points will be changes in human chorionic gonadotropin-induced androgen response, insulin resistance, reproductive hormones, fasting lipid profiles, oral glucose tolerance test, quality of life and side effects. ETHICS AND DISSEMINATION: Written informed consent will be obtained from each participant at the time of enrolling in the study. The trial has been approved by the Ethics Committee of First Affiliated Hospital of Heilongjiang University of Chinese Medicine. Results will be disseminated through a publicly accessible website. REGISTRATION DETAILS: The study has been registered at the Chinese Clinical Trials Registry (ChiCTR-TRC-12002973) and at clinicaltrials.gov (NCT 01452477). PMID- 24163210 TI - Exposure of mobile chipper operators to diesel exhaust. AB - The current boom of forest biomass is making mobile chippers increasingly popular among forest operators. This motivates concern about the potential exposure of chipper operators to noxious chemicals derived from diesel fuel combustion. The objective of this study was to determine operator exposure to BTEX (benzene, toluene, ethylbenzene, and xylenes) and polycyclic aromatic hydrocarbons (PAHs) generated from diesel combustion. This study sampled 28 mobile chipping operations in the Italian mountains, in order to determine professional exposure to BTEX and PAHs among chipper operators. IOM, Radiello(r), and XAD2 samplers were used for the purpose. Operations were divided into industrial and small scale, the former based on powerful chippers with enclosed cabs and the latter on smaller machines without enclosed cabs. We could not detect any measurable exposure to BTEX, while exposure levels for PAHs were very low, especially for what concerned recognized cancer agents. That is likely related to work environment and organization because mobile chippers work in the open-air forest environment and in the presence of very few other machines. PAH concentration was significantly higher inside cabs than outside. None of the operators involved in this research was exposed to BTEX or PAHs above occupational exposure limits. PMID- 24163208 TI - A prospective cohort study to refine and validate the Panic Screening Score for identifying panic attacks associated with unexplained chest pain in the emergency department. AB - INTRODUCTION: Panic-like anxiety (panic attacks with or without panic disorder), a highly treatable condition, is the most prevalent condition associated with unexplained chest pain in the emergency department. Panic-like anxiety may be responsible for a significant portion of the negative consequences of unexplained chest pain, such as functional limitations and chronicity. However, more than 92% of panic-like anxiety cases remain undiagnosed at the time of discharge from the emergency department. The 4-item Panic Screening Score (PSS) questionnaire was derived in order to increase the identification of panic-like anxiety in emergency department patients with unexplained chest pain. METHODS AND ANALYSIS: The goals of this prospective cohort study were to (1) refine the PSS; (2) validate the revised version of the PSS; (3) measure the reliability of the revised version of the PSS and (4) assess the acceptability of the instrument among emergency physicians. Eligible and consenting patients will be administered the PSS in a large emergency department. Patients will be contacted by phone for administration of the criterion standard for panic attacks as well as by a standardised interview to collect information for other predictors of panic attacks. Multivariate analysis will be used to refine the PSS. The new version will be prospectively validated in an independent sample and inter-rater agreement will be assessed in 10% of cases. The screening instrument acceptability will be assessed with the Ottawa Acceptability of Decision Rules Instrument. ETHICS AND DISSEMINATION: This study protocol has been reviewed and approved by the Alphonse-Desjardins research ethics committee. The results of the study will be presented in scientific conferences and published in peer-reviewed scientific journals. Further dissemination via workshops and a dedicated website is planned. PMID- 24163209 TI - PRImary care Streptococcal Management (PRISM) study: identifying clinical variables associated with Lancefield group A beta-haemolytic streptococci and Lancefield non-Group A streptococcal throat infections from two cohorts of patients presenting with an acute sore throat. AB - OBJECTIVE: To assess the association between features of acute sore throat and the growth of streptococci from culturing a throat swab. DESIGN: Diagnostic cohort. SETTING: UK general practices. PARTICIPANTS: Patients aged 5 or over presenting with an acute sore throat. Patients were recruited for a second cohort (cohort 2, n=517) consecutively after the first (cohort 1, n=606) from similar practices. MAIN OUTCOME: Predictors of the presence of Lancefield A/C/G streptococci. RESULTS: The clinical score developed from cohort 1 had poor discrimination in cohort 2 (bootstrapped estimate of area under the receiver operator characteristic (ROC) curve (0.65), due to the poor validity of the individual items in the second data set. Variables significant in multivariate analysis in both cohorts were rapid attendance (prior duration 3 days or less; multivariate adjusted OR 1.92 cohort, 1.67 cohort 2); fever in the last 24 h (1.69, 2.40); and doctor assessment of severity (severely inflamed pharynx/tonsils (2.28, 2.29)). The absence of coryza or cough and purulent tonsils were significant in univariate analysis in both cohorts and in multivariate analysis in one cohort. A five-item score based on Fever, Purulence, Attend rapidly (3 days or less), severely Inflamed tonsils and No cough or coryza (FeverPAIN) had moderate predictive value (bootstrapped area under the ROC curve 0.73 cohort 1, 0.71 cohort 2) and identified a substantial number of participants at low risk of streptococcal infection (38% in cohort 1, 36% in cohort 2 scored <=1, associated with a streptococcal percentage of 13% and 18%, respectively). A Centor score of <=1 identified 23% and 26% of participants with streptococcal percentages of 10% and 28%, respectively. CONCLUSIONS: Items widely used to help identify streptococcal sore throat may not be the most consistent. A modified clinical scoring system (FeverPAIN) which requires further validation may be clinically helpful in identifying individuals who are unlikely to have major pathogenic streptococci. PMID- 24163211 TI - Thin slices of creativity: using single-word utterances to assess creative cognition. AB - We investigated the hypothesis that individual differences in creative cognition can be manifest even in brief responses, such as single-word utterances. Participants (n = 193) were instructed to say a verb upon seeing a noun displayed on a computer screen and were cued to respond creatively to half of the nouns. For every noun-verb pair (72 pairs per subject), we assessed the semantic distance between the noun and the verb, using latent semantic analysis (LSA). Semantic distance was higher in the cued ("creative") condition than the uncued condition, within subjects. Critically, between subjects, semantic distance in the cued condition had a strong relationship to a creativity factor derived from a battery of verbal, nonverbal, and achievement-based creativity measures (beta= .50), and this relation remained when controlling for intelligence and personality. The data show that creative cognition can be assessed reliably and validly from such thin slices of behavior. PMID- 24163212 TI - Are all ostracism experiences equal? A comparison of the autobiographical recall, Cyberball, and O-Cam paradigms. AB - In the present study, we aimed to compare the primary-need depletion elicited by three common ostracism paradigms: autobiographical recall (e.g., Zhong & Leonardelli in Psychological Science 19:838-842, 2008), Cyberball (Williams, Cheung, & Choi in Journal of Personality and Social Psychology 79:748-762, 2000), and O-Cam (Goodacre & Zadro in Behavior Research Methods 42:768-774, 2010). A total of 152 participants (52 males) were randomly allocated to one of the three paradigms, and their subsequent primary needs were measured (belonging, control, self-esteem, and meaningful existence). O-Cam was found to induce greater total primary-need depletion than did Cyberball and recall, which did not differ significantly from each other. Moreover, when examining the pattern of individual need depletion elicited by each paradigm, O-Cam was found to induce significantly greater depletion of belonging, control, and meaningful existence than did the recall paradigm, and significantly greater depletion of control and self-esteem than did Cyberball. No other comparisons were found to be significant, including the comparisons between the recall and Cyberball paradigms for each individual primary need. Collectively, the findings will assist ostracism researchers in making informed choices regarding (a) which paradigm is appropriate to implement with respect to their research aims, and (b) whether the interchangeable use of paradigms within a program of research is appropriate practice. PMID- 24163213 TI - Norms on the gender perception of role nouns in Czech, English, French, German, Italian, Norwegian, and Slovak. AB - We collected norms on the gender stereotypicality of an extensive list of role nouns in Czech, English, French, German, Italian, Norwegian, and Slovak, to be used as a basis for the selection of stimulus materials in future studies. We present a Web-based tool (available at https://www.unifr.ch/lcg/ ) that we developed to collect these norms and that we expect to be useful for other researchers, as well. In essence, we provide (a) gender stereotypicality norms across a number of languages and (b) a tool to facilitate cross-language as well as cross-cultural comparisons when researchers are interested in the investigation of the impact of stereotypicality on the processing of role nouns. PMID- 24163214 TI - [Effects of heat waves on mortality in Germany]. AB - Heat waves present an increasing threat to population's health; there is increased activity in terms of research and preventive measures since the heat waves in 2003. This is the first narrative review of studies on heat wave associated mortality in Germany. The review and critical evaluation includes 12 studies. Notable differences in the research methodology were observed. Scientific knowledge on heat wave-associated mortality in Germany is insufficient. So far, most studies have focused on large cities or states/provinces. However, risk assessments play an important role in deciding upon and planning of preventive measures. PMID- 24163215 TI - [Experts reports on the ability to work within the area of tension of medical and social problems]. AB - On the basis of S 8 SGB II (Sozialgesetzbuch II), the local public health office of Bremen provides expert reports concerning the ability to work. The clients are district branches (job centres) of the Bremen employment office. The experts raised the question to what extent these expert reports were medically well founded. Against this background, the expert reports were recorded and analysed for a period of 6 months. Socio-demographic characteristics, medical diagnoses and prognoses, experts' reports regarding the ability to work, as well as the medical justification of the reports were all taken into consideration. The sex ratio and ethnic profile of people included in the study were representative of welfare recipients in Bremen as a whole. Compared with the German population as a whole, the people examined had distinctly less education and professional training. Factors indicating social impacts were found more often among women. Medical diag-noses were strikingly different compared with data from the health insurance companies. More than two thirds of the people examined had considerable restrictions or were considered unable to work. More than four fifths of the expert reports could be justified for medical reasons. The life situations of the people examined were characterised by numerous problems which included medical, social and frequently also cultural aspects, and were taken into account in the experts' reports. In view of the inability to solve the existing social problems, the experts continue, from a medical perspective, to be concerned in this area of tension. PMID- 24163216 TI - [The relationships of intelligence and memory assessed using the WAIS-IV and the WMS-IV]. AB - BACKGROUND: This study examines the relationships of intelligence and memory scores derived from WAIS-IV and WMS-IV. We were especially interested in the reciprocal predictive values of the test scales. METHODS: A sample of 137 healthy adults with an age range between 16 and 69 years was assessed with the WAIS-IV and the WMS-IV. The test order was balanced. Pearson correlations were conducted on the subtest and scale level. A series of 14 linear regression models was tested with memory performance as predictor for intelligence and vice versa. RESULTS AND CONCLUSION: A model including the 3 main memory scales of the WMS-IV was able to predict the global IQ best. It nevertheless explained only 46% of the variance. The memory and intelligence measures show significant relationships, but also represent distinct functions. WAIS-IV and WMS-IV complement one another. PMID- 24163217 TI - [Appropriate administrative measures in the case of infectious diseases in public facilities]. AB - This contribution presents a survey of the obligatory measures to be taken according to German Law in the case of the outbreak of infectious diseases in public facilities. The analysis is based on a decision by the German Federal Administrative Court in the year 2012, BVerwGE 142, 205 ff. The author subjects the intepretation of the term suspicion of an infectious disease in the sense of S 2 Nr. 7 IfSG (law for protection against infection) to a critical appraisement. The article closes with a check-list on the legally appropriate measures to be taken in the case of an outbreak of infectious diseases in public facilities that is intended for practitioners in the health services. PMID- 24163218 TI - [The assessment and course of development of cognitive abilities in the elderly]. AB - BACKGROUND: The assessment of the appropriate level of development in children belongs to the standard duties of physicians in the public health system. Due to a steady increase of dementia in Germany the assessment of cognitive abilities of the elderly is becoming more and more the focus of future activities. Such an assessment of cognitive functioning reveals whether the respective person is aging normally or whether the impaired cognitive functioning is probably based on a pathological process. OBJECTIVE: The aim of the present study is to present cognitive changes in the aged and 2 psychometric tests for the assessment of cognitive functioning: the Wechsler Adult Intelligence Scale (WAIS-IV) and the Short Cognitive Performance Test (SKT), a test for the assessment of memory impairments and impairment of attention. In addition, similarities and dissimilarities are presented. METHODS: As part of a multi-centre study in German speaking countries the data of 504 cognitively healthy persons between the age of 60 and 90 were tested with the WAIS-IV and the SKT. RESULTS AND CONCLUSION: The results revealed a significant cognitive decline in the fluid and crystal intelligence depending on age. Only 2 subtests of the WAIS-IV (General Information and Block Design) showed no significant variation due to age. The SKT scores of memory and attention correlated significantly with almost all subtests of the WAIS-IV. The highest correlations were between the SKT attention score and the WAIS-IV subtests for processing speed, perceptual reasoning and working memory. The decline in cognitive abilities is mainly due to reduced capacities in speed of information processing and working memory. PMID- 24163220 TI - Simulation of the magnetization dynamics of diluted ferrofluids in medical applications. AB - Ferrofluids, which are stable, colloidal suspensions of single-domain magnetic nanoparticles, have a large impact on medical technologies like magnetic particle imaging (MPI), magnetic resonance imaging (MRI) and hyperthermia. Here, computer simulations promise to improve our understanding of the versatile magnetization dynamics of diluted ferrofluids. A detailed algorithmic introduction into the simulation of diluted ferrofluids will be presented. The algorithm is based on Langevin equations and resolves the internal and the external rotation of the magnetic moment of the nanoparticles, i.e., the Neel and Brown diffusion. The derived set of stochastic differential equations are solved by a combination of an Euler and a Heun integrator and tested with respect to Boltzmann statistics. PMID- 24163219 TI - LXR driven induction of HDL-cholesterol is independent of intestinal cholesterol absorption and ABCA1 protein expression. AB - We investigated whether: (1) liver X receptor (LXR)-driven induction of high density lipoprotein cholesterol (HDL-C) and other LXR-mediated effects on cholesterol metabolism depend on intestinal cholesterol absorption; and (2) combined treatment with the LXR agonist GW3965 and the cholesterol absorption inhibitor ezetimibe results in synergistic effects on cholesterol metabolism that could be beneficial for treatment of atherosclerosis. Mice were fed 0.2 % cholesterol and treated with GW3965+ezetimibe, GW3965 or ezetimibe. GW3965+ezetimibe treatment elevated serum HDL-C and Apolipoprotein (Apo) AI, effectively reduced the intestinal cholesterol absorption and increased the excretion of faecal neutral sterols. No changes in intestinal ATP-binding cassette (ABC) A1 or ABCG5 protein expression were observed, despite increased mRNA expression, while hepatic ABCA1 was slightly reduced. The combined treatment caused a pronounced down-regulation of intestinal Niemann-Pick C1-like 1 (NPC1L1) and reduced hepatic and intestinal cholesterol levels. GW3965 did not affect the intestinal cholesterol absorption, but increased serum HDL-C and ApoAI levels. GW3965 also increased Apoa1 mRNA levels in primary mouse hepatocytes and HEPA1-6 cells. Ezetimibe reduced the intestinal cholesterol absorption, ABCA1 and ABCG5, but did not affect the serum HDL-C or ApoAI levels. Thus, the LXR-driven induction of HDL-C and ApoAI was independent of the intestinal cholesterol absorption and increased expression of intestinal or hepatic ABCA1 was not required. Inhibited influx of cholesterol via NPC1L1 and/or low levels of intracellular cholesterol prevented post-transcriptional expression of intestinal ABCA1 and ABCG5, despite increased mRNA levels. Combined LXR activation and blocked intestinal cholesterol absorption induced effective faecal elimination of cholesterol. PMID- 24163221 TI - Gonococcal endocarditis: a case report and review of the literature. AB - A 59-year-old Caucasian male presented with progressive dyspnea, arthralgias and fever for three days. A diastolic regurgitation murmur was detected in the aortic area. A transesophageal echocardiograph showed several vegetations and severe aortic regurgitation. Blood cultures yielded Neisseria gonorrhoeae beta-lactamase negative. The patient had not noticed any urogenital discomfort or urethral discharge. The patient successfully underwent surgery for septal abscess debridement. The patient received ceftriaxone 2 g bid for eight weeks and the clinical follow-up was uneventful. The review of the literature revealed a total of the 38 additional cases reported between 1980 and the present. The majority of the patients were young, male and with native valve involvement. There has been a clear tendency for left-sided valve involvement (especially in the aortic valve). All valve cultures were reported negative despite, in most cases, the marked tissue destruction. Polymerase chain reaction was performed in two patients and positive results were shown in both. Cultures of exudates from other locations were negative in most cases. One striking fact is the high proportion of patients who underwent surgery (72 %). Information regarding antibiotic sensitivity was available in 28 cases, with penicillin resistance reported in six patients (21 %) and intermediate sensitivity in four patients (14 %). Resistance to ciprofloxacin was reported in two cases (7 %). A rapid increase and distribution of isolates resistant to third generation cephalosporins have been recently detected. The mortality is high, particularly taking into account that most were young patients who had not presented previous heart disease. PMID- 24163222 TI - Long-term vascular, motor, and sensory donor site outcomes after ulnar forearm flap harvest. AB - Use of the ulnar forearm flap (UFF) is limited by concerns for ulnar nerve injury and impaired perfusion in the donor extremity. Twenty UFFs were performed over a 6-year period. All patients underwent postoperative bilateral upper extremity arterial duplex studies. A subset of postoperative patients (n = 10) also had bilateral upper extremity sensory and motor evaluations, and functional evaluation via the Quick Disabilities of the Arm, Shoulder and Hand (QuickDASH). Motor function was tested by digital and key grip dynamometry. Ulnar nerve sensation was tested by evaluation of one- and two-point perceived pressure thresholds and two-point discrimination using the Pressure-Specified Sensory Device (Sensory Management Services, LLC, Baltimore, MD). All UFFs were viable postoperatively. Mean follow-up was 28.8 months for vascular studies and 45.3 months for motor, sensory, and QuickDASH evaluations. Although mid and distal radial artery flow velocities were significantly higher in donor versus control extremities evaluated at less than 1 year postoperatively, there was no significant difference in extremities evaluated at later time points. Digital pressures, grip strength, key pinch strength, and ulnar sensation were equivalent between donor and control extremities. The mean QuickDASH score was 17.4 +/- 23.8. The UFF can be harvested reliably and long-term follow-up shows no evidence of impaired vascular, motor, or sensory function in the donor extremity. PMID- 24163223 TI - The evolution of perforator flap breast reconstruction: twenty years after the first DIEP flap. AB - It is over 20 years since the inaugural deep inferior epigastric perforator (DIEP) flap breast reconstruction. We review the type of flap utilized and indications in 2,850 microvascular breast reconstruction over the subsequent 20 years in the senior author's practice (Robert J. Allen). Data were extracted from a personal logbook of all microsurgical free flap breast reconstructions performed between August 1992 and August 2012. Indication for surgery; mastectomy pattern in primary reconstruction; flap type, whether unilateral or bilateral; recipient vessels; and adjunctive procedures were recorded. The DIEP was the most commonly performed flap (66%), followed by the superior gluteal artery perforator flap (12%), superficial inferior epigastric artery perforator flap (9%), inferior gluteal artery perforator flap (6%), profunda artery perforator flap (3%), and transverse upper gracilis flap (3%). Primary reconstruction accounted for 1,430 flaps (50%), secondary 992 (35%), and tertiary 425 (15%). As simultaneous bilateral reconstructions, 59% flaps were performed. With each flap, there typically ensues a period of enthusiasm which translated into surge in flap numbers. However, each flap has its own nuances and characteristics that influence patient and physician choice. Of note, each newly introduced flap, either buttock or thigh, results in a sharp decline in its predecessor. In this practice, the DIEP flap has remained the first choice in autologous breast reconstruction. PMID- 24163224 TI - Anesthesia duration as an independent risk factor for postoperative complications in free flap surgery: a review of 1,305 surgical cases. AB - Surgical dogma and objective data support the relationship between increased operative times and perioperative complications. However, there has been no large scale, multi-institutional study that evaluates the impact of increased anesthesia duration on microvascular free tissue transfer. The National Surgical Quality Improvement Program (NSQIP) database was retrospectively reviewed to identify all free-flap patients between 2006 and 2011. Included patients were subdivided into quintiles of anesthesia time. Univariate and multivariate analyses were performed to assess its impact on 30-day postoperative complications. The mean anesthesia duration for all patients was 603 +/- 222 minutes. In univariate analysis, 30-day overall/medical complications, reoperation, and free flap loss demonstrated statistically significant increases as anesthesia duration increased (p<0.05). However, in multivariate analyses, these trends and significances were abolished, with exception of the utilization of postoperative transfusions. Of interest, increasing anesthesia duration did not predict flap failure on multivariate analysis. We found that increased anesthesia time correlates with increased postoperative transfusions in free flap patients. As a result, limiting blood loss and avoiding prolonged anesthesia times should be goals for the microvascular surgeon. This is the largest multidisciplinary study to investigate the ongoing debate that longer anesthesia times impart greater risk. PMID- 24163225 TI - Complex heel reconstruction with a sural fasciomyocutaneous perforator flap. AB - Reconstruction of weight-bearing surfaces at the foot and ankle is controversial. Free tissue transfer and local fasciocutaneous perforator flaps are preferred for plantar reconstruction, but high rates of flap breakdown and ulceration have caused unsatisfactory functional outcomes. We present a modified "sural fasciomyocutaneous perforator flap" and its functional outcome. Between January 2007 and September 2010, 19 patients were treated for soft-tissue defects in the weight-bearing area with sural fasciomyocutaneous perforator flaps. The gastrocnemius, preserved in the base of the flap, was applied as padding under the calcaneus. In follow-up from 9 to 25 months (mean 13.8 months), each patient's pain score, defect size, ulcer formation, protective sensation recovery, and normal footwear were analyzed. The majority of the flaps survived with satisfactory aesthetic and functional results. One case of partial flap loss and one case of delayed ulceration were noted. With partial weight bearing at 4 weeks, satisfactory gait recovery was obtained at 5 to 8 months (in conjunction with protective sensation recovery). Sural fasciomyocutaneous perforator flap is a reliable modality in heel construction, showing advantages of low ulceration rate, durability, and good protective sensation recovery compared with conventional free tissue transfer and local fasciocutaneous perforator flap. PMID- 24163226 TI - Versatility of the greater saphenous fasciocutaneous perforator flap in coverage of the lower leg. AB - Paucity of soft tissue locally available for reconstruction of defects in the leg and foot remains a challenge. Greater saphenous fasciocutaneous perforator flap in reconstruction of the lower leg has been used effectively to cover these defects. In many situations, it is a viable alternative to free flaps and cross leg flap reconstruction. The objective of this retrospective study was to evaluate the efficacy of the greater saphenous fasciocutaneous perforator flap for reconstruction of the medial and anterior lower leg, medial malleolus, and hind foot. A total of 26 patients with soft tissue defects of the medial and anterior lower leg, medial malleolus, and hind foot were evaluated. Preoperative data, age, sex, defect etiology, defect size, flap dimension, postoperative results, and complications were recorded. All patients were followed up postoperatively. The procedure was uneventful in 25 of 26 patients. The one unsuccessful flap developed partial necrosis of the distal edge due to venous congestion, and secondary healing was achieved by conservative treatment. No patient showed signs of infection. The defect etiology in all patients was trauma of the lower extremity or its complications, most frequently open fracture (19 patients), followed by osteomyelitis of the tibia (2 patients). The greater saphenous fasciocutaneous perforator flap is versatile, reliable, and useful in coverage of medial and anterior lower leg, malleolus, and hind foot defects. This surgical technique is a safe, short-duration alternative to microsurgical reconstruction. PMID- 24163227 TI - Vascularized versus nonvascularized island median nerve grafts in the facial nerve regeneration and functional recovery of rats for facial nerve reconstruction study. AB - Histological and physiological basis of the therapeutic efficacy of the vascularized autologous nerve graft in facial nerve regeneration remains poorly understood because of no established rat model. The left median nerve and median artery/vein of Lewis rats were collectively ligated, and harvested as a vascularized island median nerve, which was transplanted to a 7-mm gap in the left buccal branch of facial nerve. Nerve regeneration was investigated. The numbers of myelinated fibers, axon diameter, and myelin thickness were significantly higher in the vascularized nerve graft group than in the nonvascularized nerve graft group. Compound muscle action potential measurement showed that the parameters of vascularized group were similar to those in the intact control group. A vascularized median nerve graft resulted in better facial nerve regeneration outcomes. PMID- 24163228 TI - Modified pathological classification of brachial plexus root injury and its MR imaging characteristics. AB - The authors described a modified pathological classification (PC) of brachial plexus injury (BPI) and its magnetic resonance (MR) imaging characteristics. The reliability and diagnostic accuracy of MR imaging for detecting nerve injury was discussed. Between 2006 and 2010, 86 patients with BPI were managed surgically in our department. Their preoperative MR images and surgical findings were analyzed retrospectively. The PC of BPI was classified into five types: (I) nerve root injury in continuity (including Sunderland grade I-IV injury); (II) postganglionic spinal nerve rupture with or without proximal stump; (III) preganglionic root injury (visible); (IV) preganglionic nerve root injury and postganglionic spinal nerves injury; (V) preganglionic root injury (invisible). The main MR imaging characteristics of BPI included traumatic meningocele, displacement of spinal cord, the absence of nerve root, "Black line" sign, nerve root/trunk injury in continuity, and thickening and edema of nerve root. The accuracy of MR imaging for detecting C5, C6, C7, C8, and T1 nerve roots injury were 93.3, 95.2, 92.3, 84, and 74.4%, respectively. The modified PC provides a detailed description of nerve root injury in BPI, and MR imaging technique is a reliable method for detecting nerve root injury. PMID- 24163229 TI - Emergent total arch replacement for acute type A aortic dissection with aberrant right subclavian artery in a systemic lupus erythematosus patient. AB - A 50-year-old man with a history of systemic lupus erythematosus and hemodialysis developed acute type A aortic dissection. Computed tomography demonstrated acute type A aortic dissection with chronic distal arch aneurysm and aberrant right subclavian artery that arose from the proximal descending aorta and ran in a retro-esophageal track. Emergent total arch replacement was performed using antegrade cerebral perfusion with circulatory arrest. Both common carotid arteries and the left subclavian artery were chosen as selective cerebral perfusion sites. The right subclavian artery was snared during cerebral perfusion. The right subclavian artery was reconstructed with the right common carotid artery in an end-to-side fashion in the anterior mediastinum. The patient's postoperative course was uneventful, and computed tomography showed excellent blood flow to all four branches. The case description is followed by a discussion of cerebral protection, reconstruction route of the right aberrant subclavian artery and steroids for systemic lupus erythematosus. PMID- 24163230 TI - Combinatorial antitumor effect of HDAC and the PI3K-Akt-mTOR pathway inhibition in a Pten defecient model of prostate cancer. AB - Increased expression of histone deacetylases (HDACs) and activation of the PI3K Akt-mTORC1 pathway are common aberrations in prostate cancer (PCa). For this reason, inhibition of such targets is an exciting avenue for the development of novel therapeutic strategies to treat patients with advanced PCa. Previous reports demonstrated that HDAC inhibitors (HDACi) increases DNA damage and induce greater apoptosis in PCa cell lines that express androgen receptor (AR). In this study we utilized the AR negative PCa cell line and observed that re-expression of AR (PC3-AR) results in greater levels of apoptosis when treated with the pan DACi, panobinostat (PAN). PAN mediated apoptosis in PC3 and PC3-AR cells was associated with increased levels of double strand DNA breaks, indicated by p gammaH2AX. Further, PAN treatment in PC3-AR cells resulted in moderate attenuation of the ATM-Akt-ERK DNA damage response pathway. For this reason, we combined PAN with the dual PI3K-mTOR inhibitor, BEZ235. Combination of PAN with BEZ235 resulted in significant attenuation of the DNA damage repair protein ATM and significantly increased anti-tumor activity compared to each single treatment. Overall, superior anti-tumor activity with combination of PAN with BEZ235 was independent of AR status. These findings suggest that this therapeutic strategy should be further developed in clinical trials. PMID- 24163231 TI - Tele-ABR using a satellite connection in a mobile van for newborn hearing testing. AB - We assessed the feasibility of conducting Auditory Brainstem Response (ABR) testing in a mobile van with satellite connectivity, with the help of trained health workers. ABR recordings in newborn babies made by telemedicine were compared with recordings made face to face. The auditory evoked response equipment was controlled by an audiologist at a nearby hospital. Videoconferencing was used during the testing process to monitor patient preparation by the village health worker. A total of 24 newborns (13 male and 11 female) aged 8-30 days underwent ABR in face-to-face and tele-mode. There was no significant difference between peak V latency measured at three intensity levels in the two modes. Agreement between the two methods of measurement was examined with a Bland-Altman plot. Almost all points were within the limits of agreement, suggesting no bias in the telemedicine measurements. Real-time tele-ABR testing as a component of newborn hearing screening is feasible in a mobile van using satellite link with the assistance of village health workers. PMID- 24163232 TI - A telehealth service model for the treatment of hypertension. AB - We evaluated the effectiveness of a home telehealth service in hypertension control. Patients with hypertension were divided into two groups based on the frequency that they measured blood pressure (BP) at home: the regular group made >3 measurements per week and the irregular group made <= 20 measurements per month. Both groups were provided with home monitoring equipment (the Citizen Telemedical Care Service System, CTCS) which contained a computer and video communication device. A total of 160 participants were enrolled and 156 completed the 12-month study. There were 101 participants in the regular BP measurement group and 55 in the irregular group. There was a significant reduction in the average systolic BP from baseline after 6 months in the regular group (P < 0.001) and after 1 month in the irregular group (P < 0.001). There was no difference in average diastolic BP between the two groups. For both groups, the systolic BP control was good, especially for irregular group. The results suggest that patients who used CTCS tele-monitoring achieved better BP control than those who self-measured BP at home only. PMID- 24163233 TI - Cost-effectiveness analysis of telemonitoring versus usual care in patients with heart failure: the TEHAF-study. AB - We examined the incremental cost-effectiveness of telemonitoring (TM) versus usual care (UC) in patients with congestive heart failure (CHF). In one university and two general hospitals, 382 patients were randomised to usual care or telemonitoring and followed for 1 year. Hospital-related and home costs were estimated, based on resource use multiplied by the appropriate unit prices. Effectiveness was expressed as QALYs gained. Information was gathered, using 3 monthly costs diaries and questionnaires. The mean age of the patients was 71 years (range 32-93), 59% were male and 64% lived with a partner. Health related quality of life improved by 0.07 points for the usual care and 0.1 points for the telemonitoring group, but the difference between groups was not significant. There were no significant differences in annual costs per patient between groups. At a threshold of ?50,000 the probability of telemonitoring being cost-effective was 48%. The cost effectiveness analysis showed a high level of decision uncertainty, probably caused by the divergence between the participating institutions. It is therefore premature to draw an unambiguous conclusion regarding cost-effectiveness for the whole group. PMID- 24163234 TI - Meta-analysis and meta-regression of telehealth programmes for patients with chronic heart failure. AB - To assess the effectiveness of telehealth used for chronic heart failure (CHF) patients, we searched for peer-reviewed, randomized controlled trials published between 2001 and 2012. A total of 33 studies met the inclusion criteria. There were 26 studies (79%) which concerned tele-monitoring and 7 (21%) which concerned case management or nurse administered telephone-based management. There were 7530 patients in all, with an average age of 69 years. A meta-analysis showed that telehealth programmes had significant overall effectiveness in reducing all-cause mortality (Fixed effect model risk ratio 0.76, 95% CI 0.66 to 0.88), CHF-related hospitalization (Random effect model risk ratio 0.72, 95% CI 0.61 to 0.85) and CHF-related length of stay (Random effect model mean difference -1.41 days, 95% CI -2.43 to -0.39). In addition, telehealth programmes showed significantly greater effectiveness in reducing mortality and hospitalizations among patients with higher New York Heart Association (NYHA) categories. With age and NYHA held constant, recording questionnaire (symptoms) data could reduce the mortality risk by 34% and the risk of CHF-related hospitalization by 15%; adding a pulse (heart rate) detector could reduce the mortality risk by 40% and the risk of CHF-related hospitalization by 43%. Finally, telehealth programmes showed a tapering effect on mortality reduction: the longer the follow-up period, the less effective they were on decreasing mortality. In conclusion, telehealth programmes demonstrated clinical effectiveness in patients with CHF compared with usual care. PMID- 24163235 TI - The effect of psychosocial interventions delivered by telephone and videophone on quality of life in early-stage breast cancer survivors and their supportive partners. AB - We examined the effectiveness of two psychosocial interventions for improving QOL in recently diagnosed breast cancer survivors and their partners. The interventions were telephone health education (THE) and interpersonal counselling. The latter was delivered by telephone (TC) or by videophone (VC) in 8 weekly one-to-one sessions. Fifty two dyads composed of a woman with breast cancer and her supportive partner were randomly assigned to THE, TC or VC. The average age of the survivors was 53 years (range 40-66), and they were mainly white, married, with a college education, and employed. Approximately half of the supportive partners were spouses. Surveys of quality of life (QOL) were made at three points in the study, each separated by 8 weeks. There was significantly higher attrition in the THE group compared to the videophone or telephone counselling groups among both survivors (44% vs. 10% and 8%) and partners (44% vs. 10% and 15%). Regardless of group, participants showed increased QOL over time. Survivors' and partners' social well-being improved in the telephone and videophone interpersonal counselling treatment groups, but not in the health education group. Telephone-delivered psychosocial interventions can be effective for managing QOL in breast cancer survivors and their supportive partners. There was no evidence of superior outcomes associated with using videophones over the conventional telephone. PMID- 24163236 TI - Video telehealth for weight maintenance of African-American women. AB - We evaluated the effect of home telehealth on weight maintenance after a group based weight loss programme. The home telehealth intervention comprised telephone counselling and home Internet-enabled digital video recorders (DVRs) with three channels of video programmes. The video content provided reinforcement and support to promote problem solving, prevent relapse and sustain motivation. Eighty-eight obese or overweight African-American women were randomized to receive monthly telephone counselling (control) or the home telehealth intervention. The weight change during maintenance was not significant in either group (0.6 kg in the intervention group, 0.0 kg in the control group), and there was no significant difference between them. Changes in diet, physical activity, social support and self-efficacy during the maintenance period did not differ significantly between groups. DVR use was low: during the intervention, the number of valid DVR viewings ranged from zero to 42 per person. DVR use was positively associated with previous attendance at the weight loss classes. Home video-based telehealth is a new method of delivering a weight loss maintenance intervention to African-American women. It had no effect on weight maintenance in the present study. PMID- 24163237 TI - Cost-effectiveness of a helpline for suicide prevention. AB - We evaluated the cost-effectiveness and budget impact of a suicide helpline in Belgium, consisting of a telephone- and a chat service. An age- and gender dependent Markov model with a ten-year time horizon and a one-year cycle length was developed, assuming a societal perspective, to predict cumulative costs and quality-adjusted life-years (QALYs) in the helpline users. The model included six transition states: the initial state (at risk), first attempt, re-attempt, follow up, suicide and death from other causes. Data on the effect of the helpline and costs associated with model states were obtained from the literature. One-way and probabilistic sensitivity analyses were performed to capture uncertainty. In addition, the budget impact of the helpline was analysed. Over ten years, the telephone- as well as the chat service could avoid about 36% of suicides and attempts in this high-risk population. In males, 0.063 QALYs (95% confidence interval, CI 0.030-0.097) and 0.035 QALYs (95%CI -0.026-0.096) were gained by users of the telephone- and chat service respectively. The corresponding values for females were 0.019 QALYs (95%CI -0.015-0.052) and a QALY-neutral result of 0.005 (95%CI -0.071-0.062). There were net societal savings of respectively ?2382 (95%CI 1953-2859) and ?2282 (95%CI 1855-2758) in male users; ?2171 (95%CI 1735 2664) and ?2458 (95%CI 1945-3025) in female users. At the population level, an investment of ?218,899 saved ?1,452,022 for the public health service (national health insurance), mainly due to the telephone service. The analysis predicted that both means of telemedicine for suicide prevention in Flanders are cost saving, and have a modest effect on QALYs. PMID- 24163238 TI - Use of mobile phone text messaging to deliver an individualized smoking behaviour intervention in Chinese adolescents. AB - We evaluated the effectiveness of a mobile phone text-messaging based smoking cessation intervention package among Chinese adolescent smokers. Students aged 16 19 years were recruited from six vocational high schools located in Shanghai. We assigned the six schools to an intervention group or a control group by cluster randomization. The 92 participants in the intervention group were given tailored information via mobile phone text-messaging for 12 weeks. The 87 participants in the control group were provided with a self-help pamphlet about smoking cessation instead. After the intervention, attitudes towards the disadvantages of smoking were significantly improved, and the level of nicotine dependence and cigarette dependence significantly decreased in the intervention group. The intervention group had a relatively higher self-reported 7-day abstinence compared to the control group and 30-day abstinence, but the differences were not significant. However, the intervention group had a significantly higher rate of smoking reduction (66% vs. 35%) and moving forward in quitting stages (52% vs. 18%) compared to the control group. The interactive and tailored assistance provided by the mobile phone text-messaging was effective in smoking behaviour intervention in Chinese adolescent smokers. PMID- 24163239 TI - The use of global positioning systems in promoting safer walking for people with dementia. AB - There are about 5 million people in Europe who have dementia, approximately half of whom need daily care. A common reason why dementia sufferers are admitted to long-term care is because of "wandering", i.e. leaving home without informing a carer, thereby potentially putting themselves at risk. Common methods of managing wandering include locking doors or alerting carers when a door is opened. A new method of managing wandering is by using electronic location devices. These depend on the satellite-based global positioning system (GPS). People can wear a location device in the form of a watch or pendant, or carry it like a mobile phone. This offers affected individuals the possibility of safe walking, with the reassurance that they can be found quickly if lost. However, it is not known how effective this method is and its use raises questions about safety and individual civil liberties. GPS location is a potentially useful method of managing wandering in dementia and there is considerable pressure on caregivers from commercial organisations to adopt the technique. Research is therefore required to determine which people are best suited for such devices, how effective they are in practice and what effect they have on important outcomes. PMID- 24163240 TI - International telepsychiatry: a review of what has been published. PMID- 24163241 TI - Design of a community-based mobile phone text message referral intervention in Tanzania. PMID- 24163242 TI - Inferring primary tumor sites from mutation spectra: a meta-analysis of histology specific aberrations in cancer-derived cell lines. AB - Next-generation sequencing technologies have led to profound characterization of mutation spectra for several cancer types. Hence, we sought to systematically compare genomic aberrations between primary tumors and cancer lines. For this, we compiled publically available sequencing data of 1651 genes across 905 cell lines. We used them to characterize 23 distinct primary tumor sites by a novel approach that is based on Bayesian spam-filtering techniques. Thereby, we confirmed the strong overall similarity of alterations between patient samples and cell culture. However, we also identified several suspicious mutations, which had not been associated with their cancer types before. Based on these characterizations, we developed the inferring cancer origins from mutation spectra (ICOMS) tool. On our cell line collection, the algorithm reached a prediction specificity rate of 79%, which strongly variegated between primary cancer sites. On an independent validation cohort of 431 primary tumor samples, we observed a similar accuracy of 71%. Additionally, we found that ICOMS could be employed to deduce further attributes from mutation spectra, including sub histology and compound sensitivity. Thus, thorough classification of site specific mutation spectra for cell lines may decipher further genome-phenotype associations in cancer. PMID- 24163243 TI - Mosaic synaptopathy and functional defects in Cav1.4 heterozygous mice and human carriers of CSNB2. AB - Mutations in CACNA1F encoding the alpha1-subunit of the retinal Cav1.4 L-type calcium channel have been linked to Cav1.4 channelopathies including incomplete congenital stationary night blindness type 2A (CSNB2), Aland Island eye disease (AIED) and cone-rod dystrophy type 3 (CORDX3). Since CACNA1F is located on the X chromosome, Cav1.4 channelopathies are typically affecting male patients via X chromosomal recessive inheritance. Occasionally, clinical symptoms have been observed in female carriers, too. It is currently unknown how these mutations lead to symptoms in carriers and how the retinal network in these females is affected. To investigate these clinically important issues, we compared retinal phenotypes in Cav1.4-deficient and Cav1.4 heterozygous mice and in human female carrier patients. Heterozygous Cacna1f carrier mice have a retinal mosaic consistent with differential X-chromosomal inactivation, characterized by adjacent vertical columns of affected and non-affected wild-type-like retinal network. Vertical columns in heterozygous mice are well comparable to either the wild-type retinal network of normal mice or to the retina of homozygous mice. Affected retinal columns display pronounced rod and cone photoreceptor synaptopathy and cone degeneration. These changes lead to vastly impaired vision guided navigation under dark and normal light conditions and reduced retinal electroretinography (ERG) responses in Cacna1f carrier mice. Similar abnormal ERG responses were found in five human CACNA1F carriers, four of which had novel mutations. In conclusion, our data on Cav1.4 deficient mice and human female carriers of mutations in CACNA1F are consistent with a phenotype of mosaic CSNB2. PMID- 24163244 TI - Targeted manipulation of the sortilin-progranulin axis rescues progranulin haploinsufficiency. AB - Progranulin (GRN) mutations causing haploinsufficiency are a major cause of frontotemporal lobar degeneration (FTLD-TDP). Recent discoveries demonstrating sortilin (SORT1) is a neuronal receptor for PGRN endocytosis and a determinant of plasma PGRN levels portend the development of enhancers targeting the SORT1-PGRN axis. We demonstrate the preclinical efficacy of several approaches through which impairing PGRN's interaction with SORT1 restores extracellular PGRN levels. Our report is the first to demonstrate the efficacy of enhancing PGRN levels in iPSC neurons derived from frontotemporal dementia (FTD) patients with PGRN deficiency. We validate a small molecule preferentially increases extracellular PGRN by reducing SORT1 levels in various mammalian cell lines and patient-derived iPSC neurons and lymphocytes. We further demonstrate that SORT1 antagonists and a small-molecule binder of PGRN588-593, residues critical for PGRN-SORT1 binding, inhibit SORT1-mediated PGRN endocytosis. Collectively, our data demonstrate that the SORT1-PGRN axis is a viable target for PGRN-based therapy, particularly in FTD-GRN patients. PMID- 24163245 TI - Cross-sectional and longitudinal changes in DNA methylation with age: an epigenome-wide analysis revealing over 60 novel age-associated CpG sites. AB - Understanding the role of epigenetic modifications, e.g. DNA methylation, in the process of aging requires the characterization of methylation patterns in large cohorts. We analysed >480 000 CpG sites using Infinium HumanMethylation450 BeadChip (Illumina) in whole blood DNA of 965 participants of a population-based cohort study aged between 50 and 75 years. In an exploratory analysis in 400 individuals, 200 CpG sites with the highest Spearman correlation coefficients for the association between methylation and age were identified. Of these 200 CpGs, 162 were significantly associated with age, which was verified in an independent cohort of 498 individuals using mixed linear regression models adjusted for gender, smoking behaviour, age-related diseases and random batch effect and corrected for multiple testing by Bonferroni. In another independent cohort of 67 individuals without history of major age-related diseases and with a follow-up of 8 years, we observed a gain in methylation at 96% (52%, significant) of the positively age-associated CpGs and a loss at all (89%, significant) of the negatively age-associated CpGs in each individual while getting 8 years older. A regression model for age prediction based on 17 CpGs as predicting variables explained 71% of the variance in age with an average accuracy of 2.6 years. In comparison with cord blood samples obtained from the Ulm Birth Cohort Study, we observed a more than 2-fold change in mean methylation levels from birth to older age at 86 CpGs. We were able to identify 65 novel CpG sites with significant association of methylation with age. PMID- 24163246 TI - CNV analysis in a large schizophrenia sample implicates deletions at 16p12.1 and SLC1A1 and duplications at 1p36.33 and CGNL1. AB - Large and rare copy number variants (CNVs) at several loci have been shown to increase risk for schizophrenia. Aiming to discover novel susceptibility CNV loci, we analyzed 6882 cases and 11 255 controls genotyped on Illumina arrays, most of which have not been used for this purpose before. We identified genes enriched for rare exonic CNVs among cases, and then attempted to replicate the findings in additional 14 568 cases and 15 274 controls. In a combined analysis of all samples, 12 distinct loci were enriched among cases with nominal levels of significance (P < 0.05); however, none would survive correction for multiple testing. These loci include recurrent deletions at 16p12.1, a locus previously associated with neurodevelopmental disorders (P = 0.0084 in the discovery sample and P = 0.023 in the replication sample). Other plausible candidates include non recurrent deletions at the glutamate transporter gene SLC1A1, a CNV locus recently suggested to be involved in schizophrenia through linkage analysis, and duplications at 1p36.33 and CGNL1. A burden analysis of large (>500 kb), rare CNVs showed a 1.2% excess in cases after excluding known schizophrenia-associated loci, suggesting that additional susceptibility loci exist. However, even larger samples are required for their discovery. PMID- 24163249 TI - Catecholamine metabolism drives generation of mitochondrial DNA deletions in dopaminergic neurons. AB - Accumulation of mitochondrial DNA deletions is observed especially in dopaminergic neurons of the substantia nigra during ageing and even more in Parkinson's disease. The resulting mitochondrial dysfunction is suspected to play an important role in neurodegeneration. However, the molecular mechanisms involved in the preferential generation of mitochondrial DNA deletions in dopaminergic neurons are still unknown. To study this phenomenon, we developed novel polymerase chain reaction strategies to detect distinct mitochondrial DNA deletions and monitor their accumulation patterns. Applying these approaches in in vitro and in vivo models, we show that catecholamine metabolism drives the generation and accumulation of these mitochondrial DNA mutations. As in humans, age-related accumulation of mitochondrial DNA deletions is most prominent in dopaminergic areas of mouse brain and even higher in the catecholaminergic adrenal medulla. Dopamine treatment of terminally differentiated neuroblastoma cells, as well as stimulation of dopamine turnover in mice over-expressing monoamine oxidase B both induce multiple mitochondrial DNA deletions. Our results thus identify catecholamine metabolism as the driving force behind mitochondrial DNA deletions, probably being an important factor in the ageing-associated degeneration of dopaminergic neurons. PMID- 24163248 TI - Cognitive control and its impact on recovery from aphasic stroke. AB - Aphasic deficits are usually only interpreted in terms of domain-specific language processes. However, effective human communication and tests that probe this complex cognitive skill are also dependent on domain-general processes. In the clinical context, it is a pragmatic observation that impaired attention and executive functions interfere with the rehabilitation of aphasia. One system that is important in cognitive control is the salience network, which includes dorsal anterior cingulate cortex and adjacent cortex in the superior frontal gyrus (midline frontal cortex). This functional imaging study assessed domain-general activity in the midline frontal cortex, which was remote from the infarct, in relation to performance on a standard test of spoken language in 16 chronic aphasic patients both before and after a rehabilitation programme. During scanning, participants heard simple sentences, with each listening trial followed immediately by a trial in which they repeated back the previous sentence. Listening to sentences in the context of a listen-repeat task was expected to activate regions involved in both language-specific processes (speech perception and comprehension, verbal working memory and pre-articulatory rehearsal) and a number of task-specific processes (including attention to utterances and attempts to overcome pre-response conflict and decision uncertainty during impaired speech perception). To visualize the same system in healthy participants, sentences were presented to them as three-channel noise-vocoded speech, thereby impairing speech perception and assessing whether this evokes domain general cognitive systems. As expected, contrasting the more difficult task of perceiving and preparing to repeat noise-vocoded speech with the same task on clear speech demonstrated increased activity in the midline frontal cortex in the healthy participants. The same region was activated in the aphasic patients as they listened to standard (undistorted) sentences. Using a region of interest defined from the data on the healthy participants, data from the midline frontal cortex was obtained from the patients. Across the group and across different scanning sessions, activity correlated significantly with the patients' communicative abilities. This correlation was not influenced by the sizes of the lesion or the patients' chronological ages. This is the first study that has directly correlated activity in a domain general system, specifically the salience network, with residual language performance in post-stroke aphasia. It provides direct evidence in support of the clinical intuition that domain-general cognitive control is an essential factor contributing to the potential for recovery from aphasic stroke. PMID- 24163247 TI - Allelic heterogeneity in NCF2 associated with systemic lupus erythematosus (SLE) susceptibility across four ethnic populations. AB - Recent reports have associated NCF2, encoding a core component of the multi protein NADPH oxidase (NADPHO), with systemic lupus erythematosus (SLE) susceptibility in individuals of European ancestry. To identify ethnicity specific and -robust variants within NCF2, we assessed 145 SNPs in and around the NCF2 gene in 5325 cases and 21 866 controls of European-American (EA), African American (AA), Hispanic (HS) and Korean (KR) ancestry. Subsequent imputation, conditional, haplotype and bioinformatic analyses identified seven potentially functional SLE-predisposing variants. Association with non-synonymous rs17849502, previously reported in EA, was detected in EA, HS and AA (P(EA) = 1.01 * 10(-54), PHS = 3.68 * 10(-10), P(AA) = 0.03); synonymous rs17849501 was similarly significant. These SNPs were monomorphic in KR. Novel associations were detected with coding variants at rs35937854 in AA (PAA = 1.49 * 10(-9)), and rs13306575 in HS and KR (P(HS) = 7.04 * 10(-7), P(KR) = 3.30 * 10(-3)). In KR, a 3-SNP haplotype was significantly associated (P = 4.20 * 10(-7)), implying that SLE predisposing variants were tagged. Significant SNP-SNP interaction (P = 0.02) was detected between rs13306575 and rs17849502 in HS, and a dramatically increased risk (OR = 6.55) with a risk allele at each locus. Molecular modeling predicts that these non-synonymous mutations could disrupt NADPHO complex assembly. The risk allele of rs17849501, located in a conserved transcriptional regulatory region, increased reporter gene activity, suggesting in vivo enhancer function. Our results not only establish allelic heterogeneity within NCF2 associated with SLE, but also emphasize the utility of multi-ethnic cohorts to identify predisposing variants explaining additional phenotypic variance ('missing heritability') of complex diseases like SLE. PMID- 24163250 TI - RADAR: a rigorously annotated database of A-to-I RNA editing. AB - We present RADAR--a rigorously annotated database of A-to-I RNA editing (available at http://RNAedit.com). The identification of A-to-I RNA editing sites has been dramatically accelerated in the past few years by high-throughput RNA sequencing studies. RADAR includes a comprehensive collection of A-to-I RNA editing sites identified in humans (Homo sapiens), mice (Mus musculus) and flies (Drosophila melanogaster), together with extensive manually curated annotations for each editing site. RADAR also includes an expandable listing of tissue specific editing levels for each editing site, which will facilitate the assignment of biological functions to specific editing sites. PMID- 24163251 TI - Functional analyses of the C-terminal half of the Saccharomyces cerevisiae Rad52 protein. AB - The Saccharomyces cerevisiae Rad52 protein is essential for efficient homologous recombination (HR). An important role of Rad52 in HR is the loading of Rad51 onto replication protein A-coated single-stranded DNA (ssDNA), which is referred to as the recombination mediator activity. In vitro, Rad52 displays additional activities, including self-association, DNA binding and ssDNA annealing. Although Rad52 has been a subject of extensive genetic, biochemical and structural studies, the mechanisms by which these activities are coordinated in the various roles of Rad52 in HR remain largely unknown. In the present study, we found that an isolated C-terminal half of Rad52 disrupted the Rad51 oligomer and formed a heterodimeric complex with Rad51. The Rad52 fragment inhibited the binding of Rad51 to double-stranded DNA, but not to ssDNA. The phenylalanine-349 and tyrosine-409 residues present in the C-terminal half of Rad52 were critical for the interaction with Rad51, the disruption of Rad51 oligomers, the mediator activity of the full-length protein and for DNA repair in vivo in the presence of methyl methanesulfonate. Our studies suggested that phenylalanine-349 and tyrosine-409 are key residues in the C-terminal half of Rad52 and probably play an important role in the mediator activity. PMID- 24163252 TI - Puf3p induces translational repression of genes linked to oxidative stress. AB - In response to stress, the translation of many mRNAs in yeast can change in a fashion discordant with the general repression of translation. Here, we use machine learning to mine the properties of these mRNAs to determine specific translation control signals. We find a strong association between transcripts acutely translationally repressed under oxidative stress and those associated with the RNA-binding protein Puf3p, a known regulator of cellular mRNAs encoding proteins targeted to mitochondria. Under oxidative stress, a PUF3 deleted strain exhibits more robust growth than wild-type cells and the shift in translation from polysomes to monosomes is attenuated, suggesting puf3Delta cells perceive less stress. In agreement, the ratio of reduced:oxidized glutathione, a major antioxidant and indicator of cellular redox state, is increased in unstressed puf3Delta cells but remains lower under stress. In untreated conditions, Puf3p migrates with polysomes rather than ribosome-free fractions, but this is lost under stress. Finally, reverse transcriptase-polymerase chain reaction (RT-PCR) of Puf3p targets following affinity purification shows Puf3p-mRNA associations are maintained or increased under oxidative stress. Collectively, these results point to Puf3p acting as a translational repressor in a manner exceeding the global translational response, possibly by temporarily limiting synthesis of new mitochondrial proteins as cells adapt to the stress. PMID- 24163253 TI - No recombination of mtDNA after heteroplasmy for 50 generations in the mouse maternal germline. AB - Variants of mitochondrial DNA (mtDNA) are commonly used as markers to track human evolution because of the high sequence divergence and exclusive maternal inheritance. It is assumed that the inheritance is clonal, i.e. that mtDNA is transmitted between generations without germline recombination. In contrast to this assumption, a number of studies have reported the presence of recombinant mtDNA molecules in cell lines and animal tissues, including humans. If germline recombination of mtDNA is frequent, it would strongly impact phylogenetic and population studies by altering estimates of coalescent time and branch lengths in phylogenetic trees. Unfortunately, this whole area is controversial and the experimental approaches have been widely criticized as they often depend on polymerase chain reaction (PCR) amplification of mtDNA and/or involve studies of transformed cell lines. In this study, we used an in vivo mouse model that has had germline heteroplasmy for a defined set of mtDNA mutations for more than 50 generations. To assess recombination, we adapted and validated a method based on cloning of single mtDNA molecules in the lambda phage, without prior PCR amplification, followed by subsequent mutation analysis. We screened 2922 mtDNA molecules and found no germline recombination after transmission of mtDNA under genetically and evolutionary relevant conditions in mammals. PMID- 24163254 TI - Ensembl Genomes 2013: scaling up access to genome-wide data. AB - Ensembl Genomes (http://www.ensemblgenomes.org) is an integrating resource for genome-scale data from non-vertebrate species. The project exploits and extends technologies for genome annotation, analysis and dissemination, developed in the context of the vertebrate-focused Ensembl project, and provides a complementary set of resources for non-vertebrate species through a consistent set of programmatic and interactive interfaces. These provide access to data including reference sequence, gene models, transcriptional data, polymorphisms and comparative analysis. This article provides an update to the previous publications about the resource, with a focus on recent developments. These include the addition of important new genomes (and related data sets) including crop plants, vectors of human disease and eukaryotic pathogens. In addition, the resource has scaled up its representation of bacterial genomes, and now includes the genomes of over 9000 bacteria. Specific extensions to the web and programmatic interfaces have been developed to support users in navigating these large data sets. Looking forward, analytic tools to allow targeted selection of data for visualization and download are likely to become increasingly important in future as the number of available genomes increases within all domains of life, and some of the challenges faced in representing bacterial data are likely to become commonplace for eukaryotes in future. PMID- 24163255 TI - The pancreatic expression database: recent extensions and updates. AB - The Pancreatic Expression Database (PED, http://www.pancreasexpression.org) is the only device currently available for mining of pancreatic cancer literature data. It brings together the largest collection of multidimensional pancreatic data from the literature including genomic, proteomic, microRNA, methylomic and transcriptomic profiles. PED allows the user to ask specific questions on the observed levels of deregulation among a broad range of specimen/experimental types including healthy/patient tissue and body fluid specimens, cell lines and murine models as well as related treatments/drugs data. Here we provide an update to PED, which has been previously featured in the Database issue of this journal. Briefly, PED data content has been substantially increased and expanded to cover methylomics studies. We introduced an extensive controlled vocabulary that records specific details on the samples and added data from large-scale meta analysis studies. The web interface has been improved/redesigned with a quick search option to rapidly extract information about a gene/protein of interest and an upload option allowing users to add their own data to PED. We added a user guide and implemented integrated graphical tools to overlay and visualize retrieved information. Interoperability with biomart-compatible data sets was significantly improved to allow integrative queries with pancreatic cancer data. PMID- 24163257 TI - The mouse Gene Expression Database (GXD): 2014 update. AB - The Gene Expression Database (GXD; http://www.informatics.jax.org/expression.shtml) is an extensive and well-curated community resource of mouse developmental expression information. GXD collects different types of expression data from studies of wild-type and mutant mice, covering all developmental stages and including data from RNA in situ hybridization, immunohistochemistry, RT-PCR, northern blot and western blot experiments. The data are acquired from the scientific literature and from researchers, including groups doing large-scale expression studies. Integration with the other data in Mouse Genome Informatics (MGI) and interconnections with other databases places GXD's gene expression information in the larger biological and biomedical context. Since the last report, the utility of GXD has been greatly enhanced by the addition of new data and by the implementation of more powerful and versatile search and display features. Web interface enhancements include the capability to search for expression data for genes associated with specific phenotypes and/or human diseases; new, more interactive data summaries; easy downloading of data; direct searches of expression images via associated metadata; and new displays that combine image data and their associated annotations. At present, GXD includes >1.4 million expression results and 250,000 images that are accessible to our search tools. PMID- 24163256 TI - A feed forward circuit comprising Spt6, Ctk1 and PAF regulates Pol II CTD phosphorylation and transcription elongation. AB - The C-terminal domain (CTD) of RNA polymerase II is sequentially modified for recruitment of numerous accessory factors during transcription. One such factor is Spt6, which couples transcription elongation with histone chaperone activity and the regulation of H3 lysine 36 methylation. Here, we show that CTD association of Spt6 is required for Ser2 CTD phosphorylation and for the protein stability of Ctk1 (the major Ser2 CTD kinase). We also find that Spt6 associates with Ctk1, and, unexpectedly, Ctk1 and Ser2 CTD phosphorylation are required for the stability of Spt6-thus revealing a Spt6-Ctk1 feed-forward loop that robustly maintains Ser2 phosphorylation during transcription. In addition, we find that the BUR kinase and the polymerase associated factor transcription complex function upstream of the Spt6-Ctk1 loop, most likely by recruiting Spt6 to the CTD at the onset of transcription. Consistent with requirement of Spt6 in histone gene expression and nucleosome deposition, mutation or deletion of members of the Spt6-Ctk1 loop leads to global loss of histone H3 and sensitivity to hydroxyurea. In sum, these results elucidate a new control mechanism for the regulation of RNAPII CTD phosphorylation during transcription elongation that is likely to be highly conserved. PMID- 24163258 TI - Replication factors transiently associate with mtDNA at the mitochondrial inner membrane to facilitate replication. AB - Mitochondrial DNA (mtDNA) is organized in discrete protein-DNA complexes, nucleoids, that are usually considered to be mitochondrial-inner-membrane associated. Here we addressed the association of replication factors with nucleoids and show that endogenous mtDNA helicase Twinkle and single-stranded DNA binding protein, mtSSB, co-localize only with a subset of nucleoids. Using nucleotide analogs to identify replicating mtDNA in situ, the fraction of label positive nucleoids that is Twinkle/mtSSB positive, is highest with the shortest labeling-pulse. In addition, the recruitment of mtSSB is shown to be Twinkle dependent. These proteins thus transiently associate with mtDNA in an ordered manner to facilitate replication. To understand the nature of mtDNA replication complexes, we examined nucleoid protein membrane association and show that endogenous Twinkle is firmly membrane associated even in the absence of mtDNA, whereas mtSSB and other nucleoid-associated proteins are found in both membrane bound and soluble fractions. Likewise, a substantial amount of mtDNA is found as soluble or loosely membrane bound. We show that, by manipulation of Twinkle levels, mtDNA membrane association is partially dependent on Twinkle. Our results thus show that Twinkle recruits or is assembled with mtDNA at the inner membrane to form a replication platform and amount to the first clear demonstration that nucleoids are dynamic both in composition and concurrent activity. PMID- 24163259 TI - Cardiac surgical patients are not the same. But who knows that: the patient, the cardiologist or the surgeon? AB - Nowadays, outcome measures get published following risk adjustment; mortality rates are adjusted for risks to give a picture of the performance of a surgeon or a unit. The risk factors associated with in-hospital death are likely to reflect concurrent disease-specific variables. Factors associated with increased resource utilisation (as measured by length of stay) reflect serious co-morbid illness. The various models are effective at predicting population behaviour, but not necessarily suited for predicting individual outcomes. Further work needs to be done both to explain the differences in risk factors seen between the various risk stratification models and to determine which models are best suited in clinical practice. This document reviews the current evidence and risk stratification tools currently employed in cardiac surgery practice. PMID- 24163260 TI - Race and survival among diabetic patients after coronary artery bypass grafting. AB - BACKGROUND: Diabetes is a known predictor of decreased long-term survival after coronary artery bypass grafting (CABG). Differences in survival by race have not been examined. METHODS: A retrospective cohort study was conducted for CABG patients between 1992 and 2011. Long-term survival was compared in patients with and without diabetes and stratified by race. Hazard ratios (HR) and 95% confidence intervals (CI) were computed using a Cox regression model. RESULTS: Out of the 13,053 patients undergoing CABG, 35% (black n = 1,655; white n = 2,884) had diabetes at the time of surgery. The median follow-up for study participants was 8.2 years. Long-term survival after CABG was similar between black and white diabetic patients (no diabetes, HR = 1.0; white diabetic patients, adjusted HR = 1.5, 95%CI = 1.4-1.6; black diabetic patients, adjusted HR = 1.5, 95%CI = 1.4-1.7). CONCLUSION: A survival disadvantage after CABG was not observed among black versus white diabetic patients in our study. PMID- 24163261 TI - Impact of smoking status on outcomes after concomitant aortic valve replacement and coronary artery bypass graft surgery. AB - BACKGROUND: There is a paucity of data on the impact of smoking status on outcomes after concomitant aortic valve replacement and coronary artery bypass graft (AVR-CABG) surgery. METHODS: Data obtained prospectively between June 2001 and December 2009 by the Australian and New Zealand Society of Cardiac and Thoracic Surgeons National Cardiac Surgery Database Program were retrospectively analyzed. Demographic and operative data were compared between patients who were nonsmokers, previous smokers, and current smokers using chi-square test and t test. The independent impact of smoking status on 14 short-term complications and long-term mortality was determined using binary logistic and Cox regression, respectively. RESULTS: Concomitant AVR-CABG surgery was performed in 2,563 patients; smoking status was recorded in 2,558 (99.8%) patients. Of these, 1,052 (41.1%) patients had no previous smoking history, 1,345 (52.6%) patients were previous smokers, and 161 (6.3%) patients were current smokers. The 30-day mortality rate was 3.5% in nonsmokers, 4.1% in previous smokers, and 3.1% in current smokers (p = nonsignificant). The incidence of perioperative complications was similar in the three groups. The mean follow-up period for this study was 36 months (range, 0-105 months). After adjusting for differences in patient variables, the incidence of late mortality was higher in previous smokers (hazard ratio [HR], 1.44; 95% confidence interval [CI], 1.14-1.81; p = 0.002) compared with nonsmokers. A trend toward increased late mortality in current smokers was noted (HR, 1.34; 95% CI, 0.86-2.08; p = 0.201). CONCLUSION: Smoking is not associated with adverse outcomes after concomitant AVR-CABG surgery. Smoking status should not, therefore, preclude these patients from undergoing this procedure. Given the adverse effect of smoking on overall cardiovascular morbidity and mortality and late postoperative mortality, patients should be encouraged to quit smoking. PMID- 24163262 TI - Identification of anaplastic lymphoma kinase as a potential therapeutic target in Basal Cell Carcinoma. AB - The pathogenesis of BCC is associated with sonic hedgehog (SHH) signaling. Vismodegib, a smoothened inhibitor that targets this pathway, is now in clinical use for advanced BCC patients, but its efficacy is limited. Therefore, new therapeutic options for this cancer are required. We studied gene expression profiling of BCC tumour tissues coupled with laser capture microdissection to identify tumour specific receptor tyrosine kinase expression that can be targeted by small molecule inhibitors. We found a >250 fold increase (FDR<10-4) of the oncogene, anaplastic lymphoma kinase (ALK) as well as its ligands, pleiotrophin and midkine in BCC compared to microdissected normal epidermis. qRT-PCR confirmed increased expression of ALK (p<0.05). Stronger expression of phosphorylated ALK in BCC tumour nests than normal skin was observed by immunohistochemistry. Crizotinib, an FDA-approved ALK inhibitor, reduced keratinocyte proliferation in culture, whereas a c-Met inhibitor did not. Crizotinib significantly reduced the expression of GLI1 and CCND2 (members of SHH-pathway) mRNA by approximately 60% and 20%, respectively (p<0.01). Our data suggest that ALK may increase GLI1 expression in parallel with the conventional SHH-pathway and promote keratinocyte proliferation. Hence, an ALK inhibitor alone or in combination with targeting SHH pathway molecules may be a potential treatment for BCC patients. PMID- 24163263 TI - Para-split laminotomy: a rescue technique for split laminotomy approach in exploring intramedullary midline located pathologies. AB - OBJECTIVE: Conventional posterior approaches, which may involve multilevel laminectomies and facetectomies, may lead to spinal deformities, instability, and subluxation. We developed the multilevel spinous process splitting and distraction laminotomy technique, which is an option for approaching midline intramedullary spinal pathologies with preservation of mechanically relevant bone and muscle structures. In some cases, midline splitting is not feasible or convenient because of anatomical differences of spinous processes and laminas. Our objective was to develop a minimally invasive rescue approach technique that makes it possible to remove intramedullary lesions but does not increase the risk of damage to the crucial posterior stabilizers of the spine. METHODS: We used the para-split laminotomy technique for opening the spinal canal not in the midline but rather in the parasagittal plane. The technique can be combined with the basic split laminotomy technique. This novel technique was used in five adult patients with midline intramedullary pathologies of the cervical and cervicothoracic spine. RESULTS: The operating field under the microscope was sufficient for tumor removal according to the keyhole concept. The approach used did not affect the extent of resection or neurologic outcome. The average number of split laminae was 6 (range: 3-10). Average follow-up was 18 months (range: 13 36 months). Histologic results were as follows: two ependymomas, two astrocytomas, and one primitive neuroectodermal tumor (PNET). To confirm the extension of resection, all patients underwent postoperative magnetic resonance imaging evaluations. The resections were complete in the cases of two ependymomas, subtotal in one astrocytoma, and partial in the other astrocytoma case and the PNET case. Computed tomography scans showed the extension of para split approaches and the moderately disturbed bony structures. Instability was detected in none of the patients on the flexion-extension lateral radiographs during the follow-up period. CONCLUSION: The minimally invasive multilevel para split laminotomy approach as a rescue technique for split laminotomy is a safe and effective surgical procedure, suitable for exploring different intramedullary pathologies located in the midline of the spinal canal. This modified surgical approach fulfills the requirements of other minimally invasive techniques and lowers the risk of damage to the crucial posterior stabilizers of the spine; furthermore, disintegration of the vertebral arches and facet joints is reduced. PMID- 24163264 TI - Insulin degludec: pharmacokinetics in patients with renal impairment. AB - BACKGROUND: Insulin degludec is a new-generation basal insulin with an ultra-long duration of action. We evaluated the pharmacokinetic properties of insulin degludec in subjects with normal renal function; mild, moderate or severe renal impairment; or end-stage renal disease (ESRD) undergoing hemodialysis. METHODS: Thirty subjects (n = 6 per group) received a single subcutaneous dose of 0.4 U/kg insulin degludec. Blood samples up to 120 h post-dose and fractionated urine samples were collected. RESULTS: The ultra-long pharmacokinetic properties of insulin degludec were preserved in subjects with renal impairment, with no statistically significant differences in absorption or clearance, compared with subjects with normal renal function. In subjects with ESRD, pharmacokinetic parameters were similar whether the insulin degludec pharmacokinetic assessment period included hemodialysis or not, and total exposure was comparable to subjects with normal renal function. Simulated mean steady-state pharmacokinetic profiles were comparable between groups. CONCLUSION: This study indicated dose adjustments due to impaired renal function should not be required for insulin degludec. PMID- 24163267 TI - Targeting IL-11 signaling in colon cancer. PMID- 24163265 TI - Menstrual cycle characteristics in fertile women from Greenland, Poland and Ukraine exposed to perfluorinated chemicals: a cross-sectional study. AB - STUDY QUESTION: Does perfluorooctane sulfonate (PFOS) and perfluorooctanate (PFOA) exposure disrupt the menstrual cyclicity? SUMMARY ANSWER: The female reproductive system may be sensitive to PFOA exposure, with longer menstrual cycle length at higher exposure. WHAT IS KNOWN ALREADY: PFOS and PFOA are persistent man-made chemicals. Experimental animal studies suggest they are reproductive toxicants but epidemiological findings are inconsistent. STUDY DESIGN, SIZE, DURATION: A cross-sectional study including 1623 pregnant women from the INUENDO cohort enrolled during antenatal care visits between June 2002 and May 2004 in Greenland, Poland and Ukraine. PARTICIPANTS/MATERIALS, SETTING, METHODS: Information on menstrual cycle characteristics was obtained by questionnaires together with a blood sample from each pregnant woman. Serum concentrations of PFOS and PFOA were measured by liquid chromatography tandem mass spectrometry. Multiple imputations were performed to account for missing data. The association between PFOS/PFOA and menstrual cycle length (short cycle: <=24 days, long cycle: >=32 days) and irregularities (>=7 days in difference between cycles) was analyzed using logistic regression with tertiles of exposure. Estimates are given as adjusted odds ratios (ORs) with 95% confidence intervals (CIs). MAIN RESULTS AND THE ROLE OF CHANCE: Higher exposure levels of PFOA were associated with longer menstrual cycles in pooled estimates of all three countries. Compared with women in the lowest exposure tertile, the adjusted OR of long cycles was 1.8 (95% CI: 1.0; 3.3) among women in the highest tertile of PFOA exposure. No significant associations were observed between PFOS exposure and menstrual cycle characteristics. However, we observed a tendency toward more irregular cycles with higher exposure to PFOS [OR 1.7 (95% CI: 0.8; 3.5)]. The overall response rate was 45.3% with considerable variation between countries (91.3% in Greenland, 69.1% in Poland and 26.3% in Ukraine). LIMITATIONS, REASONS FOR CAUTION: Possible limitations in our study include varying participation rates across countries; a selected study group overrepresenting the most fertile part of the population; retrospective information on menstrual cycle characteristics; the determination of cut-points for all three outcome variables; and lacking information on some determinants of menstrual cycle characteristics, such as stress, physical activity, chronic diseases and gynecological disorders, thus confounding cannot be excluded. WIDER IMPLICATIONS OF THE FINDINGS: The generalizability of the study results is restricted to fertile women who manage to conceive and women who do not use oral contraceptives when getting pregnant or within 2 months before getting pregnant. To our knowledge only one previous epidemiological study has addressed the possible association between perfluorinated chemical exposure and menstrual disturbances. Though pointing toward different disturbances in cyclicity, both studies suggest that exposure to PFOA may affect the female reproductive function. This study contributes to the limited knowledge on effects of exposure to PFOA and PFOS on female reproductive function and suggests that the female reproductive system may be affected by environmental exposure to PFOA. STUDY FUNDING/COMPETING INTEREST(S): Supported by a scholarship from Aarhus University Research Foundation. The collection of questionnaire data and blood samples was part of the INUENDO project supported by The European Commission (Contract no. QLK4-CT-2001-00 202), www.inuendo.dk. The Ukrainian part of the study was possible by a grant from INTAS (project 012 2205). Determination of PFOA and PFOS in serum was part of the CLEAR study (www.inuendo.dk/clear) supported by the European Commission's 7th Framework Program (FP7-ENV-2008-1-226217). No conflict of interest declared. PMID- 24163269 TI - Molecular mechanisms of crystal-related kidney inflammation and injury. Implications for cholesterol embolism, crystalline nephropathies and kidney stone disease. AB - Crystals are particles of endogenous inorganic or organic composition that can trigger kidney injury when deposited or formed inside the kidney. While decades of research have focused on the molecular mechanisms of solute supersaturation and crystal formation, the pathomechanisms of crystal-induced renal inflammation remain largely unknown. The recent discovery of the intracellular NLRP3 inflammasome as a pattern recognition platform that translates crystal uptake into innate immune activation via secretion of IL-1beta and IL-18 revised the pathogenesis of gout, silicosis, asbestosis, atherosclerosis and other crystal related disorders. As a proof of concept, the NLRP3 inflammasome was now shown to trigger inflammation and acute kidney injury (AKI) in oxalate nephropathy. It seems likely that this and potentially other innate immunity mechanisms drive crystalline nephropathies (CNs) that are associated with crystals of calcium phosphate, uric acid, cysteine, adenine, certain drugs or contrast media, and potentially of myoglobin during rhabdomyolysis and of light chains in myeloma. Here, we discuss the proven and potential mechanisms of renal inflammation and kidney injury in crystal-related kidney disorders. In addition, we list topics for further research in that field. This perspective may also provide novel therapeutic options that can help to avoid progressive tissue remodeling and chronic kidney disease in patients with kidney stone disease or other CNs. PMID- 24163270 TI - Implications of predonation GFR to recipient and donor outcomes. PMID- 24163271 TI - WITHDRAWN: Music for pain relief. PMID- 24163272 TI - WITHDRAWN: Comparative efficacy of epidural, subarachnoid, and intracerebroventricular opioids in patients with pain due to cancer. PMID- 24163273 TI - Frequency and severity of adverse drug reactions due to self-medication: a cross sectional multicentre survey in emergency departments. AB - BACKGROUND: Little is known about the relation of adverse drug reactions (ADRs) to self-use of medications. OBJECTIVE: The aim of this study was to determine the frequency and severity of ADRs related to self-medication (ADR-SM) among emergency department (ED) patients and to describe their main characteristics. METHODS: A prospective, cross-sectional, observational study was conducted over a period of 8 weeks (1 March to 20 April 2010), in the ED of 11 French academic hospitals. Adult patients presenting to the ED during randomization periods were included, with the exception of cases of self-drug poisoning, inability to complete self-medication questionnaire, or refusal. Clinical outcomes were assessed as well as history of self-medication behaviours and all drugs taken. All doubtful files and those related to ADR-SM were systematically reviewed by an expert committee. RESULTS: A total of 3,027 of 4,661 patients presenting to the ED met the inclusion criteria. Of these, 84.4 % declared a self-medication behaviour, 63.7 % took at least one non-prescribed drug during the previous 2 weeks and 59.9 % took a prescribed medication. A total of 296 patients experienced an ADR (9.78 %), of which 52 (1.72 %) were related to self medication. Those ADRs related to self-medication included prescribed drugs (n = 19), non-prescribed drugs (n = 17), treatment discontinuation (n = 14), and interactions between non-prescribed and prescribed drugs (n = 2). The ADRs attributed to non-prescribed drugs represented 1 % of all patients taking non prescribed drugs (n = 1,927). ADR severity was significantly lower for those related to self-medication (p = .032). CONCLUSION: Self-medication is frequent; its potential toxicity should not be neglected, taking into account the rate of adverse drug reactions in about 1 % of ED patient. PMID- 24163274 TI - A rare anatomical variation newly identifies the brains of C.F. Gauss and C.H. Fuchs in a collection at the University of Gottingen. PMID- 24163275 TI - Diagnosis of Guillain-Barre syndrome and validation of Brighton criteria. AB - Guillain-Barre syndrome is an acute polyradiculoneuropathy with a variable clinical presentation. Accurate diagnostic criteria are essential for patient care and research, including clinical trials and vaccine safety studies. Several diagnostic criteria for Guillain-Barre syndrome have been proposed, including the recent set by the Brighton Collaboration. In the present study we describe in detail the key diagnostic features required to meet these Brighton criteria in a study population of 494 adult patients with Guillain-Barre syndrome, previously included in therapeutic and observational studies. The patients had a median age of 53 years (interquartile range 36-66 years) and males slightly predominated (56%). All patients developed bilateral limb weakness which generally involved both upper and lower extremities. The weakness remained restricted to the legs in 6% and to the arms in 1% of the patients. Decreased reflexes in paretic arms or legs were found initially in 91% of patients and in all patients during follow up. Ten (2%) patients however showed persistence of normal reflexes in paretic arms. Disease nadir was reached within 2 weeks in 80%, within 4 weeks in 97% and within 6 weeks in all patients. A monophasic disease course occurred in 95% of patients, of whom 10% had a treatment-related fluctuation. A clinical deterioration after 8 weeks of onset of weakness occurred in 23 (5%) patients. Cerebrospinal fluid was examined in 474 (96%) patients. A mild pleocytosis (5 to 50 cells/MUl) was found in 15%, and none had more than 50 cells/MUl. An increased cerebrospinal fluid protein concentration was found only in 64% of patients, highly dependent on the timing of the lumbar puncture after onset of weakness (49% at the first day to 88% after 2 weeks). Nerve electrophysiology was compatible with the presence of a neuropathy in 99% of patients, but only 59% fulfilled the current criteria for a distinct subtype of Guillain-Barre syndrome. Patients with a complete data set (335) were classified according to the Brighton criteria, ranging from a high to a low level of diagnostic certainty, as level 1 in 61%, level 2 in 33%, level 3 in none, and level 4 in 6% of patients. Patients categorized in these levels did not differ with respect to proportion of patients with preceding events, initial clinical manifestations or outcome. The observed variability in the key diagnostic features of Guillain-Barre syndrome in the current cohort study, can be used to improve the sensitivity of the diagnostic criteria. PMID- 24163276 TI - Aberrant topology of striatum's connectivity is associated with the number of episodes in depression. AB - In major depressive disorder, depressive episodes reoccur in ~60% of cases; however, neural mechanisms of depressive relapse are poorly understood. Depressive episodes are characterized by aberrant topology of the brain's intrinsic functional connectivity network, and the number of episodes is one of the most important predictors for depressive relapse. In this study we hypothesized that specific changes of the topology of intrinsic connectivity interact with the course of episodes in recurrent depressive disorder. To address this hypothesis, we investigated which changes of connectivity topology are associated with the number of episodes in patients, independently of current symptoms and disease duration. Fifty subjects were recruited including 25 depressive patients (two to 10 episodes) and 25 gender- and age-matched control subjects. Resting-state functional magnetic resonance imaging, Harvard-Oxford brain atlas, wavelet-transformation of atlas-shaped regional time-series, and their pairwise Pearson's correlation were used to define individual connectivity matrices. Matrices were analysed by graph-based methods, resulting in outcome measures that were used as surrogates of intrinsic network topology. Topological scores were subsequently compared across groups, and, for patients only, related with the number of depressive episodes and current symptoms by partial correlation analysis. Concerning the whole brain connectivity network of patients, small-world topology was preserved but global efficiency was reduced and global betweenness-centrality increased. Aberrant nodal efficiency and centrality of regional connectivity was found in the dorsal striatum, inferior frontal and orbitofrontal cortex as well as in the occipital and somatosensory cortex. Inferior frontal changes were associated with current symptoms, whereas aberrant right putamen network topology was associated with the number of episodes. Results were controlled for effects of total grey matter volume, medication, and total disease duration. This finding provides first evidence that in major depressive disorder aberrant topology of the right putamen's intrinsic connectivity pattern is associated with the course of depressive episodes, independently of current symptoms, medication status and disease duration. Data suggest that the reorganization of striatal connectivity may interact with the course of episodes in depression thereby contributing to depressive relapse risk. PMID- 24163277 TI - Residual fatigue in Guillain-Barre syndrome is related to axonal loss. AB - OBJECTIVE: To determine the occurrence of residual loss of peripheral nerve axons by motor unit number estimation (MUNE) and conventional nerve conduction studies (NCS) in patients with and without severe fatigue. METHODS: Thirty-nine patients at a median of 8 years (range 1-23 years) after diagnosis of Guillain-Barre syndrome were neurologically examined and divided in 2 subgroups based on the presence of severe fatigue (defined as a fatigue severity score >=5). All patients were investigated with standard NCS and MUNE. Normal values for MUNE were collected in 14 healthy controls. RESULTS: MUNE of the thenar muscles was lower in the 15 patients with severe fatigue (median 125, interquartile range 65 141) compared with the 24 patients without severe fatigue (median 258, interquartile range 120-345) (p = 0.002). In the healthy controls, MUNE was 358 (245-416). Severe fatigue was also related to lower sensory nerve action potential amplitude of the median (p = 0.01) and ulnar nerve (p = 0.03). The 2 subgroups did not differ regarding neurologic deficits, disability, and the remaining conventional motor NCS. CONCLUSION: This study demonstrates that severe fatigue after Guillain-Barre syndrome is related to more pronounced axonal loss, represented by lower MUNEs and lower sensory nerve action potentials. PMID- 24163278 TI - Substance use disorders and psychiatric comorbidity in mid and later life: a review. AB - BACKGROUND: Globally, adults aged 65 years or older will increase from 516 million in 2009 to an estimated 1.53 billion in 2050. Due to substance use at earlier ages that may continue into later life, and ageing-related changes in medical conditions, older substance users are at risk for substance-related consequences. METHODS: MEDLINE and PsychInfo databases were searched using keywords: alcohol use disorder, drug use disorder, drug misuse, substance use disorder, prescription drug abuse, and substance abuse. Using the related articles link, additional articles were screened for inclusion. This review focused on original studies published between 2005 and 2013 to reflect recent trends in substance use disorders. Studies on psychiatric comorbidity were also reviewed to inform treatment needs for older adults with a substance use disorder. RESULTS: Among community non-institutionalized adults aged 50+ years, about 60% used alcohol, 3% used illicit drugs and 1-2% used nonmedical prescription drugs in the past year. Among adults aged 50+, about 5% of men and 1.4% of women had a past-year alcohol use disorder. Among alcohol users, about one in 14 users aged 50-64 had a past-year alcohol use disorder vs one in 30 elder users aged 65+. Among drug users aged 50+, approximately 10-12% had a drug use disorder. Similar to depressive and anxiety disorders, substance use disorders were among the common psychiatric disorders among older adults. Older drug users in methadone maintenance treatment exhibited multiple psychiatric or medical conditions. There have been increases in treatment admissions for illicit and prescription drug problems in the United States. CONCLUSIONS: Substance use in late life requires surveillance and research, including tracking substance use in the racial/ethnic populations and developing effective care models to address comorbid medical and mental health problems. PMID- 24163279 TI - Prenatal paracetamol exposure and child neurodevelopment: a sibling-controlled cohort study. AB - BACKGROUND: Paracetamol is used extensively during pregnancy, but studies regarding the potential neurodevelopmental sequelae of foetal paracetamol exposure are lacking. Method Between 1999 and 2008 all pregnant Norwegian women were eligible for recruitment into the prospective Norwegian Mother and Child Cohort Study. The mothers were asked to report on their use of paracetamol at gestational weeks 17 and 30 and at 6 months postpartum. We used data on 48 631 children whose mothers returned the 3-year follow-up questionnaire by May 2011. Within this sample were 2919 same-sex sibling pairs who were used to adjust for familial and genetic factors. We modelled psychomotor development (communication, fine and gross motor development), externalizing and internalizing behaviour problems, and temperament (emotionality, activity, sociability and shyness) based on prenatal paracetamol exposure using generalized linear regression, adjusting for a number of factors, including febrile illness, infections and co-medication use during pregnancy. RESULTS: The sibling-control analysis revealed that children exposed to prenatal paracetamol for more than 28 days had poorer gross motor development [beta 0.24, 95% confidence interval (CI) 0.12-0.51], communication (beta 0.20, 95% CI 0.01-0.39), externalizing behaviour (beta 0.28, 95% CI 0.15-0.42), internalizing behaviour (beta 0.14, 95% CI 0.01-0.28), and higher activity levels (beta 0.24, 95% CI 0.11-0.38). Children exposed prenatally to short-term use of paracetamol (1-27 days) also had poorer gross motor outcomes (beta 0.10, 95% CI 0.02-0.19), but the effects were smaller than with long-term use. Ibuprofen exposure was not associated with neurodevelopmental outcomes. CONCLUSION: Children exposed to long-term use of paracetamol during pregnancy had substantially adverse developmental outcomes at 3 years of age. PMID- 24163281 TI - Oral sumatriptan for the acute treatment of migraine in children and adolescents: yet another failed study. PMID- 24163280 TI - Safety and efficacy of once-daily gastroretentive gabapentin in patients with postherpetic neuralgia aged 75 years and over. AB - BACKGROUND: Treatment of postherpetic neuralgia (PHN) is more complicated in elderly patients, and multiple daily dosing, complex titration, and high incidences of adverse events can be limiting for many pharmacological treatment options. OBJECTIVE: The aim of this study was to determine whether the efficacy and tolerability of once-daily gastroretentive gabapentin (G-GR) is similar between elderly patients (>=75 years) and younger patients (<75 years). METHODS: Data from two phase III, placebo-controlled studies of 1,800 mg G-GR once daily with dinner in patients with PHN were integrated and analyzed by age subgroups (<75 years, n = 527; >=75 years, n = 192). Efficacy assessments at endpoint (week 10) included baseline-adjusted change in average daily pain (ADP) and average daily sleep interference (SIS) scores, the proportion of responders (>=30 % pain reduction), and the proportion of patients feeling "Much" or "Very Much" improved on the Patient Global Impression of Change (PGIC). RESULTS: Compared with placebo, patients in both age subgroups treated with G-GR (placebo/G-GR) had greater reductions in mean ADP (>=75: -21.9/-34.2 %, p = 0.0348; <75: -29.9/-38.3 %, p = 0.0079) and SIS (>=75: -1.3/-2.4, p = 0.0017; <75: -1.8/-2.7, p < 0.0001), more patients were responders (>=75: 30.4/52.0 %, p = 0.0025; <75: 45.0/54.7 %, p = 0.0265), and more felt "Much" or "Very Much" improved on the PGIC (>=75: 20.7/35.0 %, p = 0.0272; <75: 33.6/44.9 %, p = 0.0077). The most common (placebo/G-GR) adverse events (AEs) were dizziness (>=75: 3.3/12.0 %; <75: 1.8/10.4 %), nausea (>=75: 1.0/5.4 %; <75: 2.9/4.2 %), and somnolence (>=75: 0/5.0 %; <75: 3.7/4.2 %). For all patients, AEs rapidly decreased to low steady levels after 4-5 weeks of treatment. The incidence of serious AEs was low and they were reported more frequently in the placebo than in the G-GR group. CONCLUSIONS: Therapy with once-daily G-GR was as effective for treating pain associated with PHN in elderly patients as it was in younger patients. G-GR was well tolerated, and the incidence of the most common AEs did not appear to be age related. PMID- 24163282 TI - Oral sumatriptan for migraine in children and adolescents: a randomized, multicenter, placebo-controlled, parallel group study. AB - OBJECTIVE: The objective of this article is to evaluate the efficacy and tolerability of two doses of oral sumatriptan vs placebo in the acute treatment of migraine in children and adolescents. BACKGROUND: Currently, there is no approved prescription medication in Japan for the treatment of migraine in children and adolescents. METHODS: This was a multicenter, outpatient, single attack, double-blind, randomized, placebo-controlled, parallel-group study. Eligible patients were children and adolescents aged 10 to 17 years diagnosed with migraine with or without aura (ICHD-II criteria 1.1 or 1.2) from 17 centers. They were randomized to receive sumatriptan 25 mg, 50 mg or placebo (1:1:2). The primary efficacy endpoint was headache relief by two grades on a five-grade scale at two hours post-dose. RESULTS: A total of 178 patients from 17 centers in Japan were enrolled and randomized to an investigational product in double-blind fashion. Of these, 144 patients self-treated a single migraine attack, and all provided a post-dose efficacy assessment and completed the study. The percentage of patients in the full analysis set (FAS) population who report pain relief at two hours post-treatment for the primary endpoint was higher in the placebo group than in the pooled sumatriptan group (38.6% vs 31.1%, 95% CI: -23.02 to 8.04, P = 0.345). The percentage of patients in the FAS population who reported pain relief at four hours post-dose was higher in the pooled sumatriptan group (63.5%) than in the placebo group (51.4%) but failed to achieve statistical significance ( P = 0.142). At four hours post-dose, percentages of patients who were pain free or had complete relief of photophobia or phonophobia were numerically higher in the sumatriptan pooled group compared to placebo. Both doses of oral sumatriptan were well tolerated. No adverse events (AEs) were serious or led to study withdrawal. The most common AEs were somnolence in 6% (two patients) in the sumatriptan 25 mg treatment group and chest discomfort in 7% (three patients) in the sumatriptan 50 mg treatment group. CONCLUSIONS: There was no statistically significant improvement between the sumatriptan pooled group and the placebo group for pain relief at two hours. Oral sumatriptan was well tolerated. PMID- 24163283 TI - Strategy for cold adaptation of the tryptophan synthase alpha subunit from the psychrophile Shewanella frigidimarina K14-2: crystal structure and physicochemical properties. AB - To investigate the molecular basis of cold adaptation of enzymes, we determined the crystal structure of the tryptophan synthase alpha subunit (SfTSA) from the psychrophile Shewanella frigidimarina K14-2 by X-ray analysis at 2.6-A resolution and also examined its physicochemical properties. SfTSA was found to have the following characteristics: (i) The stabilities against heat and denaturant of SfTSA were lower than those of an alpha subunit (EcTSA) from Escherichia coli. This lower equilibrium stability originated from both a faster unfolding rate and a slower refolding rate; (ii) the heat denaturation of SfTSA was completely reversible at pH 7.0 and the solubility of denatured SfTSA was higher than that of denatured EcTSA. The two-state transition of denaturation for SfTSA was highly cooperative, whereas the denaturation process of EcTSA was considerably more complex and (iii) the global structure of SfTSA was quite similar to those of alpha subunits from other species. Relative to those other proteins, SfTSA exhibited an increase in cavity volume and a decrease in the number of ion pairs. SfTSA also lacks a hydrogen bond near loop B, related to catalytic function. These characteristics of SfTSA might provide the conformational flexibility required for catalytic activity at low temperatures. PMID- 24163285 TI - Hazards of new media: youth's exposure to tobacco Ads/promotions. AB - BACKGROUND: A gap in knowledge exists about the youth's exposure to protobacco campaigns via new electronic media outlets. In response, we use national data to delineate the associations between tobacco ads/promotions delivered through new media outlets (i.e., social network sites and text messages) and youth attitudes/beliefs about tobacco and intent to use (among youth who had not yet used tobacco). METHODS: Data were derived from the 2011 National Youth Tobacco Survey, a nationally representative sample of U.S. youth enrolled in both public and private schools (N = 15,673). Logistic regression models were used to examine associations between demographic characteristics and reported exposure to tobacco ads/promotions via social networking sites and text messages. Logistic regression models were also used to investigate associations between exposure tobacco ads/promotions and attitudes toward tobacco. RESULTS: We found that highly susceptible youth (i.e., minorities, very young youth, and youth who have not yet used tobacco) have observed tobacco ads/promotions on social networking sites and text messages. These youth are more likely to have favorable attitudes toward tobacco, including the intention to use tobacco among those who had not yet used tobacco. CONCLUSIONS: Our findings underscore the need for policy strategies to more effectively monitor and regulate tobacco advertising via new media outlets. PMID- 24163286 TI - Influence of CYP2A6*4 genotypes on maternal serum cotinine among Chinese nonsmoking pregnant women. AB - INTRODUCTION: Serum cotinine is a common biomarker for smoking and secondhand smoke (SHS) exposure, but it can be affected by the activity of nicotine metabolizing enzymes. This study investigated the influence of CYP2A6*4 genotypes on serum cotinine among nonsmoking pregnant women. METHODS: We analyzed the data from 545 Chinese nonsmoking pregnant women in a case-control study on SHS exposure and birth outcomes in southern China. Participants self-reported their status and duration of SHS exposure during pregnancy right after delivery in hospital. Research staff used polymerase chain reaction to genotype CYP2A6*4 and enzyme-linked immunosorbent assay to measure cotinine levels in maternal serum samples collected before delivery. We stratified women by their self-reported SHS exposure status and CYP2A6*4 genotypes and then compared their median levels of serum cotinine. RESULTS: Among women who self-reported non-SHS exposure (n = 317), the median serum cotinine levels were 2.83ng/ml for those with CYP2A6*1/*1 genotype, 1.39ng/ml for CYP2A6*1/*4, and 0.77ng/ml for CYP2A6*4/*4, respectively. Among women who self-reported SHS exposure (n = 228), the median cotinine levels were 3.32ng/ml for those with CYP2A6*1/*1 genotype, 2.38ng/ml for CYP2A6*1/*4, and 1.56ng/ml for CYP2A6*4/*4, respectively. Strikingly, self-reported SHS exposed women with CYP2A6*1/*4 or CYP2A6*4/*4 genotype had significantly lower (rather than higher) median cotinine levels than self-reported non-SHS-exposed women with CYP2A6*1/*1 genotype (p = .012). CONCLUSIONS: CYP2A6*4 genotype is associated with lower serum cotinine among Chinese nonsmoking pregnant women. Measuring CYP2A6*4 genotype may help to improve the validity of SHS exposure measurement by serum cotinine in pregnant women and possibly also in other nonpregnant populations. PMID- 24163284 TI - Exercise: putting action into our epigenome. AB - Most human phenotypes are influenced by a combination of genomic and environmental factors. Engaging in regular physical exercise prevents many chronic diseases, decreases mortality risk and increases longevity. However, the mechanisms involved are poorly understood. The modulating effect of physical (aerobic and resistance) exercise on gene expression has been known for some time now and has provided us with an understanding of the biological responses to physical exercise. Emerging research data suggest that epigenetic modifications are extremely important for both development and disease in humans. In the current review, we summarise findings on the effect of exercise on epigenetic modifications and their effects on gene expression. Current research data suggest epigenetic modifications (DNA methylation and histone acetylation) and microRNAs (miRNAs) are responsive to acute aerobic and resistance exercise in brain, blood, skeletal and cardiac muscle, adipose tissue and even buccal cells. Six months of aerobic exercise alters whole-genome DNA methylation in skeletal muscle and adipose tissue and directly influences lipogenesis. Some miRNAs are related to maximal oxygen consumption (VO(2max)) and VO(2max) trainability, and are differentially expressed amongst individuals with high and low VO(2max). Remarkably, miRNA expression profiles discriminate between low and high responders to resistance exercise (miR-378, -26a, -29a and -451) and correlate to gains in lean body mass (miR-378). The emerging field of exercise epigenomics is expected to prosper and additional studies may elucidate the clinical relevance of miRNAs and epigenetic modifications, and delineate mechanisms by which exercise confers a healthier phenotype and improves performance. PMID- 24163287 TI - Arabidopsis SAG protein containing the MDN1 domain participates in seed germination and seedling development by negatively regulating ABI3 and ABI5. AB - Three proteins containing a midasin homologue 1 (MDN1) domain from the yeast Solanum chacoense and Arabidopsis thaliana have important functions in yeast survival, seed development, and female gametogenesis. In this study, a novel protein containing the MDN1 domain from Arabidopsis negatively regulated abscisic acid (ABA) signalling during seed germination. Seeds of a T-DNA insertion line of this gene exhibited increased sensitivity to ABA during seed germination and seedling development (named sag). By contrast, seeds with overexpressed AtSAG (OX2) were less sensitive to ABA. The seeds of the sag mutant showed similar sensitivity to high concentrations of mannitol and NaCl during these stages. AtSAG was also highly expressed in germinating seeds. However, ABA-induced AtSAG expression remained almost unchanged. ABA-responsive marker genes, including ABI3, ABI5, Em1, Em6, RD29A, and RAB18, were upregulated in sag mutants but were downregulated in OX2. Genetic analyses indicated that the function of AtSAG in ABA signalling depended on ABI3 and ABI5. The expression of some target genes of ABI3 and ABI5, such as seed storage protein and oleosin genes, was induced higher by ABA in sag mutants than in wild-type germinated seeds, even higher than in abi5 mutants. This finding indicated that other regulators similar to ABI3 or ABI5 played a role during these stages. Taken together, these results indicate that AtSAG is an important negative regulator of ABA signalling during seed germination and seedling development. PMID- 24163288 TI - Over-expression of cancerous inhibitor of PP2A (CIP2A) in bone marrow cells from patients with a group of high-risk myelodysplastic syndromes. AB - Cancerous inhibitor of PP2A (protein phosphatase 2A) (CIP2A) is an inhibitor of PP2A, a phosphatase and tumor suppressor that regulates cell proliferation, differentiation, and survival. The aim of this study was to investigate whether CIP2A plays a role in the progression of myelodysplastic syndromes (MDS). Immunohistochemical analysis revealed that a fraction patients having refractory anemia with excess blasts (RAEB)-1 (4 out of 12) and RAEB-2 (10 out of 14) exhibited significant expression of CIP2A in bone marrow hematopoietic cells, while all patients with refractory cytopenia with unilineage or multilineage dysplasia (RCUD/RCMD) (0 out of 18) and the control group (0 out of 17) were negative. CIP2A was mainly expressed by the MPO-positive myeloid series of cells and partly by the CD34-positive cells in association with the expression of phosphorylated c-MYC (p-c-MYC) protein and the cell cycle-related proteins Ki-67, MCM2, and geminin. The percentage of p-c-MYC-positive cells in the bone marrow of CIP2A-positive MDS cases was significantly higher than that in CIP2A-negative MDS cases (P < 0.01). The expression levels of mRNA for CIP2A and PP2A exhibited positive correlation in MDS/control bone marrow. These results suggest that up regulated expression of CIP2A might play a role in the proliferation of blasts in the MDS bone marrow and in disease progression in at least some cases. PMID- 24163289 TI - Dynamics and environmental responses of PATROL1 in Arabidopsis subsidiary cells. AB - The Arabidopsis stomatal complex is composed of a pair of guard cells and surrounding anisocytic subsidiary cells. Subsidiary cells are thought to function as a supplier and receiver of bulk water and ions, and to assist turgor-driven stomatal movement, but the molecular mechanisms are largely unknown. In this work, we studied the dynamic behavior and environmental responses of PATROL1, which has been identified as a translocation factor of the plasma membrane proton pump ATPase (PM H(+)-ATPase) AHA1 in guard cells and subsidiary cells in Arabidopsis thaliana. Variable-angle epifluorescence microscopic observation revealed that green fluorescent protein (GFP)-PATROL1 localized on dot-like compartments that resided on plasma membranes for several seconds. The GFP PATROL1-labeled dots were sensitive to phosphatidylinositol 4-kinase inhibitors but not to a phosphatidylinositol 3-kinase inhibitor. GFP-PATROL1 and red fluorescent protein (RFP)-AHA1 co-localized in hyperosmotic conditions, and a mutation of PATROL1 resulted in an increase in GFP-AHA1 internalization, suggesting a role in the translocation of PM H(+)-ATPase in subsidiary cells. Interestingly, subsidiary cells showed changes in localization of GFP-PATROL1 in response to environmental stimuli that were opposite to those in guard cells. Our observations suggested that PATROL1 may contribute to stomatal movement by translocations of PM H(+)-ATPase in subsidiary cells. PMID- 24163290 TI - Trastuzumab-induced systemic capillary leak syndrome in a breast cancer patient. AB - Systemic capillary leak syndrome (SCLS) is a rare health condition. It is characterized by recurrent episodes of generalized edema and severe hypotension along with hypoproteinemia. The condition is under recognized because of its nonspecific signs and symptoms, and high mortality rate. SCLS triggered by trastuzumab, a target drug for Her2-positive breast cancer patients, has not been previously reported. A 59-year-old Chinese woman, diagnosed with breast cancer with accompanying liver and bone metastasis, was treated with 3 cycles of docetaxel with capecitabine and a regimen of 12 cycles of capecitabine with trastuzumab. The patient developed systemic capillary leak syndrome during the 16th cycle of chemotherapy. Post-diagnosis treatment regimen is also presented in the current case report. SCLS has been previously observed in breast cancer patients. However, SCLS incidence post-chemotherapeutic treatment with trastuzumab has not been reported elsewhere. Hence, our report highlights the need for rigorous investigation of the side effects of trastuzumab usage and the increasing need of insightful diagnosis to manage any incidence of SCLS. The case provides valuable experience for treating the uncommon adverse effects of trastuzumab in Her2-positive breast cancer patients. PMID- 24163291 TI - Telemedicine can improve the quality of oral anticoagulation using portable devices and self-testing at home. AB - Point-of-care testing (POCT) devices can be used to monitor anticoagulant therapy. We compared patients being monitored at home by self-testing using a POCT device and telemedicine support with a previous period of conventional monitoring at a Thrombosis Centre. A total of 114 anticoagulated patients participated. The number of blood checks (INR) was significantly higher in the home monitoring group and the interval between checks was significantly shorter. The percentage of missed INR checks was significantly higher during the conventional monitoring period compared with home monitoring. Patients were divided into two groups on the basis of the time spent within the therapeutic range (TTR) during conventional monitoring: the unstable group had TTR<70% and the stable group had TTR >=70%. In the unstable group there was a significant increase in TTR with home monitoring: 63% to 68% (P < 0.001) while in the stable group there was no significant change (77% to 75%). The study showed that oral anticoagulation management by means of self-testing is suitable and safe. PMID- 24163292 TI - Effects of a telehealth programme using mobile data transmission on primary healthcare utilisation among children in Bamako, Mali. AB - Pesinet is a non-profit organisation which operates a microinsurance programme combined with a monitoring service in low-income countries to increase primary healthcare utilisation for children. We studied the association between enrolment in the Pesinet programme and changes in utilisation of health services. We conducted a prospective controlled study in Bamako (Mali) in children under five years old. Participants in the Pesinet service were recruited from a neighbourhood of Bamako (n = 91) and participants in the control group (usual care) came from two other neighbouring districts (n = 89). Eight questionnaires were completed at 2-week intervals for each child in the study. We performed logistic regression modelling to assess the effect of the Pesinet programme on health service utilisation, adjusting for confounding variables (age and socio economic status). During the study, families reported 206 episodes of disease in the intervention group and 168 in the control group. Children from the intervention group had 85 medical consultations and those in the control group had 28. Based on the logistic regression model, there was increased utilisation of health care services among children enrolled in the Pesinet programme, with an adjusted Odds Ratio for medical consultations of 2.2. Membership of the Pesinet telehealth programme increased primary healthcare utilisation among children under five years old in Mali. PMID- 24163293 TI - The status of telerehabilitation in neurological applications. AB - We systematically reviewed the evidence for the effectiveness of tele neurorehabilitation (TNR) applications. The review included recent reports on rehabilitation for any disability associated with a neurological deficit or condition. Study quality was assessed using an approach that considered both study performance and study design. Judgements were made on whether each application had been successful, and whether further data were needed to establish the application as suitable for routine use. Nineteen credible studies that reported patient outcomes or administrative changes were identified. These studies related to 13 conditions. The focus of rehabilitation included Internet supported treatments for management of fatigue, pain and depression; promotion of physical activity; and speech therapy. Sixteen studies were of high or good quality and three were fair to good, with some limitations. In 13 of the 19 studies the TNR application was successful in providing at least equivalent outcomes to conventional approaches. Additional work would be needed on eight applications to establish suitability for routine use, and would be desirable in five. Thus the recent literature provides further support for TNR applications, showing the promise of this field in a number of areas. However, the database of credible studies remains small. PMID- 24163294 TI - The use of telemedicine to train perioperative nurses in rural settings. AB - The training available to perioperative nurses in rural areas is often inefficient and can be difficult to access. We designed a distance training programme using educational material from the Association of Perioperative Registered Nurses (AORN). Over a six-year period, we compared the performance of 22 nurses undertaking the programme via telemedicine with that of 13 nurses undertaking it conventionally, in person. The telemedicine nurses were based at six rural hospitals and interacted with their preceptors via remotely controlled videoconferencing systems. There was no significant difference in the time taken to complete the programme: 118 days in the telemedicine group and 84 days in the in-person group. There were no significant differences between groups in the AORN module scores. The average AORN final examination score was 88% for the telemedicine group and 91% for the in-person group. The scores from skills assessed were not significantly different between groups. The majority of students in the in-person and telemedicine groups considered that the programme was a success (92% and 91% respectively). The study suggests that telemedicine merits serious consideration for training in perioperative nursing specifically, and probably more generally in the nursing field. PMID- 24163295 TI - Mobile teledermatology--patient satisfaction, diagnostic and management concordance, and factors affecting patient refusal to participate in Saudi Arabia. AB - We evaluated the use of a 4G smart phone for mobile teledermatology. A dermatologist took pictures of skin images with a mobile phone (8 Mpixel camera resolution) and made a face-to-face diagnosis. The images were transmitted to a second dermatologist who viewed them on a similar mobile phone and made an independent diagnosis for comparison. Images were taken and transmitted only after receiving informed consent from the patients. A total of 166 consecutive patients were included in the study (97 male and 69 female). A questionnaire to assess patient satisfaction was administered to each patient. Most of the responders were highly satisfied with teledermatology. However, 23 patients (14%) refused photography of the skin lesions (21 female and 2 males). The main reasons for refusal to be photographed were stated as social or religious. The broad categorical diagnostic and management concordance (i.e. when considering at least one of the diagnoses to be similar) was 95%. Specific diagnostic concordance varied according to the disease. The average kappa coefficient was 0.66 for diagnostic concordance and 0.82 for management concordance. Refusal to be photographed--a problem not limited to teledermatology--needs to be considered when designing teledermatology protocols for larger scale implementation in areas like the Middle East. PMID- 24163296 TI - Accuracy and reliability of teledermatoscopy with images taken by general practitioners during everyday practice. AB - We assessed the accuracy and reliability of teledermatoscopy with images taken by a general practitioner (GP) compared to face-to-face dermatological examination. GPs selected patients for teledermatoscopy and took both macro and dermatoscopic photographs. Patients were then referred to the local dermatologist for face-to face examination. Accuracy and inter-observer reliability were calculated for the diagnosis and management plan. Image quality was rated by two observers on a three-point scale. A total of 108 teledermatoscopy consultations sent by 13 GPs were assessed by four dermatologists. Agreement was 0.61 (kappa) on diagnostic group and 0.23 on management plan. The inter-observer reliability was 0.65 on diagnostic group and 0.36 on management plan. The image quality was reported as bad in 36% of cases, reasonable in 28% and good in 36%. Agreement for cases with good quality images was 0.66 on diagnostic group and 0.42 on management plan. Teledermatoscopy in general practice had overall a lower accuracy and reliability than face-to-face consultation. In cases where a good quality image was reported, the accuracy increased, which emphasises that teledermatoscopy is highly dependent on a good quality images. PMID- 24163297 TI - Not all systematic reviews are systematic: a meta-review of the quality of systematic reviews for non-invasive remote monitoring in heart failure. AB - We carried out a critical appraisal and synthesis of the systematic reviews and meta-analyses of remote monitoring for heart failure. A comprehensive literature search identified 65 relevant publications from 3333 citations. Seventeen studies fulfilled the inclusion and exclusion criteria. Seven (41%) systematic reviews pooled results for meta-analysis. Eight (47%) considered all non-invasive remote monitoring strategies. Five (29%) focused on telemonitoring. Four (24%) included both non-invasive and invasive technologies. The reviews were appraised by two independent reviewers for their quality and risk of bias using the AMSTAR tool. According to the AMSTAR criteria, ten (58%) systematic reviews were of poor methodological quality. In the high quality reviews, the relative risk of mortality in patients who received remote monitoring ranged from 0.53 to 0.88. The high quality reviews also reported that remote monitoring reduced the relative risk of all-cause (0.52 to 0.96) and heart failure-related hospitalizations (0.72 to 0.79) and, as a consequence, healthcare costs. However, further research is required before considering widespread implementation of remote monitoring. The subset of the heart failure population that derives the most benefit from intensive monitoring, the best technology, and the optimum duration of monitoring, all need to be identified. PMID- 24163298 TI - A systematic review of telecounselling and its effectiveness in managing depression amongst minority ethnic communities. AB - Telecounselling--the provision of counselling services by telephone, videoconferencing or Internet media--can assist with disparities in the treatment and management of depression for minority ethnic groups. We therefore reviewed the evidence examining the effectiveness of telecounselling for this population. This involved a search of electronic databases, the grey literature and two peer reviewed journals. Study quality was examined using the Oxford Centre for Evidence Based Medicine guidelines. Cohen's d effect sizes were additionally calculated for between-study comparisons. The final sample comprised eight independent studies, with a total of 498 adults of Asian, African-American or Spanish origin. None of the studies met the criteria for the highest methodological rating (Level 1) and there were five studies at Level 2. Significant short-term treatment effects were associated with telephone- and Internet-mediated services, including moderate to large improvements across measures of depression, anxiety, quality of life and psychosocial functioning reported. Longer-term treatment effects were also reported, although these results were based on very limited data. The results highlight the need for additional rigorous research to determine the clinical efficacy of telecounselling as a treatment option for depression among minority communities. PMID- 24163299 TI - Patient focused Internet-based approaches to cardiovascular rehabilitation--a systematic review. AB - Cardiac rehabilitation (CR) has been shown to improve health behaviours and risk factors and the evidence suggests that home CR is as effective as hospital-based CR. Telemedicine offers the potential for more patients to engage in CR. We reviewed the evidence for patient focused Internet-based approaches to cardiovascular rehabilitation. Searches were performed in PubMed, EMBASE, Scopus and the Cochrane Controlled Trials Register. In total, nine studies involving 830 patients with heart disease that compared Internet-based cardiac rehabilitation to usual care were identified. The quality of trials was assessed using the Jadad scale. Outcome data were pooled under four subheadings: compliance; physical activity outcomes; clinical outcomes; psychosocial outcomes. Compliance rates were high but dropped over time in all studies. Physical activity measures were generally improved, as were clinical outcomes. Changes in psychosocial measures were positive, with two studies noting no change. No interventions noted a negative effect on outcomes. Despite the relatively small number of trials and the limited outcome measures, the results appeared to be positive with regard to patient outcomes and patient feedback. However, none had progressed to a clinical service. PMID- 24163300 TI - Factors in the selection of a teleradiology provider in the United States. AB - Commercial teleradiology is well established in the US. There are many factors to consider when engaging a teleradiology provider. One of the basic questions is what do you expect to gain from it? Do you want a final reading from an attending radiologist (known as a consultant radiologist in many countries) or would you be satisfied with a preliminary reading from a teleradiology provider and a final reading from your own in-house radiologist the following day? Do you simply require after-hours coverage or do you need to supplement the coverage provided by your own internal radiologists during normal working hours? Teleradiology is not without its drawbacks. It can add additional costs, particularly for after hours coverage. Teleradiology rarely provides in-house coverage for procedures, and the interpreting radiologist may sometimes be difficult to contact for consultation. Choosing a teleradiology vendor requires due diligence. When the contracting entity defines its expectations well and chooses its teleradiology vendor with care, the end result will be satisfactory for all concerned, including the patients. PMID- 24163302 TI - Returning to learning following a concussion. AB - Following a concussion, it is common for children and adolescents to experience difficulties in the school setting. Cognitive difficulties, such as learning new tasks or remembering previously learned material, may pose challenges in the classroom. The school environment may also increase symptoms with exposure to bright lights and screens or noisy cafeterias and hallways. Unfortunately, because most children and adolescents look physically normal after a concussion, school officials often fail to recognize the need for academic or environmental adjustments. Appropriate guidance and recommendations from the pediatrician may ease the transition back to the school environment and facilitate the recovery of the child or adolescent. This report serves to provide a better understanding of possible factors that may contribute to difficulties in a school environment after a concussion and serves as a framework for the medical home, the educational home, and the family home to guide the student to a successful and safe return to learning. PMID- 24163303 TI - Autologous dendritic cell based adoptive immunotherapy of patients with colorectal cancer-A phase I-II study. AB - Dendritic cell-based active immunotherapies of cancer patients are aimed to provoke the proliferation and differentiation of tumor-specific CD4(+) and CD8(+) T-lymphocytes towards protective effector cells. Isolation and in vitro differentiation of circulating blood monocytes has been established a reasonable platform for adoptively transferred DC-based immunotherapies. In the present study the safety and tolerability of vaccination by autologous tumor cell lysates (oncolysate)- or carcinoembriogenic antigen (CEA)-loaded DCs in patients with colorectal cancer was investigated in a phase I-II trial. The study included 12 patients with histologically confirmed colorectal cancer (Dukes B2-C stages). Six of the patients received oncolysate-pulsed, whereas the other six received recombinant CEA-loaded autologous DCs. The potential of the tumor antigen-loaded DCs to provoke the patient's immune system was studied both in vivo and in vitro. The clinical outcome of the therapy evaluated after 7 years revealed that none of the six patients treated with oncolysate-loaded DCs showed relapse of colorectal cancer, whereas three out of the six patients treated with CEA-loaded DCs died because of tumor relapse. Immunization with both the oncolysate- and the CEA loaded autologous DCs induced measurable immune responses, which could be detected in vivo by cutaneous reactions and in vitro by lymphocyte proliferation assay. Our results show that vaccination by autologous DCs loaded with autologous oncolysates containing various tumor antigens represents a well tolerated therapeutic modality in patients with colorectal cancer without any detectable adverse effects. Demonstration of the efficacy of such therapy needs further studies with increased number of patients. PMID- 24163304 TI - Clinicopathological sex- related relevance of musashi1 mRNA expression in esophageal squamous cell carcinoma patients. AB - The cancer stem cell theory is considered as the spotlight of cancer biology, in which a subpopulation of tumor cells show unlimited proliferative and self renewal capacities. Post-transcriptional regulation is involved in different cellular functions such as cell differentiation and proliferation which results in cellular diversity. Musashi1 (Msi1) is one of the most important RNA-binding proteins (RBPs) which are involved in translational inhibition. Although, Msi1 targets are largely unknown, p21WAF-1, a cell cycle regulator, and Numb, inhibitor of notch signaling pathway, are well-known factors which are suppressed by the Msi1 in normal and cancer stem cells. Msi1 expression in tumor tissues from 53 ESCC patients was compared to normal tissues using real-time polymerase chain reaction (PCR). Msi1 was significantely overexpressed in 41.5 % of tumor samples and we observed a significant correlation between Msi1 expression and sex, in which the males had shown a higher level of Msi1 expression in comparison with the females (2.00 Vs 0.78 fold changes, p = 0.05). In this study, we assessed whether Msi1 is expressed in ESCC samples suggesting this protein as a novel cancer stem cell marker which requires further studies. PMID- 24163305 TI - VA-LCP anterior clavicle plate: the anatomically precontoured fixation system with angular stability for clavicle shaft. AB - INTRODUCTION: The aim of this investigation was to evaluate the introduction of the VA-LCP anterior clavicle plate in the treatment of clavicle fractures. MATERIAL AND METHODS: From March 2011 to March 2013, 42 clavicle fractures were treated; 40 were middle-third and 2 lateral-third, and 13/42 (31 %) patients were treated due to painful nonunion. Patient age ranged from 16 to 81 years. RESULTS: Complications were screw placement through the AC-joint, one superficial wound infection and one neuropraxia of the nervus radialis with dropping hand. We had some difficulties prebending both lateral to low and lateral to high but without clinical consequences. In all cases, the fracture healed with full functionality. After 1 year, 4 patients underwent a removal of the hardware. CONCLUSION: The VA LCP anterior plate showed good reliability and sufficient stability with both middle-third, lateral and nonunion fractures of the clavicle. PMID- 24163306 TI - Knowledge of health insurance terminology and details among the uninsured. AB - By 2014, uninsured adults will be eligible for health insurance through exchanges with multiple plan options. Choosing health insurance is challenging even for those who have engaged in the process previously. We examined 51 uninsured adults' health insurance knowledge and preferences through semistructured qualitative interviews. Our sample was predominantly low-income and African American. Most had little or no experience with health insurance terminology. Those with limited health literacy skills understood less than those with higher health literacy. Many confused related insurance concepts. Non-health contexts (e.g., car insurance) aided understanding. Premiums, fixed costs, and specific coverage were rated very important to insurance decisions. Our study was one of the first to examine uninsured individuals' health insurance knowledge and preferences. Uninsured individuals may have different information needs and preferences than those studied in previous research. Clear information and familiar non-health contexts can be important strategies when communicating about the exchanges. PMID- 24163307 TI - Do claims-based continuity of care measures reflect the patient perspective? AB - Continuity of care (CoC) is a cornerstone of the patient-centered medical home (PCMH) and one of the primary means for achieving health care quality. Despite decades of study, however, CoC remains difficult to define and quantify. To incorporate patient experiences into health reform evaluations, it is critical to determine if and how well CoC measures traditionally derived from administrative claims capture patient experiences. In this study, we used claims data and self reported continuity experiences of 2,620 Medicare beneficiaries who completed the National Health and Health Services Use Questionnaire to compare 16 claims-based CoC indices to a multidimensional patient-reported CoC measure. Our results show that most claims-based CoC measures do not reflect older adults' perceptions of continuous patient-provider relationships, indicating that claims-based assessments should be used in tandem with patient reports for defining, quantifying, and evaluating CoC in health care delivery models. PMID- 24163309 TI - Educational level and self-care behaviour in patients with heart failure before and after nurse educational intervention. AB - BACKGROUND: Self-care is important for heart failure (HF) management and may be influenced by the patient's educational level. AIM: We assessed the relationship of educational level with baseline self-care behaviour and changes one year after a nursing intervention in HF outpatients attending a HF unit. PATIENTS AND METHOD: Three hundred and thirty-five HF patients were studied, with a median age of 67 years (P(25-75) 57-75) and a median HF duration of six months (P(25-75) 1 36). HF aetiology was mainly ischaemic heart disease (53.4%). Median ejection fraction was 30% (P(25-75) 24-37%). The functional class was mainly II (66.3%) and III (25.7%). Educational levels were: very low 17.3%; low 62.1%; medium-high 20.6%. Patients were evaluated at the first visit (baseline) and one year after the educational intervention with the nine-item European Heart Failure Self-care Behaviour Scale. RESULTS: Median patient scores differed in the baseline (19 (P(25-75) 15-26) vs. 16 (P(25-75) 13-21) vs. 15 (P(25-75) 12.5-15.5)) and the one year evaluation (15 (P(25-75) 13-17) vs. 13 (P(25-75) 11-15) vs. 12 (P(25-75) 10 14)) for the three educational levels, respectively, with statistically significant differences between levels (p=0.007 to p<0.001) except between low and medium-high education at one year (p=0.057). In the one-year evaluation, self care behaviour significantly improved in the three educational groups (p<0.001), with a similar, albeit not statistically significant, magnitude of improvement in all groups. CONCLUSIONS: Self-care behaviour at baseline and one year after a nursing intervention was better in patients with a higher education, although the improvement with the intervention was similar irrespective of the educational level. PMID- 24163310 TI - An ATP binding cassette transporter is required for cuticular wax deposition and desiccation tolerance in the moss Physcomitrella patens. AB - The plant cuticle is thought to be a critical evolutionary adaptation that allowed the first plants to colonize land, because of its key roles in regulating plant water status and providing protection from biotic and abiotic stresses. Much has been learned about cuticle composition and structure through genetic and biochemical studies of angiosperms, as well as underlying genetic pathways, but little is known about the cuticles of early diverging plant lineages. Here, we demonstrate that the moss Physcomitrella patens, an extant relative of the earliest terrestrial plants, has a cuticle that is analogous in both structure and chemical composition to those of angiosperms. To test whether the underlying cuticle biosynthetic pathways were also shared among distant plant lineages, we generated a genetic knockout of the moss ATP binding cassette subfamily G (ABCG) transporter Pp-ABCG7, a putative ortholog of Arabidopsis thaliana ABCG transporters involved in cuticle precursor trafficking. We show that this mutant is severely deficient in cuticular wax accumulation and has a reduced tolerance of desiccation stress compared with the wild type. This work provides evidence that the cuticle was an adaptive feature present in the first terrestrial plants and that the genes involved in their formation have been functionally conserved for over 450 million years. PMID- 24163311 TI - Regulation of auxin homeostasis and gradients in Arabidopsis roots through the formation of the indole-3-acetic acid catabolite 2-oxindole-3-acetic acid. AB - The native auxin, indole-3-acetic acid (IAA), is a major regulator of plant growth and development. Its nonuniform distribution between cells and tissues underlies the spatiotemporal coordination of many developmental events and responses to environmental stimuli. The regulation of auxin gradients and the formation of auxin maxima/minima most likely involve the regulation of both metabolic and transport processes. In this article, we have demonstrated that 2 oxindole-3-acetic acid (oxIAA) is a major primary IAA catabolite formed in Arabidopsis thaliana root tissues. OxIAA had little biological activity and was formed rapidly and irreversibly in response to increases in auxin levels. We further showed that there is cell type-specific regulation of oxIAA levels in the Arabidopsis root apex. We propose that oxIAA is an important element in the regulation of output from auxin gradients and, therefore, in the regulation of auxin homeostasis and response mechanisms. PMID- 24163312 TI - Convergent evolution of polysaccharide debranching defines a common mechanism for starch accumulation in cyanobacteria and plants. AB - Starch, unlike hydrosoluble glycogen particles, aggregates into insoluble, semicrystalline granules. In photosynthetic eukaryotes, the transition to starch accumulation occurred after plastid endosymbiosis from a preexisting cytosolic host glycogen metabolism network. This involved the recruitment of a debranching enzyme of chlamydial pathogen origin. The latter is thought to be responsible for removing misplaced branches that would otherwise yield a water-soluble polysaccharide. We now report the implication of starch debranching enzyme in the aggregation of semicrystalline granules of single-cell cyanobacteria that accumulate both glycogen and starch-like polymers. We show that an enzyme of analogous nature to the plant debranching enzyme but of a different bacterial origin was recruited for the same purpose in these organisms. Remarkably, both the plant and cyanobacterial enzymes have evolved through convergent evolution, showing novel yet identical substrate specificities from a preexisting enzyme that originally displayed the much narrower substrate preferences required for glycogen catabolism. PMID- 24163314 TI - Border patrol on the extrahaustorial membrane: Arabidopsis resistance protein RPW8.2 activates targeted, postpenetration defenses. PMID- 24163313 TI - Nonsense-mediated decay of alternative precursor mRNA splicing variants is a major determinant of the Arabidopsis steady state transcriptome. AB - The nonsense-mediated decay (NMD) surveillance pathway can recognize erroneous transcripts and physiological mRNAs, such as precursor mRNA alternative splicing (AS) variants. Currently, information on the global extent of coupled AS and NMD remains scarce and even absent for any plant species. To address this, we conducted transcriptome-wide splicing studies using Arabidopsis thaliana mutants in the NMD factor homologs UP FRAMESHIFT1 (UPF1) and UPF3 as well as wild-type samples treated with the translation inhibitor cycloheximide. Our analyses revealed that at least 17.4% of all multi-exon, protein-coding genes produce splicing variants that are targeted by NMD. Moreover, we provide evidence that UPF1 and UPF3 act in a translation-independent mRNA decay pathway. Importantly, 92.3% of the NMD-responsive mRNAs exhibit classical NMD-eliciting features, supporting their authenticity as direct targets. Genes generating NMD-sensitive AS variants function in diverse biological processes, including signaling and protein modification, for which NaCl stress-modulated AS-NMD was found. Besides mRNAs, numerous noncoding RNAs and transcripts derived from intergenic regions were shown to be NMD responsive. In summary, we provide evidence for a major function of AS-coupled NMD in shaping the Arabidopsis transcriptome, having fundamental implications in gene regulation and quality control of transcript processing. PMID- 24163316 TI - Silfverskiold's test in total ankle replacement with gastrocnemius recession. AB - BACKGROUND: For patients undergoing primary total ankle replacement (TAR) with an equinus contracture, gastrocnemius recession may be performed to increase dorsiflexion. We examined whether gastrocnemius recession would significantly increase dorsiflexion even with a negative Silfverskiold test. METHODS: Data were prospectively collected on a consecutive series of 29 patients who underwent TAR. All were deemed to require lengthening of the posterior soft tissue structures for unacceptable equinus contracture. Once each patient was under anesthesia, Silfverskiold's test was performed. A digital photograph was taken with the ankle at maximum passive dorsiflexion with the knee at 0 degrees of flexion and again with the knee at 30 degrees of flexion. Strayer gastrocnemius recession was then performed in standard fashion in every patient. After recession, Silfverskiold's test was again performed with photographs obtained in the same manner. The digital photographs demonstrating the results of the preoperative and postoperative Silfverskiold's tests in both knee positions were analyzed and the degree of ankle dorsiflexion measured. RESULTS: Regardless of the results of Silfverskiold's test, after gastrocnemius recession, patients had an average increase of 12.6 +/- 1.6 degrees of dorsiflexion with the knee extended compared to the same position preoperatively (P < .0001) and an increase of 10.1 +/- 2.0 degrees with the knee flexed (P < .001). In 6 patients Silfverskiold's test was markedly positive preoperatively; in this group, recession resulted in an average increase of dorsiflexion of 17.8 +/- 3.6 degrees with the knee extended (P = .004) and 13.4 +/- 5.4 degrees with the knee flexed (P = .055). For the remaining 23 patients with a negative preoperative Silfverskiold's test, dorsiflexion increased by 11.3 +/- 1.6 (P < .0001) and 9.3 +/- 2.2 degrees (P = .0003) with the knee extended and flexed, respectively. CONCLUSION: Our data show that a gastrocnemius recession resulted in a significant, reproducible increase in dorsiflexion regardless of the results of the Silfverskiold test while avoiding potential push-off and plantarflexion weakness associated with an Achilles lengthening. LEVEL OF EVIDENCE: Level IV, case series. PMID- 24163317 TI - Ultrasound morphology of the Achilles in asymptomatic patients with and without diabetes. AB - BACKGROUND: The prevalence of tendinopathies is increased in subjects with diabetes mellitus. However, there are few data on the structural abnormalities of Achilles tendons in asymptomatic diabetic patients. The aim of the study was to assess the morphologic characteristics of the Achilles tendon in subjects with diabetes in comparison with controls without diabetes. METHODS: Participants were consecutively recruited from an outpatient population. Ultrasound longitudinal and transverse scans were performed bilaterally along the full length of Achilles tendon from the musculotendinous junction to the insertion. Degenerative features (abnormal fibrillar pattern, hypo-hyperechoic areas), signs of enthesopathy (bony erosion, enthesophytes, and bursitis), and intratendinous neovessel formation were recorded. RESULTS: Asymptomatic sonographic abnormalities (ASA) were significantly increased in subjects with diabetes (35/136 [25.7%] vs 32/273 [11.7%], P = .0003). Sixty tendons with ASA were observed in the first group and 45 in the latter because ASA were bilateral in 25 and in 13 subjects, respectively. ASA were more frequently localized at the enthesis (32/60 [53.3%] vs 9/45 [20%], P = .0005) in the diabetes group, whereas, on the contrary, they were more prevalent at the midportion in controls (38/45 [84.4%] vs 36/60 [60%], P < .006). CONCLUSION: Diabetes may predispose to Achilles tendinopathy and particularly to Achilles enthesopathy. Longitudinal studies, evaluating the progression of the lesions not only in the midportion of the tendon but also at the insertion are needed to support this conclusion. LEVEL OF EVIDENCE: Level III, comparative series. PMID- 24163315 TI - The Arabidopsis eukaryotic translation initiation factor eIF5A-2 regulates root protoxylem development by modulating cytokinin signaling. AB - The phytohormone cytokinin regulates various aspects of plant growth and development, including root vascular development. In Arabidopsis thaliana, mutations in the cytokinin signaling components cause misspecification of protoxylem cell files. Auxin antagonizes cytokinin-regulated root protoxylem differentiation by inducing expression of Arabidopsis phosphotransfer protein6 (AHP6), a negative regulator of cytokinin signaling. However, the molecular mechanism of cytokinin-regulated protoxylem differentiation is not fully understood. Here, we show that a mutation in Arabidopsis fumonisin B1-resistant12 (FBR12), which encodes a eukaryotic translation initiation factor 5A, causes defective protoxylem development and reduced sensitivity to cytokinin. FBR12 genetically interacts with the cytokinin receptor cytokinin response1 (CRE1) and downstream AHP genes, as double mutants show enhanced phenotypes. FBR12 forms a protein complex with CRE1 and AHP1, and cytokinin regulates formation of this protein complex. Intriguingly, ahp6 partially suppresses the fbr12 mutant phenotype, and the fbr12 mutation causes increased expression of AHP6, indicating that FBR12 negatively regulates AHP6. Consistent with this, ectopic expression of FBR12 in the CRE1-expressing domain partially rescues defective protoxylem development in fbr12, and overexpression of AHP6 causes an fbr12-like phenotype. These results define a regulatory role of the highly conserved FBR12 in cytokinin mediated root protoxylem specification. PMID- 24163318 TI - Trace elements in parenteral nutrition: a practical guide for dosage and monitoring for adult patients. AB - Parenteral nutrition (PN) is a life-sustaining therapy for hundreds of thousands of people who have severe impairment of gastrointestinal function. Trace elements are a small but very important part of PN that can be overlooked during busy practice. Serious complications can result from trace element deficiencies and toxicities, and this is especially problematic during times of product shortages. Practical information on parenteral trace element use can be gleaned from case reports, some retrospective studies, and very few randomized controlled trials. A general knowledge of trace element metabolism and excretion, deficiency and toxicity symptoms, products, optimal dosages, and strategies for supplementation, restriction, and monitoring will equip practitioners to provide optimal care for their patients who depend on PN. PMID- 24163320 TI - Nutrition management for the promotion of growth in very low birth weight premature infants. AB - Premature infants are highly susceptible to extrauterine growth restriction. Without early and adequate nutrition support, nutrition deficits of energy and protein can quickly accrue. Growth failure has been implicated in poor neurodevelopmental outcomes and long-term morbidity, creating a major focus on neonatal nutrition alongside medical management. Optimal nutrition is paramount for optimal growth outcomes. The purpose of this article is to review the implications and long-term effects of growth failure in premature infants, specifically, those with very low birth weights. In addition, nutrition interventions and treatments will be presented to manage and improve growth outcomes of the neonate. PMID- 24163321 TI - Nutrient deficiencies associated with nutrition-focused physical findings of the oral cavity. AB - Conducting nutrition-focused physical examinations and reporting the findings from the perspective of nutrition status strengthen the practitioner's assessments, interventions, and monitoring. The nutrition-focused physical examination of the oral cavity is particularly useful to identify nutrient deficiencies early and with accuracy as the tissues in the oral mucosa have a turnover rate of <1 week. As biomarkers may not always be reliable for identifying micronutrient deficiencies, these physical examinations are important for providing comprehensive nutrition care. The purpose of this article is to discuss the methods of conducting a nutrition-focused oral screening examination and compile and document the evidence regarding the effects of micronutrient deficiencies on the oral mucosa. The information is formatted into a table that can be used as a tool when conducting an oral screening by identifying possible deficiencies based on the observations and other relevant findings. The tool will also guide the practitioner in confirming the physical findings, suggesting interventions to treat the deficiency and how to monitor the outcomes. PMID- 24163319 TI - The role of dietary protein intake in the prevention of sarcopenia of aging. AB - Sarcopenia is defined as an age-related decrease in muscle mass and performance. Several consensus definitions of sarcopenia exist, each providing different cut points and methodologies for assessing muscle mass and muscle strength. Thus, wide variation in the prevalence of sarcopenia has been reported, generally ranging up to 45% for men and 26% for women. Risk factors for sarcopenia include age, malnutrition, and physical inactivity. Additional evidence suggests a protective role for protein supplementation in older adults to preserve lean body mass and prevent frailty, accepted intervention targets for reducing the risk of sarcopenia. Protein supplements vary widely in their composition, and small trials of heterogeneous study designs have made it difficult to extrapolate findings to develop data-driven, evidence-based recommendations for protein supplementation in sarcopenia prevention. Short-term randomized controlled trials of muscle protein synthesis have demonstrated that whey protein increases synthesis more so than casein or soy isolates. Studies also suggest that essential amino acids stimulate muscle protein synthesis to a greater extent than nonessential amino acids. This review summarizes the epidemiological and clinical trial evidence establishing the current definitions for sarcopenia and provides an overview of the state of the evidence for protein supplementation to prevent and/or mitigate sarcopenia. PMID- 24163322 TI - Inadvertent exaggerated anticoagulation following use of bismuth subsalicylate in an enterally fed patient receiving warfarin therapy. AB - We report a case of an inadvertent increase in the international normalized ratio (INR) after the addition of bismuth subsalicylate for the treatment of diarrhea in an enterally fed patient receiving warfarin therapy. A 56-year-old Caucasian female presented to the trauma intensive care unit (ICU) with multiple lower extremity fractures. Warfarin was initiated for deep vein thrombosis prophylaxis due to the patient's inability to ambulate. The target INR was 2-3. Continuous intragastric enteral feeding was withheld 1 hour before and 1 hour after intragastric administration of warfarin. Bismuth subsalicylate 30 mL every 4 hours was prescribed for diarrhea. Within 3 days after starting bismuth subsalicylate therapy, the patient's INR increased from 2.56 to 3.54 and minor bleeding was noted from the patient's tracheostomy site. No significant change in warfarin dosage, variability in vitamin K intake, or medications that potentially alter warfarin metabolism were present during the unexpected rise in INR. When the bismuth subsalicylate was discontinued, the patient's INR stabilized into the target range on the same warfarin dose given at the time of the supratherapeutic INR. Salicylate displaces warfarin from plasma protein binding sites and may result in a significant increase in INR secondary to redistribution of warfarin to the free active form. Evaluation of this case report using the Drug Interaction Probability Scale and Naranjo Adverse Drug Reaction Probability Scale yielded scores consistent with a probable adverse drug interaction. Bismuth subsalicylate exaggerates warfarin's anticoagulant response and its concurrent use during warfarin therapy should be avoided. PMID- 24163324 TI - Protection of parathyroid function using carbon nanoparticles during thyroid surgery. AB - OBJECTIVE: To investigate the hypothesis that injected carbon nanoparticle (CN) suspension helps identify parathyroid glands (PGs) during thyroid cancer surgery, thereby reducing PG injury. STUDY DESIGN: A prospective, randomized controlled trial. Setting Sun Yet-san Memorial Hospital, Guangzhou, China. SUBJECTS AND METHODS: Thyroid cancer surgeries were performed on 72 consenting patients who were randomized for conventional surgery (control group) or surgery with CN suspension injection (CN group). The primary end point was the prevalence of symptomatic hypocalcemia and serum calcium levels <1.9 mmol/L. RESULTS: From 36 patients diagnosed with thyroid cancer in each group, symptomatic hypocalcemia was found in 10 patients without CN injection and 3 patients with CN suspension injection (P = .032). In total, 5.6% of patients in the CN group presented with muscle cramps compared with 22.2% of the control group (P = .041), which showed a significant difference. CONCLUSION: Our randomized study revealed that CN suspension injection was feasible and appeared to be beneficial for patients undergoing thyroid surgery because the incidence of symptomatic hypocalcemia was lower compared with controls. Therefore, this technology and technique should be more widely considered for thyroid cancer therapy. Additional studies with more patients and longer follow-up times will be needed for a thorough evaluation of this methodology. PMID- 24163323 TI - A conserved apomixis-specific polymorphism is correlated with exclusive exonuclease expression in premeiotic ovules of apomictic boechera species. AB - Apomixis (asexual seed production) is characterized by meiotically unreduced egg cell production (apomeiosis) followed by its parthenogenetic development into offspring that are genetic clones of the mother plant. Fertilization (i.e. pseudogamy) of the central cell is important for the production of a functional endosperm with a balanced 2:1 maternal:paternal genome ratio. Here, we present the APOLLO (for apomixis-linked locus) gene, an Aspartate Glutamate Aspartate Aspartate histidine exonuclease whose transcripts are down-regulated in sexual ovules entering meiosis while being up-regulated in apomeiotic ovules at the same stage of development in plants of the genus Boechera. APOLLO has both "apoalleles," which are characterized by a set of linked apomixis-specific polymorphisms, and "sexalleles." All apomictic Boechera spp. accessions proved to be heterozygous for the APOLLO gene (having at least one apoallele and one sexallele), while all sexual genotypes were homozygous for sexalleles. Apoalleles contained a 20-nucleotide polymorphism present in the 5' untranslated region that contains specific transcription factor-binding sites for ARABIDOPSIS THALIANA HOMEOBOX PROTEIN5, LIM1 (for LINEAGE ABNORMAL11, INSULIN1, MECHANOSENSORY PROTEIN3), SORLIP1AT (for SEQUENCES OVERREPRESENTED IN LIGHT-INDUCED PROMOTERS IN ARABIDOPSIS THALIANA1), SORLIP2AT, and POLYA SIGNAL1. In the same region, sexalleles contain transcription factor-binding sites for DNA BINDING WITH ONE FINGER2, DNA BINDING WITH ONE FINGER3, and PROLAMIN BOX-BINDING FACTOR. Our results suggest that the expression of a single deregulated allele could induce the cascade of events leading to asexual female gamete formation in an apomictic plant. PMID- 24163325 TI - Applying process mapping and analysis as a quality improvement strategy to increase the adoption of fruit, vegetable, and water breaks in Australian primary schools. AB - Over the past decade, public health policy in Australia has prioritized the prevention and control of obesity and invested in programs that promote healthy eating-related behaviors, which includes increasing fruit and vegetable consumption in children. This article reports on a study that used process mapping and analysis as a quality improvement strategy to improve the delivery of a nutrition primary prevention program delivered in primary schools in New South Wales, Australia. Crunch&Sip(r) has been delivered since 2008. To date, adoption is low with only 25% of schools implementing the program. We investigated the cause of low adoption and propose actions to increase school participation. We conducted semistructured interviews with key stakeholders and analyzed the process of delivering Crunch&Sip to schools. Interviews and process mapping and analysis identified a number of barriers to schools adopting the program. The analyses identified the need to simplify and streamline the process of delivering the program to schools and introduce monitoring and feedback loops to track ongoing participation. The combination of stakeholder interviews and process mapping and analysis provided important practical solutions to improving program delivery and also contributed to building an understanding of factors that help and hinder program adoption. The insight provided by this analysis helped identify usable routine measures of adoption, which were an improvement over those used in the existing program plan. This study contributed toward improving the quality and efficiency of delivering a health promoting program to work toward achieving healthy eating behaviors in children. PMID- 24163326 TI - Gender differences in the use of drug resistance strategies: an analysis of rural Asian/Pacific Islander youth. AB - This study examines gender differences in the use of drug resistance strategies for rural Asian/Pacific Islander youth. Multiethnic Asian/Pacific Islander youth (N = 213) from six middle/intermediate schools on the Island of Hawai'i participated in the study, and gender differences in their real-world use of specific strategies (e.g., refuse, explain, avoid, leave) were examined. Despite similar levels of exposure to situations where drugs and/or alcohol were offered, girls indicated significantly lower usage of most of the resistance strategies compared to boys, suggesting girls' increased risk in dealing with drug-related problem situations. Implications for gender-and culture-specific health promotion and drug prevention curricula are discussed. PMID- 24163327 TI - Attenuated Readiness Potential in the Absence of Executive Dysfunction in Adults With ADHD. AB - OBJECTIVE: Patients with ADHD display a decreased contingent negative variation in Go/NoGo tasks. It is unclear whether the attenuation is due to deficits of executive function or to disorder of motor planning. The readiness potential (RP) recorded during self-initiated movements could cast light on this question. METHOD: RP was recorded in 25 stably medicated adult ADHD patients and 21 healthy controls matched for age, education, and verbal IQ. Participants also completed neuropsychological tests of executive function. RESULTS: Compared with healthy controls, ADHD patients showed significantly diminished RP peaks and also decreased negativity in preparation of the movement at frontal locations. There were no significant group differences with regard to tests of executive function. CONCLUSION: In adults with ADHD, deficits of motor organization are also manifest in situations not involving external stimulus processing. The attenuated RP occurred in the absence of executive dysfunction. Results are consistent with partial independence between motor and executive dysfunction in ADHD. PMID- 24163329 TI - Time to abandon Evidence Based Medicine? PMID- 24163328 TI - Validation of the activPAL activity monitor in children with hemiplegic gait patterns resultant from cerebral palsy. AB - BACKGROUND: Current investigation of treatment outcomes by clinicians is currently hampered by a lack of clinically viable tools. The use of activity monitors specifically validated for a population could help resolve this situation. OBJECTIVES: The purpose of the study was to validate an activity monitor for monitoring children with cerebral palsy. The study was designed to validate the duration of time spent sitting, standing and walking and the number of steps taken when being measured by the activPAL activity monitor. STUDY DESIGN: A validation study was undertaken. METHODS: Observations of participants were carried out while completing a specifically designed activity course using video footage, which were then compared to the output from the activity monitor. RESULTS: The activity monitor was found to be valid for the time spent standing and walking, the number of steps taken and the number of transitions. CONCLUSIONS: The results demonstrated that the monitor may prove useful to clinicians as a measurement outcome device for children with hemiplegic gait patterns resultant from cerebral palsy. However, the sensitivity of the device is variable, and further investigations are necessary to confirm it would also be able to detect minor changes after interventions. CLINICAL RELEVANCE: The monitor may provide clinicians with a simplistic tool that is easily utilised, to enable audit exercises of current and future treatments. PMID- 24163330 TI - Development of poly(N-isopropylacrylamide)/alginate copolymer hydrogel-grafted fabrics embedding of berberine nanosuspension for the infected wound treatment. AB - In the present study, a novel hydrogel-grafted fabrics embedding of berberine nanosuspension was developed for the treatment of infected wound. Hydrogel grafted fabric was prepared by graft copolymerization of N-isopropylacrylamide and alginate using ceric ammonium nitrate as initiator. Berberine nanosuspension was prepared and embedded in the hydrogel-grafted fabrics to achieve sustained drug release. The prepared hydrogel-grafted fabrics embedding of berberine nanosuspension was characterized by FT-IR spectroscopy, scanning electron microscopy, and swelling degree studies. Fourier transform infrared spectroscopy revealed that berberine was embedded into the matrix of hydrogel-grafted fabrics, rather than on the surface. Scanning electron microscopy showed that a thin hydrogel layer was formed on the surface of nonwoven fibers. The swelling study showed that hydrogel-grafted fabric had water absorbing characteristic with reversible temperature sensitivity. The drug release study demonstrated that hydrogel-grafted fabrics can be used as a sustained drug delivery system of hydrophobic compounds. The berberine nanosuspension embedded hydrogel-grafted fabric was further investigated in an animal infected wound model and was found to be a very promising wound healing dressing for the treatment and healing of infected wounds. PMID- 24163331 TI - A slow-release fibrin matrix increases adeno-associated virus transduction of wound repair cells in vivo. AB - Virus-mediated gene therapy is a promising strategy for numerous tissue engineering applications. Fibrin-based scaffolds have been previously used as vehicles for localised delivery of adenovirus to wound sites. However, their utility in the delivery of adeno-associated viruses to wound repair cells has not yet been determined. The influence of fibrin concentration on efficacy of delivery of AAV-2 to wound tissue was assessed in this study. Fibrin scaffolds containing recombinant AAV-2 encoding for beta-galactosidase were polymerised in porous polyurethane discs and implanted subcutaneously in rats. A fibrin scaffold with a concentration of 50 mg/ml showed significantly elevated levels of beta galactosidase activity within explanted discs at 10 days compared to 10 mg/ml and 25 mg/ml fibrin. These findings inform efforts to optimise biodegradable scaffolds for the localised delivery of AAV in tissue engineering. PMID- 24163332 TI - Human mesenchymal stem cells response to multi-doped silicon-strontium calcium phosphate coatings. AB - The search for apatitic calcium phosphate coatings to improve implants osteointegration is, nowadays, preferentially focused in the obtaining of compositions closer to that of the inorganic phase of bone. Silicon and strontium are both present in trace concentrations in natural bone and have been demonstrated, by separate, to significantly improve osteoblastic response on calcium phosphate bioceramics. This work aims the controlled and simultaneous multi-doping of carbonated calcium phosphate coatings with both elements, Si and Sr, by pulsed laser deposition technique and the biological response of human mesenchymal stem cells to them. A complete physicochemical characterization has been also performed to analyze the coatings and significant positive effect was obtained at the osteogenic differentiation of cells, confirming the enormous potential of this multi-doping coating approach. PMID- 24163333 TI - Hierarchical encoding makes individuals in a group seem more attractive. AB - In the research reported here, we found evidence of the cheerleader effect-people seem more attractive in a group than in isolation. We propose that this effect arises via an interplay of three cognitive phenomena: (a) The visual system automatically computes ensemble representations of faces presented in a group, (b) individual members of the group are biased toward this ensemble average, and (c) average faces are attractive. Taken together, these phenomena suggest that individual faces will seem more attractive when presented in a group because they will appear more similar to the average group face, which is more attractive than group members' individual faces. We tested this hypothesis in five experiments in which subjects rated the attractiveness of faces presented either alone or in a group with the same gender. Our results were consistent with the cheerleader effect. PMID- 24163335 TI - Inefficient translation renders the Enterococcus faecalis fabK enoyl-acyl carrier protein reductase phenotypically cryptic. AB - Enoyl-acyl carrier protein (ACP) reductase catalyzes the last step of the bacterial fatty acid elongation cycle. Enterococcus faecalis is unusual in that it encodes two unrelated enoyl-ACP reductases, FabI and FabK. We recently reported that deletion of the gene encoding FabI results in an unsaturated fatty acid (UFA) auxotroph despite the presence of fabK, a gene encoding a second fully functional enoyl-ACP reductase. By process of elimination, our prior report argued that poor expression was the reason that fabK failed to functionally replace FabI. We now report that FabK is indeed poorly expressed and that the expression defect is at the level of translation rather than transcription. We isolated four spontaneous mutants that allowed growth of the E. faecalis DeltafabI strain on fatty acid-free medium. Each mutational lesion (single base substitution or deletion) extended the fabK ribosome binding site. Inactivation of fabK blocked growth, indicating that the mutations acted only on fabK rather than a downstream gene. The mutations activated fabK translation to levels that supported fatty acid synthesis and hence cell growth. Furthermore, site-directed and random mutagenesis experiments showed that point mutations that resulted in increased complementarity to the 3' end of the 16S rRNA increased FabK translation to levels sufficient to support growth, whereas mutations that decreased complementarity blocked fabK translation. PMID- 24163334 TI - A moderate toxin, GraT, modulates growth rate and stress tolerance of Pseudomonas putida. AB - Chromosomal toxin-antitoxin (TA) systems are widespread among free-living bacteria and are supposedly involved in stress tolerance. Here, we report the first TA system identified in the soil bacterium Pseudomonas putida. The system, encoded by the loci PP1586-PP1585, is conserved in pseudomonads and belongs to the HigBA family. The new TA pair was named GraTA for the growth rate-affecting ability of GraT and the antidote activity of GraA. The GraTA system shares many features common to previously described type II TA systems. The overexpression of GraT is toxic to the antitoxin deletion mutants, since the toxin's neutralization is achieved by binding of the antitoxin. Also, the graTA operon structure and autoregulation by antitoxin resemble those of other TA loci. However, we were able to delete the antitoxin gene from the chromosome, which shows the unusually mild toxicity of innate GraT compared to previously described toxins. Furthermore, GraT is a temperature-dependent toxin, as its growth-regulating effect becomes more evident at lower temperatures. Besides affecting the growth rate, GraT also increases membrane permeability, resulting in higher sensitivity to some chemicals, e.g., NaCl and paraquat. Nevertheless, the active toxin helps the bacteria survive under different stressful conditions and increases their tolerance to several antibiotics, including streptomycin, kanamycin, and ciprofloxacin. Therefore, our data suggest that GraT may represent a new class of mild chromosomal regulatory toxins that have evolved to be less harmful to their host bacterium. Their moderate toxicity might allow finer growth and metabolism regulation than is possible with strong growth-arresting or bactericidal toxins. PMID- 24163336 TI - RfaH suppresses small RNA MicA inhibition of fimB expression in Escherichia coli K-12. AB - The phase variation (reversible on-off switching) of the type 1 fimbrial adhesin of Escherichia coli involves a DNA inversion catalyzed by FimB (switching in either direction) or FimE (on-to-off switching). Here, we demonstrate that RfaH activates expression of a FimB-LacZ protein fusion while having a modest inhibitory effect on a comparable fimB-lacZ operon construct and on a FimE-LacZ protein fusion, indicating that RfaH selectively controls fimB expression at the posttranscriptional level. Further work demonstrates that loss of RfaH enables small RNA (sRNA) MicA inhibition of fimB expression even in the absence of exogenous inducing stress. This effect is explained by induction of sigma(E), and hence MicA, in the absence of RfaH. Additional work confirms that the procaine dependent induction of micA requires OmpR, as reported previously (A. Coornaert et al., Mol. Microbiol. 76:467-479, 2010, doi:10.1111/j.1365-2958.2010.07115.x), but also demonstrates that RfaH inhibition of fimB transcription is enhanced by procaine independently of OmpR. While the effect of procaine on fimB transcription is shown to be independent of RcsB, it was found to require SlyA, another known regulator of fimB transcription. These results demonstrate a complex role for RfaH as a regulator of fimB expression. PMID- 24163337 TI - Comparative metabolic systems analysis of pathogenic Burkholderia. AB - Burkholderia cenocepacia and Burkholderia multivorans are opportunistic drug resistant pathogens that account for the majority of Burkholderia cepacia complex infections in cystic fibrosis patients and also infect other immunocompromised individuals. While they share similar genetic compositions, B. cenocepacia and B. multivorans exhibit important differences in pathogenesis. We have developed reconciled genome-scale metabolic network reconstructions of B. cenocepacia J2315 and B. multivorans ATCC 17616 in parallel (designated iPY1537 and iJB1411, respectively) to compare metabolic abilities and contextualize genetic differences between species. The reconstructions capture the metabolic functions of the two species and give insight into similarities and differences in their virulence and growth capabilities. The two reconstructions have 1,437 reactions in common, and iPY1537 and iJB1411 have 67 and 36 metabolic reactions unique to each, respectively. After curating the extensive reservoir of metabolic genes in Burkholderia, we identified 6 genes essential to growth that are unique to iPY1513 and 13 genes uniquely essential to iJB1411. The reconstructions were refined and validated by comparing in silico growth predictions to in vitro growth capabilities of B. cenocepacia J2315, B. cenocepacia K56-2, and B. multivorans ATCC 17616 on 104 carbon sources. Overall, we identified functional pathways that indicate B. cenocepacia can produce a wider array of virulence factors compared to B. multivorans, which supports the clinical observation that B. cenocepacia is more virulent than B. multivorans. The reconciled reconstructions provide a framework for generating and testing hypotheses on the metabolic and virulence capabilities of these two related emerging pathogens. PMID- 24163338 TI - Characterization of two members among the five ADP-forming acyl coenzyme A (Acyl CoA) synthetases reveals the presence of a 2-(Imidazol-4-yl)acetyl-CoA synthetase in Thermococcus kodakarensis. AB - The genome of Thermococcus kodakarensis, along with those of most Thermococcus and Pyrococcus species, harbors five paralogous genes encoding putative alpha subunits of nucleoside diphosphate (NDP)-forming acyl coenzyme A (acyl-CoA) synthetases. The substrate specificities of the protein products for three of these paralogs have been clarified through studies on the individual enzymes from Pyrococcus furiosus and T. kodakarensis. Here we have examined the biochemical properties of the remaining two acyl-CoA synthetase proteins from T. kodakarensis. The TK0944 and TK2127 genes encoding the two alpha subunits were each coexpressed with the beta subunit-encoding TK0943 gene. In both cases, soluble proteins with an alpha2beta2 structure were obtained and their activities toward various acids in the ADP-forming reaction were examined. The purified TK0944/TK0943 protein (ACS IIITk) accommodated a broad range of acids that corresponded to those generated in the oxidative metabolism of Ala, Val, Leu, Ile, Met, Phe, and Cys. In contrast, the TK2127/TK0943 protein exhibited relevant levels of activity only toward 2-(imidazol-4-yl)acetate, a metabolite of His degradation, and was thus designated 2-(imidazol-4-yl)acetyl-CoA synthetase (ICSTk), a novel enzyme. Kinetic analyses were performed on both proteins with their respective substrates. In T. kodakarensis, we found that the addition of histidine to the medium led to increases in intracellular ADP-forming 2-(imidazol 4-yl)acetyl-CoA synthetase activity, and 2-(imidazol-4-yl)acetate was detected in the culture medium, suggesting that ICSTk participates in histidine catabolism. The results presented here, together with those of previous studies, have clarified the substrate specificities of all five known NDP-forming acyl-CoA synthetase proteins in the Thermococcales. PMID- 24163339 TI - Analysis of SOS-induced spontaneous prophage induction in Corynebacterium glutamicum at the single-cell level. AB - The genome of the Gram-positive soil bacterium Corynebacterium glutamicum ATCC 13032 contains three integrated prophage elements (CGP1 to -3). Recently, it was shown that the large lysogenic prophage CGP3 (~187 kbp) is excised spontaneously in a small number of cells. In this study, we provide evidence that a spontaneously induced SOS response is partly responsible for the observed spontaneous CGP3 induction. Whereas previous studies focused mainly on the induction of prophages at the population level, we analyzed the spontaneous CGP3 induction at the single-cell level using promoters of phage genes (Pint2 and Plysin) fused to reporter genes encoding fluorescent proteins. Flow-cytometric analysis revealed a spontaneous CGP3 activity in about 0.01 to 0.08% of the cells grown in standard minimal medium, which displayed a significantly reduced viability. A PrecA-eyfp promoter fusion revealed that a small fraction of C. glutamicum cells (~0.2%) exhibited a spontaneous induction of the SOS response. Correlation of PrecA to the activity of downstream SOS genes (PdivS and PrecN) confirmed a bona fide induction of this stress response rather than stochastic gene expression. Interestingly, the reporter output of PrecA and CGP3 promoter fusions displayed a positive correlation at the single-cell level (rho = 0.44 to 0.77). Furthermore, analysis of the PrecA-eyfp/Pint2-e2-crimson strain during growth revealed the highest percentage of spontaneous PrecA and Pint2 activity in the early exponential phase, when fast replication occurs. Based on these studies, we postulate that spontaneously occurring DNA damage induces the SOS response, which in turn triggers the induction of lysogenic prophages. PMID- 24163340 TI - Growth phase and pH influence peptide signaling for competence development in Streptococcus mutans. AB - The development of competence by the dental caries pathogen Streptococcus mutans is mediated primarily through the alternative sigma factor ComX (SigX), which is under the control of multiple regulatory systems and activates the expression of genes involved in DNA uptake and recombination. Here we report that the induction of competence and competence gene expression by XIP (sigX-inducing peptide) and CSP (competence-stimulating peptide) is dependent on the growth phase and that environmental pH has a potent effect on the responses to XIP. A dramatic decline in comX and comS expression was observed in mid- and late-exponential-phase cells. XIP-mediated competence development and responses to XIP were optimal around a neutral pH, although mid-exponential-phase cells remained refractory to XIP treatment, and acidified late-exponential-phase cultures were resistant to killing by high concentrations of XIP. Changes in the expression of the genes for the oligopeptide permease (opp), which appears to be responsible for the internalization of XIP, could not entirely account for the behaviors observed. Interestingly, comS and comX expression was highly induced in response to endogenously overproduced XIP or ComS in mid-exponential-phase cells. In contrast to the effects of pH on XIP, competence induction and responses to CSP in complex medium were not affected by pH, although a decreased response to CSP in cells that had exited early-exponential phase was observed. Collectively, these results indicate that competence development may be highly sensitive to microenvironments within oral biofilms and that XIP and CSP signaling in biofilms could be spatially and temporally heterogeneous. PMID- 24163341 TI - GTP dysregulation in Bacillus subtilis cells lacking (p)ppGpp results in phenotypic amino acid auxotrophy and failure to adapt to nutrient downshift and regulate biosynthesis genes. AB - The nucleotide (p)ppGpp inhibits GTP biosynthesis in the Gram-positive bacterium Bacillus subtilis. Here we examined how this regulation allows cells to grow in the absence of amino acids. We showed that B. subtilis cells lacking (p)ppGpp, due to either deletions or point mutations in all three (p)ppGpp synthetase genes, yjbM, ywaC, and relA, strongly require supplementation of leucine, isoleucine, valine, methionine, and threonine and modestly require three additional amino acids. This polyauxotrophy is rescued by reducing GTP levels. Reduction of GTP levels activates transcription of genes responsible for the biosynthesis of the five strongly required amino acids by inactivating the transcription factor CodY, which represses the ybgE, ilvD, ilvBHC-leuABCD, ilvA, ywaA, and hom-thrCB operons, and by a CodY-independent activation of transcription of the ilvA, ywaA, hom-thrCB, and metE operons. Interestingly, providing the eight required amino acids does not allow for colony formation of (p)ppGpp(0) cells when transitioning from amino acid-replete medium to amino acid limiting medium, and we found that this is due to an additional role that (p)ppGpp plays in protecting cells during nutrient downshifts. We conclude that (p)ppGpp allows adaptation to amino acid limitation by a combined effect of preventing death during metabolic transitions and sustaining growth by activating amino acid biosynthesis. This ability of (p)ppGpp to integrate a general stress response with a targeted reprogramming of gene regulation allows appropriate adaptation and is likely conserved among diverse bacteria. PMID- 24163342 TI - Mutational analysis of the P1 phosphorylation domain in Escherichia coli CheA, the signaling kinase for chemotaxis. AB - The histidine autokinase CheA functions as the central processing unit in the Escherichia coli chemotaxis signaling machinery. CheA receives autophosphorylation control inputs from chemoreceptors and in turn regulates the flux of signaling phosphates to the CheY and CheB response regulator proteins. Phospho-CheY changes the direction of flagellar rotation; phospho-CheB covalently modifies receptor molecules during sensory adaptation. The CheA phosphorylation site, His-48, lies in the N-terminal P1 domain, which must engage the CheA ATP binding domain, P4, to initiate an autophosphorylation reaction cycle. The docking determinants for the P1-P4 interaction have not been experimentally identified. We devised mutant screens to isolate P1 domains with impaired autophosphorylation or phosphotransfer activities. One set of P1 mutants identified amino acid replacements at surface-exposed residues distal to His-48. These lesions reduced the rate of P1 transphosphorylation by P4. However, once phosphorylated, the mutant P1 domains transferred phosphate to CheY at the wild type rate. Thus, these P1 mutants appear to define interaction determinants for P1-P4 docking during the CheA autophosphorylation reaction. PMID- 24163343 TI - Role of the CpxAR two-component signal transduction system in control of fosfomycin resistance and carbon substrate uptake. AB - Although fosfomycin is an old antibiotic, it has resurfaced with particular interest. The antibiotic is still effective against many pathogens that are resistant to other commonly used antibiotics. We have found that fosfomycin resistance of enterohemorrhagic Escherichia coli (EHEC) O157:H7 is controlled by the bacterial two-component signal transduction system CpxAR. A cpxA mutant lacking its phosphatase activity results in constitutive activation of its cognate response regulator, CpxR, and fosfomycin resistance. We have shown that fosfomycin resistance requires CpxR because deletion of the cpxR gene in the cpxA mutant restores fosfomycin sensitivity. We have also shown that CpxR directly represses the expression of two genes, glpT and uhpT, which encode transporters that cotransport fosfomycin with their native substrates glycerol-3-phosphate and glucose-6-phosphate, and repression of these genes leads to a decrease in fosfomycin transport into the cpxA mutant. However, the cpxA mutant had an impaired growth phenotype when cultured with glycerol-3-phosphate or glucose-6 phosphate as a sole carbon substrate and was outcompeted by the parent strain, even in nutrient-rich medium. This suggests a trade-off between fosfomycin resistance and the biological fitness associated with carbon substrate uptake. We propose a role for the CpxAR system in the reversible control of fosfomycin resistance. This may be a beneficial strategy for bacteria to relieve the fitness burden that results from fosfomycin resistance in the absence of fosfomycin. PMID- 24163344 TI - Liberate and grab it, ingest and digest it: the GbdR regulon of the pathogen Pseudomonas aeruginosa. AB - The compatible solute glycine betaine is a powerful osmostress protectant, but many microorganisms can also use it as a nutrient. K. J. Hampel et al. (J. Bacteriol. 196:7-15, 2014) defined a regulon in the notorious pathogen Pseudomonas aeruginosa that comprises modules for the harvest and import of the glycine betaine biosynthetic precursor choline and its subsequent catabolism to pyruvate. The reported data link the GbdR activator with the metabolism of host derived compounds (e.g., phosphocholine) and virulence traits of P. aeruginosa. PMID- 24163345 TI - The YmdB phosphodiesterase is a global regulator of late adaptive responses in Bacillus subtilis. AB - Bacillus subtilis mutants lacking ymdB are unable to form biofilms, exhibit a strong overexpression of the flagellin gene hag, and are deficient in SlrR, a SinR antagonist. Here, we report the functional and structural characterization of YmdB, and we find that YmdB is a phosphodiesterase with activity against 2',3' and 3',5'-cyclic nucleotide monophosphates. The structure of YmdB reveals that the enzyme adopts a conserved phosphodiesterase fold with a binuclear metal center. Mutagenesis of a catalytically crucial residue demonstrates that the enzymatic activity of YmdB is essential for biofilm formation. The deletion of ymdB affects the expression of more than 800 genes; the levels of the sigma(D) dependent motility regulon and several sporulation genes are increased, and the levels of the SinR-repressed biofilm genes are decreased, confirming the role of YmdB in regulating late adaptive responses of B. subtilis. PMID- 24163346 TI - A highly unstable transcript makes CwlO D,L-endopeptidase expression responsive to growth conditions in Bacillus subtilis. AB - The Bacillus subtilis cell wall is a dynamic structure, composed of peptidoglycan and teichoic acid, that is continually remodeled during growth. Remodeling is effected by the combined activities of penicillin binding proteins and autolysins that participate in the synthesis and turnover of peptidoglycan, respectively. It has been established that one or the other of the CwlO and LytE D,L-endopeptidase type autolysins is essential for cell viability, a requirement that is fulfilled by coordinate control of their expression by WalRK and SigI RsgI. Here we report on the regulation of cwlO expression. The cwlO transcript is very unstable, with its degradation initiated by RNase Y cleavage within the 187-nucleotide leader sequence. An antisense cwlO transcript of heterogeneous length is expressed from a SigB promoter that has the potential to control cellular levels of cwlO RNA and protein under stress conditions. We discuss how a multiplicity of regulatory mechanisms makes CwlO expression and activity responsive to the prevailing growth conditions. PMID- 24163347 TI - Quality of care in psychosis and bipolar disorder from the service user perspective. AB - According to the recovery model of mental health care, service development should incorporate the expert knowledge of service users. To date, there has been limited research into conceptualizations of mental health care quality among services users diagnosed with bipolar disorder or psychosis. To investigate service user perspectives on quality of care, we conducted six focus groups (N = 29) with inpatients and outpatients of an independent Irish mental health service. We undertook an inductive thematic analysis of the data. Participants identified proactive staff, meaningful and warm staff-patient interactions, and safety and sociability in the inpatient environment as components of good quality mental health care. Participants also discussed how the implementation of best practice guidelines does not necessarily improve quality of care from the service user perspective. This and similar qualitative research should be used to inform service development and the creation of evaluation instruments compatible with the recovery model. PMID- 24163350 TI - Intracellular pH reduction prevents excitotoxic and ischemic neuronal death by inhibiting NADPH oxidase. AB - Sustained activation of N-methyl-d-aspartate (NMDA) -type glutamate receptors leads to excitotoxic neuronal death in stroke, brain trauma, and neurodegenerative disorders. Superoxide production by NADPH oxidase is a requisite event in the process leading from NMDA receptor activation to excitotoxic death. NADPH oxidase generates intracellular H(+) along with extracellular superoxide, and the intracellular H(+) must be released or neutralized to permit continued NADPH oxidase function. In cultured neurons, NMDA induced superoxide production and neuronal death were prevented by intracellular acidification by as little as 0.2 pH units, induced by either lowered medium pH or by inhibiting Na(+)/H(+) exchange. In mouse brain, superoxide production induced by NMDA injections or ischemia-reperfusion was likewise prevented by inhibiting Na(+)/H(+) exchange and by reduced expression of the Na(+)/H(+) exchanger-1 (NHE1). Neuronal intracellular pH and neuronal Na(+)/H(+) exchange are thus potent regulators of excitotoxic superoxide production. These findings identify a mechanism by which cell metabolism can influence coupling between NMDA receptor activation and superoxide production. PMID- 24163353 TI - Correction for Ludescher et al., Improved El Nino forecasting by cooperativity detection. PMID- 24163352 TI - MicroRNA-directed program of cytotoxic CD8+ T-cell differentiation. AB - Acquisition of effector properties is a key step in the generation of cytotoxic T lymphocytes (CTLs). Here we show that inflammatory signals regulate Dicer expression in CTLs, and that deletion or depletion of Dicer in mouse or human activated CD8(+) T cells causes up-regulation of perforin, granzymes, and effector cytokines. Genome-wide analysis of microRNA (miR, miRNA) changes induced by exposure of differentiating CTLs to IL-2 and inflammatory signals identifies miR-139 and miR-150 as components of an miRNA network that controls perforin, eomesodermin, and IL-2Ralpha expression in differentiating CTLs and whose activity is modulated by IL-2, inflammation, and antigenic stimulation. Overall, our data show that strong IL-2R and inflammatory signals act through Dicer and miRNAs to control the cytolytic program and other aspects of effector CTL differentiation. PMID- 24163355 TI - Plasmonic antennas as design elements for coherent ultrafast nanophotonics. AB - Broadband excitation of plasmons allows control of light-matter interaction with nanometric precision at femtosecond timescales. Research in the field has spiked in the past decade in an effort to turn ultrafast plasmonics into a diagnostic, microscopy, computational, and engineering tool for this novel nanometric femtosecond regime. Despite great developments, this goal has yet to materialize. Previous work failed to provide the ability to engineer and control the ultrafast response of a plasmonic system at will, needed to fully realize the potential of ultrafast nanophotonics in physical, biological, and chemical applications. Here, we perform systematic measurements of the coherent response of plasmonic nanoantennas at femtosecond timescales and use them as building blocks in ultrafast plasmonic structures. We determine the coherent response of individual nanoantennas to femtosecond excitation. By mixing localized resonances of characterized antennas, we design coupled plasmonic structures to achieve well defined ultrafast and phase-stable field dynamics in a predetermined nanoscale hotspot. We present two examples of the application of such structures: control of the spectral amplitude and phase of a pulse in the near field, and ultrafast switching of mutually coherent hotspots. This simple, reproducible and scalable approach transforms ultrafast plasmonics into a straightforward tool for use in fields as diverse as room temperature quantum optics, nanoscale solid-state physics, and quantum biology. PMID- 24163356 TI - Genetics and the nephron. AB - There have been phenomenal advances in our understanding of renal biology over the last 20 years through our ability to define the genetic mutations causing kidney disease in children. This review will take you through a trip down the nephron and highlight how these conditions may present to the paediatrician and the molecular basis for their biological effects. PMID- 24163357 TI - Does radiation associated with diagnostic CT scans in children and young people increase their subsequent risk of developing cancer? PMID- 24163358 TI - Using data to improve care. AB - We look at the role of data in improving the quality of care for children and young people: how they can help to identify a problem; guide design of solutions; and evaluate changes in practice. We introduce some principles for measurement in the field of quality improvement, and discuss how to use and present data to maximise their value and impact in quality improvement initiatives. PMID- 24163360 TI - Across the high seas: abuse, desertion, and violence in transnational marriages in India. AB - This article examines the issues and concerns faced by Indian women in transnational marriages or what are popularly known as NRI marriages in India. It discusses how the Indian laws, the courts, and women try to deal with the difficulties and problems relating to issues of abuse, abandonment, and violence. It also highlights the inadequacies in laws and policies relating to such marriages in India. This article is complimentary to the article by Ann Stewart that concentrates on the "receiving" end of transnational marriages in the United Kingdom, and focuses on the ways in which the socio-legal context of the receiving State (in this case, the United Kingdom) presents difficulties for South Asian women. This article, conversely, takes a "sending" perspective, that is, the response of the home state, India, to the difficulties faced by Indian women involved in transnational marriages. PMID- 24163359 TI - Assessment of a short diabetes knowledge instrument for older and minority adults. AB - PURPOSE: The purpose of the study was to assess the performance of a Short Diabetes Knowledge Instrument (SDKI) in a large multi-ethnic sample of older adults with diabetes and to identify possible modifications to improve its ability to document diabetes knowledge. RESEARCH DESIGN AND METHODS: A sample of 593 African American, American Indian, and white female and male adults 60 years and older, with diabetes diagnosed at least 2 years prior, was recruited from 8 North Carolina counties. All completed an interview that included a 16-item questionnaire to assess diabetes knowledge. A subsample of 46 completed the questionnaire a second time at a subsequent interview. Item-response analysis was used to refine the instrument to well-performing items. The instrument consisting of the remaining items was subjected to analyses to assess validity and test retest reliability. RESULTS: Three items were removed after item-response analysis. Scores for the resulting instrument were lower among minority and older participants, as well as those with lower educational attainment and income. Scores for test-retest were highly correlated. CONCLUSIONS: The SDKI (13-item questionnaire) appears to be a valid and reliable instrument to evaluate knowledge about diabetes. Assessment in a multi-ethnic sample of older adults suggests that this instrument can be used to measure diabetes knowledge in diverse populations. Further evaluation is needed to determine whether or not this instrument can detect changes in knowledge resulting from diabetes education or other interventions. PMID- 24163361 TI - High-sensitivity troponin T as a biomarker for the development of atrial fibrillation after cardiac surgery. AB - OBJECTIVES: Atrial fibrillation (AF) occurs in ~ 30% of patients undergoing coronary artery bypass grafting (CABG) and in 40% of patients after valve surgery. High-sensitivity cardiac troponin T (hsTnT) is a specific and high sensitivity marker of myocardial injury, while N-terminal proB-type natriuretic peptide (NT-proBNP) is an established biomarker for wall remodelling. We investigated whether hsTnT and NT-proBNP levels could be used as valuable biomarkers for AF occurrence after cardiac surgery. METHODS: We included consecutive haemodynamically stable patients undergoing programmed cardiac surgery with cardiopulmonary bypass pump. We determined hsTnT and NT-proBNP levels before and after cardiac surgery and recorded AF development by prolonged electrocardiogram monitoring. RESULTS: We included 100 patients with predominantly aortic valve (n = 42) or ischaemic heart (n = 58) diseases. Twenty nine patients (29%) developed post-surgical AF. Patients developing AF had a longer hospital stay (P = 0.005). hsTnT levels increased after surgery [P < 0.001], indicating perioperative myocardial injury, with higher presurgery levels in patients who developed AF [P = 0.015]. Body mass index and EuroSCORE risk scale were independently associated with higher hsTnT levels presurgery. On univariate analysis, age (P = 0.048), male sex (P = 0.031), indexed left atrial volume (P = 0.042), beta-blockers treatment (P = 0.024), type of surgery (valve surgery vs CABG; P = 0.034), EuroSCORE risk scale (P = 0.025) and higher preoperative hsTnT levels (P = 0.009) were predictors of AF development, but NT proBNP did not reach statistical significance (P = 0.060). hsTnT levels in blood samples obtained the day after surgery were not associated with post-surgical AF development (P = 0.165). In a multivariate model, only higher hsTnT levels before cardiac surgery (>11.87 ng/l) [Odds Ratio, OR; (95% Confidence interval, CI) 4.27 (1.43-12.77), P = 0.009] and male sex [OR 5.10 (1.72-15.13), P = 0.003)] were independently associated with the occurrence of post-surgical AF. CONCLUSION: High presurgical hsTnT levels were independently predictive of patients developing AF after cardiac surgery. hsTnT levels determined post-surgery suggest that cardiac perioperative myocardial injury is not associated with postoperative AF development. NT-proBNP did not reach statistical significance as a biomarker for AF prediction. PMID- 24163362 TI - Extended recipients but not extended donors are associated with poor outcomes following lung transplantation. AB - OBJECTIVES: Extended donors (EDs) are safely used to increase the donor pool in lung transplantation (LT), but their influence in critically ill patients (extended recipients [ERs]) remains controversial. We compared LT outcomes matching optimal donors (ODs) or EDs with optimal recipients (ORs) or ERs. METHODS: Three hundred and sixty-five LTs were reviewed. ED criteria: age >55, PaO2/FiO2 < 350 mmHg, pulmonary infiltrates/purulent secretions and ischaemic times >6 h (single LT [SLT]) and >9 h (double LT [DLT]). ER criteria: pulmonary fibrosis or pulmonary hypertension, pretransplant intubation, age >60 years and bypass >2 h. Four groups were created: Group 1 (OD/OR), Group 2 (OD/ER), Group 3 (ED/OR) and Group 4 (ED/ER). Thirty-day mortality, primary graft dysfunction (PGD), onset of bronchiolitis obliterans syndrome (BOS), long-term survival and other transplant outcomes were compared between OD and ED, OR and ER and among the four groups of study. RESULTS: There were 151 SLTs and 214 DLTs. Donors: OD (n = 229) vs ED (n = 136); PGD 8 vs 10% (P = 0.43); 30-day mortality 19 vs 20% (P = 0.53) and survival (1, 5, 10 and 15 years) 67, 47, 34, 26 vs 69, 53, 46 and 29% (P = 0.33). Recipients: OR (n = 182) vs ER (n = 183); PGD 7 vs 10% (P = 0.10); 30 day mortality 15 vs 23% (P = 0.04) and survival (1, 5, 10 and 15 years): 73, 57, 46, 30 vs 61, 42, 29 and 23% (P = 0.002). Four donor/recipient (D/R) groups: Group 1 (n = 122), Group 2 (n = 106), Group 3 (n = 61), Group 4 (n = 76); PGD 10, 6, 3 and 16% (P = 0.05); 30-day mortality 13, 26, 19 and 20%, respectively (P = 0.13); survival (1, 5, 10 and 15 years) 74, 55, 44 and 35% (Group 1), 55, 39, 22 and 16% (Group 2), 70, 59, 48 and 26% (Group 3) and 68, 47, 37 and 22% (Group 4) (P = 0.004). No differences in the onset of BOS were observed among the four study groups. CONCLUSIONS: LT in critically ill recipients is associated with poor early and long-term outcomes, irrespective of the quality of the donor and length of ischaemic times. PMID- 24163363 TI - Down the ages, physicians have observed the evolution of disease over time. PMID- 24163364 TI - A positron emission tomography study of nigro-striatal dopaminergic mechanisms underlying attention: implications for ADHD and its treatment. AB - Through the combined use of (18)F-fallypride positron emission tomography and magnetic resonance imaging this study examined the neural mechanisms underlying the attentional deficits associated with attention deficit/hyperactivity disorder and their potential reversal with a single therapeutic dose of methylphenidate. Sixteen adult patients with attention deficit/hyperactivity disorder and 16 matched healthy control subjects were positron emission tomography and magnetic resonance imaging scanned and tested on a computerized sustained attention task after oral methylphenidate (0.5 mg/kg) and placebo administration in a within subject, double-blind, cross-over design. Although patients with attention deficit/hyperactivity disorder as a group showed significant attentional deficits and reduced grey matter volume in fronto-striato-cerebellar and limbic networks, they had equivalent D2/D3 receptor availability and equivalent increases in endogenous dopamine after methylphenidate treatment to that observed in healthy control subjects. However, poor attentional performers drawn from both the attention deficit/hyperactivity disorder and the control groups had significantly reduced left caudate dopamine activity. Methylphenidate significantly increased dopamine levels in all nigro-striatal regions, thereby normalizing dopamine levels in the left caudate in low performers. Behaviourally, methylphenidate improved sustained attention in a baseline performance-dependent manner, irrespective of diagnosis. This finding was accompanied by an equally performance dependent effect of the drug on dopamine release in the midbrain, whereby low performers showed reduced dopamine release in this region. Collectively, these findings support a dimensional model of attentional deficits and underlying nigro striatal dopaminergic mechanisms of attention deficit/hyperactivity disorder that extends into the healthy population. Moreover, they confer midbrain dopamine autoreceptors a hitherto neglected role in the therapeutic effects of oral methylphenidate in attention deficit/hyperactivity disorder. The absence of significant case-control differences in D2/D3 receptor availability (despite the observed relationships between dopamine activity and attention) suggests that dopamine dysregulation per se is unlikely to be the primary cause underlying attention deficit/hyperactivity disorder pathology in adults. This conclusion is reinforced by evidence of neuroanatomical changes in the same set of patients with attention deficit/hyperactivity disorder. PMID- 24163366 TI - Antibody uptake into neurons occurs primarily via clathrin-dependent Fcgamma receptor endocytosis and is a prerequisite for acute tau protein clearance. AB - Tau immunotherapy is effective in transgenic mice, but the mechanisms of Tau clearance are not well known. To this end, Tau antibody uptake was analyzed in brain slice cultures and primary neurons. Internalization was rapid (<1 h), saturable, and substantial compared with control mouse IgG. Furthermore, temperature reduction to 4 degrees C, an excess of unlabeled mouse IgG, or an excess of Tau antibodies reduced uptake in slices by 63, 41, and 62%, respectively (p = 0.002, 0.04, and 0.005). Uptake strongly correlated with total and insoluble Tau levels (r(2) = 0.77 and 0.87 and p = 0.002 and 0.0002), suggesting that Tau aggregates influence antibody internalization and/or retention within neurons. Inhibiting phagocytosis did not reduce uptake in slices or neuronal cultures, indicating limited microglial involvement. In contrast, clathrin-specific inhibitors reduced uptake in neurons (<= 78%, p < 0.0001) and slices (<= 35%, p = 0.03), demonstrating receptor-mediated endocytosis as the primary uptake pathway. Fluid phase endocytosis accounted for the remainder of antibody uptake in primary neurons, based on co-staining with internalized dextran. The receptor-mediated uptake is to a large extent via low affinity FcgammaII/III receptors and can be blocked in slices (43%, p = 0.04) and neurons (53%, p = 0.008) with an antibody against these receptors. Importantly, antibody internalization appears to be necessary for Tau reduction in primary neurons. Overall, these findings clarify that Tau antibody uptake is primarily receptor mediated, that these antibodies are mainly found in neurons with Tau aggregates, and that their intracellular interaction leads to clearance of Tau pathology, all of which have major implications for therapeutic development of this approach. PMID- 24163367 TI - Silencing of the tandem pore domain halothane-inhibited K+ channel 2 (THIK2) relies on combined intracellular retention and low intrinsic activity at the plasma membrane. AB - The tandem pore domain halothane-inhibited K(+) channel 1 (THIK1) produces background K(+) currents. Despite 62% amino acid identity with THIK1, THIK2 is not active upon heterologous expression. Here, we show that this apparent lack of activity is due to a unique combination of retention in the endoplasmic reticulum and low intrinsic channel activity at the plasma membrane. A THIK2 mutant containing a proline residue (THIK2-A155P) in its second inner helix (M2) produces K(+)-selective currents with properties similar to THIK1, including inhibition by halothane and insensitivity to extracellular pH variations. Another mutation in the M2 helix (I158D) further increases channel activity and affects current kinetics. We also show that the cytoplasmic amino-terminal region of THIK2 (Nt-THIK2) contains an arginine-rich motif (RRSRRR) that acts as a retention/retrieval signal. Mutation of this motif in THIK2 induces a relocation of the channel to the plasma membrane, resulting in measurable currents, even in the absence of mutations in the M2 helix. Cell surface delivery of a Nt-THIK2 CD161 chimera is increased by mutating the arginines of the retention motif but also by converting the serine embedded in this motif to aspartate, suggesting a phosphorylation-dependent regulation of THIK2 trafficking. PMID- 24163365 TI - The yeast anaerobic response element AR1b regulates aerobic antifungal drug dependent sterol gene expression. AB - Saccharomyces cerevisiae ergosterol biosynthesis, like cholesterol biosynthesis in mammals, is regulated at the transcriptional level by a sterol feedback mechanism. Yeast studies defined a 7-bp consensus sterol-response element (SRE) common to genes involved in sterol biosynthesis and two transcription factors, Upc2 and Ecm22, which direct transcription of sterol biosynthetic genes. The 7-bp consensus SRE is identical to the anaerobic response element, AR1c. Data indicate that Upc2 and Ecm22 function through binding to this SRE site. We now show that it is two novel anaerobic AR1b elements in the UPC2 promoter that direct global ERG gene expression in response to a block in de novo ergosterol biosynthesis, brought about by antifungal drug treatment. The AR1b elements are absolutely required for auto-induction of UPC2 gene expression and protein and require Upc2 and Ecm22 for function. We further demonstrate the direct binding of recombinant expressed S. cerevisiae ScUpc2 and pathogenic Candida albicans CaUpc2 and Candida glabrata CgUpc2 to AR1b and SRE/AR1c elements. Recombinant endogenous promoter studies show that the UPC2 anaerobic AR1b elements act in trans to regulate ergosterol gene expression. Our results indicate that Upc2 must occupy UPC2 AR1b elements in order for ERG gene expression induction to take place. Thus, the two UPC2-AR1b elements drive expression of all ERG genes necessary for maintaining normal antifungal susceptibility, as wild type cells lacking these elements have increased susceptibility to azole antifungal drugs. Therefore, targeting these specific sites for antifungal therapy represents a novel approach to treat systemic fungal infections. PMID- 24163368 TI - MicroRNA-22 is a master regulator of bone morphogenetic protein-7/6 homeostasis in the kidney. AB - Accumulating evidence suggests that microRNAs (miRNAs) contribute to a myriad of kidney diseases. However, the regulatory role of miRNAs on the key molecules implicated in kidney fibrosis remains poorly understood. Bone morphogenetic protein-7 (BMP-7) and its related BMP-6 have recently emerged as key regulators of kidney fibrosis. Using the established unilateral ureteral obstruction (UUO) model of kidney fibrosis as our experimental model, we examined the regulatory role of miRNAs on BMP-7/6 signaling. By analyzing the potential miRNAs that target BMP-7/6 in silica, we identified miR-22 as a potent miRNA targeting BMP 7/6. We found that expression levels of BMP-7/6 were significantly elevated in the kidneys of the miR-22 null mouse. Importantly, mice with targeted deletion of miR-22 exhibited attenuated renal fibrosis in the UUO model. Consistent with these in vivo observations, primary renal fibroblast isolated from miR-22 deficient UUO mice demonstrated a significant increase in BMP-7/6 expression and their downstream targets. This phenotype could be rescued when cells were transfected with miR-22 mimics. Interestingly, we found that miR-22 and BMP-7/6 are in a regulatory feedback circuit, whereby not only miR-22 inhibits BMP-7/6, but miR-22 by itself is induced by BMP-7/6. Finally, we identified two BMP responsive elements in the proximal region of miR-22 promoter. These findings identify miR-22 as a critical miRNA that contributes to renal fibrosis on the basis of its pivotal role on BMP signaling cascade. PMID- 24163370 TI - The HECT type ubiquitin ligase NEDL2 is degraded by anaphase-promoting complex/cyclosome (APC/C)-Cdh1, and its tight regulation maintains the metaphase to anaphase transition. AB - NEDD4-like ubiquitin ligase 2 (NEDL2) is a HECT type ubiquitin ligase. NEDL2 enhances p73 transcriptional activity and degrades ATR kinase in lamin misexpressed cells. Compared with the important functions of other HECT type ubiquitin ligase, there is less study concerning the function and regulation of NEDL2. Using primary antibody immunoprecipitation and mass spectrometry, we identify a list of potential proteins that are putative NEDL2-interacting proteins. The candidate list contains many of mitotic proteins, especially including several subunits of anaphase-promoting complex/cyclosome (APC/C) and Cdh1, an activator of APC/C. Cdh1 can interact with NEDL2 in vivo and in vitro. Cdh1 recognizes one of the NEDL2 destruction boxes (R(740)GSL(743)) and targets it for degradation in an APC/C-dependent manner during mitotic exit. Overexpression of Cdh1 reduces the protein level of NEDL2, whereas knockdown of Cdh1 increases the protein level of NEDL2 but has no effect on the NEDL2 mRNA level. NEDL2 associates with mitotic spindles, and its protein level reaches a maximum in mitosis. The function of NEDL2 during mitosis is essential because NEDL2 depletion prolongs metaphase, and overexpression of NEDL2 induces chromosomal lagging. Elevated expression of NEDL2 protein and mRNA are both found in colon cancer and cervix cancer. We conclude that NEDL2 is a novel substrate of APC/C-Cdh1 as cells exit mitosis and functions as a regulator of the metaphase to anaphase transition. Its overexpression may contribute to tumorigenesis. PMID- 24163369 TI - Local depletion of DNA methylation identifies a repressive p53 regulatory region in the NEK2 promoter. AB - Genome-scale mapping suggests that the function of DNA methylation varies with genomic context beyond transcriptional repression. However, the use of DNA demethylating agents (e.g. 5-aza-2'-deoxycytidine (5aza-dC)) to study epigenetic regulation often focuses on gene activation and ignores repression elicited by 5aza-dC. Here, we show that repression of NEK2, which encodes the never in mitosis A (NIMA)-related kinase, by 5aza-dC is context-specific as NEK2 transcript levels were reduced in HCT116 colon cancer cells but not in isogenic p53(-/-) cells. Bisulfite sequencing showed that DNA methylation was restricted to the distal region of the NEK2 promoter. Demethylation by 5aza-dC was associated with increased accessibility to micrococcal nuclease, i.e. nucleosome depletion. Conversely, methyltransferase accessibility protocol for individual templates (MAPit) methylation footprinting showed that nucleosome occupancy and DNA methylation at the distal promoter were significantly increased in p53(-/-) cells, suggesting dynamic regulation of chromatin structure at this region by p53 in HCT116 cells. Stabilization of endogenous p53 by doxorubicin or ectopic expression of p53, but not a p53 DNA-binding mutant, decreased NEK2 expression. Chromatin immunoprecipitation demonstrated direct and specific association of p53 with the distal NEK2 promoter, which was enhanced by doxorubicin. Luciferase reporters confirmed that this region is required for p53-mediated repression of NEK2 promoter activity. Lastly, modulation of p53 abundance altered nucleosome occupancy and DNA methylation at its binding region. These results identify NEK2 as a novel p53-repressed gene, illustrate that its repression by 5aza-dC is specific and associated with nucleosome reorganization, and provide evidence that identification of partially methylated regions can reveal novel p53 target genes. PMID- 24163372 TI - Kinetic flux profiling elucidates two independent acetyl-CoA biosynthetic pathways in Plasmodium falciparum. AB - The malaria parasite Plasmodium falciparum depends on glucose to meet its energy requirements during blood-stage development. Although glycolysis is one of the best understood pathways in the parasite, it is unclear if glucose metabolism appreciably contributes to the acetyl-CoA pools required for tricarboxylic acid metabolism (TCA) cycle and fatty acid biosynthesis. P. falciparum possesses a pyruvate dehydrogenase (PDH) complex that is localized to the apicoplast, a specialized quadruple membrane organelle, suggesting that separate acetyl-CoA pools are likely. Herein, we analyze PDH-deficient parasites using rapid stable isotope labeling and show that PDH does not appreciably contribute to acetyl-CoA synthesis, tricarboxylic acid metabolism, or fatty acid synthesis in blood stage parasites. Rather, we find that acetyl-CoA demands are supplied through a "PDH like" enzyme and provide evidence that the branched-chain keto acid dehydrogenase (BCKDH) complex is performing this function. We also show that acetyl-CoA synthetase can be a significant contributor to acetyl-CoA biosynthesis. Interestingly, the PDH-like pathway contributes glucose-derived acetyl-CoA to the TCA cycle in a stage-independent process, whereas anapleurotic carbon enters the TCA cycle via a stage-dependent phosphoenolpyruvate carboxylase/phosphoenolpyruvate carboxykinase process that decreases as the parasite matures. Although PDH-deficient parasites have no blood-stage growth defect, they are unable to progress beyond the oocyst phase of the parasite mosquito stage. PMID- 24163371 TI - Infrared microspectroscopy detects protein misfolding cyclic amplification (PMCA) induced conformational alterations in hamster scrapie progeny seeds. AB - The self-replicative conformation of misfolded prion proteins (PrP) is considered a major determinant for the seeding activity, infectiousness, and strain characteristics of prions in different host species. Prion-associated seeding activity, which converts cellular prion protein (PrP(C)) into Proteinase K resistant, infectious PrP particles (PrP(TSE)), can be monitored in vitro by protein misfolding cyclic amplification (PMCA). Thus, PMCA has been established as a valuable analytical tool in prion research. Currently, however, it is under discussion whether prion strain characteristics are preserved during PMCA when parent seeds are amplified in PrP(C) substrate from the identical host species. Here, we report on the comparative structural analysis of parent and progeny (PMCA-derived) PrP seeds by an improved approach of sensitive infrared microspectroscopy. Infrared microspectroscopy revealed that PMCA of native hamster 263K scrapie seeds in hamster PrP(C) substrate caused conformational alterations in progeny seeds that were accompanied by an altered resistance to Proteinase K, higher sedimentation velocities in gradient ultracentrifugations, and a longer incubation time in animal bioassays. When these progeny seeds were propagated in hamsters, misfolded PrP from brain extracts of these animals showed mixed spectroscopic and biochemical properties from both parental and progeny seeds. Thus, strain modifications of 263K prions induced by PMCA seem to have been partially reversed when PMCA products were reinoculated into the original host species. PMID- 24163373 TI - Histone lysine-specific demethylase 1 (LSD1) protein is involved in Sal-like protein 4 (SALL4)-mediated transcriptional repression in hematopoietic stem cells. AB - The stem cell protein SALL4 plays a critical role in hematopoiesis by regulating the cell fate. In primitive hematopoietic precursors, it activates or represses important genes via recruitment of various epigenetic factors such as DNA methyltransferases, and histone deacylases. Here, we demonstrate that LSD1, a histone lysine demethylase, also participates in the trans-repressive effects of SALL4. Based on luciferase assays, the amine oxidase domain of LSD1 is important in suppressing SALL4-mediated reporter transcription. In freshly isolated adult mouse bone marrows, both SALL4 and LSD1 proteins are preferentially expressed in undifferentiated progenitor cells and co-localize in the nuclei. Further sequential chromatin immunoprecipitation assay confirmed that these two factors share the same binding sites at the promoter regions of important hematopoietic regulatory genes including EBF1, GATA1, and TNF. In addition, studies from both gain- and loss-of-function models revealed that SALL4 dynamically controls the binding levels of LSD1, which is accompanied by a reversely changed histone 3 dimethylated lysine 4 at the same promoter regions. Finally, shRNA-mediated knockdown of LSD1 in hematopoietic precursor cells resulted in altered SALL4 downstream gene expression and increased cellular activity. Thus, our data revealed that histone demethylase LSD1 may negatively regulate SALL4-mediated transcription, and the dynamic regulation of SALL4-associated epigenetic factors cooperatively modulates early hematopoietic precursor proliferation. PMID- 24163376 TI - A framework for a decision support system for municipal solid waste landfill design. AB - A decision support system (Landfill Advisor or LFAdvisor) was developed to integrate current knowledge of barrier systems into a computer application to assist in landfill design. The program was developed in Visual Basic and includes an integrated database to store information. LFAdvisor presents the choices available for each liner component (e.g. leachate collection system, geomembrane liner, clay liners) and provides advice on their suitability for different situations related to municipal solid waste landfills (e.g. final cover, base liner, lagoon liner). Unique to LFAdvisor, the service life of each engineered component is estimated based on results from the latest research. LFAdvisor considers the interactions between liner components, operating conditions, and the existing site environment. LFAdvisor can be used in the initial stage of design to give designers a good idea of what liner components will likely be required, while alerting them to issues that are likely to arise. A systems approach is taken to landfill design with the ultimate goal of maximising long term performance and service life. PMID- 24163375 TI - Comparison of municipal solid waste treatment technologies from a life cycle perspective in China. AB - China has endured the increasing generation of municipal solid waste; hence, environmental analysis of current waste management systems is of crucial importance. This article presents a comprehensive life cycle assessment of three waste treatment technologies practiced in Hangzhou, China: landfill with and without energy recovery, and incineration with waste-to-energy. Adopting region specific data, the study covers various environmental impacts, such as global warming, acidification, nutrient enrichment, photochemical ozone formation, human toxicity and ecotoxicity. The results show that energy recovery poses a positive effect in environmental savings. Environmental impacts decrease significantly in landfill with the utilization of biogas owing to combined effects by emission reduction and electricity generation. Incineration is preferable to landfill, but toxicity-related impacts also need to be improved. Furthermore, sensitivity analysis shows that the benefit of carbon sequestration will noticeably decrease global warming potential of both landfill scenarios. Gas collection efficiency is also a key parameter influencing the performance of landfill. Based on the results, improvement methods are proposed. Energy recovery is recommended both in landfill and incineration. For landfill, gas collection systems should be upgraded effectively; for incineration, great efforts should be made to reduce heavy metals and dioxin emissions. PMID- 24163374 TI - mTOR inhibition specifically sensitizes colorectal cancers with KRAS or BRAF mutations to BCL-2/BCL-XL inhibition by suppressing MCL-1. AB - Colorectal cancers harboring KRAS or BRAF mutations are refractory to current targeted therapies. Using data from a high-throughput drug screen, we have developed a novel therapeutic strategy that targets the apoptotic machinery using the BCL-2 family inhibitor ABT-263 (navitoclax) in combination with a TORC1/2 inhibitor, AZD8055. This combination leads to efficient apoptosis specifically in KRAS- and BRAF-mutant but not wild-type (WT) colorectal cancer cells. This specific susceptibility results from TORC1/2 inhibition leading to suppression of MCL-1 expression in mutant, but not WT, colorectal cancers, leading to abrogation of BIM/MCL-1 complexes. This combination strategy leads to tumor regressions in both KRAS-mutant colorectal cancer xenograft and genetically engineered mouse models of colorectal cancer, but not in the corresponding KRAS-WT colorectal cancer models. These data suggest that the combination of BCL-2/BCL-XL inhibitors with TORC1/2 inhibitors constitutes a promising targeted therapy strategy to treat these recalcitrant cancers. PMID- 24163377 TI - Study of thermal pre-treatment on anaerobic digestion of slaughterhouse waste by TGA-MS and FTIR spectroscopy. AB - Thermogravimetric analysis coupled to mass spectrometry (TGA-MS) and Fourier transform infrared spectroscopy (FTIR) were used to describe the effect of pasteurization as a hygienic pre-treatment of animal by-products over biogas production. Piggery and poultry meat wastes were used as substrates for assessing the anaerobic digestion under batch conditions at mesophilic range. Poultry waste was characterized by high protein and carbohydrate content, while piggery waste presented a major fraction of fat and lower carbohydrate content. Results from anaerobic digestion tests showed a lower methane yield for the pre-treated poultry sample. TGA-MS and FTIR spectroscopy allowed the qualitative identification of recalcitrant nitrogen-containing compounds in the pre-treated poultry sample, produced by Maillard reactions. In the case of piggery waste, the recalcitrant compounds were not detected and its biodegradability test reported higher methane yield and production rates. TGA-MS and FTIR spectroscopy were demonstrated to be useful tools for explaining results obtained by anaerobic biodegradability test and in describing the presence of inhibitory problems. PMID- 24163378 TI - Waste management and contaminated site remediation practices after oil spill: a case study. AB - A case study is presented on waste management practices implemented after a residual fuel oil spill from a steam-generating boiler in an industrial area, and on the technical feasibility of monitored natural attenuation as a treatment option for a recently contaminated tropical soil. One day after contamination, surface soil total petroleum hydrocarbons and phenanthrene concentrations varied from 3.1 to 7.9 g kg(-1) and 149 to 287 ug kg(-1), respectively. Petroleum hydrocarbon concentrations decayed along the monitored time and after 90 days of processes the soil was considered rehabilitated for future industrial use. PMID- 24163379 TI - The cyclin-dependent kinase inhibitor p16INK4a physically interacts with transcription factor Sp1 and cyclin-dependent kinase 4 to transactivate microRNA 141 and microRNA-146b-5p spontaneously and in response to ultraviolet light induced DNA damage. AB - p16(INK4a) is a tumor suppressor protein involved in several stress-related cellular responses, including apoptosis. Recent lines of evidence indicate that p16(INK4a) is also a modulator of gene expression. However, the molecular mechanisms underlying this novel function are still obscure. Here, we present clear evidence that p16(INK4a) modulates the levels of various microRNAs, with marked positive effect on miR-141 and miR-146b-5p. This effect is mediated through the formation of the p16-CDK4-Sp1 heterocomplex, which binds to Sp1 consensus-binding motifs present in the promoters of miR-141 and miR-146b-5p, and it enables their transcription. In addition, we have shown that p16(INK4a) interacts with Sp1 through the fourth ankyrin repeat, which is crucial for Sp1 binding to the miR-141 and miR-146b-5p promoters and their transcriptional activation. The physiological importance of this association was revealed by the inability of cancer-related p16(INK4a) mutants to interact with Sp1. Moreover, we have shown p16-CDK4-Sp1-dependent up-regulation of miR-141 and miR-146b-5p following UV light-induced DNA damage and the role of these two microRNAs in mediating p16-related induction of apoptosis in response to this genotoxic stress. Together, these results indicate that p16(INK4a) associates with CDK4 not only to inhibit the cell cycle but also to enable the transcription of two important onco-microRNAs, which act as downstream effectors. PMID- 24163380 TI - The role of cell density and intratumoral heterogeneity in multidrug resistance. AB - Recent data have demonstrated that cancer drug resistance reflects complex biologic factors, including tumor heterogeneity, varying growth, differentiation, apoptosis pathways, and cell density. As a result, there is a need to find new ways to incorporate these complexities in the mathematical modeling of multidrug resistance. Here, we derive a novel structured population model that describes the behavior of cancer cells under selection with cytotoxic drugs. Our model is designed to estimate intratumoral heterogeneity as a function of the resistance level and time. This updated model of the multidrug resistance problem integrates both genetic and epigenetic changes, density dependence, and intratumoral heterogeneity. Our results suggest that treatment acts as a selection process, whereas genetic/epigenetic alteration rates act as a diffusion process. Application of our model to cancer treatment suggests that reducing alteration rates as a first step in treatment causes a reduction in tumor heterogeneity and may improve targeted therapy. The new insight provided by this model could help to dramatically change the ability of clinical oncologists to design new treatment protocols and analyze the response of patients to therapy. PMID- 24163381 TI - The authors reply. PMID- 24163382 TI - Electroconvulsive therapy in pregnancy revisited. PMID- 24163383 TI - The buffering effect of social support on hypothalamic-pituitary-adrenal axis function during pregnancy. AB - OBJECTIVE: Recent studies suggest that effective social support during pregnancy may buffer adverse effects of maternal psychological distress on fetal development. The mechanisms whereby social support confers this protective advantage, however, remain to be clarified. The aim of this study was to assess whether individual differences in social support alter the covariation of psychological distress and cortisol during pregnancy. METHODS: Eighty-two pregnant women's psychological distress and cortisol were prospectively assessed in all three trimesters using an ecological momentary assessment strategy. Appraisal of partner social support was assessed in each trimester via the Social Support Effectiveness questionnaire. RESULTS: In multilevel analysis, ambulatory assessments of psychological distress during pregnancy were associated with elevated cortisol levels (unstandardized beta = .023, p < .001). Consistent with the stress-buffering hypothesis, social support moderated the association between psychological distress and cortisol (unstandardized beta = -.001, p = .039), such that the covariation of psychological distress and cortisol increased with decreases in effective social support. The effect of social support for women with the most effective social support was a 50.4% reduction in the mean effect of distress on cortisol and a 2.3-fold increase in this effect for women with the least effective social support scores. CONCLUSIONS: Pregnant women receiving inadequate social support secrete higher levels of cortisol in response to psychological distress as compared with women receiving effective social support. Social support during pregnancy may be beneficial because it decreases biological sensitivity to psychological distress, potentially shielding the fetus from the harmful effects of stress-related increases in cortisol. PMID- 24163384 TI - Socioeconomic indices as independent correlates of C-reactive protein in the National Longitudinal Study of Adolescent Health. AB - OBJECTIVES: To examine the association between socioeconomic status (SES) and C reactive protein (CRP) to understand how SES may increase the risk of cardiovascular disease and thus identify targets for prevention measures. METHODS: Path models were used to examine direct and indirect associations of four indices of SES (objective early life built environment ratings, parental and participant education, and income) with CRP measured during early adulthood using data from the National Longitudinal Adolescent Health Study (n = 11,371; mean age = 29 years, range = 24-32 years; 53.8% women, 28.0% black participants). The present study examined potential mediation of the association of SES with CRP by way of body mass index (BMI), smoking, and alcohol consumption within white and black men and women. RESULTS: BMI was a mediator of the relation between parent education and CRP for white men (path coefficient [gamma] = -0.05, p < .001) and women (gamma = -0.05, p < .001). Smoking mediated the income-CRP (gamma = -0.01, p < .01) and the education-CRP (gamma = -0.07, p < .001) relation for white men. BMI mediated the relation between all measures of SES and CRP for white women (gamma values between -0.02 and -0.05; p values < .01). None of the risk factors mediated the SES-CRP relation in black participants. CONCLUSIONS: These findings indicate that the association of SES with CRP is influenced by both the timing and type of SES measure examined. In addition, race and sex play a role in how potential mediators are involved with the SES-CRP relationship, such that BMI and smoking were mediators in white men, whereas BMI was the sole mediator in white women. PMID- 24163385 TI - Depressive symptoms and mental stress-induced myocardial ischemia in patients with coronary heart disease. AB - OBJECTIVES: The aim of this study was to examine the associations between depressive symptoms and mental stress-induced myocardial ischemia (MSIMI) in patients with coronary heart disease (CHD). METHODS: Adult patients with documented CHD were recruited for baseline mental stress and exercise stress screening testing as a part of the enrollment process of the Responses of Myocardial Ischemia to Escitalopram Treatment trial. Patients were administered the Beck Depression Inventory II and the Center for Epidemiologic Studies Depression Scale. After a 24-48-hour beta-blocker withdrawal, participants completed three mental stress tests followed by a treadmill exercise test. Ischemia was defined as a) any development or worsening of any wall motion abnormality and b) reduction of left ventricular ejection fraction at least 8% by transthoracic echocardiography and/or ischemic ST-segment change by electrocardiography during stress testing. MSIMI was considered present when ischemia occurred in at least one mental test. Data were analyzed using logistic regression adjusting for age, sex, and resting left ventricular ejection fraction. RESULTS: One hundred twenty-five (44.2%) of 283 patients were found to have MSIMI, and 93 (32.9%) had ESIMI. Unadjusted analysis showed that Beck Depression Inventory II scores were positively associated with the probability of MSIMI (odds ratio = 0.1.30: 95% confidence interval = 1.06-1.60, p = .013) and number of MSIMI-positive tasks (all p < .005). These associations were still significant after adjustment for covariates (p values <.05). CONCLUSIONS: In patients with CHD, depressive symptoms were associated with a higher probability of MSIMI. These observations may enhance our understanding of the mechanisms contributing to the association of depressive symptoms to future cardiovascular events. Trial Registration Clinicaltrials.gov identifier: NCT00574847. PMID- 24163386 TI - Relationship between obesity and depression: characteristics and treatment outcomes with antidepressant medication. AB - OBJECTIVE: Obesity and major depressive disorder often co-occur. However, differences between obese and normal-weight depressed patients and the moderating effect of obesity on antidepressant treatment outcome are not well studied. METHODS: Adults (n = 662) with major depressive disorder in the Combining Medications to Enhance Depression Outcomes study were randomized to treatment with escitalopram plus placebo, bupropion plus escitalopram, or venlafaxine plus mirtazapine for a 12-week primary treatment phase and 16-week follow-up. Body mass index (BMI) was calculated at baseline and categorized according to World Health Organization criteria: normal or low weight (NW), overweight, Obese I and Obese II+. A repeated-effects model, unadjusted and adjusted for baseline variables, assessed outcomes. RESULTS: Obesity was common (46.2%), only 25.5% were NW. Higher BMI was associated with greater medical illness (p < .001), social phobia (p = .003), and bulimia (p = .026). Lower BMI was associated with more frequent post-traumatic stress disorder (p = .002) and drug abuse (p < .001). Treatment outcomes did not differ including Week 12 remission rates (NW 36%, overweight 40%, Obese I 43%, Obese II+ 37%; p = .69). Lower BMI was associated with more frequent (p = .024 [unadjusted] and .053 [adjusted]) and more severe (p = .008 [unadjusted] and .053 [adjusted]) adverse effects. CONCLUSIONS: BMI was related to clinical presentation and prevalence of comorbidities, but not antidepressant outcomes. Lower BMI classes had more psychiatric comorbidities, potentially obscuring the relationship between BMI and antidepressant effects. Trial Registration ClinicalTrials.gov identifier: NCT00590863. PMID- 24163387 TI - Myocardial ischemia and angiotensin-converting enzyme inhibition: comparison of ischemia during mental and physical stress. AB - OBJECTIVE: Mental stress provokes myocardial ischemia in many patients with stable coronary artery disease (CAD). Mental stress-induced myocardial ischemia (MSIMI) portends a worse prognosis, independent of standard cardiac risk factors or outcome of traditional physical stress testing. Angiotensin II plays a significant role in the physiological response to stress, but its role in MSIMI remains unknown. Our aim was to evaluate whether the use of angiotensin converting enzyme inhibitors (ACEIs) is associated with a differential effect on the incidence of MSIMI compared with ischemia during physical stress. METHODS: Retrospective analysis of 218 patients with stable CAD, including 110 on ACEI, was performed. 99m-Tc-sestamibi myocardial perfusion imaging was used to define ischemia during mental stress, induced by a standardized public speaking task, and during physical stress, induced by either exercise or adenosine. RESULTS: Overall, 40 patients (18%) developed MSIMI and 80 patients (37%) developed ischemia during physical stress. MSIMI occurred less frequently in patients receiving ACEIs (13%) compared with those not on ACEIs (24%; p = .030, adjusted odds ratio = 0.42, 95% confidence interval = 0.19-0.91). In contrast, the frequency of myocardial ischemia during physical stress testing was similar in both groups (39% versus 35% in those on and not on ACEIs, respectively); adjusted odds ratio = 0.91, 95% confidence interval = 0.48-1.73). CONCLUSION: In this retrospective study, patients using ACEI therapy displayed less than half the risk of developing ischemia during mental stress but not physical stress. This possible beneficial effect of ACEIs on MSIMI may be contributing to their salutary effects in CAD. PMID- 24163388 TI - Predictive value of social inhibition and negative affectivity for cardiovascular events and mortality in patients with coronary artery disease: the type D personality construct. AB - OBJECTIVE: Methodological considerations and selected null findings indicate the need to reexamine the Type D construct. We investigated whether associations with cardiac events in patients with coronary artery disease (CAD) involve the specific combination of negative affectivity (NA) and social inhibition (SI), or rather the main effect of either trait alone. METHODS: In this 5-year follow-up of 541 patients with CAD, the Type D construct (14-item Type D Scale) was tested by examining a) the interaction of continuous NA and SI z scores and b) a four group classification defined by low/high trait scores. End points were major adverse cardiac events (MACEs; death, myocardial infarction [MI], coronary revascularization) and cardiac death/MI. RESULTS: At follow-up, 113 patients had a MACE, including 47 patients with cardiac death/MI. After adjustment for disease severity, age, sex, and main trait effects, the interaction of NA and SI z scores was associated with MACE (odds ratio [OR] = 1.36, 95% confidence interval [CI] = 1.11-1.67). This continuous measure of Type D was also associated with cardiac death/MI (OR = 1.48, 95% CI = 1.11-1.96) and remained an independent predictor of events after adjustment for depressive symptoms. Using a cutoff of 10 on both NA and SI scales, Type D was associated with an adjusted OR of 1.74 (95% CI = 1.11 2.73) for MACE and an OR of 2.35 (95% CI = 1.26-4.38) for death/MI but was unrelated to noncardiac death. Patients with high NA or SI alone were not at increased risk. CONCLUSIONS: Continuous (NA * SI interaction) and dichotomized measures of Type D were associated with cardiovascular events in patients with CAD. Research is needed to explore moderating factors that may alter this association. PMID- 24163389 TI - Metabolic syndrome and the risk of suicide: a community-based integrated screening samples cohort study. AB - OBJECTIVE: Metabolic syndrome (MetS) is reportedly associated with mental disorders that are known to increase the risk of suicide. However, it is not known whether this association is independent of other risk indicators of suicide. This study therefore investigated whether metabolic abnormalities increase the risk of suicide during a 10-year follow-up period. METHODS: This prospective study enrolled participants from a community-based integrated screening samples cohort in Taiwan. Of the 76,297 people recruited for this study, 12,094 had MetS at baseline. The independent variables were MetS and its components such as high blood pressure and high blood lipid levels. The outcome was death from suicide (n = 146). RESULTS: MetS was associated with an increased risk of suicide risk by 16% per MetS component (95% confidence interval [CI] = 1% 33%), adjusting for demographics, life-style factors, and clinical correlates. Of the five MetS components, elevated blood pressure was independently associated with suicide-related mortality (adjusted hazard ratio [aHR] = 1.49, 95% CI = 1.03 2.15). CONCLUSIONS: This analysis of community-based longitudinal data showed that MetS and its components, particularly elevated blood pressure, correlated positively with suicide risk after controlling other factors. Therefore, public mental health interventions targeting suicide reduction may need to specifically focus on individuals with hypertension and other components of the MetS. PMID- 24163390 TI - Autophagy and thyroid carcinogenesis: genetic and epigenetic links. AB - Thyroid cancer is the most common cancer of the endocrine system and is responsible for the majority of deaths from endocrine malignancies. Although a large proportion of thyroid cancers belong to well differentiated histologic subtypes, which in general show a good prognosis after surgery and radioiodine ablation, the treatment of radio-resistant papillary-type, of undifferentiated anaplastic, and of medullary-type thyroid cancers remains unsatisfactory. Autophagy is a vesicular process for the lysosomal degradation of protein aggregates and of damaged or redundant organelles. Autophagy plays an important role in cell homeostasis, and there is evidence that this process is dysregulated in cancer cells. Recent in vitro preclinical studies have indicated that autophagy is involved in the cytotoxic response to chemotherapeutics in thyroid cancer cells. Indeed, several oncogenes and oncosuppressor genes implicated in thyroid carcinogenesis also play a role in the regulation of autophagy. In addition, some epigenetic modulators involved in thyroid carcinogenesis also influence autophagy. In this review, we highlight the genetic and epigenetic factors that mechanistically link thyroid carcinogenesis and autophagy, thus substantiating the rationale for an autophagy-targeted therapy of aggressive and radio-chemo-resistant thyroid cancers. PMID- 24163391 TI - Endocrine disruption of oestrogen action and female reproductive tract cancers. AB - Endocrine disrupting chemicals (EDC) are ubiquitous and persistent compounds that have the capacity to interfere with normal endocrine homoeostasis. The female reproductive tract is exquisitely sensitive to the action of sex steroids, and oestrogens play a key role in normal reproductive function. Malignancies of the female reproductive tract are the fourth most common cancer in women, with endometrial cancer accounting for most cases. Established risk factors for development of endometrial cancer include high BMI and exposure to oestrogens or synthetic compounds such as tamoxifen. Studies on cell and animal models have provided evidence that many EDC can bind oestrogen receptors and highlighted early life exposure as a window of risk for adverse lifelong effects on the reproductive system. The most robust evidence for a link between early life exposure to EDC and adverse reproductive health has come from studies on women who were exposed in utero to diethylstilbestrol. Demonstration that EDC can alter expression of members of the HOX gene cluster highlights one pathway that might be vulnerable to their actions. In summary, evidence for a direct link between EDC exposure and cancers of the reproductive system is currently incomplete. It will be challenging to attribute causality to any single EDC when exposure and development of malignancy may be separated by many years and influenced by lifestyle factors such as diet (a source of phytoestrogens) and adiposity. This review considers some of the evidence collected to date. PMID- 24163392 TI - Do variations in hospital mortality patterns after weekend admission reflect reduced quality of care or different patient cohorts? A population-based study. AB - BACKGROUND: Proposed causes for increased mortality following weekend admission (the 'weekend effect') include poorer quality of care and sicker patients. The aim of this study was to analyse the 7 days post-admission time patterns of excess mortality following weekend admission to identify whether distinct patterns exist for patients depending upon the relative contribution of poorer quality of care (care effect) or a case selection bias for patients presenting on weekends (patient effect). METHODS: Emergency department admissions to all 501 hospitals in New South Wales, Australia, between 2000 and 2007 were linked to the Death Registry and analysed. There were a total of 3 381 962 admissions for 539 122 patients and 64 789 deaths at 1 week after admission. We computed excess mortality risk curves for weekend over weekday admissions, adjusting for age, sex, comorbidity (Charlson index) and diagnostic group. RESULTS: Weekends accounted for 27% of all admissions (917 257/3 381 962) and 28% of deaths (18 282/64 789). Sixteen of 430 diagnosis groups had a significantly increased risk of death following weekend admission. They accounted for 40% of all deaths, and demonstrated different temporal excess mortality risk patterns: early care effect (cardiac arrest); care effect washout (eg, pulmonary embolism); patient effect (eg, cancer admissions) and mixed (eg, stroke). CONCLUSIONS: The excess mortality patterns of the weekend effect vary widely for different diagnostic groups. Recognising these different patterns should help identify at-risk diagnoses where quality of care can be improved in order to minimise the excess mortality associated with weekend admission. PMID- 24163393 TI - Development of phenotypic screening assays for gamma-globin induction using primary human bone marrow day 7 erythroid progenitor cells. AB - Sickle cell anemia (SCA) is a genetic disorder of the beta-globin gene. SCA results in chronic ischemia with pain and tissue injury. The extent of SCA symptoms can be ameliorated by treatment with drugs, which result in increasing the levels of gamma-globin in patient red blood cells. Hydroxyurea (HU) is a Food and Drug Administration-approved drug for SCA, but it has dose-limiting toxicity, and patients exhibit highly variable treatment responses. To identify compounds that may lead to the development of better and safer medicines, we have established a method using primary human bone marrow day 7 erythroid progenitor cells (EPCs) to screen for compounds that induce gamma-globin production. First, human marrow CD34(+) cells were cultured and expanded for 7 days and characterized for the expression of erythroid differentiation markers (CD71, CD36, and CD235a). Second, fresh or cryopreserved EPCs were treated with compounds for 3 days in 384-well plates followed by gamma-globin quantification by an enzyme-linked immunosorbent assay (ELISA), which was validated using HU and decitabine. From the 7408 compounds screened, we identified at least one new compound with confirmed gamma-globin-inducing activity. Hits are undergoing analysis in secondary assays. In this article, we describe the method of generating fit-for-purpose EPCs; the development, optimization, and validation of the ELISA and secondary assays for gamma-globin detection; and screening results. PMID- 24163394 TI - Regnase-1, a ribonuclease involved in the regulation of immune responses. AB - Zc3h12a is a lipopolysaccharide-inducible gene and has a CCCH-type zinc-finger domain. Zc3h12a knockout mice develop spontaneous autoimmune diseases accompanied by splenomegaly and by lymphadenopathy. Subsequent studies show that Zc3h12a is a nuclease involved in destabilization of interleukin (IL)-6 and IL-12 mRNA via the stem loop structure within the 3' UTR of these genes. Thus, we renamed it regulatory RNase-1 (Regnase-1) based on its function. IkappaB kinases phosphorylate and degrade Regnase-1 protein in macrophages in response to IL 1R/Toll-like receptor (TLR) stimulation. T-cell-specific deletion of Regnase-1 produces pathogenic T cells with hyperactivated phenotypes as well as autoimmune diseases. Regnase-1 protein is cleaved by Malt1 and inactivated in response to T cell receptor stimulation. Thus, Regnase-1 is a key molecule in the regulation of immune responses. PMID- 24163395 TI - miR-181 and metabolic regulation in the immune system. AB - Regulation of metabolism is emerging as a central mechanism to control cellular identity and function. Extensive research in the last few years has revealed that the PI3K pathway is at the forefront of establishing metabolic changes required for immune cell growth, proliferation, migration, and differentiation. However, we currently have a limited understanding of how signaling through the PI3K pathway is tightly regulated during immune responses and immune cell development. Although a growing number of miRNAs have been shown to target important metabolic pathways, including the PI3K pathway itself, almost nothing is known regarding metabolic regulation by miRNAs in the context of the immune system. Recently, we revealed that the miR-181 family is a metabolic rheostat in vivo through the nonredundant regulation of PTEN. Over the next few years, additional miRNAs with the capacity to regulate various aspects of metabolism in immune cells are likely to be identified. We propose that these miRNAs will form a network to finely tune cellular metabolic status and that miR-181 will function as the primary metabolic rheostat of this network. PMID- 24163397 TI - Reliability and validity of outcome measures of in-hospital and at-home visits in a randomized, double-blind, placebo-controlled trial for spinal muscular atrophy. AB - We used at-home assessments in a clinical trial to relieve the visit burden for participants. A total of 57 patients with type II or III spinal muscular atrophy were enrolled and 10 of them (7 type II and 3 type III) received at-home assessments. The primary end points were Gross Motor Function Measure, Manual Muscle Test, and serum biomarker. The secondary endpoints were Modified Hammersmith Functional Motor Scale and forced vital capacity. The correlation coefficients and analysis of covariance showed good reliability and validity of all outcome measures. Except for Gross Motor Function Measure and Modified Hammersmith Functional Motor Scale, there were no significant differences in measures between in-hospital and at-home groups (intersubject) or among 3 patients who received both at-home and in-hospital visits (intrasubject). We concluded that at-home assessments could provide sufficient reliability in a controlled trial. This modification could help design a successful clinical trial for spinal muscular atrophy. PMID- 24163396 TI - Effects of the use of assisted reproduction and high-caloric diet consumption on body weight and cardiovascular health of juvenile mouse offspring. AB - Maternal obesity and the use of assisted reproductive technologies (ART) are two suboptimal developmental environments that can lead to offspring obesity and cardiovascular disease. We hypothesized that these environments independently and synergistically adversely affect the offspring's weight and cardiovascular performance at ~7 weeks of age. Mice were fed either 24% fat and 17.5% high fructose (HF) corn syrup or maintenance chow (5% fat; low-fat, no-fructose (LF)). Dams were subdivided into no ART and ART groups. ART embryos were cultured in Whitten's medium and transferred into pseudopregnant recipients consuming the same diet as the donor. Offspring were fed the same diet as the mother. Body weights (BW) were measured weekly and mean arterial pressure (MAP) was collected through carotid artery catheterization at killing (55+/-0.5 days old). Expression of genes involved in cardiovascular remodeling was measured in thoracic aorta using qRT-PCR, and levels of reactive oxygen species (ROS) were measured intracellularly and extracellularly in mesenteric resistance arteries. ART resulted in increased BW at weaning. This effect decreased over time and diet was the predominant determinant of BW by killing. Males had greater MAP than females (P=0.002) and HF consumption was associated with greater MAP regardless of sex (P<0.05). Gene expression was affected by sex (P<0.05) and diet (P<0.1). Lastly, the use of ART resulted in offspring with increased intracellular ROS (P=0.05). In summary, exposure to an obesogenic diet pre- and/or post-natally affects weight, MAP, and gene expression while ART increases oxidative stress in mesenteric resistance arteries of juvenile offspring, no synergistic effects were observed. PMID- 24163398 TI - The efficacy of sublingual Lorazepam for prolonged convulsions beyond sub-saharan Africa: raising more questions than answers. PMID- 24163399 TI - Pediatric stroke outcome measure: predictor of multiple impairments in childhood stroke. AB - The ability to anticipate deficits would help with implementation of interventions for children affected by stroke. The pediatric stroke outcome measure (measure) measures neurological impairment after stroke, but there has been little research examining the relationship between the measure and functional outcomes. We hypothesized the Measure correlates with cognitive and behavioral outcomes. Thirty-six children with stroke were assessed with the Measure, and tested for cognitive ability, problem behavior, adaptive behavior, and social participation. We examined the correlation between the total Measure and outcomes and determined how subscale scores associated with outcomes. Higher total Measure scores correlated with poorer outcomes in cognitive ability, problem behaviors, adaptive behaviors, and social participation. Specific subscale scores correlated with poorer outcomes in multiple domains. The total Measure can be used to anticipate poor outcomes in multiple domains after stroke and can help the clinician in the treatment of children as they recover. PMID- 24163401 TI - Downregulation of transcription factor E4F1 in hepatocarcinoma cells: HBV dependent effects on autophagy, proliferation and metabolism. AB - The multifunctional E4F1 protein is a cellular target of the E1A adenoviral oncoprotein. Interaction between E4F1 and the hepatitis B virus (HBV) protein HBx has been demonstrated in vitro. In this study, RNA interference has been used to downregulate E4F1 in the hepatocellular carcinoma (HCC) cell line HepG2 (HBV negative) and its derivative, HBV expressing HepG2/2.2.15. Reduction of E4F1 levels induced hepatocyte vacuolation (formation of large cytoplasmic vesicles), increased autophagy and caused mitochondrial defects and metabolism changes in HepG2/2.2.15, but not in HepG2. Moreover, downregulation of E4F1 reduced DNA synthesis with partial cell cycle arrest in G1 in both cell types and this effect was more marked in HepG2/2.2.15 than in HepG2. These effects were partially prevented by RNA interference directed to either HBx or to p53. Coprecipitation and western blot experiments detected complexes between E4F1 and HBx in several HCC cell lines. Although a review of mutation and gene expression public databases did not support that E4F1 is specifically altered in liver cancer, our results suggest that E4F1 may neutralize the capacity of HBx to activate a p53 dependent, metabolic and growth arrest phenotype in liver cells, thus possibly contributing to the viability and proliferation of HBV-infected cells. PMID- 24163400 TI - Influence of promoter/enhancer region haplotypes on MGMT transcriptional regulation: a potential biomarker for human sensitivity to alkylating agents. AB - The O6-methylguanine-DNA methyltransferase gene (MGMT) encodes the direct reversal DNA repair protein that removes alkyl adducts from the O6 position of guanine. Several single-nucleotide polymorphisms (SNPs) exist in the MGMT promoter/enhancer (P/E) region. However, the haplotype structure encompassing these SNPs and their functional/biological significance are currently unknown. We hypothesized that MGMT P/E haplotypes, rather than individual SNPs, alter MGMT transcription and can thus alter human sensitivity to alkylating agents. To identify the haplotype structure encompassing the MGMT P/E region SNPs, we sequenced 104 DNA samples from healthy individuals and inferred the haplotypes using the data generated. We identified eight SNPs in this region, namely T7C (rs180989103), T135G (rs1711646), G290A (rs61859810), C485A (rs1625649), C575A (rs113813075), G666A (rs34180180), C777A (rs34138162) and C1099T (rs16906252). Phylogenetics and Sequence Evolution analysis predicted 21 potential haplotypes that encompass these SNPs ranging in frequencies from 0.000048 to 0.39. Of these, 10 were identified in our study population as 20 paired haplotype combinations. To determine the functional significance of these haplotypes, luciferase reporter constructs representing these haplotypes were transfected into glioblastoma cells and their effect on MGMT promoter activity was determined. Compared with the most common (reference) haplotype 1, seven haplotypes significantly upregulated MGMT promoter activity (18-119% increase; P < 0.05), six significantly downregulated MGMT promoter activity (29-97% decrease; P < 0.05) and one haplotype had no effect. Mechanistic studies conducted support the conclusion that MGMT P/E haplotypes, rather than individual SNPs, differentially regulate MGMT transcription and could thus play a significant role in human sensitivity to environmental and therapeutic alkylating agents. PMID- 24163402 TI - Rice DEP1, encoding a highly cysteine-rich G protein gamma subunit, confers cadmium tolerance on yeast cells and plants. AB - A rice cDNA, OsDEP1, encoding a highly cysteine (Cys)-rich G protein gamma subunit, was initially identified as it conferred cadmium (Cd) tolerance on yeast cells. Of the 426 aa constituting OsDEP1, 120 are Cys residues (28.2%), of which 88 are clustered in the C-terminal half region (aa 170-426). To evaluate the independent effects of these two regions, two truncated versions of the OsDEP1 expressing plasmids pOsDEP1(1-169) and pOsDEP1(170-426) were used to examine their effects on yeast Cd tolerance. Although OsDEP1(170-426) conferred a similar level of Cd tolerance as the intact OsDEP1, OsDEP1(1-169) provided no such tolerance, indicating that the tolerance effect is localized to the aa 170-426 C terminal peptide region. The Cd responses of transgenic Arabidopsis plants constitutively expressing OsDEP1, OsDEP1(1-169) or OsDEP1(170-426), were similar to the observations in yeast cells, with OsDEP1 and OsDEP1(170-426) transgenic plants displaying Cd tolerance but OsDEP1(1-169) plants showing no such tolerance. In addition, a positive correlation between the transcript levels of OsDEP1 or OsDEP1(170-426) in the transgenics and the Cd content of these plants upon Cd application was observed. As several Arabidopsis loss-of-function heterotrimeric G protein beta and gamma subunit gene mutants did not show differences in their Cd sensitivity compared with wild-type plants, we propose that the Cys-rich region of OsDEP1 may function directly as a trap for Cd ions. PMID- 24163403 TI - Population genetics of Braun's Rockcress (Boechera perstellata, Brassicaceae), an endangered plant with a disjunct distribution. AB - Boechera perstellata is an endangered plant found only in middle Tennessee and north central Kentucky. After sampling 4 Tennessee and 3 Kentucky populations, genetic variability and population structure were examined for this species using isozymes, chloroplast DNA, and microsatellites (averaging 35, 29, and 27 individuals per population per class of marker, respectively). The only genetic variability detected for 23 isozymes was a fixed difference between Tennessee and Kentucky populations at 1 locus. Fixed differences between populations of the 2 states were also observed for 3 chloroplast markers. Polymorphism at 19 nuclear microsatellites was 74% at the species level and averaged 21% at the population level. However, observed heterozygosity was extremely low in all populations, ranging from 0.000 to 0.005. High F IS values (0.93) suggest that Boechera perstellata is a primarily selfing species. Tennessee populations have more genetic diversity than Kentucky populations of B. perstellata. Microsatellite markers revealed substantial genetic divergence between the states and genetic differences among populations within each state. Analysis of molecular variance indicates that most variability in this species occurs between the 2 states (49%) and among populations within each state (42%), with relatively little variation found within populations (9%). These data indicate that there is very little gene flow among populations of B. perstellata and that it is important to protect as many populations as possible in order to conserve the genetic diversity of this rare species. PMID- 24163404 TI - Beta-naphthoflavone (DB06732) mediates estrogen receptor-positive breast cancer cell cycle arrest through AhR-dependent regulation of PI3K/AKT and MAPK/ERK signaling. AB - Beta-naphthoflavone (BNF, DB06732) is an agonist of aryl hydrocarbon receptor (AhR) and a putative chemotherapeutic agent that has antitumor activity against mammary carcinomas in vivo. However, the mechanism by which BNF exerts this antitumor effect remains unclear. Thus, we explored mechanisms of BNF's antitumor effects in human breast cancer cells. This study showed that BNF suppressed cell proliferation and induced cell cycle arrest in the G0/G1 phase with downregulation of cyclin D1/D3 and CDK4 and upregulation of p21(Cip1/Waf1), leading to a senescence-like phenotype in estrogen receptor (ER)-positive MCF-7 cells, but not in ER-negative MDA-MB-231 cells. In addition, BNF inhibited PI3K/AKT signaling, and the PI3K inhibitor, LY294,002, exhibited the same inhibitory effects on cyclinD1/D3, CDK4 and the cell cycle as BNF. Interestingly, BNF activated mitogen-activated protein kinase-extracellular signal-regulated kinase (MAPK-ERK) signaling, and more notably, MEK inhibitor PD98059 significantly blocked the BNF-induced cell cycle arrest and upregulation of p21(Cip1/Waf1). Furthermore, specific ERalpha and AhR siRNA studies indicate that ERalpha is required in BNF-induced p21(Cip1/Waf1) expression, and BNF-mediated cell cycle arrest and modulation of AKT and ERK signaling is AhR-dependent. Taken together, AhR-dependent inhibition of the PI3K/AKT pathway, activation of MAPK/ERK and modulation of ERalpha is a novel mechanism underlying BNF-mediated antitumor effects in breast cancer, which may represent a promising strategy to be exploited in future clinical trials. PMID- 24163405 TI - A twist in the tale. AB - A 4-year-old girl presented with retching and abdominal colic and was initially diagnosed with gastroenteritis. However, progressive pain and epigastric distension led to a surgical review and she was discovered on CT scanning to have a gastric volvulus. She required urgent laparotomy to decompress the stomach and repair a perforation on the lesser curvature. Her recovery was complicated by sepsis and reperforation necessitating further laparotomy, at which time she also underwent gastropexy. The patient required long-term jejunal feeding in the hospital and at home before finally returning to normal diet and activity. PMID- 24163406 TI - Snapper fishbone esophageal perforation closed with an over-the-scope-clip. PMID- 24163407 TI - A novel approach to tracking antigen-experienced CD4 T cells into functional compartments via tandem deep and shallow TCR clonotyping. AB - Extensive diversity in the human repertoire of TCRs for Ag is both a cornerstone of effective adaptive immunity that enables host protection against a multiplicity of pathogens and a weakness that gives rise to potential pathological self-reactivity. The complexity arising from diversity makes detection and tracking of single Ag-specific CD4 T cells (ASTs) involved in these immune responses challenging. We report a tandem, multistep process to quantify rare TCRbeta-chain variable sequences of ASTs in large polyclonal populations. The approach combines deep high-throughput sequencing (HTS) within functional CD4 T cell compartments, such as naive/memory cells, with shallow, multiple identifier-based HTS of ASTs identified by activation marker upregulation after short-term Ag stimulation in vitro. We find that clonotypes recognizing HLA class II-restricted epitopes of both pathogen-derived Ags and self-Ags are oligoclonal and typically private. Clonotype tracking within an individual reveals private AST clonotypes resident in the memory population, as would be expected, representing clonal expansions (identical nucleotide sequence; "ultraprivate"). Other AST clonotypes share CDR3beta amino acid sequences through convergent recombination and are found in memory populations of multiple individuals. Tandem HTS-based clonotyping will facilitate studying AST dynamics, epitope spreading, and repertoire changes that arise postvaccination and following Ag-specific immunotherapies for cancer and autoimmune disease. PMID- 24163408 TI - Nod1 and Nod2 enhance TLR-mediated invariant NKT cell activation during bacterial infection. AB - Invariant NKT (iNKT) cells act at the crossroad between innate and adaptive immunity and are important players in the defense against microbial pathogens. iNKT cells can detect pathogens that trigger innate receptors (e.g., TLRs, Rig-I, Dectin-1) within APCs, with the consequential induction of CD1d-mediated Ag presentation and release of proinflammatory cytokines. We show that the cytosolic peptidoglycan-sensing receptors Nod1 and Nod2 are necessary for optimal IFN-gamma production by iNKT cells, as well as NK cells. In the absence of Nod1 and Nod2, iNKT cells had a blunted IFN-gamma response following infection by Salmonella enterica serovar Typhimurium and Listeria monocytogenes. For Gram-negative bacteria, we reveal a synergy between Nod1/2 and TLR4 in dendritic cells that potentiates IL-12 production and, ultimately, activates iNKT cells. These findings suggest that multiple innate pathways can cooperate to regulate iNKT cell activation during bacterial infection. PMID- 24163409 TI - Chronic follicular bronchiolitis requires antigen-specific regulatory T cell control to prevent fatal disease progression. AB - To study regulatory T (Treg) cell control of chronic autoimmunity in a lymphoreplete host, we created and characterized a new model of autoimmune lung inflammation that targets the medium and small airways. We generated transgenic mice that express a chimeric membrane protein consisting of hen egg lysozyme and a hemoglobin epitope tag under the control of the Clara cell secretory protein promoter, which largely limited transgene expression to the respiratory bronchioles. When Clara cell secretory protein-membrane hen egg lysozyme/hemoglobin transgenic mice were crossed to N3.L2 TCR transgenic mice that recognize the hemoglobin epitope, the bigenic progeny developed dense, pseudo-follicular lymphocytic peribronchiolar infiltrates that resembled the histological pattern of follicular bronchiolitis. Aggregates of activated IFN gamma- and IL-17A-secreting CD4(+) T cells as well as B cells surrounded the airways. Lung pathology was similar in Ifng(-/-) and Il17a(-/-) mice, indicating that either cytokine is sufficient to establish chronic disease. A large number of Ag-specific Treg cells accumulated in the lesions, and Treg cell depletion in the affected mice led to an interstitial spread of the disease that ultimately proved fatal. Thus, Treg cells act to restrain autoimmune responses, resulting in an organized and controlled chronic pathological process rather than a progressive disease. PMID- 24163410 TI - The binding of TAPBPR and Tapasin to MHC class I is mutually exclusive. AB - The loading of peptide Ags onto MHC class I molecules is a highly controlled process in which the MHC class I-dedicated chaperone tapasin is a key player. We recently identified a tapasin-related molecule, TAPBPR, as an additional component in the MHC class I Ag-presentation pathway. In this study, we show that the amino acid residues important for tapasin to interact with MHC class I are highly conserved on TAPBPR. We identify specific residues in the N-terminal and C terminal domains of TAPBPR involved in associating with MHC class I. Furthermore, we demonstrate that residues on MHC class I crucial for its association with tapasin, such as T134, are also essential for its interaction with TAPBPR. Taken together, the data indicate that TAPBPR and tapasin bind in a similar orientation to the same face of MHC class I. In the absence of tapasin, the association of MHC class I with TAPBPR is increased. However, in the absence of TAPBPR, the interaction between MHC class I and tapasin does not increase. In light of our findings, previous data determining the function of tapasin in the MHC class I Ag processing and presentation pathway must be re-evaluated. PMID- 24163411 TI - Placental macrophages are impaired in chorioamnionitis, an infectious pathology of the placenta. AB - Pregnancy is dependent on maternal-fetal tolerance that may be compromised because of infections or inflammation of the placenta. In this study, we examined whether the context of placental immune tolerance affected the functions of resident macrophages and if their functions were altered during chorioamnionitis, an infectious pathology of the placenta. Macrophages from at-term placentas expressed CD14, exhibited macrophage microbicidal functions, but were less inflammatory than monocyte-derived macrophages. Moreover, placental macrophages spontaneously matured into multinucleated giant cells (MGCs), a property not exhibited by monocyte-derived macrophages, and we detected MGCs of myeloid origin in placental tissue. Compared with placental macrophages, MGCs exhibited a specific phenotype and gene expression signature, consisting of increased cytoskeleton-associated gene expression along with depressed expression of inflammatory response genes. Furthermore, placental macrophages from patients with chorioamnionitis were unable to form MGCs, but this defect was partially corrected by incubating these placental macrophages with control trophoblast supernatants. MGCs formation likely serves to regulate their inflammatory and cytocidal activities in a context that imposes semiallograft acceptance and defense against pathogens. PMID- 24163415 TI - The role of valvular regurgitation in catheter ablation outcomes of patients with long-standing persistent atrial fibrillation. AB - AIMS: The role of valvular regurgitation (VR) in outcomes of patients obtaining current ablation endpoints with long-standing persistent atrial fibrillation (LS AF) was evaluated. METHODS AND RESULTS: In all, 216 consecutive patients obtaining current ablation endpoints with LS-AF were studied. A standard two dimensional and Doppler transthoracic echocardiography (TTE) was performed in every patient before the procedure. The presentation and the grade of mitral regurgitation (MR), tricuspid regurgitation, and aortic regurgitation were evaluated. The clinical characteristics, TTE, and procedural characteristics were compared between the sinus rhythm group and the recurrent atrial tachyarrhythmia (ATa) group. After a follow-up of 18.9 +/- 2.7 months, there were 48 patients in the ATa group. The patients in the ATa group had greater MR, longer AF duration, and larger left atrium (LA). In multivariate analyses, MR, LA size, and AF duration were independent predictors of recurrent ATa. The grades of MR severity were correlated with the rate of recurrent ATa, and more severe grade of MR indicated more recurrent ATa. Compared with the patients with organic MR, the patients with functional MR had a lower rate of recurrent ATa and lesser degrees of MR. CONCLUSION: In the three types of VR, MR was associated with recurrent ATa after AF ablation. Patients with ATa recurrence had more severe MR and greater organic MR. PMID- 24163412 TI - Regulation of apoptosis and innate immune stimuli in inflammation-induced preterm labor. AB - An innate immune response is required for successful implantation and placentation. This is regulated, in part, by the a2 isoform of V-ATPase (a2V) and the concurrent infiltration of M1 (inflammatory) and M2 (anti-inflammatory) macrophages to the uterus and placenta. The objective of the present study was to identify the role of a2V during inflammation-induced preterm labor in mice and its relationship to the regulation of apoptosis and innate immune responses. Using a mouse model of infection-induced preterm delivery, gestational tissues were collected 8 h after intrauterine inoculation on day 14.5 of pregnancy with either saline or peptidoglycan (PGN; a TLR 2 agonist) and polyinosinic polycytidylic acid [poly(I:C); a TLR3 agonist], modeling Gram-positive bacterial and viral infections, respectively. Expression of a2V decreased significantly in the placenta, uterus, and fetal membranes during PGN+poly(I:C)-induced preterm labor. Expression of inducible NO synthase was significantly upregulated in PGN+poly(I:C)-treated placenta and uterus. PGN+poly(I:C) treatment disturbed adherens junction proteins and increased apoptotic cell death via an extrinsic pathway of apoptosis among uterine decidual cells and spongiotrophoblasts. F4/80(+) macrophages were increased and polarization was skewed in PGN+poly(I:C) treated uterus toward double-positive CD11c(+) (M1) and CD206(+) (M2) cells, which are critical for the clearance of dying cells and rapid resolution of inflammation. Expression of Nlrp3 and activation of caspase-1 were increased in PGN+poly(I:C)-treated uterus, which could induce pyroptosis. These results suggest that the double hit of PGN+poly(I:C) induces preterm labor via reduction of a2V expression and simultaneous activation of apoptosis and inflammatory processes. PMID- 24163417 TI - Understanding the molecular pathogenesis of methicillin-resistant Staphylococcus aureus. PMID- 24163418 TI - Immune evasion by pathogenic Leptospira strains: the secretion of proteases that directly cleave complement proteins. AB - Leptospirosis is an infectious disease of public health importance. To successfully colonize the host, pathogens have evolved multiple strategies to escape the complement system. Here we demonstrate that the culture supernatant of pathogenic but not saprophytic Leptospira inhibit the three complement pathways. We showed that the proteolytic activity in the supernatants of pathogenic strains targets the central complement molecule C3 and specific proteins from each pathway, such as factor B, C2, and C4b. The proteases cleaved alpha and beta chains of C3 and work in synergy with host regulators to inactivate C3b. Proteolytic activity was inhibited by 1,10-phenanthroline, suggesting the participation of metalloproteases. A recombinant leptospiral metalloprotease from the thermolysin family cleaved C3 in serum and could be one of the proteases responsible for the supernatant activity. We conclude that pathogenic leptospiral proteases can deactivate immune effector molecules and represent potential targets to the development of new therapies in leptospirosis. PMID- 24163416 TI - Human natural killer cells acting as phagocytes against Candida albicans and mounting an inflammatory response that modulates neutrophil antifungal activity. AB - BACKGROUND: Natural killer (NK) cells are innate lymphocytes with potent cytotoxic activity. Whereas activity of NK cells has been demonstrated against the fungal pathogens Aspergillus fumigatus and Cryptococcus neoformans, little was known about their interaction with Candida albicans. METHODS: Primary human NK cells were isolated from buffy coats, primed with a cytokine cocktail and used for confrontation assays with C. albicans. Interaction was monitored and quantified using live cell imaging, confocal microscopy, flow cytometry, and enzyme-linked immunosorbent assay. RESULTS: Human NK cells actively recognized C. albicans, resulting in degranulation and secretion of granulocyte-macrophage colony-stimulating factor, interferon gamma, and tumor necrosis factor alpha . Uniquely, activation of NK cells was triggered by actin-dependent phagocytosis. Antifungal activity of NK cells against C. albicans could be detected and mainly attributed to secreted perforin. However, NK cells were unable to inhibit filamentation of C. albicans. Human polymorphonuclear neutrophils (PMNs) counteracted the proinflammatory reaction of NK cells by preventing direct contact between NK cells and the fungal pathogen. Activation of PMNs was enhanced in the presence of NK cells, resulting in increased fungicidal activity. CONCLUSIONS: Our results show a unique pattern of NK cell interaction with C. albicans, which involves direct proinflammatory activation and modulation of PMN activity. For the first time, phagocytosis of a pathogen is shown to contribute to NK cell activation. PMID- 24163419 TI - Cancer control in Bangladesh. AB - Cancer is predicted to be an increasingly important cause of morbidity and mortality in Bangladesh in the next few decades. The estimated incidence of 12.7 million new cancer cases will rise to 21.4 million by 2030. More than two-thirds of the total expenditure on health is through out-of-pocket payments. According to the Bangladesh Bureau of Statistics, cancer is the sixth leading cause of death. International Agency for Research on Cancer has estimated cancer-related death rates in Bangladesh to be 7.5% in 2005 and 13% in 2030. The two leading causes are in males are lung and oral cancer and in females are breast cancer and cervical cancer. Bangladesh is now in severe shortage of radiation therapy machines, hospital bed, trained oncologists, medical radiation physicists and technologists. Bangladesh having different cancers associated with smoking and smokeless tobacco use, Human papilloma virus infection, Hepatitis B and C infection, Helicobacter Pylori infection, arsenic contaminated groundwater, availability of chemical carcinogens mainly formalin treated fruits, fish and vegetables at open market, tannery waste contaminated with chromium (which is used for poultry feed and fish feed preparation). A World Health Organization study revealed the annual cost of illnesses in Bangladesh attributable to tobacco usage is US$ 500 million and the total annual benefit from the tobacco sector is US$ 305 million as tax revenue. Bangladesh has developed a National Cancer Control Strategy and Action Plan with the aim of delivering a universal, quality based and timely service. Cancer prevention through tobacco control, health promotion and vaccination program, cancer early detection program for oral cavity, breast and cervix has initiated. Cancer detection and diagnostic facilities will be made available at medical colleges and district- hospitals and establish a referral chain. National capacity development, more cancer research will allow Bangladesh to deal effectively and efficiently with the cancer problems through evidence-based decision making. PMID- 24163421 TI - DAPK2 positively regulates motility of neutrophils and eosinophils in response to intermediary chemoattractants. AB - The tight regulation of granulocyte chemotaxis is crucial for initiation and resolution of inflammation. Here, we show that DAPK2, a Ca(2+)/CaM-sensitive serine/threonine kinase known to modulate cell death in various cell types, is a novel regulator of migration in granulocytes. We demonstrate that human neutrophils and eosinophils express DAPK2 but unlike other leukocytes, no DAPK1 or DAPK3 protein. When DAPK activities were blocked by inhibitors, we found that neither granulocyte lifespan nor phagocytosis was affected. However, such pharmacological inactivation of DAPK activity abolished motility of granulocytes in response to intermediary but not end-target chemoattractants ex vivo. The defect in chemotaxis in DAPK2-inactive granulocytes is likely a result of reduced polarization of the cells, mediated by a lack of MLC phosphorylation, resulting in radial F-actin and pseudopod formation. As neutrophils treated with DAPKi also showed reduced recruitment to the site of inflammation in a mouse peritonitis model, DAPK2 may be a novel target for anti-inflammatory therapies. PMID- 24163420 TI - Assessment of antibody-dependent respiratory burst activity from mouse neutrophils on Plasmodium yoelii malaria challenge outcome. AB - New tools are required to expedite the development of an effective vaccine against the blood-stage infection with the human malaria parasite Plasmodium falciparum. This work describes the assessment of the ADRB assay in a mouse model, characterizing the functional interaction between antimalarial serum antibodies and FcRs upon neutrophils. We describe a reproducible, antigen specific assay, dependent on functional FcR signaling, and show that ADRB activity is induced equally by IgG1 and IgG2a isotypes and is modulated by blocking FcR function. However, following immunization of mice with the blood stage vaccine candidate antigen MSP142, no measurable ADRB activity was induced against PEMS and neither was vaccine efficacy modulated against Plasmodium yoelii blood-stage challenge in gamma(-/-) mice compared with WT mice. In contrast, following a primary, nonlethal P. yoelii parasite challenge, serum from vaccinated mice and nonimmunized controls showed anti-PEMS ADRB activity. Upon secondary challenge, nonimmunized gamma(-/-) mice showed a reduced ability to control blood-stage parasitemia compared with immunized gamma(-/-) mice; however, WT mice, depleted of their neutrophils, did not lose their ability to control infection. Thus, whereas neutrophil-induced ADRB against PEMS does not appear to play a role in protection against P. yoelii rodent malaria, induction of ADRB activity after challenge suggests that antigen targets of anti-PEMS ADRB activity remain to be established, as well as further supporting the observation that ADRB activity to P. falciparum arises following repeated natural exposure. PMID- 24163422 TI - Changes in membrane biophysical properties induced by sphingomyelinase depend on the sphingolipid N-acyl chain. AB - Ceramide (Cer) is involved in the regulation of several cellular processes by mechanisms that depend on Cer-induced changes on membrane biophysical properties. Accumulating evidence shows that Cers with different N-acyl chain composition differentially impact cell physiology, which may in part be due to specific alterations in membrane biophysical properties. We now address how the sphingolipid (SL) N-acyl chain affects membrane properties in cultured human embryonic kidney cells by overexpressing different Cer synthases (CerSs). Our results show an increase in the order of cellular membranes in CerS2-transfected cells caused by the enrichment in very long acyl chain SLs. Formation of Cer upon treatment of cells with bacterial sphingomyelinase promoted sequential changes in the properties of the membranes: after an initial increase in the order of the fluid plasma membrane, reorganization into domains with gel-like properties whose characteristics are dependent on the acyl chain structure of the Cer was observed. Moreover, the extent of alterations of membrane properties correlates with the amount of Cer formed. These data reinforce the significance of Cer induced changes on membrane biophysical properties as a likely molecular mechanism by which different acyl chain Cers exert their specific biological actions. PMID- 24163423 TI - Mother's exercise during pregnancy programmes vasomotor function in adult offspring. AB - The intrauterine environment is influenced by maternal behaviour and programmes atherosclerotic disease susceptibility in offspring. The aim of this investigation was to test the hypothesis that mothers' exercise during pregnancy improves endothelial function in 3-, 5- and 9-month-old porcine offspring. The pregnant sows in the exercise group ran for an average of 39.35 +/- 0.75 min at 4.81 +/- 0.35 km h(-1) each day for 5 days per week for all but the last week of gestation. This induced a significant reduction in resting heart rate (exercised group, 89.3 +/- 3.5 beats min(-1); sedentary group, 102.1 +/- 3.1 beats min(-1); P < 0.05) but no significant differences in gestational weight gain (65.8 +/- 2.1 versus 63.3 +/- 1.9%). No significant effect on bradykinin-induced vasorelaxation with and without l-NAME was observed. A significant main effect was identified on sodium nitroprusside-induced vasorelaxation (P = 0.01), manifested by a reduced response in femoral arteries of all age groups from exercised-trained swine. Nitric oxide signalling was not affected by maternal exercise. Protein expression of MYPT1 was reduced in femoral arteries from 3-month-old offspring of exercised animals. A significant interaction was observed for PPP1R14A (P < 0.05) transcript abundance and its protein product CPI-17. In conclusion, pregnant swine are able to complete an exercise-training protocol that matches the current recommendations for pregnant women. Gestational exercise is a potent stimulus for programming vascular smooth muscle relaxation in adult offspring. Specifically, exercise training for the finite duration of pregnancy decreases vascular smooth muscle responsiveness in adult offspring to an exogenous nitric oxide donor. PMID- 24163424 TI - Differential effect of sympathetic activation on tissue oxygenation in gastrocnemius and soleus muscles during exercise in humans. AB - NEW FINDINGS: What is the central question of this study? The normal ability of sympathetic nerves to cause vasoconstriction is blunted in exercising skeletal muscle, a phenomenon termed 'functional sympatholysis'. Animal studies suggest that functional sympatholysis appears to occur preferentially in fast-twitch type II glycolytic compared with slow-twitch type I oxidative skeletal muscle. We asked whether these findings can be extended to humans. What is the main finding and its importance? We show that skeletal muscles composed largely of fast-twitch type II fibres may also be more sensitive to functional sympatholysis in humans, particularly at lower exercise intensities. Additionally, independent of muscle fibre type composition, the magnitude of sympatholysis is strongly related to exercise-induced increases in metabolic demand. Animal studies suggest that functional sympatholysis appears to occur preferentially in glycolytic (largely type II) compared with oxidative (largely type I) skeletal muscle. Whether these findings can be extended to humans currently remains unclear. In 12 healthy male subjects, vasoconstrictor responses in gastrocnemius (i.e. primarily type II) and soleus muscles (i.e. primarily type I) were measured using near-infrared spectroscopy to detect decreases in muscle oxygenation (HbO(2)) in response to sympathetic activation evoked by a cold pressor test (CPT). The HbO(2) responses to a CPT at rest were compared with responses during steady-state plantar flexion exercise (30 repetitions min(-1)) performed at 10, 20 and 40% maximal voluntary contraction (MVC) for 6 min. In resting conditions, HbO(2) at the gastrocnemius ( 14 +/- 1%) and soleus muscles (-16 +/- 1%) decreased significantly during CPT, with no differences between muscles. During planter flexion at 20% MVC, the change in HbO(2) in response to the CPT was blunted in gastrocnemius but not soleus, whereas during 40% MVC both muscles exhibited a significant attenuation to sympathetic activation. The decreases in HbO(2) in response to the CPT during exercise were significantly correlated with the metabolic demands of exercise (the decreases in HbO(2) in response to steady-state plantar flexion) in both gastrocnemius and soleus muscles. Collectively, these results suggest that skeletal muscles composed mainly of glycolytic type II fibres are more sensitive to functional sympatholysis, particularly at lower intensities of exercise. Moreover, the blunting of sympathetic vasoconstriction during exercise is strongly related to metabolic demand; an effect that appears independent of fibre type composition. PMID- 24163425 TI - Influence of locomotor muscle afferent inhibition on the ventilatory response to exercise in heart failure. AB - NEW FINDINGS: What is the central question of this study? Patients with heart failure often develop ventilatory abnormalities at rest and during exercise, but the mechanisms underlying these abnormalities remain unclear. This study investigated the influence of inhibiting afferent neural feedback from locomotor muscles on the ventilatory response during exercise in heart failure patients. What is the main finding and its importance? Our results suggest that inhibiting afferent feedback from locomotor muscle via intrathecal opioid administration significantly reduces the ventilatory response to exercise in heart failure patients. Patients with heart failure (HF) develop ventilatory abnormalities at rest and during exercise, but the mechanism(s) underlying these abnormalities remain unclear. We examined whether the inhibition of afferent neural feedback from locomotor muscles during exercise reduces exercise ventilation in HF patients. In a randomized, placebo-controlled design, nine HF patients (age, 60 +/- 2 years; ejection fraction, 27 +/- 2%; New York Heart Association class 2 +/- 1) and nine control subjects (age, 63 +/- 2 years) underwent constant-work submaximal cycling (65% peak power) with intrathecal fentanyl (impairing the cephalad projection of opioid receptor-sensitive afferents) or sham injection. The hypercapnic ventilatory response was measured to determine whether cephalad migration of fentanyl occurred. There were no differences in hypercapnic ventilatory response within or between groups in either condition. Despite a lack of change in ventilation, tidal volume or respiratory rate, HF patients had a mild increase in arterial carbon dioxide (P(aCO(2)) and a decrease in oxygen (P(aO(2)); P < 0.05 for both) at rest. The control subjects demonstrated no change in P(aCO(2)), P(aO(2)), ventilation, tidal volume or respiratory rate at rest. In response to fentanyl during exercise, HF patients had a reduction in ventilation (63 +/- 6 versus 44 +/- 3 l min(-1), P < 0.05) due to a lower respiratory rate (30 +/- 1 versus 26 +/- 2 breaths min(-1), P < 0.05). The reduced ventilation resulted in lower P aO 2 (97.6 +/- 2.5 versus 79.5 +/- 3.0 mmHg, P < 0.05) and increased P(aCO(2)) (37.3 +/- 0.9 versus 43.5 +/- 1.1 mmHg, P < 0.05), with significant improvement in ventilatory efficiency (reduction in the ventilatory equivalent for carbon dioxide; P < 0.05 for all). The control subjects had no change in ventilation or measures of arterial blood gases. These data suggest that inhibition of afferent feedback from locomotor muscle significantly reduces the ventilatory response to exercise in HF patients. PMID- 24163427 TI - Obesity and breast cancer: role of inflammation and aromatase. AB - Obesity is now recognised to be an inflammatory condition in which dysregulated metabolism plays an integral role. Inflammatory mediators regulate aromatase expression in the human breast as one mechanism whereby they increase the risk of breast cancer, especially in women who are obese. PMID- 24163426 TI - A specific cholesterol metabolic pathway is established in a subset of HCCs for tumor growth. AB - The liver plays a central role in cholesterol homeostasis. It exclusively receives and metabolizes oxysterols, which are important metabolites of cholesterol and are more cytotoxic than free cholesterol, from all extrahepatic tissues. Hepatocellular carcinomas (HCCs) impair certain liver functions and cause pathological alterations in many processes including cholesterol metabolism. However, the link between an altered cholesterol metabolism and HCC development is unclear. Human ACAT2 is abundantly expressed in intestine and fetal liver. Our previous studies have shown that ACAT2 is induced in certain HCC tissues. Here, by investigating tissue samples from HCC patients and HCC cell lines, we report that a specific cholesterol metabolic pathway, involving induction of ACAT2 and esterification of excess oxysterols for secretion to avoid cytotoxicity, is established in a subset of HCCs for tumor growth. Inhibiting ACAT2 leads to the intracellular accumulation of unesterified oxysterols and suppresses the growth of both HCC cell lines and their xenograft tumors. Further mechanistic studies reveal that HCC-linked promoter hypomethylation is essential for the induction of ACAT2 gene expression. We postulate that specifically blocking this HCC-established cholesterol metabolic pathway may have potential therapeutic applications for HCC patients. PMID- 24163428 TI - Action of GH on skeletal muscle function: molecular and metabolic mechanisms. AB - Skeletal muscle is a target tissue of GH. Based on its anabolic properties, it is widely accepted that GH enhances muscle performance in sports and muscle function in the elderly. This paper critically reviews information on the effects of GH on muscle function covering structure, protein metabolism, the role of IGF1 mediation, bioenergetics and performance drawn from molecular, cellular and physiological studies on animals and humans. GH increases muscle strength by enhancing muscle mass without affecting contractile force or fibre composition type. GH stimulates whole-body protein accretion with protein synthesis occurring in muscular and extra-muscular sites. The energy required to power muscle function is derived from a continuum of anaerobic and aerobic sources. Molecular and functional studies provide evidence that GH stimulates the anaerobic and suppresses the aerobic energy system, in turn affecting power-based functional measures in a time-dependent manner. GH exerts complex multi-system effects on skeletal muscle function in part mediated by the IGF system. PMID- 24163429 TI - APOE associations with severe CAA-associated vasculopathic changes: collaborative meta-analysis. AB - OBJECTIVES: Cerebral amyloid angiopathy (CAA) is associated with lobar intracerebral haemorrhage (ICH). While only the epsilon4 allele of the apolipoprotein E (APOE) gene is associated with the presence of CAA, both APOE epsilon4 and epsilon2 are associated with lobar ICH. The generally accepted explanation is that APOE-epsilon4 promotes vascular amyloid deposition, while APOE-epsilon2 promotes progression to severe CAA with associated vasculopathic changes that cause vessel rupture and ICH. We assessed the evidence for these allele-specific effects. METHODS: We systematically identified published studies with data on APOE genotype and histopathological assessment of postmortem brains for CAA severity. We obtained unpublished data from these for meta-analyses of the effects of epsilon4-containing (epsilon4+) and epsilon2-containing (epsilon2+) genotypes on progression to severe CAA. RESULTS: Of six eligible studies (543 eligible participants), data were available from 5 (497 participants, 353 with CAA). Meta-analyses showed a possible association of epsilon4+ genotypes with severe CAA (epsilon4+ vs epsilon4-: severe vs mild/moderate CAA, OR 2.5, 95% CI 1.4 to 4.5, p=0.002; severe vs moderate CAA, OR 1.7, 95% CI 0.9 to 3.1, p=0.11). For epsilon2+ versus epsilon2- genotypes, there was no significant association, but the very small number of participants with epsilon2+ genotypes (22) precluded reliable estimates. CONCLUSIONS: We found a possible association of severe CAA with APOE-epsilon4 but not APOE-epsilon2. However, our findings do not exclude a biologically meaningful association between APOE-epsilon2 and severe CAA. Further work is needed to elucidate fully the allele-specific associations of APOE with CAA and their mechanisms. PMID- 24163430 TI - The long-term outcomes of depression up to 10 years after stroke; the South London Stroke Register. AB - BACKGROUND: Post-stroke depression is a frequent chronic and recurrent problem that starts shortly after stroke and affects patients in the long term. The health outcomes of depression after stroke are unclear. AIMS: (1) To investigate the associations between depression at 3 months and mortality, stroke recurrence, disability, cognitive impairment, anxiety and quality of life (QoL), up to 5 years post-stroke. (2) To investigate these associations in patients recovering from depression by year 1. (3) To investigate associations between depression at 5 years and these outcomes up to 10 years. METHODS: Data from the South London Stroke Register (1997-2010) were used. Patients (n at registration=3240) were assessed at stroke onset, 3 months after stroke and annually thereafter. Baseline data included sociodemographics and stroke severity measures. Follow-up assessments included anxiety and depression (Hospital Anxiety and Depression scale), disability, QoL and stroke recurrence. Multivariable regression models adjusted for age, gender, ethnicity, stroke severity and disability were used to investigate the association between depression and outcomes at follow-up. RESULTS: Depression at 3 months was associated with: increased mortality (HR: 1.27 (1.04 to 1.55)), disability (RRs up to 4.71 (2.96 to 7.48)), anxiety (ORs up to 3.49 (1.71 to 7.12)) and lower QoL (coefficients up to -8.16 (-10.23-6.15)) up to year 5. Recovery from depression by 1 year did not alter these risks to 5 years. Depression in year 5 was associated with anxiety (ORs up to 4.06 (1.92 to 8.58)) and QoL (coefficients up to -11.36 (-14.86 to -7.85)) up to year 10. CONCLUSIONS: Depression is independently associated with poor health outcomes. PMID- 24163431 TI - Quantifying the pattern of optic tract degeneration in human hemianopia. AB - BACKGROUND: The existence of transsynaptic retrograde degeneration (TRD) in the human visual system has been established, however the dependence of TRD on different factors such as lesion location, size and manner of lesion acquisition has yet to be quantified. METHODS: We obtained T1-weighted structural and diffusion-weighted images for 26 patients with adult-acquired or congenital hemianopia and 12 age-matched controls. The optic tract (OT) was defined and measured in the structural and diffusion-weighted images, and degeneration assessed by comparing the integrity of tracts in the lesioned and in the undamaged hemisphere. RESULTS: OT degeneration was found in all patients with established lesions, regardless of lesion location. In patients with acquired lesions, the larger the initial lesion, the greater is the resulting TRD. However, this was not the case for congenital patients, who generally showed greater degeneration than would be predicted by lesion size. A better predictor of TRD was the size of the visual field deficit, which was correlated with degeneration across all patients. Interestingly, although diffusion-weighted imaging (DWI) is more frequently used to examine white matter tracts, in this study the T1-weighted scans gave a better indication of the extent of tract degeneration. CONCLUSIONS: We conclude that TRD of the OT occurs in acquired and congenital hemianopia, is correlated with visual field loss, and is most severe in congenital cases. Understanding the pattern of TRD may help to predict effects of any visual rehabilitation training. PMID- 24163432 TI - 14-3-3theta facilitates plasma membrane delivery and function of mechanosensitive connexin 43 hemichannels. AB - Intracellular signaling in osteocytes activated by mechanical loading is important for bone formation and remodeling. These signaling events are mediated by small modulators released from Cx43 hemichannels (HC). We have recently shown that integrin alpha5 senses the mechanical stimulation and induces the opening of Cx43 HC; however, the underlying mechanism is unknown. Here, we show that both Cx43 and integrin alpha5 interact with 14-3-3theta, and this interaction is required for the opening of Cx43 HC upon mechanical stress. The absence of 14-3 3theta prevented the interaction between Cx43 and integrin alpha5, and blocked HC opening. Furthermore, it decreased the transport of Cx43 and integrin alpha5 from the Golgi apparatus to the plasma membrane. Mechanical loading promoted the movement of Cx43 to the surface which was associated not only with an increase in 14-3-3theta levels but also its interaction with Cx43 and integrin alpha5. This stimulatory effect on forward transport by mechanical loading was attenuated in the absence of 14-3-3theta and the majority of the Cx43 accumulated in the Golgi. Disruption of the Golgi by brefeldin A reduced the association of Cx43 and integrin alpha5 with 14-3-3theta, further suggesting that the interaction is likely to occur in the Golgi. Together, these results define a previously unidentified, scaffolding role of 14-3-3theta in assisting the delivery of Cx43 and integrin alpha5 to the plasma membrane for the formation of mechanosensitive HC in osteocytes. PMID- 24163434 TI - The armadillo protein p0071 is involved in Rab11-dependent recycling. AB - p0071 is an intercellular junction protein of the p120 catenin family. We have identified Rab11a as a novel interaction partner of p0071. p0071 interacted preferentially with active Rab11a. Knockdown experiments revealed an interdependent regulation of both proteins. On the one hand, p0071 depletion induced a perinuclear accumulation of Rab11, suggesting a role of p0071 in the anterograde transport of Rab11 from the pericentrosomal region to the plasma membrane but not in retrograde transport. p0071 as well as Rab11 depletion increased transferrin receptor recycling indicating that p0071-induced Rab11 mislocalization interfered with Rab11 function and shifted recycling from the slow Rab11-dependent pathway to the fast Rab4-dependent pathway. When p0071 or Rab11 depletion was combined with a Rab4 knockdown the effect was reversed. On the other hand, Rab11a depletion increased p0071 recycling to cell contacts thereby identifying p0071 as a Rab11 cargo protein. This correlated with increased intercellular adhesion. Thus, we propose that p0071 has a key role in regulating recycling through the Rab11-dependent perinuclear recycling compartment, and links the regulation of adherens junctions to recycling to allow dynamic modulation of intercellular adhesion. PMID- 24163435 TI - Galpha73B is a downstream effector of JAK/STAT signalling and a regulator of Rho1 in Drosophila haematopoiesis. AB - JAK/STAT signalling regulates many essential developmental processes including cell proliferation and haematopoiesis, whereas its inappropriate activation is associated with the majority of myeloproliferative neoplasias and numerous cancers. Furthermore, high levels of JAK/STAT pathway signalling have also been associated with enhanced metastatic invasion by cancerous cells. Strikingly, gain of-function mutations in the single Drosophila JAK homologue, Hopscotch, result in haemocyte neoplasia, inappropriate differentiation and the formation of melanised haemocyte-derived 'tumour' masses; phenotypes that are partly orthologous to human gain-of-function JAK2-associated pathologies. Here we show that Galpha73B, a novel JAK/STAT pathway target gene, is necessary for JAK/STAT mediated tumour formation in flies. In addition, although Galpha73B does not affect haemocyte differentiation, it does regulate haemocyte morphology and motility under non-pathological conditions. We show that Galpha73B is required for constitutive, but not injury-induced, activation of Rho1 and for the localisation of Rho1 into filopodia upon haemocyte activation. Consistent with these results, we also show that Rho1 interacts genetically with JAK/STAT signalling, and that wild-type levels of Rho1 are necessary for tumour formation. Our findings link JAK/STAT transcriptional outputs, Galpha73B activity and Rho1 dependent cytoskeletal rearrangements and cell motility, therefore connecting a pathway associated with cancer with a marker indicative of invasiveness. As such, we suggest a mechanism by which JAK/STAT pathway signalling may promote metastasis. PMID- 24163433 TI - Protein kinase Darkener of apricot and its substrate EF1gamma regulate organelle transport along microtubules. AB - Regulation of organelle transport along microtubules is important for proper distribution of membrane organelles and protein complexes in the cytoplasm. RNAi mediated knockdown in cultured Drosophila S2 cells demonstrates that two microtubule-binding proteins, a unique isoform of Darkener of apricot (DOA) protein kinase, and its substrate, translational elongation factor EF1gamma, negatively regulate transport of several classes of membrane organelles along microtubules. Inhibition of transport by EF1gamma requires its phosphorylation by DOA on serine 294. Together, our results indicate a new role for two proteins that have not previously been implicated in regulation of the cytoskeleton. These results further suggest that the biological role of some of the proteins binding to the microtubule track is to regulate cargo transport along these tracks. PMID- 24163437 TI - Flagellar adhesion in Trypanosoma brucei relies on interactions between different skeletal structures in the flagellum and cell body. AB - The Trypanosoma brucei flagellum is an essential organelle anchored along the surface of the cell body through a specialized structure called the flagellum attachment zone (FAZ). Adhesion relies on the interaction of the extracellular portion of two transmembrane proteins, FLA1 and FLA1BP. Here, we identify FLAM3 as a novel large protein associated with the flagellum skeleton whose ablation inhibits flagellum attachment. FLAM3 does not contain transmembrane domains and its flagellar localization matches closely, but not exactly, that of the paraflagellar rod, an extra-axonemal structure present in the flagellum. Knockdown of FLA1 or FLAM3 triggers similar defects in motility and morphogenesis, characterized by the assembly of a drastically reduced FAZ filament. FLAM3 remains associated with the flagellum skeleton even in the absence of adhesion or a normal paraflagellar rod. However, the protein is dispersed in the cytoplasm when flagellum formation is inhibited. By contrast, FLA1 remains tightly associated with the FAZ filament even in the absence of a flagellum. In these conditions, the extracellular domain of FLA1 points to the cell surface. FLAM3 is essential for proper distribution of FLA1BP, which is restricted to the most proximal portion of the flagellum upon knockdown of FLAM3. We propose that FLAM3 is a key component of the FAZ connectors that link the axoneme to the adhesion zone, hence it acts in an equivalent manner to the FAZ filament complex, but on the side of the flagellum. PMID- 24163436 TI - Phosphorylation regulates VCIP135 function in Golgi membrane fusion during the cell cycle. AB - The Golgi apparatus in mammalian cells consists of stacks that are often laterally linked into a ribbon-like structure. During cell division, the Golgi disassembles into tubulovesicular structures in the early stages of mitosis and reforms in the two daughter cells by the end of mitosis. Valosin-containing protein p97-p47 complex-interacting protein, p135 (VCIP135), an essential factor involved in p97-mediated membrane fusion pathways, is required for postmitotic Golgi cisternae regrowth and Golgi structure maintenance in interphase. However, how VCIP135 function is regulated in the cell cycle remains unclear. Here, we report that VCIP135 depletion by RNA interference results in Golgi fragmentation. VCIP135 function requires membrane association and p97 interaction, both of which are inhibited in mitosis by VCIP135 phosphorylation. We found that wild-type VCIP135, but not its phosphomimetic mutants, rescues Golgi structure in VCIP135 depleted cells. Our results demonstrate that VCIP135 phosphorylation regulates its Golgi membrane association and p97 interaction, and thus contributes to the tight control of the Golgi disassembly and reassembly process during the cell cycle. PMID- 24163438 TI - The use of Likert scales with children. AB - OBJECTIVE: We investigated elementary school children's ability to use a variety of Likert response formats to respond to concrete and abstract items. METHODS: 111 children, aged 6-13 years, responded to 2 physical tasks that required them to make objectively verifiable judgments, using a 5-point response format. Then, using 25 items, we ascertained the consistency between responses using a "gold standard" yes/no format and responses using 5-point Likert formats including numeric values, as well as word-based frequencies, similarities to self, and agreeability. RESULTS: All groups responded similarly to the physical tasks. For the 25 items, the use of numbers to signify agreement yielded low concordance with the yes/no answer format across age-groups. Formats based on words provided higher, but not perfect, concordance for all groups. CONCLUSIONS: Researchers and clinicians need to be aware of the limited understanding that children have of Likert response formats. PMID- 24163439 TI - Mediators of 12-month outcomes of two Internet interventions for youth with type 1 diabetes. AB - OBJECTIVE: To determine mediators of 12-month outcomes of Internet interventions for youth with type 1 diabetes transitioning to adolescence. METHODS: In this multisite clinical trial, 320 youth were randomized to one of two Internet-based interventions: Coping skills (TEENCOPETM) or diabetes education (Managing Diabetes). Mediators of the interventions' effects on glycosylated hemoglobin and quality of life were examined. Data were collected at baseline and at 3, 6, and 12 months. RESULTS: Self-efficacy mediated treatment effects on quality of life in both interventions. For TEENCOPETM, stress reactivity, primary control coping, and secondary control coping mediated treatment effects, whereas for Managing Diabetes, social acceptance mediated treatment effects. There were no significant effects of either intervention on glycosylated hemoglobin. CONCLUSIONS: 2 Internet interventions for youth with type 1 diabetes resulted in improved quality of life by different mechanisms, suggesting components of both diabetes education and coping skills may help to achieve better outcomes in youth with type 1 diabetes. PMID- 24163440 TI - LLY-2707, a novel nonsteroidal glucocorticoid antagonist that reduces atypical antipsychotic-associated weight gain in rats. AB - Weight gain and diabetes have been reported during treatment with atypical antipsychotic drugs (AAPDs). Patients treated with the glucocorticoid receptor antagonist (GRA) and the progesterone receptor antagonist (PRA) mifepristone [estra-4,9-dien-3-one, 11-[4-(dimethylamino)phenyl]-17-hydroxy-17-(1-propynyl) (11beta,17beta)-(9CI)] experienced significant reduction in the weight gain observed when patients were treated with olanzapine or risperidone. To understand the pharmacology responsible for this finding, we discovered LLY-2707 [N-(5-(tert butyl)-3-(2-fluoro-5-methylpyridin-4-yl)-2-methyl-1H-indol-7 yl)methanesulfonamide], a novel and selective GRA, and evaluated its utility in preclinical models of AAPD-associated weight gain and diabetes. In vitro, LLY 2707 was a highly selective and potent GRA. GR occupancy in vivo was assessed using ex vivo binding where LLY-2707 inhibited [(3)H]dexamethasone binding to the liver. Modest but statistically significant decreases in brain ex vivo binding were observed with high doses of CORT-108297 [(R)-4alpha-(ethoxymethyl)-1-(4 fluorophenyl)-6-((4-(trifluoromethyl)phenyl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H pyrazolo[3,4-g]isoquinoline] and LLY-2707, but mifepristone inhibited at all doses. Central activity of the GRAs was confirmed by their ability to suppress amphetamine-induced increases in locomotor activity. The increases in the body weight of female rats treated with olanzapine (2 mg/kg PO) over 14 days were reduced in a dose-dependent manner by coadministration of LLY-2707. Similar decreases, although less robust, in body weight were seen with mifepristone and CORT-108297. In addition, sGRAs prevented the glucose excursion after intragastric olanzapine infusions consistent with a direct effect on the hyperglycemia observed during treatment with AAPDs. At doses effectively preventing weight gain, LLY-2707 did not substantially interfere with the dopamine D2 receptor occupancy by olanzapine. Therefore, GRA coadministration may provide a novel treatment modality to prevent the weight gain and diabetes observed during treatment with AAPDs. PMID- 24163441 TI - Induction of regulator of G-protein signaling 2 expression by long-acting beta2 adrenoceptor agonists and glucocorticoids in human airway epithelial cells. AB - In asthma and chronic obstructive pulmonary disease (COPD) multiple mediators act on Galphaq-linked G-protein-coupled receptors (GPCRs) to cause bronchoconstriction. However, acting on the airway epithelium, such mediators may also elicit inflammatory responses. In human bronchial epithelial BEAS-2B cells (bronchial epithelium + adenovirus 12-SV40 hybrid), regulator of G-protein signaling (RGS) 2 mRNA and protein were synergistically induced in response to combinations of long-acting beta2-adrenoceptor agonist (LABA) (salmeterol, formoterol) plus glucocorticoid (dexamethasone, fluticasone propionate, budesonide). Equivalent responses occurred in primary human bronchial epithelial cells. Concentrations of glucocorticoid plus LABA required to induce RGS2 expression in BEAS-2B cells were consistent with the levels achieved therapeutically in the lungs. As RGS2 is a GTPase-activating protein that switches off Galphaq, intracellular free calcium ([Ca(2+)]i) flux was used as a surrogate of responses induced by histamine, methacholine, and the thromboxane receptor agonist U46619 [(Z)-7-[(1S,4R,5R,6S)-5-[(E,3S)-3-hydroxyoct-1-enyl]-3 oxabicyclo[2.2.1]heptan-6-yl]hept-5-enoic acid]. This was significantly attenuated by salmeterol plus dexamethasone pretreatment, or RGS2 overexpression, and the protective effect of salmeterol plus dexamethasone was abolished by RGS2 RNA silencing. Although methacholine and U46619 induced interleukin-8 (IL-8) release and this was inhibited by RGS2 overexpression, the repression of U46619 induced IL-8 release by salmeterol plus dexamethasone was unaffected by RGS2 knockdown. Given a role for Galphaq-mediated pathways in inducing IL-8 release, we propose that RGS2 acts redundantly with other effector processes to repress IL 8 expression. Thus, RGS2 expression is a novel effector mechanism in the airway epithelium that is induced by glucocorticoid/LABA combinations. This could contribute to the efficacy of glucocorticoid/LABA combinations in asthma and COPD. PMID- 24163443 TI - Integration of Spatial and Social Network Analysis in Disease Transmission Studies. AB - This study presents a case study of how social network and spatial analytical methods can be used simultaneously for disease transmission modeling. The paper first reviews strategies employed in previous studies and then offers the example of transmission of two bacterial diarrheal diseases in rural Bangladesh. The goal is to understand how diseases vary socially above and beyond the effects of the local neighborhood context. Patterns of cholera and shigellosis incidence are analyzed in space and within kinship-based social networks in Matlab, Bangladesh. Data include a spatially referenced longitudinal demographic database which consists of approximately 200,000 people and laboratory-confirmed cholera and shigellosis cases from 1983 to 2003. Matrices are created of kinship ties between households using a complete network design and distance matrices are also created to model spatial relationships. Moran's I statistics are calculated to measure clustering within both social and spatial matrices. Combined spatial effects spatial disturbance models are built to simultaneously analyze spatial and social effects while controlling for local environmental context. Results indicate that cholera and shigellosis always clusters in space and only sometimes within social networks. This suggests that the local environment is most important for understanding transmission of both diseases however kinship-based social networks also influence their transmission. Simultaneous spatial and social network analysis can help us better understand disease transmission and this study has offered several strategies on how. PMID- 24163444 TI - The diamond jubilee of the Indian Journal of Anaesthesia: A look-back, for the future. PMID- 24163445 TI - Pharmaco-genomics and anaesthesia: Mysteries, correlations and facts. PMID- 24163442 TI - A proteomic perspective of Sirtuin 6 (SIRT6) phosphorylation and interactions and their dependence on its catalytic activity. AB - Sirtuin 6 (SIRT6), a member of the mammalian sirtuin family, is a nuclear deacetylase with substrate-specific NAD(+)-dependent activity. SIRT6 has emerged as a critical regulator of diverse processes, including DNA repair, gene expression, telomere maintenance, and metabolism. However, our knowledge regarding its interactions and regulation remains limited. Here, we present a comprehensive proteomics-based analysis of SIRT6 protein interactions and their dependence on SIRT6 catalytic activity. We also identify evolutionarily conserved SIRT6 phosphorylations, including four within a proline-rich disordered region, and show that the conserved S338 phosphorylation can modulate selected SIRT6 interactions. By integrating molecular biology tools, microscopy, immunoaffinity purifications, label-free quantitative mass spectrometry, and bioinformatic analyses, we have established the first large-scale SIRT6 interaction network. Relative protein abundances and gene ontology functional assessment highlighted proteins involved in transcription regulation, chromatin organization, nuclear transport, telomerase function, and RNA processing. Independent immunoisolations under increased stringency distinguished the most stable SIRT6 interactions. One prominent interaction with Ras-GTPase-activating protein-binding protein 1 (G3BP1) was further validated by microscopy, reciprocal purifications, and isolations in different cell types and of endogenous SIRT6. Interestingly, a subset of specific interactions, including G3BP1, were significantly reduced or abolished in isolations of catalytically deficient SIRT6 mutant, revealing previously unknown interplay between SIRT6 activity and its associations. Overall, our study reveals putative means of regulation of SIRT6 functions via interactions and modifications, providing an important resource for future studies on the molecular mechanisms underlying sirtuin functions. PMID- 24163446 TI - One lung ventilation strategies for infants and children undergoing video assisted thoracoscopic surgery. AB - The advantages of video assisted thoracoscopic surgery (VATS) in children have led to its increased usage over the years. VATS, however, requires an efficient technique for one lung ventilation. Today, there is an increasing interest in developing the technique for lung isolation to meet the anatomic and physiologic variations in infants and children. This article aims to provide an updated and comprehensive review on one-lung ventilation strategies for infants and children undergoing VATS. Search of terms such as 'One lung ventilation for infants and children', 'Video assisted thoracoscopic surgery for infants and children', and 'Physiologic changes during one lung ventilation for infants and children' were used. The search mechanics and engines for this review included the following: Kandang Kerbau Hospital (KKH) eLibrary, PubMed, Ovid Medline, Cochrane Central Register of Controlled Trials, and Cochrane Database of Systematic Reviews. During the search the author focused on significant current and pilot randomized control trials, case reports, review articles, and editorials. Critical decision making on what device to use based on the age, weight, and pathology of the patient; and how to use it for lung isolation are discussed in this article. Furthermore, additional information regarding the advantages, limitations, techniques of insertion and maintenance of each device for one lung ventilation in infants and children were the highlights in this article. PMID- 24163447 TI - Inhalational anaesthesia with low fresh gas flow. AB - During the inhalation of anaesthesia use of low fresh gas flow (0.35-1 L/min) has some important advantages. There are three areas of benefit: pulmonary - anaesthesia with low fresh gas flow improves the dynamics of inhaled anaesthesia gas, increases mucociliary clearance, maintains body temperature and reduces water loss. Economic - reduction of anaesthesia gas consumption resulting in significant savings of > 75% and Ecological - reduction in nitrous oxide consumption, which is an important ozone-depleting and heat-trapping greenhouse gas that is emitted. Nevertheless, anaesthesia with high fresh gas flows of 2-6 L/min is still performed, a technique in which rebreathing is practically negligible. This special article describes the clinical use of conventional plenum vaporizers, connected to the fresh gas supply to easily perform low (1 L/min), minimal (0.5 L/min) or metabolic flow anaesthesia (0.35 L/min) with conventional Primus Draeger((r)) anaesthesia machines in routine clinical practice. PMID- 24163448 TI - Bispectral index score and observer's assessment of awareness/sedation score may manifest divergence during onset of sedation: Study with midazolam and propofol. AB - BACKGROUND: Correlation between the clinical and electroencephalogram-based monitoring has been documented sporadically during the onset of sedation. Propofol and midazolam have been studied individually using the observer's assessment of awareness/sedation (OAA/S) score and Bispectral index score (BIS). The present study was designed to compare the time to onset of sedation for propofol and midazolam using both BIS and OAA/S scores, and to find out any correlation. METHODS: A total of 46 patients (18-60 years, either sex, American Society of Anesthesiologists (ASA) I/II) posted for infraumbilical surgeries under spinal anaesthesia were randomly allocated to receive either injection propofol 1 mg/kg bolus followed by infusion 3 mg/kg/h (Group P, n=23) or injection midazolam 0.05 mg/kg bolus followed by infusion 0.06 mg/kg/h (Group M, n=23). Spinal anaesthesia was given with 2.5 ml to 3.0 ml of 0.5% bupivacaine heavy. When sensory block reached T6 level, sedation was initiated. The time to reach BIS score 70 and time to achieve OAA/S score 3 from the start of study drug were noted. OAA/S score at BIS score 70 was noted. Data from 43 patients were analyzed using SPSS 12 for Windows. RESULTS: Time to reach BIS score 70 using propofol was significantly lower than using the midazolam (P<0.05). Time to achieve OAA/S score 3 using propofol was comparable with midazolam (P=0.358). CONCLUSION: A divergence exists between the time to reach BIS score 70 and time to achieve OAA/S score 3 using midazolam, compared with propofol, during the onset of sedation. PMID- 24163449 TI - The effect of dexmedetomidine infusion on propofol requirement for maintenance of optimum depth of anaesthesia during elective spine surgery. AB - BACKGROUND: Maintenance of adequate depth of anaesthesia in spine surgery is vital to prevent awareness, to reduce stress response and possible autonomic instability frequently associated with spine surgery. Dexmedetomidine, a alpha2 adrenoceptor agonist with analgesic and sedative adjuvant property has been found to reduce dose requirement of multiple anaesthetic agents both for induction and during the maintenance of anaesthesia. AIM: The aim of this study is to observe the effect of dexmedetomidine, on the requirement of propofol for induction and maintenance of adequate depth of anaesthesia during spine surgery. METHODS: It was a prospective, randomised, double-blinded, parallel group, placebo controlled and open-lebel study in tertiary care hospital. A total of 70 patients aged 20-60 years, American Society of Anaesthesiologists GradeI and II, scheduled for elective spine surgery were randomly allocated into two groups. Each patient of Group D (n=35) received an initial loading dose of dexmedetomidine at 1 MUg/kg over 10 min, started 15 min before induction of anaesthesia followed by an infusion at a rate of 0.2 MUg/kg/h. Patients of Group P (n=35) received the same volume of 0.9% normal saline solution as placebo. Requirement of propofol at induction and during maintenance was calculated maintaining bispectral index between 40 and 60. P<0.05 was considered to be statistically significant. RESULTS: Mean requirement of propofol was found to be lessened by 48.08% and 61.87% for induction and maintenance of anaesthesia respectively while using dexmedetomidine. CONCLUSION: Administration of dexmedetomidine significantly reduces the requirement of propofol while maintaining desired depth of anaesthesia without any significant complication. PMID- 24163450 TI - Paramedian epidural with midline spinal in the same intervertebral space: An alternative technique for combined spinal and epidural anaesthesia. AB - BACKGROUND: Although different techniques have been developed for administering combined spinal epidural (CSE) anaesthesia, none can be described as an ideal one. OBJECTIVES: WE PERFORMED A STUDY TO COMPARE TWO POPULAR CSE TECHNIQUES: Double segment technique (DST) and single segment (needle through needle) technique (SST) with another alternative technique: Paramedian epidural and midline spinal in the same intervertebral space (single space dual needle technique: SDT). METHODS: After institutional ethical clearance, 90 consenting patients undergoing elective lower limb orthopaedic surgery were allocated to receive CSE into one of the three groups (n=30 each): Group I: SST, Group II: SDT, Group III: DST using computerized randomization. The time for technique performance, surgical readiness, technical aspects of epidural and subarachnoid block (SAB) and morbidity were compared. RESULTS: SDT is comparable with SST and DST in time for technique performance (13.42+/-2.848 min, 12.18+/-6.092 min, 11.63+/-3.243 min respectively; P=0.268), time to surgical readiness (18.28+/ 3.624 min, 17.64+/-5.877 min, 16.87+/-3.137 min respectively; P=0.42) and incidence of technically perfect block (70%, 66.66%, 76.66%; respectively P=0.757). Use of paramedian route for epidural catheterization in SDT group decreases complications and facilitates catheter insertion. There was a significant number of cases with lack of dural puncture appreciation (SST=ten, none in SDT and DST; P=0.001) and delayed cerebrospinal fluid reflux (SST=five, none in SDT and DST; P=0.005) while performance of SAB in SST group. The incidence of nausea, vomiting, post-operative backache and headache was comparable between the three groups. CONCLUSION: SDT is an acceptable alternative to DST and SST. PMID- 24163451 TI - A comparative study in the post-operative spine surgeries: Epidural ropivacaine with dexmedetomidine and ropivacaine with clonidine for post-operative analgesia. AB - BACKGROUND: Anaesthesia for spine surgeries is not only concerned with relieving pain during surgeries but also during the post-operative period. A prospective randomised study was carried out to evaluate the efficacy of epidural route and to compare the efficacy and clinical profile of dexmedetomidine and clonidine as an adjuvant to ropivacaine, in epidural analgesia with special emphasis on their quality of analgesia and the ability to provide the smooth post-operative course. METHODS: A total of 60 subjects, 33 were men and 27 were women between the age of 18 and 65 years of American Society of Anaesthesiologists (ASA) I/II class who underwent spine surgeries were randomly allocated into two groups, ropivacaine + dexmedetomidine (RD) and ropivacaine + clonidine (RC), comprising 30 patients each. Group RD received 20 ml of 0.2% ropivacaine and 1 MUg/kg of dexmedetomidine while group RC received 20 ml of 0.2% ropivacaine and 2 MUg/kg of clonidine through the epidural catheter. Onset of analgesia, time of peak effect, duration of analgesia, cardiorespiratory parameters, side-effects and need of rescue intravenous (IV) analgesics were observed. RESULTS: The demographic profile and ASA class were comparable between the groups. None of the patients needed rescue analgesics in either group. Group RD had early onset, early peak effect, prolonged duration and stable cardiorespiratory parameters when compared with group RC. The side-effects profile was also comparable with a little higher incidence of nausea and dry mouth in both groups. CONCLUSION: Epidural route provided acceptable analgesia in spine surgeries and avoided the need of IV analgesics in either group. Dexmedetomidine is a better neuraxial adjuvant compared with clonidine for providing early onset and prolonged post-operative analgesia and stable cardiorespiratory parameters. PMID- 24163452 TI - Are active warming measures required during paediatric cleft surgeries? AB - BACKGROUND: During paediatric cleft surgeries intraoperative heat loss is minimal and hence undertaking all possible precautions available to prevent hypothermia and use of active warming measures may result in development of hyperthermia. This study aims to determine whether there will be hyperthermia on active warming and hypothermia if no active warming measures are undertaken. The rate of intraoperative temperature changes with and without active warming was also noted. METHODS: This study was conducted on 120 paediatric patients undergoing cleft lip and palate surgeries. In Group A, forced air warming at 38 degrees C was started after induction. In Group B, no active warming was done. Body temperature was recorded every 30 min starting after induction until 180 min or end of surgery. Intragroup comparison of variables was done using Paired sample test and intergroup comparison using independent sample t-test. RESULTS: In Group A, all intraoperative temperature readings were significantly higher than baseline. In Group B, there was a significant reduction in temperature at 30 and 60 min. Temperature at 90 min did not show any significant difference, but further readings were significantly higher. Maximum rise in temperature occurred in Group A between 120 and 150 min and maximum fall in temperature in Group B was seen during first 30 min. CONCLUSION: In pediatric cleft surgeries, we recommend active warming during the first 30 minutes if the surgery is expected to last for <2h, and no such measures are required if the expected duration is >2h. PMID- 24163453 TI - Diagnostic value of the upper lip bite test in predicting difficulty in intubation with head and neck landmarks obtained from lateral neck X-ray. AB - BACKGROUND: Unanticipated difficult tracheal intubation remains a primary concern of anaesthesiologists and upper lip bite test (ULBT) is one of the assessments used in predicting difficult intubation. In this study, we aimed to check the utility of lateral neck X-ray measurements in improving the diagnostic value of the ULBT. METHODS: In a prospective study conducted from January 2007 until December 2010, we recorded personal and demographic data of 4500 patients who entered the study and subjected them to standard lateral neck radiography. Before the induction of anaesthesia, clinical examination and ULBT results were recorded and during induction of anaesthesia laryngoscopic grading was evaluated and recorded in questionnaires. All the compiled data were analysed by SPSS 14.0 (SPSS Inc., Chicago, IL, USA) software. Diagnostic value for each test was calculated and compared. RESULTS: Negative predictive values (NPVs) were high in all tests. ULBT had the highest specificity and NPV compared with the other tests. The positive predictive value for all the tests had been low, but marginally high in the ULBT. CONCLUSION: Although all the tests used had relatively acceptable predictive values, combination of tests appeared to be more predictive. Highest sensitivities were observed with ULBT, mandibulohyoid distance and thyromental distance respectively. Use of radiological parameters may not be suitable as screening tools, but may help in anticipating and preparing for a difficult scenario. PMID- 24163454 TI - Emergency laparotomy for necrotising enterocolitis in a newborn with hypoplastic left heart syndrome. AB - Necrotising enterocolitis (NEC) and congenital heart disease are two distinct disease processes, but they appear to be inter-related, particularly in patients with the congenital heart condition known as hypoplastic left heart syndrome (HLHS). Both NEC and HLHS are causes of significant morbidity and mortality in the neonatal population. As medical and surgical advances allow for the palliation and correction of complex heart lesions at an earlier gestational age and lower birth weight, the already high-risk of NEC in this population is likely to increase. In this article, we report a case of a neonate with unpalliated HLHS who underwent emergency laparotomy for NEC. We also discuss the pathophysiology of these two diseases and the perioperative care of this rare group of patients. PMID- 24163455 TI - Tricuspid valve endocarditis following central venous cannulation: The increasing problem of catheter related infection. AB - A central venous catheter (CVC) is inserted for measurement of haemodynamic variables, delivery of nutritional supplements and drugs and access for haemodialysis and haemofiltration. Catheterization and maintenance are common practices and there is more to the technique than routine placement as evident when a procedure-related complication occurs. More than 15% of the patients who receive CVC placement have some complications and infectious endocarditis involving the tricuspid valve is a rare and serious complication with high morbidity and mortality. Overenthusiastic and deep insertion of the guide wire and forceful injection through the CVC may lead to injury of the tricuspid valve and predispose to bacterial deposition and endocarditis. We report a case of tricuspid valve endocarditis, probably secondary to injury of the anterior tricuspid leaflet by the guide wire or the CVC that required open heart surgery with vegetectomy and repair of the tricuspid valve. PMID- 24163456 TI - Perioperative management of an elderly patient of hypertrophic obstructive cardiomyopathy for knee arthroplasty and the role of peripheral nerve blocks. AB - This case report exemplifies how the anaesthetic technique of general anesthesia with continuous bilateral femoral nerve block for bilateral knee arthroplasty was well chosen for the management of perioperative complications in an elderly patient with hypertrophic obstructive cardiomyopathy (HOCM). A 69-year-old female patient of HOCM was scheduled for bilateral total knee replacement. Echocardiography revealed severe left ventricular outflow tract obstruction with peak systolic gradient of 56 mmHg. The surgery was conducted under general anaesthesia with invasive monitoring and bilateral continuous femoral nerve blocks for postoperative analgesia. Postoperatively, she developed pulmonary oedema due to the liberal administration of fluids. This complication was successfully managed without interrupting the management of pain. Management of patients with HOCM for noncardiac surgery requires knowledge of variable presentation of two forms of disease. Also, this case report highlights the practical advantage of continuous femoral nerve block (CFNB)s over epidural anaesthesia. PMID- 24163457 TI - Electrical storm: Role of stellate ganglion blockade and anesthetic implications of left cardiac sympathetic denervation. AB - An electrical storm is usually associated with catecholaminergic surge following myocardial ischaemia and manifest as recurrent ventricular arrhythmias, requiring frequent DC shocks. Delivering repeated DC shocks induces myocardial damage and further worsens the arrhythmias, which are resistant to the antiarrhythmic drugs. Cardiac sympathetic blockade abates the excessive catecholaminergic drive and help pacifying the malignant ventricular arrhythmias. We treated the electrical storm in a 52-year-old male with ultrasound-guided left sympathetic ganglion block followed by surgical left cardiac sympathetic denervation. The patient remained symptom-free without any incident of ventricular arrhythmias for 8 months after the surgery. The ultrasonography during blockade of the stellate ganglion enhances the success rate of the technique, reduces the quantity of local anaesthetic required to produce desired effects and prevents technical complications. Supraclavicular surgical access to the upper thoracic sympathetic chain obviates the necessity for one lung ventilation and lateral decubitus during surgery, when the patient is in hemodynamically unstable condition. Sympathectomy can be performed under general anaesthesia taking cautions to avoid sympathetic stimulation in intraoperative period. PMID- 24163458 TI - Anaesthetic management of a case of idiopathic intracranial hypertension. AB - Idiopathic intracranial hypertension (IIH) is a rare headache syndrome characterized by prolonged elevation of intracranial pressure without related pathology in either the brain or the composition of cerebrospinal fluid. Herein, we provide a brief review of the clinical presentation of IIH and the anaesthetic considerations in a female posted for transcervical resection of the endometrium and right nephrectomy with the disorder. Most of patients with IIH are reported during pregnancy and came for management of labour and delivery. To our knowledge no such case has been described previously. PMID- 24163459 TI - Cerebral salt wasting syndrome in craniopharyngioma. PMID- 24163460 TI - Predicting intraoperative cardiovascular complication in patients with anterior mediastinal mass-role of central venous pressure monitoring. PMID- 24163461 TI - Does pre-operative echocardiography delay hip fracture surgery? PMID- 24163462 TI - Anaesthetic considerations in primary repair of tracheobronchial injury following blunt chest trauma in paediatric age group: Experience of two cases. PMID- 24163463 TI - Leiomyoma of trachea: An anaesthetic challenge. PMID- 24163464 TI - Breaking the midnight fast: An observational cross-sectional audit of preoperative fasting policies and practices at a Tertiary Care Hospital. PMID- 24163465 TI - Modification of submental intubation using oral Ring-Adair-Elwyn tubes in faciomaxillary surgeries: A novel approach. PMID- 24163466 TI - Nasal intubation in an adult male with Le Fort II fracture and pneumocephalus using a nasogastric tube. PMID- 24163467 TI - Unanticipated difficult airway. PMID- 24163468 TI - Retained foreign bodies: Vigilance is the price of safety. PMID- 24163469 TI - Loss of integrity of a reinforced endotracheal tube by patient bite. PMID- 24163470 TI - Dexmedetomidine as sedative and analgesic in a patient of sickle cell disease for total hip replacement. PMID- 24163471 TI - Beware! defects in pipeline supplies can occur: Be aware of this possibility after engineering work in related areas of the hospital. PMID- 24163472 TI - Methemoglobinemia: What the anaesthetist must know. PMID- 24163474 TI - Comment: Ondansetron: Timing and dosage. PMID- 24163473 TI - A case of triple vessel disease posted for buccal mucosal graft urethroplasty under low dose spinal anaesthesia with dexmedetomedine. PMID- 24163475 TI - Response: Comparative electrocardiographic effects of intravenous ondansetron and granisetron in patients undergoing surgery for carcinoma breast: A prospective single blind randomised trial. PMID- 24163476 TI - Comment: Molar approach with backward, upward, right and posterior manoeuvre. PMID- 24163477 TI - Comment: Hard palate tumour: A nightmare for the anaesthesiologists: Role of modified molar approach. PMID- 24163478 TI - Role stress, interrole conflict, and job satisfaction among university employees: the creation and test of a model. AB - Many universities have experienced financial hardships during the recent economic downturn. To save money, several have resorted to laying off employees, which has often resulted in increased work and stress for the remaining employees. Such an increase has the potential to adversely affect employees' sense of job satisfaction. This study created and tested the fit of a conceptual model containing role stress and interrole conflict as a way to account for employees' job satisfaction. The model demonstrated an acceptable fit to the data and contained several significant paths. Implications of the results, study limitations, and future directions for research are discussed. PMID- 24163479 TI - Education of Children Left Behind in Rural China. AB - Despite China's substantial internal migration, longstanding rural-urban bifurcation has prompted many migrants to leave their children behind in rural areas. This study examines the consequences of out-migration for children's education using longitudinal data from the China Health and Nutrition Survey (N = 885). This study takes into account the complex family migration strategies and distinguishes various types of migration in China, including different forms of parental migration as well as sibling migration. Results show that migration of siblings generates benefits for children's education, which is particularly pronounced for girls and children at middle-school levels. But parental migration has not given children left behind a significant advantage in educational prospects as their parents had hoped. Younger children seem to be especially susceptible to the disruptive effect of parental out-migration. PMID- 24163481 TI - Identifying Discrimination at Work: The Use of Field Experiments. AB - Antidiscrimination law offers protection to workers who have been treated unfairly on the basis of their race, gender, religion, or national origin. In order for these protections to be invoked, however, potential plaintiffs must be aware of and able to document discriminatory treatment. Given the subtlety of contemporary forms of discrimination, it is often difficult to identify discrimination when it has taken place. The methodology of field experiments offers one approach to measuring and detecting hiring discrimination, providing direct observation of discrimination in real-world settings. In this article, we discuss the findings of two recent field experiments measuring racial discrimination in low wage labor markets. This research provides several relevant findings for researchers and those interested in civil rights enforcement: (1) it produces estimates of the rate of discrimination at the point of hire; (2) it yields evidence about the interactions associated with discrimination (many of which reveal the subtlety with which contemporary discrimination is practiced); and (3) it provides a vehicle for both research on and enforcement of antidiscrimination law. PMID- 24163480 TI - Liquid Tunable Microlenses based on MEMS techniques. AB - The recent rapid development in microlens technology has provided many opportunities for miniaturized optical systems, and has found a wide range of applications. Of these microlenses, tunable-focus microlenses are of special interest as their focal lengths can be tuned using micro-scale actuators integrated with the lens structure. Realization of such tunable microlens generally relies on the microelectromechanical system (MEMS) technologies. Here, we review the recent progress in tunable liquid microlenses. The underlying physics relevant to these microlenses are first discussed, followed by description of three main categories of tunable microlenses involving MEMS techniques, mechanically driven, electrically driven, and those integrated within microfluidic systems. PMID- 24163482 TI - Chronic Disease Burden and the Interaction of Education, Fertility, and Growth. AB - This study considers the eradication of hookworm disease from the American South as a test of the quantity-quality (Q-Q) framework of fertility. Eradication was principally a shock to the price of quality because of three factors: hookworm (i) depresses the return to human-capital investment, (ii) had a very low case fatality rate, and (iii) had negligible prevalence among adults. Consistent with the Q-Q model, we find a significant decline in fertility associated with eradication. Relative sizes of fertility and human-capital responses to hookworm indicate that the Q-Q mechanism is of a similar magnitude to secular co-movements in these same variables. PMID- 24163483 TI - The Academic Success of East Asian American Youth: The Role of Shadow Education. AB - Using data from the Education Longitudinal Study, this study assessed the relevance of shadow education to the high academic performance of East Asian American students by examining how East Asian American students differed from other racial/ethnic students in the prevalence, purpose, and effects of using the two forms - commercial test preparation service and private one-to-one tutoring - of SAT coaching, defined as the American style of shadow education. East Asian American students were most likely to take a commercial SAT test preparation course for the enrichment purpose, and benefited most from taking this particular form of SAT coaching. However, this was not the case for private SAT one-to-one tutoring. While black students were most likely to utilize private tutoring for the remedial purpose, the impact of private tutoring was trivial for all racial/ethnic groups including East Asian American students. The authors discussed broader implications of the findings on racial/ethnic inequalities in educational achievement beyond the relevance of shadow education for the academic success of East Asian American students. PMID- 24163484 TI - Dicarboxylated ethynylarenes as buffer-dependent chemosensors for Cd(II), Pb(II) and Zn(II). AB - Two dicarboxylated ethynylarenes were prepared efficiently from condensation of 1,3-bis(3-aminoph enylethynyl)benzene with two equivalents of either succinic anhydride or glutaric anhydride. These compounds behave as fluorescent chemosensors selective for Cd(II), Pb(II) and Zn(II) cations under buffered aqueous conditions, with analyte binding observed as bathochromically shifted, intensified fluorescence. It was noteworthy that the fluorescence responses varied significantly with buffer identity. A conformational restriction mechanism involving reversible interactions between the fluorophore, metal cation and buffer itself is proposed. PMID- 24163485 TI - Jane Jacobs and 'The Need for Aged Buildings': Neighborhood Historical Development Pace and Community Social Relations. AB - Jacobs argued that grand planning schemes intending to redevelop large swaths of a city according to a central theoretical framework fail because planners do not understand that healthy cities are organic, spontaneous, messy, complex systems that result from evolutionary processes. She argued that a gradual pace of redevelopment would facilitate maintenance of existing interpersonal ties. This paper operationalizes the concept of pace of development within a cross-sectional framework as the "age diversity of housing." Analysis of a population-based multilevel community survey of Chicago linked with census housing data predicts individual perceptions of neighborhood social relations (cohesion, control, intergenerational closure, and reciprocal exchange). A gradual pace of redevelopment resulting in historical diversity of housing significantly predicts social relations, lending support to Jacobs's claims. PMID- 24163486 TI - Characteristics of positive and negative secondary ions emitted from [Formula: see text] and [Formula: see text] impacts. AB - The current limitation for SIMS analyses is insufficient secondary ion yields, due in part to the inefficiency of traditional primary ions. Massive gold clusters are shown to be a route to significant gains in secondary ion yields relative to other commonly used projectiles. At an impact energy of 520 keV, [Formula: see text] is capable of generating an average of greater than ten secondary ions per projectile, with some impact events generating >100 secondary ions. The capability of this projectile for signal enhancement is further displayed through the observation of up to seven deprotonated molecular ions from a single impact on a neat target of the model pentapeptide leu-enkephalin. Positive and negative spectra of leu-enkephalin reveal two distinct emission regimes responsible for the emission of either intact molecular ions with low internal energies or small fragment species. The internal energy distribution for this projectile is measured using a series of benzylpyridinium salts and compared with the small polyatomic projectile [Formula: see text] at 110 keV as well as distributions previously reported for electrospray ionization and fast atom bombardment. These results show that [Formula: see text] offers high secondary ion yields not only for small fragment ions, e.g. CN-, typically observed in SIMS analyses, but also for characteristic molecular ions. For the leu-enkephalin example, the yields for each of these species are greater than unity. PMID- 24163487 TI - Characterization of individual nano-objects with nanoprojectile-SIMS. AB - Secondary ion mass spectrometry (SIMS) applied in the event-by-event bombardment/detection mode is uniquely suited for the characterization of individual nano-objects. In this approach, nano-objects are examined one-by-one, allowing for the detection of variations in composition. The validity of the analysis depends upon the ability to physically isolate the nano-objects on a chemically inert support. This requirement can be realized by deposition of the nano-objects on a Nano-Assisted Laser Desorption/Ionization (NALDITM) plate. The featured nanostructured surface provides a support where nano-objects can be isolated if the deposition is performed at a proper concentration. We demonstrate the characterization of individual nano-objects on a NALDITM plate for two different types of nanometric bacteriophages: Qbeta and M13. Scanning electron microscope (SEM) images verified that the integrity of the phages is preserved on the NALDITM substrate. Mass spectrometric data show secondary ions from the phages are identified and resolved from those from the underlying substrate. PMID- 24163488 TI - Simultaneous detection and localization of secondary ions and electrons from single large cluster impacts. AB - The use of large cluster primary ions (e.g. C60, Au400) in secondary ion mass spectrometry has become prevalent in recent years due to their enhanced emission of secondary ions, in particular, molecular ions (MW <= 1500 Da). The co-emission of electrons with SIs was investigated per projectile impact. It has been found that SI and electrons yields increased with increasing projectile energy and size. The use of the emitted electrons from impacts of C60 for localization has been demonstrated for cholesterol deposited on a copper grid. The instrumentation, methodologies, and results from these experiments are presented. PMID- 24163489 TI - Surface characterization of biological nanodomains using NP-ToF-SIMS. AB - This paper describes the application of nanoparticle bombardment with time-of flight secondary ion mass spectrometry (NP-ToF-SIMS) for the analysis of native biological surfaces for the case of sagittal sections of mammalian brain tissue. The use of high energy, single nanoparticle impacts (e.g. 520 keV Au400) permits desorption of intact lipid molecular ions, with enhanced molecular ion yield and reduced fragmentation. When coupled with complementary molecular ion fragmentation and exact mass measurement analysis, high energy nanoparticle probes (e.g. 520 keV Au400 NP) provide a powerful tool for the analysis of the lipid components from native brain sections without the need for surface preparation and with ultimate spatial resolution limited to the desorption volume per impact (~103 nm3). PMID- 24163490 TI - Out of sight, but not out of mind: 21-month-olds use syntactic information to learn verbs even in the absence of a corresponding event. PMID- 24163491 TI - Child Care and School Performance in Denmark and the United States. AB - Child care and early education policies may not only raise average achievement but may also be of special benefit for less advantaged children, in particular if programs are high quality. We test whether high quality child care is equalizing using rich longitudinal data from two comparison countries, Denmark and the United States. In Denmark, we find that enrollment in high-quality formal care at age 3 is associated with higher cognitive scores at age 11. Moreover, the findings suggest stronger effects for the lowest-income children and for children at the bottom of the test score distribution. In the US case, results are different. We find that enrollment in school or center based care is associated with higher cognitive scores at school entry, but the beneficial effects erode by age 11, particularly for disadvantaged children. Thus, the US results do not point to larger and more lasting effects for disadvantaged children. This may be because low income children attend poorer quality care and subsequently attend lower quality schools. PMID- 24163492 TI - Perceptual Negativity Predicts Greater Reactivity to Negative Events in Daily Life. AB - Reinforcement sensitivity theory includes the idea that people differ in their sensitivity to negative events, but relevant process-based assessments have not been developed. The present studies assessed sensitivity to negative events in terms of the extent to which negative word stimuli were perceived to be larger than neutral word stimuli. There was a general tendency to overestimate the size of negative relative to neutral words, but individuals differed substantially in this form of what is termed perceptual negativity. Of more importance, two studies (total N = 151) found systematic relationships between individual differences in perceptual negativity and reactivity to negative events in daily diary protocols. Study 1 found that within-person variations in the occurrence of daily negative events undermined goal-related optimism to a greater extent at higher, relative to lower, levels of perceptual negativity. Study 2 conceptually replicated this interaction in the context of within-person associations between the occurrence of daily negative events and antisocial behavior. These findings are important in advancing reinforcement sensitivity theory, in operationalizing a particular component of it, and in extending it to reactivity processes in daily life. PMID- 24163493 TI - A fast Monte Carlo EM algorithm for estimation in latent class model analysis with an application to assess diagnostic accuracy for cervical neoplasia in women with AGC. AB - In this article we use a latent class model (LCM) with prevalence modeled as a function of covariates to assess diagnostic test accuracy in situations where the true disease status is not observed, but observations on three or more conditionally independent diagnostic tests are available. A fast Monte Carlo EM (MCEM) algorithm with binary (disease) diagnostic data is implemented to estimate parameters of interest; namely, sensitivity, specificity, and prevalence of the disease as a function of covariates. To obtain standard errors for confidence interval construction of estimated parameters, the missing information principle is applied to adjust information matrix estimates. We compare the adjusted information matrix based standard error estimates with the bootstrap standard error estimates both obtained using the fast MCEM algorithm through an extensive Monte Carlo study. Simulation demonstrates that the adjusted information matrix approach estimates the standard error similarly with the bootstrap methods under certain scenarios. The bootstrap percentile intervals have satisfactory coverage probabilities. We then apply the LCM analysis to a real data set of 122 subjects from a Gynecologic Oncology Group (GOG) study of significant cervical lesion (S CL) diagnosis in women with atypical glandular cells of undetermined significance (AGC) to compare the diagnostic accuracy of a histology-based evaluation, a CA-IX biomarker-based test and a human papillomavirus (HPV) DNA test. PMID- 24163494 TI - The Winners in China's Urban Housing Reform. AB - Housing reform in China has proceeded on two tracks: privatization of public housing and development of a new private housing sector. During this period of transition, rents have remained relatively low in the remaining public housing, and purchase prices offered to occupants of public housing have been well below market prices. Although these rents and prices are partly based on known formulas, there is considerable variability in how much people pay for similar apartments. This study uses 2000 Census data to estimate the housing subsidy received by the remaining renters in the public sector and purchasers of public housing, based on private sector prices for housing of comparable quality and size. The paper also analyzes variation in the estimated discount from market prices that these people receive. The findings show that the biggest winners in China's transition from socialist housing allocation are those who were favored in the previous system, based on such factors as residence status, education and occupation. PMID- 24163495 TI - Influence of Late Life Stressors on the Decisions of Older Women to Relocate into Congregate Senior Housing. AB - Late-life stressors often require individuals to make substantial alterations in behavior and lifestyle and can affect their overall health and well-being Relocation is a significant life stress regardless of age. The primary aim of this study is to elucidate the push-pull factors associated with moving into congregate senior housing. The secondary aim is to investigate the decision making processes and stresses associated with moving into a congregate living environment. Interviews were conducted with 26 women who were new residents in congregate senior housing. Relocation, as expected, was considered to be stressful although individual differences were found among perceptions of relocation stresses. Women who had made the decision to relocate on their own showed evidence of better psychosocial well-being at the time of the move. One quarter of the sample chose to move in order to provide care to another person. As the options for senior housing continue to evolve and the numbers of adults reaching advanced age continue to increase, it is important to understand the factors that contribute to successful adaptation. This knowledge will enable facility administrators to implement programs and procedures to assist incoming residents with acclimating to their new homes. PMID- 24163496 TI - Letermovir Treatment of Human Cytomegalovirus Infection Antiinfective Agent. AB - Novel therapies are urgently needed for the management of cytomegalovirus (CMV) disease in high-risk patients. Currently licensed agents target the viral DNA polymerase, and although they are effective, they are fraught with toxicities to patients. Moreover, emergence of antiviral resistance is an increasing problem, particularly for patients on long-term suppressive therapy. A new agent, letermovir (AIC246), shows great promise for the management of CMV infection. Advantages include its good oral bioavailability, its lack of toxicity, and the apparent absence of drug-drug interactions. Letermovir has a novel mechanism of action, exerting its antiviral effect by interfering with the viral pUL56 gene product and in the process disrupting the viral terminase complex. This agent demonstrates substantial promise as an alternative to more toxic antivirals in patients at high risk for CMV disease, particularly in the transplantation setting. PMID- 24163497 TI - PERSONALITY TRAITS AND THE WORKING ALLIANCE IN PSYCHOTHERAPY TRAINEES: AN ORGANIZING ROLE FORTHE FIVE FACTOR MODEL? AB - Ackerman and Hilsenroth (2001, 2003) suggested that therapist personality may be meaningfully associated with the psychotherapy working alliance. We extended this line of research by examining the association between Five Factor Model (Costa & McCrae, 1997b) personality traits Neuroticism, Extraversion, Openness to Experience, Agreeableness, and Conscientiousness, and ratings of the working alliance made by clients and psychotherapy trainees. Higher trainee Neuroticism was associated with better client ratings of the alliance, but with worse trainee ratings of the alliance. Higher trainee Openness was associated with lower client ratings of the alliance, and higher trainee Agreeableness with lower trainee ratings of the alliance. Because levels of Neuroticism were low and levels of Openness high among therapist trainees, the results suggest that average rather than low Neuroticism, and average rather than high Openness facilitate better client perceptions of the alliance. Implications are discussed in terms of monitoring and training therapists who evidence these dispositions, in order to assist them in developing maximally effective alliances with clients. PMID- 24163498 TI - Meta-Analysis for Sociology - A Measure-Driven Approach. AB - Meta-analytic methods are becoming increasingly important in sociological research. In this article we present an approach for meta-analysis which is especially helpful for sociologists. Conventional approaches to meta-analysis often prioritize "concept-driven" literature searches. However, in disciplines with high theoretical diversity, such as sociology, this search approach might constrain the researcher's ability to fully exploit the entire body of relevant work. We explicate a "measure-driven" approach, in which iterative searches and new computerized search techniques are used to increase the range of publications found (and thus the range of possible analyses) and to traverse time and disciplinary boundaries. We demonstrate this measure-driven search approach with two meta-analytic projects, examining the effects of various social variables on all-cause mortality. PMID- 24163499 TI - Materials by Design-A Perspective From Atoms to Structures. AB - Biological materials are effectively synthesized, controlled, and used for a variety of purposes-in spite of limitations in energy, quality, and quantity of their building blocks. Whereas the chemical composition of materials in the living world plays a some role in achieving functional properties, the way components are connected at different length scales defines what material properties can be achieved, how they can be altered to meet functional requirements, and how they fail in disease states and other extreme conditions. Recent work has demonstrated this by using large-scale computer simulations to predict materials properties from fundamental molecular principles, combined with experimental work and new mathematical techniques to categorize complex structure property relationships into a systematic framework. Enabled by such categorization, we discuss opportunities based on the exploitation of concepts from distinct hierarchical systems that share common principles in how function is created, linking music to materials science. PMID- 24163500 TI - Synthesis of stereotetrads by regioselective cleavage of diastereomeric MEM protected 2-methyl-3,4-epoxy alcohols with diethylpropynyl aluminum. AB - The regioselectivity of the epoxide ring opening of 2-methyl-3,4-epoxy alcohols with diethylpropynylalane has been studied as a function of the C1 alcohol protecting group. An efficient selective method was developed using MEM as the protecting group. The reaction proceeded in a highly regioselective manner providing the useful 1,3-diol motif. The undesired 1,4-diol product produced by some free alcohol diastereomers was not observed. This highly stereoselective method provides access to termini-differentiated stereotetrads, which are essential building bocks for polypropionate synthesis. PMID- 24163501 TI - Ecosystem services of the Southern Ocean: trade-offs in decision-making. AB - Ecosystem services are the benefits that mankind obtains from natural ecosystems. Here we identify the key services provided by the Southern Ocean. These include provisioning of fishery products, nutrient cycling, climate regulation and the maintenance of biodiversity, with associated cultural and aesthetic benefits. Potential catch limits for Antarctic krill (Euphausia superba Dana) alone are equivalent to 11% of current global marine fisheries landings. We also examine the extent to which decision-making within the Antarctic Treaty System (ATS) considers trade-offs between ecosystem services, using the management of the Antarctic krill fishery as a case study. Management of this fishery considers a three-way trade-off between fisheries performance, the status of the krill stock and that of predator populations. However, there is a paucity of information on how well these components represent other ecosystem services that might be degraded as a result of fishing. There is also a lack of information on how beneficiaries value these ecosystem services. A formal ecosystem assessment would help to address these knowledge gaps. It could also help to harmonize decision making across the ATS and promote global recognition of Southern Ocean ecosystem services by providing a standard inventory of the relevant ecosystem services and their value to beneficiaries. PMID- 24163502 TI - Synthesis and Spectroscopic Correlation of the Diastereoisomers of 2,3-Dihydroxy 2,6,8-trimethyldeca-(4Z, 6E)-dienoic Acid: Implications for the Structures of Papuamides A-D and Mirabamides A-D. AB - All 4 diastereomeric possibilities for the 2,3-dihydroxy-2,6,8-trimethyldeca (4Z,6E)-dienoic acid (Dhtda) residue, found in the cyclic depsipeptide natural products papuamides A-D and mirabamides A-D, were stereoselectively synthesized using a Z-selective Wittig reaction of both enantiomers of 2,4-dimethylhex-2-enyl triphenylphosphonium bromide with all four diastereoisomers of ethyl-3-formyl-2 methyl-1,4-dioxaspiro[4,4]nonane-2-carboxylate. To elucidate the configuration of Dhtda, the 1H- and 13C-NMR spectra of the synthetic isomers were compared to those of the natural residue. On the basis of that comparison, it is suggested that the likely configuration of the diastereomer present in Dhtda residue is either (2R,3S,8S) or (2S,3R,8S) in the papuamides and mirabimides. PMID- 24163503 TI - Heavy ethanol intoxication increases proinflammatory cytokines and aggravates hemorrhagic shock-induced organ damage in rats. AB - Hemorrhagic shock (HS) following acute alcohol intoxication can increase proinflammatory cytokine production and induce marked immunosuppression. We investigated the effects of ethanol on physiopathology and cytokine levels following HS in acutely alcohol-intoxicated rats. Rats received an intravenous injection of 5 g/kg ethanol over 3 h followed by HS induced by withdrawal of 40% of total blood volume from a femoral arterial catheter over 30 min. Mean arterial pressure (MAP) and heart rate (HR) were monitored continuously for 48 h after the start of blood withdrawal. Biochemical parameters, including hemoglobin, ethanol, glutamic oxaloacetic transaminase (GOT), glutamic pyruvic transaminase (GPT), blood urea nitrogen (BUN), creatinine (Cre), lactic dehydrogenase (LDH), and creatine phosphokinase (CPK), were measured at 30 min before induction of HS and 0, 1, 3, 6, 9, 12, 18, 24, and 48 h after HS. Serum tumor necrosis factor- alpha (TNF- alpha ) and interleukin-6 (IL-6) levels were measured at 1 and 12 h after HS. The liver, kidneys, and lungs were removed for pathology at 48 h later. HS significantly increased HR, blood GOT, GPT, BUN, Cre, LDH, CPK, TNF- alpha , and IL-6 levels and decreased hemoglobin and MAP in rats. Acute ethanol intoxication further increased serum levels of GOT, GPT, BUN, Cre, LDH, CPK, TNF- alpha and IL 6 elevation following HS. Acutely intoxicated rats exacerbated the histopathologic changes in the liver, kidneys, and lungs following HS. PMID- 24163504 TI - Natural antioxidant-isoliquiritigenin ameliorates contractile dysfunction of hypoxic cardiomyocytes via AMPK signaling pathway. AB - Isoliquiritigenin (ISL), a simple chalcone-type flavonoid, is derived from licorice compounds and is mainly present in foods, beverages, and tobacco. Reactive oxygen species (ROS) is a critical factor involved in modulating cardiac stress response signaling during ischemia and reperfusion. We hypothesize that ISL as a natural antioxidant may protect heart against ischemic injury via modulating cellular redox status and regulating cardioprotective signaling pathways. The fluorescent probe H2DCFDA was used to measure the level of intracellular ROS. The glucose uptake was determined by 2-deoxy-D-glucose-(3)H accumulation. The IonOptix System measured the contractile function of isolated cardiomyocytes. The results demonstrated that ISL treatment markedly ameliorated cardiomyocytes contractile dysfunction caused by hypoxia. ISL significantly stimulated cardioprotective signaling, AMP-activated protein kinase (AMPK), and extracellular signal-regulated kinase (ERK) signaling pathways. The ROS fluorescent probe H2DCFDA determination indicated that ISL significantly reduced cardiac ROS level during hypoxia/reoxygenation. Moreover, ISL reduced the mitochondrial potential (Deltapsi) of isolated mouse cardiomyocytes. Taken together, ISL as a natural antioxidant demonstrated the cardioprotection against ischemic injury that may attribute to the activation of AMPK and ERK signaling pathways and balance of cellular redox status. PMID- 24163505 TI - Systemic inflammatory responses and lung injury following hip fracture surgery increases susceptibility to infection in aged rats. AB - Pulmonary infections frequently occur following hip fracture surgery in aged patients. However, the underlying reasons are not fully understood. The present study investigates the systemic inflammatory response and pulmonary conditions following hip fracture surgery as a means of identifying risk factors for lung infections using an aged rodent model. Aged, male Sprague-Dawley rats (8 animals per group) underwent a sham procedure or hip fracture plus femoral intramedullary pinning. Animals were sacrificed 1, 3, and 7 days after the injury. Markers of systemic inflammation and pulmonary injury were analyzed. Both sham-operated and injured/surgical group animals underwent intratracheal inoculation with Pseudomonas aeruginosa 1, 3, and 7 days after surgery. P. aeruginosa counts in blood and bronchoalveolar lavage (BAL) fluid and survival rates were recorded. Serum TNF- alpha , IL-6, IL-1 beta , and IL-10 levels and markers of pulmonary injury were significantly increased at 1 and 3 days following hip fracture and surgery. Animals challenged with P. aeruginosa at 1 and 3 days after injury had a significantly decreased survival rate and more P. aeruginosa recovered from blood and BAL fluid. This study shows that hip fracture and surgery in aged rats induced a systemic inflammatory response and lung injury associated with increased susceptibility to infection during the acute phase after injury and surgery. PMID- 24163506 TI - Inflammatory mediators of angiogenesis. PMID- 24163507 TI - Mediators of inflammation and immune responses in the human gastrointestinal tract. PMID- 24163508 TI - Skull base osteomyelitis in otitis externa: The utility of triphasic and single photon emission computed tomography/computed tomography bone scintigraphy. AB - BACKGROUND: Skull base osteomyelitis (SBO) refers to infection that has spread beyond the external auditory canal to the base of the skull in advanced stages of otitis externa. Clinically, it may be difficult to differentiate SBO from severe otitis externa without bony involvement. This study was performed to determine the role of three phase bone scintigraphy (TPBS) and single photon emission tomography/computed tomography (SPECT/CT) in detecting SBO. MATERIALS AND METHODS: We retrospectively analyzed records of 20 patients (14 M, 6 F) with otitis externa and suspected SBO. TPBS and SPECT/CT of the skull were performed. Findings were correlated with clinical, laboratory and diagnostic CT scan findings. RESULTS: All patients were diabetic with elevated erythrocyte sedimentation rate. A total of 18 patients had bilateral and two unilateral symptoms. Cranial nerves were involved in eight patients and microbiological culture of ear discharge fluid positive in seven. Early images showed increased temporal vascularity in nine patients and increased soft-tissue uptake in 10, while delayed images showed increased bone uptake in 19/20 patients. Localized abnormal tracer uptake was shown by SPECT/CT in the mastoid temporal (15), petrous (11), sphenoid (3) and zygomatic (1) and showed destructive changes in five. Thus, TPBS was found positive for SBO in 10/20 patients and changed the management in four. CONCLUSION: Our study suggests that TPBS with SPECT/CT is a useful non-invasive investigation for detection of SBO in otitis externa. PMID- 24163509 TI - Indigenous technology development and standardization of the process for obtaining ready to use sterile sodium pertechnetate-Tc-99m solution from Geltech generator. AB - PURPOSE OF THE STUDY: The indigenous design and technology development for processing large scale zirconium molybdate-Mo-99 (ZrMo-99) Geltech generator was successfully commissioned in Board of Radiation and Isotope Technology (BRIT), India, in 2006. The generator production facility comprises of four shielded plant facilities equipped with tongs and special process gadgets amenable for remote operations for radiochemical processing of ZrMo-99 gel. RESULTS: Over 2800 Geltech generators have been processed and supplied to user hospitals during the period 2006-2013. Geltech generator supplied by BRIT was initially not sterile. Simple elution of Tc-99m is performed by a sterile evacuated vial with sterile and pyrogen free 0.9% NaCl solution to obtain sodium (Tc-99m) pertechnetate solution. A special type online 0.22 MUm membrane filter has been identified and adapted in Geltech generator. CONCLUSIONS: The online filtration of Tc-99m from Geltech generator; thus, provided sterile Tc-99m sodium pertechnetate solution. Generators assembled with modified filter assembly were supplied to local hospital in Mumbai Radiation Medicine Centre (RMC) and S.G.S. Medical College and KEM Hospital) and excellent performances were reported by users. PMID- 24163510 TI - Development of a radiopharmaceutical dose calculator for pediatric patients undergoing diagnostic nuclear medicine studies. AB - OBJECTIVE: It is important to ensure that as low as reasonably achievable (ALARA) concept during the radiopharmaceutical (RPH) dose administration in pediatric patients. Several methods have been suggested over the years for the calculation of individualized RPH dose, sometimes requiring complex calculations and large variability exists for administered dose in children. The aim of the present study was to develop a software application that can calculate and store RPH dose along with patient record. MATERIALS AND METHODS: We reviewed the literature to select the dose formula and used Microsoft Access (a software package) to develop this application. We used the Microsoft Excel to verify the accurate execution of the dose formula. The manual and computer time using this program required for calculating the RPH dose were compared. RESULTS: The developed application calculates RPH dose for pediatric patients based on European Association of Nuclear Medicine dose card, weight based, body surface area based, Clark, Solomon Fried, Young and Webster's formula. It is password protected to prevent the accidental damage and stores the complete record of patients that can be exported to Excel sheet for further analysis. It reduces the burden of calculation and saves considerable time i.e., 2 min computer time as compared with 102 min (manual calculation with the calculator for all seven formulas for 25 patients). CONCLUSION: The software detailed above appears to be an easy and useful method for calculation of pediatric RPH dose in routine clinical practice. This software application will help in helping the user to routinely applied ALARA principle while pediatric dose administration. PMID- 24163511 TI - Scintigraphic scoring system for grading severity of gastro-esophageal reflux on 99mTc sulfur colloid gastro-esophageal reflux scintigraphy: A prospective study of 39 cases with pre and post treatment assessment. AB - AIM: The study aimed at developing a scoring system for scintigraphic grading of gastro-esophageal reflux (GER), on gastro-esophageal reflux scintigraphy (GERS) and comparison of clinical and scintigraphic scores, pre- and post-treatment. MATERIALS AND METHODS: A total of 39 cases with clinically symptomatic GER underwent 99mTc sulfur colloid GERS; scores were assigned based on the clinical and scintigraphic parameters. Post domperidone GERS was performed after completion of treatment. Follow up GERS was performed and clinical and scintigraphic parameters were compared with baseline parameters. RESULTS: Paired t-test on pre and post domperidone treatment clinical scores showed that the decline in post-treatment scores was highly significant, with P value < 0.001. The scintigraphic scoring system had a sensitivity of 93.9% in assessing treatment response to domperidone, specificity of 83.3% i.e., 83.3% of children with no decline in scintigraphic scores show no clinical response to Domperidone. The scintigraphic scoring system had a positive predictive value of 96.9% and a negative predictive value of 71.4%. CONCLUSION: GERS with its quantitative parameters is a good investigation for assessing the severity of reflux and also for following children post-treatment. PMID- 24163512 TI - Fluoro-deoxy-glucose positron emission tomography/computed tomography in lymphoma: A pictorial essay. AB - F-18 fluoro-deoxy-glucose (FDG) positron emission tomography/computed tomography (PET/CT) has emerged as a powerful imaging modality in the field of oncology. F 18 FDG PET/CT is now an established tool in the management of lymphoma. This has been shown to be useful in staging, detection of bone marrow involvement (BMI), early response assessment and end of therapy response assessment in lymphoma. Interpretation of F-18 FDG PET/CT in lymphoma is carried out by various qualitative response assessment criteria. London criteria are used for interpretation of interim PET/CT and International Harmonization Project (IHP) criteria are used to interpret PET/CT done after the end of chemotherapy. Quantitative analysis is also found to be useful in assessment of response early after two cycles of chemotherapy in patients with diffuse large B cell lymphoma (DLBCL). This pictorial essay provides few images describing the FDG avidity of lymphoma, patterns of bone marrow uptake and their relevance in predicting BMI, role of staging PET/CT, quantitative analysis in response assessment, example images of response according to London criteria and IHP criteria. Few pitfalls in imaging of lymphoma with PET/CT are also discussed in the images legend. PMID- 24163513 TI - Hemimegalencephaly: A rare cause of hemihypoperfusion on 99m technetium-ethyl cysteinate dimer brain perfusion single-photon emission computed tomography. AB - Hemimegalencephaly is a rare congenital neuronal migration disorder that can presents with the equally rare finding of hemihypoperfusion on brain perfusion single-photon emission computed tomography (SPECT). It is an extremely rare cause of intractable epilepsy. Technetium-99m ethyl cysteinate dimer (ECD) brain perfusion SPECT is useful in excluding other foci of hypoperfusion in the contralateral since hemispherectomy has been suggested to be the treatment of choice. Furthermore, hemimegalencephaly may present with hyper as well as hypoperfusion on ECD SPECT. We present the case of an 11-year-old male child with intractable seizures who showed hemihypoperfusion in the hemimegalecephalic hemisphere. PMID- 24163514 TI - Long segment jejuno-ileal duplication cyst with ectopic gastric mucosa detected on 99mTc-pertechnetate scintigraphy. AB - Enteric duplication cysts (EDC) are uncommon congenital anomalies that may occur anywhere along the digestive tract. Ectopic gastric mucosa (EGM), another rare condition, is usually present as short segments in the small intestine and may be associated with EDC. Abdominal scintigraphy with 99mTc pertechnetate may be useful in the diagnosis, since the radiotracer is concentrated by functioning gastric mucosa. In this case report, the authors describe a child with a 150 cm long jejuno-ileal duplication cyst containing EGM identified by intense 99mTc pertechnetate uptake on scintigraphy without any pharmacological intervention. PMID- 24163515 TI - Hepatic metastasis disguised as fat spared area in the background of fatty liver: Detection on FDG PET/CT. AB - Area of fat sparing in fatty liver is known to pose a diagnostic challenge in an oncological setting, especially in cancers with higher propensity for liver metastases. We report an unusual appearance of hepatic metastases in a fat spared area, on both computed tomography (CT) and positron emission tomography (PET), in a combined 18 fluorine-fluorodeoxyglucose (18 F-FDG) PET/CT study done in metastatic adenocarcinoma of colon. PMID- 24163516 TI - Brain hypoperfusion on Tc-99m-ethylene dicysteine diethyl ester single-photon emission computed tomography in Hashimoto's encephalopathy. AB - We present a 17-year-old female, previously diagnosed of autoimmune hyperthyroidism who had an acute neurological episode and presented high antithyroid antibodies titers, cerebral spinal fluid and electroencephalogram changes. Tc-99m ethylene dicysteine diethyl ester brain single-photon emission computed tomography (SPECT) showed global and patchy hypoperfusion. With glucocorticoid therapy, clinical symptoms disappeared; there was a decrease in antithyroid antibody levels and repeat brain SPECT revealed improvement of perfusion. PMID- 24163517 TI - Utility of bone scintigraphy in diagnosis of post- traumatic osteitis pubis. AB - Minor musculoskeletal injuries usually heal within few weeks with conservative treatment, but in pelvic injuries, symptoms may persist for long duration and patient need medical attention to get relief from disturbing pain symptoms. We present a case of post-trauma osteitis pubis in a 58-year-old female, who reported with lower abdominal and left side hip joint pain since 2 months, after an episode of trivial trauma to her pelvis. Technetium-99m methylene diphosphonate bone scintigraphy was performed, which confirmed the site of injury in symphysis pubis and left hip joint, by increased radiotracer localization at both of these symptomatic sites. PMID- 24163518 TI - Somatostatin receptor positron emission tomography/computed tomography (PET/CT) in the evaluation of opsoclonus-myoclonus ataxia syndrome. AB - Opsoclonus-myoclonus ataxia (OMA) syndrome is the most common paraneoplastic neurological syndrome of childhood, associated with occult neuroblastoma in 20% 50% of all cases. OMA is the initial presentation of neuroblastoma in 1%-3% of children. Conventional radiological imaging approaches include chest radiography and abdominal computed tomography (CT). Nuclear medicine techniques, in form of (123)I/(131)I-metaiodobenzylguanidine (MIBG) scintigraphy have been incorporated in various diagnostic algorithms for evaluation of OMA. We describe use of somatostatin receptor PET/CT with (68)Gallium- DOTA-DPhe(1), Tyr(3)-octreotate (DOTATATE) in diagnosis of neuroblastoma in two cases of OMA. PMID- 24163519 TI - Metastatic squamous cell carcinoma thyroid from functionally cured cancer cervix. AB - The authors report a very unusual occurrence of a metastatic squamous carcinoma to thyroid gland from a treated squamous cell carcinoma cervix 12 years before with no recurrence at the primary site. The case also has an additional complexity of rapid progression of the metastatic thyroid carcinoma to wide spread dissemination to lungs and bones while on concurrent chemo radio therapy confirming the aggressiveness of the entity. PMID- 24163520 TI - Myocardial bridge: The cause of angina in a young man. AB - Myocardial bridging is basically the systolic narrowing of epicardial coronary arteries, secondary to their tunneled course in myocardium. Though it is a benign condition it can have the symptoms like acute coronary syndrome, arrhythmias and sudden cardiac death. We report a 32-year-old male, who presented with typical exertional angina, had positive exercise treadmill and thallium-201 test. Coronary angiography revealed myocardial bridge of distal left anterior descending coronary artery. He was put on beta-blockers and was doing well at 8 years of follow-up. PMID- 24163521 TI - Incidental detection of superior sternal cleft on Technetium-99m methylene diphosphonate bone scan. AB - A sternal cleft is an extremely rare developmental anomaly, which results from failure of fusion of sternal bars which contribute to the formation of the sternum. Most cases are diagnosed in early childhood, where it is associated with serious other midline defects. A sternal cleft is seen as a photopenic area on technetium-99m methylene diphosphonate bone scan and can be confused with other conditions. We report an extremely rare case of isolated upper sternal cleft in a 45-years-old male, found incidentally on Tc-99m MDP bone scan. PMID- 24163522 TI - Rare case of isolated splenic metastases from gastric cancer detected with fluorine-18 fluorodeoxyglucose-positron emission tomography/computed tomography. AB - We report a rare case of isolated splenic metastasis from gastric cancer detected with fluorine-18 fluorodeoxyglucose-positron emission tomography/computed tomography (PET/CT). A 55-year-old man with gastric cancer 1 year post surgery, evaluated with PET/CT showed focal, intense uptake in the spleen, with no other abnormal findings. On splenectomy, the lesion was confirmed as metastasis from gastric cancer pathologically. PMID- 24163523 TI - Paget's disease diagnosed on bone scintigraphy: Case report and literature review. AB - Paget's disease of bone is a chronic bone remodeling disorder. Although most patients are asymptomatic, a variety of symptoms and complications may develop directly from bone involvement or secondarily due to compression by the expanded bone. It is usually diagnosed from radiological and biochemical abnormalities or in advanced cases it becomes clinically evident due to the expanded bone. We report a case of Paget's disease which was detected incidentally during evaluation of nephrolithiasis and polyarthritis but had normal radiographs and normal biochemical markers. PMID- 24163524 TI - Multicentric Castleman's disease: Closest mimic of lymphoma on FDG PET/CT. PMID- 24163525 TI - Pertechnetate thyroid scan in Marine-Lenhart syndrome. PMID- 24163526 TI - Incidentally detected vesico inguinal hernia on fluoro-deoxy glucose positron emission tomography-computed tomography. PMID- 24163527 TI - Liposuction and the cutaneous surgeon. PMID- 24163528 TI - Fat Ful'fill'ment: A Review of Autologous Fat Grafting. AB - For more than a century, clinicians have attempted to utilise fat for the treatment of tissue deficiencies and contour abnormalities. Autologous fat transplantation for soft-tissue augmentation has become increasingly popular in recent years. The popularity of tumescent liposuction has brought renewed interest and accessibility of fat for transplantation. Newer techniques and approaches to augmentation have provided more predictable and reproducible results. Fat augmentation has become an effective, safe and reliable method for restoring volume and correcting the atrophy that accompanies senescence. In this review, the authors have described their approach to fat transplantation. PMID- 24163529 TI - A Randomised, Open-label, Comparative Study of Tranexamic Acid Microinjections and Tranexamic Acid with Microneedling in Patients with Melasma. AB - BACKGROUND: Melasma is a common cause of facial hyperpigmentation with significant cosmetic deformity. Although several treatment modalities are available, none is satisfactory. AIM: To compare the therapeutic efficacy and safety of tranexamic acid (TA) microinjections versus tranexamic acid with microneedling in melasma. MATERIALS AND METHODS: This is a prospective, randomised, open-label study with a sample size of 60; 30 in each treatment arms. Thirty patients were administered with localised microinjections of TA in one arm, and other 30 with TA with microneedling. The procedure was done at monthly intervals (0, 4 and 8 weeks) and followed up for three consecutive months. Clinical images were taken at each visit including modified Melasma Area Severity Index MASI scoring, patient global assessment and physician global assessment to assess the clinical response. RESULTS: In the microinjection group, there was 35.72% improvement in the MASI score compared to 44.41% in the microneedling group, at the end of third follow-up visit. Six patients (26.09%) in the microinjections group, as compared to 12 patients (41.38%) in the microneedling group, showed more than 50% improvement. However, there were no major adverse events observed in both the treatment groups. CONCLUSIONS: On the basis of these results, TA can be used as potentially a new, effective, safe and promising therapeutic agent in melasma. The medication is easily available and affordable. Better therapeutic response to treatment in the microneedling group could be attributed to the deeper and uniform delivery of the medication through microchannels created by microneedling. PMID- 24163530 TI - Chemical reconstruction of skin scars therapy using 100% trichloroacetic Acid in the treatment of atrophic facial post varicella scars: a pilot study. AB - CONTEXT: Chickenpox (varicella) is a common viral disease caused by Varicella zoster virus. Facial atrophic scars after varicella infection are not uncommon and pose a cosmetic problem. Like atrophic scars of other aetiologies, they are a difficult condition to treat. There are not enough references in the literature regarding efficient treatment of post varicella scars. High strength Trichloroacetic acid (TCA), which is known to cause dermal collagen remodelling, was used to treat varicella scars in the present study. AIMS: The study was undertaken to assess the efficiency of Chemical Reconstruction of Skin Scars (CROSS) technique using 100% TCA in the treatment of atrophic facial post varicella scars. SETTINGS AND DESIGN: Open label, pilot study. MATERIALS AND METHODS: A total of 16 patients with atrophic facial post varicella scars were treated by focal application of 100% TCA solution by pressing down upon the scar surface by a toothpick (CROSS technique). Total 4 sittings were given at 2 weekly intervals and the results evaluated after 3 months of follow-up. Statistical analysis was carried out using Fischer's exact t-test. RESULTS: All of the 13 patients who completed the study showed good clinical improvement, with 69% patients grading the response as excellent (>75%) improvement, whereas the rest 31% patients reporting good (51-75%) improvement. No significant complications were seen in any patient. CONCLUSIONS: CROSS technique using 100% TCA is a safe, cheap and effective therapy for the treatment of post varicella scars. PMID- 24163531 TI - A study on fractional erbium glass laser therapy versus chemical peeling for the treatment of melasma in female patients. AB - INTRODUCTION: Melasma is a commonly acquired hypermelanosis and a common dermatologic skin disease that occurs on sun-exposed areas of face. AIMS: To assess the efficacy and safety of non-ablative 1,550 nm Erbium glass fractional laser therapy and compare results with those obtained with chemical peeling. MATERIALS AND METHODS: We selected 30 patients of melasma aged between 20 years and 50 years for the study. The patients were divided into two groups of 15 patients each. Group I patients were subjected to four sessions of 1,550 nm Erbium glass non-ablative fractional laser at 3 weeks interval. In group II patients, four sessions of chemical peeling with 70% glycolic acid was performed. RESULTS: After 12 weeks of treatment, percentage reduction in Melasma Area and Severity Index (MASI) score was seen in 62.9% in the laser group and 58.7% in the peels group. CONCLUSION: It was observed that 1,550 nm fractional laser is as effective as 70% glycolic acid peel in reducing MASI score in patients with melasma. PMID- 24163532 TI - Upper forehead skin reconstruction with h-flap. AB - INTRODUCTION: There are several options for forehead defect's reconstructions, including different local flaps, regional flaps, free flaps and skin grafts. We used double opposing rectangular advancement flaps (H-flap) in the upper forehead defects. MATERIALS AND METHODS: This is a prospective case series study that has done in Plastic surgery ward. Of the 10 patients, six were women and four were men, their median age was 61 years (range 50-79 years). Mean follow-up of patients were 15 months and there was no recurrence during this time. We reconstructed forehead after excision of tumours in the same operation. RESULTS: Aesthetic results of H-flap in all cases were great with patient satisfaction according to questionnaire sheets. CONCLUSION: This local flap is a reliable and safe way for upper forehead defects up to 6 cm lengths. Long-term follow up showed inconspicuous scars and good texture and colour match of the reconstructed forehead. We recommend this flap for upper forehead reconstruction in defects between 4 cm and 6 cm. Directions of incisions are parallel to resting skin tension line and length to width of flap considered 2:1 with excision of burrow triangle from both side. We used silicon sheet post operatively for 3 months for better aesthetic results. PMID- 24163533 TI - Aggressive curettage-cryosurgery for human papillomavirus-16 associated subungual squamous cell carcinoma in situ. AB - Squamous cell carcinoma (SCC) in situ is an uncommon tumour of the nail unit. Mohs micrographic surgery or wide surgical excision are often the preferred treatments. As an alternative therapy two patients with human papillomavirus (HPV)-16 associated SCC in situ were treated by curettage-cryosurgery. After a careful curettage with different-sized curettes freezing with liquid nitrogen in a double freeze-thaw was performed. Both patients were treated successfully and healed completely within 3 months. No adverse events were observed during a follow-up of at least 5 years and no recurrences were noted. Curettage cryosurgery might be a safe and non-resource-demanding alternative treatment for patients with subungual SCC in situ. PMID- 24163534 TI - DermafracTM: an innovative new treatment for periorbital melanosis in a dark skinned male patient. AB - Periorbital melanosis (under eye dark circles) is an often idiopathic cosmetically disturbing condition that is poorly responsive to currently available treatment modalities. We present the case of a 48-year-old man (skin phototype V) with significant idiopathic periorbital melanosis and who had good to excellent reduction in periorbital melanosis with the new DermaFracTM, which combines microneedling with simultaneous infusion of a serum containing active ingredients. The possible mechanisms of benefit are discussed. DermaFracTM may be an innovative and effective new treatment option for patients with periorbital melanosis. PMID- 24163535 TI - Treatment of facial lesions of multicentric reticulohistiocytosis by carbon dioxide laser. AB - The carbon dioxide (CO2) laser is a versatile tool that has applications in ablative lasing and caters to the needs of routine dermatological practice as well as the esthetic, cosmetic, and rejuvenation segments. We report a case of multicentric reticulohistiocytosis with cosmetically disfiguring confluent papules over the scalp, forehead, nasolabial folds, chin, and retroauricular region. We used CO2 laser in superpulse mode for ablating the lesions in three sittings. The lesions regressed completely and no recurrence was observed over a regular follow-up of 8 months. PMID- 24163536 TI - Double helix flaps for lower leg defects: report of 4 cases. PMID- 24163538 TI - Lipedema: is aesthetic cellulite an aggravating factor for limb perimeter? PMID- 24163537 TI - Fatal necrotising fasciitis after spinal anaesthesia. PMID- 24163539 TI - Ulcerated infantile haemangioma of buttock successfully treated with topical timolol. PMID- 24163540 TI - Intrascrotal non-testicular schwannoma: a rare case report. PMID- 24163541 TI - Benign subcutaneous emphysema following punch skin biopsy. PMID- 24163542 TI - Vacuum-assisted Closure and Moist Wound Dressing in Diabetic Foot. PMID- 24163543 TI - Authors' reply. PMID- 24163544 TI - Let's learn to self-introspect. PMID- 24163545 TI - Cone beam computed tomography in oral implants. AB - Cone beam computed tomography (CBCT) scanners for the oral and maxillofacial region were pioneered in the late 1990s independently by Arai et al. in Japan and Mozzo et al. CBCT has a lower dose of radiation, minimal metal artifacts, reduced costs, easier accessibility, and easier handling than multislice computed tomography (MSCT); however, the latter is still considered a better choice for the analysis of bone density using a Hounsfield unit (HU) scale. Oral implants require localized area of oral and maxillofacial area for radiation exposure; so, CBCT is an ideal choice. CBCT scans help in the planning of oral implants; they enable measurement of the distance between the alveolar crest and mandibular canal to avoid impingement of inferior alveolar nerve, avoid perforation of the mandibular posterior lingual undercut, and assess the density and quality of bone, and help in planning of the oral implant in the maxilla with special attention to the nasopalatine canal and maxillary sinus. Hence, CBCT reduces the overall exposure to radiation. PMID- 24163546 TI - Tissue response to titanium implant using scanning electron microscope. AB - Most of the surgeons now use titanium miniplates because of its biocompatibility and corrosion resistant properties; studies have shown that these titanium particles are released in the surrounding tissues causing tissue necrosis and if these implants are placed for a long period, the adverse effect of these implants are more severe. It therefore necessitates a study to find out whether these titanium particles are released into surrounding tissues from titanium miniplates used for maxillofacial fractures so that we could use these implants, that is, bone plates and screws with more confidence. PMID- 24163547 TI - Sialoblastoma: A literature review from 1966-2011. AB - Sialoblastoma is a rare congenital tumour of the salivary glands arising mainly from the parotid gland. It is usually diagnosed at birth or shortly thereafter with a significant variability in histological appearance and clinical course. In extensive search of PubMed indexed journals, we got 46 cases of "sialobalstoma/embryoma/congenital basal adenoma", with one case was of German literature and three additional cases of adult sialobalstoma. This article has extensively reviewed the clinical, histopathological and immunohistochemical features, Magnetic resonance imaging (MRI) and Computerized Tomography (CT) findings, treatment and prognosis. PMID- 24163548 TI - Advances in dental local anesthesia techniques and devices: An update. AB - Although local anesthesia remains the backbone of pain control in dentistry, researches are going to seek new and better means of managing the pain. Most of the researches are focused on improvement in the area of anesthetic agents, delivery devices and technique involved. Newer technologies have been developed that can assist the dentist in providing enhanced pain relief with reduced injection pain and fewer adverse effects. This overview will enlighten the practicing dentists regarding newer devices and methods of rendering pain control comparing these with the earlier used ones on the basis of research and clinical studies available. PMID- 24163549 TI - Buccinator-based myomucosal flaps in intraoral reconstruction: A review and new classification. AB - The buccinator-based myomucosal flaps are axial pattern flaps that are suitable in reconstruction of medium sized oral soft tissue defects; they are rich in blood supply, have appropriate thickness and considerable mucosal paddle, and they can secrete saliva. The present study describes surgical anatomy and blood supply of these flaps and demonstrates all possible modifications of these flaps (9 modifications). Many terms (> 10) have been used to refer to buccinator-based myomucosal flaps in the literatures. This report introduces a new classification system mainly based on the remaining attachments of buccinator muscle after flap elevation in pedicle variants and axial blood supply orientation in island variants. PMID- 24163550 TI - Blast injury face: An exemplified review of management. AB - Facial injuries are extremely common due to increased incidence of vehicular and industrial trauma and warfare injuries. But isolated injury to the face due to low voltage cells exploding is rare. In blast injury, the force can cause massive soft tissue injury, along with injury to facial fractures and damage to adnexa. Facial injury is not life threatening unless associated with other injuries of the skull and airway. The major risks to airway in facial trauma are due to anatomic alteration of patient's airway through bony and soft tissue disruption and increased chances of aspiration. The past several decades have seen a rapid growth in the range of procedures available for reconstructive purposes. However, the essential preliminary management is a must and needs to be structured. The patient, a 10-year-old boy, was joining three pencil batteries in series and twisting the wire with his teeth when one battery exploded causing severe injuries to midface and mandibular region. After stabilization, the patient was taken up for surgery. A cap splint with zygomatic suspension was done for the maxilla, and wiring of residual mandibular segments with lining and skin cover provided by a deltopectoral flap was done. Reconstructive surgeries for reconstruction of the upper lip and maintenance of oral continence were planned for the future. The present case stresses the importance of educating the masses about unsafe handling of low voltage devices, management of airway, massive soft tissue injury, along with facial fractures and damage to adnexa. PMID- 24163551 TI - Evaluation of the efficacy of AgNOR as a proliferative marker in oral leukoplakia: A morphometric analysis. AB - BACKGROUND: Silver stainable nucleolar organizer regions (AgNORs) are replicatory markers which may have a place in objectively characterizing dysplasia. MATERIALS AND METHODS: A study of various morphometric parameters related to AgNORs was performed in basal and parabasal layers of normal human oral epithelium, nondysplastic leukoplakia, and dysplastic leukoplakia employing photomicrographs of silver stained paraffin embedded sections using image analysis, to assess the usefulness of these parameters in distinguishing dysplastic leukoplakia from nondysplastic oral leukoplakia. RESULTS: Out of various mean AgNOR related parameters, AgNOR count, area, perimeter, and proportion were found to be higher in dysplastic leukoplakia as compared to nondysplastic leukoplakia. On statistical analysis, AgNOR count showed statistically significant differentiation between dysplastic and nondysplastic leukoplakia. While other parameters can distinguish normal oral epithelium from dysplastic and nondysplastic leukoplakia. CONCLUSION: To conclude, the AgNOR count is the most appropriate marker to differentiate between dysplastic and nondysplastic leukoplakia. PMID- 24163552 TI - Evaluation of stress patterns in bone around dental implant for different abutment angulations under axial and oblique loading: A finite element analysis. AB - INTRODUCTION: The replacement of missing anterior teeth presents peculiar challenges to the Prosthodontist. Implants are increasingly gaining favour for the same. The morphology of existing bone in the premaxilla often dictates that implants are placed at angles that are difficult to restore with conventional abutments. However, the angulated abutments might transfer unfavourable forces to the implant or bone, thereby compromising the prognosis of the treatment. Because, it is difficult to assess the generated forces clinically, a finite element analysis was chosen for the present study as it is useful tool in estimating stress distribution in the contact area of the implant with the bone. MATERIALS AND METHODS: In this study, the frontal region of the maxilla was modelled with a cortical layer 1.5 mm thick containing an inner cancellous core. The implant was cylindrical, round ended, with length 13 mm and diameter 4.1 mm. The abutment was modelled as 7 mm in height with a 5 degree occlusal taper. The different abutment angulations used were 0 degrees , 10 degrees , 15 degrees and 20 degrees . The amount of loads used were 100, 125, 150, 175 and 200 N axially, and 50 N in oblique direction, to approximate the kind of loads seen in clinical situations. RESULT: It was seen that, as the abutment angulation changes from 0 degrees to 20 degrees both the compressive as well as tensile stresses increased; but, it is within the tolerance limit of the bone. CONCLUSION: It seems reasonably safe to use angled abutments in anterior implant supported prostheses, in the maxillary arch. PMID- 24163553 TI - Osteogenic potential of cissus qudrangularis assessed with osteopontin expression. AB - PURPOSE: Fracture healing involves complex processes of cell and tissue proliferation and differentiation. Many factors are involved, including growth factors, inflammatory cytokines, antioxidants, bone breakdown (osteoclast) and bone building (osteoblast) cells, hormones, amino acids, and uncounted nutrients. We studied the osteogenic potential of Cissus quadrangularis (CQ), a plant that has been customarily used in the Indian subcontinent to hasten the process of healing in bone fractures. MATERIALS AND METHODS: Total of 60 patients (age, 20 35 years) of mandible fracture was divided in two groups. Patients of group 1 were given capsules of CQ and fracture healing was assessed with osteopontin expression during treatment. Group 2 was control group. RESULTS: Clinical and radiological analysis in our study was suggestive of better healing of fractures in group 1. All the samples of group 1 examined for osteopontin expression using western blot analysis and flow cytometry showed significant levels of expression of osteopontin protein and CD4+ T cells expressing osteopontin, respectively. CONCLUSION: We conclude that CQ accelerates fracture healing and also causes early remodeling of fracture callus. PMID- 24163554 TI - Relevance of anterior mandibular body ostectomy in mandibular prognathism. AB - PURPOSE: We tried to find out the relevance of anterior mandibular body ostectomy in deformities of the mandible specially prognathism, which is primarily limited to anterior part only. PATIENTS AND METHODS: Ten patients with skeletal deformity along with malocclusion, which was limited to anterior body of mandible were selected. Selected patients had proper molar interdigitation (even if class 3) and in general had anterior crossbite (except one). All patients had crossed their growth spurts and had no hormonal influence on facial deformity. Specific protocol, including cephelometric analysis cephalometry for orthognathic surgery, prediction tracing and model surgeries were devised. Pre and post-surgical orthodontics and body ostectomy were performed in all patients along with 18 month post-op follow-up. RESULTS: There was significant reduction in prognathism and horizontal dysplasia in all ten patients. Anterior crossbite as well as axis of incisiors over mandibular plane was corrected in all patients due to decrease in length of mandibular body. All patients showed decreased facial height and better lip competence with intact posterior occlusion and no (negligible or transient) sensory loss. CONCLUSIONS: Our study could confirm that people whose deformity is limited to the anterior part of mandible with reasonable occlusion posteriorly can get satisfactory cosmetic and functional results through body ostectomy alone rather than going for surgical procedure in the ramal area, which is liable to cause sensory and occlusal disturbances. PMID- 24163555 TI - Unilocular radiolucencies of anterior mandible in young patients: A 10 year retrospective study. AB - INTRODUCTION: Mandibular anterior region is an uncommon site for occurrence of intrabony pathologies. Unilocular presentation of a lesion is again less common than multilocular appearance. Demographically, most lesions occur in middle to elderly age group. The study is designed to review the pathologies manifesting a combination of these rare demographic and radiological criteria. MATERIALS AND METHODS: A retrospective analysis of patients with anterior unilocular radiolucencies of mandible in young patients was done. Records of past 10 years were searched. There were a total of 17 patients. Their clinical history and radiographs were reviewed from the case files and correlated with histopathological examination of the lesion. RESULTS: Nine different pathologies constituted the sample size of 17. A wide array of lesions was found to manifest similar signs and symptoms and radiographic findings namely ameloblastoma (three), adenomatoid odontogenic tumor (AOT, four), odontogenic keratocyst (OKC, three), ossifying fibroma (OF, two), idiopathic bone cavity (IBC, one), dentigerous cyst (DC, one), radicular cyst (RC, one), central giant cell granuloma (CGCG, one), and calcifying odontogenic cyst (COC, one). CONCLUSION: Anterior mandible is a rare site for occurrence of intrabony pathologies. Majority of patients are females. Lesions acquire large size before they are detected. Growth occurs more in length than in width. Root resorption is not uncommon and root displacement is almost a consistent feature. PMID- 24163556 TI - Natal and neonatal teeth among cleft lip and palate infants. AB - OBJECTIVE: Natal/neonatal teeth are reported to be more common among clefts and congenital anomalies. Data exclusively among clefts is sparse. The aim was to evaluate prevalence of natal teeth among cleft lip and palate neonates and review the causes, presentation, associated anomalies, complications and management. MATERIALS AND METHODS: Out of 641operated patients, records of 151 infants with cleft lip and palate with less than three months of age presented to the department of plastic and reconstructive surgery from 2005 to 2011 were reviewed. Out of which 107 were unilateral complete lip and palate (ULCP), 15 bilateral cleft lip and isolated cleft palate constituted 29. RESULTS: Three patients among the studied records showed neonatal teeth. Two had paired central mandibular incisor teeth along with associated other anomalies and one had a single maxillary neonatal tooth. All were present in unilateral cleft lip and none of the bilateral or isolated cleft palate infants showed neonatal teeth. The overall incidence of neonatal teeth was 1.98% and 2.8% in unilateral Cleft lip. CONCLUSION: Our study supports the incidence of 2% natal teeth among UCLP. Involvement of mandibular central incisors in contrast to the notion that maxillary alveolus is more commonly affected suggest that it is not only the anatomical disturbance but also all those possible common multifactorial etiological factors contributing to the congenital anomalies as such. Natal/neonatal teeth are rather under-diagnosed and reported than a rare phenomenon and the prevalence is higher in certain population. Riga-Fede disease unlikely to be seen in clefts with neonatal teeth due to anatomical factors. The extraction of non mobile tooth if necessary can be done during the primary surgery for the cleft lip. PMID- 24163557 TI - A case of extensive left-sided facial atrophy of Romberg. AB - Progressive facial atrophy or Parry-Romberg syndrome is characterized by slowly progressive facial atrophy involving skin, subcutaneous tissue, cartilage and bony structures. Apart from facial atrophy, it can be associated with diverse clinical manifestations including headache, partial seizures, trigeminal neuralgia, cerebral hemiatrophy and ocular abnormalities. The exact etiology is unknown although sympathetic system dysfunction, autoimmune disorders, focal scleroderma, trauma and genetic factors have been postulated. We hereby report a patient having marked left-sided facial atrophy and wasting of the tongue. Such an extensive wasting is not previously reported in the literature. PMID- 24163558 TI - Odontogenic myxoma. AB - Odontogenic myxoma is a rare intraosseous neoplasm, which is benign but locally aggressive. It rarely appears in any bone other than the jaws. It is considered to be derived from the mesenchymal portion of the tooth germ. Clinically, it is a slow-growing, expansile, painless, non-metastasizing, central tumor of jaws, chiefly the mandible. Here we report the case of a typical odontogenic myxoma in a 26-year-old female patient, which had acquired large dimensions and involved the entire left half of the mandible including the ramus, resulting in a gross facial deformity, within a span of one and a half years. PMID- 24163559 TI - Median facial dysplasia: A rare craniofacial syndrome and the surgical management of associated cleft lip. AB - Median facial dysplasia (MFD) is a distinct and unique disorder of the craniofacial region that is characteristic of deficient mid facial structures with the addition of a unilateral or bilateral cleft lip with or without a cleft palate. A cleft lip which is associated with MFD whether it is unilateral or bilateral does not represent a typical cleft lip and poses some challenges in reconstruction. The management of such cleft lip has been rarely discussed in previous literatures; the main obstacle comes in identifying the anatomical landmarks to establish an esthetic reconstruction of the lip. However, reasonably good result can be achieved when the adjacent and distant anatomical structures are correlated to aid the reconstruction. PMID- 24163560 TI - Cleft palate lateral synechia syndrome. AB - Cleft lip and palate are the most common congenital craniofacial anomaly in humans. The presence of oral synechia along with cleft palate is a rare syndrome. We encountered one case that had a cleft palate accompanied by congenital oral synechia due to a membranous adhesion between the floor of the mouth and the free margin of the cleft palate. PMID- 24163561 TI - Non-syndromic odontogenic keratocysts: A rare case report. AB - Odontogenic keratocysts are very well documented in the literature. Multiple odontogenic keratocysts (OKCs) are one of the most frequent features of nevoid basal cell carcinoma syndrome (NBCCS). It is linked with mutation in the PTCH gene (human homolog of the drosophila segment polarity gene, "patched",). Partial expression of the gene may result in occurrence of only multiple recurring OKC without any associated systemic findings. A rare case of multiple odontogenic keratocysts unassociated with any syndrome is reported, so as to add to the growing number of such cases in the literature. The possibility of this case being a partial expression of the Gorlin-Goltz syndrome is discussed. PMID- 24163562 TI - Application of PRF in surgical management of periapical lesions. AB - AIMS AND OBJECTIVES: Platelet rich fibrin is widely used in stimulation and acceleration of soft tissue and bone healing because of local and continuous delivery of growth factors and proteins, mimicking the needs of the physiological wound healing and reparative tissue processes. This article will serve to introduce a second generation platelet concentrate, platelet-rich fibrin (PRF). MATERIALS AND METHODS: Fifteen cases are presented in which conventional endodontic therapy failed to resolve the problem and periapical root-end surgery was required. RESULTS: At the end of six months, all patients showed complete bone regeneration. CONCLUSION: Production of a dense, cross-linked, physically robust PRF made of intact platelets and fibrin by high-speed centrifugation in the absence of exogenous thrombin, yields an ideal scaffold for use in tissue repair. PMID- 24163563 TI - Appearance can be deceptive: Dentigerous cyst crossing the midline. AB - Dentigerous cyst is a developmental odontogenic cyst, which develops by accumulation of fluid between reduced enamel epithelium and the tooth crown of an unerupted tooth. Dentigerous cysts are usually solitary, slow growing, asymptomatic lesions that are incidentally found during routine radiographs They most frequently involve the mandibular third molar followed in order of frequency by the maxillary canine, mandibular second pre-molar and maxillary third molar. Occasionally, these cysts become painful when infected causing swelling and erythema. The cyst is usually small, however, when large, results in the expansion and thinning of the cortex leading to pathological fracture. Radiographic features are specific to the lesion characterized by a well-defined radiolucency circumscribed by a sclerotic border, associated with the crown of an impacted or unerupted tooth. Dentigerous cysts are treated most commonly by enucleation, Marsupialization and decompression of cyst by fenestration. The criteria for selecting the treatment modality is based on the age, size, location, stage of root development, position of the involved tooth and relation of the lesion to the adjacent tooth and vital structure. The prognosis is an excellent when the cyst is enucleated and recurrence is rare. In this article, we present a case of a Dentigerous cyst in an 80-year-old man in the anterior aspect of the mandible enveloping an impacted canine and crossing the midline but with no clinical expansion or discomfort. PMID- 24163564 TI - Distraction osteogenesis for management of obstructive sleep apnea secondary to TMJ ankylosis. AB - Mandibular retrognathism due to temporomandibular joint (TMJ) ankylosis is one of the important contributing factors to the obstructive sleep apnea(OSA). Such patients suffer from number of apneic or hyponeic events during sleep, snoring, daytime sleepiness, fatigue, inability to concentrate, irritability. At the same time facial asymmetry due TMJ ankylosis lead to a progressive lack of confidence. Distraction osteogenesis is a less invasive surgical technique in the management of OSA, secondary to TMJ ankylosis. This modality not only treats the OSA but also corrects the facial asymmetry at the same time, and the results have been gratifying. PMID- 24163565 TI - Giant aneurysmal bone cyst of the mandible: A case report and review of literature. AB - Aneurysmal bone cysts are rare benign lesions of bone tissue. They are composed of vascular spaces blood-filled and surrounded by fibrous tissue septa. They are considered as pseudo cysts because of lack of epithelial lining. Here, we describe a giant case of ABC in 12-year-old female child having a massive swelling over the right side of the mandible treated with segmental resection and reconstruction with a reconstruction plate. Case is also discussed with the review of literature. PMID- 24163566 TI - Small cell neuroendocrine carcinoma of the paranasal sinus. AB - Small cell neuroendocrine carcinoma (SNEC) is an uncommon tumor. This tumor usually occurs in the lungs, the extra-pulmonary form accounts for only about 4% of all cases. Primary SNEC of the paranasal sinuses is extremely rare; only about 76 cases have been reported in literature. Unfortunately due to the rarity of this neoplasm, there are no specific recommendations pertaining to the management, treatment options are generally extrapolated from similar tumors of pulmonary origin. While Surgery was used in the past, upfront chemoradiation now seems to be evolving as the treatment of choice. We report a case of sinonasal SNEC who had undergone definitive concurrent chemoradiation and is currently disease-free for close to 2 years. The clinical presentation, imaging studies, histopathological diagnosis with immunohistochemistry correlation, management protocols, and a brief review of literature of this rare tumor is discussed. PMID- 24163567 TI - Congenital cheek teratoma with temporo-mandibular joint ankylosis managed with ultra-thin silicone sheet interpositional arthroplasty. AB - Primary cheek teratomas are rare with < 5 reported cases. None had associated temporo mandibular joint ankylosis (TMJA). The fundamental aim in the treatment of TMJA is the successful surgical resection of ankylotic bone, prevention of recurrence, and aesthetic improvement by ensuring functional occlusion. Early treatment is necessary to promote proper growth and function of mandible and to facilitate the positive psychological development of child. Inter-positional arthroplasty with ultra-thin silicone sheet was performed. Advantages include short operative time, less foreign material in the joint space leading to negligible foreign body reactions and least chances of implant extrusion. Instead of excising a large bony segment, a thin silicone sheet was interposed and then sutured ensuring preservation of mandibular height. Aggressive post-operative physiotherapy with custom made dynamic jaw exerciser was used to prevent recurrence. PMID- 24163568 TI - Obturator prosthesis for hemimaxillectomy patients. AB - Rehabilitation of hemimaxillectomy patients can be challenging. The most common problem with prosthetic treatment in such patients is in getting adequate retention, stability, and support. The size and location of the defect usually influences the amount of impairment and difficulty in prosthetic rehabilitation. The obturator prosthesis is commonly used as an effective means for rehabilitating hemimaxillectomy cases. In cases of large maxillary defects, movement of the obturator prosthesis is inevitable and requires a form of indirect retention to limit the rotation of the prosthesis. The goal of prosthodontics is rehabilitation of missing oral and extraoral structures along with restoration of the normal functions of mastication, speech, swallowing, appearance, and so on. Malignancies are common in the oral region, which are treated through surgical intervention. Surgical intervention creates communication between the oral cavity, nasal cavity, and maxillary sinus. In such cases, it is very difficult for the patient to perform various normal functions like mastication, swallowing, speaking, and so on. Prosthodontic rehabilitation with obturator prosthesis restores the missing structures and acts as a barrier between the communication among the various cavities. PMID- 24163569 TI - Multiple paranasal sinus involvement from a metastatic follicular carcinoma thyroid. PMID- 24163570 TI - Practical draining technique using Foley catheter for maxillofacial spatial infections. PMID- 24163571 TI - Positive outcomes of naso alveolar moulding in bilateral cleft lip and palate patient. PMID- 24163572 TI - Effortful Control, Behavior Problems and Peer Relations: What Predicts Academic Adjustment in Kindergarteners from Low-income Families? AB - This study examined the role of effortful control, behavior problems, and peer relations in the academic adjustment of 74 kindergarten children from primarily low-income families using a short-term longitudinal design. Teachers completed standardized measures of children's effortful control, internalizing and externalizing problems, school readiness, and academic skills. Children participated in a sociometric interview to assess peer relations. Research Findings: Correlational analyses indicate that children's effortful control, behavior problems in school, and peer relations are associated with academic adjustment variables at the end of the school year, including school readiness, reading skills, and math skills. Results of regression analyses indicate that household income and children's effortful control primarily account for variation in children's academic adjustment. The associations between children's effortful control and academic adjustment did not vary across sex of the child or ethnicity. Mediational analyses indicate an indirect effect of effortful control on school readiness, through children's internalizing problems. Practice or Policy: Effortful control emerged as a strong predictor of academic adjustment among kindergarten children from low-income families. Strategies for enhancing effortful control and school readiness among low-income children are discussed. PMID- 24163573 TI - Sometimes you just have to have a lot of bitter to make it sweet: Substance abuse and partner abuse in the lives of HIV+ men who have sex with men. AB - Although links between partner abuse (PA) and substance abuse (SA) are well documented in the literature, we know less about these relations among HIV positive men who have sex with men (MSM). We conducted a qualitative study with this group (N = 28). Participants reported (1) social modeling of SA in childhood and in adult social networks, (2) initial use of substance to cope with child abuse and neglect, and (3) the reinforcement of problematic SA by experiences of PA, whereby SA led to PA, resulting in increased SA. Recommendations for clinicians working with HIV+ MSM are discussed. PMID- 24163575 TI - AIR-WATER INTERFACIAL AREA AND CAPILLARY PRESSURE: POROUS-MEDIUM EXTURE EFFECTS AND AN EMPIRICAL FUNCTION. AB - The relationship between air-water interfacial area and capillary pressure under higher water-content conditions is investigated for four natural porous media. The results show that the magnitude of the air-water interfacial area increases with increasing capillary pressure, consistent with the decrease in water saturation. The maximum observed air-water interfacial areas are dependent upon the magnitude of residual water saturation, which itself is condition dependent. The more well-sorted porous medium exhibited a greater rate of change of air water interfacial area with capillary pressure than the more poorly-sorted porous media. The observed relationship between air-water interfacial area and capillary pressure was quantified by coupling an empirical equation describing the air water interfacial area vs. water saturation relationship with the van Genuchten equation relating water saturation and capillary pressure. This equation produced reasonable simulations of the measured data. PMID- 24163574 TI - Polarized Enhanced Backscattering Spectroscopy for Characterization of Biological Tissues at Subdiffusion Length-scales. AB - Since the early 1980's, the enhanced backscattering (EBS) phenomenon has been well-studied in a large variety of non-biological materials. Yet, until recently the use of conventional EBS for the characterization of biological tissue has been fairly limited. In this work we detail the unique ability of EBS to provide spectroscopic, polarimetric, and depth-resolved characterization of biological tissue using a simple backscattering instrument. We first explain the experimental and numerical procedures used to accurately measure and model the full azimuthal EBS peak shape in biological tissue. Next we explore the peak shape and height dependencies for different polarization channels and spatial coherence of illumination. We then illustrate the extraordinary sensitivity of EBS to the shape of the scattering phase function using suspensions of latex microspheres. Finally, we apply EBS to biological tissue samples in order to measure optical properties and observe the spatial length-scales at which backscattering is altered in early colon carcinogenesis. PMID- 24163576 TI - Excavating Culture: Summary of Results. AB - This is a companion paper to the seven articles also published in this special issue of Applied Developmental Science This paper summarizes and discusses the results from common analyses that were conducted on different datasets. The common analyses were designed to disentangle contextual and ethnic influences on parenting. Initial ethnic group differences were found in many of the datasets with multiple ethnic groups. Although certain ethnic group differences were explained by contextual influences, some ethnic group differences remained after contextual influences were controlled. Follow-up analyses with datasets containing cultural variables reveal within group differences in the degree to which ethnic differences in parenting may be accounted for by contextual factors versus culturally-specific processes. Methodological and theoretical implications are discussed and future directions are offered. PMID- 24163577 TI - Using Perseverative Interests to Improve Interactions Between Adolescents with Autism and their Typical Peers in School Settings. AB - The literature suggests that adolescents with ASD typically are not socially engaged during unstructured school activities and do not initiate social activities with typically developing peers. This study assessed whether implementing socialization opportunities in the form of lunch clubs based around aspects of the adolescents with ASD's perseverative interests would promote positive direct and generalized social interaction between the target adolescent and their typically developing peers. A repeated measures multiple baseline experimental design (with two reversals) was implemented across participants. During baseline measures, the participants did not show social engagement or initiations. During intervention, results showed large increases in both social engagement and initiations. Generalization measures also showed that the target adolescents improved their social engagements and initiations with typically developing peers throughout unstructured lunchtime activities. These results have implications for understanding variables related to social development in autism. PMID- 24163579 TI - Diversity of Alticinae in Oaxaca, Mexico: A preliminary study (Coleoptera, Chrysomelidae). AB - This is a preliminary study of the diversity of the Flea Beetles (Alticinae) of the Mexican state of Oaxaca based on fieldwork by the author in 1991, 1997, and 2010, the literature, and specimens in several institutional collections. The number of genera and species for Mexico as well as for Oaxaca increased significantly from previous studies. There are now 625 species in 90 genera recorded from Mexico with 275 species in 68 genera recorded from Oaxaca. There are 113 species known only from the state of Oaxaca and another 38 species known only from Oaxaca and the surrounding states. Oaxaca has a relatively high diversity as well as a high percentage of endemism. This study also demonstrates the effects of how even a small amount of fieldwork together with extracting specimen data from institutional collections can significantly increase the total faunistic and diversity knowledge of an area. A complete list of the genera and species known from Oaxaca is included. PMID- 24163580 TI - Review on the use of sexually dimorphic characters in the taxonomy of Diabroticites (Galerucinae, Luperini, Diabroticina). AB - Sexual dimorphism occurs frequently in Chrysomelidae Latreille, 1802 and is particularly variable in subfamily Galerucinae Latreille, 1802. This diversity has been early noted by authors a potential source of taxonomic characters. The section Diabroticites (Luperini Gistel, 1848) is one of the largest assemblies of chrysomelid genera with currently 823 valid species in 17 genera (12 based on dimorphic characteristics), being most diverse in the neotropical region. Apart from a revision work on the type specimens for the section, there are no general taxonomic studies for this group. The occurrence of sexually dimorphic characteristics in the section Diabroticites is revised and their practical taxonomic relevance evaluated. A total of 240 species was studied (145 species with males available), representing 15 out of the 17 genera included in Diabroticites. The analysis of characters was based on the study of specimens in south-american collections, literature and the aid of photos in online databases. Sexual dimorphism occurred in most species analyzed. Dimorphic features were divided in general (i. e., occur in higher taxa) and special characters (those that support the definition of species and genera). Special dimorphism was observed in every tagma, and most modifications occur in antennae. Characters used as diagnostic of genera often do not correspond to the modifications present in species included in them. Many modifications were considered by earlier authors as a single character, probably due to vague definitions. Most generic definitions are, therefore, inaccurate. The study of morphology and the homology assessment of characters are needed to increase understanding of the genera in Diabroticites. PMID- 24163581 TI - Notes on the ecology of rolled-leaf hispines (Chrysomelidae, Cassidinae) at La Gamba (Costa Rica). AB - A total of 301 adult hispine beetles of the genera Cephaloleia and Chelobasis were found in rolled leaves of plants of 17 species of Zingiberales (families Costaceae, Heliconiaceae, Maranthaceae, Musaceae, and Zingiberaceae) during a field study at La Gamba, Golfito region, Costa Rica. Of these beetles, Cephaloleia belti was recorded from 12 potential host plant species, C. distincta from 7, C. dilaticollis from 5, C., Chelobasis bicolor, C. championi, and C. histrionica from 3, Chelobasis perplexa and C. instabilis from 2, whereas C. trivittata from only one. Of the plant species, Heliconia latispatha had 7 beetle species in its leaf rolls, Calathea lutea had 5, H. imbricata and H. rostrata had 4, H. stricta and Musa paradisiaca had 3, H. wagneriana had 2, while on H. vaginalis, H. danielsiana, H. densiflora, H. longiflora, Calathea crotalifera, C. platystachya, Goeppertia lasiophylla, Alpinia purpurata, Costus pulverulentus and Costus barbatus, H. densiflora, H. vaginalis, and H. danielsana only hispines of one species were found. Cephaloleia belti occurred together with beetles of six other hispine species, whereas Cephaloleia trivittata never shared a leaf roll with another hispine species. The remaining beetle species aggregated with one to four other hispines. Adults of C. belti and C. championi were frequently seen, occasionally also with C. dilaticollis, C. histrionica, and Chelobasis perplexa, to co-occur with the carabid Calophaena ligata in the same leaf roll without any sign of interspecific aggression. A comparison of host choices and the phylogeny of the hispines and of their host plants revealed no signs that beetles used species level phylogenetic relationships within the Zingiberales to select food plants. Obviously, within this plant order, rolled-leaf hispines choose their plant hosts in a nearly opportunistic manner. Seemingly, they use differences among plants at higher taxonomic levels but within the Zingiberales, the availability of young - rolled - leaves might be the actual decisive factor. PMID- 24163582 TI - Subsocial Neotropical Doryphorini (Chrysomelidae, Chrysomelinae): new observations on behavior, host plants and systematics. AB - A summary of literature, documented observations and field studies finds evidence that mothers actively defend offspring in at least eight species and three genera of Neotropical Chrysomelinae associated with two host plant families. Reports on three Doryphora species reveal that all are oviparous and feed on vines in the Apocyanaceae. Mothers in the two subsocial species defend eggs and larvae by straddling, blocking access at the petiole and greeting potential predators with leaf-shaking and jerky advances. A less aggressive form of maternal care is found in two Platyphora and four Proseicela species associated with Solanaceae, shrubs and small trees. For these and other morphologically similar taxa associated with Solanaceae, genetic distances support morphology-based taxonomy at the species level, reveal one new species, but raise questions regarding boundaries separating genera. We urge continued study of these magnificent insects, their enemies and their defenses, both behavioral and chemical, especially in forests along the eastern versant of the Central and South American cordillera. PMID- 24163583 TI - Pachybrachis (coleoptera, chrysomelidae, cryptocephalinae) of eastern Canada. AB - Seventeen Pachybrachis species occurring in eastern Canada [Ontario (ON), Quebec (QC), New Brunswick (NB), Nova Scotia (NS), and Prince Edward Island (PE)] are treated by the authors. Two new national records were discovered, both from southernmost Ontario: P. cephalicus Fall and P. luctuosus Suffrian. Four species were new provincial records: P. cephalicus (ON), P. luctuosus (ON, QC), P. obsoletus Suffrian (NB), P. peccans (PE). A fully illustrated key to the Pachybrachis of eastern Canada is provided and supported with extensive photographs, distribution maps, and plant associations. Three species were distributed from southern Ontario into at least one province in the Maritimes (P. nigricornis (Say), P. obsoletus Suffrianand P. peccans Suffrian). Six species were distributed along the shores of the Great Lakes (Erie, Michigan, and Ontario) and rivers (Ottawa, Saguenay and St. Lawrence), but unknown from central and northern ON and QC (P. bivittatus (Say), P. hepaticus hepaticus (F. E. Melsheimer), P. othonus othonus (Say), P. pectoralis (F. E. Melsheimer), P. spumarius Suffrianand P. trinotatus (F. E. Melsheimer)). Seven species were rare, five being found exclusively from southern ON (P. calcaratus Fall, P. cephalicus, P. luridus (Fabricius), P. subfasciatus (J. E. LeConte)and P. tridens (F. E. Melsheimer)), with two having, in addition, a disjunct population in QC (P. atomarius (F. E. Melsheimer)and P. luctuosus). One species was found to be the northern most extension of an eastern United States (US) distribution into the eastern townships of QC (P. m-nigrum (F. E. Melsheimer)). There were no Pachybrachis that could be considered arctic, subarctic, or boreal species; no specimens were found from Labrador and Newfoundland, and all species had southern affinities. Pachybrachis atomarius, P. calcaratus, P. luridus, P. subfaciatus, and P. tridens, not seen over the last 30-70 years, may be extirpated from eastern Canada. PMID- 24163584 TI - Endemism patterns in the Italian leaf beetle fauna (Coleoptera, Chrysomelidae). AB - In this contribution the results of a zoogeographical analysis, carried out on the 123 endemic leaf beetle species (Coleoptera: Chrysomelidae) occurring in Italy and its immediately adjacent regions, are reported. To assess the level of faunistic similarity among the different geographic regions studied, a cluster analysis was performed, based on the endemic component. This was done by calculating the Baroni Urbani & Buser's similarity index (BUB). Finally, a parsimony analysis of endemicity (PAE) was used to identify the most important areas of endemism in Italy. PMID- 24163585 TI - Tempo and mode of evolutionary radiation in Diabroticina beetles (genera Acalymma, Cerotoma, and Diabrotica). AB - Adaptive radiation is an aspect of evolutionary biology encompassing microevolution and macroevolution, for explaining the principles of lineage divergence. There are intrinsic as well as extrinsic factors that can be postulated to explain that adaptive radiation has taken place in specific lineages. The Diabroticina beetles are a prominent example of differential diversity that could be examined in detail to explain the diverse paradigms of adaptive radiation. Macroevolutionary analyses must present the differential diversity patterns in a chronological framework. The current study reviews the processes that shaped the differential diversity of some Diabroticina lineages (i.e. genera Acalymma, Cerotoma, and Diabrotica). These diversity patterns and the putative processes that produced them are discussed within a statistically reliable estimate of time. This was achieved by performing phylogenetic and coalescent analyses for 44 species of chrysomelid beetles. The data set encompassed a total of 2,718 nucleotide positions from three mitochondrial and two nuclear loci. Pharmacophagy, host plant coevolution, competitive exclusion, and geomorphological complexity are discussed as putative factors that might have influenced the observed diversity patterns. The coalescent analysis concluded that the main radiation within Diabroticina beetles occurred between middle Oligocene and middle Miocene. Therefore, the radiation observed in these beetles is not recent (i.e. post-Panamanian uplift, 4 Mya). Only a few speciation events in the genus Diabrotica might be the result of the Pleistocene climatic oscillations. PMID- 24163586 TI - An annotated checklist of the scale insects of Iran (Hemiptera, Sternorrhyncha, Coccoidea) with new records and distribution data. AB - A list of scale insects (Hemiptera: Sternorrhyncha: Coccoidea) of Iran is present based mainly on the literature records since 1902. In total, 13 families and 275 species have been recorded and these are listed along with their locality data and host plants. The families are as follows: Asterolecaniidae, Cerococcidae, Coccidae, Diaspididae, Eriococcidae, Kermesidae, Margarodidae, Monophlebidae, Ortheziidae, Phoenicococcidae, Pseudococcidae, Putoidae and Rhizoecidae. The following ten species are recorded for the first time from Iran: Diaspidiotus lenticularis (Lindinger), Diaspidiotus wuenni (Lindinger), Fiorinia proboscidaria Green, Koroneaspis lonicerae Borchsenius, Eriococcus cingulatus Kiritchenko, Eriococcus pamiricus (Bazarov), Eriococcus reynei Schmutterer, Eriococcus sanguinairensis Goux and Eriococcus saxidesertus (Borchsenius) and Porphyrophora victoriae Jashenko. PMID- 24163587 TI - Gas-phase separation using a trapped ion mobility spectrometer. AB - In the present work we describe the principles of operation, versatility and applicability of a trapped ion mobility spectrometer (TIMS) analyzer for fast, gas-phase separation of molecular ions based on their size-to-charge ratio. Mobility-based separation using a TIMS device is shown for a series for isobar pairs. In a TIMS device, mobility resolution depends on the bath gas velocity and analysis scan speed, with the particularity that the mobility separation can be easily tuned from low to high resolution (R>50) in accordance with the analytical challenge. In contrast to traditional drift tube IMS analyzer, a TIMS device can be easily integrated in a mass spectrometer without a noticeable loss in ion transmission or sensitivity, thus providing a powerful separation platform prior to mass analysis. PMID- 24163588 TI - BMP receptor 1A determines the cell fate of the postnatal growth plate. AB - Bone morphogenic proteins (BMPs) are critical for both chondrogenesis and osteogenesis. Previous studies reported that embryos deficient in Bmp receptor (Bmpr)1a or Bmpr1b in cartilage display subtle skeletal defects; however, double mutant embryos develop severe skeletal defects, suggesting a functional redundancy that is essential for early chondrogenesis. In this study, we examined the postnatal role of Bmpr1a in cartilage. In the Bmpr1a conditional knockout (cKO, a cross between Bmpr1a flox and aggrecan-CreER (T2) induced by a one-time tamoxifen injection at birth and harvested at ages of 2, 4, 8 and 20 weeks), there was essentially no long bone growth with little expression of cartilage markers such as SOX9, IHH and glycoproteins. Unexpectedly, the null growth plate was replaced by bone-like tissues, supporting the notions that the progenitor cells in the growth plate, which normally form cartilage, can form other tissues such as bone and fibrous; and that BMPR1A determines the cell fate. A working hypothesis is proposed to explain the vital role of BMPR1A in postnatal chondrogenesis. PMID- 24163589 TI - SIRT1 deacetylates FOXA2 and is critical for Pdx1 transcription and beta-cell formation. AB - Pancreas duodenum homeobox 1 (PDX1) is essential for pancreas development and beta-cell formation; however more studies are needed to clearly illustrate the precise mechanism regarding spatiotemporal regulation of Pdx1 expression during beta-cell formation and development. Here, we demonstrate that SIRT1, FOXA2 and a number of proteins form a protein complex on the promoter of the Pdx1 gene. SIRT1 and PDX1 are expressed in the same set of cells during beta-cell differentiation and maturation. Pancreas-specific disruption of SIRT1 diminished PDX1 expression and impaired islet development. Consequently, SIRT1 mutant mice develop progressive hyperglycemia, glucose intolerance, and insulin insufficiency, which directly correlate with the extent of SIRT1 deletion. We further show that SIRT1 interacts with and deacetylates FOXA2 on the promoter of the Pdx1gene, and positively regulates its transcription. These results uncover an essential role of SIRT1 in beta-cell formation by maintaining expression of PDX1 and its downstream genes, and identify pancreas-specific SIRT1 mutant mice as a relevant model for studying insulin insufficiency. PMID- 24163591 TI - Motivated Dimension Manipulation in the Processing of Social Comparison Information. AB - Social comparisons allow individuals to gain knowledge of their traits and abilities. Individuals frequently have self-enhancement goals when processing self-relevant information. This study provided an initial test of the hypothesis that individuals engaging in social comparisons would manipulate cognitive representations of themselves and comparison targets in ways that allowed them to self-enhance. Participants were presented with upward, downward, or no social comparison information about their intelligence. They then completed a task, designed for this program of research, which assessed how participants altered cognitive representations of social comparison information. Results showed that participants altered cognitive representations in ways associated with greater perceived similarity to upward comparison targets and less similarity to downward comparison targets. This effect was moderated by self-esteem, suggesting that the process of manipulating cognitive representations of self-relevant information may serve self-enhancement motives. Understanding the cognitive processes involved in social comparisons is an important step towards accounting for the interplay of motivation and cognition in determining the outcomes individuals experience from social comparisons. PMID- 24163590 TI - Diabetes inhibits cerebral ischemia-induced astrocyte activation - an observation in the cingulate cortex. AB - The objective of this study was to study the effect of diabetic hyperglycemia on astrocytes after forebrain ischemia. Streptozotocin (STZ)-injected hyperglycemic and vehicle-injected normoglycemic rats were subjected to 15 minutes of forebrain ischemia. The brains were harvested in sham-operated controls and in animals with 1 and 6 h of recirculation following ischemia. Brain damage was accessed by haematoxylin and eosin (H&E) staining, cleaved caspase-3 immunohistochemistry and TdT-mediated-dUTP nick end labeling (TUNEL). Anti-GFAP antibody was employed to study astrocytes. The results showed that the 15-minute ischemia caused neuronal death after 1 and 6 h of reperfusion as revealed by increased numbers of karyopyknotic cells, edema, TUNEL-positive and active caspase-3-positive cells. Ischemia also activated astrocytes in the cingulated cortex as reflected by astrocyte stomata hypertrophy, elongated dendrites and increases in the number of dendrites, and immunoreactivity of GFAP. Diabetic hyperglycemia further enhanced neuronal death and suppressed ischemia-induced astrocyte activation. Further, diabetes-damaged astrocytes have increased withdrawal of the astrocyte end-foot from the cerebral blood vessel wall. It is concluded that diabetes-induced suppression and damages to astrocytes may contribute to its detrimental effects on recovery from cerebral ischemia. PMID- 24163592 TI - Moving beyond the bookshelves. PMID- 24163594 TI - Shaping opportunities for the new health sciences librarian. PMID- 24163593 TI - Student peer assessment in evidence-based medicine (EBM) searching skills training: an experiment. AB - BACKGROUND: Student peer assessment (SPA) has been used intermittently in medical education for more than four decades, particularly in connection with skills training. SPA generally has not been rigorously tested, so medical educators have limited evidence about SPA effectiveness. METHODS: EXPERIMENTAL DESIGN: Seventy one first-year medical students were stratified by previous test scores into problem-based learning tutorial groups, and then these assigned groups were randomized further into intervention and control groups. All students received evidence-based medicine (EBM) training. Only the intervention group members received SPA training, practice with assessment rubrics, and then application of anonymous SPA to assignments submitted by other members of the intervention group. RESULTS: Students in the intervention group had higher mean scores on the formative test with a potential maximum score of 49 points than did students in the control group, 45.7 and 43.5, respectively (P = 0.06). CONCLUSIONS: SPA training and the application of these skills by the intervention group resulted in higher scores on formative tests compared to those in the control group, a difference approaching statistical significance. The extra effort expended by librarians, other personnel, and medical students must be factored into the decision to use SPA in any specific educational context. IMPLICATIONS: SPA has not been rigorously tested, particularly in medical education. Future, similarly rigorous studies could further validate use of SPA so that librarians can optimally make use of limited contact time for information skills training in medical school curricula. PMID- 24163595 TI - Creating shared campus experiences: the library as culture club. PMID- 24163596 TI - When the librarian was the search engine: introduction to the special issue on new roles for health sciences librarians. PMID- 24163597 TI - Strategically aligning a mandala of competencies to advance a transformative vision. AB - OBJECTIVE: This paper offers insight into the processes that have shaped the Eskind Biomedical Library's (EBL's) strategic direction and its alignment to the institution's transformative vision. SETTING: The academic biomedical library has a notable track record for developing and pioneering roles for information professionals focused on a sophisticated level of information provision that draws from and fuels practice evolutions. STRATEGY: The medical center's overall transformative vision informs the creation of a fully aligned library strategic plan designed to effectively contribute to the execution of key organizational goals. Annual goals reflect organizational priorities and contain quantifiable and measurable deliverables. Two strategic themes, facilitating genetic literacy and preserving community history, are described in detail to illustrate the concept of goal setting. CONCLUSION: The strategic planning model reflects EBL's adaptation to the ever-changing needs of its organization. The paper provides a characterization of a workable model that can be replicated by other institutions. PMID- 24163598 TI - New activities and changing roles of health sciences librarians: a systematic review, 1990-2012. AB - OBJECTIVE: The paper identifies and documents new health sciences librarian activities and roles during the period from 1990-2012. METHODS: A systematic review of the literature was conducted using MEDLINE, Library and Information Abstracts, Library Literature, Scopus, and Web of Science. To find new roles that might not yet have been described in the literature, job announcements published in the Medical Library Association email discussion list archives from 2008-2012 were searched. For inclusion, an article needed to contain a substantive description of a new role and/or activity performed by librarians and be in the field of medical or health sciences librarianship. Papers that did not describe an actual (rather than proposed) librarian role were excluded. RESULTS: NEW ROLES IDENTIFIED THROUGH THE LITERATURE SEARCH WERE: embedded librarians (such as clinical informationist, bioinformationist, public health informationist, disaster information specialist); systematic review librarian; emerging technologies librarian; continuing medical education librarian; grants development librarian; and data management librarian. New roles identified through job announcements were digital librarian, metadata librarian, scholarly communication librarian, and translational research librarian. New twists to old roles were also identified: clinical medical librarian, instruction librarian, outreach librarian, and consumer health librarian. CONCLUSIONS: While the main purposes of health sciences librarianship remain the same, the new roles represent major new activities so that, for many librarians, daily on-the-job work is completely different. IMPLICATIONS: This list of new activities should inform students contemplating medical librarianship careers, guide formal and continuing education programs, and encourage other librarians to consider these new services. PMID- 24163599 TI - Emerging roles for biomedical librarians: a survey of current practice, challenges, and changes. AB - OBJECTIVE: This study is intended to (1) identify emerging roles for biomedical librarians and determine how common these roles are in a variety of library settings, (2) identify barriers to taking on new roles, and (3) determine how librarians are developing the capacity to take on new roles. METHODS: A survey was conducted of librarians in biomedical settings. RESULTS: Most biomedical librarians are taking on new roles. The most common roles selected by survey respondents include analysis and enhancement of user experiences, support for social media, support for systematic reviews, clinical informationist, help for faculty or staff with authorship issues, and implementation of researcher profiling and collaboration tools. Respondents in academic settings are more likely to report new roles than hospital librarians are, but some new roles are common in both settings. Respondents use a variety of methods to free up time for new roles, but predominant methods vary between directors and librarians and between academic and hospital respondents. Lack of time is the biggest barrier that librarians face when trying to adopt new roles. New roles are associated with increased collaboration with individuals and/or groups outside the library. CONCLUSION AND IMPLICATIONS: This survey documents the widespread incorporation of new roles in biomedical libraries in the United States, as well as the barriers to adopting these roles and the means by which librarians are making time for them. The results of the survey can be used to inform strategic planning, succession planning, library education, and career development for biomedical librarians. PMID- 24163600 TI - "You're just one of the group when you're embedded": report from a mixed-method investigation of the research-embedded health librarian experience. AB - OBJECTIVE: Embedded librarianship has received much attention in recent years. A model of embeddedness rarely discussed to date is that of research-embedded health librarians (REHLs). This study explores the characteristics of Canadian REHLs and the situations in which they are employed. METHODS: The authors employed a sequential, mixed-method design. An online survey provided descriptive statistics about REHLs' positions and work experiences. This informed a series of focus group interviews that expanded upon the survey. Through constant comparison, we conducted qualitative descriptive analysis of the interviews. RESULTS: Based on twenty-nine survey responses and four group interviews, we created a portrait of a "typical" REHL and discovered themes relevant to REHL work. REHLs may identify more strongly as researchers than as librarians, with corresponding professional needs and rewards. REHLs value "belonging" to the research team, involvement in full project lifecycles, and in-depth relationships with nonlibrarian colleagues. Despite widely expressed job satisfaction, many REHLs struggle with isolation from library and information science peers and relative lack of job security. CONCLUSIONS: REHLs differ from non-embedded health librarians, as well as from other types of embedded librarians. REHLs' work also differs from just a decade or two ago, prior to widespread Internet access to digital resources. IMPLICATIONS: Given that research-embedded librarianship appears to be a distinct and growing subset of health librarianship, libraries, master's of library and information science programs, and professional associations will need to respond to the support and education needs of REHLs or risk losing them to the health research field. PMID- 24163602 TI - Expanding roles in a library-based bioinformatics service program: a case study. AB - QUESTION: How can a library-based bioinformatics support program be implemented and expanded to continuously support the growing and changing needs of the research community? SETTING: A program at a health sciences library serving a large academic medical center with a strong research focus is described. METHODS: The bioinformatics service program was established at the Norris Medical Library in 2005. As part of program development, the library assessed users' bioinformatics needs, acquired additional funds, established and expanded service offerings, and explored additional roles in promoting on-campus collaboration. RESULTS: Personnel and software have increased along with the number of registered software users and use of the provided services. CONCLUSION: With strategic efforts and persistent advocacy within the broader university environment, library-based bioinformatics service programs can become a key part of an institution's comprehensive solution to researchers' ever-increasing bioinformatics needs. PMID- 24163601 TI - The librarian as research informationist: a case study. AB - QUESTION: How can an embedded research informationist add value to the scientific output of research teams? SETTING: The University of California-Los Angeles (UCLA) Louise M. Darling Biomedical Library is an academic health sciences library serving the clinical, educational, and research needs of the UCLA community. METHODS: A grant from the National Library of Medicine funded a librarian to join a UCLA research team as an informationist. The informationist meets regularly with the research team and provides guidance related to data management, preservation, and other information-related issues. MAIN RESULTS: Early results suggest that the informationist's involvement has influenced the team's data gathering, storage, and curation methods. The UCLA Library has also changed the librarian's title to research informationist to reflect the new activities that she performs. CONCLUSION: The research informationist role provides an opportunity for librarians to become effective members of research teams and improve research output. PMID- 24163603 TI - Development of the research lifecycle model for library services. AB - QUESTION: Can the niche services of individual librarians across multiple libraries be developed into a suite of standard services available to all scientists that support the entire research lifecycle? SETTING: Services at a large, research-intensive state university campus are described. METHOD: Initial data were collected via concept mapping by librarians. Additional data were collected at conferences and meetings through interactive poster presentations. MAIN RESULTS: Services of interest to scientists for each of the stages in the research lifecycle were developed by the team to reflect the wide range of strengths of team members in aggregate. CONCLUSION: Input from researchers was the most effective tool for developing the model. A flexible research lifecycle model can be developed to match the needs of different service groups and the skills of different librarians. PMID- 24163604 TI - New roles for hospital librarians: a benchmarking survey of disaster management activities. PMID- 24163605 TI - The Health Association Libraries Section survey: finding clues to changing roles. PMID- 24163606 TI - Making meaningful connections: evaluating an embedded librarian pilot project to improve nursing scholarly writing. PMID- 24163607 TI - Library-based clinical and translational research support. PMID- 24163608 TI - Assessment and impact of a new role as an embedded librarian in nursing online journal clubs. PMID- 24163610 TI - An MR brain images classifier system via particle swarm optimization and kernel support vector machine. AB - Automated abnormal brain detection is extremely of importance for clinical diagnosis. Over last decades numerous methods had been presented. In this paper, we proposed a novel hybrid system to classify a given MR brain image as either normal or abnormal. The proposed method first employed digital wavelet transform to extract features then used principal component analysis (PCA) to reduce the feature space. Afterwards, we constructed a kernel support vector machine (KSVM) with RBF kernel, using particle swarm optimization (PSO) to optimize the parameters C and sigma . Fivefold cross-validation was utilized to avoid overfitting. In the experimental procedure, we created a 90 images dataset brain downloaded from Harvard Medical School website. The abnormal brain MR images consist of the following diseases: glioma, metastatic adenocarcinoma, metastatic bronchogenic carcinoma, meningioma, sarcoma, Alzheimer, Huntington, motor neuron disease, cerebral calcinosis, Pick's disease, Alzheimer plus visual agnosia, multiple sclerosis, AIDS dementia, Lyme encephalopathy, herpes encephalitis, Creutzfeld-Jakob disease, and cerebral toxoplasmosis. The 5-folded cross validation classification results showed that our method achieved 97.78% classification accuracy, higher than 86.22% by BP-NN and 91.33% by RBF-NN. For the parameter selection, we compared PSO with those of random selection method. The results showed that the PSO is more effective to build optimal KSVM. PMID- 24163611 TI - Body composition, muscle strength, and physical function of patients with Bethlem myopathy and Ullrich congenital muscular dystrophy. AB - OBJECTIVE: To determine the contributions of body mass, adiposity, and muscularity to physical function and muscle strength in adult patients with Bethlem myopathy (BM) and Ullrich congenital muscular dystrophy (UCMD). MATERIALS AND METHODS: Evaluation involved one UCMD and 7 BM patients. Body composition was determined by body mass index (BMI) and dual-energy-X-ray-absorptiometry (DXA), muscle strength by dynamometry, physical function by the distance walked in 6 minutes (6MWD), forced vital capacity (FVC) by a spirometer. RESULTS: Six participants were of normal weight and 2 overweight based on BMI; all were sarcopenic based on appendicular fat free mass index (AFFMI); and 7 were sarcopenic obese based on AFFMI and % fat mass. Average muscle strength was reduced below 50% of normal. The 6MWD was in BM patients 30% less than normal. FVC was reduced in 4 of the BM patients. Muscle strength had a good correlation with the physical function variables. Correlation between muscle strength and BMI was poor; it was very high with AFFMI. AFFMI was the best single explicator of muscle strength and physical function. CONCLUSION: Muscle mass determined by DXA explains most of the variability of the measures of muscle strength and physical function in patients with BM and UCMD. PMID- 24163612 TI - Dual synchronization of fractional-order chaotic systems via a linear controller. AB - The problem of the dual synchronization of two different fractional-order chaotic systems is studied. By a linear controller, we realize the dual synchronization of fractional-order chaotic systems. Finally, the proposed method is applied for dual synchronization of Van der Pol-Willis systems and Van der Pol-Duffing systems. The numerical simulation shows the accuracy of the theory. PMID- 24163613 TI - The role of thiamine pyrophosphate in prevention of cisplatin ototoxicity in an animal model. AB - OBJECTIVE: The aim of this study was to evaluate the effectiveness of thiamine pyrophosphate against cisplatin-induced ototoxicity in guinea pigs. MATERIALS AND METHODS: Healthy guinea pigs (n = 18) were randomly divided into three groups. Group 1 (n = 6) received an intraperitoneal injection of saline solution and cisplatin for 7 days, group 2 (n = 6) received an intraperitoneal injection of thiamine pyrophosphate and cisplatin for 7 days, and group 3 (n = 6) received only intraperitoneal injection of saline for 7 days. The animals in all groups were sacrificed under anesthesia, and their cochleas were harvested for morphological and biochemical observations. RESULTS: In group 1, receiving only cisplatin, cochlear glutathione concentrations, superoxide dismutase, and glutathione peroxidase activities significantly decreased (P < 0.05) and malondialdehyde concentrations significantly increased (P < 0.05) compared to the control group. In group 2, receiving thiamine pyrophosphate and cisplatin, the concentrations of enzymes were near those of the control group. Microscopic examination showed that outer hair cells, spiral ganglion cells, and stria vascularis were preserved in group 2. CONCLUSION: Systemic administration of thiamine pyrophosphate yielded statistically significant protection to the cochlea of guinea pigs from cisplatin toxicity. Further experimental animal studies are essential to determine the appropriate indications of thiamine pyrophosphate before clinical use. PMID- 24163614 TI - Total economic value of wetlands products and services in Uganda. AB - Wetlands provide food and non-food products that contribute to income and food security in Uganda. This study determined the economic value of wetland resources and their contribution to food security in the three agroecological zones of Uganda. The values of wetland resources were estimated using primary and secondary data. Market price, Productivity, and Contingent valuation methods were used to estimate the value of wetland resources. The per capita value of fish was approximately US$ 0.49 person-1. Fish spawning was valued at approximately US$ 363,815 year-1, livestock pastures at US$ 4.24 million, domestic water use at US$ 34 million year-1, and the gross annual value added by wetlands to milk production at US$ 1.22 million. Flood control was valued at approximately US$ 1,702,934,880 hectare-1 year-1 and water regulation and recharge at US$ 7,056,360 hectare-1 year-1. Through provision of grass for mulching, wetlands were estimated to contribute to US$ 8.65 million annually. The annual contribution of non-use values was estimated in the range of US$ 7.1 million for water recharge and regulation and to US$ 1.7 billion for flood control. Thus, resource investment for wetlands conservation is economically justified to create incentives for continued benefits. PMID- 24163615 TI - Influence of plant population and nitrogen-fertilizer at various levels on growth and growth efficiency of maize. AB - Field experiments were conducted to evaluate plant population and N-fertilizer effects on yield and yield components of maize (Zea mays L.). Three levels of plant populations (53000, 66000, and 800,000 plants ha-1 corresponding to spacings of 75 * 25, 60 * 25, and 50 * 25 cm) and 4 doses of N (100, 140, 180, and 220 kg ha-1) were the treatment variables. Results revealed that plant growth, light interception (LI), yield attributes, and grain yield varied significantly due to the variations in population density and N-rates. Crop growth rate (CGR) was the highest with the population of 80,000 ha-1 receiving 220 kg N ha-1, while relative growth rate (RGR) showed an opposite trend of CGR. Light absorption was maximum when most of densely populated plant received the highest amount of N (220 kg N ha-1). Response of soil-plant-analysis development (SPAD) value as well as N-content to N-rates was found significant. Plant height was the maximum at the lowest plant density with the highest amount of N. Plants that received 180 kg N ha-1 with 80,000 plants ha-1 had larger foliage, greater SPAD value, and higher amount of grains cob-1 that contributed to the maximum yield (5.03 t ha-1) and the maximum harvest index (HI) compared to the plants in other treatments. PMID- 24163616 TI - Influence of concentration and activation on hydrogen peroxide diffusion through dental tissues in vitro. AB - This study evaluated the effect of physical and chemical activation on the diffusion time of different concentrations of hydrogen peroxide (HP) bleaching agents through enamel and dentin. One hundred and twenty bovine cylindrical specimens were divided into six groups (n = 20): 20% HP; 20% HP with light activation; 20% HP with manganese gluconate; 35% HP; 35% HP with light activation; and 35% HP with manganese gluconate. The specimens were fixed over transparent epoxy wells with internal cavities to simulate a pulpal chamber. This chamber was filled with an enzymatic reagent to simulate pulpal fluid. The bleaching gels were applied on enamel surface and the image of the pulpal fluid was captured by a video camera to monitor the time of peroxide penetration in each specimen. ANOVA analysis showed that concentration and type of activation of bleaching gel significantly influenced the diffusion time of HP (P < 0.05). 35% HP showed the lowest diffusion times compared to the groups with 20% HP gel. The light activation of HP decreased significantly the diffusion time compared to chemical activation. The highest diffusion time was obtained with 20% HP chemically activated. The diffusion time of HP was dependent on activation and concentration of HP. The higher concentration of HP diffused through dental tissues more quickly. PMID- 24163617 TI - Direct synthesis of ESBO derivatives-18O labelled with dioxirane. AB - This work addresses a new approach developed in our laboratory, consisting in the application of isolated dimethyldioxirane (DDO, 1a) labelled with 18O for synthesis of epoxidized glyceryl linoleate (Gly-LLL, 2). We expect that this work could contribute in improving analytical methods for the determination of epoxidized soybean oil (ESBO) in complex food matrices by adopting an 18O labelled-epoxidized triacylglycerol as an internal standard. PMID- 24163618 TI - Competitive interaction of Axonopus compressus and Asystasia gangetica under contrasting sunlight intensity. AB - Axonopus compressus is one of the native soft grass species in oil palm in Malaysia which can be used as a cover crop. The competitive ability of A. compressus to overcome A. gangetica was studied using multiple-density, multiple proportion replacements series under a glasshouse and full sunlight conditions in a poly bag for 10 weeks. A. compressus produced more dry weight and leaf area when competing against A. gangetica than in monoculture at both densities in the full sunlight and at high density in the shade. Moreover, the relative yield and relative crowding coefficients also indicated A. compressus is a stronger competitor than A. gangetica at both densities in the full sunlight and high density in the shade. It seemed that A. gangetica plants in the shade did not compete with each other and were more competitive against A. compressus as could influence A. compressus height in the shade. It is concluded that although suppression of A. gangetica by A. compressus occurred under full sunlight, irrespective of plant density, this ability reduced under shade as A. compressus density decreased. The result suggests that A. compressus in high density could be considered as a candidate for cover crops under oil palm canopy. PMID- 24163619 TI - Future prospects in the diagnosis and management of localized prostate cancer. AB - Prostate cancer (PCa) is the commonest visceral cancer in men worldwide. Introduction of serum PSA as a highly specific biomarker for prostatic diseases has led to a dramatic increase in the diagnosis of early stage PCa in last decades. Guidelines underline that benefits as well as risks and squeals of early diagnosis and treatment should be discussed with patients. There are several new biomarkers (Pro-PSA, PCA-3 test, and TMPRSS2-ERG) available on the market but new ones are awaited in order to improve specificity and sensitivity. Investigators have also focused on identifying and isolating the gene, or genes, responsible for PCa. Current definitive treatment options for clinically localized PCa with functional and oncological success rates up to 95% include surgery (radical prostatectomy), external-beam radiation therapy, and interstitial radiation therapy (brachytherapy). Potential complications of overdiagnosis and overtreatment have resulted in arguments about screening and introduced a new management approach called "active surveillance." Improvements in diagnostic techniques, especially multiparametric magnetic resonance imaging, significantly ameliorated the accuracy of tumor localization and local staging. These advances will further support focal therapies as emerging treatment alternatives for localized PCa. As a conclusion, revolutionary changes in the diagnosis and management of PCa are awaited in the near future. PMID- 24163620 TI - Investigation on the aggregation behaviors and filament morphology of tau protein by a simple 90 degrees angle light-scattering assay. AB - The in vitro aggregation of tau constructs was monitored by a simple 90 degrees angle light-scattering (LS) approach which was conducted directly on fluorescence instrument. At the optimum incident wavelength (550 nm, unpolarized), the sensitivity of LS was high enough to detect tau aggregation at micromolar range. The nucleation and elongation, different events in the aggregation process of 4RMBD construct (corresponding with the four repeated units of tau Microtubule Binding Domain) could be observed by this approach, as compared with ThS fluorescence assay. The validity of this technique was demonstrated over a range of tau concentrations with different tau filaments. Linear regression of scattering light against concentration yielded the x-intercept, the critical concentrations of tau constructs. The critical concentrations of 4RMBD and its S305N mutant are 5.26 MUM and 4.04 MUM respectively, indicating point mutation S305N, which is associated with FTDP-17, appear to enhance the heparin-induced tau aggregation in vitro. Furthermore, the slopes of concentration dependence curves, as well as the angle dependence, were discussed based on the filaments morphology examined by electron microscopy and ultrasonication experiment. PMID- 24163621 TI - Balance fatigue design of cast steel nodes in tubular steel structures. AB - Cast steel nodes are being increasingly popular in steel structure joint application as their advanced mechanical performances and flexible forms. This kind of joints improves the structural antifatigue capability observably and is expected to be widely used in the structures with fatigue loadings. Cast steel node joint consists of two parts: casting itself and the welds between the node and the steel member. The fatigue resistances of these two parts are very different; the experiment results showed very clearly that the fatigue behavior was governed by the welds in all tested configurations. This paper focuses on the balance fatigue design of these two parts in a cast steel node joint using fracture mechanics and FEM. The defects in castings are simulated by cracks conservatively. The final crack size is decided by the minimum of 90% of the wall thickness and the value deduced by fracture toughness. The allowable initial crack size could be obtained through the integral of Paris equation when the crack propagation life is considered equal to the weld fatigue life; therefore, the two parts in a cast steel node joint will have a balance fatigue life. PMID- 24163622 TI - An obesity paradox of Asian body mass index after cardiac surgery: arterial oxygenations in duration of mechanic ventilation. AB - BACKGROUND: Numerous studies have documented an obesity paradox that overweight of Caucasian patients has better prognosis after cardiac surgery. This study is to examine Asian patients' BMI to see whether an obesity paradox exists in DMV after cardiac surgery. METHODS: A retrospective study consisted of 428 patients after cardiac surgery from January 2006 to December 2010 in the medical center of Taiwan. The Asian BMI was divided into 3 groups: under-normal weight patients (BMI < 24; n = 165), overweight patients (BMI 24 to <27; n = 130), and obese patients (BMI >= 27; n = 133). Multivariable analysis and paired t were used to compare all variables. RESULTS: Overweight patients were significantly associated with the shortest DMV. Under-normal weight patients had significantly better oxygenations of AaDO2 and P/F ratio in the DMV; however, they correlated with the longest DMV, older age, more female, lower LVSV, higher BUN, more dialysis dependent, and poorer outcomes, namely, 1-year mortality, HAP, reintubation, tracheotomy, and LOS. CONCLUSIONS: Asian overweight patients after cardiac surgery have better prognosis. Under-normal weight patients have higher risk factors, longer DMV, and poorer outcomes; even though they have better arterial oxygenations, they seem to need better arterial oxygenations for successful weaning ventilator. PMID- 24163623 TI - Analyzing axial stress and deformation of tubular for steam injection process in deviated wells based on the varied (T, P) fields. AB - The axial stress and deformation of high temperature high pressure deviated gas wells are studied. A new model is multiple nonlinear equation systems by comprehensive consideration of axial load of tubular string, internal and external fluid pressure, normal pressure between the tubular and well wall, and friction and viscous friction of fluid flowing. The varied temperature and pressure fields were researched by the coupled differential equations concerning mass, momentum, and energy equations instead of traditional methods. The axial load, the normal pressure, the friction, and four deformation lengths of tubular string are got ten by means of the dimensionless iterative interpolation algorithm. The basic data of the X Well, 1300 meters deep, are used for case history calculations. The results and some useful conclusions can provide technical reliability in the process of designing well testing in oil or gas wells. PMID- 24163626 TI - Emission of carbon dioxide influenced by different water levels from soil incubated organic residues. AB - We studied the influence of different organic residues and water levels on decomposition rate and carbon sequestration in soil. Organic residues (rice straw, rice root, cow dung, and poultry litter) including control were tested under moistened and flooding systems. An experiment was laid out as a complete randomized design at 25 degrees C for 120 days. Higher CO2-C (265.45 mg) emission was observed in moistened condition than in flooding condition from 7 to 120 days. Among the organic residues, poultry litter produced the highest CO2-C emission. Poultry litter with soil mixture increased 121% cumulative CO2-C compared to control. On average, about 38% of added poultry litter C was mineralized to CO2-C. Maximum CO2-C was found in 7 days after incubation and thereafter CO2-C emission was decreased with the increase of time. Control produced the lowest CO2-C (158.23 mg). Poultry litter produced maximum cumulative CO2-C (349.91 mg). Maximum organic carbon was obtained in cow dung which followed by other organic residues. Organic residues along with flooding condition decreased cumulative CO2-C, k value and increased organic C in soil. Maximum k value was found in poultry litter and control. Incorpored rice straw increased organic carbon and decreased k value (0.003 g d-1) in soil. In conclusion, rice straw and poultry litter were suitable for improving soil carbon. PMID- 24163624 TI - Stabilizing effect of various polyols on the native and the denatured states of glucoamylase. AB - Different spectral probes were employed to study the stabilizing effect of various polyols, such as, ethylene glycol (EG), glycerol (GLY), glucose (GLC) and trehalose (TRE) on the native (N), the acid-denatured (AD) and the thermal denatured (TD) states of Aspergillus niger glucoamylase (GA). Polyols induced both secondary and tertiary structural changes in the AD state of enzyme as reflected from altered circular dichroism (CD), tryptophan (Trp), and 1 anilinonaphthalene-8-sulfonic acid (ANS) fluorescence characteristics. Thermodynamic analysis of the thermal denaturation curve of native GA suggested significant increase in enzyme stability in the presence of GLC, TRE, and GLY (in decreasing order) while EG destabilized it. Furthermore, CD and fluorescence characteristics of the TD state at 71 degrees C in the presence of polyols showed greater effectiveness of both GLC and TRE in inducing native-like secondary and tertiary structures compared to GLY and EG. PMID- 24163627 TI - A quasiphysics intelligent model for a long range fast tool servo. AB - Accurately modeling the dynamic behaviors of fast tool servo (FTS) is one of the key issues in the ultraprecision positioning of the cutting tool. Herein, a quasiphysics intelligent model (QPIM) integrating a linear physics model (LPM) and a radial basis function (RBF) based neural model (NM) is developed to accurately describe the dynamic behaviors of a voice coil motor (VCM) actuated long range fast tool servo (LFTS). To identify the parameters of the LPM, a novel Opposition-based Self-adaptive Replacement Differential Evolution (OSaRDE) algorithm is proposed which has been proved to have a faster convergence mechanism without compromising with the quality of solution and outperform than similar evolution algorithms taken for consideration. The modeling errors of the LPM and the QPIM are investigated by experiments. The modeling error of the LPM presents an obvious trend component which is about +/-1.15% of the full span range verifying the efficiency of the proposed OSaRDE algorithm for system identification. As for the QPIM, the trend component in the residual error of LPM can be well suppressed, and the error of the QPIM maintains noise level. All the results verify the efficiency and superiority of the proposed modeling and identification approaches. PMID- 24163628 TI - The unique maximal GF-regular submodule of a module. AB - An R-module A is called GF-regular if, for each a ? A and r ? R, there exist t ? R and a positive integer n such that r(n)tr(n)a = r(n)a. We proved that each unitary R-module A contains a unique maximal GF-regular submodule, which we denoted by M GF(A). Furthermore, the radical properties of A are investigated; we proved that if A is an R-module and K is a submodule of A, then MGF(K) = K?M GF(A). Moreover, if A is projective, then MGF(A) is a G-pure submodule of A and MGF(A) = M(R) . A. PMID- 24163629 TI - Community core evolution in mobile social networks. AB - Community detection in social networks attracts a lot of attention in the recent years. Existing methods always depict the relationship of two nodes using the temporary connection. However, these temporary connections cannot be fully recognized as the real relationships when the history connections among nodes are considered. For example, a casual visit in Facebook cannot be seen as an establishment of friendship. Hence, our question is the following: how to cluster the real friends in mobile social networks? In this paper, we study the problem of detecting the stable community core in mobile social networks. The cumulative stable contact is proposed to depict the relationship among nodes. The whole process is divided into timestamps. Nodes and their connections can be added or removed at each timestamp, and historical contacts are considered when detecting the community core. Also, community cores can be tracked through the incremental computing, which can help to recognize the evolving of community structure. Empirical studies on real-world social networks demonstrate that our proposed method can effectively detect stable community cores in mobile social networks. PMID- 24163631 TI - Large scale near-duplicate celebrity web images retrieval using visual and textual features. AB - Near-duplicate image retrieval is a classical research problem in computer vision toward many applications such as image annotation and content-based image retrieval. On the web, near-duplication is more prevalent in queries for celebrities and historical figures which are of particular interest to the end users. Existing methods such as bag-of-visual-words (BoVW) solve this problem mainly by exploiting purely visual features. To overcome this limitation, this paper proposes a novel text-based data-driven reranking framework, which utilizes textual features and is combined with state-of-art BoVW schemes. Under this framework, the input of the retrieval procedure is still only a query image. To verify the proposed approach, a dataset of 2 million images of 1089 different celebrities together with their accompanying texts is constructed. In addition, we comprehensively analyze the different categories of near duplication observed in our constructed dataset. Experimental results on this dataset show that the proposed framework can achieve higher mean average precision (mAP) with an improvement of 21% on average in comparison with the approaches based only on visual features, while does not notably prolong the retrieval time. PMID- 24163630 TI - Phylogenetic, expression, and bioinformatic analysis of the ABC1 gene family in Populus trichocarpa. AB - We studied 17 ABC1 genes in Populus trichocarpa, all of which contained an ABC1 domain consisting of about 120 amino acid residues. Most of the ABC1 gene products were located in the mitochondria or chloroplasts. All had a conserved VAVK-like motif and a DFG motif. Phylogenetic analysis grouped the genes into three subgroups. In addition, the chromosomal locations of the genes on the 19 Populus chromosomes were determined. Gene structure was studied through exon/intron organization and the MEME motif finder, while heatmap was used to study the expression diversity using EST libraries. According to the heatmap, PtrABC1P14 was highlighted because of the high expression in tension wood which related to secondary cell wall formation and cellulose synthesis, thus making a contribution to follow-up experiment in wood formation. Promoter cis-element analysis indicated that almost all of the ABC1 genes contained one or two cis elements related to ABA signal transduction pathway and drought stress. Quantitative real-time PCR was carried out to evaluate the expression of all of the genes under abiotic stress conditions (ABA, CdCl2, high temperature, high salinity, and drought); the results showed that some of the genes were affected by these stresses and confirmed the results of promoter cis-element analysis. PMID- 24163632 TI - Quantifying the sources of the severe haze over the Southern Hebei using the CMAQ model. AB - The Southern Hebei of China has experienced an obvious increase of the haze occurrence frequency in the recent years. It has turned out to be one of the most seriously polluted areas in China. This study is aimed at quantifying the sources of the serious haze pollution over the Southern Hebei area, using the Mesoscale Modeling System Generation 5 (MM5) and the Models-3/Community Multiscale Air Quality Model (CMAQ) modeling system. The sectoral contributions by the local and the surrounding regions to the fine particulate matter (PM2.5) concentrations in the two representative cities, Shijiazhuang and Xingtai, were analyzed by applying the method of scenario analysis. It will provide useful information to the policy making in the severe air pollution control in the Southern Hebei area. PMID- 24163633 TI - Assessing the ecological risk of polycyclic aromatic hydrocarbons in sediments at Langkawi Island, Malaysia. AB - Tourism-related activities such as the heavy use of boats for transportation are a significant source of petroleum hydrocarbons that may harm the ecosystem of Langkawi Island. The contamination and toxicity levels of polycyclic aromatic hydrocarbon (PAH) in the sediments of Langkawi were evaluated using sediment quality guidelines (SQGs) and toxic equivalent factors. Ten samples were collected from jetties and fish farms around the island in December 2010. A gas chromatography/flame ionization detector (GC/FID) was used to analyse the 18 PAHs. The concentration of total PAHs was found to range from 869 +/- 00 to 1637 +/- 20 ng g-1 with a mean concentration of 1167.00 +/- 24 ng g-1, lower than the SQG effects range-low (3442 ng g-1). The results indicated that PAHs may not cause acute biological damage. Diagnostic ratios and principal component analysis suggested that the PAHs were likely to originate from pyrogenic and petrogenic sources. The toxic equivalent concentrations of the PAHs ranged from 76.3 to 177 ng TEQ/g d.w., which is lower compared to similar studies. The results of mean effects range-median quotient of the PAHs were lower than 0.1, which indicate an 11% probability of toxicity effect. Hence, the sampling sites were determined to be the low-priority sites. PMID- 24163635 TI - The effects of water parameters on monthly seagrass percentage cover in Lawas, East Malaysia. AB - Seagrass is a valuable marine ecosystem engineer. However, seagrass population is declining worldwide. The lack of seagrass research in Malaysia raises questions about the status of seagrasses in the country. The seagrasses in Lawas, which is part of the coral-mangrove-seagrass complex, have never been studied in detail. In this study, we examine whether monthly changes of seagrass population in Lawas occurred. Data on estimates of seagrass percentage cover and water physicochemical parameters (pH, turbidity, salinity, temperature, and dissolved oxygen) were measured at 84 sampling stations established within the study area from June 2009 to May 2010. Meteorological data such as total rainfall, air temperature, and Southern Oscillation Index were also investigated. Our results showed that (i) the monthly changes of seagrass percentage cover are significant, (ii) the changes correlated significantly with turbidity measurements, and (iii) weather changes affected the seagrass populations. Our study indicates seagrass percentage increased during the El-Nino period. These results suggest that natural disturbances such as weather changes affect seagrass populations. Evaluation of land usage and measurements of other water physicochemical parameters (such as heavy metal, pesticides, and nutrients) should be considered to assess the health of seagrass ecosystem at the study area. PMID- 24163637 TI - Aircraft detection from VHR images based on circle-frequency filter and multilevel features. AB - Aircraft automatic detection from very high-resolution (VHR) images plays an important role in a wide variety of applications. This paper proposes a novel detector for aircraft detection from very high-resolution (VHR) remote sensing images. To accurately distinguish aircrafts from background, a circle-frequency filter (CF-filter) is used to extract the candidate locations of aircrafts from a large size image. A multi-level feature model is then employed to represent both local appearance and spatial layout of aircrafts by means of Robust Hue Descriptor and Histogram of Oriented Gradients. The experimental results demonstrate the superior performance of the proposed method. PMID- 24163636 TI - Synthesis and properties of macrocyclic butanoic acid conjugates as a promising delivery formulation for the nutrition of colon. AB - Butanoic acid plays a significant role in the maintenance of mucosal health and is the preferred energy substrate for the cells in the colon. Here, butanoic acid was selectively conjugated to the secondary hydroxyl group of beta -cyclodextrin through ester bond using sodium hydride as the deprotonation reagent. The preliminary release behaviors of butanoic acid in rat gastrointestinal tract contents were investigated at 37 degrees C within 12 h. In the contents of stomach, the conjugates did seldom release butanoic acid, released butanoic acid only 5.8% in the contents of small intestine, and released butanoic acid significantly up to 38.4% in the contents of colon. These results indicate that the conjugate activation took place site specifically in the rat colonic contents, via the biodegradation by glycosidases and hydrolases in the colon. Therefore, the beta -cyclodextrin conjugates of butanoic acid may be of value as an orally administered colon-specific formulation for the nutrition of colon. PMID- 24163638 TI - Semisupervised kernel marginal Fisher analysis for face recognition. AB - Dimensionality reduction is a key problem in face recognition due to the high dimensionality of face image. To effectively cope with this problem, a novel dimensionality reduction algorithm called semisupervised kernel marginal Fisher analysis (SKMFA) for face recognition is proposed in this paper. SKMFA can make use of both labelled and unlabeled samples to learn the projection matrix for nonlinear dimensionality reduction. Meanwhile, it can successfully avoid the singularity problem by not calculating the matrix inverse. In addition, in order to make the nonlinear structure captured by the data-dependent kernel consistent with the intrinsic manifold structure, a manifold adaptive nonparameter kernel is incorporated into the learning process of SKMFA. Experimental results on three face image databases demonstrate the effectiveness of our proposed algorithm. PMID- 24163639 TI - Examining the efficacy of DVD technology compared to print-based material in COPD self-management education of rural patients. AB - A pilot study (n = 41) was conducted to test the effects of three educational treatments (DVD vs. Pamphlet vs. DVD + Pamphlet) on health-related quality of life (HRQoL), COPD information needs and self-efficacy among a referred sample of Certified Federal Rural Health Clinic patients (mean age = 61.51 years +/- 6.29 years; ~61% female) suffering from COPD using a randomly-assigned, multiple-group pretest-posttest design with a control group. A MANCOVA testing planned multivariate contrasts determined patients receiving a DVD reported statistically significant higher levels of lung-specific physical functioning as compared to patients receiving a Pamphlet. Additionally, DVD patients reported clinically significant improvements on two dimensions of lung-specific HRQoL. No such improvements occurred within the Pamphlet and Control groups. The provision of self-management education as compared to usual care, however, did not improve the outcome variables examined. PMID- 24163634 TI - Recent developments of functional scaffolds for craniomaxillofacial bone tissue engineering applications. AB - Autogenous bone grafting remains a gold standard for the reconstruction critical sized bone defects in the craniomaxillofacial region. Nevertheless, this graft procedure has several disadvantages such as restricted availability, donor-site morbidity, and limitations in regard to fully restoring the complicated three dimensional structures in the craniomaxillofacial bone. The ultimate goal of craniomaxillofacial bone reconstruction is the regeneration of the physiological bone that simultaneously fulfills both morphological and functional restorations. Developments of tissue engineering in the last two decades have brought such a goal closer to reality. In bone tissue engineering, the scaffolds are fundamental, elemental and mesenchymal stem cells/osteoprogenitor cells and bioactive factors. A variety of scaffolds have been developed and used as spacemakers, biodegradable bone substitutes for transplanting to the new bone, matrices of drug delivery system, or supporting structures enhancing adhesion, proliferation, and matrix production of seeded cells according to the circumstances of the bone defects. However, scaffolds to be clinically completely satisfied have not been developed yet. Development of more functional scaffolds is required to be applied widely to cranio-maxillofacial bone defects. This paper reviews recent trends of scaffolds for crania-maxillofacial bone tissue engineering, including our studies. PMID- 24163640 TI - Continuous Time Level Crossing Sampling ADC for Bio-Potential Recording Systems. AB - In this paper we present a fixed window level crossing sampling analog to digital convertor for bio-potential recording sensors. This is the first proposed and fully implemented fixed window level crossing ADC without local DACs and clocks. The circuit is designed to reduce data size, power, and silicon area in future wireless neurophysiological sensor systems. We built a testing system to measure bio-potential signals and used it to evaluate the performance of the circuit. The bio-potential amplifier offers a gain of 53 dB within a bandwidth of 200 Hz-20 kHz. The input-referred rms noise is 2.8 uV. In the asynchronous level crossing ADC, the minimum delta resolution is 4 mV. The input signal frequency of the ADC is up to 5 kHz. The system was fabricated using the AMI 0.5 um CMOS process. The chip size is 1.5 mm by 1.5 mm. The power consumption of the 4-channel system from a 3.3 V supply is 118.8 uW in the static state and 501.6 uW with a 240 kS/s sampling rate. The conversion efficiency is 1.6 nJ/conversion. PMID- 24163641 TI - Sparkle/PM7 Lanthanide Parameters for the Modeling of Complexes and Materials. AB - The recently published Parametric Method number 7, PM7, is the first semiempirical method to be successfully tested by modeling crystal structures and heats of formation of solids. PM7 is thus also capable of producing results of useful accuracy for materials science, and constitutes a great improvement over its predecessor, PM6. In this article, we present Sparkle Model parameters to be used with PM7 that allow the prediction of geometries of metal complexes and materials which contain lanthanide trications. Accordingly, we considered the geometries of 224 high-quality crystallographic structures of complexes for the parameterization set and 395 more for the validation of the parameterization for the whole lanthanide series, from La(III) to Lu(III). The average unsigned error for Sparkle/PM7 for the distances between the metal ion and its coordinating atoms is 0.063A for all lanthanides, ranging from a minimum of 0.052A for Tb(III) to 0.088A for Ce(III), comparable to the equivalent errors in the distances predicted by PM7 for other metals. These distance deviations follow a gamma distribution within a 95% level of confidence, signifying that they appear to be random around a mean, confirming that Sparkle/PM7 is a well-tempered method. We conclude by carrying out a Sparkle/PM7 full geometry optimization of two spatial groups of the same thulium-containing metal organic framework, with unit cells accommodating 376 atoms, of which 16 are Tm(III) cations; the optimized geometries were in good agreement with the crystallographic ones. These results emphasize the capability of the use of the Sparkle Model for the prediction of geometries of compounds containing lanthanide trications within the PM7 semiempirical model, as well as the usefulness of such semiempirical calculations for materials modeling. Sparkle/PM7 is available in the software package MOPAC2012, at no cost for academics and can be obtained from http://openmopac.net. PMID- 24163643 TI - Perspectives of Community Health Advocates: Barriers to Healthy Family Eating Patterns. PMID- 24163642 TI - The Polarizable Atomic Multipole-based AMOEBA Force Field for Proteins. AB - Development of the AMOEBA (Atomic Multipole Optimized Energetics for Biomolecular Simulation) force field for proteins is presented. The current version (AMOEBA 2013) utilizes permanent electrostatic multipole moments through the quadrupole at each atom, and explicitly treats polarization effects in various chemical and physical environments. The atomic multipole electrostatic parameters for each amino acid residue type are derived from high-level gas phase quantum mechanical calculations via a consistent and extensible protocol. Molecular polarizability is modeled via a Thole-style damped interactive induction model based upon distributed atomic polarizabilities. Inter- and intramolecular polarization is treated in a consistent fashion via the Thole model. The intramolecular polarization model ensures transferability of electrostatic parameters among different conformations, as demonstrated by the agreement between QM and AMOEBA electrostatic potentials, and dipole moments of dipeptides. The backbone and side chain torsional parameters were determined by comparing to gas-phase QM (RI-TRIM MP2/CBS) conformational energies of dipeptides and to statistical distributions from the Protein Data Bank. Molecular dynamics simulations are reported for short peptides in explicit water to examine their conformational properties in solution. Overall the calculated conformational free energies and J-coupling constants are consistent with PDB statistics and experimental NMR results, respectively. In addition, the experimental crystal structures of a number of proteins are well maintained during molecular dynamics (MD) simulation. While further calculations are necessary to fully validate the force field, initial results suggest the AMOEBA polarizable multipole force field is able to describe the structure and energetics of peptides and proteins, in both gas-phase and solution environments. PMID- 24163644 TI - U-Scores for Multivariate Data in Sports. AB - In many sport competitions athletes, teams, or countries are evaluated based on several variables. The strong assumptions underlying traditional 'linear weight' scoring systems (that the relative importance, interactions and linearizing transformations of the variables are known) can often not be justified on theoretical grounds, and empirical 'validation' of weights, interactions and transformations, is problematic when a 'gold standard' is lacking. With MU-scores (u-scores for multivariate data) one can integrate information even if the variables have different scales and unknown interactions or if the events counted are not directly comparable, as long as the variables have an 'orientation'. Using baseball as an example, we discuss how measures based on MU-scores can complement the existing measures for 'performance' (which may depend on the situation) by providing the first multivariate measures for 'ability' (which should be independent of the situation). Recently, MU-scores have been extended to situations where count variables are graded by importance or relevance, such as medals in the Olympics (Wittkowski 2003) or Tour-de-France jerseys (Cherchye and Vermeulen 2006, 2007). Here, we present extensions to 'censored' variables (life-time achievements of active athletes), penalties (counting a win more than two ties) and hierarchically structured variables (Nordic, alpine, outdoor, and indoor Olympic events). The methods presented are not restricted to sports. Other applications of the method include medicine (adverse events), finance (risk analysis), social choice theory (voting), and economy (long-term profit). PMID- 24163645 TI - Probabilistic Prediction of Protein Phosphorylation Sites Using Classification Relevance Units Machines. AB - Phosphorylation is an important post-translational modification of proteins that is essential to the regulation of many cellular processes. Although most of the phosphorylation sites discovered in protein sequences have been identified experimentally, the in vivo and in vitro discovery of the sites is an expensive, time-consuming and laborious task. Therefore, the development of computational methods for prediction of protein phosphorylation sites has drawn considerable attention. In this work, we present a kernel-based probabilistic Classification Relevance Units Machine (CRUM) for in silico phosphorylation site prediction. In comparison with the popular Support Vector Machine (SVM) CRUM shows comparable predictive performance and yet provides a more parsimonious model. This is desirable since it leads to a reduction in prediction run-time, which is important in predictions on large-scale data. Furthermore, the CRUM training algorithm has lower run-time and memory complexity and has a simpler parameter selection scheme than the Relevance Vector Machine (RVM) learning algorithm. To further investigate the viability of using CRUM in phosphorylation site prediction, we construct multiple CRUM predictors using different combinations of three phosphorylation site features - BLOSUM encoding, disorder, and amino acid composition. The predictors are evaluated through cross-validation and the results show that CRUM with BLOSUM feature is among the best performing CRUM predictors in both cross-validation and benchmark experiments. A comparative study with existing prediction tools in an independent benchmark experiment suggests possible direction for further improving the predictive performance of CRUM predictors. PMID- 24163646 TI - Induction of eosinophilic esophagitis by sublingual pollen immunotherapy. AB - Sublingual immunotherapy (SLIT) is increasingly investigated and utilized for the treatment of food and pollen allergies. Previous case reports suggested that eosinophilic esophagitis (EoE) might develop as a long-term complication in children after completion of oral immunotherapy. Here, we describe a 44-year-old female with a medical history of pollinosis who for the first time in her life developed complete manifestation of EoE (peak eosinophils 164/high power field) 4 weeks after initiation of SLIT using specific soluble allergens (hazelnut, birch, alder) according to previous specific serum IgE testing. After discontinuation of SLIT, EoE resolved completely within 4 weeks without any other medical intervention. During a follow-up of 12 months the patient remained free of any esophageal symptoms. This is the first case report demonstrating a close and therefore likely causative association between pollen SLIT and EoE in an adult patient. PMID- 24163647 TI - Incidental finding of isolated colonic neurofibroma. AB - Neurofibromatosis is a genetic disorder manifested by characteristic cutaneous lesions called neurofibromas. There are two distinct neurocutaneous syndromes named neurofibromatosis type 1 (also called von Recklinghausen disease or NF1) and neurofibromatosis type 2 (NF2). NF1 is by far the most common presentation and is caused by an autosomal dominant mutation in the NF1 gene mapped to chromosome 17q11.2. The literature shows that gastrointestinal involvement is noted in systemic neurofibromatosis in up to 25% of patients, but isolated intestinal neurofibromatosis is a very rare manifestation. We herein present the case of a 70-year-old woman who was diagnosed with an isolated colonic neurofibroma without any systemic signs of neurofibromatosis; only a few case reports of this condition have been published to date. PMID- 24163648 TI - Biliary cast syndrome in an opium inhaler. AB - Biliary cast syndrome (BCS) is an uncommon complication which is mostly described in orthotopic liver transplantation. However, BCS has also been reported rarely in non-liver transplant patients. We describe a male long-term opium inhaler with BCS who underwent successful endoscopic cast removal by balloon enteroscopy guided endoscopic retrograde cholangiopancreatography. A 52-year-old man, who was a known case of opium addiction, presented with the chief complaint of epigastric pain for 1 week prior to admission. Routine laboratory evaluation revealed cholestatic liver enzyme elevation. A cholestatic pattern was seen in radiographic modalities. Endoscopic retrograde cholangiopancreatography showed a linear filling defect in the intra- and extrahepatic duct. A long biliary cast was successfully removed using an extractor balloon. After removal of the biliary cast the patient is receiving ursodeoxycholic acid and does not report any problem 4 months after treatment. It seems that biliary dyskinesia due to long term opium use can be a predisposing factor for biliary cast formation. PMID- 24163649 TI - Adult colocolic intussusception and literature review. AB - Intussusception occurs when a proximal segment of the gastrointestinal tract, called intussusceptum, telescopes into the lumen of an adjacent segment, also known as intussuscipiens. Although common in early childhood, intussusceptions are very rare in the adult population. Most intussusceptions in adults are due to a lead point, which is an identifiable pathological abnormality, in opposition to children which there are no identifiable pathological lead points. In contrast to childhood intussusception, in adults it is associated with malignant lesions, particularly in the large bowel rather than in the small bowel. Its preoperative diagnosis and treatment in adults is difficult because of nonspecific abdominal symptom and because it rarely presents with the classic triad of vomiting, abdominal pain and passage of blood per rectum. We present a 63-year-old female with an adenocarcinoma tumor being the lead point in a colocolic intussusception, who was diagnosed preoperatively with computed tomography and had a colonoscopy to rule out obstruction. She underwent right hemicolectomy with side-to-side ileocolic anastomosis and did well postoperatively. In addition, we also review the literature and discuss the value of radiological modalities, location and surgical management to try to improve the preoperative diagnosis. Computed tomography scanning with intravenous contrast is maybe the most accurate modality for diagnosis of intussusceptions in adults, and treatment is usually surgical resection without reduction, since most of the colonic lesions are malignant. PMID- 24163650 TI - Liver unidentified bright object in a septic patient. AB - The typical sonographic appearance of liver hemangiomas is a well-demarcated hyperechoic mass with homogeneous echodensity. Focal liver lesions may change their ultrasound characteristics over time. We present a case of dynamic pattern of liver hemangiomas during a state of systemic inflammation. PMID- 24163651 TI - Pyloric gland adenoma: a case report. AB - Endoscopic procedures are the gold standard in identifying, monitoring and treating gastrointestinal system lesions. The evaluation of benign, precancerous and malignant characteristics of these lesions requires good endoscopic inspection and precise pathological examination. Pyloric gland adenoma is a rare precancerous lesion defined in recent years and herein is reviewed in the present case along with the literature. PMID- 24163652 TI - Addition of Molecular Adsorbent Recirculating System (MARS((r))) Albumin Dialysis for the Preoperative Management of Jaundiced Patients with Hilar Cholangiocarcinoma. AB - The preoperative management of hilar cholangiocarcinoma (HC) with jaundice focuses on decreasing the total serum bilirubin level (SBL) by performing preoperative biliary drainage (PBD). However, it takes about 6-8 weeks for the SBL to fall at a sufficient extent. The objective of this preliminary study was to evaluate the impact of Molecular Adsorbent Recirculating System (MARS((r))) dialysis (in association with PBD) on SBL decrease. From January 2010 to January 2011, we prospectively selected all jaundiced patients admitted to our university hospital for resectable HC and requiring PBD prior to major hepatectomy. The PBD was followed by 3 sessions of MARS dialysis over a period of 72 h. A total of 10 patients with HC were screened and two of them were included (Bismuth-Corlette stage IIIa, gender ratio 1, median age 68 years). The initial SBL in the two patients was 328 and 242 MUmol/l, respectively. After three MARS dialysis sessions, the SBL had fallen by 30 and 52%, respectively. After the end of each session, there was a SBL rebound of about 10 MUmol/l. The MARS decreased the serum creatinine level, the platelet count and the prothrombin index, but did not modify the serum albumin level. Pruritus disappeared after one and two sessions, respectively. MARS-related morbidity included hypotension (n = 1), tachycardia (n = 1), thrombocytopenia (n = 2) and anaemia (n = 1). When combined with PBD, MARS dialysis appears to accelerate the decrease in SBL and thus may enable earlier surgery. This hypothesis must be validated in a larger study. PMID- 24163653 TI - Infected Walled-Off Pancreatic Necrosis following EUS-Guided Drainage Successfully Treated Using Multiple Stents in Different Sites Technique. AB - Walled-off pancreatic necrosis (WOPN) is one of the most life-threatening complications of acute severe pancreatitis. Regarding its high mortality and morbidity without appropriate treatment, the drainage procedure is still the mainstay of the treatment for this condition. There are multiple drainage options for this event. To date, endoscopic drainage alone has not been adequate for this condition, while surgical drainage has been reported to have a high morbidity. Endoscopic drainage with pancreatic necrosectomy is the most effective and safe method, while endoscopic drainage with aggressive lavage is another acceptable treatment option. The procedural details have been described elsewhere in many studies. In this report, we describe an alternative technique of drainage by endoscopy alone, without aggressive lavage procedure, that yielded an acceptable outcome with an easier procedure. PMID- 24163654 TI - Toxic Megacolon and Acute Ischemia of the Colon due to Sigmoid Stenosis Related to Diverticulitis. AB - We present a rare case of toxic megacolon accompanied by necrosis of the colon due to chronic dilation caused by stenosis of the sigmoid colon as a complication of diverticulitis. The patient presented at the emergency department with diffuse abdominal pain, fever (38.8 degrees C) and tachycardia (120 beats/min). Physical examination revealed distension and tenderness on deep palpation on the left lower quadrant without peritoneal signs. Abdominal computed tomography showed located stenosis in the sigmoid colon and marked dilation of the descending (12 cm diameter) and transverse (7.5 cm diameter) colon. A few hours later, the patient developed severe septic shock with electrolyte abnormalities. He had a history of two prior admissions to our hospital due to crises of acute diverticulitis. Based on Jalan's criteria the diagnosis was compatible with toxic megacolon. The patient's condition deteriorated suddenly and an emergency colectomy was performed. The operative findings revealed a necrotic colon. Histology examination confirmed the diagnosis of ischemia of the colon. To our knowledge this is the first published report in the literature which refers to a rare complication of diverticulitis, namely chronic stenosis which complicated to colonic ischemia and toxic megacolon. PMID- 24163655 TI - Unusual images of mass-forming intrahepatic cholangiocarcinoma. AB - We experienced a case of mass-forming intrahepatic cholangiocarcinoma which could not been diagnosed accurately without pathologic findings. A 78-year-old Japanese woman with no particular symptoms was admitted for changes in liver function tests. Ultrasonography revealed a solid liver tumor. When there are no typical imaging features, no pathognomonic clinical findings and no obvious risk factors for any specific hepatic tumor, it may be difficult to make an accurate diagnosis before surgical resection. The lesion was resected on the basis of a high degree of suspicion for malignancy and submitted for pathologic evaluation. Microscopically, the neoplasm was a moderately differentiated adenocarcinoma with abundant fibrous stroma, consistent with a mass-forming cholangiocarcinoma. This case exemplifies the importance of considering the various tumorous and non tumorous diseases in the differential diagnosis of a liver mass with atypical features, especially when malignancy cannot be excluded. PMID- 24163656 TI - Common blue nevus with satellite lesions needs a differential diagnosis from malignant melanoma. AB - Malignant blue nevus is rare, and a common blue nevus rarely needs a differential diagnosis from malignant melanoma. Although a melanocytic nevus with a satellite lesion is usually suggestive of a peripherally disseminating malignant melanoma, very few cases of blue nevus with satellite lesions have been reported thus far. To our knowledge, this is the seventh case of a blue nevus with satellitosis. Periappendageal and perivascular concentrations of the nevus cells were observed in the main papule as well as in the satellite lesions. These findings suggest that blue nevus cells could infiltrate along the perivascular area in the dermis and form multiple satellite lesions. Blue nevus should be considered as a differential diagnosis when a locally disseminating malignant melanoma is suspected. PMID- 24163657 TI - Proliferating trichilemmal tumor: a case on the nose of a 70-year-old man. AB - The authors report a case of proliferating trichilemmal tumor on the tip of the nose of a man. This tumor is usually seen in women and on the scalp, and it shows trichilemmal keratinization on histopathology. PMID- 24163658 TI - Ustekinumab treatment of erythrodermic psoriasis occurring after physical stress: a report of two cases. AB - Erythrodermic psoriasis (EP) is a severe form of psoriasis precipitated by numerous factors, including physical stress, infections, and drugs. The disease represents a therapeutic challenge, and little is known about its response to ustekinumab. Though the efficacy of ustekinumab has been extensively studied in chronic plaque psoriasis, no trials have been carried out in EP. We report the case of 2 patients, 1 male and 1 female, who showed EP despite being treated with etanercept and methotrexate for chronic plaque psoriasis, respectively. The patients were treated with ustekinumab at a dosage of 45 mg s.c. They showed a significant improvement in their Psoriasis Area and Severity Index score after only 4 weeks of ustekinumab therapy, and further improvements were observed throughout the treatment. In our experience, ustekinumab has been proven safe and effective, without increasing the dosage, in controlling and preventing the occurrence of erythrodermic flares. Ustekinumab therapy may therefore be considered a valid therapeutic option for the treatment of EP, even in cases where other biological agents have failed. PMID- 24163659 TI - Complete Response to Trastuzumab-Based Chemotherapy in a Patient with Human Epidermal Growth Factor Receptor-2-Positive Metastatic Salivary Duct Carcinoma ex Pleomorphic Adenoma. AB - INTRODUCTION: Carcinoma ex pleomorphic adenoma (CXPA) of the salivary glands has often a salivary duct carcinoma (SDC) component, which resembles ductal carcinoma of the breast and frequently overexpresses human epidermal growth factor receptor 2 (HER2). We report a case of metastatic CXPA with SDC component who was treated with trastuzumab-based chemotherapy and has had a durable complete response. CASE REPORT: A 74-year-old man was diagnosed with CXPA of the right parotid gland. The resected tumor was histologically diagnosed as CXPA with a predominant SDC component that showed strong positivity for HER2 protein and HER2 gene amplification. Multiple pulmonary metastatic lesions were detected after surgery, and combination chemotherapy with paclitaxel and trastuzumab was initiated. A complete response was confirmed after 7 treatment cycles, and no evidence of disease progression has been observed after 13 months of initiation of therapy. CONCLUSIONS: This report suggests a potential utility of trastuzumab-based chemotherapy for HER2-positive CXPA. PMID- 24163660 TI - Management of two cases of recurrent anal carcinoma. AB - Due to the low incidence of anal cancer and generally high cure rates, few second line treatment options have been evaluated in the setting of formal clinical trials. We briefly report two cases that were both found to have wild-type K-RAS, with no epidermal growth factor receptor amplification or evidence of prior persistent human papilloma virus infection. Both cases were treated with irinotecan and cetuximab with evidence of clinical benefit in the setting of a third recurrence, as well as evidence of response to other strategies employed in their management. These cases provide support for the suggestion that treatment planning in conjunction with molecular profiling may be beneficial in such uncommon clinical settings. PMID- 24163661 TI - Displacement of malignant cells into the portal triad of the liver results in reduced liver perfusion, mimicking segmental Fatty liver. AB - Liver steatosis is often observed in different clinical situations. Oncological patients undergoing systemic therapy often develop liver steatosis, which can be diagnosed with normal routine scans such as CT and ultrasound. In this case report, we show that an isolated infiltration of the portal triad with tumor cells could mimic a fatty-like infiltration of the liver. Radiologists and clinicians should be aware of this pitfall and should perform a biopsy in cases of doubt. PMID- 24163662 TI - Diffuse abdominal splenosis mimicking peritoneal metastases in a 35-year-old man with a resectable carcinoma of the ampulla of vater. AB - A 35-year-old man with a history of blunt abdominal trauma and splenic rupture was diagnosed with an ampullary adenocarcinoma. At workup, a CT scan showed multiple intra-abdominal lesions similar to peritoneal carcinosis, and the patient was referred for palliative chemotherapy. On clinical suspicion, however, a biopsy was performed on an intra-abdominal lesion, establishing the diagnosis of abdominal splenosis. A radical pancreaticoduodenectomy ad modum Whipple was performed, followed by adjuvant chemotherapy with gemcitabine. At the 18-month follow-up, the patient was free from recurrent disease. We conclude that splenosis should be considered as a differential diagnosis of peritoneal metastases in cancer patients with a history of abdominal trauma and/or splenectomy. Other reports on splenosis in cancer patients and diagnostic workup are discussed. PMID- 24163663 TI - Rare adult masseteric rhabdomyosarcoma and a review of the literature. AB - BACKGROUND: Rhabdomyosarcomas (RMSs) are a group of soft-tissue malignant tumors which derive from primitive skeletal muscle tissue that mainly affect children and adolescents. RMSs are very rare in adults, where they are usually located in the extremities. CASE PRESENTATION: A previously healthy 32-year-old male presented at our ENT (ear, nose and throat) outpatient clinic after experiencing a parotid region swelling for 2 months. The patient was treated surgically by excising the mass and by modified radical ipsilateral neck dissection. Histological and immunohistochemical examination indicated masseteric alveolar RMS with lymphatic metastasis. The patient received radiochemotherapy, and he is still alive with no evidence of disease spread 1 year after diagnosis. CONCLUSION: This is the first case of a masseter alveolar RMS to be reported in the literature in a patient older than 25 years; it highlights the broad spectrum of neoplasms that cause parotid region swellings and the importance of considering rare tumors during differential diagnosis. PMID- 24163664 TI - Malignant Transformation from Endometriosis to Atypical Endometriosis and Finally to Endometrioid Adenocarcinoma within 10 Years. AB - Atypical endometriosis is reported to possess a precancerous potential attributed to premalignant changes characterized by cytological atypia and architecture proliferation. Moreover, the coexistence of atypical endometriosis and neoplasms had been reported. However, cases of atypical endometriosis transformation to carcinoma are rarely reported. We describe the case of a 33-year-old woman who had a long therapeutic history of endometriosis. Three laparoscopic surgeries were performed to treat endometriosis. After the third surgery, she was diagnosed as having grade 1 endometrioid adenocarcinoma. The histological review of the previous surgery confirmed the diagnosis of atypical endometriosis based on the second specimen. The patient's disease progressed from a benign endometriotic cyst to atypical endometriosis and finally to endometrioid adenocarcinoma within 10 years. When we encounter cases of atypical endometriosis, it is necessary to consider the possibility of ovarian cancer and carefully follow the patients for long periods. PMID- 24163665 TI - Multimodality imaging of right-sided (tricuspid valve) papillary fibroelastoma: recognition of a surgically remediable disease. AB - Presentation of an increasingly recognized right-sided primary valve tumor of clinical importance: the tricuspid valve papillary fibroelastoma (PF). Early recognition and surgical intervention is emphasized for valvular PF, which carries a significant risk of morbidity and mortality. Newer imaging techniques, including CT and MRI, assist in localizing and differentiating PF from alternative cardiac pathology. PMID- 24163666 TI - Hypersensitivity to Etoposide in case of metastatic gestational choriocarcinoma. AB - Etoposide is commonly used in the treatment of a variety of neoplasms. Hypersensitivity reactions to etoposide are infrequently reported and include hypotension, hypertension, flushing, diaphoresis, chest discomfort, dyspnea, bronchospasm and loss of consciousness. We report the case of a 39-year-old woman who experienced acute bronchospasm, tachycardia, hypoxia and hypotension. The symptoms resolved within an hour after administration of intravenous fluids, methylprednisolone, diphenhydramine and oxygen. Subsequently, the patient was given etoposide phosphate without incident. PMID- 24163667 TI - Marked retroperitoneal lymphadenopathy in hairy cell leukemia: a case report. AB - Hairy cell leukemia (HCL) is uncommonly associated with lymphadenopathy, while retroperitoneal lymphadenopathy is extremely uncommon. We report on a patient with a 12-year history of HCL who developed painless jaundice and ascites, accompanied by positional discomfort with persistent nausea. Computed tomography examination revealed 2 large retroperitoneal masses, which at autopsy consisted of HCL with focally intermixed pancreatic and peripancreatic tissue. Lymphadenopathy was not identified above the diaphragm or below the aortic bifurcation. No vasculitis or an unusual HCL histology was identified. As previous reports, our findings suggest that HCL with massive lymphadenopathy has a specific site predilection, but it is not necessarily accompanied by vasculitis or an unusual histology. PMID- 24163669 TI - Clinical Outcome of a FIGO Stage IV Gestational Choriocarcinoma. AB - Choriocarcinoma is the most malignant tumor of gestational trophoblastic disease arising from any gestation. It has a tendency toward relapse as well as metastasis. Here, a case of relapsed high-risk choriocarcinoma (FIGO stage IV, WHO score 12) in a 37-year-old female presenting with vaginal bleedings is described. Relapse developed at the site of the surgical scar from hysterectomy that had been performed 2 years earlier. Although the patient was treated with aggressive chemotherapy, she was in a bad general condition and died from infection and liver insufficiency. PMID- 24163668 TI - Successful Salvage Chemotherapy with FOLFIRINOX for Recurrent Mixed Acinar Cell Carcinoma and Ductal Adenocarcinoma of the Pancreas in an Adolescent Patient. AB - Pancreatic tumors are rare in children and adolescents. Here, we report the case of a 15-year-old boy who presented with a mixed acinar cell carcinoma/ductal adenocarcinoma with blastomatous components. He received multimodal treatment including various chemotherapy regimens and multistep surgery including liver transplantation. Introduction of FOLFIRINOX after relapse repeatedly achieved a durable metabolic and clinical response with good quality of life. PMID- 24163670 TI - Progressive multifocal leukoencephalopathy in an immunocompetent patient? AB - BACKGROUND: Progressive multifocal leukoencephalopathy (PML) is a rapidly progressive, potentially fatal, demyelinating disease affecting immunosuppressed patients. PML is rarely reported in cases with no underlying disease or immunosuppression-associated condition. CASE REPORT: We present a 72-year-old previously healthy woman who developed a progressive neurological condition affecting the entire nervous system which led to her death within 5 months. PML was diagnosed at autopsy. CONCLUSION: PML should be considered in patients with progressive neurological disorders involving the white matter, even in the absence of previous immunomodulatory treatment or immunosuppression. PMID- 24163671 TI - Growing Evidence about the Relationship between Vessel Dissection and Scuba Diving. AB - Carotid and vertebral artery dissection are relatively frequent and risky conditions. In the last decade, different patients with extracranial (and in 1 case also intracranial) dissections associated with the practice of scuba diving were reported. The connection between the two conditions has not been fully explained so far. In the present article, we report the case of a patient presenting with Claude Bernard-Horner syndrome and homolateral XII cranial nerve palsy, manifesting a few days after diving in the cold water of a lake. The patient ended up having internal carotid artery dissection associated with the formation of a pseudoaneurysm. Here, we offer a summary of all cases reported in the literature about scuba diving and arterial dissection, and provide a critical discussion about which scuba diving-related factors can trigger the dissection of cervical vessels. PMID- 24163672 TI - New-onset refractory status epilepticus mimicking herpes virus encephalitis. AB - New-onset refractory status epilepticus (NORSE) is a recently defined clinical entity that describes patients who present with status epilepticus of unclear etiology that is highly refractory to therapy. Magnetic resonance imaging (MRI) of NORSE usually discloses no specific abnormalities except for an occasional mild T2/FLAIR hyperintense signal of the mesial temporal lobe. Here, we report a peculiar case of NORSE in which brain MRI showed massive alteration of both temporal lobes, with features strongly supporting the diagnosis of herpes virus encephalitis, but lacking any laboratory evidence of viral infection in the blood and cerebrospinal fluid. It showed also striking signal alterations in the thalamus, which got worse in the course of the disease. This report emphasizes the possibility that seizure activity alone plays a critical role in both determining the disease and whether it will be self-sustaining. PMID- 24163673 TI - Intracranial Hypertension due to Cerebral Venous Sinus Thrombosis following Head Trauma: A Report of Two Cases. AB - Cerebral venous sinus thrombosis (CVST) may occur following head trauma and contribute to intracranial hypertension that mandates immediate action. Anticoagulant therapy is the first line of treatment in CVST but may not be applicable in patients with head trauma. Here, we report on the treatment of 2 patients with CVST. In 1 patient, there was an attempt to perform thrombectomy and thrombolysis, and eventually a decompressive craniectomy was performed. In this patient, there was an excellent outcome. In the other patient, an immediate decompressive craniectomy was performed that did not improve the outcome. PMID- 24163674 TI - Malignant hemispheric cerebral infarction associated with idiopathic systemic capillary leak syndrome. AB - Idiopathic systemic capillary leak syndrome (ISCLS) is a rare condition that is characterized by unexplained episodic capillary hyperpermeability due to a shift of fluid and protein from the intravascular to the interstitial space. This results in diffuse general swelling, fetal hypovolemic shock, hypoalbuminemia, and hemoconcentration. Although ISCLS rarely induces cerebral infarction, we experienced a patient who deteriorated and was comatose as a result of massive cerebral infarction associated with ISCLS. In this case, severe hypotensive shock, general edema, hemiparesis, and aphasia appeared after serious antecedent gastrointestinal symptoms. Progressive life-threatening ischemic cerebral edema required decompressive hemicraniectomy. The patient experienced another episode of severe hypotension and limb edema that resulted in multiple extremity compartment syndrome. Treatment entailed forearm and calf fasciotomies. Cerebral edema in the ischemic brain progresses rapidly in patients suffering from ISCLS. Strict control of fluid volume resuscitation and aggressive diuretic therapy may be needed during the post-leak phase of fluid remobilization. PMID- 24163675 TI - Changes in optical coherence tomography findings in acute zonal occult outer retinopathy. AB - PURPOSE: To report a case of acute zonal occult outer retinopathy (AZOOR) in a 39 year-old woman. METHODS: Images were obtained with fundus photography and optical coherence tomography (OCT). A multifocal electroretinogram (mfERG) was also obtained to evaluate retinal function. RESULTS: The patient's right visual acuity was 0.8. Fundus photographs showed no specific abnormal findings. OCT showed attenuation of the photoreceptor inner segment/outer segment (IS/OS) line and the cone outer segment tip (COST) line in the right eye. The mfERG showed corresponding amplitude reductions. One month after the initial visit, her right visual acuity improved to 1.2. There was partial recovery of the IS/OS line; however, the COST line was still absent, and there was no apparent improvement in the mfERG responses. CONCLUSIONS: Our findings showed a discrepancy between the microstructural findings and visual function during recovery of AZOOR. PMID- 24163676 TI - Putative corneal neuralgia responding to vitamin d supplementation. AB - A patient with putative corneal neuralgia was incidentally discovered to have hypovitaminosis D. Supplementation of vitamin D appears to have led to a resolution of the patient's pain, whereas other efforts to treat the patient were unsuccessful. PMID- 24163677 TI - Orbital lymphoma mimicking lacrimal gland pleomorphic adenoma. AB - PURPOSE: To describe the case of a patient affected by orbital lymphoma mimicking pleomorphic adenoma of the lacrimal gland. METHODS: This was a retrospective case report. RESULTS: We present the case of a patient with 15-year history of slowly progressive left proptosis and inferomedial bulbar dislocation who had the presumptive diagnosis of lacrimal gland pleomorphic adenoma based on clinical and radiological features. The patient underwent lateral orbitotomy and lacrimal gland excision. Postoperative histological features were consistent with low grade B-cell non-Hodgkin lymphoma. CONCLUSION: The accepted clinico-radiological criteria used for the diagnosis of lacrimal gland fossa lesions might have a certain false-positive rate, even in recent years. The initial surgical approach with the appropriate choice between fine-needle aspiration biopsies, intraoperative biopsies and lacrimal gland excisions might be a challenge. PMID- 24163678 TI - Pathological findings of pemphigus vulgaris showing giant cobblestone-like conjunctival papillae. AB - PURPOSE: To describe the pathophysiological findings of a patient with pemphigus vulgaris (PV) showing giant conjunctival papillae. METHODS: A 64-year-old man who had mucosal-dominant PV with giant conjunctival papillae, resembling those of vernal keratoconjunctivitis (VKC), underwent an ophthalmological workup. The clinical and pathological findings were investigated. RESULTS: Ophthalmic interventions were unable to provide the desired beneficial effects, and multiple excisions were necessary to remove the proliferative conjunctival lesions. Histopathological investigations of the excised tissues demonstrated acantholysis and a subconjunctival infiltration with numerous inflammatory cells such as lymphocytes, plasma cells, and neutrophils. However, in contrast to typical VKC, mast cells and eosinophils were rarely found in the subconjunctival tissues. Direct immunofluorescent staining showed a significant deposition of immunoglobulin G and complement component 3 in the epithelial intercellular substance, consistent with mucosal-dominant PV. Then, the patient was hospitalized because of oral erosion exacerbation and malnutrition. Because of the patient's declining general condition, we administered an increasing dose of a systemic steroid with an intravenous immunoglobulin, after which his ocular lesions and symptoms improved. CONCLUSIONS: The histological conjunctival papilla findings were quite different from those of VKC papillae. If PV causes a lesion in a patient, systemic immunosuppression might be more effective than topical ophthalmic treatment because of overall immunological involvement. PMID- 24163679 TI - Intravitreal dexamethasone implant (ozurdex) in coats' disease. AB - We injected an intravitreal dexamethasone implant in two eyes of 2 pediatric patients with Coats' disease in addition to other treatment modalities, such as intravitreal ranibizumab injection and indirect laser photocoagulation. In both eyes, intraocular pressure moderately rose in a temporary fashion. The dexamethasone implant seems to be a valuable addition to the armamentarium of treatment options for Coats' disease as it necessitates fewer injections than anti-VEGF injections and thereby fewer sessions of general anesthesia in the pediatric population. PMID- 24163680 TI - Pattern dystrophy of the macula in a case of steinert disease. AB - INTRODUCTION: Myotonic dystrophies are typically associated with ocular complications like ptosis, weakness of the ocular muscle and cataracts, but also with less recognized retinal changes. CASE REPORT: A 41-year-old female with type 1 myotonic dystrophy complained of progressive vision loss. Slit lamp examination revealed the presence of typical bilateral polychromatic cataract with posterior subcapsular component. Dilated fundus examination was remarkable for bilateral macular depigmented changes. Multimodal imaging analysis of the macula suggested the presence of a butterfly-shaped pattern dystrophy. DISCUSSION: In cases of myotonic dystrophies it is of great relevance to analyze the presence of retinal changes that might limit the visual improvement following cataract extraction. PMID- 24163681 TI - Cataract surgery for tilted lens in peters' anomaly type 2. AB - BACKGROUND: Cases of cataract surgery without penetrating keratoplasty in patients with Peters' anomaly are very rare. We report a case of Peters' anomaly type 2 with tilted lens due to synechia between the lens and iris that was treated with cataract surgery without penetrating keratoplasty. CASE PRESENTATION: A 16-year-old girl had Peters' anomaly in both eyes. Corneal opacity was severe in the left eye due to high-grade dysgenesis of the anterior segment. In the right eye, corneal opacity had spread from the center of the cornea to the inferotemporal side, and there was synechia between the iris and corneal endothelium from the inferonasal side to the inferotemporal side. Opacity was observed in the anterior pole of the lens, and there was synechia between the anterior iris and the lens. Ultrasound biomicroscopy (UBM) revealed that the lens was tilted because of synechia. The tilted lens induced astigmatism, which reduced visual acuity to 20/250, in conjunction with a cataract. Cataract surgery was performed; the synechia between the lens capsule and the iris was severed, an intraocular lens was inserted, and the tilt was repaired. UBM was used postoperatively to confirm that the lens capsule synechia had been corrected and that the intraocular lens was not tilted. As a result, visual acuity improved to 20/100; glaucoma and expansion of corneal opacity were not observed. CONCLUSIONS: Severing of the synechia between the cataract and iris, during cataract surgery, in a patient with Peters' anomaly type 2 resulted in favorable postoperative visual acuity. PMID- 24163682 TI - Reverse optic capture to stabilize a toric intraocular lens. AB - PURPOSE: To describe a technique for stabilizing a rotationally unstable toric intraocular lens (IOL). METHOD: Case report and literature review. RESULTS: Surgical technique and long-term follow-up for a patient who underwent repositioning and stabilization of a mobile 1-piece acrylic toric IOL using reverse optic capture (ROC) are described. This patient presented with early, more than 70 degrees off-axis rotation. The IOL was repositioned but was very mobile within the bag and tended to rotate off-axis; hence, it was stabilized in the desired position by capturing the optic through the anterior continuous curvilinear capsulorhexis, leaving the haptics in the bag. The immediate and 2 year postoperative follow-up revealed a stable and on-axis IOL with no visual, refractive or ocular complications. CONCLUSIONS: ROC is a useful and safe technique to address the problem of toric IOLs that tend to rotate at the time of surgery or are not stable postoperatively. PMID- 24163683 TI - Heidelberg edge perimetry for the detection of early glaucomatous damage: a case report. AB - PURPOSE: To illustrate the potential role for Heidelberg edge perimetry (HEP) in the assessment of early functional loss in glaucoma. CASE REPORT: A 46-year-old male presented with raised intraocular pressure but healthy optic discs and normal standard automated perimetry (SAP). He was diagnosed with ocular hypertension, but after 16 years, he developed glaucomatous changes to the right optic disc and inferior retinal nerve fiber layer thinning. Despite the evidence of progressive structural damage, functional testing using SAP was repeatedly normal, based on conventional criteria. HEP, on the other hand, revealed an extensive superior visual field damage in agreement with the structural changes. Additionally, and in contrast to SAP, the HEP indices of Glaucoma Hemifield Test, mean deviation and pattern standard deviation were all outside normal limits. CONCLUSION: This case illustrates that HEP may have an important role in the early detection of functional damage in glaucoma, with potential advantages over SAP. PMID- 24163684 TI - Akreos Adapt AO Intraocular Lens Opacification: A Case Report. AB - A 79-year-old hyperglycemic patient was referred to the 'Santa Maria delle Croci' Hospital, Ravenna, Italy. He presented with visual impairment in the right eye. Four years ago, he had had an uneventful cataract surgery in the right eye. We observed an opacification of the intraocular lens (IOL) causing significant visual disturbance. The IOL was exchanged. Unfortunately, pathologic analysis was not performed. Patient-related factors such as hyperglycemia and hypertension might have been responsible for the opacification. To our knowledge, there is only one previous report of opacification of the Akreos Adapt AO IOL. PMID- 24163685 TI - Punctate inner choroidopathy: a clinical case report. AB - PURPOSE: To report an uncommon case of a 29-year-old Caucasian male diagnosed with unilateral choroidal neovascularization (CNV) secondary to punctate inner choroidopathy leading to visual impairment. METHODS: This is a retrospective and descriptive case report based on data from clinical records, patient observation and analysis of ancillary diagnostic tests. RESULTS: A 29-year-old Caucasian male presented to our emergency department with complaints of decreased central vision in his left eye (LE), detected a few hours before. Best-corrected visual acuity (BCVA) in the LE was counting fingers at 50 cm and BCVA in the right eye was 20/20. Fundoscopy of the LE evidenced multiple round and yellowish lesions in the macula and nasal to the optic nerve, without intraocular inflammation signs. Optical coherence tomography showed increased retinal thickness with detachment of the neuroepithelium and a slight retinal pigment epithelium detachment. Fluorescein angiography revealed hyperfluorescent lesions with blurred borders in the macula. An intravitreal injection of bevacizumab (1.25 mg/0.05 ml) was administered in the LE, which resulted in anatomic and visual improvement. CONCLUSION: We present a rare case of unilateral CNV secondary to punctate inner choroidopathy in a young, myopic male. PMID- 24163686 TI - Location of the Susceptibility Vessel Sign on T2*-Weighted MRI and Early Recanalization within 1 Hour after Tissue Plasminogen Activator Administration. AB - BACKGROUND: We have recently reported that the susceptibility vessel sign (SVS) at the proximal portion of the horizontal (M1) middle cerebral artery (MCA) on T2*-weighted MRI is a strong predictor for no early recanalization after intravenous recombinant tissue plasminogen activator (t-PA) therapy. However, it is unclear whether the presence of the SVS at other locations, such as distal M1, the vertical portion (M2) of the MCA, and distal branches (MCA distal), is a predictor for no early recanalization in acute ischemic stroke patients. METHODS: The SVS was defined as a hypointense signal of the MCA on T2*-weighted MRI on admission. The locations of the SVS were classified as M1 proximal, M1 distal, and MCA distal. M1 proximal SVS was defined as an SVS at the origin of the M1. M1 distal SVS was any M1 SVS not including the origin of the M1. MCA distal SVS was an SVS further away from M1. Early recanalization was defined as a new appearance of at least one of the distal branches on MRA within 1 h after t-PA therapy. A good outcome at 3 months was defined as a modified Rankin Scale (mRS) score of 0 1. RESULTS: Consecutive acute stroke patients admitted to our stroke center and treated with t-PA between October 2005 and October 2012 were enrolled. There were 158 patients [median age, 78 (71-84) years; 84 (53%) males; median National Institutes of Health Stroke Scale score, 16 (10-20)]. Internal carotid artery occlusion was seen in 18 (72%) of the 25 patients with M1 proximal SVS, in 3 (14%) of the 22 patients with M1 distal SVS, in 4 (9%) of the 44 patients with MCA distal SVS, and in 18 (27%) of the 67 patients with No SVS (p < 0.001). Twenty-four (96%) of the 25 patients with M1 proximal SVS had no early recanalization, while 16 (73%) of the 22 patients with M1 distal SVS, 25 (57%) of the 44 patients with MCA distal SVS, and 36 (54%) of the 67 patients with No SVS had no early recanalization (p < 0.001, 0.140, and 0.846, respectively, compared to the patients with No SVS). Multivariate analysis showed that only M1 proximal SVS was significantly associated with no early recanalization (odds ratio 16.80, 95% confidence interval 2.04-138.17, p = 0.009). Among the 95 patients with a premorbid mRS score of 0-1, none (0%) of the 16 patients with M1 proximal SVS, 5 (36%) of the 14 patients with M1 distal SVS, 12 (48%) of the 25 patients with MCA distal SVS, and 13 (33%) of the 40 patients with No SVS achieved a good outcome (p = 0.011, 1.000, and 0.295, respectively, compared to the patients with No SVS). CONCLUSION: M1 proximal SVS on T2*-weighted MRI is a strong predictor for no early recanalization, and all patients with it had a poor outcome. However, M1 distal SVS and MCA distal SVS were not predictors for no early recanalization, and half of the patients had a poor outcome. PMID- 24163687 TI - Generalized subcutaneous emphysema caused by injection of air into the penis for autoerotic purposes. AB - The injection of air or water into the scrotum has been described only a few times so far in the literature. Injection of air into the penis and its consequences has not been described at all. Here, we present the case of a young man who, acting on his previously suppressed sexual fantasies, injected air into his penis and caused generalized subcutaneous emphysema. PMID- 24163688 TI - Delayed development of pulmonary hemorrhage in a patient with positive circulating anti-neutrophil cytoplasmic antibody: a clinical dilemma. AB - Detection of circulating anti-neutrophil cytoplasmic antibody (ANCA) provides a powerful clue in the diagnosis of vasculitis, but the clinical interpretation of the results is difficult in some cases. Here, we describe the case of a 65-year old man who underwent hemodialysis due to focal segmental glomerulosclerosis and abruptly developed hemoptysis 14 years after a renal biopsy. At the time of the biopsy, computed tomography (CT) showed interstitial shadows in the lungs and pleural thickening, indicating pneumoconiosis that was accompanied by tuberculosis. Circulating myeloperoxidase-ANCA (10.5-32.5 U/ml) was subsequently noted, but the significance of this observation was unclear due to the preexisting disorders in the lungs and kidneys. Potent immunosuppressive therapies were avoided because of the pulmonary lesions and decreased renal function. There were few changes noted on follow-up CT, but infiltrative shadows emerged in the bilateral lungs, consistent with hemoptysis. The hemorrhagic shadows completely disappeared shortly after initiation of steroid therapy, with normalization of the serum ANCA level. Herein, we report this case, with an emphasis on the clinical dilemma faced in deciding the appropriate treatment. The findings in the case provide deep insights into clinical management of ANCA positive patients. PMID- 24163689 TI - Prevalence in the General Population of a CFH Sequence Variant Associated with Atypical Haemolytic Uraemic Syndrome in an Extensive Family from Southwest England. AB - BACKGROUND/AIMS: Twenty-five members of a family from the county of Devon in England have been affected by atypical haemolytic uraemic syndrome (aHUS) associated with a CFH mutation (c.3643C>G; p.Arg1215Gly). A 65-year-old male was diagnosed with aHUS after losing a renal transplant to a thrombotic microangiopathy. Subsequent mutation screening revealed the same CFH mutation without him being knowingly related to the local kindred. We designed a study to investigate the prevalence of this mutation in the local area. In addition, we examined the diagnoses of pre-existing haemodialysis patients to determine whether other patients might unknowingly be at risk of carrying the same CFH mutation. METHODS: The Exeter Ten Thousand (EXTEND) study aims to recruit 10,000 healthy volunteers over the age of 18 years living within 25 miles of Exeter in Devon. We genotyped DNA from 4,000 EXTEND subjects for CFH c.3643C>G; p.Arg1215Gly. We reviewed the diagnoses of 294 haemodialysis patients in the Devon area and genotyped 7 patients with either end-stage renal disease of unknown aetiology, malignant hypertension or renovascular disease. RESULTS: CFH c.3643C>G; p.Arg1215Gly was not detected in any of the 7 haemodialysis patients or the 4,000 individuals within the EXTEND study. CONCLUSIONS: We conclude that CFH c.3643C>G; p.Arg1215Gly is not endemic in Devon. This reinforces our existing practice of genotyping only patients with kidney disease and evidence of a thrombotic microangiopathy for this mutation. This is the first study looking at the prevalence of CFH mutations in the general population. PMID- 24163691 TI - SNiPloid: A Utility to Exploit High-Throughput SNP Data Derived from RNA-Seq in Allopolyploid Species. AB - High-throughput sequencing is a common approach to discover SNP variants, especially in plant species. However, methods to analyze predicted SNPs are often optimized for diploid plant species whereas many crop species are allopolyploids and combine related but divergent subgenomes (homoeologous chromosome sets). We created a software tool, SNiPloid, that exploits and interprets putative SNPs in the context of allopolyploidy by comparing SNPs from an allopolyploid with those obtained in its modern-day diploid progenitors. SNiPloid can compare SNPs obtained from a sample to estimate the subgenome contribution to the transcriptome or SNPs obtained from two polyploid accessions to search for SNP divergence. PMID- 24163690 TI - The super super-healing MRL mouse strain. AB - The Murphy Roths Large (MRL/MpJ) mice provide unique insights into wound repair and regeneration. These mice and the closely related MRL/MpJ-Faslpr /J and Large strains heal wounds made in multiple tissues without production of a fibrotic scar. The precise mechanism of this remarkable ability still eludes researchers, but some data has been generated and insights are being revealed. For example, MRL cells reepithelialize over dermal wound sites faster than cells of other mouse strains. This allows a blastema to develop beneath the protective layer. The MRL mice also have an altered basal immune system and an altered immune response to injury. In addition, MRL mice have differences in their tissue resident progenitor cells and certain cell cycle regulatory proteins. The difficulty often lies in separating the causative differences from the corollary differences. Remarkably, not every tissue in these mice heals scarlessly, and the specific type of wound and priming affect regeneration ability as well. The MRL/MpJ, MRL/MpJ-Faslpr /J, and Large mouse strains are also being investigated for their autoimmune characteristic. Whether the two phenotypes of regeneration and autoimmunity are related remains an enigma. PMID- 24163692 TI - Mobile Phone Short Message Service (SMS) for Weight Management in Iranian Overweight and Obese Women: A Pilot Study. AB - We conducted a text message-based intervention for weight management over three months by two months intervention and one month wash-out period. In a quasi experimental study with control (n = 40) and experimental group (n = 40), 80 overweight and obese employed women were entered. Participants were recruited via announcement. All subjects attended a face-to-face information session and received a booklet that contained food calorie chart and strategies and recommendations for weight management. The experimental group received text messages (SMS) about weight management twice a day for two months, in addition to the information and the booklet which they had received in the information session. Also, the experimental group was instructed to weekly self-weight and to send the data to the principle researcher. All subjects were measured for baseline and secondary weight in a standardized manner by a nurse, and the data were compared between the two groups. Experimental group lost more weight than the control group (1.5 kg difference, P = 0.018). Text messaging seems to be an effective channel of communication for weight management in Iranian overweight and obese women. The clinical trial registration number is IRCT201204029360N1. PMID- 24163693 TI - Prospective trial of a novel nomogram to achieve updated vancomycin trough concentrations. AB - Purpose. To determine if the use of a novel vancomycin nomogram predicts dosing regimens that achieve target trough concentrations equal to or more accurate than dosing regimens calculated using traditional pharmacokinetic calculations, evaluate the incidence of subtherapeutic and supratherapeutic troughs, and assess pharmacist's impressions of the nomogram. Methods. Prospective, open-label study in 473 patients who had a new order for vancomycin and were >18 years of age and <=120 kg. Patients were randomized to the active group, dosed using the nomogram, or to the control group, dosed using traditional pharmacokinetic calculations already in place at our institution. Results. Patients dosed via nomogram were within the appropriate trough range in 44% of cases compared to 33% in the control group (P = 0.014). Vancomycin troughs less than 10 mcg/mL were significantly decreased with the use of nomogram (P = 0.032). Incidence of supratherapeutic troughs, greater than 20 mcg/mL, was not significantly different between groups (P = 0.706), and pharmacists agreed that the nomogram was easy to use and saved their time. Conclusions. A novel vancomycin nomogram was prospectively validated and found to be more effective than traditional pharmacokinetic dosing. The nomogram is being implemented as the standard dosing protocol at our institution. PMID- 24163694 TI - Hepatoprotective Potential of Some Local Medicinal Plants against 2 Acetylaminoflourene-Induced Damage in Rat. AB - The in vivo micronucleus assay was used to examine the anticlastogenic effects of crude extracts of Bridelia ferruginea, Vernonia amygdalina, Tridax procumbens, Ocimum gratissimum, and Lawsonia inermis in Wistar albino rats. Extracts of doses of 100 mg/kg body weight were given to rats in five groups for seven consecutive days followed by a single dose of 2-AAF (0.5 mmol/kg body weight). The rats were sacrificed after 24 hours and their bone marrow smears were prepared on glass slides stained with Giemsa. The micronucleated polychromatic erythrocyte cells (mPCEs) were thereafter recorded. The hepatoprotective effects of the plant extracts against 2-AAF-induced liver toxicity in rats were evaluated by monitoring the levels of alkaline phosphatase (ALP), gamma glutamyl transferase (GGT), and histopathological analysis. The results of the 2-AAF-induced liver toxicity experiments showed that rats treated with the plant extracts (100 mg/kg) showed a significant decrease in mPCEs as compared with the positive control. The rats treated with the plant extracts did not show any significant change in the concentration of ALP and GGT in comparison with the negative control group whereas the 2-AAF group showed a significant increase (P < 0.05) in these parameters. Some of the leaf extracts also showed protective effects against histopathological alterations. This study suggests that the leaf extracts have hepatoprotective potential, thereby justifying their ethnopharmacological uses. PMID- 24163695 TI - Assessment of Safety and Therapeutic Efficacy of Rosa damascena L. and Quercus infectoria on Cardiovascular Performance of Normal and Hyperlipidemic Rabbits: Physiologically Based Approach. AB - According to the use of Quercus infectoria (QI) and Rosa damascena L. (RD) for therapeutic purposes and lack of adequate information about their cardiovascular effects, we investigated the cardiovascular indices of rabbits which chronically pretreated with these agents. Animal groups were control group (CTL), RD and QI groups with normal chow plus 1.5 g RD and QI extracts, respectively, in each kg of the diet for 45 days; Hyperlipidemic (H) group received high-fat diet for 45 days; H+RD and H+QI groups received high fat diet plus QI and RD extracts, respectively. Blood pressure was greater in H+RD group than CTL, RD, and H groups. Left ventricular developed pressure and left ventricular systolic pressure increased significantly in H+RD group versus CTL and RD groups (P < 0.05 and P < 0.0001, resp.) and in H+QI groups (P < 0.01 versus QI groups). Left ventricular end diastolic pressure (LVEDP) showed significant reduction in H+QI group versus H group. QI attenuated the values of total cholesterol, LDL, TG, and atherogenic indices of plasma when coadministrated with a high-fat diet. The results suggest the antilipidemic and antiatherogenic effects of QI. In addition, the use of RD along with a high-fat diet may increase the risk of hypertension in rabbits. PMID- 24163696 TI - Novel Regulatory Mechanisms of Pathogenicity and Virulence to Combat MDR in Candida albicans. AB - Continuous deployment of antifungals in treating infections caused by dimorphic opportunistic pathogen Candida albicans has led to the emergence of drug resistance resulting in cross-resistance to many unrelated drugs, a phenomenon termed multidrug resistance (MDR). Despite the current understanding of major factors which contribute to MDR mechanisms, there are many lines of evidence suggesting that it is a complex interplay of multiple factors which may be contributed by still unknown mechanisms. Coincidentally with the increased usage of antifungal drugs, the number of reports for antifungal drug resistance has also increased which further highlights the need for understanding novel molecular mechanisms which can be explored to combat MDR, namely, ROS, iron, hypoxia, lipids, morphogenesis, and transcriptional and signaling networks. Considering the worrying evolution of MDR and significance of C. albicans being the most prevalent human fungal pathogen, this review summarizes these new regulatory mechanisms which could be exploited to prevent MDR development in C. albicans as established from recent studies. PMID- 24163698 TI - Midwives' Experiences in Providing Care and Counselling to Women with Female Genital Mutilation (FGM) Related Problems. AB - Aim. The aim of this study was to elucidate midwives experiences in providing care and counselling to women with FGM related problems. Setting. The study was conducted at a maternity clinic in Hargeisa, Somaliland. Method. A qualitative, inductive study were performed with eight midwives living in Somaliland. The interviews had semi-structured questions. Content analysis was used for the analysis. Findings. The main findings of the present study were how midwives are challenged by culture and religion when providing FGM counselling. The most prominent challenge is the perception that FGM is an important part of the culture and from this point of view the midwives work is apprehended as interfering and subverting the Somali culture. Having personal experience of FGM emerged as a benefit when counselling women. Conclusion. There is a contradiction between the professional actions of performing FGM despite a personal belief against FGM. Midwives as a professional group could be important agents of change and further research is needed about the midwives role in this process. PMID- 24163697 TI - Uterine fibroids: pathogenesis and interactions with endometrium and endomyometrial junction. AB - Uterine leiomyomas (fibroids or myomas) are benign tumors of uterus and clinically apparent in a large part of reproductive aged women. Clinically, they present with a variety of symptoms: excessive menstrual bleeding, dysmenorrhoea and intermenstrual bleeding, chronic pelvic pain, and pressure symptoms such as a sensation of bloatedness, increased urinary frequency, and bowel disturbance. In addition, they may compromise reproductive functions, possibly contributing to subfertility, early pregnancy loss, and later pregnancy complications. Despite the prevalence of this condition, myoma research is underfunded compared to other nonmalignant diseases. To date, several pathogenetic factors such as genetics, microRNA, steroids, growth factors, cytokines, chemokines, and extracellular matrix components have been implicated in the development and growth of leiomyoma. This paper summarizes the available literature regarding the ultimate relative knowledge on pathogenesis of uterine fibroids and their interactions with endometrium and subendometrial myometrium. PMID- 24163699 TI - Comparing the gene expression profile of stromal cells from human cord blood and bone marrow: lack of the typical "bone" signature in cord blood cells. AB - With regard to the bone-regenerative capacity, bone marrow stromal cells (BMSC) can still be termed the "gold standard." Nevertheless, neonatal stromal cells from cord blood (CB) feature advantages concerning availability, immaturity, and proliferation potential. The detailed gene expression analysis and overexpression of genes expressed differentially provide insight into the inherent capacity of stromal cells. Microarray and qRT-PCR analyses revealed closely related gene expression patterns of two stromal cell populations derived from CB. In contrast to the CB-derived cell types, BMSC displayed high expression levels of BSP, OSX, BMP4, OC, and PITX2. Lentiviral overexpression of BSP but not of OSX in CB-cells increased the capacity to form a mineralized matrix. BMP4 induced the secretion of proteoglycans during chondrogenic pellet culture and extended the osteogenic but reduced the adipogenic differentiation potential. BMSC revealed the typical osteogenic gene expression signature. In contrast, the CB-derived cell types exhibited a more immature gene expression profile and no predisposition towards skeletal development. The absence of BSP and BMP4-which were defined as potential key players affecting the differentiation potential-in neonatal stromal cells should be taken into consideration when choosing a cell source for tissue regeneration approaches. PMID- 24163700 TI - A preliminary assessment of dispersion level of SO 2 in Fars industrial region, south of Iran, by GIS. AB - The city of Zarghan is located 25 km northeast of Shiraz, southern Iran. Zarghan is affected by numerous pollution sources such as oil refinery, an industrial park, and Shiraz-Tehran highway. The numerous contaminating sources around Zarghan can cause serious local air pollution. Sulfur dioxide gas is an important index of air pollution in cities. Therefore, in order to control and manage Zarghan air quality, it is important to monitor sulfur dioxide concentration in the surrounding area. It is also essential to know about the contribution level of other sources of pollution as well as dispersion radius of pollutants in the area. In this study, the concentration of sulfur dioxide was measured by passive sampling at 10 different stations. These values were interpolated in other parts of the city using ArcGIS software. The results of sampling showed that the concentration of the gas was 60 ugm(-3) around oil refinery. The level was 19 ugm(-3) in region located about 3 km from the oil refinery. It was also demonstrated that the gas concentration was not higher than the standard limit within residential area. On the other hand, the role of the local highway and industrial park was not significant in contaminating air in urban areas. PMID- 24163701 TI - Food marketing targeting youth and families: what do we know about stores where moms actually shop? AB - Although efforts are underway to examine marketing that targets the youth and families in the retail food store environment, few studies have specifically focused on stores that families identify as their primary sites for food shopping. Between November 2011 and April 2012, we examined the frequency and types of marketing techniques of 114 packaged and nonpackaged items in 24 food stores that mothers of young children in Champaign County, IL, said they commonly frequented. Chi-square tests were used to determine whether significant differences existed between items with regard to marketing by store type, store food-assistance-program acceptance (i.e., WIC), and claims. Overall, stores accepting WIC and convenience stores had higher frequencies of marketing compared to non-WIC and grocery stores. Fruits and vegetables had the lowest frequency of any marketing claim, while salty snacks and soda had the highest frequency of marketing claims. Nutrition claims were the most common across all items, followed by taste, suggested use, fun, and convenience. Television tie-ins and cartoons were observed more often than movie tie-ins and giveaways. Our results suggest an opportunity to promote healthful items more efficiently by focusing efforts on stores where mothers actually shop. PMID- 24163702 TI - Memory Systems, Processing Modes, and Components: Functional Neuroimaging Evidence. AB - In the 1980s and 1990s, there was a major theoretical debate in the memory domain regarding the multiple memory systems and processing modes frameworks. The components of processing framework argued for a middle ground: Instead of neatly divided memory systems or processing modes, this framework proposed the existence of numerous processing components that are recruited in different combinations by memory tasks and yield complex patterns of associations and dissociations. Because behavioral evidence was not sufficient to decide among these three frameworks, the debate was largely abandoned. However, functional neuroimaging evidence accumulated during the last two decades resolves the stalemate, because this evidence is more consistent with the components framework than with the other two frameworks. For example, functional neuroimaging evidence shows that brain regions attributed to one memory system can contribute to tasks associated with other memory systems and that brain regions attributed to the same processing mode (perceptual or conceptual) can be dissociated from each other. Functional neuroimaging evidence suggests that memory processes are supported by transient interactions between a few regions called process-specific alliances. These conceptual developments are an example of how functional neuroimaging can contribute to theoretical debates in cognitive psychology. PMID- 24163704 TI - Testosterone therapy in hypogonadal men results in sustained and clinically meaningful weight loss. AB - WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT: Hypogonadism is associated with increased fat mass and reduced muscle mass, which contributes to obesity and health risks, such as cardiovascular disease.Testosterone treatment of hypogonadal men improves muscle mass and reduces fat mass; however, many of these studies are of short duration.Thus, the long-term effects of testosterone on body anthropometry are not known. WHAT THIS STUDY ADDS: Long-term testosterone treatment of hypogonadal men, up to 5 years duration, produced marked and significant decrease in body weight, waist circumference and body mass index. Hypogonadism contributes to reduced muscle mass and increased adiposity. Testosterone treatment ameliorates loss of muscle mass and reduces fat accumulation associated with hypogonadism. In this study, we evaluated the long term effects of normalizing testosterone (T) levels in hypogonadal men on anthropometric parameters. Open-label, single-center, cumulative, prospective registry study of 261 men (32-84 years, mean 59.5 +/- 8.4 years, with T levels <=12 nmol L-1 [mean: 7.7 +/- 2.1]). Among the 261 men on T treatment, we followed up on 260 men for at least 2 years, 237 for 3 years, 195 for 4 years and 163 for at least 5 years. Subjects received parenteral T undecanoate 1000 mg every 12 weeks after an initial interval of 6 weeks. Body weight (BW), waist circumference (WC) and body mass index (BMI) were measured at baseline and yearly after treatment with T. BW decreased from 100.1 +/- 14.0 kg to 92.5 +/- 11.2 kg and WC was reduced from 107.7 +/- 10.0 cm to 99.0 +/- 9.1 cm. BMI declined from 31.7 +/- 4.4 m kg-2 to 29.4 +/- 3.4 m kg-2. All parameters examined were statistically significant vs. baseline and vs. the previous year over 5 years, indicating a continuous weight loss (WL) over the full observation period. The mean per cent WL was 3.2 +/- 0.3% after 1 year, 5.6 +/- 0.3%, after 2 years, 7.5 +/- 0.3% after 3 years, 9.1 +/- 0.3% after 4 years and 10.5 +/- 0.4% after 5 years. The data obtained from this uncontrolled, observational, registry study suggest that raising serum T to normal physiological levels in hypogonadal men produces consistent loss in BW, WC and BMI. These marked improvements were progressive over the 5 years of the study. PMID- 24163703 TI - Immunomodulation and immunosuppression by human herpesvirus 6A and 6B. AB - Like other members of the Herpesviridae family, human herpesvirus (HHV)-6A and HHV-6B have developed a wide variety of strategies to modulate or suppress host immune responses and, thereby, facilitate their own spread and persistence in vivo. Long considered two variants of the same virus, HHV-6A and HHV-6B have recently been reclassified as distinct viral species, although the established nomenclature has been maintained. In this review, we summarize the distinctive profiles of interaction of these two viruses with the human immune system. Both HHV-6A and HHV-6B display a tropism for CD4+ T lymphocytes, but they can also infect, in a productive or nonproductive fashion, other cells of the immune system. However, there are important differences regarding the ability of each virus to infect cytotoxic effector cells, as HHV-6A has been shown to productively infect several of these cells, whereas HHV-6B infects them inefficiently at best. In addition to direct cytopathic effects, both HHV-6A and HHV-6B can interfere with immunologic functions to varying degrees via cytokine modulation, including blockade of IL-12 production by professional antigen presenting cells, modulation of cell-surface molecules essential for T-cell activation, and expression of viral chemokines and chemokine receptors. Some of these effects are related to signaling through and downregulation of the viral receptor, CD46, a key molecule linking innate and adaptive immune responses. Increasing attention has recently been focused on the importance of viral interactions with dendritic cells, which may serve both as targets of virus mediated immunosuppression and as vehicles for viral transfer to CD4+ T cells. Our deepening knowledge of the mechanisms developed by HHV-6A and HHV-6B to evade immunologic control may lead to new strategies for the prevention and treatment of the diseases associated with these viruses. Moreover, elucidation of these viral mechanisms may uncover new avenues to therapeutically manipulate or modulate the immune system in immunologically mediated human diseases. PMID- 24163705 TI - Exploring Structure-Activity Data Using the Landscape Paradigm. AB - In this article we present an overview of the origin and applications of the activity landscape view of structure-actvitiy relationship data as conceived by Maggiora. Within this landscape, different regions exemplify different aspects of SAR trends - ranging from smoothly varying trends to discontinuous trends (also termed activity cliffs). We discuss the various definitions of landscapes and cliffs that have been proposed as well as different approaches to the numerical quantification of a landscape. We then highlight some of the landscape visualization approaches that have been developed, followed by a review of the various applications of activity landscapes and cliffs to topics in medicinal chemistry and SAR analysis. PMID- 24163706 TI - The efficacy of cognitive training programs in children and adolescents: a meta analysis. AB - BACKGROUND: Cognitive therapies are intended to improve basic cognitive functions, whatever the cause of the deficiency may be. Children and adolescents with various cognitive deficits are treated with behavioral therapeutic and computer-supported training programs. We here report the first meta-analysis of the efficacy of such programs. METHODS: We systematically searched the Medline, Embase, PsycINFO, PSYNDEX, and ERIC databases to find pertinent publications for a meta-analysis of cognitive training programs that are used in children and adolescents to improve attention, memory, and executive performance (primary goals) as well as behavior/psychopathology, intelligence, and school performance (secondary goals). The mean differences between the treatment and control groups are given here as standard deviation (SD) scores. RESULTS: 1661 potentially relevant publications were found, including 22 studies that were considered in the meta-analysis, 17 of which were randomized controlled trials. The target variables were measured with more than 90 different testing techniques. The overall effects of cognitive training on attention (SD 0.18, 95% CI -0.11-0.47) and executive function (SD 0.17, 95% CI -0.12-0.46) were consistently small. A relatively strong effect was found on memory performance (0.65 SD, 95% [-0.12 1.42), albeit with marked heterogeneity (I (2)= 82%) owing to two studies. The largest effect was found in the area of behavior and psychopathology (SD 0.58, 95% CI 0.31-0.85), but this last figure is derived mainly from studies that lacked an active control group. CONCLUSION: Cognitive therapies for children and adolescents have generally favorable, but probably nonspecific effects on behavior. On the other hand, the specific effects, however, were weak overall. Therapeutic benefit has been demonstrated only for certain individual types of therapy for specific indications. PMID- 24163708 TI - Surgical therapeutic options. PMID- 24163707 TI - The effect of mental comorbidity on service delivery planning in primary care: an analysis with particular reference to patients who request referral without prior assessment. AB - BACKGROUND: In their everyday practice, primary-care physicians are often asked to refer patients to a specialist without a prior appointment in primary care. Such referrals are problematic, and one might suspect that patients who make such requests are more likely to have mental comorbidities predisposing them toward higher utilization of health-care services. METHODS: In a cross-sectional study, 307 patients of 13 primary-care practices who requested referral to a specialist without a prior appointment in primary care were given a Patient Health Questionnaire (PHQ) containing questions that related to depression, anxiety, panic disorder, and somatoform disorder (independent variables). Further information was obtained about these patients' primary-care contacts, referrals, and days taken off from work with a medical excuse over the course of one year (dependent variables). A regression model was used to compare these patients with 977 other primary-care patients. RESULTS: The groups of patients who did and did not request specialist referral without a primary-care appointment did not differ to any statistically significant extent with respect to mental comorbidity. In the overall group, somatoform disorder was found to be associated with a high rate of primary-care contacts (odds ratio [OR] 2.4, 95% confidence interval [CI] 1.4-4.3). High rates of referral were strongly correlated (percentage of variance explained, R2) with depression (OR 2.1, 95% CI 1.1-4.0; R2 = 35.3%), anxiety (OR 4.1, 95% CI 1.8-9.6; R2 = 34.5%), panic disorder (OR 5.9, 95% CI 2.1-16.4; R2 = 34.3%), and somatoform disorder (OR 2.2, 95% CI 1.2-4.0; R2 = 34.6%). Taking a long time off from work with a medical excuse was correlated with depression (OR 2.5, 95% CI 1.2-4.8), anxiety (OR 4.2, 95% CI 1.7-10.5), and somatoform disorder (OR 2.2, 95% CI 1.2-4.2). CONCLUSION: Mental comorbidity contributes to the increased utilization of health-care services. This should be borne in mind whenever a patient requests many referrals to specialists (either with or without a prior appointment in primary care). It is important to identify "doctor hopping" patients so that the causes of their behavior can be recognized, discussed, and properly treated. PMID- 24163709 TI - In reply. PMID- 24163710 TI - Health-Related Stereotype Threat Predicts Health Services Delays Among Blacks. AB - To our knowledge, no published research has developed an individual difference measure of health-related stereotype threat (HRST). We adapted existing measures of academic stereotype threat to the health domain on a sample of black college students (N = 280). The resulting health-related stereotype threat scale-24 (HRST 24) was assessed for internal consistency, construct and incremental validity, and whether it explains variance in self-reported delays among four preventive health behaviors-blood pressure and cholesterol assays, physical exams, and routine checkups. After adjusting for several control variables, the HRST-24's (full scale alpha = 0.96) perceived black health inferiority (18 items; alpha = 0.96) and perceived physician racial bias (6 items; alpha = 0.85) sub-scales explained unique variance in delays among two of the four behaviors including a blood cholesterol check (p < .01) and routine checkup-albeit at marginal levels (p = .063) in the case of the latter. Overall, these data provide preliminary evidence of construct and incremental validity for the HRST-24 among blacks. Recommendations for administering the scale are provided and future directions for HRST research are discussed. PMID- 24163711 TI - HLA Class II Antigen Presentation in Prostate Cancer Cells: A Novel Approach to Prostate Tumor Immunotherapy. AB - Prostate cancer is a deadly disease that is in drastic need of new treatment strategies for late stage and metastatic prostate cancer. Immunotherapy has emerged as a viable option to fill this void. Clinical trials have been conducted that induce tumor clearance through cytotoxic T lymphocyte (CTL) activation, these studies have had mixed outcomes with the overlying problem being the lack of a complete immune response with sustained killing and the formation of tumor specific memory cells. To overcome this, we have outlined the need for activating the HLA class II pathway in inducing a sustained CD8+ T cell response and the development of effective memory. We have also discussed the ability of prostate cancer cells to express stable HLA class II molecules that can be manipulated for tumor antigen (Ag) processing and presentation. This review also sets to outline new directions that exist for the use of class II-restricted Ags/peptides in devising cancer vaccines as well as combined chemoimmunotherapy. A better understanding of these concepts will improve future cancer vaccine studies and further the field of cancer immunobiology. PMID- 24163712 TI - Large Fluorescence Enhancements of Fluorophore Ensembles with Multilayer Plasmonic Substrates: Comparison of Theory and Experimental Results. AB - Multilayer substrates consisting of a glass slide, silver mirror, silica layer, and silver nanoparticles were fabricated using magnetron sputtering. This new geometry of substrates with backplane mirror and dielectric photonic cavity produced large average fluorescence enhancements up to 190-fold. Fluorescence enhancements of five fluorescent probes were measured over the broad spectral range from 470 to 800 nm. Fluorescent probes were streptavidin conjugates attached to the substrate surface through a layer of biotinylated bovine serum albumin. The protein layers represent a common surface modification for surface based bioassays such as immunoassays or molecular diagnostic assays. We found that optimal enhancement is dependent on the thickness of the dielectric layer separating the silver mirror and the silver nanoparticles and on the spectral range. We performed numerical calculations for enhancement in both the excitation and emission using finite element method (FEM) the results of which were in qualitative agreement with the experimental results. The described method for fabrication multilayered substrates and the results obtained with protein layers demonstrate great potential for the design of simple and ultrasensitive fluorometric bioassays with large optical amplifications compared to the standard approaches of enzyme-based bioassays with dielectric surfaces. PMID- 24163713 TI - Linear and Nonlinear Optical Properties of Photoresponsive [60]Fullerene Hybrid Triads and Tetrads with Dual NIR Two-Photon Absorption Characteristics. AB - Two C60-(antenna)x analogous compounds having branched hybrid triad C60(>DPAF C18)(>CPAF-C2M) and tetrad C60(>DPAF-C18)(>CPAF-C2M)2 nanostructures were synthesized and characterized. The structural design was intended to facilitate the ultrafast fs intramolecular energy-transfer from photoexcited C60[>1(DPAF)* C18](>CPAF-C2M)1or2 or C60(>DPAF-C18)[>1(CPAF)*-C2M]1or2 to the C60> cage moiety upon two-photon pumping at either 780 or 980 nm, respectively. The latter nanostructure showed approximately equal extinction coefficients of optical absorption over 400-550 nm that corresponds to near-IR two-photon based excitation wavelengths at 780-1100 nm for broadband nonlinear optical (NLO) applications. Aside from their enhanced two-photon absorption (2PA) activity at 780 nm, we also demonstrated ultrafast photo-responses at 980 nm showing 2PA cross-section (sigma2) values of 995-1100 GM for the hybrid tetrad. These sigma2 values were correlated to the observed good efficiency in reducing fs light transmittance down to 35% at the light intensity of 110 GW/cm2. Accordingly, 2PA characteristics of these nanostructures at multiple NIR wavelengths provided support for their suitability in uses as broadband NLO nanomaterials at 600-1100 nm that includes the 2PA ability of two antenna, DPAF (700-850 nm) and CPAF (850 1100 nm), and the fullerene cage at shorter wavelengths (600-700 nm). PMID- 24163714 TI - Packing of Isophthalate Tetracarboxylic Acids on Au(111): Rows and Disordered Herringbone Structures. AB - Scanning tunnelling microscopy (STM) has been used to investigate the formation of hydrogen-bonded structures of the isophthalate tetracarboxylic acids, biphenyl 3,3',5,5'-tetracarboxylic acid (BPTC), terphenyl-3,3",5,5"-tetracarboxylic acid (TPTC), and quarterphenyl-3,3''',5,5'''-tetracarboxylic acid (QPTC), via deposition from solution onto Au(111). STM data reveal that ordered structures can be formed from an aqueous solution leading to the formation of rows for the shortest acid BPTC, while the longer molecules TPTC and QPTC adopt a herringbone like structure with significant degrees of disorder. The influence of solvent and substrate on the molecular ordering is discussed, and density functional theory is used to identify molecular models for these new phases. PMID- 24163715 TI - Encapsulation of Au Nanoparticles on a Silicon Wafer During Thermal Oxidation. AB - We report the behavior of Au nanoparticles anchored onto a Si(111) substrate and the evolution of the combined structure with annealing and oxidation. Au nanoparticles, formed by annealing a Au film, appear to "float" upon a growing layer of SiO2 during oxidation at high temperature, yet they also tend to become partially encapsulated by the growing silica layers. It is proposed that this occurs largely because of the differential growth rates of the silica layer on the silicon substrate between the particles and below the particles due to limited access of oxygen to the latter. This in turn is due to a combination of blockage of oxygen adsorption by the Au and limited oxygen diffusion under the gold. We think that such behavior is likely to be seen for other metal semiconductor systems. PMID- 24163716 TI - Cal Poly Pomona NUE Project: Implementing Microscale and Nanoscale Investigations Throughout the Undergraduate Curriculum. AB - NUE funded work at California State Polytechnic University involved development and implementation of nanotechnology modules for physics courses spanning all levels of the undergraduate curriculum, from freshman service courses to senior level laboratories and independent research projects. These modules demonstrate the application of fundamental physics at the nanoscale that complement macroscopic investigations. The introductory level and some of the advanced level modules have been described previously in journal papers and will be outlined briefly here. The main focus of this article, however, is to describe some newer work involving nanoscale experiments that have been developed for senior level laboratories and independent research. These experiments involve applications as diverse as tunneling diodes, gas discharge plasmas for biofilm inactivation, and quantized conductance in gold nanowires. PMID- 24163717 TI - Analyzing LC-MS/MS data by spectral count and ion abundance: two case studies. AB - In comparative proteomics studies, LC-MS/MS data is generally quantified using one or both of two measures: the spectral count, derived from the identification of MS/MS spectra, or some measure of ion abundance derived from the LC-MS data. Here we contrast the performance of these measures and show that ion abundance is the more sensitive. We also examine how the conclusions of a comparative analysis are influenced by the manner in which the LC-MS/MS data is 'rolled up' to the protein level, and show that divergent conclusions obtained using different rollups can be informative. Our analysis is based on two publicly available reference data sets, BIATECH-54 and CPTAC, which were developed for the purpose of assessing methods used in label-free differential proteomic studies. We find that the use of the ion abundance measure reveals properties of both data sets not readily apparent using the spectral count. PMID- 24163718 TI - Amplitude modulation detection by human listeners in reverberant sound fields: Effects of prior listening exposure. AB - Previous work [Zahorik et al., POMA, 15, 050002 (2012)] has reported that for both broadband and narrowband noise carrier signals in a simulated reverberant sound field, human sensitivity to amplitude modulation (AM) is higher than would be predicted based on the acoustical modulation transfer function (MTF) of the listening environment. These results may be suggestive of mechanisms that functionally enhance modulation in reverberant listening, although many details of this enhancement effect are unknown. Given recent findings that demonstrate improvements in speech understanding with prior exposure to reverberant listening environments, it is of interest to determine whether listening exposure to a reverberant room might also influence AM detection in the room, and perhaps contribute to the AM enhancement effect. Here, AM detection thresholds were estimated (using an adaptive 2-alternative forced-choice procedure) in each of two listening conditions: one in which consistent listening exposure to a particular room was provided, and a second that intentionally disrupted listening exposure by varying the room from trial-to-trial. Results suggest that consistent prior listening exposure contributes to enhanced AM sensitivity in rooms. [Work supported by the NIH/NIDCD.]. PMID- 24163719 TI - Resveratrol protects the brain of obese mice from oxidative damage. AB - Resveratrol (3,5,4'-trihydroxy-trans-stilbene) is a polyphenolic phytoalexin that exerts cardioprotective, neuroprotective, and antioxidant effects. Recently it has been shown that obesity is associated with an increase in cerebral oxidative stress levels, which may enhance neurodegeneration. The present study evaluates the neuroprotective action of resveratrol in brain of obese (ob/ob) mice. Resveratrol was administered orally at the dose of 25 mg kg(-1) body weight daily for three weeks to lean and obese mice. Resveratrol had no effect on body weight or blood glucose levels in obese mice. Lipid peroxides were significantly increased in brain of obese mice. The enzymatic antioxidants superoxide dismutase, catalase, glutathione peroxidase, glutathione reductase, glucose-6 phosphate dehydrogenase and nonenzymatic antioxidants tocopherol, ascorbic acid, and glutathione were decreased in obese mice brain. Administration of resveratrol decreased lipid peroxide levels and upregulated the antioxidant activities in obese mice brain. Our findings indicate a neuroprotective effect of resveratrol by preventing oxidative damage in brain tissue of obese mice. PMID- 24163721 TI - SPARK: A Framework for Multi-Scale Agent-Based Biomedical Modeling. AB - Multi-scale modeling of complex biological systems remains a central challenge in the systems biology community. A method of dynamic knowledge representation known as agent-based modeling enables the study of higher level behavior emerging from discrete events performed by individual components. With the advancement of computer technology, agent-based modeling has emerged as an innovative technique to model the complexities of systems biology. In this work, the authors describe SPARK (Simple Platform for Agent-based Representation of Knowledge), a framework for agent-based modeling specifically designed for systems-level biomedical model development. SPARK is a stand-alone application written in Java. It provides a user-friendly interface, and a simple programming language for developing Agent Based Models (ABMs). SPARK has the following features specialized for modeling biomedical systems: 1) continuous space that can simulate real physical space; 2) flexible agent size and shape that can represent the relative proportions of various cell types; 3) multiple spaces that can concurrently simulate and visualize multiple scales in biomedical models; 4) a convenient graphical user interface. Existing ABMs of diabetic foot ulcers and acute inflammation were implemented in SPARK. Models of identical complexity were run in both NetLogo and SPARK; the SPARK-based models ran two to three times faster. PMID- 24163722 TI - The Effect of Absenteeism and Clinic Protocol on Health Outcomes: The Case of Mother-to-Child Transmission of HIV in Kenya. AB - Absenteeism of health workers in developing countries is widespread with some estimates indicating rates of provider absence of nearly 40% (Chaudhury et. al. 2006). This is the first paper to present evidence of the impact of health provider absence combined with limitations in health clinic protocol on health outcomes. Using longitudinal data from nearly 600 ante-natal care seekers at a rural ante-natal clinic in Western Kenya, we find that nurse absence on a patient's first visit significantly reduces the probability that a woman tests for HIV over her entire pregnancy. Since the benefits of PMTCT services depend on HIV status, we proxy HIV status with self-reported pre-test expectations of being HIV-positive and estimate the heterogeneous impact of absence based on these self reported expectations. We find that women with a high pre-test expectation of testing HIV-positive and whose first ANC visit coincides with nurse attendance are 25 percentage points more likely to deliver in a hospital or health center, 7.4 percentage points more likely to receive PMTCT medication, 9 percentage points less likely to breastfeed and 10 percentage points more likely to enroll in the free AIDS treatment program at the clinic than similar women whose first visit coincides with nurse absence. The procedural shortcomings in our study setting, shortcomings that do not enable pregnant women to test on a subsequent clinic visit, appear common in other countries in sub-Saharan Africa. They suggest that nurse absence in the context of this medical system translates into sizable reductions in child and maternal health. PMID- 24163720 TI - Sexual dimorphism of cardiovascular ischemia susceptibility is mediated by heme oxygenase. AB - We investigated the gender differences in heme-oxygenase (HO) enzyme, which produces endogenous vascular protective carbon monoxide (CO). We studied (1) the activity and expression of HO enzymes in the left ventricle (LV) and aorta, (2) basal increase in basal blood pressure provoked by arginine vasopressine (AVP) in vivo, (3) the heart perfusion induced by AVP, (4) the ST segment depression provoked by adrenaline and 30 seconds later phentolamine, and (5) the aorta ring contraction induced by AVP in female and male Wistar rats. We found that HO activity and the expression of HO-1 and HO-2 were increased in female rat aorta and LV. We demonstrated that the basal blood pressure and administration of AVP provoked blood pressure response are increased in the males; the female myocardium was less sensitive towards angina. Both differences could be aggravated by the inhibition of HO. The aorta rings were more susceptible towards vasoconstriction by AVP in males; isolated heart perfusion decrease was higher in males. The HO inhibition aggravated the heart perfusion in both sexes. In conclusion, the increased HO activity and expression in females might play a role in the sexual dimorphism of cardiovascular ischemia susceptibility during the reproductive age. PMID- 24163723 TI - ADAPTIVE CUTS FOR EXTRACTING SPECIFIC WHITE MATTER TRACTS. AB - Extracting specific white matter tracts (e.g., uncinate fasciculus) from whole brain tractography has numerous applications in studying individual differences in white matter. Typically specific tracts are extracted manually, following replicable protocols which can be prohibitively expensive for large scale studies. A tract clustering framework is a suitable computational framework but from a neuroanatomical point of view, one of the key challenges is that it is very hard to design a universal similarity function for different types of white matter tracts (e.g., projection, association, commissural tracts). In this paper, we propose an adaptive cuts framework in which, using normalized cuts motivated objective function, we adaptively learn tract-tract similarity for each specific tract class using atlas based training data. Using the learnt similarity function we train an ensemble of binary support vector machines to extract specific tracts from unlabeled whole-brain tractography sets. PMID- 24163724 TI - Protein Denaturation with Guanidinium: A 2D-IR Study. AB - Guanidinium (Gdm+) is a widely used denaturant, but it is still largely unknown how it operates at the molecular level. In particular, the effect of guanidinium on the different types of secondary structure motifs of proteins is at present not clear. Here, we use two-dimensional infrared spectroscopy (2D-IR) to investigate changes in the secondary structure of two proteins with mainly alpha helical or beta-sheet content upon addition of Gdm-13C15N3.Cl. We find that upon denaturation, the beta-sheet protein shows a complete loss of beta-sheet structure, whereas the alpha-helical protein maintains most of its secondary structure. These results suggest that Gdm+ disrupts beta-sheets much more efficiently than alpha-helices, possibly because in the former, hydrophobic interactions are more important and the number of dangling hydrogen bonds is larger. PMID- 24163725 TI - Anticorrelation between the Evolution of Molecular Dipole Moments and Induced Work Function Modifications. AB - We explore the limits of modifying metal work functions with large molecular dipoles by systematically increasing the dipole moment of archetype donor acceptor molecules in self-assembled monolayers on gold. Contrary to intuition, we find that enhancing the dipoles leads to a reduction of the adsorption-induced change of the work function. Using atomistic simulations, we show that large dipoles imply electronic localization and level shifts that drive the interface into a thermodynamically unstable situation and trigger compensating charge reorganizations working against the molecular dipoles. Under certain circumstances, these are even found to overcompensate the effect that increasing the dipoles has for the work function. PMID- 24163726 TI - Serotonin uptake rates in platelets from angiotensin II-induced hypertensive mice. AB - Angiotensin II (Ang II) is a critical component of the renin-angiotensin system that contributes to hypertension. Although platelets in blood from hypertensive subjects have an abnormal biological profile, it is unclear if circulating Ang II influences platelet aggregation or thrombus formation. One of the abnormalities presented to the platelets during hypertension is an elevated plasma concentration of serotonin (5-HT) caused by reduced 5-HT uptake secondary to loss of the 5-HT transporter (SERT) on the platelet plasma membrane. In the current study, we evaluated in vivo platelet function after 7 days of subcutaneous Ang II infusion to establish hypertension in mice and additionally assessed the biology of isolated platelets exposed to Ang II in vitro. The administration of Ang II elevated systolic blood pressure, but markers of platelet activation including P selectin and PEJon/A staining were not changed. However, the aggregation response to collagen was reduced in isolated platelets from Ang II-infused mice, which also showed reduced 5-HT uptake by SERT. In vitro exposure of isolated platelets to Ang II also resulted in a loss of surface SERT associated with a reduced aggregation response to collagen. These abnormalities were reversed by increasing concentrations of the Ang II receptor antagonist, valsartan. Interestingly, SERT KO mice failed to fully develop hypertension in response to Ang II infusion and isolated platelets from these animals were insensitive to the anti-aggregatory influence of Ang II. Thus, Ang II blunts the aggregation responses of platelets and the mechanism underlying this action may involve a loss of SERT on the platelet plasma membrane. The latter event depletes intracellular 5-HT in platelets, an event that is associated with reduced aggregation. The widespread use of antihypertensive drugs that target the renin-angiotensin system suggest the potential clinical utility of our findings and emphasize the importance of understanding the impact of Ang II on platelet function. PMID- 24163727 TI - Dense Stereo Matching Method Based on Local Affine Model. AB - A new method for constructing an accurate disparity space image and performing an efficient cost aggregation in stereo matching based on local affine model is proposed in this paper. The key algorithm includes a new self-adapting dissimilarity measurement used for calculating the matching cost and a local affine model used in cost aggregation stage. Different from the traditional region-based methods, which try to change the matching window size or to calculate an adaptive weight to do the aggregation, the proposed method focuses on obtaining the efficient and accurate local affine model to aggregate the cost volume while preserving the disparity discontinuity. Moreover, the local affine model can be extended to the color space. Experimental results demonstrate that the proposed method is able to provide subpixel precision disparity maps compared with some state-of-the-art stereo matching methods. PMID- 24163728 TI - Effects of DTI spatial normalization on white matter tract reconstructions. AB - Major white matter (WM) pathways in the brain can be reconstructed in vivo using tractography on diffusion tensor imaging (DTI) data. Performing tractography using the native DTI data is often considered to produce more faithful results than performing it using the spatially normalized DTI obtained using highly non linear transformations. However, tractography in the normalized DTI is playing an increasingly important role in population analyses of the WM. In particular, the emerging tract specific analyses (TSA) can benefit from tractography in the normalized DTI for statistical parametric mapping in specific WM pathways. It is well known that the preservation of tensor orientations at the individual voxel level is enforced in tensor based registrations. However small reorientation errors at individual voxel level can accumulate and could potentially affect the tractography results adversely. To our knowledge, there has been no study investigating the effects of normalization on consistency of tractography that demands non-local preservation of tensor orientations which is not explicitly enforced in typical DTI spatial normalization routines. This study aims to evaluate and compare tract reconstructions obtained using normalized DTI against those obtained using native DTI. Although tractography results have been used to measure and influence the quality of spatial normalization, the presented study addresses a distinct question: whether non-linear spatial normalization preserves even long-range anatomical connections obtained using tractography for accurate reconstructions of pathways. Our results demonstrate that spatial normalization of DTI data does preserve tract reconstructions of major WM pathways and does not alter the variance (individual differences) of their macro and microstructural properties. This suggests one can extract quantitative and shape properties efficiently from the tractography data in the normalized DTI for performing population statistics on major WM pathways. PMID- 24163729 TI - Discovery of a Potent Anti-tumor Agent through Regioselective Mono-N-acylation of 7H-Pyrrolo[3,2-f]quinazoline-1,3-diamine. AB - 7H-Pyrrolo[3,2-f]quinazoline-1,3-diamine (1) is a privileged chemical scaffold with significant biological activities. However, the currently accessible chemical space derived from 1 is rather limited. Here we expanded the chemical space related to 1 by developing efficient methods for regioselective monoacylation at N1 , N3 and N7 , respectively. With this novel methodology, a focused library of mono-N-acylated pyrroloquinazoline-1,3-diamines were prepared and screened for anti-breast cancer activity. The structure-activity relationship (SAR) results showed that N3 -acylated compounds were in general more potent than N1 -acylated compounds while N7 -acylation significantly reduced their solubility. Among the compounds evaluated, 7f possessed 8-fold more potent activity than 1 in MDA-MB-468 cells. More importantly, 7f was not toxic to normal human cells. These results suggest that 7f is a novel compound as a potential anti-breast cancer agent without harming normal cells. PMID- 24163730 TI - Role of Oxido Incorporation and Ligand Lability in Expanding Redox Accessibility of Structurally Related Mn4 Clusters. AB - Photosystem II supports four manganese centers through nine oxidation states from manganese(II) during assembly through to the most oxidized state before O2 formation and release. The protein-based carboxylate and imidazole ligands allow for significant changes of the coordination environment during the incorporation of hydroxido and oxido ligands upon oxidation of the metal centers. We report the synthesis and characterization of a series of tetramanganese complexes in four of the six oxidation states from MnII3MnIII to MnIII2 MnIV2 with the same ligand framework (L) by incorporating four oxido ligands. A 1,3,5-triarylbenzene framework appended with six pyridyl and three alkoxy groups was utilized along with three acetate anions to access tetramanganese complexes, Mn4O x , with x = 1, 2, 3, and 4. Alongside two previously reported complexes, four new clusters in various states were isolated and characterized by crystallography, and four were observed electrochemically, thus accessing the eight oxidation states from MnII4 to MnIIIMnIV3. This structurally related series of compounds was characterized by EXAFS, XANES, EPR, magnetism, and cyclic voltammetry. Similar to the ligands in the active site of the protein, the ancillary ligand (L) is preserved throughout the series and changes its binding mode between the low and high oxido-content clusters. Implications for the rational assembly and properties of high oxidation state metal-oxido clusters are presented. PMID- 24163731 TI - Relation of people-centered public health and person-centered healthcare management: a case study to reduce burn-out. AB - Healthcare management is one practical tool for mediation and implementation of public health into clinical healthcare outcomes and is taken in our case study as an exemplar arena to demonstrate the vital importance of the person-centered approach. Healthcare personnel are frequently at risk for the 'burn-out' syndrome. However, modern measures of burn-out recognize burn-out only at a late stage when it is fully developed. There are no available methods to assess the risk for vulnerability to burnout in healthcare systems. Our aim was therefore to design a complex person-centered model for detection of high risk for burn-out at an early stage, that has been termed 'flame-out'. We accept the observation that decreased personal performance is one crucial expression of burn-out. Low personal performance and negative emotions are strongly related to low self directedness as measured by the Temperament and Character Inventory (TCI). At the same time, burn-out is characterized by decreased interest and positive emotions from work. Decreased positive emotion is directly related to low self transcendence as measured by the TCI. Burn-out is also frequently associated with feelings of social alienation or inadequacy of support, which is in turn related to low TCI Cooperativeness. However, high Persistence and Harm Avoidance are predisposing traits for burn-out in healthcare professionals who are often overly perfectionistic and compulsive, predisposing them to anxiety, depression, suicide and burn-out. Hence, people at risk for future burn-out are often highly conscientious over-achievers with intense mixtures of positive and negative emotions. The high demand for perfection comes from both intrinsic characteristics and from features of the social milieu in their psychological climate. Letting go of the unfulfillable desire to be perfect by increasing self transcendence allows acceptance of the imperfection of the human condition, thereby preventing burn-out and other negative emotions while promoting positive emotions and work in the service of others. Hence, we can evaluate vulnerable populations via a person-centered diagnostic method using the TCI and also relate wellbeing to the psychological climate of the work place. The proposed diathesis stress model can directly impact on the management of human resources and related decision-making. The introduction of such person-centered assessments can encourage and improve public health outcomes by promoting the personal wellbeing of healthcare employees. PMID- 24163732 TI - Analysis of intraspecific variation in venoms of Acanthophis antarcticus death adders from South Australia. AB - Intraspecific variation in venom composition and activity has been reported from a wide range of snakes. Geographical origin can be one cause for this variation and has recently been documented from Acanthophis antarcticus death adders sampled across four different Australian states. The present study examined whether a narrower sampling range of A. antarcticus from four collection sites within one Australian state (i.e., South Australia) would also exhibit variation in venom composition and/or activity. The present LC-MS results reveal marked differences in the venom composition from different collection sites. The most striking difference was the reduced venom complexity found in the only venom originating from a mallee scrub habitat in comparison to the venoms from coastal heath scrub habitats. Interestingly, the pharmacological activity of all venoms was found to be the same, independent of the collection site. PMID- 24163733 TI - Exploring the membrane topology of prohormone convertase 1 in AtT20 Cells: in situ analysis by immunofluorescence microscopy. AB - Prohormone convertase 1 (PC1) was previously characterized as a partially transmembrane protein in purified chromaffin granules of bovine adrenal medulla1. This was challenged with experiments on transfected PC1 in COS1 cells, a non endocrine cell line2. To address this issue, we undertook to analyze its extraction properties in vitro and its immunocytochemical localization in situ in AtT20 cells, an endocrine cell line that expresses PC1. Most of the 87 kDa form of PC1 was resistant to carbonate extraction suggesting that it had properties of a transmembrane protein. Under semi-permeabilized conditions whereby only the plasma membrane was permeabilized, the carboxy-terminus of PC1 was specifically immunostained whereas the amino-terminus was not. These results indicate that the amino-terminus of PC1 was within the lumen of the Golgi and granules, and some of the C-terminus was exposed to the cytosol. Thus, endogenous PC1 can assume a transmembrane orientation in situ in AtT20 cells. PMID- 24163734 TI - Copper triflate-mediated synthesis of 1,3,5-triarylpyrazoles in [bmim][PF6] ionic liquid and evaluation of their anticancer activities. AB - A simple, efficient, and environment friendly protocol for the synthesis of 1,3,5 triarylpyrazole and 1,3,5-triarylpyrazolines in [bimm][PF6] ionic liquid mediated by Cu(OTf)2 is described. The reaction protocol gave 1,3,5-triarylpyrazoles in good to high yields (71-84%) via a one-pot addition-cyclocondensation between chalcones and arylhydrazines, and oxidative aromatization without requirement for an additional oxidizing reagent. The catalyst can be reused up to four cycles without much loss in the catalytic activity. The pyrazoles (4a-o) and pyrazolines (3a-n) were evaluated for antiproliferative activity in SK-OV-3, HT-29, and HeLa human cancer cells lines. Among all compounds, 3b inhibited cell proliferation of HeLa cells by 80% at a concentration of 50 MUM. PMID- 24163735 TI - Family Structure, Family Stability, and Outcomes of Five-Year-Old Children. AB - This study exploits data from the Fragile Families and Child Wellbeing Study, a birth cohort study of a diverse sample of children from twenty U.S. cities (N = 3,676), to examine how cognitive, behavioural, and health outcomes of five-year old children differ according to their family structure and family stability. We define three models: one that measures family structure at birth only, a second that measures current family structure at year five conditional on family structure at birth, and a third that measures changes in family structure from birth to age five. We find that while family structure has persistent links to child outcomes, the effects are significantly altered by stability of the family structure over time. These findings remain robust even after addressing selection. PMID- 24163736 TI - Toward isozyme-selective inhibitors of histone deacetylase as therapeutic agents for the treatment of cancer. AB - Since post-translational modifications of proteins are key mechanisms for controlling cellular function, targeting the machinery involved in these modifications offers new opportunities for the development of therapeutic agents.The histone deacetylases (HDACs) represent an important family of enzymes that are involved in controlling the acetylation state of key lysine residues in histones and other proteins. The development of HDAC inhibitors for the treatment of several diseases, most notably cancer, has proceeded rapidly. Recent attention has turned towards the development of isozyme-specific inhibitors that will provide selective targeting. It is believed that the ability to target-specific HDACs rather than all family members will lead to superior therapeutics with better efficacy and lower toxicity. A review of recent patents shows that researchers are targeting a wide range of isozymes and that key advances in the structural biology of HDACs are providing important design information. PMID- 24163737 TI - Selenium-binding protein 1 as a tumor suppressor and a prognostic indicator of clinical outcome. AB - Selenium is a trace element that plays a critical role in physiological processes and cancer prevention, whose functions may be through its effects on selenium containing proteins. Selenium-binding protein 1 (SBP1) is a member of an unusual class of selenium-containing proteins that may function as a tumor suppressor in multiple cancer types and whose levels have been shown to be lower in cancers as compared to corresponding normal tissues. This review is intended to summarize recent advances in gaining an understanding of the significance of SBP1 in carcinogenesis, and suggest that SBP1 could be developed as a potential biomarker for cancer progression and prognosis. PMID- 24163738 TI - Lung cancer. PMID- 24163739 TI - Genetic susceptibility to lung cancer and co-morbidities. AB - Lung cancer is a leading cause of cancer death and disease burden in many countries. Understanding of the biological pathways involved in lung cancer aetiology is required to identify key biomolecules that could be of significant clinical value, either as predictive, prognostic or diagnostic markers, or as targets for the development of novel therapies to treat this disease, in addition to smoking avoidance strategies. Genome-wide association studies (GWAS) have enabled significant progress in the past 5 years in investigating genetic susceptibility to lung cancer. Large scale, multi-cohort GWAS of mainly Caucasian, smoking, populations have identified strong associations for lung cancer mapped to chromosomal regions 15q [nicotinic acetylcholine receptor (nAChR) subunits: CHRNA3, CHRNA5], 5p (TERT-CLPTM1L locus) and 6p (BAT3-MSH5). Some studies in Asian populations of smokers have found similar risk loci, whereas GWAS in never smoking Asian females have identified associations in other chromosomal regions, e.g., 3q (TP63), that are distinct from smoking-related lung cancer risk loci. GWAS of smoking behaviour have identified risk loci for smoking quantity at 15q (similar genes to lung cancer susceptibility: CHRNA3, CHRNA5) and 19q (CYP2A6). Other genes have been mapped for smoking initiation and smoking cessation. In chronic obstructive pulmonary disease (COPD), which is a known risk factor for lung cancer, GWAS in large cohorts have also found CHRNA3 and CHRNA5 single nucleotide polymorphisms (SNPs) mapping at 15q as risk loci, as well as other regions at 4q31 (HHIP), 4q24 (FAM13A) and 5q (HTR4). The overlap in risk loci between lung cancer, smoking behaviour and COPD may be due to the effects of nicotine addiction; however, more work needs to be undertaken to explore the potential direct effects of nicotine and its metabolites in gene-environment interaction in these phenotypes. Goals of future genetic susceptibility studies of lung cancer should focus on refining the strongest risk loci in a wide range of populations with lung cancer, and integrating other clinical and biomarker information, in order to achieve the aim of personalised therapy for lung cancer. PMID- 24163740 TI - The pivotal role of pathology in the management of lung cancer. AB - The last decade has seen significant advances in our understanding of lung cancer biology and management. Identification of key driver events in lung carcinogenesis has contributed to the development of targeted lung cancer therapies, heralding the era of personalised medicine for lung cancer. As a result, histological subtyping and molecular testing has become of paramount importance, placing increasing demands on often small diagnostic specimens. This has triggered the review and development of the first structured classification of lung cancer in small biopsy/cytology specimens and a new classification of lung adenocarcinoma from the IASLC/ATS/ERS. These have enhanced the clinical relevance of pathological diagnosis, and emphasise the role of the modern surgical pathologist as an integral member of the multidisciplinary team, playing a crucial role in clinical trials and determining appropriate and timely management for patients with lung cancer. PMID- 24163742 TI - An emerging place for lung cancer genomics in 2013. AB - Lung cancer is a disease with a dismal prognosis and is the biggest cause of cancer deaths in many countries. Nonetheless, rapid technological developments in genome science promise more effective prevention and treatment strategies. Since the Human Genome Project, scientific advances have revolutionized the diagnosis and treatment of human cancers, including thoracic cancers. The latest, massively parallel, next generation sequencing (NGS) technologies offer much greater sequencing capacity than traditional, capillary-based Sanger sequencing. These modern but costly technologies have been applied to whole genome-, and whole exome sequencing (WGS and WES) for the discovery of mutations and polymorphisms, transcriptome sequencing for quantification of gene expression, small ribonucleic acid (RNA) sequencing for microRNA profiling, large scale analysis of deoxyribonucleic acid (DNA) methylation and chromatin immunoprecipitation mapping of DNA-protein interaction. With the rise of personalized cancer care, based on the premise of precision medicine, sequencing technologies are constantly changing. To date, the genomic landscape of lung cancer has been captured in several WGS projects. Such work has not only contributed to our understanding of cancer biology, but has also provided impetus for technical advances that may improve our ability to accurately capture the cancer genome. Issues such as short read lengths contribute to sequenced libraries that contain challenging gaps in the aligned genome. Emerging platforms promise longer reads as well as the ability to capture a range of epigenomic signals. In addition, ongoing optimization of bioinformatics strategies for data analysis and interpretation are critical, especially for the differentiation between driver and passenger mutations. Moreover, broader deployment of these and future generations of platforms, coupled with an increasing bioinformatics workforce with access to highly sophisticated technologies, could see many of these discoveries translated to the clinic at a rapid pace. We look forward to these advances making a difference for the many patients we treat in the Asia-Pacific region and around the world. PMID- 24163741 TI - Molecular biology of lung cancer. AB - Lung cancers are characterised by abundant genetic diversity with relatively few recurrent mutations occurring at high frequency. However, the genetic alterations often affect a common group of oncogenic signalling pathways. There have been vast improvements in our understanding of the molecular biology that underpins lung cancer in recent years and this has led to a revolution in the diagnosis and treatment of lung adenocarcinomas (ADC) based on the genotype of an individual's tumour. New technologies are identifying key and potentially targetable genetic aberrations not only in adenocarcinoma but also in squamous cell carcinoma (SCC) of the lung. Lung cancer mutations have been identified in v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS), epidermal growth factor receptor (EGFR), BRAF and the parallel phosphatidylinositol 3-kinase (PI3K) pathway oncogenes and more recently in MEK and HER2 while structural rearrangements in ALK, ROS1 and possibly rearranged during transfection (RET) provide new therapeutic targets. Amplification is another mechanism of activation of oncogenes such as MET in adenocarcinoma, fibroblastgrowth factor receptor 1 (FGFR1) and discoidin domain receptor 2 (DDR2) in SCC. Intriguingly, many of these genetic alternations are associated with smoking status and with particular racial and gender differences, which may provide insight into the mechanisms of carcinogenesis and role of host factors in lung cancer development and progression. The role of tumour suppressor genes is increasingly recognised with aberrations reported in TP53, PTEN, RB1, LKB11 and p16/CDKN2A. Identification of biologically significant genetic alterations in lung cancer that lead to activation of oncogenes and inactivation of tumour suppressor genes has the potential to provide further therapeutic opportunities. It is hoped that these discoveries may make a major contribution to improving outcome for patients with this poor prognosis disease. PMID- 24163743 TI - Diagnostic bronchoscopy--current and future perspectives. AB - Lung cancer is the leading cause of cancer-related mortality worldwide. Standard bronchoscopy has limited ability to accurately localise and biopsy pulmonary lesions that cannot be directly visualised. The field of advanced diagnostic bronchoscopy is rapidly evolving due to advances in electronics and miniaturisation. Bronchoscopes with smaller outer working diameters, coupled with miniature radial and convex ultrasound probes, allow accurate central and peripheral pulmonary lesion localisation and biopsy while at the same time avoiding vascular structures. Increases in computational processing power allow three-dimensional reconstruction of computed tomographic raw data to enable virtual bronchoscopy (VB), providing the bronchoscopist with a preview of the bronchoscopy prior to the procedure. Navigational bronchoscopy enables targeting of peripheral pulmonary lesions (PPLs) via a "roadmap", similar to in-car global positioning systems. Analysis of lesions on a cellular level is now possible with techniques such as optical coherence tomography (OCT) and confocal microscopy (CM). All these tools will hopefully allow earlier and safer lung cancer diagnosis and in turn better patient outcomes. This article describes these new bronchoscopic techniques and reviews the relevant literature. PMID- 24163744 TI - Modern diagnostic and therapeutic interventional radiology in lung cancer. AB - Imaging has an important role in the multidisciplinary management of primary lung cancer. This article reviews the current state-of-the-art imaging modalities used for the evaluation, staging and post-treatment follow-up and surveillance of lung cancers, and image-guided percutaneous techniques for biopsy to confirm the diagnosis and for local therapy in non-surgical candidates. PMID- 24163746 TI - Exhaled breath analysis for lung cancer. AB - Early diagnosis of lung cancer results in improved survival compared to diagnosis with more advanced disease. Early disease is not reliably indicated by symptoms. Because investigations such as bronchoscopy and needle biopsy have associated risks and substantial costs, they are not suitable for population screening. Hence new easily applicable tests, which can be used to screen individuals at risk, are required. Biomarker testing in exhaled breath samples is a simple, relatively inexpensive, non-invasive approach. Exhaled breath contains volatile and non-volatile organic compounds produced as end-products of metabolic processes and the composition of such compounds varies between healthy subjects and subjects with lung cancer. Many studies have analysed the patterns of these compounds in exhaled breath. In addition studies have also reported that the exhaled breath condensate (EBC) can reveal gene mutations or DNA abnormalities in patients with lung cancer. This review has summarised the scientific evidence demonstrating that lung cancer has distinct chemical profiles in exhaled breath and characteristic genetic changes in EBC. It is not yet possible to accurately identify individuals with lung cancer in at risk populations by any of these techniques. However, analysis of both volatile organic compounds in exhaled breath and of EBC have great potential to become clinically useful diagnostic and screening tools for early stage lung cancer detection. PMID- 24163745 TI - Screening for lung cancer with low-dose computed tomography: a review of current status. AB - Screening using low-dose computed tomography (CT) represents an exciting new development in the struggle to improve outcomes for people with lung cancer. Randomised controlled evidence demonstrating a 20% relative lung cancer mortality benefit has led to endorsement of screening by several expert bodies in the US and funding by healthcare providers. Despite this pivotal result, many questions remain regarding technical and logistical aspects of screening, cost effectiveness and generalizability to other settings. This review discusses the rationale behind screening, the results of on-going trials, potential harms of screening and current knowledge gaps. PMID- 24163747 TI - Recent advances in radiotherapy for thoracic tumours. AB - Radiation Oncology technology has continued to advance at a rapid rate and is bringing significant benefits to patients. This review outlines some of the advances in technology and radiotherapy treatment of thoracic cancers including brachytherapy, stereotactic radiotherapy, tomotherapy and intensity modulated radiotherapy. The importance of functional imaging with PET and management of movement are highlighted. Most of the discussion relates to non-small cell lung cancer but management of mesothelioma and small cell lung cancer are also covered. This technology has substantial benefits to patients in terms of decreasing toxicity both in the short and longer term. PMID- 24163748 TI - The continuing role of chemotherapy for advanced non-small cell lung cancer in the targeted therapy era. AB - There have been remarkable advances in the targeted treatment of advanced non small cell lung cancer (NSCLC) over the past several years. Survival outcomes are steadily improving as management paradigms shift in the diagnosis and treatment of advanced NSCLC. Customizing treatment based on histology and molecular typing has become a standard of care in this era of targeted therapy. While new chemotherapeutic agents have proven effective, the pivotal role of platinum-based chemotherapy doublets has been confirmed. Maintenance chemotherapy has become an option, but who to employ it in remains unclear in the real-world setting. Efforts to overcome resistance to targeted agents are ongoing utilizing combination regimens of chemotherapy plus targeted agents, but optimizing combination strategies needs further exploration. This review highlights recent developments in novel chemotherapeutics and in chemotherapy strategies over the past two years. Despite advances in molecular medicine, there remains an essential role for chemotherapy in advanced NSCLC, even in the recent targeted therapy era. PMID- 24163749 TI - Chemotherapy advances in small-cell lung cancer. AB - Although chemotherapeutic advances have recently been heralded in lung adenocarcinomas, such success with small-cell lung cancer (SCLC) has been ominously absent. Indeed, the dismal outlook of this disease is exemplified by the failure of any significant advances in first line therapy since the introduction of the current standard platinum-etoposide doublet over 30 years ago. Moreover, such sluggish progress is compounded by the dearth of FDA-approved agents for patients with relapsed disease. However, over the past decade, novel formulations of drug classes commonly used in SCLC (e.g. topoisomerase inhibitors, anthracyclines, alkylating and platinum agents) are emerging as potential alternatives that could effectively add to the armamentarium of agents currently at our disposal. This review is introduced with an overview on the historical development of chemotherapeutic regimens used in this disease and followed by the recent encouraging advances witnessed in clinical trials with drugs such as amrubicin and belotecan which are forging new horizons for future treatment algorithms. PMID- 24163750 TI - Targeted therapy in lung cancer: IPASS and beyond, keeping abreast of the explosion of targeted therapies for lung cancer. AB - Advances in the treatment of non-small cell lung cancer (NSCLC) over the last decade have predominantly involved the development of therapies directed at molecular targets such as mutations in the epidermal growth factor receptor (EGFR) or rearrangements in the anaplastic lymphoma kinase (ALK) gene. Other targets have been discovered at low frequency, with multiple agents approved or in development for treatment of these rare molecular subtypes. The tumour microenvironment has also provided opportunities for therapies targeting angiogenesis and the host immune response. This review will provide an overview of current targeted therapies in NSCLC and promising treatment approaches on the horizon. PMID- 24163752 TI - A review of clinical practice guidelines for lung cancer. AB - Clinical practice guidelines are important evidence-based resources to guide complex clinical decision making. However, it is challenging for health professionals to keep abreast available guidelines and to know how and where to access relevant guidelines. This review examines currently available guidelines for lung cancer published in the English language. Important key features are listed for each identified guideline. The methodology, approaches to dissemination and implementation, and associated resources are summarised. General challenges in the area of guideline development are highlighted. The potential to collaborate more widely across lung cancer guideline developers by sharing literature searches and assessments is discussed. PMID- 24163751 TI - Surgery in 2013 and beyond. AB - Lung cancer is a leading cause of cancer related mortality. The role of surgery continues to evolve and in the last ten years there have been a number of significant changes in the surgical management of lung cancer. These changes extend across the entire surgical spectrum of lung cancer management including diagnosis, staging, treatment and pathology. Positron Emission Tomography (PET) scanning and ultrasound (EBUS) have redefined traditional staging paradigms, and surgical techniques, including video-assisted thoracoscopy (VATS), robotic surgery and uniportal surgery, are now accepted as standard of care in many centers. The changing pathology of lung cancer, with more peripheral tumours and an increase in adenocarcinomas has important implications for the Thoracic surgeon. Screening, using Low-Dose CT scanning, is having an impact, with not only a higher percentage of lower stage cancers detected, but also redefining the role of sublobar resection. The incidence of pneumonectomy has reduced as have the rates of "exploratory thoracotomy". In general, lung resection is considered for stage I and II patients with a selected role in more advanced stage disease as part of a multimodality approach. This paper will look at these issues and how they impact on Thoracic Surgical practice in 2013 and beyond. PMID- 24163753 TI - Supportive and palliative care for lung cancer patients. AB - Lung cancer patients face poor survival and experience co-occurring chronic physical and psychological symptoms. These symptoms can result in significant burden, impaired physical and social function and poor quality of life. This paper provides a review of evidence based interventions that support best practice supportive and palliative care for patients with lung cancer. Specifically, interventions to manage dyspnoea, one of the most common symptoms experienced by this group, are discussed to illustrate the emerging evidence base in the field. The evidence base for the pharmacological management of dyspnoea report systemic opioids have the best available evidence to support their use. In particular, the evidence strongly supports systemic morphine preferably initiated and continued as a once daily sustained release preparation. Evidence supporting the use of a range of other adjunctive non-pharmacological interventions in managing the symptom is also emerging. Interventions to improve breathing efficiency that have been reported to be effective include pursed lip breathing, diaphragmatic breathing, positioning and pacing techniques. Psychosocial interventions seeking to reduce anxiety and distress can also improve the management of breathlessness although further studies are needed. In addition, evidence reviews have concluded that case management approaches and nurse led follow-up programs are effective in reducing breathlessness and psychological distress, providing a useful model for supporting implementation of evidence based symptom management strategies. Optimal outcomes from supportive and palliative care interventions thus require a multi-level approach, involving interventions at the patient, health professional and health service level. PMID- 24163754 TI - Challenges for MicroRNA Microarray Data Analysis. AB - Microarray is a high throughput discovery tool that has been broadly used for genomic research. Probe-target hybridization is the central concept of this technology to determine the relative abundance of nucleic acid sequences through fluorescence-based detection. In microarray experiments, variations of expression measurements can be attributed to many different sources that influence the stability and reproducibility of microarray platforms. Normalization is an essential step to reduce non-biological errors and to convert raw image data from multiple arrays (channels) to quality data for further analysis. In general, for the traditional microarray analysis, most established normalization methods are based on two assumptions: (1) the total number of target genes is large enough (>10,000); and (2) the expression level of the majority of genes is kept constant. However, microRNA (miRNA) arrays are usually spotted in low density, due to the fact that the total number of miRNAs is less than 2,000 and the majority of miRNAs are weakly or not expressed. As a result, normalization methods based on the above two assumptions are not applicable to miRNA profiling studies. In this review, we discuss a few representative microarray platforms on the market for miRNA profiling and compare the traditional methods with a few novel strategies specific for miRNA microarrays. PMID- 24163756 TI - International heart valve bank survey: a review of processing practices and activity outcomes. AB - A survey of 24 international heart valve banks was conducted to acquire information on heart valve processing techniques used and outcomes achieved. The objective was to provide an overview of heart valve banking activities for tissue bankers, tissue banking associations, and regulatory bodies worldwide. Despite similarities found for basic manufacturing processes, distinct differences in procedural details were also identified. The similarities included (1) use of sterile culture media for procedures, (2) antibiotic decontamination, (3) use of dimethyl sulfoxide (DMSO) as a cryoprotectant, (4) controlled rate freezing for cryopreservation, and (5) storage at ultralow temperatures of below -135 degrees C. Differences in procedures included (1) type of sterile media used, (2) antibiotics combination, (3) temperature and duration used for bioburden reduction, (4) concentration of DMSO used for cryopreservation, and (5) storage duration for released allografts. For most banks, the primary reasons why allografts failed to meet release criteria were positive microbiological culture and abnormal morphology. On average, 85% of allografts meeting release criteria were implanted, with valve size and type being the main reasons why released allografts were not used clinically. The wide variation in percentage of allografts meeting release requirements, despite undergoing validated manufacturing procedures, justifies the need for regular review of important outcomes as cited in this paper, in order to encourage comparison and improvements in the HVBs' processes. PMID- 24163755 TI - NON-INVASIVE BRAIN STIMULATION IN CHILDREN: APPLICATIONS AND FUTURE DIRECTIONS. AB - Transcranial magnetic stimulation (TMS) is a neurostimulation and neuromodulation technique that has provided over two decades of data in focal, non-invasive brain stimulation based on the principles of electromagnetic induction. Its minimal risk, excellent tolerability and increasingly sophisticated ability to interrogate neurophysiology and plasticity make it an enviable technology for use in pediatric research with future extension into therapeutic trials. While adult trials show promise in using TMS as a novel, non-invasive, non-pharmacologic diagnostic and therapeutic tool in a variety of nervous system disorders, its use in children is only just emerging. TMS represents an exciting advancement to better understand and improve outcomes from disorders of the developing brain. PMID- 24163757 TI - Preoperative cardiac variables of diastolic dysfunction and clinical outcomes in lung transplant recipients. AB - Background. Orthotopic lung transplantation is now widely performed in patients with advanced lung disease. Patients with moderate or severe ventricular systolic dysfunction are typically excluded from lung transplantation; however, there is a paucity of data regarding the prognostic significance of abnormal left ventricular diastolic function and elevated pretransplant pulmonary pressures. Methods. We reviewed the characteristics of 111 patients who underwent bilateral and unilateral lung transplants from 200 to 2009 in order to evaluate the prognostic significance of preoperative markers of diastolic function, including invasively measured pulmonary capillary wedge pressure (PCWP) and echocardiographic variables of diastolic dysfunction including mitral A > E and A' > E'. Results. Out of 111 patients, 62 were male (56%) and average age was 54.0 +/- 10.5 years. Traditional echocardiographic Doppler variables of abnormal diastolic function, including A' > E' and A > E, did not predict adverse events (P = 0.49). Mildly elevated pretransplant PCWP (16-20 mmHg) and moderately/severely elevated PCWP (>20 mmHg) were not associated with adverse clinical events after transplant (P = 0.30). Additionally, all clinical endpoints did not show any statistical significance between the two groups. Conclusions. Pre-lung transplant invasive and echocardiographic findings of elevated pulmonary pressures and abnormal left ventricular diastolic function are not predictive of adverse posttransplant clinical events. PMID- 24163759 TI - Is Hyperopia an Important Risk Factor for PACG in the Dutch Population?-A Case Control Study. AB - Objectives. To determine if hyperopia is a risk factor for primary angle-closure glaucoma (PACG) in the Dutch population and to identify other biometrical parameters as risk factors for PACG including axial length (AL), anterior chamber depth (ACD), and k values. Methods. The study population consisted of PACG patients that had undergone a laser peripheral iridotomy (LPI). The control group consisted of age- and gender-matched cataract patients. The main outcome was hyperopia (spherical equivalent >=+0.5 dioptres) measured with IOL Master or autorefractor. Refractive error, ACD, AL, and k values were tested with a Mann Whitney U test and by logistic regression. Results. 117 PACG patients and 234 controls were included (mean age = 80 years +/- 3.6). The prevalence of hyperopia in patients and controls was 69.6% and 61.1%, respectively (Fisher's test P = 0.076). Mann-Whitney U test showed no statistically significant relation with refractive error (P = 0.068) or k values (P = 0.607). In contrast, ACD and AL were statistically significant (P < 0.001). Tested with logistic regression, only ACD was a significant predictor of PACG (P < 0.001). Conclusion. There was no statistically significant correlation between refractive error and PACG. ACD was strongly correlated, though, with PACG, whereas AL turned out to be a less significant risk factor. PMID- 24163758 TI - Renal transplantation from elderly living donors. AB - Acceptance of elderly living kidney donors remains controversial due to the higher incidence of comorbidity and greater risk of postoperative complications. This is a review of publications in the English language between 2000 and 2013 about renal transplantation from elderly living donors to determine trends and effects of donation, and the outcomes of such transplantation. The last decade witnessed a 50% increase in living kidney donor transplants, with a disproportionate increase in donors >60 years. There is no accelerated loss of kidney function following donation, and the incidence of established renal failure (ERF) and hypertension among donors is similar to that of the general population. The overall incidence of ERF in living donors is about 0.134 per 1000 years. Elderly donors require rigorous assessment and should have a predicted glomerular filtration rate of at least 37.5 mL/min/1.73 m(2) at the age of 80. Though elderly donors had lower glomerular filtration rate before donation, proportionate decline after donation was similar in both young and elderly groups. The risks of delayed graft function, acute rejection, and graft failure in transplants from living donors >65 years are significantly higher than transplants from younger donors. A multicentred, long-term, and prospective database addressing the outcomes of kidneys from elderly living donors is recommended. PMID- 24163760 TI - Efficacy of Ethanol Extract of Fructus lycii and Its Constituents Lutein/Zeaxanthin in Protecting Retinal Pigment Epithelium Cells against Oxidative Stress: In Vivo and In Vitro Models of Age-Related Macular Degeneration. AB - Age-related macular degeneration (AMD) is a major cause of blindness worldwide. Oxidative stress plays a large role in the pathogenesis of AMD. The present study was to evaluate the effects of Fructus lycii ethanol extract on AMD in mice and to investigate whether combination of lutein and zeaxanthin, two carotenoid pigments in Fructus lycii, could protect human retinal pigment epithelial ARPE-19 cells treated with hydrogen peroxide (H2O2) in vitro. We found that severe sediment beneath retinal pigment epithelium and thickened Bruch membrane occurred in AMD mice. However, Fructus lycii ethanol extract improved the histopathologic changes and decreased the thickness of Bruch membrane. Furthermore, the gene and protein expression of cathepsin B and cystatin C was upregulated in AMD mice but was eliminated by Fructus lycii ethanol extract. Investigations in vitro showed that ARPE-19 cell proliferation was suppressed by H2O2. However, lutein/zeaxanthin not only stimulated cell proliferation but also abrogated the enhanced expression of MMP-2 and TIMP-1 in H2O2-treated ARPE-19 cells. These data collectively suggested that Fructus lycii ethanol extract and its active components lutein/zeaxanthin had protective effects on AMD in vivo and in vitro, providing novel insights into the beneficial role of Fructus lycii for AMD therapy. PMID- 24163761 TI - RNA Interference Targeting Snail Inhibits the Transforming Growth Factor beta 2 Induced Epithelial-Mesenchymal Transition in Human Lens Epithelial Cells. AB - Epithelial-msenchymal transition (EMT) contributes to posterior capsule opacification (PCO) type of cataract. Transcription factors Snail is a key trigger of EMT activated by transforming growth factor beta (TGF beta ). This study was done to investigate the effect of Snail targeting siRNA on TGF beta 2 induced EMT in human lens epithelial cells. TGF beta 2 treatment of cultured human epithelial cell line (HLEB3) upregulated the expression of Snail and the EMT relevant molecules such as vimentin and alpha -SMA but downregulated the expression of keratin and E-cadherin. After the stimulation of TGF beta 2, the HLEB3 cells became fibroblast-like in morphology, and the junctions of cell-cell disappeared. TGF beta 2 treatment also enhanced migration ability of HLEB3 cells. TGF beta 2-induced Snail expression and EMT were significantly inhibited by Snail siRNA. By analyzing the response characteristics of HLEB3 in TGF beta 2-induced EMT model with/without Snail-specific siRNA, we concluded that Snail is an element in the EMT of HLEB3 cells induced by TGF beta 2. Snail siRNA targeting can block the induced EMT and therefore has the potential to suppress the development of PCO. PMID- 24163762 TI - Examination of the five comparable component scores of the diet quality indexes HEI-2005 and RC-DQI using a nationally representative sample of 2-18 year old children: NHANES 2003-2006. AB - Obesity has been associated with low diet quality and the suboptimal intake of food groups and nutrients. Two composite diet quality measurement tools are appropriate for Americans 2-18 years old: the Healthy Eating Index (HEI) 2005 and the Revised Children's Diet Quality Index (RC-DQI). The five components included in both indexes are fruits, vegetables, total grains, whole grains, and milk/dairy. Component scores ranged from 0 to 5 or 0 to 10 points with lower scores indicating suboptimal intake. To allow direct comparisons, one component was rescaled by dividing it by 2; then, all components ranged from 0 to 5 points. The aim of this study was to directly compare the scoring results of these five components using dietary data from a nationally representative sample of children (NHANES 2003-2006, N = 5,936). Correlation coefficients within and between indexes showed less internal consistency in the HEI; age- and ethnic-group stratified analyses indicated higher sensitivity of the RC-DQI. HEI scoring was likely to dichotomize the population into two groups (those with 0 and those with 5 points), while RC-DQI scores resulted in a larger distribution of scores. The scoring scheme of diet quality indexes for children results in great variation of the outcomes, and researchers must be aware of those effects. PMID- 24163764 TI - The postoperative component of MAGIC chemotherapy is associated with improved prognosis following surgical resection in gastric and gastrooesophageal junction adenocarcinomas. AB - AIMS: MAGIC chemotherapy has become the standard of treatment for patients undergoing curative resection for gastric and gastrooesophageal junction (GOJ) cancers. The importance of postoperative component of this regimen is uncertain. The aim of this study was to compare survival and cancer recurrence in patients who have received neoadjuvant and adjuvant chemotherapies according to MAGIC protocol with those patients completing only neoadjuvant chemotherapy. METHODS: 66 patients with gastric and GOJ adenocarcinomas treated with neoadjuvant and adjuvant chemotherapies according to the MAGIC protocol were studied. All patients underwent potentially curative surgical resection. The histological, demographic, and survival data were collected for all patients. RESULTS: The median number of neoadjuvant chemotherapy cycles received was 2 (range 1-3). Thirty-one (47%) patients underwent adjuvant chemotherapy with a median of 2 cycles (range 1-3). Patients who have completed both cycles of chemotherapy had significantly improved survival (P = 0.04). Patients with involved lymph nodes and positive longitudinal resection margins had increased incidence of recurrence (P = 0.02) and poor five-year survival (P = 0.03). CONCLUSIONS: Patients who received both neoadjuvant and adjuvant chemotherapies for gastric and gastro oesophageal junction tumours have improved outcomes compared to patients who only received neoadjuvant chemotherapy. PMID- 24163765 TI - Cross-cultural adaptation and psychometric testing of the brazilian version of the self-care of heart failure index version 6.2. AB - Objective. To adapt and evaluate the psychometric properties of the Brazilian version of the SCHFI v 6.2. Methods. With the approval of the original author, we conducted a complete cross-cultural adaptation of the instrument (translation, synthesis, back translation, synthesis of back translation, expert committee review, and pretesting). The adapted version was named Brazilian version of the self-care of heart failure index v 6.2. The psychometric properties assessed were face validity and content validity (by expert committee review), construct validity (convergent validity and confirmatory factor analysis), and reliability. Results. Face validity and content validity were indicative of semantic, idiomatic, experimental, and conceptual equivalence. Convergent validity was demonstrated by a significant though moderate correlation (r = -0.51) on comparison with equivalent question scores of the previously validated Brazilian European heart failure self-care behavior scale. Confirmatory factor analysis supported the original three-factor model as having the best fit, although similar results were obtained for inadequate fit indices. The reliability of the instrument, as expressed by Cronbach's alpha, was 0.40, 0.82, and 0.93 for the self-care maintenance, self-care management, and self-care confidence scales, respectively. Conclusion. The SCHFI v 6.2 was successfully adapted for use in Brazil. Nevertheless, further studies should be carried out to improve its psychometric properties. PMID- 24163763 TI - Comparative serological assays for the study of h5 and h7 avian influenza viruses. AB - The nature of influenza virus to randomly mutate and evolve into new types is an important challenge in the control of influenza infection. It is necessary to monitor virus evolution for a better understanding of the pandemic risk posed by certain variants as evidenced by the highly pathogenic avian influenza (HPAI) viruses. This has been clearly recognized in Egypt following the notification of the first HPAI H5N1 outbreak. The continuous circulation of the virus and the mass vaccination programme undertaken in poultry have resulted in a progressive genetic evolution and a significant antigenic drift near the major antigenic sites. In order to establish if vaccination is sufficient to provide significant intra- and interclade cross-protection, lentiviral pseudotypes derived from H5N1 HPAI viruses (A/Vietnam/1194/04, A/chicken/Egypt-1709-01/2007) and an antigenic drift variant (A/chicken/Egypt-1709-06-2008) were constructed and used in pseudotype-based neutralization assays (pp-NT). pp-NT data obtained was confirmed and correlated with HI and MN assays. A panel of pseudotypes belonging to influenza Groups 1 and 2, with a combination of reporter systems, was also employed for testing avian sera in order to support further application of pp-NT as an alternative valid assay that can improve avian vaccination efficacy testing, vaccine virus selection, and the reliability of reference sera. PMID- 24163766 TI - A Novel Interaction between Pyk2 and MAP4K4 Is Integrated with Glioma Cell Migration. AB - Glioma cell migration correlates with Pyk2 activity, but the intrinsic mechanism that regulates the activity of Pyk2 is not fully understood. Previous studies have supported a role for the N-terminal FERM domain in the regulation of Pyk2 activity as mutations in the FERM domain inhibit Pyk2 phosphorylation. To search for novel protein-protein interactions mediated by the Pyk2 FERM domain, we utilized a yeast two-hybrid genetic selection to identify the mammalian Ste20 homolog MAP4K4 as a binding partner for the Pyk2 FERM domain. MAP4K4 coimmunoprecipitated with Pyk2 and was a substrate for Pyk2 but did not coimmunoprecipitate with the closely related focal adhesion kinase FAK. Knockdown of MAP4K4 expression inhibited glioma cell migration and effectively blocked Pyk2 stimulation of glioma cell. Increased expression of MAP4K4 stimulated glioma cell migration; however, this stimulation was blocked by knockdown of Pyk2 expression. These data support that the interaction of MAP4K4 and Pyk2 is integrated with glioma cell migration and suggest that inhibition of this interaction may represent a potential therapeutic strategy to limit glioblastoma tumor dispersion. PMID- 24163767 TI - Physical exercise and brain functions in older adults. PMID- 24163768 TI - Adding to the burden: gastrointestinal symptoms and syndromes in multiple sclerosis. AB - Background. Multiple sclerosis (MS) patients often suffer from gastrointestinal (GI) symptoms. However, the full extent and prevalence of such symptoms are not clearly established. Thus, we sought to define the prevalence of GI symptoms and syndromes in those with MS. Methods. 218 MS patients completed self-reported demographic and clinical data questionnaires as well as several standardized surveys probing MS severity and GI health. Results. Nearly two thirds (65.6%) of patients endorsed at least one persistent GI symptom. Constipation (36.6%), dysphagia (21.1%), and fecal incontinence (15.1%) were common. Surprisingly, nearly 30% (28.4%) of the patients reported dyspeptic symptoms. Using validated diagnostic algorithms, patients met criteria for functional dysphagia (14.7%), functional dyspepsia (16.5%), functional constipation (31.7%), and IBS (19.3%), among others. Functional dysphagia, functional dyspepsia, and IBS were significantly more common in those with self-identified mood disorders. Conclusions. Constipation, fecal incontinence, and dysphagia are indeed frequent symptoms seen in MS patients. We also noted a ~30% prevalence of dyspepsia in this population. The mechanisms driving this association are not clear and require further study. However, due to this high prevalence, dyspeptic symptoms should be incorporated into the routine assessment of MS patients and, if found, may warrant collaborative referral with a GI specialist. PMID- 24163769 TI - Is There Extra Cost of Institutional Care for MS Patients? AB - Throughout life, patients with multiple sclerosis (MS) require increasing levels of support, rehabilitative services, and eventual skilled nursing facility (SNF) care. There are concerns that access to SNF care for MS patients is limited because of perceived higher costs of their care. This study compares costs of caring for an MS patient versus those of a typical SNF patient. We merged SNF cost report data with the 2001-2006 Nursing Home Minimum Data Set (MDS) to calculate percentage of MS residents-days and facility case-mix indices (CMIs). We estimated the average facility daily cost using hybrid cost functions, adjusted for facility ownership, average facility wages, CMI-adjusted number of SNF days, and percentage of MS residents-days. We describe specific characteristics of SNF with high and low MS volumes and examine any sources of variation in cost. MS patients were no longer more costly than typical SNF patients. A greater proportion of MS patients had no significant effect on facility daily costs (P = 0.26). MS patients were more likely to receive care in government-owned facilities (OR = 1.904) located in the Western (OR = 2.133) and Midwestern (OR = 1.3) parts of the USA (P < 0.05). Cost of SNF care is not a likely explanation for the perceived access barriers that MS patients face. PMID- 24163770 TI - Assessment of cardiovascular disease risk in South asian populations. AB - Although South Asian populations have high cardiovascular disease (CVD) burden in the world, their patterns of individual CVD risk factors have not been fully studied. None of the available algorithms/scores to assess CVD risk have originated from these populations. To explore the relevance of CVD risk scores for these populations, literature search and qualitative synthesis of available evidence were performed. South Asians usually have higher levels of both "classical" and nontraditional CVD risk factors and experience these at a younger age. There are marked variations in risk profiles between South Asian populations. More than 100 risk algorithms are currently available, with varying risk factors. However, no available algorithm has included all important risk factors that underlie CVD in these populations. The future challenge is either to appropriately calibrate current risk algorithms or ideally to develop new risk algorithms that include variables that provide an accurate estimate of CVD risk. PMID- 24163771 TI - Melanoma in buckinghamshire: data from the inception of the skin cancer multidisciplinary team. AB - Background. Melanoma incidence is increasing faster than any other cancer in the UK. The introduction of specialist skin cancer multidisciplinary teams intends to improve the provision of care to patients suffering from melanoma. This study aims to investigate the management and survival of patients diagnosed with melanoma around the time of inception of the regional skin cancer multidisciplinary team both to benchmark the service against published data and to enable future analysis of the impact of the specialisation of skin cancer care. Methods. All patients diagnosed with primary cutaneous melanoma between January 1, 2003 and December 3, 2005 were identified. Data on clinical and histopathological features, surgical procedures, complications, disease recurrence and 5-year survival were collected and analysed. Results. Two hundred and fourteen patients were included, 134 female and 80 males. Median Breslow thickness was 0.74 mm (0.7 mm female and 0.8 mm male). Overall 5-year survival was 88% (90% female and 85% male). Discussion. Melanoma incidence in Buckinghamshire is in keeping with published data. Basic demographics details concur with classic melanoma distribution and more recent trends, with increased percentage of superficial spreading and thin melanomas, leading to improved survival are reflected. PMID- 24163773 TI - Physical Activity in Adolescents following Treatment for Cancer: Influencing Factors. AB - The purpose of this study was to examine physical activity levels and influencing individual and environmental factors in a group of adolescent survivors of cancer and a comparison group. Methods. The study was conducted using a "mixed methods" design. Quantitative data was collected from 48 adolescent survivors of cancer and 48 comparison adolescents using the Godin Leisure-Time Exercise Questionnaire, the Fatigue Scale-Adolescents, and the Amherst Health and Activity Study-Student Survey. Qualitative data was collected in individual semistructured interviews. Results. Reported leisure-time physical activity total scores were not significantly different between groups. Physical activity levels were positively correlated with adult social support factors in the group of adolescent survivors of cancer, but not in the comparison group. Time was the primary barrier to physical activity in both groups. Fatigue scores were higher for the comparison but were not associated with physical activity levels in either group. The qualitative data further supported these findings. Conclusions. Barriers to physical activity were common between adolescent survivors of cancer and a comparative group. Increased knowledge of the motivators and barriers to physical activity may help health care providers and families provide more effective health promotion strategies to adolescent survivors of pediatric cancer. PMID- 24163772 TI - Financial Strain Is Associated with Malnutrition Risk in Community-Dwelling Older Women. AB - This study examined the relationship between financial strain, or difficulty acquiring necessities, and malnutrition risk in a community dwelling sample of frail and nonfrail women aged 70-79 in the Women's Health and Aging Study (n = 679). Malnutrition risk was measured with a modified version of the Mini Nutritional Assessment Short Form (MNA-SF) and defined as a score <11, financial strain was measured by (1) sufficiency of money on a monthly basis and (2) adequacy of income for food, and income was measured by ordinal categories. Mean (SD) modified MNA-SF score was 12.2 (1.80), and 14.7% of women had malnutrition risk. Women who usually did not have enough money to make ends meet had more than four-fold increased odds of malnutrition risk (OR = 4.54; 95% CI: 2.26, 9.14) compared to their counterparts who had some money left over each month. This was only slightly attenuated after control for income and education, (OR = 4.08; 95% CI: 1.95, 8.52) remaining robust. These results show an association between financial strain and malnutrition risk, independent of income, in older women. Self-reported financial strain may be preferable to income as a screener for malnutrition risk in older adults in clinical and research settings. PMID- 24163774 TI - The Association between Sleep and Injury among School-Aged Children in Iran. AB - Background. A good night's sleep plays a key role in diseases resistance, injury prevention, and mood stability. The objective of this study was to examine relationship between sleep problems and accidental injury occurrences in school aged children. Method. A retrospective study was conducted for comparing two groups of children. Children who have experienced injuries for at least two times during an academic year are the participants in the injury group (IG) and those who have not experienced any kind of injuries are placed in the noninjury group (NIG). Data was collected through parent-reported sleep patterns and problems using Children's Sleep Habits Questionnaire (CSHQ). Findings. The findings showed that global sleep problems were more in the IG than in the NIG. Multivariate logistic regression analysis showed that the daytime sleepiness and sleep duration are the two major reasons for accidental injury. In addition, significant difference was seen between the sleep patterns of the two groups. Sleep duration was also shorter in the IG, and this group had a greater percentage (63% versus 41.1%) of "short sleepers" (<9 h). Conclusion. There is a significant relationship between injury occurrence and sleep problems and sleep duration in Iranian school-aged children. PMID- 24163775 TI - Survival and failure outcomes in primary thyroid lymphomas: a single centre experience of combined modality approach. AB - Primary thyroid lymphoma (PTL) is a rare malignancy and represents 2%-5% of all thyroid malignancies and 1%-2.5% of all malignant lymphomas. We present our institute's experience in combined modality management of 16 successive patients of PTL treated from 2005 to 2010. The median age of the patients was 56.0 years. Five patients were males, and 11 patients were females. An enlarging thyroid mass was the most common presenting symptom. 14 patients had diffuse large B-cell lymphoma, and 2 patients had follicular lymphoma. The most common stage of presentation was stage II comprising 6 (37.5%) patients. All patients received CCT, and only 12 patients received involved field RT with a median dose of 36.0 Gy. 10 patients (62.5%) had CR, and 6 patients (27.5%) had PR. Eight patients had disease progression in subsequent followup and this included the initial 6 patients with PR. The 5-year DFS was 40.0%, and median DFS was 47 months. The 5 year OS was 41.0%, and median OS was 51 months. Most common presentation in our series was locally advanced tumors. Most of these patients require combined modality management. Risk-adapted and multimodality approach is the need of the hour to achieve good control rates while minimizing treatment related toxicity. PMID- 24163776 TI - Molecular Detection and Genotyping of Chlamydia psittaci in Captive Psittacines from Costa Rica. AB - Oropharyngeal and cloacal swabs from 117 captive psittacine birds presented at veterinary clinics (88) and from shelters/rescue centers of wildlife (29) were collected to determine the prevalence of C. psittaci in captive birds in Costa Rica. Samples were collected during 2009 from a total of 19 different species of parrots, with Ara macao (33), Amazona autumnalis (24), Amazona ochrocephala (21), and Ara ararauna (8) being the most representative species sampled. C. psittaci was detected in four (3.4%) birds using molecular detection (PCR). The positive samples belonged to birds presented at veterinary clinics; three of them were Ara macao and one Amazona ochrocephala. Three birds were adults; all positive birds showed no symptoms of illness and lived in homes with other birds, two in San Jose and two in Heredia. Sequencing was used to confirm the PCR positive results, showing that two samples of C. psittaci belonged to genotype A, representing the first report of the presence of this genotype in Costa Rica. The detection of this bacterium in captive psittacine birds shows that there is a potential risk for people living or having contact with them and that there is a possibility of infecting other birds. PMID- 24163777 TI - Validated reverse-phase high-performance liquid chromatography for quantification of furosemide in tablets and nanoparticles. AB - A simple, sensitive, and specific method for furosemide (FUR) analysis by reverse phase-HPLC was developed using a Spherisorb C18 ODS 2 column. A chromatographic analysis was carried out using a mobile phase consisting of acetonitrile and 10 mM potassium phosphate buffer solution: 70 : 30 (v/v) at pH 3.85, at a flow rate of 1 mL.min(-1). The UV-detection method was carried out at 233 nm at room temperature. Validation parameters including limit of detection (LOD), limit of quantitation (LOQ), linearity range, precision, accuracy, robustness, and specificity were investigated. Results indicated that the calibration curve was linear (r (2) = 0.9997) in the range of 5.2 to 25,000 ng.mL(-1), with epsilon value equal to 3.74 * 10(4) L.M(-1) .cm(-1). The LOD and LOQ were found to be 5.2 and 15.8 ng.mL(-1), respectively. The developed method was found to be accurate (RSD less than 2%), precise, and specific with an intraday and interday RSD range of 1.233-1.509 and 1.615 to 1.963%. The stability of native FUR has also been performed in simulated perilymph and endolymph media (with respective potency in each medium of 99.8 +/- 2.3% and 96.68 +/- 0.7%, n = 3) after 6 hours. This method may be routinely used for the quantitative analysis of FUR from nanocarriers, USP tablets and release media related to hearing research. PMID- 24163778 TI - Validation and uncertainty estimation of an ecofriendly and stability-indicating HPLC method for determination of diltiazem in pharmaceutical preparations. AB - A green, simple, and stability-indicating RP-HPLC method was developed for the determination of diltiazem in topical preparations. The separation was based on a C18 analytical column using a mobile phase consisted of ethanol: phosphoric acid solution (pH = 2.5) (35 : 65, v/v). Column temperature was set at 50 degrees C and quantitation was achieved with UV detection at 240 nm. In forced degradation studies, the drug was subjected to oxidation, hydrolysis, photolysis, and heat. The method was validated for specificity, selectivity, linearity, precision, accuracy, and robustness. The applied procedure was found to be linear in diltiazem concentration range of 0.5-50 MU g/mL (r (2) = 0.9996). Precision was evaluated by replicate analysis in which % relative standard deviation (RSD) values for areas were found below 2.0. The recoveries obtained (99.25%-101.66%) ensured the accuracy of the developed method. The degradation products as well as the pharmaceutical excipients were well resolved from the pure drug. The expanded uncertainty (5.63%) of the method was also estimated from method validation data. Accordingly, the proposed validated and sustainable procedure was proved to be suitable for routine analyzing and stability studies of diltiazem in pharmaceutical preparations. PMID- 24163779 TI - Ultratrace Determination of Cr(VI) and Pb(II) by Microsample Injection System Flame Atomic Spectroscopy in Drinking Water and Treated and Untreated Industrial Effluents. AB - Simple and robust analytical procedures were developed for hexavalent chromium (Cr(VI)) and lead (Pb(II)) by dispersive liquid-liquid microextraction (DLLME) using microsample injection system coupled with flame atomic absorption spectrophotometry (MIS-FAAS). For the current study, ammonium pyrrolidine dithiocarbamate (APDC), carbon tetrachloride, and ethanol were used as chelating agent, extraction solvent, and disperser solvent, respectively. The effective variables of developed method have been optimized and studied in detail. The limit of detection of Cr(VI) and Pb(II) were 0.037 and 0.054 ug/L, respectively. The enrichment factors in both cases were 400 with 40 mL of initial volumes. The relative standard deviations (RSDs, n = 6) were <4%. The applicability and the accuracy of DLLME were estimated by the analysis of Cr(VI) and Pb(II) in industrial effluent wastewater by standard addition method (recoveries >96%). The proposed method was successfully applied to the determination of Cr(VI) and Pb(II) at ultratrace levels in natural drinking water and industrial effluents wastewater of Denizli. Moreover, the proposed method was compared with the literature reported method. PMID- 24163780 TI - Enhancing the Construct and Content Validity of Rating Scales for Clinical Research: Using Qualitative Methods to Develop a Rating Scale to Assess Parental Perceptions of Their Role in Promoting Infant Exercise. AB - With a focus on the early stages of developing new assessment tools, we present an example of how researchers can apply qualitative data to the development of conceptual domains and specific items representing those domains for quantitative instruments. Specifically, our previous research examining mothers' perceptions and experiences of engaging in assisted exercise with their infants provided the foundation for the development of the Perceptions of Pediatric Activity Scale (PPAS). We describe the process we used to develop the PPAS as an exemplar for the process of incorporating qualitative data in instrument development. In addition, we address instrument development for diverse populations, and we provide examples illustrating how we extracted concepts using a concept-indicator model to construct the items in the PPAS. We conclude by noting that we are currently in the process of pilot-testing the PPAS to evaluate its utility and reliability. PMID- 24163781 TI - Correlation of transcription of MALAT-1, a novel noncoding RNA, with deregulated expression of tumor suppressor p53 in small DNA tumor virus models. AB - Although metastasis-associated lung adenocarcinoma transcript (MALAT)-1 is known to be consistently upregulated in several epithelial malignancies, little is known about its function or regulation. We therefore examined the relationship between MALAT-1 expression and candidate modulators such as DNA tumor virus oncoproteins human papillomavirus (HPV)-16 E6 and E7, BK virus T antigen (BKVTAg), mouse polyoma virus middle T antigen (MPVmTAg) and tumor suppressor genes p53 and pRb. Using suppressive subtractive hybridization (SSH) and real time reverse transcriptase polymerase chain reaction (RT-PCR) assays, MALAT-1 was shown to be increased in viral oncongene-expressing salivary gland biopsies from humans and mice. The results also indicated that MALAT-1 transcripts and promoter activity were increased in vitro when viral oncongene-expressing plasmids were introduced into different cell types. These same viral oncogenes in addition to increasing MALAT-1 transcription have also been shown to inhibit p53 and/or pRb function. In p53 mutant or inactive cell lines MALAT-1 was also shown to be highly upregulated. We hypothesize that there is a correlation between MALAT-1 over-expression and p53 deregulation. In conclusion, we show that disruption of p53, by both polyoma and papilloma oncoproteins appear to play an important role in the up-regulation of MALAT-1. MALAT-1 might therefore represent a biomarker for p53 deregulation within malignancies. PMID- 24163782 TI - Community Violence Exposure and Adolescents' School Engagement and Academic Achievement Over Time. AB - OBJECTIVE: This study examined the relationships between community violence exposure and two related, but meaningfully distinct, academic outcomes: school engagement and academic achievement (GPA). Psychological symptoms were investigated as mediators of these relationships. METHOD: One hundred eighteen youth reported on community violence exposure and school engagement twice during adolescence, and both parents and adolescents reported on psychological symptoms. Cumulative GPA was also acquired from participants. A path model and hierarchical multiple regression analyses were used to assess these relationships longitudinally. RESULTS: Earlier community violence exposure inversely predicted later school engagement, but earlier school engagement did not predict later community violence exposure. School engagement mediated the association between community violence exposure and school GPA. Internalizing and externalizing symptoms, but not posttraumatic stress symptoms, mediated the association between community violence and school engagement. CONCLUSIONS: When adolescents are exposed to community violence, they may become vulnerable to a cascade of events including psychological symptoms and decreased connectedness to school, which ultimately can lead to overall poor academic achievement. The more proximal, changeable experiences of school connectedness and psychological symptoms offer targets for interventions offsetting long-term adverse academic consequences in violence-exposed youth. PMID- 24163783 TI - A review article on the diagnosis and treatment of cerebrospinal fluid fistulas and dural tears occurring during spinal surgery. AB - BACKGROUND: In spinal surgery, cerebrospinal fluid (CSF) fistulas attributed to deliberate dural opening (e.g., for tumors, shunts, marsupialization of cysts) or inadvertent/traumatic dural tears (DTs) need to be readily recognized, and appropriately treated. METHODS: During spinal surgery, the dura may be deliberately opened to resect intradural lesions/tumors, to perform shunts, or to open/marsupialize cysts. DTs, however, may inadvertently occur during primary, but are seen more frequently during revision spinal surgery often attributed to epidural scarring. Other etiologies of CSF fistulas/DTs include; epidural steroid injections, and resection of ossification of the posterior longitudinal ligament (OPLL) or ossification of the yellow ligament (OYL). Whatever the etiology of CSF fistulas or DTs, they must be diagnosed utilizing radioisotope cisternography (RIC), magnetic resonance imaging (MRI), computed axial tomography (CT) studies, and expeditiously repaired. RESULTS: DTs should be repaired utilizing interrupted 7-0 Gore-Tex (W.L. Gore and Associates Inc., Elkton, MD, USA) sutures, as the suture itself is larger than the needle; the larger suture occludes the dural puncture site. Closure may also include muscle patch grafts, dural patches/substitutes (bovine pericardium), microfibrillar collagen (Duragen: Integra Life Sciences Holdings Corporation, Plainsboro, NJ), and fibrin glues or dural sealants (Tisseel: Baxter Healthcare Corporation, Deerfield, IL, USA). Only rarely are lumbar drains and wound-peritoneal and/or lumboperitoneal shunts warranted. CONCLUSION: DTs or CSF fistulas attributed to primary/secondary spinal surgery, trauma, epidural injections, OPLL, OYL, and other factors, require timely diagnosis (MRI/CT/Cisternography), and appropriate reconstruction. PMID- 24163785 TI - The Highs and Lows of FAIMS: Predictions and Future Trends for High Field Asymmetric Waveform Ion Mobility Spectrometry. PMID- 24163784 TI - Non-Invasive Imaging for Congenital Heart Disease: Recent Innovations in Transthoracic Echocardiography. AB - Transthoracic echocardiography (TTE) is an important tool for diagnosis and follow-up of patients with congenital heart disease (CHD). Appropriate use of TTE can reduce the need for more invasive and complex modalities, such as cardiac catheterization and cardiac magnetic resonance imaging. New echocardiographic techniques have emerged for the assessment of ventricular systolic and diastolic function: Tissue Doppler imaging, tissue tracking, strain and strain rate imaging, vector velocity imaging (VVI), myocardial performance index, myocardial acceleration during isovolumic contraction (IVA), the ratio of systolic to diastolic duration (S/D ratio), and other measurements of systolic right ventricular (RV) function like tricuspid annular plane systolic excursion (TAPSE). These modalities may become valuable indicators of ventricular performance, compliance and disease progression, with the caveat of preload dependency of the variables measured. In addition, three-dimensional (3D) echocardiography for the assessment of cardiac anatomy, valvular function, device position, ventricular volumes and ejection fraction is integrated into routine clinical care. In this review, we discuss the potential use and limitations of these new echocardiographic techniques in patients with CHD. A particular focus is on the echocardiographic assessment of right ventricular (RV) function by means of tissue Doppler imaging, tissue tracking, and three-dimensional imaging, in conditions associated with increased right ventricular volume or pressure load. PMID- 24163787 TI - Inequities in Cataract Surgery and Postsurgical Quality-of-Life Outcomes in Handan, China. AB - PURPOSE: This study aimed to describe the rate of cataract surgical coverage (CSC) and the quality-of-life (QoL) outcomes after cataract surgery in rural China. DESIGN: Cross-sectional study. METHODS: A clustered, random sampling procedure was used to select 7557 Chinese patients aged 30 years and older from Handan, China. Comprehensive eye examinations, including standardized refraction and classification of lens characteristics, were offered to all eligible subjects. Visual impairment was defined as any individual with presenting visual acuity of less than 20/60 in the better-seeing eye. The main outcome measures were CSC rate and a summary measure assessing QoL in visually impaired (VI) participants. RESULTS: Of 5592 participants older than 40 years, there were 41 cataract patients operated on and 54 VI cataract patients not operated on. The CSC rate among individuals with VI was 43.2%. Older age was significantly negatively associated with a history of cataract surgery (adjusted odds ratio, 0.44 per 10-year increase in age; 95% confidence interval, 0.26-0.74). Women were less likely to have had cataract surgery compared with men, although not significantly (adjusted odds ratio, 0.44; 95% confidence interval, 0.17-1.12). The QoL summary measure was significantly better in the cataract group operated on than that not operated on (P < 0.01). CONCLUSIONS: There is a large unmet need for cataract surgery in rural Handan, China. Those who had surgery were more likely to have better QoL outcomes than those who did not. There is a potential need to promote cataract surgery and develop age- and sex-sensitive interventions in rural China. PMID- 24163788 TI - The myADHDportal.com Improvement Program: An innovative quality improvement intervention for improving the quality of ADHD care among community-based pediatricians. AB - Though the American Academy of Pediatrics has developed and disseminated clear evidence-based guidelines for ADHD care, community-based pediatricians often have difficulty implementing these guidelines. New strategies are needed to improve the quality of care received by children with ADHD and to improve utilization of the AAP consensus guidelines by pediatricians. An evidence-based quality improvement intervention has been developed that effectively improves the quality of ADHD care delivered by community-based pediatricians. In order to facilitative widespread dissemination of this intervention model, the entire intervention has been modified for online delivery. The intervention is called the myADHDportal.com Improvement Program. The full functionality of this online intervention is described including the collection of online ADHD rating scales from parents and teachers and online communication between parents, teachers, and physicians. In addition, the web portal integrates several innovative quality improvement features including an online wizard for mapping ADHD patient flow, an online report card for monitoring quality of care, and an online wizard for guiding practices through the Plan-Do-Study-Act (PDSA) cycle process. The combination of clinical utility and quality improvement tools facilitates delivery of quality ADHD care and reduces several of the obstacles to implementing AAP-recommended practice behaviors. Initial results with this intervention model are reviewed and goals for dissemination are described. PMID- 24163789 TI - SOFI-based 3D superresolution sectioning with a widefield microscope. AB - BACKGROUND: Fluorescence-based biological imaging has been revolutionized by the recent introduction of superresolution microscopy methods. 3D superresolution microscopy, however, remains a challenge as its implementation by existing superresolution methods is non-trivial. METHODS: Here we demonstrate a facile and straightforward 3D superresolution imaging and sectioning of the cytoskeletal network of a fixed cell using superresolution optical fluctuation imaging (SOFI) performed on a conventional lamp-based widefield microscope. RESULTS AND CONCLUSION: SOFI's inherent sectioning capability effectively transforms a conventional widefield microscope into a superresolution 'confocal widefield' microscope. PMID- 24163786 TI - Paclitaxel Nano-Delivery Systems: A Comprehensive Review. AB - Paclitaxel is one of the most effective chemotherapeutic drugs ever developed and is active against a broad range of cancers, such as lung, ovarian, and breast cancers. Due to its low water solubility, paclitaxel is formulated in a mixture of Cremophor EL and dehydrated ethanol (50:50, v/v) a combination known as Taxol. However, Taxol has some severe side effects related to Cremophor EL and ethanol. Therefore, there is an urgent need for the development of alternative Taxol formulations. The encapsulation of paclitaxel in biodegradable and non-toxic nano delivery systems can protect the drug from degradation during circulation and in turn protect the body from toxic side effects of the drug thereby lowering its toxicity, increasing its circulation half-life, exhibiting improved pharmacokinetic profiles, and demonstrating better patient compliance. Also, nanoparticle-based delivery systems can take advantage of the enhanced permeability and retention (EPR) effect for passive tumor targeting, therefore, they are promising carriers to improve the therapeutic index and decrease the side effects of paclitaxel. To date, paclitaxel albumin-bound nanoparticles (Abraxane(r)) have been approved by the FDA for the treatment of metastatic breast cancer and non-small cell lung cancer (NSCLC). In addition, there are a number of novel paclitaxel nanoparticle formulations in clinical trials. In this comprehensive review, several types of developed paclitaxel nano-delivery systems will be covered and discussed, such as polymeric nanoparticles, lipid-based formulations, polymer conjugates, inorganic nanoparticles, carbon nanotubes, nanocrystals, and cyclodextrin nanoparticles. PMID- 24163790 TI - Myocilin and Optineurin: Differential Characteristics and Functional Consequences. AB - Myocilin and optineurin are two genes linked to glaucoma, a major blinding disease characterized by progressive loss of retinal ganglion cells and their axons. This review describes the characteristics of myocilin and optineurin protein products and summarizes the consequences of ectopically expressed wild type and mutant myocilin and optineurin in trabecular meshwork and/or neuronal cells. Myocilin and optineurin exhibit differential characteristics and have divergent functional consequences. They contribute to the development of glaucoma likely via distinct mechanisms. PMID- 24163792 TI - Pubmed/PMC as the First Line Resource in Biomedicine Field. PMID- 24163791 TI - Characteristics, adverse events, and racial differences among delivering mothers with peripartum cardiomyopathy. AB - OBJECTIVES: The aim of this study was to identify clinical features associated with peripartum cardiomyopathy (PPCM) and possible racial differences and to quantify in-hospital outcomes in delivering mothers with PPCM. BACKGROUND: Investigation of patient characteristics and outcomes in PPCM has been limited to small cohorts. Hospital discharge data allow assembly of the largest number of PPCM cases to date. METHODS: Hospital records from 6 states were screened for PPCM. Clinical profiles, maternal, and fetal outcomes in delivering mothers with and without PPCM were compared and stratified by race. A maternal major adverse event (MAE) was defined as death, cardiac arrest, heart transplantation, or mechanical circulatory support. Logistic regression was used to identify variables associated with PPCM. RESULTS: In total, 535 of 4,003,914 records of delivering mothers specified a diagnosis of PPCM. Prevalence of PPCM was highest among African Americans and similar in Caucasians and Hispanics. Established risk factors including age 30 years, African- American race, hypertension, preeclampsia/eclampsia, and multigestational status were associated with PPCM, and novel associations such as anemia and asthma were identified. Autoimmune disease and substance abuse, which can cause cardiomyopathy independently, were also associated with PPCM. Maternal MAE (odds ratio: 436, p < 0.0001) and stillbirth (odds ratio: 3.8, p < 0.0001) occurred more frequently among women with PPCM. CONCLUSIONS: The prevalence of PPCM at the time of delivery in Hispanics was similar to Caucasians and lower than African Americans. Autoimmune disease, substance abuse, anemia and asthma were conditions associated with PPCM not consistently identified in smaller cohorts. Peripartum cardiomyopathy was also associated with increased risk of stillbirth and maternal MAEs at delivery. PMID- 24163793 TI - Assisted reproductive technology after the birth of louise brown. AB - BACKGROUND: Public interest in Assisted Reproductive Technology (ART) has remained high since the birth of the world's first in vitro fertilization baby, Louise Brown, in the United Kingdom. ART allows scientists to manipulate the fertilization process in order to bypass some pathological obstacles such as blocked fallopian tubes and non-functioning ovaries in the females, and blocked vas deferens and low sperm count in the males. The purpose was to provide a historical outline and identify the researches that most contributed to ART. METHODS: A review of published experimental and clinical studies of assisted reproduction carried out at the University of Bristol library website (MetaLib((r))). A cross-search of seven different medical databases (AMED-Allied and Complementary Medicine Database, BIOSIS Previews on Web of Knowledge, Cochrane Library, Embase, and the Medline on Web of Knowledge, OvidSP and PubMed) was completed by using the key words to explore the major milestones and progress in the development and implementation of ART. RESULTS: A speedy advancement in the development of different assisted reproductive techniques makes infertility problem more treatable than it ever had been. CONCLUSION: Although no other field in the medicine has integrated new knowledge into the daily practice more quickly than ART yet, there is a need for social research to counterbalance the dominance of biomedical one, in particular the people's actual experiences and expectations of ART. PMID- 24163794 TI - Assessment of questionnaires measuring quality of life in infertile couples: a systematic review. AB - BACKGROUND: Infertility has potentially inappropriate effects on quality of life in infertile couples. Various general and specific questionnaires have been structured for assessing different aspects of quality of life in infertile men, women, or couples. The present systematic review was designed to assess these questionnaires and also identify different factors affecting infertile couples based on the aforesaid questionnaires. METHODS: The research strategy involved general and specific terms in relation to couples's infertility and their quality of life. A review was done for studies published from 1982 to 2012 that were indexed in Medline, ISI Web of Science and Scopus as well as abstract books on this subject. We also corresponded with the authors of the references in related studies for introducing more resources and references. RESULTS: In all reviewed studies, different aspects of the quality of life in couples were evaluated including sexual, psychological, social, communicational, environmental, occupational, medical, as well as economical ones. In total, after initial screening of all studies, 10 general and 2 specific questionnaires were retrieved. Although no meta-analysis was found in the review, infertility had a negative effect on quality of life in couples. CONCLUSION: This study revealed that some general questionnaires such as SF-36 and WHO-QOL were mostly used for assessing quality of life in infertile couples and some specific questionnaires such as FERTI-QoL and Fertility Problem Inventory were rarely used. Thus, it seems that the evaluation of quality of life in infertile couples needs valid instruments for measurement. PMID- 24163795 TI - Use of fluorescent dyes for readily recognizing sperm damage. AB - Sperm is produced by the testis and mature in the epididymis. For having a successful conception, the fertilizing sperm should have functional competent membranes, intact acrosome, functional mitochondria and an intact haploid genome. The effects of genetic and environmental factors result in sperm vulnerability to damage in the process of spermatogenesis and maturation. In recent years, the feasibility of detecting sperm damage is enhanced through the advances in technologies like fluoscerent staining techniques assisted with fluorescence microscope, flow cytometry and computer analysis systems. Fluoscerent staining techniques involve the use of fluorescent dyes, either directly or indirectly for binding them with some ingredients of sperm and evaluating the damage of the structure or function of the sperm, i.e. membrane, acrosome, mitochondria, chromosome or DNA. PMID- 24163796 TI - Reversible germ cell toxicity of sulphasalazine and ampicillin combination in male rats. AB - BACKGROUND: The antifertility effect of ampicillin (AMP, 40 mg/kg) and sulphasalazine or salicylazosulfapyridine (SASP, 300,450 and 600 mg/kg) in male rats has been reported earlier. The combination of AMP and SASP is generally used in certain pathological conditions, but the combined effect of these two drugs on the fertility is not clear. So, the aim of this study was to investigate the antifertility effect of ampicillin and sulphasalazine combination in male rats. METHODS: In the present study, forty rats were randomly divided into five groups (n=8). Group I served as the control, while Group II and III received AMP and SASP at the doses of 20 mg/kg and 200 mg/kg respectively. Moreover, group IV and V received the combination of SASP (100 mg/kg) and AMP (10 mg/kg). However, for evaluating the reversible effect of the combination, a washout period of 30 days was given in group V. After 45 days of drug treatment, each rat was sacrificed. The testes, seminal vesicles and epididymis were dissected & weighed. Furthermore, fertility tests, sperm characteristic analysis, histopathological studies, testosterone assay and tissue biochemistry were performed. The data were analyzed using ANOVA and in case ANOVA shows statistical differences, post hoc analysis was performed. RESULTS: A decrease in parameters related to fertility of males such as sperm count, sperm motility, fertility ratio, serum testosterone level, glycogen and protein content in sexual organs was observed. Although AMP and SASP significantly (p<0.001) reduced the reproductive activity separately, but their combination was found to be impairing the reproductive activity at a considerably lower dose. However, on withdrawing the treatment, all these parameters were restored which was confirmed by the histopathological analysis of the testis. CONCLUSION: The combination produces synergistic antifertility effect in male rats and the effect was reversible. The dose and efficacy of results could be extrapolated in future clinical trials. PMID- 24163797 TI - Reproductive outcome following thawed embryo transfer in management of ovarian hyperstimulation syndrome. AB - BACKGROUND: The purpose of the study was to compare clinical pregnancy and delivery rates with fresh and frozen embryo transfer in patients admitted to Shiraz- Human Assisted Reproductive Center with ovarian hyperstimulation syndrome (OHSS). METHODS: OHSS patients randomly divided in two groups, group A (n=50) with fresh embryo transfer and group B (n=50) with frozen embryo transfer. We used vitrification method for freezing the embryos. Patient age, combination of female and male factors, total number of retrieved oocytes, number of cryopreserved embryo, number of transferred embryos, clinical pregnancy and delivery rates were recorded for all patients. All statistical calculations were done using SPSS software. Generalized linear model was used to adjust the confounding factors to compare the clinical pregnancy and delivery rates between two groups. The p<0.05 was considered statistically significant. RESULTS: Mean (+/-SD) ages of these patients were 26.78+/-3.5 and 28.42+/-4.2 yrs in fresh (A) and frozen (B) embryo transfer groups respectively. Combinations of male and female factors were 28.3% and 32.1% respectively. Average numbers of oocytes retrieved in two groups were 22.14+/-4.3 and 21.02+/-4.9, and after fertilization, embryos cryopreserved per patient yielded averages of 13.82+/-3.5 and 12.5+/-4.3. Thaw and ET were performed and the means for transferred embryos were 3.22+/-0.6 and 4.1+/-0.7. We didn't find any significant differences in implicit parameters between the two groups. The pregnancy and delivery rates in OHSS patients were significantly higher in frozen embryo transfer, 63.1% and 45.6%, compared with fresh embryo transfer, 55.1% and 35.4%, respectively. CONCLUSION: The pregnancy and delivery rates in OHSS cases, both fresh and subsequently with frozen embryo transfer, were exceptionally high. There was statistically significant difference of pregnancy and delivery rates between fresh and frozen embryo transfer. As a result, an elective embryo freezing policy to moderate the severity and duration of OHSS has compromising outcomes for women at risk of OHSS. PMID- 24163798 TI - Comparison of Letrozole and Clomiphene Citrate Efficacy along with Gonadotrophins in Controlled Ovarian Hyperstimulation for Intrauterine Insemination Cycles. AB - BACKGROUND: We performed this study to investigate and compare the effects of Letrozole and gonadotrophins versus Clomiphene Citrate and gonadotrophins in women undergoing superovulation for Intrauterine Insemination (IUI). METHODS: We performed this prospective cohort study at Australian Concept and Fertility centre, Karachi Pakistan. Women younger than 40 years of age with patent fallopian tubes and infertility of more than 2 years in duration who were undergoing IUI and gonadotrophins therapy were divided into two groups, one received Letro-zole for 5 days and another received Clomiphene Citrate for 5 days. RESULTS: All 500 IUI treatment cycles conducted from March 2008 to March 2010 were included. Patients co-treated with Letrozole required fewer gonadotrophins administrations (median difference, 300 IU (95% confidence interval (CI), 225-375 IU), developed more follicles larger than 14 mm (median difference, 1 follicle, 95% CI, 1-2 follicles), and had a thicker endometrium (median difference, 1 mm, 95% CI, 0.4-1.6 mm). The pregnancy rate was not significantly different between two groups (11% vs. 12.6%). CONCLUSION: The addition of Letrozole to gonadotrophins decreases gonadotrophins requirements and improves endometrial thickness, without a significant effect on pregnancy rates. An improved pregnancy rate has been observed in older age group, >35 years with Letrozole. PMID- 24163799 TI - The Role of Psychological Adjustment in the Decision-making Process for Voluntary Termination of Pregnancy. AB - BACKGROUND: This study's objective was to evaluate the role of psychological adjustment in the decision-making process to have an abortion and explore individual variables that might influence this decision. METHODS: In this cross sectional study, we sequentially enrolled 150 women who made the decision to voluntarily terminate a pregnancy in Maternity Dr. Alfredo da Costa, in Lisbon, Portugal, between September 2008 and June 2009. The instruments were the Depression, Anxiety and Stress Scale (DASS), Satisfaction with Social Support Scale (SSSS), Emotional Assessment Scale (EAS), Decision Conflict Scale (DCS), and Beliefs and Values Questionnaire (BVQ). We analyzed the data using Student's T-tests, MANOVA, ANOVA, Tukey's post-hoc tests and CATPCA. Statistically significant effects were accepted for p<0.05. RESULTS: The participants found the decision difficult and emotionally demanding, although they also identified it as a low conflict decision. The prevailing emotions were sadness, fear and stress; but despite these feelings, the participants remained psychologically adjusted in the moment they decided to have an abortion. The resolution to terminate the pregnancy was essentially shared with supportive people and it was mostly motivated by socio-economic issues. The different beliefs and values found in this sample, and their possible associations are discussed. CONCLUSION: Despite high levels of stress, the women were psychologically adjusted at the time of making the decision to terminate the pregnancy. However, opposing what has been previously reported, the women presented high levels of sadness and fear, showing that this decision was hard to make, triggering disruptive emotions. PMID- 24163800 TI - Successful Prognosis of Brain Abscess during Pregnancy. AB - INTRODUCTION: Brain abscess in pregnancy is very rare, which mostly progresses to neurological abnormalities. CASE PRESENTATION: The patient is a 24-year-old pregnant woman. She was referred to Saitama hospital due to severe headache and nausea on October 2008. Brain MRI detected a 1.5 cm abscess mass with extensive edema in the right frontal lobe. We performed intensive therapy using some antibiotics that included cefotaxime and meropenem and depressants for intracranial pressure for six weeks. There was a good prognosis for the woman and her fetus without any sign of neurological abnormalities. CONCLUSION: Early medical intervention is required before it is too late for brain abscess in pregnancy. PMID- 24163801 TI - Intrinsic bio-signature of gene delivery nanocarriers may impair gene therapy goals. AB - Non-viral lipid/polymeric vectors have widely been used as nanocarriers (NCs) for gene delivery. They possess large surface area to volume ratio and are able to interact with biomolecules through functional moieties, resulting in inadvertent biological impacts, in particular at genomic level. Thus, their genomic bio signature needs to be investigated prior to use in vivo. Using high-throughput microarray and qPCR gene expression profiling techniques, we have reported the genomic impacts of lipid/polymeric NCs. Given the fact that the ultimate objectives of gene therapy may inevitably be impaired by nonspecific intrinsic genomic impacts of these NCs, here, we highlight their nonspecific genomic bio signature. We envision that better understanding on the genotoxicity of gene delivery NCs, as guiding premise, will help us to develop much safer NCs and also to accelerate their translation into clinical use and to provide pivotal information on safety liabilities early in discovery and developments process prior to its inevitable consequences in vivo. PMID- 24163802 TI - [Not Available]. AB - Plant mediated nanoparticles' synthesis has led to a remarkable progress via unfolding a green synthesis protocol towards nanoparticles' synthesis. It seems to have drawn quite an unequivocal attention with a view of reformulating the novel strategies as alternatives for popular conventional methods. Hence, the present review summarizes the literature reported thus far and envisions towards plants as emerging sources of nanofactories. PMID- 24163803 TI - Correlation between Cholinesterase and Paraoxonase 1 Activities:Case Series of Pesticide Poisoning Subjects. AB - INTRODUCTION: Acute exposure to pesticide due to suicidal poisoning is the most extensive cause of pesticide exposure, compared with all other causes including agricultural or industrial exposure. Organophosphate (OP) and carbamate group of pesticides can inhibit acetylcholinesterase; on the other hand, paraoxonase1 can detoxify organophosphate poisoning by hydrolyzing organophosphate metabolites. METHODS: We have compared the serum paraoxonase1 status and cholinesterase activity of subjects who attempted to commit suicide by consuming OP pesticide. Cholinesterase and paraoxonase1 activity were measured spectrophotometrically using butyrylthiocholine and phenyl acetate as substrates, respectively. RESULTS: A positive correlation was found between serum paraoxonase1 activity and cholinesterase activity among pesticide consumed subjects. CONCLUSION: Our results suggest that subjects with higher paraoxonase1 activity may have a better chance of detoxifying the lethal effect of acute organophosphate poisoning. PMID- 24163804 TI - Diagnostic and Prognostic Value of Serum Albumin for Tuberculosis in HIV Infected Patients Eligible for Antiretroviral Therapy: Datafrom an HIV Cohort Study in India. AB - INTRODUCTION: Tuberculosis is difficult to diagnose and it is the leading cause of death in HIV infected individuals in developing countries. There is an urgent need of low-cost diagnostic markers for resource-limited settings. METHODS: The study involved 1571 patients from an HIV cohort study in India with known serum albumin concentrations at the time of becoming eligible for antiretroviral therapy (ART). We investigated the diagnostic accuracy of serum albumin to predict tuberculosis within six months of ART eligibility and the prognostic value in patients who experienced tuberculosis. RESULTS: The diagnostic accuracy of serum albumin, measured by the area under the receiver operating characteristic curve, to predict tuberculosis was 0.81 (95% confidence interval 0.78-0.83). Serum albumin concentrations <3.2 g/dL were associated with 85% specificity and <4.1 g/dL were associated with negative predictive values >90%, even in settings with high tuberculosis prevalence. Hypoalbuminemia was associated with an increased risk of mortality in patients with tuberculosis. CONCLUSION: Serum albumin can be a useful low-cost diagnostic marker for tuberculosis in HIV infected patients eligible for ART. However, we failed to find thresholds to rule out or rule in tuberculosis. If these results are confirmed by other studies, serum albumin could be used to improve the diagnostic accuracy of intensive case finding algorithms for HIV-related tuberculosis. In patients who experience tuberculosis, hypoalbuminemia is associated with poor prognosis. PMID- 24163805 TI - Isolation and Molecular Identification of Streptomyces spp. with Antibacterial Activity from Northwest of Iran. AB - INTRODUCTION: Streptomyces are a group of prokaryotes that are usually found in all types of ecosystems including water and soil. This group of bacteria is noteworthy as antibiotic producers; so the isolation and characterization of new species seemed to be crucial in introduction of markedly favorable antibiotics. Therefore, in this study we aim to isolate and characterize novel strains of Streptomyces with high antibiotic production capability. METHODS: To achieve this goal, from 140 isolates collected throughout northwest of Iran, 12 selected Streptomyces isolates which exhibited high antibacterial activity against pathogenic bacteria were subjected to PCR reaction for identification via 16S rDNA gene and random amplified polymorphic DNA (RAPD) pattern analysis. RESULTS: Analysis of morphological and biochemical characteristics and the 16S rDNA gene sequence indicated that all 12 selected isolates belonged to the genus Streptomyces. Moreover, screening of the isolates with regard to their antimicrobial activity against indicator bacteria as well as their classification using RAPD analysis revealed that G614C1 and K36C5 isolates have considerable antimicrobial activity and high similarity to Streptomyces coelicolor and Sreptomyces albogriseolus, respectively. CONCLUSION: Since many isolates in this study showed inhibitory effects against pathogenic bacteria, soil of northwest of Iran could be used as a rich source to be explored for novel Streptomyces strains with high potency of antibiotic production. PMID- 24163806 TI - Genotyping of Human Papillomavirus and TP53 Mutaions at Exons 5 to 7 in Lung Cancer Patients from Iran. AB - INTRODUCTION: There is a powerful relationship between high-risk human papillomaviruses and lung cancer. In fact, inactivation of p53 is the most common genetic abnormality in lung cancer. Indeed, the frequency of HPV types and TP53 mutations in squamous cell carcinoma of lung, among patients from the northwest of Iran has been evaluated in this article. Methodes: Fifty Paraffin embedded blocks of lung SCC were selected for detection of HPV DNA by Nested PCR, and then DNA was sequenced for HPV typing. Equal numbers of positive and negative samples for the HPV DNA were examined for the presence of mutations in exons 5-7 of the TP53 gene by PCR and direct sequencing. RESULTS: Overtly 9 (18%) of 50 samples presented the HPV DNA: eight were HPV-18 and one was HPV-6. TP53 mutations were found in 5 samples (27.7%). Of these, 4 cases showed mutations in exon 5 and one case contained a mutation in exon 7.The most frequent mutation in exon 5 was the C to G transversion (c.409C>G), and also the T to A tansversion (c.770T>A) in exon 7. CONCLUSION: This study showed that HPV-18 is more likely to conscequence in the development of lung cancer among some communities. Genetic alterations, alongside with environmental factors, all play a significant role in the pathogenesis of lung cancer. PMID- 24163807 TI - Virtual screening and pharmacophore design for a novel theoretical inhibitor of macrophage stimulating factor as a metastatic agent. AB - INTRODUCTION: Metastasis is a crucial aspect of cancer. Macrophage stimulating protein (MSP) is a single chain protein and can be cleaved by serum proteases. MSP has several roles in metastasis. In this in silico study, MSP as a metastatic agent was considered as a drug target. METHODS: Crystallographic structure of MSP was retrieved from protein data bank. To find a chemical inhibitor of MSP, a library of KEGG compounds was screened and 1000 shape complemented ligands were retrieved with FindSite algorithm. Molegro Virtual Docker (MVD) software was used for docking simulation of shape complemented ligands against MSP. Moldock score was used as scoring function for virtual screening and potential inhibitors with more negative binding energy were obtained. PLANS scoring function was used for revaluation of virtual screening data. RESULTS: The top found chemical had binding affinity of -183.55 based on MolDock score and equal to -66.733 PLANTs score to MSP structure. CONCLUSION: Based on pharmacophore model of potential inhibitor, this study suggests that the chemical which was found in this research and its derivate can be used for subsequent laboratory studies. PMID- 24163808 TI - In-vitro evaluation of an experimental method for bonding of orthodontic brackets with self-adhesive resin cements. AB - BACKGROUND: Self-adhesive resin cements do not require the surface treatment of teeth and are said to release fluoride, which makes them suitable candidates for bonding of orthodontic brackets. The objectives of this study was to investigate the shear bond strength (SBS) of self-adhesive resin cements on etched on non etched surfaces in vitro and to assess their fluoride release features. MATERIALS AND METHODS: Four fluoride-releasing dual-cure self-adhesive resin cements were investigated. For SBS experiment, 135 freshly extracted human maxillary premolars were used and divided into nine groups of 15 teeth. In the control group, brackets were cemented by Transbond XT (3M Unitek, USA), in four groups self adhesive resin cements were used without acid-etching and in four groups self adhesive cements were applied on acid-etched surfaces and the brackets were then deboned in shear with a testing machine. Adhesive remnant index (ARI) scores were also calculated. For fluoride release investigation, 6 discs were prepared for each self-adhesive cement. Transbond XT and Fuji Ortho LC (GC, Japan) served as negative and positive control groups, respectively. The fluoride release of each disc into 5 ml of deionized water was measured at days 1, 2, 3, 7, 14, 28, and 56 using a fluoride ion-selective electrode connected to an ion analyzer. To prevent cumulative measurements, the storage solutions were changed daily. RESULTS: The SBS of brackets cemented with Transbond XT were significantly higher compared to self-adhesives applied on non-etched surfaces (P<0.001). However, when the self adhesive resin cements were used with enamel etching, no significant differences was found in the SBS compared to Transbond XT, except for Breeze. The comparisons of the ARI scores indicated that bracket failure modes were significantly different between the etched and non-etched groups. All self-adhesive cements released clinically sufficient amounts of fluoride for an extended period of time. CONCLUSION: For the tested cements, the strongest bonds were obtained by enamel acid-etching prior to bracket bonding. All the self-adhesive resin cements had significant long-term fluoride release and could be recommended as suitable fluoride-releasing orthodontic bonding materials. PMID- 24163809 TI - Immune parameters in the prognosis and therapy monitoring of cutaneous melanoma patients: experience, role, and limitations. AB - Cutaneous melanoma is an immune-dependent aggressive tumour. Up to our knowledge, there are no reports regarding immune parameters monitoring in longitudinal followup of melanoma patients. We report a followup for 36 months of the immune parameters of patients diagnosed in stages I-IV. The circulatory immune parameters comprised presurgery and postsurgery immune circulating peripheral cells and circulating intercommunicating cytokines. Based on our analysis, the prototype of the intratumor inflammatory infiltrate in a melanoma with good prognosis is composed of numerous T cells CD3+, few or even absent B cells CD20+, few or absent plasma cells CD138+, and present Langerhans cells CD1a+ or langerin+. Regarding circulatory immune cells, a marker that correlates with stage is CD4+/CD8+ ratio, and its decrease clearly indicates a worse prognosis of the disease. Moreover, even in advanced stages, patients that have an increased overall survival rate prove the increase of this ratio. The decrease in the circulating B lymphocytes with stage is balanced by an increase in circulating NK cells, a phenomenon observed in stage III. Out of all the tested cytokines in the followup, IL-6 level correlated with the patient's survival, while in our study, IL-8, IL-10, and IL-12 did not correlate statistically in a significant way with overall survival, or relapse-free survival. PMID- 24163810 TI - Participation of GABAA chloride channels in the anxiolytic-like effects of a fatty acid mixture. AB - Human amniotic fluid and a mixture of eight fatty acids (FAT-M) identified in this maternal fluid (C12:0, lauric acid, 0.9 MU g%; C14:0, myristic acid, 6.9 MU g%; C16:0, palmitic acid, 35.3 MU g%; C16:1, palmitoleic acid, 16.4 MU g%; C18:0, stearic acid, 8.5 MU g%; C18:1 cis, oleic acid, 18.4 MU g%; C18:1 trans, elaidic acid, 3.5 MU g%; C18:2, linoleic acid, 10.1 MU g%) produce anxiolytic-like effects that are comparable to diazepam in Wistar rats, suggesting the involvement of gamma -aminobutyric acid-A (GABA(A)) receptors, a possibility not yet explored. Wistar rats were subjected to the defensive burying test, elevated plus maze, and open field test. In different groups, three GABA(A) receptor antagonists were administered 30 min before FAT-M administration, including the competitive GABA binding antagonist bicuculline (1 mg/kg), GABA(A) benzodiazepine antagonist flumazenil (5 mg/kg), and noncompetitive GABA(A) chloride channel antagonist picrotoxin (1 mg/kg). The FAT-M exerted anxiolytic-like effects in the defensive burying test and elevated plus maze, without affecting locomotor activity in the open field test. The GABA(A) antagonists alone did not produce significant changes in the behavioral tests. Picrotoxin but not bicuculline or flumazenil blocked the anxiolytic-like effect of the FAT-M. Based on the specific blocking action of picrotoxin on the effects of the FAT-M, we conclude that the FAT-M exerted its anxiolytic-like effects through GABA(A) receptor chloride channels. PMID- 24163811 TI - Pre- and postsynaptic dopamine SPECT in idiopathic Parkinsonian diseases: a follow-up study. AB - We prospectively evaluated the diagnostic contribution of (123)I-FP-Cit (DAT) and (123)I-IBZM (IBZM) SPECT in 29 patients with Parkinson's disease (PD) (74.4 +/- 4.2 years) and 28 patients with atypical parkinsonian diseases (APD) (74.3 +/- 9.2 years). Twelve had multiple system atrophy (MSA) and 16 progressive supranuclear palsy (PSP). Sixteen age-matched healthy controls (HC) were included. DAT and IBZM SPECTs were made at baseline and after 1 year in all PD patients and in 20 (DAT) and 18 (IBZM) of the APD patients, and after 3 years in 22 (DAT) and 17 (IBZM) of the PD patients and in 10 (DAT) and 10 (IBZM) of the APD patients. The relative DAT uptake decrease was faster in PD and PSP than in HC and MSA. In PSP the DAT uptake was lower than in MSA after 1 year but not after 3 years. Baseline IBZM uptake was not significantly different between patients and HC or between PD and APD. One year after initiated dopaminergic treatment the mean IBZM uptake in the MSA patients remained high compared to PSP and after 3 years compared to PD, PSP, and HC. Thus, the pattern of uptake of these ligands over time may be of value in discriminating between these diagnoses. PMID- 24163812 TI - Videocapillaroscopic alterations in alopecia areata. AB - Alopecia areata (AA) is a common hair disorder observed in dermatological practice; however, the exact mechanisms that lead to the hair loss are still unknown. Disturbances in the blood supply of hair follicles may be one of the elements in the complex pathogenesis of AA. Nailfold videocapillaroscopy is a noninvasive technique that allows analysis of skin microcirculation in vivo. The aim of the study was the videocapillaroscopic assessment of skin microcirculation in AA patients. The study included 44 patients with patchy alopecia areata, 27 with alopecia universalis or totalis, and 40 healthy volunteers. Nailfold videocapillaroscopy was performed in all participants according to a standard protocol. Obtained images were assessed qualitatively and quantitatively. Two types of videocapillaroscopic images were distinguished in the study. Abnormal videocapillaroscopic images were found in 42% of patients. Tortuous and branching capillaries (P = 0.013, P = 0.001), decreased density of capillaries (P = 0.009), enlargement of the efferent limb (P < 0.017), or top part of the loop (P = 0.009) were observed significantly more often than in the control group. Only some patients with AA presented with microvascular abnormalities characterised by altered videocapillaroscopic images. More studies, including larger group of patients with AA, are required to determine the role of observed videocapillaroscopic alterations in AA. PMID- 24163813 TI - Evaluation of stream mining classifiers for real-time clinical decision support system: a case study of blood glucose prediction in diabetes therapy. AB - Earlier on, a conceptual design on the real-time clinical decision support system (rt-CDSS) with data stream mining was proposed and published. The new system is introduced that can analyze medical data streams and can make real-time prediction. This system is based on a stream mining algorithm called VFDT. The VFDT is extended with the capability of using pointers to allow the decision tree to remember the mapping relationship between leaf nodes and the history records. In this paper, which is a sequel to the rt-CDSS design, several popular machine learning algorithms are investigated for their suitability to be a candidate in the implementation of classifier at the rt-CDSS. A classifier essentially needs to accurately map the events inputted to the system into one of the several predefined classes of assessments, such that the rt-CDSS can follow up with the prescribed remedies being recommended to the clinicians. For a real-time system like rt-CDSS, the major technological challenges lie in the capability of the classifier to process, analyze and classify the dynamic input data, quickly and upmost reliably. An experimental comparison is conducted. This paper contributes to the insight of choosing and embedding a stream mining classifier into rt-CDSS with a case study of diabetes therapy. PMID- 24163814 TI - Age-related changes in trabecular meshwork imaging. AB - PURPOSE: To evaluate the normal aging effects on trabecular meshwork (TM) parameters using Fourier domain anterior segment optical coherence tomography (ASOCT) images. PATIENTS AND METHODS: One eye from 45 participants with open angles was imaged. Two independent readers measured TM area, TM length, and area and length of the TM interface shadow from 3 age groups (18-40, 41-60, and 61 80). Measurements were compared using stepwise regression analysis. RESULTS: The average TM parameters were 0.0487 (+/- 0.0092) mm(2) for TM area, 0.5502 (+/- 0.1033) mm for TM length, 0.1623 (+/- 0.341) mm(2) for TM interface shadow area, and 0.7755 (+/- 0.1574) mm for TM interface shadow length. Interobserver reproducibility coefficients ranged from 0.45 (TM length) to 0.82 (TM area). TM area and length were not correlated with age. While the TM interface shadow length did not correlate with age, the TM interface shadow area increased with age. Race, sex, intraocular pressure, and gonioscopy score were not correlated with any TM parameters. CONCLUSION: Although the TM measurements were not correlated with age, the TM interface shadow area increased with age. Further study is required to determine whether there is any relationship between the age related ASOCT findings of the TM interface shadow area and physiologic function. PMID- 24163815 TI - Early continence recovery after preservation of maximal urethral length until the level of verumontanum during radical prostatectomy: primary oncological and functional outcomes after 1 year of follow-up. AB - PURPOSE: To investigate the effect of preventing maximal urethral length until the level of verumontanum during radical prostatectomy on both oncologic and functional outcomes. PATIENTS AND METHODS: We recruited 329 patients, and they underwent an open radical prostatectomy by a single surgeon. The study cohort was randomized in 2 groups. A standard radical prostatectomy was performed in group A patients, while in group B the urethra was preserved until the level of verumontanum. RESULTS: There was no statistically significant difference between the study groups in terms of positive surgical margins or biochemical relapse. Regarding the functional results, the incidence of incontinence, urgency, and nocturia at 1st month, statistically significant higher rates were seen in group A. In addition, there was a statistically significant difference in the number of pads/day in favor of group B at the 1st, 3rd, and 6th months after surgery. However, this difference was eliminated at 12 months postoperatively. Similar results were seen with the scores of the ICIQ-SF and IIQ-SF questionnaires. CONCLUSIONS: Without compromising the oncological outcome, our surgical modificated technique showed earlier recovery of continence in the first 6 months, having though the same rates of continence at 12 months. PMID- 24163816 TI - Biomimetic mineralization on a macroporous cellulose-based matrix for bone regeneration. AB - The aim of this study is to investigate the biomimetic mineralization on a cellulose-based porous matrix with an improved biological profile. The cellulose matrix was precalcified using three methods: (i) cellulose samples were treated with a solution of calcium chloride and diammonium hydrogen phosphate; (ii) the carboxymethylated cellulose matrix was stored in a saturated calcium hydroxide solution; (iii) the cellulose matrix was mixed with a calcium silicate solution in order to introduce silanol groups and to combine them with calcium ions. All the methods resulted in a mineralization of the cellulose surfaces after immersion in a simulated body fluid solution. Over a period of 14 days, the matrix was completely covered with hydroxyapatite crystals. Hydroxyapatite formation depended on functional groups on the matrix surface as well as on the precalcification method. The largest hydroxyapatite crystals were obtained on the carboxymethylated cellulose matrix treated with calcium hydroxide solution. The porous cellulose matrix was not cytotoxic, allowing the adhesion and proliferation of human osteoblastic cells. Comparatively, improved cell adhesion and growth rate were achieved on the mineralized cellulose matrices. PMID- 24163817 TI - The usefulness of 3-dimensional virtual simulation using haptics in training orotracheal intubation. AB - OBJECTIVES: Airway control is the most critical treatment. The most common and basic method of endotracheal intubation is orotracheal intubation. To perform accurate and rapid tracheal intubation, appropriate education and training are required. We developed the virtual simulation program utilizing the 3-dimensional display and haptic device to exercise orotracheal intubation, and the educational effect of this program was compared with that of the mannequin method. METHOD: The control group used airway mannequin and virtual intubation group was trained with new program. We videotaped both groups during objective structured clinical examination (OSCE) with airway mannequin. The video was reviewed and scored, and the rate of success and time were calculated. RESULT: The success rate was 78.6% in virtual intubation group and 93.3% in control group (P = 0.273). There was no difference in overall score of OSCE (21.14 +/- 4.28 in virtual intubation group and 23.33 +/- 4.45 in control group, P = 0.188), the time spent in successful intubation (P = 0.432), and the number of trials (P > 0.101). CONCLUSION: The virtual simulation with haptics had a similar effect compared with mannequin, but it could be more cost effective and convenient than mannequin training in time and space. PMID- 24163818 TI - DNA damage and oxidative stress in human disease. PMID- 24163819 TI - A partial volume effect correction tailored for 18F-FDG-PET oncological studies. AB - We have developed, optimized, and validated a method for partial volume effect (PVE) correction of oncological lesions in positron emission tomography (PET) clinical studies, based on recovery coefficients (RC) and on PET measurements of lesion-to-background ratio (L/B m) and of lesion metabolic volume. An operator independent technique, based on an optimised threshold of the maximum lesion uptake, allows to define an isocontour around the lesion on PET images in order to measure both lesion radioactivity uptake and lesion metabolic volume. RC are experimentally derived from PET measurements of hot spheres in hot background, miming oncological lesions. RC were obtained as a function of PET measured sphere to-background ratio and PET measured sphere metabolic volume, both resulting from the threshold-isocontour technique. PVE correction of lesions of a diameter ranging from 10 mm to 40 mm and for measured L/B m from 2 to 30 was performed using measured RC curves tailored at answering the need to quantify a large variety of real oncological lesions by means of PET. Validation of the PVE correction method resulted to be accurate (>89%) in clinical realistic conditions for lesion diameter > 1 cm, recovering >76% of radioactivity for lesion diameter < 1 cm. Results from patient studies showed that the proposed PVE correction method is suitable and feasible and has an impact on a clinical environment. PMID- 24163820 TI - Evaluation of the presence of endocrine-disrupting compounds in dissolved and solid wastewater treatment plant samples of Gran Canaria Island (Spain). AB - Liquid and solid samples from two wastewater treatment plants (WWTPs) on Gran Canaria Island (Spain) have been tested for the presence of compounds with endocrine-disrupting properties. The selected degradation stages were sampled bimonthly from each WWTP over the 12-month period from July 2010 to July 2011. The analytical methods used for the determination of the endocrine-disrupting compounds (EDCs) were based on on-line solid phase extraction, microwave-assisted extraction (MAE), and ultrasonic-assisted extraction (UAE) coupled to UHPLC MS/MS. All of the hyphenated methodologies employed in this work showed good recoveries (72-104%) and sensitivities, with LODs lower than 7.0 ng L(-1) and 6.3 ng g(-1) for the dissolved and solid fractions, respectively. We have also evaluated the estrogenicity of the samples in terms of their estradiol equivalent concentrations (EEQs). The chemical analysis of the selected EDCs revealed fairly low concentrations for both natural and synthetic oestrogens, alkylphenolic compounds, and bisphenol-A in each of the dissolved, particulate, and sludge samples (ng L(-1) or ng g(-1)). However, the estimated estrogenic activity indicated that the majority of samples could represent an important environmental risk, clearly surpassing the threshold to exert deleterious consequences on living beings. PMID- 24163821 TI - Underestimating the toxicological challenges associated with the use of herbal medicinal products in developing countries. AB - Various reports suggest a high contemporaneous prevalence of herb-drug use in both developed and developing countries. The World Health Organisation indicates that 80% of the Asian and African populations rely on traditional medicine as the primary method for their health care needs. Since time immemorial and despite the beneficial and traditional roles of herbs in different communities, the toxicity and herb-drug interactions that emanate from this practice have led to severe adverse effects and fatalities. As a result of the perception that herbal medicinal products have low risk, consumers usually disregard any association between their use and any adverse reactions hence leading to underreporting of adverse reactions. This is particularly common in developing countries and has led to a paucity of scientific data regarding the toxicity and interactions of locally used traditional herbal medicine. Other factors like general lack of compositional and toxicological information of herbs and poor quality of adverse reaction case reports present hurdles which are highly underestimated by the population in the developing world. This review paper addresses these toxicological challenges and calls for natural health product regulations as well as for protocols and guidance documents on safety and toxicity testing of herbal medicinal products. PMID- 24163822 TI - Effect of the plasmid-DNA vaccination on macroscopic and microscopic damage caused by the experimental chronic Trypanosoma cruzi infection in the canine model. AB - The dog is considered the main domestic reservoir for Trypanosoma cruzi infection and a suitable experimental animal model to study the pathological changes during the course of Chagas disease (CD). Vaccine development is one of CD prevention methods to protect people at risk. Two plasmids containing genes encoding a trans sialidase protein (TcSP) and an amastigote-specific glycoprotein (TcSSP4) were used as DNA vaccines in a canine model. Splenomegaly was not found in either of the recombinant plasmid-immunized groups; however, cardiomegaly was absent in animals immunized only with the plasmid containing the TcSSP4 gene. The inflammation of subendocardial and myocardial tissues was prevented only with the immunization with TcSSP4 gene. In conclusion, the vaccination with these genes has a partial protective effect on the enlargement of splenic and cardiac tissues during the chronic CD and on microscopic hearth damage, since both plasmids prevented splenomegaly but only one avoided cardiomegaly, and the lesions in heart tissue of dog immunized with plasmid containing the TcSSP4 gene covered only subepicardial tissue. PMID- 24163823 TI - Catecholaminergic gene variants: contribution in ADHD and associated comorbid attributes in the eastern Indian probands. AB - Contribution of genes in attention deficit hyperactivity disorder (ADHD) has been explored in various populations, and several genes were speculated to contribute small but additive effects. We have assessed variants in four genes, DDC (rs3837091 and rs3735273), DRD2 (rs1800496, rs1801028, and rs1799732), DRD4 (rs4646984 and rs4646983), and COMT (rs165599 and rs740603) in Indian ADHD subjects with comorbid attributes. Cases were recruited following the Diagnostic and Statistical Manual for Mental Disorders-IV-TR after obtaining informed written consent. DNA isolated from peripheral blood leukocytes of ADHD probands (N = 170), their parents (N = 310), and ethnically matched controls (n = 180) was used for genotyping followed by population- and family-based analyses by the UNPHASED program. DRD4 sites showed significant difference in allelic frequencies by case-control analysis, while DDC and COMT exhibited bias in familial transmission (P < 0.05). rs3837091 "AGAG," rs3735273 "A," rs1799732 "C," rs740603 "G," rs165599 "G" and single repeat alleles of rs4646984/rs4646983 showed positive correlation with co-morbid characteristics (P < 0.05). Multi dimensionality reduction analysis of case-control data revealed significant interactive effects of all four genes (P < 0.001), while family-based data showed interaction between DDC and DRD2 (P = 0.04). This first study on these gene variants in Indo-Caucasoid ADHD probands and associated co-morbid conditions indicates altered dopaminergic neurotransmission in ADHD. PMID- 24163825 TI - Expression of Voltage-Gated Sodium Channel Nav1.8 in Human Prostate Cancer is Associated with High Histological Grade. AB - Voltage-gated sodium (Nav) channels are required for impulse conductance in excitable tissues. Navs have been linked to human cancers, including prostate. The expression and distribution of Nav isoforms (Nav1.1-Nav1.9) in human prostate cancer are not well established. Here, we evaluated the expression of these isoforms and investigated the expression of Nav1.8 in human prostate cancer tissues. Nav1.8 was highly expressed in all examined cells. Expression of Nav1.1, Nav1.2, and Nav1.9 were high in DU-145, PC-3 and PC-3M cells compared to LNCaP (hormone-dependent), C4-2, C4-2B, and CWR22Rv-1 cells. Nav1.5 and Nav1.6 were expressed in all cells examined. Nav1.7 expression was absent in PC-3M and CWR22Rv-1, but expressed in the other cells examined. Immunohistochemistry revealed intensive Nav1.8 staining correlated with more advanced pathologic stage of disease. Increased intensity of nuclear Nav1.8 correlated with increased Gleason grade. Our results revealed that Nav1.8 is universally expressed in human prostate cancer cells. Nav1.8 expression statistically correlated with pathologic stage (P=0.04) and Gleason score (P=0.01) of human prostate tissue specimens. The aberrant nuclear localization of Nav1.8 with advanced prostate cancer tissues warrant further investigation into use of Nav1.8 as a potential biomarker to differentiate between early and advanced disease. PMID- 24163824 TI - Lenalidomide and chronic lymphocytic leukemia. AB - Lenalidomide is an oral immunomodulatory drug used in multiple myeloma and myelodysplastic syndrome and most recently it has shown to be effective in the treatment of various lymphoproliferative disorders such as chronic lymphocytic leukemia (CLL) and non-Hodgkin lymphoma. The mechanism of action of lenalidomide varies depending on the pathology, and in the case of CLL, it appears to primarily act by restoring the damaged mechanisms of tumour immunosurveillance. This review discusses the potential mechanism of action and efficacy of lenalidomide, alone or in combination, in treatment of CLL and its toxic effects such as tumor lysis syndrome (TLS) and tumor flare reaction (TFR), that make its management different from other hematologic malignancies. PMID- 24163826 TI - Calcium Integrin Binding Protein Associates with Integrins alphaVbeta3 and alphaIIbbeta3 Independent of beta3 Activation Motifs. AB - The Calcium Integrin Binding protein (CIB) has been identified as interacting specifically with the cytoplasmic tail of the integrin alphaIIb domain to induce receptor activation and integrin alphaIIbbeta3 mediated cell adhesion to extracellular proteins. In K562 cells stably expressing mutated integrin alphaVbeta3, or chimeric alphaVbeta3 carrying alphaIIb cytoplasmic tail, we report that the interaction of CIB with beta3 integrins is not alphaIIbbeta3 specific but binds alphaIIb as well as alphaV cytoplasmic tail domains. A double mutation of two proline residues to alanine residues in the alphaIIb cytoplasmic domain, previously shown to disturb its conformation, inhibits chimeric alphaV/alphaIIbbeta3-CIB interaction. This demonstrates that alphaIIb cytoplasmic domain loop-like conformation is required for interaction with CIB. Moreover, mutations of beta3 cytoplasmic domain residues Tyr-747 and/or Tyr-759 to phenylalanine residues (Y747F, Y759F, and Y747,759F) as well as residues Ser-752 to proline or alanine (S752P and S752A), do not affect the alphaIIbbeta3 or alphaVbeta3 interaction with CIB. Since tyrosine residues Tyr-747 and/or Tyr-759 are the sites of tyrosine phosphorylation of beta3 subunit, these results suggest that the beta3 integrin-CIB interaction occurs through a beta3-phosphorylation independent mechanism. Likewise, ablation of conformation-dependent affinity change in beta3 Ser752Pro mutation had no affect on CIB-beta3 interaction. In summary, our results demonstrate that the alphaIIb-subunit integrin and CIB interaction is non-exclusive and requires the loop-like alphaIIb-cytoplasmic domain conformation. An interaction of CIB with alphaV-containing integrins provides an additional role for this molecule in keeping with its expression outside of platelets. PMID- 24163827 TI - Max Margin General Linear Modeling for Neuroimage Analyses. AB - General linear modeling (GLM) is one of the most commonly used approaches to perform voxel based analyses (VBA) for hypotheses testing in neuroimaging. In this paper we tie support vector machine based regression (SVR) and classical significance testing to provide the benefits of max margin estimation in the GLM setting. Using Welch-Satterthwaite approximations, we compute degrees of freedom (df) of error (also known as residual df) for epsilon-SVR. We demonstrate that epsilon-SVR can result not only in robustness of estimation but also improved residual df compared to the very commonly used ordinary least squares (OLS) estimation. This can result in higher sensitivity to signal in neuroimaging studies and also allow for better control of confounding effects of nuisance covariates. We demonstrate the application of our approach in white matter analyses using diffusion tensor imaging (DTI) data from autism and emotion regulation studies. PMID- 24163828 TI - Waiting for the evidence from ongoing trials: the role of surgery for treating clavicle fractures. PMID- 24163829 TI - Proceedings of the 4th European Meeting on Complement in Human Disease, August 17 21 2013, Jena, Germany. PMID- 24163830 TI - Reply to Frere: Covalent trapping and bacterial resistance to ceftazidime. PMID- 24163831 TI - Reversible light induced conductance switching of asymmetric diarylethenes on gold: surface and electronic studies. AB - We report on the light-induced switching of conductance of a new generation of diarylethene switches embedded in an insulating matrix of dodecanethiol on Au(111), by using scanning tunneling microscopy (STM). The diarylethene switches we synthesize and study are modified diarylethenes where the thiophene unit at one side of the molecular backbone introduces an intrinsic asymmetry into the switch, which is expected to influence its photo-conductance properties. We show that reversible conversion between two distinguishable conductance states can be controlled via photoisomerisation of the switches by using alternative irradiation with UV (lambda = 313 nm) or visible (lambda > 420 nm) light. We addressed this phenomenon by using STM in ambient conditions, based on switching of the apparent height of the molecules which convert from 4-6 A in their closed form to 0-1 A in their open form. Furthermore, the levels of the frontier molecular orbital levels (HOMO and LUMO) were evaluated for these asymmetric switches by using Scanning Tunneling Spectroscopy at 77 K, which allowed us to determine a HOMO-LUMO energy gap of 2.24 eV. PMID- 24163832 TI - Proceedings of the Seventh International Symposium on Inorganic Carbon Utilization by Aquatic Photosynthetic Organisms. August 29-September 2, 2010, Awaji City, Japan. PMID- 24163833 TI - Abstracts Presented at the 16th Joint Meeting of the International Society of Dermatopathology, February 27-28, 2013,Miami, Florida. PMID- 24163834 TI - Neuroscience. Will brain stimulation technology lead to "neuroenhancement"? PMID- 24163835 TI - Science and society. Experts warn against bans on 3D printing. PMID- 24163836 TI - Mechanical circulatory support: the Berlin Heart goes on and on . . . PMID- 24163837 TI - Coffee preparation: does it affect our health? PMID- 24163839 TI - Retraction. The effect of early and intensive statin therapy on ventricular premature beat or nonsustained ventricular tachycardia in patients with acute coronary syndrome. PMID- 24163840 TI - [Current status of preventing disease with vaccine]. PMID- 24163842 TI - [Current status of treatment for Meniere disease]. PMID- 24163841 TI - [Sleep-disordered breathing in children]. PMID- 24163844 TI - [Voice rehabilitation with voice prosthesis following laryngectomy]. PMID- 24163843 TI - [Diagnosis and treatment for migrainous related dizziness]. PMID- 24163845 TI - [Temporal bone imaging-Pathology of "Leave me alone" lesion and petrous apex]. PMID- 24163846 TI - [Robotic surgery of digestive system]. PMID- 24163847 TI - [Otorhinolaryngology and emergency treatment]. PMID- 24163848 TI - [Classification of middle ear cholesteatoma]. PMID- 24163849 TI - [Laryngeal surgery-vocal cord polyp and anaesthesia]. PMID- 24163850 TI - [Tips of measurement for vestibular evoked myogenic potential]. PMID- 24163851 TI - [Indication of endoscopic endonasal orbitotomy for orbital lesion]. PMID- 24163852 TI - [Current status and future perspective for immunotherapy in head and neck cancer patients]. PMID- 24163853 TI - [GRBAS scale]. PMID- 24163854 TI - [Treatment of middle ear disease associated MPO-ANCA]. PMID- 24163855 TI - [Diagnosis and treatment of laryngopharynx cancer]. PMID- 24163856 TI - [Indication and point of attention of pediatric tracheotomy]. PMID- 24163858 TI - [Vocal cord paralysis caused by central nerve disorder]. PMID- 24163857 TI - [Current status of hyposensitization therapy for allergic rhinitis]. PMID- 24163859 TI - [Computation caused by tooth implant]. PMID- 24163861 TI - Orbital dystopia due to orbital roof defect. AB - We performed a retrospective review of patients who presented with delayed dystopia as a consequence of an orbital roof defect due to fractures and nontraumatic causes to search for a correlation between orbital roof defect size and surgical indications for the treatment thereof. Retrospective analyses were performed in 7 patients, all of whom presented with delayed dystopia due to orbital roof defects, between January 2001 and June 2011. The causes of orbital roof defects were displaced orbital roof fractures (5 cases), tumor (1 case), and congenital sphenoid dysplasia (1 case). All 7 patients had initially been treated conservatively and later presented with significant dystopia. The sizes of the defects were calculated on computed tomographic scans. Among the 7 patients, aspiration of cerebrospinal fluid, which caused ocular symptoms, in 1 patient with minimal displaced orbital roof and reconstruction with calvarial bone, titanium micromesh, or Medpor in 6 other patients were performed. The minimal size of the orbital roof in patients who underwent orbital roof reconstruction was 1.2 cm (defect height) x 1.0 cm (defect length), 0.94 cm(2). For all patients with orbital dystopia, displacement of the globe was corrected without any complications, regardless of whether the patient was evaluated grossly or by radiology. In this retrospective study, continuous monitoring of clinical signs and active surgical management should be considered for cases in which an orbital roof defect is detected, even if no definite symptoms are noted, to prevent delayed sequelae. PMID- 24163860 TI - Novel management of intractable chylous fistula with the application of an impression paste. AB - Chylous fistula is a kind of complication during neck dissection that rarely happens, but might lead to some serious clinical outcome. The standard treatments include local compressive bandaging, negative pressure drainage, ligation of the fistula orifice, alimentary control, and, occasionally, the use of somatostatin. Among them, the simplest is compressive bandaging, but the bandage can easily become loosened and cannot achieve the necessary pressure effect. In this paper, the novel application of an impression paste, which is normally used in prosthodontic treatments, will be introduced. It might be a very practical method for the treatment of these surgical complications in hospitals where advanced treatment modalities are not available. PMID- 24163862 TI - Recurrent adult-type rhabdomyoma: a rare differential diagnosis of "swellings in the masticatory muscle". AB - Rhabdomyomas are rare benign mesenchymal tumors with skeletal muscle differentiation and a predilection for the head and neck area. A 38-year-old man presented with persistent, slowly growing, painless swelling in the left inner cheek for 21/2 years. The lesion was detected during routine dental examination and was considered to represent a mucocele. The mass was removed via a transoral surgical approach, followed by a local recurrence 6 months later that was again surgically removed. The patient is alive and well 2 months after last surgery. Adult-type rhabdomyoma is a rare, occasionally recurring, benign mesenchymal tumor that should be included in the differential diagnosis of submucosal swellings in the oral cavity including the masticatory musculature. Adult-type rhabdomyoma of the cheek and masticatory area are exceptionally rare with no more than 3 cases reported to date. PMID- 24163863 TI - Pediatric lipoblastoma of the neck. AB - BACKGROUND: Lipoblastoma is a rare, benign, and encapsulated tumor arising from embryonic white fat. Most of the cases occur in the extremities and the trunk; only a few cases in the head and the neck are reported. Thus, we present a case of lipoblastoma of the neck with a review of the literature. PATIENT AND METHOD: A 1-year-old male infant presented to our hospital, with a history of painless swelling in the left side of the neck for 3 months that was rapidly enlarged. His birth history and medical history were unremarkable. A physical examination demonstrated a soft and compressible mass in the left side of the neck. The mass was nontender to palpation and mobile without cellulitic changes in the overlying skin. A computed tomographic scan showed that the mass is heterogenous, has low attenuation in nature, and is 3.8 * 2.8 * 9 cm in size. RESULT: Under general anesthesia, transverse cervical incision was made through the neck wrinkle, and there was no invasion of any of the neck structures. Complete surgical excision demonstrated yellowish-white, irregular lobules of immature fat cells separated by a loose and myxoid connective tissue. Grossly, the mass was a homogeneous tan pink gelatinous mass. A microscopic examination demonstrated a small number of capillaries and mature fat cells, and differentiating immature lipoblastoma cells were detected in the myxoid stroma. A pathologic finding confirmed the diagnosis of lipoblastoma. The postoperative course was uneventful. The patient underwent follow-up for 1 year after the operation, and there was no evidence of recurrence. CONCLUSIONS: The most common presentation of lipoblastoma is a painless, rapidly enlarging neck mass. Published reports showed that most of them occur before the age of 3 years. Complete surgical excision is the treatment of choice. Although lipoblastoma is an extremely rare benign tumor, it should be considered in the diagnosis of neck mass in children younger than 3 years. PMID- 24163864 TI - Dislocation of temporomandibular joint: complication of sagittal split ramus osteotomy. AB - Sagittal split ramus osteotomy (SSRO) has wide-ranging indications and results in simultaneous improvements in occlusion and facial appearance. Thus, it is the most frequently used osteotomy for jaw deformities. Its main intraoperative and postoperative complications are massive bleeding, atypical fractures, inferior alveolar nerve paralysis, and relapse. This report describes a case of temporomandibular joint dislocation, a rare complication of SSRO. The patient was a 23-year-old man with mandibular prognathism which was treated by bilateral SSRO. Postoperative x-ray showed that the left temporomandibular joint was dislocated anteriorly. Thus, the patient underwent reoperation, including reduction and re-fixation. Subsequently, it was discovered that the patient had a previous history of recurrent dislocation of the temporomandibular joint. This case illustrates the need for practitioners to be mindful of temporomandibular joint dislocation as a rare complication of SSRO. PMID- 24163865 TI - Pediatric frontal sinus fracture conservative care: complete remodeling with growth and development. AB - We report a case of an 11-year-old patient presenting with a displaced anterior table frontal sinus fracture, resulting in a contour deformity. Fractures of the anterior table that result in contour irregularities may be an indication for operative management. The frontal sinus, however, continues to develop through late adolescence, and our patient's fracture remodeled completely within 1 year from injury, without operative management. This clinical report indicates that displaced anterior frontal sinus fractures in the skeletally immature have the potential to completely remodel with time, and therefore may be successfully managed non-operatively. PMID- 24163866 TI - Synchronous occurrence of odontogenic myxoma with multiple keratocystic odontogenic tumors in nevoid basal cell carcinoma syndrome. AB - The keratocystic odontogenic tumor (KCOT) is a benign developmental tumor with many distinguishing clinical and histologic features. Usually, multiple KCOTs occur as a component of nevoid basal cell carcinoma syndrome. The odontogenic myxoma is a rare benign tumor that represents about 3% of all odontogenic tumors. This article reports the case of mandible odontogenic myxoma with synchronous occurrence of multiple KCOTs, partial expression of nevoid basal cell carcinoma syndrome. A review of the international literature is also presented. PMID- 24163867 TI - Peripheral osteoma on the buccal aspect of mandible angle: a review of radiopaque masses and differential diagnosis. AB - Osteomas are radiopaque osteogenic tumors composed of slow-growing, painless, mature bone tissue. On the basis of their origin, they can be classified as central, peripheral, or extraskeletal. Osteomas occur primarily in the craniofacial region, and peripheral osteomas are most prevalent in the paranasal sinuses. We describe a rare case of peripheral osteoma on the buccal aspect of the left mandibular angle that caused facial deformity in a 68-year-old woman. We also discuss its differentiation from other similar radiologically radiopaque masses. PMID- 24163869 TI - Findings of research misconduct. PMID- 24163870 TI - Aesthetic correction of hypertrophic frontal sinus with beveled osteotomy. AB - The authors performed aesthetic correction of hypertrophic frontal sinus in 3 patients with protruded supraorbital region by using beveled osteotomy. Under general anesthesia, a bicoronal incision was performed followed by dissection through the subgaleal plane to the supraorbital ridge. Subsequently, the anterior wall of the frontal sinus was sectioned with a reciprocating saw and an osteotome by using the beveled osteotomy technique. Beveled osteotomy is a technique applied during sectioning of the anterior wall of the frontal sinus whereby the upper portion of the sinus remains intact and the lower portion of the sinus is changed. The technique used by the authors differed from the conventional method in that the existing shape of the outer wall of the frontal sinus was preserved when osteotomy was performed. This technique therefore preserves a more natural contour of the forehead and is advantageous in that it does not require additional interventions. PMID- 24163868 TI - Effect of thermal welding tonsillectomy on emergence agitation. AB - : This study sought to examine the effect of thermal welding tonsillectomy that reduces pain and length of anesthesia on emergence agitation. A total of 60 patients (age range, 3-6 years) with chronic recurrent tonsillitis with an indication for tonsillectomy were included. Patients were randomly assigned to 2 groups. The control group (the CD group) was composed of patients undergoing cold dissection (CD) tonsillectomy. The study group (TW group) included patients undergoing thermal welding (TW) tonsillectomy. All patients were given sevoflurane as an anesthetic agent. For all patients, anesthesia time, operation time, extubation time, Pediatric Anesthesia Emergence Delirium scale, pain scale, nausea/vomiting score, and delivery time were recorded. The duration of anesthesia, operation, and delivery was significantly lower in the TW group as compared with the CD group (P = 0.000 < 0001). The pain and agitation scores were significantly lower in the TW group as compared with the CD group (P = 0.000 < 0001). We assume that, besides reducing pain and allowing surgery without bleeding, the TW tonsillectomy method diminishes emergence agitation induced by anesthetic agents, such as sevoflurane. PMID- 24163871 TI - Findings of research misconduct. PMID- 24163872 TI - [The analysis on the epidemic trend of viral hepatitis in China during recent 10 years (2002-2011)]. PMID- 24163873 TI - [Clinical condition evaluation of hepatic veno-occlusive disease induced by gynura segetum]. PMID- 24163874 TI - [Transcatheter arterial chemoembolization of hepatocellular carcinoma with 350 560MUm gelatin sponge particles: efficacy, tumour response and survival]. PMID- 24163875 TI - [Summary of Seventh National Severe Liver Disease Conference]. PMID- 24163876 TI - [Do you want a scan? Do you really want it?]. PMID- 24163877 TI - [Acute abdominal pain of the upper abdomen: which imaging to choose?]. AB - The aim of this article is to review the imaging modalities to be performed in patients with acute diffuse upper abdominal pain. Conventional radiography, ultrasound and computerized tomography (CT) are most often used in this setting. The choice of the initial imaging technique will depend from the localization of the pain and the probability of a particular pathology in the involved area. PMID- 24163878 TI - [What imaging to choose for low abdominal pain?]. AB - Nowadays, we need to counterbalance the excellent diagnostic yield of the abdominal CT Scan, with the significant risks of X irradiation. The Low Dose CT Scan allows confirmation of a diagnosis of appendicitis or nephrolithiasis with comparable precision and a much lower irradiation dose. In the case of appendicitis, the ultrasound is particularly useful, provided that the patient's BMI is <30. If there is suspicion of diverticulitis, the standard CT Scan remains the first line test. The Ultrasound is the first choice exam for a woman in childbearing age presenting with an acute abdominal pain. PMID- 24163879 TI - [Imaging in the evaluation of headaches]. AB - Headache is a common complaint in primary care medicine. Most of the time, they are primary and benign headaches, with no need for further investigations; nevertheless, in the presence of red flags, a brain imaging is warranted. The diagnostic approach depends upon the most likely suspected cause and the degree of emergency. In those situations, a head CT scan without and with contrast is the exam of choice in most patients, because it is helpful for identifying intracranial lesions or bleeding. The MRI, more sensible, is preferred in the ambulatory setting for investigation and follow-up of intracranial tumoral or infectious diseases. PMID- 24163880 TI - [Diagnostic imaging for atraumatic shoulder pain]. AB - Shoulder pain is a common cause of consultation in primary care medicine. A detailed history and a carefully carried out physical exam allow to orientate the diagnosis towards an intrinsic or extrinsic cause and to the differential diagnosis. Rotator cuff injury is the most frequent affection. Plain radiography will often be done in first intention since it identifies direct or indirect signs associated with certain pathologies. Ultrasonography is an excellent way of evaluating soft tissue injury and allows a diagnosis in most cases (rotator cuff injury, tendinopathy of the long head of the biceps, bursitis, effusion, calcifications). Other imaging studies may be carried out depending on the pathology suspected. PMID- 24163881 TI - [Imaging indication for low back pain in the adult population]. AB - Low back pain is a frequent symptom-related reason for visits to a general physician. In case of acute low back pain, the only situation that requires a radiologic exam is when are present. This article specifies which anamnestic symptoms and past medical events are to be considered as such, and suggests what kind of radiologic exam should be done depending on the situation. It also mentions the psycho-social factors that favour a chronicisation of the problem and that should be identified in order to be taken care of. When low back pain becomes a chronic condition, there is a lack of scientific evidences/evidence based medicine and the actual recommendations whether or not to ask for imaging studies are based upon experts opinions. Medical follow-up is essential. PMID- 24163882 TI - [Knee pain: choosing the right imaging]. AB - Gonalgia is a frequent reason for consultation of a primary care physician. The road leading to diagnosis is mainly clinical. A detailed medical history and physical examination are capital for establishing diagnostic hypotheses and choosing the most appropriate imaging test. Initially, a simple X-ray of the knee joint is the most common exam, even though it is not always needed, especially after a minor trauma. MRI and CT-scan allow a more detailed examination of the structures; however, they should only be ordered to answer a specific question. Most of the time, echography is reserved to extra-articular pathologies and for guiding an articular tap. PMID- 24163883 TI - [Two advances: fighting resistant malaria and African meningitis]. PMID- 24163884 TI - [I want and I don't want. Wanderings of Fall]. PMID- 24163885 TI - [Albert Jacquard (1925-2013): a human geneticist]. PMID- 24163886 TI - [Overpaid premiums: a compromise between the Cantons]. PMID- 24163887 TI - [The collective attitude in France: the seventy years of Catherine Deneuve]. PMID- 24163888 TI - [Dealing with illness]. PMID- 24163889 TI - Why a special issue on atrial fibrillation? PMID- 24163890 TI - Atrial fibrillation: an old disease still being updated. PMID- 24163891 TI - The anatomy of the left atrium for electrophysiologists. PMID- 24163892 TI - The role of multi-modality cardiac imaging in patients with atrial fibrillation. PMID- 24163893 TI - Understanding drug therapy to manage atrial fibrillation. PMID- 24163894 TI - Electrical cardioversion for atrial fibrillation. PMID- 24163895 TI - Management of atrial fibrillation in the emergency department: who should be admitted? PMID- 24163896 TI - Benefit and concern about the "pill-in-the-pocket". PMID- 24163897 TI - Non-antiarrhythmic drugs for the prevention of atrial fibrillation: ACEIs, ARBs, statins and PUFAs. PMID- 24163898 TI - Atrial fibrillation and stroke: risk stratification and new anticoagulants. PMID- 24163899 TI - Rate control of atrial fibrillation: selection of patients, how to reach the target? PMID- 24163900 TI - Atrial fibrillation ablation. PMID- 24163901 TI - ["Go to the emergency room, we are swamped"]. PMID- 24163902 TI - [Reality, expectations and assumptions: becoming a general practitioner]. PMID- 24163903 TI - [Patent foramen ovale can cause cryptogenic stroke. Transcatheter closure as an alternative to medical therapy must be evaluated more]. PMID- 24163904 TI - [Young people's lifestyles can prevent mental illness]. PMID- 24163905 TI - [Young people's mental health baffles researchers]. PMID- 24163906 TI - [Eating oneself healthy... or unhealthy--food is central in our society]. PMID- 24163907 TI - [Dance can serve as a protective factor in preventing mental illness]. PMID- 24163908 TI - [Young people's sleep is often a matter of lifestyle--but not always]. PMID- 24163909 TI - [Mental illness and alcohol consumption is closely linked]. PMID- 24163910 TI - [Referral criteria for children's eyesight should be modified]. PMID- 24163911 TI - [Underlying factors should be examined in prolonged sick leave for depression]. PMID- 24163912 TI - [BMI can not safely identify 4-year-olds with high body fat]. PMID- 24163913 TI - [Yvette, 20, stopped in the patient career]. PMID- 24163914 TI - Click all about it! PMID- 24163915 TI - Staffing levels are key to safe care,finds patient safety review. PMID- 24163916 TI - NICE sets the standard for high quality postnatal care. PMID- 24163917 TI - Narrative pedagogy in midwifery education. AB - Narrative pedagogy is an approach to midwifery education which can promote strategies for teaching and learning which effectively prepare graduates for the complex nature of midwifery practice. Knowledge and skills are fundamental to midwifery practice, but knowing about how to use them is the art of practice. Teaching and learning midwifery skills and competencies is straight forward in comparison to teaching and learning about the art of midwifery, yet both are essential for safe practice. Narrative pedagogy may be one way that enhances undergraduate midwifery students' learning about the art of practice. PMID- 24163918 TI - The role of the mentor in evaluating learning. AB - This paper aims to give an overview of the role of the mentor within the sphere of the evaluation of learning, with particular emphasis on the intermediate interview and student reflection on their learning experience as formal tools for evaluation. Although the terms 'evaluation' and 'assessment' are often used in similar contexts, it is important to distinguish between the two concepts. The importance of evaluation of learning cannot be over emphasised as it is an important part of ensuring that students develop as expected (Nursing and Midwifery Council (NMC) 2008). Therefore, failure to evaluate learning can have a negative impact on the student and their learning throughout their programme of study. PMID- 24163919 TI - BSI not CSI: birth scene investigation--a community midwifery simulation. AB - Educating students in sophisticated clinical simulation centres, whereby students are exposed to low and high fidelity equipment, is gaining popularity. It is considered beneficial to create the most authentic environment to enhance learning. The Professor Bernard Knight House at the University of Glamorgan, originally designed as an environment for forensic science students, was utilised to simulate a community midwifery scenario. Midwifery students undertook a pilot simulation exercise in this environment, which they found a motivating learning experience, confirming the high level of authenticity of the environment. This is a positive learning tool. PMID- 24163920 TI - Baby massage. AB - Having initially trained as a nurse and then a midwife, massage for me was back to hands on care. In 1992, as part of my continuing professional development, I undertook an anatomy, physiology and massage course. My aim was to acquire skills that could benefit the mothers I cared for. My journey with baby massage began when I had my first son in 1993. At that time there were no courses or sessions on baby massage available but I did adapt some of the massage techniques I had learnt during my massage course to benefit me and my son. PMID- 24163921 TI - Getting needled! AB - Anxiety and stress in pregnancy can become severe and disabling, negatively impacting on both the short and long term outcomes for mother and baby. Women often seek alternative treatments for such problems, acupuncture being a popular choice. It has been shown to have an effect on the limbic system and on serotonin production, leading to increased feelings of wellbeing. Women having acupuncture in pregnancy have reported increased self esteem and control of symptoms, leading to improved wellbeing. With appropriate training, midwives may be in a good position to offer acupuncture to support women suffering with anxiety, improving outcomes for women and babies. PMID- 24163922 TI - Evidence for homeopathy in childbirth. AB - Homeopathy has been described as 'a fascinating field of study and a natural complement to the science and art of midwifery' (Brennan 1999: 298). Supported by the Royal College of Midwives' (RCM) campaign for normal birth and resulting from a growing desire by women to avoid conventional medicine, the use of homeopathic remedies in childbirth is gaining momentum. Midwives are ideally positioned to discuss homeopathy with women. To enable informed discussions, however, midwives must have evidence on homeopathy use. This article explores the evidence on homeopathy use in childbirth. PMID- 24163924 TI - Complementary therapy for induction of labour. AB - Midwives at West Middlesex hospital (WMUH) offer complementary therapies as part of antenatal care. Aromatherapy and reflex zone therapy (also known as 'reflexology', a system of using touch on areas of the feet that stimulate parts of the body) are offered to induce spontaneous labour for women with low risk pregnancies once post dates, reducing the need for medical induction of labour (IOL) and intervention and reducing the cost to the NHS. This paper discusses how this service was implemented and developed, and the audit results and feedback from women and midwives. PMID- 24163923 TI - A dream birth? Try hypnobirthing! AB - Hypnobirthing is often regarded as a method of pain relief without drugs. This is to miss the point, as it presupposes that pain is there in the first place. When a woman learns to release the preconceptions, fears and worries about birth that are endemic in our society, her experience of giving birth to her baby can be the most wonderful and empowering experience of her life. Mind and body working together can be a powerful and efficient combination. This is how birth is designed to be, as midwives and hospitals are beginning to discover. Thus hypnobirthing can provide a service that women want as well as save scarce NHS funds. PMID- 24163925 TI - Charting the history of midwifery education. AB - Despite the recent popularity of exploring the history of midwifery practice, there has been minimal attention paid to the history of midwifery education. The purpose of this paper is to display a visual map and timeline of midwifery education from the eighteenth century, when formal midwifery programmes were introduced, to the present day. The paper will be inclusive of the history of midwifery teaching through the use of the High Coombe College archives (Lorentzon et al 2008). Prior to the eighteenth century, processes for learning midwifery were informal and unregulated. Traditional apprenticeships were gradually replaced by formal, regulated educational midwifery programmes, which were assessed. Midwifery teacher training finally became established in the twentieth century. PMID- 24163926 TI - Maintaining the passion for pinards. AB - Throughout my midwifery programme I have developed a passion for the use of pinards; a skill that may be lost within midwifery. It is often acknowledged that the use of pinard stethoscopes prior to the use of electronic devices is best practice (Royal College of Midwives (RCM) 2012), yet it is a practice that seems to be losing its place. This article aims to share some of the benefits of using a pinard and encourages the reader to reflect on their own feelings towards using this tool in practice. I will analyse whether or not there is still a value for pinards following an event I experienced whilst on clinical placement. This reflection uses an adapted version of Driscoll's Model of structured reflection (Driscoll 2000). PMID- 24163927 TI - Time to reflect. AB - In an attempt to introduce creative ways of reflecting, art projects were included in group personal tutor sessions for student midwives. One was a reflective timeline drawn annually, documenting the student's own journey through a year. The intention was that this informal and interactive activity may help the students to relax and enjoy the reflective process, and also have some fun. Due to the high pressured risk management orientated nature of contemporary midwifery this was to be a welcome contrast to many of the traditional taught classes within the course. The student's evaluation of the activity exceeded all expectations in terms of demonstrating their learning from the experience and that sharing had helped them bond as a group thus supporting and understanding each other better. This exercise fostered a culture of self awareness, relationship building, caring and support for colleagues, all crucial aspects of woman centred midwifery practice. PMID- 24163928 TI - What does midwifery mean to me? PMID- 24163929 TI - Umbilical cord antiseptics for preventing sepsis and death among newborns. AB - The aim of this bi-monthly column is to highlight Cochrane Systematic Reviews of relevance to pregnancy and childbirth and to stimulate discussion on the relevance and implications of the review for practice. The Cochrane Collaboration is an international organisation that prepares and maintains high quality systematic reviews to help people make well-informed decisions about healthcare and health policy. A systematic review tries to search for, appraise and synthesise existing research to answer a specific research question. The Cochrane Database of Systematic Reviews (CDSR) is published monthly online. Residents in countries with a national license to The Cochrane Library, including the UK and Ireland, can access the Cochrane Library online free of charge through www.thecochranelibrary.com PMID- 24163930 TI - [Reported research fraud just the tip of the iceberg?]. PMID- 24163931 TI - [Children must get the opportunity to create healthy habits. Leading politicians should take responsibility to combat childhood obesity]. PMID- 24163932 TI - [Whooping cough is a risk to infants. The disease is circulating among adolescents and adults]. PMID- 24163933 TI - [Testis torsion--still a problem, despite known risks. Review of events reported to the Swedish National Board of Health and Welfare]. PMID- 24163934 TI - [Hyperbaric oxygen therapy is effective for diabetic foot ulcers. Recent randomized controlled trials have provided better knowledge]. PMID- 24163935 TI - [Treatment of early stages of Alzheimer's disease: New guidelines are in the pipeline]. PMID- 24163936 TI - [Scientific misconduct is fraud]. PMID- 24163937 TI - ["I ask nothing better than to not always be believed." Myths and truths about Axel Munthe and Jean-Martin Charcot]. PMID- 24163938 TI - Data drive ACO involvement. PMID- 24163939 TI - Realizing savings through refinancing. PMID- 24163940 TI - CMS updates expedited appeal regulations. PMID- 24163941 TI - Dining done right. PMID- 24163942 TI - Swine flu is back again: a review. AB - Flu viruses have mainly affected humans, birds and pigs worldwide. During the past 10 years these viruses are in limelight at a global level due to pandemic threats of Avian/Bird Flu and Swine Flu and their public health impacts, with added pandemic of swine flu virus recently. The current ongoing episodes of bird flu and swine flu are beyond the control, when and where or which country they start with nobody can predict. The continuous evolution and emergence of new strains indicate that the flu viruses are becoming more and more dangerous and this situation has posed a challenge to researchers to discover effective vaccines and therapeutics. Moreover, the role of pig as 'mixing bowl' for the virus to get reassorted has added to the complicated epidemiological scenario. The swine flu H1N1 reassorted subtype caused the first global pandemic in last 40 years, resulting in substantial illness, hospitalizations of millions of peoples and thousands of deaths throughout the world. A pace is there within these novel and emerging flu viruses and the scientific community, where the scientific community has to win the race so as to save the mankind. In this review, a brief overview on swine flu is presented highlighting the characteristics of the causative virus, the disease and its public health consequences, advances made in its diagnosis, vaccine and control, precautionary measures to be adapted in the wake of an outbreak. PMID- 24163943 TI - Effect of dietary levels of decorticated cow pea (Vigna unguiculata) supplemented with molasses on broiler chicks performance and carcass traits. AB - Manny legumes are used extensively as animal feed. This study was conducted to look at the effects of decorticated cow pea seeds based diets supplemented with molasses on broiler performance and carcass traits. A total of 240 unsexed one day old broiler chicks (Ross 308) were used .The birds were randomly divided into six equal groups (treatments) and each group consisted of 8 (replicates). Six experimental diets (starter and finisher) were formulated to be approximately isocaloric and isonitrogenous. The cow pea was included at three levels (0, 10 and 20%) with two levels of molasses at (0, 3%). Decorticated cowpea and raw cowpea contain 25.86 vs. 24.78% crude protein, 1.41 vs. 0.91% ether extract, 3.36 vs. 3.33% ash and 2.64 vs. 3.46% crude fiber on dry matter basis. Methionine content was high in decorticated cowpea (0.40%) compared with raw cowpea (0.35%), the vice versa hold true for lysine, 1.74 in raw seeds vs. 1.62% in decorticated seeds. Decorticated cowpea seed at 10 or 20% without molasses significantly (p<0.05) improved final body weight (1999.50-2051.32 g vs. 1986.32 in the control group). Whereas, the molasses addition at 3% significantly decreased final body weight (1838.42-1900.79 g vs. 1986.32 in the control group) and total feed intake (3150.75- 3300.75 vs. 3318.00 +/- 26.45 g in the control group). The inclusion of 20% cowpea with 3% molasses significantly improved feed conversion ratio in 20 cow pea with 3% molasses It is concluded that cow pea seeds is a good source of protein that can be used in broiler feeds safely to give satisfactory results. PMID- 24163944 TI - Biochemical analysis of two varieties of water chestnuts (Trapa sp.). AB - In this study, two varieties (Green and red) of water chestnuts (Trapa sp.) have been selected for their biochemical analysis as well as nutrient composition using standard methods. The proximate composition of green water chestnuts revealed moisture 62.5, ash 1.04, crude fiber 2.13%, total soluble sugar 0.92%, reducing sugar 0.33%, non-reducing sugar 0.59%, starch 8.7%, lipid 0.84%. One hundred gram of green variety contained water soluble protein 0.275 mg, beta Carotene 60 microg, vitamin-C 1.1 mg and total phenol 0.5 mg. The minerals contents of green variety were potassium 5.22%, sodium 0.64%, calcium 0.25%, phosphorus 6.77%, sulpher 0.38%, and iron, copper, manganese and zinc 200, 430, 90 and 600 ppm, respectively. The red variety contained moisture 62.7%, ash 1.30%, crude fiber 2.27%, total soluble sugar 0.90%, reducing sugar 0.30%, non reducing sugar 0.60%, starch 8.2%, lipid 0.83%. The red variety contained water soluble protein 0.251 mg, beta-Carotene 92 microg, vitamin-C 0.9 mg and total phenol 0.60 mg per 100 g. The red variety contained potassium 5.32%, sodium 0.59%, calcium 0.26% phosphorus 6.77%, sulpher 0.32%, Iron 200 ppm, copper 450 ppm, manganese 110 ppm and zinc 650 ppm. The free amino acids, glutamic acid, tryptophan, tyrosine, alanine, lysine and leucine were commonly found in both varieties. In addition, green and red variety contained cysteine, arginine and proline and glutamine and asparagines, respectively. Thus, the present study sheds light on the nutrient contents of the two varieties of water chestnuts and suggests that water chestnuts may play a crucial role in human nutrition. PMID- 24163945 TI - Physicochemical attributes of Nigerian natural honey from honeybees (Apis mellifera adansonii) (Hymenoptera: Apidae) and its shelf life in storage at room temperature. AB - Nigerian honey competes globally in the world honey market. The physicochemical parameters of honey samples sourced from colonies of Apis mellifera adansonii were studied with the effect of storage-time over a period of two years. This was done by analyzing and evaluating eleven common physicochemical parameters including colour, moisture content, ash content, sugar content, acidity, pH value, hydroxymethylfurfural, diastase activity, nitrogen content, insoluble matter and viscosity of honey samples with the effect of storage-time on the physicochemical parameters using Association of Official Analytical Chemists methods. Most of the honey samples showed proper maturity considering the moisture content (17.9 +/- 2.0%). The total acidity (21.5 +/- 5.6 meq kg(-1)) indicated absence of undesirable fermentation after harvest and extraction. The Mean +/- SD pH value (3.9 +/- 0.2) of the honey samples was within acceptable standards of Economic European Community (EEC) and Codex. The ash content (0.4 +/ 0.2%) (0.2-0.6%) was slightly higher than 0-0.50% of EEC and Codex standards. The fructose and glucose mean values were 38.9 +/- 0.8% and 28.3 +/- 2.4%, respectively. The Mean +/- S.D value of hydroxymethylfurfural content (8.5 +/- 2.7 mg kg(-1)) was low, while the Mean +/- SD value of diastase activity was high depicting freshness. The evaluated physicochemical parameters of two years old honey samples exhibited no significant deviation (p > 0.05) from that of the fresh samples. This study showed that natural honey if properly harvested, extracted hygienically, preserved and stored can maintain their stability relatively for at least two years at room temperature without undue interference. PMID- 24163946 TI - Chemical composition and in vitro antimicrobial and antioxidant activities of Citrus aurantium l. flowers essential oil (Neroli oil). AB - Neroli essential oil is extracted from the fragrant blossoms of the bitter orange tree. It is one of the most widely used floral oils in perfumery. In this study chemical composition and in vitro antimicrobial and antioxidant activities of neroli oil are investigated. The essential oil of fresh Citrus aurantium L. Flowers (Neroli oil) cultivated in North East of Tunisia (Nabeul) were analyzed by GC-FID and GC-MS. About 33 compounds were identified, representing 99% of the total oil. Limonene (27.5%) was the main component followed by (E)-nerolidol (17.5%), alpha-terpineol (14%), alpha-terpinyl acetate (11.7%) and (E, E) farnesol (8%). Antimicrobial activity was determined by Agar-well-diffusion method against 6 bacteria (3 Gram-positive and 3 Gram-negative), 2 yeasts and 3 fungi. Neroli oil exhibited a marked antibacterial activity especially against Pseudomonas aeruginosa. Moreover, Neroli oil exhibited a very strong antifungal activity compared with the standard antibiotic (Nystatin) as evidenced by their inhibition zones. Antioxidant activity determined by ABTS assay showed IC50 values of 672 mg L(-1). Finally, this study may be considered as the first report on the biological properties of this essential oil. The results of this study have provided a starting point for the investigations to exploit new natural substances present in the essential oil of C. aurantium L. flowers. PMID- 24163947 TI - Effects of Papaver rhoeas (L.) extract on formalin-induced pain and inflammation in mice. AB - Stress amelioration can improve its metabolic as well as other side effects. In the present study, the effects of hydro-alcoholic extract of Papver rhoeas (L.) on formalin-induced pain and inflammation were investigated in male Swiss-Webster mice (20-25 g). Formalin injects in the plantar portion of mice hind paw and pain was studied for 60 min. The plant extract and other drugs were administered intraperitoneally 30 min before formalin. Experiments showed that administration of extract (25, 50 and 100 mg kg(-1)) could induced analgesia in a dose-response manner in both phases of formalin test. More over, the extract inhibits inflammation induced by formalin injection. Naloxone (4 mg kg(-1)), dextromethorphan (20 mg kg(-1)) and NG-nitro-L-arginine-methylester (L-NAME; 10 mg kg(-1)) reduced the extract analgesia in first but not late phase. Extract administration also increased plasma corticosterone level in dose-dependent manner. It could be concluded that Papaver rhoeas (L.) extract could inhibits acute phase of formalin test in mice by opioidergic, glutamatergic and nitricergic mechanisms. In addition, the extract can induce corticosterone plasma level which may be responsible for inhibition of inflammation and chronic phase of pain induced by formalin. PMID- 24163948 TI - Behcet's syndrome in Iranian Azari people. AB - Behcet's Syndrome (BS) is a chronic recurrent multisystemic inflammatory disorder characterized by oral and genital ulcers, ocular inflammation. Behcet's syndrome has a complex genetic etiology. However, epidemiological studies recommend that genetic factors have a significant influence to its pathogenesis, alike to other autoinflammatory disorders. Epidemiological statistics, clinical records and HLA typing were studied in Iranian Azari patients with Behcet's syndrome. This investigation considered HLA associations with BS and HLA with certain clinical characteristics, age and sex in the (Tabriz) Iran which has an ethnically homogeneous population. HLA-A and HLA-B typing was performed in 290 BS patients, conforming to International Study Group criteria and in 300 blood donors, as controls. Patient records were retrospectively reviewed and patients reassessed clinically. HLA-B5, HLA-B35, HLA-51, HLA-B52 and HLA-CW4 presented significantly high frequencies in all patients. No other HLA type was associated. There was a significant HLA link with male sex in BS patients and Mean age (34 +/- 1.1) was determined. We present the frequency and correlation between Iranian Azari patients with Behcet's syndrome and particular HLA antigens. Ninety nine percent had mouth ulceration, 64% genital ulceration, 72% skin lesions and 52% ocular involvement. This study supports HLA-B5, HLA-B35, HLA-51, HLA-B52 and HLA-CW4 immunogenetic predisposition in an ethnically homogeneous (Iranian Azari) population. PMID- 24163949 TI - Bacteriological contamination of well water in Makurdi town, Benue State, Nigeria. AB - Bacteriological contamination of well water in Makurdi town, of Benue State, Nigeria was investigated. A total of 15 water samples were collected from hand dug wells and analyzed for total bacteria count as it affect the quality of drinking water for both wet and dry season. The analysis was done according to standard methods of water examination and as reported in WHO guide limit for drinking water. The investigation revealed that the wells examined were highly contaminated with bacteria. Wells 6 and 7 showed highest total bacteria counts of 7.0 x 10(5)/100 mL and 8.2 x 10(5)/100 mL in the wet season, while wells 7 and 2 showed highest total bacteria counts of 8.0 x 10(5)/100 mL and 5.5 x 10(5)/100 mL in the dry season. The contamination of all wells could be due to improper construction of wells, refuse dumping sites and various human activities around the wells. Water generally from these wells is not safe for drinking except some form of treatment is carried out. PMID- 24163950 TI - Pharmacological potentials of Cassia auriculata and Cassia fistula plants: A review. AB - People are using herbal medicines from centuries for safety, efficacy, cultural acceptability and lesser side effects. Plant and plant products have utilized with varying success to cure and prevent diseases throughout history. Therapeutically interesting and important drugs can be developed from plant sources which are used in traditional systems of medicines. Indian traditional system of medicine is based on empirical knowledge of observations and the experience over millennia and more than 5000 plants are used by different ethnic communities in India. Cassia is an indigenous medicinal plant genus, in which Cassia auriculata have large biodiversity in south India and Cassia fistula in north India. The present communication constitutes a review on the medicinal properties and pharmacological actions of Cassia auriculata and Cassia fistula used in Indian traditional medicine. These plants are known to contain various active principles of therapeutic value and to posses' biological activity against a number of diseases. PMID- 24163951 TI - Inorganic versus organic selenium supplementation: a review. AB - Selenium is an essential trace element in the diets which is required for maintenance of health, growth and biochemical-physiological functions. The area covered in this review has been rapidly unfolding in recent years and has already acquired a vast spread. This study presents a concise introductory overview of the effect of organic and inorganic selenium on growth performance, carcass traits, daily egg production, egg quality, Se uptake in various tissues and plasma and plasma glutathione peroxidase activity in animals. PMID- 24163952 TI - Performance of some Ethiopian fenugreek (Trigonella foenum-graecum L.) germplasm collections as compared with the commercial variety Challa. AB - Systematic breeding efforts on fenugreek have so far been neglected in Ethiopia. For this, 143 random samples of fenugreek accessions along with a commercial variety were used in this study to evaluate the potential of the land races. The field experiment was conducted at Haramaya University research station during 2011 main cropping season. Treatments were arranged in a 12x12 simple lattice design. The highest biomass and seed yielding accessions were generally concentrated more in the categories of yellow and green seed colors. When compared with the commercial variety, above 27% of the tested accessions performed significantly better in terms of seed yield indicating that significant yield gains could be secured by simple selection. However, further evaluation over wider environments is necessary to arrive at conclusive points for such quantitative traits. Green and yellow seeded accessions are widely distributed over all the country and over half of the accessions (63%) had green seed color. High seed yield bearing accessions were those collected from northwest and central part of Ethiopia, while accessions collected from eastern and northwestern Ethiopia were strikingly bold seed size. This variability would provide a basis for improving the crop in breeding program. PMID- 24163953 TI - The determination of water quality and metal concentrations of Ampang Hilir Lake, Selangor, Peninsular Malaysia. AB - A study of water quality parameters (temperature, conductivity, total dissolved solid, dissolved oxygen, pH and water hardness) in Ampang Hilir Lake was conducted in January, April, July and October 2010. The water quality parameters were tested and recorded at different sampling stations chosen randomly using Hydrolab Data Sonde 4 and Surveyor 4 a water quality multi probe (USA). Six metals which were cadmium, chromium, lead, nickel, zinc and copper were determined in five different compartments of the lake namely water, total suspended solids, plankton, sediment and fish. The metals concentration were determined by Inductively Coupled Plasma Mass Spectrometer (ICP-MS), Perkin Elmer Elan, model 9000.The water quality parameters were compared with National Water Quality Standard (NWQS Malaysia) while metal concentrations were compared with Malaysian and international standards. The study shows that water quality parameters are of class 2. This condition is suitable for recreational activities where body contact is allowed and suitable for sensitive fishing activities. Furthermore, metal concentrations were found to be lower than the international standards, therefore toxic effects for these metals would be rarely observed and the adverse effects to aquatic organisms would not frequently occur. PMID- 24163954 TI - Influence of sodium selenite on growth, nutrient utilization and selenium uptake in Cavia porcellus. AB - A 70 day experiment on forty guinea pigs (Cavia porcellus) was conducted to find the influence of different level of sodium selenite (inorganic selenium supplementation) on growth, nutrient utilization and selenium uptake. The sodium selenite was supplemented into a basal diet at 0, 0.1, 0.2 and 0.3 ppm, respectively and the basal diet comprised of 25% ground cowpea (Vigna unguiculata) hay, 30% ground maize (Zea mays) grain, 22% ground gram (Cicer arietinum) grain, 9.5% deoiled rice (Oryza sativa) bran, 6% soybean (Glycine max) meal, 6% fish meal, 1.5% mineral mixture (without Se), ascorbic acid (200 mg kg) and 0.1 ppm Se to meet their nutrient requirements. Daily feed intake and weekly body weights were recorded. Intake and digestibility of dry matter, organic matter, ether extract, crude fiber and nitrogen-free extract as well as uptake of calcium and phosphorus, total body weight and average daily gain were similar (p>0.05) among the four groups. However, there was a trend of increase in Se absorption of the guinea pigs with the increasing levels of Se, in the groups given 0.2 and 0.3 ppm of Se. It can be concluded that requirement of Se in guinea pigs is 0.1 ppm, as supplementation of > or =0.1 ppm sodium selenite in the diet (having 0.1 ppm Se) did not enhanced their growth rate and nutrient utilization. PMID- 24163955 TI - Chorioamnionitis and diagnostic value of C-reactive protein, erythrocyte sedimentation rate and white blood cell count in its diagnosis among pregnant women with premature rupture of membranes. AB - Several laboratory parameters have been used in these studies to diagnose chorioamnionitis leading to controversies to some extent. The aim of this study was to assess the diagnostic value of C-reactive protein (CRP), erythrocyte sedimentation rate (ESR) and white blood cell (WBC) count in chorioamnionitis among pregnant women with premature rupture of membranes (PROM). In a cross sectional diagnostic test research, 71 patients presented with PROM before the 37th week of gestation were enrolled. A blood sample was taken from all the patients. Hematologic automatic blood cell counter was used to count the blood cells and their differentiation. ESR and CRP were also measured using the same blood sample at the laboratory. Sensitivity, specificity, correct classification rate and likelihood ratios were calculated. Receiver operating curves were plotted and area under curve was estimated along with its 95% confidence interval. A total of 71 patients were studied. None of the patients had a positive drug history or a history of hypertension before the 20th week of gestation or during her previous pregnancy. Contrary to ESR, WBC count and CRP results didn't provide minimum acceptable diagnostic accuracy measures for diagnosis of chorioamnionitis. The sensitivity and specificity of a positive ESR test at a cutoff value of 52 were 66.7 and 60%, respectively. The area under curve was calculated to be 0.62. The findings of the present study were not supportive of using CRP, WBC as a reliable diagnostic test to identify chorioamnionitis in women with PROM. The results of CRP and WBC were not acceptable but ESR diagnostic value was minimally acceptable. PMID- 24163956 TI - Histological evaluation of the healing properties of Dead Sea black mud on full thickness excision cutaneous wounds in BALB/c mice. AB - Dead Sea (DS) mud and salts are known for their therapeutic and cosmetic properties. Previous studies confirmed their efficacy in treating the more frequent skin diseases such as psoriasis and atopic dermatitis. Therefore, this study aimed to evaluate the wound healing potential of natural and compounded skin-care product (facial mask) of DS black mud in BALB/c mice. Two full thickness excision round wounds were created on the dorsum region of mouse. Each wound of mice test group were treated topically with 50 microL of 0.1% natural or compounded DS black mud or 50 microL of 0.2% nitrofurazone once a day for 2 consecutive days and the mice control group were left untreated. Healing was assessed by measuring the granulation tissue weight and percentage of wound contraction at day 3, 7, 14 and 21 after wounding. In addition to period of epithelialization and histological evaluation of the regenerated wound area at day 7 and 14 after wounding. Results revealed that DS black mud accelerate wound healing process by enhancing granulation, wound contraction, epithelialization, angiogenesis and collagen deposition. This may be due to high content of minerals and trace elements that possibly act as anti-microbial, anti-inflammatory and antioxidant with enhancement effect on cell proliferation, migration and fibroblast cellular activity. However, the healing property of DS black mud compounded in skin-care product was greater than that of natural black mud, when compared to reference drug, nitrofurazone. PMID- 24163957 TI - Effect of calcium-vitamin D supplementation on metabolic profiles in pregnant women at risk for pre-eclampsia: a randomized placebo-controlled trial. AB - Increased metabolic profiles during pregnancy are associated with an increased risk of maternal and neonatal morbidity and remain a significant medical challenge. To our knowledge, no reports are available indicating the effects of calcium-vitamin D supplementation on metabolic profiles among pregnant women at risk for pre-eclampsia. This study was designed to determine the effects of consumption calcium-vitamin D supplements on metabolic profiles among Iranian pregnant women at risk for pre-eclampsia. This randomized single-blind controlled clinical trial was performed among 49 pregnant women at risk for pre-eclampsia, primigravida, aged 18-35 year old who were carrying singleton pregnancy at their third trimester. Subjects were randomly assigned to consume the placebo (n = 25) or calcium-vitamin D supplements (n = 24) for 9 weeks. Calcium-vitamin D supplements were containing 500 mg carbonate calcium plus 200 IU vitamin D3. Fasting blood samples were taken at baseline and after 9 week intervention to measures of Fasting Plasma Glucose (FPG) and serum lipid profiles. Consumption of calcium-vitamin D supplements resulted in decreased FPG and serum triglycerides levels as compared to the placebo (-9.1 vs. 0.5 mg dL(-1); p = 0.03, -11.7 vs. 49.9 mg dL(-1); p = 0.001, respectively). No significant differences were found comparing calcium-vitamin D supplements and the placebo in terms of their effect on serum total-, HDL-, LDL-cholesterol levels. Within-group differences in the placebo group revealed a significant increase in serum triglycerides levels (+49.9 mg dL(-1), p < 0.0001). In conclusion, consumption of calcium-vitamin D supplements for 9 weeks during pregnancy among pregnant women at risk for pre eclampsia resulted in decreased FPG and serum triglycerides levels as compared to the placebo group, but could not affect serum total-, HDL-, LDL-cholesterol levels. PMID- 24163958 TI - In vitro antioxidant activity, phytochemical screening, cytotoxicity and total phenolic content in extracts of Caesalpinia pulcherrima (Caesalpiniaceae) pods. AB - Caesalpinia pulcherrima L. Swartz (Caesalpiniaceae) is an ornamental plant also used as a common medicinal plant in India, Taiwan and South-East Asian countries. Majority of the diseases/disorders are mainly linked to oxidative stress due to free radicals. The aims of this study were to screen for phytochemical constituents, evaluate cytotoxicity, in vitro antioxidant activity and estimation of total phenolic content of extracts of pods of Caesalpinia pulcherrima. Phytochemical analysis revealed the presence of tannins, flavonoids, steroids and alkaloids. Brine Shrimp Lethality (BSL) bioassay was used to investigate the cytotoxic effects. The LC50(microg mL(-1)) values obtained for extracts as 750 microg mL(-1) for petroleum ether extract, 800 microg mL(-1) for chloroform extract and 900 microg mL(-1) for methanol extract. The total phenolic content of the methanolic extract was 38.04% w/w, equivalent to gallic acid. Petroleum ether, chloroform and methanolic extracts of Caesalpinia pulcherrima and standard ascorbic acid were found to be scavenger of DPPH radical with an IC50 of 124.75, 112.08, 54.34 and 13.86 microg mL(-1), respectively. Methanolic extract was good scavenger of DPPH radical. Petroleum ether, chloroform, ethyl acetate soluble fraction of methanolic extracts of pods of Caesalpinia pulcherrima and ascorbic acid were found to be scavenger of nitric oxide radical with an IC50 of 93.32, 65.12, 54.83 and 12.59 microg mL(-1), respectively. Ethyl acetate soluble fraction was found to be good scavenger of nitric oxide radical. Our conclusion provides support that the crude extracts of C. pulcherrima is a probable source of natural antioxidants and this justified its uses in folkloric medicines. PMID- 24163959 TI - Multiple endo-beta-1,4-glucanases present in the gut fluid of a defoliating beetle, Podontia quatuordecimpunctata (Coleoptera: Chrysomelidae). AB - Endo-beta-1, 4-glucanase (EC 3.2.1.4) activity was measured in the gut fluid of phytophagous insect Podontia quatuordecimpunctata Linnaeus (Coleoptera: Chrysomelidae) in different days of development. The eight day-old larva showed maximum activity with 1.73 U mg(-1) of protein, which was confirmed by gel zymography. In zymogram, using Carboxymethyl Cellulose (CMC) as substrate, four distinct cellulolytic protein bands were detected in leaf borer gut fluids through out of its development. The optimum temperature and pH were 60 degrees C and 5.0, respectively. This endo-beta-1,4-glucanase showed maximum stability at 20-45 degrees C with approximately 20% remaining activity. Zymography also showed complete loss of endo-beta-1,4 glucanase activity at 55 degrees C. This is the first report that the cellulolytic enzyme is produced in the gut of P. quatuordecimpunctata through the whole developmental stages, from the 1st instar to the adult, except for pupae. PMID- 24163960 TI - Cancer during pregnancy: a review of 10 years of experience. AB - Cancer is the second most common cause of death among women who are in reproductive ages; however it is not common during pregnancy. There are few numbers of documents concerning cancer and its related treatment outcomes and prognosis during pregnancy. The aim of this study was to review our experience about gestational cancer. In this retrospective chart review study, 25 pregnant women with any kind of diagnosed malignancy who attended hospitals in Uremia and Sanandaj city since 10 years ago were assessed. Cancer cases were verified by a pathologist using pathology and TNM system for tumors staging. Then survival duration was analyzed using Kaplan-Maier plot. From all, 10 women had gynecologic cancers and 15 had non-gynecologic cancers. Ovarian cancer was the most common malignancy. The mean of survival was 67 months for all patients (CI95%: 23.7 110.3), 67 months for gynecologic cancer group (CI95%: 40.2-93.8) and 69 months for non-gynecologic cancer group (CI95%: 0-159) (p = 0.51). According to the results, the cancer complaints and symptoms must be examined thoroughly and do not take them as pregnancy complications since delays in prognosis leads to more severe problems and makes treatment difficult. If cancer is treated carefully after three months of gestation, probably it won't have severe side effects for fetus. PMID- 24163961 TI - Nutritional intervention on malnutrition in 3-6 years old rural children in Qazvin Province, Iran. AB - Malnutrition is one of the major causes of mortality and morbidity in children. Not only include acute effects on children's health, but also it has long-term effects on their cognitive development and economic growth in the society. Wasting (weight for height with Z<-1) is one of the malnutrition indices in children. The aim of this study was to determine the effect of a cooked meal for 175 days on the anthropometric indices of weight, height and weight for height (wasting) of 3-6 years old children in all the rural nursery of Qazvin province, in Iran. In this interventional study, 2385 children (48.8% female and 51.2% male) were recruited. Data were collected by a census in 2010. The children were received a cooked meal based on 360 +/- 20 kcal energy, 17% protein, 53% carbohydrate and 30% fat per day for 175 days at lunch time. The anthropometric indices were collected before and after the intervention. The results were analyzed using paired t-test by SPSS V.16 software. Prevalence of wasting (mild and moderate) and (sever malnutrition) after intervention reduced from 14.2 and 0.95-12.6 and 0.5%, respectively (p < 0.05). Receiving a cooked meal significantly decreased wasting (15.2-13.2%) in all children (p < 0.05). Nutritional intervention with cooked meal for 175 days had significant reduction in wasting in all children. PMID- 24163962 TI - Comparison of the haemodynamic effects of pyrethroid insecticide and amodiaquine in rats. AB - Malaria infection is a common cause of morbidity and mortality especially in the tropics and subtropics. This has led to the increased prophylactic use ofpyrethroid insecticides and/or Amodiaquine (Aq) to combat the parasitic protozoan infection. The aim of this study was to investigate the comparative haemodynamic effects of pyrethroid insecticide and amodiaquine in rats. Experimental rats were randomly allocated into seven groups of five rats in each. Groups 1, 2 and 3 were exposed to pyrethroid by inhalation for 1, 2 and 3 min, respectively, while groups 4, 5 and 6 were administered Aqper oral at 5, 10 and 15 mg kg(-1) b.wt., respectively. Control rats were neither exposed to pyrethroid nor administered Aq. Pyrethroid insecticide led to reduced systolic, diastolic and mean arterial pressures, but increased pulse pressure. Aq treatment did not cause any significant variation in haemodynamic variables. Heart rate was comparable in all groups. Results from the study provide extended safety/toxicity profile for pyrethroid use and Aq treatment. Aq showed no cardiotoxic potential, while pyrethroids have hypotensive effect. It is thus recommended that exposure to pyrethroids should be minimized. PMID- 24163963 TI - Textile effluent induced genotoxic effects and oxidative stress in Clarias gariepinus. AB - Human and ecological disorder experienced in industrial settlements as a result of improper disposal of chemicals such as textile effluent calls for careful surveillance on the state of the environment. This study investigated the toxicity of textile effluent discharge using biochemical and cytogenetic responses to ascertain the acute and sub lethal effects on Clarias gariepinus. The 96 h LC50 of C. gariepinus exposed to the textile effluent was 8.203 ml L( 1). Fourteen day exposures to 1, 2, 4 and 6 ml L(-1) doses were conducted and several toxicological endpoints were evaluated. Sub lethal genotoxicity and biochemical study was also carried out for fourteen days. The genotoxicity studies utilized micronucleus test while the biochemical studies quantified serum anti-oxidant status Total Protein (TP), Catalase (CAT), Superoxide Dismutase (SOD) and Malondialdehyde (MDA) of the exposed fish. Toxicity factor indicates that the 96 h LC50 was significantly more toxic than the 24 h LC50 (p < 0.05). The textile effluent at the tested concentrations induced micronucleus and nuclear abnormalities in the peripheral blood of exposed fish. Micronucleus, notch and binucleated cell formation were significant (p < 0.05) compared to control while lobed and blebbed cells were insignificant (p < 0.05). SOD, TP and CAT significantly (p < 0.05) decreased compared to control group while MDA increased compared to control but was insignificant (p > 0.05). The results obtained from this study showed that textile effluent increase cytogenetic damage and altered anti-oxidant status in C. gariepinus. Chemicals in the effluent can be bioaccumulated and biomagnified in the aquatic organism hence affecting man. PMID- 24163964 TI - Biodiversity and molecular evolution of microalgae on different epiphytes and substrates. AB - An exploration of the microalgal biodiversity from different epiphytes and substrates of pool water in temple at Tiruchirappalli District was studied. Totally ten epiphytic forms were selected for this investigation. In that, totally 44 species of 30 genera belonging to 3 families of the Chlorophyceae, Cyanophyceae (heterocystous and non-heterocystous) and Bacillariophyceae were identified and recorded. The dominant species in this environment were Cyanobacteria (Chroococcus sp. and Oscillatoria sp., Phormidium sp.), Green algae (Tetradron sp. and Scenedesmus sp.) and Diatom (Fragilaria sp. and Navicula sp.) were documented. The molecular taxonomy of cyanobacteria were also analyzed, in this regards, DNA was extracted; 16S rDNA gene was amplified and sequenced. The evolutionary relationship was found in the epiphytic microalgae by Neighbour Joining method by construction of phylogenetic tree. PMID- 24163965 TI - Zoonotic chicken toxoplasmosis in some Egyptians governorates. AB - Toxoplasmosis is one of the most common diseases prevalent in the world, caused by a coccidian parasite Toxoplasma gondii which infects humans, animals and birds. Poultry consider reliable human source of food in addition it is considered an intermediate host in transmission of the disease to humans. Trails of isolation of local T. gondii chicken strain through bioassay of the suspected infected chicken tissues in mice was carried out and the isolated strain was confirmed as being T. gondii using Polymerase Chain Reaction (PCR). Seroprevalence of antibodies against T. gondii in chicken sera in six Egyptian governorates were conducted by enzyme linked immune-sorbent assay (ELISA) using the isolated chicken strain antigen. Moreover, comparison between the prevalence rates in different regions of the Egyptian governorates were been estimated. Isolation of local T. gondii chicken strain was accomplished from chicken tissues and confirmed by PCR technique. The total prevalence rate was 68.8% comprised of 59.5, 82.3, 67.1, 62.2, 75 and 50% in El Sharkia, El Gharbia, Kafr El sheikh, Cairo, Quena and Sohag governorates, respectively. The prevalence rates were higher among Free Range (FR) (69.5%) than commercial farm Chickens (C) (68.5%); while, the prevalence rate was less in Upper Egypt than Lower Egypt governorates and Cairo. This study is the first was used antigen from locally isolated T. gondii chicken strain for the diagnosis of chicken toxoplasmosis. The higher seroprevalence particularly in free range chickens (house-reared) refers to the public health importance of chickens as source of zoonotic toxoplasmosis to human. PMID- 24163966 TI - Investigation of selected biochemical parameters of local chickens with different age and sex in Al-Ahsa, Saudi Arabia. AB - In many species of birds, normal values for hematological and biochemical factors were measured and data base was established as their blood-profiles. In local Saudi chicken, measurement of serum biochemical values, which are important for diagnosis of clinical signs and symptoms when affected by diseases, are limited. Therefore, this study was carried out to investigate serum's biochemical values of local Saudi chicken. Therefore, forty chicks (1 month old; 20 males and 20 females) and another forty chicks (3 month old; 20 males and 20 females) were obtained from the farm of the Veterinary Research Station, King Faisal University, Al-Ahsa, Saudi Arabia and used as materials in the study. Blood samples were collected from all birds and the harvested sera were kept frozen at 20 degrees C until the time of analysis. The present findings indicated no significant difference (p > 0.05) of all examined biochemical parameters between male and female chickens or young and old birds. Interestingly, all investigated biochemical parameters in these chickens were lower than the recorded reference values of other birds except for glucose which exhibited higher values than the reference. The reported lower serum cholesterol and triacylglcerol concentrations might be reflected on their concentrations in meat and protecting human beings from atherosclerosis. Therefore, estimation of lipid profile in these birds is recommended for future study. PMID- 24163967 TI - Cytotoxicity of triphenyltin(IV) methyl- and ethylisopropyldithiocarbamate compounds in chronic myelogenus leukemia cell line (K-562). AB - Studies on the discovery of new cancer treatment by using metal-based compounds such as tin (Sn) has now greatly being synthesized and evaluated to identify their effectiveness and suitability to be developed as a new anticancer drug. APPROACH: This study was carried out to evaluate the cytotoxicity of triphenyltin(lV) methylisopropyldithiocarbamate (compound 1) and triphenyltin(IV) ethylisopropyldithiocarbamate (compound (2) on chronic myelogenus leukemia cells. The determination of their cytotoxicity (IC50) at different time of exposure and concentration was carried out through the employment of 3-(4, 5-dimethylthiazol-2 yl)-2, 5-diphenyl-tetrazolium bromide (MTT) assay. RESULTS: The IC50 values obtained for compound 1 and 2 following treatment at 24, 48 and 72 h were 0.660, 0.223, 0.370 microM and 0.677, 0.306, 0.360 microM, respectively. Cell morphological changes such as apoptotic and necrotic features were also been observed. CONCLUSION: The compounds tested were found to give cytotoxic effect against chronic myelogenus leukemia (K-562) cell at a micromolar dose. Thus, further study on their specific mechanism of actions in the human cells should be carried out to elucidate their potential as an anticancer agent. PMID- 24163968 TI - Assessment of tetracycline, lead and cadmium residues in frozen chicken vended in Lagos and Ibadan, Nigeria. AB - This study determined the levels of tetracycline and heavy metals (lead and cadmium) levels in frozen chicken. One hundred frozen chicken muscle samples were sourced from major markets in Lagos and Ibadan (fifty samples each). The samples were analyzed using high power liquid chromatography (HPLC) for tetracycline residue determination while atomic absorption spectroscopy (AAS) was used to determine the levels of lead and cadmium residues in the samples. Mean concentrations of tetracycline residue levels in the frozen chicken sampled ranged from 1.1589-1.0463ppm which is higher than the maximum residue limit set by international food safety agencies. Pb contents were higher in chicken muscles sampled from markets in Ibadan (0.0227 +/- 0.0069 microg dL(-2)) than Lagos (0.0207 +/- 0.0082 microg dL(-1)), while Cd levels were 0.0013 microg dL(-1) higher than in the Lagos samples (0.0065 +/- 0.0026 microg dL(-1)). These values were within maximum residue limits. There were no significant differences (p < 0.05) in levels of tetracycline, lead and cadmium levels from the two market locations (Lagos and Ibadan) and parts (wings and thigh muscles). However, significant differences occurred in tetracycline and Pb levels in frozen chicken sourced from Cotonou. Though not significant, tetracycline contents in the thigh muscles of the frozen chicken samples was higher than that of the wings muscles and this was attributed to the site of administration of antibiotic injection and failure to observe the pre-slaughter withdrawal period by the farmers. This study is of public health importance as the presence of these residues above the maximum residue limit in frozen chicken predisposes consumers to drug resistance, allergic reactions and poisoning as a result of toxicity. PMID- 24163969 TI - Effect of bambara groundnut flour (Vigna subterranea (L.) Verdc.) supplementation on chemical, physical, nutritional and sensory evaluation of wheat bread. AB - Bambara groundnut (Vigna subterrenea (L) Verdc) is a major source of vegetable protein in sub-Saharan Africa. And the aim of this study was to enhance the nutritional value of wheat bread through the addition of bambara groundnut flour to wheat four. For this, bambara groundnut seeds were soaked in tap water, manually decorticated, sun dried and milled into fine flour. Proximate analysis of flours of de-hulled bambara groundnut and wheat were conducted. Flour of de hulled bambara groundnut was used for bread supplementation in ratios of 5, 10 and 15%. Rheological properties of the control flour and wheat flour supplemented with 10% of de-hulled bambara groundnut flour were conducted. The total area and dough development time increased. However, water absorption, stability and extensibility respectively decreased, from 71.3; 8.5; 190 in the control flour to 71.0; 5.5; 180 in the 10% supplemented flour. The increases in the resistance to extension and proportional number from 260 to 280 and 1.37 to 1.56, respectively resulted in stiff dough. The most important effect of wheat bread supplementation was the improvement of protein quantity from 13.74 +/- 0.02% for the control bread to 15.49 +/- 0.02, 17.00 +/- 0.05 and 18.98 +/- 0.02% for the 5, 10 and 15% blending ratios, respectively. The in-vitro protein digestibility progressively increased from 84.33 +/- 0.03 in the control bread to 85.42 +/- 0.04, 86.57 +/- 0.04 and 87.64 +/- 0.03 in breads containing 5, 10 and 15% bambara groundnut flour. The sensory attributes of different types of bread showed that, a significant difference was observed in texture, colour and overall acceptability. However, the panelists gave higher score for 10% de-hulled bambara groundnut flour bread than bread made from other blends. The loaf weights, loaf volume and specific volume increased. However, while the loaf weight increased with addition of 15% de-hulled bambara groundnut flour, both of loaf volume and specific volume decreased. Nutritional value of wheat bread can be enhanced by the addition of de hulled bambara groundnut flour at a level of up to 10%. PMID- 24163970 TI - Phylogeny and evolutionary analysis of goat breeds in Jordan based on DNA sequencing. AB - Phylogeny and evolutionary analyses were performed for Jordan goat breeds based on DNA sequencing. DNA segment of 0.5-kb from sixteen goat individuals of four breeds was sequenced. The DNA sequencing was analyzed by both Arlequin and MEGA softwares. The results showed a quite evolutionary differentiation found within goat breeds between. Furthermore, phylogeny tree was reconstructed providing evidences for a close phylogenetic alliance among breeds. The resulted evolutionary sequencing and phylogeny trees provide evidences that sequencing data were worthy to describe the evolutionary and phylogeny genetics in goats breeds in Jordan. On other hand the data were given scopes for possible sequences of gene(s) and identify polymorphisms, given possibility to identify Caprine genes from other close species genome like cattle. In the future we intend, in order to clearly identify the genetic polymorphisms, to detect further genetic variation and to develop tests particularly suitable for specific interested genes genotyping. PMID- 24163971 TI - [Sudden cardiac death in athletes]. AB - Sudden deaths occurring during exercise are rare and are most commonly due to cardiac arrest. It is most commonly underlain by symptomless cardiomyopathy or coronary artery disease. Preventive work comes up against a diagnostic problem in distinguishing adaptational changes of the athletic heart from a heart disorder. To reveal the danger of cardiac arrest and reduce human tragedies international sports organizations and cardiologic expert groups recommend screening of cardiac disorders among competing athletes. PMID- 24163972 TI - [Viral infection--a diverse causative agent of cancer]. AB - Viral infections are a common cause for the development of cancer. Most common among the cancer-inducing viruses are human papillomaviruses, which cause cervical cancer among other things. Cancer viruses aim to keep their host cells alive and simultaneously use their oncogenes to interfere with cellular phenomena such as proliferation and programmed cell death. The most effective way of preventing viral cancers is to reduce the frequency of cancer virus infections by using vaccinations and by intervening in high-risk behavior. In addition, the infections must be detected and treated in advance of cancer development. PMID- 24163973 TI - [Tonsillotomy]. AB - In tonsillotomy, only the obstructive tonsillar tissue is removed without touching the surrounding tissue of the palatine tonsil. Tonsillotomies have been mainly performed for children due to tonsillar hypertrophy. Less postoperative pain is recorded after tonsillotomy compared with tonsillectomy. In addition, recovery is quicker and there are fewer complications. Tonsillotomy is an effective method in cases where the indication for surgery is tonsillar hypertrophy and associated symptoms such as snoring or difficulties in swallowing. PMID- 24163974 TI - [Chemotherapy in conjunction with blood brain barrier disruption in the treatment of primary central nervous system lymphoma]. AB - Primary central nervous system lymphoma (PCNSL) is sensitive to both chemotherapy and radiation, but the blood-brain barrier limits the usefulness of the most effective chemotherapeutic agents. On the other hand radiation therapy carries along serious long term adverse events. In BBBD-therapy the blood-brain barrier is opened with intra-arterial mannitol infusion thus permitting both the chemotherapeutics and antibodies to enter through blood-brain barrier. So far 17 patients have started the therapy in our clinics. Ten patients have reached a complete response and 8 of these responses are ongoing with follow-up times of 6 62 months. PMID- 24163975 TI - [Insulin pump therapy: for whom and why?]. AB - Insulin pump therapy utilizes continuous infusion for the basic supply of insulin. As compared with multiple daily injections, pump therapy enables a clearly more precise targeting of the insulin therapy with respect to both time and quantity. This is important for insulin-sensitive patients such as small children, adults susceptible to hypoglycemia, or diabetics, whose blood glucose level exhibits a clear-cut elevation in the small hours (the dawn phenomenon). Also a diabetic with a high HbA1c and a good motivation for treatment may significantly benefit from the pump. Insulin pump therapy requires commitment to good self-monitoring from the diabetic patient. PMID- 24163976 TI - [How to treat an elderly person's cancer?]. AB - Among the elderly having cancer, many are in good condition and wish for active treatment. Although elderly people have been shown to benefit from oncological treatments, they are more susceptible than the young to the adverse effects of treatment. Comprehensive geriatric assessment has been utilized in predicting the capability of an elderly patient to tolerate treatment. A functional status questionnaire completed by the patient her/himself has been used in the oncological unit of Helsinki University Hospital in support of a cancer drug therapy assessment. The consultations with an oncologist have been centralized and the patients have had a possibility to meet a geriatrist. PMID- 24163977 TI - [Osteomyelitis in pregnancy]. AB - Osteomyelitis is an infection of bone, which most frequently is found in weight bearing bones of lower extremities. Only 4% of acute osteomyelitis cases have been found in the pubic bones in Finland. These cases of the pubic bones are usually related to gynecological or urological procedures or trauma. Osteitis, which is much more common than osteomyelitis, is a differential diagnosis for pregnant or postpartum women. These two diseases are difficult to distinguish based on the symptoms, even if it is important because osteomyelitis needs to be cured with antibiotics but to cure osteomyelitis NSAIDs are enough. The diagnosis of osteomyelitis is based on clinical examination, radiological imaging and laboratory tests. PMID- 24163978 TI - [The effect of gastric sleeve and bypass surgery on the use and costs of medications for type 2 diabetes]. AB - The study group consisted of 96 patients who had used a medication for type 2 diabetes; of them, 33 had undergone gastric sleeve surgery and 63 bypass surgery. Both surgical methods resulted in a similar weight loss among the patients. In follow-up 39 out of 88 patients were able to manage without antidiabetic drugs two years after surgery. The costs of antidiabetic drugs two years after surgery were 79% lower than before the operation. Weight reduction surgery decreases the need for antidiabetic drugs. The greatest cost-efficiency is achieved by targeting weight-loss operations to patients using insulin therapy. PMID- 24163979 TI - [Supraglottitis in adults at a single center experience 1989-2009]. AB - Acute epiglottitis in children has almost vanished since the start of Hib vaccinations. Supraglottitis often develops in adults more slowly than in children. We reviewed all patients at Tampere University Hospital over the age of 18, who had been recorded with a diagnosis of epiglottitis or supraglottitis upon discharge from the hospital between 1989 and 2009. The most common symptoms were sore throat and pain on swallowing. Streptococcus was the most common causative agent. Most of the 308 patients had received conservative treatment. Supraglottitis should be remembered as possible diagnosis when an adult person complains of a sore throat. PMID- 24163980 TI - [Update on current care guideline: bipolar affective disorder]. AB - Bipolar affective disorder (BD) is a long-term mental disorder presenting remittent depressive, hypomanic, manic or mixed episodes of illness and low symptomatic or asymptomatic intermediate periods. It is related to a serious risk of self-destructive behaviour. Patients are typically symptomatic approximately half of the time. Treatment focuses on preventing the recurrence of episodes. The care is based on mood stabiliser and second generation antipsychotic medication in accordance with the patient's current symptoms. When added to pharmacotherapy, psychosocial interventions can improve the outcome. Patients with BD are usually treated in psychiatric outpatient clinics. PMID- 24163981 TI - [Effects of water deficiency on mitochondrial functions and polymorphism of respiratory enzymes in plants]. AB - In plants, adaptive-compensatory responses to stress always entail additional energy expenditure. A suggestion was brought forward that in plants growing under conditions of water stress there is a relationship between genetic variability of respiratory enzymes and their functional significance. With Kochia prostrate (L.) Schrad. as a case study, intraspecies genetic polymorphism under the conditions of drought has been analyzed using typical protein markers which, considering their functional importance, can be viewed as respiratory enzymes. Out of eight protein markers examined, four enzymes were singled out for which dominating combination of genotypes Dia B (a), G6pd (a), Gdh (c), and Mdh A (a) was incidental. In all populations from arid and semiarid zone, these genotypes frequency of occurrence was in the range of 0.53-1.0, i.e., it comprised more than 50% of the whole variety of combinations. Thus, it seems plausible that this combination of genotypes can be an "adaptive collection" for K. prostrata populations growing in arid habitats. A characteristic feature of the picked out enzymes is their belonging to NAD(P)(+)-depending oxidoreductases that play a key role in functioning and redox-regulation of respiratory metabolism in course of adapting to water deficiency. It is suggested that the presence of such well balanced co-adaptive genotype combinations, that provide enzymes important in terms of energetics, determine the formation of energetic and redox-balances during the process of adaptation to water stress. PMID- 24163982 TI - [Ornithine decarboxylase in mammalian organs and tissues at hibernation and artificial hypobiosis]. AB - Ornithine decarboxylase (ODC, EC 4.1.1.17.) is a short-lived and dynamically regulated enzyme of polyamines biosynthesis. Regulation of functional, metabolic and proliferative state of organs and tissues involves the modifications of the ODC enzymatic activity. The organ-specific changes in ODC activity were revealed in organs and tissues (liver, spleen, bone marrow, kidney, and intestinal mucosa) of hibernating mammals - squirrels Spermophilus undulates - during the hibernating season. At that, a positive correlation was detected between the decline and recovery of the specialized functions of organs and tissues and the respective modifications of ODC activity during hibernation bouts. Investigation of changes in ODC activity in organs and tissues of non-hibernating mammals under artificial hypobiosis showed that in Wistar rats immediately after exposure to hypothermia-hypoxia-hypercapnia (hypobiosis) the level of ODC activity was low in thymus, spleen, small intestine mucosa, neocortex, and liver. The most marked reduction in enzyme activity was observed in actively proliferating tissues: thymus, spleen, small intestine mucosa. In bone marrow of squirrels, while in a state of torpor, as well as in thymus of rats after exposure to hypothermia hypoxia-hypercapnia, changes in the ODC activity correlated with changes in the rate of cell proliferation (by the criterion of cells distribution over cell cycle). The results obtained, along with the critical analysis of published data, indicate that the ODC enzyme is involved in biochemical adaptation of mammals to natural and artificial hypobiosis. A decline in the ODC enzymatic activity indicates a decline in proliferative, functional, and metabolic activity of organs and tissues of mammals (bone marrow, mucosa of small intestine, thymus, spleen, neocortex, liver, kidneys) when entering the state of hypobiosis. PMID- 24163983 TI - [Fine root nitrogen contents and morphological adaptations of alpine plants]. AB - Nitrogen and carbon contents of fine roots were studied for 92 alpine plant species in the Northwest Caucasus. Nitrogen content ranged from 0.43% (Bromus variegatus) to 3.75% (Corydalis conorhiza) with mean value 1.3%. Carbon content ranged from 40.3% (Corydalis conorhiza) to 51.7% (Empetrum nigrum) with mean value 43.4%. C:N ratio was found to be 34:1 which is higher than the worldwide mean. Eudicot's roots had higher N concentration (1.37 +/- 0.07) than monocot's ones (0.95 +/- 0.09). Among the life forms, carbon content increased in the following order: geophytes < hemicriptophytes < chamaephytes. Specific root length positively correlated with nitrogen root content and negatively--with carbon root content. Species with larger leaves and higher specific root area had more nitrogen and less carbon in roots in comparison with species with small leaves. There were positive correlations between leaf and root nitrogen, as well as carbon, contents. Regrowth rate; seed size, aboveground biomass, and vegetation mobility were not related with root nitrogen content. Our results corroborate the poor and rich soil adaptation syndromes. Species of competitive and ruderal (sensu Grime) strategies are more typical for alpine meadows and snow bed communities. They had higher nitrogen contents in leaves and roots, larger leaves with higher water content and higher rate of seed production. On the other hand, stress-tolerant plants had higher carbon and less nitrogen concentrations in their roots and leaves, smaller leaves and specific leaf area. PMID- 24163984 TI - [Evolutionary history of Metazoa, ancestral status of the bilateria clonal reproduction, and semicolonial origin of the mollusca]. AB - Evolutionary history of any metazoan group is a history of the entire ontogenetic cycles instead of separate stages and genes only. Ontogeny in the most objective way links two key components of the biological systematics: historically independent characters attribution and phylogeny itself. A general theory encompassing "static" traditional taxonomy and dynamic evolutionary process, based on the ontogenetic transformation of the organisms' shape is suggested here to term as ontogenetic systematics. As an important practical implication of the ontogenetic systematics, a new model of the bilaterian metazoans evolution is suggested. The new model considers asexual clonal reproduction as a central feature of the ancestral ontogenetic cycles of basal Bilateria. The new scenario resolves several notable contradictions, e.g. morphological, ontogenetic and molecular similarities of Pogonophora, Vestimentifera, Phoronida simultaneously to protostomian Spiralia (Lophotrochozoa) and Deuterostomia. The suggested model implies individuation (possibly multiple) of ancestral semicolonial sedentary group as a major factor of the basal Bilateria diversification. In the late Ediacaran and early Cambrian thus existed ancestral bilaterian group that shared characters of both Spiralia and Deuterostomia and possessed polyp-shape body and cephalic secretory shield (like in modern Pterobranchia and Vestimentifera), that later on reduced in various lines. This ancestral taxon in rank of supraphylum is suggested to term as Carmaphora (shield-bearers). Presence of the enigmatic sedentary fossil of the genus Cloudina with vestimentiferan-like tubes and evident clonal reproduction already in the late Ediacaran, and most recent found of an unquestionable pterobranch already in the early Cambrian support the new model of Bilateria evolution. PMID- 24163985 TI - Prevalence of positive culture of genitourinary tract microorganisms in pregnant women with presumptive preterm labor. AB - BACKGROUND: Cultures of genitourinary tract microorganisms have been included in routine evaluation for all pregnant women who present with presumptive preterm labor However some studies found that this assessment is costly and adds little value. OBJECTIVE: To determine the proportion of pregnant women with presumptive preterm labor who had positive culture of genitourinary tract microorganisms and to determine the relationship of positive genitourinary infection and pregnancy outcomes. MATERIAL AND METHOD: This retrospective cohort study was performed at Department of Obstetrics and Gynecology, Faculty of Medicine, Siriraj Hospital, Mahidol University. Medical records of pregnant women with presumptive preterm labor who were admitted in non-private labor room between January 2003 and December 2008 were reviewed Characteristics, results of vaginal swab culture and urine culture, and clinical outcomes were analyzed and reported. RESULTS: The prevalence of positive culture of genitourinary tract microorganisms in presumptive preterm labor-women (total n = 704) was 24.3% (95% CI = 21.3-27.6), 22.1% (95% CI = 19.1-25.4) of vaginal swab culture and 5.3% (95% CI = 3.8-7.2) of urine culture. However only 9.8% were pathologic organisms. There were no statistically significant differences in characteristics and rate of preterm labor between women with a positive and a negative culture. Moreover, there were no statistically significant differences in characteristics and preterm birth outcomes between women in both groups. CONCLUSION: There were no clinical significances of positivity of pathologic bacteria from genitourinary tract as a predictor of preterm delivery and its outcomes. Although the prevalence is quite high, the value of these screenings is still questionable. PMID- 24163986 TI - Apolipoprotein E genetic polymorphisms and the development of nephropathy in type 2 diabetes. AB - BACKGROUND: Apolipoprotein E (ApoE) polymorphisms have been proposed as the risk factor for the development of diabetic nephropathy (DN). A number of studies have investigated the association between the ApoE isoforms and DN. However the findings remain inconclusive. OBJECTIVE: To determine the association between the ApoE polymorphisms and DN. MATERIAL AND METHOD: Two hundred thirty patients with type 2 diabetes were divided into two groups, patients with clinically diagnosed DN and normoalbuminuric patients. ApoE genotypes were determined by RT-PCR analysis. Student's t-test, ANOVA test, Chi-square test, odds ratio, and logistic regression was performed. RESULTS: The frequency of ApoE4 genotype was significantly lower in DN patients (8.7%) than in normoalbuminuric patients (21.7%). Logistical regression analysis showed that subjects with ApoE4 genotype (adjusted OR = 0.43; 95% CI: 0.19-0.99) were less likely to have DN than subjects with ApoE3 genotype. Furthermore, when analyzed only in patients with overt DN vs. patients with normoalbuminuria, the frequency of e4 allele was decreased in overt DN (2.8% vs. 21.7%, adjusted OR = 0.13; 95% CI: 0.03-0.57) and the frequency of e2 allele was increased (25.4% vs. 13.0%, adjusted OR = 2.34; 95% CI: 1.02- 5.38). CONCLUSION: ApoE4 genotype is associated with protection from type 2 DN, and subjects with e2 allele have increased risk of developing type 2 overt DN. PMID- 24163987 TI - Clinical results of large secundum atrial septal defect closure in adult using percutaneous transcatheter Cocoon atrial septal occluder. AB - BACKGROUND: Atrial septal defect (ASD) is a common congenital heart disease in adults. Amplatzer septal occluder is one of the most common devices used for transcatheter closure due to its high success rate and ease to implant. Cocoon atrial septal occluder is a new nitinol-based device, its shape resembles Amplatzer septal occluder but coated with platinum to prevent nickel release. Little is known about clinical outcomes of large ASD closure using Cocoon atrial septal occluder OBJECTIVE: To review our experience in closure of secundum ASD in adults by Cocoon septal occluder and to compare the clinical outcomes and results of the patients who had ASD closure with a device greater than or equal to 30 mm and less than 30 mm. MATERIAL AND METHOD: Between November 2005 and October 2008, 63 consecutive patients underwent transesophageal echocardiography (TEE)--guided transcatheter closure of secundum ASD. The patients were divided into two groups (Groups' 1 and 2) according to device diameter that is greater than or equal to 30 mm (n = 31) and less than 30 mm (n = 32), respectively. Clinical outcomes, complications, and transthoracic echocardiography (TTE) before hospital discharge, one to three months, and one-year were analyzed. RESULTS: Device implantations were successful in 27 patients (87.1%) in group 1 and 31 patients (96.9%) in group 2 (p = 0.196). The maximum size of secundum ASD in group 1 determined by TTE, TEE, and balloon sizing diameter (BSD) were 22.6 +/- 5.0 mm (range 15-32), 28.1 +/- 4.8 mm (range 19-39), and 31 +/- 3.5 mm (range 23-38) respectively. The maximum size of secundum ASD in group 2 determined by TTE, TEE, and BSD were 19.7 +/- 4.4 mm (range 12-31), 20.4 +/- 3.4 mm (range 13-26), and 23.1 +/- 2.9 mm (range 15-30) respectively. The mean device size in groups 1 and 2 were 33.5 +/- 3.1 mm and 24.6 +/- 3.3 mm, respectively. Four patients (12.9%) in group 1 had unsuccessful implantations. All of them were in the first 15 cases of using large device and two of them had device embolization requiring surgical removal. One patient (3.1%) in group 2 had an unsuccessful implantation and had device embolization requiring surgical removal. The patients in both groups gradually improved in clinical symptoms with decreased RVsystolic pressure and decreased RV size with complete ASD closure at one year CONCLUSION: Transcatheter closure of large secundum ASD by Cocoon septal occluder is feasible with hemodynamic benefit. However complication rates are higher with large ASD closure with device size greater than or equal to 30 mm especially during the early "learning curve" period. With experience, the complication rate declines and the success rate is no different from the group with smaller device size. PMID- 24163989 TI - Comparative study: single-incision laparoscopic cholecystectomy and conventional three-ports laparoscopic cholecystectomy. AB - BACKGROUND: Laparoscopic cholecystectomy is now standard treatment of gallstone disease and has traditionally been performed using multiple small sites. Single incision laparoscopic surgery has emerged as an alternative technique to improve cosmesis and minimize complications associated with multiple incisions pain and longer hospital stay. MATERIAL AND METHOD: Between January 2010 and December 2012, 40 patients were assigned to one of the two groups, SILS-C or conventional LC. Surgical indication, operative time, length of stay, and surgical complications were compared between the two groups. RESULTS: Twenty patients underwent SILS-C and 20 patients underwent conventional three ports LC. The average length of stay was 2.60 +/- 0.88 days after SILS-C compared with 2.65 +/- 0.87 days after CLC (p = 0.871). Operative time was significantly longer in the SILS-C group. An average of 65 minutes was needed to complete a SILS-C (range 35 141) versus 51 minutes (range 24-109) for a CLC (p < 0.001). There was no difference in pain score and complications between both groups but SILS-C group use less analgesic (81.00 +/- 36.55 mg in SILS-C vs. 123.00 +/- 42.31 mg in the conventional group). CONCLUSION: The Single Incision Laparoscopic Cholecystectomy (SILS-C) is feasible and safe. The results of SILS-C were comparable with the standard conventional LC. PMID- 24163990 TI - Lessons learned from 100 personal consecutive cases of pancreaticoduodenectomy at a university hospital in Thailand. AB - BACKGROUND: Pancreaticoduodenectomy (PD) is a major operation with potential disastrous complications. Experience of the surgical team with high surgical volume is an important factor contributing to better outcome. The purpose of this study was to examine results of 100 consecutive cases of PD operated by the first author. Various aspects of this technically demanding operation related to our experience were discussed and reviewed. MATERIAL AND METHOD: A retrospective study of 100 patients who had undergone PD during a period of 20.5 years was presented. The indications for PD were periampullary neoplasms or other symptomatic lesions at the pancreatic head. All patients had preoperative CT scan to evaluate extent of the disease and resectability. Preoperative biliary drainage was performed in selected cases. The operations were conducted in the same manner in most cases. Before 2000, no external drainage of the pancreatic remnant was used. Since 2000, external drainage of the pancreatic remnant was routinely used, except in one patient who had total pancreatectomy. Postoperative complications and mortality were studied. RESULTS: Carcinoma of the ampulla of Vater and carcinoma of the head of the pancreas were the leading indications for PD (34% and 30%, respectively). No preoperative tissue diagnosis was made in patients who had carcinoma of the head of the pancreas. Two patients had emergency PD because of massive gastrointestinal bleeding. Sixty seven per cent underwent pylorus preserving PD (PPPD) and 33% underwent classical PD. Twenty eight patients had no external pancreatic drainage, 71 had external pancreatic drainage, and one had total pancreatectomy. The postoperative morbidity and mortality were 44% and 2%, respectively. The postoperative pancreatic fistula rate was higher in patients without external pancreatic stent but no statistical significance was detected (21.4% vs. 12.7%, NS). There was no mortality in patients aged > 70 years (n = 29) while two patients aged < 70 died (n = 71). The difference was not statistically significant. CONCLUSION: PD could be safely performed with low pancreatic fistula and low mortality rate by experienced surgeons. Preoperative CT scan is extremely helpful in evaluation the extent of the disease and resectability. In patients with suspected carcinoma of the pancreatic head, PD should be performed without preoperative tissue diagnosis by experienced pancreatic surgeons. Elderly (aged > 70 years) is not a contraindication for PD. We strongly recommend the use of external pancreatic stent to prevent pancreatic fistula. PMID- 24163988 TI - Randomized, double-blind, split-side, comparison study of moisturizer containing licochalcone A and 1% hydrocortisone in the treatment of childhood atopic dermatitis. AB - BACKGROUND: Atopic dermatitis (AD) is a common chronic inflammatory skin lesion in children. Topical corticosteroid is the mainstay of treatment. OBJECTIVE: To compare the efficacy of moisturizer containing licochalcone A (LicA) and 1% hydrocortisone for the treatment of mild to moderate childhood AD. MATERIAL AND METHOD: This was a multicenter randomized, prospective, split-side, double-blind study in 55 children between the age of three months and 14 years. Patients with AD were treated twice daily, simultaneously with either Lic A or 1% hydrocortisone on opposite sides of the lesion. The SCORAD and transepidermal water loss (TEWL) were performed at the baseline, 2-week, and 4-week visits. Lic A was used on both sides of the body for another four weeks to see the effects and TEWL. RESULTS: In a randomized period, both products were equally effective in the treatment. SCORAD decreased significantly from baseline for both treatments throughout the first four weeks (p < 0.001). There was no statistically significant difference in SCORAD between both treatments (p = 0.321 and p = 0.146 at week 2 and 4, respectively). Lic A had statistically significant decrease in TEWL (p = 0.027 and p = 0.03 at weeks 2 and 4, respectively). One patient had infection on skin lesions of both sides of the body. Forty-three patients continued to the period of using Lic A on both sides of the body. SCORAD and TEWL were comparable to the end of the randomized period and significantly lower from baseline (p < 0.001). Skin lesions flared up in three patients (7.5%). CONCLUSION: Lic A had a similar result in terms of SCORAD compared to 1% hydrocortisone for the treatment of mild and moderate AD. TEWL was significantly lower than baseline on the side that used Lic A. Continuing use of Lic A for four weeks can maintain clinical and barrier improvement. PMID- 24163991 TI - Comparison of the clinical outcomes between unattended home APAP and polysomnography manual titration in obstructive sleep apnea patients. AB - OBJECTIVE: To compare the clinical outcomes and determine the difference in therapeutic pressure between Automatic positive airway pressure (APAP) and polysomnography manual titration. MATERIAL AND METHOD: Fifty patients of obstructive sleep apnea (OSA), moderate to severe cases, were randomized into two groups of intervention: 95-percentile pressure derived from APAP titration and an optimal pressure derived from manual titration. Clinical outcomes were assessed before and after four weeks. RESULTS: The average 95-percentile pressure derived from APAP titration was 11.7 +/- 0.3 cmH2O with median mask leak 1.3 L/min. The average optimal pressure derived from manual titration was 8.2 +/- 0.3 cmH2O. Pearson correlation analysis showed weak positive correlation (r = 0.336, p = 0.017). The Epworth Sleepiness Score (ESS), Quality of life tests: PSQI (Pittsburg Sleep Quality Index), and SF-36 (Medical Outcomes Study 36-Item Short Form Health Survey) were improved significantly in both groups, but there were no statistical significant differences between groups. CONCLUSION: An APAP titration is an effective method of pressure determination for conventional CPAP therapy and shows no difference in clinical outcomes comparing the standard titration. PMID- 24163992 TI - Oncologic and functional outcomes in advanced laryngeal and hypopharyngeal cancer treated with concurrent chemoradiation versus primary surgery followed by adjuvant treatment. AB - OBJECTIVE: To compare oncologic outcomes in advanced laryngeal and hypopharyngeal cancer (LHC) patients who received either concurrent chemoradiation (CRT) or primary surgery followed by adjuvant treatment and to examine functional outcomes in the patients treated with CRT. MATERIAL AND METHOD: The clinicopathological data of 136 patients, diagnosed as stage III or IV LHC, were retrospectively reviewed. The eligible patients were classified into two groups based on their primary treatment, CRT group and group of surgery followed by the adjuvant treatment. Oncologic outcomes were evaluated and compared at five years. Functional outcomes were recorded as tracheostomy and/or feeding tube dependency. RESULTS: Five-year overall survival rates were 66.9% for the primary surgery group and 34.8% for the CRT group (p = 0.004). Five-year disease-specific survival rates for the same two groups were 66.9% and 39.9%, respectively (p = 0.03). The three-year laryngectomy-free survival rate in the CRT group was 71.9%. At three months post-CRT 62.3% of patients depended on tracheostomy and/or a feeding tube. CONCLUSION: The primary surgery followed by adjunctive treatment among the advanced LHC cases had significantly better oncologic outcomes. Nevertheless, CRT group had a high survival rate with a preserved larynx, but with relatively inferior functional outcomes. PMID- 24163993 TI - Prevalence of chronic rhinitis in Thai patients with obstructive sleep disordered breathing. AB - OBJECTIVE: To prospectively identify the prevalence of chronic rhinitis (CR) and findings from objective nasal airway evaluation in Thai patients with obstructive sleep disordered breathing (OSDB) in a sleep clinic. MATERIAL AND METHOD: Seventy patients, 44 males and 26females, with OSDB were recruited. All were asked to complete Epworth sleepiness scale (ESS), questionnaires regarding nasal symptoms including scores to assess the severity of CR, and objective nasal airway measurements. Nasal airway resistance (NAR) was measured by active anterior rhinomanometry and nasal volume and minimal cross-sectional area (MCA) were measured by acoustic rhinometry (before topical decongestion). RESULTS: Fifty nine patients (84.3%) had a history of nasal obstruction, rhinorrhea, sneezing, and itching of either intermittent or persistent pattern, regardless of severity, for more than one month. Forty-six patients (65.7%) had active symptom of nasal obstruction. About 23% of patients had NAR higher than and 33% had MCA lower than 1 SD from the mean of normative values in healthy Asians. Both subjective and objective nasal parameters did not have a statistically significant correlation with the scores of ESS. CONCLUSION: A substantial proportion of patients with OSDB in the sleep clinic had co-existing CR symptoms and a tendency to be abnormal in objective nasal parameters when compared to general population. Careful history recording and a thorough evaluation of the nasal airway are, therefore, essential in these patients. PMID- 24163994 TI - Differentiating between abdominal tuberculous lymphadenopathy and lymphoma using multidetector computed tomography (MDCT). AB - OBJECTIVE: To evaluate the specific computed tomography (CT) imaging criteria for differentiating abdominal tuberculous lymphadenopathy from lymphoma by using abdominal multidetector computed tomography (MDCT). MATERIAL AND METHOD: A retrospective review of 31 patients with abdominal tuberculous lymphadenopathy and 85 patients with untreated lymphoma was conducted from abdominal CT scan reports in a single center; Siriraj Hospital, Mahidol University, Bangkok Thailand. CT scan was independently reviewed by two expert radiologists who were blinded to the patient's history, treatment outcome, and final diagnosis. The anatomical site, anatomical distribution, CT enhancement patterns, size of lymphadenopathy, amount and density of ascites, abdominal solid organ involvement, bowel involvement, and lung involvement were recorded RESULTS: MDCT showed that abdominal tuberculous lymphadenopathy involved predominately the mesenteric, upper and lower para-aortic, periportal, and pancreaticoduodenal regions. Untreated lymphoma affected mainly the upper and lower para-aortic, iliac, periportal, pancreaticoduodenal, and gastrohepatic regions. Mesenteric and periportal lymph nodes were involved more often in patients with abdominal tuberculous lymphadenopathy than in those with untreated lymphoma (p = 0.04). Iliac and inguinal lymph nodes were involved more often in patients with lymphoma than in those with tuberculosis (p = 0.01). Anatomical distributions were significantly different between the two groups (p< 0.01): confluence distribution was noted more often in tuberculous lymphadenopathy. The enhancement patterns had significant difference between the two groups. Peripheral enhancement was seen significantly more often in tuberculous lymphadenopathy, whereas homogeneous enhancement was found more often in lymphoma. The maximum size of enlarged lymph nodes also showed statistical difference between two groups by using t-test (p = 0.01). The mean diameters were 2.95 cm in tuberculous lymphadenopathy and 4.10 cm in lymphoma. Ascites was found significantly more often in tuberculous lymphadenopathy than in lymphoma (p = 0.03). However; the attenuation of ascites on pre-contrast images did not show statistical difference. Small bowel and large bowel thickening were demonstrated more often in tuberculous lymphadenopathy than lymphoma (p < 0.01, p = 0.01), which mostly showed target sign enhancement in tuberculosis and homogeneous enhancement in lymphoma. The presence of hepatomegaly and splenomegaly were not different between the two groups. The diagnostic interpretations of two readers showed high sensitivity (93.5%) and high specificity (98.8% by reader 1 and 97.6% by reader 2). CONCLUSION: The present study indicates that the anatomical site, anatomical distribution, enhancement patterns, and size of lymphadenopathy, persistent ascites, and small and large bowel involvement seen on contrast-enhanced MDCT is useful in differentiating between tuberculosis and untreated lymphomas. PMID- 24163995 TI - Diagnostic performance of perfusion MRI in differentiating low-grade and high grade gliomas: advanced MRI in glioma, A Siriraj project. AB - BACKGROUND: To determine the usefulness of the perfusion MRI technique at Siriraj Hospital for differentiating between high- and low-grade gliomas by using pathological results as the gold standard. MATERIAL AND METHOD: The authors prospectively investigated 64 consecutive patients who were suspected as cerebral glioma from prior conventional imaging. Cerebral perfusion study was achieved during the first pass of a bolus of gadolinium-based contrast agent. All post processing MRI images were interpreted by two board-certified neuroradiologists (more than 10-year-experience), one radiology resident and one well-trained technician, who separately performed and blinded from the pathological results. RESULTS: Forty-four patients diagnosed as glioma were included in this study. There were 26 cases of high-grade and 18 cases of low-grade gliomas. The cerebral blood volume and flow and its ratios had a strong association with the grade of glioma. The areas under the ROC curve for CB K CBVratio (rCBV), CBF and CBF ratio (rCBF) are 0.778, 0.769, 0.769, and 0.772, respectively. On the basis of equal misclassification rates, a cutoff value of 6.15 for CBV (sensitivity, 81.5%; specificity, 64.7%), a cutoff value of 2.38 for the rCBV (sensitivity, 88.9%; specificity, 64.7%), a cutoff value of 0.66 for CBF (sensitivity 81.5%; specificity 70.6%), and a cutoff value of 2.6 for the rCBF (sensitivity, 85.2%; specificity, 70.60%) best discriminated the high and low-grade gliomas. CONCLUSION: Preoperative radiologic grading of gliomas based on conventional MR imaging is sometimes unreliable. The cerebral perfusion measurements can significantly improve the sensitivity and predictive values of radiologic glioma grading. The rCBV measurement is the best parameter for tumor grading due to the highest sensitivity. PMID- 24163996 TI - Identification of stroke mimics among clinically diagnosed acute strokes. AB - BACKGROUND: Stroke is a clinically syndrome of a sudden onset of neurological deficit in a vascular cause. Stroke mimics is the non-vascular disorders with stroke-like clinical symptoms. It is important to distinguish true stroke from mimics since treatment plan may differ OBJECTIVE: To determine the incidence of the stroke mimics and identify their etiologies. MATERIAL AND METHOD: All non contrast head CT of the patients with clinically diagnosed stroke who immediately received imaging upon arrival at the emergency department of the university hospital were retrospectively reviewed in 12-month period between January 1 and December 31, 2008. Medical records, laboratory results, MRI, and 6-month clinical follow-up records were reviewed for final diagnosis. RESULTS: Seven hundred four patients were included in this study, including 363 (51.5%) men and 341 (48.5%) women with range in age from 24 to 108 years. Amongst those, 417 (59.2%) were ischemic stroke, 80 (11.40%) were hemorrhagic stroke, 186 (26.4%) were stroke mimics, and 21 (3%) were inconclusive. The etiologies among stroke-mimics were metabolic/intoxication (35, 18.8%), sepsis (28, 15.0%), seizure (21, 11.3%), syncope (20, 10.8%), subdural hemorrhage (14, 7.5%), vertigo (11, 6.0%), brain tumor (10, 5.30%), central nervous system infection (5, 2.7%), others (26, 14.0%), and unspecified (16, 8.6%). CONCLUSION: Incidence rates and etiologies of the stroke mimics were similar to the western reports. However the frequency of each mimic was not. PMID- 24163997 TI - The correlation of post-operative radioiodine uptake and Tc-99m pertechnetate thyroid scintigraphy and the result of thyroid remnant ablation. AB - OBJECTIVE: Determine the relationship between postoperative thyroid remnant using 24 h radioiodine uptake and Tc-99m pertechnetate scintigraphy, and the success of high dose radioiodine ablation. MATERIAL AND METHOD: Retrospectively enrolled 250 patients with DTC who underwent thyroidectomy and radioiodine ablation. Postoperative Tc-99m pertechnetate and 24 h 1-131 uptake were reviewed to evaluate thyroid remnant and the directly compared with ablation outcome. The successful ablation was defined using negative WBS and stimulated Tg < 10 ng/ml in the absence of TgAb at six to 12 months after treatment. The relationship between success of ablation and other variables were evaluated RESULTS: One hundred twenty four patients (49.6%) were successfully ablated after single high dose radioiodine ablation. The authors found no association with age, sex, extent of surgery, tumor histology, tumor size, mutifocal, extrathyroidal invasion, 1 131 administered dose, interval from surgery to radioiodine ablation, Tc-99m pertechnetate scan, or 24 h 1-131 uptake, and successful ablation. The initial Tg level was the only variable found to be associated with success (p < 0.001). CONCLUSION: Neither Tc-99m pertechnetate thyroid scintigraphy nor 24 h 1-131 uptake percentage in the evaluation of postsurgical thyroid remnant can predict radioiodine ablation outcome in patients with DTC. Serum Tg level at the time of ablation could be a reasonable predictor of the success of ablation. PMID- 24163998 TI - Pluripotent gene expression in mesenchymal stem cells from human umbilical cord Wharton's jelly and their differentiation potential to neural-like cells. AB - OBJECTIVE: To explore the expression of pluripotent genes in Whartons jelly derived MSCs (WJ-MSCs) and their neuronal differentiation potential. MATERIAL AND METHOD: Gelatinous connective tissues from umbilical cord Wharton's jelly were digested with trypsin and then cultured in Dulbecco's Modified Eagle's Medium. The expressions of typical MSC markers as well as pluripotent markers were examined by flow cytometry and reverse transcription PCR, respectively. MSCs at passage 3 and 5 were used for in vitro adipogenic, osteogenic and neuronal differentiation by incubation with specific induction media. RESULTS: WJ-MSCs could be easily expanded for more than 20 passages while maintaining their undifferentiated state and their marker expression profiles, being positive for typical MSC markers CD90, CD73, and CD105, and being negative for hematopoietic markers CD34 and CD45. Interestingly, the expression of several pluripotent marker genes including Oct4, Rex1, Sox2, and Nanog was detected in early passages of both cultured WJ-MSCs and BM-MSCs. WJ-MSCs were able to differentiate not only to mesodermal cells, such as adipocyte and osteoblast but also the neural-like cells as characterized by neuronal morphology and the expression of neuronal markers including MAP-2, GFAP, beta-tubulin III and Tau. CONCLUSION: The present study demonstrates that WJ-MSCs can be readily obtained and expanded in culture while maintaining their typical MSC characteristics. WJ-MSCs and BM-MSCs also expressed several genes associated with pluripotency and exhibited their plasticity by differentiation toward neuronal-cell lineage. Umbilical cord Wharton's jelly might have potential to become an alternative source of MSC for treating nervous system disorders. PMID- 24163999 TI - Rapid detection of pyrazinamide resistant Mycobacterium tuberculosis by high resolution melting curve analysis. AB - OBJECTIVE: To develop a high-resolution melting curve analysis (HRM) assay for detection of PZA resistance. MATERIAL AND METHOD: Thirty samples of PZA susceptible M. tuberculosis and eight isolates of PZA-resistant M. tuberculosis were included in the experiment. Five sets of primers were designed to cover the pncA gene and its upstream nucleotides. The pncA gene fragments were amplified by the PCR method. Determination of pncA mutation in the sample by comparing their melting behavior of the PCR products with the M. tuberculosis wild type by using Gene scanning software of the LightCycler 480 instrument. RESULTS: Mutations were clearly detected in all PZA resistant samples by the HRM, whereas all PZA susceptible samples showed no mutation in the pncA gene. Results were concordant with the drug susceptibility testing by using BACTEC MGIT 960 PZA kit and mutation detection by the DNA sequencing method. CONCLUSION: This HRM method offers a rapid and reliable screen for PZA resistant M. tuberculosis. PMID- 24164000 TI - Sexual orientation and sexual risk behaviors among male students of a university in southern Thailand. AB - OBJECTIVE: To determine the prevalence of sexual orientation, identify predictors of being homosexual or bisexual (HB), and assess the association of sexual orientation with sexual risk behaviors among university male students in southern Thailand. MATERIAL AND METHOD: A cross-sectional study was conducted on third year male university students between June 2008 and February 2009 using anonymous self-administered questionnaires. RESULTS: Among 1,101 eligible students, 1,013 (92%) responded The prevalence of heterosexuality, homosexuality, and bisexuality among respondents were 90.2%, 6.7%, and 3.1%, respectively giving a prevalence of HB of 9.8%. Significant factors predicting HB included having separated parents. Overall lifetime prevalence of men having sex with men (MSM) was 6.3% (2% in heterosexual males and 46.5% among HB males). HB males were more likely to have multiple sex partners and engage in group sex, and less likely to use condoms than were heterosexual males. CONCLUSION: The prevalence of sexual risk behaviors among these male students, especially HB, was high. PMID- 24164001 TI - Effects of an empowerment program on health behaviors and stroke risk reduction of at-risk group in Thai rural community. AB - BACKGROUND: Unhealthy behaviors such as being overweight, have hypertension, diabetes, and dyslipidemia increase the risks of stroke. Promoting healthy behaviors could reduce the incidence of stroke, death, and disabilities. Empowerment was used in this study to help people change their health behaviors. OBJECTIVE: To determine the effects of an empowerment program on health behaviors and stroke risk factors reduction of people at-risk for stroke in a rural community in Thailand. MATERIAL AND METHOD: A quasi-experimental study was conducted in sixty participants identified with moderate risk for stroke, according to the Standard Operation Procedure to Prevent and Control of Stroke 2007 of the Bureau of Non Communicable Disease, from two villages in Phitsanulok. Participants were enrolled in experimental (n = 30) and control (n = 30) groups using match pair for sex, age, blood pressure, and blood sugar. The experimental group received empowerment based on the Gibson's model of empowerment (discovering reality, critical reflection, taking charge, and holding on) at week 1, 4, and 8 while the control group received routine care. The study duration was 12 weeks. Instruments used were a questionnaire regarding health behaviors and a form for recording the BMI, blood pressure, blood sugar cholesterol, and triglyceride. Data analyses included the Analysis of Variance (ANOVA), repeated measure, and independent t-test. RESULTS: Following the implementation of the empowerment program, health behaviors of participants in the experimental group were significantly better than those of the control group (p < 0.001). Risk factors, body mass index, blood pressure, blood sugar, cholesterol, and triglyceride of participants in the experimental group were significantly lower than those in the control group (p < 0.01, p < 0.001). CONCLUSION: The empowerment program was effective in decreasing stroke risk behaviors and stroke risk factors. Future research using this empowerment intervention program should be conducted in high cardiovascular risk group and patients with other chronic diseases. PMID- 24164002 TI - Purely Cutaneous Rosai-Dorfman disease (CRDD) co-existed with capillary hemangioma successfully treated with intralesional corticosteroid. AB - Rosai-Dorfminan disease (RDD), or sinus histiocytosis with massive lymphadenopathy, is a benign idiopathic proliferative disorder of the histiocyte. Purely Cutaneous Rosai-Dorfman disease (CRDD) is a separated clinical entity without lymph node and organ involvement. The histologic features resemble RDD, but with dermal infiltration. This rare condition is benign and mostly self limited The authors report a 66-year-old Thai male patient, diagnosed as purely CRDD, with co-existing capillary hemangioma. In addition, we show that the treatment intralesional corticosteroid can produce the remission of the plaque and tumoral types of this condition. PMID- 24164003 TI - Sudden death from toluene intoxication: a case report and review of literature. AB - Toluene is an aromatic hydrocarbon (C7H8) found in gasoline, acrylic paints, varnishes, lacquers, paint thinners, adhesives, and shoe polish. Toluene toxicity can occur from unintentional or deliberate inhalation of fumes, ingestion, or transdermal absorption. Unintentional exposure to high concentrations of toluene results in severe toluene intoxication. This is a report of toluene poisoning in a middle-age man found dead at home after varnish application by spray. There was no obvious external and internal cause of death. The blood test revealed the presence of toluene. The cause of death was diagnosed as cardiopulmonary failure caused by toluene, which is a rare case report in Thailand. PMID- 24164004 TI - Poor risk assessment limits breast cancer survival. PMID- 24164005 TI - 9 things health plans must do to meet the ACA challenge. PMID- 24164006 TI - DSM-5--back to the drawing board? PMID- 24164007 TI - Anti-fraud efforts turn to prevention. PMID- 24164008 TI - Pioneer ACOs. And then there were 23. PMID- 24164009 TI - Employers need to better understand the costs of specialty pharmacy. PMID- 24164010 TI - Identifying best practices in cancer care management. PMID- 24164011 TI - UnitedHealthcare says patient engagement pays off. PMID- 24164012 TI - Multibiomarker test for rheumatoid arthritis signals new approach to diagnosis. PMID- 24164013 TI - [Symptoms in mental illness: between biological adaptation and environmental factors]. PMID- 24164014 TI - [Mental health and public health: an essential bond]. AB - The Mental Health domain is larger than psychiatry because it implies the establishment of strategies aiming at the promotion of the well-being of the population, the prevention of mental disorders and their treatment and care. Politicians, planners, users and families and society at large have a great expectations and this require health professionals to be able to provide public mental health knowledge. It is necessary to identify those specific public mental health actions to which general practitioners and specialist could contribute. To do so more knowledge in public mental health is needed and more training is necessary. PMID- 24164015 TI - [Psychiatric care for asylum seekers in Geneva: a multidisciplinary approach for individualized care]. AB - Asylum seekers constitute a vulnerable population insofar as they are submitted to numerous stress factors which facilitate the emergence of mental disorders, such as low socio-economic status, forced separation from loved ones and exposure to violence. Asylum seekers who consult at our community psychiatry facility usually have short-term residence permits, live in collective housing and do not speak the local language. The most frequent diagnoses are depressive disorder (64.7%) and post-traumatic stress disorder (34.5%). Due to their specific clinical and social situation and to the involvement of several professionals in these situations, a specialized psychiatric intervention coordinated with the rest of the network seems necessary. PMID- 24164016 TI - [Opiate substitution programs: last chance programs or deal for quality of life?]. AB - Substitution treatments have contributed to a successful policy of risk reduction. These treatments should now also include an "existential" dimension. Therefore the development of a life plan for substance abuse patients becomes a main concern. Therapist taking care of substance abuse patients should therefore ask themselves for what purpose prescribe opiate substitution treatments instead of just answering risk reduction issues. This shift requires us to move from a logic of emergency with immediate response to "passive" patients to a logic of crisis asking the patients active participation in their recovery process. PMID- 24164017 TI - [Schizophrenia: genes, environment and neurodevelopment]. AB - Psychoses are complex diseases resulting from the interaction between genetic vulnerability factors and various environmental risk factors during the brain development and leading to the emergence of the clinical phenotype at the end of adolescence. Among the mechanisms involved, a redox imbalance plays an important role, inducing oxidative stress damaging to developing neurons. As a consequence, the excitatory/inhibitory balance in cortex and the pathways connecting brain areas are both impaired. Childhood and adolescence appear as critical periods of vulnerability for deleterious environmental insults. Antioxidants, applied during the environmental impacts, should allow preventing these impairments as well as their clinical consequences. PMID- 24164018 TI - [Traumatic events and stress responses: the role of oxytocin and attachment]. AB - Being repeatedly confronted to very difficult situations since childhood influences the way indivuals will later respond to even mildly stressful events. The hypothalamic-pituitary-adrenal axis (HPA) is a complex system implicated in regulating neuroendocrine responses to stress. Its activation produces among others the < or = 3) 6-C1 to 10-Cl homolog peak areas, while the individual congeners were quantified followed the standard procedures for single analytes. Multi-point calibration solutions ranged from 0. 5 (5 for P62) to 500 microg/L for the individual congeners, and 50 to 500 microg/L for technical toxaphene, with the lowest calibration levels as lower limits of quantitation. Average congener recovery was (90.8 +/- 17.4)% (n =10) in spiked sediment with relative standard deviations of 5.4% - 12.8% (n =10), underscoring an excellently accurate and precise method. The method was applied to analyze sediment and fish tissue sample. PMID- 24164037 TI - [Determination of phthalate plasticizers in daily foods and their migration from food packages]. AB - A total of 16 phthalates in food samples (beverage, milk and wine) were analyzed by y gas chromatography-mass spectrometry (GC-MS) combined with the sample preparation of liquid-liquid extraction and dispersive solid-phase extraction ( dSPE ) . The limits of detection (LODs, S/N=3) for the 16 phathalates were fairly good, ranging form 0.005 to 0.025 mg/L. The relative standard deviations (RSDs) of the peak areas were less than 2%, showing good repeatability. In addition, the recoveries of phthalates in various matrices were generally ranging from 60% to 110%. In conclusion, the developed method can help the trace analysis of phthalates in beverage, wine and milk. In order to strictly investigate the migration of phthalates from the daily food packages like plastic wraps and storage bags, iso-octane was used as the simulant of fatty foods. The migration determined using the above aptimized method showing the significant migration exsting in plastic wraps and some unqualified products in current market is not meeting the national regulations about the migration limits of phthalates. PMID- 24164038 TI - [Isolation and identification of impurities in the natural vitamin E]. AB - Two impurities in the natural vitamin E extracted from oil deodorizer distillate were separated and characterized by high-performance liquid chromatography (HPLC), gas chromatography-mass spectrometry (GC-MS) and Fourier transform ion cyclotron resonance mass spectrometry (FTICR-MS). The impurities were purified and collected by normal-phase HPLC. The accurate masses were determined using FTICR-MS and fragmentation behavior was studied by GC-MS. The results showed that the impurities had identical MS spectra and similar electron impact (EI) fragmentation patterns. Based on the spectra, the structures of the two impurities were proposed as the enantiomers of sesamin. The presented method is rapid and effective, and can be applied for the food safety to the vitamin E manufacturing industry. PMID- 24164039 TI - [An assay for anti-factor Xa activity of low molecular weight heparins by high performance liquid size exclusion chromatography]. AB - The "gold standard" assay for monitoring low molecular weight heparins (LMWHs) activity is the chromogenic-based anti-factor Xa assay. The methodology of an anti-factor Xa assay is that LMWH is added to a known amount of excess factor Xa and excess antithrombin. It will bind to antithrombin and form a triplet complex with factor Xa, inhibiting the activity of factor Xa. However, the residual factor Xa can still hydrolyze chromogenic peptide substrate, releasing the chromophore for photometric detection. The absorbance is inversely proportional to the amount of heparin/LMWH. The results are given in anticoagulant concentration in units/ mL of anti-factor Xa, such that high values indicate high levels of anticoagulation and low values indicate low levels of anticoagulation. Herein, a novel assay method for anti-FXa activity of LMWHs using high performance liquid size exclusion chromatography (SEC) is reported, in which antithrombin III (AT Ill ) was diluted by the buffer solution contained LMWHs. Subsequently, exogenous FXa and p-nitroaniline coupled peptide substrate were added and incubated for a period, separately. The resulting mixture was separated based on size by SEC, and the free chromophore p-nitroaniline can be detected at an absorption maximum of 385 nm without interference from the absorbance of p nitroanilide substrates. Moreover, the measurements are not influenced by sample opacity or turbidity, so it is possible to test various complex samples, such as plasma. The assay is robust, sensitive, and cost effective. PMID- 24164040 TI - [Metabonomics study of lung cancer cells based on liquid l chromatography-mass spectrometry]. AB - The metabolic profiles of the polar metabolites and the non-polar metabolites in lung tumor cell lines H358, A549, HCC827, H1299, Calu-3, Calu-l, PC-9 and normal cell line MRC-5 were analyzed separately using high performance liquid chromatography-quadrupole time-of flight mass spectrometry (HPLC-Q-TOF/MS). Partial least square discriminant analysis ( PLS-DA) was used to process the metabolic data. The results showed that the metabolites of the lung cancer cell lines and normal cell line have significant differences. Further, 10 polar metabolites and 21 non-polar metabolites which had a significant contribution to classification were selected and preliminarily identified due to the accurate mass. Comparing with the normal cell line, the lung tumor cell lines present an abnormal metabolism in protein, fatty acid, and phospholipids. These results may provide important information for the early diagnosis of lung cancer. PMID- 24164041 TI - [Determination of eight defoliant residues in cotton by accelerated solvent extraction coupled with ultra performance liquid chromatography-tandem mass spectrometry]. AB - A novel method has been developed for the rapid extraction and determination of eight defoliants including thidiazuron, butiphos, methabenzthiazuron, abscisic acid, carfentra-zone-ethyl, diuron, paraquat, and pyrithiobac-sodium in cotton by accelerated solvent extraction (ASE) coupled with ultra performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS). The defoliants in cotton were extracted by ASE and the extracts were dried by a rotavapor, then redissolved in the solvents of acetonitrile and water (1:9, v/v). The chromatographic analysis was performed on an Acquity UPLC HSS T3 column (50 mmx 2. 1 mm, 1. 8 microm) by a gradient elution employing of acetonitrile and 0.05% (v/v) formic acid as mobile phases. The analytes were detected by electrospray ionization (ESI) tandem mass spectrometry with multiple reaction monitoring (MRM) in positive ion mode. Good linearities (r >0.99) were observed between 0. 01 and 0. 3 mg/L for all the compounds. The recoveries and relative standard deviations (RSDs) were obtained by spiking untreated samples with the eight defoliants at 0. 1, 0. 5 and 1.0 mg/kg. The average recoveries of the eight defoliants were from (84. 18 +/- 8.04)% to (95.99 +/- 6.76)%. The precision values expressed as RSDs were from 7. 04% to 10. 60% (n = 6). The limits of detection were 0. 8 - 29 microg/kg and the limits of quantification were 2.5 - 96 1/4g/kg for the analytes. The results ahowed that the method is simple, rapid, sensitive and accurate, and is suitable for the quantitative determination and confirmation of the eight defoliants in cotton. PMID- 24164042 TI - [Determination of zearalanol and related mycotoxins in pork by solid-phase extraction coupled with ultra performance liquid chromatography-tandem mass spectrometry]. AB - A method was established for the determination of six compounds of zearalanol and related mycotoxins in pork and its products. After hydrolysis of the target compounds in the pork by beta-glucosidase/sulfatase, they were extracted with methanol aqueous solution and further purified by an HLB column. The separation was performed on a BEH C18 column with gradient elution using acetonitrile-water as mobile phases. The analytes were determined by mass spectrometry using electrospray ionization (ESI) in negative scan mode and multiple reaction monitoring (MRM) mode. alpha-Zearalenol-D7 and beta-zearalenol-D7 were used as internal standards. The good linearities (r > 0. 999) were achieved for the six compounds over the range of 1. 0 - 100 microg/L based on the internal standard calibration. The detection limits of the method were 0.03 -0.09 microg/kg. The mean recoveries of the six target compounds spiked at three levels from 1. 0 - 10. 0 microg/kg ranged from 76. 7% to 100. 5% with the relative standard deviations (RSDs) less than 20%. The proposed method is simple, sensitive, reproducible, and complies with the regulations for the determination of trace contaminant residues in food matrice. PMID- 24164043 TI - [Simultaneous determination of 23 sedative drugs in health foods by high performance liquid chromatography-tandem mass spectrometry]. AB - An analytical method using HPLC-MS/MS was developed for qualitative and quantitative analysis of 23 sedative drugs in health foods. The method was based on the sonication-assisted extraction of the health food samples using 10 mL methanol. The extract was then isolated by centrifugation and the supernatant was separated on an Agilent Eclipse Plus C, column with gradient elution at a flow rate of 300 microL/min. A binary mobile phase was 10 mmol/L ammonium formate (solvent A) and acetonitrile/methanol (1:1, v/v; solvent B). The electrospray ionization (ESI) source in positive ion mode or negative ion mode was used for multiple reaction monitoring (MRM). The external standard method was used for the quantification. The calibration graphs were linear in their concentration ranges with the correlation coefficients more than 0. 990. The limits of detection (LOD, S/N= 3) were between 0. 02 - 1.0 microg/L. The recoveries for all the drugs in health foods were 82. 3% - 114. 8% with the relative standard deviations less than 14. 1% at three spiked levels. Thirteen kinds of health foods were tested, in which meprobamate and oxazepan were found in one sample separately, and zaleplon was found in two samples. The method is specific, sensitive, easy and quick and suitable for the confirmation and quantification of the 23 sedative drugs in health foods. PMID- 24164044 TI - [Enrichment of cis-diols active components in traditional Chinese medicines by boronate affinity monolithic column]. AB - A novel poly( 4-vinylphenylboronic acid (VPBA) -co-pentaerythritol triacrylate (PETA)) monolithic column was prepared by thermal-initiated copolymerization of VPBA and PETA in a binary porogen system comprising diethylene glycol and ethylene glycol. The fabricated monolithic column demonstrated good boronate affinity property, which can specifically capture cis-diols containing compounds. We developed such a monolithic column and applied it to enrich active components in Herba Taraxaci and Euonymus acanthocarpus. The extracts of the two traditional Chinese medicines were separated and enriched on microHPLC by the prepared monolith, and the fractions were collected and examined by HPLC. The results showed that the responses of the corresponding peaks were greatly improved, indicating that the poly( VPBA-co-PETA) monolithic column can be efficiently used to enrich active components in traditional Chinese medicines containing cis-diols group. PMID- 24164045 TI - Damnacanthal: a promising compound as a medicinal anthraquinone. AB - The Noni fruit, or scientifically known as Morinda citrifolia can be found in various parts of the world, especially in the pacific region. It is a small evergreen bushy-like tree originated from the Rubiaceae family. The plant has been used by polynesians as a medicinal herb for more than 2000 years. A substantial amount of phytochemicals can be found in the roots of this plant. Among all, damnacanthal has been found to be the most interesting, versatile and potent compound. Damnacanthal or chemically known as,3- hydroxy-1 methoxyanthraquinone-2-caboxaldehyde (C16H10O5), appears as pale yellow crystals with a melting point of 210-211 degrees C. This compound is of particular interest due to its striking pharmacological properties. Damnacanthal was shown to inhibit the oncogene Ras, p56lck tyrosine kinase, NF-KB pathway and induce apoptosis in vitro. This review aims to discuss the biological properties of damnacanthal, specifically on its anti-cancer activity that has been reported. PMID- 24164047 TI - Synthesis and stereochemistry-activity relationship of chiral thiourea derivatives as potential anticancer agents. AB - Synthesis of new chiral thiourea derivatives (27 examples) as anticancer agents has been described. Three compound 7d (NSC code 761448/1), 7e1 (NSC code 767161/1), and 7e3 (NSC code 767160/1) were found to exhibit higher anticancer activity than 5-fluorouracil against Colon cancer, Melanoma, Ovarian cancer, and Breast cancer subpanels. The effect of stereochemistry of amino acid residues on the tumor growth inhibitory activity has also been studied. PMID- 24164046 TI - Cytotoxicity and apoptosis induced by a plumbagin derivative in estrogen positive MCF-7 breast cancer cells. AB - Plumbagin [5-hydroxy- 2-methyl-1, 4-naphthaquinone] is a well-known plant derived anticancer lead compound. Several efforts have been made to synthesize its analogs and derivatives in order to increase its anticancer potential. In the present study, plumbagin and its five derivatives have been evaluated for their antiproliferative potential in one normal and four human cancer cell lines. Treatment with derivatives resulted in dose- and time-dependent inhibition of growth of various cancer cell lines. Prescreening of compounds led us to focus our further investigations on acetyl plumbagin, which showed remarkably low toxicity towards normal BJ cells and HepG2 cells. The mechanisms of apoptosis induction were determined by APOPercentage staining, caspase-3/7 activation, reactive oxygen species production and cell cycle analysis. The modulation of apoptotic genes (p53, Mdm2, NF-kB, Bad, Bax, Bcl-2 and Casp-7) was also measured using real time PCR. The positive staining using APOPercentage dye, increased caspase-3/7 activity, increased ROS production and enhanced mRNA expression of proapoptotic genes suggested that acetyl plumbagin exhibits anticancer effects on MCF-7 cells through its apoptosis-inducing property. A key highlighting point of the study is low toxicity of acetyl plumbagin towards normal BJ cells and negligible hepatotoxicity (data based on HepG2 cell line). Overall results showed that acetyl plumbagin with reduced toxicity might have the potential to be a new lead molecule for testing against estrogen positive breast cancer. PMID- 24164048 TI - Advances in the researches on the biological activities and inhibitors of phosphatidylinositol 3-kinase. AB - The PI3K/AKT/mTOR pathway is an intracellular signaling pathway, being important in apoptosis hence cancer such as breast cancer and non-small-cell lung cancer. It signaling axis controls cell proliferation and survival and has achieved major importance as a target for cancer therapy. The serine/threonine kinase Akt (also known as protein kinase B or PKB), since its initial discovery as a protooncogene, has become a major focus of attention because of its critical regulatory role in diverse cellular processes, including cancer progression and insulin metabolism. The Akt cascade is activated by receptor tyrosine kinases, integrins, B and T cell receptors, cytokine receptors, G protein coupled receptors and other stimuli that induce the production of phosphatidylinositol 3,4,5 triphosphates (PtdIns(3,4,5)P3) by phosphoinositide 3-kinase (PI3K). Therefore, PI3K plays an important role in in numerous cellular functions such as cell growth, proliferation, differentiation, motility, survival and intracellular trafficking. In this review, we introduced the structure of the PI3K, and then focused on its biological activities. In addition, we reviewed the advances in the researches of PI3K as well as related inhibitors over the last couple of decades. Finally, we also discussed the prospect and developmental trend of phosphatidylinositol 3-kinase as antitumor agents. PMID- 24164049 TI - Three-component synthesis of spiro[indoline-3,4'-pyrano[3,2-b]pyran]- 2,8'-diones using a one-pot reaction. AB - A one-pot, three-component reaction of an isatin and kojic acid with an active methylene compound such as ethyl cyanoacetate, methyl cyanoacetate and malononitrile in methanol using catalytic amount of DABCO to give 2'- amino-6' (hydroxymethyl)-8'H-spiro[indoline-3,4'-pyrano[3,2-b]pyran]-2,8'-diones in good to excellent yields under reflux conditions, is described. PMID- 24164050 TI - An in silico appraisal of azoic and disulphide derivatives for anticancer activity against HPV E6 oncoprotein to medicate cervical cancer. AB - Cervical cancer is the second largest form of cancer to infest the leading cause of death in women worldwide. There are many causes of cancer but viruses are the most common among them. Human papillomaviruses (HPVs) are found to be the causative organism in almost 99.7% of the cases. HPV16 is the most frequent HPV type in malignant neoplastic growth in about 60% of cervical carcinoma cases. There is limited success achieved in surgical removal or by immune modulation and more effective therapies are under investigation. Observing the mortality rate we theorize a need for alternative treatment approaches and propose a blueprint of compounds with desirable properties that may lead to the development of drugs to treat HPV-associated neoplasias. E6 oncoprotein of HPV16 has a potential zinc finger domain critical for binding to E6AP, causing p53 degradation and malignancy. Some azoics and disulfides were selected depending on their affinity towards E6 zinc finger and thereby preventing E6-E6AP complex formation. Combinatorial nontoxic derivatives of these azoics and disulfides were docked and validated against the oncoprotein to inhibit E6-E6AP interaction. Among these, two compounds (E)-N-(2-amino-2-oxoethyl)-N-(4-chlorophenyl) diazene-1,2 dicarboxamide and (E)-N-(2- amino-2-methylpropyl)-N-(thiophen-2-yl)diazene-1,2 dicarboxamide showed binding affinity of -23.70, -19.53 and -5.49, -4.65 Kcal/mol respectively in FlexX and Autodock4.2. These compounds are found more effective than those of the approved E6-E6AP binding inhibitors. Pharmacophores of these compounds were generated to confirm it with pharm mapping mechanism. The study may confer the way of design of new mechanism and new compounds to treat cervical cancer. PMID- 24164051 TI - Experimental reproduction of an Enterococcus cecorum infection in Pekin ducks. AB - Enterococcus cecorum (EC) was thus far only known as a pathogen for broilers and broiler breeders. Recently there was evidence of EC field outbreaks in Pekin duck flocks in Germany. In this study we experimentally reproduced an EC infection in Pekin ducks. At 12 days post hatch, groups of Pekin ducks were infected orally, via the thoracic air sac or intravenously with 1.5 * 10(9) colony-forming units (CFU) of EC per bird or via the air sac with 8.5 * 10(5) or 8.5 * 10(7) CFU per bird. Ducks of the intravenously infected group showed 100% mortality after 2 days post infection. The air sac inoculated high-dose group exhibited a mortality rate of 67%. Birds that were infected with 8.5 * 10(5) and 8.5 * 10(7) CFU showed 6.7% mortality after 7 days post infection. Dead birds displayed pneumonia, airsacculitis, pericarditis and splenitis and EC was re-isolated from these organs. Surviving birds of all groups apart from the orally infected ducks demonstrated clinical signs such as huddling, reduced mobility and diarrhoea. Furthermore, they showed gross pathological lesions including airsacculitis and splenitis and lower bodyweights than the control group at necropsy on days 7, 14 and 21 post infection. The present study clearly confirms that EC is pathogenic for Pekin ducks after experimental infection via the intravenous route or the respiratory tract. EC therefore has to be considered as an emerging avian pathogen not only in broilers but also in Pekin ducks. PMID- 24164052 TI - ADHD and transitions to adult mental health services: a scoping review. AB - There is increased awareness that attention deficit hyperactivity disorder (ADHD) continues into adulthood. Thus, health services are faced with a new challenge in providing a 'smooth' transition to adult services appropriate for young people with ADHD. This scoping review sought to identify the literature addressing transition for young people with ADHD to adult mental health services (AMHS). A scoping review, in which the search terms 'ADHD' and 'Transition' or 'Transfer' were entered into eight healthcare publication databases facilitated by NHS Evidence to identify both published and unpublished papers between 2000 and June 2013. Additional informal searches were also undertaken. Twenty-three papers were selected for this review. This review confirms the lack of research explicitly tracking transition from Paediatrics/Child and Adolescent Mental Health Services (CAMHS) to AMHS for young people with ADHD. Only four papers directly studying transition for ADHD patients were identified. Three further studies surveyed clinician perspectives. Taken together, the studies address a number of issues in relation to transition, including the developmental course of ADHD symptoms, appropriate adult care, knowledge and communication, unmet need, comorbidities, environmental demands and medication cessation/dosage during the transition period. While literature surrounding transition exists, the scope of the evidence showing successful and unsuccessful transition activity from Paediatric and CAMHS to AMHS for young people with ADHD is limited. Future quality research in the form of audits, longitudinal tracking studies and service evaluations are required if we are truly to understand and identify what is needed and currently available for successful transition to an appropriate adult service for ADHD patients. PMID- 24164053 TI - Losses and gains: chronic pain and altered brain morphology. AB - As in many fields of neuroscience, alterations in brain morphology, and specifically gray matter volume and cortical thickness, have been repeatedly linked to chronic pain disorders. Numerous studies have shown changes in cortical and subcortical brain regions suggesting a dynamic process that may be a result of chronic pain or contributing to a more generalized phenomenon in chronic pain including comorbid anxiety and depression. In this review, we provide a perspective of pain as an innate state of pain based on alterations in structure and by inference, brain function. A better neurobiological understanding of gray matter changes will contribute to our understanding of how structural changes contribute to chronic pain (disease driver) and how these changes may be reversed (disease modification or treatment). PMID- 24164055 TI - Diplopia and variable ptosis as the sole initial findings in a case of orbital plasmacytoma and multiple myeloma. AB - Plasmacytomas are monoclonal plasma cell tumors. They represent 3% of all orbital tumors. We present an unusual case of orbital plasmacytoma and advanced multiple myeloma where the sole presenting symptoms were those of diplopia and ptosis. Clinical examination revealed right hypertropia and variable left upper lid ptosis but no proptosis. The visual acuity and the rest of the ocular examination were normal in both eyes. An MRI scan of the brain and orbits revealed a frontal bone lesion consistent with a plasmacytoma. A bone marrow biopsy showed a light chain multiple myeloma with free lambda light chains. Although the literature reports diplopia and ptosis as being clinical features of orbital plasmacytomas, to our knowledge this is the first reported case where these symptoms were the only presenting features, despite widespread disease. PMID- 24164056 TI - Mean platelet volume is associated with aortic arterial stiffness in patients with Behcet's disease without significant cardiovascular involvement. AB - BACKGROUND: Behcet's disease (BD), is a chronic, systemic vasculitis, which may affect all types and sizes of blood vessels. BD is associated with endothelial dysfunction and chronic inflammation. Endothelial dysfunction is the critical early step in the process of atherogenesis, and it is commonly investigated by measuring arterial stiffness. Mean platelet volume (MPV) has been investigated in relation with both thrombosis and inflammation. We aimed to investigate the relationship between an increased arterial stiffness and MPV in patients with Behcet's disease without significant cardiovascular involvement. METHODS: We studied 36 patients (20 males, mean age: 37.6 +/- 11.7 years) who were diagnosed by the international diagnostic criteria of BD and 35 healthy controls (15 males, mean age: 35.0 +/- 10.6 years), and the two groups were matched by age and gender. MPV levels and arterial stiffness measurements were compared in these groups. RESULTS: Arterial stiffness was higher in patients with BD compared to control group. (BD and controls; 7.28 m/s, 6.64 m/s; respectively) (p: 0.02). MPV levels were also significantly higher in patients with BD compared to control group. (BD and controls; 8.86 +/- 0.81 fl, 8.39 +/- 0.96 fl, respectively) (p: 0.02). Additionally, arterial stiffness correlated positively with age, the duration of disease and MPV levels in patients with BD (p: 0.002, 0.03, 0.02 respectively). CONCLUSIONS: In our study, increased MPV is associated with arterial stiffness in patients with BD without significant cardiovascular involvement. It shows that there is a relationship between thrombosis and chronic inflammation in BD. Furthermore, MPV is also a moderate predictor of cardiovascular disease and represents an increase in platelet activation. These findings provide further evidence of a link between inflammation and thrombosis in patients with BD. PMID- 24164054 TI - Neuromedin U partly mimics thyroid-stimulating hormone and triggers Wnt/beta catenin signalling in the photoperiodic response of F344 rats. AB - In seasonal animals, photoperiod exerts profound effects on physiology, such as growth, energy balance and reproduction, via changes in the neuroendocrine axes. A key element of the photoperiodic response is the thyroid hormone level in the hypothalamus, which is controlled via retrograde transport of thyroid-stimulating hormone (TSH) from the pars tuberalis of the pituitary. TSH regulates type II deiodinase (Dio2) expression, which transforms inactive thyroid hormone to its active form, via TSH receptors expressed in the ependymal cells of the hypothalamus. In the present study, we hypothesised that a second peptide hormone, neuromedin U (NMU), may play a role in the photoperiodic response alongside TSH because the gene for NMU is also expressed in a strongly photoperiod-dependent manner in the pars tuberalis and its receptor NMU2 is expressed in the ependymal layer of the third ventricle in photoperiod-sensitive F344 rats. Consistent with other studies conducted in nonseasonal mammals, we found that acute i.c.v. injections of NMU into the hypothalamus negatively regulated food intake and body weight and increased core body temperature in F344 rats. At the same time, NMU increased Dio2 mRNA expression in the ependymal region of the hypothalamus similar to the effects of TSH. These data suggest that NMU may affect acute and photoperiodically controlled energy balance through distinct pathways. We also showed that TSH inhibits the expression of type III deiodinase (Dio3) in F344 rats, a response not mimicked by NMU. Furthermore, NMU also increased the expression of genes from the Wnt/beta-catenin pathway within the ependymal layer of the third ventricle. This effect was not influenced by TSH. These data indicate that, although NMU acts with some similarities to TSH, it also has completely distinct signalling functions that do not overlap. In summary, the present study of NMU signalling reveals the potential for a new player in the control of seasonal biology. PMID- 24164057 TI - Biofilm formation by Fusarium oxysporum f. sp. cucumerinum and susceptibility to environmental stress. AB - To the authors' knowledge, most studies on biofilm formation have focused on bacteria and yeasts. So far, biofilm formation by fungal plant pathogen has not been reported. In this study, the biofilm-forming capacity of Fusarium oxysporum f. sp. cucumerinum was evaluated. For biofilm quantification, a colorimetric 2,3 bis(2-methoxy-4-nitro-5-sulfophenyl)-5-[(phenylamino)carbonyl]-2H-tetrazolium hydroxide (XTT) reduction assay was used to observe metabolic activity. Fluorescence and confocal scanning laser microscopy revealed that the biofilms have a highly heterogeneous architecture composed of robust hyphae and extracellular polysaccharide materials. Additionally, the influence of physical factors on F. oxysporum biofilm formation and the susceptibility of biofilms to environmental stress was investigated. Biofilms were less susceptible to heat, cold, UV light and three fungicides than were their planktonic counterparts. Our findings may provide a novel perspective on the pathogenic mechanism associated with biofilms of F. oxysporum f. sp. cucumerinum. PMID- 24164058 TI - Probing spatially dependent photoinduced charge transfer dynamics to TiO2 nanoparticles using single quantum dot modified atomic force microscopy tips. AB - Using single CdSe/CdS quantum dot (QD) functionalized atomic force microscopy (AFM) tips, we demonstrate that the spatial dependence of photoinduced electron transfer dynamics from the single QD to TiO2 nanoparticles can be controlled and probed with high spatial (subdiffraction-limited) and temporal (limited by fluorescence microscopy) resolutions. This finding suggests the feasibility of using electron donor or acceptor modified AFM tips for simultaneous high resolution imaging of morphology and photoinduced charge transfer dynamics in nanomaterials. PMID- 24164059 TI - Fabrication and characterization of polymer composites for endodontic use. AB - AIM: To develop a low-density polyethylene-hydroxyapatite (HA-PE) composite with properties tailored to function as a potential root canal filling material. METHODOLOGY: Hydroxyapatite and polyethylene mixed with strontium oxide as a radiopacifier were extruded from a single screw extruder fitted with an appropriate die to form fibres. The composition of the composite was optimized with clinical handling and placement in the canal being the prime consideration. The fibres were characterized using infrared spectroscopy (FTIR), and their thermal properties determined using differential scanning calorimetry (DSC). The tensile strength and elastic modulus of the composite fibres and gutta-percha were compared, dry and after 1 month storage in simulated body fluid (SBF), using a universal testing machine. The radiopacity of the fibres was determined using digital radiography. The interaction of the composites with eugenol was evaluated and compared with gutta-percha. Data of the tensile test were submitted to two way anova and Bonferroni tests (P < 0.05). RESULTS: The endothermic peaks obtained from the DSC studies showed that the melting point of the HA/PE composites ranged between 110.5 and 111.2 degrees C, whereas gutta-percha exhibited a melting point at 52 degrees C. The tensile strength and elastic modulus of the silanated HA/PE composites were significantly higher than those of gutta-percha (P < 0.0001) under dry conditions and 1 month storage in SBF. The gutta-percha in eugenol showed a significant increase in the polymer molar mass, whereas the silanated HA/PE composites were unchanged. Radiological evaluations demonstrated that silanated HA/PE fibres were sufficiently radiopaque. CONCLUSION: Promising materials for endodontic applications have been developed, offering relevant benefits over the traditional materials in terms of mechanical and chemical properties. PMID- 24164061 TI - Higher staff numbers will save lives. PMID- 24164060 TI - Individual-based analyses reveal limited functional overlap in a coral reef fish community. AB - Detailed knowledge of a species' functional niche is crucial for the study of ecological communities and processes. The extent of niche overlap, functional redundancy and functional complementarity is of particular importance if we are to understand ecosystem processes and their vulnerability to disturbances. Coral reefs are among the most threatened marine systems, and anthropogenic activity is changing the functional composition of reefs. The loss of herbivorous fishes is particularly concerning as the removal of algae is crucial for the growth and survival of corals. Yet, the foraging patterns of the various herbivorous fish species are poorly understood. Using a multidimensional framework, we present novel individual-based analyses of species' realized functional niches, which we apply to a herbivorous coral reef fish community. In calculating niche volumes for 21 species, based on their microhabitat utilization patterns during foraging, and computing functional overlaps, we provide a measurement of functional redundancy or complementarity. Complementarity is the inverse of redundancy and is defined as less than 50% overlap in niche volumes. The analyses reveal extensive complementarity with an average functional overlap of just 15.2%. Furthermore, the analyses divide herbivorous reef fishes into two broad groups. The first group (predominantly surgeonfishes and parrotfishes) comprises species feeding on exposed surfaces and predominantly open reef matrix or sandy substrata, resulting in small niche volumes and extensive complementarity. In contrast, the second group consists of species (predominantly rabbitfishes) that feed over a wider range of microhabitats, penetrating the reef matrix to exploit concealed surfaces of various substratum types. These species show high variation among individuals, leading to large niche volumes, more overlap and less complementarity. These results may have crucial consequences for our understanding of herbivorous processes on coral reefs, as algal removal appears to depend strongly on species-specific microhabitat utilization patterns of herbivores. Furthermore, the results emphasize the capacity of the individual based analyses to reveal variation in the functional niches of species, even in high-diversity systems such as coral reefs, demonstrating its potential applicability to other high-diversity ecosystems. PMID- 24164068 TI - Service quality improves over ten years. PMID- 24164069 TI - Researchers and nurses debate merits of ward staffing levels. PMID- 24164070 TI - Report proposes better integration of hospital and community services. PMID- 24164071 TI - RCN poll finds half of nurses unwell due to work pressures. PMID- 24164082 TI - Collaborative services show positive outcomes for end of life care. AB - The authors outline the benefits of participating in the Transforming End of Life Care in Acute Hospitals Programme. The article describes the introduction at Worcestershire Acute Hospitals NHS Trust of the amber care bundle, an approach used in hospitals when clinicians are concerned that patients are acutely unwell and their potential for recovery is uncertain. The bundle is supported with staff education and carer feedback using the VOICES questionnaire, which carers or relatives fill out post-bereavement. The authors also discuss the potential to measure outcomes to indicate quality, by linking the amber care bundle quality audit and the adapted VOICES questionnaire to demonstrate the impact of the introduction of the amber care bundle. PMID- 24164083 TI - Newly qualified staff's perceptions of senior charge nurse roles. AB - Nursing roles have been recognised as pivotal to the delivery of good quality, patient-centred care. At the centre of this debate are the leadership roles of the senior charge nurse (SCN), which in recent years have come under great scrutiny. However, research suggests that these roles have become decreasingly popular as a career pathway. The aim of this study was to develop a clearer understanding of leadership as experienced by newly qualified staff nurses in the acute hospital setting by exploring their perceptions and beliefs of SCN roles. The study supports the view that SCNs remain central to setting standards of care, but suggests that the SCN leadership role appears unattractive to newly qualified staff, who cite responsibility, lack of trust and negative feedback as the most offputting factors. PMID- 24164084 TI - Introduction to economic assessment. AB - This is the first in a series of four continuing professional development articles that explain some of the principles of economic assessment and describe the most commonly cited approaches. The series aims to enable readers to critically examine economic assessments in the context of nurse-led service innovation. It introduces a tried-and-tested methodology, with associated tools and templates, used to conduct economic assessments in nursing. In this article, the principles of economic assessment are introduced and two case studies of nurse-led innovation are used to illustrate how they are applied in practice. PMID- 24164085 TI - Heart of the matter. PMID- 24164086 TI - Nicotinamide phosphoribosyltransferase inhibitors, design, preparation, and structure-activity relationship. AB - Existing pharmacological inhibitors for nicotinamide phosphoribosyltransferase (NAMPT) are promising therapeutics for treating cancer. By using medicinal and computational chemistry methods, the structure-activity relationship for novel classes of NAMPT inhibitors is described, and the compounds are optimized. Compounds are designed inspired by the NAMPT inhibitor APO866 and cyanoguanidine inhibitor scaffolds. In comparison with recently published derivatives, the new analogues exhibit an equally potent antiproliferative activity in vitro and comparable activity in vivo. The best performing compounds from these series showed subnanomolar antiproliferative activity toward a series of cancer cell lines (compound 15: IC50 0.025 and 0.33 nM, in A2780 (ovarian carcinoma) and MCF 7 (breast), respectively) and potent antitumor in vivo activity in well-tolerated doses in a xenograft model. In an A2780 xenograft mouse model with large tumors (500 mm(3)), compound 15 reduced the tumor volume to one-fifth of the starting volume at a dose of 3 mg/kg administered ip, bid, days 1-9. Thus, compounds found in this study compared favorably with compounds already in the clinic and warrant further investigation as promising lead molecules for the inhibition of NAMPT. PMID- 24164087 TI - Therapeutic effect of inhaled budesonide (Pulmicort(r) Turbuhaler) on the inflammatory response to one-lung ventilation. AB - This prospective, double-blind trial was designed to evaluate the effect of inhaled budesonide on lung function and the inflammatory response to one-lung ventilation. One hundred patients scheduled for lobectomy were allocated randomly to pre-operative nebulised budesonide or saline. Bronchoalveolar lavage fluid samples were collected from either the collapsed or the ventilated lung both before one-lung ventilation and 30 min after re-expansion of the lung. The concentrations of serum and bronchoalveolar lavage fluid cytokines were determined. Budesonide treatment, compared with saline, reduced both peak (mean (SD) 3.7 (0.4) vs 2.5 (0.2) kPa) and plateau (mean (SD) 3.1 (0.2) vs 2.2 (0.1) kPa, respectively, p < 0.001 for both) ventilatory pressures. Thirty minutes after re-expansion, lung compliance increased in the budesonide group compared with saline (57.5 (4.1) vs 40.1 (3.5) ml.cmH(2) O(-1), respectively p < 0.001). Budesonide also reduced the concentrations of tumour necrosis factor-alpha, interleukin-1beta, interleukin-6 and interleukin-8 in bronchoalveolar lavage fluid, but increased interleukin-10 30 min after re-expansion (p < 0.05 for all measures). Pre-operative nebulisation of budesonide may be effective in improving ventilatory mechanics and reducing the inflammatory response to one-lung ventilation during thoracic surgery. PMID- 24164088 TI - Rhodium-catalyzed tandem annulation and (5 + 1) cycloaddition: 3-hydroxy-1,4 enyne as the 5-carbon component. AB - A Rh-catalyzed tandem annulation and (5 + 1) cycloaddition was realized. 3 Hydroxy-1,4-enyne served as the new 5-carbon component for the (5 + 1) cycloaddition. Substituted carbazoles, dibenzofurans, and tricyclic compounds containing a cyclohexadienone moiety could be prepared efficiently. The identification of a byproduct suggests that metal carbene and ketene intermediates may be involved in the (5 + 1) cycloaddition. PMID- 24164089 TI - Conformational analysis of Gly-Ala-NHMe in D(2)O and DMSO solutions: a two dimensional infrared spectroscopy study. AB - A relevant number of experiments on short peptides has been performed in recent years. One of the major problems rises from the simultaneous presence of slightly different conformers at equilibrium in solution. In the present paper, the conformational characteristics of the Gly-l-Ala-Methyl amide dipeptide in D2O and DMSO solutions are investigated by nonlinear IR spectroscopy. The pump-probe scheme with ultrashort mid-infrared pulses, in the Amide I region, is used to determine the mutual orientation of the two C?O bonds and the dynamics due to solute-solvent interactions. The coupling between Amide I modes is evaluated from both linear and 2D spectra. The interconversion between the different conformations occurs on time scales longer than the vibrational lifetime, and the spectral diffusion observed in 2D spectra is attributed to the solvent dynamics. Quantum mechanical calculations and molecular dynamics simulations are performed to identify the most stable geometries. By comparing the experimental and the theoretical data, we establish the prevalence of beta-like polar conformers in both water and DMSO solvents. PMID- 24164090 TI - Same-gender sexual partnering: a re-analysis of trend data. AB - Numerous studies have been carried out to estimate the prevalence of same-gender sexual behavior. Among studies conducted in recent years, few confirm the commonly quoted figure of 10%. Yet several studies in the early 2000s indicated that the prevalence of same-gender sex may be increasing, especially among women. This article reexamines the trends identified in previous research by using General Social Survey data from 1988 to 2010 and by focusing on multiple measures of same-gender sex over time. Results indicate that for both women and men the likelihood of having had a same-gender sexual partner since age 18 continued to increase through the 2000s, but that the likelihood of having had a same-gender sexual partner in both the past year and in the past five years leveled off for women and reversed for men. Results also indicate that the percentage of people reporting a pattern of predominantly same-gender sexual behavior has neither increased nor decreased over time. A similar result was found among persons who reported being in a same-gender sexual relationship. Overall, results paint a more complex picture than prior studies in characterizing trends in same-gender sexual behavior. PMID- 24164091 TI - Transcription factor HAT1 is phosphorylated by BIN2 kinase and mediates brassinosteroid repressed gene expression in Arabidopsis. AB - Plant steroid hormones, brassinosteroids (BRs), play essential roles in modulating cell elongation, vascular differentiation, senescence and stress responses. BRs signal through plasma membrane-localized receptor and other components to modulate the BES1/BZR1 (BRI1-EMS SUPPRESSOR 1/BRASSINAZOLE RESISTANT 1) family of transcription factors that modulate thousands of target genes. Arabodopsis thaliana homeodomain-leucine zipper protein 1 (HAT1), which encodes a homeodomain-leucine zipper (HD-Zip) class II transcription factor, was identified through chromatin immunoprecipitation (ChIP) experiments as a direct target gene of BES1. Loss-of-function and gain-of-function mutants of HAT1 display altered BR responses. HAT1 and its close homolog HAT3 act redundantly, as the double mutant hat1 hat3 displayed a reduced BR response that is stronger than the single mutants alone. Moreover, hat1 hat3 enhanced the phenotype of a weak allele of the BR receptor mutant bri1 and suppressed the phenotype of constitutive BR response mutant bes1-D. These results suggest that HAT1 and HAT3 function to activate BR-mediated growth. Expression levels of several BR repressed genes are increased in hat1 hat3 and reduced in HAT1OX, suggesting that HAT1 functions to repress the expression of a subset of BR target genes. HAT1 and BES1 bind to a conserved homeodomain binding (HB) site and BR response element (BRRE) respectively, in the promoters of some BR-repressed genes. BES1 and HAT1 interact with each other and cooperate to inhibit BR-repressed gene expression. Furthermore, HAT1 can be phosphorylated and stabilized by GSK3 (GLYCOGEN SYNTHASE KINASE 3)-like kinase BIN2 (BRASSINOSTEROID-INSENSITIVE 2), a well established negative regulator of the BR pathway. Our results thus revealed a previously unknown mechanism by which BR signaling modulates BR-repressed gene expression and coordinates plant growth. PMID- 24164092 TI - C3 photosynthesis in the desert plant Rhazya stricta is fully functional at high temperatures and light intensities. AB - The C3 plant Rhazya stricta is native to arid desert environment zones, where it experiences daily extremes of heat, light intensity (PAR) and high vapour pressure deficit (VPD). We measured the photosynthetic parameters in R. stricta in its native environment to assess the mechanisms that permit it to survive in these extreme conditions. Infrared gas exchange analysis examined diel changes in assimilation (A), stomatal conductance (gs ) and transpiration (E) on mature leaves of R. stricta. A/ci analysis was used to determine the effect of temperature on carboxylation capacity (Vc,max ) and the light- and CO2 -saturated rate of photosynthesis (Amax ). Combined chlorophyll fluorescence and gas exchange light response curve analysis at ambient and low oxygen showed that both carboxylation and oxygenation of Rubisco acted as the major sinks for the end products of electron transport. Physiological analysis in conjunction with gene expression analysis suggested that there are two isoforms of Rubisco activase which may provide an explanation for the ability of R. stricta to maintain Rubisco function at high temperatures. The potential to exploit this ability to cope with extreme temperatures is discussed in the context of future crop improvement. PMID- 24164093 TI - The total number of lymph nodes in resected colon cancer specimens is affected by several factors but the lymph node ratio is independent of these. AB - The number of lymph nodes retrieved from the specimen may be a surrogate measure of the adequacy of extensive colon cancer surgery, but many variables may influence the total lymph node yield of any specimen. We examined which variables would be influential both for negative and positive node sampling.The combined results from 428 patients from three hospitals A to C treated in 2007-2009 with single colon cancers having R0 segmental resections were analysed. The surgical technique and pathology staining methods were slightly different between the hospitals.The mean number of lymph nodes was 15.8 (range 1-60). Twelve or more lymph nodes were harvested in 78% of the specimens. In the multivariate Poisson regression analysis of all TNM stages, the factors associated with the total lymph node harvest were age, pathology handling, tumour location and size (p < 0.001), whereas for TNM stage III alone the pathology handling (p < 0.001) and a radical operating technique (p = 0.003) were highly significant. The total number of lymph nodes was the only significant factor for the number of positive lymph nodes (Posln) according to the multivariate negative regression analysis (p = 0.02) but the analysis of the lymph node ratio (LNR) detected no statistically significant variable.Several factors, and especially the specimen processing technique, were important for the total number of harvested lymph nodes. The number of Posln varied between segments and increased with the total number of harvested lymph nodes, but for LNR no variable was important. LNR seemed to abolish the combined effect of tumour location and the total lymph node yield in prognosis assessment. PMID- 24164094 TI - Aligned magnetic domains in p- and n-type ferromagnetic nanocrystals and in pn junction nanodiodes. AB - We form pn- and np-junctions between monolayers of p- and n-type nanocrystals that exhibit current rectification in the nanodiodes when characterized with a scanning tunneling microscope (STM) tip. With the use of ferromagnetic nanocrystals, we study the effect of mutual alignment of magnetization vectors on current rectification in the junction between the two nanocrystals. We show that when the magnetization vectors of the p- and of the n-type nanocrystals are parallel to each other (and both facing toward the apex of the STM tip) tunneling current in both bias modes increases with correspondingly a higher rectification ratio. This is in contrast to the parameters of the nanodiodes in which magnetization vectors of the components are unaligned or randomized. To analyze the results, we record scanning tunneling spectroscopy of the monolayer of the components having magnetization vectors aligned or unaligned to locate their valence and conduction band edges and to determine the effect of the alignment on the band edges. Upon alignment of the magnetization vectors of the nanocrystals in a monolayer, the conduction band edge of the p-type and valence band edge of the n-type semiconductor shift towards the Fermi energy leading to a change in energy levels of the pn-junctions and accounting for the improved parameters of the nanodiodes. PMID- 24164095 TI - Opportunities and challenges for public libraries to enhance community resilience. AB - This study bridges a gap between public library and emergency management policy versus practice by examining the role of public libraries in the community resource network for disaster recovery. Specifically, this study identifies the opportunities and challenges for public libraries to fulfill their role as a FEMA designated essential community organization and enhance community resilience. The results indicate there are several opportunities for libraries to enhance community resilience by offering technology resources and assistance; providing office, meeting, and community living room space; serving as the last redundant communication channel and a repository for community information and disaster narratives; and adapting or expanding services already offered to meet the changing needs of the community. However, libraries also face challenges in enhancing community resilience, including the temptation to overcommit library capacity and staff capability beyond the library mission and a lack of long-term disaster plans and collaboration with emergency managers and government officials. Implications for library and emergency management practice and crisis research are discussed. PMID- 24164096 TI - Evidence for clinical, genetic and biochemical variability in spinal muscular atrophy with progressive myoclonic epilepsy. AB - Spinal muscular atrophy with progressive myoclonic epilepsy (SMA-PME) is a recently delineated, autosomal recessive condition caused by rare mutations in the N-acylsphingosine amidohydrolase 1 (acid ceramidase) ASAH1 gene. It is characterized by motor neuron disease followed by progressive myoclonic seizures and eventual death due to respiratory insufficiency. Here we report an adolescent female who presented with atonic and absence seizures and myoclonic jerks and was later diagnosed as having myoclonic-absence seizures. An extensive genetic and metabolic work-up was unable to arrive at a molecular diagnosis. Whole exome sequencing (WES) identified two rare, deleterious mutations in the ASAH1 gene: c.850G>T;p.Gly284X and c.456A>C;p.Lys152Asn. These mutations were confirmed by Sanger sequencing in the patient and her parents. Functional studies in cultured fibroblasts showed that acid ceramidase was reduced in both overall amount and enzymatic activity. Ceramide level was doubled in the patient's fibroblasts as compared to control cells. The results of the WES and the functional studies prompted an electromyography (EMG) study that showed evidence of motor neuron disease despite only mild proximal muscle weakness. These findings expand the phenotypic spectrum of SMA-PME caused by novel mutations in ASAH1 and highlight the clinical utility of WES for rare, intractable forms of epilepsy. PMID- 24164097 TI - Defining response and non-response to treatment in patients with overactive bladder: a systematic review. AB - OBJECTIVE: There is currently a lack of formal guidance for assessing treatment response and non-response in patients with overactive bladder (OAB). Such guidance would be useful for both clinical practice and the design of clinical trials. Our purpose was to review and assess definitions of treatment response and non-response used in patients with OAB. METHODS: We conducted a systematic review of articles published between January 1, 2005 and August 8, 2013 using PubMed. Search terms included (overactive bladder) AND ('treatment response' OR responder OR success OR satisfied OR goal OR refractory OR nonresponder OR fail OR persistent OR dissatisfied). Limits were 'humans' and 'English'. Studies conducted in subjects with neurogenic detrusor overactivity, conditions other than OAB, or OAB symptoms following lower urinary tract/pelvic surgery were excluded; case reports and letters were also excluded. RESULTS: The literature search returned 423 articles, of which 75 met the inclusion criteria and defined a specific threshold by which treatment response or non-response was determined for patients receiving behavioral therapy and/or treatment with an antimuscarinic, beta3-agonist, botulinum toxin, or neural stimulation. One published abstract from congress proceedings and three additional articles that were not identified by the search were included; thus, a total of 79 records were included. A wide variety of symptom-based definitions and patient-reported outcomes (PROs) were used. Symptom-based definitions frequently used a threshold of 50-100% improvement in general or specific symptoms; urgency urinary incontinence (UUI) was often used in studies with incontinent patients. Definitions based on PROs frequently used measures of satisfaction, general improvement, or goal achievement. Studies of patients with refractory OAB often referred to a failure to respond to >=1 other therapy, or to poor efficacy or unacceptable tolerability, without further specification. Limitations of this review are that only English language articles were included and that only the PubMed database was used for the literature search. CONCLUSIONS: There is considerable heterogeneity in the definitions of treatment response and non response in trials of patients with OAB; some standardization would be beneficial. However, there is also heterogeneity among patients of what constitutes treatment success or failure, and conceptualizations of treatment response and non-response in both clinical trials and clinical practice must take patient characteristics into account. For patients with UUI, it is recommended that the criteria for treatment response include this symptom, as measured by change in the absolute number of UUI episodes or achievement of continence, given its impact on patients' lives and associated bother. PROs provide important information that confirm symptom-based measures by demonstrating that observed changes in symptoms are meaningful to the patient. In clinical practice, measures of treatment satisfaction and goal achievement can be highly useful. PMID- 24164099 TI - Double-edged effects of arsenic compounds: anticancer and carcinogenic effects. AB - Although arsenic is known to cause cancers of lung, skin and kidney, arsenic trioxide (As2O3) has been recently recognized as one of the most effective novel anticancer agent for the treatment of acute promyelocytic leukemia (APL). These paradoxical effects of arsenic may be dose-dependent, associated with its distinctive metabolism, or correlated with its direct or indirect effects on different cellular pathways which may result in altered cellular functions. The basic mechanism through which As2O3 induces molecular remission in APL patients include direct targeting of PML and retinoic acid receptor alpha fusion protein (PML-RARalpha) by arsenic resulting in oncoprotein degradation leading to partial differentiation. Many in vitro studies have also indicated that the anticancer properties of As2O3 against non-APL blood cancers predominantly occur through induction of apoptotic pathway. Especially, release of cytochrome c or activation of the caspase cascades and apoptosis-related proteins by arsenic is thought to occur by directly targeting mitochondria. The mechanisms and the selective target sites that have been usually associated with the cytotoxic effects of arsenicals are discussed here with reference to their contribution towards the anticancer properties of arsenic. In this review we have particularly explained the in vivo or in vitro arsenic toxicity based on arsenic metabolic pathway and its different metabolites. These multiple effects and different selective target sites for arsenic and its metabolites emphasize the need for better understanding of paradoxical effects of arsenic which may provide the appropriate use of this agent in the treatment of various malignancies. PMID- 24164100 TI - Circadian phase assessment by ambulatory monitoring in humans: correlation with dim light melatonin onset. AB - The increased prevalence of circadian disruptions due to abnormal coupling between internal and external time makes the detection of circadian phase in humans by ambulatory recordings a compelling need. Here, we propose an accurate practical procedure to estimate circadian phase with the least possible burden for the subject, that is, without the restraints of a constant routine protocol or laboratory techniques such as melatonin quantification, both of which are standard procedures. In this validation study, subjects (N = 13) wore ambulatory monitoring devices, kept daily sleep diaries and went about their daily routine for 10 days. The devices measured skin temperature at wrist level (WT), motor activity and body position on the arm, and light exposure by means of a sensor placed on the chest. Dim light melatonin onset (DLMO) was used to compare and evaluate the accuracy of the ambulatory variables in assessing circadian phase. An evening increase in WT: WTOnset (WTOn) and "WT increase onset" (WTiO) was found to anticipate the evening increase in melatonin, while decreases in motor activity (Activity Offset or AcOff), body position (Position Offset (POff)), integrative TAP (a combination of WT, activity and body position) (TAPOffset or TAPOff) and an increase in declared sleep propensity were phase delayed with respect to DLMO. The phase markers obtained from subjective sleep (R = 0.811), WT (R = 0.756) and the composite variable TAP (R = 0.720) were highly and significantly correlated with DLMO. The findings strongly support a new method to calculate circadian phase based on WT (WTiO) that accurately predicts and shows a temporal association with DLMO. WTiO is especially recommended due to its simplicity and applicability to clinical use under conditions where knowing endogenous circadian phase is important, such as in cancer chronotherapy and light therapy. PMID- 24164101 TI - Renal function changes and seasonal temperature in patients undergoing cardiac surgery. AB - Some observations in humans and other mammalians suggest that serum creatinine (SC) and estimated glomerular filtration rate (eGFR) may change during the warm season. The objective of this study is to determine if temperature-dependent seasonal changes in levels of SC and eGFR are detectable in cardiac surgery patients, with associated changes in postoperative acute kidney injury (AKI) incidence. This is a single-center retrospective study based on the institutional database of cardiac surgery in the period 2000-2012. Sixteen-thousand and twenty three consecutive adult patients undergoing cardiac surgery comprised the study population. Baseline and postoperative SC and eGFR values, and AKI rate according to the month when surgery was performed were measured. The month-related changes SC and eGFR, and AKI rate, were assessed in crude and adjusted models, and their association with the correspondent meteorological data registered at the time of surgery was tested. Patients operated in the six warmest months (May through October) had a significant (p < 0.001) higher value of baseline SC (1.17 +/- 0.7 mg/dL) versus the six coldest months (1.12 +/- 0.6 mg/dL), and a significantly (p = 0.031) higher value of peak postoperative SC (1.31 +/- 0.85 mg/dL) versus the 6 coldest months (1.28 +/- 0.89), with maximum values between July and August. A similar behaviour was found for eGFR. After adjustment for other confounders, the AKI rate was not significantly different in the warmest months, even if a trend towards a higher rate in August was observed (odds ratio 1.287, 95% confidence interval 0.96-1.74, p = 0.097). Baseline (p < 0.001) and peak postoperative (p = 0.0054) serum creatinine levels were significantly higher for increasing mean ambient temperature. Humidity and wind speed were negatively associated with pre- and postoperative eGFR. In conclusion, patients operated during the warmest season, have higher levels of SC and lower levels of eGFR, without a correspondent increase in the AKI rate. Different hypotheses underlying this pattern are generated by this study, including a dehydration status, concomitant anemia, and a higher transfusion rate. PMID- 24164102 TI - Dosing related effects of zoledronic acid on bone markers and creatinine clearance in patients with multiple myeloma and metastatic breast cancer. AB - Zoledronic acid (Zol) is frequently used for the treatment of bone disease in patients with multiple myeloma and breast cancer with metastasis to bone. Therefore, there is also an interest in finding the optimal dosing regimen to optimize effects, minimize side effects and reduce costs. In our phase II clinical trial we investigated the effect of Zol treatment on the serum levels of the bone markers collagen type 1 cross-linked C-telopeptide (CTX) and bone specific alkaline phosphatase (bALP) as well as on creatinine clearance (kidney function) in response to dosing and duration of treatment for each individual patient. METHODS: We enrolled 30 multiple myeloma (MM) and 30 breast cancer (BC) patients whereof 10 of each had never received bisphosphonate and 20 had received at least six prior Zol treatments. RESULTS: We found that Zol treatment strongly reduced CTX (Spearman's correlation, rs = -0.59, p = 0.0007) and bALP (Spearman's correlation, rs = -0.51, p = 0.0042) in MM patients while only CTX (Spearman's correlation, rs = -0.42, p = 0.024) was significantly affected in BC patients. Multiple linear regression analyses done on the entire cohort showed that the average time between each dose of Zol had the strongest impact on CTX (p < 0.001) and bALP (p = 0.011) levels while the total accumulated number of Zol infusions had a less pronounced effect on CTX levels (p = 0.015). In contrast, multiple linear regression analysis showed that the total number of Zol infusions had a strong negative impact on kidney function (p = 0.014) while the average time between each dose of Zol had no significant impact. CONCLUSION: Thus, if MM and BC patients are not treated regularly every month with Zol bone turnover is not fully suppressed, while prolonged treatment with zoledronic acid compromises kidney function. We believe that these data significantly contribute to the knowledge needed to find the optimal Zol treatment schedule. PMID- 24164103 TI - A population-based study of 135 lymphomas after solid organ transplantation: The role of Epstein-Barr virus, hepatitis C and diffuse large B-cell lymphoma subtype in clinical presentation and survival. AB - BACKGROUND: Epstein-Barr virus (EBV) plays a major role in the development of post-transplant lymphoproliferative disorder (PTLD), but there is an increasing awareness of EBV-negative PTLD. The clinical presentation of EBV-negative PTLD has not been as well characterised as EBV-positive cases. Further, there is limited knowledge on the clinical importance of diffuse large B-cell lymphoma (DLBCL) cell of origin subtype post-transplant. MATERIALS AND METHODS: We studied the role of EBV, hepatitis C (HCV) and DLBCL subtype in clinical presentation and survival in 135 post-transplant lymphomas diagnosed 1980-2006 in a population based cohort of 10 010 Swedish solid organ transplant recipients. The lymphomas were re-evaluated according to WHO 2008, examined for EBV, and clinical data were collected from medical records. RESULTS: Lymphoma incidence rate was 159/100 000 person-years and is also reported by lymphoma subtype. EBV-negative lymphomas constituted 48% and were associated with HCV infection (p = 0.02), bone marrow involvement (p < 0.001), and T-cell phenotype (p = 0.002). Among DLBCL, 78% were of non-germinal centre subtype, which was associated with EBV-positivity (69%, p = 0.001), early occurrence (p = 0.03), heart/liver/lung/pancreas recipients (p = 0.02), anti-T-cell globulin (p = 0.001), and tacrolimus treatment (p = 0.02). DLBCL subtypes had similar overall survival. Five-year overall survival was 42% in all treated patients. Independent poor prognostic factors were older age, B symptoms, ECOG 2-4, kidney/pancreas/heart recipients, T-cell lymphoma, and HCV infection. CONCLUSIONS: With long follow-up, a large part of PTLD is EBV negative, due to a high proportion of T-cell lymphomas and low of polymorphic PTLD. EBV-negative PTLD have a different clinical presentation. HCV may play an aetiological role in late-onset PTLD and was revealed as a new prognostic factor for inferior survival that needs to be confirmed in larger studies. The heavier immunosuppression in non-kidney transplantations seems to play a role in the development of non-germinal centre DLBCL. DLBCL cell of origin subtype lacks prognostic importance in the transplant setting. PMID- 24164104 TI - Dosimetric inter-institutional comparison in European radiotherapy centres: Results of IAEA supported treatment planning system audit. AB - BACKGROUND AND PURPOSE: One of the newer audit modalities operated by the International Atomic Energy Agency (IAEA) involves audits of treatment planning systems (TPS) in radiotherapy. The main focus of the audit is the dosimetry verification of the delivery of a radiation treatment plan for three-dimensional (3D) conformal radiotherapy using high energy photon beams. The audit has been carried out in eight European countries - Estonia, Hungary, Latvia, Lithuania, Serbia, Slovakia, Poland and Portugal. The corresponding results are presented. MATERIAL AND METHODS: The TPS audit reviews the dosimetry, treatment planning and radiotherapy delivery processes using the 'end-to-end' approach, i.e. following the pathway similar to that of the patient, through imaging, treatment planning and dose delivery. The audit is implemented at the national level with IAEA assistance. The national counterparts conduct the TPS audit at local radiotherapy centres through on-site visits. TPS calculated doses are compared with ion chamber measurements performed in an anthropomorphic phantom for eight test cases per algorithm/beam. A set of pre-defined agreement criteria is used to analyse the performance of TPSs. RESULTS: TPS audit was carried out in 60 radiotherapy centres. In total, 190 data sets (combination of algorithm and beam quality) have been collected and reviewed. Dosimetry problems requiring interventions were discovered in about 10% of datasets. In addition, suboptimal beam modelling in TPSs was discovered in a number of cases. CONCLUSIONS: The TPS audit project using the IAEA methodology has verified the treatment planning system calculations for 3D conformal radiotherapy in a group of radiotherapy centres in Europe. It contributed to achieving better understanding of the performance of TPSs and helped to resolve issues related to imaging, dosimetry and treatment planning. PMID- 24164106 TI - Stickler syndrome type 1 accompanied by membranous vitreous anomaly in two Japanese sisters. AB - We report two cases of Stickler syndrome type 1 accompanied by a membranous vitreous anomaly in two Japanese sisters. A nine-year-old girl was referred to us for a rhegmatogeneous retinal detachment in her right eye. She had moderate myopia and a membranous vitreous anomaly in both eyes. She also had micrognathia and a saddle nose, leading to a diagnosis of Stickler syndrome type 1. The retinal detachment persisted even after scleral buckling surgery; however, the retina was reattached after 25-gauge microincision vitreous surgery 11 days later. Her seven-year-old sister had been diagnosed with Pierre Robin sequence due to micrognathia, cleft palate, and saddle nose. She was myopic by about -9.0 diopters with a membranous vitreous anomaly in both eyes and circumferential perivascular retinal degeneration in the right eye. Genetic analyses showed that both sisters and their mother carried the same mutation in the COL2A1 gene. The findings in these sisters indicate that retinal detachment is associated with Stickler syndrome type 1. Micro-incison vitreous surgery might be effective for rhegmatogeneous retinal detachment with high vitreous liquefaction. PMID- 24164105 TI - Do alcohol and marijuana use decrease the probability of condom use for college women? AB - Alcohol and marijuana use are thought to increase sexual risk taking, but event level studies conflict in their findings and often depend on reports from a limited number of people or on a limited number of sexual events per person. With event-level data from 1,856 sexual intercourse events provided by 297 college women (M age = 18 years; 71% White), we used multilevel modeling to examine associations between alcohol and marijuana use and condom use as well as interactions involving sexual partner type and alcohol-sexual risk expectancies. Controlling for alternative contraception use, partner type, regular levels of substance use, impulsivity and sensation seeking, and demographics, women were no more or less likely to use condoms during events involving drinking or heavy episodic drinking than during those without drinking. However, for drinking events, there was a negative association between number of drinks consumed and condom use; in addition, women with stronger alcohol-sexual risk expectancies were marginally less likely to use condoms when drinking. Although there was no main effect of marijuana use on condom use, these data suggest marijuana use with established romantic partners may increase risk of unprotected sex. Intervention efforts should target expectancies and emphasize the dose-response relationship of drinks to condom use. PMID- 24164107 TI - Non-adherence in difficult asthma and advances in detection. AB - Non-adherence to anti-inflammatory therapies is common in patients referred for specialist assessment at difficult-to-treat asthma services. In the difficult asthma setting, non-adherence to treatment is associated with poor baseline asthma control, increased frequency of exacerbations and asthma-related hospitalizations, as well as increased risk of death. Here, we present a review of the current literature surrounding the prevalence and risks of non-adherence in difficult asthma and we report on current methods of measuring treatment adherence and advances in the detection of non-adherence. We will also explore methods by which non-adherence in difficult asthma can be addressed. PMID- 24164108 TI - Local approaches to sacro-iliac joint pathologies: several unanswered questions. PMID- 24164109 TI - Proprotein convertase subtilisin/kexin type 9 (PCSK9) and LDL lowering in the contemporary management of dyslipidemia. AB - PCSK9 proprotein convertase subtilisin/kexin type (PCSK9) protein plays an important role in LDL cholesterol (LDL-C) metabolism, due to its role in the degradation of the LDL receptor. Preliminary clinical data of PCSK9 inhibition are quite promising and indicate that PCSK9 inhibition may be a novel strategy for the treatment of dyslipidemia particularly for those with refractory hypercholesterolemia, statin intolerance, or an elevated lipoprotein (a) level and associated cardiovascular diseases. Furthermore, development of PCSK9 inhibitor is an excellent example of "bench to bedside" concept where discovery of a genetic mutation was translated into a novel therapy to address unmet clinical needs. Although several approaches have been attempted to inhibit PCSK9 activity including small molecules, gene silencing and inhibitory antibodies, the most promising approach appears to be the use of monoclonal antibodies with a 50 70% LDL cholesterol reduction on top of maximal doses of statins. In this article, we review the pharmacology of PCSK9 and summarize findings from key clinical studies using PCSK9 inhibitors. PMID- 24164110 TI - Free energy of mixing of acetone and methanol: a computer simulation investigation. AB - The change of the Helmholtz free energy, internal energy, and entropy accompanying the mixing of acetone and methanol is calculated in the entire composition range by the method of thermodynamic integration using three different potential model combinations of the two compounds. In the first system, both molecules are described by the OPLS, and in the second system, both molecules are described by the original TraPPE force field, whereas in the third system a modified version of the TraPPE potential is used for acetone in combination with the original TraPPE model of methanol. The results reveal that, in contrast with the acetone-water system, all of these three model combinations are able to reproduce the full miscibility of acetone and methanol, although the thermodynamic driving force of this mixing is very small. It is also seen, in accordance with the finding of former structural analyses, that the mixing of the two components is driven by the entropy term corresponding to the ideal mixing, which is large enough to overcompensate the effect of the energy increase and entropy loss due to the interaction of the unlike components in the mixtures. Among the three model combinations, the use of the original TraPPE model of methanol and modified TraPPE model of acetone turns out to be clearly the best in this respect, as it is able to reproduce the experimental free energy, internal energy, and entropy of mixing values within 0.15 kJ/mol, 0.2 kJ/mol, and 1 J/(mol K), respectively, in the entire composition range. The success of this model combination originates from the fact that the use of the modified TraPPE model of acetone instead of the original one in these mixtures improves the reproduction of the entropy of mixing, while it retains the ability of the original model of excellently reproducing the internal energy of mixing. PMID- 24164111 TI - Electric field-induced, reversible lotus-to-rose transition in nanohybrid shish kebab paper with hierarchical roughness. AB - Nature uses a variety of strategies to tune wetting behavior for biological applications. By artificially mimicking these strategies, a variety of different wetting conditions can be achieved. Numerous examples exist of designed surfaces that can mimic the wetting behavior of lotus leaves or rose petals, but few surfaces that may reversibly transition between the two have been reported. In this paper, a combination of topological control over conductive, carbon-based nanomaterials and low surface energy coating was used to tune the wetting properties between "lotus" and "rose." The topological control was imparted by a hierarchical "nanohybrid shish kebab" structure, which uses solution-grown polymer single crystals on carbon nanotubes to tune the surface roughness of the latter. The low surface energy polytetrafluoroethylene (PTFE) coating was deposited by the initiated chemical vapor deposition technique. Application of electric potential on these unique nanostructures allows the surfaces to reversibly transition between "lotus" and "rose" behavior. A further irreversible transition between "rose" and the fully wetted Wenzel wetting state was also predicted and shown. These materials show remarkable promise for lab-on-a-chip devices and surface passivation for biological studies. PMID- 24164113 TI - Deformation of ferrofluid marbles in the presence of a permanent magnet. AB - This paper investigates the deformation of ferrofluid marbles in the presence of a permanent magnet. Ferrofluid marbles are formed using a water-based ferrofluid and 1 MUm hydrophobic polytetrafluoride particles. A marble placed on a Teflon coated glass plate deforms under gravity. In the presence of a permanent magnet, the marble is further deformed with a larger contact area. The geometric parameters are normalized by the radius of an undistorted spherical marble. The paper first discusses a scaling relationship between the dimensionless radius of the contact area as well as the dimensionless height and the magnetic Bond number. The dimensionless contact radius is proportional to the fourth root of the magnetic bond number. The dimensionless height scales with the inverse square root of the magnetic Bond number. In the case of a moving marble dragged by a permanent magnet, the deformation is evaluated as the difference between advancing and receding curvatures of the top view. The dimensionless height and the contact diameter of the marble do not significantly depend on the speed or the capillary number. The scaling analysis and experimental data show that the deformation is proportional to the capillary number. PMID- 24164112 TI - Electrochemical assay for the signal-on detection of human DNA methyltransferase activity. AB - Strategies to detect human DNA methyltransferases are needed, given that aberrant methylation by these enzymes is associated with cancer initiation and progression. Here we describe a nonradioactive, antibody-free, electrochemical assay in which methyltransferase activity on DNA-modified electrodes confers protection from restriction for signal-on detection. We implement this assay with a multiplexed chip platform and show robust detection of both bacterial (SssI) and human (Dnmt1) methyltransferase activity. Essential to work with human methyltransferases, our unique assay design allows activity measurements on both unmethylated and hemimethylated DNA substrates. We validate this assay by comparison with a conventional radioactive method. The advantages of electrochemistry over radioactivity and fluorescence make this assay an accessible and promising new approach for the sensitive, label-free detection of human methyltransferase activity. PMID- 24164115 TI - Antifungal cyclic lipopeptides from Bacillus amyloliquefaciens strain BO5A. AB - A bioassay-guided fractionation of Bacillus amyloliquefaciens strain BO5A afforded the isolation of two new cyclic lipopeptides (1 and 2) as the major lipid constituents (>60%) of the CHCl3-MeOH (2:1) extract. The chemical structures of the isolated metabolites were elucidated by spectroscopic methods, including 1D and 2D NMR spectroscopy, mass spectrometry (MS), secondary ion mass spectrometry (MS1, MS2), and chemical degradation. The compounds are members of the surfactins family and are based on a heptapeptide chain composed by Glu-Val Leu-Val-Asp-Leu-Leu. Its N-terminal end is N-acylated by an (R)-3-hydroxy fatty acid with linear alkyl chains of 16:0 and 15:0 (1 and 2, respectively). The 3 hydroxyl group closes a 25-membered lactone ring with the carboxylic group of the C-terminal amino acid. The isolated compounds were tested for their inhibitory activity against the four pathogenic fungi Fusarium oxysporum, Aspergillus niger, Botrytis cinerea, and Penicillium italicum and the biocontrol fungus Trichoderma harzianum. Compound 2 displayed activity against all tested pathogens. PMID- 24164116 TI - Morphology and histology of the collapsed lunate in advanced kienbock disease. AB - Morphological and histological changes of 24 collapsed lunates in advanced Kienbock disease were investigated. Articular cartilage of a collapsed lunate were consistently attenuated or disappeared. The proximal articular cartilage facing the radius is generally more affected than the distal articular cartilage facing the capitate. There was one major fracture in addition to multiple minor fractures in the collapsed lunate. Fracture patterns were classified into three types according to the directions of major fracture, namely horizontal type, dual oblique type, and vertical type. There were viable and necrotic areas in the collapsed lunate. Active new bone formation was observed at the junction between the viable and necrotic bone area of the collapsed lunate in advanced Kienbock disease. PMID- 24164117 TI - Survey of upper extremity injuries among martial arts participants. AB - PURPOSE: To survey participants at various experience levels of different martial arts (MA) about upper extremity injuries sustained during training and fighting. MATERIALS: A 21-s question survey was designed and utilised. The survey was divided into four groups (Demographics, Injury Description, Injury Mechanism, and Miscellaneous information) to gain knowledge about upper extremity injuries sustained during martial arts participation. Chi-square testing was utilised to assess for significant associations. RESULTS: Males comprised 81% of respondents. Involvement in multiple forms of MA was the most prevalent (38%). The hand/wrist was the most common area injured (53%), followed by the shoulder/upper arm (27%) and the forearm/elbow (19%). Joint sprains/muscle strains were the most frequent injuries reported overall (47%), followed by abrasions/bruises (26%). Dislocations of the upper extremity were reported by 47% of participants while fractures occurred in 39%. Surgeries were required for 30% of participants. Females were less likely to require surgery and more likely to have shoulder and elbow injuries. Males were more likely to have hand injuries. Participants of Karate and Tae Kwon Do were more likely to have injuries to their hands, while participants of multiple forms were more likely to sustain injuries to their shoulders/upper arms and more likely to develop chronic upper extremity symptoms. With advanced level of training the likelihood of developing chronic upper extremity symptoms increases, and multiple surgeries were required. Hand protection was associated with a lower risk of hand injuries. CONCLUSION: Martial arts can be associated with substantial upper extremity injuries that may require surgery and extended time away from participation. Injuries may result in chronic upper extremity symptoms. Hand protection is important for reducing injuries to the hand and wrist. PMID- 24164118 TI - Treatment of distal radial fractures with the DVR-A plate--the early Bristol experience. AB - AIM: The aim of the study was to assess how adequately distal radial fracture reduction was reproduced and maintained with the distal volar radius anatomic DVR A (Biomet, Inc) locking plate. METHODS: We looked at a consecutive series of 111 patients treated with the DVR-A plate at our institution from 2007-2010. The preoperative, intra-operative, and postoperative films were reviewed. The AO and Frykman classification was recorded. The sagittal tilt, radial inclination, and radial length were measured on intra-operative X-rays and compared with final follow-up X-rays. The last recorded range of motion at follow-up and a functional assessment using the Disabilities of the Arm, Shoulder, and Hand (DASH) score was recorded. RESULTS: At final follow-up a mean radial inclination of 22.22 degrees (11 to 38 degrees), radial height of 11.85 mm (6 to 18 mm), and sagittal tilt of 6.71 degrees volar (-9 to 19 degrees) was achieved. From initial post-operative films, to final follow-up X-rays there was a mean increase of 0.17 degrees in radial inclination, a mean loss of 0.36 mm radial height, and a mean loss of 2.17 degrees volar tilt. The mean extension was 46.8 degrees, flexion 48.3 degrees, pronation 77.4 degrees, supination 74.8 degrees, radial deviation 15.3 degrees and the ulnar deviation 19 degrees. The mean DASH score was 12.8 (0-68). CONCLUSION: The DVR-A plate achieved a highly satisfactory reduction of radial length and radial inclination, with a small loss of volar sagittal tilt at final follow-up. A good functional outcome was reported, with a satisfactory range of motion achieved. The DVR-A plate is a safe and effective treatment for unstable and intra-articular displaced distal radius fractures, particularly in younger patients, in the short term. PMID- 24164119 TI - Extensor pollicis longus tendon ruptures after the use of volar locking plates for distal radius fractures. AB - Currently, volar locking plates are commonly used to treat distal radius fractures (DRF) because of their stable biomechanical construct and because they cause less soft tissue disturbance and allow early mobilisation of the wrist. Complications such as rupture of tendons have been reported to occur with use of volar locking plates. We describe six cases of rupture of extensor pollicis longus (EPL) tendons after the use of volar locking plates. EPL tendon injuries occurred in 2.1% (6/286) of cases after DRF surgery. The causes of EPL rupture after DRF surgery were protrusion of the head tip and insufficient reduction of the dorsal roof fragment of the distal radius. These were considered iatrogenic problems. The cause of EPL rupture was unknown in three cases. We should be extremely careful when determining optimum screw length and reducing displaced dorsal roof fragments to prevent damaging the EPL tendons. PMID- 24164120 TI - Short to medium results using the remotion total wrist replacement for rheumatoid arthritis. AB - We present the clinical outcome of patients who underwent RE-MOTION Total Wrist Replacement (TWR) for the treatment of Rheumatoid arthritis involving the wrist. Ten patients were available for follow-up, ranging from one to five years after index surgery. Two patients required surgical intervention for wound breakdown, including one patient who required a radial forearm flap for skin coverage. No patients required revision surgery or conversion to fusion. Patients who did not have complications gained statistically significant pain relief and improvement in mean overall flexion. In this small case series with short to medium results patients reported an improvement in terms of flexion and pain. Despite this, the question of efficacy of TWR compared to fusion in the long term remains unanswered due to the high rate of complications. PMID- 24164121 TI - Scaphoid translation measurements in normal wrists. AB - The purpose of this study was to establish a normal measure of scaphoid position in the radioulnar plane in standard neutral, radial and ulnar deviation posteroanterior radiographs. This measurement may allow indirect evaluation of the radiocarpal ligaments and comparison between normal and pathologic states (following radius fractures, perilunate dislocations). Measurements were trialed on 74 normal wrist radiographs and 25 cadaver wrists. We evaluated the distance between the radial styloid and the scaphoid and corresponding scaphoid width. The ratio of distance/width at the mid styloid level (0.35, imprecision SD = 0.1) had the lowest random error and is therefore the most precise measurement of true scaphoid translation. This measurement is independent of scapholunate ligament integrity and may provide a better assessment of the radiocarpal component of ulnar translational instability. Abnormal movement of the scaphoid in the radioscaphoid joint likely reflects ligamentous injury. Identifying and addressing these injuries may prevent the development of arthritis. PMID- 24164122 TI - Clinical outcome and cost comparison of carpal tunnel wound closure with monocryl and ethilon: a prospective study. AB - This prospective non-randomised two-cohort study compares the use of an absorbable suture (Poliglecrapone [Monocryl]: Group A) and a non-absorbable suture (Polyamide [Ethilon]: Group B) in wound closure after elective carpal tunnel decompression. The primary outcome was scar cosmesis as assessed by the Stonybrook Scar Evaluation Scale (SBSES); the financial cost of wound closure was compared as a secondary outocome. All fifty patients completed follow-up. At six weeks, there was no significant difference in the two groups regarding scar tenderness (p = 0.5), although residual swelling was more evident in the absorbable group (p = 0.2). The mean SBSES score at six weeks was 4.72 in Group A, and 4.8 in Group B (p = 0.3). The unit cost per closed wound of Monocryl was three times than Ethilon (p < 0.05). Ethilon is thus cost-effective without compromising the cosmetic outcome, and we recommend using this as the preferred suture for closure of carpal tunnel wounds. PMID- 24164123 TI - Mid-motion deformation of median nerve during finger flexion: a new insight into the dynamic aetiology of carpal tunnel syndrome. AB - Carpal tunnel syndrome (CTS) exists in a spectrum of severity and symptoms with a dynamic component. We aim to study dynamic nerve-tendon interrelationships in normal and mild CTS wrists during a fist motion, with dynamic ultrasound. We observed that in normal wrists, the nerve arcs in an ulnar-volar direction and changes from a circular shape to a flat oval during motion. In CTS candidates, however, the curvature and distance of the nerve's path are reduced, while nerve shape remains relatively constant. In all candidates, the nerve is compressed against the flexor retinaculum, with the nerve subject to less compression in normal candidates as it moves dorsally into a recess. These findings suggest that besides mechanical compression from increased carpal tunnel contents alone, a decrease in nerve gliding movement may lead to CTS symptomatology. Furthermore, we identified that maximum nerve deformation occurs mid-motion, supporting the use of wrist splints for symptom relief. PMID- 24164124 TI - Median nerve deformation during finger motion in carpal tunnel syndrome: correlation between nerve conduction and ultrasonographic indices. AB - To compare the median nerve deformation indices between carpal tunnel syndrome (CTS) patients and controls, 60 wrists of asymptomatic volunteers and 40 wrists of idiopathic CTS patients were evaluated by ultrasound. CTS was diagnosed through clinical findings and nerve conduction studies. Deformation indices, which were determined by the ratios of the nerve cross-sectional area, perimeter, aspect ratio, and circularity in finger extension and flexion positions, were measured. The deformation indices were compared between patients and controls. The correlation coefficients between distal motor latency and deformation indices were measured in CTS patients. There were significant differences between patients and controls in the deformation indices of perimeter, aspect ratio, and circularity. There was a mild correlation between distal latency and deformation indices of the perimeter and circularity (correlation coefficient 0.315 and 0.342). The deformation indices of perimeter and circularity might be useful to identify the nerve conduction severity of CTS. PMID- 24164125 TI - Comparative study on the stiffness of transverse carpal ligament between normal subjects and carpal tunnel syndrome patients. AB - The purpose of this study was to compare the stiffness of the transverse carpal ligament (TCL) between healthy volunteers and carpal tunnel syndrome (CTS) patients using sonoelastography. We studied 17 healthy volunteers (four men, 13 women; range 37-84 years) and 18 hands of 13 patients with CTS (three men, ten women; range 41-79 years). Thickness and elasticity of the TCL were evaluated by sonoelastography. Elasticity was estimated by strain ratio of an acoustic coupler, which has a standardized elasticity as a reference medium, to the TCL (AC/T strain ratio). The AC/T strain ratios of the healthy volunteers and the CTS patients were 6.0 and 8.1, respectively (p = 0.030). The AC/T strain ratio showed a positive correlation with the duration of symptoms in the CTS patients (p = 0.035, r = 0.50). We concluded that increased stiffness of the TCL could be one of the causes for CTS. PMID- 24164126 TI - Outcomes of four-corner arthrodesis using the Hubcap circular plate. AB - We present results of four-corner carpal arthrodesis with the Acumed Hubcap circular plate performed at our unit. Eight patients underwent eight procedures over five years, for scapholunate advanced collapse (five wrists) and scaphoid non-union advanced collapse (three wrists). Outcomes included range of motion, quickDASH scores, and visual analogue scores for satisfaction. At final follow up, mean flexion-extension arc was 56 degrees , mean radial-ulnar deviation 29 degrees and mean quickDASH score was 23/100. Mean score for satisfaction was 7.7/10 (77%). Seven out of eight (87.5%) patients said they would have it done again, and would also recommend it to others. Radiological union was achieved in all cases. One screw broke in one arthrodesis without causing symptoms. The functional outcomes with our use of the Hubcap are comparable to those reported in literature to date with other circular plates (e.g. Spider plate). There were no non-unions, which is the main reported complication with these plates. PMID- 24164127 TI - Comparison of two uncemented trapezio-metacarpal cups: a finite element study. AB - Trapezium components from two uncemented total joint replacements were compared in a three-dimensional finite element model. A 100 N axial and angular load was applied in a normal and an osteoporotic bone model. The axial deformation and maximum periprosthetic stress are greater for the Elektra than the Motec CMC cup. The Motec CMC design is less sensitive to changing bone quality. The Elektra cup transmits more stress to the cortical bone rim in all load conditions, but under angular loading the proportionate increase in stress is lower. The Motec CMC design distributes the stress and contact pressure more evenly, whereas the Elektra transfers most of the load to the cortical bone rim and the screw hole base. The design features that are believed to be of greatest significance for the differences are the raised centre of rotation of the Motec CMC cup and the collar acting as a lever arm. PMID- 24164128 TI - Conservative treatment of fractures of the proximal phalanx: an option even for unstable fracture patterns. AB - PURPOSE: The purpose of the study was to assess the efficacy of the conservative management of proximal phalangeal fractures in a dorsal plaster slab. METHODS: Twenty-three consecutive patients with extra-articular proximal phalangeal fractures were included in this prospective study. Fourteen patients (62%) presented with fractures considered unstable. The fractures were reduced and the position was held with a dorsal plaster slab for three weeks. The patients were followed up for an average of seven weeks (range 2 to 45) after the injury. Range of motion of the finger and radiological evidence of union, non-union or malunion was documented after removal of the plaster. RESULTS: Ninety-one percent of fractures maintained an acceptable reduction. All cases measured less than 15 degrees of angulation. On average 1,1 mm of shortening was measured. In two (9%) cases the reduction was not accepted on follow up assessment and the fractures were managed surgically. CONCLUSION: Most extra-articular proximal phalanx fractures can be managed conservatively with acceptable results. PMID- 24164129 TI - A modified tension band wiring technique for treatment of the bony mallet finger. AB - PURPOSE: To report the outcomes of mallet fractures treated with our modified tension band wiring technique. METHODS: Eleven men and two women (mean age; 33 years) with mallet fractures in which happened more than five weeks before surgery, or with fracture fragments involving more than 2/3 or less than 1/3 of the distal phalanx articular surface or with previous surgical intervention, were subjected to this study. The fracture fragment was fixed with a modified tension band wiring technique using a stainless steel wire and an injection needle. RESULTS: All patients achieved bone union in nine weeks in average. All patients had no pain except one with mild pain. No patient showed a gap or step-off greater than 1 mm. CONCLUSIONS: Our tension band wiring technique can be used regardless of the size of the dorsal fracture fragment or the interval between injury and surgery. PMID- 24164130 TI - Necrotising soft tissue infection of bilateral upper limb caused by the injection of oral bacteria: a case report. AB - Necrotising soft tissue infection is a rare and rapid process with devastating consequence. We report one case of necrotising soft tissue infection in a bilateral upper limb with uncommon oral bacteria. Radiological imaging revealed the presence of gas in upper limb soft tissues, and an MRI showed the localised signal changes in the biceps muscle of the right upper arm, and the subcutaneous tissue of the left elbow. The patient was treated with surgical resection of the infected muscle and wide debridement of the subcutaneous tissue. Antibiotics were initiated. The patient recovered immediately without functional deficit. The unique features of this patient were possible to observe in the progression of the necrotising soft tissue infection in the bilateral upper limb with intentional injection of oral bacteria, and the effect of biceps brachii resection in a prime age worker. PMID- 24164131 TI - A case of rotational restriction of the forearm due to abnormal configuration of pronator quadratus muscle. AB - We present a case of rotational restriction of the forearm due to abnormal configuration of the pronator quadratus muscle. A 20-year-old man developed right wrist joint pain on pitching of a baseball game and thereafter displayed rotational disorder of the forearm. Magnetic resonance imaging (MRI) revealed a space-occupying lesion from the volar side of the radius to the dorsal side of the ulna. The lesion was iso-hyperintense on T1-weighted (T1W) images and showed a mixed pattern of high intensities on T2-weighted (T2W) images. His symptoms were immediately reduced after removal of the mass. Histological examination showed that the mass contained much skeletal muscle and revealed myxoid degeneration of striated muscles. We assumed that his pronator quadratus muscle had been a divided form of deep layer and superficial layer tissue, possibly congenitally. We supposed that the deep layer had degenerated due to chronic stimulation and had extended around to the dorsal side of the ulna, which caused rotational restriction from the resulting impaired distal radioulnar joint. To our knowledge, there has been no similar case reported in the literature. PMID- 24164132 TI - Isolated abductor digiti minimi palsy--an unusual case of Guyon's canal compression. AB - We present a case of isolated Abductor Digiti Minimi (ADM) palsy caused by an anomalous branch from the ulnar artery. Electrophysiology suggested selective involvement of the motor branch to the ADM in the Guyon's canal. Surgical exploration revealed an anomalous branch of the ulnar artery causing a pincer effect on the nerve to the ADM. Division and ligation of this branch effectively decompressed the nerve and the patient recovered satisfactorily. This report highlights the need to consider vascular aberrations as a differential diagnosis for ulnar neuropathy in Guyon's canal. PMID- 24164133 TI - Breaking the rules: Dupuytren's disease under Skoog's fibres. AB - Skoog and others have concluded that the Skoog fibres, or transverse ligament of the palmar aponeurosis (TLPA), are never involved in the Dupuytren's disease process. Here we present a case in which this clearly occurs. Whilst for the vast majority of Dupuytren's cases the Skoog's fibres delineate the required deep extent of dissection for pretendinous cords, this case proves an exception, highlighting an occasional need to beware of accepting the conventional wisdom. PMID- 24164134 TI - Bilateral thumb metacarpophalangeal joint fusions for severe hyperextension deformities in conjunction with carpometacarpal joint reconstructions. AB - BACKGROUND: Hyperextension of the first metacarpophalangeal (MCP) joint and adduction of the first web space of the hand are features of advanced stages of carpometacarpal (CMC) joint arthrosis. Restoration of mechanical efficiency in such patients requires stabilization of both the CMC and MCP joints. This study describes a patient with bilateral secondary hyperextension of the MCP joint greater than 50 degrees who displayed good functional outcome following staged bilateral MCP joint arthrodesis with simultaneous CMC joint reconstruction. CASE REPORT: Excision of trapezium, formation of a Weilby sling utilising flexor carpi radialis, and insertion of a Swanson's prosthesis forms the basis of CMC joint reconstruction. Fusion of the MCP joint involved placement of longitudinal K wires and tension band wiring. The patient underwent an initial right-sided procedure in 2008 and subsequently elected for the same procedure on the contralateral side 26 months later. Good functional improvement was achieved with a pre and postoperative DASH score of 49 and 8 respectively. Follow-up and radiological imaging at 34 months from her initial surgery confirmed good positions of the prostheses and solid MCP joint fusions. The patient developed postoperative interphalangeal joint pain, which responded to steroid injection. DISCUSSION: There is currently limited evidence available addressing the management of severe hyperextension deformity greater than 50 degrees of the MCP joint in the presence of CMC joint arthrosis. Staged bilateral fusion of the MCP joint and simultaneous CMC joint reconstruction in this case illustrates good, reproducible functional results and patient satisfaction with reduced postoperative return to function. PMID- 24164135 TI - Venous varix on the dorsal aspect of the thumb: report of two cases. AB - Venous varix on the volar aspect of the digits or the hand is a rare subcutaneous lesion that is usually described as a firm, blue, and painful single nodule that contains thrombus. However, there have been no reports about venous varix on the dorsal aspect of the digits or the hand, so its features are unknown. We treated two patients who each had a soft blue painless mass on the dorsal aspect of the thumb that became enlarged with the tourniquet test. Ultrasonography and/or magnetic resonance imaging were used for assisting with the preoperative diagnosis, and showed each lesion was composed of two or more varicosities. Each mass was removed and was diagnosed as a venous varix without thrombus by histological examination. PMID- 24164136 TI - Bilateral macrodystrophia lipomatosa with syndactyly: a case report and literature review. AB - Macrodystrophia lipomatosa is a rare, non-hereditary form of congenital local gigantism characterised by enlargement and hypertrophy of all mesenchymal tissue components with a disproportionate increase in adipose tissue. This form of macrodactyly has been reported in association with other anomalies including polydactyly, brachydactyly, syndactyly, and symphalangism. We describe a previously unreported case of bilateral upper extremity macrodystrophia lipomatosa with syndactyly in a 23-month-old boy. In this report, we emphasise the importance of establishing a diagnosis with imaging and review the described surgical approaches to treating this difficult condition. PMID- 24164137 TI - On-top plasty using a free metacarpal head graft for lengthening of proximal phalanx in symbrachydactyly--a case report. AB - A three-year old patient with symbrachydactyly (didactyly type) presented with a little finger that was too short to allow pinching and consisting of a floppy soft-tissue envelope with hypoplastic phalanges, although the thumb was functional. As the proximal phalanx was too small to permit distraction lengthening or conventional bone grafting, on-top plasty using a 4th metacarpal graft with a cartilage head was undertaken for lengthening the proximal phalanx of the little finger for pinch reconstruction. At ten weeks after surgery, the patient achieved satisfactory pinch function due to the lengthened and bone stabilised postoperative digit and reconstruction of functional proximal interphalangeal joint. In addition, the grafted metacarpal demonstrated satisfactory bone growth throughout the six-year follow-up period. PMID- 24164138 TI - Bipedicled homodigital neurovascular island flap for resurfacing dorsal digital defects amputation. AB - Critical defects distal to the proximal interphalangeal joint are usually treated by heterodigital or reverse-flow homodigital flaps. Drawbacks of the former are potential donor digit stiffness and scarring, while the latter might be complicated by flap congestion. A bipedicled neurovascular island transposition flap design that preserves both proximal and distal extent of digital nerve and artery was employed to treat critical dorsal skin defect in two patients with encouraging results. Technical details and cadaveric study concepts are presented. PMID- 24164139 TI - Finger tourniquets: two safe and cost effective techniques and a discussion of the literature. AB - Finger tourniquets are used in a variety of operative procedures in both the trauma and elective setting. A wide range of methods are used in clinical practise as there is no standardised method. Many of the methods in use have significant drawbacks such as the inability to exsanguinate the digit or the more concerning problem of inadvertently leaving the tourniquet on the digit on completion of the procedure. We discuss two techniques that are quick, cheap and easy that do not have these drawbacks. There is a brief discussion of the literature assessing the various attributes of published methods. We feel that the adoption of these methods could result in easier and safer finger exsanguination and haemostasis. PMID- 24164140 TI - Sesamoidectomy and volar plate repair using suture anchor for hyperextension injury of the metacarpophalangeal joint of the thumb. AB - A retrospective study for the combination of suture anchor and selective sesamoidectomy for treating volar instability of the metacarpophalangeal joint (MCPJ) of the thumb. Eleven patients with hyperextension of the MCPJ of the thumb underwent volar plate repair using a volar or voloradial approach. All the patients were reviewed radiologically and clinically using both objective and subjective criteria. The patients presented with sesamoid fractures (n = 2), sesamoid subluxation (n = 1), isolated volar plate laxity (n = 4), isolated sesamoid fracture (n = 4), and metacarpal condyle fracture (n = 2). The inner intersesamoid distance was 4.6 mm and the outer intersesamoid distance was 14.2 mm. The Disabilities of the Arm Shoulder and Hand and Michigan Hand Outcomes Questionnaire scores showed improvement. Volar plate repair using a suture anchor and selective sesamoidectomy is effective with regard to pain relief and stabilisation of volar instability of the thumb. PMID- 24164144 TI - There and up again: on the uses and misuses of neuroimaging in psychology. AB - The aim of this article is to discuss the conditions under which functional neuroimaging can contribute to the study of higher cognition. We begin by presenting two case studies--on moral and economic decision making--which will help us identify and examine one of the main ways in which neuroimaging can help advance the study of higher cognition. We agree with critics that functional magnetic resonance imaging (fMRI) studies seldom "refine" or "confirm" particular psychological hypotheses, or even provide details of the neural implementation of cognitive functions. However, we suggest that neuroimaging can support psychology in a different way--namely, by selecting among competing hypotheses of the cognitive mechanisms underlying some mental function. One of the main ways in which neuroimaging can be used for hypothesis selection is via reverse inferences, which we here examine in detail. Despite frequent claims to the contrary, we argue that successful reverse inferences do not assume any strong or objectionable form of reductionism or functional locationism. Moreover, our discussion illustrates that reverse inferences can be successful at early stages of psychological theorizing, when models of the cognitive mechanisms are only partially developed. PMID- 24164141 TI - Osteocutaneous VY flap to preserve length in coronal oblique fingertip amputation. AB - Radial or ulnar oblique amputations treated by nailbed levelling and local digital flap reconstruction can result in significantly shortened fingertip, narrowed pulp and nail shape distortion. A VY type flap containing bone, sterile matrix, and skin was conceptualised to restore nail and pulp contour for coronal oblique amputations. Technical details and a clinical case are discussed. PMID- 24164145 TI - High volumetric capacity silicon-based lithium battery anodes by nanoscale system engineering. AB - The nanostructuring of silicon (Si) has recently received great attention, as it holds potential to deal with the dramatic volume change of Si and thus improve lithium storage performance. Unfortunately, such transformative materials design principle has generally been plagued by the relatively low tap density of Si and hence mediocre volumetric capacity (and also volumetric energy density) of the battery. Here, we propose and demonstrate an electrode consisting of a textured silicon@graphitic carbon nanowire array. Such a unique electrode structure is designed based on a nanoscale system engineering strategy. The resultant electrode prototype exhibits unprecedented lithium storage performance, especially in terms of volumetric capacity, without the expense of compromising other components of the battery. The fabrication method is simple and scalable, providing new avenues for the rational engineering of Si-based electrodes simultaneously at the individual materials unit scale and the materials ensemble scale. PMID- 24164146 TI - Interaction between serum uric acid and triglycerides in relation to prehypertension in community-dwelling Japanese adults. AB - There are few data available on the association between serum uric acid (SUA) levels and blood pressure (BP) categories earlier in the disease continuum, when efforts for its prevention may be applicable. We performed a cross-sectional study to examine the association between SUA and prehypertension in a community dwelling sample of Japanese adults. Study participants without hypertension aged 19 to 90 years [567 men aged 56 +/- 15 (mean +/- standard deviation) years and 808 women aged 58 +/- 13 years] were recruited for a survey at the community based annual medical check-up. The main outcome was the presence of prehypertension [systolic BP (SBP) 120-139 mmHg and/or diastolic BP (DBP) 80-89 mmHg]. After adjustments by gender and age, both SBP (p<0.001) and DBP (p<0.001) increased significantly and progressively with increasing SUA and triglycerides (TG) as well as body mass index, LDL cholesterol, and fasting plasma glucose (FPG). Compared to those with normotension, the multivariate-adjusted odds ratio (95% confidence interval) for participants with prehypertension was 1.15 (1.05 1.26) for SUA and 3.19 (1.66-6.14) for TG. The interaction between increased SUA and TG was a significant and independent determinant for SBP (beta=-2.474, p=0.008), but not for DBP (beta=-0.608, p=0.349). Higher SUA levels are associated with prehypertension in participants without hypertriglyceridemia (<150 mg/dL), but not in participants with hypertriglyceridemia (>= 150 mg/dL). TG levels may modify the association between SUA and prehypertension. PMID- 24164147 TI - Cardiac resynchronization therapy in adult patients with repaired tetralogy of fallot and left ventricular systolic dysfunction. AB - BACKGROUND: Although left ventricular (LV) systolic dysfunction is known to occur in adults with repaired Tetralogy of Fallot (TOF), the effects of cardiac resynchronization therapy (CRT) are not well characterized. METHODS: We retrospectively divided all patients with repaired TOF and impaired LV ejection fraction (LVEF <= 40%) undergoing CRT at our institution (n = 10) into two groups: de novo CRT (group A, n = 6) or upgrade from existing device (group B, n = 4). Echocardiograms were reviewed at baseline, medium-term (>6 months post CRT), and long-term follow-up. CRT response was defined as reduction in LV end systolic volume (LVESV) >=15% at medium term. RESULTS: Age at surgical repair was 13.1 +/- 16.0 years, age at CRT was 44.4 +/- 12.5 years, and baseline LVEF was 24.0 +/- 10.5%. Group A demonstrated a preponderance of right ventricular (RV) conduction delay, whereas all patients in group B demonstrated RV pacing at baseline. At medium-term follow-up, patients in group A showed significant improvements in LVEF, LV end-diastolic volume (LVEDV), and LVESV. Group B also demonstrated a significant improvement in LVEF with favorable trends in LV volumes. Of nine patients with complete data at medium term, eight showed evidence of CRT response. Average long-term follow-up was 53.4 +/- 29.3 months. At long-term follow-up, LVEF, LVEDV, and LVESV remained numerically better than baseline, although the results were no longer significant. CONCLUSIONS: Adult patients with repaired TOF and LV systolic dysfunction demonstrate significant medium-term response to CRT, even among those with RV conduction delay. The long term impact of CRT in this population requires further characterization. PMID- 24164148 TI - Does reduced mobility through fragmented landscapes explain patch extinction patterns for three honeyeaters? AB - Habitat loss and associated fragmentation are major drivers of biodiversity decline, and understanding how they affect population processes (e.g. dispersal) is an important conservation goal. In a large-scale test employing 10 * 10 km units of replication, three species of Australian birds, the fuscous honeyeater, yellow-tufted honeyeater and white-plumed honeyeater, responded differently to fragmentation. The fuscous and yellow-tufted honeyeaters are 'decliners' that disappeared from suitable habitat in landscapes where levels of tree-cover fell below critical thresholds of 17 and 8%, respectively. The white-plumed honeyeater is a 'tolerant' species whose likelihood of occurrence in suitable habitat was independent of landscape-level tree-cover. To determine whether the absence of the two decliner species in low tree-cover landscapes can be explained by reduced genetic connectivity, we looked for signatures of reduced mobility and gene flow in response to fragmentation across agricultural landscapes in the Box-Ironbark region of north-central Victoria, Australia. We compared patterns of genetic diversity and population structure at the regional scale and across twelve 100 km(2) landscapes with different tree-cover extents. We used genetic data to test landscape models predicting reduced dispersal through the agricultural matrix. We tested for evidence of sex-biased dispersal and sex-specific responses to fragmentation. Reduced connectivity may have contributed to the disappearance of the yellow-tufted honey-eater from low tree-cover landscapes, as evidenced by male bias and increased relatedness among males in low tree-cover landscapes and signals of reduced gene flow and mobility through the agricultural matrix. We found no evidence for negative effects of fragmentation on gene flow in the other decliner, the fuscous honeyeater, suggesting that undetected pressures act on this species. As expected, there was no evidence for decreased movement through fragmented landscapes for the tolerant white-plumed honeyeater. We demonstrated effects of habitat loss and fragmentation (stronger patterns of genetic differentiation, increased relatedness among males) on the yellow-tufted honeyeater above the threshold at which probability of occurrence dropped. Increasing extent and structural connectivity of habitat should be an appropriate management action for this species and other relatively sedentary woodland specialist species for which it can be taken as representative. PMID- 24164149 TI - Self-reported health, health behaviors, attitudes, and beliefs of regional mental health consumers. AB - PURPOSE: This article reports baseline data from a randomized controlled trial investigating the impact of a specialist cardiometabolic healthcare nurse on physical health care. DESIGN AND METHODS: Survey of community-based mental health consumers randomized to a cardiometabolic health nurse intervention. FINDINGS: Findings show a high prevalence of respiratory conditions, hypercholesterolemia, hypertension, and low quality of life. Participants reported regular blood pressure but infrequent cholesterol and blood glucose testing. Few received advice about smoking cessation, diet, or physical activity. Participants were mostly satisfied with physical healthcare provision; however, positive health behaviors are lacking. PRACTICE IMPLICATIONS: An individualized intervention based on knowledge and attitudes may be necessary. PMID- 24164150 TI - Red and purple papules on the dorsum of fingers and toes in a woman. PMID- 24164151 TI - Flesh-colored papule on the areola. PMID- 24164152 TI - Psychosocial impact of onychomycosis: a review. AB - Onychomycosis (tinea unguium) is the most common nail disorder. Nonetheless, it requires lengthy, often ineffective treatments, and recurrence is frequent. Predominantly a disease of the elderly, onychomycosis is becoming more and more common. Besides interfering with normal nail function, fungal nail infections are relatively painful, unsightly in appearance, disrupt daily activities, and have a negative psychosocial connotation. Commonly reported psychosocial factors are embarrassment, low self-esteem, and social withdrawal. Yet advances in therapy have been achieved since these reports were made, and many of these treatment options have proven to be more effective. Thus, the impact of these advances on psychosocial well-being of patients with onychomycosis is worth analyzing. The objective of this paper is to review studies that investigated the psychosocial impact of onychomycosis on a variety of patient populations. An alternative, total patient approach that dermatologists and general practitioners alike could use to incorporate patients' psychosocial well-being into the holistic management of onychomycosis will also be discussed. PMID- 24164153 TI - An immunocompromised district in an immunocompromised patient. PMID- 24164154 TI - Bullous formation in a patient with familial amyloid polyneuropathy type I. PMID- 24164155 TI - Modified protocol for the application of botulinum toxin type A for hyperhidrosis of the nose. PMID- 24164156 TI - Postoperative pathergic pyoderma gangrenosum after aortic aneurysm repair. PMID- 24164157 TI - Xanthomatous lesions: atypical presentation of primary systemic amyloidosis. PMID- 24164158 TI - Plaque-type blue nevus on the palm. PMID- 24164159 TI - Lower-dose thalidomide therapy effectively treats cutaneous lupus erythematosus but is limited by neuropathic toxicity. PMID- 24164160 TI - Solitary glomangioma mimicking a venous lake at an unusual site. PMID- 24164161 TI - Diagnosis of molluscum contagiosum by crater-like morphology in handheld portable digital microscopy. PMID- 24164162 TI - Cutaneous plasmacytosis in an 88-year-old woman successfully treated with low dose oral corticosteroid. PMID- 24164163 TI - Can ultraviolet rays induce a granulomatous reaction after hyaluronic acid dermal filler injections? PMID- 24164164 TI - Activity of antioxidant enzymes in melanoma patients. PMID- 24164166 TI - Graphs of brain networks. AB - BACKGROUND: This commentary discusses the study by Telesford and colleagues in which they use network science to analyze resting state functional magnetic resonance imaging (rsfMRI) data collected in nonhuman primates. METHODS: Their findings using a network science approach in nonhuman primates are considered in the context of results from human studies. RESULTS: The network science approach to analyzing rsfMRI data from nonhuman primates yields results that are, for the most part, similar to results using alternative analyses methods in human studies. CONCLUSIONS: Network science to analyze rsfMRI may promote a better understanding of the brain as a complex system. PMID- 24164167 TI - Assessment of oral hygiene and periodontal health around posterior primary molars after their restoration with various crown types. AB - OBJECTIVE: To compare the time-dependent changes in oral hygiene and periodontal health after restoring primary posterior molars with a traditional stainless steel crown (SSC) or an aesthetic crown using various measures of periodontal health and oral hygiene. DESIGN: This investigation was a randomized, non-blinded prospective controlled clinical trial in which 264 crowns of different types were fitted onto the first and/or second primary molars of 76 children. The oral hygiene and the gingival health of the restored teeth and the antagonistic teeth were evaluated clinically and radiographically at 3- and 6-month intervals for 18 months after fitting the crowns. RESULTS: The periodontal health of the control teeth was better than that of the remaining 215 restored teeth. The oral hygiene, as measured by the simplified oral hygiene index, and gingival health, as measured by the gingival index and the volume of gingival crevicular fluid, of the restored teeth, irrespective of crown type, progressively increased during the 18-month study period. CONCLUSIONS: Oral hygiene and gingival health around a restored primary tooth deteriorate with time. Our results suggest that SSC, an open-faced SSC, or a NuSmile((r)) pediatric crown should be the preferred crown type for restoring posterior primary teeth. PMID- 24164168 TI - The Wzy O-antigen polymerase of Yersinia pseudotuberculosis O:2a has a dependence on the Wzz chain-length determinant for efficient polymerization. AB - Lipopolysaccharide is a major immunogenic structure for the pathogen Yersinia pseudotuberculosis, which contains the O-specific polysaccharide (OPS) that is presented on the cell surface. The OPS contains many repeats of the oligosaccharide O-unit and exhibits a preferred modal chain length that has been shown to be crucial for cell protection in Yersinia. It is well established that the Wzz protein determines the preferred chain length of the OPS, and in its absence, the polymerization of O units by the Wzy polymerase is uncontrolled. However, for Y. pseudotuberculosis, a wzz mutation has never been described. In this study, we examine the effect of Wzz loss in Y. pseudotuberculosis serotype O:2a and compare the lipopolysaccharide chain-length profile to that of Escherichia coli serotype O111. In the absence of Wzz, the lipopolysaccharides of the two species showed significant differences in Wzy polymerization. Yersinia pseudotuberculosis O:2a exhibited only OPS with very short chain lengths, which is atypical of wzz-mutant phenotypes that have been observed for other species. We hypothesise that the Wzy polymerase of Y. pseudotuberculosis O:2a has a unique default activity in the absence of the Wzz, revealing the requirement of Wzz to drive O-unit polymerization to greater lengths. PMID- 24164170 TI - New population of amelanotic spindle cells are clearly demonstrated in vitiliginous skin after ultraviolet radiation. AB - BACKGROUND: Phototherapy is a well-known method to treat vitiligo and is able to repopulate the skin with new melanocytes. Examination of the pathological changes in vitiligo after ultraviolet therapy revealed the presence of unusual cells. AIM OF STUDY: This study intended to investigate and confirm the repopulation of epidermis with new spindle cells, possibly as precursors for melanocytes after UV therapy. METHODS: Retrospective study was carried out on paraffin sections of biopsies obtained from 30 vitiligo patients treated successfully with ultraviolet therapy. Routine, special and immune staining were utilized to examine these biopsies. RESULTS: Amelanotic spindle cells with slightly eosinophilic cytoplasm and dark flattened nuclei were characteristically demonstrated in all examined sections after ultraviolet therapy. These cells were abundant near infundibular portion of hair follicles. They subsequently developed dendrites and became melanized. CONCLUSIONS: Melanocyte precursors can be demonstrated pathologically and immunologically on tissue samples after ultraviolet therapy. They are capable of proliferation and migration into depigmented epidermis to repopulate it with new generations of melanocytes. PMID- 24164169 TI - Hemin uptake and release by neurons and glia. AB - Hemin accumulates in intracerebral hematomas and may contribute to cell injury in adjacent tissue. Despite its relevance to hemorrhagic CNS insults, very little is known about hemin trafficking by neural cells. In the present study, hemin uptake and release were quantified in primary murine cortical cultures, and the effect of the hemin-binding compound deferoxamine (DFO) was assessed. Net uptake of (55)Fe-hemin was similar in mixed neuron-glia, neuron, and glia cultures, but was 2.6-3.6-fold greater in microglia cultures. After washout, 40-60% of the isotope signal was released by mixed neuron-glia cultures into albumin-containing medium within 24 h. Inhibiting hemin breakdown with tin protoporphyrin IX (SnPPIX) had minimal effect, while release of the fluorescent hemin analog zinc mesoporphyrin was quantitatively similar to that of (55)Fe-hemin. Isotope was released most rapidly by neurons (52.2 +/- 7.2% at 2 h), compared with glia (15.6 +/- 1.3%) and microglia (17.6 +/- 0.54%). DFO did not alter (55)Fe-hemin uptake, but significantly increased its release. Mixed cultures treated with 10 MUM hemin for 24 h sustained widespread neuronal loss that was attenuated by DFO. Concomitant treatment with SnPPIX had no effect on either enhancement of isotope release by DFO or neuroprotection. These results suggest that in the presence of a physiologic albumin concentration, hemin uptake by neural cells is followed by considerable extracellular release. Enhancement of this release by DFO may contribute to its protective effect against hemin toxicity. PMID- 24164172 TI - Psychoactive pharmaceuticals in sludge and their emission from wastewater treatment facilities in Korea. AB - Concern over the occurrence of pharmaceuticals and their metabolites in the environment is mounting due to the potential adverse effects on nontarget organisms. This study draws upon a nationwide survey of psychoactive pharmaceuticals (i.e., antischizophrenics, anxiolytics, and antidepressants) in sludge from 40 representative wastewater treatment plants (WWTPs) that receive domestic, industrial, or mixed (domestic plus industrial) wastewaters in Korea. A total of 16 psychoactive pharmaceuticals (0.12-460 ng/g dry weight) and nine of their metabolites (0.97-276 ng/g dry weight) were determined in sludge. The median concentrations of psychoactive drugs in sludge from domestic WWTPs were 1.2-3.2 times higher than the concentrations found in WWTPs that receive combined domestic and industrial wastewaters. Among the psychoactive drugs analyzed, the median environmental emission rates of alprazolam (APZ) and carbamazepine (CBZ) through domestic WWTPs (both sludge and effluent discharges combined) were calculated to be >= 15.5 MUg/capita/day, followed by quetiapine (QTP; 8.51 MUg/capita/day), citalopram (CLP; 5.45 MUg/capita/day), and venlafaxine (VLF; 3.59 MUg/capita/day). The per-capita emission rates of some of the metabolites of psychoactive drugs through WWTP discharges were higher than those calculated for parent compounds. Significant correlations (rho = 0.432-0.780, p < 0.05) were found between the concentrations of typically coprescribed antischizophrenics and antidepressants in sludge. Multiple linear regression analysis of measured concentrations of drugs in sludge revealed that several WWTP parameters such as treatment capacity, population-served, sludge production rate, composition of wastewater (domestic versus industrial), and hydraulic retention time can affect the concentrations of psychoactive drugs in sludge. PMID- 24164173 TI - Recovery of cell-free mRNA and microRNA from human semen based on their physical nature. AB - Cell-free seminal mRNA (cfs-mRNA) and microRNA (cfs-miRNA) have been found in human ejaculate and reported as promising noninvasive biomarkers for disorders of male reproductive organs and forensic identification. However, seminal plasma is particularly challenging for RNA extraction due to its complicated composition and high content of protein, DNA, and polysaccharide. Here, we report a novel, simple, and reliable method for the isolation of cfs-mRNA and cfs-miRNA from human semen based on our previous findings of their physical nature. Seminal microvesicles (0.1-0.5 um in diameter), which contain the majority of cfs-mRNA, were enriched by a microfilter. Protein complexes, which most cfs-miRNA is bound with, were enriched by an ultrafilter. Harvesting the complexes or microvesicles, in which RNAs exist, avoided the influence of other components in human semen, thus favoring RNA isolation and purification. This new method can efficiently isolate cfs-mRNA and cfs-miRNA separately based on their physical nature, with high RNA purity, and low DNA contamination. It may also be applied or modified to isolate cell-free RNAs in other fluids. PMID- 24164171 TI - Metronomic chemotherapy and anti-angiogenesis: can upgraded pre-clinical assays improve clinical trials aimed at controlling tumor growth? AB - Metronomic chemotherapy, which is continuously administered systemically at close to non-toxic doses, targets the endothelial cells (ECs) that are proliferating during tumor angiogenesis. This leads to harmful effects of an even greatly increased number contiguous tumor cells. Although pre-clinical studies of angiogenesis-related EC features in vitro and of the anti-angiogenic and anti tumor effects in vivo of metronomic chemotherapy have provided valuable insights, clinical trials with this type of therapy have been less successful in inhibiting tumor growth. One possible reason for the apparent disconnect between the pre clinical and clinical outcomes is that most of the currently used experimental angiogenesis assays and tumor models are incapable of yielding data that can be translated readily into the clinical setting. Many of the assays used suffer from unintentional artifactual effects, e.g., oxidative stress in vitro, and inflammation in vivo, which reduces the sensitivity and discriminatory power of the assays. Co-treatment with an antioxidant or the inclusion of antioxidants in the vehicle often significantly affects the angiogenesis-modulating outcome of metronomic mono-chemotherapy in vivo. This 'metronomic chemotherapy vehicle factor' merits further study, as do the observations of antagonistic effects following metronomic treatment with a combination of standard chemotherapeutic drugs in vivo. PMID- 24164174 TI - Development of antimicrobial coatings by atmospheric pressure plasma using a guanidine-based precursor. AB - Antimicrobial coatings deposited onto ultra high molecular weight polyethylene (UHMWPE) films were investigated using an atmospheric pressure - plasma enhanced chemical vapor deposition (AP-PECVD) process. Varying concentrations of a guanidine-based liquid precursor, 1,1,3,3-tetramethylguanidine, were used, and different deposition conditions were studied. Attenuated total reflectance - Fourier Transform Infrared (ATR-FTIR) spectroscopy and X-ray Photoelectron Spectroscopy (XPS) were used to study the chemical structure and elemental composition of the coatings. Conformity, morphology, and coating thickness were assessed through SEM and AFM. Optimal AP-PECVD parameters were chosen and applied to deposit guanidine coatings onto woven fabrics. The coatings exhibited high antimicrobial activity against Escherichia coli (E. coli) and Staphylococcus aureus (S. aureus) based on a modified-AATCC 100 test standard, where 2-5 log reductions were achieved. PMID- 24164175 TI - The renin-angiotensin system from conception to old age: the good, the bad and the ugly. AB - The renin-angiotensin system (RAS) plays a critical role in placentation and nephrogenesis. Failure to thrive during intrauterine life, possibly related to placental dysfunction and impaired expression of the renal RAS, as well as prematurity, results in smaller kidneys at birth and reduced nephron number. The remaining nephrons are therefore hyperfiltering from birth. Hyperfiltration, infections and Type 2 diabetes cause glomerular and tubular fibrosis, leading to further reductions in nephron number. The intrarenal RAS plays a key role in promoting tubulointerstitial fibrosis. Low birth weight and a high incidence of preterm birth program Indigenous children for early onset renal disease in adult life. Indigenous Australians have 404 000 fewer nephrons than non-Indigenous Australians. This, coupled with the high incidence of infectious diseases (particularly acute post-streptococcal glomerulonephritis) and the increasing prevalence of Type 2 diabetes, explains why end-stage renal disease is of epidemic proportions in Indigenous Australians. The existence of RAS gene polymorphisms and inflammatory cytokines may further potentiate susceptibility to renal disease in Indigenous Australians. PMID- 24164176 TI - Estimating glomerular number: why we do it and how. AB - There is currently much interest in determining the number of glomeruli, and thereby nephrons, in the kidney. Researchers have been trying to count glomeruli since the 19th century and currently four general approaches are available: (i) acid maceration; (ii) counting glomerular profiles in histological sections; (iii) model-based stereology; and (iv) design-based stereology. Although design based stereological methods are generally considered the gold-standard method, all current methods have limitations. A new approach using magnetic resonance imaging has recently been described and may ultimately enable glomerular imaging and quantification in vivo. This report considers the advantages and disadvantages of current methods for counting glomeruli and describes the new magnetic resonance approach. In addition, a method for counting glomeruli in developing kidneys is described. PMID- 24164177 TI - Regarding secondary intracranial hypertension from testostereone therapy in a transgender patient. PMID- 24164179 TI - Yellow globules in balloon cell naevus. PMID- 24164178 TI - Weight gain and tumour necrosis factor-alpha inhibitors in patients with psoriasis. AB - OBJECTIVES: To compare the effect of anti-tumour necrosis factor (TNF)-alpha therapies with agents that do not target TNF-alpha on bodyweight and body mass index (BMI) in patients with psoriasis. METHODS: A retrospective analysis of patients from the Skin and Cancer Foundation and St Vincent's Hospital Melbourne. Bodyweight and BMI were compared at baseline and weeks 12, 24 and 48. RESULTS: A total of 143 patients were studied, equating 286 treatment courses in all. Of these, 178 courses were with an anti-TNFalpha agent (54 on adalimumab, 61 on etanercept and 63 on infliximab) and 108 courses were on non-anti-TNFalpha agents (73 on efalizumab and 35 on ustekinumab). Anti-TNFalpha therapy with adalimumab and infliximab resulted in weight gain from week 12 until week 48. At week 12 the infliximab group gained 1.7 +/- 4.7 kg and adalimumab group gained 1.5k +/- 4.5 kg. This effect persisted at week 24 (infliximab: 3.4 +/- 5.7 kg; adalimumab: 2.2 +/- 4.4 kg) until the end of the study (infliximab: 1.3 +/- 2.9 kg; adalimumab: 2.4 +/- 6.4 kg). There was a trend for weight gain in the etanercept group that did not reach statistical significance. Therapy with ustekinumab and efalizumab did not result in weight gain. CONCLUSION: Therapy with adalimumab and infliximab is associated with a significant increase in bodyweight and BMI. PMID- 24164183 TI - Painful nodules on the fingers--the presenting sign of an underlying malignancy. PMID- 24164185 TI - An unvalidated online risk predictor tool for melanoma. PMID- 24164186 TI - Flare-up reaction after creeping disease. PMID- 24164188 TI - The origins of genetic variation between individual human oocytes and embryos: implications for infertility. AB - Human fertility is low in comparison with that seen in other well-studied mammals. The main reason for this state of affairs seems to be the frequent occurrence and persistence of chromosomal errors in the human conceptus. Evidence obtained over the past two decades shows that the exceptionally high incidence of chromosomal anomalies seen in human preimplantation embryos is the result of errors that may occur at various stages during gamete and embryo formation. In rare cases, an error may exist or arise in the premeiotic germ cells; much more commonly it may arise during the first or second meiotic division in the male or female. Highly efficient cell cycle checkpoints in the male ensure that the incidence of aneuploidy in mature sperm is low compared to that in the oocyte. Most 3-day-old embryos created by IVF are chromosomal mosaics, and this persists to a lesser degree to the blastocyst stage on day 5. While aneuploidy of meiotic origin is a major factor affecting the fertility of older women, embryos from most younger women will have predominantly post-zygotic mitotic errors. Couples experiencing RIF are particularly likely to produce highly abnormal (chaotic) embryos by post-zygotic mechanisms. PMID- 24164189 TI - Drug-free gel containing ultra-deformable phospholipid vesicles (TDT 064) as topical therapy for the treatment of pain associated with osteoarthritis: a review of clinical efficacy and safety. AB - BACKGROUND: Many patients with osteoarthritis (OA) experience side effects with available systemic therapies, some of which can be life threatening. The widespread use of nonsteroidal anti-inflammatory drugs (NSAIDs), often without prescription, is concerning given their potential risks. New treatments for OA are therefore required. This review discusses evidence supporting the use of TDT 064, a drug-free, topical gel containing ultra-deformable phospholipid vesicles (Sequessome * vesicles), for OA-associated pain. SCOPE: Preclinical and clinical studies investigating TDT 064 in patients with OA-associated knee pain were identified in searches of PubMed and congress abstracts. FINDINGS: The ultra deformable phospholipid vesicles (sequessome vesicles) in TDT 064 pass through the skin intact to reach the synovial space within the joint. The mechanism of action is not yet certain, but the phospholipid-based structure of these ultra deformable phospholipid vesicles, and the observation that they localize to the cartilage surface, support biolubrication as a possible mechanism of action of TDT 064. Data from randomized, phase III studies in OA knee pain in which TDT 064 was used as the drug-free vehicle control for IDEA-033 (ketoprofen in ultra deformable phospholipid vesicles) demonstrate a marked and consistent response to TDT 064 in terms of pain, stiffness, and function. In a 12 week study of >1300 patients, the effects of TDT 064 on pain and function were statistically noninferior to those of oral celecoxib, and superior to oral placebo. TDT 064 was well tolerated in all studies, and adverse events were typically mild-to-moderate effects on the skin. CONCLUSIONS: Evidence from clinical studies supports the use of TDT 064 as a drug-free topical treatment for patients with OA. Further experience with TDT 064, particularly among patients with comorbidities or NSAID contraindications, will provide more information on its potential use. PMID- 24164190 TI - Detection of specific protein-protein interactions in nanocages by engineering bipartite FlAsH binding sites. AB - Proteins that form cage-like structures have been of much recent cross disciplinary interest due to their application to bioconjugate and materials chemistry, their biological functions spanning multiple essential cellular processes, and their complex structure, often defined by highly symmetric protein protein interactions. Thus, establishing the fundamentals of their formation, through detecting and quantifying important protein-protein interactions, could be crucial to understanding essential cellular machinery, and for further development of protein-based technologies. Herein we describe a method to monitor the assembly of protein cages by detecting specific, oligomerization state dependent, protein-protein interactions. Our strategy relies on engineering protein monomers to include cysteine pairs that are presented proximally if the cage state assembles. These assembled pairs of cysteines act as binding sites for the fluorescent reagent FlAsH, which, once bound, provides a readout for successful oligomerization. As a proof of principle, we applied this technique to the iron storage protein, DNA-binding protein from starved cells from E. coli. Several linker lengths and conformations for the presentation of the cysteine pairs were screened to optimize the engineered binding sites. We confirmed that our designs were successful in both lysates and with purified proteins, and that FlAsH binding was dependent upon cage assembly. Following successful characterization of the assay, its throughput was expanded. A two-dimension matrix of pH and denaturing buffer conditions was screened to optimize nanocage stability. We intend to use this method for the high throughput screening of protein cage libraries and of conditions for the generation of inorganic nanoparticles within the cavity of these and other cage proteins. PMID- 24164191 TI - Quantifying Gp96/Grp94 complexes preparations for vaccines: a key step often inaccurate. AB - Glycoprotein 96 (Gp96)-peptide complexes are highly investigated for vaccines preparation, particularly in cancer therapy. Gp96, formerly called tumor rejection antigen (TRA)-1, is able to elicit an immune response that can protect mice against tumors, when the mice share the same haplotype than those bearing the tumors from which Gp96 was purified. Secreted Gp96-peptide complexes act as danger signals thereby stimulating the innate immunity regardless of the chaperoned peptides. In contrast, the tumor rejection antigen role of Gp96 peptide complexes is held by the chaperoned peptides in a dose-dependent manner. The purification step is crucial both for insuring the quality and the quantity of Gp96-peptide complexes. To this aim, different methods have been described but they are often suboptimal for the quantification of these complexes. In this review, we discuss a hot topic: the use of the chaperone Gp96 for vaccination purposes in cancer, and also detail the current methods for quantifying Gp96 peptide preparations. PMID- 24164192 TI - An update on autoinflammatory diseases. AB - Autoinflammatory diseases area group of clinical conditions other than autoimmune diseases, characterized by recurrent inflammatory episodes. From apathogenetic point of view they are determined by a dys regulation of innate immunity, without involvement of specific immunity (auto reactive T cells and auto antibodies). Recently, the increased knowledge in the field of auto inflammation highlighted shared immune mechanisms in the pathogenesis of both classical monogenetic and multifactorial auto inflammatory diseases and a broad spectrum of chronic age related inflammatory pathologies. The current increase in the prevalence of chronic inflammatory diseases makes this subject of topical interest. In the light of these considerations, we propose an update of auto inflammatory diseases and a new interpretation of auto inflammation with both theoretical and clinical implications. PMID- 24164193 TI - Synthetic thioamide, benzimidazole, quinolone and derivatives with carboxylic acid and ester moieties: a strategy in the design of antituberculosis agents. AB - Synthetic heterocyclic compounds have remarkable potential activity against diseases; thioamides, benzimidazoles, quinolones and derivatives with carboxylic acid and esters moieties have shown excellent activity against Mycobacterium tuberculosis. We reviewed antituberculosis activities of above compounds with reference to half maximal inhibitory concentration, minimum inhibitory concentration and structural-activity relationship which clearly indicate that electron-withdrawing groups are the main inducers of antimycobacterium activity. Comparison between clinically used drugs and new synthetic derivatives showed recent advances made in the last decade. PMID- 24164194 TI - Dual ligands targeting dopamine D2 and serotonin 5-HT1A receptors as new antipsychotical or anti-Parkinsonian agents. AB - Psychiatric disorders like schizophrenia and neurodegenerative diseases like Parkinson's disease are associated with poly-factorial pathogenic mechanisms, with several neurotransmitter systems closely involved. In addition to the cerebral dopaminergic (DA) system, the serotoninergic (5-HT) system also plays a crucial role in regulating psychoemotional, cognitive and motor functions in the central nervous system (CNS). Among the large 5-HT receptor family, accumulating data have revealed new insights into the therapeutic benefit of the 5-HT1A receptor in treating various CNS disorders, especially schizophrenia and Parkinson's disease. The present review discusses the advance of dual agents with mixed actions at the dopamine D2 and serotonin 5-HT1A receptors in the treatment of these diseases. Aripiprazole was the only marketed drug with dual D2 and 5 HT1A profile. It is a partial D2 and 5-HT1A receptor agonist and has been prescribed as an atypical antipsychotical drug. Two other drugs Cariprazine and Pardoprunox are being investigated in clinic. Most of the other candidate compounds, including Bifeprunox, Sarizotan, Mazapertine succinate, PF-217830, and Adoprazine were discontinued due to either non-optimal pharmacokinetic properties or insufficient therapeutical efficacy. Although much effort has been done to highlight the advantages of the 5-HT1A and D2 dual approach, it has to be pointed out that many of these drugs showed poly-pharmacological profile by targeting many other receptors and/or transporters besides the D2 and 5-HT1A receptors. In this regard, 'pure' compounds exclusively acting on the D2 and 5-HT1A receptors are highly needed to further validate this approach. Meanwhile, safety concerns and in vivo pharmacokinetic alerts should also be implanted to the drug design art early. PMID- 24164195 TI - Shikimate kinase, a protein target for drug design. AB - ATP: shikimate 3-phosphotransferase catalyzes the fifth chemical reaction of shikimate pathway. This metabolic route is responsible for the production of chorismate, a precursor of aromatic amino acids. This especially interesting enzymatic step is indispensable for the survival of the etiological agent of tuberculosis and not found in animals. Therefore the enzyme ATP: shikimate 3 phosphotransferase has been classified as a target for chemotherapeutic development of antitubercular drugs. The ATP:shikimate 3-phosphotransferase has also the denomination of shikimate kinase. This review highlights the available crystallographic studies of shikimate kinases that have been used to identify structural features for ligand-biding affinity. We also describe molecular docking studies focused on shikimate kinase. These computational studies were performed in order to identify the new generation of antitubercular drugs and several potential inhibitors have been described. In addition, a structural comparison of shikimate kinase ATP-binding pocket with human cyclin-dependent kinase 2 (CDK2) is described. This analysis shows the structural similarities between both enzymes, and the potential beneficial aspects of abundant structural studies of CDK2 and their inhibitors to bring further understanding of the ligand binding specificity for shikimate kinase. PMID- 24164196 TI - Recent advances in the discovery and development of novel HIV-1 NNRTI platforms (Part II): 2009-2013 update. AB - The long-term usage of HIV-1 non-nucleoside reverse transcriptase inhibitors (NNRTIs) eventually leads to rapid emergence of drug-resistant viruses and severe side effect. Therefore, it is imperative to seek the additional NNRTIs with potent and broad spectrum anti-mutant activities, and excellent pharmacokinetic profiles. The discovery of etravirine, rilpivirine and other successful examples has influenced the NNRTIs design strategy profoundly. Sustained efforts in this area have led to the identification of many promising NNRTIs hits, leads and candidates for the last few years. Hence, this review aims to highlight recent prominent advances in this field as well as contributions from our laboratory toward the discovery of novel potent NNRTIs from 2009 to 2013 (by May). PMID- 24164198 TI - Recent development of CB2 selective and peripheral CB1/CB2 cannabinoid receptor ligands. AB - Cannabinoids have potential therapeutic value e.g. in pain relief, cancer therapy, control of nausea and vomiting, and appetite stimulation, but their therapeutic benefits are limited by unwanted central nervous system (CNS) side effects. Separating the therapeutic effects of cannabinoid agonists from their undesired CNS effects can be achieved by either increasing the selectivity of the ligands for the CB2 receptor or by developing peripherally restricted CB1/CB2 ligands. A vast number of structurally diverse CB2 ligands have been developed during the past 3 years, stemming from the screening hits, which are further optimized towards lead compounds and drug candidates. Some of CB2 ligands may ultimately enter into clinical use as pain relief, anticancer, or antipruritic agents. This review focuses on the recent literature dealing with selective CB2 receptor ligands, with a particular emphasis on the CB2 agonists developed from 2009 onwards. PMID- 24164199 TI - Biodiversity as a source of bioactive compounds against snakebites. AB - Snakebites are a frequently neglected public health issue in tropical and subtropical countries. According to the World Health Organization, 5 million people are bitten annually including up to 2.5 million envenomations. Treatment with antivenom serum remains the only specific therapy for snakebite envenomation. However, it is heterologous and therefore liable to cause adverse reactions, such as early anaphylactic, pyrogenic and delayed reactions. In order to develop alternatives to the current therapy, researchers have been looking for natural products and plant extracts with antimyotoxic, anti-hemorrhagic and anti inflammatory properties. Especially due to the role the physiopathological processes triggered by snake toxins, play in paralysis, bleeding disorders, kidney failure and tissue damage. Considering the fact that studies involving snake toxins and specific inhibitors, particularly on a molecular level, are the main key to understand neutralization mechanisms and to propose models or prototypes for an alternative therapy, this article presents efforts made by the scientific community in order to produce validated data regarding 87 compounds and plant extracts obtained from 79 species. These plants, which belong to 63 genera and 40 families, have been used by traditional medicine as alternatives or complements to the current serum therapy. PMID- 24164197 TI - Phytoestrogens in postmenopause: the state of the art from a chemical, pharmacological and regulatory perspective. AB - Phytoestrogens represent a diverse group of non-steroidal natural products, which seem to have some oestrogenic effects and are often marketed as food supplements. Population exposed to phytoestrogens is potentially increasing, in part because an unfavourable risk-benefit profile of Hormone Replacement Therapy (HRT) for prolonged treatments (e.g., osteoporosis prevention) highlighted by the publication of the Women Health Initiative (WHI) trial in 2002, but also because many post-menopausal women often perceived phytoestrogens in food supplements as a safer alternative than HRT. Despite of increasing preclinical and clinical studies in the past decade, appealing evidence is still lacking to support the overall positive risk-benefit profile of phytoestrogens. Their status as food supplements seems to discourage studies to obtain new evidence, and the chance to buy them by user's initiative make it difficult to survey their prevalence and pattern of use. The aim of the present review is to: (a) outline the clinical scenario underlying the increased interest on phytoestrogens, by overviewing the evolution of the evidence on HRT and its main therapeutic goals (e.g., menopausal symptoms relief, chemoprevention, osteoporosis prevention); (b) address the chemical and pharmacological features (e.g. chemical structure, botanical sources, mechanism of action) of the main compounds (e.g., isoflavones, lignans, coumestans); (c) describe the clinical evidence on potential therapeutic applications; (d) put available evidence on their riskbenefit profile in a regulatory perspective, in light of the recent regulation on health claims of food supplements. PMID- 24164200 TI - Small molecules modulating AHL-based quorum sensing to attenuate bacteria virulence and biofilms as promising antimicrobial drugs. AB - Clinically significant antibiotic resistance is one of the greatest challenges of the twenty-first century. Yet new antibiotics are currently being developed at a much slower pace than our growing need for such drugs. Instead of focusing on conventional therapeutics that target in vitro bacterial viability, an alternative therapy is to target virulence factors and biofilms. Such anti virulence strategies have attracted more and more attention recently, for it would add both supplement and diversity to our current antimicrobial library. This approach has several potential advantages including imposing less evolutionary pressure on the development of antibiotic resistance, increasing the antibacterial targets and preserving the host endogenous microbiome. Quorum sensing is an intercellular communication process in bacterial communities, which can regulate coordinated expression of virulence factors and biofilms. N-Acyl homoserine lactones (AHLs) are autoinducers generated by a variety of Gram negative bacteria. These signals combining with their cognate LuxR-type receptors trigger the expression of virulence genes. In this critical review, we summarize various structural types of small molecules targeting AHL-based quorum sensing to attenuate bacteria virulence factors and biofilms. PMID- 24164201 TI - Combating malaria with plant molecules: a brief update. AB - Malaria is one of the deadliest diseases on the planet affecting about 50% of the population worldwide. It is a leading cause of morbidity and mortality in the developing world. Plasmodium falciparum, a tiny parasite is the major cause of malaria and is possibly the most dangerous stow-away in history. Malaria has become a major economic concern to some of the tropical and sub-tropical countries. Though a number of antimalarials have been developed from plants as such or their semi-synthetic analogues, there is again an alarming situation of drug resistance against most of the antimalarial drugs. Plants have been an excellent source of antimalarial compounds. There are several plant leads exhibiting antimalarial activity better than the existing drugs. A systematic evaluation of these plant based leads is the need of the time to develop safe, effective and affordable new antimalarials. The present review is an update of plant based antimalarial agents. PMID- 24164202 TI - Nanomedicine against malaria. AB - Malaria is arguably one of the main medical concerns worldwide because of the numbers of people affected, the severity of the disease and the complexity of the life cycle of its causative agent, the protist Plasmodium sp. The clinical, social and economic burden of malaria has led for the last 100 years to several waves of serious efforts to reach its control and eventual eradication, without success to this day. With the advent of nanoscience, renewed hopes have appeared of finally obtaining the long sought-after magic bullet against malaria in the form of a nanovector for the targeted delivery of antimalarial drugs exclusively to Plasmodium-infected cells. Different types of encapsulating structure, targeting molecule, and antimalarial compound will be discussed for the assembly of Trojan horse nanocapsules capable of targeting with complete specificity diseased cells and of delivering inside them their antimalarial cargo with the objective of eliminating the parasite with a single dose. Nanotechnology can also be applied to the discovery of new antimalarials through single-molecule manipulation approaches for the identification of novel drugs targeting essential molecular components of the parasite. Finally, methods for the diagnosis of malaria can benefit from nanotools applied to the design of microfluidic-based devices for the accurate identification of the parasite's strain, its precise infective load, and the relative content of the different stages of its life cycle, whose knowledge is essential for the administration of adequate therapies. The benefits and drawbacks of these nanosystems will be considered in different possible scenarios, including cost-related issues that might be hampering the development of nanotechnology-based medicines against malaria with the dubious argument that they are too expensive to be used in developing areas. PMID- 24164203 TI - Pharmacologic ovarian preservation in young women undergoing chemotherapy. AB - The prognosis of malignancies in young women undergoing chemotherapy has dramatically improved recently, and more attention is given to the long term quality of life, including fertility and reproductive function preservation. Some chemotherapeutic drugs are known to be associated with gonadal toxicity (cyclophosphamide, L-phenylanine mustard, busulfan and nitrogen mustard) and others have less or un-quantified effects (doxorubicin, bleomycin, vinca alkaloids, as vincristine and vinblastin, cisplatin, nitrosoureas, cytosine arabinoside). Women are in need to identify best options to minimize ovarian damage during chemotherapy through the administration of protective drugs, better choice of therapy and with advocating oncofertility preservation. We reviewed the possible options focusing on the most studied gonadotrophin-releasing hormone agonists (GnRH-a) and the psychologically promising oral contraceptives (OC). Controversy exist on the benefit of gonadotrophin releasing hormone agonist (GnRH a) or combined oral contraceptive administered at time of cancer therapy in preventing premature ovarian failure in women and the available data from both human and animal studies have been mixed. The best way to preserve fertility and ovarian function in young women undergoing chemotherapy still remains to be determined. In the absence of a best approach, each case should be evaluated individually, considering patient's wishes and expectations, the type of chemotherapy, age, obstetric history, ovarian reserve (combining multiple indicators such as basal hormone profile, anti mullerian hormone -AMH- and antral follicle count), family history of premature ovarian failure. We present a review of the available evidence on the value of administering GnRH-a and OC use to minimize or prevent the effect of chemotherapy agents on reproductive function. PMID- 24164204 TI - Overall dielectric study on the odd members of a highly nonsymmetric pyrene-based series of liquid crystal dimers. AB - Broadband dielectric spectroscopy (10(3) Hz-1.8 * 10(9) Hz) has been performed on the odd nonsymmetric liquid crystal dimers of the series alpha-(4-cyanobiphenyl 4'-oxy)-omega-(1-pyreniminebenzylidene-4'-oxy) alkanes (CBOnO.Py) with n ranging from 3 to 11, as a function of temperature. A previous thermal behavior study through heat capacity measurements has been made. Dielectric measurements enable us to obtain information about the molecular dynamics in the nematic mesophase as well as in the isotropic phase. Two orientations (parallel and perpendicular) of the molecular director with regard to the probe electric field have been investigated. In the nematic mesophase, the dielectric anisotropy is revealed to be positive for all studied compounds. Measurements of the parallel component of the dielectric permittivity are well-explained by means of the molecular theory of dielectric relaxation in nematic dimers (Stocchero, M.; Ferrarini, A.; Moro, G. J.; Dunmur, D. A.; Luckhurst, G. R. J. Chem. Phys., 2004, 121(16), 8079). The dimer is seen as a mixture of cis and trans conformers, and the model allows us to estimate their relative populations at each temperature. The main molecular motions are interpreted by the model as independent end-overend rotations of each terminal semirigid unit of the dimer. PMID- 24164205 TI - Robotically assisted titration coupled to ion mobility-mass spectrometry reveals the interface structures and analysis parameters critical for multiprotein topology mapping. AB - Multiprotein complexes have three-dimensional shapes and dynamic functions that impact almost every aspect of biochemistry. Despite this, our ability to rapidly assess the structures of such macromolecules lags significantly behind high throughput efforts to identify their function, especially in the context of human disease. Here, we describe results obtained by coupling ion mobility-mass spectrometry with automated robotic sampling of different solvent compositions. This combination of technologies has allowed us to explore an extensive set of solution conditions for a group of eight protein homotetramers, representing a broad sample of protein structure and stability space. We find that altering solution ionic strength in concert with dimethylsulfoxide content is sufficient to disrupt the protein-protein interfaces of all of the complexes studied here. Ion mobility measurements captured for both intact assemblies and subcomplexes match expected values from available X-ray structures in all cases save two. For these exceptions, we find that distorted subcomplexes result from extreme disruption conditions, and are accompanied by small shifts in intact tetramers size, thus enabling the removal of distorted subcomplex data in downstream models. Furthermore, we find strong correlations between the relative intensities of disrupted protein tetramers and the relative number and type of interactions present at interfaces as a function of disrupting agent added. In most cases, this correlation appears strong enough to quantify various types of protein interfacial interactions within unknown proteins following appropriate calibration. PMID- 24164206 TI - Identification of elaiophylin derivatives from the marine-derived actinomycete Streptomyces sp. 7-145 using PCR-based screening. AB - A PCR-based genetic screening experiment targeting the dTDP-glucose-4,6 dehydratase gene revealed that a marine sediment-derived strain, Streptomyces sp. 7-145, had the potential to produce glycosidic antibiotics. Chemical investigation of culture extracts of this strain yielded two new 6-deoxyhexose containing antibiotics, 11',12'-dehydroelaiophylin (1) and 11,11'-O-dimethyl-14' deethyl-14'-methylelaiophylin (2), together with four known elaiophylin analogues (3-6). Their structures were determined by extensive NMR, MS, and CD analyses. Compounds 1, 3, 4, and 6 showed good antibacterial activity against methicillin resistant Staphylococcus aureus and vancomycin-resistant enterococci pathogens. PMID- 24164207 TI - Pathologic findings of coronary stents: a comparison of sudden coronary death versus non-cardiac death. AB - There are few histologic studies of intracoronary stents found at autopsy. We studied histologic findings of 87 intracoronary stents from 45 autopsy hearts. There were 40 patients with chronically implanted stents and five shorter than 30 days. Of five patients with recent stent placement, the cause of death was related to the stent (in-stent thrombosis) in one case. Of the 40 patients with chronic stents, there were 16 sudden coronary deaths and 24 noncoronary deaths (controls). There were no late stent thromboses in the coronary deaths. In the coronary deaths, 26% of stents showed restenosis versus 11% in controls (p = 0.1). The rate of healed infarcts and cardiomegaly was similar in the coronary and noncoronary groups, and acute thrombi in native arteries were seen only in three hearts in the coronary group. We conclude that the cause of death is rarely impacted by in-stent findings at autopsy, especially in chronically implanted stents. PMID- 24164208 TI - Commentary on: Page M, Taylor J, Blenkin M. Expert interpretation of bitemark injuries--a contemporary qualitative study. J Forensic Sci 2013;58(3):664-72. PMID- 24164209 TI - Authors' response. PMID- 24164211 TI - Antimicrobial photodynamic efficiency of novel cationic porphyrins towards periodontal Gram-positive and Gram-negative pathogenic bacteria. AB - The Gram-negative Aggregatibacter actinomycetemcomitans and Fusobacterium nucleatum are major causative agents of aggressive periodontal disease. Due to increase in the number of antibiotic-resistant bacteria, antimicrobial Photodynamic therapy (aPDT) seems to be a plausible alternative. In this work, photosensitization was performed on Gram-positive and Gram-negative bacteria in pure culture using new-age cationic porphyrins, namely mesoimidazolium substituted porphyrin derivative (ImP) and pyridinium-substituted porphyrin derivative (PyP). The photophysical properties of both the sensitizers including absorption, fluorescence emission, quantum yields of the triplet excited states and singlet oxygen generation efficiencies were evaluated in the context of aPDT application. The studied porphyrins exhibited high ability to accumulate into bacterial cells with complete penetration into early stage biofilms. As compared with ImP, PyP was found to be more effective for photoinactivation of bacterial strains associated with periodontitis, without any signs of dark toxicity, owing to its high photocytotoxicity. PMID- 24164210 TI - Blocking dopamine d1-like receptors attenuates context-induced renewal of pavlovian-conditioned alcohol-seeking in rats. AB - BACKGROUND: Environmental contexts associated with drug use can trigger craving in humans and the renewal of drug-seeking behaviors in animals. Here, we tested the hypothesis that context-induced renewal of Pavlovian-conditioned alcohol seeking is mediated by dopamine. METHODS: Male, Long-Evans rats were trained to discriminate between two, 10-second, auditory conditioned stimuli. One stimulus (CS+) was consistently paired with 15% ethanol (EtOH) (v/v, 0.2 ml per CS+) and the second stimulus (CS-) was not. Each CS occurred 16 times per session, and entries into a fluid port where EtOH was delivered were measured. Pavlovian discrimination training (PDT) occurred in a distinctive context, referred to as Context A. Subsequently, behavior was extinguished by presenting both cues without EtOH in a different context (Context B). At test, rats were injected with a dopamine D1-like receptor antagonist (R)-(+)-7-chloro-8-hydroxy-3-methyl-1 phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride (SCH 23390; 0, 3.33, 10 MUg/kg; 1 ml/kg; s.c.) and presented with the CS+ and CS- without EtOH in the prior PDT context (Context A). RESULTS: Across training, rats developed higher response levels to the alcohol-predictive CS+, compared with the CS-. Port entries during the CS+ decreased across extinction. At test, placement into the alcohol-associated context triggered a selective increase in CS+ responses after saline, which was significantly reduced by SCH 23390 pretreatment. In separate studies, SCH 23390 did not affect lever-pressing for sucrose under reinforced or extinction conditions, but decreased port entries relative to saline in both cases. CONCLUSIONS: These data indicate that dopamine is required for context induced renewal of Pavlovian-conditioned alcohol-seeking and may also be necessary for preparatory conditioned approach behaviors. PMID- 24164212 TI - Photocatalytic synthesis and photovoltaic application of Ag-TiO2 nanorod composites. AB - A photocatalytic strategy has been developed to synthesize colloidal Ag-TiO2 nanorod composites in which each TiO2 nanorod contains a single Ag nanoparticle on its surface. In this rational synthesis, photoexcitation of TiO2 nanorods under UV illumination produces electrons that reduce Ag(I) precursor and deposit multiple small Ag nanoparticles on the surface of TiO2 nanorods. Prolonged UV irradiation induces an interesting ripening process, which dissolves the smaller nanoparticles by photogenerated oxidative species and then redeposits Ag onto one larger and more stable particle attached to each TiO2 nanorod through the reduction of photoexcited electrons. The size of the Ag nanoparticles can be precisely controlled by varying the irradiation time and the amount of alcohol additive. The Ag-TiO2 nanorod composites were used as electron transport layers in the fabrication of organic solar cells and showed notable enhancement in power conversion efficiency (6.92%) than pure TiO2 nanorods (5.81%), as well as higher external quantum efficiency due to improved charge separation and transfer by the presence of Ag nanoparticles. PMID- 24164213 TI - Factors influencing quality of patient interaction at community pharmacy drive through and walk-in counselling areas. AB - OBJECTIVE: To examine factors influencing the amount of time and information pharmacy personnel provide to patients at drive-through and walk-in counselling areas. METHODS: On-site observational data collection in 22 community pharmacies by pharmacy students. Information included observable patient characteristics such as gender, age range, English proficiency and mobility impairment; encounter characteristics included type of prescription and whether the patient was acknowledged; and counselling characteristics included types of counselling information conveyed and length of time for each encounter. KEY FINDINGS: Patient pharmacist encounters were documented at the drive-through and walk-in counselling areas 961 and 1098 times respectively. Pharmacists spent less time, and technicians more time, with patients at the drive-through counselling area. The amount of information provided to patients was significantly affected by whether the patient was receiving new versus refill prescriptions. Patients with a new prescription were twice as likely to receive more information from pharmacy personnel. There was a significant difference between the amount of counselling provided to patients at the drive-through and walk-in counselling area (rate ratio (RR) 0.92, 95% confidence interval (CI): 0.86-1.00). Patients at the drive through received a lower amount of information relative to patients using the walk-in. Amount of information provided to patients was affected by the level of pharmacy busyness (RR 0.96, 95% CI: 0.95-0.99). CONCLUSIONS: Providing patient care at the drive-through counselling area may negatively influence quality of patient care. To improve quality of pharmacy drive-through services, standardization of drive-through services in pharmacies may be needed. PMID- 24164215 TI - Is heart failure a debatable end-point for bisphosphonate treatment in older osteoporotic population? PMID- 24164214 TI - Making sense of deviance: identifying dissociating cases within the case series approach. AB - The case series approach in cognitive neuropsychology provides a means to test theories that make quantitative predictions about associations between different components of the cognitive system [Schwartz, M. F., & Dell, G. S. (2010). Case series investigations in cognitive neuropsychology. Cognitive Neuropsychology, 27, 477-494]. However, even when the predicted association is borne out the study may include outliers-observations that deviate significantly from the rest of the data. These outliers may reveal individual cases whose cognitive impairments dissociate from other cases included in the study. These dissociating cases can pose a significant challenge to the theory being tested. Using a recent case series that investigated the underlying causes of letter perseveration in spelling [Fischer-Baum, S., & Rapp, B. (2012). Underlying cause(s) of letter perseveration errors. Neuropsychologia, 50, 305-318], I discuss statistical and theoretical issues that arise when using outlier detection techniques to identify dissociating cases in a case series study. PMID- 24164216 TI - Gender, clamped hyperglycemia and arterial stiffness in patients with uncomplicated type 1 diabetes mellitus. AB - BACKGROUND: Diabetes mellitus (DM) reduces female gender-mediated protection against the development of renal disease possibly through effects on hyperglycemia. Women with DM also exhibit increased arterial stiffness, which may promote renal disease progression. The mechanisms responsible for increased arterial stiffness in women and the possible role of acute changes in ambient glycemia remain unknown. METHODS: Blood pressure, augmentation index (AIx), pulse wave velocity (PWV) and circulating mediators of the renin angiotensin system and nitric oxide (cGMP) were measured in men (n = 22) and women (n = 19) with uncomplicated type 1 DM under clamped euglycemic and hyperglycemic conditions. RESULTS: At baseline, men exhibited higher levels of angiotensin II (p = 0.030) and lower cGMP levels (p = 0.004), higher systolic blood pressure (124 +/- 2 versus 109 +/- 2 mmHg, p < 0.0001) and pulse pressure (42 +/- 2 versus 58 +/- 2 beats per minute, p < 0.0001). For arterial stiffness, radial (-8.0 +/- 2.6% versus +5.4 +/- 3.7%, p < 0.0001) and carotid AIx (-4.7 +/- 2.9 versus +12.5 +/- 3.0, p < 0.0001) were lower in men versus women. In contrast, carotid-femoral PWV was similar in men and women (5.20 +/- 0.30 versus 5.13 +/- 0.17, respectively, p = 0.853). In response to clamped hyperglycemia, systolic blood pressure increased in women (109 +/- 2 to 112 +/- 2 mmHg, p = 0.005) but not men. Serum aldosterone increased and cGMP declined in women but not in men. Clamped hyperglycemia did not influence arterial stiffness in either group and radial and carotid AIx remained higher in women. CONCLUSIONS: Arterial stiffness is higher in women with type 1 DM. This effect is not dependent on the effects of clamped hyperglycemia or neurohormonal activation. PMID- 24164217 TI - Acetate formation in the photoheterotrophic bacterium Chloroflexus aurantiacus involves an archaeal type ADP-forming acetyl-CoA synthetase isoenzyme I. AB - The bacterium Chloroflexus aurantiacus excreted significant amounts of acetate during photohetero trophic growth on glucose and in resting cell suspensions. Up to 1.5 mol acetate per mol glucose were formed. In acetate-forming cells, the activities of phosphotransacetylase and acetate kinase, usually involved in acetate formation in Bacteria, could not be detected; instead, the cells contained an acetyl-CoA synthetase (ADP-forming) (ACD) (acetyl-CoA + ADP + Pi -> acetate + ATP + CoA), an enzyme so far reported in prokaryotes to be specific for acetate-forming Archaea. ACD, which was induced 10-fold during growth on glucose, was purified and the encoding gene was identified as Caur_3920. The recombinant enzyme, a homotetrameric 300-kDa protein composed of 75-kDa subunits, was characterized as functional ACD. Substrate specificities and kinetic constants for acetyl-CoA/acetate and other acyl-CoA esters/acids were determined, showing similarity of the C. aurantiacus ACD to archaeal ACD I isoenzymes, which are involved in acetate formation from sugars. This is the first report of a functional ACD involved in acetate formation in the domain of Bacteria. PMID- 24164218 TI - Positive influence of L-carnitine on the different muscle fibres types of racing pigeons. AB - Succinate dehydrogenase (SDH), Ca(2+) ATPase, Lactate dehydrogenase (LDH), are involved in energy metabolism. These enzymes can be used as indicators of the energy capacity of aerobic cells. The study investigated the effects of L carnitine supplementation on M. pectoralis superficialis, M. pectoralis profundus, M. extensor carpi radialis muscle and M. flexor carpi ulnaris. Twenty eight racing pigeons hatched at the same time were divided randomly into three groups. Eight pigeons, which were used as the control group, were sacrificed at 92-day old. The remaining twenty pigeons continued training until they reached 157-day old, with half the pigeons getting 25 mg/head/day of L-carnitine, while the other half given the same amount of water. The pigeons were assessed by histochemical methods and reverse transcription polymerase chain reaction (RT PCR). To assess influence of L-carnitine on muscle fibre composition and the performance of three genes' mRNA, this study applied SDH localization, SDH, Ca(2+) ATPase and LDH mRNA expression to examine the results after oral administration of L-carnitine in vivo in racing pigeons. The results showed that L-carnitine significantly elevated the amount of white muscle fibre type IIa (p < 0.05). The mRNA expression quantities of SDH and LDH gene was higher via RT-PCR method. However, the expression of Ca(2+) ATPase remains similar. In conclusion, appropriate oral administration of L-carnitine of 25 mg/pigeon/day will result in an improvement of muscles related to flying. PMID- 24164219 TI - Altitudinal and spatial signature of persistent organic pollutants in soil, lichen, conifer needles, and bark of the southeast Tibetan Plateau: implications for sources and environmental cycling. AB - The southeast Tibetan Plateau (TP) of China is characterized by mountain-valley topography and is usually the main channel for the warm and humid airstream from South Asia caused by the Indian monsoon. In this study, it is hypothesized that some semivolatile organic pollutants such as organochlorine pesticides (OCPs) and polycyclic aromatic hydrocarbons (PAHs) can be transported from the densely populated and intensely agricultural Indian Subcontinent via the Indian monsoon and then cold-trapped by the mountains of the southeast TP. Samples of soils, lichens, conifer barks, and needles were collected from five transects to investigate the accumulation patterns of OCPs and PAHs in this region. The OCP concentrations were found to generally increase with increasing altitude in transects 1, 3, and 4, while such trends were insignificant in most cases for PAHs. Total organic carbon/lipid based normalization of concentrations does not strengthen the correlations with altitude in most cases. Chemical concentration ratios in soils of forest areas to clearing sites without forest cover (F/C) showed significantly positive correlation with log K(oa) and negative correlation with log K(aw) of PAHs, suggesting that the role of forests as a filter and forest soil as a final sink are more pronounced for more lipophilic compounds. A lower alpha-/gamma-HCH ratio and higher ratios of DDT/DDE and o,p'-DDT/p,p'-DDT compared with the technical products suggest the usage of lindane (gamma-HCH), DDT, and dicofol in neighboring countries. The suitability of using different sample matrices (soil, lichen, conifer bark, and needles) as passive air samplers in remote regions is evaluated. PMID- 24164220 TI - Mutational analysis of FEN1 gene in hepatocellular carcinomas. PMID- 24164222 TI - Dentistry at crossroads: the access to care crisis for patients with special needs. PMID- 24164223 TI - Intellectual disability and impact on oral health: a paired study. AB - The objective was to assess the oral health status, the treatment needed, and the type of dental health services access of intellectually disabled (ID) subjects in Teresina, Brazil. The sample consisted of 103 ID subjects matriculated in centers for special needs people and 103 siblings. Results were analyzed using paired t test, chi-square test, and odds ratio. ID subjects had fair (63.1%; p < .001) and their siblings had a good oral hygiene (n = 103 [55.3%]; p < .005). ID had more decayed (3.52; p < .005), and missing teeth (1.17; p = .001), fewer dental restorations (1.67; p = .012) and had a greater need for tooth extraction (21.4%; p = .002) than their siblings. Thirty percent of ID subjects had never received dental treatment and had difficulty accessing public health services. Their treatment needs were, therefore, higher than non-ID subjects. The access to oral health services was unsatisfactory, thus it is important to implement educational and health promotion inclusion policies for people with ID. PMID- 24164224 TI - Toothbrushing barriers for people with developmental disabilities: a pilot study. AB - PURPOSE: The aims of this study were: (1) to determine which step in tooth brushing is most difficult for individuals with developmental disabilities and (2) to determine if oral hygiene instruction improves technique. MATERIAL AND METHODS: Once per week for 6 weeks, disclosing solution was applied to the teeth of 14 subjects who were observed individually in their tooth brushing technique. Fourteen distinct steps were measured on a 4-point Likert scale. Plaque score was measured after brushing. RESULTS: The step causing greatest difficulty was "able to brush off residual, identified plaque." Steps that showed greatest improvement were "open toothpaste" and "place toothpaste on brush." The change in plaque score from the initial visit to the final visit was not statistically significant. CONCLUSION: Oral hygiene instruction in a group and individual setting increased compliance in the initial steps of tooth brushing. PMID- 24164225 TI - A study on the eruption timing of permanent dentition in patients with cerebral palsy. AB - PURPOSE: This study aimed to determine the average eruption time and sequence of permanent teeth in patients with cerebral palsy (CP) and to compare the results with the established norms for Iranian subjects. METHODS: This cross-sectional study comprised of 207 individuals with CP, 96 boys and 111 girls, ranging from 6 to 19 years. The average age at eruption of permanent teeth, excluding third molars, was given as the mean (+/- SD) and median in years for each gender. A table of percentiles of the eruption time was also determined. Comparisons were made using t-test at a significance level of 0.05. RESULTS: The sequence of eruption in children with CP was almost similar to the normal. With the exception of the second premolar and the second molar, tooth eruption was advanced in girls compared with boys. There was no difference between the left and right sides of each arch. Mandibular teeth had an earlier eruption time than maxillary teeth except for the second premolar. In general, eruption times of children with CP were later (1-33 months) than those reported previously for healthy children. CONCLUSIONS: Despite the almost similar sequence of eruption, a high tendency to delayed eruption of permanent dentition was observed in children with CP. PMID- 24164226 TI - The relationship between nurses' oral hygiene and the mouth care of their patients. AB - To investigate the extent to which a relationship may exist between nurses' own oral hygiene and their commitment and capability of following instructions for tooth brushing with conventional and triple-headed toothbrushes, to cerebral palsy (CP) children. The study included 43 individuals with CP and their 44 nurses. A structured questionnaire was designed to assess I. Demographic characteristics of the nurses II. Nurses' knowledge and maintenance of their own oral-hygiene and that of their CP patients. Nurses' ability to follow instruction for tooth-brushing was evaluated and scored using the TB-PS-I/Ashkenazi index following the first brushing, as well as on a recall visit one month later. More nurses (72.7%) reported routine tooth-brushing in the morning than in the evening (40.9%). Most nurses (73%) reported not flossing their teeth at all, and more than half reported visiting their dentist only when they suffer pain. A positive correlation was found between the nurses' knowledge of preventive oral measures and their compliance with their own oral hygiene and with that of their CP patients. Similarly, a positive correlation was found between nurses' receiving previous instruction for correct oral hygiene and their maintenance of their patients' oral hygiene. Institutions for CP patients should disseminate information on oral hygiene to staff, as a means of increasing their maintenance of their patients' oral health. PMID- 24164227 TI - Variations in tobacco control in National Dental PBRN practices: the role of patient and practice factors. AB - We engaged dental practices enrolled in The National Dental Practice-Based Research Network to quantify tobacco screening (ASK) and advising (ADVISE); and to identify patient and practice -characteristics associated with tobacco control. Dental practices (N = 190) distributed patient surveys that measured ASK and ADVISE. Twenty-nine percent of patients were ASKED about tobacco use during visit, 20% were identified as tobacco users, and 41% reported being ADVISED. Accounting for clustering of patients within practices, younger age and male gender were positively associated with ASK and ADVISE. Adjusting for patient age and gender, a higher proportion of non-whites in the practice, preventive services and proportion on public assistance were positively associated with ASK. Proportion of tobacco users in the practice and offering other preventive services were more strongly associated with ASK and ADVISE than other practice characteristics. Understanding variations in performance is an important step toward designing strategies for improving tobacco control in dentistry. PMID- 24164228 TI - Effect of low level laser therapy in the reduction of oral complications in patients with cancer of the head and neck submitted to radiotherapy. AB - The aim of this study was to assess the effect of low level laser therapy on reducing the occurrence and severity of oral complications in patients with head and neck cancer undergoing radiotherapy. Sixty head and neck cancer outpatients from a cancer hospital receiving radiotherapy were selected and randomly assigned into two groups. The laser group was irradiated with an InGaAlP laser and the control received sham laser. The assessment of complications (oral mucositis, pain) was carried out one week after starting radiotherapy, and at the fifteenth and thirtieth sessions of radiotherapy. All patients from both groups showed some degree of oral mucositis. Better outcomes were observed in the laser group when compared with the control in the follow-up sessions, indicating lower degrees of oral mucositis, pain and higher salivary flow (p < .05). These findings support the use of laser therapy as an adjuvant treatment for the control of oral complications. PMID- 24164229 TI - Loss of lingual sensitivity and slightly increased size signaling schwannoma in a patient with mixed conjunctive tissue disease. AB - The purpose of this study was to describe an unusual case of a lingual schwannoma associated with a mixed connective tissue disease (MCTD). A case report. A lingual schwannoma with loss of lingual sensitivity and slightly increased size in an 18-year-old patient with MCTD was correctly diagnosed through a biopsy and no reoccurrence was observed one year after the surgical removal of the tumor and sensitivity returned 3 months after surgery. This case was considered uncommon, making the clinical diagnosis challenging in view of the diversity of possibilities for its differential diagnosis, thus showing the importance of a biopsy to confirm the diagnosis and long term follow up in such cases. PMID- 24164230 TI - Interrupted development of dentition in children receiving bone marrow transplantation for acute lymphocytic Leukemia: a case series. AB - This case series depicts dental anomalies that may develop in children who have undergone bone marrow transplantation (BMT) for acute lymphoblastic leukemia (ALL). The most common finding in these patients was root stunting; other abnormalities included microdontia, hypodontia, taurodontia, caries, enamel pearls, and pulpal calcification. Recognition of these adverse effects of BMT on odontogenesis, as demonstrated on panoramic radiograph images, will allow healthcare providers to explain to parents and patients the possible dental outcomes associated with BMT and to optimize their dental health regimen. PMID- 24164231 TI - Reaching hypertriglyceridemia goals. PMID- 24164232 TI - Effects of 47C allele (rs4880) of the SOD2 gene in the production of intracellular reactive species in peripheral blood mononuclear cells with and without lipopolysaccharides induction. AB - Challenging of peripheral blood mononuclear cells (PBMCs) with lipopolysaccharides (LPS) has been shown to activate monocytes and macrophages, leading to the production of pro-inflammatory cytokines and reactive oxygen species (ROS). Manganese superoxide dismutase (MnSOD) is an important enzyme that may play a central role in the response to oxidative stress. 47C> T SNP of the SOD2 gene, the -9Val MnSOD is less efficient than the -9Ala version. We have previously characterized the cellular redox status of human PBMCs expressing either -9Ala (CC) or -9Val (TT) SOD2 and analyzed the responses of these cells to oxidative stress induced by LPS. Due to the observed alterations in the activities of these antioxidant enzymes, we decided to investigate their immunocontent and analyze the production of intracellular oxidants, as well as any resulting DNA damage. PBMCs were isolated from the blood of 30 healthy human volunteers (15 volunteers per allele). We then analyzed levels of nitrite, DNA damage by comet assay, TNF-alpha, carboxymethyl lysine and nitrotyrosine and assessed production of intracellular reactive species by the DCFH-DA-based assay and western blots were used to analyze protein levels. Our results show that there occurs an increase in nitric oxide production in both allele groups after challenge with LPS. A significant increase in DNA damage was observed in PBMCs after an 8-h LPS challenge. Cells expressing the SOD2 47C allele quickly adapt to a more intense metabolism by upregulating cellular detoxification mechanisms. However, when these cells are stressed over a long period, they accumulate a large quantity of toxic metabolic byproducts. PMID- 24164233 TI - A generalization of Chao's estimator for covariate information. AB - This note generalizes Chao's estimator of population size for closed capture recapture studies if covariates are available. Chao's estimator was developed under unobserved heterogeneity in which case it represents a lower bound of the population size. If observed heterogeneity is available in form of covariates we show how this information can be used to reduce the bias of Chao's estimator. The key element in this development is the understanding and placement of Chao's estimator in a truncated Poisson likelihood. It is shown that a truncated Poisson likelihood (with log-link) with all counts truncated besides ones and twos is equivalent to a binomial likelihood (with logit-link). This enables the development of a generalized Chao estimator as the estimated, expected value of the frequency of zero counts under a truncated (all counts truncated except ones and twos) Poisson regression model. If the regression model accounts for the heterogeneity entirely, the generalized Chao estimator is asymptotically unbiased. A simulation study illustrates the potential in gain of bias reduction. Comparisons of the generalized Chao estimator with the homogeneous zero-truncated Poisson regression approach are supplied as well. The method is applied to a surveillance study on the completeness of farm submissions in Great Britain. PMID- 24164234 TI - Low-temperature conditioning of "seed" cloves enhances the expression of phenolic metabolism related genes and anthocyanin content in 'Coreano' garlic (Allium sativum) during plant development. AB - Low-temperature conditioning of garlic "seed" cloves accelerated the development of the crop cycle, decreased plant growth, and increased the synthesis of phenolic compounds and anthocyanins in the outer scale leaves of the bulbs at harvest time, leading to 3-fold content increase compared with those conditioned at room temperature. Cold conditioning of "seed" cloves also altered the anthocyanin profile during bulb development and at harvest. Two new anthocyanins are reported for the first time in garlic. The high phenolics and anthocyanin contents in bulbs of plants generated from "seed" cloves conditioned at 5 degrees C for 5 weeks were preceded by overexpression of some putative genes of the phenolic metabolism [6-fold for phenylalanine ammonia lyase (PAL)] and anthocyanin synthesis [1-fold for UDP-sugar:flavonoid 3-O-glycosyltransferase (UFGT)] compared with those conditioned at room temperature. PMID- 24164235 TI - In memory of Sonia Skarlatos, PhD (1953-2013). PMID- 24164236 TI - Dr. Sonia Skarlatos-leader, colleague, and friend: from vascular biology to gene therapy and the Cardiovascular Cell Therapy research network. PMID- 24164237 TI - Dr. Sonia Skarlatos and the National Heart, Lung, and Blood institute translational research and resource programs. AB - Sonia I. Skarlatos, PhD (September 28, 1953-August 6, 2013), was the deputy director of the Division of Cardiovascular Sciences at the National Heart, Lung, and Blood Institute (NHLBI). This article reviews her work in establishing, leading, or facilitating extramural translational research programs supported by the NHLBI, specifically focusing on her work as a consistent advocate for the advancement of gene and cell therapies. PMID- 24164238 TI - An emerging adeno-associated viral vector pipeline for cardiac gene therapy. AB - The naturally occurring adeno-associated virus (AAV) isolates display diverse tissue tropisms in different hosts. Robust cardiac transduction in particular has been reported for certain AAV strains. Successful applications of these AAV strains in preclinical and clinical settings with a focus on treating cardiovascular disease continue to be reported. At the same time, these studies have highlighted challenges such as cross-species variability in AAV tropism, transduction efficiency, and immunity. Continued progress in our understanding of AAV capsid structure and biology has provided the rationale for designing improved vectors that can possibly address these concerns. The current report provides an overview of cardiotropic AAV, existing gaps in our knowledge, and newly engineered AAV strains that are viable candidates for the cardiac gene therapy clinic. PMID- 24164240 TI - Adeno-associated virus-mediated gene therapy for metabolic myopathy. AB - Metabolic myopathies are a diverse group of rare diseases in which impaired breakdown of stored energy leads to profound muscle dysfunction ranging from exercise intolerance to severe muscle wasting. Metabolic myopathies are largely caused by functional deficiency of a single gene and are generally subcategorized into three major types of metabolic disease: mitochondrial, lipid, or glycogen. Treatment varies greatly depending on the biochemical nature of the disease, and unfortunately no definitive treatments exist for metabolic myopathy. Since this group of diseases is inherited, gene therapy is being explored as an approach to personalized medical treatment. Adeno-associated virus-based vectors in particular have shown to be promising in the treatment of several forms of metabolic myopathy. This review will discuss the most recent advances in gene therapy efforts for the treatment of metabolic myopathies. PMID- 24164239 TI - Gene therapy delivery systems for enhancing viral and nonviral vectors for cardiac diseases: current concepts and future applications. AB - Gene therapy is one of the most promising fields for developing new treatments for the advanced stages of ischemic and monogenetic, particularly autosomal or X linked recessive, cardiomyopathies. The remarkable ongoing efforts in advancing various targets have largely been inspired by the results that have been achieved in several notable gene therapy trials, such as the hemophilia B and Leber's congenital amaurosis. Rate-limiting problems preventing successful clinical application in the cardiac disease area, however, are primarily attributable to inefficient gene transfer, host responses, and the lack of sustainable therapeutic transgene expression. It is arguable that these problems are directly correlated with the choice of vector, dose level, and associated cardiac delivery approach as a whole treatment system. Essentially, a delicate balance exists in maximizing gene transfer required for efficacy while remaining within safety limits. Therefore, the development of safe, effective, and clinically applicable gene delivery techniques for selected nonviral and viral vectors will certainly be invaluable in obtaining future regulatory approvals. The choice of gene transfer vector, dose level, and the delivery system are likely to be critical determinants of therapeutic efficacy. It is here that the interactions between vector uptake and trafficking, delivery route means, and the host's physical limits must be considered synergistically for a successful treatment course. PMID- 24164242 TI - Gene therapy to stimulate angiogenesis to treat diffuse coronary artery disease. AB - Cardiac gene therapy offers a strategy to treat diffuse coronary artery disease (CAD), a disorder with no therapeutic options. The use of genes to revascularize the ischemic myocardium has been the focus of two decades of preclinical research with a variety of angiogenic mediators, including vascular endothelial growth factor, fibroblast growth factor, hepatocyte growth factor, and others encoded by DNA plasmids or adenovirus vectors. The multifaceted challenge for developing efficient induction of collateral vessels in the ischemic heart requires a choice for route of delivery, dosing level, a relevant animal model, duration of treatment, and assessment of phenotype for efficacy. Overall, studies of gene therapy for ischemia in experimental models are very encouraging, with clear evidence of safety and efficacy, strongly supporting the concept that gene therapy to induce angiogenesis is a viable therapeutic approach for CAD. Clinical studies of cardiac gene therapy with angiogenic factors have added substantially to the evidence for efficacy, but definitive studies have not yet led to commercial approval. This review provides the general concepts for angiogenesis based therapeutic approaches for diffuse CAD and summarizes the results from key studies in the field with recommendations for refinement to a successful product design and evaluation. PMID- 24164241 TI - Targeting sarcoplasmic reticulum calcium ATPase by gene therapy. AB - Although pharmacologic therapies have provided gains in reducing the mortality of heart failure, the rising incidence of the disease requires new approaches to combat its health burden. Twenty-five years ago, abnormal calcium cycling was identified as a characteristic of failing human myocardium. Sarcoplasmic reticulum calcium ATPase (SERCA2a), the sarcoplasmic reticulum calcium pump, was found to be a key factor in the alteration of calcium cycling. With the advancement of gene vectors, SERCA2a emerged as an attractive clinical target for gene delivery purposes. Using adeno-associated virus constructs, SERCA2a upregulation has been found to improve myocardial function in animal models. The clinical benefits of overexpressing SERCA2a have been demonstrated in the phase I study Calcium Upregulation by Percutaneous Administration of Gene Therapy in Cardiac Disease (CUPID). This study has demonstrated that a persistent expression of the transgene SERCA2a is associated with a significant improvement in associated biochemical alterations and clinical symptoms of heart failure. In the coming years, additional targets will likely emerge that are amenable to genetic manipulations along with the development of more advanced vector systems with safer delivery approaches. PMID- 24164244 TI - Assembly of amorphous clusters under floating monolayers: a comparison of in situ and ex situ techniques. AB - We report synchrotron X-ray scattering studies of biomimetic crystallization of hydroxyapatite (the primary constituent of bone), using monolayers of fatty acid molecules floating on simulated body fluid (SBF) as well as aqueous solutions of calcium phosphate. A ~10 A thick film of amorphous material is observed to form immediately at the molecular monolayer, consistent with the proposed formation of "Posner clusters". This layer becomes denser but not significantly thicker as the subphase concentration and the temperature approach physiological conditions. The amorphous films do not crystallize within 24 h, in contrast to prior reports of more rapid crystallization using electron microscopy on ex situ samples. However, crystallization occurs almost immediately after our films are transferred onto solid substrates. These results illustrate the importance of in situ measurements for model biomineralization experiments. PMID- 24164243 TI - Describing autophagy via analysis of individual organelles by capillary electrophoresis with laser induced fluorescence detection. AB - Autophagy is a cellular process responsible for the degradation of intracellular cargo. Its dynamic nature and the multiple types of autophagy organelles present at a given time make current measurements, such as those done by Western blotting, insufficient to understand autophagy and its roles in aging and disease. Capillary electrophoresis coupled to laser induced fluorescence detection (CE-LIF) has been used previously to count and determine properties of individual organelles, but has never been used on autophagy organelles or for determination of changes of such properties. Here we used autophagy organelles isolated from L6 cells expressing GFP-LC3, which is an autophagy marker, to develop a CE-LIF method for the determination of the number of autophagy organelles, their individual GFP-LC3 fluorescence intensities, and their individual electrophoretic mobilities. These properties were compared under basal and rapamycin-driven autophagy, which showed differences in the number of detected organelles and electrophoretic mobility distributions of autophagy organelles. Vinblastine treatment was also used to halt autophagy and further characterize changes and provide additional insight on the nature of autophagy organelles. This approach revealed dramatic and opposite directions in changes of organelle numbers, GFP-LC3 contents, and electrophoretic mobilities during the duration of the vinblastine treatment. These trends suggested the identity of organelle types being detected. These observations demonstrate that individual organelle analysis by CE-LIF is a powerful technology to investigate the complexity and nature of autophagy, a process that plays critical roles in response to drug treatments, aging, and disease. PMID- 24164245 TI - Santacruzamate A, a potent and selective histone deacetylase inhibitor from the Panamanian marine cyanobacterium cf. Symploca sp. AB - A dark brown tuft-forming cyanobacterium, morphologically resembling the genus Symploca, was collected during an expedition to the Coiba National Park, a UNESCO World Heritage Site on the Pacific coast of Panama. Phylogenetic analysis of its 16S rRNA gene sequence indicated that it is 4.5% divergent from the type strain for Symploca and thus is likely a new genus. Fractionation of the crude extract led to the isolation of a new cytotoxin, designated santacruzamate A (1), which has several structural features in common with suberoylanilide hydroxamic acid [(2), SAHA, trade name Vorinostat], a clinically approved histone deacetylase (HDAC) inhibitor used to treat refractory cutaneous T-cell lymphoma. Recognition of the structural similarly of 1 and SAHA led to the characterization of santacruzamate A as a picomolar level selective inhibitor of HDAC2, a Class I HDAC, with relatively little inhibition of HDAC4 or HDAC6, both Class II HDACs. As a result, chemical syntheses of santacruzamate A as well as a structurally intriguing hybrid molecule, which blends aspects of both agents (1 and 2), were achieved and evaluated for their HDAC activity and specificity. PMID- 24164246 TI - Effect of membranes on oxygen transfer rate and consumption within a newly developed three-compartment bioartificial liver device: Advanced experimental and theoretical studies. AB - A mathematical model is developed to predict oxygen transfer in the fiber-in fiber (FIF) bioartificial liver device. The model parameters are taken from the constructed and tested FIF modules. We extended the Krogh cylinder model by including one more zone for oxygen transfer. Cellular oxygen uptake was based on Michaelis-Menten kinetics. The effect of varying a number of important model parameters is investigated, including (1) oxygen partial pressure at the inlet, (2) the hydraulic permeability of compartment B (cell region), (3) the hydraulic permeability of the inner membrane, and (4) the oxygen diffusivity of the outer membrane. The mathematical model is validated by comparing its output against the experimentally acquired values of an oxygen transfer rate and the hydrostatic pressure drop. Three governing simultaneous linear differential equations are derived to predict and validate the experimental measurements, e.g., the flow rate and the hydrostatic pressure drop. The model output simulated the experimental measurements to a high degree of accuracy. The model predictions show that the cells in the annulus can be oxygenated well even at high cell density or at a low level of gas phase PG if the value of the oxygen diffusion coefficient Dm is 16 * 10(-5) . The mathematical model also shows that the performance of the FIF improves by increasing the permeability of polypropylene membrane (inner fiber). Moreover, the model predicted that 60% of plasma has access to the cells in the annulus within the first 10% of the FIF bioreactor axial length for a specific polypropylene membrane permeability and can reach 95% within the first 30% of its axial length. PMID- 24164247 TI - Haemophagocytic syndrome with a fatal outcome triggered by parvovirus B19 infection in the skin. PMID- 24164248 TI - Signal-to-noise ratio estimation on SEM images using cubic spline interpolation with Savitzky-Golay smoothing. AB - A new technique based on cubic spline interpolation with Savitzky-Golay noise reduction filtering is designed to estimate signal-to-noise ratio of scanning electron microscopy (SEM) images. This approach is found to present better result when compared with two existing techniques: nearest neighbourhood and first-order interpolation. When applied to evaluate the quality of SEM images, noise can be eliminated efficiently with optimal choice of scan rate from real-time SEM images, without generating corruption or increasing scanning time. PMID- 24164249 TI - Adopting a patient-centred approach: an investigation into the introduction of bedside handover to three rural hospitals. AB - AIMS AND OBJECTIVES: To study empirically the process and outcomes of the implementation of nurse-to-nurse bedside handover in three rural South Australian hospitals. BACKGROUND: While the importance of handover is identified in literature, little is written about its implementation. It is, however, suggested that bedside handover is a more patient-focussed approach than others available. DESIGN: A mixed-method, pretest post-test evaluative approach involving quasi experimental and ethnographic elements was used. The self-selected sample comprised nine inpatients (five women, four men) and forty-eight self-selected enrolled/registered nursing staff (forty-seven women, one man) from three acute hospital wards in rural South Australia. Lewin's (Human Relations, 1, 1947a, 2; Readings in Social Psychology. Henry Holt, New York, 1947b, 197) 3-stage model of change provided a theoretical basis and structure for the study. METHODS: Patient perceptions were obtained using ethnographic interviewing. Staff perceptions of patient involvement were obtained through questions rated on a 7-point Likert scale and ethnographic interviewing. RESULTS: Results indicated that patients preferred the bedside handover method over the traditional closed-door office handover approach. The key differences (as defined by patients) are that the bedside handover process incorporates social aspects for the patient, patients have the opportunity to know who is looking after them and patients are included in discussion related to their care. Furthermore, results suggest that staff believed the level of patient involvement in their care had increased under the bedside handover process. CONCLUSIONS: The results demonstrate that both patients and staff perceive patients to be more involved in their care under the bedside handover approach. The literature notes a recent move towards adopting patient centred care approaches in clinical settings and the many benefits associated with this style of care. This study has proven that implementing bedside handover has resulted in a patient-centred approach. RELEVANCE TO CLINICAL PRACTICE: This study generates further knowledge about rural nursing and contributes insight into the importance of handover implementation method--areas that are not widely documented in existing literature. PMID- 24164251 TI - Merging oxidative dearomatization and aminocatalysis: one-pot enantioselective synthesis of tricyclic architectures. AB - The combination of oxidative dearomatization and trienamine/enamine activation in a single vessel is described. Under these conditions, a three-bond forming process generates functionalized tricyclic architectures with up to six contiguous stereocenters with excellent stereoselectivities from readily available planar substrates. PMID- 24164250 TI - Vision-related quality of life in patients with chronic central serous chorioretinopathy. AB - PURPOSE: To evaluate vision-related quality of life in patients with chronic central serous chorioretinopathy (CSCR). DESIGN: Prospective, cross-sectional study. METHODS: The interviewer-administered National Eye Institute visual function questionnaire (NEI-VFQ-25) was used in 30 adult consecutive patients with chronic CSCR patients. The controls were 30 gender- and age-matched people with normal visual function who came from the same socioeconomic and educational background as the participants. RESULTS: Patients with CSCR had statistically significant lower scores than controls for all the subscales, except for general health. In the study group, all subscale scores of vision-related quality of life, except general health, showed statistically significant negative correlations with the visual acuity. CONCLUSIONS: People with CSCR have worse vision-related quality of life than people without the condition. PMID- 24164252 TI - High prevalence of anaphylaxis in patients with systemic mastocytosis - a single centre experience. AB - BACKGROUND: Systemic mastocytosis (SM) is a clonal mast cells disorder characterized by the proliferation, accumulation and activation of mast cells in extracutaneous tissues. The clinical picture is heterogeneous and may range from asymptomatic to potentially fatal anaphylactic reactions due to excessive mast cell mediator release. OBJECTIVE: The aim of this study was to investigate the prevalence and trigger factors of anaphylactic reactions among adult SM patients. We also explored the clinical spectrum of mast cell mediator-related symptoms in patients with SM. METHODS: This descriptive study was performed among 84 consecutive adult (>= 18 years) patients those were diagnosed with SM according to WHO criteria. Sixty-six of the patients also underwent a comprehensive allergy work-up. RESULTS: Sixty of 84 patients with SM (71%) had bone marrow mast cell aggregates and fulfilled the major criteria for SM and 76 patients (91%) had indolent disease. Simultaneous occurrence of cutaneous mastocytosis was observed in 59 patients (70%). Thirty-six patients (43%) had had at least one episode of an anaphylactic reaction. The clinical courses of the reactions were usually severe and patients often presented with syncope attacks (72%). Most patients reacted after hymenoptera venom stings (19/36; 53%). In 39% (14/36), a clear aetiology could not be determined. While males and females were equally frequent among the patients with SM, anaphylaxis patients showed a male predominance (61%). Anaphylactic reactions occurred more frequently in patients without cutaneous engagement. The rate of allergy sensitization was significantly higher in SM patients with anaphylaxis as compared with non-anaphylaxis SM patients, 70% vs. 23%, respectively (P = 0.0002). CONCLUSIONS AND CLINICAL RELEVANCE: Anaphylaxis is more prevalent in patients with SM, predominantly in patients with atopic SM. Hymenoptera venom-induced and idiopathic anaphylaxis were the most frequent elicitors. Our findings implicate that all mastocytosis patients with anaphylaxis should undergo detailed allergological assessment before considering treatment and preventive measures. PMID- 24164253 TI - Genetic and environmental influences on alcohol use problems: moderation by romantic partner support, but not family or friend support. AB - BACKGROUND: High levels of various forms of social support (e.g., romantic partner, family, friend) have a buffering effect on alcohol use outcomes in both adolescents and adults. The etiological associations among these variables have not been well studied. One possibility is that social support may buffer against inherited genetic predispositions to alcohol problems. Previous work has examined gene-environment interactions (G*E) for alcohol use disorders, but never for social support in adult twins. METHODS: In the current study, biometric modeling techniques were implemented to examine genetic and environmental components of variance of social support and alcohol use problems in a sample of 672 adult twin pairs. Using biometric moderation models that estimate G*E in the presence of gene-environment correlation (rGE), analyses examined how genetic and environmental influences on alcohol use problems varied as a function of romantic partner support, family support, and friend support. RESULTS: Genetic and environmental components of variance for alcohol use problems varied depending on the level of romantic partner support, with greater environmental influences found at the low level of support. Family and friend support, however, failed to show moderating effects. CONCLUSIONS: The current research has implications for expanding our understanding of what types of social support may trigger or suppress genetic and environmental influences on alcohol use problems. PMID- 24164254 TI - Changes in follow-up ECG and signal-averaged ECG in patients with arrhythmogenic right ventricular cardiomyopathy. AB - BACKGROUND: Electrocardiogram (ECG) and signal-averaged ECG (SAECG) are important as diagnostic tools in arrhythmogenic right ventricular cardiomyopathy (ARVC). The aim of this study was to investigate changes in follow-up ECGs and SAECGs in patients with ARVC. METHODS: We collected 185 follow-up ECGs from 38 patients and 35 follow-up SAECGs from 18 patients during a mean follow-up period of 64 +/- 36 months. RESULTS: On baseline ECG and SAECG, epsilon waves, T-wave inversion (TWI), and terminal activation delay (TAD) of QRS >= 55 ms in right precordial leads, and late potentials (LPs) were observed in six (16%), 11 (29%), 13 (34%), and 23 (68%) patients, respectively. During the follow-up period, 15 (39%) patients had 18 changes in ECG and/or SAECG features included in modified Task Force Criteria (TFC) of ARVC. Two patients developed new epsilon waves, and another two patients had dynamic epsilon waves. Newly developed TAD of QRS >= 55 ms was observed in two patients and disappeared in one patient. Eight patients, seven with and one without TWI in V1 -V3 or beyond, showed dynamic changes. LP developed in three patients. One patient with dynamic change of TWI and another patient with dynamic change of epsilon wave and TAD of QRS >= 55 ms could not satisfy the modified TFC during follow-up. CONCLUSIONS: Follow-up ECGs and SAECGs showed changes in 39% of patients with ARVC. Larger studies with a longer follow up period are needed to investigate the clinical implications of changes in follow-up ECG and SAECG. PMID- 24164255 TI - Coronary artery disease concomitant with chronic obstructive pulmonary disease. AB - BACKGROUND: Numerous epidemiologic studies have linked the presence of chronic obstructive pulmonary disease (COPD) to coronary artery disease (CAD). However, prevalence, pathological processes, clinical manifestations and therapy are still debated, as progress towards uncovering the link between these two disorders has been hindered by the complex nature of multimorbidity. METHODS: Articles targeting CAD in patients with COPD were identified from the searches of MEDLINE and EMBASE databases in July 2013. Three authors reviewed available evidence, focusing on the latest development on disease prevalence, pathogenesis, clinical manifestations and therapeutic strategies. Both clinical trial and previous reviews have been included in this work. RESULTS: The most accredited hypothesis asserts that the main common risk factors, that is, cigarette smoke and ageing, elicit a chronic low-grade systemic inflammatory response, which affects both cardiovascular endothelial cells and airways/lung parenchyma. The development of CAD in patients with COPD potentiates the morbidity of COPD, leading to increased hospitalizations, mortality and health costs. Moreover, correct diagnosis is challenging and therapies are not clearly defined. CONCLUSIONS: Evidence from recently published articles highlights the importance of multimorbidity in patient management and future research. Moreover, many authors emphasize the importance of low-grade systemic inflammation as a common pathological mechanism and a possible future therapeutic target. PMID- 24164256 TI - Methylglyoxal induces oxidative stress and mitochondrial dysfunction in osteoblastic MC3T3-E1 cells. AB - Methylglyoxal is a reactive dicarbonyl compound produced by glycolytic processing and identified as a precursor of advanced glycation end products. The elevated methylglyoxal levels in patients with diabetes are believed to contribute to diabetic complications, including bone defects. The objective of this study was to evaluate the effect of methylglyoxal on the function of osteoblastic MC3T3-E1 cells. The data indicated that methylglyoxal decreased osteoblast differentiation and induced osteoblast cytotoxicity. Pretreatment of MC3T3-E1 cells with aminoguanidine (a carbonyl scavenger), Trolox (an antioxidant), and cyclosporin A (a blocker of the mitochondrial permeability transition pore) prevented methylglyoxal-induced cytotoxicity in MC3T3-E1 cells. However, BAPTA/AM (an intracellular Ca(2+) chelator) and dantrolene (an inhibitor of endoplasmic reticulum Ca(2+) release) did not reverse the cytotoxic effect of methylglyoxal. Methylglyoxal increased the formation of intracellular reactive oxygen species, mitochondrial superoxide, and cardiolipin peroxidation in osteoblastic MC3T3-E1 cells. Methylglyoxal also decreased the mitochondrial membrane potential and intracellular ATP and nitric oxide levels, suggesting that carbonyl stress induced loss of mitochondrial integrity contributes to the cytotoxicity of methylglyoxal. Furthermore, the results demonstrated that methylglyoxal induced protein adduct formation, inactivation of glyoxalase I, and activation of glyoxalase II. Aminoguanidine reversed all aforementioned effects of methylglyoxal. Taken together, these data support the notion that high methylglyoxal concentrations have detrimental effects on osteoblasts through a mechanism involving oxidative stress and mitochondrial dysfunction. PMID- 24164257 TI - A robust Ni(II) alpha-diimine catalyst for high temperature ethylene polymerization. AB - Sterically demanding Ni(II) alpha-diimine precatalysts were synthesized utilizing 2,6-bis(diphenylmethyl)-4-methyl aniline. When activated with methylaluminoxane, the catalyst NiBr2(ArN?C(Me)-C(Me)?NAr) (Ar = 2,6 bis(diphenylmethyl)-4 methylbenzene) was highly active, produced well-defined polyethylene at temperatures up to 100 degrees C (Mw/Mn = 1.09-1.46), and demonstrated remarkable thermal stability at temperatures appropriate for industrially used gas-phase polymerizations (80-100 degrees C). PMID- 24164258 TI - An endurance-enhancing effect of peanut meal protein hydrolysate in mice: possible involvement of a specific peanut peptide. AB - To improve the functional properties of peanut meal protein for wide utilization, hydrolysis was conducted by alcalase. Compared with saline and peanut meal protein, intragastric administration of low molecular weight (<1 kD) peanut meal peptide (PPH I) could significantly prolong swimming time, increase levels of blood sugar, non-esterified fatty acids (NEFA) and liver glycogen and decrease blood lactate content in mice. Levels of Pro, Leu, Val and His in low molecular weight peanut meal peptides were higher significantly than those in other peanut meal protein hydrolysates. Hydrophobic amino acids, such as Pro, Tyr and His, could perhaps capture free radical and increase antioxidant capacity of peanut peptide and retard fatigue induced by free radical. After separation by HPLC, a primary peptide P1, Pro-Glu-Ile-Glu-Val, was sequenced. Its N-terminal was Val, and it was rich in antioxidant amino acid, Pro and Ile. Levels of plasma glucose, NEFA and liver glycogen in PPH I group were higher than those in mice intragastric administration with peptide P1, and the swimming time is longer in PPH I group than in P1 group. So, the high content of P1 was one of the reason why PPH I had high endurance-enhancing capacity. PMID- 24164259 TI - Structural identification of DnaK binding sites within bovine and sheep bactenecin Bac7. AB - Bacterial resistance against common antibiotics is an increasing health problem. New pharmaceuticals for the treatment of infections caused by resistant pathogens are needed. Small proline-rich antimicrobial peptides (PrAMPs) from insects are known to bind intracellularly to the conventional substrate binding cleft of the E. coli Hsp70 chaperone DnaK. Furthermore, bactenecins from mammals, members of the cathelicidin family, also contain potential DnaK binding sites. Crystal structures of bovine and sheep Bac7 in complex with the DnaK substrate binding domain show that the peptides bind in the forward binding mode with a leucine positioned in the central hydrophobic pocket. In most structures, proline and arginine residues preceding leucine occupy the hydrophobic DnaK binding sites -1 and -2. Within bovine Bac7, four potential DnaK binding sites were identified. PMID- 24164260 TI - Blood-brain barrier transport of short proline-rich antimicrobial peptides. AB - Infections by antibiotic-resistant bacteria are becoming a great risk for human health, leading to an urgent need for new efficient antibacterial therapies. The short, proline-rich antimicrobial peptides from insects gained a lot of interest as a potential antibacterial treatment, having a low toxicity profile and being mainly active against Gram-negative bacteria. To know whether these antimicrobial peptides can be used for the treatment of cerebral infections, the blood-brain barrier transport characteristics of these peptides were investigated. This study describes the results of the in vivo blood-brain barrier experiments in mice, as well as the in vitro metabolic stability in mouse plasma and brain of apidaecin Api137, oncocin, drosocin and drosocin Pro5Hyp. The four investigated peptides showed a significant influx into the brain with a K(in) ranging between 0.37 and 0.86 uL/g x min and brain distribution volumes of 19.6 to 25.8 uL/g. Only for drosocin, a significant efflux was determined, with a k(out) of 0.22 min(-1). After entering the brain, oncocin was for approximately 80% trapped in the endothelial cells, while the other peptides reached the brain parenchyma for about 70%. All peptides were stable in plasma and brain during the experiments, with estimated metabolic half-lives ranging between 47 min and 637 min. We conclude that the investigated short, proline-rich antimicrobial peptides show an influx into the brain, which make them a promising antibacterial treatment of cerebral infections. PMID- 24164261 TI - Cellular internalization and cytotoxicity of the antimicrobial proline-rich peptide Bac7(1-35) in monocytes/macrophages, and its activity against phagocytosed Salmonella typhimurium. AB - Bac7(1-35) is an active fragment of the bovine cathelicidin antimicrobial peptide Bac7, which selectively inactivates Gram-negative bacteria both in vitro and in mice infected with Salmonella typhimurium. It has a non-lytic mechanism of action, is rapidly internalized by susceptible bacteria and mammalian cells and likely acts by binding to internal targets. In this study we show that Bac7(1-35) accumulates selectively within primed macrophages with respect to resting monocytes. Confocal microscopy analysis showed that the peptide mainly distributes in the cytoplasm and perinuclear region of macrophages within 3 hours of incubation, without affecting cell viability. Cytotoxicity studies showed that the peptide does not induce necrotic or apoptotic damage up to concentrations 50 100-fold higher than minimal inhibitory concentrations (MIC). Moreover, Bac7(1 35) did not affect the ability of macrophages to engulf S. typhimurium, a species that may proliferate within this cell type. Conversely, when added to macrophages after phagocytosis, Bac7(1-35) caused a significant reduction in the number of recovered bacteria, indicating that it can kill the engulfed microorganisms directly and/or indirectly, via activation of the defense response of the cells. PMID- 24164262 TI - The designer proline-rich antibacterial peptide A3-APO prevents Bacillus anthracis mortality by deactivating bacterial toxins. AB - Proline-rich antibacterial peptides protect experimental animals from bacterial challenge even if they are unable to kill the microorganisms in vitro. Their major in vivo modes of action are inhibition of bacterial protein folding and immunostimulation. Here we investigated whether the proline-rich antibacterial peptide dimer A3-APO was able to inhibit Bacillus cereus enterotoxin production in vitro and restrict the proliferation of lethal toxin-induced Bacillus anthracis replication in mouse macrophages. After 24 h incubation, peptide A3-APO and its single chain metabolite reduced the amount of properly folded B. cereus diarrhoeal enterotoxin production in a concentration-dependent manner leading to only 10-25% of the original amount of toxin detectable by a conformation sensitive immunoassay. Likewise, after 4 h incubation, A3-APO restricted the proliferation of B. anthracis in infected macrophages by 40-45% compared to untreated cells both intracellularly and in the extracellular cell culture milieu. Although the peptide had a minimal inhibitory concentration of >512 mg/L against B. anthracis in vitro, in systemic mouse challenge models it improved survival by 20- 37%, exhibiting statistically significant cumulative efficacy when administered at 3x5 mg/kg intraperitoneally or intramuscularly. We hypothesize that the activity in isolated murine macrophages and in vivo is due to deactivation of bacterial toxins. Bacterial protein folding inhibition in synergy with other types of antimicrobial modes offers a remarkable novel strategy in combating resistant or life-threatening infections. PMID- 24164263 TI - In vivo activity of optimized apidaecin and oncocin peptides against a multiresistant, KPC-producing Klebsiella pneumoniae strain. AB - The peptides Api88 and Onc72 are highly efficient to treat Escherichia coli bacteremia in mice. Here we extended the animal studies to a systemic murine infection model using a multidrug-resistant carbapenemase-producing Klebsiella pneumoniae clinical isolate. When administered intraperitoneally three times at 2.5, 5 and 10 mg/kg bodyweight to CD-1 mice infected with a KPC-producing K. pneumoniae strain, both Api88 and Onc72 reduced the bacterial counts by at least 5 log10 units, indicating that both peptides are active in vivo. Both peptide treatments increased significantly the survival rates and average survival times compared to untreated animals for all doses except for the highest dose of Onc72. This dose reduced the bacterial counts so fast that it most likely induced a sudden release of large amounts of toxic materials from the killed bacteria reducing the survival time even below that of untreated mice. In conclusion, both peptides were efficient in the lethal murine K. pneumoniae infection model, but the treatment protocol (i.e. dose and time points) has to be further optimized based on future pharmacokinetic studies. PMID- 24164264 TI - Antimicrobial resistance in the 21st century: a multifaceted challenge. AB - Antimicrobial resistance, the ability of (pathogenic) bacteria to withstand the action of antibiotic drugs, has recently been rated of having an impact on humans similar to that of global climate change. Indeed, during the last years medicine has faced the development of highly resistant bacterial strains, which were, as a consequence of worldwide travel activity, dispersed all over the globe. This is even more astonishing if taking into account that antibiotics were introduced into human medicine not even hundred years ago. Resistance covers different principle aspects, natural resistance, acquired resistance and clinical resistance. In the modern microbiology laboratory, antimicrobial resistance is determined by measuring the susceptibility of micro-organisms in vitro in the presence of antimicrobials. However, since the efficacy of an antibiotic depends on its pharmacokinetic and pharmacodynamics properties, breakpoints are provided to translate minimal inhibitory concentration to categorical efficacy (i.e. susceptible or resistant). Resistance in one microorganism against one particular drug may drive treatment decisions of clinicians, thereby fostering selection pressure to resistance development against another antibiotic. Thereby, bacteria may acquire more and more resistance traits, ending up with multi-resistance. To this end, antimicrobial resistance becomes a public health concern, not only in terms of limited treatment options but also due to its economic burden. The current paper provides a summary of the main topics associated with antimicrobial resistance as an introduction to this special issue. PMID- 24164265 TI - Hydroxyproline substitutions stabilize non-glycosylated drosocin against serum proteases without challenging its antibacterial activity. AB - The increasing incidence of multi- and pan-resistant pathogens demands novel compounds to fight Grampositive and especially Gram-negative bacteria. Among the currently investigated compound classes, antimicrobial peptides (AMPs) inhibiting specific bacterial targets appear especially promising for systemic therapy of infections, although unmodified linear peptides are typically rapidly degraded by serum proteases. Proline-rich AMPs have been heavily investigated in recent years due to their low toxicity and proven in vivo efficacy. Here, we report novel unglycosylated drosocin analogs with extended half-life in mouse serum and improved activity against Gram-negative pathogens Escherichia coli and Klebsiella pneumoniae. Substituting proline (Pro) residues in positions 3, 5, 10, and 14 with trans-4-hydroxy-Lproline ((t)Hyp) improved the antibacterial activity, whereas substitution of Pro-16 reduced the activity. Drosocin analogs with (t)Hyp in positions 3 and 5 were also four to eight times more stable in mouse serum than the unmodified analog. The new compounds were not toxic against human HeLa, HEK293, and HepG2 cell lines and showed no hemolytic activity against human erythrocytes at peptide concentrations of at least 600 ug/mL. PMID- 24164266 TI - Cellular uptake of apidaecin 1b and related analogs in Gram-negative bacteria reveals novel antibacterial mechanism for proline-rich antimicrobial peptides. AB - Proline-rich antimicrobial peptides (PrAMPs) freely penetrate through the outer membrane into the periplasm of Gram-negative bacteria, before they are actively translocated by a permease/transporter-mediated uptake into the cytoplasm where they are reported to inhibit chaperone DnaK. Here we have studied the PrAMP apidaecin 1b, which is produced in honey bees in response to bacterial infections, and optimized apidaecin analogs for their bacterial uptake. The peptides were labeled with 5(6)-carboxyfluorescein and their internalization in Escherichia coli and Klebsiella pneumoniae was visualized by fluorescence microscopy and quantified by flow cytometry for four different time points over an incubation period of 4 h. Apidaecin 1b entered only 40% to 50% of the cells at detectable quantities, whereas designer peptides Api88, Api134 and Api155 entered more than 95% of the bacteria within 30 min at around fourfold higher quantities than the native peptide. Interestingly, a shortened version designated as (1 17)Api88, bound DnaK as efficiently as the 18-residue long Api88 and entered the bacteria at similar kinetics as Api88, but was unable to inhibit the bacterial growth. Similar conflicts with currently proposed mechanisms of PrAMPs were also obtained for some Ala-substituted analogs and reverse apidaecin sequences. Although peptides with C-terminal amides enter the cells much more efficiently than homologous C-terminal acids, this improved cell penetration does not improve the antibacterial activities. These studies suggest that PrAMPs utilize additional modes of action to kill sensitive organisms. PMID- 24164267 TI - Antimicrobial peptides incorporating non-natural amino acids as agents for plant protection. AB - The control of plant pathogens is mainly based on copper compounds and antibiotics. However, the use of these compounds has some limitations. They have a high environmental impact and the use of antibiotics is not allowed in several countries. Moreover, resistance has been developed to these pathogens. The identification of new agents able to fight plant pathogenic bacteria and fungi will represent an alternative to currently used antibiotics or pesticides. Antimicrobial peptides are widely recognized as promising candidates, however naturally occurring sequences present drawbacks that limit their development. These include susceptibility to protease degradation and low bioavailability. To overcome these problems, research has focused on the introduction of unnatural amino acids into lead peptide sequences. In particular, we have improved the biological profile of antimicrobial peptides active against plant pathogenic bacteria and fungi by incorporating triazolyl, biaryl and D-amino acids into their sequence. These modifications and their influence on the biological activity are summarized. PMID- 24164268 TI - Dual mode of action of amylolysin: a type-B lantibiotic produced by Bacillus amyloliquefaciens GA1. AB - The partial genome sequencing of Bacillus amyloliquefaciens GA1 led to the identification of the aml gene cluster involved in the synthesis of the novel lantibiotic named amylolysin. Pure amylolysin was shown to have an antibacterial activity toward Gram-positive bacteria including methicillin resistant Staphylococcus aureus. The lantibiotic was also found efficient to inhibit the growth of Listeria monocytogenes strains on poultry meat upon a long storage at 4 degrees C. In silico analyses of the aml gene cluster revealed the presence of a characteristic motif involved in interaction with peptidoglycan precursor lipid II. In the present work, this interaction was further investigated using the LiaRS based reporter gene that is able to sense specifically antibiotics that interfere with lipid II cycle. Beside this, the pore-forming ability of amylolysin was evidenced by means of membrane depolarization measurements and cell leaking experiments. PMID- 24164269 TI - In vitro and in vivo activities of novel cyclic lipopeptides against staphylococcal biofilms. AB - A worldwide public health problem has resulted from the alarming spread of multi drug resistant bacteria combined with the frequent occurrence of biofilm-type infections, creating a growing need for new therapies. In this study, we have demonstrated that novel cyclic lipopeptides, such as 1, cyclo-[D-Ala-(12 guanidinododecanoyl)Thr-D-Val-Val-DaThr-D-Asn], and 2, cyclo-[D-Ala-(12 guanidinododecanoyl)Dap-D-Val-Val-D-aThr-D-Asn], derived from the fusaricidin/ LI F natural products efficiently inhibit the growth of Staphylococcus aureus biofilm in vitro at their minimum inhibitory concentrations (MICs). Complete S. aureus biofilm eradication was observed at 3 x MIC for 1 and 4 x MIC for 2. Promising in vivo activity was demonstrated by the ability of depsipeptide 1 to reduce the proliferation of methicillinresistant S. aureus US300 in a porcine wound model. Due to their unique structure and potent antibacterial and antibiofilm activities, cyclic lipopeptides that belong to the fusaricidin/LI-F family of antibiotics represent particularly attractive lead structures for the development of new antibacterial agents capable of treating complicated biofilm associated infections. PMID- 24164270 TI - Regulation and function of antimicrobial peptides in immunity and diseases of the lung. AB - Cationic antimicrobial peptides (AMPs) are among the best studied antimicrobial factors expressed in the respiratory tract. AMPs are released by epithelial cells and immune cells into the airway surface liquid covering the epithelial surfaces of the lung where they act as endogenous antibiotics. Plenty of studies showed that AMPs possess additional, often immunomodulatory functions besides their antimicrobial activities. AMPs are chemotactic for immune cells and modulate cellular mechanisms, such as proliferation of epithelial cells, epithelial regeneration, and angiogenesis. The expression and activity of AMPs are impacted by lung diseases and AMPs can have adverse effects in lung diseases. In this review, we discuss the regulation and functions of AMPs in host defense and respiratory tract diseases. PMID- 24164271 TI - IMAP 2012: Antimicrobial peptides to combat (multi)drug-resistant pathogens. PMID- 24164272 TI - Effect of ultra-low-dose estradiol and dydrogesterone on arterial stiffness in postmenopausal women. AB - Abstract Background Ultra-low-dose estradiol is known to improve menopausal symptoms and increase bone mineral density. However, the effect of ultra-low-dose estradiol on vascular function has not been clarified. Objectives We examined the effects of ultra-low-dose estradiol on brachial-ankle pulse wave velocity (baPWV) and circulating markers of cardiovascular risk. Patients and methods Twenty-eight postmenopausal women were enrolled in this study. Fourteen women received oral estradiol (0.5 mg) and dydrogesterone (5 mg) every day for 12 months (ultra-low dose group) as hormone replacement therapy (HRT) and 14 women as a control group did not receive HRT. The baPWV, lipid profiles, homeostasis model assessment of insulin resistance (HOMA-IR) and vascular inflammatory markers were measured. Results The baPWV level significantly decreased in the ultra-low-dose group (p = 0.037), while the baPWV level did not significantly change in the control group. HOMA-IR tended to decrease in the ultra-low-dose group (p = 0.076). Systolic blood pressure and diastolic blood pressure did not change significantly in either group. Conclusion An HRT regimen using oral ultra-low-dose estradiol and dydrogesterone has an effect on arterial stiffness and insulin resistance. PMID- 24164273 TI - Insight into highly efficient coremoval of copper and p-nitrophenol by a newly synthesized polyamine chelating resin from aqueous media: competition and enhancement effect upon site recognition. AB - Highly efficient coremoval of Cu(II) and p-nitrophenol (PNP) was accomplished using a newly synthesized polyamine chelating resin (CEAD) as compared to three other commercial resins. The mutual effects and inner mechanisms of their adsorption onto CEAD were systematically investigated by binary, preloading, thermodynamic, and dynamic adsorption procedures. PNP was adsorbed onto both hydrophobic and hydrophilic sites, while Cu(II) only interacted with hydrophilic amine group sites. In both preloading and binary systems, the adsorption of PNP was inhibited to the same degree by the presence of Cu(II) because of selective recognition and direct competition. On the other hand, the presence of PNP obviously enhanced the adsorption of Cu(II) by more than 7%, which was related to PNP loading on the hydrophobic surface. As proved by structural characterization, hydroxyl groups facing outward create new sites for coordination with Cu(II). Moreover, ionic strength exerted some positive influence on the properties of CEAD. Finally, more than 98% of PNP and 99% of Cu(II) could be sequentially recovered with dilute NaClO3 and HCl. These superior properties demonstrated with CEAD indicate that it could be applied to wastewaters containing both heavy metals and PNP, even for high saline aqueous media. PMID- 24164274 TI - Electrodiffusion kinetics of ionic transport in a simple membrane channel. AB - We employ numerical techniques for solving time-dependent full Poisson-Nernst Planck (PNP) equations in 2D to analyze transient behavior of a simple ion channel subject to a sudden electric potential jump across the membrane (voltage clamp). Calculated spatiotemporal profiles of the ionic concentrations and electric potential show that two principal exponential processes can be distinguished in the electrodiffusion kinetics, in agreement with original Planck's predictions. The initial fast process corresponds to the dielectric relaxation, while the steady state is approached in a second slower exponential process attributed to the nonlinear ionic redistribution. Effects of the model parameters such as the channel length, height of the potential step, boundary concentrations, permittivity of the channel interior, and ionic mobilities on electrodiffusion kinetics are studied. Numerical solutions are used to determine spatiotemporal profiles of the electric field, ionic fluxes, and both the conductive and displacement currents. We demonstrate that the displacement current is a significant transient component of the total electric current through the channel. The presented results provide additional information about the classical voltage-clamp problem and offer further physical insights into the mechanism of electrodiffusion. The used numerical approach can be readily extended to multi-ionic models with a more structured domain geometry in 2D or 3D, and it is directly applicable to other systems, such as synthetic nanopores, nanofluidic channels, and nanopipettes. PMID- 24164275 TI - Twenty years on: Cochrane and nursing. PMID- 24164277 TI - Comparative studies of the binding of six phthalate plasticizers to pepsin by multispectroscopic approach and molecular modeling. AB - To explore the binding mechanism of phthalate plasticizers with digestive proteases, their effects on conformation and activity of pepsin by multispectroscopic approach and molecular modeling were investigated. Fluorescence spectra combined with UV-vis and circular dichroism (CD) spectra measurements indicated that the six phthalate plasticizers induced the changes of tertiary and secondary structure of pepsin. The solvent polarity of environment around both Trp and Tyr residues on pepsin were affected by phthalate plasticizers. By analyzing the fluorescence quenching and theoretical calculation data, it was concluded that a binding site exists for each phthalate plasticizer in pepsin with different binding ability. The hydrophobic, hydrogen bonding, and pi-pi stacking interactions were involved in the interactions between pepsin and phthalate plasticizers. Moreover, the activity assay indicated that phthalate plasticizers were not powerfully inhibitors or activators for pepsin. These studies demonstrated that phthalate plasticizers could cause some negative effects on pepsin. The present studies may provide a way to analyze the biological safety of phthalate plasticizers on digestive proteases or other proteins. PMID- 24164278 TI - A comparison of marginal and conditional models for capture-recapture data with application to human rights violations data. AB - Human rights data presents challenges for capture-recapture methodology. Lists of violent acts provided by many different groups create large, sparse tables of data for which saturated models are difficult to fit and for which simple models may be misspecified. We analyze data on killings and disappearances in Casanare, Colombia during years 1998 to 2007. Our estimates differ whether we choose to model marginal reporting probabilities and odds ratios, versus modeling the full reporting pattern in a conditional (log-linear) model. With 2629 observed killings, a marginal model we consider estimates over 9000 killings, while conditional models we consider estimate 6000-7000 killings. The latter agree with previous estimates, also from a conditional model. We see a twofold difference between the high sample coverage estimate of over 10,000 killings and low sample coverage lower bound estimate of 5200 killings. We use a simulation study to compare marginal and conditional models with at most two-way interactions and sample coverage estimators. The simulation results together with model selection criteria lead us to believe the previous estimates of total killings in Casanare may have been biased downward, suggesting that the violence was worse than previously thought. Model specification is an important consideration when interpreting population estimates from capture recapture analysis and the Casanare data is a protypical example of how that manifests. PMID- 24164279 TI - Self-assembly of graphene oxide with a silyl-appended spiropyran dye for rapid and sensitive colorimetric detection of fluoride ions. AB - Fluoride ion (F(-)), the smallest anion, exhibits considerable significance in a wide range of environmental and biochemical processes. To address the two fundamental and unsolved issues of current F(-) sensors based on the specific chemical reaction (i.e., the long response time and low sensitivity) and as a part of our ongoing interest in the spiropyran sensor design, we reported here a new F(-) sensing approach that, via assembly of a F(-)-specific silyl-appended spiropyran dye with graphene oxide (GO), allows rapid and sensitive detection of F(-) in aqueous solution. 6-(tert-Butyldimethylsilyloxy)-1',3',3'-trimethylspiro [chromene- 2,2'-indoline] (SPS), a spiropyran-based silylated dye with a unique reaction activity for F(-), was designed and synthesized. The nucleophilic substitution reaction between SPS and F(-) triggers cleavage of the Si-O bond to promote the closed spiropyran to convert to its opened merocyanine form, leading to the color changing from colorless to orange-yellow with good selectivity over other anions. With the aid of GO, the response time of SPS for F(-) was shortened from 180 to 30 min, and the detection limit was lowered more than 1 order of magnitude compared to the free SPS. Furthermore, due to the protective effect of nanomaterials, the SPS/GO nanocomposite can function in a complex biological environment. The SPS/GO nanocomposite was characterized by XPS and AFM, etc., and the mechanism for sensing F(-) was studied by (1)H NMR and ESI-MS. Finally, this SPS/GO nanocomposite was successfully applied to monitoring F(-) in the serum. PMID- 24164280 TI - Inhibition of ErbB-2 induces TFF3 downregulation in breast cancer cell lines. AB - ErbB-2 gene plays an important role in carcinoma formation whose overexpression was observed in many types of tumors, including breast cancer. Dysregulation of Trefoil factor 3 (TFF3), which is thought to function in the development and progression of breast cancer, was found to be upregulated in ErbB2-overexpressing breast cancers and cells. However, a putative interaction between ErbB-2 and TFF3 in breast cancer remains unknown. To determine whether TFF3 has an important role in breast tumor, its levels were measured by immunohistochemistry in 130 cases of breast infiltrating duct carcinoma and 30 cases of normal breast tissue with a specific monoclonal antibody raised against human TFF3. Patients who were positive for ErbB-2 also had high expression levels of TFF3 (p < 0.05). Also, after infecting the SK-BR-3 cells with lentivirus-mediated ErbB2-specific shRNA (Lenti-ShERBB2), we detected the expressions of ErbB-2 and TFF3 by real-time polymerase chain reaction and Western blotting, respectively. Compared with the control groups, ErbB-2 mRNA expression was decreased in the Lenti-ShERBB2 infection group, and Western blotting indicated a concordant ErbB-2 protein reduction. On the other hand, TFF3 expression at both mRNA and protein levels was significantly downregulated by ErbB-2 silencing in SK-BR-3. These findings are a proof of the foundation for a certain relationships of ErbB-2 and TFF3, which may serve as novel therapeutic markers of ErbB2-overexpressing breast cancers in the future. PMID- 24164281 TI - Prenatal assessment of a fast-growing giant epignathus. AB - Epignathus is a very rare fetal tumor. We report a case of fast-growing giant epignathus with severe distortion of the right part of the face and orbit. A thorough prenatal work-up was performed by the association of Magnetic Resonance Imaging and Ultrasonography. A multidisciplinary approach was crucial to assess the operability and provide careful counseling to help parents understand and reach decision. PMID- 24164282 TI - 25-Hydroxyvitamin D status, arterial stiffness and the renin-angiotensin system in healthy humans. AB - Vitamin D deficiency is associated with increased arterial stiffness. We sought to clarify the influence of vitamin D in modulating angiotensin II-dependent arterial stiffness. Thirty-six healthy subjects (33 +/- 2 years, 67% female, mean 25-hydroxyvitamin D 69 +/- 4 nmol/L) were studied in high salt balance. Arterial stiffness, expressed as brachial pulse wave velocity (bPWV) and aortic augmentation index (AIx), was measured by tonometry at baseline and in response to angiotensin II infusion (3 ng/kg/min * 30 min then 6 ng/kg/min * 30 min). The primary outcome was change in bPWV after an angiotensin II challenge. Results were analyzed according to plasma 25-hydroxyvitamin D status: deficient (<50 nmol/L) and sufficient (>= 50 nmol/L). There were no differences in baseline arterial stiffness between vitamin D deficient (25-hydroxyvitamin D 40 +/- 2 nmol/L) and sufficient (25-hydroxyvitamin D 80 +/- 4 nmol/L) groups. Compared with sufficient vitamin D status, vitamin D deficiency was associated with a decreased arterial response to angiotensin II challenge (Deltabrachial pulse wave velocity: 0.48 +/- 0.44 m/s versus 1.95 +/- 0.22 m/s, p=0.004; Deltaaortic augmentation index: 9.4 +/- 3.4% versus 14.2 +/- 2.7%, p=0.3), which persisted for brachial pulse wave velocity response after adjustment for covariates (p=0.03). Vitamin D deficiency is associated with increased arterial stiffness in healthy humans, possibly through an angiotensin II-dependent mechanism. PMID- 24164283 TI - Streptomycin use in apple orchards did not increase abundance of mobile resistance genes. AB - Streptomycin is used as a first-line defense and tetracycline as a second-line defense, in the fight against fire blight disease in apple and pear orchards. We have performed the first study to quantitatively analyze the influence of streptomycin use in agriculture on the abundance of streptomycin and tetracycline resistance genes in apple orchards. Flowers, leaves, and soil were collected from three orchard sites in 2010, 2011, and 2012. Gene abundance distribution was analyzed using two-way anova and principal component analysis to investigate relationships between gene abundance data over time and treatment. The mobile antibiotic resistance genes, strA, strB, tetB, tetM, tetW, and the insertion sequence IS1133, were detected prior to streptomycin treatment in almost all samples, indicating the natural presence of these resistance genes in nature. Statistically significant increases in the resistance gene abundances were occasional, inconsistent, and not reproducible from one year to the next. We conclude that the application of streptomycin in these orchards was not associated with sustained increases in streptomycin or tetracycline resistance gene abundances. PMID- 24164285 TI - Silica nanoparticles for micro-particle imaging velocimetry: fluorosurfactant improves nanoparticle stability and brightness of immobilized iridium(III) complexes. AB - To establish highly luminescent nanoparticles for monitoring fluid flows, we examined the preparation of silica nanoparticles based on immobilization of a cyclometalated iridium(III) complex and an examination of the photophysical studies provided a good insight into the Ir(III) microenvironment in order to reveal the most suitable silica nanoparticles for micro particle imaging velocimetry (MU-PIV) studies. Iridium complexes covalently incorporated at the surface of preformed silica nanoparticles, [Ir-4]@Si500-Z, using a fluorinated polymer during their preparation, demonstrated better stability than those without the polymer, [Ir-4]@Si500, as well as an increase in steady state photoluminescence intensity (and therefore particle brightness) and lifetimes which are increased by 7-fold compared with nanoparticles with the same metal complex attached covalently throughout their core, [Ir-4]?Si500. Screening of the nanoparticles in fluid flows using epi-luminescence microscopy also confirm that the brightest, and therefore most suitable particles for microparticle imaging velocimetry (MU-PIV) measurements are those with the Ir(III) complex immobilized at the surface with fluorosurfactant, that is [Ir-4]@Si500-Z. MU-PIV studies demonstrate the suitability of these nanoparticles as nanotracers in microchannels. PMID- 24164284 TI - Amphibole, but not chrysotile, asbestos induces anti-nuclear autoantibodies and IL-17 in C57BL/6 mice. AB - Abstract Exposure to amphibole asbestos has been associated with production of autoantibodies in mice and humans, and increases the risk of systemic autoimmune disease. However, epidemiological studies of chrysotile exposure have not indicated a similar induction of autoimmune responses. To demonstrate this difference in controlled exposures in mice, and to explore possible mechanistic explanations for the difference, C57BL/6 mice were exposed intratracheally to amphibole or chrysotile asbestos, or to saline only. Serum antinuclear antibodies (ANA), antibodies to extractable nuclear antigens (ENA), serum cytokines, and immunoglobulin isotypes were evaluated 8 months after the final treatment. The percentages of lymphocyte sub-sets were determined in the spleen and lungs. The results show that amphibole, but not chrysotile, asbestos increases the frequency of ANA/ENA in mice. Amphibole and chrysotile both increased multiple serum cytokines, but only amphibole increased IL-17. Both fibers decreased IgG1, without significant changes in other immunoglobulin isotypes. Although there were no gross changes in overall percentages of T- and B-cells in the spleen or lung, there was a significant increase in the normally rare populations of suppressor B cells (CD19(+), CD5(+), CD1d(+)) in both the spleen and lungs of chrysotile exposed mice. Overall, the results suggest that, while there may be an inflammatory response to both forms of asbestos, there is an autoimmune response in only the amphibole-exposed, but not the chrysotile-exposed mice. These data have critical implications in terms of screening and health outcomes of asbestos exposed populations. PMID- 24164287 TI - Prenatal exposure to acid-suppressive drugs and the risk of allergic diseases in the offspring: a cohort study. AB - BACKGROUND: Recent studies reported increased risks for the development of asthma in children after prenatal exposure to acid-suppressive drugs. As a result of common pathogenesis, associations could also be present for other allergic diseases. METHODS: Using the prescription database IADB.nl, we conducted a cohort study amongst 33 536 children in the Netherlands, with a maximum follow-up of 8 years. Maternal exposure was defined as >=1 dispensed prescription for proton pump inhibitors (PPIs) and/or Histamine 2-antagonists (H2As) during pregnancy. Children were considered to have a drug-treated allergic disease if they received either >=2 prescriptions for dermal (atopic dermatitis), inhaled (asthma) or nasal (allergic rhinitis) steroids within a 12-month period. Clustered Cox proportional hazard regression was used to estimate crude and adjusted hazard ratios (aHR) with 95% confidence intervals (95% CI). RESULTS: The aHR for the development of any allergic disease was 1.37 (95% CI: 1.14-1.66) for children exposed to PPIs or H2As. Prenatal exposure to PPIs and/or H2As was associated with atopic dermatitis, asthma and allergic rhinitis with aHRs of 1.32 (95% CI 1.06-1.64), 1.57 (95% CI 1.20-2.05) and 2.40 (95% CI 1.42-4.04), respectively. The aHR for the development of two or more (aHR 2.13 95% CI: 1.43-3.19) and three allergic diseases (aHR 5.18 95% CI: 2.16-12.42) were even more elevated after prenatal exposure to PPIs or H2As. CONCLUSION: Prenatal exposure to PPIs and H2As appeared associated with an increased risk for the development of atopic dermatitis, asthma and allergic rhinitis in the offspring, especially with the development of multiple allergic diseases. Because our study has limitations inherent to observational studies, prospective studies are now warranted to confirm our findings. PMID- 24164286 TI - Allosteric inhibition of the NS2B-NS3 protease from dengue virus. AB - Dengue virus is the flavivirus that causes dengue fever, dengue hemorrhagic disease, and dengue shock syndrome, which are currently increasing in incidence worldwide. Dengue virus protease (NS2B-NS3pro) is essential for dengue virus infection and is thus a target of therapeutic interest. To date, attention has focused on developing active-site inhibitors of NS2B-NS3pro. The flat and charged nature of the NS2B-NS3pro active site may contribute to difficulties in developing inhibitors and suggests that a strategy of identifying allosteric sites may be useful. We report an approach that allowed us to scan the NS2B NS3pro surface by cysteine mutagenesis and use cysteine reactive probes to identify regions of the protein that are susceptible to allosteric inhibition. This method identified a new allosteric site utilizing a circumscribed panel of just eight cysteine variants and only five cysteine reactive probes. The allosterically sensitive site is centered at Ala125, between the 120s loop and the 150s loop. The crystal structures of WT and modified NS2B-NS3pro demonstrate that the 120s loop is flexible. Our work suggests that binding at this site prevents a conformational rearrangement of the NS2B region of the protein, which is required for activation. Preventing this movement locks the protein into the open, inactive conformation, suggesting that this site may be useful in the future development of therapeutic allosteric inhibitors. PMID- 24164288 TI - Skin and plasma autofluorescence during hemodialysis: a pilot study. AB - Skin autofluorescence (AF) is related to the accumulation of advanced glycation end products (AGEs) and is one of the strongest prognostic markers of mortality in hemodialysis (HD) patients. The aim of this pilot study was to investigate whether changes in skin AF appear after a single HD session and if they might be related to changes in plasma AF. Skin and plasma AF were measured before and after HD in 35 patients on maintenance HD therapy (nine women and 26 men, median age 68 years, range 33-83). Median dialysis time was 4 h (range 3-5.5). Skin AF was measured noninvasively with an AGE Reader, and plasma AF was measured before and after HD at 460 nm after excitation at 370 nm. The HD patients had on average a 65% higher skin AF value than age-matched healthy persons (P < 0.001). Plasma AF was reduced by 14% (P < 0.001), whereas skin AF was not changed after a single HD treatment. No significant influence of the reduced plasma AF on skin AF levels was found. This suggests that the measurement of skin AF can be performed during the whole dialysis period and is not directly influenced by the changes in plasma AF during HD. PMID- 24164289 TI - Identification and characterization of novel surfactins produced by fungal antagonist Bacillus amyloliquefaciens 6B. AB - The broad-spectrum fungal antagonist, Bacillus amyloliquefaciens 6B (BA6B), isolated from the Jakhao coast of Kutch, India, was investigated for its antifungal metabolites using mass spectrometry. The cyclic lipopeptides harvested from the cell-free fermentation broth of BA6B by acid precipitation and subsequently dissolved in methanol were subjected to liquid chromatography coupled with electrospray ionization mass spectrometry (LC-ESI-MS/MS) for their identification and sequence determination. The 26 types of surfactin variants were identified from the methanolic extract by LC-ESI-MS/MS analysis. Among 26 surfactin species, several new cyclic as well as acyclic surfactin variants based on the variation in the beta-hydroxy fatty acid (beta-OH FA) chain length and/or in amino acid positions 4, 5, 6, and 7 were identified. The mass spectrometric analysis of crude extract also enabled the identification of 11 unique molecular mass ions with minimum two or maximum four types of isobaric peptide variants. PMID- 24164290 TI - Immunodetection of a brown planthopper (Nilaparvata lugens Stal) salivary catalase-like protein into tissues of rice, Oryza sativa. AB - Saliva plays an important role in host plant-phloem-feeding insect molecular interactions. To better elucidate the role of insect saliva, a series of experiments were conducted to establish if catalase from the salivary glands of the brown planthopper (BPH; Nilaparvata lugens Stal) was secreted into rice host plant tissue during feeding. Catalase is the main enzyme that decomposes hydrogen peroxide (H2O2) at high concentrations. H2O2 is a part of the free radicals system that mediates important physiological roles including signalling and defence. Previous studies have suggested that H2O2 is involved in the rice endogenous response to BPH feeding. If, the BPH secretes catalase into host plant tissue this will counter the effects of H2O2, from detoxification to interfering with plant signalling and defence mechanisms. When BPHs were fed on a hopper resistant rice variety for 24 h, catalase activity in the salivary glands increased 3.5-fold compared with hoppers fed on a susceptible rice variety. Further supporting evidence of the effects of BPH catalase was demonstrated by immunodetection analyses where results from two independent sources: BPH-infested rice tissue and BPH-probed artificial diets, suggest that the BPH secretes catalase-like protein during feeding. The possible physiological roles of BPH secreted catalase are discussed. PMID- 24164291 TI - Negative urgency and ventromedial prefrontal cortex responses to alcohol cues: FMRI evidence of emotion-based impulsivity. AB - BACKGROUND: Recent research has highlighted the role of emotion-based impulsivity (negative and positive urgency personality traits) for alcohol use and abuse, but has yet to examine how these personality traits interact with the brain's motivational systems. Using functional magnetic resonance imaging (fMRI), we tested whether urgency traits and mood induction affected medial prefrontal responses to alcohol odors (AcO). METHODS: Twenty-seven social drinkers (mean age = 25.2, 14 males) had 6 fMRI scans while viewing negative, neutral, or positive mood images (3 mood conditions) during intermittent exposure to AcO and appetitive control (AppCo) aromas. RESULTS: Voxel-wise analyses (p < 0.001) confirmed [AcO > AppCo] activation throughout medial prefrontal cortex (mPFC) and ventromedial PFC (vmPFC) regions. Extracted from a priori mPFC and vmPFC regions and analyzed in Odor (AcO, AppCo) * Mood factorial models, AcO activation was greater than AppCo in left vmPFC (p < 0.001), left mPFC (p = 0.002), and right vmPFC (p = 0.01) regions. Mood did not interact significantly with activation, but the covariate of trait negative urgency accounted for significant variance in left vmPFC (p = 0.01) and right vmPFC (p = 0.01) [AcO > AppCo] activation. Negative urgency also mediated the relationship between vmPFC activation and both (i) subjective craving and (ii) problematic drinking. CONCLUSIONS: The trait of negative urgency is associated with neural responses to alcohol cues in the vmPFC, a region involved in reward value and emotion-guided decision-making. This suggests that negative urgency might alter subjective craving and brain regions involved in coding reward value. PMID- 24164292 TI - Addition of mesenchymal stem cells enhances the therapeutic effects of skeletal myoblast cell-sheet transplantation in a rat ischemic cardiomyopathy model. AB - INTRODUCTION: Functional skeletal myoblasts (SMBs) are transplanted into the heart effectively and safely as cell sheets, which induce functional recovery in myocardial infarction (MI) patients without lethal arrhythmia. However, their therapeutic effect is limited by ischemia. Mesenchymal stem cells (MSCs) have prosurvival/proliferation and antiapoptotic effects on co-cultured cells in vitro. We hypothesized that adding MSCs to the SMB cell sheets might enhance SMB survival post-transplantation and improve their therapeutic effects. METHODS AND RESULTS: Cell sheets of primary SMBs of male Lewis rats (r-SMBs), primary MSCs of human female fat tissues (h-MSCs), and their co-cultures were generated using temperature-responsive dishes. The levels of candidate paracrine factors, rat hepatocyte growth factor and vascular endothelial growth factor, in vitro were significantly greater in the h-MSC/r-SMB co-cultures than in those containing r SMBs only, by real-time PCR and enzyme-linked immunosorbent assay (ELISA). MI was generated by left-coronary artery occlusion in female athymic nude rats. Two weeks later, co-cultured r-SMB or h-MSC cell sheets were implanted or no treatment was performed (n=10 each). Eight weeks later, systolic and diastolic function parameters were improved in all three treatment groups compared to no treatment, with the greatest improvement in the co-cultured cell sheet transplantation group. Consistent results were found for capillary density, collagen accumulation, myocyte hypertrophy, Akt-signaling, STAT3 signaling, and survival of transplanted cells of rat origin, and were related to poly (ADP ribose) polymerase-dependent signal transduction. CONCLUSIONS: Adding MSCs to SMB cell sheets enhanced the sheets' angiogenesis-related paracrine mechanics and, consequently, functional recovery in a rat MI model, suggesting a possible strategy for clinical applications. PMID- 24164293 TI - Short- and long-term outcomes of endoscopic papillary large balloon dilation with or without sphincterotomy for removal of large bile duct stones. AB - OBJECTIVE: Removal of large bile duct stones by endoscopic papillary large balloon dilation (EPLBD) with endoscopic sphincterotomy (EST) has been proven safe and effective. Little evidence supports the benefits of a preceding EST in reducing complications. Recent studies suggest that large bile duct stone removal by EPLBD alone may be safe and effective. MATERIAL AND METHODS: We removed large bile duct stones by EPLBD with EST from March 2008 to February 2010 and without EST from March 2010 to October 2011. Efficacy and safety of EPLBD with or without EST and late biliary complication outcomes were assessed. RESULTS: Forty-two patients (men/women, 27/15; mean age, 76 years) underwent EPLBD: 14 underwent EPLBD with EST and 28 underwent EPLBD without EST. The mean stone size was 14 mm (9-30 mm). Overall complete stone removal rate was 98%, with 83% achieved in 1 session. Complete duct clearance by EPLBD alone was achieved in 79%. Mechanical lithotripsy was required in 4 (10%) patients. Extracorporeal shock wave lithotripsy and electrohydraulic lithotripsy were required in 4 (10%) and 1 (2%) patients, respectively. Pancreatitis and perforation occurred in 2 (5%) and 1 (2%) patients, respectively. Patients treated by EPLBD with EST and by EPLBD alone did not differ in complication outcomes. Six (14%) patients had recurrent bile duct stones, with a significant correlation to dilated common bile duct (p = 0.0351). CONCLUSIONS: EPLBD is safe and effective in patients with large bile duct stones. Preceding EST may be unnecessary. PMID- 24164294 TI - Visible-light-mediated nucleophilic addition of an alpha-aminoalkyl radical to isocyanate or isothiocyanate. AB - A visible-light photoredox synthesis of alpha-amino amide or alpha-amino thioamide from N,N-dimethylaniline derivatives and aryl isocyanate or aryl isothiocyanate was developed. Bis[2-(4,6-difluorophenyl)pyridinato C(2),N](picolinato)iridium(III) (FIrpic) was found to be the effective catalyst among six catalysts screened. The reaction involves generation of alpha aminoalkyl radicals from tertiary amines, followed by radical addition to the electron-deficient carbon of isocyanate and isothiocyanate. PMID- 24164295 TI - Patients with psoriasis have an increased amount of epicardial fat tissue. AB - BACKGROUND: Psoriasis is associated with coronary artery disease, and ischemic heart disease is associated with increased amounts of epicardial fat tissue (EFT). There has as yet been no study published on the accumulation of EFT in patients with psoriasis. AIM: To compare epicardial fat accumulation and coronary artery calcium score (CACS) in patients with psoriasis and controls. METHODS: We enrolled 38 patients with psoriasis and 38 controls matched for age and gender. Epicardial fat area (EFA) and CACS were evaluated by multidetector computed tomography. RESULTS: Mean EFA in patients with psoriasis was significantly higher than in controls (13.8 +/- 8.4 vs. 9.7 +/- 6.4 cm(2) , respectively, P = 0.02), but mean CACS did not differ significantly between the two groups (55.2 +/- 65.4 vs. 27.8 +/- 29.3; P > 0.05). Multiple linear regression analyses indicated that EFA was significantly associated with waist circumference and presence of coronary artery calcification in both patients and controls, whereas EFA was significantly associated waist circumference and age in patients only (P < 0.05). CONCLUSIONS: Patients with psoriasis had a higher level of EFA compared with controls, and EFA was independently associated with the presence of CAC in all study subjects. PMID- 24164296 TI - Morphology, mineralogy, and solid-liquid phase separation characteristics of Cu and Zn precipitates produced with biogenic sulfide. AB - The morphology, mineralogy, and solid-liquid phase separation of the Cu and Zn precipitates formed with sulfide produced in a sulfate-reducing bioreactor were studied at pH 3, 5, and 7. The precipitates formed at pH 7 display faster settling rates, better dewaterability, and higher concentrations of settleable solids as compared to the precipitates formed at pH 3 and 5. These differences were linked to the agglomeration of the sulfidic precipitates and coprecipitation of the phosphate added to the bioreactor influent. The Cu and Zn quenched the intensity of the dissolved organic matter peaks identified by fluorescence excitation emission matrix spectroscopy, suggesting a binding mechanism that decreases supersaturation, especially at pH 5. X-ray absorption fine structure spectroscopy analyses confirmed the precipitation of Zn-S as sphalerite and Cu-S as covellite in all samples, but also revealed the presence of Zn sorbed on hydroxyapatite. These analyses further showed that CuS structures remained amorphous regardless of the pH, whereas the ZnS structure was more organized at pH 5 as compared to the ZnS formed at pH 3 and 7, in agreement with the cubic sphalerite-type structures observed through scanning electron microscopy at pH 5. PMID- 24164297 TI - Up-regulation of two distinct p53-DNA binding functions by covalent poly(ADP ribosyl)ation: transactivating and single strand break sensing. AB - We used a [(32)P] p53 sequence-specific oligodeoxynucleotide and Electrophoretic Mobility-Shift-Assays to monitor p53 DNA sequence-specific binding with p53 R267W, a nonbinding point mutant; and p53-Delta30, a deletion-mutant which lacks the carboxy-terminus that recognizes DNA-strand-breaks. Recombinant p53 and poly(ADP-ribose)polymerase-1 (PARP-1) were incubated with labeled betaNAD(+) with/without DNA. The poly(ADP-ribosyl)ation of each protein increased with incubation-time and betaNAD(+) and p53 concentration(s). Since p53-Delta30 was efficiently labeled, poly(ADP-ribosyl)ation target site(s) of wt-p53 must reside outside its carboxy-terminal-domain. The poly(ADP-ribosyl)ation of p53-Delta30 did not diminish its DNA binding; Instead, it enhanced DNA-sequence-specific binding. Therefore, we conclude that DNA-sequence-specific-binding and DNA-nick sensing of mutant-p53 are differentially regulated by poly(ADP-ribosyl)ation. PMID- 24164298 TI - H2AX a promising biomarker for lung cancer: a review. AB - Histone's H2A variant (H2AX) phosphorylation is an early indicator of DNA double strand breaks formation and DNA damage response. Thus, it may act as a novel biomarker to monitor genotoxic events that can drive cancer development and tumor progression. This review will focus on the possible applications of H2AX as a key regulator of DNA damage response in lung cancer and as a biomarker of: sensitivity of lung tumors to chemotherapy and radiotherapy, treatment with PARP inhibitors, bystander effect, multistep lung carcinogenesis, environmental smoking, and chemical genotoxicity, chemoprevention, prognosis, and also as therapeutic targets in lung cancers. PMID- 24164299 TI - Routine histopathologic characteristics can predict oncotype DX(TM) recurrence score in subsets of breast cancer patients. AB - This study assessed whether routine pathologic parameters could predict Oncotype DX(TM) recurrence score (RS) in 72 breast cancers diagnosed from 2008-2012. Comparing patients with low RS (0-17) vs. intermediate RS (18-30) vs. high RS (>30), the mean Nottingham score increased (5.5 vs. 6.3 vs. 7.2, respectively, p = .001) and the mean PR Allred score decreased (6.7 vs. 4.9 vs. 3.3, respectively, p = .001). A high RS was least likely for low-grade tumors (0% had high RS, p = .005), and strong PR positivity (9% had high RS, p = .017). A low RS was least likely for cancers that were both high grade and PR weak/negative. PMID- 24164300 TI - Overexpression of glucose transporter-1 (GLUT-1) predicts poor prognosis in epithelial ovarian cancer. AB - Illumina microarray was used to identify differentially expressed genes in three epithelial ovarian cancer (EOC) cells. To validate the microarray data, mRNA and protein level of glucose transporter-1 (GLUT-1) was examined. GLUT-1 had an EOC/normal cells ratio of 5.51 based on microarray. Real-time PCR and immunohistochemistry demonstrated that GLUT-1 expression was significantly increased in EOC (p = .029 and p < .001, respectively). On survival analysis, GLUT-1 overexpression (HR = 4.80, p = .027) and lymph node metastases (HR = 8.35, p = .016) conferred a significantly worse overall survival. In conclusion, GLUT-1 expression is remarkably upregulated in EOC and predicts a poor overall survival. PMID- 24164301 TI - Combination treatment for glioblastoma cells with tumor necrosis factor-related apoptosis-inducing ligand and oncolytic adenovirus delta-24. AB - Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) exhibits cancer selective killing activity representing a promising anticancer therapeutic strategy. Adenovirus Delta-24 is another interested anticancer agent selectively killing cells with a defective p16/Rb/E2F pathway. However, many types of cancer, including gliomas, could develop resistance to Delta-24 or TRAIL-induced apoptosis. In this study, we investigated whether TRAIL, in combination with adenovirus Delta-24, could result in an enhanced antiglioma effect in vitro in a panel of glioblastoma cell lines (U87MG, U251MG, D54, and T98G). The treatment of glioblastoma cell lines with TRAIL and Delta-24 adenovirus in combination showed markedly enhanced effect, compared to each agent alone. PMID- 24164302 TI - DNA interaction with diaminobenzidine studied with optical tweezers and dynamic light scattering. AB - We have studied the interaction of the DNA molecule with the ligand 3,3' diaminobenzidine (DAB) by performing single molecule stretching experiments with optical tweezers and dynamic light scattering (DLS) on the DNA-DAB complexes. In the stretching experiments, the persistence and contour lengths of the complexes were measured as a function of DAB concentration, allowing one to infer the main binding mechanism and also to determine the physicochemical parameters of the interaction. In the DLS experiments, the effective size of the complexes, measured as the hydrodynamic radius, was monitored as a function of DAB concentration. We found a qualitative agreement between the results obtained from the two techniques by comparing the behaviors of the hydrodynamics radius and the radius of gyration, since this last one can be expressed as a function of the persistence and contour lengths. PMID- 24164303 TI - Comparative study of metal resistance and accumulation of lead and zinc in two poplars. AB - In our study, we tested two poplars, Populus beijingensis and Populus cathayana, as model species for their potential for phytoremediation by measuring changes in biomass, pigments, superoxide radicals (O2(-)), cellular ultrastructure and their ability for O2(-) quenching and heavy metal accumulation when exposed to Pb, Zn and their interaction in a hydroponic system. Exposure to Pb did not cause a significant decrease in biomass in either P. beijingensis or P. cathayana. Correspondingly, no obvious impairment in cellular organelles was observed in either species, although the former species translocated a higher fraction of Pb to its shoots than the latter. In contrast, there were significant decreases in biomass and pigment content, and serious impairments in ultrastructure in both species when exposed to either Zn alone or to a combined treatment. Under such conditions, P. beijingensis showed smaller losses of biomass and pigments but a greater ability to quench O2(-) and maintained relatively intact cellular organelles compared with P. cathayana. Under the combined stress, there were no obvious additive effects on biomass, pigments or cellular impairment, whereas synergistic effects on metal absorption and accumulation in both species were observed when compared with exposure to either alone. Thus, the attribute of synergistic uptake and translocation in both species validates their potential to remediate soil contaminated by multiple metals. Moreover, our results indicated that P. beijingensis is a better potential candidate for phytoremediation than P. cathayana, due to its greater phytoremediation efficiency as well as its higher tolerance capacity. PMID- 24164304 TI - Optimization and validation of high-performance liquid chromatography method for individual curcuminoids in turmeric by heat-refluxed extraction. AB - Turmeric is a plant in the Zingiberaceae family which contains curcuminoids as anticancer agents and has been widely used as a main ingredient in curry powder. However, there is a lack of suitable high performance liquid chromatography-diode array detection (HPLC-DAD) methods for reducing sample preparation time and peak resolution improvement of curcuminoids (bisdemethoxycurcumin, demethoxycurcumin, and curcumin). No significant differences in yield concentrations were observed after 60 min of heat-refluxed extraction (p < 0.05). Simultaneous chromatographic separation of all three curcuminoids achieved satisfactory results with a separation factor of 1.08 and a resolution factor of 3.39 with validation results in compliance with FDA guidelines. The expanded relative measurement uncertainty results 5.71-6.60 complied with CODEX draft. The method was successfully applied to the turmeric samples (n = 107, range 2.70-4.41 g/100 g, total curcuminoids 3.58 g/100 g). These results show that heat-refluxed extraction can be carried out easily with excellent precision and accuracy of total curcuminoids in turmeric samples. PMID- 24164305 TI - Predicting enzyme subclasses by using random forest with multicharacteristic parameters. AB - In order to predict enzyme subclasses, this paper builds a new enzyme database in term of previous ideas and methods. Based on protein sequence, by selecting increment of diversity value, low-frequency of power spectral density, matrix scoring values and motif frequency as characteristic parameters to describe the sequence information, a Random Forest algorithm for predicting enzyme subclass is proposed. Using the Jack-knife test, the overall success rate identifying the 18 subclasses of oxidoreductases, the 8 subclasses of transferases, the 5 subclasses of hydrolases, the 6 subclasses of lyases, the 6 subclasses of isomerases, and the 6 subclasses of ligases are 90.86%, 95.24%, 96.42%, 98.60%, 97.53% and 98.03%. Furthermore, the same way is used to the previous database, the better results are obtained. PMID- 24164306 TI - Novel leucine rich repeat domains in proteins from unicellular eukaryotes and bacteria. AB - Leucine rich repeats (LRRs) are present in over 20,000 proteins from viruses to eukaryotes. Two to sixty-two LRRs occur in tandem. Each repeat is typically 20-30 residues long and can be divided into an HCS (Highly conserved segment) and a VS (Variable segment). The HCS part consists of an eleven or a twelve residue stretch, LxxLxLxxNx(x/-)L, in which "L" is Leu, Ile, Val, or Phe, "N" is Asn, Thr, Ser, or Cys, "x" is a non-conserved residue, and "-" is a possible deletion site. Eight classes have been recognized. However, there are many unclassified or unrecognized LRRs. Here we performed to search novel LRRs using protein sequence database. The novel LRR domains are present over three hundred proteins, which include fungal ECM33 protein and Monosiga brevicollis LRR receptor kinase, from unicellular eukaryotes and bacteria. The HCS part is clearly different from that of the known LRRs and consists of a twelve or a thirteen residue stretch, VxGx(L/F)x(L/C)xxNx(x/-)L, that is characterized by the addition of Gly between the first conserved Val and the second conserved Leu. The novel LRRs identified here form a new family. The novel LRR domains were classified into four classes. The VS parts of the two classes are consistent with those of known, normal "SDS22 like" and "IRREKO" classes, while the other two classes have unique VS parts. The structures, functions, and evolution of the novel LRR domains and their proteins are described. The present results should stimulate various experimental studies. PMID- 24164307 TI - Patient-centred care in type 2 diabetes - an altered professional role for diabetes specialist nurses. AB - Little research has been done to try to understand how patient-centred care is understood and practised by healthcare professionals specialising in patients with diabetes. Experiences from patient-centred practices need to be highlighted as a way of motivating diabetes specialist nurses to take a patient-centred approach. The aim of this study was to describe diabetes specialist nurses' experiences of practising patient-centred care in the context of a type 2 diabetes intervention. The study design was descriptive and used qualitative methods. Focus group interviews complemented by individual semi-structured interviews were analysed by qualitative content analysis. The main theme of the diabetes specialist nurses' experiences of practising patient-centred care was an altered professional role. The main theme was based on two themes: ambivalence towards practising patient-centred care and enriched relationships with the patients. The ambivalence towards practising patient-centred care was based on the three subthemes: a position of withdrawn expertise, inconvenience of changing routines and insights that patient-centred care is difficult but possible. Their experiences of enriched relationships with patients were based on the two subthemes: courage to discuss the severity of diabetes and increased engagement in patients' daily lives. The diabetes specialist nurses' experiences with practising patient-centred care included doubts about their ability to practise in such a way and about the feasibility of such care. At the same time, their enriched relationships with patients were seen as an opportunity to engage in patients' lives. Training and support for practising patient-centred care may improve diabetes specialist nurses skills in patient-centred care and self management support in type 2 diabetes. PMID- 24164308 TI - Altered global methylation and hydroxymethylation status in vulvar lichen sclerosus: further support for epigenetic mechanisms. AB - BACKGROUND: Epigenetics refers to functionally relevant changes in the genome other than those of DNA sequence that can lead to changes in gene expression or cellular phenotype. There is evidence that epigenetics is relevant in the pathogenesis of autoimmune diseases such as vulvar lichen sclerosus (VLS), as well as in cancer, including cutaneous squamous cell carcinoma, which is frequently associated with VLS. OBJECTIVES: To study the global methylation and hydroxymethylation status in healthy controls and VLS lesions before and after long-term ultraviolet (UV)A1 treatment. METHODS: We studied 12 controls and 10 patients with VLS who were treated with medium-dose UVA1 four times weekly for 3 months. Immunohistochemistry and mutation analyses (polymerase chain reaction) were performed for 5-methylcytosine (5mC), 5-hydroxymethylcytosine (5hmC), isocitrate dehydrogenases (IDHs) and the ten-eleven translocation (TET)2 enzyme. RESULTS: After 3 months of treatment, 5mC was significantly increased in VLS compared with baseline and controls. However, compared with controls 5hmC levels were significantly reduced in baseline VLS, but normalized after UVA1 treatment. Compared with controls, IDH1 expression was significantly higher in both treated and baseline VLS. By contrast, IDH2 levels were significantly reduced in baseline VLS compared with controls and UVA1-treated VLS. However, gene sequencing of the IDH1, IDH2 and TET2 genes did not reveal evidence of mutations. CONCLUSIONS: VLS is associated with altered expression of IDH enzymes and aberrant hydroxymethylation, indicating an epigenetic background for the pathogenesis of VLS. UVA1 phototherapy may cause normalization of 5hmC patterns, but also global DNA hypermethylation in VLS lesions, raising concerns with respect to an increased risk of photocarcinogenesis. PMID- 24164309 TI - Clinical efficacy of new aloe vera- and myrrh-based oral mucoadhesive gels in the management of minor recurrent aphthous stomatitis: a randomized, double-blind, vehicle-controlled study. AB - OBJECTIVE: To evaluate the clinical efficacy, and safety of newly customized natural oral mucoadhesive gels, containing either aloe vera or myrrh as active ingredients, in the management of minor recurrent aphthous stomatitis (MiRAS). SUBJECTS AND METHODS: Ninety subjects with MiRAS were recruited from Oral Medicine Clinic, at Faculty of Dentistry, King Abdulaziz University, Saudi Arabia, for this randomized, double-blind, placebo-controlled study. Two new natural gels, containing aloe vera and myrrh, were prepared in a concentration of (0.5% w/w), in addition to a plain mucoadhesive gel used as a placebo. Patients with fresh ulcers (<48-h duration) were instructed to apply either one of the three gels four times a day for a period of 5 days. Clinical efficacy was investigated in the form of changes in ulcer size, pain intensity, erythema, and exudation at days 4 and 6 of study entry. Participants were interviewed for the emergence of any side effects. RESULTS: 76.6% of patients using aloe gel showed complete ulcer healing, 86.7%, and 80% of them revealed subsidence of erythema and exudation, respectively, especially at day 6 visit, whereas 76.7% of myrrh treated patients revealed almost absence of pain at day 6. No side effects were encountered with the use of any of the three gels. CONCLUSION: The new formulated aloe- and myrrh-based gels proved to be effective in topical management of MiRAS. Aloe was superior in decreasing ulcer size, erythema, and exudation; whereas myrrh resulted in more pain reduction. PMID- 24164310 TI - Selection and identification of DNA aptamers against okadaic acid for biosensing application. AB - This work describes the selection and identification of DNA aptamers that bind with high affinity and specificity to okadaic acid (OA), a lipophilic marine biotoxin that accumulates in shellfish. The aptamers selected using systematic evolution of ligands by exponential enrichment (SELEX) exhibited dissociation constants in the nanomolar range. The aptamer with the highest affinity was then used for the fabrication of a label-free electrochemical biosensor for okadaic acid detection. The aptamer was first immobilized on the gold electrode by a self assembly approach through Au-S interaction. The binding of okadaic acid to the aptamer immobilized on the electrode surface induces an alteration of the aptamer conformation causing a significant decrease in the electron-transfer resistance monitored by electrochemical impedance spectroscopy. The aptasensor showed a linear range for the concentrations of OA between 100 pg/mL and 60 ng/mL with a detection limit of 70 pg/mL. The dissociation constant of okadaic acid with the aptamer immobilized on the electrode surface showed good agreement with that determined using fluorescence assay in solution. Moreover, the aptasensor did not show cross-reactivity toward toxins with structures similar to okadaic acid such as dinophysis toxin-1 and 2 (DTX-1, DTX-2). Further biosensing applications of the selected aptamers are expected to offer promising alternatives to the traditional analytical and immunological methods for OA detection. PMID- 24164311 TI - CYP4A11 gene T8590C polymorphism is associated with essential hypertension in the male western Chinese Han population. AB - BACKGROUND: CYP4A11 is a member of the cytochrome P450 enzymes and is responsible for metabolizing arachidonic acid to 20-hydroxyeicosatetraenoic acid, a metabolite involved in the regulation of blood pressure. This study aimed to evaluate whether or not the CYP4A11 gene polymorphism T8590C (rs1126742) is involved in essential hypertension in the western Chinese Han population. METHODS: In a case-control study, the participants included 864 (523 males and 341 females) patients with essential hypertension and 661 (422 males and 239 females) healthy subjects. The T8590C polymorphism of the CYP4A11 gene was analyzed by using the TaqMan(r) SNP Genotyping Assay. RESULTS: For men, the frequencies of the CC genotype and the C allele were higher in essential hypertension than in the control group (p=0.022 and p=0.016, respectively). After adjustment of confounding factor such as diabetes, smoking, BMI, TG and TC, the significant difference was observed in CC genotype (OR=1.897, 95% confidence interval [CI] 1.026-3.508; p=0.041). No difference was found in all participants and females. CONCLUSIONS: The CC genotype and C allele were associated with essential hypertension in the male western Chinese Han population. PMID- 24164312 TI - High performance solid-state electric double layer capacitor from redox mediated gel polymer electrolyte and renewable tamarind fruit shell derived porous carbon. AB - The activated carbon was derived from tamarind fruit shell and utilized as electrodes in a solid state electrochemical double layer capacitor (SSEDLC). The fabricated SSEDLC with PVA (polyvinyl alcohol)/H2SO4 gel electrolyte delivered high specific capacitance and energy density of 412 F g(-1) and 9.166 W h kg(-1), respectively, at 1.56 A g(-1). Subsequently, Na2MoO4 (sodium molybdate) added PVA/H2SO4 gel electrolyte was also prepared and applied for SSEDLC, to improve the performance. Surprisingly, 57.2% of specific capacitance (648 F g(-1)) and of energy density (14.4 Wh kg(-1)) was increased while introducing Na2MoO4 as the redox mediator in PVA/H2SO4 gel electrolyte. This improved performance is owed to the redox reaction between Mo(VI)/Mo(V) and Mo(VI)/Mo(IV) redox couples in Na2MoO4/PVA/H2SO4 gel electrolyte. Similarly, the fabricated device shows the excellent capacitance retention of 93% for over 3000 cycles. The present work suggests that the Na2MoO4 added PVA/H2SO4 gel is a potential electrolyte to improve the performance instead of pristine PVA/H2SO4 gel electrolyte. Based on the overall performance, it is strongly believed that the combination of tamarind fruit shell derived activated carbon and Na2MoO4/PVA/H2SO4 gel electrolyte is more attractive in the near future for high performance SSEDLCs. PMID- 24164313 TI - Immune stimulation following dermal exposure to unsintered indium tin oxide. AB - In recent years, several types of pulmonary pathology, including alveolar proteinosis, fibrosis, and emphysema, have been reported in workers in the indium industry. To date, there remains no clear understanding of the underlying mechanism(s). Pulmonary toxicity studies in rats and mice have demonstrated the development of mediastinal lymph node hyperplasia and granulomas of mediastinal lymph nodes and bronchus-associated lymphoid tissues following exposure to indium tin oxide. Given the association between exposure to other metals and the development of immune-mediated diseases, these studies were undertaken to begin to investigate the immuno-modulatory potential of unsintered indium tin oxide (uITO) in a mouse model. Using modifications of the local lymph node assay, BALB/c mice (five animals/group) were exposed topically via intact or breached skin or injected intradermally at the base of the ear pinnae with either vehicle or increasing concentrations 2.5-10% uITO (90:10 indium oxide/tin oxide, particle size <50 nm). Dose-responsive increases in lymphocyte proliferation were observed with a calculated EC3 of 4.7% for the intact skin study. Phenotypic analysis of draining lymph node cells following intradermal injection with 5% uITO yielded a profile consistent with a T-cell-mediated response. These studies demonstrate the potential for uITO to induce sensitization and using lymphocyte proliferation as a biomarker of exposure, and demonstrate the potential for uITO to penetrate both intact and breached skin. PMID- 24164315 TI - Heteroprotein complex coacervation: bovine beta-lactoglobulin and lactoferrin. AB - Lactoferrin (LF) and beta-lactoglobulin (BLG), strongly basic and weakly acidic bovine milk proteins, form optically clear coacervates under highly limited conditions of pH, ionic strength I, total protein concentration C(P), and BLG:LF stoichiometry. At 1:1 weight ratio, the coacervate composition has the same stoichiometry as its supernatant, which along with DLS measurements is consistent with an average structure LF(BLG2)2. In contrast to coacervation involving polyelectrolytes here, coacervates only form at I < 20 mM. The range of pH at which coacervation occurs is similarly narrow, ca. 5.7-6.2. On the other hand, suppression of coacervation is observed at high C(P), similar to the behavior of some polyelectrolyte-colloid systems. It is proposed that the structural homogeneity of complexes versus coacervates with polyelectrolytes greatly reduces the entropy of coacervation (both chain configuration and counterion loss) so that a very precise balance of repulsive and attractive forces is required for phase separation of the coacervate equilibrium state. The liquid-liquid phase transition can however be obscured by the kinetics of BLG aggregation which can compete with coacervation by depletion of BLG. PMID- 24164314 TI - Evaluation of a novel ultra-sensitive nanoparticle probe-based assay for ricin detection. AB - A gold nanoparticle (GNP) probe-based assay (GNPA) modified from the bio-barcode assay (BCA) was developed for ultrasensitive detection of ricin, a potential biothreat agent. In the GNPA, a chain of ricin was captured by a GNP probe coated with polyclonal antibodies and single-stranded signal DNA. A magnetic microparticle (MMP) probe coated with ricin A chain monoclonal antibody was then added to form an immuno-complex. After being magnetically separated, the immuno complex containing the single-stranded signal DNA was characterized by PCR and real-time PCR. A detection limit of 10(-2) fg/ml was determined for the ricin A chain; this is eight orders of magnitude more sensitive than that achieved with an ELISA and two orders more sensitive than that obtained with the BCA. The coefficients of variation (CV) of the intra- and inter-assay values ranged from 3.82-6.46%. The results here show that this novel assay is an ultrasensitive method for detection of ricin proteins and may be suitable for the ultrasensitive detection of other proteins. PMID- 24164316 TI - Genetic interaction of the stress response factors ChAP1 and Skn7 in the maize pathogen Cochliobolus heterostrophus. AB - The transcription factors ChAP1 and Skn7 of the maize pathogen Cochliobolus heterostrophus are orthologs of Yap1 and Skn7 in yeast, where they are predicted to work together in a complex. Previous work showed that in C. heterostrophus, as in yeast, ChAP1 accumulates in the nucleus in response to reactive oxygen species (ROS). The expression of genes whose products counteract oxidative stress depends on ChAP1, as shown by impaired ability of a Deltachap1 mutant to induce these 'antioxidant' genes. In this study, we found that under oxidative stress, antioxidant gene expression is also partially impaired in the Deltaskn7 mutant but to a milder extent than in the Deltachap1 mutant, whereas in the double mutant - Deltachap1-Deltaskn7 - none of the tested genes was induced, with the exception of one catalase gene, CAT2. Both single mutants are capable of infecting the plant, showing similar virulence to the WT. The double mutant, however, showed clearly decreased virulence, pointing to additive contributions of ChAP1 and Skn7. Possible mechanisms are discussed, including additive regulation of gene expression by oxidative stress. PMID- 24164318 TI - Continuous ethanol production from sugarcane molasses using a newly designed combined bioreactor system by immobilized Saccharomyces cerevisiae. AB - Continuous ethanol fermentation using polyvinyl alcohol (PVA), immobilized yeast, and sugarcane molasses (22 and 35 degrees Bx) with 8 g/L urea was run in a combined bioreactor system consisting of three-stage tubular bioreactors in series. The effect of the dilution rate (D) at 0.0037, 0.0075, 0.0117, 0.0145, 0.018, and 0.0282 H(-1) on continuous ethanol fermentation was investigated in this study. The results showed that D had a significant effect on fermentation efficiency, sugar-utilized rate, ethanol yield, and ethanol productivity in this designed continuous fermentation system. The D had a linear relationship with residual sugar and ethanol production under certain conditions. The highest fermentation efficiency of 83.26%, ethanol yield of 0.44 g/g, and the lowest residual sugar content of 6.50 g/L were achieved at 0.0037 H(-1) in the fermentation of 22 degrees Bx molasses, indicating that the immobilization of cells using PVA, sugarcane pieces, and cotton towel is feasible and the established continuous system performs well. PMID- 24164317 TI - Role of maternal elimination diets and human milk IgA in the development of cow's milk allergy in the infants. AB - BACKGROUND: The role of maternal avoidance diets in the prevention of food allergies is currently under debate. Little is known regarding the effects of such diets on human milk (HM) composition or induction of infant humoral responses. OBJECTIVE: To assess the association of maternal cow's milk (CM) avoidance during breastfeeding with specific IgA levels in HM and development of cow's milk allergy (CMA) in infants. METHODS: We utilized HM and infant serum samples from a prospective birth cohort of 145 dyads. Maternal serum and HM samples were assessed for casein and beta-lactoglobulin (BLG)-specific IgA and IgG by ELISA; 21 mothers prophylactically initiated a strict maternal CM avoidance diet due to a sibling's history of food allergy and 16 due to atopic eczema or regurgitation/vomiting seen in their infants within the first 3 months of life. Infants' sera were assessed for casein and BLG-specific IgG, IgA and IgE; CMA was confirmed by an oral food challenge. The impact of HM on BLG uptake was assessed in transcytosis assays utilizing Caco-2 intestinal epithelial cell line. RESULTS: Mothers avoiding CM had lower casein- and BLG-specific IgA in HM than mothers with no CM restriction (P = 0.019 and P = 0.047). Their infants had lower serum casein- and BLG-specific IgG(1) (P = 0.025 and P < 0.001) and BLG specific IgG(4) levels (P = 0.037), and their casein- and BLG-specific IgA levels were less often detectable than those with no CM elimination diet (P = 0.003 and P = 0.007). Lower CM-specific IgG4 and IgA levels in turn were associated with infant CMA. Transcytosis of BLG was impaired by HM with high, but not low levels of specific IgA. CONCLUSIONS: Maternal CM avoidance was associated with lower levels of mucosal-specific IgA levels and the development of CMA in infants. CLINICAL RELEVANCE: HM IgA may play a role in preventing excessive, uncontrolled food antigen uptake in the gut lumen and thereby in the prevention of CMA. PMID- 24164319 TI - Molecular and functional characterization of vacuolar-ATPase from the American dog tick Dermacentor variabilis. AB - Vacuolar (V)-ATPase is a proton-translocating enzyme that acidifies cellular compartments for various functions such as receptor-mediated endocytosis, intracellular trafficking and protein degradation. Previous studies in Dermacentor variabilis chronically infected with Rickettsia montanensis have identified V-ATPase as one of the tick-derived molecules transcribed in response to rickettsial infection. To examine the role of the tick V-ATPase in tick Rickettsia interactions, a full-length 2887-bp cDNA (2532-bp open reading frame) clone corresponding to the transcript of the V0 domain subunit a of D. variabilis V-ATPase (DvVATPaseV0a) gene encoding an 843 amino acid protein with an estimated molecular weight of ~96 kDa was isolated from D. variabilis. Amino acid sequence analysis of DvVATPaseV0a showed the highest similarity to VATPaseV0a from Ixodes scapularis. A potential N-glycosylation site and eight putative transmembrane segments were identified in the sequence. Western blot analysis of tick tissues probed with polyclonal antibody raised against recombinant DvVATPaseV0a revealed the expression of V-ATPase in the tick ovary. Transcriptional profiles of DvVATPaseV0a demonstrated a greater mRNA expression in the tick ovary, compared with the midgut and salivary glands; however, the mRNA level in each of these tick tissues remained unchanged after infection with R. montanensis for 1 h. V ATPase inhibition bioassays resulted in a significant decrease in the ability of R. montanensis to invade tick cells in vitro, suggesting a role of V-ATPase in rickettsial infection of tick cells. Characterization of tick-derived molecules involved in rickettsial infection is essential for a thorough understanding of rickettsial transmission within tick populations and the ecology of tick-borne rickettsial diseases. PMID- 24164320 TI - Adipokine profile in celiac patients: differences in comparison with patients suffering from diarrhea-predominant IBS and healthy subjects. AB - OBJECTIVE. The role of adipokines such as resistin, leptin, and adiponectin could be pivotal in the molecular crosstalk between the inflamed intestine and the surrounding mesenteric adipose tissue. Our aims were to a) evaluate their circulating concentrations in patients with active celiac disease (ACD) and compare them to those in patients with diarrhea-predominant irritable bowel syndrome (IBS-d) and healthy subjects; b) establish the impact of genetic variability in resistin; and c) evaluate whether a 1-year gluten-free diet (GFD) modifies circulating concentrations of resistin, leptin, and adiponectin in celiac patients. MATERIAL AND METHODS. The study included 34 ACD patients, 29 IBS d patients, and 27 healthy controls. Circulating concentrations of resistin, leptin, adiponectin, IL-6, and IL-8 were evaluated at the time of enrollment. Resistin +299 G/A polymorphism was also analysed. In CD patients, biochemical measurements were repeated after a 1-year GFD. RESULTS. Along with higher IL-6 and IL-8 plasma levels, higher resistin and adiponectin concentrations were found in ACD and IBS-d patients compared with controls (p: 0.0351 and p: 0.0020, respectively). Resistin values proved to be predictable from a linear combination of IL-8 and +299 polymorphism. GFD affected resistin (p: 0.0009), but not leptin and adiponectin concentrations. CONCLUSIONS. Our data suggest that these adipokines are involved in modulating inflammatory processes in both CD and IBS-d patients. Alterations in the adipokine profile as well as the higher prevalence of the resistin +299 G/A SNP A allele compared to controls support the hypothesis that, at least in well-defined cases of IBS, a genetic component may also be supposed. PMID- 24164322 TI - (E)-beta-borylstyrene in the Diels-Alder reaction with 3,5-dibromo-2-pyrone for the syntheses of (+/-)-1-epi-pancratistatin and (+/-)- pancratistatin. AB - New synthetic routes to (+/-)-1-epi-pancratistatin and (+/-)-pancratistatin were devised using (E)-beta-borylstyrene as a dienophile for the key Diels-Alder reaction with 3,5-dibromo-2-pyrone. The boronate in the cycloadduct was oxidized to provide the pivotal C1-hydroxyl group of the titled compounds. PMID- 24164324 TI - Mechanistic insights for formation of an organometallic Co-C bond in the methyl transfer reaction catalyzed by methionine synthase. AB - Methionine synthase (MetH) catalyzes the transfer of a methyl group from methyltetrahydrofolate (CH3-H4Folate) to the cob(I)alamin intermediate to form an organometallic Co-C bond, a reaction similar to that of CH3 H4Folate:corrinoid/iron-sulfur protein (CFeSP) methyltransferase (MeTr). How precisely it is formed remains elusive because the displacement of a methyl group from the tertiary amine is not a facile reaction. To understand the electronic structure and mechanistic details of the MetH-cob(I)alamin:CH3-H4Folate reaction complex, we applied quantum mechanics/molecular mechanics (QM/MM) computations. The hybrid QM/MM calculations reveal the traditionally assumed SN2 mechanism for formation the CH3-cob(III)alamin resting state where the activation energy barrier for the SN2 reaction was found to be ~8-9 kcal/mol, which is comparable with respect to the determined experimental rate constant. However, the possibility of an electron transfer (ET) based radical mechanism consistent with the close-lying diradical states observed from triplet and open-shell singlet states has also been suggested as an alternative, where first an electron transfer from His-on cob(I)alamin to the pterin ring of the protonated CH3 H4Folate takes place, forming the Co(II)(d(7))-pterin radical (pi*)(1) diradical state, followed by a methyl radical transfer. Although the predicted energy barrier for the ET-mediated radical reaction is comparable to that of the SN2 pathway, the major advantage of ET is that a methyl radical can be transferred at a longer distance, which does not require the close proximity of two binding modules of MetH as does the SN2 type. In addition, based on the energy barrier of the transition state (TS) in both the protonated (~8-9 kcal/mol) and the unprotonated N5 (39 kcal/mol) species of the CH3-H4Folate, it can be inferred that the protonation event must takes place either prior to or during the methyl transfer reaction in a ternary complex. The results of the present study including mechanistic insights can have implications to a broad class of corrinoid-methyltransferases, which utilize a CH3-H4Folate substrate or its related analogues as methyl donor. PMID- 24164323 TI - Identification of two novel Shank3 transcripts in the developing mouse neocortex. AB - SHANK3 is a synaptic scaffolding protein enriched in the post-synaptic density of excitatory synapses. Since several SHANK3 mutations have been identified in a particular phenotypic group of patients with autism spectrum disorder (ASD), SHANK3 is strongly suspected of being involved in the pathogenesis and neuropathology of ASD. Several SHANK3 isoforms are known to be produced in the developing brain, but they have not been fully investigated. Here, we identified two different amino-terminus truncated Shank3 transcripts. One transcript, designated as Shank3c-3, produces an isoform that contains the entire carboxyl terminus, but the other transcript, designated as Shank3c-4, produces a carboxyl terminus truncated isoform. During development, expression of the novel Shank3 transcripts increased after birth, transiently decreased at P14 and then gradually increased again thereafter. We also determined that methyl CpG-binding protein 2 (MeCP2) is involved in regulating expression of the novel Shank3 transcripts. MeCP2 is a transcriptional regulator that has been identified as the causative molecule of Rett syndrome, a neurodevelopmental disorder that includes autistic behavior. We demonstrated a difference between the expression of the novel Shank3 transcripts in wild-type mice and Mecp2-deficient mice. These findings suggest that the SHANK3 isoforms may be implicated in the synaptic abnormality in Rett syndrome. SHANK3 is a synaptic scaffolding protein and is suspected of being implicated in the pathogenesis and neuropathology of ASD. We here identified two different amino-terminus truncated Shank3 transcripts, Shank3c-3 and Shank3c-4, expressed from the intron 10 of the Shank3 gene, and also suggested the epigenetic regulation of their expression via methyl CpG binding protein 2 (MeCP2) that has been identified as the causative molecule of Rett syndrome. PMID- 24164325 TI - A rapidly enlarging nodule on the scalp. PMID- 24164321 TI - Developmental biology of Streptomyces from the perspective of 100 actinobacterial genome sequences. AB - To illuminate the evolution and mechanisms of actinobacterial complexity, we evaluate the distribution and origins of known Streptomyces developmental genes and the developmental significance of actinobacteria-specific genes. As an aid, we developed the Actinoblast database of reciprocal blastp best hits between the Streptomyces coelicolor genome and more than 100 other actinobacterial genomes (http://streptomyces.org.uk/actinoblast/). We suggest that the emergence of morphological complexity was underpinned by special features of early actinobacteria, such as polar growth and the coupled participation of regulatory Wbl proteins and the redox-protecting thiol mycothiol in transducing a transient nitric oxide signal generated during physiologically stressful growth transitions. It seems that some cell growth and division proteins of early actinobacteria have acquired greater importance for sporulation of complex actinobacteria than for mycelial growth, in which septa are infrequent and not associated with complete cell separation. The acquisition of extracellular proteins with structural roles, a highly regulated extracellular protease cascade, and additional regulatory genes allowed early actinobacterial stationary phase processes to be redeployed in the emergence of aerial hyphae from mycelial mats and in the formation of spore chains. These extracellular proteins may have contributed to speciation. Simpler members of morphologically diverse clades have lost some developmental genes. PMID- 24164326 TI - Transcriptome profiling in response to different types of ionizing radiation and identification of multiple radio marker genes in rice. AB - Ionizing radiation (IR) affects gene expression from plant genomes. To monitor the genome-wide transcriptional changes induced by three types of IR, we used the rice Affymetrix GeneChip microarray to identify genes that are up- or down regulated by gamma rays (GAs), cosmic rays (CRs) and ion beams (IBs). The overall expression patterns in rice seedlings generated from seeds exposed to GAs and IBs were similar but differed for CRs exposure. Expression profiles of genes involved in metabolic pathways and cellular response were identified using MapMan analysis. This result revealed that IRs induced gene expression related to sucrose-starch metabolisms; sugar and starch accumulation was significantly increased in response to three types of IR in rice. In addition, we compared the genes commonly up- or down-regulated by exposure to three types of IR and identified 53 candidate radio marker genes (RMGs) that were differentially regulated by radiation exposure but not by other stresses. Among these genes, we selected six RMGs commonly applicable to different types of IR by specific coexpression networks using the algorithm for the reconstruction of accurate cellular networks (aracne) and confirmed the expression of these genes by reverse transcription-polymerase chain reaction (RT-PCR) analysis. Our results provided insight into the mechanisms of the responses to different types of IR and identified multiple marker genes to predict sensitivity to three types of IR. PMID- 24164327 TI - The novel HLA-B allele, HLA-B*07:110, was identified by sequencing genomic DNA. PMID- 24164329 TI - Oxidative stability of omega-3 polyunsaturated fatty acids enriched eggs. AB - Omega-3 polyunsaturated fatty acids (n-3 PUFA) enriched eggs have a growing market share in the egg industry. This study examined the stability of n-3 PUFA enriched eggs fortified with antioxidants (vitamin E or organic Selenium [Sel Plex] or both) following cooking and storage. The total fat content was not affected by cooking or simulated retail storage conditions, whereas, n-3 fatty acids were reduced. The content of n-3 fatty acids in boiled eggs was higher than in fried eggs. Lipid oxidation was significantly affected by the different cooking methods. Fried eggs contained higher levels of malondialdehyde (MDA, 2.02 MUg/kg) and cholesterol oxidation products (COPs, 13.58 MUg/g) compared to boiled (1.44 and 10.15 MUg/kg) and raw eggs (0.95 and 9.03 MUg/kg, respectively, for MDA and COPs). Supplementation of antioxidants reduced the formation of MDA by 40% and COPs by 12% in fried eggs. Although the content of MDA was significantly increased after 28 days of storage, COPs were not affected by storage. Our study indicated that the n-3 PUFA in enriched eggs was relatively stable during storage and home cooking in the presence of antioxidants. PMID- 24164328 TI - Non-adherent mesenchymal progenitors from adipose tissue stromal vascular fraction. AB - In primary human bone marrow cultures, the initial adherent cell fraction has been shown to provide a microenvironment for self-renewal of primitive non adherent mesenchymal progenitors (non-adherent progenitors of bone marrow stroma [BM-NAMP]), with increased differentiation potential compared to adherent colony forming units-fibroblast (CFU-f). The present study investigates whether NAMP exist also in cultures of stromal vascular fraction (SVF) cells derived from human adipose tissue. Adipose-tissue NAMP (AT-NAMP) were shown to be stably non adherent and their number correlated with the number of the initial adhering CFU f. Unlike BM-NAMP, AT-NAMP did not propagate in suspension in serial replating experiments and the number of colonies steadily decreased with each replating step. However, when AT-NAMP were kept on the initially adhering SVF cells, they could significantly expand without loss of clonogenic, proliferation, and differentiation potential. Although AT-NAMP progeny differentiated into mesodermal lineages similar to that of adherent CFU-f, it was enriched in early mesenchymal progenitor populations, characterized by increased expression of SSEA 4 and CD146. Furthermore, FGF-2 supported AT-NAMP survival and could not be replaced by another mitogenic factor, such as platelet derived growth factor BB. In conclusion, these data suggest that the SVF adherent fraction provides niche signals that regulate the expansion of adipose non-adherent mesenchymal progenitors with the maintenance of their potency. The biological differences described between BM- and AT-NAMP further qualify the properties of the stroma from different tissues and will be relevant for the selection of a cell source for specific regeneration strategies. PMID- 24164330 TI - Transcriptional profiling suggests that multiple metabolic adaptations are required for effective proliferation of Pseudomonas aeruginosa in jet fuel. AB - Fuel is a harsh environment for microbial growth. However, some bacteria can grow well due to their adaptive mechanisms. Our goal was to characterize the adaptations required for Pseudomonas aeruginosa proliferation in fuel. We have used DNA-microarrays and RT-PCR to characterize the transcriptional response of P. aeruginosa to fuel. Transcriptomics revealed that genes essential for medium- and long-chain n-alkane degradation including alkB1 and alkB2 were transcriptionally induced. Gas chromatography confirmed that P. aeruginosa possesses pathways to degrade different length n-alkanes, favoring the use of n C11-18. Furthermore, a gamut of synergistic metabolic pathways, including porins, efflux pumps, biofilm formation, and iron transport, were transcriptionally regulated. Bioassays confirmed that efflux pumps and biofilm formation were required for growth in jet fuel. Furthermore, cell homeostasis appeared to be carefully maintained by the regulation of porins and efflux pumps. The Mex RND efflux pumps were required for fuel tolerance; blockage of these pumps precluded growth in fuel. This study provides a global understanding of the multiple metabolic adaptations required by bacteria for survival and proliferation in fuel containing environments. This information can be applied to improve the fuel bioremediation properties of bacteria. PMID- 24164331 TI - The Furlow palatoplasty for velopharyngeal dysfunction: velopharyngeal changes, speech improvements, and where they intersect. AB - OBJECTIVE: We investigated how Furlow palatoplasty changes velopharyngeal morphology and speech characteristics, as well as how the anatomical and clinical results might be related. We hypothesized that Furlow palatoplasty would result in measurable velar elongation, tightening of the genu angle, and retropositioning of the levator sling and that the achievement of these modifications might be associated with clinical speech improvement. DESIGN: Retrospective analysis of preoperative and postoperative videofluoroscopic and speech data. SETTING: Tertiary care center. PATIENTS/PARTICIPANTS: A total of 29 patients with velopharyngeal insufficiency in the setting of previous cleft palate repair or submucous cleft palate. INTERVENTIONS: Furlow palatoplasty for treatment of velopharyngeal insufficiency. OUTCOME MEASURES: Lateral videofluoroscopy and perceptual speech examination were conducted preoperatively and postoperatively in order to measure velopharyngeal dimensions and speech quality. We describe anatomical and speech changes associated with the Furlow palatoplasty and undertake an exploratory analysis of the relationship between surgical changes to the velopharynx and clinical outcomes. RESULTS: Furlow palatoplasty results in significant velar elongation, increased acuity of the genu angle, and retropositioning of the levator sling. Postoperative speech improvement was identified on the three subscales of resonance, nasal emission, and stops/plosives. Speech improvement and the absence of need for reoperation were most consistently associated with tightening of the genu angle. CONCLUSIONS: Furlow palatoplasty lengthens the palate, while both tightening and retropositioning the levator sling. These changes reflect transverse recruitment of lateral velar tissues, along with transverse tightening and anterior release of the muscle fibers, respectively. Levator tightening is most consistently associated with improved speech outcomes. PMID- 24164332 TI - Binge drinking prior to pregnancy detection in a nonhuman primate: behavioral evaluation of offspring. AB - BACKGROUND: Minimal scientific information is available to inform public health policy on binge drinking prior to pregnancy detection. The nonhuman primate provides a valuable animal model for examining consequences to reproduction and offspring function that may result from this common pattern of alcohol abuse. METHODS: Adult female rhesus monkeys were dosed with 1.5 g/kg per day ethanol (EtOH) by gavage 2 d/wk beginning 7 months prior to mating and continuing to pregnancy detection at 19 to 20 days gestation. Postnatal evaluation of control (n = 6) and EtOH-treated (n = 4) infants included a neonatal neurobehavioral assessment, a visual paired comparison (cognitive) test at 35 days of age, and mother-infant interaction at 100 to 112 days of age. RESULTS: Alcohol-exposed neonates did not differ from controls in posture and reflex measures. Longer durations of visual fixation, suggesting slower visual processing, and greater novelty preference were seen in the alcohol group. At early weaning age, as infants spent more time away from their dams, more of the reunions between mother and infant were initiated by the mothers in the alcohol-exposed group, suggesting a more immature mother-infant interaction. CONCLUSIONS: Intermittent high-dose alcohol exposure (binge drinking) discontinued at early pregnancy detection in rhesus monkey can result in altered behavioral function in the infant. Mediating effects on ovum, reproductive tract, and early embryo can be explored in this model. Studies of longer-term consequences in human populations and animal models are needed. PMID- 24164333 TI - An overview of psychosocial assessment procedures in reconstructive hand transplantation. AB - There have been more than 90 hand and upper extremity transplants performed worldwide. Functional and sensory outcomes have been reported in several studies, but little is known about the psychosocial outcomes. A comprehensive systematic literature review was performed, addressing the psychosocial impact of reconstructive hand transplantation. This review provides an overview of psychosocial evaluation protocols and identifies standards in this novel and exciting field. Essentials of the psychosocial assessment are discussed and a new protocol, the 'Chauvet Protocol', representing a standardized assessment protocol for future multicenter psychosocial trials is being introduced. PMID- 24164334 TI - The effect of pressure on high- and low-working-memory students: an elaboration of the choking under pressure hypothesis. AB - SAMPLE: Fifty-three third and fourth graders from China participated in this study. METHOD: Participants' working memory (WM) was assessed by the Automated Operation Span task. Then, they solved mental addition problems of different types under low- and high-pressure conditions. Performance was analysed as a function of pressure condition, working memory capacity, and problem type. RESULTS: On 'no carry' mental addition problems, there was no difference between the two groups of children regardless the presence of pressure. For problems with carries, low WM (LWM) children performed worse on all tasks compared with high WM (HWM) children in the no-pressure condition, but pressure influenced the LWM and HWM differently depending on the nature of the carrying task. On 'hidden carry' mental addition trials (for which guessing strategies were minimally effective), LWM performance was much lower than HWM performance under pressure. By contrast, performance was similar between LWM and HWM groups under pressure on the 'normal carry' trials that allowed for non-resource-intensive heuristic strategies. CONCLUSION: Whether high- or low-working-memory elementary-school-aged children were more or less affected by pressure was dependent on task-difficulty and the types of strategies that could be used to solve the problems. PMID- 24164335 TI - Brachial-ankle pulse wave velocity for the prediction of the presence and severity of coronary artery disease. AB - The predictability of brachial-ankle pulse wave velocity (baPWV) for the presence and severity of coronary artery disease (CAD) was investigated by measuring baPWV in 501 subjects scheduled for coronary angiography. Severity of CAD was measured using modified Gensini stenosis score (GSS) and classified as a vessel disease score (VDS) of 0-3. The presence of CAD was defined as diameter stenosis>50%. Subjects were grouped in tertile by level of baPWV (<14, 14-17, >17 m/s). Subjects with CAD showed higher mean age, prevalence of men and diabetes, and systolic blood pressure. The prevalence of hypertension, use of antihypertensive medications and use of statin was not different. Subjects with CAD had higher baPWV than subjects without CAD (16.70 +/- 3.46 versus 15.21 +/- 3.19 m/s, p<0.001). Multiple linear regression analysis showed significant correlation of baPWV and modified GSS (p=0.0337). ANCOVA adjusted with age, gender, body mass index, presence of hypertension or diabetes, status of smoking, use of antihypertensive medications and risk of hypercholesterolemia showed a statistically significant association of baPWV with VDS (p<0.0001). Highest tertile of baPWV had a statistically significant effect on the severity of CAD from an ANCOVA model. The predictive power of highest tertile of baPWV for the presence of CAD was 3.600 [95% confidence interval (CI) 1.884-6.881, p<0.0001]. It is concluded that increased baPWV is a reliable predictor of the presence and severity of CAD, suggesting that baPWV>17 m/s may be a threshold value for the presence and severity of CAD. PMID- 24164336 TI - Analgesia Nociception Index (ANI) to predict intraoperative haemodynamic changes: results of a pilot investigation. AB - BACKGROUND: The Analgesia Nociception Index has been described to reflect different levels of intraoperative nociceptive stimulation during total intravenous anaesthesia. The association between this index and haemodynamic changes during sevoflurane-based anaesthesia was investigated in 30 patients with the hypothesis that changes in the Analgesia Nociception Index may coincide with or even predict haemodynamic changes. METHODS: The Analgesia Nociception Index as well as blood pressure and heart rate were observed during induction, at skin incision, at times of an Analgesia Noceception Index decrease > 20% ('event') and pre-/post-fentanyl administration. RESULTS: The Analgesia Nociception Index decreased with airway manipulation [mean: 52 (before) vs. 33 (after); P < 0.005] and after skin incision [mean: 63 (before) vs. 38 (after); P < 0.001], and it increased after fentanyl administration [53 (before) vs. 59 (after); P < 0.05]. However, its predictive probability to indicate heart rate and blood pressure increases of >10% was low (heart rate 0.61; blood pressure 0.59). CONCLUSIONS: The Analgesia Nociception Index appears to reflect different levels of stimulation during sevoflurane-based general anaesthesia. However, it was of little predictive value to pre-empt significant haemodynamic changes. PMID- 24164337 TI - The Th17 cell population and the immune homeostasis of the gastrointestinal tract. AB - Th17 cells are a recently discovered subset of CD4(+) T lymphocytes filling a hole in the repertoire of effector T cells. Th17 cells produce multiple cytokines, with pivotal impact on immune homeostasis, inflammation, and influencing a wide range of intestinal cell targets. The current issue of the International Reviews of Immunology is entirely dedicated to the various roles of Th17 T cells in the immune homeostasis and inflammation occurring in the gut. In addition to describing diverse Th17-mediated molecular pathways, a specific focus is being given to Th17 cell plasticity. This enables the Th17 cells to shift towards a Th1 profile, or to express IL-22, a protective cytokine in experimental colitis. Participation of microbiota-specific Th17 cells to normal immune homeostasis, and their role in the pathogenesis of inflammatory bowel disease (IBD), or of gluten specific-Th17 cells in celiac disease, are also being discussed. Neutralizing antibodies against IL-17A and IL-17F have commenced clinical testing in IBD. In conclusion, Th17 cells emerge as a key immune cell population and further elucidation of their roles and functional plasticity are warranted to support the discovery of novel therapies against IBD and other intestinal disorders. PMID- 24164338 TI - Role of acid sphingomyelinase in the regulation of mast cell function. AB - BACKGROUND: Degranulation of mast cells is stimulated by store-operated Ca(2+) entry (SOCE). In other cell types, Ca(2+) -entry is modified by ceramide. Exogenously added ceramide has been shown to trigger mast cell apoptosis. Effects of endogenously produced ceramide in mast cells remained, however, elusive. Ceramide may be produced from sphingomyelin by acid sphingomyelinase (Asm). OBJECTIVE: This study explored the impact of Asm on mast cell functions. METHODS: Mast cells were isolated from bone marrow (BMMCs) or peritoneal lavage of gene targeted mice lacking Asm (asm(-/-)) and their wild-type littermates (asm(+/+)). BMMC maturation and apoptosis-associated annexin V binding were determined by flow cytometry. Asm activity was assessed enzymatically, cytosolic Ca(2+) activity ([Ca(2+)]i) utilizing Fura-2 fluorescence, current across the cell membrane by whole-cell patch clamp, degranulation from hexosaminidase-release and migration utilizing a transwell chamber. In vivo anaphylaxis was derived from decrease in body temperature. RESULTS: Peritoneal mast cell number, BMMC phenotype, spontaneous BMMC apoptosis as well as BMMC CD117, CD34 and FcepsilonRI expression were similar in both genotypes. In asm(+/+) BMMCs, stimulation with antigen resulted in a fast ~2.5-fold increase in Asm activity. Release of Ca(2+) from internal stores and hence several Ca(2+) -dependent functions were strongly impaired in asm(-/-) BMMCs. Thus, antigen-induced increase in [Ca(2+)]i in IgE sensitized cells, antigen- but not ionomycin-induced currents through Ca(2+) activated K(+) -channels (KCa 3.1), IgE/antigen-triggered beta-hexosaminidase release, and antigen-induced migration were all lower in asm(-/-) BMMCs than in asm(+/+) BMMCs. Pharmacological inhibition of Asm by amitriptyline (500 nm, 3 h) in asm(+/+) BMMCs similarly decreased antigen-induced increase in [Ca(2+)]i , KCa 3.1 currents, beta-hexosaminidase release and migration. The decrease in body temperature upon the induction of systemic anaphylaxis was significantly less pronounced in asm(-/-) mice than in asm(+/+) mice, an observation pointing to in vivo significance of Asm. CONCLUSIONS AND CLINICAL RELEVANCE: Asm is a novel, powerful regulator of mast cell function and thus a potential target in the treatment of allergic reactions. PMID- 24164339 TI - Melatonin's protective effect against UV radiation: a systematic review of clinical and experimental studies. AB - BACKGROUND: Ultraviolet (UV) radiation is the main etiologic factor for skin cancer. The endogenous hormone melatonin has been proposed to have protective effects against sunlight. AIM: The aim of this review was to evaluate melatonin's protective effects against UV radiation and to clarify the cellular mechanisms behind this effect. METHOD: Medline, Embase and Cinahl were searched up to January 2013 to identify studies evaluating melatonin's protective effect against UV radiation (UVR)-induced skin erythema in humans and damage on a cellular level. RESULTS: Four human studies have investigated melatonin's protective effect on UVR-induced skin damage. Melatonin was shown to have protective effects when applied before UVR, but no effect if applied after exposure. A total of 16 experimental studies evaluated melatonin's protective effect against UVR-induced damage to cellular structures and pathways. DISCUSSION/CONCLUSION: The protection against UVR-induced skin damage was conducted by melatonin acting directly as an antioxidant, and indirectly by regulating gene expression and inducing a DNA stabilizing effect. As these results were obtained using artificial UVR and without investigating possible side effects, studies using natural sunlight and evaluating possible side effects of topical melatonin administration are warranted. PMID- 24164340 TI - Erythematous plaque on the abdomen of an infant. PMID- 24164341 TI - Rhodium(III)-catalyzed direct regioselective synthesis of 7-substituted indoles. AB - An efficient, atom-economic one-pot method was developed for the preparation of 7 substituted indoles via rhodium(III)-catalyzed oxidative cross-coupling. Regioselective olefination of indoline derivatives followed by one-pot subsequent oxidation provided the desired products in good to excellent yields. PMID- 24164342 TI - Ruminal bioremediation of the high energy melting explosive (HMX) by sheep microorganisms. AB - The ability of ruminal microorganisms to degrade octahydro-1,3,5,7-tetranitro 1,3,5,7-tetrazocine (high melting explosive, HMX) as consortia from whole rumen fluid (WRF), and individually as 23 commercially available ruminal strains, was compared under anaerobic conditions. Compound degradation was monitored by high performance liquid chromatography, followed by liquid chromatography-tandem mass spectrometry (LC-MS/MS) for delineation of the metabolic pathway. In WRF, 30 MUM HMX was degraded to 5 MUM HMX within 24 h. Metabolites consistent with m/z 149, 193 and 229 were present throughout the incubation period. We propose that peaks with an m/z of 149 and 193 are arrived at through reduction of HMX to nitroso or hydroxylamino intermediates, then direct enzymatic ring cleavage to produce these HMX derivatives. Possible structures of m/z 229 are still being investigated and require further LC-MS/MS analysis. None of the 23 ruminal strains tested were able to degrade HMX as a pure culture when grown in either a low carbon or low nitrogen basal medium over 120 h. We conclude that microorganisms from the rumen, while sometimes capable as individuals in the bioremediation of other explosives, excel as a community in the case of HMX breakdown. PMID- 24164344 TI - Slow folding-unfolding kinetics of an octameric beta-peptide bundle. AB - beta-Peptide foldamers offer attractive frameworks for examining the effect of backbone flexibility on the dynamics of protein folding. Herein, we study the folding-unfolding kinetics of a beta-peptide, Acid-1Y,1 which folds in aqueous solution into an octameric bundle of peptides in a conformation known as the 14 helix. Acid-1Y is comprised exclusively of beta-amino acids, which differ from alpha-amino acids by the addition of a single methylene into the backbone. We aim to understand how the additional degree of freedom and increased backbone flexibility in the beta-amino acid affect folding dynamics and to measure folding rates of this octameric beta-peptide. Previously, we found that the T-jump induced relaxation kinetics of a monomeric beta-peptide that forms a monomeric 14 helix occurred on the nanosecond time scale2 and were noticeably slower than a similar alanine-based alpha-helical peptide.3 Additionally, in comparison to similar alpha-helices, the relaxation rates showed a weaker dependence on temperature. Here, we find that the T-jump induced relaxation kinetics of the octameric beta-peptide occurs on an even slower time scale (minutes) and the unfolding relaxation rates show a large dependence on temperature. These differences indicate that folding energy landscapes of beta-peptide secondary and quaternary structure are markedly distinct from one another and also from their alpha-helical counterparts. PMID- 24164345 TI - Inflammatory bowel disease in Icelandic children 1951-2010. Population-based study involving one nation over six decades. AB - AIM AND BACKGROUND. We describe the changes in incidence and disease location of inflammatory bowel disease (IBD) in children in one country over six decades. Iceland is an island with centralized health information. Children with IBD are cared for in only two hospitals. Iceland is therefore well suited for nationwide epidemiologic studies. MATERIAL AND METHODS. All IBD patients 16 years and younger diagnosed in Iceland from 1950-2010 were included. Patients were identified retrospectively from 1950-1989, and prospectively from 1990-2010, by reviewing pathology and charts for all patients diagnosed with IBD. Criteria for the diagnosis of ulcerative colitis (UC) were history of blood in stools for >3 weeks, characteristic endoscopic appearance of continuous inflammation of the colon, and histologic appearance of acute and chronic inflammation of the colon without granulomata. Criteria of Crohn's disease (CD) were history of abdominal pain, blood in stools, and endoscopic, radiologic, and histologic features of CD. RESULTS. One hundred and ten children were diagnosed with IBD, 61 with UC, 44 with CD, and 5 with indeterminate disease. The median age was 13.7 +/- 2.6, with sex distribution varying from decade to decade. From 1980 until 2000, there was a dramatic increase in the incidence of IBD from 1.2 per 100,000 children <16 years of age to 5.6 per 100,000. However, in the past decade, the incidence has plateaued. CONCLUSION. In this population-based pediatric study, we report an increase in the incidence of IBD from 1950-2000. Incidence in Icelandic children is lower than in published studies from other Northern European countries. PMID- 24164346 TI - De novo characterization of the Dialeurodes citri transcriptome: mining genes involved in stress resistance and simple sequence repeats (SSRs) discovery. AB - The citrus whitefly, Dialeurodes citri (Ashmead), is one of the three economically important whitefly species that infest citrus plants around the world; however, limited genetic research has been focused on D. citri, partly because of lack of genomic resources. In this study, we performed de novo assembly of a transcriptome using Illumina paired-end sequencing technology (Illumina Inc., San Diego, CA, USA). In total, 36,766 unigenes with a mean length of 497 bp were identified. Of these unigenes, we identified 17,788 matched known proteins in the National Center for Biotechnology Information database, as determined by Blast search, with 5731, 4850 and 14,441 unigenes assigned to clusters of orthologous groups (COG), gene ontology (GO), and SwissProt, respectively. In total, 7507 unigenes were assigned to 308 known pathways. In depth analysis of the data showed that 117 unigenes were identified as potentially involved in the detoxification of xenobiotics and 67 heat shock protein (Hsp) genes were associated with environmental stress. In addition, these enzymes were searched against the GO and COG database, and the results showed that the three major detoxification enzymes and Hsps were classified into 18 and 3, 6, and 8 annotations, respectively. In addition, 149 simple sequence repeats were detected. The results facilitate the investigation of molecular resistance mechanisms to insecticides and environmental stress, and contribute to molecular marker development. The findings greatly improve our genetic understanding of D. citri, and lay the foundation for future functional genomics studies on this species. PMID- 24164347 TI - Kinetics and mechanism of the oxidation of N-acetyl homocysteine thiolactone with aqueous iodine and iodate. AB - The kinetics of N-acetyl homocysteine thiolactone (NAHT) oxidation by aqueous iodine and iodate were studied by spectrophotometric techniques. The iodate-NAHT reaction is slow and results in the formation of N-acetyl homocysteine thiolactone sulfoxide as the sole product (NAHTSO). The stoichiometry of the reaction was deduced as: IO3(-) + 3NAHT -> I(-) + 3NAHTSO (S1). In excess iodate conditions, the iodide produced in S1 is oxidized to give iodine: IO3(-) + 5I(-) + 6H(+) -> 3I2 + 3H2O (S2). Thus in excess iodate conditions the overall stoichiometry of the reaction is a linear combination of S1 and S2 that eliminates iodide, 5S1 + S2: 2IO3(-)+ 5NAHT+ 2H(+) -> I2 + 5NAHTSO + H2O. There was a 1:1 stoichiometry for the NAHT - I2 reaction: NAHT+ I2 + H2O -> NAHTSO +2I( ) + 2H(+) (S3). All reactions, S1, S2 and S3 occur simultaneously and since they are all comparable in rate; complex dynamics were observed. Iodide catalyzes S1 and S2 but inhibits S3. Iodide is a product of both S1 and S3. It has the most profound effect on the overall global dynamics observed. The overall reaction scheme which involved S1, S2 and S3 was modeled by a simple 12-reaction mechanistic scheme which gave a very good fit to experimental data. PMID- 24164348 TI - Anti-Emm in a pregnant patient--case report. AB - A 23-year-old primigravida of North African origin presented with a positive antibody screen at booking at 15 weeks of gestation. An antibody to a high frequency antigen (HFA) of unknown identity was detected, which was reactive with the red blood cells of the father. This led to several challenges including antibody identification, clinical monitoring to detect signs of haemolytic disease of the foetus and newborn (HDFN) and compatible blood in case perinatal transfusion was needed. Anti-Emm was identified 2 months post-partum. This is the first published case which describes a pregnant patient with anti-Emm. PMID- 24164349 TI - Urban and rural patterns in emergent pediatric transfer: a call for regionalization. AB - CONTEXT: National groups call for the regionalization of health care, to direct patients with high-risk conditions to designated hospitals with greater capabilities. Currently there is limited information detailing the characteristics and specific needs of acutely ill and injured children who require transfer to another institution, especially in underserved rural communities. PURPOSE: To determine the epidemiology of pediatric transfers from urban and rural emergency departments (EDs). METHODS: We analyzed data in the National Hospital Ambulatory Medical Care Survey from 1995 to 2010. Eligible children were <18 years of age seen in a United States ED, and transferred to another hospital after initial evaluation. FINDINGS: Of all 283,232,058 pediatric ED visits, less than 0.5% resulted in a transfer, yielding a population-based estimate of 900,100 transfers nationally during this period. Urban and rural EDs showed similar transfer rates. Children transferred from rural EDs were older and more likely to arrive by emergency medical services than children transferred from urban EDs (12.1 vs 8.2 years of age, P < .01). Children from rural EDs were more than twice as likely to be transferred for a psychiatric indication (43.5% vs 19.5%, P < .01). CONCLUSIONS: Emergency pediatric transfers are uncommon in the United States; transfer rates are similar in urban and rural settings. Rural children have additional obstacles to care, especially in access to emergency mental health services. Programs to study and implement regionalization of care should consider diverse patient populations and target improvement in coordination of care, transfer times, and outcomes. PMID- 24164350 TI - Microfluidic fabrication of monodisperse polylactide microcapsules with tunable structures through rapid precipitation. AB - We describe a versatile and facile route to the continuous production of monodisperse polylactide (PLA) microcapsules with controllable structures. With the combination of microfluidic emulsification, solvent diffusion, and internal phase separation, uniform PLA microcapsules with a perfluorooctyl bromide (PFOB) core were successfully obtained by simply diluting monodisperse ethyl acetate (EA)-in-water emulsion with pure water. Rapid extraction of EA from the droplets into the aqueous phase enabled the solidification of the polymer droplets in a nonequilibrium state during internal phase separation between a concentrated PLA/EA phase and a PFOB phase. Higher-molecular-weight PLA generated structural complexity of the microcapsules, yielding core-shell microcapsules with covered with small PFOB droplets. Removal of the PFOB via freeze drying gave hollow microcapsules with dimpled surfaces. The core-shell ratios and the diameter of these microcapsules could be finely tuned by just adjusting the concentration of PFOB and flow rates on emulsification, respectively. These biocompatible microcapsules with controllable size and structures are potentially applicable in biomedical fields such as drug delivery carriers of many functional molecules. PMID- 24164351 TI - Stem cell trials for cardiovascular medicine: ethical rationale. AB - Stem cell-based interventions provide new treatment prospects for many disease conditions, including cardiovascular disorders. Clinical trials are necessary to collect adequate evidence on (long-term) safety and efficacy of novel interventions such as stem cells, but the design and launch of clinical trials, from first-in-human studies to larger randomized controlled trials (RCTs), is scientifically and ethically challenging. Stem cells are different from traditional pharmaceuticals, surgical procedures, and medical devices in the following ways: the novelty and complexity of stem cells, the invasiveness of the procedures, and the novel aim of regeneration. These specifics, combined with the characteristics of the study population, will have an impact on the design and ethics of RCTs. The recently closed JUVENTAS trial will serve as an example to identify the (interwoven) scientific and ethical challenges in the design and launch of stem cell RCTs. The JUVENTAS trial has investigated the efficacy of autologous bone marrow cells in end-stage vascular patients, in a double-blind sham-controlled design. We first describe the choices, considerations, and experiences of the JUVENTAS team. Subsequently, we identify the main ethical and scientific challenges and discuss what is important to consider in the design of future stem cell RCTs: assessment of risks and benefits, the choice for outcome measures, the choice for the comparator, the appropriate selection of participants, and adequate informed consent. Additionally, the stem cell field is highly in the spotlight due to the (commercial) interests and expectations. This warrants a cautious pace of translation and scrupulous set up of clinical trials, as failures could put the field in a negative light. At the same time, knowledge from clinical trials is necessary for the field to progress. We conclude that in the scientifically and ethically challenging field of stem cell RCTs, researchers and clinicians have to maneuver between the Skylla of hyper accelerated translation without rigorously conducted RCTs and the Charybdis of the missed opportunity of valuable knowledge. PMID- 24164352 TI - A molecular dynamics examination on mutation-induced catalase activity in coral allene oxide synthase. AB - Coral allene oxide synthase (cAOS) catalyzes the formation of allene oxides from fatty acid hydroperoxides. Interestingly, its active site differs from that of catalase by only a single residue yet is incapable of catalase activity. That is, it is unable to catalyze the decomposition of hydrogen peroxide to molecular oxygen and water. However, the single active-site mutation T66V allows cAOS to exhibit catalase activity. We have performed a series of molecular dynamics (MD) simulations in order to gain insights into the differences in substrate (8R hydroperoxyeicosatetraenoic) and H2O2 active site binding between wild-type cAOS and the T66V mutant cAOS. It is observed that in wild-type cAOS the active site Thr66 residue consistently forms a strong hydrogen-bonding interaction with H2O2 (catalase substrate) and, importantly, with the aid of His67 helps to pull H2O2 away from the heme Fe center. In contrast, in the T66V-cAOS mutant the H2O2 is much closer to the heme's Fe center and now forms a consistent Fe...O2H2 interaction. In addition, the His67...H2O2 distance shortens considerably, increasing the likelihood of a Cpd I intermediate and hence exhibiting catalase activity. PMID- 24164354 TI - Biological system responses to zearalenone mycotoxin exposure by integrated metabolomic studies. AB - This study aims to investigate the effect of zearalenone supplementation on rat metabolism. Rats received biweekly intragastric administration of zearalenone mycotoxin (3 mg/kg body weight) for 2 weeks. Urine and plasma samples after zearalenone administration were analyzed by NMR-based metabolomics. Zearalenone exposure significantly elevated the plasma levels of glucose, lactate, N-acetyl glycoprotein, O-acetyl glycoprotein, and propionate but reduced the plasma levels of tyrosine, branched-chain amino acids, and choline metabolites. Zearalenone supplementation decreased the urine levels of butyrate, lactate, and nicotinate. However, it increased the urine levels of allantoin, choline, and N methylnicotinamide at 0-8 h after the last zearalenone administration and those of 1-methylhistidine, acetoacetate, acetone, and indoxyl sulfate at 8-24 h after the last zearalenone administration. These results suggest that zearalenone exposure can cause oxidative stress and change common systemic metabolic processes, including cell membrane metabolism, protein biosynthesis, glycolysis, and gut microbiota metabolism. PMID- 24164355 TI - Binge drinking in Spain, 2008-2010. AB - BACKGROUND: Most alcohol-related research has focused on northern and eastern Europe and the United States. Data on Mediterranean countries point to drinking patterns approaching the sporadic and excessive patterns found in northern and eastern Europe. This is the first study to estimate the prevalence of binge drinking (BD) and the joint distribution of BD, regular heavy alcohol consumption, and alcohol abuse or dependence (AAD) in a nationally representative sample of the adult population of Spain. METHODS: Cross-sectional study conducted in 2008 to 2010 with 9,130 persons aged 18 to 64 years. BD was defined as intake of >=80 g of alcohol in men (>=60 g in women) during any drinking occasion in the previous month, with >=3 BD episodes discriminating between frequent and sporadic BD. Regular alcohol consumption was measured with a validated diet history, and the threshold between moderate and heavy drinking was >=40 g of alcohol/d in men (>=24 g in women). AAD was defined by a CAGE score >=2. RESULTS: BD prevalence was 10% (95% confidence interval [CI]: 8.8 to 11.2) in men and 4.2% (95% CI: 3.5 to 4.8) in women, and proved highest among 18- to 24-year-olds (19.5% in men and 10.3% in women). During the latest BD episode, men consumed a mean of 114 g of alcohol versus 85.3 g in women; spirits accounted for 65.2 and 66.2% of total intake, respectively. The mean number of monthly BD episodes was 2.3 in men and 2 in women. Among binge drinkers, 61% were 18- to 34-year-olds, over 80% had regular moderate drinking, 25% reported frequent BD, and 22.8% reported AAD. In multivariate analyses, sporadic BD and frequent BD were associated with AAD independently of regular alcohol intake. CONCLUSIONS: Prevalence of BD in Spain is moderately high. Prevention interventions should consider that the majority of binge drinkers are young men with regular moderate consumption and no AAD traits. PMID- 24164356 TI - Diagnostic and prognostic value of MRI T2 quantification in heart transplant patients. AB - This study was designed retrospectively to assess the value of myocardial T2 to detect or predict ongoing acute heart rejection, in heart transplant patients, with a 1.5-T MRI magnet. One hundred and ninety-six myocardial T2 quantifications were performed on sixty consecutive heart transplant patients during routine follow-up. T2 values were assessed (i) with regard to the results of concomitant biopsies and (ii) with a Cox multivariate model for the prediction of subsequent rejections, defined by a >= grade 2 at biopsy or highly suspected in the absence of biopsy (>10% drop in ejection fraction with subsequent reversibility under treatment). T2 values were proposed as main covariate, after logit transformation and adjustment for other confounding parameters such as delay since graft surgery and delay before biopsy. T2 values were strongly linked (i) to the presence of rejection on concomitant biopsy (P < 0.0001) and (ii) to the risk of subsequent rejection on Cox multivariate model (P < 0.001). T2 values above 60 ms were associated with relative risk of rejection higher than 2.0 and rapidly increasing. In conclusion, myocardial T2 yields a high diagnostic and prognostic value for graft rejection in heart transplant patients. PMID- 24164353 TI - Actin dynamics in growth cone motility and navigation. AB - Motile growth cones lead growing axons through developing tissues to synaptic targets. These behaviors depend on the organization and dynamics of actin filaments that fill the growth cone leading margin [peripheral (P-) domain]. Actin filament organization in growth cones is regulated by actin-binding proteins that control all aspects of filament assembly, turnover, interactions with other filaments and cytoplasmic components, and participation in producing mechanical forces. Actin filament polymerization drives protrusion of sensory filopodia and lamellipodia, and actin filament connections to the plasma membrane link the filament network to adhesive contacts of filopodia and lamellipodia with other surfaces. These contacts stabilize protrusions and transduce mechanical forces generated by actomyosin activity into traction that pulls an elongating axon along the path toward its target. Adhesive ligands and extrinsic guidance cues bind growth cone receptors and trigger signaling activities involving Rho GTPases, kinases, phosphatases, cyclic nucleotides, and [Ca++] fluxes. These signals regulate actin-binding proteins to locally modulate actin polymerization, interactions, and force transduction to steer the growth cone leading margin toward the sources of attractive cues and away from repellent guidance cues. PMID- 24164357 TI - Nationally representative levels of selected volatile organic compounds in Canadian residential indoor air: population-based survey. AB - A comprehensive, population-based national indoor air survey was conducted in 2009-2011 in Canada. A total of 84 volatile organic carbons (VOCs) from 3218 houses, 546 apartments, and 93 other dwelling types were measured using passive sampling followed by thermal desorption GC/MS. A total of 12 VOCs were measured in both this study and the 1992 Canadian national study. Arithmetic means of VOCs in this study were 2-5 times lower than those in the 1992 study with the exception of a higher styrene level (1.13 MUg . m(-3)). Comparing the geometric means of the 24 VOCs showed that levels for the VOCs in this study were comparable to those reported in Europe. They were generally within a factor of 2; 1,4-dichlorobenzene (0.21 MUg . m(-3)) and 1,2,4-trimethylbenzene (0.51 MUg . m( 3)) were noticeably lower in this study than in the European studies. There were 47 VOCs detected in more than 50% of Canadian households; 33 of them were higher in houses than in apartments for all nonsmoking homes, while only 4 were lower in houses than in apartments. A total of 11 of 47 VOCs were higher in smoking homes compared to nonsmoking homes, while the rest had similar levels. Principal component analysis identified several groups of VOCs with possible common sources. PMID- 24164358 TI - Inorganic tin compounds do not induce micronuclei in human lymphocytes in the absence of metabolic activation. AB - The genotoxic evaluation (in vitro analysis) of a series of eight inorganic tin(II) and tin(IV) compounds [tin(II) acetate, tin(II) chloride, tin(II) ethylhexanoate, tin(II) oxalate, tin(II) oxide, tin(IV) acetate, tin(IV) chloride and tin(IV) oxide], for the detection of micronuclei in human blood lymphocytes, was performed in the absence of metabolic activation by the cytokinesis-block micronucleus assay. Human lymphocytes were treated for over one cell cycle (31 hours), with concentrations ranging from 1 to 75 MUM (1, 5, 10, 20, 50 and 75 MUM), of tin(II) and tin(IV) salts dissolved in dimethyl sulfoxide. The above listed concentrations cover the values that have been detected in humans with no occupational exposure to tin compounds. The experimental results show the absence of genotoxicity for all inorganic compounds tested in the specific concentrations and experimental conditions. Cytotoxic effects of tin(II) and tin(IV) compounds were evaluated by the determination of cytokinesis block proliferation index and cytotoxicity percentage. Our observations on the cytotoxicity pattern of the tested tin(II) and tin(IV) compounds indicate that they are cytotoxic in several tested concentrations to human lymphocytes treated in vitro. The observed differences in cytotoxicity of each tested compound might reflect differences in their chemical structure. PMID- 24164359 TI - Sign epistasis limits evolutionary trade-offs at the confluence of single- and multi-carbon metabolism in Methylobacterium extorquens AM1. AB - Adaptation of one set of traits is often accompanied by attenuation of traits important in other selective environments, leading to fitness trade-offs. The mechanisms that either promote or prevent the emergence of trade-offs remain largely unknown, and are difficult to discern in most systems. Here, we investigate the basis of trade-offs that emerged during experimental evolution of Methylobacterium extorquens AM1 to distinct growth substrates. After 1500 generations of adaptation to a multi-carbon substrate, succinate (S), many lineages had lost the ability to use one-carbon compounds such as methanol (M), generating a mixture of M(+) and M(-) evolved phenotypes. We show that trade-offs in M(-) strains consistently arise via antagonistic pleiotropy through recurrent selection for loss-of-function mutations to ftfL (formate-tetrahydrofolate ligase), which improved growth on S while simultaneously eliminating growth on M. But if loss of FtfL was beneficial, why were M trade-offs not found in all populations? We discovered that eliminating FtfL was not universally beneficial on S, as it was neutral or even deleterious in certain evolved lineages that remained M(+) . This suggests that sign epistasis with earlier arising mutations prevented the emergence of mutations that drove trade-offs through antagonistic pleiotropy, limiting the evolution of metabolic specialists in some populations. PMID- 24164360 TI - Aldehyde dehydrogenase 2 partly mediates hypotensive effect of nitrite on L-NAME induced hypertension in normoxic rat. AB - Nitrite has become a topic of interest in the field of medical research because of its potential therapeutic role as an alternative source of nitric oxide (NO). While the bioconversion of nitrite to NO occurs via either nonenzymatic or enzymatic reduction under acidic or hypoxic conditions, little is known about its conversion to NO under normoxic conditions. Because of a recent report of aldehyde dehydrogenase 2 (ALDH2)-catalyzed glyceryl trinitrate (GTN) vasorelaxation by denitration of GTN to 1,2-glyceryl dinitrate (1,2-GDN) and nitrite, we therefore investigated a catalytic activity of ALDH2 for nitrite reduction and subsequent effect on N(omega)-nitro-l-arginine methyl ester (l NAME)-induced hypertension in normoxic rat. Male Sprague-Dawley rats treated with l-NAME in drinking water for 3 weeks developed hypertension with significantly reduced plasma levels of nitrite and nitrate. The intravenous injection of sodium nitrite lowered the arterial pressure in a dose-dependent manner (17, 50 and 150 MUmol/kg). Pretreatment with ALDH2 inhibitors (cyanamide and chloral hydrate) partially inhibited the hypotensive responses to sodium nitrite. In addition, cyanamide significantly delayed the nitrite clearance from plasma and most of the organs examined during the experimental period. These results suggest that ALDH2 may be at least in part involved in nitrite-mediated hypotensive effects and nitrite catalysis in many organs of normoxic rats. PMID- 24164361 TI - The effect of biomass fuel exposure on the prevalence of asthma in adults in India - review of current evidence. AB - INTRODUCTION: The combustion of biomass fuels is a major source of respiratory disease among individuals in the developing world. Over two million people world wide rely on biomass fuels to supply their household energy needs with an estimated 1.6 million deaths annually being attributable to biomass smoke exposure. As a developing country, India relies heavily on the use of solid fuels as a source of energy. These materials supply 75% of the country's domestic energy need and are attributed as the cause of over 600 000 deaths annually. Diseases such as chronic bronchitis and acute lower respiratory tract infections are strongly correlated to biomass smoke exposure. While not as strongly correlated, accumulating evidence suggests that asthma prevalence may be related to solid fuel smoke. METHODS: This review examines the current literature linking biomass smoke exposure to the reporting of asthma symptoms. A PubMed search was performed using key terms biomass, asthma, India and respiratory disease. Preference was given to recent articles that surveyed the adult population within India. RESULTS: The reviewed articles showed an increased odds ratio for reporting a diagnosis of asthma or symptoms consistent with asthma following biomass smoke exposure. While the literature supports a strong association between household air pollution and the development of chronic bronchitis and acute lower respiratory tract infections in India, this review establishes a more firm relationship between reported asthma symptoms and biomass smoke exposure. CONCLUSION: The exposure to biomass fuel smoke results in respiratory diseases in developing countries. Among these diseases, asthma appears to be a preventable pulmonary pathology that is associated with household air pollution. Measures to reduce exposure may decrease the burden of disease which could help advance social and economic progress in these nations. Further research and out-reach efforts are needed to reduce the total burden of lung diseases, including asthma, across the developing world. This reduction could save millions of dollars annually and lower morbidity and mortality in the affected populations. PMID- 24164362 TI - Poorly differentiated thyroid carcinomas: application of the Turin proposal provides prognostic results similar to those from the assessment of high-grade features. AB - AIMS: To investigate the performance of two proposed methods for assessing the prognosis of poorly differentiated thyroid carcinomas (PDTC): the Turin proposal and Hiltzik's histological grade (HHG). This was done using a series of 82 thyroid carcinomas of follicular origin. RESULTS: The two methods were able to classify patients accurately into two different prognosis groups. Although the Turin proposal and HHG displayed discrepant cases, they provided similar prognostic information. The Turin proposal gave accurate numbers and thresholds of PTDC criteria (loss of follicular architecture and mitoses, necrosis or convoluted nuclei). One Turin criterion, convoluted nuclei, failed to provide any prognostic value. Hiltzik's histological grade was also a simple and reliable method, allowing detection of tumours with high-grade features (mitosis and/or tumour necrosis), notably some papillary carcinomas that displayed an intermediate prognosis. We show that Ki67 labelling (>= 4%) was an independent factor and predictor of cause-specific survival. CONCLUSION: With similar performances in predicting prognosis, the Turin proposal and HHG provided complementary results in identifying a larger group of 'intermediate prognosis' thyroid carcinomas, which require adequate treatment and follow-up. PMID- 24164364 TI - [Prevalence of hyponatremia in patients on department of internal medicine]. AB - INTRODUCTION: Hyponatremia is the most common electrolyte disorder detected by bio-chemical laboratories in the present time and interest about it increases because of new informations about its consequences. AIM: Objective of our work was to determine the prevalence of hyponatremia in patients hospitalized at clinic of internal medicine and to analyze its most common causes. PATIENTS AND RESULTS: The total number of hospitalized patients for a period of 6 months was 1,203. Severe hyponatremia, i.e. S Na < 130 mmol/ l was detected in 83 cases, i.e. 6.9% of all patients. 14 patients, i.e. 1.15% have more severe hyponatremia with S Na < 120 mmol/ l. The most common type of hyponatremia was hypervolemic hyponatremia (n = 41; 49.4%) associated with liver cirrhosis and hearth failure, less common was euvolemic hyponatremia (n = 28; 33.7%) and least common was hypovolemic hyponatremia (n = 14; 16.9%). The most common cause of euvolemic hyponatremia was syndrome of inappropriate antidiuretic hormone secretion (SIADH) and thiazide diure-tics therapy. Next to thiazide diuretics, other common cause of euvolemic hyponatremia, and so SIADH, was therapy by selective serotonin reuptake inhibitors (SSRI). CONCLUSION: The authors point out, that it is necessary to control serum sodium concentration on regular base in case of longterm therapy by thiazide diuretics or SSRI, especially in elderly patients. PMID- 24164363 TI - Ynamides in ring forming transformations. AB - The ynamide functional group activates carbon-carbontriple bonds through an attached nitrogen atom that bears an electron-withdrawing group. As a result, the alkyne has both electrophilic and nucleophilic properties. Through the selection of the electron-withdrawing group attached to nitrogen, chemists can modulate the electronic properties and reactivity of ynamides, making these groups versatile synthetic building blocks. The reactions of ynamides also lead directly to nitrogen-containing products, which provides access to important structural motifs found in natural products and molecules of medicinal interest. Therefore, researchers have invested increasing time and research in the chemistry of ynamides in recent years. This Account surveys and assesses new organic transforma-tions involving ynamides developed in our laboratory and in others around the world. We showcase the synthetic power of ynamides for rapid assembly of complex molecular structures. Among the recent reports of ynamide transformations, ring-forming reactions provide a powerful tool for generating molecular complexity quickly. In addition to their synthetic utility, such reactions are mechanistically interesting. Therefore, we focus primarily on the cyclization chemistry of ynamides. This Account highlights ynamide reactions that are useful in the rapid synthesis of cyclic and polycyclic structural manifolds. We discuss the mechanisms active in the ring formations and describe representative examples that demonstrate the scope of these reactions and provide mechanistic insights. In this discussion, we feature examples of ynamide reactions involving radical cyclizations, ring-closing metathesis, transition metal and non-transition metal mediated cyclizations, cycloaddition reactions, and rearrangements. The transformations presented rapidly introduce structural complexity and include nitrogen within or in close proximity to a newly formed ring (or rings). Thus, ynamides have emerged as powerful synthons for nitrogen containing heterocycles and nitrogen-substituted rings, and we hope this Account will promote continued interest in the chemistry of ynamides. PMID- 24164365 TI - [The impact of a 14- day regular physical exercise regime on the concentration of the classes and subclasses of lipoprotein particles in young subjects with a sedentary lifestyle]. AB - Recommendations from the cardiological professional companies working in the area of primary prevention of cardiovascular diseases put an emphasis on regular aerobic physical activity. Its positive effect on both cardiovascular and overall mortality has repea-tedly been proven by the observations of prospective and cross sectional epidemiological studies. One of the possible explanations of this positive effect is a change in the concentration of lipoprotein classes and their subclasses, which is expressed as a change in their average size. In a group of young healthy men and women with a sedentary lifestyle we observed the effect of medium intensive physical exercise in the form of a 30- minute slow run per day lasting for 14 days. The concentration of lipoprotein classes and subclasses were determined through the method of a linear electrophoresis in polyacrylamide gel. In the observed group we found a statistically significant decrease of VLDL, large IDL particles, medium sized LDL, small dense LDL, and medium sized HDL particles. In the light of current knowledge all these lipoprotein particles are deemed as atherogenic. Thus, as little as 14 days of regular exercising has a positive effect on the concentration of plasmatic lipoproteins, and emphasises the role of regular physical activity in the primary prevention of cardiovascular diseases. PMID- 24164366 TI - [Ultra high risk chronic lymphocytic leukemia - characteristics and treatment options]. AB - Chronic lymphocytic leukemia (CLL) is the most common form adult leukemia in western world. The disease is typically cha-racterized by heterogeneous clinical behavior ranging from indolent course to rapidly progressive disease. Using clinical and bio-logical factors we can stratify patients with CLL and prospectively identify those who can be expected unfavorable course. There is a special group known as ultra highrisk chronic lymphocytic leukemia with an extremely poor prognosis. These are about 10- 15% of all patients with CLL. They do not respond to standard treatment and their survival is short with a median of 2- 3 years. For highrisk patients are considered: patients with a proven TP53 defect, refractory to purine analogues or with early relapse after chemoimmunotherapy based on fludarabine ( 24 months). While the standard 1st line treatment protocol in younger patients is chemoimmunotherapy FCR, in case of ultra highrisk CLL other methods like allogeneic hematopoietic stem cell transplantation or clinical trials testing the new drugs should be considered. In particular, allogeneic hematopoietic stem cell transplantation is a very promising treatment modality that offers longterm disease control and cure regardless of the unfavorable CLL subtype. Transplantation treatment should be therefore considered in all younger patients with ultra highrisk CLL, who should be without delay referred to a center for intensive hematological treatment. PMID- 24164367 TI - [Methods of skin microcirculation assessment]. AB - Microcirculation plays an important role in pathophysiology of a number of severe diseases. At present there exist many techniques that enable evaluation of microvascular perfusion. Some of them found their scientific and clinical use even in the Czech Republic. In last decade, articles referring about individual methods can be found even on the pages of Vnitrni lekarstvi journal. The aim of this work is to provide a comprehensive overview of methods that have been used for examination of the microcirculation to date. After a short review of the anatomy and physiology of the microcirculation, the article provides synopsis of the theoretical and practical use of individual methods including their advantages and disadvantages. PMID- 24164368 TI - [The current approach to the treatment of the patients with metastatic colorectal cancer]. AB - Colorectal cancer is one of the most common malignant tumors. Despite the constant promotion of prevention remains around 20- 30% of cases dia-gnosed in the metastatic stage and approximately 50- 60% of patients developed the late dissemination. In 80- 90% of them we can find already unresectable metastases. Although surgical treatment is basic modality of therapy, with using mo-dern targeted therapy in combination with chemotherapy we can achieve longterm complete remission in the cases of advanced tumor and we can significantly prolonged the life of patients with this disease now. About 40- 50% patients in advanced stages who underwent metastasectomy survives 5-years and 10year survival rate is up to 25%. When administered systemic treatment median overall survival in these cases reaches around 24 months. PMID- 24164369 TI - [Management of dyslipidaemias - present and future. Guidelines of the Angiology Section of the Slovak Medical Chamber (2013)]. AB - AIM: The aim of Guidelines of the Angiology Section of the Slovak Medical Chamber is to address a last European guidelines for the management of dyslipidaemias, as well as results in evidencebased medicine (EBM) in order to assess their contribution to our expanding knowledge on reducing of residual organovascular risk. DISCUSSION: Lipid metabolism can be disturbed in different ways, leading to changes in plasma lipoprotein function and/ or levels. This by itself and through interaction with other vascular risk factors and endothelial dysfunction may affect the development of atherosclerosis and other vascular diseases. Therefore, dyslipidaemias cover a broad spectrum of lipid abnormalities, some of which are of great importance in organovascular prevention. Dyslipidaemias may be related to other diseases (secondary dyslipidaemias) or to the interaction between genetic predisposition and environmental factors. Dyslipidaemias may also have a different meaning in certain subgroups of patients which may relate to genetic predisposition and/ or co morbidities. This requires particular attention complementary to the management of the total CV risk. Optimal LDLcholesterol levels are the primary strateging task in the therapeutical preventive approaches. However, at present increasing attention has focused on the role of inflamation, levels of HDLcholesterol and triglycerides in the process of atherosclerosis. Statins represent basic pillar in dyslipidemia treatment. Despite the intensive management of all conventional vascular risk factors and the intensified treatment with statins, residual organovascular risk remains high. Therefore the interest is focused on finding the place of combined antidyslipidemic treatment and the development of new antidyslipidemics. CONCLUSION: Strategies for preventing of organovascular diseases have emphasized vascular risk factors effective modification using treatment approaches supported by evidencebased medicine (EBM). PMID- 24164370 TI - [Tricuspid valve infective endocarditis in intravenous drug abuser]. AB - Infective endocarditis can be divided from practical point of view into native valve endocarditis and prosthetic valve endocarditis. With regard to aquired endocarditis, endocarditis in intravenous drug abusers can be separetly differentiated. Echocardiography and microbio-logical cultures are essential for dia-gnosis. Treatment consists of antibio-tic therapy and often surgical procedure is required. We present a case report of an intravenous drug abuser with a tricuspid valve endocarditis, successfully treated with antibio-tic therapy and a following surgical valve repair. PMID- 24164371 TI - Sick-leave decisions for patients with severe subjective health complaints presenting in primary care: a cross-sectional study in Norway, Sweden, and Denmark. AB - OBJECTIVES: The primary objective of this study was to explore whether general practitioners (GPs) in Norway, Sweden, and Denmark make similar or different decisions regarding sick leave for patients with severe subjective health complaints (SHC). The secondary objective was to investigate if patient diagnoses, the reasons attributed for patient complaints, and GP demographics could explain variations in sick leave decisions. DESIGN: A cross-sectional study. METHOD: Video vignettes of GP consultations with nine different patients. SUBJECTS: 126 GPs in Norway, Sweden, and Denmark. SETTING: Primary care in Norway, Sweden, and Denmark. MAIN OUTCOME MEASURE: Sick leave decisions made by GPs. RESULTS: "Psychological" diagnoses in Sweden were related to lower odds ratio (OR) of granting sick leave than in Norway (OR = 0.07; 95% CI = 0.01-0.83) Assessments of patient health, the risk of deterioration, and their ability to work predicted sick leave decisions. Specialists in general medicine grant significantly fewer sick leaves than non-specialists. CONCLUSION: Sick-leave decisions made by GPs in the three countries were relatively similar. However, Swedish GPs were more reluctant to grant sick leave for patients with "psychological" diagnoses. Assessments regarding health-related factors were more important than diagnoses in sick-leave decisions. Specialist training may be of importance for sick-leave decisions. PMID- 24164372 TI - Red cell storage in E-Sol 5 and Adsol additive solutions: paired comparison using mixed and non-mixed study designs. AB - BACKGROUND AND OBJECTIVES: If transfusion of older stored red cells is found to negatively affect clinical outcome, one possible alternative to shortened outdate is the use of new additive solutions (AS) that ameliorate the storage lesion. Erythro-Sol (E-Sol), a previously developed next-generation AS, has been reformulated into E-Sol 5, which is compatible with current anticoagulants and AS volumes. The effect of E-Sol 5 on red cells during storage compared to current AS has not been reported. MATERIALS AND METHODS: Paired, ABO-matched whole-blood units were collected into CPD anticoagulant, pooled, split and processed into plasma and red cell units with either 110 ml of Adsol or 105 ml of E-Sol 5 within 8 h of collection. In Study 1, paired units in E-Sol 5 and Adsol were sampled on Day 0 and every 7 days up to Day 42 (n = 10). In Study 2, paired units in E-Sol 5 and Adsol were sampled only on Day 0 and Day 42 (n = 10). RESULTS: In Study 1, 2,3 DPG levels were maintained until Day 28 in E-Sol 5 units and Day 14 in Adsol units. ATP levels were higher in E-Sol 5 units until Day 21, after which they were comparable between the two groups. In both studies, metabolic activity was greater in E-Sol 5 units with respect to glucose consumption and lactate production. Morphology scores were higher, and haemolysis and microparticles generated were lower in E-Sol 5 vs. Adsol units. Weekly mixing of units lowered haemolysis and microparticle levels and increased potassium content on Day 42 in both additive solutions. CONCLUSION: Regardless of whether units are mixed weekly or are stored non-mixed, E-Sol 5 slows the progression of the red cell storage lesion and improves the overall in vitro quality of RBC throughout storage. PMID- 24164373 TI - Photochemical ring-opening in 2,3-diphenyl aziridines. Transient-spectral and kinetic behavior of azomethine ylides and related photointermediates. AB - By employing laser pulses at various wavelengths for nanosecond flash photolysis, a comprehensive time-resolved study has been performed on transient azomethine ylides photogenerated from several 2,3-diphenyl aziridines in fluid solutions under three different conditions, namely, by direct 266 nm excitation, under reversible electron-transfer sensitization by 1,4-dicyanonaphthalene singlet excited state, and via energy transfer from acetone triplet. Under each of the three conditions of photoexcitation, azomethine ylides are readily formed as transient species, characterized by broad, structureless absorption spectra with maxima at 470-500 nm and mostly complex decay kinetics in MUs-ms time domain. Under acetone triplet sensitization, a second, shorter-lived transient species with absorption maximum at ~360 nm is observed to grow and decay in the same time range as that of the growth of ylides. This species has been identified as the ring-opened precursor ylide triplet. The azomethine ylides are practically nonquenchable by oxygen, except that under acetone triplet sensitization in air saturated acetonitrile, their decay is significantly enhanced. The latter is explained in terms of quenching through dipolarophilic reaction with singlet oxygen. A value of 1.6 * 10(9) M(-1) s(-1) has been estimated for the rate constant for reaction between singlet oxygen and ylide from trans-2,3 diphenylaziridine. We also report rate constants, in the range 2 * 10(3) to 4 * 10(9) M(-1) s(-1), for the quenching of azomethine ylides by two dipolarophiles, namely, maleic anhydride and dimethyl acetylene dicarboxylate. The dipolarophilic reactivity of ylides carrying bulky substituents on the N atom is relatively subdued. Acetic acid proved to be a modest quencher of ylides with rate constants close to 10(6) M(-1) s(-1). PMID- 24164374 TI - BRAF V600 co-testing is technically feasible in conventional thyroid fine needle aspiration (FNA) cytology smears and can reduce the need for completion thyroidectomy. AB - INTRODUCTION: While fine needle aspiration cytology (FNAC) is the mainstay of diagnosis in thyroid nodules, molecular markers of thyroid cancer have recently been shown to be of value in improving the diagnosis and reducing the rates of unnecessary surgery. METHOD: A technical method is presented for the assessment of the BRAF V600 gene mutation in thyroid cancer using a simple adaptation of a commercially available kit. After standard preparation and reporting of conventionally stained alcohol-fixed Papanicolaou or air-dried Giemsa-stained slides the coverslip is removed from one slide, the DNA is extracted and submitted for PCR analysis. RESULTS: Assessment of the BRAF V600 mutational status is feasible in very small quantities of DNA, requiring just greater than 5 ng per case from a single pre-stained FNA slide using this method. From the 14 cases examined thus far, one Thy4/Bethesda Class V case (suspicious of malignancy) has been identified with a BRAF V600 mutation and this patient, after multidisciplinary discussion, received a total thyroidectomy. CONCLUSION: Based on this methodology and other published results for the BRAF mutation, we believe that it is now feasible and cost effective for the UK NHS to BRAF co-test all Thy4/Bethesda Class V thyroid FNAs, as the additional cost of BRAF testing will still be much less than the cost of submitting all Thy4 (Bethesda Class V) patients to a partial and then a later completion thyroidectomy. PMID- 24164376 TI - Effect of nicotine on dual-species biofilms of Streptococcus mutans and Streptococcus sanguinis. AB - Both Streptococcus mutans and Streptococcus sanguinis are normal bacterial inhabitants of dental plaque. Streptococcus mutans is the major agent causing dental caries. It has been well documented that nicotine affects the growth of S. mutans. This study investigated the effect of nicotine on mono- and dual-species growth of S. mutans and S. sanguinis. The results indicate that nicotine has no significant effect on S. sanguinis grown in either mono- or dual-species biofilms. However, nicotine significantly increased (P < 0.05) the growth of S. mutans in dual-species biofilm formation. In addition, the CFU level of S. sanguinis was higher than S. mutans without nicotine in the culture. With the addition of nicotine, the level of S. mutans biofilm was significantly enhanced as the nicotine concentration increased over the level of S. sanguinis in dual species biofilm, and we also got the same result from the fluorescence in situ hybridization detecting the two bacteria grown in biofilm formation. The exopolysaccharide (EPS) of S. mutans has also been increased by the increasing nicotine concentration, while the EPS of S. sanguinis was decreased or inhibited by the affected nicotine. The data further confirm that nicotine is able to enhance the growth of S. mutans. PMID- 24164375 TI - Evaluation of a home-based colorectal cancer screening intervention in a rural state. AB - PURPOSE: Distance from health care facilities can be a barrier to colorectal cancer (CRC) screening, especially for colonoscopy. Alternatively, an improved at home stool-based screening tool, the fecal immunochemical test (FIT), requires only a single sample and has a better sensitivity-specificity balance compared to traditional guaiac fecal occult blood tests. Our objective was to determine if FITs mailed to asymptomatic, average-risk patients overdue for screening resulted in higher screening rates versus mailing educational materials alone or no intervention (ie, usual care). METHODS: Veterans ages 51-64, asymptomatic, at average risk for CRC, overdue for screening and in a veterans administration (VA) catchment area covering a large rural population were randomly assigned to 3 groups: (1) education only (Ed) group: mailed CRC educational materials and a survey of screening history and preferences (N = 499); (2) FIT group: mailed the FIT, plus educational materials and survey (N = 500); and (3) usual care (UC) group: received no mailings (N = 500). FINDINGS: At 6 months postintervention, 21% of the FIT group had received CRC screening by any method compared to 6% of the Ed group (and 6% of the UC group) (P < .0001). Of the 105 respondents from the FIT group, 71 (68%) were eligible to take the FIT. Of those, 64 (90%) completed the FIT and 8 (12%) tested positive. CONCLUSIONS: This low-intensity intervention of mailing FITs to average risk patients overdue for screening resulted in a significantly higher screening rate than educational materials alone or usual care, and may be of particular interest in rural areas. PMID- 24164377 TI - Protective effects of simultaneous splenectomy on small-for-size liver graft injury in rat liver transplantation. AB - Splenectomy is an effective technique in living donor liver transplantation (LDLT) with small-for-size (SFS) liver grafts for overcoming SFS liver graft injury. However, the protective mechanism of splenectomy is still unclear. The aim of this study was to investigate how splenectomy could attenuate SFS graft injury through the measurement of biochemical factors, particularly the expression of endothelin (ET)-1, which is a key molecule of microcirculatory disorders by mediating sinusoidal vasoconstriction. We performed rat orthotopic liver transplantation using SFS liver grafts with or without splenectomy. We investigated intragraft expression of ET-1 mRNA and hepatic protein levels of ET 1. In addition, portal pressure, hepatic injury and morphological changes, and survival rate were evaluated. In result, intragraft ET-1 mRNA expression after SFS liver transplantation was significantly downregulated by splenectomy, and hepatic expression of ET-1 in SFS grafts was rarely observed. Splenectomy inhibited the increase in portal pressure, ameliorated SFS liver graft injury and improved the graft survival rate after SFS liver transplantation. In conclusion, splenectomy improved the SFS liver injury and decreased the expression of ET-1 by attenuating portal hypertension on SFS liver transplantation. Downregulation of intragraft ET-1 expression plays important roles in the protective mechanism of splenectomy in SFS liver transplantation. PMID- 24164378 TI - Platelet activating factor induces transient blood-brain barrier opening to facilitate edaravone penetration into the brain. AB - The blood-brain barrier (BBB) greatly limits the efficacy of many neuroprotective drugs' delivery to the brain, so improving drug penetration through the BBB has been an important focus of research. Here we report that platelet activating factor (PAF) transiently opened BBB and facilitated neuroprotectant edaravone penetration into the brain. Intravenous infusion with PAF induced a transient BBB opening in rats, reflected by increased Evans blue leakage and mild edema formation, which ceased within 6 h. Furthermore, rat regional cerebral blood flow (rCBF) declined acutely during PAF infusion, but recovered slowly. More importantly, this transient BBB opening significantly increased the penetration of edaravone into the brain, evidenced by increased edaravone concentrations in tissue interstitial fluid collected by microdialysis and analyzed by Ultra performance liquid chromatograph combined with a hybrid quadrupole time-of-flight mass spectrometer (UPLC-MS/MS). Similarly, incubation of rat brain microvessel endothelial cells monolayer with 1 MUM PAF for 1 h significantly increased monolayer permeability to (125)I-albumin, which recovered 1 h after PAF elimination. However, PAF incubation with rat brain microvessel endothelial cells for 1 h did not cause detectable cytotoxicity, and did not regulate intercellular adhesion molecule-1, matrix-metalloproteinase-9 and P-glycoprotein expression. In conclusion, PAF could induce transient and reversible BBB opening through abrupt rCBF decline, which significantly improved edaravone penetration into the brain. Platelet activating factor (PAF) transiently induces BBB dysfunction and increases BBB permeability, which may be due to vessel contraction and a temporary decline of regional cerebral blood flow (rCBF) triggered by PAF. More importantly, the PAF induced transient BBB opening facilitates neuroprotectant edaravone penetration into brain. The results of this study may provide a new approach to improve drug delivery into the brain. PMID- 24164379 TI - An integrative approach to detect subtle trophic niche differentiation in the sympatric trawling bat species Myotis dasycneme and Myotis daubentonii. AB - Bats are well known for species richness and ecological diversity, and thus, they provide a good opportunity to study relationships and interaction between species. To assess interactions, we consider distinct traits that are probably to be triggered by niche shape and evolutionary processes. We present data on the trophic niche differentiation between two sympatric European trawling bat species, Myotis dasycneme and Myotis daubentonii, incorporating a wide spectrum of methodological approaches. We measure morphological traits involved in foraging and prey handling performance including bite force, weightlifting capacity and wing morphology. We then measure resulting prey consumption using both morphological and molecular diet analyses. These species closely resemble each other in morphological traits, however, subtle but significant differences were apparent in bite force and lift capacity, which are related to differences in basic body and head size. Both morphological and molecular diet analyses show strong niche overlap. We detected subtle differences in less frequent prey items, as well as differences in the exploitation of terrestrial and aquatic-based prey groups. Myotis dasycneme feeds more on aquatic prey, like Chironomidae and their pupal stages, or on the aquatic moth Acentria ephemerella. Myotis daubentonii feeds more on terrestrial prey, like Brachycera, or Coleoptera. This suggests that these bats use different microhabitats within the habitat where they co occur. PMID- 24164380 TI - Incommensurately modulated delta"-Au(1+x)Cd(2-x) formed by an unquenchable phase transformation from the gamma-brass delta'-phase. AB - The synthesis and structural determination of the compound delta"-Au(1+x)Cd(2-x) (0.07 <= x <= 0.08) is reported. The structure may be formally derived from that of xi-CoZn13, but elemental ordering causes an incommensurate modulation as determined by single-crystal X-ray diffraction at room temperature. The compound delta"-Au(3.23)Cd(5.76) crystallizes in the monoclinic super space group C2/m(0beta1/2)00 with lattice parameters a = 14.790(2) A, b = 8.251(1) A, c = 12.744(1) A, beta = 115.182(9) degrees and a q-vector q = (0beta1/2), beta = 0.579b*. The delta"-phase is stable up to 652(1) K. PMID- 24164381 TI - Decellularized kidney matrix for perfused bone engineering. AB - The vascularization of tissue-engineered constructs is yet an unsolved problem. Here, recent work on the decellularization of whole organs has opened new perspectives on tissue engineering. However, existing decellularization protocols last several days and derived biomatrices have only been reseeded with cells from the same tissue origin or stem cells differentiating into these types of tissue. Within the present work, we demonstrate a novel standardized, time-efficient, and reproducible protocol for the decellularization of solid tissues to derive a ready to use biomatrix within only 5 h. Furthermore, we prove that biomatrices are usable as potential scaffolds for tissue engineering of vascularized tissues, even beyond tissue and maybe even species barriers. To prove this, we seeded human primary osteoblasts into a rat kidney bioscaffold. Here, seeded cells spread homogeneously within the matrix and proliferate under dynamic culture conditions. The cells do not only maintain their original phenotype within the matrix, they also show a strong metabolic activity and remodel the biomatrix toward a bone-like extracellular matrix. Thus, the decellularization technique has the ability to become a platform technology for tissue engineering. It potentially offers a universally applicable and easily producible scaffold that addresses the yet unsolved problem of vascularization. PMID- 24164382 TI - The long-term efficacy of azathioprine in steroid-dependent ulcerative colitis. AB - OBJECTIVE. The long-term efficacy of azathioprine (AZA) in steroid-dependent ulcerative colitis (UC) is still unclear. We aimed to evaluate the efficacy of AZA in patients with steroid-dependent UC. MATERIAL AND METHODS. We retrospectively reviewed the medical records of 106 patients with steroid dependent UC who were administered AZA. Three-year outcomes of AZA therapy were evaluated. The outcome of the treatment was defined as (1) success, indicating induction and maintenance of remission throughout the study period (complete success) or remission followed by infrequent and short relapses (partial success); or (2) failure, indicating the absence of remission, frequent or prolonged relapses, infliximab administration, or colectomy. RESULTS. Of the 106 patients, 73 (68.9%) continued on AZA for >6 months (AZA therapy group) and 33 (31.1%) discontinued AZA within 6 months due to intolerance (AZA intolerance group, n = 20), colectomy (n = 6), or follow-up loss (n = 7). Three-year outcomes for 106 patients were success in 54.7% (complete success, 35.8%; partial success, 18.9%), failure in 32.1% (frequent or prolonged relapses, 12.3%; infliximab administration, 5.6%; colectomy, 14.2%), and follow-up loss or death in 13.2%. The success rate increased to 71.2% (complete success, 46.6%; partial success, 24.7%) when the analysis was confined to the 73 patients who continued AZA for > 6 months. The 3-year success rate was higher in the AZA therapy group (71.2%) than the AZA intolerance group (25.0%) (p < 0.001). CONCLUSIONS. AZA is an effective treatment for steroid-dependent UC. The efficacy of AZA is well sustained over 3 years. PMID- 24164384 TI - Mutant frequency in comparison to oxidative DNA damage induced by ochratoxin A in L5178Y tk+/- (3.7.2C) mouse lymphoma cells. AB - Ochratoxin A (OTA) is a naturally occurring mycotoxin that contaminates animal feed and human food. OTA is nephrotoxic, hepatotoxic, immunosuppressive and a potent renal carcinogen in rodents. In the present study, we evaluated the genotoxicity of OTA in L5178Y tk(+/-) (3.7.2C) mouse lymphoma cells using the microwell version of the mouse lymphoma gene mutation assay (MLA) and the comet assay modified to detect oxidative DNA damage. Cells were treated for 4 hours with 0, 5, 10, 25, 50 or 100 uM of OTA in the presence and absence of exogenous metabolic activation (S9). Benzo[a]pyrene (1 ug/mL) and 4-nitroquinoline-1-oxide (0.1 ug/mL) were used as positive control with and without S9, respectively. OTA treatment produced dose-dependent increases in cytotoxicity and tk mutant frequency, with significant increases in mutant frequency detected at concentrations >=25 uM with and without S9. Similarly treated cells were used for the comet assay conducted with and without formamidopyrimidine-DNA glycosylase for the determination of oxidative DNA damage. OTA exposure resulted in a significant increase in both direct and oxidative DNA damage, with induction of oxidative damage being greater. The results indicate that OTA is mutagenic in mouse lymphoma assay; and that OTA-generated oxidative DNA damage is, at least partially, responsible for its mutagenicity in the assay. PMID- 24164383 TI - Alcohol activates the hedgehog pathway and induces related procarcinogenic processes in the alcohol-preferring rat model of hepatocarcinogenesis. AB - BACKGROUND: Alcohol consumption promotes hepatocellular carcinoma (HCC). The responsible mechanisms are not well understood. Hepatocarcinogenesis increases with age and is enhanced by factors that impose a demand for liver regeneration. Because alcohol is hepatotoxic, habitual alcohol ingestion evokes a recurrent demand for hepatic regeneration. The alcohol-preferring (P) rat model mimics the level of alcohol consumption by humans who habitually abuse alcohol. Previously, we showed that habitual heavy alcohol ingestion amplified age-related hepatocarcinogenesis in P rats, with over 80% of alcohol-consuming P rats developing HCCs after 18 months of alcohol exposure, compared with only 5% of water-drinking controls. METHODS: Herein, we used quantitative real-time PCR and quantitative immunocytochemistry to compare liver tissues from alcohol-consuming P rats and water-fed P rat controls after 6, 12, or 18 months of drinking. We aimed to identify potential mechanisms that might underlie the differences in liver cancer formation and hypothesized that chronic alcohol ingestion would activate Hedgehog (HH), a regenerative signaling pathway that is overactivated in HCC. RESULTS: Chronic alcohol ingestion amplified age-related degenerative changes in hepatocytes, but did not cause appreciable liver inflammation or fibrosis even after 18 months of heavy drinking. HH signaling was also enhanced by alcohol exposure, as evidenced by increased levels of mRNAs encoding HH ligands, HH-regulated transcription factors, and HH target genes. Immunocytochemistry confirmed increased alcohol-related accumulation of HH ligand producing cells and HH-responsive target cells. HH-related regenerative responses were also induced in alcohol-exposed rats. Three of these processes (i.e., deregulated progenitor expansion, the reverse Warburg effect, and epithelial-to mesenchymal transitions) are known to promote cancer growth in other tissues. CONCLUSIONS: Alcohol-related changes in Hedgehog signaling and resultant deregulation of liver cell replacement might promote hepatocarcinogenesis. PMID- 24164385 TI - Functional and hypoglycemic properties of nopal cladodes (O. ficus-indica) at different maturity stages using in vitro and in vivo tests. AB - Nopal (Opuntia ficus-indica) cladodes are recommended for their therapeutic properties; their maturity stage may affect their biological properties. Cladodes of three maturity stages, from the same crop and location, were dehydrated and evaluated for some of their physicochemical and nutritional characteristics and antidiabetic properties. The flours of small and medium cladodes (SCF and MCF, respectively) had higher contents of dietary fiber, water absorption, swelling, and viscosity compared to those of the large cladode flour (LCF). Streptozotocin induced diabetic rats, treated with MCF and SCF (doses of 50 mg/kg body weight), showed reduction of postprandial blood glucose on 46.0 and 23.6%, respectively (p < 0.05), in relation to the control; and LCF had no significant effect. In vitro, glucose diffusion tests showed similar ranking by the two former samples, whereas the latter was close to the control. Cladode maturity stages showed different fiber content and produced suspensions with differences in viscosity, which may affect in vitro and in vivo glucose responses. PMID- 24164386 TI - The protective effect of Liu-Wei-Di-Huang-Fang in salt-sensitive hypertension rats. AB - Abstract Hypertension is considered as a chronic and complex disease relating to multiple systemic systems. Apart from lowering blood pressure, the final purpose of the treatment lies in reducing the variability of blood pressure and other risk factors. Traditional Chinese medicine (TCM) has a long history of treating hypertension. This study was designed to determine the effect of Liu-Wei-Di-Huang Fang (L-W-D-H-F), a compound used in traditional Chinese herbal medicine, to treat salt-sensitive hypertension (SSHT) induced by a high-salt and high-fat diet. L-W-D-H-F was prepared from six plant extracts. It was dissolved in 0.9% sodium chloride solution prior to use. Male Sprague-Dawley (6 weeks) rats were randomly divided into four groups: normal diet (CON); HSF (Without Drug Intervention); VAL (Valsartan 13.33 mg/kg/day); and LW (L-W-D-H-F 8.13 g/kg/day). Six weeks after blood pressure treatment, plasma biochemical analyses and histological and functional examination of the kidney were performed. L-W-D-H-F decreased the levels of mean arterial pressure (MAP), fasting blood glucose (FG), insulin (INS), high-density lipoprotein cholesterol (HDL-c), homeostasis model assessment of basal insulin resistance (HOMA-IR) and angiotensin II (Ang II) from plasma and Ang II and renin from kidney. It also promoted the excretion of urinary Na(+), reducing the loss of urinary K(+) and microalbuminuria (MAU), and improved the glomerular afferent arteriole, arterioles and each kidney unit. Together, these results suggest that L-W-D-H-F is capable of moderately reducing MAP in salt-sensitive hypertension and can work at different levels on multiple differential targets. PMID- 24164387 TI - Advances in understanding the pathogenesis of autoimmune disorders: focus on chemokines and lymphocyte trafficking. AB - Lymphocyte trafficking is a key step in the pathogenesis of various autoimmune diseases. Recruitment of autoreactive lymphocytes to inflamed tissues is a defining feature of numerous persistent organ-specific autoimmune conditions and various therapies are now used in several of these diseases which appear to specifically block lymphocyte migration. Thus, better understanding of the molecular events involved in homing of autoreactive pathogenic lymphocytes may present novel opportunities for pharmacological intervention in autoimmune diseases, such as multiple sclerosis, rheumatoid arthritis, type-1 diabetes and psoriasis. This review describes recent progress in understanding lymphocyte trafficking in autoimmunity, focusing on the involvement of the chemokine and chemokine receptor superfamily. Possible strategies to improve therapeutics for autoimmune diseases arising from these studies are discussed. PMID- 24164388 TI - Selective aerobic oxidation mediated by TiO(2) photocatalysis. AB - TiO2 is one of the most studied metal oxide photocatalysts and has unparal-leled efficiency and stability. This cheap, abundant, and non-toxic material has the potential to address future environmental and energy concerns. Understanding about the photoinduced interfacial redox events on TiO2 could have profound effect on the degradation of organic pollutants, splitting of H2O into H2 and O2, and selective redox organic transformations. Scientists traditionally accept that for a semiconductor photocatalyst such as TiO2 under the illumination of light with energy larger than its band gap, two photocarriers will be created to carry out their independent reduction and oxidation processes. However, our recent discoveries indicate that it is the concerted rather than independent effect of both photocarriers of valence band hole (hvb(+)) and conduction band electron (ecb(-)) that dictate the product formation during interfacial oxidation event mediated by TiO2 photocatalysis. In this Account, we describe our recent findings on the selective oxidation of organic substrates with O2 mediated by TiO2 photocatalysis. The transfer of O-atoms from O2 to the corresponding products dominates the selective oxidation of alcohols, amines, and alkanes mediated by TiO2 photocatalysis. We ascribe this to the concerted effect of both hvb(+) and ecb(-) of TiO2 in contribution to the oxidation products. These findings imply that O2 plays a unique role in its transfer into the products rather than independent role of ecb(-) scavenger. More importantly, ecb(-) plays a crucial role to ensure the high selectivity for the oxygenation of organic substrates. We can also use the half reactions such as those of the conduction band electron of TiO2 for efficient oxidation reactions with O2. To this end, efficient selective oxidation of organic substrates such as alcohols, amines, and aromatic alkanes with O2 mediated by TiO2 photocatalysis under visible light irradiation has been achieved. In summary, the concerted effect of hvb(+) and ecb(-) to implement one oxidation event could pave the way for selective oxofunctionalization of organic substrates with O2 by metal oxide photocatalysis. Furthermore, it could also deepen our understanding on the role of O2 and the elusive nature of oxygen species at the interface of TiO2, which, in turn, could shed new light on avant garde photocatalytic selective redox processes in addressing the energy and environmental challenges of the future. PMID- 24164390 TI - The evolving classification of soft tissue tumours - an update based on the new 2013 WHO classification. AB - The new World Health Organization (WHO) classification of soft tissue tumours was published in early 2013, almost 11 years after the previous edition. While the number of newly recognized entities included for the first time is fewer than that in 2002, there have instead been substantial steps forward in molecular genetic and cytogenetic characterization of this family of tumours, leading to more reproducible diagnosis, a more meaningful classification scheme and providing new insights regarding pathogenesis, which previously has been obscure in most of these lesions. This brief overview summarizes changes in the classification in each of the broad categories of soft tissue tumour (adipocytic, fibroblastic, etc.) and also provides a short summary of newer genetic data which have been incorporated in the WHO classification. PMID- 24164389 TI - Phenotypic and genotypic convergences are influenced by historical contingency and environment in yeast. AB - Different organisms have independently and recurrently evolved similar phenotypic traits at different points throughout history. This phenotypic convergence may be caused by genotypic convergence and in addition, constrained by historical contingency. To investigate how convergence may be driven by selection in a particular environment and constrained by history, we analyzed nine life-history traits and four metabolic traits during an experimental evolution of six yeast strains in four different environments. In each of the environments, the population converged toward a different multivariate phenotype. However, the evolution of most traits, including fitness components, was constrained by history. Phenotypic convergence was partly associated with the selection of mutations in genes involved in the same pathway. By further investigating the convergence in one gene, BMH1, mutated in 20% of the evolved populations, we show that both the history and the environment influenced the types of mutations (missense/nonsense), their location within the gene itself, as well as their effects on multiple traits. However, these effects could not be easily predicted from ancestors' phylogeny or past selection. Combined, our data highlight the role of pleiotropy and epistasis in shaping a rugged fitness landscape. PMID- 24164391 TI - The authors' conclusion that their study brings into question "the impact of motivational interviewing in terms of its ability to improve routine diabetes care in practice" is deserving of significant inquiry. PMID- 24164393 TI - Beryllium-cyclobutadiene multidecker inverse sandwiches: electronic structure and second-hyperpolarizability. AB - Beryllium forms stable sandwich and inverse sandwich complexes with the cyclobutadiene molecule. Two types of multidecker complexes are designed. Multidecker inverse sandwiches are found to be thermally more stable than the corresponding sandwich complexes. The average distance between two consecutive metals and the two consecutive cyclobutadiene rings increase gradually on increasing size of the chosen inverse sandwich complexes. The density functional theory functionals B3LYP, BHHLYP, BLYP, M06, CAM-B3LYP, and B2PLYP in conjunction with the 6-311++G (d, p) basis set have been employed for calculating the third order electric response properties of the chosen beryllium-cyclobutadiene complexes and the results obtained for each functional are found to have a consistent trend. Compared to the normal sandwich compounds the second hyperpolarizability of inverse sandwiches is predicated to be larger, which fairly correlates with the extent of ground-state polarization. The significant enhancement of cubic polarizability of higher-order multidecker inverse sandwiches arises from the strong coupling between the ground and the low lying charge transfer excited states. The rather strong enhancement of second hyperpolarizability on increasing size of the beryllium-multidecker inverse sandwiches may provide a new route to design efficient nonlinear optical materials. PMID- 24164392 TI - Urine liver-type fatty acid-binding protein and kidney injury molecule-1 in HIV infected patients receiving combined antiretroviral treatment based on tenofovir. AB - The aim of this study was to determine the presence of kidney tubular damage in the absence of overt evidence of glomerular dysfunction (GFR>60 ml/min without proteinuria) in HIV-infected patients receiving antiretroviral therapy. Urine kidney injury molecule-1 (KIM-1) and liver-type fatty acid-binding protein (L FABP) levels were measured by ELISA and expressed as a ratio to creatinine. Sixty six patients (median age 38 years) and 10 healthy controls (median age 35.5 years) were included in the study. Patients with chronic diseases such as diabetes, hypertension, heart disease, or kidney disease were excluded from the study. All patients received tenofovir/emtricitabine combined with one of three other components, namely efavirenz, atazanavir/norvir, or lopinavir/norvir. A lower concentration of L-FABP/creatinine was observed in HIV-infected as compared to healthy individuals (p=0.0353); KIM-1/creatinine was also lower in comparison with healthy controls but not statistically significantly. Patients receiving efavirenz had higher levels of L-FABP/creatinine in comparison to healthy controls (p=0.0039). Patients with anti-HCV had higher concentrations of L FABP/creatinine as compared to the HIV-monoinfected individuals (not statistically significant) and to healthy subjects (p=0.0356). All four patients with L-FABP>17.5 MUg/g creatinine were HIV/HCV coinfected. On multivariate logistic regression urine L-FABP above 5.5 MUg/g creatinine was independently associated with body weight (OR=0.93 p=0.039). This study suggests that HIV/HCV coinfected patients with lower body weight treated with tenofovir may be at an increased risk of tubular dysfunction and should be monitored more closely. The use of protease inhibitors was not associated with an increased risk of tubular disorders. PMID- 24164394 TI - Developmental defects of enamel and dentine: challenges for basic science research and clinical management. AB - Abnormalities of enamel and dentine are caused by a variety of interacting factors ranging from genetic defects to environmental insults. The genetic changes associated with some types of enamel and dentine defects have been mapped, and many environmental influences, including medical illnesses that can damage enamel and dentine have been identified. Developmental enamel defects may present as enamel hypoplasia or hypomineralization while dentine defects frequently demonstrate aberrant calcifications and abnormalities of the dentine pulp complex. Clinically, developmental enamel defects often present with problems of discolouration and aesthetics, tooth sensitivity, and susceptibility to caries, wear and erosion. In contrast, dentine defects are a risk for endodontic complications resulting from dentine hypomineralization and pulpal abnormalities. The main goals of managing developmental abnormalities of enamel and dentine are early diagnosis and improvement of appearance and function by preserving the dentition and preventing complications. However, despite major advances in scientific knowledge regarding the causes of enamel and dentine defects, further research is required in order to translate the knowledge gained in the basic sciences research to accurate clinical diagnosis and successful treatment of the defects. PMID- 24164395 TI - What are the causes of the ill effects of chronic hemodialysis? Toward a reduction in the risk of electrolyte-related sudden death. PMID- 24164396 TI - Induction of insulin-like growth factor-I by cepharanthine from dermal papilla cells: a novel potential pathway for hair growth stimulation. PMID- 24164397 TI - Differential effects of ethanol on regional glutamatergic and GABAergic neurotransmitter pathways in mouse brain. AB - This study investigates the effects of ethanol on neuronal and astroglial metabolism using (1)H-[(13)C]-NMR spectroscopy in conjunction with infusion of [1,6-(13)C2]/[1-(13)C]glucose or [2-(13)C]acetate, respectively. A three compartment metabolic model was fitted to the (13)C turnover of GluC3 , GluC4, GABAC 2, GABAC 3, AspC3 , and GlnC4 from [1,6-(13)C2 ]glucose to determine the rates of tricarboxylic acid (TCA) and neurotransmitter cycle associated with glutamatergic and GABAergic neurons. The ratio of neurotransmitter cycle to TCA cycle fluxes for glutamatergic and GABAegic neurons was obtained from the steady state [2-(13)C]acetate experiment and used as constraints during the metabolic model fitting. (1)H MRS measurement suggests that depletion of ethanol from cerebral cortex follows zero order kinetics with rate 0.18 +/- 0.04 MUmol/g/min. Acute exposure of ethanol reduces the level of glutamate and aspartate in cortical region. GlnC4 labeling was found to be unchanged from a 15 min infusion of [2-(13)C]acetate suggesting that acute ethanol exposure does not affect astroglial metabolism in naive mice. Rates of TCA and neurotransmitter cycle associated with glutamatergic and GABAergic neurons were found to be significantly reduced in cortical and subcortical regions. Acute exposure of ethanol perturbs the level of neurometabolites and decreases the excitatory and inhibitory activity differentially across the regions of brain. Depletion of ethanol and its effect on brain functions were measured using (1)H and (1)H [(13)C]-NMR spectroscopy in conjunction with infusion of (13)C-labeled substrates. Ethanol depletion from brain follows zero order kinetics. Ethanol perturbs level of glutamate, and the excitatory and inhibitory activity in mice brain. PMID- 24164399 TI - Fine needle aspiration cytology diagnosis of an ocular hydatid cyst. PMID- 24164398 TI - Computed tomography-guided tissue engineering of upper airway cartilage. AB - Normal laryngeal function has a large impact on quality of life, and dysfunction can be life threatening. In general, airway obstructions arise from a reduction in neuromuscular function or a decrease in mechanical stiffness of the structures of the upper airway. These reductions decrease the ability of the airway to resist inspiratory or expiratory pressures, causing laryngeal collapse. We propose to restore airway patency through methods that replace damaged tissue and improve the stiffness of airway structures. A number of recent studies have utilized image-guided approaches to create cell-seeded constructs that reproduce the shape and size of the tissue of interest with high geometric fidelity. The objective of the present study was to establish a tissue engineering approach to the creation of viable constructs that approximate the shape and size of equine airway structures, in particular the epiglottis. Computed tomography images were used to create three-dimensional computer models of the cartilaginous structures of the larynx. Anatomically shaped injection molds were created from the three dimensional models and were seeded with bovine auricular chondrocytes that were suspended within alginate before static culture. Constructs were then cultured for approximately 4 weeks post-seeding and evaluated for biochemical content, biomechanical properties, and histologic architecture. Results showed that the three-dimensional molded constructs had the approximate size and shape of the equine epiglottis and that it is possible to seed such constructs while maintaining 75%+ cell viability. Extracellular matrix content was observed to increase with time in culture and was accompanied by an increase in the mechanical stiffness of the construct. If successful, such an approach may represent a significant improvement on the currently available treatments for damaged airway cartilage and may provide clinical options for replacement of damaged tissue during treatment of obstructive airway disease. PMID- 24164400 TI - Redo living-donor lobar lung transplantation for bronchiolitis obliterans associated with antibody-mediated rejection. AB - Living-donor lobar lung transplantation (LDLLT) is an established therapy for patients with end-stage lung disease, but living-donor lobar lung retransplantation (re-LDLLT) is rarely reported. We previously reported a case of unilateral antibody-mediated rejection after LDLLT in the presence of newly formed donor-specific antibodies against a right-lobe donor. The same patient developed contralateral bronchiolitis obliterans, resulting in bilateral bronchiolitis obliterans, but re-LDLLT was successful. Pathological findings of the explanted lungs were consistent with the clinical course of the patient. One year after re-LDLLT, the patient is doing well without any anti-human leukocyte antigen antibodies. Four lobes from four different donors were transplanted in this patient. The first two lobes were rejected eventually, but the two lobes implanted later presented no signs of rejection at least for 1 year after the transplant. Herein, we report this rare case and compare the clinical course and pathological findings. PMID- 24164401 TI - Bronsted acid catalyzed enantioselective indole aza-Claisen rearrangement mediated by an arene CH-O interaction. AB - Although the aromatic aza-Claisen rearrangement is a general strategy for accessing substituted aromatic amines, there are no highly enantioselective examples of this process. We report the first Bronsted acid catalyzed enantioselective indole aza-Claisen rearrangement for the synthesis of chiral 3 amino-2-substituted indoles. We present evidence for an arene CH-O interaction as a source of activation and stereoinduction, which is an unprecedented phenomenon in enantioselective Bronsted acid catalysis. The products of this reaction can be transformed into 3-aminooxindoles, which are prevalent in many biologically active small molecules. PMID- 24164402 TI - Circulating levels of TNF-related apoptosis inducing ligand (TRAIL). PMID- 24164403 TI - Esophageal stricture induced by an ultraslim upper endoscope in a novel rabbit model of corrosive injury. AB - OBJECTIVE: Benign esophageal strictures are regularly encountered problems in clinical practice. The management of refractory benign esophageal stricture, which fails to establish adequate food passage despite multiple dilatation sessions, has been considered challenging. Experimental animal models are essential for the development of effective treatment methods. The aim of this study was to establish a new animal model of benign esophageal stricture using rabbits. MATERIAL AND METHODS: Corrosive injury of the esophagus was induced by administration of 1 ml of 1.5% sodium hydroxide in eight rabbits using an ultraslim upper endoscope equipped with a 5-Fr polytetrafluoroethylene tube and 5 Fr balloon catheter. Two weeks after corrosive injury, endoscopic examination was performed to confirm the state of the injury site. Four weeks after corrosive injury, the esophageal stricture was assessed by endoscopy and esophagography. All animals were then euthanized. RESULTS: Two weeks after corrosive injury, endoscopic examination showed that ulceration had been induced. Four weeks after corrosive injury, endoscopic, radiologic and gross examinations showed that esophageal stricture had been induced without complications in all animals. The esophageal lumen diameter was reduced by an average of 51.8% (range, 48.3% 57.2%), and the mean stricture length was 25.7 mm (range, 20.1-29.3 mm). Microscopic examination revealed focal ulceration and submucosal thickening secondary to fibrosis. CONCLUSIONS: Rabbit esophageal stricture induced by endoscopic delivery of a small amount of low-concentration sodium hydroxide is a relatively simple, safe, and reproducible animal model. This model may be useful in the development of new treatment methods for esophageal stricture. PMID- 24164404 TI - Analysis of N-glycoproteins using genomic N-glycosite prediction. AB - Protein glycosylation has long been recognized as one of the most common post translational modifications. Most membrane proteins and extracellular proteins are N-linked glycosylated, and they account for the majority of current clinical diagnostic markers or therapeutic targets. Quantitative proteomic analysis of detectable N-linked glycoproteins from cells or tissues using mass spectrometry has the potential to provide biological basis for disease development and identify disease associated glycoproteins. However, the information of low abundance but important peptides is lost due to the lack of MS/MS fragmentation or low quality of MS/MS spectra for low abundance peptides. Here, we show the feasibility of formerly N-glycopeptide identification and quantification at MS1 level using genomic N-glycosite prediction (GenoGlyco) coupled with stable isotopic labeling and accurate mass matching. The GenoGlyco Analyzer software uses accurate precursor masses of detected N-deglycopeptide peaks to match them to N-linked deglycopeptides that are predicted from genes expressed in the cells. This method results in more robust glycopeptide identification compared to MS/MS based identification. Our results showed that over three times the quantity of N deglycopeptide assignments from the same mass spectrometry data could be produced in ovarian cancer cell lines compared to a MS/MS fragmentation method. Furthermore, the method was also applied to N-deglycopeptide analysis of ovarian tumors using the identified deglycopeptides from the two ovarian cell lines as heavy standards. We show that the described method has a great potential in the analysis of detectable N-glycoproteins from cells and tissues. PMID- 24164406 TI - Response to the letter to the editor. PMID- 24164405 TI - Febuxostat (Feburic tablet) in the management of hyperuricemia in a general practice cohort of Japanese patients with a high prevalence of cardiovascular problems. AB - Hyperuricemia is increasing in prevalence and this is paralleled by an increased incidence of acute gout. In addition, there is growing evidence of an association between high serum levels of uric acid (sUA) and cardiovascular disease (CVD). In this preliminary report, we present 12-16 week results from a multicenter, general practice study in which we evaluated the usefulness of febuxostat in a cohort of untreated patients with hyperuricemia with a high prevalence of CVD. Febuxostat titrated from 10 mg/day up to 40 mg/day resulted in statistically significant and clinically relevant reductions in sUA after 12-16 weeks. A "responder" level of 6.0 mg/dL or lower was achieved in 95 of 100 (95%) patients. Significant reductions in sUA were achieved regardless of the presence/absence of coexisting diseases (e.g. CVD, renal insufficiency, diabetes and obesity) or the class of antihypertensive agent being used by the patient. No serious adverse reactions were noted with febuxostat. Although allopurinol has been used generally for hyperuricemia/gout, it is excreted fully via the kidneys, restricting its use in patients with reduced renal function, and its three-times daily administration leads to poor adherence. Based on the results of this study, febuxostat may provide an easier option than allopurinol for clinicians specializing in CVDs. PMID- 24164407 TI - Thermodynamic and kinetic properties of a new myrtillin-vescalagin hybrid pigment. AB - During red wine maturation in contact with oak wood, C-glucosidic ellagitannins can react with anthocyanins, leading to new pigments. In this work the thermodynamic and kinetic constants of the network pH-dependent equilibrium of a new myrtillin (delphinidin 3-O-glucoside)-vescalagin hybrid pigment (1 deoxyvescalagin-(1beta->8)-myrtillin) have been determined by UV-visible absorption and stopped-flow experiments and compared to those determined for myrtillin. The vescalagin substitution at the C-8' center of myrtillin entails important variations in the pigment behavior upon pH changes. The hybrid pigment showed lower pK'a and pKa values and a much higher value of Kt. As a consequence, at moderately acidic pH values (4 < pH < 6), the percentage of the hemiketal is much lower and the quinoidal base and the (E)-chalcone represent higher percentages relative to those for myrtillin. Therefore, the hybrid pigment can provide in slightly acidic or neutral solutions an exceptionally different color compared to that of myrtillin. PMID- 24164408 TI - Syntheses, structures, magnetic properties, and density functional theory magneto structural correlations of bis(MU-phenoxo) and bis(MU-phenoxo)-MU-acetate/bis(MU phenoxo)-bis(MU-acetate) dinuclear Fe(III)Ni(II) compounds. AB - The bis(MU-phenoxo) Fe(III)Ni(II) compound [Fe(III)(N3)2LNi(II)(H2O)(CH3CN)](ClO4) (1) and the bis(MU-phenoxo)-MU acetate/bis(MU-phenoxo)-bis(MU-acetate) Fe(III)Ni(II) compound {[Fe(III)(OAc)LNi(II)(H2O)(MU-OAc)](0.6).[Fe(III)LNi(II)(MU OAc)2](0.4)}(ClO4).1.1H2O (2) have been synthesized from the Robson type tetraiminodiphenol macrocyclic ligand H2L, which is the [2 + 2] condensation product of 4-methyl-2,6-diformylphenol and 2,2'-dimethyl-1,3-diaminopropane. Single-crystal X-ray structures of both compounds have been determined. The cationic part of the dinuclear compound 2 is a cocrystal of the two species [Fe(III)(OAc)LNi(II)(H2O)(MU-OAc)](+) (2A) and [Fe(III)LNi(II)(MU-OAc)2](+) (2B) with weights of 60% of the former and 40% of the latter. While 2A is a triply bridged bis(MU-phenoxo)-MU-acetate system, 2B is a quadruply bridged bis(MU phenoxo)-bis(MU-acetate) system. Variable-temperature (2-300 K) magnetic studies reveal antiferromagnetic interaction in 1 and ferromagnetic interaction in 2 with J values of -3.14 and 7.36 cm(-1), respectively (H = -2JS1.S2). Broken-symmetry density functional calculations of exchange interaction have been performed on complexes 1 and 2 and also on previously published related compounds, providing good numerical estimates of J values in comparison to experiments. The electronic origin of the difference in magnetic behavior of 1 and 2 has been well understood from MO analyses and computed overlap integrals of BS empty orbitals. The role of acetate and thus its complementarity/countercomplementarity effect on the magnetic properties of diphenoxo-bridged Fe(III)Ni(II) compounds have been determined on computing J values of model compounds by replacing bridging acetate and nonbridging acetate ligand(s) by water ligands in the model compounds derived from 2A,B. The DFT calculations have also been extended to develop several magneto-structural correlations in these types of complexes, and the correlations focus on the role of Fe-O-Ni bridge angle, average Fe/Ni-O bridge distance, Fe-O Ni-O dihedral angle, and out-of-plane shift of the phenoxo group. PMID- 24164409 TI - Interprofessional social and emotional intelligence skills training: study findings and key lessons. AB - Frequently changing demands in health care systems have focused attention on the need for emotional competence (EC) - social and emotional intelligence skills, to adapt efficiently, responsively and productively. This paper reports on findings from a workshop that introduced practical EC skills to nearly 1000 participants in education, medicine, mental health and substance abuse counseling. The holistic EC presentations were designed to teach concepts and principles providing each participant with the opportunity for individualized learning. Ninety percent of the participants rated these presentations as valuable and useful. Following this positive response, the approach was adapted to train health professionals serving diverse populations. This report shares our experience teaching various professionals and describes preliminarily testing of the adapted EC training program on a small group of health professionals, whose responsibilities included teamwork, program design, teaching clients and patients EC basics to support healthy practices and self-care. Their positive response supports the need for expanded study and further investigation. PMID- 24164410 TI - Short communication: A low-cost method for analyzing nevirapine levels in hair as a marker of adherence in resource-limited settings. AB - The measurement of antiretroviral concentrations in hair is emerging as an important technology to objectively quantify adherence to combination antiretroviral therapy. Hair levels of antiretrovirals are the strongest independent predictor of virologic success in large prospective cohorts of HIV infected patients and surpass self-report in predicting outcomes. Hair is easy to collect and store, but validated methods to analyze antiretroviral levels in hair using liquid chromatography tandem mass spectrometry (LC-MS/MS) are expensive. We report here on the development of a thin-layer chromatography (TLC) assay for the semiquantitative analysis of nevirapine in hair. TLC assay results from 11 samples were consistent with results using LC-MS/MS [Spearman correlation coefficient 0.99 (95% CI 0.95-0.996)]. This simple, low-cost method of analyzing nevirapine concentrations in hair may provide a novel monitoring tool for antiretroviral adherence in resource-limited settings and merits further study in clinical settings. PMID- 24164411 TI - Cells or signals: which moves to drive skin pattern formation? AB - During its development, the skin produces an array of evenly spaced hair follicles. How the location of each follicle is determined to produce this pattern has been the subject of study and speculation for several decades. A central unresolved issue is the extent to which movement of scattered, precommitted follicle cells might play a role in this process. Xavier et al. now report the identification of subpopulations of dermal cells in developing sheep skin which are positive for Delta1 expression, suggesting that these cells may represent precommitted dermal papilla cells and that dermal Notch pathway signalling plays a role in hair follicle patterning. PMID- 24164412 TI - Synthesis of heterometallic compounds with uncommon combinations of elements for oxide nanomaterials using organometallics. AB - Oxide nanomaterials with interesting electronic and magnetic properties have applications including superconductors, magnetic core materials, high-frequency devices, and gas sensors. They can also serve as efficient oxide lattices for luminescent ions. Highly phase-pure BaHfO3 nanopowders are extremely desirable as matrices for luminescent doping, and barium hafnate is an attractive host lattice for new X-ray phosphors, which are much more effective than the phosphors currently used in radiology and computed tomography. This wide range of applications creates a strong impetus for novel and inexpensive methods for their synthesis. Classically, mixed-cation oxide ceramics are synthesized according to conventional solid-state reactions involving oxides, carbonates, or nitrates at relatively high temperatures (~1500 degrees C). These procedures are inefficient and often lead to inhomogeneous by-products and poor control over the stoichiometry and phase purity. Among the new preparation techniques are those involving metal alkoxides and aryloxides with strictly defined metal stoichiometries at the molecular level. In this Account, we describe several structurally interesting heterometallic alkoxoorganometallic compounds prepared via reactions of organometallic compounds (MMe3 where M = Al, In, Ga) with group 2 alkoxides having additional protonated hydroxyl group(s) in the alcohol molecule present in the metal coordination sphere. Using lower temperatures than in the conventional solid-state thermal routes involving carbonate/oxide mixtures, we can easily transform these new complexes, with rarely found combinations of metallic precursors (Ba/In, Sr/Al, and Ba/Ga), into highly pure binary oxide materials that can be used, in a similar manner to perovskites and spinels, as host matrices for various lanthanide ions. Furthermore, our studies on titanium, zirconium, and hafnium metallocenes showed them to be attractive and cheap precursors for an extensive range of novel molecular and supramolecular materials. This unique synthetic method comprises elimination of the cyclopentadienyl ring (as CpH) from Cp2MCl2 (M = Ti, Zr, Hf) in the presence of M'(OR)2 (M' = Ca, Sr, Ba; ROH = CH3OCH2CH2OH), in an alcohol as a proton source. The resulting compounds are suitable for obtaining highly phase-pure perovskite like oxides including BaTiO3, BaHfO3, SrHfO3, etc. PMID- 24164414 TI - Transition metal complexes coupled to vacancies in oxides: origin of different properties of Cr3+ in MgO bounded to a <100> or <110> Mg2+ vacancy. AB - Despite the importance of vacancies over the properties of insulating oxides its influence on neighboring transition metal ions is far from being understood. This work is devoted to find the origin of various up to now unexplained properties of chromium bounded either to a <100> or a <110> Mg(2+) vacancy in MgO. In these model systems particular attention is paid to understand, by means of ab initio calculations, why the cubic field splitting parameter, 10Dq, is surprisingly 1600 cm(-1) higher for a <100> than for a <110> vacancy, a fact behind the suppression of the sharp (2)E -> (4)A2 luminescence in the latter case. Our calculations, which reproduce the main experimental facts, prove that the average Cr(3+)-O(2-) distance is the same within 0.8% for both systems, and thus, the low 10Dq value for a <110> vacancy is shown to be due mainly to the electrostatic potential from the missing Mg(2+) ion, which increases the energy of antibonding t(2g) (~xy, xz, yz) levels. By contrast, for a <100> Mg(2+) vacancy that potential provides a supplementary increase of the e(g) (~x(2) - y(2), 3z(2 )- r(2)) level energy and thus of 10Dq. The existence of the (2)E -> (4)A2 luminescence for Cr(3+)-doped MgO under perfect cubic symmetry or with a <100> vacancy is shown to be greatly helped by the internal electric field created by the rest of the lattice ions on the CrO6(9-) unit, whose importance is usually ignored. The present results underline the role of ab initio calculations for unveiling the subtle effects induced by a close vacancy on the properties of transition metal ions in oxides. At the same time they stress the failure of the empirical superposition model for deriving the equilibrium geometry of C4v and C2v centers in MgO:Cr(3+). PMID- 24164413 TI - Plasma cortisol concentration increases within 6 hours of stabling in RAO affected horses. AB - REASONS FOR PERFORMING STUDY: In many inflammatory diseases plasma cortisol concentration (CORT) increases at the onset of acute inflammation, but the situation in recurrent airway obstruction (RAO) of horses is unknown. STUDY DESIGN: Split-plot repeated measures design with one grouping factor (disease) and two repeated factors (day and 3-hour intervals). OBJECTIVE: To test the hypothesis that CORT increases as acute exacerbations of RAO develop. METHODS: Four RAO-susceptible and 4 control horses were placed in a low dust environment (LDEnv) for 2 days followed by 2 days in a high dust environment (HDEnv). Exacerbations of RAO were indicated by increases in maximal change in pleural pressure (DeltaPplmax) and decreases in breathing frequency variability (BFV), which was continuously measured by respiratory inductance plethysmography. Plasma samples for determination of CORT were collected every 6 h. RESULTS: In control horses, DeltaPplmax and BFV were unaffected by the HDEnv, whereas in RAO-affected horses DeltaPplmax increased and BFV decreased significantly. In the LDEnv, there was a circadian variation in CORT in both control and RAO-affected horses. In HDEnv, CORT was unaffected in control horses, but increased significantly in RAO affected horses between 6 and 12 h after entering the HDEnv. CONCLUSIONS: Plasma cortisol concentration increases concurrently with the development of acute exacerbations of RAO. PMID- 24164415 TI - Kinetic changes in gait during low magnitude military load carriage. AB - Indian infantry soldiers carry smaller magnitudes of loads for operational requirements. The ground reaction forces (GRFs) and impulse responses of 10 healthy male Indian infantry soldiers were collected while they walked carrying operational loads between 4.2 and 17.5 kg (6.5-27.2% of mean body weight (BW)) and a control condition of no external load (NL). The GRF and impulse components were normalised for BW, and data for each load condition were compared with NL in each side applying one-way analysis of variance followed by Dunnett's post hoc test. Right foot data were compared with corresponding left foot GRF data for all load conditions and NL. There were significant increases in vertical and anteroposterior GRFs with increase in load. Left and right feet GRF data in corresponding load conditions were significantly different in anteroposterior plane. No significant change was observed in the temporal components of support phase of gait. Changes in impulse parameter were observed in the anteroposterior and vertical planes while carrying load greater than 23 and 16.6% of BW for the right foot and left foot, respectively. Result indicates that smaller magnitudes of loads produced kinetic changes proportional to system weight, similar to heavier loads with the possibility of increased injury risk. Observed smaller asymmetric changes in gait may be considered as postural adjustment due to load. Unique physical characteristics of Indian soldiers and the probable design shortcomings of the existing backpack might have caused significant changes in GRF and peak impulse during smaller load carriage. PMID- 24164416 TI - Nonadherence in dialysis patients: prevalence, measurement, outcome, and psychological determinants. AB - Nonadherence to aspects of the management of End-Stage Kidney Disease (ESKD) is common. Estimates of nonadherence vary with assessment method. Whilst readily available and free from report bias, physiological proxies-frequently used as measures of adherence-are often confounded by clinical factors including residual kidney function and dialysis adequacy. Despite variation in estimates of its prevalence, it is clear that suboptimal adherence to dialysis prescriptions, medication and diet can lead to adverse clinical outcomes. Several factors can help explain nonadherence in ESKD including mood, self-efficacy, social support, illness, and treatment perceptions. Psychological interventions have been shown to improve ESKD adherence, yet achieving long-term behavior change remains challenging. Identifying individuals who struggle to adhere to aspects of the dialysis regime, and tailoring theory-led interventions to improve and support adherence is a clear clinical need requiring further empirical enquiry. PMID- 24164417 TI - Implementation of approach bias re-training in alcoholism-how many sessions are needed? AB - BACKGROUND: Computerized cognitive bias modification (CBM) programs have generated promising results regarding the treatment of alcohol dependence and anxiety disorders. However, there is hardly any research yet on the implementation of alcohol-CBM into clinical practice. This article addresses the question of the optimal number of training sessions for a specific form of CBM: approach bias re-training in alcohol-dependent patients. METHODS: Participants were 111 alcohol-dependent patients of an inpatient rehabilitation clinic. In addition to treatment as usual, they took part in a 12-session CBM protocol, aimed at re-training alcohol approach tendencies, with an adapted Alcohol Approach-Avoidance Task. Learning curves and 2-level fitted mean trends were analyzed. Furthermore, parameters of the fitted mean trend and information on the most effective number of training sessions were used to predict 1-year follow-up data. RESULTS: Two-level analyses revealed 6 training sessions to be the mean optimum, yet many patients improve further after that. Prediction of the individual optimum (speed of response) and parameters of the fitted mean trends failed. The linear term of the graph describing the mean trend of training effects, but not the speed of response, predicted 1-year follow-up data. CONCLUSIONS: Suggestions for practical implementations of CBM are discussed. PMID- 24164418 TI - Minimally invasive autopsy employing post-mortem CT and targeted coronary angiography: evaluation of its application to a routine Coronial service. AB - AIMS: Post-mortem imaging is a potential alternative to traditional medicolegal autopsy. We investigate the reduction in number of invasive autopsies required by use of post-mortem CT +/- coronary angiography. METHODS AND RESULTS: A total of 120 adult deaths referred to the Coroner were investigated by CT, with coronary angiography employed only for the second series of 60 cases, in order to determine the added value of angiography. The confidence of imaging cause of death was classified as definite (no autopsy), probable, possible or unascertained. Invasive autopsy was not required in 38% of cases without coronary angiography and 70% of cases with angiography. Full autopsy, including brain dissection, was required in only 9% of cases. There was complete agreement between autopsy and radiological causes of death in the cases with a 'probable' imaging cause of death, indicating that cases for which imaging provides an accurate cause of death without autopsy were identified correctly. In two patients, CT demonstrated unsuspected fractures, not detected at subsequent autopsy. CONCLUSIONS: A two-thirds reduction in the number of invasive coronial autopsies can be achieved by use of post-mortem CT plus coronary angiography. At the same time, use of post-mortem CT may improve accuracy of diagnosis, particularly for traumatic deaths. PMID- 24164419 TI - Evolution of carotenoid pigmentation in caciques and meadowlarks (Icteridae): repeated gains of red plumage coloration by carotenoid C4-oxygenation. AB - Many animals use carotenoid pigments to produce yellow, orange, and red coloration. In birds, at least 10 carotenoid compounds have been documented in red feathers; most of these are produced through metabolic modification of dietary precursor compounds. However, it is poorly understood how lineages have evolved the biochemical mechanisms for producing red coloration. We used high performance liquid chromatography to identify the carotenoid compounds present in feathers from 15 species across two clades of blackbirds (the meadowlarks and allies, and the caciques and oropendolas; Icteridae), and mapped their presence or absence on a phylogeny. We found that the red plumage found in meadowlarks includes different carotenoid compounds than the red plumage found in caciques, indicating that these gains of red color are convergent. In contrast, we found that red coloration in two closely related lineages of caciques evolved twice by what appear to be similar biochemical mechanisms. The C4-oxygenation of dietary carotenoids was responsible for each observed transition from yellow to red plumage coloration, and has been commonly reported by other researchers. This suggests that the C4-oxygenation pathway may be a readily evolvable means to gain red coloration using carotenoids. PMID- 24164421 TI - A CD47-blocking TRAIL fusion protein with dual pro-phagocytic and pro-apoptotic anticancer activity. PMID- 24164420 TI - Preemptive treatment of Cytomegalovirus infection in kidney transplant recipients with letermovir: results of a Phase 2a study. AB - Cytomegalovirus (CMV) infection remains a significant cause of morbidity and mortality in transplant recipients. Letermovir (AIC246), is a novel anti-HCMV drug in development, acting via a novel mechanism of action. In this proof-of concept trial with first administration of letermovir to patients, 27 transplant recipients with active CMV replication were randomly assigned to a 14-day oral treatment regimen of either letermovir 40 mg twice a day, letermovir 80 mg once a day, or local standard of care (SOC) in a multicenter, open-label trial. Efficacy, safety, and limited pharmacokinetic parameters were assessed. All groups had a statistically significant decrease in CMV-DNA copy number from baseline (40 mg BID: P = 0.031; 80 mg QD: P = 0.018; SOC: P = 0.001), and comparison of viral load reduction between treatment groups showed no statistically significant differences. Viral clearance was achieved for 6 of 12 patients (50%) in the letermovir groups versus two of seven SOC patients (28.6%). Letermovir treatment was generally well tolerated, no patient developed CMV disease during the trial. Both letermovir treatment regimens resulted in equally high trough level plasma concentrations. The efficacy, safety, and pharmacokinetics observed in these viremic transplant recipients indicate that letermovir is a promising new anti-CMV drug. PMID- 24164422 TI - Uneven distribution of hepatic copper concentration and diagnostic value of double-sample biopsy in Wilson's disease. AB - BACKGROUND AND AIMS. Determination of hepatic copper (Cu) concentration is important in Wilson's disease (WD) diagnosis. The aim of this study was to evaluate uneven distribution of liver Cu concentration and the utility of double sample biopsy in WD diagnosis. METHODS. Thirty-five WD patients (20 male; mean age 41 +/- 9 years) were enrolled in the study and double-liver samples for biopsy were obtained. A further 30 WD patients, in whom Cu determination was performed using single-liver samples, were also enrolled as controls. RESULTS. A marked difference in hepatic Cu concentration was observed between the two sample groups (p < 0.0001). This difference is statistically significant for all levels of liver fibrosis (p < 0.001) and for the comparison of hepatic and neurological phenotypes (p < 0.01). The sensitivity of the Cu concentrations obtained from the double-sample biopsies for the conventional cut-off value of 250 mg/g dry weight of tissue was 85.7% compared to 80% in the single-sample biopsies. By lowering the cut-off value from 250 to 50 ug/g of dry weight of tissue, the sensitivity of Cu content to diagnose WD increased to 97% for double-sample liver biopsy compared to 93% for single-sample liver biopsy. CONCLUSIONS. Liver Cu content was unevenly distributed in the WD subjects, irrespective of fibrosis levels and disease phenotypes; hence WD can be misdiagnosed using single-sample liver Cu measurement. Double-sample biopsy sensitivity is greater than that obtained with single-sample biopsy and should therefore be considered to evaluate liver Cu concentration at initial diagnosis in all patients. PMID- 24164423 TI - CaMKII activity is essential for improvement of memory-related behaviors by chronic rivastigmine treatment. AB - Because the cholinergic system is down-regulated in the brain of Alzheimer's disease patients, cognitive deficits in Alzheimer's disease patients are significantly improved by rivastigmine treatment. To address the mechanism underlying rivastigmine-induced memory improvements, we chronically treated olfactory bulbectomized (OBX) mice with rivastigmine. The chronic rivastigmine treatments for 12-13 days starting at 10 days after OBX operation significantly improved memory-related behaviors assessed by Y-maze task, novel object recognition task, passive avoidance task, and Barnes maze task, whereas the single rivastigmine treatment failed to improve the memory. Consistent with the improved memory-related behaviors, long-term potentiation in the hippocampal CA1 region was markedly restored by rivastigmine treatments. In immunoblotting analyses, the reductions of calcium/calmodulin-dependent protein kinase II (CaMKII) autophosphorylation and calcium/calmodulin-dependent protein kinase IV (CaMKIV) phosphorylation in the CA1 region in OBX mice were significantly restored by rivastigmine treatments. In addition, phosphorylation of AMPAR subunit glutamate receptor 1 (GluA1) (Ser-831) and cAMP-responsive element binding protein (Ser-133) as downstream targets of CaMKII and CaMKIV, respectively, in the CA1 region was also significantly restored by chronic rivastigmine treatments. Finally, we confirmed that rivastigmine-induced improvements of memory-related behaviors and long-term potentiation were not obtained in CaMKIIalpha(+/-) mice. On the other hand, CaMKIV(-/-) mice did not exhibit the cognitive impairments. Taken together, the stimulation of CaMKII activity in the hippocampus is essential for rivastigmine-induced memory improvement in OBX mice. PMID- 24164425 TI - What is meant by patient-centredness being value-based? AB - OBJECTIVE: To examine whether it is possible to further specify what is meant when we maintain that patient-centredness as a communication skill is a value based clinical procedure. DESIGN AND MAIN OUTCOME MEASURES: Since a core element in patient-centredness is associated with patients feeling respected, a study regarding encounters where patients felt respected was analysed. RESULTS: Similarities were found between the core elements of patient-centredness in terms of inviting, listening, and summarizing, and patients feeling respected in terms of listening, having their questions answered, and believing in what they tell their GP. CONCLUSION: Even though what is respected cannot be specified, the authors' analysis indicates that feeling respected is frequently and strongly associated with encounters reflecting core aspects of patient-centredness. In this sense, patient-centredness might be considered value-based. Future research might shed light on what is actually respected: is it the patient's autonomy, integrity, dignity, or honour? PMID- 24164424 TI - Cyclic nucleotide-gated channel subunit glycosylation regulates matrix metalloproteinase-dependent changes in channel gating. AB - Cyclic-nucleotide gated (CNG) channels are essential for phototransduction within retinal photoreceptors. We have demonstrated previously that the enzymatic activity of matrix metalloproteinase-2 and -9, members of the matrix metalloproteinase (MMP) family of extracellular, Ca(2+)- and Zn(2+)-dependent proteases, enhances the ligand sensitivity of both rod (CNGA1 and CNGB1) and cone (CNGA3 and CNGB3) CNG channels. Additionally, we have observed a decrease in the maximal CNG channel current (Imax) that begins late during MMP-directed gating changes. Here we demonstrate that CNG channels become nonconductive after prolonged MMP exposure. Concurrent with the loss of conductive channels is the increased relative contribution of channels exhibiting nonmodified gating properties, suggesting the presence of a subpopulation of channels that are protected from MMP-induced gating effects. CNGA subunits are known to possess one extracellular core glycosylation site, located at one of two possible positions within the turret loop near the pore-forming region. Our results indicate that CNGA glycosylation can impede MMP-dependent modification of CNG channels. Furthermore, the relative position of the glycosylation site within the pore turret influences the extent of MMP-dependent proteolysis. Glycosylation at the site found in CNGA3 subunits was found to be protective, while glycosylation at the bovine CNGA1 site was not. Relocating the glycosylation site in CNGA1 to the position found in CNGA3 recapitulated CNGA3-like protection from MMP-dependent processing. Taken together, these data indicate that CNGA glycosylation may protect CNG channels from MMP-dependent proteolysis, consistent with MMP modification of channel function having a requirement for physical access to the extracellular face of the channel. PMID- 24164426 TI - Metabonomic profiling revealed an alteration in purine nucleotide metabolism associated with cardiac hypertrophy in rats treated with thiazolidinediones. AB - Thiazolidinediones (TZDs) including rosiglitazone (RSG) and pioglitazone (PIO) are synthetic agonists selective for peroxisome proliferator-activated receptor gamma (PPARgamma) and have been clinically used to treat type-II diabetes as insulin sensitizers. Recent meta-analyses have shown that TZDs are associated with an increased risk for the development of heart failure. To elucidate the mechanism underlying such a cardiac adverse effect, we used a (1)H NMR-based approach to examine the metabonomic profiles in the cardiac tissues treated with RSG (15 mg/kg body weight/day) or PIO (45 mg/kg/day) for 4 weeks and found that the TZD treatments resulted in a significantly altered metabolic profile in hearts, which was associated with cardiac hypertrophy. Multivariate analysis demonstrated that TZDs led to an accumulation in adenosine monophosphate (AMP) and a depletion of inosine. Consistently, AMP kinase, a signal pathway sensitive to the change in the intracellular concentrations of AMP, was activated in the cardiac tissues from the TZDs-treated rats. Quantitative real-time reverse transcriptase polymerase chain reaction showed a significant induction of the genes involved in the de novo synthesis of purine nucleotide but a reduction of those for the catabolism. Furthermore, the putative PPAR-responsive elements were identified in the 5'-flanking regions of the TZD-up-regulated genes such as adenylosuccinate synthase gene (Adss) and phosphoribosl pyrophosphate synthetase 1 (Prps1), and the binding of PPARgamma to these motifs was confirmed by using chromatin immunoprecipitation assay. In conclusion, these results demonstrated that TZDs induced alterations in purine nucleotide metabolism in rat hearts via transcriptional regulation of the PPARgamma-target genes, which may play an important role in the development of cardiac hypertrophy associated with TZDs. PMID- 24164427 TI - Methotrexate-loaded PEGylated chitosan nanoparticles: synthesis, characterization, and in vitro and in vivo antitumoral activity. AB - Cancer nanotherapeutics are rapidly progressing and being implemented to solve several limitations of conventional drug delivery systems. In this paper, we report a novel strategy of preparing methotrexate (MTX) nanoparticles based on chitosan (CS) and methoxypoly(ethylene glycol) (mPEG) used as nanocarriers to enhance their targeting and prolong blood circulation. MTX and mPEG-conjugated CS nanoparticles (NPs) were prepared and evaluated for their targeting efficiency and toxicity in vitro and in vivo. The MTX-mPEG-CS NP size determined by dynamic light scattering was 213 +/- 2.0 nm with a narrow particle size distribution, and its loading content (LC %) and encapsulation efficiency (EE) were 44.19 +/- 0.64% and 87.65 +/- 0.79%, respectively. In vitro release behavior of MTX was investigated. In vivo optical imaging in mice proved that MTX was released from particles subsequently and targeted to tumor tissue, showing significantly prolonged retention and specific selectivity. The 3-(4,5-dimethylthiazol-2-yl) 2,5-diphenyltetrazolium bromide (MTT) assay obviously indicated that the higher inhibition efficiency of MTX-mPEG-CS NPs meant that much more MTX was transferred into the tumor cells. A significant right-shift in the flow cytometry (FCM) assay demonstrated that MTX-loaded nanoparticles were far superior to a pure drug in the inhibition of growth and proliferation of Hela cells. These results suggest that MTX-mPEG-CS NPs could be a promising targeting anticancer chemotherapeutic agent, especially for cervical carcinoma. PMID- 24164428 TI - Dark-field microscopy in the assessment of large colon microperfusion and mucosal injury in naturally occurring surgical disease of the equine large colon. AB - REASON FOR PERFORMING STUDY: Intraoperative assessment of colonic viability can be challenging and largely subjective. Objective methods are often impractical. Viability is related to re-establishment of colonic perfusion; particularly microvascular perfusion. This study evaluated the utility of dark-field microscopy (DFM) of the colonic serosa as an objective method of assessing microperfusion. OBJECTIVES: To measure microvascular perfusion indices (MPI) of the pelvic flexure serosa in horses with surgical colonic lesions and correlate these with macroperfusion indices (MaPI) and histomorphometry. STUDY DESIGN: Prospective, clinical, case-control study. METHODS: Control horses and horses with colonic volvulus (LCV), displacement, and/or simple obstruction undergoing surgery had DFM video loops performed on the pelvic flexure. Total vessel density, perfused vessel density, proportion of perfusion vessels and microvascular flow index were calculated from video analysis. Macroperfusion indices (arterial blood pressure and heart rate) were recorded. Histomorphometry was used to determine a mucosal injury score. Differences between lesions for MPI, MaPI and histomorphometry were compared using ANOVA or Kruskal-Wallis statistic. Spearman correlations between MPI with MaPI were performed. Linear regression was used to assess the relationship between MPI and histomorphometry. P<0.05 was significant. RESULTS: Horses with LCV had lower perfused vessel density, proportion of microvascular perfusion vessels and flow index than horses with nonstrangulating obstructions and control horses. Macroperfusion indices were not correlated with MPI but MPI were correlated with histomorphometry. CONCLUSIONS: Dark-field microscopy is achievable in the operating room and can quantify MPI from the colonic serosa in different colonic lesions. Macroperfusion indices were not related with colonic MPI. Microvascular perfusion indices can predict the severity of histopathological change at the pelvic flexure. Derangements of MPI may be more useful indicators of colonic pathology and viability and offer a more objective assessment of intestinal injury than subjective methods. Further study is needed to determine the utility of DFM in predicting survival in horses with LCV. PMID- 24164429 TI - Correlation of the electronic and geometric structures in mononuclear copper(II) superoxide complexes. AB - The geometry of mononuclear copper(II) superoxide complexes has been shown to determine their ground state where side-on bonding leads to a singlet ground state and end-on complexes have triplet ground states. In an apparent contrast to this trend, the recently synthesized (HIPT3tren)Cu(II)O2(*-) (1) was proposed to have an end-on geometry and a singlet ground state. However, reexamination of 1 with resonance Raman, magnetic circular dichroism, and (2)H NMR spectroscopies indicate that 1 is, in fact, an end-on superoxide species with a triplet ground state that results from the single Cu(II)O2(*-) bonding interaction being weaker than the spin-pairing energy. PMID- 24164430 TI - Clinical characteristics of resistant hypertension evaluated by ambulatory blood pressure monitoring. AB - Strict control of blood pressure is important to prevent cardiovascular disease, although it is sometimes difficult to decrease blood pressure to target levels. The aim of this study was to investigate the clinical characteristics of resistant hypertension evaluated by ambulatory blood pressure monitoring. One hundred in-hospital patients, whose 24-hour average blood pressure was higher than 130/80 mmHg even after treatment with more than three antihypertensive drugs, were included in the present analysis. Circadian variation of blood pressure was evaluated by nocturnal fall in systolic blood pressure. Average blood pressures of all patients were high in both daytime and nighttime, 150.0/82.9 and 143.8/78.2 mmHg, respectively. Twenty patients had been treated with hemodialysis or peritoneal dialysis. In 63 patients out of the other 80 patients (79%), estimated glomerular filtration rate (eGFR) was also decreased (<60 mL/min/1.73 m2). The patients classified into dipper, non-dipper, riser and extreme-dipper were 20%, 43%, 34% and 3%, respectively. In addition, in 17 patients whose eGFR was preserved, 12 patients showed a non-dipper or riser pattern, suggesting that it was difficult to account for this altered circadian blood pressure variation only by renal dysfunction. These results show that a large number of the patients with resistant hypertension suffered from renal dysfunction, although it was difficult to explain altered circadian blood pressure variation based on renal dysfunction alone. PMID- 24164433 TI - Genetic characterization of a betanodavirus isolated from a clinical disease outbreak in farm-raised tilapia Oreochromis niloticus (L.) in Thailand. AB - Betanodavirus infection was diagnosed in larvae of farm-raised tilapia Oreochromis niloticus (L.), in central Thailand. Extensive vacuolar degeneration and neuronal necrosis were observed in histological sections with positive immunohistochemical staining for betanodavirus. Molecular phylogenetic analysis was performed based on the nucleotide sequences (1333 bases) of the capsid protein gene. The virus strain was highly homologous (93.07-93.88%) and closely related to red-spotted grouper nervous necrosis virus (RGNNV). PMID- 24164432 TI - Epigallocatechin gallate induces embryonic toxicity in mouse blastocysts through apoptosis. AB - Catechins, a family of polyphenols found in tea, evoke various responses, including cell death. However, the side effects of these compounds, particularly those on embryonic development, have not been characterized in detail. A previous study by our group showed that (-)-epigallocatechin-3-gallate (EGCG), a catechin highly abundant in green tea, induces different cell-death modes in MCF-7 cells, depending on the treatment dosage. In the current study, we examined the effects of EGCG on mouse embryos at the blastocyst stage, subsequent embryonic attachment and outgrowth in vitro and in vivo implantation by embryo transfer. Blastocysts treated with 25-50 MUM of EGCG exhibited a significant increase in apoptosis and a corresponding decrease in total cell number. Notably, the implantation success rate of blastocysts pretreated with EGCG was lower than that of their control counterparts. Moreover, in vitro treatment with 25-50 MUM of EGCG led to increased resorption of postimplantation embryos and decreased fetal weight. EGCG appeared to induce injury in mouse blastocysts through intrinsic apoptotic signaling processes to impair sequent embryonic development. These results collectively highlight the potential of EGCG to induce embryonic cytotoxicity. PMID- 24164434 TI - There's an app for that. PMID- 24164431 TI - Short communication: Transmitted HIV drug resistance in antiretroviral-naive pregnant women in north central Nigeria. AB - The World Health Organization (WHO) recommends periodic surveillance of transmitted drug resistance (TDR) in communities in which antiretroviral therapy (ART) has been scaled-up for greater than 3 years. We conducted a survey of TDR mutations among newly detected HIV-infected antiretroviral (ARV)-naive pregnant women. From May 2010 to March 2012, 38 ARV-naive pregnant women were recruited in three hospitals in Jos, Plateau state, north central Nigeria. Eligible subjects were recruited using a modified version of the binomial sequential sampling technique recommended by WHO. HIV-1 genotyping was performed and HIV-1 drug resistance mutations were characterized according to the WHO 2009 surveillance drug resistance mutation (SDRM) list. HIV subtypes were determined by phylogenetic analysis. The women's median age was 25.5 years; the median CD4(+) cell count was 317 cells/MUl and the median viral load of 16 was 261 copies/ml. Of the 38 samples tested, 34 (89%) were successfully genotyped. The SDRM rate was <5% for all ART drug classes, with 1/34 (2.9%) for NRTIs/NNRTIs and none for protease inhibitors 0/31 (0%). The specific SDRMs detected were M41L for nucleoside reverse transcriptase inhibitors (NRTIs) and G190A for nonnucleoside reverse transcriptase inhibitors (NNRTIs). HIV-1 subtypes detected were CRF02_AG (38.2%), G' (41.2%), G (14.7%), CRF06-CPX (2.9%), and a unique AG recombinant form (2.9%). The single ARV-native pregnant woman with SDRMs was infected with HIV-1 subtype G'. Access to ART has been available in the Jos area for over 8 years. The prevalence of TDR lower than 5% suggests proper ART administration, although continued surveillance is warranted. PMID- 24164435 TI - Sam L. Pool, MD. 1927-2013. PMID- 24164437 TI - Identification of multiple sources of groundwater contamination by dual isotopes. AB - Chlorinated solvents are one of the most commonly detected groundwater contaminants in industrial areas. Identification of polluters and allocation of contaminant sources are important concerns in the evaluation of complex subsurface contamination with multiple sources. In recent years, compound specific isotope analyses (CSIA) have been employed to discriminate among different contaminant sources and to better understand the fate of contaminants in field-site studies. In this study, the usefulness of dual isotopes (carbon and chlorine) was shown in assessments of groundwater contamination at an industrial complex in Wonju, Korea, where groundwater contamination with chlorinated solvents such as trichloroethene (TCE) and carbon tetrachloride (CT) was observed. In November 2009, the detected TCE concentrations at the study site ranged between nondetected and 10,066 ug/L, and the CT concentrations ranged between nondetected and 985 ug/L. In the upgradient area, TCE and CT metabolites were detected, whereas only TCE metabolites were detected in the downgradient area. The study revealed the presence of separate small but concentrated TCE pockets in the downgradient area, suggesting the possibility of multiple contaminant sources that created multiple comingling plumes. Furthermore, the variation of the isotopic (delta(13) C and delta(37) Cl) TCE values between the upgradient and downgradient areas lends support to the idea of multiple contamination sources even in the presence of detectable biodegradation. This case study found it useful to apply a spatial distribution of contaminants coupled with their dual isotopic values for evaluation of the contaminated sites and identification of the presence of multiple sources in the study area. PMID- 24164436 TI - Structural models of ligand-gated ion channels: sites of action for anesthetics and ethanol. AB - The molecular mechanism(s) of action of anesthetic, and especially, intoxicating doses of alcohol (ethanol [EtOH]) have been of interest even before the advent of the Research Society on Alcoholism. Recent physiological, genetic, and biochemical studies have pin-pointed molecular targets for anesthetics and EtOH in the brain as ligand-gated ion channel (LGIC) membrane proteins, especially the pentameric (5 subunit) Cys-loop superfamily of neurotransmitter receptors including nicotinic acetylcholine (nAChRs), GABAA (GABAA Rs), and glycine receptors (GlyRs). The ability to demonstrate molecular and structural elements of these proteins critical for the behavioral effects of these drugs on animals and humans provides convincing evidence for their role in the drugs' actions. Amino acid residues necessary for pharmacologically relevant allosteric modulation of LGIC function by anesthetics and EtOH have been identified in these channel proteins. Site-directed mutagenesis revealed potential allosteric modulatory sites in both the trans-membrane domain (TMD) and extracellular domain (ECD). Potential sites of action and binding have been deduced from homology modeling of other LGICs with structures known from crystallography and cryo electron microscopy studies. Direct information about ligand binding in the TMD has been obtained by photoaffinity labeling, especially in GABAA Rs. Recent structural information from crystallized procaryotic (ELIC and GLIC) and eukaryotic (GluCl) LGICs allows refinement of the structural models including evaluation of possible sites of EtOH action. PMID- 24164438 TI - Expression of astrocytic genes coding for proteins implicated in neural excitation and brain edema is altered after acute liver failure. AB - In vitro and in vivo studies have suggested that reduced astrocytic uptake of neuronally released glutamate, alterations in expression of glial fibrillary acidic protein (GFAP) and aquaporin-4 (AQP-4) contribute to brain edema in acute liver failure (ALF). However, there is no evidence to date to suggest that these alterations occur in patients with ALF. We analyzed the mRNA expression of excitatory amino acid transporters (EAAT-1, EAAT-2), GFAP, and AQP-4 in the cerebral cortex obtained at autopsy from eight patients with ALF and from seven patients with no evidence of hepatic or neurological disorders by real-time PCR, and protein expression was assessed using immunoblotting and immunohistochemistry. We demonstrated a significant decrease in GFAP mRNA and protein levels in ALF patients compared to controls. While the loss of EAAT-2 protein in ALF samples was post-translational in nature, EAAT-1 protein remained within normal limits. Immunohistochemistry confirmed that, in all cases, the losses of EAAT-2 and GFAP were uniquely astrocytic in their localization. AQP-4 mRNA expression was significantly increased and its immunohistochemistry demonstrated increased AQP-4 immunoreactivity in the glial end-feet process surrounding the microvessels. These findings provide evidence of selective alterations in the expression of genes coding for key astrocytic proteins implicated in central nervous system (CNS) excitability and brain edema in human ALF. We investigated the gene expression of astrocytic proteins involved in astrocyte swelling causing brain edema in autopsied brain tissues of patients with acute liver failure. This study demonstrated loss of GFAP expression and up regulation of AQP-4 protein expression leading to cerebral edema, and loss of EAAT-2 expression implicated in excitatory neurotransmission. These findings may provide new drug targets against CNS complications of acute liver failure. PMID- 24164439 TI - Knock-down of filaggrin does not affect lipid organization and composition in stratum corneum of reconstructed human skin equivalents. AB - Human skin mainly functions as an effective barrier against unwanted environmental influences. The barrier function strongly relies on the outermost layer of the skin, the stratum corneum (SC), which is composed of corneocytes embedded in an extracellular lipid matrix. The importance of a proper barrier function is shown in various skin disorders such as atopic dermatitis (AD), a complex human skin disorder strongly associated with filaggrin (FLG) null mutations, but their role in barrier function is yet unclear. To study the role of FLG in SC barrier properties in terms of SC lipid organization and lipid composition, we generated an N/TERT-based 3D-skin equivalent (NSE) after knock down of FLG with shRNA. In these NSEs, we examined epidermal morphogenesis by evaluating the expression of differentiation markers keratin 10, FLG, loricrin and the proliferation marker ki67. Furthermore, the SC was extensively analysed for lipid organization, lipid composition and SC permeability. Our results demonstrate that FLG knock-down (FLG-KD) did not affect epidermal morphogenesis, SC lipid organization, lipid composition and SC permeability for a lipophilic compound in NSEs. Therefore, our findings indicate that FLG-KD alone does not necessarily affect the functionality of a proper barrier function. PMID- 24164440 TI - Integrative review: nurses' and physicians' experiences and attitudes towards inpatient-witnessed resuscitation of an adult patient. AB - AIM: An integrative review of attitudes and experiences of healthcare professionals regarding family-witnessed resuscitation. BACKGROUND: Allowing family members to be present during resuscitation has been a topic of debate in the last years. Increased focus on family centred care led to preparation of official statements concerning this phenomenon. While in some countries witnessed resuscitation is accepted and used, there are many places where it is not respected and remains controversial. DESIGN: Integrative literature review. DATA SOURCES: Databases: CINAHL, PsycINFO and PubMed. REVIEW METHODS: Cooper's five stage integrative review method has been used. Results were limited to original publications in English, published between 2007-2012, describing nurses' and doctors' experiences and attitudes on inpatient family-witnessed resuscitation of an adult patient. RESULTS: Fifteen articles were included. Healthcare professionals indicated different opinions on family-witnessed resuscitation. Perceptions vary in different cultural settings. There are both positive and negative effects of this practice on the family members and the rescue team. There is a lack of local guidelines. CONCLUSION: Further research with larger sample sizes and different cultural settings would help identify outcomes following the family presence during resuscitation practice. Qualitative research is needed to examine the impact of those outcomes and develop policies and guidelines on cultural variability. PMID- 24164441 TI - Concurrent validity of walking speed values calculated via the GAITRite electronic walkway and 3 meter walk test in the chronic stroke population. AB - The purpose of this study was to provide novel information regarding the concurrent validity (primary aim) and reliability (secondary aim) of walking speed (WS) calculated via the GAITRite electronic walkway system and 3 meter walk test (3MWT) in the chronic stroke population. The 3MWT is a feasible option for clinicians working in environments where space is limited. Psychometric properties of the test have not been established. Participants with chronic stroke were stratified into three groups: (1) household ambulators (HA) (self selected WS < 0.4 m/s, 12 participants, 31 observations); (2) limited community ambulators (LCA) (self-selected WS 0.4-0.8 m/s, 24 participants, 60 observations); and (3) community ambulators (CA) (self-selected WS > 0.8 m/s, 26 participants, 71 observations). Three consecutive trials of GAITRite and 3MWT were performed at participant's self-selected WS. Average WS measurements differed significantly (p < 0.05) between GAITRite and 3MWT for all three groups. HA group: GAITRite 0.25 (0.11) m/s, 3MWT 0.27 (0.11) m/s; LCA group: GAITRite 0.56 (0.11) m/s, 3MWT 0.52 (0.10) m/s; CA group: GAITRite 1.03 (0.16) m/s, 3MWT 0.89 (0.15) m/s. Both WS measures had excellent within-session reliability (ICC's ranging from 0.85 to 0.97, SEM95 from 0.04 to 0.12 m/s and MDC95 from 0.05 to 0.16 m/s). Reliability was highest for HA on both measures. Although both the 3MWT and the GAITRite are reliable measures of WS for individuals with chronic stroke, the two measures do not demonstrate concurrent validity. PMID- 24164442 TI - Diversity and distribution of Halomonas in Rambla Salada, a hypersaline environment in the southeast of Spain. AB - We have studied the diversity and distribution of Halomonas populations in the hypersaline habitat Rambla Salada (Murcia, southeastern Spain) by using different molecular techniques. Denaturing gradient gel electrophoresis (DGGE) using specific primers for the 16S rRNA gene of Halomonas followed by a multivariate analysis of the results indicated that richness and evenness of the Halomonas populations were mainly influenced by the season. We found no significant differences between the types of samples studied, from either watery sediments or soil samples. The highest value of diversity was reached in June 2006, the season with the highest salinity. Furthermore, canonical correspondence analysis (CCA) demonstrated that both salinity and pH significantly affected the structure of the Halomonas community. Halomonas almeriensis and two denitrifiers, H. ilicicola and H. ventosae were the predominant species. CARD-FISH showed that the percentage of Halomonas cells with respect to the total number of microorganisms ranged from 4.4% to 5.7%. To study the functional role of denitrifying species, we designed new primer sets targeting denitrification nirS and nosZ genes. Using these primers, we analyzed sediments from the upwelling zone collected in June 2006, where we found the highest percentage of denitrifiers (74%). Halomonas ventosae was the predominant denitrifier in this site. PMID- 24164443 TI - High prevalence of celiac disease in Swedish children and adolescents with type 1 diabetes and the relation to the Swedish epidemic of celiac disease: a cohort study. AB - AIM: The aim was to determine the prevalence and clinical and temporal relationship of celiac disease (CD) in a population of Swedish children with type 1 diabetes mellitus (T1DM) before, during, and after the Swedish epidemic of CD (birth cohorts 1984-1996). METHODS: Retrospective chart review between 1995 and 2005 was conducted of 1151 children (0-18 years old, born 1981-2004) with T1DM. RESULTS: A prevalence of 9.1% (95% CI: 7.2-11.2) of CD in T1DM children was found. No significant difference in prevalence of CD was observed in different birth years, in contrast to the Swedish epidemic of CD. Sixty-two percent of children diagnosed with CD after T1DM onset had pathological levels of antibodies within the first 24 months. The presence or absence of gastrointestinal symptoms had no predictable value for biopsy-confirmed CD or not. CONCLUSION: The onset of CD in the T1DM population does not follow the pattern of the general population during the Swedish epidemic of CD. The shared genetic component in the human leukocyte antigen region in cases with comorbidity of CD and T1DM may overrule other CD-causing factors in the general population. Children with T1DM should be screened for CD at diagnosis and repeatedly at least during the first 2 years, even if asymptomatic. PMID- 24164444 TI - Dimensionality dependent water splitting mechanisms on free manganese oxide clusters. AB - The interaction of ligand-free manganese oxide nanoclusters with water is investigated, aiming at uncovering phenomena which could aid the design of artificial water-splitting molecular catalysts. Gas phase measurements in an ion trap in conjunction with first-principles calculations provide new mechanistic insight into the water splitting process mediated by bi- and tetra-nuclear singly charged manganese oxide clusters, Mn2O2(+) and Mn4O4(+). In particular, a water induced dimensionality change of Mn4O4(+) is predicted, entailing transformation from a two-dimensional ring-like ground state structure of the bare cluster to a cuboidal octa-hydroxy-complex for the hydrated one. It is further predicted that the water splitting process is facilitated by the cluster dimensionality crossover. The vibrational spectra calculated for species occurring along the predicted pathways of the reaction of Mn4O4(+) with water provide the impetus for future explorations, including vibrational spectroscopic experiments. PMID- 24164445 TI - Three noninvasive methods in the evaluation of subclinical cardiovascular disease in patients with acromegaly: epicardial fat thickness, aortic stiffness and serum cell adhesion molecules. AB - CONTEXT: Several studies have reported increased risk of cardiovascular disease due to early development of endothelial dysfunction and structural vascular changes in patients with acromegaly. OBJECTIVE: The aim of this study was to evaluate subclinical cardiovascular disease with epicardial fat thickness (EFT), aortic stiffness and serum levels of cell adhesion molecules (CAMs) in patients with acromegaly. DESIGN: Cross-sectional study. PATIENTS: Twenty-seven patients with active acromegaly (AA), 13 patients with remission acromegaly (RA) and 37 age- and sex-matched healthy controls were studied. MEASUREMENTS: Epicardial fat thickness was evaluated by transthoracic echocardiography (TTE). Aortic stiffness (beta) index, aortic strain (AoS) and aortic distensibility (AoD) were calculated from the aortic diameters measured by TTE. Serum levels of CAMs such as intercellular adhesion molecule (ICAM)-1, vascular cell adhesion molecule (VCAM) 1 and E-selectin were measured. RESULTS: Epicardial fat thickness was significantly increased in patients with RA and AA as compared to controls 9.71 +/- 1.54 and 10.08 +/- 1.95 mm vs 5.74 +/- 0.92 mm, P < 0.001, respectively). A significant positive correlation was found between the EFT and growth hormone (GH) levels (r = 0.365, P = 0.024). beta-index was similarly higher in patients with RA and AA than controls (15.68 +/- 7.27 and 11.90 +/- 8.24 vs 6.85 +/- 2.87, P < 0.001, respectively). AoS and AoD were significantly decreased in patients with RA and AA as compared to the control group (3.81 +/- 1.94 and 3.68 +/- 1.99 vs 8.19 +/- 4.19%, P < 0.001, respectively; and 1.21 +/- 0.66 and 1.18 +/- 0.63 vs 2.58 +/- 1.50, 10(-6) cm(2) /dyn, P < 0.001, respectively). Serum ICAM-1 and VCAM-1 levels were significantly higher in patients as compared to the control group (P < 0.001 vs P = 0.032, respectively). There were no significant differences in EFT, AoD, AoS, beta-index and serum CAMs between two patients groups (AA vs RA, P > 0.05). There was a significant negative correlation between E-selectin and AoD (r = -0.45, P = 0.008). In multiple linear regression analysis, EFT was found to be associated with GH levels (beta-coefficient = 0.575, P = 0.008). CONCLUSION: This study suggests that EFT and risk of subclinical cardiovascular disease are increased in patients with acromegaly. Serum GH level is an independent risk factor for EFT. PMID- 24164447 TI - Unraveling the molecular structure of the catalytic domain of matrix metalloproteinase-2 in complex with a triple-helical peptide by means of molecular dynamics simulations. AB - Herein, we present the results of a computational study that employed various simulation methodologies to build and validate a series of molecular models of a synthetic triple-helical peptide (fTHP-5) both in its native state and in a prereactive complex with the catalytic domain of the MMP-2 enzyme. First, the structure and dynamical properties of the fTHP-5 substrate are investigated by means of molecular dynamics (MD) simulations. Then, the propensity of each of the three peptide chains in fTHP-5 to be distorted around the scissile peptide bond is assessed by carrying out potential of mean force calculations. Subsequently, the distorted geometries of fTHP-5 are docked within the MMP-2 active site following a semirigid protocol, and the most stable docked structures are fully relaxed and characterized by extensive MD simulations in explicit solvent. Following a similar approach, we also investigate a hypothetical ternary complex formed between two MMP-2 catalytic units and a single fTHP-5 molecule. Overall, our models for the MMP-2/fTHP-5 complexes unveil the extent to which the triple helix is distorted to allow the accommodation of an individual peptide chain within the MMP active site. PMID- 24164446 TI - Intravenous immunoglobulin-induced haemolysis: a case report and review of the literature. AB - OBJECTIVES: To review the incidence and clinical features of intravenous immunoglobulin (IVIg)-induced haemolysis. BACKGROUND: Haemolysis can be a severe complication of IVIg administration. It is due to the passive transfer of blood group antibodies and may result in significant anaemia and renal failure. METHODS: We report a case of severe IVIg-induced haemolysis; review the data reported to vigilance groups (The Medicines and Healthcare Products Regulatory Agency, European Union Drug Regulatory Authorities, Food and Drug Administration and the Canada Vigilance Centre) between January 1998 and May 2012; and systematically review IVIg-induced haemolysis case reports (between January 1948 and January 2013). RESULTS: Nine hundred-twenty five cases of IVIg-induced haemolysis were identified from a review of cases reported to vigilance groups; 62 case reports were included in the systematic review. The majority of these were due to administration of doses of at least 2 g kg(-1) of IVIg (97%). IVIg induced haemolysis was reported most commonly for patients with blood group A (65%) or AB (26%). One case report noted that in two patients with IVIg-induced haemolysis both received IVIg from the same batch. CONCLUSION: We make the following recommendations for the management of suspected cases of IVIg-induced haemolysis: Stop IVIg infusion and perform tests for haemolysis. Check titres of anti-blood group antibodies in IVIg. Provide supportive management for patient with fluid and/or red blood cell transfusions if necessary. Consider quarantine of the IVIg batch if found to be high titre for anti-A/B. Report reaction to regulatory/vigilance body. PMID- 24164448 TI - Minimal residual disease diagnostics in acute lymphoblastic leukaemia: impact of primer characteristics and size of junctional regions. PMID- 24164449 TI - Frontal plane fractures of the accessory carpal bone and implications for the carpal sheath of the digital flexor tendons. AB - REASONS FOR PERFORMING STUDY: Accurate radiological and ultrasonographic descriptions of frontal plane fractures of the accessory carpal bone (ACB) are lacking, and implications of these fractures for the carpal sheath and its contents have not previously been reported. OBJECTIVES: Aims were as follows: 1) to describe the location and radiological features of frontal plane fractures of the ACB; 2) to document communication of displaced fractures with the carpal sheath and consequent injury to the deep digital flexor tendon (DDFT); 3) to describe ultrasonographic identification of lesions; and 4) to report tenoscopic evaluation and treatment. STUDY DESIGN: Retrospective case series. METHODS: Analysis of frontal plane fractures of the ACB referred to a single hospital between 2006 and 2012, including review of radiographic, ultrasonographic and tenoscopic images. RESULTS: Nine fractures were identified, of which 8 displaced fractures all communicated with the carpal sheath. Comminuted fragments and/or protruding fracture margins lacerated the lateral margin of the enclosed DDFT. This was identifiable ultrasonographically and confirmed at tenoscopy in 7 cases. Treatment in these horses consisted of removal of torn tendon tissue together with fragmentation and protuberant fracture edges, and 7 of 7 cases returned to work. One horse with a nondisplaced fracture was managed with immobilisation; the fracture healed, and the horse returned to work. One horse with a displaced fracture was retired to stud. CONCLUSIONS: Frontal plane fractures of the ACB occur palmar to the groove in its lateral margin for the tendon of insertion of ulnaris lateralis. Comminuted fragments can displace distally within the carpal sheath to a mid-metacarpal level or abaxially to lie extrathecally, lateral to the parent bone. Displaced fractures communicate with the carpal sheath and traumatise the DDFT. PMID- 24164450 TI - The genotoxic and cytotoxic effects of nimesulide in the mouse bone marrow. AB - Genotoxicity of nimesulide (NM) was evaluated by employing bone marrow (BM) chromosomal aberration (CA) and micronucleus assays in Swiss albino mice. For BM CA assay, mice of either sex were treated orally with 1.5, 2.5 and 5 mg body weight solution of NM in 0.2 mL of 0.05% CMC (carboxy methyl cellulose) daily for 4, 13, 28 and 40 weeks. Treatment induced dose-dependent and significantly depressed mitotic activity and increase in CAs per cell in the BM cells after 13 weeks of treatment at all dose levels. In micronucleus assay, male mice were treated orally with the same dose levels and sampling durations as for CA assay. Treatment increased the percentage of micronucleated polychromatic erythrocytes frequency and showed a statistically significant reduction in polychromatic erythrocyte/normochromatic erythrocyte ratio, as compared to control groups. Cyclophosphamide (40 mg/kg) was used as clastogen (positive control) and yielded the expected positive results. Cytotoxicity was observed in the 8-week recovery period after 40 weeks of dosing, but it was not significant. On the basis of these findings, it may be concluded that in the long term, NM, or its biotransformed product, is genotoxic and cytotoxic for BM cells of mice in vivo. PMID- 24164451 TI - Hemodynamic correlates of low umbilical cord vitamin D and ionized calcium. AB - Vitamin D deficiency and hypocalcemia are associated with gestational hypertension. Therefore, we hypothesized that umbilical cord [Ca(2+)] and [vitamin D] are correlated with perinatal blood pressures. Mothers and newborns comprised vitamin D sufficient (vitamin D >= 50 nM, range 52-111 nM, n = 14), and vitamin D deficient groups (vitamin D < 50 nM, range 13-49 nM, n = 29). Cord [Ca2+] was negatively correlated with maternal systolic pressure (SBP) (r = 0.56, p < 0.01) and positively correlated with neonatal SBP (r = +0.55, p < 0.01) in the vitamin D deficient group. We conclude that low umbilical cord [vitamin D] and [Ca2+] may predispose mothers to higher and newborns to lower blood pressures. PMID- 24164453 TI - Abstracts of the Second Chinese Congress on Gerontology and Health Industry. September 13-15, 2013. Suzhou, China. PMID- 24164454 TI - Near full-length genome characterization of a new CRF01_AE/CRF08_BC recombinant transmitted between a heterosexual couple in Guangxi, China. AB - Human immunodeficiency virus type 1 (HIV-1) subtype CRF01_AE is transmitted mainly by sexual activity in Guangxi, southwestern China. Other subtypes, including CRF07_BC, CRF08_BC, and subtype B, are also prevalent in this region. Cocirculation of multiple subtypes, as well as a high rate of drug use, creates favorable conditions for the emergence of recombinant viruses in Guangxi. In the present study, we identified a new HIV-1 unique recombinant form (CRF01_AE /08BC) transmitted from the infected index patient to his seronegative sexual partner. This is the first near full-length genome characterization of a CRF01_AE /08BC recombinant virus in Guangxi, and provides an important basis for future analysis on potential new recombinant transmission events. PMID- 24164457 TI - Mixed breeding system in the hermaphroditic land slug Arion intermedius (Stylommatophora, Arionidae). AB - Theory suggests that hermaphroditic plants and animals should be either entirely outcrossing or entirely selfing. As such, very few hermaphroditic plants and basommatophoran snails have a mixed breeding system. However, reliable estimates of selfing rates are lacking for most hermaphroditic animals. This partly prevents to delineate the relative contributions of the selective factors that determine selfing and outcrossing rates in hermaphroditic animal taxa. Here, we studied the population genetic structure of, and breeding system in, 11 populations of the hermaphroditic land slug Arion intermedius using five polymorphic microsatellite loci. Moreover, genotype frequencies deviated significantly from Hardy-Weinberg equilibrium expectations for most of the loci in all populations suggesting some level of selfing. Estimates of the selfing level s, suggest moderate levels of outcrossing (mean s based on FIS = 0.84; mean s based on the two-locus heterozygosity disequilibrium = 0.20, or with a ML approach = 0.22). Our study therefore suggests that A. intermedius has a mixed breeding system. A re-analysis of allozyme data from another arionid slug ( subgenus Carinarion) indicates that mixed breeding may be more common in arionid slugs than hitherto was assumed. These results seem therefore at variance with current theoretical and empirical predictions and opens perspectives for the study on the evolutionary factors driving mixed breeding systems in animals. PMID- 24164455 TI - Complex formation and processing of the minor transformation pilins of Bacillus subtilis. AB - Transformation in most bacteria is dependent on orthologues of Type 2 secretion and Type 4 pilus system proteins. In each system, pilin proteins (major and minor) are required to make the pilus structure and are essential to the process, although the precise roles of the minor pilins remain unclear. We have explored protein-protein interactions among the competence minor pilins of Bacillus subtilis through in vitro binding studies, immunopurification and mass spectrometry. We demonstrate that the minor pilins directly interact, and the minor pilin ComGG interacts with most of the known proteins required for transformation. We find that ComGG requires other ComG proteins for its stabilization and for processing by the pre-pilin peptidase. These observations, C-terminal mutations in ComGG that prevent processing and the inaccessibility of pre-ComGG to externally added protease suggest a model in which pre-ComGG must be associated with other minor pilins for processing to take place. We propose that ComGG does not become a transmembrane protein until after processing. These behaviours contrast with that of pre-ComGC, the major pilin, which is accessible to externally added protease and requires only the peptidase to be processed. The roles of the pilins and of the pilus in transformation are discussed. PMID- 24164456 TI - Inappropriate feeding behaviors and dietary intakes in children with fetal alcohol spectrum disorder or probable prenatal alcohol exposure. AB - BACKGROUND: Prenatal alcohol exposure (PAE) is a leading cause of significant neurobehavioral and neurocognitive deficits. Its potential consequences for eating behaviors, nutritional status, and other nutritional issues in childhood have received little attention. METHODS: Nineteen children (11 boys, 8 girls) of mean age 9.6 years, referred for fetal alcohol spectrum disorder (FASD) screening and assessment, were analyzed with physical exams and caregiver questionnaires to identify possible abnormalities in food and eating behaviors. Fourteen children contributed 24-hour diet recalls and were assessed for nutritional status. RESULTS: Seventy-nine percent of participants were diagnosed with FASD and 63.2% had confirmed PAE. Fifty percent of girls were overweight or obese, whereas 37% of boys had reduced stature, weight, or body mass index for their age. Recurring feeding problems included constant snacking (36.8%), lack of satiety (26.3%), and picky eating/poor appetite (31.6%). None had oral feeding problems. Constipation was common (26.3%). Macronutrient intakes were largely normal, but sugar consumption was excessive (140 to 190% of recommendations) in 57% of subjects. Vitamin A intake exceeded the upper limit for 64% of participants, whereas >=50% had intakes <80% of recommended daily allowances (RDAs) for choline, vitamin E, potassium, beta-carotene, and essential fatty acids; 100% had vitamin D intakes <80% of the RDA. CONCLUSIONS: PAE may be associated with altered acquisition and distribution of body mass with increasing age. Disordered eating was common. The increased feeding behaviors surrounding lack of satiety suggest that self regulation may be altered. Constipation could reflect low dietary fiber or altered gastrointestinal function. These exploratory data suggest that children with PAE may be at risk for nutritional deficiencies, which are influenced by inappropriate food preferences, disordered eating patterns, medication use, and the stressful dynamics surrounding food preparation and mealtime. PMID- 24164458 TI - Characterization of DNA damage-induced cellular senescence by ionizing radiation in endothelial cells. AB - PURPOSE: Inhibition of growth in mammalian cells in response to damage or stress is known as cellular senescence. Increasing evidence suggests that double-strand breaks (DSB) commonly mediate cellular senescence. Recently, radiation exposure has been reported to induce premature senescence. MATERIALS AND METHODS: We investigated whether ionizing radiation (IR) at 4 Gy induces cellular senescence with DNA damage response in human umbilical vein endothelial cells (HUVEC). To determine alterations in gene expression on IR exposure, we have developed a DNA microarray analysis system that contains genes known to be involved in replicative senescence. RESULTS: The damage by IR exposure is shown to result in a variety of senescence-like phenotypes such as changes in cell morphology, decrease in cell proliferation, increase in senescence- associated beta galactosidase (SA-beta-gal) staining, and suppression of angiogenic activity. Moreover, the expression levels of several genes associated with cell cycle regulation are remarkably increased in IR-exposed endothelial cells. We found that IGFBP5 (insulin-like growth factor binding protein 5), PLAT (plasminogen activator), SNAI2 (snail homolog 2), JAG1 (jagged 1), SPRY4 (Sprouty homolog 4), and CD44 were upregulated, whereas CFB (complement factor B), VCAM1 (vascular cell adhesion molecule 1), AQP1 (aquaporin 1), LOXL1 (lysyl oxidase-like 1), and RBPMS (RNA-binding protein with multiple splicing) were down- regulated in both radiation-damaged and old cells. CONCLUSIONS: These results imply that the IR induced phenotype may be enhanced by alterations in genes associated with senescence. PMID- 24164460 TI - Reconceptualizing children's complex discharge with health systems theory: novel integrative review with embedded expert consultation and theory development. AB - AIM: To report a novel review to develop a health systems model of successful transition of children with complex healthcare needs from hospital to home. BACKGROUND: Children with complex healthcare needs commonly experience an expensive, ineffectual and prolonged nurse-led discharge process. Children gain no benefit from prolonged hospitalization and are exposed to significant harm. Research to enable intervention development and process evaluation across the entire health system is lacking. DESIGN: Novel mixed-method integrative review informed by health systems theory. DATA SOURCES: CINAHL, PsychInfo, EMBASE, PubMed, citation searching, personal contact. REVIEW METHODS: Informed by consultation with experts. English language studies, opinion/discussion papers reporting research, best practice and experiences of children, parents and healthcare professionals and purposively selected policies/guidelines from 2002 December 2012 were abstracted using Framework synthesis, followed by iterative theory development. RESULTS: Seven critical factors derived from thirty-four sources across five health system levels explained successful discharge (new programme theory). All seven factors are required in an integrated care pathway, with a dynamic communication loop to facilitate effective discharge (new programme logic). Current health system responses were frequently static and critical success factors were commonly absent, thereby explaining ineffectual discharge. CONCLUSION: The novel evidence-based model, which reconceptualizes 'discharge' as a highly complex longitudinal health system intervention, makes a significant contribution to global knowledge to drive practice development. Research is required to develop process and outcome measures at different time points in the discharge process and future trials are needed to determine the effectiveness of integrated health system discharge models. PMID- 24164459 TI - Comparative effect of lurasidone and blonanserin on cortical glutamate, dopamine, and acetylcholine efflux: role of relative serotonin (5-HT)2A and DA D2 antagonism and 5-HT1A partial agonism. AB - Atypical antipsychotic drugs (AAPDs) have been suggested to be more effective in improving cognitive impairment in schizophrenia than typical APDs, a conclusion supported by differences in receptor affinities and neurotransmitter efflux in the cortex and the hippocampus. More potent serotonin (5-HT)2A than dopamine (DA) D2 receptors antagonism, and direct or indirect 5-HT1A agonism, characterize almost all AAPDs. Blonanserin, an AAPD, has slightly greater affinity for D2 than 5-HT2A receptors. Using microdialysis and ultra performance liquid chromatography mass spectrometry/mass spectrometry, we compared the abilities of the typical APD, haloperidol, three AAPDs, blonanserin, lurasidone, and olanzapine, and a selective 5-HT1A partial agonist, tandospirone, and all, except haloperidol, were found to ameliorate the cognitive deficits produced by the N-methyl-d-aspartate antagonist, phencyclidine, altering the efflux of neurotransmitters and metabolites in the rat cortex and nucleus accumbens. Blonanserin, lurasidone, olanzapine, and tandospirone, but not haloperidol, increased the efflux of cortical DA and its metabolites, homovanillic acid and 3,4-dihydroxyphenylacetic acid. Olanzapine and lurasidone increased the efflux of acetylcholine; lurasidone increased glutamate as well. None of the compounds significantly altered the efflux of 5-HT or its metabolite, 5-hydroxyindole acetic acid, or GABA, serine, and glycine. The ability to increase cortical DA efflux was the only shared effect of the compounds which ameliorates the deficit in cognition in rodents following phencyclidine. PMID- 24164461 TI - A novel assay for detecting fusion pore formation: implications for the fusion mechanism. AB - Membrane fusion is broadly envisioned as a two- or three-step process proceeding from contacting bilayers through one or two semistable, nonlamellar lipidic intermediate structures to a fusion pore. A true fusion event requires mixing of contents between compartments and is monitored by the movement of soluble molecules between trapped compartments. We have used poly(ethylene glycol) (PEG) to rapidly generate an ensemble aggregated state A that proceeds sequentially through intermediates (I1 and/or I2) to a final fusion pore state (FP) with rate constants k1, k2, and k3. Movement of moderately sized solutes (e.g., Tb3+/dipicolinic acid) has been used to detect pores assigned to intermediate states as well as to the final state (FP). Analysis of ensemble kinetic data has required that mixing of contents occurs with defined probabilities (alphai) in each ensemble state, although it is unclear whether pores that form in different states are different. We introduce here a simple new assay that employs fluorescence resonance energy transfer (FRET) between a 6-carboxyfluorescein (donor) and tetramethylrhodamine (acceptor), which are covalently attached to complementary sequences of 10 bp oligonucleotides. Complementary sequences of fluorophore-labeled oligonucleotides were incorporated in vesicles separately, and the level of FRET increased in a simple exponential fashion during PEG mediated fusion. The resulting rate constant corresponded closely to the slow rate constant of FP formation (k3) derived from small molecule assays. Additionally, the total extent of oligonucleotide mixing corresponded to the fraction of content mixing that occurred in state FP in the small molecule assay. The results show that both large "final pores" and small (presumably transient) pores can form between vesicles throughout the fusion process. The implications of this result for the mechanism of membrane fusion are discussed. PMID- 24164462 TI - A cross-sectional study of subclinical and clinical thyroid disorders in women with microscopic colitis compared to controls. AB - BACKGROUND AND AIMS. Microscopic colitis (MC), predominantly affecting women, is associated with thyroid disorders, although purely defined of which type, or compared with controls. Its association with subclinical thyroid disorders, and related increased risk of cardiovascular diseases, has never been examined. The aim was to examine the prevalence of autoantibodies and subclinical and clinical thyroid dysfunction in female patients with MC compared with controls. METHODS. Women younger than 73 years old with biopsy-verified MC from the Department of Gastroenterology in Skane, during 2002-2010, were invited. Out of 240 identified, 133 were finally included. A questionnaire about medical history was completed and blood samples were collected. Serum was analyzed for free thyroxin and triiodothyronine, thyroid-stimulating hormone and anti-thyroid peroxidase (anti TPO) antibodies. A population-based group of 737 women served as controls. RESULT. The prevalence of thyroid disorders in patients was higher compared to controls [odds ratio (OR) = 2.98, 95% confidence interval (CI) = 1.78-4.99], but the prevalence of subclinical disorders was not different (OR = 1.18, 95% CI = 0.48-2.85). Anti-TPO antibodies were present in 10.6% of MC patients and 18.6% of controls. Twenty-five MC patients had hypothyroidism: 15 with Hashimoto's hypothyroidism, 6 with completed treatment of thyrotoxicosis and 4 with completed surgery after nontoxic goiter. CONCLUSION. Thyroid disorders, autoimmune hypothyroidism being most frequent, are more prevalent in patients with MC than in controls, whereas the prevalence of subclinical thyroid disorders in MC patients does not differ significantly from controls. PMID- 24164463 TI - The balance between pro- and anti-inflammatory cytokines is crucial in human allergic contact dermatitis pathogenesis: the role of IL-1 family members. AB - The interleukin (IL)-1 family includes 11 members that are important in inflammatory processes. It includes various agonists and two antagonists, IL-1Ra and IL-36Ra. Our aim was to investigate whether the IL-1 family is involved in allergic contact dermatitis (ACD). The expression of IL-1 family members was evaluated by PCR and immunohistochemistry in the positive patch test reaction site (involved skin) and in the uninvolved skin of ACD patients. We also examined these cytokines in an ex vivo model of ACD. The antagonistic activity of IL-36Ra was evaluated by injecting recombinant IL-36Ra in uninvolved skin biopsies of ACD patients. IL-1Ra and IL-36Ra expression was quantified in mononuclear cells of nickel-sensitized patients challenged in vitro with nickel. IL-33 involvement in ACD was investigated by intra-dermal injection of anti-IL-33 in the uninvolved skin of patients ex vivo. Results showed that IL-1beta, IL-1Ra, IL-36alpha, IL 36beta, IL-36gamma and IL-33 expression, but not IL-36Ra expression, was enhanced in ACD-involved skin. Immunohistochemical analysis and ex vivo skin cultures confirmed these results. Injection of anti-IL-33 in ACD-uninvolved skin inhibited IL-8 expression, whereas IL-36Ra inhibited IL-36alpha, IL-36beta, IL-36gamma and IL-8 expression. Nickel induced IL-1Ra expression in lymphocytes of nickel sensitized patients. Hence, various IL-1 agonists and antagonists may be involved in ACD pathogenesis. PMID- 24164464 TI - Adverse effects of rifampicin in dogs and serum alanine aminotransferase monitoring recommendations based on a retrospective study of 344 dogs. AB - BACKGROUND: Rifampicin has been reported to have potent activity against Staphylococci, including meticillin-resistant Staphylococcus pseudintermedius. There is limited documented information regarding adverse effects and recommendations for serum biochemistry monitoring. HYPOTHESIS/OBJECTIVES: The aims of this retrospective study were as follows: (i) to document the occurrence of adverse events in dogs receiving oral rifampicin; (ii) to determine the relationship between adverse events and the dosage/duration of therapy and concurrent medications; and (iii) to report findings associated with changes on serum alanine aminotransferase (ALT). ANIMALS: Client-owned dogs. METHODS: A retrospective review of 344 medical records was carried out. Serum ALT concentrations and adverse effects were recorded and analysed. Correlations between different time intervals (days 0-9, 10-18, 19-27, 28-36 and >36) and serum ALT elevation were compared. RESULTS: Dogs received 2.9-16 mg/kg/day of rifampicin. Adverse events occurred in 16.27% of dogs (56 of 344) and included vomiting (6.97%), anorexia (6.10%) and lethargy (3.77%). Adverse events were significantly more common in dogs concurrently treated with trimethoprim sulfamethoxazole (P = 0.018), doxycycline (P = 0.044), levothyroxine sodium (P = 0.044), cephalosporins (P = 0.002) and nonsteroidal anti-inflammatories (P < 0.001). Twenty-five of 94 dogs (26.59%) had serum elevations of ALT. These increases were significantly associated with the duration of therapy during two time periods, 19-27 days (P = 0.04) and >36 days (P = 0.01). CONCLUSIONS AND CLINICAL IMPORTANCE: Significant adverse events were noted in association with concurrent drug administration and with serum ALT elevations. Pretreatment and weekly serum biochemistry monitoring is recommended to identify dogs at risk for hepatotoxicosis. PMID- 24164466 TI - Thermally reversible aggregation of Gold nanoparticles in polymer nanocomposites through hydrogen bonding. AB - The ability to tune the state of dispersion or aggregation of nanoparticles within polymer-based nanocomposites, through variations in the chemical and physical interactions with the polymer matrix, is desirable for the design of materials with switchable properties. In this study, we introduce a simple and effective means of reversibly controlling the association state of nanoparticles based on the thermal sensitivity of hydrogen bonds between the nanoparticle ligands and the matrix. Strong hydrogen bonding interactions provide excellent dispersion of gold nanoparticles functionalized with poly(styrene-r-2 vinylpyridine) [P(S-r-2VP)] ligands in a poly(styrene-r-4-vinyl phenol) [P(S-r 4VPh)] matrix. However, annealing at higher temperatures diminishes the strength of these hydrogen bonds, driving the nanoparticles to aggregate. This behavior is largely reversible upon annealing at reduced temperature with redispersion occurring on a time-scale of ~30 min for samples annealed 50 degrees C above the glass transition temperature of the matrix. Using ultraviolet-visible absorption spectroscopy (UV-vis) and transmission electron microscopy (TEM), we have established the reversibility of aggregation and redispersion through multiple cycles of heating and cooling. PMID- 24164465 TI - Implementing an evidence-based fall prevention program in an outpatient clinical setting. AB - OBJECTIVES: To investigate the dissemination potential of a Tai Ji Quan-based program, previously shown to be efficacious for reducing risk of falls in older adults, through outpatient clinical settings. DESIGN: A single-group pre/post design in which participants attended a twice-weekly Tai Ji Quan training program for 24 weeks. SETTING: Communities in Lane County, Oregon. PARTICIPANTS: Independently living individuals (N=379) aged 65 and older. MEASUREMENTS: Using the Reach, Effectiveness, Adoption, Implementation and Maintenance framework, the primary outcome was the proportion of participating healthcare providers who made referrals. Secondary outcomes were the proportion of referred individuals agreeing to participate and enrolling in the program, and measures of program implementation, maintenance, and effectiveness (on measures of falls, balance, gait, physical performance, and balance efficacy). RESULTS: Of the 252 providers invited to participate, 157 made referrals (62% adoption rate). Of 564 individuals referred, 379 (67% reach) enrolled in the program, which was successfully implemented in senior and community centers with good fidelity, 283 completed the program (75% retention), and 212 of these attended 75% or more of the 48 sessions. Participants reported a reduction in falls, with an incidence rate of 0.13 falls per person-month, and showed significant improvement from baseline in all outcome measures. A 3-month postintervention follow-up indicated encouraging levels of program maintenance among providers, participants, and community centers. CONCLUSION: Healthcare providers successfully implemented a protocol to refer individuals at risk of falling to a Tai Ji Quan-based program. The evidence-based program appears readily scalable and exportable, with potential for substantial clinical and public health effect. PMID- 24164468 TI - Investigations on the transfer of porphyrin from o/w emulsion droplets to liposomes with two different methods. AB - CONTEXT: Due to their small particle size, colloidal fat emulsions are suitable for intravenous administration. In order to obtain information on their potential in vivo performance, it is important to find a simple and effective in vitro assay to evaluate the drug release behavior of such particles. OBJECTIVE: Two in vitro methods were studied to measure the transfer of a lipophilic model drug from colloidal o/w emulsion droplets (donor) to liposomes (acceptor), which serve as model membranes mimicking cell membranes in the body. In the first method (column method) the acceptor particles were neutral unilamellar vesicles. In the second method (MLV method), multilamellar vesicles (MLV) were used as acceptor. MATERIALS AND METHODS: The donor nanoemulsions were prepared by high pressure homogenization. Z-average particle size, polydispersity index and zeta potential were determined. RESULTS: The transfer of porphyrin was moderate to the acceptor MLV and rapid to the acceptor unilamellar vesicles. The amount of transferred porphyrin at the end of the experiment depended on the transfer method and the donor/acceptor ratio. With both acceptors the transfer of porphyrin stopped at a concentration lower than the theoretical equilibrium values. DISCUSSION: Many factors such as acceptor particle size and donor to acceptor lipid molar ratio affect the drug transfer from the donor particles to the different acceptors. CONCLUSION: Both methods seem to be suitable to study the drug transfer from such colloidal emulsion and the use of lipophilic acceptor particles is a better approach to the conditions in blood. PMID- 24164467 TI - Prediction of in vivo plasma concentration-time profile from in vitro release data of designed formulations of milnacipran using numerical convolution method. AB - The aim of this study was to predict the in vivo plasma drug level of milnacipran (MIL) from in vitro dissolution data of immediate release (IR 50 mg and IR 100 mg) and matrix based controlled release (CR 100 mg) formulations. Plasma drug concentrations of these formulations were predicted by numerical convolution method. The convolution method uses in vitro dissolution data to derive plasma drug levels using reported pharmacokinetic (PK) parameters of a test product. The bioavailability parameters (Cmax and AUC) predicted from convolution method were found to be 106.90 ng/mL, 1138.96 ng/mL h for IR 50 mg and 209.80 ng/mL, 2280.61 ng/mL h for IR 100 mg which are similar to those reported in the literature. The calculated PK parameters were validated with percentage predication error (% PE). The % PE values for Cmax and AUC were found to be 7.04 and -7.35 for IR 50 mg and 11.10 and -8.21 for IR 100 mg formulations. The Cmax, Tmax, and AUC for CR 100 mg were found to be 120 ng/mL, 10 h and 2112.60 ng/mL h, respectively. Predicted plasma profile of designed CR formulation compared with IR formulations which indicated that CR formulation can prolong the plasma concentration of MIL for 24 h. Thus, this convolution method is very useful for designing and selection of formulation before animal and human studies. PMID- 24164469 TI - Folate-conjugated albumin nanoparticles for rheumatoid arthritis-targeted delivery of etoricoxib. AB - OBJECTIVE: The present study discusses folic acid-etoricoxib-bovine serum albumin nanoparticles (F-ETX-NPs) using folic acid as an over expressed folate receptor ligand for activated macrophages in targeting of rheumatoid arthritis. MATERIALS AND METHODS: For this purpose etoricoxib-loaded BSA nanoparticles (ETX-NPs) were prepared by desolvation method and activated folic acid conjugation with free amine group of BSA was confirmed by FTIR study and zeta potential measurements. RESULTS: The F-ETX-NPs showed spherical in shape with 215.8 +/- 3.2 nm average size + 7.8 mV zeta potential, 72 +/- 1.3% etoricoxib entrapment efficiency and showed 93.1 +/- 2.2% cumulative etoricoxib release upto 72 h. The etoricoxib concentration from F-ETX-NPs was found to be 9.67 +/- 0.34 ug/g in inflamed joint after 24 h administration revealed remarkably targeting potential to the activated macrophages cells and keep at a high level during the experiment. DISCUSSION AND CONCLUSION: These results suggest that F-ETX-NPs are potentially vector for activated macrophages cells targeting of rheumatoid arthritis. PMID- 24164470 TI - Processing of pharmaceutical materials by electrospraying under reduced pressure. AB - CONTEXT: Electrospraying was used in drug particle production. OBJECTIVE: The aim of the research was to evaluate the possibilities to produce drug particles with desired pharmaceutical properties by electrospraying. In particular, the effect of drying pressure on particle properties was studied. MATERIALS AND METHODS: A poorly water soluble model drug (budesonide) was dissolved in chloroform, and the solution was atomized by electrospraying. Following this, the charged droplets were neutralized and dried in a drying chamber. The pressure in the drying chamber was varied. The dried particles were collected and analyzed. RESULTS: The pressure reduction had a slight impact on particle size distribution. The particles produced in reduced pressure turned out to be notably more porous than the particles produced in atmospheric pressure. The pressure reduction also affects the degree of crystallinity of the product. The dissolution of the particles produced in reduced pressures was faster to a certain extent than that of the particles produced in atmospheric pressure. DISCUSSION AND CONCLUSIONS: A setup for electrospraying materials in a reduced pressure was presented. The pressure reduction had a notable impact on particle morphology. The possibilities to tailor the particle properties during electrospraying were studied. PMID- 24164471 TI - Seasonal changes in microbial community structure and activity imply winter production is linked to summer hypoxia in a large lake. AB - Carbon and nutrient cycles in large temperate lakes such as Lake Erie are primarily driven by phototrophic and heterotrophic microorganisms, although our understanding of these is often constrained to late spring through summer due to logistical constraints. During periods of > 90% ice cover in February of 2008, 2009, and 2010, we collected samples from an icebreaker for an examination of bacterial production as well as microbial community structure. In comparison with summer months (August 2002 and 2010), we tested hypotheses concerning seasonal changes in microbial community diversity and production. Bacterial production estimates were c. 2 orders of magnitude higher (volume normalized) in summer relative to winter. Our observations further demonstrate that the microbial community, including single-celled phototrophs, varied in composition between August and February. Sediment traps deployed and collected over a 3 year period (2008-2011) confirmed that carbon export was ongoing and not limiting winter production. The results support the notion that active primary producers in winter months export carbon to the sediments that is not consumed until the warmer seasons. The establishment of this linkage is a critical observation in efforts to understand the extent and severity of annual summertime formations of a zone of regional hypoxia in Lake Erie. PMID- 24164472 TI - Bortezomib-induced peripheral neuropathy is related to altered levels of brain derived neurotrophic factor in the peripheral blood of patients with multiple myeloma. PMID- 24164473 TI - Recurrent airway obstruction: a review. AB - Recurrent airway obstruction is a widely recognised airway disorder, characterised by hypersensitivity-mediated neutrophilic airway inflammation and lower airway obstruction in a subpopulation of horses when exposed to suboptimal environments high in airborne organic dust. Over the past decade, numerous studies have further advanced our understanding of different aspects of the disease. These include clarification of the important inhaled airborne agents responsible for disease induction, improving our understanding of the underlying genetic basis of disease susceptibility and unveiling the fundamental immunological mechanisms leading to establishment of the classic disease phenotype. This review, as well as giving a clinical overview of recurrent airway obstruction, summarises much of the work in these areas that have culminated in a more thorough understanding of this debilitating disease. PMID- 24164474 TI - Identification of a novel HIV-1 circulating recombinant form (CRF62_BC) in western Yunnan of China. AB - We report here a novel HIV-1 circulating recombinant form (CRF62_BC) that was isolated from three epidemiologically unlinked individuals [one from an injecting drug user (IDU); two from heterosexuals] in Dehong prefecture of western Yunnan province. CRF62_BC harbored two subtype B segments in the pol and vpu-env regions in a subtype C backbone. Subregion tree analysis demonstrated that subtype B regions originated from a Thai-B (subtype B') lineage and the subtype C region was from an India C lineage. CRF62_BC is the fourth CRF composed of subtypes B' and C known to date after CRF07_BC, CRF08_BC, and CRF57_BC, which were originally found among IDUs in China. The emergence of CRF62_BC may indicate the continual generation of new recombinant strains in various high-risk populations in western Yunnan. This may complicate the development of effective vaccines to limit the HIV-1 epidemic and increase the difficulty of AIDS prevention and control in China. PMID- 24164475 TI - Detection of atrial electrical and mechanical dysfunction in non-dipper pre hypertensive subjects. AB - INTRODUCTION: A relationship between atrial conduction time and hypertension was shown in previous studies. Increased atrial electromechanical intervals used to predict atrial fibrillation by measured tissue Doppler imaging (TDI). So we aimed to search if there was any association between the non-dipping status and atrial electromechanical intervals in pre-hypertensive patients. METHODS: Forty-one non dipper and 33 dipper pre-hypertensive subjects enrolled in the study. Systolic and diastolic blood pressures were measured with a mercury sphygmomanometer. Twenty-four hours blood pressure was measured with cuff-oscillometric method. All patients were evaluated by transthoracic echocardiography. Using tissue Doppler imaging (TDI), atrial electromechanical coupling (PA) was measured from the lateral mitral annulus (PA lateral), septal mitral annulus (PA septum) and right ventricular tricuspid annulus (PA tricuspid). RESULTS: Systolic and diastolic blood pressures were significantly higher in subjects with non-dipper phenomenon than dipper ones at night. Twenty-four hours average systolic and diastolic blood pressures were higher in non-dipper pre-hypertensive subjects, but this elevation was not significant. Left and right intraatrial (PA lateral-PA septum and PA septum-PA tricuspid) and interatrial (PA lateral-PA tricuspid) electromechanical coupling intervals were measured significantly higher in non-dipper pre hypertensive patients (31.3 +/- 3.9 versus 24.1 +/- 2.3, p = 0.001; 19.5 +/- 4.3 versus 13.8 +/- 2.1, p = 0.001; and 11.4 +/- 2.8 versus 8.8 +/- 1.5, p = 0.001). Also, interatrial electromechanical delay was negatively correlated with dipping levels. CONCLUSION: This study showed that prolonged atrial electromechanical intervals were related non-dipper pattern in pre-hypertensive patients. Prolonged electromechanical intervals may be an early sign of subclinical atrial dysfunction and arrhythmias' in non-dipper pre-hypertensive patients. PMID- 24164476 TI - Misrepair of DNA double-strand breaks in patient with unidentified chromosomal fragility syndrome and family history of radiosensitivity. AB - PURPOSE: To test the hypothesis that differences in DNA double-strand breaks (DSB) repair fidelity underlies differences in radiosensitivity. MATERIALS AND METHODS: A primary fibroblast culture (C42) derived from a pediatric cancer patient treated with reduced radiation doses consequent to a family history of radiosensitivity reminiscent of chromosomal fragility syndrome, was compared to a normal control (C29). DNA DSB rejoining and repair fidelity were studied by Southern blotting and hybridization to specific fragments: Alu repetitive sequence representing the overall DSB rejoining capacity in the genome and a 3.2 Mbp NotI restriction fragment on chromosome 21 for DSB repair fidelity. RESULTS: Although both assays showed statistically significant difference (p <= 0.05) between the two cell strains in residual misrepaired (un-or mis-rejoined) DSB (24 h after 30 or 80 Gy), the residual damage was lower in the Alu enriched genome assay compared to NotI assay (0.01-0.07 and 0.10-0.37, respectively). CONCLUSIONS: These results suggest that, in comparison to classic DSB repair experiment, an assay of measuring DNA DSB repair fidelity can provide better resolution and a more accurate estimate of misrepair of radiation-induced DNA damage, which underlies genomic instability and increased radiosensitivity. PMID- 24164478 TI - Functional up-regulation of endopeptidase neurolysin during post-acute and early recovery phases of experimental stroke in mouse brain. AB - In this study, we provide evidence for the first time that membrane-bound endopeptidase neurolysin is up-regulated in different parts of mouse brain affected by focal ischemia-reperfusion in a middle cerebral artery occlusion model of stroke. Radioligand binding, enzymatic and immunoblotting experiments in membrane preparations of frontoparietal cortex, striatum, and hippocampus isolated from the ischemic hemisphere of mouse brain 24 h after reperfusion revealed statistically significant increase (>= twofold) in quantity and activity of neurolysin compared with sham-operated controls. Cerebellar membranes isolated from the ischemic hemisphere served as negative control supporting the observations that up-regulation of neurolysin occurs in post-ischemic brain regions. This study also documents sustained functional up-regulation of neurolysin in frontoparietal cortical membranes for at least 7 days after stroke, which appears not to be transcriptionally or translationally regulated, but rather depends on translocation of cytosolic neurolysin to the membranes and mitochondria. Considering diversity of endogenous neurolysin substrates (neurotensin, bradykinin, angiotensins I/II, substance P, hemopressin, dynorphin A(1-8), metorphamide, somatostatin) and the well-documented role of these peptidergic systems in pathogenesis of stroke, resistance to ischemic injury and/or post-stroke brain recovery, our findings suggest that neurolysin may play a role in processes modulating the brain's response to stroke and its recovery after stroke. PMID- 24164477 TI - A screen of zebrafish mutants identifies ethanol-sensitive genetic loci. AB - BACKGROUND: Fetal alcohol spectrum disorders (FASD) are a highly variable set of phenotypes caused by fetal alcohol exposure. Numerous factors influence FASD phenotypes, including genetics. The zebrafish is a powerful vertebrate model system with which to identify these genetic factors. Many zebrafish mutants are housed at the Zebrafish International Resource Center (ZIRC). These mutants are readily accessible and an excellent source to screen for ethanol (EtOH)-sensitive developmental structural mutants. METHODS: We screened mutants obtained from ZIRC for sensitivity to EtOH teratogenesis. Embryos were treated with 1% EtOH (41 mM tissue levels) from 6 hours postfertilization onward. Levels of apoptosis were evaluated at 24 hours postfertilization. At 4 days postfertilization, the craniofacial skeleton, peripheral axon projections, and sensory neurons of neuromasts were examined. Fish were genotyped to determine whether there were phenotype/genotype correlations. RESULTS: Five of 20 loci interacted with EtOH. Notable among these was that vangl2, involved in convergent extension movements of the embryonic axis, interacted strongly with EtOH. Untreated vangl2 mutants had normal craniofacial morphology, while severe midfacial defects including synophthalmia and narrowing of the palatal skeleton were found in all EtOH treated mutants and a low percentage of heterozygotes. The cell cycle gene, plk1, also interacted strongly with EtOH. Untreated mutants have slightly elevated levels of apoptosis and loss of ventral craniofacial elements. Exposure to EtOH results in extensive apoptosis along with loss of neural tissue and the entire craniofacial skeleton. Phenotypes of hinfp, mars, and foxi1 mutants were also exacerbated by EtOH. CONCLUSIONS: Our results provide insight into the gene-EtOH interactions that may underlie EtOH teratogenesis. They support previous findings that EtOH disrupts elongation of the embryonic axis. Importantly, these results show that the zebrafish is an efficient model with which to test for gene-EtOH interactions. Understanding these interactions will be crucial to understanding of the FASD variation. PMID- 24164481 TI - Undertaking qualitative health research in social virtual worlds. AB - AIMS: This paper discusses the methodological challenges of using the 3D social virtual world Second Life for research and offers some solutions on a range of research issues including research ethics committee approval, gaining consent, recruitment of sample, data collection and engagement with 'in - world culture'. BACKGROUND: The attraction of social virtual worlds to researchers is their ability to mimic the physical world, as they, are seen as 'places' where people have a feeling of presence (being there) and social presence (being there with others) through the use of a 'customisable' avatar (digital self-representation). Emerging research demonstrating the persuasive nature of avatars on health behaviours through virtual worlds, online games and the 3D web has increased the use of and interest in these areas for delivering health information, advice and support. However, conducting research can be challenging in a 3D world where people are represented as anonymous avatars in an environment unlike any other online media. DATA SOURCES: 25 semi-structured interviews were conducted in Second Life from September 2011-June 2012. IMPLICATIONS FOR NURSING: Nurses wishing to undertake research in social virtual worlds should spend time in-world to acquire technical skills and gain an understanding of the culture of the world. CONCLUSION: Our experience of an interview-based study in virtual worlds indicates that researchers require several virtual world technical skills to create innovative tools to recruit, gain consent and collect data and an understanding of in-world culture, language and social norms to increase the chances of successful research. PMID- 24164479 TI - Cytokinesis in Trypanosoma brucei differs between bloodstream and tsetse trypomastigote forms: implications for microtubule-based morphogenesis and mutant analysis. AB - Trypanosomes use a microtubule-focused mechanism for cell morphogenesis and cytokinesis. We used scanning electron and video microscopy of living cells to provide the first detailed description of cell morphogenesis and cytokinesis in the early-branching eukaryote Trypanosoma brucei. We outline four distinct stages of cytokinesis and show that an asymmetric division fold bisects the two daughter cells, with a cytoplasmic bridge-like structure connecting the two daughters immediately prior to abscission. Using detection of tyrosinated alpha-tubulin as a marker for new or growing microtubules and expression of XMAP215, a plus end binding protein, as a marker for microtubule plus ends we demonstrate spatial asymmetry in the underlying microtubule cytoskeleton throughout the cell division cycle. This leads to inheritance of different microtubule cytoskeletal patterns and demonstrates the major role of microtubules in achieving cytokinesis. RNA interference techniques have led to a large set of mutants, often with variations in phenotype between procyclic and bloodstream life cycle forms. Here, we show morphogenetic differences between these two life cycle forms of this parasite during new flagellum growth and cytokinesis. These discoveries are important tools to explain differences between bloodstream and procyclic form RNAi phenotypes involving organelle mis-positioning during cell division and cytokinesis defects. PMID- 24164482 TI - Differential pharmacological activity of JN403 between alpha7 and muscle nicotinic acetylcholine receptors. AB - The differential action of the novel agonist JN403 at neuronal alpha7 and muscle nicotinic receptors (AChRs) was explored by using a combination of functional and structural approaches. Single-channel recordings reveal that JN403 is a potent agonist of alpha7 but a very low-efficacy agonist of muscle AChRs. JN403 elicits detectable openings of alpha7 and muscle AChRs at concentrations ~1000-fold lower and ~20-fold higher, respectively, than that for ACh. Single-channel activity elicited by JN403 is very similar to that elicited by ACh in alpha7 but profoundly different in muscle AChRs, where openings are brief and infrequent and do not appear in clusters at any concentration. JN403 elicits single-channel activity of muscle AChRs lacking the epsilon subunit, with opening events being more frequent and prolonged than those of wild-type AChRs. This finding is in line with the molecular docking studies predicting that JN403 may form a hydrogen bond required for potent activation at the alpha-delta but not at the alpha epsilon binding site. JN403 does not elicit detectable Ca2+ influx in muscle AChRs but inhibits (+/-)-epibatidine-elicited influx mainly by a noncompetitive mechanism. Such inhibition is compatible with single-channel recordings revealing that JN403 produces open-channel blockade and early termination of ACh-elicited clusters, and it is therefore also a potent desensitizing enhancer of muscle AChRs. The latter mechanism is supported by the JN403-induced increase in the level of binding of [3H]cytisine and [3H]TCP to resting AChRs. Elucidation of the differences in activity of JN403 between neuronal alpha7 and muscle AChRs provides further insights into mechanisms underlying selectivity for alpha7 AChRs. PMID- 24164480 TI - A novel Zap70 mutation with reduced protein stability demonstrates the rate limiting threshold for Zap70 in T-cell receptor signalling. AB - Loss of zeta-associated protein 70 (Zap70) results in severe immunodeficiency in humans and mice because of the critical role of Zap70 in T-cell receptor (TCR) signalling. Here we describe a novel mouse strain generated by N-ethyl-N nitrosourea mutagenesis, with the reduced protein stability (rps) mutation in Zap70. The A243V rps mutation resulted in decreased Zap70 protein and a reduced duration of TCR-induced calcium responses, equivalent to that induced by a 50% decrease in catalytically active Zap70. The reduction of signalling through Zap70 was insufficient to substantially perturb thymic differentiation of conventional CD4 and CD8 T cells, although Foxp3(+) regulatory T cells demonstrated altered thymic production and peripheral homeostasis. Despite the mild phenotype, the Zap70(A243V) variant lies just above the functional threshold for TCR signalling competence, as T cells relying on only a single copy of the Zap70(rps) allele for TCR signalling demonstrated no intracellular calcium response to TCR stimulation. This addition to the Zap70 allelic series indicates that a rate-limiting threshold for Zap70 protein levels exists at which signalling capacity switches from nearly intact to effectively null. PMID- 24164483 TI - Helicobacter pylori infection is associated with advanced colorectal neoplasia. AB - OBJECTIVE: The aim of this article was to evaluate the prevalence of Helicobacter pylori infection in patients diagnosed with advanced colorectal neoplasia undergoing a colonoscopy compared to patients without neoplasia. MATERIAL AND METHODS: This cross-sectional study investigated the association of neoplastic lesions diagnosed on colonoscopy with H. pylori infection in a consecutive series of subjects who had undergone a pancolonoscopy in a single academic medical center. All patients were tested by ELISA and the immunoblot technique for serum anti-H. pylori and CagA protein IgG antibodies. Multivariate analyses were adjusted for potential-relevant confounders, including age, sex, smoking, childhood socioeconomic status, and family history of colorectal cancer. RESULTS: Two hundred and seventy-three patients were included in the study: 75% (84/112), diagnosed with neoplastic colorectal lesions and 48% (77/161) without neoplastic lesions, were found to be seropositive for H. pylori infection (p < 0.001). H. pylori infection was found in 66/77 (86 %) patients with advanced neoplasia, 18/35 (51%) patients with nonadvanced neoplasia, and 48% (77/161) patients without neoplasia (p < 0.001). In the adjusted analysis, H. pylori infection was found to be associated with advanced colorectal neoplasia (odds ratio, OR 9.57; 95% CI 4.31-21.2; p < 0.001) and CRC (OR 7.98;95% CI 3.16-20.16; p < 0.001). There was no association in patients who were CagA positive. CONCLUSION: H. pylori infection is associated with the development of advanced colorectal neoplasia. More studies are needed to confirm our findings. PMID- 24164484 TI - Impact of TRPV3 on the development of allergic dermatitis as a dendritic cell modulator. AB - The transient receptor potential channel vanilloid subfamily V member 3 (TRPV3), which functions as a thermosensor in keratinocytes, plays an important role in the development of allergic and itchy dermatitis in rodents. Although real-time PCR analysis using lesional and non-lesional skin samples from patients with atopic dermatitis showed that TRPV3 was expressed in lesional skin, the role that TRPV3 plays in patients with dermatitis is still relatively obscure. Here, we determined whether TRPV3 was a dendritic cell (DC) modulator using DS-Nh mice with a gain-of-function mutation in TRPV3 (TRPV3Gly573Ser), because increasing skin temperature is associated with the modulation of dermal dendritic cells (DCs). Interestingly, increased responses to haptens by skin and DCs were observed in DS-Nh mice compared with those from DS mice with wild-type TRPV3. Increased thymic stromal lymphopoietin (TSLP) responses were also observed in keratinocytes from DS-Nh mice compared with those from DS mice. Taken together, we propose that the DS-Nh mouse is a good model to use in order to better understand the role of this orphan channel and that TRPV3 may represent a new therapeutic target in certain types of dermatitis through the control of DCs. PMID- 24164485 TI - High-intensity telemedicine-enhanced acute care for older adults: an innovative healthcare delivery model. AB - Accessing timely acute medical care is a challenge for older adults. This article describes an innovative healthcare model that uses high-intensity telemedicine services to provide rapid acute care for older adults without requiring them to leave their senior living community (SLC) residences. This program, based in a primary care geriatrics practice that cares for SLC residents, is designed to offer acute care through telemedicine for complaints that are felt to need attention before the next available outpatient visit but not to require emergency department (ED) resources. This option gives residents access to care in their residence. Measures used to evaluate the program include successful completion of telemedicine visits, satisfaction of residents and caregivers with telemedicine care, and site of care that would have been recommended had telemedicine been unavailable. During the first 2 years of the program's operation, 281 of 301 requested telemedicine visits were completed successfully. Twelve residents were sent to an ED for care after the telemedicine visit. Ninety-four percent of residents reported being satisfied or very satisfied with telemedicine care. Had telemedicine not been available, residents would have been sent to an ED (48.1%) or urgent care center (27.0%) or been scheduled for an outpatient visit (24.4%). The project demonstrated that high-intensity telemedicine services for acute illnesses are feasible and acceptable and can provide definitive care without requiring ED or urgent care use. Continuation of the program will require evaluation demonstrating equal or better resident-level outcomes and the development of sustainable business models. PMID- 24164486 TI - On the characterization of medicated plasters containing NSAIDs according to novel indications of USP and EMA: adhesive property and in vitro skin permeation studies. AB - Abstract This work aims to establish if the assays recently introduced by EMA (Guideline on quality of transdermal patches-draft) and USP (Specific tests for transdermal delivery systems) to characterize transdermal patches (TP) are suitable for medicated plasters (MP). Six approved MP differing for type and characteristics of adhesive and backing layer were selected and characterized in terms of adhesive performances by tack, shear adhesion, peel adhesion and release liner removal tests and in vitro skin permeation. As far as the adhesive properties are concerned, the major drawback is related to the measurement of shear adhesion of MP made of an adhesive hydrogel and/or a stretchable backing layer which could be solved by reducing the applied load. Moreover, a concern on the mass balance prescribed by EMA draft for the acceptance of the results of in vitro penetration studies remains. Indeed, the acceptance range is narrow than that reported by Ph. Eur. requirement for uniformity of content. Finally, a novel calculation for evaluating the in vitro efficiency of MP in releasing the loaded drug through the skin was proposed. PMID- 24164487 TI - Incorporating mobile nanospheres in the lumen of hybrid microcapsules for enhanced enzymatic activity. AB - Physical encapsulation of enzymes in microcapsules, as a mild, controllable method, has been widely utilized for enzyme immobilization. However, this method often suffers from the big mass transfer resistance from the capsule lumen. In this study, a novel biocatalysis system with enhanced catalytic activity is constructed through coencapsulating enzymes and nanospheres in the lumen of protamine/silica hybrid microcapsules, which are synthesized through the synergy of biomimetic silicification and layer-by-layer (LbL) assembly. When utilized as the host for catalase (CAT) encapsulation, the hybrid microcapsules maintain high mechanical stability, high enzyme loading, and low enzyme leaching. Particularly, because of the existence of mobile nanospheres, the mass transfer resistance in the microcapsules is significantly reduced because of the vigorous agitation, thus acquiring an enhanced catalytic activity. Our strategy may also find applications in drug delivery and biosensor fields. PMID- 24164489 TI - Radiolucent periapical lesions and bone mineral density in post-menopausal women. AB - PURPOSE: To investigate the relationship between radiolucent periapical lesions and bone mineral density in post-menopausal women. MATERIAL AND METHODS: Seventy five post-menopausal women were recruited for the study. Bone mineral density was measured using dual-energy X-ray absorptiometry. Three groups were established: healthy bone group, osteopenic group and osteoporotic group. Periapical radiolucencies were diagnosed on the basis of examination of digital panoramic radiographs. Statistical analysis was carried out using anova and chi-squared tests, and logistic regression analysis. RESULTS: In both the osteopenic and osteoporotic groups, 25% of women showed at least one periapical radiolucency, whereas this was only 7.4% in the healthy bone group (odds ratio = 4.2; p = 0.061). After multivariate logistic regression analysis adjusting for covariates (age, number of teeth, number of root-filled teeth and number of teeth with coronal restorations), a marginally significant association was evident between bone mineral density and the presence of periapical radiolucencies (odds ratio = 1.9; CI 95% = 1.0-3.8; p = 0.050). CONCLUSIONS: After adjusting for covariates, low bone mineral density is marginally associated with a higher frequency of radiolucent periapical lesions. PMID- 24164490 TI - Putative paraneoplastic pemphigus and myasthenia gravis in a cat with a lymphocytic thymoma. AB - BACKGROUND: Paraneoplastic pemphigus (PNP) is a rare and severe autoimmune blistering skin disease of humans. It is associated mainly with haematopoietic neoplasia and a unique autoantibody profile. At this time and in animals, PNP has only been reported in dogs. OBJECTIVES: To report clinical, histological and immunological findings in a cat with suspected thymoma-associated PNP. ANIMAL: An 8-year-old female spayed Himalayan cat. RESULTS: The cat presented with a thoracic mass diagnosed as a lymphocytic thymoma. Two weeks postremoval, the cat developed myasthenia gravis, which was controlled with prednisolone and pyridostigmine. The myasthenia gravis resolved, but the cat developed severe cutaneous erosions and ulcers primarily affecting the caudal ventral abdomen and perineum, but also the ventral chest, axillae and medial pinnae. Histopathological analysis revealed changes consistent with pemphigus vulgaris and erythema multiforme, a combination of lesions highly suggestive of PNP. Direct immunofluorescence revealed intercellular epidermal IgG deposition in the lower epidermis, especially in areas of suprabasal clefts. Indirect immunofluorescence revealed antikeratinocyte IgG to basal keratinocytes and bladder epithelial cells. Immunological results supported a diagnosis of PNP. Skin lesions were treated with prednisolone and chlorambucil and, after clinical remission was obtained, the drugs were tapered and eventually discontinued without further recurrence of skin lesions. CONCLUSIONS AND CLINICAL IMPORTANCE: In this cat, clinical, microscopic and immunological findings were consistent with a diagnosis of PNP, with thymoma being the suspected cause. PMID- 24164491 TI - Contribution of chemical water properties to the differential responses of bacterioneuston and bacterioplankton to ultraviolet-B radiation. AB - The surface microlayer (SML) is characterized by different physicochemical properties from underlying waters (UW). However, whether these differences in abiotic factors underlie the distinct sensitivity of bacterioneuston (i.e. SML bacteria) and bacterioplankton to environmental stressors remains to be addressed. We investigated the contribution of abiotic factors to the UV-B sensitivity of bacterioneuston and bacterioplankton. Nutrients (especially nitrogen and phosphate) emerged as important determinants of bacterial UV-B sensitivity. The role of particles, nutrients, and dissolved organic components on bacterial UV-B sensitivity was further evaluated using dilution cultures. Filtered samples were twofold more UV sensitive than unfiltered samples, suggesting a UV-protective effect of particles. High nutrient concentrations attenuated bacterial UV-B sensitivity (up to 40%), compared with unamended conditions, by influencing bacterial physiology and/or community composition. Suspending cells in natural water, particularly from the SML, also attenuated UV B sensitivity (up to 23%), compared with suspension in an artificial mineral solution. Bioassays using Pseudomonas sp. strain NT5I1.2B revealed that chemical water properties influence UV-induced oxidative damage. UV-B sensitivity was associated with high cell-specific activities. The chemical environment of the SML and UW influences UV-B effects on the corresponding bacterial communities. Maintaining low cell activities might be advantageous in stressful environments, like the SML. PMID- 24164492 TI - Influence of C-reactive protein levels and age on the value of D-dimer in diagnosing pulmonary embolism. AB - BACKGROUND: Recently, the number of performed CT-angiographies to diagnose pulmonary embolism (PE) rised markedly, while the incidence of PE hardly increased. This low yield of CT-angiography leads to more patients exposed to radiation and higher costs. AIM: The diagnostic value of age, C-reactive protein (CRP) and D-dimer in PE was investigated. Additionally an age-adjusted D-dimer cutoff level [age-adjusted cutoff = age/100 mg/L] was compared with the conventional cutoff level in diagnosing PE for patients >=50 yr. METHODS: This observational study (2004-2007) included all consecutive patients suspected for PE presenting on the emergency department with a performed CT-angiography after measuring CRP and D-dimer levels. RESULTS: Of 4609 patients suspected for PE, 1164 patients underwent CT-angiography of whom 309 (26.5%) had PE. Correlation between CRP and D-dimer was 0.42 (P < 0.001). D-dimer and age correlated positively (rs = 0.33, P < 0.001), but only in patients >50 yr and independent of PE. Multivariate regression analysis showed significant contribution of age, D dimer and age-adjusted D-dimer for diagnosing PE, but not for CRP. Using an age adjusted D-dimer cutoff value increased specificity from 37% to 50%, whereas sensitivity declined from 96% to 90%. Applying this age-adjusted cutoff level in patients >=70 yr, specificity increased from 18% to 40%, while sensitivity decreased from 96% to 88%. CONCLUSIONS: In the prediction of PE, age and D-dimer levels are relevant, while CRP level is not. Using an age-adjusted D-dimer cutoff in older patients remarkably improves the specificity of D-dimer testing with a minor decline in sensitivity. This may increase the yield of CT-angiography in diagnosing PE. PMID- 24164493 TI - Human microtubule-associated protein tau mediates targeted killing of CD30(+) lymphoma cells in vitro and inhibits tumour growth in vivo. AB - Hodgkin lymphoma (HL) and systemic anaplastic large cell lymphoma (sALCL) are rare lymphoproliferative cancer types. Although most HL patients can be cured by chemo- and radio-therapy, 4-50% of patients relapse and have a poor prognosis. The need for improved therapeutic options for patients with relapsed or refractory disease has been addressed by CD30-specific antibody-based immunotherapeutics. However, available CD30-specific monoclonal antibodies (mAbs), antibody drug conjugates (ADCs) or chimeric immunotoxins suffer from the requirement of a functional host immunity, undesirable immune reactions or heterogeneity and instability, respectively. Here, we present a new fusion protein comprised of the CD30-specific antibody single-chain fragment Ki4(scFv) and the human pro-apoptotic effector protein, microtubule-associated protein tau (MAPT). Ki4(scFv)-MAP selectively induced apoptosis in rapidly proliferating L540cy, L428, and Karpas 299 cells in a dose-dependent manner. Tubulin polymerization assays confirmed that Ki4(scFv)-MAP stabilizes microtubules, suggesting a mechanism for its pro-apoptotic action. Dose-finding experiments proved that Ki4(scFv)-MAP is well tolerated in mice compared to the previously reported Ki4(scFv)-ETA'. Ki4(scFv)-MAP significantly inhibited growth of subcutaneous L540cy xenograft tumours in mice. Our data present a novel approach for the treatment of CD30(+) lymphomas, combining the binding specificity of a target-specific antibody fragment with the selective cytotoxicity of MAPT towards proliferating lymphoma cells. PMID- 24164495 TI - A comparison of euthymic bipolar patients with unaffected first-degree relatives and healthy controls in terms of neuropsychological functions. AB - OBJECTIVE: Cognitive dysfunction in bipolar disorder (BD) is well established in the literature. The neurocognitive deficits have been considered to be endophenotypic markers of BD, and studies have examined whether neurocognitive deficits exist in first-degree relatives of individuals with BD I. We hypothesized that performance in tests of neurocognitive function would be impaired in euthymic BD I patients and their unaffected first-degree relatives compared to that of healthy controls. METHODS: We compared the performance of bipolar patients, their first-degree relatives, and healthy controls in a battery of neurocognitive tests to reveal possible endophenotypes of BD. A diagnostic interview and neuropsychological test battery were administered to 30 BD I patients, 55 of their unaffected first-degree relatives and 32 healthy controls. RESULTS: The patients and their first-degree relatives were significantly impaired in executive function assessed using the Wisconsin Card Sorting Test (WCST) and Trail Making Test-B (TMT-B) relative to the controls (WCST; perseverative errors: p < 0.0005, categories completed: p = 0.002, TMT-B; p = 0.002). There were no significant differences between the groups in terms of attention, psychomotor speed, verbal memory, or learning. CONCLUSION: Our study suggests that the deficits in executive function may be endophenotypic markers of genetic vulnerability to BD I. PMID- 24164494 TI - Radiation exposure prior to traumatic brain injury induces responses that differ as a function of animal age. AB - PURPOSE: Uncontrolled radiation exposure due to radiological terrorism, industrial accidents or military circumstances is a continuing threat for the civilian population. Age plays a major role in the susceptibility to radiation; younger children are at higher risk of developing cognitive deterioration when compared to adults. Our objective was to determine if an exposure to radiation affected the vulnerability of the juvenile hippocampus to a subsequent moderate traumatic injury. MATERIALS AND METHODS: Three-week-old (juvenile) and eight-week old young adult C57BL/J6 male mice received whole body cesium-137 ((137)Cs) irradiation with 4 gray (Gy). One month later, unilateral traumatic brain injury was induced using a controlled cortical impact system. Two months post irradiation, animals were tested for hippocampus-dependent cognitive performance in the Morris water-maze. After cognitive testing, animals were euthanized and their brains frozen for immunohistochemical assessment of activated microglia and neurogenesis in the hippocampal dentate gyrus. RESULTS: All animals were able to learn the water maze task; however, treatment effects were seen when spatial memory retention was assessed. Animals that received irradiation as juveniles followed by a moderate traumatic brain injury one month later did not show spatial memory retention, i.e., were cognitively impaired. In contrast, all groups of animals that were treated as adults showed spatial memory retention in the probe trials. CONCLUSION: Although the mechanisms involved are not clear, our results suggest that irradiation enhanced a young animal's vulnerability to develop cognitive injury following a subsequent traumatic injury. PMID- 24164496 TI - The role of obsessive beliefs in patients with major depressive disorder. AB - AIM: The aim of this study is to evaluate the differences in obsessional beliefs between patients with major depressive disorder (MDD) and matched healthy controls using the obsessive-beliefs questionnaire (OBQ). METHODS: The study sample included 74 outpatients with MDD and 74 healthy subjects. The two groups were matched for age, gender, and education level. The diagnoses were based on the Diagnostic and Statistical Manual of Mental Disorder (DSM-IV). The severity of depression was measured with the Hamilton Depression Rating Scale (HAM-D). All participants filled out the 44-item OBQ. RESULTS: The total and subscale OBQ scores [Responsibility/Threat Estimation (RT), Perfectionism/Certainly (PC), and Importance/Control of Thoughts (ICT)], were significantly higher in patients with MDD than those of the control group. There was a positive correlation between HAM D scores and the OBQ subscale scores (RT, PC, and ICT) in the patients. CONCLUSION: Obsessional beliefs appear to be related to MDD. PMID- 24164497 TI - NLRP3 and ASC differentially affect the lung transcriptome during pneumococcal pneumonia. AB - Streptococcus pneumoniae is the most frequently isolated causative pathogen of community-acquired pneumonia, a leading cause of mortality worldwide. Inflammasomes are multiprotein complexes that play crucial roles in the regulation of inflammation. Nod-like receptor family, pyrin domain containing (NLRP) 3 is a sensor that functions in a single inflammasome, whereas adaptor apoptosis-associated speck-like protein containing a caspase activation and recruitment domain (ASC) is a common adaptor of several inflammasomes. We investigated the role of NLRP3 and ASC during S. pneumoniae pneumonia by comparing bacterial growth and spreading, and host innate immune responses in wild-type mice and mice deficient for either NLRP3 (Nlrp3(-/-)) or ASC (Asc(-/ )). Asc(-/-) mice had increased bacterial dissemination and lethality compared with Nlrp3(-/-) mice, although the cytokine response was impaired in both mouse strains. By detailed analysis of the early inflammatory response in the lung by whole-genome transcriptional profiling, we identified several mediators that were differentially expressed between Nlrp3(-/-) and Asc(-/-) mice. Of these, IL-17, granulocyte/macrophage colony-stimulating factor, and integrin-alphaM were significantly attenuated in Asc(-/-) relative to Nlrp3(-/-) mice, as well as a number of genes involved in the adaptive immune response. These differences may explain the increased susceptibility of Asc(-/ -) mice during S. pneumoniae infection, and suggest that either ASC-dependent NLRP3-independent inflammasomes or inflammasome-independent ASC functions may be involved. PMID- 24164499 TI - Self-expandable stents for benign esophageal leakages and perforations: long-term single-center experience. AB - OBJECTIVE: To date, there is no standardized treatment for esophageal perforations and leakages caused by underlying benign diseases, and it is still debated whether a conservative, endoscopic treatment or a surgical approach is preferable. However, some cases series have successfully demonstrated the feasibility of a temporary placement of self-expanding stents. DESIGN: All patients with benign leakages of the esophagus or gastroesophageal junction or fistulas at gastroesophageal anastomosis were collected during the past 12 years and analyzed retrospectively. The patients treated with endoscopic stenting were analyzed for sustained success, complications, time to stenting, lesion size, number of stents used, need for percutaneous drainage. RESULTS: Eighty-five of eight-eight patients were included in this analysis. Three patients were conservatively managed only. The success rate of stent treatment with an average of 1.3 stents was 79%. Success was highest (94%, n = 30 of 32, no complications or mortality) in iatrogenic lesions that were immediately diagnosed and treated. Spontaneous lesions, including lesions due to Boerhaave's syndrome, were healed in 73% and anastomotic leakages were closed in 71%. Fistula had a lower success rate of 43%. Use of multiple stents sequentially placed was necessary in 23% of the cases. Percutaneous drainage was necessary in 25% of all cases. CONCLUSION: Temporary stent placement for benign leakages of the esophagus is safe and seems to improve treatment success. Adjacent fluid collections should be drained percutaneously. PMID- 24164498 TI - MoeH5: a natural glycorandomizer from the moenomycin biosynthetic pathway. AB - The biosynthesis of the phosphoglycolipid antibiotic moenomycin A attracts the attention of researchers hoping to develop new moenomycin-based antibiotics against multidrug resistant Gram-positive infections. There is detailed understanding of most steps of this biosynthetic pathway in Streptomyces ghanaensis (ATCC14672), except for the ultimate stage, where a single pentasaccharide intermediate is converted into a set of unusually modified final products. Here we report that only one gene, moeH5, encoding a homologue of the glutamine amidotransferase (GAT) enzyme superfamily, is responsible for the observed diversity of terminally decorated moenomycins. Genetic and biochemical evidence support the idea that MoeH5 is a novel member of the GAT superfamily, whose homologues are involved in the synthesis of various secondary metabolites as well as K and O antigens of bacterial lipopolysaccharide. Our results provide insights into the mechanism of MoeH5 and its counterparts, and give us a new tool for the diversification of phosphoglycolipid antibiotics. PMID- 24164500 TI - Epstein-Barr virus antibodies mark systemic lupus erythematosus and scleroderma patients negative for anti-DNA. AB - Systemic lupus erythematosus (SLE) is an autoimmune disease that can attack many different body organs; the triggering event is unknown. SLE has been associated with more than 100 different autoantibody reactivities - anti-dsDNA is prominent. Nevertheless, autoantibodies to dsDNA occur in only two-thirds of SLE patients. We previously reported the use of an antigen microarray to characterize SLE serology. We now report the results of an expanded study of serology in SLE patients and scleroderma (SSc) patients compared with healthy controls. The analysis validated and extended previous findings: two-thirds of SLE patients reacted to a large spectrum of self-molecules that overlapped with their reactivity to dsDNA; moreover, some SLE patients manifested a deficiency of natural IgM autoantibodies. Most significant was the finding that many SLE patients who were negative for autoantibodies to dsDNA manifested abnormal antibody responses to Epstein-Barr virus (EBV): these subjects made IgG antibodies to EBV antigens to which healthy subjects did not respond or they failed to make antibodies to EBV antigens to which healthy subjects did respond. This observation suggests that SLE may be associated with a defective immune response to EBV. The SSc patients shared many of these serological abnormalities with SLE patients, but differed from them in increased IgG autoantibodies to topoisomerase and centromere B; 84% of SLE patients and 58% of SSc patients could be detected by their abnormal antibodies to EBV. Hence an aberrant immune response to a ubiquitous viral infection such as EBV might set the stage for an autoimmune disease. PMID- 24164502 TI - Nickel/bis(oxazoline)-catalyzed asymmetric Negishi arylations of racemic secondary benzylic electrophiles to generate enantioenriched 1,1-diarylalkanes. AB - A tertiary stereogenic center that bears two different aryl substituents is found in a variety of bioactive compounds, including medicines such as Zoloft and Detrol. We have developed an efficient method for the synthesis of enantioenriched 1,1-diarylalkanes from readily available racemic benzylic alcohols. Formation of a benzylic mesylate (which is not isolated), followed by treatment with an arylzinc reagent, LiI, and a chiral nickel/bis(oxazoline) catalyst, furnishes the Negishi cross-coupling product in high ee and good yield. A wide array of functional groups (e.g., an aryl iodide, a thiophene, and an N Boc-indole) are compatible with the mild reaction conditions. This method has been applied to a gram-scale synthesis of a precursor to Zoloft. PMID- 24164501 TI - mPEG-PAMAM-G4 nucleic acid nanocomplexes: enhanced stability, RNase protection, and activity of splice switching oligomer and poly I:C RNA. AB - Dendrimer chemistries have virtually exploded in recent years with increasing interest in this class of polymers as gene delivery vehicles. An effective nucleic acid delivery vehicle must efficiently bind its cargo and form physically stable complexes. Most importantly, the nucleic acid must be protected in biological fluids and tissues, as RNA is extremely susceptible to nuclease degradation. Here, we characterized the association of nucleic acids with generation 4 PEGylated poly(amidoamine) dendrimer (mPEG-PAMAM-G4). We investigated the formation, size, and stability over time of the nanoplexes at various N/P ratios by gel shift and dynamic light scatter spectroscopy (DLS). Further characterization of the mPEG-PAMAM-G4/nucleic acid association was provided by atomic force microscopy (AFM) and by circular dichroism (CD). Importantly, mPEG-PAMAM-G4 complexation protected RNA from treatment with RNase A, degradation in serum, and various tissue homogenates. mPEG-PAMAM-G4 complexation also significantly enhanced the functional delivery of RNA in a novel engineered human melanoma cell line with splice-switching oligonucleotides (SSOs) targeting a recombinant luciferase transcript. mPEG-PAMAM-G4 triconjugates formed between gold nanoparticle (GNP) and particularly manganese oxide (MnO) nanorods, poly IC, an anticancer RNA, showed enhanced cancer-killing activity by an MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) cell viability assay. PMID- 24164503 TI - Recent progress in the treatment of cardiovascular disease using olmesartan. AB - Angiotensin II (Ang II) evokes inflammatory responses and plays a central role in atherosclerosis mediated by Ang II type 1 (AT1) receptor. AT1 receptor blockers (ARBs) prevent the diverse effects of Ang II. Unique molecule-specific, or off target effects of ARBs are due to their slightly different structures, although all ARBs have common, or class, effects. In nonsignificant coronary stenotic lesions, it is important that we use aggressive medical treatments using ARBs in addition to statins and oral hypoglycemic agents, to induce the regression and stabilization of coronary plaque. This review focuses on current evidence regarding the molecule-specific effects of ARB olmesartan to prevent the increase in coronary atheroma volume. PMID- 24164504 TI - Bioactivation of drugs in the skin: relationship to cutaneous adverse drug reactions. AB - Drug-induced skin rashes are poorly understood idiosyncratic reactions, and current methods cannot predict their occurrence. Most idiosyncratic drug reactions are thought to be caused by chemically reactive metabolites, and the skin is a frequent site of idiosyncratic reactions; however, the skin has a very limited capacity to metabolize drugs. To balance this, the skin represents a protective barrier with a very active immune response against pathogens and other types of skin injury. Therefore its response to reactive metabolites is quite different from that of the liver. The purpose of this review is to integrate emerging findings into proposed mechanisms of drug and carcinogen metabolism in the skin that are likely responsible for rashes and other immune responses of the skin. Current evidence suggests the skin possesses significant sulfotransferase and flavin monooxygenases activities, but very low cytochromes P450 activity. However, there are skin-specific P450s that are not present in the liver. The manner in which the skin responds to neoantigens through local antigen presentation and innate immune sensing is reviewed with a focus on insights gained from the contact hypersensitivity (CHS) field. The roles of keratinocytes and Langerhans cells, and the emerging function of NOD-like receptors, are highlighted. PMID- 24164505 TI - Effect of local and global structural order on the performance of perylene diimide excimeric solar cells. AB - Herein, we present a detailed study of the structure-function relationship in the organic photovoltaic (OPV) blend film composed of N,N'-bis(1-ethylpropyl) perylene-3,4,9,10-tetracarboxylic diimide (EP-PDI) and the low energy gap copolymer of poly[4,8-bis-substituted-benzo[1,2-b:4,5-b']dithiophene-2,6-diyl-alt 4-substituted-thieno[3,4-b]thiophene-2,6-diyl] (PBDTTT-E-O). The hierarchical organization in the photoactive layers and in extruded fibers of PBDTTT-E-O:EP PDI was studied by fluorescence optical microscopy, atomic force microscopy, and wide-angle X-ray scattering (WAXS). WAXS revealed a nanophase-separated structure where PBDTTT-E-O domains of 4.3 nm in size coexist with EP-PDI domains of 20 nm size. Thermal annealing results in an increase of the PBDTTT-E-O domains, but it does not affect the size of the EP-PDI domains. Only the length of the EP-PDI columns in each domain is increased by thermal treatment. The photophysical characterization of the PBDTTT-E-O:EP-PDI layers and the electrical characterization of the corresponding OPV and unipolar carrier devices were performed. The quenching of the EP-PDI excimer luminescence is correlated with the photocurrent generation efficiency of the OPV devices. At high annealing temperatures the EP-PDI columnar length becomes larger than the previously reported diffusion length of the PDI excimer, and fewer excimers dissociate at the EP-PDI/polymer interfaces, leading to reduced photocurrent generation. The charge transport properties of the PBDTTT-E-O:EP-PDI blend film were studied as a function of the active layer microstructure that was tuned by thermal treatment. Thermal processing increases electron mobility, but the poor connectivity of the EP-PDI domains keeps hole mobility six times higher. In respect to the as-spun OPV device, a 3-fold increase is found in the power conversion efficiency of the device annealed at 100 degrees C. The high surface roughness of the PBDTTT-E O:EP-PDI photoactive layer impedes the efficient extraction of charges, and a thin and smooth perylene-3,4,9,10-tetracarboxylic bisbenzimidazole overlayer is required for increasing the device performance to a power conversion efficiency (PCE) ~ 1.7%. The inversion in the polarity of the device contacts resulted in an inverted device with PCE ~ 1.9%. We provide rational guidelines for the accurate tuning of the layer microstructure in PDI-based photoactive layers of efficient OPV devices. Local disorder in the EP-PDI aggregates is essential (i) for the optimum electron transport that is ensured by the efficient connectivity of the EP-PDI columns in adjacent EP-PDI domains and (ii) for preventing the stabilization of the neutral photoexcitations in the EP-PDI domains in the form of slowly diffusive excimers. The high photocurrent generation efficiency achieved suggests the EP-PDI excimers are formed faster than the activation of triplet states, and photocurrent losses are minimized. PMID- 24164506 TI - Hospital lighting and its association with sleep, mood and pain in medical inpatients. AB - AIMS: To describe light exposure, sleep-wake patterns, mood, pain and their relationships in adult medical inpatients. BACKGROUND: The hospital environment may contribute to patient discomfort by providing a lighting structure that interferes with circadian rhythmicity, sleep, mood and pain. DESIGN: A descriptive correlational design was used in this preliminary study. METHODS: Between May 2011-April 2012, data were collected from a convenience sample of 23 women and 17 men admitted to a large academically affiliated hospital in the United States. Over 72 hours, light exposure and sleep-wake patterns were continuously measured with wrist actigraph/light meters for each participant. Mood was measured daily using the Profile Of Mood States BriefTM Form. Subjective pain scores were abstracted from medical records. RESULTS: Light exposure levels were low: mean daytime light intensity was 104.80 lux. Sleep time was fragmented and low: mean 236.35 minutes of sleep/night. Intra-daily stability scores indicated little sleep-wake synchronization with light. Fatigue and total mood disturbance scores were high and inversely associated with light. Pain levels were also high and positively associated with fatigue, but not directly with light exposure. Low light exposure significantly predicted fatigue and total mood disturbance. CONCLUSION: Medical inpatients were exposed to light levels insufficient for circadian entrainment. Nevertheless, higher light exposure was associated with less fatigue and lower total mood disturbance in participants with pain, suggesting the need for further investigation to determine if manipulating light exposure for medical inpatients would be beneficial in affecting sleep-wake disturbances, mood and pain. PMID- 24164507 TI - Methodological and practical limitations to visually determining intoxication. PMID- 24164508 TI - Triphenylamine-benzimidazole derivatives: synthesis, excited-state characterization, and DFT studies. AB - The synthesis and comprehensive characterization of the excited states of four novel triphenylamine-benzimidazole derivatives has been undertaken in solution (ethanol and methylcyclohexane) at room temperature. This includes the determination of the absorption, fluorescence, and triplet-triplet absorption spectra, together with quantum yields of fluorescence, internal conversion, intersystem crossing, and singlet oxygen. From the overall data the radiative and radiationless rate constants could be obtained, and it is shown that the compounds are highly emissive with the radiative decay dominating, with more than 70% of the quanta loss through this deactivation channel. The basic structure of the triphenylamine-benzimidazole derivatives (1a) was modified at position 5 of the heterocyclic moiety with electron-donating (OH (1b), OCH3 (1c)) or electron withdrawing groups (CN, (1d)). It was found that the photophysical properties remain basically unchanged with the different substitutions, although a marked Stokes shift was observed with 1d. The presence and nature of a charge-transfer transition is discussed with the help of theoretical (DFT and TDFT) data. All compounds displayed exceptionally high thermal stability (between 399 and 454 degrees C) as seen by thermogravimetric analysis. PMID- 24164509 TI - Fluoride intake from fluids and urinary fluoride excretion by young children in Kuwait: a non-fluoridated community. AB - OBJECTIVES: To determine the pattern of fluid consumption, fluoride intake from the fluids and urinary fluoride excretion by children aged 1-9 years in Kuwait, a nonfluoridated community. METHODS: Using the cluster sampling technique, children aged 1-9 years were chosen from 2000 randomly selected households in Kuwait. Questionnaires were then administered to their mothers to determine the children's daily fluid intake. Fluoride concentrations in tap water as well as all brands of bottled water and beverages consumed by the children were measured, using the fluoride ion-specific electrode. Fluoride excretion was determined in 400 randomly selected children, based on fluoride/creatinine ratio. RESULTS: The mean daily fluid consumption by the children was high, being 1115-1545 ml. About 40% of the fluid intake was plain (tap and bottled) water and approximately 10% of the children drank bottled water exclusively. Fluoride concentration in tap water was low (0.04+/-SD 0.02 ppm), but was higher in bottled water (0.28+/-SD 0.40 ppm). Mean daily fluoride ingestion from fluids was 0.013-0.018 mg/kg body weight (bw). Even after allowing for fluoride ingestion from other sources, mean daily fluoride ingestion was still below 0.1 mg/kg bw set by the United States of America Institute of Medicine as the lowest-observed-adverse-effect level for moderate enamel fluorosis in children aged up to 8 years. Furthermore, the mean daily urinary fluoride excretion of 128-220 MUg was below the provisional standard of 360-480 MUg for optimal fluoride usage by children aged 3-5 years. CONCLUSION: Fluoride ingestion from fluids and urinary fluoride excretion by the children were below the recommendations for optimal fluoride usage. Thus, there is room for an upward adjustment of fluoride level in public drinking water supplies in Kuwait, as a caries preventive measure. PMID- 24164510 TI - Role of anti-CD40 antibody-mediated costimulation blockade on non-Gal antibody production and heterotopic cardiac xenograft survival in a GTKO.hCD46Tg pig-to baboon model. AB - BACKGROUND: Recently, we have shown that an immunosuppression regimen including costimulation blockade via anti-CD154 antibody significantly prolongs the cardiac xenograft survival in a GTKO.hCD46Tg pig-to-baboon heterotopic xenotransplantation model. Unfortunately, many coagulation disorders were observed with the use of anti-CD154 antibody, and recipient survival was markedly reduced by these complications. MATERIAL AND METHODS: In this experiment, we replaced anti-CD154 antibody with a more clinically acceptable anti-CD40 antibody while keeping the rest of the immunosuppressive regimen and the donor pig genetics the same. This was carried out to evaluate the antibody's role in xenograft survival and prevention of coagulopathies. Two available clones of anti CD40 antibody were tested. One mouse anti-human CD40 antibody, (clone 3A8), activated B lymphocytes in vitro and only modestly suppressed antibody production in vivo. Whereas a recombinant mouse non-human primate chimeric raised against macaque CD40, (clone 2C10R4), blocked B-cell activation in vitro and completely blocked antibody production in vivo. RESULTS: The thrombotic complications seen with anti-CD154 antibody were effectively avoided but the graft survival, although extended, was not as prolonged as observed with anti-CD154 antibody treatment. The longest survival for the 3A8 antibody group was 27 days, and the longest graft survival in the 2C10R4 antibody group was 146 days. All of the grafts except two rejected and were explanted. Only two recipient baboons had to be euthanized due to unrelated complications, and the rest of the baboons remained healthy throughout the graft survival period or after graft explantation. In contrast to our anti-CD 154 antibody-treated baboons, the non Gal antibody levels started to rise after B cells made their appearance around 8 weeks post-transplantation. CONCLUSIONS: Anti-CD40 antibody at the current dose does not induce any coagulopathies but while effective, had reduced efficacy to induce similar long-term graft survival as with anti-CD154 antibody perhaps due to ineffective control of B-cell function and antibody production at the present dose. More experiments are required to determine antibody affinity and effective dose for inducing long-term cardiac xenograft survival. PMID- 24164511 TI - Skin diseases in pet rabbits: a retrospective study of 334 cases seen at the University of California at Davis, USA (1984-2004). AB - BACKGROUND: Rabbits are growing in popularity as companion animals, and dermatology problems are often the presenting complaint when seeing a veterinarian. HYPOTHESIS/OBJECTIVES: To document skin diseases and their prevalence in pet domestic rabbits (Oryctolagus cuniculus) in northern California, USA; to investigate predilections for breed, age or sex for the most common conditions over a 20 year period. ANIMALS: Three hundred and thirty-four pet rabbits from the overall hospital population met inclusion criteria. METHODS: A retrospective study was carried out by searching the computerized medical records of rabbits seen at the Veterinary Medical Teaching Hospital (VMTH) from 1 January 1984 to 31 December 2004 using key words relevant to dermatology. RESULTS: Twenty-nine per cent of pet rabbits seen at the VMTH had skin disease. Lop-eared rabbits were over-represented, whereas mixed-breed rabbits and castrated males were under-represented in the dermatology caseload compared with the hospital population. Pododermatitis was the most common skin disease; abscesses, alopecia, otitis externa and ectoparasites also were common. Several species of bacteria other than Pasteurella spp. were isolated from abscesses. Despite the frequent mention of myxomatosis and venereal spirochetosis in the rabbit literature, few cases (three and two, respectively) were diagnosed. Castrated males were 3.7 times more likely to present with alopecia than intact males; rabbits <1 year of age were 3.6 times more likely to present with Psoroptes infestation/otitis than adult rabbits. CONCLUSIONS AND CLINICAL IMPORTANCE: Cutaneous conditions in pet rabbits in the USA are common. Bacterial culture should be performed and antibiotic susceptibility determined in all rabbits with abscesses, particularly those not responding to typical anti Pasteurella antibiotics. PMID- 24164512 TI - Macroscopic, flexible, high-performance graphene ribbons. AB - Tailoring the structure and properties of graphene fibers is an important step toward practical applications. Here, we report macroscopic, long graphene ribbons formed by combining electrostatic interaction and shear stress during the wet spinning process. The graphene ribbons are flexible and can be woven into complex structures, and the ribbon morphology can be tailored by controlling the orientation of wrinkles to obtain elasticity within a modest strain. We demonstrate several potential applications of pure or Pt-graphene hybrid ribbons as elastic strain sensors, counter electrodes for dye-sensitized fiber solar cells with cell efficiencies reaching 4.69% under standard illumination and 6.41% with a back reflector, and woven fabric supercapacitor electrodes. Our method can directly fabricate meter-long graphene ribbons with controlled structure and high performance as both energy conversion and energy storage materials. PMID- 24164513 TI - Structure-activity relationships and molecular modeling of sphingosine kinase inhibitors. AB - The design, synthesis, and evaluation of the potency of new isoform-selective inhibitors of sphingosine kinases 1 and 2 (SK1 and SK2), the enzyme that catalyzes the phosphorylation of d-erythro-sphingosine to produce the key signaling lipid, sphingosine 1-phosphate, are described. Recently, we reported that 1-(4-octylphenethyl)piperidin-4-ol (RB-005) is a selective inhibitor of SK1. Here we report the synthesis of 43 new analogues of RB-005, in which the lipophilic tail, polar headgroup, and linker region were modified to extend the structure-activity relationship profile for this lead compound, which we explain using modeling studies with the recently published crystal structure of SK1. We provide a basis for the key residues targeted by our profiled series and provide further evidence for the ability to discriminate between the two isoforms using pharmacological intervention. PMID- 24164516 TI - Vouchers and free market ideology. PMID- 24164517 TI - Tiger mother: popular and psychological scientific perspectives on Asian culture and parenting. PMID- 24164514 TI - The use of whole food animal studies in the safety assessment of genetically modified crops: limitations and recommendations. AB - There is disagreement internationally across major regulatory jurisdictions on the relevance and utility of whole food (WF) toxicity studies on GM crops, with no harmonization of data or regulatory requirements. The scientific value, and therefore animal ethics, of WF studies on GM crops is a matter addressable from the wealth of data available on commercialized GM crops and WF studies on irradiated foods. We reviewed available GM crop WF studies and considered the extent to which they add to the information from agronomic and compositional analyses. No WF toxicity study was identified that convincingly demonstrated toxicological concern or that called into question the adequacy, sufficiency, and reliability of safety assessments based on crop molecular characterization, transgene source, agronomic characteristics, and/or compositional analysis of the GM crop and its near-isogenic line. Predictions of safety based on crop genetics and compositional analyses have provided complete concordance with the results of well-conducted animal testing. However, this concordance is primarily due to the improbability of de novo generation of toxic substances in crop plants using genetic engineering practices and due to the weakness of WF toxicity studies in general. Thus, based on the comparative robustness and reliability of compositional and agronomic considerations and on the absence of any scientific basis for a significant potential for de novo generation of toxicologically significant compositional alterations as a sole result of transgene insertion, the conclusion of this review is that WF animal toxicity studies are unnecessary and scientifically unjustifiable. PMID- 24164518 TI - The differential influence of contextual risks on psychosocial functioning and participation of Australian aboriginal youth. AB - This study investigated the differential influence of contextual risks for positive psychosocial functioning and participation in education or employment in a representative sample of 12- to 17-year-old Aboriginal youth (N = 674) using data drawn from the Western Australian Aboriginal Child Health Survey (WAACHS) 2000-2002. The authors modeled the influence of 3 empirical risk measures (risk factor, cumulative risk, and single risks) on positive psychosocial functioning and participation in education or employment. Results showed different risks for different developmental outcomes. Single sociodemographic risks were associated with reduced likelihood of positive psychosocial functioning, whereas cumulative risk and composite Family Health and Community Risk measures were associated with reduced likelihood of participation in education or employment. Methodological issues and implications for interventions to support young Aboriginal people's adaptation are discussed. PMID- 24164519 TI - A longitudinal study of demographic factors associated with stressors and symptoms in African refugees. AB - The objectives of this study were to assess differences in premigration, transit, and resettlement stressor exposure and post traumatic stress disorder (PTSD) symptoms as a function of demographic characteristics (i.e., gender, ethnicity, age, time in United States) and to examine the concurrent and longitudinal relations between stressor exposure and PTSD symptoms. The sample consisted of adult (18-78 years) Somali and Oromo refugee men and women (N = 437). Qualitative data regarding participants' self-nominated worst stressors collected at Time 2 (T2) informed the development of quantitative scales assessing premigration, transit, and resettlement stress created using items collected at Time 1 (T1). PTSD symptoms were measured at both T1 and T2. Quantitative analyses showed that levels of stressor exposure and PTSD symptoms differed as a function of refugee demographic characteristics. For example, Oromo, more recent, women, and older refugees reported more premigration and resettlement stressors. Oromo refugees and refugee men reported more PTSD symptoms in regression analyses with other factors controlled. Premigration, transit, and resettlement stressor exposure generally was associated with higher PTSD symptom levels. Results underscore the importance of assessing stress exposure comprehensively throughout the refugee experience and caution against overgeneralizing between and within refugee groups. PMID- 24164515 TI - Toxicological evaluation of proteins introduced into food crops. AB - This manuscript focuses on the toxicological evaluation of proteins introduced into GM crops to impart desired traits. In many cases, introduced proteins can be shown to have a history of safe use. Where modifications have been made to proteins, experience has shown that it is highly unlikely that modification of amino acid sequences can make a non-toxic protein toxic. Moreover, if the modified protein still retains its biological function, and this function is found in related proteins that have a history of safe use (HOSU) in food, and the exposure level is similar to functionally related proteins, then the modified protein could also be considered to be "as-safe-as" those that have a HOSU. Within nature, there can be considerable evolutionary changes in the amino acid sequence of proteins within the same family, yet these proteins share the same biological function. In general, food crops such as maize, soy, rice, canola etc. are subjected to a variety of processing conditions to generate different food products. Processing conditions such as cooking, modification of pH conditions, and mechanical shearing can often denature proteins in these crops resulting in a loss of functional activity. These same processing conditions can also markedly lower human dietary exposure to (functionally active) proteins. Safety testing of an introduced protein could be indicated if its biological function was not adequately characterized and/or it was shown to be structurally/functionally related to proteins that are known to be toxic to mammals. PMID- 24164520 TI - Parental styles in the intergenerational transmission of trauma stemming from the Khmer Rouge regime in Cambodia. AB - The impact of parental styles in intergenerational transmission of trauma among mothers who survived the Khmer Rouge regime in Cambodia, in power from 1975 to 1979, and their teenaged children was examined in 2 studies. In Study 1, 46 Cambodian female high school students and their mothers were recruited. Each daughter completed anxiety and depression measures as well as assessment of her mother's role-reversing, overprotective, and rejecting parental styles, whereas the mothers completed measures of their trauma exposure during the Khmer Rouge regime and PTSD symptoms. In support of trauma transmission, the mother's PTSD symptoms were predictive of her daughter's anxiety. Moreover, the mother's role reversing parental style was shown to mediate the relationship between her own and her daughter's symptoms. In support of their generalizability, the results were replicated in Study 2 in a Cambodian-American refugee sample comparing 15 mental health treatment-seeking mothers and their teenaged children with 17 nontreatment-seeking mother-child pairs. The implications of the findings within the larger literature on intergenerational trauma transmission stemming from genocide are discussed. PMID- 24164521 TI - The relative impacts of uncertainty and mothers' communication on hopelessness among Palestinian refugee youth. AB - The life of adolescent refugees has been described as uncertainty laden. Yet no quantitative data exist to elucidate that experience of uncertainty, investigate its implications in that population, or explore potential moderators. This study applies the Entropy Model of Uncertainty (Hirsh, Mar, & Peterson, 2012) and the stress-buffering hypothesis (for review, see Hegelson, 2003) to examine the experience of uncertainty among adolescent Palestinians living in refugee camps in Lebanon. It then tests the role of mothers' uncertainty-related communication for adolescent hopelessness. One hundred and sixty-two adolescents across 2 refugee camps in Lebanon participated in the study. Results support the existence of elevated levels of uncertainty about both personal and macrosecurity, show an association between uncertainty regarding personal security and levels of hopelessness, and suggest that uncertainty's negative impact may overwhelm the role of mothers' supportive communication as a buffer against hopelessness. Interestingly, the data also suggest surprisingly little hopelessness in this population. PMID- 24164523 TI - Cultural aspects within caregiver interactions of ultra-orthodox Jewish women and their family members with mental illness. AB - The role of cultural dynamics and norms within families of persons with mental illness has been an underexplored subject, although the familial context has been recognized as influential. This subject was studied with 24 ultra-Orthodox Jewish mothers of persons with mental illness who live in a relatively closed religious community. While participating in the Keshet educational program designed for family caregivers in mental health, they wrote Meaningful Interactional Life Episodes that involved a dialogue exchange in their lives. Qualitative analysis of 50 episodes illuminates the significant role that religious and cultural norms have in the perceptions of what are considered stressors and the dynamics in these families surrounding these stressors. The necessity and value of incorporating cultural competence into family educational programs and interventions is emphasized, as this may contribute to the potential use and success of mental health service models within a population that essentially underutilizes these services. PMID- 24164522 TI - Political violence, health, and coping among Palestinian women in the West Bank. AB - Political violence poses a considerable threat to the health of individuals. Protective factors, however, may help people to build resilience in the face of political violence. This study examined the influence of lifetime and past 30-day experiences of political violence on the mental and physical health of adult Palestinian women from the West Bank (N = 122). Two hypotheses were examined: (a) Reports of political violence exposure would be related to reports of poorer physical and mental health and (b) several coping variables (proactive coping; self-reliance; reliance on political, family, and religious support; and political or civic engagement) would function as moderators of the effects of political violence, buffering or weakening its effects on physical and mental health outcomes. Both lifetime and past 30-day measures of political violence were positively correlated with posttraumatic stress disorder symptoms. Proactive coping, reliance on self, and political or civic engagement significantly interacted with political violence to affect health in a counterintuitive direction; those with higher scores on these more internalized and individualistic coping strategies demonstrated worse health as political violence increased. Reliance on religious support, and, in particular, support from and participation in activities of religious institutions, emerged as a significant protective factor. Results underscore the importance of looking not only at whether political violence affects health, but also at how the relationships between political violence and health might occur, including the potential protective influence of resources within people's social environments. PMID- 24164524 TI - The differential impact of terrorism on two Israeli communities. AB - The authors evaluated 2 cohorts of individuals from different Israeli communities (Sderot and Otef Aza) that are repeatedly subjected to potentially lethal missile attacks. Although both communities border the Gaza Strip and face similar levels of threat, the authors hypothesized that the Sderot cohort would endorse higher rates of stress-related symptoms because it has fewer mitigating economic and psychosocial resources. The authors further hypothesized that there would be a significant relationship between exposure to terror and psychopathology regardless of community context. To test these predictions, the authors compared the levels of exposure to terror, posttraumatic stress disorder (PTSD), and depression in representative samples of adults from the 2 communities (n = 298 and n = 152, respectively). Residents of Sderot had a much higher rate of probable PTSD (35.2% vs. 6.6%), and community context was the most important predictor of PTSD and depression. The study also revealed a significant relationship between exposure and psychopathology, but for Sderot residents only. The conclusion is that researchers, mental health workers, and policy makers should pay attention to the influence of community characteristics, such as the availability of resources, the general sense of support, and the level of solidarity, on the mental health response to exposure to terror. PMID- 24164525 TI - Stress-related changes in toddlers and their mothers following the attack of September 11. AB - Unlike other forms of disaster, terrorism is not confined to a particular place or time, and recent evidence indicates that the 9/11 terrorist attack was a significant macrolevel stressor affecting the health and mental health of United States citizens. No studies, however, have reported symptoms in toddlers and their mothers both before and after the attacks. To address this gap, we examined the effects of the 9/11 terrorist attacks on mothers and their 33-month-old toddlers. The attacks occurred during data collection at 33 months of a longitudinal study. Thirty-three-month-old toddlers and mothers who were assessed after the attacks were compared with those assessed before the attacks. When changes were examined from a previous wave of data collected at 15 months, those in the after-attack group showed poorer health, lower child acceptance, and marginally more anxiety, and their toddlers cried more and slept less, whereas the before-attack group showed no changes. Our findings contribute to research documenting widespread effects of the 9/11 terrorist attack on stress-related symptoms and suggest that greater attention must be placed on the needs of our youngest citizens and their caregivers. PMID- 24164526 TI - Childhood antecedents of incarceration and criminal justice involvement among homeless veterans. AB - Although criminal justice involvement and incarceration are common problems for homeless veterans, few studies have examined childhood risk factors for criminal justice involvement among veterans. This study examined the association between three types of childhood problems, family instability, conduct disorder behaviors, and childhood abuse, and criminal justice involvement and incarceration in adulthood. Data from 1,161 homeless veterans across 19 sites participating in the Housing and Urban Development-Veterans Affairs Supportive Housing program were examined. After controlling for sociodemographics and mental health diagnoses, veterans who reported more conduct disorder behaviors during childhood tended to report more criminal charges of all types, more convictions, and longer periods of incarceration during adulthood. However, the variance explained in criminal behavior by childhood was not large, suggesting that there are other factors that affect the trajectory by which homeless veterans become involved in the criminal justice system. Further research is needed to intervene in the pathway to the criminal justice system and guide efforts to prevent incarceration among veterans. PMID- 24164527 TI - The challenges of reintegration for service members and their families. AB - The ongoing wars in Afghanistan and Iraq have posed a number of reintegration challenges to service members. Much of the research focuses on those service members experiencing psychological problems and being treated at the VA. In this article, we contend that much of the distress service members experience occurs following deployment and is a consequence of the difficulties encountered during their efforts to successfully reintegrate into their families and communities. We propose a new conceptual framework for intervening in this reintegration distress that is psycho-educational in nature as well as a new delivery model for providing such services. An example of this new intervention framework is presented. PMID- 24164528 TI - Child trafficking and commercial sexual exploitation: a review of promising prevention policies and programs. AB - Child trafficking, including commercial sexual exploitation (CSE), is one of the fastest growing and most lucrative criminal activities in the world. The global enslavement of children affects countless numbers of victims who are trafficked within their home countries or transported away from their homes and treated as commodities to be bought, sold, and resold for labor or sexual exploitation. All over the world, girls are particularly likely to be trafficked into the sex trade: Girls and women constitute 98% of those who are trafficked for CSE. Health and safety standards in exploitative settings are generally extremely low, and the degree of experienced violence has been linked with adverse physical, psychological, and social-emotional development. The human-rights-based approach to child trafficking provides a comprehensive conceptual framework whereby victim focused and law enforcement responses can be developed, implemented, and evaluated. This article highlights promising policies and programs designed to prevent child trafficking and CSE by combating demand for sex with children, reducing supply, and strengthening communities. The literature reviewed includes academic publications as well as international and governmental and nongovernmental reports. Implications for social policy and future research are presented. PMID- 24164529 TI - The mothering experiences of sex-trafficked women: between here and there. AB - This qualitative study focuses on the mothering experiences of women from the former Soviet Union (FSU) who were sex-trafficked to Israel. In-depth interviews were conducted with 8 women who gave birth either in the FSU or in Israel. The women's stories reflect 3 experiential spheres, those of "the good mother," "the sacrificing mother," and "the mother who wants for herself." These mothering spheres were found to exist against the backdrop of a life between 2 countries, where the women's mothering is split between "here" and "there." Furthermore, it was found that the women's sex-trafficking experience continually threatened to invade the 3 mothering spheres and destabilize the balance among them. The splits and conflicts among the mothering spheres are examined from a gendered perspective with emphasis on mother-daughter relationships and on the social constructions of mothering and prostitution. PMID- 24164530 TI - Characteristics, needs, and help seeking of partner violence victims mandated to community services by courts and child protective services. AB - The rapid growth of a subpopulation of women victimized by intimate partner violence (IPV) garnered the attention of 2 human service agencies in 1 Southeastern United States city. These agencies noted a shift in their clientele from female IPV victims who voluntarily sought agency services to victims who were mandated to agency services by child protective services (CPS), the court system, or both. Court-referred victims had been arrested for perpetrating IPV against their male partners. CPS-referred victims were experiencing concerning levels of IPV in their families, whether or not the victim had ever perpetrated IPV. Moreover, this subpopulation of women tended to be primary caregivers of children. In response to the growth of this subpopulation, the agencies collaborated to design and implement a program targeting female IPV victims who were primary caregivers for their children and who had been mandated to the agencies' services. The research team partnered with the agencies to conduct an investigation of this community-developed program and its participants. This article presents an exploratory, descriptive study that investigates (a) the characteristics of service-mandated, parenting IPV victims; (b) the needs of service-mandated, parenting IPV victims; and (c) the types of help-seeking behavior these women had engaged in before their service referral. Study findings indicate that, although the participants showed parenting strengths and active help-seeking efforts, this sample of women was characterized by severe IPV experiences and serious mental health needs. PMID- 24164531 TI - Does job stability mediate the relationship between intimate partner violence and mental health among low-income women? AB - Intimate partner violence (IPV) has detrimental consequences for women's mental health. To effectively intervene, it is essential to understand the process through which IPV influences women's mental health. The current study used data from 5 waves of the Women's Employment Study, a prospective study of single mothers receiving Temporary Assistance for Needy Families (TANF), to empirically investigate the extent to which job stability mediates the relationship between IPV and adverse mental health outcomes. The findings indicate that IPV significantly negatively affects women's job stability and mental health. Further, job stability is at least partly responsible for the damaging mental health consequences of abuse, and the effects can last up to 3 years after the IPV ends. This study demonstrates the need for interventions that effectively address barriers to employment as a means of enhancing the mental health of low income women with abusive partners. PMID- 24164532 TI - Radioprotectants to reduce the risk of radiation-induced carcinogenesis. AB - PURPOSE: Development of radioprotective agents has focused primarily on cytoprotection from relatively high doses of therapeutic radiation and nuclear disasters. Epidemiological studies and radiobiological models report the potential for stochastic effects from relatively low-dose radiation exposure. Diagnostic studies like computed tomography (CT) expose the patient to a small but significant amount of radiation, which has been reported to increase the risk for carcinogenesis. Young patients expected to undergo multiple CT studies may benefit from a protective agent given prior to CT. This review includes published data of agents that have been shown to protect against radiation-induced carcinogenesis. A discussion follows regarding the data that describes the extent of radiation exposure during CT, as well as technical modifications, which also reduce radiation exposure. RESULTS/CONCLUSIONS: Most experiments have used in vivo animal models or in vitro cell lines. Ethical barriers prevent large-scale human studies, although, there are two prospective human studies from the Chernobyl nuclear accident. Collectively, all of these studies provide evidence of statistically significant reductions in radiation-induced carcinogenesis. Protection is achieved by several mechanisms, which include free radical scavenging, caloric restriction, non-steroidal anti-inflammatory agents, humoral factors, and an oxidative agent. Enhanced efficacy is achieved when targeting multiple mechanisms. The data presented provides the scientific foundation for future development of a radioprotectant that may reduce the risk of carcinogenesis from low-dose exposure when certain at-risk populations undergo diagnostic studies like CT. PMID- 24164533 TI - Peripheral blood CD4/CD19 cell ratio is an independent prognostic factor in classical Hodgkin lymphoma. AB - Classical Hodgkin lymphoma (cHL) is characterized by the presence of tumoral cells in a rich background of T and B cells, macrophages and other inflammatory cells. The contribution of these non-tumoral cells to the pathogenesis of HL is still poorly understood. In our study we evaluated the prognostic significance of peripheral blood B, T and natural killer (NK) cells at diagnosis in 118 immunocompetent patients with cHL treated at our institution between January 2006 and December 2010. Fifty-four (46%) were male and 64 (54%) female. Median age at diagnosis was 33 years (range 15-82), and 71 patients (60%) presented an advanced stage (IIB-IV), 54 (46%) had bulky disease and 55 (47%) presented B symptoms. At the end of treatment, 94 patients (80%) had a complete response (CR) and 24 (20%) had a partial response. After a median follow-up of 54 months, 18 patients (15%) had relapsed. The variables that had a negative impact on progression-free survival (PFS) at univariate analysis were advanced stage, bone marrow involvement, International Prognostic Score (IPS) >= 3, positive interim positron emission tomography (int-PET), NK cells < 200/MUL, CD19 cells < 85/MUL, CD3/CD19 ratio >= 13 and CD4/CD19 ratio >= 10. At multivariate analysis, advanced stage, positive int-PET and CD4/CD19 ratio >= 10 were independent prognostic factors of PFS. New biological markers could be predictive of the response to treatment and survival in cHL. A CD4/CD19 ratio >= 10 seems to be associated with a worse outcome. PMID- 24164534 TI - MicroRNA signature in BCR-ABL1-like and BCR-ABL1-positive childhood acute lymphoblastic leukemia: similarities and dissimilarities. PMID- 24164535 TI - Implementing sponge physiological and genomic information to enhance the diversity of its culturable associated bacteria. AB - In recent years new approaches have emerged for culturing marine environmental bacteria. They include the use of novel culture media, sometimes with very low nutrient content, and a variety of growth conditions such as temperature, oxygen levels, and different atmospheric pressures. These approaches have largely been neglected when it came to the cultivation of sponge-associated bacteria. Here, we used physiological and environmental conditions to reflect the environment of sponge-associated bacteria along with genomic data of the prominent sponge symbiont Candidatus Poribacteria sp. WGA-4E, to cultivate bacteria from the Red Sea sponge Theonella swinhoei. Designing culturing conditions to fit the metabolic needs of major bacterial taxa present in the sponge, through a combined use of diverse culture media compositions with aerobic and microaerophilic states, and addition of antibiotics, yielded higher diversity of the cultured bacteria and led to the isolation of novel sponge-associated and sponge-specific bacteria. In this work, 59 OTUs of six phyla were isolated. Of these, 22 have no close type strains at the species level (< 97% similarity of 16S rRNA gene sequence), representing novel bacteria species, and some are probably new genera and even families. PMID- 24164538 TI - Controllable direct arylation: fast route to symmetrical and unsymmetrical 4,7 diaryl-5,6-difluoro-2,1,3-benzothiadiazole derivatives for organic optoelectronic materials. AB - Arylation in the 4- and 7-positions of 2,1,3-benzothiadiazole (BT) and its monofluoro- (MFBT) and difluoro- (DFBT) derivatives by (hetero)aryl bromides using Pd-catalyzed C-H activation has been investigated. MFBT and DFBT can be diarylated in moderate to high yields (up to 96% for DFBT) by a variety of aryl bromides. DFBT can be sequentially arylated using two different aryl bromides to give differentially substituted DFBT derivatives. The moderate to high yields of doubly arylated MFBT and DFBT and the ability to obtain differentially substituted products can be applied to a variety of organic photonic and electronic materials. PMID- 24164537 TI - No impact of high-dose cytarabine and asparaginase as early intensification with intermediate-risk paediatric acute lymphoblastic leukaemia: results of randomized trial TCCSG study L99-15. AB - The Tokyo Children's Cancer Study Group conducted a randomized controlled study to evaluate the effect of experimental early intensification using high-dose cytarabine and L-asparaginase in paediatric intermediate-risk (IR) acute lymphoblastic leukaemia (ALL). A total of 310 IR ALL patients were randomized to receive either experimental early intensification (n = 156) or standard early intensification including standard-dose cytarabine arm (n = 154) after induction therapy. The experimental arm consisted of high-dose cytarabine and L asparaginase, while the standard arm consisted of standard-dose cytarabine, oral 6-mercaptopurine and cyclophosphamide. The probabilities of event-free survival at 8 years in the experimental and standard arms were 72.3 +/- 3.7% and 77.5 +/- 3.5%, respectively (P = 0.32). The 8-year overall survival rates for these two arms were 85.0 +/- 3.0% and 86.9 +/- 2.8%, respectively (P = 0.72). The frequency of infectious events was significantly higher in the experimental arm (66.4%) than in the standard arm (24.6%) (P < 0.001). In conclusion, experimental early intensification including high-dose cytarabine followed by L-asparaginase had no advantage over standard early intensification in paediatric IR ALL patients. PMID- 24164536 TI - An anaerobic bacterium, Bacteroides thetaiotaomicron, uses a consortium of enzymes to scavenge hydrogen peroxide. AB - Obligate anaerobes are periodically exposed to oxygen, and it has been conjectured that on such occasions their low-potential biochemistry will predispose them to rapid ROS formation. We sought to identify scavenging enzymes that might protect the anaerobe Bacteroides thetaiotaomicron from the H2 O2 that would be formed. Genetic analysis of eight candidate enzymes revealed that four of these scavenge H2 O2 in vivo: rubrerythrins 1 and 2, AhpCF, and catalase E. The rubrerythrins served as key peroxidases under anoxic conditions. However, they quickly lost activity upon aeration, and AhpCF and catalase were induced to compensate. The AhpCF is an NADH peroxidase that effectively degraded low micromolar levels of H2 O2 , while the catalytic cycle of catalase enabled it to quickly degrade higher concentrations that might arise from exogenous sources. Using a non-scavenging mutant we verified that endogenous H2 O2 formation was much higher in aerated B. thetaiotaomicron than in Escherichia coli. Indeed, the OxyR stress response to H2 O2 was induced when B. thetaiotaomicron was aerated, and in that circumstance this response was necessary to forestall cell death. Thus aeration is a serious threat for this obligate anaerobe, and to cope it employs a set of defences that includes a repertoire of complementary scavenging enzymes. PMID- 24164539 TI - Pulmonary involvement in patients with thrombotic thrombocytopenic purpura. AB - OBJECTIVES: To determine the frequency of pulmonary involvement in patients with thrombotic thrombocytopenic purpura (TTP). METHODS: The experience of the Oklahoma TTP-HUS (hemolytic-uremic syndrome) Registry, a population-based cohort of consecutive patients without selection or referral bias, 1995-2012, was analyzed. Evidence for pulmonary involvement in patients with TTP was also documented with a systematic review of published reports. RESULTS: Only one of 74 Registry patients with acquired severe ADAMTS13 deficiency (activity <10%) had clinically important pulmonary involvement (transient PaO2 , 42 mm Hg; arterial O2 saturation, 78%; normal chest X-ray). No clinically important pulmonary involvement occurred in the remaining 73 patients. The systematic review identified 144 articles with search terms for TTP and pulmonary involvement; seven, published 1978-2002, had evaluable individual patient data. Five articles described single patients; only one patient was documented to have severe acquired ADAMTS13 deficiency; in none of the five patients was pulmonary involvement clearly related to TTP. Two articles were case series of seven patients each; no patients had ADAMTS13 activity measured. Each of the 14 patients had potential etiologies other than TTP for pulmonary involvement. CONCLUSIONS: Only one of 74 patients in the Oklahoma Registry had clinically important pulmonary involvement. A systematic review of published reports documented no clear evidence for pulmonary involvement resulting from TTP. Clinically important pulmonary involvement may be rare in patients with TTP because (i) pulmonary microvasculature may be inherently resistant to the formation of platelet thrombi and (ii) pulmonary function can be maintained in spite of multiple microvascular thrombi. PMID- 24164541 TI - Role of nicotinamide adenine dinucleotide phosphate oxidase in mediating vesicant induced interleukin-6 secretion in human airway epithelial cells. AB - Aerosolized exposure to the chemical warfare vesicant sulfur mustard and its analog nitrogen mustard (HN2) is known to induce airway lesions associated with secretion of proinflammatory cytokines such as IL-6. We have shown recently that HN2 challenge induced IL-6 secretion in human airway epithelial cells, a process mediated via epidermal growth factor receptor (EGFR) signaling. In this study, we evaluated the role of redox signaling in regulating HN2-induced, EGFR-mediated IL 6 secretions in primary cultured normal human bronchial epithelial cells (NHBECs) in the air-liquid interface. HN2-induced EGFR phosphorylation and IL-6 secretion in NHBECs were inhibited by the antioxidant N-acetyl-L-cysteine (NAC) and by the flavoprotein inhibitor diphenyleneiodonium chloride (DPI). These observations suggested that the inflammatory response in NHBECs after HN2 challenge was mediated via oxidative stress. HN2 exposure induced increased reactive oxygen species (ROS) formation and nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activity in NHBECs, findings that were inhibited by NAC and DPI treatment. Among NADPH oxidase isoforms, mRNA expression of dual oxidase (DUOX)1 and DUOX2 were up-regulated by HN2. Furthermore, knockdown of DUOX1 or DUOX2 by short hairpin RNA resulted in inhibition of ROS generation, EGFR pathway activation, and IL-6 secretion in NHBECs. These results provide evidence that redox signaling plays a pivotal role in the HN2-induced airway inflammation and underscore the importance of DUOX1 and DUOX2 in vesicant-induced IL-6 secretion in human airway epithelial cells. PMID- 24164540 TI - CD49a promotes T-cell-mediated hepatitis by driving T helper 1 cytokine and interleukin-17 production. AB - It is becoming increasingly clear that the T-cell-mediated immune response is important in many diseases. In this study, we used concanavalin A (Con A) induced hepatitis to investigate the role of CD49a in the molecular and cellular mechanism of the T-cell-mediated immune response. We found that CD49a(-/-) mice had significantly reduced levels of serum alanine aminotransferase and were protected from Con A-induced hepatitis. CD49a deficiency led to decreased production of interferon-gamma (IFN-gamma) and interleukin-17A (IL-17A) after Con A injection. Furthermore, we found that hepatic CD4(+) T cells and invariant natural killer T cells up-regulated CD49a expression, along with enhanced activation after Con A injection, leading to production of inflammatory cytokines by these T cells. Blockade of CD49a in vivo ameliorated Con A-induced hepatitis with reduced production of IFN-gamma and IL-17A. Hence, CD49a promoted Con A induced hepatitis through enhancing inflammatory cytokine production (IFN-gamma and IL-17A) by CD4(+) T and invariant natural killer T cells. The protective effect of CD49a blockade antibody suggested a new target therapeutic molecule for intervention of T-cell-mediated liver injury. PMID- 24164542 TI - Novel GO-COO-beta-CD/CA inclusion: its blood compatibility, antibacterial property and drug delivery. AB - GO-COO-beta-CD/CA inclusion (carboxylated graphene-beta cyclodextrin/chlorhexidine acetate) was fabricated with a graphene-based drug carrier. The reaction time and ratio of carrier to drug were optimized by X-ray diffraction spectra to ensure the complete wrapping of CA. Hemolysis test and recalcification test demonstrated that the inclusion possessed good blood compatibility due to the inherent biocompatibility of beta-CD molecules in the carrier. The inclusion displayed excellent inhibition effect on both gram negative bacteria of Escherichia coli and gram positive bacteria of Staphylococcus Aureus, while showing no cytotoxicity. More importantly, the drug efficiency was greatly improved with CA dosage as less as one-third of the pure drug due to the synergistic effect of the drug and carrier. Dynamic simulation implies that the delivery profile of CA from the inclusion is in accordance with the first-order dynamic equation, i.e. ln(1-Mt/M) = -kt. PMID- 24164544 TI - Novel synthesis of palladium (II) complexes derived from 3-arylsydnone-4 carbaldehyde N(4)-phenylthiosemicarbazones and biological activity. AB - OBJECTIVES: The aim of this research is to investigate whether the oxygen atom O(6) in the sydnone ring of 3-arylsydnone-4-carbaldehyde N(4) phenylthiosemicarbazones (HArSYTSCs, 3a-d) is a good electron donor atom upon metal complexation. Furthermore, ligands 3a-d and the corresponding palladium complexes (Pd(ArSYTSC)Cl, 4a-d) would be expected to find their potent biological activities. METHODS: The desired palladium complexes 4a-d were first synthesized from thiosemicarbazones 3a-d. Then, the antiproliferative activity of ligands 3a d and complexes 4a-d were tested against human hepatocellular carcinoma and human cervical epithelioid carcinoma (HeLa) cells by 3-(4,5-dimethylthiazol-2-yl)-2,5 diphenyl trazolium bromide (MTT) assay. KEY FINDINGS: According to X-ray analyses, ligands 3a-d are bonded to the Pd (II) center in an O, N, S-tridentate coordination mode through sydnone carbonyl oxygen O(6), azomethine nitrogen and the thiolate sulfur atom. The carbonyl oxygen of the sydnone ring is found to be a good electron donor site upon metal complexation. Moreover, MTT assay results reveal that the palladium complexes 4a-d have greater antiproliferative activity than 5-fluorouracil. In particular, the complexes exhibit obvious better activity than the corresponding ligands 3a-d against HeLa cell. CONCLUSIONS: The results indicate that the synthesized novel palladium complexes have greater antiproliferative activity than both 5-fluorouracil and the corresponding ligands against HeLa cell. Accordingly, the study of sydnonyl complexes bearing anticancer activities may support the development of coordination chemistry. PMID- 24164545 TI - Assessment of ventricular tachycardia scar substrate by intracardiac echocardiography. AB - BACKGROUND: Intracardiac echocardiography (ICE) is increasingly used to guide complex ablation procedures. This study aimed to assess the scar substrate of ventricular tachycardia (VT) by ICE in patients undergoing VT ablation. METHODS: In 22 patients undergoing VT ablation (10 ischemic, 12 nonischemic), the Biosense CARTOSOUND module (Biosense Webster, Diamond Bar, CA, USA) was used for three dimensional reconstruction of the ventricles. The characteristics and appearance with ICE imaging of voltage-defined scar zones (bipolar voltage <0.5 mV), border zones (0.5-1.5 mV), and normal myocardium (>1.5 mV) on electroanatomic maps were evaluated. The standard image analysis software Image J (National Institutes of Health, Bethesda, MD, USA) was used to analyze signal intensity (mean pixel signal intensity unit [SIU]) and heterogeneity (standard deviation of signal intensity in analyzed area) on ICE images. RESULTS: A total of 83 myocardial areas were analyzed from two-dimensional ICE images (15 scars, 31 border zones, and 37 normal). Voltage-defined scar zones had increased signal intensities compared to border zones (149 SIU vs 104 SIU, P < 0.0001) and normal myocardium (88 SIU, P < 0.0001). Border zones were more likely to have heterogeneous densities compared to normal myocardium (standard deviation of signal intensity 20 SIU vs 12 SIU, P < 0.0001). In receiver-operator characteristic analyses, signal intensity >= 137 SIU differentiated scar from nonscar zones (area under curve 0.91, P < 0.0001). Software-based color enhancement of areas with signal intensity >= 137 SIU allowed identification of the VT substrate in all 15 patients with voltage-defined scar zones. CONCLUSIONS: ICE provides important information about the VT anatomical substrate and may have potential to identify areas of scarred myocardium. PMID- 24164546 TI - Amphiphilic copolymers based on poly[(hydroxyethyl)-D,L-aspartamide]: a suitable functional coating for biocompatible gold nanostars. AB - Novel amphiphilic copolymers have been synthesized based on a biocompatible poly(hydroxyethylaspartamide) (PHEA) backbone, bearing both anchoring groups for gold nanoparticles, such as thiols and disulfide, and conjugable moieties, such as amino groups, the latter as points suitable for appending further functional agents. The strategy was to functionalize alpha,beta-poly[(N-2-hydroxyethyl)-D,L aspartamide] (PHEA) with PEG2000-NH2 and with ethylenediamine (EDA) obtaining a partially pegylated copolymer with a large number of pendant primary amino groups. A fraction of the latter was conjugated with molecules bearing terminal thiol moieties such as 12-mercaptododecanoic acid (MDA) and disulfide groups such as lipoic acid (LA), obtaining the two amphiphilic derivatives PHEA-PEG2000-EDA MDA (PPE-MDA) and PHEA-PEG2000-EDA-LA (PPE-LA), which also proved intrinsically able to self-assemble in polymeric micelles. The two copolymers efficiently coated gold nanostars (GNSs, size ~ 40 nm), wrapping around the surface increasing only slightly the hydrodynamic diameter (reaching ~ 45 nm), imparting them stability and a pH-switchable surface charge, due to the unreacted amino groups. Remarkably, the poor solvation and the huge steric hindrance experienced by the amino groups lowers the observed logarithmic protonation constants to 5.6 5.7. In vitro experiments demonstrated that PPE-MDA and PPE-LA copolymers have an intrinsic excellent biocompatibility in both the human brain neuroblastoma (SH SY5Y) and human bronchial epithelial (16-HBE) cell lines. Interaction of the same cell lines with "nude" GNS and GNS coated with PPE-LA was also studied, disclosing a completely satisfactory biocompatibility of the latter. PMID- 24164543 TI - Soluble receptor for advanced glycation end products predicts 28-day mortality in critically ill patients with sepsis. AB - OBJECTIVE: Multiple biomarkers are used to assess sepsis severity and prognosis. Increased levels of the soluble receptor for advanced glycation end products (sRAGE) were previously observed in sepsis but also in end-organ injury without sepsis. We evaluated associations between sRAGE and (i) 28-day mortality, (ii) sepsis severity, and (iii) individual organ failure. Traditional biomarkers procalcitonin (PCT), C-reactive protein (CRP) and lactate served as controls. METHODS: sRAGE, PCT, CRP, and lactate levels were observed on days 1 (D1) and 3 (D3) in 54 septic patients. We also assessed the correlation between the biomarkers and acute respiratory distress syndrome (ARDS), acute kidney injury (AKI) and acute heart failure. RESULTS: There were 38 survivors and 16 non survivors. On D1, non-survivors had higher sRAGE levels than survivors (p = 0.027). On D3, sRAGE further increased only in non-survivors (p < 0.0001) but remained unchanged in survivors. Unadjusted odds ratio (OR) for 28-day mortality was 8.2 (95% CI: 1.02-60.64) for sRAGE, p = 0.048. Receiver operating characteristic analysis determined strong correlation with outcome on D3 (AUC = 0.906, p < 0.001), superior to other studied biomarkers. sRAGE correlated with sepsis severity (p < 0.00001). sRAGE showed a significant positive correlation with PCT and CRP on D3. In patients without ARDS, sRAGE was significantly higher in non-survivors (p < 0.0001) on D3. CONCLUSION: Increased sRAGE was associated with 28-day mortality in patients with sepsis, and was superior compared to PCT, CRP and lactate. sRAGE correlated with sepsis severity. sRAGE was increased in patients with individual organ failure. sRAGE could be used as an early biomarker in prognostication of outcome in septic patients. PMID- 24164547 TI - EQUIP: European Society for Quality and Safety in Family Practice: quality improvement in general practice in the context of a European project. PMID- 24164548 TI - Ammonium tolerance in the cyanobacterium Synechocystis sp. strain PCC 6803 and the role of the psbA multigene family. AB - Ammonium is one of the major nutrients for plants, and a ubiquitous intermediate in plant metabolism, but it is also known to be toxic to many organisms, in particular to plants and oxygenic photosynthetic microorganisms. Although previous studies revealed a link between ammonium toxicity and photodamage in cyanobacteria under in vivo conditions, ammonium-induced photodamage of photosystem II (PSII) has not yet been investigated with isolated thylakoid membranes. We show here that ammonium directly accelerated photodamage of PSII in Synechocystis sp. strain PCC6803, rather than affecting the repair of photodamaged PSII. Using isolated thylakoid membranes, it could be demonstrated that ammonium-induced photodamage of PSII primarily occurred at the oxygen evolution complex, which has a known binding site for ammonium. Wild-type Synechocystis PCC6803 cells can tolerate relatively high concentrations of ammonium because of efficient PSII repair. Ammonium tolerance requires all three psbA genes since mutants of any of the three single psbA genes are more sensitive to ammonium than wild-type cells. Even the poorly expressed psbA1 gene, whose expression was studied in some detail, plays a detectable role in ammonium tolerance. PMID- 24164549 TI - The attitude toward xenocorneal transplantation in wait-listed subjects for corneal transplantation in Korea. AB - Shortage of donor cornea is a significant problem in Asia, and xenocorneal transplantation is being actively studied to alleviate this problem. However, the attitudes of subjects who await corneal transplants toward xenocorneal transplantation are not known at all. Thus, this study aimed to investigate the attitudes of subjects on the waiting lists for corneal transplants, toward corneal xenotransplantation. A telephone questionnaire survey comprising six items was conducted in 132 subjects among the wait-listed individuals (n = 590) who were awaiting corneal transplantation or had undergone corneal transplantation at Seoul National University Hospital from July, 2003 to August, 2012. Among six inquiries, four questions were used to analyze attitudes toward corneal xenotransplantation. Each question pertained to (1) the acceptance of xenocorneal transplantation, (2) willingness to participate in clinical trials, (3) worries in xenocorneal transplantation, and (4) the concern of self-identity or social life after xenocorneal transplantation. To analyze demographic factors influencing the question, the subjects were arbitrarily divided into two groups: the young (age < 60 yr, n = 58) and the elderly (age >= 60 yr, n = 74) or the less-educated (n = 53) and the well-educated with high school diploma, college graduation, or higher education (n = 79). Collected demographic data were analyzed as influencing factors on each question using a chi-square and logistic regression tests. In this study, 42.4% of the subjects (n = 56) expressed favorable views on xenocorneal transplantation using porcine corneas to cure visual loss from corneal blindness. Among those subjects expressing favorable views (n = 56), the willingness to participate in clinical trials, knowing they and their spouses must undergo long-term surveillance, was 62.5% (n = 35). There were 76.5% of subjects (n = 101) expressing worries regarding xenocorneal transplantation, while 28.8% of subjects (n = 38) expressed their concerns about self-identity or social life after xenotransplantation. Younger subjects expressed more worry about xenotransplantation than elderly subjects. The well educated expressed less concern over self-identity and social life than the less educated. This survey among subjects who are wait-listed for corneal transplant or who have received a corneal transplant demonstrates that there is an interest in xenocorneal transplantation as an alternate procedure, although there are worries about the procedure that should be further explored in educational campaigns and future studies of the general population. PMID- 24164550 TI - Core-shell nanostructured "black" rutile titania as excellent catalyst for hydrogen production enhanced by sulfur doping. AB - Modification of rutile titanium dioxide (TiO2) for hydrogen generation and water cleaning is a grand challenge due to the chemical inertness of rutile, while such inertness is a desired merit for its stability in photoelectrochemical applications. Herein, we report an innovative two-step method to prepare a core shell nanostructured S-doped rutile TiO2 (R'-TiO2-S). This modified black rutile TiO2 sample exhibits remarkably enhanced absorption in visible and near-infrared regions and efficient charge separation and transport. As a result, the unique sulfide surface (TiO(2-x):S) boosts the photocatalytic water cleaning and water splitting with a steady solar hydrogen production rate of 0.258 mmol h(-1) g(-1). The black titania is also an excellent photoelectrochemical electrode exhibiting a high solar-to-hydrogen conversion efficiency of 1.67%. The sulfided surface shell is proved to be an effective strategy for enhancing solar light absorption and photoelectric conversion. PMID- 24164551 TI - High photoresponse in hybrid graphene-carbon nanotube infrared detectors. AB - Efficient exciton dissociation is crucial to obtaining high photonic response in photodetectors. This work explores implementation of a novel exciton dissociation mechanism through heterojunctions self-assembled at the graphene/MWCNT (multiwall carbon nanotube) interfaces in graphene/MWCNT nanohybrids. Significantly enhanced near-infrared photoresponsivity by nearly an order of magnitude has been achieved on the graphene/MWCNT nanohybrids as compared to the best achieved so far on carbon nanotube (CNT) only infrared (IR) detectors. This leads to a high detectivity up to 1.5 * 10(7) cm.Hz(1/2).W(-1) in the graphene/MWCNT nanohybrid, which represents a 500% improvement over the best D* achieved on MWCNT film IR detectors and may be further improved with optimization on the interfacial heterojunctions. This approach of the self-assembly of graphene/CNT nanohybrids provides a pathway toward high-performance and low-cost carbon nanostructure IR detectors. PMID- 24164552 TI - Twelve tips for overnight teaching. AB - BACKGROUND: The European Working Time Directive and the United States' duty hour restrictions have changed resident physicians' schedules, specifically increasing overnight shifts and decreasing overall time spent in the hospital. As residents' perception of night shifts is that they have little educational value, efforts to improve educational opportunities and night attending teaching are desirable. However, resources about and recommendations for best practices for overnight teaching by faculty are scarce. AIM: To provide 12 tips to highlight strategies intended to optimize attending physicians' overnight teaching skills and strategies. METHOD: The tips provided are based on our experiences and reflections as in-house faculty supervising residents working overnight, by our experience and group discussions as medical educators, and the available literature. RESULTS: The 12 tips presented offer specific strategies to optimize attending physicians' overnight teaching for resident physicians, specifically highlighting the unique logistics, pedagogy and follow-up of overnight teaching. CONCLUSION: Preparation for teaching is important in any environment, but understanding the unique timing and circumstances associated with overnight teaching is vital to ensure that overnight teaching is effective. Acknowledging and addressing the physical and cognitive obstacles associated with overnight teaching and learning is necessary to maximize the educational value of overnight teaching. PMID- 24164553 TI - Practical advice on calculating confidence intervals for radioprotection effects and reducing animal numbers in radiation countermeasure experiments. AB - The dose of a substance that causes death in P% of a population is called an LDP, where LD stands for lethal dose. In radiation research, a common LDP of interest is the radiation dose that kills 50% of the population by a specified time, i.e., lethal dose 50 or LD50. When comparing LD50 between two populations, relative potency is the parameter of interest. In radiation research, this is commonly known as the dose reduction factor (DRF). Unfortunately, statistical inference on dose reduction factor is seldom reported. We illustrate how to calculate confidence intervals for dose reduction factor, which may then be used for statistical inference. Further, most dose reduction factor experiments use hundreds, rather than tens of animals. Through better dosing strategies and the use of a recently available sample size formula, we also show how animal numbers may be reduced while maintaining high statistical power. The illustrations center on realistic examples comparing LD50 values between a radiation countermeasure group and a radiation-only control. We also provide easy-to-use spreadsheets for sample size calculations and confidence interval calculations, as well as SAS(r) and R code for the latter. PMID- 24164554 TI - Stable micron-scale holes are a general feature of canonical holins. AB - At a programmed time in phage infection cycles, canonical holins suddenly trigger to cause lethal damage to the cytoplasmic membrane, resulting in the cessation of respiration and the non-specific release of pre-folded, fully active endolysins to the periplasm. For the paradigm holin S105 of lambda, triggering is correlated with the formation of micron-scale membrane holes, visible as interruptions in the bilayer in cryo-electron microscopic images and tomographic reconstructions. Here we report that the size distribution of the holes is stable for long periods after triggering. Moreover, early triggering caused by an early lysis allele of S105 formed approximately the same number of holes, but the lesions were significantly smaller. In contrast, early triggering prematurely induced by energy poisons resulted in many fewer visible holes, consistent with previous sizing studies. Importantly, the unrelated canonical holins P2 Y and T4 T were found to cause the formation of holes of approximately the same size and number as for lambda. In contrast, no such lesions were visible after triggering of the pinholin S(21) 68. These results generalize the hole formation phenomenon for canonical holins. A model is presented suggesting the unprecedentedly large size of these holes is related to the timing mechanism. PMID- 24164555 TI - A retrospective population-based comparison of HER2 immunohistochemistry and fluorescence in situ hybridization in breast carcinomas: impact of 2007 American Society of Clinical Oncology/College of American Pathologists criteria. AB - CONTEXT: In 2007 the American Society of Clinical Oncology/College of American Pathologists made new recommendations for HER2 testing and redefined HER2 positivity. OBJECTIVE: To analyze results from simultaneous HER2 testing with immunohistochemistry and fluorescence in situ hybridization (FISH) in 2590 invasive breast carcinomas between 2002 and 2010, using 2 scoring systems. DESIGN: Cases from between 2002 and 2006 were scored by using original US Food and Drug Administration criteria (N = 1138) and those from between 2007 and 2010 were evaluated according to American Society of Clinical Oncology/College of American Pathologists criteria (N = 1452). Concordance between testing methods and clinicopathologic associations were determined. RESULTS: Overall concordance between immunohistochemistry/FISH in the 9-year period was 96.2% (kappa = 0.82), and positive concordance was lower. After 2007, the proportion of HER2/neu positive and HER2/neu-negative cases was not significantly changed when using immunohistochemistry (10.5% versus 8.9%, P = .22 and 69.4% versus 63%, P = .13, respectively), but the number of equivocal cases was higher (19.9% versus 28%, P < .001). While the proportion of negative cases by FISH remained unchanged after 2007 (86.5% versus 88.2%, P = .76), the number of positive cases was lower (13.4% versus 9.2%, P < .001). In addition, 38 cases (2.6%) were FISH equivocal, 16 of which were also equivocal by immunohistochemistry. Overall, immunohistochemistry/FISH concordance was 95.9% between 2002 and 2006 (kappa = 0.82) and 96.4% after 2007 (kappa = 0.82). However, an approximately 13% lower positive assay concordance was noted in the last period. CONCLUSIONS: Application of American Society of Clinical Oncology/College of American Pathologists recommendations is associated with comparable overall immunohistochemistry/FISH concordance, reduced positive concordance, and increased equivocal results. PMID- 24164556 TI - The presence of anti-HLA donor-specific antibodies in lung allograft recipients does not correlate with C4d immunofluorescence in transbronchial biopsy specimens. AB - CONTEXT: C4d immunofluorescence (IF) is a surrogate for development of donor specific antibodies (DSAs) against human leukocyte antigen (HLA) class I and II antigens in kidney and heart biopsy specimens for monitoring of antibody-mediated (humoral) allograft rejection (AMR). Use of C4d IF in monitoring of lung allografts has shown conflicting results. OBJECTIVE: To determine if C4d IF can be used as a reliable marker for AMR and if it correlates with the presence of DSAs and histologic findings on biopsy. DESIGN: All transbronchial biopsies in lung allograft recipients, performed at our institution in a 3-year period, were reviewed. A cohort of 92 patients with 110 corresponding biopsies met the inclusion criteria of (1) having a resulted DSA within 2 weeks of biopsy and (2) having C4d immunofluorescence studies performed and confirmed. RESULTS: Twenty nine patients (31.5%) were positive for DSAs and 63 patients (68.5%) did not develop DSAs. Positive C4d capillary IF was seen in 18 of 110 total biopsy specimens (16.4%). Eight of these biopsy samples were from patients positive for DSAs and 10 were from patients negative for DSAs. The correlation coefficient between the presence of DSAs and C4d IF was 0.1628 (P = .09). CONCLUSIONS: A significant proportion of DSA-positive patients had negative C4d IF results and frequently have no histologic changes on biopsy specimens. DSA-negative patients can be positive for C4d and may show the same histologic changes as reported for DSA-positive patients. Diagnosis of AMR in lung may require a collaborative approach combining clinical data, DSA status, and histology. PMID- 24164557 TI - Concise synthesis and biological evaluation of 2-Aroyl-5-amino benzo[b]thiophene derivatives as a novel class of potent antimitotic agents. AB - The biological importance of microtubules make them an interesting target for the synthesis of antitumor agents. The 2-(3',4',5'-trimethoxybenzoyl)-5 aminobenzo[b]thiophene moiety was identified as a novel scaffold for the preparation of potent inhibitors of microtubule polymerization acting through the colchicine site of tubulin. The position of the methoxy group on the benzo[b]thiophene was important for maximal antiproliferative activity. Structure activity relationship analysis established that the best activities were obtained with amino and methoxy groups placed at the C-5 and C-7 positions, respectively. Compounds 3c-e showed more potent inhibition of tubulin polymerization than combretastatin A-4 and strong binding to the colchicine site. These compounds also demonstrated substantial antiproliferative activity, with IC50 values ranging from 2.6 to 18 nM in a variety of cancer cell lines. Importantly, compound 3c (50 mg/kg), significantly inhibited the growth of the human osteosarcoma MNNG/HOS xenograft in nude mice. PMID- 24164559 TI - The relationship between experience and mental workload in anaesthetic practice: an observational study. AB - Mental workload is seen as a key factor in defining performance and expertise in some complex work environments, but there are no validated instruments for assessing mental workload in anaesthesia. We studied the mental workload of 20 anaesthetists of varying levels of experience, during five routine cases each, by measuring the delay in their responses to a frequently, but randomly, administered vibrotactile stimulus as a secondary task. We delivered, and recorded response times for, 6096 stimuli, with a median (range) of 55.5 (9-178) responses per case. Subjects learnt rapidly to respond to the device and there was no evidence of a 'learning curve' that might bias our results. There was limited evidence of a relationship between workload and experience; for instance, in trainees completing simple cases, mental workload had a negative linear relationship with training grade (rho = -0.360, p = 0.006). However, average differences between trainees and qualified practitioners in response times to the stimulus were overshadowed by differences between subjects at the same level of experience. Finally, although the number of 'hands full' responses was small, removing these from the analysis had a greater effect than expected, suggesting that the 'hands full' condition is not random, but varies with experience and may be independently associated with expertise. This method appears feasible for use in clinical practice and may, with refinement, aid the identification and tracking of the development of expertise in anaesthetic trainees. PMID- 24164560 TI - Deep-sea methane seep sediments in the Okhotsk Sea sustain diverse and abundant anammox bacteria. AB - Marginal sea methane seep sediments sustain highly productive chemosynthetic ecosystems and are hotspots of intense biogeochemical cycling. Rich methane supply stimulates rapid microbial consumption of oxygen; these systems are thus usually hypoxic to anoxic. This and reported evidence for resident nitrogen fixation suggest the presence of an anaerobic ammonium-oxidizing (anammox) bacterial community in methane seep sediments. To test this hypothesis, we employed detection of genes encoding 16S rRNA gene and hydrazine dehydrogenase (hzo) to investigate the structure, abundance and distribution of the anammox bacterial community in the methane seep sediments of the Okhotsk Sea. Diverse complements of Candidatus Scalindua-related 16S rRNA and hzo gene sequences were obtained. Most of the deep-sea sites harbored abundant hzo genes with copy numbers as high as 10(7) g(-1) sediment. In general, anammox bacterial signatures were significantly more abundant in the deep-water sediments. Sediment porewater NO3-, NOx- (i.e. NO3- + NO2-), NOx-/NH4+ and sediment silt content correlated with in situ distribution patterns of anammox bacterial marker genes, likely because they determine anammox substrate availability and sediment geochemistry, respectively. The abundance and distribution of anammox bacterial gene markers indicate a potentially significant contribution of anammox bacteria to the marine N cycle in the deep-sea methane seep sediments. PMID- 24164558 TI - Immunocytochemical characterisation of olfactory ensheathing cells of zebrafish. AB - Continuous lifelong neurogenesis is typical of the vertebrate olfactory system. The regenerative ability of olfactory receptor neurons is dependent on the glial cell type specific to the olfactory pathway, designated 'olfactory ensheathing cells'. Several studies to date have focused on mammalian olfactory ensheathing cells, owing to their potential roles in cell-based therapy for spinal cord injury repair. However, limited information is available regarding this glial cell type in non-mammalian vertebrates, particularly anamniotes. In the current immunocytochemical study, we analysed the features of olfactory ensheathing cells in the zebrafish, Danio rerio. Fish provide a good model for studying glial cells associated with the olfactory pathway of non-mammalian vertebrates. In particular, zebrafish has numerous valuable features that enable its use as a prime model organism for genetic, neurobiological and developmental studies, as well as toxicology and genomics research. Paraffin sections from decalcified heads of zebrafish were processed immunocytochemically to detect proteins used in the research on mammalian olfactory ensheathing cells, including glial fibrillary acid protein (GFAP), S100, neural cell adhesion molecule (NCAM), polysialylated NCAM (PSA-NCAM), vimentin (VIM), p75NTR and galactin (Gal)-1. Notably, GFAP, S100, NCAM and Gal-1 were clearly observed, whereas no vimentin staining was detected. Weak immunostaining for PSA-NCAM and p75NTR was evident. Moreover the degree of marker expression was not uniform in various tracts of the zebrafish olfactory pathway. The immunostaining patterns of the zebrafish olfactory system are distinct from those of other fish to some extent, suggesting interspecific differences. We also showed that the olfactory pathway of zebrafish expresses markers of mammalian olfactory ensheathing cells. The olfactory systems of vertebrates have similarities but there are also marked variations between them. The issue of whether regional and interspecific differences in immunostaining patterns of olfactory pathway markers have functional significance requires further investigation. PMID- 24164561 TI - Enhanced fungicide resistance in Isaria fumosorosea following ionizing radiation induced mutagenesis. AB - The application of entomopathogenic fungi such as Isaria fumosorosea to combat insect pests on plants is complicated by their sensitivity to commonly used fungicides. In this study, I. fumosorosea mutants with enhanced resistance to the fungicide benomyl were induced by irradiation using either ion beams or gamma rays, or a combination of the two. When grown on agar containing benomyl, mycelial growth was observed for five of the six mutant isolates at benomyl concentrations that were more than 2000-fold those observed for the wild-type isolate (EC50 : > 5000 mg L(-1) c.f. EC50 : 2.5 mg L(-1) for the wild-type isolate). The mutant isolates evaluated also showed enhanced resistance to other fungicides at recommended field application rates. No differences were observed at the beta-tubulin locus between the wild-type and the mutant isolates, suggesting that the enhanced benomyl resistance was not attributable to mutations in that gene. Ion beams and gamma rays are thus potentially useful tools for inducing beneficial fungal mutations and thereby improving the potential for application of entomopathogenic fungi as microbial control agents. PMID- 24164562 TI - Detection and identification of mycobacteria in fixed stained smears and formalin fixed paraffin-embedded tissues using PCR. AB - OBJECTIVE: To determine the feasibility of using polymerase chain reaction to amplify DNA from methanol-fixed, Romanowsky-stained and Ziehl-Neelsen-stained smears to confirm the presence of mycobacteria. MATERIALS AND METHODS: Tissue was obtained from 10 archival slides and 27 slides from a prospective series of consecutive cases. Phosphate buffered saline (500 MUL) was pipetted onto a stained smear (on a glass slide) using a disposable filtered pipette tip. The material adherent to the slide was scraped from its surface and drawn up into the saline. Routine DNA extraction and purification was carried out before nested polymerase chain reaction testing targeting the 16S-23S internal transcribed spacer region or a TaqMan real-time polymerase chain reaction. The real-time polymerase chain reaction was also used on thick sections cut from formalin-fixed paraffin-embedded tissue blocks from 24 canine leproid granulomas. RESULTS: Mycobacterial DNA was detected in 34 of 37 slides. Polymerase chain reaction products could not be amplified from three archived smears stained using the Ziehl-Neelsen acid-fast method, probably because its harsher fixation damaged the DNA. With the nested polymerase chain reaction, species identification using internal transcribed spacer sequence analysis was achieved in all instances, diagnosing a wide range of mycobacteria. The real-time polymerase chain reaction detected Mycobacterium sp. CLG DNA within all 24 formalin-fixed paraffin-embedded specimens tested. CLINICAL SIGNIFICANCE: This technique should provide a non invasive and cost-effective means of diagnosing mycobacterial infections. PMID- 24164563 TI - Postallogeneic monitoring with molecular markers detected by pretransplant next generation or Sanger sequencing predicts clinical relapse in patients with myelodysplastic/myeloproliferative neoplasms. AB - Relapse is the major cause of treatment failure after allogeneic stem-cell transplantation (AHSCT) for patients with myelodysplastic syndrome/myeloproliferative syndrome neoplasms (MDS/MPN). We evaluated the impact of molecular mutations on outcome and the value of molecular monitoring post transplantation. We screened 45 patients with chronic myelomonocytic leukemia (n = 39 patients, including seven with transformed-acute myeloid leukemia), MDS/MPN unclassifiable (n = 5), and atypical BCR-ABL1-negative CML (n = 1) for mutations in ASXL1, CBL, NRAS, and TET2 genes by molecular genetics including a sensitive next-generation sequencing (NGS) technique. In 36 patients, sufficient DNA was available for molecular analyses. In particular, TET2 and CBL mutations were screened applying amplicon deep sequencing. In 89% of cases, at least one mutation could be detected: ASXL1: n = 18 (50%); CBL: n = 7 (19%); TET2: n = 15 (42%); and NRAS: n = 11 (32%). Survival after AHSCT at 5 yr was 46% (95% CI 28 64%) and was not influenced by any mutation. After a median of 6 months after AHSCT in 33% of the patients, one of the molecular markers was still detectable, resulting in a higher incidence of relapse than in patients with undetectable mutations (50% vs. 15%, P = 0.04). In conclusion, pretransplant molecular mutation analysis can help to detect biomarkers in patients with MPN/MDS, which may be subsequently used as minimal residual disease markers after AHSCT. PMID- 24164564 TI - Effects of surface band bending and scattering on thermoelectric transport in suspended bismuth telluride nanoplates. AB - A microdevice was used to measure the in-plane thermoelectric properties of suspended bismuth telluride nanoplates from 9 to 25 nm thick. The results reveal a suppressed Seebeck coefficient together with a general trend of decreasing electrical conductivity and thermal conductivity with decreasing thickness. While the electrical conductivity of the nanoplates is still within the range reported for bulk Bi2Te3, the total thermal conductivity for nanoplates less than 20 nm thick is well below the reported bulk range. These results are explained by the presence of surface band bending and diffuse surface scattering of electrons and phonons in the nanoplates, where pronounced n-type surface band bending can yield suppressed and even negative Seebeck coefficient in unintentionally p-type doped nanoplates. PMID- 24164565 TI - Be aware of Drinkaware. AB - In 2006, Drinkaware was established as a charity in the United Kingdom following a memorandum of understanding between the Portman Group and various UK government agencies. This debate piece briefly reviews the international literature on industry social aspects organizations, examines the nature of Drinkaware's activities and considers how the public health community should respond. Although the British addiction field and the wider public health community have distanced themselves from the Portman Group, they have not done so from Drinkaware, even though Drinkaware was devised by the Portman Group to serve industry interests. Both long-standing and more recent developments indicate very high levels of industry influence on British alcohol policy, and Drinkaware provides one mechanism of influence. We suggest that working with, and for, industry bodies such as Drinkaware helps disguise fundamental conflicts of interest and serves only to legitimize corporate efforts to promote partnership as a means of averting evidence-based alcohol policies. We invite vigorous debate on these internationally significant issues and propose that similar industry bodies should be carefully studied in other countries. PMID- 24164566 TI - Environmental needs and facilitators available for children and adolescents with cerebral palsy: adaptation and validation of the European Child Environment Questionnaire (ECEQ) Spanish version. AB - PURPOSE: The objective of this study is to present the process of translating, adapting and validating the European Child Environment Questionnaire (ECEQ) in the Spanish context. METHOD: The participants were 200 parents of children and adolescents with cerebral palsy (CP) aged 8-18 years, from seven regions in Spain. The adaptation of the ECEQ original version was carried out through the translation and back translation into Spanish. Construct validity was assessed by Factor analysis, Rasch model, and analysing group differences in need and availability of environmental features (EFs) according to level GMFCS. RESULTS: We obtained a high rate of parental response. The ECEQ Spanish version contains 59 items and we identified four domains: Products and technology - home, school and community - services, systems and policies, support and relations, and Attitudes. Seventeen items were dropped as they did not fit well into plausible domains. Construct validity in terms of distinguishing between groups with expected for both need and availability. CONCLUSION: The ECEQ Spanish version was more appropriate to assess the needs of and access to EFs in the following domains: Products and technology and services, systems and policies, and it proved less appropriate for the support and relations, and attitudes domains. Implications for Rehabilitation Identification of barriers and environmental facilitators are key aspects to ensure the participation of children and adolescents with CP. The ECEQ is a useful tool for identifying needs and availability of the environmental features for children and adolescents with CP in Spain. This tool contains 59 items that are consistent with ICF framework. The Spanish version of ECEQ provides valuable information, which could be helpful to guide public services and organization services in order to optimize participation of children and adolescents with CP. PMID- 24164567 TI - Supporting the growth of peer-professional workforces in healthcare settings: an evaluation of a targeted training approach for volunteer leaders of the STEPS Program. AB - PURPOSE: To examine the effectiveness of a targeted training approach to foster and support a peer-professional workforce in the delivery of a community rehabilitation program for adults with acquired brain injury (ABI) and their families. METHOD: A prospective longitudinal design was used to evaluate the effectiveness of a targeted two-day training forum for peer (n = 25) and professional (n = 15) leaders of the Skills to Enable People and Communities Program. Leaders completed a set of questionnaires (General Self-Efficacy Scale - GSES, Rosenberg Self-Esteem Scale, Volunteer Motivation Inventory - VMI and Community Involvement Scale - CIS) both prior to and immediately following the forum. Data analysis entailed paired sample t-test to explore changes in scores over time, and independent sample t-tests for comparisons between the two participant groups. RESULTS: The results indicated a significant increase in scores over time for the GSES (p = 0.047). Improvements in leaders' volunteer motivations and community involvement were also observed between the two time intervals. The between group comparisons highlighted that the peer leader group scored significantly higher than the professional leader group on the CIS and several domains of the VMI at both time intervals. CONCLUSION: The study provides an enhanced understanding of the utility of innovative workforce solutions for community rehabilitation after ABI; and further highlights the benefits of targeted training approaches to support the development of such workforce configurations. PMID- 24164568 TI - Destructive periodontal disease in adult Indians from Northeast Brazil: cross sectional study of prevalence and risk indicators. AB - AIM: The aim of this cross-sectional study was to evaluate the prevalence of destructive periodontal disease and its risk indicators in adult Kiriri Indians from Northeast Brazil. MATERIALS AND METHODS: Full-mouth periodontal examinations were performed on a sample of 215 Indians (>=19 years). Bivariate analyses and logistic models were applied to assess associations between periodontitis and its putative risk factors. RESULTS: Prevalence of clinical attachment loss of >=3, >=5 and >=7 mm was 97.8%, 63.8% and 30.8% respectively. Percentage of teeth per individual showing clinical attachment loss of >=3, >=5 and >=7 mm was 49.8%, 18.4% and 8.0% respectively. After adjustment for covariates, individuals aged >=35 years (OR = 5.83, 95% CI: 3.09-11.00; p < 0.001), men (OR = 2.18, 95% CI: 1.15-4.11; p = 0.02) and diabetics (OR = 3.92, 95% CI 1.03-14.99; p = 0.05) had a higher risk for destructive periodontitis, classified according to the CDC/AAP case definition. CONCLUSION: Though periodontitis was highly prevalent in Kiriri Indians, only few teeth showed advanced disease, and periodontitis was associated with higher age, male sex and diabetes. A public health action that includes programs of prevention and treatment targeting high-risk groups is vital to improve the periodontal status of this population. PMID- 24164569 TI - Clinical and microbiological effects of Lactobacillus reuteri probiotics in the treatment of chronic periodontitis: a randomized placebo-controlled study. AB - AIM: The aim of this randomized placebo-controlled clinical trial was to evaluate the effects of Lactobacillus reuteri-containing probiotic lozenges as an adjunct to scaling and root planing (SRP). MATERIAL AND METHODS: Thirty chronic periodontitis patients were recruited and monitored clinically and microbiologically at baseline, 3, 6, 9 and 12 weeks after therapy. All patients received one-stage full-mouth disinfection and randomly assigned over a test (SRP + probiotic, n = 15) or control (SRP + placebo, n = 15) group. The lozenges were used two times a day for 12 weeks. RESULTS: At week 12, all clinical parameters were significantly reduced in both groups, while there was significantly more pocket depth reduction (p < 0.05) and attachment gain (p < 0.05) in moderate and deep pockets; more Porphyromonas gingivalis reduction was observed in the SRP + probiotic group. CONCLUSIONS: The results indicate that oral administration of L. reuteri lozenges could be a useful adjunct to SRP in chronic periodontitis. PMID- 24164570 TI - Membranes over the lateral window in sinus augmentation procedures: a two-arm and split-mouth randomized clinical trials. AB - OBJECTIVE: This study evaluates whether or not, among other factors, membrane coverage of antrostomy defects improves implant survival in sinus augmentation procedures. MATERIALS AND METHODS: We performed a two-arm and split-mouth randomized controlled clinical trial on 104 and 5 patients respectively. In the two-arm study, antrostomy defects were membrane-covered in 66 procedures and uncovered in 69, before placing a total of 265 implants that were followed up for 1 year. In the split-mouth study, following bilateral sinus augmentation, antrostomy defects were membrane-covered on one side and left uncovered on the contra-lateral. Bone biopsies from each sinus were histologically analysed 6 months later. RESULTS: In the two-arm study, implant survival rates were similar (p = 0.08) in the membrane-covered (96.1%) and uncovered (94.2%) groups. In the split-mouth study, bone augmentation was similar in both groups (p = 0.52). Delayed implant placement (p = 0.04), thick Schneider's membrane (>=2 mm) (p < 0.01), treatment for hypertension (p = 0.04) and non-smoking (p = 0.01) seemed to be associated with lower risk of implant failure. CONCLUSIONS: Implant survival in sinus lifting procedures could be influenced significantly by timing of implant placement, Schneider's membrane thickness, antihypertensive treatment and smoking habits, but not by antrostomy membrane coverage. PMID- 24164571 TI - Left atrial volume best predicts recurrence after catheter ablation in patients with persistent and longstanding persistent atrial fibrillation. AB - INTRODUCTION: Patients with persistent and longstanding persistent atrial fibrillation (AF) have a higher recurrence rate after antral pulmonary vein isolation (PVI). We sought to determine the clinical, invasive, and noninvasive diastolic function parameters that are associated with AF recurrence after ablation in patients with persistent and longstanding persistent nonvalvular AF. METHODS AND RESULTS: We studied 125 consecutive patients with persistent and longstanding persistent AF who underwent antral PVI at our institution between April 2009 and April 2011. Standard clinical parameters, left atrial (LA) pressure measured at transseptal puncture, and standard diastolic function parameters on transthoracic echocardiographic (TTE) parameters were assessed. TTE was performed in sinus rhythm the first day following radiofrequency catheter ablation. Ablation eliminated AF in 83 of 125 (66.4%) patients (mean age 61.3 +/- 8.9, 81% male) during 17.8 +/- 7.7 months of follow-up. Using logistic regression analysis, AF duration prior to ablation (P = 0.04, odds ratio [OR]: 1.03, 95% confidence interval [CI] 1.0-1.06) was found to be the only clinical parameter significantly associated with AF recurrence. According to multiple logistic regression analysis, the indexed LA minimum volume of 26 cm(3) /m(2) (P = 0.009, OR: 4.9 95% CI 1.5-16.2) was the only independent imaging parameter associated with AF recurrence. CONCLUSION: Indexed minimal LA volume is highly associated with ablation success in patients with persistent and longstanding persistent AF. PMID- 24164572 TI - Benchmarking in vitro covalent binding burden as a tool to assess potential toxicity caused by nonspecific covalent binding of covalent drugs. AB - Despite several advantages of covalent inhibitors (such as increased biochemical efficiency, longer duration of action on the target, and lower efficacious doses) over their reversible binding counterparts, there is a reluctance to use covalent inhibitors as a drug design strategy in pharmaceutical research. This reluctance is due to their anticipated reactions with nontargeted macromolecules. We hypothesized that there may be a threshold limit for nonspecific covalent binding, below which a covalent binding drug may be less likely to cause toxicity due to irreversible binding to off-target macromolecules. Estimation of in vivo covalent binding burden from in vitro data has previously been used as an approach to distinguish those agents more likely to cause toxicity (e.g., hepatotoxicity) via metabolic activation to reactive metabolites. We have extended this approach to nine covalent binding drugs to determine in vitro covalent binding burden. In vitro covalent binding burden was determined by incubating radiolabeled drugs with pooled human hepatocytes. These data were scaled to an estimate of in vivo covalent binding burden by combining the in vitro data with daily dose. Scaled in vivo daily covalent binding burden of marketed covalent drugs was found to be under 10 mg/day, which is in agreement with previously reported threshold value for metabolically activated reversible drugs. Covalent binding was also compared to the intrinsic reactivities of the covalent inhibitors assessed using nucleophiles glutathione and N-alpha-acetyl lysine. The intrinsic reactivity did not correlate with observed in vitro covalent binding, which demonstrated that the intrinsic reactivity of the electrophilic groups of covalent drugs does not exclusively account for the extent of covalent binding. The ramifications of these findings for consideration of using a covalent strategy in drug design are discussed. PMID- 24164573 TI - Developmental enamel defects in children born preterm: a systematic review. AB - The purpose of this review was to evaluate the association between developmental enamel defects and children born preterm. An identical search was performed in PubMed and Embase and was limited to human studies and studies written in English, German, Danish, Swedish, or Norwegian. Reviews, case studies, and case series were excluded. A total of 283 articles were identified. Twenty-three publications, of which 19 were follow-up studies, two were case-control studies, and two were cross-sectional surveys, were enrolled in the review. The majority of the studies (n = 17) dealt with enamel hypoplasia of the primary teeth. Thirteen studies reported an association between preterm birth and enamel hypoplasia, and, in addition, few studies reported an increased risk of enamel opacities in the primary teeth, in children with a birth weight <1500 g. Seven studies dealt with enamel disturbances of the permanent teeth, four of which suggested an increased risk of enamel opacities. This systematic review suggests an increased risk of enamel hypoplasia in primary teeth of children born preterm and enamel opacities in very-low birth-weight children. A larger number of well designed studies are, however, needed in order to increase the validity of the studies. PMID- 24164574 TI - AGAMOUS-LIKE13, a putative ancestor for the E functional genes, specifies male and female gametophyte morphogenesis. AB - Arabidopsis AGL13 is a member of the AGL6 clade of the MADS box gene family. GUS activity was specifically detected from the initiation to maturation of both pollen and ovules in AGL13:GUS Arabidopsis. The sterility of the flower with defective pollen and ovules was found in AGL13 RNAi knockdown and AGL13 + SRDX dominant-negative mutants. These results indicate that AGL13 acts as an activator in regulation of early initiation and further development of pollen and ovules. The production of similar floral organ defects in the severe AGL13 + SRDX and SEP2 + SRDX plants and the similar enhancement of AG nuclear localization efficiency by AGL13 and SEP3 proteins suggest a similar function for AGL13 and E functional SEP proteins. Additional fluorescence resonance energy transfer (FRET) analysis indicated that, similar to SEP proteins, AGL13 is able to interact with AG to form quartet-like complexes (AGL13-AG)2 and interact with AG-AP3-PI to form a higher-order heterotetrameric complex (AGL13-AG-AP3-PI). Through these complexes, AGL13 and AG could regulate the expression of similar downstream genes involved in pollen morphogenesis, anther cell layer formation and the ovule development. AGL13 also regulates AG/AP3/PI expression by positive regulatory feedback loops and suppresses its own expression through negative regulatory feedback loops by activating AGL6, which acts as a repressor of AGL13. Our data suggest that AGL13 is likely a putative ancestor for the E functional genes which specifies male and female gametophyte morphogenesis in plants during evolution. PMID- 24164577 TI - Meta-analysis of the success of block following combined spinal-epidural vs epidural analgesia during labour. AB - Observational studies suggest that combined spinal-epidural analgesia (CSE) is associated with more reliable positioning, lower epidural catheter replacement rates, and a lower incidence of unilateral block compared with epidural analgesia. However, evidence from high-quality trials still needs to be assessed systematically. We performed a systematic review that included 10 randomised controlled trials comparing CSE and epidural analgesia in 1722 labouring women in labour. The relative risk of unilateral block was significantly reduced after CSE vs epidural analgesia (0.48, 95% CI 0.24-0.97), but significant between-study heterogeneity was present (I(2) = 69%, p = 0.01). No differences were found for rates of epidural catheter replacement, epidural top-up, and epidural vein cannulation. On the basis of current best evidence, a consistent benefit of CSE over epidural analgesia cannot be demonstrated for the outcomes assessed in our review. A large randomised controlled trial with adequate power is required. PMID- 24164578 TI - How we make nephrology easier to learn: computer-based modules at the point-of care. AB - BACKGROUND: Novel educational tools, such as case-based learning in a web-based module format, are an effective approach to teaching clinical concepts to medical trainees, especially if the situations are clinically relevant and the intervention is delivered at the point-of-care. Though studies have evaluated the effectiveness of point-of-care reference materials, limited literature addresses active web-based interventions designed for completion at the point-of-care. AIMS: By taking advantage of existing technological resources and integrating an effective learning modality into the clinical environment, we can increase trainee understanding of high-yield topics in clinical nephrology. METHODS: We designed interactive, case-based computer-based modules in Principles of Dialysis, Hyponatremia, and Acid-Base abnormalities, with interwoven multiple choice and free text questions with immediate feedback, supplemental practice questions, and enrichment material to be completed in the clinical environment. All medicine trainees at an urban, academic institution were invited to participate in a needs assessment, pre and post knowledge tests, and module completion. RESULTS: Most trainees believed the modules were "very" or "extremely helpful" in understanding the selected topic and that they would likely change their clinical practice. Those who completed the modules performed better on a post-intervention knowledge assessment. Free-text feedback was overwhelmingly supportive of the modules. CONCLUSION: Our findings confirmed that a novel, simplified approach to renal content by making it readily applicable to a clinical context and available at the point-of-care improves trainee understanding of high-yield topics in nephrology. PMID- 24164580 TI - Wearable textile battery rechargeable by solar energy. AB - Wearable electronics represent a significant paradigm shift in consumer electronics since they eliminate the necessity for separate carriage of devices. In particular, integration of flexible electronic devices with clothes, glasses, watches, and skin will bring new opportunities beyond what can be imagined by current inflexible counterparts. Although considerable progresses have been seen for wearable electronics, lithium rechargeable batteries, the power sources of the devices, do not keep pace with such progresses due to tenuous mechanical stabilities, causing them to remain as the limiting elements in the entire technology. Herein, we revisit the key components of the battery (current collector, binder, and separator) and replace them with the materials that support robust mechanical endurance of the battery. The final full-cells in the forms of clothes and watchstraps exhibited comparable electrochemical performance to those of conventional metal foil-based cells even under severe folding unfolding motions simulating actual wearing conditions. Furthermore, the wearable textile battery was integrated with flexible and lightweight solar cells on the battery pouch to enable convenient solar-charging capabilities. PMID- 24164579 TI - Association of Klotho polymorphisms with healthy aging: a systematic review and meta-analysis. AB - Today it is clearly evident that genetic background constitutes an integral part of aging and longevity. Many studies on long-lived people have been conducted emphasizing the role of certain genes in long life. Classic case-control studies, genome-wide association studies, and high-throughput sequencing have permitted identification of a variety of genetic variants seemingly associated with longevity. Over the years, aging research has focused on the insulin/insulin-like growth factor-1 (IGF-1) signaling pathway because of its evolutionarily conserved correlation with life-span extension in model animals. Indeed, many single nucleotide polymorphisms (SNPs) associated with longevity were identified in genes encoding proteins that take part in this metabolic pathway. Closely related to this pathway is the Klotho gene. It encodes a type-I membrane protein expressed in two forms, membrane and secreted. The latter form suppresses oxidative stress and growth factor signaling and regulates ion channels and transporters. In particular, its over-expression seems to be able to suppress insulin/IGF-1 signaling extending life span. Thus, our aim was to assemble the results in the literature concerning the association between the functional variant of the Klotho "KL-VS" stretch, which contains six polymorphisms in linkage disequilibrium, and successful aging to quantify the possible effect of the variants. The results of our systematic review indicate that the Klotho KL-VS variant is associated with healthy aging. PMID- 24164576 TI - Gene regulation by non-coding RNAs. AB - The past two decades have seen an explosion in research on non-coding RNAs and their physiological and pathological functions. Several classes of small (20-30 nucleotides) and long (>200 nucleotides) non-coding RNAs have been firmly established as key regulators of gene expression in myriad processes ranging from embryonic development to innate immunity. In this review, we focus on our current understanding of the molecular mechanisms underlying the biogenesis and function of small interfering RNAs (siRNAs), microRNAs (miRNAs) and Piwi-interacting RNAs (piRNAs). In addition, we briefly review the relevance of small and long non coding RNAs to human physiology and pathology and their potential to be exploited as therapeutic agents. PMID- 24164582 TI - Does research into medical education on tobacco and alcohol get the respect it deserves? AB - Implementation of effective clinical interventions as part of routine medical care to combat problem drinking and tobacco use is recognized to be low. Insufficient training is an important barrier preventing physicians from delivering interventions recommended in current guidelines. High-impact medical journals publish almost nothing on how to address this. If they start to take an interest perhaps we will see more progress and many thousands of lives saved at minimal cost. PMID- 24164581 TI - Conformationally constrained ortho-anilino diaryl ureas: discovery of 1-(2-(1' neopentylspiro[indoline-3,4'-piperidine]-1-yl)phenyl)-3-(4 (trifluoromethoxy)phenyl)urea, a potent, selective, and bioavailable P2Y1 antagonist. AB - Preclinical antithrombotic efficacy and bleeding models have demonstrated that P2Y1 antagonists are efficacious as antiplatelet agents and may offer a safety advantage over P2Y12 antagonists in terms of reduced bleeding liabilities. In this article, we describe the structural modification of the tert-butyl phenoxy portion of lead compound 1 and the subsequent discovery of a novel series of conformationally constrained ortho-anilino diaryl ureas. In particular, spiropiperidine indoline-substituted diaryl ureas are described as potent, orally bioavailable small-molecule P2Y1 antagonists with improved activity in functional assays and improved oral bioavailability in rats. Homology modeling and rat PK/PD studies on benchmark compound 3l will also be presented. Compound 3l was our first P2Y1 antagonist to demonstrate a robust oral antithrombotic effect with mild bleeding liability in the rat thrombosis and hemostasis models. PMID- 24164583 TI - Signal enhancement of silicon nanowire-based biosensor for detection of matrix metalloproteinase-2 using DNA-Au nanoparticle complexes. AB - Silicon nanowires have been used in the development of ultrasensitive biosensors or chemical sensors, which is originated in its high surface-to-volume ratio and function as field-effect transistor (FET). In this study, we developed an ultrasensitive DNA-gold (Au) nanoparticle complex-modified silicon nanowire field effect transistor (SiNW-FET) biosensor to detect matrix metalloproteinase-2 (MMP 2), which has been of particular interest as protein biomarker because of its relation to several important human diseases, through an enzymatic cleavage reaction of a specific peptide sequence (IPVSLRSG). SiNW patterns with a width of 100 nm and height of 100 nm were fabricated on a p-type silicon-on-insulator (SOI) wafer by electron-beam lithography. Next, negatively charged DNA-Au nanoparticle complexes coupled with the specific peptide (KKGGGGGG-IPVSLRSG EEEEEE) were applied on the SiNWs to create a more sensitive system, which was then bound to aldehyde-functionalized SiNW. The enhanced negatively charged nanoparticle complexes by attached DNA were used to enhance the conductance change of the p-SiNW by MMP-2 cleavage reaction of the specific peptide. MMP-2 was successfully measured within a range of 100 fM to 10 nM, and the conductance signal of the p-type SiNW by the MMP-2 cleavage reaction was enhanced over 10 fold by using the DNA-Au nanoparticle complexes compared with using SiNW-attached negative single peptide sequences. PMID- 24164585 TI - Does the impact of osteoarthritis vary by age, gender and social deprivation? A community study using the International Classification of Functioning, Disability and Health. AB - Abstract Purpose: The aim of the study was to explore if the impact of osteoarthritis varies with respect to age, gender and social deprivation. Impact was defined as impairment, activity limitations and participation restriction (International Classification of Functioning, Disability and Health (ICF)). Investigating the functioning of the ICF model for subgroups is important both practically and theoretically. METHOD: The sample comprised a community sample of 763 people diagnosed with osteoarthritis. Uncontaminated measures of the ICF constructs were developed using discriminant content validity from a pool of 134 items, including the WOMAC and SF-36. Multigroup Structural Equation Modelling was used to explore if the same pathways exist for subgroups of gender, age and social deprivation. RESULTS: Different significant paths were found for gender and social deprivation: impairment did not predict participation restriction for women and those most deprived, whereas these paths were significant for men and those less deprived. No difference in the paths was found for age. CONCLUSIONS: The impact of osteoarthritis appears to vary with respect to gender and social deprivation but not age. This suggests both that osteoarthritis per se does not adequately explain the health outcomes observed and that different clinical approaches may be appropriate for people of different gender and levels of deprivation. Implications of Rehabilitation The ICF model appears to vary with respect to gender and social deprivation for people with osteoarthritis. The ICF model did not appear to vary with respect to age for people with osteoarthritis. Different treatments and interventions for osteoarthritis may need to be targeted for specific gender and social deprivation groups. PMID- 24164584 TI - History of myocardial iron loading is a strong risk factor for diabetes mellitus and hypogonadism in adults with beta thalassemia major. AB - Endocrinopathies are common complications of transfusional hemosiderosis among patients with beta thalassemia major (TM). Previous studies had shown associations between some endocrinopathies and iron overload of the myocardium, liver and/or endocrine organs as assessed by MRI techniques. This retrospective analysis of 92 patients with TM (median age 36 yr) from a tertiary adult thalassemia unit in UK aimed to determine independent risk factors associated with endocrinopathies among these patients. Unlike previous studies, longitudinal data on routine measurements of iron load [worst myocardial and liver T2* values since 1999, worst LIC by MRI-R2 since 2008 and average 10-yr serum ferritin (SF)] up to April 2010 together with demographic features and age of initiating chelation were analyzed for associations with endocrinopathies. The most common endocrinopathies in this cohort were hypogonadism (67%) and diabetes mellitus (DM) (41%), and these were independently associated with myocardial T2* <20 ms (P < 0.001 and P = 0.008, respectively) and increased age (P = 0.002 and P = 0.016, respectively). DM and hypogonadism were independently associated with average SF >1250 MUg/L (P = 0.003) and >2000 MUg/L (P = 0.047), respectively. DM was also associated with initial detection of abnormal myocardial T2* at an older age (30 yr vs. 24 yr, P = 0.039). An abnormal myocardial T2* may therefore portend the development of DM and hypogonadism in patients with TM. PMID- 24164587 TI - The role of prophylaxis topical antibiotics in cardiac device implantation. AB - BACKGROUND: Combined systemic and topical antibiotic prophylaxes are used in cardiac electronic implantable device (CEID) procedures, but very few studies have assessed prophylactic use of topical antibiotics after CEID implantation. OBJECTIVE: To evaluate the efficacy of topical antibiotic prophylaxis in the prevention of surgical site infection after CEID implantation procedures. METHODS: This was a prospective randomized, placebo-controlled, single-center, single-operator study. All patients (n = 1,008) received standard systemic antibiotic prophylaxis. Patients were randomized into four groups and received various topical prophylaxes after procedure. All patients were followed for at least 12 months. Surgical site inflammation and infection were graded based on degree of inflammation, discharge, wound culture, and blood culture. RESULT: Fifty-eight patients developed surgical site inflammation and infection. Fourteen patients had culture-positive wound infections. Among them, 13 patients had superficial wound infections with Staphylococcus species. Only one had pocket infection with Pseudomonas bacteremia. The surgical site infection rate was higher in those with longer procedural time, associated with 2.3 times more likelihood of infection (P = 0.01). Patients with an associated malignancy were associated with 3.6 times more likelihood of infection (P < 0.01). CONCLUSIONS: Careful skin preparation prior to incision is important, whereas the use of topical antibiotics after closure has not shown significant benefit. Patients with malignancy and longer procedural times are more likely to develop infection. There is a trend for less infection with cephalic approach. Systemic antibiotics with staphylococcal coverage are needed as most of the wound culture positive infections are caused by Staphylococcus species. PMID- 24164588 TI - H-bonding activation in highly regioselective acetylation of diols. AB - H-bonding activation in the regioselective acetylation of vicinal and 1,3-diols is presented. Herein, the acetylation of the hydroxyl group with acetic anhydride can be activated by the formation of H-bonds between the hydroxyl group and anions. The reaction exhibits high regioselectivity when a catalytic amount of tetrabutylammonium acetate is employed. Mechanistic studies indicated that acetate anion forms dual H-bonding complexes with the diol, which facilitates the subsequent regioselective monoacetylation. PMID- 24164589 TI - Highly efficient and mild electrochemical mineralization of long-chain perfluorocarboxylic acids (C9-C10) by Ti/SnO2-Sb-Ce, Ti/SnO2-Sb/Ce-PbO2, and Ti/BDD electrodes. AB - The electrochemical mineralization of environmentally persistent long-chain perfluorinated carboxylic acids (PFCAs), i.e., perfluorononanoic acid (C8F17COOH, PFNA) and perfluorodecanoic acid (C9F19COOH, PFDA) was investigated in aqueous solutions (0.25 mmol L(-1)) over Ti/SnO2-Sb-Ce (SnO2), Ti/SnO2-Sb/Ce-PbO2 (PbO2), and Ti/BDD (BDD) anodes under galvanostatic control at room temperature. Based on PFCA decay rate, total organic carbon (TOC) reduction, defluorination ratio, safety, and energy consumption, the performance of PbO2 electrode was comparable with that of BDD electrode. After 180 min electrolysis, the PFNA removals on BDD and PbO2 electrodes were 98.7 +/- 0.4% and 97.1 +/- 1.0%, respectively, while the corresponding PFDA removals were 96.0 +/- 1.4% and 92.2 +/- 1.9%. SnO2 electrode yielded lower PFCA removals and led to notable secondary pollution by Sb ions. The primary mineralization product, F(-), as well as trace amounts of intermediate PFCAs with shortened chain lengths, were detected in aqueous solution after electrolysis. On the basis of these results, a degradation mechanism including three potential routes is proposed: via formation of short chain PFCAs by stepwise removal of CF2; direct mineralization to CO2 and HF; conversion to volatile fluorinated organic compounds. The results presented here demonstrate that electrochemical technique exhibits high efficiency in mineralizing PFNA and PFDA under mild conditions, and is promising for the treatment of long-chain PFCAs in wastewater. PMID- 24164590 TI - Surface-induced alkene oligomerization: does thermal hydrosilylation really lead to monolayer protected silicon nanocrystals? AB - Surface functionalization of hydride-terminated silicon nanocrystals (SiNCs) with dodecene via thermal hydrosilylation has been reexamined. We observed the formation of dodecyl oligomers (n <= 4) during the reaction under an argon atmosphere at various predesigned temperatures (100-190 degrees C). In a comparative study, surface hydrosilylation and ligand oligomerization were found to be more pronounced under air (n <= 7) at the same temperatures. These observations strongly suggest that hydrogen abstraction by oxygen accelerates hydrosilylation and generates sufficient silyl radical as initiator to interact with unsaturated bonds, promote chain propagation, and generate ligand oligomers. We further propose that, to inhibit ligand oligomerization and obtain monolayer coverage on SiNC surfaces, it is feasible to apply comparatively low temperatures, inert atmosphere, and dilute ligand concentration during thermal hydrosilylation. PMID- 24164592 TI - In beauty we trust: children prefer information from more attractive informants. AB - Preschool children were presented with slides on a computer screen showing a novel object, together with two informants, one with an attractive and one with a less attractive face. Children were asked which informant they would like to ask about the name of the novel object. After hearing the informants provide conflicting names, they were asked who they thought was correct. Children were more likely to endorse names provided by the person with the more attractive face, a bias that cannot be justified on epistemic grounds. The implications of this finding are discussed. PMID- 24164591 TI - Redox signaling mediates the expression of a sulfate-deprivation-inducible microRNA395 in Arabidopsis. AB - MicroRNA395 (miR395) is a conserved miRNA that targets a low-affinity sulfate transporter (AST68) and three ATP sulfurylases (APS1, APS3 and APS4) in higher plants. In this study, At2g28780 was confirmed as another target of miR395 in Arabidopsis. Interestingly, several dicots contained genes homologous to At2g28780 and a cognate miR395 complementary site but possess a gradient of mismatches at the target site. It is well established that miR395 is induced during S deprivation in Arabidopsis; however, the signaling pathways that mediate this regulation are unknown. Several findings in the present study demonstrate that redox signaling plays an important role in induction of miR395 during S deprivation. These include the following results: (i) glutathione (GSH) supplementation suppressed miR395 induction in S-deprived plants (ii) miR395 is induced in Arabidopsis seedlings exposed to Arsenate or Cu(2+) , which induces oxidative stress (iii), S deprivation-induced oxidative stress, and (iv) compromised induction of miR395 during S deprivation in cad2 mutant (deficient in GSH biosynthesis) that is defective in glutaredoxin-dependent redox signaling and ntra/ntrb (defective in thioredoxin reductases a and b) double mutants that are defective in thioredoxin-dependent redox signaling. Collectively, these findings strongly support the involvement of redox signaling in inducing the expression of miR395 during S deprivation in Arabidopsis. PMID- 24164593 TI - Lasting effects of snow accumulation on summer performance of large herbivores in alpine ecosystems may not last. AB - One of the clearest predictions from the IPCC is that we can expect much less snow cover due to global warming in the 21st century, especially in the lower alpine areas. In alpine ecosystems, snow accumulation in depressions gives rise to distinct snow-bed vegetation types, assumed to play a key role in ecosystem function. A delayed plant phenology yields high-quality forage in late summer for wild and domestic herbivores. Yet, the mechanistic pathways for how declining snow may affect future performance of large herbivores beyond the effect of phenology remain poorly documented. Here, we link unique individual-based data on diet choice, habitat selection and performance of domestic sheep over a 10-year period to manually GPS-recorded spatial positions of snow cover in early summer (0.57% to 43.3% in snow beds on 1st of July) in an alpine ecosystem. Snowy winters gave a higher proportion of easily digestible herbs in the diet and a more variable use of snow-bed and meadow vegetation types resulting in faster growing lambs. These patterns were consistent between two density treatment levels although slightly more marked for diet at low density, suggesting that effects of simple mitigation efforts such as managing population numbers will be meagre. Our study thus yields novel insight into the strong impact of melting snow on ecosystem function in alpine habitats, which are likely to affect productivity of both domestic and wild ungulate populations. PMID- 24164594 TI - Cyclophilin-A: a novel biomarker for untreated male essential hypertension. AB - Vascular cytokines, total nitrite, and cyclophilin-A (CyP-A) may be related to the pathogenesis of untreated hypertension. Forty males with normotensive and untreated essential hypertension were recruited in this cytokines survey. Body mass index (BMI), hyperlipidemia, and plasma CyP-A were increased in the hypertensive group (p < 0.05). However, only BMI (p = 0.022) and plasma CyP-A (p = 0.020) were found to be significant contributors to hypertension by multiple regression analysis. CyP-A was also positively correlated with systolic blood pressure (p = 0.029) and diastolic blood pressure (p = 0.047). These findings indicated that plasma CyP-A is a critical molecular biomarker in the early pathogenesis of essential hypertension. PMID- 24164595 TI - Midkine neurite growth-promoting factor 2 expression as a potential prognostic marker of adjuvant therapy in head and neck squamous cell carcinoma. AB - OBJECTIVE: The prognostic function of neurite growth-promoting factor 2 (Midkine (MK)) in adjuvant treatment of head and neck squamous cell carcinoma (HNSCC) is unclear. This study examined whether MK expression may predict treatment response and survival in resectable HNSCC patients. METHODS: In this retrospective study, MK expression in 144 HNSCC patients was analyzed by immunohistochemistry. A subset of patients (n = 10) had MK expression levels analyzed by western blot and semi-quantitative reverse transcription polymerase chain reaction. Data were analyzed using the Log-rank test and alpha = 0.05. RESULTS: Expression of MK was associated with poorer five-year progression-free and overall survival rates in HNSCC patients (p = 0.002). CONCLUSION: MK might play an important role in the progression of HNSCC and may be a useful prognostic factor. PMID- 24164596 TI - Replication of the Escherichia coli chromosome in RNase HI-deficient cells: multiple initiation regions and fork dynamics. AB - DNA replication in Escherichia coli is normally initiated at a single origin, oriC, dependent on initiation protein DnaA. However, replication can be initiated elsewhere on the chromosome at multiple ectopic oriK sites. Genetic evidence indicates that initiation from oriK depends on RNA-DNA hybrids (R-loops), which are normally removed by enzymes such as RNase HI to prevent oriK from misfiring during normal growth. Initiation from oriK sites occurs in RNase HI-deficient mutants, and possibly in wild-type cells under certain unusual conditions. Despite previous work, the locations of oriK and their impact on genome stability remain unclear. We combined 2D gel electrophoresis and whole genome approaches to map genome-wide oriK locations. The DNA copy number profiles of various RNase HI deficient strains contained multiple peaks, often in consistent locations, identifying candidate oriK sites. Removal of RNase HI protein also leads to global alterations of replication fork migration patterns, often opposite to normal replication directions, and presumably eukaryote-like replication fork merging. Our results have implications for genome stability, offering a new understanding of how RNase HI deficiency results in R-loop-mediated transcription replication conflict, as well as inappropriate replication stalling or blockage at Ter sites outside of the terminus trap region and at ribosomal operons. PMID- 24164597 TI - The REL3-mediated TAS3 ta-siRNA pathway integrates auxin and ethylene signaling to regulate nodulation in Lotus japonicus. AB - The ta-siRNA pathway is required for lateral organ development, including leaf patterning, flower differentiation and lateral root growth. Legumes can develop novel lateral root organs--nodules--resulting from symbiotic interactions with rhizobia. However, ta-siRNA regulation in nodule formation remains unknown. To explore ta-siRNA regulation in nodule formation, we investigated the roles of REL3, a key component of TAS3 ta-siRNA biogenesis, during nodulation in Lotus japonicus. We characterized the symbiotic phenotypes of the TAS3 ta-siRNA defective rel3 mutant, and analyzed the responses of the rel3 mutant to auxin and ethylene in order to gain insight into TAS3 ta-siRNA regulation of nodulation. The rel3 mutant produced fewer pink nitrogen-fixing nodules, with substantially decreased infection frequency and nodule initiation. Moreover, the rel3 mutant was more resistant than wild-type to 1-naphthaleneacetic acid (NAA) and N-1 naphthylphthalamic acid (NPA) in root growth, and exhibited insensitivity to auxins but greater sensitivity to auxin transport inhibitors during nodulation. Furthermore, the rel3 mutant has enhanced root-specific ethylene sensitivity and altered responses to ethylene during nodulation; the low-nodulating phenotype of the rel3 mutant can be restored by ethylene synthesis inhibitor L-alpha-(2 aminoethoxyvinyl)-glycine (AVG) or action inhibitor Ag(+). The REL3-mediated TAS3 ta-siRNA pathway regulates nodulation by integrating ethylene and auxin signaling. PMID- 24164598 TI - A challenge with Porphyromonas gingivalis differentially affects the osteoclastogenesis potential of periodontal ligament fibroblasts from periodontitis patients and non-periodontitis donors. AB - AIM: Porphyromonas gingivalis (Pg) may cause an immune-inflammatory response in host cells leading to bone degradation by osteoclasts. We investigated the osteoclast-inducing capacity of periodontal ligament fibroblasts from periodontitis patients and non-periodontitis donors after a challenge with viable Pg. MATERIALS AND METHODS: PDLFs from periodontitis patients (n = 8) and non periodontitis donors (n = 7) were incubated for 6 h with or without viable Pg and subsequently co-cultured with osteoclast precursors from peripheral blood mononuclear cells (PBMCs). The number of multinucleated tartrate-resistant acid phosphatase-positive cells was determined at 21 days. Expression of osteoclastogenesis-associated genes was assessed after infection of PDLFs mono cultures and in PDLFs-PBMCs co-cultures. Resorption activity was analysed on bone slices. RESULTS: Pg induced the expression of osteoclastogenesis-associated genes by PDLFs. After bacterial challenge the formation of osteoclast-like cell was decreased in co-cultures of PBMCs with non-periodontitis PDLFs, but not with PDLFs from periodontitis patients. CONCLUSION: PDLFs from sites free of periodontitis respond to an infection with Pg by tempering formation of osteoclast-like cells, probably promoting clearance of the infection. PDLFs from periodontitis sites are desensitized to a Pg challenge in terms of their osteoclast-inducing capacity. PMID- 24164600 TI - Quantification of deep traps in nanocrystal solids, their electronic properties, and their influence on device behavior. AB - We implement three complementary techniques to quantify the number, energy, and electronic properties of trap states in nanocrystal (NC)-based devices. We demonstrate that, for a given technique, the ability to observe traps depends on the Fermi level position, highlighting the importance of a multitechnique approach that probes trap coupling to both the conduction and the valence bands. We then apply our protocol for characterizing traps to quantitatively explain the measured performances of PbS NC-based solar cells. PMID- 24164599 TI - Discovery of the first M5-selective and CNS penetrant negative allosteric modulator (NAM) of a muscarinic acetylcholine receptor: (S)-9b-(4-chlorophenyl)-1 (3,4-difluorobenzoyl)-2,3-dihydro-1H-imidazo[2,1-a]isoindol-5(9bH)-one (ML375). AB - A functional high throughput screen and subsequent multidimensional, iterative parallel synthesis effort identified the first muscarinic acetylcholine receptor (mAChR) negative allosteric modulator (NAM) selective for the M5 subtype. ML375 is a highly selective M5 NAM with submicromolar potency (human M5 IC50 = 300 nM, rat M5 IC50 = 790 nM, M1-M4 IC50 > 30 MUM), excellent multispecies PK, high CNS penetration, and enantiospecific inhibition. PMID- 24164601 TI - Diffuse gastroduodenitis associated with ulcerative colitis: treatment by infliximab. AB - Diffuse gastroduodenitis resembling ulcerative colitis in respect to macro- and microscopic findings occurs in ulcerative colitis, although it is rare. Reports of gastroduodenitis associated with ulcerative colitis treated with infliximab are rare. A 58-year-old man had tarry stool in March 2011. He had a history of ulcerative colitis that was diagnosed in 1984. He underwent subtotal colectomy in 1991. Endoscopy and radiography revealed diffuse friable mucosa throughout the duodenum and an ulcer in the middle of the descending portion, resulting in a narrow portion.In the stomach, numerous small aphthae were observed in the antrum. Biopsy specimens of the duodenum and antrum showed marked inflammatory cell infiltration in both areas and cryptitis in the duodenum. Standard induction therapy of infliximab was started in April. The ulcer in the descending portion became a scar without diffuse mucosal friability in September 2011. PMID- 24164602 TI - Extended hemangioma from pharynx to esophagus that could be misdiagnosed as an esophageal varix on endoscopy. AB - Giant hemangioma in the neck and head is an uncommon vascular neoplasm and has an unpredictable clinical behavior. We report a hemangioma that extended from the pharynx to the esophagus that could have been misdiagnosed as an esophageal varix. A 42-year-old man with dilated varices-like vessels on his esophagus that were incidentally detected by endoscopy was referred to our hospital for further evaluation. On re-examined endoscopy, multiple vascular dilatations were noted in the pharynx, expanding into the esophagogastric junction. These dilatations looked like esophageal varices that are found in patients with liver cirrhosis. There was no significant abnormality, including liver cirrhosis, on the abdomino pelvic computed tomography scan. On the endoscopic esophageal biopsy, dilatedsubmucosal blood vessels were diagnosed as hemangioma. In consultation with an otorhinolaryngologist for evaluation of the risk of hemangioma, it was determined that the hemangioma was not dangerous to the patient as long as it did not cause hoarseness, dyspnea or dysphagia. We planned regular 6-month follow ups. We report a case of extended hemangioma that could possibly have been misdiagnosed as an esophageal varix on endoscopy. Even if head and neck hemangioma is uncommon, careful consideration during endoscopy is required to avoid the misdiagnosis of varices or hemangioma. PMID- 24164604 TI - Impact of the NICU environment on language deprivation in preterm infants. AB - It is unclear whether the atypical language development commonly seen in preterm infants is a consequence of language deficiency experienced during their prolonged NICU stay. This review provides a novel viewpoint, which highlights the potential impact of the NICU design on the developmental origin of language disabilities in preterm infants. CONCLUSION: Further research is needed to identify evidence-based design solutions for providing preterm infants with a healthier linguistic hospital environment that aids growth and development. PMID- 24164606 TI - Drug development study designs have reached the danger zone. PMID- 24164607 TI - Could hydrogen sulfide be the next blockbuster treatment for inflammatory disease? PMID- 24164605 TI - Sonoporation increases therapeutic efficacy of inducible and constitutive BMP2/7 in vivo gene delivery. AB - An ideal novel treatment for bone defects should provide regeneration without autologous or allogenous grafting, exogenous cells, growth factors, or biomaterials while ensuring spatial and temporal control as well as safety. Therefore, a novel osteoinductive nonviral in vivo gene therapy approach using sonoporation was investigated in ectopic and orthotopic models. Constitutive or regulated, doxycycline-inducible, bone morphogenetic protein 2 and 7 coexpression plasmids were repeatedly applied for 5 days. Ectopic and orthotopic gene transfer efficacy was monitored by coapplication of a luciferase plasmid and bioluminescence imaging. Orthotopic plasmid DNA distribution was investigated using a novel plasmid-labeling method. Luciferase imaging demonstrated an increased trend (61% vs. 100%) of gene transfer efficacy, and micro-computed tomography evaluation showed significantly enhanced frequency of ectopic bone formation for sonoporation compared with passive gene delivery (46% vs. 100%) dependent on applied ultrasound power. Bone formation by the inducible system (83%) was stringently controlled by doxycycline in vivo, and no ectopic bone formation was observed without induction or with passive gene transfer without sonoporation. Orthotopic evaluation in a rat femur segmental defect model demonstrated an increased trend of gene transfer efficacy using sonoporation. Investigation of DNA distribution demonstrated extensive binding of plasmid DNA to bone tissue. Sonoporated animals displayed a potentially increased union rate (33%) without extensive callus formation or heterotopic ossification. We conclude that sonoporation of BMP2/7 coexpression plasmids is a feasible, minimally invasive method for osteoinduction and that improvement of bone regeneration by sonoporative gene delivery is superior to passive gene delivery. PMID- 24164610 TI - Effects of red wine on established markers of arterial structure and function in human studies: current knowledge and future research directions. AB - Evidence from observational studies suggests that mild-to-moderate consumption of red wine is associated with reduced cardiovascular morbidity and mortality. Various individual chemical components of red wine also show salutary effects on vascular homeostasis, that is, enhanced endothelial function and arterial distensibility, both in vitro and in animal studies. However, testing the beneficial potential of red wine in primary and secondary cardiovascular prevention on established surrogate cardiovascular markers requires further study with longer term intervention trials. This report reviews and critically appraises the published evidence for the effects of red wine on endothelium dependent vasodilation, arterial stiffness and arterial wave reflections in healthy subjects and in patients with cardiovascular disease. Suggestions for future research directions are also provided. PMID- 24164608 TI - Hepatic actions of vitamin D receptor ligands: a sunshine option for chronic liver disease? PMID- 24164611 TI - Pharmacokinetic behavior presents drug therapy challenges. AB - There are conditions that cause a substantial change in drug clearance to such a degree that how a specific drug is managed to optimize drug response and minimize drug toxicity presents a challenge. This review will focus on recent literature (within the past 5 years) that evaluates pathophysiologic and genetic conditions and drug interactions which can change drug clearance to the magnitude that response is affected. Situations discussed that cause an increase in drug clearance will include: augmented renal clearance in critically ill patients; ultrafast drug metabolism caused by gene duplication; and enzyme induction interactions caused by rifampin. Situations discussed that result in a reduction in clearance will include: multiple organ failure in critically ill, patients with non-functioning CYP2D6 and CYP2C8/9 alleles, and CYP3A4 drug interactions with erythromycin and clarithromycin. In each case evaluated clearance is changed to the magnitude such that managing drug therapy can be difficult. PMID- 24164612 TI - Topical corticosteroid therapy for the prevention of acute radiation dermatitis: a systematic review of randomized controlled trials. AB - Acute radiation dermatitis (ARD) is a common side effect of radiation therapy and is characterized by erythema, dry desquamation or moist desquamation. This wet desquamation is a very painful condition for the patient and often leads to interruption of radiotherapy. The objective of this article is to assess the efficacy of topical corticosteroids in the prevention of ARD compared with placebo, other topical medication or no treatment. The prophylactic application of topical corticosteroid among patients undergoing radiotherapy appears to significantly reduce the incidence of ARD, specifically moist desquamation, compared with other treatments. Future trials with a more standardized measure of radiation dermatitis grading are recommended. Further research may also be conducted to determine if a mildly potent, midpotent or super potent topical steroid will be more effective in preventing ARD. PMID- 24164614 TI - Targeted drugs in combination with radiotherapy for the treatment of solid tumors: current state and future developments. AB - The continuously rising use of novel drugs, especially of molecules belonging to the group of targeted drugs is now shaping the therapeutic landscape. However, treatment combinations of targeted drugs with radiotherapy are still rare. Only the monoclonal antibody cetuximab (Erbitux(r)) has been approved for the treatment of locally advanced squamous cell cancer of the head and neck in combination with radiotherapy. Several targeted compounds are in advanced stages of clinical development for combination treatments with radiotherapy, of which substances with either anti-EGFR or anti-angiogenic mechanisms, such as trastuzumab, panitumumab, erlotinib, cilengitide and bevacizumab are the most promising. Aim of this article is to provide, mainly from a radio-oncological point of view, an overview about the current state as well as to give an outlook on the near future of the most advanced targeted combined treatment concepts for solid tumors. PMID- 24164613 TI - Beyond humanization and de-immunization: tolerization as a method for reducing the immunogenicity of biologics. AB - Immune responses to some monoclonal antibodies (mAbs) and biologic proteins interfere with their efficacy due to the development of anti-drug antibodies (ADA). In the case of mAbs, most ADA target 'foreign' sequences present in the complementarity determining regions (CDRs). Humanization of the mAb sequence is one approach that has been used to render biologics less foreign to the human immune system. However, fully human mAbs can also drive immunogenicity. De immunization (removing epitopes) has been used to reduce biologic protein immunogenicity. Here, we discuss a third approach to reducing the immunogenicity of biologics: introduction of Treg epitopes that stimulate Treg function and induce tolerance to the biologic protein. Supplementing humanization (replacing xeno-sequences with human) and de-immunization (reducing T effector epitopes) with tolerization (introducing Treg epitopes) where feasible, as a means of improving biologics 'quality by design', may lead to the development of ever more clinically effective, but less immunogenic, biologics. PMID- 24164615 TI - Novel anticoagulants for stroke prevention in atrial fibrillation: safety issues in the elderly. AB - Vitamin K antagonists (VKAs) are the most widely used anticoagulants for stroke prevention in patients with atrial fibrillation (AF). Recently, the US FDA approved three novel anticoagulants that work through inhibition of coagulation cascade independent of Vitamin K-dependent enzymatic reactions and, therefore, should have less food-drug interactions. Since AF is a disease of the aging heart, it is important to assess safety and efficacy of these new anticoagulants in elderly patients. We reviewed age-related changes in pharmacokinetics and pharmacodynamics observed with senescence and the effects of these changes on novel anticoagulants, known and anticipated drug and food interactions, and challenges related to bleeding complications and temporary discontinuation prior to surgery or interventional procedure. Although advantageous to VKA in age groups represented in trials, there are lack of data on VKA usage in older elderly patients; additional research and post-marketing analysis in older elderly patients are needed. PMID- 24164616 TI - Evaluation of outcomes of intravenous to oral antimicrobial conversion initiatives: a literature review. AB - Inappropriate use of antimicrobial agents could result in antimicrobial resistance that could impact clinical cure outcomes (by increasing morbidity in terms of increased adverse events and risk of secondary and hospital-acquired infections and mortality) and increase costs to health care institutions. Thus, appropriate antimicrobial use has become vital for balancing patient safety and costs and is therefore a focus for health care institutions. This is often achieved through efforts of antimicrobial stewardship programs that include intravenous to oral conversion initiatives with clinical pharmacists playing an instrumental role in their development and implementation with medical staff approval. However, the delivery and effectiveness of these programs are quite variable. Therefore, for guiding the successful delivery and evaluations of these programs in the future, the objective of this literature review is to document the impact of intravenous to oral conversion programs in terms of clinical and economic outcomes at various institutions worldwide along with the pharmacist's role in these programs. PMID- 24164618 TI - Doctoral programs in health professions education. AB - The interest to pursue doctoral degrees in the health professions is increasing exponentially. Some reasons for this increase include innovations in curriculum and instructional strategies, competency-based assessment, particularly at the postgraduate level, and accreditation requirements. Through various electronic search methods, interviews, review of documents and site visits, 24 structured doctoral programs were identified worldwide that offer a PhD in health professions education (HPE) or medical education. A number of other programs were also identified that do not follow a structured curriculum; however, through supervision and guidance, candidates could complete a number of publishable projects thus meeting the requirements for a doctorate degree. Also, some institutions train fellows for doctoral degrees in HPE without necessarily advertising or labeling the programs as a PhD in medical or HPE. There are also discipline-specific PhDs, such as medicine and dentistry, which focus on education. For example, a student interested in studying surgical technical skills could be directed to take a PhD in kinesiology. It is time for institutions and individuals to start thinking about disciplinary diversity and not focus exclusively on studies of medical education. PMID- 24164619 TI - Cytosine DNA methylation influences drug resistance in Escherichia coli through increased sugE expression. AB - Escherichia coli K-12 strains contain the orphan cytosine-5 DNA methyltransferase enzyme Dcm (DNA cytosine methyltransferase). Two recent reports indicate that Dcm has an influence on stationary phase gene expression in E. coli. Herein, we demonstrate that dcm knockout cells overexpress the drug resistance transporter SugE, which has been linked to ethidium bromide (ETBR) resistance. SugE expression also increased in the presence of the DNA methylation inhibitor 5 azacytidine, suggesting that Dcm-mediated DNA methylation normally represses sugE expression. The effect of Dcm on sugE expression is primarily restricted to early stationary phase, and RpoS is required for robust sugE expression. Dcm knockout cells are more resistant to ETBR than wild-type cells, and complementation with a plasmid-borne dcm gene restores ETBR sensitivity. SugE knockout cells are more sensitive to ETBR than wild-type cells. These data indicate that Dcm influences the sensitivity to an antimicrobial compound through changes in gene expression. PMID- 24164620 TI - Noncanonical self-assembly of multifunctional DNA nanoflowers for biomedical applications. AB - DNA nanotechnology has been extensively explored to assemble various functional nanostructures for versatile applications. Mediated by Watson-Crick base-pairing, these DNA nanostructures have been conventionally assembled through hybridization of many short DNA building blocks. Here we report the noncanonical self-assembly of multifunctional DNA nanostructures, termed as nanoflowers (NFs), and the versatile biomedical applications. These NFs were assembled from long DNA building blocks generated via rolling circle replication (RCR) of a designer template. NF assembly was driven by liquid crystallization and dense packaging of building blocks, without relying on Watson-Crick base-pairing between DNA strands, thereby avoiding the otherwise conventional complicated DNA sequence design. NF sizes were readily tunable in a wide range, by simply adjusting such parameters as assembly time and template sequences. NFs were exceptionally resistant to nuclease degradation, denaturation, or dissociation at extremely low concentration, presumably resulting from the dense DNA packaging in NFs. The exceptional biostability is critical for biomedical applications. By rational design, NFs can be readily incorporated with myriad functional moieties. All these properties make NFs promising for versatile applications. As a proof-of principle demonstration, in this study, NFs were integrated with aptamers, bioimaging agents, and drug loading sites, and the resultant multifunctional NFs were demonstrated for selective cancer cell recognition, bioimaging, and targeted anticancer drug delivery. PMID- 24164621 TI - Fluorescence enhancement of imidazolium ionic liquid by its confinement on PVC for in situ selective quantification of hemoglobin. AB - A hydrophilic ionic liquid (methylimidazolium chloride, NmimCl)-polyvinyl chloride ionomer (NmimCl-PVC) was prepared by immobilizing and confining N methylimidazole onto PVC chains. The NmimCl-PVC ionomer exhibits a 4-fold enhancement on the fluorescence intensity with respect to that of NmimCl, attributing to the confinement of ionic liquid by the PVC chain. The fluorescence is excitation-dependent with a maximum at lambdaem 430 nm when excited at 325 nm. In addition, the fluorescence intensity of NmimCl-PVC ionomer increases remarkably with the loading ratio of N-methylimidazole in the range of 4.3-15.1%. The fluorescence quantum yield and lifetime were derived to be 0.112/7.1 ns for the NmimCl-PVC ionomer and 0.063/8.8 ns for NmimCl. Furthermore, hemoglobin is selectively adsorbed by NmimCl-PVC and causes significant fluorescence quenching of the ionomer via dynamic quenching and energy transfer between NmimCl-PVC and hemoglobin. A solid surface fluorimetric procedure was developed for surface adsorption and preconcentration of hemoglobin followed by in situ detection. A linear dynamic range of 0.3-26.2 MUg mg(-1) is achieved with a detection limit of 0.1 MUg mg(-1). Regarding hemoglobin in aqueous solution, the linear range 5-300 MUg mL(-1) is achieved along with a detection limit of 2 MUg mL(-1). PMID- 24164622 TI - In vitro validation of an ultra-sensitive scanning fluorescence microscope for analysis of circulating tumor cells. AB - Analysis of circulating tumor cells (CTC) holds promise of providing liquid biopsies from patients with cancer. However, current methods include enrichment procedures. We present a method (CytoTrack), where CTC from 7.5 mL of blood is stained, analyzed and counted by a scanning fluorescence microscope. The method was validated by breast cancer cells (MCF-7) spiked in blood from healthy donors. The number of cells spiked in each blood sample was exactly determined by cell sorter and performed in three series of three samples spiked with 10, 33 or 100 cells in addition with three control samples for each series. The recovery rate of 10, 33 and 100 tumor cells in a blood sample was 55%, 70% and 78%, percent coefficient of variation (CV%) for samples was 59%, 32% and 18%, respectively. None of the control samples contained CTC. In conclusion, the method has been validated to highly sensitively detect breast cancer cells in spiking experiments and should be tested on blood samples from breast cancer patients. The method could benefit from automation that could reduce the CV%, and further optimization of the procedure to increase the recovery. PMID- 24164623 TI - Transthyretin aggregate-specific antibodies recognize cryptic epitopes on patient derived amyloid fibrils. AB - Amyloidosis involves the extracellular deposition of proteinaceous amyloid fibrils and accessory molecules in organ(s) and/or tissue(s), and is associated with a host of human diseases, including Alzheimer disease, diabetes, and heart disease. Unfortunately, the amyloidoses are currently incurable, and there is an urgent need for less invasive diagnostics. To address this, we have generated 22 monoclonal antibodies (mAbs) against aggregates formed by a blood transport protein, transthyretin (TTR), which primarily forms amyloid fibrils in a patient's heart and/or peripheral nerves. Four of the mAbs, 2T5C9, 2G9C, T1F11, and TB2H7, demonstrated diagnostic potential in enzyme-linked immunosorbent assays (ELISA) by their low to sub-nanomolar cross-reactivity with recombinant wild-type (WT) and mutant TTR aggregates and lack of binding to native TTR or amyloid fibrils formed by other peptides or proteins. Notably, in the presence of normal human sera, three of the four mAbs, 2T5C9, 2G9C, and T1F11, retained low nM binding to TTR amyloid fibrils derived from two patients with familial amyloidotic polyneuropathy (FAP). The two most promising mAbs, 2T5C9 and 2G9C, were also shown by immunohistochemistry to have low nM binding to TTR amyloid deposits in cardiac tissue sections from two FAP patients. Taken together, these findings strongly support further investigations on the diagnostic utility of TTR aggregate specific mAbs for patients with TTR amyloidoses. PMID- 24164624 TI - Parallel invasions produce heterogenous patterns of life history adaptation: rapid divergence in an invasive insect. AB - Biotic invasions provide a natural experiment in evolution: when invasive species colonize new ranges, they may evolve new clines in traits in response to environmental gradients. Yet it is not clear how rapidly such patterns can evolve and whether they are consistent between regions. We compare four populations of the invasive cabbage white butterfly (Pieris rapae) from North America and Japan, independently colonized by P. rapae 150 years ago and 300 years ago, respectively. On each continent, we employed a northern and southern population to compare the effects of latitude on body mass, development rate and immune function. For each population, we used a split-sibling family design in which siblings were reared at either warm (26.7 degrees C) or cool (20 degrees C) temperatures to determine reaction norms for each trait. Latitudinal patterns in development time were similar between the two continents. In contrast, there were strong geographical differences in reaction norms for body size, but no consistent effects of latitude; there were no detectable effects of latitude or continent on immune function. These results imply that some life history traits respond consistently to selection along climatic gradients, whereas other traits may respond to local environmental factors, or not at all. PMID- 24164625 TI - Typology of religiosity/spirituality in relation to perceived health, depression, and life satisfaction among older Korean immigrants. AB - OBJECTIVES: The objectives of this study were (1) to identify distinct subtypes of older Korean immigrants based on their levels of religiosity/spirituality (R/S) and (2) to determine if the identified subtypes differed by demographic characteristics, perceived health, depression, and life satisfaction. METHOD: Factor mixture models were evaluated with a nonprobability sample of older Korean immigrants (N=200) residing in the New York City area in 2009 to classify typologies of R/S. Multiple regression was used to test the associations between the R/S subtypes and outcomes (perceived health, depression, and life satisfaction) while controlling for demographics. RESULTS: Two substantively distinct latent profiles were identified: normally religious/spiritual ('average R/S') and minimally religious/spiritual ('low R/S'). The average R/S subgroup (74.4%) showed higher means than those in the low R/S subgroup (25.6%) on all six R/S class indicators. Subtypes did not differ on age, education, income, marital status, living arrangements, or years in the USA. However, males were more likely than females to be 'average R/S.' The 'average R/S' subtype had significantly greater life satisfaction than their 'low R/S' counterpart. No differences between the two subtypes were found on perceived health or depression. CONCLUSION: Findings highlight the importance of the classifications of R/S for mental health outcomes, and they indicate that relationships among R/S, various demographic characteristics, and physical/mental health are complex. Future research should validate and refine this classification of R/S in order to help identify particular sources of health risks/behaviors, relevant treatments, and health-promoting interventions within homogenous subtypes of older Korean immigrants. PMID- 24164626 TI - Quantitative profiling and pattern analysis of triacylglycerol species in Arabidopsis seeds by electrospray ionization mass spectrometry. AB - Plant triacylglycerols (TAGs), or vegetable oils, provide approximately 25% of dietary calories to humans and are becoming an increasingly important source of renewable bioenergy and industrial feedstocks. TAGs are assembled by multiple enzymes in the endoplasmic reticulum from building blocks that include an invariable glycerol backbone and variable fatty acyl chains. It remains a challenge to elucidate the mechanism of synthesis of hundreds of different TAG species in planta. One reason is the lack of an efficient analytical approach quantifying individual molecular species. Here we report a rapid and quantitative TAG profiling approach for Arabidopsis seeds based on electrospray ionization tandem mass spectrometry with direct infusion and multiple neutral loss scans. The levels of 93 TAG molecular species, identified by their acyl components, were determined in Arabidopsis seeds. Quantitative TAG pattern analyses revealed that the TAG assembly machinery preferentially produces TAGs with one elongated fatty acid. The importance of the selectivity in oil synthesis was consistent with an observation that an Arabidopsis mutant overexpressing a patatin-like phospholipase had enhanced seed oil content with elongated fatty acids. This quantitative TAG profiling approach should facilitate investigations aimed at understanding the biochemical mechanisms of TAG metabolism in plants. PMID- 24164628 TI - Adenosine A2A receptor as a drug discovery target. AB - The adenosine A2A receptor is a G-protein-coupled receptor (GPCR) that has been extensively studied during the past few decades because it offers numerous possibilities for therapeutic applications. Herein we describe adenosine A2A receptor distribution, signaling pathways, pharmacology, and molecular structure, followed by a summary and SAR discussion of the most relevant series of adenosine A2A agonists and antagonists. This review also provides an update of the A2A ligands that are undergoing or have undergone clinical studies, including the two currently marketed agonists adenosine and regadenoson. PMID- 24164627 TI - Subtype diversity and reassortment potential for co-circulating avian influenza viruses at a diversity hot spot. AB - Biological diversity has long been used to measure ecological health. While evidence exists from many ecosystems that declines in host biodiversity may lead to greater risk of disease emergence, the role of pathogen diversity in the emergence process remains poorly understood. Particularly, because a more diverse pool of pathogen types provides more ways in which evolutionary innovations may arise, we suggest that host-pathogen systems with high pathogen diversity are more prone to disease emergence than systems with relatively homogeneous pathogen communities. We call this prediction the diversity-emergence hypothesis. To show how this hypothesis could be tested, we studied a system comprised of North American shorebirds and their associated low-pathogenicity avian influenza (LPAI) viruses. These viruses are important as a potential source of genetic innovations in influenza. A theoretical contribution of this study is an expression predicting the rate of viral subtype reassortment to be proportional to both prevalence and Simpson's Index, a formula that has been used traditionally to quantify biodiversity. We then estimated prevalence and subtype diversity in host species at Delaware Bay, a North American AIV hotspot, and used our model to extrapolate from these data. We estimated that 4 to 39 virus subtypes circulated at Delaware Bay each year between 2000 and 2008, and that surveillance coverage (percentage of co-circulating subtypes collected) at Delaware Bay is only about 63.0%. Simpson's Index in the same period varied more than fourfold from 0.22 to 0.93. These measurements together with the model provide an indirect, model-based estimate of the reassortment rate. A proper test of the diversity-emergence hypothesis would require these results to be joined to independent and reliable estimates of reassortment, perhaps obtained through molecular surveillance. These results suggest both that subtype diversity (and therefore reassortment) varies from year to year and that several subtypes contributing to reassortment are going undetected. The similarity between these results and more detailed studies of one host, ruddy turnstone (Arenaria interpres), further suggests that this species may be the primary host for influenza reassortment at Delaware Bay. Biological diversity has long been quantified using Simpson's Index. Our model links this formula to a mechanistic account of reassortment in multipathogen systems in the form of subtype diversity at Delaware Bay, USA. As a theory of how pathogen diversity may influence the evolution of novel pathogens, this work is a contribution to the larger project of understanding the connections between biodiversity and disease. PMID- 24164631 TI - An azophenine radical-bridged Fe2 single-molecule magnet with record magnetic exchange coupling. AB - One-electron reduction of the complex [(TPyA)2Fe(II)2((NPh)L(2-))](2+) (TPyA = tris(2-pyridylmethyl)amine, (NPh)LH2 = azophenine = N,N',N",N'''-tetraphenyl-2,5 diamino-1,4-diiminobenzoquinone) affords the complex [(TPyA)2Fe(II)2((NPh)L(3 *))](+). X-ray diffraction and Mossbauer spectroscopy confirm that the reduction occurs on (NPh)L(2-) to give an S = 1/2 radical bridging ligand. Dc magnetic susceptibility measurements demonstrate the presence of extremely strong direct antiferromagnetic exchange between S = 2 Fe(II) centers and (NPh)L(3-*) in the reduced complex, giving an S = 7/2 ground state with an estimated coupling constant magnitude of |J| >= 900 cm(-1). Mossbauer spectroscopy and ac magnetic susceptibility reveal that this complex behaves as a single-molecule magnet with a spin relaxation barrier of U(eff) = 50(1) cm(-1). To our knowledge, this complex exhibits by far the strongest magnetic exchange coupling ever to be observed in a single-molecule magnet. PMID- 24164629 TI - Improving oral implant osseointegration in a murine model via Wnt signal amplification. AB - AIM: To determine the key biological events occurring during implant failure and then we use this knowledge to develop new biology-based strategies that improve osseointegration. MATERIALS AND METHODS: Wild-type and Axin2(LacZ/LacZ) adult male mice underwent oral implant placement, with and without primary stability. Peri-implant tissues were evaluated using histology, alkaline phosphatase (ALP) activity, tartrate resistant acid phosphatase (TRAP) activity and TUNEL staining. In addition, mineralization sites, collagenous matrix organization and the expression of bone markers in the peri-implant tissues were assessed. RESULTS: Maxillary implants lacking primary stability show histological evidence of persistent fibrous encapsulation and mobility, which recapitulates the clinical problems of implant failure. Despite histological and molecular evidence of fibrous encapsulation, osteoblasts in the gap interface exhibit robust ALP activity. This mineralization activity is counteracted by osteoclast activity that resorbs any new bony matrix and consequently, the fibrous encapsulation remains. Using a genetic mouse model, we show that implants lacking primary stability undergo osseointegration, provided that Wnt signalling is amplified. CONCLUSIONS: In a mouse model of oral implant failure caused by a lack of primary stability, we find evidence of active mineralization. This mineralization, however, is outpaced by robust bone resorption, which culminates in persistent fibrous encapsulation of the implant. Fibrous encapsulation can be prevented and osseointegration assured if Wnt signalling is elevated at the time of implant placement. PMID- 24164630 TI - Voltammetric microwell array for oxidized guanosine in intact ds-DNA. AB - Oxidative stress in humans causes damage to biomolecules by generating reactive oxygen species (ROS). DNA can be oxidatively damaged by ROS, which may lead to carcinogenesis. Here we report a microfluidic electrochemical array designed to rapidly detect oxidation in intact DNA in replicate measurements. Sensor arrays were fabricated by wet-chemistry patterning of gold compact discs. The eight sensor array is incorporated into a 60 MUL microfluidic channel connected to a pump and sample valve. The array features 7 nm thick osmium bipyridyl poly(vinylpyridine) chloride [Os(bpy)2(PVP)10Cl](+) films assembled layer-by layer with polyions onto the gold sensors. 8-Hydroxy-7,8-hydro-2'-deoxyguanosine (8-oxodG) is selectively oxidized by [Os(bpy)2(PVP)10Cl](+) in intact ds-DNA to provide catalytic square wave voltammograms (SWV). The device is easy-to-use, fast, inexpensive, reusable, and can detect one 8-oxodG per 6600 nucleobases. The mass detection limit is 150-fold lower than a previously reported dip-and-read voltammetric sensor for oxidized DNA. Fast assays (<1 min) and moderate sample consumption (15 pmol DNA) suggest potential for research and clinical applications. Practical use is illustrated by detecting DNA oxidation from cigarette smoke and ash extracts in dispersions with NADPH and Cu(2+). PMID- 24164632 TI - Effect of midazolam on cardiopulmonary function during colonoscopy with conscious sedation. AB - BACKGROUND AND AIM: Conscious sedation of patients with midazolam reduces anxiety and pain and improves colonoscopy success rates. However, it may lead to adverse effects such as hypoxia and hypotension. The present study investigated the effects of midazolam on cardiopulmonary function during colonoscopy with conscious sedation. METHODS: Between January 2011 and September 2011, 126 consecutive patients undergoing colonoscopy were enrolled and divided into two groups: (i) sedation with midazolam (midazolam group, n=65); and (ii) no sedation (control group, n=61). Systolic blood pressure (SBP), diastolic blood pressure (DBP), heart rate (HR), and peripheral oxygen saturation (SpO(2) ), were recorded before, during and after the endoscopic procedure. RESULTS: In the midazolam group, SBP and DBP decreased more during colonoscopy than in the control group. However, the frequency of a significant change in SBP was similar in both groups. During colonoscopy, HR and SpO(2) decreased significantly in the midazolam group compared to those in the control group. SpO(2) levels returned to normal after the procedure. CONCLUSIONS: Midazolam induced decreases in SBP, DBP, HR and SpO(2) during colonoscopy. Clinically significant changes in SBP, HR, and SpO(2) , however, were similar in the midazolam and control groups. These results suggest that midazolam has a tolerable effect on cardiopulmonary function and may be safely used during colonoscopy. PMID- 24164633 TI - Prevalence rates of sexual difficulties and associated distress in heterosexual men and women: results from an Internet survey in Flanders. AB - As most epidemiological surveys on sexual problems have not included assessment of associated distress, the principal aim of this study was to provide prevalence estimates of both DSM-IV-TR-defined (American Psychiatric Association [APA], 2000 ) and less commonly assessed sexual difficulties and dysfunction (e.g., lack of responsive sexual desire, lack of subjective arousal). A secondary aim was to obtain information about comorbidity between sexual desire and sexual arousal difficulties/dysfunction. This study comprised an online survey completed by 35,132 heterosexual Flemish men and women (aged 16 to 74 years). Results indicated that sexual dysfunctions were far less common than sexual difficulties, and some uncommonly assessed sexual problems (e.g., "lack of responsive desire" in women; "hyperactive sexual desire" in men) were quite prevalent. In women, there was a high comorbidity between "lack of spontaneous sexual desire" and "lack of responsive sexual desire"; between "lack of genital arousal" and "lack of subjective sexual arousal"; and between sexual desire and sexual arousal difficulties/dysfunctions. The implications of these findings for epidemiological research on sexual dysfunction and for the newly defined DSM-5 Female Sexual Interest/Arousal Disorder (APA, 2013 ) are discussed. PMID- 24164634 TI - Specificity of learning a sport skill to the visual condition of acquisition. AB - The authors' main purpose was to determine whether learning of a real-world sport skill (basketball free throws) is specific to the sources of afferent visual information available during practice. Twenty-eight male high school students (inexperienced in the experimental task) were randomly assigned to a full vision or target only vision group. Participants trained under full vision or target only condition for 15 sessions. Following training, in immediate tests, they were examined under full vision and then under target only conditions. Ten days later, in delayed tests, they performed the task under full vision and then under target only conditions. Results showed both groups performed the task similarly across the experimental period. Interestingly, it was found that immediate and delayed retention performance is specific to the training visual context. The groups' performances dropped significantly when we tested them at a visual condition that differed from what they had experienced while learning the task. Performance of the task seemed to have integrated with the visual information available during the task acquisition. These findings provide evidence for the specificity of practice hypothesis in the field of motor learning and control. PMID- 24164635 TI - TMS reveals a direct influence of spinal projections from human SMAp on precise force production. AB - The corticospinal (CS) system plays an important role in fine motor control, especially in precision grip tasks. Although the primary motor cortex (M1) is the main source of the CS projections, other projections have been found, especially from the supplementary motor area proper (SMAp). To study the characteristics of these CS projections from SMAp, we compared muscle responses of an intrinsic hand muscle (FDI) evoked by stimulation of human M1 and SMAp during an isometric static low-force control task. Subjects were instructed to maintain a small cursor on a target force curve by applying a pressure with their right precision grip on a force sensor. Neuronavigated transcranial magnetic stimulation was used to stimulate either left M1 or left SMAp with equal induced electric field values at the defined cortical targets. The results show that the SMAp stimulation evokes reproducible muscle responses with similar latencies and amplitudes as M1 stimulation, and with a clear and significant shorter silent period. These results suggest that (i) CS projections from human SMAp are as rapid and efficient as those from M1, (ii) CS projections from SMAp are directly involved in control of the excitability of spinal motoneurons and (iii) SMAp has a different intracortical inhibitory circuitry. We conclude that human SMAp and M1 both have direct influence on force production during fine manual motor tasks. PMID- 24164636 TI - Global benchmarking of medical student learning outcomes? Implementation and pilot results of the International Foundations of Medicine Clinical Sciences Exam at The University of Queensland, Australia. AB - OBJECTIVE: To report pilot results for international benchmarking of learning outcomes among 426 final year medical students at the University of Queensland (UQ), Australia. METHODS: Students took the International Foundations of Medicine (IFOM) Clinical Sciences Exam (CSE) developed by the National Board of Medical Examiners, USA, as a required formative assessment. IFOM CSE comprises 160 multiple-choice questions in medicine, surgery, obstetrics, paediatrics and mental health, taken over 4.5 hours. OUTCOMES: Significant implementation issues; IFOM scores and benchmarking with International Comparison Group (ICG) scores and United States Medical Licensing Exam (USMLE) Step 2 Clinical Knowledge (CK) scores; and correlation with UQ medical degree cumulative grade point average (GPA). RESULTS: Implementation as an online exam, under university-mandated conditions was successful. Mean IFOM score was 531.3 (maximum 779-minimum 200). The UQ cohort performed better (31% scored below 500) than the ICG (55% below 500). However 49% of the UQ cohort did not meet the USMLE Step 2 CK minimum score. Correlation between IFOM scores and UQ cumulative GPA was reasonable at 0.552 (p < 0.001). CONCLUSIONS: International benchmarking is feasible and provides a variety of useful benchmarking opportunities. PMID- 24164637 TI - gadA gene locus in Lactobacillus brevis NCL912 and its expression during fed batch fermentation. AB - Normally, Lactobacillus brevis has two glutamate decarboxylase (GAD) genes; gadA and gadB. Using PCR, we cloned the gadA gene from L. brevis strain NCL912, a high yield strain for the production of gamma-aminobutyric acid (GABA). However, despite using 61 different primer pairs, including degenerate primers from conserved regions, we were unable to use PCR to clone gadB from the NCL912 strain. Furthermore, we could not clone it by genomic walking over 3000 bp downstream of the aldo-keto reductase gene, a single-copy gene that is located 1003 bp upstream of gadB in L. brevis ATCC367. Altogether, the data suggest that L. brevis NCL912 does not contain a gadB gene. By genomic walking, we cloned regions upstream and downstream of the gadA gene to obtain a 4615 bp DNA fragment that included the complete gadA locus. The locus contained the GAD gene (gadA) and the glutamate:GABA antiporter gene (gadC), which appear to be transcribed in an operon (gadCA), and a transcriptional regulator (gadR) of gadCA. During whole fed-batch fermentation, the expression of gadR, gadC and gadA was synchronized and correlated well with GABA production. The gadA locus we cloned from NCL912 has reduced homology compared with gadA loci of other L. brevis strains, and these differences might explain the ability of NCL912 to produce higher levels of GABA in culture. PMID- 24164638 TI - Two different avipoxviruses associated with pox disease in Magellanic penguins (Spheniscus magellanicus) along the Brazilian coast. AB - A novel avipoxvirus caused diphtheritic lesions in the oesophagus of five and in the bronchioli of four Magellanic penguins (Spheniscus magellanicus) and also cutaneous lesions in eight Magellanic penguins housed in outdoor enclosures in a Rehabilitation Centre at Florianopolis, Santa Catarina State, Brazil. At the same time, another avipoxvirus strain caused cutaneous lesions in three Magellanic penguins at a geographically distinct Rehabilitation Centre localized at Vila Velha, Espirito Santo State, Brazil. Diagnosis was based on clinical signs, histopathology and use of the polymerase chain reaction (PCR). Clinical signs in the penguins included cutaneous papules and nodules around eyelids and beaks, depression and restriction in weight gain. The most common gross lesions were severely congested and haemorrhagic lungs, splenomegaly and cardiomegaly. Histological examination revealed Bollinger inclusion bodies in cutaneous lesions, mild to severe bronchopneumonia, moderate periportal lymphocytic hepatitis, splenic lymphopenia and lymphocytolysis. Other frequent findings included necrotizing splenitis, enteritis, oesophagitis, dermatitis and airsacculitis. Cytoplasmic inclusion bodies were seen within oesophageal epithelial cells in five birds and in epithelial cells of the bronchioli in four penguins. DNA from all samples was amplified from skin tissue by PCR using P4b targeting primers already described in the literature for avipoxvirus. The sequences showed two different virus strains belonging to the genus Avipoxvirus of the Chordopoxvirinae subfamily, one being divergent from the penguinpox and avipoxviruses already described in Magellanic penguins in Patagonia, but segregating within a clade of canarypox-like viruses implicated in diphtheritic and respiratory disease. PMID- 24164639 TI - Is excess male infant mortality from sudden infant death syndrome and other respiratory diseases X-linked? AB - AIM: Male excess infant mortality is well known but unexplained. In 2004, we reported sudden infant death syndrome (SIDS) and other infant respiratory deaths showed a ~50% male excess in the United States between 1979 and 2002. This study analyses expanded US data from 1968 to 2010 to see whether infant respiratory deaths still show similar ~50% male excess and may be X-linked. METHODS: The analysis compared infant mortality data from the US Centers for Disease Control and Prevention, 1968-2010, with 11 World Health Organization International Classification of Diseases (ICD) rubric groups for respiratory deaths by accidents, congenital anomalies, respiratory diseases and causes unknown. RESULTS: The 11 ICD groupings presented male excesses of ~50% and combining the 453,953 US cases produced a male fraction of 0.6034, a 52.1% male excess. A further 72,380 non-US respiratory cases showed a similar 0.6055 male fraction, a 53.5% male excess. CONCLUSION: The constant ~50% male excess for quite different causes of respiratory death suggests they all have a common terminal event and that is acute anoxic encephalopathy. We hypothesise that this constant male excess phenomenon must be caused by a single X-linked gene, with a recessive condition, leading to a predisposition to succumb to acute anoxic encephalopathy. PMID- 24164640 TI - Three-dimensional echocardiographic optimization improves outcome in cardiac resynchronization therapy compared to ECG optimization: a randomized comparison. AB - AIMS: There is little consensus on optimal atrioventricular (AV) and ventricular to-ventricular (VV) intervals in cardiac resynchronization therapy (CRT). The aim of this study was to examine a novel combination of Doppler echocardiography (DE) and three-dimensional echocardiography (3DE) for individualized AV- and VV interval optimization compared to conventional electrocardiogram (ECG) optimization. METHODS: In this double-blind, randomized controlled trial, 77 patients (male: 57, age: 68 +/- 10 years) with severely reduced ejection fraction (EF), New York Heart Association (NYHA) class III or IV, and wide QRS complex (>120 ms) have been included. Patients were randomized to either AV- and VV interval optimization using DE and 3DE (group 1, n = 39) or ECG (group 2, n = 38). 3DE was performed in all patients for the evaluation of left ventricular (LV) dimensions, EF and systolic dyssynchrony index (SDI), and NYHA class obtained before CRT and after 3 months. Primary endpoint of the study was clinical response to CRT, defined as a reduction of NYHA class by >=1 score. Secondary endpoints were change of EF, LV volumes, and SDI. RESULTS: There were significantly more responders in group 1 (82%) than in group 2 (58%, P = 0.021). Similarly, group 1 showed a larger increase in EF (7.0 +/- 6.0% vs 3.4 +/- 5.6%, P = 0.015) and a more pronounced reduction of SDI (-4.5 +/- 5.9% vs -1.5 +/- 5.6%, P = 0.039) than group 2. CONCLUSION: Compared with conventional ECG optimization, this novel echocardiographic optimization protocol resulted in a significantly higher response rate, improved LV systolic function, and may be used to select the optimal AV and VV intervals in CRT. PMID- 24164641 TI - Hybrid transparent conductive film on flexible glass formed by hot-pressing graphene on a silver nanowire mesh. AB - Polycrystalline graphene and metallic nanowires (NWs) have been proposed to replace indium tin oxide (ITO), the most widely used transparent electrode (TE) film on the market. However, the trade-off between optical transparency (Topt) and electrical sheet resistance (Rs) of these materials taken alone makes them difficult to compete with ITO. In this paper, we show that, by hot-press transfer of graphene monolayer on Ag NWs, the resulting combined structure benefits from the synergy of the two materials, giving a Topt-Rs trade-off better than that expected by simply adding the single material contributions Ag NWs bridge any interruption in transferred graphene, while graphene lowers the contact resistance among neighboring NWs and provides local conductivity in the uncovered regions in-between NWs. The hot-pressing not only allows graphene transfer but also compacts the NWs joints, thus reducing contact resistance. The dependence on the initial NW concentration of the effects produced by the hot press process on its own and the graphene transfer using hot press was investigated and indicates that a low concentration is more suitable for the proposed geometry. A TE film with Topt of 90% and Rs of 14 Omega/sq is demonstrated, also on a flexible glass substrate about 140 MUm thick, a very attractive platform for efficient flexible electronic and photonic devices. PMID- 24164642 TI - Interspecific patterns of phenotypic selection do not predict intraspecific patterns. AB - We estimated linear (beta) and nonlinear (gamma) selection gradients to quantify host plant-mediated selection on the trait gall size in each of 22 unequally sampled subpopulations of the cynipid gall wasp Belonocnema treatae. We characterized the relationship between variation in subpopulation sample size and the magnitude of and the variance among selection gradients. We then tested the hypothesis that the intraspecific patterns we observed would follow two patterns that have emerged from published estimates of linear and nonlinear selection gradients compiled across species, namely that the average magnitude of beta and gamma and the variance among estimated beta and gamma decrease with increasing sample size. For both beta and gamma, intraspecific patterns of phenotypic selection in relation to sample size were not predicted by interspecific patterns. Thus, our results suggest that when selection is heterogeneous among subpopulations, variation in the biological basis for selection is more important in influencing estimates of selection than is variation in study size. Our study highlights the value of inspecting selection in relation to sampling effort at the level at which understanding the sources of variation in selection is most important, among populations within species. PMID- 24164643 TI - Laparoscopic radical prostatectomy demonstrates less morbidity than open radical prostatectomy: an analysis of the American College of Surgeons-National Surgical Quality Improvement Program database with a focus on surgical trainee involvement. AB - INTRODUCTION: Complication rates of open radical prostatectomies (ORPs) and laparoscopic radical prostatectomies (LRPs) performed by highly experienced surgeons in centers of excellence are well known. Using a standardized, national, risk-adjusted surgical database, we compared 30-day outcomes following ORP and LRP and analyzed how trainee involvement influenced outcomes. METHODS: The American College of Surgeons-National Surgical Quality Improvement Program (ACS NSQIP) is a risk-adjusted data collection analyzing preoperative risk factors, demographics, and 30-day postoperative outcomes. From 2005 to 2011, we identified 10,669 total prostatectomies. Of these, 2278 were ORP and 8391 were LRP. Data on trainee involvement were available on 63% of cases. RESULTS: Comparison of all 10,669 prostatectomies showed a decreased incidence of overall morbidity, serious morbidity, surgical site infections, mortality, wound disruption, urinary tract infection, bleeding, and sepsis or septic shock (p<0.05) for LRP compared with ORP. Trainee involvement was associated with a higher incidence of bleeding, overall and serious morbidity (p<0.001). This difference is isolated to postgraduate year (PGY) 6-10 trainees performing ORP (p<0.001). Overall and serious morbidity was equivalent between PGY groups 1-10 versus attending without trainee performing LRP and PGY groups 1-5 versus attending without trainee performing ORP. Operative times were shorter for ORP versus LRP by an average of 38 minutes (p<0.05), and in cases involving trainees, operative times decreased with trainee experience for both procedures. The length of stay was shorter for LRP compared with ORP (3.2 vs. 1.8 days, p<0.001). CONCLUSIONS: The large sample size, standardized data definitions, and quality control measures of the ACS NSQIP database allow for in-depth analysis of subtle, but significant differences in outcomes between groups. Trainee involvement in LRP appears safe to patients. However, the increased morbidity in ORP involving trainees may be mitigated by awareness, simulation laboratories, and standardized competency assessment. PMID- 24164644 TI - Inhibitory effect of co-administration of atorvastatin and endothelin-1 receptor antagonist on the progression of atherosclerosis in rabbit. AB - Atorvastatin, a hydroxymethylglutaryl-CoA reductase inhibitor, and endothelin-1 (ET-1) receptor antagonist have been separately indicated to ameliorate disease progression in atherosclerosis. However, no study has evaluated the effect of their combination on atherosclerosis. The objective of the current study was to evaluate the direct in vivo effects of a combination regimen of atorvastatin and ET-1 receptor antagonist on male New Zealand white rabbit models of atherosclerosis (injury-induced). Thirty-two atherosclerotic rabbits were divided into four experimental groups: (a) injury group - fed high-fat diet; (b) ET-1 receptor antagonist preventive group - fed high-fat diet, but with intragastric administration of the ET-1 receptor antagonist, darusentan; (c) combined preventive group - fed high-fat diet, but with intragastric administration of both darusentan and atorvastatin; and (d) treatment group - fed high-fat diet for the first 8 weeks, followed by normal diet and intragastric administration of both darusentan and atorvastatin up to 16 weeks. A further eight non atherosclerotic rabbits were fed normal diet and classified as the control group. At the end of 8 and 16 weeks, compared with the injury group, the combined preventive group had significant reduction in both the concentration of serum lipids and inflammatory factors and atherosclerosis formation, indicative of a multifaceted anti-atherosclerotic impact. The relative area of atherosclerotic lesions in the injury group (30.84%) was significantly higher than the control group (4.62%; p < 0.05). The combined preventive group showed a significantly robust effect on lowering serum lipid, inflammatory cytokines, and maintained homeostatic balance of free radicals, and important downstream effectors like ET 1 and matrixmetalloproteinase-9. Our data show that atorvastatin and ET-1 receptor antagonist co-administration may decrease lipid levels, stabilize plaques and relieve vascular inflammation. By reducing the plaque burden, this regimen may minimize the risk of atherosclerotic plaque rupture or arterial occlusion. PMID- 24164645 TI - Oral health education and therapy reduces gingivitis during pregnancy. AB - BACKGROUND: Pregnant women demonstrate increases in gingivitis despite similar plaque levels to non-pregnant counterparts. AIM: To evaluate an intensive protocol aimed at reducing gingivitis in pregnant women and provide pilot data for large-scale randomized controlled trials investigating oral hygiene measures to reduce pregnancy gingivitis and alter maternity outcomes. MATERIALS AND METHODS: One hundred and twenty participants between 16 and 24 weeks gestation with Gingival Index (GI) scores >=2 at >=50% of tooth sites were enrolled. Plaque index (PI), gingival inflammation (GI), probing depth (PD), and clinical attachment levels (CAL) were recorded at baseline and 8 weeks. Dental prophylaxis was performed at baseline and oral hygiene instructions at baseline, 4 and 8 weeks. Pregnancy outcomes were recorded at parturition. Mixed-model analysis of variance was used to compare clinical measurements at baseline and 8 weeks. RESULTS: Statistically significant reductions in PI, GI, PD, and CAL occurred over the study period. Mean whole mouth PI and GI scores decreased approximately 50% and the percentage of sites with PI and GI >=2 decreased from 40% to 17% and 53% to 21.8%, respectively. Mean decreases in whole mouth PD and CAL of 0.45 and 0.24 mm, respectively, were seen. CONCLUSIONS: Intensive oral hygiene regimen decreased gingivitis in pregnant patients. PMID- 24164647 TI - On the history of hepatitis C virus cell culture systems. AB - HCV infections are a major global health burden. After the identification of the virus in 1989, insights into viral replication and drug development have long been hampered by the lack of efficient cell culture models. Their establishment was an important prerequisite for the development of selective antivirals. This review describes the initial difficulties to achieve HCV replication in cell culture, finally leading to the establishment of subgenomic replicons and the infectious virus model (HCVcc). The review further summarizes the current state of HCV cell culture systems with respect to available virus isolates, engineered genomes, and cell types allowing efficient HCV propagation. Finally, we comment on how these cell culture models contributed to the development of directly acting antivirals. PMID- 24164648 TI - Case of mumps orchitis after vaccination. AB - We present a case of mumps orchitis after vaccination. A 35-year-old man visited the emergency unit of our hospital for fever and right testicular pain on 7 January 2012. Two weeks before the visit, he underwent vaccination for mumps. After 7 days of hospitalization, the patient recovered from fever and testicular pain. Scrotal magnetic resonance imaging suggested right orchitis, and an increased level of serum mumps immunoglobulin M and immunoglobulin G indicated an initial infection of mumps virus. The peak value of immunoglobulin G showed 106 enzyme immunoassay unit 5 weeks after vaccination, which was 10-fold higher than the ordinary rise of a vaccinated individual. This fact leads to two possibilities. One is this happened as an adverse event of vaccination, and the other is that he actually had a wild-type infection at the same time as vaccination. There are some reports regarding adverse events of mumps vaccine; however, they might include wild-type infection. PMID- 24164649 TI - MADS reloaded: evolution of the AGAMOUS subfamily genes. AB - AGAMOUS subfamily proteins are encoded by MADS-box family genes. They have been shown to play key roles in the determination of reproductive floral organs such as stamens, carpels and ovules. However, they also play key roles in ensuring a fixed number of floral organs by controlling floral meristem determinacy. Recently, an enormous amount of sequence data for nonmodel species have become available together with functional data on AGAMOUS subfamily members in many species. Here, we give a detailed overview of the most important information about this interesting gene subfamily and provide new insights into its evolution. PMID- 24164646 TI - Magic angle spinning NMR reveals sequence-dependent structural plasticity, dynamics, and the spacer peptide 1 conformation in HIV-1 capsid protein assemblies. AB - A key stage in HIV-1 maturation toward an infectious virion requires sequential proteolytic cleavage of the Gag polyprotein leading to the formation of a conical capsid core that encloses the viral RNA genome and a small complement of proteins. The final step of this process involves severing the SP1 peptide from the CA-SP1 maturation intermediate, which triggers the condensation of the CA protein into the capsid shell. The details of the overall mechanism, including the conformation of the SP1 peptide in CA-SP1, are still under intense debate. In this report, we examine tubular assemblies of CA and the CA-SP1 maturation intermediate using magic angle spinning (MAS) NMR spectroscopy. At magnetic fields of 19.9 T and above, outstanding quality 2D and 3D MAS NMR spectra were obtained for tubular CA and CA-SP1 assemblies, permitting resonance assignments for subsequent detailed structural characterization. Dipolar- and scalar-based correlation experiments unequivocally indicate that SP1 peptide is in a random coil conformation and mobile in the assembled CA-SP1. Analysis of two CA protein sequence variants reveals that, unexpectedly, the conformations of the SP1 tail, the functionally important CypA loop, and the loop preceding helix 8 are modulated by residue variations at distal sites. These findings provide support for the role of SP1 as a trigger of the disassembly of the immature CA capsid for its subsequent de novo reassembly into mature cores and establish the importance of sequence-dependent conformational plasticity in CA assembly. PMID- 24164650 TI - Ultralow thermal conductivity of atomic/molecular layer-deposited hybrid organic inorganic zincone thin films. AB - Atomic layer deposition (ALD) and molecular layer deposition (MLD) techniques with atomic level control enable a new class of hybrid organic-inorganic materials with improved functionality. In this work, the cross-plane thermal conductivity and volumetric heat capacity of three types of hybrid organic inorganic zincone thin films enabled by MLD processes and alternate ALD-MLD processes were measured using the frequency-dependent time-domain thermoreflectance method. We revealed the critical role of backbone flexibility in the structural morphology and thermal conductivity of MLD zincone thin films by comparing the thermal conductivity of MLD zincone films with an aliphatic backbone to that with aromatic backbone. Much lower thermal conductivity values were obtained in ALD/MLD-enabled hybrid organic-inorganic zincone thin films compared to that of the ALD-enabled W/Al2O3 nanolaminates reported by Costescu et al. [Science 2004, 303, 989-990], which suggests that the dramatic material difference between organic and inorganic materials may provide a route for producing materials with ultralow thermal conductivity. PMID- 24164651 TI - Pollen mixing in pollen generalist solitary bees: a possible strategy to complement or mitigate unfavourable pollen properties? AB - Generalist herbivorous insects, which feed on plant tissue that is nutritionally heterogeneous or varies in its content of secondary metabolites, often benefit from dietary mixing through more balanced nutrient intake or reduced exposure to harmful secondary metabolites. Pollen is similarly heterogeneous as other plant tissue in its content of primary and secondary metabolites, suggesting that providing their offspring with mixed pollen diets might be a promising strategy for pollen generalist bees to complement nutrient imbalances or to mitigate harmful secondary metabolites of unfavourable pollen. In the present study, we compared larval performance of the pollen generalist solitary bee species Osmia cornuta (Megachilidae) on five experimental pollen diets that consisted of different proportions of unfavourable pollen diet of Ranunculus acris (Ranunculaceae) and favourable pollen diet of Sinapis arvensis (Brassicaceae). In addition, we microscopically analysed the pollen contained in the scopal brushes of field-collected females of O. cornuta and three closely related species to elucidate to what degree these pollen generalist bees mix pollen of different hosts in their brood cells. In striking contrast to a pure Ranunculus pollen diet, which had a lethal effect on most developing larvae of O. cornuta, larval survival, larval development time and adult body mass of both males and females remained nearly unaffected by the admixture of up to 50% of Ranunculus pollen diet to the larval food. Between 42% and 66% of all female scopal pollen loads analysed contained mixtures of pollen from two to six plant families, indicating that pollen mixing is a common behaviour in O. cornuta and the three related bee species. The present study provides the first evidence that the larvae of pollen generalist bees can benefit from the nutrient content of unfavourable pollen without being negatively affected by its unfavourable chemical properties if such pollen is mixed with favourable pollen. We conclude that the widespread pollen mixing by females of pollen generalist bees should also be considered as a possible strategy to exploit flowers with unfavourable pollen and to optimize larval food quality. PMID- 24164652 TI - Wheat syntenome unveils new evidences of contrasted evolutionary plasticity between paleo- and neoduplicated subgenomes. AB - Bread wheat derives from a grass ancestor structured in seven protochromosomes followed by a paleotetraploidization to reach a 12 chromosomes intermediate and a neohexaploidization (involving subgenomes A, B and D) event that finally shaped the 21 modern chromosomes. Insights into wheat syntenome in sequencing conserved orthologous set (COS) genes unravelled differences in genomic structure (such as gene conservation and diversity) and genetical landscape (such as recombination pattern) between ancestral as well as recent duplicated blocks. Contrasted evolutionary plasticity is observed where the B subgenome appears more sensitive (i.e. plastic) in contrast to A as dominant (i.e. stable) in response to the neotetraploidization and D subgenome as supra-dominant (i.e. pivotal) in response to the neohexaploidization event. Finally, the wheat syntenome, delivered through a public web interface PlantSyntenyViewer at http://urgi.versailles.inra.fr/synteny-wheat, can be considered as a guide for accelerated dissection of major agronomical traits in wheat. PMID- 24164653 TI - Adaptive and non-adaptive changes in activity-deprived presynaptic terminals. AB - How the number of docked vesicles is regulated is still unclear. Following chronic activity blockade the number of docked vesicles increases, providing a model through which to address this issue. We tested the hypotheses that the number of docked vesicles is regulated with the size of the terminal, and by the level of Rab3-interacting molecule 1/2 (RIM1/2). We immobilized mouse hippocampal slice cultures by high-pressure freezing after 3 days of tetrodotoxin treatment and analysed them by electron microscopy. The number of docked vesicles, the size of the active zones and the amount of GluA2 were increased after activity blockade. However, there was no modification of either the total number of synaptic vesicles or the area of presynaptic profiles. Surprisingly, immunocytochemistry showed no change in the mean level of RIM1/2 per terminal but its distribution was modified. Additionally, there was no modification of the mean frequency or amplitude of miniature excitatory postsynaptic currents, but the distribution of amplitudes was modified. These results indicate a specific homeostatic regulation of the synaptic junction. The number of docked vesicles does not seem to be regulated by the amount of RIM1/2. The modification of the distribution, but not the amount, of RIM1/2 may explain the contradiction between the morphological and electrophysiological findings. PMID- 24164654 TI - Genetic variants of synaptic vesicle and presynaptic plasma membrane proteins in idiopathic generalized epilepsy. AB - BACKGROUND: The aim of this study was to analyze the role of the genetic variants of two synaptic vesicle proteins (VAMP2 and Synaptotagmin XI) and two presynaptic plasma membrane proteins (Syntaxin 1A and SNAP-25) in patients with idiopathic generalized epilepsy (IGE). METHOD: Eighty-five patients with IGE and 93 healthy subjects were included in the study. We analyzed the functional polymorphisms of VAMP2, Synaptotagmin XI, Syntaxin 1A and SNAP-25 genes with polymerase chain reaction and restriction fragment length polymorphism methods. RESULTS: In the patients with IGE, significant differences alleles and genotypes of 26 bp Ins/Del polymorphism of the VAMP2 gene and the 33-bp promoter region of Synaptotagmin XI were observed, however no associaton was found regarding Intron 7 rs1569061 of Syntaxin 1A gene, MnlI rs3746544 and DdeI rs1051312 polymorphisms of SNAP-25 gene compared with healthy subjects. Carriers of the C allele of Synaptotagmin XI had worse measures compared with the T allele of Synaptotagmin XI. In the haplotype analysis, the frequency of the T alleles of rs1569061 and of the C alleles of the 33-bp promoter region of Synaptotagmin XI was found to be significantly higher in patients with IGE as compared with the healthy subjects. CONCLUSION: The genetic variations of VAMP2, Synaptotagmin XI might be indication of the relationship between these genes and IGE. PMID- 24164656 TI - Control of arm movements for quick change of movement direction. AB - The authors investigated the control strategy for changing movement direction during arm movements by analyzing the changes in a triphasic electromyographic pattern. Subjects performed a 40 degrees flexion (basic) and a 40 degrees flexion-extension to return to the start position (return) under two conditions: performing a predetermined task (SF) and performing each task in response to a signal (ST). The results revealed the agonist burst for the return task under the ST condition resembled that of the basic task under the SF condition, and the antagonist burst increased after presenting the modification signal. In conclusion, the strategy for quick change of movement direction was to increase the antagonist burst by an additional command from the central nervous system without cancelling the planned movement. PMID- 24164657 TI - Late development of complete atrioventricular block may be immune mediated and congenital in origin. AB - AIM: To investigate the correlation between maternal autoantibodies and age at diagnosis of isolated complete atrioventricular (AV) block (CAVB) and to study signs of late progression of foetal immune-mediated insults in cases of postnatally diagnosed CAVB. METHODS: Patients with CAVB (n = 190) identified in a population-based manner were included. Maternal autoantibody profile was correlated with age at CAVB diagnosis. A structured review of medical records was performed if a late CAVB diagnosis (>27 days post-partum) was associated with a sero-positive mother. RESULTS: Maternal Ro/La autoantibodies were observed in 88% of cases with a congenital diagnosis. Thirteen cases with a sero-positive mother and late CAVB diagnosis were found (age-range: 4 months-43 years). In two cases, CAVB was diagnosed in conjunction with infections, one case had a family history of cardiomyopathy and two cases had nontypical clinical presentations, indicating alternative pathogenetic mechanisms. In the remaining eight cases, no likely factors inducing CAVB, other than maternal autoantibodies, could be identified. CONCLUSION: Our observations support the hypothesis that late progression to CAVB can be the result of an immune-mediated pathogenetic mechanism during foetal life. An autoantibody-associated diagnosis after the neonatal period is therefore possible, and testing of maternal serology at the time of diagnosis is recommended. PMID- 24164658 TI - Repeated and predictable patterns of ecotypic differentiation during a biological invasion: lake-stream divergence in parapatric Swiss stickleback. AB - The relative importance of ecological selection and geographical isolation in promoting and constraining genetic and phenotypic differentiation among populations is not always obvious. Interacting with divergent selection, restricted opportunity for gene flow may in some cases be as much a cause as a consequence of adaptation, with the latter being a hallmark of ecological speciation. Ecological speciation is well studied in parts of the native range of the three-spined stickleback. Here, we study this process in a recently invaded part of its range. Switzerland was colonized within the past 140 years from at least three different colonization events involving different stickleback lineages. They now occupy diverse habitats, ranging from small streams to the pelagic zone of large lakes. We use replicated systems of parapatric lake and stream populations, some of which trace their origins to different invasive lineages, to ask (i) whether phenotypic divergence occurred among populations inhabiting distinct habitats, (ii) whether trajectories of phenotypic divergence follow predictable parallel patterns and (iii) whether gene flow constrains divergent adaptation or vice versa. We find consistent phenotypic divergence between populations occupying distinct habitats. This involves parallel evolution in several traits with known ecological relevance in independent evolutionary lineages. Adaptive divergence supersedes homogenizing gene flow even at a small spatial scale. We find evidence that adaptive phenotypic divergence places constraints on gene flow over and above that imposed by geographical distance, signalling the early onset of ecological speciation. PMID- 24164659 TI - Surgical treatment for women with breast cancer in relation to socioeconomic and insurance status. AB - Based on the National Breast Cancer Audit of the Royal Australasian College of Surgeons an association between patient age and type of breast cancer surgery received has already been demonstrated. The aim of this study is to assess the patterns of surgical treatment for women with early breast cancer in relation to socioeconomic and insurance status. Data on patient demographics, diagnostic, and surgical procedures and cancer characteristics in 115,872 episodes of early breast cancer reported to the National Breast Cancer Audit between 1998 and 2012 is used for this study. Tumor size, histologic grade, number of tumors, lymph node positivity, and lymphovascular invasion are the major prognostic factors adjusted for. Reconstruction following mastectomy is the most likely surgical procedure for the higher socioeconomic and privately insured patients. Mastectomy alone is the most likely surgical procedure for the lower socioeconomic and for public patients. No surgery is the most likely surgical outcome for the lower socioeconomic and the least likely for the higher socioeconomic population. Open biopsy is the most likely diagnostic procedure for the lower socioeconomic and fine needle aspiration for the higher socioeconomic population. Socioeconomic and insurance status, are both independently associated with the types of treatment and diagnostic procedure for women with breast cancer. Opportunities present to investigate an association of these factors with morbidity and survival outcomes. PMID- 24164660 TI - Metformin inhibits hepatitis B virus protein production and replication in human hepatoma cells. AB - Hepatitis B virus surface antigen (HBsAg) plays an important role in maintaining the tolerance and may interfere with host innate and adaptive immune responses; therefore, novel therapeutic strategies to reduce HBsAg loads in patients infected with hepatitis B virus (HBV) are emerging as an attractive but challenging issue. Metformin could regulate hepatic metabolism while the latter interacts with HBV infection. We hypothesized that metformin could affect HBsAg expression and HBV replication and may work synergistically when combined with current antivirals. In our study, a notably inhibitory effect on HBsAg production, as well as a moderate inhibition in HBV replication and HBeAg expression was observed following metformin treatment. The 50% effective concentration (EC50) for extracellular HBsAg and intracellular HBsAg in HBV producing HepG2.2.15 cells was 2.85 mm and 2.75 mm, respectively, with a similarly selective index of about 18. When administered in combination, metformin enhanced the inhibitory effects of interferon-alpha2b on HBsAg expression and HBV replication and provided a complimentary role in HBsAg expression for lamivudine (LMV). This novel action of metformin derives partially from its inhibition on multiple HBV cis-acting elements. By the virtues of preferably hepatocyte distribution and safety profile, collectively, our results suggest that metformin would be potentially clinically helpful as an HBsAg production inhibitor. PMID- 24164661 TI - Carrier concentration dependent conduction in insulator-doped donor/acceptor chain compounds. AB - On the basis of the concept that the design of a mixed valence system is a key route to create electronic conducting frameworks, we propose a unique idea to rationally produce mixed valency in an ionic donor/acceptor chain (i.e., D(+)A(-) chain). The doping of a redox-inert (insulator) dopant (P) into a D(+)A(-) chain in place of neutral D enables the creation of mixed valency A(0)/A(-) domains between P units: P-(D(+)A(-))nA(0)-P, where n is directly dependent on the dopant ratio, and charge transfer through the P units leads to electron transport along the framework. This hypothesis was experimentally demonstrated in an ionic DA chain synthesized from a redox-active paddlewheel [Ru2(II,II)] complex and TCNQ derivative by doping with a redox-inert [Rh2(II,II)] complex. PMID- 24164662 TI - The Tryton Side Branch StentTM for the treatment of coronary bifurcation lesions. AB - Coronary bifurcation lesions account for approximately 15% of all percutaneous coronary interventions (PCI) performed. Although clinical outcomes after PCI have been improved considerably, PCI of bifurcation lesions remains to be associated with adverse clinical events, when compared with non-bifurcation PCI. Therefore, several dedicated bifurcation devices have been developed to improve clinical outcomes. The Tryton Side Branch Stent(TM) is such device and is used in combination with a regular tubular balloon expandable stent in the main branch. Multiple single and multicenter registries and a patient pooled analysis including 900 patients have shown promising results regarding clinical outcomes after bifurcation PCI with Tryton. The pivotal Tryton IDE randomized trial is currently underway comparing the Tryton stent with side branch balloon angioplasty as side branch treatment in bifurcation lesions challenging the current dogma of provisional single stent strategy as treatment for coronary bifurcation lesions. PMID- 24164663 TI - Clinical data on injectable tissue fillers: a review. AB - Treatment with injectable tissue fillers for aesthetic purposes is increasingly popular. In parallel with this success, questions related to the safety of these treatments and the products involved are being raised more prominently. To gain insight in the safety aspects of injectable tissue fillers, we performed a literature review to collect studies reporting clinical data of injectable tissue fillers. We found several case reports where serious complications after more than three years are described. However, there are only a limited number of well defined prospective clinical studies available with follow-up periods longer than three years. Furthermore, causes of complications, that is, treatment or product related, are often not specified in literature. Considering the intended functional period of fillers in combination with the known occurrence of long term complications, there is a need for well-defined prospective clinical studies. In order to be able to discriminate between product failure (a product safety issue) or application methodology (a physician expertise or training issue), better identification of observed complications and whether they are product or treatment related, is needed. For the safe use of the fillers it is important that treatment with injectable tissue fillers is performed by a trained physician, who knows the product specifications and its applications. PMID- 24164664 TI - Lipoblastoma: an interesting differential of paediatric lipoma. PMID- 24164665 TI - Validation of imputation between equine genotyping arrays. PMID- 24164666 TI - Changes in predator community structure shifts the efficacy of two warning signals in Arctiid moths. AB - Polymorphism in warning coloration is puzzling because positive frequency dependent selection by predators is expected to promote monomorphic warning signals in defended prey. We studied predation on the warning-coloured wood tiger moth (Parasemia plantaginis) by using artificial prey resembling white and yellow male colour morphs in five separate populations with different naturally occurring morph frequencies. We tested whether predation favours one of the colour morphs over the other and whether that is influenced either by local, natural colour morph frequencies or predator community composition. We found that yellow specimens were attacked less than white ones regardless of the local frequency of the morphs indicating frequency-independent selection, but predation did depend on predator community composition: yellows suffered less attacks when Paridae were abundant, whereas whites suffered less attacks when Prunellidae were abundant. Our results suggest that spatial heterogeneity in predator community composition can generate a geographical mosaic of selection facilitating the evolution of polymorphic warning signals. This is the first time this mechanism gains experimental support. Altogether, this study sheds light on the evolution of adaptive coloration in heterogeneous environments. PMID- 24164667 TI - Interfaces in nano-/microcrystalline multigrade CVD diamond coatings. AB - The interfaces of multilayered CVD diamond films grown by the hot-filament technique were characterized with high detail using HRTEM, STEM-EDX, and EELS. The results show that at the transition from micro- (MCD) to nanocrystalline diamond (NCD), a thin precursor graphitic film is formed, irrespectively of the NCD gas chemistry used (with or without argon). On the contrary, the transition of the NCD to MCD grade is free of carbon structures other than diamond, the result of a higher substrate temperature and more abundant atomic H in the gas chemistry. At those transitions WC nanoparticles could be found due to contamination from the filament, being also present at the first interface of the MCD layer with the silicon nitride substrate. PMID- 24164668 TI - Mechanism-based inhibition of HsaD: a C-C bond hydrolase essential for survival of Mycobacterium tuberculosis in macrophage. AB - Mycobacterium tuberculosis remains the leading cause of death by a bacterial pathogen worldwide. Increasing prevalence of multidrug-resistant organisms means prioritizing identification of targets for antituberculars. 2-hydroxy-6-oxo-6 phenylhexa-2,4-dienoate hydrolase (HsaD), part of the cholesterol metabolism operon, is vital for survival within macrophage. The C-C bond hydrolase, HsaD, has a serine protease-like catalytic triad. We tested a range of serine protease and esterase inhibitors for their effects on HsaD activity. As well as providing a potential starting point for drug development, the data provides evidence for the mechanism of C-C bond hydrolysis. This screen also provides a route to initiate development of fragment-based inhibitors. PMID- 24164670 TI - In vitro studies on the role of glycosaminoglycans in crystallization intensity during infectious urinary stones formation. AB - Proteus mirabilis cause urinary tract infections which are recurrent and can lead to formation of urinary calculi. Both bacterial and the host factors are involved in the development of urolithiasis. To determine the impact of glycosaminoglycans (GAGs) in the formation of P. mirabilis-induced urinary stones, we investigated the in vitro crystallization, aggregation and adhesion of crystals in the presence of GAGs naturally appearing in urine. Crystallization experiments were performed in synthetic urine infected with P. mirabilis in the presence of: hyaluronic acid (HA), heparan sulfate (HS), chondroitin sulfate A, B and C (ChSA, ChSB, ChSC). The intensity of crystallization and aggregation were established by counting particles and phase-contrast microscopy. To analyze the adhesion of crystals, we used normal urothelium and (45)Ca isotope-labeled crystals. In the presence of ChSC, both the size of the crystals formed and their number were higher compared with the control. GAGs increased crystals adhesion to the cells, but only for ChSA this effect was significant. Chondroitin sulfates, which accelerate the first stages of infection-induced stones formation, may play an important role in the pathogenesis of infectious urolithiasis. PMID- 24164671 TI - The fate of nontargeted endocardial leads during the extraction of one or more targeted leads in pediatrics and congenital heart disease. AB - INTRODUCTION: Extraction of targeted endocardial leads can lead to inadvertent damage or dislodgement of nontargeted leads, though the frequency of this has not been reported in pediatrics and congenital heart disease (CHD). METHODS: This is a retrospective review of lead extraction procedures from 2002 to 2010 from two pediatric and CHD centers evaluating unplanned interventions on nontargeted leads during the extraction of one or more targeted leads. RESULTS: Nontargeted leads were present in the 22 lead extraction procedures performed on 20 patients with median age 15 years (interquartile range, 11.5-18.5 years): 11 (55%) with structurally normal hearts and nine (45%) with CHD. Twenty of 23 targeted leads (86%) were extracted with complete success. Of the 22 nontargeted leads, including 17 atrial leads and five ventricular leads, seven (32%) required further intervention including: five extracted due to damage, dislodgement, or change in device location; one abandoned due to damage; and one dislodged requiring a second procedure for repositioning. The remaining 15 nontargeted leads (68%) were unharmed. Nontargeted leads requiring further intervention had a shorter lead duration in situ (median 2 years, interquartile range 0.5-3.5 years) than unharmed nontargeted leads (median 6.6 years, interquartile range 4.1-9.1 years; P = 0.01). Age at extraction, CHD, implantable cardioverter defibrillator leads, atrial lead position, or primary extraction modality did not predict further intervention for nontargeted leads. Major complications occurred in one procedure (4.5%) with no deaths. CONCLUSIONS: In pediatrics and CHD, nontargeted leads are frequently damaged or dislodged during the extraction of targeted leads. The risk of lead damage or dislodgement has implications for procedural planning and counseling for patients and families of pediatric and CHD patients requiring lead extraction. PMID- 24164673 TI - Influence of task constraints and device properties on motor patterns in a realistic control situation. AB - The influences of task difficulty (index difficulty: 2-4), input device of different length, range of motion and mode of resistance (joystick or rotorcraft stick), and directions of movement (leftward rightward) on motor patterns in a realistic control situation were examined with a multilevel analysis (joint kinematics and muscular variables, and global task performance). Eight subjects controlled the displacements of a virtual object during a slalom task characterized by a realistic inertial model. Pilots adapted the endpoint kinematic organization to increasing accuracy constraints to preserve task success whatever the device and the direction. However, the rotorcraft stick manipulation remains highly complex in comparison to the joystick due to poorer proprioceptive information, higher inertial constraints, and an asymmetrical muscle control. PMID- 24164672 TI - Precise marker excision system using an animal-derived piggyBac transposon in plants. AB - Accurate and effective positive marker excision is indispensable for the introduction of desired mutations into the plant genome via gene targeting (GT) using a positive/negative counter selection system. In mammals, the moth-derived piggyBac transposon system has been exploited successfully to eliminate a selectable marker from a GT locus without leaving a footprint. Here, we present evidence that the piggyBac transposon also functions in plant cells. To demonstrate the use of the piggyBac transposon for effective marker excision in plants, we designed a transposition assay system that allows the piggyBac transposition to be visualized as emerald luciferase (Eluc) luminescence in rice cells. The Eluc signal derived from piggyBac excision was observed in hyperactive piggyBac transposase-expressing rice calli. Polymerase chain reaction, Southern blot analyses and sequencing revealed the efficient and precise transposition of piggyBac in these calli. Furthermore, we have demonstrated the excision of a selection marker from a reporter locus in T0 plants without concomitant re integration of the transposon and at a high frequency (44.0% of excision events), even in the absence of negative selection. PMID- 24164674 TI - Editorial Comment to Denonvilliers' space expansion by transperineal injection of hydrogel: implications for focal therapy of prostate cancer. PMID- 24164675 TI - Estrogen potentiates the behavioral and nucleus accumbens dopamine response to continuous haloperidol treatment in female rats. AB - Estrogen has been shown to enhance the effects of antipsychotics in humans. To investigate the mechanisms of how this may occur, the current study examined estradiol's effects on dopaminergic transmission and behavior in amphetamine sensitized and non-sensitized female rats. Sixty-four ovariectomized female Sprague-Dawley rats were used for this study. Half of the rats were sensitized to four once-daily injections of 1 mg/kg amphetamine and the other half served as controls. Rats received chronic administration of either low-dose haloperidol (0.25 mg/kg/day) or saline vehicle via osmotic minipumps implanted subcutaneously. The groups were further subdivided with respect to estradiol treatment: low chronic estrogen (subcutaneous estradiol implant, 0.36 mg/pellet: 90-day release, plus an additional oil vehicle injection every second day) and high pulsatile estrogen (subcutaneous estradiol implant plus an additional 10 MUg/kg estradiol injection every second day). Motor activity was assessed at day 2 and day 12 during haloperidol treatment, while nucleus accumbens dopamine availability was assessed via microdialysis 10 days into antipsychotic treatment. Haloperidol treatment along with high, but not low, estradiol replacement was effective in reducing amphetamine-induced locomotor activity in sensitized rats. High estradiol treatment also augmented the effects of chronic haloperidol in reducing dopaminergic release in sensitized rats. These data suggest that estradiol levels affect both the behavioral and the dopamine responses to chronic antipsychotic treatment. PMID- 24164676 TI - Vancomycin syringe study shows significant reduction in dosing variability after introducing a revised protocol. PMID- 24164677 TI - Safety of cosmetic dermatologic procedures during pregnancy. AB - BACKGROUND: Safety of cosmetic procedures in pregnant women has not been extensively studied. Maternal and fetal health risks are important to consider in any procedure performed. With the increasing popularity of cosmetic procedures, dermatologic surgeons will be faced with scenarios necessitating knowledge regarding the safety of such procedures during pregnancy. Furthermore, dermatologic surgeons may inadvertently perform cosmetic procedures during the first trimester, before the patient is aware of the pregnancy. OBJECTIVE: To investigate the safety of cosmetic procedures during pregnancy and the postpartum period. METHODS AND MATERIALS: A literature search of PubMed and Google Scholar was conducted of all English-language articles published from 1960 through 2012. RESULTS: Definitive recommendations on the safety of procedures such as chemical peels, injectables, fillers, and most laser therapies during pregnancy cannot be made. The safety of onabotulinum toxin usage is well documented in the neurology literature, although isolated events of miscarriage have been reported with high doses of toxin in women with a previous history of miscarriage. Carbon dioxide laser therapy for genital condylomas has considerable evidence supporting its safety during pregnancy. CONCLUSION: There is a lack of controlled trials addressing the safety of cosmetic procedures during pregnancy and postpartum periods. It is advisable to delay elective cosmetic procedures until after the baby is born. PMID- 24164678 TI - Review: iron metabolism and the role of iron in neurodegenerative disorders. AB - Iron plays a role for the biogenesis of two important redox-reactive prosthetic groups of enzymes, iron sulphur clusters (ISC) and heme. A part of these biosynthetic pathways takes plays in the mitochondria. While several important proteins of cellular iron uptake and storage and of mitochondrial iron metabolism are well-characterized, limited knowledge exists regarding the mitochondrial iron importers (mitoferrins). A disturbed distribution of iron, hampered Fe-dependent biosynthetic pathways and eventually oxidative stress resulting from an increased labile iron pool are suggested to play a role in several neurodegenerative diseases. Friedreich's ataxia is associated with mitochondrial iron accumulation and hampered ISC/heme biogenesis due to reduced frataxin expression, thus representing a monogenic mitochondrial disorder, which is clearly elicited solely by a disturbed iron metabolism. Less clear are the controversially discussed impacts of iron dysregulation and iron-dependent oxidative stress in the most common neurodegenerative disorders, i.e. Alzheimer's disease (AD) and Parkinson's disease (PD). Amyotrophic lateral sclerosis (ALS) may be viewed as a disease offering a better support for a direct link between iron, oxidative stress and regional neurodegeneration. Altogether, despite significant progress in molecular knowledge, the true impact of iron on the sporadic forms of AD, PD and ALS is still uncertain. Here we summarize the current knowledge of iron metabolism disturbances in neurodegenerative disorders. PMID- 24164680 TI - Interactive forces between sodium dodecyl sulfate-suspended single-walled carbon nanotubes and agarose gels. AB - Selective adsorption onto agarose gels has become a powerful method to separate single-walled carbon nanotubes (SWCNTs). A better understanding of the nature of the interactive forces and specific sites responsible for adsorption should lead to significant improvements in the selectivity and yield of these separations. A combination of nonequilibrium and equilibrium studies are conducted to explore the potential role that van der Waals, ionic, hydrophobic, pi-pi, and ion-dipole interactions have on the selective adsorption between agarose and SWCNTs suspended with sodium dodecyl sulfate (SDS). The results demonstrate that any modification to the agarose gel surface and, consequently, the permanent dipole moments of agarose drastically reduces the retention of SWCNTs. Because these permanent dipoles are critical to retention and the fact that SDS-SWCNTs function as macro-ions, it is proposed that ion-dipole forces are the primary interaction responsible for adsorption. The selectivity of adsorption may be attributed to variations in polarizability between nanotube types, which create differences in both the structure and mobility of surfactant. These differences affect the enthalpy and entropy of adsorption, and both play an integral part in the selectivity of adsorption. The overall adsorption process shows a complex behavior that is not well represented by the Langmuir model; therefore, calorimetric data should be used to extract thermodynamic information. PMID- 24164679 TI - T-cell immunoglobulin and mucin domain 2 (TIM-2) is a target of ADAM10-mediated ectodomain shedding. AB - T-cell immunoglobulin and mucin domain (TIM)-2 is expressed on activated B cells. Here, we provide evidence that murine TIM-2 is a target of ADAM10-mediated ectodomain shedding, resulting in the generation of a soluble form of TIM-2. We identified ADAM10 but not ADAM17 as the major sheddase of TIM-2, as shown by pharmacological ADAM10 inhibition and with ADAM10-deficient and ADAM17-deficient murine embryonic fibroblasts. Ionomycin-induced or 2'(3')-O-(4-benzoylbenzoyl) ATP triethylammonium salt-induced shedding of TIM-2 was abrogated by deletion of 10 juxtamembrane amino acids from the stalk region but not by deletion of two further N-terminally located blocks of 10 amino acids, indicating a membrane proximal cleavage site. TIM-2 lacking the intracellular domain was cleaved after ionomycin or 2' (3')-O-(4-benzoylbenzoyl) ATP triethylammonium salt treatment, indicating that this domain was not involved in the regulation of ectodomain shedding. Moreover, TIM-2 shedding was negatively controlled by calmodulin. Shed and soluble TIM-2 interacted with H-ferritin. In summary, we describe TIM-2 as a novel target for ADAM10-mediated ectodomain shedding, and reveal the involvement of ADAM proteases in cellular iron homeostasis. PMID- 24164681 TI - Do not jump to easy conclusions! Lessons from pitfall in the molecular diagnosis of ARSACS. PMID- 24164682 TI - Stepwise protonation and electron-transfer reduction of a primary copper-dioxygen adduct. AB - The protonation-reduction of a dioxygen adduct with [LCu(I)][B(C6F5)4], cupric superoxo complex [LCu(II)(O2(*-))]+ (1) (L = TMG3tren (1,1,1-tris[2-[N(2) (1,1,3,3-tetramethylguanidino)]ethyl]amine)) has been investigated. Trifluoroacetic acid (HOAcF) reversibly associates with the superoxo ligand in ([LCu(II)(O2(*-))]+) in a 1:1 adduct [LCu(II)(O2(*-))(HOAcF)](+) (2), as characterized by UV-visible, resonance Raman (rR), nuclear magnetic resonance (NMR), and X-ray absorption (XAS) spectroscopies, along with density functional theory (DFT) calculations. Chemical studies reveal that for the binding of HOAcF with 1 to give 2, Keq = 1.2 * 10(5) M(-1) (-130 degrees C) and DeltaH degrees = -6.9(7) kcal/mol, DeltaS degrees = -26(4) cal mol(-1) K(-1)). Vibrational (rR) data reveal a significant increase (29 cm(-1)) in vO-O (= 1149 cm(-1)) compared to that known for [LCu(II)(O2(*-))](+) (1). Along with results obtained from XAS and DFT calculations, hydrogen bonding of HOAcF to a superoxo O-atom in 2 is established. Results from NMR spectroscopy of 2 at -120 degrees C in 2 methyltetrahydrofuran are also consistent with 1/HOAcF = 1:1 formulation of 2 and with this complex possessing a triplet (S = 1) ground state electronic configuration, as previously determined for 1. The pre-equilibrium acid association to 1 is followed by outer-sphere electron-transfer reduction of 2 by decamethylferrocene (Me10Fc) or octamethylferrocene (Me8Fc), leading to the products H2O2, the corresponding ferrocenium salt, and [LCu(II)(OAcF)](+). Second order rate constants for electron transfer (ket) were determined to be 1365 M(-1) s(-1) (Me10Fc) and 225 M(-1) s(-1) (Me8Fc) at -80 degrees C. The (bio)chemical relevance of the proton-triggered reduction of the metal-bound dioxygen-derived fragment is discussed. PMID- 24164683 TI - Single institutional series of neuroendocrine tumors managed in the Australian Capital Territory. AB - AIMS: Retrospective review of neuroendocrine tumors (NETs) treated within the Australian Capital Territory to describe the local epidemiology and assess prognostic clinicopathological factors. METHODS: Patients with histologically proven non-pulmonary low to intermediate grade NETs were identified from our hospital clinical database. Data were analyzed according to epidemiological, clinical and histopathological characteristics. RESULTS: Of the 107 included patients, the most common primary tumor site was jejunum/ileum (32%), followed by rectum (22%) and pancreas (11.2%). In total, 32% had distant metastases at presentation, most commonly in the liver. Most patients were symptomatic at diagnosis, while 22.4% of cases were found incidentally. Second malignancies, in particular of gastrointestinal origin, were diagnosed in 33.6%. Surgical debulking was the most common treatment (59.8%) while 18% had multimodality therapy. With a median follow-up of 25 months from diagnosis, about 78% of patients are still alive. Median time to first relapse was 15 months and the 5 year survival rate was 80% for NETs of jejunum/ileum. Univariate survival analysis revealed tumor location, high Ki67 index, raised plasma chromogranin A, and urine 5-hydroxyindoleacetic acid upon diagnosis to be associated with shorter 5-year survival. CONCLUSION: The epidemiologic characteristics and long-term outcome in our series are comparable to other reported studies. This analysis presents some important prognostic factors which could be used for risk stratification in patients with NETs. PMID- 24164685 TI - Percutaneous axillary vein approach in pediatric pacing: comparison with subclavian vein approach. AB - AIMS: The subclavian vein approach has been used for 20 years in our center for pacemaker (PM) implantation in children, but it carries risks of hemothorax/pneumothorax and lead fracture, which could be reduced by axillary vein approach. METHODS AND RESULTS: This is a prospective study enrolling the first 48 consecutive pediatric patients (age: 12.3 +/- 4.6 years) who underwent PM/implantable cardioverter-defibrillator leads implantation through axillary vein (guided by contrast venography) between 2009 and 2012 (group I). A comparison was made with the outcomes of the subclavian vein approach (group II) in 41 patients, age 12.3 +/- 4.8 years, consecutively enrolled between 2006 and 2011. The two groups showed no significant differences for the variables examined except for follow-up, longer in group II, and for alternative ventricular pacing sites, more frequent in group I. Axillary vein diameter was 7.9 +/- 1.7 mm and showed positive correlation with height (r = 0.77). The axillary vein approach was effective in 93.7% of patients. The unsuccessful procedures occurred in patients with significantly lower age and smaller venous diameters. The subclavian vein approach was effective in 100% of patients. Sixty-two leads were implanted in group I, 54 in group II. There were neither intraoperative complications in both the groups, nor significant differences for early and late complications. CONCLUSIONS: The axillary vein approach for PM implantation in children is effective and safe for physicians skilled with subclavian vein approach. Younger patients with smaller vein diameters are at low risk for unsuccessful procedure. PMID- 24164684 TI - Transcriptional downregulation of agr expression in Staphylococcus aureus during growth in human serum can be overcome by constitutively active mutant forms of the sensor kinase AgrC. AB - The temporal and cell density-dependent regulation of expression of virtually all the Staphylococcus aureus virulon is under the control of the agr (accessory gene regulatory) operon. The expression of the agr operon is subject to transcriptional regulation by the AgrA/C two-component response regulator/sensor kinase pair. During bacteraemia, a frequent syndrome caused by methicillin resistant S. aureus (MRSA), the transcriptional downregulation of agr expression has been attributed to the sequestration of the quorum-signalling molecule auto inducing peptide (AIP) by the human serum component apolipoprotein B as part of an innate immune response to infection. However, it is not known whether transcriptional downregulation of agr expression during growth in human serum is additionally subjected to regulation by transcription regulatory proteins that either directly or indirectly affect transcription from the agr operon promoters. Here, using chromosomal fluorescence reporters of agr expression in S. aureus, we show that the transcriptional downregulation of agr expression in human serum can be overcome using constitutive active mutant forms of AgrC. Therefore, it seems that the sequestration of the AIP is likely to be the only mechanism by which the host innate immune response limits agr expression at the transcriptional level to maintain the host-pathogen balance towards a noninvasive outcome. PMID- 24164686 TI - Synthesis, microstructure, and cathodoluminescence of [0001]-oriented GaN nanorods grown on conductive graphite substrate. AB - One-dimensional GaN nanorods with corrugated morphology have been synthesized on graphite substrate without the assistance of any metal catalyst through a feasible thermal evaporation process. The morphologies and microstructures of GaN nanorods were characterized by X-ray powder diffraction (XRD), scanning electron microscopy (SEM) and high-resolution transmission electron microscopy (HRTEM). The results from HRTEM analysis indicate that the GaN nanorods are well crystallized and exhibit a preferential orientation along the [0001] direction with Ga(3+)-terminated (1011) and N(3-)-terminated (1011) as side facets, finally leading to the corrugated morphology surface. The stabilization of the electrostatic surface energy of {1011} polar surface in a wurtzite-type hexagonal structure plays a key role in the formation of GaN nanorods with corrugated morphology. Room-temperature cathodoluminescence (CL) measurements show a near band-edge emission (NBE) in the ultraviolet range and a broad deep level emission (DLE) in the visible range. The crystallography and the optical emissions of GaN nanorods are discussed. PMID- 24164690 TI - Reaction mechanism of monoamine oxidase from QM/MM calculations. AB - The flavoenzyme monoamine oxidase (MAO) is essential for the enzymatic decomposition of neurotransmitters. While it is commonly accepted that the rate limiting step of the reaction is the stereoselective abstraction of a hydrogen from the substrate, the precise mechanism is unknown. We modeled the reaction of human MAO-B with benzylamine by means of QM/MM calculations based on density functional theory. Oxidation of the unprotonated substrate was found to proceed with rates in good agreement with experimental values, while the protonated substrate does not react at room temperature. Our results support a concerted asynchronous polar nucleophilic mechanism. The lone pair of the amine-nitrogen interacts with a carbon atom of the flavin cofactor. During the reaction, this lone pair, as well as a proton, are transferred to the cofactor. Analysis of the electronic structure during the reaction rules out a radical mechanism. PMID- 24164687 TI - Exacerbation phenotyping in chronic obstructive pulmonary disease. AB - Acute exacerbations of chronic obstructive pulmonary disease (AECOPD) are crucial events but causes remain poorly defined. A method to clinically 'phenotype' AECOPD have been proposed, and 52 hospitalized chronic obstructive pulmonary disease exacerbations according to underlying aetiology have now been prospectively phenotyped. Multiple exacerbation phenotypes were identified. A subpopulation coinfected with virus and bacteria had a significantly longer length of hospital stay, and this pilot study indicates that exacerbation phenotyping may be advantageous. PMID- 24164691 TI - Increase in neuroexcitability of unmyelinated C-type vagal ganglion neurons during initial postnatal development of visceral afferent reflex functions. AB - BACKGROUND: Baroreflex gain increase up closely to adult level during initial postnatal weeks, and any interruption within this period will increase the risk of cardiovascular problems in later of life span. We hypothesize that this short period after birth might be critical for postnatal development of vagal ganglion neurons (VGNs). METHODS: To evaluate neuroexcitability evidenced by discharge profiles and coordinate changes, ion currents were collected from identified A- and C-type VGNs at different developmental stages using whole-cell patch clamping. RESULTS: C-type VGNs underwent significant age-dependent transition from single action potential (AP) to repetitive discharge. The coordinate changes between TTX-S and TTX-R Na(+) currents were also confirmed and well simulated by computer modeling. Although 4-AP or iberiotoxin age dependently increased firing frequency, AP duration was prolonged in an opposite fashion, which paralleled well with postnatal changes in 4-AP- and iberiotoxin-sensitive K(+) current activity, whereas less developmental changes were verified in A-types. CONCLUSION: These data demonstrate for the first time that the neuroexcitability of C-type VGNs increases significantly compared with A-types within initial postnatal weeks evidenced by AP discharge profiles and coordinate ion channel changes, which explain, at least in part, that initial postnatal weeks may be crucial for ontogenesis in visceral afferent reflex function. PMID- 24164692 TI - Incipient post-zygotic barrier in a model system of ecological speciation with gene flow. AB - The role of post-zygotic isolation in nonallopatric ecological speciation is still mostly unknown and information on the nature and strength of these barriers in well-known speciation models is essential for a deeper understanding of such processes. The Galician ecotypes of the marine snail Littorina saxatilis represent one of the best studied cases of nonallopatric ecological speciation. Here, we test the existence of incipient post-zygotic isolation by comparing the fertility of male hybrids with that of both pure forms [ridged and banded (RB) and smooth and unbanded (SU) ecotypes]. We analysed the degree of sperm DNA fragmentation (SDF) of individuals morphologically classified as RB, SU and hybrids, sampled from two locations. SDF analyses were chosen to study sperm quality because, in other animal species, SDF rates correlate with important parameters for speciation research, such as fertilization and abortion rates and viability of adult progeny. In the present work, hybrids showed significantly higher SDF rates than RB and SU males in one location and significantly higher variances in both locations. These results suggest the existence of an incipient post-zygotic barrier, the strength of which may vary across the Galician shore, and highlight the potential of SDF analyses for speciation research. PMID- 24164693 TI - Computational fluid dynamics analysis of salivary flow and its effect on sialolithogenesis. AB - OBJECTIVE: Sialolithiasis is a common disease caused by intraductal stones, formed by reduction in salivary flow, salivary stagnation, and metabolic events. We used computational fluid dynamics to investigate changes in salivary flow field around parotid stones of different shapes. MATERIALS AND METHODS: Three dimensional configurations of the Stensen's duct were reconstructed from computed tomography sialographic images. Fluid dynamics modeling was used to analyze the salivary flow field around stones under unstimulated and stimulated conditions. RESULTS: The majority of sialoliths were oval-shaped (59/98), followed by irregular (24/98) and round (15/98). Salivary velocity was significantly higher around streamlined stones, compared with round (P = 0.013) and oval (P = 0.025) types. Changes in salivary flow field around sialoliths were found to affect the pattern of mineral deposition in saliva. The area of low velocity around the round stone was double the size observed around the streamlined stone during the unstimulated state, whereas in the stimulated state, local vortexes were formed on the downstream side of round and oval stones. CONCLUSIONS: Salivary flow field around sialoliths plays an important role in the progression of multicentric stones, and analysis of the salivary dynamics during sialolithiasis may provide deeper understandings of the condition and aid in developing successful treatment strategies. PMID- 24164694 TI - Bilateral nasolabial cysts. PMID- 24164695 TI - A frameshift mutation in the cubilin gene (CUBN) in Beagles with Imerslund Grasbeck syndrome (selective cobalamin malabsorption). AB - Mammals are unable to synthesize cobalamin or vitamin B12 and rely on the uptake of dietary cobalamin. The cubam receptor expressed on the intestinal endothelium is required for the uptake of cobalamin from the gut. Cubam is composed of two protein subunits, amnionless and cubilin, which are encoded by the AMN and CUBN genes respectively. Loss-of-function mutations in either the AMN or the CUBN gene lead to hereditary selective cobalamin malabsorption or Imerslund-Grasbeck syndrome (IGS). We investigated Beagles with IGS and resequenced the whole genome of one affected Beagle at 15* coverage. The analysis of the AMN and CUBN candidate genes revealed a homozygous deletion of a single cytosine in exon 8 of the CUBN gene (c.786delC). This deletion leads to a frameshift and early premature stop codon (p.Asp262Glufs*47) and is, thus, predicted to represent a complete loss-of-function allele. We tested three IGS-affected and 89 control Beagles and found perfect association between the IGS phenotype and the CUBN:c.786delC variant. Given the known role of cubilin in cobalamin transport, which has been firmly established in humans and dogs, our data strongly suggest that the CUBN:c.786delC variant is causing IGS in the investigated Beagles. PMID- 24164696 TI - Vitamin B12 and folate deficiency: should we use a different cutoff value for hematologic disorders? AB - INTRODUCTION: Anemia and macrocytosis are well-defined expected hematologic findings of vitamin B12 and folate deficiency; however, some previous studies did not show a significant association of subnormal B12 with anemia and macrocytosis. METHODS: We retrospectively analyzed 17 713 laboratory patient records to evaluate vitamin B12 and folate levels in relation to anemia and macrocytosis. RESULTS: In an age- and sex-adjusted logistic regression model, low B12 status but not marginal B12 status was significantly associated with anemia [ORs respectively, 1.291 (95% CI, 1.182-1.410), 1.022 (95% CI, 0.943-1.108)] and macrocytosis [ORs, respectively, 3.853 (95% CI, 3.121-4.756), 1.031 (95% CI, 0.770-1.381)]. Also low folate status but not marginal folate status was significantly associated with anemia [adjusted ORs, respectively, 1.819 (95% CI, 1.372-2.411), 1.101 (95% CI, 0.931-1.301)] and macrocytosis [adjusted ORs, respectively, 2.945 (95% CI, 1.747-4.965), 1.228 (95% CI, 0.795-1.898)]. CONCLUSION: Our results show that increased anemia and macrocytosis are observed at values below commonly used B12 lower-reference thresholds. Determining a hematologic cutoff value may help physicians in clinical practice. PMID- 24164697 TI - Cost-effectiveness of a national exercise referral programme for primary care patients in Wales: results of a randomised controlled trial. AB - BACKGROUND: A recent HTA review concluded that there was a need for RCTs of exercise referral schemes (ERS) for people with a medical diagnosis who might benefit from exercise. Overall, there is still uncertainty as to the cost effectiveness of ERS. Evaluation of public health interventions places challenges on conventional health economics approaches. This economic evaluation of a national public health intervention addresses this issue of where ERS may be most cost effective through subgroup analysis, particularly important at a time of financial constraint. METHOD: This economic analysis included 798 individuals aged 16 and over (55% of the randomised controlled trial (RCT) sample) with coronary heart disease risk factors and/or mild to moderate anxiety, depression or stress. Individuals were referred by health professionals in a primary care setting to a 16 week national exercise referral scheme (NERS) delivered by qualified exercise professionals in local leisure centres in Wales, UK. Health related quality of life, health care services use, costs per participant in NERS, and willingness to pay for NERS were measured at 6 and 12 months. RESULTS: The base case analysis assumed a participation cost of L385 per person per year, with a mean difference in QALYs between the two groups of 0.027. The incremental cost effectiveness ratio was L12,111 per QALY gained. Probabilistic sensitivity analysis demonstrated an 89% probability of NERS being cost-effective at a payer threshold of L30,000 per QALY. When participant payments of L1 and L2 per session were considered, the cost per QALY fell from L12,111 (base case) to L10,926 and L9,741, respectively. Participants with a mental health risk factor alone or in combination with a risk of chronic heart disease generated a lower ICER (L10,276) compared to participants at risk of chronic heart disease only (L13,060). CONCLUSIONS: Results of cost-effectiveness analyses suggest that NERS is cost saving in fully adherent participants. Though full adherence to NERS (62%) was higher for the economics sample than the main sample (44%), results still suggest that NERS can be cost-effective in Wales with respect to existing payer thresholds particularly for participants with mental health and CHD risk factors. TRIAL REGISTRATION: Current Controlled Trials ISRCTN47680448. PMID- 24164698 TI - Detection and characterization of Bifidobacterium crudilactis and B. mongoliense able to grow during the manufacturing process of French raw milk cheeses. AB - BACKGROUND: The study of a production chain of raw milk cheeses (St Marcellin, Vercors area, France) led to the isolation of two Bifidobacterium populations: B. crudilactis and B. mongoliense, that were able to grow along the production chain. The aims of this study were to further detect and characterize these bacteria along the process and evaluate the ability of some strains to survive or grow in adverse conditions. RESULTS: Using PCR coupled with restriction fragment length polymorphism, B. crudilactis and B. mongoliense were detected in respectively 77% and 30% of St Marcellin cheeses from production chain after 21 days of ripening. They were present in more than half of all analyzed retail cheeses with counts going from 1.6 to 5 log cfu g-1 for B. crudilactis and 1.4 to 7 log cfu g-1 for B. mongoliense. Bifidobacterium mongoliense was sensitive to pH 2, with an observed decrease of at least 3 log for both studied strains (FR49/f/2 and FR41/2) after 1 h incubation. At pH 3, no significant decrease was observed. Good survival was observed for the same strains in presence of pancreatic juice with a decrease of less than one log. Survival of strain FR49/f/2 was better than FR41/2 with a decrease of 3 logarithms (in presence of 1% bile salts) and almost 2 logarithms (in presence of 0.5% bile salts). The genotypic analyses using total DNA-DNA hybridization, GC% content, 16S rRNA gene sequencing and multilocus sequencing analysis (MLSA) confirmed the classification of Bifidobacterium. crudilactis and B. mongoliense into two different clusters well separated from other bifidobacteria clusters. CONCLUSIONS: According to the observed characteristics such as survival in adverse conditions and their ability to grow under 12 degrees C during the manufacturing process of the cheeses, which has never been described for bifidobacteria and which is a very interesting technological asset, these B. crudilactis and B. mongoliense strains should be further investigated for a potential use in new food or in food supplements. PMID- 24164699 TI - Phosphorylation of STAT3 correlates with HER2 status, but not with survival in pancreatic ductal adenocarcinoma. AB - Activation of signal-transcriptional factor signal transducer and activator of transcription 3 (STAT3) is associated with more aggressive behaviour in a variety of human malignancies. As selective STAT3 inhibitors exist, this protein might represent a novel therapeutic target. Although STAT3 seems to play an important role in progression of pancreatic ductal carcinoma (PDAC), only few data on this subject exist. The aim of our study was the investigation of STAT3 activation and its correlation with its possible regulator HER2. Expression of tyrosine-705 phosphorylated STAT3 (pSTAT3) was determined immunohistochemically in 79 PDACs. HER2 status assessed by immunohistochemistry and double colour silver in situ hybridization was available from a previous study. PSTAT3 expression was seen in 33 (41.8%) patients. Six patients were scored as HER2 positive having strong correlation with pSTAT3 expression (p = 0.004, Fisher's exact test). No association of pSTAT3 expression with patients' age, tumour staging and grading, perineural invasion of tumour cells or survival time was seen. pSTAT3 is frequently expressed in PDAC. Nevertheless, its immediate clinical relevance seems to be low. However, further research needs to determine whether STAT3 status in PDAC is predictive for the response to novel targeting therapies. PMID- 24164700 TI - Genetic variability of respiratory complex abundance, organization and activity in mouse brain. AB - Mitochondrial dysfunction is implicated in the etiology and pathogenesis of numerous human disorders involving tissues with high energy demand. Murine models are widely used to elucidate genetic determinants of phenotypes relevant to human disease, with recent studies of C57BL/6J (B6), DBA/2J (D2) and B6xD2 populations implicating naturally occurring genetic variation in mitochondrial function/dysfunction. Using blue native polyacrylamide gel electrophoresis, immunoblots and in-gel activity analyses of complexes I, II, III, IV and V, our studies are the first to assess abundance, organization and catalytic activity of mitochondrial respiratory complexes and supercomplexes in mouse brain. Remarkable strain differences in supercomplex assembly and associated activity are evident, without differences in individual complexes I, II, III or IV. Supercomplexes I1 III2 IV2-3 exhibit robust complex III immunoreactivity and activities of complexes I and IV in D2, but with little detected in B6 for I1 III2 IV2 , and I1 III2 IV3 is not detected in B6. I1 III2 IV1 and I1 III2 are abundant and catalytically active in both strains, but significantly more so in B6. Furthermore, while supercomplex III2 IV1 is abundant in D2, none is detected in B6. In aggregate, these results indicate a shift toward more highly assembled supercomplexes in D2. Respiratory supercomplexes are thought to increase electron flow efficiency and individual complex stability, and to reduce electron leak and generation of reactive oxygen species. Our results provide a framework to begin assessing the role of respiratory complex suprastructure in genetic vulnerability and treatment for a wide variety of mitochondrial-related disorders. PMID- 24164702 TI - Comparison of outcomes for malignant melanoma of the face treated using Mohs micrographic surgery and wide local excision. AB - BACKGROUND: Mohs micrographic surgery (MMS) is an accepted treatment for nonmelanoma skin cancer and has an evolving role in melanoma. OBJECTIVE: To review oncologic outcomes of MMS and wide local excision (WLE) treatments for facial melanoma. METHODS AND MATERIALS: A retrospective review of patients with invasive melanoma of the face between 1997 and 2007 identified from the Alberta Cancer Registry (Canada) was performed. Outcome measures were local recurrence (recurrence <2 cm from excision scar), distant recurrence (regional or systemic), and disease-specific survival. RESULTS: One hundred fifty-one patients were available for analysis (60 MMS, 91 WLE). Median follow-up time was 48 months. The groups differed in tumor location and mitotic rate. Overall, there was no significant difference in 5-year local recurrence (7.9% WLE vs 6.2% MMS, p = .58), regional or systemic recurrence (18.8% vs 8.8%, p = 0.37) or disease specific survival (82.8% vs 92.4%, p = .59). Breslow thickness was the only consistent predictor of local recurrence or other recurrence and disease-specific survival on multivariate analysis. Subset analysis of tumors with Breslow thickness less than 2 mm did not reveal any difference in outcomes. CONCLUSION: Mohs micrographic surgery has oncologic outcomes of local recurrence, distant recurrence and overall survival similar to those of WLE for invasive facial melanoma. PMID- 24164703 TI - Proximal nail fold intralesional steroid injection responsible for Hoigne syndrome. AB - BACKGROUND: Hoigne syndrome is the most common name given to a condition which has been called in different ways. OBJECTIVE: We want to show that an intralesional injection of prednisolone into the proximal nail fold may produce dorsal pain, dyspnoea and headaches within the 2 min following the injection and to explain the pathophysiology of his condition. METHODS: We studied the different drugs responsible for Hoigne syndrome by comparing the size of the crystals taking into account the diameter of pulmonary capillaries. The drug Company informed us that the size of the microcrystals were 2-4 MUm vs. the 8 MUm on average of the diameter of the pulmonary capillaries. CONCLUSION: All the symptoms of Hoigne syndrome can be explained, especially the neuropsychiatric and neuropulmonary ones. Therefore, dermatologists should be aware of this phenomenon when they inject steroids in psoriatic nail patients. PMID- 24164701 TI - Cytoplasmic replication of Staphylococcus aureus upon phagosomal escape triggered by phenol-soluble modulin alpha. AB - Staphylococcus aureus is a Gram-positive human pathogen that is readily internalized by professional phagocytes such as macrophages and neutrophils but also by non-professional phagocytes such as epithelial or endothelial cells. Intracellular bacteria have been proposed to play a role in evasion of the innate immune system and may also lead to dissemination within migrating phagocytes. Further, S. aureus efficiently lyses host cells with a battery of cytolytic toxins. Recently, phenol-soluble modulins (PSM) have been identified to comprise a genus-specific family of cytolytic peptides. Of these the PSMalpha peptides have been implicated in killing polymorphonuclear leucocytes after phagocytosis. We questioned if the peptides were active in destroying endosomal membranes to avoid lysosomal killing of the pathogen and monitored integrity of infected host cell endosomes by measuring the acidity of the intracellular bacterial microenvironment via flow cytometry and by a reporter recruitment technique. Isogenic mutants of the methicillin-resistant S. aureus (MRSA) strains USA300 LAC, USA400 MW2 as well as the strongly cytolytic methicillin-sensitive strain 6850 were compared with their respective wild type strains. In all three genetic backgrounds, PSMalpha mutants were unable to escape from phagosomes in non professional (293, HeLa, EAhy.926) and professional phagocytes (THP-1), whereas mutants in PSMbeta and delta-toxin as well as beta-toxin, phosphatidyl inositol dependent phospholipase C and Panton Valentine leucotoxin escaped with efficiencies of the parental strains. S. aureus replicated intracellularly only in presence of a functional PSMalpha operon thereby illustrating that bacteria grow in the host cell cytoplasm upon phagosomal escape. PMID- 24164704 TI - Standard and extended lymphadenectomy for adenocarcinoma of the pancreatic head: a meta-analysis and systematic review. AB - BACKGROUND AND AIM: Although some retrospective studies have recommended that pancreaticoduodenectomy with extended lymphadenectomy might improve the survival of patients with adenocarcinoma of the head of the pancreas, the procedure remains controversial. METHODS: Using PubMed, EMBASE, and The Cochrane Library databases, a systematic literature review was performed to identify randomized, controlled trials comparing standard and extended lymphadenectomy in pancreaticoduodenectomy for adenocarcinoma of the head of the pancreas. RESULTS: Four trials including 423 patients satisfied the inclusion criteria. Extended lymphadenectomy failed to improve the overall survival of patients with adenocarcinoma of the head of the pancreas (hazard ratio 1.09; 95% confidence interval 0.84-1.41; P = 0.51). Additionally, postoperative mortality and morbidity were comparable between the standard and extended groups, while extended lymphadenectomy was associated with poor quality of life within 1 year after the operation. CONCLUSIONS: Extended lymphadenectomy do not benefit overall survival. Considering the poor quality of life associated with extended lymphadenectomy, pancreaticoduodenectomy with standard lymphadenectomy is suitable for patients with adenocarcinoma of the head of the pancreas. PMID- 24164705 TI - Efficacy of an oral and tropically stable lipid-based formulation of Amphotericin B (iCo-010) in an experimental mouse model of systemic candidiasis. AB - OBJECTIVE: An oral lipid based formulation that exhibits tropical stability (iCo 010) was developed to enhance the absorption of orally administered amphotericin B (AmB). iCo-010 has previously shown high efficacy in an acute model of systemic candidiasis in rats, directing the focus of this study to be its efficacy in a chronic model of systemic candidiasis in mice. METHODS: Mice were infected with 0.6 to 1*108 CFUs of Candida albicans ATCC 18804 strain by tail vein injection and were left for three days to develop the infection after which time treatment was initiated. The infected animals were assigned to the following treatment groups: no treatment (control) or iCo-010 at 5, 10 and 20 mg/kg administered by oral gavage once daily (QD) for 5 consecutive days. The animals were sacrificed 7 days after the last dose and the concentration of AmB and the fungal burden were assessed within the liver, kidneys, heart, lungs, spleen and brain. RESULTS: Although the infection was relatively low (~ 60-100 CFUs/ 1 ml tissue homogenate) in the liver, lungs and heart, the infection level was very high (70 000 CFUs / 1 ml tissue homogenate) in the kidney tissues for the control group. The highest concentrations of AmB were recovered in the kidneys and the spleen. The fungal burden in the tissues was lowered by 69-96% in the treatment groups when compared to the control group. CONCLUSION: Oral iCo-010 is an effective treatment of systemic candidiasis in the mouse model. PMID- 24164707 TI - HLA-G polymorphism and breast cancer. AB - The aim of this study was to explore a possible influence of the HLA-G coding polymorphisms on the susceptibility to breast cancer development in Brazilian subjects; however, none of the HLA-G variation sites evaluated was influencing breast cancer susceptibility indicating that the variation in the HLA-G coding region is not a risk factor for breast cancer. PMID- 24164706 TI - The COP9 signalosome is involved in the regulation of lipid metabolism and of transition metals uptake in Saccharomyces cerevisiae. AB - The COP9 signalosome (CSN) is a highly conserved eukaryotic protein complex which regulates the cullin RING family of ubiquitin ligases and carries out a deneddylase activity that resides in subunit 5 (CSN5). Whereas CSN activity is essential for the development of higher eukaryotes, several unicellular fungi including the budding yeast Saccharomyces cerevisiae can survive without a functional CSN. Nevertheless, the budding yeast CSN is biochemically active and deletion mutants of each of its subunits exhibit deficiency in cullins deneddylation, although the biological context of this activity is still unknown in this organism. To further characterize CSN function in budding yeast, we present here a transcriptomic and proteomic analysis of a S. cerevisiae strain deleted in the CSN5/RRI1 gene (hereafter referred to as CSN5), coding for the only canonical subunit of the complex. We show that Csn5 is involved in modulation of the genes controlling amino acid and lipid metabolism and especially ergosterol biosynthesis. These alterations in gene expression correlate with the lower ergosterol levels and increased intracellular zinc content which we observed in csn5 null mutant cells. We show that some of these regulatory effects of Csn5, in particular the control of isoprenoid biosynthesis, are conserved through evolution, since similar transcriptomic and/or proteomic effects of csn5 mutation were previously observed in other eukaryotic organisms such as Aspergillus nidulans, Arabidopsis thaliana and Drosophila melanogaster. Our results suggest that the diverged budding yeast CSN is more conserved than was previously thought. PMID- 24164708 TI - The impact of Wolbachia, male age and mating history on cytoplasmic incompatibility and sperm transfer in Drosophila simulans. AB - Most insects harbour a variety of maternally inherited endosymbionts, the most widespread being Wolbachia pipientis that commonly induce cytoplasmic incompatibility (CI) and reduced hatching success in crosses between infected males and uninfected females. High temperature and increasing male age are known to reduce the level of CI in a variety of insects. In Drosophila simulans, infected males have been shown to mate at a higher rate than uninfected males. By examining the impact of mating rate independent of age, this study investigates whether a high mating rate confers an advantage to infected males through restoring their compatibility with uninfected females over and above the effect of age. The impact of Wolbachia infection, male mating rate and age on the number of sperm transferred to females during copulation and how it relates to CI expression was also assessed. As predicted, we found that reproductive compatibility was restored faster in males that mate at higher rate than that of low mating and virgin males, and that the effect of mating history was over and above the effect of male age. Nonvirgin infected males transferred fewer sperm than uninfected males during copulation, and mating at a high rate resulted in the transfer of fewer sperm per mating irrespective of infection status. These results indicate that the advantage to infected males of mating at a high rate is through restoration of reproductive compatibility with uninfected females, whereas uninfected males appear to trade off the number of sperm transferred per mating with female encounter rate and success in sperm competition. This study highlights the importance Wolbachia may play in sexual selection by affecting male reproductive strategies. PMID- 24164709 TI - Recursive algorithms for phylogenetic tree counting. AB - BACKGROUND: In Bayesian phylogenetic inference we are interested in distributions over a space of trees. The number of trees in a tree space is an important characteristic of the space and is useful for specifying prior distributions. When all samples come from the same time point and no prior information available on divergence times, the tree counting problem is easy. However, when fossil evidence is used in the inference to constrain the tree or data are sampled serially, new tree spaces arise and counting the number of trees is more difficult. RESULTS: We describe an algorithm that is polynomial in the number of sampled individuals for counting of resolutions of a constraint tree assuming that the number of constraints is fixed. We generalise this algorithm to counting resolutions of a fully ranked constraint tree. We describe a quadratic algorithm for counting the number of possible fully ranked trees on n sampled individuals. We introduce a new type of tree, called a fully ranked tree with sampled ancestors, and describe a cubic time algorithm for counting the number of such trees on n sampled individuals. CONCLUSIONS: These algorithms should be employed for Bayesian Markov chain Monte Carlo inference when fossil data are included or data are serially sampled. PMID- 24164710 TI - Online survey on twitter: a urological experience. PMID- 24164711 TI - Overexpression of adiponectin improves neurobehavioral outcomes after focal cerebral ischemia in aged mice. AB - AIMS: To study whether adiponectin (APN) could improve neurological outcomes in aged mice after ischemic stroke. METHODS: Adeno-associated virus carrying APN gene was injected into aged and young adult mice 7 days before transient middle cerebral artery occlusion (tMCAO). Atrophic volumes and neurobehavioral deficiencies were determined up to 28 days after tMCAO. Focal angiogenesis was determined based on blood vessel number in the ischemic regions. RESULTS: Increased atrophic volume and more sever neurobehavioral deficits were found in the aged mice compared with young adult mice (P < 0.05). AAV-APN gene transfer attenuated atrophic volume and improved neurobehavioral outcomes, along with increased focal angiogenesis in both aged and young adult mice, compared with control animals (P < 0.05). In addition, the attenuation of atrophic volume and the improvement in neurobehavioral outcomes were much more significant in aged mice than in young adult mice after AAV-APN administration (P < 0.05). The number of microvessels in aged AAV-APN mouse ischemic brain was higher than in young adult AAV-APN treated mouse brain (P < 0.05). CONCLUSIONS: Our results demonstrate that APN overexpression reduces ischemic brain injury and improves neurobehavioral function recovery in aged mice than in young mice, suggesting APN is more beneficial in aged animals after ischemic stroke. PMID- 24164712 TI - Bleeding manifestations apparently unrelated to coagulation or other organic disorders: A tentative classification and diagnostic clues. AB - OBJECTIVE: To study the features of bleeding conditions apparently not associated with vascular, platelet, or clotting dysfunctions. METHOD: Conditions that may meet these criteria are: Munchausen syndrome factitious or fictitious, suicidal or homicidal bleeding, bleeding due to self-punishment, stigmatization, the battered child syndrome, and psychogenic bleeding. RESULTS: The importance of these variegate conditions is not trivial in clinical practice. Differential diagnosis may be difficult and involve other specialists besides hematologists. Occasionally, invasive procedures are involved. DISCUSSION: The occurrence of bleeding in patients, without a clotting defect or a systemic disorder and a negative family history for bleeding represents a diagnostic challenge. A careful examination of the physical and psychological status of the patient and an appropriate evaluation of the environment in which bleeding occurs, is always needed. PMID- 24164713 TI - Serum liver enzymes--should we count on them? PMID- 24164714 TI - Conductance measurement of pyridyl-based single molecule junctions with Cu and Au contacts. AB - We studied the conductance of pyridyl-based single molecule junctions with Cu contacts by using an electrochemical jump-to-contact scanning tunneling microscopy break junction (ECSTM-BJ) approach. The single molecule junctions of 4,4'-bipyridine (BPY), 1,2-di(pyridin-4-yl)ethene (BPY-EE) and 1,2-di(pyridin-4 yl)ethane (BPY-EA) bridged with Cu clusters show three sets of conductance values. These values are smaller than the conductance values of single molecule junctions with Au electrodes measured by the traditional scanning tunneling microscopy break junction in acidic or neutral solutions, which can be attributed to the different electronic coupling efficiencies between molecules and electrodes. The consistent conductance of pyridyl-based molecules in acidic and neutral solutions may show that the protonated pyridyl group contacts to the electrode through the deprotonated form. PMID- 24164715 TI - On the Derjaguin offset in boundary-lubricated nanotribological systems. AB - We performed molecular dynamics simulations of boundary-lubricated sliding, varying the boundary lubricant type, its molecular surface coverage, the substrate roughness, and the load. The resulting load versus friction behavior was then analyzed to study how changes in lubricant type, coverage, and roughness affect the extrapolated friction force at zero load, the so-called Derjaguin offset. A smooth-particle-based evaluation method by the authors, applied here for the first time to visualize the sliding interface between the two layers of boundary lubricant, allowed the definition and calculation of a dimensionless normalized sliding resistance area, which was then related to the Derjaguin offset. This relationship excellently reflects the molecular surface coverage, which determines the physical condition of the lubricant, and can differentiate between some lubricant-specific frictional properties. PMID- 24164716 TI - Does moderate or severe nonspecific knee injury affect radiographic osteoarthritis incidence and progression? AB - BACKGROUND: Knee injuries can lead to radiographic osteoarthritis (ROA). Injuries may be "specific" (SI) including ligament or meniscal tears or patellar trauma, or "nonspecific" (NSI). Our objective is to understand the effect of knee NSI on ROA incidence and progression. METHODS: 163 people (sample-weighted for population representativeness) aged 40+ with history of knee pain had radiographs assessed on Kellgren Lawrence (KL) grade (0/1 collapsed) at baseline and follow up (median 3.2 years apart). Progression was an increase in KL score. SIs and NSIs were labeled "severe" (walking aid for >=1 week) or "moderate". One model treated SI and NSI as dichotomous (yes/no), and another as trichotomous (none/moderate/severe). Models were adjusted for age, sex, BMI, KL grade and follow-up time. RESULTS: SI/NSI history was none, moderate (7.8/24.4%) or severe (11.0/10.8%). Duration at baseline since SI/NSI ranged from <1 year to several decades (SI/NSI mean 4.6/6.5 years). SI was significantly associated with ROA incidence and progression (odds ratio (OR) = 2.90; 95% CI = 1.04, 8.09), but NSI showed no significant effect (OR = 1.36; 95% CI = 0.61, 3.02). In the trichotomous model, severe SI was significant (OR = 4.35, 95% CI = 1.26, 15.02), while moderate SI was not (OR = 1.51, 95% CI = 0.33, 6.84). NSI showed no effect: moderate OR = 1.51, 95% CI = 0.61, 3.74; severe OR = 0.90, 95% CI = 0.24, 3.40. This study had 80% power to detect an NSI OR of 2.9. CONCLUSION: We find no evidence that history of NSI affects knee ROA incidence and progression in a population with knee pain, adjusting for SI, age, sex, BMI, KL grade and follow up time. PMID- 24164717 TI - Treatment of pruritus with Prometheus dialysis and absorption system in a patient with benign recurrent intrahepatic cholestasis. AB - Benign recurrent intrahepatic cholestasis (BRIC) is an autosomal recessive liver disorder characterized by recurrent episodes of jaundice and itching. Episodes of cholestasis last variously from 1 week to several months, may start at any age and usually resolve spontaneously. No effective treatment has been found as yet. We report a case of genetically proven BRIC in a male patient who developed three episodes of pruritus and jaundice at the age of 14, 16 and 19 years. During the third episode, he did not respond to pharmacological medical therapy, and fractionated plasma separation and absorption (FPSA, Prometheus) was performed to manage intractable pruritus. The treatment immediately alleviated pruritus, lowered serum bilirubin concentration and induced sustained remission in the 5 year follow up. FPSA seems to be a safe and effective way of treatment for BRIC in patients with severe pruritus and prolonged jaundice. PMID- 24164718 TI - Effects of chronic exposure of clonal beta-cells to elevated glucose and free fatty acids on incretin receptor gene expression and secretory responses to GIP and GLP-1. AB - AIM: The incretin effect, mediated by glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1), is impaired in type 2 diabetes. METHODS: This study examines the effects of prolonged exposure to elevated glucose and free fatty acids in clonal BRIN BD11 cells on GIP and GLP-1 action. RESULTS: Glucotoxic conditions (18 h) had no effect on GIP- or GLP-1 mediated insulinotropic responses. In contrast, 48 h glucotoxic culture impaired (p < 0.05 to p < 0.001) insulin release in response to GLP-1, and particularly GIP. Culture under lipotoxic conditions (18 h) impaired (p < 0.05 to p < 0.001) the insulin-releasing effect of GIP, but was without effect on GLP-1. However, 48 h lipotoxic culture compromised both GIP (p < 0.05 to p < 0.001) and GLP-1 (p < 0.05 to p < 0.01) insulin-releasing actions. Glucolipotoxic culture (18 h) completely annulled the insulinotropic action of GIP, whereas GLP-1 effects were similar to control. However, when glucolipotoxic culture was extended to 48 h, both GIP- and GLP-1-mediated effects were (p < 0.05 to p < 0.001) impaired. Assessment of cell viability, number and insulin content revealed detrimental (p < 0.05 to p < 0.001) effects under all culture conditions, barring 18 h glucotoxic and lipotoxic culture. Finally, GIP-R gene and protein expression was increased (p < 0.05 to p < 0.01) under glucotoxic culture, with decreased (p < 0.05 to p < 0.001) expression following glucolipotoxic culture. GLP-1-R gene expression followed a similar trend, but protein levels were generally reduced under all culture conditions. CONCLUSION: The results indicate that impaired insulinotropic response to GIP and GLP-1 under diabetic milieu involves mechanisms beyond simple expression of respective receptors. PMID- 24164721 TI - Can interchangeability of lincosamides be assumed in clinical practice? Comparative MICs of clindamycin and lincomycin for Streptococcus pyogenes, Streptococcus agalactiae and Staphylococcus aureus. PMID- 24164719 TI - Effects of blood triglycerides on cardiovascular and all-cause mortality: a systematic review and meta-analysis of 61 prospective studies. AB - The relationship of triglycerides (TG) to the risk of death remains uncertain. The aim of this study was to determine the associations between blood triglyceride levels and cardiovascular diseases (CVDs) mortality and all-cause mortality. Four databases were searched without language restriction for relevant studies: PubMed, ScienceDirect, EMBASE, and Google Scholar. All prospective cohort studies reporting an association between TG and CVDs or all-cause mortality published before July 2013 were included. Risk ratios (RRs) with 95% confidence intervals (CIs) were extracted and pooled according to TG categories, unit TG, and logarithm of TG using a random-effects model with inverse-variance weighting. We identified 61 eligible studies, containing 17,018 CVDs deaths in 726,030 participants and 58,419 all-cause deaths in 330,566 participants. Twelve and fourteen studies, respectively, reported the effects estimates of CVDs and total mortality by TG categories. Compared to the referent (90-149 mg/dL), the pooled RRs (95% CI) of CVDs mortality for the lowest (< 90 mg/dL), borderline high (150-199 mg/dL), and high TG (>= 200 mg/dL) groups were 0.83 (0.75 to 0.93), 1.15 (1.03 to 1.29), and 1.25 (1.05 to 1.50); for total mortality they were 0.94 (0.85 to 1.03), 1.09 (1.02 to 1.17), and 1.20 (1.04 to 1.38), respectively. The risks of CVDs and all-cause deaths were increased by 13% and 12% (p < 0.001) per 1-mmol/L TG increment in twenty-two and twenty-two studies reported RRs per unit TG, respectively. In conclusion, elevated blood TG levels were dose-dependently associated with higher risks of CVDs and all-cause mortality. PMID- 24164720 TI - CYP709B3, a cytochrome P450 monooxygenase gene involved in salt tolerance in Arabidopsis thaliana. AB - BACKGROUND: Within the Arabidopsis genome, there are 272 cytochrome P450 monooxygenase (P450) genes. However, the biological functions of the majority of these P450s remain unknown. The CYP709B family of P450s includes three gene members, CYP709B1, CYP709B2 and CYP709B3, which have high amino acid sequence similarity and lack reports elucidating biological functions. RESULTS: We identified T-DNA insertion-based null mutants of the CYP709B subfamily of genes. No obvious morphological phenotypes were exhibited under normal growth conditions. When the responses to ABA and salt stress were studied in these mutants, only the cyp709b3 mutant showed sensitivity to ABA and salt during germination. Under moderate salt treatment (150 mM NaCl), cyp709b3 showed a higher percentage of damaged seedlings, indicating a lower tolerance to salt stress. CYP709B3 was highly expressed in all analyzed tissues and especially high in seedlings and leaves. In contrast, CYP709B1 and CYP709B2 were highly expressed in siliques, but were at very low levels in other tissues. Under salt stress condition, CYP709B3 gene expression was induced after 24 hr and remained at high expression level. Expression of the wild type CYP709B3 gene in the cyp709b3 mutant fully complemented the salt intolerant phenotype. Furthermore, metabolite profiling analysis revealed some differences between wild type and cyp709b3 mutant plants, supporting the salt intolerance phenotype of the cyp709b3 mutant. CONCLUSIONS: These results suggest that CYP709B3 plays a role in ABA and salt stress response and provides evidence to support the functions of cytochrome P450 enzymes in plant stress response. PMID- 24164722 TI - CCR5-Delta32: implications in SLE development. AB - Systemic lupus erythematosus (SLE) is a prototypical autoimmune disease with strong genetic and environmental components. Previous studies have shown increased levels of several chemokines in active SLE. C-C chemokine receptor type 5 (CCR5) is involved in the recruitment of inflammatory cells into tissues, and mechanisms modulating CCR5 expression and function may interfere in SLE development, influencing the clinical course of the disease. The aim of this study was to evaluate the possible association between the CCR5?32 base-pair deletion polymorphism and SLE disease in a group of Portuguese patients. A total of 219 patients with SLE and 205 healthy individuals were studied. The frequency of CCR5/?32 heterozygotes was lower in patients with SLE than in controls (8% vs. 15% OR = 0.5162; P = 0.0319), suggesting a protective association between CCR5?32 allele and SLE. These results highlight the protective role of Th1 cells that express CCR5 in SLE pathogenesis. PMID- 24164724 TI - Multiple cerebral cryptococcomas in an immunocompetent man: an unlikely diagnosis. PMID- 24164723 TI - Psychosis 101: evaluating a training programme for northern and remote youth mental health service providers. AB - BACKGROUND: Most of the early psychosis intervention (EPI) training has focused on family physicians participants. In Northern Ontario, there is a shortage of primary care. This paper will present evaluation results of a pilot training programme for rural and remote youth mental health service providers. METHOD: A mixed methods approach was used. We evaluated a 2-day workshop about EPI for non medical mental health workers delivered onsite and simultaneously by videoconferencing. There were 19 participants across four agencies. Seven were onsite and 12 were offsite. Participants' knowledge was measured using a validated questionnaire at pre-intervention and at 3-, 6- and 9-month follow up. A repeated measures ANOVA was used to evaluate knowledge acquisition between the two modes of training. At 6 months, focus group interviews were conducted to explore their experiences of the mode of intervention delivery and evaluation. Emerging themes were iteratively derived through a series of discussions involving independent coders. RESULTS: Only 15 complete datasets were available of the 19 original participants. Differences in knowledge acquisition between the two groups did not reach statistical difference. Six-month focus group data indicated that participants improved their relationship with EPI services and they were part of a strengthened network with other providers in the region. Post intervention, the accuracy of referrals from participating agencies increased dramatically, with an increase in proportion of referrals who were eligible for EPI services. The follow-up process engaged participants in learning and re engaged them with the material taught during the training session. CONCLUSIONS: The results about developing service partnerships and relationship with specialist services are encouraging for policy and service decision-makers to address mental health service needs in northern and remote areas. PMID- 24164725 TI - Variations on the theme: allosteric control in hemoglobin. AB - Conformational selection between pre-existing structural states of an oligomeric protein was the conceptual step behind the formulation of Monod-Wyman-Changeux (MWC) allosteric theory. Variations on the basic theme of allosteric control are briefly illustrated in this paper by reference to some hemoglobins from different species whose functional properties were found to respond to specific physiological requirements. In my opinion the enormous success of the allosteric theory may be attributed not only to its efficiency in accounting for data and its formal mathematical elegance, but also because the selective mechanism conforms to the founding concept of Darwinian evolution. PMID- 24164726 TI - Not your ordinary yeast: non-Saccharomyces yeasts in wine production uncovered. AB - Saccharomyces cerevisiae and grape juice are 'natural companions' and make a happy wine marriage. However, this relationship can be enriched by allowing 'wild' non-Saccharomyces yeast to participate in a sequential manner in the early phases of grape must fermentation. However, such a triangular relationship is complex and can only be taken to 'the next level' if there are no spoilage yeast present and if the 'wine yeast' - S. cerevisiae - is able to exert its dominance in time to successfully complete the alcoholic fermentation. Winemakers apply various 'matchmaking' strategies (e.g. cellar hygiene, pH, SO2 , temperature and nutrient management) to keep 'spoilers' (e.g. Dekkera bruxellensis) at bay, and allow 'compatible' wild yeast (e.g. Torulaspora delbrueckii, Pichia kluyveri, Lachancea thermotolerans and Candida/Metschnikowia pulcherrima) to harmonize with potent S. cerevisiae wine yeast and bring the best out in wine. Mismatching can lead to a 'two is company, three is a crowd' scenario. More than 40 of the 1500 known yeast species have been isolated from grape must. In this article, we review the specific flavour-active characteristics of those non-Saccharomyces species that might play a positive role in both spontaneous and inoculated wine ferments. We seek to present 'single-species' and 'multi-species' ferments in a new light and a new context, and we raise important questions about the direction of mixed-fermentation research to address market trends regarding so-called 'natural' wines. This review also highlights that, despite the fact that most frontier research and technological developments are often focussed primarily on S. cerevisiae, non-Saccharomyces research can benefit from the techniques and knowledge developed by research on the former. PMID- 24164727 TI - Consent and capacity in children and young people. PMID- 24164728 TI - Safety netting in healthcare settings: what it means, and for whom? AB - Everyday thousands of children are presented to health care practitioners by concerned parents with the vast majority being simple self-limiting illness. However serious bacterial illness, chronic inflammatory conditions and mental health problems are repeatedly missed with significant morbidity, mortality, financial and social implications. A conceptual framework detailing the mechanism of effective Safety Netting has yet to be described however and there is increasing evidence parents want guidance on when to seek medical advice (a key part of safety netting) prior to initial consultation. This article explores current understanding of safety netting in relation to child health and argues there is a need to develop a more standardised approach. PMID- 24164729 TI - Infant mortality fell by a third in India from 2003 to 2012. PMID- 24164730 TI - Epigenetic repression of miR-129-2 in cancer. PMID- 24164731 TI - Free functional muscle transplantation of an anomalous femoral adductor with a very large muscle belly: a case report. AB - We report the case of a 34-year-old man with a total brachial plexus injury that was treated by free functional muscle transplantation to restore simultaneously elbow flexion and finger extension. The muscle had a very large muscle belly (12 cm width), which was considered anatomically to be a fusion of the gracilis and the adductor longus muscles. Although the muscle possessed two major vascular pedicles with almost equal diameters, only the proximal vascular pedicle was anastomosed to the recipient vessels during the transplantation surgery, resulting in partial necrosis of the muscle. Several authors have reported on the successful simultaneous transplantation of the gracilis and adductor longus muscles, because they are supplied generally by a single common vascular pedicle. However, the present study suggests that when a surgeon encounters an aberrant femoral adductor with a very large muscle belly that can be considered to be a fusion of these muscles, the surgeon should assess intraoperatively the vascularity of the muscle using Doppler sonography, indocyanine green fluorescence injection, or other techniques. PMID- 24164733 TI - Differential effects of current specific treatments on behavioral and psychological symptoms in patients with Alzheimer's disease: a 12-month, randomized, open-label trial. AB - BACKGROUND: Behavioral and psychological symptoms of dementia (BPSD) occur in up to 80% of Alzheimer's disease (AD) patients and represent one of the most common reasons for early institutionalization and increase in management costs. OBJECTIVES: This study evaluated the effects of four drugs (memantine, donepezil, rivastigmine, galantamine) in BPSD in AD patients. METHODS: This was a prospective, longitudinal, randomized, open-label, 4-arm, parallel-group, 12 month clinical trial carried out in 177 AD patients. The severity of BPSD was evaluated at baseline and after treatment with memantine (n = 48), donepezil (n = 42), rivastigmine (n = 46), and galantamine (n = 41), by using the Neuropsychiatric Inventory (NPI) and the Behavioural Pathology in Alzheimer's Disease (BEHAVE-AD) scales. RESULTS: The NPI and BEHAVE-AD total scores improved from baseline to month 12 in all groups. The improvements in both scales were statistically significant in the memantine, donepezil, and rivastigmine groups, but not in the galantamine group. Responder analyses showed that treatment with memantine and rivastigmine resulted in more patients improving on NPI and BEHAVE AD score, respectively. Agitation/aggression was the NPI item with the highest improvements (significantly versus baseline in the memantine and in the rivastigmine groups), while aggression and anxiety/phobias were the mostly improved BEHAVE-AD items (significantly in the rivastigmine group for both and in the rivastigmine group only for anxiety/phobias). All treatments were well tolerated: most of adverse events reported were transient and of mild-to-moderate intensity. CONCLUSIONS: This study suggests that specific drugs for AD, especially memantine and rivastigmine, may be effective in the improvement of BPSD in patients with mild to moderate AD, without major side effects. PMID- 24164734 TI - Acute aerobic exercise increases brain-derived neurotrophic factor levels in elderly with Alzheimer's disease. AB - Studies indicate the involvement of brain-derived neurotrophic factor (BDNF) in the pathogenesis of Alzheimer's disease (AD). Decreased BDNF levels may constitute a lack of trophic support and contribute to cognitive impairment in AD. The benefits of acute and chronic physical exercise on BDNF levels are well documented in humans, however, exercise effects on BDNF levels have not been analyzed in older adults with AD. The aim of this study was to investigate the effects of acute aerobic exercise on BDNF levels in older adults with AD and to verify associations among BDNF levels, aerobic fitness, and level of physical activity. Using a controlled design, twenty-one patients with AD (76.3 +/- 6.2 years) and eighteen healthy older adults (74.6 +/- 4.7 years) completed an acute aerobic exercise. The outcomes included measures of BDNF plasma levels, aerobic fitness (treadmill grade, time to exhaustion, VO2, and maximal lactate) and level of physical activity (Baecke Questionnaire Modified for the Elderly). The independent t-test shows differences between groups with respect to the BDNF plasma levels at baseline (p = 0.04; t = 4.53; df = 37). In two-way ANOVA, a significant effect of time was found (p = 0.001; F = 13.63; df = 37), the aerobic exercise significantly increased BDNF plasma levels in AD patients and healthy controls. A significant correlation (p = 0.04; r = 0.33) was found between BDNF levels and the level of physical activity. The results of our study suggest that aerobic exercise increases BDNF plasma levels in patients with AD and healthy controls. In addition to that, BDNF levels had association with level of physical activity. PMID- 24164736 TI - Glutaminyl cyclase in human cortex: correlation with (pGlu)-amyloid-beta load and cognitive decline in Alzheimer's disease. AB - Brains of Alzheimer's disease (AD) patients are characterized in part by the formation of high molecular weight aggregates of amyloid-beta (Abeta) peptides, which interfere with neuronal function and provoke neuronal cell death. The pyroglutamate (pGlu) modification of Abeta was demonstrated to be catalyzed by the enzyme glutaminyl cyclase (QC) and to enhance pathogenicity and neurotoxicity. Here, we addressed the role of QC in AD pathogenesis in human cortex. Two sets of human postmortem brain tissue from a total of 13 non-demented controls and 11 AD cases were analyzed by immunohistochemistry and unbiased stereology, quantitative RT-PCR, and enzymatic activity assays for the expression level of QC in temporal and entorhinal cortex. Additionally, cortical Abeta and pGlu-Abeta concentrations were quantified by ELISA. Data on QC expression and Abeta peptide concentrations were correlated with each other and with the Mini Mental State Examination (MMSE) of individual cases. In control cases, QC expression was higher in the more vulnerable entorhinal cortex than in temporal cortex. In AD brains, QC mRNA expression and the immunoreactivity of QC were increased in both cortical regions and frequently associated with pGlu-Abeta deposits. The analyses of individual cases revealed significant correlations between QC mRNA levels and the concentration of insoluble pGlu-Abeta aggregates, but not of unmodified Abeta peptides. Elevated pGlu-Abeta load showed a better correlation with the decline in MMSE than elevated concentration of unmodified Abeta. Our observations provide evidence for an involvement of QC in AD pathogenesis and cognitive decline by QC-catalyzed pGlu-Abeta formation. PMID- 24164735 TI - Association of mediterranean diet with mild cognitive impairment and Alzheimer's disease: a systematic review and meta-analysis. AB - BACKGROUND/OBJECTIVE: To conduct a systematic review of all studies to determine whether there is an association between the Mediterranean diet (MeDi) and cognitive impairment. METHODS: We conducted a comprehensive search of the major databases and hand-searched proceedings of major neurology, psychiatry, and dementia conferences through November 2012. Prospective cohort studies examining the MeDi with longitudinal follow-up of at least 1 year and reporting cognitive outcomes (mild cognitive impairment [MCI] or Alzheimer's disease [AD]) were included. The effect size was estimated as hazard-ratio (HR) with 95% confidence intervals (CIs) using the random-effects model. Heterogeneity was assessed using Cochran's Q-test and I2-statistic. RESULTS: Out of the 664 studies screened, five studies met eligibility criteria. Higher adherence to the MeDi was associated with reduced risk of MCI and AD. The subjects in the highest MeDi tertile had 33% less risk (adjusted HR = 0.67; 95% CI, 0.55-0.81; p < 0.0001) of cognitive impairment (MCI or AD) as compared to the lowest MeDi score tertile. Among cognitively normal individuals, higher adherence to the MeDi was associated with a reduced risk of MCI (HR = 0.73; 95% CI, 0.56-0.96; p = 0.02) and AD (HR = 0.64; 95% CI, 0.46-0.89; p = 0.007). There was no significant heterogeneity in the analyses. CONCLUSIONS: While the overall number of studies is small, pooled results suggest that a higher adherence to the MeDi is associated with a reduced risk of developing MCI and AD, and a reduced risk of progressing from MCI to AD. Further prospective-cohort studies with longer follow-up and randomized controlled trials are warranted to consolidate the evidence. Systematic review registration number: PROSPERO 2013: CRD42013003868. PMID- 24164737 TI - Isorhynchophylline treatment improves the amyloid-beta-induced cognitive impairment in rats via inhibition of neuronal apoptosis and tau protein hyperphosphorylation. AB - The progressive accumulation of amyloid-beta (Abeta) in the form of senile plaques has been recognized as a key causative factor leading to the cognitive deficits seen in Alzheimer's disease (AD). Recent evidence indicates that Abeta induces neurotoxicity in the primary neuronal cultures as well as in the brain. Previously, we have demonstrated that isorhynchophylline (IRN), the major chemical ingredient of Uncaria rhynchophylla, possessed potent neuroprotective effects. In the present study, we aimed to investigate the effect of IRN on cognitive function, neuronal apoptosis, and tau protein hyperphosphorylation in the hippocampus of the Abeta25-35-treated rats and to elucidate its action mechanisms. We showed that Abeta25-35 injection caused spatial memory impairment, neuronal apoptosis, and tau protein hyperphosphorylation. Treatment with IRN (20 or 40 mg/kg) for 21 days could significantly ameliorate the cognitive deficits induced by Abeta25-35 in the rats. In addition, IRN attenuated the Abeta25-35 induced neuronal apoptosis in hippocampus by down-regulating the protein and mRNA levels of the ratio of Bcl-2/Bax, cleaved caspase-3 and caspase-9, as well as suppressing the tau protein hyperphosphorylation at the Ser396, Ser404, and Thr205 sites. Mechanistic study showed that IRN could inhibit the glycogen synthase kinase 3beta (GSK-3beta) activity, and activate the phosphorylation of phosphatidylinositol 3-kinase (PI3K) substrate Akt. These results indicate that down-regulation of GSK-3beta activity and activation of PI3K/Akt signaling pathway are intimately involved in the neuroprotection of IRN. The experimental findings provide further evidence to affirm the potential of IRN as a worthy candidate for further development into a therapeutic agent for AD and other tau pathology-related neurodegenerative diseases. PMID- 24164738 TI - Simvastatin treatment preserves synaptic plasticity in AbetaPPswe/PS1dE9 mice. AB - Epidemiological evidence suggests that chronic treatment with simvastatin may protect against the development of Alzheimer's disease (AD), but as yet it is unclear how this effect is mediated. Extensive data also indicates that the amyloid beta-protein (Abeta) plays a central role in the disease process, and it has been suggested that the protective effects of simvastatin may be mediated by reducing Abeta production or by counteracting the toxic effects of Abeta. Accordingly, using the AbetaPPswe/PS1dE9 mouse model of AD, we investigated the effects of simvastatin on long-term potentiation (LTP), amyloid biology, and two key kinases involved in Abeta-mediated toxicity. Since burgeoning data indicate that both fibrillar and non-fibrillar forms of Abeta play a prominent role in AD pathogenesis, we were careful to investigate the effects of simvastatin on three biochemically distinct pools of Abeta. In untreated AbetaPPswe/PS1dE9 mice, there was a dramatic and significant increase in the levels of water-soluble Abeta between 6 and 8 months, but this remained constant between 8 and 18 months. In contrast, the concentrations of detergent-soluble and formic acid (FA)-soluble Abeta species increased across all ages examined, thus demonstrating that while amyloid deposition continued, the levels of water-soluble Abeta remained relatively constant. LTP was normal at 6 months, but was significantly impaired at 8 and 18 months. Importantly, a diet supplemented with 0.04% simvastatin for one month (at 7 months) positively affected synaptic plasticity in AbetaPPswe/PS1dE9 mice and did not significantly alter levels of water-soluble, detergent-soluble, or FA-soluble Abeta, but did increase phosphorylation of both Akt and GSK-3, while tau and tau phosphorylation were unaltered. These results indicate that the protective effects of simvastatin may be mediated by maintaining signaling pathways that help to protect and rescue LTP. PMID- 24164739 TI - A new paradigm of quality of care in rheumatoid arthritis: how our new therapeutics have changed the game. AB - Demonstrating the effectiveness of expensive new rheumatoid arthritis (RA) therapeutics is imperative to determine whether the quality of care has improved with the introduction of these agents. Our current RA quality measures are primarily process based, but they must become outcomes based to better demonstrate quality. New RA quality measures must be multidimensional, accounting for all of the important outcomes in RA: radiographic, functional status, and disease activity. To fully understand the potential benefits of new therapeutics in RA, outcome measures must be integrated with routine practice. PMID- 24164740 TI - Double transfer UV-curing nanoimprint lithography. AB - A challenge in the fabrication of nanostructures into non-planar substrates is to form a thin, uniform resist film on non-planar surfaces. This is critical to the fabrication of nanostructures via a lithographic technique due to the subsequent pattern transfer process. Here we report a new double transfer UV-curing nanoimprint technique that can create a nanopatterned thin film with a uniform residual layer not only on flat substrates but also on highly curved surfaces. Surface relief gratings with pitches down to 200 nm are successfully imprinted on the cylindrical surface of optical fibers, and further transferred into a SiO2 matrix using reactive ion etching (RIE), demonstrating that our technique is applicable for fabricating high-resolution nanostructures on non-planar substrates. PMID- 24164741 TI - Divergent processing of monetary and social reward in behavioral variant frontotemporal dementia and Alzheimer disease. PMID- 24164742 TI - Development and application of the Chinese version of the adult strabismus quality of life questionnaire (AS-20): a cross-sectional study. AB - BACKGROUND: Patients with strabismus experience visual dysfunction, self-image disorders, low self-esteem, and social and emotional barriers, which adversely influence their health-related quality of life (HRQoL). Currently no strabismus specific questionnaire is available in China to identify patients' quality of life and to evaluate the effectiveness of strabismus treatment. The aims of the present study were to validate the Chinese-language version of the Adult Strabismus Quality of Life Questionnaire (AS-20) and to evaluate the impacts of strabismus on the quality of life among Chinese strabismus patients. METHODS: Two hundred and fifty-five Chinese adults with strabismus, one hundred visually normal adults and one hundred patients with other eye diseases completed the Chinese version of AS-20. Psychometric properties of the Chinese AS-20 were examined by Cronbach's alpha coefficient, test-retest and split-half reliability, and construct and criterion-related validity. Independent-samples t test and one way ANOVA analyses were conducted to explore the impact of demographic factors and clinical characteristics on HRQoL in Chinese strabismic adults. RESULTS: The final AS-20 in Chinese (AS-C) included 18 items and two subscales: psychosocial (12 items) and function (6 items). The Cronbach's alpha was 0.908 for overall scale, with 0.913 and 0.808 for 'psychosocial' and 'function' subscales respectively, indicating high internal consistency reliability. The mean of the overall AS-C score among strabismus patients was 62.80 +/- 18.94, significantly lower than that in visually normal adults (t = -18.693, P < 0.001), and in patients with other eye diseases (t = -5.512, P < 0.001). CONCLUSIONS: The AS-C is a culturally appropriate tool to evaluate the HRQoL in Chinese strabismus adults. The psychosocial health well-being and overall quality of life in strabismic patients should receive greater emphasis. PMID- 24164743 TI - CpG island methylator phenotype and its relationship with prognosis in adult acute leukemia patients. AB - OBJECTIVE: To investigated the relationship between CpG island methylator phenotype (CIMP) and prognosis in adults with acute leukemia. METHODS: Bone marrow samples from 53 acute myeloid leukemia and 50 acute lymphoblastic leukemia patients were collected. The methylation status of 18 tumor suppressor genes was determined using methylation-specific polymerase chain reaction. RESULTS: Greater than 30% of acute leukemia patients had methylated p15, p16, CDH1, CDH13, RUNX3, sFRP1, ID4, and DLC-1 genes; methylation of >=4 were defined as CIMP positive. Age, type of leukemia, white blood cell count, and CIMP status were significantly associated with recurrence-free survival (RFS) and overall survival (OS) (P < 0.05). CIMP status was an independent prognostic factor for OS (hazard ratio: 2.07, 95% confidence interval: 1.03-4.15, P = 0.040). CIMP-negative patients had significantly improved RFS and OS (P < 0.05). p16 and DLC1 methylation was significantly associated with RFS and OS (P < 0.05). CONCLUSIONS: CIMP may serve as an independent risk factor for evaluating the prognosis of patients with acute leukemia. PMID- 24164744 TI - Pre- and postoperative nutritional assessment and health-related quality of life in recipients of living donor liver transplantation. AB - AIM: The nutritional state of living donor liver transplantation (LDLT) recipients is one of the most important factors affecting postoperative outcome. Although the assessment of health-related quality of life (HRQOL) is of increasing importance, few studies have examined this in conjunction with LDLT recipient nutritional state. METHODS: Ten LDLT recipients with end-stage liver disease were recruited for this study. Measurements of energy expenditure, anthropometrics and laboratory data were performed before and 1, 6 and 12-24 months after LDLT. HRQOL was measured by using the 36-item Short-Form (SF-36) before and 1, 3, 6 and 12-24 months after LDLT. RESULTS: The preoperative value of non-protein respiratory quotient (npRQ) was 0.796 +/- 0.026 and it increased significantly after the operation. Serum non-esterified fatty acid (NEFA) levels were high in the preoperative state, but had significantly decreased 1 month after the operation. A negative correlation between npRQ and NEFA was observed throughout the study period. Cholinesterase and albumin levels improved to normal levels within 6 and 12-24 months, respectively. The recovery of the physical component summary of the SF-36 was observed after the improvement of all domains of laboratory data and energy metabolism based on the nutritional state. CONCLUSION: This study demonstrated that the recovery of metabolic function, laboratory data and HRQOL in LDLT recipients are variable, and it took more than 6 months to normalize the liver protein synthetic capacity and physical HRQOL score periods. Therefore, long-term nutritional support is required in LDLT recipients. PMID- 24164745 TI - Successful carbon dioxide laser treatment for verrucous epidermal nevi on the nipple. PMID- 24164746 TI - A "tale of two countries": Narratives of hearts, patients and doctors in the Spanish press. AB - In this article we explore how the Spanish written press--ABC, La Vanguardia, and Blanco y Negro--and the official newsreel No-Do, created and disseminated a narrative about heart transplantations at the end of the 1960s. We consider how Franco's regime used Christiaan Barnard's heart transplants to legitimize the Spanish dictatorship and as a means of signifying scientific progress, modernization and national pride. The Spanish press created the plot of the first transplantations like that of a television series, presenting daily installments on the patients' progress, dramatizing the stories and ensuring the public's emotional attachment. The three main characters in the story: donors, patients and surgeons, formed a symbolic, indivisible narrative triangle endowed with singular meaning. This Spanish narrative of organ transplant technology was deployed through what we have called "a tale of two countries", that, emulating the South African's success, constructed in Martinez-Bordiu, Franco's son-in-law, a home-grown, masculine scientific personality capable of performing heart surgery and endorsing Franco's investment in scientific modernization. PMID- 24164747 TI - The Bio:Fiction film festival: Sensing how a debate about synthetic biology might evolve. AB - Synthetic biology (SB) is a new techno-scientific field surrounded by an aura of hope, hype and fear. Currently it is difficult to predict which way the public debate - and thus the social shaping of technology - is heading. With limited hard evidence at hand, we resort to a strategy that takes into account speculative design and diegetic prototyping, accessing the Bio:Fiction science film festival, and its 52 short films from international independent filmmakers. Our first hypothesis was that these films could be used as an indicator of a public debate to come. The second hypothesis was that SB would most likely not follow the debate around genetic engineering (framing technology as conflict) as assumed by many observers. Instead, we found good evidence for two alternative comparators, namely nanotechnology (technology as progress) and information technology (technology as gadget) as stronger attractors for an upcoming public debate on SB. PMID- 24164748 TI - Predicting response to chemoradiotherapy in rectal cancer: are we there yet? PMID- 24164749 TI - The importance of not overstaging mesorectal lymph nodes seen on MRI. PMID- 24164753 TI - Three patients with mood disorders showing catatonia and frontotemporal lobes atrophy. AB - Here we report the cases of three patients with mood disorders showing catatonia and frontotemporal lobe atrophy. Catatonia is a syndrome linked to frontal dysfunction that most frequently occurs in patients with mood disorders. The diagnostic criteria of catatonia and frontotemporal dementia partly overlap. In the present patients, catatonia might be closely related to frontal dysfunction caused by frontotemporal lobe atrophy. With regard to therapeutics for catatonia, we found that administering a low dose of lorazepam alone or after electroconvulsive therapy may be useful for treating and preventing catatonia. We also found that administering glutaminate antagonists such as memantine may be useful for treating lorazepam-resistant catatonia. PMID- 24164754 TI - IgG4-related sclerosing cholangitis: the cholangiocarcinoma mimic. PMID- 24164755 TI - Prevalence of chronic wounds and structural quality indicators of chronic wound care in Dutch nursing homes. AB - The aim of this study was to measure the prevalence of (infected) chronic wounds in Dutch nursing homes and to explore which signs and symptoms are used to diagnose infected chronic wounds. Moreover, it was to determine which structural quality indicators related to chronic wound care at ward and institutional levels were fulfilled. In April 2012, as part of the annual National Prevalence Measurement of Care Problems of Maastricht University [Landelijke Prevalentiemeting Zorgproblemen (LPZ)], a multi-center cross-sectional point prevalence measurement was carried out together with an assessment of relevant care quality indicators. The prevalence was 4.2%; 16 of 72 (22%) chronic wounds were considered to be infected. Increase of exudate (81.3%; n = 13), erythema (68.8%; n = 11), pain (56.3%; n = 9) and wound recalcitrance (56.3%; n = 9) were considered to be diagnostic signs and symptoms of a chronic wound infection. Although at institutional level most quality indicators were fulfilled, at ward level this was not the case. Despite the relatively low number of residents, we consider our population as representative for the nursing home population. It may be an advantage to appoint specific ward nurses and to provide them specifically with knowledge and skills concerning chronic wounds. PMID- 24164756 TI - What diagnostic tools are available to document death by H2S exposure? AB - The Occupational Medicine Forum is prepared by the ACOEM Occupational and Environmental Medical Practice Committee and does not necessarily represent an official ACOEM position. The Forum is intended for health professionals and is not intended to provide medical or legal advice, including illness prevention, diagnosis or treatment, or regulatory compliance. Such advice should be obtained directly from a physician and/or attorney. PMID- 24164757 TI - Pesticide risk perception and biomarkers of exposure in Florida female farmworkers. AB - OBJECTIVE: To compare workplace characteristics, workplace behaviors, and the health beliefs of female farmworkers of childbearing age with actual biomarkers of exposure to organophosphate pesticides and to the fungicide mancozeb. METHODS: Hispanic and Haitian farmworkers between the ages of 18 and 40 years working in nursery or fernery operations were recruited to participate in a cross-sectional survey, examining demographics, work practices, work-related hygiene, and pesticide exposure beliefs. Single-void (spot) urine samples were analyzed for organophosphate and ethylenethiourea metabolites. RESULTS: Women in nurseries worried less frequently about the effects of pesticides on their health than those in fernery operations. In summary, organophosphate and ethylenethiourea levels in nursery workers were significantly higher than levels in fernery workers and the control group. CONCLUSIONS: Results showed that perceived pesticide exposure did not correspond to actual metabolite levels within differing agricultural subpopulations. PMID- 24164759 TI - Health risk factors associated with presenteeism in the workplace. AB - OBJECTIVE: An emerging concern in the workplace is the productivity of employees who come to work instead of staying home when they are ill, also referred to as presenteeism. This study examined the health risks associated with presenteeism. METHODS: Using a cross-sectional correlational design, we used data from a 2010 self-reported wellness surveys. A negative binomial regression model was used to explore the association between employee health risks and presenteeism. RESULTS: The findings revealed that workplace stress (beta = 0.76; P < 0.001), stress at home (beta = 0.87; P < 0.001), and financial stress (beta = 0.59; P < 0.001) were related to presenteeism. Other health risks were not associated with presenteeism. CONCLUSIONS: We found that only stress was related to presenteeism, and other health risks were unrelated to presenteeism. PMID- 24164758 TI - Asbestos-related radiographic findings among household contacts of workers exposed to Libby vermiculite: impact of workers' personal hygiene practices. AB - OBJECTIVE: To explore the potential impact of worker hygiene by determining the prevalence of radiographic changes consistent with asbestos exposure among household contacts of workers exposed to Libby vermiculite that contained amphibole fibers. METHODS: Workers and household contacts had chest radiographs and completed questionnaires regarding hygiene and potential exposure pathways. RESULTS: Participants included 191 household contacts of 118 workers. One household contact (0.5%) had localized pleural thickening, and three (1.6%) had irregular opacities at profusion category 1/0 or greater. Worker radiographs demonstrated pleural changes in 45% and irregular opacities at profusion category 1/0 or greater in 8%. CONCLUSIONS: Libby vermiculite-exposed workers demonstrated an elevated prevalence of pleural and interstitial chest radiographic changes. There was, however, no increased prevalence of similar changes among household contacts, likely because of personal hygiene measures taken by the majority of workers. PMID- 24164761 TI - Access to health programs at the workplace and the reduction of work presenteeism: a population-based cross-sectional study. AB - OBJECTIVE: To examine access to health programs at workplace as a determinant of presenteeism among adults. METHODS: Data source was a subsample of the 2009-2010 Canadian Community Health Survey. The outcome was self-reported reduced activities at work (presenteeism). The explanatory variable was self-reported access to a health program at workplace. Logistic regression was used to measure the association between outcome and explanatory variables adjusting for potential confounders. RESULTS: Adjusting for sex, age, education, income, work stress, and chronic conditions, presenteeism was not associated with having access to a health program at workplace (adjusted odds ratio, 1.23; 95% confidence interval, 0.91 to 1.65). The odds of presenteeism were higher in workers who reported high work stress and those with chronic medical conditions. CONCLUSIONS: This study found that access to health programs at workplace is not significantly associated with a decline in presenteeism. PMID- 24164762 TI - Factors associated with fatal mining injuries among contractors and operators. AB - OBJECTIVE: To explore factors associated with fatal accidents among contractors and operators by using the Mine Safety and Health Administration database. METHODS: Cross-sectional data on 157,410 miners employed by operators or contractors during 1998-2007 were analyzed using logistic regression and multiple imputation. RESULTS: Univariate odds of fatal versus nonfatal accident were 2.8 (95% confidence interval, 2.3 to 3.4) times higher for contractors than operators. In a multivariable model, fatality was associated with contractor, less experience at the current mine, and occurrence at more than 8 hours into the workday (P < 0.05 for each). Differences in odds of fatality by employment type were more pronounced in surface mines. CONCLUSIONS: Contractors had a higher proportion of fatal injuries. Fatality also varied by mine experience, the number of hours worked before injury, work location, and mine type. PMID- 24164763 TI - Chemical control measures for dermal exposure in Australian workplaces. AB - OBJECTIVE: To investigate the relationships between occupational, workplace, and demographic factors and the provision of multilevel exposure protection systems. METHODS: Respondents reporting dermal chemical exposure at work were asked about protective measures provided to them in the workplace, which we classified as personal protection or awareness measures. An ordered logistic model was used to investigate the odds of workers reporting that both, either or neither, types of exposure control measures were provided in their workplaces. RESULTS: Larger workplace size and permanent and fixed-term employment were associated with exposure protection systems incorporating both hazard awareness and personal protective measures. CONCLUSION: Our results indicate that employment in small workplaces, nonpermanent and self-employed workers may be important intervention targets for improving workers' exposure protection. WHAT THIS PAPER ADDS: Chemical exposures in workplaces are an important occupational health and safety problem; however, there is little published information available about the provision of basic exposure controls to workers with dermal chemical exposures across industrial sectors. Using data from a large community-based survey,we found that workers in small workplaces and workers with less secure employment arrangements were more likely than others to report less comprehensive exposure control mitigation strategies. Small workplaces, temporary and casual workers, and industrial sectors in which these employment situations are common are likely to be worthwhile targets for efforts to improve exposure management systems for workers with dermal exposure to chemicals. PMID- 24164760 TI - Association between shiftwork and glomerular filtration rate in police officers. AB - OBJECTIVE: To investigate associations between shiftwork and glomerular filtration rate among white/Hispanic (n = 273) and African American (n = 81) police officers. METHODS: Analysis of variance/analysis of variance was utilized to compare mean values of estimated glomerular filtration rate (eGFR) across shiftwork categories. RESULTS: Shiftwork was significantly associated with eGFR among white/Hispanic officers only: day (88.6 +/- 2.8), afternoon (90.6 +/- 2.9), and night shift (83.1 +/- 3.1 mL/min/1.73 m); afternoon versus night, P = 0.007. Percentage of hours worked on the night shift was inversely associated with mean levels of eGFR, trend P = 0.001. Body mass index modified the association between shiftwork and eGFR (interaction P = 0.038). Among officers with body mass index 25 kg/m or higher, those who worked the night shift had the lowest mean eGFR (afternoon vs night, P = 0.012; day vs night, P = 0.029). CONCLUSIONS: Night shift work was associated with decreased kidney function among white/Hispanic officers. Longitudinal studies are warranted among all races. PMID- 24164764 TI - Workplace violence investigations and activation of the threat management teams in a multinational corporation. AB - OBJECTIVES: We examined threat management investigations conducted by a large multinational company. METHODS: The company provided a database, removing any identifiers, of investigations by the corporate Threat Management Teams in 2009 and 2010. Rates were calculated using worker population data. RESULTS: During the 2-year study period, the company investigated threat management cases at a rate of 13.9 per 10,000 employees per year. Cases that activated a Threat Management Team were more likely to lead to corrective action (odds ratio = 2.0; 95% confidence interval = 1.08 to 3.87) and referral to the Employee Assistance Program (odds ratio = 4.8; 95% confidence interval = 3.00 to 7.77), but were not related to likelihood of termination. CONCLUSION: When the multidisciplinary teams were involved, cases were more likely to result in some type of action but were not more likely to lead to termination. PMID- 24164765 TI - Low levels of exposure to libby amphibole asbestos and localized pleural thickening. AB - OBJECTIVE: To explore the relationship between low levels of exposure to Libby amphibole asbestos (LAA) and pleural abnormalities, specifically localized pleural thickening (LPT). METHODS: Three studies presenting the risks associated with quantitative LAA exposure estimates were reviewed, paying particular attention to lower exposure ranges. RESULTS: Studies reviewed were conducted among workers exposed to LAA at mining and milling operations in Libby, Montana, at a vermiculite processing facility in Marysville, Ohio, and community residents exposed to LAA from a vermiculite processing facility in Minneapolis, Minnesota. Pleural abnormalities were evaluated using radiographs. Despite differences in study populations and design, each study found that cumulative inhalation LAA exposure was associated with increased risk of LPT even at low levels of exposure. CONCLUSIONS: Inhalation exposure to LAA is associated with increased risk of LPT even at the lowest levels of exposure in each study. PMID- 24164766 TI - The relation of co-occurring musculoskeletal pain and depressive symptoms with work ability. AB - OBJECTIVE: To examine the relationship of musculoskeletal pain and depressive symptoms, occurring alone or both together, with self-rated current work ability and thoughts of early retirement. METHODS: In a nationally representative sample drawn in 2000-2001, we studied actively working subjects aged 30 to 64 years (n = 4009). RESULTS: Musculoskeletal pain was associated with moderate/poor physical work ability (adjusted odds ratio [OR] = 2.9; 95% confidence interval [CI], 2.0 to 4.2) and mental work ability (OR = 1.6; 95% CI, 1.2 to 2.2). Depressive symptoms were associated with moderate/poor mental work ability only (adjusted OR = 4.2; 95% CI, 2.3 to 7.9). Moreover, only musculoskeletal pain was associated with thoughts of early retirement (OR = 1.4; 95% CI, 1.1 to 1.8). There was an interaction between musculoskeletal pain and depressive symptoms regarding physical work ability and thoughts of early retirement. CONCLUSION: Co-occurrence of musculoskeletal pain and depressive symptoms is strongly related to poor self rated physical work ability. PMID- 24164767 TI - The 3-year disease management effect: understanding the positive return on investment. AB - OBJECTIVE: Conventional wisdom suggests that health promotion programs yield a positive return on investment (ROI) in year 3. In the case of the University of Minnesota's program, a positive ROI was achieved in the third year, but it was due entirely to the effectiveness of the disease management (DM) program. The objective of this study is to investigate why. METHODS: Differences-in differences regression equations were estimated to determine the effect of DM participation on spending (overall and service specific), hospitalizations, and avoidable hospitalizations. RESULTS: Disease management participation reduced expenditures overall, and especially in the third year for employees, and reduced hospitalizations and avoidable hospitalizations. CONCLUSIONS: The positive ROI at Minnesota was due to increased effectiveness of DM in the third year (mostly due to fewer hospitalizations) but also to the simple durability of the average DM effect. PMID- 24164768 TI - Development and evaluation of a new occupational medicine teaching module to advance self-efficacy and knowledge among medical students. AB - OBJECTIVES: Self-efficacy is defined as a person's beliefs in his or her abilities to successfully complete a task, and has been shown to influence student motivation and academic achievement. The purpose of this study was to evaluate the impact of a new European teaching module in occupational medicine on undergraduate students' self-efficacy and knowledge in the subject matter. METHODS: Pre-, in-between, and posttraining tests were used to assess self efficacy and knowledge building of 261 third-year medical students on occupational health issues. Determinants of self-efficacy and knowledge were also identified. Repeated measurement data were analyzed with multilevel statistical procedures. RESULTS: The level of self-efficacy and knowledge in occupational medicine increased after the training. Students who frequently attended the lectures scored significantly higher than sporadic attendees. There was no relation between the level of self-efficacy and the final knowledge score. CONCLUSIONS: Teaching with the new occupational medicine module was effective. Lecture attendance is an important determinant of self-efficacy and performance. Self-efficacy was not associated with knowledge score. Encouraging classroom participation may enhance student achievement. PMID- 24164769 TI - Receiving workplace mental health accommodations and the outcome of mental disorders in employees with a depressive and/or anxiety disorder. AB - OBJECTIVES: To investigate the association between receiving workplace accommodations and the 1-year risk of mood/anxiety disorders. METHODS: A general population sample of employees in Alberta, Canada, with a prior or current mental disorder (N = 715) was observed for 1 year. Mental disorders were determined on the basis of the Diagnostic and Statistical Manual, 4th revision, criteria. RESULTS: In participants who needed but did not receive any accommodations, 30.8% had a mood/anxiety disorder 1 year later. Receiving needed accommodations was associated with a lowered risk of 24.5%. Logistic regression showed that the percentage of having accommodation needs met was significantly associated with the risk of a mental disorder 1 year later (odds ratio = 0.27; 95% confidence interval = 0.11 to 0.65). CONCLUSIONS: Receiving needed accommodations was associated with better outcomes for mental disorders. Studies are needed to confirm the effectiveness of specific accommodations for enhancing the prognosis of mood/anxiety disorders. PMID- 24164770 TI - Maternal residential proximity to major roads in north west England and adverse pregnancy outcomes. AB - OBJECTIVE: To investigate the effects of maternal residential proximity to major roads on adverse pregnancy outcomes. METHODS: Major road networks in North West England were linked to the maternal residence of 190,909 births (2004 to 2008). Distance between the residence and the nearest major road was calculated and dichotomized at 200 m. Logistic regression analyses were performed to investigate the association between distance to the major road with small for gestational age, low birth weight, and preterm birth. Analyses were adjusted for maternal age, ethnicity, socioeconomic status, parity, birth season, smoking, and body mass index. RESULTS: No significant associations were observed between preterm birth (odds ratio [OR] = 1.04; 95% confidence interval [CI] = 0.98 to 1.11), low birth weight (OR = 0.99; 95% CI = 0.93 to 1.05) and small for gestational age (OR = 1.00; 95% CI = 0.95 to 1.06) and living less than 200 m from a major road. CONCLUSIONS: These results, from a study with high statistical power, suggest that living less than 200 m from a major road per se does not pose any great risk of an adverse perinatal outcome. Nevertheless, it may be limited to this geographic location. Further work is needed to quantify individual pollutant effects in pregnancy. PMID- 24164771 TI - A systematic review and meta-analysis of acute stroke unit care: what's beyond the statistical significance? AB - BACKGROUND: The benefits of stroke unit care in terms of reducing death, dependency and institutional care were demonstrated in a 2009 Cochrane review carried out by the Stroke Unit Trialists' Collaboration. METHODS: As requested by the Belgian health authorities, a systematic review and meta-analysis of the effect of acute stroke units was performed. Clinical trials mentioned in the original Cochrane review were included. In addition, an electronic database search on Medline, Embase, the Cochrane Central Register of Controlled Trials, and Physiotherapy Evidence Database (PEDro) was conducted to identify trials published since 2006. Trials investigating acute stroke units compared to alternative care were eligible for inclusion. Study quality was appraised according to the criteria recommended by Scottish Intercollegiate Guidelines Network (SIGN) and the GRADE system. In the meta-analysis, dichotomous outcomes were estimated by calculating odds ratios (OR) and continuous outcomes were estimated by calculating standardized mean differences. The weight of a study was calculated based on inverse variance. RESULTS: Evidence from eight trials comparing acute stroke unit and conventional care (general medical ward) were retained for the main synthesis and analysis. The findings from this study were broadly in line with the original Cochrane review: acute stroke units can improve survival and independency, as well as reduce the chance of hospitalization and the length of inpatient stay. The improvement with stroke unit care on mortality was less conclusive and only reached borderline level of significance (OR 0.84, 95% CI 0.70 to 1.00, P = 0.05). This improvement became statistically non significant (OR 0.87, 95% CI 0.74 to 1.03, P = 0.12) when data from two unpublished trials (Goteborg-Ostra and Svendborg) were added to the analysis. After further also adding two additional trials (Beijing, Stockholm) with very short observation periods (until discharge), the difference between acute stroke units and general medical wards on death remained statistically non-significant (OR 0.86, 95% CI 0.74 to 1.01, P = 0.06). Furthermore, based on figures reported by the clinical trials included in this study, a slightly higher proportion of patients became dependent after receiving care in stroke units than those treated in general medical wards - although the difference was not statistically significant. This result could have an impact on the future demand for healthcare services for individuals that survive a stroke but became dependent on their care givers. CONCLUSIONS: These findings demonstrate that a well-conducted meta analysis can produce results that can be of value to policymakers but the choice of inclusion/exclusion criteria and outcomes in this context needs careful consideration. The financing of interventions such as stroke units that increase independency and reduce inpatient stays are worthwhile in a context of an ageing population with increasing care needs. One limitation of this study was the selection of trials published in only four languages: English, French, Dutch and German. This choice was pragmatic in the context of this study, where the objective was to support health authorities in their decision processes. PMID- 24164772 TI - Approaches to study yeast cell aging and death. AB - For millennia, yeast has been exploited to obtain fermentation products, such as foods and beverages. For c. 50 years, yeast has been an established model organism for basic and applied research, and more specifically, for c. 15 years, this unicellular organism has been applied to dissect molecular mechanisms of cell aging and programmed cell death. In this review, we present an overview of approaches to study cell aging and death in yeast, including lifespan assessments, calorie restriction, cell viability, survival, and death markers. PMID- 24164773 TI - On challenging the American Board of Prosthodontics (ABP) examination. PMID- 24164775 TI - Electrosprayed core-shell polymer-lipid nanoparticles for active component delivery. AB - A key challenge in the production of multicomponent nanoparticles for healthcare applications is obtaining reproducible monodisperse nanoparticles with the minimum number of preparation steps. This paper focus on the use of electrohydrodynamic (EHD) techniques to produce core-shell polymer-lipid structures with a narrow size distribution in a single step process. These nanoparticles are composed of a hydrophilic core for active component encapsulation and a lipid shell. It was found that core-shell nanoparticles with a tunable size range between 30 and 90 nm and a narrow size distribution could be reproducibly manufactured. The results indicate that the lipid component (stearic acid) stabilizes the nanoparticles against collapse and aggregation and improves entrapment of active components, in this case vanillin, ethylmaltol and maltol. The overall structure of the nanoparticles produced was examined by multiple methods, including transmission electron microscopy and differential scanning calorimetry, to confirm that they were of core-shell form. PMID- 24164776 TI - Par-4 prevents breast cancer recurrence. AB - Therapy resistance and disease recurrence are two of the most challenging aspects in breast cancer treatment. A recent article in Cancer Cell makes a significant contribution toward a better understanding of this therapeutic problem by establishing downregulation of the tumor suppressor Par-4 as the primary determinant of breast cancer recurrence. This viewpoint brings forth the importance of their findings and its implications on future research and therapy. PMID- 24164777 TI - Placebo effect in burning mouth syndrome: a systematic review. AB - Placebo controls play a critical role in the evaluation of any pharmacotherapy. This review surveys the placebo arm in 12 randomized controlled trials (RCTs) investigating burning mouth syndrome (BMS) and documents a positive placebo response in 6 of them. On average, treatment with placebos produced a response that was 72% as large as the response to active drugs. The lack of homogeneity in the use of placebos adds to the difficulty in comparing results and aggregating data. Future RCTs investigating BMS would benefit from larger sample sizes, adequate follow-up periods, and use of a standard placebo. PMID- 24164778 TI - Challenges of the management of mass casualty: lessons learned from the Jos crisis of 2001. AB - BACKGROUND: Jos has witnessed a series of civil crises which have generated mass casualties that the Jos University Teaching Hospital has had to respond to from time to time. We review the challenges that we encountered in the management of the victims of the 2001 crisis. METHODOLOGY: We reviewed the findings of our debriefing sessions following the sectarian crisis of September 2001 and identified the challenges and obstacles experienced during these periods. RESULTS: Communication was a major challenge, both within and outside the hospital. In the field, there was poor field triage and no prehospital care. Transportation and evacuation was hazardous, for both injured patients and medical personnel. This was worsened by the imposition of a curfew on the city and its environs. In the hospital, supplies such as fluids, emergency drugs, sterile dressings and instruments, splints, and other consumables, blood and food were soon exhausted. Record keeping was erratic. Staff began to show signs of physical and mental exhaustion as well as features of anxiety and stress. Tensions rose between different religious groups in the hospital and an attempt was made by rioters to attack the hospital. Patients suffered poor subsequent care following resuscitation and/or surgery and there was neglect of patients on admission prior to the crisis as well as non trauma medical emergencies. CONCLUSION: Mass casualties from disasters that disrupt organized societal mechanisms for days can pose significant challenges to the best of institutional disaster response plans. In the situation that we experienced, our disaster plan was impractical initially because it failed to factor in such a prolongation of both crisis and response. We recommend that institutional disaster response plans should incorporate provisions for the challenges we have enumerated and factor in peculiarities that would emanate from the need for a prolonged response. PMID- 24164779 TI - Effects on obese women of the sugar sucrose added to the diet over 28 d: a quasi randomised, single-blind, controlled trial. AB - To investigate whether obese women can compensate for sucrose added to the diet when it is given blind, rather than gaining weight or exhibiting dysfunctional regulation of intake, in the present study, forty-one healthy obese (BMI 30-35 kg/m2) women (age 20-50 years), not currently dieting, were randomly assigned to consume sucrose (n 20) or aspartame (n 21) drinks over 4 weeks in a parallel single-blind design. Over the 4 weeks, one group consumed 4 * 250 ml sucrose drinks (total 1800 kJ/d) and the other group consumed 4 * 250 ml aspartame drinks. During the baseline week and experimental weeks, body weight and other biometric data were measured and steps per day, food intake using 7 d unweighed food diaries, and mood using ten- or seven-point Likert scales four times a day were recorded. At the end of the experiment, the participants weighed 1.72 (SE 0.47) kg less than the value predicted by the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) model; the predicted body weight accounted for 94.3% of the variance in the observed body weight and experimental group accounted for a further 1.1% of the variance in the observed body weight, showing that women consuming sucrose drinks gained significantly less weight than predicted. The reported daily energy intake did not increase significantly, and sucrose supplements significantly reduced the reported voluntary sugar, starch and fat intake compared with aspartame. There were no effects on appetite or mood. Over 4 weeks, as part of everyday eating, sucrose given blind in soft drinks was partially compensated for by obese women, as in previous experiments with healthy and overweight participants. PMID- 24164780 TI - Physiological hypoxia prevents bile salt-induced apoptosis in human and rat hepatocytes. AB - BACKGROUND & AIMS: Hydrophobic bile salts such as glycochenodeoxycholate (GCDC) accumulate in cholestatic liver disease and induce hepatocellular apoptosis, promoting profibrotic signalling. The tissue microenvironment is an integral player in cellular pathophysiology, but it is not routinely incorporated into laboratory studies. Tissue oxygen partial pressure (pO2) may be an underestimated component of the microenvironment: in the liver, a pO2 of 30-45 mmHg (approximately 6% O2) is physiological, because of predominant portal blood supply. It was the aim of this project to investigate the impact of physiological hypoxia (i.e. 6% O2) on hepatocellular function, namely, bile salt-induced apoptosis. METHODS: Human hepatoma cells (HepG2-Ntcp) and primary rat hepatocytes were cultured at standard laboratory (hyperoxic) conditions (21% O2) and at physiological hypoxia (6% O2) in parallel for 1-8 days to study hepatocellular apoptosis and activation of signalling pathways. Standard laboratory analyses were applied for bile salt uptake, caspase-3/-7 activity, western blotting and gene-array analysis. RESULTS: Culturing at physiological hypoxia protected both human and rat hepatocytes against GCDC-induced apoptosis: caspase-3/-7 activation was diminished by 3.1 +/- 0.5-fold in human HepG2-Ntcp and completely abolished in primary rat hepatocytes. Bile salt uptake was unaffected. Induction of hypoxia inducible factor-1alpha indicated adaption to physiological hypoxia. The MEK/ERK cascade was activated and anti-apoptotic mediators were induced: N-Myc down regulated gene, gelsolin and carbonic anhydrase IX were upregulated 12.4-, 6.5- and 5.2-fold respectively. CONCLUSIONS: We conclude from these data that (i) physiological hypoxia protects hepatocytes from bile salt-induced apoptosis, (ii) tissue pO2 is a crucial, underestimated component of the microenvironment and should (iii) be considered when studying hepatocellular physiology in vitro. PMID- 24164781 TI - Preservice laboratory education strengthening enhances sustainable laboratory workforce in Ethiopia. AB - BACKGROUND: There is a severe healthcare workforce shortage in sub Saharan Africa, which threatens achieving the Millennium Development Goals and attaining an AIDS-free generation. The strength of a healthcare system depends on the skills, competencies, values and availability of its workforce. A well-trained and competent laboratory technologist ensures accurate and reliable results for use in prevention, diagnosis, care and treatment of diseases. METHODS: An assessment of existing preservice education of five medical laboratory schools, followed by remedial intervention and monitoring was conducted. The remedial interventions included 1) standardizing curriculum and implementation; 2) training faculty staff on pedagogical methods and quality management systems; 3) providing teaching materials; and 4) procuring equipment for teaching laboratories to provide practical skills to complement didactic education. RESULTS: A total of 2,230 undergraduate students from the five universities benefitted from the standardized curriculum. University of Gondar accounted for 252 of 2,230 (11.3%) of the students, Addis Ababa University for 663 (29.7%), Jimma University for 649 (29.1%), Haramaya University for 429 (19.2%) and Hawassa University for 237 (10.6%) of the students. Together the universities graduated 388 and 312 laboratory technologists in 2010/2011 and 2011/2012 academic year, respectively. Practical hands-on training and experience with well-equipped laboratories enhanced and ensured skilled, confident and competent laboratory technologists upon graduation. CONCLUSIONS: Strengthening preservice laboratory education is feasible in resource-limited settings, and emphasizing its merits (ample local capacity, country ownership and sustainability) provides a valuable source of competent laboratory technologists to relieve an overstretched healthcare system. PMID- 24164782 TI - Laser therapy in the treatment of connective tissue diseases: a review. AB - BACKGROUND: Connective tissue diseases (CTD), including lupus erythematosus (LE), scleroderma, sarcoidosis, and dermatomyositis, present with clinically unique cutaneous manifestations often resistant to conventional therapy. The use of lasers in the treatment of various dermatologic conditions continues to expand, presenting an opportunity for incorporation of another mechanism of action in the treatment of CTD. OBJECTIVES: To review the use of laser therapy in the treatment of LE, scleroderma, sarcoidosis, and dermatomyositis. MATERIALS AND METHODS: A MEDLINE search was conducted to find articles detailing treatment of CTD with laser therapy. RESULTS: Thirty-nine published articles were identified. The outcomes and results of case reports were reviewed for each CTD when possible. CONCLUSIONS: Laser therapy offers novel and often effective treatment for recalcitrant cutaneous conditions in LE, scleroderma, sarcoidosis, and dermatomyositis. Review of the literature revealed a limited number of reports, many describing outdated technologies and techniques. It is therefore difficult to draw substantial conclusions regarding safety and the known association with photosensitivity. More-recent reports suggest that, with continued evolution of technology and understanding of CTD, lasers will have an expanding role in the treatment of cutaneous manifestations of CTD. PMID- 24164783 TI - Resection of a malignant paraganglioma located behind the retrohepatic segment of the inferior vena cava. AB - BACKGROUND: Resection of a retrocaval paraganglioma is technically challenging due to limited tumor accessibility and proximity to the vena cava. CASE PRESENTATION: A large, malignant paraganglioma was found behind the retrohepatic segment of the inferior vena cava of a 60-year-old male. During resection of this rare paraganglioma, the left lateral lobe of the liver, a portion of the caudate lobe of the liver, and the gallbladder were also removed. Unfortunately, the patient died six months after surgery due to hepatic metastasis. CONCLUSION: This case demonstrates that a partial hepatectomy may be necessary to improve tumor accessibility during resection of a retrocaval paraganglioma, particularly if the tumor is proximal to the vena cava. Furthermore, palliative treatments may help prevent tumor recurrence and metastasis of malignant paragangliomas. PMID- 24164784 TI - Comparative study of percutaneous radiofrequency ablation and hepatic resection for small, poorly differentiated hepatocellular carcinomas. AB - AIM: Histologically, poorly differentiated hepatocellular carcinomas (HCC) are considered highly malignant. Here, we aimed to evaluate the relative efficacy and safety of hepatic resection or radiofrequency ablation (RFA) for treating this malignancy. METHODS: Between April 2004 and May 2011, we enrolled 48 patients who had poorly differentiated HCC that had been diagnosed postoperatively by pathological assessment. All the tumors had a maximum diameter of 3 cm and all patients had three or less tumors. Fifteen of these patients underwent hepatic resection (HR group) and 33 patients underwent RFA (RF group). The patient background, tumor characteristics, overall survival rate and recurrence-free survival rate were assessed in both groups. RESULTS: The mean maximum tumor diameter was 2.5 and 2.0 cm in the HR and RF groups, respectively. The prothrombin activity level was 94% and 86% in the HR and RF groups, respectively. The 1-, 3- and 5-year cumulative survival rates were 89.1%, 68.7% and 68.7%, respectively, in the HR group, and 59.2%, 40.9% and 32.7%, respectively, in the RF group. The 1-, 3- and 5-year recurrence-free survival rates were 85.1%, 64.8% and 48.6%, respectively, in the HR group, and 29.0%, 7.2% and 7.2%, respectively, in the RF group. There was a significant difference between these groups (P < 0.05). CONCLUSION: As hepatic resection has greater efficacy than RFA in the treatment of poorly differentiated HCC, even in cases with a small tumor size, we recommend its use for this malignancy. PMID- 24164785 TI - A prospective case controlled study of the short-term outcome following hemicolectomy for benign compared with malignant colonic polyps. AB - AIM: The number of patients diagnosed with advanced colonic polyps has increased due to screening. The outcome of hemicolectomy for benign lesions is poorly documented. We present a case-matched study comparing the results of hemicolectomy for benign and malignant polyps performed in two institutions. METHODS: Data for consecutive patients undergoing surgery for benign colonic polyps (BCPs) were prospectively collected in two hospitals. Each patient was matched for age, sex, ASA grade, site and type of resection (laparoscopic, open and converted) with two controls who underwent surgery for colon cancer (CC). The length of stay (LOS) and 30-day outcome were analysed adjusting for potential confounders. Multilevel linear and logistic regression analyses were performed. RESULTS: Forty-six patients having hemicolectomy for BCP were matched with 81 patients with CC. The median size of BCP was 4 cm [interquartile range (IQR) 2.5 5.4 cm]. Patients with a BCP had a marginally longer LOS [median 5.5 (IQR 4-8) days and 5 (IQR 3-7) days (P = 0.04)]. Twenty-one (46%) of 46 patients with BCP had a postoperative complication compared with 25 (31%) of 81 CC patients (P = 0.12, OR = 2.11, 95% CI 0.82-5.41). Four (9%) of 46 patients with BCP underwent re-operation and a further three (7%) were readmitted compared with one (1%) and two (2%) of 81 patients with CC (P = 0.07 and 0.28). There was no mortality in either group. CONCLUSION: Complications following hemicolectomy for BCP or CC are not significantly different. The results of the study provide further impetus to develop local full thickness colonic excision for benign colonic lesions as an alternative to major surgery. PMID- 24164786 TI - The reporting of functional outcome instruments in the Journal of Orthopaedic Trauma over a 5-year period. AB - OBJECTIVES: Orthopaedic journals, such as the Journal of Orthopaedic Trauma, frequently publish studies reporting functional outcome instruments, but little information has been provided regarding the validity and overall strength of these instruments. This study analyzes the trends in reported functional outcome instruments in articles published in the Journal of Orthopaedic Trauma over a 5 year period and examines the utilization rate, "overall" strength, and validity of these functional outcome instruments for the populations being studied. METHODS: Articles that were published in the Journal of Orthopaedic Trauma from January 2006 to December 2010 were reviewed, and each article was assigned to 1 of 4 different categories, based on the subspecialty focus and body region. The total number of articles reporting the use of functional outcome instruments, articles with at least 1 functional outcome instrument found in the AO Handbook, and the total number of functional outcome instruments reported were recorded. Each functional outcome instrument was assigned to 1 of 3 categories (generic, nonvalidated, validated), and each validated instrument was also examined to determine whether the category of interest for which it was used was one in which it was previously validated in. RESULTS: A total of 171 articles (34%) of the articles initially reviewed met the inclusion criteria. The average number of articles per year that reported functional outcome instruments was 56% (range, 47%-65%), and the average number of articles that reported at least 1 validated outcome instrument was 51% (range, 44%-61%). The average percentage of validated scores that were appropriately used within the category of interest was 23% (range, 13%-41%). CONCLUSIONS: Even though the 56% utilization rate of functional outcome instruments in The Journal of Orthopaedic Trauma is much higher than other journals, it is still low given the importance of measuring and attaining excellent functional outcomes. It is clear that future effort should be given to validating outcome measures for correct evaluation of orthopaedic trauma patients. PMID- 24164787 TI - Indices affecting outcome of neglected femoral neck fractures after valgus intertrochanteric osteotomy. AB - OBJECTIVES: To evaluate preoperative neck resorption and postoperative valgus orientation as predictors of union and functional outcome after valgus intertrochanteric osteotomy for treatment of neglected femoral neck fractures and nonunions. DESIGN: Retrospective cohort study. SETTING: Tertiary care center. PATIENTS/PARTICIPANTS: Forty consecutive patients with neglected femoral neck fracture and nonunions were treated with valgus intertrochanteric osteotomy, and follow-up was available in 32 patients (average age, 43 years; range, 14-60 years; average nonunion duration, 6 +/- 7 months; range, 1-36 months). INTERVENTION: Valgus intertrochanteric osteotomy. MAIN OUTCOME MEASUREMENTS: Clinical outcome was assessed with Harris hip score. Plain radiographs were evaluated for union, avascular necrosis, preoperative bone deficiency (neck resorption ratio), and postoperative femoral head fragment alignment (head-shaft angle). RESULTS: Follow-up at 5 +/- 3 years (range, 2-12 years) after surgery showed union in 29 patients (91%), and Harris hip score was 82 +/- 13 points (range, 63-100 points). The 3 patients with persistent nonunion at the neck of femur had neck resorption ratio <0.52. Increased postoperative head-shaft angle was associated with lower follow-up Harris hip score; postoperative valgus alignment >15 degrees compared with the contralateral side was associated with poor functional outcome. The presence of avascular necrosis did not affect the outcome. CONCLUSIONS: Valgus intertrochanteric osteotomy resulted in union and satisfactory functional outcome in most patients who had neglected femoral neck fractures and nonunions. Preoperative neck resorption ratio <0.5 was a risk factor for nonunion, and excessive valgus alignment was a risk factor for poor functional outcome after osteotomy. LEVEL OF EVIDENCE: Prognostic Level II. See Instructions for Authors for a complete description of levels of evidence. PMID- 24164788 TI - Restrictions in quality of life after intramedullary nailing of tibial shaft fracture: a retrospective follow-up study of 223 cases. AB - OBJECTIVE: To evaluate the long-term outcome after intramedullary nailing of tibial shaft fracture. DESIGN: Retrospective, cross-sectional study. SETTING: Level I, Trauma Center. METHODS: Retrospective review of 294 patients treated with intramedullary nailing after tibial shaft fracture from 1998 to 2008. The participants completed Knee injury and Osteoarthritis Outcome Score, and these data were compared with published reference population. INTERVENTION: Intramedullary nailing of tibial shaft fracture. MAIN OUTCOME MEASURES: Knee Injury and Osteoarthritis Outcome Score. RESULTS: A total of 223 patients agreed to participate (76%). Mean time of follow-up was 7.9 years. Compared to reference population, the study group reported 44% higher incidence of knee pain, 39% higher incidence of function in daily living limitations, 58% higher incidence of limitations in quality of life, and 60% higher incidence of limitations during sports activities. Comparison of age-related differences between the study group and reference population showed that the age group of 18-34 years reported the most difficulties. CONCLUSIONS: Compared with reference population, 60% of the patients experienced limitations in activity and restrictions in quality of life and 44% reported knee pain. This was mainly evident among the young participants. LEVEL OF EVIDENCE: Therapeutic Level III. See Instructions for Authors for a complete description of levels of evidence. PMID- 24164789 TI - Electromagnetic navigation reduces surgical time and radiation exposure for proximal interlocking in retrograde femoral nailing. AB - OBJECTIVES: To compare the time required for proximal locking screw placement between a standard freehand technique and the navigated technique, and to quantify the reduction in ionizing radiation exposure. METHODS: A fresh frozen cadaver model was used for 48 proximal interlocking screw procedures. Each procedure consisted of insertion of 2 anteroposterior locking screws. Standard fluoroscopic technique was used for 24 procedures, and an electromagnetic navigation system was used for the remaining 24 procedures. Procedure duration was recorded using an electronic timer and radiation doses were documented. RESULTS: Mean total insertion time for both proximal interlocking screws was 405 +/- 165.7 seconds with the freehand technique and 311 +/- 78.3 seconds in the navigation group (P = 0.002). All procedures resulted in successful locking screw placement. Mean ionizing radiation exposure time for proximal locking was 29.5 +/ 12.8 seconds. CONCLUSIONS: Proximal locking screw insertion using the navigation technique evaluated in this work was significantly faster than the standard fluoroscopic method. The navigated technique is effective and has the potential to prevent ionizing radiation exposure. PMID- 24164790 TI - Validating your outcomes. PMID- 24164791 TI - Invited commentary. PMID- 24164792 TI - A modified staged surgical intervention for blepharophimosis-ptosis-epicanthus inversus syndrome: 125 cases with encouraging results. AB - BACKGROUND: Blepharophimosis-ptosis-epicanthus inversus syndrome (BPES) is a rare autosomal dominant condition characterized by typical eyelid malformations that include blepharophimosis, ptosis, epicanthus inversus, and telecanthus. METHODS: We retrospectively reviewed 125 consecutive BPES patients who underwent staged surgical intervention from July 2003 to December 2011. All patients underwent initial medial and lateral canthoplasties, followed by blephroptosis correction 6 to 12 months afterward. The parameters that were studied included horizontal palpebral fissure length (PFL), vertical interpalpebral fissure height, inner intercanthal distance (IICD), the ratio of IICD to PFL, and frontalis function (FF). Facial photographs were taken preoperatively and postoperatively. Paired and group t tests were used for statistical analysis to evaluate surgical outcomes. RESULTS: After consecutive operations, the mean PFL increased from 19.5 to 25.7 mm (mean difference, 6.2 mm; P < 0.01). The mean interpalpebral fissure height increased from 3.4 to 8.5 mm (mean difference, 5.1 mm; P < 0.01). The mean IICD decreased from 38.0 to 30.9 mm (mean difference, 7.1 mm; P < 0.01). The mean FF was 7.3 mm for BPES patients approximately 5 years old and 10.4 mm for patients approximately 7 years old. There was no difference between children who underwent muscle flap suspension and healthy children of the same age (P > 0.05). CONCLUSIONS: The modified staged surgical intervention, including Y-V flap, von Ammon, and frontalis muscle flap suspension, provided effective results both in function and cosmesis for BPES. The FF was not weakened by surgery. PMID- 24164793 TI - Validation of a screening instrument for the fear of injection in dialysis patients. AB - BACKGROUND: Very little research has been conducted on the fear of injection (FOI) in patients on dialysis. However, feedback from hospital practice indicate that FOI is widespread. OBJECTIVES: The aim of this study was to develop and validate a screening instrument to assess FOI in dialysis patients. METHOD AND DESIGN: A group of patients (n = 86) completed the Dialysis Fear of Injection Questionnaire (DFIQ) and the Hospital Anxiety and Depression Scale (HADS). In semi-structured interviews, these patients were also asked about their FOI, general anxiety and depressive symptoms. Various analyses were used to examine the factor structure, sensitivity, accuracy and cut-off score. RESULTS: The most optimal set of items consists of 9 items. These items have the sensitivity of 0.88, a specificity of 0.72 and a cut-off value of 3.5. The Cronbach's alpha is 0.87. CONCLUSION: The DFIQ appears to be a good predictor for the presence of FOI. APPLICATION TO PRACTICE: Nurses can use this validated screening instrument to detect FOI. The cut-off score provides a good indication for psychological counselling. PMID- 24164795 TI - Cellular redox homeostasis, reactive oxygen species and replicative ageing in Saccharomyces cerevisiae. AB - Ageing cells undergo changes in redox homeostasis and acquire high levels of reactive oxygen species (ROS). Because accumulation of ROS involves a change in redox state of cells, functions that are involved in setting redox and maintaining redox homeostasis are very relevant to an understanding of the possible roles of redox homeostasis and ROS in ageing. This review discusses these aspects of ROS in relation to replicative ageing in the model organism Saccharomyces cerevisiae, with reference to ROS generated in cells; cellular responses to oxidative stress; and how cells maintain redox homeostasis in different cellular compartments. It also considers when ROS generation begins as cells age, which ROS species are relevant to ageing and which cellular compartments and processes may contribute ROS to the ageing process. The discussion also covers the heterogeneity of cells with respect to ROS accumulation at particular cell ages, and the possibility of testing the oxidative theory of ageing in yeast cells. PMID- 24164794 TI - Factors influencing insulin acceptance among type 2 diabetes mellitus patients in a primary care clinic: a qualitative exploration. AB - BACKGROUND: Many Type 2 Diabetes Mellitus (T2DM) patients refuse insulin therapy even when they require this modality of treatment. However, some eventually accept insulin. This study aimed to explore the T2DM patients' reasons for accepting insulin therapy and their initial barriers to use insulin. METHODS: This qualitative study interviewed twenty-one T2DM patients at a primary care clinic who had been on insulin for more than a year through three in-depth interviews and three focus group discussions. A semi structured interview protocol was used and the sessions were audio-recorded. Subsequently, thematic analysis was conducted to identify major themes. RESULTS: The participants' acceptance of insulin was influenced by their concerns and beliefs about diabetes and insulin. Concerns about complications of poorly controlled diabetes and side effects of other treatment regime had resulted in insulin acceptance among the participants. They also had a strong belief in insulin benefits and effectiveness. These concerns and beliefs were the results of having good knowledge about the diabetes and insulin, experiential learning, as well as doctors' practical and emotional support that helped them to accept insulin therapy and become efficient in self-care management. These factors also allayed their negative concerns and beliefs towards diabetes and insulin, which were their barriers for insulin acceptance as it caused fear to use insulin. These negative concerns were related to injection (self-injection, needle phobia, injection pain), and insulin use (inconvenience, embarrassment, lifestyle restriction, negative social stigma, and poor self-efficacy), whereas the negative beliefs were 'insulin could cause organ damage', 'their diabetes was not serious enough', 'insulin is for life-long', and 'insulin is for more severe disease only'. CONCLUSIONS: Exploring patients' concerns and beliefs about diabetes and insulin is crucial to assist physicians in delivering patient centered care. By understanding this, physicians could address their concerns with aim to modify their patients' misconceptions towards insulin therapy. In addition, continuous educations as well as practical and emotional support from others were found to be valuable for insulin acceptance. TRIAL REGISTRATION: Universiti Kebangsaan Malaysia FF-214-2009. PMID- 24164796 TI - Interleukin-17F single-nucleotide polymorphism (7488T>C) and its association with susceptibility to leprosy. AB - The objective of this study was to investigate the association, if any, between the interleukin-17F (7488T>C) (rs763780) polymorphism and susceptibility to leprosy and to elucidate the relationship between IL-17F genotypes and clinical profile of the disease. DNA was extracted from the peripheral venous blood of leprosy cases (n = 140), which were classified as per WHO classification into paucibacillary (PB) (n = 53) and multibacillary (MB) (n = 87) categories and healthy controls (n = 84) without any signs and symptoms of leprosy. The IL-17F (7488 T/C) polymorphism was genotyped using amplification refractory mutation system - polymerase chain reaction (Allele-specific amplification). In both PB and MB categories of leprosy cases, the homozygous TT genotype frequency was significantly higher than that of the healthy controls (78.70% vs. 29.76%, P < 0.05). The heterozygous TC genotype was higher in the controls than in the leprosy cases (57.14% vs. 17.68%, P < 0.05). TT genotype was more associated with the type 1 reactional states and tuberculoid/borderline tuberculoid groups in leprosy than the TC genotype. This study reveals that the IL-17F (7488T>C) single nucleotide polymorphism is associated with susceptibility to leprosy and polymorphism confers decrease in risk of contracting leprosy in the north Indian cohort. PMID- 24164797 TI - Radiation-induced necrosis and calcinosis of the breast: a case report. PMID- 24164798 TI - Emergency care should take priority in plan to introduce seven day working in NHS, says BMA. PMID- 24164799 TI - Role of matrix metalloproteinases in non-healing venous ulcers. AB - Chronic venous ulceration (CVU) of the lower limbs is a common condition affecting 1% of the adult population in Western countries, which is burdened with a high complication rate and a marked reduction in the quality of life often due to prolonged healing time. Several metalloproteinases (MMPs) such as MMP-9 together with neutrophil gelatinase-associated lipocalin (NGAL) appear to be involved in the onset and healing phases of venous ulcer, but it is still unclear how many biochemical components are responsible for prolonged healing time in those ulcers. In this study, we evaluate the role of MMP-1 and MMP-8 in long lasting and refractory venous ulcers. In a 2-year period we enroled 45 patients (28 female and 17 male, median age 65) with CVU. The enroled population was divided into two groups: group I were patients with non-healing ulcers (ulcers that had failed to heal for more than 2 months despite appropriate treatments) and group II were patients with healing ulcers (ulcers in healing phases). MMP-1 and MMP-8 were measured in fluids and tissues of healing and non-healing ulcers by means of enzyme-linked immunosorbent assay (ELISA) and Western blot analysis, respectively. In particular the patterns of the collagenases MMP-1 and MMP-8 in healing wounds were distinct, with MMP-8 appearing in significantly greater amounts especially in the non-healing group. Our findings suggest that MMP-1, and MMP-8 are overexpressed in long lasting CVU. Therefore, this dysregulation may represent the main cause of the pathogenesis of non-healing CVU. PMID- 24164800 TI - Genomics and the classification of mental illness: focus on broader categories. AB - Coinciding with the release of the fifth edition of the Diagnostic and Statistical Manual of Mental Disorders, two recently published molecular genetics analyses suggest large overlaps in genetic liability to schizophrenia, bipolar disorder and major depressive disorder. This indicates that a broader category of severe mental illness may be an important target for future large-scale etiological and therapeutic investigations. Studies of patient groups not restricted to current diagnostic categories may lead to a genetically informed nosology. PMID- 24164801 TI - NPM1, FLT3-ITD, CEBPA, and c-kit mutations in 312 Chinese patients with de novo acute myeloid leukemia. AB - OBJECTIVES: To explore NPM1, FLT3-ITD, CEBPA, and c-kit mutations in patients with acute myeloid leukemia (AML) from Chinese population. METHODS: In this study, we retrospectively analyzed the prevalence and clinical profile of NPM1, FLT3-ITD, CEBPA, and c-kit mutations in 312 patients with de novo AML. RESULTS: The frequencies of NPM1, FLT3-ITD, c-kit, and CEBPA mutations were 15.4, 14.0, 7.64, and 25.6%, respectively. The occurrence rate of NPM1 mutations increased with age in patients younger than 60 years. NPM1, c-kit, and CEBPA mutations were all associated with French-American-British subtypes. Patients with NPM1 mutations and FLT3-ITD presented with higher peripheral white blood cell counts and marrow blast percentages. CONCLUSION: Both this and previous studies may suggest low frequencies of NPM1 and FLT3-ITD mutations in AML patients from the Chinese population, and they may have a synergistic function in stimulating proliferation of leukemia cells. PMID- 24164802 TI - Stereotactic planning software for human neurotransplantation: suitability in 22 surgical cases of Huntington's disease. AB - PURPOSE: Intrastriatal neural transplantation using multiple grafts is an experimental approach to the treatment of Huntington's disease (HD). Brain atrophy makes stereotactic plans in these patients a tedious procedure with a risk of suboptimal spatial distribution of the grafts in transplantation procedures. Here we present a self-developed software to optimize the surgical stereotactic planning for bilateral neurotransplantation procedures. It allows close to symmetrical distribution of the stereotactic coordinates in relation to the mid-commissural point (MCP), proposing automatically the planning coordinates for the first transplanted hemisphere and mirrored coordinates to be used in the contra-lateral hemisphere. METHODS: Twenty-two consecutive HD patients underwent bilateral stereotactic striatal transplantation. Two caudate nucleus and four putaminal tracks were planned bilaterally. For the second, contra-lateral transplantation, the coordinates were mirrored in order to determine contralateral targets and trajectories. Intra-individual comparison between software given coordinates and finally used coordinates was performed. RESULTS: No statistical significance was found comparing a) the differences between coordinates proposed by the software and the final coordinates and b) the distribution of the transplantation sites in relation to the midline for the right vs. left hemisphere. No intra- or postoperative transplantation-related adverse events occurred. CONCLUSIONS: The use of model-based and mirrored coordinates allowed optimal spatial distribution of the grafts. Minor changes were required comparing right to left coordinates giving proof-of principle. The initial use of the software suggests that it may be useful in experimental transplantation trials where neural cell grafts are to be implanted into predefined target sites in the human brain, whether unilateral or bilateral. PMID- 24164803 TI - Mapping nanoscale thermal transfer in-liquid environment-immersion scanning thermal microscopy. AB - Nanoscale heat transport is of increasing importance as it often defines performance of modern processors and thermoelectric nanomaterials, and affects functioning of chemical sensors and biosensors. Scanning thermal microscopy (SThM) is the leading tool for nanoscale mapping of thermal properties, but it is often negatively affected by unstable tip-surface thermal contacts. While operating SThM in-liquid environment may allow unimpeded thermal contact and open new application areas, it has so far been regarded as impossible due to increased heat dissipation into the liquid, and the perceived reduced spatial thermal resolution. Nevertheless, in this paper we show that such liquid immersion SThM (iSThM) is fully feasible and, while its thermal sensitivity and spatial resolution is somewhat below that of in-air SThM, it has sufficient thermal contrast to detect thermal conductivity variations in few tens of nm thick graphite nanoflake and metal-polymer nanostructured interconnects. Our results confirm that thermal sensing in iSThM can provide nanoscale resolution on the order of 30 nm, that, coupled with the absence of tip snap-in due to the elimination of capillary forces, opens the possibility for nanoscale thermal mapping in liquids, including thermal phenomena in energy storage devices, catalysts and biosystems. PMID- 24164805 TI - Evidence of rebalanced coagulation in acute liver injury and acute liver failure as measured by thrombin generation. AB - BACKGROUND & AIMS: Patients with liver disease often show profound abnormalities in their haemostatic system. Studies using thrombin generation demonstrate rebalanced coagulation in patients with chronic liver disease. Our aim was to evaluate the haemostatic profile in patients with acute liver injury/failure (ALI/ALF) compared with healthy controls. METHODS: Thrombin generation was measured in the presence and absence of thrombomodulin (TM) to activate protein C (PC) with endogenous thrombin potential (ETP; the area under the thrombin generation curve) a key parameter. Routine coagulation assays were also performed. RESULTS: Thirty two patients with ALI/ALF and 40 controls were recruited. Patients had grossly abnormal coagulation profiles with decreased pro- and anticoagulant factors compared with controls (P < 0.001 for all comparisons), except for median Factor VIII which was increased 247 U/dl [interquartile range: 214-347] in patients compared with 120 U/dl [97-139; P < 0.001] in controls. Mean ETP was significantly lower in patients 886 nM.min (+/- 436) compared with controls 1596 nM.min (+/- 259; P < 0.001). However, when the assay was repeated with TM to activate PC, there was no significant difference in mean ETP + TM between patients and controls (632 +/- 418 vs 709 +/- 301 nM.min respectively; P = 0.666). Furthermore, the ETP ratio (ETP + TM/ETP) was significantly higher in patients 0.89 (0.60-0.97) compared with controls 0.48 (0.3-0.6; P = 0.002) and negatively correlated with PC (R = -0.487, P = 0.003) and Factor V (R = -0.431, P = 0.01). CONCLUSION: ALI/ALF patients have normal ETP in the presence of TM. This supports rebalanced coagulation mediated by acquired PC resistance because of the reduction in PC, Factor V and concomitant increase in Factor VIII. PMID- 24164804 TI - Associations between self-reported sleep duration and sleeping disorder with concentrations of fasting and 2-h glucose, insulin, and glycosylated hemoglobin among adults without diagnosed diabetes. AB - BACKGROUND: There is limited information from population-based investigations of the associations between sleep duration and sleep disorders and parameters of glucose homeostasis. The objective of the present study was to examine cross sectional associations between sleep duration and sleep disordered breathing with concentrations of insulin, fasting and 2-h glucose, and HbA1c. METHODS: Data from 11 815 adults aged >=20 years without diagnosed diabetes (5002 with an oral glucose tolerance test) from the National Health and Nutrition Examination Survey 2005-2010 were used. Information about sleep duration (2005-2010) and sleep apnea and sleep-disordered breathing (2005-2008) was obtained via questionnaire. RESULTS: An estimated 36.0% of participants reported sleeping <=6 h/night, 62.0% reported sleeping 7-9 h/night, and 2.0% reported sleeping >=10 h/night. In 2005 2008, 33.0% reported snoring >=5 nights per week, 5.9% reported they snorted, gasped, or stopped breathing >=5 nights/week, and 4.2% reported sleep apnea. Sleep duration was significantly associated with fasting concentrations of insulin and concentrations of HbA1c only in models that did not adjust for body mass index (BMI). Concentrations of fasting and 2-h glucose were significantly associated with sleep duration in models that adjusted only for age. Snoring frequency was positively associated with concentrations of insulin and HbA1c. Frequency of snorting or stopping breathing and sleep apnea status were associated with concentrations of insulin and of HbA1c only when BMI was not accounted for. CONCLUSION: In a representative sample of US adults, concentrations of insulin and HbA1c were significantly associated with short sleep duration, possibly mediated by BMI. PMID- 24164806 TI - Transepithelial ion transport across duct cells of the salivary gland. AB - Fluid and electrolyte secretions are vital for all epithelia and when aberrant lead to numerous pathophysiological conditions. Electrolyte transport across epithelia generates the osmotic force for fluid movement and is mediated by several membrane proteins expressed on both apical and basolateral poles of epithelial cells. Sodium and chloride are crucial for regulation of fluid secretion, thus regulating salivary volume. Bicarbonate (HCO3-), on the other hand, is the major pH buffer; hence, aberrant HCO3- secretion is a major factor in diseases such as cystic fibrosis (CF) causing altered mucin hydration and solubilization. Here, the structure-function mechanisms of the major membrane transporters involved in salivary duct electrolyte transport are reviewed focusing on transepithelial movement of Cl(-) and HCO3-. PMID- 24164809 TI - The microbiology and immunology of normal physiologic birth: a plea for the nature of mother. PMID- 24164810 TI - Not all studies with small samples are pilot studies. PMID- 24164807 TI - Diverse spectrum of rare deafness genes underlies early-childhood hearing loss in Japanese patients: a cross-sectional, multi-center next-generation sequencing study. AB - BACKGROUND: Genetic tests for hereditary hearing loss inform clinical management of patients and can provide the first step in the development of therapeutics. However, comprehensive genetic tests for deafness genes by Sanger sequencing is extremely expensive and time-consuming. Next-generation sequencing (NGS) technology is advantageous for genetic diagnosis of heterogeneous diseases that involve numerous causative genes. METHODS: Genomic DNA samples from 58 subjects with hearing loss from 15 unrelated Japanese families were subjected to NGS to identify the genetic causes of hearing loss. Subjects did not have pathogenic GJB2 mutations (the gene most often associated with inherited hearing loss), mitochondrial m.1555A>G or 3243A>G mutations, enlarged vestibular aqueduct, or auditory neuropathy. Clinical features of subjects were obtained from medical records. Genomic DNA was subjected to a custom-designed SureSelect Target Enrichment System to capture coding exons and proximal flanking intronic sequences of 84 genes responsible for nonsyndromic or syndromic hearing loss, and DNA was sequenced by Illumina GAIIx (paired-end read). The sequences were mapped and quality-checked using the programs BWA, Novoalign, Picard, and GATK, and analyzed by Avadis NGS. RESULTS: Candidate genes were identified in 7 of the 15 families. These genes were ACTG1, DFNA5, POU4F3, SLC26A5, SIX1, MYO7A, CDH23, PCDH15, and USH2A, suggesting that a variety of genes underlie early-childhood hearing loss in Japanese patients. Mutations in Usher syndrome-related genes were detected in three families, including one double heterozygous mutation of CDH23 and PCDH15. CONCLUSION: Targeted NGS analysis revealed a diverse spectrum of rare deafness genes in Japanese subjects and underscores implications for efficient genetic testing. PMID- 24164811 TI - Scope of practice and scope of employment: what's the difference? PMID- 24164812 TI - Internet resources. PMID- 24164813 TI - Perinatal outcomes of prenatal probiotic and prebiotic administration: an integrative review. AB - The purpose of this integrative review was to identify, critique, and synthesize the maternal and neonatal evidence on the prenatal use of probiotics and prebiotics to inform perinatal health professionals. A comprehensive literature search resulted in 37 studies of prenatal probiotics and 1 on antepartal prebiotics published from 1990 through 2011 that reported maternal, fetal, and/or neonatal outcomes. The methodologic quality of the studies reviewed was high, although investigators used different probiotic combinations and inconsistently reported perinatal clinical outcomes. The extraction of perinatal outcome variables resulted in identification of 9 maternal and 5 neonatal categories. Prenatal probiotics significantly reduced the incidence of bacterial vaginosis, increased colonization with vaginal Lactobacillus and intestinal Lactobacillus rhamnosus, altered immune markers in serum and breast milk, improved maternal glucose metabolism, and reduced the incidence of gestational diabetes and preeclampsia. Antepartally, probiotics were associated with significantly higher counts of Bifidobacterium and Lactococcus lactis (healthy intestinal flora) in neonatal stool. Prenatal prebiotics significantly increased maternal intestinal Bifidobacterium. No adverse events were reported and there was evidence of safety and tolerance of prenatal probiotics and prebiotics in the scientific investigations reviewed. It is recommended that in future investigations of prenatal probiotics researchers explicitly report maternal and neonatal outcomes. PMID- 24164814 TI - Early educational and behavioral RCT interventions to reduce maternal symptoms of psychological trauma following preterm birth: a systematic review. AB - Early behavioral and educational interventions have been developed to reduce maternal symptoms of psychological trauma (depression, anxiety, parenting stress, acute stress disorder, and posttraumatic stress disorder) following preterm birth (PTB). Aims of this systematic review were to critically assess study methodology and provide a synthesis of existing randomized control trial (RCT) interventions and to estimate effects of the interventions in reducing the maternal symptoms across studies. Four electronic databases were systematically searched to locate relevant RCTs using preestablished eligibility criteria. Data from 8 qualifying RCTs were synthesized. Two reviewers independently assessed study methodology using appraisal checklists. Considerable heterogeneity precluded calculation of pooled estimates. There is evidence that mothers of very preterm infants of low birth-weight experience major depression for up to 12 months following PTB. Sound interventions implemented during and following infant hospitalization and grounded in coping and self-regulation had a small to moderate effect in reducing maternal depression and anxiety and parenting stress for up to 2 months and 12 months respectively. Clinicians can use existing evidence to help guide best practices. Future high-quality RCTs and meta-analysis require that researchers improve study methodology and include analysis of data on maternal hormonal stress and history of psychological symptoms including during the pregnancy. PMID- 24164815 TI - Extubation success in premature infants with respiratory distress syndrome treated with bi-level nasal continuous positive airway pressure versus nasal intermittent positive pressure ventilation. AB - Infants born prematurely with respiratory distress syndrome are at high risk for complications from mechanical ventilation. Strategies are needed to minimize their days on the ventilator. The purpose of this study was to compare extubation success rates in infants treated with 2 different types of continuous positive airway pressure devices. A retrospective cohort study design was used. Data were retrieved from electronic medical records for patients in a large, metropolitan, level III neonatal intensive care unit. A sample of 194 premature infants with respiratory distress syndrome was selected, 124 of whom were treated with nasal intermittent positive pressure ventilation and 70 with bi-level variable flow nasal continuous positive airway pressure (bi-level nasal continuous positive airway pressure). Infants in both groups had high extubation success rates (79% of nasal intermittent positive pressure ventilation group and 77% of bi-level nasal continuous positive airway pressure group). Although infants in the bi level nasal continuous positive airway pressure group were extubated sooner, there was no difference in duration of oxygen therapy between the 2 groups. Promoting early extubation and extubation success is a vital strategy to reduce complications of mechanical ventilation that adversely affect premature infants with respiratory distress syndrome. PMID- 24164817 TI - Taiwanese parents' perceptions of their very low-birth-weight infant with developmental disabilities. AB - This study explores the perceptions and experiences of Taiwanese parents in coping with the unfolding evidence of a disability, their response to the official diagnosis, and their views about their child's developmental disability. This descriptive qualitative study is a partial analysis of data from a larger study including 19 Taiwanese parents of very low-birth-weight infants with developmental disability at 6 and 12 months of corrected age. Four themes were generated: uncertainty and worry about developmental progress, search for meaning and supernatural will, desire for normality and attitude toward services, and finding a balance point in family life and relationships. The parents of very low birth-weight infants face uncertainty about developmental and other potential problems in the infant's early age. Adequate information related to infant development needs to be integrated into follow-up clinic and early intervention services. Early intervention programs should not only focus on the needs of these infants but also provide support and care to the whole family. Understanding parental beliefs and values toward developmental disabilities can help neonatal and pediatric professionals to provide optimal early intervention to these families. PMID- 24164816 TI - Caring for a preterm infant at home: a mother's perspective. AB - The purpose of this phenomenological study was to examine the experiences of mothers of preterm infants during the first 6 months at home following discharge from a neonatal intensive care unit (NICU). A purposeful sample of 8 mothers was gathered and interviews were conducted over a 4-month period. Each interview was audio recorded and took place in the study participant's home or another place of her choosing. Interviews were transcribed verbatim and analyzed independently with themes being identified and organized for each participant. From these analyses, the themes of fear, exhaustion, determination, and thankfulness were identified as being common to all study participants and became the basis for developing the essence of the phenomenon. The essence of this experience for these mothers was their resolve to do whatever was necessary to ensure the best possible outcomes for their infants. The data gathered from these personal interviews will serve to further inform our understanding of this important time from the perspective of those who experienced it, as well as aid in the design of interventions to address the specific needs of these mothers prior to NICU discharge. PMID- 24164818 TI - Infant formula samples: perinatal sources and breast-feeding outcomes at 1 month postpartum. AB - The purpose was to describe sources of infant formula samples during the perinatal period and assess their associations with breast-feeding outcomes at 1 month postpartum. Subjects included expectant mothers who anticipated breast feeding at least 1 month. Infant feeding history and sources of formula samples were obtained at 1 month postpartum. Associations between sources and breast feeding outcomes were assessed using partial correlation. Of the 61 subjects who initiated breast-feeding, most were white (87%), married (75%), college-educated (75%), and planned exclusive breast-feeding (82%). Forty-two subjects (69%) continued breast-feeding at 1 month postpartum. Subjects received formula samples from the hospital (n = 40; 66%), physician's office (n = 10; 16%), and mail (n = 41; 67%). There were no significant correlations between formula samples from the hospital, physician's office, and/or mail and any or exclusive breast-feeding at 1 month (P > .05). In addition to the hospital, a long-standing source of formula samples, mail was also frequently reported as a route for distribution. The lack of statistically significant associations between formula samples and any or exclusive breast-feeding at 1 month may be related to small sample size and unique characteristics of the group studied. PMID- 24164819 TI - The perils of Pauline, a tribute to nursing. PMID- 24164822 TI - Transplantation for liver tumors in children: time to (re)set the guidelines? PMID- 24164823 TI - The emergence of eosinophilic disorders in pediatric transplant recipients. PMID- 24164824 TI - Alemtuzumab induction with tacrolimus monotherapy in 25 pediatric renal transplant recipients. AB - ALA induction in transplantation has been shown to reduce the need for maintenance immunosuppression. We report the outcome of 25 pediatric renal transplants between 2007 and 2010 using ALA induction followed by tacrolimus maintenance monotherapy. Patient ages were 1-19 yr (mean 14 +/- 4.1 yr). Time of follow-up was 7-51 months (mean 26 +/- 13 months). Tacrolimus monotherapy was maintained in 48% of patients, and glucocorticoids were avoided in 80% of recipients. Mean plasma creatinine and GFR at one yr post-transplant were 0.88 +/ 0.3 mg/dL and 104.4 +/- 25 mL/min/1.73m(2) , respectively. One, two, and three yr actuarial patient and graft survival rates were 100%. The incidence of early AR (<12 months after transplantation) was 12%, while the incidence of late AR (after 12 months) was 16%. Forty-four percent of the recipients recovered normal, baseline renal function after an episode of AR, and 44% had persistent renal dysfunction (plasma creatinine 1.0-1.8 mg/dL). One graft was lost four yr after transplantation due to medication non-compliance. Four (16%) patients developed BK or CMV infection. In our experience, ALA induction with tacrolimus monotherapy resulted in excellent short- and mid-term patient and graft survival in low immunologic risk pediatric renal transplant recipients. PMID- 24164825 TI - Solid tumors following kidney transplantation in children. AB - Kidney transplant recipients have an increased risk of cancer. Data on non-LPD malignancies (solid tumors) in pediatric renal transplant recipients are limited. We performed a cohort study using the NAPRTCS transplant registry to describe the incidence of non-LPD malignancy compared with the general pediatric population. The observed incidence rate of non-LPD malignancy in the NAPRTCS transplant registry was 72.1 per 100,000 person-years (SIR 6.7; 95% CI, 5.3, 8.5); a 6.7 fold increased risk compared with the general pediatric population (10.7 cases per 100,000 person-years). Non-LPD malignancy was diagnosed in 35 subjects at a median of 726 days post-transplant. The most common type of malignancy was renal cell carcinoma. The increased risk of non-LPD malignancy was seen in all patients regardless of age, gender, race, etiology of end-stage kidney disease, and transplant era. The specific type of immunosuppression was not identified as a risk factor. In this first large-scale study of North American pediatric renal transplant recipients, we observed a 6.7-fold increased risk of non-LPD malignancy compared with the general pediatric population. Further examination of this unique patient population may provide greater insight into the impact of transplant and immunosuppression on malignancy risk. PMID- 24164826 TI - Post-transplant lymphoproliferative disorder: no relationship to recombinant human growth hormone use in Australian and New Zealand pediatric kidney transplant recipients. AB - PTLD is a potentially life-limiting complication of pediatric transplantation. Previous registry-based studies in renal transplantation have suggested a link between rhGH use and PTLD. In this study, demographic and transplant data on those aged <18 yr and transplanted between 1991 and 2008 were collected from the ANZDATA Registry. Associations between gender, age at time of transplant, recipient CMV and EBV status, use of monoclonal antibody therapy, and use of rhGH were studied as potential predictors of PTLD. Among 650 transplants, there were 20 cases (3.1%) of PTLD, with half presenting within two yr post-transplant. Eight patients exposed to rhGH at any time developed PTLD, and this association was not statistically significant (RR = 1.5[0.6-3.4], p = 0.36). On multivariate analysis, there were no significant predictors for PTLD. In this study, previously identified potential risk factors were not identified as significant predictors for the development of PTLD. Although limited sample size may affect our ability to infer safety, this large retrospective cohort study does not suggest an increased risk of PTLD in pediatric kidney transplant recipients who received rhGH treatment. PMID- 24164828 TI - Empiric switch from calcineurin inhibitor to sirolimus-based immunosuppression in pediatric heart transplantation recipients. AB - Sirolimus is used in heart transplant patients with CAV and CNI-induced nephropathy. However, little is known regarding the tolerability, rejection rate, and effect on renal function when used empirically in children. We describe our experience with the empiric use of a sirolimus-based immunosuppressive regimen in pediatric heart transplantation recipients. We reviewed records of patients in whom conversion was attempted to a CNI-free sirolimus-based regimen. Rejection episodes and measures of renal function were recorded. We attempted to convert 20 patients, of which 16 were successful. In total, six of 20 patients (30%) experienced adverse effects. Of the 16 converted, four patients converted to sirolimus due to CNI-induced disease (three nephropathy, one CAV), while 12 patients (mean age 5.5 yr, range 0.1-21 yr; 33% female; 33% with a history of congenital heart disease) were empirically switched to sirolimus at a mean of 2.3 yr after transplant. Follow-up was available for a mean of 2.5 yr after conversion (range 0.5-8.3 yr). The rate of rejection while taking CNIs was 0.18 rejection episodes per patient-year (total of five episodes), compared with 0.03 rejection episodes per patient-year (total of one episode) while on sirolimus. Renal function, in terms of GFR, significantly improved after sirolimus conversion at latest follow-up (from 86 +/- 37 mL/min to 130 +/- 49 mL/min, p = 0.02). Here, we demonstrate the potential benefit of empiric use of sirolimus in pediatric heart transplant patients in a CNI-free regimen. Larger and longer studies are needed to further clarify risks of rejection and adverse effect profiles. PMID- 24164827 TI - Peripheral blood biomarkers for the characterization of alloimmune reactivity after pediatric liver transplantation. AB - Individualization of immunosuppressive medications is an important objective in transplantation medicine. Reliable biomarkers to distinguish between patients dependent from intensive immunosuppressive therapy and those where therapy can be minimized among pediatric transplant recipients receiving immunosuppressive medications are still not established. We evaluated the potential of cross sectional quantification of regulatory T cells, lymphocyte subsets, and cytokine concentrations as biomarkers in 60 pediatric liver transplant recipients with AR, CR, or normal graft function and in 11 non-transplanted patients. Transplant recipients presenting with AR had significantly higher CD8+ T-cell counts, significantly higher concentrations of IL-2, and increased levels of IFN-gamma compared with asymptomatic patients or controls. Regulatory T-cell numbers did not differ between children with rejection and children with good graft function. A tendency toward increased concentrations of IL-4 and TGF-beta was detected in transplant recipients with good graft function. Cross-sectional parameters of peripheral regulatory T cells in pediatric liver transplant recipients do not seem to be valuable biomarkers for individualizing immunosuppressive therapy prior to the weaning process. Lymphocyte subsets, IL-2, IFN-gamma, IL-4, and TGF beta serum concentrations may be helpful to identify children in whom immunosuppression can be reduced or discontinued. PMID- 24164829 TI - Intra-operative extracorporeal membrane oxygenation use in pediatric lung transplantation--the Zurich experience. AB - There is a lack of data regarding use of ECMO in children undergoing lung transplantation. We evaluated our experience of ECMO in pediatric lung transplant recipients. All patients (<18 yr) who underwent lung transplants between 1997 and 2011 were included (17 children; nine males; median age 16 yr), and the use of intra-operative ECMO evaluated. Transplant procedures were carried out with intra operative ECMO in seven children (all bilateral lung transplants). Demographics of ECMO and non-ECMO patients were comparable. One child was already on ECMO pre operative. Lung graft size reduction was undertaken in five ECMO and four non ECMO cases, respectively. Five patients were taken off ECMO intra-operatively; the other patients were weaned off ECMO within 48 h post-operatively. Three months survival was 100%. By 12 months post-transplantation, one patient each died in the ECMO and in the non-ECMO group. At the end of the study, six of seven ECMO cases were still alive (median survival 48.5 months); one patient required a retransplant at 53 months. Our small case series suggests that lung transplant procedures can be safely carried out in selected children on intra-operative ECMO support; however, our pediatric experience regarding this scenario is very limited but probably almost unique. PMID- 24164830 TI - VPS 45-associated primary infantile myelofibrosis--successful treatment with hematopoietic stem cell transplantation. AB - PMF of infancy is a recently described autosomal recessive disorder presenting with severe bone marrow failure, accelerated neutrophil apoptosis, and significant platelet dysfunction, caused by a mutation in the VPS45 gene. In this study, we update our group of patients with PMF, highlighting different aspects of this disease, and evaluating the effectiveness of HSCT for the treatment of this disorder. Update of clinical data, hematological features, molecular studies, treatment and final outcome of four children diagnosed with VPS 45 associated PMF of infancy. The patients described had clinical and hematological findings consistent with MF. Molecular studies showed that all patients were homozygous for the Thr224Asn mutation in the VPS 45 gene. HSCT was carried out in three patients and was successful in two. VPS 45-associated MF is a novel primary immune deficiency that can be successfully corrected by HSCT if applied early in the course of disease using appropriate conditioning. The diagnosis of VPS 45 associated PMF should be considered in all children presenting with SCN with subsequent development of pancytopenia. Long-term follow-up of these patients is necessary to identify extra-hematological manifestations of VPS45 deficiency. PMID- 24164831 TI - Buying time: The use of extracorporeal membrane oxygenation as a bridge to lung transplantation in pediatric patients. AB - To describe our experience to date of four children with end-stage lung disease who have been bridged with ECMO to successful lung transplantation in our institution. Between March 2006 and June 2012, a total of 21 pediatric patients successfully underwent lung transplantation within The Alfred's lung transplantation program. This included four children who were bridged on ECMO prior to transplantation according to the "ECMO bridge to transplant" protocol and whose clinical notes and outcomes were reviewed. Lung transplantation is an established life-saving treatment for patients with severe lung disease, but remains limited due to scarcity of suitable donor organs. This is a particular issue in the pediatric setting, where the smaller child waits disproportionately longer compared with adult patients for size-matched donor lungs. As ECMO has become more widely accepted, its use as a bridge to lung transplantation in pediatric patients with severe acute lung injury or end-stage chronic lung disease has been considered. The medical notes from the four pediatric patients were retrospectively reviewed. Our report describes excellent short- and medium term outcomes in a small number of children who have been bridged to transplant on ECMO. PMID- 24164832 TI - Chimerism of allogeneic mesenchymal cells in bone marrow, liver, and spleen after mesenchymal stem cells infusion. AB - Although an infusion of culture-expanded MSCs is applied in clinic to improve results of HSCs transplantation and for a treatment of musculoskeletal disorders, homing, and engraftment potential of culture-expanded MSC in humans is still obscure. We report two female patients who received allogeneic BM transplantation as a treatment of hematological diseases and a transplantation of MSCs from third party male donors. Both patients died within one yr of infectious complications. Specimens of paraffin-embedded blocks of tissues from transplanted patients were taken. The aim of the study was to estimate possible homing and engraftment of allogeneic BM-derived MSCs in some tissues/organs of recipient. Sensitive real time quantitative PCR analysis was applied with SRY gene as a target. MSC chimerism was found in BM, liver, and spleen of both patients. We conclude that sensitive RQ-PCR analysis is acceptable for low-level chimerism evaluation even in paraffin-embedded tissue specimens. PMID- 24164834 TI - Juvenile dermatomyositis management: moving but in need of a push. PMID- 24164835 TI - Promptness? - yes, haste? - no. PMID- 24164833 TI - Liquid calories, energy compensation and weight: what we know and what we still need to learn. PMID- 24164836 TI - Referral strategy for early recognition of axial spondyloarthritis: consensus recommendations from the Hong Kong Society of Rheumatology. AB - Low back pain is one of commonest problems prompting a visit to the family physician. Up to 5% of patients with chronic low back pain in the primary care setting are diagnosed as having spondyloarthritis, which includes the prototype disease ankylosing spondylitis. Making a diagnosis of ankylosing spondylitis is often delayed for years, leading to significant pain, impairment of quality of life, disability and productivity loss. A recent breakthrough in the treatment of spondyloarthritis is the anti-tumor necrosis factor-alpha biologics, which lead to rapid relief of pain and inflammation, and improvement in all clinical parameters of the disease. Patients with early spondyloarthritis often respond better than those with late established disease. With proper recognition of inflammatory back pain, and the use of magnetic resonance imaging, spondyloarthritis can now be diagnosed much earlier before features are evident on plain radiographs. Referral to the rheumatologist based on onset of back pain (> 3 months) before the age of 45 years, and an inflammatory nature of the pain, or the presence of human leukocyte antigen-B27, or sacroiliitis by imaging, have been confirmed in multi-center international studies to be a pragmatic approach to enable early diagnosis of spondyloarthritis. This referral strategy has recently been adopted by the Hong Kong Society of Rheumatology for primary care physicians and non-rheumatology specialists. PMID- 24164837 TI - Prevalence of musculoskeletal disorders in southeastern Iran: a WHO-ILAR COPCORD study (stage 1, urban study). AB - OBJECTIVE: The purpose of this study was to determine the prevalence of musculoskeletal complaints and rheumatic diseases in southeast of Iran. METHODS: Subjects were selected based on a cluster sampling from 20 districts of urban areas in Zahedan, Iran. Subjects 15 years old and over were randomly selected and interviewed by trained interviewers in their houses. The Community Oriented Program for the Control of Rheumatic Disease (COPCORD) and Core Questionnaire (CCQ) were used in this study. The people with musculoskeletal complaints (pain, stiffness and swelling) were examined by the rheumatologist. Laboratory tests and radiographic exams were carried out when necessary to further categorize diagnoses. RESULTS: Data were collected from October 10, 2008 to September 15, 2009. Two thousand and one hundred subjects including 921 (43.9%) males and 1179 (56.1%) females were interviewed. The average age of the population was 33.1 +/- 14.7 years. The prevalence of complaints within the past 7 days prior to the interview was 54.13%. The most common sites of complaint were as follows: knee (30.59%), dorsolumbar (28.83%), shoulder (22.26%) and neck (17.07%). The most common rheumatic diseases were osteoarthritis and low back pain with the prevalence of 18.66% and 17.71%, respectively. Finally, the prevalence of rheumatoid arthritis was 0.98%. CONCLUSION: Musculoskeletal complaints are highly common in southeast Iran. Knee and low back pain were the most common sites of complaints. The most frequent diagnosed diseases were osteoarthritis of knee followed by low back pain and soft tissue rheumatism. Rheumatoid arthritis was the most prevalent inflammatory disease. PMID- 24164838 TI - IL-22+ CD4+ T cells in patients with rheumatoid arthritis. AB - AIM: Interleukin (IL)-22 regulates the pathogenesis of autoimmune diseases. The role of IL-22(+) T-cells in the pathogenesis of rheumatoid arthritis (RA) is unclear. This study aimed at examining the levels of plasma IL-22 and the frequency of IL-22(+) CD4(+) T-cells in patients with RA. METHODS: A total of 30 RA patients and 18 gender- and age-matched healthy controls were recruited. Their peripheral blood mononuclear cells were isolated and stimulated with phorbol 12 myristate 13-acetate (PMA) and ionomycin for 6 h. The frequency of IL-22(+) , interferon (IFN)-gamma(+) and IL-17A(+) CD4(+) T-cells was characterized by flow cytometry. The levels of plasma IFN-gamma, IL-17A and IL-22, serum C-reactive protein (CRP), rheumatoid factor (RF), anticyclic citrullinated peptide antibody (CCP) and erythrocyte sedimentation rate (ESR) were measured. RESULTS: The frequency of IFNgamma(-) IL-17A(-)IL-22(+), IFNgamma(-)IL-17A(+)IL-22(+), and IFNgamma(+) IL-17A(-)IL-22(+) T-cells in CD4(+) T-cells and the levels of plasma IFNgamma, IL-17 and IL-22 in RA patients were significant higher than those in healthy controls. The percentages of IL-17A(+)IL-22(+)CD4(+) T-cells were correlated positively with the frequency of Th22 or Th17 cells in the RA patients. The percentages of IL-22(+)CD4(+) T-cells were correlated positively with the values of disease activity score (DAS28) in the RA patients. The percentages of Th22 cells were correlated positively with the levels of plasma IL 22 in the RA patients. CONCLUSION: Our data suggest that IL-22(+)CD4(+) T-cells may contribute to the pathogenesis of RA and that therapeutic targeting of IL-22 may be valuable for the intervention of RA. PMID- 24164839 TI - Hepatitis B virus reactivation in HBsAg-positive patients with rheumatic diseases undergoing anti-tumor necrosis factor therapy or DMARDs. AB - OBJECTIVE: The aim of this study was to assess the effects of anti-tumor necrosis factor (TNF) agents or disease-modifying antirheumatic drugs (DMARDs) on hepatitis B virus (HBV) reactivation in hepatitis B surface antigen (HBsAg) positive patients with rheumatic diseases. METHODS: Evidence of HBV reactivation after anti-TNF therapy or DMARDs in HBsAg-positive patients with rheumatic disease was summarized by performing a systematic review. RESULTS: A total of 122 HBsAg-positive rheumatic disease-positive patients undergoing treatment with an anti-TNF agent or with DMARDs were identified in nine studies. In eight of the studies, the anti-TNF agents used were etanercept in 56 cases, adalimumab in 25 cases and infliximab in 14 cases. Follow-up periods ranged from 6 to 52 months. Antiviral prophylaxis was administrated in 48 of the 122 patients (39.3%). HBV reactivation in HBsAg-positive patients taking an anti-TNF agent or DMARD was reported in 15 cases (15/122 = 12.3%). Ten of the 15 patients provided individual data on HBV reactivation: four patients had rheumatoid arthritis, four had ankylosing spondylitis and two had psoriatic arthritis; four received etanercept, and two received infliximab. In one of the four etanercept-treated cases in which the patient had elevated HBV-DNA levels, antiviral prophylaxis was also administered. Antiviral treatment was also administered in seven patients receiving other treatments: lamivudine in one, adefovir in one and entecavir in five. Clinical outcomes were satisfactory in all 10 cases of HBV reactivation. CONCLUSIONS: Hepatitis B virus reactivation was found in 15 (12.3%) patients among the 122 HBsAg-positive patients with rheumatic diseases treated with anti TNF agents or DMARDs. PMID- 24164840 TI - A multi-center, observational study shows high proportion of Australian rheumatoid arthritis patients have inadequate disease control. AB - OBJECTIVES: To evaluate the disease activity and current pharmacological interventions used to achieve remission in rheumatoid arthritis (RA) patients in Australia. METHODS: Rheumatoid arthritis patients treated in participating Australian clinics were included in the study. Patient demographics, disease onset, medications and disease measures were analyzed. Data, de-identified to the patient, clinic and clinician were captured using an electronic clinical management program. The disease activity score (DAS28) was used to classify patients into the disease activity states of remission, low disease activity (LDA), moderate disease activity (MDA) and high disease activity (HDA). Choice of therapy was at the discretion of the treating clinician. RESULTS: A total of 5686 patients, 72.9% female, 26.9% male, with mean age 61.1 (SD 13.6) years and mean disease duration of 11.5 (SD 10.5) years were analyzed. DAS28 ESR (erythrocyte sedimentation rate) scores were recorded for 2973 patients, with 41.6% in remission, 18.6% LDA, 31.6% MDA and 8.2% HDA. Of those in remission, 17% received a biological disease modifying anti-rheumatic drug (bDMARD), 73% methotrexate (MTX), 19% leflunomide (LEF) and 28% prednisolone. Of the patients with MDA, 20% received a bDMARD, 76% MTX, 24% LEF and 39% prednisolone. Of the patients in HDA, 27% received a bDMARD, 78% MTX, 31% LEF and 60% with prednisolone. CONCLUSIONS: Cross-sectional assessment of this large cohort of Australian RA patients found a large proportion remain in moderate or high disease activity; suggesting a considerable evidence-practice gap. Improvement in disease control in this group may reduce future health burdens. PMID- 24164841 TI - TULUP (TUnisian LUPus): a multicentric study of systemic lupus erythematosus in Tunisia. AB - AIM: Clinical features of systemic lupus erythematosus (SLE) have been described from different geographical regions around the world. However, data from North African countries, including Tunisia, are scarce. METHODS: The aim of this retrospective multicenter study was to analyze demographic, clinical, laboratory features and outcome of SLE in Tunisia throughout 14 Departments of Internal Medicine and to compare them with those of other ethnic and geographic groups. RESULTS: Seven hundred and forty-nine cases of SLE were recorded (American College of Rheumatology criteria) during a 17-year period (1989-2006). They were 676 women and 73 men with an average age at SLE onset of approximately 30.66 years. Our Tunisian patients were characterized by a high frequency of photosensitivity (67.6%), malar rash (68.7%), renal involvement (49.5%) and anti Sm antibodies (44.8%). Infections were the main complications. Fifty-six (7.5%) patients died during the study period. CONCLUSION: Potential limitations and biases in our study need discussion. Specific recruitment of patients in tertiary referral centers may be the source of selection bias and adding to the frequency of moderate or even severe diseases. The therapeutic management and outcome monitoring were heterogeneous due to the fact that patients were evaluated by different doctors. However, this study remains the most representative of Tunisian SLE patients recruited from all parts of Tunisia. PMID- 24164842 TI - Hospital based prospective longitudinal clinical and immunologic study of 179 patients of primary anti-phospholipid syndrome. AB - AIM: To study the clinical and immunological features of primary antiphospholipid syndrome (APS), and to analyze the differences between primary APS and APS associated with autoimmune rheumatic disease (ARD/APS). METHODS: This prospective, longitudinal study, carried out from December 2004 to July 2011 included 179 patients with primary APS and 52 patients of ARD/APS diagnosed as per modified 2006 Sapporo's Criteria. RESULTS: Out of 179 patients of primary APS, 12 were male and 167 were female. The mean age at the time of study entry was 27 +/- 4.33 years. Venous thrombosis was noted in 33 (18.43%) patients. Seventeen patients had deep vein thrombosis and 11 (7.19%) had cortical vein and/or cortical sinus thrombosis. Arterial thrombosis was noted in 19 (10.61%) patients, out of which nine had intracranial arterial thrombosis. Thirty-two (17.85%) had recurrent early fetal losses (< 10 weeks) and 97 (54.18%) had late fetal loss (> 10 weeks). Immunoglobulin G (IgG) and IgM aCLA were present in 141 (78.77%) and 32 (17.87%) patients respectively, whereas lupus anticoagulant was present in 99 (55.3%) patients. In patients with bad obstetric outcome, lupus anticoagulant positivity was significantly more prevalent (P < 0.05) than aCLA positivity. Both venous and arterial thrombosis were significantly more common (P < 0.05) in ARD/APS. However, late fetal loss was significantly more prevalent (P < 0.001) in primary APS. CONCLUSION: Primary APS may lead to a variety of clinical manifestations due to venous and/or arterial thrombosis, which at times may be lethal. It is also an important cause of early and late pregnancy loss(es) and other pregnancy morbidities. PMID- 24164843 TI - Juvenile dermatomyositis at a tertiary care hospital: is there any change in the last decade? AB - INTRODUCTION: Juvenile dermatomyositis (JDM) is a rare multisystem disorder of childhood primarily involving the skeletal muscles and skin. PATIENTS AND METHODS: The case records of patients with JDM seen at our centre in the last 10 years were reviewed and data on clinical presentation, management, outcome and complications were retrieved. RESULTS: Eighteen patients (nine boys) were diagnosed as JDM with median age at presentation of 12.5 years, duration of illness of 9.25 months and follow-up duration of 24 months. At presentation, rash was seen in all patients, 17 had muscle weakness, fever in 11 and arthritis in six. Gottron's lesions and heliotrope rash were seen in 14 and 11 patients, respectively. Calcinosis was seen in five patients and lipoatrophy in two patients. Four patients had dysphagia, one each had dilated cardiomyopathy and respiratory failure. Electromyograph was abnormal in 15 patients and antinuclear antibodies were positive in nine patients. Prednisolone and methotrexate were used in 17 patients. Other disease-modifying anti-rheumatic drugs used were hydroxychloroquine, azathioprine, cyclophosphamide and cyclosporine. Sixteen patients achieved remission. Five patients had pyogenic infections and one patient died of this. In addition two patients had tuberculosis. CONCLUSION: Compared to our experience in the previous decade we saw more girls, used methotrexate upfront but the median duration of illness and prevalence of calcinosis (30%) was the same, suggesting that we need to improve awareness about JDM among paediatricians for early referral. PMID- 24164844 TI - Clinical features and disease course of patients with juvenile dermatomyositis. AB - OBJECTIVE: To describe the clinical features and course of a cohort of patients with juvenile dermatomyositis (JDM) at a tertiary referral pediatric centre in Australia and examine changes in diagnostic and therapeutic approach over time. METHODS: Retrospective review of patients diagnosed with JDM at the Royal Children's Hospital, Melbourne, between 1989 and 2010. RESULTS: Fifty-seven patients were identified. The female : male ratio was 2 : 1 and median age at diagnosis was 7.1 years (2.2-15.3). At diagnosis, 95% had weakness, all had typical rash and 68% had nailfold capillary changes. Calcinosis was not present in any patients at diagnosis and occurred in 18% over time. Creatine kinase, lactate dehydrogenase, aspartate aminotransferase, alanine aminotransferase and aldolase levels were abnormal in 65%, 92%, 88%, 58% and 100%, respectively. Magnetic resonance imaging (MRI) was abnormal in 97% of patients, electomyograph (EMG) in 83% and muscle biopsy in all four patients in whom it was performed. MRI was used in 86% (24/28) of patients diagnosed after 2000. Muscle biopsy was used in four and EMG in no patients over the same period. Treatment used throughout the disease course included oral steroids (93%), high-dose pulse intravenous steroids (82%), methotrexate (63%), intravenous immunoglobulin (32%) and cyclosporin (18%). The disease was monophasic in 46.7% (21/45), polyphasic in 17.7% (8/45) and chronic in 35.5% (16/45). CONCLUSIONS: Australian patients with JDM have similar characteristics to previously described cohorts. In practice, MRI has replaced the invasive diagnostic tests included in the Bohan and Peter criteria for the diagnosis of JDM. The early use of disease-modifying anti rheumatic drugs has become the most common treatment approach. PMID- 24164845 TI - Methotrexate in ocular manifestations of Behcet's disease: a longitudinal study up to 15 years. AB - BACKGROUND: Ocular manifestations of Behcet's disease (BD) need aggressive treatment to prevent severe loss of vision or blindness. Cytotoxic drugs are the main therapeutic agents and the first line treatment. Methotrexate is the least toxic, used mainly for posterior uveitis. We present here the outcome of eye lesions with methotrexate and prednisolone, in a longitudinal study of up to 15 years, on 682 patients (5447 eye-years of follow-up). PATIENTS AND METHODS: Methotrexate was started at 7.5-15 mg/week. Prednisolone was added at 0.5 mg/kg/daily, then adjusted as needed. INCLUSION CRITERIA: (i) fulfilling the International Criteria for Behcet's Disease; and (ii) having active posterior uveitis (PU). Visual acuity (VA) was calculated on a scale of 10. Activity indexes were calculated for PU and retinal vasculitis (RV) for each eye. Total Inflammatory Activity Index (TIAI) demonstrating the inflammatory index of both eyes of the patient, and Total Adjusted Disease Activity Index (TADAI) showing both TIAI + VA were also calculated. RESULTS: Overall results: the mean VA improvement was 0.4 (P < 001), PU 1.2 (P < 0.001) and RV 0.6 (P < 0.001). VA improved in 46.5%, PU in 75.4%, and RV in 53.7% of eyes. TIAI improved in 74% of patients and TADAI in 69.4%. VA was aggravated in 37.2%, PU in 11.1%, and RV in 30.3% of eyes. TIAI was aggravated in 17.4% and TADAI in 21.6% of the patients. The remaining kept their baseline values. CONCLUSION: All parameters improved, PU better than RV. Improvement of VA was the least, mainly due to secondary cataracts. PMID- 24164846 TI - Effects of sesame seed supplementation on clinical signs and symptoms in patients with knee osteoarthritis. AB - AIM: Up to now there have been no human studies to evaluate the effect of sesame (Sesamum indicum L.) in osteoarthritis patients; this study was designed to assess the effect of administration of sesame on clinical signs and symptoms in patients with knee osteoarthritis (OA). METHODS: Fifty patients with knee OA referred to the only specialty and subspecialty orthopedic centers in the north west of Iran, were selected and divided into two groups, namely control and sesame groups. Twenty-five patients in the control group received standard treatment while 25 patients in the sesame group received 40 g/day sesame by oral administration during 2 months of the study along with standard drug therapy. The KOOS Questionnaire, Timed Up and Go (TUG) and Visual Analog Scale (VAS) tests were used for clinical assessments. RESULTS: There was significant difference in pain intensity between the two groups (P = 0.004) after treatment. The mean score of the KOOS Questionnaire in both treatment and control groups was significantly increased (P = 0.001 and P = 0.001, respectively) compared with baseline. The mean score of the TUG Questionnaire in both treatment and control groups was significantly decreased (P = 0.001 and P = 0.001, respectively) compared with baseline. There was significant difference in post-treatment scores of the KOOS Questionnaire (P = 0.009) and TUG (P = 0.002) between the two groups. CONCLUSIONS: The present study showed a positive effect of sesame in improving clinical signs and symptoms in patients with knee OA and indicated the fact that sesame might be a viable adjunctive therapy in treating OA. PMID- 24164847 TI - Serum leptin in Egyptian patients with fibromyalgia syndrome: relation to disease severity. AB - AIM: Recently, a large body of studies has focused on the leptin levels in psychiatric disorders. This study aimed to measure serum leptin levels in fibromyalgia syndrome (FMS) due to a significantly higher prevalence of psychiatric disorder and to determine the relationship between leptin and FMS. METHODS: The present study was a cross-sectional descriptive study. Fifty FMS female patients and 50 healthy females serving as a control group were included. Serum samples tested for serum leptin levels were determined by a specific enzyme linked immunosorbent assay (ELISA). RESULTS: Serum leptin levels were significantly lower in FMS patients compared to the control group. The mean serum leptin in patients with FMS was 7.1 +/- 6.8 ng/mL compared to 9.4 +/- 4.5 ng/mL in the controls (mean difference, -2.48, 95% CI: -4.78, -0.18, P = 0.035). Serum leptin level is inversely correlated with visual analogue scale (VAS) of pain (P = 0.016), VAS of fatigue (P = 0.002), VAS of global severity (P = 0.011), VAS of anxiety (P = 0.027), global self-rating index (P = 0.020), Health Assessment Questionnaire score (P = 0.016), fibromyalgia impact questionnaire (FIQ) (P = 0.025), Beck Depression Inventory (P = 0.002), tender points (TPs) count (P = 0.041), TPs score (P = 0.015), and Pittsburg Sleep Quality Index (P = 0.006). Mean serum leptin levels were also significantly lower in FMS patients with post exertion pain (P = 0.010), depression (P = 0.029), mood disturbance (P = 0.018), anxiety (P = 0.030), short memory difficulties (P = 0.017), sleep disturbance (P = 0.028), restless leg syndrome (P = 0.016), temperomandibular joint syndrome affection (P = 0.043), palpitation (P = 0.022), and irritable bowel syndrome (P = 0.028) than those without. CONCLUSION: We found a significant decrease in serum leptin in FMS patients compared to controls and this decrease correlated with disease severity. PMID- 24164848 TI - Clinical profile of benign joint hypermobility syndrome from a tertiary care military hospital in India. AB - BACKGROUND AND AIMS: Joint hypermobility when associated with symptoms in the absence of systemic rheumatologic disease is termed as benign joint hypermobility syndrome (BJHS). BJHS is often an under-recognised and a poorly managed entity. Indian studies on BJHS are very few and none have been carried out in any of the service rheumatology centres. Hence this retrospective study was carried out at a tertiary medical institute of the Indian Army to assess the varied clinical profile of BJHS. METHODS: All patients consecutively diagnosed as BJHS at the rheumatology clinic of the Army Hospital (Research and Referral) Delhi from May 2010 to May 2011 were included in the study. Their age, sex, presenting features, clinical profile, laboratory and radiological parameters were studied. RESULTS: The mean age of these patients was 30 +/- 5.71 years with a median duration of symptoms of 42 (06-120) months. There were 45 males and 39 females (male : female = 1.15 : 1.00). The median Beighton's score in these patients was 6/9 (range 4 9). Most of our patients were military personnel (43/84), and all had knee joint pain with evidence of degenerative changes in 19 and synovitis in two patients. Eleven patients including nine military personnel had evidence of soft tissue rheumatism with associated fibromyalgia in four and anxiety disorder in one. Out of 18 patients with a Beighton's score of >= 7, nine had incidental findings of lateral head tilt on frontal observation. There was evidence of carpal tunnel syndrome in a patient with wrist synovitis and one patient had associated skin laxity without features of Ehlers-Danlos syndrome. CONCLUSION: BJHS is often under-recognized in clinical practice and is usually missed because of a lack of awareness. A high index of clinical suspicion to diagnose this entity is essential due to its associated morbidities, especially among those exposed to strenuous physical activities. PMID- 24164849 TI - Successful treatment of extensive intestinal perforations from Behcet's disease involving the whole gut: a case report. AB - Intestinal perforation resulting from Behcet's disease has been previously well recognized. To date, fewer than 100 cases of this nature have been reported. Nearly the entire digestive system can be involved, including esophageal, gastric, duodenal, ileum, colon and anal tissues. Most of the reported perforations are single or assembled. Herein, an 8-year-old Chinese girl who developed Behcet's disease with extensive intestinal perforations throughout the gut was successfully treated and is presented. The diagnosis of Behcet's disease was established based on the typical presentations of recurrent oral aphthous ulcers, genital ulcers, typical eye lesions and a positive skin prick test. The extensive intestinal perforations were confirmed by laparotomy. Taking her developmental requirements into consideration, a simple perforation repair was carried out, followed by routine administration of immunosuppressive treatment, and the symptoms were temporarily relieved. Unfortunately, another ileocecal perforation occurred after 1.5 years, and an ileocolectomy was carried out. After the procedure, the girl recovered well. Clinicians should be aware of Behcet's disease as a unique source of intestinal perforation. Although it is encountered rarely in clinical settings, this condition should be considered in each case of intestinal perforation. An ileocolectomy was the necessary choice for radical treatment, even in the case of a pediatric patient. PMID- 24164850 TI - A case of multi-system IGG4-related disease. PMID- 24164851 TI - A rare case of reactive arthritis associated with Enterobius vermicularis infection. PMID- 24164852 TI - Bilateral acute sacroiliitis due to isotretinoin therapy: a case report. PMID- 24164853 TI - Spontaneous splenic rupture complicating granulomatosis with polyangiitis (Wegener's granulomatosis). PMID- 24164854 TI - Brucella aortitis: the missing link. PMID- 24164856 TI - Mohs micrographic surgery for lentigo maligna and lentigo maligna melanoma using Mel-5 immunostaining: an update from the University of Minnesota. AB - BACKGROUND: Mohs micrographic surgery (MMS) is gaining acceptance as a treatment for lentigo maligna (LM) and lentigo maligna melanoma (LMM), especially with the use of melanocyte-staining immunohistochemical (IHC) stains. In 2006, we reported our 4-year experience with Mel-5 immunostaining, with only one recurrence noted in 200 patients after a mean follow-up of 38.4 months.(1) OBJECTIVES: We present an update regarding our 13-year experience with the use of Mel-5. METHODS AND MATERIALS: Patients with primary or recurrent LM or LMM (n = 260) underwent MMS with Mel-5; 174 were followed up to evaluate for recurrence, with a mean follow up of 34 months. The 200 patients described in the initial case series from 1999 to 2003 were also followed. RESULTS: Of the 460 patients treated from January 1999 to December 2011, five recurrences were noted in four patients; one in the initial case series and four in this new, updated series, including one re recurrence from the initial series. One melanoma-related death occurred in a patient intermittently lost to follow-up. CONCLUSION: MMS with Mel-5 immunostaining continues to yield excellent results in the treatment of LM and LMM. PMID- 24164858 TI - Stoma siting and the 'arcuate line' of Douglas: might it be of relevance to later herniation? AB - AIM: Preoperative stoma site marking aims to select an appropriate location for stoma positioning but there are no fixed anatomical points of reference. A stoma raised below the arcuate line (AL) of the posterior rectus sheath may be a contributing factor to later herniation. METHOD: The patients' preferred position for a stoma was marked preoperatively by a nurse stomatherapist in 75 unselected cases. The position of the AL was determined in relation to standard anatomical landmarks (umbilicus, xiphoid process, pubic symphysis and the anterior superior iliac spines). RESULTS: The proportion of patients whose stoma trephine was sited below the AL varied with the anatomical landmark examined. Measurements of symphysis pubis to xiphoid process or height above the iliac spines revealed 36 41% of chosen sites were at or below the AL. In 16 of 29 (55%) women the marked sites were at or below the AL. Of 44 patients who had their site marked above the AL, 23 (53%) were within 2 cm of the AL. In obese patients and those with a waist circumference greater than 100 cm over 50% had their site marked at or within 2 cm of the AL. CONCLUSION: To ensure a stoma site is above the AL of the posterior rectus sheath its centre should be at least 4 cm above a horizontal line between the anterior superior iliac spines. This might reduce later herniation rates. PMID- 24164857 TI - Longitudinal, mixed method study to look at the experiences and knowledge of non melanoma skin cancer from diagnosis to one year. AB - BACKGROUND: Skin cancer is the most common type of cancer in humans and the incidence is increasing worldwide. Our objective was to understanding the needs, experiences and knowledge of individuals with Non Melanoma Skin Cancer (NMSC) from diagnosis up until one year. METHODS: Patients with NMSC completed questionnaires at diagnosis, treatment, 8 weeks post treatment and 12 months post diagnosis. Body image, psychological morbidity and Quality of Life (QOL) were assessed at each time point, with the exception of QOL that was not assessed at diagnosis. Knowledge of NMSC was assessed at baseline and 8 weeks. A sub-sample of participants was also interviewed to allow a more in-depth exploration of patients' experiences. RESULTS: 76 participants completed the initial questionnaire, of which 15 were interviewed. Patients were anxious about a diagnosis of skin cancer, however they were no more depressed or anxious than the general population. QOL significantly improved from diagnosis to 8 weeks and from diagnosis to one year. Knowledge of NMSC was poor and did not improve after treatment. Hairdressers were highlighted as playing an important role in raising awareness and encouraging individuals to seek medical help. Most participants were aware of the need to check their skin for suspicious lesions but were not sure what to look for. At one year participants had forgotten their experience and were not overly concerned about skin cancer. CONCLUSION: There is a need to raise awareness of the signs and symptoms of NMSC. Information on skin cancer needs to be tailored to the individual both at the start of treatment and during the follow up months, ensuring that participants' needs and expectations are met. Targeting education at individuals in the community who regularly come into contact with skin should help in early identification of NMSC. This is important since skin cancer caught early is easily treatable and delay in presentation leads to larger and more complex lesions which impacts in terms of increased morbidity and increased health care costs. PMID- 24164855 TI - Yeast sirtuins and the regulation of aging. AB - The sirtuins are a phylogenetically conserved family of NAD(+) -dependent protein deacetylases that consume one molecule of NAD(+) for every deacetylated lysine side chain. Their requirement for NAD(+) potentially makes them prone to regulation by fluctuations in NAD(+) or biosynthesis intermediates, thus linking them to cellular metabolism. The Sir2 protein from Saccharomyces cerevisiae is the founding sirtuin family member and has been well characterized as a histone deacetylase that functions in transcriptional silencing of heterochromatin domains and as a pro-longevity factor for replicative life span (RLS), defined as the number of times a mother cell divides (buds) before senescing. Deleting SIR2 shortens RLS, while increased gene dosage causes extension. Furthermore, Sir2 has been implicated in mediating the beneficial effects of caloric restriction (CR) on life span, not only in yeast, but also in higher eukaryotes. While this paradigm has had its share of disagreements and debate, it has also helped rapidly drive the aging research field forward. S. cerevisiae has four additional sirtuins, Hst1, Hst2, Hst3, and Hst4. This review discusses the function of Sir2 and the Hst homologs in replicative aging and chronological aging, and also addresses how the sirtuins are regulated in response to environmental stresses such as CR. PMID- 24164859 TI - Renal cell carcinoma in acquired renal cystic disease following renal transplantation. PMID- 24164860 TI - The surface condition effect of Cu2O flower/grass-like nanoarchitectures grown on Cu foil and Cu film. AB - Cu2O flower/grass-like nanoarchitectures (FGLNAs) were fabricated directly on two category specimens of Cu foils and Cu film using thermal oxidation method. The FGLNAs are approximately 3.5 to 12 MUm in size, and their petals are approximately 50 to 950 nm in width. The high compressive stress caused by a large oxide volume in the Cu2O layer on the specimen surface played an important role in the growth of FGLNAs. The effects of surface conditions, such as the surface stresses, grain size, and surface roughness of Cu foil and Cu film specimens, on the FGLNA growth were discussed in detail. PACS: 81. Materials science; 81.07.-b Nanoscale materials and structures: fabrication and characterization; 81.16.Hc Catalytic methods. PMID- 24164861 TI - Herpes simplex virus type 2 and HIV disease progression: a systematic review of observational studies. AB - BACKGROUND: Herpes simplex virus type 2 (HSV-2) is a common co-infection among HIV-infected adults that is hypothesized to accelerate HIV disease progression. METHODS: We searched Medline, EMBASE, relevant conference proceedings (2006-12) and bibliographies of identified studies without language restriction for cohort studies examining the impact of HSV-2 on highly active antiretroviral therapy untreated HIV disease in adults. The exposure of interest was HSV-2 seropositivity or clinical/laboratory markers of HSV-2 activity. The primary outcome was HIV disease progression, defined as antiretroviral initiation, development of AIDS/opportunistic infection, or progression to CD4 count thresholds (<= 200 or <= 350 cells/mm(3)). Secondary outcomes included HIV plasma viral load and CD4 count. RESULTS: Seven studies were included. No definitive relationship was observed between HSV-2 seropositivity and time to antiretroviral initiation (n=2 studies), CD4 <= 350 (n=1), CD4 <= 200 (n=1), death (n=1), viral load (n=6) or CD4 count (n=3). Although two studies each observed trends towards accelerated progression to clinical AIDS/opportunistic infection in HSV-2 seropositives, with pooled unadjusted hazard ratio=1.85 (95% CI=1.12,3.06; I2=2%), most OIs observed in the study for which data were available can occur at high CD4 counts and may not represent HIV progression. In contrast, a single study HSV-2 disease activity found that the presence of genital HSV-2 DNA was associated with a 0.4 log copies/mL increase in HIV viral load. CONCLUSIONS: Despite an observation that HSV-2 activity is associated with increased HIV viral load, definitive evidence linking HSV-2 seropositivity to accelerated HIV disease progression is lacking. The attenuating effects of acyclovir on HIV disease progression observed in recent trials may result both from direct anti-HIV activity as well as from indirect benefits of HSV-2 suppression. PMID- 24164862 TI - Impact of sleep-disordered breathing on myocardial salvage and infarct size in patients with acute myocardial infarction. AB - AIMS: Sleep-disordered breathing (SDB) may be a risk factor for expansion of infarct size early after acute myocardial infarction (MI) by exposing the heart to repetitive oxygen desaturations and increased cardiac afterload. The objective of this study was to assess the impact of SDB on myocardial salvage and infarct size within 3 months after acute MI. METHODS AND RESULTS: Patients with acute MI and percutaneous coronary intervention were enrolled in this prospective observational study. All patients underwent cardiovascular magnetic resonance (CMR) to define salvaged myocardium and infarct size within three to five days and at 3 months after acute MI. Patients were stratified according to apnoea hypopnoea index (AHI) assessed by polysomnography at baseline into those with (AHI >= 15/h) and without (AHI < 15/h) SDB. Of the 56 patients included, 29 (52%) had SDB. The area at risk between both groups was similar (40 +/- 12% vs. 40 +/- 14%, P = 0.925). Patients with SDB had significantly less salvaged myocardium (myocardial salvage index 52% vs. 77%, P < 0.001), smaller reduction in infarct size (0.3% vs. 6.5%, P < 0.001) within 3 months after acute MI, a larger final infarct size (23% vs. 12%, P < 0.001), and a lower final left ventricular ejection fraction (48% vs. 54%, P = 0.023). In a multivariate analysis, including established risk factors for large MI, AHI was independently associated with less myocardial salvage and a larger infarct size 3 months after acute MI. CONCLUSIONS: Sleep-disordered breathing was associated with less myocardial salvage and a smaller reduction in infarct size. These findings suggest a contribution of SDB to impaired healing of MI. PMID- 24164864 TI - Renal impairment, worsening renal function, and outcome in patients with heart failure: an updated meta-analysis. AB - AIMS: Chronic kidney disease (CKD) and worsening renal function (WRF) have been associated with poor outcome in heart failure (HF). METHODS AND RESULTS: Articles were identified by literature search of MEDLINE (from inception to 1 July 2012) and Cochrane. We included studies on HF patients and mortality risk with CKD and/or WRF. In a secondary analysis, we selected studies investigating predictors of WRF. We retrieved 57 studies (1,076,104 patients) that investigated CKD and 28 studies (49,890 patients) that investigated WRF. The prevalence of CKD was 32% and associated with all-cause mortality: odds ratio (OR) 2.34, 95% confidence interval (CI) 2.20-2.50, P < 0.001). Worsening renal function was present in 23% and associated with unfavourable outcome (OR 1.81, 95% CI 1.55-2.12, P < 0.001). In multivariate analysis, moderate renal impairment: hazard ratio (HR) 1.59, 95% CI 1.49-1.69, P < 0.001, severe renal impairment, HR 2.17, 95% CI 1.95-2.40, P < 0.001, and WRF, HR 1.95, 95% CI 1.45-2.62, P < 0.001 were all independent predictors of mortality. Across studies, baseline CKD, history of hypertension and diabetes, age, and diuretic use were significant predictors for the occurrence of WRF. CONCLUSION: Across all subgroups of patients with HF, CKD, and WRF are prevalent and associated with a strongly increased mortality risk, especially CKD. Specific conditions may predict the occurrence of WRF and thereby poor prognosis. PMID- 24164863 TI - Left ventricular dyssynchrony in patients with heart failure and preserved ejection fraction. AB - AIMS: Mechanical dyssynchrony has been postulated to play a pathophysiologic role in heart failure with preserved ejection fraction (HFpEF). METHODS AND RESULTS: We quantified left ventricular (LV) systolic dyssynchrony in 130 HFpEF patients with NYHA class II-IV symptoms, ejection fraction (EF) >=45%, and NT-proBNP levels >400 pg/mL enrolled in the PARAMOUNT trial, and compared them to 40 healthy controls of similar age and gender. Dyssynchrony was assessed by 2D speckle tracking as standard deviation (SD) of time to peak longitudinal systolic strain in 12 ventricular segments and related to measures of systolic and diastolic function. Heart failure with preserved ejection fraction patients (62% women, mean age of 71 +/- 9 years, body mass index of 30.2 +/- 5.9 kg/m(2), systolic blood pressure 139 +/- 15 mmHg) demonstrated significantly greater dyssynchrony than controls (SD of time to peak longitudinal strain; 90.6 +/- 50.9 vs. 56.4 +/- 33.5 ms, P < 0.001), even in the subset of patients (n = 63) with LVEF >=55% and narrow QRS (<=100 ms). Among HFpEF patients, dyssynchrony was related to wider QRS interval, higher LV mass, and lower early diastolic tissue Doppler myocardial velocity (E'). Greater dyssynchrony remained significantly associated with worse diastolic function even after restricting the analysis to patients with EF>=55% and adjusting for age, gender, systolic blood pressure, LV mass index, and LVEF. CONCLUSION: Heart failure with preserved EF is associated with greater mechanical dyssynchrony compared with healthy controls of similar age and gender. Within an HFpEF population, the severity of dyssynchrony is related to the width of QRS complex, LV hypertrophy, and diastolic dysfunction. PMID- 24164865 TI - Continued low uptake of treatment for hepatitis C virus infection in a large community-based cohort of inner city residents. AB - BACKGROUND & AIMS: Despite advances in HCV treatment, recent data on treatment uptake is sparse. HCV treatment uptake and associated factors were evaluated in a community-based cohort in Vancouver, Canada. METHODS: The CHASE study is a cohort of inner city residents recruited from January 2003-June 2004. HCV status and treatment were retrospectively and prospectively determined through data linkages with provincial virology and pharmacy databases. Logistic regression analyses were used to identify factors associated with HCV treatment uptake. RESULTS: Among 2913, HCV antibody testing was performed in 2405, 64% were HCV antibody positive (n = 1533). Individuals with spontaneous clearance (18%, n = 276) were excluded. Among the remaining 1257 HCV antibody-positive participants (mean age 42, 71% male), 29% were Aboriginal. At enrolment, the majority reported recent injecting (60%) and non-injecting drug use (87%). Between January 1998 and March 2010, 6% (77 of 1257) initiated HCV treatment. In adjusted analyses, Aboriginal ethnicity [adjusted odds ratio (AOR) 0.23; 95% CI 0.10, 0.51] and crack cocaine use (AOR 0.61; 95% CI 0.37, 0.99) were associated with a decreased odds of receiving HCV treatment, while methamphetamine injecting (AOR 0.16; 95% CI 0.02, 1.18) trended towards a lower odds of receiving treatment. HCV treatment uptake ranged from 0.2 (95% CI 0.0, 0.7) per 100 person-years (PYs) in 2003 to 1.6 (95% CI 0.9, 2.6) per 100 PYs in 2009. CONCLUSION: HCV treatment uptake remains low in this large community-based cohort of inner city residents with a high HCV prevalence and access to universal healthcare. PMID- 24164866 TI - Food firms' pledge on saturated fat is "thinnest of thin interventions". PMID- 24164867 TI - Use of glucagon-like peptide-1 receptor agonists and bone fractures: a meta analysis of randomized clinical trials. AB - BACKGROUND: Patients with type 2 diabetes mellitus (T2DM) are at a higher risk of bone fractures independent of the use of antidiabetic medications. Furthermore, antidiabetic medications could directly affect bone metabolism. Recently, the use of dipeptidyl peptidase-4 inhibitors has been associated with a lower rate of bone fracture. The aim of the present meta-analysis was to assess whether patients with T2DM treated with glucagon-like peptide-1 receptor agonists (GLP 1Ra) present a lower incidence of bone fracture compared with patients using other antidiabetic drugs. METHODS: A search on Medline, Embase, and http://www.clinicaltrials.gov, as well as a manual search for randomized clinical trials of T2DM treated with either a GLP-1Ra or another antidiabetic drug for a duration of >=24 weeks was conducted by two authors (GM, AM) independently. RESULTS: Although 28 eligible studies were identified, only seven trials reported the occurrence of at least a bone fracture in one arm of the trial. The total number of fractures was 19 (13 and six with GLP-1Ra and comparator, respectively). The pooled Mantel-Haenszel odds ratio for GLP-1Ra was 0.75 (95% confidence interval 0.28-2.02, P = 0.569) in trials versus other antidiabetic agents. CONCLUSIONS: Although preliminary, our study highlighted that the use of GLP-1Ra does not modify the risk of bone fracture in T2DM compared with the use of other antidiabetic medications. PMID- 24164868 TI - Opposing effects of pro- and anti-inflammatory cytokine gene polymorphisms on the risk for breast cancer in western Indian women: a pilot study. AB - In an earlier study, the genotypes associated with higher level of transforming growth factor-beta1 (TGF-beta1) were found to reduce the risk for breast cancer in western Indian women. This observation implied that gene polymorphisms affecting the levels of pro- and anti-inflammatory cytokines may influence the risk for breast cancer in this population. Hence, we performed genotyping for three more functional single-nucleotide polymorphisms (SNPs) responsible for variations in the levels of cytokines associated with inflammation. To that effect, polymorphisms in genes coding for IL-4 (IL-4 C-590T; rs2243250), IFN gamma (IFN-G A + 874T; rs2430561) and MCP-1 (MCP-1 A-2578G; rs1024611) were examined in premenopausal, healthy women (N = 239) and patients with breast cancer (N = 182) from western India. In carriers of the IL-4*590T allele, a reduced risk for the disease (dominant model; OR = 0.61, 95% CI 0.37-0.98) was seen similar to that seen in TGF-B1*10C carriers. An opposite trend was observed with respect to the alleles associated with higher expression of MCP-1 or IFN gamma. In individuals positive for three or more alleles associated with higher levels of either pro- or anti-inflammatory cytokines, an additive effect on the modulation of risk for the disease was evident (for TGF-B1 & IL-4, OR = 0.33, 95% CI 0.12-0.87; for IFN-G & MCP-1, OR = 2.29, 95% CI 0.95-5.51). In the context of contrasting observations in other populations, these results indicate a significant contribution of anti-inflammatory genotypes in the modulation of risk for breast cancer in western Indian women. PMID- 24164869 TI - TNFalpha contributes for attenuating both Y397FAK and Y416Src phosphorylations in osteoblasts. AB - OBJECTIVE: Our poor understanding of how inflammatory mediators can affect osteoblast behavior led us to investigate the tumor necrosis factor (TNF)alpha induced focal adhesion kinase (FAK) and Src phosphorylation. MATERIAL AND METHODS: MC3T3-E1 pre-osteoblast cells were harvested at specific time points after either TNFalpha treatment or RAW267 stimulated conditioned medium, and thereafter cell extracts were prepared for Immunoblotting assay. ELISA detected TNFalpha content at conditioned medium. Tumor necrosis factor-alpha-neutralizing antibodies also were used. RESULTS: It was possible to show that TNFalpha provokes attenuation at Y-phosphorylation of both FAK (at Y397 ) and Src (at Y416 ) proteins (P < 0.05), suggesting a decrease in their activities. The very similar profile was observed when osteoblasts were incubated with conditioned medium from lipopolysaccharide (LPS)-stimulated macrophages, it being significantly different than control (FAK and Src, P < 0.05). Nevertheless, in order to validate these findings, we decided to pre-incubate osteoblasts with anti-TNFalpha neutralizing antibody (2 MUg ml(-1) ) prior exposing to conditioned medium. Importantly, our results revealed that there was a diminution on those conditioned medium effects when the same biological parameters were evaluated (P < 0.05). Moreover, we also showed that TNFalpha impairs osteoblast adhesion, suggesting an interesting role on osteoblast performance. CONCLUSIONS: Altogether, these results suggest that LPS-stimulated macrophage mediators attenuate both FAK and Src activations in osteoblast, suggesting a novel role for TNFalpha on osteoblast performance. PMID- 24164870 TI - Ballistic glancing angle deposition of inclined Ag nanorods limited by adatom diffusion. AB - The growth dynamics of 1D nanorods (NRs) composed of noble metals is ambiguous during glancing angle deposition (GLAD). The continuum equation (CE) model describes ballistic deposition limited by adatom diffusion, not verified in GLAD of noble metal NRs. In this work, GLAD is operated at Ts (substrate temperature) below room temperature to create inclined Ag NRs, and the CE fits the growth orientation of NRs with deposition angles at fixed Ts well. The CE fitting evaluates the diffusion activation energy (Ed) as 0.23 eV, showing that Ag NRs are poly-crystalline with dominant (111), as confirmed by XRD. This work introduces an effective approach to study the growth thermodynamics of 1D nanostructures and evaluate the Ed of adatoms with relatively low melting points. PMID- 24164871 TI - Prevalence, incidence and predictive factors for hand eczema in young adults - a follow-up study. AB - BACKGROUND: Hand eczema is common in the general population and affects women twice as often as men. It is also the most frequent occupational skin disease. The economic consequences are considerable for society and for the affected individuals. METHODS: To investigate the prevalence and incidence of hand eczema and to evaluate risk factors for development of hand eczema in young adults. Subjects and methods; This is a prospective follow-up study of 2,403 young adults, 16 - 19 years old in 1995 and aged 29 - 32 years, 13 years later, in 2008. They completed a postal questionnaire that included questions regarding one year prevalence of hand eczema, childhood eczema, asthma, rhino-conjunctivitis and factors considered to affect hand eczema such as hand-washing, washing and cleaning, cooking, taking care of small children and usage of moisturisers. These factors were evaluated with the multinominal logistic regression analysis. RESULTS: The one-year prevalence of hand eczema was 15.8% (females 20.3% and males 10.0%, p < 0.001). The incidence was 11.6 cases per 1000 person-years (females 14.3 and males 5.2, p < 0.001). Childhood eczema was the most important risk factor for hand eczema. The odds ratios were 13.17 when having hand eczema 1995 and 2008 compared to 5.17 in 2008 (p < 0.001). A high frequency of hand washing was important in predicting hand eczema only when having 1-year prevalence 2008, OR 1.02 (p = 0.038). CONCLUSIONS: After 13 years an increased 1 year prevalence of hand eczema was found. The significant risk factors for hand eczema changed over time from endogenous to exogenous factors. PMID- 24164872 TI - A self-controlled comparative clinical trial to explore the effectiveness of three topical hemostatic agents for stopping severe epistaxis in pediatrics with inherited coagulopathies. AB - OBJECTIVE: The aim of this study was to assess the effectiveness of localized treatments to persistently stop epistaxis in patients with inherited bleeding disorders. METHODS: In a self-controlled comparative clinical trial, to offer the best solution to stop epistaxis at home (within 10 minutes), patients with inherited bleeding disorders were treated using three different topical hemostatic agents, including Tranexamic acid impregnated tampon, EpiCell tampon prepared from oxidized regenerated cellulose pad, and ChitoHem tampon (reinforced with chitosan). The results of using these different products on three groups of randomly selected patients were ultimately compared using the chi(2) and Fisher's exact test statistics. RESULTS: A total of 31 patients, 5 females and 26 males with a mean age of 5.6 years, were included in the study. Twenty-three patients had Glanzmann disease, four had von-Willebrand disease, two had Bernard soulier syndrome, two had activated factor VII deficiency, and one patient had impaired secretion of adenosine deaminase. The study exhibited that statistically there was no significant difference between EpiCell tampon and Tranexamic acid impregnated tampon treatments with respect to the hemostasis duration. However, ChitoHem tampon was more efficient than Tranexamic acid impregnated tampon (P value <0.001) and EpiCell tampon (P value < 0.05). CONCLUSION: ChitoHem tampon, the chitosan-reinforced product, was the best therapy solution to stop epistaxis. We recommend further research on the use of other hemostatic agents for localized bleeding in patients with inherited bleeding disorders. PMID- 24164873 TI - Phenotypic variability in ARCA2 and identification of a core ataxic phenotype with slow progression. AB - Autosomal recessive cerebellar ataxia 2 (ARCA2) is a recently identified recessive ataxia due to ubiquinone deficiency and biallelic mutations in the ADCK3 gene. The phenotype of the twenty-one patients reported worldwide varies greatly. Thus, it is difficult to decide which ataxic patients are good candidates for ADCK3 screening without evidence of ubiquinone deficiency. We report here the clinical and molecular data of 10 newly diagnosed patients from seven families and update the disease history of four additional patients reported in previous articles to delineate the clinical spectrum of ARCA2 phenotype and to provide a guide to the molecular diagnosis. First signs occurred before adulthood in all 14 patients. Cerebellar atrophy appeared in all instances. The progressivity and severity of ataxia varied greatly, but no patients had the typical inexorable ataxic course that characterizes other childhood-onset recessive ataxias. The ataxia was frequently associated with other neurological signs. Importantly, stroke-like episodes contributed to significant deterioration of the neurological status in two patients. Ubidecarenone therapy markedly improved the movement disorders, including ataxia, in two other patients. The 7 novel ADCK3 mutations found in the 10 new patients were two missense and five truncating mutations. There was no apparent correlation between the genotype and the phenotype. Our series reveals that the clinical spectrum of ARCA2 encompasses a range of ataxic phenotypes. On one end, it may manifest as a pure ataxia with very slow progressivity and, on the other end, as a severe infantile encephalopathy with cerebellar atrophy. The phenotype of most patients, however, lies in between. It is characterized by a very slowly progressive or apparently stable ataxia associated with other signs of central nervous system involvement. We suggest undergoing the molecular analysis of ADCK3 in patients with this phenotype and in those with cerebellar atrophy and a stroke like episode. The diagnosis of patients with a severe ARCA2 phenotype may also be performed on the basis of biological data, i.e. low ubiquinone level or functional evidence of ubiquinone deficiency. This diagnosis is crucial since the neurological status of some patients may be improved by ubiquinone therapy. PMID- 24164874 TI - [Case-control study on the risk factors of type 2 diabetes of Dong nationality in Western Hunan]. AB - OBJECTIVE: To explore the risk factors of type 2 diabetes mellitus (T2DM) of Dong nationality in Western Hunan, and to provide a scientific basis for the prevention and treatment of T2DM in the district. METHODS: In the case-control study, the subjects were divided into a T2DM group, an impaired glucose regulation (IGR) group and a normal glucose tolerance (NGT) group through oral glucose tolerance test (OGTT). A questionnaire survey was conducted, and physical measurements and the detection of blood glucose, blood lipids and serum insulin were done. RESULTS: Univariate analysis found significant difference in age, fasting insulin (FINS), HOMA insulin resistance index (HOMA-IRI), HOMA beta-cell function index (HOMA-betaC), trigalloyl glycerol (TG), high density lipoprotein cholesterol (HDL-C), systolic blood pressure, and diastolic blood pressure in the glucose metabolism among different groups (P<0.05). Body mass index (BMI), waist/hip ratio (WHR), family history of diabetes, number of physical activities per week, dinner taste, fat and protein-rich foods, fresh vegetables and fruits intake were associated with T2DM. Multifactor non-conditional ordinal logistic regression indicated that age was the risk factor of T2DM and IGR. Compared with the group whose age was<=50, the odds ratios of the groups of 50>70 were 1.85, 2.83 and 2.64 respectively, P<0.05. The risk of suffering from diabetes of the overweighted or obese people was 2.13 times that of a normal BMI group, P<0.01. The other influencing factors included WHR (OR=2.06), family history of diabetes (OR=11.36), and fat and protein-rich foods (OR=1.90). CONCLUSION: The main influencing factors of T2DM of Dong nationality in Western Hunan include age, BMI, WHR, family history of diabetes, fat and protein-rich foods. We must strengthen the health eduation of T2DM of Dong nationality in Western Hunan to reduce the risk of T2DM. PMID- 24164875 TI - [3.0T-MR high resolution proton density weighted imaging for transverse cervical ligament in healthy adolescents]. AB - OBJECTIVE: To explore the imaging characteristics of the transverse ligament in healthy adolescents, and further understand the imaging characteristics of the ligament injury. METHODS: We used 3.0T-MR to scan the transverse ligament with proton-weighted sequence in 32 young volunteers, scanned coronally, horizontally and sagittally, and then observed the morphology, thickness, running and signal characteristics of the ligament. RESULTS: The anatomy and signal characteristics of the transverse cervical ligament were clearly displayed by high resolution proton density weighted imaging (PDWI). The whole picture of the transverse ligament was effectively displayed by coronal combined with horizontal image. The transverse ligament was located in the rear of the odontoid, and connected to the inside of both sides of the block like half-arc. The length was (20.4+/-3.3) mm, the ligament center was the thickest, and both sides gradually became thinner. The middle width of the ligament was (7.3+/-0.6) mm, the ligament ends narrowed down, and the middle was (2.1+/-0.4) mm thick; 75% of the transverse ligament showed homogeneous low signal in PDWI, while 25% of the local transverse ligament had high signal. CONCLUSION: High resolution PDWI with 3.0T-MR is a effective method to evaluate the structure of the transverse cervical ligament. Local high signal may not necessarily be the sign of ligament injure. There may also be some high signal in the normal adolescent ligament, so we must pay much attention to clinical diagnosis and treatment. PMID- 24164876 TI - [Effect of dexmedetomidine hydrochloride on H2O2-induced oxidative stress in alveolar macrophages]. AB - OBJECTIVE: To evaluate whether dexmedetomidine hydrochloride, an alpha2 adrenergic receptor agonist, can prevent oxidative damage to alveolar macrophages induced by H2O2. METHODS: We used methyl thiazolyl tetrazolium (MTT) colorimetry to test the effect of different concentrations and action time of H2O2 on the survival rate of alveolar macrophages, and then we chose the appropriate H2O2 concentration and action time to build NR8383 cell oxidative damage model. After pre-conditioning of 0.01, 0.10, and 1.00 MUmol/L dexmedetomidine hydrochloride for 24 hours, MTT colorimetry was used to demonstrate the survival rate of NR8383 cells damaged by H2O2, and the release of lactate dehydrogenase (LDH) and TNF alpha by H2O2-damaged NR8383 cells was detected by corresponding kit. RESULTS: At 50-300 MUmol/L, H2O2 caused concentration-dependent oxidative damage in the alveolar macrophages, decreased the cell survival rate, and increased LDH and TNF alpha release. At 0.01-1.00 MUmol/L dexmedetomidine hydrochloride concentration dependently protected NR8383 cells from oxidative damage induced by H2O2, significantly increased the cell survival rate, decreased LDH and TNF-alpha release, and this effect of dexmedetomidine hydrochloride was dose-dependent. Yohimbine, an alpha2 - adrenergic receptor antagonist, completely neutralized the protective effect of dexmedetomidine hydrochloride on NR8383 cells without affecting the oxidative damage of NR8383 cells. CONCLUSION: Dexmedetomidine hydrochloride can prevent alveolar macrophages from oxidative damage induced by H2O2, which may play a protective role through alpha2 - adrenergic receptors. PMID- 24164877 TI - [Effect of GLP-1 on high glucose-induced human umbilical vein endothelial cell apoptosis and mechanism]. AB - OBJECTIVE: To investigate the effects of glucagon-like peptide-1 (GLP-1) on high glucose-induced apoptosis of human umbilical vein endothelial cells (HUVECs) and the mechanism involved. METHODS: HUVECs were cultured under varying conditions for 48 h, and the cell viability was spectrophotometrically measured by MTT assay. Flow cytometry detected the ratio of cell apoptosis. Western blot detected the protein levels of p-Akt and p-eNOS, while NO assay kit detected the NO concentration. RESULTS: Treatment of high glucose (33 mmol/L) for 48 h significantly decreased the HUVECs viability and induced the apoptosis of HUVECs, concomitant with decreased Akt and eNOS phosphorylation leves and subsequent NO production. Treatment with GLP-1 (3 nmol/L) for 48 h in the high glucose group increased the HUVECs viability (P<0.01), decreased the ratio of HUVECs early apoptosis (P<0.05), ameliorated the reduced protein levels of p-Akt and p-eNOS caused by high glucose, and increased the NO production (P<0.05). The anti apoptotic effect and the increased NO production of GLP-1were inhibited by PI3K inhibitor wortmannine (100 nmol/L) or eNOS inhibitor L-NAME (100 MUmol/L). The effect on p-Akt, p-eNOS of GLP-1 was inhibited by wortmannine (100 nmol/L) while L-NAME (100 MUmol/L) did not have any influence on the expression of p-Akt. CONCLUSION: GLP-1 can ameliorate high glucose-induced HUVECs apoptosis, which is probably related to the up-regulation of PI3K/Akt/eNOS pathway. PMID- 24164878 TI - [Identification of contraction related proteins in corpus myometrium at labor]. AB - OBJECTIVE: To explore the molecular mechanism of human corpus myometrium contraction related proteins and parturition. METHODS: The proteins of human corpus of myometrium tissues from full term non-in labor (38- 41 weeks amenorrhea) and full term in labor (38-41 weeks amenorrhea) gravidas were separated by 2-dimensional gel electrophoresis (2-GE), respectively. Then gels were stained by Coomassie brilliant blue G250, scanned by Image scanner and analyzed with PDQuest software. The differentially expressed protein spots of corpus myometrium between the 2 groups were identified by peptide mass finger print based on matrix-assisted laser desorption/ionization time of flight mass spectrometry (MALDI-TOF-MS) and database searching. Three identified differentially expressed proteins were confirmed by Western blot. RESULTS: Well resolved and reproducible 2D-GE maps of human corpus myometrium from non-in labor and in-labor gravidas were acquired. Twenty more than 2-fold differentially expressed protein spots were identified by MALDI-TOF-MS. These proteins were involved in cell structure, calcium binding, chaperone, energy metabolism, signal transduction, and antioxidant. CONCLUSION: Twenty contraction related proteins of human corpus myometrium have been identified, indicating that cell structure and calcium-binding are important reasons for the contraction of human corpus myometrium. PMID- 24164879 TI - [Serum vitamin D levels in postmenopausal women with type 2 diabetes mellitus]. AB - OBJECTIVE: To investigate the correlation between serum vitamin D levels and index of glucose and lipid metabolism in postmenopausal women with type 2 diabetes mellitus (T2DM). METHODS: A total of 44 postmenopausal women with T2DM and 41 healthy postmenopausal women were matched with age, body mass index and menopausal duration. The serum vitamin D was detected by enzyme-linked immuno sorbent assay (ELISA). RESULTS: Compared with the control group, the level of 25(OH)D3 in postmenopausal women with T2DM was lower, with no statistical significance. Multiple regression analysis revealed that only BMI(bj'=-0.372, P<0.05) was independently related to 25(OH)D3 with statistical significance. The percentages of 25(OH)D3 deficiency in all subjects in the control group and in the T2DM group were 84.7%, 80.5%, and 88.6%, respectively. The 25(OH)D3 deficiency in the T2DM group was more prevalent than that in the control group, with no statistical difference (P=0.372). The binary logistic regression analysis showed the serum 25(OH)D3 level was not related to the risk of diabetes. CONCLUSION: Compared with the control group, a lower 25(OH)D3 level and a higher rate of 25(OH)D3 deficiency is found in T2DM subjects. When rectified by BMI, these is no significant difference. In postmenopausal women, hypovitaminosis D is associated with obesity and dyslipidemia, but not with the risk of T2DM. PMID- 24164880 TI - [Quality of life and related factors among family members of tuberculosis patients]. AB - OBJECTIVE: To understand the quality of life and related factors among family members of tuberculosis patients and provide a reference for the improvement of their quality of life. METHODS: A total of 222 family members of tuberculosis patients at 4 tuberculosis hospitals in Changsha and 327 healthy controls were surveyed with structured questionnaire, the short version of the WHO quality of life scale (WHOQOL-BREF). RESULTS: The mean score of the family members of tuberculosis patients in the psychological domain, physical domain and environmental domains was lower than that of the control group (P<0.01). Multiple linear regression showed that gender, age, monthly income, educational level, patient condition and knowledge of tuberculosis prevention and treatment were the factors affecting their quality of life. CONCLUSION: The quality of life of the family members of tuberculosis patients is lower than that of the control group. PMID- 24164881 TI - [Effect of hydrogen sulfide on the expression of CSE, NF-kappaB, and IL-8 mRNA in GES-1 cells with Helicobacter pylori infection]. AB - OBJECTIVE: To investigate the effect of hydrogen sulfide (H2S) on the expression of CSE, NF-kappaB, and IL-8 mRNA in GES-1 cells with Helicobacter pylori (H. pylori) infection and to explore its mechanism on gastric mucosa inflammation caused by H. pylori. METHODS: GES-1 cells were cultured for 24 h and divided into a control group (neither H. pylori nor NaHS), an H. pylori group, a NaHS group (which was further divided into 4 groups at 50, 100, 200, or 400 MUmol/L NaHS), and H. pylori + NaHS group (which was further divided into 4 groups at 50, 100, 200, or 400 MUmol/L NaHS). Each group was then cultured for 3, 6, or 12 h. The expression of CSE, NF-kappaB, and IL-8 mRNA was measured by RT-PCR, and their correlation was analyzed. RESULTS: The expression of CSE, NF-kappaB, and IL-8 mRNA in GES-1 cells in the H. pylori group was higher than that in the control group. The expression of CSE in the 200 MUmol/L NaHS group and 400 MUmol/L NaHS group was lower than that of the control group (P<0.05), whereas the expression of NF-kappaB and IL-8 in all NaHS groups had no statistical differences compared with the control group (P>0.05). The expression of CSE, NF-kappaB, and IL-8 mRNA in all groups of NaHS, H. pylori + 200 MUmol/L NaHS group, and H. pylori + 400 MUmol/L NaHS group was lower than that in the H. pylori group (P<0.05). There was positive correlation among the expressions of CSE, NF-kappaB, and IL-8 mRNA in the H. pylori group, the H. pylori + 200 MUmol/L NaHS group, and the H. pylori + 400 MUmol/L NaHS group (P<0.05). CONCLUSION: H. pylori can induce NF-kappaB and IL-8 mRNA expression and upregulate CSE mRNA expression. At 200 and 400 MUmol/L, NaHS can suppress H. pylori-induced NF-kappaB and IL-8 mRNA expression and ameliorate the morphology of H. pylori-induced GES-1 injury, which may protect gastric epithelial cells by H. pylori infection. PMID- 24164882 TI - [Effect of chronic intermittent hypoxia on the expression of fractalkine in rat liver]. AB - OBJECTIVE: To investigate the effect of chronic intermittent hypoxia (CIH) on liver injury and the expression of fractalkine in rats and explore its possible mechanism. METHODS: A CIH murine model was established to mimic the pathophysiology of obstructive sleep apnea-hypopnea syndrome (OSAHS) in humans. Thirty healthy male Spraque-Dawley rats were randomly assigned to 3 groups: a 5% CIH group, a 5% CIH+RH (removal of hypoxia) group and a control group ( 10 rats in each group). The 5% CIH and 5% CIH+RH groups were exposed to CIH for 3 weeks, 8 h/d, and the frequency of hypoxia was 20 times/h. The 5% CIH+RH group was then exposed to normal gaseous environment for another 3 weeks. After the experiment, liver sections were stained with hematoxylin-eosin (HE) and the liver pathology was observed. The expression of fractalkine in the liver tissues was detected by immunohistochemical method. RESULTS: 1) Compared with the control group, the hepatic steatosis and inflammatory activities in the 5% CIH and 5% CIH+RH groups were more severe (all P<0.01 ); compared with the 5% CIH group, the hepatic steatosis and inflammatory activity in the 5% CIH+RH group were dramatically reduced (P<0.01 ). 2) Compared with the control group, the fractalkine expression in the 5% CIH and 5% CIH+RH groups was increased (both P<0.01). The fractalkine expression in the 5% CIH+RH group was dramatically downregulated compared with that in the 5% CIH group (P<0.01). CONCLUSION: CIH can induce liver injury and high fractalkine expression in rat liver tissues. PMID- 24164883 TI - [Association of ApoAI gene rs12721026 polymorphism with cerebral hemorrhage in Changsha Han population and its effect on plasma lipid levels]. AB - OBJECTIVE: To explore the association between apolipoprotein AI (ApoAI) gene rs12721026 polymorphism and cerebral hemorrhage (CH) in Changsha Han population, and to evaluate the effect of rs12721026 polymorphism on plasma lipid levels. METHODS: A total of 273 patients with CH and 140 healthy controls were collected. The rs12721026 polymorphism of ApoAI was analyzed by SNaPshot genotyping analysis and DNA sequencing. The total cholesterol (TG), triglyceride (TC), HDL-C and LDL C were examined by oxidase method. RESULTS: There was no significant difference in the genotype and allele frequencies of rs12721026 polymorphism between the CH group and the control group (P>0.05). Both in the CH group and in the control group, the level of HDL-C of the TT gene type of rs12721026 was significantly higher than that of the GT/GG gene type (P<0.05). There was no significant difference in the levels of TG, TC and LDL-C among different subgroups of gene types. CONCLUSION: There may be no association between apoAI gene rs12721026 polymorphism with CH in Changsha Han population, which may still influence the HDL-C levels. PMID- 24164884 TI - [Dosimetric comparison of left-side whole breast irradiation with IMRT and hybrid IMRT]. AB - OBJECTIVE: To evaluate the potential dosimetric benefits and optimal indications of intensity modulated radiation therapy (IMRT) and hybrid intensity modulated radiation therapy (Hybrid IMRT) for the left side breast cancer patients after breast-conservation therapy. METHODS: Eight patients with left breast carcinoma who received breast-conservation surgery were selected for this study. Two plans were designed in 3-dimensional treatment planning system. The dose distributions of target volume and normal tissues, conformal index (CI) and heterogeneous index (HI) were analyzed by dose-volume histogram (DVH). RESULTS: The PTV coverage was the same in the two radiotherapy plans. A better dose uniformity throughout the whole breast in Hybrid IMRT plan was achieved. The CI, the percentage of PTV receiving more than 105% prescribed dose (V105%), the percentage of PTV receiving more than 110% prescribed dose (V110%), and the Dmax, Dmin and Dmean of PTV were similar in the two plans. We compared the Hybrid IMRT with IMRT: V13 of the ipsilateral lung decreased from 27.66% to 20.7%, V5 of the contralateral lung decreased from 8.01% to 2.25%, V10 and V20 of the heart decreased from 35.23% and 16.77% to 19.22% and 10.6% respectively, V5 and V10 of the contralateral breast decreased from 35% and 10.39% to 20.38% and 5.7% respectively, all with significant difference. V30 and V40 of the ipsilateral lung and V40 of the heart increased by 1.28%, 1.48%, and 2.48%, with significant difference. CONCLUSION: Hybrid IMRT is a better choice for patients whose treatment position is inaccurate or cannot be repeated well. PMID- 24164885 TI - [Expression of Th1/Th2 inflammatory cytokines in rat treatment model of ulcerative colitis]. AB - OBJECTIVE: To investigate the expression of Th1/Th2 inflammatory cytokines IL-2, interferon-gamma (IFN-gamma), IL-4, and IL-10 in rat treatment model of dextran sulfate sodium (DSS) -induced ulcerative colitis. METHODS: Forty Sprague Dawley (SD) male rats were divided into a normal group, a colitis model group, a sulfasalazine(SASP)-treatment group (SASP group) and a Jiechangning-treatment group ( Jiechangning group) (each group n=10). Disease activity index (DAI) and colorectal histological damage scale were assessed. The expression levels of cytokines IL-2, IFN-gamma, IL-4, and IL-10 in the serum and the colon mucosa tissues were detected by enzyme-linked immuno sorbent assay (ELISA) and real time polymerase chain reaction (RT-PCR). RESULTS: Compared with the colitis model group, the DAI and colorectal histological damage scale were decreased in the Jiechangning group (both P<0.05), but there was no obvious difference compared with the SASP group (P>0.05). There was no significant difference in IL-2 expression both in the serum and the colon mucosa tissues before or after the treatment in various groups (P>0.05). Compared with the colitis model group, IFN gamma level both in the serum and the colon mucosa tissues was decreased in the SASP group and the Jiechangning group, with significant difference in the serum (both P<0.05), but there was significant difference in the colon mucosa tissues only in the Jiechangning group (P<0.05). The serum IL-4 level in the SASP group and the Jiechangning group was increased compared with that in the colitis control group, with significant difference only in the Jiechangning group (P<0.05). There was no difference in IL-4 level in the colon mucosa tissues whether treated or not (P>0.05). IL-10 level both in the serum and the colon mucosa tissues in the SASP group and the Jiechangning group was increased compared with that in the colitis model group, with significant difference (all P<0.05). There was no difference in the expression level of cytokines IL-2, IFN gamma, IL-4, and IL-10 both in the serum and the colon mucosa tissues between the SASP group and the Jiechangning group (all P>0.05). CONCLUSION: DSS can break the balance of Th1/Th2 expression in the colon. Jiechangning enema can ameliorate DSS induced acute experimental colitis in rats by decreasing IFN-gamma level and increasing IL-10 level both in the serum and the colon mucosa tissues to regulate the Th1/Th2 balance and improve immunity. PMID- 24164886 TI - [Identification of pathogenic microorganism by sequencing 16S rRNA gene]. AB - OBJECTIVE: To identify 14 bacteria by sequencing the 16S rRNA gene and establish the basis for clinical application in the future. METHODS: DNA samples of the 14 bacteria were extracted. The 16S rRNA genes were amplified by PCR and sequenced with common primers. The sequences of the 16S rRNA genes were aligned by online software Blastn in nucleotide database. The bacteria were identified according to the homology of their 16S rRNA genes. RESULTS: Twelve bacteria were classified to species, the other 2 bacteria were classified to genus. CONCLUSION: 16S rRNA gene sequence analysis is useful in identifying pathogenic bacteria. PMID- 24164887 TI - [Effect of different denture cleaning methods on roughness in resin denture base]. AB - OBJECTIVE: To determine the effect of different denture cleaning methods on surface roughness in resin denture base. METHODS: We established 20 wafer samples of fuser base resin (14 mm*14 mm*3 mm), and then randomly divided them into 4 groups: group A was the control group, which were placed in water, while group B, C and D were the experimental groups, whose cleaning methods were toothbrush and water, toothbrush and toothpaste, denture cleaning tablets, respectively. Each procedure in group B and C lasted for 3 seconds, but group D lasted 5 min and repeated for 1080 times. We cleaned twice a day to simulate the method of cleaning dentures. Surface roughness was checked after different procedures by laser scanning confocal microscopy. RESULTS: Significant difference on surface roughness was found between group B, C and A (P<0.05), while no significant difference in the surface roughness between group A and D (P>0.05). CONCLUSION: Significant surface roughness alterations have been observed in toothbrush and toothpaste group, but no change has been found in denture cleaning tablets group, which does not produce scratches on the surface of resin denture base. PMID- 24164888 TI - [Prenatal anxiety and cesarean section with non-medical indication]. AB - OBJECTIVE: To explore the relationship between prenatal anxiety and cesarean section (c-section) with non-medical indication. METHODS: Nested case-control study was used to analyze the risk factors for c-section with no medical needs: 433 pregnant women with gestational age longer than 24 weeks were enrolled in this study. According to the mode of delivery, we divided them into a vaginal delivery group, a c-section group without medical need and a c-section group with medical need. RESULTS: The c-section rate was 62.1%, 55.8% of which was c-section without medical need at family request. The score of state anxiety (S-AI) and trait anxiety (T-AI) was 42.53+/-11.04 and 44.40+/-10.23 respectively, much higher than that of normal population. After the adjustment of maternal social economic status and other prenatal statuses for this pregnancy, the prenatal anxiety was still associated with c-section with non-medical indication. The adjusted odd ratio for prenatal anxiety state, prenatal trait anxiety state and c section with non-medical indication was 1.41 (95% CI: 1.06-1.87) and 1.23 (95% CI: 1.08-1.40), respectively. CONCLUSION: Prenatal anxiety state is a risk factor for c-section with non-medical indication. PMID- 24164889 TI - [Recent development of robotic coronary artery bypass graft]. AB - As an evolutionary process, the robotic technology has been recently applied in the minimally invasive surgery. The robotic surgical system can provide cardiac surgeons with less invasive manner and dexterity manipulation in coronary artery bypass graft. The robotic minimally invasive coronary artery bypass graft usually includes robotic internal thoracic artery harvesting, robotic assistant coronary artery bypass graft and totally robotic coronary artery bypass graft. PMID- 24164890 TI - [MR subtraction in the differentiation of benign and malignant tumors]. AB - OBJECTIVE: To evaluate dynamic contrast-enhanced MRI in conjunction with MR subtraction in the differential diagnosis of benign and malignant breast tumors at 3 Tesla. METHODS: A total of 78 patients with breast tumors enrolled in this study, including 45 malignant lesions and 33 benign lesions verified by histopathology. Dynamic MR contrast enhanced imaging was done by T1 high resolution isotropic volume excitation sequence. MR subtraction was used to retrospectively analyze the MR dynamic image. A dynamic phase subtraction (DPS) map is a map image with pixel-by-pixel subtraction of an early-phase image from a delayed maximum enhancement phase image obtained in a dynamic study. The sensitivity and specificity were calculated with or without subtraction in the diagnosis of benign and malignant breast tumors. RESULTS: The sensitivity of benign breast masses increased from 0.879 to 0.939, and the specificity increased from 0.818 to 0.909 with reference to the DPS map. There was statistical difference between with or without DPS (Z=2.023, P=0.043). The sensitivity of breast malignant masses increased from 0.889 to 0.933, and the specificity increased from 0.867 to 0.911 with reference to the DPS map, with statistical difference between with or without DPS map (Z=2.294, P=0.021). The pattern of TIC changed from continuous to a plateau in 8 patients, from a plateau to washout in 10, and from continuous to washout in 5. No changes were observed in the other 55 patients. CONCLUSION: MR Subtraction is a simple and useful technique to identify breast lesions. It helps to accurately set the location of the ROI TIC and improve the detection rate of benign and malignant breast tumors. PMID- 24164891 TI - Letter to the editor: Critique of Bahorik et al. (2013)--'Under-reporting of drug use among individuals with schizophrenia: prevalence and predictors'. PMID- 24164892 TI - Abnormal screening for gestational diabetes, maternal mood disorder, and preterm birth. AB - OBJECTIVE: Gestational diabetes mellitus (GDM) affects 7% of pregnant mothers, and those with GDM have increased rates of perinatal complications. Major depressive disorder (MDD) and its pharmacologic treatments are associated with obesity and adverse pregnancy outcomes. In this prospective study, we investigated the relationship between abnormal GDM screens, maternal mood disorders, and adverse outcomes. METHODS: We examined mothers with MDD, those with bipolar disorder (BD), and healthy controls (HC) at 20, 30, and 36 weeks of gestation and delivery. We obtained demographic data and pre-pregnancy body mass index (BMI), and confirmed diagnoses with the Structured Clinical Interview for DSM-IV. We evaluated smoking, alcohol use, substance use, and medication treatments with the Longitudinal Interval Follow-up Evaluation interview. Mothers received the one-hour 50-g glucose challenge test (GCT) at 26-28 weeks of gestation. Outcome variables were preterm birth, birth weight (BW) and peripartum events. RESULTS: We enrolled 62 HC, 50 BD, 41 past MDD, and 39 current MDD mother infant pairs. Mean GCT levels and the frequency of abnormal GCT (>140 mg/dL) did not differ across groups. Rates of smoking (chi(2) = 20.68, df = 3, p < 0.001), substance use (chi(2) = 21.76, df = 3, p < 0.001), and pre-pregnancy obesity [BMI >= 30 (chi(2) = 9.97, df = 3, p = 0.019)] differed significantly across groups. Mothers with BD received medications associated with weight gain significantly more often than others [13/45 (29%), p < 0.001). After adjusting for group differences, GCT levels were associated significantly with increased odds for preterm birth (odds ratio = 1.29, 95% confidence interval: 1.0-1.7, p = 0.05) and increased perinatal events (beta = 0.11, p = 0.04) but were not associated with BW. CONCLUSIONS: In mothers with or without mood disorders, having increased GCT levels contributes to a higher likelihood for adverse pregnancy outcomes. Mothers with BD or current MDD can have additional risks for adverse outcomes and may benefit from early referral for high-risk services and supportive management in pregnancy. PMID- 24164893 TI - Crumbs3 is essential for proper epithelial development and viability. AB - First identified in Drosophila, the Crumbs (Crb) proteins are important in epithelial polarity, apical membrane formation, and tight junction (TJ) assembly. The conserved Crb intracellular region includes a FERM (band 4.1/ezrin/radixin/moesin) binding domain (FBD) whose mammalian binding partners are not well understood and a PDZ binding motif that interacts with mammalian Pals1 (protein associated with lin seven) (also known as MPP5). Pals1 binds Patj (Pals1-associated tight-junction protein), a multi-PDZ-domain protein that associates with many tight junction proteins. The Crb complex also binds the conserved Par3/Par6/atypical protein kinase C (aPKC) polarity cassette that restricts migration of basolateral proteins through phosphorylation. Here, we describe a Crb3 knockout mouse that demonstrates extensive defects in epithelial morphogenesis. The mice die shortly after birth, with cystic kidneys and proteinaceous debris throughout the lungs. The intestines display villus fusion, apical membrane blebs, and disrupted microvilli. These intestinal defects phenocopy those of Ezrin knockout mice, and we demonstrate an interaction between Crumbs3 and ezrin. Taken together, our data indicate that Crumbs3 is crucial for epithelial morphogenesis and plays a role in linking the apical membrane to the underlying ezrin-containing cytoskeleton. PMID- 24164894 TI - Transcriptome-wide RNA interaction profiling reveals physical and functional targets of hnRNP L in human T cells. AB - The RNA processing factor hnRNP L is required for T cell development and function. However, the spectrum of direct targets of hnRNP L activity in T cells has yet to be defined. In this study, we used cross-linking and immunoprecipitation followed by high-throughput sequencing (CLIP-seq) to identify the RNA binding sites of hnRNP L within the transcriptomes of human CD4(+) and cultured Jurkat T cells. We find that hnRNP L binds preferentially to transcripts encoding proteins involved in RNA processing and in Wnt and T cell receptor (TCR) signaling. This binding is largely conserved across both quiescent and activated T cells, in agreement with the critical role of hnRNP L throughout T cell biology. Importantly, based on the binding profile of hnRNP L, we validate numerous instances of hnRNP L-dependent alternative splicing of genes critical to T cell function. We further show that alternative exons with weak 5' splice site sequences specifically show a strong correlation between hnRNP L binding and hnRNP L-dependent splicing regulation. Together, these data provide the first transcriptome-wide analysis of the RNA targets of hnRNP L in lymphoid cells and add to the functional understanding of hnRNP L in human biology. PMID- 24164895 TI - Hypoxia-inducible factor 1 regulation through cross talk between mTOR and MT1 MMP. AB - Hypoxia-inducible factor 1 (HIF-1) plays a key role in the cellular adaptation to hypoxia. Although HIF-1 is usually strongly suppressed by posttranslational mechanisms during normoxia, HIF-1 is active and enhances tumorigenicity in malignant tumor cells that express the membrane protease MT1-MMP. The cytoplasmic tail of MT1-MMP, which can bind a HIF-1 suppressor protein called factor inhibiting HIF-1 (FIH-1), promotes inhibition of FIH-1 by Mint3 during normoxia. To explore possible links between HIF-1 activation by MT1-MMP/Mint3 and tumor growth signals, we surveyed a panel of 252 signaling inhibitors. The mTOR inhibitor rapamycin was identified as a possible modulator, and it inhibited the mTOR-dependent phosphorylation of Mint3 that is required for FIH-1 inhibition. A mutant Mint3 protein that cannot be phosphorylated exhibited a reduced ability to inhibit FIH-1 and promoted tumor formation in mice. These data suggest a novel molecular link between the important hub proteins MT1-MMP and mTOR that contributes to tumor malignancy. PMID- 24164896 TI - Cdk1 regulates the temporal recruitment of telomerase and Cdc13-Stn1-Ten1 complex for telomere replication. AB - In budding yeast (Saccharomyces cerevisiae), the cell cycle-dependent telomere elongation by telomerase is controlled by the cyclin-dependent kinase 1 (Cdk1). The telomere length homeostasis is balanced between telomerase-unextendable and telomerase-extendable states that both require Cdc13. The recruitment of telomerase complex by Cdc13 promotes telomere elongation, while the formation of Cdc13-Stn1-Ten1 (CST) complex at the telomere blocks telomere elongation by telomerase. However, the cellular signaling that regulates the timing of the telomerase-extendable and telomerase-unextendable states is largely unknown. Phosphorylation of Cdc13 by Cdk1 promotes the interaction between Cdc13 and Est1 and hence telomere elongation. Here, we show that Cdk1 also phosphorylates Stn1 at threonine 223 and serine 250 both in vitro and in vivo, and these phosphorylation events are essential for the stability of the CST complexes at the telomeres. By controlling the timing of Cdc13 and Stn1 phosphorylations during cell cycle progression, Cdk1 regulates the temporal recruitment of telomerase complexes and CST complexes to the telomeres to facilitate telomere maintenance. PMID- 24164897 TI - Temporal production of the signaling lipid phosphatidic acid by phospholipase D2 determines the output of extracellular signal-regulated kinase signaling in cancer cells. AB - The Ras-extracellular signal-regulated kinase (ERK) cascade is an important signaling module in cells. One regulator of the Ras-ERK cascade is phosphatidic acid (PA) generated by phospholipase D (PLD) and diacylglycerol kinase (DGK). Using a newly developed PA biosensor, PASS (phosphatidic acid biosensor with superior sensitivity), we found that PA was generated sequentially by PLD and DGK in epidermal growth factor (EGF)-stimulated HCC1806 breast cancer cells. Inhibition of PLD2, one of the two PLD members, was sufficient to eliminate most of the PA production, whereas inhibition of DGK decreased PA production only at the later stages of EGF stimulation, suggesting that PLD2 precedes DGK activation. The temporal production of PA by PLD2 is important for the nuclear activation of ERK. While inhibition of both PLD and DGK had no effect on the overall ERK activity, inhibition of PLD2 but not PLD1 or DGK blocked the nuclear ERK activity in several cancer cell lines. The decrease of active ERK in the nucleus inhibited the activation of Elk1, c-fos, and Fra1, the ERK nuclear targets, leading to decreased proliferation of HCC1806 cells. Together, these findings reveal that PA production by PLD2 determines the output of ERK in cancer cell growth factor signaling. PMID- 24164898 TI - Identification of the immunoproteasome as a novel regulator of skeletal muscle differentiation. AB - While many of the molecular details of myogenesis have been investigated extensively, the function of immunoproteasomes (i-proteasomes) in myogenic differentiation remains unknown. We show here that the mRNA of i-proteasome subunits, the protein levels of constitutive and inducible proteasome subunits, and the proteolytic activities of the 20S and 26S proteasomes were significantly upregulated during differentiation of skeletal muscle C2C12 cells. Knockdown of the i-proteasome catalytic subunit PSMB9 by short hairpin RNA (shRNA) decreased the expression of both PSMB9 and PSMB8 without affecting other catalytic subunits of the proteasome. PSMB9 knockdown and the use of i-proteasome-specific inhibitors both decreased 26S proteasome activities and prevented C2C12 differentiation. Inhibition of the i-proteasome also impaired human skeletal myoblast differentiation. Suppression of the i-proteasome increased protein oxidation, and these oxidized proteins were found to be more susceptible to degradation by exogenous i-proteasomes. Downregulation of the i-proteasome also increased proapoptotic proteins, including Bax, as well as cleaved caspase 3, cleaved caspase 9, and cleaved poly(ADP-ribose) polymerase (PARP), suggesting that impaired differentiation is likely to occur because of significantly increased apoptosis. These results demonstrate for the first time that i proteasomes, independent of constitutive proteasomes, are critical for skeletal muscle differentiation of mouse C2C12 cells. PMID- 24164900 TI - Therapeutic targeting of the Jak/STAT pathway. AB - Antibodies that block cytokine function provide a powerful therapeutic tool especially for the treatment of autoimmune diseases. Cytokines are a group of small hydrophilic glycoproteins that bind their receptors on the cell surface and subsequently activate intracellular signalling cascades, such as the JAK/STAT pathway. A bulk of evidence has demonstrated that genetic mutations in signalling molecules can cause immunodeficiencies and malignant cell growth. As a result, several drug companies have begun to develop therapeutics that inhibit the function of JAK tyrosine kinases. Currently, two JAK inhibitors, tofacitinib and ruxolitinib, are used in the clinic for treating rheumatoid arthritis and myeloproliferative diseases, respectively. Inhibiting JAK function has been shown to efficiently prevent the uncontrolled growth of cancerous cells and to harness overly active immune cells. In the future, other small molecule compounds are likely to come into clinical use, and intense work is ongoing to develop inhibitors that specifically target the constitutively active mutant JAKs. This MiniReview will summarize the basic features of the JAK/STAT pathway, its role in human disease and the therapeutic potential of JAK/STAT inhibitors. PMID- 24164899 TI - Role of the HIN domain in regulation of innate immune responses. AB - The oligonucleotide/oligosaccharide binding (OB) fold is employed by proteins to bind nucleic acids during replication, transcription, and translation. Recently, a variation of the OB fold consisting of a tandem pair of OB folds named the HIN (hematopoietic expression, interferon-inducible nature, and nuclear localization) domain was shown to play essential roles in the regulation of innate immune responses originating from binding of nucleic acids in the cytoplasm or the nucleus of the cell. Although the two OB folds of the HIN domain are linked via a long linker region, conserved hydrophobic contacts between the two OB folds hold them together firmly, resulting in a single compact domain. This overall topology of the HIN domain seems to be highly conserved, and proteins containing the HIN domain have been grouped in the PYHIN family. Structures of the recently solved HIN domains reveal that these domains exhibit either absent in melanoma2 (Aim2) HIN-like or p202 HINa-like modes of DNA binding. These two modes of DNA binding seem to result in different responses and as a consequence confer distinct roles on the proteins. This review summarizes our current understanding of the structure and function of the HIN domains in context with the innate immune responses. PMID- 24164901 TI - Are we getting necrotizing soft tissue infections right? A 10-year review. AB - BACKGROUND: The Alfred Hospital is a referral centre for necrotizing soft tissue infections (NSTIs) in the state of Victoria and receives around 20 such patients each year. We sought to compare our practice and outcomes against published data, and to examine management at referring hospitals to determine whether adjustments to current practices are required. METHODS: A retrospective chart review of patients admitted to the Alfred Hospital between 1 January 2001 and 31 December 2010 with a diagnosis of necrotizing fasciitis was conducted. Demographic, etiologic, treatment and outcome data were collected and analysed. RESULTS: Two hundred and nineteen patients were identified with a mean age of 54.76 years and a preponderance of men (63.47%). The overall mortality rate for the patient group was 15.98%. More than 80% of patients were transferred from another facility. Nearly 40% of patients did not undergo surgical debridement within 24 h of presentation to a hospital and 30.6% were not debrided prior to transfer. Patients underwent a median of three procedures at the Alfred Hospital and the majority of patients required admission to the intensive care unit (68.95%). CONCLUSION: NSTIs remain a surgical emergency with high rates of mortality and resource requirements. The mortality rate at our institution compares well with other published series. Many patients experienced delays before undergoing debridement and in many cases were transferred without debridement. The trend towards transferring NSTI patients to centres accustomed to treating burns and major trauma seems logical, but should not delay life-saving surgical debridement. Timing of transfer does not seem to affect mortality. PMID- 24164902 TI - Comparison of acoustic radiation force impulse/serum noninvasive markers for fibrosis prediction in liver transplant. AB - OBJECTIVES: Fibrosis, related to several causes, can be diagnosed in children and adolescents' liver grafts that are >1 year old. At present, liver biopsy is the gold standard for assessing liver damage in the posttransplant setting. We aimed to evaluate the accuracy of noninvasive biomarkers of fibrosis, namely, acoustic radiation force impulse (ARFI), aspartate-to-platelet ratio index, and aspartate aminotransferase/alanine aminotransferase (AST/ALT) ratio index, either alone or in combination, for predicting fibrosis in pediatric patients submitted to liver transplantation. METHODS: We prospectively assessed liver fibrosis in 30 children/adolescents with liver transplant through biopsy (liver transplant follow-up during 12 months). ARFI with Virtual Touch Software (Acuson 2000) was performed, and blood samples were taken to determine liver function and platelet count. Two groups were analyzed according to the histopathologic stage of fibrosis, namely, none/mild (F0-F1) versus significant fibrosis (F2-4). RESULTS: The mean age of the 30 patients was 11 years (3-18 years), with a mean posttransplant period of assessment of 6.5 years. Twenty-four patients (80%) presented stage F0-F1 fibrosis and 6 patients (20%) presented stage F2-4. The area under the curve using receiver operating characteristic analysis for ARFI, aspartate-to-platelet ratio index, and AST/ALT ratio index for significant fibrosis was 0.76 (P = 0.052), 0.74 (P = 0.066), and 0.69 (P = 0.162), respectively. Through multivariate logistic regression analysis, the only independent predictor of significant fibrosis was ARFI (odds ratio 10.7, 95% confidence interval 1.2-95.7; P = 0.045). The combination of ARFI and AST/ALT ratio index presented a good diagnostic accuracy of fibrosis (area under the curve of 0.83; P = 0.013). CONCLUSIONS: ARFI may serve as a potential method for assessing significant fibrosis in pediatric patients with liver transplant, particularly in combination with AST/ALT ratio index. PMID- 24164903 TI - Impact of eating restriction on gastrointestinal motility in adolescents with IBS. AB - OBJECTIVE: Gastrointestinal disturbances as a result of changes in eating patterns have been described in eating disorders. Many patients who experience irritable bowel syndrome report changes in eating patterns as a way to cope with their symptoms. Little is known about the consequences of these practices. The aim of this study was to explore whether repeated eating restriction (defined as not eating >= 4 hours while hungry) is associated with motility disturbances. METHODS: Of 17 patients with irritable bowel syndrome, subjects were divided into those who habitually restrict their eating (n = 8) and those without eating restriction (n = 9) (age range 15-21, mean 19.2; 64.7% girls). Whole-gut transit time was measured by radiopaque markers, gastric sensitivity was measured by water load test (drinking max of 800 mL of water in 5 minutes or until full), and gastric dysrhythmias by an electrogastrogram. RESULTS: Restrictors drank less water (mean 464.4 mL) than nonrestrictors (mean 613 mL; P = 0.02). No difference was found in gastric dysrhythmias (62.5% vs 77.8%; P = 0.5). Whole-gut transit tended to be slower in the restrictors (mean 51.0 hours) than in nonrestrictors (mean 37.5 hours), but this was not significant. CONCLUSIONS: Eating restriction appears to be associated with increased gastric sensation. More data are needed from larger studies to determine whether eating behaviors are associated with other motility disturbances. PMID- 24164904 TI - Maintenance of efficacy and safety of rabeprazole in children with endoscopically proven GERD. AB - OBJECTIVE: The aim of the present study was to evaluate 24-week maintenance of efficacy and safety of rabeprazole in children with endoscopically proven gastroesophageal reflux disease (GERD). METHODS: Children ages 1 to 11 years who achieved endoscopic/histologic healing (defined as grade 0 of the Hetzel-Dent Classification scale and/or grade 0 of the Histological Features of Reflux Esophagitis scale) in a 12-week treatment phase were continued on the same dose for an additional 24 weeks during the maintenance phase. The dose was determined by weight: children weighing 6 to 14.9 kg (low-weight cohort) received 5 or 10 mg and children weighing >= 15 kg (high-weight cohort) received 10 or 20 mg. RESULTS: Healing was maintained in 90% of children (100% [low-weight cohort]; 89% [10 mg, high-weight cohort]; 85% [20 mg, high-weight cohort]). The Total GERD Symptom and Severity score continued to improve slightly in all of the children across all dose groups (P = 0.026) during the maintenance phase, except the 10-mg dose group (low-weight cohort), which experienced a slight worsening of 3.6 points. Overall, 71% children felt better on the GERD Symptom Relief score (P < 0.001); 95% of investigators and 92% of parent/caregivers rated "Good to Excellent" on the Global Treatment Satisfaction scale and Clinical Global Impressions Improvement scale, respectively. Overall incidence of treatment emergent adverse events was 63%; upper respiratory tract infections (13%) and vomiting (11%) were the most commonly reported (>10%). CONCLUSIONS: Rabeprazole was effective in maintaining endoscopic/histologic healing during a 24-week maintenance period in children with endoscopically proven GERD. The clinical effect and safety profile were largely similar across dose groups. PMID- 24164905 TI - Effect of gastrojejunal feedings on visits and costs in children with neurologic impairment. AB - OBJECTIVE: The objective of the present study was to determine the effect of gastrojejunal tube (GJT) feedings in children with neurologic impairment (NI) on gastroesophageal reflux disease (GERD)- and/or dysfunctional swallowing-related visits and their associated costs. METHODS: The present study is a retrospective cohort study of children with NI and GERD who underwent GJT placement at the study hospital from December 1999 to October 2006. Visits (emergency department, radiology, and hospitalizations) were reviewed from the time of birth until 1 year following GJT placement and classified as either not GERD and/or dysfunctional swallowing related or GERD and/or dysfunctional swallowing related (eg, pneumonias). Incident rate ratios (IRRs) were calculated by dividing the post-GJT visit rate by the pre-GJT visit rate. Other outcomes included associated costs, fundoplications, and deaths. RESULTS: Thirty-three patients met inclusion criteria. The IRR for total visits was 1.78 (95% confidence interval [CI] 1.12 2.81) and for GERD- and/or dysfunctional swallowing-related visits 2.88 (95% CI 1.68-4.94). Feeding tube-related visits (IRR 5.36, 95% CI 2.73-10.51) accounted for the majority. GERD- and/or dysfunctional swallowing-related costs per child per year were low overall, with no difference from pre-GJT versus post-GJT placement ($1851 vs $4601, P = 0.89). Seven (21%) children underwent Nissen fundoplication and 4 (12%) died within 1 year of GJT placement. Two deaths involved jejunal perforation. CONCLUSIONS: Children with NI and GERD who are treated with GJT feedings have significantly more GERD- and/or dysfunctional swallowing-related visits in the following year. The majority of these visits are because of the procedural complications, which are inexpensive. There is, however, mortality associated with the GJT and some children proceed to a fundoplication. PMID- 24164906 TI - Exogenous pigment in Peyer patches of children suspected of having IBD. AB - OBJECTIVES: The base of human Peyer patches of the terminal ileum has been noted to contain black granular pigment deposits, composed of titanium dioxide and aluminosilicate, which are food additives typically present in a Western diet, and pharmaceuticals. In the present study, we investigated the distribution of exogenous pigment throughout the gastrointestinal tract of children suspected of having inflammatory bowel disease (IBD), the correlation between their age and the presence and amount of pigment in Peyer patches, and its relation to pediatric IBD. METHODS: Biopsies (upper and lower gastrointestinal tract) from children suspected of having IBD who underwent endoscopy, were reassessed by a blinded, expert pathologist. The amount of pigment in biopsies was scored using a semiquantitative scale (range 0 to +++). RESULTS: A total of 151 children were included: 62 with Crohn disease (CD), 26 with ulcerative colitis, and 63 with non IBD. In 63 children (42%), deposits of black pigment were found only in biopsies from the terminal ileum, located in Peyer patches. A significant correlation was found between increasing age and the amount of pigment (P = 0.004). Pigment deposits were found significantly less in the patients with CD compared with those in patients with ulcerative colitis and those with non-IBD (26% vs 62% and 49%, P = 0.002). CONCLUSIONS: These results provide support for the hypothesis that the amount of pigment, only present in Peyer patches in the terminal ileum, becomes denser with increasing age. Absence of pigment in Peyer patches in a higher number of patients with CD suggests that microparticles may have become involved in the inflammatory process, possibly because of disrupted autophagy. PMID- 24164907 TI - Size dependence of the magnetic properties of Ni nanoparticles prepared by thermal decomposition method. AB - By means of thermal decomposition, we prepared single-phase spherical Ni nanoparticles (23 to 114 nm in diameter) that are face-centered cubic in structure. The magnetic properties of the Ni nanoparticles were experimentally as well as theoretically investigated as a function of particle size. By means of thermogravimetric/differential thermal analysis, the Curie temperature TC of the 23-, 45-, 80-, and 114-nm Ni particles was found to be 335 degrees C, 346 degrees C, 351 degrees C, and 354 degrees C, respectively. Based on the size-and-shape dependence model of cohesive energy, a theoretical model is proposed to explain the size dependence of TC. The measurement of magnetic hysteresis loop reveals that the saturation magnetization MS and remanent magnetization increase and the coercivity decreases monotonously with increasing particle size, indicating a distinct size effect. By adopting a simplified theoretical model, we obtained MS values that are in good agreement with the experimental ones. Furthermore, with increase of surface-to-volume ratio of Ni nanoparticles due to decrease of particle size, there is increase of the percentage of magnetically inactive layer. PMID- 24164911 TI - Hepatic encephalopathy without cirrhosis. PMID- 24164912 TI - Comment on Tozer et al.: surgical management of rectovaginal fistula in a tertiary referral centre--many techniques are needed. PMID- 24164914 TI - Expert consensus on blood pressure management of diabetic patients in China. AB - This Expert Consensus proposed by the Chinese Society of Endocrinology (CSE) updates concepts on hypertension management in patients with diabetes. It focuses on clinical outcomes literature published within the past 5 years and currently in press, and incorporates these new observations into modifications of established guidelines. Complications and mortality in diabetic patients are increased when hypertension is present. The present update focuses on questions such as what to do when a diabetic patient has an elevated blood pressure level when therapy is initiated and whether combinations of agents should be used as soon as possible. Although the strategies and principles of treatment remain unchanged, approaches to specific patient-related issues influencing cardiovascular outcomes in people with diabetes have changed. Finally, an updated integrated management of multiple cardiovascular risk factors is provided and is suggested as a starting point to achieve blood pressure goals. In addition to controlling blood pressure, the CSE suggests that individualized strategies are equally important and that attention should be paid to other factors, including safety (which is the most important), feasibility, and health economic evaluation. PMID- 24164913 TI - FGF-23 and cognitive performance in hemodialysis patients. AB - Although cognitive impairment is common in hemodialysis patients, the etiology of and risk factors for its development remain unclear. Fibroblast growth factor 23 (FGF-23) levels are elevated in hemodialysis patients and are associated with increased mortality and left ventricular hypertrophy. Despite FGF-23 being found within the brain, there are no prior studies assessing whether FGF-23 levels are associated with cognitive performance. We measured FGF-23 in 263 prevalent hemodialysis patients in whom comprehensive neurocognitive testing was also performed. The cross-sectional association between patient characteristics and FGF-23 levels was assessed. Principal factor analysis was used to derive two factors from cognitive test scores, representing memory and executive function, which carried a mean of 0 and a standard deviation of 1. Multivariable linear regression adjusting for age, sex, education status, and other relevant covariates was used to explore the relationship between FGF-23 and each factor. Mean age was 63 years, 46% were women and 22% were African American. The median FGF-23 level was 3098 RU/mL. Younger age, lower prevalence of diabetes, longer dialysis vintage, and higher calcium and phosphorus were independently associated with higher FGF-23 levels. Higher FGF-23 was independently associated with a lower memory score (per doubling of FGF-23, beta = -0.08 SD [95% confidence interval, CI: -0.16, -0.01]) and highest quartile vs. lowest quartile (beta = 0.42 SD [-0.82, -0.02]). There was no definite association of FGF 23 with executive function when examined as a continuous variable (beta = -0.03 SD [ 0.10, 0.04]); however, there was a trend in the quartile analysis (beta = -0.28 SD [-0.63, 0.07], P = 0.13, for 4th quartile vs. 1st quartile). FGF-23 was associated with worse performance on a composite memory score, including after adjustment for measures of mineral metabolism. High FGF-23 levels in hemodialysis patients may contribute to cognitive impairment. PMID- 24164915 TI - Volarea - a bioinformatics tool to calculate the surface area and the volume of molecular systems. AB - We have developed a computer program named 'VolArea' that allows for a rapid and fully automated analysis of molecular structures. The software calculates the surface area and the volume of molecular structures, as well as the volume of molecular cavities. The surface area facility can be used to calculate the solvent-exposed surface area of a molecule or the contact area between two molecules. The volume algorithm can be used to predict not only the space occupied by any molecular structure, but also the volume of cavities, such as tunnels or clefts. The software finds wide application in the characterization of systems, such as protein/ligand complexes, enzyme active sites, protein/protein interfaces, enzyme channels, membrane pores, solvent tunnels, among others. Some examples are given to illustrate its potential. VolArea is as a plug-in of the widely distributed software Visual Molecular Dynamics (VMD) and is freely available at http://www.fc.up.pt/PortoBioComp/Software/Volarea/Home.html. PMID- 24164916 TI - Elastic-resilience-induced dispersion of carbon nanotubes: a novel way of fabricating high performance elastomer. AB - State-of-the-art processes cannot achieve rubber/multi-walled carbon nanotube (MWCNT) composites with satisfactory performance by using pristine MWCNTs and conventional processing equipment. In this work, high performance rubber/MWCNT composites featuring a combination of good mechanical properties, electrical and thermal conductivities and damping capacity over a wide temperature range are fabricated based on a well-developed master batch process. It is demonstrated that the MWCNTs are dispersed homogeneously due to the disentanglement induced by well-wetting and shearing, and the elastic-resilience-induced dispersion of the MWCNTs by rubber chains via the novel processing method. To further enhance the efficacy of elastic-resilience-induced dispersion for MWCNTs, a slightly pre crosslinked network is constructed in the master batch. Consequently, we obtain rubber/MWCNT composites with unprecedented performance by amplifying the reinforcing effect of relatively low MWCNT loading. This work provides a novel insight into the fabrication of high performance functional elastomeric composites with pristine CNTs by taking advantage of the unique elastic resilience of rubber chains as the driving force for the disentanglement of CNTs. PMID- 24164919 TI - Onychodystrophy treated using fractional carbon dioxide laser therapy and topical steroids: new treatment options for nail dystrophy. PMID- 24164920 TI - The use of the Thoracic Morbidity and Mortality system for the internal analysis of performance: a case-matched temporal audit. AB - OBJECTIVES: The aim of the present study was to evaluate the usefulness of the Thoracic Morbidity and Mortality (TMM) scoring system in auditing the quality of care of our unit. METHODS: We analysed the performance of our unit comparing the incidence of complications and mortality occurring after anatomic lung resections during two different periods: early period (January 2000 to December 2009: 830 lobectomy, 134 pneumonectomy and 78 segmentectomy) and recent period (January 2010 to August 2012: 191 lobectomy, 8 pneumonectomy and 19 segmentectomy). The cardiopulmonary complications as traditionally defined in the European Society of Thoracic Surgeons (ESTS) database were also classified according to the TMM system: this method grades the postoperative adverse events from 1 to 5 reflecting an increasing severity of management regardless the type of complication. Complications graded higher than 2 are regarded as major complications. To account for confounders, several baseline and surgical factors were used to build a propensity score that was applied to match the patients of the most recent group with their early-group counterparts. These two matched groups were compared in terms of cardiopulmonary morbidity (codified by ESTS definitions) and mortality rates and incidence of major complications according to the TMM system. RESULTS: The propensity score analysis yielded 209 well matched pairs of patients operated on in the two periods. The two groups had similar rates of ESTS-defined cardiopulmonary complications (recent: 38 patients vs early: 37 patients, P = 0.9). The use of the TMM system revealed a higher incidence of major (grade > 2) complications rate in the recent period (recent: 29 patients vs early: 14 patients, P = 0.02). CONCLUSIONS: The TMM scoring system for classifying the postoperative complications revealed a decline of quality of care of our unit otherwise undetected by applying traditional outcome measures. This tool can be used as an additional graded outcome endpoint to refine internal audit of performance. PMID- 24164921 TI - Work function maps and surface topography characterization of nitroaromatic-ended dendron films on graphite. AB - Surface topography and work function maps were simultaneously obtained for carbon surfaces modified by a dendritic molecule: 3,5-Bis (3,5-dinitrobenzoylamino) benzoic acid. The dendrons were spontaneously assembled onto highly ordered pyrolytic graphite samples, exhibiting an increase in the surface potential. This fact is consistent with the incorporation of an electron-acceptor functional group that remains electroactive on the surface. PMID- 24164917 TI - Childhood adversity moderates the effect of ADH1B on risk for alcohol-related phenotypes in Jewish Israeli drinkers. AB - Childhood adversity and genetic variant ADH1B-rs1229984 have each been shown to influence heavy alcohol consumption and disorders. However, little is known about how these factors jointly influence these outcomes. We assessed the main and additive interactive effects of childhood adversity (abuse, neglect and parental divorce) and the ADH1B-rs1229984 on the quantitative phenotypes 'maximum drinks in a day' (Maxdrinks) and DSM-Alcohol Use Disorder (AUD) severity, adjusting for demographic variables, in an Israeli sample of adult household residents (n = 1143) evaluated between 2007 and 2009. Childhood adversity and absence of the protective ADH1B-rs1229984 A allele were associated with greater mean Maxdrinks (mean differences: 1.50; 1.13, respectively) and AUD severity (mean ratios: 0.71; 0.27, respectively). In addition, childhood adversity moderated the ADH1B rs1229984 effect on Maxdrinks (P < 0.01) and AUD severity (P < 0.05), in that there was a stronger effect of ADH1B-rs1229984 genotype on Maxdrinks and AUD severity among those who had experienced childhood adversity compared with those who had not. ADH1B-rs1229984 impacts alcohol metabolism. Therefore, among those at risk for greater consumption, e.g. those who experienced childhood adversity, ADH1B-rs1229984 appears to have a stronger effect on alcohol consumption and consequently on risk for AUD symptom severity. Evidence for the interaction of genetic vulnerability and early life adversity on alcohol-related phenotypes provides further insight into the complex relationships between genetic and environmental risk factors. PMID- 24164923 TI - Home improvement and gardening can prolong life in over 60s, study finds. PMID- 24164922 TI - Vectorial secretion of interleukin-8 mediates autocrine signalling in intestinal epithelial cells via apically located CXCR1. AB - BACKGROUND: In the intestinal mucosa, several adaptations of TLR signalling have evolved to avoid chronic inflammatory responses to the presence of commensal microbes. Here we investigated whether polarized monolayers of intestinal epithelial cells might regulate inflammatory responses by secreting IL-8 in a vectorial fashion (i.e. apical versus basolateral) depending on the location of the TLR stimulus. RESULTS: In the Caco-2 BBE model of polarized villus-like epithelium, apical stimulation with TLR2 and TLR5 ligands resulted in the apical secretion of IL-8. The CXCR1 receptor for IL-8 was expressed only on the apical membrane of Caco-2 BBE cells and differentiated epithelial cells in the human small intestine and colon. Transcriptome analyses revealed that Caco-2 BBE cells respond to stimulation with IL-8 supporting the hypothesis that IL-8 induces G protein-coupled receptor signalling. CONCLUSIONS: These results show that IL-8 induces autocrine signalling via an apical CXCR1 in Caco-2 BBE intestinal epithelial cells and that this receptor is also expressed on the apical surface of differentiated human intestinal epithelial cells in vivo, suggesting an autocrine function for IL-8 secreted in the lumen. PMID- 24164924 TI - Impact of vancomycin resistance on mortality in neutropenic patients with enterococcal bloodstream infection: a retrospective study. AB - BACKGROUND: Vancomycin-resistant Enterococcus (VRE) bloodstream infection (BSI) is generally associated with the delayed administration of adequate antibiotics. The identification of risk factors and outcomes of VRE BSI is necessary for establishing strategies for managing neutropenic fever in patients with hematological malignancies. METHODS: We retrospectively analysed consecutive cases of enterococcal BSI in patients with neutropenia after chemotherapy or stem cell transplantation between July 2009 and December 2011 at a single center. RESULTS: During the 30-month period, among 1,587 neutropenic patients, the incidence rate of enterococcal BSI was 1.76 cases per 1,000 person-days. Of the 91 enterococcal BSIs, there were 24 cases of VRE. VRE BSI was associated with E. faecium infection (P < .001), prolonged hospitalization (P = .025) and delayed administration (>= 48 hours after the febrile episode) of adequate antibiotics (P = .002). The attributable mortality was 17% and 9% for VRE and vancomycin susceptible Enterococcus (VSE), respectively (P = .447). The 30-day crude mortality was 27% and 23% for VRE and VSE, respectively (OR 1.38, 95% CI 0.53 3.59; P = .059). Only SAPS-II was an independent predictive factor for death (adjusted OR 1.12, 95% CI 1.08-1.17; P < .001). CONCLUSIONS: In conclusion, vancomycin resistance showed some trend towards increasing 30-day mortality, but is not statistically significant despite the delayed use of adequate antibiotics (>=48 hours). Only underlying severity of medical condition predicts poor outcome in a relatively homogeneous group of neutropenic patients. PMID- 24164925 TI - Patch cloning method for multiple site-directed and saturation mutagenesis. AB - BACKGROUND: Various DNA manipulation methods have been developed to prepare mutant genes for protein engineering. However, development of more efficient and convenient method is still demanded. Homologous DNA assembly methods, which do not depend on restriction enzymes, have been used as convenient tools for cloning and have been applied to site-directed mutagenesis recently. This study describes an optimized homologous DNA assembly method, termed as multiple patch cloning (MUPAC), for multiple site-directed and saturation mutagenesis. RESULTS: To demonstrate MUPAC, we introduced five back mutations to a mutant green fluorescent protein (GFPuv) with five deleterious mutations at specific sites and transformed Escherichia coli (E. coli) with the plasmids obtained. We observed that the over 90% of resulting colonies possessed the plasmids containing the reverted GFPuv gene and exhibited fluorescence. We extended the test to introduce up to nine mutations in Moloney Murine Leukemia Virus reverse transcriptase (M MLV RT) by assembling 11 DNA fragments using MUPAC. Analysis of the cloned plasmid by electrophoresis and DNA sequencing revealed that approximately 30% of colonies had the objective mutant M-MLV RT gene. Furthermore, we also utilized this method to prepare a library of mutant GFPuv genes containing saturation mutations at five specific sites, and we found that MUPAC successfully introduced NNK codons at all five sites, whereas other site remained intact. CONCLUSIONS: MUPAC could efficiently introduce various mutations at multiple specific sites within a gene. Furthermore, it could facilitate the preparation of experimental gene materials important to molecular and synthetic biology research. PMID- 24164927 TI - Delusional misidentification syndromes and dementia: a border zone between neurology and psychiatry. AB - The delusional misidentification syndromes (DMSs) are psychopathologic phenomena in which a patient consistently misidentifies persons, places, objects, or events. Although often described in relation to psychotic states including schzofrenia, it is, nevertheless, widely considered that these syndromes have an anatomical basis because of their frequent association with organic brain disease; studies have pointed to the presence of identifiable lesions, especially in the right frontal lobe and adjacent regions, in a considerable proportion of patients. The purpose of this article is to examine the phenomenon in people with dementia. We searched the electronic databases for original research and review articles on DMS in patients with dementia using the search terms "Delusional Misidentification Syndrome, Capgras syndrome, Fregoli syndrome, reduplicative paramnesia, and dementia." The DMSs are a frequent problem in dementia. The violence and dangerousness in patients with dementia having these syndromes are well documented, and forensic aspects are highlighted. Pathogenetic viewpoint and management are considered. PMID- 24164926 TI - Stimulation of suicidal erythrocyte death by ribavirin. AB - Ribavirin is widely used in the treatment for viral disease such as chronic viral hepatitis. Side effects limiting the use of the drug include haemolytic anaemia. If challenged by stimulators of haemolysis, erythrocytes may enter suicidal death or eryptosis, thus preventing the release of haemoglobin into circulating blood. Eryptosis is characterized by cell shrinkage and by cell membrane scrambling with phosphatidylserine translocation to the erythrocyte surface. Eryptosis may be triggered by increase in cytosolic Ca2+ activity ([Ca2+]i). This study explored whether ribavirin modifies [Ca2+]i and elicits eryptosis. Cell volume has been estimated from forward scatter, phosphatidylserine abundance at the erythrocyte surface from annexin V binding, haemolysis from haemoglobin release and [Ca2+]i from Fluo-3 fluorescence. A 48-hr exposure to ribavirin (>=8 MUg/ml) was followed by a significant increase in [Ca2+]i, a significant decrease in forward scatter and a significant increase in annexin V binding. The annexin V binding after ribavirin treatment was significantly blunted but not abolished in the nominal absence of extracellular Ca2+. In conclusion, ribaverin stimulates eryptosis, an effect at least in part due to entry of extracellular Ca2+. PMID- 24164928 TI - Linking family dynamics and the mental health of Colombian dementia caregivers. AB - This cross-sectional, quantitative, self-report study examined the relationship between family dynamics (cohesion, flexibility, pathology/ functioning, communication, family satisfaction, and empathy) and mental health (depression, burden, stress, and satisfaction with life [SWL]) in 90 dementia caregivers from Colombia. Hierarchical multiple regressions controlling for caregiver demographics found that family dynamics were significantly associated with caregiver depression, stress, and SWL and marginally associated with burden. Within these regressions, empathy was uniquely associated with stress; flexibility with depression and marginally with SWL; and family communication marginally with burden and stress. Nearly all family dynamic variables were bivariately associated with caregiver mental health variables, such that caregivers had stronger mental health when their family dynamics were healthy. Family-systems interventions in global regions with high levels of familism like that in the current study may improve family empathy, flexibility, and communication, thereby producing better caregiver mental health and better informal care for people with dementia. PMID- 24164929 TI - Neuropsychiatric symptoms and regional neocortical atrophy in mild cognitive impairment and Alzheimer's disease. AB - BACKGROUND: To assess the relationship between regional neocortical atrophy and psychotic symptoms in adults with mild cognitive impairment (MCI) and Alzheimer's disease (AD). METHODS: Rates of change in regional neocortical atrophy as measured by longitudinal magnetic resonance imaging scans and the occurrence of psychotic symptoms and/or the long-term use of antipsychotic medications in 389 outpatients with MCI or AD in Alzheimer's Disease Neuroimaging Initiative. RESULTS: Atrophy rate of 3 specific neocortical regions, lateral frontal, lateral parietal, and anterior cingulate gyrus, was significantly associated with the onset of psychosis including delusions, agitation, wandering, and hallucinations and/or the need for chronic antipsychotic medications. Atrophy rate of the lateral frontal lobe correlated most significantly with onset of psychotic symptoms or need for chronic antipsychotic medications. CONCLUSIONS: Psychosis was associated with volume loss in specific regions of the lateral frontal and parietal lobes as well as anterior cingulate gyrus. PMID- 24164931 TI - Pharmacological treatments for frontotemporal dementias: a systematic review of randomized controlled trials. AB - The objective of this review is to summarize the current data on the pharmacological treatments for frontotemporal dementias from randomized controlled trials. A systematic search of 4 major databases, PubMed, Medline, PsychINFO and Cochrane, found a total of 9 randomized controlled, double-blinded clinical trials. Of these, 2 trials used the selective serotonin reuptake inhibitor (SSRI), paroxetine; 1 trial used trazodone; 2 trials used stimulants (methylphenidate and dextroamphetamine); 1 trial used the acetylcholinesterase inhibitor, galantamine; 2 trials used the N-methyl-d-aspartate antagonist, memantine; and 1 trial used the neuropeptide oxytocin. The analysis of the available data indicates that SSRIs, trazodone, and the amphetamines may be effective in reducing some behavioral symptoms, but none of these medications had an impact on cognition. Available data indicate that these medications were well tolerated in all the trials. PMID- 24164930 TI - Cerebrospinal fluid tau protein in differential diagnosis of Alzheimer's disease and vascular dementia in Chinese population: a meta-analysis. AB - BACKGROUND: To assess whether biomarker tau protein could differentiate between Alzheimer's disease (AD) and vascular dementia (VaD). METHODS: We conducted a comprehensive search to identify studies on tau protein, patients with AD, and patients with VaD. Cerebrospinal fluid (CSF) tau protein levels were compared to discriminate among patients with AD, healthy controls, and patients with VaD by a meta-analysis. RESULTS: Patients with AD exhibit significantly higher CSF tau protein levels than healthy controls or patients with VaD in the Chinese population. CONCLUSION: Our findings suggested that CSF tau protein levels were found to be significantly associated with AD in the Chinese population. Measurement of tau protein could help in attenuating the strict distinction between AD and VaD. PMID- 24164932 TI - Serum trace metal levels in Alzheimer's disease and normal control groups. AB - OBJECTIVE: To determine whether serum trace metals are related to abnormal cognition in Alzheimer's disease (AD). METHODS: We studied serum lead (Pb), cadmium (Cd), mercury (Hg), and arsenic(As) in 89 patients with AD and in 118 cognitively normal individuals. We analyzed the results of the blood tests and the food intake. RESULTS: Serum Pb levels correlated with word list recall (P = .039) and word list recognition (P = .037). Without age adjustment, serum Cd levels (P = .044) were significantly higher in the AD group. After stratified age adjustment, the levels of selected trace metals did not differ significantly between AD and normal individuals. Food intakes regarding selected trace metals were not significantly different between the 2 groups. CONCLUSIONS: In this study, serum Pb, Cd, Hg, and As levels were not directly related to abnormal cognition in AD. Serum Pb levels were significantly negatively correlated with verbal memory scores. PMID- 24164933 TI - Change and predictors of change in social skills of nursing home residents with dementia. AB - BACKGROUND: Social skills are of primary importance for those with dementia and their care providers, yet we know little about the extent to which basic social skills can be maintained over time and the predictors of change. METHODS: A total of 18 nursing homes with 149 newly admitted residents with moderate to severe dementia, 195 direct care staff, and 135 family members, in British Columbia, Canada, contributed data on change in social skills from admission to 6 months and 1 year later. RESULTS: Three-quarters of residents maintained or improved their basic social skills during both the time periods. Decline was explained primarily by cognitive status at the time of admission, notably present orientation. However, staff-to-resident communication becomes more important over time. CONCLUSIONS: Social skills appear to present an opportunity to maintain interaction with these residents. The findings also suggest that a focus on the present orientation before and following admission and on staff-to-resident communication may be beneficial. PMID- 24164935 TI - Improving arteriovenous fistula rate: Effect on hemodialysis quality. AB - Vascular access (VA) is the lifeline for patients with end-stage renal disease on regular hemodialysis (HD). Tunneled catheters have been associated with increased risk of luminal thrombosis, infection, hospitalization, and high cost. Our aims were to follow the "Fistula First Initiative," avoid or reduce the rate of catheter insertion, improve the rate of arteriovenous fistula (AVF) use, and study the effect of increased AVF use on quality of dialysis and patient's outcome. A VA program has been established in collaboration with an enthusiastic and professional vascular surgery team to manage 358 patients who have been on regular HD treatment for a period ranging from 1 to 252 months. The mean +/- standard deviation age of patients was 52 +/- 15 years with 62% male patients. Over a period of 2 years, 408 procedures were performed. These include 293 AVFs and 56 arteriovenous grafts (AVGs). Other procedures include 39 permanent catheter insertions, 8 AVF aneurysmectomy, removal of 6 AVGs, embolectomy of 4 AVGs, excision of 1 AVG lymphocele, and ligation of 1 AVF. This program resulted in significant increase in AVF rate from 35% to 82%; reduction in catheter rate from 62% to 10.9%; infection rate down from 6.6% to 0.6%; VA clotting down from 5.1% to 1.0%; and increase in average blood flow rate from 214 +/- 32 to 298 +/- 37 mL/min (P < 0.01). These results have been associated with improved average single pool Kt/V from 0.88 +/- 0.19 to 1.28 +/- 0.2 (P < 0.01); increased hemoglobin from 9.2 +/- 1.2 to 10.9 +/- 0.9 g/dL (P < 0.01); improved serum albumin from 3.2 +/- 0.5 to 3.7 +/- 0.4 g/dL (P < 0.05); reduction in administered erythropoietin dose by 19%; and significant drop in hospitalization rate from 6.1% to 3.8%. These results confirm the great benefits of AVF on quality of HD and patient outcome, and clearly affirm that AVF should always be considered first. PMID- 24164934 TI - Global long interspersed nuclear element 1 DNA methylation in a Colombian sample of patients with late-onset Alzheimer's disease. AB - Alterations in DNA methylation have implicated as an epigenetic event in the pathogenesis of late-onset Alzheimer's disease (LOAD). The objective of this work was to evaluate global DNA methylation levels for long interspersed nuclear element 1 (LINE-1) repetitive sequences in Colombian patients with LOAD and controls. The LINE-1 DNA methylation levels in peripheral blood samples from 28 Colombian patients with LOAD and 30 healthy participants were assessed using a methylation-sensitive high-resolution melting (MS-HRM) quantitative assay. We did not find differences in LINE-1 methylation levels between patients with Alzheimer's disease (AD; median 76.2%, interquartile range [IQR]: 69.8-81.9) and control participants (median 79.8%, IQR: 73.2-83.8; P = .3). Additional stratified analyses did not show differences in LINE-1 methylation levels for male or female patients versus controls nor for apolipoprotein E4 carriers and noncarriers. This is the first report of LINE-1 methylation levels in patients with LOAD using the cost-effective MS-HRM technique, and this is the first global DNA methylation study in Latin American patients with AD. PMID- 24164936 TI - Galactose uncovers face recognition and mental images in congenital prosopagnosia: the first case report. AB - A woman in her early 40s with congenital prosopagnosia and attention deficit hyperactivity disorder observed for the first time sudden and extensive improvement of her face recognition abilities, mental imagery, and sense of navigation after galactose intake. This effect of galactose on prosopagnosia has never been reported before. Even if this effect is restricted to a subform of congenital prosopagnosia, galactose might improve the condition of other prosopagnosics. Congenital prosopagnosia, the inability to recognize other people by their face, has extensive negative impact on everyday life. It has a high prevalence of about 2.5%. Monosaccharides are known to have a positive impact on cognitive performance. Here, we report the case of a prosopagnosic woman for whom the daily intake of 5 g of galactose resulted in a remarkable improvement of her lifelong face blindness, along with improved sense of orientation and more vivid mental imagery. All these improvements vanished after discontinuing galactose intake. The self-reported effects of galactose were wide-ranging and remarkably strong but could not be reproduced for 16 other prosopagnosics tested. Indications about heterogeneity within prosopagnosia have been reported; this could explain the difficulty to find similar effects in other prosopagnosics. Detailed analyses of the effects of galactose in prosopagnosia might give more insight into the effects of galactose on human cognition in general. Galactose is cheap and easy to obtain, therefore, a systematic test of its positive effects on other cases of congenital prosopagnosia may be warranted. PMID- 24164937 TI - The results of primary repair after distal biceps tendon rupture. AB - OBJECTIVE: The aim of the study was to present the long term results of primary tenodesis in the treatment of distal biceps tendon rupture. METHODS: Patients previously treated for distal tendon rupture were evaluated. In all cases anatomical reattachment with a single-incision through the anterior approach was performed with either a screw and washer (modified McReynolds technique) or a Mitek Anchor. Analysis was performed using clinical and radiological examination and DASH score at the end of 2011. RESULTS: Twenty-one patients (21 males; mean age: 47.5 years) were treated for distal biceps tendon rupture. Fixation was performed using the modified McReynolds technique in 11 and Mitek Anchor in 10 patients. The McReynold technique had excellent result in 63.6% of patients, a 9.1% risk of implant failure and a mean DASH score of 7.8. The Mitek Anchor technique had excellent result in 60% of patients, a 10% risk of implant failure and a mean DASH score of 7.4. CONCLUSION: Operative treatment for distal biceps tendon rupture appears to be a safe and effective method and consistently yields good results. PMID- 24164938 TI - The comparison of Ethibond sutures and semitendinosus autograft in the surgical treatment of acromioclavicular dislocation. AB - OBJECTIVE: The aim of this study was to compare the results of the surgical reconstruction of the acromioclavicular joint (ACJ) dislocations using No. 5 Ethibond suture or semitendinosus autograft. METHODS: This analytical cross sectional study was conducted on the medical records of 39 patients (35 males and 4 females; mean age: 32.6+/-11.8 years), with complete ACJ joint dislocation (Type 3 to 6). Twenty one patients underwent reconstruction using No. 5 Ethibond suture (Group A) and 18 patients using semitendinosus tendon autograft (Group B). The patients' database records were queried for the information regarding the evaluations during follow-up period (mean: 25.7 months) such as radiographic evaluations, Constant score, VAS score and infection. RESULTS: The mean Constant score was 91+/-1 and 92+/-2.1 in Groups A and B, respectively. There was a reduction of ACJ based on Zanca view in 15 patients in Group A and 12 patients in Group B. There was subluxation of ACJ by less than 25% in six patients in Group A and five in Group B, in that, the difference was not significant. Patients expressed acceptable satisfaction and equal pain severity in rest and daily activity in both groups. No deep infection has been observed. CONCLUSION: Since both surgical techniques led to satisfactory results, reduction of ACJ, excellent functional score and acceptable patient satisfaction, No. 5 Ethibond suture technique could be recommended as the treatment of choice due to the absence of morbidity in removing semitendinosus autograft tendon. PMID- 24164939 TI - Arthroscopic treatment of femoroacetabular impingement: early outcomes. AB - OBJECTIVE: The aim of the study was to assess the early outcomes of the arthroscopic treatment of femoroacetabular impingement. METHODS: Forty-two femoroacetabular impingement (FAI) patients (mean age: 35.1 years, range: 16 to 52 years) treated arthroscopically between 2006 and 2011 in our clinic were retrospectively analyzed. Twenty-five patients had Cam, 6 Pincer and 11 combined femoroacetabular impingement. Mean follow-up time was 28.2 (range: 10 to 72) months. Patients were assessed clinically and functionally using the Non Arthritic Hip Score (NAHS), modified Harris Hip Score (mHHS), Oxford Hip Score, WOMAC score, and Visual Analogue Scale (VAS) pain scores preoperatively and at the final follow-up. RESULTS: In clinical and functional assessments, there were increases of 24.8 points in mean NAHS, 23.3 in mHHS, 20.6 in WOMAC score and 9.6 in Oxford Hip Score. VAS pain score decreased by 4.9 points in comparison to the preoperative scores. There were no major complications. However, transient pudendal nerve neuropraxia was present in two patients, transient lateral femoral cutaneous nerve neuropraxia in one and asymptomatic heterotopic ossification in one patient. CONCLUSION: Short-term clinical results of the arthroscopic treatment of the FAI appear to be satisfactory. PMID- 24164940 TI - Prevalence of bone mineral density testing and osteoporosis management following low- and high-energy fractures. AB - OBJECTIVE: The aim of this study was to report the prevalence of post-fracture bone mineral density (BMD) testing and osteoporosis treatment in patients admitted to the orthopedic department for low-energy or high-energy fractures and to identify factors affecting prevalence of post-fracture BMD testing and osteoporosis treatment. METHODS: A total of 265 patients aged 45 years or older admitted with low-energy or high-energy fractures were reviewed between January 2010 and May 2011. Information regarding age, gender, fracture site and history of post-fracture BMD testing and osteoporosis treatment, including data reporting experiences of attending orthopedists (young: <10, senior: >10 years of experience) were recorded. RESULTS: Of the 265 patients (175 female, 90 male), 259 (97.7%) patients had low-energy fractures and 6 (2.3%) suffered high-energy fractures. Of 259 low-energy fractures, 99 (38.2%) underwent BMD testing and had mean total T-scores of -2.04+/-1.01 (proximal-femur) and -2.12+/-1.27 (lumbar spine). Only one high-energy fracture patient (16.7%) underwent BMD testing, with a T-score of -1.1 (proximal-femur) and -2.7 (lumbar-spine). Eighty-six (32.5%) patients (85 low-energy fractures; 1 high-energy fracture) with diagnosis of osteopenia/osteoporosis from BMD testing were treated with calcium, vitamin D, and bisphosphonates. Bone mineral density testing was significantly higher in low energy fracture patients who were treated by a young orthopedist, a common fracture site (proximal-femur, distal-radius, vertebrae) or were female (p<0.05). CONCLUSION: Bone mineral density investigation and treatment rates are currently suboptimal. The current gap in adequate care necessitates multidisciplinary intervention in order to lessen the incidence of future fractures, particularly in patients over the age of 45. PMID- 24164941 TI - The patellar shift index: a reliable and valid measure for patellofemoral congruence following total knee arthroplasty with unresurfaced patella. AB - OBJECTIVE: The aim of this study was to develop a new radiographic measure, the patellar shift index (PSI), for the precise estimation of patellar position relative to the trochlea after a total knee replacement with an unresurfaced patella. METHODS: This study included radiographs of 51 patients suffering from anterior knee pain following total knee arthroplasty. Patellofemoral axial radiographs were analyzed to compare the reliability of the PSI to the classical measures of patellofemoral congruence, the lateral patellar tilt (LPT) and patellar displacement (PD). Intra-rater reliability of the PSI, LPT and PD was estimated using the intraclass correlation coefficient (ICC) and the inter-rater reliability using Krippendorff's alpha (Kalpha). Agreement proportion of was calculated for the PD. Face validity of the PSI was also tested. RESULTS: The PSI had excellent intra (mean ICC=0.91) and inter-rater (Kalpha=0.92) reliability, as did LPT (mean ICC=0.96; Kalpha=0.89). The calculation of PD caused a low level of agreement (47.1%) between evaluators in terms of which images could be measured. The exclusion of these radiographs resulted in a high PD intra (ICC=0.96) and inter-rater (Kalpha=0.97) reliability. CONCLUSION: The PSI appears to be a reliable and valid measure for patellofemoral congruence in a replaced knee joint with an unresurfaced patella. The superiority of the PSI is the result of its consideration of the geometry and size of the replaced knee joint and independence from radiographic magnification. PMID- 24164942 TI - Etiology of coxarthrosis in patients with total hip replacement. AB - OBJECTIVE: We aimed to find out the distribution of etiological factors in patients who had total hip replacement for coxarthrosis. METHODS: The medical records of the 965 hips of 886 patients operated with total hip replacement between 2001 and 2012 in two separate arthroplasty clinics were analyzed by two separate senior surgeons. Each patient's pre- and postoperative X-rays and demographic data such as gender, age, side and probable etiologic factors were noted. RESULTS: Six hundred and eighty-four patients were women and 202 were men. The mean age were 62.7+/-14.3 (range: 16 to 91) in women, 58.8+/-17.1 (range: 25 to 91) in men. 52.1% of the surgeries were performed on the right side, 39% on the left, and 8.9% bilaterally. In women 36.2% of the cases were primary coxarthrosis, while the etiology was developmental dysplasia of the hip (DDH) in 43.5% of the cases, avascular necrosis in 10%, romatoid diseases in 7%, slipped capital femoral epiphysis in 5%, posttraumatic coxarthrosis in 3.9%, pathologic coxarthrosis in 1.9%, and Perthes sequel in 1.7%. In men, 24.4% of the cases were primary coxarthrosis, while the etiology was avascular necrosis in 21% of the cases, DDH in 17.6%, posttraumatic coxarthrosis in 16.8%, romatoid diseases in 10.9%, Perthes sequel in 4.2%, slipped capital femoral epiphysis in 2.5%, and pathologic coxarthrosis in 2.5%. The most common etiologic factor was DDH with a rate of 37.1%. CONCLUSION: Despite the heterogeneity of our study population, our results may reflect the distribution of coxarthrosis etiologies in Turkey. Developmental dysplasia of the hip appears to be the most frequent cause of coxarthrosis among the patients undergoing total hip replacement. PMID- 24164943 TI - Legg-Calve-Perthes disease in children with Down syndrome. AB - OBJECTIVE: The aim of this study was to describe the features of Perthes disease in patients with Down syndrome. METHODS: The data of this retrospective case series were collected between 2000 and 2011. Patients were assessed according to demographic, clinical and radiographic classifications. RESULTS: The study included 7 hips of 6 patients (5 males, 1 female). Mean age at first visit was 6.1 (range: 3.5 to 12.7) years and mean follow-up period was 52.3 (range: 30.2 to 90.8) months. Initial complaints were pain and limping with limited range of motion at the first visit. Range of motion tended toward early improvement despite continuous radiographic changes. One patient had late onset Perthes disease and developed rapid femoral head collapse managed with total hip arthroplasty. CONCLUSION: Perthes disease in children with Down syndrome must be followed despite clinical improvement. Radiographic characteristics of Perthes disease in patients with Down syndrome do not differ from those without it. PMID- 24164944 TI - Injuries in elite youth football players: a prospective three-year study. AB - OBJECTIVE: The aim of this study was to investigate the incidence and nature of injuries and the influence of age on injury patterns in elite youth football. METHODS: Fifty-two players of the Under-17 (U-17) male national youth football team were followed during their progression to U-18 and U-19. Individual player exposure and injuries were recorded during the three year study period. RESULTS: Injury incidence was five times higher during matches than training. When medical attention and time loss injuries were considered, injury incidence increased during matches and decreased during training with increasing age. Traumatic injuries were more frequent in matches and were linked with increased age. Overuse injuries were two times higher during training than matches in the U-17 team. The majority of traumatic match injuries (78.3%) led to time loss and the majority of time loss injuries occurred due to traumatic mechanism (62.1%). The majority of muscle and entire ligament injuries occurred during training and contusions during competition. Re-injury rate was 25% and were all overuse injuries. CONCLUSION: Injury incidences increased during matches and decreased during training. More match injuries were caused by traumatic mechanisms as players aged. Player age might contribute to injury incidence and characteristics in youth football. PMID- 24164945 TI - Long-term results of porous-coated cementless total knee arthroplasty with screw fixation. AB - OBJECTIVE: The aim of this study was to evaluate the long-term results of porous coated, cementless total knee arthroplasty with screw fixation. METHODS: This study included 68 knees of 54 patients (43 female, 11 male; mean age: 56.9 years, range 46 to 70 years). Cruciate-retaining cementless total knee prostheses were implanted in all patients diagnosed with primary osteoarthritis. Clinical, functional and radiological evaluations were performed according to the Knee Society's Knee Scoring System (KSS). Prosthesis survival was analyzed using Kaplan-Meier curves. Mean follow-up time was 9.2 (range: 8 to 12) years. RESULTS: Preoperative mean knee and function scores were 42.3 (range: 32 to 61) and 39.1 (range: 35 to 66), respectively, while they were 88.6 (range: 54 to 96) and 82.8 (range: 50 to 100), respectively at the final follow-up (p<0.05). Mean preoperative knee flexion was 98 degrees (range: 80 degrees to 110 degrees ) and 112 degrees (range: 85 degrees to 130 degrees ) at the final follow-up (p<0.05). Preoperative and postoperative mean alignments were 9.2 degrees varus and 5.4 degrees valgus, respectively. Revisions were performed due to aseptic loosening of the tibial component in one patient, periprosthetic fracture in one and dislocation of the patella in one. Two superficial infections (3%) were observed. There was no osteolysis around the screws during the follow-up period. The overall rate of implant survival was 95.6% (range: 91.56% to 99.60%; 95% CI) at 12 years. CONCLUSION: Long-term outcomes of porous-coated, cementless total knee arthroplasty with screw fixation were successful in terms of clinical and radiological evaluation and yielded a high survival rate. PMID- 24164946 TI - The effect of pronation and inclination on the measurement of the hallucal distal metatarsal articular set angle. AB - OBJECTIVE: In this study, we tried to evaluate the effect of pronation and the inclination of the first metatarsal on the measurement of distal metatarsal articular angle (DMAA) in 10 cadaver first metatarsals. METHODS: Ten cadaver first metatarsals were fixed to a device. This device can change the inclination and pronation angles of the metatarsal. 15-30-45 degrees of inclination and 0-10 20 degrees of pronation were applied to the metatarsals. After applying radio opaque putty to the medial and lateral articular edges and metatarsal dorsal diaphyseal ridge, the X-ray and digital images were taken at different degrees of inclination and pronation. A graphics software did the measurement of DMAA. The statistical analysis was done by paired sample t-test. RESULTS: The inclination had no effect on DMAA (p>0.1). The pronation of the first metatarsal was found to have a positive effect on DMAA (p<0.005). As the degree of pronation increased, the degree of DMAA was found to also increase. We found no difference between the measurements of the X-ray and the digital images. CONCLUSION: According to the current data, the measurement of DMAA is not suitable for making clinical and surgical decisions. The inclination of the first metatarsal can change, depending on the height of the medial longitudinal arch. By doing this study, we are trying to simulate the pes cavus and pes planus deformity on the radiologic measurement of pronation of the hallux. According to our results, inclination has no effect on the measurement of DMAA. However, the measurement of DMAA is expected to be dependent on the rotational deformity of the hallux. PMID- 24164947 TI - Characterization of powdered fish heads for bone graft biomaterial applications. AB - OBJECTIVE: The aim of this study was to define the chemical composition, morphology and crystallography of powdered fish heads of the species Argyrosomus regius for bone graft biomaterial applications. METHODS: Two sizes of powder were prepared by different grinding methods; Powder A (coarse, d50=68.5 um) and Powder B (fine, d50=19.1 um). Samples were analyzed using X-ray diffraction (XRD), X-ray fluorescence (XRF), scanning electron microscopy (SEM), thermogravimetry (TG), and energy dispersive X-ray spectroscopy (EDS). RESULTS: The powder was mainly composed of aragonite (CaCO3) and calcite (CaCO3). The XRD pattern of Powder A and B matched standard aragonite and calcite patterns. In addition, the calcium oxide (CaO) phase was found after the calcination of Powder A. Thermogravimetry analysis confirmed total mass losses of 43.6% and 47.3% in Powders A and B, respectively. CONCLUSION: The microstructure of Powder A was mainly composed of different sizes and tubular shape, whereas Powder B showed agglomerated particles. The high quantity of CaO and other oxides resemble the chemical composition of bone. In general, the powder can be considered as bone graft after transformation to hydroxyapatite phase. PMID- 24164948 TI - Aneurysmal bone cyst-like areas as a sign of metastatic disease in the spinal column. AB - Aneurysmal bone cysts (ABCs) are vascular lesions with well-defined radiological signs. A fairly common MRI finding in both ABC and other primary bone tumors with high vascularity is the presence of cysts with fluid-fluid levels. Metastatic lesions with fluid-fluid leveling have not previously been defined in the literature. We report three cases of fluid-fluid leveling of the axial skeleton in metastatic lesions. Two patients had single-level and one multi-level neoplastic disease with distinctive cysts showing fluid-fluid levels on MRI evaluation. Diagnosis of gastric carcinoma in two patients and breast carcinoma in the third was achieved with trocar biopsies. At the time of this report all patients had completed initial oncologic treatments and were disease free. PMID- 24164949 TI - Fracture dislocation of the proximal humerus with ipsilateral shaft fracture: a report of two cases. AB - We report two cases of ipsilateral proximal humerus fracture dislocation and shaft fracture in young adults. Fractures were treated with prosthetic replacement for the proximal humerus and open reduction and internal fixation for the shaft fracture due to the extent and complexity of the injury. PMID- 24164950 TI - Osteoblastoma of the trapezoid bone and triquetral bone: report of two cases. AB - Osteoblastoma is a benign local aggressive tumor mostly localized in the vertebra or long bones. Carpal location and recurrence are extremely rare. Treatment options include either curettage or wide en bloc resection which causes functional disability in the hand and wrist and should be reserved only for recurrence. We present a case of recurrent trapezoid osteoblastoma previously treated with curettage of the trapezoid bone and a case of primary triquetral osteoblastoma. PMID- 24164952 TI - The role of S100 staining in the pathological assessment of perineural invasion in rectal cancer. PMID- 24164951 TI - Data-driven quantification of the robustness and sensitivity of cell signaling networks. AB - Robustness and sensitivity of responses generated by cell signaling networks has been associated with survival and evolvability of organisms. However, existing methods analyzing robustness and sensitivity of signaling networks ignore the experimentally observed cell-to-cell variations of protein abundances and cell functions or contain ad hoc assumptions. We propose and apply a data-driven maximum entropy based method to quantify robustness and sensitivity of Escherichia coli (E. coli) chemotaxis signaling network. Our analysis correctly rank orders different models of E. coli chemotaxis based on their robustness and suggests that parameters regulating cell signaling are evolutionary selected to vary in individual cells according to their abilities to perturb cell functions. Furthermore, predictions from our approach regarding distribution of protein abundances and properties of chemotactic responses in individual cells based on cell population averaged data are in excellent agreement with their experimental counterparts. Our approach is general and can be used to evaluate robustness as well as generate predictions of single cell properties based on population averaged experimental data in a wide range of cell signaling systems. PMID- 24164953 TI - Association between hyperoxia and mortality after stroke: a multicenter cohort study. AB - OBJECTIVE: To test the hypothesis that hyperoxia was associated with higher in hospital mortality in ventilated stroke patients admitted to the ICU. DESIGN: Retrospective multicenter cohort study. SETTING: Primary admissions of ventilated stroke patients with acute ischemic stroke, subarachnoid hemorrhage, and intracerebral hemorrhage who had arterial blood gases within 24 hours of admission to the ICU at 84 U.S. ICUs between 2003 and 2008. Patients were divided into three exposure groups: hyperoxia was defined as PaO2 >= 300 mm Hg (39.99 kPa), hypoxia as any PaO2<60 mm Hg (7.99 kPa) or PaO2/FiO2 ratio <= 300, and normoxia, not defined as hyperoxia or hypoxia. The primary outcome was in hospital mortality. PARTICIPANTS: Two thousand eight hundred ninety-four patients. METHODS: Patients were divided into three exposure groups: hyperoxia was defined as PaO2 more than or equal to 300 mm Hg (39.99 kPa), hypoxia as any PaO2 less than 60 mm Hg (7.99 kPa) or PaO2/FIO2 ratio less than or equal to 300, and normoxia, not defined as hyperoxia or hypoxia. The primary outcome was in hospital mortality. INTERVENTIONS: Exposure to hyperoxia. RESULTS: Over the 5 year period, we identified 554 ventilated patients with acute ischemic stroke (19%), 936 ventilated patients with subarachnoid hemorrhage (32%), and 1,404 ventilated patients with intracerebral hemorrhage (49%) of whom 1,084 (38%) were normoxic, 1,316 (46%) were hypoxic, and 450 (16%) were hyperoxic. Mortality was higher in the hyperoxia group as compared with normoxia (crude odds ratio 1.7 [95% CI 1.3-2.1]; p < 0.0001) and hypoxia groups (crude odds ratio, 1.3 [95% CI, 1.1-1.7]; p < 0.01). In a multivariable analysis adjusted for admission diagnosis, other potential confounders, the probability of being exposed to hyperoxia, and hospital-specific effects, exposure to hyperoxia was independently associated with in-hospital mortality (adjusted odds ratio, 1.2 [95% CI, 1.04 1.5]). CONCLUSION: In ventilated stroke patients admitted to the ICU, arterial hyperoxia was independently associated with in-hospital death as compared with either normoxia or hypoxia. These data underscore the need for studies of controlled reoxygenation in ventilated critically ill stroke populations. In the absence of results from clinical trials, unnecessary oxygen delivery should be avoided in ventilated stroke patients. PMID- 24164954 TI - Serum biomarkers of brain injury to classify outcome after pediatric cardiac arrest*. AB - OBJECTIVES: Morbidity and mortality in children with cardiac arrest largely result from neurologic injury. Serum biomarkers of brain injury can potentially measure injury to neurons (neuron-specific enolase), astrocytes (S100b), and axons (myelin basic protein). We hypothesized that serum biomarkers can be used to classify outcome from pediatric cardiac arrest. DESIGN: Prospective observational study. SETTING: Single tertiary pediatric hospital. PATIENTS: Forty three children with cardiac arrest. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: We measured serum neuron-specific enolase, S100b, and myelin basic protein on days 1-4 and 7 after cardiac arrest. We recorded demographics, details of the cardiac arrest and resuscitation, and Pediatric Cerebral Performance Category at hospital discharge and 6 months. We analyzed the association of biomarker levels at 24, 48, and 72 hours with favorable (Pediatric Cerebral Performance Category 1-3) or unfavorable (Pediatric Cerebral Performance Category 4-6) outcome and mortality. Forty-three children (49% female; mean age of 5.9 +/- 6.3) were enrolled and 17 (40%) died. Serum S100b concentrations peaked earliest, followed by neuron-specific enolase and finally myelin basic protein. Serum neuron-specific enolase and S100b concentrations were increased in the unfavorable versus favorable outcome group and in subjects who died at all time points (all p < 0.05). Serum myelin basic protein at 24 and 72 hours correctly classified survival but not good versus poor outcome. Using best specificity, serum S100b and neuron-specific enolase had optimal positive and negative predictive values at 24 hours to classify both favorable versus unfavorable outcome and survival, whereas serum myelin basic protein's best accuracy occurred at 48 hours. Receiver operator curves for serum S100b and neuron-specific enolase to classify favorable versus unfavorable outcome at 6 months were superior to clinical variables. CONCLUSIONS: Preliminary data show that serum S100b, neuron specific enolase, and myelin basic protein may aid in outcome classification of children surviving cardiac arrest. PMID- 24164955 TI - Pediatric and neonatal extracorporeal membrane oxygenation: does center volume impact mortality?*. AB - OBJECTIVE: Extracorporeal membrane oxygenation, an accepted rescue therapy for refractory cardiopulmonary failure, requires a complex multidisciplinary approach and advanced technology. Little is known about the relationship between a center's case volume and patient mortality. The purpose of this study was to analyze the relationship between hospital extracorporeal membrane oxygenation annual volume and in-hospital mortality and assess if a minimum hospital volume could be recommended. DESIGN: Retrospective cohort study. SETTING: A retrospective cohort admitted to children's hospitals in the Pediatric Health Information System database from 2004 to 2011 supported with extracorporeal membrane oxygenation was identified. Indications were assigned based on patient age (neonatal vs pediatric), diagnosis, and procedure codes. Average hospital annual volume was defined as 0-19, 20-49, or greater than or equal to 50 cases per year. Maximum likelihood estimates were used to assess minimum annual case volume. PATIENTS: A total of 7,322 pediatric patients aged 0-18 were supported with extracorporeal membrane oxygenation and had an indication assigned. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Average hospital extracorporeal membrane oxygenation volume ranged from 1 to 58 cases per year. Overall mortality was 43% but differed significantly by indication. After adjustment for case-mix, complexity of cardiac surgery, and year of treatment, patients treated at medium-volume centers (odds ratio, 0.86; 95% CI, 0.75-0.98) and high-volume centers (odds ratio, 0.75; 95% CI, 0.63-0.89) had significantly lower odds of death compared with those treated at low-volume centers. The minimum annual case load most significantly associated with lower mortality was 22 (95% CI, 22-28). CONCLUSIONS: Pediatric centers with low extracorporeal membrane oxygenation average annual case volume had significantly higher mortality and a minimum volume of 22 cases per year was associated with improved mortality. We suggest that this threshold should be evaluated by additional study. PMID- 24164956 TI - Deciphering the relationship between vulnerability to ethanol-induced behavioral sensitization and ethanol consumption in outbred mice. AB - Ethanol (EtOH)-induced behavioral sensitization (EIBS) is proposed to play a role in early and recurring steps of alcohol dependence, but its impact on alcohol abuse is not clear. EIBS development is dependent upon animal species, strain and also individual factors. We proposed here to decipher the co-expression of EIBS and EtOH intake in individual animals among outbred Swiss mice, which exhibit heterogeneity that parallels what may occur in humans. To do so, mice were exposed to a two-bottle choice with free access to water or 10% EtOH for 6 days just before and immediately after chronic intraperitoneal 2.5 g/kg ethanol injections once a day for 10 consecutive days. Based on their sensitization scores, mice were split into resistant and sensitized animals. First, we showed that individual susceptibility to EIBS is inversely correlated with voluntary EtOH consumption. Exposure to repeated EtOH during EIBS development increased subsequent EtOH intake among the entire population. Very interestingly, subsequent analyses suggested that the less the mice are sensitized the more they increase their EtOH intake; however, resistant mice were sensitive to EtOH adulteration with quinine, whereas sensitized ones maintained their EtOH intake levels, therefore exhibiting a compulsive-like drinking pattern. In addition, we showed that resistant mice do not exhibit a weaker sensitivity to the aversive properties of EtOH that may contribute to their higher level of EtOH intake compared to sensitized mice. This study confirms and extends previous data showing a deep relationship between propensity for EtOH consumption and susceptibility to EIBS in Swiss mice. PMID- 24164957 TI - Nucleotide based validation of Ocimum species by evaluating three candidate barcodes of the chloroplast region. AB - The genus Ocimum comprises of several medicinally important species which frequently fall prey to adulteration due to misidentification. A proficient method is hence required to solve the problems that exist in differentiating its various morphotypes. In plants, candidate DNA barcodes of the chloroplast and nuclear regions have proved to be a great success in the validation of several plant families. Hence, this study involves the use of the molecular-based DNA barcoding method to identify some of the most common and useful species of the genus Ocimum (Tulsi). Here, DNA amplification of three candidate barcodes of the chloroplast genome viz. matK, rbcL and psbA-trnH was performed, to access their ability to produce high sequence variability. The discrimination among species was performed using the Kimura 2-parameter and maximum composite likelihood methods. On analysing the sequence data, the psbA-trnH region proved to be the most suitable candidate barcode and gave an overall variation of 7.3% at the interspecies level. A clear differentiation was found at the species level, showing a maximum distance of 0.264 between dissimilar species. Also, phylogenetic analysis led to the successful identification of hybrids, while it failed to do so at the variety level. Hence, it can be inferred that DNA barcoding is ideal for species-level identification of the genus Ocimum. PMID- 24164958 TI - Class II HLA epitope matching-A strategy to minimize de novo donor-specific antibody development and improve outcomes. AB - De novo donor-specific antibody (dnDSA) develops in 15-25% of renal transplant recipients within 5 years of transplantation and is associated with 40% lower graft survival at 10 years. HLA epitope matching is a novel strategy that may minimize dnDSA development. HLAMatchmaker software was used to characterize epitope mismatches at 395 potential HLA-DR/DQ/DP conformational epitopes for 286 donor-recipient pairs. Epitope specificities were assigned using single antigen HLA bead analysis and correlated with known monoclonal alloantibody epitope targets. Locus-specific epitope mismatches were more numerous in patients who developed HLA-DR dnDSA alone (21.4 vs. 13.2, p < 0.02) or HLA-DQ dnDSA alone (27.5 vs. 17.3, p < 0.001). An optimal threshold for epitope mismatches (10 for HLA-DR, 17 for HLA-DQ) was defined that was associated with minimal development of Class II dnDSA. Applying these thresholds, zero and 2.7% of patients developed dnDSA against HLA-DR and HLA-DQ, respectively, after a median of 6.9 years. Epitope specificity analysis revealed that 3 HLA-DR and 3 HLA-DQ epitopes were independent multivariate predictors of Class II dnDSA. HLA-DR and DQ epitope matching outperforms traditional low-resolution antigen-based matching and has the potential to minimize the risk of de novo Class II DSA development, thereby improving long-term graft outcome. PMID- 24164959 TI - Analysis of the microbial ecology between Helicobacter pylori and the gastric microbiota of Mongolian gerbils. AB - Animal models are essential for in vivo analysis of Helicobacter-related diseases. Mongolian gerbils are used frequently to study Helicobacter pylori induced gastritis and its consequences. The presence of some gastric microbiota with a suppressive effect on H. pylori suggests inhibitory gastric bacteria against H. pylori infection. The aim of the present study was to analyse the microbial ecology between H. pylori and the gastric microbiota of Mongolian gerbils. Gastric mucosa samples of H. pylori-negative and -positive gerbils were orally inoculated to five (Group 1) and six (Group 2) gerbils, respectively, and the gerbils were challenged with H. pylori infection. The colonization rate (40 %) of H. pylori in Group 1 gerbils was lower than the rate (67 %) in Group 2 gerbils. Culture filtrate of the gastric mucosa samples of Group 1 gerbils inhibited the in vitro growth of H. pylori. Three lactobacilli species, Lactobacillus reuteri, Lactobacillus johnsonii and Lactobacillus murinus, were isolated by anaerobic culture from the gerbils in Groups 1 and 2, and identified by genomic sequencing. It was demonstrated that the three different strains of lactobacilli exhibited an inhibitory effect on the in vitro growth of H. pylori. The results suggested that lactobacilli are the dominant gastric microbiota of Mongolian gerbils and the three lactobacilli isolated from the gastric mucosa samples with an inhibitory effect on H. pylori might have an anti-infective effect against H. pylori. PMID- 24164960 TI - Delayed surgical intervention of sternoclavicular joint infection with increased complications. PMID- 24164961 TI - The effect of caffeine ingestion on delayed onset muscle soreness. AB - The beneficial effects of caffeine on aerobic activity and resistance training performance are well documented. However, less is known concerning caffeine's potential role in reducing perception of pain and soreness during exercise. In addition, there is no information regarding the effects of caffeine on delayed onset muscle soreness (DOMS). The primary purpose of this study was to examine the effect of caffeine ingestion on muscle soreness, blood enzyme activity, and performance after a bout of elbow flexion/extension exercise. Nine low-caffeine consuming males (body mass: 76.68 +/- 8.13 kg; height: 179.18 +/- 9.35 cm; age: 20 +/- 1 year) were randomly assigned to ingest either caffeine or placebo 1 hour before completing 4 sets of 10 bicep curls on a preacher bench, followed by a fifth set in which subjects completed as many repetitions as possible. Soreness and soreness on palpation intensity were measured using three 0-10 visual analog scales before exercise, and 24, 48, 72, 96, and 120 hours after exercise. After a washout period, subjects crossed over to the other treatment group. Caffeine ingestion resulted in significantly (p <= 0.05) lower levels of soreness on day 2 and day 3 compared with placebo. Total repetitions in the final set of exercise increased with caffeine ingestion compared with placebo. This study demonstrates that caffeine ingestion immediately before an upper-body resistance training out enhances performance. A further beneficial effect of sustained caffeine ingestion in the days after the exercise bout is an attenuation of DOMS. This decreased perception of soreness in the days after a strenuous resistance training workout may allow individuals to increase the number of training sessions in a given time period. PMID- 24164962 TI - Downregulation of miR-106b induced breast cancer cell invasion and motility in association with overexpression of matrix metalloproteinase 2. AB - Breast cancer (BC) is one of the most common cancers in women, and it can often metastasize to the bone. The mechanism of BC bone metastasis remains unclear and requires in-depth investigation. In a previous study, we found the expression of matrix metalloproteinase 2 (MMP2) to be significantly more pronounced at metastatic bone sites than at orthotopic sites. MicroRNA expression profiling showed miR-106b to be markedly downregulated during BC bone metastasis. However, the specific manner in which MMP2 and miR-106b are involved in the BC bone metastasis is still unclear. In the present study, we found MMP2 expression in orthotopic tumor tissue to be related to the risk of bone metastasis in BC patients. MiR-106b levels in orthotopic tumor tissue showed a negative correlation with MMP2 expression and breast cancer bone metastasis. MMP2 was shown to be a direct target of miR-106b. Both gain- and loss-of-function studies showed that MMP2 could promote the migration and invasion of BC cells and that miR-106b could suppress both. The blockage of MMP2 by RNA interference mimicked the anti-migration and anti-invasion effects of miR-106b, and introduction of MMP2 antagonized the function of miR-106b. MMP2 was also found to regulate the ERK signaling cascade and so adjust the bone microenvironment to favor osteoclastogenesis and bone metastasis. These results suggest that MMP2 upregulation plays an important role in BC bone metastasis through ERK pathways, and miR-106b directly regulates MMP2 expression. The miR-106b/MMP2/ERK pathway may be a promising therapeutic target for inhibiting BC bone metastasis. PMID- 24164963 TI - Higher serum chloride concentrations are associated with acute kidney injury in unselected critically ill patients. AB - BACKGROUND: Chloride administration has been found to be harmful to the kidney in critically ill patients. However the association between plasma chloride concentration and renal function has never been investigated. METHODS: This was a retrospective study conducted in a tertiary 24-bed intensive care unit from September 2010 to November 2012. Data on serum chloride for each patient during their ICU stay were abstracted from electronic database. Cl0 referred to the initial chloride on ICU entry, Cl(max), Cl(min) and Cl(mean) referred to the maximum, minimum and mean chloride values before the onset of AKI, respectively. AKI was defined according to the conventional AKIN criteria. Univariate and multivariable analysis were performed to examine the association of chloride and AKI development. RESULTS: A total of 1221 patients were included into analysis during study period. Three hundred and fifty-seven patients (29.2%) developed AKI. Cl(max) was significantly higher in AKI than in non-AKI group (111.8 +/- 8.1 vs 107.9 +/- 5.4 mmol/l; p < 0.001); Cl0 was not significantly different between AKI and non-AKI patients; Cl(mean) was significantly higher in AKI than non-AKI (104.3 +/- 5.8 vs 103.4 +/- 4.5; = 0.0047) patients. Cl(max) remained to be associated with AKI in multivariable analysis (OR: 1.10, 95% CI: 1.08-1.13). CONCLUSION: Chloride overload as represented by Cl(mean) and Cl(max) is significantly associated with the development of AKI. PMID- 24164965 TI - Obesity, hyperglycemia and endothelial function in inner city Bronx adolescents: a cross-sectional study. AB - BACKGROUND: Along with the rise in obesity, cardiovascular disease (CVD) has become the major cause of death in developed countries. Although overt coronary heart disease rarely manifests during childhood, atherosclerosis can begin by the second decade of life. Therefore, identifying reliable risk markers of early vascular disease in childhood could be important. Alteration in endothelial function (EF) is an early preclinical marker of the atherosclerotic process and can be assessed non-invasively using reactive hyperemia peripheral arterial tonometry (RH-PAT). The purpose of this study was to investigate if obesity in children is associated with lower EF as measured with RH-PAT, and if obese children with impaired glucose regulation have further impairment in RH-PAT measured EF compared to obese children with normal glucose tolerance. METHODS: Cardiovascular risk factors, adipocytokines and EF using RH-PAT were evaluated in lean (n = 14) and obese (n = 37) adolescents (age 12-18 years). Based on an oral glucose tolerance test, the obese group was subdivided into: obese with normal (NGT, n = 22) and obese with impaired glucose regulation (IGR, n = 15). RESULTS: RH-PAT score was lower in obese subjects compared to lean controls (1.70 +/- 0.02 vs. 1.98 +/- 0.09, P = 0.02), indicating worse EF. This difference remained significant when adjusted for age, sex and ethnicity (P = 0.02). We observed a pattern of worsening EF with increasing metabolic burden, with RH-PAT scores of 1.98 +/- 0.09,1.73 +/- 0.08 and 1.65 +/- 0.12 in the lean, obese-NGT and obese IGR groups, respectively, ptrend = 0.03. Obese subjects were more insulin resistant [higher HOMA] (p = 0.03), and had higher levels of leptin (p = 0.004), hsCRP (p = 0.0004), and TNF-alpha (p = 0.03) compared to lean subjects. Adjusting for insulin resistance and adipocytokines substantially attenuated the obesity association with RH-PAT, suggesting that insulin resistance and inflammation may mediate the association of EF with obesity. CONCLUSIONS: Risk factors for adult cardiovascular disease, including impaired EF, insulin resistance and inflammation, are evident in obese adolescents. Whether early detection of these cardiovascular risk factors will be useful for informing interventions to prevent disease progression needs further study. TRIAL REGISTRATION: Clinical Trials Identifier: NCT01879033. PMID- 24164964 TI - One patient--three head and neck primaries: nasopharyngeal, tongue and thyroid cancers. AB - BACKGROUND: We report a rare case of three head and neck malignancies in one patient. Squamous cell carcinoma of tongue and papillary thyroid carcinoma occurred as metachronous cancers in a patient with primary nasopharyngeal carcinoma. These three pathologically distinct malignancies of head and neck region in one patient is a rare phenomenon and is not reported so far. CASE PRESENTATION: A 60 year old Saudi female patient presented in March 2011 with locally advanced nasopharyngeal carcinoma. After completion of concurrent chemoradiation in June 2011, she developed two new primaries i-e thyroid cancer and tongue cancer in May 2012 along with recurrent nasopharyngeal carcinoma. We discuss histopathologic features, diagnostic tools and treatment modalities for this rarely existing case. CONCLUSION: High index of suspicion and thorough work up is essential in follow up of patients with head and neck primary cancers. The effect of field cancerization and environmental factors need to be explored in greater depths in such selected cases. However, which patients are at increased risk of triplet primaries, is still unknown. PMID- 24164966 TI - Identification of type II inhibitors targeting BRAF using privileged pharmacophores. AB - V-RAF murine sarcoma viral oncogene homologue B1 (BRAF) is the most frequently mutated protein kinase in human cancers. The most common mutant BRAF V600E constitutively activates the RAS/RAF/MEK/ERK signaling pathway. BRAF has been validated as an important therapeutic target in human cancers. Phenylaminopyrimidine and unsymmetrical diaryl urea are two privileged pharmacophores in kinase inhibitor drug discovery. Herein, we describe the design of a novel hybrid pharmacophore, 4-phenylaminopyrimidine urea, using the above two pharmacophores. A new series of compounds were in turn synthesized and evaluated to successfully identify selective inhibitors of BRAF and oncogenic BRAF V600E. Once daily oral dosing of lead compound 3 demonstrated sustained antitumor efficacy in A549 human non-small-cell lung cancer xenograft model. Molecular docking suggested that compound 3 might be a type II kinase inhibitor binding to the DFG-out conformation of BRAF. PMID- 24164967 TI - The diversity and biogeography of the Coleoptera of Churchill: insights from DNA barcoding. AB - BACKGROUND: Coleoptera is the most diverse order of insects (>300,000 described species), but its richness diminishes at increasing latitudes (e.g., ca. 7400 species recorded in Canada), particularly of phytophagous and detritivorous species. However, incomplete sampling of northern habitats and a lack of taxonomic study of some families limits our understanding of biodiversity patterns in the Coleoptera. We conducted an intensive biodiversity survey from 2006-2010 at Churchill, Manitoba, Canada in order to quantify beetle species diversity in this model region, and to prepare a barcode library of beetles for sub-arctic biodiversity and ecological research. We employed DNA barcoding to provide estimates of provisional species diversity, including for families currently lacking taxonomic expertise, and to examine the guild structure, habitat distribution, and biogeography of beetles in the Churchill region. RESULTS: We obtained DNA barcodes from 3203 specimens representing 302 species or provisional species (the latter quantitatively defined on the basis of Molecular Operational Taxonomic Units, MOTUs) in 31 families of Coleoptera. Of the 184 taxa identified to the level of a Linnaean species name, 170 (92.4%) corresponded to a single MOTU, four (2.2%) represented closely related sibling species pairs within a single MOTU, and ten (5.4%) were divided into two or more MOTUs suggestive of cryptic species. The most diverse families were the Dytiscidae (63 spp.), Staphylinidae (54 spp.), and Carabidae (52 spp.), although the accumulation curve for Staphylinidae suggests that considerable additional diversity remains to be sampled in this family. Most of the species present are predatory, with phytophagous, mycophagous, and saprophagous guilds being represented by fewer species. Most named species of Carabidae and Dytiscidae showed a significant bias toward open habitats (wet or dry). Forest habitats, particularly dry boreal forest, although limited in extent in the region, were undersampled. CONCLUSIONS: We present an updated species list for this region as well as a species-level DNA barcode reference library. This resource will facilitate future work, such as biomonitoring and the study of the ecology and distribution of larvae. PMID- 24164970 TI - Cross talk between matrix elasticity and mechanical force regulates myoblast traction dynamics. AB - Growing evidence suggests that critical cellular processes are profoundly influenced by the cross talk between extracellular nanomechanical forces and the material properties of the cellular microenvironment. Although many studies have examined either the effect of nanomechanical forces or the material properties of the microenvironment on biological processes, few have investigated the influence of both. Here, we performed simultaneous atomic force microscopy and traction force microscopy to demonstrate that muscle precursor cells (myoblasts) rapidly generate a significant increase in traction when stimulated with a local 10 nN force. Cells were cultured and nanomechanically stimulated on hydrogel substrates with controllable local elastic moduli varying from ~16-89 kPa, as confirmed with atomic force microscopy. Importantly, cellular traction dynamics in response to nanomechanical stimulation only occurred on substrates that were similar to the elasticity of working muscle tissue (~64-89 kPa) as opposed to substrates mimicking resting tissue (~16-51 kPa). The traction response was also transient, occurring within 30 s, and dissipating by 60 s, during constant nanomechanical stimulation. The observed biophysical dynamics are very much dependent on rho kinase and myosin-II activity and likely contribute to the physiology of these cells. Our results demonstrate the fundamental ability of cells to integrate nanoscale information in the cellular microenvironment, such as nanomechanical forces and substrate mechanics, during the process of mechanotransduction. PMID- 24164971 TI - Impact of cytokine expression in the pre-implanted donor lung on the development of chronic lung allograft dysfunction subtypes. AB - The long-term success of lung transplantation continues to be challenged by the development of chronic lung allograft dysfunction (CLAD). The purpose of this study was to investigate the relationship between cytokine expression levels in pre-implanted donor lungs and the posttransplant development of CLAD and its subtypes, bronchiolitis obliterans syndrome (BOS) and restrictive allograft syndrome (RAS). Of 109 patients who underwent bilateral lung or heart-lung transplantation and survived for more than 3 months, 50 BOS, 21 RAS and 38 patients with No CLAD were identified by pulmonary function test results. Using donor lung tissue biopsies sampled from each patient, expression levels of IL-6, IL-1beta, IL-8, IL-10, interferon-gamma and tumor necrosis factor-alpha mRNA were measured. IL-6 expression levels were significantly higher in pre-implanted lungs of patients that ultimately developed BOS compared to RAS and No CLAD (p = 0.025 and 0.011, respectively). Cox regression analysis demonstrated an association between high IL-6 expression levels and BOS development (hazard ratio = 4.98; 95% confidence interval = 2.42-10.2, p < 0.001). In conclusion, high IL-6 mRNA expression levels in pre-implanted donor lungs were associated with the development of BOS, not RAS. This association further supports the contention that early graft injury impacts on both late graft function and early graft function. PMID- 24164968 TI - Maternal magnesium sulphate exposure predicts neonatal magnesium blood concentrations. AB - Tocolytic use of magnesium sulphate is associated with excess neonatal mortality and has been proposed to follow a dose-response relationship. This study aimed to define the correlation between maternal and neonatal magnesium blood concentrations. Magnesium blood concentrations were retrospectively obtained for mother-neonate pairs who were cared for at an Intermountain Healthcare facility from January 2009 to October 2011. Complete data were available for 231 mother neonate pairs. Mean (+/-SD) maternal and neonatal magnesium concentrations were 5.43+/-1.69 and 2.98+/-0.94 mg/dL, respectively. Maternal and neonatal magnesium concentrations were highly correlated (p<0.001). In univariate analyses, residual unexplained variability was high (r2=0.19). However, further multivariate analyses revealed that caesarian section, severe pre-eclampsia and Apgar score at 5 min. were significantly associated with neonatal magnesium concentrations (p<0.05 for all). Maternal magnesium concentrations correlate with neonatal exposure. This finding suggests that maternal monitoring deserves further evaluation as a marker of foetal toxicity. PMID- 24164973 TI - The permanent catheter. AB - An elderly woman receiving hemodialysis via a right brachiocephalic arteriovenous fistula presented to the clinic for elective removal of a tunneled hemodialysis catheter inserted 5 years ago. The catheter had not been removed earlier at the patient's request. Removal was now unsuccessful in the clinic. Exploration in the operating room revealed the innominate vein had fibrosed around the length of the catheter. The procedure was abandoned, catheter cut short and the remnant left in situ. This case serves as a reminder to exercise caution if there is difficulty in removing the catheter even after the cuff is dissected free, and to remove them once a working fistula or graft is available. Failing which, the patient bears an unnecessary risk of line infection, or as in this case, the catheter may unintentionally end up what its common misnomer "perm-cath" alludes to--becoming truly "permanent." PMID- 24164972 TI - Long-lasting, experience-dependent alcohol preference in Drosophila. AB - To understand the molecular and neural mechanisms underlying alcohol addiction, many models ranging from vertebrates to invertebrates have been developed. In Drosophila melanogaster, behavioral paradigms from assaying acute responses to alcohol and to behaviors more closely modeling addiction have emerged in recent years. However, both the CAFE assay, similar to a two-bottle choice consumption assay, as well as conditioned odor preference, where ethanol is used as the reinforcer, are labor intensive and have low throughput. To address this limitation, we have established a novel ethanol consumption preference assay, called FRAPPE, which allows for fast, high throughput measurement of consumption in individual flies, using a fluorescence plate reader. We show that naive flies do not prefer to consume ethanol, but various pre-exposures, such as ethanol vapor or voluntary ethanol consumption, induce ethanol preference. This ethanol primed preference is long lasting and is not driven by calories contained in ethanol during the consumption choice. Our novel experience-dependent model of ethanol preference in Drosophila-a highly genetically tractable organism therefore recapitulates salient features of human alcohol abuse and will facilitate the molecular understanding of the development of alcohol preference. PMID- 24164974 TI - Clinical profile of hospitalized HIV-infected children in Bangladesh, a low-HIV prevalence country. AB - BACKGROUND: Bangladesh has a low HIV prevalence and data on the risk factors and clinical presentation of HIV-infected children are lacking. OBJECTIVE: To describe the clinical characteristics of hospitalized HIV-infected children in Bangladesh and determine the factors associated with a low CD4 count. METHODS: An anonymous, retrospective review was undertaken of the medical records of all patients admitted to the HIV unit of the iccdr,b Dhaka Hospital between February 2009 and July 2012. Demographic, clinical and laboratory data were extracted from the electronic medical record system. HIV-infected children with a low absolute CD4 count (<200 cells/MUl) were compared with HIV-infected children with a CD4 count ?200 cells/MUl. RESULTS: Of 266 HIV-infected patients, 24 were children (9%), 13 (54%) of whom were male. Ages ranged from 2 to 17 years (median 7). Of the 21 (88%) children who acquired the infection by vertical transmission, median age at diagnosis was 5.2 years, and the parents of 19 (79%) reported a history of external migration. Children commonly presented with prolonged fever (n = 14, 58%), recurrent cough (n = 14, 58%), failure to thrive (n = 11, 46%) and recurrent diarrhoea (n = 4, 17%). Six (25%) patients had tuberculosis, four (16.7%) had herpes zoster and four (16.7%) were diagnosed with Pneumocystis jirovecii pneumonia. One child died during hospitalization. Children with a low CD4 count (<200 cells/MUl) more often had severe wasting (95% CI 1.2-453.97) and severe under-nutrition (95% CI 1.39-196.25) than those with a higher CD4 count*. CONCLUSION: The majority of HIV-infected children presenting to an inpatient speciality ward in Dhaka acquired HIV through vertical transmission, and most of the parents had a history of external migration. Further studies are needed to determine the optimal strategy for preventing mother-to-child transmission and for early identification and treatment of HIV-infected children in this low prevalence country. PMID- 24164975 TI - A multicentre comparison of a fast track or conventional postoperative protocol following laparoscopic or open elective surgery for colorectal cancer surgery. AB - AIM: The introduction of multimodal or fast track (FT) rehabilitation and laparoscopy in colorectal surgery has improved patient recovery and shortened hospital stay (HS). This study aimed to determine the influence of laparoscopic or open surgery on the postoperative recovery of colorectal cancer patients having a conventional care (CC) or FT protocol in the postoperative period. METHOD: A multicentre prospective study was controlled with a retrospective group. The prospective group included 300 patients having elective colorectal resection for cancer. The retrospective control group included 201 patients with the same characteristics who were treated before the introduction of the programme. The patients were divided into four groups including laparoscopy + FT, open surgery + FT, laparoscopy + CC, and open surgery + CC. The primary end points were HS and morbidity. Secondary end-points included mortality and reoperation rates. RESULTS: The overall median HS was 7 days. The median HS for laparoscopy + FT was 5 days, open + FT 6 days, laparoscopy + CC 9 days and open + CC 10 days (P < 0.001). In the regression model the laparoscopy + FT group had the greatest reduction in HS (P < 0.001). A significant reduction in HS was observed in the laparoscopy + FT group compared with laparoscopy + CC (P < 0.001). The overall patient morbidity was 30.6%. The logistic regression model adjusted for propensity score showed no statistically significant differences between the study groups regarding all other end-points. CONCLUSION: Colorectal cancer patients who underwent laparoscopic surgery within a multimodal rehabilitation protocol experienced the shortest HS and the lowest morbidity. PMID- 24164976 TI - Inter- and intra-rater reproducibility of automated and integrated pressure-flow analysis of esophageal pressure-impedance recordings. AB - BACKGROUND: Automated impedance manometry pressure-flow analysis (AIM analysis) determines pressure measurements relative to bolus flow and has to date shown subtle variations in esophageal motility in relation to dysphagia. In this study, we assessed intra- and inter-rater reproducibility of AIM metrics derived using purpose designed software. METHODS: Fifty patients referred for evaluation of gastro-esophageal reflux symptoms (33 men, age 52 +/- 1.9 years) underwent combined high-resolution impedance manometry and completed a dysphagia questionnaire. From 10 liquid and 10 viscous swallows, a subset of four swallows (two saline and two viscous) was systematically selected from each patient for manual and AIMplot analysis, which was performed twice by five observers (two experts, three non-experts). Intra- and inter-rater agreement were determined using intraclass correlation coefficients. KEY RESULTS: AIMplot-based analysis showed high intra-rater and inter-rater reproducibility for all metrics (mean ICCs of 0.95 and 0.94, respectively). Reproducibility of metrics derived for liquid and viscous did not differ (ICCs of 0.96 and 0.91 for liquid and viscous, respectively). In addition, metrics derived by experts had an equivalent level of reproducibility compared to non-experts (ICCs of 0.96 and 0.94, respectively). Variables that could be derived with commercial software (ManoViewTM) correlated highly with variables from AIMplot-based analysis, such as 4-s integrated relaxation pressure (r = 0.85) and the 20-mmHg isobaric contour defect (r = 0.92). CONCLUSIONS & INFERENCES: Esophageal AIM analysis is highly reproducible, independent of an observer's level of experience in esophageal motility. Therefore, AIM analysis produces data that are reliable for clinical and research purposes. PMID- 24164977 TI - Thirty years and counting. PMID- 24164978 TI - Managing the Australasian Journal on Ageing: a 30-year journey. PMID- 24164979 TI - Identifying seminal papers in the Australasian Journal on Ageing 1982-2011: a Delphi consensus approach. AB - AIMS: The aim of this study was to identify seminal Australasian Journal on Ageing papers published over 30 years through a Delphi consensus process. METHOD: The main data collection was a three-round Delphi consensus study with 38 past and current members of the Australasian Journal on Ageing Editorial Board, Editorial Team and Management Committee. RESULTS: Three papers were agreed as top ranking. One of the top-ranking articles was also highly cited. One article was published in the 1990 s, two in 2001. CONCLUSIONS: While it is difficult to judge how well the top-ranking papers represent seminal papers arising over 30 years, these papers do represent three different research strengths in Australasia, they do span three different disciplines, and they do reflect some of the diversity that characterises ageing research in Australasia over 30 years. PMID- 24164980 TI - The role of the Australasian Journal on Ageing in the Asia-Oceania region. AB - The role of the Australasian Journal on Ageing (AJA) in the Asia-Oceania region has been developing over the 30 years of the journal's publication, and review of its current and potential future roles is timely in the context of a number of developments in the region. This review describes the regional reach of the AJA, presents an analysis of regional content published over the 5 years to 2012, discusses the regional context with reference to other journals published in the region, and proposes several strategies for advancing the AJA's regional role. Pursuing these strategies would realise the AJA's potential as a vehicle for promoting the exchange of multidisciplinary knowledge on ageing. PMID- 24164981 TI - The changing demographics of Australia over the last 30 years. PMID- 24164982 TI - Thirty years of the United Nations and global ageing: an Australian perspective. AB - Over the past three decades, the United Nations (UN) has slowly devoted increasing attention to global ageing. Concern for individually based welfare or health-care programs for older people in developed countries has progressed to also consider the contributions of older people and implications of ageing for socioeconomic advancement in developing countries, including those in Asia Oceania. These shifts are evident in the International Plans of Action on Ageing from Vienna in 1982 to Madrid in 2002; recent 10-year reviews of the Madrid Plan; and current advocacy for inclusion of ageing in the influential UN Millennium Plan post-2015. Australia has demonstrated progressive policies and contributed to ageing developments by the UN, International Federation on Ageing the World Health Organization and the International Association of Gerontology. Key ideas driving further action are the importance of valuing people at all ages, addressing inequalities over the life-course and implementing human rights approaches to ageing. PMID- 24164983 TI - Advances in research, education and practice in geriatric medicine, 1982-2012. AB - Over the last 30 years, major advances in the provision of services for frail older people in Australasia have taken place. This has been spurred on by the accumulation of the evidence for benefits of the multidisciplinary team model of comprehensive geriatric assessment and management. Current research is now uncovering mechanisms of frailty associated with the ageing process and will lead to further interventions in the management of the health problems of older people. These interventions will almost certainly include both medical and lifestyle strategies. Although there have been major improvements in the education of health professionals in aspects of geriatrics, more concerted efforts are required for the ageing population. PMID- 24164984 TI - Advances in gerontology research and education: perspectives from the Australian Association of Gerontology. PMID- 24164985 TI - Graham Davison and Tony Broe talk with Sue Ogle. PMID- 24164987 TI - Increased serum asymmetric dimethylarginine level is an independent predictor of contrast-induced nephropathy. AB - OBJECTIVES: The aim of our study was to evaluate whether serum asymmetric dimethylarginine (ADMA) level is an independent predictor of contrast-induced nephropathy (CIN). STUDY DESIGN: The study involved 90 consecutive patients with stable angina pectoris who underwent coronary angiography and ventriculography. Baseline serum creatinine (SCr) levels ranged between >=1.2 and <2 mg/dl. All patients were hydrated with intravenous isotonic saline at a rate of 1 ml/kg per hour for 6 hours before and 12 hours after the procedure. The primary end point was the occurrence of CIN. The secondary end point was the change in SCr levels at day 2 after the contrast exposure. Serum ADMA was determined by the ELISA method. RESULTS: The CIN rate was 11.1%. We detected a statistically significantly higher serum ADMA level in the CIN(+) group compared to that of the CIN(-) group [210.6 ng/ml (115.6-217.2) vs. 91.5 ng/ml (65.2-122.1), p=0.01]. Mehran risk score and diabetes mellitus (DM) ratio were higher in the CIN(+) group compared to those values in the CIN(-) group [8 (5.75-10) vs. 5 (5-7), p=0.01 and 70% vs. 26.3%, p=0.01, respectively]. Serum ADMA level, Mehran risk score and DM were independent predictors of CIN (odds ratio (OR) 1.030, 95% confidence interval (CI) 1.011-1.050, p=0.002; OR 1.565, 95% CI 1.102-2.223, p=0.012; OR 9.422, 95% CI 1.441-61.598, p=0.019, respectively). A serum ADMA level of >124.7 ng/ml had 80% sensitivity and 76% specificity in predicting the development of CIN. In addition, we found a positive correlation between SCr change and serum ADMA level (p=0.001, r=0.35). CONCLUSION: Our study demonstrates that increased serum ADMA level is an independent predictor of CIN. PMID- 24164988 TI - [Relationship between D-dimer and systemic embolism in patients with infective endocarditis]. AB - OBJECTIVES: The aim of this study was to investigate the value of plasma D-dimer (DD) levels for predicting systemic embolism in patients with infective endocarditis (IE). STUDY DESIGN: A total of 42 patients (mean age: 46+/-16 years; 78% males) with IE were included. Clinical, laboratory and echocardiographic findings of the patients were evaluated. RESULTS: Increased plasma DD levels were determined in 13 patients with systemic embolism (p=0.016). Moreover, when patients were divided in two groups as DD >500 ng/dl and DD <500 ng/dl, systemic embolism was increased in the DD >500 ng/dl group (p=0.036). Receiver operating characteristics (ROC) curve analysis was performed to detect the best cut-off value of DD in the prediction of systemic embolism. DD >425 ng/dl yielded an area under the curve (AUC) value of 0.735 (95% CI 0.560-0.909, p=0.016). DD >425 ng/dl demonstrated a sensitivity of 77% and specificity of 62% for the prediction of clinical embolism. Hematocrit (r=-0.31, p=0.045), platelet count (r=-0.40, p=0.009), albumin (r=-0.37, p=0.026), and globulin (r=0.38, p=0.028) levels were correlated with DD levels. CONCLUSION: Plasma DD levels are increased in patients with IE who suffered from clinically significant systemic embolism. Further studies are needed to determine the predictive value of DD levels for clinically silent systemic embolism. PMID- 24164989 TI - Using the D-dimer test in infective endocarditis. PMID- 24164990 TI - No relevant association between coronary artery ectasia and mean platelet volume, gamma-glutamyltransferase and uric acid levels. AB - OBJECTIVES: In this study, we aimed to investigate whether there is an association between mean platelet volume (MPV), gamma-glutamyltransferase (GGT) and uric acid and coronary artery ectasia (CAE) in a large patient population. STUDY DESIGN: A total of 406 patients (245 male, 161 female; mean age: 55+/-9 years) were selected retrospectively as the study population from among 3265 individuals who underwent coronary angiography between August 2011 and December 2012. Information regarding blood tests of the patients obtained during hospitalization was extracted from the institute electronic database. RESULTS: MPV, GGT and uric acid levels were significantly higher in subjects with stenotic coronary artery disease (CAD) and in subjects with both CAD and CAE compared with subjects with isolated CAE and subjects with normal coronary arteries (NCA). There were no significant differences between the isolated CAE and NCA groups in terms of MPV (8.6+/-1.2 fL vs. 8.6+/-1.1, respectively, p=0.993), serum GGT (33+/ 15 U/L vs. 30+/-15 U/L, respectively, p=0.723) and uric acid levels (5.4+/-1.6 mg/dl vs. 5.2+/-1.7 mg/dl, respectively, p=0.845). CONCLUSION: Unlike previous studies, our study failed to demonstrate any association between CAE and MPV, uric acid and GGT levels. PMID- 24164991 TI - Association between neutrophil to lymphocyte ratio and pulmonary arterial hypertension. AB - OBJECTIVES: Pulmonary hypertension (PH) is composed of a heterogeneous group of disorders marked by increased pulmonary artery resistance leading to right heart failure, with high mortality. Evidence is increasing to propose that inflammation plays a significant role in the pathophysiological mechanism. Increased prevalence of PH in patients with systemic inflammatory diseases is already known. Herein, we sought to evaluate the association between neutrophil to lymphocyte ratio (N/L ratio) and pulmonary arterial hypertension (PAH). STUDY DESIGN: Twenty-five patients with PAH and 25 controls were evaluated. Baseline clinical and echocardiographic variables were obtained. Complete blood counts in all patients and controls were reviewed retrospectively. RESULTS: The N/L ratio was higher in patients with PAH compared to healthy volunteers (p=0.05). A cut off value of 1.65 for N/L ratio predicted the presence of PAH with 72% sensitivity and 69% specificity. After multivariate analysis, only N/L ratio remained a significant predictor of PAH. CONCLUSION: We showed for the first time that N/L ratio was significantly increased in patients with PAH compared to controls. PMID- 24164992 TI - [Relation of heart-type fatty acid-binding protein with the degree and extent of atherosclerosis in patients with non-ST elevation acute coronary syndrome]. AB - OBJECTIVES: The relationship between markers of myocardial ischemia and severity of coronary artery disease (CAD) has been investigated in several studies. In this study, we examined the relationship between severity of CAD and heart-type fatty acid-binding protein (H-FABP), a new marker of ischemia in patients with non-ST-segment elevation acute coronary syndrome (ACS). STUDY DESIGN: This prospective study comprised 49 patients who were referred to the emergency room with a diagnosis of non-ST elevation myocardial infarction. Troponins, creatine kinase-MB, lactate dehydrogenase, and aspartate aminotransferase levels were measured quantitatively, while blood H-FABP levels were measured qualitatively in the 4th-8th hour from the onset of symptoms. All patients underwent coronary angiography within 72 hours after admission. Clinical and coronary angiographic characteristics of patients with positive and negative values of H-FABP were compared. Gensini and SYNTAX scores were used to determine the severity of CAD. RESULTS: There were no statistically significant differences in mean age, gender distribution, risk factors for CAD, ischemic changes on ECG, or Gensini and SYNTAX scores between the H-FABP-negative and -positive groups (p>0.05). The duration of chest pain in the H-FABP-positive group was significantly longer than in the negative group (p<0.001). Troponin, CK-MB, and AST levels as well as thrombolysis in myocardial infarction (TIMI) risk scores were found to be significantly higher in the H-FABP-positive group (p<0.05). CONCLUSION: H-FABP is a useful marker for the diagnosis and risk evaluation of patients with non-ST elevation ACS. However, it is insufficient in evaluating the severity of CAD. PMID- 24164993 TI - Relation of plasma matrix metalloproteinase-8 levels late after myocardial infarction with left ventricular volumes and ejection fraction. AB - OBJECTIVES: Enhanced matrix metalloproteinase-8 (MMP-8) activity in the early post-myocardial infarction (MI) period has been related to early remodeling. However, it has been demonstrated that plasma MMP-8 level has a biphasic profile, and the relation between the late plasma levels and remodeling is unclear. We evaluated the plasma MMP-8 levels and its correlates 20+/-3 months after acute MI. STUDY DESIGN: 58 post-MI patients and 26 control subjects underwent quantitative single-photon emission computed tomography (SPECT) and echocardiography. The plasma MMP-8 levels were measured and its correlates were investigated. RESULTS: The MMP-8 levels were significantly higher in post-MI patients [median 3.88 ng/ml, interquartile range (1.88-6.43) vs. 0.67 ng/ml (0.34 2.47); p<0.001]. Plasma MMP-8 levels were significantly correlated with left ventricular ejection fraction (LVEF) (rho=0.34, p=0.009), end diastolic volume index (EDVi) (rho=-0.39, p=0.002) and end systolic volume index (ESVi) (rho= 0.40, p=0.002). CONCLUSION: Plasma MMP-8 levels were found to still be high in post-MI patients 20+/-3 months after the index event. The levels were significantly correlated with left ventricular volume indices and LVEF. We speculate that, in contrast to the relation between the higher early MMP-8 activity and the extent of cardiac remodeling, higher late levels may be associated with relative preservation of left ventricular systolic function. PMID- 24164994 TI - [Left ventricular thrombus formation in a patient with normal ejection fraction]. AB - Left ventricular (LV) thrombi usually occur in the presence of impaired LV function, such as in dilated cardiomyopathy, aneurysm or following myocardial infarction. Thrombus formation in a normally functioning LV is extremely rare. We report a patient with LV thrombus formation despite a normal systolic function. The patient, who was admitted to the emergency service with transient loss of consciousness and diagnosed with cerebral embolism, was found to have a pedunculated and hypermobile mass in the LV apex by echocardiography. The LV mass was excised by urgent surgery due to its high embolic risk. The histopathological examination revealed that the LV mass was a thrombus. This case highlights that although very rare, LV thrombus formation may occur in patients with normal ejection fraction. PMID- 24164995 TI - [Rapidly improving acute myocarditis after a scorpion sting]. AB - Scorpion stings are usually benign, but especially cardiovascular death has been reported due to complications. Local reactions at the site of the sting as well as organ dysfunction may be due to the effects of a systemic toxin. As a result of the toxic effects of the scorpion toxin on the cardiovascular system, hypertension, arrhythmia, myocarditis, acute heart failure, and pulmonary edema may occur. In this report, we present a 49-year-old male patient who was admitted to our hospital with acute pulmonary edema and respiratory distress following scorpion sting at the wrist. In this case, detection of diffuse left ventricular systolic dysfunction on presentation, immediate improvement with medical treatment, and increased troponin levels in the absence of critical stenosis on coronary angiography suggest the diagnosis of acute myocarditis associated with scorpion bite. PMID- 24164996 TI - A new hope in the treatment of coronary vasospasm: bosentan. AB - Atherosclerosis is the most important cause of acute coronary syndromes. The mediators that trigger vasospasm, including endothelin and serotonin, are synthesized and secreted into circulation from atherosclerotic plaques and surrounding tissues. A 68-year-old man was hospitalized due to acute coronary syndrome four times in a one-year period. The patient presented to emergency service again with heartburn and a pressure-like pain in his upper abdomen in February 2012. He was admitted to the coronary care unit with the detection of a more than three-fold increase in troponin values and ischemic changes on electrocardiography. By decision of the cardiology council, the endothelin receptor antagonist, bosentan was added to the treatment. There were no contraindications to this medication according to his blood and hepatic indicators. After confirmation of the Social Security Institution, bosentan was started as 62.5 mg twice a day. After the first month, the dose was increased to 125 mg b.i.d. As of completion of the eighth month of treatment with bosentan, the patient had not been hospitalized due to angina attack or acute coronary syndrome. PMID- 24164998 TI - A huge intracardiac thrombus developed in the presence of antithrombin III deficiency in a patient with end-stage renal failure. AB - In this study, we report a 15-year-old female with end-stage renal disease undergoing hemodialysis, who admitted with acute respiratory failure and generalized edema. Abdominal tomography detected thrombi in the right renal vein, in the hepatic segment of the inferior vena cava and in iliac veins. Levels of proteins C and S, antinuclear antigen, anti-dsDNA, C3, and C4 were in normal limits. The thrombi persisted despite treatment with nadroparin, heparin with fresh frozen plasma and warfarin. Due to heparin resistance, antithrombin III levels were measured and were found abnormally low. The first echocardiographic examination was in normal limits but the second echocardiography revealed a huge thrombus occluding the tricuspid valve. Urgent thrombectomy was planned but the patient died in the intensive care unit due to severe pulmonary edema. PMID- 24164997 TI - Heart failure after transvenous closure of atrial septal defect associated with atrial standstill and thiamine-responsive megaloblastic anemia. AB - Despite advances in device closure for atrial septal defect, post-closure heart failure remains a clinical problem in adult patients but is seen only rarely in children. An eight-year-old boy, who had been followed by a local pediatrician with the diagnosis of diabetes mellitus and congenital heart disease, was consulted to us for cardiac re-evaluation. Electrocardiography demonstrated absent P waves, and echocardiography revealed enlargement of the right ventricle and both atria and secundum atrial septal defect. With the diagnosis of atrial standstill, secundum atrial septal defect and thiamine-responsive megaloblastic anemia, acute heart failure developed after transvenous closure of the atrial septal defect, which improved dramatically with thiamine and supportive treatment. PMID- 24164999 TI - Chest pain with myocardial ischemia in a child: should we think about coronary slow flow phenomenon? AB - The coronary slow flow phenomenon (CSFP) is an angiographic finding characterized by delayed opacification of epicardial coronary arteries in the absence of stenotic lesion. Herein, we present a 13-year-old boy with recurrent chest pain who was diagnosed with acute ST-segment elevation myocardial infarction associated with CSFP, which has not been reported previously in the pediatric age group. Coronary angiography revealed only the presence of slow flow in the left anterior descending (LAD) coronary artery. Myocardial perfusion scintigraphy revealed a reversible perfusion defect in the LAD territory, which regressed partially at rest and showed complete improvement after dipyridamole infusion. All the symptoms, electrocardiogram abnormalities and cardiac markers returned to normal after dipyridamole treatment during the follow-up. We conclude that CSFP should be kept in mind in the differential diagnosis of chest pain with myocardial ischemia in the pediatric age group. PMID- 24165000 TI - [How to perform electrical cardioversion?]. PMID- 24165001 TI - Championing cardiovascular health innovation in Europe. PMID- 24165002 TI - [Championing cardiovascular health innovation in Europe]. PMID- 24165003 TI - An unusual cause of implantable cardioverter defibrillator malfunction: Twiddler syndrome. PMID- 24165004 TI - A rare coronary artery anomaly: posterior descending artery arising from septal perforator artery. PMID- 24165005 TI - Non-obstructive supracardiac total anomalous pulmonary venous return in a 3-year old patient who was admitted with complaint of mild cyanosis. PMID- 24165006 TI - Cardiac metastasis of an esophageal cancer: a rare cause of ventricular tachycardia and left ventricle outlet obstruction. PMID- 24165007 TI - Cor triatriatum sinister with non-fenestration in a seven-month-old patient. PMID- 24165008 TI - Malrotated kidney as a complication of partial nephrectomy. PMID- 24165011 TI - HIV-1 Tat protein binds to TLR4-MD2 and signals to induce TNF-alpha and IL-10. AB - BACKGROUND: HIV-1 infection results in hyper-immune activation and immunological disorders as early as the asymptomatic stage. Here, we hypothesized that during early HIV-1 infection, HIV-1 Tat protein acts on monocytes/macrophages to induce anti-inflammatory and proinflammatory cytokines and participates in immune dysregulation. RESULTS: In this work we showed that Tat protein: i) by its N terminal domain induces production of both IL-10 and TNF-alpha in a TLR4-MD2 dependent manner, ii) interacts specifically with TLR4-MD2 and MD2 with high affinity but not with CD14, iii) induces in vivo TNF-alpha and IL-10 in a TLR4 dependent manner. CONCLUSIONS: Collectively, our data showed for the first time that, HIV-1 Tat interacts physically with high affinity with TLR4-MD2 to promote proinflammatory cytokines (TNF-alpha) and the immunosuppressive cytokine IL-10 both involved in immune dysregulation during early HIV-1 infection and AIDS progression. PMID- 24165012 TI - Present and past Helicobacter pylori infection in Mexican school children. AB - BACKGROUND: In developing countries, more than 50% of children have serological evidence of Helicobacter pylori infection. However, serological tests for H. pylori did not differentiate between active and past infection. The objectives of this study were to estimate the frequency of active and past H. pylori infection utilizing functional urea breath test (UBT) and serological tests and evaluate factors associated with the infection. METHODS: A total of 675 school children, 6 13 years of age, participated. UBT was performed to detect active H. pylori infection. Blood samples were obtained to determine iron status and Immunoglobulin G (IgG) responses to the H. pylori whole-cell and to Cag A antigens by antigen-specific enzyme-linked immunosorbent assays. Weight, height, and sociodemographic characteristics were recorded. RESULTS: A total of 37.9% (95% Confidence Intervals (CI): 34.2-41.6) of school children had active or past H. pylori infection; of them, 73.8% (CI95% 68.4-79.2) were carrying CagA-positive strain, 26.5% (CI95% 23.2-29.8) had active infection, and 11.4% (95%CI: 9.0-13.8) had evidence of past H. pylori infection. School children with iron deficiency and low height for age had higher risk of H. pylori infection: [OR to active or past infection was 2.30 (CI 95% 1.01-5.23) and to active infection it was 2.64 (CI 95% 1.09-6.44)] compared to school children with normal iron status and height for age or with normal iron status but low height for age or with iron deficiency and normal height for age. CONCLUSIONS: The estimated prevalence of infection depends of the test utilized. Frequency of H. pylori infection and carrying CagA-positive strains was high in this population. Malnutrition was associated with active H. pylori infection. PMID- 24165013 TI - Periodontal conditions in patients with Marfan syndrome - a multicenter case control study. AB - BACKGROUND: Marfan syndrome (MFS) is a disorder of the connective tissues. Alterations of the elastic fibers may manifest in different tissues especially in the skeletal, cardiovascular and ocular system. Oral manifestations like orthodontic or skeletal anomalies and fragility of the temporomandibular joint have been well described by various authors. However, no data are available regarding a possible periodontal involvement of MFS. Hence, the aim of the present study was to investigate for the first time if MFS may increase the susceptibility to periodontitis. METHODS: A comprehensive periodontal examination including documentation of probing pocket depth, gingival recession, clinical attachment level, and bleeding on probing was conducted in all patients. In addition, dental conditions were assessed by determining the Index for Decayed, Missing and Filled Teeth (DMFT) and a self-administered questionnaire was filled out by patients. For statistical analysis, the unpaired t-Test was applied (level of significance: p < 0.05). Both groups were matched concerning well known periodontal risk factors like age, gender and smoking habits. RESULTS: 82 participants, 51 patients with MFS (30 female and 21 male, mean age: 40.20 +/- 15.35 years) and 31 sound controls (17 female and 14 male, mean age: 40.29 +/- 13.94 years), were examined. All assessed periodontal and dental parameters were not significantly different between groups. CONCLUSIONS: Based on our data, patients with MFS did not reveal a higher prevalence of periodontitis compared to the control group. However, Marfan patients showed a tendency to more inflammation signs, which can be explained by the crowded teeth. Therefore, a regular professional cleaning of the teeth is recommendable (i.e., 6 months intervals) in order to reduce the bacterial biofilm in the oral cavity and thus resulting in a decreased risk of systemic diseases, specifically endocarditis. PMID- 24165014 TI - Attitudes toward fertility and childbearing scale: an assessment of a new instrument for women who are not yet mothers in Sweden. AB - BACKGROUND: Women in high-resource countries often postpone childbearing. Postponed childbearing may lead to increased health risks for both mother and child and may also result in childlessness. Attitudes among men and women about fertility and childbearing have been studied in different phases of fertile life, but instruments that assess attitudes toward fertility and childbearing among women without children are lacking. The aim of this study is to develop and evaluate a specific instrument, the Attitudes toward Fertility and Childbearing Scale (AFCS), to assess and compare attitudes toward fertility and childbearing using a national sample of Swedish women, who are not yet mothers. METHODS: This study reports on the development of a new instrument and was carried out in three steps: (1) Statements were constructed based on two qualitative studies; (2) Data were collected through web-based questionnaires, and (3) Data were analyzed using statistical tests for construct validity with exploratory factor analysis, internal consistency reliability, and comparative statistics. Student's t-test and analysis of variance (ANOVA) were performed to analyze differences between the components and background characteristics. One hundred and thirty-eight women participated; they were 20-30 years of age, not mothers, and able to read and speak Swedish. RESULTS: The instrument showed acceptable sample adequacy, factorability, and reliability using Cronbach's alpha. Three components were revealed, each one representing a specific underlying dimension of the construct: 1) importance of fertility for the future (Cronbach's alpha, 0.901); 2) childbearing as a hindrance at present (Cronbach's alpha, 0.908); and 3) social identity (Cronbach's alpha, 0.805). Women who were students scored higher in importance of fertility for the future than did women who were unemployed. Women living in metropolitan areas and larger cities were more likely to score highly in childbearing as a hindrance at present than women living in middle-sized cities or in the countryside. Women in the age group from 25-26 agreed to the largest extent with childbearing as a hindrance at present. CONCLUSIONS: The instrument shows acceptable factorability and reliability. Three components were found to be the best solution. Further evaluation is necessary. PMID- 24165015 TI - Assessing variation in the costs of care among patients awaiting liver transplantation. AB - Previous economic analyses of liver transplantation have focused on the cost of the transplant and subsequent care. Accurate characterization of the pretransplant costs, indexed to severity of illness, is needed to assess the economic burden of liver disease. A novel data set linking Medicare claims with transplant registry data for 15,710 liver transplant recipients was used to determine average monthly waitlist spending (N = 249,434 waitlist months) using multivariable linear regression models to adjust for recipient characteristics including Model for End-Stage Liver Disease (MELD) score. Characteristics associated with higher spending included older age, female gender, hepatocellular carcinoma, diabetes, hypertension and increasing MELD score (p < 0.05 for all). Spending increased exponentially with severity of illness: expected monthly spending at a MELD score of 30 was 10 times higher than at MELD of 20 ($22,685 vs. $2030). Monthly spending within MELD strata also varied geographically. For candidates with a MELD score of 35, spending varied from $19,548 (region 10) to $36,099 (region 7). Regional variation in waitlist costs may reflect the impact of longer waiting times on greater pretransplant hospitalization rates among high MELD score patients. Reducing the number of high MELD waitlist patients through improved medical management and novel organ allocation systems could decrease total spending for end-stage liver care. PMID- 24165016 TI - Sexual life and sexual wellness in individuals with complete androgen insensitivity syndrome (CAIS) and Mayer-Rokitansky-Kuster-Hauser Syndrome (MRKHS). AB - INTRODUCTION: Sexual wellness depends on a person's physical and psychological constitution. Complete Androgen Insensitivity Syndrome (CAIS) and Mayer Rokitansky-Kuster-Hauser Syndrome (MRKHS) can compromise sexual well-being. AIMS: To compare sexual well-being in CAIS and MRKHS using multiple measures: To assess sexual problems and perceived distress. To gain insight into participants' feelings of inadequacy in social and sexual situations, level of self-esteem and depression. To determine how these psychological factors relate to sexual (dys)function. To uncover what participants see as the source of their sexual problems. METHODS: Data were collected using a paper-and-pencil questionnaire. Eleven individuals with CAIS and 49 with MRKHS with/without neovagina treatment were included. Rates of sexual dysfunctions, overall sexual function, feelings of inadequacy in social and sexual situations, self-esteem and depression scores were calculated. Categorizations were used to identify critical cases. Correlations between psychological variables and sexual function were computed. Sexually active subjects were compared with sexually not active participants. A qualitative content analysis was carried out to explore causes of sexual problems. MAIN OUTCOME MEASURES: An extended list of sexual problems based on the Diagnostic and Statistical Manual of Mental Disorders, 4th ed., text revision, by the American Psychiatric Association and related distress. Female Sexual Function Index (FSFI), German Questionnaire on Feelings of Inadequacy in Social and Sexual Situations (FUSS social scale, FUSS sexual scale), Rosenberg Self-Esteem Scale (RSE), Brief Symptom Inventory (BSI) subscale depression. Open question on alleged causes of sexual problems. RESULTS: The results point to a far-reaching lack of sexual confidence and sexual satisfaction in CAIS. In MRKHS apprehension in sexual situations is a source of distress, but sexual problems seem to be more focused on issues of vaginal functioning. MRKHS women report being satisfied with their sex life. CONCLUSION: Different conditions can affect individuals in diagnosis-specific ways despite some shared clinical features. Professionals should adopt an interdisciplinary approach and provide custom-made care in order to promote sexual well-being in patients. PMID- 24165017 TI - The prevalence of IgG4-related hypophysitis in 170 consecutive patients with hypopituitarism and/or central diabetes insipidus and review of the literature. AB - OBJECTIVE: The prevalence and clinical characteristics of IgG4-related hypophysitis remain unclear due to the limited number of case reports. Therefore, in this study, we screened consecutive outpatients with hypopituitarism and/or diabetes insipidus (DI) to estimate its prevalence. METHODS: A total of 170 consecutive outpatients with hypopituitarism and/or central DI were screened at Kobe University Hospital for detecting IgG4-related hypophysitis by pituitary magnetic resonance imaging, measuring serum IgG4 concentrations, assessing the involvement of other organs, and carrying out an immunohistochemical analysis to detect IgG4-positive cell infiltration. RESULTS: Among the screened cases, 116 cases were excluded due to diagnosis of other causes such as tumors and congenital abnormalities. Additionally, 22 cases with isolated ACTH deficiency were analyzed and were found not to meet the criteria of IgG4-related hypophysitis. The remaining 32 cases were screened and seven were diagnosed with IgG4-related hypophysitis, of which three cases were diagnosed by analyzing pituitary specimens. IgG4-related hypophysitis was detected in 30% (seven of 23 patients) of hypophysitis cases and 4% of all hypopituitarism/DI cases. The mean age at the onset of IgG4-related hypophysitis was 61.8+/-8.8 years, and the serum IgG4 concentration was 191.1+/-78.3 mg/dl (normal values 5-105 mg/dl and values in IgG4-related disease (RD) >=135 mg/dl). Pituitary gland and/or stalk swelling was observed in six patients, and an empty sella was observed in one patient. Multiple co-existing organ involvement was observed in four of the seven patients prior to the onset of IgG4-related hypophysitis. CONCLUSION: These data suggest that the prevalence of IgG4-related hypophysitis has been underestimated. We should also consider the possibility of the development of hypopituitarism/DI caused by IgG4-related hypophysitis during the clinical course of other IgG4-RDs. PMID- 24165018 TI - Triglycerides-to-HDL ratio as a new marker of endothelial dysfunction in obese prepubertal children. AB - OBJECTIVE: To investigate whether there is an association of the triglyceride-to HDL cholesterol (TG:HDL-C) ratio with cardiovascular risk factors and early signs of vascular damage in obese prepubertal children. DESIGN AND METHODS: In 50 obese (27 boys, 7.8+/-1.4 years) and 37 normal-weight (20 boys; 7.3+/-1.5 years) prepubertal children, anthropometric measurements, oxidative stress markers (urinary isoprostanes (PGF2alpha (prostaglandin F2alpha)), soluble receptor for advanced glycation end-products (sRAGE)) and insulin sensitivity (homeostasis model assessment of insulin resistance (HOMA-IR) and whole-body insulin sensitivity index (WBISI)) were evaluated. Lipids profile was assessed and the TG:HDL-C ratio was calculated. In addition, high-resolution ultrasound was performed to assess carotid intima-media thickness (cIMT). RESULTS: Obese children showed significantly higher values of the TG:HDL-C ratio (1.9+/-1.1 vs 1.2+/-0.6, P=0.002) compared with controls. After dividing the population in tertiles of the TG:HDL-C ratio (<1.04, 1.04-1.67, >1.67), cIMT (P=0.0003), and HOMA-IR (P=0.0001) progressively increased from the lower to the upper tertile, whereas WBISI (P=0.0003) and sRAGE (P=0.05) progressively decreased. In a regression model, the TG:HDL ratio was significantly and positively associated with cIMT (r=0.493; P=0.0005). A cutoff point for TG:HDL-C ratio of 1.12 had 81% sensitivity and 49% specificity in the identification of children with cIMT values in the upper quartile (Area under the curve values from receiver operating characteristic curves=0.633+/-0.065, P=0.045). CONCLUSION: This study confirms the reliability of the TG:HDL-C ratio as a useful marker of cardiovascular risk. Interestingly, our results underline that the TG:HDL-C ratio is directly related with early signs of vascular damage already present in prepubertal children. PMID- 24165019 TI - Cushing's disease and hypertension: in vivo and in vitro study of the role of the renin-angiotensin-aldosterone system and effects of medical therapy. AB - OBJECTIVE/METHODS: Cushing's disease (CD) is often accompanied by hypertension. CD can be treated surgically and, given the expression of somatostatin subtype 5 and dopamine 2 receptors by corticotroph pituitary adenomas, pharmacologically. Indeed, we recently observed that stepwise medical combination therapy with the somatostatin-analog pasireotide, the dopamine-agonist cabergoline, and ketoconazole (which directly suppresses steroidogenesis) biochemically controlled CD patients and lowered their blood pressure after 80 days. Glucocorticoids (GC) modulate the renin-angiotensin-aldosterone system (RAAS) among others by increasing hepatic angiotensinogen expression and stimulating mineralocorticoid receptors (MR). This study therefore evaluated plasma RAAS components in CD patients before and after drug therapy. In addition, we studied whether cabergoline/pasireotide have direct relaxant effects in angiotensin II (Ang II) constricted iliac arteries of spontaneously hypertensive rats, with and without concomitant GR/MR stimulation with dexamethasone or hydrocortisone. RESULTS: Baseline concentrations of angiotensinogen were elevated, while renin and aldosterone were low and suppressed, respectively, even in patients treated with RAAS-blockers. This pattern did not change after 80 days of treatment, despite blood pressure normalization, nor after 4 years of remission. In the presence of dexamethasone, pasireotide inhibited Ang II-mediated vasoconstriction. CONCLUSIONS: The low plasma renin concentrations, even under RAAS blockade, in CD may be the consequence of increased GC-mediated MR stimulation and/or the elevated angiotensinogen levels in such patients. The lack of change in RAAS parameters despite blood pressure and cortisol normalization suggests persisting consequences of long-term exposure to cortisol excess. Finally, pasireotide may have a direct vasodilating effect contributing to blood pressure lowering. PMID- 24165020 TI - The role of androgen receptor CAG repeat polymorphism and other factors which affect the clinical response to testosterone replacement in metabolic syndrome and type 2 diabetes: TIMES2 sub-study. AB - CONTEXT: The TIMES2 (testosterone replacement in hypogonadal men with either metabolic syndrome or type 2 diabetes) study reported beneficial effects of testosterone replacement therapy (TRT) on insulin resistance and other variables in men with diabetes or metabolic syndrome. The androgen receptor CAG repeat polymorphism (AR CAG) is known to affect stimulated AR activity and has been linked to various clinically relevant variables. OBJECTIVE: To assess the role of AR CAG in the alteration of clinical response to TRT in the TIMES2 study. DESIGN: Subgroup analysis from a multicentre, randomised, double-blind, placebo controlled and parallel group study. SETTING: Outpatient study recruiting from secondary and primary care. PATIENTS: A total of 139 men with hypogonadism and type 2 diabetes or metabolic syndrome, of which 73 received testosterone during the TIMES2 study. INTERVENTION: Testosterone 2% transdermal gel vs placebo. MAIN OUTCOME MEASURE: Regression coefficient of AR CAG from linear regression models for each variable. RESULTS: AR CAG was independently positively associated with change in fasting insulin, triglycerides and diastolic blood pressure during TRT with a trend to association with HOMA-IR - the primary outcome variable. There was a trend to negative association between AR CAG and change in PSA. There was no association of AR CAG with change in other glycaemic variables, other lipid variables or obesity. CONCLUSION: AR CAG affected the response of some variables to TRT in the TIMES2 study, although the association with HOMA-IR did not reach significance. Various factors may have limited the power of our study to detect the significant associations between AR CAG, testosterone levels and change in variables with testosterone treatment. Analysis of similar data sets from other clinical trials is warranted. PMID- 24165022 TI - YB1 binds to and represses the p16 tumor suppressor gene. AB - Y box binding protein 1 (YB1) has multiple functions associated with drug resistance, cell proliferation and metastasis through transcriptional and translational regulation. Increased expression of YB1 is closely related to tumor growth and aggressiveness. We showed that YB1 protein levels were decreased through replicative and premature senescence and were correlated with increased expression levels of p16(INK) (4A) tumor suppressor gene. Depletion of YB1 was associated with increased levels of p16 in human and murine primary cells. Forced expression of YB1 in mouse embryonic fibroblasts resulted in decreased expression of p16 and increased cell proliferation. Senescence-associated expression of beta galactosidase was repressed in YB1-over-expressing cells. Chromatin immunoprecipitation assays showed that YB1 directly associates with the p16 promoter. Taken together, all our findings indicate that YB1 directly binds to and represses p16 transcription, subsequently resulting in the promotion of cell growth and prevention of cellular senescence. PMID- 24165023 TI - Longest neurite-specific activation of Rap1B in hippocampal neurons contributes to polarity formation through RalA and Nore1A in addition to PI3-kinase. AB - In a developing nervous system, axon-dendrite formation is instructed by extrinsic cues, and the mechanism whereby a developing neuron interprets these cues using intracellular signaling is particularly important. Studies using dissociated hippocampal neurons have identified many signaling pathways underlying neuronal polarization. Among the components of these pathways, Rap1B is essential for axon specification in hippocampal cultures. However, spatiotemporal regulation of Rap1B activity in polarizing neurons and how it affects neuronal polarization remain unclear. Herein, we investigated spatiotemporal activity-change of Rap1B and its target molecules in hippocampal neurons. FRET imaging showed that specific activation of Rap1B was observed at the tip of a future axon. To dissect downstream signaling, we used three effector mutants of Rap1B. Expression of Rap1B-G12V/E37G and G12V/Y40C mutants resulted in supernumerary axons. The targets of Rap1B-G12V/E37G were RalA and Nore1A, whereas Rap1B-G12V/Y40C activated PI3-kinase. RalA was activated in the tip of stage 3 axons, and RalA-S28N expression reduced the fraction of neurons with supernumerary axons induced by Rap1B-G12V/E37G. Furthermore, Nore1A depletion reduced the number of cells without axons. These results indicate that specific activation of Rap1B contributes to neuronal polarization via interaction with RalA and Nore1A in addition to PI3-kinase. PMID- 24165024 TI - Establishment and characterization of a mutagenized cell line exhibiting the 'cell-in-cell' phenotype at a high frequency. AB - Cell-in-cell structures represent live cell events in which one cell internalizes another. Because formation of cell-in-cell structures is a rare event in most cell types and the event is associated with cell death, there has been limited clarification of this phenomenon, and its physiological role and molecular mechanism are yet to be precisely elucidated. In this study, we established a mutagenized cell line that exhibited cell-in-cell structures at a more than 10 fold higher frequency as compared to the parent cells. Interestingly, both engulfment and invasion were increased in the mutagenized cell line as compared with that in the parent cell line in the suspension culture condition. This finding indicates that this mutagenized cell line showed an interchangeable status in terms of its ability to form cell-in-cell structures, and the system described here could be useful for elucidation of the mechanisms regulating the formation of cell-in-cell structures, including engulfment and invasion, in a given cellular environment. Further studies using this cell line are warranted to understand the mechanism of formation and biological significance of the cell-in cell formation. PMID- 24165025 TI - Effects and mechanisms of gastric electrical stimulation on visceral pain in a rodent model of gastric hyperalgesia secondary to chemically induced mucosal ulceration. AB - BACKGROUND: Gastric electrical stimulation (GES) has been suggested as a potential treatment for patients with gastric motility disorders. The aim of this study was to examine the effects and mechanisms of GES on visceral pain in awaken rats. METHODS: Under anesthesia, acetic acid was injected into the submucosal layer of the stomach wall in Sprague-Dawley (SD) male rats. Each rat was chronically placed with an intragastric balloon and two pairs of electrodes on gastric serosa for GES and at the neck muscles for electromyography (EMG) recordings respectively. The study was composed of four experiments. Exp 1 was designed to determine optimal GES parameters in reducing EMG response to gastric distention (GD). Exp 2 was performed to investigate the effect of GES on gastric tone/accommodation. Exp 3 was to investigate if the opioid pathway was involved in the analgesic effects of GES. Exp 4 was to assess the effectiveness of GES on the spinal cord neurons (T9-T10) responding to GD. KEY RESULTS: (i) Gastric electrical stimulation with a train on of 0.1 s and off of 0.4 s, 0.25 ms, 100 Hz, and 6 mA significantly reduced GD-induced EMG responses at GD 40, 60, and 80 mmHg. (ii) The inhibitory effects of GES on the GD-induced EMG responses were blocked by Naloxone. (iii) GES inhibited 90% of high-threshold (HT) spinal neurons in response to GD. However, GES with the same parameters only suppressed 36.3% low-threshold (LT) neuronal response to GD. CONCLUSIONS & INFERENCES: Gastric electrical stimulation with optimal parameters inhibits visceral pain; the analgesic effect of GES on visceral pain is mediated via the endogenous opioid system and the suppression of spinal afferent neuronal activities. PMID- 24165026 TI - Development of bullous pemphigoid after change of dialysis membrane. AB - A 75-year-old Japanese man presented with pruritic blisters and macules on his trunk and extremities. He had been on hemodialysis for 4 years because of chronic renal failure, and in recent months, a polymethylmethacrylate membrane had been used for dialysis. After a change in dialysis membrane to a cellulose triacetate membrane, pruritic tense blisters developed on the extremities in combination with marked blood eosinophilia. Physical examination showed erythematous macules and tense blisters on the trunk and extremities. A biopsy specimen of an erythematous macule showed subepidermal vesicles and eosinophils that attached to the dermal-epidermal junction. Serum level of eosinophilic cationic protein was elevated. From clinical, histological, and immunological findings, a diagnosis of bullous pemphigoid was made. New blisters continued to erupt during the period in which the patient used the cellulose triacetate membrane dialyzer, and even after the use of clobetasol propionate. It resolved only after the patient came back to the use of a synthetic membrane dialyzer. We discontinued the use of clobetasol propionate, and neither bullous eruptions nor blood eosinophilia recurred. These observations suggest that cellulose membrane may be involved in the development of bullous pemphigoid through activation of eosinophils in the blood and the skin lesion, as in the present case. PMID- 24165027 TI - Ten years of progress--improved hysterectomy outcomes in Finland 1996-2006: a longitudinal observation study. AB - OBJECTIVES: To study the outcome of various hysterectomies in 2 years 1996 (N =10110) and 2006 (N=5279). The hypothesis was that the change in operative practices in 10 years has resulted in improvements. DESIGN: 2 prospective nationwide cohort evaluations with the same questionnaire. SETTING: All national operative hospitals in Finland. PARTICIPANTS: Patients scheduled to either abdominal hysterectomy (AH), vaginal hysterectomy (VH) or laparoscopic hysterectomy (LH) for benign disease. OUTCOME MEASURES: Patients' characteristics, surgery-related details and complications (organ injury, infection, venous thromboembolism and haemorrhage). RESULTS: The overall complication rates fell in LH and markedly in VH (from 22.2% to 11.7%, p<0.001). The overall surgery-related infectious morbidity decreased in all groups and significantly in VH (from 12.3% to 5.2%, p<0.001) and AH (from 9.9% to 7.7%, p<0.05). The incidence of bowel lesions in VH sank from 0.5% to 0.1% and of ureter lesions in LH from 1.1% to 0.3%. In 2006 there were no deaths compared with three in 1996. CONCLUSIONS: The rate of postoperative complications fell markedly in the decade from 1996 to 2006. This parallels with the recommendation of the recent meta-analyses by Cochrane collaboration; the order of preference of hysterectomies was for the first time precisely followed in this nationwide study. TRIAL REGISTRATION: The 2006 study was registered in the Clinical Trials of Protocol Registration System Data (NCT00744172). PMID- 24165028 TI - Testing for sexually transmitted infections among students: a discrete choice experiment of service preferences. AB - OBJECTIVES: To assess preferences among students for sexually transmitted infection (STI) testing services, with a view to establishing strength of preference for different service attributes. DESIGN: Online discrete choice experiment (DCE) questionnaire. SETTING: South East of England. PARTICIPANTS: A convenience sample of 233 students from two universities. OUTCOMES: Adjusted ORs in relation to service characteristics. RESULTS: The study yielded 233 responses. Respondents' ages ranged from 16 to 34 years with a mean age of 22 years. Among this sample, the respondents demonstrated strong preferences for a testing service which provided tests for all STIs including syphilis, herpes and HIV (OR 4.1; 95% CI 3.36 to 4.90) and centres staffed by a doctor or nurse with specialist knowledge of STIs (OR 2.1; 95% CI 1.78 to 2.37). Receiving all test results, whether positive or negative, was also significantly preferable to not being notified when tests were all negative ('no news is good news'; OR 1.3; 95% CI 1.16 to 1.5). The length of time waiting for an appointment and the method by which results are received were not significant service characteristics in terms of preferences. Patient level characteristics such as age, sex and previous testing experience did not predict the likelihood of testing. CONCLUSIONS: This study demonstrates that of the examined attributes, university students expressed the strongest preference for a comprehensive testing service. The next strongest preferences were for being tested by specialist STI staff and receiving negative as well as positive test results. However, it remains unclear how strong these preferences are in relation to characteristics which were not part of the study design and whether or not they are cost-effective. PMID- 24165029 TI - Increased waist circumference and prevalence of type 2 diabetes and hypertension in Chinese adults: two population-based cross-sectional surveys in Shanghai, China. AB - OBJECTIVE: To evaluate the changes in body mass index (BMI) and waist circumference (WC) and their associations with the prevalence of hypertension and type 2 diabetes mellitus (T2DM) in Chinese adults. DESIGN: 2 consecutive population-based cross-sectional surveys. SETTING: A total of 12 districts and seven counties in Shanghai, China. PARTICIPANTS: 12 329 randomly selected participants of the survey in 2002-2003, and 7423 randomly selected participants of the survey in 2009. All participants were residents of Shanghai aged 35-74 years. OUTCOME MEASURES: Measured BMI and WC. Previously diagnosed and newly identified hypertension and T2DM by measured blood pressure, fasting and postload glucose. RESULTS: While the participants of the two surveys were comparable in BMI in each age group, the participants of the 2009 survey had significantly larger WC than those of the 2002-2003 survey, with an annual percentage change being higher among participants aged 45-49 years in men and women. The increase in prevalence of T2DM was observed in all age groups and also appeared more evident in participants aged 45-49 years. The prevalence of hypertension was observed to increase more rapidly in elderly men and middle-aged women. Obesity, both overt and central, was associated with the risk of the two diseases, but BMI was more strongly linked to hypertension while WC appeared more evidently related with T2DM. CONCLUSIONS: The prevalence of central obesity and related chronic diseases has been increasing in Shanghai, China. Our findings provide useful information for the projection of the growing burden of T2DM and hypertension in Chinese adults. PMID- 24165030 TI - Design of a randomised controlled trial of adapted physical activity during adjuvant treatment for localised breast cancer: the PASAPAS feasibility study. AB - INTRODUCTION: After a diagnosis of localised breast cancer, overweight, obesity and weight gain are negatively associated with prognosis. In contrast, maintaining an optimal weight through a balanced diet combined with regular physical activity appears to be effective protective behaviour against comorbidity or mortality after a breast cancer diagnosis. The primary aim of the Programme pour une Alimentation Saine et une Activite Physique Adaptee pour les patientes atteintes d'un cancer du Sein (PASAPAS) randomised controlled trial is to evaluate the feasibility of implementing an intervention of adapted physical activity (APA) for 6 months concomitant with the prescription of a first line of adjuvant chemotherapy. Secondary aims include assessing the acceptability of the intervention, compliance to the programme, process implementation, patients' satisfaction, evolution of biological parameters and the medicoeconomic impact of the intervention. METHODS AND ANALYSIS: The study population consists of 60 women eligible for adjuvant chemotherapy after a diagnosis of localised invasive breast cancer. They will be recruited during a 2-year inclusion period and randomly allocated between an APA intervention arm and a control arm following a 2:1 ratio. All participants should benefit from personalised dietetic counselling and patients allocated to the intervention arm will be offered an APA programme of two to three weekly sessions of Nordic walking and aerobic fitness. During the 6 month intervention and 6-month follow-up, four assessments will be performed including blood draw, anthropometrics and body composition measurements, and questionnaires about physical activity level, diet, lifestyle factors, psychological criteria, satisfaction with the intervention and medical data. ETHICS AND DISSEMINATION: The study was approved by the French Ethics Committee (Comite de Protection des Personnes Sud-Est IV) and the national agencies for biomedical studies and for privacy. All participants will give written informed consent. The study findings will be disseminated through the scientific public and serve as a foundation for future randomised controlled trials of efficacy. PMID- 24165031 TI - Sleep well--be well study: improving school transition by improving child sleep: a translational randomised trial. AB - INTRODUCTION: The transition to primary school appears crucial for a child's future academic and psychological well-being. Addressing conditions which negatively affect children during this period, such as poor sleep, may improve these outcomes. Sleep problems are common and in a previous efficacy randomised controlled trial, we demonstrated that sleep problems can be identified and improved using school-based screening followed by a brief behavioural intervention. This trial will determine whether the same intervention is beneficial and cost-effective when delivered by an existing school-based health workforce. METHODS/DESIGN: We will recruit 334 children with sleep problems from approximately 40 schools after screening for behavioural sleep problems in the first year of formal education (Grade Prep). Schools in Melbourne, Australia will be invited to participate from a randomly ordered list of eligible schools and we will approach all caregivers of Grade Prep children. Children who have a parent reported moderate or severe sleep problem will be randomised into either 'usual care' or 'intervention' groups. Trained nurses from the Primary School Nursing programme will deliver the sleep intervention programme. INTERVENTION: Two to three contacts between the nurse and the parent; initial 45 min face-to-face meeting or phone call, 15 min phone call 2 weeks later and an optional second 30 min face-to-face meeting. FOLLOW-UP: 6 and 12 months postrandomisation using parent and teacher surveys and child face-to-face assessments. PRIMARY OUTCOME: child psychosocial functioning at 6 months. SECONDARY OUTCOMES: child psychosocial functioning at 12 months and child sleep, behaviour, working memory, academic achievement and parent mental health at 6 and 12 months. Cost effectiveness analysis will compare incremental costs to difference in child psychosocial functioning at 6 months. REGISTRATION: International Standard Randomised Controlled Trial Number Register (ISRCTN92448857). PMID- 24165032 TI - CPAP: a guide for clinicians in developing countries. AB - Despite the provision of oxygen, antibiotics and treatment guidelines, the case fatality rate for hypoxaemic pneumonia is still high in many hospitals in developing countries. Methods of delivering continuous positive airway pressure (CPAP) are now available which are simple to use, safe and relatively inexpensive. This paper describes two methods which may be appropriate where resources are limited: (i) bubble-CPAP using oxygen concentrators with an air oxygen mix function and low resistance nasal oxygen prongs, and (ii) high-flow nasal cannula oxygen therapy. More research is needed on the implementation, cost and effectiveness of CPAP in the management of pneumonia and in neonatal care in developing countries. PMID- 24165033 TI - Molecular biomarkers of prognosis in melanoma: how far are we from the clinic? PMID- 24165034 TI - Clinicopathological characteristics at primary melanoma diagnosis as risk factors for brain metastasis. AB - To better identify melanoma patients who are, at the time of primary melanoma diagnosis, at high risk of developing brain metastases, primary melanoma characteristics were examined as risk factors for brain metastasis development. In a study of two patient cohorts, clinicopathological characteristics prospectively collected at primary cutaneous melanoma diagnosis for patients with/without brain metastasis were assessed in univariate and multivariate analyses using data from two prospectively collected databases: the Melanoma Cooperative Group (MCG) (1972-1982) and the Interdisciplinary Melanoma Cooperative Group (IMCG) (2002-2009). Candidate risk factors were evaluated in association with time to brain metastasis using either the log-rank test or Cox proportional hazards regression analysis with/without considering competing risks. Out of 2341 total patients included in the study, 222 (9.5%) developed brain metastases (median follow-up: 98 months). The median time to brain metastases was 30.5 months and the median survival time after brain metastases was 4 months. Increased hazard ratios (HRs) for brain metastasis were found among thicker (logarithmic value in mm) (MCG: HR=1.97, P<0.0001; IMCG: HR=1.31, P=0.018), ulcerated (MCG: HR=1.93, P=0.01; IMCG: HR=3.14, P<0.0001), and advanced stage (MCG: HR=2.08, P=0.008; IMCG: HR=2.56, P=0.0002) primary melanomas on the basis of multivariate Cox regression analysis assuming the presence of competing risks. Primary cutaneous melanoma thickness, ulceration, and stage were identified and validated as risk factors associated with time to melanoma brain metastasis. PMID- 24165035 TI - Glycosphingolipids: synthesis and functions. AB - Glycosphingolipids (GSLs) comprise a heterogeneous group of membrane lipids formed by a ceramide backbone covalently linked to a glycan moiety. Hundreds of different glycans can be linked to tens of different ceramide molecules, giving rise to an astonishing variety of structurally different compounds, each of which has the potential for a specific biological function. GSLs have been suggested to modulate membrane-protein function and to contribute to cell-cell communication. Although GSLs are dispensable for cellular life, they are indeed collectively required for the development of multicellular organisms, and are thus considered to be key molecules in 'cell sociology'. Consequently, the GSL make-up of individual cells is highly dynamic and is strictly linked to the cellular developmental and environmental state. In the present review, we discuss some of the available knowledge, open questions and future perspectives relating to the study of GSL biology. PMID- 24165038 TI - Five-year actual survival after pancreatoduodenectomy for pancreatic head cancer. AB - BACKGROUND: The aim of this study was to analyse retrospectively the long-term results of patients who were operated for adenocarcinoma of the pancreatic head and identify significant prognostic factors. METHODS: Eighty patients who were surgically treated for adenocarcinoma of the pancreatic head between 1995 and 2006 met the inclusion criteria and were subject to retrospective analysis. Possible prognostic factors were evaluated and independent predictors of survival were determined. RESULTS: A classic Whipple procedure was performed in 47 patients and a pylorus-preserving pancreatoduodenectomy in 32 patients; one patient underwent total pancreatectomy. Five-year survival rate in this group of patients was 13.6%. Median survival time was 24 months. Univariable analysis demonstrated stage of disease, tumour size and grade and nodal status as significant predictive factors of survival. Multivariable analysis indicated tumour size, nodal status and disease stage as significant prognostic indicators in terms of survival. CONCLUSIONS: Long-term survival in pancreatic cancer is still very low. Prognostic factors include differentiation of the tumour, disease stage and nodal status. So far, there has been no reliable method that can accurately predict which patient will mostly benefit from surgical resection. This means that pancreatic cancer resection should nearly always be attempted. PMID- 24165037 TI - Transcription elongation regulator 1 (TCERG1) regulates competent RNA polymerase II-mediated elongation of HIV-1 transcription and facilitates efficient viral replication. AB - BACKGROUND: Control of RNA polymerase II (RNAPII) release from pausing has been proposed as a checkpoint mechanism to ensure optimal RNAPII activity, especially in large, highly regulated genes. HIV-1 gene expression is highly regulated at the level of elongation, which includes transcriptional pausing that is mediated by both viral and cellular factors. Here, we present evidence for a specific role of the elongation-related factor TCERG1 in regulating the extent of HIV-1 elongation and viral replication in vivo. RESULTS: We show that TCERG1 depletion diminishes the basal and viral Tat-activated transcription from the HIV-1 LTR. In support of a role for an elongation mechanism in the transcriptional control of HIV-1, we found that TCERG1 modifies the levels of pre-mRNAs generated at distal regions of HIV-1. Most importantly, TCERG1 directly affects the elongation rate of RNAPII transcription in vivo. Furthermore, our data demonstrate that TCERG1 regulates HIV-1 transcription by increasing the rate of RNAPII elongation through the phosphorylation of serine 2 within the carboxyl-terminal domain (CTD) of RNAPII and suggest a mechanism for the involvement of TCERG1 in relieving pausing. Finally, we show that TCERG1 is required for HIV-1 replication. CONCLUSIONS: Our study reveals that TCERG1 regulates HIV-1 transcriptional elongation by increasing the elongation rate of RNAPII and phosphorylation of Ser 2 within the CTD. Based on our data, we propose a general mechanism for TCERG1 acting on genes that are regulated at the level of elongation by increasing the rate of RNAPII transcription through the phosphorylation of Ser2. In the case of HIV-1, our evidence provides the basis for further investigation of TCERG1 as a potential therapeutic target for the inhibition of HIV-1 replication. PMID- 24165036 TI - Overexpression of Heat Shock Transcription Factor 1 enhances the resistance of melanoma cells to doxorubicin and paclitaxel. AB - BACKGROUND: Heat Shock Transcription Factor 1 (HSF1) is activated under stress conditions. In turn, it induces expression of Heat Shock Proteins (HSPs), which are well-known regulators of protein homeostasis. Elevated levels of HSF1 and HSPs were observed in many types of tumors. The aim of the present study was to determine whether HSF1 could have an effect on the survival of cancer cells treated with chemotherapeutic cytotoxic agents. METHODS: We constructed mouse (B16F10) and human (1205Lu, WM793B) melanoma cells overexpressing full or mutant form of human HSF1: a constitutively active one with a deletion in regulatory domain or a dominant negative one with a deletion in the activation domain. The impact of different forms of HSF1 on the expression of HSP and ABC genes was studied by RT-PCR and Western blotting. Cell cultures were treated with increasing amounts of doxorubicin, paclitaxel, cisplatin, vinblastine or bortezomib. Cell viability was determined by MTT, and IC50 was calculated. Cellular accumulation of fluorescent dyes and side population cells were studied using flow cytometry. RESULTS: Cells overexpressing HSF1 and characterized by increased HSPs accumulation were more resistant to doxorubicin or paclitaxel, but not to cisplatin, vinblastine or bortezomib. This resistance correlated with the enhanced efflux of fluorescent dyes and the increased number of side population cells. The expression of constitutively active mutant HSF1, also resulting in HSPs overproduction, did not reduce the sensitivity of melanoma cells to drugs, unlike in the case of dominant negative form expression. Cells overexpressing a full or dominant negative form of HSF1, but not a constitutively active one, had higher transcription levels of ABC genes when compared to control cells. CONCLUSIONS: HSF1 overexpression facilitates the survival of melanoma cells treated with doxorubicin or paclitaxel. However, HSF1-mediated chemoresistance is not dependent on HSPs accumulation but on an increased potential for drug efflux by ABC transporters. Direct transcriptional activity of HSF1 is not necessary for increased expression of ABC genes, which is probably mediated by HSF1 regulatory domain. PMID- 24165039 TI - The STAGE technique (superficial tunica albuginea geometric-based excision) for the correction of biplanar congenital penile curvature. AB - INTRODUCTION: Congenital penile curvature can present with both uniplanar and biplanar defects, the latter of which entails more technically demanding surgery. AIM: The study aims to demonstrate the efficacy and safety of our novel superficial tunica albuginea geometric-based excision (STAGE) technique based on multiple, small, superficial elliptical tunica albuginea excisions and geometrical principles for correcting biplanar congenital penile curvature. METHODS: The study represents a retrospective analysis of 145 patients with disabling congenital biplanar ventrolateral (n = 131; 90.3%) or dorsolateral (n = 14; 9.7%) curvature of the penis, which underwent stepwise STAGEs between June 2006 and March 2012. Multiple 3-mm elliptical excisions of the superficial tunica albuginea were performed without compromising the inner layer of the tunica albuginea, thus resulting in a stepwise correction of the curvature and improved distribution of the bending force of the curvature. MAIN OUTCOME MEASURES: Functional outcome regarding penile straightening, erectile function, and patient satisfaction were evaluated. Furthermore, clinical data concerning the early postoperative outcome were analyzed retrospectively. RESULTS: The mean follow-up period was 21 months (range 6-62 months). Mean age at surgery was 23.8 years (range 15-47 years). Mean degree of curvature was 65 degrees (range 45-90 degrees ). There was no recurrent curvature. Complete correction of the penile axis was obtained in 98.6% (n = 143). No change in erectile function according to International Index of Erectile Function-5 score was visible (P = 0.748). The mean loss of penile length was 0.7 cm (range 0.3-0.9 cm). The excellent functional outcomes resulted in a high level of patient satisfaction, including improved self-esteem, libido, sexual intercourse, and psychosexual relief. Two patients had a residual curvature of up to 30 degrees requiring a reoperation. No intra- or postoperative complications were encountered. CONCLUSIONS: We recommend the STAGE technique as the optimal surgical intervention for correcting both uniplanar and biplanar congenital deviations. PMID- 24165041 TI - Preliminary estimation of the prevalence of chemotherapy-induced dysgeusia in Japanese patients with cancer. AB - BACKGROUND: Although dysgeusia is a common adverse event in chemotherapy patients; it has not been evaluated using objective methods, and its prevalence and frequency have not been quantified. METHODS: Salt-impregnated taste strips were used to objectively assess dysgeusia in patients receiving chemotherapy at Akita University (n = 38) and those off chemotherapy (n = 9). Participant characteristics, and ongoing and previous chemotherapies were evaluated, and their associations with dysgeusia analyzed. RESULTS: Dysgeusia developed in 38.8% (14/38) of chemotherapy patients, and was most prevalent in patients receiving 5 fluorouracil (5-FU) or its oral analogs (48.1%, 13/27). Particularly, dysgeusia developed in 55.6% (10/18) of patients receiving oral 5-FU analogs; however, prevalence in patients receiving and off chemotherapy was not significantly different. Patients aged >=70 years also tended to experience dysgeusia (75.0%, 6/8). CONCLUSIONS: Association with dysgeusia may be higher for some chemotherapeutic drugs. Dysgeusia should be routinely assessed in chemotherapy patients with objective methods such as paper strips; interventions for its prevention may be required. PMID- 24165042 TI - Normothermic acellular ex vivo liver perfusion (NEVLP) reduces liver and bile duct in DCD liver grafts. PMID- 24165043 TI - Novel system using microliter order sample volume for measuring arterial radioactivity concentrations in whole blood and plasma for mouse PET dynamic study. AB - This study aimed to develop a new system, named CD-Well, for mouse PET dynamic study. CD-Well allows the determination of time-activity curves (TACs) for arterial whole blood and plasma using 2-3 uL of blood per sample; the minute sample size is ideal for studies in small animals. The system has the following merits: (1) measures volume and radioactivity of whole blood and plasma separately; (2) allows measurements at 10 s intervals to capture initial rapid changes in the TAC; and (3) is compact and easy to handle, minimizes blood loss from sampling, and delay and dispersion of the TAC. CD-Well has 36 U-shaped channels. A drop of blood is sampled into the opening of the channel and stored there. After serial sampling is completed, CD-Well is centrifuged and scanned using a flatbed scanner to define the regions of plasma and blood cells. The length measured is converted to volume because the channels have a precise and uniform cross section. Then, CD-Well is exposed to an imaging plate to measure radioactivity. Finally, radioactivity concentrations are computed. We evaluated the performance of CD-Well in in vitro measurement and in vivo (18)F fluorodeoxyglucose and [(11)C]2-carbomethoxy-3beta-(4-fluorophenyl) tropane studies. In in vitro evaluation, per cent differences (mean+/-SE) from manual measurement were 4.4+/-3.6% for whole blood and 4.0+/-3.5% for plasma across the typical range of radioactivity measured in mouse dynamic study. In in vivo studies, reasonable TACs were obtained. The peaks were captured well, and the time courses coincided well with the TAC derived from PET imaging of the heart chamber. The total blood loss was less than 200 uL, which had no physiological effect on the mice. CD-Well demonstrates satisfactory performance, and is useful for mouse PET dynamic study. PMID- 24165044 TI - Novel MRI tests of orocecal transit time and whole gut transit time: studies in normal subjects. AB - BACKGROUND: Colonic transit tests are used to manage patients with Functional Gastrointestinal Disorders. Some tests used expose patients to ionizing radiation. The aim of this study was to compare novel magnetic resonance imaging (MRI) tests for measuring orocecal transit time (OCTT) and whole gut transit time (WGT), which also provide data on colonic volumes. METHODS: 21 healthy volunteers participated. Study 1: OCTT was determined from the arrival of the head of a meal into the cecum using MRI and the Lactose Ureide breath test (LUBT), performed concurrently. Study 2: WGT was assessed using novel MRI marker capsules and radio opaque markers (ROMs), taken on the same morning. Studies were repeated 1 week later. KEY RESULTS: OCTT measured using MRI and LUBT was 225 min (IQR 180-270) and 225 min (IQR 165-278), respectively, correlation r(s) = 0.28 (ns). WGT measured using MRI marker capsules and ROMs was 28 h (IQR 4-50) and 31 h +/- 3 (SEM), respectively, correlation r(s) = 0.85 (p < 0.0001). Repeatability assessed using the intraclass correlation coefficient (ICC) was 0.45 (p = 0.017) and 0.35 (p = 0.058) for MRI and LUBT OCTT tests. Better repeatability was observed for the WGT tests, ICC being 0.61 for the MRI marker capsules (p = 0.001) and 0.69 for the ROM method (p < 0.001) respectively. CONCLUSIONS & INFERENCES: The MRI WGT method is simple, convenient, does not use X-ray and compares well with the widely used ROM method. Both OCTT measurements showed modest reproducibility and the MRI method showed modest inter-observer agreement. PMID- 24165045 TI - The significance of the alteration of 8-OHdG in serous ovarian carcinoma. AB - BACKGROUND: Oxidative damage and DNA repair dysfunction are associated with carcinogenesis. 8-OHdG is one of the major oxidative DNA adducts. Present work aims to investigate whether the expression of 8-OHdG and its key repair gene hOGG1 play distinctive role in two types of serous ovarian cancer. MATERIALS AND METHODS: 8-OHdG level in DNA from tumor and matched tumor-adjacent normal tissue in 48 high-grade papillary serous carcinomas (HG-SOC), 24 low-grade papillary serous carcinomas (LG-SOC), 20 serous cystadenomas, and 16 non-tumor control ovaries was tested. The Cox proportional hazards model and the log-rank test were used to assess the associations between the 8-OHdG level in two types of serous cancer and patients' survival. Real-time polymerase chain reaction and protein immunoblot were employed to detect hOGG1 mRNA and protein levels in tumor and adjacent normal tissues. Immunohistochemistry was used to determine the expression of hOGG1 and p53. RESULTS: There was no difference of average 8 OHdG/106dG DNA level either between HG-SOC (27.8 +/- 8.9), LG-SOC (25.2 +/- 7.4) and benign serous cystadenoma (26.5 +/- 7.7, p = 0.35); or between the tumor adjacent normal tissue of HG-SOC (18.8 +/- 5.2), LG-SOC (21.4 +/- 6.5), benign serous cystadenoma (20.5 +/- 9.1) and non-tumor ovary (21.6 +/- 4.9, p = 0.62). The 8-OHdG/106dG level was significantly higher in tumor comparing to that in matched normal tissue adjacent to carcinoma in HG-SOC (1.52 +/- 0.52, p = 0.02), but not in LG-SOC or benign serous cystadenoma. Increased level of 8-OHdG in tumor DNA was an independent factor of overall survival in serous ovarian carcinoma upon multivariate analysis (p < 0.01). Increased level of 8-OHdG in tumor DNA indicates poorer overall and progression-free survival durations than counterparts (47.3 vs 105.7 months and 13.5 vs 45.3 months, respectively). Protein levels of hOGG1 were remarkably decreased in HG-SOC (p < 0.01), but not in LG-SOC and serous cystadenoma compared with the tissue adjacent to carcinoma. A positive result on p53 immunostaining was associated with lower hOGG1 expression in HG-SOC (p = 0.04). CONCLUSION: Increased 8-OHdG level and decreased expression of hOGG1 in tumor were found in HG-SOC but not LG-SOC. Increased 8 OHdG level in tumor DNA was significantly associated with poorer overall survival and progression-free survival in serous ovarian carcinoma. PMID- 24165046 TI - Vaccine-mediated protection against Helicobacter pylori is not associated with increased salivary cytokine or mucin expression. AB - BACKGROUND: The development of an effective vaccine against Helicobacter pylori is impeded by the inability to reliably produce sterilizing immunity and our lack of knowledge regarding mechanisms of protective immunity against this pathogen. It has previously been described that salivary glands are essential for vaccine mediated protection against H. pylori, but the mechanism responsible for this effect has not been identified. In this study we tested the hypothesis that vaccines reduce H. pylori colonization by inducing an immune-mediated change in salivary gland mucin secretion. MATERIALS AND METHODS: Sublingual and submandibular salivary glands were removed from untreated mice, from mice infected with H. pylori and from mice vaccinated against H. pylori then challenged with live bacteria. Cytokine levels in these salivary glands were quantified by ELISA, and salivary mucins were quantified by real-time PCR. Salivary antibody responses were determined by Western blot. RESULTS: Vaccine mediated protection against H. pylori did not produce any evidence of a positive increase in either salivary cytokine or mucin levels. In fact, many cytokines were significantly reduced in the vaccinated/challenged mice, including IL-17A, IL-10, IL-1beta, as well as the mucin Muc10. These decreases were associated with an increase in total protein content within the salivary glands of vaccinated mice which appeared to be the result of increased IgA production. While this study showed that vaccination increased salivary IgA levels, previous studies have demonstrated that antibodies do not play a critical role in protection against H. pylori that is induced by current vaccine formulations and regimes. CONCLUSIONS: The effector mechanism of protective immunity induced by vaccination of mice did not involve immune changes within the salivary glands, nor increased production of salivary mucins. PMID- 24165047 TI - The effect of the sympathetic nervous system on splenic natural killer cell activity in mice administered the Lactobacillus pentosus strain S-PT84. AB - Splenic sympathetic nerve activity (SNA) modulates cellular immune functions such as splenic natural killer cell activity. Lactobacillus pentosus strain S-PT84 enhances splenic natural killer cell activity. Here, we examined whether S-PT84 affects splenic natural killer activity through splenic SNA in BALB/c mice. Splenic SNA was significantly decreased following the administration of S-PT84. This phenomenon was inhibited by pretreatment with thioperamide (histamine H3 receptor antagonist), suggesting that S-PT84 directly affected splenic SNA. Thioperamide also inhibited the increase in splenic natural killer activity by S PT84. Thus, the change in splenic natural killer activity by S-PT84 may be partially modulated through SNA. PMID- 24165048 TI - Calcium/calmodulin-dependent protein kinase II in dorsal horn neurons in long term diabetes. AB - The aim of this study was to investigate the expression of total calcium/calmodulin-dependent protein kinase II (CaMKII) and its phosphorylated alpha isoform in the dorsal horn of the spinal cord in an animal model of long term diabetes. Diabetes was induced in Sprague-Dawley rats using 55 mg/kg streptozotocin, and expression of total CaMKII, the phosphorylated alpha-CaMKII isoform, and isolectin B4 was analyzed by immunohistochemical analysis in the dorsal horn of the spinal cord 6 and 12 months after diabetes induction. Results were compared with those for control rats of the same age. Increased expression of total CaMKII and its activated alpha isoform was seen in the dorsal horn of diabetic rats 6 months after diabetes induction. The increase in CaMKII fluorescence was restored to control values after 12 months. The expression of activated alpha-CaMKII 12 months after diabetes induction was most pronounced in laminae I-VI of the dorsal horn, not corresponding with the highest expression of isolectin B4 in laminae I-III. Increased expression of CaMKII in the dorsal horn during long-term diabetes could be involved in the development of neuropathic symptoms in diabetes. The expression pattern of CaMKII during long-term diabetes indicates that it affects the entire sensory input. PMID- 24165049 TI - Peripheral nerve adjustment for postherpetic neuralgia: a randomized, controlled clinical study. AB - OBJECTIVE: To observe the therapeutic effect of peripheral nerve adjustment for the treatment of postherpetic neuralgia (PHN). METHODS: One hundred and two patients with PHN were randomly assigned to three groups; the control group (A), the experimental group (B), which was subjected to peripheral nerve adjustment, and patients who received a sham peripheral nerve adjustment, thus serving as a positive control group (C). The patients' Visual Analogue Scale (VAS) and total oral rescue dosage for pain management were recorded at days 1, 3, 7, 14, and 28 following treatment. Quality of life (QOL), 36-Item Short-Form Health Survey (SF 36), and side effects were recorded following treatment. RESULTS: We observed that the average VAS score was significantly lower in the treatment group (B) than in the control groups A and C following treatment (P < 0.05). In addition, the QOL and SF-36 scores for group B improved substantially following treatment compared to groups A and C, and this effect was maintained up to 180 days after treatment (P < 0.05). The average dosage of pain medication was also lower in group B, compared to groups A and C, following treatment (P < 0.05). CONCLUSIONS: We conclude that peripheral nerve adjustment can relieve PHN pain and improve patients' quality of life. The possible mechanisms involved may include the reduction of both peripheral and central sensitization, the modulation of nerve plasticity, and an increase in endogenous analgesic molecules. PMID- 24165050 TI - Challenges for an enzymatic reaction kinetics database. AB - The scientific literature contains a tremendous amount of kinetic data describing the dynamic behaviour of biochemical reactions over time. These data are needed for computational modelling to create models of biochemical reaction networks and to obtain a better understanding of the processes in living cells. To extract the knowledge from the literature, biocurators are required to understand a paper and interpret the data. For modellers, as well as experimentalists, this process is very time consuming because the information is distributed across the publication and, in most cases, is insufficiently structured and often described without standard terminology. In recent years, biological databases for different data types have been developed. The advantages of these databases lie in their unified structure, searchability and the potential for augmented analysis by software, which supports the modelling process. We have developed the SABIO-RK database for biochemical reaction kinetics. In the present review, we describe the challenges for database developers and curators, beginning with an analysis of relevant publications up to the export of database information in a standardized format. The aim of the present review is to draw the experimentalist's attention to the problem (from a data integration point of view) of incompletely and imprecisely written publications. We describe how to lower the barrier to curators and improve this situation. At the same time, we are aware that curating experimental data takes time. There is a community concerned with making the task of publishing data with the proper structure and annotation to ontologies much easier. In this respect, we highlight some useful initiatives and tools. PMID- 24165051 TI - Ectopic pregnancy implanted over the uterine artery. PMID- 24165052 TI - Core outcomes for clinical trials: moving ahead. PMID- 24165053 TI - Letter to the editor: web-based education for placental complications of pregnancy. PMID- 24165054 TI - Letter to the editor: in response. PMID- 24165055 TI - Mode of delivery following successful external cephalic version: comparison with spontaneous cephalic presentations at delivery. AB - OBJECTIVE: To compare the obstetric outcomes of pregnant women after successful external cephalic version (ECV) (cases) with a large group of pregnant women with a spontaneously occurring cephalic fetal position at delivery (controls). METHODS: We conducted a retrospective matched cohort study in a teaching hospital in the Netherlands. Delivery outcomes of women with a successful ECV were compared with those of women with spontaneously occurring cephalic presentations, controlling for maternal age, parity, gestational age at delivery, and onset of labour (spontaneous or induced). Exclusion criteria were a history of Caesarean section, delivery at < 35 weeks, and elective Caesarean section. The primary outcome was the prevalence of Caesarean section and instrumental delivery in both groups; secondary outcomes were the characteristics of cases requiring intervention such as Caesarean section or instrumental delivery. RESULTS: Women who had a successful ECV had a significantly higher Caesarean section rate than the women in the control group (33/220 [15%] vs. 62/1030 [6.0 %]; P < 0.001). There was no difference in the incidence of instrumental delivery (20/220 [9.1%] vs. 103/1030 [10%]). Comparison of characteristics of women in the cases group showed that nulliparity, induction of labour, and occiput posterior presentation were associated with Caesarean section and instrumental deliveries. CONCLUSION: Compared with delivery of spontaneous cephalic presenta-tions, delivery of cephalic presenting babies following successful ECV is associated with an increased rate of Caesarean section, especially in nulliparous women and women whose labour is induced. PMID- 24165056 TI - Predictors and clinical implications of a false negative glucose challenge test in pregnancy. AB - OBJECTIVE: A common approach to screening for glucose intolerance in pregnant women is the use of a 50g glucose challenge test (GCT) in the late second trimester, followed by a diagnostic oral glucose tolerance test (OGTT) when the GCT is positive (1-hour post-challenge blood glucose >= 7.8 mmol/L). As women with a negative GCT do not undergo the diagnostic OGTT, it is possible that they could have undiagnosed gestational diabetes (GDM) or gestational impaired glucose tolerance (GIGT). Thus, we sought to characterize predictors of a false negative GCT and its clinical implications. METHODS: Two hundred two women with a negative GCT screening test underwent subsequent OGTT, which enabled their stratification into two groups: (1) those with normal glucose tolerance on OGTT (n = 166) and (2) those with either GDM (n = 8) or GIGT (n = 28). RESULTS: The 36 women found to have GDM or GIGT at the time of OGTT had higher GCT glucose values than those with normal glucose tolerance (mean 6.6 mmol/L vs. 5.9 mmol/L, P < 0.001), as well as poorer insulin sensitivity (P = 0.004) and pancreatic beta-cell function (P < 0.001). On logistic regression analysis, the only significant independent predictor of GDM/GIGT was the GCT glucose value (OR 2.19; 95% CI 1.40 to 3.41, P < 0.001). However, there was no clear GCT glucose threshold for identifying GDM/GIGT, consistent with its modest area under the receiver operating characteristic curve (0.71). Importantly, there were also no differences between the two groups in median length of gestation, median birth weight, prevalence of macrosomia, or proportion of low Apgar scores. CONCLUSION: False negative GCTs cannot be readily predicted by risk factors. However, their clinical implications at delivery may be benign. PMID- 24165057 TI - Understanding the pregnancy decision-making process among couples seeking induced abortion. AB - OBJECTIVE: The role of partners in the abortion experience is complex and poorly understood. We sought to examine how women and their partners navigate the pregnancy decision-making process. METHODS: Thirty couples presenting for abortion completed questionnaires exploring experiences leading to the abortion. Participants were sequestered from their partners during completion of the study, and booklets were coded to allow comparison within couples. This portion of the study explored partner involvement in the decision-making process. RESULTS: One half of women had decided on abortion before informing their partner of the pregnancy. Of those who were undecided at the time of disclosure, all sought their partner's advice. Most participants (84%) were happy with the amount of discussion that took place with their partners, although one fifth of women and nearly one third of men could have discussed it more. More women than men were happy with the discussions that took place (96.6% vs. 70.4%). Two thirds of respondents viewed the decision to have an abortion as being made by both partners, one quarter viewed the decision as being mostly the woman's choice, and 5% viewed the decision as being mostly the male partner's choice. CONCLUSION: Although making the choice to have an abortion rests with the woman, her partner may play a role in the decision-making process, particularly when the woman is undecided. For many couples presenting for abortion, the decision is seen as being made jointly by both partners. Further research may identify opportunities to foster greater partner support throughout a woman's abortion experience. PMID- 24165058 TI - Maternal and newborn health profile in a first nations community in Canada. AB - OBJECTIVES: We sought to characterize maternal health profiles and birth outcomes among First Nations people living in Southern Ontario. METHODS: We performed a retrospective chart review of all 453 women from the Six Nations Reserve, Ontario, who were pregnant between 2005 and 2010. Maternal health behaviours, past medical history, physical measurements, birth outcomes, and newborn characteristics were abstracted. Key maternal and newborn characteristics were compared with those of a cohort of non-First Nations women recruited from nearby Hamilton, Ontario. RESULTS: The average age of women in the study cohort was 25.1 +/- 6.2 (mean +/- SD) years, and 75.8% were multiparous. The mean pre-pregnancy BMI was 28.3 +/- 6.6 kg/m(2), and the average weight gain in pregnancy was 14.9 +/- 8.3 kg. Mean weight gain during pregnancy was inversely associated with pre pregnancy BMI, and 57.1% of women gained more than the recommended weight. The prevalence of type 2 diabetes or gestational diabetes was 4.7%, hypertension was present before or during pregnancy in 5.6%, and 35% used tobacco during pregnancy. The mean gestational age at delivery was 39.5 +/- 1.7 weeks and the mean crude birth weight was 3619 +/- 557 g. The main determinants of newborn weight included sex of the newborn, pre-pregnancy BMI, and weight gain during pregnancy. Compared with a contemporary cohort of 622 non-First Nations mothers and newborns, First Nations mothers were, on average, younger (25.1 vs. 32.1 years; P < 0.001), had a higher mean pre-pregnancy BMI (28.3 vs. 26.8 kg/m(2); P < 0.001), and were more likely to use tobacco during pregnancy (35.0% vs. 14.4%; P < 0.001). First Nations newborns had significantly higher mean birth weight (+176 grams) and length (+2.3 cm) than non-First Nations newborns. CONCLUSION: First Nations mothers from the Six Nations Reserve tended to have a high pre pregnancy BMI, tended to gain more than the recommended weight during pregnancy, and commonly used tobacco during pregnancy. Programs to prevent overweight/obesity and excess weight gain during pregnancy and to minimize smoking are required among women of child-bearing age in this community. PMID- 24165059 TI - Complete chorioamniotic separation and persistence of a yolk sac associated with triploidy. AB - BACKGROUND: Triploidy is a highly lethal condition, and is thus very rarely observed in live births. It may result in significant medical risk to the pregnant woman. CASE: A 32-year-old multigravid woman presented for prenatal care. Ultrasound examination at 14+3 weeks of gestation revealed a viable fetus with appropriate fetal biometry, but with evidence of chorioamniotic separation (CAS) and persistence of the yolk sac. Two weeks later, repeat ultrasound showed a large multicystic placenta and early fetal symmetrical growth restriction with persistence of CAS and yolk sac, raising the suspicion of fetal aneuploidy. Amniocentesis showed a fetal karyotype of 69,XXX. The histology of the placental tissue was a partial hydatidiform mole. CONCLUSION: Persistence of chorioamniotic separation and yolk sac during the early second trimester cannot be considered a reassuring finding. In such cases, fetal karyotyping should be considered, especially when an additional abnormality is found. PMID- 24165060 TI - Successful pregnancy, epidural anaesthesia, labour, and delivery in a woman with Sturge-Weber syndrome and previous hemispherectomy. AB - BACKGROUND: The outcomes of pregnancy and subsequent delivery of healthy neonates in women who have undergone previous near total hemispherectomy for Sturge-Weber syndrome (SWS) have rarely been reported. CASE: A woman with SWS had two successful and uncomplicated pregnancies and deliveries under epidural anaesthesia after undergoing a near total hemispherectomy with subsequent unilateral cerebral palsy. Non-contrast MRI of the brain revealed post hemispherectomy changes with no residual meningeal angiomatosis. CONCLUSION: As more women who undergo surgical resection for underlying SWS grow into the child bearing years, additional reports of pregnancy and delivery outcomes in this patient population can be expected and will be valuable. PMID- 24165061 TI - Fetal pharmacotherapy 1: prenatal glucocorticoids. PMID- 24165062 TI - Investigation and management of non-immune fetal hydrops. AB - OBJECTIVE: To describe the current investigation and management of non-immune fetal hydrops, with a focus on treatable or recurring etiologies. OUTCOMES: To provide better counselling and management in cases of prenatally diagnosed non immune hydrops. EVIDENCE: Published literature was retrieved through searches of PubMed or MEDLINE, CINAHL, and The Cochrane Library in 2011 using key words (non immune hydrops fetalis, fetal hydrops, fetal therapy, fetal metabolism). Results were restricted to systematic reviews, randomized controlled trials/controlled clinical trials, observational studies, and significant case reports. Additional publications were identified from the bibliographies of these articles. There were no date or language restrictions. Searches were updated on a regular basis and incorporated in the guideline to May 2012. Grey (unpublished) literature was identified through searching the websites of health technology assessment and health technology-related agencies, clinical practice guideline collections, clinical trial registries, and national and international medical specialty societies. BENEFITS, HARMS, AND COSTS: These guidelines educate readers about the causes of non-immune fetal hydrops and its prenatal counselling and management. It also provides a standardized approach to non-immune fetal hydrops, emphasizing the search for prenatally treatable conditions and recurrent genetic etiologies. VALUES: The quality of evidence in this document was rated using the criteria described in the Report of the Canadian Task Force on Preventive Health Care (Table 1). RECOMMENDATIONS: 1. All patients with fetal hydrops should be referred promptly to a tertiary care centre for evaluation. Some conditions amenable to prenatal treatment represent a therapeutic emergency after 18 weeks. (II-2A) 2. Fetal chromosome analysis and genetic microarray molecular testing should be offered where available in all cases of non-immune fetal hydrops. (II-2A) 3. Imaging studies should include comprehensive obstetrical ultrasound (including arterial and venous fetal Doppler) and fetal echocardiography. (II-2A) 4. Investigation for maternal-fetal infections, and alpha-thalassemia in women at risk because of their ethnicity, should be performed in all cases of unexplained fetal hydrops. (II-2A) 5. To evaluate the risk of fetal anemia, Doppler measurement of the middle cerebral artery peak systolic velocity should be performed in all hydropic fetuses after 16 weeks of gestation. In case of suspected fetal anemia, fetal blood sampling and intrauterine transfusion should be offered rapidly. (II-2A) 6. All cases of unexplained fetal hydrops should be referred to a medical genetics service where available. Detailed postnatal evaluation by a medical geneticist should be performed on all cases of newborns with unexplained non-immune hydrops. (II-2A) 7. Autopsy should be recommended in all cases of fetal or neonatal death or pregnancy termination. (II-2A) Amniotic fluid and/or fetal cells should be stored for future genetic testing. (II-2B). PMID- 24165063 TI - The prevention of early-onset neonatal group B streptococcal disease. AB - OBJECTIVE: To review the evidence in the literature and to provide recommendations on the management of pregnant women in labour for the prevention of early-onset neonatal group B streptococcal disease. The key revisions in this updated guideline include changed recommendations for regimens for antibiotic prophylaxis, susceptibility testing, and management of women with pre-labour rupture of membranes. OUTCOMES: Maternal outcomes evaluated included exposure to antibiotics in pregnancy and labour and complications related to antibiotic use. Neonatal outcomes of rates of early-onset group B streptococcal infections are evaluated. EVIDENCE: Published literature was retrieved through searches of MEDLINE, CINAHL, and The Cochrane Library from January 1980 to July 2012 using appropriate controlled vocabulary and key words (group B streptococcus, antibiotic therapy, infection, prevention). Results were restricted to systematic reviews, randomized control trials/controlled clinical trials, and observational studies. There were no date or language restrictions. Searches were updated on a regular basis and incorporated in the guideline to May 2013. Grey (unpublished) literature was identified through searching the websites of health technology assessment and health technology-related agencies, clinical practice guideline collections, clinical trial registries, and national and international medical specialty societies. VALUES: The quality of evidence in this document was rated using the criteria described in the Report of the Canadian Task Force on Preventive Health Care (Table 1). BENEFITS, HARMS, AND COSTS: The recommendations in this guideline are designed to help clinicians identify and manage pregnancies at risk for neonatal group B streptococcal disease to optimize maternal and perinatal outcomes. No cost-benefit analysis is provided. SUMMARY STATEMENT: There is good evidence based on randomized control trial data that in women with pre-labour rupture of membranes at term who are colonized with group B streptococcus, rates of neonatal infection are reduced with induction of labour. (I) There is no evidence to support safe neonatal outcomes with expectant management in this clinical situation. RECOMMENDATIONS: 1. Offer all women screening for colonization with group B streptococcus at 35 to 37 weeks' gestation with culture taken from one swab first to the vagina and then to the rectum (through the anal sphincter). (II-1A) This includes women with planned Caesarean delivery because of their risk of labour or ruptured membranes earlier than the scheduled Caesarean delivery. (II-2B) 2. Because of the association of heavy colonization with early onset neonatal disease, provide intravenous antibiotic prophylaxis for group B streptococcus at the onset of labour or rupture of the membranes to: * any woman positive for group B streptococcus by vaginal/rectal swab culture screening done at 35 to 37 weeks' gestation (II-2B); * any woman with an infant previously infected with group B streptococcus (II 3B); * any woman with documented group B streptococcus bacteriuria (regardless of level of colony-forming units) in the current pregnancy. (II-2A) 3. Manage all women who are < 37 weeks' gestation and in labour or with rupture of membranes with intravenous group B streptococcus antibiotic prophylaxis for a minimum of 48 hours, unless there has been a negative vaginal/rectal swab culture or rapid nucleic acid-based test within the previous 5 weeks. (II-3A) 4. Treat all women with intrapartum fever and signs of chorioamnionitis with broad spectrum intravenous antibiotics targeting chorioamnionitis and including coverage for group B streptococcus, regardless of group B streptococcus status and gestational age. (II-2A) 5. Request antibiotic susceptibility testing on group B streptococcus-positive urine and vaginal/rectal swab cultures in women who are thought to have a significant risk of anaphylaxis from penicillin. (II-1A) 6. If a woman with pre-labour rupture of membranes at >= 37 weeks' gestation is positive for group B streptococcus by vaginal/rectal swab culture screening, has had group B streptococcus bacteriuria in the current pregnancy, or has had an infant previously affected by group B streptococcus disease, administer intravenous group B streptococcus antibiotic prophylaxis. Immediate obstetrical delivery (such as induction of labour) is indicated, as described in the Induction of Labour guideline published by the Society of Obstetricians and Gynaecologist in September 2013. (II-2B) 7. At >= 37 weeks' gestation, if group B streptococcus colonization status is unknown and the 35- to 37-week culture was not performed or the result is unavailable and the membranes have been ruptured for greater than 18 hours, administer intravenous group B streptococcus antibiotic prophylaxis. (II-2B) 8. If a woman with pre-labour rupture of membranes at < 37 weeks' gestation has an unknown or positive group B streptococcus culture status, administer intravenous group B streptococcus prophylaxis for 48 hours, as well as other antibiotics if indicated, while awaiting spontaneous or obstetrically indicated labour. (II-3B). PMID- 24165065 TI - Nursing in Critical Care. What's in this issue? PMID- 24165064 TI - Total and high-density lipoprotein cholesterol in adults: National Health and Nutrition Examination Survey, 2011-2012. AB - High levels of total cholesterol and low levels of high-density lipoprotein (HDL) cholesterol (the "good cholesterol") are risk factors for coronary heart disease (1-5). To identify persons who may be at risk for developing coronary heart disease, adults are advised to have their cholesterol checked at least once every 5 years (i.e., to be screened for cholesterol) (6). A previous study reported declining trends in the percentage of adults with high total cholesterol during 1999-2010 (7). This report presents estimates of the percentages of adults aged 20 and over with high total cholesterol, low HDL cholesterol, and screened for cholesterol, based on data from 2011-2012, and compares them with corresponding estimates from 2009-2010. Analysis is based on measured cholesterol only and does not take into account whether lipid-lowering medications were taken. PMID- 24165066 TI - Building emotional resilience: small steps towards big change. PMID- 24165067 TI - Building a community of practice in critical care nursing. PMID- 24165068 TI - Touch massage: a pilot study of a complex intervention. AB - OBJECTIVES: To report and evaluate a complex touch massage intervention according to the British Medical Research Council framework. This study aimed to evaluate the effects of touch massage on levels of anxiety and physiological stress in patients scheduled for elective aortic surgery. BACKGROUND: The use of touch massage has increased during the past decade but no systematic studies have been implemented to investigate the effectiveness of such treatment. It is important to conduct multidisciplinary investigations into the effects of complex interventions such as touch massage. For this, the British Medical Research Council has provided a useful framework to guide the development, piloting, evaluation and reporting of complex intervention studies. METHOD: A pilot study with a randomized controlled design including 20 patients (10 + 10) scheduled for elective aortic surgery. Selected outcome parameters included; self-reported anxiety, measured by the State-Trait Anxiety Inventory Form Y instrument, and physiological stress, measured by heart rate variability, blood pressure, respiratory frequency, oxygen saturation and concentrations of cortisol, insulin and glucose in serum. RESULTS: There were significant differences in self reported anxiety levels before and after touch massage (p = 0.007), this was not observed in the control group (p = 0.833). There was a significant difference in self-reported anxiety levels between the touch massage group and the control group after touch massage and rest (p = 0.001). There were no significant differences in physiological stress-related outcome parameters between patients who received touch massage and controls. CONCLUSION: In our study, touch massage decreased anxiety levels in patients scheduled for elective aortic surgery, and the British Medical Research Council framework was a useful guideline for the development, evaluation and reporting of a touch massage intervention. RELEVANCE TO CLINICAL PRACTICE: Touch massage can reduce patients' anxiety levels and is thus an important nursing intervention in intensive and post-operative care. PMID- 24165069 TI - Caring and technology in an intensive care unit: an ethnographic study. AB - BACKGROUND: Critical care practice is a mixture of caring and technological activities. There is debate about whether the balance between these two elements is correct and a concern that critical care units can dehumanize the patient. This research sought to examine aspects that might affect this balance between the caring and technology within the critical care setting. AIM: What aspects affect registered health care professionals' ability to care for patients within the technological environment of a critical care unit? METHODOLOGY: A qualitative approach using ethnography was utilized as this methodology focuses on the cultural elements within a situation. Data collection involved participant observation, document review and semi-structured interviews to triangulate methods as this aids rigour for this approach. A purposeful sample to examine registered health care professionals currently working within the study area was used. A total of 19 participants took part in the study; 8 nurses were observed and 16 health care professionals were interviewed, including nurses, a doctor and 2 physiotherapists. The study took place on a District General Hospital intensive care unit and ethical approval was gained. FINDINGS: An overarching theme of the 'Crafting process' was developed with sub themes of 'vigilance', 'focus of attention, 'being present' and 'expectations' with the ultimate goal of achieving the best interests for the individual patient. CONCLUSION: The areas reflected in this study coincide with the care, compassion, competency, commitment, communication and courage ideas detailed by the Department of Health (2012). Thus, further research to detail more specifically how these areas are measured within critical care may be useful. RELEVANCE TO PRACTICE: Caring is a complex concept that is difficult to outline but this article can inform practitioners about the aspects that help and hinder caring in the technical setting to inform training. PMID- 24165070 TI - Patients' and relatives' experiences of transfer from intensive care unit to wards. AB - AIMS: This literature review looks at the evidence around transferring patients from intensive care units (ICU) to wards. The literature informs us that patients and their families experience problems when being transferred from an ICU environment and that this increases overall anxiety. BACKGROUND: The effects of surviving critical illness often have a profound psychological impact on patients and families This study examines the experiences of adult patients, and their families, following their transfer from the ICU to the ward. FINDINGS: Five themes emerged from this literature review: physical responses, psychological responses, information and communication, safety and security, and the needs of relatives. CONCLUSIONS: This review reminds us that these problems can be reduced if information and communication around time of transfers were improved. RELEVANCE TO CLINICAL PRACTICE: As critical care nurses it is essential that we prepare patients and families for transfer to wards. PMID- 24165071 TI - Staff perception of patient discharge from ICU to ward-based care. AB - BACKGROUND: The quality of information exchange between intensive care unit (ICU) and ward nurses, when patients are transferred out of intensive care, is important to the continuity of safe care. AIM: This research aimed to explore nurses' experiences of the discharge process from ICU to the ward environment. DESIGN: The study was conducted in a New Zealand Metropolitan hospital, using an exploratory descriptive design we adapted a questionnaire based on Whittaker and Ball's research on ICU patient handover. METHOD: The questionnaires were then analysed using a descriptive thematic approach. RESULTS: The response rate of 48% included 45 ICU and 47 ward nurses. Key findings were that the written and verbal communication needs differ dependent upon setting and the timing of a discharge. Timing of handover also requires negotiation. CONCLUSIONS: Being able to negotiate the timing and nature of handover is important for nurses. In addition, standardized approaches to communication are believed to enhance patient safety. RELEVANCE TO CLINICAL PRACTICE: Standardized handover, with content and processes that are mutually negotiated, is crucial to providing the safest environment for patients. PMID- 24165072 TI - Patients and ICU nurses' perspectives of non-pharmacological interventions for pain management. AB - BACKGROUND: Pain is a major stressor for critically ill patients. To maximize pain relief, non-pharmacological interventions are an interesting avenue to explore. AIMS AND OBJECTIVES: The study aim was to describe the perspectives of patients/family members and nurses about the usefulness, relevance and feasibility of non-pharmacological interventions for pain management in the intensive care unit (ICU). DESIGN: A qualitative descriptive design was used. METHODS: Patients/family members (n = 6) with a previous experience of ICU hospitalization and ICU nurses (n = 32) were recruited. Using a semi-structured discussion guide, participants were asked to share their perspective about non pharmacological interventions that they found useful, relevant and feasible for pain management in the ICU. Interventions were clustered into five categories: a) cognitive-behavioural, b) physical, c) emotional support, d) helping with activities of daily living and, e) creating a comfortable environment. RESULTS: A total of eight focus groups (FGs) with patients/family members (two FGs) and ICU nurses (six FGs) were conducted. Overall, 33 non-pharmacological interventions were discussed. The top four non-pharmacological interventions found to be useful, relevant and feasible in at least half of the FGs were music therapy and distraction (cognitive-behavioural category), simple massage (physical category) and family presence facilitation (emotional support category). Interestingly, patients/family members and nurses showed different interests towards some interventions. For instance, patients discussed more about active listening/reality orientation, while nurses talked mostly about teaching/positioning. CONCLUSIONS: Four non-pharmacological interventions reached consensus in patients and nurses' FGs to be useful, relevant and feasible for pain management in the ICU. Other interventions seemed to be influenced by personal experience or professional role of the participants. RELEVANCE TO CLINICAL PRACTICE: While more evidence is required to conclude to their effectiveness, ICU nurses can use non-pharmacological interventions complementary to pharmacological treatment of pain as they are low cost and safe. PMID- 24165085 TI - An approach to surgical fixation of traumatic costosternal diastasis. PMID- 24165086 TI - The evolution of genomic imprinting: costs, benefits and long-term consequences. AB - Genomic imprinting refers to a pattern of gene expression in which a specific parent's allele is either under-expressed or completely silenced. Imprinting is an evolutionary conundrum because it appears to incur the costs of diploidy (e.g. presenting a larger target than haploidy to mutations) while foregoing its benefits (protection from harmful recessive mutations). Here, we critically evaluate previously proposed evolutionary benefits of imprinting and suggest some additional ones. We discuss whether each benefit is capable of explaining both the origin and maintenance of imprinting, and examine how the different benefits interact. We then outline the many costs of imprinting. Simple models show that circulating deleterious recessives can prevent the initial spread of imprinting, even if imprinting would be evolutionarily stable if it could persist long enough to purge these. We also show that imprinting can raise or lower the mutation load, depending on the selective regime and the degree of dominance. We finish by discussing the population-level consequences of imprinting, which can be both positive and negative. Imprinting offers many insights into evolutionary conflict, the interaction between individual- and population-level fitness effects, and the 'gene's-eye view' of evolution. PMID- 24165087 TI - Ultrasound mapping of pelvic endometriosis: does the location and number of lesions affect the diagnostic accuracy? A multicentre diagnostic accuracy study. AB - BACKGROUND: Endometriosis is a common condition which causes pain and reduced fertility. Treatment can be difficult, especially for severe disease, and an accurate preoperative assessment would greatly help in the managment of these patients. The objective of this study is to assess the accuracy of pre-operative transvaginal ultrasound scanning (TVS) in identifying the specific features of pelvic endometriosis and pelvic adhesions in comparison with laparoscopy. METHODS: Consecutive women with clinically suspected or proven pelvic endometriosis, who were booked for laparoscopy, were invited to join the study. They all underwent a systematic transvaginal ultrasound examination in order to identify discrete endometriotic lesions and pelvic adhesions. The accuracy of ultrasound diagnosis was determined by comparing pre-operative ultrasound to laparoscopy findings. RESULTS: 198 women who underwent preoperative TVS and laparoscopy were included in the final analysis. At laparoscopy 126/198 (63.6%) women had evidence of pelvic endometriosis. 28/126 (22.8%) of them had endometriosis in a single location whilst the remaining 98/126 (77.2%) had endometriosis in two or more locations. Positive likelihood ratios (LR+) for the ultrasound diagnosis of ovarian endometriomas, moderate or severe ovarian adhesions, pouch of Douglas adhesions, and bladder deeply infiltrating endometriosis (DIE), recto-sigmoid colon DIE, rectovaginal DIE, uterovesical fold DIE and uterosacral ligament DIE were >10, whilst for pelvic side wall DIE and any ovarian adhesions the + LH was 8.421 and 9.81 respectively.The negative likelihood ratio (LR-) was: <0.1 for bladder DIE; 0.1-0.2 for ovarian endometriomas, moderate or severe ovarian adhesions, and pouch of Douglas adhesions; 0.5-1 for rectovaginal, uterovesical fold, pelvic side wall and uterosacral ligament DIE. The accuracy of TVS for the diagnosis of both total number of endometriotic lesions and DIE lesions significantly improved with increasing total number of lesions. CONCLUSIONS: Our study has shown that the TVS diagnosis of endometriotic lesion is very specific and false positive results are rare. Negative findings are less reliable and women with significant symptoms may still benefit from further investigation even if TVS findings are normal. The accuracy of ultrasound diagnosis is significantly affected by the location and number of endometriotic lesions. PMID- 24165088 TI - Single dose of glycoprotein K (gK)-deleted HSV-1 live-attenuated virus protects mice against lethal vaginal challenge with HSV-1 and HSV-2 and induces lasting T cell memory immune responses. AB - BACKGROUND: Herpes simplex virus type-1(HSV-1) and HSV-2 are important human pathogens that cause significant ocular and urogenital complications, respectively. We have previously shown that HSV-1 virions lacking glycoprotein K (gK) are unable to enter into neurons via synaptic axonal membranes and be transported in either retrograde or anterograde manner. Here, we tested the ability of HSV-1 (F) gK-null to protect against lethal challenge with either highly virulent ocular HSV-1 (McKrae strain), or genital HSV-2 (G strain). The gK null virus vaccine efficiently protected mice against lethal vaginal infection with either HSV-1(McKrae) or HSV-2 (G). RESULTS: Female mice were immunized via a single intramuscular injection with 106 PFU of the gK-null virus. Immunized mice were treated with Depo-Provera fourteen days after vaccination and were challenged via the vaginal route one week later. Ninety percent of mice vaccinated with the gK-null virus survived HSV-1 (McKrae) challenge, while 70% of these mice survived after HSV-2 (G) challenge. Moreover, all vaccinated mice exhibited substantially reduced disease symptoms irrespective of HSV-1 or HSV-2 challenge as compared to the mock vaccinated challenge group. T-cell memory immune responses to specific glycoprotein B (gB) and glycoprotein D (gD) peptide epitopes were detectable at 7 months post vaccination. CONCLUSIONS: These results suggest that the highly attenuated, non-neurotropic gK-null virus may be used as an effective vaccine to protect against both virulent HSV-1 and HSV-2 genital infections and induce lasting immune responses. PMID- 24165090 TI - Comparative study of layered and volumetric rescanning for different scanning speeds of proton beam in liver patients. AB - In recent years, particle therapy has become a widely accepted form of cancer treatment and technological advances in beam delivery technology (i.e. pencil beam scanning (PBS)) have enabled the application of highly conformal dose distributions to static targets. Current research focuses on the possibilities for the treatment of mobile targets with these techniques. Of different motion mitigation methods being investigated, rescanning is perhaps the easiest to apply clinically. In general however, different PBS delivery systems exhibit a different temporal parameter space between delivery and target motions, due to the system specific beam position adjustment times (BPATs). Depending on these BPATs, dosimetric effects appearing during irradiation of moving targets vary significantly. In this work, volumetric and layered rescanning were compared for four different scenarios--a combination of fast and slow BPATs laterally (4 ms and 10 ms) and in depth (80 ms and 1 s); and nine different treatment plan arrangements for two clinical liver cases. 4D dose calculations were performed assuming regular, sinusoidal rigid motion as a worst-case motion scenario to model interplay effects. Calculations were sampled over three different starting phases resulting in a total of 432 dose distributions. It was found that layered rescanning is the method of choice for slow scanning systems, both in terms of dose homogeneity (D5-95 values are lower by up to 16% with layered rescanning) and in the estimated treatment delivery times (reduction of up to 300 s with layered rescanning). Analysis of dose homogeneity showed that layered rescanning leads to a smoother decrease in dose inhomogeneity as a function of the number of rescans than volumetric rescanning, which shows larger fluctuations. However, layered rescanning appears to be more sensitive to the starting phase. When analyzing the performance of both approaches and different scanning speeds as a function of delivery time, layered rescanning appears to be the only viable approach for slow energy changing systems, even approaching the performance of fast energy changing systems, as long as lateral scanning speeds are kept high. Similar results were found for multiple field plans and when analyzing different field directions. PMID- 24165089 TI - Copy number alterations in small intestinal neuroendocrine tumors determined by array comparative genomic hybridization. AB - BACKGROUND: Small intestinal neuroendocrine tumors (SI-NETs) are typically slow growing tumors that have metastasized already at the time of diagnosis. The purpose of the present study was to further refine and define regions of recurrent copy number (CN) alterations (CNA) in SI-NETs. METHODS: Genome-wide CNAs was determined by applying array CGH (a-CGH) on SI-NETs including 18 primary tumors and 12 metastases. Quantitative PCR analysis (qPCR) was used to confirm CNAs detected by a-CGH as well as to detect CNAs in an extended panel of SI-NETs. Unsupervised hierarchical clustering was used to detect tumor groups with similar patterns of chromosomal alterations based on recurrent regions of CN loss or gain. The log rank test was used to calculate overall survival. Mann-Whitney U test or Fisher's exact test were used to evaluate associations between tumor groups and recurrent CNAs or clinical parameters. RESULTS: The most frequent abnormality was loss of chromosome 18 observed in 70% of the cases. CN losses were also frequently found of chromosomes 11 (23%), 16 (20%), and 9 (20%), with regions of recurrent CN loss identified in 11q23.1-qter, 16q12.2-qter, 9pter p13.2 and 9p13.1-11.2. Gains were most frequently detected in chromosomes 14 (43%), 20 (37%), 4 (27%), and 5 (23%) with recurrent regions of CN gain located to 14q11.2, 14q32.2-32.31, 20pter-p11.21, 20q11.1-11.21, 20q12-qter, 4 and 5. qPCR analysis confirmed most CNAs detected by a-CGH as well as revealed CNAs in an extended panel of SI-NETs. Unsupervised hierarchical clustering of recurrent regions of CNAs revealed two separate tumor groups and 5 chromosomal clusters. Loss of chromosomes 18, 16 and 11 and gain of chromosome 20 were found in both tumor groups. Tumor group II was enriched for alterations in chromosome cluster d, including gain of chromosomes 4, 5, 7, 14 and gain of 20 in chromosome cluster b. Gain in 20pter-p11.21 was associated with short survival. Statistically significant differences were observed between primary tumors and metastases for loss of 16q and gain of 7. CONCLUSION: Our results revealed recurrent CNAs in several candidate regions with a potential role in SI-NET development. Distinct genetic alterations and pathways are involved in tumorigenesis of SI-NETs. PMID- 24165092 TI - Evaluation of sexual functions of the pregnant women. AB - INTRODUCTION: Pregnant women may avoid sexual intercourse or may unavoidably undergo problems in their sexual lives because of various complaints they suffer from. AIM: The study aims to evaluate sexual functions of the pregnant women and to determine the factors that negatively affect their sexual health. METHODS: This is a descriptive research study conducted to evaluate sexual functions of pregnant women. Three hundred six pregnant women admitted to the Women Birth Polyclinics within the Women Birth and Children's Hospital between October 1, 2010 and March 31, 2011 were included in the study. The data were gathered using a personal information form and the Female Sexual Function Index (FSFI). Kruskall Wallis variance analysis and Mann-Whitney U-tests were used for the statistical analysis. MAIN OUTCOMES MEASURES: The main outcome is an assessment of the FSFI domains in pregnancy and relationships between pregnancy complaints and sexual functions. RESULTS: The results indicated that the mean age of the pregnant women was 25.6 +/- 5.4 and their length of marriage was 5.93 +/- 5.4 years. The study revealed that 88.9% of the pregnant women had sexual desire disorders, 86.9% had sexual arousal disorder, 42.8% had lubrication disorders, 69.6% had orgasm disorders, and 48% had sexual satisfaction disorders. Statistically significant differences were found in correlations between FSFI medians and the characteristics of the pregnant women in terms of age, educational level, length and type of marriage, and gestational week. There were also statistically significant differences in correlations between the pregnancy characteristics in terms of backache, constipation, respiratory difficulty, leg ache, and cramp problems (P < 0.05). CONCLUSIONS: It was determined that the sexual lives of the pregnant women were negatively affected not only by factors such as old age, low educational status, arranged marriages lasting for more than 10 years, undesired pregnancy, and gestational week but also by health problems such as backache, constipation, respiratory difficulty, leg ache, and cramp problems. PMID- 24165091 TI - Analysis of the levels of lysine-specific demethylase 1 (LSD1) mRNA in human ovarian tumors and the effects of chemical LSD1 inhibitors in ovarian cancer cell lines. AB - BACKGROUND: Lysine-specific demethylase 1 (LSD1, also known as KDM1A and AOF2) is a chromatin-modifying activity that catalyzes the removal of methyl groups from lysine residues in histone and non-histone proteins, regulating gene transcription. LSD1 is overexpressed in several cancer types, and chemical inhibition of the LSD1 activity has been proposed as a candidate cancer therapy. Here, we examine the levels of LSD1 mRNA in human ovarian tumors and the cytotoxicity of several chemical LSD1 inhibitors in a panel of ovarian cancer cell lines. METHODS: We measured LSD1 mRNA levels in a cohort of n = 177 normal and heterogeneous tumor specimens by quantitative real time-PCR (qRT-PCR). Tumors were classified by FIGO stage, FIGO grade, and histological subtypes. We tested the robustness of our analyses in an independent cohort of n = 573 serous tumor specimens (source: TCGA, based on microarray). Statistical analyses were based on Kruskal-Wallis/Dunn's and Mann Whitney tests. Changes in LSD1 mRNA levels were also correlated with transcriptomic alterations at genome-wide scale. Effects on cell viability (MTS/PMS assay) of six LSD1 inhibitors (pargyline, TCP, RN-1, S2101, CAS 927019-63-4, and CBB1007) were also evaluated in a panel of ovarian cancer cell lines (SKOV3, OVCAR3, A2780 and cisplatin-resistant A2780cis). RESULTS: We found moderate but consistent LSD1 mRNA overexpression in stage IIIC and high-grade ovarian tumors. LSD1 mRNA overexpression correlated with a transcriptomic signature of up-regulated genes involved in cell cycle and down regulated genes involved in the immune/inflammatory response, a signature previously observed in aggressive tumors. In fact, some ovarian tumors showing high levels of LSD1 mRNA are associated with poor patient survival. Chemical LSD1 inhibition induced cytotoxicity in ovarian cancer lines, which roughly correlated with their reported LSD1 inhibitory potential (RN-1,S2101 >> pargyline,TCP). CONCLUSIONS: Our findings may suggest a role of LSD1 in the biology of some ovarian tumors. It is of special interest to find a correlation of LSD1 mRNA overexpression with a transcriptomic signature relevant to cancer. Our findings, therefore, prompt further investigation of the role of LSD1 in ovarian cancer, as well as the study of its enzymatic inhibition in animal models for potential therapeutic purposes in the context of this disease. PMID- 24165093 TI - Role of extended lymphadenectomy in the treatment of pancreatic head adenocarcinoma: review and meta-analysis. AB - BACKGROUND: Extended lymph node dissection has been established as the method of choice in the treatment of many digestive malignancies, but its role in the treatment of adenocarcinoma of the pancreas remains controversial. OBJECTIVES: The goal is to evaluate the role of extended lymph node dissection in pancreatic head adenocarcinoma and to review how it affects survival, morbidity, mortality and post-operative quality of life. METHODS: A computerized search was made of the Medline database from January 1973 to October 2012. Fifteen non-duplicated studies, four randomized and 11 non-randomized, comparing extended radical pancreaticoduodenectomy (ERP) and standard pancreaticoduodenectomy were reviewed. Five-year overall survivals were compared using the MetaXL software in eight of these studies, where the necessary data were available. RESULTS: The 5-year survival after ERP ranged from 6 to 33.4% and the local recurrence incidence from 8 to 36.1%, while the incidence of severe diarrhoea, one of the main complications, ranged from 10.8 to 42.4%. Meta-analysis showed that there was no significant difference in the 5-year overall survival (95% confidence interval (CI): -0.21-0.20, Z=0.07, P=0.94) for randomized control trials, (95% CI: -0.51 0.02, Z=1.85, P=0.07) for non-randomized control trials and (95% CI: -0.26-0.06, Z=1.20, P=0.23) for all the studies. CONCLUSIONS: Although ERP is a safe procedure, it did not offer a significant improvement in survival, while at the same time leading to an increased incidence of severe diarrhoea for at least 1 year, thus leaving the standard pancreaticoduodenectomy as the surgical method of choice for the treatment of pancreatic head adenocarcinoma. PMID- 24165095 TI - Impairment of the proximal to distal tonic gradient in the human diabetic stomach. AB - BACKGROUND: Little has been known about the contractile characteristics of diabetic stomach. We investigated spontaneous contractions and responses to acetylcholine in the gastric muscle in diabetic patients and non-diabetic control subjects according to the region of stomach. METHODS: Gastric specimens were obtained from 26 diabetics and 55 controls who underwent gastrectomy at Samsung Medical Center between February 2008 and November 2011. Isometric force measurements were performed using circular muscle strips from the different regions of stomach under basal condition and in response to acetylcholine. KEY RESULTS: Basal tone of control was higher in the proximal stomach than in the distal (0.63 g vs 0.46 g, p = 0.027). However, in diabetics, basal tone was not significantly different between the proximal and distal stomach (0.75 g vs 0.62 g, p = 0.32). The distal stomach of diabetics had higher basal tone and lower frequency than that of control (0.62 g vs 0.46 g, p = 0.049 and 4.0/min vs 4.9/min, p = 0.049, respectively). After exposure to acetylcholine, dose dependent increases of basal tone, peak, and area under the curve (AUC) were noticed in both proximal and distal stomach of the two groups. In the proximal stomach, however, the dose-dependent increase of basal tone and AUC was less prominent in diabetics than in control. CONCLUSIONS & INFERENCES: On the contrary to control, the proximal to distal tonic gradient was not observed in diabetic stomach. Diabetic stomach also had lower frequency of spontaneous contraction in the distal stomach and less acetylcholine-induced positive inotropic effect in the proximal stomach than control. PMID- 24165094 TI - Allodynia and descending pain modulation in migraine: a resting state functional connectivity analysis. AB - OBJECTIVE: Most migraineurs develop cutaneous allodynia during migraines, and many have cutaneous sensitization between attacks. Atypical pain modulation via the descending pain system may contribute to this sensitization and allodynia. The objective of this study was to test the hypothesis that compared with non allodynic migraineurs, allodynic migraineurs have atypical periaqueductal gray (PAG) and nucleus cuneiformis (NCF) resting-state functional connectivity (rs-fc) with other pain processing regions. DESIGN: Ten minutes resting-state blood oxygen-level-dependent data were collected from 38 adult migraineurs and 20 controls. Seed-based analyses compared whole-brain rs-fc with PAG and with NCF in migraineurs with severe ictal allodynia (N = 8) to migraineurs with no ictal allodynia (N = 8). Correlations between the strength of functional connections that differed between severely allodynic and non-allodynic migraineurs with allodynia severity were determined for all migraineurs (N = 38). PAG and NCF rs fc in all migraineurs was compared with rs-fc in controls. RESULTS: Migraineurs with severe allodynia had stronger PAG and NCF rs-fc to other brainstem, thalamic, insula and cerebellar regions that participate in discriminative pain processing, as well as to frontal and temporal regions implicated in higher order pain modulation. Evidence that these rs-fc differences were specific for allodynia included: 1) strong correlations between some rs-fc strengths and allodynia severity among all migraineurs; and 2) absence of overlap when comparing rs-fc differences in severely allodynic vs non-allodynic migraineurs with those in all migraineurs vs controls. CONCLUSION: Atypical rs-fc of brainstem descending modulatory pain regions with other brainstem and higher order pain-modulating regions is associated with migraine-related allodynia. PMID- 24165096 TI - Producing a successful PeRLs video. AB - Academic Emergency Medicine publishes selected peer-reviewed videos that present state-of-the-art research, practice, and evidence in the field of emergency medicine. These videos are referred to as peer-reviewed lectures (PeRLs). This commentary reviews considerations for creating, filming, and producing high quality PeRLs videos. PMID- 24165097 TI - Transcranial direct current stimulation in a patient with schizoaffective disorder manic episode. PMID- 24165098 TI - Biological activity of sporolides A and B from Salinispora tropica: in silico target prediction using ligand-based pharmacophore mapping and in vitro activity validation on HIV-1 reverse transcriptase. AB - Sporolides A and B are novel polycyclic macrolides from the obligate marine actinomycetes, Salinispora tropica. The unique and novel structure of sporolides makes them interesting candidates for targeting diverse biological activities. Biological target prediction of sporolides was carried out using ligand-based pharmacophore screening against known inhibitors and drugs. Validation of pharmacophore screening was carried out for the identified hits. New biological targets predicted for sporolides using this method were HIV-1 reverse transcriptase, adenosine A3 receptor, endothelin receptor ET-A, oxytocin receptor, voltage-gated L-type calcium channel alpha-1C subunit/calcium channel alpha/Delta subunit 1. Drug-likeness properties were predicted for the selected compounds using QikProp module. Sporolides A and B showed maximum docking score with HIV-1 reverse transcriptase. Structural interaction fingerprints analysis indicated similar binding pattern of the sporolides with the HIV-1 reverse transcriptase. Sporolide B exhibited good inhibitory activity against HIV-1 reverse transcriptase in in vitro fluorescent assay. PMID- 24165099 TI - Fads in psychiatry. PMID- 24165101 TI - Psychiatry and fads: why is this field different from all other fields? AB - Fads in psychiatry are little more than bad ideas with short half-lives. They have arisen because of the great discontinuities that have swept psychiatry unlike other specialties in the 20th century: the transition in the 1920s from asylum-based biological psychiatry to psychoanalysis, and the transition in the 1960s from psychoanalysis to a biological model based on psychopharmacology. In no other medical specialty has the knowledge base been scrapped and rebuilt, and then again scrapped and rebuilt. In these great transitions, when psychiatry each time has had to reconstruct from scratch, bad ideas have crept in with good. Psychiatry, in its heavy use of consensus conferences, is often unable to employ science as a means of discarding fads, which, once installed, are often difficult to remove. Each of the great paradigms of psychiatry in the last hundred years has given rise to fads, and psychopharmacology is no exception, with faddish uses of neurotransmitter doctrine claiming centre stage. Only when psychiatry becomes firmly linked to the neurosciences will its subjugation to the turbulence of faddism be moderated. PMID- 24165102 TI - Why is psychiatry prone to fads? AB - Psychiatry has long been prone to fads. The main reason is that mental illness is poorly understood and can be difficult to treat. Most diagnostic fads have involved the extension of well-known categories into broader spectra. The most prominent treatment fads have involved the overuse of pharmacological interventions and a proliferation of methods for psychotherapy. The best antidote to fads is a commitment to evidence-based psychiatry. PMID- 24165103 TI - Should psychiatry be expanding its boundaries? PMID- 24165104 TI - Protective factors for mental disorders and psychological distress in female, compared with male, service members in a representative sample. AB - OBJECTIVE: Although military interest in promoting psychological resilience is growing, resources protective against psychopathology have been understudied in female service members. Using a representative sample of Canadian Forces personnel, we investigated whether religious attendance, spirituality, coping, and social support were related to mental disorders and psychological distress in female service members, and whether sex differences occurred in these associations. METHOD: Religious attendance and spirituality were self-reported. Coping items were taken from 3 scales and produced 3 factors (active, avoidance, and self-medication). Social support was assessed with the Medical Outcomes Study Social Support Survey. Past-year mental disorders were diagnosed with the World Mental Health Composite International Diagnostic Interview. The Kessler Psychological Distress Scale assessed distress. Multivariate regression models investigated links between correlates and psychological outcomes within each sex. For associations that were statistically significant in only one sex, sex by correlate interactions were computed. RESULTS: In female service members, inverse relations were found between social support and MDD, any MDD or anxiety disorder, suicidal ideation, and distress. No associations were found between religious attendance and outcomes, and spirituality was associated with an increased likelihood of some outcomes. Active coping was related to less psychological distress, while avoidance coping and self-medication were linked to a higher likelihood of most outcomes. Although several statistically significant associations were found in only one sex, only one sex by correlate interaction was statistically significant. CONCLUSIONS: Social support was found to be inversely related to several negative mental health outcomes in female service members. Few differences between men and women reached statistical significance. Future research should identify additional helpful resources for female service members. PMID- 24165105 TI - Antenatal depression in a multi-ethnic, community sample of Canadian immigrants: psychosocial correlates and hypothalamic-pituitary-adrenal axis function. AB - OBJECTIVES: Immigrant women living in Canada present with higher rates of prenatal depressive symptomatology than Canadian-born women; however, the associated psychosocial correlates remain understudied. Antenatal depression and stress negatively affect maternal health and infant development, in part through changes in maternal hypothalamic-pituitary-adrenal (HPA) axis activity. We aimed to examine the factors associated with prenatal depressive symptoms, including altered HPA axis function, in an ethnically diverse community sample of Canadian immigrant women. METHODS: Seventy-eight pregnant immigrant women were recruited from the community at 19 weeks' gestation and provided information on health, mood, stressful life events (SLEs), and social support. Fifty-seven of these women also provided saliva samples for measurement of the cortisol awakening response and nighttime cortisol levels. RESULTS: Seventeen per cent of the sample had a high level of prenatal depressive symptoms, and these women reported more perceived stress, more somatic symptoms, lower social support, and were less often working or attending school during pregnancy. Controlling for wake time, parity, and region of origin, high levels of prenatal depressive symptoms were associated with elevated nighttime cortisol levels, whereas SLEs were not associated with any measures of HPA axis activity. CONCLUSIONS: High levels of prenatal depressive symptoms are common in immigrant women living in Canada, and are associated with identifiable factors. Preliminary evidence suggests a similar pattern of HPA axis activity characterizing depressive symptomatology in this subpopulation as previously seen in clinically depressed patients. PMID- 24165106 TI - Diagnostic stability of first-episode psychotic disorders and persistence of comorbid psychiatric disorders over 1 year. AB - OBJECTIVE: Diagnostic stability is an important indicator of the reliability and validity of psychiatric diagnoses and has implications in clinical practice and research. While several studies have investigated the diagnostic stability of first-episode psychosis (FEP) disorders, less is known about psychiatric comorbidity in FEP and the persistence of such comorbid conditions over time. Our study aimed to confirm the diagnostic stability of FEP disorders and determine the variation in persistence of comorbid substance use disorders (SUDs), mood disorders, and anxiety disorders over 1 year. METHOD: The Structured Clinical Interview for DSM-IV-TR Axis I Disorders-Patient Edition was conducted at first presentation and repeated after 1 year (or reconstructed) for 214 FEP patients at the Prevention and Early Intervention Program for Psychoses-Montreal. RESULTS: Psychotic disorder diagnoses were retained by 76.2% of patients at 1 year, schizophrenia being the most stable diagnosis (92.1%). Most diagnostic shifts were to schizophrenia and schizophrenia spectrum disorders. Comorbid SUDs, anxiety disorders, and mood disorders persisted for 50.7%, 64.0%, and 16.7% of patients, respectively. Many new cases of each of these disorders also emerged at 1-year follow-up. CONCLUSIONS: These findings demonstrate the stability of primary psychotic disorder diagnoses and greater fluidity of comorbid psychiatric diagnoses, with anxiety disorders persisting as comorbid conditions more than mood disorders and SUDs. These results highlight the importance of repeating a structured diagnostic assessment longitudinally, especially for consideration of comorbid conditions. PMID- 24165107 TI - An updated review of the optimal lithium dosage regimen for renal protection. AB - OBJECTIVE: Despite several decades of research, there is still uncertainty regarding the optimal lithium dosage regimen associated with a decreased risk of renal effects, such as polyuria, in patients with bipolar affective disorder. We present an updated review of the literature to provide an informed dosing regimen recommendation for prescribers. METHOD: Major databases MEDLINE and Embase were searched using terms, such as lithium, drug administration schedule, dose response relationship, once daily, twice daily, and sustained release. In addition, the bibliographies of related publications were manually searched. RESULTS: A total of 20 trials were included. Some trials showed a reduction in urine volume with single daily dosing (SDD), while others showed no change. The only trial evaluating patients newly started on lithium found a reduction in urinary frequency with SDD after 21 days. Trials examining renal biopsy results found that multiple daily doses were associated with more pathologic damage to the kidneys. SDD regimens were generally well tolerated, and no reduction in efficacy was noted in any of the trials. CONCLUSIONS: The available evidence is contradictory as to whether SDD of lithium reduces polyuria; however, no trial has demonstrated any downfall of SDD in terms of prophylactic efficacy or adverse effects. Given the added benefits of SDD, such as improved compliance, we recommend patients newly started on lithium should be converted to a SDD of lithium at bedtime once an appropriate daily dose is determined. PMID- 24165108 TI - Normothermic acellular machine perfusion and bile duct injury in pig livers retrieved after cardiac death. PMID- 24165109 TI - Automatic delirium prediction system in a Korean surgical intensive care unit. AB - BACKGROUND: In Korea, regular screening for delirium is not considered essential. In addition, delirium is often associated with vague concepts, making it harder to identify high-risk patients and impeding decision-making. AIMS: To assess the impact of the Automatic PREdiction of DELirium in Intensive Care Units (APREDEL ICU) system on nursing-sensitive and patient outcomes for surgical ICU patients and to evaluate nurse satisfaction with the system and its usability. METHODS: A pre-post research design was adopted. Our study included 724 patients admitted before the implementation of the APREDEL-ICU (January to December 2010) and 1111 patients admitted after the system was installed (May 2011 to April 2012). The APREDEL-ICU uses a pop-up window message to inform the nursing staff of patients at risk for delirium, allowing evidence-based nursing interventions to be applied to the identified patients. A total of 42 nurses were surveyed to determine the system's usability and their level of satisfaction with it. RESULTS: After the implementation of APREDEL-ICU, high-risk patients, determined using a prediction algorithm, showed a slight decrease in the incidence of delirium, but the changes were not significant. However, significant decreases in the number and duration of analgesic/narcotic therapies were observed after the implementation of the system. Nurse self-evaluation results showed an improvement in all categories of knowledge regarding delirium care. CONCLUSION: The use of a prediction and alerting system for ICU patients at high risk of delirium showed a potential increase in the quality of delirium care, including early detection and proper intervention. PMID- 24165111 TI - How can we judge the 'long term' outcomes of novel interventions in Parkinson's disease? AB - Despite all recent advances in symptomatic therapy of Parkinson's disease (PD), the underlying neurodegenerative process cannot yet be slowed and the long-term clinical picture is characterized by severe motor as well as nonmotor disability, loss of independent function and premature death. This has a major and increasing social and economic burden on ageing populations. There is a pressing unmet need for developing therapies capable of not only providing symptomatic relief, but that can also modify or slow down the progression of disability in PD. In this article we discuss our own experience of the long-term effects of fetal cell transplantation used as experimental restorative treatment in PD, and we consider these observations in relation to the long-term clinical course of PD as we currently comprehend it in the era of symptomatic treatment. PMID- 24165110 TI - Effects of Panax notoginseng saponin on alpha, beta, and gamma secretase involved in Abeta deposition in SAMP8 mice. AB - Our previous studies have shown that Panax notoginseng saponins (PNS) play a protective role in learning dysfunction of Alzheimer's disease, inhibit the deposition of Abeta1-40 and Abeta1-42, and reduce the content of App in the brain of SAMP8. In this study, we aimed to investigate the effects of PNS on alpha, beta, and gamma secretase involved in Abeta generation in SAMP8 mice. The results showed that PNS increased alpha-secretase activity perhaps by enhancing the level of ADAM9 expression, which itself was achieved by upregulating the expression of the ADAM9 gene. In addition, PNS significantly decreased BACE1 protein level by downregulating the level of BACE1 gene expression and consequently precluded the activity of beta secretase. However, PNS treatment did not modify gamma-secretase activity. Together, our study shows that PNS modulates the levels of protein and gene expressions involved with alpha and beta secretase, thereby increasing alpha secretase activity and reducing beta-secretase activity, which may be one of the mechanisms of PNS precluding Abeta generation. Accordingly, PNS may be a promising agent for Alzheimer's disease. PMID- 24165112 TI - Bright red line along the small bowel: a finding of eosinophilic gastroenteritis. PMID- 24165113 TI - Uric acid as a cardiovascular risk factor or not? PMID- 24165114 TI - Factors related to venous ulceration: a cross-sectional study. AB - The aim of the study was to determine the factors related to venous ulceration. Patients with venous ulceration (278 patients) were compared with 1401 patients in other categories of clinical classification of venous disease (clinical, etiologic, anatomic, and pathophysiological [CEAP]). Demographic, anthropometric, and clinical data were collected. Univariate and multivariate logistic regression analyses were used. According to multivariate analyses, risk factors for venous ulceration were age, male sex, personal history of superficial and deep venous thrombosis, diabetes, high blood pressure, skeletal or joint disease in the legs and emphysema or chronic obstructive pulmonary disease, higher body mass index and physical inactivity, parental history of ankle ulcer as well as reflux in deep and perforator veins, deep obstruction, and combination of reflux and obstruction. It seems reasonable to pay special attention to patients in whom the postulated risk factors for venous ulceration are present. PMID- 24165116 TI - Bayesian design for dichotomous repeated measurements with autocorrelation. AB - In medicine and health sciences, binary outcomes are often measured repeatedly to study their change over time. A problem for such studies is that designs with an optimal efficiency for some parameter values may not be efficient for other values. To handle this problem, we propose Bayesian designs which formally account for the uncertainty in the parameter values for a mixed logistic model which allows quadratic changes over time. Bayesian D-optimal allocations of time points are computed for different priors, costs, covariance structures and values of the autocorrelation. Our results show that the optimal number of time points increases with the subject-to-measurement cost ratio, and that neither the optimal number of time points nor the optimal allocations of time points appear to depend strongly on the prior, the covariance structure or on the size of the autocorrelation. It also appears that for subject-to-measurement cost ratios up to five, four equidistant time points, and for larger cost ratios, five or six equidistant time points are highly efficient. Our results are compared with the actual design of a respiratory infection study in Indonesia and it is shown that, selection of a Bayesian optimal design will increase efficiency, especially for small cost ratios. PMID- 24165115 TI - Left atrial function predicts heart failure events in patients with newly diagnosed left ventricular systolic heart failure during short-term follow-up. AB - We assessed the effect of left atrial (LA) function index, LA ejection fraction, LA kinetic energy, and maximal LA volume on 6 months clinical outcome in patients with newly diagnosed systolic heart failure (HF). During a 36-month period, 179 consecutive patients (17% female, mean age 63 +/- 14 years) were enrolled. During the follow-up, 46 patients had an event (32% event rate; 15 were fatal). Those with an adverse event were older, had lower creatinine clearance, advanced New York Heart Association stage, higher prevalence of ischemic HF, and lower values for right ventricle systolic wave in the tissue Doppler imaging evaluation, compared with those without an event. Multivariate analysis revealed that LA function and ischemic etiology of HF were the most significant prognostic indicators after index hospitalization. This study reveals the important role of LA function for the short-term prognosis of patients with newly diagnosed systolic HF in sinus rhythm. PMID- 24165117 TI - Echocardiographic image tracker with a speckle adaptive noise reduction filter for the automatic measurement of the left atrial volume curve. AB - AIMS: Since tracking accuracy in left atrial (LA) images decreases due to low image quality around the LA in the apical view, a practical tracking method for LA images has not yet been proposed. The aim of this study was to assess an accurate and high-speed LA volume tracking (LAVT) method for the automatic measurement of LA volume (LAV) curves. METHODS AND RESULTS: We used three approved protocols in this study: (i) LAV curves were measured by LAVT on computer-simulated images; (ii) in 20 healthy volunteers, we assessed the feasibility and accuracy of this method compared with expert's measurements; and (iii) echocardiography and multi-detector row computed tomography (MDCT) imaging were performed on the same day in 20 patients with suspected coronary artery disease. On computer-simulated images, mean absolute percentage LAVT error in one cardiac cycle was 3% in filtered images and 16% in original images. In 20 healthy volunteers, there are strong correlations between LAVT and the expert's LA measurements (LA maximum volume; R = 0.93, P < 0.001). In 400 LA images with 20 patients, an excellent correlation was obtained between LAVs using echocardiography and MDCT (R = 0.98, P < 0.001), with a small bias (-14% of the mean) and narrow limits of agreement (+15% of the mean). The mean time required for the LAVT analysis was 1.8 min, for the MDCT analysis was 35.8 min, and for the manual echocardiographic analysis was 14.0 min. CONCLUSION: This LAVT method is fast, valid, accurate, and reproducible for determining LAV in both simulated images and the clinical setting. PMID- 24165118 TI - Accessory mitral valve tissue: an updated review of the literature. AB - Accessory mitral valve tissue (AMVT) is a rare congenital cardiac anomaly sometimes responsible for left ventricular outflow tract (LVOT) obstruction. It is diagnosed during both neonate-childhood and adult periods in patients usually symptomatic for dyspnoea, chest pain, palpitations, fatigue, or syncope. Nevertheless, AMVT is often an incidental finding. AMVT is most often associated with other cardiac and vascular congenital malformations, such as septal defects and transposition of the great arteries. Surgery is indicated only in cases of significant LVOT obstruction and in patients undergoing correction of other cardiac malformations or exploration of an intracardiac mass. Two-dimensional echocardiography, both transthoracic and transoesophageal, is considered the main imaging modality for AMVT diagnosis and patient follow-up. The recent introduction of three-dimensional echocardiography allows a more realistic characterization of this entity. We present three clinical cases in which AMVT was incidentally diagnosed during standard echocardiography and an updated review of the literature highlighting the usefulness of echocardiography for AMVT morphological and functional characterization as well as the most relevant clinical implications due to its discovery. PMID- 24165119 TI - Coronary artery aneurysm following stent implantation: insights from serial multiple intravascular imaging modalities. PMID- 24165120 TI - Autocrine/paracrine function of nicotinic acid adenine dinucleotide phosphate (NAADP) for glucose homeostasis in pancreatic beta-cells and adipocytes. AB - Nicotinic acid adenine dinucleotide phosphate (NAADP) is a second messenger for mobilizing Ca(2+) from intracellular stores in various cell types. Extracellular application of NAADP has been shown to elicit intracellular Ca(2+) signals, indicating that it is readily transported into cells. However, little is known about the functional role of this NAADP uptake system. Here, we show that NAADP is effectively transported into selected cell types involved in glucose homeostasis, such as adipocytes and pancreatic beta-cells, but not the acinar cells, in a high glucose-dependent manner. NAADP uptake was inhibitable by Ned 19, a NAADP mimic; dipyridamole, a nucleoside inhibitor; or NaN3, a metabolic inhibitor or under Ca(2+)-free conditions. Furthermore, NAADP was found to be released from pancreatic islets upon stimulation by high glucose. Consistently, administration of NAADP to type 2 diabetic mice improved glucose tolerance. We propose that NAADP is functioning as an autocrine/paracrine hormone important in glucose homeostasis. NAADP is thus a potential antidiabetic agent with therapeutic relevance. PMID- 24165121 TI - Stabilization of the ADP/metaphosphate intermediate during ATP hydrolysis in pre power stroke myosin: quantitative anatomy of an enzyme. AB - It has been proposed recently that ATP hydrolysis in ATPase enzymes proceeds via an initial intermediate in which the dissociated gamma-phosphate of ATP is bound in the protein as a metaphosphate (PgammaO3(-)). A combined quantum/classical analysis of this dissociated nucleotide state inside myosin provides a quantitative understanding of how the enzyme stabilizes this unusual metaphosphate. Indeed, in vacuum, the energy of the ADP(3-) . PgammaO3(-) . Mg(2+) complex is much higher than that of the undissociated ATP(4-). The protein brings it to a surprisingly low value. Energy decomposition reveals how much each interaction in the protein stabilizes the metaphosphate state; backbone peptides of the P-loop contribute 50% of the stabilization energy, and the side chain of Lys-185(+) contributes 25%. This can be explained by the fact that these groups make strong favorable interactions with the alpha- and beta-phosphates, thus favoring the charge distribution of the metaphosphate state over that of the ATP state. Further stabilization (16%) is achieved by a hydrogen bond between the backbone C=O of Ser-237 (on loop Switch-1) and a water molecule perfectly positioned to attack the PgammaO3(-) in the subsequent hydrolysis step. The planar and singly negative PgammaO3(-) is a much better target for the subsequent nucleophilic attack by a negatively charged OH(-) than the tetrahedral and doubly negative PgammaO4(2-) group of ATP. Therefore, we argue that the present mechanism of metaphosphate stabilization is common to the large family of nucleotide-hydrolyzing enzymes. Methodologically, this work presents a computational approach that allows us to obtain a truly quantitative conception of enzymatic strategy. PMID- 24165122 TI - Conformational stability of inositol 1,3,4,5,6-pentakisphosphate 2-kinase (IPK1) dictates its substrate selectivity. AB - Inositol 1,3,4,5,6-pentakisphosphate 2-kinase (IPK1) converts inositol 1,3,4,5,6 pentakisphosphate(IP5) to inositol hexakisphosphate (IP6). IPK1 shares structural similarity with protein kinases and is suspected to employ a similar mechanism of activation. Previous studies revealed roles for the 1- and 3-phosphates of IP5 in IPK1 activation and revealed that the N-lobe of IPK1 is unstable in the absence of inositol phosphate (IP). Here, we demonstrate the link between IPK1 substrate specificity and the stability of its N-lobe. Limited proteolysis of IPK1 revealed that N-lobe stability is dependent on the presence of the 1-phosphate of the substrate, whereas overall stability of IPK1 was increased in ternary complexes with nucleotide and IPs possessing 1- and 3-phosphates that engage the N-lobe of IPK1. Thus, the 1- and 3-phosphates possess dual roles in both IPK1 activation and IPK1 stability. To test whether kinase stability directly contributed to substrate selectivity of the kinase, we engineered IPK1 mutants with disulfide bonds that artificially stabilized the N-lobe in an IP-independent manner thereby mimicking its substrate-bound state in the absence of IP. IPK1 E82C/S142C exhibited a DTT-sensitive 5-fold increase in kcat for 3,4,5,6-inositol tetrakisphosphate (3,4,5,6-IP4) as compared with wild-type IPK1. The crystal structure of the IPK1 E82C/S142C mutant confirmed the presence of the disulfide bond and revealed a small shift in the N-lobe. Finally, we determined that IPK1 E82C/S142C is substantially more stable than wild-type IPK1 under nonreducing conditions, revealing that increased stability of IPK1 E82C/S142C correlates with changes in substrate specificity by allowing IPs lacking the stabilizing 1 phosphate to be used. Taken together, our results show that IPK1 substrate selection is linked to the ability of each potential substrate to stabilize IPK1. PMID- 24165123 TI - The hydrogenase activity of the molybdenum/copper-containing carbon monoxide dehydrogenase of Oligotropha carboxidovorans. AB - The reaction of the air-tolerant CO dehydrogenase from Oligotropha carboxidovorans with H2 has been examined. Like the Ni-Fe CO dehydrogenase, the enzyme can be reduced by H2 with a limiting rate constant of 5.3 s(-1) and a dissociation constant Kd of 525 MUM; both kred and kred/Kd, reflecting the breakdown of the Michaelis complex and the reaction of free enzyme with free substrate in the low [S] regime, respectively, are largely pH-independent. During the reaction with H2, a new EPR signal arising from the Mo/Cu-containing active site of the enzyme is observed which is distinct from the signal seen when the enzyme is reduced by CO, with greater g anisotropy and larger hyperfine coupling to the active site (63,65)Cu. The signal also exhibits hyperfine coupling to at least two solvent-exchangeable protons of bound substrate that are rapidly exchanged with solvent. Proton coupling is also evident in the EPR signal seen with the dithionite-reduced native enzyme, and this coupling is lost in the presence of bicarbonate. We attribute the coupled protons in the dithionite reduced enzyme to coordinated water at the copper site in the native enzyme and conclude that bicarbonate is able to displace this water from the copper coordination sphere. On the basis of our results, a mechanism for H2 oxidation is proposed which involves initial binding of H2 to the copper of the binuclear center, displacing the bound water, followed by sequential deprotonation through a copper-hydride intermediate to reduce the binuclear center. PMID- 24165124 TI - Crystal structure and site-directed mutagenesis of 3-ketosteroid Delta1 dehydrogenase from Rhodococcus erythropolis SQ1 explain its catalytic mechanism. AB - 3-Ketosteroid Delta(1)-dehydrogenases are FAD-dependent enzymes that catalyze the 1,2-desaturation of 3-ketosteroid substrates to initiate degradation of the steroid nucleus. Here we report the 2.0 A resolution crystal structure of the 56 kDa enzyme from Rhodococcus erythropolis SQ1 (Delta(1)-KSTD1). The enzyme contains two domains: an FAD-binding domain and a catalytic domain, between which the active site is situated as evidenced by the 2.3 A resolution structure of Delta(1)-KSTD1 in complex with the reaction product 1,4-androstadiene-3,17-dione. The active site contains four key residues: Tyr(119), Tyr(318), Tyr(487), and Gly(491). Modeling of the substrate 4-androstene-3,17-dione at the position of the product revealed its interactions with these residues and the FAD. The C1 and C2 atoms of the substrate are at reaction distance to the N5 atom of the isoalloxazine ring of FAD and the hydroxyl group of Tyr(318), respectively, whereas the C3 carbonyl group is at hydrogen bonding distance from the hydroxyl group of Tyr(487) and the backbone amide of Gly(491). Site-directed mutagenesis of the tyrosines to phenylalanines confirmed their importance for catalysis. The structural features and the kinetic properties of the mutants suggest a catalytic mechanism in which Tyr(487) and Gly(491) work in tandem to promote keto-enol tautomerization and increase the acidity of the C2 hydrogen atoms of the substrate. With assistance of Tyr(119), the general base Tyr(318) abstracts the axial beta-hydrogen from C2 as a proton, whereas the FAD accepts the axial alpha hydrogen from the C1 atom of the substrate as a hydride ion. PMID- 24165125 TI - Bile acids modulate signaling by functional perturbation of plasma membrane domains. AB - Eukaryotic cell membranes are organized into functional lipid and protein domains, the most widely studied being membrane rafts. Although rafts have been associated with numerous plasma membrane functions, the mechanisms by which these domains themselves are regulated remain undefined. Bile acids (BAs), whose primary function is the solubilization of dietary lipids for digestion and absorption, can affect cells by interacting directly with membranes. To investigate whether these interactions affected domain organization in biological membranes, we assayed the effects of BAs on biomimetic synthetic liposomes, isolated plasma membranes, and live cells. At cytotoxic concentrations, BAs dissolved synthetic and cell-derived membranes and disrupted live cell plasma membranes, implicating plasma membrane damage as the mechanism for BA cellular toxicity. At subtoxic concentrations, BAs dramatically stabilized domain separation in Giant Plasma Membrane Vesicles without affecting protein partitioning between coexisting domains. Domain stabilization was the result of BA binding to and disordering the nonraft domain, thus promoting separation by enhancing domain immiscibility. Consistent with the physical changes observed in synthetic and isolated biological membranes, BAs reorganized intact cell membranes, as evaluated by the spatial distribution of membrane-anchored Ras isoforms. Nanoclustering of K-Ras, related to nonraft membrane domains, was enhanced in intact plasma membranes, whereas the organization of H-Ras was unaffected. BA-induced changes in Ras lateral segregation potentiated EGF-induced signaling through MAPK, confirming the ability of BAs to influence cell signal transduction by altering the physical properties of the plasma membrane. These observations suggest general, membrane-mediated mechanisms by which biological amphiphiles can produce their cellular effects. PMID- 24165126 TI - Stepwise folding of an autotransporter passenger domain is not essential for its secretion. AB - Autotransporters are a superfamily of virulence proteins produced by Gram negative bacteria. They consist of an N-terminal beta-helical domain ("passenger domain") that is secreted into the extracellular space and a C-terminal beta barrel domain ("beta-domain") that anchors the protein to the outer membrane. Because the periplasm lacks ATP, vectorial folding of the passenger domain in a C to-N-terminal direction has been proposed to drive the secretion reaction. Consistent with this hypothesis, mutations that disrupt the folding of the C terminus of the passenger domain of the Escherichia coli O157:H7 autotransporter EspP have been shown to cause strong secretion defects. Here, we show that point mutations introduced at specific locations near the middle or N terminus of the EspP beta-helix that perturb folding also impair secretion, but to a lesser degree. Surprisingly, we found that even multiple mutations that potentially abolish the stability of several consecutive rungs of the beta-helix only moderately reduce secretion efficiency. Although these results provide evidence that the free energy derived from passenger domain folding contributes to secretion efficiency, they also suggest that a significant fraction of the energy required for secretion is derived from another source. PMID- 24165127 TI - A novel glucagon-like peptide-1 (GLP-1)/glucagon hybrid peptide with triple acting agonist activity at glucose-dependent insulinotropic polypeptide, GLP-1, and glucagon receptors and therapeutic potential in high fat-fed mice. AB - Glucagon-like peptide-1 (GLP-1), glucose-dependent insulinotropic polypeptide (GIP), and glucagon bind to related members of the same receptor superfamily and exert important effects on glucose homeostasis, insulin secretion, and energy regulation. The present study assessed the biological actions and therapeutic utility of novel GIP/glucagon/GLP-1 hybrid peptides. Nine novel peptides were synthesized and exhibited complete DPP-IV resistance and enhanced in vitro insulin secretion. The most promising peptide, [dA(2)]GLP-1/GcG, stimulated cAMP production in GIP, GLP-1, and glucagon receptor-transfected cells. Acute administration of [dA(2)]GLP-1/GcG in combination with glucose significantly lowered plasma glucose and increased plasma insulin in normal and obese diabetic (ob/ob) mice. Furthermore, [dA(2)]GLP-1/GcG elicited a protracted glucose lowering and insulinotropic effect in high fat-fed mice. Twice daily administration of [dA(2)]GLP-1/GcG for 21 days decreased body weight and nonfasting plasma glucose and increased circulating plasma insulin concentrations in high fat-fed mice. Furthermore, [dA(2)]GLP-1/GcG significantly improved glucose tolerance and insulin sensitivity by day 21. Interestingly, locomotor activity was increased in [dA(2)]GLP-1/GcG mice, without appreciable changes in aspects of metabolic rate. Studies in knock-out mice confirmed the biological action of [dA(2)]GLP-1/GcG via multiple targets including GIP, GLP-1, and glucagon receptors. The data suggest significant promise for novel triple-acting hybrid peptides as therapeutic options for obesity and diabetes. PMID- 24165128 TI - Lithium down-regulates histone deacetylase 1 (HDAC1) and induces degradation of mutant huntingtin. AB - Lithium is an effective mood stabilizer that has been clinically used to treat bipolar disorder for several decades. Recent studies have suggested that lithium possesses robust neuroprotective and anti-tumor properties. Thus far, a large number of lithium targets have been discovered. Here, we report for the first time that HDAC1 is a target of lithium. Lithium significantly down-regulated HDAC1 at the translational level by targeting HDAC1 mRNA. We also showed that depletion of HDAC1 is essential for the neuroprotective effects of lithium and for the lithium-mediated degradation of mutant huntingtin through the autophagic pathway. Our studies explain the multiple functions of lithium and reveal a novel mechanism for the function of lithium in neurodegeneration. PMID- 24165129 TI - 12/15-lipoxygenase contributes to platelet-derived growth factor-induced activation of signal transducer and activator of transcription 3. AB - We showed previously that the small molecule indirubin-3'-monoxime (I3MO) prevents vascular smooth muscle cell (VSMC) proliferation by selectively inhibiting signal transducer and activator of transcription 3 (STAT3). Looking for the underlying upstream molecular mechanism, we here reveal the important role of reactive oxygen species (ROS) for PDGF-induced STAT3 activation in VSMC. We show that neither NADPH-dependent oxidases (Noxes) nor mitochondria, but rather 12/15-lipoxygenase (12/15-LO) are pivotal ROS sources involved in the redox-regulated signal transduction from PDGFR to STAT3. Accordingly, pharmacological and genetic interference with 12/15-LO activity selectively inhibited PDGF-induced Src activation and STAT3 phosphorylation. I3MO is able to blunt PDGF-induced ROS and 15(S)-hydroxyeicosatetraenoic acid (15(S)-HETE) production, indicating an inhibitory action of I3MO on 12/15-LO and consequently on STAT3. We identify 12/15-LO as a hitherto unrecognized signaling hub in PDGF triggered STAT3 activation and show for the first time a negative impact of I3MO on 12/15-LO. PMID- 24165130 TI - Crystal structure of Clostridium botulinum whole hemagglutinin reveals a huge triskelion-shaped molecular complex. AB - Clostridium botulinum HA is a component of the large botulinum neurotoxin complex and is critical for its oral toxicity. HA plays multiple roles in toxin penetration in the gastrointestinal tract, including protection from the digestive environment, binding to the intestinal mucosal surface, and disruption of the epithelial barrier. At least two properties of HA contribute to these roles: the sugar-binding activity and the barrier-disrupting activity that depends on E-cadherin binding of HA. HA consists of three different proteins, HA1, HA2, and HA3, whose structures have been partially solved and are made up mainly of beta-strands. Here, we demonstrate structural and functional reconstitution of whole HA and present the complete structure of HA of serotype B determined by x-ray crystallography at 3.5 A resolution. This structure reveals whole HA to be a huge triskelion-shaped molecule. Our results suggest that whole HA is functionally and structurally separable into two parts: HA1, involved in recognition of cell-surface carbohydrates, and HA2-HA3, involved in paracellular barrier disruption by E-cadherin binding. PMID- 24165131 TI - MT-LOOP-dependent localization of membrane type I matrix metalloproteinase (MT1 MMP) to the cell adhesion complexes promotes cancer cell invasion. AB - Localization of membrane type I matrix metalloproteinase (MT1-MMP) to the leading edge is thought to be a crucial step during cancer cell invasion. However, its mechanisms and functional impact on cellular invasion have not been clearly defined. In this report, we have identified the MT-LOOP, a loop region in the catalytic domain of MT1-MMP ((163)PYAYIREG(170)), as an essential region for MT1 MMP to promote cellular invasion. Deletion of the MT-LOOP effectively inhibited functions of MT1-MMP on the cell surface, including proMMP-2 activation, degradation of gelatin and collagen films, and cellular invasion into a collagen matrix. This is not due to loss of the catalytic function of MT1-MMP but due to inefficient localization of the enzyme to beta1-integrin-rich cell adhesion complexes at the plasma membrane. We also found that an antibody that specifically recognizes the MT-LOOP region of MT1-MMP (LOOPAb) inhibited MT1-MMP functions, fully mimicking the phenotype of the MT-LOOP deletion mutant. We therefore propose that the MT-LOOP region is an interface for molecular interactions that mediate enzyme localization to cell adhesion complexes and regulate MT1-MMP functions. Our findings have revealed a novel mechanism regulating MT1-MMP during cellular invasion and have identified the MT-LOOP as a potential exosite target region to develop selective MT1-MMP inhibitors. PMID- 24165133 TI - Kindlin binds migfilin tandem LIM domains and regulates migfilin focal adhesion localization and recruitment dynamics. AB - Focal adhesions (FAs), sites of tight adhesion to the extracellular matrix, are composed of clusters of transmembrane integrin adhesion receptors and intracellular proteins that link integrins to the actin cytoskeleton and signaling pathways. Two integrin-binding proteins present in FAs, kindlin-1 and kindlin-2, are important for integrin activation, FA formation, and signaling. Migfilin, originally identified in a yeast two-hybrid screen for kindlin-2 interacting proteins, is a LIM domain-containing adaptor protein found in FAs and implicated in control of cell adhesion, spreading, and migration. By binding filamin, migfilin provides a link between kindlin and the actin cytoskeleton. Here, using a combination of kindlin knockdown, biochemical pulldown assays, fluorescence microscopy, fluorescence resonance energy transfer (FRET), and fluorescence recovery after photobleaching (FRAP), we have established that the C terminal LIM domains of migfilin dictate its FA localization, shown that these domains mediate an interaction with kindlin in vitro and in cells, and demonstrated that kindlin is important for normal migfilin dynamics in cells. We also show that when the C-terminal LIM domain region is deleted, then the N terminal filamin-binding region of the protein, which is capable of targeting migfilin to actin-rich stress fibers, is the predominant driver of migfilin localization. Our work details a correlation between migfilin domains that drive kindlin binding and those that drive FA localization as well as a kindlin dependence on migfilin FA recruitment and mobility. We therefore suggest that the kindlin interaction with migfilin LIM domains drives migfilin FA recruitment, localization, and mobility. PMID- 24165134 TI - [Conflict of interest in scientific research]. PMID- 24165132 TI - Characterization of fibrinogen binding by glycoproteins Srr1 and Srr2 of Streptococcus agalactiae. AB - The serine-rich repeat glycoproteins of Gram-positive bacteria comprise a large family of cell wall proteins. Streptococcus agalactiae (group B streptococcus, GBS) expresses either Srr1 or Srr2 on its surface, depending on the strain. Srr1 has recently been shown to bind fibrinogen, and this interaction contributes to the pathogenesis of GBS meningitis. Although strains expressing Srr2 appear to be hypervirulent, no ligand for this adhesin has been described. We now demonstrate that Srr2 also binds human fibrinogen and that this interaction promotes GBS attachment to endothelial cells. Recombinant Srr1 and Srr2 bound fibrinogen in vitro, with affinities of KD = 2.1 * 10(-5) and 3.7 * 10(-6) M, respectively, as measured by surface plasmon resonance spectroscopy. The binding site for Srr1 and Srr2 was localized to tandem repeats 6-8 of the fibrinogen Aalpha chain. The structures of both the Srr1 and Srr2 binding regions were determined and, in combination with mutagenesis studies, suggest that both Srr1 and Srr2 interact with a segment of these repeats via a "dock, lock, and latch" mechanism. Moreover, properties of the latch region may account for the increased affinity between Srr2 and fibrinogen. Together, these studies identify how greater affinity of Srr2 for fibrinogen may contribute to the increased virulence associated with Srr2-expressing strains. PMID- 24165135 TI - Detection of fiber-digesting bacteria in the forestomach contents of llamas (Lama glama) by PCR. AB - The high fibrolytic activity and large biomass of strictly-anaerobic bacteria that inhabit the rumen makes them primarily responsible for the degradation of the forage consumed by ruminants. Llamas feed mainly on low quality fibrous roughages that are digested by an active and diverse microflora. The products of this fermentation are volatile fatty acids and microbial biomass, which will be used by the animals. The aim of this study was to detect the three major fiber digesting anaerobic bacteria in the forestomach contents of llamas by PCR. In this study, we detected Ruminococcus albus, Ruminococcus flavefaciens and Fibrobacter succinogenes in the forestomach contents of eight native llamas from Argentina. PMID- 24165136 TI - [Morphological and molecular identification of Cysticercus fasciolaris isolated from rodent hosts (Rattus norvegicus) in Buenos Aires province (Argentina)]. AB - In a rodent (Rattus norvegicus) survey in Buenos Aires province, metacestodes of tapeworms were found encysted in the liver of the host. The aim of this work was the morphological and molecular identification of this parasite. To achieve the molecular characterization of the parasite, ribosomal (28S) and mitochondrial (COI) DNA were amplified and sequenced. Based on both morphological and molecular data using bioinformatic tools, the metacestode was identified as Cysticercus fasciolaris. The adult form of this tapeworm (Taenia taeniaeformis) commonly infects felid and canid mammalian hosts. This is the first report on the molecular identification of Cysticercus fasciolaris in Buenos Aires province (Argentina). PMID- 24165137 TI - [Coproantigens detection for the diagnosis of canine Echinococcosis in the border area of La Quiaca-Villazon]. AB - Cystic Echinococcosis is a major public health issue. Immunodiagnostic techniques based on the identification of parasite antigens in dog dry faeces have been developed as alternatives for the surveillance of canine Echinococcosis. The environmental conditions favouring the parasite cycle were met in the border of La Quiaca-Villazon, given the presence of definitive (dog) and intermediate hosts (sheep and goats). The most important activity in La Puna is sheep and goat rearing; slaughtering is carried out almost exclusively in the field by sheep's owners, and preventive health measures do not apply. The aim of this study was to determine the presence of dogs parasitized by Echinococcus granulosus in this border region. A hundred and sixty eight (168) stool specimens were collected during 2006. La Quiaca samples were taken from the following selected areas: the semi-rural area of Barrios, the rural areas of Santa Catalina, Yavi Chico, El Portillo, Pumahuasi and Cara Cara and the urban area of La Quiaca; selected urban areas in Villazon and the semi-rural area of Ojo de Agua, Lampaya and Matancillas. The samples were analyzed by copro-ELISA -Western blot test. The cities of San Francisco and Barrios had a prevalence of 14.3% and 6.7%, respectively. A prevalence of 3.4% was observed in the urban area of Villazon, which indicates that dogs become infected in the rural areas and bring the risk into the city. Lampaya showed a prevalence of 30%. These findings suggest the need to implement strategies for the control of hydatidosis, both in urban and rural areas to avoid the increase and spread of Echinococcosis in the region. PMID- 24165138 TI - First clinical isolates of Cronobacter spp. (Enterobacter sakazakii) in Argentina: characterization and subtyping by pulsed-field gel electrophoresis. AB - Cronobacter species are opportunistic pathogens associated with severe infections in neonates and immunocompromised infants. From January 2009 through September 2010, two cases of neonatal infections associated with Cronobacter malonaticus and one case associated with Cronobacter sakazakii, two of them fatal, were reported in the same hospital. These are the first clinical isolates of Cronobacter spp. in Argentina. The objective of this work was to characterize and subtype clinical isolates of Cronobacter spp. in neonate patients, as well as to establish the genetic relationship between these isolates and the foodborne isolates previously identified in the country. Pulsed-field gel electrophoresis analysis showed a genetic relationship between the C. malonaticus isolates from two patients. Different results were found when the pulsed-field gel electrophoresis patterns of clinical isolates were compared with those deposited in the National Database of Cronobacter spp. PMID- 24165139 TI - [Serological diagnosis of HTLV-1/2: combination of screening assays to define the serological status in blood donors]. AB - Alternative algorithms were evaluated in order to reduce the number of false reactive results for antibodies against HTLV-1/2. From 20,210 samples tested, 0.37% (74/20,210) was reactive by ELISA Murex. Of these, 23 were confirmed as positive by the indirect immunofluorescence assay whereas 51 were negative, being the positive predictive value (PPV) 31.08%. From a combination of the ELISA Murex assay with the particle agglutination assay (PA) and ELISA MP, the following results were obtained: 26/74 were reactive by ELISA Murex and PA, PPV 88.5% and 32/74 were reactive by ELISA Murex and ELISA MP, PPV 71.8 %. The ROC curve analysis determined that for an RP 4.74, the values for sensitivity, specificity, PPV and NPV by ELISA Murex were 100%, 98.04%, 95.8% and 100%, respectively. We propose that reactive samples by ELISA Murex with an RP d 4.74 should be retested in duplicate by PA, and the resulting concordantly nonreactive samples should be defined as negative for HTLV-1/2. PMID- 24165140 TI - [First report of Echinococcus vogeli in a paca in Misiones province, Argentina]. AB - We report the first finding of Echinococcus vogeli in a paca, Cuniculus paca, in the tropical forest of Misiones, in the north of Argentina. The presence of the bush dog, Speothos venaticus, E. vogelis only natural definitive host, was also reported. The polycystic hydatids, 2 to 3 cm in diameter, were only found in the liver of an adult paca. The size range of the hooks and the relative proportion blade/handle did not show significant differences with respect to the ones reported for E. vogeli. The size of E. granulosus hooks, measured for comparison purposes, was significantly smaller (p E. vogeli in Argentina. The probability of finding neotropical echinococcosis in humans reinforces the need to expand the search for E. vogeli in Argentina. Echinococcosis due to E. vogeli is very aggressive and may cause death in about a third of the human population affected. PMID- 24165141 TI - Arsenic tolerance of cyanobacterial strains with potential use in biotechnology. AB - The arsenic content of various water bodies in Argentina is higher than the acceptable levels for human and animal uses. Cyanobacteria are widely distributed in aquatic environments and can bioaccumulate arsenic (As). This study presents the response of indigenous cyanobacteria to As(III) and As(V), including the species Tolypothrix tenuis, Nostoc muscorum and Nostoc minutum, previously used with biotechnological purposes. As(III) resulted more toxic than As(V) in all cases, causing cell death in the range of 5-20 mg/l. T. tenuis growth was sensitive to As(V) with lethal inhibition at 625 mg/l, whereas the Noctoc species were stimulated. EC50 values found were 73.34 mg/l for N. muscorum and 989.3 mg/l for N. minutum. Batch cultures of N. minutum showed improvements in both growth parameters and photosynthetic pigment content in the presence of 1,000 mg/l As(V). Increases of 66.7%, 75.5%, 40% and 20.7% in cell productivity, chlorophyll a, total carotenoids and C-phycocyanin respectively were observed, reaching a bioaccumulated arsenic value of 37.4 1/4g/g at the stationary growth phase. PMID- 24165142 TI - [Comparison of techniques for coliform bacteria extraction from sediment of Xochimilco Lake, Mexico]. AB - The need to separate bacteria from sediment in order to appropriately count them has led to test the efficacy of different techniques. In this research, traditional techniques such as manual shaking, homogenization, ultrasonication, and surfactant are compared. Moreover, the possibility of using a set of enzymes (pancreatine) and an antibiotic (ampicillin) for sediment coliform extraction is proposed. Samples were obtained from Xochimilco Lake in Mexico City. The most probable number of coliform bacteria was determined after applying the appropriate separation procedure. Most of the techniques tested led to numbers similar to those of the control (manual shaking). Only with the use of ampicillin, a greater total coliform concentration was observed (Mann-Whitney, z = 2.09; p = 0.03). It is possible to propose the use of ampicillin as a technique for total coliform extraction; however, it is necessary to consider sensitivity of bacteria to the antibiotic. PMID- 24165144 TI - [Intestinal parasitoses in Argentina: major causal agents found in the population and in the environment]. AB - Intestinal parasitic diseases are widely spread in the world, with the highest prevalence in developing countries. Children are mainly affected, showing a decrease in physical and mental development, as well as the expected manifestations of the disease. This situation can be greatly enhanced in children with poor nutritional status. The World Health Organization considers intestinal parasitic diseases a major cause of morbidity, closely linked to poverty and poor personal hygiene, inappropriate handling of raw food, lack of sanitation, lack of potable water supply, and environmental fecal contamination. Some parasitic diseases are cosmopolitan while others have variable geographic distribution, due to different factors such as the presence of exclusive intermediate hosts. In the past few years, globalization allowed the spread of certain parasites from endemic to non-endemic regions. Even though people's customs influence on the frequency of certain parasites, environmental conditions are a determinant factor for parasite survival. In our country, due to the variety of soils and climatic conditions, several causative agents of these parasitoses can be found. The aim of this work was to review the literature on the intestinal parasitic agents found in Argentina in human fecal samples and its environment, as parasitic contamination constitutes a direct indicator of the infection risk by intestinal parasites. PMID- 24165143 TI - [Emergence of colistin-resistant Klebsiella pneumoniae. Microbiological and epidemiological characterization of the isolates producing and non-producing KPC type carbapenemase]. AB - Sixty-four colistin-resistant Klebsiella pneumoniae isolates recovered from clinical specimens from 57 patients admitted to Hospital de Clinicas Jose de San Martin during the period 2010-2012 were studied to describe the microbiological and epidemiological characteristics and factors associated with the emergence of colistin-resistance. Fifty-four colistin-susceptible K. pneumoniae isolates from the same period were also included in the study. The genetic relatedness among the isolates was studied by a PCR assay. Fifty percent of the resistant isolates were KPC-2 producers, 45.3% were ESBL producers and 4.7% only showed resistance to aminopenicilins. All KPC-producers (resistant and susceptible to colistin) were genotipically indistinguishable except for one, whereas the presence of 7 clonal types, which were different from the ones identified in the colistin susceptible isolates, were detected among ESBL producers. The previous use of colistin was the main factor associated with the acquisition of resistance, and in the case of non-KPC producers the stay in ICU was another significant factor observed. Colistin resistance emerged in our hospital in the year 2010, reaching 3% in nosocomial isolates and maintaining this rate in successive years, due to the selection of resistant subpopulations in the epidemic clonal type in KPC producers and due to the dispersion of colistin-resistant clonal types in non-KPC producing-isolates. PMID- 24165145 TI - [Detection of lactic acid isomers: metabolites of lactic acid bacteria isolated from Colombian sourdough]. PMID- 24165146 TI - [Mycological diagnosis of skin wounds in oncological patients]. PMID- 24165147 TI - Electroacupuncture upregulates ERK signaling pathways and promotes adult hippocampal neural progenitors proliferation in a rat model of depression. AB - BACKGROUND: In this study, we investigate the proliferation of adult neural stem cells (NSCs) in a chronic unpredictable stress (CUS) rat model of depression, the effects of electroacupunture (EA) on depressive-like symptoms and the corresponding signaling pathways. METHODS: SD rats were subjected to 4 weeks of CUS to induce depressive-like behaviors. EA was performed at the Du-20 (Bai-Hui) and GB-34 (Yang-Ling-Quan) acupoints. Rats were injected with BrdU and the brains were cut into sections. Double-labeling with BrdU/Sox2 and p-ERK/Nestin was performed to demonstrate the in vivo proliferation of adult NSCs in hippocampus and ERK activation in NSCs. Hippocampal microdialysates of different groups were collected to observe the in vitro effects on NSCs. RESULTS: After 8 treatments, EA generated a clear antidepressant effect on the stressed rats and promoted the NSC proliferation. ERK activation might be involved in the antidepressant-like effects of EA treatment. Hippocampal microdialysates from EA-treated stressed rats influenced NSCs to form larger neural spheres and exhibit higher p-ERK level in vitro, compared to the untreated stressed rats. Meanwhile, the antidepressant like effects of EA involved contribution from both acupoint specificity and electrical stimulus. CONCLUSIONS: EA might interfere with the hippocampal microenvironment and enhance the activation of ERK signaling pathways. This could mediate, at least in part, the beneficial effects of EA on NSC proliferation and depressive-like behaviors. PMID- 24165148 TI - Microsatellite markers from the Ion Torrent: a multi-species contrast to 454 shotgun sequencing. AB - The development and screening of microsatellite markers have been accelerated by next-generation sequencing (NGS) technology and in particular GS-FLX pyro sequencing (454). More recent platforms such as the PGM semiconductor sequencer (Ion Torrent) offer potential benefits such as dramatic reductions in cost, but to date have not been well utilized. Here, we critically compare the advantages and disadvantages of microsatellite development using PGM semiconductor sequencing and GS-FLX pyro-sequencing for two gymnosperm (a conifer and a cycad) and one angiosperm species. We show that these NGS platforms differ in the quantity of returned sequence data, unique microsatellite data and primer design opportunities, mostly consistent with the differences in read length. The strength of the PGM lies in the large amount of data generated at a comparatively lower cost and time. The strength of GS-FLX lies in the return of longer average length sequences and therefore greater flexibility in producing markers with variable product length, due to longer flanking regions, which is ideal for capillary multiplexing. These differences need to be considered when choosing a NGS method for microsatellite discovery. However, the ongoing improvement in read lengths of the NGS platforms will reduce the disadvantage of the current short read lengths, particularly for the PGM platform, allowing greater flexibility in primer design coupled with the power of a larger number of sequences. PMID- 24165150 TI - Hereditary cancer risk assessment: essential tools for a better approach. AB - Hereditary cancer risk assessment (HCRA) is a multidisciplinary process of estimating probabilities of germline mutations in cancer susceptibility genes and assessing empiric risks of cancer, based on personal and family history. It includes genetic counseling, testing and management of at-risk individuals so that they can make well-informed choices about cancer surveillance, surgical treatment and chemopreventive measures, including biomolecular cancer therapies. Providing patients and family members with an appropriate HCRA will contribute to a better process of making decisions about their personal and family risks of cancer. Following individuals at high risk through screening protocols, reassuring those at low risk, and referring those at increased risk of hereditary cancer to a cancer genetics center may be the best suitable approach of HCRA. PMID- 24165149 TI - Primary tumor vascularity, HIF-1alpha and VEGF expression in vulvar squamous cell carcinomas: their relationships with clinicopathological characteristics and prognostic impact. AB - BACKGROUND: Increased vascularity is a crucial event in the tumor progression and has prognostic significance in various cancers. However, the ultimate role of angiogenesis in the pathogenesis and clinical outcome of vulvar carcinoma patients is still not settled. METHODS: Tumor vascularity using CD34 stained slides measured by Chalkley counting method as well as hypoxia-inducible factor (HIF)-1alpha and vascular endothelial growth factor (VEGF) immunoexpression was examined in 158 vulvar squamous cell carcinomas. Associations between vascular Chalkley count, HIF-1alpha and VEGF expression and clinicopathological factors and clinical outcome were evaluated. RESULTS: High CD34 Chalkley count was found to correlate with larger tumor diameter (P = 0.002), deep invasion (P < 0.001) and HIF-1alpha (P = 0.04), whereas high VEGF expression correlate significantly with poor tumor differentiation (P = 0.007). No significant association between CD34 Chalkley counts and VEGF expression and disease-specific survival was observed. High HIF-1alpha expression showed better disease specific survival in both univariate and multivariate analyses (P = 0.001). CONCLUSIONS: A significant association between high tumor vascularity and larger tumor size as well as deeper tumor invasion suggests an important role of angiogenesis in the growth and progression of vulvar carcinomas. HIF-1alpha expression in vulvar carcinomas was a statistically independent prognostic factor. PMID- 24165151 TI - Flocculation increases the efficacy of depth filtration during the downstream processing of recombinant pharmaceutical proteins produced in tobacco. AB - Flocculation is a cost-effective method that is used to improve the efficiency of clarification by causing dispersed particles to clump together, allowing their removal by sedimentation, centrifugation or filtration. The efficacy of flocculation for any given process depends on the nature and concentration of the particulates in the feed stream, the concentration, charge density and length of the flocculant polymer, the shear rate, the properties of the feed stream (e.g. pH and ionic strength) and the properties of the target products. We tested a range of flocculants and process conditions using a design of experiments approach to identify the most suitable polymers for the clarification step during the production of a HIV-neutralizing monoclonal antibody (2G12) and a fluorescent marker protein (DsRed) expressed in transgenic tobacco leaves. Among the 23 different flocculants we tested, the greatest reduction in turbidity was achieved with Polymin P, a branched, cationic polyethylenimine with a charge density of 13.0 meq/g. This flocculant reduced turbidity by more than 90% under a wide range of process conditions. We developed a model that predicted its performance under different process conditions, and this enabled us to increase the depth filter capacity three-sevenfold depending on the process scale, depth filter type and plant species. The costs of filter consumables were reduced by more than 50% compared with a process without flocculant, and there was no loss of recovery for either 2G12 or DsRed. PMID- 24165152 TI - Peripheral nerve field stimulation for chronic headache: 60 cases and long-term follow-up. AB - OBJECTIVE: The objective of this study is to evaluate the efficacy of peripheral nerve field stimulation (PNFS) for the treatment of chronic headache conditions. MATERIALS AND METHODS: For more than a four-year period, 83 patients underwent a trial of a PNFS system targeting the nerve regions including occipital and supraorbital and infraorbital nerves, which best corresponded with their area of head pain. Sixty patients reported a successful trial and underwent a subsequent implant of the PNFS system. Questionnaires, along with patients' charts, were used to assess outcomes as follows: pain (11-point numerical pain rating scale), analgesic use, depression (Zung Depression Scale), disability (Neck Disability Index), patient satisfaction, and surgical complications. Patients were followed up for an average of 12.9 +/- 9.4 months (range 3-42 months). RESULTS: An average pain reduction of 4.8 +/- 2.3 pain scale points was observed (preimplant 7.4 +/- 1.6; follow-up 2.6 +/- 2.1 [p <= 0.001]). Of the 60 patients implanted, 41 reported >50% pain relief. Medication use was reduced in 83% of patients who were previously taking analgesics or prophylactic medications. Similarly, reductions in degree of disability and depression also were observed. Of the 60 cases, ten surgical revisions were required; however, no long-term complications were reported. CONCLUSIONS: PNFS for chronic headache is an evolving therapy. This study demonstrates that this reversible and effective treatment can be a promising pain relief strategy for this often intractable condition. PMID- 24165153 TI - Laboratory testing and standardisation. PMID- 24165154 TI - Pharmacokinetics of plasma-derived and recombinant factor IX: using population pharmacokinetics with sparse sampling data needs further study. AB - The concept of using pharmacokinetics for prophylactic dose tailoring with limited blood sampling in clinical practice has been demonstrated for factor VIII but not for factor IX. The pharmacokinetics of factor IX are more complicated than for factor VIII and also differ between plasma-derived and recombinant factor IX. Therefore, the pharmacokinetics of factor IX need to be further explored in clinical trials including comparative studies of prophylaxis with different factor IX concentrates. These are the main conclusions drawn from two of the last manuscripts written by Professor Sven Bjorkman and published in Haemophilia. Professor Bjorkman suddenly and unexpectedly died last summer. Thanks to the academic network created around his skill and through his enthusiasm for the pharmacokinetics of clotting factors and ability to convey his wisdom to others, this work will continue. Sven Bjorkman opened a new era in hemophilia prophylaxis. PMID- 24165155 TI - Comparative pharmacokinetics of factor VIII and recombinant factor IX: for which coagulation factors should half-life change with age? AB - The half-life of factor VIII (FVIII) increases with the age of the patient, while studies on recombinant factor IX (rFIX) and factor VIIa (rFVIIa) have not demonstrated corresponding age-related changes. The purpose of this analysis was to relate the changes in FVIII and rFIX pharmacokinetics (PK) with age to developmental changes in body size and fluid volumes and explain why the elimination half-life of FVIII, but not of rFIX, would change with age, and to consider how the findings could be applied prospectively to other coagulation factors. Published PK data for FVIII from 186 patients aged 1-74 years and for rFIX from 56 patients aged 4-56 years were used. The relationships of FVIII and rFIX clearance (CL) with body weight could be described by allometric expressions. Relative changes in CL with age or weight were similar for FVIII and rFIX. The age-related change in volume of distribution at steady state (V(ss)) of rFIX was parallel to the change in CL in the children while for FVIII the change was much less pronounced. Elimination half-life was clearly age-dependent for FVIII while only a very weak trend could be seen for rFIX. Limited data suggest that rFVIIa in this respect resembles rFIX, with parallel changes in CL and V(ss) producing insignificant change in half-life. To what extent the elimination half life of a coagulation factor would show a correlation with age can in principle be predicted from the characteristics of its CL and distribution. PMID- 24165156 TI - HIV-1 tropism: a comparison between RNA and proviral DNA in routine clinical samples from Chilean patients. AB - BACKGROUND: HIV in Chile has a notification rate of 0.01%. Coreceptor antagonists are a family of antiretroviral drugs that are used with the prior knowledge of patients HIV-1 tropism. Viral RNA-based tropism detection requires a plasma viral load >=1000 copies/mL, while proviral DNA-based detection can be performed regardless of plasma viral load. This test is useful in patients with low or undetectable viral loads and would benefit with a proper therapy. The aim of this study was to determine the correlation between HIV RNA and proviral genotypic DNA tropism tests. FINDINGS: Forty three Chilean patients were examined using population-based V3 sequencing, and a geno2pheno false-positive rate (FPR) cutoff values of 5, 5.75, 10 and 20%. With cutoff 5.75% a concordance of 88.4% in tropism prediction was found after a simultaneous comparison between HIV tropism assessment by RNA and DNA. In total, five discrepancies (11.6%) were found, 3 patients were RNA-R5/DNA-X4 and two were RNA-X4/DNA-R5. Proviral DNA enabled the prediction of tropism in patients with a low or undetectable viral load. For cutoff 5 and 5.75% genotypic testing using proviral DNA showed a similar sensitivity for X4 as RNA. We found that the highest sensitivity for detecting the X4 strain occurred with proviral DNA and cutoff of 10 and 20%. Viral loads were higher among X4 strain carriers than among R5 strain carriers (p < 0.05). CONCLUSIONS: A high degree of concordance was found between tropism testing with RNA and testing with proviral DNA. Our results suggest that proviral DNA-based genotypic tropism testing is a useful option for patients with low or undetectable viral load who require a different therapy. PMID- 24165158 TI - MET and AXL inhibitor NPS-1034 exerts efficacy against lung cancer cells resistant to EGFR kinase inhibitors because of MET or AXL activation. AB - In non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) mutations, acquired resistance to EGFR-tyrosine kinase inhibitors (EGFR TKI) can occur through a generation of bypass signals such as MET or AXL activation. In this study, we investigated the antitumor activity of NPS-1034, a newly developed drug that targets both MET and AXL, in NSCLC cells with acquired resistance to gefitinib or erlotinib (HCC827/GR and HCC827/ER, respectively). Characterization of H820 cells and evaluation of NPS-1034 efficacy in these cells were also performed. The resistance of HCC827/GR was mediated by MET activation, whereas AXL activation led to resistance in HCC827/ER. The combination of gefitinib or erlotinib with NPS-1034 synergistically inhibited cell proliferation and induced cell death in both resistant cell lines. Accordingly, suppression of Akt was noted only in the presence of treatment with both drugs. NPS-1034 was also effective in xenograft mouse models of HCC827/GR. Although the H820 cell line was reported previously to have T790M and MET amplification, we discovered that AXL was also activated in this cell line. There were no antitumor effects of siRNA or inhibitors specific for EGFR or MET, whereas combined treatment with AXL siRNA or NPS-1034 and EGFR-TKIs controlled H820 cells, suggesting that AXL is the main signal responsible for resistance. In addition, NPS-1034 inhibited cell proliferation as well as ROS1 activity in HCC78 cells with ROS1 rearrangement. Our results establish the efficacy of NPS-1034 in NSCLC cells rendered resistant to EGFR-TKIs because of MET or AXL activation or ROS1 rearrangement. PMID- 24165159 TI - GLI1 interferes with the DNA mismatch repair system in pancreatic cancer through BHLHE41-mediated suppression of MLH1. AB - The mismatch repair (MMR) system is indispensable for the fidelity of DNA replication, the impairment of which predisposes to the development and progression of many types of cancers. To date, GLI1 transcription factor, a key molecule of the Hedgehog signaling pathway, has been shown to regulate the expression of several genes crucial for a variety of cancer cell properties in many types of cancers, including pancreatic ductal adenocarcinoma (PDAC), but whether GLI1 could control the MMR system was not known. Here, we showed that GLI1 and GLI2 indirectly suppressed the expression of MLH1 in PDAC cells. Through GLI1 target gene screening, we found that GLI1 and GLI2 activated the expression of a basic helix-loop-helix type suppressor BHLHE41/DEC2/SHARP1 through a GLI binding site in the promoter. Consistent with a previous report that BHLHE41 suppresses the MLH1 promoter activity, we found that the activation of GLI1 led to the BHLHE41-dependent suppression of MLH1, and a double knockdown of GLI1 and GLI2 conversely increased the MLH1 protein in PDAC cells. Using TALEN-based modification of the MLH1 gene, we further showed that GLI1 expression was indeed associated with an increased tolerance to a methylating agent, methylnitrosourea cooperatively with a lower copy number status of MLH1. Finally, GLI1 expression was immunohistochemically related positively with BHLHE41 and inversely with MLH1 in PDAC cells and precancerous lesions of the pancreas. On the basis of these results, we propose that GLI1 depresses the MMR activity and might contribute to the development and progression of PDAC. PMID- 24165161 TI - Prevalence of neuropathic pain according to the IASP grading system in patients with chronic non-malignant pain. AB - OBJECTIVE: The primary objective was to determine the prevalence of neuropathic pain according to the new International Association for the Study of Pain (IASP) grading system. The secondary objective was to compare the system classification of neuropathic pain with the classification of neuropathic pain according to a patient-administered screening questionnaire. SETTING: A Multidisciplinary Pain Center. SUBJECTS: One hundred twenty patients with a variety of chronic pain conditions referred to a multidisciplinary pain center. METHODS: Consecutively referred patients filled out the PainDETECT Questionnaire before the first consultation. During the first consultation, patients had pain history taken and bedside examination performed by a pain specialist. Patients were classified according to the score on the PainDETECT Questionnaire and graded according to the IASP grading system about the certainty of neuropathic pain. RESULTS: According to the IASP grading system, 22 patients (18.3%) classified as probable or definite neuropathic pain and 90 patients (75%) as unlikely neuropathic pain. According to the PainDETECT Questionnaire, 55 patients (45%) were classified as likely neuropathic pain and 13 patients (10.8%) as unlikely neuropathic pain. Eleven patients (20%) who were classified as neuropathic pain according to PainDETECT were also classified as probable or definite neuropathic pain by the new IASP grading system. CONCLUSIONS: According to the new IASP grading system, less than 20% of the patients referred to a multidisciplinary pain center fulfilled the criteria for neuropathic pain. The classification of neuropathic pain with the IASP system varies from the classification of neuropathic pain with the use of a self-administered screening questionnaire. PMID- 24165160 TI - Gut microbiota protects against gastrointestinal tumorigenesis caused by epithelial injury. AB - Inflammation is a critical player in the development of both colitis-associated and sporadic colon cancers. Several studies suggest that the microbiota contribute to inflammation and tumorigenesis; however, studies to understand the role of the microbiota in colon tumor development in germ-free (GF) mice are limited. We therefore studied the effects of the microbiota on the development of inflammation and tumors in GF and conventionally raised specific pathogen-free (SPF) mice treated with azoxymethane (AOM) and dextran sulfate sodium (DSS). We discovered that GF mice developed significantly more and larger tumors compared with that in SPF mice after AOM and DSS treatment despite the lack of early acute inflammation in response to chemically induced injury by DSS. Although the extent of intestinal epithelial damage and apoptosis was not significantly different in GF and SPF mice, there was a delay in intestinal epithelial repair to DSS-induced injury in GF mice resulting in a late onset of proinflammatory and protumorigenic responses and increased epithelial proliferation and microadenoma formation. Recolonization of GF mice with commensal bacteria or administration of lipopolysaccharide reduced tumorigenesis. Thus, although commensal bacteria are capable of driving chronic inflammation and tumorigenesis, the gut microbiota also have important roles in limiting chemically induced injury and proliferative responses that lead to tumor development. PMID- 24165164 TI - Beyond topoisomerase inhibition: antitumor 1,4-naphthoquinones as potential inhibitors of human monoamine oxidase. AB - Monoamine oxidase (MAO) action has been involved in the regulation of neurotransmitters levels, cell signaling, cellular growth, and differentiation as well as in the balance of the intracellular polyamine levels. Although so far obscure, MAO inhibitors are believed to have some effect on tumors progression. 1,4-naphthoquinone (1,4-NQ) has been pointed out as a potential pharmacophore for inhibition of both MAO and DNA topoisomerase activities, this latter associated with antitumor activity. Herein, we demonstrated that certain antitumor 1,4-NQs, including spermidine-1,4-NQ, lapachol, and nor-lapachol display inhibitory activity on human MAO-A and MAO-B. Kinetic studies indicated that these compounds are reversible and competitive MAO inhibitors, being the enzyme selectivity greatly affected by substitutions on 1,4-NQ ring. Molecular docking studies suggested that the most potent MAO inhibitors are capable to bind to the MAO active site in close proximity of flavin moiety. Furthermore, ability to inhibit both MAO-A and MAO-B can be potentialized by the formation of hydrogen bonds between these compounds and FAD and/or the residues in the active site. Although spermidine-1,4-NQs exhibit antitumor action primarily by inhibiting topoisomerase via DNA intercalation, our findings suggest that their effect on MAO activity should be taken into account when their application in cancer therapy is considered. PMID- 24165162 TI - Personalized estimates of radiation dose from dedicated breast CT in a diagnostic population and comparison with diagnostic mammography. AB - This study retrospectively analyzed the mean glandular dose (MGD) to 133 breasts from 132 subjects, all women, who participated in a clinical trial evaluating dedicated breast CT in a diagnostic population. The clinical trial was conducted in adherence to a protocol approved by institutional review boards and the study participants provided written informed consent. Individual estimates of MGD to each breast from dedicated breast CT was obtained by combining x-ray beam characteristics with estimates of breast dimensions and fibroglandular fraction from volumetric breast CT images, and using normalized glandular dose coefficients. For each study participant and for the breast corresponding to that imaged with breast CT, an estimate of the MGD from diagnostic mammography (including supplemental views) was obtained from the DICOM image headers for comparison. This estimate uses normalized glandular dose coefficients corresponding to a breast with 50% fibroglandular weight fraction. The median fibroglandular weight fraction for the study cohort determined from volumetric breast CT images was 15%. Hence, the MGD from diagnostic mammography was corrected to be representative of the study cohort. Individualized estimates of MGD from breast CT ranged from 5.7 to 27.8 mGy. Corresponding to the breasts imaged with breast CT, the MGD from diagnostic mammography ranged from 2.6 to 31.6 mGy. The mean (+/- inter-breast SD) and the median MGD (mGy) from dedicated breast CT exam were 13.9 +/- 4.6 and 12.6, respectively. For the corresponding breasts, the mean (+/- inter-breast SD) and the median MGD (mGy) from diagnostic mammography were 12.4 +/- 6.3 and 11.1, respectively. Statistical analysis indicated that at the 0.05 level, the distributions of MGD from dedicated breast CT and diagnostic mammography were significantly different (Wilcoxon signed ranks test, p = 0.007). While the interquartile range and the range (maximum-minimum) of MGD from dedicated breast CT was lower than diagnostic mammography, the median MGD from dedicated breast CT was approximately 13.5% higher than that from diagnostic mammography. The MGD for breast CT is based on a 1.45 mm skin layer and that for diagnostic mammography is based on a 4 mm skin layer; thus, favoring a lower estimate for MGD from diagnostic mammography. The median MGD from dedicated breast CT corresponds to the median MGD from four to five diagnostic mammography views. In comparison, for the same 133 breasts, the mean and the median number of views per breast during diagnostic mammography were 4.53 and 4, respectively. Paired analysis showed that there was approximately equal likelihood of receiving lower MGD from either breast CT or diagnostic mammography. Future work will investigate methods to reduce and optimize radiation dose from dedicated breast CT. PMID- 24165165 TI - Historical aspects of appendicitis in children. AB - Evidence of appendicitis exists from ancient Egyptian mummies but the appendix was not discovered as an anatomical entity until the renaissance in Western European literature. Much confusion reigned over the cause of right iliac fossa inflammatory disease until the late 19th century, when the appendix was recognized as the cause of the great majority of cases. Coining the term 'appendicitis' and making the case for early surgery, Fitz in 1886 set the scene for recovery from appendicitis through operative intervention. PMID- 24165166 TI - Advances in laparoscopic colorectal surgery: a review on NOTES and transanal extraction of specimen. AB - Laparoscopic colorectal surgery has rapidly developed since the 1980s. Relative to open surgery, it offers the benefits of less invasiveness and earlier recovery. However, when a mini-laparotomy wound is needed to retrieve the specimen, the benefits of minimally invasive surgery may be compromised as a result of pain- and wound-related complications. The introduction of natural orifice transluminal endoscopic surgery (NOTES) makes "scarless" surgery a possibility; pain- and wound-related complications are totally abolished. However, a number of technical issues need to be overcome before this technique can be used widely. The development of natural orifice specimen extraction surgery abandons the need for a specimen-retrieval incision and helps overcome the technical hurdles of NOTES. As a bridge between true "scarless" surgery and conventional laparoscopic surgery, hybrid procedures combining laparoscopic resection and natural orifice specimen extraction surgery currently play an important role in minimally invasive colorectal surgery. PMID- 24165167 TI - A case of emphysematous pyelonephritis. PMID- 24165168 TI - Pudendal afferents mapping in posterior sacral rhizotomies. AB - BACKGROUND: The effectiveness of pudendal afferents mapping in posterior sacral rhizotomies needs to be reviewed. OBJECTIVE: To evaluate the effectiveness of pudendal afferents mapping for both the dorsal penile or clitoral nerve and the inferior anal nerve to decrease the risk of postoperative bowel and bladder dysfunction when the sacral nerve roots are candidates for rhizotomies. METHODS: A retrospective review of 101 Asian children who underwent functional posterior rhizotomies with pudendal afferents mapping for spastic paresis was performed. RESULTS: Pudendal mapping was successful in 75 of 81 patients. The highest activity of afferent fibers of the dorsal penile or clitoral nerve was demonstrated at the S1 roots in 13.3%, at the S2 in 79.3%, and at the S3-5 in 7.3%. Considerable activity of the dorsal penile or clitoral nerve was recorded at 40% of the S1 roots, at 99.3% of the S2 roots, and at 52% of the S3-5 roots. The highest activity of afferent fibers of the inferior anal nerve was demonstrated at S2 roots in 42% and at S3-5 roots in 58%. Considerable activity of the inferior anal nerve was recorded at 10.7% of S1 roots, at 89.3% of S2 roots, and at 76.7% of S3-5 roots. The pathological S1 roots were divided into 3 to 4 rootlets, and the rootlets with significant afferent activity were preserved. None of the 75 patients experienced long-term bowel or bladder complications. CONCLUSION: Pudendal afferent mapping identified the sacral rootlets involved with genital and anal sensation. The preservation of such rootlets in sacral rhizotomies is considered to be important for minimizing postoperative bladder and bowel dysfunction. PMID- 24165169 TI - Open ulnar nerve decompression using small incision and alternate positioning. PMID- 24165170 TI - A new way to consider cerebrovascular disease pathogenesis. PMID- 24165171 TI - In reply: Open ulnar nerve decompression using small incision and alternate positioning. PMID- 24165172 TI - Sexual function in patients with deep infiltrating endometriosis. AB - INTRODUCTION: Endometriosis is a benign condition that causes pain and infertility. Sexual dysfunction, particularly deep dyspareunia, is common in patients with endometriosis and interferes with quality of life and conjugal satisfaction. AIM: The study aims to assess sexual function in women with deep infiltrating endometriosis. METHOD: Fifty-seven women diagnosed with deep infiltrating endometriosis were recruited from Hospital Universitario Pedro Ernesto (HUPE) between July and December 2011. The control group comprised 38 healthy women recruited at the HUPE family planning clinic. MAIN OUTCOME MEASURES: The main outcomes are full-scale and individual domain scores on the Female Sexual Function Index (FSFI), a validated questionnaire for functional assessment of sexual function in women. RESULTS: Patients with endometriosis had more pain in intercourse than controls, which correlates with lower scores in the FSFI pain domain. However, there were no statistically significant between-group differences in overall (full-scale) FSFI scores. CONCLUSION: Women with endometriosis exhibit significant dysfunction in the pain domain of the FSFI questionnaire, but this finding was not sufficient to affect the overall sexual function. PMID- 24165173 TI - Low but sufficient anidulafungin exposure in critically ill patients. AB - The efficacy of anidulafungin is driven by the area under the concentration-time curve (AUC)/MIC ratio. Patients in intensive care may be at risk for underexposure. In critically ill patients with an invasive Candida infection, the anidulafungin exposure and a possible correlation with disease severity or plasma protein levels were explored. Concentration-time curves were therefore obtained at steady state. Anidulafungin concentrations were measured with a validated liquid chromatography-tandem mass spectrometry (LC-MS/MS) method. The MIC values of the Candida species were determined with the Etest. The target AUC/MIC ratio was based on European Committee on Antimicrobial Susceptibility Testing (EUCAST) data. Twenty patients were included. The patients received a maintenance dose of 100 mg once daily after a loading dose of 200 mg on the first day. The mean (+/ standard deviation) AUC, maximum concentration of drug in plasma (Cmax), and minimum concentration of drug in plasma (Cmin) were 69.8 +/- 24.1 mg . h/liter, 4.7 +/- 1.4 mg/liter, and 2.2 +/- 0.8 mg/liter, respectively. The MIC values of all cultured Candida species were below the EUCAST MIC breakpoints. The exposure to anidulafungin in relation to the MIC that was determined appeared sufficient in all patients. The anidulafungin exposure was low in our critically ill patients. However, combined with the low MICs of the isolated Candida strains, the lower exposure observed in comparison to the exposure in the general patient population resulted in favorable AUC/MIC ratios, based on EUCAST data. No correlation was observed between anidulafungin exposure and disease severity or plasma protein concentrations. In patients with less-susceptible Candida albicans or glabrata strains, we recommend considering determining the anidulafungin exposure to ensure adequate exposure. (This trial has been registered at ClinicalTrials.gov under registration no. NCT01047267.). PMID- 24165174 TI - Characterizing in vivo pharmacodynamics of carbapenems against Acinetobacter baumannii in a murine thigh infection model to support breakpoint determinations. AB - Pharmacodynamic profiling data of carbapenems for Acinetobacter spp. are sparse. This study aimed to determine the pharmacodynamic targets of carbapenems for Acinetobacter baumannii based on a range of percentages of the dosing interval in which free drug concentrations remained above the MIC (fT>MIC) in the neutropenic murine thigh infection model. fT>MIC values of 23.7%, 32.8%, and 47.5% resulted in stasis, 1-log reductions, and 2-log reductions in bacterial density after 24 h, respectively. The pharmacodynamic targets of carbapenems for A. baumannii demonstrated in vivo are similar to those of other Gram-negative bacteria. PMID- 24165175 TI - Potential efficacy of citicoline as adjunct therapy in treatment of cerebral malaria. AB - Cerebral malaria (CM) is characterized by a dysregulated immune response that results in endothelial membrane destabilization and increased microparticle (MP) production. Citicoline (CTC) is a membrane stabilizer used for the treatment of neurological disorders. We evaluated the efficacy of CTC as adjunct therapy to aid recovery from experimental CM. We show that CTC reduces MP production in vitro; in combination with artesunate in vivo, confers partial protection against CM; and prolongs survival. PMID- 24165176 TI - Are vancomycin trough concentrations adequate for optimal dosing? AB - The current vancomycin therapeutic guidelines recommend the use of only trough concentrations to manage the dosing of adults with Staphylococcus aureus infections. Both vancomycin efficacy and toxicity are likely to be related to the area under the plasma concentration-time curve (AUC). We assembled richly sampled vancomycin pharmacokinetic data from three studies comprising 47 adults with various levels of renal function. With Pmetrics, the nonparametric population modeling package for R, we compared AUCs estimated from models derived from trough-only and peak-trough depleted versions of the full data set and characterized the relationship between the vancomycin trough concentration and AUC. The trough-only and peak-trough depleted data sets underestimated the true AUCs compared to the full model by a mean (95% confidence interval) of 23% (11 to 33%; P = 0.0001) and 14% (7 to 19%; P < 0.0001), respectively. In contrast, using the full model as a Bayesian prior with trough-only data allowed 97% (93 to 102%; P = 0.23) accurate AUC estimation. On the basis of 5,000 profiles simulated from the full model, among adults with normal renal function and a therapeutic AUC of >=400 mg . h/liter for an organism for which the vancomycin MIC is 1 mg/liter, approximately 60% are expected to have a trough concentration below the suggested minimum target of 15 mg/liter for serious infections, which could result in needlessly increased doses and a risk of toxicity. Our data indicate that adjustment of vancomycin doses on the basis of trough concentrations without a Bayesian tool results in poor achievement of maximally safe and effective drug exposures in plasma and that many adults can have an adequate vancomycin AUC with a trough concentration of <15 mg/liter. PMID- 24165177 TI - Antibiotic resistance genes in the bacteriophage DNA fraction of human fecal samples. AB - A group of antibiotic resistance genes (ARGs) (blaTEM, blaCTX-M-1, mecA, armA, qnrA, and qnrS) were analyzed by real-time quantitative PCR (qPCR) in bacteriophage DNA isolated from feces from 80 healthy humans. Seventy-seven percent of the samples were positive in phage DNA for one or more ARGs. blaTEM, qnrA, and, blaCTX-M-1 were the most abundant, and armA, qnrS, and mecA were less prevalent. Free bacteriophages carrying ARGs may contribute to the mobilization of ARGs in intra- and extraintestinal environments. PMID- 24165178 TI - Emergence of the 16S rRNA methylase RmtG in an extended-spectrum-beta-lactamase producing and colistin-resistant Klebsiella pneumoniae isolate in Chile. PMID- 24165179 TI - Plasmodium vivax chloroquine resistance and anemia in the western Brazilian Amazon. AB - Data on chloroquine (CQ)-resistant Plasmodium vivax in Latin America is limited, even with the current research efforts to sustain an efficient malaria control program in all these countries where P. vivax is endemic and where malaria still is a major public health issue. This study estimated in vivo CQ resistance in patients with uncomplicated P. vivax malaria, with use of CQ and primaquine simultaneously, in the Brazilian Amazon. Of a total of 135 enrolled subjects who accomplished the 28-day follow-up, parasitological failure was observed in 7 (5.2%) patients, in whom plasma CQ and desethylchloroquine (DCQ) concentrations were above 100 ng/dl. Univariate analysis showed that previous exposure to malaria and a higher initial mean parasitemia were associated with resistance but not with age or gender. In the multivariate analysis, only high initial parasitemia remained significant. Hemoglobin levels were similar at the beginning of the follow-up and were not associated with parasitemia. However, at day 3 and day 7, hemoglobin levels were significantly lower in patients presenting CQ resistance. The P. vivax dhfr (pvdhfr), pvmrp1, pvmdr1, and pvdhps gene mutations were not related to resistance in this small sample. P. vivax CQ resistance is already a problem in the Brazilian Amazon, which could be to some extent associated with the simultaneous report of anemia triggered by this parasite, a common complication of the disease in most of the areas of endemicity. PMID- 24165180 TI - Structural origins of oxacillinase specificity in class D beta-lactamases. AB - Since the discovery and use of penicillin, the increase of antibiotic resistance among bacterial pathogens has become a major health concern. The most prevalent resistance mechanism in Gram-negative bacteria is due to beta-lactamase expression. Class D beta-lactamases are of particular importance due to their presence in multidrug-resistant Acinetobacter baumannii and Pseudomonas aeruginosa. The class D enzymes were initially characterized by their ability to efficiently hydrolyze isoxazolyl-type beta-lactams like oxacillin. Due to this substrate preference, these enzymes are traditionally referred to as oxacillinases or OXAs. However, this class is comprised of subfamilies characterized by diverse activities that include oxacillinase, carbapenemase, or cephalosporinase substrate specificity. OXA-1 represents one subtype of class D enzyme that efficiently hydrolyzes oxacillin, and OXA-24/40 represents another with weak oxacillinase, but increased carbapenemase, activity. To examine the structural basis for the substrate selectivity differences between OXA-1 and OXA 24/40, the X-ray crystal structures of deacylation-deficient mutants of these enzymes (Lys70Asp for OXA-1; Lys84Asp for OXA-24) in complexes with oxacillin were determined to 1.4 A and 2.4 A, respectively. In the OXA-24/40/oxacillin structure, the hydrophobic R1 side chain of oxacillin disrupts the bridge between Tyr112 and Met223 present in the apo OXA-24/40 structure, causing the main chain of the Met223-containing loop to adopt a completely different conformation. In contrast, in the OXA-1/oxacillin structure, a hydrophobic pocket consisting of Trp102, Met99, Phe217, Leu161, and Leu255 nicely complements oxacillin's nonpolar R1 side chain. Comparison of the OXA-1/oxacillin and OXA-24/40/oxacillin complexes provides novel insight on how substrate selectivity is achieved among subtypes of class D beta-lactamases. By elucidating important active site interactions, these findings can also inform the design of novel antibiotics and inhibitors. PMID- 24165181 TI - Multicenter prospective observational study of the comparative efficacy and safety of vancomycin versus teicoplanin in patients with health care-associated methicillin-resistant Staphylococcus aureus bacteremia. AB - The purpose of this study was to compare the clinical efficacy and safety of vancomycin to those of teicoplanin for the treatment of adult patients with health care-associated methicillin-resistant Staphylococcus aureus (HA-MRSA) bacteremia. A multicenter observational study was prospectively conducted in 15 teaching hospitals in Korea between February 2010 and July 2011. Adult patients (>=18 years old) with HA-MRSA bacteremia who were initially treated with vancomycin (VAN) (n = 134) or teicoplanin (TEC) (n = 56) were enrolled. Clinical and microbiological responses and drug-related adverse events were compared between the two treatment groups using univariate and multivariate logistic regression analyses. The vancomycin and teicoplanin MICs were determined by Etest. The MRSA-related mortality, duration of fever, and duration of MRSA bacteremia in the treatment groups were not significantly different. There was no significant difference in the occurrence of drug-related adverse events. Among the 190 MRSA isolates, the VAN MICs ranged from 0.5 to 2 MUg/ml (MIC50 and MIC90, 1.5 MUg/ml), and the TEC MIC ranged from 0.5 to 8 MUg/ml (MIC50, 3 MUg/ml; MIC90, 6 MUg/ml). In multivariate analyses, the antibiotic type (vancomycin or teicoplanin) was not associated with treatment outcomes. This study indicates that teicoplanin is an effective and safe alternative to vancomycin for the treatment of HA-MRSA bacteremia. PMID- 24165183 TI - Efficacy of an experimental azithromycin cream for prophylaxis of tick transmitted lyme disease spirochete infection in a murine model. AB - As an alternative to oral prophylaxis for the prevention of tick transmission of Borrelia burgdorferi, we tested antibiotic cream prophylactic formulations in a murine model of spirochete infection. A 4% preparation of doxycycline cream afforded no protection, but a single application of 4% azithromycin cream was 100% protective when applied directly to the tick bite site at the time of tick removal. Indeed, the azithromycin cream was 100% effective when applied at up to 3 days after tick removal and protected 74% of mice exposed to tick bite when applied at up to 2 weeks after tick removal. Azithromycin cream was also protective when applied at a site distal to the tick bite site, suggesting that it was having a systemic effect in addition to a local transdermal effect. Mice that were protected from tick-transmitted infection did not seroconvert and did not infect larval ticks on xenodiagnosis. Azithromycin cream formulations appear to hold promise for Lyme disease prophylaxis. PMID- 24165182 TI - In Silico prediction and experimental evaluation of furanoheliangolide sesquiterpene lactones as potent agents against Trypanosoma brucei rhodesiense. AB - As a continuation of our earlier study on the in vitro antiprotozoal activity of 40 natural sesquiterpene lactones (STLs), we extended the set of tested compounds from our laboratories to 59. On the basis of this extended data set, further enriched by literature data for 10 compounds tested under the same conditions, our quantitative structure-activity relationship (QSAR) analyses for activity against T. brucei rhodesiense (etiologic agent of human African trypanosomiasis, or sleeping sickness) were continued, and the QSAR model thus obtained with 69 structures was used to predict the activity of a virtual library of 1,750 STL structures. As a major result from these calculations, furanoheliangolide-type compounds, a subclass of STLs hitherto untested against T. brucei rhodesiense, were predicted to have an exceptionally high level of in vitro activity. Four representative compounds of this type, goyazensolide, 4,5-dihydro-2',3'-epoxy-15 deoxygoyazensolide, budlein A, and 4,15-isoatriplicolide tiglate, were therefore tested. They displayed 50% inhibitory concentrations (IC50s) of 0.07, 0.20, 0.07, and 0.015 MUM, respectively, so that the in silico prediction was experimentally confirmed. 4,15-Isoatriplicolide tiglate is the most potent STL against T. b. rhodesiense found. Furanoheliangolide STLs were thus identified as interesting leads against this parasite which deserve more detailed investigations. PMID- 24165184 TI - Detection of CMY-99, a novel acquired AmpC-Type beta-lactamase, and VIM-1 in Proteus mirabilis isolates in Bulgaria. PMID- 24165185 TI - Evaluation of the anti-Schistosoma mansoni activity of thiosemicarbazones and thiazoles. AB - Schistosomiasis is a chronic and debilitating disease caused by a trematode of the genus Schistosoma and affects over 207 million people. Chemotherapy is the only immediate recourse for minimizing the prevalence of this disease and involves predominately the administration of a single drug, praziquantel (PZQ). Although PZQ has proven efficacy, there is a recognized need to develop new drugs as schistosomicides since studies have shown that repeated use of this drug in areas of endemicity may cause a temporary reduction in susceptibility in isolates of Schistosoma mansoni. Hydrazones, thiosemicarbazones, phthalimides, and thiazoles are thus regarded as privileged structures used for a broad spectrum of activities and are potential candidates for sources of new drug prototypes. The present study determined the in vitro schistosomicidal activity of 10 molecules containing these structures. During the assays, parameters such motility and mortality, oviposition, morphological changes in the tegument, cytotoxicity, and immunomodulatory activity caused by these compounds were evaluated. The results showed that compounds formed of thiazole and phthalimide led to higher mortality of worms, with a significant decline in motility, inhibition of pairing and oviposition, and a mortality rate of 100% starting from 144 h of exposure. These compounds also stimulated the production of nitric oxide and tumor necrosis factor alpha (TNF-alpha), thereby demonstrating the presence of immunomodulatory activity. The phthalyl thiazole LpQM-45 caused significant ultrastructural alterations, with destruction of the tegument in both male and female worms. According to the present study, phthalyl thiazole compounds possess antischistosomal activities and should form the basis for future experimental and clinical trials. PMID- 24165186 TI - Prevalence and molecular characterization of fluoroquinolone-resistant Mycobacterium tuberculosis isolates in China. AB - China is one of the countries with the highest burdens of multidrug-resistant (MDR) and fluoroquinolone (FQ)-resistant tuberculosis (TB) globally. Nevertheless, knowledge about the prevalence and molecular characterization of FQ resistant Mycobacterium tuberculosis isolates from this region remains scant. In this study, 138 M. tuberculosis isolates determined by the agar proportion susceptibility method to be resistant to ofloxacin (OFX) were enrolled from a national drug resistance survey of China. All these strains were tested for susceptibility to ofloxacin, levofloxacin, moxifloxacin, gatifloxacin, and sparfloxacin using liquid Middlebrook 7H9 medium. The entire gyrA and gyrB genes conferring FQ resistance were sequenced, and spoligotyping was performed to distinguish different genotypes. Overall, the prevalence of resistance in China was highest for ofloxacin (3.76%), intermediate for levofloxacin (3.18%) and moxifloxacin (3.12%), and lowest for sparfloxacin (1.91%) and gatifloxacin (1.33%). Mutations in the gyrA gene were observed in 89 (64.5%) out of the 138 OFX-resistant M. tuberculosis strains. Positions 94 and 90 were the most frequent sites of mutation conferring FQ resistance on these strains, accounting for high level FQ resistance. Furthermore, the Beijing genotype showed no association with high-level FQ resistance or distribution in hot spots in the quinolone resistance determining region (QRDR) of gyrA. Our findings provide essential implications for the feasibility of genotypic tests relying on detection of mutations in the QRDR of gyrA and the shorter first-line treatment regimens based on FQs in China. PMID- 24165187 TI - Molecular epidemiology and mechanisms of tigecycline resistance in clinical isolates of Acinetobacter baumannii from a Chinese university hospital. AB - Because of its remarkable ability to acquire antibiotic resistance and to survive in nosocomial environments, Acinetobacter baumannii has become a significant nosocomial infectious agent worldwide. Tigecycline is one of the few therapeutic options for treating infections caused by A. baumannii isolates. However, tigecycline resistance has increasingly been reported. Our aim was to assess the prevalence and characteristics of efflux-based tigecycline resistance in clinical isolates of A. baumannii collected from a hospital in China. A total of 74 A. baumannii isolates, including 64 tigecycline-nonsusceptible A. baumannii (TNAB) and 10 tigecycline-susceptible A. baumannii (TSAB) isolates, were analyzed. The majority of them were determined to be positive for adeABC, adeRS, adeIJK, and abeM, while the adeE gene was found in only one TSAB isolate. Compared with the levels in TSAB isolates, the mean expression levels of adeB, adeJ, adeG, and abeM in TNAB isolates were observed to increase 29-, 3-, 0.7-, and 1-fold, respectively. The efflux pump inhibitors (EPIs) phenyl-arginine-beta naphthylamide (PAbetaN) and carbonyl cyanide 3-chlorophenylhydrazone (CCCP) could partially reverse the resistance pattern of tigecycline. Moreover, the tetX1 gene was detected in 12 (18.8%) TNAB isolates. To our knowledge, this is the first report of the tetX1 gene being detected in A. baumannii isolates. ST208 and ST191, which both clustered into clonal complex 92 (CC92), were the predominant sequence types (STs). This study showed that the active efflux pump AdeABC appeared to play important roles in the tigecycline resistance of A. baumannii. The dissemination of TNAB isolates in our hospital is attributable mainly to the spread of CC92. PMID- 24165188 TI - Potent sub-MIC effect of GSK1322322 and other peptide deformylase inhibitors on in vitro growth of Staphylococcus aureus. AB - Peptide deformylase (PDF), a clinically unexploited antibacterial target, plays an essential role in protein maturation. PDF inhibitors, therefore, represent a new antibiotic class with a unique mode of action that provides an alternative therapy for the treatment of infections caused by drug-resistant pathogens, including methicillin-resistant Staphylococcus aureus (MRSA). GSK1322322 is a novel PDF inhibitor that is in phase II clinical development for the treatment of lower respiratory tract and skin infections. We have discovered that PDF inhibitors can prevent S. aureus in vitro growth for up to 6 h at concentrations 8- to 32-fold below their MICs. This phenomenon seems specific to PDF inhibitors, as none of the antimicrobial agents with alternative mechanisms of action tested show such a potent and widespread effect. It also appears limited to S. aureus, as PDF inhibitors do not show such an inhibition of growth at sub-MIC levels in Streptococcus pneumoniae or Haemophilus influenzae. Analysis of the effect of GSK1322322 on the early growth of 100 randomly selected S. aureus strains showed that concentrations equal to or below 1/8* MIC inhibited growth of 91% of the strains tested for 6 h, while the corresponding amount of moxifloxacin or linezolid only affected the growth of 1% and 6% of strains, respectively. Furthermore, the sub-MIC effect demonstrated by GSK1322322 appears more substantial on those strains at the higher end of the MIC spectrum. These effects may impact the clinical efficacy of GSK1322322 in serious infections caused by multidrug-resistant S. aureus. PMID- 24165189 TI - Oxantel disrupts polymicrobial biofilm development of periodontal pathogens. AB - Bacterial pathogens commonly associated with chronic periodontitis are the spirochete Treponema denticola and the Gram-negative, proteolytic species Porphyromonas gingivalis and Tannerella forsythia. These species rely on complex anaerobic respiration of amino acids, and the anthelmintic drug oxantel has been shown to inhibit fumarate reductase (Frd) activity in some pathogenic bacteria and inhibit P. gingivalis homotypic biofilm formation. Here, we demonstrate that oxantel inhibited P. gingivalis Frd activity with a 50% inhibitory concentration (IC50) of 2.2 MUM and planktonic growth of T. forsythia with a MIC of 295 MUM, but it had no effect on the growth of T. denticola. Oxantel treatment caused the downregulation of six P. gingivalis gene products and the upregulation of 22 gene products. All of these genes are part of a regulon controlled by heme availability. There was no large-scale change in the expression of genes encoding metabolic enzymes, indicating that P. gingivalis may be unable to overcome Frd inhibition. Oxantel disrupted the development of polymicrobial biofilms composed of P. gingivalis, T. forsythia, and T. denticola in a concentration-dependent manner. In these biofilms, all three species were inhibited to a similar degree, demonstrating the synergistic nature of biofilm formation by these species and the dependence of T. denticola on the other two species. In a murine alveolar bone loss model of periodontitis oxantel addition to the drinking water of P. gingivalis-infected mice reduced bone loss to the same level as the uninfected control. PMID- 24165190 TI - Evaluating aziridinyl nitrobenzamide compounds as leishmanicidal prodrugs. AB - Many of the nitroaromatic agents used in medicine function as prodrugs and must undergo activation before exerting their toxic effects. In most cases, this is catalyzed by flavin mononucleotide (FMN)-dependent type I nitroreductases (NTRs), a class of enzyme absent from higher eukaryotes but expressed by bacteria and several eukaryotic microbes, including trypanosomes and Leishmania. Here, we utilize this difference to evaluate whether members of a library of aziridinyl nitrobenzamides have activity against Leishmania major. Biochemical screens using purified L. major NTR (LmNTR) revealed that compounds containing an aziridinyl 2,4-dinitrobenzyl core were effective substrates for the enzyme and showed that the 4-nitro group was important for this activity. To facilitate drug screening against intracellular amastigote parasites, we generated leishmanial cells that expressed the luciferase reporter gene and optimized a mammalian infection model in a 96-well plate format. A subset of aziridinyl-2,4-dinitrobenzyl compounds possessing a 5-amide substituent displayed significant growth-inhibitory properties against the parasite, with the most potent agents generating 50% inhibitory concentrations of <100 nM for the intracellular form. This antimicrobial activity was shown to be LmNTR specific since L. major NTR(+/-) heterozygote parasites were slightly resistance to most aziridinyl dinitrobenzyl agents tested. When the most potent leishmanicidal agents were screened against the mammalian cells in which the amastigote parasites were propagated, no growth inhibitory effect was observed at concentrations of up to 100 MUM. We conclude that the aziridinyl nitrobenzamides represent a new lead structure that may have the potential to treat leishmanial infections. PMID- 24165191 TI - Prevention of biofilm colonization by Gram-negative bacteria on minocycline rifampin-impregnated catheters sequentially coated with chlorhexidine. AB - Resistant Gram-negative bacteria are increasing central-line-associated bloodstream infection threats. To better combat this, chlorhexidine (CHX) was added to minocycline-rifampin (M/R) catheters. The in vitro antimicrobial activity of CHX-M/R catheters against multidrug resistant, Gram-negative Acinetobacter baumannii, Enterobacter cloacae, Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa, and Stenotrophomonas maltophilia was tested. M/R and CHX-silver sulfadiazine (CHX/SS) catheters were used as comparators. The novel CHX-M/R catheters were significantly more effective (P < 0.0001) than CHX/SS or M/R catheters in preventing biofilm colonization and showed better antimicrobial durability. PMID- 24165192 TI - A small-molecule inhibitor of hepatitis C virus infectivity. AB - One of the most challenging goals of hepatitis C virus (HCV) research is to develop well-tolerated regimens with high cure rates across a variety of patient populations. Such a regimen will likely require a combination of at least two distinct direct-acting antivirals (DAAs). Combining two or more DAAs with different resistance profiles increases the number of mutations required for viral breakthrough. Currently, most DAAs inhibit HCV replication. We recently reported that the combination of two distinct classes of HCV inhibitors, entry inhibitors and replication inhibitors, prolonged reductions in extracellular HCV in persistently infected cells. We therefore sought to identify new inhibitors targeting aspects of the HCV replication cycle other than RNA replication. We report here the discovery of the first small-molecule HCV infectivity inhibitor, GS-563253, also called HCV infectivity inhibitor 1 (HCV II-1). HCV II-1 is a substituted tetrahydroquinoline that selectively inhibits genotype 1 and 2 HCVs with low-nanomolar 50% effective concentrations. It was identified through a high throughput screen and subsequent chemical optimization. HCV II-1 only permits the production and release of noninfectious HCV particles from cells. Moreover, infectious HCV is rapidly inactivated in its presence. HCV II-1 resistance mutations map to HCV E2. In addition, HCV-II prevents HCV endosomal fusion, suggesting that it either locks the viral envelope in its prefusion state or promotes a viral envelope conformation change incapable of fusion. Importantly, the discovery of HCV II-1 opens up a new class of HCV inhibitors that prolong viral suppression by HCV replication inhibitors in persistently infected cell cultures. PMID- 24165194 TI - Monitoring gene expression in a single Xenopus oocyte using multiple cytoplasmic collections and quantitative RT-PCR. AB - Oocytes and eggs of the African clawed frog, Xenopus laevis, are commonly used in gene expression studies. However, monitoring transcript levels in the individual living oocytes remains challenging. To address this challenge, we used a technique based on multiple repeated collections of nanoliter volumes of cytoplasmic material from a single oocyte. Transcript quantification was performed by quantitative RT-PCR. The technique allowed monitoring of heterologous gene expression in a single oocyte without affecting its viability. We also used this approach to profile the expression of endogenous genes in living Xenopus oocytes. Although frog oocytes are traditionally viewed as a homogenous cell population, a significant degree of gene expression variation was observed among the individual oocytes. A lognormal distribution of transcript levels was revealed in the oocyte population. Finally, using this technique, we observed a dramatic decrease in the content of various cytoplasmic mRNAs in aging unfertilized eggs but not in oocytes, suggesting a link between mRNA degradation and egg apoptosis. PMID- 24165195 TI - The D1-D2 region of the large subunit ribosomal DNA as barcode for ciliates. AB - Ciliates are a major evolutionary lineage within the alveolates, which are distributed in nearly all habitats on our planet and are an essential component for ecosystem function, processes and stability. Accurate identification of these unicellular eukaryotes through, for example, microscopy or mating type reactions is reserved to few specialists. To satisfy the demand for a DNA barcode for ciliates, which meets the standard criteria for DNA barcodes defined by the Consortium for the Barcode of Life (CBOL), we here evaluated the D1-D2 region of the ribosomal DNA large subunit (LSU-rDNA). Primer universality for the phylum Ciliophora was tested in silico with available database sequences as well as in the laboratory with 73 ciliate species, which represented nine of 12 ciliate classes. Primers tested in this study were successful for all tested classes. To test the ability of the D1-D2 region to resolve conspecific and congeneric sequence divergence, 63 Paramecium strains were sampled from 24 mating species. The average conspecific D1-D2 variation was 0.18%, whereas congeneric sequence divergence averaged 4.83%. In pairwise genetic distance analyses, we identified a D1-D2 sequence divergence of <0.6% as an ideal threshold to discriminate Paramecium species. Using this definition, only 3.8% of all conspecific and 3.9% of all congeneric sequence comparisons had the potential of false assignments. Neighbour-joining analyses inferred monophyly for all taxa but for two Paramecium octaurelia strains. Here, we present a protocol for easy DNA amplification of single cells and voucher deposition. In conclusion, the presented data pinpoint the D1-D2 region as an excellent candidate for an official CBOL barcode for ciliated protists. PMID- 24165196 TI - Complete life cycle of a pennellid Peniculus minuticaudae Shiino, 1956 (Copepoda: Siphonostomatoida) infecting cultured threadsail filefish, Stephanolepis cirrhifer. AB - The complete life cycle of a pennellid copepod Peniculus minuticaudae Shiino, 1956 is proposed based on the discovery of all post-embryonic stages together with the post-metamorphic adult females infecting the fins of threadsail filefish Stephanolepis cirrhifer (Monacanthidae) cultured in a fish farm at Ehime Prefecture, Japan. The hatching stage was the infective copepodid. The life cycle of P. minuticaudae consists of six stages separated by moults: the copepodid, four chalimi and adult. In this study, the adult males were observed frequently in precopulatory amplexus with various stages of females however, copulation occurs only between adults. Fertilized pre-metamorphic adult females carrying spermatophores may detach from the host and settle again before undergoing massive differential growth into the post-metamorphic adult female. Comparison of the life cycle of P. minuticaudae has been made with three known pennellids: Lernaeocera branchialis (Linnaeus, 1767), Cardiodectes medusaeus (Wilson, 1908) and Lernaeenicus sprattae (Sowerby, 1806). Among the compared species, P. minuticaudae is the first ectoparasitic pennellid to be discovered to complete its life cycle on a single host without any change in infection site preferences between infective copepodid and fertilized pre-metamorphic female. PMID- 24165197 TI - 60-Hz frequency effect on gait in Parkinson's disease with subthalamic nucleus deep brain stimulation. AB - OBJECTIVE: Gait dysfunction is common in advancing Parkinson's disease and has a disappointing response to dopamine replacement and subthalamic nucleus deep brain stimulation programming parameters. Low-frequency stimulation, less than 130 Hz in combination with increased voltage, has been shown to decrease freezing episodes and number of steps with little impact on overall performance measured by the Unified Parkinson's Disease Rating Scale. This was in the setting of delivering the same total energy, which required both a change in voltage and frequency. We wanted to determine if the benefit came from low frequency alone. MATERIALS AND METHODS: We enrolled 20 Parkinson's patients who were at least three months in postbilateral subthalamic deep brain stimulation and reported gait changes. Subjects held their Parkinson's medications overnight, and following a baseline evaluation, they were randomly assigned to both 60 and 130 Hz stimulation in a blinded fashion with all other parameters held constant. Each subject was set at each frequency twice during the study, with a 60-min stimulation interval prior to each gait evaluation. RESULTS: There was no significant difference between the two frequencies, with the primary outcome measure of stride length. Two of the 20 patients reported a significant subjective improvement in their gait with no statistical difference in their outcomes. There also was less tremor control at 60 Hz. CONCLUSION: We were unable to demonstrate improved gait with lower frequency stimulation as suggested by prior studies. This may have been because of the decreased energy delivered from the lower frequency and unchanged voltage. PMID- 24165199 TI - Antimicrobial activity and cytotoxicity of the ethanol extract, fractions and eight compounds isolated from Eriosema robustum (Fabaceae). AB - BACKGROUND: The aim of this study was to evaluate the antimicrobial activity and the cytotoxicity of the ethanol crude extract, fractions and isolated compounds from the twigs of Eriosema robustum, a plant used for the treatment of coughs and skin diseases. METHODS: Column chromatographic and spectroscopic techniques were used to isolate and identify eight compounds, robusflavones A (1) and B (2), orostachyscerebroside A (3), stigmasterol (4), 1-O-heptatriacontanoyl glycerol (5), eicosanoic acid (6), 3-O-beta-D-glucopyranoside of sitosterol (7) and 6 prenylpinocembrin (8), from E. robustum. A two-fold serial microdilution method was used to determine the minimum inhibitory concentration (MIC) against fungi and bacteria, and the 3-(4,5-dimethylthiazolyl-2)-2,5-diphenyltetrazolium bromide reduction assay was used to evaluate the cytotoxicity. RESULTS: Fraction B had significant antimicrobial activity against Aspergillus fumigatus and Cryptoccocus neoformans (MIC 0.08 mg/ml), whilst the crude extract and fraction A had moderate activity against A. fumigatus and Candida albicans (MIC 0.16 mg/ml). Fraction A however had excellent activity against Staphylococcus aureus (MIC 0.02 mg/ml), Enterococcus faecalis and Escherichia coli (MIC 0.04 mg/ml). The crude extract had significant activity against S. aureus, E. faecalis and E. coli. Fraction B had good activity against E. faecalis and E. coli (MIC 0.08 mg/ml). All the isolated compounds had a relatively weak antimicrobial activity. An MIC of 65 MUg/ml was obtained with robusflavones A (1) and B (2) against C. albicans and A. fumigatus, orostachyscerebroside A (3) against A. fumigatus, and robusflavone B (2) against C. neoformans. Compound 8 had the best activity against bacteria (average MIC 55 MUg/ml). The 3 fractions and isolated compounds had LC50 values between 13.20 to > 100 MUg/ml against Vero cells yielding selectivity indices between 0.01 and 1.58. CONCLUSION: The isolated compounds generally had a much lower activity than expected based on the activity of the fractions from which they were isolated. This may be the result of synergism between different compounds in the complex extracts or fractions. The results support the traditional use of E. robustum to treat infections. The crude extract had a good activity and low preparation cost, and may be useful in topical applications to combat microbial infections. PMID- 24165198 TI - SORBS2 and TLR3 induce premature senescence in primary human fibroblasts and keratinocytes. AB - BACKGROUND: Genetic aberrations are required for the progression of HPV-induced cervical precancers. A prerequisite for clonal expansion of cancer cells is unlimited proliferative capacity. In a cell culture model for cervical carcinogenesis loss of genes located on chromosome 4q35->qter and chromosome 10p14-p15 were found to be associated with escape from senescence. Moreover, by LOH and I-FISH analyses a higher frequency of allele loss of these regions was also observed in cervical carcinomas as compared to CIN3. The aim of this study was to identify candidate senescence-related genes located on chromosome 4q35 >qter and chromosome 10p14-p15 which may contribute to clonal expansion at the transition of CIN3 to cancer. METHODS: Microarray expression analyses were used to identify candidate genes down-regulated in cervical carcinomas as compared to CIN3. In order to relate these genes with the process of senescence their respective cDNAs were overexpressed in HPV16-immortalized keratinocytes as well as in primary human fibroblasts and keratinocytes using lentivirus mediated gene transduction. RESULTS: Overall fifteen genes located on chromosome 4q35->qter and chromosome 10p14-p15 were identified. Ten of these genes could be validated in biopsies by RT-PCR. Of interest is the novel finding that SORBS2 and TLR3 can induce senescence in primary human fibroblasts and keratinocytes but not in HPV immortalized cell lines. Intriguingly, the endogenous expression of both genes increases during finite passaging of primary keratinocytes in vitro. CONCLUSIONS: The relevance of the genes SORBS2 and TLR3 in the process of cellular senescence warrants further investigation. In ongoing experiments we are investigating whether this increase in gene expression is also characteristic of replicative senescence. PMID- 24165200 TI - Regulation of TGF-beta family signalling by ubiquitination and deubiquitination. AB - Members of the transforming growth factor-beta (TGF-beta) family, including TGF betas, activin and bone morphogenetic proteins (BMPs), are multifunctional proteins that regulate a wide variety of cellular responses, such as proliferation, differentiation, migration and apoptosis. TGF-beta family signalling is mainly mediated by membranous serine/threonine kinase receptors and intracellular Smad proteins. This signalling is tightly regulated by various post translational modifications including ubiquitination. Several E3 ubiquitin ligases play a crucial role in the recognition and ubiquitin-dependent degradation of TGF-beta family receptors, Smad proteins and their interacted proteins to regulate positively and negatively TGF-beta family signalling. In contrast, non-degradative ubiquitin modifications also regulate TGF-beta family signalling. Recently, in addition to protein ubiquitination, deubiquitination by deubiquitinating enzymes has been reported to control TGF-beta family signalling pathways. Interestingly, more recent studies suggest that TGF-beta signalling is not only regulated via ubiquitination and/or deubiquitination, but also it relies on ubiquitination for its effect on other pathways. Thus, ubiquitin modifications play key roles in TGF-beta family signal transduction and cross-talk between TGF beta family signalling and other signalling pathways. Here, we review the current understandings of the positive and negative regulatory mechanisms by ubiquitin modifications that control TGF-beta family signalling. PMID- 24165201 TI - Unscheduled return visits (URV) in adults to the emergency department (ED): a rapid evidence assessment policy review. AB - Unscheduled return visits (URV) to the emergency department (ED) may be an important quality indicator of performance of individual clinicians as well as organisations and systems responsible for the delivery of emergency care. The aim of this study was to perform a rapid evidence assessment policy-based literature review of studies that have looked at URVs presenting to the ED. A rapid evidence assessment using SCOPUS and PUBMED was used to identify articles looking at unplanned returns to EDs in adults; those relating to specific complaints or frequent attenders were not included. After exclusions, we identified 26 articles. We found a reported URV rate of between 0.4% and 43.9% with wide variation in the time period defined for a URV, which ranged from 24 h to undefined. Thematic analysis identified four broad subtypes of URVs: related to patient factors, to the illness, to the system or organisation and to the clinician. This review informed the development of national clinical quality indicators for England. URV rates may serve as an important indicator of quality performance within the ED. However, review of the literature shows major inconsistencies in the way URVs are defined and measured. Furthermore, the review has highlighted that there are potentially at least four subcategories of URVs (patient related, illness related, system related and clinician related). Further work is in progress to develop standardised definitions and methodologies that will allow comparable research and allow URVs to be used reliably as a quality indicator for the ED. PMID- 24165202 TI - Home birth in North America: attitudes and practice of US certified nurse midwives and Canadian registered midwives. AB - INTRODUCTION: Scope of practice, competencies, and philosophy of maternity practice are similar among midwives in the United States and Canada. However, there are marked differences in intrapartum practice sites between registered midwives (RMs) and certified nurse-midwives (CNMs). METHODS: This study linked data from 2 national surveys: 1) a 2007 survey of CNM members of the American College of Nurse-Midwives (n = 1893); and 2) the Canadian Birth Place Study of maternity providers, including RM members of the Canadian Association of Midwives (n = 451) to compare the demographics, practice experience, and attitudes to home birth between these 2 types of North American midwives. A Provider Attitudes To Planned Home Birth scale-international (PAPHB-i) was developed for this analysis. Descriptive and bivariate analyses are presented. RESULTS: Educational exposure to planned home birth varied greatly when comparing CNMs and RMs, as did practice patterns regarding continuity of care, primary and gynecologic care, and involvement with research and teaching. Registered midwives were almost 4 times more likely than CNMs to have practiced in the home (99.1% vs 26.0%). Certified nurse-midwives scored significantly lower than RMs on the PAPHB-i scale (36.5 vs 41.0), indicating less favorable attitudes toward home birth overall. Certified nurse-midwives were less confident than RMs in their management skills for home birth practice. Age, exposure to planned home birth during midwifery education, and practice experience in the home setting emerged as significant covariates of attitudes toward home birth. Significantly more RMs and CNMs with home birth experience expressed concerns about disapproval of hospital-based peers, but they were significantly less likely to agree that midwives face other systemic barriers than CNMs with no home birth experience. DISCUSSION: Differences in favorability toward and confidence with practice during planned home births among CNMs and RMs were predicted associated with differences in educational and practice exposure to planned home birth. We recommend that clinical experiences and theoretical content about planned home birth and preparation for multidisciplinary collaboration across settings be integrated as essential and required components of all health professional education programs. PMID- 24165203 TI - Chronic cadmium treatment induces tubular nephropathy and osteomalacic osteopenia in ovariectomized cynomolgus monkeys. AB - In an attempt to establish a primate model of chronic cadmium toxicosis, we ovariectomized cynomolgus monkeys and treated them with CdCl2 by repeated intravenous injections for 13 to 15 months. The animals showed normocytic normochromic anemia. The cadmium treatment resulted in increases of urinary enzyme activity indicative of renal tubular degeneration. Histopathology of the kidney revealed renal proximal tubular atrophy accompanied by interstitial fibrosis. Decreased bone mineral density was evident in the trabecular and cortical zones of the lumbar vertebra and femur, with osteoid accumulation around the trabeculae and Haversian canals. Iron deposition at the mineralization front and osteoclasts hyperplasia were indicative of impairment of bone mineralization and an increase of resorption. Blood inorganic phosphorus and 1alpha,25(OH)2 vitamin D3 levels decreased and urinary deoxypyridinoline level increased in cadmium-treated animals. The renal and bone lesions closely resemble those of itai-itai disease patients, the most severe case of cadmium toxicosis in terms of clinical chemistry and histopathology. Thus, ovariectomized monkeys chronically exposed to cadmium can serve as a primate itai-itai disease model, which is beneficial for developing novel therapeutic methods, investigating the mechanisms of the renal and bone lesions, and establishing more clearly defined criteria for diagnosing the disease. PMID- 24165204 TI - Brown adipose tissue as an anti-obesity tissue in humans. AB - During the 11th Stock Conference held in Montreal, Quebec, Canada, world-leading experts came together to present and discuss recent developments made in the field of brown adipose tissue biology. Owing to the vast capacity of brown adipose tissue for burning food energy in the process of thermogenesis, and due to demonstrations of its presence in adult humans, there is tremendous interest in targeting brown adipose tissue as an anti-obesity tissue in humans. However, the future of such therapeutic approaches relies on our understanding of the origin, development, recruitment, activation and regulation of brown adipose tissue in humans. As reviewed here, the 11th Stock Conference was organized around these themes to discuss the recent progress made in each aspect, to identify gaps in our current understanding and to further provide a common groundwork that could support collaborative efforts aimed at a future therapy for obesity, based on brown adipose tissue thermogenesis. PMID- 24165205 TI - Depression: cognition relations after stroke. AB - BACKGROUND: Poststroke depression and cognitive dysfunction are common and are independent predictors of poor recovery. AIMS: We assessed whether and how depression and cognition were correlated in the subacute period after stroke. METHOD: We prospectively recruited 207 nondemented patients (Mini Mental State Examination >= 23) presenting with a first-ever ischemic stroke (127 males), mean age of 48.5 years (16.4 standard deviation), median 12 days after infarction, as assessed on magnetic resonance imaging. We administered a comprehensive neuropsychological battery involving cognitive domains including instrumental functions, memory, executive functions, and working memory. Depression was quantified with the Beck Depression Inventory. RESULTS: Depression (Beck Depression Inventory > 9) was identified in 30.4% of the patients (95% confidence interval 24.2-37.2%). Median Beck Depression Inventory was 6. Median Mini Mental State Examination was 30. Cognitive dysfunctioning in at least one neuropsychological test was present in 89% (95% confidence interval 84-93%). Each point increase of Beck Depression Inventory was associated with an odd of 1.1 (95% confidence interval 1.04-1.19) of changing to a worse category of cognition. Stroke location was not correlated with depression. All cognitive domains were significantly correlated with depression. In multivariate analysis, the executive functions (P = 0.001) and the working memory (P = 0.009) were the best predictors of depression when adjusted for demographic and stroke characteristics. CONCLUSIONS: The rates of depression and cognitive impairment were in the range of previous stroke studies. Our study suggested a strong relation between depression and cognition characterized by executive functions and working memory dysfunctioning. PMID- 24165206 TI - Severe influenza and S. aureus pneumonia: for whom the bell tolls? PMID- 24165207 TI - A case of peritoneal mesothelioma masquerading as a urachal mass. PMID- 24165209 TI - An experience of using Traumastem P in control of spontaneous nose bleeding in patients with inherited bleeding disorders in southern Iran. PMID- 24165208 TI - Bluetongue virus infection induces aberrant mitosis in mammalian cells. AB - BACKGROUND: Bluetongue virus (BTV) is an arbovirus that is responsible for 'bluetongue', an economically important disease of livestock. Although BTV is well characterised at the protein level, less is known regarding its interaction with host cells. During studies of virus inclusion body formation we observed what appeared to be a large proportion of cells in mitosis. Although the modulation of the cell cycle is well established for many viruses, this was a novel observation for BTV. We therefore undertook a study to reveal in more depth the impact of BTV upon cell division. METHODS: We used a confocal microscopy approach to investigate the localisation of BTV proteins in a cellular context with their respective position relative to cellular proteins. In addition, to quantitatively assess the frequency of aberrant mitosis induction by the viral non-structural protein (NS) 2 we utilised live cell imaging to monitor HeLa mCherry tubulin cells transfected with a plasmid expressing NS2. RESULTS: Our data showed that these 'aberrant mitoses' can be induced in multiple cell types and by different strains of BTV. Further study confirmed multiplication of the centrosomes, each resulting in a separate mitotic spindle during mitosis. Interestingly, the BTV NS1 protein was strongly localised to the centrosomal regions. In a separate, yet related observation, the BTV NS2 protein was co localised with the condensed chromosomes to a region suggestive of the kinetochore. Live cell imaging revealed that expression of an EGFP-NS2 fusion protein in HeLa-mCherry tubulin cells also results in mitotic defects. CONCLUSIONS: We hypothesise that NS2 is a microtubule cargo protein that may inadvertently disrupt the interaction of microtubule tips with the kinetochores during mitosis. Furthermore, the BTV NS1 protein was distinctly localised to a region encompassing the centrosome and may therefore be, at least in part, responsible for the disruption of the centrosome as observed in BTV infected mammalian cells. PMID- 24165210 TI - Vancomycin monotherapy vs. combination therapy for the treatment of persistent methicillin-resistant Staphylococcus aureus bacteremia. PMID- 24165212 TI - Cheers to peer reviewers! PMID- 24165211 TI - History of syphilis: between poetry and medicine. AB - INTRODUCTION: The origin of syphilis is a matter of debate and two "historical" hypotheses explain its emergence. AIM: We present here a review about syphilis history. METHODS: A review of literature about syphilis history using the following keywords: "syphilis," "history," and "treponema." RESULTS: The Columbian opinion is that syphilis came from the New World (America) with the crews of Christopher Columbus's fleet. As Naples fell before the invading army of Charles the VIII in 1495, a plague broke out among the French leader's troops. When the army disbanded shortly after the campaign, the troops, composed largely of mercenaries, returned to their homes and disseminated the disease across Europe. Indeed, there were reports that indigenous peoples of the New World suffered from a similar condition. CONCLUSION: Regardless of the Columbian and the Pre-Columbian theories, syphilis remains an international disease, growing nowadays with HIV infection. Despite history, politics, paleopathology and molecular approaches, the origin of the disease remains an enigma. PMID- 24165213 TI - Experiences of healthcare team members involved in facial transplant surgery and patient care. AB - BACKGROUND: Situations that highlight the healthcare team member vulnerability, present ethically laden questions, or are innovative in nature may have a long term personal and professional impact on caregivers and, consequently, directly or indirectly affect patient care. The ethical experiences and perceptions of the healthcare team members involved in facial transplantation procedures and patient care have not been explored. OBJECTIVE: The objective of this study was to explore healthcare team member experiences of caring for facial transplantation patients, using an ethical framework. METHODS: This study used a qualitative descriptive design to explore the experiences of 26 multidisciplinary healthcare team members, including professional, ancillary, and support staff who have participated in facial transplantation procedures and patient care. Individual, private, semistructured interviews were conducted. RESULTS: Two main themes emerged: individual sense of purpose and esprit de corps. Individual sense of purpose describes the meaning of the experience that involvement in facial transplantation had for the participants and comprises three subthemes: "getting it right, "transforming a life," and "spirituality." The theme esprit de corps conveys the morale of the healthcare team members involved in facial transplantation and was expressed through three subthemes: "leadership," "teamwork," and "environment." DISCUSSION: Many potential ethical dilemmas were mitigated by an overwhelming sense of moral obligation to help patients with complex cosmetic, functional, and mechanical facial deficits. Participants in this study unanimously believed that the risk-benefit ratio of the procedure and subsequent treatment supported its implementation. PMID- 24165214 TI - Patient-centered communication and health assessment with youth. AB - BACKGROUND: Patient-centered communication is fundamental to individualizing healthcare, but there has been limited evaluation of provider communication with youth. OBJECTIVES: The aim was to compare communication outcomes after use of an event history calendar (EHC) and Guidelines for Adolescent Preventive Services (GAPS) to structure interactions during a clinic visit. Patient and provider descriptions of EHC and GAPS communication experiences were also obtained. METHODS: This is a secondary analysis of data obtained during a randomized controlled trial. A sequential explanatory mixed-methods approach was used. A split-plot design with one between factor (EHC, GAPS) and one within factor (pretest, posttest) was used for the quantitative portion. Qualitative data were collected from open-ended questions, audiotaped visits, and exit interviews. Providers (n = 9) at three clinics were assigned at random and trained to implement either the EHC or GAPS protocol. Male and female youth (n = 186) were randomly assigned to the EHC or GAPS intervention. Before their clinic visit, youth completed assessments of past communication experiences with healthcare providers (pretest); communication during the current visit was assessed immediately after the visit (posttest). RESULTS: Communication outcomes from pretest to posttest improved for youth in both the EHC and GAPS groups. Post hoc subgroup analysis suggested that men and Arab Americans derived more benefit from the EHC intervention in some aspects of communication. Qualitatively, the EHC group identified improved outcomes in validating patient perspective, being viewed in context, reaching a shared understanding of needs and preferences, and being helped to share power in the healthcare interaction. DISCUSSION: EHC and GAPS provided effective frameworks for structuring communication during a clinic visit. Compared with GAPS, the integrated time-linked assessment captured by the EHC enhanced patient-centered communication in select groups. PMID- 24165215 TI - Smoking patterns, depression, and sociodemographic variables among Flemish women during pregnancy and the postpartum period. AB - BACKGROUND: Relationships among feelings of depression, smoking behavior, and educational level during pregnancy have been documented. Feelings of depression may contribute to persistent smoking during pregnancy. No longitudinal studies assessing feelings of depression in women with different antepartum and postpartum smoking patterns are available. OBJECTIVES: The aim was to determine relationships between depressive symptoms, sociodemographic characteristics, and smoking pattern during and after pregnancy. METHODS: An observational, prospective, noninterventional study was conducted. Data were collected during two stages of pregnancy (T0: <;16 weeks and T1: 32-34 weeks) and postpartum (T2: >6 weeks) in 523 Flemish women. Feelings of depression (measured using the Beck Depression Inventory [BDI]), smoking behavior, and sociodemographic variables were analyzed using a general linear mixed model implemented in SAS Proc MIXED. RESULTS: Smokers and initial smokers reported significantly more depressive symptoms at all time points compared with recent ex-smokers, nonsmokers, and initial nonsmokers (p <; .001). The three-way interaction among time point, smoking pattern, and educational level was significant (p = .02). Evolution of mean BDI over time differed by educational level. Among participants with a secondary school certificate or less, differences were observed between smokers and nonsmokers, recent ex-smokers and initial nonsmokers, and nonsmokers and initial nonsmokers. Among participants with a college or university degree, no differences were observed. DISCUSSION: A wide variety of smoking patterns were observed during pregnancy and early postpartum. Smoking patterns were associated with depression and showed complex interactions with educational level. Assessment and intervention for both smoking and depression are needed throughout the perinatal period to support the health of mothers, their infants, and families. PMID- 24165216 TI - Train-the-trainer intervention to increase nursing teamwork and decrease missed nursing care in acute care patient units. AB - BACKGROUND: Teamwork is essential for patient safety and results in less missed nursing care. OBJECTIVES: The aim of this study was to test the impact of a train the-trainer intervention on the level of satisfaction with nursing teamwork and the amount of missed nursing care. METHODS: This study used a quasiexperimental design with repeated measures taken at pretest, posttest, and 2 months after completion of the intervention. The sample for this study was the nursing staff on three medical-surgical units in three separate acute care hospitals (one unit in each hospital). Three nurses from each unit underwent a training program and then taught the skills and knowledge they acquired to the staff members on their units in three-hour-long sessions. The training involved staff role-playing scenarios based on teamwork problems that occur regularly on inpatient units in acute care hospitals followed by debriefing, which focused on teamwork behaviors (e.g., leadership, team orientation, backup, performance monitoring) and missed nursing care. Four measures were used to test the efficacy of this intervention: The Nursing Teamwork Survey, the MISSCARE Survey, and questions about the knowledge of and satisfaction with teamwork. Return rates for the surveys ranged from 73% to 84%. Follow-up tests individually comparing pretest, posttest, and delayed posttest were conducted within the mixed model and used the Bonferroni correction for multiple comparisons. RESULTS: Teamwork increased (F = 6.91, df = 259.01, p = .001) and missed care decreased (F = 3.59, df = 251.29, p = .03) over time. Nursing staff also reported a higher level of satisfaction with teamwork and an increase of teamwork knowledge after the intervention. DISCUSSION: The intervention tested in this study shows promise of being an effective and efficient approach to increase nursing teamwork and decrease missed nursing care. PMID- 24165218 TI - Toothbrushing versus toothbrushing plus tongue cleaning in reducing halitosis and tongue coating: a systematic review and meta-analysis. AB - BACKGROUND: Halitosis affects people of all ages. Among hospitalized patients, oral care includes toothbrushing and mouth rinses. Tongue cleaning is not included in most guidelines or nursing education curricula. OBJECTIVES: The aim of this study was to compare the effectiveness of two types of oral care, toothbrushing alone and toothbrushing plus tongue cleaning, on halitosis and tongue coating (TC). METHODS: A systematic review and meta-analysis of randomized controlled trials were conducted to compare toothbrushing and toothbrushing plus tongue cleaning during oral care to reduce halitosis and TC. The databases included PubMed, ProQuest, CINAHL, the Cochrane Central Register of Controlled Trials, experts, and bibliographic review. A quality assessment of study reports and methodology was conducted using the CONSORT checklist and the Jadad Scale. The measurement of volatile sulfide compounds (VSCs) evaluated halitosis, whereas TC was measured with assessment indexes. RESULTS: Seven experimental data sets were obtained from five randomized clinical trials. There were 188 male and 63 female subjects within an age range of 17-80 years. All intervention groups indicate a large effect size of toothbrushing plus tongue cleaning decreases volatile sulfur compounds and TC by 0.745 and 0.922, respectively, compared with toothbrushing only. DISCUSSION: The use of toothbrushing plus tongue cleaning compared with toothbrushing alone significantly reduced the indicators of halitosis and TC. However, there is insufficient evidence to recommend frequency, duration, or delivery method of tongue cleaning. Further research is needed to articulate a comprehensive clinical guideline. Oral care is an important nursing intervention. Tongue cleaning should be incorporated into current nursing procedures. PMID- 24165217 TI - Factors associated with weight gain after smoking cessation therapy in Japan. AB - BACKGROUND: Smoking cessation is often followed by weight gain, which may attenuate motivation to sustain a quit attempt. OBJECTIVES: The aim was to identify factors associated with weight gain in smokers who received smoking cessation therapy (SCT) in Japan. METHODS: The weight change in 283 smokers between baseline and 12 months after finishing SCT was observed. Factors associated with marked weight gain of 3.5 kg or more were identified using stepwise logistic regression. RESULTS: Smoking cessation success was 83% (234/283) at the completion of SCT but decreased to 69% (194/283) 12 months later. Twelve months after the end of SCT, age 50 and over (OR = 0.38, 95% CI [0.19, 0.76]) and varenicline use (OR = 0.30, 95% CI [0.11, 0.78]) were protected against marked weight gain, whereas presence of a comorbidity (OR = 3.33, 95% CI [1.10, 10.00]), high level of nicotine dependence at baseline (OR = 2.07, 95% CI [1.09, 3.92]), and successfully quitting smoking (OR = 4.57, 95% CI [1.94, 10.08]) were associated with marked weight gain. DISCUSSION: Understanding the factors associated with weight gain after smoking cessation can help in the design of nursing interventions to lessen or prevent weight gain among smokers who try to quit. PMID- 24165219 TI - Managing threats against control in old age: a narrative inquiry. AB - BACKGROUND: The desire to retain personal control over self and life circumstances continues into old age; it exists in tension with late-life vulnerabilities. OBJECTIVES: This article investigates how older adults respond to threats against control in light of changes surrounding health and identity. METHODS: Community-dwelling African American (n = 10) and European-American older adults (n = 10), aged 70 years and older, with varied self-reported health statuses were qualitatively interviewed. Open-ended interviews explored older adults' perceptions of control and threats to control in older age. RESULTS: Three themes linked older adults' responses to threats to control. Older adults (a) proactively monitored physical and mental health, (b) maintained roles that shaped important aspects of identity, and (c) fostered personal growth and development by generative practices. Responses of participants who had difficulty countering threats to control are also offered. DISCUSSION: This study shows that the construct of control is not abstract; it is interpreted and applied by older adults in the contexts of everyday life. Respondents used personal resources honed throughout the life course to respond to threats to control. Older adults viewed control as a cultural construct with nuanced meanings that recalled past roles and current changes that occur with age. Suggestions are offered for how health professionals can assist older adults with the cognitive and emotional tasks required to deal with threats to personal control surrounding health and identity. PMID- 24165220 TI - Linking clinical research data to population databases. AB - BACKGROUND: Most clinical nursing research is limited to funded study periods. However, if clinical research data can be linked to population databases, researchers can study relationships between study measures and poststudy long term outcomes. OBJECTIVES: The objective was to describe the feasibility of linking research participant data to data from population databases in order to study long-term poststudy outcomes. As an exemplar, participants were linked from a completed oncology nursing research trial to outcomes data in two state population databases. METHODS: Participant data from a previously completed symptom management study were linked to the Utah Population Database and the Utah Emergency Department Database. The final data set contained demographic, cancer diagnosis and treatment and baseline data from the oncology study linked to poststudy long-term outcomes from the population databases. RESULTS: One hundred twenty-nine of 144 (89.6%) study were linked to their individual data in the population databases. Of those, 73% were linked to hospitalization records, 60% were linked to emergency department visit records, and 28% were identified as having died. DISCUSSION: Study participant data were successfully linked to population databases data to describe poststudy emergency department visit and hospitalization numbers and mortality. The results suggest that data linkage success can be improved if researchers include linkage and human subjects protection plans related to linkage in the initial study design. PMID- 24165221 TI - Factors associated with onset of delirium among internal medicine inpatients in Spain. AB - BACKGROUND: Delirium increases mortality and length of stay among hospital inpatients. Little is known about the incidence of delirium among inpatients receiving care in internal medicine nursing units in Spain. OBJECTIVES: The aim of this study was to estimate frequency of delirium onset among internal medicine inpatients and identify factors associated with delirium onset using nursing records and administrative databases. METHODS: Retrospective cohort study of 744 patients hospitalized in an internal medicine department in October 2010 and January, May, and October 2011. Data concerning occurrence of delirium, age, gender, living in a nursing residence, Barthel Index of activities of daily living, Norton scale for pressure ulcer risk, intravenous fluid therapy, urinary catheterization, presence of pressure ulcers, major diagnostic category at discharge, length of stay, and mean weight in the diagnosis-related group were gathered for each patient. Backward stepwise logistic regression was used to identify factors associated with onset of delirium. RESULTS: Ninety-seven (13%) patients experienced delirium. Factors associated with delirium were age (OR = 1.03, 95% CI [1.01, 1.06]), Barthel Index (OR = 0.99. 95% CI [0.98, 0.99]), and urinary catheterization (OR = 2.00, 95% CI [1.19, 3.68]). CONCLUSION: Increased age and presence of a urinary catheter were associated with increased onset of delirium, whereas higher levels of independence in activities of daily living were protective. PMID- 24165222 TI - Using transient elastography to detect chronic liver diseases in a primary care nurse consultancy. AB - BACKGROUND: Chronic liver diseases (CLDs) are significant causes of death in adults in many countries and are usually diagnosed at late stages. Early detection may allow time for treatment to prevent disease progression. OBJECTIVES: The aim of this study was to assess the feasibility of screening for unrecognized CLDs in a primary care nurse consultancy and report findings from screening. METHODS: Two experienced nurses in a primary care nurse consultancy were trained to perform transient elastography (TE). Subjects aged from 18 to 70 years were identified randomly from the health registry and invited to participate in a feasibility pilot study. Exclusion criteria were past or current history of liver diseases. Nurses collected demographic and clinical data and performed TE tests using Fibroscan to measure liver stiffness; a cutoff score of 6.8 kPa or greater was used as an indicator of the presence of CLD with fibrosis. RESULTS: Accurate measurements were obtained in 495 of 502 participants (98.6%). Prevalence of elevated liver stiffness was observed in 28 of 495 subjects (5.7%). Compared to patients with normal liver stiffness, patients with increased liver stiffness were older, were more frequently male, and had higher frequency of metabolic syndrome. Nonalcoholic fatty liver was the most common cause of CLD. DISCUSSION: Following training in procedures for conducting TE, nurses in a primary care clinic were able to detect unrecognized CLDs in presumably healthy subjects. Early detection of CLDs is feasible in primary care clinics and may facilitate identification of undiagnosed CLD in adults. PMID- 24165223 TI - Up-regulation of survivin by AKT and hypoxia-inducible factor 1alpha contributes to cisplatin resistance in gastric cancer. AB - This study investigated the contribution of survivin and its upstream regulators, AKT and hypoxia-inducible factor 1alpha (HIF-1alpha), to the resistance of gastric cancer cells to cisplatin (CDDP). We found that over-expression of survivin increased the resistance of SGC7901 and BGC823 gastric cancer cells to CDDP. Its over-expression abrogated CDDP-induced inhibition of cell proliferation and CDDP-induced cell apoptosis. In contrast, down-regulation of survivin expression using small hairpin RNA (shRNA) vectors and the small-molecule inhibitor YM155, or inhibition of survivin function using a recombinant cell permeable dominant-negative survivin protein (dNSur9), promoted CDDP-induced apoptosis. CDDP-resistant sub-lines generated from the parental SGC7901 and BGC823 cells by exposure to increasing concentrations of CDDP expressed higher levels of HIF-1alpha and survivin in response to hypoxia, and higher levels of phosphorylated AKT (pAKT). Specific inhibition of AKT reduced the expression of HIF-1alpha and survivin, whereas specific inhibition or depletion of HIF-1alpha reduced survivin expression but had no effect on the expression of phosphorylated AKT. The expression levels of survivin affected the therapeutic efficacy of CDDP in treating gastric tumors in mice. Specific inhibition of survivin, AKT and HIF 1alpha enhanced the sensitivity of CDDP-resistant cells to CDDP. Specific inhibition of survivin, AKT and HIF-1alpha synergized with CDDP to suppress the growth of gastric tumors that had been engineered to overexpress survivin. In summary, the results provide evidence that up-regulation of survivin by AKT and HIF-1alpha contributes to CDDP resistance, indicating that inhibition of these pathways may be a potential strategy for overcoming CDDP resistance in the treatment of gastric cancer. PMID- 24165224 TI - Subtenon injection of natural leukocyte interferon alpha-2a in diabetic macular edema: a case report. AB - BACKGROUND: To report the effect of subtenon injections of natural leukocyte interferon alpha-2a (IFNalpha) on best corrected visual acuity (BCVA) and central macular thickness (CMT) in a patient with diabetic macular edema (DME). CASE PRESENTATION: A 66-year-old man affected by DME, with glycated hemoglobin (HbA1c) at 6.9%, refractory to laser grid treatment and intravitreal injections of triamcinolone, was selected to receive a cycle of three subtenon injections/week of IFNalpha (1*106 IU/ml). BCVA and CMT, using spectral domain ocular coherence tomography (SD-OCT), were evaluated preoperatively and at 1 week, 1 month, 4 months, and 1 year postoperatively. BCVA and CMT were significantly improved at 1 week after the three injections (20/200 vs. 20/40 and 498 MUm vs. 237 MUm, respectively). BCVA remained stable during the 1-year follow-up. CMT was slightly increased, but was still lower than the baseline value (215 MUm, 255 MUm, and 299 MUm during the follow-up visits). No adverse events were recorded, with the exception of mild subconjunctival hemorrhage at the injection site. CONCLUSIONS: IFNalpha, with its immunomodulatory, anti-proliferative and anti-angiogenic actions, was effective in improving BCVA and reducing CMT in refractory DME. Further randomized controlled studies are required to assess the effect of IFNalpha alone or in combination with other therapies for DME treatment. PMID- 24165225 TI - Midterm results using a medial pivot total knee replacement compared with the Australian National Joint Replacement Registry data. AB - BACKGROUND: In order to emulate normal knee kinematics more closely, and thereby potentially improve wear characteristics and implant longevity, the medial pivot type knee replacement geometry was designed. In the current study the outcome of 50 consecutive knee replacements using a medial pivot-type knee replacement was compared with the results in the Australian Orthopaedic Association National Joint Replacement Registry. METHODS: Pre- and post-operatively at follow-up evaluation consisted of the Knee Society score system and the Western Ontario and McMaster Universities Arthritis Index Score. Patient satisfaction was documented using 5-point Likert-type scales. Standard radiographs were used to assess signs of radiographic failure. Revisions were subcategorized into major total, major partial and minor. Patient records were cross-referenced against the Australian Orthopaedic Associations National Joint Replacement Registry's and the outcome compared with the registry's subset of data on the medial pivot knee used. RESULTS: According to the patients' Knee Society score system and Western Ontario and McMaster Universities Arthritis Index scores, there was good pain relief and functional improvement; none of the implants showed radiographic signs of failure. There was one minor revision. There was no statistically significant difference in revision rate compared with the registry results. DISCUSSION: The medial pivot knee-type implant in this series provided pain relief, functional improvement and a revision rate, similar to what is reported in the literature after a longer follow-up period, which is reassuring for those who use this type of implant on a day-to-day basis. PMID- 24165226 TI - Education research: priority designs and common misperceptions. AB - In this commentary, common misperceptions about education research, and specifically for emergency medicine education research, are addressed. Recommendations for designing and publishing high-quality projects are also provided. PMID- 24165227 TI - Intravitreal bevacizumab for the treatment of choroidal metastasis. PMID- 24165228 TI - Sicker patients with end-stage liver disease cost more: a quick fix?: an editorial on assessing variation in the costs of care among patients awaiting liver transplantation. PMID- 24165230 TI - Redescription of Setaria graberi Shoho in Troncy, Graber & Thal, 1976 (Nematoda: Filarioidea) based on specimens from Redunca arundinum (Bovidae) in South Africa. AB - The filarial onchocercid Setaria graberi Shoho in Troncy, Graber & Thal, 1976 is redescribed from the abdominal cavity of Southern reedbuck, Redunca arundinum (Boddaert), in South Africa, including illustrations and scanning electron micrographs of important morphological features. Morphometric data for this species are provided for the first time. Setaria graberi is characterised by the possession of bifid deirids, and females having a distinctly bulbous tail. The slightly raised peribuccal crown forms a dumbbell-shaped unit with the cephalic elevations in apical view; the dorsal and ventral elevations, spaced 73-115 MUm apart in females and 71-93 MUm in males, carry two well-separated tips each. In dorsoventral view, the cephalic elevations appear more or less rectangular with a slightly notched apex and are narrow in comparison to the width of the anterior end. They are triangular in lateral view. Four cephalic and four external labial papillae are arranged in a laterally elongated rectangle each. The species is distinguished from other Setaria Viborg, 1795 species that possess bifid deirids or occur in members of the same host genus. The presence of S. graberi in R. arundinum in South Africa constitutes a new host and geographic record. PMID- 24165229 TI - Activation of amygdala opioid receptors by electroacupuncture of Feng-Chi (GB20) acupoints exacerbates focal epilepsy. AB - BACKGROUND: The effect of seizure suppression by acupuncture of Feng-Chi (GB20) acupoints has been documented in the ancient Chinese literature, Lingshu Jing (Classic of the Miraculous Pivot), however, there is a lack of scientific evidence to prove it. This current study was designed to elucidate the effect of electroacupuncture (EA) stimulation of bilateral Feng-Chi (GB20) acupoints on the epileptic activity by employing an animal model of focal epilepsy. METHODS: Administration of pilocarpine into the left central nucleus of amygdala (CeA) induced the focal epilepsy in rats. Rats received a 30-min 100 Hz EA stimulation of bilateral Feng-Chi acupoints per day, beginning at 30 minutes before the dark period and performing in three consecutive days. The broad-spectrum opioid receptor antagonist (naloxone), MU-receptor antagonist (naloxonazine), delta receptor antagonist (naltrindole) and kappa-receptor antagonist (nor binaltorphimine) were administered directly into the CeA to elucidate the involvement of CeA opioid receptors in the EA effect. RESULTS: High-frequency (100 Hz) EA stimulation of bilateral Feng-Chi acupoints did not suppress the pilocarpine-induced epileptiform electroencephalograms (EEGs), whereas it further increased the duration of epileptiform EEGs. We also observed that epilepsy occurred while 100 Hz EA stimulation of Feng-Chi acupoints was delivered into naive rats. EA-induced augmentation of epileptic activity was blocked by microinjection of naloxone, MU- (naloxonazine), kappa- (nor-binaltorphimine) or delta-receptor antagonists (natrindole) into the CeA, suggesting that activation of opioid receptors in the CeA mediates EA-exacerbated epilepsy. CONCLUSIONS: The present study suggests that high-frequency (100 Hz) EA stimulation of bilateral Feng-Chi acupoints has no effect to protect against pilocarpine-induced focal epilepsy; in contrast, EA further exacerbated focal epilepsy induced by pilocarpine. Opioid receptors in the CeA mediated EA-induced exacerbation of focal epilepsy. PMID- 24165231 TI - Bone health in eating disorders. AB - Eating disorders (EDs) put adolescents and young adults at risk for impaired bone health. Low bone mineral density (BMD) with ED is caused by failure to accrue peak bone mass in adolescence and bone loss in young adulthood. Although ED patients diagnosed with bone loss may be asymptomatic, some suffer bone pains and have increased incidence of fractures. Adolescents with ED are prone to increased prevalence of stress fractures, kyphoscoliosis and height loss. The clinical picture of the various EDs involves endocrinopathies that contribute to impaired bone health. Anorexia nervosa (AN) is characterized by low bone turnover, with relatively higher osteoclastic (bone resorptive) than osteoblastic (bone formation) activity. Bone loss in AN occurs in both the trabecular and cortical bones, although the former is more vulnerable. Bone loss in AN has been shown to be influenced by malnutrition and low weight, reduced fat mass, oestrogen and androgen deficiency, glucocorticoid excess, impaired growth hormone-insulin-like growth factor 1 axis, and more. Bone loss in AN may not be completely reversible despite recovery from the illness. Treatment modalities involving hormonal therapies have limited effectiveness, whereas increased caloric intake, weight gain and resumption of menses are essential to improved BMD. PMID- 24165233 TI - Locally advanced squamous cell carcinoma presenting with internal mammary artery hemorrhage. PMID- 24165234 TI - De Garengeot's hernia. PMID- 24165235 TI - Vorinostat is a potential precipitant for severe gastrointestinal toxicity. PMID- 24165236 TI - Shotgun pellet embolization to the middle cerebral artery. PMID- 24165237 TI - Abdominal intercostal hernia: a rare complication after blunt trauma. PMID- 24165238 TI - Trauma with a touch of fresh water: necrotizing fasciitis caused by Aeromonas hydrophilia after a motorcycle accident. PMID- 24165239 TI - Intercostal herniation of the gallbladder after thoracotomy with right lower lobe lung resection. PMID- 24165240 TI - Spontaneous rupture of a splenic hamartoma. PMID- 24165241 TI - Ileocecal resection for bowel endometriosis. PMID- 24165242 TI - The impact of seatbelt use and airbag deployment on blunt thoracic aortic injury. PMID- 24165243 TI - The Department of Surgery at the University of Wisconsin. AB - Education is deeply embedded in the Wisconsin state history. When Wisconsin became a state in 1848, the legislature soon after founded a university with the understanding that scholarship would contribute to its success. The close connection between the state and the university came to be known as "The Wisconsin Idea," a philosophy that all teaching, research, outreach, and public service conducted by the University of Wisconsin should be carried out for the good of citizens throughout the region. Although service to the state and its people still remains integral to the fiber of our university, the University of Wisconsin has since become a national leader among academic institutions. PMID- 24165244 TI - Edoardo Bassini (1844-1924): father of modern-day hernia surgery. PMID- 24165246 TI - Sigmoid volvulus in 16-year-old boy with an associated anomalous congenital band. AB - Sigmoid volvulus, a condition generally seen in debilitated elderly patients, is extremely rare in the pediatric age group. Frequent predisposing conditions that accompany pediatric sigmoid volvulus include intestinal malrotation, omphalomesenteric abnormalities, Hirschsprung's disease, imperforate anus and chronic constipation. A 16-year-old previously healthy African American male presented with a 12 hour history of sudden onset abdominal pain and intractable vomiting. CT was consistent with sigmoid volvulus. A contrast enema did not reduce the volvulus, but it was colonoscopically reduced. Patient condition initially improved after colonoscopy, but he again became distended with abdominal pain, so he was taken to the operating room. On exploratory laparotomy, a band was discovered where the mesenteries of the sigmoid and small bowel adhered and created a narrow fixation point around which the sigmoid twisted. A sigmoidectomy with primary anastomosis was performed. The diagnosis of sigmoid volvulus may be more difficult in children, with barium enema being the most consistently helpful. Seventy percent of cases do not involve an associated congenital problem, suggesting that some pediatric patients may have congenital redundancy of the sigmoid colon and elongation of its mesentery. The congenital band found in our patient was another potential anatomic factor that led to sigmoid volvulus. Pediatric surgeons, accustomed to unusual problems in children, may thus encounter a condition generally found in the debilitated elderly patient. PMID- 24165245 TI - The impact of in-house attending surgeon supervision on the rates of preventable and potentially preventable complications and death at the start of the new academic year. AB - The purpose of this study was to examine the impact of in-house attending surgeon supervision on the rate of preventable deaths (PD) and complications (PC) at the beginning of the academic year. All trauma patients admitted to the Los Angeles County + University of Southern California Medical Center over an 8-year period ending in December 2009 were reviewed. Morbidity and mortality reports were used to extract all PD/PC. Patients admitted in the first 2 months (July/August) of the academic year were compared with those admitted at the end of the year (May/June) for two distinct time periods: 2002 to 2006 (before in-house attending surgeon supervision) and 2007 to 2009 (after 24-hour/day in-house attending surgeon supervision). During 2002 to 2006, patients admitted at the beginning of the year had significantly higher rates of PC (1.1% for July/August vs 0.6% for May/June; adjusted odds ratio [OR], 1.9; 95% confidence interval [CI], 1.1 to 3.2; P < 0.001). There was no significant difference in mortality (6.5% for July/August vs 4.6% for May/June; adjusted OR, 1.1; 95% CI,0.8 to 1.5; P = 0.179). During 2007 to 2009, after institution of 24-hour/day in-house attending surgeon supervision of fellows and housestaff, there was no significant difference in the rates of PC (0.7% for July/August vs 0.6% for May/June; OR, 1.1; 95% CI, 0.8 to 1.3; P = 0.870) or PD (4.6% for July/August vs 3.7% for May/June; OR, 1.3; 95% CI, 0.9 to 1.7; P = 0.250) seen at the beginning of the academic year. At an academic Level I trauma center, the institution of 24 hour/day in-house attending surgeon supervision significantly reduced the spike of preventable complications previously seen at the beginning of the academic year. PMID- 24165247 TI - One-stage versus two-stage management for concomitant gallbladder stones and common bile duct stones in patients with obstructive jaundice. AB - No consensus exists regarding the optimal management of concomitant gallbladder stones and common bile duct stones (CBDS). Previous studies showed a significant association between the presence of obstructive jaundice and increased risk of postoperative complications and conversion to open surgery. This retrospective study evaluated the effectiveness and safety of one-stage (laparoscopic cholecystectomy [LC] plus laparoscopic common bile duct exploration) management versus two-stage (preoperative endoscopic retrograde cholangiopancreatography/endoscopic sphincterotomy + LC) management for patients with obstructive jaundice, concomitant gallbladder stones, and CBDS. One-stage management (n = 88) or two-stage management (n = 122) was used for 210 eligible patients between January 2009 and March 2011. Both types of management proved to be effective and safe. No significant difference was observed in terms of stone clearance from the common bile duct (CBD), postoperative morbidity, mortality, or conversion to open surgery. However, one-stage management was more cost-effective and decreased the number of procedures. In addition, postoperative hospital stay and operative time were shorter for patients who received one-stage management. Especially for patients with CBD greater than 1 cm in diameter, one-stage management is a better choice. PMID- 24165248 TI - Mechanism of injury is not a predictor of trauma center admission. AB - Most trauma systems use mechanism of injury (MOI) as an indicator for trauma center transport, often overburdening the system as a result of significant overtriage. Before 2005 our trauma center accepted all MOI. After 2005 we accepted only those patients meeting anatomic and physiologic (A&P) triage criteria. Patients entered into the trauma center database were divided into two groups: 2001 to 2005 (Group 1) and 2007 to 2010 (Group 2) and also categorized based on trauma team activation for either A&P or MOI criteria. Overtriage was defined as patient discharge from the emergency department within 6 hours of trauma activation. A total of 9899 patients were reviewed. Group 1 had 6584 patients with 3613 (55%) activated for A&P criteria and 2971 (45%) for MOI. Group 2 had 3315 patients with 3149 (95%) activated for A&P criteria and 166 (5%) for MOI. Accepting only those patients meeting A&P criteria resulted in a decrease in the overtriage rate from 66 to 9 per cent. By accepting only those patients meeting A&P criteria, we significantly reduced our overtriage rate. Patients meeting MOI criteria were transported to community hospitals and transferred to the trauma center if major injuries were identified. Trauma center transport for MOI results in significant overtriage and may not be justified. PMID- 24165250 TI - The pathological features of surgically managed adrenal cysts: a 15-year retrospective review. AB - Adrenal cysts are rare. Most are benign but some may contain malignancy. There are no established guidelines for their surgical management. The purpose of this study was to determine the pathological findings and likelihood of malignancy in hormonally inactive adrenal cysts after adrenalectomy. Using the pathology registries at two centers, we identified patients who underwent excision of an adrenal cyst between 1994 and 2009. Hormonally active cysts including pheochromocytomas were excluded. Charts were reviewed for patient demographics, presentation, surgical management, and postoperative course. Of 551 adrenalectomy specimens, 15 (2.7%) contained an inactive adrenal cyst or cystic component. Cysts were more likely to be in women (67%) and right-sided (73%). Three patients (20%) were symptomatic from their lesion. Laparoscopic adrenalectomy was performed in nine patients (60%). Pathology revealed eight hemorrhagic cysts, four lymphangiomas, one hemangioma, one epithelial cyst, and one metastatic pulmonary adenocarcinoma. Laboratory and radiographic workup are essential in determining whether adrenal cysts have hormonal function or a solid tissue component before adrenalectomy. Although nonfunctional adrenal cysts may contain malignancy, most are benign. It is reasonable to observe asymptomatic, nonfunctioning, benign-appearing adrenal cysts in patients in whom follow-up can be ensured. PMID- 24165249 TI - Standard retrograde pancreatosplenectomy versus radical antegrade modular pancreatosplenectomy for body and tail pancreatic adenocarcinoma. AB - Pancreatic surgery remains the only established curative treatment for pancreatic cancer. Radical antegrade pancreatosplenectomy (RAMPS) is a modification of the standard retrograde pancreatosplenectomy (SRPS) developed to achieve a complete N1 node resection and R0 resection (posterior extent). The aim of this study is to compare the short-, mid-, and long-term outcomes of RAMPS and SRPS. From a database that included 143 consecutive patients who underwent resection for pancreatic carcinoma at the St. Andrea Hospital, University of Rome, 25 patients who underwent pancreatosplenectomy were retrospectively reviewed. Among these 25 patients, eight (32%) underwent RAMPS (Group 1) and 17 (68%) underwent SRPS (Group 2). Clinicopathologic and oncological characteristics of the RAMPS group were compared with those of the SRPS group. RAMPS was longer than SRPS (315 vs 265 minutes, respectively, P < 0.001). No differences were encountered for perioperative outcomes (estimated blood loss, intraoperative blood transfusions, postoperative morbidity and mortality, and hospital stay). The margin status rates were similar: noteworthy, the two patients with positive tangential margins belonged to Group 2. No between-group differences in survival were encountered: the actuarial 5-year overall survival for Groups 1 and 2 were 26 and 29 per cent, respectively (P = 0.6608; hazard ratio, 1.2621; 95% confidence interval, 0.4462 to 3.5699). RAMPS and SRPS did not differ statistically in terms of perioperative outcomes. RAMPS seems to allow better control of tangential margins; however, no difference was found in actuarial survival compared with standard pancreatosplenectomy. PMID- 24165252 TI - Proposed classification of pseudomyxoma peritonei: influence of signet ring cells on survival. AB - The nomenclature and classification of pseudomyxoma peritonei (PMP) is confusing and controversial. Numerous classification systems have been proposed, none of which are easily reproducible or a useful guide for treatment. Patients with PMP of appendiceal origin were identified from our institution's database. Kaplan Meier analyses were performed based on a proposed new PMP classification, a three tiered grading system designated PMP1, PMP2, and PMP3. These results were compared with the established schemes by Ronnett and Bradley et al. There were 211 patients included in the analysis with a mean age of 51 +/- 12 years at diagnosis. For PMP1, 86 patients (40.8%) included cases with abundant extracellular mucin and columnar nonstratified epithelium without dysplasia or atypia. For PMP3, 50 patients (23.7%) consisted of PMP with any percentage of signet ring cells (SRCs), For PMP2, 75 patients (35.5%) included all other patients. The mean age (+/- standard deviation) for PMP 1, 2, and 3 were 51 +/- 12, 51 +/- 12, and 51 +/- 10 years, respectively (P = 0.90). The three groups had similar sex distribution (P = 0.24) and resection status (P = 0.47). Kaplan-Meier analyses showed median survivals of 120, 88, and 40 months and 5-year survival rates of 85.7, 63.05, and 32.2 per cent (P < 0.0001) for PMP 1, 2, and 3, respectively. Three distinct categories, PMP1, 2, and 3, were identified, which provide better stratification in terms of overall survival and represent differences in tumor biology that may impact treatment recommendations. PMID- 24165251 TI - Anatomical versus nonanatomical resection in patients with hepatocellular carcinoma located in the left lateral segment. AB - To date, no reported studies comparing anatomical resection (AR) and nonanatomical resection (NAR) for hepatocellular carcinoma (HCC) have restricted cases by tumor location. Thus, right hepatectomy and left lateral sectionectomy are both analyzed together as AR, whereas limited resection of both peripherally and centrally located liver tumors is categorized as NAR. This categorization may result in inaccurate conclusions in the analyses comparing AR and NAR. We conducted a retrospective comparison between AR (n = 30) and NAR (n = 57) for solitary and small (5 cm or less) HCC limited to the left lateral segment (LLS) to clarify whether AR is superior to NAR for HCC in LLS. The 1-, 3-, and 5-year recurrence-free survival rates were 83.3, 71.3, and 52.9 per cent for the AR group and 82.5, 51.0, and 40.7 per cent for the NAR group, respectively (P = 0.10). The 3-, 5-, and 7-year overall survival rates were 96.0, 82.8, and 77.9 per cent for the AR group and 84.1, 77.0, and 54.2 per cent for the NAR group, respectively (P = 0.07). The postoperative complication, recurrence patterns, and secondary treatment types after recurrence were not significantly different between the two groups. The multivariate analysis including the confounders related to background liver function indicated AR to be a significant protective factor against recurrence, although AR did not influence overall survival. AR was superior to NAR in preventing recurrence without increasing postoperative risks among patients with small solitary HCC limited to the LLS, although AR could not improve overall survival. PMID- 24165253 TI - Preliminary report of a sutureless onlay technique for incisional hernia repair using fibrin glue alone for mesh fixation. AB - The Rives repair for ventral/incisional (V/I) hernias involves sublay mesh placement requiring retrorectus dissection and transfascial stitches. Chevrel described a repair by onlaying mesh after a unique primary fascial closure. Although Chevrel fixated mesh to the anterior fascia with sutures, he used fibrin glue for fascial closure reinforcement. We describe an onlay technique with mesh fixated to the anterior fascia solely with fibrin glue without suture fixation. From January 2010 to January 2012, 50 patients underwent a V/I hernia onlay technique with fibrin glue mesh fixation. Records were reviewed for technical details, demographics, mesh characteristics, and postoperative outcomes. Primary fascial closure with interrupted permanent suture was done with or without myofascial advancement flaps. Onlay polypropylene mesh was placed providing 8 cm of overlap. Fibrin glue was applied over the prosthesis and subcutaneous drains were placed. Mean age was 62.4 years. Mean body mass index was 30.1 kg/m(2). Average mesh size was 14.5 cm * 19.1 cm. Mean operative time was 144.4 minutes (range, 38 to 316 minutes). Mean discharge was postoperative Day 2.9 (range, 0 to 15 days). Morbidity included eight seromas, one hematoma, and three wound infections. Seventeen patients required components separation. Mean follow-up was 19.5 months with no recurrences. This is the first series describing fibrin glue alone for mesh fixation for V/I hernia repair. It allows for immediate prosthesis fixation to the anterior fascia. Early results are promising. Potential advantages include less operative time, less technical difficulty, and less long term pain. A prospective trial is needed to evaluate this approach. PMID- 24165254 TI - Matrix metalloproteinases in pathogenesis of hemorrhoidal disease. AB - The aim of this study is to investigate the accuracy of serum matrix metalloproteinase (MMP) levels in an effort to find a reliable factor that may play an important role in pathogenesis of hemorrhoidal disease. Twenty control subjects and 21 Grade I, 19 Grade II, 20 Grade III, and 21 Grade IV patients with internal hemorrhoid were included in this prospective study. The mean ages of control subjects were 47.65 +/- 6.71 standard deviation (SD) years (range, 37 to 60 years). The mean age of internal Grade I, Grade II, Grade III, and Grade IV patients with internal hemorrhoid were 48.85 +/- 6.44, 47.20 +/- 6.75, 44.90 +/- 6.13, and 42.95 +/- 3.49 SD years (ranges, 38 to 58, 38 to 60, 34 to 55, and 38 to 50 years), respectively. Ten milliliters of blood was taken from all subjects. Enzyme-linked immunosorbent assay (ELISA) for MMP-1, -2, -7, and -9 levels were performed using an ELISA kit (R&D Systems) following the manufacturer's instructions. There was an important difference between Grade I and Grade II groups in the serum levels of MMP-9 (P < 0.01). Patients with Grade III hemorrhoidal disease had significantly higher serum levels of all MMP than patients with Grade I and Grade II hemorrhoidal disease (P < 0.001). Also, patients with Grade 4 hemorrhoidal disease had higher serum levels of MMP-7 and 9 according to Grade I, II, and III groups (P < 0.01, 0.001). High serum levels of MMP are present in patients with hemorrhoids, suggesting the possible mechanism in the pathogenesis of hemorrhoids. PMID- 24165255 TI - Vancomycin intermittent dosing versus continuous infusion for treatment of ventilator-associated pneumonia in trauma patients. AB - Current guidelines for the empiric treatment of ventilator-associated pneumonia (VAP) recommend that vancomycin is dosed 15 mg/kg and administered twice daily for a target trough level of 15 to 20 MUg/mL. This study compared conventional intermittent vancomycin infusion (IVI) with continuous vancomycin infusion (CVI). Our prospective, randomized study compared CVI with IVI in trauma patients with suspected VAP. The primary outcome measure was a serum vancomycin level within the target level 48 hours after initiation of therapy. Treatment groups were compared using standard statistical methods. The study included 73 patients, 36 IVI and 37 CVI. Eighteen patients were withdrawn from the study as a result of discontinuation of the drug before 48 hours or failure to draw levels at the appropriate time, resulting in 27 IVI and 28 CVI study patients. There were no differences between treatment groups in gender (P = 0.97), Injury Severity Score (P = 0.70), total body weight (P = 0.36), or age (P = 0.81). The mean serum vancomycin level for the IVI group was 8.9 +/- 3.9 MUg/mL, and the CVI level was 19.8 +/- 6.13 MUg/mL (P < 0.0001). Two patients in the IVI group (7.4%) were in the therapeutic range compared with 16 (57.1%) in the CVI group (P < 0.0001). Six patients in the CVI group (21.4%) and none of the IVI patients had supratherapeutic levels. Four patients developed renal insufficiency, three IVI (11.1%) and one CVI (3.6%) (P = 0.36). The current American Trauma Society dosing recommendations for vancomycin for presumptive VAP treatment are inadequate. Continuous vancomycin infusion should be adopted as the standard dosing strategy. PMID- 24165256 TI - Submucosal anoderm-preserving hemorrhoidectomy revisited: a modified technique for the surgical management of hemorrhoidal crisis. AB - Submucosal hemorrhoidectomy (Parks' procedure) is a recognized method for treating acute hemorrhoidal crisis. Anoderm preservation has been stressed in various techniques described for elective or emergency excisional hemorrhoidal management. Mucopexy techniques have been proven useful as an adjunct to minimally resectional techniques. A modified submucosal technique with anoderm preservation and mucopexy was applied to 45 patients who presented on an emergency basis with hemorrhoidal crisis. External piles were minimally removed, the minimum possible amount of diseased mucosa was excised, a linear incision was used at the anoderm to enter the subanodermal/mucosal plane to achieve the submucosal excision, and a mucopexy was added at the approximation of the mucosal flaps. Postoperative morbidity was minimal and pain after the procedure remained at acceptable levels. This technique allows for an excision limited to the pathology with important anatomic tissue preservation. This results in conservation of the sensitive and useful anoderm, a decreased risk of stenosis, and addresses the mucosal prolapse. The level of postoperative pain with this technique is acceptable and long-term follow-up reveals a high degree of patient satisfaction. PMID- 24165257 TI - Role of preoperative adrenergic blockade with doxazosin on hemodynamic control during the surgical treatment of pheochromocytoma: a retrospective study of 48 cases. AB - Authors evaluated the effects of selective adrenergic blockade by means of doxazosin on blood pressure in 48 patients operated on for pheochromocytoma by a multicenter retrospective study. Age, tumor size, surgical approach, and operative time were analyzed as predictive factors of intraoperative hypertensive crises. Forty-eight patients underwent adrenalectomy--four open surgery and 44 laparoscopic surgery--for pheochromocytoma of adrenal glands from 1998 to 2008 after preoperative administration of doxazosin. Perioperative cardiovascular status modifications and surgical medium- and long-term outcomes were analyzed. There was no mortality, conversion rate was 4.5 per cent, and morbidity rate was 8.3 per cent. Intraoperative hypertensive crises (180/90 mmHg or higher) were observed in 14.5 per cent (seven of 48) of patients and were treated pharmacologically with no aftermath. None of the examined variables influenced the occurrence of intraoperative hypertensive episodes. Postoperative hypotension (lower than 90/60 mmHg) was observed in four of 48 patients (8.3%) and was treated by crystalloids and hydrocortisone. In the surgical treatment of pheochromocytoma, the preoperative adrenergic blockade by doxazosin does not prevent intraoperative hypertensive crises. Nevertheless, in our series, they were of short duration and were not associated with major cardiovascular complications. Perioperative hemodynamic instability was managed by preoperative pharmacological treatment, allowing low morbidity. PMID- 24165258 TI - Anion gap as a predictor of trauma outcomes in the older trauma population: correlations with injury severity and mortality. AB - The relationship among traumatic injury, the associated metabolic/physiologic responses, and mortality is well established. Tissue hypoperfusion and metabolic derangement may not universally correlate with initial clinical presentation. We hypothesized that anion gap (AG) could be a useful gauge of trauma-related physiologic response and mortality in older patients with relatively lower injury acuity. We retrospectively analyzed data from 711 trauma patients older than 45 years. Parameters examined included demographics, injury characteristics, laboratories, morbidity, and mortality. Univariate and survival analyses were performed using PASW 18. A stepwise correlation exists between increasing Injury Severity Score and AG. Although AG less than 8 to 15 was not associated with a significant increase in mortality, greater mortality was seen for AG greater than 16 with further stepwise increases for AGs greater than 22. Anion gap correlated moderately with serum lactate and poorly with base excess. Increasing AG also correlated with morbidity and greater incidence of intensive care admissions. The presence of any complication increased from 28.6 per cent for patients with AG 12 or less to 45.5 per cent for patients with AG 22 or greater (P < 0.04). These findings support the contention that "low acuity" trauma patients with high AGs may not appear acutely ill but may harbor significant underlying metabolic and physiologic disturbances that could contribute to morbidity and mortality. Higher AG values (i.e., greater than 16) may be associated with worse clinical outcomes. PMID- 24165259 TI - Early intravenous ibuprofen decreases narcotic requirement and length of stay after traumatic rib fracture. AB - Pain control after traumatic rib fracture is essential to avoid respiratory complications and prolonged hospitalization. Narcotics are commonly used, but adjunctive medications such as nonsteroidal anti-inflammatory drugs may be beneficial. Twenty-one patients with traumatic rib fractures treated with both narcotics and intravenous ibuprofen (IVIb) (Treatment) were retrospectively compared with 21 age- and rib fracture-matched patients who received narcotics alone (Control). Pain medication requirements over the first 7 hospital days were evaluated. Mean daily IVIb dose was 2070 +/- 880 mg. Daily intravenous morphine equivalent requirement was 19 +/- 16 vs 32 +/- 24 mg (P < 0.0001). Daily narcotic requirement was significantly decreased in the Treatment group on Days 3 through 7 (P < 0.05). Total weekly narcotic requirement was significantly less among Treatment patients (P = 0.004). Highest and lowest daily pain scores were lower in the Treatment group (P < 0.05). Hospital length of stay was 4.4 +/- 3.4 versus 5.4 +/- 2.9 days (P = 0.32). There were no significant complications associated with IVIb therapy. Early IVIb therapy in patients with traumatic rib fractures significantly decreases narcotic requirement and results in clinically significant decreases in hospital length of stay. IVIb therapy should be initiated in patients with traumatic rib fractures to improve patient comfort and reduce narcotic requirement. PMID- 24165260 TI - Prehospital clinical clearance of the cervical spine: a prospective study. AB - Physician clinical clearance of the cervical spine after blunt trauma is practiced in many trauma centers. Prehospital clinical clearance of the cervical spine (c-spine) performed by emergency medical services (EMS) personnel can decrease cost, improve patient comfort, decrease complications, and decrease prehospital time. The purpose of this study was to assess whether EMS personnel can effectively clinically clear the c-spine of injury in the prehospital setting. All paramedics from a single urban fire department were trained in clinical clearance of the c-spine. During the 14-month period from January 2008 through March 2009, clinical examination of the c-spine was performed by paramedics on blunt trauma patients in the prehospital setting. Paramedics immobilized the c-spine and delivered the patients to the University of South Alabama Medical Center. After trauma center arrival, paramedics documented their clinical examination of the c-spine in a computerized data collection form. Paramedic clinical findings were compared with trauma surgeon clinical examination findings and computed tomographic findings of the c-spine. All patients had prehospital Glasgow Coma Score 14 or greater. Patients were not excluded for distracting injuries. One hundred ninety-three blunt trauma patients were entered. Sixty-five (34%) c-spines were clinically cleared by EMS. There were no known missed injuries in this patient group. Eight (6%) patients who were not clinically cleared by EMS were diagnosed with c-spine injury. Trauma surgeons clinically cleared 135 (70%) of the patients with no known missed injury. EMS personnel in the prehospital setting may reliably and effectively perform clinical clearance of the c-spine. Further prospective study for prehospital c spine clinical clearance is warranted. PMID- 24165261 TI - National emergency medical service system metrics: concerning trends in prehospital times for acutely injured patients. PMID- 24165262 TI - A novel surgical approach for the treatment of severe alkaline reflux after total gastrectomy and Roux-en-Y reconstruction. PMID- 24165263 TI - Treatment of long-term complications after primary surgery for congenital choledochal cysts. PMID- 24165264 TI - Cystic lesions of the adrenal gland. PMID- 24165265 TI - Penetrating thoracic arrow injury: a flashback to the Wild West. PMID- 24165266 TI - Single-incision laparoscopic cholecystectomy: no benefit over conventional laparoscopic cholecystectomy. PMID- 24165267 TI - Erroneous cardiac ECG-gated PET list-mode trigger events can be retrospectively identified and replaced by an offline reprocessing approach: first results in rodents. AB - The assessment of left ventricular function, wall motion and myocardial viability using electrocardiogram (ECG)-gated [(18)F]-FDG positron emission tomography (PET) is widely accepted in human and in preclinical small animal studies. The nonterminal and noninvasive approach permits repeated in vivo evaluations of the same animal, facilitating the assessment of temporal changes in disease or therapy response. Although well established, gated small animal PET studies can contain erroneous gating information, which may yield to blurred images and false estimation of functional parameters. In this work, we present quantitative and visual quality control (QC) methods to evaluate the accuracy of trigger events in PET list-mode and physiological data. Left ventricular functional analysis is performed to quantify the effect of gating errors on the end-systolic and end diastolic volumes, and on the ejection fraction (EF). We aim to recover the cardiac functional parameters by the application of the commonly established heart rate filter approach using fixed ranges based on a standardized population. In addition, we propose a fully reprocessing approach which retrospectively replaces the gating information of the PET list-mode file with appropriate list mode decoding and encoding software. The signal of a simultaneously acquired ECG is processed using standard MATLAB vector functions, which can be individually adapted to reliably detect the R-peaks. Finally, the new trigger events are inserted into the PET list-mode file. A population of 30 mice with various health statuses was analyzed and standard cardiac parameters such as mean heart rate (119 ms +/- 11.8 ms) and mean heart rate variability (1.7 ms +/- 3.4 ms) derived. These standard parameter ranges were taken into account in the QC methods to select a group of nine optimal gated and a group of eight sub-optimal gated [(18)F]-FDG PET scans of mice from our archive. From the list-mode files of the optimal gated group, we randomly deleted various fractions (5% to 60%) of contained trigger events to generate a corrupted group. The filter approach was capable to correct the corrupted group and yield functional parameters with no significant difference to the optimal gated group. We successfully demonstrated the potential of the fully reprocessing approach by applying it to the sub optimal group, where the functional parameters were significantly improved after reprocessing (mean EF from 41% +/- 16% to 60% +/- 13%). When applied to the optimal gated group the fully reprocessing approach did not alter the functional parameters significantly (mean EF from 64% +/- 8% to 64 +/- 7%). This work presents methods to determine and quantify erroneous gating in small animal gated [(18)F]-FDG PET scans. We demonstrate the importance of a quality check for cardiac triggering contained in PET list-mode data and the benefit of optionally reprocessing the fully recorded physiological information to retrospectively modify or fully replace the cardiac triggering in PET list-mode data. We aim to provide a preliminary guideline of how to proceed in the presence of errors and demonstrate that offline reprocessing by filtering erroneous trigger events and retrospective gating by ECG processing is feasible. Future work will focus on the extension by additional QC methods, which may exploit the amplitude of trigger events and ECG signal by means of pattern recognition. Furthermore, we aim to transfer the proposed QC methods and the fully reprocessing approach to human myocardial PET/CT. PMID- 24165268 TI - Impact of wait times on spinal cord stimulation therapy outcomes. AB - OBJECTIVE: Presently, the long-term success rate of spinal cord stimulation (SCS) ranges from 47% to 74%. SCS efficacy is inversely proportional to the passage of time between development of chronic pain syndrome and time of implantation. To improve outcomes, implantation should be performed early. This study identifies sources of delay and offers suggestions for improvement. METHODS: A retrospective analysis of 437 SCS patients examines delays to accessing SCS at various points in the referral stream, from initial diagnosis, family physician, and various specialist treatments, to implantation. Analysis of variance evaluated the effect of age, sex, treating specialty, and their interactions on implantation delay. A multiple linear regression model was developed to assess factors contributing to implantation delay. RESULTS: From time of onset of chronic pain to implantation, patients endured a delay of 65.4 +/- 2.04 months. Initial physician contact occurred at a mean of 3.4 +/- 0.12 months after development of pain syndrome. Family physicians managed cases for 11.9 +/- 0.45 months and various specialists for an additional 39.8 +/- 1.22 months. Neurosurgeons were quickest to refer to an implant physician (average wait-time 32.28 +/- 2.64 months), while orthopedic surgeons and nonimplanting anesthesiologists took the longest, contributing to wait times of 51.60 +/- 5.04 months and 58.08 +/- 5.76 months, respectively. Once the decision for implantation was made, the implanting physician required 3.31 +/ 0.09 months to organize the procedure. A gradual decline in wait times was observed from 1980 to present. CONCLUSION: To improve SCS success rates, physicians involved in the treatment for chronic pain should refer these cases early to an implant physician once failure of medical management becomes apparent. PMID- 24165269 TI - Reducing recurrent stroke: methodology of the motivational interviewing in stroke (MIST) randomized clinical trial. AB - RATIONALE: Recurrent stroke is prevalent in both developed and developing countries, contributing significantly to disability and death. Recurrent stroke rates can be reduced by adequate risk factor management. However, adherence to prescribed medications and lifestyle changes recommended by physicians at discharge after stroke is poor, leading to a large number of preventable recurrent strokes. Using behavior change methods such as Motivational Interviewing early after stroke occurrence has the potential to prevent recurrent stroke. AIMS AND/OR HYPOTHESIS: The overall aim of the study is to determine the effectiveness of motivational interviewing in improving adherence to medication and lifestyle changes recommended by treating physicians at and after hospital discharge in stroke patients 12 months poststroke to reduce risk factors for recurrent stroke. DESIGN: Recruitment of 430 first-ever stroke participants will occur in the Auckland and Waikato regions. Randomization will be to intervention or usual care groups. Participants randomized to intervention will receive four motivational interviews and five follow-up assessments over 12 months. Nonintervention participants will be assessed at the same time points. STUDY OUTCOMES: Primary outcome measures are changes in systolic blood pressure and low density lipoprotein levels 12 months poststroke. Secondary outcomes include self reported adherence and barriers to prescribed medications, new cardiovascular events (including stroke), changes in quality of life, and mood. DISCUSSION: The results of the motivational interviewing in stroke trial will add to our understanding of whether motivational interviewing may be potentially beneficial in the management of stroke and other diseases where similar lifestyle factors or medication adherence are relevant. PMID- 24165270 TI - Incarcerated obturator hernia: a rare clinical entity. PMID- 24165271 TI - Prostaglandin D2 receptor D-type prostanoid receptor 2 mediates eosinophil trafficking into the esophagus. AB - Eosinophilic esophagitis is characterized by eosinophil-predominant inflammation in the esophagus. How eosinophils migrate and infiltrate into the esophagus, however, is less clear. Our previous study demonstrated that mast cell activation led to eosinophil infiltration in the esophagus. Prostaglandin D2 (PGD2) is an important mediator released from activated mast cells. The present study aims to determine whether PGD2 induces eosinophil infiltration into the esophagus via a d type prostanoid receptor 2 (DP2) receptor-dependent mechanism. Using an in vivo guinea pig model, PGD2, d-type prostanoid receptor 1 (DP1) agonist, or DP2 agonist were injected into the esophagus. Esophageal tissues were removed 2 hours after injections and proceeded to either hematoxylin-eosin (HE) staining or immunofluorescent staining of eosinophil major basic protein (MBP) to compare each treatment-induced eosinophil infiltration in the esophagus. In a separate study, ovalbumin (OVA)-sensitized guinea pigs were pretreated with either DP2 or DP1 antagonists, followed by inhalation of OVA to induce mast cell activation. Esophageal tissues were then processed for immunofluorescent staining of MBP. PGD2 injection in the esophagus led to an increase of eosinophil infiltration in esophageal epithelium at the injection site as revealed by HE staining. Increased infiltration of eosinophils was further confirmed by the increased presence of MBP-labeled immunopositive (MBP-LI) cells in esophageal epithelium. Injection with DP2 agonist 15(R)-PGD2, but not DP1 agonist BW 245C, mimicked the PGD2 induced response. In OVA-sensitized animals, antigen inhalation increased MBP-LI cells in esophageal epithelium. Pretreatment with DP2 antagonist BAY-u3405, but not DP1 antagonist BW 868C, inhibited the antigen inhalation-induced increase of MBP-LI cells in esophageal epithelium. These data support the hypothesis that PGD2 induces eosinophil trafficking into the esophageal epithelium via a DP2 mediated pathway, suggesting a role of DP2 antagonist in the prevention of eosinophilic esophagitis. PMID- 24165272 TI - A comparative randomized prospective study to evaluate efficacy and safety of combination of tamsulosin and tadalafil vs. tamsulosin or tadalafil alone in patients with lower urinary tract symptoms due to benign prostatic hyperplasia. AB - INTRODUCTION: Lower urinary tract symptoms (LUTS) associated with benign prostatic hyperplasia (BPH) and erectile dysfunction are common disorders of advancing age. AIM: To evaluate the efficacy and safety of tamsulosin and tadalafil in patients with LUTS due to BPH. METHODS: In this prospective randomized study, 133 men complaining of LUTS due to BPH were included. Forty five patients received tamsulosin 0.4 mg/day alone (Group A), 44 patients received tadalafil 10 mg/day (Group B), and combination therapy (tamsulosin and tadalafil both) was instituted in 44 patients (Group C). After a 2-week medication free run-in period, they were evaluated for International Prostatic Symptom Score (IPSS), International Index of Erectile Function score (IIEF5), quality of life (IPSS QoL), maximum urinary flow rate (Qmax), post-void residual urine (PVR) volume, and safety parameters before and at 3 months of treatment. MAIN OUTCOME MEASURES: There were primary (IPSS, IPSS QoL index, Qmax, and PVR) and secondary (erectile function [EF] domain scores from IIEF5) efficacy end points. Safety assessment included laboratory tests and patient's reporting of adverse event. RESULTS: A significant improvement in IPSS score was observed in all the 3 groups A, B, and C (-50.90%, P < 0.05; -33.50%, P < 0.05; and -53.90%, P < 0.05, respectively). IIEF5 score increased significantly in these three groups (+39.28%, P < 0.05; +45.96%, P < 0.05; and +60.23%, P < 0.05, respectively). A significant increase in Qmax and decrease in PVR were also observed (33.99%, P < 0.05; 29.78%, P < 0.05; and 37.04%, P < 0.05) and (-60.90%, P < 0.05; -49.45%, P < 0.05; and -62.97%, P < 0.05, respectively). The QoL scores improved significantly (-73.35%, P < 0.05; -70.26%, P < 0.05; and -79.65%, P < 0.05, respectively). Side effects were dyspepsia, heartburn, headache, flushing, myalgia, and backache. Adverse effect dropout was 3.7%. No participant experienced any severe or serious adverse events. CONCLUSIONS: In patients with LUTS due to BPH, tamsulosin and tadalafil alone or in combination cause a significant improvement in patients with LUTS. Their EF also improves with these medications. The improvement is better with combination therapy compared with single agent alone. PMID- 24165273 TI - The association between epilepsy and autism symptoms and maladaptive behaviors in children with autism spectrum disorder. AB - Epilepsy is common in children with autism spectrum disorder (ASD) but little is known about how seizures impact the autism phenotype. The association between epilepsy and autism symptoms and associated maladaptive behaviors was examined in 2,645 children with ASD, of whom 139 had epilepsy, from the Simons Simplex Collection. Children with ASD and epilepsy had significantly more autism symptoms and maladaptive behaviors than children without epilepsy. However, after adjusting for IQ, only hyperactivity symptoms remained significantly increased (13% higher) in the epilepsy group. Among children with ASD without co-occurring intellectual disability, children with epilepsy had significantly more irritability (20% higher) and hyperactivity (24% higher) symptoms. This is the largest study to date comparing the autism phenotype in children with ASD with and without epilepsy. Children with ASD and epilepsy showed greater impairment than children without epilepsy, which was mostly explained by the lower IQ of the epilepsy group. These findings have important clinical implications for patients with ASD. PMID- 24165274 TI - Psychotropic medication trends among children and adolescents with autism spectrum disorder in the Medicaid program. AB - This study characterized psychotropic medication use among Medicaid-enrolled children and adolescents with autism spectrum disorders by examining trends over time, including length of treatment and polypharmacy using 4 years of administrative claims data from 41 state Medicaid programs (2000-2003). The data set included nearly 3 million children and adolescents who were 17 years or younger. Approximately, 65% of children with autism spectrum disorder received a psychotropic medication. The results indicate an increasing overall trend in the use of psychotropic drugs among children and adolescents with autism spectrum disorders. Among the different classes of psychotropic drugs, antipsychotics were the most common. Increasing trends in polypharmacy were observed both within and between medication classes. PMID- 24165275 TI - Long non-coding RNA HOTAIR in carcinogenesis and metastasis. AB - Long non-coding RNAs (lncRNAs) have gained massive attention in recent years as a potentially new and crucial layer of gene regulation. LncRNAs are prevalently transcribed in the genome, but their roles in gene regulation and disease development are largely unknown. HOX antisense intergenic RNA (HOTAIR), a lncRNA located in the HOXC locus, has been shown to repress HOXD gene expression and promote breast cancer metastasis. Mechanistically, HOTAIR interacts with and recruits polycomb repressive complex 2 (PRC2) and regulates chromosome occupancy by EZH2 (a subunit of PRC2), which leads to histone H3 lysine 27 trimethylation of the HOXD locus. Moreover, HOTAIR is pervasively overexpressed in most human cancers compared with noncancerous adjacent tissues. This review summarizes the studies on the HOTAIR lncRNA over the past 6 years. PMID- 24165276 TI - In silico analysis of the molecular machinery underlying aqueous humor production: potential implications for glaucoma. AB - BACKGROUND: The ciliary body epithelia (CBE) of the eye produce the aqueous humor (AH). The equilibrium between the AH production by the CBE and the outflow through the trabecular meshwork ultimately determines the intraocular pressure (IOP). An increased IOP is a major risk factor for primary open angle glaucoma (POAG). This study aims to elucidate the molecular machinery of the most important function of the CBE: the AH production and composition, and aims to find possible new molecular clues for POAG and AH production-lowering drugs. METHODS: We performed a gene expression analysis of the non-pigmented (NPE) and pigmented epithelia (PE) of the human CBE of post mortem eyes. We used 44 k Agilent microarrays against a common reference design. Functional annotations were performed with the Ingenuity knowledge database. RESULTS: We built a molecular model of AH production by combining previously published physiological data with our current genomic expression data. Next, we investigated molecular CBE transport features which might influence AH composition. These features included caveolin- and clathrin vesicle-mediated transport of large biomolecules, as well as a range of substrate specific transporters. The presence of these transporters implies that, for example, immunoglobins, thyroid hormone, prostaglandins, cholesterol and vitamins can be secreted by the CBE along with the AH. In silico, we predicted some of the molecular apical interactions between the NPE and PE, the side where the two folded epithelia face each other. Finally, we found high expression of seven POAG disease genes in the plasma membrane of extracellular space of the CBE, namely APOE, CAV1, COL8A2, EDNRA, FBN1, RFTN1 and TLR4 and we found possible new targets for AH lowering drugs in the AH. CONCLUSIONS: The CBE expresses many transporters, which account for AH production and/or composition. Some of these entries have also been associated with POAG. We hypothesize that the CBE may play a more prominent role than currently thought in the pathogenesis of POAG, for example by changing the composition of AH. PMID- 24165277 TI - Detection of lamivudine-resistant variants and mutations related to reduced antigenicity of HBsAg in individuals from the cities of Santos and Sao Paulo, Brazil. AB - BACKGROUND: Continuous long-term treatment is recommended to reduce the hepatitis B virus (HBV) viral load. However, as a consequence, resistance mutations can emerge and be transmitted to other individuals. The polymerase (POL) gene overlaps the surface (S) gene. Thus, during treatment, mutations in the POL gene may lead to changes in hepatitis B surface antigen (HBsAg). The purpose of this study was to evaluate the frequency of lamivudine and vaccine escape mutations in HBsAg-positive blood donors from the city of Santos and in untreated HBV mono infected patients from the city of Sao Paulo, Brazil. METHODS: HBV DNA was extracted from 80 serum samples, of which 61 were from volunteer blood donors and 19 were from untreated HBV patients. A fragment of the POL/S genes containing 593 base pairs was amplified using nested PCR. Thirty four were PCR-positive and sequencing was performed using an ABI Prism 3130 Genetic Analyzer. Alignments and mutation mapping were performed using BioEdit software. RESULTS: HBV DNA from 21 blood donors and 13 untreated patient samples were characterized using nucleotide sequencing PCR products from the POL/S genes. We were able to detect one sample with the resistance mutation to lamivudine rtM204V + rtL180M (2.94%), which was found in a volunteer blood donor that has never used antiviral drugs. The other samples showed only compensatory mutations, such as rtL80F (5.88%), rtL80V (2.94%), rtL82V + rtV207L (2.94%), rtT128P (5.88%), rtT128N/S (2.94%) and rtS219A (5.88%). We found modifications in the S gene in 14 of the 34 samples (41.16%). The mutations detected were as follows: sM133L + sI195T (2.94%), sI195M (2.94%), sP120T (2.94%), sY100S/F (2.94%), sY100C (17.64%), sI/T126P + sQ129P (2.94%), sM198I + sF183C (2.94%) and sS210R (5.88%). CONCLUSIONS: Our results suggest the transmission of lamivudine-resistant forms. Thus, the evaluation of HBV-infected subjects for lamivudine resistance would improve treatment regime. Moreover, the mutations in the S gene may impair HBsAg antigenicity and contribute to HBsAg failure detection and vaccine escape. PMID- 24165279 TI - Emerging trends of long non-coding RNAs in gene activation. AB - The RNA world has gained increasing importance in the recent past as its role beyond coding for proteins and components of translational machinery is becoming more and more prominent. Recent studies have shown pervasive transcription throughout the genome generating a large number of non-coding RNAs (ncRNAs) but few of these RNAs have been shown to perform regulatory functions. Among the regulatory RNAs, the long non-coding RNAs (lncRNAs) form an interesting class which, with their ability to bind to a variety of targets, can play pivotal roles in cellular processes including regulation of gene expression. While lncRNAs are well known for their role in repressing gene expression, their role in gene activation is only emerging from recent studies. Here we review how the lncRNAs can mediate gene activation by a variety of mechanisms and explore their importance in biological processes. PMID- 24165280 TI - Nursing2013 survey results: Drug administration by enteral feeding tube. PMID- 24165278 TI - Direct contact and environmental contaminations are responsible for HEV transmission in pigs. AB - Hepatitis E virus (HEV) can cause enterically-transmitted hepatitis in humans. The zoonotic nature of Hepatitis E infections has been established in industrialized areas and domestic pigs are considered as the main reservoir. The dynamics of transmission in pig herds therefore needs to be understood to reduce the prevalence of viremic pigs at slaughter and prevent contaminated pig products from entering the food chain. An experimental trial was carried out to study the main characteristics of HEV transmission between orally inoculated pigs and naive animals. A mathematical model was used to investigate three transmission routes, namely direct contact between pigs and two environmental components to represent within-and between-group oro-fecal transmission. A large inter-individual variability was observed in response to infection with an average latent period lasting 6.9 days (5.8; 7.9) in inoculated animals and an average infectious period of 9.7 days (8.2; 11.2). Our results show that direct transmission alone, with a partial reproduction number of 1.41 (0.21; 3.02), can be considered as a factor of persistence of infection within a population. However, the quantity of virus present in the environment was found to play an essential role in the transmission process strongly influencing the probability of infection with a within pen transmission rate estimated to 2 . 10(-6)g ge(-1)d(-1)(1 . 10(-7); 7 . 10(-6)). Between-pen environmental transmission occurred to a lesser extent (transmission rate: 7 . 10(-8)g ge(-1) d(-1)(5 . 10(-9); 3 . 10(-7)) but could further generate a within-group process. The combination of these transmission routes could explain the persistence and high prevalence of HEV in pig populations. PMID- 24165281 TI - [Multidisciplinary meetings dedicated to bone metastases: a historical perspective and rationale]. AB - Bone metastases of solid tumors have a strong impact on patient's autonomy and vital outcome. Drugs specifically targeting bone remodeling as well as local treatment (radiotherapy, osteoplasty, surgery) make the management of bone metastasis a multidisciplinary process. Multidisciplinary teams (MDTs) dedicated to bone metastasis aim at providing the diagnosis of certainty, defining treatment indications and monitoring follow-up. The MDTs are the place for innovation in imaging and treatments of bone metastases. PMID- 24165283 TI - Recurrent hyperaldosteronism after adrenalectomy: an indication for careful radiologic and histologic re-evaluation. PMID- 24165284 TI - Successful lung transplantation in a case with diffuse pulmonary arteriovenous malformations and hereditary hemorrhagic telangiectasia. AB - Diffuse pulmonary arteriovenous malformations (AVMs) are associated with a poor prognosis and the therapeutic strategy remains controversial. We describe a pediatric patient with diffuse pulmonary AVMs associated with hereditary hemorrhagic telangiectasia (HHT), who presented with two cerebral AVMs in the parietal and occipital lobes as well. Of note, successful bilateral lung transplantation not only improved the hypoxemia but also resulted in size reduction of the cerebral AVMs. Although it is essential to consider involvements other than pulmonary AVMs, especially brain AVMs, to decide the indication, lung transplantation can be a viable therapeutic option for patients with diffuse pulmonary AVMs and HHT. PMID- 24165282 TI - Intrathecal baclofen treatment in dystonic cerebral palsy: a randomized clinical trial: the IDYS trial. AB - BACKGROUND: Dystonic cerebral palsy is primarily caused by damage to the basal ganglia and central cortex. The daily care of these patients can be difficult due to dystonic movements. Intrathecal baclofen treatment is a potential treatment option for dystonia and has become common practice. Despite this widespread adoption, high quality evidence on the effects of intrathecal baclofen treatment on daily activities is lacking and prospective data are needed to judge the usefulness and indications for dystonic cerebral palsy. The primary aim of this study is to provide level one clinical evidence for the effects of intrathecal baclofen treatment on the level of activities and participation in dystonic cerebral palsy patients. Furthermore, we hope to identify clinical characteristics that will predict a beneficial effect of intrathecal baclofen in an individual patient. METHODS/DESIGN: A double blind placebo-controlled multi center randomized clinical trial will be performed in 30 children with dystonic cerebral palsy. Patients aged between 4 and 25 years old with a confirmed diagnosis of dystonic cerebral palsy, Gross Motor Functioning Classification System level IV or V, with lesions in the cerebral white matter, basal ganglia or central cortex and who are eligible for intrathecal baclofen treatment will be included. Group A will receive three months of continuous intrathecal baclofen treatment and group B will receive three months of placebo treatment, both via an implanted pump. After this three month period, all patients will receive intrathecal baclofen treatment, with a follow-up after nine months. The primary outcome measurement will be the effect on activities of and participation in daily life measured by Goal Attainment Scaling. Secondary outcome measurements on the level of body functions include dystonia, spasticity, pain, comfort and sleep related breathing disorders. Side effects will be monitored and we will study whether patient characteristics influence outcome. DISCUSSION: The results of this study will provide data for evidence-based use of intrathecal baclofen in dystonic cerebral palsy. PMID- 24165285 TI - Kyphoplasty increases vertebral height, decreases both pain score and opiate requirements while improving functional status. AB - Vertebral compression fractures can result from advanced osteoporosis, or less commonly from metastatic or traumatic insults to the vertebral column, and result in disabling pain and decreased functional capacity. Various vertebral augmentation options including kyphoplasty aim at preventing the sequelae of pain and immobility that can develop as the result of the vertebral fractures. The mechanism for pain relief following kyphoplasty is not entirely understood, and the restoration of a portion of the lost vertebral height is a subject of debate. We retrospectively reviewed radiographic imaging, pain relief, analgesic intake and functional outcomes in 67 consecutive patients who underwent single- or multilevel kyphoplasty with the primary goal of quantifying the restoration of lost vertebral height. We observed a mean of 45% of the lost vertebral height restored postprocedurally. Secondarily, kyphoplasty was associated with significant decreases in pain scores, daily morphine consumption and improvement in patient-reported functional measures. PMID- 24165286 TI - Body mass index and leukocyte telomere length in adults: a systematic review and meta-analysis. AB - The objective of this study was to provide a systematic review and meta-analysis of studies on the relationship between body mass index (BMI) and leukocyte telomere length (LTL). Relevant studies were identified by a systematic search of MEDLINE, Embase and Web of Knowledge databases. Pooled correlation and regression coefficients were calculated using meta-analysis methods for both cross-sectional and longitudinal studies. Studies without suitable data for meta-analysis were summarized separately. Overall, 29 studies were included, of which 16 were eligible for meta-analysis, including two longitudinal studies. The majority of studies reported an inverse relationship between BMI and telomere length. For cross-sectional studies, the pooled estimates for correlation and regression coefficients were -0.057 (95% confidence interval [CI]: -0.102 to -0.012) and 0.008 kBP kg m-2 (95% CI: -0.016 to 0.000), respectively. The two longitudinal studies were small (70 and 311 subjects), covered different age ranges and yielded inconsistent results. No evidence of any gender difference was observed. Despite some variation between studies and very limited data from longitudinal studies, the results of this meta-analysis suggest a biologically plausible inverse association between BMI and LTL in adults. However, the associations require clarification, in particular by large longitudinal studies with careful control for possible confounding factors in overall, age- and sex-specific analyses. PMID- 24165287 TI - Methodology of a population-based stroke and TIA incidence and outcomes study: the Auckland Regional Community Stroke Study (ARCOS IV) 2011-2012. AB - BACKGROUND: Stroke is a leading cause of death and disability worldwide. Stroke burden is immense as it leads to premature deaths, leaves survivors with ongoing disabilities, and has a major financial impact on the individual, their families, and the community. Reliable, high-quality evidence is needed on stroke risk factors, incidence, and outcomes to provide information on how best to reduce this burden. Population-based studies are regarded as the 'gold-standard' of measuring disease burden but are not common due to the logistical and financial challenges they present. The Auckland Regional Community Stroke Studies are among a few in the world that have been carried out at a population level and at regular intervals. AIM: The aim of the fourth Auckland Regional Community Stroke Studies IV is to examine the current measures of stroke incidence, prevalence, and outcomes as well the trends over four decades. This article describes the methodology of the Auckland Regional Community Stroke Studies IV with stroke and transient ischemic attacks cases registered over a 12-month period from March 1, 2011 to February 29, 2012. CONCLUSIONS: The methodology described may be used as a guide in order to design similar population-based stroke incidence and outcome studies in other countries and populations, thus facilitating the collection of most consistent and accurate stroke epidemiological data. PMID- 24165289 TI - The role of arthropathy in the development of osteoporosis in patients with haemophilia: do we need more? PMID- 24165288 TI - ST2 in emergency department patients with noncardiac dyspnea. AB - OBJECTIVES: Serum levels of soluble ST2, a member of the interleukin-1 receptor family, predict mortality in emergency department (ED) patients with dyspnea secondary to acute heart failure and acute coronary syndrome. Elevated levels of ST2 have also been described in pulmonary disease, but it is unclear if these are associated with adverse outcomes. The hypothesis for this study was that elevated ST2 levels would be associated with 180-day mortality and 180-day return ED visits or hospital readmission in patients presenting to the ED with noncardiac causes of dyspnea. METHODS: This prospective observational cohort study enrolled a convenience sample of patients presenting to a single academic tertiary care ED with a chief complaint of dyspnea. Exclusion criteria included dyspnea due to chest wall trauma, airway obstruction, and known cardiac etiology (new onset heart failure, prior heart failure with current brain natriuretic peptide > 500 pg/mL, presumed ischemic chest pain, elevated troponin, electrocardiogram changes indicating myocardial infarction or ischemia, heart transplant). ST2 levels were measured at ED presentation and compared between those with and without adverse outcomes. Staff were blinded to ST2 levels. Differences between groups were assessed using the Mann-Whitney U test. RESULTS: Of the 82 patients enrolled, 45 (55%) were female, 48 (59%) were African American, and 34 (42%) were hospitalized. The most frequent ED or hospital diagnosis was chronic obstructive pulmonary disease (COPD) or asthma, in 29 (35%) patients. At 180 days, 36 of 81 patients (44%) had return ED visits, 21 of 81 patients (26%) were readmitted, and five of 82 patients (6%) were deceased. Median ST2 level was 227 ng/mL in patients who died versus 32 ng/mL in those who survived (difference = 195 ng/mL, 95% confidence interval [CI] = 48 to 342 ng/mL, p = 0.006). Median ST2 level was 59 ng/mL in readmitted patients versus 31 ng/mL in nonreadmitted patients (difference = 28 ng/mL, 95% CI = -3 to 60 ng/mL, p = 0.036). Median ST2 levels were 41 ng/mL in patients with return ED visits versus 31 ng/mL in those without return visits (difference = 10 ng/mL, 95% CI = -10 to 20 ng/mL, p = 0.23). CONCLUSIONS: Patients with noncardiac dyspnea who died or required readmission to the hospital within 180 days had higher levels of ST2 compared with nonadmitted survivors. Further research into ST2 as a prognostic tool in pathologic processes not involving the heart, such as pulmonary disease, is warranted. PMID- 24165290 TI - Analysing clinical reasoning characteristics using a combined methods approach. AB - BACKGROUND: Despite a major research focus on clinical reasoning over the last several decades, a method of evaluating the clinical reasoning process that is both objective and comprehensive is yet to be developed.The aim of this study was to test whether a dual approach, using two measures of clinical reasoning, the Clinical Reasoning Problem (CRP) and the Script Concordance Test (SCT), provides a valid, reliable and targeted analysis of clinical reasoning characteristics to facilitate the development of diagnostic thinking in medical students. METHODS: Three groups of participants, general practitioners, and third and fourth (final) year medical students completed 20 on-line clinical scenarios -10 in CRP and 10 in SCT format. Scores for each format were analysed for reliability, correlation between the two formats and differences between subject-groups. RESULTS: Cronbach's alpha coefficient ranged from 0.36 for SCT 1 to 0.61 for CRP 2, Statistically significant correlations were found between the mean f-score of the CRP 2 and total SCT 2 score (0.69); and between the mean f-score for all CRPs and all mean SCT scores (0.57 and 0.47 respectively). The pass/fail rates of the SCT and CRP f-score are in keeping with the findings from the correlation analysis (i.e. 31% of students (11/35) passed both, 26% failed both, and 43% (15/35) of students passed one but not the other test), and suggest that the two formats measure overlapping but not identical characteristics. One-way ANOVA showed consistent differences in scores between levels of expertise with these differences being significant or approaching significance for the CRPs. CONCLUSION: SCTs and CRPs are overlapping and complementary measures of clinical reasoning. Whilst SCTs are more efficient to administer, the use of both measures provides a more comprehensive appraisal of clinical skills than either single measure alone, and as such could potentially facilitate the customised teaching of clinical reasoning for individuals. The modest reliability of SCTs and CRPs in this study suggests the need for an increased number of items for testing. Further work is needed to determine the suitability of a combined approach for assessment purposes. PMID- 24165291 TI - Curcumin suppresses malignant glioma cells growth and induces apoptosis by inhibition of SHH/GLI1 signaling pathway in vitro and vivo. AB - AIMS: To study the role of curcumin on glioma cells via the SHH/GLI1 pathway in vitro and vivo. METHODS: The effects of curcumin on proliferation, migration, apoptosis, SHH/GLI1 signaling, and GLI1 target genes expression were evaluated in multiple glioma cell lines in vitro. A U87-implanted nude mice model was used to study the role of curcumin on tumor volume and the suppression efficacy of GLI1. RESULTS: Curcumin showed cytotoxic effects on glioma cell lines in vitro. Both mRNA and protein levels of SHH/GLI1 signaling (Shh, Smo, GLI1) were downregulated in a dose- and time-dependent manner. Several GLI1-dependent target genes (CyclinD1, Bcl-2, Foxm1) were also downregulated. Curcumin treatment prevented GLI1 translocating into the cell nucleus and reduced the concentration of its reporter. Curcumin suppressed cell proliferation, colony formation, migration, and induced apoptosis which was mediated partly through the mitochondrial pathway after an increase in the ratio of Bax to Bcl2. Intraperitoneal injection of curcumin in vivo reduced tumor volume, GLI1 expression, the number of positively stained cells, and prolonged the survival period compared with the control group. CONCLUSION: This study shows that curcumin holds a great promise for SHH/GLI1 targeted therapy against gliomas. PMID- 24165292 TI - Respective effects of phlebotomy losses and erythropoietin treatment on the need for blood transfusion in very premature infants. AB - BACKGROUND: The benefit to risk ratio of the treatment with erythropoietin (EPO) as a means of limiting the number of transfusions in very preterm infants during hospitalization, seems to be modest since the adoption of restrictive transfusion criteria and of policy limiting phlebotomy losses. We therefore aim to evaluate the factors associated with the number of late blood transfusion in very preterm infants in a unit where the routine use of EPO has been discontinued. METHODS: A comparative "before-after" study was carried out in premature infants born before 32 weeks postmenstrual age (PMA), over a period of one year before (EPO group) and one year after (non-EPO group) the discontinuation of EPO therapy. RESULTS: A total of 48 infants were included in the study (EPO = 21; non-EPO = 27). The number of infants transfused after the 15 day of life (D15) and the number of transfusions per infant after D15 were not significantly different between the two groups. In a multivariate analysis, the gestational age and the volume of blood drawn off during the first month of life significantly influenced the need for transfusions after the 15th day of life, independently of the treatment with EPO. The hemoglobin levels measured at different times of hospitalization (median postnatal age: 16, 33 and 67 days) were not significantly different between the two groups. CONCLUSIONS: Our study shows that the discontinuation of EPO did not change the number of late transfusions. Even when a policy limiting phlebotomy losses is used, blood loss is an important and independent risk factor for late transfusion of very preterm infants. PMID- 24165293 TI - Innate immune response after acute myocardial infarction and pharmacomodulatory action of tacrolimus in reducing infarct size and preserving myocardial integrity. AB - BACKGROUND: This study investigated the association between innate immune reaction and myocardial damage after acute myocardial infarction (AMI) and anti inflammatory role of tacrolimus in reducing infarct size. Male mini-pigs (n=18) were equally categorized into sham control (SC), untreated AMI (by ligation of left anterior descending coronary artery), and AMI-Tacrolimus (AMI-Tac) (0.5 mg intra-coronary injection 30 minutes post-AMI). Cardiac magnetic resonance imaging (MRI) was performed at post-AMI days 2, 5 and 21 before sacrificing the animals. RESULTS: By post-AMI day 21, left ventricular ejection fraction (LVEF) was lowest in untreated AMI animals, significantly higher in SC than in AMI-Tac group (all p<0.003). Infarct areas at basal, middle, and apical levels, numbers of CD14+ and iNOS+ cells in infarct area (IA) and peri-IA, and protein expression of CD14, CD68, and Ly6g from circulating inflammatory cells showed an opposite pattern compared with that of LVEF in all groups (all p<0.005). Protein expressions of MCP-1, MIP-1, TNF-alpha, NF-kappaB, iNOS, and IL-12 in IA and peri-IA exhibited an identical pattern compared to that of CD14, CD68, and Ly6g from circulating inflammatory cells (all p<0.01). Expressions of myocardial damage biomarkers in IA and peri-IA [gamma-H2AX, beta-myosin heavy chain (MHC), Smad3, TGF-beta] were highest in AMI and higher in AMI-Tac than in SC, whereas expressions of myocardial integrity biomarkers (connexin43, mitochondrial cytochrome-C, alpha MHC, BMP-2, Smad1/5) were opposite to those of damage biomarkers (all p<0.001). CONCLUSION: Innate immune responses were markedly augmented and LVEF was significantly reduced after AMI but were remarkably improved after tacrolimus treatment. PMID- 24165294 TI - A relationship between bruxism and orofacial-dystonia? A trigeminal electrophysiological approach in a case report of pineal cavernoma. AB - BACKGROUND: In some clinical cases, bruxism may be correlated to central nervous system hyperexcitability, suggesting that bruxism may represent a subclinical form of dystonia. To examine this hypothesis, we performed an electrophysiological evaluation of the excitability of the trigeminal nervous system in a patient affected by pineal cavernoma with pain symptoms in the orofacial region and pronounced bruxism. METHODS: Electrophysiological studies included bilateral electrical transcranial stimulation of the trigeminal roots, analysis of the jaw jerk reflex, recovery cycle of masseter inhibitory reflex, and a magnetic resonance imaging study of the brain. RESULTS: The neuromuscular responses of the left- and right-side bilateral trigeminal motor potentials showed a high degree of symmetry in latency (1.92 ms and 1.96 ms, respectively) and amplitude (11 mV and 11.4 mV, respectively), whereas the jaw jerk reflex amplitude of the right and left masseters was 5.1 mV and 8.9 mV, respectively. The test stimulus for the recovery cycle of masseter inhibitory reflex evoked both silent periods at an interstimulus interval of 150 ms. The duration of the second silent period evoked by the test stimulus was 61 ms and 54 ms on the right and left masseters, respectively, which was greater than that evoked by the conditioning stimulus (39 ms and 35 ms, respectively). CONCLUSIONS: We found evidence of activation and peripheral sensitization of the nociceptive fibers, the primary and secondary nociceptive neurons in the central nervous system, and the endogenous pain control systems (including both the inhibitory and facilitatory processes), in the tested subject. These data suggest that bruxism and central orofacial pain can coexist, but are two independent symptoms, which may explain why numerous experimental and clinical studies fail to reach unequivocal conclusions. PMID- 24165295 TI - Cell surface hydrophobicity: a key component in the degradation of polyethylene succinate by Pseudomonas sp. AKS2. AB - AIM: Polyethylene succinate (PES) contains hydrolysable ester bonds that make it a potential substitute for polyethylene (PE) and polypropylene (PP). Towards bioremediation of PES, we have already reported that a new strain of Pseudomonas, Pseudomonas sp. AKS2, can efficiently degrade PES and hypothesized that cell surface hydrophobicity plays an important role in this degradation process. In this study, our efforts were targeted towards establishing a correlation between cell surface hydrophobicity and PES degradation. METHODS AND RESULTS: We have manipulated cell surface hydrophobicity of AKS2 by varying concentrations of glucose and ammonium sulphate in the growth medium and subsequently examined the extent of PES degradation. We observed an increase in PES degradation by AKS2 with an increase in cell surface hydrophobicity. The increased surface hydrophobicity caused an enhanced biofilm formation on PES surface that resulted in better polymer degradation. CONCLUSION: The current study establishes a direct correlation between cell surface hydrophobicity of an organism and its potential to degrade a nonpolar polymer like PES. SIGNIFICANCE AND IMPACT OF THE STUDY: Cell surface hydrophobicity manipulation can be used as an important strategy to increase bioremediation of nonpolar polymer like PES. PMID- 24165296 TI - Jejunogastric intussusception: a rare cause of gastric outlet obstruction. PMID- 24165297 TI - Presence or absence of intestinal metaplasia but not its burden is associated with prevalent high-grade dysplasia and cancer in Barrett's esophagus. AB - Universal agreement on the inclusion of intestinal metaplasia to diagnose Barrett's esophagus (BE) is lacking. Our aim was to determine the association of intestinal metaplasia and its density with the prevalence of dysplasia/cancer in columnar lined esophagus (CLE). Patients with CLE but no intestinal metaplasia (CLE-no IM) were identified by querying the clinical pathology database using SNOMED codes for distal esophageal biopsies. CLE-IM patients were identified from a prospectively maintained database of BE patients. Subsequently, relative risks for prevalent dysplasia and cancer were calculated. Since patients with CLE-no IM are not usually enrolled in surveillance, only prevalent dysplasia/cancer on index endoscopy was analyzed. Goblet cell density and percent intestinal metaplasia were estimated. All biopsy slides were reviewed for dysplasia by two experienced gastrointestinal pathologists. Two hundred sixty-two CLE-IM and 260 CLE-no IM patients were included (age 64+/-12 vs. 60+/-11 years, P=0.001; whites 92% vs. 82%, P=0.001; males 99.7% vs. 99.3%, P=NS; CLE length 3.4+/-3.2 vears 1.4+/-0.4 cm, P=0.001 and hiatus hernia 64% vs. 56%, P=0.013). The odds of finding low-grade dysplasia and of high-grade dysplasia (HGD)/cancer were 12.5 fold (2.9-53.8, P=0.007) and 4.2-fold (95% CI 1.4-13, P=0.01) higher, respectively, in the CLE-IM group. Reanalysis after controlling for important variables of age, race, and length did not significantly alter the overall results. In CLE-IM group, when patients with high (>50/LPF) versus low goblet cell density (<50/LPF) and <10% versus >10% intestinal metaplasia were compared, the odds of HGD/cancer, OR 1.5 (0.5-4.9, P=0.5) and 1.97 (0.54-7.22), respectively, were not significantly higher. Demonstration of intestinal metaplasia continues to be an essential element in the definition of BE, but its quantification may not be useful for risk stratification of HGD/cancer in BE. PMID- 24165299 TI - Psychophysics, fitting, and signal processing for combined hearing aid and cochlear implant stimulation. AB - The addition of acoustic stimulation to electric stimulation via a cochlear implant has been shown to be advantageous for speech perception in noise, sound quality, music perception, and sound source localization. However, the signal processing and fitting procedures of current cochlear implants and hearing aids were developed independently, precluding several potential advantages of bimodal stimulation, such as improved sound source localization and binaural unmasking of speech in noise. While there is a large and increasing population of implantees who use a hearing aid, there are currently no generally accepted fitting methods for this configuration. It is not practical to fit current commercial devices to achieve optimal binaural loudness balance or optimal binaural cue transmission for arbitrary signals and levels. There are several promising experimental signal processing systems specifically designed for bimodal stimulation. In this article, basic psychophysical studies with electric acoustic stimulation are reviewed, along with the current state of the art in fitting, and experimental signal processing techniques for electric acoustic stimulation. PMID- 24165300 TI - Time course and cost of misdirecting auditory spatial attention in younger and older adults. AB - OBJECTIVES: The effects of directing, switching, and misdirecting auditory spatial attention in a complex listening situation were investigated in 8 younger and 8 older listeners with normal-hearing sensitivity below 4 kHz. DESIGN: In two companion experiments, a target sentence was presented from one spatial location and two competing sentences were presented simultaneously, one from each of two different locations. Pretrial, listeners were informed of the call-sign cue that identified which of the three sentences was the target and of the probability of the target sentence being presented from each of the three possible locations. Four different probability conditions varied in the likelihood of the target being presented at the left, center, and right locations. In Experiment 1, four timing conditions were tested: the original (unedited) sentences (which contained about 300 msec of filler speech between the call-sign cue and the onset of the target words), or modified (edited) sentences with silent pauses of 0, 150, or 300 msec replacing the filler speech. In Experiment 2, when the cued sentence was presented from an unlikely (side) listening location, for half of the trials the listener's task was to report target words from the cued sentence (cue condition); for the remaining trials, the listener's task was to report target words from the sentence presented from the opposite, unlikely (side) listening location (anticue condition). RESULTS: In Experiment 1, for targets presented from the likely (center) location, word identification was better for the unedited than for modified sentences. For targets presented from unlikely (side) locations, word identification was better when there was more time between the call-sign cue and target words. All listeners benefited similarly from the availability of more compared with less time and the presentation of continuous compared with interrupted speech. In Experiment 2, the key finding was that age related performance deficits were observed in conditions requiring anticue but not cue responses. CONCLUSIONS: The findings from Experiment 1 suggest that for both age groups, stream continuity mediates the process of allocating and maintaining auditory spatial attention when the target originates at an expected location, but that time is needed for the reallocation of auditory spatial attention when the target originates at an unexpected location. The findings from Experiment 2 suggest that when attention is momentarily misdirected, difficulties disengaging attention may help explain why older adults with good hearing report difficulty communicating in multi-talker listening situations. PMID- 24165301 TI - Decline in older persons' ability to recognize speech in noise: the influence of demographic, health-related, environmental, and cognitive factors. AB - OBJECTIVES: The first aim was to investigate whether the rate of decline in older persons' ability to recognize speech in noise over time differs across age and gender. The second aim was to determine extent demographic, health-related, environmental, and cognitive factors influence the change in speech-in-noise recognition over time. DESIGN: Data covering 3 to 7 years of follow-up (mean: 4.9 years) of a large sample of the Longitudinal Aging Study Amsterdam were used (n = 1298; 3025 observations; baseline ages: 57 to 93 years). Hearing ability was measured by a digit triplet speech-in-noise test (SNT) yielding a speech reception threshold in noise (SRTn). Multilevel analyses were used to model the change in SRTn over time. First, interaction terms were used to test differences in rate of decline across subgroups. Second, for each of the following factors the authors determined the influence on the change in SRTn: age, gender, educational level, cardiovascular conditions, information processing speed, fluid intelligence, global cognitive functioning, smoking, and alcohol use. This was done by calculating the percentage change in Btime after adding the particular factor to the model. RESULTS: On average, respondents' SRTn increased (i.e., deteriorated) significantly over time by 0.18 dB signal-to-noise ratio per annum. Rates were accelerated for older ages (Btime = 0.13, 0.14, 0.25, 0.27 for persons who were 57 to 65, 65 to 75, 75 to 85, and 85 to 93 years of age, respectively). Only information processing speed relevantly influenced the change in SRTn over time (17% decrease in Btime). CONCLUSIONS: Decline in older persons' speech-in noise recognition over time accelerated for older ages. Decline in information processing speed explained a moderate proportion of the SRTn decline. This indicates the relevance of declining cognitive abilities in the ability of older persons to recognize speech in noisy environments. PMID- 24165302 TI - Validity of automated threshold audiometry: a systematic review and meta analysis. AB - OBJECTIVES: A systematic literature review and meta-analysis on the validity (test-retest reliability and accuracy) of automated threshold audiometry compared with the gold standard of manual threshold audiometry was conducted. DESIGN: A systematic literature review was completed in peer-reviewed databases on automated compared with manual threshold audiometry. Subsequently a meta-analysis was conducted on the validity of automated audiometry. METHODS: A multifaceted approach, covering several databases and using different search strategies was used to ensure comprehensive coverage and to cross-check search findings. Databases included: MEDLINE, Scopus, and PubMed; a secondary search strategy was the review of references from identified reports. Reports including within subject comparisons of manual and automated threshold audiometry were selected according to inclusion/exclusion criteria before data were extracted. For the meta-analysis weighted mean differences (and standard deviations) on test-retest reliability for automated compared with manual audiometry were determined to assess the validity of automated threshold audiometry. RESULTS: In total, 29 reports on automated audiometry (method of limits and the method of adjustment techniques) met the inclusion criteria and were included in this review. Most reports included data on adult populations using air conduction testing with limited data on children, bone conduction testing and the effects of hearing status on automated audiometry. Meta-analysis test-retest reliability for automated audiometry was within typical test-retest variability for manual audiometry. Accuracy results on the meta-analysis indicated overall average differences between manual and automated air conduction audiometry (0.4 dB, 6.1 SD) to be comparable with test-retest differences for manual (1.3 dB, 6.1 SD) and automated (0.3 dB, 6.9 SD) audiometry. No significant differences (p > 0.01; summarized data analysis of variance) were seen in any of the comparisons between test-retest reliability of manual and automated audiometry compared with differences between manual and automated audiometry. CONCLUSION: Automated audiometry provides an accurate measure of hearing threshold, but validation data are still limited for (1) automated bone conduction audiometry; (2) automated audiometry in children and difficult-to-test populations and; (3) different types and degrees of hearing loss. PMID- 24165305 TI - Quantitative relationship between body weight gain in adulthood and incident type 2 diabetes: a meta-analysis. AB - This meta-analysis quantified the risk of type 2 diabetes mellitus (T2DM) preceded by body weight (BW) gain in the general population. Systematic literature searches retrieved 15 eligible studies. The BW gain was divided into early weight-gain, which was defined as BW gain from early adulthood (18-24 years of age) to cohort entry (>=25 years of age), and late weight-gain, which was defined as BW gain from cohort entry. The pooled relative risk (RR; 95% confidence interval [CI]) of T2DM for an increment of BW gain standardized into a 5-kg m(-2) increment in the body mass index (BMI) was 3.07 (2.49-2.79) for early weight-gain and 2.12 (1.74-2.58) for late weight-gain. When limiting analysis to studies that concurrently examined T2DM risk for current BMI (defined in both groups as BMI at cohort entry), a larger magnitude of T2DM risk was revealed for early weight-gain compared with current BMI (RR [95% CI], 3.38 [2.20-5.18] vs. 2.39 [1.58-3.62]), while there was little difference between late weight-gain (RR [95% CI], 2.21 [1.91-2.56]) and current BMI (RR [95% CI], 2.47 [1.97-3.30]). The meta-analysis suggested that BW gain was a quantifiable predictor of T2DM, as well as current obesity in adults. Particularly, BW gain in early rather than middle-to-late adulthood played an important role in developing T2DM. PMID- 24165306 TI - Cautery versus scalpel for abdominal skin incisions: a double blind, randomized crossover trial of scar cosmesis. AB - BACKGROUND: The purpose of this study was to determine whether there is any difference in cosmetic outcome between using cutting diathermy and using a scalpel to make abdominal skin incisions. METHOD: This was a prospective, randomized, double-blind crossover study. The primary end point was wound cosmesis as judged by the patient. In each case, one-half of the skin incision was made using diathermy, and one-half using a scalpel blade. Patients were contacted at 6 months post-operatively, and were asked which half of the wound looked better to them. A panel of 18 surgeons was also shown photographs of the wounds taken after 6 months, and were asked the same question. RESULTS: Of the 31 patients with complete follow-up, 11 (35%) reported no difference between the two halves of the wound. Nine (29%) preferred the half incised with diathermy, and 11 (35%) preferred the half incised with the scalpel (P = 0.82, chi-squared test). Twenty-four patients consented to having their wound photographed. There was no difference in the surgeons' preference between the diathermy and scalpel halves of the incision (P = 0.35, signed-rank test). CONCLUSION: We found the use of cutting diathermy to make abdominal skin incisions to be cosmetically equivalent to cutting with the scalpel. As previous studies have not shown adverse wound outcomes using this technique, and considering the safety concerns for theatre staff when the scalpel is used, the routine use of cutting diathermy for skin incisions in abdominal surgery is justified. PMID- 24165303 TI - Effect of calibration method on distortion-product otoacoustic emission measurements at and around 4 kHz. AB - OBJECTIVES: Distortion-product otoacoustic emissions (DPOAEs) collected after sound pressure level (SPL) calibration are susceptible to standing waves that affect measurements at the plane of the probe microphone due to overlap of incident and reflected waves. These standing-wave effects can be as large as 20 dB, and may affect frequencies both above and below 4 kHz. It has been shown that forward pressure level (FPL) calibration minimizes standing-wave effects by isolating the forward-propagating component of the stimulus. Yet, previous work has failed to demonstrate more than a small difference in test performance and behavioral-threshold prediction with DPOAEs after SPL and FPL calibration. One potential limitation in prior studies is that measurements were restricted to octave and interoctave frequencies; as a consequence, data were not necessarily collected at the standing-wave null frequency. In the present study, DPOAE responses were measured with f2 set to each participant's standing-wave frequency in an effort to increase the possibility that differences in test performance and threshold prediction would be observed for SPL and FPL calibration methods. DESIGN: Data were collected from 42 normal-hearing participants and 93 participants with hearing loss. DPOAEs were measured with f2 set to 4 kHz and at each participant's notch frequency after SPL and FPL calibration. DPOAE input/output functions were obtained from -10 to 80 dB in 5 dB steps for each calibration/stimulus condition. Test performance was evaluated using clinical decision theory. Both area under receiver operating characteristic curves for all stimulus levels and cumulative distributions when L2 = 50 dB (a level at which the best performance was observed regardless of calibration method) were used to evaluate the accuracy with which auditory status was determined. A bootstrap procedure was used to evaluate the significance of the differences in test performance between SPL and FPL calibrations. DPOAE predictions of behavioral threshold were evaluated by correlating actual behavioral thresholds and predicted thresholds using a multiple linear regression model. RESULTS: First, larger DPOAE levels were measured after SPL calibration than after FPL calibration, which demonstrated the expected impact of standing waves. Second, for both FPL and SPL calibration, test performance was best for moderate stimulus levels. Third, differences in test performance between calibration methods were evident at low- and high-stimulus levels. Fourth, there were small but statistically significant improvements in test performance after FPL calibration for clinically relevant conditions. Fifth, calibration method had no effect on threshold prediction. CONCLUSIONS: Standing waves after SPL calibration have an impact on DPOAE levels. Although the effect of calibration method on test performance was small, test performance was better after FPL calibration than after SPL calibration. There was no effect of calibration method on predictions of behavioral threshold. PMID- 24165307 TI - Latino youths' sexual values and condom negotiation strategies. AB - CONTEXT: Young Latinos in the United States are at high risk for STDs and are less likely than other youth to use condoms. To our knowledge, no studies have examined the relationship between sexual values and condom negotiation strategies among young Latinos. METHODS: Cross-sectional data collected in 2003-2006 from 571 Latino women and men aged 16-22 in the San Francisco Bay Area were used to examine associations between sexual values (e.g., considering sexual talk disrespectful or female virginity important) and use of strategies to engender or avoid condom use. Linear regression analyses were used to identify such associations while adjusting for potential covariates and gender interactions. RESULTS: Among women, sexual comfort and comfort with sexual communication were positively associated with frequency of direct communication to foster condom use; the importance of female premarital virginity and levels of sexual self acceptance were positively associated with expressing dislike of condoms to avoid using them; and levels of sexual self-acceptance were negatively associated with expressing dislike of condoms to avoid using them. Moreover, the degrees to which women considered sexual talk disrespectful and female virginity important were positively associated with the frequency with which they shared risk information as a condom use strategy. Among both sexes, the importance that respondents placed on premarital female virginity was negatively associated with use of direct communication strategies. CONCLUSION: Researchers designing interventions to influence Latino youths' sexual decision making and behaviors should consider including program components that address sexual values. PMID- 24165308 TI - Acute amnesia and seizures in a young female. AB - Limbic encephalitis is a condition characterised by an acute or sub-acute onset of memory disorder, associated with seizures and psychiatric manifestations. Investigations such as brain MRI usually reveal a high intensity signal in the medial temporal lobe and cerebrospinal fluid analysis shows mild pleocytosis and oligoclonal bands. It may occur in association with cancer, infection, or as an isolated clinical condition, often accompanying autoimmune disorders. Immune mediated limbic encephalitis is now subclassified according to the presence and type of autoantibodies, which has significant consequences regarding the effectiveness of treatment and prognosis. Glutamic acid decarboxylase (GAD) is an enzyme that catalyses glutamic acid into gamma aminobutyric acid. Anti-GAD antibodies are associated with different neurological and non-neurological disorders, but only a few cases of limbic encephalitis associated with anti-GAD antibodies have been reported in the literature, most of them non-paraneoplastic. Here, we report the case of a young female patient with a medical history of psoriasis who developed an acute onset and chronic evolution of anterograde amnesia, associated with drug-resistant epilepsy. Brain MRI showed hyperintensity in the medial temporal lobes and the biochemical studies revealed intrathecal synthesis of anti-GAD antibodies. Screening tests for tumours were negative. Despite antiepileptic drugs, intravenous immunoglobulins and immunosuppressive treatment, the patient did not show clinical improvement and one year later, she continues to present refractory temporal epilepsy and cognitive deficits. PMID- 24165309 TI - American Society of Ophthalmic Plastic and Reconstructive Surgery fellowship survey: fellows selection criteria for training programs. AB - PURPOSE: To investigate the characteristics that American Society of Ophthalmic Plastic and Reconstructive Surgery fellows seek in fellowship training programs. METHODS: A 14-question anonymous SurveyMonkey survey was created for the 2011 to 2014 American Society of Ophthalmic Plastic and Reconstructive Surgery graduates. The survey evaluated fellow demographics, the interview process, and qualities fellows seek in fellowship training programs. A Likert scale was used to rate different qualities (1: not important, 9: very important), and summary statistics are reported as overall means and standard deviations. Analysis of variance comparisons were made between the different Ophthalmic Plastic and Reconstructive Surgery fellow graduate years, gender, and future practice goals. RESULTS: In total, 87 surveys were e-mailed with 67 responses, a 77% response rate. The qualities with the highest mean were variety of surgical procedures (mean +/- standard deviation: 8.6 +/- 0.7), volume of procedures/surgeries (8.6 +/- 0.7), personality of the program director (8.2 +/- 1.3), and interview (7.7 +/- 1.4). The characteristics that ranked the lowest in descending order were presence of a county hospital (5.1 +/- 2.2), proximity to family (4.8 +/- 2.7), didactics (4.7 +/- 1.9), and benefits (4.4 +/- 2.0). There was no statistically significant difference when comparing the groups according to gender and year of graduation. Fellows who want to pursue a career in academic medicine ranked academic fellowships higher in importance (8.0 +/- 1.0) than those who wanted a career in private practice (5.3 +/- 2.2). CONCLUSIONS: American Society of Ophthalmic Plastic and Reconstructive Surgery fellows place an emphasis on surgical experience, the program director's personality, and the interview process when ranking fellowship training programs. This information is valuable for program directors to better recruit fellows. PMID- 24165310 TI - Preparation to care for confused older patients in general hospitals: a study of UK health professionals. AB - BACKGROUND AND OBJECTIVE: in the UK, two-thirds of patients in general hospitals are older than 70, of whom half have dementia or delirium or both. Our objective was to explore doctors, nurses and allied health professionals' perceptions of their preparation to care for confused older patients on general hospital wards. METHODS: : using a quota sampling strategy across 11 medical, geriatric and orthopaedic wards in a British teaching hospital, we conducted 60 semi-structured interviews with doctors, nurses and allied healthcare professionals and analysed the data using the Consensual Qualitative Research approach. RESULTS: : there was consensus among participants that education, induction and in-service training left them inadequately prepared and under-confident to care for confused older patients. Many doctors reported initial assessments of confused older patients as difficult. They admitted inadequate knowledge of mental health disorders, including the diagnostic features of delirium and dementia. Handling agitation and aggression were considered top priorities for training, particularly for nurses. Multidisciplinary team meetings were highly valued but were reported as too infrequent. Participants valued specialist input but reported difficulties gaining such support. Communication with confused patients was regarded as particularly challenging, both in terms of patients making their needs known, and staff conveying information to patients. Participants reported emotional and behavioural responses including frustration, stress, empathy, avoidance and low job satisfaction. CONCLUSION: : our findings indicate that a revision of training across healthcare professions in the UK is required, and that increased specialist support should be provided, so that the workforce is properly prepared to care for older patients with cognitive problems. PMID- 24165311 TI - PROGgene: gene expression based survival analysis web application for multiple cancers. AB - BACKGROUND: Identification of prognostic mRNA biomarkers has been done for various cancer types. The data that are published from such studies are archived in public repositories. There are hundreds of such datasets available for multiple cancer types in public repositories. Wealth of such data can be utilized to study prognostic implications of mRNA in different cancers as well as in different populations or subtypes of same cancer. DESCRIPTION: We have created a web application that can be used for studying prognostic implications of mRNA biomarkers in a variety of cancers. We have compiled data from public repositories such as GEO, EBI Array Express and The Cancer Genome Atlas for creating this tool. With 64 patient series from 18 cancer types in our database, this tool provides the most comprehensive resource available for survival analysis to date. The tool is called PROGgene and it is available at http://www.compbio.iupui.edu/proggene. CONCLUSIONS: We present this tool as a hypothesis generation tool for researchers to identify potential prognostic mRNA biomarkers to follow up with further research. For this reason, we have kept the web application very simple and straightforward. We believe this tool will be useful in accelerating biomarker discovery in cancer and quickly providing results that may indicate disease-specific prognostic value of specific biomarkers. PMID- 24165312 TI - The role of imaging in the evaluation of focal mastalgia. PMID- 24165313 TI - Concordance between core needle biopsy and surgical excision specimens for tumour hormone receptor profiling according to the 2011 St. Gallen Classification, in clinical practice. AB - To focus on and compare the tumor hormone receptor profiles on core needle biopsy (CNB) and subsequent surgical excision specimens in a large clinical series of invasive breast carcinoma patients, with regard to guidelines proposed at the St. Gallen International Expert Consensus on the Primary Therapy of Early Breast Cancer 2011. A total of 993 consecutive patients who had hormone receptors (HR) assays performed on both CNB and subsequent surgical excision specimens of invasive carcinomas were included (1,110 tumors). Concordant tumor HR profiles between CNB and surgical excision specimens were noted in 1,085 of 1,110 tumors (97.75%). Among 138 tumors considered negative on CNB (both HR assays <1%), 10 cases (7.2%) displayed an HR profile positive on surgical excision specimen. Discrepancies between CNBs and surgical excision specimens are very seldom noted. HR assay evaluation on surgical excision specimens should only be considered in patients when both HR assays are negative on CNBs. PMID- 24165315 TI - Imaging manifestation of mammary fibromatosis. PMID- 24165316 TI - Arguments against the sentinel lymph node biopsy for a select group of invasive breast cancer patients suitable for breast-conserving surgery and adjuvant systemic therapy. PMID- 24165317 TI - Jeddah breast cancer pilot screening program: the first program in the western region of the Kingdom of Saudi Arabia. PMID- 24165314 TI - Features of occult invasion in biopsy-proven DCIS at breast MRI. AB - The purpose of this study is to determine if MRI BI-RADS criteria or radiologist perception correlate with presence of invasive cancer after initial core biopsy of ductal carcinoma in situ (DCIS). Retrospective search spanning 2000-2007 identified all core-biopsy diagnoses of pure DCIS that coincided with preoperative MRI. Two radiologists fellowship-trained in breast imaging categorized lesions according to ACR MRI BI-RADS lexicon and estimated likelihood of occult invasion. Semiquantitative signal enhancement ratio (SER) kinetic analysis was also performed. Results were compared with histopathology. 51 consecutive patients with primary core biopsy-proven DCIS and concurrent MRI were identified. Of these, 13 patients (25%) had invasion at excision. Invasion correlated significantly with presence of a mass for both readers (p = 0.012 and 0.001), rapid initial enhancement for Reader 1 (p = 0.001), and washout kinetics for Reader 2 (p = 0.012). Significant correlation between washout and invasion was confirmed by SER (p = 0.006) when threshold percent enhancement was sufficiently high (130%), corresponding to rapidly enhancing portions of the lesion. Radiologist perception of occult invasion was strongly correlated with true presence of invasion. These results provide evidence that certain BI-RADS MRI criteria, as well as radiologist perception, correlate with occult invasion after an initial core biopsy of DCIS. PMID- 24165318 TI - Breast sparganosis. PMID- 24165319 TI - Response to "breast sparganosis". PMID- 24165320 TI - Stroke prevention in New Zealand: can we do better? AB - There are approximately 45,000 stroke survivors in New Zealand and this number is projected to increase to 50,000 survivors, with annual costs to the health system exceeding $700 million by 2015 if no effective primary stroke prevention strategies are introduced. However, development of evidence-based stroke prevention strategies requires answering several research questions. In this article, we summarize some key research questions that are particularly pertinent to stroke prevention in New Zealand. PMID- 24165321 TI - GDNF increases cell motility in human colon cancer through VEGF-VEGFR1 interaction. AB - Glial cell line-derived neurotrophic factor (GDNF), a potent neurotrophic factor, has been shown to affect cancer cell metastasis and invasion. However, the molecular mechanisms underlying GDNF-induced colon cancer cell migration remain unclear. GDNF is found to be positively correlated with malignancy in human colon cancer patients. The migratory activities of two human colon cancer cell lines, HCT116 and SW480, were found to be enhanced in the presence of human GDNF. The expression of vascular endothelial growth factor (VEGF) was also increased in response to GDNF stimulation, along with VEGF mRNA expression and transcriptional activity. The enhancement of GDNF-induced cancer cell migration was antagonized by a VEGF-neutralizing antibody. Our results also showed that the expression of VEGF receptor 1 (VEGFR1) was increased in response to GDNF stimulation, whereas GDNF-induced cancer cell migration was reduced by a VEGFR inhibitor. The GDNF induced VEGF expression was regulated by the p38 and PI3K/Akt signaling pathways. Treatment with GDNF increased nuclear hypoxia-inducible factor 1 alpha (HIF1alpha) accumulation and its transcriptional activity in a time-dependent manner. Moreover, GDNF increased hypoxia responsive element (HRE)-containing VEGF promoter transcriptional activity but not that of the HRE-deletion VEGF promoter construct. Inhibition of HIF1alpha by a pharmacological inhibitor or dominant negative mutant reduced the GDNF-induced migratory activity in human colon cancer cells. These results indicate that GDNF enhances the migration of colon cancer cells by increasing VEGF-VEGFR interaction, which is mainly regulated by the p38, PI3K/Akt, and HIF1alpha signaling pathways. PMID- 24165322 TI - MCL1 is critical for mitochondrial function and autophagy in the heart. AB - MCL1 (myeloid cell leukemia sequence 1 [BCL2-related]) is an anti-apoptotic BCL2 family protein that is upregulated in several human cancers. In malignancies, overexpression of MCL1 promotes cell survival and confers chemotherapeutic resistance. MCL1 is also highly expressed in normal myocardium, but the functional importance of MCL1 in myocytes has not been explored. We recently discovered that MCL1 plays an essential role in myocardial homeostasis and autophagy. Here, we discuss how loss of MCL1 in the adult mouse heart leads to mitochondrial dysfunction, impaired autophagy and development of heart failure. PMID- 24165323 TI - Characterization of the mechanical behavior of intrapulmonary percussive ventilation. AB - A new device delivering intrapulmonary percussive ventilation (IPV), called Impulsator(r) (Percussionaire Corporation, Sandpoint, ID, USA), has recently been introduced in an effort to provide effective clearance and to promote homogeneity of ventilation in the lungs of patients with cystic fibrosis. In order to optimize the treatment based on its use, a better understanding of its functioning is still necessary. In fact, up to now, a complete characterization of this device has not been carried out, thus reducing its effective utilization in clinical practice. With the aim of overcoming this lack, in this study, data concerning flow and pressure delivered during in vitro IPV were acquired under different combinations of device settings and respiratory loads. Quantitative information was obtained about the physical variables administered by the device like percussive frequency, ratio of inspiratory to expiratory time, flow and pressure magnitudes and volume exchanged. The analysis of the data determined the relations among these variables and between them and the mechanical loads, laying the basis for an optimal clinical application of the device. PMID- 24165324 TI - Leucine-rich repeat kinase 2 regulates tau phosphorylation through direct activation of glycogen synthase kinase-3beta. AB - Leucine-rich repeat kinase 2 (LRRK2) has been identified as the causal molecule for autosomal-dominant Parkinson's disease (PD). Experimental evidence indicates that LRRK2 may play an important role in the pathology induced by abnormal phosphorylation of tau. In the present study, we demonstrated that LRRK2 directly associates with GSK-3beta, and that this interaction enhances the kinase activity of GSK-3beta. Furthermore, we found that LRRK2-mediated activation of GSK-3beta induces high phosphorylation of tau at Ser396 in SH-SY5Y cells. From our present findings, we conclude that LRRK2 may function as a novel enhancer for GSK-3beta and as a physiological regulator of neurite outgrowth and axonal transport through regulation of the GSK-3beta-mediated phosphorylation of tau at the cellular level. Since LRRK2 is detected in tau-positive inclusions in brain tissue affected by various neurodegenerative disorders, including PD, LRRK2 stimulated phosphorylation of tau by GSK-3beta may be involved in development of pathological features in the initial stage of PD. PMID- 24165325 TI - Participant experiences of an internet-based intervention and randomised control trial: interview study. AB - BACKGROUND: There are an increasing number of interventions being delivered online, and an expanding body of research to assess the effectiveness of such interventions. Yet, little is known about the motivations for participating in online research. Furthermore, internet interventions and online research studies are characterised by poor adherence and high attrition rates. This study aimed to explore participant motivations for taking part in an online trial of an internet intervention and the reasons for continuing. METHODS: Semi-structured telephone interviews were conducted with twenty members of the intervention arm of an internet-based randomised control trial evaluating an online cognitive behavioural tool to improve mental wellbeing. The qualitative interviews were analysed using the Framework Approach to identify themes and subthemes, through familiarization with the data, identifying a thematic framework, charting, indexing, mapping and interpreting the data. RESULTS: A number of key themes emerged. Trusted brands were key to participants feeling secure in engaging with the trial due to the association with institutions such as the UK National Health Service and the lead University conducting the research. Participants had a number of motivations for signing up with the study; altruism, low mood and as a replacement for a physical health professional. Participants felt the need for the language used in the intervention to be tailored to them as individuals. The majority of those interviewed also described multiple benefits from the intervention, which could have been a reason for them to persist. CONCLUSION: The nascent field of research on internet delivered healthcare needs to take account of participant views, as have been identified in this trial and future studies would benefit from applying its findings. PMID- 24165326 TI - Alefacept promotes immunosuppression-free renal allograft survival in nonhuman primates via depletion of recipient memory T cells. AB - Renal allograft tolerance has been achieved in MHC-mismatched primates via nonmyeloablative conditioning beginning 6 days prior to planned kidney and donor bone marrow transplantation (DBMT). To extend the applicability of this approach to deceased donor transplantation, we recently developed a novel-conditioning regimen, the "delayed protocol" in which donor bone marrow (DBM) is transplanted several months after kidney transplantation. However, activation/expansion of donor-reactive CD8(+) memory T cells (TMEM) occurring during the interval between kidney and DBM transplantation impaired tolerance induction using this strategy. In the current study, we tested whether, Alefacept, a fusion protein which targets LFA-3/CD2 interactions and selectively depletes CD2(high) CD8(+) effector memory T cells (TEM) could similarly induce long-term immunosuppression-free renal allograft survival but avoid the deleterious effects of anti-CD8 mAb treatment. We found that Alefacept significantly delayed the expansion of CD2(high) cells including CD8(+) TEM while sparing naive CD8(+) T and NK cells and achieved mixed chimerism and long-term immunosuppression-free renal allograft survival. In conclusion, elimination of CD2(high) T cells represents a promising approach to prevent electively the expansion/activation of donor-reactive TEM and promotes tolerance induction via the delayed protocol mixed chimerism approach. PMID- 24165327 TI - DNA methylation as a biomarker for preeclampsia. AB - BACKGROUND: Preeclampsia contributes significantly to pregnancy-associated morbidity and mortality as well as future risk of cardiovascular disease in mother and offspring, and preeclampsia in offspring. The lack of reliable methods for early detection limits the opportunities for prevention, diagnosis, and timely treatment. PURPOSE: The purpose of this study was to explore distinct DNA methylation patterns associated with preeclampsia in both maternal cells and fetal-derived tissue that represent potential biomarkers to predict future preeclampsia and inheritance in children. METHOD: A convenience sample of nulliparous women (N = 55) in the first trimester of pregnancy was recruited for this prospective study. Genome-wide DNA methylation was quantified in first trimester maternal peripheral white blood cells and placental chorionic tissue from normotensive women and those with preeclampsia (n = 6/group). RESULTS: Late onset preeclampsia developed in 12.7% of women. Significant differences in DNA methylation were identified in 207 individual linked cytosine and guanine (CpG) sites in maternal white blood cells collected in the first trimester (132 sites with gain and 75 sites with loss of methylation), which were common to approximately 75% of the differentially methylated CpG sites identified in chorionic tissue of fetal origin. CONCLUSION: This study is the first to identify maternal epigenetic targets and common targets in fetal-derived tissue that represent putative biomarkers for early detection and heritable risk of preeclampsia. Findings may pave the way for diagnosis of preeclampsia prior to its clinical presentation and acute damaging effects, and the potential for prevention of the detrimental long-term sequelae. PMID- 24165328 TI - A series of four fractured ExeterTM stems in hip arthroplasty. AB - We describe the cases of four patients who presented with painful hips and were found to have fractured cemented ExeterTM V40TM stems. Failure was multifactorial. Fractured ExeterTM stems are rarely reported and this series raises a concern that a population of patients may be at risk of such morbidity. PMID- 24165329 TI - Advanced wear of an OxiniumTM femoral head implant following polyethylene liner dislocation. AB - OxiniumTM (Smith & Nephew, Memphis, TN, US) has been used in hip arthroplasty since 2003. The surface coating is hard and provides low wear rates but if this surface coating is damaged, the soft metal core is at risk of accelerated wear. Previous reports have described accelerated wear following intra and postoperative hip dislocation. We report a case of advanced wear of an in situ OxiniumTM femoral head implant following a cracked acetabular liner. The liner had disengaged from the titanium shell, allowing the OxiniumTM head to articulate directly with the shell. The disengaged liner led to dislocation of the OxiniumTM head, with associated pronounced wear of the head and the acetabular cup. The patient had a successful revision procedure. We advise close follow-up of patients with OxiniumTM implants, especially if associated with dislocation and closed reduction. PMID- 24165330 TI - Renal cell carcinoma metastases to gallbladder. AB - A 74-year old man underwent a radical cholecystectomy for presumed gallbladder cancer. The histology of the resected specimen in fact revealed the lesion to be metastatic renal cell carcinoma from his resected right nephrectomy performed 14 years previously. PMID- 24165331 TI - Hepatocolonic fistula: a rare consequence of retained gallstones after laparoscopic cholecystectomy. AB - Spillage of gallstones during laparoscopic cholecystectomy occurs in up to 30% of cases but complications due to stone retention are less frequent. We report the first case of a hepatocolonic fistula as a consequence of a retained gallstone. PMID- 24165332 TI - Elective day-case laparoscopic cholecystectomy: a formal assessment of the need for outpatient follow-up. AB - INTRODUCTION: Elective laparoscopic cholecystectomy (LC) is performed routinely as day-case surgery. Most hospital trusts have a policy of no routine postoperative outpatient follow-up although there are no formal guidelines on this. The aim of this retrospective study was to identify the incidence of complications, the degree of symptom resolution and patient satisfaction with a view to formally appraising the need for outpatient follow-up. METHODS: Patients who underwent LC in the period between February 2011 and June 2012 were contacted retrospectively by telephone. A standardised questionnaire was used to ascertain the incidence of surgical site infection (SSI), other complications, symptom resolution and patient satisfaction. RESULTS: A total of 211 responses were collected. The rate of SSI was 7.6% (n=16), with the only specific risk factor being smoking (p=0.027). All other complications had a combined incidence of 7% (n=15). There was complete resolution of symptoms in 64% of patients. Of the 36% of patients with residual symptoms, 45% described abdominal discomfort or pain, 41% described reflux symptoms and 14% complained of diarrhoea. Patient satisfaction was very high (96%), yet 33% of patients visited their general practitioner postoperatively in relation to their surgery. CONCLUSIONS: Patients are highly satisfied with elective day-case LC. However, SSI is not uncommon, occurring in 1 in 13 patients. Although the majority of patients experience complete symptom resolution, a significant proportion do not. In our experience, routine outpatient follow-up is not required. Nevertheless, the lack of formal follow-up may prove a missed learning opportunity, potentially resulting in inappropriate patient selection for surgery. PMID- 24165333 TI - Reconstruction of perineal defects. AB - INTRODUCTION: Perineal defects are commonly encountered in an oncological setting although they may also present as a result of trauma and infection (eg following Fournier's gangrene). Reconstruction of these poses functional as well as aesthetic challenges. Skin coverage and tissue volume may both be required in addition to anogenital preservation or reconstruction. General prerequisites of an adequate reconstruction of perineal defects include provision of skin cover, well vascularised tissue to fill the dead space (reducing fluid collection and infection), vulvovaginal reconstruction and no faecal or urinary contamination. METHODS: A literature search was performed using PubMed and MEDLINE (r) . The search terms included 'perineal defects', 'perineal reconstruction', 'perforator flaps for perineum', 'vulval flaps', 'secondary healing of wound' and 'vacuum assisted closure'. Backward chaining of reference lists from retrieved papers was also used to expand the search. FINDINGS: Modern developments have led to an increased expectation in improved quality of life as the main goal of reconstruction, therefore necessitating surgery with less morbidity and early return to normal activity. Progress in microsurgical procedures has been the main recent advance in perineal reconstruction and, in future, refinements in perforator flap design and tissue engineering techniques will lead to even better reconstructions. PMID- 24165334 TI - The effectiveness of hyaluronic acid intra-articular injections in managing osteoarthritic knee pain. AB - INTRODUCTION: Knee osteoarthritis (OA) is a common and progressive joint disease. Treatment options for knee OA vary from simple analgesia in mild cases to knee replacement for advanced disease. Knee pain due to moderate OA can be targeted with intra-articular injections. Steroid injections have been used widely in managing acute flare-ups of the disease. In recent years, viscosupplementation has been used as a therapeutic modality for the management of knee OA. The principle of viscosupplementation is based on the physiological properties of the hyaluronic acid (HA) in the synovial joint. Despite a sound principle and promising in vitro studies, clinical studies have been less conclusive on the effectiveness of HA in managing osteoarthritic knee pain. The aim of this systematic review was to assess the effectiveness of HA intra-articular injections in the management of osteoarthritic knee pain. METHODS: A systematic review of the literature was performed using MEDLINE(r), EmbaseTM and CINAHL(r) (Cumulative Index to Nursing and Allied Health Literature). The databases were searched for randomised controlled trials available on the effectiveness of HA intra-articular injections in managing osteoarthritic knee pain. RESULTS: The search yielded 188 studies. Of these, 14 met the eligibility criteria and were reviewed in chronological order. CONCLUSIONS: HA intra-articular injections have a modest effect on early to moderate knee OA. The effect peaks at around 6-8 weeks following administration, with a doubtful effect at 6 months. PMID- 24165335 TI - Minimally invasive endoscopic therapy for the management of Boerhaave's syndrome. AB - INTRODUCTION: Boerhaave's syndrome represents the most lethal of all gastrointestinal perforations. In 2009 a treatment algorithm was published based on current level 4 evidence indicating that all septic patients should be treated surgically, early presentations without sepsis endoscopically and delayed presentations without sepsis conservatively. No provision was made for septic patients unfit for surgical intervention. Using a case series, we demonstrate how minimally invasive endoscopic therapies can be used successfully to manage such a cohort. METHODS: Between September 2008 and January 2010, five patients presented to Wishaw General Hospital with Boerhaave's syndrome, all with an associated septic profile and none fit for surgery. They were managed using minimally invasive endoscopic therapies including endoscopic placement of oesophageal stents, elimination of mediastinal/pleural contamination using video assisted thorascopic lavage, management of subsequent collections using sinus tract endoscopy and mini-laparotomy with transhiatal endoscopic drainage, and closure of oesophagocutaneous fistulas using the Surgisis(r) (Cook Surgical, Bloomington, IN, US) anal fistula plug sited endoscopically with a rendezvous technique. RESULTS: Oesophageal re-epithelialisation and resolution of sepsis was achieved in all five cases on days 50, 50, 51, 59 and 103. Four patients are alive today. The fifth died on day 109 in hospital as a consequence of co-morbidity. Two patients required oesophageal dilatation for benign oesophageal strictures. CONCLUSIONS: Minimally invasive endoscopic therapy can be used successfully to achieve oesophageal re-epithelialisation and resolution of sepsis in patients unfit for surgical intervention. It offers a feasible treatment for patients not accounted for in today's literature and expands on currently described endoscopic therapies. PMID- 24165336 TI - Outcomes following Boerhaave's syndrome. AB - INTRODUCTION: Boerhaave's syndrome is associated with high mortality and morbidity. This study aimed to assess outcome following treatment in a specialist upper gastrointestinal surgical unit. METHODS: Patients were identified from a prospectively collected database (Lothian Surgical Audit) and their records reviewed. Primary outcomes were mortality and serious morbidity. Secondary outcomes included time to theatre, operation undertaken and length of hospital stay. RESULTS: Twenty patients with Boerhaave's syndrome were identified between 1997 and 2011. Four patients (20%) died in hospital. The mean time to theatre from symptom onset was 2.4 days. This was 7.3 days in the patients who died compared with 1.5 days in survivors. Five patients underwent primary repair of rupture, eleven underwent direct closure over a T-tube and one rupture was irreparable. Three patients were managed non-operatively and all survived. Outcomes were similar for the different surgical groups. There was one death following primary closure (20%) and two after T-tube drainage (18%). The mean length of hospital stay was 35.7 days after T-tube drainage and 20.5 days after primary repair. The 3 patients with small, self-contained leaks had a mean length of stay of 5.7 days. CONCLUSIONS: Aggressive surgical management with direct repair is associated with good survival in patients with Boerhaave's syndrome. Delayed time to theatre is associated with increased mortality. Patients with small, contained leaks without signs of sepsis can be managed non-operatively with a good outcome. PMID- 24165337 TI - Postoperative numbness of the knee following total knee arthroplasty. AB - INTRODUCTION: The infrapatellar branch of the saphenous nerve is often injured during total knee arthroplasty (TKA), leading to numbness in its distribution distal to the incision. This is illustrated in a patient who suffered full thickness burns to the lateral aspect of the knee from a hot water bottle. However, the proportion of patients who are informed of this phenomenon (as well as the effect of informing the patient of numbness) has not previously been studied according to the authors' knowledge. The aim of this study was to establish the proportion of patients with whom postoperative numbness was discussed during the consent procedure and whether this discussion was documented. METHODS: A total of 73 patients (103 TKAs) agreed to take part in this study between 16 May and 9 July 2011. Patients were asked about their recollection of numbness being mentioned prior to the procedure as well as whether they experienced postoperative numbness. Statistical analysis was performed using SPSS(r). RESULTS: Subjective numbness was noted in 27% of the patients in this study. The prevalence of numbness decreased with time. Patients whose consent process included a discussion of numbness were 3.3 times more likely to report numbness after TKA (p=0.003). CONCLUSIONS: Patient education regarding postoperative numbness increases the patient's awareness of any insensate skin that may develop. Numbness after TKA does improve with time but does not resolve completely. It is therefore recommended by the authors that numbness is discussed preoperatively with the patient and that this discussion is documented. PMID- 24165339 TI - Impact of change of knee prosthesis on early clinical outcomes in a large volume arthroplasty centre. AB - INTRODUCTION: The aim of our study was to investigate the effect of changing the default knee prosthesis in a high volume dedicated arthroplasty unit from DePuy's PFC((r)) Sigma((r)) to Smith & Nephew's GenesisTM II. METHODS: A retrospective analysis was performed of prospective data on primary total knee replacements (TKRs) from January 2009 until December 2011. This provided information on the operative time, length of stay, pain at mobilisation, radiography analysis, any complications, and readmission at 30 and 60 days. RESULTS: The total numbers of primary TKRs using the PFC((r)) and GenesisTM II prostheses were 1,061 and 1,268 respectively. The results showed a slight increase (maximum of five minutes) in the operative time for all the surgeons except one surgeon, whose operative time reduced by an average of seven minutes. There was no significant adverse outcome after the change in the knee implant. There was no clinically significant increase in the length of stay, pain at mobilisation or complication rates. There was a twofold increase in the wastage of the implant in the GenesisTM II group in the initial learning period. CONCLUSIONS: Through a competitive process of implant tendering, we have successfully introduced a new implant into a large elective orthopaedic unit. This has resulted in significant financial savings without adversely affecting our clinical practice or patient outcome. PMID- 24165338 TI - High prevalence of vitamin D deficiency in elderly patients with advanced osteoarthritis scheduled for total knee replacement associated with poorer preoperative functional state. AB - Vitamin D deficiency has been reported previously in patients with osteoarthritis undergoing total hip arthroplasty. We found a high prevalence of vitamin D deficiency in elderly patients with advanced knee osteoarthritis scheduled for total knee replacement and also a significant association with a lower preoperative functional state. A review of the literature is given on vitamin D deficiency in patients with knee osteoarthritis and the association with lower outcome scores after arthroplasty is discussed. PMID- 24165340 TI - Patient satisfaction with the use of an enhanced recovery programme for primary arthroplasty. AB - INTRODUCTION: Enhanced recovery programmes (ErPs) are increasingly being used for arthroplasty. One of the core aims of an ErP is to improve the quality of patient experience. However, there is currently no published evaluation of patient satisfaction in relation to this new programme of care within orthopaedic surgery. The aim of this study was to compare the ErP against the standard care programme (SCP) at one centre. METHODS: A satisfaction survey addressing patient opinions on the key objectives of the ErP was conducted by telephone, using a set script. Of the 226 patients contacted, 143 (63.3%) responded (69 from the ErP and 74 from the SCP). Of the respondents, 71 received a total hip arthroplasty and 72 a total knee arthroplasty. Patients were contacted at a mean time from operation to survey of 27.2 weeks. They were asked to rate satisfaction on a five-point scale and complete the EQ-5DTM health questionnaire (EuroQol, rotterdam, Netherlands) to measure healthcare outcomes. RESULTS: The mean patient satisfaction score of 4.07 for speed of recovery in the ErP group was significantly higher than the SCP group's score of 3.68 (p=0.037). Adjusting for the preoperative health score, the postoperative health score was higher for ErP patients at 74.1 compared with 64.7 for SCP patients (p=0.0029). Furthermore, the percentage of patients who had a better than expected recovery was significantly greater in the ErP group at 85.5% compared with 58.1% (p=0.0004) in the SCP group. CONCLUSIONS: We believe that the previously established reduction in length of hospital stay delivered by ErPs is not achieved at the expense of the patient's experience. PMID- 24165341 TI - Managing supracondylar fractures of the distal humerus in children in a district general hospital. AB - INTRODUCTION: Controversy exists regarding the timing of surgery in children with displaced supracondylar fractures of the humerus. METHODS: We reviewed retrospectively the postoperative outcomes and complications in these children managed in a district general hospital. RESULTS: There were 81 children with displaced supracondylar fractures (64 Gartland type III and 17 type IIA). Of these, 46 children were treated within 6 hours of presentation and 35 were treated later. The rate of open reduction was higher in children treated early (23%) than in late cases (11%). There was no significant difference in the postoperative outcomes and complications between the groups. CONCLUSIONS: In children with a supracondylar fracture, the timing of surgical treatment (before or after six hours from presentation to hospital) had no effect on postoperative complications and outcomes. PMID- 24165342 TI - 22-year longitudinal study of repetitive colonoscopy in patients with a family history of colorectal cancer. AB - INTRODUCTION: We report the outcomes of a long-term surveillance programme for individuals with a family history of colorectal cancer. METHODS: The details of patients undergoing a colonoscopy having been referred on the basis of family history of colorectal cancer were entered prospectively into a database. Further colonoscopy was arranged on the basis of the findings. The outcomes assessed included incidence of cancer and adenoma identification at initial and subsequent colonoscopy. RESULTS: The records of 2,293 patients (917 men; median patient age: 51 years) were entered over 22 years, giving data on 3,982 colonoscopies. Eight adverse events (0.2%) were recorded. Twenty-seven cancers were found at first colonoscopy and thirteen developed during the follow-up period. There were significantly more cancers identified in those with more than one first-degree relative with cancer than in other groups (p=0.01). The number of adenomas identified at subsequent surveillance colonoscopies remained constant with between 9.3% and 12.0% of patients having adenomas that were removed. Two-thirds (68%) of patients with cancer and three-quarters (77%) with adenomas fell outside the British Society of Gastroenterology (BSG) 2006 guidelines. CONCLUSIONS: Repeated colonoscopy continues to yield significant pathology including new cancers. These continue to occur despite removal of adenomas at prior colonoscopies. The majority of patients with cancers and adenomas fell outside the BSG 2006 guidelines; more would have fallen outside the 2010 guidelines. PMID- 24165343 TI - Ultrasonography guided rectus sheath catheters versus epidural analgesia for open colorectal cancer surgery in a single centre. AB - INTRODUCTION: Epidural anaesthesia (EA) has been the accepted standard for postoperative analgesia in open abdominal surgery. However, it is not without significant risk. This study aimed to audit the effect of EA and ultrasonography placed rectus sheath catheters (RSCs) on analgesia as well as the incidence of postoperative complications following open colorectal cancer surgery. METHODS: A three-year retrospective case note review was undertaken of all patients undergoing open colorectal cancer surgery at the Royal Devon and Exeter Hospital NHS Foundation Trust who received either EA or RSC for postoperative analgesia under the care of the senior authors. A single surgeon and single anaesthetist were practitioners. RESULTS: The case notes of 120 patients were reviewed retrospectively: 85 patients had EA and 24 RSC while 11 patients were excluded from the study. The EA group experienced a significantly higher incidence of hypotension (systolic blood pressure <130 mmHg) than the RSC group on the first postoperative day (p=0.0001). There was no significant difference in pain score or opiate sparing properties between the groups (p=0.92). There was no significant difference in postoperative respiratory tract infection, anastomotic leak or wound complications between the groups (p=0.2, p=1.0 and p=0.5 respectively). The RSC group had a higher incidence of ileus than the EA group (4/24 vs 2/85, p=0.026). However, the numbers were too small to draw a reliable conclusion. CONCLUSIONS: The use of ultrasonography guided RSCs has demonstrated effective postoperative analgesia equivalent to EA with the potential benefits of a reduced incidence of hypotension. A prospective randomised trial is now underway to compare RSC and EA in open abdominal and pelvic surgery. PMID- 24165344 TI - On-site cytotechnician evaluation of the adequacy of fine needle aspiration in a neck lump clinic. AB - INTRODUCTION: The gold standard for assessing neck lumps is a one-stop clinic with an on-site cytopathologist who can provide an immediate fine needle aspiration (FNA) report. However, this has considerable resource implications and is not available in all units. In our department, surgeons perform FNAs guided by palpation. The FNA is evaluated for specimen adequacy by an on-site cytotechnician. This study evaluated the impact of the cytotechnician on the adequacy of neck lump FNA. METHODS: FNA performed between June 2010 and February 2012 was examined. The FNA performed at a neck lump clinic with an assessment of adequacy by an on-site cytotechnician were considered the test group. All other neck lump FNAs from other sources without an assessment of adequacy by an on-site cytotechnician were considered the control group. RESULTS: Of the FNAs, 134 met the inclusion criteria for this study. Of these, 87 FNAs (65%) were analysed for adequacy by the on-site cytotechnician and the remaining 47 (35%) were not. The results demonstrated an FNA inadequacy with and without on-site cytotechnician assessment of 29.9% and 40.4% respectively. This is equivalent to an absolute risk reduction of an inadequate FNA of 10.5%, which equates to a number needed to treat of 9.5, ie the cytotechnician needs to assess 9.5 (ie the cytotechnician [...] specimen). CONCLUSIONS: In neck lump clinics where on-site cytopathology is not available, an on-site cytotechnician is a compromise measure that does reduce the number of inadequate FNAs. PMID- 24165345 TI - Current UK practice in emergency laparotomy. AB - INTRODUCTION: Emergency laparotomy is a common procedure, with 30,000-50,000 performed annually in the UK. This large scale study reports the current spectrum of emergency laparotomies, and the influence of the surgical procedure, underlying pathology and subspecialty of the operating surgeon on mortality. METHODS: Anonymised data on consecutive patients undergoing an emergency laparotomy were submitted for a three-month period. The primary outcome measure was unadjusted 30-day mortality. Appendicectomy and cholecystectomy were among the procedures excluded. RESULTS: Data from 1,708 patients from 35 National Health Service hospitals were analysed. The overall 30-day mortality rate was 14.8%. 'True' emergency laparotomies (ie those classified by the National Confidential Enquiry into Patient Outcome and Death as immediate or urgent) comprised 86.5% of cases. The mortality rate rose from 8.0% among expedited cases to 14.3% among urgent cases and to 25.7% among laparotomies termed immediate. Among the most common index procedures, small bowel resection exhibited the highest 30-day mortality rate of 21.1%. The presence of abdominal sepsis was associated with raised 30-day mortality (17.5% in the presence of sepsis vs 12.6%, p=0.027). Colorectal procedures comprised 44.3% and within this group, data suggest that mortality from laparotomy may be influenced by surgical subspecialisation. CONCLUSIONS: This report of a large number of patients undergoing emergency laparotomy in the UK confirms a remarkably high mortality by modern standards across the range. Very few pathologies or procedures can be considered anything other than high risk. The need for routine consultant involvement and critical care is evident, and the case distribution helps define the surgical skill set needed for a modern emergency laparotomy service. Preliminary data relating outcomes from emergency colonic surgery to surgical subspecialty require urgent further study. PMID- 24165347 TI - Use of a 5mm port for inserting a feeding jejunostomy catheter: a cheaper and safer method. PMID- 24165346 TI - Admission inflammatory markers and isolation of a causative organism in patients with spontaneous spinal infection. AB - INTRODUCTION: The purpose of this study was to investigate the significance of the inflammatory markers on admission in the isolation of a causative pathogen in patients with spinal infection. Spinal infection is treated frequently at spinal units and can encompass a broad range of clinical entities. Its diagnosis is often delayed because of the difficulty of identifying the responsible pathogen. METHODS: Patients with spinal infection treated in our institution over a period of eight years were identified and their notes studied retrospectively. Admission C-reactive protein (CRP), white cell count (WCC) as well as co-morbidities and mode of pathogen identification were recorded. Overall, 96 patients were included in the study. RESULTS: The CRP levels on admission were correlated significantly with the overall potential for isolation of a pathogen (p<0.0001) and positive biopsy cultures (p=0.0016). Admission WCC levels were associated significantly with the overall potential for isolation of a pathogen (p=0.0003) and positive biopsy cultures (p=0.0023). Both CRP and WCC levels were significantly negatively correlated with the duration of the preceding symptoms (p=0.0003 and p<0.0001 respectively). Delay in presentation was significantly negatively correlated with organism isolation (p=0.0001). Multivariate analyses identified the delay in presentation as the strongest independent variable for organism isolation (p=0.014) in cases of spontaneous spinal infection when compared with the admission CRP level (p=0.031) and WCC (p=0.056). CONCLUSIONS: In spontaneous spinal infection, delay in presentation is the strongest independent variable for organism isolation. High inflammatory marker levels on admission are a useful prognostic marker for the overall potential of isolating a causative organism either by blood cultures or by biopsy in patients with negative blood cultures. Furthermore, the admission inflammatory marker levels allow for treating surgeons to counsel their patients of the likelihood of achieving a positive microbiological yield from biopsy. PMID- 24165348 TI - How to manage gallstone spillage during laparoscopic cholecystectomy. PMID- 24165349 TI - An alternative non-suture method of fixing wound drains to simplify planned removal and reduce morbidity. PMID- 24165350 TI - Simple inexpensive method for intraoperative video and audio documentation. PMID- 24165352 TI - Factors associated to referral of tuberculosis suspects by private practitioners to community health centres in Bali Province, Indonesia. AB - BACKGROUND: The contrast between the low proportion of tuberculosis (TB) suspects referred from private practitioners in Bali province and the high volume of TB suspects seeking care at private practices suggests problems with TB suspect referral from private practitioners to the public health sector. We aimed to identify key factors associated with the referral of TB suspects by private practitioners. METHODS: We conducted a case-control study conducted in Bali province, Indonesia. The cases were private practitioners who had referred at least one TB suspect to a community health centre between 1 January 2007 and the start of data collection, while the controls were private practitioners who had not referred a single TB suspect in the same time. RESULTS: The following factors were independently associated with referral of TB suspects by private practitioners: having received information about the directly observed treatment short-course (DOTS) strategy (OR 2.0; 95% CI 1.1-3.8), ever having been visited by a district TB program officer (OR 2.1; 95% CI 1.0-4.5), availability of TB suspect referral forms in the practice (OR 2.8; 95% CI 1.5-5.2), and less than 5 km distance between the private practice and the laboratory for smear examination (OR 2.2; 95% CI 1.2-4.0). CONCLUSIONS: Education and exposure of private practitioners to the TB program improves referral of TB suspects from private practitioners to the national TB program. We recommend that the TB program provides all private practitioners with information about the DOTS strategy and TB suspect referral forms, and organizes regular visits to private practitioners. PMID- 24165353 TI - Understanding patterns and processes in models of trophic cascades. AB - Climate fluctuations and human exploitation are causing global changes in nutrient enrichment of terrestrial and aquatic ecosystems and declining abundances of apex predators. The resulting trophic cascades have had profound effects on food webs, leading to significant economic and societal consequences. However, the strength of cascades-that is the extent to which a disturbance is diminished as it propagates through a food web-varies widely between ecosystems, and there is no formal theory as to why this should be so. Some food chain models reproduce cascade effects seen in nature, but to what extent is this dependent on their formulation? We show that inclusion of processes represented mathematically as density-dependent regulation of either consumer uptake or mortality rates is necessary for the generation of realistic 'top-down' cascades in simple food chain models. Realistically modelled 'bottom-up' cascades, caused by changing nutrient input, are also dependent on the inclusion of density dependence, but especially on mortality regulation as a caricature of, e.g. disease and parasite dynamics or intraguild predation. We show that our conclusions, based on simple food chains, transfer to a more complex marine food web model in which cascades are induced by varying river nutrient inputs or fish harvesting rates. PMID- 24165354 TI - From Spain, to Europe. PMID- 24165355 TI - Simulated evaluation of two triage scales in an emergency department in Israel. AB - At the time of this study, the Sheba Medical Center Emergency Department (ED) in Israel had no formal triage system in place. To evaluate the interobserver reliability of two triage scales among nurses in our ED, the time-based Australasian Triage Scale (ATS) and the resource-based Emergency Severity Index (ESI), 10 nurses participated in a workshop on ATS and ESI. They then independently assessed 100 simulated triage scenarios taken from actual ED patients, and completed a survey. Intraclass correlation coefficients were calculated. The intraclass correlation coefficient for ATS was 0.64 (95% confidence interval: 0.57, 0.71), whereas for ESI, it was 0.52 (95% confidence interval: 0.45, 0.61). The nurses felt that ESI was slightly easier to use. Using conventional interpretations, the agreement for ATS is considered substantial, whereas that for ESI is considered moderate. Conversely, the nurses found the ESI somewhat easier to use. PMID- 24165357 TI - The association between body composition and foot structure and function: a systematic review. AB - The aim of this systematic review was to investigate the relationship between body composition and foot structure and function. Six electronic databases (Ovid MEDLINE, Ovid EMBASE, Ovid AMED, CINAHL, Scopus and The Cochrane Library) and reference lists from relevant papers were searched on 2 September 2013. Sixteen papers that reported on the association between body composition and foot structure and function met our inclusion criteria and were reviewed. The evidence indicates that obesity is strongly associated with planus (low-arched) foot posture, pronated dynamic foot function and increased plantar pressures when walking. However, there is limited evidence to support an association between other body composition measures, such as fat mass, with foot structure or function. PMID- 24165356 TI - Aromatase inhibitor associated musculoskeletal symptoms are associated with reduced physical activity among breast cancer survivors. AB - Physical activity (PA) has numerous health benefits for breast cancer survivors. Recent data suggest that some breast cancer survivors treated with aromatase inhibitors may experience aromatase inhibitor associated musculoskeletal symptoms. It is unknown whether aromatase inhibitor associated musculoskeletal symptoms are associated with reduced PA and what other risk factors are associated with such PA reductions. We conducted a cross-sectional study at a large university-based breast cancer clinic among breast cancer survivors prescribed an aromatase inhibitor. At routine follow-up, we surveyed participants about aromatase inhibitor associated musculoskeletal symptoms, as well as pre aromatase inhibitor, and current, PA levels. Among 300 participants, 90 (30%) reported a reduction of PA since the initiation of aromatase inhibitor therapy. Those with aromatase inhibitor associated musculoskeletal symptoms were more likely to report decreased PA (62% versus 38%, p = 0.001) compared with those without aromatase inhibitor associated musculoskeletal symptoms. In multivariate analyses, aromatase inhibitor associated musculoskeletal symptoms (odds ratio [OR] = 2.29 [95% confidence interval [CI]: 1.36-3.86]), and body mass index (OR = 1.06 [95% CI: 1.02-1.12]) were associated with reductions in PA. In subgroup analysis among breast cancer survivors with aromatase inhibitor associated musculoskeletal symptoms, self-reported lower extremity joint pain (OR = 1.23 [95% CI: 1.00-1.50]) and impaired lower extremity physical function (OR = 1.07 [95% CI: 1.01-1.14]) were associated with reductions in PA. Breast cancer survivors with aromatase inhibitor associated musculoskeletal symptoms were more likely to report reductions in PA since initiating aromatase inhibitor therapy compared with those without aromatase inhibitor associated musculoskeletal symptoms. Our findings suggest that tailored interventions targeting lower extremity functional limitations are needed to enable breast cancer survivors with aromatase inhibitor associated musculoskeletal symptoms to participate in PA. PMID- 24165358 TI - Measuring and reducing the stroke burden in New Zealand. PMID- 24165359 TI - The abnormal proplatelet formation in MYH9-related macrothrombocytopenia results from an increased actomyosin contractility and is rescued by myosin IIA inhibition. AB - BACKGROUND: Mutations in the MYH9 gene cause autosomal dominant MYH9-related diseases (MYH9-RD) that associate macrothrombocytopenia with various other clinical conditions. The mechanisms giving rise to giant platelets remain poorly understood. OBJECTIVES/PATIENTS: To study the proplatelet formation (PPF) derived from megakaryocytes (MKs) generated in vitro from 11 patients with MYH9-RD with different mutations, compared with controls. METHODS: Proplatelet formation from cultured patients' MKs was evaluated with or without blebbistatin or the ROCK inhibitor Y27632. Myosin IIA and actin distribution were studied in spreading MKs on different surfaces by immunoconfocal analysis. Kinetic studies of contractility were performed on spreading MKs and the impact of blebbistatin on the maturation of the patients' MKs was evaluated by electron microscopy. RESULTS AND CONCLUSIONS: We show that in vitro MKs of 11 patients formed significantly fewer proplatelets than controls. MKs from MYH9-RD displayed an abnormal spreading on polylysine, fibronectin and collagen, with a disorganized actin network and a marked increase in stress fiber formation. Traction force microscopy studies demonstrated an elevated level of contractile forces in adherent mutated MKs. The myosin II inhibitor blebbistatin and the ROCK inhibitor Y27632 both rescued the proplatelet formation defect and normalized the ultrastructural characteristics of MYH9-RD MKs. Altogether, our results show that in MYH9-RD, mutations modify the overall MYH9 function and provoke a proplatelet defect through an excess of actomyosin contractility in spreading MKs. These results may promote new therapeutic strategies aimed at reducing this actomyosin contractility. PMID- 24165360 TI - Nonword repetition and phoneme elision skills in school-age children who do and do not stutter. AB - Nonword repetition and phoneme elision represent the combined influence of several speech and language processes. In the present study we investigated nonword repetition and phoneme elision performance in school-age children who stutter (CWS) and children who do not stutter (CNS). Participants were 14 CWS (mean = 11.7 years, SD = 2.1 years) and age- and sex-matched CNS (mean = 11.8 years, SD = 2.0 years). Each talker group was further subdivided into two age groups: younger (N = 7; 8-11.5 years) and older (N = 7; 11.6-15 years). Repeated measures analyses were conducted on the accuracy and response time (in seconds) data. In nonword repetition, the CWS showed a trend for lower per cent of correct phonemes at the two-syllable level compared with the CNS. In phoneme elision, the younger CWS showed a significantly lower accuracy rate than the older CWS at the two- and three-syllable nonword lengths, while similar differences were not evident between the younger versus older CNS at any of the nonword lengths. No accuracy difference in phoneme elision was noted between the two talker groups. Group differences in speech initiation times were also not evident in either of the tasks. Findings from nonword repetition offer tentative support for difficulties experienced by school-age CWS in phonemic encoding/working memory abilities. Findings from the phoneme elision task suggest a complex pattern of age-dependent performance by the CWS. Comparison of response accuracy and speech initiation times in both the tasks failed to show speed-accuracy trade-off strategies in either of the groups. PMID- 24165361 TI - Effect of maxillary osteotomy on speech in cleft lip and palate: perceptual outcomes of velopharyngeal function. AB - BACKGROUND: Abnormal facial growth is a well-known sequelae of cleft lip and palate (CLP) resulting in maxillary retrusion and a class III malocclusion. In 10 50% of cases, surgical correction involving advancement of the maxilla typically by osteotomy methods is required and normally undertaken in adolescence when facial growth is complete. Current evidence for the impact of the surgery on velopharyngeal function is weak and mixed. AIMS: The first objective of the study was to investigate the nature of the effect of maxillary osteotomy on the perceptual outcomes of velopharyngeal function in CLP. The second objective was to establish if speech changes seen early at 3 months post-operation persisted for a year after/following surgery', when it is considered that the maxilla is relatively stable. METHODS & PROCEDURES: Twenty consecutive patients with CLP undergoing maxillary osteotomy by a single surgeon were seen pre-operatively (T1), 3 months (T2) and 12 months (T3) post-operation. A non-cleft control group (NonCLP) undergoing surgery was also recruited. Speech data were collected using the Cleft Audit Protocol for Speech-Augmented (CAPS-A). A velopharyngeal composite score-summary (VPC-SUM) was derived from specific CAPS-A-rated parameters. An external CAPS-A-trained therapist, blinded to the study, rated the randomized samples and inter-rater reliability was established. OUTCOMES & RESULTS: For the CLP group, hypernasality and nasal turbulence increased significantly post-operation. Planned comparisons were significant for T1-T2 only with a medium effect size. For hypernasality, the CLP group differed statistically from the NonCLP group at T2 and T3. For nasal turbulence, the CLP group differed statistically from the NonCLP group at T2. For VPC-SUM, there were statistically significant changes post-operatively between T1-T2 and T1-T3 only with medium effect sizes for the CLP group only. CONCLUSIONS & IMPLICATIONS: This study provides evidence that maxillary osteotomy affects patients with and without CLP differently. In patients with CLP, surgery may impact negatively on velopharyngeal function for speech and changes seen early on at 3 months post operatively appear to persist at 12 months postoperatively. The findings in this study have implications for the speech care pathway of patients with CLP undergoing maxillary osteotomy in terms of assessment, review and management. PMID- 24165362 TI - Comprehension of sarcasm, metaphor and simile in Williams syndrome. AB - BACKGROUND: Although people with Williams syndrome (WS) are often characterized as friendly and sociable with relatively good general language abilities, there is emerging evidence of pragmatic difficulties and trouble comprehending aspects of non-literal language. AIMS: The main aim was to investigate the comprehension of sarcasm, metaphor and simile in WS relative to typically developing controls. A secondary aim was to examine the association between non-literal language comprehension and a range of other cognitive abilities, both in WS and in the typically developing population. METHODS & PROCEDURES: Twenty-six participants with WS were compared with 26 typically developing chronological age-matched controls (TDCA) and 26 typically developing mental age-matched controls (TDMA). Participants listened to stories in which characters made non-literal comments. They were then asked what each character meant by their comment. In order to investigate the second aim of the study, cognitive abilities were also assessed using the Woodcock-Johnson (Revised) Tests of Cognitive Ability, including expressive vocabulary, verbal working memory, perceptual integration, inferential reasoning and overall cognitive ability. OUTCOMES & RESULTS: Comprehension of non literal language in WS was significantly below TDCA levels, but was not significantly different to TDMA levels. For typically developing controls, each of the cognitive measures was strongly correlated with each of the measures of non-literal language comprehension. The same relationships were not always found for participants with WS. In particular, sarcasm comprehension in WS was not significantly correlated with any of the assessed cognitive abilities, and expressive vocabulary was not significantly correlated with any measure of non literal comprehension. CONCLUSIONS & IMPLICATIONS: Comprehension of simile in WS is below TDCA levels but seems on par with their mental age level. It appears that comprehension of sarcasm and metaphors is above the cognitive capabilities and mental age level of most individuals with WS. Further, the pattern of correlations between non-literal comprehension and cognitive abilities in WS relative to controls suggests that perhaps the linguistic and cognitive systems that underpin non-literal language comprehension in typically developing individuals interact and integrate in different ways in WS. PMID- 24165363 TI - Video feedback intervention: a case series in the context of childhood hearing impairment. AB - BACKGROUND: Recent research shows that parental sensitivity can explain a significant and unique amount of growth in speech and language outcomes in children with cochlear implants. In this intervention study we explored the impact of an intervention designed to support parental sensitivity on children's communication development. AIMS: This study tests the effect of a complex intervention in the context of childhood hearing impairment using a case study design of three families. Propositions for each case were made using parental report of the child's development in an attempt to identify change in outcome measurements that were not likely to be due to general development in the child or a halo effect from the intervention. METHODS AND RESULTS: Multiple pre- and post-intervention measures were taken. Outcome measures were mother-child contingencies to vocal utterances, emotional availability and an assessment of early communication in the child. Results for each case showed that improvements in some outcome measurements were found after the intervention and were maintained at follow-up. CONCLUSIONS & IMPLICATIONS: Taking account of developmental change in intervention studies with children is challenging. Single subject intervention studies can be designed to allow research interventions to be tailored to meet families' specific needs. Video interaction guidance may support pre-linguistic communicative development in children with hearing impairment. PMID- 24165364 TI - Story discourse and use of mental state language between mothers and school-aged children with and without visual impairment. AB - BACKGROUND: Lack of sight compromises insight into other people's mental states. Little is known about the role of maternal language in assisting the development of mental state language in children with visual impairment (VI). AIMS: To investigate mental state language strategies of mothers of school-aged children with VI and to compare these with mothers of comparable children with typically developing vision. To investigate whether the characteristics of mother-child discourse were associated with the child's socio-communicative competence. METHODS & PROCEDURES: Mother-child discourse with twelve 6-12-year-old children with VI was coded during a shared book-reading narrative and compared with 14 typically sighted children matched in age and verbal ability. OUTCOMES & RESULTS: Mothers of children with VI elaborated more and made significantly more references to story characters' mental states and descriptive elaborations than mothers of sighted children. Mental state elaborations of mothers in the VI group related positively with the level produced by their children, with the association remaining after mothers' overall verbosity and children's developmental levels were controlled for. Frequency of maternal elaborations, including their mental state language, was related to socio-communicative competence of children with VI. CONCLUSIONS & IMPLICATIONS: The findings offer insights into the potential contribution of maternal verbal scaffolding to mentalistic language and social-communicative competences of children with VI. PMID- 24165365 TI - Investigation of practices to support the complex communication needs of children with hearing impairment and cerebral palsy in a rural district of Kenya: a case series. AB - BACKGROUND: Rehabilitation services are scarce in low-income countries, where under-representation of some specialist professions has led to the role extension of others. An example of this can be found in Kilifi in Kenya where the role of speech and language therapy has been taken on by occupational therapists and teachers. AIMS: To investigate the communication practices used by these professional groups to support children with complex communication needs in a rural part of Kenya and to explore the ways in which this might be seen to facilitate or obstruct improved communication by asking the following questions: What are the critical features of interactional discourse in practitioner-child dyads with caregiver-child dyads providing a natural comparison? What communicative modalities and practice techniques are invoked? And how does this information relate to extending professional roles? METHODS & PROCEDURES: An in depth, descriptive study of a case series was conducted in a school for deaf children and the occupational therapy department of a district general hospital. A mixed methodology was used involving naturalistic observation and applied linguistics analysis. A convenience sample was established comprising six practitioner-child dyads assigned to partnership types: (A) three children with hearing impairment and their teachers; and (B) three children with cerebral palsy and their occupational therapists. As a natural comparator, the same three children in B were also observed with their mothers (partnership type C). Dyadic interaction was video recorded on three occasions. The video data were sampled, transcribed into standard orthography and translated. Codes were applied to determine turn structure, linguistic move types and communicative modalities. Sequential analysis was conducted on the move types. OUTCOMES & RESULTS: Partnership type A dyads showed a fairly even turn distribution between teacher and child. A common pattern was teacher-initiated Instruct and Model/Prompt, followed by child response in the form of an Action. The most frequently used modality was Sound Production and Hands-on-Articulators, which corresponded to articulation drill practice. Partnership type B dyads revealed a tendency towards adult domination of turns. The majority of adult-initiated moves required no response from the child. The practice technique Hands-on-Articulators involved manipulating the oral musculature of the child. Partnership type C dyads showed resonances of type B dyads, although focused more on Motor-Action in relation to task performance. CONCLUSIONS & IMPLICATIONS: The assignment of speech and language therapy duties to teachers and occupational therapists has resulted in suboptimal practice for children with complex communication needs. PMID- 24165366 TI - Public attitudes toward stuttering in Poland. AB - BACKGROUND: People who stutter often experience negative judgments and reactions to their stuttering from the nonstuttering majority. Many are stigmatized because of their stuttering and threatened with social exclusion, placing them at risk for compromised quality of life. AIMS: The purpose of this investigation was to measure public attitudes toward stuttering in Poland. METHODS & PROCEDURES: A sample of 268 respondents (mean age = 29 years; range = 15-60 years) from numerous different geographic and urban-rural settings in Poland filled out a Polish translation of the Public Opinion Survey of Human Attributes-Stuttering (POSHA-S). OUTCOMES & RESULTS: Polish respondents displayed attitudes toward stuttering and people who stutter that were generally similar or "average" in comparison with other samples around the world from the POSHA-S database. CONCLUSIONS & IMPLICATIONS: Although generally typical of other Western societies studied, attitudes of adolescents and adults from Poland were notably different in some ways, such as in the beliefs that emotional trauma or viruses and disease can cause stuttering as well as in the self reaction that they would feel uncomfortable speaking with a stuttering person. Overall, social exclusion and stigma are as likely among Poles who stutter as among most other populations studied. PMID- 24165367 TI - Linguistic and pragmatic skills in toddlers with cochlear implant. AB - BACKGROUND: An increasing number of deaf children received cochlear implants (CI) in the first years of life, but no study has focused on linguistic and pragmatic skills in children with CI younger than 3 years of age. AIMS: To estimate the percentage of children who had received a CI before 2 years of age whose linguistic skills were within the normal range; to compare linguistic skills of children implanted by 12 months of age with children implanted between 13 and 26 months of age; and to describe the relationship among lexical, grammar and pragmatic skills. METHODS & PROCEDURES: The participants consisted of children who were included on the patient lists of the Service of Audio-Vestibology of the Circolo Hospital in Varese, Italy, and met the following criteria: chronological age between 18 and 36 months; CI activated between 8 and 30 months of age; absence of other reported deficits; hearing parents; and not less than 6 months of CI experience. Language development was evaluated through MacArthur-Bates CDI; pragmatic skills (assertiveness and responsiveness) were evaluated through the Social Conversational Skills Rating Scale. The scores obtained were transformed into z-scores and compared with normative data. The relationship among lexical, grammar and pragmatic skills were tested using Spearman Rho correlations. Children with CI were divided into groups based on the age at CI activation and the differences between the two groups were tested using the Student's t-test. OUTCOMES & RESULTS: Data from 23 deaf children were collected. Fewer than half of the children were within the normal range for lexical production and use of sentences; more than one-third of them fell below the normal range for both lexical and grammar skills. No significant difference was found in vocabulary size or early grammar skills when comparing children who received the CI by 12 months of age with those implanted during the second year of life. Despite the strong relationship among lexical, grammar and pragmatic skills, the delays found for grammar and pragmatic skills were greater than expected based on the vocabulary size. Age at diagnosis of hearing loss was the only predictor of vocabulary size. CONCLUSIONS & IMPLICATIONS: CI may provide deaf children with a good opportunity to develop language skills, but severe difficulties in early social experiences and interaction mediated by language still remain. Delays in these aspects suggest that interventions improving pragmatic skills are recommended even on very young children with CI. PMID- 24165368 TI - Which are the best predictors of theory of mind delay in children with specific language impairment? AB - BACKGROUND: The relationship between language and theory of mind (ToM) development in participants with specific language impairment (SLI) it is far from clear due to there were differences in study design and methodologies of previous studies. AIMS: This research consisted of an in-depth investigation of ToM delay in children with SLI during the typical period of acquisition, and it studied whether linguistic or information-processing variables were the best predictors of this process. It also took into account whether there were differences in ToM competence due to the degree of pragmatic impairment within the SLI group. METHODS & PROCEDURES: Thirty-one children with SLI (3;5-7;5 years old) and two control groups (age matched and language matched) were assessed with False Belief (FB) tasks, a wide battery of language measures and additional information-processing measures. OUTCOMES & RESULTS: The members of the SLI group were less competent than their age-matched peers at solving FB tasks, but they performed similarly to the language-matched group. Regression analysis showed that overall linguistic skills of children with SLI were the best predictor of ToM performance, and especially grammar abilities. No differences between SLI subgroups were found according to their pragmatic level. CONCLUSIONS & IMPLICATIONS: A delay in ToM development in children with SLI around the critical period of acquisition is confirmed more comprehensively, and it is shown to be more strongly related to their general linguistic level than to their age and other information-processing faculties. This finding stresses the importance of early educational and clinical programmes aimed at reducing deleterious effects in later development. PMID- 24165373 TI - Epileptic and electroencephalographic manifestations of guanidinoacetate methyltransferase deficiency. AB - AIM: Describe the seizure-related manifestations of guanidinoacetate methyltransferase (GAMT) deficiency in two new cases and compare these to the related literature. METHODS: We reviewed the clinical and electroencephalographic manifestations of two siblings with GAMT deficiency. We also performed a thorough literature review of all cases of GAMT deficiency, using the PubMed database, and compared our findings to those previously reported. RESULTS: One sibling presented with Lennox-Gastaut syndrome while the second had manifestations of late-onset West syndrome. Based on a literature search, we found that the clinical picture of GAMT deficiency has been described in a total of 58 cases, including our two patients, 45 of whom had at least some description of EEG and/or seizure manifestation. Epilepsy was present in 81%, with age at onset usually between 10 months and 3 years. Drug resistance was observed in approximately 45%. Initial seizures were febrile, tonic, or tonic-clonic. Drop attacks and generalised seizures were the most frequent seizure type. Absence and febrile seizures also occurred. Less frequently, focal seizures and late-onset infantile spasms (one prior case) were observed. Multifocal spikes and generalised <3-Hz-spike slow waves were common while only one prior single case report of hypsarrhythmia was described. Lennox-Gastaut syndrome was common, while progressive myoclonic epilepsy was also, less frequently, reported. CONCLUSIONS: To our knowledge, this is the second report of the occurrence of West syndrome in GAMT deficiency. The majority of patients with GAMT deficiency have seizures and approximately half are drug-resistant. Late-onset of hypsarrhythmia and/or epileptic spasms could potentially prove to be a distinctive, albeit infrequent, feature of this treatable metabolic disorder. PMID- 24165374 TI - Trust, openness and continuity of care influence acceptance of antibiotics for children with respiratory tract infections: a four country qualitative study. AB - BACKGROUND: Clinician-parent interaction and health system influences on parental acceptance of prescribing decisions for children with respiratory tract infections (RTIs) may be important determinants of antibiotic use. OBJECTIVE: To achieve a deeper understanding of parents' acceptance, or otherwise, of clinicians' antibiotic prescribing decisions for children with RTIs. METHODS: Qualitative interviews with parents of child patients who had recently consulted in primary care with a RTI in four European countries, with a five-stage analytic framework approach (familiarization, developing a thematic framework from interview questions and emerging themes, indexing, charting and interpretation). RESULTS: Fifty of 63 parents accepted clinicians' management decisions, irrespective of antibiotic prescription. There were no notable differences between networks. Parents ascribed their acceptance to a trusting and open clinician-patient relationship, enhanced through continuity of care, in which parents felt able to express their views. There was a lack of congruence about antibiotics between parents and clinicians in 13 instances, mostly when parents disagreed about clinicians' decision to prescribe (10 accounts) rather than objecting to withholding antibiotics (three accounts). All but one parent adhered to the prescribing decision, although some modified how the antibiotic was administered. CONCLUSIONS: Parents from contrasting countries indicated that continuity of care, open communication in consultations and clinician-patient trust was important in acceptance of management of RTI in their children and in motivating adherence. Interventions to promote appropriate antibiotic use in children should consider a focus on eliciting parents' perspectives and promoting and building on continuity of care within a trusting clinician-patient relationship. PMID- 24165375 TI - Multinodular/plexiform schwannoma of the ulnar nerve. PMID- 24165376 TI - Counseling reduces HPV persistence in coinfected couples. AB - INTRODUCTION: Human papillomavirus (HPV) infection is a very common sexually transmitted disease. A variable concordance and clearance time between partners of infected heterosexual couples have been shown. AIM: Aims of this study were evaluation of prevalent sites of HPV infection, frequency, genotype concordance, and course of viral infection in counseled and non-counseled infected heterosexual couples. METHODS: Prospective, controlled study among 74 consecutive HPV-infected heterosexual couples seeking their first medical intervention for sexually transmitted infections. MAIN OUTCOME MEASURES: HPV detection and genotyping were performed at enrollment and during 24 months follow-up by polymerase chain reaction and INNO-LiPA assay in samples obtained from both partners. Samples were collected in males from coronal sulcus, urethra, semen, and oropharynx, and from cervix and oropharynx in females. Moreover, HPV fluorescence in situ hybridization was analyzed on semen samples. RESULTS: The study was completed by 49 couples. The specific HPV-type concordance among infected couples was 69.4%. Among couples who declared performing oral sex, oropharyngeal infection was 22.7% of couples, and was more prevalent in females than males (18.1% and 4.5%, respectively). Thereafter, couples were randomly divided in two groups: a control group of 24 couples followed up for HPV-related lesions, and an experimental group counseled of 25 couples followed up for HPV related lesions and counseled to avoid known risk factors for HPV infection. In patients who received counseling, the number of infected sites diminished faster during the follow-up and a higher number of couples had clearance. Only in the counseled group were there no infected couples at the end of the 24-month follow up period. CONCLUSIONS: This study confirms that HPV infection affects many sites in both males and females and shows a significant prevalence of oropharyngeal infection in couples performing oral sex. Targeted counseling in heterosexual couples appears to reduce the number of infected sites and to speed up viral clearance. PMID- 24165377 TI - Assessment of three techniques for delivering stem cells to the heart using PET and MR imaging. AB - BACKGROUND: Stem cell therapy has a promising potential for the curing of various degenerative diseases, including congestive heart failure (CHF). In this study, we determined the efficacy of different delivery methods for stem cell administration to the heart for the treatment of CHF. Both positron emission tomography (PET) and magnetic resonance imaging (MRI) were utilized to assess the distribution of delivered stem cells. METHODS: Adipose-derived stem cells of male rats were labeled with super-paramagnetic iron oxide (SPIO) and 18 F fluorodeoxyglucose (FDG). The left anterior descending coronary artery (LAD) of the female rats was occluded to induce acute ischemic myocardial injury. Immediately after the LAD occlusion, the double-labeled stem cells were injected into the ischemic myocardium (n = 5), left ventricle (n = 5), or tail vein (n = 4). In another group of animals (n = 3), the stem cells were injected directly into the infarct rim 1 week after the LAD occlusion. Whole-body PET images and MR images were acquired to determine biodistribution of the stem cells. After the imaging, the animals were euthanized and retention of the stem cells in the vital organs was determined by measuring the cDNA specific to the Y chromosome. RESULTS: PET images showed that retention of the stem cells in the ischemic myocardium was dependent on the cell delivery method. The tail vein injection resulted in the least cell retention in the heart (1.2% +/- 0.6% of total injected cells). Left ventricle injection led to 3.5% +/- 0.9% cell retention and direct myocardial injection resulted in the highest rate of cell retention (14% +/- 4%) in the heart. In the animals treated 1 week after the LAD occlusion, rate of cell retention in the heart was only 4.5% +/-1.1%, suggesting that tissue injury has a negative impact on cell homing. In addition, there was a good agreement between the results obtained through PET-MR imaging and histochemical measurements. CONCLUSION: PET-MR imaging is a reliable technique for noninvasive tracking of implanted stem cells in vivo. Direct injection of stem cells into the myocardium is the most effective way for cell transplantation to the heart in heart failure models. PMID- 24165378 TI - Dengue in international travelers: quo vadis? PMID- 24165379 TI - Can the safety of the yellow fever vaccine be evaluated by a retrospective study of databases? PMID- 24165380 TI - Acceptability of hypothetical dengue vaccines among travelers. AB - BACKGROUND: Dengue viruses have spread widely in recent decades and cause tens of millions of infections mostly in tropical and subtropical areas. Vaccine candidates are being studied aggressively and may be ready for licensure soon. METHODS: We surveyed patients with past or upcoming travel to dengue-endemic countries to assess rates and determinants of acceptance for four hypothetical dengue vaccines with variable efficacy and adverse event (AE) profiles. Acceptance ratios were calculated for vaccines with varied efficacy and AE risk. RESULTS: Acceptance of the four hypothetical vaccines ranged from 54% for the vaccine with lower efficacy and serious AE risk to 95% for the vaccine with higher efficacy and minor AE risk. Given equal efficacy, vaccines with lower AE risk were better accepted than those with higher AE risk; given equivalent AE risk, vaccines with higher efficacy were better accepted than those with lower efficacy. History of Japanese encephalitis vaccination was associated with lower vaccine acceptance for one of the hypothetical vaccines. US-born travelers were more likely than non-US born travelers to accept a vaccine with 75% efficacy and a risk of minor AEs (p = 0.003). Compared with North American-born travelers, Asian- and African-born travelers were less likely to accept both vaccines with 75% efficacy. CONCLUSIONS: Most travelers would accept a safe and efficacious dengue vaccine if one were available. Travelers valued fewer potential AEs over increased vaccine efficacy. PMID- 24165381 TI - Prevalence of dengue virus infection in US travelers who have lived in or traveled to dengue-endemic countries. AB - BACKGROUND: Dengue virus (DENV) infections may occur in travelers. OBJECTIVES: To determine prevalence of anti-DENV IgG antibody in travelers who lived in or visited dengue-endemic countries and to describe risk factors and characteristics associated with infection and subsequent anti-DENV IgG antibody presence. METHODS: Participants were enrolled from travel clinics of the Boston Area Travel Medicine Network from August 2008 through June 2009. Demographic information, trip duration, travel history, and a blood sample were collected. Serum samples were tested for anti-DENV IgG antibody by indirect IgG enzyme-linked immunosorbent assay (ELISA), and antibody-mediated virus neutralization by plaque reduction neutralization test (PRNT) for anti-DENV IgG antibody-positive and selected negative samples. Participants were stratified into group 1: born in dengue-endemic countries; group 2: born in nonendemic countries but lived continuously for >=1 year in a dengue-endemic country; group 3: born in nonendemic countries and traveled to a dengue-endemic country for >=2 weeks but <1 year. RESULTS: Six hundred travelers were enrolled. Anti-DENV IgG antibody was identified in 113 (19%) when tested by ELISA (51% in group 1, 40% in group 2, and 6.9% in group 3) and in 71 (12%) by PRNT (42% primary monotypic and 58% heterotypic reactive responses). Sensitivity and specificity of the ELISA based on PRNT results were 85% to 100% and 79% to 94%, assuming up to 15% misclassification of ELISA negative results. Presence of anti-DENV IgG antibody by ELISA was associated with years lived in dengue-endemic countries and birthplace in the Caribbean for group 1, receipt of Japanese encephalitis vaccine in group 3, and self-reported history of dengue in all three groups. CONCLUSIONS: Nineteen percent of participants who were born, lived in, or traveled to dengue endemic countries had anti-DENV IgG antibody by ELISA; 12% had antibodies by PRNT, 85% of whom had no history of dengue. Presence of DENV antibodies was associated with years lived in dengue-endemic countries and self-reported history of dengue. PMID- 24165382 TI - Efficacy of a travelers' diarrhea vaccine system in travelers to India. AB - BACKGROUND: A patch vaccine containing heat-labile toxin (LT) from enterotoxigenic Escherichia coli (ETEC) has demonstrated to be beneficial in reducing the rate and severity of travelers' diarrhea in Latin America. To evaluate the efficacy of this transdermal vaccine system in an area with a different diarrheal pathogen profile, an additional phase 2 study was conducted in European travelers to India. METHODS: For this multicenter, randomized, double blinded, placebo-controlled field study 723 subjects were recruited; 603 (299 LT vaccine, 304 placebo) were included in the per-protocol-population (PPP). RESULTS: Although the LT patch induced a measurable LT immune response in recipients, it failed to protect against LT ETEC or all-cause diarrhea. In the PPP the incidence rate of diarrhea as per primary endpoint was 6.0% (18 of 299) in the vaccine group and 5.9% (18 of 304) in the placebo group. Additionally, lower than expected rates of LT ETEC diarrheas were observed in India. The vaccine delivery system frequently produced rash and pruritus at the site of application, long term hyperpigmentation persisted in a minority of LT recipients, and also few site reactions were noted in the placebo group. CONCLUSIONS: The evaluated patch vaccine failed to satisfy mainly with respect to protective efficacy. Noninvasive prophylactic agents against travelers' diarrhea, particularly vaccines against the most frequent pathogens, thus continue to be badly needed. PMID- 24165383 TI - Dengue fever and international travel. AB - BACKGROUND: Dengue is a leading public health problem with an expanding global burden. Dengue virus is also a significant cause of illness in international travelers with an increasing number of cases of dengue fever identified in travelers returning from dengue-endemic countries. METHODS: This review focuses on the clinical illness of dengue infection in international travelers and provides a summary of the risk of infection for travelers, clinical features of infection, and an overview of dengue vaccines and their potential applicability to travelers. RESULTS: Four prospective studies of travelers to dengue-endemic destinations have shown that the dengue infection incidence ranges from 10.2 to 30 per 1,000 person-months. This varies according to travel destination and duration and season of travel. Dengue is also a common cause of fever in returned travelers, accounting for up to 16% of all febrile illnesses in returned travelers. Although the majority of infections are asymptomatic, a small proportion of travelers develop dengue hemorrhagic fever. The diagnosis of dengue in travelers requires a combination of serological testing for IgG and IgM together with either nucleic acid or NS1 antigen testing. Several vaccine candidates have now entered into clinical trials including ChimeriVax Dengue, which is currently in phase 3 trials, live-attenuated chimeric vaccines (DENV DENV Chimera, Inviragen), live-attenuated viral vaccines, recombinant protein subunit vaccines, and DNA vaccines. CONCLUSIONS: Dengue infection in international travelers is not infrequent and may be associated with substantial morbidity. Furthermore, an accurate diagnosis of dengue in travelers requires the use of a combination of diagnostic tests. Although a vaccine is not yet available a number of promising candidates are under clinical evaluation. For now travelers should be provided with accurate advice regarding preventive measures when visiting dengue-endemic areas. PMID- 24165384 TI - Epidemiology and prevention of hepatitis A in travelers. AB - BACKGROUND: Hepatitis A is the second most common vaccine-preventable travel associated infectious disease and hepatitis A virus (HAV) is the most common cause of viral hepatitis. The incidence of infection is closely related to sanitary conditions and the level of economic development. METHODS: We evaluated HAV incidence, infection-related risk factors, and HAV vaccination rates in international travelers through retrospective analyses using major databases, such as CENTRAL, MEDLINE, EMBASE, and the current literature describing epidemiological data for HAV infection in recent years. RESULTS AND CONCLUSIONS: We found that the incidence of HAV infection in developed countries is very low. As international travel increases, the incidence of hepatitis A among travelers remains high and likely leads to regional outbreaks. Travelers should visit the Centers for Disease Control and Prevention website or Infectious Disease Prevention Center of their countries to learn about the incidence of infectious diseases associated with their destination before going abroad to determine if they should be vaccinated. PMID- 24165385 TI - Cluster of zoonotic cutaneous leishmaniasis (Leishmania major) in European travelers returning from Turkmenistan. AB - We report a cluster of cutaneous leishmaniasis due to Leishmania major in four immunocompetent travelers returning from Western Turkmenistan and having atypical and/or multiple lesions. Treatments with pentamidine or fluconazole were effective. Physicians should be aware that some virulent strains of L major currently circulate in Central Asia. PMID- 24165386 TI - The incidence of HBV and HCV infection in Australian travelers. PMID- 24165387 TI - HBV and HCV infections in travelers. PMID- 24165388 TI - Response to letters. PMID- 24165389 TI - Multiple meningiomas characterized by benign and malignant tumor entities. PMID- 24165390 TI - Identification of properties important to protein aggregation using feature selection. AB - BACKGROUND: Protein aggregation is a significant problem in the biopharmaceutical industry (protein drug stability) and is associated medically with over 40 human diseases. Although a number of computational models have been developed for predicting aggregation propensity and identifying aggregation-prone regions in proteins, little systematic research has been done to determine physicochemical properties relevant to aggregation and their relative importance to this important process. Such studies may result in not only accurately predicting peptide aggregation propensities and identifying aggregation prone regions in proteins, but also aid in discovering additional underlying mechanisms governing this process. RESULTS: We use two feature selection algorithms to identify 16 features, out of a total of 560 physicochemical properties, presumably important to protein aggregation. Two predictors (ProA-SVM and ProA-RF) using selected features are built for predicting peptide aggregation propensity and identifying aggregation prone regions in proteins. Both methods are compared favourably to other state-of-the-art algorithms in cross validation. The identified important properties are fairly consistent with previous studies and bring some new insights into protein and peptide aggregation. One interesting new finding is that aggregation prone peptide sequences have similar properties to signal peptide and signal anchor sequences. CONCLUSIONS: Both predictors are implemented in a freely available web application (http://www.abl.ku.edu/ProA/). We suggest that the quaternary structure of protein aggregates, especially soluble oligomers, may allow the formation of new molecular recognition signals that guide aggregate targeting to specific cellular sites. PMID- 24165391 TI - The effect of physical activity on psychological distress, cortisol and obesity: results of the Farming Fit intervention program. AB - BACKGROUND: Rural and regional Australians have a higher likelihood of mental illness throughout their lifetime than people living in major cities, although the underlying reasons are not yet well defined. Additionally, rural populations experience more lifestyle associated co-morbidities including obesity, diabetes and cardiovascular disease. Research conducted by the National Centre for Farmer Health between 2004 and 2009 revealed a positive correlation between obesity and psychological distress among the farming community. Chronic stress is known to overstimulate the regulation of the hypothalamic-pituitary-adrenal (HPA) axis and cortisol secretion which are associated with abdominal adiposity. Increasing physical activity may normalise cortisol secretion and thereby positively impact both physical and mental health. This paper assesses the effects of increasing physical activity on obesity, health behaviors and mental health in Victorian farming men and women. METHODS: Farming Fit was a six month quasi-experimental (convenience sample) longitudinal design control-intervention study. Overweight or obese (BMI >=25 kg/m2) farm men (n = 43) and women (n = 29) were recruited with demographic, health behaviors, anthropometric, blood pressure and biochemistry data collected at baseline and at a six months. Salivary cortisol and depression anxiety stress scale results were collected at baseline, three and six months. The intervention group (n = 37) received a personalized exercise program and regular phone coaching to promote physical activity. RESULTS: The intervention group showed significant reductions in body weight and waist circumference. Results indicated that following the six month exercise program, the intervention group were 2.64 +/- 0.65 kg lighter (p < 0.001), had reduced waist circumference by 2.01 +/- 0.86 cm (p = 0.02) and BMI by 0.97 +/- 0.22 kg/m2 (p < 0.001) relative to the control group. CONCLUSION: Increasing physical activity altered measures of obesity in farm men and women but did not affect mental health measures or cortisol secretion levels. TRIAL REGISTRATION: ACTRN12610000827033. PMID- 24165392 TI - The Multi Centre Canadian Acellular Dermal Matrix Trial (MCCAT): study protocol for a randomized controlled trial in implant-based breast reconstruction. AB - BACKGROUND: The two-stage tissue expander/implant (TE/I) reconstruction is currently the gold standard method of implant-based immediate breast reconstruction in North America. Recently, however, there have been numerous case series describing the use of one-stage direct to implant reconstruction with the aid of acellular dermal matrix (ADM). In order to rigorously investigate the novel application of ADM in one-stage implant reconstruction, we are currently conducting a multicentre randomized controlled trial (RCT) designed to evaluate the impact on patient satisfaction and quality of life (QOL) compared to the two stage TE/I technique. METHODS/DESIGNS: The MCCAT study is a multicenter Canadian ADM trial designed as a two-arm parallel superiority trial that will compare ADM facilitated one-stage implant reconstruction compared to two-stage TE/I reconstruction following skin-sparing mastectomy (SSM) or nipple-sparing mastectomy (NSM) at 2 weeks, 6 months, and 12 months. The source population will be members of the mastectomy cohort with stage T0 to TII disease, proficient in English, over the age of 18 years, and planning to undergo SSM or NSM with immediate implant breast reconstruction. Stratified randomization will maintain a balanced distribution of important prognostic factors (study site and unilateral versus bilateral procedures). The primary outcome is patient satisfaction and QOL as measured by the validated and procedure-specific BREAST-Q. Secondary outcomes include short- and long-term complications, long-term aesthetic outcomes using five standardized photographs graded by three independent blinded observers, and a cost effectiveness analysis. DISCUSSION: There is tremendous interest in using ADM in implant breast reconstruction, particularly in the setting of one-stage direct to implant reconstruction where it was previously not possible without the intermediary use of a temporary tissue expander (TE). This unique advantage has led many patients and surgeons alike to believe that one-stage ADM-assisted implant reconstruction should be the procedure of choice and should be offered to patients as the first-line treatment. We argue that it is crucial that this technique be scientifically evaluated in terms of patient selection, surgical technique, complications, aesthetic outcomes, cost-effectiveness, and most importantly patient-reported outcomes before it is promoted as the new gold standard in implant-based breast reconstruction. TRIAL REGISTRATION: ClinicalTrials.gov: NCT00956384. PMID- 24165393 TI - A historical perspective on protein crystallization from 1840 to the present day. AB - Protein crystallization has been known since 1840 and can prove to be straightforward but, in most cases, it constitutes a real bottleneck. This stimulated the birth of the biocrystallogenesis field with both 'practical' and 'basic' science aims. In the early years of biochemistry, crystallization was a tool for the preparation of biological substances. Today, biocrystallogenesis aims to provide efficient methods for crystal fabrication and a means to optimize crystal quality for X-ray crystallography. The historical development of crystallization methods for structural biology occurred first in conjunction with that of biochemical and genetic methods for macromolecule production, then with the development of structure determination methodologies and, recently, with routine access to synchrotron X-ray sources. Previously, the identification of conditions that sustain crystal growth occurred mostly empirically but, in recent decades, this has moved progressively towards more rationality as a result of a deeper understanding of the physical chemistry of protein crystal growth and the use of idea-driven screening and high-throughput procedures. Protein and nucleic acid engineering procedures to facilitate crystallization, as well as crystallization methods in gelled-media or by counter-diffusion, represent recent important achievements, although the underlying concepts are old. The new nanotechnologies have brought a significant improvement in the practice of protein crystallization. Today, the increasing number of crystal structures deposited in the Protein Data Bank could mean that crystallization is no longer a bottleneck. This is not the case, however, because structural biology projects always become more challenging and thereby require adapted methods to enable the growth of the appropriate crystals, notably macromolecular assemblages. PMID- 24165394 TI - Medical and economic burden of influenza in the elderly population in central and eastern European countries. AB - Influenza affects 5-15% of the population during an epidemic. In Western Europe, vaccination of at-risk groups forms the cornerstone of influenza prevention. However, vaccination coverage of the elderly (> 65 y) is often low in Central and Eastern Europe (CEE); potentially because a paucity of country-specific data limits evidence-based policy making. Therefore the medical and economic burden of influenza were estimated in elderly populations in the Czech Republic, Hungary, Kazakhstan, Poland, Romania, and Ukraine. Data covering national influenza vaccination policies, surveillance and reporting, healthcare costs, populations, and epidemiology were obtained via literature review, open-access websites and databases, and interviews with experts. A simplified model of patient treatment flow incorporating cost, population, and incidence/prevalence data was used to calculate the influenza burden per country. In the elderly, influenza represented a large burden on the assessed healthcare systems, with yearly excess hospitalization rates of ~30/100,000. Burden varied between countries and was likely influenced by population size, surveillance system, healthcare provision, and vaccine coverage. The greatest burden was found in Poland, where direct costs were over EUR 5 million. Substantial differences in data availability and quality were identified, and to fully quantify the burden of influenza in CEE, influenza reporting systems should be standardized. This study most probably underestimates the real burden of influenza, however the public health problem is recognized worldwide, and will further increase with population aging. Extending influenza vaccination of the elderly may be a cost-effective way to reduce the burden of influenza in CEE. PMID- 24165395 TI - Development of a transportable neutron activation analysis system to quantify manganese in bone in vivo: feasibility and methodology. AB - This study was conducted to investigate the methodology and feasibility of developing a transportable neutron activation analysis (NAA) system to quantify manganese (Mn) in bone using a portable deuterium-deuterium (DD) neutron generator as the neutron source. Since a DD neutron generator was not available in our laboratory, a deuterium-tritium (DT) neutron generator was used to obtain experimental data and validate the results from Monte Carlo (MC) simulations. After validation, MC simulations using a DD generator as the neutron source were then conducted. Different types of moderators and reflectors were simulated, and the optimal thicknesses for the moderator and reflector were determined. To estimate the detection limit (DL) of the system, and to observe the interference of the magnesium (Mg) gamma line at 844 keV to the Mn gamma line at 847 keV, three hand phantoms with Mn concentrations of 30 parts per million (ppm), 150 ppm, and 500 ppm were made and irradiated by the DT generator system. The Mn signals in these phantoms were then measured using a 50% high-efficiency high purity germanium (HPGe) detector. The DL was calculated to be about 4.4 ppm for the chosen irradiation, decay, and measurement time. This was calculated to be equivalent to a DL of about 3.3 ppm for the DD generator system. To achieve this DL with one 50% high-efficiency HPGe detector, the dose to the hand was simulated to be about 37 mSv, with the total body equivalent dose being about 23uSv. In conclusion, it is feasible to develop a transportable NAA system to quantify Mn in bone in vivo with an acceptable radiation exposure to the subject. PMID- 24165396 TI - Unimodal response of fish yield to dissolved organic carbon. AB - Here, we demonstrate a contrasting effect of terrestrial coloured dissolved organic material on the secondary production of boreal nutrient poor lakes. Using fish yield from standardised brown trout gill-net catches as a proxy, we show a unimodal response of lake secondary productivity to dissolved organic carbon (DOC). This suggests a trade-off between positive and negative effects, where the initial increase may hinge upon several factors such as energy subsidising, screening of UV-radiation or P and N load being associated with organic carbon. The subsequent decline in production with further increase in DOC is likely associated with light limitations of primary production. We also show that shallow lakes switch from positive to negative effects at higher carbon loads than deeper lakes. These results underpin the major role of organic carbon for structuring productivity of boreal lake ecosystems. PMID- 24165397 TI - Heart transplantation for Chagas cardiomyopathy in the United States. AB - Since an initial case in 2006, we noted multiple patients undergoing heart transplantation (HTx) for Chagas cardiomyopathy (CC) at our transplant program. The clinical characteristics, laboratory results and outcomes of patients with CC undergoing HTx in the United States have not been reported previously. In 2010, we implemented a systematic screening and management program for patients undergoing HTx for CC. Before HTx, all patients with idiopathic dilated cardiomyopathy who were born in a Chagas disease endemic country were screened for Trypanosoma cruzi (TC) infection with serology. After HTx, monitoring for TC reactivation was performed using clinical visits, echocardiography, endomyocardial biopsy and serial whole blood polymerase chain reaction (PCR) testing. Between June 2006 and January 2012, 11 patients underwent HTx for CC. One patient was empirically treated due to the presence of TC amastigotes in explanted cardiac tissue. Two patients experienced allograft dysfunction due to TC reactivation and three patients experienced subclinical reactivation (positive PCR results), which were treated. Chagas disease is a common cause of dilated cardiomyopathy in patients from endemic countries undergoing HTx at a transplant program in the United States. Reactivation is common after transplantation and can cause adverse outcomes. PMID- 24165398 TI - Severe postoperative haemarthrosis following a total knee replacement in a haemophiliac patient caused by a pseudoaneurysm: early treatment with arterial embolization. PMID- 24165401 TI - NMC: robust revalidation for public protection. PMID- 24165400 TI - NMC to implement new revalidation for nurses. PMID- 24165402 TI - COPD self-management supportive care: chaos and complexity theory. AB - This paper uses the emergent theories of chaos and complexity to explore the self management supportive care of chronic obstructive pulmonary disease (COPD) patients within the evolving primary care setting. It discusses the concept of self-management support, the complexity of the primary care context and consultations, smoking cessation, and the impact of acute exacerbations and action planning. The author hopes that this paper will enable the acquisition of new insight and better understanding in this clinical area, as well as support meaningful learning and facilitate more thoughtful, effective and high quality patient-centred care within the context of primary care. PMID- 24165399 TI - let-7-repressesed Shc translation delays replicative senescence. AB - The p66Shc adaptor protein is an important regulator of lifespan in mammals, but the mechanisms responsible are still unclear. Here, we show that expression of p66Shc, p52Shc, and p46Shc is regulated at the post-transcriptional level by the microRNA let-7a. The levels of let-7a correlated inversely with the levels of Shc proteins without affecting Shc mRNA levels. We identified 'seedless' let-7a interaction elements in the coding region of Shc mRNA; mutation of the 'seedless' interaction sites abolished the regulation of Shc by let-7a. Our results further revealed that repression of Shc expression by let-7a delays senescence of human diploid fibroblasts (HDFs). In sum, our findings link let-7a abundance to the expression of p66Shc, which in turn controls the replicative lifespan of HDFs. PMID- 24165403 TI - An exploration of self-efficacy and self-management in COPD patients. AB - AIM: This study examined if self-efficacy in managing chronic obstructive pulmonary disease is associated with better mood, less breathlessness and fewer exacerbations; what helps or hinders patients in managing their chronic obstructive pulmonary disease (COPD); and patients' suggestions to improve the self-management support they receive. BACKGROUND: COPD is the fifth leading cause of death in the UK, and it has been suggested that supporting self-efficacy and self-management could improve patient outcomes and reduce demands for NHS resources. METHODS: An exploratory, descriptive survey involving the collection of both quantitative and semistructured qualitative data was chosen. Participants were randomly selected from four GP practices across the north east of Scotland. RESULTS: Higher levels of self-efficacy were associated with lower levels of breathlessness, lower levels of anxiety and lower levels of depression in COPD patients. There was no association between high self-efficacy and exacerbation rates. CONCLUSION: Increasing self-efficacy and reducing anxiety and depression in patients living with COPD are important focus points for self-management support. PMID- 24165404 TI - Wound care and learning disabilities: use of the Avance NPWT system. AB - Over the past two decades, topical negative pressure wound therapy has gained wide acceptance as a genuine strategy in the treatment algorithm for a wide variety of acute and chronic wounds (Bovill et al, 2008) and over 1000 peer reviewed publications describing the clinical efficacy and safety of negative pressure wound therapy (NPWT) for all wound types have been published over this period (Vig et al, 2011). Wound care and learning disabilities are very rarely discussed as joint issues. This case study aims to highlight the successful use of topical NPWT on a patient with moderate learning disabilities and examines how wound management should be individualised to meet the needs of the patient. PMID- 24165405 TI - Professional wellbeing and caring: exploring a complex relationship. AB - There is growing concern about lack of compassion in nursing. Impact of Injuries, which is the parent study (Kendrick et al, 2011) of this independent nested study, collected patient accounts of care received by physiotherapists and nurses. While physiotherapists were generally described as caring, nursing care was less consistent and sometimes uncaring. This embedded study conducted semi structured interviews in 2012 with 11 physiotherapists and 12 nurses in four English hospitals to obtain perspectives on the provision of care. Physiotherapists presented a distinct identity with caring both integral to the role and sustained by structural and organisational factors. Nurses had a diffuse identity with limited control within a medical and business model of care. They appeared 'under siege' and were nostalgic for caring, which was frequently subordinate to other demands. Both nurses and physiotherapists faced challenges but nurses felt the context of their work was not conducive to caring. This article draws comparisons between these professions and makes informed recommendations to improve nursing practice and patient care. PMID- 24165406 TI - Person-centred care: rhetoric and reality in a public healthcare system. AB - Recent scandals in the NHS have undermined confidence in this institution. A key factor in substandard care is the competing demands on practitioners. Individualised care may be hindered by paternalism and collective organisation, while practitioners are expected to pursue evidence-based practice and person centred care without acknowledging their differing goals. Drawing on a common theme from major philosophical conflicts in health services, this paper argues that instead of increasing managerial control, organisations should be empowering nurses to provide compassionate, person-centred care. PMID- 24165407 TI - Caring for young adults on a paediatric ward. AB - The need for adolescents and young adults (AYA) to have suitable age-specific inpatient facilities has been recognised for many years, yet has received relatively little attention. This article reports the successful introduction of an inpatient facility for AYA, aged 17-24 years, on a general paediatric ward in a small district general hospital. From December 2010, a young person's unit (YPU) consisting of an 8-bed area was opened within a 24-bed children's ward. Nursing care was provided by the ward staff, all of whom had been trained in the care of young adults. Policies regarding admission criteria, safeguarding, patient choice, visiting and 'house rules' were drafted, implemented and modified as necessary. Discussions with the adult clinicians (for medical care) and site managers were held to ensure smooth running of the system, and to address any concerns or difficulties. Paediatric patients had priority of admission at times of bed crisis. During 2012, there were a total of 2351 inpatient admissions to the paediatric ward, of whom 379 (16%) were YPU patients aged from 17-24 years. Median length of stay was 2 days for patients aged 17-24 years as compared with 1 day for patients aged less than or equal to 16 years. Patients who chose admission to the paediatric ward tended to be younger, in transition from paediatric to adult services for chronic conditions, or with special needs. Patient surveys showed a high level of satisfaction with the facility. Young adults can be cared for safely and effectively on a paediatric ward with minimal additional costs. The essential ingredients for success include discussion with affected parties to address specific concerns, and the establishment of a clear, simple and unambiguous admission policy. PMID- 24165408 TI - Clinical supervision: from staff nurse to nurse consultant. Part 7: the manager's role. PMID- 24165409 TI - The quality of care provided in NHS trusts reviewed. PMID- 24165410 TI - We need to improve community mental health care services. PMID- 24165411 TI - Raising concerns in an open culture. PMID- 24165412 TI - Setting the record straight. PMID- 24165413 TI - Practice size, financial sharing and quality of care. AB - BACKGROUND: Although we are observing a general move towards larger primary care practices, surprisingly little is known about the influence of key components of practice organization on primary care. We aimed to determine the relationships between practice size, and revenue sharing agreements, and quality of care. METHODS: As part of a large cross sectional study, group practices were randomly selected from different primary care service delivery models in Ontario. Patient surveys and chart reviews were used to assess quality of care. Multilevel regressions controlled for patient, provider and practice characteristics. RESULTS: Positive statistically significant associations were found between the logarithm of group size and access, comprehensiveness, and disease prevention. Negative significant associations were found between logarithm group size and continuity. No differences were found for chronic disease management and health promotion. Practices that shared revenues were found to deliver superior health promotion compared to those who did not. Interacting group size with the presence of a revenue-sharing arrangement had a negative impact on health promotion. CONCLUSIONS: Despite the limitations of our study, our findings have provided preliminary evidence of the tradeoffs inherent with increasing practice size. Larger group size is associated with better access and comprehensiveness but worse continuity of care. Revenue sharing in group practices was associated with higher health promotion compared to sharing only common costs. Further work is required to better inform policy makers and practitioners as to whether the pattern revealed in larger practices mitigates any of the previously reported benefits of continuity of primary care. We found few benefits of revenue sharing- even then the effect of revenue sharing on health promotion seemed diminished in larger practices. PMID- 24165414 TI - Sigmoid malignancy presenting as recto-sigmoid intussusception. PMID- 24165415 TI - Epileptic headache: closing Pandora's box. PMID- 24165416 TI - Impact of haplotypes of TNF in the natural course of infective endocarditis. AB - Based on previous findings for the role of single nucleotide polymorphisms (SNPs) of TNF for the predisposition for bloodstream infections, this study investigates the role of these SNPs at the promoter positions -376, -308, -238 in infective endocarditis (IE). In a case-control study, 83 patients with IE and 83 controls were enrolled. Blood genotyping for the presence of G or A alleles of the three SNPs was carried out using restriction fragment length polymorphisms. Haplotypes were calculated. Patients were mostly infected by Staphylococcus aureus (32.5%) and by species of enterococci (14.3%) and streptococci (14.3%). Carriage of the minor frequency A alleles at -238 of the promoter region of TNF was greater than in controls (8.4% versus 1.2%, p 0.003). The presence of any of the three GGA/GAA/AGA haplotypes was more frequent in patients with IE (OR 8.22, 95CI% 1.8 37.4, p 0.001). After multivariate logistic regression analysis, it was found that the only factor related to fatal outcome was carriage of the wild-type GGG haplotype (OR, 3.29, 95CI%, 1.05-10.29, p 0.04). GGA, AGA and GAA haplotypes were more frequent in patients with IE than in controls, suggesting a predisposition for IE and a potential protective role against fatal outcome, as the wild-type GGG haplotype was independently related with death. PMID- 24165417 TI - Nonfluent aphasia and cognitive impairment caused by anterior cerebral artery infarction. PMID- 24165418 TI - Meta-analyses: editor's dream or nightmare? PMID- 24165419 TI - Why follow up breast cancer patients? PMID- 24165420 TI - The burden of urgency urinary incontinence on health and wellbeing. PMID- 24165421 TI - Diabetes in sub-Saharan Africa: an economic and public health emergency. PMID- 24165422 TI - What is wrong with meta-analysis? The importance of clinical heterogeneity in myocardial regeneration research. AB - The author discusses the significance and potential pitfalls in performing a meta analysis underscoring the importance of a usual forgotten issue in meta-analysis called clinical heterogeneity. Clinical heterogeneity can mislead results and misinform clinicians. Practical examples from the literature are given, and the results of meta-analyses are compared with the results of subsequent large randomised clinical trials addressing similar questions from a historical and contemporary point of view, highlighting clinical heterogeneity. The contemporary aspect culminates with the presentation of a meta-analysis evaluating myocardial cell regeneration with an emphasis in clinical heterogeneity, helping clinicians to understand the issue and better appraise future meta-analyses. PMID- 24165423 TI - Clinical and ethical challenges of palliative sedation therapy. The need for clear guidance and professional competencies. AB - Palliative sedation therapy (PST) has become a frequent practice in end-of-life care and advocated in the literature as a less problematic alternative to practices of physician-assisted dying, such as ending patients' lives on request or assisted suicide . However, in clinical practice, patients, healthcare professionals and other parties involved in decisions about PST are facing numerous clinical and ethical challenges. This perspective aims to analyse important challenges associated with professional decision-making about PST and to explore the recommendations of guidelines, which have been published in recent years. PMID- 24165424 TI - The characteristics and outcomes of hospitalised and outpatient-treated first onset schizophrenia patients: a 5-year register linkage study. AB - AIM: We compared the course and outcome of schizophrenia in two groups: (i) hospitalised patients (HP) (n = 5980) who were identified based on their first hospital admission for schizophrenia and (ii) outpatient-treated patients (OTP) who received disability pension because of schizophrenia but who had no hospital admissions for schizophrenia or other psychotic disorder before having been granted a disability pension for schizophrenia (n = 1220). Outcomes were compared using data on mortality, psychiatric hospital utilisation, relapse rate and occupational functioning. METHODS: A nationwide register-based 5-year follow-up study of all first-onset schizophrenia cases between 1998 and 2003 in Finland. The data were linked with the register information of hospital admissions, disability pensions and National Causes of Death Registers. RESULTS: When outcome of treatment was evaluated using mortality rate, relapses, hospital treatment and involuntary admissions as outcome measures, results indicated that OTP group had got along better with their illnesses than HP group. The mortality rates, number of psychiatric treatment days and relapse rate during the 5-year follow up were significantly lower in OTP group. Within the OTP group, there was a notable subgroup of never HP (n = 737, 60.4%), who did not require any psychiatric hospitalisation during the 5-year follow up. CONCLUSIONS: Patients first identified as outpatients had better outcomes than patients first identified following a hospitalisation. Future studies are required to establish whether outpatient treatment is associated with more favourable prognosis, even after fully adjusting for severity of initial symptoms. The higher suicide mortality of hospital-treated patients suggests that hospital treatment of first-onset patients does not protect from suicide. PMID- 24165425 TI - Contralateral relapse after surgery for breast cancer: evaluation of follow-up paradigms. AB - BACKGROUND: Early treatment of breast cancer patients with loco-regional relapse or contralateral disease has been shown to improve survival. There is no current consensus on the optimal follow-up strategy. This study estimates the risk of isolated contralateral relapse (CR) after breast cancer surgery and its change over time, together with the efficacy of clinical examination, self-examination and mammography in the detection of CR. METHODS: Data from patients treated for early breast cancer at Guy's Hospital between 1990 and 1997 were collected and those with isolated contralateral recurrences were analysed. Life table analysis was performed and CR, CR-free and cumulative CR rates were calculated. Correlations were evaluated using Pearson's correlation coefficient. RESULTS: One thousand one hundred and forty-three women were included in the study and 23 patients had isolated CR. The median probability of CR was a constant 0.24% per year. Only one recurrence was found clinically at follow up, while the majority was detected through mammography and self-palpation. CONCLUSIONS: The risk of CR is low and constant with time. Contralateral mammography is useful and can detect the vast majority of contralateral recurrences. These findings may have practical implications especially on the planning of postmastectomy follow up. PMID- 24165426 TI - Doublets versus single-agent therapy as first-line therapy for elderly patients with advanced non-small cell lung cancer? A systematic review of randomised controlled trials. AB - INTRODUCTION: Although the standard treatment for advanced non-small cell lung cancer (NSCLC) patients is platinum-based doublet chemotherapy, single-agent therapy is still preferred in elderly patients. Comparison of the efficacy of various combinations of doublets with single-agent chemotherapy is somehow contradictory. This study conducted a systematic review to evaluate the efficacy and tolerability of the third-generation agent-based doublets vs. single-agent chemotherapy in elderly NSCLC patients. METHODS: Electronic (PubMed, EMBASE and Cochrane Library database) and manual searches were conducted to collect data from published, randomised, phase 2 and 3 trials which compared doublets with a third-generation single-agent chemotherapy in elderly patients. Pooled relative risks (RRs) were calculated for the incidences of overall response rate (ORR), 1 year survival rate (1-y SR), and grade 3/4 toxicities. RESULTS: Seven eligible trials (2219 patients) were selected from 1170 studies that were initially identified. A significant difference in ORR favouring doublets over single agents was observed [RR, 1.59; 95% confidence interval (95% CI), 1.36-1.86; p < 0.0001] with a slightly, but not significantly improved 1-y SR (RR, 1.19; 95% CI, 0.98 1.45, p = 0.007). Subgroup analysis suggested that platinum (RR, 1.94; 95% CI, 1.47-2.55, p < 0.0001) or non-platinum- (RR, 1.45; 95% CI, 1.20-1.75, p < 0.0001) based doublets could improve ORR, and the grade 3/4 thrombocytopaenia (RR, 6.64; 95% CI, 1.78-24.86, p = 0.005) and anaemia (RR, 2.86; 95% CI, 1.62-5.05, p < 0.0001) were preferred to occur in platinum-based doublets. CONCLUSIONS: Doublets appear to be more effective and tolerable than single-agent therapy for treating elderly advanced NSCLC patients, and therefore could be considered as a treatment option for elderly populations with good physical status. PMID- 24165427 TI - Does concomitant diabetes affect treatment responses in overactive bladder patients? AB - AIMS: To compare the efficacy and tolerability of a muscarinic receptor antagonist, darifenacin, in the treatment of overactive bladder (OAB) patients with concomitant diabetes as compared with those without comorbidities. METHODS: Post hoc exploratory analysis of a published, large, non-interventional study in OAB patients treated with darifenacin including 532 diabetics and 1315 controls. Associations of diabetes with treatment responses were evaluated by multiple regression models. RESULTS: Diabetics (largely type 2 patients) and controls differed in baseline age, body weight, duration of OAB symptoms and presence of co-medications. However, they exhibited similar OAB symptom episode frequency and problem rating and received similar starting doses of darifenacin. Presence of diabetes was associated with a significantly smaller reduction of OAB symptoms, but the effect attributable to diabetes was small relative to the overall treatment response. The presence of diabetes was not associated with differences in tolerability. DISCUSSION AND CONCLUSIONS: We conclude that a muscarinic receptor antagonist has comparable efficacy and tolerability in the treatment of OAB patients with and without concomitant diabetes. PMID- 24165428 TI - Barriers to the delivery of diabetes care in the Middle East and South Africa: a survey of 1,082 practising physicians in five countries. AB - AIMS: Developing countries face a high and growing burden of type 2 diabetes. We surveyed physicians in a diverse range of countries in the Middle East and Africa (Egypt, Kingdom of Saudi Arabia, United Arab Emirates, South Africa and Lebanon) with regard to their perceptions of barriers to type 2 diabetes care identified as potentially important in the literature and by the authors. METHODS: One thousand and eighty-two physicians completed a questionnaire developed by the authors. RESULTS: Most physicians enrolled in the study employed guideline-driven care; 80-100% of physicians prescribed metformin (with lifestyle intervention, where there are no contraindications) for newly diagnosed type 2 diabetes, with lifestyle intervention alone used where metformin was not prescribed. Sulfonylureas were prescribed widely, consistent with the poor economic status of many patients. About one quarter of physicians were not undertaking any form of continuing medical education, and relatively low proportions of practices had their own diabetes educators, dieticians or diabetic foot specialists. Physicians identified the deficiencies of their patients (unhealthy lifestyles, lack of education and poor diet) as the most important barriers to optimal diabetes care. Low-treatment compliance was not ranked highly. Access to physicians did not appear to be a problem, as most patients were seen multiple times per year. CONCLUSIONS: Physicians in the Middle East and South Africa identified limitations relating to their patients as the main barrier to delivering care for diabetes, without giving high priority to issues relating to processes of care delivery. Further study would be needed to ascertain whether these findings reflect an unduly physician-centred view of their practice. More effective provision of services relating to the prevention of complications and improved lifestyles may be needed. PMID- 24165429 TI - The effect of pioglitazone and extended-release niacin on HDL-cholesterol in diabetes patients in a real-world setting. AB - OBJECTIVE: This retrospective study was designed to assess the effects of the combination of pioglitazone and extended-release niacin on the lipid panel, particularly HDL-cholesterol, when used in patients with type 2 diabetes in an endocrinology specialty practice. METHODS: The electronic medical records of 434 adult patients with type 2 diabetes receiving extended-release niacin and pioglitazone were screened for review. Patients with type 2 diabetes and hyperlipidemia were included for review if they received the combination of pioglitazone at doses >= 15 mg/day and extended-release niacin (Niaspan) at doses >= 1000 mg/day for >=6 months. Statistical analysis used paired t-tests with p < 0.05 as statistically significant. Both ANOVA and the Tukey-Kramer test for multiple comparisons (alpha = 0.05) were also used. RESULTS: A total of 47 patients, 83% were men with average age of 58, met all eligibility criteria for the study. Compared with baseline, a statistically significant increase in HDL-C (+ 25.13%, p < 0.0001) was observed at the conclusion of combination therapy. The HDL-C levels progressively increased with duration of combination treatment, and were not correlated with concomitant statin use. Significant decreases in total cholesterol and triglycerides were detected, and HbA1c decreased 0.84% during combination therapy for all therapies combined. CONCLUSION: The combination of pioglitazone and extended-release niacin in patients with type 2 diabetes and hyperlipidemia, used in commonly prescribed doses for at least 6 months, resulted in statistically significant improvements in HDL-C, total cholesterol, and triglycerides, and did not result in deteriorations in glycemic control. PMID- 24165430 TI - Illicit drug use and cardiometabolic disease risk: an analysis of 2005-2008 National Health and Nutrition Examination Survey data. AB - PURPOSE: To explore the association between illicit drug use (IDU) and cardiometabolic disease risk factors (CDRF) in a nationally representative sample of adults. METHODS: The 2005-2008 National Health and Nutrition Examination Surveys data from 20- to 45-year-old adults (n = 8738) were utilised to analyze the relationship between IDU (ever used, repeated use and current use) and CDRF (hyperlipidemia, hyperinsulinemia, hypertension, elevated C-reactive protein, body mass index, waist circumference and cigarette use) via chi square and logistic regression analyses. Age, gender, race/ethnicity, education level, poverty to income ratio (PIR), and alcohol use were included as confounders in the models. RESULTS: Individuals who reported drug use (DU) at least once in lifetime were more likely to have CDRF than non-DU (NDU) (OR = 1.3, p = 0.004). Females with DU, IDU at least once in lifetime, and with repeated IDU were about 1.5 times more likely than their NDU counterparts to have CDRF (p < 0.0001, p = 0.02, p = 0.02, respectively). CONCLUSION: Results from this study suggest that healthcare professionals should be aware that patients with a history of DU may be at heightened risk for cardiometabolic disease. Females in particular have a heightened cluster of CDRF across drug-use categories. PMID- 24165431 TI - A comparison of risk factors as predictors of cardiovascular and non cardiovascular mortality in the elderly people--relevance of N-terminal pro-B type natriuretic peptide and low systolic blood pressure. AB - BACKGROUND: Many risk factors are known to predict ischaemic events and mortality in the elderly people, but their ranking of importance remains uncertain. This study was designed to identify and compare the main predictors of total mortality (TM), cardiovascular mortality (CVM) and non-cardiovascular mortality (NCVM) in older adults. METHODS: Nine hundred and seventy-nine community resident adults aged >= 65 years, free of previous heart failure and cardiovascular events, participated in the study. The univariate and multivariate (Cox regression) relationships of baseline cardiovascular risk factors, treatments and laboratory data with TM, CVM and NCVM were assessed after a median follow up of 6.7 years. RESULTS: Overall, there were 104 deaths (30 because of CVM and 74 to NCVM). In multivariate analysis, the following factors remained independently associated with mortality: NT pro-B-type natriuretic peptide (NT-proBNP) upper quintile (>= 237 pg/ml for men, >= 280 pg/ml for women): hazard ratio (HR) vs. the rest of the population (95% confidence interval) 2.34 (1.52-3.60), p < 0.001 for TM; HR 5.41 (2.32-12.65), p < 0.001 for CVM; systolic blood pressure lower quintile (<= 130 mmHg): HR 3.06 (1.80-5.21), p < 0.001 for NCVM; diabetes: HR 2.46 (1.29-4.72), p = 0.007 for NCVM; erythrocyte sedimentation rate (ESR) upper decile (>= 41 mm/h): HR 2.33 (1.16-4.69), p = 0.02 for NCVM; platelet count lower quintile (<= 177 * 10(9) /l): HR 2.09 (1.20-3.64), p = 0.009 for NCVM; ever-smoker status: HR 2.08 (1.23-3.52), p = 0.007 for NCVM. CONCLUSIONS: In elderly community dwellers, NT proBNP was the strongest predictor of TM and CVM, while especially low systolic blood pressure, together with diabetes, ESR, reduced platelet count and ever smoker status, were the main predictors of NCVM. PMID- 24165432 TI - Safety and efficacy of exercise training in elderly heart failure patients: a systematic review and meta-analysis. AB - OBJECTIVES: It is unclear whether exercise training is effective and safe for elderly patients with chronic heart failure (CHF). The purpose of this meta analysis was to systematically analyse the completed trials assessing the safety and efficacy of exercise training in elderly patients with heart failure. METHODS: We searched electronic databases up to September 2012 for randomised controlled trials (RCTs) evaluating exercise training in the elderly heart failure patients (>= 60 years). The safety and efficacy of exercise training were assessed by all-cause mortality, hospitalisations, 6-min walking distance (6MWD), peakVO2 and/or health-related quality of life (HRQoL). RESULTS: Seven prospective RCTs were included with a total of 530 patients, and the patients' mean age ranged from 70 to 81 years. The majority were male, low-to-medium risk and New York Heart Association class II and III with a left ventricular ejection fraction of < 45%. Exercise training increased the 6MWD significantly by 50.05 m (95% CI: 28.37-71.73) and improved generic HRQoL (95% CI: 0.06-0.18). There was no significant difference in mortality, hospitalisations, peakVO2 and disease specific HRQoL between exercise group and control group. CONCLUSIONS: In elderly CHF patients (mean age 70-81), exercise training increase 6MWD and improve generic HRQoL, but has no effects on mortality, hospitalisations, peakVO2 and disease-specific HRQoL. The long-term efficacy and safety of exercise training in elderly heart failure patients require further study based on large and rational designed controlled clinical trials. PMID- 24165433 TI - Considering the affordability of ticagrelor when used according to NICE guidance. PMID- 24165434 TI - Age- and gender-associated differences in electrical impedance values of skeletal muscle. AB - Electrical impedance measurements of skeletal muscle may be sensitive to age associated declines in muscle health. In an effort to evaluate this concept further, we performed electrical impedance myography (EIM) using a handheld array on 38 individuals aged 19-50 years and 41 individuals aged 60-85 years. Individuals either had seven upper extremity or seven lower extremity muscles measured. The 50 kHz reactance, resistance and phase were used as the major outcome variables. Although the phase values were similar in both groups, both reactance and resistance values were lower in the lower extremities of the older individuals as compared to the younger (-23 +/- 6%, p = 0.001 for reactance and 27 +/- 7%, p = 0.005 for resistance), whereas changes in upper extremity values were not significantly different (-9 +/- 5%, p = 0.096 for reactance and +5 +/- 9%, p = 0.55 for resistance). When analyzing the genders separately, it became clear that this reduction in lower extremity values was most pronounced in men and less consistently present in women. These findings suggest that age- and gender-associated differences in muscle condition are detectable using EIM. The relationship of these easily obtained parameters to standard functional, imaging, and pathological markers of sarcopenia deserves further study. PMID- 24165435 TI - Moving beyond methods: the need for a diverse programme in climate change research. AB - Understanding effects of climate change on ecosystems will require a diverse range of approaches. We proposed using downscaled climate models to generate realistic weather scenarios as experimental treatments. Kreyling et al. propose a gradient approach to determine the shape of response functions. These approaches are different, but highly complementary. PMID- 24165436 TI - Automatic and deliberate affective associations with sexual stimuli in women with lifelong vaginismus before and after therapist-aided exposure treatment. AB - INTRODUCTION: The intense fear response to vaginal penetration in women with lifelong vaginismus, who have never been able to experience coitus, may reflect negative automatic and deliberate appraisals of vaginal penetration stimuli which might be modified by exposure treatment. AIMS: The aim of this study is to examine whether (i) sexual stimuli elicit relatively strong automatic and deliberate threat associations in women with vaginismus, as well as relatively negative automatic and deliberate global affective associations, compared with symptom-free women; and (ii) these automatic and more deliberate attitudes can be modified by therapist-aided exposure treatment. METHODS: A single target Implicit Association Test (st-IAT) was used to index automatic threat associations, and an Affective Simon Task (AST) to index global automatic affective associations. Participants were women with lifelong vaginismus (N = 68) and women without sexual problems (N = 70). The vaginismus group was randomly allocated to treatment (n = 34) and a waiting list control condition (n = 34). MAIN OUTCOME MEASURES: Indices of automatic threat were obtained by the st-IAT and automatic global affective associations by the AST, visual analogue scales (VAS) were used to assess deliberate appraisals of the sexual pictures (fear and global positive affect). RESULTS: More deliberate fear and less global positive affective associations with sexual stimuli were found in women with vaginismus. Following therapist-aided exposure treatment, the strength of fear was strongly reduced, whereas global positive affective associations were strengthened. Automatic associations did not differ between women with and without vaginismus and did not change following treatment. CONCLUSIONS: Relatively stronger negative (threat or global affect) associations with sexual stimuli in vaginismus appeared restricted to the deliberate level. Therapist-aided exposure treatment was effective in reducing subjective fear of sexual penetration stimuli and led to more global positive affective associations with sexual stimuli. The impact of exposure might be further improved by strengthening the association between vaginal penetration and positive affect (e.g., by using counter-conditioning techniques). PMID- 24165437 TI - Transplant tolerance by Treg therapy. PMID- 24165438 TI - Growth reaction norms of domesticated, wild and hybrid Atlantic salmon families in response to differing social and physical environments. AB - BACKGROUND: Directional selection for growth has resulted in the 9-10th generation of domesticated Atlantic salmon Salmo salar L. outgrowing wild salmon by a ratio of approximately 3:1 when reared under standard hatchery conditions. In the wild however, growth of domesticated and wild salmon is more similar, and seems to differ at the most by a ratio of 1.25:1. Comparative studies of quantitative traits in farmed and wild salmon are often performed by the use of common-garden experiments where salmon of all origins are reared together to avoid origin-specific environmental differences. As social interaction may influence growth, the large observed difference in growth between wild and domesticated salmon in the hatchery may not be entirely genetically based, but inflated by inter-strain competition. This study had two primary aims: (i) investigate the effect of social interaction and inter-strain competition in common-garden experiments, by comparing the relative growth of farmed, hybrid and wild salmon when reared together and separately; (ii) investigate the competitive balance between wild and farmed salmon by comparing their norm of reaction for survival and growth along an environmental gradient ranging from standard hatchery conditions to a semi-natural environment with restricted feed. RESULTS: The main results of this study, which are based upon the analysis of more than 6000 juvenile salmon, can be summarised as; (i) there was no difference in relative growth between wild and farmed salmon when reared together and separately; (ii) the relative difference in body weight at termination between wild and farmed salmon decreased as mortality increased along the environmental gradient approaching natural conditions. CONCLUSIONS: This study demonstrates that potential social interactions between wild and farmed salmon when reared communally are not likely to cause an overestimation of the genetic growth differences between them. Therefore, common-garden experiments represent a valid methodological approach to investigate genetic differences between wild and farmed salmon. As growth of surviving salmon of all origins became more similar as mortality increased along the environmental gradient approaching natural conditions, a hypothesis is presented suggesting that size-selective mortality is a possible factor reducing growth differences between these groups in the wild. PMID- 24165439 TI - The hows and whys of constructing a native recombinant cholera vaccine. AB - Emergence of different ctxB genotypes within virulent Vibrio cholerae populations accentuates the need to develop a vaccine that has the potential to protect against all cholera toxin genotypes. Oral administration of rCTB-alone and in combination with 2 dominant domestic killed whole cells of V. cholerae (O1 Ogawa El Tor and O1 Inaba El Tor) plus one standard V. cholerae (O1 Ogawa classic ATCC 14035)-has shown satisfactory protection as a potent vaccine candidate against toxigenic V. cholerae. PMID- 24165442 TI - Diagnosis and treatment of overactive bladder. PMID- 24165443 TI - Comparison of motor and sensory response of InterStim(r) for overactive bladder syndrome. AB - AIMS: To determine the correlation of InterStim amplitudes required to evoke motor and sensory responses in subjects with overactive bladder (OAB) and to determine if subjects reprogrammed to achieve motor response have improvement in voiding diary parameters. METHODS: Descriptive pilot study of patients with an existing sacral nerve stimulation (SNS) device for OAB. Subjects completed voiding diaries and reported subjective improvement at current settings. Subject's implantable pulse generator was interrogated while surface electromyography (EMG) was performed using a rectal sponge electrode. Electromyography was evaluated for baseline motor response demonstrated by compound muscle action potential (cMAP) at current settings. Stimulation amplitude was reduced to zero then incrementally increased. Amplitudes evoking subject sensation and motor response were recorded and used for correlation calculation. Subjects without baseline motor response were reprogrammed to achieve cMAP, and voiding diaries were completed after reprogramming. RESULTS: Thirty-one subjects were recruited. Twelve (39%) had motor response (cMAP) at baseline settings. Subjects with motor response were significantly more likely to report sensation of stimulation versus those without (55% vs 17%; P = 0.04). Amplitudes evoking motor response were found to be significantly correlated to those for sensory response (r = 0.90; P < 0.0005). Sixteen of 19 subjects without baseline motor response were successfully reprogrammed to achieve cMAP. Improvements in nocturia, incontinence, and urgency incontinence episodes (14.4%, 19.8%, 18.2%; nonsignificant) were seen in the reprogrammed group. CONCLUSION: Sacral nerve stimulation motor and sensory amplitudes were highly correlated in our cohort, and subjects with motor response were significantly more likely to feel sensation of stimulation. This supports the theory that both motor efferent and sensory afferent portions of the sacral nerve may contribute to SNS mechanism. PMID- 24165440 TI - Cross-sectional prevalence survey of intimate partner violence perpetration and victimization in Canadian military personnel. AB - BACKGROUND: Intimate partner violence (IPV) is prevalent and is associated with a broad range of adverse consequences. In military organizations, IPV may have special implications, such as the potential of service-related mental disorders to trigger IPV. However, the Canadian Armed Forces (CAF) have limited data to guide their prevention and control efforts. METHODS: Self-reported IPV perpetration, victimization, and their correlates were assessed on a cross sectional survey of a stratified random sample of currently-serving Canadian Regular Forces personnel (N = 2157). The four primary outcomes were perpetration or victimization of any physical and/or sexual or emotional and/or financial IPV over the lifespan of the current relationship. RESULTS: Among the 81% of the population in a current relationship, perpetration of any physical and/or sexual IPV was reported in 9%; victimization was reported in 15%. Any emotional and/or financial abuse was reported by 19% (perpetration) and 22% (victimization). Less physically injurious forms of abuse predominated. Logistic regression modelling showed that relationship dissatisfaction was independently associated with all four outcomes (OR range = 2.3 to 3.7). Probable depression was associated with all outcomes except physical and/or sexual IPV victimization (OR range = 2.5 - 2.7). PTSD symptoms were only associated with physical and/or sexual IPV perpetration (OR = 3.2, CI = 1.4 to 7.9). High-risk drinking was associated with emotional and/or financial abuse. Risk of IPV was lowest in those who had recent deployment experience; remote deployment experience (vs. never having deployed) was an independent risk factor for all IPV outcomes (OR range = 2.0 - 3.4). CONCLUSIONS: IPV affects an important minority of military families; less severe cases predominate. Mental disorders, high-risk drinking, relationship dissatisfaction, and remote deployment were independently associated with abuse outcomes. The primary limitations of this analysis are its use of self-report data from military personnel (not their intimate partners) and the cross sectional nature of the survey. Prevention efforts in the CAF need to target the full spectrum of IPV. Mental disorders, high-risk drinking, and relationship dissatisfaction are potential targets for risk reduction. Additional research is needed to understand the association of remote deployment with IPV. PMID- 24165444 TI - Cost-effectiveness of test phase implantation strategies for InterStim(r) sacral neuromodulation. AB - OBJECTIVE: Sacral neuromodulation with InterStim can be performed with staged implants or peripheral nerve evaluation followed by a combined stage I/II procedure. In both, unilateral or bilateral leads can be placed for the testing phase. Our objective was to determine the cost-effectiveness of these strategies in patients with refractory overactive bladder. METHODS: A cost-effectiveness model compared 6 strategies, namely, unilateral and bilateral testing for both stage I and peripheral nerve evaluation, combined stage I/II, and no treatment. Costs were derived from a societal perspective using Medicare physician fee schedules and published studies. Quality-adjusted life-years (QALYs) were assigned using utility values. Results were reported using incremental cost effectiveness ratios. Model robustness was assessed using probabilistic sensitivity analysis. Monte Carlo analysis sampled statistical distributions for each variable to examine the effects of varying all values simultaneously. RESULTS: No InterStim treatment was the least expensive but also the least effective option. Unilateral and bilateral stage I were the only cost-effective options with incremental cost-effectiveness ratios of $3533 and $7600, respectively. Because bilateral stage I was more effective, it is preferred. Probabilistic sensitivity analysis showed bilateral stage I was most likely to be cost-effective at willingness-to-pay thresholds greater than $6000 per QALY. At lower thresholds, no treatment was more economically acceptable. CONCLUSIONS: Bilateral and unilateral stage I lead placement were the only cost-effective strategies. Bilateral stage I was preferred due to greater effectiveness. In probabilistic sensitivity analysis, bilateral stage I was the most likely cost effective strategy at all willingness-to-pay thresholds greater than $6000 per QALY confirming model robustness. PMID- 24165445 TI - Subsequent pregnancy outcomes after obstetric anal sphincter injuries (OASIS). AB - OBJECTIVES: To describe obstetric outcomes in women with a prior obstetric anal sphincter injury (OASIS) and to identify risk factors for recurrence. METHODS: A retrospective chart review of women who sustained an OASIS between November 2005 and March 2010 at a tertiary care hospital was performed to identify risk factors for recurrence. RESULTS: One thousand six hundred twenty-nine patients had an OASIS. Of these, 758 patients (90%) subsequently delivered during the aforementioned timeframe; 685 patients had a subsequent vaginal delivery. Of the women, 3.2% had a recurrent OASIS. Recurrence was associated with larger birth weight (27% >=4000 g vs 11.6% <4000 g; P = 0.04) and delivery mode (25.0%, 12.5%, and 2.7% for forceps-assisted, vacuum-assisted, and spontaneous deliveries, respectively (P = 0.0001)), whereas a history of fourth-degree laceration, prior wound complication, or episiotomy at subsequent delivery were not (P = 0.5, P = 0.5, and P = 0.4, respectively). CONCLUSIONS: Recurrent OASIS occurred in a small percentage of women (3.2%) who subsequently delivered vaginally. Recurrent OASIS was associated with operative vaginal delivery and birth weight 4000 g or greater. Neither episiotomy at first delivery nor at subsequent delivery conferred an increased recurrence risk. PMID- 24165446 TI - Pelvic mesh complications in women before and after the 2011 FDA public health notification. AB - OBJECTIVES: On July 13, 2011, the US Food and Drug Administration (FDA) released a public health notification with concerns regarding vaginal mesh for the treatment of pelvic organ prolapse. Our study compares the frequency and type of mesh complications related to female pelvic floor disorders presenting to our center before and after this notification. METHODS: We performed a retrospective cohort study comparing the percentage of women found to have mesh complications related to pelvic floor disorders for the year preceding and the 6 months following the FDA notification. The 2011 International Urogynecological Association/International Continence Society (IUGA/ICS) guidelines were used to classify mesh complications. RESULTS: We identified 109 women in the 12 months before and 98 women in the 6 months after the FDA notification who presented for new consultation with a history of pelvic mesh placement. Of the women with prior mesh, a higher percentage had a mesh complaint after the FDA notification (31.2% before vs 45.9% after notification; P = 0.029). There was no difference in the frequency of diagnosed mesh complications (38.5% before vs 43.9% after notification; P = 0.435) or the types of complications seen as classified by the IUGA/ICS guidelines. The rate of complications among women with a prior sacral colpopexy (35%) or midurethral sling (30%) was higher than expected for both time periods. CONCLUSIONS: Whereas the number of patient-perceived mesh complications increased after the FDA notification, neither the frequency, type, or location of complications changed. The complications were not limited to transvaginal mesh, and an unexpectedly high proportion of the complications were related to sacral colpopexy and midurethral sling procedures. PMID- 24165447 TI - Clinical characteristics associated with unsuccessful pessary fitting outcomes. AB - OBJECTIVES: To identify clinical characteristics and quality of life/symptom questionnaire scores associated with unsuccessful vaginal pessary trials in the treatment of pelvic organ prolapse (POP). METHODS: This was a retrospective study of pessary fittings between 2006 and 2012 at our tertiary care urogynecology unit. One hundred one patients with symptomatic POP filled out detailed history and validated pelvic floor quality-of-life and symptom questionnaires at baseline. They were examined and POP was staged. After discussion of treatment options, they agreed to attempt a trial of pessary (TOP). Unsuccessful TOP was defined as an inability to continue pessary use beyond 4 weeks from initial fitting. Stepwise logistic regression analysis was performed to build a prediction model for the odds of unsuccessful TOP. RESULTS: The main reason for unsuccessful TOP was patient discomfort. Multivariate stepwise logistic regression showed that age 65 or younger (odds ratio [OR], 3.13; P = 0.042), smoking history (OR, 3.42; P = 0.049), genital hiatus/total vaginal length ratio greater than 0.8 (OR, 6.70; P = 0.042), and lower POP Quantification overall stage (OR, 2.84; P = 0.017) were associated with increased likelihood of unsuccessful TOP. Other variables such as sexual activity and concurrent urinary or POP symptoms did not affect the outcome. CONCLUSIONS: Several clinical characteristics influenced the likelihood of unsuccessful TOP. These may be taken into account for clinical counseling. Pessaries remain a good treatment option, as many clinical variables did not seem to influence the success of fittings. PMID- 24165448 TI - Development and validation of a ureteral anastomosis simulation model for surgical training. AB - OBJECTIVE: To develop and validate a new ureteral anastomosis simulation model. METHODS: We designed a training model to simulate the task of ureteral anastomosis required for ureteroneocystostomy that is suitable for robotic and laparoscopic approaches. Face validity was measured using questions related to surgical authenticity and educational value of the model. Construct validity was measured by comparing scores using Global Operative Assessment of Laparoscopic Skills Scale (GOALS) scale between "procedure experts," "robotic experts," and "trainees" groups. One-way analysis of variance was used to compare differences in the scores and operating times between the 3 groups. Associations between previous surgical experience and performance scores were measured using the Spearman rho correlation coefficient. RESULTS: Four urologists experienced with robotically assisted ureteroneocystostomies were included in the procedure experts group. The robotic experts group consisted of 5 gynecologists experienced in robotic surgery. The trainees group consisted of 12 urology and gynecology upper-level residents and fellows. All experts agreed or strongly agreed that the model was authentic to the live procedure and a useful training tool. Mean (SD) total GOALS scores were significantly better for the procedure experts group compared to the robotic experts group and to the trainees group (P=0.02 vs P=0.004, respectively). The robotic experts group's GOALS scores were also significantly higher than that of the trainees group (P=0.05). There were no differences in mean times required to complete the procedure. Surgical experience moderately correlated with scores on all 3 assessment scales. CONCLUSIONS: Superior performance on the model by more experienced surgeons demonstrates evidence of construct validity. This authentic and useful model allows surgeons to learn and practice the ureteral anastomosis portion of the ureteral reimplantation surgeries before operating on a live patient. PMID- 24165449 TI - Long-term symptom improvement and overall satisfaction after prolapse and incontinence graft removal. AB - OBJECTIVES: We report long-term symptom improvements and overall satisfaction in patients after removal of grafts used in pelvic reconstruction in a tertiary referral center. METHODS: We analyzed patients who underwent graft removal for treatment of related complications and who were followed for at least 2 years. Symptoms were determined by patient self-assessment questionnaires. RESULTS: Seventy-nine patients underwent partial or complete graft removal from 2005 to 2011 and met inclusion criteria. The mean follow-up time was 4.0 years (median, 3.4 years; range, 2.0-7.6 years). Forty-seven percent (37 patients) had implants for both prolapse and incontinence, 40% (32 patients) had incontinence implants only, and 13% (10 patients) had prolapse implants only. Thirty percent of those with both implants presented with multiple symptoms compared to 50% of those with prolapse implants and 44% of those with incontinence implants only. At follow-up, 75% (56 patients) reported that their symptoms were better and 15% (11 patients) reported that their symptoms were worse. Of patients who underwent graft removal for pain alone, 74% (17 patients) improved whereas17% (4 patients) were worse. When asked about spending the rest of their lives with their current symptoms, 49% (38 patients) reported positively whereas 44% (34 patients) reported negatively. Forty-one patients underwent one or more additional treatments. CONCLUSIONS: Graft-related complications are often treated with surgical excision. In a cohort of 79 patients in whom implants were removed an average of 4 years earlier, 75% still report symptom improvement and 49% report good quality of life. However, many patients still feel dissatisfied and sought additional treatment during long-term follow-up. These data can be used to counsel patients considering removal of pelvic reconstruction grafts. PMID- 24165450 TI - Stem cell homing factor, CCL7, expression in mouse models of stress urinary incontinence. AB - OBJECTIVES: Animal models of vaginal distention (VD) have demonstrated increased expression of chemokine (C-C motif) ligand 7 (CCL7) In this study, we investigated the expression of CCL7 in mice models of simulated birth trauma induced urinary incontinence using VD and pudendal nerve transection (PNT). METHODS: Forty-nine mice were divided into 6 groups: VD, sham VD, PNT, sham PNT, anesthesia, and age-matched controls. The urethra, vagina, and rectum were harvested for the expression of CCL7 immediately or 24 hours after assigned procedure. Venous sampling for quantification of serum CCL7 was also performed. An analysis of variance model was used to compare the relative expression of CCL7 in each group. RESULTS: Urethral CCL7 expression in the VD group was significantly higher than control group after 24 hours (P < 0.01). There was no difference in the urethral CCL7 expression in PNT, sham PNT, sham VD, or anesthesia groups compared with the controls. No statistically significant difference was noted in the vaginal and rectal expression of CCL7 between any of the groups except for sham PNT. Statistically significant differences were noted in the serum CCL7 expression in the VD, PNT, and sham PNT (P < 0.01 in all) groups after 24 hours compared with the control group. CONCLUSIONS: This study demonstrates overexpression of urethral CCL7 after VD but not PNT. This suggests that nerve injury does not contribute to the CCL7 overexpression. The overexpression of CCL7 in the serum of mice after VD suggests a translational potential where CCL7 measurement could be used as a surrogate for injury after delivery. PMID- 24165452 TI - Intraoperative Crede maneuver for tape adjustment during transobturator sling placement: does it improve continence? AB - OBJECTIVE: This study evaluated the efficacy of intraoperative extrinsic manual compression on the bladder, or Crede maneuver (CM) for tape adjustment during transobturator tape (TOT) sling procedure versus the traditional method where tension-free tape is adjusted the same for all patients. METHODS: All patients undergoing TOT sling procedure for stress urinary incontinence (SUI) between May 2008 and June 2011 by the first author were assessed. Tape adjustment was either performed in a traditional manner, leaving a tonsil clamp-size space between the sling and posterior urethra, or by using CM after filling the bladder to 300 ml capacity. Patients were considered cured at postoperative visits if they had no SUI symptoms and negative Cough Stress Test (CST) result, improved if they had some SUI symptoms and negative CST result, and failed if symptomatic and had positive CST result. The Fisher exact test and the Wilcoxon rank sum test were used to evaluate the baseline differences between the 2 groups, along with multiple logistic regression to evaluate independent predictors of cure. RESULTS: The continence rate was 77.67% in the traditional group (87/112) and 79.65% (137/172) in the CM group (P = 0.76). Older patients and smokers were less likely to be continent (odds ratio, 0.95; P = 0.015; and odds ratio, 0.22; P = 0.003, respectively). Five (4.5%) of the 112 patients in the traditional group and 12 (6.9%) of the 172 patients in the CM group had adverse outcomes including transient urinary retention, mesh erosion, or dysuria (P = 0.45). CONCLUSION: Using CM for intraoperative tape adjustment does not improve continence rates compared to the traditional method of TOT sling placement. PMID- 24165451 TI - Safety assessment of myogenic stem cell transplantation and resulting tumor formation. AB - OBJECTIVES: To assess for stem cell migration to liver and lung after transplantation in injured rat anal sphincters. To evaluate histological findings of unanticipated ectopic foci of growth. METHODS: This is a prospective study involving 33 female virginal Sprague-Dawley rats. Anal sphincters were transected and repaired under sterile technique. Animals received injections of 5.0 * 10 myogenic stem cells (24 rats) or sham control (9 rats) and were killed on day 30. Liver and lung samples were obtained. Upon encountering abnormal foci of growth, further staining protocols were employed. Enzyme-linked immunosorbent assay studies evaluated stem cell media for in vitro growth factor secretion. RESULTS: No evidence of cell migration to liver or lung was found at the time of euthanasia in any study animal. Ectopic foci of growth were noted in 2 transplant rats. Further histological evaluations of these growths were consistent with benign tumors: no nuclear abnormalities and no evidence of proliferation at day 30. Enzyme-linked immunosorbent assay studies demonstrated positive secretion of vascular endothelial growth factor and insulin growth factor into the media of cultured rat myogenic stem cells. CONCLUSIONS: Whereas distant migration was not encountered in the liver or lung, 2 transplanted rats developed abnormal foci of growth, that is, tumors, from the external anal sphincter-raising further safety questions. Additional evaluation of these foci seemed benign. Possible explanations include cell trapping, stem cell overgrowth, and/or paracrine factors. The lack of cell migration supports that future investigation of safety parameters could focus locally. PMID- 24165453 TI - On the catalytic mechanism and stereospecificity of Escherichia coli L-threonine aldolase. AB - L-threonine aldolases (L-TAs) represent a family of homologous pyridoxal 5' phosphate-dependent enzymes found in bacteria and fungi, and catalyse the reversible cleavage of several L-3-hydroxy-alpha-amino acids. L-TAs have great biotechnological potential, as they catalyse the formation of carbon-carbon bonds, and therefore may be exploited for the bioorganic synthesis of L-3 hydroxyamino acids that are biologically active or constitute building blocks for pharmaceutical molecules. Many L-TAs, showing different stereospecificity towards the Cbeta configuration, have been isolated. Because of their potential to carry out diastereoselective syntheses, L-TAs have been subjected to structural, functional and mechanistic studies. Nevertheless, their catalytic mechanism and the structural bases of their stereospecificity have not been elucidated. In this study, we have determined the crystal structure of low-specificity L-TA from Escherichia coli at 2.2-A resolution, in the unliganded form and cocrystallized with L-serine and L-threonine. Furthermore, several active site mutants have been functionally characterized in order to elucidate the reaction mechanism and the molecular bases of stereospecificity. No active site catalytic residue was revealed, and a structural water molecule was assumed to act as the catalytic base in the retro-aldol cleavage reaction. Interestingly, the very large active site opening of E. coli L-TA suggests that much larger molecules than L-threonine isomers may be easily accommodated, and L-TAs may actually have diverse physiological functions in different organisms. Substrate recognition and reaction specificity seem to be guided by the overall microenvironment that surrounds the substrate at the enzyme active site, rather than by one ore more specific residues. PMID- 24165456 TI - Unmet needs in outcome measures of Psoriatic Arthritis: focus on axial radiographic and nail involvement. AB - OBJECTIVES: This article reviews some unmet needs on the outcome measures in Psoriatic Arthritis (PsA). In particular, the radiological assessment of axial PsA and the assessment of nail involvement still remain problematic and this, in turn, could affect the best management. At present, the radiological assessment of spine has been evaluated by using scoring systems borrowed from Ankylosing Spondylitis (AS). In particular, the Bath Ankylosing Spondylitis Radiology Index (BASRI) and the modified Stoke Ankylosing Spondylitis Spine Score (m-SASSS) have been validated for the axial PsA and a new index for assessing the radiological axial involvement in PsA was also developed, called Psoriatic Arthritis Spondylitis Radiology Index (PASRI). Nail involvement has been evaluated by two different instruments: the Nail Psoriasis Severity Index (NAPSI) and its modified version (mNAPSI). Both are good instruments but only a few data are available on these instruments when adopted at a daily clinical practice level. PMID- 24165457 TI - Controlled outcome studies of child clinical hypnosis. AB - Background Hypnosis is defined as "as an interaction in which the hypnotist uses suggested scenarios ("suggestions") to encourage a person's focus of attention to shift towards inner experiences". Aim of the work The focus of this review is to summarize the findings of controlled outcome studies investigating the potential of clinical hypnosis in pediatric populations. We will examine the following themes: anesthesia, acute and chronic pain, chemotherapy-related distress, along with other specific medical issues. Results Hypnosis is an effective method to reduce pain and anxiety before, during and after the administration of anesthetics, during local dental treatments, invasive medical procedures and in burn children. Hypnosis can be successfully used to manage recurrent headaches, abdominal pain, irritable bowel syndrome and chemotherapy-related distress. Hypnosis has an important role in managing symptoms and improving the quality of life of children suffering from asthma and cystic fibrosis and in facilitating the treatment of insomnia in school-age children. Finally, hypnosis can be effectively used for the treatment of some habitual disorders such as nocturnal enuresis and dermatologic conditions, including atopic dermatitis and chronic eczema Conclusions Clinical hypnosis seems to be a useful, cheap and side-effects free tool to manage fear, pain and several kinds of stressful experiences in pediatric populations. Children who receive self-hypnosis trainings achieve significantly greater improvements in their physical health, quality of life, and self-esteem. PMID- 24165455 TI - Activity-dependent regulation of dendritic growth and maintenance by glycogen synthase kinase 3beta. AB - Activity-dependent dendritic development represents a crucial step in brain development, but its underlying mechanisms remain to be fully elucidated. Here we report that glycogen synthase kinase 3beta (GSK3beta) regulates dendritic development in an activity-dependent manner. We find that GSK3beta in somatodendritic compartments of hippocampal neurons becomes highly phosphorylated at serine-9 upon synaptogenesis. This phosphorylation-dependent GSK3beta inhibition is mediated by neurotrophin signalling and is required for dendritic growth and arbourization. Elevation of GSK3beta activity leads to marked shrinkage of dendrites, whereas its inhibition enhances dendritic growth. We further show that these effects are mediated by GSK3beta regulation of surface GABAA receptor levels via the scaffold protein gephyrin. GSK3beta activation leads to gephyrin phosphorylation to reduce surface GABAA receptor clusters, resulting in neuronal hyperexcitability that causes dendrite shrinkage. These findings thus identify GSK3beta as a key player in activity-dependent regulation of dendritic development by targeting the excitatory-inhibitory balance of the neuron. PMID- 24165454 TI - Type 1 diabetes and cardiovascular disease. AB - The presence of cardiovascular disease (CVD) in Type 1 diabetes largely impairs life expectancy. Hyperglycemia leading to an increase in oxidative stress is considered to be the key pathophysiological factor of both micro- and macrovascular complications. In Type 1 diabetes, the presence of coronary calcifications is also related to coronary artery disease. Cardiac autonomic neuropathy, which significantly impairs myocardial function and blood flow, also enhances cardiac abnormalities. Also hypoglycemic episodes are considered to adversely influence cardiac performance. Intensive insulin therapy has been demonstrated to reduce the occurrence and progression of both micro- and macrovascular complications. This has been evidenced by the Diabetes Control and Complications Trial (DCCT) / Epidemiology of Diabetes Interventions and Complications (EDIC) study. The concept of a metabolic memory emerged based on the results of the study, which established that intensified insulin therapy is the standard of treatment of Type 1 diabetes. Future therapies may also include glucagon-like peptide (GLP)-based treatment therapies. Pilot studies with GLP-1 analogues have been shown to reduce insulin requirements. PMID- 24165458 TI - Nonsteroideal Anti-inflammatory Drugs (NSAIDs) in clinical practice: managing gastric and cardiovascular risks. AB - For many years, non-steroidal inflammatory drugs (NSAIDs) were commonly used in the treatment of acute pain due to inflammation.With the arrival on the market of NSAIDs with selective action on COX-2 there was a reduction of side effects in the stomach, but not eliminating the possible cardiovascular complications. The availability of NSAIDs such self-medication can aggravate this type of problem, it is therefore the clinician a fair and accurate assessment of the risk ? benefit based on the characteristics of the individual patient. PMID- 24165459 TI - Modulation of expression of Programmed Death-1 by administration of probiotic Dahi in DMH-induced colorectal carcinogenesis in rats. AB - Interaction of probiotic bacteria with the host immune system elicits beneficial immune modulating effects. Although, there are many published studies on interaction of probiotics with immune system focusing on activation of immune system by bacterial cell wall through the engagement of Toll-like receptor family; very few studies have focused on molecules involved in the T-cell activation, and not much work has been executed to study the correlation of probiotics and programmed death-1 in colorectal carcinogenesis in animal models. Hence, the present study was carried out to assess the effect of probiotic Dahi on expression of programmed death (PD-1) in colorectum of 1, 2-dimethylhydrazine treated Wistar rats. METHODS: DMH was injected subcutaneously at the rate of 40 mg/kg body weight per animal twice a week for 2 weeks. A total of 168 male Wistar rats were randomly allocated to seven groups, each group having twenty-four animals. The rats were euthanized at the 8th, 16th and 32nd week of the experiment and examined for the expression of PD-1 in colorectal tissues by immunohistochemical staining. RESULTS: Expression of PD-1 was observed in colorectal tissues of normal and DMH-treated rats. Feeding rats with probiotic Dahi or the treatment with piroxicam decreased the expression of PD-1 in DMH induced colorectal mucosa, and the combined treatment with probiotic Dahi and piroxicam was significantly more effective in reducing the expression of PD-1. CONCLUSION: PD-1 expressed independent of carcinogen administration in normal colonic mucosa and may play a role in modulation of immune response in DMH induced colorectal carcinogenesis. The present study suggests that probiotic Dahi can be used as an effective chemopreventive agent in the management of colorectal cancer. PMID- 24165460 TI - Are percutaneous pinning the best treatment for gartland type iii supracondylar humeral fractures in children? AB - Background. Supracondylar humeral fractures are the most frequent fractures of the elbow in children. Gartland type III fractures require a surgical treatment. The preferred management is closed reduction and percutaneous pinning with K wires. Methods. We have treated 15 patients (mean age 6,5 years) with Gartland type III fractures. In 14 patients the percutaneous reduction with K-wires was possible but in 1 case the open reduction was necessary due to the irreducibility of the fracture. In all cases a cycle of rehabilitation was performed. Results. All patients have been evaluated using Flynn's criteria with a mean follow-up of 24 months. All cases resulted excellent except the one that required open reduction, that resulted good. Conclusions. Percutaneous pinning is at our days the gold standard of treatment but open reduction must always be considered mandatory when an anatomical closed reduction is not possible. Rehabilitation is also fundamental though the young age of the patients. PMID- 24165461 TI - Are there any strategies to improve neonatal outcomes associated with epidural analgesia in labor? AB - BACKGROUND AND AIM OF THE WORK: This study was aimed at evaluating the relationship between epidural analgesia and perinatal outcomes and at verifying the advisability of procedural changes in assistance to labor. SUBJECTS AND METHODS: From January to December 2012, we conducted a retrospective case-control study on 1,963 laboring pregnant women admitted to the Parma University Hospital. We considered two groups: Group 1 received epidural analgesia and Group 2 received no analgesia. Women with elective cesarean sections, multiple pregnancies or deliveries at <34 weeks were excluded. We recorded maternal data (age, type of delivery, obstetric procedures, premature rupture of membranes, screenings for Group-B Streptococcus) and neonatal data (birth weight, gestational age, 1- and 5-minute Apgar scores, diagnosis at discharge). RESULTS: Of the 1,963 laboring women, 287 requested analgesia and 1,676 did not. We found no significant differences between the two groups in the rates of cesarean section, clavicle fracture, and 1-minute Apgar score between 4 and 7. By contrast, we observed a higher rate of instrumental deliveries (p<0.01), fetal occiput posterior position (p<0.05), neonatal cephalohematoma (p=0.01) in Group 1 than in Group 2 . In Group 1 we also found a higher number of newborns with 1 minute Apgar score of 3 or less (p=0.016). In addition, a significantly higher number of women in Group 1 had fever during labor (p=0.003, odds ratio 5.01). CONCLUSIONS: Our results suggest that strategies should be activated to overcome or limit the side-effects of analgesia in labor through prospective and multidisciplinary studies. PMID- 24165462 TI - Rescue of traumatized riders in world circuits: a comparison between skidboard vs scoop Exl65 and aluminium scoop stretchers. AB - We compared the following stretchers to identify the better and safer to immobilize a fallen rider on the track. The stretchers were: Northwall's Innovation Skidboard, Ferno's Scoop EXL65 and anonymous aluminium scoop stretcher. We performed tests on track with several repetitions on a 25 meters path including asphalt, curb, natural and synthetic grass, and gravel. The Dainese Company supplied a suit and a helmet with sensors equipped to receive data. Dainese engineers processed data too. We timed the performance made by teams of three operators, men and women in different roles. The Skidboard turned out to be the most innovative and secure spine board, because generates less energy than other stretchers and reduces, almost cancels, the harmful consequences of the patient's fall on the ground. Exl65 generates more spin and longitudinal stresses than Skidboard, especially the cervical spine. Skidboard is faster than other stretchers to complete the fallen rider's rescue on the track. It is the only spineboard that allows to tie the patient to the stretchers from head to toe, which does not happen with the aluminum scoop and only partially with the Exl65. Skidboard is better than others to rescue fallen and traumatized riders on the tracks quickly and safely. PMID- 24165463 TI - Which factors may affect the willingness to take the HIV test? A research on Italian adults' sample. AB - Background and aim. Why people do not take the HIV test? The literature on the health-related behaviors associated with HIV infection has highlighted the role played by socio-demographical, behavioral, and cognitive variables. Less often has been studies the impact of psychosocial and normative factors that can affect willingness to test HIV. The aim of this study was to investigate which were the main psycho-social factors that promote/inhibit the intention to take the HIV test. Method. A questionnaire was submitted to a sample of 775 Italian adults (50. 7% female; mean age = 37.24; SD = 10.94; range 17 - 66 years). Results. Logistic Regression Analysis shown that age, risk behaviors, and personal concern are significantly predictors of the intention even if a positive attitude towards HIV test is the strongest predictor. Results showed also that the normative component of attitude (perception of social disapproval) and emotional component (shame and embarrassment) discouraged people from taking the test, while the cognitive-rational component did not. Conclusions. Are the perception of social disapproval by "significant others" and the social emotions of shame and embarrassment that discourage people from taking the test. Implications will be discussed. PMID- 24165464 TI - Abdominal Mondor's disease presenting as acute abdominal pain. AB - We describe here the case of 41 yrs old male patient, who was admitted to the emergency department complaining for abdominal pain lasting for two days. The patient self-reported a history of idiopathic deep vein thrombosis five yrs before the visit. A subcutaneous cordlike induration, tender and painful, was clearly palpable in the left lower abdominal quadrant. Routine blood tests did not reveal any substantial abnormality, except increased D-dimer concentration. Ultrasound evaluation of the abdominal wall revealed diffuse thrombosis of the left superficial inferior epigastric vein, involving several small tributaries branches, extended until 1.5 cm from the confluence with the common femoral vein, which was finally classified as an atypical case of Abdominal Mondor's disease. Complete thrombophilia screening was negative. The patient was discharged with warfarin therapy 48 hours from admission. At 30 days follow-up, the patient self reported a nearly complete recovery. PMID- 24165465 TI - Segmental colitis associated with diverticulosis: a clinical entity to know and to look for. AB - Patients with diverticulosis may develop inflammatory manifestations with segmentary involvement of the colon (segmental colitis associated with diverticulosis, SCAD), an often underestimated clinical condition. We observed the case of a 59 year-old man who presented with abdominal pain, change in bowel habit and hematochezia. Endoscopic and histological evaluation showed features suggestive for SCAD. Medical therapy has been confirmed successful in this patient. PMID- 24165466 TI - Dancing eye syndrome as first symptom of neuroblastoma. AB - BACKGROUND: "Dancing eye syndrome", also called Kinsbourne syndrome or Opsoclonus Myoclonus-Ataxia Syndrome (OMS) is a rare neurological disorder that in children is frequently associated to occult, low-grade neuroblastoma (NB) (>50% of the cases). OMS may also be triggered by infections and it is often associated to developmental impairment and disability. CASE PRESENTATION: We discuss the case of a 16 months old female with acutely onset of OMS associated to occult stage III NB. CONCLUSIONS: OMS represents a diagnostic challenge for pediatric clinicians. The suspect of OMS imposes the search for an occult NB in order to promptly treat a life-threatening event like tumor and to prevent the neurological sequels linked to OMS. PMID- 24165467 TI - Glycemia (hemoglobin A1c) and incident venous thromboembolism in the Atherosclerosis Risk in Communities cohort study. AB - Diabetes has been inconsistently associated with increased risk of venous thromboembolism (VTE) and there is little direct evidence on the associations of glycemia levels with VTE. We used data from the Atherosclerosis Risk in Communities study to test the hypothesis that glycemia, as measured by hemoglobin A1c (A1c), is positively associated with VTE. Participants aged 45-64 years (n = 12,298) had A1c measured in 1990 and were followed for incident VTE (n = 345) through 2005. Because A1c is affected by diabetes treatment, analyses were stratified by history of diagnosed diabetes. Owing to evidence of non-linearity, we categorized A1c according to clinical cut-points: <5.7, 5.7-6.4, and >= 6.5% in those with no diagnosed diabetes; <7.0 and >= 7.0% in those with diagnosed diabetes. After adjustment for potential confounders, the hazard ratios (95% CIs) for VTE across increasing A1c categories were 1 (referent), 1.02 (0.77, 1.35) and 0.72 (0.41, 1.29) for those without diagnosed diabetes, and 1.30 (0.77, 2.17) and 1.41 (0.95, 2.09) for those with diagnosed diabetes. To explore the relation, we employed various models to adjust for potential confounding variables and modeled A1c as tertiles. We consistently found elevated hazard ratios in those with diagnosed diabetes, though the association was not statistically significant in every model. Hazard ratios in those without diagnosed diabetes were close to 1. In conclusion, our results are mildly suggestive that diagnosed diabetes and high levels of glucose, per se, may increase the risk of VTE. Elevated glucose was not related to VTE in those without diagnosed diabetes. PMID- 24165469 TI - A non-invasive technique for visualization of microvessels in asymptomatic patients with middle cerebral artery steno-occlusion. AB - We determined whether 7T magnetic resonance angiography (MRA) could be used for clearly observing microvessels in a clinically asymptomatic patient with steno occlusion of the middle cerebral artery (MCA). We utilized 3T magnetic resonance imaging to obtain the brain images of a clinically asymptomatic patient and noted MCA steno-occlusion. In comparison with 3T MRA, 7T MRA could clearly delineate the microvessels, including lenticulostriate arteries and presumed collaterals, and our observation was comparable to that with conventional digital subtraction angiography. We report an interesting case of a clinically asymptomatic patient with MCA steno-occlusion. PMID- 24165471 TI - Tubular colorectal duplication presenting as rectovaginal fistula. PMID- 24165468 TI - Soluble TNF and IL-6 receptors: indicators of vascular health in women without cardiovascular disease. AB - Cytokine receptor subunits are released from cells in a regulated manner and circulate in soluble forms at concentrations that are orders of magnitude greater than the concentrations of the cytokines themselves. The purpose of this study was to determine if the circulating concentrations of soluble receptor subunits for interleukin-1 beta (IL-1beta), tumor necrosis factor alpha (TNFalpha) and interleukin-6 (IL-6) might serve as early indicators of vascular dysfunction independent of the traditional cardiovascular disease (CVD) risk factors in women. Healthy women, aged 20-50 years (n = 36), were assessed for circulating concentrations of the cytokines IL-1beta, IL-6 and TNFalpha and the soluble cytokine receptor subunits interleukin-1 receptor type I (sIL-1RI), sIL-1RII, sIL 6Ralpha, glycoprotein 130 (s-gp130), soluble TNF receptor type 1 (sTNFR1), and sTNFR2, along with traditional CVD risk factors. Cytokine receptor subunit expression on mononuclear cells and the release of these subunits in vitro were also determined. Brachial artery flow-mediated dilation (FMD), carotid intima media thickness (cIMT) and carotid-femoral pulse wave velocity (cfPWV) were assessed by ultrasonography and Doppler probes. Circulating sIL-6Ralpha correlated negatively with FMD (r = -0.56, p = 0.007) independent of age and other CVD risk factors. Circulating sTNFR1 correlated positively with cfPWV (r = 0.60, p = 0.002). TNFR1 receptor expression on monocytes correlated positively with cIMT (r = 0.51, p = 0.004). Plasma concentrations of IL-1beta, IL-6 and TNFalpha were not significantly associated with FMD, cIMT or cfPWV. These data suggest that the receptors for IL-6 and TNFalpha, rather than the cytokines themselves, may be better indicators of early vascular changes that are associated with CVD. PMID- 24165472 TI - A review of immune tolerance induction with Haemate P in haemophilia A. AB - Immune tolerance induction (ITI) has been shown to successfully eliminate factor VIII (FVIII) inhibitors in haemophilia patients with inhibitors. We performed a literature search to identify reports from January 1980 to October 2012 on the use of the plasma-derived, von Willebrand factor (VWF)-containing FVIII concentrate Haemate P/Humate-P in the setting of ITI. Six reports were identified that specifically evaluated the use of Haemate P/Humate-P including 32 children and 9 adults. Dosing regimens ranged from 20 IU kg(-1) every 2-3 days in patients with low-responding (LR; n = 5) inhibitors to 300 IU kg(-1) day(-1) in patients with high-responding (HR; n = 36) inhibitors. Complete success was achieved in all five LR patients, in all three HR patients with good prognostic factors (age <=7 years, pre-ITI inhibitor titre <10 BU, historical inhibitor titre <200 BU, time between inhibitor detection and ITI start <2 years), and in 24 of 33 (73%) HR patients with poor prognostic factors. The time to complete success was 0.5-4 months in good-prognosis patients and 0.5-42 months in poor-prognosis patients. Few adverse events were observed during ITI, and no cases of inhibitor relapse were reported with follow-up periods of up to 12 years. On the basis of this retrospective review of a diverse range of studies and case reports, we conclude that Haemate P/Humate-P for ITI in patients with inhibitors is effective and produces high rates of ITI success. PMID- 24165473 TI - Laparoscopic bridging vs. anatomic open reconstruction for midline abdominal hernia mesh repair [LABOR]: single-blinded, multicenter, randomized, controlled trial on long-term functional results. AB - BACKGROUND: Re-approximation of the rectal muscles along the midline is recommended by some groups as a rule for incisional and ventral hernia repairs. The introduction of laparoscopic repair has generated a debate because it is not aimed at restoring abdominal wall integrity but instead aims just to bridge the defect. Whether restoration of the abdominal integrity has a real impact on patient mobility is questionable, and the available literature provides no definitive answer. The present study aims to compare the functional results of laparoscopic bridging with those of re-approximation of the rectal muscle in the midline as a mesh repair for ventral and incisional abdominal defect through an "open" access. We hypothesized that, for the type of defect suitable for a laparoscopic bridging, the effect of an anatomical reconstruction is near negligible, thus not a fixed rule. METHODS AND DESIGN: The LABOR trial is a multicenter, prospective, two-arm, single-blinded, randomized trial. Patients of more than 60 years of age with a defect of less than 10 cm at its greatest diameter will be randomly submitted to open Rives or laparoscopic defect repair. All the participating patients will have a preoperative evaluation of their abdominal wall strength and mobility along with volumetry, respiratory function test, intraabdominal pressure and quality of life assessment.The primary outcome will be the difference in abdominal wall strength as measured by a double leg lowering test performed at 12 months postoperatively. The secondary outcomes will be the rate of recurrence and changes in baseline abdominal mobility, respiratory function tests, intraabdominal pressure, CT volumetry and quality of life at 6 and 12 months postoperatively. DISCUSSION: The study will help to define the most suitable treatment for small-medium incisional and primary hernias in patients older than 60 years. Given a similar mid-term recurrence rate in both groups, if the trial shows no differences among treatments (acceptance of the null hypothesis), then the choice of whether to submit a patient to one intervention will be made on the basis of cost and the surgeon's experience. TRIAL REGISTRATION: Current Controlled Trials ISRCTN93729016. PMID- 24165474 TI - Increasing prevalence despite decreasing incidence of ischaemic heart disease and myocardial infarction. A national register based perspective in Denmark, 1980 2009. AB - AIMS: Mortality from ischaemic heart disease (IHD) including acute myocardial infarction (AMI) in Denmark peaked around 1977, after which a marked decline has occurred as a result of decreasing incidence and increasing effect of treatment. IHD is a chronic, relapsing condition, and the effect of these changes on the prevalence of IHD is not known. METHODS AND RESULTS: Changes in incidence and prevalence in 2000-2009 are presented, using nationwide data from public registers. An incident case is defined as a subject registered with a diagnosis of IHD/AMI and without a prior diagnosis for the past 20 years (beginning in 1980). A prevalent case is defined as a subject surviving the first year after the incident diagnosis. Regarding IHD, age-standardised incidence rates declined significantly from 2000 to 2009 for both sexes (females 445 to 340/100,000, males 822 to 678/100,000), reflecting a reduction in the annual number of new cases from 19.345 to 16.757. In contrast, prevalence rates increased slightly (females 2389 to 2616/100,000, males 5447 to 5579/100,000). Due to an increased proportion of elderly in the population, the number of prevalent cases increased from 125,000 in 2000 to 150,000 in 2009. The number of subjects having survived an AMI increased from 67,000 to 72,000. About 3% of the Danish population is afflicted by IHD. CONCLUSION: Decreasing incidence, reduced case fatality and demographic development result in an increased prevalence of IHD, since the decline in incidence is more than offset by a larger decline in case fatality. The epidemic of IHD is far from over, in spite of the marked success of prevention and treatment. PMID- 24165475 TI - Alveolar-capillary membrane diffusion measurement by nitric oxide inhalation in heart failure. AB - BACKGROUND: In heart failure, lung diffusion is reduced, it correlates with prognosis and exercise capacity, and it is a therapy target. DESIGN: Diffusion is measured as CO total diffusion (DL(CO)), which has two components: membrane diffusion (Dm) and capillary volume, the latter related to CO and O2 competition for hemoglobin. DL(CO) needs to be corrected for hemoglobin. Diffusion can also be measured with NO (DL(NO)), which has a very high affinity for hemoglobin, and thus, the resistance of hemoglobin being trivial, it directly represents Dm. Therefore, Dm is directly calculated from DL(NO) through a correction factor. DL(NO) has never been measured in heart failure. The study aims at determining, in heart failure, DL(NO), Dm correction factor, and whether Dm(NO) provides Dm estimates comparable to Dm(CO). METHODS: We measured DL(CO), Dm(CO) by multi maneuver Roughton-Forster method, and DL(CO) and DL(NO) by single-breath maneuver in 50 heart failure and 50 healthy subjects. RESULTS: DL(CO) was 21.9 +/- 4.8 ml/mmHg per min and 16.8 +/- 5.1 in healthy subjects and heart failure subjects, respectively (p < 0.001). DL(NO) was 88.6 +/- 20.5 ml/mmHg per min and 72.5 +/- 22.3, respectively (p < 0.001). The correction factors to obtain Dm from DL(NO) were 2.68 (entire population), 2.63 (healthy subjects) and 2.75 (heart failure subjects). Dm(CO) and Dm(NO) were 34.7 +/- 10.9 ml/mmHg per min and 33.8 +/- 7.6 in healthy subjects and 25.9 +/- 2.0 and 26.4 +/- 8.1 in heart failure subjects. CONCLUSIONS: DL(NO) and Dm(NO) measurements are feasible in heart failure. Dm(CO) and Dm(NO) provide comparable results. The correction factor to calculate Dm from DL(NO) in heart failure is 2.75, which is little different from the 2.63 value we observed in healthy subjects. PMID- 24165477 TI - Workshop report: 4th European crystal network meeting. PMID- 24165476 TI - Legionella spp. in UK composts--a potential public health issue? AB - Over the past 5 years, a number of cases of legionellosis in Scotland have been associated with compost use; however, studies investigating sources of infection other than water systems remain limited. This study delivers the first comprehensive survey of composts commonly available in the UK for the presence of Legionella species. Twenty-two store-bought composts, one green-waste compost and one home-made compost were tested for Legionella by culture methods on BCYE-alpha medium, and the findings were confirmed by macrophage infectivity potentiator (mip) speciation. Twenty-two of the samples were retested after an enrichment period of 8 weeks. In total, 15 of 24 composts tested positive for Legionella species, a higher level of contamination than previously seen in Europe. Two isolates of Legionella pneumophila were identified, and Legionella longbeachae serogroup 1 was found to be one of the most commonly isolated species. L. longbeachae infection would not be detected by routine Legionella urinary antigen assay, so such testing should not be used as the sole diagnostic technique in atypical pneumonia cases, particularly where there is an association with compost use. The occurrence of Legionella in over half of the samples tested indicates that compost could pose a public health risk. The addition of general hygiene warnings to compost packages may be beneficial in protecting public health. PMID- 24165478 TI - Vortioxetine for major depressive disorder: a systematic review of the efficacy and safety profile for this newly approved antidepressant - what is the number needed to treat, number needed to harm and likelihood to be helped or harmed? AB - OBJECTIVE: To describe the efficacy and safety of vortioxetine for the treatment of major depressive disorder (MDD). DATA SOURCES: The pivotal registration trials were accessed by querying http://www.ncbi.nlm.nih.gov/pubmed/, http://www.clinicaltrialsregister.eu and http://www.clinicaltrials.gov for the search terms 'vortioxetine' and 'Lu AA21004', and by obtaining posters presented at congresses. Product labelling provided additional information. STUDY SELECTION: All available clinical reports of studies were identified. DATA EXTRACTION: Descriptions of the principal results and calculation of number needed to treat (NNT) and number needed to harm (NNH) for relevant dichotomous outcomes were extracted from the available study reports and other sources of information. DATA SYNTHESIS: Vortioxetine is a multi-modal antidepressant that functions as a human 5-HT3A and 5-HT7 receptor antagonist, 5-HT1B receptor partial agonist, 5-HT1A receptor agonist, and inhibitor of the serotonin transporter. The recommended dose range is 5-20 mg/day. Approval for the treatment of MDD was based on a clinical development programme that included six positive 6-8 week studies, including one study in elderly people, and one positive maintenance study in adults. In the informative short-term studies in non-elderly patients, NNT for response with vortioxetine vs. placebo was 7 (95% CI 6-9), and NNT for remission vs. placebo was 11 (95% CI 8-17). NNH for discontinuation because of an adverse event (AE) was 36 (95% CI 24-70). The most commonly encountered AEs (incidence >= 5% and at least twice the rate of placebo) as identified in product labelling were nausea, constipation and vomiting, with NNH values vs. placebo of 6 (95% CI 6-7), 64 (95% CI 37-240), and 28 (95% CI 23 38), respectively. Changes in weight were not clinically relevant. CONCLUSIONS: Vortioxetine represents another option for the treatment of MDD. Vortioxetine appears to have a favourable weight-gain profile. Additional information regarding the time course of response/remission and for the commonly occurring AE of nausea would be helpful to better characterise this agent. Pending clinical trials include those examining cognitive dysfunction that can accompany MDD. PMID- 24165479 TI - The long-term effects of phase advance shifts of photoperiod on cardiovascular parameters as measured by radiotelemetry in rats. AB - Cardiovascular parameters, such as blood pressure and heart rate, exhibit both circadian and ultradian rhythms which are important for the adequate functioning of the system. For a better understanding of possible negative effects of chronodisruption on the cardiovascular system we studied circadian and ultradian rhythms of blood pressure and heart rate in rats exposed to repeated 8 h phase advance shifts of photoperiod. The experiment lasted 12 weeks, with three shifts per week. Spectral power as a function of frequency for both circadian and harmonic ultradian rhythms was expressed as the circadian-ultradian power ratio. The circadian rhythms of blood pressure, heart rate and locomotor activity were recorded during the control light:dark (LD) regimen with higher values during the D in comparison with the L. Phase advance shifts resulted in a diminished circadian-ultradian power ratio for blood pressure, heart rate and locomotor activity indicating suppressed circadian control of these traits greater in heart rate than blood pressure. In conclusion, rats kept under irregular LD conditions have suppressed circadian control of heart rate, blood pressure and locomotor activity and rely more on an acute response to the LD regime. Their ability to anticipate regular loads can be weakened and in this way chronodisruption can contribute to the pathogenesis of cardiovascular diseases. PMID- 24165480 TI - Unfolded protein response signaling by transcription factor XBP-1 regulates ADAM10 and is affected in Alzheimer's disease. AB - In Alzheimer's disease (AD), disturbed homeostasis of the proteases competing for amyloid precursor protein processing has been reported: a disintegrin and metalloproteinase 10 (ADAM10), the physiological alpha-secretase, is decreased in favor of the amyloid-beta-generating enzyme BACE-1. To identify transcription factors that modulate the expression of either protease, we performed a screening approach: 48 transcription factors significantly interfered with ADAM10/BACE-1 promoter activity. One selective inducer of ADAM10 gene expression is the X-box binding protein-1 (XBP-1). This protein regulates the unfolded protein-response pathway. We demonstrate that particularly the spliced XBP-1 variant dose dependently regulates ADAM10 expression, which can be synergistically enhanced by 100 nM insulin. Analysis of 2 different transgenic mouse models (APP/PS1 and 5xFAD) revealed that at early time points in pathology XBP-1 metabolism is induced. This is accompanied by a 2-fold augmented ADAM10 amount as compared with nontransgenic littermates (P=0.011). Along with aging of the mice, the system is counterregulated, and XBP-1 together with ADAM10 expression level decreased to ~50% as compared with control animals. Analyses of expression levels in human AD brains showed that ADAM10 mRNA correlated with active XBP-1 (r=0.3120), but expression did not reach levels of healthy age-matched controls, suggesting deregulation of XBP-1 signaling. Our results demonstrate that XBP-1 is a driver of ADAM10 gene expression and that disturbance of this pathway might contribute to development or progression of AD. PMID- 24165481 TI - Argonaute-1 functions as a mitotic regulator by controlling Cyclin B during Drosophila early embryogenesis. AB - The role of Ago-1 in microRNA (miRNA) biogenesis has been thoroughly studied, but little is known about its involvement in mitotic cell cycle progression. In this study, we established evidence of the regulatory role of Ago-1 in cell cycle control in association with the G2/M cyclin, cyclin B. Immunostaining of early embryos revealed that the maternal effect gene Ago-1 is essential for proper chromosome segregation, mitotic cell division, and spindle fiber assembly during early embryonic development. Ago-1 mutation resulted in the up-regulation of cyclin B-Cdk1 activity and down-regulation of p53, grp, mei-41, and wee1. The increased expression of cyclin B in Ago-1 mutants caused less stable microtubules and probably does not produce enough force to push the nuclei to the cortex, resulting in a decreased number of pole cells. The role of cyclin B in mitotic defects was further confirmed by suppressing the defects in the presence of one mutant copy of cyclin B. We identified involvement of 2 novel embryonic miRNAs- miR-981 and miR--317-for spatiotemporal regulation of cyclin B. In summary, our results demonstrate that the haploinsufficiency of maternal Ago-1 disrupts mitotic chromosome segregation and spindle fiber assembly via miRNA-guided control during early embryogenesis in Drosophila. The increased expression of cyclin B-Cdk1 and decreased activity of the Cdk1 inhibitor and cell cycle checkpoint proteins (mei-41 and grp) in Ago-1 mutant embryos allow the nuclei to enter into mitosis prematurely, even before completion of DNA replication. Thus, our results have established a novel role of Ago-1 as a regulator of the cell cycle. PMID- 24165482 TI - A novel regulatory mechanism of Pim-3 kinase stability and its involvement in pancreatic cancer progression. AB - Translationally controlled tumor protein (TCTP/TPT1) was identified from a yeast 2-hybrid screen and shown to interact with Pim-3, a member of the proto-oncogene Pim family with serine/threonine kinase activity. TCTP was aberrantly expressed in human pancreatic cancer cells and malignant ductal epithelial cells, but not in normal pancreatic duct epithelial cells adjacent to tumor foci of human pancreatic cancer tissue. Moreover, TCTP colocalized with Pim-3 both in human pancreatic cancer cells and in clinical tissues. Mapping studies revealed that the interaction between Pim-3 and TCTP occurred through the C-terminal region of Pim-3 and N-terminal region of TCTP. Although Pim-3 had no effect on TCTP expression or phosphorylation, overexpression of TCTP increased the amount of Pim 3 in a dose-dependent manner. Interestingly, RNAi-mediated ablation of TCTP expression reduced Pim-3 protein but not mRNA, through a mechanism involving the ubiquitin-proteasome degradation system. As a consequence of Pim-3 instability and subsequent degradation, tumor growth in vitro and in vivo was inhibited by arresting cell-cycle progression and enhancing apoptosis. Furthermore, TCTP and Pim-3 expression were significantly correlated in pancreatic adenocarcinoma specimens, and patients with highly expressed TCTP and Pim-3 presented with a more advanced tumor stage. These observations indicate that TCTP enhances Pim-3 stability to simultaneously promote and prevent cell-cycle progression and apoptosis, respectively. Hence, TCTP and Pim-3 serve a pivotal role in human pancreatic cancer with important ramifications for clinical diagnostic and therapeutic implications. IMPLICATIONS: The present study provides a new idea and experimental evidence for recognizing TCTP/Pim-3 pathway as a target for therapy in human pancreatic cancer. PMID- 24165483 TI - FBXW7 mediates chemotherapeutic sensitivity and prognosis in NSCLCs. AB - Non-small cell lung cancer (NSCLC) is a leading cause of cancer-related deaths worldwide. To improve the prognosis of patients with NSCLCs, new and validated therapeutic targets are critically needed. In this study, we focused on F-box and WD repeat domain containing-7 (FBXW7), an E3 ubiquitin ligase, that regulates the degradation of MCL1, Myc, cyclin E, and TOP2A. Importantly, loss of FBXW7 was associated with increased sensitivity of tumors to a class I-specific histone deacetylase (HDAC) inhibitor, MS-275. Immunohistochemical analysis revealed increased expression of FBXW7 targets, MCL1 and TOP2A, in NSCLC tumors with low expression of FBXW7. Moreover, clinical specimens exhibiting low FBXW7 expression presented with more progressive cancer and significantly shorter cancer-specific survival than patients with high FBXW7 expression. Mechanistic study of NSCLC cell lines with silenced FBXW7 revealed enhanced MS-275 sensitivity and taxol resistance. Interestingly, taxol resistance was eliminated by MS-275 treatment, suggesting the potential of HDAC inhibitors for the treatment of aggressive taxol resistant NSCLCs that lack FBXW7. IMPLICATIONS: FBXW7 status impacts chemosensitivity and is a prognostic marker in NSCLCs. VISUAL OVERVIEW: http://mcr.aacrjournals.org/content/early/2013/12/19/1541-7786.MCR-13 0341/F1.large.jpg. PMID- 24165486 TI - More codeine fatalities after tonsillectomy in North American children. Time to revise prescribing practice! PMID- 24165487 TI - Head and neck surgical research in the UK: more trials, but a few tribulations. PMID- 24165490 TI - Re: Response to Drs Carey et al. PMID- 24165491 TI - Re: Secondary tracheo-oesophageal fistula creation without rigid oesophagoscopy. PMID- 24165492 TI - Re: Nasal septal button as palatal obturator in oro-naso-antral fistula. PMID- 24165493 TI - Chin lift: a simple but effective novel method of fibreoptic laryngoscopy in the clinic. PMID- 24165494 TI - Response to Mr Flood. PMID- 24165496 TI - Phosphatidylethanolamine-binding protein 1 (PEBP1) as a potential target for the treatment for depression. PMID- 24165497 TI - Volatile communication between plants that affects herbivory: a meta-analysis. AB - Volatile communication between plants causing enhanced defence has been controversial. Early studies were not replicated, and influential reviews questioned the validity of the phenomenon. We collected 48 well-replicated studies and found overall support for the hypothesis that resistance increased for individuals with damaged neighbours. Laboratory or greenhouse studies and those conducted on agricultural crops showed stronger induced resistance than field studies on undomesticated species, presumably because other variation had been reduced. A cumulative analysis revealed that early, non-replicated studies were more variable and showed less evidence for communication. Effects of habitat and plant growth form were undetectable. In most cases, the mechanisms of resistance and alternative hypotheses were not considered. There was no indication that some response variables were more likely to produce large effects. These results indicate that plants of diverse taxonomic affinities and ecological conditions become more resistant to herbivores when exposed to volatiles from damaged neighbours. PMID- 24165498 TI - Early rehospitalization after kidney transplantation: assessing preventability and prognosis. AB - Early rehospitalization after kidney transplantation (KT) is common and may predict future adverse outcomes. Previous studies using claims data have been limited in identifying preventable rehospitalizations. We assembled a cohort of 753 adults at our institution undergoing KT from January 1, 2003 to December 31, 2007. Two physicians independently reviewed medical records of 237 patients (32%) with early rehospitalization and identified (1) primary reason for and (2) preventability of rehospitalization. Mortality and graft failure were ascertained through linkage to the Scientific Registry of Transplant Recipients. Leading reasons for rehospitalization included surgical complications (15%), rejection (14%), volume shifts (11%) and systemic and surgical wound infections (11% and 2.5%). Reviewer agreement on primary reason (85% of cases) was strong (kappa = 0.78). Only 19 rehospitalizations (8%) met preventability criteria. Using logistic regression, weekend discharge (odds ratio [OR] 1.59, p = 0.01), waitlist time (OR 1.10, p = 0.04) and longer initial length of stay (OR 1.42, p = 0.03) were associated with early rehospitalization. Using Cox regression, early rehospitalization was associated with mortality (hazard ratio [HR] 1.55; p = 0.03) but not graft loss (HR 1.33; p = 0.09). Early rehospitalization has diverse causes and presents challenges as a quality metric after KT. These results should be validated prospectively at multiple centers to identify vulnerable patients and modifiable processes-of-care. PMID- 24165499 TI - ATP evokes inward currents in corpus cavernosum myocytes. AB - INTRODUCTION: Although adenosine triphosphate (ATP) has often been reported to relax the corpus cavernosum, this may be mediated by indirect effects, such as release of nitric oxide from the endothelium. Recent data suggest that P2X(1) receptors may be up-regulated in diabetes, and these exert an anti-erectile effect by causing the corpus cavernosum smooth muscle cells (CCSMCs) to contract. However, to date, there is no functional evidence that ATP can directly stimulate CCSMC. AIMS: This study aims to (i) to directly examine the effect of ATP on membrane currents in freshly isolated CCSMC, where influences of endothelium and other cells are absent; and (ii) to determine the receptor subtypes, ionic currents, and Ca(2+) signals stimulated by ATP. METHODS: CCSMCs were enzymatically dispersed from male New Zealand White rabbits for patch clamp recording and measurement of intracellular Ca(2+) in fluo-4-loaded cells using spinning disk confocal microscopy. MAIN OUTCOME MEASURES: Patch clamp recordings were made of ATP-evoked membrane currents and spontaneous membrane currents. Spinning disk confocal imaging of intracellular Ca(2+) was performed, and the response to ATP was recorded. RESULTS: ATP evoked repeatable inward currents in CCSMC (1st application: -675 +/- 101 pA; 2nd application: -694 +/- 120 pA, N = 9, P = 0.77). ATP-induced currents were reduced by suramin from -380 +/- 121 to -124 +/- 37 pA (N = 8, P < 0.05), by alpha,beta-methylene ATP from -755 +/- 235 to 139 +/- 49 pA (N = 5, P < 0.05), and by NF449 from -419 +/- to -51 +/- 13 pA (N = 6, P < 0.05). In contrast, MRS2500, a P2Y1(1,12,13) antagonist, had no effect on ATP responses (control: -838 +/- 139 pA; in MRS2500: -822 +/- 184 pA, N = 13, P = 0.84) but blocked inward currents evoked by 2-MeSATP, a P2Y1,12,13 agonist (control: -623 +/- 166 pA; in MRS2500: -56 +/- 25 pA, N = 6, P < 0.05). The ATP evoked inward current was unaffected by changing the transmembrane Cl(-) gradient but reversed in direction when extracellular Na(+) was reduced, indicating that it was a cation current. CONCLUSIONS: ATP directly stimulates CCSMC by evoking a P2X-mediated cation current. PMID- 24165500 TI - Vanishing kidney disease. PMID- 24165501 TI - Standard anticoagulation for mesenteric vein thrombosis, revealing a 'zebra' diagnosis: hereditary haemorrhagic telangiectasia--the dripping truth! AB - A 60-year-old man was treated in the hospital for mesenteric vein thrombosis and discharged home on anticoagulation. On warfarin the patient started to bleed profusely from the nose and tongue. He was evaluated by ENT (ears, nose and throat); a nasal endoscopy revealed several vascular ectasias. Subsequent detailed history and general physical examination established the diagnosis of hereditary haemorrhagic telangiectasia also known as Osler-Weber-Rendu syndrome. On further evaluation, pulmonary arteriovenous malformations were diagnosed on imaging and treated by intervention radiology. In hindsight, the diagnosis could have been made in the general practitioner's office with just a routine thorough history and a physical examination at a new patient visit. We report this case to stress upon the importance of vigilant clinical, medical and family history and a thorough examination to establish an early diagnosis of this not-so-rare entity. PMID- 24165502 TI - A Portuguese case of Hirayama disease. AB - Hirayama disease, also known as monomelic amyotrophy or juvenile spinal muscular atrophy of the distal upper extremity features the impairment of the anterior horn cells of the distal cervical spinal cord secondary to dural sac anterior displacement during cervical flexion. We describe a case of a 17-year-old boy with a history of scoliosis, evaluated in the emergency department for decreased muscle strength and atrophy of the left upper limb with progressive worsening for about 6 months. We performed electrophysiological studies that showed severe neurogenic atrophy involving the C7-T1 left myotomes. Brain and spine MRI performed showed flattening of the lower cervical cord and dura mater anterior displacement during cervical flexion. These findings were consistent with the diagnosis of Hirayama disease. PMID- 24165503 TI - Gastric xanthelasma: an unusual endoscopic finding. AB - Gastric xanthelasma is a rarely encountered finding in upper gastrointestinal (GI) endoscopy. It is characterised by yellowish-white plaque in the stomach especially in the antrum or the pyloric region. Histologically it consists of foamy macrophages in the lamina propria. It is a benign condition but its appearance mimics malignancy and it is found to be associated with various conditions, some of which are considered premalignant so, histological confirmation is necessary. We present a case of a 44-year-old man who presented to the medicine outpatient department for intermittent pain in epigastrium for the last 2 years. His physical examination was normal. His haematological and biochemical investigations were also normal. His upper GI endoscopy revealed yellowish-white plaque in fundus of the stomach, which was diagnosed as gastric xanthelasma by histological examination with associated chronic gastritis. PMID- 24165504 TI - Changes following nipple areolar complex reconstruction and tattooing resembling a recurrent Paget's disease of the breast. PMID- 24165505 TI - Hypokalemic rhabdomyolysis: an unusual presentation of Sjogren's syndrome. AB - Hypokalaemic rhabdomyolysis represents a medical emergency requiring rapid diagnosis and appropriate aetiological treatment. Renal tubular acidosis is a common cause of hypokalemia which can be idiopathic or secondary to systemic disorders such as Sjogren's syndrome. It can remain asymptomatic or manifest with metabolic abnormalities including hypokalemia paralysis, hypocalcaemia and hyperchloremic metabolic acidosis. Rhabdomyolysis presenting with severe hypokalemia as the first manifestation of Sjogren's syndrome is rare. We report a case of a 59-year-old woman who presented to our department with severe weakness of all limbs. Laboratory examination demonstrated hypokalemic rhabdomyolysis caused by distal renal tubular acidosis. Investigations revealed Sjogren's syndrome as the underlying cause of the metabolic disorders. PMID- 24165506 TI - A cardiac cause for deafness. AB - We describe a case of a 49-year-old diabetic man with a history of myocardial infarction, presenting with deafness for 2 weeks. Initial assessment by otorhinolaryngologists was suggestive of sensorineural hearing loss. Subsequently, the cardiac evaluation showed an apical clot in the left ventricle. Careful neurological reassessment and a cranial MRI yielded a diagnosis of cortical deafness with auditory agnosia secondary to bilateral temporal infarcts. Doppler and MRI ruled out carotid artery thrombosis. The temporal infarcts were therefore considered to be cardioembolic in origin. Cardioembolic stroke is an important differential diagnosis for patients presenting with neurological symptoms on a background of cardiac disease. PMID- 24165507 TI - Neuroimaging in amyotrophic lateral sclerosis. PMID- 24165508 TI - Elevated free thyroxine and non-suppressed thyrotropin. AB - A young man was diagnosed with hyperthyroidism 10 years prior to current presentation after a random health screening revealed an elevated free thyroxine (fT4) of 36.9 pmol/L. During that time, he saw multiple physicians and was treated with carbimazole intermittently. His repeat thyroid function tests showed persistently elevated fT4 ranging 25-35.7 pmol/L and non-suppressed thyroid stimulating hormone (TSH) concentrations of 6.78-22.1 mIU/L. He had a smooth, firm and non-tender goitre. At our institution, laboratory interference was first excluded by serial dilution study (TSH) and retesting of TSH and fT4 on alternate assay, which gave reproducible results. His normal alpha-subunit and sex hormone binding globulin, partially suppressed TSH by high dose triiodothyronine (T3), and positive TSH response to thyrotropin-releasing hormone stimulation were consistent with resistance to thyroid hormone syndrome. The diagnosis was confirmed by direct sequencing of thyroid hormone receptor-beta gene, revealing a heterozygous R320 L mutation that causes reduced T3 affinity and reduced corepressor dissociation. PMID- 24165509 TI - Oral pemphigus as first sign of an inflammatory myofibroblastic tumour in an 18 year-old male patient. PMID- 24165510 TI - 3'-UTR-dependent regulation of mRNA turnover is critical for differential distribution patterns of cyclic gene mRNAs. AB - Somite segmentation, a prominent periodic event in the development of vertebrates, is instructed by cyclic expression of several genes, including Hes7 and Lunatic fringe (Lfng). Transcriptional regulation accounts for the cyclic expression. In addition, because the expression patterns vary in a cycle, rapid turnover of mRNAs should be involved in the cyclic expression, although its contribution remains unclear. Here, we demonstrate that 3'-UTR-dependent rapid turnover of Lfng and Hes7 plays a critical role in their dynamic expression patterns. The regions active in the transcription of Lfng and Hes7 are wholly overlapped in the posterior presomitic mesoderm (PSM) of the mouse embryo. However, their distribution patterns are slightly different; Hes7 mRNA shows a broader distribution pattern than Lfng mRNA in the posterior PSM. Lfng mRNA is less stable than Hes7 mRNA, where their 3'-UTRs are responsible for the different stability. Using transgenic mice expressing Venus under the control of the Hes7 promoter, which leads to cyclic transcription in the PSM, we reveal that the Lfng 3'-UTR provides the narrow distribution pattern of Lfng mRNA, whereas the Hes7 3' UTR contributes the relatively broad distribution pattern of Hes7 mRNA. Thus, we conclude that 3'-UTR-dependent mRNA stability accounts for the differential distribution patterns of Lfng and Hes7 mRNA. Our findings suggest that 3'-UTR dependent regulation of mRNA turnover plays a crucial role in the diverse patterns of mRNA distribution during development. PMID- 24165513 TI - Internal herniation of the caecum through the foramen of Winslow. PMID- 24165512 TI - Hepatitis C: is a vaccine the solution? AB - Hepatitis C Virus (HCV) infection is a major cause of chronic hepatitis, cirrhosis, and hepatocellular carcinoma. Following acute infection, 20% of people eliminate the virus over weeks or months and are often asymptomatic. The remaining 80% of people will develop chronic disease, of which approximately 20% will eventually develop liver cirrhosis and 1-5% will develop liver cancer. About 150 million people are chronically infected with HCV, and more than 350,000 people die every year from hepatitis C related liver diseases. The economic cost of hepatitis C is significant both to the individual and to the society. In the United States the average lifetime cost of the disease was estimated at $33,407 USD with the cost of a liver transplant approximately $200,000 USD. PEG-IFN and ribavirin treatment is also expensive and, at an average cost of approximately GB L7000 in the UK for a treatment course, is unaffordable in developing countries. Hepatitis C, not only brings down the quality of the life of individuals but also affect progress of the nation by adding financial burden. If we prevent the disease from occurring or find a perfect cure of the disease, in form of a prophylactic or therapeutic vaccine, it will be a boon to not only to the individual but to the nation as a whole. PMID- 24165515 TI - Synthesis and physical properties of a ball-like three-dimensional pi-conjugated molecule. AB - Curved pi-conjugated molecules with closed and three-dimensional (3D) structures, such as fullerenes and carbon nanotubes, have been the subject of intensive research due to their potential applications in molecular electronics. However, basic molecular skeletons of 3D molecules are limited because of the lack of a rational and selective synthetic method by organic synthesis. Here we report the synthesis of a 3D pi-conjugated molecule based on the platinum-mediated assembly of four molecules of a stannylated trisubstituted benzene derivative forming a hexanuclear platinum complex with an octahedral shape, from which reductive elimination of platinum gave the target molecule. As many supramolecular transition metal-ligand complexes with 3D cages and polyhedral structures have been synthesized by self-assembly of ligands and metals, the current assembly/reductive elimination strategy could provide a variety of new 3D pi conjugated molecules with different structures and topologies, which are challenging to obtain using conventional synthetic methods. PMID- 24165514 TI - Genetic diversity of natural orchardgrass (Dactylis glomerata L.) populations in three regions in Europe. AB - BACKGROUND: Dactylis glomerata (orchardgrass or cocksfoot) is a forage crop of agronomic importance comprising high phenotypic plasticity and variability. Although the genus Dactylis has been studied quite well within the past century, little is known about the genetic diversity and population patterns of natural populations from geographically distinct grassland regions in Europe. The objectives of this study were to test the ploidy level of 59 natural and semi natural populations of D. glomerata, to investigate genetic diversity, differentiation patterns within and among the three geographic regions, and to evaluate selected populations for their value as genetic resources. RESULTS: Among 1861 plants from 20 Swiss, 20 Bulgarian and 19 Norwegian populations of D. glomerata, exclusively tetraploid individuals were identified based on 29 SSR markers. The average expected heterozygosity (HE,C) ranged from 0.44 to 0.59 and was highest in the Norwegian region. The total number of rare alleles was high, accounting for 59.9% of the amplified alleles. 80.82% of the investigated individuals could be assigned to their respective geographic region based on allele frequencies. Average genetic distances were low despite large geographic distances and ranged from D = 0.09 to 0.29 among populations. CONCLUSIONS: All three case study regions revealed high genetic variability of tetraploid D. glomerata within selected populations and numerous rare and localized alleles which were geographically unique. The large, permanent grassland patches in Bulgaria provided a high genetic diversity, while fragmented, semi-natural grassland in the Norwegian region provided a high amount of rare, localized alleles, which have to be considered in conservation and breeding strategies. Therefore, the selected grassland populations investigated conserve a large pool of genetic resources and provide valuable sources for forage crop breeding programs. PMID- 24165516 TI - Yoga therapy: the synchrony of art and science. PMID- 24165517 TI - Scientific Svadhyaya: developing guidelines for yoga therapy research and practice. PMID- 24165518 TI - Capturing what matters: measurement theory in yoga research. PMID- 24165519 TI - Dosage as a critical variable in yoga therapy research. PMID- 24165520 TI - iRest yoga-nidra on the college campus: changes in stress, depression, worry, and mindfulness. AB - OBJECTIVES: There is evidence that yoga practice is associated with decreased stress, worry, and depression, and with improved mindfulness-based skills. These findings had not been previously replicated for a sample of college students. This study evaluated whether iRest yoga-nidra practice was associated with reduced perceived stress, worry, and depression, and increased mindfulness in a sample of college student s. METHODS: Sixty-six students age 18-56 completed an 8 week iRest yoga-nidra intervention that was offered for 8 semesters. Assessment occurred 1 week prior to intervention onset and during the class period following the intervention. Qualitative data were collected at Weeks 4 and 8. RESULTS: Statistically significant pre- to posttest improvements in perceived stress, worry, and depression were found. Pre-existing depression accounted for most of the change in worry and perceived stress scores. Pre- to post test improvements in mindfulness-based skills were also detected. CONCLUSIONS: iRest yoga-nidra practice may reduce symptoms of perceived stress, worry, and depression and increase mindfulness-based skills. PMID- 24165521 TI - Effects of a 4-month Ananda Yoga program on physical and mental health outcomes for persons with multiple sclerosis. AB - OBJECTIVES: Yoga has been found to be effective for addressing problems with strength, flexibility, balance, gait, anxiety, depression, and concentration. Varying degrees of these problems occur in individuals with multiple sclerosis (MS). This study examined the effects of a comprehensive, 4-month yoga program on strength, mobility, balance, respiratory function, and quality of life for individuals with MS. METHODS: Twenty four individuals with MS participated in an intensive Ananda Yoga training followed by 17 weeks of home practice. RESULTS: Significant improvements in functional strength, balance, and peak expiratory flow and a trend toward improvements in mental health and quality of life outcomes were detected following the intervention. CONCLUSIONS: The results of this exploratory study suggest that yoga can have a positive impact on physical functioning and quality of life for persons with mild to moderate MS. PMID- 24165522 TI - The effects of yoga on eating disorder symptoms and correlates: a review. AB - BACKGROUND: Yoga is a popular adjunct therapy for eating disorders (EDs). A systematic review and synthesis of the yoga literature is needed to guide treatment recommendations and future research. This article provides a review of studies that used yoga for preventing and treating EDs. METHOD: Databases were searched for peer-reviewed articles about yoga practice and ED symptoms and correlates. RESULTS: Of the 14 articles reviewed, 40% used cross-sectional designs to examine risk and protective factors for EDs among yoga practitioners, and 60% used longitudinal designs to assess the effectiveness of yoga interventions for preventing and treating EDs. Yoga practitioners were reported to be at decreased risk for EDs, and ED risk and symptoms were reduced or unchanged after yoga interventions. CONCLUSIONS: Well-controlled studies are needed to understand whether the positive effects of yoga on ED symptoms and correlates are related to the type of yoga practiced, the amount/frequency of practice, and/or other variables. PMID- 24165523 TI - Discrepancies between perceptions of real and ideal yoga teachers and their relationship to emotional well-being. AB - OBJECTIVES: Although more individuals are adopting yoga into their lives, little research has examined practitioners' expectations and experiences of their yoga instructor's behavior. Discrepancies between real and ideal behaviors of yoga instructors may lead to unsatisfactory experiences and decrease the potential impact of yoga practice. This study investigated differences between yoga practitioners' real and ideal perceptions of their yoga teacher's behavior and the relationship between discrepant beliefs and students' symptoms of depression, anxiety,and stress. METHODS: The Perceptions of Yoga Teacher Questionnaire (PYTQ), a recently developed survey of student attitudes regarding yoga teachers' behavior, was administered ina national online survey of yoga students and teachers. Greater discrepancy between real and idea yoga teacher behavior was anticipated to be positively associated with practitioners' symptoms of depression, anxiety, and stress. RESULTS: Pearson correlations corrected for multiple comparisons revealed that yoga students and teachers are generally satisfied with their teacher's behaviors. Significant discrepancies between real and ideal teacher behavior were found for both groups. Higher discrepancy scores were associated with symptoms of stress and anxiety but not depression for students, but not for teachers. CONCLUSIONS: These preliminary findings provide insight into the relationship between expectancies and real yoga teacher behaviors and their links to student emotional adjustment.More research in this area is warranted. PMID- 24165524 TI - Hatha yoga practice for type 2 diabetes mellitus patients: a pilot study. AB - OBJECTIVE: This study was conducted to examine the impact of Hatha yoga on glycemic control, psychological and physiological stress, and self-care for individuals with type 2 diabetes mellitus (T2DM). METHODS: Ten sedentary individuals with T2DM who were non-insulin dependent, free of diabetes-related complications, and had no previous yoga experience completed therapeutic yoga classes for 6 weeks, 3 times per week . Glycemic control measures included fasting blood glucose, glycated hemoglobin, and fasting insulin. The State-Trait Anxiety Inventory, Perceived Stress Scale, and salivary cortisol were used to assess levels of stress, and the Summary of Diabetes Self-care Activities questionnaire was used to assess regimen adherence. RESULTS: No significant changes in glucose control or physiological stress were found; however, significant changes in perceived stress, state anxiety, and self-care behaviors were detected. CONCLUSIONS: Preliminary findings support further investigation of the benefits of Hatha yoga as a complementary therapy for those with T2DM. PMID- 24165525 TI - Bringing yoga therapy into mainstream health care: lessons from the Cleveland Clinic and their relationship to emotional well-being. PMID- 24165526 TI - The use of touch in yoga teaching and therapy: principles and guidelines for effective practices. PMID- 24165527 TI - The benefits of yoga for adults with type 2 diabetes: a review of the evidence and call for a collaborative, integrated research initiative. AB - Type 2 diabetes (T2DM) is a global public health crisis. Research suggests that yoga holds promise for T2DM management. This article summarizes evidence regarding the efficacy of yoga for T2DM management and encourages the development of an integrated research agenda and a collaborative work group to test it. We present a brief overview of the global rise in T2DM and its consequences and costs, review the evidence regarding the potential benefits of yoga for T2DM management, outline limitations in the literature, discuss possible mechanisms underlying the effects of yoga on T2DM, and suggest how a collaborative, multinational effort by yoga therapist and research communities might contribute to research and inform clinical practice. Yoga protocols that serve T2DM patients and a research framework for creating an evidence base to support the use of yoga for T2DM management are clearly needed. PMID- 24165528 TI - Translating knowledge: a framework for evidence-informed yoga programs in oncology. AB - Empirical research suggests that yoga may positively influence the negative psychosocial and physical side effects associated with cancer and its treatment. The translation of these findings into sustainable, evidence-informed yoga programming for cancer survivors has lagged behind the research. This article provides (a) an overview of the yoga and cancer research, (b) a framework for successfully developing and delivering yoga to cancer populations, and (c) an example of a successful community-based program. The importance of continued research and knowledge translation efforts in the context of yoga and integrative oncology are highlighted. PMID- 24165529 TI - Joint ventures: helping those with rheumatoid arthritis live well. AB - OBJECTIVES: Rheumatoid arthritis (RA) is an autoimmune, chronic inflammatory disorder that causes pain, swelling, stiffness, loss of joint function, and reduced quality of life. Yoga therapy may help individuals with RA manage stress and increase well-being. This study focused on the identification of therapeutic objectives and a methodology to achieve symptom relief, regain function, and enhance quality of life for individuals with RA. METHODS: Four women with RA participated in private yoga therapy sessions for 2.5 months. Assessment based, tailored home practices were developed and modified to address participant - identified goals. RESULTS: Participants reported decreased pain, fatigue, swelling, and flares; increased energy; pain-free range of motion and strength around affected joints; and a heightened sense of well-being. CONCLUSIONS: Tailored yoga therapy that emphasizes stress reduction may be beneficial for individuals with RA. PMID- 24165530 TI - Haemophilia Joint Health Score in healthy adults playing sports. AB - To evaluate outcome of prophylactic clotting factor replacement in children with haemophilia, the Haemophilia Joint Health Score (HJHS) was developed aiming at scoring early joint changes in children aged 4-18. The HJHS has been used for adults on long-term prophylaxis but interpretation of small changes remains difficult. Some changes in these patients may be due to sports-related injuries. Evaluation of HJHS score in healthy adults playing sports could improve the interpretation of this score in haemophilic patients. The aim of this study was to evaluate the HJHS scores in a cohort of young, healthy men participating in sports. Concomitant with a project collecting MRI images of ankles and knees in normal young adults, HJHS scores were assessed in 30 healthy men aged 18-26, participating in sports one to three times per week. One physiotherapist assessed their clinical function using the HJHS 2.1. History of joint injuries was documented. MRI images were scored by a single radiologist, using the International Prophylaxis Study Group additive MRI score. Median age of the study group was 24.3 years (range 19.0-26.4) and median frequency of sports activities was three times per week (range 1-4). Six joints (five knees, one ankle) had a history of sports-related injury. The median overall HJHS score was 0 out of 124 (range 0-3), with 60% of subjects showing no abnormalities on HJHS. All joints were normal on MRI. These results suggest that frequent sports participation and related injuries are not related with abnormalities in HJHS scores. PMID- 24165531 TI - New Jersey political update: Special elections, general elections and hot topic issues in Trenton. PMID- 24165532 TI - Protecting residents' health during Sandy recovery. PMID- 24165533 TI - Minimally invasive robotic surgery: the good & the bad a discussion with Domenico Savatta, MD. Interviewed by Theresa Foy DiGeronimo. PMID- 24165534 TI - Cannabis for cash only: the lack of insurance coverage and reimbursement for medical marijuana. PMID- 24165535 TI - New pharmacy standards and their potential effects on patient care. PMID- 24165536 TI - Courtroom as classroom-today's lesson: medical malpractice. PMID- 24165537 TI - The road to EMR noncompliance and fraud is paved with cut and paste. PMID- 24165538 TI - Hurricane Sandy uncovers the value of IT investments and crisis preparation. PMID- 24165539 TI - Social media and the medical community. PMID- 24165540 TI - An Interview with Nancy Romeo, BSN, MPA: A healthcare executive's insider view of healthcare today. Interviewed by Marlene Taft and Catherine E. Williams. PMID- 24165541 TI - Social cohesion matters in health. AB - INTRODUCTION: The concept of social cohesion has invoked debate due to the vagueness of its definition and the limitations of current measurements. This paper attempts to examine the concept of social cohesion, develop measurements, and investigate the relationship between social cohesion and individual health. METHODS: This study used a multilevel study design. The individual-level samples from 29 high-income countries were obtained from the 2000 World Value Survey (WVS) and the 2002 European Value Survey. National-level social cohesion statistics were obtained from Organization of Economic Cooperation and Development datasets, World Development Indicators, and Asian Development Bank key indicators for the year 2000, and from aggregating responses from the WVS. In total 47,923 individuals were included in this study. The factor analysis was applied to identify dimensions of social cohesion, which were used as entities in the cluster analysis to generate a regime typology of social cohesion. Then, multilevel regression models were applied to assess the influences of social cohesion on an individual's self-rated health. RESULTS AND DISCUSSION: Factor analysis identified five dimensions of social cohesion: social equality, social inclusion, social development, social capital, and social diversity. Then, the cluster analysis revealed five regimes of social cohesion. A multi-level analysis showed that respondents in countries with higher social inclusion, social capital, and social diversity were more likely to report good health above and beyond individual-level characteristics. CONCLUSIONS: This study is an innovative effort to incorporate different aspects of social cohesion. This study suggests that social cohesion was associated with individual self-rated after controlling individual characteristics. To achieve further advancement in population health, developed countries should consider policies that would foster a society with a high level of social inclusion, social capital, and social diversity. Future research could focus on identifying possible pathways by which social cohesion influences various health outcomes. PMID- 24165542 TI - Identification of Leishmania at the species level with matrix-assisted laser desorption ionization time-of-flight mass spectrometry. AB - Matrix-assisted laser desorption ionization time-of-flightMALDI-TOF mass spectrometry (MS) is now widely recognized as a powerful tool with which to identify bacteria and fungi at the species level, and sometimes in a rapid and accurate manner. We report herein an approach to identify, at the species level, Leishmania promastigotes from in vitro culture. We first constructed a reference database of spectra including the main Leishmania species known to cause human leishmaniasis. Then, the performance of the reference database in identifying Leishmania promastigotes was tested on a panel of 69 isolates obtained from patients. Our approach correctly identified 66 of the 69 isolates tested at the species level with log (score) values superior to 2. Two Leishmania isolates yielded non-interpretable MALDI-TOF MS patterns, owing to low log (score) values. Only one Leishmania isolate of Leishmania peruviana was misidentified as the closely related species Leishmania braziliensis, with a log (score) of 2.399. MALDI-TOF MS is a promising approach, providing rapid and accurate identification of Leishmania from in vitro culture at the species level. PMID- 24165543 TI - Postischemic administration of a potent PTEN inhibitor reduces spontaneous lung infection following experimental stroke. PMID- 24165544 TI - Violence, mental health and violence risk factors among community women: an epidemiological study based on two national household surveys in the UK. AB - BACKGROUND: Females who perpetrated violence in the community have important mental health and public protection implications. There is a dearth of research in this area. This study investigated the prevalence of psychiatric morbidity, personality disorders as well as victim characteristics and violence risk factors of women in the community who self-reported violence against others. METHODS: The study sample consisted of 8,275 community women aged 16-74 years obtained from the 2000 and 2007 UK national psychiatric morbidity surveys. Self report incidences of violence, personality disorders and the presence of psychiatric symptoms were assessed by interviews and/or established structured psychiatric assessment protocols. RESULTS: Weighted prevalence of female violence, which primarily involved partners and friends, was 5.5% in 2000 and 5.1% in 2007. Violence-prone women also had significantly higher prevalence of common mental disorders and comorbidity (adjusted odds ratio 3.3 and 2.9 respectively) than non violent women. Multivariate analyses identified eight significant risk factors that characterized violence prone women: young age, residing in social-assisted housing, presence of early conduct problems, victim of domestic violence, self harming, excessive drinking and past criminal justice involvements. CONCLUSION: A higher prevalence of common mental disorders and some types of personality disorder was found among violence prone women compared to their non-violence prone counterparts. The identified violence risk factors could be used to develop a quick and easily administered rating tool suitable for use by non-mental health trained frontline workers such as police and social support workers in the community to identify violence-prone women. Mental health and support services then can be provided to them for mental health care and violence prevention purposes. PMID- 24165546 TI - New carbon allotropes with helical chains of complementary chirality connected by ethene-type pi-conjugation. AB - We here identify by ab initio calculations two distinct three-dimensional three connected (3D3C) chiral framework structures of carbon in and I41/amd symmetry, respectively, which comprise 3-fold and 4-fold helical chains with complementary chirality. The helical carbon chains are connected by an ethene-type planar pi conjugation, and the resulting structures contain a network of sp(2) carbon bonds with one-third being double bonds between the chains and two-thirds single bonds along the chains. Phonon and electronic band structure calculations show that these chiral carbene structures are dynamically stable and exhibit a large band gap (2.4 ~ 2.9 eV). This semiconducting nature reflects a key distinction from previously proposed metallic isomers of helical or zigzag carbon chains with twisted pi states that are dynamically unstable. The present results solve the long-sought 3D3C all-sp(2) carbon structures and may help design other covalent bonding networks. PMID- 24165545 TI - Ozurdex (a slow-release dexamethasone implant) in proliferative vitreoretinopathy: study protocol for a randomised controlled trial. AB - BACKGROUND: Proliferative vitreoretinopathy (PVR) is the commonest cause of late anatomical failure in rhegmatogenous retinal detachment. Visual and anatomical outcomes remain poor despite advances in vitreoretinal surgical techniques with reported primary failure rates of up to nearly 50%. Numerous adjunctive medications have been evaluated in clinical trials with no agent gaining widespread acceptance and use.This study was designed to investigate the benefits of using a slow-release dexamethasone implant delivered intra-operatively in patients undergoing vitrectomy surgery for retinal detachment with established PVR. METHODS/DESIGN: For the study, 140 patients requiring vitrectomy surgery with silicone oil for retinal detachment with established PVR will be randomised to receive either standard treatment or study treatment in a 1:1 treatment allocation ratio. Both groups will receive the standard surgical treatment appropriate for their eye condition and routine peri-operative treatment and care, differing only in the addition of the supplementary adjunctive agent in the treatment group. The investigated primary outcome measure is stable retinal reattachment with removal of silicone oil without additional vitreoretinal surgical intervention at 6 months. DISCUSSION: This is the first randomised controlled clinical trial to investigate the use of an adjunctive slow-release dexamethasone implant in patients undergoing vitrectomy surgery for retinal detachments with proliferative vitreoretinopathy. TRIAL REGISTRATION: EudraCT No: 2011-004498-96. PMID- 24165547 TI - Pathways and substrate-specific regulation of amino acid degradation in Phaeobacter inhibens DSM 17395 (archetype of the marine Roseobacter clade). AB - Combining omics and enzymatic approaches, catabolic routes of nine selected amino acids (tryptophan, phenylalanine, methionine, leucine, isoleucine, valine, histidine, lysine and threonine) were elucidated in substrate-adapted cells of Phaeobacter inhibens DSM 17395 (displaying conspicuous morphotypes). The catabolic network [excluding tricarboxylic acid (TCA) cycle] was reconstructed from 71 genes (scattered across the chromosome; one-third newly assigned), with 69 encoded proteins and 20 specific metabolites identified, and activities of 10 different enzymes determined. For example, Ph. inhibens DSM 17395 does not degrade lysine via the widespread saccharopine pathway but might rather employ two parallel pathways via 5-aminopentanoate or 2-aminoadipate. Tryptophan degradation proceeds via kynurenine and 2-aminobenzoate; the latter is metabolized as known from Azoarcus evansii. Histidine degradation is analogous to the Pseudomonas-type Hut pathway via N-formyl-l-glutamate. For threonine, only one of the three genome-predicted degradation pathways (employing threonine 3 dehydrogenase) is used. Proteins of the individual peripheral degradation sequences in Ph. inhibens DSM 17395 were apparently substrate-specifically formed contrasting the non-modulated TCA cycle enzymes. Comparison of genes for the reconstructed amino acid degradation network in Ph. inhibens DSM 17395 across 27 other complete genomes of Roseobacter clade members revealed most of them to be widespread among roseobacters. PMID- 24165548 TI - Heterogeneity of deformation of aortic wall at the microscopic level: contribution of heterogeneous distribution of collagen fibers in the wall. AB - There is growing evidence of heterogeneous distribution of collagen fibers in the aortic wall. To investigate the effects of collagen microstructure on local aortic wall deformation, porcine thoracic aortas were sliced into 100 MUm-thick sections perpendicular to their radial direction and stretched biaxially with a laboratory-made tensile tester under a microscope equipped with a birefringence imaging system. Strain tensor components were calculated from fluorescent images of the cell nuclei for each 50 * 50 MUm2 area. Retardance Ret and slow axis azimuth theta were measured as indices of collagen density and fiber direction, respectively. Aortic wall deformation was highly heterogeneous: standard deviations of strains were significantly larger, by 3-5 times, in aortic slices than in homogeneous silicone sheets. A significant negative correlation was found between maximum principal strain and Ret (R=-0.077), and a positive correlation between minimum principal strain direction and theta (R=0.345). These indicate that the aorta is less distensible in areas with higher collagen density and in the direction of collagen fiber alignment. Microscopic heterogeneity may induce heterogeneous responses of smooth muscle cells and have crucial effects on mechanical homeostasis in the aortic wall. PMID- 24165549 TI - Hypoxia suppresses stretch-induced elongation and orientation of macrophages. AB - BACKGROUND: Cells in the arterial wall are normally subjected to approximately 10% cyclic stretch due to pulsatile blood flow. In addition, cells in the walls of abdominal aortic aneurysms (AAA) experience hypoxic conditions caused by the accumulation of intraluminal thrombus. Such combined stimulation by hypoxia and stretch can induce abnormal functions in macrophages that infiltrate into the AAA walls; however, the details of these effects are unknown. OBJECTIVE: The aim of this study is to know the influence of a combination of cyclic stretch and hypoxia on the macrophage morphology. METHODS: Morphological changes, such as aspect ratio and orientation, in macrophages exposed to 10% cyclic stretch and 2.2% O2 hypoxia during 24 h were evaluated with usage of ImageJ software. We also assessed expression of hypoxia-inducible factor-alpha (HIF-1alpha), an intracellular signaling factor, in macrophages by western blotting. RESULTS: The results indicate that hypoxia significantly suppresses stretch-induced orientation in the direction of the stretch and elongation of macrophages. We also found that the combination of cyclic stretch and hypoxia significantly increased HIF-1alpha expression. CONCLUSIONS: These results suggest that hypoxia suppresses morphological responses of macrophages to cyclic stretch by elevating HIF-1alpha expression. PMID- 24165550 TI - Preparation of size-controlled silver nanoparticles and chitosan-based composites and their anti-microbial activities. AB - We previously reported a simple method for the preparation of size-controlled spherical silver nanoparticles (Ag NPs) generated by autoclaving a mixture of silver-containing glass powder and glucose. The particle size is regulated by the glucose concentration, with concentrations of 0.25, 1.0 and 4.0 wt% glucose providing small (3.48 +/- 1.83 nm in diameter), medium (6.53 +/- 1.78 nm) and large (12.9 +/- 2.5 nm) particles, respectively. In this study, Ag NP/chitosan composites were synthesized by mixing each of these three Ag NP suspensions with a 75% deacetylated (DAc) chitosan suspension (pH 5.0) at room temperature. The Ag NPs were homogeneously dispersed and stably embedded in the chitosan matrices. The Ag NP/chitosan composites were obtained as yellow or brown flocs. It was estimated that approximately 60, 120 and 360 MUg of the small, medium and large Ag NPs, respectively, were maximally embedded in 1 mg of chitosan. The bactericidal and anti-fungal activities of the Ag NP/chitosan composites increased as the amount of Ag NPs in the chitosan matrix increased. Furthermore, smaller Ag NPs (per weight) in the chitosan composites provided higher bactericidal and anti-fungal activities. PMID- 24165551 TI - Enhancement of fracture healing by electrical stimulation in the comminuted intraarticular fracture of distal radius. AB - Effectiveness of an alternating electric current (AC) stimulation in prevention of bone deformity for comminuted intraarticular fracture of distal radius were verified by comparing postoperative results treated with a wrist-bridging external fixator combined with or without an AC stimulator (EF and NEF, respectively), and a palmar locking plate (LP). This study evaluated 92 cases (mean age 67.9 +/- 11.4 years) of type C2 and 60 cases (mean age 69.7 +/- 9.5 years) of type C3 distal radius fractures, as classified by the Association for Osteosynthesis. In total, 55 and 24 cases were treated with EF and NEF, respectively; and 73 cases were treated with LP. Callus appeared 27.5 +/- 4.6 days postoperatively and the external skeletal fixation period was significantly shorter in the EF group than in the NEF group. The decrease in radial length was significantly lower in the EF group when compared to the LP group. There were no significant differences among the groups for the other radiographic and functional parameters. AC stimulation combined to the external fixation may be a promising method to prevent postoperative deformity in the severely comminuted intraarticular fractures by accelerating callus maturation and facilitating new bone bridging across the gap of fracture site. PMID- 24165552 TI - Biomechanical comparison of the K-ROD and Dynesys dynamic spinal fixator systems a finite element analysis. AB - Dynamic spinal fixators, such as the Dynesys (DY) and K-ROD (KD) systems, are designed to restore spinal stability and to provide flexibility. The long-term complications of implant breakage and the biomechanics of the adjacent and the bridged levels using the KD system are still unknown. Therefore, this study aims to investigate and compare the biomechanical effects of the KD system and the DY system. Finite element (FE) models of the degenerated lumbar spine, the DY system, and the KD system were each reconstructed. Hybrid-controlled analysis was applied in the three FE models. The FE results indicated that the KD system supplies the most stiffness during extension and the least stiffness during flexion, in contrast to the DY system. In contrast to the DY system, the KD system increased the facet contact force of the adjacent level, but this system decreased the screw stress on the cranial adjacent disc and the pedicle during flexion. PMID- 24165553 TI - OH- deficiency in dental enamel, crown and root dentine as studied by 1H CRAMPS. AB - High-resolution solid-state NMR based on combined rotation and multipulse spectroscopy (CRAMPS) has been applied to study chemical structures of dental tissues. The samples of human enamel, crown dentine and root dentin studied in this work were used without chemical pre-treatment. The quantitative 1H NMR spectra permit an assignment to different structures and a quantification of the content of hydroxyl groups. While there is 40% hydroxyl content in the enamel, there is significantly less in the dentin, 14% in the crown and 9% in the root. Thus this study provides the direct evidence of OH- ion deficiency in all dental tissues supporting earlier findings that bone and dental mineral apatite is poorly hydroxylated. PMID- 24165554 TI - Discrimination of Parkinsonian tremor from essential tremor using statistical signal characterization of the spectrum of accelerometer signal. AB - A new technique for discrimination of Parkinson tremor from essential tremor is presented in this paper. This technique is based on Statistical Signal Characterization (SSC) of the spectrum of the accelerometer signal. The data has been recorded for diagnostic purposes in the Department of Neurology of the University of Kiel, Germany. Two sets of data are used. The training set, which consists of 21 essential-tremor (ET) subjects and 19 Parkinson-disease (PD) subjects, is used to obtain the threshold value of the classification factor differentiating between the two subjects. The test data set, which consists of 20 ET and 20 PD subjects, is used to test the technique and evaluate its performance. Three of twelve newly derived SSC parameters show good discrimination results. Specific results of those three parameters on training data and test data are shown in detail. A linear combination of the effects of those parameters on the discrimination results is also included. A total discrimination accuracy of 90% is obtained. PMID- 24165555 TI - Laser sintered porous polycaprolacone scaffolds loaded with hyaluronic acid and gelatin-grafted thermoresponsive hydrogel for cartilage tissue engineering. AB - The aim of this study is to evaluate a soft/hard bi-phase scaffold for cartilage tissue engineering. Chondrocyte proliferation, glycoaminoglycan production and total collagen content are compared between laser-sintered porous polycaprolactone (PCL) scaffolds with and without a thermoresponsive hydrogel grafted with hyaluronic acid and gelatin. The in vitro results show that scaffolds loaded with hydrogel have a higher initial chondrocyte attachment than PCL scaffolds. At day 21 and 28, scaffolds loaded with hydrogel have a significantly higher glycosaminoglycan (GAG) production than PCL scaffolds alone, and total collagen content including collagen type II in the hydrogel-loaded group is three times higher than the group without hydrogel. It is concluded that the laser-sintered porous PCL scaffold has good cytocompatibility, and that the hydrogel phase is able to enhance initial chondrocytes attachment as well as GAG and collagen production of chondrocytes. This study suggests that a soft/hard bi phase scaffold may be used for cartilage tissue engineering to enhance in vitro chondrogenesis. PMID- 24165556 TI - Biocompatibility evaluation of electrospun silk fibroin nanofibrous mats with primarily cultured rat hippocampal neurons. AB - In this study, electrospinning was performed to fabricate silk fibroin (SF) nanofibrous mats, which were used as substrates for in vitro culture of rat hippocampal neurons. The light and electron micrographs demonstrated that the electrospun SF nanofibrous mat supported the survival and growth of the attached hippocampal neurons. MTT assay and immunocytochemistry in couple with Western blot analysis respectively indicated there was no significant difference in both the cell viability and expression levels of some proteins, including GAP-43, MAP 2, NF, and beta-tubulin, between hippocampal neurons cultured in the electrospun SF nanofibrous mat extract and in plain neuronal medium. Our results indicated that electrospun SF nanofibrous mats were biocompatible to primary culture of hippocampal neurons without cytotoxic effects on the cell phenotype and functions, raising a potential possibility of using these mats for CNS therapeutic applications. PMID- 24165557 TI - Magnetic resonance imaging detection of an uncommon granuloma formation after endothelial progenitor cells transplantation. AB - Magnetic resonance imaging (MRI) has been recognized as a non-invasive technique for visualizing the ultrastructure of a tissue at high resolution. The work reported here showed the utility of MRI for visualizing the fate of EPCs, and demonstrate how it can be used to further our understanding of angiogenesis mechanisms.The recently developed contrast agent dextran mono-N-succinimidyl 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetate-gadolinium3+ (Dex-DOTA-Gd3+) was used to label endothelial progenitor cells (EPCs). The faith of the transplanted labeled cells in the rat models of ischemic hind limbs was studied by images obtained by MRI.The pattern of migration of Dex-DOTA-Gd3+-labeled EPCs could be observed and tracked by MRI for a long time and analyzed the change in the migration of the labeled cells. The ability of Dex-DOTA-Gd3+ to provide a clear pattern of cell migration to the limb was confirmed and most importantly, a different behavioral pattern was identified in the migration of labeled cells when an anomaly appeared in the MRI acquisition images 5 days post transplantation. PMID- 24165560 TI - IL-15 expanded CD8+CD122+ cells: when do they suppress? PMID- 24165561 TI - Intimate partner violence and condom and diaphragm nonadherence among women in an HIV prevention trial in southern Africa. AB - BACKGROUND: We longitudinally examined the effect of intimate partner violence (IPV) on condom and diaphragm nonadherence among women in the Methods for Improving Reproductive Health in Africa study, a phase III HIV prevention trial in southern Africa. METHODS: Recent IPV (fear of violence, emotional abuse, physical violence, or forced sex, in past 3 months), condom nonadherence, and diaphragm nonadherence were assessed at baseline, 12 month, and exit visits (up to 24 months). The association between IPV and (1) condom nonadherence or (2) diaphragm nonadherence across visits was modeled using Generalized Estimating Equations adjusting for potential confounders. RESULTS: Of 4505 participants, 55% reported recent IPV during their trial participation. Women reported fearing violence (41%), emotional abuse (38%), being physically assaulted (16%), and forced sex (15%) by their regular male partner. IPV was associated with condom nonadherence in both study arms [adjusted odds ratio (AOR): 1.41, 95% confidence interval (CI): 1.24 to 1.61 (control arm) and AOR: 1.47, 95% CI: 1.28 to 1.69, (intervention arm)] and with diaphragm nonadherence (AOR 1.24, 95% CI: 1.06 to 1.45) adjusting for age, study sites, number of sex partners, and knowledge of male partner infidelity. Modeling effects of each form of IPV separately on nonadherence outcomes yielded similar results. CONCLUSIONS: Prevalence of recent IPV was high and associated with condom and diaphragm nonadherence during the trial. Counseling in prevention trials should proactively address IPV, for its own sake, and in product and risk-reduction counseling. Strategies to encourage men's positive involvement in product use and prevent IPV perpetration should be considered. PMID- 24165563 TI - Potential pitfalls in the diagnosis of Hb Handsworth in areas with high prevalence of HbS. AB - Hb Handsworth is a rare alpha-globin structural variant caused by a missense mutation either on the alpha2 or alpha1-globin gene (HBA2 or HBA1: c.55G>C, p.Gly18Arg). This variant might be erroneously diagnosed as HbS unless secondary confirmative tests are carried out. We encountered a child with a prominent peak eluting in the 'S' window on high-performance liquid chromatography (HPLC). Sickle solubility test, gel electrophoresis, and selective direct nucleotide sequencing of alpha1, alpha2, and beta globin genes were performed on the patient's sample. In addition, previous HPLC results on a cord blood sample were retrieved. Sickle solubility test was negative. Gel electrophoresis revealed a band migrating at the S region with an extra faint band seen on acid gel electrophoresis. Molecular analysis of alpha2 globin gene revealed heterozygous state of Hb Handsworth. Hb Handsworth is a rare variant that can mimic HbS on HPLC. Failure to recognize this rare variant in regions where HbS is highly prevalent may result in serious misdiagnosis and subsequent incorrect genetic counseling. PMID- 24165562 TI - Body composition and gene expression QTL mapping in mice reveals imprinting and interaction effects. AB - BACKGROUND: Shifts in body composition, such as accumulation of body fat, can be a symptom of many chronic human diseases; hence, efforts have been made to investigate the genetic mechanisms that underlie body composition. For example, a few quantitative trait loci (QTL) have been discovered using genome-wide association studies, which will eventually lead to the discovery of causal mutations that are associated with tissue traits. Although some body composition QTL have been identified in mice, limited research has been focused on the imprinting and interaction effects that are involved in these traits. Previously, we found that Myostatin genotype, reciprocal cross, and sex interacted with numerous chromosomal regions to affect growth traits. RESULTS: Here, we report on the identification of muscle, adipose, and morphometric phenotypic QTL (pQTL), translation and transcription QTL (tQTL) and expression QTL (eQTL) by applying a QTL model with additive, dominance, imprinting, and interaction effects. Using an F2 population of 1000 mice derived from the Myostatin-null C57BL/6 and M16i mouse lines, six imprinted pQTL were discovered on chromosomes 6, 9, 10, 11, and 18. We also identified two IGF1 and two Atp2a2 eQTL, which could be important trans regulatory elements. pQTL, tQTL and eQTL that interacted with Myostatin, reciprocal cross, and sex were detected as well. Combining with the additive and dominance effect, these variants accounted for a large amount of phenotypic variation in this study. CONCLUSIONS: Our study indicates that both imprinting and interaction effects are important components of the genetic model of body composition traits. Furthermore, the integration of eQTL and traditional QTL mapping may help to explain more phenotypic variation than either alone, thereby uncovering more molecular details of how tissue traits are regulated. PMID- 24165564 TI - Sexual desire in trans persons: associations with sex reassignment treatment. AB - INTRODUCTION: Sex steroids and genital surgery are known to affect sexual desire, but little research has focused on the effects of cross-sex hormone therapy and sex reassignment surgery on sexual desire in trans persons. AIM: This study aims to explore associations between sex reassignment therapy (SRT) and sexual desire in a large cohort of trans persons. METHODS: A cross-sectional single specialized center study including 214 trans women (male-to-female trans persons) and 138 trans men (female-to-male trans persons). MAIN OUTCOME MEASURES: Questionnaires assessing demographics, medical history, frequency of sexual desire, hypoactive sexual desire disorder (HSDD), and treatment satisfaction. RESULTS: In retrospect, 62.4% of trans women reported a decrease in sexual desire after SRT. Seventy-three percent of trans women never or rarely experienced spontaneous and responsive sexual desire. A third reported associated personal or relational distress resulting in a prevalence of HSDD of 22%. Respondents who had undergone vaginoplasty experienced more spontaneous sexual desire compared with those who planned this surgery but had not yet undergone it (P = 0.03). In retrospect, the majority of trans men (71.0%) reported an increase in sexual desire after SRT. Thirty percent of trans men never or rarely felt sexual desire; 39.7% from time to time, and 30.6% often or always. Five percent of trans men met the criteria for HSDD. Trans men who were less satisfied with the phalloplasty had a higher prevalence of HSDD (P = 0.02). Trans persons who were more satisfied with the hormonal therapy had a lower prevalence of HSDD (P = 0.02). CONCLUSION: HSDD was more prevalent in trans women compared with trans men. The majority of trans women reported a decrease in sexual desire after SRT, whereas the opposite was observed in trans men. Our results show a significant sexual impact of surgical interventions and both hormonal and surgical treatment satisfaction on the sexual desire in trans persons. PMID- 24165566 TI - Competency frameworks: which format for which target? AB - In veterinary medical education, it is now necessary to design competency frameworks (CFs) that list expected competencies at graduation. Three different CFs with different formats and contents have been published in Europe, such as the Day One Skills (DOS), the recommendations of the World Organization for Animal Health(OIE), and the Veterinary Professional (VetPro). In the current study, on the basis of a survey among Belgian veterinarians, a fourth document was designed that lists the necessary knowledge, skills, and attitudes grouped into families according to professional situations. The objectives of this study were to assess the perception of CFs by various categories of stakeholders, identify the possible uses of CFs, and determine whether one format should be preferred to another. We used a qualitative approach based on semi-structured face-to-face interviews with different stakeholders after they had reviewed the four different documents (CFs). This study showed that an obligation to design CFs was clearly perceived by academic and professional authorities. Teachers and veterinarians may be either enthusiastic or apprehensive about CFs, while students perceive the usefulness of the documents to plan and assess their learning objectives. Three main roles of CFs were identified: they can be used as communication tools, regulatory tools, or educational tools. However, not one of the documents used in this study was perceived to fulfill all roles. It is therefore likely that no one ideal document yet exists and a combination of formats is necessary. PMID- 24165567 TI - Glia protein aquaporin-4 regulates aversive motivation of spatial memory in Morris water maze. AB - AIMS: Although extensive investigation has revealed that an astrocyte-specific protein aquaporin-4 (AQP4) participates in regulating synaptic plasticity and memory, a functional relationship between AQP4 and learning processing has not been clearly established. This study was designed to test our hypothesis that AQP4 modulates the aversive motivation in Morris water maze (MWM). METHODS AND RESULTS: Using hidden platform training, we observed that AQP4 KO mice significantly decreased their swimming velocity compared with wild-type (WT) mice. To test for a relationship between velocities and escape motivation, we removed the platform and subjected a new group of mice similar to the session of hidden platform training. We found that KO mice exhibited a gradual reduction in swimming velocity, while WT mice did not alter their velocity. In the subsequent probe trial, KO mice after no platform training significantly decreased their mean velocity compared with those KO mice after hide platform training. However, all of KO mice were not impaired in their ability to locate a visible, cued escape platform. CONCLUSIONS: Our findings, along with a previous report that AQP4 regulates memory consolidation, implicate a novel role for this glial protein in modulating the aversive motivation in spatial learning paradigm. PMID- 24165568 TI - Highly confined ions store charge more efficiently in supercapacitors. AB - Liquids exhibit specific properties when they are adsorbed in nanoporous structures. This is particularly true in the context of supercapacitors, for which an anomalous increase in performance has been observed for nanoporous electrodes. This enhancement has been traditionally attributed in experimental studies to the effect of confinement of the ions from the electrolyte inside sub nanometre pores, which is accompanied by their partial desolvation. Here we perform molecular dynamics simulations of realistic supercapacitors and show that this picture is correct at the microscopic scale. We provide a detailed analysis of the various environments experienced by the ions. We pick out four different adsorption types, and we, respectively, label them as edge, planar, hollow and pocket sites upon increase of the coordination of the molecular species by carbon atoms from the electrode. We show that both the desolvation and the local charge stored on the electrode increase with the degree of confinement. PMID- 24165565 TI - Non-antigenic and antigenic interventions in type 1 diabetes. AB - Type 1 diabetes (T1D) results from autoimmune destruction of the pancreatic beta cells. Current T1D therapies are exclusively focused on regulating glycemia rather than the underlying immune response. A handful of trials have sought to alter the clinical course of T1D using various broad immune-suppressors, e.g., cyclosporine A and azathioprine.(1-3) The effect on beta-cell preservation was significant, however, these therapies were associated with unacceptable side effects. In contrast, more recent immunomodulators, such as anti-CD3 and antigenic therapies such as DiaPep277, provide a more targeted immunomodulation and have been generally well-tolerated and safe; however, as a monotherapy there appear to be limitations in terms of therapeutic benefit. Therefore, we argue that this new generation of immune-modifying agents will likely work best as part of a combination therapy. This review will summarize current immune-modulating therapies under investigation and discuss how to move the field of immunotherapy in T1D forward. PMID- 24165569 TI - miR-125b targets erythropoietin and its receptor and their expression correlates with metastatic potential and ERBB2/HER2 expression. AB - BACKGROUND: The microRNA 125b is a double-faced gene expression regulator described both as a tumor suppressor gene (in solid tumors) and an oncogene (in hematologic malignancies). In human breast cancer, it is one of the most down regulated miRNAs and is able to modulate ERBB2/3 expression. Here, we investigated its targets in breast cancer cell lines after miRNA-mimic transfection. We examined the interactions of the validated targets with ERBB2 oncogene and the correlation of miR-125b expression with clinical variables. METHODS: MiR-125b possible targets were identified after transfecting a miRNA mimic in MCF7 cell line and analyzing gene expression modifications with Agilent microarrays and Sylamer bioinformatic tool. Erythropoietin (EPO) and its receptor (EPOR) were validated as targets of miR-125b by luciferase assay and their expression was assessed by RT-qPCR in 42 breast cancers and 13 normal samples. The molecular talk between EPOR and ERBB2 transcripts, through miR-125b, was explored transfecting MDA-MD-453 and MDA-MB-157 with ERBB2 RNA and using RT-qPCR. RESULTS: We identified a panel of genes down-regulated after miR-125b transfection and putative targets of miR-125b. Among them, we validated erythropoietin (EPO) and its receptor (EPOR) - frequently overexpressed in breast cancer--as true targets of miR-125b. Moreover, we explored possible correlations with clinical variables and we found a down-regulation of miR-125b in metastatic breast cancers and a significant positive correlation between EPOR and ERBB2/HER2 levels, that are both targets of miR-125b and function as competing endogenous RNAs (ceRNAs). CONCLUSIONS: Taken together our results show a mechanism for EPO/EPOR and ERBB2 co-regulation in breast cancer and confirm the importance of miR-125b in controlling clinically-relevant cancer features. PMID- 24165570 TI - Diagnostic performance of urinary kidney injury molecule-1 and neutrophil gelatinase-associated lipocalin for acute kidney injury in an obstructive nephropathy patient. AB - AIM: We investigated the diagnostic performance of urinary kidney injury molecule 1 (KIM-1) and neutrophil gelatinase-associated lipocalin (NGAL) for acute kidney injury (AKI) in 90 obstructive nephropathy patients. METHODS: Urine samples were obtained preoperatively and 4, 8, 12, 24, 48 and 72 h postoperatively, and urinary KIM-1 and NGAL contents were measured by enzyme linked immunosorbent assay and corrected against urine creatinine content. The receiver operating characteristic (ROC) curves were used to determine the area under the curve (AUCs) of urinary KIM-1 and NGAL for AKI. RESULTS: The baseline urinary KIM-1 contents were higher in AKI patients than non-AKI patients (P < 0.01). Urinary NGAL contents were also higher in AKI patients than non-AKI patients (P < 0.001). The area under the curve (AUC) of urinary KIM-1 was 0.900 (P = 0.004) and at a cutoff of 338.26 pg/mg Cr, the sensitivity was 90% and the specificity was 75%. The AUC of urinary NGAL was 0.900 (P = 0.004) and at a cutoff of 261.76 ng/mg Cr, the sensitivity was 90% and the specificity was 87.5%. The combined AUC of urinary KIM-1 and NGAL was 0.938 (P = 0.002) with a sensitivity of 90% and a specificity of 100%. Cox regression analysis revealed that urinary KIM-1content 72 h after operation correlated with the prognosis of AKI patients (P = 0.009). When kidney viability was stratified by urinary KIM-1 content 72 h postoperatively, Kaplan-Meier analysis showed that patients with a urinary content of KIM-1 < 138.20 pg/mg had a higher kidney viability rate than those with a urinary content of KIM-1 > 138.20 pg/mg. CONCLUSION: Urinary KIM-1 and NGAL had a good accuracy for detecting AKI. KIM-1 72 h postoperatively can predict the renal outcome of obstructive nephropathy. PMID- 24165571 TI - Prospective study of percutaneous radiofrequency nerve ablation for chronic plantar fasciitis. AB - BACKGROUND: Chronic plantar heel pain is one of the most painful foot conditions and is generally associated with plantar fasciitis. This study reports 2-year follow-up results of radiofrequency nerve ablation (RFNA) of the calcaneal branches of the inferior calcaneal nerve in patients with chronic heel pain associated with plantar fasciitis. METHODS: After receiving approval from the institutional review board, we prospectively evaluated the results of the RFNA of the calcaneal branches of the inferior calcaneal nerve on 35 feet in 29 patients with plantar heel pain between 2008 and 2011. All of the patients who were treated had been complaining of heel pain for more than 6 months and had failed conservative treatment. All of the patients were evaluated (quantitatively) using the average 10-point Visual Analog Scale (VAS) before treatment, as well as at their 1-month, 1-year, and 2-year follow-up after the procedure. We also evaluated 26 feet in 20 patients with American Orthopaedic Foot and Ankle Society scale (AOFAS) scores before the treatment, as well as at their 1-month, 1-year, and 2-year follow-up after the procedure. RESULTS: The average VAS score of the feet was 9.2 +/- 1.9 before treatment, 0.5 +/- 1.3 at 1 month after the procedure, 1.5 +/- 2.1 at 1-year follow-up, and 1.3 +/- 1.8 at 2-year follow-up (P < .001). The average AOFAS scores of the patients were 66.9 +/- 8.1 (range, 44 80) before treatment, 95.2 +/- 6.1 (range, 77-100) at 1 month after the procedure, 93 +/- 7.5 (range, 71-100) at the 1-year follow-up, and 93.3 +/- 7.9 (range, 69-100) at the 2-year follow-up. At the 1- and 2-year follow-up, 85.7% of the patients rated their treatment as very successful or successful. CONCLUSION: These findings suggest that RFNA of the calcaneal branches of the inferior calcaneal nerve was an effective pain treatment option for chronic heel pain associated with plantar fasciitis that did not respond to other conservative treatment options. LEVEL OF EVIDENCE: Level IV, retrospective case series. PMID- 24165572 TI - Cohort study on the percutaneous treatment of displaced intra-articular fractures of the calcaneus. AB - BACKGROUND: To reduce the high rate of soft tissue complications in the treatment of displaced intra-articular fractures of the calcaneus, several minimally invasive techniques have been developed. Little evidence exists on the clinical outcome of these techniques. METHODS: We performed a study on a cohort of 46 fractures treated by the 3-point distraction technique. In 41 fractures, clinical outcome was available. Fractures were classified according to the Essex-Lopresti and Sanders classifications. The clinical outcome was determined using the 3 most frequently used outcome scores. RESULTS: The clinical outcome of our cohort of percutaneous treated intra-articular calcaneal fractures was good to excellent in 69% with the American Orthopaedic Foot and Ankle Society ankle-hindfoot scale (AOFAS) score. This percentage increases to 100% for tongue type fractures alone but decreases to 52% for joint depression type fractures. Infectious complications occurred in 1 (2.4%) and secondary arthrodesis was needed in 3 fractures (7.3%). The Sanders classification showed no prognostic value. The Essex-Lopresti classification was a strong prognosticator with a median AOFAS score of 92 (interquartile range [IQR], 87.8-97.8) for tongue type fractures and 75 (IQR, 63.0-85.0) for joint depression type fractures (P < .001). CONCLUSION: The treatment of displaced intra-articular calcaneal fractures by the 3-point distraction technique was an acceptable alternative to open surgery and other percutaneous techniques. It had a low amount of infectious complications with comparable outcome to open treatment. The computed tomography-based Essex Lopresti classification had a strong prognostic value when fractures were treated by the 3-point distraction technique. The results of this study support the use of the 3-point distraction technique, especially in tongue type fractures. LEVEL OF EVIDENCE: Level IV, retrospective case series. PMID- 24165573 TI - Risk factors for posttraumatic synostosis and outcomes following operative treatment of ankle fractures. AB - BACKGROUND: Distal tibiofibular synostosis is a known but poorly described complication of ankle fractures. The objective of this study was to evaluate the relationship between ankle fracture fixation method and other risk factors in the development of synostosis in posttraumatic operative ankle fractures. Outcomes of patients with no synostosis, incomplete bony bridging, or complete synostosis also were compared. METHODS: All operative ankle fractures from a single surgeon's prospectively collected clinical database were evaluated for the presence of distal tibiofibular synostosis not earlier than 3 months postoperatively. All fractures were treated in a fracture-specific and ligament specific fashion. Syndesmotic screws, when used, were routinely removed no sooner than 4 months after operation. Patient demographic and medical history data as well as injury and fixation profile were evaluated. Incidence of complications was also reviewed. Foot and Ankle Outcome Score (FAOS) and range of motion (ROM) were compared between the groups. RESULTS: Of the 564 ankle fractures included in the study, 91 demonstrated complete synostosis and 46 demonstrated incomplete bony bridging. Multivariate analysis revealed male sex (odds ratio [OR] = 2.82, P < .001), syndesmotic screw fixation (OR = 2.46, P < .001), and tibiotalar dislocation (OR = 1.74, P = .032) to remain significant independent risk factors for the development of incomplete bony bridging or complete synostosis while adjusting for confounding risk factors. Ankles with synostosis also demonstrated significant reduction in dorsiflexion (P = .017), plantarflexion (P = .024), and inversion (P < .001), though patient-reported outcome measures were equivalent with patients without synostosis. CONCLUSION: Syndesmotic screw fixation, male sex, and tibiotalar dislocation were significant risk factors in the formation of postoperative distal tibiofibular synostosis, though patient-reported outcome measures seemed equivalent among patients with and without synostosis. LEVEL OF EVIDENCE: Level III, case control study of prospectively collected registry data. PMID- 24165574 TI - Contrast enhanced ultrasonography prediction of cystic renal mass in comparison to histopathology. AB - OBJECTIVES: To investigate the value of contrast-enhanced ultrasonography (CEUS) in histologic subtype prediction of cystic renal mass. METHODS: Eighty-seven cystic renal masses were scanned by CEUS, and the CEUS findings and pathological results were recorded. The CEUS features of different histologic subtype cystic renal masses were analyzed and compared. RESULTS: Among 87 renal cystic masses, 63 masses were malignant and 24 were benign. CEUS characteristics of benign and malignant cystic renal masses were significantly different. Different subtype cystic renal cell carcinoma had different CEUS imaging appearances. Multilocular cystic renal cell carcinomas (MCRCC) were more likely to be of Bosniak classification III. Clear cell renal cell carcinomas (CCRCC) were significantly more likely to appear as a multilocular cystic pattern combined with Bosniak classification IV. Cystic papillary renal cell carcinomas (PRCC) were more likely to appear as an unilocular cystic pattern combined with Bosniak classification IV. MCRCC combined with benign cystic masses were more likely to be classified as Bosniak classification III, which was significantly different from CCRCCs and PRCCs. CONCLUSIONS: CEUS can be helpful in differentiating MCRCCs and benign cystic masses from CCRCCs and PRCCs. CEUS might be useful in histologic subtype prediction and clinical management of cystic renal mass. PMID- 24165575 TI - Characteristics in the beat-to-beat laser-Doppler waveform indices in subjects with diabetes. AB - MOTIVATIONS: The present study performed laser-Doppler flowmetry (LDF) measurements on the skin surface around the ankle with the aim of verifying if beat-to-beat analysis of the LDF waveform can help to discriminate the microcirculatory-blood-flow (MBF) characteristics between diabetic, prediabetic, and healthy subjects. METHODS: 84 subjects were assigned to three groups (diabetic, prediabetic, and normal) according to the results of oral glucose tolerance tests. Beat-to-beat analysis was performed on the pulsatile LDF waveform to obtain foot delay time (FDT), flow rise time (FRT), and the corresponding MBF-variability parameters (FDTCV and FRTCV). RESULTS: Relative to the control group, FDT and FRT were significantly shorter in prediabetic subjects, FDT was significantly shorter in diabetic subjects, and FRTCV and FDTCV were significantly larger in prediabetic and diabetic subjects. There were no significant associations for FRT after adjustment for age and gender. CONCLUSION: The present results indicate that FRT may help to discriminate differences in the elastic properties of local vascular beds during diabetes or even during prediabetic stages. The proposed blood-filling-volume model can help to explain the underlying mechanism. The present findings may aid the noninvasive early detection of diabetes-associated vascular damage, and could be used in the development of home-care and telemedicine applications. PMID- 24165576 TI - The role of contrast-enhancend ultrasonography (CEUS) in comparison with 99mTechnetium-sestamibi scintigraphy for localization diagnostic of primary hyperparathyroidism. AB - INTRODUCTION: Correct preoperative detection of parathyroid gland adenoma (PA) in the case of primary hyperparathyroidism (pHPT) is the requirement for unilateral cervical exploration associated with lower morbidity. We present our experience with contrast-enhanced ultrasonography (CEUS) as diagnostic tool for the preoperative localization of PA in pHPT in comparison to the (99m)Technetium sestamibi scintigraphy. METHODS: Between 8/2009-5/2013 143 patients with pHPT received surgical interventions in the Department of Surgery at the University Hospital of Regensburg. In all patients contrast-enhanced ultrasonography (CEUS) was performed as diagnostic tool for the localization of pathological parathyroid glands. By one experienced examiner CEUS was performed after bolus injection of 1 2.4 ml contrast agent with storage of digital cine loops from the arterial phase (15-45 s) to the late phase (3 Min). Criteria for a parathyroid adenoma were marginal hypervascularisation in the arterial phase and wash out in the late phase. 74 patients received (99m)Technetium-sestamibi scintigraphy. The sensitivity of both diagnostic tools was analyzed in comparison to the intraoperative and histological findings. RESULTS: CEUS revealed a sensitivity of 95.9% for the detection of pathological parathyroid glands and even of 97.1% for patients without scintigrapy in comparison to 60.8% for (99m)Technetium-sestamibi scintigraphy. Sensitivity of CEUS in patients with negative scintigraphy was 96.3%. In multivariate regression analysis detection of small PA compared to scintigraphy was better by trend but did not reach significance (p = 0.019). Follow-up with a minimum of 8 weeks showed normal serum levels of calcium and parathyroid hormone in all patients except one. CONCLUSIONS: CEUS represents a new diagnostic method for the localization of parathyroid gland adenomas independent on findings in scintigraphy. In the present of appropriate expertise in CEUS no further diagnostic procedures are required. PMID- 24165578 TI - Outcomes of breast cancer in Brazil related to health care coverage: a retrospective cohort study. AB - BACKGROUND: Breast cancer is the most common malignancy in women in Brazil. Differences between patients with public versus private healthcare coverage about general characteristics, disease presentation, treatment of primary tumors, and clinical outcomes have not been fully investigated. METHODS: A national, retrospective cohort of 3,142 patients drawn from a representative sample of Brazilian medical centers was selected. Clinical and demographic data and type of healthcare coverage were retrieved by chart review. Groups were compared using the chi(2) test. The log-rank test was used for comparison of disease-free survival (DFS), postrelapse, and overall survival (OS). Multivariate Cox regression modeling with adjustment for patient characteristics and stage at diagnosis was performed. All P values are two sided. RESULTS: Patients with public health coverage presented with more advanced disease at diagnosis (P < 0.001). DFS and OS for patients presenting with stage 0-II disease did not differ according to the type of healthcare coverage, whereas a significant difference in outcomes was seen for stage III-IV patients (P = 0.002 and P = 0.008, respectively). In a Cox multivariate analysis, no association was found for the type of health coverage with either DFS or OS, but there was an association for postrelapse survival (P < 0.001). CONCLUSION: In Brazil, patients with breast cancer with public health coverage present with more advanced disease, and this possibly explains worse DFS and OS when compared with those with private coverage. IMPACT: Earlier diagnosis and treatment of breast cancer could improve outcomes of women with public health coverage in Brazil. PMID- 24165577 TI - Access to nutritious food, socioeconomic individualism and public health ethics in the USA: a common good approach. AB - Good nutrition plays an important role in the optimal growth, development, health and well-being of individuals in all stages of life. Healthy eating can reduce the risk of chronic diseases, such as heart disease, stroke, diabetes and some types of cancer. However, the capitalist mindset that shapes the food environment has led to the commoditization of food. Food is not just a marketable commodity like any other commodity. Food is different from other commodities on the market in that it is explicitly and intrinsically linked to our human existence. While possessing another commodity allows for social benefits, food ensures survival. Millions of people in United States of America are either malnourished or food insecure. The purpose of this paper is to present a critique of the current food system using four meanings of the common good--as a framework, rhetorical device, ethical concept and practical tool for social justice. The first section of this paper provides a general overview of the notion of the common good. The second section outlines how each of the four meanings of the common good helps us understand public practices, social policies and market values that shape the distal causal factors of nutritious food inaccessibility. We then outline policy and empowerment initiatives for nutritious food access. PMID- 24165579 TI - No link between breast cancer and meningioma: results from a large monoinstitutional retrospective analysis. AB - BACKGROUND: The etiology of meningioma is largely unknown, although breast cancer has been suggested to play a role. METHODS: A monoinstitutional, retrospective analysis was performed at European Institute of Oncology on 12,330 patients with breast cancer. The cumulative incidence of meningioma was estimated using the Kaplan-Meier method and the log-rank test was used to assess differences between groups. RESULTS: In total, 33 patients with meningioma were identified from a study population of 12,330, with a 10-year cumulative incidence of meningioma of 0.37%. We did not find a significantly increased risk of meningioma among patients with breast cancer or an association between the hormonal receptor status and the risk of meningioma (P = 0.65). CONCLUSIONS: Our results do not support a role of breast cancer or endocrine treatments in meningioma development. IMPACT: This analysis adds new information on a debated topic. PMID- 24165580 TI - The histone variant MacroH2A regulates Ca(2+) influx through TRPC3 and TRPC6 channels. AB - The histone variant macroH2A replaces canonical H2A in the designated region of chromatin where its incorporation has the potential to establish a functionally distinct chromatin domain. The transient receptor potential canonical (TRPC) channels are a family of Ca(2+)-permeable cationic channels controlling changes in the cytosolic Ca(2+) concentration. The proper regulation of Trpc gene expression requires chromatin remodeling, but little is known about the nature of these regulatory processes. Here, we show that macroH2A1 represses two Trpc family genes, Trpc3 and Trpc6, and attenuates Ca(2+)-dependent proliferative responses in bladder cancer cells. MacroH2A1 recruits histone deacetylase 1 (HDAC1) and HDAC2 to facilitate its persistent action, resulting in a compromise of histone acetylation across the Trpc3 and Trpc6 loci. Further, macroH2A1 depletion augments histone acetylation and Ca(2+) influx, leading to increased cell growth and invasion. Our data provide new insights into TRPC3/TRPC6-mediated Ca(2+) signaling and indicate a central role for macroH2A1 in regulating transcriptional competence of Trpc3 and Trpc6 genes. PMID- 24165581 TI - One lignanoid compound and four triterpenoid compounds with anti-inflammatory activity from the leaves of Elaeagnus oldhamii maxim. AB - One lignanoid compound, isoamericanol B (1), along with four triterpenoid compounds-cis-3-O-p-hydroxycinnamoyloleanolic acid (2), trans-3-O-p-hydroxy cinnamoyloleanolic acid (3), cis-3-O-p-hydroxycinnamoylursolic acid (4), trans-3 O-p-hydroxycinnamoylursolic acid (5) have been isolated for the first time from the leaves of Elaeagnus oldhamii Maxim. Compounds 1-4 significantly inhibited the expression of NO (nitric oxide) produced in lipopolysaccharide (LPS)-stimulated RAW 264.7 cells. The IC50 value for inhibition of nitrite production of compound 1 was about 10.3 +/- 0.4 MUg/mL. In the cell viability test, however, among compounds 1-4 compound 1 did not significantly change cell viability. Therefore, in this study compound 1 possessed anti-inflammatory effects. The result suggests compound 1 as a potential lead compound for the treatment of inflammatory diseases. PMID- 24165582 TI - 11beta-hydroxyandrostenedione returns to the steroid arena: biosynthesis, metabolism and function. AB - The biological significance of 11beta-hydroxyandrostenedione (11OHA4) has eluded researchers for the past six decades. It is now known that 11OHA4 is biosynthesized in the androgen arm of the adrenal steroidogenesis pathway and subsequently metabolized by steroidogenic enzymes in vitro, serving as precursor to recognized and novel androgenic steroids. These in vitro findings extend beyond the adrenal, suggesting that 11OHA4 could be metabolized in steroid responsive peripheral tissues, as is the case for androgen precursor metabolites of adrenal origin. The significance thereof becomes apparent when considering that the metabolism of 11OHA4 in LNCaP androgen dependent prostate cancer cells yields androgenic steroid metabolites. It is thus possible that 11OHA4 may be metabolized to yield ligands for steroid receptors in not only the prostate but also in other steroid-responsive tissues. Future investigations of 11OHA4 may therefore characterize it as a vital steroid with far-reaching physiological consequences. An overview of the research on 11OHA4 since its identification in 1953 will be presented, with specific focus on the most recent works that have advanced our understanding of its biological role, thereby underscoring its relevance in health and disease. PMID- 24165584 TI - Isosakuranetin-5-O-rutinoside: a new flavanone with antidepressant activity isolated from Salvia elegans Vahl. AB - Ursolic acid (1) and a new flavanone, 5-O-(6-rhamnosylglucoside)-7-hydroxy-4' methoxyflavanone (2), were isolated from the leaves of Salvia elegans Vahl. These natural products displayed antidepressant activity in mice as determined by means of a forced swimming test (FST) evaluation. Structural elucidation was carried out by chemical derivatization (acetylation) and spectroscopic analyses, such as 1H- and 13C-NMR and two-dimensional (2-D) COSY, heteronuclear multiple quantum coherence (HMQC), and heteronuclear multiple-bond correlation (HMBC) spectroscopy experiments. PMID- 24165583 TI - Anti-inflammatory effect of neoechinulin a from the marine fungus Eurotium sp. SF 5989 through the suppression of NF-kB and p38 MAPK Pathways in lipopolysaccharide stimulated RAW264.7 macrophages. AB - In the course of a bioassay-guided study of metabolites from the marine fungus Eurotium sp. SF-5989, two diketopiperazine type indole alkaloids, neoechinulins A and B, were isolated. In this study, we investigated the anti-inflammatory effects of neoechinulins A (1) and B (2) on lipopolysaccharide (LPS)-stimulated RAW264.7 macrophages. Neoechinulin A (1) markedly suppressed the production of nitric oxide (NO) and prostaglandin E2 (PGE2) and the expression of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) in a dose dependent manner ranging from 12.5 uM to 100 uM without affecting the cell viability. On the other hand, neoechinulin B (2) affected the cell viability at 25 uM although the compound displayed similar inhibitory effect of NO production to neoechinulin A (1) at lower doses. Furthermore, neoechinulin A (1) decreased the secretion of pro-inflammatory cytokines, such as tumor necrosis factor-alpha (TNF-alpha) and interleukin-1beta (IL-1beta). We also confirmed that neoechinulin A (1) blocked the activation of nuclear factor-kappaB (NF-kappaB) in LPS-stimulated RAW264.7 macrophages by inhibiting the phosphorylation and degradation of inhibitor kappa B (IkappaB)-alpha. Moreover, neoechinulin A (1) decreased p38 mitogen-activated protein kinase (MAPK) phosphorylation. Therefore, these data showed that the anti inflammatory effects of neoechinulin A (1) in LPS-stimulated RAW264.7 macrophages were due to the inhibition of the NF-kappaB and p38 MAPK pathways, suggesting that neoechinulin A (1) might be a potential therapeutic agent for the treatment of various inflammatory diseases. PMID- 24165585 TI - Collective librations of water molecules in the crystal lattice of rubidium bromide: experiment and simulation. AB - Terahertz spectroscopy of RbBr reveals four prominent absorption lines at room temperature and a further 15 lines at 10 K. Via density-functional-theory (DFT) numerical modelling using the PBE0 hybrid GGA functional, all the absorptions are identified as correlated librations of water molecules in the RbBr lattice. Each libration mode is a combination of rocking, wagging and twisting motions of the water molecules. The number of libration lines and numerical modelling show that the C2v symmetry of water in RbBr is broken. Our modelling shows that the distribution of libration amplitudes and phases for different water molecules in the RbBr unit cell varies greatly between the different modes. All librational lines red-shift with increasing temperature. The rate of change for most lines is in the range 60-90 MHz K(-1) (or (2-3) * 10(-3) cm(-1) K(-1)). Two lines shift more rapidly with temperature, at rates of 240 and 300 MHz K(-1) (or (8 and 10) * 10(-3) cm(-1) K(-1)), respectively. Furthermore, the temperature dependence of the linewidth distinguishes two groups of lines. For one group, with weak linear temperature dependence of linewidth, cubic anharmonic terms in the RbBr crystal field are significant. This group is mainly associated with fully symmetric correlated librations. For the second group, with strong non-linear temperature dependence of the linewidth, quartic anharmonic terms in the RbBr crystal field are significant. However, the distribution of libration amplitudes, as well as the type of libration modes, influence the temperature dependence of the red shift, the linewidth, and the intensity, as well. Our combined experimental and theoretical investigation confirms the necessity of obtaining low-temperature data to observe all the calculated modes; moreover, the richness of detail in the temperature dependence of the data invites further modelling spanning a range of temperatures. PMID- 24165586 TI - Human application of ex vivo expanded umbilical cord-derived mesenchymal stem cells: enhance hematopoiesis after cord blood transplantation. AB - Delayed hematopoietic reconstitution after cord blood (CB) transplantation (CBT) needs to be overcome. Bone marrow-derived mesenchymal stem cells (BMMSCs) have been found to enhance engraftment after hematopoietic stem cell transplantation. However, getting BMMSCs involves an invasive procedure. In this study, umbilical cord-derived mesenchymal stem cells (UCMSCs) were isolated from Wharton's jelly and cryopreserved in the UCMSCs bank. Compared with BMMSCs, we found that UCMSCs had superior proliferative potential. We found that NOD/SCID mice cotransplanted with CB and UCMSCs demonstrated significant human CD45(+) cell engraftment compared with those transplanted with CB alone. Then, 20 patients with high-risk leukemia were prospectively randomized to either receive cotransplantation of CB and ex vivo expanded banked UCMSCs or to receive CBT alone. No serious adverse events were observed in the patients receiving UCMSC infusion. The time to undergo neutrophil engraftment and platelet engraftment was significantly shorter in the eight patients receiving cotransplantation than that in the 12 patients receiving CBT alone (p=0.003 and p=0.004, respectively). Thus, application of ex vivo expanded banked UCMSCs in humans appears to be feasible and safe. UCMSCs can enhance engraftment after CBT, but further studies are warranted. PMID- 24165587 TI - Analysis of the National Surgical Quality Improvement Program database in 19,100 patients undergoing implant-based breast reconstruction: complication rates with acellular dermal matrix. AB - BACKGROUND: The use of acellular dermal matrices has become increasingly popular in immediate and delayed tissue expander/implant-based breast reconstruction. However, it is unclear whether their use is associated with increased postoperative complication rates. Using the American College of Surgeons National Surgical Quality Improvement Program database, the authors assessed baseline differences in demographics and comorbidities with and without acellular dermal matrix and determined whether postoperative complication rates varied. METHODS: Using the national surgical database (2005 to 2011), tissue expander/implant based breast reconstruction cases were extracted using Current Procedural Terminology codes. Differences in preoperative demographics and comorbidities were assessed using chi-square and t test analysis using SPSS. The authors analyzed variations in complication rates and determined whether demographics and comorbidities affected outcomes using multivariate logistical analysis. A post hoc power study was calculated. RESULTS: Of 19,100 cases, 3301 involved acellular dermal matrix use. Overall complication rates were not statistically significant (acellular dermal matrix, 5.3 percent; non-acellular dermal matrix, 4.9 percent; p=0.396). Several risk factors were statistically significant associated factors of complications. Higher body mass index was associated with wound complications in both cohorts. In the non-acellular dermal matrix group, body mass index, smoking, and diabetes were associated with major complications, and radiotherapy and steroid use with minor complications. CONCLUSIONS: Acellular dermal matrix use did not appear to increase complication rates in tissue expander/implant based breast reconstruction in this survey of a national surgical database. There was no significant difference in complication rates between the acellular dermal matrix and non-acellular dermal matrix groups. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, III. PMID- 24165589 TI - Discussion: a matched cohort study of superomedial pedicle vertical scar breast reduction (100 breasts) and traditional inferior pedicle Wise-pattern reduction (100 breasts): an outcomes study over 3 years. PMID- 24165590 TI - Biplanar oncoplastic surgery: a novel approach to breast conservation for small and medium sized breasts. AB - Biplanar oncoplastic surgery represents a novel technique with which to address partial breast reconstruction defects in small to medium sized breasts. Traditional oncoplastic volume displacement techniques may correct contour irregularities but do not address volumetric asymmetries. Volume replacement techniques classically rely on autologous tissue flaps. A biplanar approach, with a combination of glandular rearrangement techniques and volume enhancement with submuscular implants, can result in an alternative approach in select patients to achieve symmetry. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, V. PMID- 24165588 TI - A matched cohort study of superomedial pedicle vertical scar breast reduction (100 breasts) and traditional inferior pedicle Wise-pattern reduction (100 breasts): an outcomes study over 3 years. AB - BACKGROUND: The superomedial pedicle vertical scar breast reduction is gaining popularity for its round, projecting breast and shorter incision when compared with the traditional Wise-pattern reduction using an inferior pedicle. However, there is a paucity of large-volume institutional outcomes studies identifying how this technique fares against more traditional methods of reduction. METHODS: A retrospective review of a prospectively maintained database of bilateral breast reductions over a 3-year period was performed. One hundred superomedial breast reductions (50 patients) were matched to 100 inferior pedicle breast reductions (50 patients). Matching was implemented based on age (+/-3 years) and size of reduction (+/-200 g). Patient demographics, size of reduction, nipple-areola complex sensitivity, minor and major postoperative complications, and symptomatic relief were assessed. Statistical analysis was performed with SAS Version 9.2. RESULTS: Two hundred twelve patients underwent 424 bilateral breast reductions between January of 2009 and June of 2012 at a single institution. Mean volume of tissue reduced was 815 g per breast (range, 200 to 2068 g) and 840 g per breast (range, 250 to 2014 g), respectively. All patients achieved symptomatic relief. No statistical difference in major or minor complications was seen between the two cohorts. No statistical difference in major or minor complications was seen between the two cohorts. No significant difference in complications was seen between small- and large-volume reductions. CONCLUSION: Superomedial pedicle vertical scar breast reduction is a novel, alternative mammaplasty technique with excellent functional and aesthetic outcomes which can be used for a wide range of macromastia without a significant difference in complication rates when compared with traditional Wise pattern inferior pedicle reduction mammaplasty. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, III. PMID- 24165591 TI - Extended lower lid blepharoplasty for eyelid and midface rejuvenation. AB - Many techniques have been described for lower eyelid surgery, and the evolution of these procedures has seen significant advances, from simple skin excision to fat preservation and repositioning. Lower lid blepharoplasty can address lid cheek junction and tear-trough deformities, which cause significant aesthetic concerns for patients, giving the appearance of fatigue and sadness. However, there is potential for serious functional and aesthetic complications, including dry eyes, scleral show, and ectropion. In addition, many surgeons perceive a steep learning curve and difficulty of reliably obtaining excellent cosmetic results. However, the authors have found that an extended lower blepharoplasty can significantly improve eyelid and midface contour, creating substantial aesthetic improvements without visible scars or an operated appearance. In this article, the authors review the relevant pathoanatomical causes of periorbital contour deformities and the evolution and history of lower eyelid surgery, and present the results of their extended blepharoplasty technique in over 300 patients. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, V. PMID- 24165592 TI - Aesthetic evaluation of lipoabdominoplasty in overweight patients. AB - BACKGROUND: The aim of this study was to evaluate the aesthetic results of lipoabdominoplasty in overweight patients (body mass index, 25 to 29.9) compared with normal weight patients (body mass index, 18.5 to 24.9). METHODS: The authors performed a retrospective and comparative analysis of late follow-up results after lipoabdominoplasty performed from 2000 to 2009 in two groups of 30 patients, one with a body mass index of 25 to 29.9 and one with a body mass index of 18 to 24.9. Aesthetic results were evaluated using a scale with five objective parameters, developed in the Faculty of Medicine, University of Sao Paulo. There were seven evaluators: three plastic surgeons, three nondoctors, and the surgeon performing the procedure. RESULTS: For all evaluators, the postoperative average grade was significantly higher than before surgery for the entire group of patients (n=60) and in each subgroup. The average grades for the normal weight group were consistently significantly higher than for the overweight group, both preoperatively and postoperatively, for all evaluators. However, the mean difference between the preoperative and postoperative grades, which measures the aesthetic improvement provided by the operation, was higher in the overweight group. Postoperatively, the average grade of the surgeon was significantly higher than for all other evaluator groups. CONCLUSIONS: The normal weight group showed superior grades, both before and after lipoabdominoplasty, for all evaluators. However, the gain between preoperative and postoperative grades was higher in the overweight patient group, indicating that lipoabdominoplasty was beneficial even in these cases. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, III. PMID- 24165593 TI - Discussion: aesthetic evaluation of lipoabdominoplasty in overweight patients. PMID- 24165594 TI - Discussion: risk factor analysis for capsular contracture: a 5-year Sientra study analysis using round, smooth, and textured implants for breast augmentation. PMID- 24165595 TI - Discussion: risk factor analysis for capsular contracture: a 5-year Sientra study analysis using round, smooth, and textured implants for breast augmentation. PMID- 24165596 TI - Breast implant rupture: causes, incidence, clinical impact, and management. AB - BACKGROUND: Rupture has long been considered one of the key complications of silicone-gel breast implants. The incidence of rupture has been correlated with implant generation, and extensive data on current-generation breast implants, including prospective multicenter clinical trials, are now available from numerous sources. METHODS: Device-retrieval data from breast implant manufacturers were reviewed to identify common factors that likely contribute to rupture. The cumulative incidence of rupture from a prospective clinical study was estimated in multiple ways using the Kaplan-Meier method to demonstrate the need for a uniform calculation methodology. RESULTS: The complexity of identifying, analyzing, and understanding rupture is addressed, and the clinical management of rupture in older generation breast implants lacking highly cohesive gels and barrier layers is reviewed. The data suggest that iatrogenic damage is the most frequent cause of rupture. Data from one manufacturer's prospective breast implant core study are presented to address the complexity of rupture-rate calculations-a single-time-point rupture rate varies from 9.0 to 12.2 percent, depending on which statistical parameters are used. CONCLUSIONS: The significant contribution of iatrogenic damage to overall rupture rate suggests that rupture may be more often operator-related than device-dependent. In addition, there is a critical need to implement uniform statistical methodology using follow-up data only through the patient's last magnetic resonance imaging scan, as rupture rates can vary greatly depending on the statistical methodology selected. Adoption of a uniform standard for rupture rate calculations would enable both patients and surgeons to base clinical decisions on more accurate and consistent information. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, IV. PMID- 24165597 TI - Enhancement of fat graft survival by bone marrow-derived mesenchymal stem cell therapy. AB - BACKGROUND: Adipose-derived stem cells can improve fat graft survival, but there is no literature reporting whether bone marrow-derived mesenchymal stem cells enhance fat graft survival. The authors explored the feasibility of enhancing fat graft survival using bone marrow-derived mesenchymal stem cells. METHODS: Third passage expanded rabbit bone marrow-derived mesenchymal stem cells were characterized by adipocyte and osteocyte differentiation and by CD29 and CD31 expression. Three were three groups of nude mice in this experiment: group A, mesenchymal stem cells; group B, expanded mesenchymal stem cells; group C, Dulbecco's medium as a blank control. The transplanted mixture contained 0.3 ml of adipose granule and 0.2 ml of cell components of 5*106 cells. Four months later, grafts were harvested, weighed, and analyzed. RESULTS: Expanded cells were successfully isolated and identified by fibroblast-like adherent shape and osteogenic and adipogenic differentiation. The results were 24.6+/-3.4 percent for CD29 and 1.8+/-0.4 percent for CD31 in group A, and 45.0+/-4.9 percent for CD29 and 1.6+/-0.3 percent for CD31 in group B. Fat graft survival rates were 0.2052+/-0.0015 g, 0.1761+/-0.0014 g, and 0.1350+/-0.0020 g in groups A, B, and C, respectively (p<0.05). Fat grafts in group A exhibited the best survival and morphologic integrity, uniform lipid droplets, and rich blood vessels; those in group B exhibited modest survival, less integrity, less uniform lipid droplets, and connective tissue septa; and those in group C exhibited some large bubbles, varied sizes of lipid droplets, and significant fibrous septa (p<0.05). The vascular densities for groups A, B, and C were 30.4+/-1.5, 27.2+/-1.3, and 23.3+/ 1.9 capillaries/mm2, respectively (p<0.05). CONCLUSIONS: Bone marrow-derived mesenchymal stem cells and expanded bone marrow-derived mesenchymal stem cells are capable of improving fat graft survival; bone marrow-derived mesenchymal stem cells are more potent than expanded bone marrow-derived mesenchymal stem cells for doing so. PMID- 24165598 TI - Stimulation of the follicular bulge LGR5+ and LGR6+ stem cells with the gut derived human alpha defensin 5 results in decreased bacterial presence, enhanced wound healing, and hair growth from tissues devoid of adnexal structures. AB - BACKGROUND: Discovery of leucine-rich repeat-containing G-protein-coupled receptors 5 and 6 (LGR5 and LGR6) as markers of adult epithelial stem cells of the skin and intestine permits researchers to draw on the intrinsic cellular fundamentals of wound healing and proliferation dynamics of epithelial surfaces. In this study, the authors use the intestine-derived human alpha defensin 5 to stimulate epithelial proliferation, bacterial reduction, and hair production in burn wound beds to provide the field with initial insight on augmenting wound healing in tissues devoid of adnexal stem cells. METHODS: Murine third-degree burn wound beds were treated with (1) intestine-derived human alpha defensin 5, (2) skin-derived human beta defensin 1, and (3) sulfadiazine to determine their roles in wound healing, bacterial reduction, and hair growth. RESULTS: The human alpha defensin 5 peptide significantly enhanced wound healing and reduced basal bacterial load compared with human beta defensin 1 and sulfadiazine. Human alpha defensin 5 was the only therapy to induce LGR stem cell migration into the wound bed. In addition, gene heat mapping showed significant mRNA up-regulation of key wound healing and Wnt pathway transcripts such as Wnt1 and Wisp1. Ex vivo studies showed enhanced cell migration in human alpha defensin 5-treated wounds compared with controls. CONCLUSIONS: Application of human alpha defensin 5 increases LGR stem cell migration into wound beds, leading to enhanced healing, bacterial reduction, and hair production through the augmentation of key Wnt and wound healing transcripts. These findings can be used to derive gut protein-based therapeutics in wound healing. PMID- 24165599 TI - Functional evaluation in the rat sciatic nerve defect model: a comparison of the sciatic functional index, ankle angles, and isometric tetanic force. AB - BACKGROUND: The sciatic functional index has long been the standard method of assessing motor recovery in the rat sciatic nerve model. The relative subjective nature of the assessment has led to development of newer methods, including video gait analysis and quantitative measurement of isometric tetanic muscle force. METHODS: Forty male Lewis rats, each with a 10-mm segmental defect in the sciatic nerve, were divided randomly into two groups: rats in group I underwent repair with reversed autograft, and those in group II received a collagen conduit. Video gait analyses were performed at 0, 4, 8, and 12 weeks, and sciatic functional index and ankle angles in four different walking phases were recorded. Isometric tetanic force of the tibialis anterior muscle was also measured at 12 weeks and correlated with sciatic functional index and video gait analysis data. RESULTS: The sciatic functional index results did not correlate with isometric tetanic force. Significantly, the sciatic functional index could not be measured in 26 percent of the rats at 8 weeks and 59 percent of the rats at 12 weeks secondary to toe contractures. Among various ankle angle measurements, only the ankle angle in toe-off phase correlated well with isometric tetanic force. CONCLUSIONS: Toe contractures occurred more frequently in rats with better nerve recovery, and interfered with evaluation of the motor recovery using the sciatic functional index method. Ankle angle in toe-off phase measured from video gait analysis is a useful parameter that reflects functional recovery of the muscle force. PMID- 24165600 TI - Current trends in the management of proximal interphalangeal joint injuries of the hand. AB - Injuries to the proximal interphalangeal joint are commonly encountered by the hand surgeon. Proper diagnosis and treatment are vital for optimal outcomes. Proper treatment of these injuries requires a working knowledge of the anatomy of the joint and an appreciation for principles for reduction, stabilization, and early rehabilitation to provide the best outcomes possible. Injuries can include fractures of the head of the proximal phalanx, dislocations, fracture dislocations, and fractures of the base of the middle phalanx. Similar to other aspects of plastic surgery, there is little high-level evidence guiding treatment and thus most treatment is based on level III or IV evidence. The goal for treatment of any injury around the proximal interphalangeal joint is to establish a congruent joint and allow for early motion. Stiffness and posttraumatic arthritis are common following these injuries. Salvage procedures are limited to arthrodesis and arthroplasty, neither of which can restore the normal function of the hand. PMID- 24165601 TI - Distal digital replantation. AB - BACKGROUND: Hand surgeons have been hesitant to perform distal digital replantation because of the technical challenges and the perception of a high cost-to-benefit ratio. Recent studies, however, have shown high survival rates and excellent functional and aesthetic results, providing renewed enthusiasm for distal replantation. METHODS: The authors reviewed the literature and summarize key points regarding the surgical treatment, perioperative care, and outcomes of distal digital replantation. They describe specific techniques and considerations for surgical repair in each of four distal zones as described by Sebastin and Chung. RESULTS: Zone 1A replantation involves an artery-only anastomosis of a longitudinal pulp artery. Venous anastomosis first becomes possible in zone 1B. Zone 1C involves periarticular amputations where arthrodesis of the distal interphalangeal joint is usually indicated. Repair of the artery, vein, and nerve is technically optimal in zone 1D, where venous anastomosis should be performed. Overall, survival rates for distal digital replantation are similar to those reported for more proximal replantation. The literature reports good outcomes regarding nail salvage, fingertip sensibility, and range of motion, with restoration of length and aesthetic appearance. CONCLUSIONS: Distal replantation performed at institutions that specialize in microsurgery and specifically tailored to the level of injury is associated with good survival, function, and patient satisfaction and superior aesthetic outcome. More prospective data are needed to evaluate the cost of treatment, psychological outcomes, and functional outcomes of distal replantation compared with revision amputation. PMID- 24165602 TI - Discussion: computer-assisted versus conventional free fibula flap technique for craniofacial reconstruction: an outcomes comparison. PMID- 24165603 TI - The concept and method of closed reduction and internal fixation: a new approach for the treatment of simple zygoma fractures. AB - BACKGROUND: The authors have developed a new minimally invasive surgical procedure for simple zygoma fractures, a closed reduction and internal fixation method, that uses a cannulated cortical screw system. METHODS: From 2007 to 2012, 42 selected patients with simple zygoma fractures without ocular problems or shear at the zygomatic frontal portion were treated with this method. The mean age of the patients was 33 years (range, 13 to 77 years). RESULTS: The authors achieved good repositioning, equivalent to results achieved with conventional procedures in all cases. No notable complication occurred except for minor infection in two cases. Mean operative time was 32 minutes (range, 19 to 58 minutes). Postoperative relapse was found only in the posterior direction (p<0.001), but the distance of that was so small (mean, 0.47 mm) that it did not cause any problem clinically. CONCLUSIONS: Although further improvement might be needed, such as screw specification, the closed reduction and internal fixation method has many advantages: short operative time, less effect on soft tissue, maintenance of bone healing potential, and decreased postoperative pain and swelling. The authors concluded that this method has the potential to become a future surgical procedure for simple zygoma fractures. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, IV. PMID- 24165604 TI - Discussion: the concept and method of closed reduction and internal fixation: a new approach for the treatment of simple zygoma fractures. PMID- 24165605 TI - Mandibular distraction in unilateral craniofacial microsomia: longitudinal results until the completion of growth. AB - BACKGROUND: The purpose of this study was to evaluate the results of long-term follow-up in patients with relatively severe unilateral craniofacial microsomia after mandibular distraction. METHODS: The sample consisted of 26 patients with an average age of 6.08 years at the time of distraction. All patients had nonsyndromic unilateral craniofacial microsomia (Pruzansky-Kaban types IIA, IIB, and III). Follow-up for all patients continued until the completion of growth. The 26 clinical records and posteroanterior cephalograms of the patients, taken before distraction (time 0) and approximately 1, 4, and 11 years (time 1, time 2, and time 3, respectively) after distraction, were used. Four items (i.e., supraorbital tilting angle and occlusal tilting angle to the horizontal reference line, and maxillary and mandibular tilting angles to the vertical reference line) were analyzed at each of the four time intervals. RESULTS: The overall mean distraction amount was 23 mm vertically and 21 mm horizontally. The average cephalometric follow-up was 131.7 months. In this study, the mandibular horizontal and vertical changes after distraction showed a gradual return of the asymmetry with growth in all patients. There were no statistically significant differences in any of the analyzed angles between the preoperative and final records, except for the supraorbital tilting angle. CONCLUSIONS: The longitudinal results achieved by distraction osteogenesis were unstable and generally led to relapse, although they were very good in the early postoperative period. Therefore, further efforts are suggested to find a solution that prevents relapse. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, IV. PMID- 24165606 TI - Quantitative measurement of evolution of postparetic ocular synkinesis treated with botulinum toxin type A. AB - BACKGROUND: The Sunnybrook Facial Grading System is considered one of the best scales available to grade facial motility and postparetic synkinesis. To measure facial landmarks and movement excursion, a new software, the Facial Assessment by Computer Evaluation, has been proposed. The aim of this study was to quantify eye synkinesis improvement after botulinum toxin type A injections using the new software and to compare this method with the Sunnybrook grading system. METHODS: The study included 40 injection sessions on 29 Caucasian outpatients with facial synkinesis. Before and 2 weeks after the injection, patients were evaluated using the Italian version of the Sunnybrook system. Eyelid fissure size at rest, during lip puckering, and while smiling was measured with the new software. RESULTS: After botulinum infiltration, the Sunnybrook grading system showed a global facial improvement with reduction of synkinesis and increase of static and dynamic symmetry. The Facial Assessment software detected an increase of ocular fissure measure at rest, during lip puckering, and especially during smiling, and the improvement was positively correlated with initial asymmetry. A single point of the Sunnybrook system synkinesis score corresponded to a mean difference of 0.77 mm during smiling and 1.0 mm during lip puckering. CONCLUSIONS: The Facial Assessment by Computer Evaluation measure allowed the authors to quantify the improvement of eye synkinesis after botulinum toxin type A injection. The Sunnybrook Facial Grading System provided an immediate instrument with which to monitor treatment in routine clinical practice, whereas the Facial Assessment system gave a more accurate quantitative assessment. CLINICAL QUESTION/LEVEL OF EVIDENCE: Diagnostic, II. PMID- 24165607 TI - Discussion: quantitative measurement of evolution of postparetic ocular synkinesis treated with botulinum toxin type A. PMID- 24165608 TI - Cadaveric study of the posterior pedicle nasoseptal flap: a novel flap for reconstruction of pharyngeal defects and velopharyngeal insufficiency. AB - BACKGROUND: The posterior pedicle nasoseptal flap has been the workhorse for endoscopic reconstruction of medium to large cranial base defects, with excellent outcomes and minimal flap failures. The authors present the anatomical foundations for the use of the nasoseptal flap for reconstruction of soft palate and pharyngeal defects and for surgical treatment of velopharyngeal insufficiency in a cadaveric model. METHODS: Posterior pedicle nasoseptal flaps were endoscopically harvested and transposed to the naso/oropharynx in seven cadavers. The reach and relationships of the flap with nasopharyngeal and oropharyngeal structures were documented. RESULTS: A total of nine nasoseptal flaps (bilateral in two specimens) were transposed into the nasopharynx and oropharynx. The most anterior aspect of the flap was visualized transorally several millimeters inferior to the soft palate in all specimens. Six flaps were sutured transorally to the posterior pharyngeal wall and three were sutured to defects of the soft palate. The width of a fully harvested flap (entire septal mucosa) was more than twice the width of the posterior nasopharyngeal/oropharyngeal wall in all specimens. Nasoseptal flaps were easily tailored endoscopically and transorally with standard instrumentation to fit the defects. CONCLUSIONS: In a cadaveric model, the nasoseptal flap can be transposed into the nasopharynx and upper oropharynx and is a potential alternative for pharyngeal reconstruction and surgical treatment of velopharyngeal insufficiency in patients in whom traditional flaps are not available. The application of this technique for reconstruction of pharyngeal and velar defects is novel, and further studies evaluating clinical outcomes are needed. PMID- 24165609 TI - Reconstruction of the nasolabial fold using a fascia lata sheet graft: a modified technique. AB - A refinement over existing static facial sling techniques to reconstruct the nasolabial fold in longstanding facial palsy is presented. The innovative use of fascia lata sheet graft instead of strips facilitates greater intraoperative control over the contour of the reconstructed fold and provides a wide area of attachments of the graft. This technique has a reduced incidence of complications and can be adjusted with minimal scarring as a secondary procedure if necessary. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, V. PMID- 24165610 TI - Discussion: percutaneous aponeurotomy and lipofilling: a regenerative alternative to flap reconstruction? PMID- 24165611 TI - Discussion: percutaneous aponeurotomy and lipofilling: a regenerative alternative to flap reconstruction? PMID- 24165612 TI - Does mesh location matter in abdominal wall reconstruction? A systematic review of the literature and a summary of recommendations. AB - BACKGROUND: Mesh implantation during abdominal wall reconstruction decreases rates of ventral hernia recurrence and has become the dominant method of repair. The authors provide a comprehensive comparison of surgical outcomes and complications by location of mesh placement following ventral hernia repair with onlay, interposition, retrorectus, or underlay mesh. METHODS: A systematic search of the English literature published from 1996 to 2012 in the PubMed, MEDLINE, and Cochrane library databases was conducted to identify patients who underwent abdominal wall reconstruction using either prosthetic or biological mesh for ventral hernia repair. Demographic information was obtained from each study. RESULTS: Sixty-two relevant articles were included with 5824 patients treated with mesh repair of a ventral hernia between 1996 and 2012. Mesh position included onlay (19.6 percent), underlay (60.7 percent), interposition (6.4 percent), and retrorectus (12.4 percent). Prosthetic mesh was used in 80 percent of repairs and biological mesh in 20 percent. The weighted mean incidences of early events were as follows: wound complications, 19 percent; wound infections, 8 percent; seroma or hematoma formation, 11 percent; and reoperation, 10 percent. The weighted mean incidences of late complications included 8 percent for hernia recurrence and 2 percent for mesh explantation. Recurrence rates were highest for onlay (17 percent) or interposition (17 percent) reinforcement. The infection rate was also highest in the interposition cohort (25 percent). Seroma rates were lowest following a retrorectus repair (4 percent). CONCLUSIONS: Mesh reinforcement of a ventral hernia repair is safe and efficacious, but the location of the reinforcement appears to influence outcomes. Underlay or retrorectus mesh placement is associated with lower recurrence rates. PMID- 24165613 TI - A prospective analysis of 100 consecutive lymphovenous bypass cases for treatment of extremity lymphedema. AB - BACKGROUND: The authors prospectively evaluated the efficacy of lymphovenous bypass in patients with lymphedema secondary to cancer treatment. METHODS: The authors prospectively enrolled 100 consecutive patients with extremity lymphedema secondary to cancer treatment. Sixty-five patients underwent lymphovenous bypass with indocyanine green fluorescent lymphangiography. Evaluation included qualitative assessment and quantitative volumetric analysis before and 3, 6, and 12 months after bypass. RESULTS: Lymphovenous bypass was performed in 89 upper extremities and 11 lower extremities. For upper extremity lymphedemas, the mean preoperative volume differential was 32 percent. Symptom improvement was reported by 96 percent of patients and quantitative improvement was noted by 74 percent. The overall mean volume differential reduction was 33 percent at 3 months, 36 percent at 6 months, and 42 percent at 12 months after surgery. The mean volume differential reductions at 3, 6, and 12 months after lymphovenous bypass in patients with stage 1 or 2 lymphedema (58, 52, and 61 percent, respectively) were significantly larger than those in the patients with stage 3 or 4 lymphedema (12, 16, and 17 percent, respectively). Eleven bypasses were performed in seven patients with lower extremity lymphedema, with a mean preoperative volume differential of 38 percent. Only four (57 percent) of these patients reported symptom improvement; postoperative volume measurements were available for only two of these four. CONCLUSIONS: Lymphovenous bypass can be effective in reducing lymphedema severity, particularly in patients with early-stage upper extremity lymphedema. Indocyanine green lymphangiography accurately identified functional lymphatic vessels and may have a role in objectively assessing lymphedema severity and patient selection. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, IV. PMID- 24165614 TI - Plastic surgeons and the management of trauma: from the JFK assassination to the Boston Marathon bombing. AB - The fiftieth anniversary of the death by assassination of President John Kennedy is an opportunity to pay homage to his memory and also reflect on the important role plastic surgeons have played in the management of trauma. That reflection included a hypothetical scenario, a discussion of the surgical treatment of Kennedy (if he survived) and Governor Connally. The scenario describes the management of cranioplasty in the presence of scalp soft-tissue contracture, reconstruction of the proximal trachea, reconstitution of the abdominal wall, and restoration of a combined radius and soft-tissue defect. The development of diagnostic and therapeutic advances over the past 50 years in the care of maxillofacial trauma is described, including the evolution of imaging, timing of surgery, and operative techniques. Finally, contemporary measures of triage in situations involving mass casualties, as in the Boston Marathon bombings, complete the dedication to President Kennedy. PMID- 24165615 TI - The assassination of John F. Kennedy: revisiting the medical data. AB - Doubt continues to surround the assassination of President Kennedy to this day. Unfortunately, the controversy was not diminished by the multiple commissions and panels that were convened to investigate it. This was in large part because these various panels continued to propagate much of the confusion and lack of precision that plagued the initial medical reports, and introduced some new confusion of their own. Much of this controversy was driven by incomplete information, poor documentation and analysis, and the puzzling decision to withhold key medical evidence both from investigators and the public. However, the preponderance of evidence does show that the single-shooter, three-bullet theory is plausible both medically and scientifically. PMID- 24165616 TI - The Boston marathon bombings: the early plastic surgery experience of one Boston hospital. AB - BACKGROUND: On April 15, 2013, at approximately 2:49 p.m. EDT, two improvised explosive devices detonated near the finish line of the 117th Boston Marathon. Patients were transported from the scene to several trauma centers, including the authors' institution. METHODS: Plastic surgical assessment of patients began in the Emergency Department and then rapidly expanded as the scope of the incident became clear. Daily interdisciplinary meetings involving the acute care surgery, orthopedic surgery, plastic surgery, and nursing services were convened in order to coordinate operating room schedules and treatment plans. An interdisciplinary weekly clinic continued until all patient goals had been reached. RESULTS: Twenty four patients were treated at Beth Israel Deaconess Medical Center within the first 24 hours of the Boston Marathon bombing. Seven were triaged directly to the operating room from the Emergency Department. The Division of Plastic Surgery was directly involved with the care of 11 patients, all of whom were treated surgically within 24 hours of the bombing. Patients were aged 23 to 50 years old. All 11 patients sustained lower extremity injuries with gross contamination. Four patients also sustained significant upper extremity trauma. Injuries included extremity amputations and fractures, soft-tissue loss, impaction of nails and other debris, burns, ocular injury, and ruptured tympanic membranes. CONCLUSIONS: Twenty-four patients received acute care at Beth Israel Deaconess Medical Center following the Boston Marathon bombing. Institution of dedicated interdisciplinary daily rounds, protected operating room block time, and joint follow-up clinic allowed for efficient early diagnosis and treatment of patients' injuries. PMID- 24165617 TI - Where were you when...? Plastic surgeons remember John F. Kennedy. PMID- 24165618 TI - Evolution of face transplant: an argument for a national donor registry. PMID- 24165619 TI - The assassination of JFK: a plastic surgery perspective 50 years later. PMID- 24165622 TI - Inframammary approach to nipple-areola-sparing mastectomy. AB - BACKGROUND: Different approaches have been advocated for performing nipple-areola sparing mastectomy. The inframammary approach has been viewed as having limited applications, particularly in large breasts. The authors review their experience with nipple-areola-sparing mastectomy using the inframammary approach for different breast sizes. METHODS: Between 2005 and 2012, 118 nipple-areola-sparing mastectomies with staged implant-based reconstruction were performed in 80 consecutive patients. Patients with different breast sizes underwent inframammary nipple-areola-sparing mastectomy, except those patients who had very large breasts or those who requested a breast lift. Oncologic data related to tumor size, selection criteria, and recurrences are presented. All nipple-areola sparing mastectomies and reconstructions were performed by the same surgeons (J.K.H. and A.H.S), who operated as a team in performing the mastectomies. RESULTS: Patients were followed up from 6 to 97 months (mean, 33.5 months). There were four recurrences (5 percent), three of which were attributed to the biological behavior of the tumor. The aesthetic outcomes of the reconstructions were analyzed based on nipple location, breast contour, and symmetry: 35 patients (44 percent) had a very good result, 28 (35 percent) had a good result, nine (11 percent) had a fair result, and eight (10 percent) had a poor result. Risk factors and complications affecting the final aesthetic outcome are discussed. CONCLUSIONS: The inframammary approach for nipple-areola-sparing mastectomy is the authors' procedure of choice for small, medium, and large breasts. The team approach to the mastectomy facilitates the procedure, reduces skin-related complications, and results in a better aesthetic outcome. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, IV. PMID- 24165623 TI - Comparing five alternative methods of breast reconstruction surgery: a cost effectiveness analysis. AB - BACKGROUND: The purpose of this study was to assess the cost-effectiveness of five standardized procedures for breast reconstruction to delineate the best reconstructive approach in postmastectomy patients in the settings of nonirradiated and irradiated chest walls. METHODS: A decision tree was used to model five breast reconstruction procedures from the provider perspective to evaluate cost-effectiveness. Procedures included autologous flaps with pedicled tissue, autologous flaps with free tissue, latissimus dorsi flaps with breast implants, expanders with implant exchange, and immediate implant placement. All methods were compared with a "do-nothing" alternative. Data for model parameters were collected through a systematic review, and patient health utilities were calculated from an ad hoc survey of reconstructive surgeons. Results were measured in cost (2011 U.S. dollars) per quality-adjusted life-year. Univariate sensitivity analyses and Bayesian multivariate probabilistic sensitivity analysis were conducted. RESULTS: Pedicled autologous tissue and free autologous tissue reconstruction were cost-effective compared with the do-nothing alternative. Pedicled autologous tissue was the slightly more cost-effective of the two. The other procedures were not found to be cost-effective. The results were robust to a number of sensitivity analyses, although the margin between pedicled and free autologous tissue reconstruction is small and affected by some parameter values. CONCLUSIONS: Autologous pedicled tissue was slightly more cost-effective than free tissue reconstruction in irradiated and nonirradiated patients. Implant based techniques were not cost-effective. This is in agreement with the growing trend at academic institutions to encourage autologous tissue reconstruction because of its natural recreation of the breast contour, suppleness, and resiliency in the setting of irradiated recipient beds. PMID- 24165624 TI - Decision regret following breast reconstruction: the role of self-efficacy and satisfaction with information in the preoperative period. AB - BACKGROUND: The relationship between satisfaction with information and decision regret has not been previously studied in breast reconstruction patients. The objective of this study, therefore, was to assess this relationship and the factors that may influence satisfaction with preoperative information, including self-efficacy (confidence with seeking medical knowledge). METHODS: All patients who underwent breast reconstruction between January of 2009 and March of 2011 were approached to complete the Modified Stanford Self-Efficacy Scale (1 to 10), the satisfaction with information subscale of the BREAST-Q (1 to 100), and the Decision Regret Scale (1 to 100). Two multinomial logistic regression models were built to assess the relationship between patient-reported satisfaction with information and decision regret, and to evaluate the relationship among satisfaction with information, self-efficacy level, and sociodemographic characteristics. RESULTS: In 100 participants (71 percent response rate), the mean Decision Regret Scale score was 9.3+/-17.3 of 100, and the majority of patients experienced no regret (60 percent). We found that regret was significantly reduced when patients were more satisfied with the preoperative information that they received from their plastic surgeons (beta=0.95; 95 percent CI, 0.93 to 0.96). Furthermore, patients reported higher satisfaction with information when they possessed more self-efficacy irrespective of their sociodemographic characteristics (beta=1.06; 95 percent CI, 1.04 to 1.09). CONCLUSIONS: Patients who possess lower levels of self-efficacy are at greater risk for experiencing dissatisfaction with the information that they receive in the preoperative period, and ultimately suffered more regret over their decision to undergo breast reconstruction. CLINICAL QUESTION/LEVEL OF EVIDENCE: Risk, IV. PMID- 24165625 TI - Long-term sensory recovery of nipple-areola complex following superolateral pedicled reduction mammaplasty. AB - BACKGROUND: The aim of this study was to investigate nipple-areola complex sensation at 48-month follow-up following superolateral pedicled reduction mammaplasty using the pressure-specified sensory device. METHODS: Data regarding nipple-areola complex sensation for static and moving one- and two-point discrimination were collected from 30 active group hypertrophic-breasted patients undergoing superolateral pedicled reduction mammaplasty preoperatively, at 6 months, and at 48 months, and from a control group of 30 unoperated women with normal-sized breasts. Breast volume was assessed using the BREAST-V instrument. RESULTS: For the nipple, static one-point discrimination showed that mean pressure thresholds for the active group at 48 months were 4.10 and 4.19 times higher than preoperatively and in the control group (p<0.001), respectively; moving one-point discrimination showed that mean pressure thresholds for the active group at 48 months were 4.08 and 3.23 times higher than preoperatively and in the control group (p<0.001), respectively. For the areola, static one-point discrimination showed that mean pressure thresholds in the active group at 48 months were 4.12 and 4.83 times higher than preoperatively and in the control group (p<0.001), respectively; moving one-point discrimination showed that mean pressure thresholds from the active group at 48 months were 4.56 and 4.46 times higher than preoperatively and in the control group (p<0.001), respectively. CONCLUSIONS: Despite a slight worsening at 6 months after surgery, patients who had undergone superolateral pedicled reduction mammaplasty showed significant nipple-areola complex sensibility reduction at 48-month follow-up. Although the nipple-areola complex of hypertrophic-breasted patients was seen to be nonsignificantly less sensitive than normal-sized breasts, a significant decrease of sensation was observed following reduction mammaplasty. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, II. PMID- 24165626 TI - Outcomes assessment of combination face lift and perioral phenol-croton oil peel. AB - BACKGROUND: Face-lift surgery when combined with perioral phenol-croton oil peel is an underappreciated tool for face rejuvenation. The procedure results in significant central face skin tightening and wrinkle reduction. METHODS: A retrospective review of 47 consecutive patients who underwent simultaneous face lift and perioral peel was performed. The objective measures used to evaluate the change in appearance of the patients included (1) a validated patient satisfaction questionnaire, (2) an evaluation of apparent age, and (3) an evaluation of perioral wrinkles by independent reviewers using a validated model. The assessment of apparent age was performed as follows: preoperative and postoperative photographs were shown randomly to six reviewers, who were asked to estimate the patient's age. The apparent age was compared with the patient's actual age, and the reduction in apparent age was calculated. Improvement in perioral rhytides was evaluated by using the Glogau classification system (range, 1 to 4). RESULTS: Survey results documented overall patient satisfaction, which was rated as 6.5 on a scale of 1 to 7 (with higher scores indicating greater satisfaction). Patients' postoperative apparent age estimate was 8.2 years younger than their real age (p=0.0002). The Glogau classification system score demonstrated a mean reduction of 1.15 (3.3 preoperatively as compared with 2.15 postoperatively, p<0.0001). CONCLUSION: Outcomes measurements, including patient satisfaction, objective evaluation of wrinkle improvement, and significant reduction in apparent age, document the power of this technique. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, IV. PMID- 24165627 TI - Co-culture of human adipose-derived stem cells with tenocytes increases proliferation and induces differentiation into a tenogenic lineage. AB - BACKGROUND: Seeding acellularized tendons with cells is an approach for creating tissue-engineered tendon grafts with favorable biomechanical properties. It was the authors' aim to evaluate whether human adipose-derived stem cells could replace tenocytes for scaffold seeding. METHODS: Adipose-derived stem cells and tenocytes were co-cultured in different ratios (3:1, 1:1, and 1:3) and with three different methods: (1) direct co-culture, (2) tenocyte-conditioned media on adipose-derived stem cells, and (3) an insert system to keep both cell types in the same media without contact. Proliferation, collagen production, and tenogenic marker expression were measured by hematocytometry, immunocytochemistry, enzyme linked immunosorbent assay, and real-time polymerase chain reaction. RESULTS: Proliferation and collagen production were similar for tenocytes and adipose derived stem cells alone. Phenotype difference between adipose-derived stem cells and tenocytes was indicated by higher tenascin C and scleraxis expression in tenocytes. Proliferation was increased in direct co-cultures, especially at an adipose-derived stem cells-to-tenocyte ratio of 3:1, and for tenocytes in adipose derived stem cell-conditioned media. Direct co-culture caused significant up regulation in tenascin C expression in adipose-derived stem cells (4.0-fold; p<005). In tenocyte-conditioned media, tenascin C expression was up-regulated 2.5 fold (p<0.05). In the insert system, tenascin C expression was up-regulated 2.3 fold (p<0.05). CONCLUSIONS: Adipose-derived stem cells are good candidates for tendon tissue engineering because they are similar to tenocytes in proliferation and collagen production. With an optimal ratio of 3:1, they increase proliferation in co-culture and change their phenotype toward a tenogenic direction. PMID- 24165628 TI - Early kinetics of integration of collagen-glycosaminoglycan regenerative scaffolds in a diabetic mouse model. AB - BACKGROUND: Collagen-glycosaminoglycan scaffolds, originally designed to treat severe burns, are now commonly used in patients with complex wounds associated with diabetes mellitus. In this study, the authors investigated how the thickness of the scaffold would affect cellular integration with the diabetic host and whether this can be accelerated using subatmospheric pressure wound therapy devices. METHODS: Collagen-glycosaminoglycan scaffolds, 500 to 2000-MUm thick, were applied to dorsal wounds in genetically diabetic mice. In addition, 1000-MUm collagen-glycosaminoglycan scaffolds with and without silicone were treated with a subatmospheric pressure device (-125 mmHg). On days 5 and 10, cellular and vascular integration of tissues was studied by histology, immunohistochemistry, corrosion casting, and qRT-polymerase chain reaction. RESULTS: Cells and vessels from the wound surface populated the scaffold to form layers with varying cellular density. Areas of high cell density and proliferation were noted at the bottom of the scaffold. Increasing the thickness of the scaffold did not affect the extent of cellular ingrowth, so that thicker scaffolds had a thicker residual acellular layer on the surface. The thickness of cellular ingrowth was stable between days 5 and 10, whereas vessels seen in the scaffolds on day 10 were not yet present on day 5. Subatmospheric pressure devices applied to silicone-covered collagen-glycosaminoglycan scaffolds minimized the granulation tissue formation beneath the scaffold, which enhanced vessel ingrowth. CONCLUSIONS: The early kinetics of cellular integration into collagen-glycosaminoglycan scaffolds is independent of scaffold thickness in a diabetic wound model. Scaffold adherence to the wound and integration can be improved using a subatmospheric pressure device. PMID- 24165629 TI - Table saw injuries: epidemiology and a proposal for preventive measures. AB - BACKGROUND: Table saws are ubiquitous devices in professional, home, and school woodshops that have the potential to cause severe injuries. Many of these injuries results in finger and thumb tendon, nerve, and vascular damage or amputation. Long-term outcomes of these injuries can include functional and sensory deficits. Table saw manufacturers are required to equip saws with blade guards to prevent blade contact; nevertheless, treatment of table saw injuries is a common occurrence in U.S. emergency departments. METHODS: The authors performed a literature search using PubMed and the Cumulative Index to Nursing and Allied Health Literature to compile epidemiology data relevant to table saw injuries. The authors also reviewed the U.S. Consumer Product Safety Commission's briefing package on table saw blade contact injuries. RESULTS: Over 30,000 table saw injuries occur annually. Fingers and hands are the most frequently injured body parts, and lacerations are the most common injuries. Individuals suffering from occupational injuries tend to be younger than those injured during amateur woodworking. A small but important minority of injuries are to students participating in school shop classes. Medical costs for the treatment of table saw injuries are estimated at more than $2 billion every year. CONCLUSIONS: SawStop technology stops the saw blade when contact with skin is made, resulting in a small cut rather than a more complicated laceration or amputation. The application of this novel technology in saw designs can prevent serious injuries that deleteriously affect lives at the personal and societal levels. PMID- 24165630 TI - Reconstruction of the distal ulnar epiphysis with vascularized proximal fibula including epiphysis in children after osteochondroma resection: report of two cases. AB - BACKGROUND: Osteochondromas, especially multiple hereditary osteochondromas, usually cause various deformities of the joints. The authors sometimes find ulnar shortening and acquired wrist varus deformity in distal ulnar osteochondromas and even radial head dislocation resulting in ulnar shortening. In this study, the authors present the clinical outcomes of distal ulnar epiphysis reconstruction in two children using vascularized proximal fibula including the epiphysis after osteochondroma resection. METHODS: The authors used vascularized proximal fibula including the epiphysis as a substitute to reconstruct the distal ulnar epiphysis after osteochondroma resection and investigated the clinical outcome in two patients (aged 4 and 9 years). RESULTS: The wrist deformity was corrected successfully for both cases. Bone union between fibular grafts and hosts was found 2 months postoperatively. The reconstructed distal ulna and contralateral limbs were growing almost simultaneously. The morphology and function were also satisfactory at 1- and 8-year follow-up, respectively. CONCLUSIONS: It is possible to reconstruct the distal ulna after osteochondroma resection and simultaneously keep the ulna in longitudinal growth by using vascularized proximal fibula including the epiphysis in children. However, the growth plate in the reconstructed distal ulnar epiphysis might be prematurely closed approximately 8 years after reconstruction. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, V. PMID- 24165631 TI - Planning surgical reconstruction in Treacher-Collins syndrome using virtual simulation. AB - BACKGROUND: Treacher-Collins syndrome is a rare autosomal dominant condition of varying phenotypic expression. The surgical correction in this syndrome is difficult, and the approach varies between craniofacial departments worldwide. The authors aimed to design standardized tools for planning orbitozygomatic and mandibular reconstruction in Treacher-Collins syndrome using geometric morphometrics. METHODS: The Great Ormond Street Hospital database was retrospectively identified for patients with Treacher-Collins syndrome. Thirteen children (aged 2 to 15 years) who had suitable preoperative three-dimensional computed tomographic head scans were included. Six Treacher-Collins syndrome three-dimensional computed tomographic head scans were quantitatively compared using a template of 96 anatomically defined landmarks to 26 age-matched normal dry skulls. RESULTS: Thin-plate spline videos illustrated the characteristic deformities of retromicrognathia and maxillary and orbitozygomatic hypoplasia in the Treacher-Collins syndrome population. Geometric morphometrics was used in the virtual reconstruction of the orbitozygomatic and mandibular region in Treacher Collins syndrome patients. Intrarater and interrater reliability of the landmarks was acceptable and within a standard deviation of less than 1 mm on 97 percent and 100 percent of 10 repeated scans, respectively. CONCLUSIONS: Virtual normalization of the Treacher-Collins syndrome skull effectively describes characteristic skeletal deformities and provides a useful guide to surgical reconstruction. Size-matched stereolithographic templates derived from thin-plate spline warps can provide effective intraoperative templates for zygomatic and mandibular reconstruction in the Treacher-Collins syndrome patient. CLINICAL QUESTION/LEVEL OF EVIDENCE: Diagnostic, V. PMID- 24165632 TI - Analysis of health-related quality-of-life outcomes and their predictive factors in pediatric patients who undergo otoplasty. AB - BACKGROUND: There are limited data on the effect of otoplasty on health-related quality of life in children with prominent ears. Predictors of health-related quality-of-life outcomes in otoplasty have not been well studied. METHODS: In this retrospective cohort study, 79 patients aged 18 years and younger who underwent otoplasty, and their parents, were asked to complete a survey, which included the Glasgow Children's Benefit Inventory and the Pediatric Quality of Life Inventory, to assess the parent-reported health-related quality-of-life changes and the current health-related quality of life, respectively. Other collected data included demographics, medical history, preoperative psychosocial experiences, motivations and expectations for surgery, postoperative complications, and general satisfaction. RESULTS: Fifty patients (63 percent) replied. Of those, 88 percent reported being more satisfied with the appearance of their ears after otoplasty and 93 percent would choose to have this procedure again if given a second chance. The mean Glasgow Children's Benefit Inventory total score was 24.4 and the mean Pediatric Quality of Life Inventory total score was 94.3 for the Child Self-Report and 93.3 for the Parent Proxy-Report, indicating a positive health-related quality-of-life outcome. Linear regression analysis showed that history of teasing and expectations of a "life-changing" event were significant predictors of the Glasgow Children's Benefit Inventory total score (p<0.01). CONCLUSIONS: In this study, parents reported a significant improvement in their children's health-related quality of life following otoplasty. The children themselves also reported having a generally high health related quality of life after surgery. Possible positive predictive factors to consider include preoperative psychosocial status and expectations. CLINICAL QUESTION/LEVEL OF EVIDENCE: Risk, II. PMID- 24165633 TI - Analysis of surgical treatments for earlobe keloids: analysis of 174 lesions in 145 patients. AB - BACKGROUND: Treatments for earlobe keloids include surgical excision, postoperative radiotherapy, steroid injection, taping stabilization, and pressure therapy. However, to date, there is no universally accepted treatment strategy for earlobe keloid therapy. METHODS: A total of 174 lesions in 145 patients who attended the keloid/scar specialist clinic at the Department of Plastic, Reconstructive, and Aesthetic Surgery, Nippon Medical School, between 2006 and 2011 were included and were classified as having primary keloids or recurring keloids. Mild scars, such as hypertrophic scars, were excluded from this study. Appropriate surgical approaches, postoperative adjuvant therapies, such as radiotherapy, and postsurgical self-management were applied. The postsurgical radiotherapy modalities were 15 Gy administered in three fractions over 3 days and 10 Gy administered in two fractions over 2 days. Recurrence during the following 18-month follow-up period was recorded. RESULTS: Of the 174 lesions, 85.6 percent were primary keloids and 14.4 percent were recurrent keloids. Their recurrence rates were 4.7 percent and 0 percent, respectively. The overall recurrence rate was 4.0 percent. Complications during the 18-month follow-up period were not observed. The groups treated with 15-Gy and 10-Gy postsurgical radiotherapy did not differ significantly in terms of recurrence rate (p>0.05). CONCLUSIONS: Earlobe keloids can be treated by customized plans that involve appropriate surgical modalities, postoperative radiotherapy, and self-management. Postsurgical radiotherapy with 10 Gy of radiotherapy administered in two fractions over 2 days can be used successfully to treat earlobe keloids. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, IV. PMID- 24165634 TI - Validated model for predicting postoperative respiratory failure: analysis of 1706 abdominal wall reconstructions. AB - BACKGROUND: Abdominal wall reconstruction can be associated with significant rates of respiratory events. In this current study, the authors aim to characterize perioperative risk factors associated with postoperative respiratory failure and derive a model with which to predict postoperative respiratory failure. METHODS: The authors reviewed the 2005 to 2010 American College of Surgeons National Surgical Quality Improvement Program databases, identifying encounters for Current Procedural Terminology codes for both hernia repair (49560, 49561, 49565, 49566, and 49568) and component separation (15734). A predictive model of postoperative respiratory failure was developed using logistic regression analyses and validated using a bootstrap technique. RESULTS: Of 1706 patients undergoing complex abdominal reconstructions in the study period, 102 (6.0 percent) experienced postoperative respiratory failure. Patients experiencing postoperative respiratory failure had longer admissions (21.0+/-18.5 versus 5.9+/-5.5 days, p<0.001) and a higher mortality rate (14.7 percent versus 0.1 percent, p<0.001). Multivariate logistic regression revealed eight variables significantly associated with postoperative respiratory failure. A history of chronic obstructive pulmonary disease (p<0.001), dyspnea at rest (p=0.032), dependent functional status (p=0.032), malnutrition (p<0.001), recurrent incarcerated hernia (p=0.006), concurrent intraabdominal procedure (p=0.041), American Society of Anesthesiologists score greater than 3 (p<0.001), and prolonged operative time (p<0.001) were independently associated with higher rates of postoperative respiratory failure. The multivariate model was internally validated using a bootstrap technique and had good discrimination (c statistic=0.78). CONCLUSIONS: A validated predictive model and clinical risk assessment tool of postoperative respiratory failure following abdominal wall reconstruction is presented. Respiratory complications were associated with significantly longer hospital stays and higher rates of mortality. Data derived from this large cohort can be used to risk-stratify patients and to enhance perioperative decision-making. CLINICAL QUESTION/LEVEL OF EVIDENCE: Risk, III. PMID- 24165635 TI - The inferior gluteal artery myocutaneous flap with vascularized fascia lata to reconstruct extended abdominoperineal defects. AB - Abdominoperineal resections have evolved to the point where increasing amounts of skin and pelvic floor are removed, resulting in extensive defects. Many patients receive neoadjuvant chemoradiotherapy and may require adjuvant treatment; thus, primary wound healing is essential. Existing reconstructive techniques may be inadequate and predispose to postoperative complications including wound breakdown and perineal herniation. The authors have developed a novel innervated gluteal flap reconstruction with significant advantages, including preservation of abdominal wall integrity, prone harvest, reliable vascularity, bulky volume, and tailored inset. This robust technique addresses all components required for successful perineal reconstruction comprising dead space obliteration, reconstruction and maintenance of perineal floor integrity, and importation of nonirradiated skin to facilitate primary wound healing. Indications can be extended to include reconstruction of the posterior vaginal wall and large sarcoma/sacrectomy defects. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, IV. PMID- 24165636 TI - Practical management of tendon disorders in the hand. AB - LEARNING OBJECTIVES: After reviewing this article, the participant should be able to: 1. Recognize and treat common tendinopathies such as trigger finger and de Quervain tenosynovitis. 2. Recognize and treat flexor tendon and extensor tendon injuries. 3. Define the different zones where flexor tendon and extensor tendon injuries occur and identify the surgical challenges related to each zone. SUMMARY: Common tendon disorders in the hand range from simple trigger fingers to more complex zone II flexor tendon injuries. The goal of treatment in all cases is to aim for optimal early strength and to create conditions favorable for early rehabilitation to decrease the risk of tendon scarring and subsequent poor range of motion. This CME article reviews the presentation, evaluation, state-of-the art treatment, and outcomes of the treatment of trigger finger, de Quervain tenosynovitis, and flexor tendon and extensor tendon injuries. New developments in the different areas are highlighted to inform the reader of emerging techniques in the treatment of tendon disorders of the hand. PMID- 24165637 TI - From germ theory to germ therapy: skin microbiota, chronic wounds, and probiotics. AB - BACKGROUND: Microorganisms living throughout the body comprise the human "microbiota" and play an important role in health and disease. Recent research suggests that alterations in the skin microbiota may underlie chronic wound pathology. Probiotics are bacteria or yeast that confer a health benefit on the host and may have a role in preventing and treating nonhealing wounds by modulating host-microbe interactions. METHODS: The English literature on skin microbiota, chronic wounds, biofilms, and probiotics is reviewed. RESULTS: Recent evidence indicates that disruption of microbial communities and bacteria-host interactions may contribute to impaired wound healing. Preclinical and human studies highlight the potential of probiotics to prevent or treat various infectious, immune-mediated, and inflammatory diseases. CONCLUSIONS: Advances in molecular sequencing and microbiology have shed light on the importance of the human microbiota in development, health, and disease. Probiotics represent a novel approach to altering the microbial environment with beneficial bacteria. Ongoing challenges include the need for better understanding of therapeutic mechanisms, improved regulation of manufacturing practices, and validation in controlled human trials. Current evidence suggests that probiotic-based therapies have considerable potential to exploit host-microbe relationships and improve clinical outcomes. PMID- 24165638 TI - The volumetric analysis of fat graft survival in breast reconstruction. PMID- 24165639 TI - Reply: the volumetric analysis of fat graft survival in breast reconstruction. PMID- 24165640 TI - Outcomes of traditional cosmetic abdominoplasty in a community setting: a retrospective analysis of 1008 patients. PMID- 24165641 TI - Breast implant procedures under conscious sedation: a 6-year experience in 461 consecutive patients. PMID- 24165642 TI - Reply: breast implant procedures under conscious sedation: a 6-year experience in 461 consecutive patients. PMID- 24165643 TI - Anatomy of the supratrochlear nerve: implications for the surgical treatment of migraine headaches. PMID- 24165644 TI - Reply: anatomy of the supratrochlear nerve: implications for the surgical treatment of migraine headaches. PMID- 24165645 TI - Rib-sparing and internal mammary artery-preserving microsurgical breast reconstruction with the free DIEP flap. PMID- 24165646 TI - Reply: rib-sparing and internal mammary artery-preserving microsurgical breast reconstruction with the free DIEP flap. PMID- 24165647 TI - Scarpa fascia preservation during abdominoplasty: randomized clinical study of efficacy and safety. PMID- 24165648 TI - Reply: scarpa fascia preservation during abdominoplasty: randomized clinical study of efficacy and safety. PMID- 24165649 TI - The influence of procedure delay on resource use: a national study of patients with open tibial fracture. PMID- 24165650 TI - Reply: the influence of procedure delay on resource use: a national study of patients with open tibial fracture. PMID- 24165651 TI - Herbal products that may contribute to hypertension. PMID- 24165652 TI - Importance of the chin in lower facial contour: narrowing genioplasty to achieve a feminine and slim lower face. PMID- 24165653 TI - New incision method for effective execution of endonasal septoplasty. PMID- 24165654 TI - Modified lateral SMASectomy. PMID- 24165655 TI - Deepithelialized oral vestibular flap (boot flap) to correct whistling lip deformity. PMID- 24165656 TI - Analysis of formal complaints in 1840 consecutive primary breast augmentations. PMID- 24165657 TI - Reconstruction of radial forearm donor-site defects with Integra and staged full thickness skin graft. PMID- 24165658 TI - Inclusion of the perforating branch of the tenth intercostal artery in the distal skin paddle of the divided latissimus dorsi flap. PMID- 24165659 TI - Cocaine-induced full-thickness tissue necrosis: a case series. PMID- 24165660 TI - The detection of biomarkers of tobacco smoke exposure in wound fluid: a pilot study. PMID- 24165661 TI - Merkel cell carcinoma: diagnosis, management, and outcomes. PMID- 24165662 TI - Sheep head model for plastic surgery training. PMID- 24165663 TI - Development and regeneration ability of the wax coverage in Nepenthes alata pitchers: a cryo-SEM approach. AB - The morphogenesis of the composite epicuticular wax coverage and regeneration ability of the upper wax layer in Nepenthes alata pitchers were studied using a cryo-scanning electron microscopy. Examination of pitchers of different ages revealed six stages in the wax coverage development. In the first stage, wax crystals resemble those found recently in mature pitches of N. dicksoniana and N. ventricosa. Platelets of the upper wax layer originate from broadened tips of stalks during the last developmental stage. Contrary to previous hypotheses, we found that wax crystals of both layers as well as the stalks connecting them are oriented perpendicularly to the pitcher wall. No changes in the height of the wax coverage were detected in 4-8 weeks after mechanical removal of the upper wax layer from mature pitchers on plants. This indicates that the wax coverage in N. alata pitchers is unable to regenerate. PMID- 24165664 TI - Self-inflicted burns: a systematic review of the literature. AB - Suicide attempts by self-immolation are relatively rare in North America, but the physical, psychological, and social effects on the patients, families, and staff are significant. An understanding of the characteristics of the self-inflicted burn population is imperative to better inform acute, postacute, and long-term care. The goal of the present systematic review is to summarize existing literature findings on self-inflicted burns in the United States. Seven databases were searched for articles published between 1970 and 2011 in the English language, which investigated self-burning. Thirty-two articles met selection criteria for inclusion. Review of the literature revealed that published studies on self-inflicted burns are scarce, inconclusive, and weak in design. Most studies contained limited contextual information and limited data on the long term outcomes of survivors of self-inflicted burn injuries. Despite lack of consistency in data-collection methods and contradictory findings across studies, this review provides insight into both the characteristics of self-immolators and the context in which self-immolation events occur. A picture emerged of a group of individuals who act impulsively in the context of psychiatric and or alcohol/drug disorder, and individuals who may be reacting to stressful life events and loss. Although sparse, the existing data examining long-term outcomes in the self-inflicted burn population indicate that survivors can be successfully rehabilitated, provided that early and intense psychiatric and social interventions are in place. Future investigations are needed to further inform the development of best practices for every phase of treatment and recovery of self-inflicted burn survivors. PMID- 24165665 TI - Chemical burns in children caused by wipes. PMID- 24165666 TI - Burn-injured youth may be at increased risk for long-term anxiety disorders. AB - This study aimed to determine the prevalence of long-term anxiety disorder in burn-injured youth. It is well documented that inpatient pediatric burn patients experience heightened anxiety. However, the prevalence of anxiety disorder in pediatric burn survivors warrants further investigation. Participants completed the Screen for Anxiety Related Disorders, a 41-item self-report measuring anxiety disorder symptomatology. Respondents included 197 pediatric burn survivors, 105 boys, 92 girls, who were between 8 and 18 years of age; the mean age was 12.4 +/- 2.4 years. Mean age at time of injury was 5.8 +/- 3.7 years, with 79% of youth reporting visible scars. There were 77 participants (39%) who screened positive for a possible anxiety disorder with a total anxiety score >=25, and 28% with a total mean score of >=30, more specific to the likely presence of anxiety disorder. Nearly half of the participants (44%) reported symptoms indicating the presence of separation anxiety with a mean score of >=5, and 28% had symptoms indicating the presence of panic disorder and school avoidance disorder. Significant sex differences were observed for anxiety, with girls scoring significantly higher than boys on total anxiety P <= .001 and on all four subscales. Youth attending burn camps for >=5 years reported significantly lower anxiety scores. This study supports the screening of burn-injured youth for anxiety disorder and highlights the importance of educating parents and burn care professionals regarding the symptoms of anxiety disorders. This can help to ensure that pediatric burn survivors receive treatment when anxiety disorder symptoms are present. Screening appears to be especially important for girls. PMID- 24165667 TI - "Burn catatonia": a case report and literature review. AB - Thermal injuries have been recognized to cause significant neuropsychiatric symptoms and disability in their sufferers since the middle of the 20th century, when Drs. Stanley Cobb and Erich Lindemann of the Massachusetts General Hospital (Boston, MA) studied survivors of the Cocoanut Grove nightclub fire in Boston. Although "burn encephalopathy" or burn-induced delirium is a common occurrence in the acute phase, catatonia in burn patients is not often reported. This report describes a case of malignant catatonia occurring in a 51-year-old male patient acutely suffering from burns acquired in a chemical explosion, effectively treated with reinstitution of a selective serotonin reuptake inhibitor. The literature on burn encephalopathy and catatonia in burns is reviewed. Few examples of burn catatonia exist. Burn encephalopathy is common, and may occur in patients with low TBSA burns such as described in the case above. Descriptions of burn encephalopathy are numerous, but have not included catatonia as a possible etiology. Catatonia in burn patients as an etiology of burn encephalopathy is likely underrecognized. Clinicians should be aware of the possibility of catatonia when a patient's confusional state after a burn does not respond to usual care. PMID- 24165668 TI - A case of burn-induced bullous pemphigoid. PMID- 24165669 TI - A prospective clinical study of flow-mediated dilatation in burn injury. AB - The authors investigated endothelial function using flow-mediated dilatation (FMD) in burn patients. This study was done in burn patients with specific criteria on admission. Blood lipid profile at 1st day, high-sensitivity C reactive protein, and FMD were assessed at 1st and 7th days, as well as at 1st and 3rd months. The highest values of high-sensitivity C-reactive protein were detected on the 7th day, which were significantly higher than those at 1st and 3rd months. The lowest value of FMD was observed on the 7th day. FMD values were higher during the 1st month compared with the 7th day. The highest value of FMD was detected in the 3rd month. It was found that FMD values measured at 7th day and 1st month were significantly lower in patients with a burn percentage of 40 or greater. Our results suggest that inflammation is more prominent on 7th day following burn. The decrease in FMD values on 7th day after injury can be attributed to endothelial damage. The increase in FMD on 3rd month after burn is attributable to effective burn treatment and gradual decrease of inflammatory mediators. The data from this study suggest that there is endothelial dysfunction and low-grade inflammation in burn patients. This condition is more prominent in patients with a burn ratio greater than 40%. Burn patients more frequently have impaired FMD, which may be indicative of arterial endothelial dysfunction and a marker for increased atherosclerosis. PMID- 24165671 TI - Keeping New Delhi metallo-beta-lactamase-1 at the door. AB - New Delhi metallo-beta-lactamase-1 is a recently described gene that codes for carbapenem resistance. Inherently transferable between Gram-negative bacteria on a plasmid that also confers extended antibiotic resistance, it represents a potentially serious problem for susceptible patients, such as burn victims, and is spreading globally at a rapid rate. The authors present a case of a septic burn patient returning from India, whose microbiological cultures grew bacteria expressing New Delhi metallo-beta-lactamase-1. His TBSA was 14%. His length of stay as an inpatient was 95 days. This is the first case report of this resistance strain from a U.K. burns unit. Isolation, barrier nursing and the use of hydrogen peroxide vapor decontamination proved effective in limiting transmission and spread. The authors are of the opinion that their experience has implications for the management of similar cases in the future. PMID- 24165670 TI - Wound Coverage Technologies in Burn Care: Established Techniques. AB - Major advances in burn care have reduced post-burn morbidity and mortality. The development and incorporation of new wound healing modalities into the clinical arena have contributed to this improvement by allowing standard-of-care regimens to be established. These regimens range from early excision to the use of cultured epithelial autograft. Here, we review the wound care options that are now well established and used by many burn surgeons. PMID- 24165672 TI - Autophagy genes coordinate with the class II PI/PtdIns 3-kinase PIKI-1 to regulate apoptotic cell clearance in C. elegans. AB - Phagocytosis and autophagy are two lysosome-mediated cellular degradation pathways designed to eliminate extracellular and intracellular constituents, respectively. Recent studies suggest that these two processes intersect. Several autophagy proteins have been shown to participate in clearance of apoptotic cells, but whether and how the autophagy pathway is involved is unclear. Here we showed that loss of function mutations in 19 genes acting at overlapping or distinct stages of autophagy caused increased numbers of cell corpses in C. elegans embryos. In contrast, genes that mediate specific clearance of P granules or protein aggregates through autophagy are dispensable for cell corpse removal. We showed that defective autophagy impairs phagosome maturation and that autophagy genes act in parallel to the class II phosphoinositide (PI)/phosphatidylinositol (PtdIns) 3-kinase PIKI-1 to regulate phagosomal PtdIns3P in a similar manner as VPS-34. Our data indicate that autophagy may coordinate with PIKI-1 to promote phagosome maturation, thus ensuring efficient clearance of apoptotic cells. PMID- 24165673 TI - Unconventional gene regulation in the CNS. PMID- 24165674 TI - Sleep aromatherapy curbs conditioned fear. PMID- 24165675 TI - Best-laid schemes for interneuron origin of mice and men. PMID- 24165676 TI - Adolescent dopamine slows spine maturation. PMID- 24165677 TI - One in a thousand: defining the limits of olfactory perception. PMID- 24165678 TI - Deciphering the functions and regulation of brain-enriched A-to-I RNA editing. AB - Adenosine-to-inosine (A-to-I) RNA editing, in which genomically encoded adenosine is changed to inosine in RNA, is catalyzed by adenosine deaminase acting on RNA (ADAR). This fine-tuning mechanism is critical during normal development and diseases, particularly in relation to brain functions. A-to-I RNA editing has also been hypothesized to be a driving force in human brain evolution. A large number of RNA editing sites have recently been identified, mostly as a result of the development of deep sequencing and bioinformatic analyses. Deciphering the functional consequences of RNA editing events is challenging, but emerging genome engineering approaches may expedite new discoveries. To understand how RNA editing is dynamically regulated, it is imperative to construct a spatiotemporal atlas at the species, tissue and cell levels. Future studies will need to identify the cis and trans regulatory factors that drive the selectivity and frequency of RNA editing. We anticipate that recent technological advancements will aid researchers in acquiring a much deeper understanding of the functions and regulation of RNA editing. PMID- 24165679 TI - Maintaining genome stability in the nervous system. AB - Active maintenance of genome stability is a prerequisite for the development and function of the nervous system. The high replication index during neurogenesis and the long life of mature neurons highlight the need for efficient cellular programs to safeguard genetic fidelity. Multiple DNA damage response pathways ensure that replication stress and other types of DNA lesions, such as oxidative damage, do not affect neural homeostasis. Numerous human neurologic syndromes result from defective DNA damage signaling and compromised genome integrity. These syndromes can involve different neuropathology, which highlights the diverse maintenance roles that are required for genome stability in the nervous system. Understanding how DNA damage signaling pathways promote neural development and preserve homeostasis is essential for understanding fundamental brain function. PMID- 24165680 TI - mTOR complexes in neurodevelopmental and neuropsychiatric disorders. AB - The mechanistic target of rapamycin (mTOR) acts as a highly conserved signaling "hub" that integrates neuronal activity and a variety of synaptic inputs. mTOR is found in two functionally distinct complexes, mTORC1 and mTORC2, that crucially control long-term synaptic efficacy and memory storage. Dysregulation of mTOR signaling is associated with neurodevelopmental and neuropsychiatric disorders. In this Review, we describe the most recent advances in studies of mTOR signaling in the brain and the possible mechanisms underlying the many different functions of the mTOR complexes in neurological diseases. In addition, we discuss the medical relevance of these findings. PMID- 24165681 TI - Emerging roles for post-transcriptional regulation in circadian clocks. AB - Circadian clocks temporally organize behavior and physiology across the 24-h day. Great progress has been made in understanding the molecular basis of timekeeping, with a focus on transcriptional feedback networks that are post-translationally modulated. Yet emerging evidence indicates an important role for post transcriptional regulation, from splicing, polyadenylation and mRNA stability to translation and non-coding functions exemplified by microRNAs. This level of regulation affects virtually all aspects of circadian systems, from the core timing mechanism and input pathways that synchronize clocks to the environment and output pathways that control overt rhythmicity. We hypothesize that post transcriptional control confers on circadian clocks enhanced robustness as well as the ability to adapt to different environments. As much of what is known derives from nonneural cells or tissues, future work will be required to investigate the role of post-transcriptional regulation in neural clocks. PMID- 24165683 TI - Lipoprotein glomerulopathy in China. AB - Lipoprotein glomerulopathy (LPG), a rare renal disease, is mainly reported in Japan and China. Chinese cases of LPG showed similar clinical and pathological features as reports from other countries. Three types of APOE mutation have been detected in those patients: APOE Maebashi (142Arg-144Leu-0) and APOE Kyoto (Arg25 Cys) were initially reported, and APOE Guangzhou (Arg150-Pro) is a novel mutation in Chinese patients with LPG. Asymptomatic carriers of all three mutations exist in families, but serum lipid and apolipoprotein E (apoE) levels are markedly elevated. In most of Chinese patients with LPG, long-term treatment with statins or bezafibrates appears to decrease proteinuria. LPG provides a disease model by which to explore pathogenic roles of apoE in common diseases. PMID- 24165684 TI - Results of the 4D study: ten years of follow-up? AB - Despite the exceedingly high cardiovascular risk in hemodialysis patients, it is uncertain whether statin regimens lead to clinical benefit in this population. KDIGO (Kidney Disease Improving Global Outcomes) guidelines summarize the evidence, stating that initiation of statin treatment is not recommended for most prevalent hemodialysis patients. Since the 4D and AURORA trials did not cover all age and risk ranges, an individualized treatment approach is accepted. Thus, patients and physicians may reasonably choose statin treatment if they are interested in an apparent, but relatively small, uncertain reduction in cardiovascular events. Since very high low-density lipoprotein cholesterol might increase the likelihood of benefit from statins in a dialysis patient, patients who meet this criterion may be more inclined to receive a statin. Other factors that might influence a patient's decision to receive statins could include more severe comorbidity or higher current pill burden-both favoring non-treatment--and recent myocardial infarction or greater life expectancy-both favoring treatment. The latter may be especially true for dialysis patients in Japan. PMID- 24165682 TI - Do transgenesis and marker-assisted backcross breeding produce substantially equivalent plants? A comparative study of transgenic and backcross rice carrying bacterial blight resistant gene Xa21. AB - BACKGROUND: The potential impact of genetically modified (GM) plants on human health has attracted much attention worldwide, and the issue remains controversial. This is in sharp contrast to the broad acceptance of plants produced by breeding through Marker Assisted Backcrossing (MAB). RESULTS: Focusing on transcriptome variation and perturbation to signaling pathways, we assessed the molecular and biological aspects of substantial equivalence, a general principle for food safety endorsed by the Food and Agricultural Organization and the World Health Organization, between a transgenic crop and a plant from MAB breeding. We compared a transgenic rice line (DXT) and a MAB rice line (DXB), both of which contain the gene Xa21 providing resistance to bacterial leaf blight. By using Next-Generation sequencing data of DXT, DXB and their parental line (D62B), we compared the transcriptome variation of DXT and DXB. Remarkably, DXT had 43% fewer differentially expressed genes (DEGs) than DXB. The genes exclusively expressed in DXT and in DXB have pathogen and stress defense functions. Functional categories of DEGs in DXT were comparable to that in DXB, and seven of the eleven pathways significantly affected by transgenesis were also perturbed by MAB breeding. CONCLUSIONS: These results indicated that the transgenic rice and rice from MAB breeding are substantial equivalent at the transcriptome level, and paved a way for further study of transgenic rice, e.g., understanding the chemical and nutritional properties of the DEGs identified in the current study. PMID- 24165685 TI - Obsessive-compulsive symptoms and obsessive-compulsive disorder in adolescents: a population-based study. AB - OBJECTIVES: To estimate the prevalence of obsessive-compulsive symptoms (OCS) and disorder (OCD) among adolescents and to describe OCD characteristics according to gender. METHODS: Participants were selected by cluster sampling at seven high schools in southern Brazil. In the first stage, 2,323 students were screened for OCS; in the second stage, adolescents scoring >= 21 on the OCI-R scale were individually interviewed. OCD diagnosis was established using a semi-structured interview (Schedule for Affective Disorders and Schizophrenia for School Aged Children: Present and Lifetime Version - K-SADS-PL). RESULTS: The past-month estimated prevalence of OCS was 18.3%, and the point estimated prevalence of OCD, 3.3%. Girls showed higher scores (OCS: 24.8 vs. 14.4%; OCD: 4.9 vs. 1.4%; p < 0.001). Only 9.3% of OCD adolescents had been diagnosed and 6.7% received treatment. The most frequent/severe DY-BOCS dimensions were miscellaneous (86.7%; mean score 6.3 +/- 3.8) and symmetry (85.3%; 5.9 +/- 3.8). Female OCD adolescents predominantly showed depression (p = 0.032), and male adolescents, tic disorders (p = 0.006). CONCLUSIONS: OCD is underdiagnosed in adolescents, and few are treated. Future studies should investigate the relationship between OCS and the onset of OCD. PMID- 24165686 TI - Preoperative coping mechanisms have no predictive value for postoperative pain in breast cancer. AB - OBJECTIVE: This study evaluated the relationship between psychological coping mechanisms and symptoms of anxiety and depression in the preoperative and postoperative periods in relation to the intensity of postoperative pain among patients undergoing breast cancer surgery. METHODS: Female patients who were scheduled to receive immediate surgical treatment for breast cancer were invited to participate, and answered the following questionnaires: The Hospital Anxiety and Depression Scale (HADS), the Self Report Questionnaire (SRQ-20), the Coping Strategies Questionnaire (CSQ), and the visual analogue scale (VAS). RESULTS: Of the 139 patients, 122 (87.8%) had an aggressive procedure. Eighty-five patients (61.2%) had a history of preoperative pain while 54 (38.7%) had not. There was no difference in VAS scores between patients subjected to aggressive or non aggressive surgery. Only the CSQ subscale catastrophizing showed correlation with VAS at 24 hours and with HADS/D postoperatively. The HADS scores indicated both anxiety and depression, but did not distinguish patients subjected to aggressive or non-aggressive surgery. CONCLUSIONS: The majority of patients did not exhibit depression and anxiety. Coping mechanisms and pain in the preoperative period did not have a strong predictive value for additional postoperative pain, but those with a higher anxiety score had greater pain. PMID- 24165688 TI - Drugs for Parkinson's disease. AB - Levodopa combined with carbidopa is still the most effective treatment for symptoms of Parkinson's disease. Dopamine agonists, the next most effective class of drugs, can be used alone before the introduction of levodopa or as an adjunct to levodopa.Addition of a peripherally-acting COMT inhibitor or an MAO-B inhibitor to levodopa can reduce motor fluctuations in patients with advanced disease.Amantadine may have mild symptomatic benefit and can decrease levodopa induced dyskinesias.Anticholinergics are rarely used because of their adverse effects, but can be a useful addition to levodopa for control of tremor and drooling.Subcutaneous apomorphine should be available for rescue use in patients with 'off' episodes. Deep brain stimulation is an option for patients with levodopa-induced motor complications and relatively intact cognition. PMID- 24165687 TI - Enhancing intervertebral disc repair and regeneration through biology: platelet rich plasma as an alternative strategy. AB - Intervertebral disc degeneration (IDD) is a common orthopedic disease associated with mechanical changes that may result in significant pain. Current treatments for IDD mainly depend on conservative therapies and spinal surgeries that are only able to relieve the symptoms but do not address the cause of the degeneration and even accelerate the degeneration of adjacent segments. This has prompted research to improve our understanding of the biology of intervertebral disc healing and into methods to enhance the regenerative process. Recently, biological therapies, including active substances, gene therapy and tissue engineering based on certain cells, have been attracting more attention in the field of intervertebral disc repair and regeneration. Early selection of suitable biological treatment is an ideal way to prevent or even reverse the progressive trend of IDD. Growth factors have been enjoying more popularity in the field of regeneration of IDD and many have been proved to be effective in reversing the degenerative trend of the intervertebral disc. Identification of these growth factors has led to strategies to deliver platelet-derived factors to the intervertebral disc for regeneration. Platelet-rich plasma (PRP) is the latest technique to be evaluated for promoting intervertebral disc healing. Activation of the PRP leads to the release of growth factors from the alpha-granules in the platelet cytoplasm. These growth factors have been associated with the initiation of a healing cascade that leads to cellular chemotaxis, angiogenesis, synthesis of collagen matrix, and cell proliferation. This review describes the current understanding of IDD and related biological therapeutic strategies, especially the promising prospects of PRP treatment. Future limitations and perspectives of PRP therapy for IDD are also discussed. PMID- 24165690 TI - Investigation of facet effects on the catalytic activity of Cu2O nanocrystals for efficient regioselective synthesis of 3,5-disubstituted isoxazoles. AB - Cubic, octahedral, and rhombic dodecahedral Cu2O nanocrystals bound by respectively {100}, {111}, and {110} facets were successfully employed to catalyze the [3 + 2] cycloaddition reaction for the regioselective synthesis of 3,5-disubstituted isoxazoles. Surfactant-free nanocrystals having the same total surface area were used for the catalysis. Strongly facet-dependent organocatalytic activity has been observed. Rhombic dodecahedra with fully exposed surface copper atoms on the (110) planes are the most efficient catalysts, followed by octahedra and the least active nanocubes. The particles are also recyclable catalysts. Cu2O rhombic dodecahedra were also used for the syntheses of 3,5-disubstituted isoxazoles from a wide variety of aromatic imidoyl chlorides and terminal alkynes in ethanol at 50 degrees C with excellent yields. Furthermore, a one-pot multi-component synthetic approach was demonstrated to form isoxazoles directly from readily available aldehyde precursors. This work clearly shows that precise facet engineering of Cu2O crystals can lead to significantly improved organocatalytic efficiency. PMID- 24165689 TI - Assessment of liver function in two groups of outdoor workers exposed to arsenic. AB - PURPOSE: To evaluate whether the exposure to arsenic (As) causes alterations of liver enzymes in two groups of outdoor workers. METHODS: Total urinary As and the levels of AST/GOT, ALT/GPT, and GGT were measured on 80 traffic policemen and 50 police drivers. Personal air samples were obtained for assessing the exposure to As on a subgroup of 20 traffic policemen and 20 police drivers. RESULTS: Mean values of personal exposure to As, urinary As, AST/GOT, and ALT/GPT were significantly higher in traffic policemen than in the police drivers. Multiple linear regression models showed associations between urinary As and airborne As, ALT/GPT and the job variables, and BMI and urinary As. CONCLUSIONS: These findings contribute toward the evaluation of the hepatic effects of exposure to As in the urban workers. PMID- 24165692 TI - [-2]proPSA is an early marker for prostate cancer aggressiveness. AB - BACKGROUND: The aim of the study was to evaluate the correlation between preoperative [-2]proPSA, the Gleason Score (GS) and the risk of non-organ confined (NOC) disease in patients undergoing radical prostatectomy (RP). METHODS: Beckman Coulter Access immunoassay was used to study serum specimens of 381 patients enrolled in a prostate cancer (PCa) early detection program. Inclusion criteria were three or more available serum specimens over 4 years before diagnosis. The values obtained were correlated with the GSs and pathological stages of specimens obtained at RP. RESULTS: [-2]proPSA levels were significantly higher in the cancer group (n=208) than in the benign group (n=173). Already 4 years before diagnosis [-2]proPSA differed significantly between PCa and benign prostate in all measured time points, however, highest prediction value was 2 and 1 years before diagnosis (P<0.001). When stratified [ 2]proPSA levels according to GS of RP specimens, [-2]proPSA was highest in patients with >=GS8 and lowest in those with <=GS6.The difference in [-2]proPSA values between GS>=8 and GS<=7 was highly significant (P<0.01) already 3 years before diagnosis. Investigating the correlation between extraprostatic extension and the preoperative [-2]proPSA levels we found preoperative [-2]proPSA values significantly higher in men with NOC PCa compared with organ-confined (OC) cancers.The highest predictive value of [-2]proPSA to differ between OC and extraprostatic extension was found 3 and 2 years before RP. CONCLUSIONS: Patients with high [-2]proPSA levels in the years before cancer diagnosis are at a higher risk of having aggressive PCas. Thus, the [-2]proPSA should be included in the treatment decision-making for managing screen-detected PCa. PMID- 24165691 TI - Patients with nephrolithiasis had lower fetuin-A protein level in urine and renal tissue. AB - Fetuin-A acts as an inhibitor of systemic and local ectopic calcification and inflammatory response, but the role of fetuin-A in the etiology of urolithiasis is still unclear. We aim to investigate the expression of fetuin-A in the serum, urine and renal tissue of patients with or without nephrolithiasis. 48 patients with nephrolithiasis (group A) and 32 individuals without urolithiasis (group B, control group) were enrolled into our study. Level of fetuin-A in serum and urine was measured by ELISA, and expression of fetuin-A in renal tissue was localized and assessed by immunohistochemistry, real-time polymerase chain reaction, and Western blotting, respectively. Indexes of oxidative stress in kidney were evaluated. Other routine serum and urine chemistries for inpatients were measured biochemically. The results showed that fetuin-A expressed widely in the proximal and distal renal tubule, the thin segment of Henle's loop and the collecting duct epithelium. There were no differences in serum fetuin-A level between the two groups. Compared with control group, cellular expression of P47phox and fetuin-A mRNAs in the renal tissue of patients with nephrolithiasis increased, the level of MDA in renal tissue and the level of urinary calcium also increased, but urinary and renal fetuin-A protein and the activities of SOD in renal tissue decreased. Correlation analysis showed that there was a negative correlation between the level of renal fetuin-A protein and the expression of P47phox mRNA and MDA. These results revealed that nephrolithiasis patients had lower fetuin-A protein level in urine and renal tissue. PMID- 24165693 TI - A paper indicator for triple-modality sensing of nitrite based on colorimetric assay, Raman spectroscopy, and electron paramagnetic resonance spectroscopy. AB - Paper indicators based on colorimetric assays are widely used for nitrite detection, but their application to liquids with strong colours is restricted. We report a novel paper indicator that allows for sensing nitrite by colorimetric assay, Raman spectroscopy, and electron paramagnetic resonance spectroscopy with non-overlapping signal wavelength ranges through non-contact means. The paper indicator was prepared by impregnating poly(4-aminostyrene), 2-naphthol and single-walled carbon nanotubes in a regular filter paper. All three ingredients were essential to realize the triple-modality sensing. This method is simple and inexpensive, and promises to have wider applicability than the existing paper indicators. PMID- 24165694 TI - The pendulum swings back to scoliosis screening: screening policies for early detection and treatment of idiopathic scoliosis - current concepts and recommendations. AB - This editorial article initiates the school scoliosis screening thematic series of the Scoliosis journal. The various issues on screening policies are discussed; clinical and practical recommendations of setting up school screening programs are also described. PMID- 24165695 TI - Evolution of radioactive dose rates in fresh sediment deposits along coastal rivers draining Fukushima contamination plume. AB - Measurement of radioactive dose rates in fine sediment that has recently deposited on channel bed-sand provides a solution to address the lack of continuous river monitoring in Fukushima Prefecture after Fukushima Dai-ichi nuclear power plant (FDNPP) accident. We show that coastal rivers of Eastern Fukushima Prefecture were rapidly supplied with sediment contaminated by radionuclides originating from inland mountain ranges, and that this contaminated material was partly exported by typhoons to the coastal plains as soon as by November 2011. This export was amplified during snowmelt and typhoons in 2012. In 2013, contamination levels measured in sediment found in the upper parts of the catchments were almost systematically lower than the ones measured in nearby soils, whereas their contamination was higher in the coastal plains. We thereby suggest that storage of contaminated sediment in reservoirs and in coastal sections of the river channels now represents the most crucial issue. PMID- 24165696 TI - Randomized, double-blind, placebo-controlled, trial of transforaminal epidural etanercept for the treatment of symptomatic lumbar disc herniation. AB - STUDY DESIGN: Multicenter, randomized, double-blind, placebo-controlled trial. OBJECTIVE: To examine the safety and efficacy of three different doses of the tumor necrosis factor alpha (TNF-alpha) inhibitor etanercept versus placebo for the treatment of symptomatic lumbar disc herniation (LDH). SUMMARY OF BACKGROUND DATA: TNF-alpha is considered to be a major cause of radicular leg pain associated with symptomatic LDH. Systemic administration of TNF-alpha inhibitors for sciatica has indicated a trend toward efficacy. METHODS: Forty-nine subjects aged between 18 and 70 years, with persistent lumbosacral radicular pain secondary to LDH, and an average leg pain intensity of 5/10 or more were randomized to 1 of 4 groups: 0.5-mg, 2.5-mg, 12.5-mg etanercept, or placebo. Subjects received 2 transforaminal epidural injections, 2 weeks apart, and were assessed for efficacy up to 26 weeks after the second injection. The primary outcome measure was the change in mean daily worst leg pain (WLP). Secondary outcomes included average leg pain, worst back pain, average back pain, in-clinic pain, Oswestry Disability Index, patient global impression of change, and tolerability. RESULTS: Forty-three of the 49 randomized patients completed the study. Patients receiving 0.5-mg etanercept showed a clinically and statistically significant (P< 0.1) reduction in mean daily WLP compared with the placebo cohort from 2 to 26 weeks for both the per protocol population (-5.13 vs. -1.95; P= 0.066) and the intention-to-treat population (-4.40 vs. -1.84; P= 0.058). Fifty percent of these subjects reported a 100% reduction in WLP 4 weeks post-treatment compared with 0% of subjects in the placebo cohort. Improvements in all secondary outcomes were also observed in the 0.5-mg etanercept cohort. The overall incidence of adverse events was similar in placebo and all etanercept cohorts. CONCLUSION: Two transforaminal injections of etanercept provided clinically significant reductions in mean daily WLP and worst back pain compared with placebo for subjects with symptomatic LDH. Epidural etanercept may offer patients with sciatica a safe and effective nonoperative treatment. PMID- 24165697 TI - The influence of depression and anxiety symptoms on health-related quality of life in patients with atrial fibrillation and atrial flutter. AB - BACKGROUND: The health-related quality of life (HRQoL) of patients with atrial fibrillation (AF) and atrial flutter (AFL) is an important issue in cardiovascular health management. Determinants of poor HRQoL of AF/AFL patients require further elucidation. OBJECTIVES: The purpose of this study was to evaluate the influencing factors related to the HRQoL of AF/AFL patients. METHODS: In 150 consecutively recruited patients in a multicenter, cross sectional study from April 2010 to February 2011, depression and anxiety were measured with the Beck Depression Inventory II and the State Trait Anxiety Inventory, respectively, whereas HRQoL was assessed with the generic Medical Outcomes Survey 36-Item Short-Form Survey version 2 and the Symptom Checklist. Linear regression modeling was performed to determine predictors of HRQoL among variables, including the patients' age, gender, race, marital status, type of AF/AFL, frequency of AF/AFL symptoms, time since diagnosis, and anxiety and depression symptoms. RESULTS: Female patients with AF/AFL reported poorer physical HRQoL than male patients did (P < .001, R2 = 0.391). Symptoms of depression and anxiety were found to be associated with poorer HRQoL (P < .001, R2 = 0.482). Anxiety was the strongest predictor of the mental component of the Medical Outcomes Survey 36-Item Short-Form Survey version 2 and the Symptom Checklist. Younger patients had worse AF/AFL-related symptoms and severity than older patients did (P < .001, R2 = 0.302). Increased frequency of symptomatic episodes was associated with worse AF/AFL-related symptoms and severity. CONCLUSION: In conclusion, depression and anxiety symptoms and female gender emerged as clear indicators of poor HRQoL in AF/AFL patients. These risk factors should be used to identify patients who may require additional evaluation and treatment efforts to manage their cardiac conditions or HRQoL. Interventions to improve HRQoL in these individuals require further investigation. PMID- 24165698 TI - Adherence to a low-sodium diet in patients with heart failure is best when family members also follow the diet: a multicenter observational study. AB - BACKGROUND: Adherence to a low-sodium diet (LSD) is difficult without continuous support from spouses or family members. Whether having a family member follow an LSD improves patient adherence has not been tested objectively. OBJECTIVE: The aim of this study was to examine the effect of family adherence to an LSD on patient adherence to an LSD and to examine whether this effect differed by relationship status and living arrangement. METHODS: In this secondary data analysis, we analyzed data from 379 outpatients with heart failure who had objective evidence of adherence to an LSD (ie, a 24-hour urinary sodium excretion). The t test, analysis of variance, and logistic regressions were used to compare levels of adherence among groups that were categorized by family adherence to an LSD, relationship status, and living arrangement with family member and to predict the likelihood of being adherent to an LSD (24-hour urinary sodium excretion <3000 mg) by the groups. RESULTS: Compared with patients whose family did not follow an LSD, patients whose family member followed an LSD had lower average urinary sodium excretion (3651 vs 4280 mg; P = .003) and were 1.6 times more likely to be adherent to an LSD (95% confidence interval, 1.03-2.4; P = .035). Patients whose spouses followed the LSD had lower sodium excretion than did patients whose spouses did not follow the LSD (3730 vs 4534 mg; P = .012). Patients whose nonspousal family member followed an LSD were 4 times more likely to be adherent than were patients whose spousal member did not follow an LSD (odds ratio, 3.94; 95% confidence interval, 1.81-8.58; P = .001). CONCLUSIONS: Living with a spouse or other family member improved patient adherence to LSD only when the spouse or family member also followed the LSD. These results suggest that interventions aimed at improving LSD adherence should target patient and family member dyads to encourage family members to follow the LSD with patients. PMID- 24165699 TI - Is health-related quality of life a predictor of hospitalization or mortality among women or men with atrial fibrillation? AB - BACKGROUND: Little is known about predictors of mortality or hospitalization in women compared with men in patients with atrial fibrillation (AF). Although there are established gender differences in patients with coronary artery disease (CAD), differences have not been established in AF. OBJECTIVES: The aim of this study was to examine clinical and health-related quality of life (HRQOL) predictors of mortality and 1-year hospitalization in women compared with men with AF. METHODS: Limited-use data from the National Institutes of Health/National Heart, Lung, and Blood Institute Atrial Fibrillation Follow-up Investigation of Rhythm Management clinical trial provided the sample of 693 patients with AF, 262 women and 431 men. Clinical predictors examined were heart failure (HF), CAD, left ventricular ejection fraction, diabetes, stroke, and age. Predictors of HRQOL included overall HRQOL (Medical Outcomes Study Short Form-36 physical [PCS] and mental component scores) and cardiovascular HRQOL using Quality of Life Index-Cardiac Version. RESULTS: Mortality did not differ (women, 11.4%; men, 14.5%; chi(2)1 = 0.437, P = .509) according to gender, with mean 3.5 year follow-up. Different variables independently predicted mortality for women and men. For women, diabetes (hazard ratio [HR], 3.415; P = .003), HF (HR, 2.346; P = .027), stroke (HR, 2.41; P = .032), and age (HR, 1.117; P = .002), and for men, CAD (HR, 1.914; P = 02), age (HR, 1.103, P = < .001), worse PCS (HR, 1.089, P = .001), and worse Quality of Life Index-Cardiac Version score (HR, 1.402, P = .025) independently predicted mortality.One-year hospitalization (women, 38.9%; men, 36.4%) did not differ by gender (chi(2)1 = 0.914, P = .339). Different variables independently predicted 1-year hospitalization-for women: diabetes (odds ratio [OR], 2.359; P = .022), worse PCS (OR, 1.070; P = .003), and rhythm control trial arm (OR, 2.111; P = .006); for men: HF (OR, 2.072; P = .007), worse PCS (OR, 1.045; P = .019), living alone (OR, 1.913; P = .036), and rhythm control trial arm (OR, 2.113; P < .001). CONCLUSION: Only clinical status predicted mortality among women; HRQOL and clinical status predicted mortality among men. Both clinical and HRQOL variables predicted hospitalization for women and men. Increased monitoring of HRQOL and interventions designed to target the clinical and HRQOL predictors could impact mortality and hospitalization. Nursing interventions may prove effective for modifying most of the predictors of mortality and hospitalization for women and men with AF. PMID- 24165701 TI - Decline in health-related quality of life 6 months after coronary artery bypass graft surgery: the influence of anxiety, depression, and personality traits. AB - BACKGROUND: Although coronary artery bypass graft (CABG) is known to improve health-related quality of life (HRQoL), this improvement does not seem to be realized in all patients who had undergone CABG surgery. OBJECTIVE: The aim of this study was to test the direct and indirect influence of personality trait Type D on no change-deterioration trajectories HRQoL and the mediating influence of increased symptoms of anxiety and depression. METHODS: The hypothesized influence of personality trait Type D on the relationship between increased anxiety and depression and no change-deterioration trajectories in HRQoL was tested with path analysis using structural equation modeling. RESULTS: The results of the current study show that Type D personality comprised a vulnerability factor for poor patient-reported outcomes (ie, HRQoL and distress), and despite significant and clinically relevant benefits also for Type D patients after CABG, their well-being remained poorer than that of non-Type D participants at 6 months. Increased levels of anxiety largely mediated the influence of Type D personality on no change-deterioration trajectories in both physical and mental HRQoL, whereas increased symptoms of depression explained deterioration in physical and mental HRQoL without the influence of Type D personality. CONCLUSION: There is evidence that increased symptoms of psychological distress is a strong predictor of no change-deterioration trajectories in HRQoL and that this relationship is influenced by personality trait Type D. We conclude that mediating factors, especially increased anxiety and depression, should be treated adequately in post-CABG clinical routine. PMID- 24165700 TI - The relationship between physical activity and metabolic syndrome in people with chronic obstructive pulmonary disease. AB - BACKGROUND: The prevalence of metabolic syndrome has been reported to be 20% to 50% in people with chronic obstructive pulmonary disease (COPD). Because such people are sedentary and physically inactive, they are at risk of metabolic syndrome. The extent of this problem, however, is not fully understood. OBJECTIVES: This study examined the relationship of sedentary time and physical activity to metabolic syndrome and the components of metabolic syndrome in a population-based sample of people with COPD. METHODS: This was a secondary analysis of existing cross-sectional data. Subjects with COPD (n = 223) were drawn from the National Health and Nutrition Examination Survey data set (2003 2006). Physical activity was measured by accelerometry. Waist circumference, triglyceride level, high-density lipoprotein cholesterol level, blood pressure, and fasting glucose level were used to describe metabolic syndrome. Descriptive and inferential statistics were used for analysis. RESULTS: Fifty-five percent of the sample had metabolic syndrome. No significant differences in sedentary time and level of physical activity were found in people with COPD and metabolic syndrome and people with COPD only. However, those with a mean activity count of greater than 240 counts per minute had a lower prevalence of metabolic syndrome. Waist circumference and glucose level were significantly associated with the time spent in sedentary, light, and moderate to vigorous physical activity. CONCLUSION: Metabolic syndrome is highly prevalent in people with COPD, and greater physical activity and less sedentary time are associated with lower rates of metabolic syndrome. This suggests that interventions to decrease the risk of metabolic syndrome in people with COPD should include both reducing sedentary time and increasing the time and intensity of physical activity. PMID- 24165702 TI - Validity of the aberrant behavior checklist in children with autism spectrum disorder. AB - The Aberrant Behavior Checklist (ABC) is a widely used measure in autism spectrum disorder (ASD) treatment studies. We conducted confirmatory and exploratory factor analyses of the ABC in 1,893 children evaluated as part of the Autism Treatment Network. The root mean square error of approximation was .086 for the standard item assignment, and in exploratory factor analysis, the large majority of items continued to load on the originally assigned factors. Correlations between the ABC subscales and multiple external variables including the Child Behavior Checklist and demographic variables supported the convergent and divergent validity of the ABC as a measure of behavior problems in ASD. Finally, we examined the impact of participant characteristics on subscale scores and present normative data. PMID- 24165703 TI - Investigation on combustion derived BaMgAl10O17:Eu2+ phosphor powder and its corresponding PVP/BaMgAl10O17:Eu2+ nanocomposite. AB - This work focuses on the study of BaMgAl10O17:Eu(2+) (BAM:Eu) nanophosphors prepared by a microwave-assisted combustion procedure and more especially on the polymer/BAM:Eu nanocomposite film suitable for optical devices such as solid state-lighting. Powder presented a specific nanomorphology, highly friable and thus easily ground into fine particles. They were then homogeneously dispersed into a polymer solution (poly(N-vinylpyrrolidone) or PVP) to elaborate a polymer phosphor nanocomposite. The structural, morphological and optical features of the nanocomposite film have been studied and compared to those of a pristine PVP film and BAM:Eu powder. All the characterizations (XRD, SEM, SAXS, etc.) proved that the blue phosphor nanoparticles are well incorporated into the polymer nanocomposite film which exhibited the characteristic blue emission of Eu(2+) under UV light excitation. Furthermore, the photostability of the polymer/phosphor nanocomposite film has been studied after exposure to accelerated artificial photoageing at wavelengths above 300 nm. PMID- 24165704 TI - The role of the nervous system in hematopoietic stem cell mobilization. AB - Hematopoietic stem cells (HSCs) and blood cell progenitors, such as maturing leucocytes, steadily enter from bone marrow (BM) into the circulation under steady-state conditions, and their mobilization is dramatically amplified during stress conditions and by mediators such as granulocyte colony-stimulating factor (G-CSF). This mobilization is dependent upon bone remodeling, the proteolytic enzymes of bone marrow-derived stromal cells, and adhesion molecules such as integrin, but the main mechanisms controlling this traffic are still unclear. The nervous system, as the most important regulator of the body, can affect the mobilization network by secreting catecholamines, so that denervation of catecholaminergic fibers in the BM of mice could lead to declining mobilization in steady state and stress situations, even in the presence of other intact environmental factors in the BM. Thus, due to the importance of the nervous system, we have attempted to give a general overview of how the nervous system is involved in the mobilization of HSCs in this review. Then, we will try to describe the mobilization process induced by the nervous system, which consists of 3 mechanisms: stromal cell-derived factor 1 (SDF-1)/CXC chemokine receptor type 4 (CXCR4), proteolytic enzymes, and bone remodeling. PMID- 24165705 TI - Photodegradation of beta-sheet amyloid fibrils associated with Alzheimer's disease by using polyoxometalates as photocatalysts. AB - Herein we report that POMs can not only inhibit Abeta aggregation but also photodegrade Abeta, especially the oligomers, showing enhanced inhibition effects. PMID- 24165707 TI - Paroxetine (Brisdelle) for hot flashes. PMID- 24165706 TI - Effects of plasma-emulating light emitting diode (LED) versus conventional LED on cytotoxic effects of orthodontic cements as a function of polymerization capacity. AB - OBJECTIVES: The study was aimed at evaluating, in vitro, cytotoxicity of four resin-based orthodontic cements (RBOC) as a function of degree of conversion (DC) and the light curing unit (LCU) employed on mouse fibroblast (L929). MATERIALS AND METHODS: Nine samples were manufactured for each group of cements using plasma-emulating light-emitting diode (LED) and conventional LED. Toxicity was assessed by immersing four specimens to culture medium (24 h/37 degrees C) for extracting residual monomer or cytotoxic substance. Cell mitochondrial activity of L929 cell was evaluated using methyl tetrazolium (MTT) test. DC was evaluated by Fourier transform infrared spectroscopy for five samples. RESULTS: Cements, LCUs, and interaction between cements and LCUs were found to play a statistically significant role in cytotoxicity (p < 0.0001). Opal band cement (OPAL) plasma LED was found noncytotoxic (90-100% cell viability). The other RBOC-LCU combinations were slightly cytotoxic (60-90% cell viability). Cements (p < 0.01) and LCUs (p < 0.05) had a statistically significant effect on DC. Conversely, interaction between cement and LCU had no statistically significant role on DC (p > 0.05). OPAL plasma LED displayed the highest levels of DC. The correlations between cell viability and DC were positive for three RBOCs. CONCLUSION: Therefore, high intensity LCUs can be said to efficiently affect polymerization, so higher DC rates may achieve higher cell viability rates. CLINICAL RELEVANCE: Cements and LCUs must be matched to each another to result in higher DC and maximal biocompatibility. Dual cure systems presented relatively high cell survival and higher DC, thus expressing superior to single-cure systems with plasma LED. PMID- 24165708 TI - Boletero Balance for wrinkles and folds. PMID- 24165709 TI - Topiramate extended-release (Trokendi XR) for epilepsy. PMID- 24165710 TI - In brief: miltefosine for amebic meningeoencephalitis available from CDC. PMID- 24165711 TI - [Decriminalization of doping and public health]. PMID- 24165712 TI - Self-reported early detection activities for breast cancer in Colombia in 2010: impact of socioeconomic and demographic characteristics. AB - OBJECTIVE: To explore which socioeconomic and demographic characteristics influence Colombian women to utilize screening mammography (SMMG). MATERIALS AND METHODS: Data of women aged 40-49 years (n=12 345) and 50-69 years (n=14 771) from the Colombian national survey of demography and health 2010 was analyzed. Risk estimates (odds ratios, OR) of self-reported SMMG use were obtained using logistic regression. RESULTS: Among women aged 50-69 years, high wealth index (OR=4.7; CI95%, 3.9-5.8), affiliation to special or contributory health insurance regime (OR=3.4; CI95% 2.6-4.6 and OR=2.5; CI95% 2.1-3.0 respectively), health consultation in previous year (OR=2.7; CI95% 2.3-3.1), high education level (OR=2.3; CI95% 1.8-2.9) and very good self-reported health (OR=1.5; CI95% 1.1 2.0) positively influenced SMMG utilization. Among women aged 40-49 years, likelihood of having a SMMG was high after a health consultation in the previous year. CONCLUSIONS: Socioeconomic and demographic differences in use of SMMG need to be contemplated in screening recommendations before considering an organized population-based programme. PMID- 24165713 TI - [Hemoglobin values for pregnant women residing at middle altitude]. AB - OBJECTIVE: To determine maternal hemoglobin behavior during pregnancy for middle altitude residents and to compare it with that reported in other populations with or without iron supplementation. MATERIALS AND METHODS: Hematological values from 227 pregnant women residing at 2 240 m altitude (Mexico City), with low obstetric and perinatal risk, and receiving supplementary iron, were compared with reference values obtained from other populations of pregnant women residing at different altitudes, after correcting for altitude. RESULTS: While the hemoglobin values for the first and second trimester of pregnancy in our studied population were similar to those reported for iron-supplemented populations (p>0.05), the third trimester values were similar to those reported for a population without this supplement (p>0.05). CONCLUSIONS: Despite receiving supplementary iron, hemoglobin values during pregnancy from women residing at middle altitude show similar behavior to that reported for pregnant women without iron supplementation. PMID- 24165714 TI - Thinness, overweight and obesity in indigenous youth in Oaxaca, 1970 and 2007. AB - OBJECTIVE: To evaluate change in body mass index (BMI) and weight status of indigenous youth in Oaxaca between the 1970s and 2007. MATERIALS AND METHODS: Heights and weights were measured in cross-sectional samples of school children 6 14 years in the 1970s (2 897) and 2007 (4 305); BMI was calculated. International Obesity Task Force cutoffs for weight status were used. BMI and prevalence of severe and moderate thinness, overweight and obesity were compared by year. RESULTS: BMI increased significantly across time. Primary change in weight status occurred in overweight, 1970s, <2%; 2007, 7 to 12%. Little change occurred in thinness (<2%) and obesity (<= 1%) in both surveys, except in children 6-9 years (obesity=4% in 2007). CONCLUSION: BMI and prevalence of overweight increased across all ages from the 1970s to 2007, but children 6-9 years appeared to be more at risk for obesity than youth 10-14 years. Prevalence of thinness was unchanged. PMID- 24165715 TI - [The role of the Fund against Catastrophic Expenditures in Health on the coverage of patients with cataract]. AB - OBJECTIVE: To describe the effect of the Fund against Catastrophic Expenditures in Health on the provision of services for patients with cataract. MATERIALS AND METHODS: We used administrative dataset on hospital discharges and official figures on population to estimate the rate of care and the coverage for cataract. To estimate the variation on resources, we used data from the National System of Health Information. RESULTS: Coverage for this disease had a significant increase between 2000 and 2010, passing from 24 per thousand cataract patients receiving attention to 58.8 per thousand. This growth is mainly due to the incorporation of cataract to the catalog of diseases covered by the Fund against Catastrophic Expenditures in Health, although this variation is not based on additional resources but in a higher productivity. The growth of services is noticeable in Aguascalientes, Coahuila, Distrito Federal and Nayarit. CONCLUSIONS: Our results suggest that policy-making based on evidence have actually brought benefits for Mexican population. PMID- 24165717 TI - [Barriers to the utilization of HIV/AIDS surveillance data in Mexico]. AB - OBJECTIVE: Qualitative study to identify and understand the barriers to using HIV/AIDS surveillance data experienced at the state level in Mexico. MATERIALS AND METHODS: Eighteen individuals were interviewed in Michoacan, Morelos and Mexico City, including representatives from government and non-government organizations. Transcripts were analyzed thematically based on expected barriers to data utilization drawn from the literature. RESULTS: Four categories of barriers were identified: knowledge and accessibility to existing data, limits on using data, decision-making barriers, and resource barriers. DISCUSSION: This study highlights the factors that influence how local programs use surveillance data to improve their programmatic activities. Two specific areas are identified for potential improvements: awareness and accessibility of surveillance data available, and improving local capacity of officials to use them. PMID- 24165716 TI - [Design and application in Cuba of a construct to identify social dimensions associated with HIV/AIDS discrimination]. AB - OBJECTIVE: This paper presents the design and application in Cuba of a social construct to identify the social dimensions associated with discrimination attitudes towards people with positive diagnosis to HIV. MATERIALS AND METHODS: A combination of qualitative and quantitative methodology was used for the measurement and validation of a construct, and also the K-mean procedure and factor analysis techniques. All these techniques were applied to "Survey on HIV prevention indicators" 2005, 2006 and 2009. RESULTS: A tool for the identification of the most frequent discriminatory attitudes in a specific social context was validated. This instrument allows clustering the population into different typologies, by level of discrimination, and also, to distinguish some social dimensions of this phenomenon. CONCLUSIONS: The results allow distinguishing frequent discriminatory attitudes in any population, focusing the actions in the direction of gradually reducing them, and to evaluate the temporal behavior of this phenomenon. PMID- 24165718 TI - Clinical characteristics and HPV type in recurrent respiratory papillomatosis in Colombia. AB - OBJECTIVE: Describe factors associated with aggressive forms of recurrent respiratory papillomatosis (RRP). MATERIALS AND METHODS: One hundred eighty-nine RRP cases diagnosed between 1985 and 2009 were identified in pathological records. HPV was detected by the SPF-10 method with broad spectrum primers, (version 1). RESULTS: 113 patients had only one surgery (less aggressive) and 76, two or more interventions (more aggressive). The likelihood of aggressive lesions decreased with increasing age at diagnosis and HPV-11 was associated with no significant increase in the risk of aggressiveness. CONCLUSIONS: The age at diagnosis was the main determinant of RRP aggressiveness. PMID- 24165719 TI - At the edge of individual cognitive-behavioural policies: how to walk the public health path to effectively improve population health? AB - Most countries worldwide have recognised the significance of contextual social determinants of health (SDH) on population health. This essay challenges current public health views focused on individual risk-factors and motivates an evidence informed debate in this matter. I argue that despite both international consensus and a growing body of evidence to support the relevance of addressing such more distant SDH through public policies, most governments remain focused on the modification of individual health-risk behaviours like smoking, excessive alcohol consumption, heavily fatted diets and lack of physical exercise. Decades after following this same policy path, many countries have not achieved the expected reduction in rates of health-risk behaviours, and some have even experienced an increase in these risky behaviours over time. Policies addressing contextual SDH might take longer to implement, but could be more effective in the long-run, as structural modifications promote more sustainable changes to a larger proportion of the population. PMID- 24165720 TI - Discourses and polarities concerning health promotion in the Brazilian health system. AB - This paper presents theoretical reflections on health promotion in the Brazilian public health context. Some characteristics and problems of the international debate are highlighted, but our focus is the position of health promotion as it is discussed in the Brazilian health system. We follow the foucauldian perspective of biopower and resistence to discuss the selected texts and documents related to health promotion that were considered relevant for the purpose of this investigation. Health promotion is discussed as a field of discourses, practices, knowledge production and power. We concentrate our analysis on the debate proposed by collective health researchers on the repercussions of the Lalonde Report in the international Health Promotion Charts, and on the connexion between health promotion and the Brazilian health system. The discussion demonstrates that health promotion work requires constant attention and significant effort from managers, technicians, and health system users, and that each step forward reveals new challenges and calls for new actions. PMID- 24165721 TI - [The Mexican Public Health School and its continental interaction: 1945-1982]. AB - This article analyzes a 37 year period during which the Mexican School of Public Health gave priority to teaching over research, related with American projects that promoted students exchange and became part of the group of Latin American Schools of Public Health that created the Latin American association of Public Health Schools (ALAESP). Due to the contribution of the Pan-American Health Organization, the association got together on a regular basis between 1959 and 1979 and the Mexican representatives participated in the discussions held to improve performance within schools and make sure they were all oriented towards the three main priorities: teaching, research and implementation of services in the community. Based upon this context, which was ruled by the OPS, we now analyze the role of the Mexican school in the generation of human resources for health and its performance within the context of Latin American Schools. PMID- 24165723 TI - Taking pan-cancer analysis global. AB - Although federated cooperation is politically desirable, uniform data quality and standards are essential and should not be reinvented from scratch. The International Cancer Genome Consortium (ICGC) will do well to start with the data standards of The Cancer Genome Atlas (TCGA) and the Pediatric Cancer Genome Consortium if it is to succeed in genomic analysis across cancer types. PMID- 24165724 TI - On the robustness of germ cell migration and microRNA-mediated regulation of chemokine signaling. PMID- 24165725 TI - Reply to: "On the robustness of germ cell migration and microRNA-mediated regulation of chemokine signaling". PMID- 24165726 TI - Linking the SWI/SNF complex to prostate cancer. AB - Genes encoding subunits of the SWI/SNF chromatin-remodeling complex constitute, collectively, one of the most frequently mutated targets in cancer. Although mutations in SWI/SNF genes are uncommon in prostate cancer, a new study shows that SChLAP1, a long noncoding RNA frequently expressed in aggressive prostate tumors, drives cancer by directly disrupting SNF5, a core subunit of the SWI/SNF complex. PMID- 24165727 TI - Mining the epigenetic landscape in ALL. AB - The significance of epigenomic aberrations in cancer development has been underscored by the discovery of mutations in key chromatin modifiers, most notably in hematological malignancies. A new study of pediatric acute lymphoblastic leukemia (ALL) demonstrates the usefulness of mapping global epigenetic signatures and applying these data in a framework to identify and characterize underlying somatic genetic alterations in human cancers. PMID- 24165728 TI - No pain, more gain. AB - A new study shows that a specific mutation in SCN11A, which encodes the Nav1.9 voltage-gated sodium channel, underlies a human disorder characterized by insensitivity to pain. This finding provides fresh insights into human pain perception and suggests a new avenue for the development of analgesic drugs. PMID- 24165736 TI - Emerging role of autophagy in pediatric neurodegenerative and neurometabolic diseases. AB - Pediatric neurodegenerative diseases are a heterogeneous group of diseases that result from specific genetic and biochemical defects. In recent years, studies have revealed a wide spectrum of abnormal cellular functions that include impaired proteolysis, abnormal lipid trafficking, accumulation of lysosomal content, and mitochondrial dysfunction. Within neurons, elaborated degradation pathways such as the ubiquitin-proteasome system and the autophagy-lysosomal pathway are critical for maintaining homeostasis and normal cell function. Recent evidence suggests a pivotal role for autophagy in major adult and pediatric neurodegenerative diseases. We herein review genetic, pathological, and molecular evidence for the emerging link between autophagy dysfunction and lysosomal storage disorders such as Niemann-Pick type C, progressive myoclonic epilepsies such as Lafora disease, and leukodystrophies such as Alexander disease. We also discuss the recent discovery of genetically deranged autophagy in Vici syndrome, a multisystem disorder, and the implications for the role of autophagy in development and disease. Deciphering the exact mechanism by which autophagy contributes to disease pathology may open novel therapeutic avenues to treat neurodegeneration. To this end, an outlook on novel therapeutic approaches targeting autophagy concludes this review. PMID- 24165737 TI - 17q21 locus and ORMDL3: an increased risk for childhood asthma. AB - Genetic variations in the 17q21 locus are strongly associated with childhood nonallergic asthma. Expression of the 17q21 genes, orosomucoid like 3 (ORMDL3) and gasdermin B (GSMDB), is affected by these disease-associated variants. However, until recently, no functional connection of the protein products coded by these genes with asthma was known. Lately, it has been identified that ORMDL3 function has been related to various cellular processes that could be relevant for the pathogenesis of asthma. This includes dysregulation of the unfolded protein response (UPR) associated with airway remodeling and also an effect of ORMDL3-dysregulated sphingolipid synthesis on bronchial hyperreactivity. These findings are crucial for a better understanding of the mechanism of childhood asthma and may lead to asthma therapeutics that target pathways previously not thought to be related to this common pediatric respiratory disease. Furthermore, this may validate the unbiased genome-wide association study (GWAS) approach for complex diseases such as asthma, to better define pathomechanisms and drug targets. PMID- 24165738 TI - Single-camera polarization-sensitive full-field optical coherence tomography with polarization switch. AB - We present a single-channel detection-based polarization-sensitive full-field optical coherence tomography (PS-FF-OCT) for simultaneous acquisition of high resolution OCT and linear retardance images. A linearly polarized sub-10-fs laser was used as a broadband light source for the OCT system. A bi-stable polarization switching device, composed of a ferroelectric liquid crystal cell and an analyzer, was employed to get the horizontal and the vertical polarization components of a full-field interference signal. The time-switched two perpendicular interference signals were sequentially recorded by a single charge coupled device camera, then processed to extract en-face functional images of a biological sample. The rat tail tendon was imaged ex vivo to confirm the imaging feasibility of the proposed system, which showed axial and transverse resolutions of 2 and 1.3 MUm, respectively. PMID- 24165739 TI - Dynamic near-infrared imaging reveals transient phototropic change in retinal rod photoreceptors. AB - Stiles-Crawford effect (SCE) is exclusively observed in cone photoreceptors, but why the SCE is absent in rod photoreceptors is still a mystery. In this study, we employed dynamic near infrared light imaging to monitor photoreceptor kinetics in freshly isolated frog and mouse retinas stimulated by oblique visible light flashes. It was observed that retinal rods could rapidly (onset: ~10 ms for frog and 5 ms for mouse; time-to-peak: ~200 ms for frog and 30 ms for mouse) shift toward the direction of the visible light, which might quickly compensate for the loss of luminous efficiency due to oblique illumination. In contrast, such directional movement was negligible in retinal cones. Moreover, transient rod phototropism could contribute to characteristic intrinsic optical signal (IOS). We anticipate that further study of the transient rod phototropism may not only provide insight into better understanding of the nature of vision but also promise an IOS biomarker for functional mapping of rod physiology at high resolution. PMID- 24165740 TI - Changes induced by peripheral nerve injury in the morphology and nanomechanics of sensory neurons. AB - Peripheral nerve injury in vivo promotes a regenerative growth in vitro characterized by an improved neurite regrowth. Knowledge of the conditioning injury effects on both morphology and mechanical properties of live sensory neurons could be instrumental to understand the cellular and molecular mechanisms leading to this regenerative growth. In the present study, we use differential interference contrast microscopy, fluorescence microscopy, and atomic force microscopy (AFM) to show that conditioned axotomy, induced by sciatic nerve injury, does not increase somatic size of sensory neurons from adult mice lumbar dorsal root ganglia but promotes the appearance of longer and larger neurites and growth cones. AFM on live neurons is also employed to investigate changes in morphology and membrane mechanical properties of somas of conditioned neurons following sciatic nerve injury. Mechanical analysis of the soma allows distinguishing neurons having a regenerative growth from control ones, although they show similar shapes and sizes. PMID- 24165741 TI - Wide velocity range Doppler optical microangiography using optimized step scanning protocol with phase variance mask. AB - We propose a simple and optimized method for acquiring a wide velocity range of blood flow using Doppler optical microangiography. After characterizing the behavior of the scanner in the fast scan axis, a step-scanning protocol is developed by utilizing repeated A-scans at each step. Multiple velocity range images are obtained by the high-pass filtering and Doppler processing of complex signals between A-scans within each step with different time intervals. A phase variance mask is then employed to segment meaningful Doppler flow signals from noisy phase background. The technique is demonstrated by imaging in vivo mouse brain with skull left intact to provide bidirectional images of cerebral blood flow with high quality and wide velocity range. PMID- 24165742 TI - Feasibility of confocal fluorescence microscopy for real-time evaluation of neoplasia in fresh human breast tissue. AB - Breast cancer management could be improved by developing real-time imaging tools to assess tissue architecture without extensive processing. We sought to determine whether confocal fluorescence microscopy (CFM) provides sufficient information to identify neoplasia in breast tissue. Breast tissue specimens were imaged following proflavine application. Regions of interest (ROIs) were selected in histologic slides and in the corresponding region on confocal images, and then divided into sets for training and validation. Readers reviewed images in the training set and evaluated images in the validation set for the presence of neoplasia. Accuracy was assessed using histologic diagnosis as the gold standard. Seventy tissue specimens from 31 patients were imaged; 235 ROIs were identified and diagnosed as neoplastic or non-neoplastic. A training set was assembled using 23 matched ROIs; 49 matched ROIs were assembled into a validation set. Neoplasia was identified in histologic images: 93% sensitivity, 97% specificity [area under the curve (AUC=0.987)] and in confocal images: 93% sensitivity 93% specificity (AUC=0.957). CFM produced images of architectural features in breast tissue comparable with conventional histology, while requiring little processing. Potential applications include assessment of excised tissue margins and evaluation of tissue adequacy for bio-banking and genomic studies. PMID- 24165743 TI - Characterization of blood using terahertz waves. AB - We show that terahertz (THz) time-domain spectroscopy (TDS) can be used to characterize the blood. The complex optical constants of blood and its constituents, such as water, plasma, and red blood cells (RBCs), were obtained in the THz frequency region. The volume percentage of RBCs in blood was extracted and compared with the conventional RBC counter results. The THz absorption constants are shown to vary linearly with the RBC concentration in both normal saline and whole blood. The excellent linearity between the THz signal and the RBC concentration was also confirmed in a polyurethane resin tube using a THz imaging method. These results demonstrate that THz-TDS imaging can facilitate the quantitative analysis of blood. PMID- 24165744 TI - Substantiation of medical and technical requirements for noninvasive spectrophotometric diagnostic devices. AB - A scientific approach to the formulation of medical and technical requirements (MTRs) for noninvasive spectrophotometric diagnostic devices using optical technologies such as laser Doppler flowmetry and absorption spectroscopy is proposed. The theoretical modeling framework, metrological certification, and testing of these devices are still in the early stages of development. The theoretical estimation of the received signal levels for wavelengths between 514 and 940 nm is highly dependent on the blood volume level in the subject tissue. The proposed approach allows, in particular, the calculation of technical and metrological performance constraints of the instruments, such as the ranges of the sensitivity and power-related signal-to-noise ratios for different spectral channels and different biomedical (biochemical and physiological) parameters. Substantiation of specialized MTRs for the noninvasive spectrophotometric diagnostic devices can enable them to develop to the level of standardized measurement techniques. PMID- 24165745 TI - Mineral loss and color change of enamel after bleaching and staining solutions combination. AB - Pigments of food and beverages could affect dental bleaching efficacy. The aim of this investigation was to evaluate color change and mineral loss of tooth enamel as well as the influence of staining solutions normally used by adolescent patients undergoing home bleaching. Initial hardness and baseline color were measured on enamel blocks. Specimens were divided into five groups (n=5): G1 (control) specimens were kept in artificial saliva throughout the experiment (3 weeks); G2 enamel was exposed to 10% carbamide peroxide for 6 h daily, and after this period, the teeth were cleaned and stored in artificial saliva until the next bleaching session; and G3, G4, and G5 received the same treatments as G2, but after bleaching, they were stored for 1 h in cola soft drink, melted chocolate, or red wine, respectively. Mineral loss was obtained by the percentage of hardness reduction, and color change was determined by the difference between the data obtained before and after treatments. Data were subjected to analysis of variance and Fisher's test (alpha=0.05). G3 and G5 showed higher mineral loss (92.96 +/- 5.50 and 94.46 +/- 1.00, respectively) compared to the other groups (p <= 0.05). G5 showed high-color change (9.34 +/- 2.90), whereas G1 presented lower color change (2.22 +/- 0.44) (p <= 0.05). Acidic drinks cause mineral loss of the enamel, which could modify the surface and reduce staining resistance after bleaching. PMID- 24165746 TI - Environmental context shapes the bacterial community structure associated to Peltigera cyanolichens growing in Tierra del Fuego, Chile. AB - The structure of the associated bacterial community of bipartite cyanolichens of the genus Peltigera from three different environmental contexts in the Karukinka Natural Park, Tierra del Fuego, Chile, was assessed. The sampling sites represent different habitat contexts: mature native forest, young native forest and grassland. Recently it has been determined that the bacterial community associated to lichens could be highly structured according to the mycobiont or photobiont identities, to the environmental context and/or to the geographic scale. However, there are some inconsistencies in defining which of these factors would be the most significant on determining the structure of the microbial communities associated with lichens, mainly because most studies compare the bacterial communities between different lichen species and/or with different photobiont types (algae vs. cyanobacteria). In this work bipartite lichens belonging to the same genus (Peltigera) symbiotically associated with cyanobacteria (Nostoc) were analyzed by TRFLP to determine the structure of the bacterial community intimately associated with the lichen thalli and the one present in the substrate where they grow. The results indicate that the bacterial community intimately associated differs from the one of the substrate, being the former more influenced by the environmental context where the lichen grows. PMID- 24165747 TI - Production of glucose-6-phosphate by glucokinase coupled with an ATP regeneration system. AB - A process of glucose-6-phosphate (G-6-P) production coupled with an adenosine triphosphate (ATP) regeneration system was constructed that utilized acetyl phosphate (ACP) via acetate kinase (ACKase). The genes glk and ack from Escherichia coli K12 were amplified and cloned into pET-28a(+), then transformed into E. coli BL21 (DE3) and the recombinant strains were named pGLK and pACK respectively. Glucokinase (glkase) in pGLK and ACKase in pACK were both overexpressed in soluble form. G-6-P was efficiently produced from glucose and ACP using a very small amount of ATP. The conversion yield was greater than 97 % when the reaction solution containing 10 mM glucose, 20 mM ACP-Na2, 0.5 mM ATP, 5 mM Mg2+, 50 mM potassium phosphate buffer (pH 7.0), 4.856 U glkase and 3.632 U ACKase were put into 37 degrees C water bath for 1 h. PMID- 24165749 TI - Acetone-butanol-ethanol fermentation of corn stover by Clostridium species: present status and future perspectives. AB - Sustainable vehicle fuel is indispensable in future due to worldwide depletion of fossil fuel reserve, oil price fluctuation and environmental degradation. Microbial production of butanol from renewable biomass could be one of the possible options. Renewable biomass such as corn stover has no food deficiency issues and is also cheaper in most of the agricultural based countries. Thus it can effectively solve the existing issue of substrate cost. In the last 30 years, a few of Clostridium strains have been successfully implemented for biobutanol fermentation. However, the commercial production is hindered due to their poor tolerance to butanol and inhibitors. Metabolic engineering of Clostridia strains is essential to solve above problems and ultimately enhance the solvent production. An effective and efficient pretreatment of raw material as well as optimization of fermentation condition could be another option. Furthermore, biological approaches may be useful to optimize both the host and pathways to maximize butanol production. In this context, this paper reviews the existing Clostridium strains and their ability to produce butanol particularly from corn stover. This study also highlights possible fermentation pathways and biological approaches that may be useful to optimize fermentation pathways. Moreover, challenges and future perspectives are also discussed. PMID- 24165748 TI - Olive mill wastewater treatment in single-chamber air-cathode microbial fuel cells. AB - Olive mill wastewaters create significant environmental issues in olive processing countries. One of the most hazardous groups of pollutants in these wastewaters is phenolic compounds. Here, olive mill wastewater was used as substrate and treated in single-chamber air-cathode microbial fuel cells. Olive mill wastewater yielded a maximum voltage of 381 mV on an external resistance of 1 kOmega. Notable decreases in the contents of 3,4-dihydroxybenzoic acid, tyrosol, gallic acid and p-coumaric acid were detected. Chemical oxygen demand removal rates were 65 % while removal of total phenolics by the process was lower (49 %). Microbial community analysis during the olive mill wastewater treating MFC has shown that both exoelectrogenic and phenol-degrading microorganisms have been enriched during the operation. Brevundimonas-, Sphingomonas- and Novosphingobium-related phylotypes were enriched on the anode biofilm, while Alphaproteobacteria and Bacteriodetes dominated the cathode biofilm. As one of the novel studies, it has been demonstrated that recalcitrant olive mill wastewaters could be treated and utilized for power generation in microbial fuel cells. PMID- 24165750 TI - Pseudomonas aeruginosa and Achromobacter sp.: nitrifying aerobic denitrifiers have a plasmid encoding for denitrifying functional genes. AB - In the present work, novel heterotrophic nitrifying and aerobic denitrifying bacteria have been isolated from greenwater system of coastal aquaculture. Based on the 16S rRNA gene, FAME analysis and biochemical test, the isolates have been identified as Pseudomonas aeruginosa and Achromobacter sp. These have been named as P. aeruginosa strain DBT1BNH3 and Achromobacter sp. strain DBTN3. Denitrifying functional genes such as nitrite reductase (nirS), nitric oxide reductase (qnorB) and nitrous oxide reductase (nosZ) genes have been identified. These strains found to have a 27 kb plasmid coding for nirS and nosZ. The possibility of horizontal transfer of plasmid among Pseudomonadaceae and Alcaligenaceae families in coastal aquaculture has been explored. Further, we have studied combined nitrification and oxygen tolerant denitrification potential in the same isolates. PMID- 24165752 TI - The influence of volume ratio of ultrafiltrate of sample on the analysis of non protein binding drugs in human plasma. AB - In human plasma, the total concentration of non-protein binding (NPB) drugs is equal to the free drug concentration because NPB drugs do not or hardly bind to plasma proteins. Thus, centrifuge ultrafiltration (CF-UF) has been used in the determination of the concentration of NPB drugs in human plasma. However, with only a common centrifugation, the recovery and the reproducibility were not as excellent as expected. In addition, we discovered that the values of the volume ratio of ultrafiltrate to sample solution (Vu/Vs) were different and could not be well controlled, which may affect the determination of the drug concentration. The problem also affected the determination of other NBP drugs. In the present work, we used biapenem as a representative drug to study the effect of Vu/Vs on the analysis of NPB drugs concentration in human plasma. The results showed that a Vu/Vs value of less than 0.4 had no effect on the analysis of free drug concentration, while a Vu/Vs value of more than 0.4 was associated with increased recovery rate and overestimation of drug concentration. Therefore, to maintain a Vu/Vs value of less than 0.4 and even at a constant value is the key to accurately determine the concentration of NPB drugs in plasma. Fortunately, with an HFCF-UF device, the Vu/Vs could be well controlled and kept at 0.08 in this study. The recovery rates were almost 100% and the analysis precision was greatly improved. In pharmacokinetics studies, this method was successfully employed to determine the concentration of biapenem with excellent accuracy and reproducibility. HFCF-UF may become a feasible platform for the determination of NPB drugs. PMID- 24165751 TI - Enterohepatic bacterial infections dysregulate the FGF15-FGFR4 endocrine axis. AB - BACKGROUND: Enterohepatic bacterial infections have the potential to affect multiple physiological processes of the body. Fibroblast growth factor 15/19 (FGF15 in mice, FGF19 in humans) is a hormone that functions as a central regulator of glucose, lipid and bile acid metabolism. FGF15/19 is produced in the intestine and exert its actions on the liver by signaling through the FGFR4 betaKlotho receptor complex. Here, we examined the in vivo effects of enterohepatic bacterial infection over the FGF15 endocrine axis. RESULTS: Infection triggered significant reductions in the intestinal expression of Fgf15 and its hepatic receptor components (Fgfr4 and Klb (betaKlotho)). Infection also resulted in alterations of the expression pattern of genes involved in hepatobiliary function, marked reduction in gallbladder bile volumes and accumulation of hepatic cholesterol and triglycerides. The decrease in ileal Fgf15 expression was associated with liver bacterial colonization and hepatobiliary pathophysiology rather than with direct intestinal bacterial pathogenesis. CONCLUSIONS: Bacterial pathogens of the enterohepatic system can disturb the homeostasis of the FGF15/19-FGFR4 endocrine axis. These results open up a possible link between FGF15/19-FGFR4 disruptions and the metabolic and nutritional disorders observed in infectious diseases. PMID- 24165753 TI - Synergistic influence of polyoxometalate surface corona towards enhancing the antibacterial performance of tyrosine-capped Ag nanoparticles. AB - We illustrate a new strategy to improve the antibacterial potential of silver nanoparticles (AgNPs) by their surface modification with the surface corona of biologically active polyoxometalates (POMs). The stable POM surface corona was achieved by utilising zwitterionic tyrosine amino acid as a pH-switchable reducing and capping agent of AgNPs. The general applicability of this approach was demonstrated by developing surface coronas of phosphotungstic acid (PTA) and phosphomolybdic acid (PMA) around AgNPs. Our investigations on Gram negative bacterium Escherichia coli demonstrate that in conjugation with AgNPs, the surface corona of POMs enhances the physical damage to the bacterial cells due to synergistic antibacterial action of AgNPs and POMs, and the ability of tyrosine reduced AgNPs (AgNPs(Y)) to act as an excellent carrier and stabiliser for the POMs. The further extension of this study towards Gram positive bacterium Staphylococcus albus showed a similar toxicity pattern, whereas these nanomaterials were found to be biocompatible for PC3 epithelial mammalian cells, suggesting the potential of these materials towards specific antimicrobial targeting for topical wound healing applications. The outcomes of this work show that facile tailorability of nanostructured surfaces may play a considerable role in controlling the biological activities of different nanomaterials. PMID- 24165754 TI - ASNC ImageGuideTM: cardiovascular imaging data registry. PMID- 24165755 TI - Risky behaviours of Jamaican adolescents with sickle cell disease. AB - OBJECTIVES: To describe the risky behaviours of Jamaican teens with sickle cell disease (SCD) and compare them to a national sample of Jamaican youth. METHODS: One hundred twenty two SCD adolescents, 15-19 years old, completed the standardized questionnaire used in the Jamaican Youth Risk and Resiliency Behaviour Survey (JYRRBS), which was a nationally representative survey of 1317 Jamaican youths. Information was obtained on socio-demographics, smoking, alcohol use, and sexual activity. Secondary data from the JYRRBS were extracted to measure the difference in risky behaviours between the groups. RESULTS: Almost 50% of SCD and 58% of national teens reported having had sexual intercourse. More SCD teens used alcohol (77.7% vs. 60.7%; P value = 0.001). Risky behaviours tended to coexist and living with a parent (odds ratio: 0.62, P value <0.01) and currently attending school (odds ratio: 0.43, P value <0.001) lowered the likelihood of having had sex. DISCUSSION: SCD teens engage in many risky behaviours and health care professionals should screen and counsel them at each visit. PMID- 24165756 TI - Long term control of a maxillary sinus mucoepidermoid carcinoma with low dose radiation therapy: a case report. AB - Mucoepidermoid carcinoma of the maxillary sinus is a rare malignancy of the head and neck. The location of this tumour near vital structures and its large size at presentation makes surgical resection with negative margins challenging. In incurable cases, relief from symptoms such as epistaxis may be achieved with radiation therapy. We present a case of mucoepidermoid carcinoma of the maxillary sinus that was effectively palliated with a short course of radiation therapy, achieving complete cessation of bleeding, decrease in tumour size, and long term control. We surveyed the literature on mucoepidermoid carcinomas and propose that some tumours may be particularly radiosensitive, benefiting from even short courses of radiation therapy. PMID- 24165759 TI - Tar heel footprints in health care: Jenny Faulkner. PMID- 24165758 TI - British Society of Gastroenterology guidelines on the diagnosis and management of Barrett's oesophagus. AB - These guidelines provide a practical and evidence-based resource for the management of patients with Barrett's oesophagus and related early neoplasia. The Appraisal of Guidelines for Research and Evaluation (AGREE II) instrument was followed to provide a methodological strategy for the guideline development. A systematic review of the literature was performed for English language articles published up until December 2012 in order to address controversial issues in Barrett's oesophagus including definition, screening and diagnosis, surveillance, pathological grading for dysplasia, management of dysplasia, and early cancer including training requirements. The rigour and quality of the studies was evaluated using the SIGN checklist system. Recommendations on each topic were scored by each author using a five-tier system (A+, strong agreement, to D+, strongly disagree). Statements that failed to reach substantial agreement among authors, defined as >80% agreement (A or A+), were revisited and modified until substantial agreement (>80%) was reached. In formulating these guidelines, we took into consideration benefits and risks for the population and national health system, as well as patient perspectives. For the first time, we have suggested stratification of patients according to their estimated cancer risk based on clinical and histopathological criteria. In order to improve communication between clinicians, we recommend the use of minimum datasets for reporting endoscopic and pathological findings. We advocate endoscopic therapy for high grade dysplasia and early cancer, which should be performed in high-volume centres. We hope that these guidelines will standardise and improve management for patients with Barrett's oesophagus and related neoplasia. PMID- 24165757 TI - The association of cytochrome P450 genetic polymorphisms with sulfolane formation and the efficacy of a busulfan-based conditioning regimen in pediatric patients undergoing hematopoietic stem cell transplantation. AB - Cytochrome P450 enzymes (CYPs) and flavin-containing monooxygenases (FMOs) likely have a role in the oxidation of intermediate metabolites of busulfan (Bu). In vitro studies to investigate the involvement of these enzymes are cumbersome because of the volatile nature of the intermediate metabolite tetrahydrothiophene (THT) and the lack of sensitive quantitation methods. This study explored the association between the CYP2C9, CYP2C19, CYP2B6 and FMO3 genotypes and sulfolane (Su, a water soluble metabolite of Bu) plasma levels in children undergoing hematopoietic stem cell transplantation (HSCT). The relationship between these genotypes and the effectiveness of myeloablative conditioning was also analyzed. Sixty-six children receiving an intravenous Bu-based myeloablative conditioning regimen were genotyped for common functional variant alleles in CYP2C9 (*2 and *3), CYP2C19 (*2 and *17), FMO3 (rs2266780, rs2266782 and rs1736557) and CYP2B6 (*5 and *9). The plasma levels of Bu and its metabolite Su were measured after the ninth Bu dose in a subset of 44 patients for whom plasma samples were available. The ratio of Bu to Su was considered the metabolic ratio (MR) and was compared across the genotype groups. Higher MRs were observed in CYP2C9*2 and *3 allele carriers (mean+/-s.d.: 7.8+/-3.6 in carriers vs 4.4+/-2.2 in non-carriers; P=0.003). An increased incidence of graft failure was observed among patients with an MR>5 compared with those with MR values <5 (20% vs 0%; P=0.02). In contrast, a significantly higher incidence of relapse and graft failure (evaluated as event-free survival) was observed in patients with malignant disease who carried CYP2B6 alleles with reduced function on both chromosomes compared with carriers of at least one normal allele (100% vs 40%; P=0.0001). These results suggest that CYP2C9 has a role in the oxidation reactions of THT and indicate that it may be possible to predict the efficacy of Bu-based myeloablative conditioning before HSCT on the basis of CYP genotypes and Bu MRs. PMID- 24165760 TI - Descriptive review of asbestosis and silicosis hospitalization trends in North Carolina, 2002-2011. AB - BACKGROUND: Asbestosis and silicosis are debilitating pulmonary conditions resulting from inhalation of asbestos fibers or silica dust. PURPOSE: We provide a descriptive analysis of asbestosis and silicosis hospitalizations in North Carolina to assess trends over a 10-year period. METHODS: Events were defined as inpatient hospital discharges during the period 2002-2011 with an International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) diagnosis code of 501 or 502. Using statewide discharge data for 2002-2011, we calculated asbestosis and silicosis hospitalization rates in North Carolina (by demographics, hospital length of stay, cost, and payment type) and compared them with national rates. RESULTS: In North Carolina, average annual age-standardized hospitalization rates for asbestosis and silicosis were 71.2 hospitalizations per 1 million residents and 6.2 hospitalizations per 1 million residents, respectively. Rates for asbestosis and silicosis decreased significantly (less than .01 for both conditions) between 2002 and 2011, by 46% and 67%, respectively. Men had significantly higher rates than women (less than .01), more than half of hospitalizations were among persons aged 65-84 years, and Medicare was the predominant payment source. The highest silicosis rates by county were clustered in Western North Carolina; no geographic patterns were observed for asbestosis. The estimated average annual cost statewide for these hospitalizations was $10,170,417 for asbestosis and $886,143 for silicosis. LIMITATIONS: ICD-9-CM misclassification and duplicate hospitalization records may have biased the observed rates of asbestosis and silicosis. CONCLUSIONS: Decreases in hospitalization rates in North Carolina may be due to misdiagnosis, underreporting, or the declining use of asbestos in industries. Obtaining complete exposure histories at diagnosis is useful for continued public health surveillance. PMID- 24165761 TI - The prevalence, characteristics, and impact of chronic obstructive pulmonary disease in North Carolina. AB - BACKGROUND: Chronic obstructive pulmonary disease (COPD) is a leading cause of morbidity and mortality. We describe the prevalence, characteristics, and impact of COPD in North Carolina. METHODS: We determined the prevalence of self-reported COPD and characteristics of affected persons using data from the 2009 North Carolina Behavioral Risk Factor Surveillance System (BRFSS) survey. We also determined the number of persons with COPD in nursing homes and adult care or family care homes. We drew conclusions about the impact of COPD from data regarding mortality, hospitalizations, emergency department visits, prednisone use, and health impairment. RESULTS: The age-adjusted prevalence of COPD among BRFSS survey respondents was 5.6%, and about 10,000 adults in nursing homes, adult care homes, or family care homes had COPD; thus we estimate that nearly 408,000 adults in North Carolina had COPD in 2009. Rates of self-reported COPD were highest among elderly individuals, smokers, individuals with less education, and those with lower incomes. Mental and physical impairment were significantly worse in those with COPD, two-thirds of whom reported that dyspnea affected their quality of life. Prednisone use was reported by 27.4% of persons with COPD, 11.4% of respondents with COPD had been hospitalized for this condition within the preceding year, and COPD admissions accounted for 1.44% of all hospital charges. Asthma, heart disease, stroke, and diabetes mellitus were significantly more common in persons with COPD. In terms of mortality, COPD was the fourth leading cause of death (n = 4,324); 77% of COPD deaths were among persons who had no education beyond high school, and 53% of those who died were women. COPD was reported in 17.1% of deaths from all causes, 21% of deaths from asthma, 10.1% of deaths from lung cancer, and 6.7% of deaths from heart disease. LIMITATIONS: These data are based on population and health care database estimates and are approximations. CONCLUSION: COPD has substantial effects on the health of North Carolinians. PMID- 24165762 TI - Staying just a step ahead. PMID- 24165763 TI - Respiratory diseases: meeting the challenges of screening, prevention, and treatment. AB - Respiratory conditions, both acute and chronic, continue to have a significant impact on worldwide health because of their high prevalence, the high disease burden they place on individual health, and their enormous cost to the health care system. There are also unmeasured indirect economic costs due to loss of productivity. Despite advances in our understanding of the complex pathophysiology of respiratory diseases, as well as the availability of relatively straightforward primary prevention measures, the prevalence of chronic respiratory diseases continues to rise. In addition, periodic outbreaks of acute infectious respiratory conditions result in significant cost and even mortality, and the incidence of these conditions fluctuates widely from year to year. Although we have seen recent developments in medical therapies for respiratory diseases, and there are established and well-publicized disease management guidelines, morbidity and mortality remain high. One intervention that has lagged behind has been smoking prevention and cessation, which is the mainstay of prevention for chronic obstructive pulmonary disease and lung cancer. The persistence of these conditions underscores vulnerabilities within our national and regional health care systems. Several of the articles in this issue of the NCMJ describe innovative programs to address these challenges. PMID- 24165764 TI - Community Care of North Carolina's approach to asthma management. AB - Community Care of North Carolina (CCNC) takes a comprehensive approach to asthma management. Support from CCNC helps providers follow evidence-based practice guidelines; data guide continuous quality improvement initiatives and inform the care of individual patients and populations; and care managers work with high risk patients. PMID- 24165765 TI - Mission Children's Hospital's Regional Asthma Disease Management Program. PMID- 24165766 TI - Air pollution ignores state borders. PMID- 24165767 TI - Tobacco cessation in 2013: what every clinician should know. AB - Given the many deaths caused by smoking, clinicians should offer evidence-based treatment to every patient who uses tobacco. This commentary discusses health system changes that promote treatment for tobacco use, new protocols for tobacco cessation therapies, and emerging tobacco products that are being marketed as harm-reduction tools. PMID- 24165768 TI - Engaging a network of primary care practices in an effort to better assist patients in quitting tobacco use. PMID- 24165769 TI - Computed tomography screening for lung cancer: where are we now? AB - Low-dose computed tomography (LDCT) screening has been shown to result in detection of earlier-stage lung cancers, with a 20% reduction in cancer-related deaths. LDCT screening offers significant potential benefits to selected patients; however, many questions remain, including questions about the applicability of lung cancer screening in clinical practice. PMID- 24165770 TI - Chronic obstructive pulmonary disease: epidemiology, management, and impact on North Carolina. AB - Chronic obstructive pulmonary disease (COPD) affects millions of people worldwide, resulting in morbidity, mortality, and substantial utilization of health care resources. This review focuses on the epidemiology of COPD, management strategies, and the health and economic impact of this condition in North Carolina. PMID- 24165771 TI - The race to eliminate tuberculosis. AB - Tuberculosis is a major cause of morbidity and mortality worldwide, but the number of cases is now lower than ever before, both in the United States and in North Carolina. Although case rates are declining, public health funding for tuberculosis is also declining; it remains to be seen whether tuberculosis will be successfully eliminated or whether it will reemerge in the United States. PMID- 24165772 TI - Treatment of latent tuberculosis infection in North Carolina: strategies for improving adherence. PMID- 24165773 TI - Coughing up answers: a community's response to pertussis. AB - Pertussis is a highly contagious but vaccine-preventable disease. In spite of relatively high immunization rates, the number of cases continues to rise. A recent outbreak of pertussis in Alamance County, North Carolina, led to changes in response efforts and improved communication among partners, but it also left public health workers with many unanswered questions. PMID- 24165774 TI - Tdap vaccination in pregnancy: new guidance, new challenges. PMID- 24165775 TI - Prevention and control of influenza: no easy task. AB - Every influenza season presents different challenges: Novel viruses emerge, new groups of people are identified as being at high risk for complications, vaccine effectiveness varies, and resistance to antiviral agents develops. Health care providers must partner with public health professionals to prevent influenza and to reduce the morbidity and mortality associated with this illness. PMID- 24165776 TI - Mandatory influenza vaccination program proves successful in its first year. PMID- 24165777 TI - Pharmacists: medication experts who help prevent disease. PMID- 24165778 TI - The impact of pneumonia guidelines and core measures on patient-oriented outcomes. AB - Over the past decade, evidence-based guidelines have led to the development of national core measures for the management of pneumonia. Although it does not signify causation, implementation of these standards strongly correlates with a decrease in the incidence of pneumonia and with decreasing death rates from pneumonia. PMID- 24165779 TI - Pneumococcal vaccination status of North Carolina adults in 2011. PMID- 24165780 TI - Translating tuberculosis research into practice: collaboration between academic researchers and public health departments in North Carolina. AB - Successful collaborations between academic researchers and local health departments are vital for public health research, but developing and maintaining such partnerships is often difficult. However, in the North Carolina Tuberculosis Control Program, such partnerships have flourished and have led to notable improvements in patient care. PMID- 24165781 TI - A DFT study of the mechanism of copper-catalyzed synthesis of 2H-indazoles from aryl azide. AB - DFT calculations have been performed to study the reaction mechanism of N-N bond formation from aryl azide catalyzed by the copper(I) iodide complex. We studied various activation modes for the azide group, and found that the azide group is activated by the Cu(MU-I)2Cu(TMEDA) dimer coordinating to the N-atom of phenyl imine and the internal N-atom of azide. PMID- 24165782 TI - Trends in the history of certification and recertification of the American Board of Internal Medicine. AB - This commentary reviews the trends of pass rates for certification and recertification in internal medicine. This is true for certification since the 1930s and recertification since 2000. Predictors of performance, such as program director ratings and the in-training examination, are discussed in addition to positive clinical outcomes in relation to recertification. Differences in examinations pass rates due to gender, geographic location and number of attempts are reviewed. Recent trends in internal medicine demonstrate a decline, which may be multifactorial in reasoning. This is not unique to internal medicine as declines in certification rates have been noted in general surgery as well. Methods of preparing for the examination are discussed to maximize performance on the examination. PMID- 24165784 TI - Perchlorate levels in soil and waters from the Atacama Desert. AB - Perchlorate is an anion that originates as a contaminant in ground and surface waters. The presence of perchlorate in soil and water samples from northern Chile (Atacama Desert) was investigated by ion chromatography-electrospray mass spectrometry. Results indicated that perchlorate was found in five of seven soils (cultivated and uncultivated) ranging from 290 +/- 1 to 2,565 +/- 2 MUg/kg. The greatest concentration of perchlorate was detected in Humberstone soil (2,565 +/- 2 MUg/kg) associated with nitrate deposits. Perchlorate levels in Chilean soils are greater than those reported for uncultivated soils in the United States. Perchlorate was also found in superficial running water ranging from 744 +/- 0.01 to 1,480 +/- 0.02 MUg/L. Perchlorate water concentration is 30-60 times greater than levels established by the United States Environmental Protection Agency (24.5 MUg/L) for drinking. PMID- 24165783 TI - Renoprotective effects of direct renin inhibition in glomerulonephritis. AB - The development of glomerulonephritis causes glomerular injury and renal dysfunction and is thought to increase renin release, thus activating the renin angiotensin system (RAS). The aims of this study were to demonstrate activation of the intrarenal RAS and determine the effects of direct renin inhibition (DRI) on the progression of glomerulonephritis. Rats were treated with anti-Thy1.1 antibody with or without DRI, aliskiren (30 mg/kg/d). In the glomerulonephritic rats, protein, microalbumin excretion levels, urinary angiotensinogen excretion, glomerular expansion score and intrarenal transforming growth factor-beta and plasminogen activator inhibitor-1 mRNA levels were augmented compared with control rats; however, hypertension was not observed in the glomerulonephritic rats, and aliskiren treatment did not modify their blood pressure. The increases in urinary protein (94.7 +/- 13.0 mg/d) and microalbumin (7.52 +/- 2.6 mg/d) excretion were reduced by aliskiren (43.6 +/- 4.5 mg/d of protein and 2.57 +/- 0.7 mg/d of microalbumin). Furthermore, the progression of glomerular expansion and elevation of intrarenal transforming growth factor-beta and plasminogen activator inhibitor-1 levels were prevented by aliskiren. Importantly, aliskiren suppressed the augmentation of urinary angiotensinogen levels, the increased angiotensinogen expression in the kidneys and the increases in Ang II levels in renal medulla induced by the anti-Thy1.1 antibody. These results suggest that DRI with aliskiren prevents intrarenal RAS activation leading to mitigation of the development of glomerulonephritis. In addition, the renoprotective effects of DRI on glomerulonephritis occur in a blood pressure-independent manner. Accordingly, treatment with aliskiren may be an effective approach to treat glomerulonephritis and other intrarenal RAS-associated kidney diseases. PMID- 24165785 TI - Interference-free determination of trace copper in freshly ripened honeys by flame atomic absorption spectrometry following a preconcentration by solid-phase extraction and a two-step elution process. AB - A fast and straightforward procedure aimed at separating copper (Cu) ions from monosacharides and preconcentrating their traces before flame atomic absorption spectrometry (FAAS) measurements was developed, and its suitability was evaluated by the analysis of freshly ripened honeys on the content of this environmentally and physiologically relevant element. This procedure included the passage (at 20 mL/min) of 10 % (m/v) solutions of honeys (100 mL) through resin beds of Dowex 50 W * 8-400 to retain Cu by solid-phase extraction (SPE) and separate it from the glucose and fructose matrix. In turn, SPE columns were rinsed at 20 mL/min with 20 mL of water and subsequently washed with 20 mL of a 0.5 mol/L HNO3 solution (at 2.0 mL/min) to elute potassium and sodium. Preconcentrated Cu was stripped (at 2.0 mL/min) with 5.0 mL of a 2.0 mol/L HCl solution and determined by FAAS. The proposed procedure was used for the analysis of six ripened monoflower and multiflower honeys, enabling the measurement of Cu within the range of 0.17-0.42 MUg/g and with a precision of 3-10%. Recoveries of Cu added to respective honey solutions were within 94-102%, proving the good accuracy of this procedure. The detection limit of Cu achieved with this SPE preconcentration/separation procedure and FAAS detection was 3.6 ng/g. PMID- 24165786 TI - Evidence of effectiveness of health care professionals using handheld computers: a scoping review of systematic reviews. AB - BACKGROUND: Handheld computers and mobile devices provide instant access to vast amounts and types of useful information for health care professionals. Their reduced size and increased processing speed has led to rapid adoption in health care. Thus, it is important to identify whether handheld computers are actually effective in clinical practice. OBJECTIVE: A scoping review of systematic reviews was designed to provide a quick overview of the documented evidence of effectiveness for health care professionals using handheld computers in their clinical work. METHODS: A detailed search, sensitive for systematic reviews was applied for Cochrane, Medline, EMBASE, PsycINFO, Allied and Complementary Medicine Database (AMED), Global Health, and Cumulative Index to Nursing and Allied Health Literature (CINAHL) databases. All outcomes that demonstrated effectiveness in clinical practice were included. Classroom learning and patient use of handheld computers were excluded. Quality was assessed using the Assessment of Multiple Systematic Reviews (AMSTAR) tool. A previously published conceptual framework was used as the basis for dual data extraction. Reported outcomes were summarized according to the primary function of the handheld computer. RESULTS: Five systematic reviews met the inclusion and quality criteria. Together, they reviewed 138 unique primary studies. Most reviewed descriptive intervention studies, where physicians, pharmacists, or medical students used personal digital assistants. Effectiveness was demonstrated across four distinct functions of handheld computers: patient documentation, patient care, information seeking, and professional work patterns. Within each of these functions, a range of positive outcomes were reported using both objective and self-report measures. The use of handheld computers improved patient documentation through more complete recording, fewer documentation errors, and increased efficiency. Handheld computers provided easy access to clinical decision support systems and patient management systems, which improved decision making for patient care. Handheld computers saved time and gave earlier access to new information. There were also reports that handheld computers enhanced work patterns and efficiency. CONCLUSIONS: This scoping review summarizes the secondary evidence for effectiveness of handheld computers and mhealth. It provides a snapshot of effective use by health care professionals across four key functions. We identified evidence to suggest that handheld computers provide easy and timely access to information and enable accurate and complete documentation. Further, they can give health care professionals instant access to evidence-based decision support and patient management systems to improve clinical decision making. Finally, there is evidence that handheld computers allow health professionals to be more efficient in their work practices. It is anticipated that this evidence will guide clinicians and managers in implementing handheld computers in clinical practice and in designing future research. PMID- 24165787 TI - Lung cancer screening with low-radiation dose computed tomography after liver transplantation. AB - Background The prognosis of non-cutaneous malignancies after liver transplantation is dismal, mainly because most cases are diagnosed at advanced stages. In the last decade, studies have shown the potential role of screening for lung cancer with low-radiation dose computed tomography. Material and Methods Fifty-nine liver transplant recipients with a cumulative dose of smoking greater than 10 pack-years were enrolled in a lung cancer screening program using yearly low-radiation dose computed tomography. Results Lung cancer was diagnosed in 7 patients (11.8%), 5 of which were in stage Ia at diagnosis. Patients with lung cancer were significantly older (median age 66 vs. 58 years), had a higher cumulative history of smoking, and had emphysema more frequently than patients without cancer. Conclusions Screening for lung cancer with low-radiation dose computed tomography in liver transplant recipients results in the diagnosis of lung cancer in early stages. PMID- 24165788 TI - Vascular access: viewing the vein. AB - Venepuncture and cannulation are procedures regularly carried out by health professionals and form a critical component of patient care. Venepuncture, or the collection of blood from a vein, is usually performed for laboratory analysis to assist with diagnosis and treatment of the patient. PMID- 24165789 TI - Use of winged infusion devices in intravenous therapy. AB - This article has been written to highlight the licensed use of winged infusion devices for short-term intravenous (IV) therapy. There is limited published literature on the subject, yet this clinical audit has demonstrated that the use of winged infusion devices has clear advantages for patients and nurses. The audit was conducted in the community setting but could be replicated in any community or hospital environment where short-term intravenous therapy of non vesicant fluids are administered. For the purpose of this audit, non-vesicant antibiotics were administered. PMID- 24165790 TI - Patients' experiences of community IV therapy. AB - AIM: To explore patients' experiences of receiving community intravenous therapy (CIVT) compared with traditional inpatient hospital care. METHOD: The study used a qualitative descriptive methodology. Semi-structured interviews were conducted with eight participants, transcribed verbatim and thematically analysed. RESULTS: Five themes were identified: 'finances'; 'travelling'; 'hospital admission'; 'being at home'; and 'safety'. DISCUSSION: The study revealed that participants felt privileged and valued when they were treated at home. CIVT allowed them the comfort of being in a familiar environment and the convenience of doing what they wanted, when they wanted. CONCLUSION: This study concurs that patients do prefer to be treated at home rather than being admitted to secondary care. The findings from this study suggest that participants appreciated the opportunity to receive CIVT. PMID- 24165791 TI - Plane and practice parallels: our journey to AVA 2013. AB - It was an unremarkable start to our trip to Nashville for the 27th annual meeting of the Association of Vascular Access (AVA). Poster (check), presentation (check), meeting point at the airport (check), luggage within weight limit (check), hand luggage minus sharp items and liquids (check). PMID- 24165792 TI - Needle-free drug delivery. AB - Need is said to be the mother of invention. There are a number of necessities that have driven the development of needle-free injection devices. Yet the ability to deliver all medication in a pain-free manner that is clinically effective has yet to be achieved. PMID- 24165793 TI - Periphally inserted central catheters-a 'serous' complication. AB - Peripherally inserted central catheter (PICC) placement in the upper arm appears to have led to an increased incidence of the inadvertent puncture of lymph vessels, which transport lymph fluid around the body. The fluid flows from the lymph vessel in the arm, through the subcutaneous tract created by the PICC, accumulating in discharge of serous fluid at the exit site. The symptoms may be minimal or excessive and currently there are no published data or guidance as to how to manage this complication. Possible management strategies are proposed in this article. They involve the assessment of the amount and persistence of the discharge, with removal indicated when symptoms persist or when the volume is excessive. PMID- 24165794 TI - Nurse-led PICC insertion: is it cost effective? AB - AIMS: Repeated attempts to cannulate small veins can cause considerable distress for patients and expend substantial staff time. For longer term venous access, a peripherally inserted central catheter (PICC) may be used instead of a peripheral cannula. Previous studies indicate that insertion of a PICC costs three times more than a cannula but the lifespan is substantially longer. This study aimed to compare insertion cost, patient satisfaction, and infection rates of PICCs for the two main staff groups (trained nurses and radiologists) inserting these devices in a district general hospital. MATERIALS AND METHODS: The study took place over 4 months in 2012-13. A questionnaire was attached to all identified PICCs in stock at Raigmore Hospital to collect details of the date of insertion, patient involved, time taken, attendant staff grade and experience level, consumables used and insertion success. The lead author's personal observation of PICC insertion by different staff groups allowed estimation of staff time, costs and success rates. Patient experience and satisfaction was assessed before and after insertion using a patient questionnaire. PICC longevity, infection rates and failures were assessed by review of patient notes. RESULTS: The radiologist group had a statistically significant (p< 0.01) increased cost (42%) over the nurse group. Patient satisfaction regarding explanation of treatment before insertion was higher in the nurse group. Insertion success and infection rates were higher in the radiologist group. CONCLUSION: The authors conclude that the majority of PICCs can be safely performed without x-ray screening in a ward-based environment. This is likely to be the most cost-effective solution for large volume services. PMID- 24165796 TI - Trimetallic nanostructures: the case of AgPd-Pt multiply twinned nanoparticles. AB - We report the synthesis, structural characterization, and atomistic simulations of AgPd-Pt trimetallic (TM) nanoparticles. Two types of structure were synthesized using a relatively facile chemical method: multiply twinned core shell, and hollow particles. The nanoparticles were small in size, with an average diameter of 11 nm and a narrow distribution, and their characterization by aberration corrected scanning transmission electron microscopy allowed us to probe the structure of the particles at an atomistic level. In some nanoparticles, the formation of a hollow structure was also observed, that facilitates the alloying of Ag and Pt in the shell region and the segregation of Ag atoms on the surface, affecting the catalytic activity and stability. We also investigated the growth mechanism of the nanoparticles using grand canonical Monte Carlo simulations, and we have found that Pt regions grow at overpotentials on the AgPd nanoalloys, forming 3D islands at the early stages of the deposition process. We found very good agreement between the simulated structures and those observed experimentally. PMID- 24165795 TI - Dominant-activating germline mutations in the gene encoding the PI(3)K catalytic subunit p110delta result in T cell senescence and human immunodeficiency. AB - The p110delta subunit of phosphatidylinositol-3-OH kinase (PI(3)K) is selectively expressed in leukocytes and is critical for lymphocyte biology. Here we report fourteen patients from seven families who were heterozygous for three different germline, gain-of-function mutations in PIK3CD (which encodes p110delta). These patients presented with sinopulmonary infections, lymphadenopathy, nodular lymphoid hyperplasia and viremia due to cytomegalovirus (CMV) and/or Epstein-Barr virus (EBV). Strikingly, they had a substantial deficiency in naive T cells but an over-representation of senescent effector T cells. In vitro, T cells from patients exhibited increased phosphorylation of the kinase Akt and hyperactivation of the metabolic checkpoint kinase mTOR, enhanced glucose uptake and terminal effector differentiation. Notably, treatment with rapamycin to inhibit mTOR activity in vivo partially restored the abundance of naive T cells, largely 'rescued' the in vitro T cell defects and improved the clinical course. PMID- 24165797 TI - Inhibition of the hypoxia-inducible factor pathway by a G-quadruplex binding small molecule. AB - The hypoxia-inducible transcription factor (HIF) co-ordinates the response of tumours to low oxygen by stimulating genes involved in metabolism and angiogenesis. HIF pathway activation is associated with decreased progression free survival and increased mortality; compounds that target this pathway are potential agents for the treatment of a range of solid tumour malignancies. Renal cancers are likely to be particularly sensitive to inhibition of the HIF pathway since ~80% show constitutive activation of HIF. We have previously described the di-substituted naphthalene derivative, CL67, which binds to a G-quadruplex higher order structure in the HIF promoter sequence in vitro. We show here that CL67 blocks HIF expression leading to inhibition of HIF-transactivation and down regulation of downstream target genes and proteins in renal carcinoma cell lines and in a mouse xenograft model of renal cancer. This inhibition is independent of pathways that control HIF abundance through oxygen-dependant degradation and oxygen dependant HIF sub-unit expression. PMID- 24165798 TI - Contractile fatigue of the quadriceps muscle predicts improvement in exercise performance after pulmonary rehabilitation. AB - RATIONALE: We hypothesized that among patients with chronic obstructive pulmonary disease, those who develop quadriceps contractile fatigue (QCF) after exhaustive submaximal cycle exercise would have a greater response to exercise training than those who do not develop QCF (NQCF). METHODS: Patients (N = 132) had measurement of QCF at baseline. Six-minute walk distance (6 MWD), maximal incremental cycle exercise testing, and quality of life measured by the Chronic Respiratory Questionnaire were obtained before and after pulmonary rehabilitation (PR). RESULTS: Eighty of the 132 patients (60.6%) developed QCF following constant workload exhaustive cycle exercise. Patients who developed QCF had a significantly greater improvement in 6 MWD following PR (45.3 +/- 45.2 m) than those who did not (27.5 +/- 45.7 m; P= .032). When baseline differences between patients who developed QCF and NQCF were accounted for, the difference in 6 MWD remained significant. Patients who developed QCF were not more likely to identify leg fatigue as the factor limiting exercise (56.2% of QCF group stated that leg fatigue was the limiting factor compared with 47.9% in the NQCF group; P= .46). When baseline differences were accounted for, the symptom causing exercise termination was not a predictor of the response to PR. CONCLUSION: Patients who were capable of developing QCF had a significantly greater improvement in 6 MWD after PR compared to NQCF. Symptoms causing exercise termination could not be used to predict the development of contractile fatigue or the response to PR. PMID- 24165799 TI - Liquid phase deposited titania coating to enable in vitro apatite formation on Ti6Al4V alloy. AB - A recently developed "GRAPE((r)) technology" provides titanium or titanium alloy implants with spontaneous apatite-forming ability in vitro, which requires properly designed gaps and optimum heat treatment in air. In this study, titanium alloy and commercially pure (cp) titanium substrates were thermally oxidized in air before aligning pairs of specimens in the GRAPE((r)) set-up, i.e., titanium alloy and cp titanium substrates were aligned parallel to each other with optimum gap width (spatial design). A liquid phase deposition (LPD) technique was employed for titania coatings on titanium alloy substrate. Then, they were soaked in Kokubo's simulated body fluid (SBF, pH 7.4, 36.5 degrees C) for 7 days to confirm the in vitro apatite formation on the substrates under the specific spatial design. Anatase-type titania coatings fabricated by using LPD technique led to the deposition of apatite particles within 7 days and showed apatite X-ray diffraction. On the other hand, thermally oxidized titanium alloy substrate in air and non-treated specimens did not show any apatite X-ray diffraction. These results indicated that the heterogeneous nucleation of apatite induced on anatase type titania coating prepared by LPD technique when it was aligned parallel to thermally oxidized cp titanium substrate with optimum gap width. PMID- 24165800 TI - Ultrasensitive and fast fluorescent bioassay based on fluorescence enhancement of silver nanoparticles. AB - An ultrasensitive, fast and specific fluorescent platform for protein detection is developed. In this protocol, silver nanoparticles were conjugated with paramagnetic particles (MPs-Ag) for target capture, concentration and separation; fluorescent dyes functionalized silver nanoparticles (Tag) for generating signals. The presented method is highly sensitive and specific with a detection limit of 2.2 pM for thrombin, and no significant interference was observed for other proteins such as human serum albumin (HSA), lysozyme and IgG. This novel approach combining the magnetic separation and concentration of MPs-Ag, aptamer recognition and fluorescence enhancement of Tag, can be successfully used to enhance the sensitivity of detecting ultra-low levels of target proteins or biomolecules. PMID- 24165802 TI - Cyclometalated heteronuclear Pt/Ag and Pt/Tl complexes: a structural and photophysical study. AB - To investigate the factors influencing the luminescent properties of polymetallic cycloplatinated complexes a detailed study of the photophysical and structural properties of the heteronuclear complexes [Pt2Me2(bhq)2(MU-dppy)2Ag2(MU acetone)](BF4)2, 2, [PtMe(bhq)(dppy)Tl]PF6, 3, and [Pt2Me2(bhq)2(dppy)2Tl]PF6, 4, [bhq = benzo[h]quinoline, dppy = 2-(diphenylphosphino)pyridine] was conducted. Complexes 3 and 4 synthesized by the reaction of [PtMe(bhq)(dppy)], 1, with TlPF6 (1 or 1/2 equiv.) and stabilized by unsupported Pt-Tl bonds as revealed by multinuclear NMR spectroscopy and confirmed by X-ray crystallography for 3. DFT calculations for the previously reported butterfly Pt2Ag2 cluster 2 reveal that in the optimized geometry the bridging acetone molecule is removed and the metal core displays a planar-shaped geometry in which according to a QTAIM calculation and natural bond orbital (NBO) analysis the Ag...Ag metallophilic interaction is strengthened. In contrast to the precursor 1, which is only emissive in glassy solutions ((3)MLCT 485 nm), all 2-4 heteropolynuclear complexes display intense emissions in the solid state and in glassy solutions. Time-dependent density functional theory (TD-DFT) is used to elucidate the origin of the electronic transitions in the heteronuclear complexes 2 and 3. The low energy absorption and intense orange emission for cluster 2 (solid 77 K and glass) are attributed to metal-metal to ligand charge transfer (MM'LCT) with a minor L'LCT contribution. For 3 and 4 two different bands are developed: the high energy band (602-630 nm) observed for 4 at 77 K (solid, glass) and in diluted glasses for 3 is ascribed to emission from discrete Pt2Tl units of mixed (3)L'LCT/(3)LM'CT origin. However, the low energy band (670-690 nm) observed at room temperature (solid) for both complexes and also in concentrated glasses for 3 is assigned to (3)pipi excited states arising from intermolecular interactions. PMID- 24165803 TI - Method for optodynamic source localization during Er:YAG laser ablation. AB - We present an improved optodynamic (OD) method which enables measurement of the distance between the OD source on the ablated surface and a piezoelectric sensor above it, with a relative error of about 1%. The method is based on the point explosion model and allows determination of the distance to the OD source and the released energy for each detected OD signal. We estimate the distance and released energy on the basis of two measured OD signal characteristics: the time of flight and the duration of the compressive phase. We show that the finite aperture of the sensor needs to be taken into account to improve measurement accuracy. We present experimental validation of the method using an Er:YAG laser and water as a tissue phantom. We observe an excellent agreement between the measured and theoretical OD signals and between the measured and estimated distances. The method opens the way to practicable implementations of on-line OD monitoring of laser ablation in surgery and medicine. PMID- 24165804 TI - Current status of drug therapies for osteoporosis and the search for stem cells adapted for bone regenerative medicine. AB - A number of factors can lead to bone disorders such as osteoporosis, in which the balance of bone resorption vs. bone formation is upset (i.e., more bone is resorbed than is formed). The result is a loss of bone mass, with a concomitant decrease in bone density. Drugs for osteoporosis can be broadly classified as "bone resorption inhibitors", which impede bone resorption by osteoclasts, and "bone formation accelerators", which augment bone formation by osteoblasts. Here, we describe representative drugs in each class, i.e., the bisphosphonates and the parathyroid hormone. In addition, we introduce two novel bone formation accelerators, SST-VEDI and SSH-BMI, which are currently under investigation by our research group. On the other hand, regenerative therapy, characterized by (ideally) the use of a patient's own cells to regenerate lost tissue, is now a matter of global interest. At present, candidate cell sources for regenerative therapy include embryonic stem cells (created from embryos based on the fertilization of oocytes), induced pluripotent stem cells (created artificially by using somatic cells as the starting material), and somatic stem cells (found in the tissues of the adult body). This review summarizes the identifying features and the therapeutic potential of each of these stem cell types for bone regenerative medicine. Although a number of different kinds of somatic stem cells have been reported, we turn our attention toward two that are of particular interest for prospective applications in bone repair: the dedifferentiated fat cell, and the deciduous dental pulp-derived stem cell. PMID- 24165805 TI - Automatic feature selection of motor imagery EEG signals using differential evolution and learning automata. AB - Brain-computer interfacing (BCI) has been the most researched technology in neuroprosthesis in the last two decades. Feature extractors and classifiers play an important role in BCI research for the generation of suitable control signals to drive an assistive device. Due to the high dimensionality of feature vectors in practical BCI systems, implantation of efficient feature selection algorithms has been an integral area of research in the past decade. This article proposes an efficient feature selection technique, realized by means of an evolutionary algorithm, which attempts to overcome some of the shortcomings of several state of-the-art approaches in this field. The outlined scheme produces a subset of salient features which improves the classification accuracy while maintaining a trade-off with the computational speed of the complete scheme. For this purpose, an efficient memetic algorithm has also been proposed for the optimization purpose. Extensive experimental validations have been conducted on two real-world datasets to establish the efficacy of our approach. We have compared our approach to existing algorithms and have established the superiority of our algorithm to the rest. PMID- 24165806 TI - Biomechanics of thoracolumbar junction vertebral fractures from various kinematic conditions. AB - Thoracolumbar spine fracture classifications are mainly based on a post-traumatic observation of fracture patterns, which is not sufficient to provide a full understanding of spinal fracture mechanisms. This study aimed to biomechanically analyze known fracture patterns and to study how they relate to fracture mechanisms. The instigation of each fracture type was computationally simulated to assess the fracture process. A refined finite element model of three vertebrae and intervertebral connective tissues was subjected to 51 different dynamic loading conditions divided into four categories: compression, shear, distraction and torsion. Fracture initiation and propagation were analyzed, and time and energy at fracture initiation were computed. To each fracture pattern described in the clinical literature were associated one or several of the simulated fracture patterns and corresponding loading conditions. When compared to each other, torsion resulted in low-energy fractures, compression and shear resulted in medium energy fractures, and distraction resulted in high-energy fractures. Increased velocity resulted in higher-energy fracture for similar loadings. The use of a finite element model provided quantitative characterization of fracture patterns occurrence complementary to clinical and experimental studies, allowing to fully understand spinal fracture biomechanics. PMID- 24165807 TI - Tonotopic morphometry of the lamina reticularis of the guinea pig cochlea with associated microstructures and related mechanical implications. AB - Morphometry of the lamina reticularis of the guinea pig cochlea was performed using scanning electron microscopy. Seventy-four geometrical parameters of the lamina reticularis, the bundles of stereocilia, and individual stereocilia, in all rows of hair cells and within the individual hair cells, were measured at ten equally spaced locations along the longitudinal direction of the cochlea. Variations of the parameters versus the longitudinal coordinate were statistically analyzed and fitted with polynomials (constant, linear, or quadratic). Our data show that a unique set of geometrical parameters of inner and outer hair cells is typical for every frequency-dependent position at the lamina reticularis. Morphology of the outer hair cell structures varies more than respective parameters of the inner hair cells. Mechanical modeling using the obtained geometrical parameters provides a novel glance at the mechanical characteristics with respect to the cochlear tonotopy. PMID- 24165809 TI - Anteroposterior condylar position: a comparative study between subjects with normal occlusion and patients with Class I, Class II Division 1, and Class III malocclusions. AB - BACKGROUND: The present study aimed to determine and compare the anteroposterior position of the condyle in the mandibular fossa between groups of asymptomatic subjects with normal occlusion and asymptomatic subjects with Class I, Class II Division 1, and Class III malocclusions. MATERIAL AND METHODS: Thirty persons with normal occlusion, 30 with Class I malocclusion, 30 with Class II Division 1, and 30 with Class III had computed tomography scans of their temporomandibular joints. The anterior joint space/posterior joint space (AJS/PJS) ratio was determined for the right and left joints. The paired t test was used to analyze the AJS/PJS ratio between both sides for each group. The ANOVA test was applied to verify the differences between the groups for the measurements of the right and left sides. In case the ANOVA test confirmed significance, the Dunnett's t test was performed to compare the groups of malocclusion with that of normal occlusion. RESULTS: The paired t test between the AJS/PJS relationships in the right and left sides showed the following p values: Class I (0.168), Class II Division 1 (0.662), Class III (0.991), and normal occlusion (0.390). The ANOVA test showed a p value of 0.445 for the comparisons of the right side and 0.040 for the left side. The Dunnett's t test demonstrated a statistically significant difference between the Class II group and the normal occlusion group (p value of 0.026) in the joints of the left side. CONCLUSIONS: Bilateral symmetry and lack of condyle centralization were common characteristics among all groups. The greatest condylar decentralization was observed in the Class II group, whereas the least condylar decentralization was found in the normal occlusion group. PMID- 24165810 TI - Continuous coflow synthesis of hybrid palladium nanocrystals as catalysts for borylation reaction. AB - The combination of highly active Pd nanocrystal (NC) types with tailored surface properties (various ligands) - e.g. organic-inorganic hybrid NCs - as catalysts opens avenues towards new synthetic pathways, implying a faster practical alternative for adjusting and screening the reaction conditions. Pd@dppf and Pd@PCy3 NCs have been successfully prepared via a continuous supercritical fluid assisted coflow route with promising results as catalysts in borylation reaction. It has been found that the ligands not only influence the catalytic properties of the systems, but also contribute to Pd metal core characteristics (size, shape and time stability). PMID- 24165808 TI - PD-1 modulates steady-state and infection-induced IL-10 production in vivo. AB - Programmed death-1 (PD-1) plays an important role in mediating immune tolerance through mechanisms that remain unclear. Herein, we investigated whether PD-1 prevents excessive host tissue damage during infection with the protozoan parasite, Toxoplasma gondii. Surprisingly, our results demonstrate that PD-1 deficient mice have increased susceptibility to T. gondii, with increased parasite cyst counts along with reduced type-1 cytokine responses (IL-12 and IFN gamma). PD-1-/- DCs showed no cell intrinsic defect in IL-12 production in vitro. Instead, PD-1 neutralization via genetic or pharmacological approaches resulted in a striking increase in IL-10 release, which impaired type-1-inflammation during infection. Our results indicate that the absence of PD-1 increases IL-10 production even in the absence of infection. Although the possibility that such increased IL-10 protects against autoimmune damage is speculative, our results show that IL-10 suppresses the development of protective Th1 immune response after T. gondii infection. PMID- 24165811 TI - Choosing weapons in Barrett's esophagus. PMID- 24165812 TI - Validation of the Prague C&M classification of Barrett's esophagus in clinical practice. AB - BACKGROUND AND STUDY AIMS: The Prague C&M classification for Barrett's esophagus has found widespread acceptance but has only been validated by Barrett's experts scoring video sequences. To date, validation has been lacking for its application in routine practice during real-time endoscopy. The aim of this study was to evaluate agreement between Barrett's experts and community hospital endoscopists when using this classification to describe Barrett's esophagus and hiatal hernia length during real-time endoscopy. PATIENTS AND METHODS: Patients underwent two consecutive endoscopies performed by different endoscopists. The study was performed in two cohorts: one cohort was seen by Barrett's experts and the other cohort by community hospital endoscopists. Landmarks were recorded according to the Prague classification. Outcomes were interobserver agreement (assessed with intraclass correlation coefficient [ICC]), absolute agreement, and relative agreement. RESULTS: A total of 187 patients were included, with median extent of C3M5 (IQR C1 - 7 M4 - 9) for Barrett's esophagus and 3 cm (IQR 2-5) for hiatal hernia length. ICC was 0.91 (95 % confidence interval [CI] 0.88-0.93) for maximum length, 0.92 (95% CI 0.90-0.94) for circumferential extent, and 0.59 (95% CI 0.49 0.68) for hiatal hernia length. Absolute agreement within <= 1 cm was 74% (95% CI 68-80) for circumference, 68% (95% CI 62-75) for length, and 63% (95% CI 56 - 70) for hiatal hernia length. Relative agreement was 91% for Barrett's esophagus and 80 % for hiatal hernia length. Barrett's experts and community hospital endoscopists showed no differences in agreement. Shorter Barrett's segments (<= 5 cm) had lower agreement compared with longer segments (> 5 cm). CONCLUSIONS: Agreement was good for Barrett's esophagus and reasonable for hiatal hernia length. These findings strengthen the value of the Prague C&M classification to describe Barrett's esophagus and hiatal hernia length. Although absolute agreement during real-time endoscopy was high, one should anticipate that Barrett's values may vary by 1 - 2 cm between two endoscopies. PMID- 24165813 TI - Impact of preoperative endoscopic ultrasound-guided fine needle aspiration on postoperative recurrence and survival in cholangiocarcinoma patients. AB - BACKGROUND AND STUDY AIM: Endoscopic ultrasound-guided fine needle aspiration (EUS-FNA) is frequently performed for suspected biliary tumors for diagnosis and staging but carries a theoretical risk of needle-track seeding. We aimed to evaluate the impact of preoperative EUS-FNA on long-term outcomes for patients with cholangiocarcinoma (CCA). PATIENTS AND METHODS: In a retrospective single center study of consecutive patients with CCA with preoperative EUS-FNA, main outcome measures were overall survival and progression-free survival. RESULTS: In 150 patients with confirmed CCA, 61 underwent preoperative FNA. Median overall survival was 18.5 months (95% confidence limits [CL] 15.4, 25.7): 111 patients died and 39 survived. Of the 150 patients, 119 underwent curative-intent surgical resection, with median progression-free survival of 17.8 months (95% CL 14.5, 22.8); 89/119 patients had tumor recurrence or died, and 30/119 remained alive and disease-free. On multivariable analysis, overall survival was associated with: undergoing curative-intent surgery (hazard ratio [HR] 5.79, P = 0.001), lack of lymph node involvement (HR 1.89, P = 0.011), younger age (HR 1.51 for every 10 years, P < 0.0015), and small tumor size (HR 1.11 for every 1 cm, P = 0.029). For patients undergoing curative-intent surgery, on multivariable analysis, improved progression-free survival was associated with: lack of lymph node involvement (HR 1.88, P = 0.010), smaller tumor size (HR 1.16 for every 1 cm smaller, P = 0.003), and younger age (HR 1.53 for every 10 years, P < 0.001). Number of needle passes showed no statistically significant impact on overall survival. CONCLUSION: Preoperative EUS-FNA in patients with CCA does not appear to adversely affect overall or progression-free survival. PMID- 24165814 TI - Bacteriobilia and fungibilia are associated with outcome in patients with endoscopic treatment of biliary complications after liver transplantation. AB - BACKGROUND AND STUDY AIMS: To determine the importance of bacteriobilia and fungibilia in patients with endoscopic treatment of biliary complications after orthotopic liver transplantation (OLT). PATIENTS AND METHODS: In a prospective study at a tertiary center, 213 patients underwent 857 endoscopic retrograde cholangiographies (ERCs) after OLT. Findings at first ERC were: anastomotic stricture in 24.4%, nonanastomotic stricture in 18.3%, leakage in 11.3%, and gallstones in 4.7%. RESULTS: Bile samples from first ERC showed Gram-positive bacterial isolates in 102/180 (57%) and Gram-negative in 44/180 (24%). Main species were Enterococcus spp. (40%; 72/180) and Escherichia coli (10%; 18 /180). Enteric bacteria (present in 47%) and Candida spp. (present in 18%) were both associated with clinical signs of cholangitis, but not with laboratory signs of inflammation. Multiresistant strains (present in 12% of samples) showed no association with clinical or laboratory parameters. Detection of microbiological isolates was independent of endoscopic findings and treatment. In patients with successful endoscopic intervention, the actuarial survival free of retransplantation was significantly lower in those with detection of enteric bacteria, being 51.8 months (95% confidence interval [CI] 42.9-60.6) vs. 62.9 months (95% CI 59.1-66.7); P = 0.025). Fungibilia was associated with significantly lower actuarial retransplantation-free survival, independently of successful endoscopic treatment (mean 35.1 months [95% CI 23.5-46.7] vs. 53.1 months [(95% CI 48.0-58.2]; P = 0.019). CONCLUSIONS: Bacteriobilia and fungibilia can frequently be detected by routine microbiological sampling in patients after OLT. Regular bile sampling is recommended since the presence of difficult-to treat multiresistant strains is unpredictable. Survival is affected by this altered biliary microbiological environment after OLT. PMID- 24165815 TI - A simple tissue-handling technique performed in the endoscopy suite improves histologic section quality and diagnostic accuracy for serrated polyps. AB - BACKGROUND AND STUDY AIMS: Surveillance intervals after colonoscopic resection of serrated polyps are partially predicated on the histology of the polyp(s) removed during the index exam. Histologic discrimination between sessile serrated adenomas/polyps (SSA/P) and hyperplastic polyps is challenging. We devised and tested a simple tool--an envelope--that gastroenterologists can integrate into routine colonoscopy practice to address this problem. METHODS: In the "modified protocol," immediately after polypectomy each serrated polyp was flattened and enclosed in a paper envelope before being placed in formalin. In the pathology laboratory, each polyp was sectioned after processing. A two-site, prospective, randomized, single-blinded trial was performed to compare this modified protocol with the conventional protocol. Serrated polyps located proximal to the splenic flexure and 5-20 mm in diameter were included. A novel orientation score that measured the number of well-oriented crypts per unit area of polyp (higher orientation score = better orientation) was validated. Orientation score, SSA/P diagnosis rate, and inter-pathologist agreement were measured. RESULTS: A total of 375 polyps were enrolled, of which 264 were identified for analysis. The mean orientation scores in the modified and conventional protocol groups were 3.11 and 1.13, respectively (P < 0.0001). SSA/Ps were diagnosed in 103/135 cases (76.3%) in the modified protocol group vs. 54/129 (41.9%) in the conventional protocol group (P < 0.0001). Inter-pathologist agreement was higher with the modified than the conventional protocol (77.0% vs. 62.8%; P = 0.015). CONCLUSION: Standard polyp handling techniques may be sub-optimal for interpretation of serrated polyps resected at colonoscopy, and may lead to inadvertent histologic "under grading" of many lesions. Our intervention improved histopathologic interpretation and increased the SSA/P diagnosis rate. PMID- 24165816 TI - Recognizing sessile serrated adenomas/polyps: a diagnostic challenge for pathologists. PMID- 24165817 TI - Target-controlled infusion vs. manually controlled infusion of propofol with alfentanil for bidirectional endoscopy: a randomized controlled trial. AB - BACKGROUND AND STUDY AIMS: The best anesthesia methods for analgesia and sedation during gastrointestinal endoscopy are still debated. The aim of this study was to compare the recovery time, clinical presentations, and satisfaction between target-controlled infusion (TCI) and manually controlled infusion (MCI) in same day bidirectional endoscopy (esophagogastroduodenoscopy followed by colonoscopy). PATIENTS AND METHODS: A total of 220 patients with American Society of Anesthesiology physical status 1 or 2 were enrolled and randomized into the TCI or MCI groups. The clinical presentations, vasoactive drug demand, propofol consumption, and adverse events were recorded for both groups peri-procedurally. The concentrations of propofol in the plasma (Cp) and at the site of drug effect (Ce) by computerized simulation were also monitored in both groups. Finally, the satisfaction of patients, endoscopists, and nurse anesthetists was assessed by questionnaire after the examinations. RESULTS: Compared with the MCI group, the TCI group had a faster recovery time (17.91 +/- 7.72 minutes vs. 14.58 +/- 8.55 minutes; P = 0.002), less moderate hypotension (7.37 +/- 15.46 % vs. 1.82 +/- 5.15 %; P < 0.001), and shorter period of bradypnea (13.81 +/- 15.92 % vs. 9.18 +/- 12.00 %; P = 0.013). In addition, the TCI group reduced the relative risk of moderate desaturation by 50 % compared with the MCI group (30.9 % vs. 15.5 %; 95 % confidence interval 1.191-3.360; P = 0.007). CONCLUSIONS: The study demonstrated that TCI of propofol combined with alfentanil was associated with a faster recovery time, and better hemodynamic and respiratory stability than MCI in same-day bidirectional endoscopy. CLINICAL TRIAL REGISTRATION: CGMH IRB Identifier 97-0969B. PMID- 24165818 TI - Patient-controlled sedation in endoscopy: are patients leading us? PMID- 24165819 TI - Hand hygiene in the endoscopy unit: a surgical perspective. PMID- 24165820 TI - Hemostatic clips and magnetic resonance imaging. Are there any compatibility issues? PMID- 24165822 TI - Endoscopy in inflammatory bowel disease: recommendations from the IBD Committee of the French Society of Digestive Endoscopy (SFED). PMID- 24165824 TI - Cascade signal amplification for ultrasensitive electrochemical DNA detection. AB - In this work, by integrating multiple signal enhancement approaches, a new cascade signal amplification strategy is described to achieve highly sensitive electrochemical DNA detection. The presence of the target DNA leads to the unfolding of the biotin-modified hairpin probes on the sensor surface. With the addition of the primer sequences and polymerase, the target DNA is recycled and reused through isothermal strand-displacement polymerase reactions (ISDPR) to unfold a large number of the probes, which offer numerous binding sites to capture alkaline phosphatase (ALP)-loaded nanoparticle labels. These surface captured ALP enzymes catalyze the conversion of p-aminophenylphosphate to p aminophenol, which generates amplified catalytic current responses due to the redox-recycling process during the potential sweep in the presence of the co reactant NADH. With the synergistic signal amplifications by ISDPR-assisted target recycling, multi-ALP enzyme labels and redox-recycling, the proposed method offers highly sensitive detection of DNA down to 0.1 fM with single-base discrimination capability. Due to the significantly high sensitivity, the developed cascade signal amplification strategy can be potentially extended to detect various DNA targets at ultralow levels for early diagnoses of different diseases. PMID- 24165823 TI - Splanchnic oxygen saturation immediately after weaning from cardiopulmonary bypass can predict early postoperative outcomes in children undergoing congenital heart surgery. AB - This study compared the abilities of cerebral, renal, and splanchnic regional oxygen saturation (rSO2) immediately after weaning from cardiopulmonary bypass (CPB) to predict early postoperative outcomes for children undergoing congenital heart surgery. The study enrolled 73 children (ages 0.1-72 months) undergoing corrective or palliative cardiac surgery requiring CPB. Laboratory and hemodynamic variables were analyzed at the time of successful weaning from CPB. Using near-infrared spectroscopy, cerebral, renal, and splanchnic rSO2 values were obtained simultaneously. Early postoperative outcome measures included the maximum vasoactive inotropic score (VIS(max)) during the first 36 postoperative hours, the duration of mechanical ventilation, and the postoperative hospital length of stay. In the univariate analysis, cerebral, renal, and splanchnic rSO2 values correlated significantly with early postoperative outcomes. However, splanchnic rSO2 was the only independent factor predicting VIS(max) (beta = 0.302, P = 0.021), duration of mechanical ventilation (beta = -0.390, P = 0.002), and postoperative hospital length of stay (beta = -0.340, P = 0.001) by multivariate analyses. Splanchnic rSO2 had a larger receiver operating characteristic area under the curve (AUC) for determining high VIS(max), prolonged mechanical ventilation, and longer postoperative hospital stay (AUC 0.775, 0.792, and 0.776, respectively) than cerebral (AUC 0.630, 0.638, and 0.632, respectively) and renal (AUC 0.703, 0.716, and 0.715, respectively) rSO2. After weaning from CPB, splanchnic rSO2 may be superior to rSO2 measured from brain and kidney in predicting an increased requirement for vasoactive inotropic support, a prolonged mechanical ventilation, and a longer postoperative hospital stay for children. PMID- 24165826 TI - The optimal practice of evidence-based medicine: incorporating patient preferences in practice guidelines. PMID- 24165827 TI - Selective apoptosis of multiple myeloma cells in primary samples induced by arsenic trioxide. AB - OBJECTIVES: Currently, multiple myeloma (MM) is an incurable disease. Despite the fact that arsenic trioxide (ATO) shows promising results in vitro, data from treatment of patients with MM are disappointing. Due to these discrepancies, we compared the efficacy and selectivity of ATO at two different concentrations in samples from MM patients. METHODS: The extent of apoptosis induced by 2 and 5 uM ATO was evaluated by flow cytometry using annexin V. 34 diagnostic bone marrow samples obtained from MM patients were analysed. RESULTS: 5 uM ATO efficiently induced apoptosis in primary samples. Besides efficacy, also selectivity of action on MM cells in comparison to remaining haematopoietic cells was demonstrated for 5 uM ATO but not for 2 uM ATO. DISCUSSION: Our study on primary samples confirmed that ATO has a potential role in therapeutic management of MM. Further controlled studies on MM patients are needed. PMID- 24165825 TI - Genomic surveys and expression analysis of bZIP gene family in castor bean (Ricinus communis L.). AB - The basic leucine zipper (bZIP) transcription factors comprise a family of transcriptional regulators present extensively in plants, involved in regulating diverse biological processes such as flower and vascular development, seed maturation, stress signaling and pathogen defense. Castor bean (Ricinus communis L. Euphorbiaceae) is one of the most important non-edible oilseed crops and its seed oil is broadly used for industrial applications. We performed a comprehensive genome-wide identification and analysis of the bZIP transcription factors that exist in the castor bean genome in this study. In total, 49 RcbZIP transcription factors were identified, characterized and categorized into 11 groups (I-XI) based on their gene structure, DNA-binding sites, conserved motifs, and phylogenetic relationships. The dimerization properties of 49 RcbZIP proteins were predicted on the basis of the characteristic features in the leucine zipper. Global expression profiles of 49 RcbZIP genes among different tissues were examined using high-throughput sequencing of digital gene expression profiles, and resulted in diverse expression patterns that may provide basic information to further reveal the function of the 49 RcbZIP genes in castor bean. The results obtained from this study would provide valuable information in understanding the molecular basis of the RcbZIP transcription factor family and their potential function in regulating the growth and development, particularly in seed filling of castor bean. PMID- 24165828 TI - Complex magnetic structure of clusters and chains of Ni and Fe on Pt(111). AB - We present an approach to control the magnetic structure of adatoms adsorbed on a substrate having a high magnetic susceptibility. Using finite Ni-Pt and Fe-Pt nanowires and nanostructures on Pt(111) surfaces, our ab initio results show that it is possible to tune the exchange interaction and magnetic configuration of magnetic adatoms (Fe or Ni) by introducing different numbers of Pt atoms to link them, or by including edge effects. The exchange interaction between Ni (or Fe) adatoms on Pt(111) can be considerably increased by introducing Pt chains to link them. The magnetic ordering can be regulated allowing for ferromagnetic or antiferromagnetic configurations. Noncollinear magnetic alignments can also be stabilized by changing the number of Pt-mediated atoms. An Fe-Pt triangularly shaped nanostructure adsorbed on Pt(111) shows the most complex magnetic structure of the systems considered here: a spin-spiral type of magnetic order that changes its propagation direction at the triangle vertices. PMID- 24165829 TI - Impact of anesthesia for cancer surgery: Continuing professional development. AB - PURPOSE: A number of original publications and review articles have addressed the issue of perioperative immune modulation and cancer outcome. The objective of this module is to review current understanding surrounding the pathways involved and the evidence implicating commonly used anesthetic agents. PRINCIPAL FINDINGS: Drugs commonly used in anesthetic practice have been shown to affect various components of the immune system in laboratory animal and human in vitro models. It has been hypothesized that these effects may favour tumour recurrence and metastasis formation. Inhalational agents and opiates have potential negative immunomodulatory effects; on the other hand, regional anesthesia and propofol may have positive effects on immune function modulation. However, the clinical relevance of these studies to human cancer outcome is unknown since clinical trials are equivocal, and results of in vitro and animal model studies cannot be extrapolated to clinical practice. Furthermore, there is a lack of rigorous clinical trials demonstrating clinical outcome benefit for one technique over another. It remains unclear how anesthetic drugs influence the immune system in relation to tumour cell elimination and clinical cancer outcome. CONCLUSIONS: Recommendations for a specific anesthetic technique based on cancer outcome alone cannot be made. A pragmatic solution would be to offer regional anesthesia in isolation or combined with propofol infusion to cancer patients if appropriate and if local expertise is available. Regional anesthesia offers excellent analgesia, a low incidence of postoperative nausea and vomiting, and a favourable immunological profile based on current understanding of laboratory evidence. PMID- 24165831 TI - The long-term implications of war captivity for mortality and health. AB - The current study aims to (1) assess the long-term impact of war captivity on mortality and various health aspects and (2) evaluate the potential mediating role of posttraumatic stress disorder (PTSD) and depressive symptoms. Israeli ex prisoners of war (ex-POWs) (N = 154) and a matched control group of combat veterans (N = 161) were assessed on health conditions and self-rated health 18 years post-war (1991: T1). The whole population of ex-POWs, and the T1 sample of controls were then contacted 35 years after the war (2008: T2), and invited to participate in a second wave of measurement (ex-POWs: N = 171; controls: N = 116) Captivity was implicated in premature mortality, more health-related conditions and worse self-rated health. PTSD and depressive symptoms mediated the relationship between war captivity and self-rated health, and partially mediated the relationship between war captivity and health conditions, and these effects were amplified with age. Aging ex-POWs who develop psychiatric symptomatology should be considered a high-risk group entering a high-risk period in the life cycle. It is important to monitor ex-POWs and provide them with appropriate medical and psychological treatment as they age. PMID- 24165832 TI - The salient self: the left intraparietal sulcus responds to social as well as perceptual-salience after self-association. AB - Perceptual learning is associated with experience-based changes in stimulus salience. Here, we use a novel procedure to show that learning a new association between a self-label and a neutral stimulus produces fast alterations in social salience measured by interference when targets associated with other people have to be selected in the presence of self-associated distractors. Participants associated neutral shapes with either themselves or a friend, over a short run of training trials. Subsequently, the shapes had to be identified in hierarchical (global-local) forms. The data show that giving a shape greater personal significance by associating it with the self had effects on visual selection equivalent to altering perceptual salience. Similar to previously observed effects linked to when perceptually salient distractors are ignored, effects of a self-associated distractor also increased activation in the left intraparietal cortex sulcus. The results show that self-associations to sensory stimuli rapidly modulate neural responses in a manner similar to changes in perceptual saliency. The self-association procedure provides a new way to understand how personal significance affects behavior. PMID- 24165833 TI - Analysis of cortical shape in children with simplex autism. AB - We used surface-based morphometry to test for differences in cortical shape between children with simplex autism (n = 34, mean age 11.4 years) and typical children (n = 32, mean age 11.3 years). This entailed testing for group differences in sulcal depth and in 3D coordinates after registering cortical midthickness surfaces to an atlas target using 2 independent registration methods. We identified bilateral differences in sulcal depth in restricted portions of the anterior-insula and frontal-operculum (aI/fO) and in the temporoparietal junction (TPJ). The aI/fO depth differences are associated with and likely to be caused by a shape difference in the inferior frontal gyrus in children with simplex autism. Comparisons of average midthickness surfaces of children with simplex autism and those of typical children suggest that the significant sulcal depth differences represent local peaks in a larger pattern of regional differences that are below statistical significance when using coordinate-based analysis methods. Cortical regions that are statistically significant before correction for multiple measures are peaks of more extended, albeit subtle regional differences that may guide hypothesis generation for studies using other imaging modalities. PMID- 24165836 TI - New evidence of the reproductive organs of Glossopteris based on permineralized fossils from Queensland, Australia. II: pollen-bearing organ Ediea gen. nov. AB - Ediea homevalensis H. Nishida, Kudo, Pigg & Rigby gen. et sp. nov. is proposed for permineralized pollen-bearing structures from the Late Permian Homevale Station locality of the Bowen Basin, Queensland, Australia. The taxon represents unisexual fertile shoots bearing helically arranged leaves on a central axis. The more apical leaves are fertile microsporophylls bearing a pair of multi-branched stalks on their adaxial surfaces that each supports a cluster of terminally borne pollen sacs. Proximal to the fertile leaves there are several rows of sterile scale-like leaves. The pollen sacs (microsporangia) have thickened and dark, striate walls that are typical of the Arberiella type found in most pollen organs presumed to be of glossopterid affinity. An examination of pollen organs at several developmental stages, including those containing in situ pollen of the Protohaploxypinus type, provides the basis for a detailed analysis of these types of structures, which bear similarities to both compression/impression Eretmonia type glossopterid microsporangiate organs and permineralized Eretmonia macloughlinii from Antarctica. These fossils demonstrate that at least some Late Permian pollen organs were simple microsporophyll-bearing shoot systems and not borne directly on Glossopteris leaves. PMID- 24165834 TI - Contribution of intracolumnar layer 2/3-to-layer 2/3 excitatory connections in shaping the response to whisker deflection in rat barrel cortex. AB - This computational study integrates anatomical and physiological data to assess the functional role of the lateral excitatory connections between layer 2/3 (L2/3) pyramidal cells (PCs) in shaping their response during early stages of intracortical processing of a whisker deflection (WD). Based on in vivo and in vitro recordings, and 3D reconstructions of connected pairs of L2/3 PCs, our model predicts that: 1) AMPAR and NMDAR conductances/synapse are 0.52 +/- 0.24 and 0.40 +/- 0.34 nS, respectively; 2) following WD, connection between L2/3 PCs induces a composite EPSPs of 7.6 +/- 1.7 mV, well below the threshold for action potential (AP) initiation; 3) together with the excitatory feedforward L4-to-L2/3 connection, WD evoked a composite EPSP of 16.3 +/- 3.5 mV and a probability of 0.01 to generate an AP. When considering the variability in L4 spiny neurons responsiveness, it increased to 17.8 +/- 11.2 mV; this 3-fold increase in the SD yielded AP probability of 0.35; 4) the interaction between L4-to-L2/3 and L2/3-to L2/3 inputs is highly nonlinear; 5) L2/3 dendritic morphology significantly affects L2/3 PCs responsiveness. We conclude that early stages of intracortical signaling of WD are dominated by a combination of feedforward L4-L2/3 and L2/3 L2/3 lateral connections. PMID- 24165837 TI - Mass spectrometry and potentiometry studies of Pb(II)-, Cd(II)- and Zn(II) cystine complexes. AB - Cd(II)-, Pb(II)- and Zn(II)-cystine complexes were investigated by potentiometric and different mass spectrometric (MS) methodologies. Laser desorption mass spectrometry has provided both the composition and structure of metal-cystine complexes according to the speciation models proposed on the basis of the potentiometric data. Detection of neutral complexes was achieved by protonation or electrochemical reduction during mass spectrometric experiments. The redox activity of metal-cystine complexes was confirmed by laser desorption and charge transfer matrix assisted laser assisted MS experiments, which allowed us to observe the formation of complexes with a reduction of cystine. The stoichiometry of Cd(II)-, Pb(II)- and Zn(II)-cystine complexes was defined by observing the isotopic pattern of the investigated compound. The results suggest that interaction occurs through the carboxylate group of the ligand. PMID- 24165840 TI - Dietary and supplemental calcium intake and mortality. PMID- 24165841 TI - Dietary and supplemental calcium intake and mortality. PMID- 24165842 TI - Dietary and supplemental calcium intake and mortality. PMID- 24165843 TI - Dietary and supplemental calcium intake and mortality--reply. PMID- 24165844 TI - Glucagon-like peptide 1-based drugs and pancreatic safety. PMID- 24165845 TI - Glucagon-like peptide 1-based drugs and pancreatic safety. PMID- 24165846 TI - Glucagon-like peptide 1-based drugs and pancreatic safety--reply. PMID- 24165847 TI - Duty hour reform: only a small piece of a larger problem. PMID- 24165848 TI - Duty hour reform: only a small piece of a larger problem--reply. PMID- 24165849 TI - The "new normal". PMID- 24165850 TI - The "new normal"--reply. PMID- 24165854 TI - Echocardiographic severity grading in aortic stenosis: no holy grail, only lessons towards patient individualisation. PMID- 24165853 TI - Characteristics and publication patterns of obstetric studies registered in ClinicalTrials.gov. AB - Physiologic changes during pregnancy alter the pharmacokinetics, safety, and efficacy of many drugs. For clinicians, there is often uncertainty regarding the safety of these drugs due to a scarcity of published data. This study aimed to comprehensively evaluate the characteristics and publication patterns of obstetric studies registered in ClinicalTrials.gov from 2007 to 2012. Primary outcome measures, funding sources, inclusion criteria, and the reporting of study results were evaluated. A manual review of Medline/PubMed was performed to identify publications associated with studies registered in ClinicalTrials.gov. Of 93,709 total studies, there were 5,203 (6%) obstetric studies registered in ClinicalTrials.gov. Interventional studies accounted for 70% and 30% were observational. Clinical trials of drugs (49%), procedures (13%), and behavioral interventions (12%) were most common. Among interventional drug trials, 84% featured randomized allocation to study arms and 93% included measures of safety and/or efficacy as primary endpoints. Of 946 (18%) studies completed more than 2 years ago, only 11% had reported results and <7% had been published. In an area with a great need for evidence of safe and effective therapies, the low publication rate of completed studies incorporating elements of high-quality trial design is concerning. The sources of this trend should be closely investigated. PMID- 24165855 TI - Reduced Klotho is associated with the presence and severity of coronary artery disease. AB - OBJECTIVE: Klotho is involved in vascular health. We aimed to analyse in a cross sectional study the relationship between Klotho and human coronary artery disease (CAD). METHODS: The study included 371 subjects who underwent coronary angiography and 70 patients who underwent elective cardiac surgery recruited between May 2008 and June 2009. The presence and severity (stenosis index) of CAD, cardiovascular risk factors, Klotho gene expression in the thoracic aorta, and serum soluble Klotho concentrations were evaluated. RESULTS: The soluble Klotho concentration was lower (p<0.001) in patients with significant CAD (n=233). The maximal stenosis observed in every epicardial artery and the stenosis severity index was significantly lower in patients within the higher soluble Klotho concentrations (p<0.0001). Multiple regression analysis showed that serum Klotho concentrations were inverse and significantly associated with CAD (adjusted R(2)=0.67, p<0.001). Multivariate logistic regression analysis showed that risk factors for significant CAD included age, diabetes, smoking and inflammation, whereas high serum Klotho values were associated with a lower risk for CAD. Lower mRNA expression level of Klotho was observed in 46 patients with significant CAD, as compared with subjects without CAD (p=0.01). Logistic regression analysis showed that high Klotho gene expression was independently associated with lower risk for CAD. CONCLUSIONS: Patients with significant CAD present lower soluble concentrations of Klotho, as well as reduced levels of Klotho gene expression in the vascular wall. Reduced serum Klotho concentrations and decreased vascular Klotho gene expression were associated with the presence and severity of CAD independently of established cardiovascular risk factors. PMID- 24165856 TI - Li(4)NiTeO(6) as a positive electrode for Li-ion batteries. AB - Layered Li4NiTeO6 was shown to reversibly release/uptake ~2 lithium ions per formula unit with fair capacity retention upon long cycling. The Li electrochemical reactivity mechanism differs from that of Li2MO3 and is rooted in the Ni(4+)/Ni(2+) redox couple, that takes place at a higher potential than conventional LiNi1-xMnxO2 compounds. We explain this in terms of inductive effect due to Te(6+) ions (or the TeO6(6-) moiety). PMID- 24165857 TI - Highly sensitive contactless conductivity microchips based on concentric electrodes for flow analysis. AB - In this communication, we describe for the first time the integration of concentric electrodes (wrapping around the microchannel) in microchips. The use of such electrodes has been shown to be effective towards improvement of the sensitivity and detectability in pressure-driven flow platforms incorporating C(4)D. PMID- 24165858 TI - Magnetic PEGylated Pt3Co nanoparticles as a novel MR contrast agent: in vivo MR imaging and long-term toxicity study. AB - Magnetic resonance (MR) imaging using magnetic nanoparticles as the contrast agent has been extensively explored in biomedical imaging and disease diagnosis. Herein, we develop biocompatible polymer coated ultra-small Pt3Co magnetic nanoparticles as a new T2-weighted MR imaging contrast agent. A unique class of alloy Pt3Co nanoparticles is synthesized through a thermal decomposition method. After being modified with polyethylene glycol (PEG), the obtained Pt3Co-PEG nanoparticles exhibit an extremely high T2-weighted relaxivity rate (r2) up to 451.2 mM s(-1), which is much higher than that of Resovist(r), a commercial T2-MR contrast agent used in the clinic. In vitro experiments indicate no obvious cytotoxicity of Pt3Co-PEG nanoparticles to various cell lines. After intravenous injection of Pt3Co-PEG nanoparticles, in vivo T2-weighted MR imaging of tumor bearing mice reveals strong tumor contrast, which is much higher than that offered by injecting Resovist(r). We further study the long-term biodistribution and toxicology of this new type of MR contrast nanoparticles after intravenous injection into healthy mice. Despite the significant retention of Pt3Co-PEG nanoparticles in the mouse liver and spleen, no appreciable toxicity of these nanoparticles to the treated animals has been noted in our detailed histological and hematological analysis over a course of 60 days. Our work demonstrates that functionalized Pt3Co nanoparticles may be a promising new type of T2-weighted MR contrast agent potentially useful in biomedical imaging and diagnosis. PMID- 24165859 TI - Biological embedding of early life adversity. PMID- 24165860 TI - Trajectory of change in pain, depression, and physical functioning after physical activity adoption in fibromyalgia. AB - Fibromyalgia is associated with widespread pain, depression, and declines in physical functioning. The purpose of this study was to examine the trajectory of these symptoms over time related to physical activity adoption and maintenance via motivational interviewing versus education, to increase physical activity. There were no treatment group differences; we divided the sample (n = 184) based on changes in physical activity. Repeated measures analyses demonstrated differential patterns in depression, pain, and physical functioning at 24 and 36 weeks. Findings suggest increased physical activity may serve as a multiple target intervention that provides moderate to large, long-lasting benefits for individuals with fibromyalgia. PMID- 24165861 TI - Divergent pathways to influence: Cognition and behavior differentially mediate the effects of optimism on physical and mental quality of life in Chinese university students. AB - Previous research has indicated that both cognitive and behavioral variables mediate the positive effect of optimism on quality of life; yet few attempts have been made to accommodate these constructs into a single explanatory framework. Adopting Fredrickson's broaden-and-build perspective, we examined the relationships between optimism, self-rated health, resilience, exercise, and quality of life in 365 Chinese university students using path analysis. For physical quality of life, a two-stage model, in which the effects of optimism were sequentially mediated by cognitive and behavioral variables, provided the best fit. A one-stage model, with full mediation by cognitive variables, provided the best fit for mental quality of life. This suggests that optimism influences physical and mental quality of life via different pathways. PMID- 24165862 TI - Co-occurrence and coaction of stress management with other health risk behaviors. AB - This study provides a preliminary investigation of the role of stress management in multiple behavior change. Risk status on stress management and five health behaviors (healthy eating, exercise, alcohol, smoking, and depression management) was assessed before and after a multiple behavior change intervention. Findings suggested a link between stress management and a worse health risk behavior profile at baseline. Results also showed relationships between improved stress management over 6 months and heightened odds of improving on specific behaviors as well as improving one's overall behavioral risk profile. Particularly strong links between stress management and energy balance and other affective behaviors were observed. PMID- 24165863 TI - Biophysical characterization of a recombinant aminopeptidase II from the thermophilic bacterium Bacillus stearothermophilus. AB - In the present study, the biophysical properties of His6-tagged Bacillus stearothermophilus aminopeptidase II (His6-tagged BsAmpII) are characterized in detail by gel-filtration, analytical ultracentrifugation, and various spectroscopic techniques. Using size-exclusion chromatography and analytical ultracentrifugation, we demonstrate that His6-tagged BsAmpII exists predominantly as a dimer in solution. The enzyme is active and stable at pHs ranging from 6.5 to 8.5. Far-UV circular dichroism analysis reveals that the secondary structures of His6-tagged BsAmpII are significantly altered in the presence of SDS, whereas the presence of 5-10% acetone and ethanol was harmless to the folding of the enzyme. Thermal unfolding of His6-tagged BsAmpII was found to be irreversible and led to the formation of aggregates. The native enzyme started to unfold beyond 0.6 M guanidine hydrochloride and had a midpoint of denaturation at 1.34 M. This protein remained active at concentrations of urea below 2.7 M but experienced an irreversible unfolding by >5 M denaturant. Taken together, this work lays a foundation for potential biotechnological applications of His6-tagged BsAmpII. PMID- 24165864 TI - A microfibre assembly of an iron-carbon composite with giant magnetisation. AB - Iron carbide is among the oldest known materials. The utility of this ancient advanced material is greatly extended in its nanostructured forms. We demonstrate for the first time that one-dimensional iron carbide microfibres can be assembled in liquid using strong magnetic field-assisted laser ablation. The giant saturation magnetisation of these particles was measured a 261 emu/g at room temperature, which is the best value reported to date for iron nitride and carbide nanostructures, is 5.5 times greater than the 47 emu/g reported for Fe3C nanoparticles, and exceeds the 212 emu/g for bulk Fe. The magnetic field-induced dipolar interactions of the magnetic nanospheres and the nanochains played a key role in determining the shape of the product. These findings lead to a variety of promising applications for this unique nanostructure including its use as a magnetically guided transporter for biomedicine and as a magnetic recording material. PMID- 24165865 TI - Joule heating effects on reservoir-based dielectrophoresis. AB - Reservoir-based dielectrophoresis (rDEP) is a recently developed technique that exploits the inherent electric field gradients at a reservoir-microchannel junction to focus, trap, and sort particles. However, the locally amplified electric field at the junction is likely to induce significant Joule heating effects that are not considered in previous studies. This work investigates experimentally and numerically these effects on particle transport and control in rDEP processes in PDMS/PDMS microchips. It is found that Joule heating effects can reduce rDEP focusing considerably and may even disable rDEP trapping. This is caused by the fluid temperature rise at the reservoir-microchannel junction, which significantly increases the local particle velocity due to fluid flow and particle electrophoresis while has a weak impact on the particle velocity due to rDEP. The numerical predictions of particle stream width and electric current, which are the respective indicators of rDEP manipulation and fluid temperature, are demonstrated to both match the experimental measurements with a good accuracy. PMID- 24165866 TI - Cathemerality in wild ring-tailed lemurs (Lemur catta) in the spiny forest of Tsimanampetsotsa National Park: camera trap data and preliminary behavioral observations. AB - Cathemerality consists of discrete periods of activity during both the day and night. Though uncommon within Primates, cathemerality is prevalent in some lemur genera, such as Eulemur, Hapalemur, and Prolemur. Several researchers have also reported nighttime activity in Lemur catta, yet these lemurs are generally considered "strictly diurnal". We used behavioral observations and camera traps to examine cathemerality of L. catta at the Tsimanampetsotsa National Park, Madagascar. Nighttime activity occurred throughout the study period (September 2010-April 2011), and correlated with warm overnight temperatures but not daytime temperatures. Animals spent 25% of their daytime active behaviors on the ground, but appeared to avoid the ground at night, with only 5% of their time on the ground. Furthermore, at night, animals spent the majority of their active time feeding (53% nighttime, 43% daytime). These findings imply that both thermoregulation and diet play a role in the adaptive significance of cathemerality. Additionally, predator avoidance may have influenced cathemerality here, in that L. catta may limit nighttime activity as a result of predation threat by forest cats (Felis sp.) or fossa (Cryptoprocta ferox). Further data are needed on cathemeral lemurs generally, but particularly in L. catta if we are to fully understand the evolutionary mechanisms of cathemerality in the Lemuridae. PMID- 24165867 TI - Cumulative probability of prostate cancer detection in biopsy according to free/total PSA ratio in men with total PSA levels of 2.1-10.0 ng/ml at population screening. AB - PURPOSE: The aim of this study was to investigate the cumulative probability of prostate cancer detection according to free/total prostate-specific antigen (PSA) ratio in men with PSA levels of 2.1-10.0 ng/ml and also likelihood of detecting clinically insignificant prostate cancer in population-based screening. METHODS: A total of 1,277 men aged between 55 and 69 years with total PSA (tPSA) levels of 2.1-10.0 ng/ml screened in population screening in Kanazawa city and underwent systematic transrectal ultrasonography-guided prostate biopsy between 2000 and 2011 were enrolled. The cumulative probability of prostate cancer detection in biopsy according to age, serum tPSA, and free-to-total PSA (f/t PSA) ratio was investigated. The clinicopathological features of screening-detected prostate cancer were also investigated. RESULTS: Of the 1,277 subjects in the study population, 320 (25.0 %) were diagnosed with prostate cancer during the observation period. The probabilities of prostate cancer detection at 3 years were 64.5, 41.2, 28.5, and 14.3 % for the men with f/t PSA ratio <=0.08, 0.09 0.13, 0.14-0.22, and >=0.23, respectively; the differences in probabilities of prostate cancer detection among men with different f/t PSA ratios were statistically significant. Among 320 patients, 84 (26.3 %) had favorable clinicopathological features that made them suitable for active surveillance. The f/t PSA ratio in unfavorable cancer patients was significantly lower that that in favorable cancer patients. CONCLUSION: The present study demonstrated that the f/t PSA ratio was a strong predictor of future cancer detection and unfavorable cancerous features in prostate biopsy in men with total PSA levels of 2.1-10.0 ng/ml at population screening. PMID- 24165868 TI - Is gray water the key to unlocking water for resource-poor areas of the Middle East, North Africa, and other arid regions of the world? AB - Support for the use of treated gray water as an alternative water resource in the Middle East and North Africa is high, especially given the lack of religious restrictions against its use, but several obstacles have kept application of treated gray water near 1 % in some areas. The largest of obstacles include the cost of treatment and the ambiguity surrounding the health safety of gray water and treated gray water. This paper aims to provide an overview of current gray water practices globally, with specific focus on household-level gray water practices in the Middle East and North Africa region, and highlight the need for cost reduction strategies and epidemiological evidence on the use of household level gray water and treated gray water. Such actions are likely to increase the application of treated gray water in water-deprived areas of the Middle East and North Africa. PMID- 24165869 TI - Evaluating the impact of distance measures on deforestation simulations in the fluvial landscapes of amazonia. AB - Land use and land cover change (LUCC) models frequently employ different accessibility measures as a proxy for human influence on land change processes. Here, we simulate deforestation in Peruvian Amazonia and evaluate different accessibility measures as LUCC model inputs. We demonstrate how the selection, and different combinations, of accessibility measures impact simulation results. Out of the individual measures, time distance to market center catches the essential aspects of accessibility in our study area. The most accurate simulation is achieved when time distance to market center is used in association with distance to transport network and additional landscape variables. Although traditional Euclidean measures result in clearly lower simulation accuracy when used separately, the combination of two complementary Euclidean measures enhances simulation accuracy significantly. Our results highlight the need for site and context sensitive selection of accessibility variables. More sophisticated accessibility measures can potentially improve LUCC models' spatial accuracy, which often remains low. PMID- 24165870 TI - Toward a sustainable utilization of land resources in China: problems, policies, and practices. AB - China's economy is growing explosively with double-digit rates of growth. However, behind the scenes of this economic miracle, a dark underbelly exists. The potential impact of the unsustainable use of land resources is increasing. Each parcel of land has a stationary geographic location, while its utilization is optional. The re-adjustment and optimization of land use patterns ought to be encouraged. Spatial reconstruction refers to the combination of various land elements, which can promote the rational and efficient allocation of land resources through a four-layer action framework: the development of unused land, urban renewal, ecological reconstruction, and spatial displacement. The feasibility and validity of these methods are illustrated by practical cases in different provinces in China. We thus propose that pursuing sustainable development and building an ecological civilization will be necessary for China in future decades. PMID- 24165871 TI - Role of gastrografin challenge in early postoperative small bowel obstruction. AB - INTRODUCTION: Early small bowel obstruction following abdominal surgery presents a diagnostic and therapeutic challenge. Abdominal imaging using Gastrografin has been shown to have diagnostic and therapeutic properties when used in the setting of small bowel obstruction outside the early postoperative period (>6 weeks). We hypothesize that a GG challenge will reduce need for re-exploration. METHODS: Patients with early small bowel obstruction who underwent a Gastrografin challenge between 2010 and 2012 were case controlled, based on age +/-5 years, sex, and operative approach to an equal number of patients that did not receive the challenge. RESULTS: One hundred sixteen patients received a Gastrografin challenge. There were 87 males in each group with an average age of 62 years. A laparoscopic approach in the index operation was done equally between groups (18 vs. 18 %). There was no difference between groups in operative re-exploration rates (14 vs. 10 %); however, hospital duration of stay was greater in patients who received Gastrografin challenge (17 vs. 13 days). Two in hospital deaths occurred, one in each group, both of infectious complications. CONCLUSION: Use of the Gastrografin challenge in the immediate postoperative period appeared to be safe. There was no difference, however, in the rate of re-exploration between groups. PMID- 24165873 TI - "A debate: is surgical intervention for cystic neoplasms of the pancreas being overutilized". PMID- 24165872 TI - Perioperative outcomes of pancreaticoduodenectomy compared to total pancreatectomy for neoplasia. AB - PURPOSE: Total pancreatectomy (TP) eliminates the risk and morbidity of pancreatic leak after pancreaticoduodenectomy (PD). However, TP is a more extensive procedure with guaranteed endocrine and exocrine insufficiency. Previous studies conflict on the net benefit of TP. METHODOLOGY: A comparison of patients undergoing non-emergent, curative-intent TP or PD for pancreatic neoplasia using the National Surgical Quality Improvement Project data from 2005 2011 was done. Main outcome measures were mortality and major and minor morbidities. RESULTS: Of the 6,314 (97%) who underwent PD and the 198 (3%) who underwent TP, malignancy was present in 84% of patients. The two groups were comparable at baseline. Mortality was higher after TP (6.1%) than DP (3.1%), p = 0.02. Adjusting for differences on multivariable analysis, TP carried increased mortality (OR 2.64, 95% CI 1.3-5.2, p = 0.005). TP was also associated with increased rates of major morbidity (38 vs. 30%, p = 0.02) and blood transfusion (16 vs. 10%, p = 0.01). Infectious and septic complications occurred equally in both groups. CONCLUSION: The morbidity of a pancreatic fistula can be eliminated by TP. However, based on our findings, TP is associated with increased major morbidity and mortality. TP cannot be routinely recommended for to reduce perioperative morbidity when pancreaticoduodenectomy is an appropriate surgical option. PMID- 24165874 TI - Operative resection is currently overutilized for cystic lesions of the pancreas. PMID- 24165875 TI - Ability of FDG-PET/CT in the detection of gallbladder cancer. AB - PURPOSE: To assess the value of FDG-PET/CT in the evaluation of gallbladder carcinomas (GBC). METHODS: A prospective cohort of patients with suspicion of or confirmed GBC was studied with FDG-PET/CT. Diagnostic accuracy parameters were calculated in comparison with pathology and/or the clinical course of patients. Clinical impact of PET/CT imaging was estimated. RESULTS: Forty-nine patients were enrolled (34 malignant tumors, 15 benign lesions; 37 staging, 12 restaging). Overall diagnostic accuracy was 95.9% for the diagnosis of the primary lesion, 85.7% for lymph node involvement and 95.9% for metastatic disease. Mean SUVmax in malignant gallbladder lesions was 7.92 +/- 6.25 Analysis of ROC curves showed a SUVmax cut-off value of 3.62 for malignancy (S: 78.1%; Sp: 88.2%). Diagnostic accuracy in the restaging group reached 100%. FDG-PET/CT changed the management of 22.4% of the population. COMMENTS: Diagnosis of malignancy or benignity of suspicious gallbladder lesions is accurately made with FDG PET/CT, allowing a precise staging of GBC due to its ability to identify unsuspected metastatic disease. SUVmax has a complementary role in addition to visual analysis. PMID- 24165876 TI - Strong localized surface plasmon resonance effects of Ag/TiO2 core-shell nanowire arrays in UV and visible light for photocatalytic activity. AB - Periodic arrays of silver/titanium dioxide (Ag/TiO2) open core-shell nanowires have been investigated as enhanced plasmonic photocatalytic structures. Sequential top-down nanofabrication processes based on nanoimprinting, oblique angle evaporation, and selective electrodeposition were employed for the fabrication of various TiO2-shelled Ag nanowire arrays. Numerical simulation proves that the periodic array of Ag/TiO2 core-shell nanowire structures enables strong localized surface plasmon resonance (LSPR), which improves the electron generation and photocatalytic activities of the TiO2 shell. Enhanced photocatalytic performance was confirmed by the decomposition of methylene blue solution. Furthermore, the film composed of a Ag/TiO2 core-shell nanowire array shows photocatalytic reproducibility in the UV and visible light regions and mechanical robustness due to the periodic grating-like metal nanostructures. Our method allows reliable, controllable, and facile fabrication of large-scale plasmonic photocatalytic nanostructured films on various substrates such as glass, polymer, etc. PMID- 24165877 TI - Insights into the activation of the helicase Prp43 by biochemical studies and structural mass spectrometry. AB - Splicing of precursor messenger RNA is a hallmark of eukaryotic cells, which is carried out by the spliceosome, a multi-megadalton ribonucleoprotein machinery. The splicing reaction removes non-coding regions (introns) and ligates coding regions (exons). The spliceosome is a highly dynamic ribonucleoprotein complex that undergoes dramatic structural changes during its assembly, the catalysis and its disassembly. The transitions between the different steps during the splicing cycle are promoted by eight conserved DExD/H box ATPases. The DEAH-box protein Prp43 is responsible for the disassembly of the intron-lariat spliceosome and its helicase activity is activated by the G-patch protein Ntr1. Here, we investigate the activation of Prp43 by Ntr1 in the presence and absence of RNA substrate by functional assays and structural proteomics. Residues 51-110 of Ntr1 were identified to be the minimal fragment that induces full activation. We found protein-protein cross-links that indicate that Prp43 interacts with the G-patch motif of Ntr1 through its C-terminal domains. Additionally, we report on functionally important RNA binding residues in both proteins and propose a model for the activation of the helicase. PMID- 24165878 TI - Resveratrol and EGCG bind directly and distinctively to miR-33a and miR-122 and modulate divergently their levels in hepatic cells. AB - Modulation of miR-33 and miR-122 has been proposed to be a promising strategy to treat dyslipidemia and insulin resistance associated with obesity and metabolic syndrome. Interestingly, specific polyphenols reduce the levels of these mi(cro)RNAs. The aim of this study was to elucidate the effect of polyphenols of different chemical structure on miR-33a and miR-122 expression and to determine whether direct binding of the polyphenol to the mature microRNAs (miRNAs) is a plausible mechanism of modulation. The effect of two grape proanthocyanidin extracts, their fractions and pure polyphenol compounds on miRNA expression was evaluated using hepatic cell lines. Results demonstrated that the effect on miRNA expression depended on the polyphenol chemical structure. Moreover, miR-33a was repressed independently of its host-gene SREBP2. Therefore, the ability of resveratrol and epigallocatechin gallate to bind miR-33a and miR-122 was measured using (1)H NMR spectroscopy. Both compounds bound miR-33a and miR-122 and differently. Interestingly, the nature of the binding of these compounds to the miRNAs was consistent with their effects on cell miRNA levels. Therefore, the specific and direct binding of polyphenols to miRNAs emerges as a new posttranscriptional mechanism by which polyphenols could modulate metabolism. PMID- 24165879 TI - Evaluation of TRAP-sequencing technology with a versatile conditional mouse model. AB - Gene expression profiling of various cell lineages has provided invaluable insights into the molecular mechanisms regulating cellular development and differentiation. However, in vivo molecular profiling of rare and interspersed cell populations, such as endothelial cells, has remained challenging. We have generated a versatile floxed translating ribosome affinity purification (TRAP) mouse model, mCherryTRAP, for Cre-dependent translational profiling of distinct cell lineages from intact tissues. To identify cell type-specific transcripts using TRAP, the data have to be filtered to remove both background transcripts not expressed in the profiled cell type and transcripts expressed in all cell populations of the tissue/organ. Filtering has previously been achieved using transcribed RNA from the tissue/organ. Using the mCherryTRAP model, we demonstrate extensive differential expression of RNAs between the translatome and transcriptome of embryonic brains and kidneys. We evaluate the implications of these data for TRAP studies of abundant and rare cell populations. Finally, we demonstrate the applicability of the technology to study organ-specific endothelial cell differentiation. PMID- 24165880 TI - EBI metagenomics--a new resource for the analysis and archiving of metagenomic data. AB - Metagenomics is a relatively recently established but rapidly expanding field that uses high-throughput next-generation sequencing technologies to characterize the microbial communities inhabiting different ecosystems (including oceans, lakes, soil, tundra, plants and body sites). Metagenomics brings with it a number of challenges, including the management, analysis, storage and sharing of data. In response to these challenges, we have developed a new metagenomics resource (http://www.ebi.ac.uk/metagenomics/) that allows users to easily submit raw nucleotide reads for functional and taxonomic analysis by a state-of-the-art pipeline, and have them automatically stored (together with descriptive, standards-compliant metadata) in the European Nucleotide Archive. PMID- 24165881 TI - SIMAP--the database of all-against-all protein sequence similarities and annotations with new interfaces and increased coverage. AB - The Similarity Matrix of Proteins (SIMAP, http://mips.gsf.de/simap/) database has been designed to massively accelerate computationally expensive protein sequence analysis tasks in bioinformatics. It provides pre-calculated sequence similarities interconnecting the entire known protein sequence universe, complemented by pre-calculated protein features and domains, similarity clusters and functional annotations. SIMAP covers all major public protein databases as well as many consistently re-annotated metagenomes from different repositories. As of September 2013, SIMAP contains >163 million proteins corresponding to ~70 million non-redundant sequences. SIMAP uses the sensitive FASTA search heuristics, the Smith-Waterman alignment algorithm, the InterPro database of protein domain models and the BLAST2GO functional annotation algorithm. SIMAP assists biologists by facilitating the interactive exploration of the protein sequence universe. Web-Service and DAS interfaces allow connecting SIMAP with any other bioinformatic tool and resource. All-against-all protein sequence similarity matrices of project-specific protein collections are generated on request. Recent improvements allow SIMAP to cover the rapidly growing sequenced protein sequence universe. New Web-Service interfaces enhance the connectivity of SIMAP. Novel tools for interactive extraction of protein similarity networks have been added. Open access to SIMAP is provided through the web portal; the portal also contains instructions and links for software access and flat file downloads. PMID- 24165882 TI - YeastNet v3: a public database of data-specific and integrated functional gene networks for Saccharomyces cerevisiae. AB - Saccharomyces cerevisiae, i.e. baker's yeast, is a widely studied model organism in eukaryote genetics because of its simple protocols for genetic manipulation and phenotype profiling. The high abundance of publicly available data that has been generated through diverse 'omics' approaches has led to the use of yeast for many systems biology studies, including large-scale gene network modeling to better understand the molecular basis of the cellular phenotype. We have previously developed a genome-scale gene network for yeast, YeastNet v2, which has been used for various genetics and systems biology studies. Here, we present an updated version, YeastNet v3 (available at http://www.inetbio.org/yeastnet/), that significantly improves the prediction of gene-phenotype associations. The extended genome in YeastNet v3 covers up to 5818 genes (~99% of the coding genome) wired by 362 512 functional links. YeastNet v3 provides a new web interface to run the tools for network-guided hypothesis generations. YeastNet v3 also provides edge information for all data-specific networks (~2 million functional links) as well as the integrated networks. Therefore, users can construct alternative versions of the integrated network by applying their own data integration algorithm to the same data-specific links. PMID- 24165883 TI - IMG 4 version of the integrated microbial genomes comparative analysis system. AB - The Integrated Microbial Genomes (IMG) data warehouse integrates genomes from all three domains of life, as well as plasmids, viruses and genome fragments. IMG provides tools for analyzing and reviewing the structural and functional annotations of genomes in a comparative context. IMG's data content and analytical capabilities have increased continuously since its first version released in 2005. Since the last report published in the 2012 NAR Database Issue, IMG's annotation and data integration pipelines have evolved while new tools have been added for recording and analyzing single cell genomes, RNA Seq and biosynthetic cluster data. Different IMG datamarts provide support for the analysis of publicly available genomes (IMG/W: http://img.jgi.doe.gov/w), expert review of genome annotations (IMG/ER: http://img.jgi.doe.gov/er) and teaching and training in the area of microbial genome analysis (IMG/EDU: http://img.jgi.doe.gov/edu). PMID- 24165884 TI - The effect of single- and multiple-dose etravirine on a drug cocktail of representative cytochrome P450 probes and digoxin in healthy subjects. AB - The effect of etravirine on cytochrome P450 (CYP) enzymes and P-glycoprotein were evaluated in two randomized, crossover trials in healthy subjects. A modified Cooperstown 5 + 1 cocktail was utilized to determine the effects of etravirine on single-dose pharmacokinetics of model CYP probes. The cocktail was administered alone, then, after a 14-day washout, etravirine 200 mg twice daily (bid) was given for 14 days with cocktail on days 1 and 14. In a separate study, digoxin (0.5 mg) was administered alone, then, after a 14-day washout, etravirine 200 mg bid was administered for 12 days with digoxin on day 8. In the cocktail study, the AUClast least squares mean (LSM) ratios (90% confidence intervals [CIs]) for cocktail + etravirine versus cocktail were 0.93 (0.88, 0.99; paraxanthine), 0.58 (0.44, 0.75; 7-OH-S-warfarin), 0.43 (0.20, 0.96; 5-OH-omeprazole), 0.85 (0.78, 0.94; dextrorphan), and 0.69 (0.64, 0.74; midazolam). Digoxin AUC0-8h was slightly increased with etravirine coadministration (LSM ratio 1.18 [0.90, 1.56]). These data suggest that etravirine is a weak CYP3A isozyme inducer and minimally inhibits CYP2C9, 2C19, and P-glycoprotein activity. PMID- 24165885 TI - Ventral tegmental area/midbrain functional connectivity and response to antipsychotic medication in schizophrenia. AB - Medication management in schizophrenia is a lengthy process, as the lack of clinical response can only be confirmed after at least 4 weeks of antipsychotic treatment at a therapeutic dose. Thus, there is a clear need for the discovery of biomarkers that have the potential to accelerate the management of treatment. Using resting-state functional MRI, we examined the functional connectivity of the ventral tegmental area (VTA), the origin of the mesocorticolimbic dopamine projections, in 21 healthy controls and 21 unmedicated patients with schizophrenia at baseline (pre-treatment) and after 1 week of treatment with the antipsychotic drug risperidone (1-week post-treatment). Group-level functional connectivity maps were obtained and group differences in connectivity were assessed on the groups' participant-level functional connectivity maps. We also examined the relationship between pre-treatment/1-week post-treatment functional connectivity and treatment response. Compared with controls, patients exhibited significantly reduced pre-treatment VTA/midbrain connectivity to multiple cortical and subcortical regions, including the dorsal anterior cingulate cortex (dACC) and thalamus. After 1 week of treatment, VTA/midbrain connectivity to bilateral regions of the thalamus was re-established. Pre-treatment VTA/midbrain connectivity strength to dACC was positively correlated with good response to a 6 week course of risperidone, whereas pre-treatment VTA/midbrain connectivity strength to the default mode network was negatively correlated. Our findings suggest that VTA/midbrain resting-state connectivity may be a useful biomarker for the prediction of treatment response. PMID- 24165887 TI - Endoscopic submucosal tunnel dissection for large esophageal neoplastic lesions. AB - BACKGROUND AND STUDY AIM: Endoscopic submucosal dissection (ESD) is recommended for en bloc R0 resection of superficial esophageal neoplasms larger than 20 mm, but is high risk and time-consuming. In the tunnel technique, incisions at the lower and upper lesion edges are joined by a submucosal tunnel and then lateral incisions are made. The mucosa is thereby easily separated from the muscular layer. We report our experience of esophageal tunnel ESD. PATIENTS AND METHODS: We retrospectively reviewed all consecutive esophageal tunnel ESDs performed at our unit between January 1 2010 and January 11 2013. Lesions were superficial esophageal neoplasms, UT1N0 at EUS. RESULTS: 11 patients underwent tunnel ESD (nine squamous cell carcinomas, two adenocarcinomas). Mean dissected surface area was 13.25 cm(2). Mean procedure duration was 76.7 minutes. All 11 resections were en bloc and 9/11 were R0. Complications were one subcutaneous emphysema with spontaneous resolution, and stenosis in 4/11 patients (36.4%) with resolution after 1-5 dilations. CONCLUSION: Tunnel ESD of superficial esophageal neoplasms is an interesting option, seeming to be faster and more effective than standard ESD, without higher morbidity. PMID- 24165886 TI - Ammonia mediates methamphetamine-induced increases in glutamate and excitotoxicity. AB - Ammonia has been identified to have a significant role in the long-term damage to dopamine and serotonin terminals produced by methamphetamine (METH), but how ammonia contributes to this damage is unknown. Experiments were conducted to identify whether increases in brain ammonia affect METH-induced increases in glutamate and subsequent excitotoxicity. Increases in striatal glutamate were measured using in vivo microdialysis. To examine the role of ammonia in mediating changes in extracellular glutamate after METH exposure, lactulose was used to decrease plasma and brain ammonia. Lactulose is a non-absorbable disaccharide, which alters the intestinal lumen through multiple mechanisms that lead to the increased peripheral excretion of ammonia. METH caused a significant increase in extracellular glutamate that was prevented by lactulose. Lactulose had no effect on METH-induced hyperthermia. To determine if ammonia contributed to excitotoxicity, the effect of METH and lactulose treatment on calpain-mediated spectrin proteolysis was measured. METH significantly increased calpain-specific spectrin breakdown products, and this increase was prevented with lactulose treatment. To examine if ammonia-induced increases in extracellular glutamate were mediated by excitatory amino-acid transporters, the reverse dialysis of ammonia, the glutamate transporter inhibitor, DL-threo-beta-benzyloxyaspartic acid (TBOA), or the combination of the two directly into the striatum of awake, freely moving rats was conducted. TBOA blocked the increases in extracellular glutamate produced by the reverse dialysis of ammonia. These findings demonstrate that ammonia mediates METH-induced increases in extracellular glutamate through an excitatory amino-acid transporter to cause excitotoxicity. PMID- 24165888 TI - Randomized controlled trials are needed to close the evidence gap in the prevention of preterm birth. PMID- 24165890 TI - The CRISPR/Cas system mediates efficient genome engineering in Bombyx mori. PMID- 24165891 TI - Characterization of two distinct neuraminidases from avian-origin human-infecting H7N9 influenza viruses. AB - An epidemic of an avian-origin H7N9 influenza virus has recently emerged in China, infecting 134 patients of which 45 have died. This is the first time that an influenza virus harboring an N9 serotype neuraminidase (NA) has been known to infect humans. H7N9 viruses are divergent and at least two distinct NAs and hemagglutinins (HAs) have been found, respectively, from clinical isolates. The prototypes of these viruses are A/Anhui/1/2013 and A/Shanghai/1/2013. NAs from these two viruses are distinct as the A/Shanghai/1/2013 NA has an R294K substitution that can confer NA inhibitor oseltamivir resistance. Oseltamivir is by far the most commonly used anti-influenza drug due to its potency and high bioavailability. In this study, we show that an R294K substitution results in multidrug resistance with extreme oseltamivir resistance (over 100 000-fold) using protein- and virus-based assays. To determine the molecular basis for the inhibitor resistance, we solved high-resolution crystal structures of NAs from A/Anhui/1/2013 N9 (R294-containing) and A/Shanghai/1/2013 N9 (K294-containing). R294K substitution results in an unfavorable E276 conformation for oseltamivir binding, and consequently loss of inhibitor carboxylate interactions, which compromises the binding of all classical NA ligands/inhibitors. Moreover, we found that R294K substitution results in reduced NA catalytic efficiency along with lower viral fitness. This helps to explain why K294 has predominantly been found in clinical cases of H7N9 infection under the selective pressure of oseltamivir treatment and not in the dominant human-infecting viruses. This implies that oseltamivir can still be efficiently used in the treatment of H7N9 infections. PMID- 24165893 TI - An antibiotic-altered microbiota provides fuel for the enteric foe. AB - Antibiotic therapies disrupt the intestinal microbiota and render the host susceptible to enteric infections. A recent report by Ng et al. explores the ability of two intestinal pathogens (Salmonella enterica serovar Typhimurium and Clostridium difficile) to use this disruption to their advantage and consume host carbohydrates that would otherwise be unavailable in the presence of a normal gut microbiota. PMID- 24165892 TI - Molecular basis for the selective and ABA-independent inhibition of PP2CA by PYL13. AB - PYR1/PYL/RCAR family proteins (PYLs) are well-characterized abscisic acid (ABA) receptors. Among the 14 PYL members in Arabidopsis thaliana, PYL13 is ABA irresponsive and its function has remained elusive. Here, we show that PYL13 selectively inhibits the phosphatase activity of PP2CA independent of ABA. The crystal structure of PYL13-PP2CA complex, which was determined at 2.4 A resolution, elucidates the molecular basis for the specific recognition between PP2CA and PYL13. In addition to the canonical interactions between PYLs and PP2Cs, an extra interface is identified involving an element in the vicinity of a previously uncharacterized CCCH zinc-finger (ZF) motif in PP2CA. Sequence blast identified another 56 ZF-containing PP2Cs, all of which are from plants. The structure also reveals the molecular determinants for the ABA irresponsiveness of PYL13. Finally, biochemical analysis suggests that PYL13 may hetero-oligomerize with PYL10. These two PYLs antagonize each other in their respective ABA independent inhibitions of PP2Cs. The biochemical and structural studies provide important insights into the function of PYL13 in the stress response of plant and set up a foundation for future biotechnological applications of PYL13. PMID- 24165895 TI - Leveraging electronic health records to notify pediatric patients of a drug recall. PMID- 24165894 TI - miR-142-3p regulates the formation and differentiation of hematopoietic stem cells in vertebrates. AB - Previous studies on developmental hematopoiesis have mainly focused on signaling and transcription factors, while the appreciation of epigenetic regulation including that of microRNAs is recent. Here, we show that in zebrafish and mouse, miR-142-3p is specifically expressed in hematopoietic stem cells (HSCs). Knockdown of miR-142a-3p in zebrafish led to a reduced population of HSCs in the aorta-gonad-mesonephros (AGM) region as well as T-cell defects in the thymus. Mechanistically, miR-142a-3p regulates HSC formation and differentiation through the repression of interferon regulatory factor 7 (irf7)-mediated inflammation signaling. Finally, we show that miR-142-3p is also involved in the development of HSCs in mouse AGM, suggesting that it has a highly conserved role in vertebrates. Together, these findings unveil the pivotal roles that miR-142a-3p plays in the formation and differentiation of HSCs by repressing irf7 signaling. PMID- 24165896 TI - The Indian Spice Turmeric Delays and Mitigates Radiation-Induced Oral Mucositis in Patients Undergoing Treatment for Head and Neck Cancer: An Investigational Study. AB - PURPOSE: Radiation-induced oral mucositis is an acute morbidity seen in patients undergoing treatment for head and neck cancers. In this study, we evaluated the efficacy of turmeric in preventing radiation-induced mucositis. METHODS: This was a single-blinded, randomized, controlled clinical trial and was conducted with head and neck cancer patients requiring 70 Gy of radiation or chemoradiotherapy (daily radiotherapy plus carboplatin once a week). Eligible patients (n = 80) were randomly assigned to receive either turmeric gargle (n = 40) or povidone iodine ([n = 40] active comparator condition) during chemo/radiotherapy during the period of treatment. Oral mucositis was assessed using the RTOG (Radiation Therapy Oncology Group) grading system before the start, during, and at the end of the treatment by an investigator unaware of the treatment. The primary endpoint of this study was the incidence of mucositis every week during the 7 week period. The secondary endpoint was the effect of turmeric gargle on the incidence of treatment breaks, loss of scheduled treatment days, and decrease in body weight at the end of the treatment. RESULTS: This study clearly suggests that when compared with the cohorts using povidone-iodine gargle, the group using turmeric as a mouthwash had delayed and reduced the levels of radiation-induced oral mucositis and was statistically significant at all time points (P< 0.001 toP< 0.0001). Additionally, the cohorts using turmeric had decreased intolerable mucositis (P< 0.001) and lesser incidence of treatment breaks in the first half of the treatment schedule before 4 weeks (P< 0.01) and reduced change in body weight (P< 0.001). CONCLUSIONS: Gargling with turmeric by head and neck cancer patients undergoing radiation therapy provided significant benefit by delaying and reducing the severity of mucositis. Turmeric is readily available, relatively inexpensive, and highly accepted making it useful in cancer treatment. PMID- 24165897 TI - Variations in the pre-ejection period induced by deep breathing do not predict the hemodynamic response to early haemorrhage in healthy volunteers. AB - Monitoring that can predict fluid responsiveness is an unsettled matter for spontaneously breathing patients. Mechanical ventilation induces cyclic variations in blood pressure, e.g. pulse pressure variation, whose magnitude predicts fluid responsiveness in mechanically ventilated patients. In this study, we hypothesised that a deep breathing manoeuvre with its effect on heart rate variability (HRV) could induce similar cyclic variations in blood pressure in spontaneously breathing healthy subjects and that the magnitude of these variations could predict the hemodynamic response to controlled haemorrhage. 37 blood donors were instructed to perform two simple deep breathing manoeuvres prior to blood donation; one manoeuvre with a respiratory cycle every 10 s (0.1 Hz) and one every 6 s (0.167 Hz). The variation in the pre-ejection period (?PEP) was captured with the electrocardiographic and plethysmographic curves, while the hemodynamic response to haemorrhage was estimated with the cardiac output change assessed with ultrasonography. Respiratory HRV was estimated with root mean square of successive differences (RMSSD). Deep breathing induced cyclic changes in ?PEP magnitude was significantly correlated to RMSSD (p < 0.005). ?PEP indexed to RMSSD increased significantly following haemorrhage at the 0.167 Hz respiratory frequency (p = 0.01). At none of the respiratory manoeuvres was ?PEP nor ?PEP/RMSSD prior to haemorrhage correlated to changes in cardiac output following haemorrhage. Deep breathing induces cyclic changes in blood pressure that are strongly dependent on HRV. These blood pressure variations do, however, not predict the cardiac output response to controlled haemorrhage. PMID- 24165898 TI - On the predictability of future impact in science. AB - Correctly assessing a scientist's past research impact and potential for future impact is key in recruitment decisions and other evaluation processes. While a candidate's future impact is the main concern for these decisions, most measures only quantify the impact of previous work. Recently, it has been argued that linear regression models are capable of predicting a scientist's future impact. By applying that future impact model to 762 careers drawn from three disciplines: physics, biology, and mathematics, we identify a number of subtle, but critical, flaws in current models. Specifically, cumulative non-decreasing measures like the h-index contain intrinsic autocorrelation, resulting in significant overestimation of their "predictive power". Moreover, the predictive power of these models depend heavily upon scientists' career age, producing least accurate estimates for young researchers. Our results place in doubt the suitability of such models, and indicate further investigation is required before they can be used in recruiting decisions. PMID- 24165899 TI - Efficient algorithm for simulation of isoelectric focusing. AB - IEF simulation is an effective tool to investigate the transport phenomena and separation performance as well as to design IEF microchip. However, multidimensional IEF simulations are computationally intensive as one has to solve a large number of mass conservation equations for ampholytes to simulate a realistic case. In this study, a parallel scheme for a 2D IEF simulation is developed to reduce the computational time. The calculation time for each equation is analyzed to identify which procedure is suitable for parallelization. As expected, simultaneous solution of mass conservation equations of ampholytes is identified as the computational hot spot, and the computational time can be significantly reduced by parallelizing the solution procedure for that. Moreover, to optimize the computing time, electric potential behavior during transient state is investigated. It is found that for a straight channel the transient variation of electric potential along the channel is negligible in a narrow pH range (5~8) IEF. Thus the charge conservation equation is solved for the first time step only, and the electric potential obtain from that is used for subsequent calculations. IEF simulations are carried out using this algorithm for separation of cardiac troponin I from serum albumin in a pH range of 5-8 using 192 biprotic ampholytes. Significant reduction in simulation time is achieved using the parallel algorithm. We also study the effect of number of ampholytes to form the pH gradient and its effect in the focusing and separation behavior of cardiac troponin I and albumin. Our results show that, at the completion of separation phase, the pH profile is stepwise for lower number of ampholytes, but becomes smooth as the number of ampholytes increases. Numerical results also show that higher protein concentration can be obtained using higher number of ampholytes. PMID- 24165900 TI - Trends in the surgical treatment of gastric adenocarcinoma. AB - BACKGROUND: In past decade, the treatment of gastric adenocarcinoma has evolved as a result of the publication of two seminal randomized controlled trials. We aimed to examine treatment trends for resectable gastric cancer (stage I-III) using the National Cancer Data Base (NCDB). Our hypothesis was that the use of chemotherapy and chemoradiotherapy in addition to surgery for the treatment of gastric adenocarcinoma has increased from 2000 to 2009. METHODS: Patients diagnosed with stage I-III gastric adenocarcinoma between 2000 and 2009 were selected from the NCDB Hospital Comparison Benchmark Reports. Attention was paid to the initial treatment regimen and data on hospital setting were collected and analyzed. The Cochran-Armitage test for trend was used to assess changes in treatment over time. RESULTS: A total of 50,778 patients with stage I-III gastric adenocarcinoma were included in the analysis. Between 2000 and 2009, the use of surgery alone decreased significantly across all three stages at both teaching hospitals and community hospitals (p < 0.0001 for all cases). In the same period, the use of chemotherapy in addition to surgery increased significantly across all three stages and at both hospital settings (p < 0.0001 for all cases). Surgery plus chemoradiotherapy increased for stage I-III disease at community hospitals (p < 0.05 for all) but only increased significantly for stage II disease at teaching hospitals (p < 0.01). Incidentally, nonsurgical treatment increased across all three stages at both hospital settings (p < 0.001 for all cases). CONCLUSIONS: Data from the NCDB from 2000 to 2009 demonstrate that there has been an increasing use of chemotherapy in addition to surgery for resectable gastric cancer. PMID- 24165901 TI - Reducing persistent postoperative pain and disability 1 year after breast cancer surgery: a randomized, controlled trial comparing thoracic paravertebral block to local anesthetic infiltration. AB - BACKGROUND: The objective of this study was to compare the effect of thoracic paravertebral block (TPVB) and local anesthetic (LA) on persistent postoperative pain (PPP) 1 year following breast cancer surgery. Secondary objectives were to compare the effect on arm morbidity and quality of life. METHODS: Women scheduled for elective breast cancer surgery were randomly assigned to either TPVB or LA followed by general anesthesia. An NRS value of >3 at rest or with movement 1 year following surgery defined PPP. Blinded interim analysis suggested rates of PPP much lower than anticipated, making detection of the specified 20 % absolute reduction in the primary outcome impossible. Recruitment was stopped, and all enrolled patients were followed to 1 year. RESULTS: A total of 145 participants were recruited; 65 were randomized to TPVB and 64 to LA. Groups were similar with respect to demographic and treatment characteristics. Only 9 patients (8 %; 95 % CI 4-14 %) met criteria for PPP 1 year following surgery; 5 were in the TPVB and 4 in the LA group. Brief Pain Inventory severity and interference scores were low in both groups. Arm morbidity and quality of life were similar in both groups. The 9 patients with PPP reported shoulder-arm morbidity and reduced quality of life. CONCLUSIONS: This study reports a low incidence of chronic pain 1 year following major breast cancer surgery. Although PPP was uncommon at 1 year, it had a large impact on the affected patients' arm morbidity and quality of life. PMID- 24165902 TI - Poly(lactic acid) nanoparticles of the lead anticancer ruthenium compound KP1019 and its surfactant-mediated activation. AB - Nanoparticle formulations offer besides the advantage of passive drug targeting also the opportunity to increase the stability of drugs. KP1019 is a lead ruthenium(III) compound which has been successfully tested in a clinical phase I trial. However, it is characterized by low stability in aqueous solution especially at physiological pH. To overcome this limitation, poly(lactic acid) (PLA) nanoparticles of KP1019 with two different surfactants (Pluronic F68 and Tween 80) were prepared by a single oil-in-water (o/w) emulsion. Cytotoxicity measurements comparing different aged Tween 80 nanoparticles revealed that the color change from brown to green was associated with an up to 20 fold increased activity compared to "free" KP1019. Further investigations suggested that this is based on the formation of enhanced intracellular reactive oxygen species levels. Additional studies revealed that the origin of the green color is a reaction between KP1019 and Tween 80. Kinetic studies of this reaction mixture using UV Vis, ESI-MS and ESR spectroscopy indicated on the one hand a coordination of Tween 80 to KP1019, and on the other hand, the color change was found to correlate with a reduction of the Ru(III) center by the surfactant. Together, the results provide a first experimental approach to stabilize a biologically active Ru(II) species of KP1019 in aqueous solution, which probably can be also used to selectively generate this activated species in the tumor tissue via delivery of KP1019 using Tween 80 nanoparticles. PMID- 24165903 TI - Electrophysiological evidence for greater attention to threat when cognitive control resources are depleted. AB - In this study, we investigated the time course of attentional bias for threat related (angry) facial expressions under conditions of high versus low cognitive (working memory) load. Event-related potential (ERP) and reaction time (RT) data were recorded while participants viewed pairs of faces (angry paired with neutral face) displayed for 500 ms and followed by a probe. Participants were required to respond to the probe while performing a concurrent task of holding in working memory a sequence of digits that were either in the same order (low memory load) or in a random mixed order (high memory load). The ERP results revealed that higher working memory load resulted in enhanced lateralized neural responses to threatening relative to neutral faces, consistent with greater initial orienting of attention to threatening faces (early N2pc: 180-252 ms) and enhanced maintenance of processing representations of threat (late N2pc, 252-320 ms; SPCN, 320-500 ms). The ERP indices showed significant positive relationships with each other, and also with the behavioral index of attentional bias to threat (reflected by faster RTs to probes replacing angry than neutral faces at 500 ms), although the latter index was not significantly influenced by memory load. Overall, the findings indicate that depletion of cognitive control resources, using a working memory manipulation, increases the capacity of task-irrelevant threat cues to capture and hold attention. PMID- 24165904 TI - Posttraumatic stress disorder is associated with limited executive resources in a working memory task. AB - Patients with posttraumatic stress disorder (PTSD) can show declines in working memory. A dual-task design was used to determine whether these impairments are linked to executive control limitations. Participants performed a Sternberg memory task with either one or four letters. In the dual-task condition, the maintenance period was filled with an arrow flanker task. PTSD patients were less accurate on the working memory task than were controls, especially in the dual task condition. In the single-task condition, both groups showed similar patterns of brain potentials from 300 to 500 ms when discriminating old and new probes. However, when taxed with an additional task, the event-related potentials (ERPs) of the PTSD group no longer differentiated old and new probes. In contrast, interference resolution processes in both the single- and dual-task conditions of the flanker task were intact. The lack of differentiation in the ERPs reflects impaired working memory performance under more difficult, dual-task conditions. Exacerbated difficulty in performing a working memory task with concurrent task demands suggests a specific limitation in executive control resources in PTSD. PMID- 24165905 TI - Thermal responsive micelles for dual tumor-targeting imaging and therapy. AB - Two kinds of thermally responsive polymers P(FAA-NIPA-co-AAm-co-ODA) and P(FPA NIPA-co-AAm-co-ODA) containing folate, isopropyl acrylamide and octadecyl acrylate were fabricated through free radical random copolymerization for targeted drug delivery. Then the micelles formed in aqueous solution by self assembly and were characterized in terms of particle size, lower critical solution temperature (LCST) and a variety of optical spectra. MTT assays demonstrated the low cytotoxicity of the control micelle and drug-loaded micelle on A549 cells and Bel 7402 cells. Then fluorescein and cypate were used as model drugs to optimize the constituents of micelles for drug entrapment efficiency and investigate the release kinetics of micelles in vitro. The FA and thermal co mediated tumor-targeting efficiency of the two kinds of micelles were verified and compared in detail at cell level and animal level, respectively. These results indicated that the dual-targeting micelles are promising drug delivery systems for tumor-targeting therapy. PMID- 24165906 TI - Pharmacokinetics and pharmacodynamics of tiotropium solution and tiotropium powder in chronic obstructive pulmonary disease. AB - The aim of the study was to characterize pharmacokinetics of tiotropium solution 5 ug compared to powder 18 ug and assess dose-dependency of tiotropium solution pharmacodynamics in comparison to placebo. In total 154 patients with chronic obstructive pulmonary disease (COPD) were included in this multicenter, randomized, double-blind within-solution (1.25, 2.5, 5 ug, and placebo), and open label powder 18 ug, crossover study, including 4-week treatment periods. Primary end points were peak plasma concentration (Cmax,ss ), and area under the plasma concentration-time profile (AUC0-6h,ss ), both at steady state. The pharmacodynamic response was assessed by serial spirometry (forced expiratory volume in 1 second/forced vital capacity). Safety was evaluated as adverse events and by electrocardiogram/Holter. Tiotropium was rapidly absorbed with a median tmax,ss of 5-7 minutes postdosing for both devices. The gMean ratio of solution 5 ug over powder 18 ug was 81% (90% confidence interval, 73-89%) for Cmax,ss and 76% (70-82%) for AUC0-6h,ss , indicating that bioequivalence was not established. Dose ordering for bronchodilation was observed. Powder 18 ug and solution 5 ug were most effective, providing comparable bronchodilation. All treatments were well tolerated with no apparent relation to dose or device. Comparable bronchodilator efficacy to powder18 ug at lower systemic exposure supports tiotropium solution 5 ug for maintenance treatment of COPD. PMID- 24165907 TI - Asthma: the importance of dysregulated barrier immunity. AB - Chronic asthma is an inflammatory disease of the airway wall that leads to bronchial smooth muscle hyperreactivity and airway obstruction, caused by inflammation, goblet cell metaplasia, and airway wall remodeling. In response to allergen presentation by airway DCs, T-helper lymphocytes of the adaptive immune system control many aspects of the disease through secretion of IL-4, IL-5, IL 13, IL-17, and IL-22, and these are counterbalanced by cytokines produced by Treg cells. Many cells of the innate immune system such as mast cells, basophils, neutrophils, eosinophils, and innate lymphoid cells also play an important role in disease pathogenesis. Barrier epithelial cells are being ever more implicated in disease pathogenesis than previously thought, as these cells have in recent years been shown to sense exposure to allergens via pattern recognition receptors and to activate conventional and inflammatory-type DCs and other innate immune cells through the secretion of thymic stromal lymphopoietin, granulocyte macrophage colony stimulating factor, IL-1, IL-33, and IL-25. Understanding this cytokine crosstalk between barrier epithelial cells, DCs, and immune cells provides important insights into the mechanisms of allergic sensitization and asthma progression as discussed in this review. PMID- 24165910 TI - Risk factors: Noncardiac surgery and stents. PMID- 24165909 TI - Silent cerebral infarcts associated with cardiac disease and procedures. AB - The occurrence of clinically silent cerebral infarcts (SCIs) in individuals affected by cardiac disease and after invasive cardiac procedures is frequently reported. Indeed, atrial fibrillation, left ventricular thrombus formation, cardiomyopathy, and patent foramen ovale have all been associated with SCIs. Furthermore, postprocedural SCIs have been observed after left cardiac catheterization, transcatheter aortic valve implantation, CABG surgery, pulmonary vein isolation, and closure of patent foramen ovale. Such SCIs are often described as precursors to symptomatic stroke and are associated with cognitive decline, dementia, and depression. Increased recognition of SCIs might advance our understanding of their relationship with heart disease and invasive cardiac procedures, facilitate further improvement of therapies or techniques aimed at preventing their occurrence and, therefore, decrease the risk of adverse neurological outcomes. In this Review, we provide an overview of the occurrence and clinical significance of, and the available diagnostic modalities for, SCIs related to cardiac disease and associated invasive cardiac procedures. PMID- 24165911 TI - Prevention: Rosuvastatin can prevent contrast-induced AKI. PMID- 24165913 TI - Long-term results of endoscopic resection for type I gastric neuroendocrine tumors. AB - BACKGROUND: A number of different therapies, including endoscopic resection, have been suggested for the treatment of Type 1 gastric neuroendocrine tumors (NETs). The current study aimed to determine the long-term efficacy of endoscopic resection for Type 1 gastric NETs. METHODS: Twenty-two patients (from 1999 to 2012) with Type 1 gastric NETs were included in the study. All patients were treated with endoscopic resection and received regular followed-up appointments at a tertiary referral center. RESULTS: All patients were initially diagnosed with hypergastrinemia, atrophic gastritis and intestinal metaplasia. Polyps' diameters were >1 cm in 4 patients, and between 0.5 and 1 cm in 18 patients. All detectable lesions were successfully resected. One patient required surgery due to gastric perforation during endoscopic mucosal resection. Recurrence was detected in four patients (18%) and endoscopic resection was performed again. Local or distant metastasis was not observed in any patient during follow-up. Median follow-up time was 7 years, with a maximum of 14 years. Seventeen patients (78%) completed a 5-year follow-up period, and overall disease-free survival rate was 100%. CONCLUSIONS: Long-term follow-ups with 22 patients suggest that endoscopic resection of Type 1 gastric NETs is a safe and effective treatment option with a relatively low recurrence rate. PMID- 24165915 TI - Cost-effectiveness analysis in health care based on the capability approach. AB - It is well known that Sen's capability approach and preference utilitarianism have different distributional values. The purpose of this paper is to discuss how Sen's capability approach might be operationalised for allocation decisions and cost-effectiveness analysis in health care. The paper identifies several requirements for measuring health or well-being in line with the capability approach. Among them is the need for objective assessments of capabilities. This paper also shows that from the perspective of the capability approach a portion of productivity changes are irrelevant for allocation decisions. PMID- 24165914 TI - [The occurrence of plasticisers (phthalates) in communal facilities under special consideration of results from LUPE 3]. AB - Children are a very susceptible subgroup of the general population and therefore health authorities have a special interest to prevent them from health hazards. In a study of 3 German Bundeslander the indoor air and dust samples of altogether 63 German daycare centres were analysed for the presence of phthalate diesters in 2011/12 (LUPE 3 study). Inhalable dust and gas phases were collected with a glass fibre filter and polyurethane foam over approximately 6 h while children were attending these facilities. Settled dust was collected by vacuuming the floor of the room using an ALK dust sampler. Indoor air and dust were analysed using a GC/MS system. Median values in the dust samples were 888 mg/kg for di-2 ethylhexyl phthalate (DEHP), 302 mg/kg for diisononyl phthalate (DiNP), 34 mg/kg for diisodecyl phthalate (DiDP), 21 mg/kg for di-n-butyl phthalate (DnBP), and 20 mg/kg for diisobutyl phthalate (DiBP). For DEHP and DiNP maximum values of 10,086 mg/kg and 7,091 mg/kg were observed, respectively. DEHP and DiNP were responsible for 70% and 24% of the total phthalate concentration in the dust. In indoor air phthalates are found mainly in the particulate phase of the filters. Only the more volatile phthalates dimethyl phthalate and diethyl phthalate were found also in the gas phase. The median values in the indoor air were 470 ng/m3 for DiBP, 230 ng/m3 for DnBP, 190 ng/m3 for DEHP, and 100 ng/m3 for DiNP. DnBP and DiBP were together responsible for 55% of the total phthalate concentration in the indoor air. Overall, our study showed that the concentrations of phthalates in indoor air of daycare centers are slightly higher and in dust samples lower compared with schools. PMID- 24165916 TI - [Patient education for self-management of oral anticoagulation - situation in Hesse]. AB - AIM: Oral anticoagulation (OAC) has been shown to be highly effective in preventing thromboembolic complications. Self-management can enable patients with a long-term indication for OAC to be actively involved in the therapy, but in Germany the implementation of self-management is linked to mandatory training. To illustrate significant structural disparities between education centres in Hesse, all such centres were identified and a list generated, specifying the differences. METHOD: Using our own questionnaire, we interviewed all known patient education centres in Hesse between January and July 2012, and conducted a descriptive analysis of their structural features. RESULTS: There were 44 datasets for statistical interpretation. We distinguished between centres with ASA certification (n=19) and centres without (n=25). On average, certified centres provide 6 h of training (range 2-9) compared to 5.5 h (range 1-12) in uncertified centers. Certified centres hold more group sessions per year (on average 17 vs. 8) and more individual training sessions (on average 10 vs. 5). Certified centres train 10-365 patients per year and uncertified centers between 5 and 77. Certified centres offer retraining more frequently (84% vs. 40%) and more often conclude the training with a written test (74% vs. 44%). Only 9 centres provide materials for patients with a migration background. CONCLUSION: The results show that in Hesse, severe structural discrepancies exist in training programmes for self-management of OAC, and it can be assumed that patients participating in trainings in different Hessian education centres face very differing conditions. To improve the quality of the trainings and to ensure patients have similar levels of knowledge, it is imperative that centres be regularly inspected with the help of proven quality indicators. PMID- 24165912 TI - Genome-wide association study identifies 8 novel loci associated with blood pressure responses to interventions in Han Chinese. AB - BACKGROUND: Blood pressure (BP) responses to dietary sodium and potassium intervention and cold pressor test vary considerably among individuals. We aimed to identify novel genetic variants influencing individuals' BP responses to dietary intervention and cold pressor test. METHODS AND RESULTS: We conducted a genome-wide association study of BP responses in 1881 Han Chinese and de novo genotyped top findings in 698 Han Chinese. Diet-feeding study included a 7-day low-sodium (51.3 mmol/d), a 7-day high-sodium (307.8 mmol/d), and a 7-day high sodium plus potassium supplementation (60 mmol/d). Nine BP measurements were obtained during baseline observation and each intervention period. The meta analyses identified 8 novel loci for BP phenotypes, which physically mapped in or near PRMT6 (P=7.29 * 10(-9)), CDCA7 (P=3.57 * 10(-8)), PIBF1 (P=1.78 * 10(-9)), ARL4C (P=1.86 * 10(-8)), IRAK1BP1 (P=1.44 * 10(-10)), SALL1 (P=7.01 * 10(-13)), TRPM8 (P=2.68 * 10(-8)), and FBXL13 (P=3.74 * 10(-9)). There was a strong dose response relationship between the number of risk alleles of these independent single-nucleotide polymorphisms and the risk of developing hypertension during the 7.5-year follow-up in the study participants. Compared with those in the lowest quartile of risk alleles, odds ratios (95% confidence intervals) for those in the second, third, and fourth quartiles were 1.39 (0.97, 1.99), 1.72 (1.19, 2.47), and 1.84 (1.29, 2.62), respectively (P=0.0003 for trend). CONCLUSIONS: Our study identified 8 novel loci for BP responses to dietary sodium and potassium intervention and cold pressor test. The effect size of these novel loci on BP phenotypes is much larger than those reported by the previously published studies. Furthermore, these variants predict the risk of developing hypertension among individuals with normal BP at baseline. PMID- 24165917 TI - [Depression and memory: comparison of memory performances in depressive and healthy adults]. AB - BACKGROUND: This study examines whether patients suffering from a major depression episode or recurrent depression reveal impairments in different memory components compared to healthy controls. Memory functions are examined and compared by assessing the examinees' performances on free recall and recognition tasks. METHODS: Performances of 200 depressed inpatients and outpatients as well as 200 healthy controls on memory tasks were assessed using a psychometric test battery. Data was evaluated by analyzing the differences of mean values and the heterogeneity of relevant effect sizes. RESULTS AND CONCLUSION: Depressed patients showed lower performances on all episodic memory tasks compared to healthy controls. The size of deficits turned out to vary depending on the type of affective disorder and the type of memory task. PMID- 24165918 TI - [Occupational health and practice management of primary care practitioners during influenza pandemic 2009/10 in Germany - a survey of 1150 physicians participating in syndromic influenza surveillance at Robert Koch Institute]. AB - BACKGROUND: In preparation of an influenza pandemic, public health authorities and professional organisations recommend physicians to change practice management for patients with acute respiratory infections (ARI), in order to reduce transmission and protect practice staff. This study evaluates the implementation of these recommendations during the influenza pandemic 2009/10. METHODS: In 2010, we sent a standardised paper-and-pencil questionnaire on information sources, practice management, occupational safety and vaccination to physicians participating in the national sentinel syndromic influenza surveillance in Germany. Taken measures were compared according to specialisation of physicians. RESULTS: Out of 1,150 physicians, 760 replied (66%). The recommendations were considered reasonable by 64%. Physicians used hand disinfection (76%), gloves (62%) and facial masks (52%) more frequently than usual. Overall, 68% changed their practice management during the pandemic. Physicians separated ARI patients spatially (74%) and in time (38%) from others. In 72%, physicians were vaccinated against pandemic influenza. The physicians found time and effort spent on the sentinel appropriate (82%), even during the influenza pandemic. Paediatricians considered the recommendations less practicable than GPs or internists. CONCLUSION: The majority of participating physicians considered the recommendations on occupational safety reasonable and changed their practice management accordingly. However, the recommendations might not reflect the special needs of paediatricians. PMID- 24165919 TI - [Relationship between self-reported ADHD symptoms and WAIS-IV performance]. AB - This study has examined the relationship between cognitive functions and self reported symptoms in ADHD adults. Cognitive functions were investigated with the Wechsler Adult Intelligence Scale-IV (WAIS-IV) in N=113 ADHD adults. The severity of self-reported symptoms was based on a screening questionnaire (ADHS-E). Results indicated only weak correlations between self-reported ADHD symptoms and WAIS-IV performance. The ADHS-E scale "Emotion & Affect" accounted for a small but significant variance on most WAIS-IV indices and turned out to be the most important variable to explain performance. The findings suggest that concurrent and discrepant information contribute to a differentiated examination on adult ADHD and that both objective performance diagnostics and self-reports complement each other within the diagnostic process. PMID- 24165920 TI - [The image of general practitioners from the perspective of patients with and without a Turkish migration background - a qualitative study]. AB - OBJECTIVE: In order to improve the medical care of people with migration background, the existing specialties in medical understanding must be taken into account. The aim of this study was to explore the image of general practitioners from the viewpoint of patients and to evaluate possible differences in the perception of patients with and without a Turkish migration background. METHODS: 5 focus groups with participants with and without migration background were assessed in German language. In addition to a predefined interview guideline, the collage technique was used in order to explore the image of the practitioners through pictures. The content analysis was conducted according to Mayring using the software program ATLAS.ti. RESULTS: The patients revealed a highly positive image about the general practitioners. By means of the collage technique some negative aspects could be identified which were not discussed in the focus groups. Only minimal differences in the opinions of participants with and without Turkish migration background could be observed. These were a strongly negative attribution to the general practitioners with regard to financial aspects by the participants without migration background on the one hand and a rather paternalistic viewpoint by the participants with Turkish migration background on the other hand. Asked about an image change of general practitioners, the overall opinion has changed over the years from doctors being considered to be "powerful" and "unapproachable" to a "normal" level. Major reasons for this image change were attributed to the fact that patients are becoming increasingly informed about medical issues through the internet and the high work pressure of general practitioners. The image of general practitioners in Turkey was perceived more negative as compared to Germany. CONCLUSION: The image of general practitioners from the perspective of patients is predominantly positive. Altogether, only minor differences in the perception of German speaking patients with and without Turkish migration background could be identified. Therefore, specific ways of proceeding or qualification measures for general practitioners do not seem necessary in this context. PMID- 24165922 TI - The effects of poverty on childhood brain development: the mediating effect of caregiving and stressful life events. AB - IMPORTANCE The study provides novel data to inform the mechanisms by which poverty negatively impacts childhood brain development. OBJECTIVE To investigate whether the income-to-needs ratio experienced in early childhood impacts brain development at school age and to explore the mediators of this effect. DESIGN, SETTING, AND PARTICIPANTS This study was conducted at an academic research unit at the Washington University School of Medicine in St Louis. Data from a prospective longitudinal study of emotion development in preschool children who participated in neuroimaging at school age were used to investigate the effects of poverty on brain development. Children were assessed annually for 3 to 6 years prior to the time of a magnetic resonance imaging scan, during which they were evaluated on psychosocial, behavioral, and other developmental dimensions. Preschoolers included in the study were 3 to 6 years of age and were recruited from primary care and day care sites in the St Louis metropolitan area; they were annually assessed behaviorally for 5 to 10 years. Healthy preschoolers and those with clinical symptoms of depression participated in neuroimaging at school age/early adolescence. EXPOSURE Household poverty as measured by the income-to needs ratio. MAIN OUTCOMES AND MEASURES Brain volumes of children's white matter and cortical gray matter, as well as hippocampus and amygdala volumes, obtained using magnetic resonance imaging. Mediators of interest were caregiver support/hostility measured observationally during the preschool period and stressful life events measured prospectively. RESULTS Poverty was associated with smaller white and cortical gray matter and hippocampal and amygdala volumes. The effects of poverty on hippocampal volume were mediated by caregiving support/hostility on the left and right, as well as stressful life events on the left. CONCLUSIONS AND RELEVANCE The finding that exposure to poverty in early childhood materially impacts brain development at school age further underscores the importance of attention to the well-established deleterious effects of poverty on child development. Findings that these effects on the hippocampus are mediated by caregiving and stressful life events suggest that attempts to enhance early caregiving should be a focused public health target for prevention and early intervention. Findings substantiate the behavioral literature on the negative effects of poverty on child development and provide new data confirming that effects extend to brain development. Mechanisms for these effects on the hippocampus are suggested to inform intervention. PMID- 24165924 TI - Controllable emission of a dipolar source coupled with a magneto-dielectric resonant subwavelength scatterer. AB - We demonstrate experimentally and theoretically that a local excitation of a single scatterer of relative dielectric permittivity epsilon = 6 permits to excite broad dipolar and quadrupolar electric and magnetic resonances that shape the emission pattern in an unprecedented way. By suitably positioning the feed with respect to the sphere at a lambda/3 distance, this compact antenna is able to spectrally sort the electromagnetic emission either in the forward or in the backward direction, together with a high gain in directivity. Materials with epsilon = 6 can be found in the whole spectrum of frequencies promising Mie antennas to become an enabling technology in numbers of applications, ranging from quantum single photon sources to telecommunications. PMID- 24165925 TI - Historical land-use influences the long-term stream turbidity response to a wildfire. AB - Wildfires commonly result in an increase in stream turbidity. However, the influence of pre-fire land-use practices on post-fire stream turbidity is not well understood. The Lower Cotter Catchment (LCC) in south-eastern Australia is part of the main water supply catchment for Canberra with land in the catchment historically managed for a mix of conservation (native eucalypt forest) and pine (Pinus radiata) plantation. In January 2003, wildfires burned almost all of the native and pine forests in the LCC. A study was established in 2005 to determine stream post-fire turbidity recovery within the native and pine forest areas of the catchment. Turbidity data loggers were deployed in two creeks within burned native forest and burned pine forest areas to determine turbidity response to fire in these areas. As a part of the study, we also determined changes in bare soil in the native and pine forest areas since the fire. The results suggest that the time, it takes turbidity levels to decrease following wildfire, is dependent upon the preceding land-use. In the LCC, turbidity levels decreased more rapidly in areas previously with native vegetation compared to areas which were previously used for pine forestry. This is likely because of a higher percentage of bare soil areas for a longer period of time in the ex-pine forest estate and instream stores of fine sediment from catchment erosion during post-fire storm events. The results of our study show that the previous land-use may exert considerable control over on-going turbidity levels following a wildfire. PMID- 24165923 TI - Interaction with both ZNRF3 and LGR4 is required for the signalling activity of R spondin. AB - R-spondin proteins sensitize cells to Wnt signalling and act as potent stem cell growth factors. Various membrane proteins have been proposed as potential receptors of R-spondin, including LGR4/5, membrane E3 ubiquitin ligases ZNRF3/RNF43 and several others proteins. Here, we show that R-spondin interacts with ZNRF3/RNF43 and LGR4 through distinct motifs. Both LGR4 and ZNRF3 binding motifs are required for R-spondin-induced LGR4/ZNRF3 interaction, membrane clearance of ZNRF3 and activation of Wnt signalling. Importantly, Wnt-inhibitory activity of ZNRF3, but not of a ZNRF3 mutant with reduced affinity to R-spondin, can be strongly suppressed by R-spondin, suggesting that R-spondin primarily functions by binding and inhibiting ZNRF3. Together, our results support a dual receptor model of R-spondin action, where LGR4/5 serve as the engagement receptor whereas ZNRF3/RNF43 function as the effector receptor. PMID- 24165921 TI - Myelin architecture: zippering membranes tightly together. AB - Rapid nerve conduction requires the coating of axons by a tightly packed multilayered myelin membrane. In the central nervous system, myelin is formed from cellular processes that extend from oligodendrocytes and wrap in a spiral fashion around an axon, resulting in the close apposition of adjacent myelin membrane bilayers. In this review, we discuss the physical principles underlying the zippering of the plasma membrane of oligodendrocytes at the cytoplasmic and extracellular leaflet. We propose that the interaction of the myelin basic protein with the cytoplasmic leaflet of the myelin bilayer triggers its polymerization into a fibrous network that drives membrane zippering and protein extrusion. In contrast, the adhesion of the extracellular surfaces of myelin requires the down-regulation of repulsive components of the glycocalyx, in order to uncover weak and unspecific attractive forces that bring the extracellular surfaces into close contact. Unveiling the mechanisms of myelin membrane assembly at the cytoplasmic and extracelluar sites may help to understand how the myelin bilayers are disrupted and destabilized in the different demyelinating diseases. PMID- 24165926 TI - Prescription opioid analgesics increase the risk of depression. AB - BACKGROUND: Prescription opioid analgesic use has quintupled recently. Evidence linking opioid use with depression emanates from animal models and studies of persons with co-occurring substance use and major depression. Little is known about depressogenic effects of opioid use in other populations. OBJECTIVE: The purpose of this study was to determine whether prescription opioids are associated with increased risk of diagnosed depression. DESIGN: Retrospective cohort study, new user design. PATIENTS: Medical record data from 49,770 US Department of Veterans Affairs (VA) health care system patients with no recent (24-month) history of opioid use or a diagnosis of depression in 1999 and 2000. MAIN MEASURES: Propensity scores were used to control for bias by indication, and the data were weighted to balance the distribution of covariates by duration of incident opioid exposure. Cox proportional hazard models with adjustment for painful conditions were used to estimate the association between duration of prescription opioid use and the subsequent risk of development of depression between 2001 and 2007. KEY RESULTS: Of 49,770 patients who were prescribed an opioid analgesic, 91 % had a prescription for < 90 days, 4 % for 90-180 days, and 5 % for > 180 days. Compared to patients whose prescription was for < 90 days, the risk of depression increased significantly as the duration of opioid prescription increased (HR = 1.25; 95 % CI: 1.05-1.46 for 90-180 days, and HR = 1.51; 95 % CI:1.31-1.74 for > 180 days). CONCLUSIONS: In this sample of veterans with no recent (24-month) history of depression or opioid analgesic use, the risk of development of depression increased as the duration of opioid analgesic exposure increased. The potential for depressogenic effect should be considered in risk-benefit discussions, and patients initiating opioid treatment should be monitored for development of depression. PMID- 24165928 TI - In vitro and numerical support for combinatorial irreversible electroporation and electrochemotherapy glioma treatment. AB - Irreversible electroporation (IRE) achieves targeted volume non-thermal focal ablation using a series of brief electric pulses to kill cells by disrupting membrane integrity. Electrochemotherapy (ECT) uses lower numbers of sub-lethal electric pulses to disrupt membranes for improved drug uptake. Malignant glioma (MG) brain tumors are difficult to treat due to diffuse peripheral margins into healthy neural tissue. Here, in vitro experimental data and numerical simulations investigate the feasibility for IRE-relevant pulse protocols with adjuvant ECT drugs to enhance MG treatment. Cytotoxicity curves were produced on two glioma cell lines in vitro at multiple pulse strengths and drug doses with Bleomycin or Carboplatin. Pulses alone increased cytotoxicity with higher pulse numbers and strengths, reaching >90% by 800 V/cm with 90 pulses. Chemotherapeutic addition increased cytotoxicity by >50% for 1 ng/mL concentrations of either drug relative to 80 pulses alone with J3T cells at electric fields >=400 V/cm. In addition to necrosis, transmission electron microscopy visualizes apoptotic morphological changes and Hoescht 33342 staining shows apoptotic cell fractions varying with electric field and drug dose relative to controls. Numerically simulated treatment volumes in a canine brain show IRE combined with ECT expands therapeutic volume by 2.1-3.2 times compared to IRE alone. PMID- 24165927 TI - Microfluidic chip-based liquid chromatography coupled to mass spectrometry for determination of small molecules in bioanalytical applications: an update. AB - Many microfluidic chip-based LC-MS systems have been utilized for high-throughput analysis in various fields of bioanalytical applications such as proteomic, glycomic, pharmaceutical, and clinical research. This review is an update of a previous review article (Electrophoresis 2012, 33, 635-643) to mainly cover the most recent advancements in chip-based LC-MS for determining small molecules in bioanalysis. First, the different types of microfluidic chip devices for chip based LC-MS analysis will be discussed. Following the discussion of the recent developments in the chip-based instrumentation, the applications of chip-based LC MS for determining small molecules, such as glycans, pharmaceutical drugs, drugs of abuse, drug metabolites, and biomarkers in various biological sample matrixes will also be included in this review. PMID- 24165929 TI - Evaluation of integrated psychological services in a university-based primary care clinic. AB - Primary care is increasingly moving toward integration of psychological services; however few studies have been conducted to test the efficacy of such an integrated approach. This paper presents a program evaluation of psychological services provided by doctoral trainees in clinical and counseling psychology within a primary care clinic at an urban academic medical center. It includes: (1) a description of the program, including types of patients served, their presenting problems, and treatments administered and; (2) evidence of the impact of behavioral health services on primary care patients' emotional adjustment and progress on behavioral goals. Intake and follow-up measures of depression, anxiety, smoking, insomnia, chronic pain, and weight loss were collected on 452 adult patients (mean age = 52; 59 % African-American; 35 % uninsured) who were provided brief interventions (mean visits = 2.2) over a 16-month period. Although conclusions are limited by the lack of a control or comparison group, preliminary findings indicate that the integrated behavioral health services provided were effective. Implications and future directions are discussed. PMID- 24165930 TI - Bisamino(diphosphonite) with dangling olefin functionalities: synthesis, metal chemistry and catalytic utility of Rh(I) and Pd(II) complexes in hydroformylation and Suzuki-Miyaura reactions. AB - Bisamino(diphosphonite), p-C6H4{N{P(OC6H4C3H5-o)2}2}2 (1), was prepared by reacting p-C6H4{N(PCl2)2}2 with four equivalents of o-allylphenol in 85% yield. Compound 1 on treatment with [M(CO)4(HNC5H10)2] (M = Mo or W) gave cis [{M(CO)4}2{p-C6H4{N(P(OC6H4C3H5-o)2)2}2}] (2, M = Mo; 3, M = W). The reaction of 1 with [Fe(eta(5)-C5H5)(CO)2]2 yielded the complex [{Fe(eta(5)-C5H5)(MU-CO)}2{p C6H4{N(P(OC6H4C3H5-o)2)2}2}] (4). Treatment of 1 with Fe(CO)5 furnished a mononuclear complex, [{Fe(CO)3}2{p-C6H4{N{P(OC6H4C3H5-o)2}2}2}] (5). The ruthenium(II) complex, [{(eta(6)-p-cymene)Ru(MU-Cl)3RuCl}2{p-C6H4{N(P(OC6H4C3H5 o)2)2}2}] (6), was obtained on treatment of ligand 1 with [(eta(6)-p cymene)Ru(Cl)2]2. The reaction between 1 and [Rh(COD)Cl]2 (COD = 1,5 cyclooctadiene) in dichloromethane resulted in the formation of a dinuclear complex [{RhCl}2{p-C6H4{N(P(OC6H4C3H5-o)2)2}2}] (7), in which the allyl double bond of one of the phenoxy groups coordinates to the metal center. When ligand 1 was reacted with two equivalents of [Pd(COD)Cl2], a dinuclear complex [{PdCl2}2{p C6H4{N(P(OC6H4C3H5-o)2)2}2}] (8) was obtained. With copper(I) halides, ligand 1 afforded tetranuclear complexes, [{(Cu(MU-X)(NCCH3))2}2{p-C6H4{N(P(OC6H4C3H5 o)2)2}2}] (9, X = Cl; 10, X = Br; 11, X = I). Reaction of 1 with four equivalents of [AuCl(SMe2)] produced a tetranuclear complex, [(AuCl)4{p-C6H4{N{P(OC6H4C3H5 o)2}2}2}] (12). Complex 8 shows excellent catalytic activity in the Suzuki Miyaura cross-coupling reaction under microwave conditions and complex 7 catalyzes hydroformylation of styrenes with good TONs. PMID- 24165932 TI - Daniel Colon-Ramos: observing and making connections. Interview by Caitlin Sedwick. PMID- 24165931 TI - Biodegradable polymeric micelle-encapsulated quercetin suppresses tumor growth and metastasis in both transgenic zebrafish and mouse models. AB - Quercetin (Que) loaded polymeric micelles were prepared to obtain an aqueous formulation of Que with enhanced anti-tumor and anti-metastasis activities. A simple solid dispersion method was used, and the obtained Que micelles had a small particle size (about 31 nm), high drug loading, and high encapsulation efficiency. Que micelles showed improved cellular uptake, an enhanced apoptosis induction effect, and stronger inhibitory effects on proliferation, migration, and invasion of 4T1 cells than free Que. The enhanced in vitro antiangiogenesis effects of Que micelles were proved by the results that Que micelles significantly suppressed proliferation, migration, invasion, and tube formation of human umbilical vein endothelial cells (HUVECs). Subsequently, transgenic zebrafish models were employed to investigate anti-tumor and anti-metastasis effects of Que micelles, in which stronger inhibitory effects of Que micelles were observed on embryonic angiogenesis, tumor-induced angiogenesis, tumor growth, and tumor metastasis. Furthermore, in a subcutaneous 4T1 tumor model, Que micelles were more effective in suppressing tumor growth and spontaneous pulmonary metastasis, and prolonging the survival of tumor-bearing mice. Besides, immunohistochemical and immunofluorescent assays suggested that tumors in the Que micelle-treated group showed more apoptosis, fewer microvessels, and fewer proliferation-positive cells. In conclusion, Que micelles, which are synthesized as an aqueous formulation of Que, possess enhanced anti-tumor and anti-metastasis activity, which can serve as potential candidates for cancer therapy. PMID- 24165933 TI - The vesicular ATPase: a missing link between acidification and exocytosis. AB - The vesicular adenosine triphosphatase (ATPase) acidifies intracellular compartments, including synaptic vesicles and secretory granules. A controversy about a second function of this ATPase in exocytosis has been fuelled by questions about multiple putative roles of acidification in the exocytic process. Now, Poea-Guyon et al. (2013. J. Cell Biol. http://dx.doi.org/10.1083/jcb.201303104) present new evidence that the vesicular ATPase performs separate acidification and exocytosis roles and propose a mechanism for how these two functions are causally linked. PMID- 24165935 TI - Inheritance of yeast nuclear pore complexes requires the Nsp1p subcomplex. AB - In the yeast Saccharomyces cerevisiae, organelles and macromolecular complexes are delivered from the mother to the emerging daughter during cell division, thereby ensuring progeny viability. Here, we have shown that during mitosis nuclear pore complexes (NPCs) in the mother nucleus are actively delivered through the bud neck and into the daughter cell concomitantly with the nuclear envelope. Furthermore, we show that NPC movement into the daughter cell requires members of an NPC subcomplex containing Nsp1p and its interacting partners. NPCs lacking these nucleoporins (Nups) were blocked from entry into the daughter by a putative barrier at the bud neck. This selection process could be observed within individual cells such that NPCs containing Nup82p (an Nsp1p-interacting Nup) were transferred to the daughter cells while functionally compromised NPCs lacking Nup82p were retained in the mother. This mechanism is proposed to facilitate the inheritance of functional NPCs by daughter cells. PMID- 24165934 TI - Cell biology in neuroscience: the interplay between Hebbian and homeostatic synaptic plasticity. AB - Synaptic plasticity, a change in the efficacy of synaptic signaling, is a key property of synaptic communication that is vital to many brain functions. Hebbian forms of long-lasting synaptic plasticity-long-term potentiation (LTP) and long term depression (LTD)-have been well studied and are considered to be the cellular basis for particular types of memory. Recently, homeostatic synaptic plasticity, a compensatory form of synaptic strength change, has attracted attention as a cellular mechanism that counteracts changes brought about by LTP and LTD to help stabilize neuronal network activity. New findings on the cellular mechanisms and molecular players of the two forms of plasticity are uncovering the interplay between them in individual neurons. PMID- 24165936 TI - The transmission of nuclear pore complexes to daughter cells requires a cytoplasmic pool of Nsp1. AB - Nuclear pore complexes (NPCs) are essential protein assemblies that span the nuclear envelope and establish nuclear-cytoplasmic compartmentalization. We have investigated mechanisms that control NPC number in mother and daughter cells during the asymmetric division of budding yeast. By simultaneously tracking existing NPCs and newly synthesized NPC protomers (nups) through anaphase, we uncovered a pool of the central channel nup Nsp1 that is actively targeted to the bud in association with endoplasmic reticulum. Bud targeting required an intact actin cytoskeleton and the class V myosin, Myo2. Selective inhibition of cytoplasmic Nsp1 or inactivation of Myo2 reduced the inheritance of NPCs in daughter cells, leading to a daughter-specific loss of viability. Our data are consistent with a model in which Nsp1 releases a barrier that otherwise prevents NPC passage through the bud neck. It further supports the finding that NPC inheritance, not de novo NPC assembly, is primarily responsible for controlling NPC number in daughter cells. PMID- 24165937 TI - Par1b links lumen polarity with LGN-NuMA positioning for distinct epithelial cell division phenotypes. AB - Columnar epithelia establish their luminal domains and their mitotic spindles parallel to the basal surface and undergo symmetric cell divisions in which the cleavage furrow bisects the apical domain. Hepatocyte lumina interrupt the lateral domain of neighboring cells perpendicular to two basal domains and their cleavage furrow rarely bifurcates the luminal domains. We determine that the serine/threonine kinase Par1b defines lumen position in concert with the position of the astral microtubule anchoring complex LGN-NuMA to yield the distinct epithelial division phenotypes. Par1b signaling via the extracellular matrix (ECM) in polarizing cells determined RhoA/Rho-kinase activity at cell-cell contact sites. Columnar MDCK and Par1b-depleted hepatocytic HepG2 cells featured high RhoA activity that correlated with robust LGN-NuMA recruitment to the metaphase cortex, spindle alignment with the substratum, and columnar organization. Reduced RhoA activity at the metaphase cortex in HepG2 cells and Par1b-overexpressing MDCK cells correlated with a single or no LGN-NuMA crescent, tilted spindles, and the development of lateral lumen polarity. PMID- 24165938 TI - Extracellular cell wall beta(1,3)glucan is required to couple septation to actomyosin ring contraction. AB - Cytokinesis has been extensively studied in different models, but the role of the extracellular cell wall is less understood. Here we studied this process in fission yeast. The essential protein Bgs4 synthesizes the main cell wall beta(1,3)glucan. We show that Bgs4-derived beta(1,3)glucan is required for correct and stable actomyosin ring positioning in the cell middle, before the start of septum formation and anchorage to the cell wall. Consequently, beta(1,3)glucan loss generated ring sliding, oblique positioned rings and septa, misdirected septum synthesis indicative of relaxed rings, and uncoupling between a fast ring and membrane ingression and slow septum synthesis, suggesting that cytokinesis can progress with defective septum pushing and/or ring pulling forces. Moreover, Bgs4-derived beta(1,3)glucan is essential for secondary septum formation and correct primary septum completion. Therefore, our results show that extracellular beta(1,3)glucan is required for cytokinesis to connect the cell wall with the plasma membrane and for contractile ring function, as proposed for the equivalent extracellular matrix in animal cells. PMID- 24165941 TI - LKB1 and AMPK maintain epithelial cell polarity under energetic stress. PMID- 24165939 TI - The V-ATPase membrane domain is a sensor of granular pH that controls the exocytotic machinery. AB - Several studies have suggested that the V0 domain of the vacuolar-type H(+) adenosine triphosphatase (V-ATPase) is directly implicated in secretory vesicle exocytosis through a role in membrane fusion. We report in this paper that there was a rapid decrease in neurotransmitter release after acute photoinactivation of the V0 a1-I subunit in neuronal pairs. Likewise, inactivation of the V0 a1-I subunit in chromaffin cells resulted in a decreased frequency and prolonged kinetics of amperometric spikes induced by depolarization, with shortening of the fusion pore open time. Dissipation of the granular pH gradient was associated with an inhibition of exocytosis and correlated with the V1-V0 association status in secretory granules. We thus conclude that V0 serves as a sensor of intragranular pH that controls exocytosis and synaptic transmission via the reversible dissociation of V1 at acidic pH. Hence, the V-ATPase membrane domain would allow the exocytotic machinery to discriminate fully loaded and acidified vesicles from vesicles undergoing neurotransmitter reloading. PMID- 24165940 TI - Atg38 is required for autophagy-specific phosphatidylinositol 3-kinase complex integrity. AB - Autophagy is a conserved eukaryotic process of protein and organelle self degradation within the vacuole/lysosome. Autophagy is characterized by the formation of an autophagosome, for which Vps34-dervied phosphatidylinositol 3 phosphate (PI3P) is essential. In yeast, Vps34 forms two distinct protein complexes: complex I, which functions in autophagy, and complex II, which is involved in protein sorting to the vacuole. Here we identify and characterize Atg38 as a stably associated subunit of complex I. In atg38Delta cells, autophagic activity was significantly reduced and PI3-kinase complex I dissociated into the Vps15-Vps34 and Atg14-Vps30 subcomplexes. We find that Atg38 physically interacted with Atg14 and Vps34 via its N terminus. Further biochemical analyses revealed that Atg38 homodimerizes through its C terminus and that this homodimer formation is indispensable for the integrity of complex I. These data suggest that the homodimer of Atg38 functions as a physical linkage between the Vps15-Vps34 and Atg14-Vps30 subcomplexes to facilitate complex I formation. PMID- 24165942 TI - Stress assignment in reading Italian: friendship outweighs dominance. AB - Stress assignment to polysyllabic words is the only aspect of the pronunciation of written Italian that cannot be predicted by rule. It could be a function of stress dominance in the language or of stress neighborhood (i.e., the number of words sharing an ending and a stress pattern). In two experiments, we investigated stress assignment in Italian adult and, most importantly, young readers. Word frequency and number of stress friends influenced reading times and accuracy, outweighing any effect of stress dominance. In the presence of a majority of stress friends, the reading of low-frequency words was only affected by stress neighborhood. These effects were the same in fourth graders and adult readers. We argue that distributional information based on the number of stress friends-rather than stress dominance-is the most effective factor in assigning stress to words in reading. PMID- 24165943 TI - Body mass index as a predictive factor of periodontal therapy outcomes. AB - Body mass index (BMI) and obesity are associated with the prevalence, extent, and severity of periodontitis. This study investigated the predictive role of overweight/obesity on clinical response following non-surgical periodontal therapy in patients with severe periodontitis. Two hundred sixty adults received an intensive course of non-surgical periodontal therapy. Periodontal status at baseline and 2 months was based upon probing pocket depths (PPD), clinical attachment levels (CAL), and whole-mouth gingival bleeding (FMBS) as assessed by two calibrated examiners. Generalized estimating equations (GEE) were used to estimate the impact of BMI and overweight/obesity on periodontal treatment response while controlling for baseline status, age, smoking status (smoker or non-smoker), and full-mouth dental plaque score. BMI (continuous variable) and obesity (vs. normal weight) were associated with worse mean PPD (p < .005), percentage of PPD > 4 mm (p = .01), but not with FMBS (p > .05) or CAL (p > .05) at 2 months, independent of age, smoking status, or dental plaque levels. The magnitude of this association was similar to that of smoking, which was also linked to a worse clinical periodontal outcome (p < .01). BMI and obesity appear to be independent predictors of poor response following non-surgical periodontal therapy. PMID- 24165944 TI - Janos Veres: the man behind the needle. PMID- 24165945 TI - Ampullary adenomas and option for follow-up. PMID- 24165946 TI - Hiatal surface area as a basis for a new classification of hiatal hernia. PMID- 24165947 TI - Efficient clinical trials in Japan: Bridging studies versus participation in global clinical trials. AB - The required number of Japanese subjects was compared between the Bridging (BG) filing strategy described in ICH-E5 for drugs approved from 1998 to 2012, in which foreign phase 3 results were used together with a BG study conducted to confirm optimum Japanese dose, and global clinical trial (GCT) strategies in which the number was simulated from the foreign phase 3 studies. The simulated number from the GCT strategy was smaller than that of the BG, suggesting that the GCT strategy could be expected to reduce Japanese clinical trial costs. However, two exceptions were found, namely for preventive drugs and drugs for children, because of the large scales of foreign phase 3 studies. PMID- 24165949 TI - Drug therapy: smuggling trastuzumab into the brain. PMID- 24165950 TI - Targeted therapies: programmed death: improving DLBCL. PMID- 24165951 TI - Gynaecological cancer: vintafolide--targeting the folate receptor with a cytotoxic offers hope. PMID- 24165948 TI - Treatment-related cardiotoxicity in survivors of childhood cancer. AB - Treatment advances and higher participation rates in clinical trials have rapidly increased the number of survivors of childhood cancer. However, chemotherapy and radiation treatments are cardiotoxic and can cause cardiomyopathy, conduction defects, myocardial infarction, hypertension, stroke, pulmonary oedema, dyspnoea and exercise intolerance later in life. These cardiotoxic effects are often progressive and irreversible, emphasizing a need for effective prevention and treatment to reduce or avoid cardiotoxicity. Medical interventions, such as angiotensin-converting enzyme inhibitors, beta-blockers, and growth hormone therapy, might be used to treat cardiotoxicity in childhood cancer survivors. Preventative strategies should include the use of dexrazoxane, which provides cardioprotection without reducing the oncological efficacy of doxorubicin chemotherapy; less-toxic anthracycline derivatives and the use of antioxidant nutritional supplements might also be beneficial. Continuous-infusion doxorubicin provides no benefit over bolus infusion in children. Identifying patient-related (for example, obesity and hypertension) and drug-related (for example, cumulative dose) risk factors for cardiotoxicity could help tailor treatments to individual patients. However, all survivors of childhood cancer are at increased risk of cardiotoxicity, suggesting that survivor screening recommendations for assessment of global risk of premature cardiovascular disease should apply to all survivors. Optimal, evidence-based monitoring strategies and multiagent preventative treatments still need to be identified. PMID- 24165953 TI - Flagella as a novel alignment medium for the measurement of residual dipolar couplings in proteins. AB - The two flexible rod-like flagella (~500 nm in diameter and 5-15 MUm long) of Chlamydomonas reinhardtii, a unicellular green alga, can weakly align molecules in an external magnetic field, thereby enabling the measurement of various residual dipolar couplings in solution NMR spectroscopy. PMID- 24165954 TI - Immune activation by histones: plusses and minuses in inflammation. AB - Histones are highly cationic proteins that are essential components of the cell nucleus, interacting with DNA to form the nucleosome and regulating transcription. Histones, however, can transit from the cell nucleus during cell death and, once in an extracellular location, can serve as danger signals and activate immune cells. An article in this issue of the European Journal of Immunology [Eur. J. Immunol. 2013. 43: 3336-3342] reports that histones can activate monocyte-derived DCs via the NRLP3 inflammasome to induce the production of IL-1beta. As such, histones, which can also stimulate TLRs, may drive events in the immunopathogenesis of a wide range of acute and chronic diseases marked by sterile inflammation. While the mechanism of this stimulation is not known, the positive charge of histones may provide a structural element to promote interaction with cells and activation of downstream signaling systems. PMID- 24165955 TI - Lateral pelvic lymph node dissection can be omitted in lower rectal cancer in which the longest lateral pelvic and perirectal lymph node is less than 5 mm on MRI. AB - BACKGROUND AND OBJECTIVES: The goal of the study was to examine the use of magnetic resonance imaging (MRI) for identification of patients with lower rectal cancer who may benefit from lateral pelvic lymph node dissection (LPLD). METHODS: Diagnoses and oncological outcomes were examined in 160 cases. Patients in whom the long-axis diameter of the longest detected lymph node was < 5 mm or >= 5 mm were classified as LPLN(-) (n = 102) and LPLN(+) (n = 58), respectively. RESULTS: Diagnostic results gave a 21.6% positive predictive value (PPV) and a 95.0% negative predictive value (NPV) for the LPLN. These values were 59.6% and 91.5%, respectively, for the perirectal lymph node (PRLN). Multivariate analysis showed that a pathologic PRLN (pPRLN)(+) status was an independent prognostic factor for relapse-free survival (RFS) (P = 0.0424) in the LPLN(-) group. The 5-year RFS did not differ significantly between cases that did not and did undergo LPLD (90.0% vs. 83.8%) in the LPLN(-) and pPRLN(-) groups. CONCLUSIONS: The low PPV and high NPV indicate that it is difficult to identify patients who may benefit from LPLD. However, the results show that LPLD has no benefit in LPLN(-) and PRLN(-) cases and that these cases can be identified based on MRI findings. PMID- 24165958 TI - Effects of curcumin supplementation on exercise-induced oxidative stress in humans. AB - The purpose of this study was to investigate the effects of curcumin supplementation on exercise-induced oxidative stress in humans. 10 male participants, ages 26.8+/-2.0 years (mean+/-SE), completed 3 trials in a random order: (1) placebo (control), (2) single (only before exercise) and (3) double (before and immediately after exercise) curcumin supplementation trials. Each participant received oral administration of 90 mg of curcumin or the placebo 2h before exercise and immediately after exercise. Each participant walked or ran at 65% of V2max on a treadmill for 60min. Blood samples were collected pre-exercise, immediately after exercise and 2h after exercise. The concentrations of serum derivatives of reactive oxygen metabolites measured immediately after exercise were significantly higher than pre-exercise values in the placebo trial (308.8+/ 12.9 U. CARR, P<0.05), but not in the single (259.9+/-17.1 U. CARR) or double (273.6+/-19.7 U. CARR) curcumin supplementation trials. Serum biological antioxidant potential concentrations measured immediately after exercise were significantly elevated in the single and double curcumin supplementation trials compared with pre-exercise values (P<0.05). These findings indicate that curcumin supplementation can attenuate exercise-induced oxidative stress by increasing blood antioxidant capacity. PMID- 24165959 TI - Systematic bias between running speed and metabolic power data in elite soccer players: influence of drill type. AB - The aims of the present study were to: i) evaluate the agreement between estimates of high-intensity activity during soccer small-sided games (SSGs) based on running speed alone and estimated metabolic power derived from a combination of running speed and acceleration; ii) evaluate whether any bias between the 2 approaches is dependent upon playing position or drill characteristics. 3 types of SSGs (5vs5, 7vs7 and 10vs10) were completed by 26 English Premier League outfield players. A total of 420 individual drill observations were collected over the in-season period using portable global positioning system technology. High-intensity activity was estimated using the total distance covered at speeds>14.4 km . h(-1) (TS) and the equivalent metabolic power threshold of > 20 W . kg(-1) (TP). We selected 0.2 as the minimally important standardised difference between methods. High-intensity demands were systematically higher (~100%, p<0.001) when expressed as TP vs. TS irrespective of playing position and SSG. The magnitude of this difference increased as the size of SSG decreased (p<0.01) with a difference of ~200% observed in the 5vs5 SSG. A greater difference between TP and TS was also evident in central defenders compared to other positions (p<0.05) particularly during the 5vs5 SSG (~350%). We conclude that the high-intensity demands of SSGs in elite soccer players are systematically underestimated by running speed alone particularly during "small" SSGs and especially for central defenders. Estimations of metabolic power provide a more valid estimation as to the true demands of SSGs. PMID- 24165960 TI - A learning protocol improves the validity of the Borg 6-20 RPE scale during indoor cycling. AB - The present study assessed the effectiveness of an RPE learning protocol for improving the validity of the Borg 6-20 RPE scale for self-regulating exercise intensity during Indoor Cycling (IC). 16 healthy adults performed 5 IC sessions. Heart rate (HR) was continuously monitored. In sessions 1 and 5, participants perceptually regulated exercise intensity to produce pre-determined RPE levels equivalent to estimated HR levels. Sessions 2, 3 and 4 focused on the RPE learning protocol. The RPE-measured HR correlation was 0.59 in session 1 and 0.67 in session 5 (both P<0.001). The intraclass correlation coefficient between measured HR and estimated HR was 0.85 in session 1 and 0.90 in session 5. There was bias in session 1 (3.69 bpm [SD=12.44]; P<0.001) but not in session 5 (0.99 bpm [SD=9.7]; P=0.178; mean HR difference session 5 vs. 1: -2.70 bpm [95% CI: 4.49 to -0.91]; P=0.003; Cohen's d=0.24). There was association between the HR difference and the magnitude of the measurement in session 1 (beta=0.208; P<0.01) but not in session 5 (beta=-0.072; P=0.34). These preliminary results suggested that an RPE learning protocol might slightly improve the validity of the Borg 6 20 RPE scale for exercise intensity self-regulation during IC sessions in healthy adults. PMID- 24165961 TI - Screening and evaluating aminated cationic functional moieties for potential CO(2) capture applications using an anionic MOF scaffold. AB - Three cations with different amine density, guanidinium, aminoguanidinium, and diaminoguanidinium, were loaded into anionic via cation-exchange. The structures and compositions of the cation-exchange products were characterized, and their N2 and CO2 adsorption properties were studied and compared. PMID- 24165962 TI - The institute of medicine report sodium intake in populations: assessment of evidence: summary of primary findings and implications for clinicians. PMID- 24165963 TI - [Not Available]. PMID- 24165964 TI - Betting patterns for sports and races: a longitudinal analysis of online wagering in Australia. AB - Online wagering is increasing in popularity as it is easily accessible through websites which market these services widely. However, few studies have examined online betting based on actual behavioural data. This paper describes the results of an analysis of 2,522,299 bets placed with an Australian online wagering operator over a 1-year period. The majority of bets placed were for a win (45.31 %) and were placed on races (86.74 %) or sports (11.29 %). Sports betting was dominated by ball sports, reflecting popular interest in these events. More than three-quarters (77.63 %) of the bets were losses and there was large variation in bet size between bet types and events bet on although average bets were higher than in previously reported studies. The most popular bets placed to win, had a relatively high rate of losses and lowest average returns, which may reflect less sophisticated betting behaviour. More specific handicap and total bets were placed by fewer customers, but were larger bets with the greatest returns. Similarly, bets placed on less popular sporting events had greater average returns potentially reflecting greater customer sophistication and knowledge raising the possibility of a proportion of bettors being more 'skilled'. As the first paper to analyze the types of bets placed on events and outcomes the results support the notion that wagering is an entertainment activity, and the majority of customers are motivated by factors other than simply winning money. PMID- 24165966 TI - Diarrhea in a post-renal transplant child: questions. PMID- 24165965 TI - Tumor gangliosides accelerate murine tumor angiogenesis. AB - Tumor cells shed gangliosides and populate their microenvironment with these biologically active membrane glycosphingolipids. In vitro, ganglioside enrichment amplifies receptor tyrosine kinase signaling and activation of vascular endothelial cells. However, a long-standing question is whether in the actual microenvironment of a neoplasm, in vivo, tumor cell ganglioside shedding stimulates angiogenesis. Here we tested the hypothesis that tumor gangliosides have a critical proangiogenic role in vivo using novel murine tumor cells, GM3synthase/GM2synthase double knockout (DKO) cells, genetically completely incapable of ganglioside synthesis and impaired in tumor growth versus wild-type (WT) ganglioside-rich cells. We studied angiogenesis during tumor formation by these ganglioside-depleted cells, quantifying vessel formation, angiogenic factor production/release, and consequences of reconstitution with purified WT gangliosides. DKO cells formed virtually avascular tumors, much smaller than ganglioside-rich WT tumors and displaying a striking paucity of blood vessels, despite levels of VEGF and other angiogenic factors that were similar to those of WT cells. Transient enrichment of the ganglioside milieu of the DKO cell inoculum by adding purified WT gangliosides partially restored angiogenesis and tumor growth. We conclude that tumor gangliosides trigger robust angiogenesis important for tumor growth. Our findings suggest strategies to eliminate their synthesis and shedding by tumor cells should be pursued. PMID- 24165968 TI - Asymmetric organocatalytic Strecker-type reactions of aliphatic N,N dialkylhydrazones. AB - The enantioselective organocatalytic Strecker-type reaction of aliphatic N,N dialkylhydrazones is presented. Using trimethylsilyl cyanide (TMSCN) as the cyanide source, the reaction can be efficiently catalyzed by a tert-leucine derived bifunctional thiourea to afford the corresponding hydrazino nitriles in good to excellent yields (50-96%) and moderate to good enantioselectivities, up to 86% ee. Further transformations of the nitrile functionality allow access to useful protected hydrazino acids and imidazolidinones. Interestingly, some of the hydrazino nitriles and their derivatives could be recrystallized in high recovery, yielding essentially pure enantiomers. PMID- 24165967 TI - Staphylococcus aureus urinary tract infections in children are associated with urinary tract abnormalities and vesico-ureteral reflux. AB - BACKGROUND: Staphylococcus aureus is an uncommon cause of pediatric urinary tract infection (UTI). Data regarding urinary tract malformations in children with S. aureus UTI is limited. METHODS: The medical records of all children aged 0 to 16 years at Shaare Zedek Medical Center between 2001 and 2013 and who were diagnosed with S. aureus UTI were reviewed for demographic, clinical, and laboratory data. Patients with Escherichia coli UTIs during the same period were included as controls. RESULTS: S. aureus was the cause of UTI in 26 children, of whom six were bacteremic. Compared to children with E. coli UTI, children with S. aureus had higher rates of abnormal findings in ultrasound (77 vs. 22%; p < 0.001). Similarly, more patients with S. aureus UTI had abnormal voiding cystourethrogram (53 vs. 23%; p < 0.001) or vesicoureteral reflux (50 vs. 23%; p < 0.001). The median duration of hospitalization for patients with S. aureus UTI was significantly longer than for patients with E. coli UTI (8 vs. 2.3 days; p = 0.0003). CONCLUSIONS: S. aureus is an uncommon urinary pathogen among children. The finding of S. aureus UTI requires thorough search for urinary abnormalities. PMID- 24165969 TI - Langerhans cell maturation is accompanied by induction of N-cadherin and the transcriptional regulators of epithelial-mesenchymal transition ZEB1/2. AB - Langerhans cells (LCs) are a unique subset of dendritic cells (DCs) that express epithelial adhesion molecules, allowing them to form contacts with epithelial cells and reside in epidermal/epithelial tissues. The dynamic regulation of epithelial adhesion plays a decisive role in the life cycle of LCs. It controls whether LCs remain immature and sessile within the epidermis or mature and egress to initiate immune responses. So far, the molecular machinery regulating epithelial adhesion molecules during LC maturation remains elusive. Here, we generated pure populations of immature human LCs in vitro to systematically probe for gene-expression changes during LC maturation. LCs down-regulate a set of epithelial genes including E-cadherin, while they upregulate the mesenchymal marker N-cadherin known to facilitate cell migration. In addition, N-cadherin is constitutively expressed by monocyte-derived DCs known to exhibit characteristics of both inflammatory-type and interstitial/dermal DCs. Moreover, the transcription factors ZEB1 and ZEB2 (ZEB is zinc-finger E-box-binding homeobox) are upregulated in migratory LCs. ZEB1 and ZEB2 have been shown to induce epithelial-to-mesenchymal transition (EMT) and invasive behavior in cancer cells undergoing metastasis. Our results provide the first hint that the molecular EMT machinery might facilitate LC mobilization. Moreover, our study suggests that N cadherin plays a role during DC migration. PMID- 24165970 TI - Mapping plasmonic near-field profiles and interferences by surface-enhanced Raman scattering. AB - Mapping near-field profiles and dynamics of surface plasmon polaritons is crucial for understanding their fundamental optical properties and designing miniaturized photonic devices. This requires a spatial resolution on the sub-wavelength scale because the effective polariton wavelength is shorter than free-space excitation wavelengths. Here by combining total internal reflection excitation with surface enhanced Raman scattering imaging, we mapped at the sub-wavelength scale the spatial distribution of the dominant perpendicular component of surface plasmon fields in a metal nanoparticle-film system through spectrally selective and polarization-resolved excitation of the vertical gap mode. The lateral field extension at the junction, which is determined by the gap-mode volume, is small enough to distinguish a spot size ~0.355lambda0 generated by a focused radially polarized beam with high reproducibility. The same excitation and imaging schemes are also used to trace near-field nano-focusing and interferences of surface plasmon polaritons created by a variety of plasmon lenses. PMID- 24165972 TI - Palliative surgery in patients with unresectable colorectal liver metastases: a propensity score matching analysis. AB - BACKGROUND AND OBJECTIVES: The current study was primarily intended to determine the best surgical treatment for patients with unresectable liver metastatic colorectal cancer (CRC). In addition, we assessed whether the improvement in survival resulting from palliative resection (PR) of the primary tumor was a function of the extent of liver metastasis. METHODS: The demographics, tumor characteristics, and survival outcomes of 261 patients who underwent palliative surgery for unresectable liver metastatic CRC were analyzed. A propensity-score model was used to compare the group of patients receiving PR and non-resection (NR). RESULTS: There were 195 PR patients and 66 NR. The median survival of PR and NR patients was 21 months and 10 months, respectively (P < 0.001). In a Cox multivariate analysis of 51 propensity-score matched pairs, PR resulted in longer survival than NR (Hazard Ratio for NR 1.481; 95% confidence interval: 1.003 2.185; P = 0.048). The extent of liver metastasis only led to better survival of PR than NR patients among patients with limited liver metastasis not among those with extensive liver metastasis (P = 0.001). CONCLUSIONS: PR appears to result in better survival than NR when the patient's overall condition permits an aggressive approach, especially in patients with limited liver metastases. PMID- 24165973 TI - Speciation analysis of mercury in water samples by dispersive liquid-liquid microextraction coupled to capillary electrophoresis. AB - In this study, a method of pretreatment and speciation analysis of mercury by dispersive liquid-liquid microextraction along with CE was developed. The method was based on the fact that mercury species including methylmercury (MeHg), ethylmercury (EtHg), phenylmercury (PhHg), and Hg(II) were complexed with 1-(2 pyridylazo)-2-naphthol to form hydrophobic chelates and l-cysteine could displace 1-(2-pyridylazo)-2-naphthol to form hydrophilic chelates with the four mercury species. Factors affecting complex formation and extraction efficiency, such as pH value, type, and volume of extractive solvent and disperser solvent, concentration of the chelating agent, ultrasonic time, and buffer solution were investigated. Under the optimal conditions, the enrichment factors were 102, 118, 547, and 46, and the LODs were 1.79, 1.62, 0.23, and 1.50 MUg/L for MeHg, EtHg, PhHg, and Hg(II), respectively. Method precisions (RSD, n = 5) were in the range of 0.29-0.54% for migration time, and 3.08-7.80% for peak area. Satisfactory recoveries ranging from 82.38 to 98.76% were obtained with seawater, lake, and tap water samples spiked at three concentration levels, respectively, with RSD (n = 5) of 1.98-7.18%. This method was demonstrated to be simple, convenient, rapid, cost-effective, and environmentally benign, and could be used as an ideal alternative to existing methods for analyzing trace residues of mercury species in water samples. PMID- 24165974 TI - Nucleophilic substitution reactions of 10- and 11-membered fluorodioxy ansa cyclotriphosphazene derivatives. AB - The reactions of cyclophosphazenes with 10-membered ansa-{N3P3Cl4[OCH2(CF2)3CH2O] (1a)} and 11-membered ansa-{N3P3Cl4[OCH2(CF2)4CH2O] (1b)} rings with the sodium salts of methanol in a THF solution at different molar ratios were used to investigate the reaction pathways and mechanism of nucleophilic substitution at the PCl2 and PCl(OR) phosphorus atoms. The reactions afforded eleven products, whose structures have been characterized by elemental analysis, mass spectrometry, (1)H, (19)F and (31)P NMR spectroscopy and X-ray crystallography; mono-methoxy derivatives (2a, 3a, 3b), di-methoxy derivatives (5a-7a, 5b), tri methoxy derivatives (8a, 8b) and the tetra-methoxy derivatives (9a, 9b). The X ray crystallographic studies of four compounds (6a-8a and 8b) demonstrated unambiguously that nucleophilic substitution reactions at the ansa-ring PCl(OR) phosphorus atoms of the cyclotriphosphazene compounds N3P3Cl4[OCH2(CF2)nCH2O] n = 3 (1a) and 4 (1b) occurred with a retention of configuration for both the 10- and 11-membered fluorodioxy ansa rings, respectively. The results confirmed that the reactions with 1a containing the 10-membered ansa-ring occurred competitively at both the PCl2 and P(OR)Cl moieties with an approximate 8 : 1 preference at the PCl2 group, whereas reactions with 1b containing the 11-membered ansa-ring occurred exclusively at the PCl2 group before the P(OR)Cl moiety. The results were mainly rationalized in terms of the P-Cl bond lengths of the reactants and the cation-assisted mechanism of reaction. PMID- 24165975 TI - LPS-induced effects on angiotensin I-converting enzyme expression and shedding in human pulmonary microvascular endothelial cells. AB - Angiotensin I-converting enzyme (kininase II, ACE, and CD143) availability is a determinant of local angiotensin and kinin concentrations and their physiological actions. Until now, it is unclear whether the decrease of pulmonary ACE activity in sepsis-described in clinical studies-is due to an enzyme compensatory downregulation (reduced ACE-mRNA expression) to shedding of ACE or endothelial damage. To address these questions, ACE distribution under septic conditions was studied in vitro by treating pulmonary microvascular endothelial cells (HPMEC) and human umbilical vein endothelial cells (HUVEC) with lipopolysaccharide from Escherichia coli (LPS). Primary isolated HUVEC and HPMEC were compared by detecting ACE activity, membrane-bound ACE, as well as shedding and mRNA production of ACE with and without LPS (1 ng/ml-1 MUg/ml). ACE mRNA expression was detected by real-time PCR, and shedded ACE was measured in cell culture supernatant by ELISA. Additionally, membrane-bound protein expression was investigated by immunohistochemistry in situ. In septic ARDS, the distribution of ACE protein was significantly reduced in all lung endothelial cells (p<0.001). After stimulation with LPS, cultivated HPMEC showed more markedly than HUVEC, a concentration-dependent reduction of ACE protein expression compared to the respective untreated controls. Real-time PCR demonstrated a reduced ACE mRNA expression after LPS stimulation, predominantly in HPMEC. Specifically, in HPMEC, a concentration-dependent increase of shedded ACE was shown 24 h after LPS treatment. HPMEC cultures are an apt model for the investigation of pulmonary ACE expression in sepsis. This study suggests that reduced pulmonary microvascular endothelial ACE expression in septic ARDS is caused by two processes: (initial) increased shedding of ACE accompanied by a compensatory downregulation of ACE mRNA and membrane-bound protein expression. PMID- 24165976 TI - A randomized, placebo-controlled study of the pharmacokinetics, pharmacodynamics, and tolerability of the oral JAK2 inhibitor fedratinib (SAR302503) in healthy volunteers. AB - Fedratinib (SAR302503/TG101348) is a Janus kinase 2 (JAK2)-selective inhibitor in clinical development for the treatment of myelofibrosis. In this randomized, placebo-controlled, Phase 1 study, the pharmacokinetics, pharmacodynamics and tolerability of ascending single doses of fedratinib (10-680 mg) were assessed in healthy male subjects. Fedratinib was rapidly absorbed, with peak plasma concentration observed approximately 3 hours after dosing. The mean terminal half life of fedratinib was approximately 67 hours, which was unaffected by dose. Fedratinib exposure increased in a greater than dose-proportional manner. Suppression of signal transducer and activator of transcription 3 (STAT3) phosphorylation, indicative of JAK2 inhibition, was observed at 3 hours post-dose for subjects in the 300, 500, and 680 mg groups, with the level of suppression increasing with dose. The relationship between fedratinib exposure and suppression of STAT3 phosphorylation was described using an inhibitory effect sigmoid Emax model, with an EC50 of 1,210 ng/mL in healthy subjects. The most common adverse events were mild gastrointestinal toxicities. PMID- 24165977 TI - Can expedited FDA drug approval without expedited follow-up be trusted? PMID- 24165978 TI - Pattern recognition receptor-initiated innate antiviral response in mouse adipose cells. AB - Although wide range of viruses can infect adipose tissues, innate antiviral response of adipose cells has not been investigated. This study focused on innate antiviral system in mouse adipose cells. Major virus sensors including Toll-like receptor 3 (TLR3), melanoma differentiation-associated antigen 5 (MDA5) and retinoic acid-inducible gene I (RIG-I) are constitutively expressed in preadipocytes and adipocytes. Poly(I:C), a common agonist of TLR3, MDA5 and RIG I, induced the expression of type I interferons (IFN-alpha/beta) in the two types of adipose cells through the activation of IFN-regulatory factor 3 and upregulated pro-inflammatory factors such as TNF-alpha and IL-6 through the activation nuclear factor kappa B. Moreover, poly(I:C) induced multiple antiviral proteins including IFN-stimulating gene 15, 2'5'-oligoadenylate synthetase and Mx GTPase 1 in preadipocytes and adipocytes. The poly(I:C)-induced innate antiviral response was reduced by TLR3 deficiency and knockdown of MDA5 or RIG-I. Poly(I:C) also inhibited the differentiation of preadipocytes to adipocytes and suppressed the expression of leptin, adiponectin and resistin in mature adipocytes. The results demonstrated that adipose cells are equipped with innate antiviral system, which may modulate the function of adipocytes. PMID- 24165980 TI - IRF4 links antigen affinity to CD8+ T-cell metabolism. PMID- 24165979 TI - The adaptor protein Crk in immune response. AB - The adaptor proteins Crk (CT10 (chicken tumor virus number 10) regulator of kinase), including CrkI, CrkII and Crk-like, are important signal molecules that regulate a variety of cellular processes. Considerable progress has been made in understanding the roles of the Crk family proteins in signal transduction, with a focus on cellular transformation and differentiation. However, since Crk was identified in 1988, very few studies have addressed how Crk regulates the immune response. Recent work demonstrates that Crk proteins function as critical signal molecules in regulating immune cell functions. Emerging data on the roles of Crk in activation and inhibitory immunoreceptor signaling suggest that Crk proteins are potential immunotherapeutic targets in cancer and infectious diseases. The aim of this review is to summarize recent key findings regarding the role of Crk in immune responses mediated by T, B and natural killer (NK) cells. In particular, the roles of Crk in NK cell functions are discussed. PMID- 24165981 TI - Regulation of plasmacytoid dendritic cell development in mice by aryl hydrocarbon receptor. AB - Aryl hydrocarbon receptor (AhR) has an important role in the regulation of cell responses to different environmental stimuli, as well as to various endogenous ligands. Although AhR was previously implicated in the regulation of dendritic cell (DC) activation, very little is known about its potential role in the development of these cells. Here we report our unexpected findings that AhR may regulate the differentiation of plasmacytoid DCs (pDCs). Agonist of AhR markedly decreased the generation of pDCs in vitro, whereas the AhR antagonist had an opposite effect. The differentiation of conventional DCs (cDCs) was not affected. AhR-knockout mice had a substantial accumulation of pDCs in peripheral lymphoid organs; whereas no changes in cDCs were seen. Thus, this study has identified AhR as a transcription factor involved in the development of one population of DCs pDCs. PMID- 24165982 TI - Identification of a resident T-cell memory core transcriptional signature. PMID- 24165984 TI - Drinking motives among HIV primary care patients. AB - Heavy drinking among individuals with HIV is associated with poor medication adherence and other health problems. Understanding reasons for drinking (drinking motives) in this population is therefore important and could inform intervention. Using concepts of drinking motives from previous alcohol research, we assessed these motives and drinking in 254 HIV-positive primary care patients (78.0 % male; 94.5 % African American or Hispanic) prior to their participation in an alcohol intervention trial. Three motives had good factor structure and internal consistency: "drinking to cope with negative affect", "drinking for social facilitation" (both associated with heavier drinking), and "drinking due to social pressure" (associated with less drinking). Drinking motives may provide important content for alcohol intervention; clinical trials could indicate whether inclusion of such content improves intervention efficacy. Discussing motives in session could help providers assist clients in better managing psychological and social aspects of their lives without reliance on alcohol. PMID- 24165983 TI - Socially-integrated transdisciplinary HIV prevention. AB - Current ideas about HIV prevention include a mixture of primarily biomedical interventions, socio-mechanical interventions such as sterile syringe and condom distribution, and behavioral interventions. This article presents a framework for socially-integrated transdisciplinary HIV prevention that may improve current prevention efforts. It first describes one socially-integrated transdisciplinary intervention project, the Transmission Reduction Intervention Project. We focus on how social aspects of the intervention integrate its component parts across disciplines and processes at different levels of analysis. We then present socially-integrated perspectives about how to improve combination antiretroviral treatment (cART) processes at the population level in order to solve the problems of the treatment cascade and make "treatment as prevention" more effective. Finally, we discuss some remaining problems and issues in such a social transdisciplinary intervention in the hope that other researchers and public health agents will develop additional socially-integrated interventions for HIV and other diseases. PMID- 24165985 TI - Modeling the impact of post-diagnosis behavior change on HIV prevalence in Southern California men who have sex with men (MSM). AB - Our objective here is to demonstrate the population-level effects of individual level post-diagnosis behavior change (PDBC) in Southern Californian men who have sex with men (MSM), recently diagnosed with HIV. While PDBC has been empirically documented, the population-level effects of such behavior change are largely unknown. To examine these effects, we develop network models derived from the exponential random graph model family. We parameterize our models using behavioral data from the Southern California Acute Infection and Early Disease Research Program, and biological data from a number of published sources. Our models incorporate vital demographic processes, biology, treatment and behavior. We find that without PDBC, HIV prevalence among MSM would be significantly higher at any reasonable frequency of testing. We also demonstrate that higher levels of HIV risk behavior among HIV-positive men relative to HIV-negative men observed in some cross-sectional studies are consistent with individual-level PDBC. PMID- 24165986 TI - AKT hyperactivation confers a Th1 phenotype in thymic Treg cells deficient in TGF beta receptor II signaling. AB - The generation of CD4+Foxp3+ Treg cells in the thymus is crucial for immune homeostasis and self-tolerance. Recent studies have shown Treg-cell plasticity when Th-related transcriptional factors and cytokines are present. However, the mechanisms that maintain the stability of Treg cells are poorly understood. Here, using mice with a T-cell-specific deletion of the transforming growth factor-beta receptor 2 (Tgfbr2-/- mice), we identify the restriction of AKT activation as a key event for the control of Treg-cell stability in Th1 inflammation. AKT regulation was evident in thymic CD4+Foxp3+ Treg cells before they egressed to peripheral tissues. CD4+Foxp3+ thymocytes from mice with the Tgfbr2 deletion expressed high levels of CXCR3 and T-bet, and produced IFN-gamma and TNF-alpha. Thymic Tgfbr2-/- Treg cells also showed an increase in the activation of AKT pathway. Enhanced AKT activity induced the expression of IFN-gamma both in natural and inducible Treg cells. Inhibition of AKT activity markedly attenuated the expression of IFN-gamma and TNF-alpha in thymic Tgfbr2-/- Treg cells in vivo. In addition, mixed bone marrow transplantation showed that TGF-beta signaling maintained Treg-cell stability in an intrinsic manner. Our results demonstrate that AKT hyperactivation contributes to the conversion of Treg cells to a Th1 phenotype. PMID- 24165987 TI - Immigrant status, acculturation and risk of overweight and obesity in adolescents living in Madrid (Spain): the AFINOS study. AB - Prior studies have identified a link between length of residence and overweight (including obesity) in immigrant populations. However, this link has not been confirmed in Europe. This study compares overweight prevalences in native Spanish and immigrant adolescents living in the Madrid region (Spain), and whether length of residence affects the risk of immigrant adolescents being overweight. The study population was a representative sample of adolescents aged 13-17 years (n = 2,081, 1,055 girls) who lived in Madrid. Data were collected from November 2007 to February 2008 through a cross-sectional survey in which self-reported height and weight were used to calculate BMI. Overall, no significant difference was detected in overweight risk between the Spanish and immigrant adolescents. However, immigrant adolescents residing in Spain for 6 years or under did show a higher overweight risk than both the Spanish adolescents (OR 1.57) and immigrants who had lived in Spain for longer than 6 years (OR 1.98). Changes in lifestyle associated to a longer duration of residence in Spain seems to have a slightly protective effect on the risk of being overweight in immigrant adolescents. PMID- 24165988 TI - Functional limitations and nativity status among older Arab, Asian, black, Hispanic, and white Americans. AB - To examine the association between nativity status (foreign and US-born) by race/ethnicity (Arab, Asian, black, Hispanic, white) on having a functional limitation. We used American Community Survey data (2001-2007; n = 1,964,777; 65+ years) and estimated odds ratios (95% confidence intervals). In the crude model, foreign-born Blacks and Arabs were more likely, while Asians and Hispanics were less likely to report having a functional limitation compared to white. In the fully adjusted model, Blacks, Hispanics, and Asians were less likely, while Arabs were more likely to report having a functional limitation. In the crude model, US born Blacks and Hispanics were more likely, while Asians and Arabs were less likely to report having a functional limitation compared to whites. Policies and programs tailored to foreign-born Arab Americans may help prevent or delay the onset of disability, especially when initiated shortly after their arrival to the US. PMID- 24165989 TI - [Management of peripheral vascular disease based on current guidelines. Peripheral artery occlusive disease of the iliac and femoral arteries and carotid artery stenosis]. AB - The article summarizes the recommendations of current European and American guidelines concerning the diagnosis and treatment of peripheral arterial occlusive disease and carotid artery stenosis. In comparison to older recommendations, current guidelines concerning endovascular treatment and concomitant medical therapy have been changed in recent years. With the exception of very complex and long lesions, endovascular methods are seen as the therapy of choice for revascularization of the iliac and femoral arteries. For cardiovascular risk reduction, patients with symptomatic peripheral arterial disease and stenosis of the carotid arteries should receive antiplatelet as well as statin therapy and should not be treated different from patients with coronary artery disease. PMID- 24165990 TI - [Etiology, diagnosis, management, and treatment of myocarditis. Position paper from the ESC Working Group on Myocardial and Pericardial Diseases]. AB - Despite great advances in the pathophysiology and etiology of myocarditis, the clinical diagnosis of myocarditis in daily clinical practise remains challenging. Often the diagnosis was not clear because of the heterogeneity of clinical symptoms and the lack of guidelines for adequate diagnostic requirements and consecutive treatment options. The European Society of Cardiology (ESC) Working Group on Myocardial and Pericardial Diseases established a working group of experts to improve the diagnosis and management of myocarditis and to provide a common consensus statement as a reference for future registries and controlled trials. The goal was to bridge the gap between clinical- and tissue-based diagnosis by formulating a concept concerning essential diagnostics and treatment of these patients that would be accepted across Europe. Only in this manner is it possible to establish a basis for national and international registries and double-blind randomized treatment trials for the etiologically differentiated treatment of myocarditis, which appear promising due to numerous studies in recent years. In this paper, two members from the expert working group summarize the most important aspects of this position paper on the etiology, diagnosis, management, and treatment of myocarditis, which were published in the July 2013 issue of European Heart Joumal. PMID- 24165992 TI - Electrochemotherapy for the management of cutaneous and subcutaneous metastasis: a series of 39 patients treated with palliative intent. AB - BACKGROUND AND OBJECTIVES: Electrochemotherapy (ECT) is technique for local control of skin metastasis. This study is primarily aimed at assessing the clinical activity of ECT in a prospective cohort of patients, and evaluating the association between primary tumor histology, number of metastatic lesions and size of tumor deposits and objective response rate. METHODS AND RESULTS: Thirty nine patients with skin metastases from melanoma and other tumors underwent intravenous bleomycin ECT with palliative intent. No serious adverse events (SAE) or CTC grade 3 or 4 were observed. Overall response rate (ORR) was 66.6%. Response rate significantly correlated at univariate analysis both with the number (< or >10) and the size (< or >2 cm) of metastases. No relationship was observed for the histology of primary tumor. At multivariate analysis the size of the nodules under 2 cm was associated with a positive response and the correlation was statistically significant. CONCLUSIONS: ORR was 66.6% and all patients obtained a subjective clinical benefit from the treatment with minimal side effects. The most suitable patients were the ones with nodules <2 cm. PMID- 24165993 TI - Applications and reactivity trends of homoleptic p-block metal amido reagents. AB - This review aims to develop an understanding of reactivity trends of p-block metal bases M(NR2)n (M = Sn: n = 2; M = Al, Ga, As, Sb: n = 3) towards organic substrates EHy containing one or more E-H bonds (E = B, N, P, S). These compounds not only act as good bases for the deprotonation of E-H bonds but recent advances in p-block amido chemistry have shown that, in addition, they can effect the dehydrogenic homo-coupling of primary phosphines and amines to give E-E bonded products. They have also been found to be active in stoichiometric and catalytic dehydrocoupling of amine-boranes, which has direct applications in hydrogen storage devices, revealing that these p-block catalysts offer potential alternatives to the extensive range of expensive and often highly toxic heavy metal catalysts. This perspective analyses three distinct reactivity patterns of p-block metal bases; deprotonation, stoichiometric dehydrocoupling and catalytic dehydrocoupling and attempts to rationalise reactivity in relation to the redox stability of the p-block metal. PMID- 24165994 TI - A copper-catalysed amidation of aldehydes via N-hydroxysuccinimide ester formation. AB - A copper-catalysed oxidative amidation of aldehydes via N-hydroxysuccinimide ester formation is reported. The methodology employed to prepare amides directly from aldehydes has a very wide scope, is high yielding, and does not need dry conditions. This cross-coupling reaction appears to be simple and makes use of cheap, abundant and easily available reagents. PMID- 24165995 TI - Nutrition: New diabetes nutrition recommendations--food for thought. PMID- 24165996 TI - Diabetes: Bariatric surgery for T2DM--cure, or remission and relapse? PMID- 24165997 TI - Therapy: One plus one equals zero--drug combinations mitigate adverse effects. PMID- 24165998 TI - Parathyroid gland: Hypoparathyroidism: replacing PTH. PMID- 24165999 TI - Reproductive endocrinology: Hormone therapy to treat menopause--breaking a taboo. PMID- 24166001 TI - Fast, single-step, and surfactant-free oligonucleotide modification of gold nanoparticles using DNA with a positively charged tail. AB - Fast modification of large gold nanoparticles with DNA is achieved by using DNA with a polycationic tail. The conjugated DNA is available for specific hybridization, and therefore can be used for DNA-based assays or for constructing nanoparticle superstructures based on DNA hybridization. PMID- 24166002 TI - Motion-induced radiation from electrons moving in Maxwell's fish-eye. AB - In Cerenkov radiation and transition radiation, evanescent wave from motion of charged particles transfers into radiation coherently. However, such dissipative motion-induced radiations require particles to move faster than light in medium or to encounter velocity transition to pump energy. Inspired by a method to detect cloak by observing radiation of a fast-moving electron bunch going through it by Zhang et al., we study the generation of electron-induced radiation from electrons' interaction with Maxwell's fish-eye sphere. Our calculation shows that the radiation is due to a combination of Cerenkov radiation and transition radiation, which may pave the way to investigate new schemes of transferring evanescent wave to radiation. PMID- 24166000 TI - Fertility preservation in women. AB - In women, ~10% of cancers occur in those <45 years old. Chemotherapy, radiotherapy and bone marrow transplantation can cure >90% of girls and young women with diseases that require such treatments. However, these treatments can result in premature ovarian failure, depending on the follicular reserve, the age of the patient and the type and dose of drugs used. This article discusses the different fertility preservation strategies: medical therapy before chemotherapy; ovarian transposition; embryo cryopreservation; oocyte vitrification; and ovarian tissue cryopreservation. The indications, results and risks of these options are discussed. Whether medical therapy should be used to protect the gonads during chemotherapy remains a source of debate. Fertility preservation needs to be completed before chemotherapy and/or irradiation is started and might take 2-3 weeks with established techniques such as embryo or oocyte cryopreservation. Further studies are needed in patients with cancer to confirm the excellent outcomes obtained in patients without cancer or in egg donation programmes. For prepubertal girls or cases where immediate therapy is required, cryopreservation of ovarian tissue is the only available option. Finally, possible future approaches are reviewed, including in vitro maturation of nonantral follicles, the artificial ovary, oogonial stem cells and drugs to prevent follicle loss. PMID- 24166003 TI - Influence of congenital central nervous system malformations on postoperative complications following placement of cerebrospinal fluid shunts in pediatric and adolescent patients. AB - BACKGROUND: This retrospective study was designed to evaluate whether patients with hydrocephalus associated with central nervous system (CNS) anomalies, compared with patients with hydrocephalus and absent CNS anomalies, present with significantly higher rate of postoperative complications, including more serious clinical presentation, increased life threat, and higher postoperative or late mortality rate. METHODS: We performed a retrospective study using medical records of 100 patients of pediatric and adolescent age (0-18 years) between 2004 and 2010 treated with operative cerebrospinal fluid (CSF) shunt placement. RESULTS: In both groups of patients, there were 43 postoperative complications, including 12 mechanical obstructions of the CSF drainage systems, 13 disconnections, 11 dislocations of proximal catheter, 6 inflammatory complications (meningitis), and 1 latex allergy. Patients with hydrocephalus associated with CNS anomalies were presented with statistically higher rate of postoperative complications (U = 303.5, z = -3.27, p = 0.001), higher number of operations, at least one complication more per patient, more complicated clinical course, higher life threat, and higher late mortality rate. CONCLUSIONS: After installing the CSF drain system, children and adolescents with hydrocephalus associated with anomalies of the CNS require regular and careful follow-up. PMID- 24166005 TI - Adaptive lambda square dynamics simulation: an efficient conformational sampling method for biomolecules. AB - A novel, efficient sampling method for biomolecules is proposed. The partial multicanonical molecular dynamics (McMD) was recently developed as a method that improved generalized ensemble (GE) methods to focus sampling only on a part of a system (GEPS); however, it was not tested well. We found that partial McMD did not work well for polylysine decapeptide and gave significantly worse sampling efficiency than a conventional GE. Herein, we elucidate the fundamental reason for this and propose a novel GEPS, adaptive lambda square dynamics (ALSD), which can resolve the problem faced when using partial McMD. We demonstrate that ALSD greatly increases the sampling efficiency over a conventional GE. We believe that ALSD is an effective method and is applicable to the conformational sampling of larger and more complicated biomolecule systems. PMID- 24166004 TI - Alginate encapsulation parameters influence the differentiation of microencapsulated embryonic stem cell aggregates. AB - Pluripotent embryonic stem cells (ESCs) have tremendous potential as tools for regenerative medicine and drug discovery, yet the lack of processes to manufacture viable and homogenous cell populations of sufficient numbers limits the clinical translation of current and future cell therapies. Microencapsulation of ESCs within microbeads can shield cells from hydrodynamic shear forces found in bioreactor environments while allowing for sufficient diffusion of nutrients and oxygen through the encapsulation material. Despite initial studies examining alginate microbeads as a platform for stem cell expansion and directed differentiation, the impact of alginate encapsulation parameters on stem cell phenotype has not been thoroughly investigated. Therefore, the objective of this study was to systematically examine the effects of varying alginate compositions on microencapsulated ESC expansion and phenotype. Pre-formed aggregates of murine ESCs were encapsulated in alginate microbeads composed of a high or low ratio of guluronic to mannuronic acid residues (High G and High M, respectively), with and without a poly-L-lysine (PLL) coating, thereby providing four distinct alginate bead compositions for analysis. Encapsulation in all alginate compositions was found to delay differentiation, with encapsulation within High G alginate yielding the least differentiated cell population. The addition of a PLL coating to the High G alginate prevented cell escape from beads for up to 14 days. Furthermore, encapsulation within High M alginate promoted differentiation toward a primitive endoderm phenotype. Taken together, the findings of this study suggest that distinct ESC expansion capacities and differentiation trajectories emerge depending on the alginate composition employed, indicating that encapsulation material physical properties can be used to control stem cell fate. PMID- 24166006 TI - Construal level and temporal judgments of the past: the moderating role of knowledge. AB - The vast majority of work in construal level theory has found a robust relationship between construal level and temporal judgments for future events: Distance is associated with the abstract, and nearness is associated with the concrete. Our work looks at the past and proposes a critical moderator that reverses this relationship: knowledge. Through experiments involving real news events, we demonstrate that people with less knowledge about events felt nearer to them when recalling them in a concrete mindset versus an abstract one. However, this relationship reverses for those with greater knowledge: They feel closer to past events when recalling them in an abstract mindset versus a concrete one. We provide evidence that this reversal stems from feelings of metacognitive ease that inform temporal judgments when knowledge (which drives what information is held available and accessible in memory) and construal mindset (which drives what information is sought from memory) coincide. Our findings suggest that in memory, there are instances where the abstract seems near and the concrete seems distant. PMID- 24166007 TI - Detection and characterization of invasive circulating tumor cells derived from men with metastatic castration-resistant prostate cancer. AB - The Vitatex cell-adhesion matrix (CAM) platform allows for isolation of invasive circulating tumor cells (iCTCs). Here we sought to determine the utility of prostate-specific membrane antigen (PSMA) as a metastatic castration-resistant prostate cancer (mCRPC) iCTC biomarker, to identify solitary cells and clusters of iCTCs expressing either epithelial, mesenchymal, or stem cell markers, and to explore the feasibility of iCTC epigenomic analysis. CTCs were isolated and enumerated simultaneously using the Vitatex and CellSearch platforms in 23 men with mCRPC. CAM-avid iCTCs were identified as nucleated cells capable of CAM uptake, but without detectable expression of hematopoietic lineage (HL) markers including CD45. iCTCs were enumerated immunocytochemically (ICC) and by flow cytometry. Whole-genome methylation status was determined for iCTCs using the Illumina HumanMethylation27 BeadChip. Thirty-four samples were collected for iCTC analysis. A median of 27 (range 0-800) and 23 (range 2-390) iCTCs/mL were detected by ICC and flow, respectively. In a subset of 20 samples, a median of seven CTCs/mL (range 0-85) were detected by the CellSearch platform compared to 26 by the CAM platform. iCTC clusters were observed in 17% of samples. iCTCs expressing PSMA as well as markers of EMT and stemness were detectable. The iCTC methylation profile highly resembled mCRPC. More CTCs were recovered using the CAM platform than the CellSearch platform, and the CAM platform allowed for the detection of iCTC clusters, iCTCs expressing EMT and stem-cell markers, and characterization of the iCTC methylome. Correlation with clinical data in future studies may yield further insight into the functional significance of these findings. PMID- 24166008 TI - Chemical mechanism of surface-enhanced Raman scattering spectrum of pyridine adsorbed on Ag cluster: ab initio molecular dynamics approach. AB - The surface-enhanced Raman scattering (SERS) spectrum of pyridine adsorbed on Ag20 cluster (pyridine-Ag20 ) at room temperature is calculated by performing ab initio molecular dynamics simulations in connection with a Fourier transform of the polarizability autocorrelation function to investigate the static chemical enhancement behind the SERS spectrum. The five enhanced vibrational modes of pyridine, namely, upsilon6a, upsilon1, upsilon12, upsilon9a, and upsilon8a, can be assigned and identified by using a new analytical scheme, namely, single frequency-pass filter, which is based on a Fourier transform filtering technique. To understand the factors evoking the enhancement in the SERS spectrum, the dynamic properties of molecular structures and charges for both of the free pyridine and adsorbed pyridine are analyzed. The calculated results indicate that the vibrational amplitudes of adsorbed pyridine are enhanced due to both of the electron transfer from pyridine to Ag20 cluster and the softening of pyridine bond. In addition, the N-Ag stretching within pyridine-Ag20 will couple with these five vibrational modes of pyridine. Consequently, the electron transfer between pyridine and Ag20 cluster induced by different molecular vibrational modes prompts the redistribution of electron density of pyridine. These factors collectively cause the noticeable change in polarizability during molecular vibrations and hence result in the enhancement of Raman peaks. PMID- 24166009 TI - Animal ethics committee guidelines and shark research : comment on "ethics of species research and preservation" by Rob Irvine. PMID- 24166010 TI - Kinetics of 25-hydroperoxycholesterol formation during photo-oxidation of crystalline cholesterol. AB - BACKGROUND: 25-Hydroxycholesterol (25-OH), a side-chain product of cholesterol oxidation, has emerged as one of the important issues in food chemistry and biochemistry, because of its involvement in several human pathologies. This oxysterol is derived from both enzymatic and non-enzymatic pathways. However, the latter mechanism has been scarcely studied in either food or model systems. In this work, a kinetic model was developed to evaluate the formation of 25-OH and its precursor 25-hydroperoxycholesterol (25-OOH) during photo-oxidation of cholesterol for 28 days under fluorescent light. 25-OOH was estimated by an indirect method, using thin-layer chromatography coupled with gas chromatography mass spectrometry. RESULTS: Peroxide value (POV) and cholesterol oxidation products (COPs) were determined. POV showed a hyperbolic behavior, typical of a crystalline system in which the availability of cholesterol is the limiting factor. Further reactions of hydroperoxides were followed; in particular, after photo-oxidation, 25-OOH (0.55 mg g(-1) ) and 25-OH (0.08 mg g(-1) ) were found in cholesterol, as well as seven other oxysterols, including 7-hydroxy and 5,6-epoxy derivatives. The application of kinetic models to the data showed good correlation with theoretical values, allowing derivation of the kinetic parameters for each oxidation route. CONCLUSIONS: The results of this work confirm that cholesterol in the crystalline state involves different oxidation patterns as compared to cholesterol in solution. Moreover, the numerical fit proved that hydroperoxidation is the rate-limiting step in 25-OH formation. PMID- 24166011 TI - Light-induced excited spin state trapping effect on [Fe(mepy)3tren](PF6)2 solvated crystals. AB - A spin-crossover solvated compound [Fe(mepy)3tren](PF6)2.C7H8.C2H3N has been prepared and its switching properties have been compared to those reported for the non-solvated solid. The thermal spin transition occurs at 88 K with the opening of a 3.5 K wide hysteresis loop, while a fairly steep transition at 215 K without hysteresis has been previously reported for the non-solvated analogue. This feature has been rationalized by the analysis of the high-spin (HS) and low spin (LS) structures, evidencing a relative stabilization of the high-spin state, as well as strong intermolecular interactions in the solvated compound. The photoswitching of the solvated solid, based on the light-induced excited spin state trapping effect, leads to a quantitative transformation from the low-spin to the high-spin state at 10 K. The long lifetime of the metastable HS state at 10 K allows the measurement of the photo-induced HS structure, where the cooperative interactions are enhanced, compared to those of the thermally populated HS structure. Then,the HS-to-LS relaxations have been studied between 45 and 60 K. They are sigmoidal in shape and can be well fitted in the frame of the mean-field approximation. The relative stability of the photo-induced HS state in this family of spin crossover compounds is not directly related to their thermal spin transition temperature. This unexpected observation is rationalized by a careful analysis of their structural characteristics. PMID- 24166013 TI - Transcranial Doppler ultrasonography in children with sickle cell anemia: Clinical and laboratory correlates for elevated blood flow velocities. AB - BACKGROUND: Transcranial Doppler (TCD) sonography of major cerebral arteries is now recommended for routine screening for stroke risk in children with sickle cell disease (SCD). METHODS: We performed TCD studies on children with sickle cell anemia (SCA) seen at the pediatric hematology clinic over a period of 2 years. TCD scans were repeated yearly in children with normal flow velocities and every 3 months in children with elevated velocities. Findings were correlated with clinical variables, hematologic indices, and arterial oxygen saturation. Predictors of elevated velocities were identified by multiple linear regressions. RESULTS: We enrolled 237 children and performed a total of 526 TCD examinations. Highest time-averaged maximum flow velocities were >=170 cm/s in 72 (30.3%) cases and >=200 cm/s in 20 (8.4%). Young age, low hematocrit, low hemoglobin, and arterial oxygen desaturation <95% showed significant correlations with presence of increased cerebral flow velocities. CONCLUSIONS: Low hematocrit, low hemoglobin concentration, young age, and low arterial oxygen desaturation predicted elevated cerebral blood flow velocities and, invariably, increased stroke risk, in children with SCA. Children who exhibit these features should be given high priority for TCD examination in the setting of limited resources. PMID- 24166014 TI - Improved isoelectric focusing chromatography on strong anion exchange media via a new model that custom designs mobile phases using simple buffers. AB - Isoelectric chromatofocusing (ICF), a mode of chromatography by which proteins are separated based on changes in their charge state with pH, is widely used at analytical scales and finding increasing interest in biologics manufacturing due to its exceptional resolving power. Here, a method is described for using simple monoprotic and diprotic buffers to create stable mobile phases for sample loading on a strong anion exchange column and for achieving an elution pH gradient of desired shape covering any pH range from pH 10.0 to 3. The buffers used are selected to satisfy cost constraints, and to permit facile detection of eluted biologics by UV spectroscopy and mass spectrometry. The method exploits a new model described here that combines multiple-chemical and adsorption-equilibria theory to enable in silico tailoring of elution pH profiles using mixtures of these simple buffers. It is shown to provide a versatile platform for optimizing and conducting ICF of protein mixtures on strong anion exchange media. PMID- 24166015 TI - [Importance of neurobiology for modular psychotherapy]. AB - In the context of continuing education in psychiatry and psychotherapy, modular psychotherapy is of special importance. In modular psychotherapy, general interventions, e.g. for regulation of emotions, have an important function. In this review examples are given to describe the importance of neurobiology for the understanding and the improvement of these mechanisms. In addition, the use of neurobiological investigations within classical psychotherapy trials in the fields of borderline personality disorder and posttraumatic stress disorder will be depicted. PMID- 24166016 TI - [Stalking: diagnostics, risk assessment, principles of treatment and forensic psychiatric assessment]. AB - Stalking is a widespread phenomenon describing a pattern of intrusive and threatening behavior that leads to the victim's perception of being harassed, threatened and frightened. Physical assault and even homicide may sometimes occur in the context of stalking. For psychiatry the following tasks result: (1) diagnosis and classification of stalking cases, (2) risk assessment of stalking cases, (3) counselling and treatment of victims of stalking and, (4) treatment and assessment of stalkers. Empirical findings and instructions are presented for these four areas. PMID- 24166017 TI - [Psychiatric psychotherapeutic research in Germany: taking stock and international comparison]. AB - This article is based on an evaluation carried out by the DGPPN in 2011 surveying 50 German university and non-university institutions about the scientific research output focussing on psychiatric and psychotherapeutic research. The results of the survey show that on average there are 1 to 2 professors with 12 assistants scientifically active per institution. According to self-disclosure an estimated 1.8 million Euros of external funds are raised each year.Compared to international standards regarding the illnesses major depression, schizophrenia and alcohol abuse, Germany ranks second and third place behind the USA and the UK or Canada in terms of publication output. In terms of authors and institutions, German scientists and universities rank in the upper third to upper tenth for these illnesses. These data show that psychiatric research in Germany is not only internationally competitive but outstanding in its excellent achievements in these fields. Unfortunately, many funding programmes are limited to a 3-6 year period. In view of this fact and in order to achieve a long-term improvement in the translation of funding structures, as in the US (NIMH) or the UK (MRC) to benefit the mentally ill the implementation of a German centre for mental disorders is inevitable. PMID- 24166018 TI - A patient privacy protection scheme for medical information system. AB - In medical information systems, there are a lot of confidential information about patient privacy. It is therefore an important problem how to prevent patient's personal privacy information from being disclosed. Although traditional security protection strategies (such as identity authentication and authorization access control) can well ensure data integrity, they cannot prevent system's internal staff (such as administrators) from accessing and disclosing patient privacy information. In this paper, we present an effective scheme to protect patients' personal privacy for a medical information system. In the scheme, privacy data before being stored in the database of the server of a medical information system would be encrypted using traditional encryption algorithms, so that the data even if being disclosed are also difficult to be decrypted and understood. However, to execute various kinds of query operations over the encrypted data efficiently, we would also augment the encrypted data with additional index, so as to process as much of the query as possible at the server side, without the need to decrypt the data. Thus, in this paper, we mainly explore how the index of privacy data is constructed, and how a query operation over privacy data is translated into a new query over the corresponding index so that it can be executed at the server side immediately. Finally, both theoretical analysis and experimental evaluation validate the practicality and effectiveness of our proposed scheme. PMID- 24166019 TI - eHealth in Denmark: a case study. AB - Denmark is widely regarded as a leading country in terms of eHealth integration and healthcare delivery services. The push for eHealth adoption over that past 20 years in the Danish health sector has led to the deployment of multiple eHealth technologies. However, in reality the Danish healthcare suffers from eHealth system fragmentation which has led to eHealth's inability to reach full potential in delivering quality healthcare service. This paper will presents a case study of the current state of eHealth in the Danish healthcare system and discuss the current challenges the country is facing today. PMID- 24166020 TI - Increased intraoperative epidural pressure in lumbar spinal stenosis patients with a positive nerve root sedimentation sign. AB - PURPOSE: The sedimentation sign (SedSign) has been shown to discriminate well between selected patients with and without lumbar spinal stenosis (LSS). The purpose of this study was to compare the pressure values associated with LSS versus non-LSS and discuss whether a positive SedSign may be related to increased epidural pressure at the level of the stenosis. METHODS: We measured the intraoperative epidural pressure in five patients without LSS and a negative SedSign, and in five patients with LSS and a positive SedSign using a Codman(TM) catheter in prone position under radioscopy. RESULTS: Patients with a negative SedSign had a median epidural pressure of 9 mmHg independent of the measurement location. Breath and pulse-synchronous waves accounted for 1-3 mmHg. In patients with monosegmental LSS and a positive SedSign, the epidural pressure above and below the stenosis was similar (median 8-9 mmHg). At the level of the stenosis the median epidural pressure was 22 mmHg. A breath and pulse-synchronous wave was present cranial to the stenosis, but absent below. These findings were independent of the cross-sectional area of the spinal canal at the level of the stenosis. CONCLUSIONS: Patients with LSS have an increased epidural pressure at the level of the stenosis and altered pressure wave characteristics below. We argue that the absence of sedimentation of lumbar nerve roots to the dorsal part of the dural sac in supine position may be due to tethering of affected nerve roots at the level of the stenosis. PMID- 24166022 TI - Detecting lies about consumer attitudes using the timed antagonistic response alethiometer. AB - The Timed Antagonistic Response Alethiometer (TARA) is a true-false statement classification task that diagnoses lying on the basis of slower average response speeds. Previous research (Gregg in Applied Cognitive Psychology, 21, 621-647, 2007) showed that a computer-based TARA was about 80 % accurate when its statements conveyed demographic facts or religious views. Here, we tested the TARA's diagnostic potential when its statements conveyed attitudes-here, toward both branded and generic consumer products-across different versions of the TARA (Exps. 1a, 1b, and 1c), as well as across consecutive administrations (Exp. 2). The results generalized well across versions, and maximal accuracy rates exceeding 80 % were obtained, although accuracy declined somewhat upon readministration. Overall, the TARA shows promise as a comparatively cheap, convenient, and diagnostic index of lying about attitudes. PMID- 24166023 TI - Cholesterol-aided construction of distinct self-organized materials from a luminescent gold(I)-isocyanide complex exhibiting mechanochromic luminescence. AB - A cholesterol-functionalized gold(i)-isocyanide complex exhibiting mechanochromic luminescence properties was self-organized into distinct microscopic structures with different photoluminescence properties through vapor-diffusion of a poor solvent into its dichloromethane solution. The structure-optical property relationship of these microstructures could be related to the mechanically induced phase transition. PMID- 24166021 TI - Factors influencing arthrodesis rates in a rabbit posterolateral spine model with iliac crest autograft. AB - PURPOSE: The rabbit posterolateral intertransverse spine arthrodesis model has been widely used to evaluate spinal biologics. However, to date, the validity and reproducibility of performance of iliac crest bone graft, the most common and critical control group, has not been firmly established. We evaluated original research publications that utilized this model, identified which experimental conditions affected fusion rates, and developed an algorithm to predict fusion rates for future study designs. METHODS: A MEDLINE search was performed for publications through December, 2011 that utilized this model to evaluate fusion rates elicited by iliac crest autograft. All study parameters were recorded, and logistic regression analyses were performed to determine the effects of these variables on fusion rates as determined by either manual palpation or radiographs. RESULTS: Seventy studies with 959 rabbits in 102 groups met the inclusion criteria. Excluding studies that measured fusion at 4 or fewer weeks or intentionally tried to decrease the fusion rate, the overall fusion rate for autograft was 58.3 +/- 16.3 % (mean +/- SD) as determined by manual palpation and 66.4 +/- 17.8 % by plain radiographs. Regression analysis demonstrated a difference between these outcome measures with a trend towards significance (p = 0.09). Longer time points and larger volumes of autograft resulted in significantly greater reported fusion rates (p < 0.0001 and p < 0.05, respectively). Neither strain, age, weight, nor vertebral level significantly affected fusion rates. CONCLUSIONS: Although experimental conditions varied across studies, time point evaluation and autograft volume significantly affected fusion rates. Despite some variability demonstrated across certain studies, we demonstrated that when the time point and volume of autograft were controlled for, the iliac crest control group of the rabbit posterolateral spinal arthrodesis model is both reliable and predictably affected by different experimental conditions. PMID- 24166024 TI - Role of radical antegrade modular pancreatosplenectomy for adenocarcinoma of the body and tail of the pancreas. AB - BACKGROUND: Studies have claimed that in the surgical treatment of pancreas body and tail cancer, radical antegrade modular pancreatosplenectomy (RAMPS) is associated with effective tangential margin and extensive lymph node dissection. In the present study, the authors have compared the surgical outcomes between RAMPS and conventional distal pancreatosplenectomy (DPS) in patients with adenocarcinoma of the pancreas body and tail, and also identified prognostic factors associated with survival after surgery. METHODS: Retrospective review of 92 consecutive patients who underwent surgical resection for pancreas body and tail adenocarcinoma with curative intent between 1995 and 2010. Median follow-up duration was 16.1 months. RESULTS: Of the 92 patients, 38 patients received RAMPS and 54 patients received DPS. Patients who underwent RAMPS had a greater number of retrieved lymph nodes than patients undergoing DPS [median 14 (5-52) vs. 9 (1 36), p < 0.05]. Conventional DPS, no adjuvant chemoradiation therapy (CRT), and non-curative resection were associated with poor overall survival (OS) on univariate analysis. After multivariate analysis for these variables, only the lack of adjuvant CRT and resection margin status were found to adversely affect OS. CONCLUSIONS: While the RAMPS procedure is effective in performing an extensive LN dissection, it is not associated with better retroperitoneal resection margin or retrieval of more positive LNs, and it does not lead to better curability or OS survival compared to DPS. Lack of adjuvant CRT and resection margin status are poor prognostic factors in patients with pancreas body and tail cancer. PMID- 24166025 TI - Predictive factors of thyroid cancer in patients with Graves' disease. AB - BACKGROUND: The best preoperative examination in Graves' disease with thyroid cancer still remains uncertain. The objectives of the present study were to investigate the prevalence of thyroid cancer in Graves' disease patients, and to identify the predictive factors and ultrasonographic features of thyroid cancer that may aid the preoperative diagnosis in Graves' disease. METHODS: This retrospective study included 423 patients with Graves' disease who underwent surgical treatment from 2002 to 2012 at our institution. The clinical features and ultrasonographic findings of thyroid nodules were recorded. The diagnosis of thyroid cancer was determined according to the pathological results. RESULTS: Thyroid cancer was discovered in 58 of the 423 (13.7 %) surgically treated Graves' disease patients; 46 of those 58 patients had thyroid nodules, and the other 12 patients were diagnosed with incidentally discovered thyroid carcinomas without thyroid nodules. Among the 58 patients with thyroid cancer, papillary microcarcinomas were discovered in 50 patients, and multifocality and lymph node involvement were detected in the other 8 patients. Multivariate regression analysis showed younger age was the only significant factor predictive of metastatic thyroid cancer. Ultrasonographic findings of calcification and intranodular blood flow in thyroid nodules indicate that they are more likely to harbor thyroid cancers. CONCLUSIONS: Because the influencing factor of metastatic thyroid cancers in Graves' disease is young age, every suspicious nodule in Graves' disease patients should be evaluated and treated carefully, especially in younger patients because of the potential for metastasis. PMID- 24166026 TI - Does "conversion chemotherapy" really improve survival in metastatic colorectal cancer patients with liver-limited disease? AB - BACKGROUND: The clinical benefits of conversion chemotherapy followed by liver resection for initially unresectable colorectal liver metastases are still controversial. The criteria for unresectability vary from one team to another. To clarify this issue, we retrospectively assessed the survival and characteristics of metastatic colorectal cancer (mCRC) patients with liver-limited disease (LLD) who underwent conversion therapy. METHOD: Our criteria for resectability depended on the size of the remnant liver volume (>30 %) and expected function after removal of all metastases. Between December 2007 and September 2011, a total of 115 patients were diagnosed as having mCRC with LLD and received chemotherapy. Among them, 47 had tumors that were initially diagnosed as resectable. They underwent hepatic resection after chemotherapy (resected group). Of the 67 tumors were initially diagnosed as unresectable, 12 became resectable after chemotherapy (conversion group), leaving 55 tumors that remained unresectable after chemotherapy (unresected group). RESULTS: The median follow-up was 25.2 months. Hepatic resection was more invasive in the conversion group than in the resected group. Median disease-free survival was significantly higher in the resected group than in the conversion group (p = 0.013). Overall survival (OS) was also higher in the resected group, but the difference was not significant (p = 0.36). However, OS was significantly higher in the conversion group than in the unresected group (p = 0.034). Multivariate analysis of the resected and conversion groups showed that OS was significantly negatively influenced by abnormal carcinoembryonic antigen levels at surgery (p = 0.037) and a hospital stay >30 days (p = 0.009). CONCLUSIONS: Our results showed that conversion chemotherapy could contribute to longer OS in mCRC patients with LLD. PMID- 24166027 TI - Accidentally ingested toothpicks causing severe gastrointestinal injury: a practical guideline for diagnosis and therapy based on 136 case reports. AB - BACKGROUND: Ingested toothpicks are a relatively rare event, but may cause serious gut injuries with peritonitis, sepsis, or death. Numerous case reports describing the clinical course in this setting are available but there is no concise guideline. The aim of the present study was to develop practical guidelines to aid clinicians in the diagnosis and management of acute tooth pick ingestion. METHOD: Our Medline search identified 116 publications containing case reports of ingested toothpicks. We then performed a retrospective analysis of patients' characteristics, medical history, diagnostics, therapy, and clinical outcome. RESULTS: A total of 136 cases (74 % male, age 52 [5-92] years) have been reported in the literature. From the available information, more than 50 % (n = 48) of patients were not aware of having swallowed a toothpick. The most common presenting symptoms were abdominal pain (82 %), fever (39 %), and nausea (31 %). The toothpick caused gut perforation in 79 % of all patients. The locations of toothpicks prior removal were esophagus (2 %), stomach (20 %), duodenum (23 %), small intestine (18 %), and large intestine (37 %). The diagnostic procedures included endoscopy (63 %), computed tomography scan (63 %), and ultrasound (47 %); however, in 35 % of cases these investigations failed to detect the toothpick. Therapy was surgery in most cases (58 %). The overall mortality was 9.6 %. CONCLUSIONS: Toothpick ingestion is a medical emergency. Perforations of the intestine are common and the associated mortality is high. Adequate therapy depends on localization of the toothpick in the gastrointestinal tract. Ingested toothpicks should be kept in mind as an important differential diagnosis in patients with acute abdomen. PMID- 24166028 TI - Evolution: proteins partner up in a vigorous relationship. PMID- 24166029 TI - Gene regulation: from genetic variation to phenotype via chromatin. PMID- 24166030 TI - Development: seeing the pattern. PMID- 24166032 TI - Ischemic heart disease and breast cancer radiotherapy: the way forward. PMID- 24166033 TI - Airtight metallic sealing at room temperature under small mechanical pressure. AB - Metallic seals can be resistant to air leakage, resistant to degradation under heat, and capable of carrying mechanical loads. Various technologies--such as organic solar cells and organic light emitting diodes--need, at least benefit from, such metallic seals. However, these technologies involve polymeric materials and can tolerate neither the high-temperature nor the high-pressure processes of conventional metallic sealing. Recent progress in nanorod growth opens the door to metallic sealing for these technologies. Here, we report a process of metallic sealing using small well-separated Ag nanorods; the process is at room temperature, under a small mechanical pressure of 9.0 MPa, and also in ambient. The metallic seals have an air leak rate of 1.1 * 10(-3) cm(3)atm/m(2)/day, and a mechanical shear strength higher than 8.9 MPa. This leak rate meets the requirements of organic solar cells and organic light emitting diodes. PMID- 24166031 TI - Genome dynamics during experimental evolution. AB - Evolutionary changes in organismal traits may occur either gradually or suddenly. However, until recently, there has been little direct information about how phenotypic changes are related to the rate and the nature of the underlying genotypic changes. Technological advances that facilitate whole-genome and whole population sequencing, coupled with experiments that 'watch' evolution in action, have brought new precision to and insights into studies of mutation rates and genome evolution. In this Review, we discuss the evolutionary forces and ecological processes that govern genome dynamics in various laboratory systems in the context of relevant population genetic theory, and we relate these findings to evolution in natural populations. PMID- 24166034 TI - Molecular signatures for the phylum (class) Thermotogae and a proposal for its division into three orders (Thermotogales, Kosmotogales ord. nov. and Petrotogales ord. nov.) containing four families (Thermotogaceae, Fervidobacteriaceae fam. nov., Kosmotogaceae fam. nov. and Petrotogaceae fam. nov.) and a new genus Pseudothermotoga gen. nov. with five new combinations. AB - All species from the phylum Thermotogae, class Thermotogae, are currently part of a single family, Thermotogaceae. Using genomic data from 17 Thermotogae species, detailed phylogenetic and comparative genomic analyses were carried out to understand their evolutionary relationships and identify molecular markers that are indicative of species relationships within the phylum. In the 16S rRNA gene tree and phylogenetic trees based upon two different large sets of proteins, members of the phylum Thermotogae formed a number of well-resolved clades. Character compatibility analysis on the protein sequence data also recovered a single largest clique that exhibited similar topology to the protein trees and where all nodes were supported by multiple compatible characters. Comparative genomic analyses have identified 85 molecular markers, in the form of conserved signature indels (CSIs), which are specific for different observed clades of Thermotogae at multiple phylogenetic depths. Eleven of these CSIs were specific for the phylum Thermotogae whereas nine others supported a clade comprising of the genera Thermotoga, Thermosipho and Fervidobacterium. Ten other CSIs provided evidence that the genera Thermosipho and Fervidobacterium shared a common ancestor exclusive of the other Thermotogae and four and eight CSIs in other proteins were specific for the genera Thermosipho and Fervidobacterium, respectively. Two other deep branching clades, one consisting of the genera Kosmotoga and Mesotoga and the other comprising of the genera Petrotoga and Marinitoga, were also supported by multiple CSIs. Based upon the consistent branching of the Thermotogae species using different phylogenetic approaches, and numerous identified CSIs supporting the distinctness of different clades, it is proposed that the class Thermotogae should be divided into three orders (Thermotogales, Kosmotogales ord. nov. and Petrotogales ord. nov.) containing four families (Thermotogaceae, Fervidobacteriaceae fam. nov., Kosmotogaceae fam. nov. and Petrotogaceae fam. nov.). Additionally, the results of our phylogenetic/compatibility studies along with the species distribution patterns of 22 identified CSIs, provide compelling evidence that the current genus Thermotoga is comprised of two evolutionary distinct groups and that it should be divided into two genera. It is proposed that the emended genus Thermotoga should retain only the species Thermotoga maritima, Tt. neapolitana, Tt. petrophila, Tt. naphthophila, Thermotoga sp. EMP, Thermotoga sp. A7A and Thermotoga sp. RQ2 while the other Thermotoga species (viz. Tt. lettingae, Tt. thermarum, Tt. elfii, Tt. subterranean and Tt. hypogea) be transferred to a new genus, Pseudothermotoga gen. nov. PMID- 24166035 TI - Synthesis of nitric oxide probes with fluorescence lifetime sensitivity. AB - We present the rationale, synthesis and evaluation of the first activatable fluorescent probe that utilizes fluorescence lifetime change for detection of nitric oxide. The new probe DAP-LT1 features a near-infrared polymethine skeleton with a diaminobenzene functionality incorporated into the meso-position. The probe is partially quenched, and upon reaction with nitric oxide shows an increase in the fluorescence lifetime from 1.08 ns to 1.24 ns. PMID- 24166036 TI - Scrub typhus meningitis or meningoencephalitis. AB - Orientia tsutsugamushi induces vasculitis leading to symptoms of systemic organ invasion including meningitis and meningoencephalitis. We conducted a retrospective case-control study of scrub typhus patients to investigate the clinical and laboratory features of patients with scrub typhus meningitis or meningoencephalitis, and the therapeutic outcomes, and to determine the predictor factors. Cases were 22 patients with scrub typhus meningitis or meningoencephalitis, and controls were 303 patients without meningitis or meningoencephalitis. Multivariate analysis showed that the presence of pneumonitis was associated with the occurrence of scrub typhus meningitis and meningoencephalitis (odds ratio [OR] 8.9; P < 0.001; confidence interval [CI] 2.9 27.2). Although appropriate antimicrobials such as doxycycline agents were administered at an early stage, meningitis or meningoencephalitis still occurred in some cases. Physicians should be aware that meningitis or meningoencephalitis may develop during appropriate drug therapy such as doxycycline. Close observation and great care are essential for patients with risk factors, particularly pneumonitis. PMID- 24166037 TI - Investigation of Crimean-Congo hemorrhagic fever virus transmission from patients to relatives: a prospective contact tracing study. AB - We investigated the possibility of transmission of Crimean-Congo hemorrhagic fever (CCHF) virus through respiratory and physical contact. In this prospective study, we traced 116 close relatives of confirmed CCHF cases who were in close contact with the patients during the acute phase of the infection and evaluated the type of contact between patients and their relatives. These relatives were followed for clinical signs or symptoms indicative of CCHF disease, blood samples of those with and without clinical signs were analyzed for CCHF virus immunoglobulin M and G (IgM and IgG, respectively) by enzyme-linked immunosorbent assay. No close relatives developed any signs or symptoms of CCHF and were negative for CCHF virus IgM and IgG. The results suggest that CCHF virus is not easily transmitted from person to person through respiratory or physical contact. PMID- 24166038 TI - Spatial analysis of Crimean Congo hemorrhagic fever in Iran. AB - Crimean Congo hemorrhagic fever (CCHF) is a viral zoonotic disease. During 1999 2011, 871 human cases of CCHF were diagnosed in Iran. A history of serologic conversion for CCHF virus was seen in 58.7% of 2,447 sheep samples, 25.0% of 1,091 cattle samples and 24.8% of 987 goat samples from different parts of Iran. Spatial analysis showed that the main foci of this disease in humans during these years were in eastern Iran (P < 0.01) and the second most common foci were in northeastern and central Iran. Two livestock foci were detected in the northeastern northwestern Iran. On the basis of the results of this study, infection likely entered Iran from eastern and western neighboring countries. PMID- 24166039 TI - Contributions of non-governmental organizations to WHO targets for control of soil-transmitted helminthiases. AB - Soil-transmitted helminthiases (STH) may affect up to 1 billion children globally. The World Health Organization (WHO) recommends regular preventive chemotherapy for at-risk individuals. The WHO Preventive Chemotherapy (PCT) Databank tracks annual treatments reported by national Ministries of Health (MOHs) to evaluate progress to coverage goals. Non-governmental organizations (NGOs) deliver STH treatments; the extent to which they are included in MOH reports to the WHO is unclear. The Global NGO Deworming Inventory solicited treatment reports from NGOs to compare with the PCT Databank. In 2010, NGOs delivered 65.4 million STH treatments, which is an estimated 25.1% of the total delivered. Of these treatments, 23.3 million (35.6%) were not reported to the WHO; 22.3 million (95.7%) were from countries that had not submitted STH treatment reports to the WHO. Reporting from NGOs to MOHs and from MOHs to the WHO should be strengthened to ensure that progress to WHO treatment goals is monitored with better completeness and assessed accurately. PMID- 24166040 TI - A confirmed case of Rickettsia parkeri infection in a traveler from Uruguay. AB - The first confirmed case of Rickettsia parkeri infection in Uruguay is reported. To date, in South America, molecularly confirmed cases of human infection have been found in Argentina and probably, Brazil. Our patient returned to Spain after a 7-day trip to Colonia Suiza (Southwestern Uruguay). He presented fever (39 degrees C), chills, and two eschars (tache noire-like) surrounded by an indurated, erythematous halo on the inner side of the left ankle besides a maculopapular rash on the legs. After treatment with doxycycline for 7 days, he fully recovered. R. parkeri infection was diagnosed by molecular-based detection of the microorganism in a swab specimen of the eschar. Diagnosis was supported by seroconversion between acute- and convalescent-phase sera specimens. PMID- 24166041 TI - Throat swab samples for diagnosis of Q fever. AB - Oropharyngeal swabs collected from patients with Q fever from France and from febrile patients from Senegal were tested by molecular assays for Coxiella burnetii. One positive result (0.08%) occurred for only one patient with acute Q fever. Throat swabs cannot replace blood serum samples as diagnostic tools for Q fever. PMID- 24166042 TI - Clinical manifestations and risk factors of amebic liver abscess in Southeast Taiwan compared with other regions of Taiwan. AB - Amebic liver abscess (ALA) had previously been endemic in Taiwan, particularly in the southern region, although its occurrence in the southeastern area was unknown. Thus, we conducted a retrospective study for southeastern Taiwan. We identified 14 patients who were diagnosed with ALA between July of 1995 and July of 2008. These patients were predominantly male and older in age. Most patients lived in rural areas (85.7%). Alcoholism (78.6%) and diabetes (35.7%) were risk factors for ALA. No human immunodeficiency virus (HIV) infections were detected. The most common clinical symptoms were fever (100%) and abdominal pain (100%). Short mean durations of symptoms, high bilirubin levels, and low albumin levels were also noted. Most patients (92.86%) had a single lesion, particularly in the right liver lobe (71.4%). Six patients also had secondary Klebsiella pneumoniae bacterial infections. Clinicians should be aware of the different risk factors in different regions when diagnosing amebic liver abscess in Taiwan. PMID- 24166043 TI - Group 1 Vaccinia virus zoonotic outbreak in Maranhao State, Brazil. AB - In Brazil, several exanthematic autochthone Vaccinia virus (VACV) outbreaks affecting dairy cattle and rural workers have been reported since 1999. Although outbreaks had been first described in the Brazilian Southeast, VACV outbreaks were notified in all Brazilian regions in < 10 years. However, in this context, VACV outbreaks had not been described in some Brazilian States, likely because of a lack of notification, or yet unknown epidemiological reasons. Here, we describe the first VACV outbreak in Maranhao State, northeastern Brazil. The virus isolated from this outbreak showed several biological and molecular features that resemble other Group 1 Brazilian VACV, including a deletion signature in the A56R gene. This study raises new questions about diversity and epidemiology of Brazilian VACV. PMID- 24166044 TI - Intestinal parasite co-infection among pulmonary tuberculosis cases without human immunodeficiency virus infection in a rural county in China. AB - Epidemiologic studies of co-infection with tuberculosis (TB) and intestinal parasites in humans have not been extensively investigated in China. A cross section study was conducted in a rural county of Henan Province, China. Pulmonary TB (PTB) case-patients receiving treatment for infection with Mycobacterium tuberculosis and healthy controls matched for geographic area, age, and sex were surveyed by using questionnaires. Fecal and blood specimens were collected for detection of intestinal parasites, routine blood examination, and infection with human immunodeficiency virus. The chi-square test was used for univariate analysis and multivariate logistic regression models were used to adjust for potential confounding factors. A total of 369 persons with PTB and 366 healthy controls were included; all participants were negative for human immunodeficiency virus. The overall prevalence of intestinal parasites in persons with PTB was 14.9%, including intestinal protozoa (7.9%) and helminthes (7.6%). The infection spectrum of intestinal parasites was Entamoeba spp. (1.4%), Blastocystis hominis (6.2%), Trichomonas hominis (0.3%), Clonorchis sinensis (0.3%), Ascaris lumbricoides (0.5%), Trichuris trichiura (2.2%), and hookworm (4.6%). The prevalence of intestinal parasites showed no significant difference between persons with PTB and healthy controls after adjusting for potential confounding factors. There was no factor that affected infection rates for intestinal parasites between the two groups. Infection with intestinal parasites of persons with PTB was associated with female sex (adjusted odds ratio [AOR] = 2.05, 95% confidence interval [CI] = 1.01-4.17), body mass index <= 19 (AOR = 3.02, 95% CI = 1.47-6.20), and anemia (AOR = 2.43, 95% CI = 1.17-5.03). Infection of healthy controls was only associated with an annual labor time in farmlands > 2 months (AOR = 4.50, 95% CI = 2.03-10.00). In addition, there was no significant trend between rates of infection with intestinal parasites and duration of receiving treatment for infection with M. tuberculosis in persons with PTB. The prevalence of intestinal parasites was not higher in persons with PTB, and there was no evidence that PTB increased susceptibility to intestinal parasites in this study. However, for patients with PTB, women and patients with comorbidities were more likely to be infected with intestinal parasites. PMID- 24166045 TI - Intervention to promote patients' adherence to antimalarial medication: a systematic review. AB - Non-adherence as a major contributor to poor treatment outcomes. This study aimed to explore the effectiveness of existing interventions promoting adherence to antimalarial drugs by systematic review. The following databases were used to identify potential articles: MEDLINE, EMBASE, the Cochrane CENTRAL, and CINAHL (through March 2013). From 1,813 potential papers identified, 16 studies met the selection criteria comprising 9,247 patients. Interventions were classified as packaging aids, visual media, combined visual media and verbal information, community education, medication supervision, and convenient regimen. These interventions were shown to increase adherence to antimalarial drugs (median relative risk = 1.4, interquartile range 1.2-2.0). Although a most effective intervention did not emerge, community education and visual media/verbal information combinations may well have most potential to improve adherence to antimalarial medication. These interventions should be implemented in combination to optimize their beneficial effects. The current understanding on improved adherence would facilitate to contain outbreaks of malaria cost effectively. PMID- 24166047 TI - Environmental specimen banks as a resource for mercury and mercury isotope research in marine ecosystems. AB - Environmental specimen banks (ESBs) have been a fundamental tool for many nations to monitor contaminant temporal and spatial trends, study fate and transport, and assess the severity and risks of pollution. The specimens archived in ESBs are among the longest time-series, most geographically robust, and highest integrity samples available for performing environmental research. Mercury (Hg) remains one of the world's most ubiquitous environmental contaminants, and ESBs have played a prominent role in Hg research. Historically this has involved measuring concentrations of Hg species in various environmental matrices, but the emerging field of Hg stable isotope research provides a new analytical approach that can augment these traditional techniques. Signatures of Hg isotope fractionation have been effectively used for source apportionment and for elucidating Hg biogeochemical cycling. As the research surrounding Hg stable isotopes continues to mature, ESBs can play a useful role in analytical quality control, provide a robust and economical sample archive to expand and diversify the inventory of Hg isotope measurements, and be used to develop and test hypotheses to evaluate whether broadly prevailing paradigms are supported. Samples archived in ESBs are available for request by external collaborators in order to perform high impact research, and should be utilized more effectively to address emerging global environmental concerns. PMID- 24166046 TI - Detection of Leptospira-specific antibodies using a recombinant antigen-based enzyme-linked immunosorbent assay. AB - We produced three highly purified recombinant antigens rLipL32, rLipL41, and rLigA-Rep (leptospiral immunoglobulin-like A repeat region) for the detection of Leptospira-specific antibodies in an enzyme-linked immunosorbent assay (ELISA). The performance of these recombinant antigens was evaluated using 121 human sera. Among them, 63 sera were microscopic agglutination test (MAT)-confirmed positive sera from febrile patients in Peru, 22 sera were indigenous MAT-negative febrile patient sera, and 36 sera were from patients with other febrile diseases from Southeast Asia, where leptospirosis is also endemic. Combining the results of immunoglobulin M (IgM) and IgG detection from these three antigens, the overall sensitivity is close to 90% based on the MAT. These results suggest that an ELISA using multiple recombinant antigens may be used as an alternative method for the detection of Leptospira-specific antibodies. PMID- 24166048 TI - Advancing cancer care: the quality spiral: Sir Thomas Myles Lecture. AB - HYPOTHESIS: Good patient care, research and education should be so inextricably linked that each should drive the other towards improvements in quality of care, innovation and discovery. DISCUSSION: Each element of good clinical cancer care, including specialisation, multidisciplinary management, audit and systematic organisation, provides a powerful stimulus to research. The qualities required for good research inevitably enhance educational activity. High quality in education and training are essential in improving cancer care. Obstacles to good medical care are identified and the importance of supporting doctors is emphasised. The question of permanent staff-grade medical appointments or the grade of physician assistants is raised. Challenges to university-based and hospital-based research are outlined. Attention is drawn to issues concerning the training of cancer specialists, particularly in surgical oncology. CONCLUSION: Good patient care stimulates research, research drives educational activity and education improves care. Interaction of these elements of medicine and science constitutes an interdependent upward spiral towards excellence. PMID- 24166049 TI - A treatment for large defects of the tibia caused by infected nonunion: Ilizarov method with bone segment extension. AB - OBJECTIVES: To investigate the efficacy of the Ilizarov technique with bone segment extension in tibial infected nonunion. METHODS: From September 2003 to June 2011, we treated 30 patients (21 males, 9 females; age 19-49 years, mean 34.1 years) for tibial infected nonunion with bone defects. Eleven cases were compound fractures internally fixed with steel plates, nine were compound fractures internally fixed with IM Nails, eight were compound fractures externally fixed with external fixation devices, and two were closed fractures internally fixed with steel plates. All 30 patients underwent debridement followed by the Ilizarov technique using bone segment extension. RESULTS: After follow-up of 12 months-6 years (mean 29 months), stable union of fracture was achieved in all 30 patients. The time from bone fracture to union was 6-24 months, mean 8.8 months; external fixation was in place for 8-14 months, mean 10 months. External fixation index was 41 days/cm. Complications were three cases of pin site infection, one skin allergy, two fractures malunion, one early mineralization and one wire breakage. There were no cases of deep infection, nonunion or stiffness of the knee joint. According to the Paley fracture healing score criteria, 30 cases had excellent outcomes and two were good. CONCLUSIONS: The Ilizarov technique with bone segment extension is effective in treating tibial infected nonunion with large bone defects. PMID- 24166050 TI - V-ATPase inhibition by archazolid leads to lysosomal dysfunction resulting in impaired cathepsin B activation in vivo. AB - The myxobacterial agent archazolid inhibits the vacuolar proton pump V-ATPase. V ATPases are ubiquitously expressed ATP-dependent proton pumps, which are known to regulate the pH in endomembrane systems and thus play a crucial role in endo- and exocytotic processes of the cell. As cancer cells depend on a highly active secretion of proteolytic proteins in order to invade tissue and form metastases, inhibition of V-ATPase is proposed to affect the secretion profile of cancer cells and thus potentially abrogate their metastatic properties. Archazolid is a novel V-ATPase inhibitor. Here, we show that the secretion pattern of archazolid treated cancer cells includes various prometastatic lysosomal proteins like cathepsin A, B, C, D and Z. In particular, archazolid induced the secretion of the proforms of cathepsin B and D. Archazolid treatment abrogates the cathepsin B maturation process leading to reduced intracellular mature cathepsin B protein abundance and finally decreased cathepsin B activity, by inhibiting mannose-6 phoshate receptor-dependent trafficking. Importantly, in vivo reduced cathepsin B protein as well as a decreased proteolytic cathepsin B activity was detected in tumor tissue of archazolid-treated mice. Our results show that inhibition of V ATPase by archazolid reduces the activity of prometastatic proteases like cathepsin B in vitro and in vivo. PMID- 24166052 TI - Maternal and breast pump factors associated with breast pump problems and injuries. AB - BACKGROUND: Benefits of using a breast pump are well documented, but pump-related problems and injuries and the associated risk factors have not been reported. OBJECTIVES: This study aimed to describe breast pump-related problems and injuries and identify factors associated with these problems and injuries. METHODS: Data were from the Infant Feeding Practices Study II; mothers were recruited from a nationally distributed consumer opinion panel. Mothers were asked about breast pump use, problems, and injuries at infant ages 2, 5, and 7 months. Survival analysis was used to identify factors associated with pump related problems and injuries. RESULTS: The sample included 1844 mothers. About 62% and 15% of mothers reported pump-related problems and injuries, respectively. The most commonly reported problem was that the pump did not extract enough milk and the most commonly reported injury was sore nipples. Using a battery-operated pump and intending to breastfeed less than 12 months were associated with higher risks of pump-related problems and injury. Learning from a friend to use the pump was associated with lower risk of pump-related problems, and using a manual pump and renting a pump were associated with a higher risk of problems. CONCLUSION: Our results suggest that problems and injuries associated with breast pump use can happen to mothers of all socioeconomic characteristics. Breastfeeding mothers may reduce their risks of problems and injury by not using battery-operated pumps and may reduce breast pump problems by not using manual pumps and by learning breast pump skills from a person rather than following written or video instructions. PMID- 24166053 TI - Donor human milk bank data collection in north america: an assessment of current status and future needs. AB - BACKGROUND: The Human Milk Banking Association of North America (HMBANA) is a nonprofit association that standardizes and facilitates the establishment and operation of donor human milk (DHM) banks in North America. Each HMBANA milk bank in the network collects data on the DHM it receives and distributes, but a centralized data repository does not yet exist. In 2010, the Food and Drug Administration recognized the need to collect and disseminate systematic, standardized DHM bank data and suggested that HMBANA develop a DHM data repository. OBJECTIVES: This study aimed to describe data currently collected by HMBANA DHM banks and evaluate feasibility and interest in participating in a centralized data repository. METHODS: We conducted phone interviews with individuals in different HMBANA milk banks and summarized descriptive statistics. RESULTS: Eight of 13 (61.5%) sites consented to participate. All respondents collected donor demographics, and half (50%; n = 4) rescreened donors after 6 months of continued donation. The definition of preterm milk varied between DHM banks (<= 32 to <= 40 weeks). The specific computer program used to house the data also differed. Half (50%; n = 4) indicated that they would consider participation in a centralized repository. CONCLUSIONS: Without standardized data across all HMBANA sites, the creation of a centralized data repository is not yet feasible. Lack of standardization and transparency may deter implementation of donor milk programs in the neonatal intensive care unit setting and hinder benchmarking, research, and quality improvement initiatives. PMID- 24166051 TI - Low 25(OH) vitamin D3 levels are associated with adverse outcome in newly diagnosed, intensively treated adult acute myeloid leukemia. AB - BACKGROUND: Several studies have suggested that low 25(OH) vitamin D3 levels may be prognostic in some malignancies, but no studies have evaluated their impact on treatment outcome in patients with acute myeloid leukemia (AML). METHODS: Vitamin D levels were evaluated in 97 consecutive, newly diagnosed, intensively treated patients with AML. MicroRNA expression profiles and single nucleotide polymorphisms (SNPs) in the 25(OH) vitamin D3 pathway genes were evaluated and correlated with 25(OH) vitamin D3 levels and treatment outcome. RESULTS: Thirty four patients (35%) had normal 25(OH) vitamin D3 levels (32-100 ng/mL), 34 patients (35%) had insufficient levels (20-31.9 ng/mL), and 29 patients (30%) had deficient levels (<20 ng/mL). Insufficient/deficient 25(OH) vitamin D3 levels were associated with worse relapse-free survival (RFS) compared with normal vitamin D3 levels. In multivariate analyses, deficient 25(OH) vitamin D3 , smoking, European Leukemia Network genetic group, and white blood cell count retained their statistical significance for RFS. Several microRNAs and SNPs were associated with 25(OH) vitamin D3 levels, although none remained significant after multiple test corrections; one 25(OH) vitamin D3 receptor SNP, rs10783219, was associated with a lower complete remission rate (P = .0442) and with shorter RFS (P = .0058) and overall survival (P = .0011). CONCLUSIONS: It remains to be determined what role microRNA and SNP profiles play in contributing to low 25(OH) vitamin D3 level and/or outcome and whether supplementation will improve outcomes for patients with AML. PMID- 24166054 TI - Sonographic classification of draining pathways of obstructed hepatic veins in Budd-Chiari syndrome. AB - PURPOSE: To describe and propose a sonographic classification of the blood draining pathways of obstructed hepatic veins in Budd-Chiari syndrome. METHODS: This retrospective study included 206 patients with hepatic vein obstructions who underwent sonographic examination. We evaluated the afflicted hepatic veins, as well as the course, orifice, blood flow direction of draining veins, and communicating branches. Results were classified and compared with digital subtraction angiography and computed tomography angiography. RESULTS: Of 618 hepatic veins in 206 patients, 542 were obstructed. The blood-draining pathways were classified as hepatic vein-accessory hepatic vein (131/206), hepatic vein hepatic vein/accessory hepatic+hepatic vein (49/206), and, less frequently, collateral pathways (26/206). Blood was drained from obstructed hepatic veins to the inferior vena cava, right atrium, para-umbilical veins, or hepatic subcapsular veins through communicating branches of various number and diameters. Doppler signals were obtained from the draining veins. CONCLUSIONS: Sonography provides accurate information regarding the blood-draining pathways of obstructed hepatic veins in Budd-Chiari syndrome, which may be helpful for treatment and follow-up. PMID- 24166055 TI - Effect of extraction solvents and plant parts used on the antihyperlipidemic and antioxidant effects of Garcinia atroviridis: a comparative study. AB - BACKGROUND: Garcinia atroviridis is a seasonal fruit plant found in many parts of South East Asia. The fruit rind is used in cooking and traditionally consumed for various reasons, including to lower blood cholesterol. A comparative study was undertaken to investigate the influence of extraction solvents and plant parts used on the lipid-lowering and antioxidant activities of Garcinia atroviridis. RESULTS: Aqueous extracts showed better antihyperlipidemic activity than the methanol extracts. Aqueous extract of ripe fruit showed the most potent antihyperlipidemic activity, comparable to that of atorvastatin. It significantly reduced the total cholesterol (P < 0.05), triglycerides (P < 0.01), low-density lipoprotein (P < 0.01), very-low-density lipoprotein (P < 0.01) and atherogenic index (P < 0.01). In contrast, antioxidant activities of methanol extracts of all parts of G. atroviridis were higher than their respective aqueous extracts, whereby the stem and leaves extracts showed better antioxidant activities than the fruits. CONCLUSION: Aqueous and methanol extracts of G. atroviridis showed higher antihyperlipidemic and antioxidant effects, respectively. Total phenolic and flavonoid contents showed significant correlations with antioxidant but not with antihyperlipidemic activities, indicating the involvement of other compounds. Contrary to the traditional belief, the present findings suggest that the fruit has higher antihyperlipidemic potential than the fruit rind. PMID- 24166057 TI - [Rational medical therapy for tumors]. PMID- 24166056 TI - [New therapy concepts for castration-resistant prostate cancer: between hormone manipulation, targeted therapy and chemotherapy]. AB - Within the last 2 years the therapeutic landscape of castration-resistant prostate cancer (CRPC) has dramatically changed. While chemotherapy with docetaxel has only shown a survival benefit in CRPC patients in the last 10 years, in the meantime 4 approved drugs are available for this indication and approval for immunotherapy with sipuleucel-T is expected. Docetaxel still plays a significant role in the treatment of CRPC but is also a cesura in the therapeutic sequence. For asymptomatic or minimally symptomatic, chemotherapy naive CRPC patients a significant survival benefit was shown for treatment with the androgen biosynthesis inhibitor abiraterone. Clinical data for the antiandrogen enzalutamide are expected shortly for this indication. For patients where docetaxel has failed abiraterone, enzalutamide and cabazitaxel have shown survival benefits in phase III trials. The radionuclide alpharadin not only palliated morbidity induced by bone metastases but also prolonged survival of CRPC patients. This review deals with the various drugs with respect to mode of action, clinical results and indications and will focus on new treatment options, such as targeted therapy with cabozantinib or immunotherapy with sipuleucel-T and prostvac. PMID- 24166058 TI - [On the occasion of Prof. Dr. med. Dr. h.c. Jurgen B. Sokeland's 80th birthday]. PMID- 24166059 TI - [Stem cell therapy and tissue engineering in regenerative urology]. AB - BACKGROUND: So far there is no clinically established, effective tissue engineering therapy for dysfunction or defects of the lower urinary tract. The concentration of experimental data, initial clinical studies and individual case reports underlines that stem cell treatment for bladder storage and voiding problems, erectile dysfunction and other urothelial defects of the lower urinary tract could close the gap between individualized therapy and potential biomedical applications. RESULTS: As a result of fundamental research work over the last decade a characterization of various stem cell populations and evaluation of different urological therapy options could be performed. Thereby, aspects of optimal administration, migration, secretion of bioactive factors and stage of differentiation of stem cells with respect to an improved efficiency of treatment were investigated. Because successful tissue regeneration depends on angiogenesis and innervation, particular attention was paid to these important factors. CONCLUSIONS: Various clinical indications for stem cell treatment and tissue reconstruction that may be required after radical prostatectomy, such as stress urinary incontinence, urethral reconstruction and erectile dysfunction have materialized and are currently being verified in preclinical studies and phase I trials. PMID- 24166060 TI - Understanding the linked kinetics of benzo(a)pyrene and 3-hydroxybenzo(a)pyrene biomarker of exposure using physiologically-based pharmacokinetic modelling in rats. AB - 3-hydroxybenzo(a)pyrene (3-OHBaP) in urine has been proposed as a biomarker of occupational exposure to polycyclic aromatic hydrocarbons. However, to reconstruct exposure doses in workers from biomarker measurements, a thorough knowledge of the kinetics of the benzo(a)pyrene (BaP) and 3-OHBaP given different routes of exposure is needed. A rat physiologically-based pharmacokinetic model of BaP and 3-OHBaP was built. Organs (tissues) represented as compartments were based on in vivo experimental data in rats. Tissue: blood partition coefficients, permeability coefficients, metabolism rates, excretion parameters, and absorption fractions and rates for different routes-of-entry were obtained directly from published in vivo time courses of BaP and 3-OHBaP in blood, various tissues and excreta of rats. The latter parameter values were best-fitted by least square procedures and Monte Carlo simulations. Sensitivity analyses were then carried out to ensure the stability of the model and the key parameters driving the overall modeled kinetics. This modeling pointed out critical determinants of the kinetics: (1) hepatic metabolism of BaP and 3-OHBaP elimination rate as the most sensitive parameters; (2) the strong partition of BaP in lungs compared to other tissues, followed by adipose tissues and liver; (3) the strong partition of 3 OHBaP in kidneys; (4) diffusion-limited tissue transfers of BaP in lungs and 3 OHBaP in lungs, adipose tissues and kidneys; (5) significant entero-hepatic recycling of 3-OHBaP. Very good fits to various sets of experimental data in rats from four different routes-of-entry (intravenous, oral, dermal and inhalation) were obtained with the model. PMID- 24166061 TI - Neuronal cell differentiation of mesenchymal stem cells originating from canine amniotic fluid. AB - The amniotic fluid contains mesenchymal stem cells (MSCs) and can be readily available for tissue engineering. Regenerative treatments such as tissue engineering, cell therapy, and transplantation show potential in clinical trials of degenerative diseases. Disease presentation and clinical responses in the Canis familiaris not only are physiologically similar to human compared with other traditional mammalian models but is also a suitable model for human diseases. The aim of this study was to investigate whether canine amniotic-fluid derived mesenchymal stem cells (cAF-MSCs) can differentiate into neural precursor cells in vitro when exposed to neural induction reagent. During neural differentiation, cAF-MSCs progressively acquire neuron-like morphology. Messenger RNA (mRNA) expression levels of neural-specific genes, such as NEFL, NSE, and TUBB3 (betaIII-tubulin) dramatically increased in the differentiated cAF-MSCs after induction. In addition, protein expression levels of nestin, betaIII tubulin, and tyrosine hydroxylase remarkably increased in differentiated cAF MSCs. This study demonstrates that cAF-MSCs have great potential for neural precursor differentiation in vitro. Therefore, amniotic fluid may be a suitable alternative source of stem cells and can be applied to cell therapy in neurodegenerative diseases. PMID- 24166062 TI - Environmental structure and competitive scoring advantages in team competitions. AB - In most professional sports, playing field structure is kept neutral so that scoring imbalances may be attributed to differences in team skill. It thus remains unknown what impact environmental heterogeneities can have on scoring dynamics or competitive advantages. Applying a novel generative model of scoring dynamics to roughly 10 million team competitions drawn from an online game, we quantify the relationship between the structure within a competition and its scoring dynamics, while controlling the impact of chance. Despite wide structural variations, we observe a common three-phase pattern in the tempo of events. Tempo and balance are highly predictable from a competition's structural features alone and teams exploit environmental heterogeneities for sustained competitive advantage. Surprisingly, the most balanced competitions are associated with specific environmental heterogeneities, not from equally skilled teams. These results shed new light on the design principles of balanced competition, and illustrate the potential of online game data for investigating social dynamics and competition. PMID- 24166063 TI - Whole-body protein turnover response to short-term high-protein diets during weight loss: a randomized controlled trial. AB - To determine whole-body protein turnover responses to high-protein diets during weight loss, 39 adults (age, 21+/-1 years; VO2peak, 48+/-1 ml kg(-1) min(-1); body mass index, 25+/-1 kg m(2)) were randomized to diets providing protein at the recommend dietary allowance (RDA), 2 * -RDA or 3 * -RDA. A 10-day weight maintenance period preceded a 21-day, 40% energy deficit. Postabsorptive (FASTED) and postprandial (FED) whole-body protein turnover was determined during weight maintenance (day 10) and energy deficit (day 31) using [1-(13)C]leucine. FASTED flux, synthesis and breakdown were lower (P<0.05) for energy deficit than weight maintenance. Protein flux and synthesis were higher (P<0.05) for FED than FASTED. Feeding attenuated (P<0.05) breakdown during weight maintenance but not energy deficit. Oxidation increased (P<0.05) between dietary protein levels and feeding stimulated oxidation, although oxidative responses to feeding were higher (P<0.05) for energy deficit than weight maintenance. FASTED net balance decreased between dietary protein levels, but in the FED state, net balance was lower for 3 * -RDA as compared with RDA and 2 * -RDA (diet-by-state, P<0.05). Consuming dietary protein at levels above the RDA, particularly 3 * -RDA, during short-term weight loss increases protein oxidation with concomitant reductions in net protein balance. PMID- 24166064 TI - Neuropsychological assessment as a predictor of weight loss in obese adolescents. AB - BACKGROUND: Obese individuals are known to be more impulsive than their normal weight counterparts. Impulsivity has been postulated to be a predictor of weight loss. DESIGN: A pre-post study was designed to determine for the first time whether impulsivity changed with weight loss during a lifestyle and physical activity intervention programme lasting 2-8 weeks. SUBJECTS: Fifty-three obese adolescents with a body mass index (BMI) of 33.75 +/- 7.9 attending a residential camp were tested and compared at baseline with 50 non-obese adolescents with a mean BMI of 20.6 +/- 2.3. MEASUREMENTS: Inhibitory control was measured with the CANTAB (Cambridge Cognition, Cambridge, UK) Stop Signal Task. MATLAB (The Mathswork Inc., Natick, MA, USA) was used to measure the temporal discounting constant. RESULTS: The obese group was more impulsive than the normal weight adolescents. BMI reduced significantly from 33.76 kg m(-2) to 30.93 kg m(-2) after completing camp. The stop signal reaction time (SSRT) decreased from 225.38 +/- 94.22 to 173.76 +/- 107.05 ms (n=47, P=0.0001). A reduction in inhibitory control during camp was predictive of those who showed the greatest reduction in BMI (Wilks' Lambda=0.9, F(1,50)=4.85, P=0.034). The number of weeks in camp (Wilks' Lambda=0.83, F(1,50)=9.826, P=0.003) and the age of the adolescents (Wilks' Lambda=0.87, F(1,50)=5.98, P=0.02) were significantly associated with a reduction in inhibitory control as measured by the SSRT. A longer stay in camp was associated with a greater reduction in SSRT (B=25.45, t=2.02, P=0.05). Increasing age had a significant moderating role in the reduction of inhibitory control (B=-0.3, t=-0.034, P=0.05). Temporal discounting for monetary reward also fell significantly during camp. CONCLUSION: This study highlights the potential to identify those who are obese by using an easy-to-measure psychometric test. Furthermore, it is the first study to report a reduction in impulsivity and an improvement in well-being as part of a government-approved residential camp for obese adolescents. The potential mechanisms for change in impulsivity with weight are discussed. PMID- 24166065 TI - Improved acylated ghrelin suppression at 2 years in obese patients with type 2 diabetes: effects of bariatric surgery vs standard medical therapy. AB - OBJECTIVE: Roux-en-Y gastric bypass (RYGB) produces more durable glycemic control than sleeve gastrectomy (SG) or intensive medical therapy (IMT). However, the contribution of acylated ghrelin (AG), a gluco-regulatory/appetite hormone, to improve glucose metabolism and body composition in patients with type 2 diabetes (T2D) following RYGB is unknown. DESIGN: STAMPEDE (Surgical Treatment and Medication Potentially Eradicate Diabetes Efficiently) was a prospective, randomized controlled trial. SUBJECTS: Fifty-three (body mass index: 36+/-3 kg m( 2), age: 49+/-9 years) poorly controlled patients with T2D (HbA1c (glycated hemoglobin): 9.7+/-2%) were randomized to IMT, IMT+RYGB or IMT+SG and underwent a mixed-meal tolerance test at baseline, 12, and 24 months for evaluation of AG suppression (postprandial minus fasting) and beta-cell function (oral disposition index; glucose-stimulated insulin secretion * Matsuda index). Total/android body fat (dual-energy X-ray absorptiometry) was also assessed. RESULTS: RYGB and SG reduced body fat comparably (15-23 kg) at 12 and 24 months, whereas IMT had no effect. Beta-cell function increased 5.8-fold in RYGB and was greater than IMT at 24 months (P<0.001). However, there was no difference in insulin secretion between SG vs IMT at 24 months (P=0.32). Fasting AG was reduced fourfold following SG (P<0.01) and did not change with RYGB or IMT at 24 months. AG suppression improved more following RYGB than SG or IMT at 24 months (P=0.01 vs SG, P=0.07 vs IMT). At 24 months, AG suppression was associated with increased postprandial glucagon-like peptide-1 (r=-0.32, P<0.02) and decreased android fat (r=0.38; P<0.006). CONCLUSIONS: Enhanced AG suppression persists for up to 2 years after RYGB, and this effect is associated with decreased android obesity and improved insulin secretion. Together, these findings suggest that AG suppression is partly responsible for the improved glucose control after RYGB surgery. PMID- 24166066 TI - Validating measures of free-living physical activity in overweight and obese subjects using an accelerometer. AB - BACKGROUND: Free-living physical activity can be assessed with an accelerometer to estimate energy expenditure but its validity in overweight and obese subjects remains unknown. OBJECTIVE: Here, we validated published prediction equations derived in a lean population with the TracmorD accelerometer (DirectLife, Philips Consumer Lifestyle) in a population of overweight and obese. We also explored possible improvements of new equations specifically developed in overweight and obese subjects. DESIGN: Subjects were 11 men and 25 women (age: 41+/-7 years; body mass index: 31.0+/-2.5 kg m(-2)). Physical activity was monitored under free living conditions with TracmorD, whereas total energy expenditure was measured simultaneously with doubly-labeled water. Physical activity level (PAL) and activity energy expenditure (AEE) were calculated from total energy expenditure and sleeping metabolic rate. RESULTS: The published prediction equation explained 47% of the variance of the measured PAL (P<0.001). PAL estimates were unbiased (errors (bias+/-95% confidence interval): -0.02+/-0.28). Measured and predicted AEE/body weight were highly correlated (r(2)=58%, P<0.001); however, the prediction model showed a significant bias of 8 kJ kg(-1) per day or 17.4% of the average AEE/body weight. The new prediction equation of AEE/body weight developed in the obese group showed no bias. CONCLUSIONS: In conclusion, equations derived with the TracmorD allow valid assessment of PAL and AEE/body weight in overweight and obese subjects. There is evidence that estimates of AEE/body weight could be affected by gender. Equations specifically developed in overweight and obese can improve the accuracy of predictions of AEE/body weight. PMID- 24166067 TI - Regulation of human subcutaneous adipose tissue blood flow. AB - Subcutaneous adipose tissue represents about 85% of all body fat. Its major metabolic role is the regulated storage and mobilization of lipid energy. It stores lipid in the form of triacylglycerol (TG), which is mobilized, as required for use by other tissues, in the form of non-esterified fatty acids (NEFA). Neither TG nor NEFA are soluble to any extent in water, and their transport to and out of the tissue requires specialized transport mechanisms and adequate blood flow. Subcutaneous adipose tissue blood flow (ATBF) is therefore tightly linked to the tissue's metabolic functioning. ATBF is relatively high (in the fasting state, similar to that of resting skeletal muscle, when expressed per 100 g tissue) and changes markedly in different physiological states. Those most studied are after ingestion of a meal, when there is normally a marked rise in ATBF, and exercise, when ATBF also increases. Pharmacological studies have helped to define the physiological regulation of ATBF. Adrenergic influences predominate in most situations, but nevertheless the regulation of ATBF is complex and depends on the interplay of many different systems. ATBF is downregulated in obesity (when expressed per 100 g tissue), and its responsiveness to meal intake is reduced. However, there is little evidence that this leads to adipose tissue hypoxia in human obesity, and we suggest that, like the downregulation of catecholamine-stimulated lipolysis seen in obesity, the reduction in ATBF represents an adaptation to the increased fat mass. Most information on ATBF has been obtained from studying the subcutaneous abdominal fat depot, but more limited information on lower-body fat depots suggests some similarities, but also some differences: in particular, marked alpha-adrenergic tone, which can reduce the femoral ATBF response to adrenergic stimuli. PMID- 24166068 TI - Weight loss surgery improves the metabolic status in an obese rat model but does not affect bladder fibrosis associated with high fat diet feeding. AB - BACKGROUND: Bladder dysfunction has one of the highest prevalences as a comorbidity of obesity in industrialized countries. The aetiopathogenesis of obesity-associated bladder dysfunction is still obscure, but there is growing evidence that general metabolic changes in obese patients may be in part responsible. As demonstrated recently, high fat diet (HFD) significantly alters the protein expression in the urinary bladder, activates multiple signalling pathways associated with cell survival and inflammation and ultimately provokes bladder fibrosis in an obese rat model. The study aimed to elucidate the role of matrix metalloproteases (MMPs) and their specific tissue inhibitors of metalloproteases (TIMPs) in obesity-related bladder extracellular matrix (ECM) remodelling and the effect of weight loss surgery via sleeve gastrectomy (SG) on phenotype and molecular parameters. METHODS: Twenty-four male Sprague-Dawley rats were used for (i) characterization of the HFD phenotype and (ii) evaluation of alterations following SG. Metabolic status, the degree of bladder fibrosis and tissue expression and activity of MMP2, MMP9, MMP14, TIMP1 and TIMP2 were analysed by immunohistochemistry, enzyme-linked immunosorbent assay and activity assays. Statistical differences were calculated by analysis of variance or independent Student's t-test. A P-value <0.05 was considered statistically significant. RESULTS: In HFD rats, we found significant alterations in lipid metabolism, fat mass, free fatty acid profile, insulin resistance and inflammatory markers. Voided volume was significantly decreased, and bladder showed marked fibrosis. MMPs and TIMPs were differentially regulated depending on animal status (controls, chow diet, HFD, and SG- and sham-operated animals) in both urothelium and detrusor smooth muscle. Although animal weight and most metabolic parameters were positively affected by SG, bladder fibrosis persisted. The limitations of this study were 1 month follow-up and lack of direct measurement of bladder function. CONCLUSIONS: Early diagnosis of the bladder dysfunction associated with obesity is essential to allow targeted early intervention, that is, before manifestation of potentially irreversible ECM fibrotic alterations. PMID- 24166069 TI - Ileal transposition surgery produces ileal length-dependent changes in food intake, body weight, gut hormones and glucose metabolism in rats. AB - BACKGROUND: Enhanced stimulation of the lower gut is hypothesized to play a key role in the weight loss and resolution of diabetes following bariatric surgeries. Ileal transposition (IT) permits study of the effects of direct lower gut stimulation on body weight, glucose homeostasis and other metabolic adaptations without the confounds of gastric restriction or foregut exclusion. However, the underlying mechanisms and the length of the ileum sufficient to produce metabolic benefits following IT surgery remain largely unknown. OBJECTIVE: To determine the effects of transposing varying lengths of the ileum to upper jejunum on food intake, body weight, glucose tolerance and lower gut hormones, and the expression of key markers of glucose and lipid metabolism in skeletal muscle and adipose tissue in rats. METHODS: Adult male Sprague-Dawley rats (n=9/group) were subjected to IT surgery with translocation of 5, 10 or 20 cm of the ileal segment to proximal jejunum or sham manipulations. Daily food intake and body weight were recorded, and an intraperitoneal glucose tolerance test was performed. Blood samples were assayed for hormones and tissue samples for mRNA (RT-qPCR) and/or protein abundance (immunoblotting) of regulatory metabolic markers. RESULTS: We demonstrate that IT surgery exerts ileal length-dependent effects on multiple parameters including: (1) decreased food intake and weight gain, (2) improved glucose tolerance, (3) increased tissue expression and plasma concentrations of glucagon-like peptide-1 (GLP-1) and peptide YY (PYY), and decreased leptin concentrations and (4) upregulation of key markers of glucose metabolism (glucose transporter-4 (GLUT-4), insulin receptor substrate 1 (IRS-1), adenosine monophosphate-activated protein kinase (AMPK), hexokinase (HK) and phosphofructokinase (PFK)) together with a downregulation of lipogenic markers (fatty acid synthase (FAS)) in muscle and adipose tissue. CONCLUSIONS: Together, our data demonstrate that the reduction in food intake and weight gain, increase in lower gut hormones, glycemic improvements and associated changes in tissue metabolic markers following IT surgery are dependent on the length of the transposed ileum. PMID- 24166070 TI - The natural history of focal fibrocartilaginous dysplasia in the young child with tibia vara. AB - BACKGROUND: Focal fibrocartilaginous dysplasia is an uncommon disorder that affects young children causing unilateral deformity of the tibia. The lesion is seen in other similar conditions but this anomaly shows peculiar clinical characteristic. METHODS: Eleven young patients have been seen between the years 2002-2010 and followed up clinically and radiographically from 3 to 9 years. Family history, previous episode of trauma, infections, and bone disease in the children were not recountered. RESULTS: All cases were treated conservatively and self-corrected by the last follow-up. One case (9.09%) displayed a 4 degrees of varus, and one case (9.09%) displayed a 5 degrees of varus and one (9.09%) a slight leg length discrepancy. CONCLUSION: According to our results and those reported in the literature, focal fibrocartilaginous dysplasia is a benign affection that does not need treatment with a Levine and Drennan angle of <30 degrees . PMID- 24166071 TI - Geometry of the clavicle and reliability of measurement using PACS. AB - PURPOSE: To investigate the geometry of the clavicle and to assess the reliability of Picture Archiving Communication System (PACS) for its measurement. METHODS: One hundred pairs of dry clavicles from 78 males and 22 females were measured on radiographs using PACS. Measurements included all of the following parameters: length, width, medial and lateral angulation. The intraclass correlation coefficient (ICC) for the inter-observer and intra-observer reliability was calculated. RESULTS: The mean left clavicle length among males and females was 149.25 +/- 9.64 and 133.30 +/- 8.32 mm, respectively. The respective mean right clavicle length among the males and females was 147.77 +/- 9.99 and 132.08 +/- 6.92 mm. The clavicles from male cadavers were significantly longer, wider and thicker than those from females, on both the left and right (P < 0.05). Among both the male and female clavicles, the left side was significantly longer than the right (P < 0.05). There was good to excellent intra observer reliability (ICC > 0.70) for all parameters. Inter-observer reliability was also found good to excellent for all parameters except for medial clavicular angulation; for which there was fair reliability (ICC = 0.697). CONCLUSION: The geometry of the clavicle is influenced by sex and side. Use of PACS as a measurement tool is reliable. Data from this study will be useful for pre contouring plate or improving future designs of the anatomical plate of the clavicle. PMID- 24166072 TI - The subclavius posticus muscle: an unusual cause of thoracic outlet syndrome. AB - We present the case of a 30-year-old female, complaining of thoracic outlet compression symptoms caused by a supernumerary muscle, the subclavius posticus, accompanied by a caudally inserted middle scalenus muscle on the second rib. This rare anatomic variant was clearly shown on CT angiography and MRI images and surgical treatment was successful. As first described by Rosenmuller in 1800, subclavius posticus is a supernumerary muscle originating from the cranial surface of the sternal end of the first rib, running laterodorsally beneath the clavicle, and inserting into the superior border of the scapula. Its role in thoracic outlet syndrome has been seldom demonstrated in living patients nor described in imaging, although it is theoretically easily recognizable on modern imaging modalities. It should be taken into account during workout of patients with thoracic outlet syndrome, since it can be potentially treated. PMID- 24166073 TI - Association of a modified frailty index with mortality after femoral neck fracture in patients aged 60 years and older. AB - BACKGROUND: Frailty, a multidimensional syndrome entailing loss of energy, physical ability, cognition, and health, plays a significant role in elderly morbidity and mortality. No study has examined frailty in relation to mortality after femoral neck fractures in elderly patients. QUESTIONS/PURPOSES: We examined the association of a modified frailty index abbreviated from the Canadian Study of Health and Aging Frailty Index to 1- and 2-year mortality rates after a femoral neck fracture. Specifically we examined: (1) Is there an association of a modified frailty index with 1- and 2-year mortality rates in patients aged 60 years and older who sustain a low-energy femoral neck fracture? (2) Do the receiver operating characteristic (ROC) curves indicate that the modified frailty index can be a potential tool predictive of mortality and does a specific modified frailty index value demonstrate increased odds ratio for mortality? (3) Do any of the individual clinical deficits comprising the modified frailty index independently associate with mortality? METHODS: We retrospectively reviewed 697 low-energy femoral neck fractures in patients aged 60 years and older at our Level I trauma center from 2005 to 2009. A total of 218 (31%) patients with high energy or pathologic fracture, postoperative complication including infection or revision surgery, fracture of the contralateral hip, or missing documented mobility status were excluded. The remaining 481 patients, with a mean age of 81.2 years, were included. Mortality data were obtained from a state vital statistics department using date of birth and Social Security numbers. Statistical analysis included unequal variance t-test, Pearson correlation of age and frailty, ROC curves and area under the curve, Hosmer-Lemeshow statistics, and logistic regression models. RESULTS: One-year mortality analysis found the mean modified frailty index was higher in patients who died (4.6 +/- 1.8) than in those who lived (3.0 +/- 2; p < 0.001), which was maintained in a 2-year mortality analysis (4.4 +/- 1.8 versus 3.0 +/- 2; p < 0.001). In ROC analysis, the area under the curve was 0.74 and 0.72 for 1- and 2-year mortality, respectively. Patients with a modified frailty index of 4 or greater had an odds ratio of 4.97 for 1-year mortality and an odds ratio of 4.01 for 2-year mortality as compared with patients with less than 4. Logistic regression models demonstrated that the clinical deficits of mobility, respiratory, renal, malignancy, thyroid, and impaired cognition were independently associated with 1- and 2-year mortality. CONCLUSIONS: Patients aged 60 years and older sustaining a femoral neck fracture, with a higher modified frailty index, had increased 1- and 2-year mortality rates, and the ROC analysis suggests that this tool may be predictive of mortality. Patients with a modified frailty index of 4 or greater have increased risk for mortality at 1 and 2 years. Clinical deficits of mobility, respiratory, renal, malignancy, thyroid, and impaired cognition also may be independently associated with mortality. The modified frailty index may be a useful tool in predicting mortality, guiding patient and family expectations and elucidating implant/surgery choices. Further prospective studies are necessary to strengthen the predictive power of the index. LEVEL OF EVIDENCE: Level IV, prognostic study. See Instructions for Authors for a complete description of levels of evidence. PMID- 24166074 TI - High-energy femur fractures increase morbidity but not mortality in elderly patients. AB - BACKGROUND: Trauma centers are projected to have an increase in the number of elderly patients with high-energy femur fractures. Greater morbidity and mortality have been observed in these patients. Further clarification regarding the impact of high-energy femur fractures is necessary in this population. QUESTIONS/PURPOSES: Our purpose was to assess the influence of high-energy femur fractures on mortality and morbidity in patients 60 years and older. Specifically, we asked (1) if the presence of a high-energy femur fracture increases in-hospital, 6-month, and 1-year mortality in patients 60 years and older, and (2) if there is a difference in morbidity (number of complications, intensive care unit [ICU] and total hospital length of stay, discharge disposition, accompanying fractures, and surgical intervention) between patients 60 years and older with and without high-energy femur fractures. METHODS: A retrospective review of 242 patients was performed. Patients with traumatic brain injury or spine injury with a neurologic deficit were excluded. A control group, including patients admitted secondary to high-energy trauma without femur fractures, was matched by gender and Injury Severity Score (ISS). In-hospital mortality, 6-month and 1-year mortality, complications, ICU and total hospital length of stay, discharge disposition, accompanying fractures, surgical intervention, and covariates were recorded. Statistical analyses using Fisher's exact test, ANOVA, Kaplan-Meier estimates, and Cox regression models were performed to show differences in mortality (in-hospital, 6-month, 1-year), complications, length of ICU and total hospital stay, discharge disposition, surgical intervention, and accompanying fractures between elderly patients with and without femur fractures. The average ages of the patients were 72.8 years (+/ 9 years) in the femur fracture group and 71.8 years (+/- 9 years) in the control group. Sex, age, ISS, and comorbidities were homogenous between groups. RESULTS: In-hospital (p = 0.45), 6-month (p = 0.79), and 1-year mortality (p = 0.55) did not differ in patients with and without high-energy femur fractures. Elderly patients with high-energy femur fractures had an increased number of complications (p = 0.029), longer total hospital length of stay (p = 0.039), were discharged more commonly to rehabilitation centers (p < 0.005), had more accompanying long bone fractures (p = 0.002), and were more likely to have surgery (p < 0.001). Average ICU length of stay was similar between the two groups (p = 0.17). CONCLUSIONS: High-energy femur fractures increased morbidity in patients 60 years and older; however, no increase in mortality was observed in our patients. Concomitant injuries may play a more critical role in this population. Additional studies are necessary to clarify the role of high-energy femur fracture mortality in this age group. LEVEL OF EVIDENCE: Level III, therapeutic study. See the Instructions for Authors for a complete description of levels of evidence. PMID- 24166075 TI - Are race and sex associated with the occurrence of atypical femoral fractures? AB - BACKGROUND: Prior studies have suggested that Asian patients and women may be more likely to sustain atypical femoral fractures in association with bisphosphonate use. However, they do not account for confounders such as asymptomatic patients who are long-term bisphosphonate users or patients sustaining osteoporotic fractures. QUESTIONS/PURPOSES: The purpose of this study was to determine the differences in sex and racial association with atypical femoral fractures by comparing demographic characteristics of patients who sustained an atypical bisphosphonate-associated fracture with patients on long term bisphosphonates without fractures and with patients who sustained osteoporotic fractures. METHODS: Three groups from prospective registries were identified: (1) patients with atypical femur fractures associated with long-term bisphosphonate use (BFF) (n = 54); (2) patients on long-term bisphosphonates but with no associated fractures (BNF) (n = 119); and (3) patients with osteoporotic proximal femur fractures not associated with bisphosphonates (PFF) (n = 216). Age, sex, and self-reported race/ethnicity were documented and compared. Multivariate and univariate analyses were done as well as age- and sex-stratified analyses. RESULTS: Age and sex distributions of the BFF and BNF patients were similar. There was a higher percentage of Asian patients in the BFF group (17%) than in the BNF group (3%; p = 0.004) as well as Hispanics (13% versus 3% in BNF; p = 0.011). Patients in the BFF group were younger than those in the PFF group (67.5 versus 78.4 years; p < 0.001) and had fewer males (7% versus 14%; p < 0.001). CONCLUSIONS: These data suggest that Asians are at higher risk for atypical bisphosphonate-associated fractures. We recommend closer followup in Asian patients who are taking bisphosphonates. LEVEL OF EVIDENCE: Level III, prognostic study. See Guidelines for Authors for a complete description of levels of evidence. PMID- 24166076 TI - Peripheral nerve blocks in shoulder arthroplasty: how do they influence complications and length of stay? AB - BACKGROUND: Regional anesthesia has proven to be a highly effective technique for pain control after total shoulder arthroplasty. However, concerns have been raised about the safety of upper-extremity nerve blocks, particularly with respect to the incidence of perioperative respiratory and neurologic complications, and little is known about their influence, if any, on length of stay after surgery. QUESTIONS/PURPOSES: Using a large national cohort, we asked: (1) How frequently are upper-extremity peripheral nerve blocks added to general anesthesia in patients undergoing total shoulder arthroplasty? (2) Are there differences in the incidence of and adjusted risk for major perioperative complications and mortality between patients receiving general anesthesia with and without nerve blocks? And (3) does resource utilization (blood product transfusion, intensive care unit admission, length of stay) differ between groups? METHODS: We searched a nationwide discharge database for patients undergoing total shoulder arthroplasty under general anesthesia with or without addition of a nerve block. Groups were compared with regard to demographics, comorbidities, major perioperative complications, and length of stay. Multivariable logistic regressions were performed to measure complications and resource use. A negative binomial regression was fitted to measure length of stay. RESULTS: We identified 17,157 patients who underwent total shoulder arthroplasty between 2007 and 2011. Of those, approximately 21% received an upper extremity peripheral nerve block in addition to general anesthesia. Patients receiving combined regional-general anesthesia had similar mean age (68.6 years [95% CI: 68.2-68.9 years] versus 69.1 years [95% CI: 68.9-69.3 years], p < 0.0043), a slightly lower mean Deyo (comorbidity) index (0.87 versus 0.93, p = 0.0052), and similar prevalence of individual comorbidities, compared to those patients receiving general anesthesia only. Addition of regional anesthesia was not associated with different odds ratios for complications, transfusion, and intensive care unit admission. Incident rates for length of stay were also similar between groups (incident rate ratio = 0.99; 95% CI: 0.97-1.02; p = 0.467) CONCLUSIONS: Addition of regional to general anesthesia was not associated with an increased complication profile or increased use of resources. In combination with improved pain control as known from previous research, regional anesthesia may represent a viable management option for shoulder arthroplasty. However, further research is necessary to better clarify the risk of neurologic complications. LEVEL OF EVIDENCE: Level IV, therapeutic study. See Instructions for Authors for a complete description of levels of evidence. PMID- 24166077 TI - Providers' attitudes toward evidence-based practices: is it just about providers, or do practices matter, too? AB - Evidence-based practice (EBP) attitudes were measured in a sample of Los Angeles County mental health service providers. Three types of data were collected: provider demographic characteristics, attitudes toward EBP in general, and attitudes toward specific EBPs being implemented in the county. Providers could reliably rate characteristics of specific EBPs, and these ratings differed across interventions. Preliminary implementation data indicate that appealing features of an EBP relate to the degree to which providers use it. These findings suggest that assessing EBP-specific attitudes is feasible and may offer implementation relevant information beyond that gained solely from providers' general attitudes toward EBP. PMID- 24166078 TI - Risk and risk reduction of major coronary events associated with contemporary breast radiotherapy. PMID- 24166079 TI - Chlorpropham and phenisopham: phototransformation and ecotoxicity of carbamates in the aquatic environment. AB - In this study, a comparison of two carbamic pesticides, chlorpropham and phenisopham, was carried out in terms of both photodegradability and ecotoxicity. The photochemical behaviour of the two pesticides was investigated under environmental-like conditions (aqueous media, UVB or solar irradiation). The photochemical kinetic parameters were calculated by irradiating 5 * 10(-5) M solutions (H2O-CH3CN, 9 : 1 v/v) using UVB lamps. For chlorpropham and phenisopham similar half-life times (39.0 and 55.0 min) were determined. Irradiation by sunlight leads to longer degradation half-life times (about 3 months), while it is possible to observe the formation of the same photoproducts. The well-known dechlorination reaction to a hydroxyphenylcarbamate was observed for chlorpropham. Phenisopham undergoes photo-Fries reaction to give rearranged products (hydroxybenzamides) and fragmentation products (hydroxyphenylcarbamate and N-ethylaniline). Acute and chronic toxicity tests of pesticides and their photoproducts were performed on organisms from two levels of the freshwater aquatic chain, the anostraca crustacean Thamnocephalus platyurus, the rotifer Brachionus calyciflorus and the alga Pseudokirchneriella subcapitata. The acute results showed that chlorpropham had median lethal concentrations for the crustacean T. platyurus and the rotifer B. calyciflorus of 10.16 and 35.19 mg L( 1), respectively, and phenisopham did not show any acute toxicity as the derivatives up to 10 mg L(-1). The only exception was N-ethylaniline which exhibited an acute LC50 value of 0.46 mg L(-1). Phenisopham was the most toxic in the long term exposure while its five derivatives showed lower chronic potential for rotifers and algae. The same trend was observed for chlorpropham except for rotifers. PMID- 24166080 TI - Placental methylation markers in normal and trisomy 21 tissues. AB - OBJECTIVE: The objective of this study is to combine multiplex ligation-dependent probe amplification (MLPA) and bisulfite sequencing to determine DNA methylation markers for noninvasive prenatal diagnosis of Down syndrome. METHODS: DNA methylation ratios (MR) of four fragments (CGI149, CGI045, HLCS-1, and HLCS-2) on chromosome 21 were evaluated in blood cells from 13 nonpregnant women, 15 euploidies, and 11 Down Syndrome (DS) placentae. Ratios were measured by bisulfite sequencing and methylation-specific (MS)-MLPA. RESULTS: The MS-MLPA and bisulfite sequencing results were concordant. CGI149, CGI045, and HLCS-2 were unmethylated in all nonpregnant blood cells. CGI149, CGI045, HLCS-1, and HLCS-2 were methylated in most of the euploid (13, 11, 15, and 15, respectively) and DS placentae (10, 11, 11, and 11, respectively). The median placental DNA MR in CGI149 was 0.4578 (interquartile range, 0.3568-0.5169) and 0.5918 (interquartile range, 0.5618-0.6659) in euploid and DS placentae, respectively (p = 0.001). Using placental MR at 0.5390 as a threshold, we detected DS at 90.9% sensitivity and 93.3% specificity. CONCLUSION: The MS-MLPA is an effective alternative to bisulfite sequencing in assessing placental MR. CGI149 is a potential marker for the noninvasive diagnosis of Down syndrome. PMID- 24166081 TI - Patterns of cancer screening in primary care from 2005 to 2010. AB - BACKGROUND: Cancer screening recommendations vary widely, especially for breast, prostate, and skin cancer screening. Guidelines are provided by the American Cancer Society, the US Preventive Services Task Force, and various professional organizations. The recommendations often differ with regard to age and frequency of screening. The objective of this study was to determine actual rates of screening in the primary care setting. METHODS: Data from the National Ambulatory Medical Care Survey were used. Only adult visits to non-federally employed, office-based physicians for preventive care from 2005 through 2010 were examined. Prevalence rates for breast, pelvic, and rectal examinations were calculated, along with the rates for mammograms, Papanicolaou smears, and prostate-specific antigen tests. Factors associated with screening, including age, race, smoking status, and insurance type, were examined using t tests and chi-square tests. RESULTS: In total, 8521 visits were examined. The rates of most screening examinations and tests were stable over time. Clinical breast examinations took place significantly more than mammography was ordered (54.8% vs 34.6%; P<.001). White patients received more mammography (P=.031), skin examinations (P<.010), digital rectal examinations (P<.010), and prostate-specific antigen tests (P=.003) than patients of other races. Patients who paid with Medicare or private insurance received more screening than patients who had Medicaid or no insurance (P<.010). CONCLUSIONS: Current cancer screening practices in primary care vary significantly. Cancer screening may not follow evidence-based practices and may not be targeting patients considered most at risk. Racial and socioeconomic disparities are present in cancer screening in primary care. PMID- 24166082 TI - Viral hepatitis: eltrombopag is useful for patients with HCV and thrombocytopenia. PMID- 24166083 TI - Liver support strategies: cutting-edge technologies. AB - The treatment of end-stage liver disease and acute liver failure remains a clinically relevant issue. Although orthotopic liver transplantation is a well established procedure, whole-organ transplantation is invasive and increasingly limited by the unavailability of suitable donor organs. Artificial and bioartificial liver support systems have been developed to provide an alternative to whole organ transplantation, but despite three decades of scientific efforts, the results are still not convincing with respect to clinical outcome. In this Review, conceptual limitations of clinically available liver support therapy systems are discussed. Furthermore, alternative concepts, such as hepatocyte transplantation, and cutting-edge developments in the field of liver support strategies, including the repopulation of decellularized organs and the biofabrication of entirely new organs by printing techniques or induced organogenesis are analysed with respect to clinical relevance. Whereas hepatocyte transplantation shows promising clinical results, at least for the temporary treatment of inborn metabolic diseases, so far data regarding implantation of engineered hepatic tissue have only emerged from preclinical experiments. However, the evolving techniques presented here raise hope for bioengineered liver support therapies in the future. PMID- 24166084 TI - Metal free sulfenylation and bis-sulfenylation of indoles: persulfate mediated synthesis. AB - A method which avoids metal and halogen for the synthesis of 3-arylthioindoles from indoles and diaryl disulfides using ammonium persulfate in methanol has been presented. Moreover, double C-H sulfenylation of indoles at 2 and 3-positions has also been achieved using iodine and ammonium persulfate. PMID- 24166085 TI - Pharmacokinetic variability of flecainide in younger Japanese patients and mechanisms for renal excretion and intestinal absorption. AB - The aims of the present study were to evaluate the variability of pharmacokinetics of flecainide in young Japanese patients and to investigate the mechanisms of renal excretion and intestinal absorption of the drug using cultured epithelial cells. First the plasma concentration data of flecainide was analysed in 16 Japanese patients aged between 0.07 and 18.30 years using a one compartment model. Considerable interindividual variability was observed in the oral clearance (CL/F) and the apparent volume of distribution (V/F) of flecainide in the young patients. Flecainide was transported selectively in the basolateral to-apical direction in P-glycoprotein-expressing renal epithelial LLC-GA5-COL150 cell monolayers. The uptake of flecainide into intestinal epithelial LS180 cells was decreased significantly by acidification of the extracellular medium, and was inhibited by tertiary amines, such as diphenhydramine and quinidine. These findings in the present study suggest that flecainide is excreted by P glycoprotein in the renal tubule and is taken up by the postulated H(+)/tertiary amine antiporter in the intestine, and that functional variability of not only the hepatic drug-metabolizing enzymes, but also the transporters in the kidney and intestine, may be responsible for the interindividual variability of systemic clearance (CL) and/or the bioavailability (F) of flecainide. PMID- 24166086 TI - Always expect the unexpected: lung abscess due to pseudomonas aeruginosa mimicking pulmonary aspergilloma in acute B-cell leukemia. AB - We report on a case of Pseudomonas aeruginosa sepsis and consecutive lung abscess in a 13-year-old patient with acute B-cell leukemia. At first, radiographic findings strongly suggested presence of pulmonary aspergilloma and only microbiological testing of the surgically enucleated mass revealed the correct underlying pathogen and confirmed final diagnosis. PMID- 24166087 TI - Clinical phenotype and functional analysis of a rare XIAP/BIRC4 mutation. AB - X-linked lymphoproliferative syndromes (XLP) are rare primary immunodeficiencies. Mutations within the XIAP/BIRC4 gene characterize XLP type 2 and cause XIAP deficiency. We present the case of a 5-year-old boy with a novel mutation of the XIAP/BIRC4 gene and describe the immunological phenotype for the first time. We characterized the distinct immunological phenotype and evaluated the family history accordingly. PMID- 24166088 TI - Treatment of adolescents and young adults (AYA) with cancer in a multidisciplinary setting: on the way to a highly specialized AYA unit. AB - Further survival improvements of adolescents and young adults (AYA) with cancer are clearly affected by biological characteristics of the malignancies and age specific needs. Multidisciplinary teams drawing expertice from both pediatric and adult cancer teams as well as clinical trials are required to meet the age specific needs of AYA patients with cancer. In 2011, the first AYA unit was established at the University Hospital Halle (Saale), where patients with newly diagnosed cancer aged 15-25 are treated interdisciplinary by pediatric and adult oncologists. The enrollment into pediatric or adult clinical trials is controlled by age 18. Over the last 2 years, 19 AYA with cancer have been treated at the unit; and, in turn patients and their relatives reflected a high satisfaction with the offered novel health care approach. In the scope of the future Comprehensive Cancer Center at the University Hospital Halle (Saale), a complete ward is planned for all admitted AYA up to 25 years with cancer. The patients will be treated by a tumor-specialized multidisciplinary team of adult or pediatric oncologists and oncological surgeons. Therefore, we intend to establish a special teaching curriculum for physicians, nurses and psychosocial health care staff. Rather than age, cancer biology of a malignancy, surveillance data of late side effects as well as the age-specific needs of AYA patients will be crucial for best treatment options. PMID- 24166089 TI - Colonization and infection due to multi-resistant bacteria in neonates: a single center analysis. AB - BACKGROUND: In the last years the prevalence of multi-resistant pathogens (MRPs) has increased. Systemic infections remain important for neonatal morbidity and mortality. PATIENTS: Neonates born between January 2011 and December 2012 and admitted to the neonatology before their tenth day of life were included into this retrospective analysis. Vancomycin-resistant Enterococci, Methicillin resistant Staphylococcus aureus, Gram-negative bacilli with Extend Spectrum Beta Lactamase or AMP-C resistance were defined as multi-resistant pathogens (MRPs). MRP positive and negative patients were analyzed regarding clinical risk factors and the incidence of systemic infections. RESULTS: 635 neonates were admitted during the analysis period. In 31 patients MRPs were detected. 2 patients developed MRP-associated infections. Both were discharged without long term health risks. Low gestational age and need for mechanical ventilation were risk factors for colonization with MRPs in the univariat analysis. The incidence density (per 1 000 patient days) for all MRE increased from 0.76 in 2011 to 3.51 in 2012. In contrast the sepsis rate remained stable (14.9% and 14.2%). 2 MRP colonization clusters were detected by routine microbiology swabs. Both could be controlled by appropriate hygienic measures. CONCLUSIONS: The prevalence of Gram negative MRPs increased in neonates. Microbiological screening seems to be helpful for early detection of colonization and thus prevention of nosocomial infections with MRPs. Despite the increased attention towards the problems associated with multiresistant bacteria, there are still major efforts needed for prevention and early treatment of sepsis with non-resistant bacteria. PMID- 24166090 TI - Multimodal therapy of recurrent severe acute disseminated encephalomyelitis: the role of immunoadsorption. PMID- 24166091 TI - Crohn's disease in a patient with juvenile idiopathic arthritis after starting etanercept therapy - causal link or only temporal coincidence? PMID- 24166092 TI - Psammomatoid juvenile ossifying fibroma of the maxilla: radical surgery with maxillary resection in a 7-year-old girl. PMID- 24166093 TI - The EuroNet paediatric hodgkin network - modern imaging data management for real time central review in multicentre trials. AB - Since 2007, children and adolescents with Hodgkin lymphomas are treated in the Europe-wide EuroNet-PHL trials. A real time central review process for stratification of the patients enhances quality control and efficient therapy management. This process includes reading of all cross-sectional-images. Since reference evaluation is time critical, a fast, easy to handle and safe data transfer is important. In addition, immediate and constant access to all the data has to be guaranteed in case of queries and for regulatory reasons. To meet the mentioned requirements the EuroNet Paediatric Hodgkin Data Network (funded by the European Union - Project Number: 2007108) was established between 2008 and 2011. A respective tailored data protection plan was formulated. The aim of this article is to describe the networks' mode of operation and the advantages for multi-centre trials that include centralized image review. PMID- 24166094 TI - Targeted Therapy for Neuroblastoma: ALK Inhibitors. AB - Treatment for neuroblastoma, the most common extracranial childhood tumor, spans a broad range of aggressiveness that mirrors the risk profiles of disease subtypes, with high-risk neuroblastoma still presenting a clinical challenge. Currently, most patients with relapsed neuro-blastoma die of disease and present a major challenge for treatment. New therapeutic options are urgently needed to improve patient survival. Activating mutations in the gene encoding the anaplastic lymphoma kinase (ALK) remain the most frequent druggable mutations identified in neuroblastomas to date. Preclinical data support an oncogene addiction of neuroblastoma cells to mutated ALK and demonstrate that ALK inhibitory therapy strongly combats tumor models. Most recently, pediatric phase I testing has been completed for the first approved ALK inhibitor, Crizotinib, showing very encouraging antitumoral results in neuroblastoma patients. Subsequently, an international phase I study with the second generation ALK inhibitor, LDK-378, will be launched that makes ALK inhibitory therapy also available to pediatric patients in Germany. PMID- 24166095 TI - Improving outcomes for teenagers and young adults (TYA) with cancer. AB - The management of TYA with cancer is characterized by biological features in comparison to children. Therefore specialized treatment units have been established within professional structures of care for this group, and a European multidisciplinary framework for the treatment of TYA with cancer was founded.Objectives are to promote interdisciplinary collaboration and provide strategic concepts to improve patient care centered to the special needs of this age group. Access to clinical trials for all TYA in the EU will be improved and research initiated, examining biology, epidemiology and health services.Special goals of the interprofessional cooperation are:Different measurements are discussed improving outcomes for TYA is proceeding at different speeds in different parts of the world. In some there are established teams, bringing together paediatric and adult specialists from many healthcare professions, reviewing and contributing to the optimal care of all TYA with cancer as part of national health policy. PMID- 24166096 TI - The emerging role of miR-375 in cancer. AB - MicroRNAs (miRNAs) are evolutionarily conserved, small noncoding RNAs that are believed to play fundamental roles in various biological processes through regulation of gene expression at the level of posttranscription. MiR-375 was first identified as a pancreatic islet-specific miRNA regulating insulin secretion. However, further study revealed that miR-375 is a multifunctional miRNA participating in pancreatic islet development, glucose homeostasis, mucosal immunity, lung surfactant secretion and more importantly, tumorigenesis. Recently, miR-375 has been found significantly downregulated in multiple types of cancer, and suppresses core hallmarks of cancer by targeting several important oncogenes like AEG-1, YAP1, IGF1R and PDK1. The alteration of miR-375 in cancer is caused by a variety of mechanisms, including the dysregulation of transcription factors, aberrant promoter methylation and so on. Reduced expression of miR-375 in tissue or circulation may indicate the presence of neoplasia as well as a poor prognosis of many malignant cancers. Moreover, miR 375 stands for a promising direction for developing targeted therapies due to its capacity to inhibit tumor cell growth in vitro and in vivo. Here, we summarize the present understanding of the tumor suppressive role of miR-375 in cancer progression; the mechanisms underlying the dysregulation of miR-375; the potential use of miR-375 in prognosis and diagnosis and the therapeutic prospects of miR-375 in cancer. PMID- 24166097 TI - A systematic review of Gymnema sylvestre in obesity and diabetes management. AB - The prevalence of obesity is associated with many health-related problems. Currently, more than 300 million people are considered to be obese. According to the World Health Organization (WHO), by 2030, 87 and 439 million people will be affected in India and the world, respectively. Today, herbal medicines are gaining interest in the treatment of obesity and diabetes, because of their minimal side effects. Gymnemic acid - an active component isolated from Gymnema sylvestre - has anti-obesity and antidiabetic properties, decreases body weight and also inhibits glucose absorption. Several components extracted from Gymnema prevent the accumulation of triglycerides in muscle and liver, and also decrease fatty acid accumulation in the circulation. In this paper, an attempt has been made to review the effects of various extracts from Gymnema sylvestre in the regulation of carbohydrate and lipid metabolism in both animal and clinical studies. PMID- 24166098 TI - Bulk modulus for polar covalent crystals. AB - A microscopic empirical model of bulk modulus based on atomic-scale parameters is proposed. These parameters include the bond length, the effective bonded valence electron (EBVE) number, and the coordination number product of two bonded atoms, etc. The estimated bulk moduli from our model are in good agreement with experimental values for various polar covalent crystals including ionic crystals. Our current work sheds lights on the nature of bulk modulus, provides useful clues for design of crystals with low compressibility, and is applicable to complex crystals such as minerals of geophysical importance. PMID- 24166099 TI - Trends in emergency department visits for ambulatory care sensitive conditions by elderly nursing home residents, 2001 to 2010. PMID- 24166101 TI - The use of immobilized cytochrome P4502C9 in PMMA-based plug flow bioreactors for the production of drug metabolites. AB - Cytochrome P450 enzymes play a key role in the metabolism of pharmaceutical agents. To determine metabolite toxicity, it is necessary to obtain P450 metabolites from various pharmaceutical agents. Here, we describe a bioreactor that is made by immobilizing cytochrome P450 2C9 (CYP2C9) to a poly(methyl methacrylate) surface and, as an alternative to traditional chemical synthesis, can be used to biosynthesize P450 metabolites in a plug flow bioreactor. As part of the development of the CYP2C9 bioreactor, we have studied two different methods of attachment: (1) coupling via the N-terminus using N hydroxysulfosuccinimide 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide and (2) using the Ni(II) chelator 1-acetato-4-benzyl-triazacyclononane to coordinate the enzyme to the surface using a C-terminal histidine tag. Additionally, the propensity for metabolite production of the CYP2C9 proof-of-concept bioreactors as a function of enzyme attachment conditions (e.g., time and enzyme concentration) was examined. Our results show that the immobilization of CYP2C9 enzymes to a PMMA surface represents a viable and alternative approach to the preparation of CYP2C9 metabolites for toxicity testing. Furthermore, the basic approach can be adapted to any cytochrome P450 enzyme and in a high-throughput, automated process. PMID- 24166102 TI - Carotenoid and fatty acid compositions of an indigenous Ettlia texensis isolate (Chlorophyceae) under phototrophic and mixotrophic conditions. AB - Ettlia oleoabundance (formerly known as Neochloris oleoabundance) is an attractive candidate for biodiesel production because of its high lipid accumulation, and it's taking the majority of the attention among the strains of Ettlia genus; however, potential of the other genus members is unknown. An indigenous strain from Salda Lake (South West Turkey) identified by 18S rDNA sequencing as Ettlia texensis (GenBank accession no: JQ038221), and its fatty acid and carotenoid compositions under phototrophic and mixotrophic conditions was investigated to evaluate the potential of the strain for commercial uses. A threefold increase was observed in total lipid content (total fatty acids; from 13% to 37%) in mixotrophic culture respect to the phototrophic growth conditions. The oleic acid (C18:1) and alpha-linolenic acid (18:3) were the major unsaturated fatty acids accounting for 40% and 13.2% of total fatty acids in mixotrophic culture, respectively. Carotenoid analyses of the mixotrophic culture revealed the metabolite canthaxanthin, a commercially valuable carotenoid used mainly for food coloring, was the major constituent among other pigments. The possible use of E. texensis in biotechnological applications is discussed. PMID- 24166103 TI - Production and characteristics of a bioflocculant by Klebsiella pneumoniae YZ-6 isolated from human saliva. AB - The production and characterization of a bioflocculant, MBF-6, by Klebsiella pneumoniae was investigated. Optimum culture conditions for bioflocculant production were an initial medium pH of 7, an incubation temperature of 30 degrees C, and an inoculum size of 1% (v/v) of cell density 1.0 * 10(8) cfu/mL. The carbon, nitrogen, and cation sources for optimum bioflocculant production were glucose, peptone, and ZnCl2. The bioflocculant mainly consisted of protein (3.4%) and sugar (95.1%). Fourier transform infrared (FTIR) spectrum revealed the presence of carboxyl and hydroxyl groups while the thermogravimetric analysis (TGA) showed a degradation temperature (T(d)) of 81.4 degrees C. MBF-6 had a good flocculating rate in kaolin suspension without cation addition and was stable over a wide range of pH and temperature. Investigation on the flocculation efficacy of the characterized MBF-6 for wastewater treatment of dairy, woolen, brewery, and sugar industries suggested it to be effective. PMID- 24166104 TI - Human saliva-based quantitative monitoring of clarithromycin by flow injection chemiluminescence analysis: a pharmacokinetic study. AB - Human saliva quantitative monitoring of clarithromycin (CLA) by chemiluminescence (CL) with flow injection analysis was proposed for the first time, which was based on the quenching effect of CLA on luminol-bovine serum albumin (BSA) CL system with a linear range from 7.5 * 10(-4) to 2.0 ng/ml. This proposed approach, offering a maximum sample throughput of 100 h(-1), was successfully applied to the quantitative monitoring of CLA levels in human saliva during 24 h after a single oral dose of 250 mg intake, with recoveries of 95.2 ~ 109.0% and relative standard deviations lower than 6.5 % (N = 7). Results showed that CLA reached maximum concentration of 2.28 +/- 0.02 MUg/ml at approximately 3 h, and the total elimination ratio was 99.6 % in 24 h. The pharmacokinetic parameters including absorption rate constant (0.058 +/- 0.006 h(-1)), elimination rate constant (0.149 +/- 0.009 h(-1)) and elimination half-life time (4.66 +/- 0.08 h) were obtained. A comparison of human saliva and urine monitoring was also given. The mechanism study of BSA-CLA interaction revealed the binding of CLA to BSA is an entropy driven and spontaneous process through hydrophobic interaction, with binding constant K BSA-CLA of 4.78 * 10(6) l/mol and the number of binding sites n of 0.82 by flow injection-chemiluminescence model. Molecular docking analysis further showed CLA might be in subdomain IIA of BSA, with K BSA-CLA of 6.82 * 10(5) l/mol and DeltaG of -33.28 kJ/mol. PMID- 24166106 TI - Safety and pharmacology of gemcitabine and capecitabine in patients with advanced pancreatico-biliary cancer and hepatic dysfunction. AB - PURPOSE: We assessed the impact of hepatic dysfunction on the safety and pharmacology of gemcitabine/capecitabine in patients with advanced pancreatico biliary cancer. METHODS: We included 12 patients receiving 3 weekly gemcitabine 1,000 mg/m(2) day 1, 8 and oral capecitabine 650 mg/m(2) b.i.d. over 2 weeks until disease progression or intolerable toxicity. Patients were included into one normal hepatic function cohort [total bilirubin (TB) <=15 MUmol/L] and 3 cohorts with increasing TB (16-39, 40-80, >80 MUmol/L). Three patients with a creatinine clearance <60 ml/min were also included. Patients were sampled for gemcitabine, difluoro-deoxy uridine, intracellular gemcitabine triphosphates, capecitabine, 5'-deoxy-5-fluorocytidine, 5'-deoxy-5-fluorouridine and 5 fluorouracil up to 4 h after initiation of chemotherapy on day 1, and up to 90 min on day 8. All compounds were analyzed using validated liquid chromatography tandem mass spectrometry. Nonlinear mixed-effect modeling was used for population analysis. RESULTS: Hepatic dysfunction was caused by intrahepatic cholestasis in 4 out of 8 patients (50 %) and extrahepatic cholestasis in another 4 patients (50 %). Dose-limiting toxicity was increasing hyperbilirubinemia and severe neutropenia in 2 patients each. Hepatic dysfunction was not associated with dose limiting toxicity or severe hematological or non-hematological toxicity. However, hepatic dysfunction was associated with low clearance of both gemcitabine (p = 10(-3)) and capecitabine (p = 10(-5)), and low intracellular gemcitabine triphosphate concentrations (p = 10(-3)). CONCLUSIONS: Gemcitabine/capecitabine can be given at the standard dose in patients with severe hyperbilirubinemia, though the present data suggest that gemcitabine's activity may be limited due to poor intracellular activation. In patients with severe hyperbilirubinemia, initial monotherapy with capecitabine should be considered, followed by the addition of gemcitabine with improving hyperbilirubinemia. PMID- 24166107 TI - Phase II study of concurrent thoracic radiotherapy in combination with weekly paclitaxel plus carboplatin in locally advanced non-small cell lung cancer: LOGIK0401. AB - OBJECTIVES: Concurrent chemoradiotherapy for regionally advanced stage III non small cell lung cancer is the standard treatment method. However, the clinical implications of consolidation chemotherapy following chemoradiation have been unclear. Therefore, we conducted a phase II study of concurrent weekly carboplatin plus paclitaxel treatment in combination with radiotherapy followed by vinorelbine monotherapy. The primary endpoint was the 1-year survival rate. PATIENTS AND METHODS: Chemonaive PS 0-1 patients with stage IIIA/B NSCLC were enrolled. During the concurrent chemoradiation phase, patients were treated with weekly paclitaxel 40 mg/m(2) plus carboplatin AUC 2. The primary tumor and involved nodes received 60 Gy in 2-Gy fractions over 6 weeks. During the consolidation phase, vinorelbine 25 mg/m(2) on days 1 and 8 was repeated for three cycles. RESULTS: A total of 40 eligible patients (72.5 % male; median age, 63 years; range 29-74 years) were analyzed for efficacy. Squamous cell carcinoma was the most common histology (47.5 %), and more patients had clinical stage IIIB (55 %) cancer. The average radiation dose was 56.5 Gy, and the average number of carboplatin plus paclitaxel cycles was 4.93. Seventeen patients proceeded to the consolidation chemotherapy phase, and 14 completed three cycles of vinorelbine monotherapy. The objective response rate was 75.0 %, including 1 patient who achieved a complete response. Progression-free survival and overall survival (OS) were 46 weeks [95 % confidence interval (CI) 31-64 weeks] and 110 weeks (95 % CI 90-184 weeks), respectively. The OS rate at 1 and 2 years was 85.0 % (95 % CI 69.6-93.0 %) and 53.9 % (95 % CI 37.1-68.0 %), respectively. CONCLUSION: Concurrent chemoradiation with weekly carboplatin and paclitaxel followed by vinorelbine consolidation is effective for stage III non-small cell lung cancer and shows a generally mild toxicity profile. PMID- 24166109 TI - Diallel analysis for sex-linked and maternal effects. AB - Genetic models including sex-linked and maternal effects as well as autosomal gene effects are described. Monte Carlo simulations were conducted to compare efficiencies of estimation by minimum norm quadratic unbiased estimation (MINQUE) and restricted maximum likelihood (REML) methods. MINQUE(1), which has 1 for all prior values, has a similar efficiency to MINQUE(theta), which requires prior estimates of parameter values. MINQUE(1) has the advantage over REML of unbiased estimation and convenient computation. An adjusted unbiased prediction (AUP) method is developed for predicting random genetic effects. AUP is desirable for its easy computation and unbiasedness of both mean and variance of predictors. The jackknife procedure is appropriate for estimating the sampling variances of estimated variances (or covariances) and of predicted genetic effects. A t-test based on jackknife variances is applicable for detecting significance of variation. Worked examples from mice and silkworm data are given in order to demonstrate variance and covariance estimation and genetic effect prediction. PMID- 24166108 TI - "I am a nice person when I do yoga!!!" A qualitative analysis of how yoga affects relationships. AB - PURPOSE: To develop a better understanding of how yoga practice affects one's interpersonal relationships. DESIGN: Qualitative. METHOD: Content analysis was used to qualitatively analyze written comments (n = 171) made regarding yoga improving interpersonal relationships in a large cross-sectional survey of yoga practitioners (N = 1,067). FINDINGS: Four themes were identified: Yoga practice leads to personal transformation, increases social interaction, provides coping mechanisms to weather relationship losses and difficulties, and leads to spiritual transcendence. Practitioners believed that their interpersonal relationships improved because their attitude and perspective had changed, making them more patient, kind, mindful, and self-aware. They expressed an aspect of community that was both practical (they met new friends) and spiritual (they felt they belonged). They thought they could better weather difficulties such as divorce and death. A number discussed feeling a sense of purpose and that their practice contributed to a greater good. CONCLUSIONS: There appears to be an aspect of community associated with yoga practice that may be beneficial to one's social and spiritual health. Yoga could be beneficial for populations at risk for social isolation, such as those who are elderly, bereaved, and depressed, as well as individuals undergoing interpersonal crises. PMID- 24166110 TI - The physical map of the chloroplast DNA from Asparagus officinalis L. AB - The genus Asparagus consists of 100-300 species of both dioecious and hermaphrodite plants. Since there are diploid, tetraploid, and hexaploid plants in this genus, RFLP (restriction fragment length polymorphism) analysis of chloroplast DNA (ctDNA) is suitable for examining the phylogenetic relationships. We have constructed a physical map of the ctDNA of garden asparagus (A. officinalis L. cv 'Mary Washington 500 W') using five restriction endonucleases, namely, BamHI, PstI, SalI, HindIII, and XhoI. Asparagus ctDNA was digested with restriction enzymes and cloned into plasmid and lambda phage vectors, and a clone bank was constructed that covered 70% of the genome. A physical map was constructed by Southern hybridization of total DNA from asparagus with homologous and heterologous probes. The asparagus ctDNA was about 155 kb long and it contained two inverted repeats (23kb each) separated by a large single-copy region (90kb) and a small single-copy region (19kb). Fifteen genes, encoding photosynthesis-related proteins, rDNAs, and tRNAs, were localized on the physical map of asparagus ctDNA. Comparing the length and the gene order of asparagus ctDNA with that of other plants, we found that asparagus ctDNA was similar to tobacco ctDNA but different from rice ctDNA. The restriction patterns of the ctDNAs from several varieties of A. officinalis and three species of Asparagus were analyzed. The restriction patterns of the varieties of A. officinalis were very similar, but polymorphisms were detected among the three species of Asparagus. PMID- 24166111 TI - Both common and specific genetic factors are involved in polygenic resistance of pepper to several potyviruses. AB - Absolute resistance to potato virus Y pathotype 0 (PVY 0), potyvirus E and chili veinal mottle virus (CVMV) and a partial resistance to potato virus Y pathotype 1,2 (PVY 1,2) were found in an Indian pepper line, 'Perennial'. In the doubled haploid (DH) progeny from the F1 of a cross 'Perennial' by 'Yolo Wonder', resistance to CVMV was confered by two independent genes, one with a clear dominant effect. Resistance to PVY and potyvirus E was quantitatively expressed and controlled by several recessive genetic factors. Genetic analysis showed that fewer resistance factors were necessary to explain resistance to PVY (0) and potyvirus E than resistance to PVY(1,2). Genetic correlations between resistances to the different potyviruses in the DH progeny showed that most of genetic factors involved in PVY(0) resistance appear to be also involved in potyvirus E resistance, and some of these polyvalent factors may be also involved in PVY(1,2) resistance but, in this case, additional specific genes were necessary. One of the two CVMV resistance genes seems to be implicated in potyvirus E resistance. Thus, the polygenic resistance of 'Perennial' to these potyviruses was due both to polyvalent genetic factors, i.e. factors that apparently interact with several viruses, and strain-specific genetic factors. PMID- 24166112 TI - The analysis of the NSW wheat variety database. I. Modelling trial error variance. AB - The retrospective analysis of a large database on wheat variety testing in New South Wales (NSW) is considered. This analysis involved three key steps. Initially error variance heterogeneity is modelled, indicating significant differences in error variance due to trial location, year of trialling, sowing date and trial mean yield. The implication of this modelling for the estimaion of variance components is discussed. PMID- 24166113 TI - The analysis of the NSW wheat variety database. II. Variance component estimation. AB - The efficiency of various trialling systems for wheat variety evaluation in New South Wales (NSW) is considered. This involved the estimation of the variance components due to genotype, genotype-by-year, genotype-by-location and genotype by-year-by-location. It is shown that there is a significant reduction in the magnitude of these variance components by the inclusion of the interaction of genotype maturity, winter habit and aluminium tolerance with environment. PMID- 24166114 TI - Diversity and inheritance of inter-simple sequence repeat polymorphisms in Douglas-fir (Pseudotsuga menziesii) and sugi (Cryptomeria japonica). AB - We studied inter-simple sequence repeat (ISSR) polymorphism and inheritance in Douglas-fir [Pseudotsuga menziesii (Mirb.) Franco] and sugi (Cryptomeria japonica D. Don) megagametophytes using primers that anneal to simple repeats of various lengths, sequences, and non-repetitive motifs at the 5' and 3' ends. Products were visualized on agarose gels with ethidium bromide staining. More than 60% of the 96 primers tested gave interpretable banding patterns in both Douglas-fir and sugi, and the useful primers were in complete agreement among species. Dinucleotide repeat primers were the majority of those tested, and gave all of the useful banding patterns. The 24 best primers were used for segregation studies, yielding a total of 77 loci distributed among two Douglas-fir families and one sugi family. Approximately 90% of the 24 primers showed polymorphism within at least one of the three families. The average number of variable loci per primer was 1.6. Primers based on (AG) n repeats gave the largest number of polymorphic loci; 16 primer-family combinations yielded 24 segregating loci. However, primer based on (GT) n repeats gave the most loci per primer studied (mean of 2.0). All markers displayed apparent dominance (band presence vs absence), and all but three segregation ratios (4%) fit Mendelian expectations: Because they employ longer primers than do RAPDs, have a high degree of polymorphism, conform well to Mendelian expectations, and do not require use of acrylamide gels for analysis, ISSRs may be useful markers for PCR-based genome maps and population studies of conifers. PMID- 24166115 TI - Rapid identification of white-Engelmann spruce species by RAPD markers. AB - Fragments of random amplified polymorphic DNA (RAPDs) were used as markers to distinguish Picea glauca (Moench) Voss (white spruce) and Picea engelmannii Parry (Engelmann spruce). These species and their putative hybrids are difficult to differentiate morphologically and are collectively known as interior spruce. Four oligodeoxynucleotide decamer primers showed species-specific amplification products between white spruce and Engelmann spruce. These fragments are highly conserved among seed lots and individual trees of each species from diverse geographic origins. The consistency and reproducibility of these species-specific amplification products were tested in more than two amplification reactions. Therefore, RAPD markers can provide genetic markers for easy and rapid identification of the specific genetic entry of these spruce species and their reported putative hybrids. According to the frequencies of the species-specific RAPD markers, it is possible to estimate the hybrid fraction, indicative of true introgression between the two species. These results are useful for quick identification of both species and their hybrid swarms at any stage in the sporophyte phase of the life cycle, for determining the occurrence and the magnitude of introgressive hybridization in an overlap zone between the two species, and for certification purposes in operational re-forestation and tree improvement programs. PMID- 24166116 TI - A comparison of genetic information from open-pollinated and control-pollinated progeny tests in two eucalypt species. AB - Genetic-parameter estimates and parental breeding-value predictions were compared from open-pollinated and control-pollinated progeny populations of Eucalyptus globulus and two populations of E. nitens. For E. globulus there were two types of open-pollinated populations (native stand open-pollinated and seed orchard open-pollinated) and two types of control-pollinated populations (intra provenance and interprovenance full-sib families). For E. nitens there were two populations, a seed orchard open-pollinated population and intra-provenance full sib families. Progeny tests were established across multiple sites and 2-year height and diameter were measured and volume calculated. Genetic parameters from native stand open-pollinated E. globulus were unlike the parameters from the other three E. globulus populations; heritability estimates were severely inflated, presumably due to high levels, and possibly differential levels, of inbreeding depression relative to the other populations. Estimates of dominance variance in the E. globulus full-sib populations were high, but were zero in the E. nitens population. Correlations among parental breeding values, predicted using data from the different populations, were generally low and non significant, with two exceptions: predictions from the two E. globulus full-sib populations were significantly correlated (r=0.54, P = 0.001), as were predictions from the E. nitens seed orchard OP and full-sib population (r = 0.61, P = 0.08). There was some indication that superior parents of E. globulus native stand open-pollinated families also tended to have above-average breeding values based on the performance of intra-provenance full-sib offspring. The consequences of these results for exploitation of base-population collections from native stands are discussed. PMID- 24166117 TI - Divergence and allelomorphic relationship of a soybean virus resistance gene based on tightly linked DNA microsatellite and RFLP markers. AB - The use of genetically diverse resistance sources is important in breeding for durable disease resistance. Detection and evaluation of resistance genes by conventional inheritance experiments, however, often require laborious screening and genetic testing. In the present study, a marker-assisted screening for resistance sources was initiated in soybean [Glycine max (L.) Merr] using one DNA microsatellite and two RFLP markers tightly linked to a soybean mosaic virus (SMV) resistance gene (Rsv1). The three marker loci were used to screen 67 diverse soybean cultivars, breeding lines, and plant introductions. Five variants were found at the microsatellite locus (HSP176L), and the two RFLP loci (pA186 and pK644a) near Rsv1 show a remarkably higher level of restriction polymorphism than Rsv1-independent RFLP loci. Several specific variants at the three marker loci were found to be correlated with virus resistance, among which HSP176L-2 can be detected by PCR, thus may be useful for germplasm screening. The grouping of the 67 accessions according to their multilocus marker variants agrees with the available pedigree information. When all, or most, of the cultivars within a given group with the same Rsv1-linked marker variant are resistant, their SMV resistance is most likely conferred by Rsv1. These putatively Rsv1-carrying groups contain a total of 38 SMV-resistant lines including six differential cultivars that are known to carry Rsv1. The remaining seven resistant accessions (Columbia, Holladay, Peking, Virginia, FFR-471, PI 507403, and PI 556949) do not carry resistance marker variants, and at least some of them could be sources of resistance genes independent of Rsv1. PMID- 24166118 TI - Lysine accumulation in maize cell cultures transformed with a lysine-insensitive form of maize dihydrodipicolinate synthase. AB - Lysine is one of the nutritionally limiting amino acids in food and feed products made from maize (Zea mays L.). Two enzymes in the lysine biosynthesis pathway, aspartate kinase (AK) and dihydrodipicolinate synthase (DHPS), have primary roles in regulating the level of lysine accumulation in plant cells because both enzymes are feedback-inhibited by lysine. An isolated cDNA clone for maize DHPS was modified to encode a DHPS much less sensitive to lysine inhibition. The altered DHPS cDNA was transformed into maize cell suspension cultures to determine the effect on DHPS activity and lysine accumulation. Partially purified DHPS (wildtype plus mutant) from transformed cultures was less sensitive to lysine inhibition than wild-type DHPS from nontransformed cultures. Transformed cultures had cellular free lysine levels as much as four times higher than those of nontransformed controls. Thus, we have shown that reducing the feedback inhibition of DHPS by lysine can lead to increased lysine accumulation in maize cells. Increasing the capacity for lysine synthesis may be an important step in improving the nutritional quality of food and feed products made from maize. PMID- 24166119 TI - A testcross procedure for selecting exotic strains to improve pure-line cultivars in predominantly self-fertilizing species. AB - Methods for identifying germplasm carrying alleles with the potential to improve a particular single-cross hybrid have been proposed and discussed in recent years. There is a need for similar methods to be used in breeding crops for which pure-line cultivars, rather than hybrids, are the goal. The objective of this research was to develop a method to identify germplasm lines with the potential to contribute favorable alleles not present in a specified pure line or set of pure lines. Given a set of adapted pure lines (A 1, A 2 ..., A m) to be improved and a set of germplasm lines (P 1 P 2 ..., P f), the procedure consists of producing all f x m possible hybrids and evaluating them along with the parents. The testcross statistic T ij is defined by T ij=gamma(F ij-A j)+(1-gamma) (F ij-P i), where A j, P i, and F ij represent the performance of thej (th) adapted line, the i (th) germplasm line, and their hybrid, respectively. The statistic [Formula: see text] is the mean value of T ij over all adapted parents A j. If gamma=(1/2)(1+d'), where d' = the mean degree of dominance, then T ij measures the potential for alleles from P i to improve A j and [Formula: see text] measures the potential for alleles from P i to improve the set A 1, A 2 ..., A m. Use of data on soybean and peanut hybrids published by other researchers suggests that the value assumed for d' has little effect on the P i chosen. The ability of the T ij and [Formula: see text] statistics to identify germplasm strains carrying rare favorable alleles should be assessed in empirical studies. PMID- 24166120 TI - Association of RFLP markers with loci conferring broad-based resistance to the soybean cyst nematode (Heterodera glycines). AB - Soybean cyst nematode (SCN) is a major soybean yield-limiting pest. The present study was conducted to map broad-based SCN resistance loci from the cultivar 'Hartwig'. Two-hundred F2?3 lines derived from the cross 'Williams 82' x 'Hartwig' were screened with a fourth-generation SCN inbred and 56 polymorphic molecular markers. Allele states and phenotypes were analyzed using stepwise regression and the model selection was made at P [Symbol: see text] 0.01. Four unlinked RFLP markers (A006, A567, A487, A112) were associated with SCN resistance and the partial coefficient of determinations (R(2)) were 91%, 1%, 1%, and 1%. We have mapped a new, major SCN resistance locus (A006) and three minor loci (A567, A487, A112). This complete mapping will accelerate the transfer of broad-based resistance without linkage drag and aid in the determination of relationships among various SCN-resistant germplasm sources. PMID- 24166121 TI - Verification of barley seed dormancy loci via linked molecular markers. AB - Seed dormancy is a relatively complex trait in barley (Hordeum vulgare L.). Several dormancy loci were identified previously by quantitative trait locus analysis. Three reciprocal crosses were made in the present study between parents carrying specific dormancy alleles via linked molecular markers to verify individual dormancy locus effects and potential expression. Analyses of F2 progenies revealed that the dormancy allele at the locus flanked by the markers Ale and ABC302 on the long arm of chromosome 7 had a major effect on dormancy, and was at least partly epistatic to the dormancy locus in the ABC309-MWG851 interval near the telomere of the long arm of chromosome 7. In the absence of the dormancy allele in the Ale-ABC302 interval, the allele in the ABC309-MWG851 interval exerted moderate to large effects on dormancy. Cytoplasmic effects on dormancy were also observed. The germination percentages of progeny with relatively high levels of dormancy were more variable than those of non-dormant or less-dormant progeny, apparently due to environmental effects. Removal of the dormancy allele in the Ale-ABC302 interval, or introducing the dormancy allele in the ABC309-MWG851 interval, should suffice for adjusting dormancy levels in breeding programs to suit various production situations and end uses. The verification of dormancy loci via linked molecular markers allows manipulation of these loci in applied breeding programs. PMID- 24166122 TI - A phylogenetic analysis of Pisum based on morphological characters, and allozyme and RAPD markers. AB - Cladistic analyses of 17 wild and cultivated pea taxa were performed using morphological characters, and allozyme and RAPD (random amplified polymorphic DNA) markers. Both branch-and-bound and bootstrap searches produced cladograms that confirmed the close relationships among the wild species and cultivars of Pisum proposed by a variety of systematic studies. Intraspecific rankings were supported for northern P. humile, southern P. humile, P. elatius and P. sativum, which together comprise a single-species complex. P. fulvum, while clearly the most divergent of the pea taxa, could also be assigned to the same species complex without violating the hierarchial logic of the cladogram. Its inclusion or exclusion depends on whether the level of interfertility it displays with other pea taxa or its overall morphological and chromosomal distinction are emphasized. As suggested by previous studies, northern P. humile was the most likely sister taxon to cultivated P. sativum; although, rigorous phylogenetic evaluation revealed a close genealogical affinity among P. elatius, northern P. humile and P. sativum. Despite their limited number, the 16 morphological characters and allozyme markers used precisely organized the pea taxa into established taxonomic groupings, perhaps in part reflecting the role morphology has played historically in pea classification. The RAPD data also generally supported these same groupings and provided additional information regarding the relationships among the taxa. Given that RAPDs are relatively quick and easy to use, are refractory to many environmental influences, can be generated in large numbers, and can complement traditional characters that may be limited in availability, they provide a valuable new resource for phylogenetic studies. PMID- 24166123 TI - Recombination around the Tm2a and Mi resistance genes in different crosses of Lycopersicon peruvianum. AB - The amount of recombination in three different intraspecific crosses of the wild tomato species Lycopersicon peruvianum was investigated for the short arm of chromosome 6 that harbors the Mi nematode resistance gene and the centromeric region of chromosome 9 that contains the Tm2a virus resistance gene. These two genes have been introgressed into the cultivated tomato and are associated with a significant reduction in recombination in the respective region when crossed to other L. esculentum lines. For both regions and all crosses within L. peruvianum significantly more recombination (up to more than ten fold) was observed in the gametes derived from the female parent than in those from the male parent. In general, the differences were more pronounced for chromosome 6 than for chromosome 9. The amount of recombination in the three intraspecific L. peruvianum crosses was compared with the amount of recombination observed in the standard interspecific cross used for the construction of a saturated genetic map of tomato (L. esculentum x L. pennellii). In two of three cases for each region, more recombination was observed in the intraspecific crosses and in one case for each region significantly less recombination was found in the intraspecific cross when compared to the interspecific cross. Specifically for the Mi-carrying region, crosses within L. peruvianum exhibited up to 15-fold more recombination than crosses between resistant and susceptible L. esculentum lines, and such crosses will allow the fine mapping of this gene for the purpose of map-based cloning. PMID- 24166124 TI - Sex ratio in silver foxes: effects of domestication and the star gene. AB - The course of changes in secondary sex ratio (proportion of males at birth) in silver foxes bred at the fur farm of this Institute was analyzed. Data collected over several years of breeding of a domesticated (experimental) population selected for amenability to domestication and of a commercial (control) were compared. A tendency to increase in secondary sex ratio was demonstrated in both populations. However, the proportion of males at birth was higher in domestic foxes. This proportion, calculated from the combined data for 1978-1993, was 0.538+/-0.005 and 0.511+/-0.007 in the selected and commercial populations, respectively. The minimal departure of the observed sex ratio from 0.5 was demonstrated for litters with five pups, which is close to the average litter size in fox populations. The proportion of males increases with both increasing and decreasing litter size. An analysis of secondary sex ratio with respect to maternal age revealed a minimal departure of sex ratio from the expected in offspring from foxes of optimal reproductive age (2-4 years). An effect of the autosomal semidominant coat color mutation star on male excess at birth was also found: secondary sex ratio was higher (0.583+/-0.015) in offspring of mothers heterozygous for the star mutation than from standard types of the domesticated population. The increase in secondary sex ratio in the analyzed fox populations is viewed as a correlated response to selection for domestication. The hormonal mechanisms mediating the effects of both this selection and the star mutation on sex ratio at birth are discussed. PMID- 24166125 TI - Identification of Haynaldia villosa chromosomes added to wheat using a sequential C-banding and genomic in situ hybridization technique. AB - Genomic in situ hybridization (GISH) offers a convenient and effective method for cytological detection, but can not determine the identity of the chromosomes involved. We integrated C-banding with GISH to identify Haynaldia villosa chromosomes in a wheat background. All chromosomes of H. villosa showed C-bands, either in telomeric regions or in both telomeric and centromeric regions, which allowed unequivocal identification of each H. villosa chromosome. The seven pairs of H. villosa chromosomes were differentiated as 1-7 according to their characteristic C-bands. Using a sequential C-banding and GISH technique, we have analyzed somatic cells of F3 plants from the amphiploid Triticum aestivum-H. villosa x 'Yangmai 158' hybrids. Three plants (94009/5-4,94009/5-8 and 94009/5-9) were shown to contain H. villosa chromosome(s). 94009/5-4 (2n = 45) had three H. villosa chromosomes (2, 3 and 4); 94009/5-8 (2n = 45) possessed one chromosome 4 and a pair of chromosome 5, and 94009/5-9 (2n = 43) was found to have one chromosome 6 of H. villosa. The combination of GISH with C-banding described here provides a direct comparison of the cytological and molecular landmarks. Such a technique is particularly useful for identifying and localizing alien chromatin and DNA sequences in plants. PMID- 24166126 TI - The dosage effect of the wildtype GBSS allele is linear for GBSS activity but not for amylose content: absence of amylose has a distinct influence on the physico chemical properties of starch. AB - A gene-dosage population was obtained by crossing two genotypes that were duplex for the GBSS allele. Nulliplex, simplex, duplex or triplex/quadruplex plants could be identified by monitoring the segregation of red and blue microspores after staining with iodine. GBSS activity was significantly different for all groups and showed an almost linear dosage effect for the wildtype GBSS gene. A dosage effect was found for amylose content that was not linear. The amylose content was similar for both the duplex and triplex/quadruplex group. Within the simplex group, differences in amylose content were found, which might be due to a different genetic background. There was no linear correlation between GBSS activity and amylose content. A certain level of GBSS activity led to a maximum amount of amylose, and further increase in GBSS activity did not result in a further increase in amylose content. The presence of one or more wildtype GBSS allele(s), and therefore the presence of amylose in the starch granules, had a great influence on the physico-chemical properties of the starch suspensions. PMID- 24166127 TI - Correction: power of tests for QTL detection using replicated progenies derived from a diallel cross. PMID- 24166129 TI - The association between pollen size and Renner complex in Oenothera villaricae and O. picensis ssp. picensis and their hybrids: evidence for preanthesis pollen competition. AB - In both Oenothera villaricae Dietrich and O. picensis ssp. picensis, chromosomes are transmitted as two Renner complexes. Reciprocal combinations of the Renner complexes produce eight different F1 hybrids, but only seven are viable. Each species, and each F1 hybrid, produces three sizes of pollen, approximately 50% small sterile grains, 15% medium-sized viable grains and 35% large viable grains. Medium- and large-sized grains were separated manually and subjected to random amplified polymorphic DNAs (RAPDs) analysis. A pattern of RAPD amplifications was obtained which indicates that, for each species and F1 hybrid, one specific Renner complex characterizes the medium- and another the large-sized viable pollen. The results indicate that pollen size is determined in part by the pollen genotype and in part by the genotype of the other pollen grains developing within the same anther. PMID- 24166128 TI - Use of deterministic sampling for exploring likelihoods in linkage analysis for quantitative traits. AB - Deterministic sampling was used to numerically evaluate the expected log likelihood surfaces of QTL-marker linkage models in large pedigrees with simple structures. By calculating the expected values of likelihoods, questions of power of experimental designs, bias in parameter estimates, approximate lower-bound standard errors of estimates and correlations among estimates, and suitability of statistical models were addressed. Examples illustrated that bracket markers around the QTL approximately halved the standard error of the recombination fraction between the QTL and the marker, although they did not affect the standard error of the QTL's effect, that overestimation of the distance between the markers caused overestimation of the distance between the QTL and marker, that more parameters in the model did not affect the accuracy of parameter estimates, that there was a moderate positive correlation between the estimates of the QTL effect and its recombination distance from the marker, and that selective genotyping did not introduce bias into the estimates of the parameters. The method is suggested as a useful tool for exploring the power and accuracy of QTL linkage experiments, and the value of alternative statistical models, whenever the likelihood of the model can be written explictly. PMID- 24166130 TI - Cytomegalovirus oral ulcers. PMID- 24166131 TI - Klebsiella spp. in endoscopy-associated infections: we may only be seeing the tip of the iceberg. AB - PURPOSE: Two endoscopy-associated nosocomial outbreaks caused by carbapenemase producing Klebsiella pneumoniae (CPKP) were recently observed in two German hospitals. In this study, we performed a systematic search of the medical literature in order to elucidate the epidemiology of Klebsiella spp. in endoscopy associated outbreaks. METHODS: Medline, the Outbreak Database ( http://www.outbreak-database.com ) and reference lists of articles extracted from these databases were screened for descriptions of endoscopy-associated nosocomial outbreaks. The data extracted and analysed were: (1) the type of medical department affected; (2) characterisation of pathogen to species and conspicuous resistance patterns (if applicable); (3) type of endoscope and the grade of its contamination; (4) number and the types of infections; (5) actual cause of the outbreak. RESULTS: A total of seven nosocomial outbreaks were identified, of which six were outbreaks of endoscopic retrograde cholangiopancreatography related infections and caused by contaminated duodenoscopes. Including our own outbreaks in the analysis, we identified one extended-spectrum beta-lactamase producing K. pneumoniae strain and six CPKP strains. Insufficient reprocessing after the use of the endoscope was the main reason for subsequent pathogen transmission. CONCLUSIONS: There were only two reports of nosocomial outbreaks due to Klebsiella spp. in the first three decades of endoscopic procedures, but seven additional outbreaks of this kind have been reported within the last 4 years. It is very likely that many of such outbreaks have been missed in the past because this pathogen belongs to the physiological gut flora. However, with the emergence of highly resistant (carbapenemase-producing) strains, strict adherence to infection control guidelines is more important than ever. PMID- 24166132 TI - Postulates on electromagnetic activity in biological systems and cancer. AB - A framework of postulates is formulated to define the existence, nature, and function of a coherent state far from thermodynamic equilibrium in biological systems as an essential condition for the existence of life. This state is excited and sustained by energy supply. Mitochondria producing small packets of energy in the form of adenosine and guanosine triphosphate and strong static electric field around them form boundary elements between biochemical-genetic and physical processes. The transformation mechanism of chemical energy into useful work for biological needs and the excitation of the coherent state far from thermodynamic equilibrium are fundamental problems. The exceptional electrical polarity of biological objects and long-range interactions suggest a basic role of the endogenous electromagnetic field generated by living cells. The formulated postulates encompass generation, properties and function of the electromagnetic field connected with biological activity and its pathological deviations. Excited longitudinal polar oscillations in microtubules in eukaryotic cells generate the endogenous electromagnetic field. The metabolic activity of mitochondria connected with water ordering forms conditions for excitation. The electrodynamic field plays an important role in the establishment of coherence, directional transport, organization of morphological structures, interactions, information transfer, and brain activity. An overview of experimental results and physical models supporting the postulates is included. The existence of the endogenous biological electromagnetic field, its generation by microtubules and supporting effects produced by mitochondria have a reasonable experimental foundation. Cancer transformation is a pathological reduction of the coherent energy state far from thermodynamic equilibrium. Malignancy, i.e. local invasion and metastasis, is a direct consequence of mitochondrial dysfunction, disturbed microtubule polar oscillations and the generated electromagnetic field. PMID- 24166133 TI - Comparison of the surgical treatment strategies for Siewert type II squamous cell carcinoma in the same area as esophagogastric junction carcinoma: data from a single Japanese high-volume cancer center. AB - PURPOSE: Siewert type II esophagogastric junction adenocarcinoma (ADC) and squamous cell carcinoma (SCC) existing in the same area have distinct clinicopathological characteristics. The objective of this study was to examine differences in the surgical treatment and survival data, according to the histological subtype, in a single high-volume cancer center. METHODS: We retrospectively examined data from a total of 123 patients. Seventy-two patients with Siewert type II ADC and 51 patients with SCC in the same area. RESULTS: In terms of the clinicopathological factors, the SCC patients had more advanced stage disease and thoracotomy was more frequently performed than in the ADC patients. The 5-year overall survival (OS) rates did not differ significantly between SCC and ADC, regardless of whether or not mediastinal, splenic hilum and para-aortic lymph node dissection was performed. Based on the calculated index for the frequency of nodal metastasis and the five-year OS rate for involvement at each level, only node nos. 1, 2, 3 and 7 had a high index (>5) in both groups. The multivariate Cox regression analysis showed that only age (<65), the pN category and residual tumor classification were independently associated with the outcome. CONCLUSIONS: Differences in the histological type of esophagogastric junction cancer were not independent prognostic factors for survival, and there appears to be a benefit to dissecting the number 1, 2, 3 and 7 lymph nodes. PMID- 24166134 TI - The global burden of skin disease in 2010: an analysis of the prevalence and impact of skin conditions. AB - The Global Burden of Disease (GBD) Study 2010 estimated the GBD attributable to 15 categories of skin disease from 1990 to 2010 for 187 countries. For each of the following diseases, we performed systematic literature reviews and analyzed resulting data: eczema, psoriasis, acne vulgaris, pruritus, alopecia areata, decubitus ulcer, urticaria, scabies, fungal skin diseases, impetigo, abscess, and other bacterial skin diseases, cellulitis, viral warts, molluscum contagiosum, and non-melanoma skin cancer. We used disability estimates to determine nonfatal burden. Three skin conditions, fungal skin diseases, other skin and subcutaneous diseases, and acne were in the top 10 most prevalent diseases worldwide in 2010, and eight fell into the top 50; these additional five skin problems were pruritus, eczema, impetigo, scabies, and molluscum contagiosum. Collectively, skin conditions ranged from the 2nd to 11th leading cause of years lived with disability at the country level. At the global level, skin conditions were the fourth leading cause of nonfatal disease burden. Using more data than has been used previously, the burden due to these diseases is enormous in both high- and low-income countries. These results argue strongly to include skin disease prevention and treatment in future global health strategies as a matter of urgency. PMID- 24166136 TI - Prenatal genetic counseling referrals for advanced maternal age: still room for improvement. AB - OBJECTIVE: The objective of this study is to evaluate genetic risks already present before pregnancy in a cohort of pregnant women referred for prenatal genetic counseling exclusively for advanced maternal age (AMA). METHOD: We retrospectively reviewed the records of 1353 women referred over 1 year (2010) for pre-test genetic counseling with the only indication of AMA at three Italian Clinical Genetic Services. RESULTS: Of the 1353 women fulfilling the inclusion criteria of the study, 87 (6.4%) had cumulatively 94 genetic risk factors not previously identified (one risk factor in 80 patients and two risk factors in seven). Twenty-six risk factors (27.7%) concerned heterogeneous or multifactorial conditions and 68 (72.3%) Mendelian or chromosomal disorders and consanguinity.In nine out of these 87 women, the estimated risk for the offspring of a genetic disease or a significant structural anomaly was >5%. Additional testing according to the identified risks was performed in 36 of these 87 women/families. CONCLUSIONS: The proportion of cases with additional risk factors is smaller than reported in previous studies, but it remains substantial and confirms the need for strategies to increase awareness of the public and health professionals responsible for the care of women in childbearing age. PMID- 24166137 TI - DAPK and cytoskeleton-associated functions. AB - Death-associated protein kinase (DAPK) undergoes activation in response to various death stimuli, and they have been associated with an increase in DAPK catalytic activity. One of the most prominent features of DAPK-induced cell death is the effect on the cytoskeleton, including loss of matrix attachment, and membrane blebbing. One known cytoskeletal-associated substrate of DAPK is the myosin-II light chain, phosphorylated by DAPK on Ser(19), thus stabilizing actin stress fibres. Moreover, paxillin, a component of focal adhesions, was found to be localized in close proximity to the tips of the DAPK-positive filaments, indicating that stress fibres containing DAPK extend to focal contacts. Forced expression of DAPK in multiple cell types results in morphological changes such as cell rounding, membrane blebbing, shrinking and detachment. During directed migration, DAPK functions as a potent inhibitor of cell polarization, as evidenced by its perturbation of the formation of static protrusion at the leading edge. Furthermore, DAPK inhibits random migration by suppressing directional persistence. One of the studies considered DAPK as an anoikis inducer. Others showed that DAP-kinase inhibits the activities of cell surface integrins by converting them into an inactive conformation. Biochemical experiments have established the DAPK binding to Syntaxin1 and its subsequent phosphorylation at Ser(188) in a Ca(2+) dependent manner. This phosphorylation event has been shown to decrease the binding of Syntaxin to MUNC18-1, a protein critically involved in synaptic vesicle docking. Here, we have investigated the structural interactions that modulate DAPK phosphorylation with Syntaxin and its functional role in binding to the MUNC18-1 to regulate vesicle docking. This review will summarize our current knowledge of the role of DAPK on cytoskeleton reorganization and report the mechanisms that regulate these changes. PMID- 24166135 TI - Preclinical studies of a specific PPARgamma modulator in the control of skin inflammation. AB - Peroxisome proliferator-activated receptor gamma (PPARgamma) antagonizes inflammatory signals by interfering with NF-kappaB nuclear translocation. Consistently, PPARgamma agonists have been proposed in various inflammatory skin disorders, but their wide use has been limited by severe side effects. Classes of compounds with specific PPARgamma agonism have been designed to selectively target inflammatory pathways. Among these compounds, GED-0507-34L has been developed and recently used in phase II clinical trials for inflammatory bowel diseases. This study was aimed at assessing the role of GED-0507-34L in preclinical models of inflammatory skin diseases. The compound modulated PPARgamma function and suppressed the inflammatory process inhibiting NF-kappaB nuclear translocation with the consequent reduction of inflammatory cytokines expression, such as IL-6, IL-8, IL-12, IL-21, IL-23, tumor necrosis factor-alpha (TNF-alpha), and cyclooxygenase-2 (COX-2) in normal human keratinocytes and lymphocytes treated with lipopolysaccharide (LPS) or TNF-alpha. Moreover, an altered proliferation and expression of differentiation markers induced by TNF alpha were also counteracted. In psoriasis-like skin lesions elicited in mice by IL-21, topical application of GED-0507-34L reduced cellular infiltrate and epidermal hyperplasia, normalizing the differentiation process. The results indicate that GED-0507-34L possesses anti-inflammatory properties useful for the management of patients with inflammatory skin diseases including psoriasis. Phase I trial on patients is ongoing. PMID- 24166138 TI - The functions and regulations of DAPK in cancer metastasis. AB - Metastasis is responsible for most cancer deaths but it remains a poorly understood process. Recent evidence has emerged that death-associated protein kinase (DAPK) is a candidate of metastasis suppressor. DAPK downregulation or inactivation has been observed in a number of metastatic cancers through epigenetic, transcriptional, post-transcriptional, or post-translational mechanism. In certain cases, DAPK downregulation correlates with metastatic recurrence. Animal studies further show that DAPK impedes both early-stage and late-stage metastatic process, which suggests that DAPK possesses multiple mechanisms to suppress metastasis. Cell-based studies revealed that DAPK mediates several types of cell death, including apoptosis, autophagic death and necrosis, depending on death stimuli and cell context. DAPK also regulates cytoskeleton proteins to mediate death-associated cell morphological alterations and to inhibit cell motility. Besides tumor cells, DAPK can influence on stromal cells to regulate their survival and functions. These effects likely all contribute to the metastasis suppressive role of DAPK. The detail molecular mechanisms of these anti-metastatic effects of DAPK are reviewed in this article. PMID- 24166139 TI - Prometaphase arrest-dependent phosphorylation of Bcl-2 and Bim reduces the association of Bcl-2 with Bak or Bim, provoking Bak activation and mitochondrial apoptosis in nocodazole-treated Jurkat T cells. AB - Treatment of Jurkat T cells with the microtubule-depolymerizing agent nocodazole (NOC) caused prometaphase arrest and apoptosis. NOC-induced mitochondrial apoptotic events including Bak activation, Deltapsim loss, cytochrome c release, and caspase cascade activation were blocked by Bcl-2 overexpression. However, mitotic arrest, Cdc25C activation, upregulation of cyclin B1 levels, Cdk1 activation, Bcl-2 phosphorylation at Thr-56 and Ser-70, and Bim phosphorylation were retained. The treatment of Jurkat T cells concomitantly with NOC and the G1/S-blocking agent hydroxyurea resulted in G1/S arrest and complete abrogation of all apoptotic events. The association of Bcl-2 with Bim or Bak declined after the prometaphase arrest-dependent phosphorylation of Bcl-2 and Bim, whereas the association of Bcl-2 with Bax remained relatively constant. Although Bax was redistributed from the cytosol to the mitochondria, resulting in an increase in the mitochondrial level of Bax following NOC treatment, the subcellular localization of Bcl-2, Bim, Bak and apoptosis-inducing factor was confined to the mitochondrial fraction irrespective of NOC treatment. Experiments using selective caspase inhibitors showed that mitochondria-dependent activation of caspase-9 and -3 was crucial for NOC-induced apoptosis. NOC-induced phosphorylation of Bcl-2 and Bim, Deltapsim loss, and mitochondria-dependent apoptotic events were significantly suppressed by a Cdk1 inhibitor roscovitine, but not by the JNK inhibitor SP600125 or the p38 MAPK inhibitor SB203580. These results show that the prometaphase arrest-dependent phosphorylation of Bcl-2 and Bim, which was mediated by Cdk1, could reduce the association of Bcl-2 with Bak or Bim to allow Bak activation and mitochondrial apoptotic events in Jurkat T cells exposed to NOC. PMID- 24166140 TI - Can maternal recalled birth size be used as a proxy measure of birth weight? An evaluation based on a population health survey in Oman. AB - To evaluate the utility of maternal recalled birth size (BS) as a proxy measure for actual birth weight (BW) when BW data are missing. Data for the study come from the 2000 National Health Survey of Oman. Frequency distribution, sensitivity and specificity analysis, bivariate, and multivariate statistical techniques were used for data analysis. The BW data exhibited a moderate level of heaping on measurements ending in 0 or 5, suggesting that health personnel often round when recording. About 31% of actual BW data were missing due to non-availability of health cards. Maternal assessment of BS was found to be closely linked to BW on an aggregate level. However, on an individual level, there was misclassification of birth weights across all categories of BS. The overall agreement between recalled BS and recorded BW was moderate (kappa = 0.44). Infants with missing BW records were more likely to be low birth weight (LBW). Maternal recalled BS appeared to be a poor proxy for BW. Estimates of LBW based on maternal assessments of BS as small should be considered as an underestimate of its actual prevalence. As infants with missing BW data have different characteristics from those with recorded BW, estimates of LBW depending solely on available BW records will produce a biased prevalence. Health personnel should record actual BW without rounding. They should inform mothers of the birth weight and advise them to retain health cards for future reference. PMID- 24166141 TI - Phosphine-catalyzed [3 + 2] cycloaddition of Morita-Baylis-Hillman carbonates with sulfamate-derived cyclic imines. AB - Phosphine-catalyzed [3 + 2] cycloaddition of Morita-Baylis-Hillman carbonates with sulfamate-derived cyclic imines has been developed, affording sulfamate fused dihydropyrroles in moderate to good yields. PMID- 24166142 TI - Diabetic nephropathy: Sirt1 attenuates diabetic albuminuria. PMID- 24166143 TI - Critical care: Mortality risk in the CRISTAL trial. PMID- 24166144 TI - Dialysis: Systemic IL-6 levels predict survival after peritoneal dialysis. AB - In a recent study, Lambie and colleagues suggest that systemic and local intraperitoneal inflammation, evidenced by elevated levels of interleukin-6, are independent processes and have different consequences for patients undergoing peritoneal dialysis. Prevention of inflammation in these patients will, therefore, require different therapeutic approaches. PMID- 24166145 TI - Immunity activation in brain cells in epilepsy: mechanistic insights and pathological consequences. AB - The search of targets for developing novel drugs that can control seizures resistant to available treatments in children and adults represents a great challenge for basic science. In the past decade, emerging evidence pointed out to the crucial role played by glia, the innate immunity brain-resident cells, in the generation of hyperexcitable neuronal networks underlying seizures. Molecular and pharmacological studies targeting glia, and the inflammatory mediators released by these cells in experimental models of epilepsy, highlighted novel targets for drug intervention aimed at interfering with the disease mechanisms, therefore providing putative disease-modifying treatments. This article will focus on the role of immunity activation in the brain and the concomitant release by glia of inflammatory molecules with neuromodulatory properties, in the pathogenesis of epileptic seizures, cell loss, and comorbidities. PMID- 24166146 TI - Role of autoantibodies in acquired inflammatory demyelinating diseases of the central nervous system in children. AB - The recent detection of aquaporin-4 (AQP4) and myelin oligodendrocyte glycoprotein (MOG) autoantibodies in acquired inflammatory demyelinating diseases, such as neuromyelitis optica, or acute disseminated encephalomyelitis, and multiple sclerosis, in children strongly indicates that B-cell-dependent mechanisms contribute to the pathogenesis. This review aims to give an overview of the role of autoantibodies in inflammatory demyelinating pediatric diseases, with a focus on antibodies to AQP4 and MOG. PMID- 24166147 TI - Rare inflammatory diseases of the white matter and mimics of multiple sclerosis and related disorders. AB - The spectra of white matter neuroinflammatory diseases and pathological processes inducing inflammatory lesions in the white matter of the central nervous system are wider in children than in adults. The definitions of multiple sclerosis (MS) and of the related clinically isolated syndromes (CIS) and acute disseminated encephalomyelitis (ADEM) have been recently revised leading to a new consensus definition. However, other entities with similarities to these diseases may also develop with monophasic or relapsing white matter inflammation. These conditions include congenital immunogenetic diseases (such as hemophagocytic lymphohistiocytosis), vasculitis, and autoantibody-mediated encephalopathies (Hashimoto encephalopathy, encephalitis with anti-N-methyl-D-aspartate receptor antibodies and neuromyelitis optica). Moreover, infectious diseases, such as Lyme disease, tumors (oligodendroglioma and lymphoma), and even genetic or metabolic diseases should also be considered if the clinical course of the disease does not follow the typical pattern for ADEM or MS. This short review describes these different entities and provides information for the differential diagnosis of inflammatory diseases of the white matter. PMID- 24166148 TI - Molecular determinants of outcome with mammalian target of rapamycin inhibition in endometrial cancer. AB - BACKGROUND: Targeting the phosphatidylinositol 3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) pathway is of increasing interest as a therapeutic strategy in many tumors. The aim of this study was to identify molecular markers associated with mTOR inhibitor activity in women with metastatic endometrial cancer. METHODS: Archival tumor samples were collected from 94 women with recurrent or metastatic endometrial cancer who participated in 3 National Cancer Insitute of Canada Clinical Trials Group phase 2 trials investigating single agent mTOR inhibitors: IND160A and IND160B (temsirolimus) and IND192 (ridaforolimus). Analyses included mutational profiling using the OncoCarta Panel version 1.0 and immunohistochemical expression of the tumor suppressor gene PTEN (phosphatase and tensin homologue) and stathmin, a marker of PI3K activation. Associations between biomarker results and clinical outcomes were assessed. RESULTS: Mutations were found in 32 of 73 analyzed tumors, PIK3CA (21 patients) was the most common mutated gene. Co-mutations were seen in 8 tumors, most frequently KRAS and PIK3CA (4 cases). PTEN loss was observed in 46 of 85 samples analyzed and increased stathmin expression was observed in 15 of 65 analyzed samples. No correlation was observed between biomarkers and response or progression. In patients taking concurrent metformin, there was a trend toward lower progression, of 11.8% versus 32.5% (P = .14). CONCLUSIONS: No predictive biomarker or combination of biomarkers for mTOR inhibitor activity were identified in this study. Restriction and enrichment of study entry, especially based on archival tumor tissue, should be undertaken with caution in trials using these agents. PMID- 24166149 TI - Infrared stabilization of rice bran and its effects on gamma-oryzanol content, tocopherols and fatty acid composition. AB - BACKGROUND: Rice bran is a nutritionally valuable by-product of paddy milling. In this study an experimental infrared (IR) stabilization system was developed to prevent rice bran rancidity. The free fatty acid content of raw and IR-stabilized rice bran samples was monitored every 15 days during 6 months of storage. In addition, energy consumption was determined. RESULTS: The free fatty acid content of rice bran stabilized at 600 W IR power for 5 min remained below 5% for 165 days. No significant change in gamma-oryzanol content or fatty acid composition but a significant decrease in tocopherol content was observed in stabilized rice bran compared with raw bran. IR stabilization was found to be comparable to extrusion with regard to energy consumption. CONCLUSION: IR stabilization was effective in preventing hydrolytic rancidity of rice bran. By optimizing the operational parameters of IR stabilization, this by-product has the potential for use in the food industry in various ways as a value-added commodity. PMID- 24166150 TI - Comparative efficacy, pharmacokinetic, pharmacodynamic activity, and interferon stimulated gene expression of different interferon formulations in HIV/HCV genotype-1 infected patients. AB - The effect of different formulations of interferon on therapeutic response in patients coinfected with HIV and HCV is unclear. In this study, the safety, tolerability, viral kinetics (VK) modeling and host responses among HIV/HCV coinfected patients treated with pegylated-IFN or albinterferon alfa-2b (AlbIFN) with weight-based ribavirin were compared. Three trials treated 57 HIV/HCV coinfected genotype-1 patients with PegIFN alfa-2b (1.5 ug/kg/week) (n = 30), PegIFN alfa-2a (180 ug/week) (n = 10), and AlbIFN (900 ug/q2week) (n = 17) in combination with weight-based ribavirin (RBV). HCV RNA, safety labs, and interferon stimulated gene expression (ISG) was evaluated. Adverse events were documented at all study visits. HCV viral kinetics using a full pharmacokinetic/pharmacodynamic model was also evaluated. Baseline patient characteristics were similar across the three studies. All three formulations exhibited comparable safety and tolerability profiles and efficacy. VK/PK/PD parameters for all three studies as measured by mean efficiency and rate of infected cell loss were similar between the three groups. Host responses (ISG expression and immune activation markers) were similar among the three groups. All three regimens induced significant ISG at week 4 (P < 0.05) and ISG expression strongly correlated with therapeutic response (r = 0.65; P < 0.01). In summary, a comprehensive analysis of responses to three different interferon formulations in HIV/HCV coinfected patients demonstrated similar effects. Notably, interferon-based therapy results in a blunted host response followed by modest antiviral effect in HIV/HCV coinfected patients. This suggests that future treatment options that do not rely on host immune responses such as direct antiviral agents would be particularly beneficial in these difficult to treat patients. PMID- 24166151 TI - Band-gap-graded Cu2ZnSn(S1-x,Se(x))4 solar cells fabricated by an ethanol-based, particulate precursor ink route. AB - Solution processing of earth-abundant Cu2ZnSn(S1-x,Sex)4 (CZTSSe) absorber materials is an attractive research area in the economical and large-scale deployment of photovoltaics. Here, a band-gap-graded CZTSSe thin-film solar cell with 7.1% efficiency was developed using non-toxic solvent-based ink without the involvement of complex particle synthesis, highly toxic solvents, or organic additives. Despite the high series resistance due to the presence of a thick Mo(S,Se)x layer and Zn(S,Se) aggregates, a high short-circuit current density (JSC) was generated. In addition, there was no significant difference in open circuit voltages (VOC) between CZTS (0.517 V) and CZTSSe (0.505-0.479 V) cells, despite a significant band gap change from 1.51 eV to 1.24 eV. The high JSC and less loss of VOC are attributed to the effect of band gap grading induced by Se grading in the CZTSSe absorber layer. Our environmentally benign ink approach will enable the realization of low-cost, large-area, high-efficiency thin-film solar cells. PMID- 24166152 TI - The health role of local area coordinators in Scotland: a mixed methods study. AB - The study set out to explore whether local area coordinators (LACs) and their managers view the health role of LACs as an essential component of their work and identify the health-related activities undertaken by LACs in Scotland. A mixed methods cross-sectional phenomenological study involving local authority service managers (n = 25) and LACs (n = 40) was adopted. Quantitative data from LACs were obtained using online and postal questionnaires. Qualitative data from local authority service managers and LACs were collected using one-to-one interviews and focus groups. Thematic analysis was undertaken of the qualitative data. The results indicate that there is a need to develop further the wider public health role of LACs to incorporate health-related activities focused on broader community-based outcomes such as empowerment and community integration. By adopting a public health role, LACs will be able to contribute to the reduction of health inequalities in people with learning disabilities. PMID- 24166154 TI - An endophytic sanguinarine-producing fungus from Macleaya cordata, Fusarium proliferatum BLH51. AB - Fermentation processes using sanguinarine-producing fungi other than Macleaya cordata may be an alternative way to produce sanguinarine (SA), which is a quaternary benzo[c]phenanthridine alkaloid possessing antibacterial, anthelmintic, and anti-inflammatory properties. In this study, a SA-producing endophytic fungus strain BLH51 was isolated from the leaves of M. cordata grown in the Dabie Mountain, China. Strain BLH51 produced SA when grown in potato dextrose liquid medium. The amount of SA produced by this endophytic fungus was quantified to be 178 MUg/L by HPLC, substantially lower than that produced by the host tissue. The fungal SA--which was analyzed by thin layer chromatography and high-performance liquid chromatography--was shown to be identical to authentic SA. Strain BLH51 was identified as Fusarium proliferatum based on the morphological characteristics and nuclear ribosomal DNA ITS sequence analysis. To the best of our knowledge, this is the first report concerning the isolation and identification of endophytic SA-producing fungi from the host plant, which further proved that endophytic fungi are valuable reservoirs of bioactive compounds. PMID- 24166155 TI - Type 2 quorum sensing monitoring, inhibition and biofilm formation in marine microrganisms. AB - The quorum sensing (QS) dependent behaviour of micro-organisms, in particular expression of virulence genes, biofilm formation and dispersal, have provided impetus for investigating practical approaches to interfere with microbial QS. This study tests Halomonas pacifica and Marinobacter hydrocarbonoclasticus, two halophilic marine micro-organism, for their AI-2 dependent QS signalling and the effect of two well-known quorum-sensing inhibitors (QSIs), patulin and penicillic acid, on biofilm formation. We report, for the first time, the successful amplification of a putative luxS gene in H. pacifica using degenerated primers and AI-2 dependent QS as well as inhibition using QSIs. Penicillic acid had a strong inhibitory effect on AI-2 induction of H. pacifica at non-growth inhibitory concentrations, while patulin has an adverse effect only at the highest concentration (25 MUM). QSIs effect on biofilm forming capability was isolate specific, with maximum inhibition at 25 MUM of patulin in H. pacifica. In M. hydrocarbonoclasticus, no adverse effects were noted at any tested concentration of either QSIs. Detection of bioluminescence and the presence of a putative luxS gene provide biochemical and genetic evidence for the production of a signalling molecule(s) which is the essential first step in characterizing H. pacifica QS. This study highlights the importance of AI-2 dependent QS in a marine setting, not previously reported. It further suggests that QSI compounds must be selected in the specific system in which they are to function, and they cannot easily be transferred from one QS system to another. PMID- 24166156 TI - Hybrid soft-lithography/laser machined microchips for the parallel generation of droplets. AB - Microfluidic chips have been developed to generate droplets and microparticles with control over size, shape, and composition not possible using conventional methods. However, it has remained a challenge to scale-up production for practical applications due to the inherently limited throughput of micro-scale devices. To address this problem, we have developed a self-contained microchip that integrates many (N = 512) micro-scale droplet makers. This 3 * 3 cm(2) PDMS microchip consists of a two-dimensional array of 32 * 16 flow-focusing droplet makers, a network of flow channels that connect them, and only two inputs and one output. The key innovation of this technology is the hybrid use of both soft lithography and direct laser-micromachining. The microscale resolution of soft lithography is used to fabricate flow-focusing droplet makers that can produce small and precisely defined droplets. Deeply engraved (h ~ 500 MUm) laser machined channels are utilized to supply each of the droplet makers with its oil phase, aqueous phase, and access to an output channel. The engraved channels' low hydrodynamic resistance ensures that each droplet maker is driven with the same flow rates for highly uniform droplet formation. To demonstrate the utility of this approach, water droplets (d ~ 80 MUm) were generated in hexadecane on both 8 * 1 and 32 * 16 geometries. PMID- 24166157 TI - Effect of herbicide adjuvants on the biodegradation rate of the methylthiotriazine herbicide prometryn. AB - A microbial community, selected by its ability to degrade triazinic herbicides was acclimatized by successive transfers in batch cultures. Initially, its ability to degrade prometryn, was evaluated using free cells or cells attached to fragments of a porous support. As carbon, nitrogen and sulfur sources, prometryn, (98.8 % purity), or Gesagard, a herbicide formulation containing 44.5 % prometryn and 65.5 % of adjuvants, were used. In batch cultures, a considerable delay in the degradation of prometryn, presumptively caused by the elevated concentration of inhibitory adjuvants, occurred. When pure prometryn was used, volumetric removal rates remarkably higher than those obtained with the herbicide formulation were estimated by fitting the raw experimental data to sigmoidal decay models, and differentiating them. When the microbial consortium was immobilized in a continuously operated biofilm reactor, the negative effect of adjuvants on the rate and removal efficiency of prometryn could not be detected. Using the herbicide formulation, the consortium showed volumetric removal rates greater than 20 g m(-3) h(-1), with prometryn removal efficiencies of 100 %. The predominant bacterial strains isolated from the microbial consortium were Microbacterium sp., Enterobacter sp., Acinetobacter sp., and Flavobacterium sp. Finally, by comparison of the prometryn removal rates with others reported in the literature, it can be concluded that the use of microbial consortia immobilized in a biofilm reactor operated in continuous regime offer better results than batch cultures of pure microbial strains. PMID- 24166158 TI - Fluidized-bed denitrification for mine waters. Part II: effects of Ni and Co. AB - The dispersion of nitrogenous compounds and heavy metals into the environment is frequent during mining activities. The effects of nickel (Ni) and cobalt (Co) on denitrification of simulated mine waters were investigated in batch bioassays and fluidized-bed reactors (FBRs). At pH 7, batch tests revealed that Co did not exhibit inhibition on denitrification even at 86.6 mg/L. Ni showed to be inhibitory at 50 and 100 mg/L by decreasing nitrate removal efficiencies of 18 and 65 %, respectively. In two FBRs, operated at 7-8 and 22 degrees C, 5.5 mg/L Ni did not affect nitrate and nitrite removals because of FBR potential of diluting soluble Ni feed concentration. On the contrary, the effluent pH clearly decreased in both FBR1 and FBR2 because of nickel sulfide precipitation and Ni inhibition of the last two steps of denitrification. When Ni injection was stopped, the process recovered more slowly at 22 than 7-8 degrees C. This is the first study reporting the effect of Ni on denitrification in biological FBRs. PMID- 24166159 TI - Fluidized-bed denitrification for mine waters. Part I: low pH and temperature operation. AB - Mining often leads to nitrate and metal contamination of groundwater and water bodies. Denitrification of acidic water was investigated in two up-flow fluidized bed reactors (FBR) and using batch assays. Bacterial communities were enriched on ethanol plus nitrate in the FBRs. Initially, the effects of temperature, low-pH and ethanol/nitrate on denitrification were revealed. Batch assays showed that pH 4.8 was inhibitory to denitrification, whereas FBR characteristics permitted denitrification even at feed pH of 2.5 and at 7-8 degrees C. Nitrate and ethanol were removed and the feed pH was neutralized, provided that ethanol was supplied in excess to nitrate. Subsequently, Fe(II) and Cu impact on denitrification was investigated within batch tests at pH 7. Iron supplementation up to 100 mg/L resulted in iron oxidation and soluble concentrations ranging from 0.4 to 1.6 mg/L that stimulated denitrification. On the contrary, 0.7 mg/L of soluble Cu significantly slowed denitrification down resulting in about 45 % of inhibition in the first 8 h. Polymerase chain reaction-denaturant gradient gel electrophoresis demonstrated the co-existence of different denitrifying microbial consortia in FBRs. Dechloromonas denitrificans and Hydrogenophaga caeni were present in both FBRs and mainly responsible for nitrate reduction. PMID- 24166160 TI - Detection of segregation distortions in an indica-japonica rice cross using a high-resolution molecular map. AB - We have constructed a high-resolution rice genetic map containing 1383 DNA markers covering 1575 cM on the 12 linkage groups of rice using 186 F2 progeny from a cross between a japonica variety, 'Nipponbare', and an indica variety, 'Kasalath'. Using this high-resolution molecular linkage map, we detected segregation distortion in a single wide cross of rice. The frequencies of genotypes for 1181 markers with more than 176 genotype data were plotted along this map to detect segregation distortion. Several types of distorted segregation were observed on 6 of the chromosomes. We could detect 11 major segregation distortions at ten positions on chromosomes 1, 3, 6, 8, 9, and 10. The strongest segregation distortion was at 107.2 cM on chromosome 3 and may be the gametophyte gene 2 (ga-2). The 'Kasalath' genotype at this position was transmitted to the progeny with about a 95% probability through the pollen gamete. At least 8 out of the 11 segregation distortions detected here are new. The use of the high resolution molecular linkage map for improving our understanding of the genetic nature and cause of these segregation distortions is discussed. PMID- 24166161 TI - Molecular characterization of RAPD and SCAR markers linked to the Tm-1 locus in tomato. AB - We have cloned and sequenced six RAPD fragments tightly linked to the Tm-1 gene which confers tomato mosaic virus (ToMV) resistance in tomato. The terminal ten bases in each of these clones exactly matched the sequence of the primer for amplifying the corresponding RAPD marker, except for one in which the 5'-endmost two nucleotides were different from those of the primer. These RAPD clones did not cross-hybridize with each other, suggesting that they were derived from different loci. From Southern-hybridization experiments, five out of the six RAPD clones were estimated to be derived from middle- or high-repetitive sequences, but not from any parts of the ribosomal RNA genes (rDNA), which are known to be tightly linked with the Tm-1 locus. The remaining clone appeared to be derived from a DNA family consisting of a few copies. These six RAPD fragments were converted to sequence characterized amplified region (SCAR) markers, each of which was detectable using a pair of primers having the same sequence as that at either end of the corresponding RAPD clone. All pairs of SCAR primers amplified distinct single bands whose sizes were the same as those of the RAPD clones. In four cases, the SCAR markers were present in the line with Tm-1 but absent in the line without it, as were the corresponding RAPD markers. In the two other cases, the products of the same size were amplified in both lines. When these SCAR products were digested with different restriction endonucleases which recognize 4 bp sequences, however, polymorphisms in fragment length were found between the two lines. These co-dominant markers are useful for differentiating heterozygotes from both types of homozygote. PMID- 24166162 TI - Efficient isolation of non-chimeric tetraploids artificially induced in a stable culture of Haplopappus gracilis. AB - A method for reducing cytochimerism and inducing homogeneous tetraploids in Haplopappus gracilis (2n = 4) was developed in which masses of shoot primordia treated with 0.5 mg/ml of colcemid for 3 days were cut into small meristematic domes. All of the shoot primordia sampled just after the colcemid treatment were cytochimeras that were mixoploids of 2x, 4x and 8x cells. However, when they were allowed to recover in a colcemid-free medium, the frequency of 4x cells spontaneously increased in most of the shoot primordia. Thirty days after the recovery, chimeric masses containing shoot primordia, each of which consisted uniformly of 4x or 2x cells, were observed. In order to obtain a completely homogeneous tetraploid mass, we then cut these primordia into small pieces, each of which had approximately one meristematic dome. Subsequent to this homogeneous tetraploid masses were easily obtained. Tetraploid shoot primordia could propagate with chromosomal stability over a year, and plants regenerated from these tetraploid shoot primordia were also completely tetraploid. These results show that non-chrimeric masses can be easily isolated from artificially induced cytochimeras using masses of shoot primordia as material. PMID- 24166164 TI - Intergeneric somatic hybrid plantlets between Dianthus barbatus and Gypsophila paniculata obtained by electrofusion. AB - Hypocotyl-derived protoplasts of Dianthus barbatus that had been pretreated with iodoacetamide were fused electrically with cell suspension culture-derived protoplasts of Gypsophila paniculata that could divide to form callus but could not regenerate shoots under the culture conditions used in this study. Electrofusion-derived calli which produced shoots were selected as putative somatic hybrids, and plantlets were subsequently regenerated from 2 of these selected calli. These plantlets, which in vitro produced flowers precociously, were identified as intergeneric somatic hybrids by nuclear ribosomal DNA analysis. Normal plants have not been established up to the present. PMID- 24166163 TI - Plant regeneration from immature embryos of 48 elite CIMMYT bread wheats. AB - Forty-eight bread wheat (Triticum aestivum L.) released cultivars and elite advanced lines were evaluated for their ability to produce embryogenic callus using three different media. Basal N6 medium supplemented with dicamba (E1), MS medium containing 2,4-D (E3) or MS medium containing 2,4-D plus different amino acids (E5) were used for callus initiation and maintenance. Plant regeneration was achieved on basal MS medium with indole-3-acetic acid (IAA) and 6-benzylamino purine (BAP) and rooting on MS with 1-naphthaleneacetic acid (NAA). Percentage regeneration varied widely with both genotype and initiation medium, with values ranging from 2% to 94%. The number of plantlets produced per embryo ranged from 6 to 42. Thirteen genotypes showed at least 50% regeneration after culture on E5 medium; 3 genotypes after culture on E3 initiation medium and 1 after initiation on E1. After four subcultures, over a 16-week period, 41 genotypes (85%) lost their ability to regenerate plants while the remaining 7 lines (15%) retained plant regeneration potential but at reduced levels. E3 medium was found to be the best for maintaining regeneration potential after four subcultures. PMID- 24166165 TI - C-banding analysis on wild Emmer (Triticum dicoccoides Korn) strains with and without spontaneous reciprocal translocations. AB - C-banding polymorphism was analyzed in eight strains of wild Emmer, Triticum dicoccoides Korn, which included six translocation homozygotes reported previously. Polymorphisms were detected in all of the strains examined, and the breakpoints of five spontaneous translocations were successfully identified by C bands. Of the eight breakpoints that could be precisely identified, one was located in the centromeric region while the remaining seven were located in proximal to distal euchromatic regions. The two breakpoints of one translocation could only be approximately localized to proximal regions due to the scarcity of C-bands. The present results are in contrast with those observed on T. araraticum, another wild tetraploid wheat belonging to the Timopheevi group, in which most of the breakpoints were located in centromeric regions. In T. dicoccoides, the six translocation chromosome types were derived from the standard karyotype primarily by a mechanism other than centric breakage-fusion. PMID- 24166166 TI - Inheritance of high oleic acid content in the seed oil of soybean mutant M23. AB - A mutant line, M23, of soybean [Glycine max (L.) Merr.] was found to have two fold increases in oleic acid content in the seed oil compared with the original variety, Bay. Our objective was to determine the inheritance of the high oleic acid content in this mutant. Reciprocal crosses were made between M23 and Bay. There were no maternal and cytoplasmic effects for oleic acid content. The F1 seeds and F1 plants were significantly different from either parents or the midparent value, indicating partial dominance of oleic acid content in these crosses. The oleic acid content segregated in the F2 seeds and F2 plants in a trimodal pattern with normal, intermediate and high classes, satisfactorily fitting a 1?2?1 ratio. The seeds of a backcross between M23 and F1 segregated into intermediate and high classes in a ratio of 1?1. These results indicated that oleic acid content was controlled by two alleles at a single locus with a partial dominant effect. Thus, the allele in M23 was designated ol and the genotypes of M23 and Bay were determined to be olol and 0l0l, respectively. The oleic acid contents of the F2 seeds and F2 plants were inversely related with the linoleic acid content which segregated in a trimodal pattern with normal, intermediate and low classes in a 1?2?1 ratio. Thus, it was assumed that the low linoleic acid content in M23 was also controlled by the ol alleles. Because a diet with high oleic acid content reduces the content of low density lipoprotein cholesterol in blood plasma, the mutant allele, ol, would be useful in improving soybean cultivars for high oleic acid content. PMID- 24166167 TI - Two new loci for hybrid sterility in cultivated rice (Oryza sativa L.). AB - Female gamete abortion in Indica-Japonica crosses of rice was earlier identified to be due to an allelic interaction at the S-5 locus on chromosome 6. Recently, in other crosses of rice, similar allelic interactions were found at loci designated as S-7 and S-8, located on chromosomes 7 and 6 respectively. All of them are independent of each other. At the S-5 locus, Indica and Japonica rice have S-5 (i) and S-5 (j) alleles respectively and Javanicas, such as Ketan Nangka, have a neutral allele S-5 (n) .The S-5 (i) /S-5 (j) genotype is semi sterile due to partial abortion of female gametes carrying S-5 (j) , but both the S-5 (n) /S-5 (i) and S-5 (n) /S-5 (j) genotypes are fertile. The S-5 (n) allele is thus a "wide-compatibility gene" (WCG), and parents homozygous for this allele are called wide-compatible varieties (WCV). Such parents when crossed with Indica or Japonica varieties do not show F1 hybrid sterility. Wide-compatible parents have been used to overcome sterility barriers in crosses between Indica and Japonica rice. However, a Javanica variety, Ketan Nangka (WCV), showed typical hybrid sterility when crossed to the Indian varieties N22 and Jaya. Further, Dular, another WCV from India, showed typical hybrid sterility when crossed to an IRRI line, IR2061-628-1-6-4-3(IR2061-628). By genetic analyses using isozyme markers, a new locus causing hybrid sterility in crosses between Ketan Nangka and the Indicas was located near isozyme loci Est-1 and Mal-1 on chromosome 4, and was designated as S-9. Another new locus for hybrid sterility in the crosses between Dular and the IR2061-628 was identified and was found linked to four isozyme loci, Sdh-1, Pox-2, Acp-1 and Acp-2, on chromosome 12. It was designated as S-15. On the basis of allelic interactions causing female-gamete abortion, two alleles were found at S-9, S-9 (kn) in Ketan Nangka and S-9 (i) in N22 and Jaya. In the heterozygote, S-9 (kn) /S-9 (i) , which was semisterile, female gametes carrying S-9 (kn) were aborted. The hybrid of Dular and IR2061-628, with a genetic constitution of S-15 (Du) /S-15 (i) , was semi-sterile and the female gametes carrying S-15 (Du) were aborted. A Japonica tester variety, Akihikari, and an Indica variety, IR36, were found to have neutral alleles, S-9 nand S-15 n, at these loci, in addition to S-7 nand at S-7. The accumulation of three neutral alleles into a breeding line should help solve the hybrid sterility problem in wide crosses of rice. PMID- 24166168 TI - Advanced backcross QTL analysis: a method for the simultaneous discovery and transfer of valuable QTLs from unadapted germplasm into elite breeding lines. AB - Advanced backcross QTL analysis is proposed as a method of combining QTL analysis with variety development. It is tailored for the discovery and transfer of valuable QTL alleles from unadapted donor lines (e.g., land races, wild species) into established elite inbred lines. Following this strategy, QTL analysis is delayed until the BC2 or BC3 generation and, during the development of these populations, negative selection is exercised to reduce the frequency of deleterious donor alleles. Simulations suggest that advanced backcross QTL analysis will be effective in detecting additive, dominant, partially dominant, or overdominant QTLs. Epistatic QTLs or QTLs with gene actions ranging from recessive to additive will be detected with less power than in selfing generations. QTL-NILs can be derived from advanced backcross populations in one or two additional generations and utilized to verify QTL activity. These same QTL NILs also represent commercial inbreds improved (over the original recurrent inbred line) for one or more quantitative traits. The time lapse from QTL discovery to construction and testing of improved QTL-NILs is minimal (1-2 years). If successfully employed, advanced backcross QTL analysis can open the door to exploiting unadapted and exotic germplasm for the quantitative trait improvement of a number of crop plants. PMID- 24166169 TI - Inheritance of resistance to potyviruses in Phaseolus vulgaris L. IV. Inheritance, linkage relations, and environmental effects on systemic resistance to four potyviruses. AB - We have examined the genetics of systemic resistance in Phaseolus vulgaris to azuki bean mosaic virus (AzMV) and cowpea aphid-borne mosaic virus (CABMV) and the relationship of this resistance to a phenotypically similar resistance to watermelon mosaic virus (WMV) and soybean mosaic virus (SMV). In P. vulgaris cv 'Great Northern 1140' (GN1140), resistance to SMV and WMV has been attributed to the genes Smv and Wmv, respectively, which have been shown to segregate as a unit. Systemic resistance to AzMV is conferred by two incompletely dominant alleles, Azm1 and Azm2, at unlinked loci. At least three resistance alleles must be present at these two loci for systemic resistance to be expressed in the plant. Systemic resistance to CABMV in GN 1140 is conditioned by a dominant allele that has been designated Cam2. Under some environmental conditions, a recessive allele at an unlinked locus, cam3, also controls a resistant response to CABMV. Resistance to AzMV and CABMV does not assort independently from Wmv/Smv, but also does not consistently cosegregate, suggesting that perhaps in each case one of the factors involved in resistance is associated with Smv/Wmv. PMID- 24166170 TI - Advanced backcross QTL analysis in a cross between an elite processing line of tomato and its wild relative L. pimpinellifolium. AB - Approximately 170 BC2 plants from a cross between an elite processing inbred (recurrent parent) and the wild species Lycopersicon pimpinellifolium LA1589 (donor parent) were analyzed with segregating molecular markers covering the entire tomato genome. Marker data were used to identify QTLs controlling a battery of horticultural traits measured on BC2F1 and BC3 families derived from the BC2 individuals. Despite its overall inferior appearance, L. pimpinellifolium was shown to possess QTL alleles capable of enhancing most traits important in processing tomato production. QTL-NIL lines, containing specific QTLs modifying fruit size and shape, were subsequently constructed and shown to display the transgressive phenotypes predicted from the original BC2 QTL analysis. The potential of exploiting unadapted and wild germplasm via advanced backcross QTL analysis for the enhancement of elite crop varieties is discussed. PMID- 24166171 TI - Genetic analysis of organogenesis in the cotyledons of zygotic embryos of sunflower (Helianthus annuus L.). AB - Crosses were made between five cytoplasmic male-sterile and five restorer sunflower inbred lines. Twenty-five F1 hybrids and their parents were studied for their organogenesis ability in a randomized block design with four replications. Each replication per genotype consisted of ten petri dishes with four expiants. Regeneration medium consisted of full MS medium modified by the addition of hormones and solidified with 6 g/l agar. Statistical analysis showed that both general and specific combining abilities were significant for all of the organogenesis parameters studied, and both showed several significant positive or negative values. General combining ability values were usually higher than those of specific combining ability, indicating the importance of additive genetic control for organogenesis parameters in sunflower. Narrow-sense heritability for the number of explants producing shoots and roots was 65.8%, which suggests that organogenesis of currently inferior inbred lines in sunflower should be improved in a crossing program. PMID- 24166172 TI - Identification of QTLs affecting traits of agronomic importance in a recombinant inbred population derived from a subspecific rice cross. AB - To detect QTLs controlling traits of agronomic importance in rice, two elite homozygous lines 9024 and LH422, which represent the indica and japonica subspecies of rice (Oryza sativa), were crossed. Subsequently a modified single seed-descent procedure was employed to produce 194 recombinant inbred lines (F8). The 194 lines were genotyped at 141 RFLP marker loci and evaluated in a field trial for 13 quantitative traits including grain yield. Transgressive segregants were observed for all traits examined. The number of significant QTLs (LOD [Symbol: see text] 2.0) detected affecting each trait ranged from one to six. The percentage of phenotypic variance explained by each QTL ranged from 5.1% to 73.7%. For those traits for which two or more QTLs were detected, increases in the traits were conditioned by indica alleles at some QTLs Japonica alleles at others. No significant evidence was found for epistasis between markers associated with QTLs and all the other markers. Pleitropic effects of single QTLs on different traits are suggested by the observation of clustering of QTLs. No QTL for traits was found to map to the vicinity of major gene loci governing the same traits qualitatively. Evidence for putative orthologous QTLs across rice, maize, oat, and barley is discussed. PMID- 24166173 TI - Genetic relationships among annual species of Cicer(Fabaceae) using isozyme variation. AB - In order to determine the pattern of genetic diversity within and among the species of Cicer and to estimate interspecific genetic relationships, allelic variation was assayed for 23 isozyme loci in 63 accessions of 11 species of Cicer using starch gel electrophoresis. The total allozymic variation observed in the genus (H t )was equal to 0.60. When partitioned (G st), 96% of this allelic diversity was found among rather than within species. The allelic diversity among species (D st)and allelic diversity within species (H s)were equal to 0.58 and 0.02, respectively. Cicer reticulatum and C. pinnatifidum had the highest proportion of polymorphic loci (17.39%) and the highest mean number of alleles per locus (1.22 and 1.17, respectively). UPGMA cluster analysis of Nei's unbiased genetic distance revealed four genetic groups. One includes C. reticulatum, C. arietinum and C. echino spermum where the first 2 species represent a putative derivative-progenitor pair. A second cluster contains C. bijugum, C. pinnatifidum and C. judaicum. Cicer yamashitae, C. chorassanicum, C. anatolicum and C. songoricum form a third group. Finally, C. cuneatum, which has a very distinct isozyme profile and peculiar morphological features, is the only member of a fourth species group. This species grouping agrees partially with those obtained from crossability and cytogenetic studies. The results suggest that the annual habit arose from perennial progenitors at least twice in the genus Cicer. PMID- 24166174 TI - Export of beta-1,3-glucanase from mutant rice cells rechallenged and stressed with lysine plus threonine. AB - Mutant rice cells (Oryza sativa L.) grown in liquid suspension cultures exported greater quantities of protein and beta-glucanases than controls. These mutants were isolated from anther calli resistant to 1 mM lysine plus threonine (LT), regenerated and reestablished as cell suspension cultures from seeds. Cellular protein levels are genetically conditioned, and the levels of extracellular proteins and enzyme activities are inversely related to that of the cellular portions. The rechallenge of cells with 1 mM LT inhibited the expression of both beta-1,3-glucanases and beta-1,4-glucosidases but had no significant effect upon the levels of chitinase activity. Mutant cells were more sensitive than controls to stress caused by exogenous LT. In general, under exogenous LT stress the mutant/control ratio for extracellular glucanases increased as the assay conditions were changed from a basic to an acidic pH. The specific activity of betaglucanases was highest in media and lowest in cells. Both the mutant and control cells exported beta-glucanases into the suspension medium, but the level of activity in media was greater in that in which the mutant was suspended. The export was probably modulated by the internal protein levels which were highest in mutant cells without LT. Seedlings from mutants with enhanced lysine also had enhanced acidic beta-glucanase activity. PMID- 24166175 TI - Screening apples for OPD20/600 using sequence-specific primers. AB - Apple scab, caused by Venturia inaequalis (Cke.) Wint., is the most serious disease of apple trees in many areas of the world. Resistance to V. inaequalis, derived from the small-fruited species Malus floribunda 821, is determined by a major dominant gene, Vf. Using random decamer primers, we identified a RAPD marker, OPD20/600, which is linked to the Vf gene. OPD20/600 was then cloned and sequenced. Sequence-specific primers based on the marker were used to further screen M. floribunda 821, 7 scab-susceptible apple cultivars, 10 scab-resistant apple cultivars, and 28 scab-resistant Coop selections. The sequence-specific primers allowed identification of polymorphisms of OPD20/600 based on the presence or absence of a single band. The advantages of sequence-specific primers over decamer primers for developing genetic markers are discussed. PMID- 24166176 TI - Diallel analysis for aluminium tolerance in tropical soybeans [Glycine max (L.) Merrill]. AB - The soybean is a major crop in the agricultural systems of the Brazilian Cerrados (Savannahs), whose soils are acidic, devoid of nutrients and need to be amended before they are cultivated. However, below the ploughed layer there is a scarcity of nutrients and toxic aluminium (Al). These limit root growth, subsequently causing nutritional imbalance and drought stress. Our aim in the investigation described here was to identify genetic differences in the aluminium tolerance of soybeans by a 9 * 9 diallel cross among contrasting varieties grown in high-Al areas and in hydroponics. Combining ability analysis indicated predominantly additive gene effects, and the additive-dominance model explained most of the genetic differences in this germ plasm for mineral element absorption and root growth under aluminium stress. The relationship between the two factors suggest that conjugation hydroponics and field evaluations in breeding programmes would further improve soybeans with respect to yield stability under tropical cultivation conditions. PMID- 24166177 TI - Using RAPDs to study phylogenetic relationships in Rosa. AB - Nineteen species of rose (Rosa sp.) were analysed using Random Amplified Polymorphic DNA markers (RAPD). Each 10-base-long arbitrary primer produced a specific DNA banding pattern that grouped plants belonging to the same species and botanical sections as predicted from their genetic background. One hundred and seventy-five amplification products were examined by cluster analysis to assess the genetic relationships among species and their genetic distances. All of the accessions belonging to 1 species grouped together before branching to other species. Dendrograms constructed for intra- and inter-specific studies showed a good correlation with previous classifications by different authors based on morphological and cariological studies. Our results show that the RAPD technique is a sensitive and precise tool for genomic analysis in rose, being useful in assigning unclassified accessions to specific taxonomic groups or else allowing accessions classified by traditional criteria to be re-classified. PMID- 24166178 TI - Downy mildew incidence of pearl millet hybrids with different male-sterility inducing cytoplasms. AB - The use of different sources of cytoplasmic male sterility (CMS) in hybrid seed production of pearl millet [Pennisetum glaucum (L.) R. Br.] is advocated to avoid possible disease epidemics occurring due to cytoplasmic uniformity. The effects of commercially unexploited, but potentially exploitable, sources of CMS, like A2, A3 and A4, on downy mildew [Sclerospora graminicola (Sacc.) Schroet] incidence were studied by using the disease incidence of isonuclear hybrids with male-sterile and fertile cytoplasm. The mean downy mildew incidence of hybrids carrying different male-sterile cytoplasm was similar to that of hybrids retaining the fertile cytoplasm. The cytoplasm accounted for only 0.6% of the total variation and its effect was non-significant; pollinators could explain most of the variation in determining the disease incidence of hybrids. This suggested that these male-sterile cytoplasms are not linked to downy mildew susceptibility and thus can be exploited commercially to broaden the cytoplasmic base of the male-sterile lines and, ultimately, of hybrids. PMID- 24166179 TI - Molecular mapping of the Arabidopsis locus RPP11 which conditions isolate specific hypersensitive resistance against downy mildew in ecotype RLD. AB - Isolate WELA of the plant pathogenic oomycete fungus Peronospora parasitica causes downy mildew in the Arabidopsis thaliana ecotypes Weiningen (Wei-0) and La er, whereas ecotypes RLD and Col-0 are resistant. Genetic crosses between resistant RLD and susceptible Wei-0 showed that resistance was inherited in a simple Mendelian fashion as a monogenic dominant trait. The interactions between different isolates of P. parasitica and ecotypes of A. thaliana show race specific variation and fit a gene-for-gene relationship. The RPP11 resistance gene was mapped by following the co-segregation of the resistance phenotype with RFLP markers in a mapping population of 254 F3 families derived from RLD x Wei-0 F2 individuals. Linkage analysis using version 1.9 of the MAPMAKER program placed the RPP11 resistance locus on chromosome III between marker m249 (two recombinants) and marker g2534 (six recombinants). Markers g2534 and g4117 are on YAC EG7H1. Marker g4117 and one end probe (N5) generated from YAC EG7H1 showed no recombinants. The YAC end probe N5, which was generated by plasmid rescue, was used to screen clones in the Eric Ward YAC library and a YAC was fished (EW19B12) which also hybridised with m249. Thus, a YAC contig has been established over the region where the resistance locus maps. Because the YACs were made with ecotype Columbia DNA it is necessary to isolate the equivalent region from RLD in order to clone the resistance locus. To this end a phage lambda-DASH (TM) genomic library was prepared from RLD and a contig covering the relevant region of the YACs is currently under construction. PMID- 24166181 TI - Circaseptan (weekly) rhythms in smoking cessation considerations. PMID- 24166180 TI - Possible role of Cdx2 in the serrated pathway of colorectal cancer characterized by BRAF mutation, high-level CpG Island methylator phenotype and mismatch repair deficiency. AB - Colorectal cancer is a heterogeneous disease at the histomorphological, clinical and molecular level. Approximately 20% of cases may progress through the "serrated" pathway characterized by BRAF mutation and high-level CpG Island Methylator Phenotype (CIMP). A large subgroup are additionally microsatellite instable (MSI) and demonstrate significant loss of tumor suppressor Cdx2. The aim of this study is to determine the specificity of Cdx2 protein expression and CpG promoter hypermethylation for BRAF(V600E) and high-level CIMP in colorectal cancer. Cdx2, Mlh1, Msh2, Msh6, and Pms2 were analyzed by immunohistochemistry using a multi-punch tissue microarray (TMA; n = 220 patients). KRAS and BRAF(V600E) mutation analysis, CDX2 methylation and CIMP were investigated. Loss of Cdx2 was correlated with larger tumor size (P = 0.0154), right-sided location (P = 0.0014), higher tumor grade (P < 0.0001), more advanced pT (P = 0.0234) and lymphatic invasion (P = 0.0351). Specificity was 100% for mismatch repair (MMR) deficiency (P < 0.0001), 92.2% (P < 0.0001) for BRAF(V600E) and 91.8% for CIMP high. Combined analysis of BRAF(V600E)/CIMP identified Cdx2 loss as sensitive (80%) and specific (91.5%) for mutation/high status. These results were validated on eight well-established colorectal cancer cell lines. CDX2 methylation correlated with BRAF(V600E) (P = 0.0184) and with Cdx2 protein loss (P = 0.0028). These results seem to indicate that Cdx2 may play a role in the serrated pathway to colorectal cancer as underlined by strong relationships with BRAF(V600E), CIMP high and MMR-deficiency. Whether this protein can only be used as a "surrogate" marker, or is functionally involved in the progression of these tumors remains to be elucidated. PMID- 24166182 TI - TMEM106B and APOE polymorphisms interact to confer risk for late-onset Alzheimer's disease in Han Chinese. AB - Recent large genome-wide association studies have found variants in TMEM106B (top SNP rs1990622) as a strong risk factor for frontotemporal lobar degeneration. Moreover, the TMEM106B risk variant is also implicated in the pathologic presentation of Alzheimer's disease (AD). Here, we evaluated the association between TMEM106B rs1990622 polymorphism and late-onset AD (LOAD) in a Northern Han Chinese population consists of 1,133 LOAD patients and 1,159 controls. Our data demonstrate that TMEM106B and APOE interact to increase AD risk. PMID- 24166184 TI - Mycotoxigenic moulds and mycotoxins in flours consumed in Turkey. AB - BACKGROUND: Aflatoxins (AFs) and ochratoxin A (OTA) are metabolites produced by several fungi of the genera Aspergillus and Penicillium and have been found to contaminate human foods and animal feeds. The aim of this study was to investigate the abundance and diversity of total microfungi and mycotoxigenic fungi in 25 samples of different grain-based flours from four regions of Turkey (Thrace and Central, Northwest and West Anatolia) and to evaluate the level of AF and OTA contamination. Microscopic and polymerase chain reaction analyses were used to identify fungi, while high-performance liquid chromatography was used for the detection of AFs and OTA. RESULTS: A total of 551 fungal strains were obtained from the samples and identified morphologically and by multi-locus gene sequencing. All samples were contaminated with fungi ((2-4.8) * 10(4) colony forming units g(-1) ) and three of them exceeded the European Commission (EC) limits. The data also revealed that 70.5 and 14.7% of the fungal isolates were positive for AF and OTA production respectively. In addition, 21 samples were contaminated by AFs (14.98 and 22.4 ug kg(-1) for AFB1 ) and OTA (3.02 and 4.76 ug kg(-1) ) and three of them exceeded the EC limits. CONCLUSION: This study is the first report on problems with the occurrence of microfungi, mycotoxin contamination, AFs and OTA in different grain-based flour samples from Turkey and highlights developable points of current limits for food and public health safety. PMID- 24166185 TI - An efficient methodology for measurement of the average electrical properties of single one-dimensional NiO nanorods. AB - We utilized a metal tantalum (Ta) ball-probe to measure the electrical properties of vertical-aligned one-dimensional (1D) nickel-oxide (NiO) nanorods. The 1D NiO nanorods (on average, ~105 nm wide and ~700 nm long) are synthesized using the hot-filament metal-oxide vapor deposition (HFMOVD) technique, and they are cubic phased and have a wide bandgap of 3.68 eV. When the 1D NiO nanorods are arranged in a large-area array in ohmic-contact with the Ta ball-probe, they acted as many parallel resistors. By means of a rigorous calculation, we can easily acquire the average resistance RNR and resistivity rhoNR of a single NiO nanorod, which were approximately 3.1 * 10(13) Omega and 4.9 * 10(7) Omega.cm, respectively. PMID- 24166186 TI - CK8 phosphorylation induced by compressive loads underlies the downregulation of CK8 in human disc degeneration by activating protein kinase C. AB - Cytokeratin 8 (CK8) is a member of the cytokeratins family with multiple functions on the basis of its unique structural hallmark. The aberrant expression of CK8 and its phosphorylation are pertinent with various diseases. We have previously shown that CK8 exists in normal human nucleus pulposus (NP) cells and decreases as the intervertebral disc degenerates. However, the underlying molecular regulatory machinery of CK8 in intervertebral disc degeneration (IDD) has not been clarified. Here, we collected NP samples from patients with idiopathic scoliosis as control and IDD as degenerate groups. We found that CK8 expression decreased in IDD with an increased phosphorylation in degenerate NP cells. Moreover, NP cells were cultured under different compressive load schemes for diverse time duration. We found that compressive loads resulted in phosphorylation and disassembly of CK8 in a time-dependent and degree-dependent manner in vitro. The activation of protein kinase C was a significant molecular factor contributing to this phenomenon. Taken together, this study is the first to address the molecular mechanisms of CK8 downregulation in NP cells. Importantly, our findings provide clues regarding a molecular link between compressive loads and CK8 alterations, which shed a novel light on the etiology of IDD. PMID- 24166183 TI - Hypercholesterolemia induces short-term spatial memory impairments in mice: up regulation of acetylcholinesterase activity as an early and causal event? AB - Epidemiological studies have indicated hypercholesterolemia in midlife as a risk factor for dementia in later life, bringing cholesterol to the forefront of Alzheimer's disease research. Herein, we modeled mild hypercholesterolemia in mice to evaluate biochemical and behavioral alterations linked to hypercholesterolemia. Swiss mice were fed a high fat/cholesterol diet (20 % fat and 1.25 % cholesterol) for an 8-week period (from 12 to 18 weeks old) and were tested on the object location, forced swimming and elevated plus-maze tasks. We also investigated hypercholesterolemia-induced changes on acetylcholinesterase (AChE) activity, oxidative damage, amyloid precursor protein (APP) processing and blood brain barrier (BBB) integrity within the prefrontal cortex and hippocampus. It was found that increased AChE activity within the prefrontal cortex and hippocampus is an early event associated with hypercholesterolemia-induced short term memory impairments. We observed no signs of antioxidant imbalance and/or oxidative damage or changes in cortical and hippocampal densities of beta-site amyloid precursor protein-cleaving enzyme 1 and aquaporin-4, biomarkers of APP processing and BBB integrity, respectively. In addition, we treated SH-SY5Y human neuroblastoma cells with low-density lipoprotein (LDL) cholesterol in an attempt to manipulate cell cholesterol content. Notably, LDL cholesterol increased in a dose-dependent manner the activity of AChE in SH-SY5Y cells. The present findings provide new evidence that increased AChE activity within the prefrontal cortex and hippocampus is an early event associated with hypercholesterolemia-induced cognitive impairments. PMID- 24166187 TI - Deregulation of the NLRP3 inflammasome in hepatic parenchymal cells during liver cancer progression. AB - Hepatocellular carcinoma (HCC) is one of the most prevalent malignant tumors worldwide, and it is always the consequence of chronic hepatitis and liver cirrhosis. The nucleotide-binding domain, leucine-rich family (NLR), pyrin containing 3 (NLRP3) inflammasome has been shown to orchestrate multiple innate and adaptive immune responses. However, little is known about its role in cancer. This study was performed to investigate the role of the NLRP3 inflammasome in the development and progression of HCC. The expression of NLRP3 inflammasome components was analyzed in HCC tissues and corresponding non-cancerous liver tissues at both the mRNA and protein levels. Our data demonstrate that the expression of all of the NLRP3 inflammasome components was either completely lost or significantly downregulated in human HCC, and that the deficiency correlated significantly with advanced stages and poor pathological differentiation. In addition, our data provide an overview of the expression of NLRP3 inflammasome components in the multi-stage development of HCC and indicate a surprising link between deregulation of the NLRP3 inflammasome molecular platform and HCC progression. In conclusion, this study presents a dynamic expression pattern of NLRP3 inflammasome components in multi-stage hepatocarcinogenesis and demonstrates that deregulated expression of the inflammasome is involved in HCC progression. PMID- 24166188 TI - Amount of therapy matters in very early aphasia rehabilitation after stroke: a clinical prognostic model. AB - BACKGROUND AND AIM: The effects of very early aphasia therapy on recovery are equivocal. This article examines predictors of very early aphasia recovery through statistical modeling. METHODS: This study involved a secondary analysis of merged data from two randomized, single-blind trials conducted in Australian acute and subacute hospitals. Study 1 (n = 59) compared daily therapy to usual ward care for up to 4 weeks poststroke in patients with moderate to severe aphasia. Study 2 (n = 20) compared daily group therapy to daily individual therapy for 20 1-hour sessions over 5 weeks, in patients with mild to severe aphasia. The primary outcome measure was the Western Aphasia Battery Aphasia Quotient (AQ) at therapy completion. This analysis used regression modeling to examine the effects of age, baseline AQ and baseline modified Rankin Scale (mRS), average therapy amount, therapy intensity, and number of therapy sessions on aphasia recovery. RESULTS: Baseline AQ (p = 0.047), average therapy amount (p = 0.030), and baseline mRS (p = 0.043) were significant predictors in the final regression model, which explained 30% (p < 0.001) of variance in aphasia recovery. CONCLUSION: The amount of very early aphasia therapy could significantly affect communication outcomes at 4 to 5 weeks poststroke. Further studies should include amount of therapy provided to enhance reliability of prognostic modeling in aphasia recovery. PMID- 24166189 TI - Communicating with inpatients with memory impairments. AB - Many patients with acquired brain injury have acute impairments in declarative memory, the memory system responsible for learning facts and remembering events, whereas implicit memory for skills, habits, and emotional associations remains intact. The combination of impaired declarative memory and preserved implicit memory has implications for communicating with patients in inpatient rehabilitation, not only in therapy sessions but also in nontherapy interactions with rehabilitation staff. The aim of this study was to describe communication patterns among inpatients with declarative memory impairments and rehabilitation staff members during the early stage postinjury. Participants were five adults with acquired brain injury and declarative memory impairments. Each participant was observed for a full inpatient rehabilitation day. Results showed that staff and visitors frequently asked participants declarative questions to which answers were not verifiable (e.g., questions about preinjury events). Answers that could be verified often were incorrect but were accepted by staff as correct. Results suggest that acute rehabilitation staff may need training in communicating with patients with declarative memory impairments. We suggest strategies to create a more supportive communication environment for inpatients with memory impairment. PMID- 24166190 TI - Approaches to the rehabilitation of dysphagia in acute poststroke patients. AB - Dysphagia occurs frequently following stroke and may result in serious health consequences including pneumonia, malnutrition, dehydration, and mortality. Prevention of these negative health outcomes requires early identification and treatment of dysphagia. The speech-language pathologist, as part of a multidisciplinary team, holds the primary responsibility for selection of an effective dysphagia rehabilitation program for these patients. Because much research has focused on patients with chronic dysphagia, this review will focus on treatment of patients within the acute phase of recovery poststroke. Although some acute patients may experience transient dysphagia that resolves spontaneously, many will go on to develop chronic dysphagia that may be prevented with provision of early and intensive treatment. An overview of dysphagia following stroke will be provided with information regarding incidence, complications, evaluation, and causes of dysphagia. A thorough discussion of evidence supporting varying approaches to dysphagia rehabilitation will follow with inclusion of several current, novel, and experimental techniques. The importance of the multidisciplinary team and regular reevaluation will be emphasized as well. PMID- 24166191 TI - Language-enriched exercise plus socialization for older adults with dementia: translation to rural communities. AB - Interventions that stimulate and engage individuals with dementia physically, cognitively, and socially offer promise for improving health and well-being and for potentially slowing functional losses with disease progression. We describe a volunteer-based intervention that combines physical exercise, cognitive linguistic stimulation, and social outings for older persons living with dementia in rural communities. One-year follow-up data, although clearly preliminary (n = 8), suggest stability in global cognition, mood, and aspects of physical fitness. Challenges to implementing dementia interventions in rural areas are discussed. PMID- 24166193 TI - The economic burden of complications occurring in major surgical procedures: a systematic review. AB - OBJECTIVES: On the basis of a systematic review, we aimed to establish the cost and drivers of cost and/or resource use of intra- and perioperative complications occurring as a result of selected major surgical procedures, as well as to understand the relationship between costs and severity of complication and, consequently, the economic burden they represent. We also assessed the clinical and economic methodologies used to derive costs and resource use across the studies with a view to providing guidance on reporting standards for these studies. METHODS: We searched EMBASE, MEDLINE and Econlit (from 2002 to 2012) for study publications including resource use/cost data relating to surgical complications. RESULTS: We identified 38 relevant studies on pancreatic (n = 14), urologic (n = 4), gynaecological (n = 6), thoracic (n = 13) and hepatic surgery (n = 1). All studies showed that complications lead to higher resource use and hospital costs compared with surgical procedures without complications. Costs depend on type of complication and complication severity, and are driven primarily by prolonged hospitalisation. There was considerable heterogeneity between studies with regard to patient populations, outcomes and procedures, as well as a lack of consistency and transparency of reporting of costs/resource use. Complication severity grading systems were used infrequently. CONCLUSIONS: The overall conclusions of included studies are consistent: complications represent an important economic burden for health care providers. We conclude that more accurate and consistent data collection is required to serve as input for good-quality economic analyses, which in turn can inform hospital decisions on cost-efficient allocation of their limited resources. PMID- 24166192 TI - Early identification and treatment of communication and swallowing deficits in Parkinson disease. AB - Parkinson disease (PD) is a complex, progressive, neurodegenerative disorder that leads to a wide range of deficits including fine and gross sensorimotor impairment, autonomic dysfunction, mood disorders, and cognitive decline. Traditionally, the focus for diagnosis and treatment has been on sensorimotor impairment related to dopamine depletion. It is now widely recognized, however, that PD-related pathology affects multiple central nervous system neurotransmitters and pathways. Communication and swallowing functions can be impaired even in the early stages, significantly affecting health and quality of life. The purpose of this article is to review the literature on early intervention for communication and swallowing impairment in PD. Overarching themes were that (1) studies and interpretation of data from studies in early PD are limited; (2) best therapy practices have not been established, in part due to the heterogeneous nature of PD; and (3) as communication and swallowing problems are pervasive in PD, further treatment research is essential. PMID- 24166194 TI - Efficacy and safety of bevacizumab in recurrent sex cord-stromal ovarian tumors: results of a phase 2 trial of the Gynecologic Oncology Group. AB - BACKGROUND: The Gynecologic Oncology Group conducted this phase 2 trial to estimate the antitumor activity of bevacizumab and to determine the nature and degree of toxicity in patients with recurrent sex cord-stromal tumors of the ovary. METHODS: A prospective, multi-institutional cooperative group trial was performed in women with recurrent, measurable ovarian stromal tumors. Patients were allowed to have unlimited prior therapy, excluding bevacizumab. Bevacizumab 15 mg/kg was administered intravenously on day 1 of every 21-day cycle until patients developed disease progression or adverse effects that prohibited further treatment. The primary endpoint was the response rate (RR). Inhibin A and B levels were measured before each cycle, and the values were examined in relation to response and progression. RESULTS: Thirty-six patients were enrolled, and all were eligible and evaluable. Patients received a median of 9 cycles of treatment (range, 2-37 cycles). Six patients (16.7%) had partial responses (90% confidence interval, 7.5%-30.3%), 28 patients (77.8%) had stable disease, and 2 patients (5.6%) had progressive disease. This met the criterion for declaring the regimen active. The median progression-free survival was 9.3 months, and the median overall survival was not reached in during reporting period. Two grade 4 toxicities occurred, including hypertension and proteinuria; and the most common grade 3 toxicities were hypertension (n = 5) and pain (n = 5). Inhibin A and B values were lower in patients who responded to treatment. CONCLUSIONS: Bevacizumab has activity in the treatment of recurrent sex cord-stromal tumors of the ovary, and its toxicity is acceptable. Further investigation is warranted. PMID- 24166195 TI - Recent modifications to the investigation of diving related deaths. AB - The investigation of deaths that involve diving using a compressed breathing gas (SCUBA diving) is a specialized area of forensic pathology. Diving related deaths occur more frequently in certain jurisdictions, but any medical examiner or coroner's office may be faced with performing this type of investigation. In order to arrive at the correct conclusion regarding the cause and manner of death, forensic pathologists and investigators need to have a basic understanding of diving physiology, and should also utilize more recently developed technology and ancillary techniques. In the majority of diving related deaths, the cause of death is drowning, but this more often represents a final common pathway due to a water environment. The chain of events leading to the death is just as important to elucidate if similar deaths are to be minimized in the future. Re-enactment of accident scenarios, interrogation of dive computers, postmortem radiographic imaging, and slight alterations in autopsy technique may allow some of these diving related deaths to the better characterized. The amount and location of gas present in the body at the time of autopsy may be very meaningful or may simply represent a postmortem artifact. Medical examiners, coroners, and forensic investigators should consider employing select ancillary techniques to more thoroughly investigate the factors contributing a death associated with SCUBA diving. PMID- 24166196 TI - Assisted suicide and killing of a household pet: pre-autopsy post-mortem imaging of a victim and a dog. PMID- 24166199 TI - Localized surface plasmon resonance: a unique property of plasmonic nanoparticles for nucleic acid detection. AB - Localized surface plasmon resonance (LSPR) of noble metal nanoparticles (a.k.a. plasmonic nanoparticles) opens up a new horizon for advanced biomolecule sensing. However, an effective and practical sensing system still requires meticulous design to achieve good sensitivity and distinctive selectivity for routine use and high-throughput detection. In particular, the detection of DNA and RNA is crucial in biomedical research and clinical diagnostics. This review describes the fundamental aspects of LSPR and provides an overall account of how it is exploited to assist in nucleic acid sensing. The detection efficiency of each LSPR-based approach is assessed with respect to the assay design, the selection of plasmonic nanoparticles, and the choice of nucleic acid probes which influence the duplex hybridization. Judicious comparison is made among various LSPR-based approaches in terms of the assaying time, the sensitivity or lowest sensing concentration (i.e. limit of detection or LOD), and the single-base mismatch (SBM) selectivity. PMID- 24166198 TI - Cotransplantation of human umbilical cord-derived mesenchymal stem cells and umbilical cord blood-derived CD34+ cells in a rabbit model of myocardial infarction. AB - The objective of the study is to investigate the effect of hypoxic preconditioning on the immunomodulatory properties of human umbilical cord derived mesenchymal stem cells (hUC-MSCs) and the effect of cotransplantation of hUC-MSCs and human umbilical cord blood (hUCB)-derived CD34(+) cells in a rabbit model of myocardial infarction. hUC-MSCs with or without hypoxic preconditioning by cobalt chloride were plated in a 24-well plate, and then cocultured with hUCB CD34(+) cells and PBMCs for 96 h at 37 degrees C in a 5% CO2 incubator. For the negative control, hUC-MSCs were omitted. The groups were divided as follows: A1 = HP-MSCs + hUCB-CD34(+) cells + PBMC, A2 = hUC-MSCs + hUCB-CD34(+) cells + PBMC, Negative Control = hUCB-CD34(+) cells + PBMC. Culture supernatants of each group were collected, and the IL-10 and IFN-gamma levels were measured by ELISA. A rabbit model of MI was established using a modified Fujita method. The animals were then randomized into three groups and received intramyocardial injections of 0.4 ml of PBS alone (n = 8, PBS group), hUC-MSCs in PBS (n = 8, hUC-MSCs group), or hUC-MSCs + CD34(+) cells in PBS (n = 8, Cotrans group), at four points in the infarct border zone. Echocardiography was performed at baseline, 4 weeks after MI induction, and 4 weeks after cell transplantation, respectively. Stem cell differentiation and neovascularization in the infracted area were characterized for the presence of cardiac Troponin I (cTnI) and CD31 by immunohistochemical staining, and the extent of myocardial fibrosis was evaluated by hematoxylin and eosin (H&E) and Masson's trichrome. IFN-gamma was 27.00 +/- 1.11, 14.20 +/- 0.81, and 7.22 +/- 0.14 pg/ml, and IL-10 was 31.68 +/- 3.08, 61.42 +/- 1.08, and 85.85 +/- 1.80 pg/ml for the Control, A1 and A2 groups, respectively, which indicated that hUCB-CD34(+) cells induced immune reaction of peripheral blood mononuclear cells, whereas both hUC-MSCs and HP-MSCs showed an immunosuppressive effect, which, however, was attenuated by hypoxic preconditioning. The Cotrans group had less collagen deposition in the infarcted myocardium and better heart function than the hUC-MSCs or PBS group. The presence of cTnI-positive cells and CD31 positive tubular structures indicated the differentiation of stem cells into cardiomyocytes and neovascularization. The microvessel density was 12.19 +/- 3.05/HP for the hUC-MSCs group and 31.63 +/- 2.45/HP for the Cotrans group, respectively (P < 0.01). As a conclusion, both hUC-MSCs and HP-MSCs have an immunosuppressive effect on lymphocytes, which, however, can be attenuated by hypoxic preconditioning. Cotransplantation of hUC-MSCs and hUCB-CD34(+) cells can improve heart function and decrease collagen deposition in post-MI rabbits. Thus, a combined regimen of hUC-MSCs and hUCB-CD34(+) cells would be more desirable than either cells administered alone. This is most likely due to the increase of cardiomyocytes and enhanced angiogenesis in the infarcted myocardium. PMID- 24166197 TI - MicroRNA-205 suppresses the oral carcinoma oncogenic activity via down-regulation of Axin-2 in KB human oral cancer cell. AB - MicroRNA (miRNA) is a small noncoding RNA molecule, 19-25 nucleotides in length, which regulates several pathways including cell development, cell proliferation, carcinogenesis, apoptosis, etc. In this study, the over-expression of microRNA 205 (miR-205) increased the number of apoptotic cells by at least 4 times compared to the control. In addition, over-expressed miRNA in KB oral cancer cells triggered apoptosis via the caspase cascade, including the cleavage of caspase-9, caspase-7, caspase-3, and PARP. Flow cytometry showed that apoptotic cell death was increased significantly by 35.33% in KB oral cancer cells with over-expressed miR-205 compared to the control. The microarray data showed that axis inhibitor protein 2 (Axin2) was down-regulated in KB oral cancer cells transfected with miR-205. In addition, Axin2 was down-regulated by approximately 50% by over-expressed miR-205 at both the mRNA and protein levels. Interestingly, Axin2 was up-regulated in KB oral cancer compared to human normal oral keratinocytes. Furthermore, the cell cytotoxicity and apoptotic population of KB oral cancer cells were increased significantly after Axin2 siRNA transfection. These results suggest that Axin2 is might be as potential oncogene in KB oral cancer cells. The luciferase assay showed that over-expressed miR-205 in KB oral cancer cells suppressed AXIN2 expression through an interaction with its own binding site at AXIN2 3'UTR (64-92). These results suggest that miR-205 is a novel anti-oncogenic miRNA in KB oral cancer cells, and may have potential applications in oral cancer therapy. PMID- 24166200 TI - Synthesis and physical properties of zethrene derivatives bearing donor/acceptor substituents at 7,14-positions. AB - Zethrene derivatives substituted by phenylethynyl groups bearing electron donating and/or accepting groups were synthesised by iodine-induced transannular cyclisation of dehydrodinaphtho[10]annulene as the pivotal step followed by Sonogashira coupling reaction. Their physical properties were investigated to elucidate the effects of the substituents on the electronic configuration of the zethrene backbone. PMID- 24166201 TI - Epilepsy: Psychiatric comorbidities and premature death in epilepsy. PMID- 24166202 TI - Scalp current density mapping in the analysis of mismatch negativity paradigms. AB - MMN oddball paradigms are frequently used to assess auditory (dys)functions in clinical populations, or the influence of various factors (such as drugs and alcohol) on auditory processing. A widely used procedure is to compare the MMN responses between two groups of subjects (e.g. patients vs controls), or between experimental conditions in the same group. To correctly interpret these comparisons, it is important to take into account the multiple brain generators that produce the MMN response. To disentangle the different components of the MMN, we describe the advantages of scalp current density (SCD)-or surface Laplacian-computation for ERP analysis. We provide a short conceptual and mathematical description of SCDs, describe their properties, and illustrate with examples from published studies how they can benefit MMN analysis. We conclude with practical tips on how to correctly use and interpret SCDs in this context. PMID- 24166207 TI - New developments in the evolution and application of the WHO/IPCS framework on mode of action/species concordance analysis. AB - The World Health Organization/International Programme on Chemical Safety mode of action/human relevance framework has been updated to reflect the experience acquired in its application and extend its utility to emerging areas in toxicity testing and non-testing methods. The underlying principles have not changed, but the framework's scope has been extended to enable integration of information at different levels of biological organization and reflect evolving experience in a much broader range of potential applications. Mode of action/species concordance analysis can also inform hypothesis-based data generation and research priorities in support of risk assessment. The modified framework is incorporated within a roadmap, with feedback loops encouraging continuous refinement of fit-for-purpose testing strategies and risk assessment. Important in this construct is consideration of dose-response relationships and species concordance analysis in weight of evidence. The modified Bradford Hill considerations have been updated and additionally articulated to reflect increasing experience in application for cases where the toxicological outcome of chemical exposure is known. The modified framework can be used as originally intended, where the toxicological effects of chemical exposure are known, or in hypothesizing effects resulting from chemical exposure, using information on putative key events in established modes of action from appropriate in vitro or in silico systems and other lines of evidence. This modified mode of action framework and accompanying roadmap and case examples are expected to contribute to improving transparency in explicitly addressing weight of evidence considerations in mode of action/species concordance analysis based on both conventional data sources and evolving methods. PMID- 24166209 TI - Novel clinical features of recurrent human respiratory syncytial virus infections. AB - Children and elderly individuals are often infected easily and repeatedly with human respiratory syncytial virus (HRSV); however, the features of recurrent infection in the same individual are defined poorly. To clarify the clinical significance of repeated HRSV infections in relation to subgroup epidemiology, this study performed prospective and longitudinal analyses in children with lower respiratory tract infections over 20 consecutive epidemics between 1985 and 2005 at a pediatric outpatient clinic in Kawasaki, Japan. HRSV infections were confirmed by 2 types of reverse-transcription PCR. Samples obtained from patients with repeated infections were subjected to sequence analysis and cloning analysis. A total of 1,312 lower respiratory tract infections observed in 1,010 patients were diagnosed as HRSV infections. Repeated HRSV infections occurred in 208 of the 1,010 patients. Analysis of the patients with repeated infections revealed that children were often infected multiple times even within a single short epidemic. Some patients were re-infected with strains having the same or virtually identical N gene sequences. In patients infected more than 4 times, cloning analysis revealed more frequent dual infections with both subgroups (23.8%). The HRSV-A subgroup caused subsequent homologous infections more frequently than did HRSV-B; furthermore, HRSV-A infections provided no protection from a second homologous infection. In contrast, HRSV-B infections offered significant protection against a second homologous infection. Statistical analysis revealed alleviation of symptoms with a reduced rate of dyspnoeic attacks only in the group re-infected with homologous HRSV-A strains. Thus, this study elucidates new clinical features of recurrent HRSV infection. PMID- 24166210 TI - Examining radiographic outcomes over time. AB - Statistical analysis plays a critical role in data interpretation in all fields and particularly so for clinical data where important treatment decisions are made. We provide here an in-depth and illustrative analysis to examine patterns and radiographic scores in an early disease rheumatoid arthritis cohort over a 3 year follow-up period. The total Sharp radiographic scores were interpolated from the rates at 6 months, 1, 2, and 3 years and were transformed to count data after rounding. The generalized estimating equations approach and two-part models were applied to analyze the longitudinal radiographic scores using the clinical, demographic, and therapeutic characteristics of the patients after adjusting for the pattern outcomes. Total Sharp scores were modeled, assuming that they were Poisson distributed or had a negative binomial distribution with either an AR(1) working correlation matrix or an exchangeable working correlation matrix. To account for the excessive zero counts, we used two-part models that include the zero-inflated Poisson and the zero-inflated negative binomial to fit the data. This is an innovation because two-part models have not been used in rheumatology even though they are highly appropriate for analyzing data from rheumatic studies. In addition, we analyzed data using generalized estimating equations and compared results from different models using formal statistical goodness-of-fit criteria and arrive at the best model for predicting purposes. PMID- 24166208 TI - Testing accommodation or modification? The effects of integrated object representation on enhancing geometry performance in children with and without geometry difficulties. AB - According to the National Council of Teachers of Mathematics, geometry and spatial sense are fundamental components of mathematics learning. However, learning disabilities (LD) research has shown that many K-12 students encounter particular geometry difficulties (GD). This study examined the effect of an integrated object representation (IOR) accommodation on the test performance of students with GD compared to students without GD. Participants were 118 elementary students who took a researcher-developed geometry problem solving test under both a standard testing condition and an IOR accommodation condition. A total of 36 students who were classified with GD scored below 40% correct in the geometry problem solving test in the standard testing condition, and 82 students who were classified without GD scored equal to or above 40% correct in the same test and condition. All students were tested in both standard testing condition and IOR accommodation condition. The results from both ANOVA and regression discontinuity (RD) analyses suggested that students with GD benefited more than students without GD from the IOR accommodation. Implications of the study are discussed in terms of providing accommodations for students with mathematics learning difficulties and recommending RD design in LD research. PMID- 24166211 TI - Validation of a Persian version of the Fibromyalgia Impact Questionnaire (FIQ-P). AB - The aim of this study is to translate, adapt, and validate a Persian version of the Fibromyalgia (FM) Impact Questionnaire (FIQ-P). The FIQ-P was adapted following the translation and back-translation approach; then, it was administered to thirty females with FM. Participants also completed two other validated questionnaires, the Medical Outcome Survey Short Form-36 (SF-36) and the Beck Depression Inventory (BDI). Internal consistency within the FIQ-P items and its test-retest reliability were assessed with Cronbach's alpha and Spearman's correlation coefficient, respectively. Construct validity was analyzed by Spearman's r when correlating the FIQ-P to other questionnaires. The translated version was concordant. Adaptation affected two sub-items of physical function. Participants' mean age +/- standard deviation was 40.4 +/- 9.0 years. Internal consistency proved good with alpha = 0.80. Test-retest coefficient ranged from 0.50 for the item "work days missed" to 0.79 for all FIQ-P items. Fair and statistically significant (P < 0.01) correlations were found between the FIQ-P items and two other questionnaires, SF-36 (r = -0.57) and BDI (r = 0.53). We concluded that the FIQ-P is a valid and reliable instrument for measuring health status of Persian-speaking FM patients. PMID- 24166212 TI - Could the complement component C4 or its fragment C4d be a marker of the more severe conditions in patients with primary Sjogren's syndrome? AB - Our aim is to evaluate the complement component C4 (C4) and its fragment C4d (C4d) levels, focusing on their associations with other markers of B cells' activity in patients with primary Sjogren's syndrome (pSS). Humoral factors C4, C4d, B cell-activating factor (BAFF), kappa and lambda free light chains (FLCs) and IgG (by immunoassay) were investigated in 58 patients with pSS and in 28 healthy controls. We observed significantly higher levels of BAFF, kappa and lambda FLC and IgG, and significantly lower level of C4 in pSS patients, while the level of C4d was similar in the both groups. Significantly higher levels of BAFF, kappa and lambda FLCs, IgG, and significantly lower C4 level were found in anti-SSA/SSB antibodies (Abs) seropositive pSS patients' group comparing with healthy controls. Level of C4d was significantly lower in anti-SSA/SSB Abs seropositive pSS patients comparing with seronegative pSS patients and healthy controls. C4d correlated with C4, anti-SSB Abs level and kappa/lambda ratio. Significantly higher kappa FLC and IgG levels were found in anti-SSA/SSB Abs seronegative pSS patients comparing with healthy controls. Anti-SSA/SSB seropositivity in pSS patients is associated with the decreased level of C4d. These results show that C4d can be an appropriate marker of antibody response and complement activation in pSS patients with Abs, and possibly may show the more severe condition-exhaustion of C4. Further studies are required to determine whether C4d assessment could be a relevant biomarker for the more severe condition and the worse prognosis of pSS. PMID- 24166213 TI - Incidence of malignancy in Takayasu arteritis in Korea. AB - Cancer is associated with autoimmune diseases. This study aimed to estimate the incidence of cancer in a cohort of patients with Takayasu arteritis (TA) and to compare this incidence with the general population cancer rate in South Korea in a retrospective cohort study. The medical records of TA patients who underwent medical care at our institution between 1979 and 2009 were reviewed. The 2008 National Cancer Registry was used as the reference to calculate the standardized incidence ratio (SIR). The mean age of 180 patients was 48.6 +/- 14.3 years, and 87.2 % of the patients were female. During the follow-up of 2,285 person years, 10 females developed cancer. Breast cancer was the most common malignancy with three cases, followed by two endometrial, one gastric, one colon, one pancreatic, one myelodysplastic syndrome (MDS) with refractory anemia with excess blasts, and one multiple myeloma. The SIR of cancer in TA was comparable with that of the general population at 1.3 [95 % confidence interval (CI) 0.6-2.3]; however, the risk of MDS was significantly increased (SIR 51.3; 95 % CI 1.3-285.7). While two patients with hematologic malignancies died, all TA patients with non-hematologic malignancies were still alive during the follow-up period. The overall risk of malignancy is not increased in TA. Further work is needed to determine if TA is associated with an increased risk of certain hematologic malignancies. PMID- 24166214 TI - Imaging and radioimmunotherapy of multiple myeloma with anti-idiotypic Nanobodies. PMID- 24166216 TI - Large, high quality single-crystals of the new Topological Kondo Insulator, SmB6. AB - SmB6 has recently been predicted to be a Topological Kondo Insulator, the first strongly correlated heavy fermion material to exhibit topological surface states. High quality crystals are necessary to investigate the topological properties of this material. Single crystal growth of the rare earth hexaboride, SmB6, has been carried out by the floating zone technique using a high power xenon arc lamp image furnace. Large, high quality single-crystals are obtained by this technique. The crystals produced by the floating zone technique are free of contamination from flux materials and have been characterised by resistivity and magnetisation measurements. These crystals are ideally suited for the investigation of both the surface and bulk properties of SmB6. PMID- 24166215 TI - Long-term results of a randomized phase 3 trial comparing idarubicin and daunorubicin in younger patients with acute myeloid leukaemia. PMID- 24166218 TI - Moving along the yellow brick (card) road? PMID- 24166217 TI - Costs and outcomes evaluation of patient navigation after abnormal cancer screening: evidence from the Patient Navigation Research Program. AB - BACKGROUND: Navigators can facilitate timely access to cancer services, but to the authors' knowledge there are little data available regarding their economic impact. METHODS: The authors conducted a cost-consequence analysis of navigation versus usual care among 10,521 individuals with abnormal breast, cervical, colorectal, or prostate cancer screening results who enrolled in the Patient Navigation Research Program study from January 1, 2006 to March 31, 2010. Navigation costs included diagnostic evaluation, patient and staff time, materials, and overhead. Consequences or outcomes were time to diagnostic resolution and probability of resolution. Differences in costs and outcomes were evaluated using multilevel, mixed-effects regression modeling adjusting for age, race/ethnicity, language, marital status, insurance status, cancer, and site clustering. RESULTS: The majority of individuals were members of a minority (70.7%) and uninsured or publically insured (72.7%). Diagnostic resolution was higher for navigation versus usual care at 180 days (56.2% vs 53.8%; P = .008) and 270 days (70.0% vs 68.2%; P < .001). Although there were no differences in the average number of days to resolution between the 2 groups (110 days vs 109 days; P = .63), the probability of ever having diagnostic resolution was higher for the navigation group versus the usual-care group (84.5% vs 79.6%; P < .001). The added cost of navigation versus usual care was $275 per patient (95% confidence interval, $260-$290; P < .001). There was no significant difference in stage distribution among the 12.4% of patients in the navigation group vs 11% of the usual-care patients diagnosed with cancer. CONCLUSIONS: Navigation adds costs and modestly increases the probability of diagnostic resolution among patients with abnormal screening test results. Navigation is only likely to be cost effective if improved resolution translates into an earlier cancer stage at the time of diagnosis. PMID- 24166219 TI - Desideratum for evidence based epidemiology. AB - BACKGROUND: There is great variation in choices of method and specific analytical details in epidemiological studies, resulting in widely varying results even when studying the same drug and outcome in the same database. Not only does this variation undermine the credibility of the research but it limits our ability to improve the methods. METHODS: In order to evaluate the performance of methods and analysis choices we used standard references and a literature review to identify 164 positive controls (drug-outcome pairs believed to represent true adverse drug reactions), and 234 negative controls (drug-outcome pairs for which we have confidence there is no direct causal relationship). We tested 3,748 unique analyses (methods in combination with specific analysis choices) that represent the full range of approaches to adjusting for confounding in five large observational datasets on these controls. We also evaluated the impact of increasingly specific outcome definitions, and performed a replication study in six additional datasets. We characterized the performance of each method using the area under the receiver operator curve (AUC), bias, and coverage probability. In addition, we developed simulated datasets that closely matched the characteristics of the observational datasets into which we inserted data consistent with known drug-outcome relationships in order to measure the accuracy of estimates generated by the analyses. DISCUSSION: We expect the results of this systematic, empirical evaluation of the performance of these analyses across a moderate range of outcomes and databases to provide important insights into the methods used in epidemiological studies and to increase the consistency with which methods are applied, thereby increasing the confidence in results and our ability to systematically improve our approaches. PMID- 24166220 TI - Variation in choice of study design: findings from the Epidemiology Design Decision Inventory and Evaluation (EDDIE) survey. AB - BACKGROUND: Researchers using observational data to understand drug effects must make a number of analytic design choices that suit the characteristics of the data and the subject of the study. Review of the published literature suggests that there is a lack of consistency even when addressing the same research question in the same database. OBJECTIVE: To characterize the degree of similarity or difference in the method and analysis choices made by observational database research experts when presented with research study scenarios. RESEARCH DESIGN: On-line survey using research scenarios on drug-effect studies to capture method selection and analysis choices that follow a dependency branching based on response to key questions. SUBJECTS: Voluntary participants experienced in epidemiological study design solicited for participation through registration on the Observational Medical Outcomes Partnership website, membership in particular professional organizations, or links in relevant newsletters. MEASURES: Description (proportion) of respondents selecting particular methods and making specific analysis choices based on individual drug-outcome scenario pairs. The number of questions/decisions differed based on stem questions of study design, time-at-risk, outcome definition, and comparator. RESULTS: There is little consistency across scenarios, by drug or by outcome of interest, in the decisions made for design and analyses in scenarios using large healthcare databases. The most consistent choice was the cohort study design but variability in the other critical decisions was common. CONCLUSIONS: There is great variation among epidemiologists in the design and analytical choices that they make when implementing analyses in observational healthcare databases. These findings confirm that it will be important to generate empiric evidence to inform these decisions and to promote a better understanding of the impact of standardization on research implementation. PMID- 24166221 TI - How well do various health outcome definitions identify appropriate cases in observational studies? AB - BACKGROUND: Observational data can be useful for drug safety research, but accurate measurement of adverse health outcomes is paramount. Best practices for identifying important health outcomes of interest (HOI) are needed. OBJECTIVES: To evaluate the extent to which health outcome definitions commonly used in observational database studies identify cases that are consistent with expert panel assessment of the underlying data. METHODS: Competing HOI definitions were used to identify potential cases of acute liver injury (ALI; n = 208), acute kidney injury (AKI; n = 200), and myocardial infarction (MI; n = 204) in the Truven MarketScan Lab Database (MSLR). Panelists reviewed patient-level data and answered questions about whether they believed the case actually reflected the HOI and their certainty of case classification on a 10-point scale (1 = unlikely to 10 = likely). Each patient was reviewed independently by two panelists. Case disagreements were resolved through consensus meetings. Positive predictive value (PPV) was calculated as the number of cases deemed to be true over the total number of sampled cases. Kappa statistics assessed inter-rater agreement. RESULTS: PPV ranged from 0 to 52 % across ALI definitions, 12 to 82 % across AKI definitions, and 1 to 56 % across MI definitions. Certainty scores on the 10 point scale paralleled the PPV, with a range of mean values from 1.7 to 4.8 across ALI definitions, 3.1 to 6.0 across AKI definitions, and 2.8 to 5.7 across MI definitions. Inter-rater agreement was low to moderate (Kappa range 0.0-0.6). IMPLICATIONS/CONCLUSIONS: Existing HOI definitions had relatively low PPV based on expert panel review. Experts commonly disagreed on case classification. Additional work is needed to refine HOI case definitions if observational data are to be reliably used for health outcome assessment. PMID- 24166223 TI - Managing data quality for a drug safety surveillance system. AB - OBJECTIVE: The objective of this study is to present a data quality assurance program for disparate data sources loaded into a Common Data Model, highlight data quality issues identified and resolutions implemented. BACKGROUND: The Observational Medical Outcomes Partnership is conducting methodological research to develop a system to monitor drug safety. Standard processes and tools are needed to ensure continuous data quality across a network of disparate databases, and to ensure that procedures used to extract-transform-load (ETL) processes maintain data integrity. Currently, there is no consensus or standard approach to evaluate the quality of the source data, or ETL procedures. METHODS: We propose a framework for a comprehensive process to ensure data quality throughout the steps used to process and analyze the data. The approach used to manage data anomalies includes: (1) characterization of data sources; (2) detection of data anomalies; (3) determining the cause of data anomalies; and (4) remediation. FINDINGS: Data anomalies included incomplete raw dataset: no race or year of birth recorded. Implausible data: year of birth exceeding current year, observation period end date precedes start date, suspicious data frequencies and proportions outside normal range. Examples of errors found in the ETL process were zip codes incorrectly loaded, drug quantities rounded, drug exposure length incorrectly calculated, and condition length incorrectly programmed. CONCLUSIONS: Complete and reliable observational data are difficult to obtain, data quality assurance processes need to be continuous as data is regularly updated; consequently, processes to assess data quality should be ongoing and transparent. PMID- 24166222 TI - Defining a reference set to support methodological research in drug safety. AB - BACKGROUND: Methodological research to evaluate the performance of methods requires a benchmark to serve as a referent comparison. In drug safety, the performance of analyses of spontaneous adverse event reporting databases and observational healthcare data, such as administrative claims and electronic health records, has been limited by the lack of such standards. OBJECTIVES: To establish a reference set of test cases that contain both positive and negative controls, which can serve the basis for methodological research in evaluating methods performance in identifying drug safety issues. RESEARCH DESIGN: Systematic literature review and natural language processing of structured product labeling was performed to identify evidence to support the classification of drugs as either positive controls or negative controls for four outcomes: acute liver injury, acute kidney injury, acute myocardial infarction, and upper gastrointestinal bleeding. RESULTS: Three-hundred and ninety-nine test cases comprised of 165 positive controls and 234 negative controls were identified across the four outcomes. The majority of positive controls for acute kidney injury and upper gastrointestinal bleeding were supported by randomized clinical trial evidence, while the majority of positive controls for acute liver injury and acute myocardial infarction were only supported based on published case reports. Literature estimates for the positive controls shows substantial variability that limits the ability to establish a reference set with known effect sizes. CONCLUSIONS: A reference set of test cases can be established to facilitate methodological research in drug safety. Creating a sufficient sample of drug-outcome pairs with binary classification of having no effect (negative controls) or having an increased effect (positive controls) is possible and can enable estimation of predictive accuracy through discrimination. Since the magnitude of the positive effects cannot be reliably obtained and the quality of evidence may vary across outcomes, assumptions are required to use the test cases in real data for purposes of measuring bias, mean squared error, or coverage probability. PMID- 24166224 TI - Empirical performance of a new user cohort method: lessons for developing a risk identification and analysis system. AB - BACKGROUND: Observational healthcare data offer the potential to enable identification of risks of medical products, but appropriate methodology has not yet been defined. The new user cohort method, which compares the post-exposure rate among the target drug to a referent comparator group, is the prevailing approach for many pharmacoepidemiology evaluations and has been proposed as a promising approach for risk identification but its performance in this context has not been fully assessed. OBJECTIVES: To evaluate the performance of the new user cohort method as a tool for risk identification in observational healthcare data. RESEARCH DESIGN: The method was applied to 399 drug-outcome scenarios (165 positive controls and 234 negative controls across 4 health outcomes of interest) in 5 real observational databases (4 administrative claims and 1 electronic health record) and in 6 simulated datasets with no effect and injected relative risks of 1.25, 1.5, 2, 4, and 10, respectively. MEASURES: Method performance was evaluated through Area Under ROC Curve (AUC), bias, and coverage probability. RESULTS: The new user cohort method achieved modest predictive accuracy across the outcomes and databases under study, with the top-performing analysis near AUC >0.70 in most scenarios. The performance of the method was particularly sensitive to the choice of comparator population. For almost all drug-outcome pairs there was a large difference, either positive or negative, between the true effect size and the estimate produced by the method, although this error was near zero on average. Simulation studies showed that in the majority of cases, the true effect estimate was not within the 95 % confidence interval produced by the method. CONCLUSION: The new user cohort method can contribute useful information toward a risk identification system, but should not be considered definitive evidence given the degree of error observed within the effect estimates. Careful consideration of the comparator selection and appropriate calibration of the effect estimates is required in order to properly interpret study findings. PMID- 24166225 TI - Empirical performance of the case-control method: lessons for developing a risk identification and analysis system. AB - BACKGROUND: Considerable attention now focuses on the use of large-scale observational healthcare data for understanding drug safety. In this context, analysts utilize a variety of statistical and epidemiological approaches such as case-control, cohort, and self-controlled methods. The operating characteristics of these methods are poorly understood. OBJECTIVE: Establish the operating characteristics of the case-control method for large scale observational analysis in drug safety. RESEARCH DESIGN: We empirically evaluated the case-control approach in 5 real observational healthcare databases and 6 simulated datasets. We retrospectively studied the predictive accuracy of the method when applied to a collection of 165 positive controls and 234 negative controls across 4 outcomes: acute liver injury, acute myocardial infarction, acute kidney injury, and upper gastrointestinal bleeding. RESULTS: In our experiment, the case-control method provided weak discrimination between positive and negative controls. Furthermore, the method yielded positively biased estimates and confidence intervals that had poor coverage properties. CONCLUSIONS: For the four outcomes we examined, the case-control method may not be the method of choice for estimating potentially harmful effects of drugs. PMID- 24166226 TI - Empirical performance of the self-controlled case series design: lessons for developing a risk identification and analysis system. AB - BACKGROUND: The self-controlled case series (SCCS) offers potential as an statistical method for risk identification involving medical products from large scale observational healthcare data. However, analytic design choices remain in encoding the longitudinal health records into the SCCS framework and its risk identification performance across real-world databases is unknown. OBJECTIVES: To evaluate the performance of SCCS and its design choices as a tool for risk identification in observational healthcare data. RESEARCH DESIGN: We examined the risk identification performance of SCCS across five design choices using 399 drug health outcome pairs in five real observational databases (four administrative claims and one electronic health records). In these databases, the pairs involve 165 positive controls and 234 negative controls. We also consider several synthetic databases with known relative risks between drug-outcome pairs. MEASURES: We evaluate risk identification performance through estimating the area under the receiver-operator characteristics curve (AUC) and bias and coverage probability in the synthetic examples. RESULTS: The SCCS achieves strong predictive performance. Twelve of the twenty health outcome-database scenarios return AUCs >0.75 across all drugs. Including all adverse events instead of just the first per patient and applying a multivariate adjustment for concomitant drug use are the most important design choices. However, the SCCS as applied here returns relative risk point-estimates biased towards the null value of 1 with low coverage probability. CONCLUSIONS: The SCCS recently extended to apply a multivariate adjustment for concomitant drug use offers promise as a statistical tool for risk identification in large-scale observational healthcare databases. Poor estimator calibration dampens enthusiasm, but on-going work should correct this short-coming. PMID- 24166227 TI - Empirical performance of a self-controlled cohort method: lessons for developing a risk identification and analysis system. AB - BACKGROUND: Observational healthcare data offer the potential to enable identification of risks of medical products, but appropriate methodology has not yet been defined. The self-controlled cohort method, which compares the post exposure outcome rate with the pre-exposure rate among an exposed cohort, has been proposed as a potential approach for risk identification but its performance has not been fully assessed. OBJECTIVES: To evaluate the performance of the self controlled cohort method as a tool for risk identification in observational healthcare data. RESEARCH DESIGN: The method was applied to 399 drug-outcome scenarios (165 positive controls and 234 negative controls across 4 health outcomes of interest) in 5 real observational databases (4 administrative claims and 1 electronic health record) and in 6 simulated datasets with no effect and injected relative risks of 1.25, 1.5, 2, 4, and 10, respectively. MEASURES: Method performance was evaluated through area under ROC curve (AUC), bias, and coverage probability. RESULTS: The self-controlled cohort design achieved strong predictive accuracy across the outcomes and databases under study, with the top performing settings exceeding AUC >0.76 in all scenarios. However, the estimates generated were observed to be highly biased with low coverage probability. CONCLUSIONS: If the objective for a risk identification system is one of discrimination, the self-controlled cohort method shows promise as a potential tool for risk identification. However, if a system is intended to generate effect estimates to quantify the magnitude of potential risks, the self-controlled cohort method may not be suitable, and requires substantial calibration to be properly interpreted under nominal properties. PMID- 24166228 TI - Empirical performance of the calibrated self-controlled cohort analysis within temporal pattern discovery: lessons for developing a risk identification and analysis system. AB - BACKGROUND: Observational healthcare data offer the potential to identify adverse drug reactions that may be missed by spontaneous reporting. The self-controlled cohort analysis within the Temporal Pattern Discovery framework compares the observed-to-expected ratio of medical outcomes during post-exposure surveillance periods with those during a set of distinct pre-exposure control periods in the same patients. It utilizes an external control group to account for systematic differences between the different time periods, thus combining within- and between-patient confounder adjustment in a single measure. OBJECTIVES: To evaluate the performance of the calibrated self-controlled cohort analysis within Temporal Pattern Discovery as a tool for risk identification in observational healthcare data. RESEARCH DESIGN: Different implementations of the calibrated self-controlled cohort analysis were applied to 399 drug-outcome pairs (165 positive and 234 negative test cases across 4 health outcomes of interest) in 5 real observational databases (four with administrative claims and one with electronic health records). MEASURES: Performance was evaluated on real data through sensitivity/specificity, the area under receiver operator characteristics curve (AUC), and bias. RESULTS: The calibrated self-controlled cohort analysis achieved good predictive accuracy across the outcomes and databases under study. The optimal design based on this reference set uses a 360 days surveillance period and a single control period 180 days prior to new prescriptions. It achieved an average AUC of 0.75 and AUC >0.70 in all but one scenario. A design with three separate control periods performed better for the electronic health records database and for acute renal failure across all data sets. The estimates for negative test cases were generally unbiased, but a minor negative bias of up to 0.2 on the RR-scale was observed with the configurations using multiple control periods, for acute liver injury and upper gastrointestinal bleeding. CONCLUSIONS: The calibrated self-controlled cohort analysis within Temporal Pattern Discovery shows promise as a tool for risk identification; it performs well at discriminating positive from negative test cases. The optimal parameter configuration may vary with the data set and medical outcome of interest. PMID- 24166229 TI - Evaluation of disproportionality safety signaling applied to healthcare databases. AB - OBJECTIVE: To evaluate the performance of a disproportionality design, commonly used for analysis of spontaneous reports data such as the FDA Adverse Event Reporting System database, as a potential analytical method for an adverse drug reaction risk identification system using healthcare data. RESEARCH DESIGN: We tested the disproportionality design in 5 real observational healthcare databases and 6 simulated datasets, retrospectively studying the predictive accuracy of the method when applied to a collection of 165 positive controls and 234 negative controls across 4 outcomes: acute liver injury, acute myocardial infarction, acute kidney injury, and upper gastrointestinal bleeding. MEASURES: We estimate how well the method can be expected to identify true effects and discriminate from false findings and explore the statistical properties of the estimates the design generates. The primary measure was the area under the curve (AUC) of the receiver operating characteristic (ROC) curve. RESULTS: For each combination of 4 outcomes and 5 databases, 48 versions of disproportionality analysis (DPA) were carried out and the AUC computed. The majority of the AUC values were in the range of 0.35 < AUC < 0.6, which is considered to be poor predictive accuracy, since the value AUC = 0.5 would be expected from mere random assignment. Several DPA versions achieved AUC of about 0.7 for the outcome Acute Renal Failure within the GE database. The overall highest DPA version across all 20 outcome-database combinations was the Bayesian Information Component method with no stratification by age and gender, using first occurrence of outcome and with assumed time-at risk equal to duration of exposure + 30 d, but none were uniformly optimal. The relative risk estimates for the negative control drug-event combinations were very often biased either upward or downward by a factor of 2 or more. Coverage probabilities of confidence intervals from all methods were far below nominal. CONCLUSIONS: The disproportionality methods that we evaluated did not discriminate true positives from true negatives using healthcare data as they seem to do using spontaneous report data. PMID- 24166230 TI - Empirical performance of LGPS and LEOPARD: lessons for developing a risk identification and analysis system. AB - BACKGROUND: The availability of large-scale observational healthcare data allows for the active monitoring of safety of drugs, but research is needed to determine which statistical methods are best suited for this task. Recently, the Longitudinal Gamma Poisson Shrinker (LGPS) and Longitudinal Evaluation of Observational Profiles of Adverse events Related to Drugs (LEOPARD) methods were developed specifically for this task. LGPS applies Bayesian shrinkage to an estimated incidence rate ratio, and LEOPARD aims to detect and discard associations due to protopathic bias. The operating characteristics of these methods still need to be determined. OBJECTIVE: Establish the operating characteristics of LGPS and LEOPARD for large scale observational analysis in drug safety. RESEARCH DESIGN: We empirically evaluated LGPS and LEOPARD in five real observational healthcare databases and six simulated datasets. We retrospectively studied the predictive accuracy of the methods when applied to a collection of 165 positive control and 234 negative control drug-outcome pairs across four outcomes: acute liver injury, acute myocardial infarction, acute kidney injury, and upper gastrointestinal bleeding. RESULTS: In contrast to earlier findings, we found that LGPS and LEOPARD provide weak discrimination between positive and negative controls, although the use of LEOPARD does lead to higher performance in this respect. Furthermore, the methods produce biased estimates and confidence intervals that have poor coverage properties. CONCLUSIONS: For the four outcomes we examined, LGPS and LEOPARD may not be the designs of choice for risk identification. PMID- 24166231 TI - A comparison of the empirical performance of methods for a risk identification system. AB - BACKGROUND: Observational healthcare data offer the potential to enable identification of risks of medical products, and the medical literature is replete with analyses that aim to accomplish this objective. A number of established analytic methods dominate the literature but their operating characteristics in real-world settings remain unknown. OBJECTIVES: To compare the performance of seven methods (new user cohort, case control, self-controlled case series, self-controlled cohort, disproportionality analysis, temporal pattern discovery, and longitudinal gamma poisson shrinker) as tools for risk identification in observational healthcare data. RESEARCH DESIGN: The experiment applied each method to 399 drug-outcome scenarios (165 positive controls and 234 negative controls across 4 health outcomes of interest) in 5 real observational databases (4 administrative claims and 1 electronic health record). MEASURES: Method performance was evaluated through Area Under the receiver operator characteristics Curve (AUC), bias, mean square error, and confidence interval coverage probability. RESULTS: Multiple methods offer strong predictive accuracy, with AUC > 0.70 achievable for all outcomes and databases with more than one analytical approach. Self-controlled methods (self-controlled case series, temporal pattern discovery, self-controlled cohort) had higher predictive accuracy than cohort and case-control methods across all databases and outcomes. Methods differed in the expected value and variance of the error distribution. All methods had lower coverage probability than the expected nominal properties. CONCLUSIONS: Observational healthcare data can inform risk identification of medical product effects on acute liver injury, acute myocardial infarction, acute renal failure and gastrointestinal bleeding. However, effect estimates from all methods require calibration to address inconsistency in method operating characteristics. Further empirical evaluation is required to gauge the generalizability of these findings to other databases and outcomes. PMID- 24166232 TI - Replication of the OMOP experiment in Europe: evaluating methods for risk identification in electronic health record databases. AB - BACKGROUND: The Observational Medical Outcomes Partnership (OMOP) has just completed a large scale empirical evaluation of statistical methods and analysis choices for risks identification in longitudinal observational healthcare data. This experiment drew data from four large US health insurance claims databases and one US electronic health record (EHR) database, but it is unclear to what extend the findings of this study apply to other data sources. OBJECTIVE: To replicate the OMOP experiment in six European EHR databases. RESEARCH DESIGN: Six databases of the EU-ADR (Exploring and Understanding Adverse Drug Reactions) database network participated in this study: Aarhus (Denmark), ARS (Italy), HealthSearch (Italy), IPCI (the Netherlands), Pedianet (Italy), and Pharmo (the Netherlands). All methods in the OMOP experiment were applied to a collection of 165 positive and 234 negative control drug-outcome pairs across four outcomes: acute liver injury, acute myocardial infarction, acute kidney injury, and upper gastrointestinal bleeding. Area under the receiver operator characteristics curve (AUC) was computed per database and for a combination of all six databases using meta-analysis for random effects. We provide expected values of estimation error as well, based on negative controls. RESULTS: Similarly to the US experiment, high predictive accuracy was found (AUC >0.8) for some analyses. Self-controlled designs, such as self-controlled case series, IC temporal pattern discovery and self-controlled cohort achieved higher performance than other methods, both in terms of predictive accuracy and observed bias. CONCLUSIONS: The major findings of the recent OMOP experiment were also observed in the European databases. PMID- 24166233 TI - Evaluating performance of risk identification methods through a large-scale simulation of observational data. AB - BACKGROUND: There has been only limited evaluation of statistical methods for identifying safety risks of drug exposure in observational healthcare data. Simulations can support empirical evaluation, but have not been shown to adequately model the real-world phenomena that challenge observational analyses. OBJECTIVES: To design and evaluate a probabilistic framework (OSIM2) for generating simulated observational healthcare data, and to use this data for evaluating the performance of methods in identifying associations between drug exposure and health outcomes of interest. RESEARCH DESIGN: Seven observational designs, including case-control, cohort, self-controlled case series, and self controlled cohort design were applied to 399 drug-outcome scenarios in 6 simulated datasets with no effect and injected relative risks of 1.25, 1.5, 2, 4, and 10, respectively. SUBJECTS: Longitudinal data for 10 million simulated patients were generated using a model derived from an administrative claims database, with associated demographics, periods of drug exposure derived from pharmacy dispensings, and medical conditions derived from diagnoses on medical claims. MEASURES: Simulation validation was performed through descriptive comparison with real source data. Method performance was evaluated using Area Under ROC Curve (AUC), bias, and mean squared error. RESULTS: OSIM2 replicates prevalence and types of confounding observed in real claims data. When simulated data are injected with relative risks (RR) >= 2, all designs have good predictive accuracy (AUC > 0.90), but when RR < 2, no methods achieve 100 % predictions. Each method exhibits a different bias profile, which changes with the effect size. CONCLUSIONS: OSIM2 can support methodological research. Results from simulation suggest method operating characteristics are far from nominal properties. PMID- 24166234 TI - Alternative outcome definitions and their effect on the performance of methods for observational outcome studies. AB - BACKGROUND: A systematic risk identification system has the potential to test marketed drugs for important Health Outcomes of Interest or HOI. For each HOI, multiple definitions are used in the literature, and some of them are validated for certain databases. However, little is known about the effect of different definitions on the ability of methods to estimate their association with medical products. OBJECTIVES: Alternative definitions of HOI were studied for their effect on the performance of analytical methods in observational outcome studies. METHODS: A set of alternative definitions for three HOI were defined based on literature review and clinical diagnosis guidelines: acute kidney injury, acute liver injury and acute myocardial infarction. The definitions varied by the choice of diagnostic codes and the inclusion of procedure codes and lab values. They were then used to empirically study an array of analytical methods with various analytical choices in four observational healthcare databases. The methods were executed against predefined drug-HOI pairs to generate an effect estimate and standard error for each pair. These test cases included positive controls (active ingredients with evidence to suspect a positive association with the outcome) and negative controls (active ingredients with no evidence to expect an effect on the outcome). Three different performance metrics where used: (i) Area Under the Receiver Operator Characteristics (ROC) curve (AUC) as a measure of a method's ability to distinguish between positive and negative test cases, (ii) Measure of bias by estimation of distribution of observed effect estimates for the negative test pairs where the true effect can be assumed to be one (no relative risk), and (iii) Minimal Detectable Relative Risk (MDRR) as a measure of whether there is sufficient power to generate effect estimates. RESULTS: In the three outcomes studied, different definitions of outcomes show comparable ability to differentiate true from false control cases (AUC) and a similar bias estimation. However, broader definitions generating larger outcome cohorts allowed more drugs to be studied with sufficient statistical power. CONCLUSIONS: Broader definitions are preferred since they allow studying drugs with lower prevalence than the more precise or narrow definitions while showing comparable performance characteristics in differentiation of signal vs. no signal as well as effect size estimation. PMID- 24166236 TI - Development times, clinical testing, postmarket follow-up, and safety risks for the new drugs approved by the US food and drug administration: the class of 2008. AB - IMPORTANCE: The US Food and Drug Administration (FDA) has advanced multiple proposals to promote biomedical innovation by making new drugs available more quickly but with shorter, smaller, and more selective clinical trials and less rigorous end points. OBJECTIVE: To inform the debate about appropriate standards, we studied the development times, clinical testing, postmarket follow-up, and safety risks for the new drugs approved by the FDA in 2008, when most provisions of current law, regulation, and policies were in effect. DESIGN: Descriptive study of the drugs classified as new molecular entities using preapproval FDA evaluation documents, agency drug information databases, prescribing information, and other primary data sources. MAIN OUTCOMES AND MEASURES: Comparison of drugs that received standard review and those deemed sufficiently innovative to receive expedited review with regard to clinical development and FDA review time, the size and duration of efficacy trials, safety issues, and postmarket follow-up. RESULTS: In 2008, the FDA approved 20 therapeutic drugs, 8 with expedited review and 12 with standard review. The expedited drugs took a median of 5.1 years (range, 1.6-10.6 years) of clinical development to obtain marketing approval compared with 7.5 years (range, 4.7-19.4 years) for the standard review drugs (P = .05). The expedited drugs were tested for efficacy in a median of 104 patients receiving the active drug (range, 23-599), compared with a median of 580 patients (range, 75-1207) for standard review drugs (P = .003). Nonclinical testing showed that 6 therapeutic drugs were animal carcinogens, 5 were in vitro mutagens, and 14 were animal teratogens. Other safety concerns resulted in 5 Boxed Warnings; 8 drugs required risk management plans. The FDA required 85 postmarket commitments. By 2013, 5 drugs acquired a new or expanded Boxed Warning; 26 of 85 (31%) of the postmarketing study commitments had been fulfilled, and 8 (9%) had been submitted for agency review. CONCLUSIONS AND RELEVANCE: For new drugs approved by the FDA in 2008, those that received expedited review were approved more rapidly than those that received standard review. However, considerably fewer patients were studied prior to approval, and many safety questions remained unanswered. By 2013, many postmarketing studies had not been completed. PMID- 24166235 TI - The impact of drug and outcome prevalence on the feasibility and performance of analytical methods for a risk identification and analysis system. AB - BACKGROUND: A systematic risk identification system has the potential to study all marketed drugs. However, the rates of drug exposure and outcome occurrences in observational databases, the database size and the desired risk detection threshold determine the power and therefore limit the feasibility of the application of appropriate analytical methods. Drugs vary dramatically for these parameters because of their prevalence of indication, cost, time on the market, payer formularies, market pressures and clinical guidelines. OBJECTIVES: Evaluate (i) the feasibility of a risk identification system based on commercially available observational databases, (ii) the range of drugs that can be studied for certain outcomes, (iii) the influence of underpowered drug-outcome pairs on the performance of analytical methods estimating the strength of their association and (iv) the time required from the introduction of a new drug to accumulate sufficient data for signal detection. METHODS: As part of the Observational Medical Outcomes Partnership experiment, we used data from commercially available observational databases and calculated the minimal detectable relative risk of all pairs of marketed drugs and eight health outcomes of interest. We then studied an array of analytical methods for their ability to distinguish between pre-determined positive and negative drug-outcome test pairs. The positive controls contained active ingredients with evidence of a positive association with the outcome, and the negative controls had no such evidence. As a performance measure we used the area under the receiver operator characteristics curve (AUC). We compared the AUC of methods using all test pairs or only pairs sufficiently powered for detection of a relative risk of 1.25. Finally, we studied all drugs introduced to the market in 2003-2008 and determined the time required to achieve the same minimal detectable relative risk threshold. RESULTS: The performance of methods improved after restricting them to fully powered drug-outcome pairs. The availability of drug-outcome pairs with sufficient power to detect a relative risk of 1.25 varies enormously among outcomes. Depending on the market uptake, drugs can generate relevant signals in the first month after approval, or never reach sufficient power. CONCLUSION: The incidence of drugs and important outcomes determines sample size and method performance in estimating drug-outcome associations. Careful consideration is therefore necessary to choose databases and outcome definitions, particularly for newly introduced drugs. PMID- 24166238 TI - John Charles Brocklehurst. PMID- 24166239 TI - A 12-month follow-up study of people with dementia referred to general hospital liaison psychiatry services. AB - BACKGROUND: new services for patients with dementia in general hospitals are being widely developed. Little is known of outcomes after hospital for such patients. OBJECTIVE: to establish outcomes for patients with dementia referred to general hospital psychiatric services. DESIGN: prospective cohort study. SETTING: two UK general hospitals. SUBJECTS: referrals with dementia to liaison psychiatric services. METHOD: eligible referrals (n = 112), and their carers, were assessed during admission, and at 6 and 12 months, using battery of health measurements. RESULTS: mortality at 6 months was 31% and at 12 months 40%. At baseline, 13% lived in a care home, rising to 84% by 6 months. Quality of life scores remained stable over 12 months, while carer stress fell significantly. Baseline clinical and demographic variables did not predict quality of life or carer stress at 6 and 12 months. CONCLUSIONS: dementia liaison services in general hospitals currently focus on poor outcome cases. PMID- 24166240 TI - Experimental arthritis: Antihistamines as treatments for autoimmune disease? PMID- 24166244 TI - Rheumatoid arthritis: Changes in ACPA Fc glycosylation patterns prior to RA onset. PMID- 24166243 TI - Osteoarthritis: Carboxypeptidase B inhibits complement and cartilage loss. PMID- 24166241 TI - Pragmatic approaches to therapy for systemic lupus erythematosus. AB - Systemic lupus erythematosus (SLE) is a complex autoimmune disease with substantial clinical heterogeneity. Current treatments for SLE are effective at reducing morbidity and mortality but fail to provide a cure, and they frequently have adverse effects. Traditional treatments include NSAIDs and antimalarial agents, which are the first-line therapies for mild SLE. In addition, glucocorticoids and cytotoxic or immunosuppressive agents--such as azathioprine, mycophenolate mofetil, cyclophosphamide, cyclosporine and methotrexate--are used for SLE with organ involvement. Advances in understanding the immunopathogenesis of SLE have led to the development of targeted immunotherapies, such as the anti BAFF antibody belimumab, which has been approved as an add-on therapy for patients who have active disease despite receiving standard therapy. This Review presents an overview of the current therapies and nonpharmacological management approaches for SLE, and discusses the best approaches for treating specific disease manifestations such as lupus nephritis, neuropsychiatric lupus and cutaneous lupus erythematosus. PMID- 24166242 TI - Role of cytokines in intervertebral disc degeneration: pain and disc content. AB - Degeneration of the intervertebral discs (IVDs) is a major contributor to back, neck and radicular pain. IVD degeneration is characterized by increases in levels of the proinflammatory cytokines TNF, IL-1alpha, IL-1beta, IL-6 and IL-17 secreted by the IVD cells; these cytokines promote extracellular matrix degradation, chemokine production and changes in IVD cell phenotype. The resulting imbalance in catabolic and anabolic responses leads to the degeneration of IVD tissues, as well as disc herniation and radicular pain. The release of chemokines from degenerating discs promotes the infiltration and activation of immune cells, further amplifying the inflammatory cascade. Leukocyte migration into the IVD is accompanied by the appearance of microvasculature tissue and nerve fibres. Furthermore, neurogenic factors, generated by both disc and immune cells, induce expression of pain-associated cation channels in the dorsal root ganglion. Depolarization of these ion channels is likely to promote discogenic and radicular pain, and reinforce the cytokine-mediated degenerative cascade. Taken together, an enhanced understanding of the contribution of cytokines and immune cells to these catabolic, angiogenic and nociceptive processes could provide new targets for the treatment of symptomatic disc disease. In this Review, the role of key inflammatory cytokines during each of the individual phases of degenerative disc disease, as well as the outcomes of major clinical studies aimed at blocking cytokine function, are discussed. PMID- 24166245 TI - Withdrawal of technological life support following subarachnoid hemorrhage. AB - BACKGROUND: Prognostication of mortality or severe disability often prompts withdrawal of technological life support in patients following aneurysmal subarachnoid hemorrhage (aSAH). We assessed admission factors impacting decisions to withdraw treatment after aSAH. METHODS: Prospectively collected data of aSAH patients admitted to our institution between 1991 and 2009 were reviewed. Patients given comfort care measures were identified, including early withdrawal of treatment (<72 h after admission). Independent predictors of treatment withdrawal were assessed with multivariable analysis. RESULTS: The study included 1,134 patients, of whom 72 % were female, 58 % white, and 38 % black or African American. Mean age was 52.5 +/- 14.0 years. In-hospital mortality was 18.3 %. Of the 207 patients who died, treatment was withdrawn in 72 (35 %) and comfort measures instituted early in 31 (15 %). Among patients who died, WOLST was associated with older age (63.6 +/- 14.2 years, WOLST vs. 55.6 +/- 13.7 years, no WOLST, p < 0.001); GCS score <8 (62 % of WOLST vs. 44 % with no WOLST, p = 0.010); HH >3 (72 % of WOLST vs. 53 % with no WOLST, p = 0.008); and hydrocephalus (81 % of WOLST vs. 63 % with no WOLST, p = 0.009). Independent predictors of WOLST were poorer Hunt and Hess grade (AOR 1.520, 95 % CI 1.160 1.992, p = 0.002) and older age (AOR 1.045, 95 % CI 1.022-1.068, p < 0.001) with the latter also impacting early WOLST decisions. CONCLUSIONS: Older age and poor clinical grade on presentation predicted WOLST, and age predicted decisions to withdraw treatment earlier following aSAH. While based on prognosis, and in some cases patient wishes, this may also constitute a self-fulfilling prophecy in others. PMID- 24166246 TI - Coagulation and brain. PMID- 24166248 TI - Nuclear DNA changes within Helianthus annuus L.: variations in the amount and methylation of repetitive DNA within homozygous progenies. AB - Complex alterations in the redundancy and methylation of repeated DNA sequences were shown to differentiate the nuclear genome of individuals belonging to single progenies of homozygous plants of the sunflower. DNA was extracted from seedlings obtained from seeds collected at the periphery of flowering heads (P DNA) or from seedlings obtained from seeds collected in their middle (M DNA). Three fractions of repeated sequences were isolated from genomic DNA: a highly repetitive fraction (HR), which reassociates within an equivalent Cot of about 2 * 10(-1), and two medium repetitive fractions (MR1 and MR2) having Cot ranges of about 2 * 10(-1)-2 and 2-10(2), respectively. Denaturation kinetics allowed different sequence families to be recognized within each fraction of repetitive DNA, and showed significant differences in sequence redundancy to occur between P and M DNA, particularly as far as the MR2 fraction is concerned. Most DNA sequence families are more represented in P DNA than in M DNA. However, the redundancy of certain sequences is greater in the latter than in the former. Each repetitive DNA fraction was hybridized to Southern blots of genomic P or M DNA which was digested to completion by three pairs of isoschizomeric restriction endonucleases which are either insensitive or sensitive to the methylation of a cytosine in the recognition site. The results obtained showed that the repetitive DNA of H. annuus is highly methylated. Clear-cut differences in the degree of methylation of P and M DNA were found, and these differences were particularly apparent in the MR2 fraction. It is suggested that alterations in the redundancy of given DNA sequences and changes in their methylation patterns are complementary ways to produce continuous genotypic variability within the species which can be exploited in environmental adaptation. PMID- 24166249 TI - Assignment of RFLP linkage groups to their respective chromosomes in aneuploids of sugi (Cryptomeria japonica). AB - Aneuploids of sugi (Cryptomeria japonica) were found in the open-pollinated progenies of triploidplus tree clones. Seven trisomics and one hypotriploid were used to assign the chromosomes to the RFLP linkage groups constructed previously. The Southern blots containing their genomic DNA were hybridized with the labeled DNA clones corresponding to the loci in the linkage map. The additional dosage in autoradiographs showed that the cloned DNA fragment was located on the extra chromosome in the trisomics. On the other hand, the extra chromosome in two trisomics and the chromosome lacking the triplet in the hypotriploid were cytologically identified as chromosome 10 by consistent presence of a secondary constriction in the proximal region of its short arm. As a result, three linkage groups were assigned to their respective chromosomes, namely chromosome 10 and two other chromosomes. PMID- 24166250 TI - Flow cytometric and Feulgen densitometric analysis of genome size variation in Pisum. AB - A DAPI and ethidium bromide flow cytometric and Feulgen densitometric analysis of genome size variation in Pisum was conducted. The material included 38 accessions of P. sativum of widely different geographic origin and altogether 14 samples of P. elatius, P. abyssinicum, P. humile and P. fulvum. The relative genome size values obtained with the three staining methods were strongly correlated. No evidence for genome size variation was found among P. sativum cultivars. In particular, certain Italian cultivars, for which strongly deviating C-values have been reported, proved to be invariant. The only occasion when ambiguous evidence for marginal genome size variation was found was when all 38 accessions taxonomically affiliated with P. sativum were considered. Pisum abyssinicum and P. fulvum differed from P. sativum by about 1.066-and 1.070-fold, respectively; 1 accession of P. humile differed by 1.089-fold, and 2 of P. elatius by 1.122- and 1.195-fold, respectively (ethidiumbromide comparison), while the other accessions of these taxa were not different from P. sativum. This variation may indicate taxonomic inhomogeneity and demands further investigation. Cultivated P. sativum has long been suspected of not being constant with respect to genome size. As shown here, these findings were not based on genuine differences, but rather were technical in origin. PMID- 24166251 TI - Cytoplasmic male sterility (CMS) in Lolium perenne L. 2. The mitochondrial genome of a CMS line is rearranged and contains a chimaeric atp 9 gene. AB - The most striking difference between the mtDNAs of the fertile L. perenne line LPSB21 and the male-sterile line CMS9B290, is the presence in the former and the absence in the latter of a 5.6-kb HindIII fragment. This difference between fertile and sterile lines was the starting point for a detailed molecular analysis of the mitochondrial genome in the region spanning the 5.6-kb HindIII fragment in fertile L. perenne and the corresponding region in CMS9B290. Restriction mapping and Southern-blot analyses indicated that rearrangement of the mitochondrial genome consistent with a deletion/insertion event had occurred in the sterile line. Nucleotide-sequence analysis of the rearranged region in CMS9B290 revealed the presence of (1) a novel chimaeric gene, orf-C9, comprising the first six codons of atp9 fused to a further 118 codons of an unknown sequence and (2) a truncated version of an open reading frame, orf-L, originally identified in LPSB21 mtDNA. Northern-blot analysis confirmed the absence of orf-L transcripts and the presence of orf-C9 transcripts in the mtRNA of CMS9B290. PMID- 24166252 TI - Intergeneric transfer of a partial genome and direct production of monosomic addition plants by microprotoplast fusion. AB - Results are reported on the transfer of single, specific chromosomes carrying kanamycin resistance (Kan(R)) and beta-glucuronidase (GUS) traits from a transformed donor line of potato (Solanum tuberosum) to a recipient line of the tomato species Lycopersicon peruvianum through microprotoplast fusion. Polyethylene glycol-induced mass fusion between donor potato microprotoplasts containing one or a few chromosomes and normal recipient diploid L. peruvianum protoplasts gave several Kan(R) calli. A high frequency of plants regenerated from Kan(R) calli expressed both Kan(R) and GUS, and contained one or two copies of npt-II and a single copy of gus. Genomic in situ hybridization showed that several microprotoplast hybrid plants had one single potato donor chromosome carrying npt-II and gus genes and the complete chromosome complement of the recipient L. peruvianum (monosomic additions). Several monosomic-addition hybrid plants could be regenerated within the short time of 3 months and they were phenotypically normal, resembling the recipient line. These results suggest that the transfer of single chromosomes is tolerated better than is the transfer of the whole donor genome. The unique advantages of microprotoplast fusion are discussed: these include the direct production of monosomic addition lines for the transfer and introgression of economically important traits in sexually incongruent species, the construction of chromosome-specific DNA libaries, high resolution physical mapping and the identification of alien chromosome domains related to gene expression. PMID- 24166253 TI - Abundance and length polymorphism of microsatellite repeats in Beta vulgaris L. AB - Simple sequence repeats (SSRs) are known to exhibit high degrees of variability even among closely related individuals. Their usage as nuclear genetic markers requires their conversion into sequence-tagged sites (STSs). In this paper we present the development of simple sequences as STSs for Beta vulgaris. This species comprises wild, cultivated, and weedy forms; the latter are thought to originate from accidental hybridisation between the other two. Two partial genomic libraries were screened with simple sequence motifs (AT, CA, CT, ATT, GTG, and CA, CT, respectively). Clones of 22 CA, nine CT, eight ATT, and one GTG sequence were obtained. AT micro satellites were present in compound motifs, not recognised by the probe. Sequence comparisons revealed that 20 CA clones containing short motifs (<16 bp) were variants of a previously described approximately 320-bp satellite DNA (Schmidt et al. 1991), and hence did not correspond to unique loci. Polymorphism of one (ATT)15 and three (CT)n, with n=15, 17 and 26, was detected by PCR on a sample of 64 plants from the different forms of B. vulgaris. 13 (ATT), 13 (CT), nine (CT) alleles and one (CT) allele were detected. One of the ATT alleles was much larger than the others (>800 bp). Genetic variability was high among wild beets, lower among cultivated beets, and intermediate among weed beets. One allele of each locus was found at high frequencies in cultivated beets and, to a lower extent, in weed beets. The combination of three polymorphic loci allowed the individual identification of 17/17 wild and 15/15 weed beets, and 21/32, mostly homozygous, cultivated beets. PMID- 24166254 TI - Random amplified polymorphic DNA (RAPD) markers in hop, Humulus lupulus: level of genetic variability and segregation in F1 progeny. AB - The level of genetic variation in 24 hop genotypes was studied using the recently developed technique for producing random amplified polymorphic DNAs (RAPDs). Of the 60 primers screened, eight produced polymorphic RAPD bands, 38 produced bands that were monomorphic for all genotypes and 19 did not produce any amplification product. It appeared that the level of polymorphism among the genotypes was generally low. Three of the primers, A11, A17 and C9, were used to determine the stability and segregation of RAPD markers in five families with a total of 182 F1 progeny. The segregation ratios of these markers in the f1 progeny suggested that they were inherited in a Mendelian manner. RAPD markers were stable and may be useful for the construction of linkage maps in hop. PMID- 24166247 TI - Hemostasis and alterations of the central nervous system. AB - Modulation of coagulation has been successfully applied to ischemic disorders of the central nervous system (CNS). Some components of the coagulation system have been identified in the CNS, yet with limited exception their functions have not been clearly defined. Little is known about how events within the cerebral tissues affect hemostasis. Nonetheless, the interaction between cerebral cells and vascular hemostasis and the possibility that endogenous coagulation factors can participate in functions within the neurovascular unit provide intriguing possibilities for deeper insight into CNS functions and the potential for treatment of CNS injuries. Here, we consider the expression of coagulation factors in the CNS, the coagulopathy associated with focal cerebral ischemia (and its relationship to hemorrhagic transformation), the use of recombinant tissue plasminogen activator (rt-PA) in ischemic stroke and its study in animal models, the impact of rt-PA on neuron and CNS structure and function, and matrix protease generation and matrix degradation and hemostasis. Interwoven among these topics is evidence for interactions of coagulation factors with and within the CNS. How activation of hemostasis occurs in the cerebral tissues and how the brain responds are difficult questions that offer many research possibilities. PMID- 24166255 TI - Genetic characterization of storage proteins in a set of F1-derived haploid lines in bread wheat. AB - Wheat storage proteins were evaluated by SDS-PAGE in a population of 206 doubled haploid (DH) lines, produced from a cross between bread wheat cvs Chinese Spring (CS) and Courtot (CT). The analysis of gliadins and high- and low-molecular weight glutenins gave rise to 11 protein markers between parental varieties. Among these, one each was encoded at the Glu-A1, Gli-A1, Gli-A2, Gli-A5, Glu-B3, Gli-B1 and Gli-D1 loci and four were encoded at the Glu-D3 locus. Only the Gli-A2 marker showed a distorted segregation. A distance of 1.94 cM was evaluated between the Gli-A1 locus and the recently found Gli-A5 locus. Among the DH lines, only nine exhibited an unexpected pattern. The chromosome allocation was determined for almost all the LMW-GS and gliadin bands of CS using nullitetrasomic and ditelosomic lines. Two C LMW-GS were found to be coded by 6DS. Similarly, substitution lines into CT allowed the allelic determination of numerous LMW-GS and gliadin bands. A correspondence between gliadin markers separated in SDS-PAGE and in A-PAGE revealed that the common allele Gli-Aa between CS and CT determined in A-PAGE was able to be separated into two alleles when SDS-PAGE was used. PMID- 24166256 TI - Relationship between inbreeding depression and inbreeding coefficient in maritime pine (Pinus pinaster). AB - The relationship between inbreeding depression and inbreeding coefficient (F) for several important traits was investigated in an 11-year trial of maritime pine (Pinus pinaster). Five levels of inbreeding (F=0; 0.125; 0.25; 0.5; 0.75) were obtained in a mating design involving ten plus-trees, or their progenies, as parents (total of 51 families). For F=0.75, the mean inbreeding depressions were 27% for height, 37% for circumference at breast height (63% for bole volume), 23% for basal straightness (better straightness of the inbred trees), and 89% for female fertility (number of cones). Large differences were observed among inbred families for the same level of inbreeding. The evolution of depression with F was more or less linear, depending on the traits. Significant differences among F levels appeared very early for height (from 5-years of age). Inbreeding depression was much more expressed during unfavorable years than during favorable years for yearly height growth. When compared with other Pinus species, maritime pine appears to be less affected by inbreeding, especially for the percentage of filled seeds and general vigor. A reduced genetic load in maritime pine may result from the evolutionary history of the species and its scattered distribution. PMID- 24166257 TI - Inheritance of resistance to the bean-pod weevil (Apion godmani Wagner) in common beans from Mexico. AB - The bean-pod weevil (BPW), Apion godmani Wagner, often causes heavy losses in crops of common bean (Phaseolus vulgaris L.). Farmers need resistant bean cultivars to minimize losses, cut production costs, stabilize seed yield, and reduce pesticide use and consequent health hazards. To design effective breeding methods, breeders need new and better sources of resistance and increased knowledge of their modes of inheritance. We therefore: (1) compared sources of resistance to BPW, (2) studied the inheritance of resistance, and (3) determined whether the sources possess similar or different genes for BPW resistance. The following sources of resistance, originating from the Mexican highlands, were evaluated for 3 years at INIFAP-Santa Lucia de Prias, Texcoco, Mexico: 'Amarillo 153', 'Amarillo 169', 'Hidalgo 58', 'J 117', 'Pinto Texcoco', 'Pinto 168', and 'Puebla 36'. All except 'Puebla 36' were crossed with the susceptible cultivar 'Jamapa'. 'Amarillo 153' and 'Puebla 36' were crossed with another susceptible cultivar, 'Bayo Mex'. The parents, F1 hybrids, and F2 populations were evaluated for BPW damage in 1992. Backcrosses of the F1 of Jamapa/Pinto 168 to the respective susceptible and resistant parents were also evaluated in 1992. All seven resistant accessions were crossed in all possible combinations, excluding reciprocals. The resulting 21 F1 hybrids and 21 F2 populations were evaluated for BPW damage in 1994. 'J 117' had the highest level of resistance to BPW. 'Pinto Texcoco' and 'Puebla 36' had the highest mean damage score of all seven sources of resistance. The F1 hybrids between susceptible parents and resistant sources were generally intermediate. Two genes segregating independently controlled the BPW resistance in each accession. One gene, Agm, has no effect when present alone, whereas the other gene, Agr, alone conferred intermediate resistance. When both genes were present, resistance to BPW was higher. Based on mean BPW damage scores, all 21 F1 hybrids and their F2 populations, derived from crosses among seven resistant accessions, were resistant. However, data from individual plant damage scores in F2 populations of Amarillo 169/Pinto 168 and Pinto Texcoco/Pinto 168 suggested that at least one gene in each of the three accessions was non allelic. Data also indicated that 'Amarillo 169' had a dominant gene that conferred high levels of BPW resistance, irrespective of the alleles at the other locus; and that 'Pinto Texcoco' and 'Pinto 168' possessed two different genes for intermediate resistance. PMID- 24166258 TI - Higher recombination frequencies in female compared to male meisoses in Brassica oleracea. AB - Linkage maps of the nine chromosomes of Brassica oleracea, based on 75 informative molecular markers, have been compared in first and second backcross progeny from a cross between two doubled haploid lines. The second backcross progeny showed greater recombination frequencies for 75% of the pairs of adjacent markers, but there was no obvious indication that this effect was localised to particular regions of the chromosomes. Four chromosomes increased in genetic length more than twofold, while overall, the total map was 66% longer. The possible causes of this discrepancy are analysed. A sex difference in chiasma distribution and/or frequency at meiosis is thought to be the most likely explanation. The implications of this finding for mapping and map-based applications are discussed. PMID- 24166259 TI - Evaluation of agronomic traits and analysis of exotic germ plasm polymorphism in adapted x exotic maize crosses. AB - The utilization of exotic germ plasm is difficult due to its non-adaptability. This study investigates the possibility of exotic germ plasm loss during adaptation, and the effect of an additional cross with elite material on the breeding value of exotic x adapted material. The study was conducted on a temperate x highland tropical composite (or pool) developed in order to broaden the genetic variability of maize in north western Europe. The frequency of unique exotic alleles and the isoenzymatic polymorphism at four loci were analysed in the pool itself, in the pool after mild selection, and in the selected pool crossed with elite material. Based on these data, no significant deviation seemed to occur during the mild selection and the cross. The pool and the pool x elite germ plasm cross were evaluated in testcrosses with two complementary testers for both grain and forage production. The pool was later in maturity, more susceptible to lodging, and yielded less than the pool x elite germ plasm crosses for all evaluations. The highest estimates of genetic variance were obtained in the pool for earliness and height traits, and for yield. However, based on the predicted genotypic mean of the selected population, the pool had a lower breeding value than the pool x elite germ plasm cross. The pool x elite germ plasm cross is thus preferred to initiate selection. PMID- 24166260 TI - Phylogenetic relationships of Thlaspi s.l. (subtribe Thlaspidinae, Lepidieae) and allied genera based on chloroplast DNA restriction-site variation. AB - Chloroplast DNA restriction-site variation was analyzed in 30 accessions representing 20 species from the major lineages in Thlaspi s.l. (previously described as genera by Meyer 1973, 1979) and allied genera from the subtribe Thlaspidinae (Peltaria, Teesdalia, Cochlearia, Ionopsidium, Aethionema). A total of 161 variable restriction sites were detected. Phylogenetic analyses indicated a division of Thlaspi s.l. into three groups consistent with Meyer's genera Thlaspi s. str., Microthlaspi and Noccaea/Raparia. The genus Thlaspi s.l. as currently described proved to be paraphyletic because one of its major lineages, i.e. Thlaspi s. str., appeared to be more closely related to other genera (Peltaria, Teesdalia) than to the remaining lineages of Thlaspi s.l., i.e. Noccaea/Raparia and Microthlaspi. Sequence divergence values (100 x p) between the Thlaspi s.l. lineages were similar to values between these groups and related genera (Teesdalia, Peltaria), respectively. Chloroplast DNA variation was also used to assess subtribal classification of the genera studied. The cpDNA data were inconsistent with the controversial taxonomic classifications based on morphology. The molecular data would suggest that (1) the subtribe Thlaspidinae, as traditionally described, is not monophyletic; (2) the Thlaspidinae should be reduced to a group consisting of Thlaspi s. str., Peltaria, Teesdalia, Microthlaspi, Noccaea/Raparia, and that Aethionema should be excluded from the Thlaspidinae; and (3) Cochlearia and Ionopsidium represent the subtribe Cochleariinae. PMID- 24166261 TI - The genetics of adult-plant blackleg (Leptosphaeria maculans) resistance from Brassica juncea in B. napus. AB - The genetic control of adult-plant blackleg (Leptosphaeria maculans) resistance in a Brassica napus line (579NO48-109-DG-1589), designated "R13" possessing Brassica juncea-like resistance (JR), was elucidated by the analysis of segregation ratios in F2 and F3 populations from a cross between "R13" and the highly blackleg-susceptible B. napus cultivar "Tower". The F2 segregration ratios were bimodal, demonstrating that blackleg resistance in "R13" was controlled by major genes. Analysis of the segregation ratios for 13 F3 families indicated that blackleg resistance in these families was controlled by three nuclear genes, which exhibited a complex interaction. Randomly sampled plants of F3 progeny all had the normal diploid somatic chromosome number for B. napus. The similarities between the action of the three genes found in this study with those controlling blackleg resistance in B. juncea is discussed. PMID- 24166262 TI - Registration of S alleles in Brassica campestris L by the restriction fragment sizes of SLGs. AB - Polymorphism of SLG (the S-locus glycoprotein gene) in Brassica campestris was analyzed by PCR-RFLP using SLG-specific primers. Nucleotide sequences of PCR products from 15 S genotypes were determined in order to characterise the exact DNA fragment sizes detected in the PCR-RFLP analysis. Forty-seven lines homozygous for 27 S-alleles were used as plant material. One combination of primers, PS5 + PS 15, which had a nucleotide sequence specific to a class-I SLG, gave amplification of a single DNA fragment of approximately 1.3kb from the genomic DNA of 15 S genotypes. All the DNA fragments showed different electrophroetic profiles from each other after digestion with MboI or MspI. Different lines having the same S genotype had an identical electrophoretic profile even between the lines collected in Turkey and in Japan. Another class-I SLG-specific primer, PS 18, gave amplification of a 1.3-kb DNA fragment from three other S genotypes in combination with PS 15, and the PCR product also showed polymorphism after cleavage with the restriction endonucleases. Genetic analysis, Southern-hybridization analysis, and determination of the nucleotide sequences of the PCR products suggested that the DNA fragments amplified with these combinations of primers are class-I SLGs. Expected DNA fragment sizes in the present PCR-RFLP condition were calculated from the determined nucleotide sequence of SLG PCR products. A single DNA fragment was also amplified from six S genotypes by PCR with a combination of primers, PS3 + PS21, having a nucleotide sequence specific to a class-II SLG. The amplified DNA showed polymorphisnm after cleavage with restriction endonucleases. The cleaved fragments were detected by Southern-hybridization analysis using a probe of S (5) SLG cDNA, a class-IISLG. Partial sequencing revealed a marked similarity of these amplified DNA fragments to a class-II SLG, demonstrating the presence of class-I and class-II S alleles also in B. campestris. The high SLG polymorphism detected by the present investigation suggests the usefulness of the PCR-RFLP method for the identification of S alleles in breeding lines and for listing S alleles in B. campestris. PMID- 24166263 TI - Mapping quantitative trait loci for seedling vigor in rice using RFLPs. AB - Improving seedling vigor is an important objective of modern rice (Oryza saliva L.) breeding programs. The purpose of this study was to identify and map quantitative trait loci (QTL) underlying seedling vigor-related traits using restriction fragment length polymorphisms (RFLPs). An F2 population of 204 plants was developed from a cross between a low-vigor japonica cultivar 'Labelle' (LBL) and a high-vigor indica cultivar 'Black Gora' (BG). A linkage map was constructed of 117 markers spanning 1496 Haldane cM and encompassing the 12 rice chromosomes with an average marker spacing of 14 cM. The length of the shoots, roots, coleoptile and mesocotyl were measured on F3 families in slantboard tests conducted at two temperatures (18 degrees and 25 degrees C). By means of interval analysis, 13 QTLs, each accounting for 7% to 38% of the phenotypic variance, were identified and mapped in the two temperature regimes at a log likelihood (LOD) threshold of 2.5. Four QTLs controlled shoot length, 2 each controlled root and coleoptile lengths and 5 influenced mesocotyl length. Single point analysis confirmed the presence of these QTLs and detected additional loci for shoot, root and coleoptile lengths, these latter usually accounting for less than 5% of the phenotypic variation. Only 3 QTLs detected both by interval and singlepoint analyses were expressed under both temperature regimes. Additive, dominant and overdominant modes of gene action were observed. Contrary to what was predicted from parental phenotype, the low-vigor LBL contributed 46% of the positive alleles for shoot, root and coleoptile lengths. Positive alleles from the high-vigor parent BG were identified for increased root, coleoptile and mesocotyl lengths. However, BG contributed alleles with only minor effects for shoot length, the most important determinant of seedling vigor in water-seeded rice, suggesting that it would not be an ideal donor parent for introducing faster shoot growth alleles into temperate japonica cultivars. PMID- 24166264 TI - Analysis of somatic hybrids between two sterile dihaploid Solanum tuberosum L. breeding lines. Restoration of fertility and complementation of G. pallida Pa2 and Pa3 resistance. AB - Fourteen somatic hybrids generated by electrofusion of mesophyll protoplasts from a non-flowering dihaploid S. tuberosum clone, DHAK-11, and a male-sterile dihaploid clone S. tuberosum, DHAK-33, were grown in the greenhouse and subjected to morphological assessments and tests for fertility and resistance to the white potato cyst nematode Globodera pallida pathotypes Pa2 and Pa3. The ploidy level of the hybrids ranged from 38 to 63 chromosomes. All hybrids developed flowers with violet petals except for one, hy-56, that possessed red petals. The colour of the tuber skin was purple in all hybrids except in hy-56 where the tuber skin was red. All of the hybrids were female fertile and generated viable seeds. Near tetraploid hybrids produced the highest number of seeds per fruit and these seeds had a normal size. Hybrids with 58 or more chromosomes produced smaller seeds and less seeds per fruit. The germination frequency of the seeds was not influenced by the chromosome number of the hybrids. Pollen viability was determined and the male fertility of three hybrids was tested. Pollination with these three hybrids gave rise to fruit development, but only one produced viable seeds. The hybrids were tested for resistance to G. pallida pathotypes Pa2 and Pa3. A high level of resistance to Pa3, inherited from one parental clone, DHAK-11, and a high level of resistance to Pa2, inherited from the other parental clone, DHAK-33, was combined in four hybrids. These results demonstrate, that protoplast fusion is an efficient method for restoring the fertility of somatic hybrids generated from sterile parent clones, and is a powerful procedure for the complementation of multigenetic disease resistance traits in potato breeding lines. PMID- 24166265 TI - Karyotyping of three Pinaceae species via fluorescent in situ hybridization and computer-aided chromosome analysis. AB - The positions of 18/25S rRNA genes, 5S RNA genes and of Arabidopsis-type telomeric repeats were localized by fluorescent in situ hybridization (FISH) on the chromosomes of three coniferous species; Picea abies, Larix decidua and Pinus sylvestris, each with 2n=24 chromosomes. Computer-aided chromosome analysis was performed on the basis of the chromosome length, the arm length ratio and the position of the hybridization signals. This enabled the chromosomes of the Norway spruce, 4 chromosomes of the European larch and 3 of the karyotype of the Scots pine to be individually distinguished. With respect to the chromosomal positions of rDNA and 5S rDNA loci, chromosome pair I of P. sylvestris is suggested to be homoeologous to pair II of P. abies, while another chromosome pair of P. sylvestris might be homoeologous to chromosome pair III of L. decidua. PMID- 24166266 TI - Interspecific crosses of onion with distant Allium species and characterization of the presumed hybrids by means of flow cytometry, karyotype analysis and genomic in situ hybridization. AB - Interspecific crosses were made by hand-pollination of Allium cepa with pollen of 19 species belonging to nine sections of two subgenera of the genus Allium. In all cases viable plantlets were obtained from ovary culture. The efficiency depended on the relationship of the pollen donor to A. cepa. The hybrid character of the regenerants was checked by morphological comparisons with the parents and/or by one or more cytological methods such as flow cytometric DNA measurement, karyotype analysis, and genomic in situ hybridization (GISH). Hybrids were confirmed for 18 new species combinations. The viable hybrid of the most distant cross resulted from crossing A. cepa with A. sphaerocephalon. The relevance of the verification methods and the potential use of the hybrids for breeding purposes are demonstrated. PMID- 24166267 TI - Characterization of the Citrus genome through analysis of restriction fragment length polymorphisms. AB - Studies on the nature of restriction fragment length polymorphisms (RFLPs) were undertaken to characterize the Citrus genome. This type of analysis has not been carried out with any other perennial crop. Citrus reticulata Blanco cv Clementine, C. xparadisi Macf. cv Duncan, and an F1 hybrid (LB 1-21) were used to determine what probe/enzyme combinations revealed polymorphisms in Southern analysis, and a backcross family (LB 1-21x'Clementine') of 65 randomly selected hybrid seedlings was used for some analyses. A majority (73%) of the clones examined from a PstI genomic library appeared to detect single-copy sequences based on RFLP banding patterns, while clones from a cDNA library revealed a lower percentage of single copy sequences. When hybridization stringencies were lowered, 21% of the genomic clones examined revealed greater copy numbers. PstI digestion of 'Duncan' DNA indicated abundant methylation, so the relatively high frequency of multiple-copy sequences observed at moderate stringency cannot be attributed to a lack of methylation of the Citrus DNA. The polymorphisms in banding patterns observed primarily resulted from insertions and/or deletions rather than from base substitutions, and a model is presented to account for the varying patterns obtained from individual probes with different restriction enzymes. Finally, a model for transposon activity in Citrus is proposed, based on observations made during the course of these studies. PMID- 24166268 TI - Contrasting patterns of genetic diversity in two tropical pines: Pinus kesiya (Royle ex Gordon) and P. merkusii (Jungh et De Vriese). AB - We studied allozyme and chloroplast (cp) DNA variation in natural populations of Pinus kesiya and P. merkusii from Thailand and Vietnam. The results showed striking differences between the two species in the amount and distribution of allozyme variation. P. kesiya harboured considerable allozyme variation and showed weak interpopulational differentiation. In contrast, P. merkmii had very low intrapopulational variability but a high level of interpopulational differentiation. The average Nei's genetic distance separating the two species was exceptionally high (0.701) taking into account their close taxonomic placement in the same subsection Sylvestres. The constructed phylogenetic trees revealed very early divergence of P. kesiya and P. merkusii. The present analysis of cpDNA variation also confirmed the dissimilar character of these two species and was compatible with other evidence indicating the outstanding position of P. merkusii as compared to other Asian members of the subsection Sylvestres. Analysis of cpDNA variation in sympatric populations of P. kesiya and P. merkusii revealed that they are pure representatives of the species in question. This result indicates that despite an overlapping distribution P. kesiya and P. merkusii do not hybridise in nature. We suggest that the distinctive character of P. merkusii is a result of an early separation from other Eurasian pines. Despite spatial proximity, P. kesiya and P. merkusii are kept apart by strong reproductive barriers. The low genetic variability of P. merkusii may be explained by previous bottlenecks, reduced gene flow among populations, and an inbreeding due to small population size and asynchronous flowering. PMID- 24166269 TI - PCR analysis of oilseed rape cultivars (Brassica napus L. ssp. oleifera) using 5' -anchored simple sequence repeat (SSR) primers. AB - Primers complementary to simple sequence repeats (SSRs) and with variable three base 'anchors' at their 5' end, were used in PCR analyses to compare pooled DNA samples from various Brassica napus and B. rapa cultivars. Amplification products were resolved on polyacrylamide gels and detected by silver-nitrate staining. The resulting banding patterns were highly repeatable between replicate PCRs. Two of the primers produced polymorphisms at 33 and 23 band positions, respectively, and could each discriminate 16 of the 20 cultivars studied. Combined use of both primers allowed all 20 cultivars to be distinguished. The UPGMA dendrogram, based on the cultivar banding profiles, demonstrated clustering on the basis of winter/spring growth habit, high/low glucosinolate content, and cultivar origin (i.e. the breeder involved). Intracultivar polymorphism was investigated using a minimum of ten individuals for each cultivar and was found to vary considerably between cultivars. It is concluded that anchored SSR-PCR analysis is a highly informative and reproducible method for fingerprinting oilseed rape populations, but that intra-cultivar variation should be investigated before using banding profiles from pooled samples for the identification of individuals. PMID- 24166270 TI - Mapping of the K(+)/Na (+) discrimination locus Kna1 in wheat. AB - In saline environments, bread wheat, Triticum aestivum L. (genomes AABBDD), accumulates less Na(+) and more K(+) in expanding and young leaves than durum wheat, T. turgidum L. (genomes AABB). Higher K(+)/Na(+) ratios in leaves of bread wheat correlate with its higher salt tolerance. Chromosome 4D from bread wheat was shown in previous work to play an important role in the control of this trait and was recombined with chromosome 4B in the absence of the Ph1 locus. A population of plants disomic for 4D/4B recombined chromosomes in the genetic background of T. turgidum was developed to investigate the genetic control of K(+)/Na(+) discrimination by chromosome 4D. Evidence was obtained that the trait is controlled by a single locus, designated Kna1, in the long arm of chromosome 4D. In the present work, K(+)/Na(+) discrimination was determined for additional families with 4D/4B chromosomes. The concentrations of Na(+) and K(+)/Na(+) ratios in the youngest leaf blades clustered in two nonoverlapping classes, and all recombinant families could be unequivocally assigned to Kna1 and kna1 classes. The Kna1 locus scored this way was mapped on a short region in the 4DL arm and was completely linked to Xwg199, Xabc305, Xbcd.402, Xpsr567, and Xpsr375; it was also mapped as a quantitative trait. The results of the QTL analysis, based on the K(+)/Na(+) ratios in the young leaves of greenhousegrown plants and flag leaves of field-grown plants, agreed with the position of Knal determined as a qualitative trait. Several aspects of gene introgression by manipulation of the Ph1 locus are discussed. PMID- 24166271 TI - Production and identification of somatic hybrids between Solanum tuberosum and S. papita by using the rolC gene as a morphological selectable marker. AB - A successful hybridization of a diploid clone of Solanum tuberosum with a rolC transgenic, diploid S. papita clone is reported. By using leaf expiants of this S. papita clone, which after transformation expressed kanamycin resistance, intact protoplasts were obtained, but these protoplasts did not develop to microcalli or regenerate to mature plants. However, protoplasts of the S. tuberosum clone showed a high capacity to regenerate plants from isolated protoplasts. On a medium containing Kanamycin only calli regenerated to plants, which revealed a rolC phenotype (reduced apical dominance with a large number of adventitious shoots and a pale green color of leaves) and later on turned out to be true hybrids. Self fusions of S. papita never developed to microcalli and those of S. tuberosum ceased to develop on the kanamycin-containing medium. Identification of somatic hybrids was done by RFLP and RAPD analysis. In the greenhouse, out of four selected hybrids only FK3.1 was successfully crossed with two standard S. tuberosum varieties (Datura, Desiree). Out of all the seeds germinated, only rolC-negative F(1) seedlings were further characterized. Within the seedling population obvious differences were evident in respect of the S. papita and S. tuberosum characteristics. PMID- 24166272 TI - Mapping of QTLs involved in nematode resistance, tuber yield and root development in Solanum sp. AB - A backcross population, derived from the cross (S. tuberosumxS. spegazzinii)xS. tuberosum was used to map QTLs involved in nematode resistance, tuber yield and root development. Complete linkage maps were available for the interspecific hybrid parent as well as the S. tuberosum parent, and interval mapping for all traits was performed for both. Additionally, the intra- and inter-locus interactions of the QTLs were examined. The Gro1.2 locus, involved in resistance to G. rostochiensis pathotype Ro1, that was previously mapped in the S. tuberosumxS. spegazzinii F1 population, was located more precisely on chromosome 10. A new resistance locus, Gro1.4, also conferring resistance to G. rostochiensis pathotype Ro1, was found on chromosome 3. Different alleles of this locus originating from both parents contributed to the resistant phenotype, indicating multiallelism at this locus. No interlocus interactions were observed between these two resistance loci. For resistance to G. pallida no QTLs were detected. One minor QTL involved in tuber yield was located on chromosome 4. Two QTLs involved in root development and having large effects were mapped on chromosomes 2 and 6 and an epistatic interaction was found between these two loci. PMID- 24166273 TI - Growth performance of hybrid families by crossing selfed lines of Betula pendula Roth. AB - Hybrid breeding is an effective approach in many agricultural crops. In allogamous tree species severe inbreeding depression and long reproductive cycles generally prohibit its use. However, three generations of selfing in silver birch (Betula pendula Roth) were obtained by forcing trees to flowering under greenhouse conditions. Hybrids were produced by crossing first-, second and third generation selfed lines. The effects of different levels of parental inbreeding on the growth performance of hybrid families were observed in a 9-year-old field progeny test. Also, provenance crosses were carried out between selfed lines from different parts of Finland and several other European countries. Observations of growth performance of the provenance hybrids were made in the same trial. The results indicated that the mean stem volumes were significantly different between classes of parental in breeding coefficients (FP) (P<0.0001), and were positively correlated with FP (r=0.9106, P<0.05). Within-family variation of the hybrid families decreased with an increase of FP. The performance of the provenance crosses between parents at a relatively close distance did not depart significantly from the standard controls. However, when the cross distance was extended far to the south, hybrids grew faster, indicating either higher heterozygosity or an extended growth period. PMID- 24166274 TI - Model fitting and model testing in the method of joint mapping of quantitative trait loci. AB - A previous paper proposed a new method of QTL mapping called joint mapping (JM). Some problems have been found in model fitting and model testing due to the neglect of the correlations among different observations of the dependent variable in this model. The present paper reports a method of solving the problems. The coefficient of correlation between two observations of the dependent variable is derived. A generalized least square (GLS) approach is developed for model fitting and a strategy and procedure of model testing based on a chi-square test is suggested. A simulated example is given. The example shows that the JM method is quite efficient in mapping multiple linked QTLs. PMID- 24166275 TI - Estimation of additive genetic variance in commercial layer poultry and simulated populations under selection. AB - Changes in genetic parameters over generations for a selected commercial population and simulated populations of poultry with different sizes were studied. The traits analyzed from the commercial population were rate of lay, age at first egg, egg weight, deformation, and body weight. In the simulated population, a trait measured on both sexes and a sex-limited trait, measured only on one sex, each with a heritability of 0.1 and 0.5, were analyzed. In the commercial and simulated populations, males and females were selected on the basis of family selection indexes and data was available only after many generations of selection. Parameters for each generation were estimated by fitting an animal model using derivative free maximum likelihood (DFREML) with different data structures. In structure 1, data included the given (base) generation for which the parameters were to be estimated, and all subsequent generations. In structure 2, only data on birds in the given generation and their progeny were included. In both structures, parents of base-generation birds were assumed unrelated and pedigrees traced back to these parents. With commercial data using structure 1, estimates of sigma a (2) and h(2) decreased by 14 to 37% across five generations. With structure 2, no trends were observed, though estimates were lower than for structure 1. For simulated data, with a heritability of 0.1, both structures yielded apparently unbiased estimates of the observed additive genetic variances in the (selected) base generation, no matter how many generations of data were utilized, for both sex-limited and normal traits. However, with a heritability of 0.5 the estimated additive genetic variance for both types of trait decreased with a decrease in the number of generations used in the estimation. Estimates based on the first two generations underestimated, while estimates based on five generations of data overestimated, the observed genetic variances in the defined base. The combinations of conditions that lead to varying degrees of bias remain undefined. PMID- 24166277 TI - Errata. PMID- 24166276 TI - Inheritance of oilseed rape (Brassica napus) RAPD markers in a backcross progeny with Brassica campestris. AB - Different cultivars/transgenic lines of oilseed rape (Brassica napus) were crossed (as females) with different cultivars/populations of Brassica campestris. All cross combinations produced seed, with an average seed set per pollination of 9.8. Backcrossing of selected interspecific hybrids (as females) to B. campestris resulted in a much lower seed set, average 0.7 seed per pollination. In the single backcross progeny where a large enough population (92 plants) was obtained for analysis, 33 B. napus specific RAPD markers were investigated to determine the extent of transfer of oilseed rape genetic material into this population. Markers were transferred to the backcross generation with frequencies ranging from 26% to 91%. Almost all of the markers (30/33) were transferred in a frequency not significantly different from 50%. Analysis of the pairwise segregation of markers revealed that 23 markers could be assigned to six linkage groups, most probably reflecting six B. napus C-chromosomes. The presence of backcross plants with recombinant genotypes suggests that complex genetic processes can take place during interspecific hybridisation and backcrossing in these Brassica species. The implications of our results for the possible choice of integration sites of transgenes in oilseed rape are discussed. PMID- 24166278 TI - Direct growth of nanotubes and graphene nanoflowers on electrochemical platinum electrodes. AB - Multi-walled carbon nanotubes and graphene nanoflowers were grown by a catalytic chemical vapor deposition process on metal surfaces. Electrodeposition was used as a versatile technique to obtain three different iron catalyst coatings on platinum microelectrodes. The influence of growth parameters on carbon deposits was investigated. Characterization was carried out by scanning electron microscopy and Raman spectroscopy. A chemical treatment in sulphuric acid produced an increased voltammetric background current. In Raman spectra, the effect of the chemical treatment is seen as a more pronounced sp(3) hybridisation mode of C resulting from surface functionalization of the C nanomaterials. Overall, the hybrid electrodes we produced exhibit a promising performance for oxidase-based array biosensors. Therefore, our study opens the possibility of integrating the hybrid electrodes in biochip applications. PMID- 24166279 TI - Loss of glucocorticoid receptor activation is a hallmark of BRCA1-mutated breast tissue. AB - Glucocorticoids (GCs) regulate cell homeostasis and can affect carcinogenesis. An inherited germline mutation in the BRCA1 gene, a tumor suppressor gene, confers a predisposition to breast and ovarian cancers. BRCA1 participates in the maintenance of genome stability through DNA repair, in cellular homeostasis through gene transcription, and in signaling regulation. The interaction between BRCA1 and the glucocorticoid receptor (GR) signaling pathway was studied in normal breast tissues and triple-negative breast cancers from BRCA1 mutation carriers. A loss of the active Ser211 phosphorylated form of GR was found in the mutant as compared to the non-mutant. In in vitro studies, the BRCA1 status in breast cancer cell lines regulates GC-dependent proliferation/apoptosis and impacts GC-dependent gene expression. The lack of BRCA1 inhibited dexamethasone actions on its target genes' expression and the opposite effect was seen with BRCA1 overexpression. BRCA1 overexpression enhances MAPK p38 phosphorylation, resulting in an amplification of GR phosphorylation on Ser 211 and GR basal expression. Our results indicate that BRCA1 is essential to develop an efficient GC signalization. GR P-Ser211 levels may constitute an important diagnostic factor for screening BRCA1 loss of expression in tumors from BRCA1 mutation carriers as well as in sporadic BRCAness tumors. This marker may help to optimize therapeutic strategies. PMID- 24166280 TI - Cure of metastatic growth of EMT6 tumor cells in mice following manipulation of CD200:CD200R signaling. AB - In previous studies, we observed that regulation of expression of CD200, both on cells of a transplantable breast cancer, EMT6, and of the host, as well as of the receptor, CD200R in host mice, regulated local tumor growth and metastasis in immunocompetent animals. This in turn led to an improved ability to document immunity to EMT6 in CD200R1KO mice. In the current study, we have explored the ability to cure BALB/c CD200KO or CD200R1KO mice of tumors <=1 cm(3) in size by surgical resection of localized tumor, followed by immunization with irradiated EMT6 cells along with CpG as adjuvant. While control animals treated in this fashion developed significant pulmonary and liver metastases within 30 days of surgery, significant protection was seen in both CD200KO or CD200R1KO mice, with no macroscopic lung/liver metastases observed in CD200R1KO mice on sacrifice at day 300. Following surgical resection and immunization, draining lymph nodes from control mice contained tumor cells cloned at limiting dilution in vitro even before pulmonary and hepatic metastasis was seen. In contrast, within the limits of detection of the assay used (sensitivity ~1 in 10(7) cells), no tumor cells were detected at limiting dilution in similarly treated CD200R1KO mice, and significant reductions were seen in CD200KO mice. Infusion of anti-CD4, but less so anti-CD8, mAb into surgically treated and immunized CD200R1KO mice attenuated protection from both macroscopic (liver/lung) and microscopic (assayed by limiting dilution of DLN) metastasis. Adoptive transfer of lymphocytes from treated CD200R1KO mice to surgically treated control mice also attenuated metastatic growth of tumor, which was abolished by pretreatment of transferred cells with anti-CD4 mAb. Our data suggest that CD200:CD200R attenuates a potentially tumor-protective CD4 host response to breast cancer. PMID- 24166282 TI - Phase II randomized trial of weekly and every-3-week ixabepilone in metastatic breast cancer patients. AB - This multicenter, open-label, randomized phase II trial compared the efficacy and tolerability of weekly ixabepilone versus the standard 3 weekly dosing regimen. Patients with human epidermal growth factor receptor 2-negative, metastatic breast cancer (MBC) were randomly assigned to receive either ixabepilone 16 mg/m(2) as a 1-h intravenous (IV) infusion weekly on days 1, 8, and 15 of a 28 day cycle (1 week off therapy; n = 85), or 40 mg/m(2) as a 3-h IV infusion on day 1 of a 21-day cycle (n = 91), until disease progression or unacceptable toxicity. Randomization was stratified by (i) measurable versus nonmeasurable (evaluable) disease, (ii) <=two versus >two prior chemotherapy regimens for MBC, and (iii) hormone receptor (HR)-positive versus HR-negative breast cancer. The primary endpoint was rate of progression-free survival (PFS) at 6 months. Of 176 randomized patients, 171 were treated. The 6-month PFS rate was significantly higher in patients treated with ixabepilone every 3 weeks (42.7, 95 % confidence interval [CI] 31.5-53.5) compared with those who received ixabepilone weekly (28.6, 95 % CI 18.9-38.9; log-rank P = 0.03). Every-3-week dosing significantly prolonged median PFS versus weekly dosing (5.3 vs. 2.9 months; log-rank P = 0.05). The every-3-week regimen was associated with higher rates of grade 3/4 toxicities, particularly neutropenia (38.2 vs. 6.1 %) and a higher rate of patient withdrawal due to adverse events. These results suggest that every-3-week ixabepilone is more effective than weekly treatment in MBC, albeit with more toxicity. PMID- 24166281 TI - A clinical trial of lovastatin for modification of biomarkers associated with breast cancer risk. AB - Pre-clinical and epidemiologic studies provide rationale for evaluating lipophilic statins for breast cancer prevention. We conducted a single-arm, biomarker modulation trial of lovastatin among women with increased risk of breast cancer. Eligibility criteria included a deleterious germline mutation in BRCA1, BRCA2, CDH1, or TP53; lifetime breast cancer risk of >=20 % as estimated by the Claus model; or personal history of estrogen receptor and progesterone receptor-negative breast cancer. Participants received 40 mg of lovastatin orally twice daily for 6 months. We evaluated the following biomarkers before and after lovastatin use: breast duct cytology (primary endpoint), serum lipids, C-reactive protein, insulin-like growth factor-1, IGF binding protein-3, lipid peroxidation, oxidative DNA damage, 3-hydroxy-3-methylglutaryl CoA reductase genotype, and mammographic density. Thirty women were enrolled, and 26 (86.7 %) completed the study. For the primary endpoint of changes in breast duct cytology sampled by random periareolar fine needle aspiration, most participants [57.7 %, 95 % confidence interval (CI) 38.9-74.5 %] showed no change after lovastatin; 19.2 % (CI 8.1-38.3 %) had a favorable change in cytology, 7.7 % (95 % CI 1.0-25.3 %) had an unfavorable change, and 15.4 % (95 % CI 5.5-34.2 %) had equivocal results due to acellular specimens, usually after lovastatin. No significant changes were observed in secondary biomarker endpoints. The study was generally well tolerated: 4 (13.3 %) participants did not complete the study, and one (3.8 %) required a dose reduction. This trial was technically feasible, but demonstrated no significant biomarker modulation; contributing factors may include insufficient sample size, drug dose and/or duration. The results are inconclusive and do not exclude a favorable effect on breast cancer risk. PMID- 24166284 TI - A coumarin-based fluorescent probe for biological thiols and its application for living cell imaging. AB - In this work, compound 1 has been rationally designed and synthesized as a new fluorescent probe for biological thiols. Notably, probe 1 has almost no background fluorescence (Phif < 0.0001) in aqueous solutions; however, it exhibited fluorescence turn-on response to thiols with high sensitivity (a 246 fold fluorescence enhancement and a low detection limit of 0.22 MUM for Cys). Moreover, probe 1 showed excellent thiol specificity over other biologically relevant species. The kinetic studies indicated that the probe responded to thiols rapidly, and the pseudo-first-order rate constants of probe 1 reaction with Cys, Hcy, and GSH were determined to be 1.85842, 0.67656, and 0.51519 min( 1), respectively. A possible detection mechanism was proposed to involve the Michael addition of the thiol to the alpha,beta-unsaturated ketone, followed by a cleavage of the hemiketal group, thereby leading to the formation of a fluorescent 7-hydroxyl coumarin derivative. Furthermore, the optical responses of probe 1 to thiols were studied by TD-DFT calculations. Finally, probe 1 has been successfully applied to the detection of biological thiols in human blood serum. And the intracellular imaging applications established that probe 1 can be used to detect different concentrations of intracellular thiols in living cells. PMID- 24166283 TI - Multimodality PET/MRI agents targeted to activated macrophages. AB - The recent emergence of multimodality imaging, particularly the combination of PET and MRI, has led to excitement over the prospect of improving detection of disease. Iron oxide nanoparticles have become a popular platform for the fabrication of PET/MRI probes owing to their advantages of high MRI detection sensitivity, biocompatibility, and biodegradability. In this article, we report the synthesis of dextran-coated iron oxide nanoparticles (DIO) labeled with the positron emitter (64)Cu to generate a PET/MRI probe, and modified with maleic anhydride to increase the negative surface charge. The modified nanoparticulate PET/MRI probe (MDIO-(64)Cu-DOTA) bears repetitive anionic charges on the surface that facilitate recognition by scavenger receptor type A (SR-A), a ligand receptor found on activated macrophages but not on normal vessel walls. MDIO (64)Cu-DOTA has an average iron oxide core size of 7-8 nm, an average hydrodynamic diameter of 62.7 nm, an r1 relaxivity of 16.8 mM(-1) s(-1), and an r 2 relaxivity of 83.9 mM(-1) s(-1) (37 degrees C, 1.4 T). Cell studies confirmed that the probe was nontoxic and was specifically taken up by macrophages via SR A. In comparison with the nonmodified analog, the accumulation of MDIO in macrophages was substantially improved. These characteristics demonstrate the promise of MDIO-(64)Cu-DOTA for identification of vulnerable atherosclerotic plaques via the targeting of macrophages. PMID- 24166285 TI - The role of urine markers, white light cystoscopy and fluorescence cystoscopy in recurrence, progression and follow-up of non-muscle invasive bladder cancer. AB - Non-muscle invasive bladder cancer (NMIBC) accounts for approximately 70 % of all bladder cancer cases and represents a heterogeneous pathological entity, characterized by a variable natural history and oncological outcome. The combination of cystoscopy and urine cytology is considered the gold standard in the initial diagnosis of bladder cancer, despite the limited sensitivity. The first step in NMIBC management is transurethral resection of the bladder tumour (TURBT). This procedure is marked by a significant risk of leaving residual disease. The primary landmark in NMIBC is the high recurrence rate. Fluorescence cystoscopy improves the bladder cancer detection rate, especially for flat lesions, and improves the recurrence-free survival by decreasing residual tumour. Progression to muscle invasive tumours constitutes the second important landmark in NMIBC evolution. Stage, grade, associated CIS and female gender are the major prognostic factors in this regard. The evolution to MIBC has a major negative impact upon the survival rate and quality of life of these patients. Fluorescence cystoscopy improves the detection rate of bladder cancer but does not improve the progression-free survival. Urine markers such as ImmunoCyt and Uro Vysion (FISH) have also limited additional value in diagnosis and prognosis of NMIBC patients. Major drawbacks are the requirement of a specialized laboratory and the additional costs. In this review, the risks of recurrence and progression are analysed and discussed. The impact of white light cystoscopy, fluorescence cystoscopy and urine markers is reviewed. Finally, the means and recommendations regarding follow-up are discussed. PMID- 24166286 TI - Transperineal reanastomosis for the treatment for highly recurrent anastomotic strictures as a last option before urinary diversion. AB - PURPOSE: To evaluate safety and efficacy of open transperineal reanastomosis (TPRA) for highly recurrent anastomotic strictures (AS) after radical prostatectomy. While the majority of AS can be managed successfully by endoscopic treatment, in highly recurrent AS, open reanastomosis represents a viable therapeutic option. METHODS: Retrospective analysis by standardized questionnaire, inquiring for recurrence, incontinence, sexual function, satisfaction and changes in quality of life (QoL) in 15 patients undergoing TPRA 08/2007-03/2010. RESULTS: Mean patient age was 65 years (51-75) and mean follow up 20.5 months (5.8-37.0). Success rate was 93.3 % (14/15). The single recurrence was successfully treated by cold knife incision. Incontinence was found in 93.3 % (14/15) preoperatively and aggravated in 60 % (9/15) after surgery; no de novo incontinence occurred. Implantation of an artificial urinary sphincter (AUS) has been performed successfully in 10 patients, 2 refused implantation and 2 are scheduled for surgery. Erectile dysfunction was present in 86.7 % (13/15); 13.3 % (2/15) reported a severely declined rigidity. Compared to preoperative status, 33.3 % (5/15) complained about impaired erectile function after TPRA. A good or very good subjective overall health status and an improvement in QoL were noted in 86.7 % (13/15). Patient satisfaction with the outcome of TPRA was high or very high in 13; two were undecided. CONCLUSIONS: After repeated endoscopic treatment, TPRA is a valuable therapeutic option in selected patients with an overall success rate of 93.3 % (14/15) for anastomotic patency, which can even be raised to 100 % by further transurethral surgery. Incontinence can be easily treated by implantation of an AUS. PMID- 24166287 TI - The use of a ureteral access sheath does not improve stone-free rate after ureteroscopy for upper urinary tract stones. AB - PURPOSE: To evaluate the impact of a ureteral access sheath (UAS) on stone-free (SF) rate after flexible ureteroscopy for upper urinary tract stones. MATERIALS AND METHODS: We retrospectively reviewed 280 patients who underwent flexible ureteroscopy (URS) for upper urinary tract stone between 2009 and 2012. Patients were divided into two groups based on whether a UAS was used (n = 157) or not (n = 123). SF rate was evaluated at one and three months after surgery by abdominal imaging. Quantitative and qualitative variables were compared with Student's t test and chi2 test, respectively. A logistic regression model was used to determine the predictive factors of SF status. RESULTS: Stone size was similar in both groups (15.1 vs. 13.7 mm, p = 0.21). SF rates at one and 3 months were comparable in UAS and non-UAS groups (76 vs. 78% and 86 vs. 87%, p = 0.88 and 0.89, respectively). Complication rates were similar in both groups (12.7 vs. 12.1%, p = 0.78). In multivariable analysis, stone size was the only predictive factor of SF rate (p = 0.016). CONCLUSION: The routine use of a UAS did not improve SF rate in patients undergoing flexible URS for upper urinary tract calculi. PMID- 24166288 TI - Prediction of metastatic status in non-seminomatous testicular cancer. AB - PURPOSE: To examine the significance of 90 biomarkers for predicting metastatic status in non-seminomatous germ cell tumors (NSGCT). By predicting metastatic status, it may be possible to eliminate unnecessary therapeutic or diagnostic efforts. MATERIALS AND METHODS: We investigated 552 males who were diagnosed with non-metastatic (n = 273) and metastatic (n = 279) NSGCT between 2000 and 2011. The sample included cancers of different histologies: embryonal cell carcinoma (n = 131), teratoma (n = 55), and mixed histology (n = 366). We collected and analyzed more than 90 parameters via logistic regression: demographic characteristics, medical history, histopathological parameters, and levels of tumor markers and hormones. RESULTS: Testis histology (p = 0.004), clinical symptoms (p = 0.0005), tumor length (p = 0.005), infiltration of the rete testis (p = 0.008), invasion of lymphatic (pL1) and blood vessels (pV1) (p < 0.0001), and levels of enzymes such as LDH, betaHCG, AFP, and FSH (p values as small as <0.0001) were associated with metastatic status. With one model, we identified 14 out of 76 (18.4 %) metastatic NSGCT cases with 93-100 % certainty (positive predictive value) at 99 % specificity by the peripheral blood levels of LDH (day of operation) in combination with FSH measurements (1 day after operation). A second model included pV, tumor length, and FSH (1 day after operation). It identified 25 out of 90 (27.8 %) non-metastatic NSGCT with approximately 90 % certainty (negative predictive value) at 94-98 % sensitivity. CONCLUSIONS: No single parameter was able to discriminate metastatic from non-metastatic NSGCT, but combinations of parameters in two predictive models accurately identified the metastatic status in 23 % of the cases in our sample. PMID- 24166289 TI - Secondary chemoprevention of localized prostate cancer by short-term androgen deprivation to select indolent tumors suitable for active surveillance: a prospective pilot phase II study. AB - PURPOSE: To investigate the impact of 3-month androgen deprivation therapy (st ADT) a secondary chemoprevention of indolent-localized prostate cancer (PCa). METHODS: A prospective phase II study enrolled men over 4 years with low-risk PCa and the following characteristics: PSA < 10 ng/mL, Gleason score of 6 (3 + 3) or less, three positive cores or less, and tumor stage T2a or less. Patients received a single sub-cutaneous injection of 22.5 mg of leuprolide acetate with Atrigel 3-month depot associated with a daily oral intake of bicalutamide 50 mg/day during 15 days around the injection. Follow-up included PSA and bioavailable testosterone blood tests every 3 months and yearly surveillance biopsies. Primary end point was the presence of PCa on biopsy at last follow-up. Secondary end points were detailed pathological features and adverse events. RESULTS: Overall, 98 men were included and 45 of them (45.9 %) had a negative biopsy after a median follow-up of 13 months [11-19.5]. Of the 53 patients with positive biopsy, 17 had pathologic progression because of upgraded Gleason score (11 patients), four or more positive cores (three patients) or both (three patients). The only significant predictive factor biopsy outcome was the number of positive cores at diagnosis. CONCLUSIONS: Secondary chemoprevention by st-ADT for localized PCa could be useful to pinpoint indolent tumors suitable for AS. Indeed, after st-ADT nearly one patient out of two had negative biopsies and 17 % had pathological progression. This is an innovative option to consider as an alternative to current AS protocols contingent upon confirmation in subsequent studies. PMID- 24166291 TI - Capsular incision in normal prostatic tissue during robot-assisted radical prostatectomy: a new concept or a waste of time? AB - PURPOSE: Because radical prostatectomy with robot-assisted surgery can lead to unwanted prostatic capsular incisions, capsular incision in normal prostatic tissue (CINPT) is not rare. To study the relationship between positive surgical margins (PSM) and CINPT after robot-assisted radical prostatectomy. METHODS: From September 2009 to January 2013, 203 consecutive robot-assisted prostatectomies were carried out by the same surgeon. A transperitoneal Montsouris technique was used for all cases, but modified to suit the use of the four-arm DaVinci device. The data were recorded prospectively in our database. Preoperative data were patient's age, body mass index, prostate-specific antigen level, prostate weight, percentage of positive biopsy, clinical stage, and Gleason score. Postoperative data were preservation of the bladder neck and neurovascular bundles (NVB), the presence of extended pelvic lymph-node dissection (ePLND), pathological stage, Gleason score, margin status, blood loss, and operative room times. The CINPT and no-CINPT groups were analysed and compared retrospectively. RESULTS: The CINPT rates were 23.2 versus 18.2 % for PSM. CINPT contrary to PSM seemed to be more frequent in low-risk prostate cancer. NVB preservation led to more CINPT (p = 0.01). At the multivariate analysis, only the absence of ePLND significantly affected the CINPT status (p = 0.03) and the absence of CINPT positively affected the PSM rate (p = 0.03). CONCLUSIONS: Capsular incision in normal prostatic tissue is not a predictive factor of PSM but reflected risk-taking during surgery especially when NVB preservation is indicated in low-risk prostate cancer. It can therefore only be considered a means to evaluate a surgical technique, but not a real predictor of PSM. PMID- 24166290 TI - Perforation during TUR of bladder tumours influences the natural history of superficial bladder cancer. AB - OBJECTIVES: Bladder perforation is the second most common complication during transurethral resection of bladder tumours. It is unknown whether perforation affects the natural history of the tumour through cell seeding. The aim of this study was to study the impact of perforation on the oncologic outcomes of bladder carcinoma. MATERIALS AND METHODS: Between 2003 and 2007, 926 consecutive patients underwent transurethral resection of bladder tumours at our institution; 327 cases were staged >= pT2 and were treated immediately with cystectomy and/or multimodal therapy and therefore excluded from the study. An additional 34 cases without urothelial carcinoma were excluded. Of the remaining 565 patients with non-muscle invasive bladder cancer, 457 (80.8 %) were male and 108 (19.2 %) were female with a mean age of 69.5 years in men and 67.3 years in women. Thirty-seven patients (6.5 %) experienced bladder perforation at the time of tumour resection. This group of patients (Group 1) was compared to the remaining 528 patients (Group 2) who did not experience a bladder perforation. RESULTS: Patients with bladder wall perforation experienced a shorter disease-free survival in both univariate (p = 0.003) and multivariate analyses (p = 0.006). In addition, subsequent recurrences revealed stage progression of recurrent disease (p = 0.05) and trended to a higher number of cystectomies in the perforated group of patients (p = 0.06). Nevertheless, perforation did not appear to influence overall survival (p = 0.127) or cancer-specific survival (p = 0.141). CONCLUSION: The results indicate that bladder perforation during resection of superficial bladder tumours is burdened by a shortened disease-free survival and T-stage progression. PMID- 24166292 TI - Atomically resolved spectroscopic study of Sr2IrO4: experiment and theory. AB - Particularly in Sr2IrO4, the interplay between spin-orbit coupling, bandwidth and on-site Coulomb repulsion stabilizes a J(eff) = 1/2 spin-orbital entangled insulating state at low temperatures. Whether this insulating phase is Mott- or Slater-type, has been under intense debate. We address this issue via spatially resolved imaging and spectroscopic studies of the Sr2IrO4 surface using scanning tunneling microscopy/spectroscopy (STM/S). STS results clearly illustrate the opening of an insulating gap (150 ~ 250 meV) below the Neel temperature (TN), in qualitative agreement with our density-functional theory (DFT) calculations. More importantly, the temperature dependence of the gap is qualitatively consistent with our DFT + dynamical mean field theory (DMFT) results, both showing a continuous transition from a gapped insulating ground state to a non-gap phase as temperatures approach TN. These results indicate a significant Slater character of gap formation, thus suggesting that Sr2IrO4 is a uniquely correlated system, where Slater and Mott-Hubbard-type behaviors coexist. PMID- 24166293 TI - M2 receptors exert analgesic action on DRG sensory neurons by negatively modulating VR1 activity. AB - The peripheral application of the M2 cholinergic agonist arecaidine on sensory nerve endings shows anti-nociceptive properties. In this work, we analyze in vitro, the mechanisms downstream M2 receptor activation causing the analgesic effects, and in vivo the effects produced by M2 agonist arecaidine administration on nociceptive responses in a murine model of nerve growth factor (NGF)-induced pain. Cultured DRG neurons treated with arecaidine showed a decreased level of VR1 and SP transcripts. Conversely, we found an increased expression of VR1 and SP transcripts in DRG from M2/M4(-/-) mice compared to WT and M1(-/-) mice, confirming the inhibitory effect in particular of M2 receptors on SP and VR1 expression. Patch-clamp experiments in the whole-cell configuration showed that arecaidine treatment caused a reduction of the fraction of capsaicin-responsive cells, without altering the mean capsaicin-activated current in responsive cells. We also demonstrated that arecaidine prevents PKCepsilon translocation to the plasma membrane after inflammatory agent stimulation, mainly in medium-small sensory neurons. Finally, in mice, we have observed that intraperitoneal injection of arecaidine reduces VR1 expression blocking hyperalgesia and allodynia caused by NGF intraplantar administration. In conclusion, our data demonstrate that in vivo M2 receptor activation induces desensitization to mechanical and heat stimuli by a down-regulation of VR1 expression and by the inhibition of PKCepsilon activity hindering its translocation to the plasma membrane, as suggested by in vitro experiments. PMID- 24166294 TI - Tunable color generation of transparent composite films reinforced with luminescent nanofillers. AB - A new composite film based on calcined layered rare earth hydroxides and poly(vinyl alcohol) shows a visible light transmittance comparable to that of the pure matrix, highly reinforced mechanical strength as well as tunable photoluminescence in rolled and folded shapes. PMID- 24166296 TI - Absence of mutations in cereblon (CRBN) and DNA damage-binding protein 1 (DDB1) genes and significance for IMiD therapy. PMID- 24166297 TI - Enhancers of Polycomb EPC1 and EPC2 sustain the oncogenic potential of MLL leukemia stem cells. AB - Through a targeted knockdown (KD) screen of chromatin regulatory genes, we identified the EP400 complex components EPC1 and EPC2 as critical oncogenic cofactors in acute myeloid leukemia (AML). EPC1 and EPC2 were required for the clonogenic potential of human AML cells of multiple molecular subtypes. Focusing on MLL-mutated AML as an exemplar, Epc1 or Epc2 KD-induced apoptosis of murine MLL-AF9 AML cells and abolished leukemia stem cell potential. By contrast, normal hematopoietic stem and progenitor cells (HSPC) were spared. Similar selectivity was observed for human primary AML cells versus normal CD34(+) HSPC. In keeping with these distinct functional consequences, Epc1 or Epc2 KD-induced divergent transcriptional consequences in murine MLL-AF9 granulocyte-macrophage progenitor like (GMP) cells versus normal GMP, with a signature of increased MYC activity in leukemic but not normal cells. This was caused by accumulation of MYC protein and was also observed following KD of other EP400 complex genes. Pharmacological inhibition of MYC:MAX dimerization, or concomitant MYC KD, reduced apoptosis following EPC1 KD, linking the accumulation of MYC to cell death. Therefore, EPC1 and EPC2 are components of a complex that directly or indirectly serves to prevent MYC accumulation and AML cell apoptosis, thus sustaining oncogenic potential. PMID- 24166299 TI - The pathway of miRNA maturation. AB - MicroRNAs (miRNAs) are a novel class of 17-23 nucleotide short, nonprotein-coding RNA molecules which have emerged to be key players in posttranscriptional gene regulation. In this chapter we give an in-depth review of the classic, canonical mammalian miRNA maturation pathway and discuss new, noncanonical alternatives such as the mirtron pathway which were recently described. PMID- 24166300 TI - MicroRNA maturation and human disease. AB - Numerous studies describe alterations in the levels of specific microRNAs (miRNAs) that are associated with human pathologies. Some of these alterations may give rise to the development of novel diagnostic tools, while certain miRNAs additionally could serve as novel drug targets. Moreover, components of the miRNA maturation machinery may be up- or down-regulated in human disease. In such cases, the consequences for the expression of individual miRNAs are however only poorly understood. Herein, we review the current knowledge of how miRNAs are linked to human disease and which parts of the miRNA maturation machinery could serve as future drug targets. PMID- 24166301 TI - Approaches to the modulation of miRNA maturation. AB - The therapeutic importance of microRNA (miRNA) regulation has recently been realized as these small, noncoding RNAs have been demonstrated to be involved with a plethora of diseases and disorders. Due to the complex miRNA maturation process, the expression of these important biomolecules can be manipulated at various stages of the pathway. This review examines both in vivo and in vitro mechanisms and assays that have been developed to regulate miRNA levels. Modulation of miRNA maturation can be accomplished via several therapeutic agents, including small molecules and oligonucleotides, in both specific and nonspecific fashions. Due to the relevance of miRNAs, these novel therapeutic approaches represent new tools for the treatment of various cancers and other deleterious disorders. PMID- 24166298 TI - An international study of intrachromosomal amplification of chromosome 21 (iAMP21): cytogenetic characterization and outcome. AB - Intrachromosomal amplification of chromosome 21 (iAMP21) defines a distinct cytogenetic subgroup of childhood B-cell precursor acute lymphoblastic leukaemia (BCP-ALL). To date, fluorescence in situ hybridisation (FISH), with probes specific for the RUNX1 gene, provides the only reliable detection method (five or more RUNX1 signals per cell). Patients with iAMP21 are older (median age 9 years) with a low white cell count. Previously, we demonstrated a high relapse risk when these patients were treated as standard risk. Recent studies have shown improved outcome on intensive therapy. In view of these treatment implications, accurate identification is essential. Here we have studied the cytogenetics and outcome of 530 iAMP21 patients that highlighted the association of specific secondary chromosomal and genetic changes with iAMP21 to assist in diagnosis, including the gain of chromosome X, loss or deletion of chromosome 7, ETV6 and RB1 deletions. These iAMP21 patients when treated as high risk showed the same improved outcome as those in trial-based studies regardless of the backbone chemotherapy regimen given. This study reinforces the importance of intensified treatment to reduce the risk of relapse in iAMP21 patients. This now well-defined patient subgroup should be recognised by World Health Organisation (WHO) as a distinct entity of BCP-ALL. PMID- 24166302 TI - Expression profiling of components of the miRNA maturation machinery. AB - The quantitative real-time polymerase chain reaction (qRT-PCR) is a valuable and well-proven technique used to investigate the expression level of multiple components of the microRNA (miRNA) maturation machinery. Here, we describe how to determine the messenger RNA expression levels of components of the miRNA machinery starting from the isolation of the RNA from a tissue biopsy to performance of the qRT-PCR. PMID- 24166304 TI - In vivo processing assay based on a dual-luciferase reporter system to evaluate DROSHA enzymatic activity. AB - Luciferase reporter assays are widely used to study promoter activity, transcription factors, intracellular signaling, protein interactions (Jia et al., PloS One 6:e26414), miRNA processing (Allegra and Mertens, Biochem Biophys Res Commun 406:501-505), and target recognition (Jin et al., Methods Mol Biol 936:117 127). Here we describe the use of a dual-luciferase reporter system to evaluate the enzymatic activity of a key enzyme involved in RNA maturation-DROSHA. This dual system is a simple and fast method for the quantification of the DROSHA processing activity in live cells. PMID- 24166303 TI - Primary microRNA processing assay reconstituted using recombinant Drosha and DGCR8. AB - In animals, the Microprocessor complex cleaves primary transcripts of microRNAs (pri-miRNAs) to produce precursor microRNAs in the nucleus. The core components of Microprocessor include the Drosha ribonuclease and its RNA-binding partner protein DiGeorge critical region 8 (DGCR8). DGCR8 has been shown to tightly bind an Fe(III) heme cofactor, which activates its pri-miRNA processing activity. Here we describe how to reconstitute pri-miRNA processing using recombinant human Drosha and DGCR8 proteins. In particular, we present the procedures for expressing and purifying DGCR8 as an Fe(III) heme-bound dimer, the most active form of this protein, and for estimating its heme content. PMID- 24166305 TI - Assaying Dicer-mediated miRNA maturation by means of fluorescent substrates. AB - Assaying Dicer-mediated miRNA maturation is a valuable tool not only for validating miRNA maturation itself but also for testing Dicer activity in cell lysate and for screening small molecules inhibiting miRNA maturation in a high throughput format. The classical assay for miRNA maturation relies on radioactive labeling of a pre-miRNA and subsequent gel electrophoresis and autoradiography. Here we present a fluorescently labeled and quenched pre-miRNA beacon that can be ligated easily out of two single labeled RNA strands. Upon Dicer cleavage of the beacon, fluorophore and quencher are separated, which results in an increase of fluorescence over time. Unlike (32)P-labeled probes, our fluorescently labeled pre-miRNA beacon is stable for at least 5 years under storage conditions. Dicer or miRNA maturation assays can be easily performed in a 384-well plate format, consuming less than 1 pmol of RNA beacon per reaction. PMID- 24166306 TI - A fluorescence correlation spectroscopy-based enzyme assay for human Dicer. AB - We used fluorescence correlation spectroscopy (FCS) to establish an in vitro assay to investigate RNase activity of human Dicer (Werner et al., Biol Chem 393(3):187-193). FCS allows investigating the interactions of different particles due to their differing diffusion mobility, provided that one of the interacting partners exhibit a fluorescence label. In our case we used a fluorophore-labeled double-stranded RNA (dsRNA) as substrate to monitor Dicer activity. The dsRNA was cleaved by the enzyme resulting in a five-nucleotide-short single-stranded RNA (ssRNA) fragment carrying the fluorophore, which could be distinguished from the substrate and unlabeled second product by FCS. Furthermore, we refer to additional (control) experiments to confirm obtained data. PMID- 24166307 TI - Detection of microRNA maturation using unmodified pre-microRNA and branched rolling circle amplification. AB - The ever-increasing number of different miRNAs and their association with a vast number of cellular dysfunctions and diseases have initiated several groups to investigate miRNA maturation, which ultimately leads to down regulation of a target messenger RNA (mRNA) and its downstream product. A rapid, convenient, and reliable assay to detect the Dicer-mediated miRNA-maturation step may facilitate research in this field. Here we describe the in vitro detection of the Dicer mediated miRNA maturation step using unmodified pre-miRNA and branched rolling circle amplification. PMID- 24166308 TI - Quantitative RT-PCR specific for precursor and mature miRNAs. AB - Quantification of microRNAs (miRNAs) in cells or primary tissues is one of the most important steps in elucidating their biological functions. However, miRNAs are challenging molecules for PCR amplification due to the stable hairpin of the precursor form and the small size of the mature miRNA, which is roughly the same length as the primers used in standard PCR. To date, different assays were introduced for the specific and sensitive quantification of the mature form of miRNAs. In this chapter we describe the extraction of RNA from microdissected tissue and the quantification of miRNAs using two different methods (stem-loop qRT-PCR and polyT adaptor qRT-PCR). PMID- 24166309 TI - Cellular microRNA sensors based on luciferase reporters. AB - Recently, microRNAs (miRNAs) have been linked to a variety of human diseases including cancer and viral infections. Small molecule modifiers of miRNAs could represent new therapeutic agents and be used as tools for elucidating the biological roles of miRNAs. In order to identify small molecule modifiers of miRNAs, functional assays for specific miRNAs must be developed and optimized. Here, we report the construction of a luciferase reporter assay for miRNA miR-122 function and the development of a stable Huh7 cell line that can be used for high throughput screening of small molecule miR-122 inhibitors. The steps described here can be applied not only to Huh7 cells and miR-122 but also to virtually any cell line and miRNA combination. PMID- 24166310 TI - Identification of inhibitors of microRNA function from small molecule screens. AB - Aberrant expression of microRNAs (miRNAs) has been linked to many human diseases including cancer, immune disorders, heart disease, and viral infections. Thus, small molecule inhibitors of miRNAs have potential as new therapeutic agents, as probes for the elucidation of detailed mechanisms of miRNA function, and as tools for the discovery of new targets for the treatment of human diseases. In order to identify small molecule inhibitors of specific miRNAs, functional assays have been developed and applied to the screening of small molecule libraries. Here, we report the application of a luciferase-based reporter assay of miRNA miR-122 function to the discovery of small molecule miR-122 inhibitors. PMID- 24166311 TI - Inhibition of miRNA maturation by peptide nucleic acids. AB - Molecules able to interfere in miRNA genesis and function are potent tools to unravel maturation and processing pathways. Antisense oligonucleotides or analogs are actually employed for the inhibition of miRNA function. Here we illustrate how Peptide Nucleic Acids oligomers targeting pre-miRNA are exploited to inhibit miRNA maturation. PMID- 24166312 TI - Molecular methods for validation of the biological activity of peptide nucleic acids targeting microRNAs. AB - The involvement of microRNAs in human pathologies is a firmly established fact. Accordingly, the pharmacological modulation of their activity appears to be a very appealing issue in the development of new types of drugs (miRNA therapeutics). One of the most interesting issues is the possible development of miRNA therapeutics for development of anti-cancer molecules. In this respect appealing molecules are based on peptide nucleic acids (PNAs), displaying a pseudo-peptide backbone composed of N-(2-aminoethyl)glycine units and found to be excellent candidates for antisense and antigene therapies. The major limit in the use of PNAs for alteration of gene expression is the low uptake by eukaryotic cells. The aim of this chapter is to describe methods for determining the activity of PNAs designed to target oncomiRNAs, using as model system miR-221 and its target p27(Kip1) mRNA. The effects of PNAs targeting miR-221 are here presented discussing data obtained using as model system the human breast cancer cell line MDA-MB-231, in which miR-221 is up-regulated and p27(Kip1) down regulated. PMID- 24166313 TI - Lentiviral overexpression of miRNAs. AB - Deregulation of microRNAs (miRNAs) has been attributed to almost any human disease analyzed to date. This calls for models and experimental strategies for functional analyses of miRNAs enabling miRNA overexpression or suppression in target cell and/or tissues. Lentiviral vector (LV)-based technologies allow the long-term overexpression of miRNAs in nearly all cell types in an easy and rapid manner and are therefore popular tools for this application. In this chapter we describe the cloning of LV miRNA expression vectors as well as the production of virus particles for target cell infection and stable expression of miRNAs. PMID- 24166314 TI - Omega 3 chronic supplementation attenuates myocardial ischaemia-reperfusion injury through reinforcement of antioxidant defense system in rats. AB - Currently, controversial clinical data about the protective effects in the consumption of n-3 polyunsaturated fatty acids (PUFAs) in ischaemic heart diseases exist. Improved myocardial resistance to ischaemia-reperfusion (IR) injury results in non-lethal myocardial infarction, which is a relevant factor in the myocardial function. We hypothesized that chronic supplementation with PUFAs reduced infarct size (IS) and induced an improvement on oxidative stress-related parameters in IR model. Rats were supplemented with two doses of PUFAs D1 (n = 7) (0.6 g kg(-1) d(-1) ) and D2 (n = 7) (1.2 g kg(-1) d(-1) ) for 8 weeks. Control group (n = 7) received only standard diet. In ex vivo model, all rat hearts were subjected to 30 min of global ischaemia followed by 120 min of reperfusion. The IS and left ventricular function were assessed. Lipid peroxidation, reduced glutathione (GSH)/oxidized glutathione (GSSG) ratio and antioxidant enzyme activity were measured in the whole heart. The results show a reduction in IS in a dose-dependent manner with PUFAs D1 (30.6%) and D2 (48.5%) and higher values of left ventricular developed pressure, at the end of the reperfusion, for each dose, respectively (p < 0.05). The two PUFAs groups showed higher values of GSH/GSSG ratio and lipid peroxidation, and higher values of activity of antioxidant enzymes catalase, superoxide dismutase and glutathione peroxidase at basal condition (p < 0.05). At the end of reperfusion, the GSH/GSSG ratio and antioxidants enzyme activity did not show a significant drop in their values (p > 0.05). These findings suggested that the supplementation with PUFAs induces cardioprotection against IR injury, associated with reinforcement of the antioxidant defense system. PMID- 24166315 TI - Somatic mutations caused by excision of the transposable element, Tpn1, from the DFR gene for pigmentation in sub-epidermal layer of periclinally chimeric flowers of Japanese morning glory and their germinal transmission to their progeny. AB - Pigmentation in flowers of Japanese morning glory is intense in the epidermal layer, lighter in the subepidermis, and much lighter in the internal tissues; by contrast coloration in stems occurs only in the sub-epidermal layer. The a-3 (f) mutant of Japanese morning glory bears white flowers with normal-colored flecks and sectors, and its variegation also occurs in leaves and stems. The mutable line can produce chimeric flowers pigmented uniformly in the sub-epidermal tissue and variegated in the epidermal layer, and stems of these flowers are also pigmented. Since they give selfed progeny that segregate to give a ratio of three germinal revertants bearing fully colored flowers to one flecked mutant, it has been [OR Imai (1934) has] postulated that somatic mutations in the sub-epidermal layer can be transmitted to the next generation and that the germ cells in the reproductive organs must form from the cells of the sub-epidermal layer. Recently, we found that the 6.4-kb En/Spm-related transposable element, Tpn1, resides within the DFR-B gene for anthocyanin biosynthesis in the mutable a-3 (f) line. To test whether somatic mutations caused by Tpn1 excision from the DFR-B gene in the subepidermis of periclinally chimeric flowers are transmissible to their progeny, we have examined the structure of the DFR-B region in the germinal revertants derived from the chimeric flowers and compared the sequences generated by the somatic excision of Tpn1 in periclinally chimeric flowers with those in their germinal revertants. Our results confirm that somatic mutations caused by Tpn1 excision from the DFR-B gene in the sub-epidermal tissue of chimeric flowers can be transmitted to their progeny, which results in the generation of germinal revertants. PMID- 24166316 TI - Reconsideration of pollen dispersal data from field trials of transgenic potatoes. AB - During the initial field evaluation of transgenic plants, it is usual to isolate them genetically from other plants of the same species. Several field experiments on potatoes, using transgenes as markers, have shown that transgene dispersal by pollen to other potato plants is limited and very unlikely at distances over 10 m. In a recent study in Sweden, a frequency of transgene-containing progeny of over 30% is reported from non-transgenic potato plants grown at distances of 10 1000 m from transgenic plants containing nptII and gus marker genes. Data from the Swedish study is discussed along with other relevant observations, and it is concluded that the high frequency of gene dispersal in that study results from a high frequency of false positives during PCR analysis of the nptII gene. From the data available in potato, it is concluded that a distance of 20 m is generally adequate for the initial field evaluation of transgenic potatoes containing novel gene constructs. PMID- 24166317 TI - Improving chickpea yield by incorporating resistance to ascochyta blight. AB - Ascochyta blight [Ascochyta rabiei (Pass.) Lab.] is the most destructive disease of chickpea (Cicer arietinum L.), but it can be managed effectively by the use of resistant cultivars. Therefore, a breeding programme was initiated during 1977-78 at ICARDA, Syria, to breed blight-resistant, high-yielding chickpeas with other desirable agronomic traits. Crosses were made in main season at Tel Hadya, Syria, and the F1s were grown in the off season at Terbol, Lebanon. The F2, F4 and F5 generations were grown in a blight nursery in the main season where blight epidemic was artificially created. The plants and progenies were scored for blight resistance and other traits. The F3 and F6 generations were grown in the off season under normal day length to eliminate late-maturing plants. The pedigree method of breeding was followed initially, but was later replaced by the F4-derived family method. The yield assessment began with F7 lines, first at ICARDA sites and later internationally. A total of 1584 ascochyta blight resistant chickpea lines were developed with a range of maturity, plant height, and seed size not previously available to growers in the blight-endemic areas in the Mediterranean region. These included 92 lines resistant to six races of the ascochyta pathogen, and 15 large-seeded and 28 early maturity lines. New cultivars produced 33% more seed yield than the original resistant sources. The yield of chickpea declined by 340 kg ha(-1), with an increase in blight severity by one class on a 1-9 scale, reaching zero yield with the 8 and 9 classes. Development of blight-resistant lines made the introduction of winter sowing possible in the Mediterranean region with the prospect of doubling chickpea production. Twenty three cultivars have been released so far in 11 countries. PMID- 24166318 TI - Identification of quantitative trait loci for plant height, lodging, and maturity in a soybean population segregating for growth habit. AB - The use of molecular markers to identify quantitative trait loci (QTLs) has the potential to enhance the efficiency of trait selection in plant breeding. The purpose of the present study was to identify additional QTLs for plant height, lodging, and maturity in a soybean, Glycine max (L.) Merr., population segregating for growth habit. In this study, 153 restriction fragment length polymorphisms (RFLP) and one morphological marker (Dt1) were used to identify QTLs associated with plant height, lodging, and maturity in 111 F2-derived lines from a cross of PI 97100 and 'Coker 237'. The F2-derived lines and two parents were grown at Athens, Ga., and Blackville, S.C., in 1994 and evaluated for phenotypic traits. The genetic linkage map of these 143 loci covered about 1600 cM and converged into 23 linkage groups. Eleven markers remained unlinked. Using interval-mapping analysis for linked markers and single-factor analysis of variance (ANOVA), loci were tested for association with phenotypic data taken at each location as well as mean values over the two locations. In the combined analysis over locations, the major locus associated with plant height was identified as Dt1 on linkage group (LG) L. The Dt1 locus was also associated with lodging. This locus explained 67.7% of the total variation for plant height, and 56.4% for lodging. In addition, two QTLs for plant height (K007 on LG H and A516b on LG N) and one QTL for lodging (cr517 on LG J) were identified. For maturity, two independent QTLs were identified in intervals between R051 and N100, and between B032 and CpTI, on LG K. These QTLs explained 31.2% and 26.2% of the total variation for maturity, respectively. The same QTLs were identified for all traits at each location. This consistency of QTLs may be related to a few QTLs with large effects conditioning plant height, lodging, and maturity in this population. PMID- 24166319 TI - Estimation of unbiased recombination values in the presence of misclassification of a trait using RFLP maps. AB - The effect of misclassification of phenotypes of a trait on the estimation of recombination value was investigated. The effect was larger for closer linkage. If a locus is dominant and linked with the misclassfied trait locus in the repulsion phase, then the effect on the recombination value between the two loci is largest. A method for estimating the unbiased recombination value and the misclassification rate using maximum likelihood associated with an EM algorithm is also presented. This method was applied to a numerical example from rice genome data. It was concluded that the present method combined with the metric multi-dimensional scaling method is useful for the detection of misclassified markers and for the estimation of unbiased recombination values. PMID- 24166320 TI - Comparison of four molecular markers in measuring relationships among the wild potato relatives Solanum section Etuberosum (subgenus Potatoe). AB - We evaluated chloroplast DNA (cpDNA), isozymes, single to low-copy nuclear DNA (RFLPs), and random amplified polymorphic DNAs (RAPDs) in terms of concordance for genetic distance of 15 accessions each of Solanum etuberosum and S. palustre, and 4 accessions of S. fernandezianum. These self-compatible, diploid (2n=24), and morphologically very similar taxa constitute all species in Solanum sect. Etuberosum, a group of non-tuber-bearing species closely related to Solanum sect. Petota (the potato and its wild relatives). Genetic distance and multidimentional scaling results show general concordance of isozymes, RFLPs and RAPDs between all three taxa; cpDNA shows S. etuberosum and S. palustre to be more similar to each other than to S. fernandezianum. Interspecific sampling variance shows a gradation of resolution from allozyme (low) to RAPD to RFLP (high); while intraspecific comparisons graded from RFLPs (low) to RAPDs (high; lack of sufficient allozyme variability within species precluded comparisons for allozymes). Experimental error was low in RFLPs and RAPDs. PMID- 24166321 TI - Analysis of the barley and rice genomes by comparative RFLP linkage mapping. AB - Comparative genetic mapping of rice and barley, both major crop species with extensive genetic resources, offers the possibility of uniting two well established and characterized genetic systems. In the present study, we screened 229 molecular markers and utilized 110 polymorphic orthologous loci to construct comparative maps of the rice and barley genomes. While extensive chromosomal rearrangements, including inversions and intrachromosomal translocations, differentiate the rice and barley genomes, several syntenous chromosomes are evident. Indeed, several chromosomes and chromosome arms appear to share nearly identical gene content and gene order. Seventeen regions of conserved organization were detected, spanning 287 cM (24%) and 321 cM (31%) of the rice and barley genomes, respectively. The results also indicate that most (72%) of the single-copy sequences in barley are also single copy in rice, suggesting that the large barley genome arose by unequal crossing over and amplification of repetitive DNA sequences and not by the duplication of single-copy sequences. Combining these results with those previously reported for comparative analyses of rice and wheat identified nine putatively syntenous chromosomes among barley, wheat and rice. The high degree of gene-order conservation as detected by comparative mapping has astonishing implications for interpreting genetic information among species and for elucidating chromosome evolution and speciation. PMID- 24166322 TI - Genetics of seedling and adult plant resistance to net blotch (Pyrenophora teres f. teres) and spot blotch (Cochliobolus sativus) in barley. AB - Net blotch (caused by Pyrenophora teres f. teres) and spot blotch (Cochliobolus sativus) are important foliar diseases of barley in the midwestern region of the USA. To determine the number and chromosomal location of Mendelian and quantitative trait loci (QTL) controlling resistance to these diseases, a doubled haploid population ('Steptoe'/'Morex') was evaluated to the pathogens at the seedling stage in the greenhouse and at the adult plant stage in the field. Alleles at two or three unlinked loci were found to confer resistance to the net blotch pathogen at the seedling stage depending on how progeny exhibiting an intermediate infection response were classified. This result was corroborated in the quantitative analysis of the raw infection response data as 2 major QTL were identified on chromosomes 4 and 6M. A third QTL was also identified on chromosome 6P. Seven QTL were identified for net blotch resistance at the adult plant stage and mapped to chromosomes 1P, 2P, 3P, 3M, 4, 6P, and 7P. The 7 QTL collectively accounted for 67.6% of the phenotypic variance under a multiple QTL model. Resistance to the spot blotch pathogen was conferred by a single gene at the seedling stage. This gene was mapped to the distal region of chromosome 1P on the basis of both qualitative and quantitative data analyses. Two QTL were identified for spot blotch resistance at the adult plant stage: the largest QTL effect mapped to chromosome 5P and the other mapped to chromosome 1P near the seedling resistance locus. Together, the 2 QTL explained 70.1% of the phenotypic variance under a multiple QTL model. On the basis of the chromosomal locations of resistance alleles detected in this study, it should be feasible to combine high levels of resistance to both P. teres f. teres and C. sativus in barley cultivars. PMID- 24166323 TI - RFLP-based maps of the homoeologous group-6 chromosomes of wheat and their application in the tagging of Pm12, a powdery mildew resistance gene transferred from Aegilops speltoides to wheat. AB - Genetic maps of the homoeologous group-6 chromosomes of bread wheat, Triticum aestivum, have been constructed spanning 103 cM on 6A, 90 cM on 6B and 124 cM on 6D. These maps were transferred to a Chinese Spring (CS) x line #31 cross to locate a dominant powdery mildew resistance gene, Pm12, introgressed into line #31 from Aegilops speltoides. Pm12 was shown to lie on the short arm of translocation chromosome 6BS-6SS.6SL in line #31, but could not be mapped more precisely due to the lack of recombination between the 6S Ae. speltoides segment and chromosome 6B. Possible strategies to reduce the size of the alien segment, which probably encompasses the complete long arm and more than 82% of the short arm of chromosome 6B, are discussed. PMID- 24166324 TI - Transfer of Brassica tournefartii (TT) genes to allotetraploid oilseed Brassica species (B. juncea AABB, B. napus AACC, B. carinata BBCC): homoeologous pairing is more pronounced in the three-genome hybrids (TACC, TBAA, TCAA, TCBB) as compared to allodiploids (TA, TB, TC). AB - For the transfer of genes from B. tournefortii (TT) to the allotetraploid oilseed brassicas, B. juncea AABB, B. carinata BBCC and B. napus AACC, B. tournefortii was first crossed with the three basic diploid species, B. campestris (AA), B. nigra (BE) and B. oleracea (CC), to produce the allodiploids TA, TB and TC. These were tetraploidized by colchicine treatment to produce the allotetraploids TTAA, TTBB and TTCC, which were further crossed with B. juncea and B. napus to produce three-genome hybrids with substitution-type genomic configurations: TACC, TBAA and TCAA. These hybrids along with another hybrid TCBB produced earlier, the three allodiploids, their allotetraploids and the four diploid parent species were studied for their male meiotic behaviour. The diploid parent and the allotetraploids (TTAA, TTBB and TTCC) showed regular meiosis although the pollen viability was generally low in the allotetraploids. In the allodiploids (TA, TB and TC) only some end-to-end associations were observed without any clearly discernible chiasmata or exchange points. Chromosomes involved in end-to-end associations were randomly distributed at the metaphase/anaphase-I stages. In contrast, the three-genome hybrids (TACC, TBAA, TCAA and TCBB) showed normal bivalents whose number exceeded the expected bivalent values. Bivalents arising out of homoeologous pairing were indistinguishable from normal pairs by their disjunction pattern but could be distinguished on the basis of the heteromorphy of the homoeologous chromosomes. The three-genome hybrids could be backcrossed to allotetraploid oilseed brassicas as they had some fertility. In contrast, the allodiploids could neither be selfed nor back-crossed. On the basis of their meiotic stability, in terms of more pronounced homoeologous pairing and fertility for backcrossing, the three-genome configurations provide the best possible situation for the introgression of alien genes from the secondary gene pool to the allotetraploid oilseed crops B. juncea, B. napus and B. carinata. PMID- 24166325 TI - RFLP analysis of resistance to Columbia root-knot nematode derived from Solanum bulbocastanum in a BC2 population. AB - The mapping of resistance toMeloidogyne chitwoodi derived from Solarium bulbocastanum is reported. A population suitable for mapping was developed as follows. A somatic hybrid of nematode-resistant S. bulbocastanum and cultivated tetraploid potato was produced. This was backcrossed to tetraploid potato, and a single resistant BC1 was selected and backcrossed again to the same recurrent tetraploid parent. The mapping population consisted of 64 BC2 progeny scored for restriction fragment length polymorphic (RFLP) markers and 62 of these were evaluated for the reproductive efficiency of race 1 of M. chitwoodi. Forty-eight polymorphic RFLP markers, originally derived from tomato and mapped in diploid cultivated potato, were assigned to 12 chromosomes of S. bulbocastanum. Of the 62 progeny screened for nematode resistance, 18 were non-hosts and four were poor hosts. The rest were highly susceptible (good hosts). Analysis of the resistance (including non-hosts and poor hosts) as both a qualitative trait and as a meristic trait on which QTL analysis was applied supported the same genetic hypothesis. Genetic control was localized solely to factor(s) lying at one end of chromosome 11. The level of expression of resistance in the S. bulbocastanum parent and the resistant portion of the BC2 was essentially the same. This fact, together with the highly significant LOD scores for one end of the chromosome-11 marker array, supports a genetic model equivalent to monogenic dominant control. PMID- 24166326 TI - Allotetraploid hybrids between citrus and seven related genera produced by somatic hybridization. AB - We have developed an efficient protoplast-fusion method to produce somatic hybrid allopolyploid plants that combine Citrus with seven related genera, including four that are sexually incompatible. In this paper we report the creation of 18 new allotetraploid hybrids of Citrus, including ten among sexually incompatible related genera, that may have direct cultivar potential as improved citrus rootstocks. All hybrids were confirmed by cytological and RAPD analyses. If fertile, the attributes of these hybrids may be amenable to further genetic manipulation by breeding at the tetraploid level. Wide somatic hybridization of Citrus via protoplast fusion bypasses biological barriers to the natural allopolyploidization of Citrus, and creates new evolutionary opportunities that would be difficult or impossible to achieve by natural or conventional hybridization. PMID- 24166327 TI - Comparison of rice lines derived through anther culture and the pedigree method in relation to blast (Pyricularia grisea Sacc.) resistance. AB - Crosses were made between Fanny (highly susceptible to blast) and 11 cultivars differing in blast resistance. Using the pedigree method (PM) segregating generations were evaluated and selected for blast resistance. Via anther culture (AC), doubled-haploids were obtained from F1 plants and from F2 blast-susceptible plants. Pedigree and anther culture-derived lines were planted together and evaluated for blast resistance under rainfed conditions at the Santa Rosa Experiment Station, Villavicencio, Colombia. The principal objective was to compare PM and AC in terms of their efficiency in producing rice lines resistant to blast. Results of a stratified analysis showed an association between method and blast resistance. Results of the logit-model analysis showed that AC produced a significantly (P=0.0001) higher proportion of lines with initial blast resistance (leaf- and neck-blast reaction <=4) than did PM across all cross types. Stable blast resistance was assessed based on field performance over 3 years. AC was superior to PM in generating stable resistance for only some cross types. Consequently, with a few exceptions, AC can be used as effectively as PM to develop rice cultivars resistant to blast, with savings in time and labor. Additionally, blast-resistant lines were obtained either by the pedigree method or by anther culture from crosses between blast-susceptible cultivars (Fanny/CICA4 and Fanny/Colombial). This excludes somaclonal variation as a possible mechanism responsible for this resistance and suggests that a recombination of minor genes could have occurred and was fixed through either method. However, the stability of the resistance was greater in pedigree-derived lines. The implications of these findings for rice blast-resistance breeding are discussed. PMID- 24166328 TI - Isolation and identification of Triticum aestivum L. em. Thell. cv Chinese Spring T. peregrinum Hackel disomic chromosome addition lines. AB - Analyses of RFLPs, isozymes, morphological markers and chromosome pairing were used to isolate 12 Triticum aestivum cv Chinese Spring (genomes A, B, and D)-T. peregrinum (genomes S(v) and U(v)) disomic chromosome addition lines. The evidence obtained indicates that each of the 12 lines contains an intact pair of T. peregrinum chromosomes. One monosomic addition line, believed to contain an intact 6S(v) chromosome, was also isolated. A CS-7U(v) chromosome addition line was not obtained. Syntenic relationships in common with the standard Triticeae arrangement were found for five of the seven S(v) genome chromosomes. The exceptions were 4S(v) and 7S(v). A reciprocal translocation exists between 4S(1) and 7S(1) in T. longissimum and evidence was obtained that the same translocation exists in T. peregrinum. In contrast, evidence for syntenic relationships in common with the standard Triticeae arrangements were found for only one U(v) chromosome of T. peregrinum.; namely, chromosome 2U(v). All other U(v) genome chromosomes are involved in at least one translocation, and the same translocations were found in the U genome of T. umbellulatum. Evidence was also obtained indicating that the centromeric regions of 4U and 4U(v) are homoeologous to the centromeric regions of Triticeae homoeologous group-6 chromosomes, that the centromeric regions of 6U and 6U(v) are homoeologous to the centromeric regions of group-4 chromosomes, and that 4U and 4U(v) are more closely related overall to Triticeae homoeologous group-6 chromosomes than they are to group-4 chromosomes. PMID- 24166329 TI - Genetic diversity in the orange subfamily Aurantioideae. I. Intraspecies and intragenus genetic variability. AB - Despite the great economic importance of citrus, its phylogeny and taxonomy remain a matter of controversy. Moreover pathogens of increased virulence and dramatic environmental changes are currently spreading or emerging. The objectives of the present paper, measuring genetic variability and studying its pattern of distribution, are crucial steps to optimize sampling strategies in the search of genotypes that tolerate or resist these threatening factors within the huge array of Citrus and Citrus related species. Their intraspecific and intrageneric variability was studied comparatively by means of ten enzymatic systems using eight different measures. The analysis of ten enzymatic systems allowed us to distinguish all the species and all but one artificial hybrid. The species with the lowest genotypic variability are C. myrtifolia, C. deliciosa (willow leaf mandarin), C. paradisi (grapefruit), C. limon (lemon) and C. sinensis (sweet orange), while Severinia buxifolia shows the highest value. A broad spectrum of heterozygosity values was found in the collection. Lemons (C. limon, C. meyeri, C. karna, C. volkameriana), limes (C. aurantifolia, C. limettioides, C. lattifolia) and C. bergamia show a very high percentage of heterozygosity which indicates an origin through interspecific hybridization. Two main factors limit genetic intraspecific variability: apomictic reproduction, where nucellar embryos are much more vigorous than the zygotic ones, and nurserymen selecting against variability in the seedling stage of the rootstocks or in propagating the scion cultivars vegetatively. Additionally, self pollination appears in some species mainly used as rootstocks which would explain their low heterozygosity values. Genetic differences between species and genera are in general high, which suggests that adaptation might have played an important role during the evolution of the orange subfamily. PMID- 24166330 TI - Mapping loci controlling flowering time in Brassica oleracea. AB - The timing of the transition from vegetative to reproductive phase is a major determinant of the morphology and value of Brassica oleracea crops. Quantitative trait loci (QTLs) controlling flowering time in B. oleracea were mapped using restriction fragment length polymorphism (RFLP) loci and flowering data of F3 families derived from a cabbage by broccoli cross. Plants were grown in the field, and a total of 15 surveys were made throughout the experiment at 5-15 day intervals, in which plants were inspected for the presence of flower buds or open flowers. The flowering traits used for data analysis were the proportion of annual plants (PF) within each F3 family at the end of the experiment, and a flowering-time index (FT) that combined both qualitative (annual/biennial) and quantitative (days to flowering) information. Two QTLs on different linkage groups were found associated with both PF and FT and one additional QTL was found associated only with FT. When combined in a multi-locus model, all three QTLs explained 54.1% of the phenotypic variation in FT. Epistasis was found between two genomic regions associated with FT. Comparisons of map positions of QTLs in B. oleracea with those in B. napus and B. rapa provided no evidence for conservation of genomic regions associated with flowering time between these species. PMID- 24166331 TI - Somatic hybrids between the cultivated potato Solanum tuberosum L. and the 1EBN wild species Solanum pinnatisectum Dun.: morphological and molecular characterization. AB - Interspecific somatic hybrids between the 1EBN-wild species Solanum pinnatisectum (S. pnt) and four different diploid breeding lines of Solanum tuberosum (S. tbr) were produced by electrofusion. S. pnt exhibits resistance to Phytophthora infestans and Erwinia blackleg. Somatic hybrids were identified by RFLP analysis using the oligonucleotide (GATA)4 as a probe. In three of four combinations all regenerates obtained were somatic hybrids. All 86 somatic hybrids between the breeding line H256/1 and S. pnt were analyzed in detail with respect to morphological and molecular characters; 50% of the somatic hybrids showed normal intermediate leaf morphology. Tubers of somatic hybrid plants grown in the greenhouse as well as in the field were evenly shaped and remarkably similar to those of the S. tbr breeding line. Analysis of relative DNA content by flow cytometry revealed that 75% of the somatic hybrids were tetraploid, some were hypotetraploid and others polyploid or mixoploid. Slotblot and RFLP analyses were carried out using repetitive and some single-copy DNA probes. The genome portion of the S. tbr breeding line was determined by slot-blot analysis using the species-specific repetitive probe pSA287. Obviously, most somatic hybrids contain the complete genomes of both fusion partners. In some of the somatic hybrids, a significantly lower intensity of the S. pnt-specific hybridization signal indicated a certain degree of asymmetry. PMID- 24166332 TI - [Should psychiatrists render an opinion on insanity?]. PMID- 24166333 TI - [Neuropsychiatry as practised in a highly specialised department of a psychiatric teaching hospital: a successful interdisciplinary approach]. AB - BACKGROUND: Psychiatric disorders can be interpreted as a general dysregulation of the interplay between brain and behaviour. This is why, since the late 1990’s, the terms biological psychiatry and behavioural neurology have been gradually replaced by the term neuropsychiatry. Neuropsychiatry, when practiced in combination with clinical neuropsychology, have given rise to a paradigm that is not based solely on the usual classification models but is directed primarily towards diagnosis and treatment that are based on a functional-dimensional approach. AIM: To discuss the daily practice and organisation in a specialised department for neuro-psychiatry located in a psychiatric teaching hospital. METHOD: The interdisciplinary approach is explained and analysed on the basis of 10 case studies. RESULTS: Most of the patients referred to the specialised department already had a long history of visits to the health care facilities where they had been treated by a variety of specialists in single disciplines. Often, however, this trajectory did not involve periodical re-evaluation and updating of the original diagnosis. If this strategy had been adopted, then a clear diagnosis with simplified treatment programme might have been devised which could have resulted in a patient’s successful reintegration into society. CONCLUSION: It is essential that the interdisciplinary approach is adopted in specialised centres for neuropsychiatry because it can make an important contribution to individual patient care and to the spread of specialised knowledge that can benefit the entire field of psychiatry. PMID- 24166334 TI - [What is neuropsychiatry?]. PMID- 24166336 TI - [Predictive methods versus clinical titration for the initiation of lithium therapy. A systematic review]. AB - BACKGROUND: When lithium is administered, the clinician needs to know when the lithium in the patient’s blood has reached a therapeutic level. At the initiation of treatment the level is usually achieved gradually through the application of the titration method. In order to increase the efficacy of this procedure several methods for dosing lithium and for predicting lithium levels have been developed. AIM: To conduct a systematic review of the publications relating to the various methods for dosing lithium or predicting lithium levels at the initiation of therapy. METHOD: We searched Medline systematically for articles published in English, French or Dutch between 1966 and April 2012 which described or studied a method for dosing lithium or for predicting the lithium level reached following a specific dosage. We screened the reference lists of relevant articles in order to locate additional papers. RESULTS: We found 38 lithium prediction methods, in addition to the clinical titration method. These methods can be divided into two categories: the ‘a priori’ methods and the ‘test-dose’ methods, the latter requiring the administration of a test dose of lithium. CONCLUSION: The lithium prediction methods generally achieve a therapeutic blood level faster than the clinical titration method, but none of the methods achieves convincing results. On the basis of our review, we propose that the titration method should be used as the standard method in clinical practice. PMID- 24166335 TI - [Multidimensional family therapy and cognitive behavioral therapy in adolescents with a cannabis use disorder: a randomised controlled study]. AB - BACKGROUND: More and more adolescents with cannabis problems are seeking treatment at addiction clinics. There is an urgent need for new types of treatment in this field. AIM: To evaluate the effectiveness of multidimensional family therapy (MDFT) and cognitive behavioral therapy (CBT) in adolescents with a cannabis use disorder. METHOD: One hundred and nine adolescents were randomly assigned to outpatient MDFT or CBT. Both types of therapy groups had a planned treatment course lasting 5 to 6 months. After 12 months the two groups were compared in terms of changes in cannabis use and in terms of secondary outcome measures, including delinquency. RESULTS: Adolescents in both treatment groups showed significant and relevant reductions in cannabis use and delinquency over 12 months. Although the MDFT treatment lasted longer and was more intensive than the CBT treatment, there was no difference in the key outcome measures of the treatments. Secondary analyses indicated that older adolescents and those without comorbid psychiatric problems derived considerably more benefit from CBT, whereas younger adolescents and those with comorbid psychiatric problems benefited much more from MDFT. CONCLUSION: MDFT and CBT are equally effective in reducing cannabis use and delinquent behavior in adolescents with a cannabis use disorder. Age and comorbid psychiatric problems turned out to be important moderators of the treatment results of MDFT and CBT and could therefore be used as a starting point for matching adolescent substance abusers to the most appropriate type of treatment. PMID- 24166337 TI - [The role of sleep in ADHD: possibilities for prevention of ADHD?]. AB - BACKGROUND: Personalized medicine aims to provide the right treatment for the right person at the right time, as opposed to the currently employed 'one-size fits-all ' approach. This development relies on identification of ADHD subgroups using biomarkers. One important ADHD subgroup is characterised by impaired vigilance regulation, as quantified by the EEG and this sub-group responds well to stimulant medication and neurofeedback. Recent insights suggest a clear association between reduced sleep duration and ADHD complaints in this sub-group of ADHD patients. A recently published model explains how different treatments e.g. chronobiological treatments and neurofeedback impact on this neural circuitry and mediate ADHD symptom improvement. AIM: To test this recently published model predicting a relationship between solar intensity and ADHD prevalence. METHOD: A literature survey on studies using identical methods to estimate the prevalence of ADHD in different geographical areas and compare those to worldwide solar intensity data. RESULTS: A clear relationship between solar intensity and the worldwide prevalence of ADHD was found, explaining 34-57% of the variance in ADHD prevalence, where a lower prevalence of ADHD was found in areas with high solar-intensity. CONCLUSION: The preventative effect of high solar intensity may be related to improvement of circadian clock disturbances. These findings likely apply to a substantial sub-group of ADHD patients and have major implications for our understanding of the etiology and possibly prevention of ADHD. PMID- 24166338 TI - [Results of the ABC ' buddy project' whereby students were paid to befriend worryingly inactive youngsters with a psychotic disorder]. AB - BACKGROUND: Psychology students ('buddies’) could earn ? 25,- by visiting a patient, on one afternoon or evening per week, in order to provide friendship and engage the patient in a joint activity. An additional sum of ? 20,- was made available to finance the joint activity. AIM: To find out whether this activity and social participation of patients who had a buddy increased more than in patients without a buddy. METHOD: In a quasi-experimental study 28 young, worryingly inactive patients who had a buddy were matched individually with patients without a buddy. Measurements were taken prior to the buddy contacts and after a period of 18 months. General functioning was used as a secondary outcome measure, in addition to the measure of activities and social participation. RESULTS: No patients in either group showed any improvement in activity, participation level and general functioning. CONCLUSION: Recruiting and paying buddies to befriend and stimulate worryingly inactive youngsters with a psychotic disorder did not increase the youngsters' activity, their social participation or their general functioning. PMID- 24166339 TI - [Development of (hypo)mania during discontinuation of venlafaxine in two patients with bipolar disorder]. AB - The scientific literature frequently warns that patients with bipolar disorder risk developing a (hypo)mania on starting a course of antidepressants. In this case report, however, two patients with bipolar disorder developed a (hypo)mania while their dosage of venlafaxine was being gradually tapered off. We discuss a pharmacodynamic explanation for the induction of (hypo)mania during discontinuation of venlafaxine. We also discuss alternative explanations, such as a venlafaxine withdrawal syndrome; induction of rapid cycling; difficulties in distinguishing an agitated depression and a dysphoric mania and the naturalistic course of a bipolar disorder. PMID- 24166340 TI - [Reaction on 'an adolescent with autism and a somatic high-risk profile receiving treatment with antipsychotics refuses blood tests']. PMID- 24166344 TI - Stones: Coenzyme Q10 protects kidney during ESWL. PMID- 24166342 TI - Urological aspects of HIV and AIDS. AB - The use of highly active antiretroviral therapy (HAART) in HIV-infected people has led to a dramatic decrease in the incidence of opportunistic infections and virus-related malignancies such as non-Hodgkin lymphoma and Kaposi sarcoma, but not cervical or anal cancer. Advanced-stage cervical cancer is associated with a high incidence of urological complications such as hydronephrosis, renal failure, and vesicovaginal fistula. Adult male circumcison can significantly reduce the risk of male HIV acquisition. Although HAART does not completely eradicate HIV, compliance with medication increases life expectancy. HIV infection or treatment can result in renal failure, which can be managed with dialysis and transplantation (as for HIV-negative patients). Although treatment for erectile dysfunction--including phosphodiesterase 5 inhibitors, intracavernosal injection therapy, and penile prosthesis--can increase the risk of HIV transmission, treatment decisions for men with erectile dysfunction should not be determined by HIV status. The challenges faced when administering chemotherapy to HIV-infected patients with cancer include late presentation, immunodeficiency, drug interactions, and adverse effects associated with compounded medications. Nonetheless, HIV-infected patients should receive the same cancer treatment as HIV-negative patients. The urologist is increasingly likely to encounter HIV positive patients who present with the same urological problems as the general population, because HAART confers a prolonged life expectancy. Performing surgery in an HIV-infected individual raises safety issues for both the patient (if severely immunocompromised) and the surgeon, but the risk of HIV transmission from patients on fully suppressive HAART is small. PMID- 24166346 TI - Kidney cancer: Characterizing late recurrence of renal cell carcinoma. PMID- 24166349 TI - One-dimensional CdS/ZnO core/shell nanofibers via single-spinneret electrospinning: tunable morphology and efficient photocatalytic hydrogen production. AB - One dimensional core/shell nanostructures consisting of two different semiconductors with appropriate band alignment are promising for photocatalytic hydrogen production due to their efficient light harvesting and fast carrier transport. In this work, CdS/ZnO core/shell nanofibers were successfully synthesized by one-pot single-spinneret electrospinning. The ZnO layered structures (60 nm in thickness) were uniformly grown onto continuous CdS core fibers (220 nm in diameter and several micrometers in length). The as-fabricated CdS/ZnO core/shell nanofibers as nanoheterojunction photocatalysts exhibited excellent visible light photocatalytic activity and stability for hydrogen production. The possible formation mechanism of the CdS/ZnO core/shell nanofibers was also proposed based on the experimental observations. Moreover, the morphologies and components of the as-prepared nanofibers can be controlled easily by tuning the annealing temperature and Zn/Cd ratios of the precursor solution. PMID- 24166348 TI - Anti-N-methyl-D-aspartate receptor encephalitis: a patient with refractory illness after 25 months of intensive immunotherapy. AB - IMPORTANCE: N-methyl-D-aspartate receptor (NMDAR) antibody encephalitis is an autoimmune encephalitis that can be paraneoplastic and usually responds to treatment. It is quickly becoming the most common paraneoplastic encephalitis. OBSERVATIONS: We present a case of a woman in her late 30s who developed psychiatric symptoms that progressed to encephalopathy, seizures, autonomic instability, and hyperkinetic movements. The patient was found to have an ovarian teratoma and serum and cerebrospinal fluid NMDAR antibodies. Despite resection of the teratoma and treatment with immunosuppressive therapy, the patient progressed to a minimally conscious state. She was supported medically in our institution for 25 months. During her hospitalization, she was treated with multiple immunosuppressive agents. With each treatment, we analyzed the serum and cerebrospinal fluid for NMDAR antibodies. While there was some initial reduction in the serum antibodies, the spinal fluid antibodies remained persistently elevated. The patient did not have any clinical improvement and eventually died after the family decided to withdraw care. CONCLUSIONS AND RELEVANCE: As far as we know, this case represents the longest active treatment without improvement of a patient with anti-NMDAR encephalitis. The patient had persistently high cerebrospinal fluid and serum antibody titers, which may be of prognostic significance. PMID- 24166351 TI - Hepatitis C virus genotype 1: how genetic variability of the core protein affects the response to pegylated-interferon and ribavirin therapy. AB - Hepatitis C virus subgenotypes 1a and 1b are found worldwide and cause 60% of all hepatitis C cases. It has been reported recently that viral genetic variations have a critical impact on the patient treatment outcome. In particular, polymorphisms of the HCV core protein have been linked to poor treatment response. However, most of these studies were conducted on Asian populations, Japanese in particular who are infected with HCV subgenotype 1b. Hence, we aimed in this study to examine the core protein polymorphisms in Saudi patients who are infected with chronic HCV genotype 1 (1a and 1b subtypes) and its association with treatment outcome. Direct sequencing of full-length core protein and data mining analyses were utilized. Results have shown that the response to treatment is dependent on subgenotypes. Indeed, HCV-1b showed different point mutations that are associated with treatment outcome where the point mutations at positions 70 (Arg(70) Gln) and 75 (Thr(75) Ala) in HCV-1b are significantly associated with PEG-IFN/RBV treatment response. In contrast, HCV-1a showed no significant association between core protein mutations and response to treatment. In addition, analyses of HCV-1a core protein sequences revealed a highly conserved region especially in the responder group. This study provides a new insight in the genetic variability of full-length core protein in HCV genotype 1 in Saudi infected patients. PMID- 24166350 TI - Cardiovascular disease in survivors of hematopoietic cell transplantation. AB - Hematopoietic cell transplantation (HCT) is increasingly offered as a curative option for many patients with hematologic malignancies. Improvements in HCT strategies and supportive care have resulted in a growing number of long-term survivors. However, these survivors are at an increased risk of developing long term debilitating chronic health conditions, including premature cardiovascular disease. These complications are more common than in the general population, and there are well-described associations between therapeutic exposures, traditional cardiovascular risk factors, and subsequent cardiovascular disease risk. The authors present herein an overview of the current state of knowledge regarding pathogenesis and risk factors for some of the more commonly occurring cardiovascular complications after HCT, highlighting existing surveillance recommendations and future directions for research to minimize cardiovascular morbidity in these survivors. PMID- 24166352 TI - The promoter SNP, but not the alternative splicing SNP, is linked to multiple sclerosis among Jordanian patients. AB - Multiple sclerosis is a chronic inflammatory autoimmune disease of the human central nervous system. A number of studies with compelling evidence have provided correlation between single nucleotide polymorphisms in interleukin-7 receptor alpha and multiple sclerosis (MS) in several populations. One such variation, rs6897932, is located within the coding region and results in the generation of a soluble receptor, whereas another one, rs11567685, is located in the promoter region and affects gene expression. In this study, we investigated the frequencies of these two SNPs and their association to MS in 200 healthy controls and 200 MS patients based on a simple PCR-RFLP strategy not reported previously. The frequencies of the high risk alleles for both SNPs were in a high range among healthy and MS subjects relative to previous studies. In addition, whereas no association was found between the alternative splicing SNP, rs6897932, and MS, a significant link was found between the promoter SNP, rs11567685, and MS. These results are in contrast to other studies and may have important implications as to the molecular contribution of IL-7Ralpha in multiple sclerosis. PMID- 24166353 TI - Upregulation of CREM-1 relates to retinal ganglion cells apoptosis after light induced damage in vivo. AB - Previous studies have shown activation of cyclic AMP response element-binding protein (CREB) family is involved in the retinal ganglion cells (RGCs) protection. However, the function of cyclic AMP response element modulator-1 (CREM-1), one member of the CREB family, is still with limited acquaintance. To investigate whether CREM-1 is involved in RGCs death, we performed a light induced retinal damage model in adult rats. Upregulation of CREM-1 was observed in retina after light-induced damage by performing western blot. Immunofluorescent labeling indicated that upregulated CREM-1 was localized mainly in the RGCs. We also investigated co-localization of CREM-1 with active-caspase-3 and TUNEL (apoptotic markers) in the retina after light-induced damage. In addition, the expression patterns of B cell lymphoma/leukemia-2 and Bcl-2 associated X protein were parallel with that of CREM-1. Collectively, we hypothesized upregulation of CREM-1 in the retina was associated with RGCs death after light-induced damage. PMID- 24166354 TI - MicroRNA-124 (miR-124) regulates Ku70 expression and is correlated with neuronal death induced by ischemia/reperfusion. AB - MicroRNAs are small, non-coding RNA molecules that regulate gene expression, and miR-124 is the most abundant miRNA in the brain. Studies have shown that miR-124 is clearly reduced in the ischemic brain after stroke; however, the role of miR 124 after stroke is less well studied. Using TargetScan, MicroCosm Targets version 5, and microRNA.org databases, we identified miR-124 as a possible regulator of the DNA repair protein Ku70. We validated that Ku70 is a target for miR-124 with a luciferase reporter activity assay. Moreover, adult rats subjected to focal cerebral ischemia exhibited a substantial reduction of miR-124 expression, which was inversely upregulated by Ku70 expression. In vivo treatment with miR-124 antagomir effectively enhanced Ku70 mRNA and protein levels in the ischemic region. Furthermore, knockdown of cerebral miR-124 reduced cell death and infarct size and improved neurological outcomes. Our data demonstrate that miR-124 is an endogenous regulator of Ku70 that improves ischemia/reperfusion (I/R)-induced brain injury and dysfunction. PMID- 24166356 TI - Bridging the Gap: establishing the necessary infrastructure and knowledge for teaching and research in neuroscience in Africa. AB - Advances in neuroscience research over the last few decades have increased our understanding of how individual neurons acquire their specific properties and assemble into complex circuits, and how these circuits are affected in disease. One of the important motives driving neuroscience research is the development of new scientific techniques and interdisciplinary cooperation. Compared to developed countries, many countries on the African continent are confronted with poor facilities, lack of funding or career development programs for neuroscientists, all of which deter young scientists from taking up neuroscience as a career choice. This article highlights some steps that are being taken to promote neuroscience education and research in Africa. PMID- 24166355 TI - Predictors of effectiveness of multidisciplinary rehabilitation treatment on motor dysfunction in multiple sclerosis. AB - OBJECTIVES: To identify clinical predictors of effectiveness of a motor rehabilitation treatment in a cohort of multiple sclerosis (MS) patients. MATERIALS AND METHODS: We analysed 212 consecutive patients who underwent a short term (3-7 weeks) intensive (two hours per day, five days per week), individualised, goal-oriented inpatient rehabilitation program. Activity limitation and impairment were measured on admission and discharge of the rehabilitation trial using the motor sub-items of the Functional Independence Measure (mFIM) and the Expanded Disability Status Scale (EDSS) score. Multivariate logistic regression models have been tested to evaluate the role of clinical baseline features on rehabilitation effectiveness. RESULTS: According to pre-defined outcome measures, 75.1% of MS patients improved in either activity limitation (>=5 points delta mFIM) or impairment (>=1.0 delta EDSS score if baseline EDSS was <=5.5, or >=0.5 if baseline EDSS was >5.5), and 35.4% of MS patients improved in both outcomes. A relapsing-remitting course of disease, a more severe baseline impairment and activity limitation level, a shorter disease duration and a less severe balance dysfunction were predictive of the effectiveness of rehabilitation. DISCUSSION: These data confirm that an intensive inpatient rehabilitation program is able to produce a short-term relevant improvement on clinical and functional outcome measures and suggest some clinical features which can be considered as potential predictors of the outcome of rehabilitative intervention. PMID- 24166357 TI - Di- and triheteroarylalkanes via self-condensation and intramolecular Friedel Crafts type reaction of heteroaryl alcohols. AB - An efficient synthetic approach to diheteroarylmethanes and 1,3 diheteroarylpropenes has been developed via Yb(III)-catalyzed sequential self condensation of 2-furfuryl (or 2-thienyl or 3-indolyl) alcohols followed by intramolecular Friedel-Crafts type reaction and elimination of an aldehyde. This method offers a powerful entry and a potential alternative to the traditional synthesis of diheteroarylalkanes, which are precursors to the synthesis of several intriguing heteroaryls and more significantly, to the synthesis of biofuels. PMID- 24166359 TI - The Mohawk homeobox transcription factor regulates the differentiation of tendons and volar plates. AB - BACKGROUND: Mohawk (Mkx) is a homeodomain-containing transcription factor that is expressed in various mesoderm-derived tissues, particularly in developing tendons. In this study, we investigate the exact expression pattern and functions of Mkx in forelimbs. METHODS: We analyzed the forelimbs of Mkx knockout mice [from embryonic day (E) 18.5 to postnatal day (P) 28 weeks] by using knocked-in Venus signals, Masson trichrome staining, and hematoxylin and eosin (H&E) staining. RESULTS: We detected Venus signals in forelimb tendons, pulleys, and volar plates (VPs) in P21 mice. In-depth histological analysis showed that compared to the wild-type mice, the Mkx knockout mice showed significant hypoplasia in the flexor digitorum profundus tendons from E18.5. The VPs and pulleys appeared normal until P0; however, by P14, they became increasingly thicker in Mkx-null mice compared to wild-type mice. The fiber alignment was particularly disrupted in VPs of Mkx-null mice. CONCLUSIONS: These results suggest that Mkx is an important regulator of the differentiation of VPs and pulleys, as well as of tendon differentiation. PMID- 24166360 TI - Approaching the strong coupling limit in single plasmonic nanorods interacting with J-aggregates. AB - We studied scattering and extinction of individual silver nanorods coupled to the J-aggregate form of the cyanine dye TDBC as a function of plasmon--exciton detuning. The measured single particle spectra exhibited a strongly suppressed scattering and extinction rate at wavelengths corresponding to the J-aggregate absorption band, signaling strong interaction between the localized surface plasmon of the metal core and the exciton of the surrounding molecular shell. In the context of strong coupling theory, the observed "transparency dips" correspond to an average vacuum Rabi splitting of the order of 100 meV, which approaches the plasmon dephasing rate and, thereby, the strong coupling limit for the smallest investigated particles. These findings could pave the way towards ultra-strong light-matter interaction on the nanoscale and active plasmonic devices operating at room temperature. PMID- 24166362 TI - MoS2-an integrated protective and active layer on n(+)p-Si for solar H2 evolution. AB - A new MoS2 protected n(+)p-junction Si photocathode for the renewable H2 evolution is presented here. MoS2 acts as both a protective and an electrocatalytic layer, allowing H2 evolution at 0 V vs. RHE for more than 5 days. Using a MoSx surface layer decreases the overpotential for H2 evolution by 200 mV. PMID- 24166361 TI - Tobacco smoking, NBS1 polymorphisms, and survival in lung and upper aerodigestive tract cancers with semi-Bayes adjustment for hazard ratio variation. AB - PURPOSE: Although single nucleotide polymorphisms (SNPs) of NBS1 have been associated with susceptibility to lung and upper aerodigestive tract (UADT) cancers, their relations to cancer survival and measures of effect are largely unknown. METHODS: Using follow-up data from 611 lung cancer cases and 601 UADT cancer cases from a population-based case-control study in Los Angeles, we prospectively evaluated associations of tobacco smoking and 5 NBS1 SNPs with all cause mortality. Mortality data were obtained from the Social Security Death Index. We used Cox regression to estimate adjusted hazard ratios (HR) for main effects and ratios of hazard ratios (RHR) derived from product terms to assess hazard ratio variations by each SNP. Bayesian methods were used to account for multiple comparisons. RESULTS: We observed 406 (66 %) deaths in lung cancer cases and 247 (41 %) deaths in UADT cancer cases with median survival of 1.43 and 1.72 years, respectively. Ever tobacco smoking was positively associated with mortality for both cancers. We observed an upward dose-response association between smoking pack-years and mortality in UADT squamous cell carcinoma. The adjusted HR relating smoking to mortality in non-small cell lung cancer (NSCLC) was greater for cases with the GG genotype of NBS1 rs1061302 than for cases with AA/AG genotypes (semi-Bayes adjusted RHR = 1.97; 95 % limits = 1.14, 3.41). CONCLUSIONS: A history of tobacco smoking at cancer diagnosis was associated with mortality among patients with lung cancer or UADT squamous cell carcinoma. The HR relating smoking to mortality appeared to vary with the NBS1 rs1061302 genotype among NSCLC cases. PMID- 24166364 TI - Bioluminescence imaging: basics and practical limitations. AB - Over the last three decades, imaging has been a thriving field with continuous egression of more reliable and highly sophisticated tools and techniques allowing better understanding of biological processes in living organisms. This field continues to expand and its applications broaden to encompass limitless applications in various biomedical research areas. It is however, of utmost importance to understand the capabilities and limitations of this technique as new challenges and hurdles continue to arise. This chapter describes the general properties of bioluminescence imaging and commonly used reporters while underlining the challenges and limitations with these modalities. PMID- 24166363 TI - [Interleukin-6 inhibition as a potential therapeutic target in rheumatic diseases]. AB - As a pro-inflammatory cytokine, the 21-kDa glycoprotein interleukin-6 (IL-6) plays a crucial role in the initiation of acute inflammation, as well in the perpetuation of a chronic inflammatory immune response. Thus, IL-6 might be involved in the pathogenesis of various autoimmune diseases. So far, the IL-6 rezeptor-antibody tocilizumab (TCZ, RoActemtra(r)) is the only approved drug for the treatment of IL-6-mediated disease, including rheumatoid arthritis (RA), systemic juvenile idiopathic (sJIA) and polyarticular juvenile arthritis (pJiA), as well as Castleman's disease (in Japan only). In recent years, an emerging number of case reports and small uncontrolled case series have reported on the successful treatment of various other chronic inflammatory diseases, which has resulted in the idea of a broad therapeutic potential for IL-6 blockade. Numerous IL-6 targets are currently in phase II/III study programs for RA as well as for other indications. This review focuses on the development of tocilizumab and other IL-6 targets as a therapeutic option for various diseases in rheumatology. PMID- 24166365 TI - Extraction and quantification of adenosine triphosphate in mammalian tissues and cells. AB - Adenosine 5'-triphosphate (ATP) is the "energy currency" of organisms and plays central roles in bioenergetics, whereby its level is used to evaluate cell viability, proliferation, death, and energy transmission. In this chapter, we describe an improved and efficient method for extraction of ATP from tissues and cells using phenol-based reagents. The chaotropic extraction reagents reported so far co-precipitate ATP with insoluble proteins during extraction and with salts during neutralization. In comparison, the phenol-based reagents extract ATP well without the risks of co-precipitation. The extracted ATP can be quantified by the luciferase assay or high-performance liquid chromatography. PMID- 24166366 TI - Neuronal network imaging in acute slices using Ca2+ sensitive bioluminescent reporter. AB - Genetically encoded indicators are valuable tools to study intracellular signaling cascades in real time using fluorescent or bioluminescent imaging techniques. Imaging of Ca(2+) indicators is widely used to record transient intracellular Ca(2+) increases associated with bioelectrical activity. The natural bioluminescent Ca(2+) sensor aequorin has been historically the first Ca(2+) indicator used to address biological questions. Aequorin imaging offers several advantages over fluorescent reporters: it is virtually devoid of background signal; it does not require light excitation and interferes little with intracellular processes. Genetically encoded sensors such as aequorin are commonly used in dissociated cultured cells; however it becomes more challenging to express them in differentiated intact specimen such as brain tissue. Here we describe a method to express a GFP-aequorin (GA) fusion protein in pyramidal cells of neocortical acute slices using recombinant Sindbis virus. This technique allows expressing GA in several hundreds of neurons on the same slice and to perform the bioluminescence recording of Ca(2+) transients in single neurons or multiple neurons simultaneously. PMID- 24166367 TI - Gaussia luciferase-based mycoplasma detection assay in mammalian cell culture. AB - Mycoplasma contamination in mammalian cell culture is a common problem with serious consequences on experimental data, and yet many laboratories fail to perform regular testing. In this chapter, we describe a simple and sensitive mycoplasma detection assay based on the bioluminescent properties of the Gaussia luciferase reporter. PMID- 24166369 TI - Video-rate bioluminescence imaging of protein secretion from a living cell. AB - We have established a method of video-rate bioluminescence imaging to visualize exocytotic protein secretion from a single living cell using Gaussia luciferase (GLase) as a reporter protein. The luminescence signals produced by the enzymatic reaction of secreted GLase (luciferase) and coelenterazine (luciferin) are detected with an electron-multiplying charge-coupled device camera. An exocytotic event of protein secretion can be visualized using the protein fused to GLase with a time resolution of 30-500 ms. Signal analyses of the bioluminescence video images reveal a number of exocytotic sites, the frequency of exocytotic events, and the amount of secreted protein on a whole cell. Furthermore, the method can distinguish between secreted and cell surface-bound proteins. Our method is a direct approach to investigate the secretion and localization of proteins on the whole surface of living cells. PMID- 24166368 TI - Split Gaussia luciferase for imaging ligand-receptor binding. AB - Ligand binding to cell surface receptors activates signaling pathways in normal and pathologic conditions, and internalized ligand-receptor complexes may continue to signal from endosomes. Accessibility of cell surface receptors and the central function of ligand-receptor binding in signal transduction make ligand binding a prime target for therapeutic agents. We describe a Gaussia luciferase complementation method for imaging ligand-receptor binding in cell based assays and living mice. While we illustrate this imaging method for chemokine ligand CXCL12 and its receptors CXCR4 and CXCR7, this imaging strategy can be generalized to a large number of ligand-receptor interactions. PMID- 24166370 TI - Bioluminescence reporter gene-based detection of microRNAs. AB - MicroRNAs (miRNAs) are an abundant class of small noncoding RNA molecules that inhibit the expression of cognate genes in multicellular organisms. These small RNAs have been demonstrated to play crucial roles in a variety of biological processes including cell differentiation, proliferation, and survival. Knowledge of specific expression patterns of miRNAs is critical for functional studies. Here, we describe a bioluminescence reporter gene-based method to measure miRNA activity in cultured cells and mice using a Gaussia luciferase reporter gene controlled by miRNA binding sites in its 3'untranslated region. This method can be used to noninvasively monitor the expression patterns of functionally active miRNAs involved in different biological processes or diseases in mice. PMID- 24166371 TI - Monitoring of transcriptional dynamics of HIF and NFkappaB activities. AB - Genetic experiments over the last few decades have identified many regulatory proteins critical for DNA transcription. The dynamics of their transcriptional activities shape the differential expression of the genes they control. Here we describe a simple method, based on the secreted luciferase, to measure the activities of two transcription factors NFkappaB and HIF. This technique can effectively monitor dynamics of transcriptional events in a population of cells and be up-scaled for high-throughput screening and promoter analysis, making it ideal for data-demanding applications such as mathematical modelling. PMID- 24166373 TI - Fabrication of bioluminescent capsules and live-cell imaging. AB - The plasma membrane of living cells is an interface of material transfers and an antenna for outer signals. This chapter provides a guide on how to fabricate bioluminescent capsules for illuminating intracellular signaling and cargo protein delivery. The capsule consists of four components, which are, in consecutive order: a secretion peptide (SP), a host luciferase body (leader), a guest protein or peptide (cargo), and a membrane localization signal (MLS). Any guest protein, including a luciferase or a fluorescent protein, may be sandwiched between the host luciferase body and MLS and may be deliverable to the plasma membrane (PM), where the capsule waits for outer signals and to quickly release the embedded luciferase in response to a specific signal. The present strategy provides an efficient molecular vehicle for cargo proteins and imaging of intracellular molecular events in living cells without substrate-derived demerits of luciferases. PMID- 24166372 TI - Real-time bioluminescent tracking of cellular population dynamics. AB - Cellular population dynamics are routinely monitored across many diverse fields for a variety of purposes. In general, these dynamics are assayed either through the direct counting of cellular aliquots followed by extrapolation to the total population size, or through the monitoring of signal intensity from any number of externally stimulated reporter proteins. While both viable methods, here we describe a novel technique that allows for the automated, non-destructive tracking of cellular population dynamics in real-time. This method, which relies on the detection of a continuous bioluminescent signal produced through expression of the bacterial luciferase gene cassette, provides a low cost, low time-intensive means for generating additional data compared to alternative methods. PMID- 24166374 TI - The bioluminescent imaging of spontaneously occurring tumors in immunocompetent ODD-luciferase bearing transgenic mice. AB - The imaging of spontaneously occurring tumors in mice poses many technical and logistical problems. Recently a mouse model was generated in which a chimeric protein consisting of HIF-1alpha oxygen-dependent degradation domain (ODD) fused to luciferase was ubiquitously expressed in all tissues. Hypoxic stress leads to the accumulation of ODD-luciferase in the tissues of this mouse model which can be identified by noninvasive bioluminescence measurement. Crossing this transgenic mouse with tumorigenic mice yields solid tumors with hypoxic cores that may be successfully imaged and characterized using the technique described herein. PMID- 24166375 TI - Blood-based assay with secreted Gaussia luciferase to monitor tumor metastasis. AB - Only a few techniques are currently available for quantifying systemic metastases in preclinical models. Cancer cell expression of naturally secreted Gaussia luciferase (Gluc) provides a useful circulating biomarker that enables the monitoring of metastatic tumor burden and of treatment response from minimal drops of blood. This blood-based Gluc assay exhibits several distinct advantages: (1) It is highly sensitive in quantifying metastatic tumor growth, particularly when compared to whole-body bioluminescence imaging (BLI) alone; (2) It is quantitative by nature and reflects viable tumor burden in a minimally invasive manner; (3) Through longitudinal collection of blood samples, treatment response can be monitored in real-time; and (4) Gluc bioluminescence provides a means to localize and assess metastatic colonization using BLI. By elucidating the progression of systemic metastases and therapeutic response in animal models, the blood-based Gluc assay is emerging as a valuable quantitative tool for novel drug development. PMID- 24166377 TI - Bioluminescent imaging of bacteria during mouse infection. AB - Diagnostic imaging is a powerful tool that has recently been applied towards the study of infectious diseases. Optical imaging of bioluminescently labeled bacteria in infected animals allows for real-time analysis of bacterial proliferation and dissemination during infection without sacrificing the animal. Imaging also allows for tracking of disease progression in an individual subject over time, has the potential to reveal previously overlooked sites of infection, and reduces the number of research animals used in pathogenesis studies. Here, we describe the use of a deep-cooled CCD camera imager to record light emitted from bacteria during infection. We also describe the process of correlating bioluminescence to bacterial numbers by ex vivo imaging of necropsied tissues. Together these techniques can be used to estimate bacterial burdens in host tissues both in vivo and ex vivo using bioluminescent imaging. PMID- 24166376 TI - Bioluminescence imaging of fungal biofilm development in live animals. AB - Fungal biofilms formed on various types of medical implants represent a major problem for hospitalized patients. These biofilms and related infections are usually difficult to treat because of their resistance to the classical antifungal drugs. Animal models are indispensable for investigating host-pathogen interactions and for identifying new antifungal targets related to biofilm development. A limited number of animal models is available that can be used for testing novel antifungal drugs in vivo against C. albicans, one of the most common pathogens causing fungal biofilms. Fungal load in biofilms in these models is traditionally analyzed postmortem, requiring host sacrifice and enumeration of microorganisms from individual biofilms in order to evaluate the amount of colony forming units and the efficacy of antifungal treatment. Bioluminescence imaging (BLI) made compatible with small animal models for in vivo biofilm formation is a valuable noninvasive tool to follow-up biofilm development and its treatment longitudinally, reducing the number of animals needed for such studies. Due to the nondestructive and noninvasive nature of BLI, the imaging procedure can be repeated in the same animal, allowing follow-up of the biofilm growth in vivo without removing the implanted device or detaching the biofilm from its substrate. The method described here introduces BLI of C. albicans biofilm formation in vivo on subcutaneously implanted catheters in mice. One of the main challenges to overcome for BLI of fungi is the hampered intracellular substrate delivery through the fungal cell wall, which is managed by using extracellularly located Gaussia luciferase. Although detecting a quantifiable in vivo BLI signal from biofilms formed on the inside of implanted catheters is challenging, BLI proved to be a practical tool in the study of fungal biofilms. This method describing the use of BLI for in vivo follow-up of device-related fungal biofilm formation has the potential for efficient in vivo screening for interesting genes of the pathogen and the host involved in C. albicans biofilm formation as well as for testing novel antifungal therapies. PMID- 24166378 TI - Cell-based bioluminescence screening assays. AB - Drug screening is an essential and widely used technique for drug discovery in various biomedical fields notably in oncology. Here we describe a functional screening assay based on the bioluminescence detection of a secreted luciferase for monitoring cell viability of cancer cells in a high-throughput format. This assay allows the screening of large libraries comprising thousands of compounds and the identification of potential anticancer molecules in a rapid, facile, and cost-effective manner. PMID- 24166379 TI - Bioluminescence-based monitoring of virus vector-mediated gene transfer in mice. AB - In vivo bioluminescence imaging (BLI) is a powerful technology that gives information on biological processes in living animals over multiple time points. Importantly BLI can also yield anatomical localization of signal which can provide important information when performing biodistribution studies of different macromolecules. This is of particular interest for gene therapy vectors such as adeno-associated virus (AAV) vectors in which knowledge of in vivo gene expression profiles help characterize what target tissues or organs the vector may be useful for. It can also be utilized to assess novel vector systems for their ability to overcome specific in vivo barriers of effective gene therapy. Here we describe BLI of AAV-encoded firefly luciferase (Fluc) expression in mice after intravascular delivery. This protocol can be amended for use with different virus vectors (e.g., lentivirus, adenovirus) as well as nonviral gene delivery (e.g., plasmid DNA, liposomes). PMID- 24166380 TI - Simultaneous in vivo monitoring of regulatory and effector T lymphocytes using secreted Gaussia luciferase, Firefly luciferase, and secreted alkaline phosphatase. AB - Regulatory T cells (Tregs) are amongst the most widely studied cells in a variety of immune-mediated conditions, including transplantation and Graft Versus Host Disease (GVHD), cancer and autoimmunity; indeed, there is great interest in the tolerogenic potential of Treg-based therapy. Consequently, the need to establish the mechanisms that determine Treg survival and longevity, in addition to developing new tools to monitor these parameters, is paramount. Using both a mouse model of GVHD and a mouse model of Type 1 Diabetes (T1D), we describe herein a dual reporter system based on Gluc and multiplexed with SEAP and non secreted Firefly luciferase (Fluc), which permits simultaneous imaging and noninvasive tracking of two different T-cell populations (CD4(+)CD25(+) Tregs and CD4(+)CD25(-) Tcon cells) in vivo by transducing the cells with different lentiviruses bearing distinct color signatures. This new technology promises to overcome the limitations of the conventional methods currently available to study lymphocyte survival in vivo. Furthermore, this novel technique has applications not only in autoimmunity and alloimmunity, but also in the wider field of immunology. PMID- 24166381 TI - Multiplex functional bioluminescent reporters using Gaussia luciferase fused to epitope tags in an immunobinding assay. AB - The use of Gaussia luciferase in a multiplex assay can have several advantages over the singleplex method for an experimental setup. Issues such as intersample variability, screening purposes, efficiency, and in vivo applications can be addressed using a multiplex assay. Here we describe a functional reporter multiplex method using Gaussia luciferase fused to epitope tags to identify the different reporters that are expressed. Tag specific antibodies are used to bind and separate the tagged luciferase reporters. PMID- 24166382 TI - Noninvasive in vivo monitoring of extracellular vesicles. AB - Extracellular vesicles (EVs) including exosomes and microvesicles are nanometer sized vesicles released by cells to deliver lipids, cellular proteins, mRNAs, and noncoding RNAs, thereby facilitating intercellular communication without direct cell-to-cell contacts. Due to their nanoscale size, EVs have been visualized under microscopy in vitro. We here describe a strategy to label EVs with Gaussia luciferase for noninvasive bioluminescence imaging and monitoring of systemically administered EVs in vivo. PMID- 24166383 TI - In vitro and in vivo demonstrations of Fluorescence by Unbound Excitation from Luminescence (FUEL). AB - Bioluminescence imaging is a powerful technique that allows for deep-tissue analysis in living, intact organisms. However, in vivo optical imaging is compounded by difficulties due to light scattering and absorption. While light scattering is relatively difficult to overcome and compensate, light absorption by biological tissue is strongly dependent upon wavelength. For example, light absorption by mammalian tissue is highest in the blue-yellow part of the visible energy spectrum. Many natural bioluminescent molecules emit photonic energy in this range, thus in vivo optical detection of these molecules is primarily limited by absorption. This has driven efforts for probe development aimed to enhance photonic emission of red light that is absorbed much less by mammalian tissue using either direct genetic manipulation, and/or resonance energy transfer methods. Here we describe a recently identified alternative approach termed Fluorescence by Unbound Excitation from Luminescence (FUEL), where bioluminescent molecules are able to induce a fluorescent response from fluorescent nanoparticles through an epifluorescence mechanism, thereby significantly increasing both the total number of detectable photons as well as the number of red photons produced. PMID- 24166384 TI - Mapping quantitative trait loci associated with root penetration ability in rice (Oryza sativa L.). AB - Root penetration ability is an important factor for rice drought resistance in areas with soils subject to both compaction and periodic water deficits. However, breeding for root penetration ability is inhibited by the difficulties associated with measuring root traits. Our objective was to identify restriction fragment length polymorphisms (RFLPs) associated with root penetration ability. Using wax petrolatum layers as a proxy for compacted soil, we counted the number of vertical root axes penetrating through the layer, the total number of vertical root axes and the number of tillers per plant of 202 recombinant inbred (RI) lines over three replications. As a measure of root penetration ability, we used a root penetration index defined as the percent of the total number of vertical root axes that penetrated through a wax-petrolatum layer. The RI population exhibited a wide range in the number of penetrating roots axes (10-115 roots), the total number of roots axes (74-226 roots), tillers per plant (6-18), and in the root penetration index (0.11-0.71). Single-marker and interval quantitative trait analyses were conducted to identify RFLP loci associated with the number of penetrating roots, total root number, root penetration index, and tiller number. Four quantitative trait loci (QTLs) were associated with the number of penetrated roots, 19 with the total root number, six QTLs with the root penetration index and ten with tiller number. Individually, these QTLs accounted for a maximum of 8% of the variation in the number of penetrating roots, 19% of the variation in total root number, 13% of the variation in root penetration index and 14% of the variation in tiller number as estimated from regressions. The multimarker regression model accounting for the greatest proportion of the variation in the root penetration index was a three-marker model that accounted for 34% of the variation. Two-marker models accounted for 13% of the variation in the number of penetrated roots, 25% of the variation in total root number, and 21% of the variation in tiller number. This is the first research paper to apply RFLP quantitative trait analysis to dissect genetic loci associated with the total number of roots, root penetration ability and tiller number. PMID- 24166385 TI - Genetic diversity and its relationship to hybrid performance and heterosis in rice as revealed by PCR-based markers. AB - Ten elite inbred lines (four japonica, six indica), chosen from those widely used in the hybrid rice breeding program at Human Hybrid Rice Research Center in China, were crossed to produce all possible hybrids excluding reciprocals. The 45 F1 hybrids along with the ten parents were evaluated for eight traits of agronomic importance, including yield potential, in a replicated field trial. The ten parents were analyzed with 100 arbitrary decamer oligonucleotide primers and 22 microsatellite (simple sequence repeats, SSRs) primer sets via polymerase chain reaction (PCR). Out of the 100 random primers used, 74 were informative and amplified 202 non-redundant bands (variants) with a mean of 2.73 bands per polymorphic primer. All 22 microsatellite primer sets representing 23 loci in the rice genome showed polymorphisms among the ten parents and revealed 90 alleles with an average of 3.91 per SSR locus. Cluster analysis based on Nei's genetic distance calculated from the 291 (202 RAPDs, 89 SSRs) non-redundant variants separated the ten parental lines into two major groups that corresponds to indica and japonica subspecies, which is consistent with the pedigree information. Strong heterosis was observed in hybrids for most of the traits examined. For the 43 diallel crosses (excluding 2 crosses not heading), yield potential, its components (including panicles per plant, spikelets per panicle and 1000-grain weight) and their heterosis in F1 hybrids showed a significant positive correlation with genetic distance. When separate analyses were performed for the three subsets, yield potential and its heterosis showed significant positive correlations with genetic distance for the 15 indica x indica crosses and the 6 japonica x japonica crosses; however, yield potential and its heterosis were not correlated with genetic distance for the 22 indica x japonica crosses. Results indicated that genetic distance measures based on RAPDs and SSRs may be useful for predicting yield potential and heterosis of intra-subspecific hybrids, but not inter-subspecies hybrids. PMID- 24166386 TI - Combined genetic analysis of partial blast resistance in an upland rice population and recurrent selection for line and hybrid values. AB - The CNA-IRAT 5 upland rice population has been improved for 4 years by recurrent selection for blast resistance in Brazil. In order to predict the efficiency of recurrent selection in different test systems and to compare the relative advantage of hybrids versus pure line breeding, a combined genetic analysis of partial blast resistance in the CNA-IRAT 5 population was undertaken. A three level hierarchical design in inbreeding and a factorial design were derived from the base population. Partial blast resistance of lines and hybrids was evaluated in the greenhouse and in the field by inoculation with one virulent blast isolate. The means and genetic variances of the hybrids and lines were estimated. Genetic advance by recurrent selection was predicted from estimates of variance components. The inheritance of partial blast resistance was mainly additive but non-additive effects were detected at both levels of means and variances. Mean heterosis ranged from 4%-8% for lesion size and lesion density to 10-12% for leaf and panicle resistance. High dominance or homozygous dominance variances relative to additive variance and negative covariance between additive and homozygous dominance effects were estimated. A low frequency of favourable alleles for partial resistance would explain the observed organisation of genetic variability in the base population. Recurrent selection will efficiently improve partial blast resistance of the CNA-IRAT 5 population. Genetic advance for line or hybrid values was expected to be higher testing doubled haploid lines than S1 lines, or than general combining ability. Two components of partial resistance assessed in the greenhouse, lesion size and lesion density, could be used as indirect selection criteria to improve field resistance. On the whole, hybrid breeding for partial blast resistance appeared to be slightly more advantageous than pure line breeding. PMID- 24166387 TI - Detection and characterization of a glutenin subunit with unusual high Mr at the Glu-A1 locus in hexaploid wheat. AB - A hexaploid wheat landrace collected from the Baluchistan province of Pakistan was found to possess a novel high-molecular-weight glutenin subunit (HMW-GS). The subunit has a very slow electrophoretic mobility as revealed by SDS-PAGE, and its molecular weight is comparable to that of the highest molecular weight glutenin subunit ("2.2" encoded in the D-genome) reported so far in hexaploid wheat varieties and landraces of Japanese origin. Evidence obtained from (PCR) gene amplification studies using the primers specific for Glu-1 loci proved that the gene coding for this novel subunit belongs to the Glu-A1 locus located on the long arm of chromosome 1A. Digestion of the amplified gene (PCR product) with restriction enzymes indicated that the novel gene differs from prevailing Glu-A1 alleles (null, 1 and 2(*)) by an extra DNA fragment of approximately 600 base pairs. The results also indicated that the novel subunit is most probably a derivative of subunit 2(*) that has very likely incorporated the 600-bp fragment following a process of unequal crossing over. The present findings were further substantiated by reserved phase high performance liquid chromatography (RP-HPLC) analysis. PMID- 24166388 TI - PCR-based DNA markers linked to a gall midge resistance gene, Gm4t, has potential for marker-aided selection in rice. AB - Rice DNAs from a gall midge resistant variety, 'Abhaya', a susceptible variety, 'Tulsi' and their F3 progeny were screened using 500 random primers in conjunction with bulked-segregant analysis in a polymerase chain reaction (PCR) with a view to detecting random amplified polymorphic DNAs (RAPDs) linked to the gene, Gm4t, which confers resistance to gall midge, a dipteran insect pest of rice. A total of 454 primers were able to produce a distinct amplification pattern, and 3695 bands/loci were amplified between the phenotypically different parents. Of these, 304 bands were polymorphic between the parents, with 19 being phenotypespecific. One of these primers, E20, amplified 2 bands, E20570 and E20583, which are tightly linked to resistance and susceptibility, respectively. These specific bands were cloned and sequenced, and a 94% sequence homology was found between the two fragments. Two specific 20-mer oligonucleotides were synthesized, based on the sequence information of E20583, for use in PCR amplification directly from genomic DNAs. These PCR primers were able to amplify phenotype-specific bands, a 583-bp fragment in susceptible F3 lines and a 570-bp fragment in resistant F3 lines that had been derived from a cross between the parents, indicating their potential and utility for marker-aided selection of the Gm4t gene in rice. Its use would facilitate the early and efficient selection of resistant genes in plant breeding programmes and even in those areas where the insect is not known to occur. These phenotype-specific bands are single-copy sequences and are being mapped to ascertain their chromosomal location in rice. PMID- 24166389 TI - Path coefficient analysis of the effects of stripe rust and cultivar mixtures on yield and yield components of winter wheat. AB - Four club wheat cultivars and three two-component cultivar mixtures, planted at five frequencies, were grown in three environments in both the presence and absence of stripe rust. The effect of stripe rust on wheat yield was through the yield components, with weight of individual seed being the component most affected by rust. In some cases, yield component compensation was indicated by the presence of negative correlations among the yield components. Path analysis of the yield components revealed that components with the highest correlations to yield also had the largest direct effects on yield. Of the yield components, number of heads per unit area exerted the largest direct influence on yield. The direct effects of number of seeds per head and weight of individual seed were similar, although number of seeds per head was more important in the absence of rust than in its presence. The pure stands and mixtures differed considerably with respect to correlation coefficients, but were very similar for direct effects of yield components on yield. Most of these discrepancies were due to opposing indirect effects, which were not evident from correlation coefficients alone. PMID- 24166390 TI - A genetic linkage map for Pinus radiata based on RFLP, RAPD, and microsatellite markers. AB - A genetic linkage map for radiata pine (Pinus radiata D. Don) has been constructed using segregation data from a three-generation outbred pedigree. A total of 208 loci were analyzed including 165 restriction fragment length polymorphism (RFLP), 41 random amplified polymorphic DNA (RAPD) and 2 microsatellite markers. The markers were assembled into 22 linkage groups of 2 or more loci and covered a total distance of 1382 cM. Thirteen loci were unlinked to any other marker. Of the RFLP loci that were mapped, 93 were detected by loblolly pine (P. taeda L.) cDNA probes that had been previously mapped or evaluated in that species. The remaining 72 RFLP loci were detected by radiata pine probes from a PstI genomic DNA library. Two hundred and eighty RAPD primers were evaluated, and 41 loci which were segregating in a 1?1 ratio were mapped. Two microsatellite markers were also placed on the map. This map and the markers derived from it will have wide applicability to genetic studies in P. radiata and other pine species. PMID- 24166391 TI - Change in ribosomal DNA spacer-length composition in maize recurrent selection populations. 2. Analysis of BS10, BS11, RBS10, and RSSSC. AB - Four maize (Zea mays L.) populations selected for grain yield (BS10, Iowa Two-ear Synthetic; BS11, formerly Pioneer Two-ear Composite; RBS10, Illinois strain of BS10; and RSSSC, Illinois strain of Iowa Stiff Stalk Synthetic) were assayed for molecular variation in the ribosomal DNA (rDNA) intergenic spacer (IGS) at initial and advanced cycles of selection. RSSSC and RBS10 underwent reciprocal recurrent selection with an inbred tester in a high-yield environment, whereas BS10 and BS11 were subjected to full-sib reciprocal recurrent selection. Maize rDNA, which encodes the ribosomal RNA genes, is highly repetitive and shows IGS length variation within and among individuals. Five different ribosomal spacer length variants (rslvs) and a polymorphic SstI restriction site in the IGS were detected in the four populations. The five rslvs and the polymorphic restriction fragment were observed in 20 different combinations or hybridization fragment patterns (HP). RSSSC, RBS10, and BS11 showed significant changes in the overall rslv and HP frequencies between cycle 0 and the advanced cycle of selection, whereas BS10 did not. In general, two specific HPs were more frequent in the majority of the advanced cycles of the four populations. The frequency changes between initial and advanced cycles were more dramatic for HPs than rslvs. These results are consistent with earlier findings and further support the hypothesis that certain rDNA HPs and/or linked loci may be responding to selection for grain yield and may be associated with a selective advantage in US Corn Belt environments. PMID- 24166392 TI - A localized linkage map of the citrus tristeza virus resistance gene region. AB - A localized genetic linkage map was developed of the region surrounding the citrus tristeza virus (CTV) resistance gene (designated Ctv) from Poncirus trifoliate L., a sexually compatible Citrus relative. Bulked segregant analysis (BSA) was used to identify potential resistance-associated RAPD fragment markers in four intergeneric backcross families that were segregating for CTV resistance. Eight RAPD fragments were found that were consistently linked to Ctv in the four families. Map distances and locus order were determined with MAPMAKER 3.0, using the results obtained from 59 individuals in the largest family. Also, a consensus map was constructed with JOINMAP 1.3, using pooled results from the four backcross families. Marker orders were identical, except for 1 marker, on these independently developed maps. Family-specific resistance-associated markers were also identified, as were numerous susceptibility-associated markers. The identification of markers tightly linked to Ctv will enable citrus breeders to identify plants likely to be CTV-resistant by indirect, marker-assisted selection, rather than by labor-intensive direct challenge with the pathogen. These markers also provide a basis for future efforts to isolate Ctv for subsequent genetic manipulation. PMID- 24166393 TI - Distribution of sequences related to the Bg transposable element of maize in Zea and related genera. AB - Thirty-four accessions from Zea and 10 accessions from related genera were assayed for the presence of Bg, a transposable element originally found in maize (Zea mays ssp. mays). Bg-like sequences, identified as hybridizing bands on Southern blots, were visualized in all Zea accessions and were present in approximately equal numbers in teosinte and maize. With the exception of Tripsacum dactyloides, all accessions from related genera failed to hybridize with the Bg probes, even at reduced stringency. A comparison of the restriction patterns of related inbred lines revealed numerous common hybridizing fragments. An index of molecular similarity (MS) was used to determine the degree of similarity between pairs of inbred lines. Computed MS values endorse an inbred relationship and are in good agreement with published results of cluster analysis on these inbred lines. PMID- 24166394 TI - Isolation and identification of a non-specific tandemly repeated DNA sequence in Oryza species. AB - A tandemly repeated DNA sequence (RRS7) was isolated from Oryza alta (CCDD). RRS7 related sequences were also found tandemly arrayed in genomes AA, BB, BBCC, CC, and EE, and a small amount of RRS7-related sequences were detected in genome FF and the Oryza species with unknown genomes. DNA sequence analysis of the 1844-bp insert of RRS7 revealed that it contained six tandemly repeated units, of which five were 155 bp in length and one was 194 bp in length and contained an imperfect internal 39-bp duplication. Southern blot analysis showed that the boundary sequence contained in RRS7 is a single-copy sequence. A 155-bp consensus sequence derived from the six monomeric repeats contained no internal repeat and showed no significant homology to other currently known sequences. The results of Southern blot and sequence analysis revealed that there are at least two subfamilies present in the RRS7 family; these are represented by the DraI site and the MspI site, respectively. Restriction digestion with two pairs of isoschizomers MboI/Sau3A and MspI/HpaII demonstrated that most of the C residues in the GATC sites and the internal C in the CCGG sites of the RRS7 family in O. Alta were methylated. The usefulness of the RRS7 family in determining the evolutionary relationship of the genome DD and other Oryza genomes is discussed. PMID- 24166395 TI - QTL analysis of pest resistance in the wild tomato Lycopersicon pennellii: QTLs controlling acylsugar level and composition. AB - Some accessions of Lycopersicon pennellii, a wild relative of the tomato Lycopersicon esculentum, are resistant to a number of important pests of cultivated tomato due to the accumulation of acylsugars, which constitute 90% of the exudate of type-IV trichomes in L. pennellii LA716. An interspecific F2 population, created by the cross L. esculentum x L. pennellii LA 716, was surveyed for acylsugar accumulation and subjected to RFLP/QTL analysis to determine the genomic regions associated with the accumulation of acylglucoses, acylsucroses, and total acylsugars, as well as with acylglucoses as a percentage of total acylsugars (mole percent acylglucoses). Data were analyzed using MAPMAKER/QTL with and without a log10 transformation. A threshold value of 2.4 (default value for MAPMAKER/QTL) was used, as well as 95% empirically derived threshold values. Five genomic regions, two on chromosome 2 and one each on chromosomes 3, 4 and 11, were detected as being associated with one or more aspects of acylsugar production. The L. esculentum allele is partially dominant to the L. pennellii allele in the regions on chromosomes 2 and 11, but the L. pennellii allele is dominant in the region on chromosome 3. Throughout this study, we report the comparative effects of analytical methodology on the identification of acylsugar QTLs. Similarities between our results and published results for the genus Solanum are also discussed. PMID- 24166396 TI - Detection of genetic diversity using RAPD-PCR and sugar analysis in watermelon [Citrullus lanantus (Thunb.) Mansf.] germplasm. AB - RAPD (random amplified polymorphic DNA) markers generated by 15 arbitrary decamers were used to determine the frequency of DNA polymorphism in 39 watermelon [Citrullus lanantus (Thunb.) Mansf.] germplasms. Of the 15 primers tested, all except 1 (primer 275) directed the amplification of polymorphic products. A total of 162 amplification products were generated across all 39 genotypes. Among the 162 fragments, 35 (21%) appeared to be reliable polymorphic markers. The mean value by marker difference in this comparison was 0.24, and the highest, 0.69. Eight RAPD markers could be utilized in the unique variety discrimination 8 watermelon genotypes. From the phenograms constructed by UPGMA based on the comparison of RAPD markers, four clusters were resolved. Each group was also characterized and identified with morphological and genetic characteristics for each genotype. The free sugars of the edible parts of watermelons were analyzed by HPLC (high-performance liquid chromatography). Results from the phylogenetic analysis of band sharing data were consistent with sweetness as measured by HPLC. In conclusion, RAPD assays can be used for providing alternative markers for identifying genotypes and quantitative characteristics in watermelon. PMID- 24166397 TI - C-banding variation in the Moroccan oat species Avena agadiriana (2n=4x=28). AB - The C-banding technique was used to describe the chromosomes of a relatively recently-discovered Moroccan oat species, Avena agadiriana (2n=4x=28). A substantial amount of polymorphism for arm ratios and C-banding patterns was observed among five accessions of this species. However a common set of ten putatively homologous chromosomes was identifiable among the five accessions. The chromosomes of A. Agadiriana do not closely match those of any of the previously described diploid or tetraploid oat species in terms of their arm ratios and C banding patterns. However, their overall C-banded appearance generally resembles the A/B/D groups of chromosomes of Avena species, rather than the more hetrochromatic C genomes. Implications of these findings in terms of chromosome evolution in the genus Avena are discussed. PMID- 24166398 TI - Ribosomal DNA variations in Erianthus, a wild sugarcane relative (Andropogoneae Saccharinae). AB - Variation at the 18S+26S and 5S ribosomal DNA loci was assessed on 62 Erianthus Michx. clones, representing 11 species, and 15 clones from two Saccharum L. species used as a reference. Genus-specific markers for Erianthus Michx. sect. Ripidium Henrard (Old World species) were identified. Ribosomal DNA units in Erianthus sect. Ripidium exhibited an additional BamHI site compared to Saccharum, and 5S units showed length and restriction-site differences between Erianthus and Saccharum. These markers will be useful to follow introgression in Saccharum x Erianthus hybrids. Six ribosomal units (for 18+26S genes) were revealed in Erianthus sect. Ripidium, differing by restriction-site positions and/or length. These results provided new information on species relationships and evolution within the genus Erianthus. The Indonesian and Indian forms of E. arundinaceus (Retz.) Jeswiet gave different restriction patterns, which were similar to those of E. bengalense (Retz.) R. C. Bharadwaja and E. procerus (Roxb.) Raizade, respectively. The two 2n=20 species, E. ele-phantinus Hook.f. and E. ravennae (L.) P. Beauv., could also be differentiated at this locus. Two of the New World Erianthus species studied, E. rufipilus (Steud.) Griseb. and E. longisetosus Andersson, appeared more like Erianthus sect. Ripidium, whereas E. trinii Hack, and E. brevibardis Michx. showed patterns consistent with Miscanthus sinensis Andersson and S. spontaneum L., respectively. Finally, the comparison of rDNA restriction maps among Erianthus sect. Ripidium, Saccharum, sorghum and maize, led to unexpected conclusions concerning the relationships between the different genera and the position of Erianthus in the "Saccharum complex". PMID- 24166399 TI - Preparation of pea (Pisum sativum L.) chromosome and nucleus suspensions from single root tips. AB - A high-yield method for the isolation of intact nuclei and chromosomes in suspension from a variable number of pea root tips (1-10) has been developed. This procedure is based on a two-step cell-cycle synchronization of root-tip meristems to obtain a high mitotic index, followed by formaldehyde fixation and mechanical isolation of chromosomes and nuclei by homogenization. In the explant, up to 50% of metaphases were induced through a synchronization of the cell cycle at the G1/S interface with hydroxyurea (1.25 mM), followed, after a 3-h release, by a block in metaphase with amiprophos-methyl (10 MUM). The quality and quantity of nuclei and chromosomes were related to the extent of the fixation. Best results were obtained after a 30-min fixation with 2% and 4% formaldehyde for nuclei and chromosomes, respectively. The method described here allowed the isolation of nuclei and chromosomes, even from a single root tip, with a yield of 1*10(5)/root and 1.4*10(5)/root, respectively. Isolated suspensions were suitable for flow cytometric analysis and sorting and PRINS labelling with a rDNA probe. PMID- 24166400 TI - Variation in the inheritance of expression among subclones for unselected (uidA) and selected (bar) transgenes in maize (Zea mays L.). AB - Variation in the inheritance of expression among subclones for an unselected (uidA) and a selected (bar) transgene was analyzed in two individual transformation events in maize. The unselectable gene (uidA) and the selectable gene (bar), on two separate plasmids, were transferred to maize (Hi-II derivative) by particle bombardment of embryogenic calli or suspension cells. A total of 188 fertile T1 plants were obtained from one transformant (transformation event BG which integrated uidA and bar). A total of 98 fertile T1 plants were obtained from a second transformant (transformation event B which integrated bar). Through self-pollination and/or cross-pollination in the greenhouse, approximately 10 000 T2 progeny were obtained from event BG, and more than 1000 T2 progeny were obtained from event B. Segregation of transgene expression was analyzed statistically in a total of 2350 T2 progeny from 40 T1 subclones of event BG and in 217 T2 progeny from six T1 subclones from event B. Variation in the inheritance of expression among subclones for the two transgenes (uidA and bar) was observed in the two transformants. A significant difference was observed between the use of the female or male as the transgenic parent in the inheritance of expression for the two transgenes in event BG. No inheritance through the pollen was observed in two of four T1 subclones analyzed in event B. Co-expression analysis of event BG showed that both transgenes were co-expressed in 67.7% of the T2 plants which expressed at least one of the two transgenes. Of the T2 expressing plants, 30.4% expressed only bar, and 1.9% expressed only uidA. Inactivation of the unselected (uidA) and the selected (bar) transgenes was observed in individual T2 plants. PMID- 24166401 TI - Synthesis of hexaploid (AABBCC) somatic hybrids: a bridging material for transfer of 'tour' cytoplasmic male sterility to different Brassica species. AB - Most of the alloplasmic cytoplasmic male sterility (CMS) systems are known to be associated with a number of floral abnormalities that result from nuclear cytoplasmic incompatibilities. One such system, 'tour', which is derived from Brassica tournefortii, induces additional floral abnormalities and causes chlorosis in Brassica spp. While the restorer for this CMS has been reported to be present in B. napus, in B. juncea, where the abnormalities are more pronounced, no restorer has yet been identified. Rectification of these floral abnormalities through mitochondrial recombinations and chloroplast replacement might result in the improvement of this CMS system. As organelle recombinations can possibly be achieved only by somatic cell hybridization, fusion experiments were carried out between hygromycin-resistant B. juncea AABB carrying 'tour' cytoplasm and phosphinotricin-resistant, normal B. oleracea CC to generate AABBCC hexaploid somatic hybrids. The presence of selectable marker genes facilitated the selection of hybrids in large numbers. The resulting hybrids showed wide variation in floral morphology and organelle composition. Regenerants with normal, male-sterile flowers having recombinant 'tour'-or 'oleracea'-type mitochondria and 'oleracea'-type chloroplasts were obtained. Hybrids with male fertile flowers were also obtained that had recombined 'tour' mitochondria. The AABBCC hexaploid hybrids synthesized in the present study were successfully utilized as a bridging material for transferring variability in the organelle genome simultaneously to all the digenomic Brassica species, and all of these hybrids are now being stabilized through repeated backcrosses to the allopolyploid crop brassicas. PMID- 24166402 TI - DNA fingerprint variability within and among parental lines and its correlation with performance of F1 laying hens. AB - Genetic diversity within and among nine pure lines of Beijing White Leghorn chickens was determined by DNA fingerprinting using human ministatellite probes 33.6 and alpha-globin 3'HVR, as well as bacteriophage M13. Within lines similarity coefficients ranged from 0.497 to 0.628, significantly higher than that within a sample of white chicken from a local market. Relationships among lines were established by clustering analysis based on inter-line coefficients of difference calculated from DNA fingerprints of pooled DNA. A complete diallel crossing among the nine pure lines was conducted. By using linear correlation analysis, it was found that the maximum distance between parental lines was positively correlated with egg number, egg production, survival rate and their corresponding heterosis percentages within a pair of reciprocal crosses. Similar relationships were found where only the higher of the reciprocal crosses were used in the analysis. It was also shown that similarity coefficients within a sire line or dam line were positively correlated with 40-week egg number and its heterosis percentage and the heterosis percentage for 40-week egg production, but negatively correlated with the 40-week survival rate of the cross-bred populations. PMID- 24166403 TI - Production and identification of new structural chromosome mutations in barley (Hordeum vulgare L.). AB - A total of 52 reciprocal translocations and 9 pericentric inversions were induced and identified in both standard and cytologically marked barley karyotypes using gamma-rays as the clastogenic agent. An analysis based upon Giemsa N-banding patterns and arm length measurements of the reconstructed chromosomes enabled a rather precise cytological localization of intra- and interchange breakpoints. This analysis was significantly facilitated and improved, especially for the identification of pericentric inversions, when the reconstructed karyotype T-1586 was used as starting material. The majority, if not all, of the aberration breakpoints proved to be localized in interband regions or in medial and terminal parts of the chromosomes, i.e., in regions which are deficient in constitutive heterochromatin. A great number of the structural mutations produced in this study contain specific cytological markers covering nearly all of the chromosomes of barley karyotype. This material might be of considerable interest in solving various problems of barley cytogenetics and chromosome engineering and especially in constructing a physical map of barley genome. PMID- 24166404 TI - Genetic analysis of anther culture response in wheat carrying alien translocations. AB - A bread wheat cultivar, 'Saratovskaya 29', (S29), its nearly isogenic lines carrying alien translocations [Lr9 from Aegilops umbellulata (Eg29) and (Lr19) from Agropyron elongatum (Ps29)] and two F1 hybrids between three nearly isogenic lines of S29 that differed by the Lr19+Rht1,Pro1+Pro2 and Ppd1+Ppd2 gene complexes, namely the S29 (Lr19+Rht1)/S29 (Ppd1+Ppd2) F1 and the S29 (Pro1+Pro2)/S29 (Lr19+Rht1) F1 were studied for their culture response with the following results. (1) Translocations with Lr9 and Lr19 decreased embryo frequency and green plant regeneration. (2) Both F1 hybrids showed a decrease in embryo frequency. One of the F1 hybrids, S29 (Lr19+Rht1)/S29 (Ppd1+Ppd2) showed a decrease, with respect to S29 for green plant regeneration; the other F1 S29 (Pro1+Pro2)/S29 (Lr19+Rht1), equalled S29 for green plant regeneration. (3) The gene complex of the F1 hybrid S29 (Pro1+Pro2)/S29 (Lr19+Rht1) was better than that of the F1 hybrid S29 (Lr19+Rht1)/S29 (Ppd1+Ppd2) for embryo induction and green plant regeneration. This effect was possibly induced by interactions between the Pro1+Pro2 and Lr19+Rht1 genes or was the result of direct actions of the Pro1+Pro2 genes. PMID- 24166405 TI - Production of hybrids, amphiploids and backcross progenies between a cold tolerant wild species, Erucastrum abyssinicum and crop brassicas. AB - Three intergeneric hybrids were produced between a cold-tolerant wild species, Erucastrum abyssinicum and three cultivated species of Brassica, B. juncea, B. carinata and B. oleracea, through ovary culture. The hybrids were characterized by morphology, cytology and DNA analysis. Amphiploidy was induced in all the F1 hybrids through colchicine treatment. Stable amphiploids and backcross progenies were obtained from two of the crosses, E. abyssinicum x B. juncea and E. abyssinicum x B. carinata. The amphiploid, E. abyssinicum x B. juncea was successfully used as a bridge species to produce hybrids with B. napus, B. campestris and B. nigra. These hybrids and backcross progenies provide useful genetic variability for the improvement of crop brassicas. PMID- 24166408 TI - Polyamines and suicide risk. PMID- 24166407 TI - Playing Super Mario induces structural brain plasticity: gray matter changes resulting from training with a commercial video game. AB - Video gaming is a highly pervasive activity, providing a multitude of complex cognitive and motor demands. Gaming can be seen as an intense training of several skills. Associated cerebral structural plasticity induced has not been investigated so far. Comparing a control with a video gaming training group that was trained for 2 months for at least 30 min per day with a platformer game, we found significant gray matter (GM) increase in right hippocampal formation (HC), right dorsolateral prefrontal cortex (DLPFC) and bilateral cerebellum in the training group. The HC increase correlated with changes from egocentric to allocentric navigation strategy. GM increases in HC and DLPFC correlated with participants' desire for video gaming, evidence suggesting a predictive role of desire in volume change. Video game training augments GM in brain areas crucial for spatial navigation, strategic planning, working memory and motor performance going along with evidence for behavioral changes of navigation strategy. The presented video game training could therefore be used to counteract known risk factors for mental disease such as smaller hippocampus and prefrontal cortex volume in, for example, post-traumatic stress disorder, schizophrenia and neurodegenerative disease. PMID- 24166406 TI - Imaging glutamate in schizophrenia: review of findings and implications for drug discovery. AB - Currently, all treatments for schizophrenia (SCZ) function primarily by blocking D(2)-type dopamine receptors. Given the limitations of these medications, substantial efforts have been made to identify alternative neurochemical targets for treatment development in SCZ. One such target is brain glutamate. The objective of this article is to review and synthesize the proton magnetic resonance spectroscopy ((1)H MRS) and positron emission tomography (PET)/single photon emission computed tomography (SPECT) investigations that have examined glutamatergic indices in SCZ, including those of modulatory compounds such as glutathione (GSH) and glycine, as well as data from ketamine challenge studies. The reviewed (1)H MRS and PET/SPECT studies support the theory of hypofunction of the N-methyl-D-aspartate receptor (NMDAR) in SCZ, as well as the convergence between the dopamine and glutamate models of SCZ. We also review several advances in MRS and PET technologies that have opened the door for new opportunities to investigate the glutamate system in SCZ and discuss some ways in which these imaging tools can be used to facilitate a greater understanding of the glutamate system in SCZ and the successful and efficient development of new glutamate-based treatments for SCZ. PMID- 24166409 TI - Genome-wide association study of alcohol dependence:significant findings in African- and European-Americans including novel risk loci. AB - We report a GWAS of alcohol dependence (AD) in European-American (EA) and African American (AA) populations, with replication in independent samples of EAs, AAs and Germans. Our sample for discovery and replication was 16 087 subjects, the largest sample for AD GWAS to date. Numerous genome-wide significant (GWS) associations were identified, many novel. Most associations were population specific, but in several cases were GWS in EAs and AAs for different SNPs at the same locus,showing biological convergence across populations. We confirmed well known risk loci mapped to alcohol-metabolizing enzyme genes, notably ADH1B (EAs: Arg48His, P=1.17 * 10(-31); AAs: Arg369Cys, P=6.33 * 10(-17)) and ADH1C in AAs (Thr151Thr, P=4.94 * 10(-10)), and identified novel risk loci mapping to the ADH gene cluster on chromosome 4 and extending centromerically beyond it to include GWS associations at LOC100507053 in AAs (P=2.63 * 10(-11)), PDLIM5 in EAs (P=2.01 * 10(-8)), and METAP in AAs (P=3.35 * 10(-8)). We also identified a novel GWS association (1.17 * 10(-10)) mapped to chromosome 2 at rs1437396, between MTIF2 and CCDC88A, across all of the EA and AA cohorts, with supportive gene expression evidence, and population-specific GWS for markers on chromosomes 5, 9 and 19. Several of the novel associations implicate direct involvement of, or interaction with, genes previously identified as schizophrenia risk loci. Confirmation of known AD risk loci supports the overall validity of the study; the novel loci are worthy of genetic and biological follow-up. The findings support a convergence of risk genes (but not necessarily risk alleles) between populations, and, to a lesser extent, between psychiatric traits. PMID- 24166410 TI - HPA axis genetic variation, cortisol and psychosis in major depression. AB - Genetic variation underlying hypothalamic pituitary adrenal (HPA) axis overactivity in healthy controls (HCs) and patients with severe forms of major depression has not been well explored, but could explain risk for cortisol dysregulation. In total, 95 participants were studied: 40 patients with psychotic major depression (PMD); 26 patients with non-psychotic major depression (NPMD); and 29 HCs. Collection of genetic material was added one third of the way into a larger study on cortisol, cognition and psychosis in major depression. Subjects were assessed using the Brief Psychiatric Rating Scale, the Hamilton Depression Rating Scale and the Structured Clinical Interview for Diagnostic and Statistical Manual of Mental Disorders. Blood was collected hourly for determination of cortisol from 1800 to 0900 h and for the assessment of alleles for six genes involved in HPA axis regulation. Two of the six genes contributed significantly to cortisol levels, psychosis measures or depression severity. After accounting for age, depression and psychosis, and medication status, only allelic variation for the glucocorticoid receptor (GR) gene accounted for a significant variance for mean cortisol levels from 1800 to 0100 h (r(2)=0.288) and from 0100 to 0900 h (r(2)=0.171). In addition, GR and corticotropin-releasing hormone receptor 1 (CRHR1) genotypes contributed significantly to psychosis measures and CRHR1 contributed significantly to depression severity rating. PMID- 24166411 TI - The SORL1 gene and convergent neural risk for Alzheimer's disease across the human lifespan. AB - Prior to intervention trials in individuals genetically at-risk for late-onset Alzheimer's disease, critical first steps are identifying where (neuroanatomic effects), when (timepoint in the lifespan) and how (gene expression and neuropathology) Alzheimer's risk genes impact the brain. We hypothesized that variants in the sortilin-like receptor (SORL1) gene would affect multiple Alzheimer's phenotypes before the clinical onset of symptoms. Four independent samples were analyzed to determine effects of SORL1 genetic risk variants across the lifespan at multiple phenotypic levels: (1) microstructural integrity of white matter using diffusion tensor imaging in two healthy control samples (n=118, age 18-86; n=68, age 8-40); (2) gene expression using the Braincloud postmortem healthy control sample (n=269, age 0-92) and (3) Alzheimer's neuropathology (amyloid plaques and tau tangles) using a postmortem sample of healthy, mild cognitive impairment (MCI) and Alzheimer's individuals (n=710, age 66-108). SORL1 risk variants predicted lower white matter fractional anisotropy in an age-independent manner in fronto-temporal white matter tracts in both samples at 5% family-wise error-corrected thresholds. SORL1 risk variants also predicted decreased SORL1 mRNA expression, most prominently during childhood and adolescence, and significantly predicted increases in amyloid pathology in postmortem brain. Importantly, the effects of SORL1 variation on both white matter microstructure and gene expression were observed during neurodevelopmental phases of the human lifespan. Further, the neuropathological mechanism of risk appears to primarily involve amyloidogenic pathways. Interventions targeted toward the SORL1 amyloid risk pathway may be of greatest value during early phases of the lifespan. PMID- 24166414 TI - Antithrombotic therapy during and after percutaneous coronary intervention in patients with atrial fibrillation. PMID- 24166412 TI - Alpha-2A adrenergic receptor gene variants are associated with increased intra individual variability in response time. AB - Intra-individual variability in response time has been proposed as an important endophenotype for attention deficit hyperactivity disorder (ADHD). Here we asked whether intra-individual variability is predicted by common variation in catecholamine genes and whether it mediates the relationship between these gene variants and self-reported ADHD symptoms. A total of 402 non-clinical Australian adults of European descent completed a battery of five cognitive tasks and the Conners' Adult ADHD Rating Scale. Exclusion criteria included the presence of major psychiatric or neurologic illnesses and substance dependency. A total of 21 subjects were excluded due to incomplete data or poor quality cognitive or genotyping data. The final sample comprised 381 subjects (201 males; mean age=21.2 years, s.d.=5.1 years). Principal components analysis on variability measures yielded two factors (response selection variability vs selective attention variability). Association of these factors with catecholamine gene variants was tested using single-step linear regressions, with multiple comparisons controlled using permutation analysis. The response selection variability factor was associated with two ADRA2A single-nucleotide polymorphisms (SNPs) (rs1800544, rs602618), p corrected=0.004, 0.012, respectively, whereas the selective attention variability factor was associated with a TH SNP (rs3842727), p corrected=0.024. A bootstrapping analysis indicated that the response selection variability factor mediated the relationship between the ADRA2A SNP rs1800544 and self-reported ADHD symptoms. Thus this study finds evidence that DNA variation in the ADRA2A gene may be causally related to ADHD-like behaviors, in part through its influence on intra-individual variability. Evidence was also found for a novel association between a TH gene variant and intra-individual variability. PMID- 24166413 TI - Serotonin 2C receptor antagonists induce fast-onset antidepressant effects. AB - Current antidepressants must be administered for several weeks to produce therapeutic effects. We show that selective serotonin 2C (5-HT2C) antagonists exert antidepressant actions with a faster-onset (5 days) than that of current antidepressants (14 days) in mice. Subchronic (5 days) treatment with 5-HT2C antagonists induced antidepressant behavioral effects in the chronic forced swim test (cFST), chronic mild stress (CMS) paradigm and olfactory bulbectomy paradigm. This treatment regimen also induced classical markers of antidepressant action: activation of cAMP response element-binding protein (CREB) and induction of brain-derived neurotrophic factor (BDNF) in the medial prefrontal cortex (mPFC). None of these effects were induced by subchronic treatment with citalopram, a prototypical selective serotonin reuptake inhibitor (SSRI). Local infusion of 5-HT2C antagonists into the ventral tegmental area was sufficient to induce BDNF in the mPFC, and dopamine D1 receptor antagonist treatment blocked the antidepressant behavioral effects of 5-HT2C antagonists. 5-HT2C antagonists also activated mammalian target of rapamycin (mTOR) and eukaryotic elongation factor 2 (eEF2) in the mPFC, effects recently linked to rapid antidepressant action. Furthermore, 5-HT2C antagonists reversed CMS-induced atrophy of mPFC pyramidal neurons. Subchronic SSRI treatment, which does not induce antidepressant behavioral effects, also activated mTOR and eEF2 and reversed CMS induced neuronal atrophy, indicating that these effects are not sufficient for antidepressant onset. Our findings reveal that 5-HT2C antagonists are putative fast-onset antidepressants, which act through enhancement of mesocortical dopaminergic signaling. PMID- 24166415 TI - Implantable cardioverter-defibrillator leads: design, diagnostics, and management. PMID- 24166416 TI - ECG Response: October 29, 2013. PMID- 24166417 TI - Acute pericarditis secondary to hydatid cyst rupture: diagnosis by multimodality imaging. PMID- 24166418 TI - Combined transcatheter aortic valve replacement and emergent alcohol septal ablation. PMID- 24166420 TI - Letter by schooling and leung regarding article, "the global cardiovascular risk transition: associations of four metabolic risk factors with macroeconomic variables in 1980 and 2008". PMID- 24166421 TI - Response to letter regarding article, "the global cardiovascular risk transition: associations of four metabolic risk factors with macroeconomic variables in 1980 and 2008". PMID- 24166424 TI - Primary multilocular hydatid cyst of neck with unique presentation: a rare case report and literature review. AB - Hydatid cyst (HC) is a parasitic infection caused by larva form of Echinococcus. It occurs frequently in liver and lungs. Primary HC of neck is extremely rare occurrence and here we report it with unusual presentation. A 35-year-old male presented with slowly growing painless swelling in right side of neck for 6-7 years. The swelling measured 11 * 6 cm and cough impulse elicited on local examination. MRI scan revealed a multiloculated cystic lesion in neck. Fine needle aspiration cytology yielded fluid aspirate and smear showed fragment of laminated membrane, suggestive of HC. The intact cyst was removed surgically and histopathologic examination confirmed the diagnosis of HC. Both clinicians and radiologists should consider HC in differential diagnosis of head and neck swelling for proper management. PMID- 24166423 TI - Children who develop type 1 diabetes early in life show low levels of carnitine and amino acids at birth: does this finding shed light on the etiopathogenesis of the disease? AB - BACKGROUND: Children and adolescents with overt type 1 diabetes (T1D) have been found to show an altered carnitine profile. This pattern has not previously been analyzed in neonates before onset of the disease. MATERIALS AND METHODS: Fifty children who developed T1D during the first 6 years of life, born and living in the Tuscany and Umbria Regions of Italy, were identified and 200 controls were recruited into the study. All newborns were subjected to extended neonatal screening by mass spectrometry at 48-72 h of life. Four controls for each of the 50 index cases were taken randomly and blinded in the same analytical batch. The panel used for neonatal screening consists of 13 amino acids, free carnitine, 33 acyl-carnitines and 21 ratios. All Guthrie cards are analyzed within 2 days of collection. RESULTS: Total and free carnitine were found to be significantly lower in neonates who later developed T1D compared with controls. Moreover, the concentrations of the acyl-carnitines - acetyl-L-carnitine (C2), proprionylcarnitine (C3), 3-hydroxyisovalerylcarnitine (C5OH), miristoylcarnitine (C4), palmitoylcarnitine (C16) and stearoylcarnitine (C18) - were also significantly low in the cases vs controls. Furthermore, total amino-acid concentrations, expressed as the algebraic sum of all amino acids tested, showed a trend toward lower levels in cases vs controls. CONCLUSIONS: We found that carnitine and amino-acid deficit may be evident before the clinical appearance of T1D, possibly from birth. The evaluation of these metabolites in the neonatal period of children human leukocyte antigen genetically at 'risk' to develop T1D, could represent an additional tool for the prediction of T1D and could also offer the possibility to design new strategies for the primary prevention of the disease from birth. PMID- 24166426 TI - Thirty years of transgenic research in plants. AB - In 1983, the first transgenic tissues and plants were generated by means of disarmed Agrobacterium tumefaciens strains, in which the oncogenes had been replaced by antibiotic resistance markers. Hence, this Special Issue of The International Journal of Developmental Biology celebrates 30 years of transgenic research in plants! Eminent scientists working in the field of plant transformation or plant biotechnology have contributed to this publication and reviewed the state of the art of their particular subdomain or summarized the importance of transgenic research in the discovery of new mechanisms and the establishment of an entirely new field, such as epigenetics. PMID- 24166425 TI - alpha-Fetoprotein is a surrogate marker for predicting treatment failure in telaprevir-based triple combination therapy for genotype 1b chronic hepatitis C Japanese patients with the IL28B minor genotype. AB - Even when treated with telaprevir-based triple therapy, some patients fail to achieve a sustained virological response. This study identified factors related closely to treatment failure. A total of 146 Japanese genotype 1b chronic hepatitis C patients were enrolled in this prospective, multicenter study and received a 24-week regimen of triple therapy. The end-of-treatment response rate was significantly lower in patients with the interleukin 28B (IL28B) (rs8099917) non-TT genotype (85.2%) than in those with the TT genotype (100%, P = 0.0002). Multiple logistic regression analysis identified high alpha-fetoprotein levels as an independent factor related to non-end-of-treatment response in patients with the non-TT genotype. A cut-off value of 20 ng/ml was determined for a non-end-of treatment response; sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and accuracy were 75.0%, 95.7%, 75.0%, 75.0%, and 92.6%, respectively. Multiple logistic regression analysis for a sustained virological response identified the IL28B TT genotype, low alpha-fetoprotein levels, non-responders, and a rapid virological response. The sustained virological response rate was significantly lower in patients with the non-TT genotype (59.3%) than in those with the TT genotype (96.7%, P < 0.0001). In patients with the non-TT genotype, alpha-fetoprotein was the most significant predictor for non-sustained virological response by univariate analysis. A cut off value of 7.4 ng/ml alpha-fetoprotein was determined for non-sustained virological response; sensitivity, specificity, PPV, NPV, and accuracy were 63.6%, 87.5%, 77.8%, 77.8%, and 77.8%, respectively. For the non-TT patients, serum alpha-fetoprotein levels may be a surrogate marker for predicting treatment failure in telaprevir-based therapy for genotype 1b chronic hepatitis C. PMID- 24166427 TI - Fundamental discoveries and simple recombination between circular plasmid DNAs led to widespread use of Agrobacterium tumefaciens as a generalized vector for plant genetic engineering. AB - Fundamental research aimed to determine the limits of the Agrobacterium transfer DNA (T-DNA) element that stably inserted into plant nuclear DNA to cause crown gall tumor formation. The T-DNA borders were discovered to be exceedingly precise, revealing that T-DNA insertion into the plant genome was reproducible and exact. Deletion of the internal regions of the T-DNA, to remove the tumor forming genes, while retaining the T-DNA borders, resulted again in efficient DNA transfer to plant cells, but now such cells were capable of completely normal growth and differentiation. Thus, the internal region of the T-DNA was not needed for DNA transfer, and one could envisage insertion of any DNA of interest in between the T-DNA borders. Thus began plant genetic engineering. PMID- 24166428 TI - From the tumor-inducing principle to plant biotechnology and its importance for society. AB - This dialogue was held between the Guest Editors of the Special Issue on "Plant Transgenesis" of the Int. J. Dev. Biol. and Marc Van Montagu. Research in the group of Marc Van Montagu and Jeff Schell in the 1970s was essential to reveal how the phytopathogenic bacterium Agrobacterium tumefaciens transfers DNA to host plants to cause crown gall disease. Knowledge of the molecular mechanism underlying gene transfer, subsequently led to the development of plant transgene technology, an indispensable tool in fundamental plant research and plant improvement. In the early 1980s, Marc Van Montagu founded a start-up company, Plant Genetic Systems, which successfully developed insect-resistant plants, herbicide-tolerant plants and a hybrid seed production system based on nuclear male sterility. Even before the first transgenic plant had been produced, Marc Van Montagu realized that the less developed countries might benefit most from plant biotechnology and throughout his subsequent career, this remained a focus of his efforts. After becoming emeritus professor, he founded the Institute of Plant Biotechnology Outreach (IPBO), which aims to raise awareness of the major role that plant biotechnology can play in sustainable agricultural systems, especially in less developed countries. Marc Van Montagu has been honored with many prizes and awards, the most recent being the prestigious World Food Prize 2013. In this paper, we look to the past and present of plant biotechnology and to the promises this technology holds for the future, on the basis of the personal perspective of Marc Van Montagu. PMID- 24166429 TI - Transgenic plants: from first successes to future applications. AB - This dialogue was held between the Guest Editors of the Special Issue on "Plant Transgenesis" of the Int. J. Dev. Biol. and Marc De Block. He was one of the first scientists worldwide to obtain transgenic plants transformed with the chimeric selectable marker genes encoding neomycin phosphotransferase and bialaphos that confer resistance against the antibiotic kanamycin and the herbicide Basta(r)/glufosinate, respectively at the Department of Genetics of Ghent University and, later on, at the spin-off company, Plant Genetic Systems. Today, these two genes are still the most frequently utilized markers in transgene technology. Marc De Block chose to work on the improvement of crops in an industrial environment to help realize the production of superior seeds or products. He was part of the team that developed the male sterility/restorer system in canola (Brassica napus var. napus) that led to the first hybrid lines to be commercialized as successful products of transgene technology. In more than 30 years of research, he developed transformation procedures for numerous crops, designed histochemical, biochemical and physiological assays to monitor plant performance, and made original and innovative contributions to plant biology. Presently, he considers transgenic research part of the toolbox for plant improvement and essential for basic plant research. PMID- 24166430 TI - The roles of bacterial and host plant factors in Agrobacterium-mediated genetic transformation. AB - The genetic transformation of plants mediated by Agrobacterium tumefaciens represents an essential tool for both fundamental and applied research in plant biology. For a successful infection, culminating in the integration of its transferred DNA (T-DNA) into the host genome, Agrobacterium relies on multiple interactions with host-plant factors. Extensive studies have unraveled many of such interactions at all major steps of the infection process: activation of the bacterial virulence genes, cell-cell contact and macromolecular translocation from Agrobacterium to host cell cytoplasm, intracellular transit of T-DNA and associated proteins (T-complex) to the host cell nucleus, disassembly of the T complex, T-DNA integration, and expression of the transferred genes. During all these processes, Agrobacterium has evolved to control and even utilize several pathways of host-plant defense response. Studies of these Agrobacterium-host interactions substantially enhance our understanding of many fundamental cellular biological processes and allow improvements in the use of Agrobacterium as a gene transfer tool for biotechnology. PMID- 24166431 TI - Higher plant transformation: principles and molecular tools. AB - In higher plants, genetic transformation, which is part of the toolbox for the study of living organisms, had been reported only 30 years ago, boosting basic plant biology research, generating superior crops, and leading to the new discipline of plant biotechnology. Here, we review its principles and the corresponding molecular tools. In vitro regeneration, through somatic embryogenesis or organogenesis, is discussed because they are prerequisites for the subsequent Agrobacterium tumefaciens-mediated transferred (T)-DNA or direct DNA transfer methods to produce transgenic plants. Important molecular components of the T-DNA are examined, such as selectable marker genes that allow the selection of transformed cells in tissue cultures and are used to follow the gene of interest in the next generations, and reporter genes that have been developed to visualize promoter activities, protein localizations, and protein-protein interactions. Genes of interest are assembled with promoters and termination signals in Escherichia coli by means of GATEWAY-derived binary vectors that represent the current versatile cloning tools. Finally, future promising developments in transgene technology are considered. PMID- 24166432 TI - Genetic transformation of major cereal crops. AB - Of the more than 50,000 edible plant species in the world, at least 10,000 species are cereal grains. Three major cereal crops, rice (Oryza sativa), maize (Zea mays), and wheat (Triticum sp.), provide two-thirds of the world's food energy intake. Although crop yields have improved tremendously thanks to technological advances in the past 50 years, population increases and climate changes continue to threaten the sustainability of current crop productions. Whereas conventional and marker-assisted breeding programs continue to play a major role in crop improvement, genetic engineering has drawn an intense worldwide interest from the scientific community. In the past decade, genetic transformation technologies have revolutionized agricultural practices and millions of hectares of biotech crops have been cultured. Because of its unique ability to insert well-characterized gene sequences into the plant genome, genetic engineering can also provide effective tools to address fundamental biological questions. This technology is expected to continue to be an indispensable approach for both basic and applied research. Here, we overview briefly the development of the genetic transformation in the top seven cereals, namely maize, rice, wheat, barley (Hordeum vulgare), sorghum (Sorghum sp.), oat (Avena sativa), and millets. The advantages and disadvantages of the two major transformation methods, Agrobacterium tumefaciens-mediated and biolistic methods, are also discussed. PMID- 24166433 TI - Transgenes and their contributions to epigenetic research. AB - Shortly after gene transfer technologies had been established for different plant species, the first reports emerged about transgenes showing unexpected segregation patterns due to unstable expression. Initially, the erratic expression behavior of transgenes was considered a nuisance that impeded the impact and efficiency of a new technology. With the investigation of transgene silencing effects, however, it soon became clear that transgenes had helped us in a rather unexpected way to identify novel molecular pathways that were highly relevant to plant development and evolution. This article gives an account of a journey that started with the analysis of transgene-related silencing events and that led to the discovery of a new molecular world of small RNAs and epigenetic marks that regulate plant gene expression and adaptation to environmental changes. PMID- 24166434 TI - High-throughput analysis of rice genes by means of the heterologous full-length cDNA overexpressor (FOX)-hunting system. AB - Mutant populations are indispensable tools for investigating plant gene functions. Gain-of-function technology is one of the approaches used for the systematic production of mutant resources and activation tagging is a well established method to generate gain-of-function mutants in plants. As an alternative approach for the systematic generation of a gain-of-function mutant population, we developed the Full-length cDNA OvereXpressor (FOX)-hunting system in which full-length cDNAs (fl-cDNAs) are overexpressed in plants to quickly identify candidate genes. The FOX-hunting system was used for high-throughput analysis of rice (Oryza sativa) genes heterologously expressed in Arabidopsis thaliana (rice FOX Arabidopsis lines). A large screening to identify and characterize rice genes with rice FOX Arabidopsis lines revealed that one of the isolated genes, BROAD-SPECTRUM RESISTANCE 1 (BSR1) conferred multiple or broad spectrum disease resistance in both a dicotyledonous and monocotyledonous plant. We found that expression of rice fl-cDNAs without a homolog in Arabidopsis affected morphological traits. In addition, overexpression of homologous genes of rice and Arabidopsis led to a similar phenotype. Thus, we conclude that the FOX hunting system is an excellent heterologous system and offers a new tool with which to explore gene function in rice. PMID- 24166435 TI - From jellyfish to biosensors: the use of fluorescent proteins in plants. AB - The milestone discovery of green fluorescent protein (GFP) from the jellyfish Aequorea victoria, its optimisation for efficient use in plantae, and subsequent improvements in techniques for fluorescent detection and quantification have changed plant molecular biology research dramatically. Using fluorescent protein tags allows the temporal and spatial monitoring of dynamic expression patterns at tissue, cellular and subcellular scales. Genetically-encoded fluorescence has become the basis for applications such as cell-type specific transcriptomics, monitoring cell fate and identity during development of individual organs or embryos, and visualising protein-protein interactions in vivo. In this article, we will give an overview of currently available fluorescent proteins, their applications in plant research, the techniques used to analyse them and, using the recent development of an auxin sensor as an example, discuss the design principles and prospects for the next generation of fluorescent plant biosensors. PMID- 24166436 TI - Fluorescent protein marker lines in maize: generation and applications. AB - Fluorescent proteins (FP) have significantly impacted the way that we study plants in the past two decades. In the post-genomics era, these FP tools are in higher demand by plant scientists for studying the dynamics of protein localization, function, and interactions, and to translate sequence information to biological knowledge that can benefit humans. Although FP tools have been widely used in the model plant Arabidopsis, few FP resources have been developed for maize, one of the most important food crops worldwide, and an ideal species for genetic and developmental biology research. In an effort to provide the maize and cereals research communities with a comprehensive set of FP resources for different purposes of study, we generated more than 100 stable transformed maize FP marker lines, which mark most compartments in maize cells with different FPs. Additionally, we are generating driver and reporter lines, based on the principle of the pOp-LhG4 transactivation system, allowing specific expression or mis expression of any gene of interest to precisely study protein functions. These marker lines can be used not only for static protein localization studies, but will be useful for studying protein dynamics and interactions using kinetic microscopy methods, such as fluorescence recovery after photobleaching (FRAP), fluorescence correlation spectroscopy (FCS), and fluorescence resonance energy transfer (FRET). PMID- 24166437 TI - The use of fluorescence-activated cell sorting in studying plant development and environmental responses. AB - Fluorescence-Activated Cell Sorting (FACS) is a powerful tool that enables plant growth and development to be studied at the cellular level. Flow cytometry is used to isolate subpopulations of cells, such as those of specific cell types, or cells at particular developmental stages that have been marked with fluorescent proteins. Transgenic technology has given us the ability to generate plants that express fluorescent proteins, not just constitutively in particular cell types, but also dynamically in response to endogenous or external factors. By processing such transgenic lines with FACS, it is possible to isolate distinct populations of cells in a wide range of likely response states for further analysis. This is particularly useful for investigating biological mechanisms in plants because the control of growth and development is manifest at the cell type level. Furthermore, the specificity of the resulting data enables fine modelling of the transcriptional networks that exert systems-level control of the transcriptome; hence key regulators of responses and processes in the plant can be identified. In this review, the current state of the art for FACS methods in plants is explored by means of case studies of research in which cell sorting allowed us to make significant new discoveries. PMID- 24166438 TI - The moss Physcomitrella patens: methods and tools from cultivation to targeted analysis of gene function. AB - To comprehensively understand the major processes in plant biology, it is necessary to study a diverse set of species that represent the complexity of plants. This research will help to comprehend common conserved mechanisms and principles, as well as to elucidate those mechanisms that are specific to a particular plant clade. Thereby, we will gain knowledge about the invention and loss of mechanisms and their biological impact causing the distinct specifications throughout the plant kingdom. Since the establishment of transgenic plants, these studies concentrate on the elucidation of gene functions applying an increasing repertoire of molecular techniques. In the last two decades, the moss Physcomitrella patens joined the established set of plant models based on its evolutionary position bridging unicellular algae and vascular plants and a number of specific features alleviating gene function analysis. Here, we want to provide an overview of the specific features of P. patens making it an interesting model for many research fields in plant biology, to present the major achievements in P. patens genetic engineering, and to introduce common techniques to scientists who intend to use P. patens as a model in their research activities. PMID- 24166439 TI - Engineering metabolic pathways in plants by multigene transformation. AB - Metabolic engineering in plants can be used to increase the abundance of specific valuable metabolites, but single-point interventions generally do not improve the yields of target metabolites unless that product is immediately downstream of the intervention point and there is a plentiful supply of precursors. In many cases, an intervention is necessary at an early bottleneck, sometimes the first committed step in the pathway, but is often only successful in shifting the bottleneck downstream, sometimes also causing the accumulation of an undesirable metabolic intermediate. Occasionally it has been possible to induce multiple genes in a pathway by controlling the expression of a key regulator, such as a transcription factor, but this strategy is only possible if such master regulators exist and can be identified. A more robust approach is the simultaneous expression of multiple genes in the pathway, preferably representing every critical enzymatic step, therefore removing all bottlenecks and ensuring completely unrestricted metabolic flux. This approach requires the transfer of multiple enzyme-encoding genes to the recipient plant, which is achieved most efficiently if all genes are transferred at the same time. Here we review the state of the art in multigene transformation as applied to metabolic engineering in plants, highlighting some of the most significant recent advances in the field. PMID- 24166440 TI - Transformation of leguminous plants to study symbiotic interactions. AB - Legume plants are important in agriculture because they represent an important source of protein for human and animal consumption. This high protein content results from their capacity to use atmospheric nitrogen for their nutrition as a consequence of their symbiotic interaction with rhizobia. Understanding this interaction at the molecular level is a prerequisite for its better use in agriculture and for the long term objective of its transfer to other crops. Agrobacterium-mediated transformation is a tool of choice for studying this interaction and for unraveling the function of the different genes discovered through classical genetic approaches. However, legume plants are often recalcitrant to regeneration and transformation. This paper describes the technology developments (regeneration, transformation, insertion mutagenesis) related to Agrobacterium transformations that were established in the legume plants, as well as different examples of the technology developments or gene discoveries resulting from these studies. PMID- 24166441 TI - Role of plant expression systems in antibody production for passive immunization. AB - Passive immunization is a method to achieve immediate protection against infectious agents by administering pathogen-specific antibodies. It has proven to be lifesaving for many acute infections, and it is now also used for cancer treatment. Passive immunization therapies, however, are extremely expensive because they require large amounts of specific antibodies that are produced predominantly in mammalian expression systems. The cost for manufacturing plant made antibodies is estimated to be comparatively low since plant production systems require relatively less capital investments. In addition, they are not prone to mammalian pathogens, which also eases downstream processing along with making it a safe expression system. Moreover, some of the recent developments in transient expression have enabled rapid, cGMP (current Good Manufacturing Practices) compliant manufacturing of antibodies. Whether lower production costs will be reflected in a lower market price for purified antibodies will be known when more plant-produced antibodies come to the market. Promisingly, the current molecular techniques in the field of in planta expression have enabled high-level production of a variety of antibodies in different plant organs, like roots/tubers/fruits, leaves and seeds, of a variety of plants, like potato, tobacco, maize, rice, tomato and pea, providing a very wide range of possible plant-based passive immunization therapies. For instance, the production of antibodies in edible tissues would allow for a unique, convenient, needle-less, oral passive immunization at the gastric mucosal surface. The technological advances, together with the innate capacity of plant tissues to assemble complex antibodies, will enable carving a niche in the antibody market. This non exhaustive review aims to shed light on the role of plants as a flexible expression system for passive immunotherapy, which we envisage to progress alongside the conventional production platforms to manufacture specialized antibodies. PMID- 24166443 TI - Transfer of knowledge about flowering and vegetative propagation from model species to bulbous plants. AB - The extensive characterization of plant genes and genome sequences summed to the continuous development of biotechnology tools, has played a major role in understanding biological processes in plant model species. The challenge for the near future is to generate methods and pipelines for an efficient transfer of this knowledge to economically important crops and other plant species. In the case of flower bulbs, which are economically very important for the ornamental industry, flowering time control and vegetative propagation constitute the most relevant processes for agronomical improvements. Those processes have been reasonably studied in reference species, making them excellent candidates for translational investigations in bulbous plant species. The approaches that can be taken for the transfer of biological knowledge from model to non-model species can be roughly categorized as "bottom-up" or "top-down". The former approach usually goes from individual genes to systems, also known as a "gene-by-gene" approach. It assumes conservation of molecular pathways and therefore makes use of sequence homology searches to identify candidate genes. "Top-down" methodologies go from systems to genes, and are e.g. based on large scale transcriptome profiling via heterologous microarrays or RNA sequencing, followed by the identification of associations between phenotypes, genes, and gene expression patterns and levels. In this review, examples of the various knowledge transfer approaches are provided and pros and cons are discussed. Due to the latest developments in transgenic research and next generation sequencing and the emerging of systems biology as a matured research field, transfer of knowledge concerning flowering time and vegetative propagation capacity in bulbous species are now within sight. PMID- 24166442 TI - Biotechnology of nutrient uptake and assimilation in plants. AB - Plants require a complex balance of mineral nutrients to reproduce successfully. Because the availability of many of these nutrients in the soil is compromised by several factors, such as soil pH, cation presence, and microbial activity, crop plants depend directly on nutrients applied as fertilizers to achieve high yields. However, the excessive use of fertilizers is a major environmental concern due to nutrient leaching that causes water eutrophication and promotes toxic algae blooms. This situation generates the urgent need for crop plants with increased nutrient use efficiency and better-designed fertilization schemes. The plant biology revolution triggered by the development of efficient gene transfer systems for plant cells together with the more recent development of next generation DNA and RNA sequencing and other omics platforms have advanced considerably our understanding on the molecular basis of plant nutrition and how plants respond to nutritional stress. To date, genes encoding sensors, transcription factors, transporters, and metabolic enzymes have been identified as potential candidates to improve nutrient use efficiency. In addition, the study of other genetic resources, such as bacteria and fungi, allows the identification of alternative mechanisms of nutrient assimilation, which are potentially applicable in plants. Although significant progress in this respect has been achieved by conventional breeding, in this review we focus on the biotechnological approaches reported to date aimed at boosting the use of the three most limiting nutrients in the majority of arable lands: nitrogen, phosphorus, and iron. PMID- 24166444 TI - Directed genome engineering for genome optimization. AB - The ability to develop nucleases with tailor-made activities for targeted DNA double-strand break induction at will at any desired position in the genome has been a major breakthrough to make targeted genome optimization feasible in plants. The development of site specific nucleases for precise genome modification has expanded the repertoire of tools for the development and optimization of traits, already including mutation breeding, molecular breeding and transgenesis.Through directed genome engineering technology, the huge amount of information provided by genomics and systems biology can now more effectively be used for the creation of plants with improved or new traits, and for the dissection of gene functions. Although still in an early phase of deployment, its utility has been demonstrated for engineering disease resistance, herbicide tolerance, altered metabolite profiles, and for molecular trait stacking to allow linked transmission of transgenes. In this article, we will briefly review the different approaches for directed genome engineering with the emphasis on double strand break (DSB)-mediated engineering to-wards genome optimization for crop improvement and towards the acceleration of functional genomics. PMID- 24166445 TI - Gene targeting in plants: 25 years later. AB - Only five years after the initiation of transgenic research in plants, gene targeting (GT) was achieved for the first time in tobacco. Unfortunately, the frequency of targeted integration via homologous recombination (HR) was so low in comparison to random integration that GT could not be established as a feasible technique in higher plants. It took another 25 years and great effort to develop the knowledge and tools necessary to overcome this challenge, at least for some plant species. In some cases, the overexpression of proteins involved in HR or the use of negative selectable markers improved GT to a certain extent. An effective solution to this problem was developed in 1996, when a sequence specific endonuclease was used to induce a double-strand break (DSB) at the target locus. Thus, GT frequencies were enhanced dramatically. Thereafter, the main limitation was the absence of tools needed to induce DSBs at specific sites in the genome. Such tools became available with the development of zinc finger nucleases (ZFNs), and a breakthrough was achieved in 2005 when ZFNs were used to target a marker gene in tobacco. Subsequently, endogenous loci were targeted in maize, tobacco and Arabidopsis. Recently, our toolbox for genetic engineering has expanded with the addition of more types of site-specific endonucleases, meganucleases, transcription activator-like effector nucleases (TALENs) and the CRISPR/Cas system. We assume that targeted genome modifications will become routine in the near future in crop plants using these nucleases along with the newly developed in planta GT technique. PMID- 24166446 TI - From Agrobacterium to viral vectors: genome modification of plant cells by rare cutting restriction enzymes. AB - Researchers and biotechnologists require methods to accurately modify the genome of higher eukaryotic cells. Such modifications include, but are not limited to, site-specific mutagenesis, site-specific insertion of foreign DNA, and replacement and deletion of native sequences. Accurate genome modifications in plant species have been rather limited, with only a handful of plant species and genes being modified through the use of early genome-editing techniques. The development of rare-cutting restriction enzymes as a tool for the induction of site-specific genomic double-strand breaks and their introduction as a reliable tool for genome modification in animals, animal cells and human cell lines have paved the way for the adaptation of rare-cutting restriction enzymes to genome editing in plant cells. Indeed, the number of plant species and genes which have been successfully edited using zinc finger nucleases (ZFNs), transcription activator-like effector nucleases (TALENs) and engineered homing endonucleases is on the rise. In our review, we discuss the basics of rare-cutting restriction enzyme-mediated genome-editing technology with an emphasis on its application in plant species. PMID- 24166447 TI - Engineered plant minichromosomes. AB - Minichromosomes offer an enormous potential for plant breeding and biotechnology, because they may simultaneously transfer and stably express multiple genes. Segregating independently of their host chromosomes, they provide a platform for accelerating plant breeding. Minichromosomes can be established from cloned components in vivo (bottom up) or via engineering of natural chromosomes (top down). When they possess functional centromeres and telomeres, they should be stably inherited, but their meiotic transmission rate is below that of endogenous chromosomes. To achieve the customized generation and control the regular transmission of minichromosomes are important challenges for applied research in chromosome biology. Here, construction and biology of plant minichromosomes are compared with data available for yeast and animal systems. PMID- 24166448 TI - Transformation of the mitochondrial genome. AB - Although mitochondrial transformation is highly desirable in mammals and plants, it is only possible in two unicellular organisms, the budding yeast Saccharomyces cerevisiae and the unicellular green alga Chlamydomonas reinhardtii. Here, we give an overview of the attempts made to transform mitochondria of mammals and plants and the possible reasons for their failure. This review briefly describes the mitochondrial transformation principles in yeast and describes in more detail the transformation and its applications in Chlamydomonas. PMID- 24166449 TI - Direct-acting oral anticoagulants: the brain gets a break. PMID- 24166450 TI - Curing "moral disability": brain trauma and self-control in Victorian science and fiction. AB - While, historically, the disabled body has appeared in literature as "monstrous," burgeoning psychological theories of the Victorian period predicated an unusual shift. In a culture of sexual anxiety and fears of devolution and moral decay, the physically disabled and "weak" are portrayed as strangely free from moral corruption. Unlike the cultural link between deviance and disability witnessed in the medical literature and eugenic approach to generation, authors of narrative fiction-particularly Charles Dickens, but Wilkie Collins, Charlotte Yonge, and others as well-portray disabled characters as "purified," and trauma itself as potentially sanitizing. This present paper argues that such constructions were made possible by developments in the treatment of insanity. "Curing 'Moral Disability': Brain Trauma and Self-Control in Victorian Fiction," examines the concept of trauma-as-cure. Throughout the Victorian period, case studies on brain trauma appeared in widely circulated journals like the Lancet, concurrently with burgeoning theories about psychological disturbance and "moral insanity." While not widely practiced until the early twentieth century, attempts at surgical "cures" aroused curiosity and speculation-the traumatic event that could free sufferers from deviance. This work provides a unique perspective on representations of disability as cure in the nineteenth century as a means of giving voice to the marginalized, disabled, and disempowered. PMID- 24166451 TI - Fighting through fiction. PMID- 24166452 TI - Facile control of long range orientation in mesoporous carbon films with thermal zone annealing velocity. AB - Ordered mesoporous carbons exhibit appealing properties for many applications, but their function and performance can depend critically on their structure. The in-plane orientation of 2D cylinders from the cooperative assembly of Pluronic P123 and resol has been controlled by application of cold zone annealing (CZA). By varying the moving rate, the preferential in-plane orientation of the self assembled cylinders can be tuned through the entire 180 degrees range possible from phi = 50 degrees to phi = -130 degrees (relative to the moving direction). At a moving rate of 2 MUm s(-1), this simple and easy CZA process leads to cylinders that are well aligned parallel to the moving direction with a high orientational factor of S = 0.98. Moreover, the in-plane oriented cylinders can be nearly perfectly aligned transverse to the moving direction (S = 0.95) by simply decreasing the moving velocity to 0.5 MUm s(-1). We attribute the parallel alignment to the flow that develops from the motion of the thermal gradients, while the transverse alignment is related to flow cessation (inertial effect). The preferential orientation is retained through the carbonization process, but there is some degradation in orientation due to insufficient crosslinking of the resol during CZA; this effect is most prominent for the higher moving rates (less time for crosslinking), but can be overcome by post-CZA annealing at uniform elevated temperatures to further crosslink the resol. CZA is a simple and powerful method for fabricating well-aligned and self-assembled mesoporous carbon films over large areas. PMID- 24166453 TI - Direct differentiation of homogeneous human adipose stem cells into functional hepatocytes by mimicking liver embryogenesis. AB - The potential of adult human adipose tissue stem cells (hASCs) to differentiate into hepatocytes has generated much excitement over the possible use of hASCs in therapeutic applications. An understanding of the molecular mechanisms that underlie the plasticity of hASCs toward hepatocytes will help to make this possibility a reality. Herein, we show that a homogenous population of hASCs characterized by a high level of CD73, CD90, and CD105 express the pluripotent transcription factors OCT4, SOX2, NANOG, and SALL4 under proliferation conditions. A high level of activin A allows for hASCs acquiring the fate of definitive endoderm (DE) cells and expressing the specific transcription factors HEX, FOXA2, SOX17, and GATA4 synchronously. Using a reproducible three-stage method by mimicking liver embryogenesis, hASCs were directed to differentiate into functional hepatocytes. In the first stage, hASCs were induced to become DE cells by 2 days cultured in serum-free medium and 3 days of activin A treatment. Next, the presence of fibroblast growth factor (FGF) 4 and bone morphogenetic protein (BMP) 2 in the medium for 5 days induced efficient hepatic differentiation from DE cells. After 10 days of further maturated by the sequential exposure to hepatocyte growth factor (HGF), oncostatin M (OSM), and dexamethasone (DEX), the hASC-derived hepatocytes expressed mature hepatocytes marker and exhibited functional characterization, including albumin secretion, glycogen storage, urea production, activity of drug transporters, and cytochrome P450 activity. These findings will be useful for the implementation of hASC derived hepatocytes in therapeutic purposes, metabolic analyses, drug toxicity screening, and studies of hepatocyte function. PMID- 24166454 TI - The Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation incorporating both cystatin C and creatinine best predicts individual risk: a cohort study in 444 patients with chronic kidney disease. AB - BACKGROUND: The recently introduced CKD-EPIcreat-cys equation surpassed creatinine-based equations for GFR estimation in a large cross-sectional analysis. However, its performance to predict individual risk of CKD progression and death in patients with various underlying CKD etiologies is unknown. METHODS: We recruited 444 patients with CKD GFR categories 2-4 (eGFR 15-89 mL/min/1.73 m2); baseline eGFR was estimated by the established MDRD and CKD-EPIcreat equations and by the novel CKD-EPIcreat-cys equation. RESULTS: Patients were followed for 2.7+/-1.2 years for the occurrence of the combined predefined endpoint event: death, need for renal replacement therapy or halving of eGFR. The endpoint occurred in 62 patients. Reclassification from MDRD determined categories to CKD-EPIcreat-cys categories yielded net reclassification improvements for those with the endpoint event (NRIevents) of 27.4% (95% CI: 16.7 40.0%) and for those without the event (NRInon-events) of -3.1% (-8.2 to 1.6%). Similarly, reclassification from CKD-EPIcreat categories to CKD-EPIcreat-cys categories yielded an NRIevents of 22.6% (10.2-34.3%) and NRInon-events of -11.3% (-15.9 to -6.5%). Addition of albuminuria to each eGFR equation increased the calculated risk of the outcome for a net 26-32% of those who subsequently reached the endpoint, and reduced the calculated risk in a net 21-23% in non-event patients, but only minimally. CONCLUSIONS: The CKD-EPIcreat-cys equation assigned patients who went on to have the event to more appropriate CKD risk categories than MDRD and CKD-EPIcreat, but patients without the event to less appropriate categories than CKD-EPIcreat. Addition of albuminuria marginally improved risk classification for those who had the event. PMID- 24166455 TI - Intensified home hemodialysis: clinical benefits, risks and target populations. AB - Intensive home hemodialysis (IHHD) has emerged as an alternate treatment option for patients with end-stage renal disease and has several established and potential clinical benefits. These clinical advantages need to be tempered against a growing appreciation of the risks of IHHD, including a potentially higher rate of vascular access interventions. Identifying who might be an eligible and optimal candidate for IHHD is paramount to its expansion as an important form of renal replacement therapy. In the following review, we will provide a working definition of IHHD, discuss its major clinical benefits/risks and identify potential target populations to whom this therapy can be provided. PMID- 24166456 TI - Role of PCSK9 and IDOL in the pathogenesis of acquired LDL receptor deficiency and hypercholesterolemia in nephrotic syndrome. AB - BACKGROUND: Nephrotic syndrome (NS) leads to elevation of serum total and LDL cholesterol. This is largely due to impaired LDL clearance, which is caused by hepatic LDL receptor (LDLR) deficiency despite normal LDLR mRNA expression, pointing to a post-transcriptional process. The mechanism(s) by which NS causes LDLR deficiency is not known. By promoting degradation of LDLR, Proprotein Convertase Subtilisin/Kexin type 9 (PCSK9) and inducible degrader of the LDL receptor (IDOL) play a major role in post-translational regulation of LDLR. We, therefore, tested the hypothesis that LDLR deficiency despite its normal gene expression in NS may be due to upregulation of hepatic PCSK9 and IDOL. METHODS: LDLR, IDOL and PCSK9 expressions and nuclear translocation of liver X receptor (LXR) that regulates IDOL expression were determined in the liver of rats with puromycin-induced NS and control (CTL) rats. RESULTS: Compared with the CTLs, the NS rats showed marked elevation of serum total and LDL cholesterol and a significant reduction in hepatic LDLR protein expression. This was accompanied by marked upregulation of hepatic PCSK9 and IDOL expressions and heightened LXR activation. CONCLUSIONS: LDLR deficiency, hypercholesterolemia and elevated plasma LDL in NS are associated with upregulation of PCSK9 and IDOL. Interventions targeting these pathways may be effective in the management of hypercholesterolemia and the associated cardiovascular and other complications of NS. PMID- 24166458 TI - Iron toxicity: relevance for dialysis patients. AB - Iron deficiency is common among patients with advanced kidney disease, particularly those requiring hemodialysis. Intravenous iron is a convenient treatment to supplement iron and is widely used among hemodialysis patients. Its efficacy is well established that, with treatment, hemoglobin levels rise and erythropoiesis-stimulating agent dose requirements are reduced. However, the safety of intravenous iron with respect to patient-centered outcomes has not been adequately studied. A variety of studies have indicated potential safety concerns, but most have been of small numbers of patients and with end points studied that have unclear clinical relevance. In this study, issues related to iron toxicity are reviewed. PMID- 24166457 TI - Repulsive guidance cue semaphorin 3A in urine predicts the progression of acute kidney injury in adult patients from a mixed intensive care unit. AB - BACKGROUNDS: Predicting the development of acute kidney injury (AKI) in the critical care setting is challenging. Although several biomarkers showed somewhat satisfactory performance for detecting established AKI even in a heterogeneous disease-oriented population, identification of new biomarkers that predict the development of AKI accurately is urgently required. METHODS: A single-center prospective observational cohort study was undertaken to evaluate for the first time the reliability of the newly identified biomarker semaphorin 3A for AKI diagnosis in heterogeneous intensive care unit populations. In addition to five urinary biomarkers of L-type fatty acid-binding protein (L-FABP), neutrophil gelatinase-associated lipocalin (NGAL), IL-18, albumin and N-acetyl-beta-d glucosaminidase (NAG), urinary semaphorin 3A was measured at intensive care unit (ICU) admission. RESULTS AND CONCLUSION: Three hundred thirty-nine critically ill adult patients were recruited for this study. Among them, 131 patients (39%) were diagnosed with AKI by the RIFLE criteria and 66 patients were diagnosed as AKI at post-ICU admission (later-onset AKI). Eighty-four AKI patients showed worsening severity during 1 week observation (AKI progression). Although L-FABP, NGAL and IL-18 showed significantly higher area under the curve (AUC)-receiver operating characteristic (ROC) values than semaphorin 3A in detecting established AKI, semaphorin 3A was able to detect later-onset AKI and AKI progression with similar AUC-ROC values compared with the other five biomarkers [AUC-ROC (95% CI) for established AKI 0.64 (0.56-0.71), later-onset AKI 0.71 (0.64-0.78), AKI progression 0.71 (0.64-0.77)]. Urinary semaphorin 3A was not increased in non progressive established AKI, while the other biomarkers were elevated regardless of further progression. Finally, sepsis did not have any impact on semaphorin 3A while the other urinary biomarkers were increased with sepsis. Semaphorin 3A is a new biomarker of AKI which may have a distinct predictive use for AKI progression when compared with other AKI biomarkers. PMID- 24166459 TI - The prognostic value of time needed on dialysis in patients with delayed graft function. AB - INTRODUCTION: We hypothesize that in patients with delayed graft function (DGF), the need for a longer time needed on dialysis (TND) post-kidney transplant is associated with poorer long-term function and an increase in complications. METHODS: This was a retrospective chart review involving collaboration between Western University (WU) Renal Transplant Program of London, Ontario and the Saskatchewan renal transplant program (SRTP). A total of 774 patients (567 WU and 207 SRTP) received kidney transplants between 2004 and 2011, of which 83 patients with deceased donor transplants (59 WU and 24 SRTP) developed DGF, defined as the need for dialysis in the first week posttransplant. RESULTS: Patients with DGF were divided into three groups depending on TND [group 1: <7 days (n = 52), group 2: 7-14 days (n = 13) and group 3 (n = 18): >14 days]. The creatinine clearance (CrCl) at 30 days (42.5, 33.8, 20.0 cc/min; P < 0.001) and 1 year (56.7, 49.2, 37.3 cc/min, P = 0.031) were significantly different between the three groups. Multivariate regression analysis identified length of TND posttransplant (beta = 0.5, P < 0.001) and donation after cardiac death (DCD) donor (beta = 19.5, P < 0.001) as the most significant predictors of CrCl at 1 year in these patients with DGF. DCD kidneys with DGF had a higher CrCl at 1 year and fewer readmissions in the first year compared with non-DCD kidneys with DGF. DISCUSSION: Our study suggests that increased TND is associated with worse CrCl at 1 year. The data also support the hypothesis of a different mechanism for DGF in DCD and non-DCD kidneys. PMID- 24166460 TI - Fluid flow shear stress over podocytes is increased in the solitary kidney. AB - BACKGROUND: Glomerular hyperfiltration is emerging as the key risk factor for progression of chronic kidney disease (CKD). Podocytes are exposed to fluid flow shear stress (FFSS) caused by the flow of ultrafiltrate within Bowman's space. The mechanism of hyperfiltration-induced podocyte injury is not clear. We postulated that glomerular hyperfiltration in solitary kidney increases FFSS over podocytes. METHODS: Infant Sprague-Dawley rats at 5 days of age and C57BL/6J 14 week-old adult mice underwent unilateral nephrectomy. Micropuncture and morphological studies were then performed on 20- and 60-day-old rats. FFSS over podocytes in uninephrectomized rats and mice was calculated using the recently published equation by Friedrich et al. which includes the variables-single nephron glomerular filtration rate (SNGFR), filtration fraction (f), glomerular tuft diameter (2RT) and width of Bowman's space (s). RESULTS: Glomerular hypertrophy was observed in uninephrectomized rats and mice. Uninephrectomized rats on Day 20 showed a 2.0-fold increase in SNGFR, 1.0-fold increase in 2RT and 2.1-fold increase in FFSS, and on Day 60 showed a 1.9-fold increase in SNGFR, 1.3 fold increase in 2RT and 1.5-fold increase in FFSS, at all values of modeled 's'. Similarly, uninephrectomized mice showed a 2- to 3-fold increase in FFSS at all values of modeled SNGFR. CONCLUSIONS: FFSS over podocytes is increased in solitary kidneys in both infant rats and adult mice. This increase is a consequence of increased SNGFR. We speculate that increased FFSS caused by reduced nephron number contributes to podocyte injury and promotes the progression of CKD. PMID- 24166462 TI - Efficacy and safety of radiofrequency catheter ablation for atrial fibrillation in chronic hemodialysis patients. AB - BACKGROUND: Radiofrequency catheter ablation (RFCA) is increasingly performed for the treatment of atrial fibrillation (AF), but it is problematic because the use of anti-arrhythmic agents is largely restricted in patients undergoing hemodialysis (HD) therapy. However, little is known about the long-term clinical outcomes of AF after RFCA in HD patients. METHODS: Between 2002 and 2008, 16 HD patients (age: 63.8 +/- 7.4 years, 75.0% men) underwent RFCA for AF at the Toyota Kosei Hospital. We investigated the long-term results and mortality of RFCA for AF in HD patients and compared them with those of 111 non-HD patients (age: 58.6 +/- 10.0 years, 78.3% male) who received the same procedures. RESULTS: During the follow-up (64.3 +/- 25.4 months in HD patients, 70.5 +/- 20.2 months in non-HD patients) after the initial RFCA procedure, sinus rhythm was restored in 4 HD patients (25%) and in 45 non-HD patients (40.5%). Multiple procedures were performed in 12 HD patients and in 57 non-HD patients. After the final procedure, 13 HD patients (81.3%) and 92 non-HD patients (82.9%) were free of atrial arrhythmia and symptoms. Of importance, Kaplan-Meier analysis did not demonstrate any significant differences in the atrial arrhythmia-free rate after the last procedure between HD patients and the control group matched after propensity score analysis despite higher all-cause mortality in HD patients than in non-HD patients. CONCLUSIONS: During 5-years of follow-up, the use of multiple RFCA procedures for AF in patients undergoing HD was favorable, whereas the use of a single procedure was disappointing. Multiple RFCA procedures can be an efficient approach to the treatment of AF in HD patients. PMID- 24166463 TI - LMX1B mutations with nails and kneecaps: a new paradigm? PMID- 24166461 TI - Consensus statement on screening, diagnosis, classification and treatment of endemic (Balkan) nephropathy. AB - Currently used diagnostic criteria in different endemic (Balkan) nephropathy (EN) centers involve different combinations of parameters, various cut-off values and many of them are not in agreement with proposed international guidelines. Leaders of EN centers began to address these problems at scientific meetings, and this paper is the outgrowth of those discussions. The main aim is to provide recommendations for clinical work on current knowledge and expertise. This document is developed for use by general physicians, nephrologists, urologist, public health experts and epidemiologist, and it is hoped that it will be adopted by responsible institutions in countries harboring EN. National medical providers should cover costs of screening and diagnostic procedures and treatment of EN patients with or without upper urothelial cancers. PMID- 24166464 TI - A population approach to renal replacement therapy epidemiology: lessons from the EVEREST study. AB - The marked variation that exists in renal replacement therapy (RRT) epidemiology between countries and within countries requires careful systematic examination if the root causes are to be understood. While individual patient-level studies are undoubtedly important, there is a complementary role for more population-level, area-based studies--an aetiological approach. The EVEREST Study adopted such an approach, bringing RRT incidence rates, survival and modality mix together with macroeconomic factors, general population factors and renal service organizational factors for up to 46 countries. This review considers the background to EVEREST, its key results and then the main methodological lessons and their potential application to ongoing work. PMID- 24166465 TI - Intra-renal transfection of heat shock protein 90 alpha or beta (Hsp90alpha or Hsp90beta) protects against ischemia/reperfusion injury. AB - BACKGROUND: We previously reported that radicicol (Hsp90 inhibitor) induced a reduction in the renal blood flow and glomerular filtration rate, in part due to a reduction in urinary NO2/NO3 excretion, suggesting that Hsp90 regulates renal vascular tone in physiological conditions. However, there is a lack of information concerning Hsp90alpha or Hsp90beta role on eNOS activity and their association with acute kidney injury (AKI) characterized by an inadequate NO production. This study evaluated the effects of Hsp90alpha or Hsp90beta intra renal transfection under ischemia/reperfusion (IR) injury. METHODS: Uninephrectomized (Nx) rats were intra-renally transfected through injections with Hsp90alpha or Hsp90beta cloned into pcDNA3.1(+) or empty vector (EV) at 48 h before inducing IR, as indicated in the following groups: (i) Nx+sham, (ii) Nx+IR, (iii) Nx+IR+EV, (iv) Nx+IR+Hsp90alpha and (v) Nx+IR+Hsp90beta. After 24 h, physiological, histopathological, biochemical and molecular studies were performed. RESULTS: IR-induced renal dysfunction, structural injury, tubular proliferation, the elevation of urinary Hsp72 and the reduction of urinary NO2/NO3 excretion. These alterations were associated with reduced eNOS-Hsp90 coupling and changes in the eNOS phosphorylation state mediated through a reduction in PKCalpha and increased Rho kinase expression. In contrast, intra renal transfection of Hsp90alpha or Hsp90beta prevented IR injury that was associated with the restoration of eNOS-Hsp90 coupling, eNOS activating phosphorylation and PKCalpha and Rho kinase levels. CONCLUSIONS: Here we showed that eNOS-Hsp90 uncoupling plays a critical role in promoting NO reduction during IR. This effect was effectively reversed through Hsp90alpha or Hsp90beta intra renal transfection, suggesting their implication in regulating NO/eNOS pathway and the renal vascular tone. PMID- 24166466 TI - p-cresyl sulphate has pro-inflammatory and cytotoxic actions on human proximal tubular epithelial cells. AB - BACKGROUND: p-Cresyl sulphate (p-CS) and p-cresyl glucuronide (p-CG) are uraemic toxins that exhibit pro-inflammatory features in leukocytes and are associated with the progression of chronic kidney disease (CKD). Tubular cells are key targets of nephrotoxic agents and tubular cell death and activation contribute to the progression of CKD. However, the potential toxicity of these compounds on tubular cells is not fully understood. More specifically, apoptosis has never been studied. METHODS: HK-2 human proximal tubular epithelial cells were studied. Cell death was evaluated by flow cytometry of DNA content and by morphology. Gene expression was studied by real-time (RT)-PCR. Protein expression was studied by western blot and flow cytometry. RESULTS: Long-term (7 days) exposure to p-CS induced apoptosis in HK-2 cells in a concentration-dependent manner. In addition, short-term (3 h) exposure to p-CS promoted the expression of the TWEAK receptor Fn14, cooperated with TWEAK in promoting cell death and increased inflammatory gene expression. Albumin was cytotoxic and increased the inflammatory response to p-CS concentrations found in the circulation of non-dialysis CKD patients. In contrast, no biological actions of p-CG were observed on HK-2 cells, either alone or in combination with p-CS. CONCLUSIONS: This study demonstrates for the first time that p-CS has pro-apoptotic and pro-inflammatory effects on tubular cells. These results identify mechanisms by which uraemic toxicity may contribute to CKD progression. PMID- 24166467 TI - Do FGF23 levels change over time and if yes, what do such changes mean? PMID- 24166468 TI - Rationale and design of the Mineralocorticoid Receptor Antagonists in End-Stage Renal Disease Study (MiREnDa). AB - BACKGROUND: End-stage renal disease (ESRD) patients exhibit an extraordinarily high annual mortality secondary to cardiac and vascular causes, particularly sudden cardiac death (SCD). Left ventricular (LV) hypertrophy is a frequent finding and constitutes an independent predictor of mortality risk in these patients. Mineralocorticoid receptor antagonists (MRAs) are cardioprotective in heart failure patients and effectively reduce LV mass, but are considered inappropriate in patients with severe renal impairment, given their potential to cause hyperkalaemia. Recent data from small clinical studies suggest that MRAs may be safe in patients undergoing regular haemodialysis, but cardiovascular (CV) protection in these patients is unclear. We here review the literature on CV effects of MRA in dialysis patients and report the design of the Mineralocorticoid Receptor antagonists in End-stage renal Disease (MiREnDa) trial. METHODS: The MiREnDa trial is a prospective randomized, placebo controlled, double-blind, parallel group, multi-centre, intervention study investigating the effects of spironolactone (50 mg daily) compared with placebo in maintenance haemodialysis patients. The change in LV mass index (LVMI) as assessed by cardiac magnet resonance imaging (CMR) constitutes the primary efficacy end point. Secondary end points include changes in LV geometry and function, office and 24-h ambulatory blood pressure, cardiac arrhythmias, vascular function parameters, measures of heart failure and quality of life. Pre dialysis potassium levels and the incidence of threatening hyperkalaemia (pre dialysis potassium >=6.5 mmol/L) constitute safety end points. CONCLUSIONS: MiREnDa will investigate CV efficacy and safety of spironolactone in haemodialysis patients [clinical trials.gov NCT01691053]. PMID- 24166469 TI - The role of heparanase and the endothelial glycocalyx in the development of proteinuria. AB - Proteinuria is a hallmark of many glomerular diseases and an independent risk factor for the progression of renal failure. Proteinuria results from damage to the glomerular filtration barrier (GFB), which plays a critical role in size- and charge-selective filtration. The GFB consists of three layers, which is the fenestrated endothelium that is covered by the glycocalyx, the podocytes and the intervening glomerular basement membrane. Defects in one of the three layers in the GFB can lead to the development of proteinuria. Heparan sulphate (HS) is a negatively charged polysaccharide that is abundantly expressed in all layers of the GFB. HS expression in the GFB is reduced in the majority of patients with proteinuria, which is associated with an increased glomerular expression of the HS-degrading enzyme heparanase. The primary role of HS in the development of proteinuria has been challenged after the establishment of several genetically engineered mouse models with an altered HS expression that did not display development of overt proteinuria. However, in a recent study, we showed that heparanase is essential for the development of proteinuria in diabetic nephropathy, which suggests that loss of HS contributes to the development of proteinuria. Recent studies also further highlight the importance of the glomerular endothelial glycocalyx in charge-selective filtration and the development of proteinuria. This review aims to summarize our current knowledge on the role of in particular HS and heparanase in the development of proteinuria. PMID- 24166470 TI - Should current criteria for detecting and repairing arteriovenous fistula stenosis be reconsidered? Interim analysis of a randomized controlled trial. AB - BACKGROUND: The vascular access guidelines recommend that arteriovenous fistulas (AVFs) with access dysfunction and an access blood flow (Qa) <300-500 mL/min be referred for stenosis imaging and treatment. Significant (>50%) stenosis, however, may be detected in a well-functioning AVF with a Qa > 500 mL/min, too, but whether it is worth correcting or not remains to be seen. METHODS: In October 2006, we began an open randomized controlled trial enrolling patients with an AVF with subclinical stenosis and Qa > 500 mL/min, to see how elective stenosis repair [treatment group (TX)] influenced access failure (thrombosis or impending thrombosis requiring access revision), or loss and the related cost compared with stenosis correction according to the guidelines, i.e. after the onset of access dysfunction or a Qa < 400 mL/min [control group (C)]. An interim analysis was performed in July 2012, by which time the trial had enrolled 58 patients (30 C and 28 TX). RESULTS: TX led to a relative risk of 0.47 [95% confidence interval (CI): 0.17-1.15] for access failure (P = 0.090), 0.37 [95% CI: 0.12-0.97] for thrombosis (P = 0.033) and 0.36 [95% CI: 0.09-0.99] for access loss (P = 0.041). In the setting of our study (in which all surgery was performed as in patient procedure) no significant differences in costs emerged between the two strategies. The mean incremental cost-effectiveness ratio for TX was ?282 or ?321 to avoid one episode of thrombosis or access loss, respectively. CONCLUSIONS: Our interim analysis showed that elective repair of subclinical stenosis in AVFs with Qa > 500 mL/min cost-effectively reduces the risk of thrombosis and access loss in comparison with the approach of the Kidney Disease Outcomes Quality Initiative (KDOQI) guidelines, raising the question of whether the currently recommended criteria for assessing and treating stenosis should be reconsidered. PMID- 24166474 TI - Biotin-responsive Basal Ganglia disease: a treatable differential diagnosis of leigh syndrome. AB - Biotin-responsive basal ganglia disease (BBGD) is an autosomal recessive disorder, which is caused by mutations in the SLC19A3 gene. BBGD typically causes (sub)acute episodes with encephalopathy and subsequent neurological deterioration. If untreated, the clinical course may be fatal. Our report on a 6 year-old child with BBGD highlights that the disease is a crucial differential diagnosis of Leigh syndrome. Therefore, biotin and thiamine treatment is recommended for any patient with symmetrical basal ganglia lesions and neurological symptoms until BBGD is excluded. In addition, we exemplify that deformation-field-based morphometry of brain magnetic resonance images constitutes a novel quantitative tool, which might be very useful to monitor disease course and therapeutic effects in neurometabolic disorders. PMID- 24166472 TI - KCa3.1 mediates activation of fibroblasts in diabetic renal interstitial fibrosis. AB - BACKGROUND: Fibroblast activation plays a critical role in diabetic nephropathy (DN). The Ca2+-activated K+ channel KCa3.1 mediates cellular proliferation of many cell types including fibroblasts. KCa3.1 has been reported to be a potential molecular target for pharmacological intervention in a diverse array of clinical conditions. However, the role of KCa3.1 in the activation of myofibroblasts in DN is unknown. These studies assessed the effect of KCa3.1 blockade on renal injury in experimental diabetes. METHODS: As TGF-beta1 plays a central role in the activation of fibroblasts to myofibroblasts in renal interstitial fibrosis, human primary renal interstitial fibroblasts were incubated with TGF-beta1+/- the selective inhibitor of KCa3.1, TRAM34, for 48 h. Two streptozotocin-induced diabetic mouse models were used in this study: wild-type KCa3.1+/+ and KCa3.1-/- mice, and secondly eNOS-/- mice treated with or without a selective inhibitor of KCa3.1 (TRAM34). Then, markers of fibroblast activation and fibrosis were determined. RESULTS: Blockade of KCa3.1 inhibited the upregulation of type I collagen, fibronectin, alpha-smooth muscle actin, vimentin and fibroblast specific protein-1 in renal fibroblasts exposed to TGF-beta1 and in kidneys from diabetic mice. TRAM34 reduced TGF-beta1-induced phosphorylation of Smad2/3 and ERK1/2 but not P38 and JNK MAPK in interstitial fibroblasts. CONCLUSIONS: These results suggest that blockade of KCa3.1 attenuates diabetic renal interstitial fibrogenesis through inhibiting activation of fibroblasts and phosphorylation of Smad2/3 and ERK1/2. Therefore, therapeutic interventions to prevent or ameliorate DN through targeted inhibition of KCa3.1 deserve further consideration. PMID- 24166473 TI - Ganglioside GD2 as a therapeutic target for antibody-mediated therapy in patients with osteosarcoma. AB - BACKGROUND: Survival outcomes for patients with osteosarcoma have remained stagnant over the past 30 years. Targeting of ganglioside GD2, a glycosphingolipid on the cell surface of some tumors, with immunotherapy has resulted in improved outcomes for patients with neuroblastoma. In the current study, the expression pattern of GD2 was examined in osteosarcoma. METHODS: Immunohistochemistry was performed on osteosarcoma samples from patients at the time of initial biopsy, definitive surgery, and disease recurrence. The intensity and location of staining were scored. Cell-based enzyme-linked immunoadsorbent assay was performed on osteosarcoma cell lines to quantitate the level of GD2 expression. RESULTS: Forty-four osteosarcoma samples were evaluated by immunohistochemistry, including 8 samples from the initial biopsy, 28 samples from the definitive surgery, and 8 samples from the time of disease recurrence. GD2 was expressed on all 44 osteosarcoma samples. Osteosarcoma tissue obtained at the time of disease recurrence demonstrated a higher intensity of staining compared with samples obtained at initial biopsy and definitive surgery (P = .016). The majority of osteosarcoma cell lines expressed GD2 at higher levels than the neuroblastoma cell line BE(2)-C. CONCLUSIONS: Ganglioside GD2 is highly expressed on osteosarcomas. Clinical trials are needed to assess the efficacy of targeting GD2 in patients with osteosarcoma. PMID- 24166475 TI - Ester vs. amide on folding: a case study with a 2-residue synthetic peptide. AB - Although known for their inferiority as hydrogen-bonding acceptors when compared to amides, esters are often found at the C-terminus of peptides and synthetic oligomers (foldamers), presumably due to the synthetic readiness with which they are obtained using protected peptide coupling, deploying amino acid esters at the C-terminus. When the H-bonding interactions deviate from regularity at the termini, peptide chains tend to "fray apart". However, the individual contributions of C-terminal esters in causing peptide chain end-fraying goes often unnoticed, particularly due to diverse competing effects emanating from large peptide chains. Herein, we describe a striking case of a comparison of the individual contributions of C-terminal ester vs. amide carbonyl as a H-bonding acceptor in the folding of a peptide. A simple two-residue peptide fold has been used as a testing case to demonstrate that amide carbonyl is far superior to ester carbonyl in promoting peptide folding, alienating end-fraying. This finding would have a bearing on the fundamental understanding of the individual contributions of stabilizing/destabilizing non-covalent interactions in peptide folding. PMID- 24166476 TI - On the use of [18F]DOPA as an imaging biomarker for transplanted islet mass. AB - AIM: Islet transplantation is being developed as a potential cure for patients with type 1 diabetes. There is a need for non-invasive imaging techniques for the quantification of transplanted islets, as current transplantation sites are associated with a substantial loss of islet viability. The dopaminergic metabolic pathway is present in the islets; therefore, we propose Fluorine-18 labeled L-3,4 dihydroxyphenylalanine ([18F]DOPA) as a biomarker for transplanted islet mass. METHODS: The expression of enzymes involved in the dopaminergic metabolic pathway was investigated in both native and transplanted human islets. The specific uptake of [18F]DOPA in islets and immortalized beta cells was studied in vitro by selective blocking of dopa decarboxylase (DDC). Initial in vivo PET imaging of viable subcutaneous human islets was performed using [18F]DOPA. RESULTS: DDC and vesicular monoamine transporter 2 are co-localized with insulin in the native human pancreas, and the expression is retained after transplantation. Islet uptake of the [18F]DOPA could be modulated by inhibiting DDC, indicating that the uptake followed the normal dopaminergic metabolic pathway. In vivo imaging revealed [18F]DOPA uptake at the site of the functional islet graft. CONCLUSION: Based on the in vitro and in vivo results presented in this study, we propose to further validate [18F]DOPA-PET as a sensitive imaging modality for imaging extrahepatically transplanted islets. PMID- 24166477 TI - In toto differentiation of human amniotic membrane towards the Schwann cell lineage. AB - Human amniotic membrane (hAM) is a tissue containing cells with proven stem cell properties. In its decellularized form it has been successfully applied as nerve conduit biomaterial to improve peripheral nerve regeneration in injury models. We hypothesize that viable hAM without prior cell isolation can be differentiated towards the Schwann cell lineage to generate a possible alternative to commonly applied tissue engineering materials for nerve regeneration. For in vitro Schwann cell differentiation, biopsies of hAM of 8 mm diameter were incubated with a sequential order of neuronal induction and growth factors for 21 days and characterized for cellular viability and the typical glial markers glial fibrillary acidic protein (GFAP), S100beta, p75 and neurotrophic tyrosine kinase receptor (NTRK) using immunohistology. The secretion of the neurotrophic factors brain-derived neurotrophic factor (BDNF) and glial cell-derived neurotrophic factor (GDNF) was quantified by ELISA. The hAM maintained high viability, especially under differentiation conditions (90.2 % +/- 41.6 day 14; 80.0 % +/- 44.5 day 21 compared to day 0). Both, BDNF and GDNF secretion was up-regulated upon differentiation. The fresh membrane stained positive for GFAP and p75 and NTRK, which was strongly increased after culture in differentiation conditions. Especially the epithelial layer within the membrane exhibited a change in morphology upon differentiation forming a multi-layered epithelium with intense accumulations of the marker proteins. However, S100beta was expressed at equal levels and equal distribution in fresh and cultured hAM conditions. Viable hAM may be a promising alternative to present formulations used for peripheral nerve regeneration. PMID- 24166479 TI - The effect of anthropogenic activity on the occurrence of Culicoides species in the South-Western Khomas Region, Namibia. AB - Certain species of midges in the genus Culicoides (Diptera: Ceratopogonidae) are vectors of several serious orbiviral (Reoviridae) diseases, one of which, African horse sickness (AHS), was reported in the South-Western area of Khomas Region, Namibia, where it had been believed to be absent. Culicoides imicola, AHS principal vector, was collected in several farms in the area during the winter of 2009. The objective of this study was to determine whether Culicoides midges, especially C. imicola, were favoured at anthropogenic impacted/homestead sites in the arid Khomas Region, where they were not expected to occur under natural, veld conditions. The natural 'background' Culicoides communities where determined from collections made at veld sites, which were then compared to corresponding collections made at homestead sites. Altogether, 10,178 Culicoides midges were collected at homesteads and were then compared to 1,733 individuals collected at veld sites. Culicoides midge numbers were likely boosted in anthropogenic impacted areas/homesteads. This was also the case for the Culicoides species that are vector of AHS. This study indicated the significance of human settlement in the Khomas Region in terms of Culicoides midge abundance and distribution and showed the implications that this may have on the transmission of Culicoides vectored diseases. PMID- 24166478 TI - First cases of Schmallenberg virus in Italy: surveillance strategies. AB - Following the first report of Schmallenberg virus (SBV) in the brain of a dystocic goat foetus in 2012 in Northern Italy, immediate response actions were adopted to avoid the virus circulation. The brain tested positive by 2 different one-step real-time RT-PCR protocols; these results were also confirmed by partial sequencing of the viral genome. At that time this was the first detection of the new Orthobunyavirus genus within the Bunyaviridae family in Italy. An epidemiological investigation in the involved farm was carried out in collaboration with the CESME - National Reference Centre for the study and verification of Foreign Animal Diseases (Istituto Zooprofilattico Sperimentale dell'Abruzzo e del Molise 'G. Caporale', Italy). Epidemiological information on the flock was provided and analysed, whole blood and serum samples were also collected from all animals in the farm for both virological and serological investigations. All blood samples tested negative for SBV, whereas serological positive results were obtained by virus-neutralization (VN). Epidemiological investigations indicated the possible virus circulation in the area. The subsequent surveillance actions were mainly based on the standardization and reenforcement of passive surveillance protocols, a risk-based serological surveillance programme through VN and an entomological surveillance programme in the involved geographical areas were also put in place. Eventually SBV local circulation was confirmed by real time RT-PCR in 6 Culicoides pools, collected between September and November 2011 in 3 farms in the surroundings of the area of SBV outbreak. PMID- 24166480 TI - Prevalence of antibodies against Parainfluenza virus type 3, Respiratory syncitial virus and bovine Herpesvirus type 1 in sheep from Northern Prefectures of Japan. AB - Ovine sera collected in the Prefectures of Hokkaido, Aomori and Iwate in the Northern Japan were examined for the presence of antibodies against Respiratory syncytial virus (RSV), bovine Herpesvirus type 1 (infectious bovine rhinotracheitis: IBR) and Parainfluenza virus type 3 (PIV3) using serum neutralisation (SN) and enzyme-linked immunosorbent assay (ELISA) tests. Twenty three animals (11.73%) out of the 196 tested were sero-positive to PIV3. Sixteen animals (8.69%) out of the 184 tested reacted to RSV. No animals were positive to IBR antigen. Sero-conversions to PIV3 were detected in Hokkaido and Iwate (14.92% and 8.82%, respectively). Antibodies against RSV were detected in Hokkaido (9.23%) and Aomori (14.28%). Although no diagnostic measures were in place, the infections did not appear to be related to any reduction in sheep productivity. PMID- 24166481 TI - Seafood a potential source of some zoonotic bacteria in Zagazig, Egypt, with the molecular detection of Listeria monocytogenes virulence genes. AB - This article describes the results of a study conducted on 71 fresh seafood samples (fish and shellfish) marketed in Zagazig city, Sharkia province, Egypt, as well as on 50 human stool samples collected at the Zagazig University Hospital. The samples were examined for the presence of Listeria monocytogenes and Escherichia coli. The investigation of L. monocytogenes virulence genes was performed using Polymerase Chain Reaction (PCR), while the microbiological quality of the seafood samples was evaluated using the coliform count and aerobic plate count (APC) as indicators. Out of the examined 71 seafood samples, 20 (28.2%) were identified as L. monocytogenes, 15 (75%) of which were confirmed as virulent strains. Also, out of 50 human stool samples, only 1 (2%) was identified as virulent L. monocytogenes. E. coli serotypes were isolated from only 11.3% of seafood and 30% of human stool samples. In shellfish, the APC and most probable number of coliforms (MPC) were higher than those obtained from other fish samples. Multiplex PCR targeting internalin genes allowed simultaneous identification of L. monocytogenes and differentiation of virulent strains, thus enabling more timely detection of cases and sources of food borne listeriosis. The article concludes by stressing that the isolation of potentially virulent L. monocytogenes and E. coli from both seafood samples and humans emphasises the potential public health hazard caused by eating raw or undercooked shellfish. PMID- 24166482 TI - Coproscopy survey of gastrointestinal parasites in owned dogs of Kerman city, Iran. AB - A coproscopy survey was conducted on 100 owned dogs in Kerman city from July 2011 to July 2012 with the objective to assess the presence of Gastrointestinal parasites with zoonotic potential. Faecal samples from 100 dogs were examined for the presence of parasites. Samples (n=100) collected from dogs of different ages and genders were analysed using 5 techniques, i.e. centrifugal flotation in sucrose solution, centrifugal flotation in 33% Zinc sulphate solution, Ziehl Neelsen staining, trichrome staining, and iodine staining. The overall proportion of Gastrointestinal parasitic infection was 16% (16/100). The most frequently observed parasites in this study were Toxocara canis (9%), followed by Taeniidae eggs (3%), Cryptosporidium spp. (3%), Troglotrema salmincola (1%), Toxoscaris leonina (1%) and Isospora canis (1%). Most of the dogs (62%) included in the study were regularly dewormed and no significant association was found between parasitic infection and sex, age and breed of the dogs. It is noteworthy that this is the first report of Troglotrema salmincola infection in Iran. PMID- 24166484 TI - Predictors of long-term adherence to evidence-based cardiovascular disease medications in outpatients with stable atherothrombotic disease: findings from the REACH Registry. AB - BACKGROUND: Despite overall improvements in cardiovascular-disease therapies and outcomes, medication nonadherence remains an important barrier to effective secondary prevention of atherothrombotic disease. HYPOTHESIS: Long-term medication adherence in outpatients with stable atherothrombotic disease is impacted by demographic and clinical factors. METHODS: We examined data from the prospective international Reduction of Atherothrombosis for Continued Health (REACH) Registry. Analyses were derived from 25 737 patients with established atherothrombotic disease with complete adherence data at enrollment and at year 4. Adherence was defined as patients' self-report of taking medications based on class I American College of Cardiology/American Heart Association guidelines for secondary prevention as defined, including antiplatelet agents, statins, and antihypertensive medications. RESULTS: Among patients with atherothrombotic disease, 12 500 (48.6%) were deemed adherent to guideline-recommended medications. Adherent patients were younger, white, and had less polyvascular disease. Hispanic and East Asian patients were less likely to be adherent as compared with white patients (odds ratio [OR]: 0.72, 95% confidence interval [CI]: 0.59-0.88; and OR: 0.67, 95% CI: 0.53-0.83, respectively). Patients who had a nonfatal MI or underwent coronary angioplasty/stenting during follow-up were more likely to be adherent compared with patients without these events (OR: 1.73, 95% CI: 1.25-2.38; and OR: 2.15, 95% CI: 1.72-2.67, respectively). On the other hand, nonfatal stroke during follow-up was inversely associated with adherence (OR: 0.77, 95% CI: 0.61-0.97). CONCLUSIONS: Using a large international registry of outpatients with atherothrombotic disease, we found that age, region, race/ethnicity, and incident cardiovascular events were predictive of long-term guideline adherence for secondary prevention, suggesting that certain patient groups may benefit from targeted interventions to improve adherence. PMID- 24166485 TI - Screening and risk factors for anal cancer precursors in men infected with HIV in Taiwan. AB - Homosexual men infected with human immunodeficiency virus (HIV) are at a greater risk of developing anal cancer. Men who are infected with HIV and visited the outpatient clinics in Taoyuan General Hospital were enrolled to this study. During March to December 2011, thin preparation anal Pap smear and human papillomavirus (HPV) genotyping were performed in 230 subjects, of which 69 subjects underwent anoscopic biopsy. Their mean age was 32.9 +/- 8.1 years, and 181 (78.6%) men were homosexual. The proportion and 95% confidence interval (CI) of subjects with anal dysplasia in cytology was 23.0% (17.56-28.44), including 13.4% (9.26-18.14) with atypical squamous cells of undetermined significance, 7.0% (3.70-10.30) with low-grade squamous intraepithelial lesions, and 2.6% (0.54 4.66) with high-grade squamous intraepithelial lesions. For participants having atypical squamous cells of undetermined significance or higher grades, multivariate logistic regression models yielded adjusted odds ratios (95% CI) of 12.61 (1.63-97.56) for homosexuality, 1.62 (1.31-2.00) for number of oncogenic HPV types, and 1.01 (1.00-1.02) for number of lifetime sexual partners. For detection of histological grade II or III anal intraepithelial neoplasm in anoscopic biopsies, the sensitivity of sequential tests for oncogenic HPV and cytology with atypical squamous cells of undetermined significance or higher grades was 100%. The positive likelihood ratio was 3.09 (P = 0.05). It is important to consider anal cancer precursors among homosexual men who are infected with HIV. Anal cytology and oncogenic HPV genotyping testing are effective screening methods. PMID- 24166483 TI - Vaccine-elicited human T cells recognizing conserved protein regions inhibit HIV 1. AB - Virus diversity and escape from immune responses are the biggest challenges to the development of an effective vaccine against HIV-1. We hypothesized that T cell vaccines targeting the most conserved regions of the HIV-1 proteome, which are common to most variants and bear fitness costs when mutated, will generate effectors that efficiently recognize and kill virus-infected cells early enough after transmission to potentially impact on HIV-1 replication and will do so more efficiently than whole protein-based T-cell vaccines. Here, we describe the first ever administration of conserved immunogen vaccines vectored using prime-boost regimens of DNA, simian adenovirus and modified vaccinia virus Ankara to uninfected UK volunteers. The vaccine induced high levels of effector T cells that recognized virus-infected autologous CD4(+) cells and inhibited HIV-1 replication by up to 5.79 log10. The virus inhibition was mediated by both Gag- and Pol- specific effector CD8(+) T cells targeting epitopes that are typically subdominant in natural infection. These results provide proof of concept for using a vaccine to target T cells at conserved epitopes, showing that these T cells can control HIV-1 replication in vitro. PMID- 24166486 TI - GWAS meta analysis identifies TSNARE1 as a novel Schizophrenia / Bipolar susceptibility locus. AB - We carried out a GWAS meta-analysis of combined mixed-ancestry schizophrenia, schizoaffective, and bipolar cohorts that resulted in the identification of six genome-wide significant loci, including one novel locus at chr8q24.3, encompassing TSNARE1 (P = 1.28 * 10(-9)). The analysis included a total of 13,394 cases and 34,676 controls. While the function of TSNARE1 remains unknown, bioinformatic predictions based on phylogenetic ancestry indicate it may have a vertebrate-specific function in intracellular protein transport and synaptic vesicle exocytosis. PMID- 24166487 TI - Persistent geotropic direction-changing positional nystagmus with a null plane: the light cupula. AB - OBJECTIVES/HYPOTHESIS: The aim of this study was to characterize the clinical features and typical positional nystagmus in patients with persistent geotropic direction-changing positional nystagmus (DCPN) and address the possible pathophysiology of the disease. Furthermore, the proportion of light cupula among the patients showing geotropic DCPN was investigated to assume the incidence of light cupula in those patients. STUDY DESIGN: Prospective case series. METHODS: We conducted a prospective case series study in 19 patients with persistent geotropic DCPN. Positional nystagmus during the bow and lean test and the supine head roll test was analyzed using videonystagmography. RESULTS: All of the 19 patients showed persistent geotropic DCPN without latency. A null plane in which the nystagmus ceases was identified in all of 19 patients, and the intensity of nystagmus was stronger on one side in13 patients (68%) on supine head roll test. Overall, the affected side could be identified in 18 patients (95%). About 14.2% (19 of 134) of patients with geotropic DCPN could be diagnosed as having light cupula in the horizontal semicircular canal. CONCLUSIONS: The patients with light cupula show persistent geotropic DCPN without latency. Affected side(s) can be determined by the direction and intensity of the characteristic positional nystagmus and the side of the null plane. The pathophysiology and treatment of light cupula still remain to be elucidated. PMID- 24166488 TI - The Kallikrein Panel for prostate cancer screening: its economic impact. AB - BACKGROUND: Current diagnostic testing for prostate cancer results in numerous unnecessary biopsy procedures and creates a substantial financial burden. A statistical prediction model for prostate cancer has been developed, based on four Kallikrein markers in blood. This systematic review and meta-analysis examines the aggregated results from published studies of the Kallikrein Panel. METHODS: Literature searches to identify relevant studies were conducted. A meta analysis of the results was performed using inverse variance, mean difference with corresponding 95% confidence intervals (CI). The results of the meta analysis were used to assess the Kallikrein Panel's effect on healthcare costs. RESULTS: The Kallikrein Panel has been evaluated in more than 8,500 patients (2,780 with prostate cancer and 598 with high grade prostate cancer). Meta analysis demonstrates a statistically significant improvement of 8-10% in predictive accuracy. In addition, 48% to 56% of current prostate biopsies could be avoided. Use of the Kallikrein Panel could result in annual US savings approaching $1 billion. CONCLUSIONS: The Kallikrein Panel has the potential to improve patient outcomes and reduce costs. The panel provides significantly improved specificity. Because the Kallikrein Panel has been studied in a range of clinical settings, it is a test that could be readily and widely used in practice. PMID- 24166491 TI - Growth in percutaneous coronary intervention capacity relative to population and disease prevalence. AB - BACKGROUND: The access to and growth of percutaneous coronary intervention (PCI) has not been fully explored with regard to geographic equity and need. Economic factors and timely access to primary PCI provide the impetus for growth in PCI centers, and this is balanced by volume standards and the benefits of regionalized care. METHODS AND RESULTS: Geospatial and statistical analyses were used to model capacity, growth, and access of PCI hospitals relative to population density and myocardial infarction (MI) prevalence at the state level. Longitudinal data were obtained for 2003-2011 from the American Hospital Association, the U.S. Census, and the Centers for Disease Control and Prevention (CDC) with geographical modeling to map PCI locations. The number of PCI centers has grown 21.2% over the last 8 years, with 39% of all hospitals having interventional cardiology capabilities. During the same time, the US population has grown 8.3%, from 217 million to 235 million, and MI prevalence rates have decreased from 4.0% to 3.7%. The most densely concentrated states have a ratio of 8.1 to 12.1 PCI facilities per million of population with significant variability in both MI prevalence and average distance between PCI facilities. CONCLUSIONS: Over the last decade, the growth rate for PCI centers is 1.5* that of the population growth, while MI prevalence is decreasing. This has created geographic imbalances and access barriers with excess PCI centers relative to need in some regions and inadequate access in others. PMID- 24166489 TI - Changes in clinical and microbiological periodontal profiles relate to progression of carotid intima-media thickness: the Oral Infections and Vascular Disease Epidemiology study. AB - BACKGROUND: No prospective studies exist on the relationship between change in periodontal clinical and microbiological status and progression of carotid atherosclerosis. METHODS AND RESULTS: The Oral Infections and Vascular Disease Epidemiology Study examined 420 participants at baseline (68 +/- 8 years old) and follow-up. Over a 3-year median follow-up time, clinical probing depth (PD) measurements were made at 75 766 periodontal sites, and 5008 subgingival samples were collected from dentate participants (average of 7 samples/subject per visit over 2 visits) and quantitatively assessed for 11 known periodontal bacterial species by DNA-DNA checkerboard hybridization. Common carotid artery intima medial thickness (CCA-IMT) was measured using high-resolution ultrasound. In 2 separate analyses, change in periodontal status (follow-up to baseline), defined as (1) longitudinal change in the extent of sites with a >= 3-mm probing depth (Delta%PD >= 3) and (2) longitudinal change in the relative predominance of bacteria causative of periodontal disease over other bacteria in the subgingival plaque (Deltaetiologic dominance), was regressed on longitudinal CCA-IMT progression adjusting for age, sex, race/ethnicity, diabetes, smoking status, education, body mass index, systolic blood pressure, and low-density lipoprotein cholesterol and high-density lipoprotein cholesterol. Mean (SE) CCA-IMT increased during follow-up by 0.139 +/- 0.008 mm. Longitudinal IMT progression attenuated with improvement in clinical or microbial periodontal status. Mean CCA-IMT progression varied inversely across quartiles of longitudinal improvement in clinical periodontal status (Delta%PD >= 3) by 0.18 (0.02), 0.16 (0.01), 0.14 (0.01), and 0.07 (0.01) mm (P for trend<0.0001). Likewise, mean CCA-IMT increased by 0.20 (0.02), 0.18 (0.02), 0.15 (0.02), and 0.12 (0.02) mm (P<0.0001) across quartiles of longitudinal improvement in periodontal microbial status (Deltaetiologic dominance). CONCLUSION: Longitudinal improvement in clinical and microbial periodontal status is related to a decreased rate of carotid artery IMT progression at 3-year average follow-up. PMID- 24166490 TI - Vitamin E serum levels and bleeding risk in patients receiving oral anticoagulant therapy: a retrospective cohort study. AB - BACKGROUND: Hemorrhagic risk assessment is a crucial issue in patients with nonvalvular atrial fibrillation (NVAF) who are receiving oral anticoagulant therapy (OAT). Our aim was to analyze the relationship between vitamin E, which possesses anticoagulant properties, and bleeding events in NVAF patients. METHODS AND RESULTS: In this retrospective observational study we analyzed baseline serum cholesterol-adjusted vitamin E (vit E/chol) levels in 566 consecutive patients (59% males, mean age 73.6 years) receiving OAT followed up for a mean time of 22 months. Mean time in therapeutic INR range (TTR) was 64%. The overall incidence rate of any bleeding event was 9.2/100 person-years. Compared to patients who did not bleed, those who experienced bleeding events (n=92, 73 minor and 15 major bleedings and 4 cerebral hemorrhages according to International Society on Thrombosis and Haemostasis [ISTH] ) classification) showed a significant difference for history of coronary heart disease (P=0.039), HAS-BLED score (P=0.002), and vit E/chol levels (P<0.001). Higher vit E/chol serum levels were found in patients who bled compared to those who did not (5.27 +/- 1.93 versus 4.48 +/- 1.97 MUmol/cholesterol; P<0.001), with a progressive increase from minor (5.16 +/- 1.91 MUmol/mmol cholesterol, P=0.006) to major bleedings (5.72 +/- 2.0 MUmol/mmol cholesterol, P=0.008). A Cox proportional hazard model demonstrated that serum vit E/chol quartiles (global P=0.0189) and HAS-BLED scores (P=0.005) predicted bleeding events. CONCLUSIONS: In a NVAF population being treated with warfarin, serum vitamin E predicted hemorrhagic events. Further study is necessary to see if the relationship between serum levels of vitamin E and bleeding is still maintained with the use of new anticoagulants. PMID- 24166493 TI - Detection of cerebrospinal fluid leaks by intrathecal contrast-enhanced magnetic resonance myelography. PMID- 24166492 TI - Flank sequences of miR-145/143 and their aberrant expression in vascular disease: mechanism and therapeutic application. AB - BACKGROUND: Many microRNAs (miRNAs) are downregulated in proliferative vascular disease. Thus, upregulation of these miRNAs has become a major focus of research activity. However, there is a critical barrier in gene therapy to upregulate some miRNAs such as miR-145 and miR-143 because of their significant downregulation by the unclear endogenous mechanisms under disease conditions. The purpose of this study was to determine the molecular mechanisms responsible for their downregulation and to overcome the therapeutic barrier. METHODS AND RESULTS: In cultured proliferative rat vascular smooth muscle cells (VSMCs) in vitro and in diseased rat and mouse arteries in vivo, we have identified that the impairment of pri-miR-145 into pre-miR-145 is the critical step related to the downregulation of miR-145, in which the PI3-kinase/Akt/p53 pathway is involved. We further identified that the flank sequences of pri-miR-145 are the critical structural components responsible for the aberrant miR-145 expression. Switching of the flank sequence of downregulated miR-145 and miR-143 to the flank sequence of miR-31 confers resistance to their downregulation. The genetically engineered miR-145 (smart miR-145) restored the downregulated miR-145 in proliferative rat VSMCs and in rat carotid arteries with balloon injury and mouse atherosclerotic aortas and demonstrated much better therapeutic effects on the abnormal growth of VSMCs, expression of its target gene, KLF5 expression, VSMC marker gene expression, and vascular neointimal growth. CONCLUSIONS: The flank sequences of miR-145 and miR-143 play a critical role in their aberrant expression in VSMCs and vascular walls. The genetically engineered "smart" miRNAs based on their flank sequences may have broadly therapeutic applications for many vascular diseases. PMID- 24166494 TI - A gene signature of bone metastatic colonization sensitizes for tumor-induced osteolysis and predicts survival in lung cancer. AB - Bone metastasis of lung adenocarcinoma (AC) is a frequent complication of advanced disease. The purpose of this study was to identify key mediators conferring robust prometastatic activity with clinical significance. We isolated highly metastatic subpopulations (HMS) using a previously described in vivo model of lung AC bone metastasis. We performed transcriptomic profiling of HMS and stringent bioinformatics filtering. Functional validation was assessed by overexpression and lentiviral silencing of single, double and triple combination in vivo and in vitro. We identified HDAC4, PITX1 and ROBO1 that decreased bone metastatic ability after their simultaneous abrogation. These effects were solely linked to defects in osseous colonization. The molecular mechanisms related to bone colonization were mediated by non-cell autonomous effects that include the following: (1) a marked decrease in osteoclastogenic activity in vitro and in vivo, an effect associated with reduced pro-osteoclastogenic cytokines IL-11 and PTHrP expression levels, as well as decreased in vitro expression of stromal rankl in conditions mimicking tumor-stromal interactions; (2) an abrogated response to TGF-beta signaling by decreased phosphorylation and levels of Smad2/3 in tumor cells and (3) an impaired metalloproteolytic activity in vitro. Interestingly, coexpression of HDAC4 and PITX1 conferred high prometastatic activity in vivo. Further, levels of both genes correlated with patients at higher risk of metastasis in a clinical lung AC data set and with a poorer clinical outcome. These findings provide functional and clinical evidence that this metastatic subset is an important determinant of osseous colonization. These data suggest novel therapeutic targets to effectively block lung AC bone metastasis. PMID- 24166495 TI - SS18-SSX fusion protein-induced Wnt/beta-catenin signaling is a therapeutic target in synovial sarcoma. AB - Synovial sarcoma is a high-grade soft tissue malignancy characterized by a specific reciprocal translocation t(X;18), which leads to the fusion of the SS18 (SYT) gene to one of three SSX genes (SSX1, SSX2 or SSX4). The resulting chimeric SS18-SSX protein is suggested to act as an oncogenic transcriptional regulator. Despite multimodal therapeutic approaches, metastatic disease is often lethal and the development of novel targeted therapeutic strategies is required. Several expression-profiling studies identified distinct gene expression signatures, implying a consistent role of Wnt/beta-catenin signaling in synovial sarcoma tumorigenesis. Here we investigate the functional and therapeutic relevance of Wnt/beta-catenin pathway activation in vitro and in vivo. Immunohistochemical analyses of nuclear beta-catenin and Wnt downstream targets revealed activation of canonical Wnt signaling in a significant subset of 30 primary synovial sarcoma specimens. Functional aspects of Wnt signaling including dependence of Tcf/beta catenin complex activity on the SS18-SSX fusion proteins were analyzed. Efficient SS18-SSX-dependent activation of the Tcf/beta-catenin transcriptional complex was confirmed by TOPflash reporter luciferase assays and immunoblotting. In five human synovial sarcoma cell lines, inhibition of the Tcf/beta-catenin protein protein interaction significantly blocked the canonical Wnt/beta-catenin signaling cascade, accompanied by the effective downregulation of Wnt targets (AXIN2, CDC25A, c-MYC, DKK1, CyclinD1 and Survivin) and the specific suppression of cell viability associated with the induction of apoptosis. In SYO-1 synovial sarcoma xenografts, administration of small molecule Tcf/beta-catenin complex inhibitors significantly reduced tumor growth, associated with diminished AXIN2 protein levels. In summary, SS18-SSX-induced Wnt/beta-catenin signaling appears to be of crucial biological importance in synovial sarcoma tumorigenesis and progression, representing a potential molecular target for the development of novel therapeutic strategies. PMID- 24166496 TI - Prohibitin is required for transcriptional repression by the WT1-BASP1 complex. AB - The Wilms' tumor-1 protein (WT1) is a transcriptional regulator that can either activate or repress genes controlling cell growth, apoptosis and differentiation. The transcriptional corepressor BASP1 interacts with WT1 and mediates WT1's transcriptional repression activity. BASP1 is contained within large complexes, suggesting that it works in concert with other factors. Here we report that the transcriptional repressor prohibitin is part of the WT1-BASP1 transcriptional repression complex. Prohibitin interacts with BASP1, colocalizes with BASP1 in the nucleus, and is recruited to the promoter region of WT1 target genes to elicit BASP1-dependent transcriptional repression. We demonstrate that prohibitin and BASP1 cooperate to recruit the chromatin remodeling factor BRG1 to WT1 responsive promoters and that this results in the dissociation of CBP from the promoter region of WT1 target genes. As seen with BASP1, prohibitin can associate with phospholipids. We demonstrate that the recruitment of PIP2 and HDAC1 to WT1 target genes is also dependent on the concerted activity of BASP1 and prohibitin. Our findings provide new insights into the function of prohibitin in transcriptional regulation and uncover a BASP1-prohibitin complex that plays an essential role in the PIP2-dependent recruitment of chromatin remodeling activities to the promoter. PMID- 24166497 TI - Oncoprotein stabilization in brain tumors. AB - Proteins involved in promoting cell proliferation and viability need to be timely expressed and carefully controlled for the proper development of the brain but also efficiently degraded in order to prevent cells from becoming brain cancer cells. A major pathway for targeted protein degradation in cells is the ubiquitin proteasome system (UPS). Oncoproteins that drive tumor development and tumor maintenance are often deregulated and stabilized in malignant cells. This can occur when oncoproteins escape degradation by the UPS because of mutations in either the oncoprotein itself or in the UPS components responsible for recognition and ubiquitylation of the oncoprotein. As the pathogenic accumulation of an oncoprotein can lead to effectively sustained cell growth, viability and tumor progression, it is an indisputable target for cancer treatment. The most common types of malignant brain tumors in children and adults are medulloblastoma and glioma, respectively. Here, we review different ways of how deregulated proteolysis of oncoproteins involved in major signaling cancer pathways contributes to medulloblastoma and glioma development. We also describe means of targeting relevant oncoproteins in brain tumors with treatments affecting their stability or therapeutic strategies directed against the UPS itself. PMID- 24166498 TI - MicroRNAs, miR-154, miR-299-5p, miR-376a, miR-376c, miR-377, miR-381, miR-487b, miR-485-3p, miR-495 and miR-654-3p, mapped to the 14q32.31 locus, regulate proliferation, apoptosis, migration and invasion in metastatic prostate cancer cells. AB - miRNAs act as oncogenes or tumor suppressors in a wide variety of human cancers, including prostate cancer (PCa). We found a severe and consistent downregulation of miRNAs, miR-154, miR-299-5p, miR-376a, miR-376c, miR-377, miR-381, miR-487b, miR-485-3p, miR-495 and miR-654-3p, mapped to the 14q32.31 region in metastatic cell lines as compared with normal prostatic epithelial cells (PrEC). In specimens of human prostate (28 normals, 99 primary tumors and 13 metastases), lower miRNA levels correlated significantly with a higher incidence of metastatic events and higher prostate specific antigen (PSA) levels, with similar trends observed for lymph node invasion and the Gleason score. We transiently transfected 10 members of the 14q32.31 cluster in normal prostatic epithelial cell lines and characterized their affect on malignant cell behaviors, including proliferation, apoptosis, migration and invasion. Finally, we identified FZD4, a gene important for epithelial-to-mesenchymal transition in (PCa), as a target of miR-377. PMID- 24166499 TI - Merlin sumoylation is required for its tumor suppressor activity. AB - Merlin, encoded by the Neurofibromatosis 2 (NF2) gene, is a multifunctional tumor suppressor that integrates and regulates extracellular cues and intracellular signaling pathways, both at the plasma membrane and in the nucleus, to control cell proliferation, migration and invasion. Molecular mechanisms regulating merlin's tumor-suppressive activity have not been clearly defined. Here we report that merlin can be sumoylated on Lysine residue (K76) in vitro and in vivo. Sumoylation mediates merlin's intramolecular and intermolecular binding activities and regulates its cytoplasm/nucleus trafficking. Interestingly, sumoylation of merlin is regulated by its phosphorylation via Akt and PAK2 kinases. Mutation of K76 into arginine (R) abolishes its sumoylation, disrupts merlin cortical cytoskeleton residency and attenuates its stability. Using a K76R mutant merlin in a subcutaneous U87MG xenograft model, we demonstrate that merlin sumoylation is required for tumor-suppressive activity. Taken together, our findings indicate that merlin is sumoylated and that this post-translational modification is essential for tumor suppression. PMID- 24166500 TI - Essential roles of Crk and CrkL in fibroblast structure and motility. AB - Cytosolic proteins containing SH2 and SH3 domains, such as Crk and Crk-like (CrkL), are broadly expressed adapters that interact with a variety of proteins to fulfill key roles in signal transduction pathways triggered by activation of receptor and non-receptor tyrosine kinases. Crk and CrkL are similar to each other in structure and biochemical function, although they provide both distinct, as well as overlapping, biological roles during development. We developed a systematic approach to investigate Crk family functions at the cellular level by generating a conditional knock-out system for ablation of Crk and CrkL in cultured fibroblasts. The loss of both Crk and CrkL from fibroblasts resulted in reduced cell surface area and adoption of a rounded, refractile cellular phenotype. These morphological alterations were accompanied by a decrease in focal adhesion sites, reduced actin stress fibers and a collapse of microtubule structures. In addition, cells exhibited decreases in spontaneous motility and wound-healing behavior. Reduced p130Cas phosphorylation and actin levels closely followed the loss of Crk and CrkL, and stabilization of polymerized actin by jasplakinolide suppressed the morphological conversion. Ablation of Crk or CrkL alone conferred a much more modest phenotype suggesting that Crk and CrkL have overlapping functions that are critical for maintaining cell structure. The morphological alterations could be partially rescued by reintroduction of CrkII, and, to a lesser extent, CrkL. Taken together, our results suggest that Crk and CrkL have critical roles in cell structure and motility by maintaining cytoskeletal integrity. PMID- 24166501 TI - Aurora-A is a determinant of tamoxifen sensitivity through phosphorylation of ERalpha in breast cancer. AB - Despite the clinical success of tamoxifen, its resistance remains a major challenge in breast cancer. Here we show that Aurora-A determines tamoxifen sensitivity by regulation of oestrogen receptor (ER)alpha. Ectopic expression of Aurora-A decreases and depletion of Aurora-A enhances tamoxifen sensitivity in ERalpha-positive breast cancer. Elevated Aurora-A was significantly associated with the recurrence of ERalpha-positive tumours. Notably, Aurora-A inhibitor MLN8237, which is currently in clinical trial, synergizes with tamoxifen and overcomes tamoxifen resistance. Furthermore, Aurora-A interacts with and phosphorylates ERalpha on serine-167 and -305, leading to increase in ERalpha DNA binding and transcriptional activity. Elevated levels of Aurora-A are significantly associated with disease-free survival in ERalpha-positive but not ERalpha-negative breast cancers. These data suggest that Aurora-A has a pivotal role in tamoxifen resistance and ERalpha is a bona fide substrate of Aurora-A. Thus, Aurora-A represents a prognostic marker in ERalpha-positive tumour and a critical therapeutic target in tamoxifen-resistant breast cancer, and Aurora-A inhibitor could be used as either an independent or concurrent agent in tamoxifen resistant tumour. PMID- 24166502 TI - Loss of the desmosomal cadherin desmoglein-2 suppresses colon cancer cell proliferation through EGFR signaling. AB - Desmosomal cadherins mediate cell-cell adhesion in epithelial tissues and have been known to be altered in cancer. We have previously shown that one of the two intestinal epithelial desmosomal cadherins, desmocollin-2 (Dsc2) loss promotes colonic epithelial carcinoma cell proliferation and tumor formation. In this study we show that loss of the other intestinal desmosomal cadherin, desmoglein-2 (Dsg2) that pairs with Dsc2, results in decreased epithelial cell proliferation and suppressed xenograft tumor growth in mice. Dsg2-deficient cells demonstrated a compensatory increase in Dsc2 expression, and small interfering RNA-mediated loss of Dsc2 restored proliferation in Dsg2-deficient cells. Dsg2 downregulation inhibited epidermal growth factor receptor (EGFR) signaling and cell proliferation through altered phosphorylation of EGFR and downstream extracellular signal-regulated kinase activation in parallel with inhibited EGFR receptor internalization. Additionally, we demonstrated a central role of Dsc2 in controlling EGFR signaling and cell proliferation in intestinal epithelial cells. Consistent with these findings, analyses of human colon cancers demonstrated increased Dsg2 protein expression. Taken together, these data demonstrate that partner desmosomal cadherins Dsg2 and Dsc2 play opposing roles in controlling colonic carcinoma cell proliferation through differential effects on EGFR signaling. PMID- 24166503 TI - microRNA-18a induces apoptosis in colon cancer cells via the autophagolysosomal degradation of oncogenic heterogeneous nuclear ribonucleoprotein A1. AB - It is well known that microRNAs (miRs) are abnormally expressed in various cancers and target the messenger RNAs (mRNAs) of cancer-associated genes. While (miRs) are abnormally expressed in various cancers, whether miRs directly target oncogenic proteins is unknown. The present study investigated the inhibitory effects of miR-18a on colon cancer progression, which was considered to be mediated through its direct binding and degradation of heterogeneous nuclear ribonucleoprotein A1 (hnRNP A1). An MTT assay and xenograft model demonstrated that the transfection of miR-18a induced apoptosis in SW620 cells. A binding assay revealed direct binding between miR-18a and hnRNP A1 in the cytoplasm of SW620 cells, which inhibited the oncogenic functions of hnRNP A1. A competitor RNA, which included the complementary sequence of the region of the miR-18a-hnRNP A1 binding site, repressed the effects of miR-18a on the induction of cancer cell apoptosis. In vitro single and in vivo double isotope assays demonstrated that miR-18a induced the degradation of hnRNP A1. An immunocytochemical study of hnRNP A1 and LC3-II and the inhibition of autophagy by 3-methyladenine and ATG7, p62 and BAG3 siRNA showed that miR-18a and hnRNP A1 formed a complex that was degraded through the autophagolysosomal pathway. This is the first report showing a novel function of a miR in the autophagolysosomal degradation of an oncogenic protein resulting from the creation of a complex consisting of the miR and a RNA binding protein, which suppressed cancer progression. PMID- 24166504 TI - Glucose deprivation increases monocarboxylate transporter 1 (MCT1) expression and MCT1-dependent tumor cell migration. AB - The glycolytic end-product lactate is a pleiotropic tumor growth-promoting factor. Its activities primarily depend on its uptake, a process facilitated by the lactate-proton symporter monocarboxylate transporter 1 (MCT1). Therefore, targeting the transporter or its chaperon protein CD147/basigin, itself involved in the aggressive malignant phenotype, is an attractive therapeutic option for cancer, but basic information is still lacking regarding the regulation of the expression, interaction and activities of both proteins. In this study, we found that glucose deprivation dose-dependently upregulates MCT1 and CD147 protein expression and their interaction in oxidative tumor cells. While this posttranslational induction could be recapitulated using glycolysis inhibition, hypoxia, oxidative phosphorylation (OXPHOS) inhibitor rotenone or hydrogen peroxide, it was blocked with alternative oxidative substrates and specific antioxidants, pointing out at a mitochondrial control. Indeed, we found that the stabilization of MCT1 and CD147 proteins upon glucose removal depends on mitochondrial impairment and the associated generation of reactive oxygen species. When glucose was a limited resource (a situation occurring naturally or during the treatment of many tumors), MCT1-CD147 heterocomplexes accumulated, including in cell protrusions of the plasma membrane. It endowed oxidative tumor cells with increased migratory capacities towards glucose. Migration increased in cells overexpressing MCT1 and CD147, but it was inhibited in glucose-starved cells provided with an alternative oxidative fuel, treated with an antioxidant, lacking MCT1 expression, or submitted to pharmacological MCT1 inhibition. While our study identifies the mitochondrion as a glucose sensor promoting tumor cell migration, MCT1 is also revealed as a transducer of this response, providing a new rationale for the use of MCT1 inhibitors in cancer. PMID- 24166505 TI - HSP-90 inhibitor ganetespib is synergistic with doxorubicin in small cell lung cancer. AB - Small cell lung cancer (SCLC) at advanced stage is considered an incurable disease. Despite good response to initial chemotherapy, the responses in SCLC patients with metastatic disease are of short duration and resistance inevitably occurs. Although several target-specific drugs have altered the paradigm of treatment for many other cancers, we have yet to witness a revolution of the same magnitude in SCLC treatment. Anthracyclines, such as doxorubicin, have definite activity in this disease, and ganetespib has shown promising activity in preclinical models but underwhelming activity as a single agent in SCLC patients. Using SCLC cell lines, we demonstrated that ganetespib (IC50: 31 nM) was much more potent than 17-allylamino-17-demethoxygeldanamycin (17-AAG), a geldanamycin derivative (IC50: 16 MUM). Ganetespib inhibited SCLC cell growth via induction of persistent G2/M arrest and Caspase 3-dependent cell death. MTS assay revealed that ganetespib synergized with both doxorubicin and etoposide, two topoisomerase II inhibitors commonly used in SCLC chemotherapy. Expression of receptor interacting serine/threonine-protein kinase 1 (RIP1), a protein that may function as a pro-survival scaffold protein or a pro-death kinase in TNFR1-activated cells, was induced by doxorubicin and downregulated by ganetespib. Depletion of RIP1 by either RIP1 small interfering RNA (siRNA) or ganetespib sensitized doxorubicin-induced cell death, suggesting that RIP1 may promote survival in doxorubicin-treated cells and that ganetespib may synergize with doxorubicin in part through the downregulation of RIP1. In comparison to ganetespib or doxorubicin alone, the ganetespib+doxorubicin combination caused significantly more growth regression and death of human SCLC xenografts in immunocompromised mice. We conclude that ganetespib and doxorubicin combination exhibits significant synergy and is efficacious in inhibiting SCLC growth in vitro and in mouse xenograft models. Our preclinical study suggests that ganetespib and doxorubicin combination therapy may be an effective strategy for SCLC treatment, which warrants clinical testing. PMID- 24166506 TI - Depletion of minichromosome maintenance protein 7 inhibits glioblastoma multiforme tumor growth in vivo. AB - Minichromosome maintenance (MCM) proteins are key elements that function as a part of the pre-replication complex to initiate DNA replication in eukaryotes. Consistent with their roles in initiating DNA replication, overexpression of MCM family members has been observed in several malignancies. Through bioinformatic analysis of The Cancer Genome Atlas's data on glioblastoma multiforme (GBM), we found that the genomic region containing MCM7 gene was amplified in more than 80% of the present cases. To validate this finding and to identify the possible contribution of the remaining members of the MCM family to GBM progression, we used quantitative real-time PCR to analyze the gene expression profiles of all MCM family members in Grade IV (GBM) tissue samples and observed a significant upregulation in GBM samples compared with normal white matter tissues. In addition, we compared the observed gene expression profiles with those of Grade II and Grade III astrocytoma samples and determined that the observed upregulation was restricted and specific to Grade IV. MCM7 was the most upregulated gene in the gene set we analyzed, and therefore we wanted to identify the role of MCM7 in GBM progression. We determined that siRNA-mediated knockdown of MCM7 expression reduced GBM cell proliferation and also inhibited tumor growth in both xenograft and orthotopic mouse models of GBM. Taken together, our data suggest that MCM7 can be a potential prognostic marker and a novel therapeutic target in GBM therapy. PMID- 24166508 TI - A comparative survey of functional footprints of EGFR pathway mutations in human cancers. AB - Genes functioning in epidermal growth factor receptor (EGFR) signaling pathways are among the most frequently activated oncogenes in human cancers. We have conducted a comparative analysis of functional footprints (that is, effect on signaling and transcriptional landscapes in cells) associated with oncogenic and tumor suppressor mutations in EGFR pathway genes in human cancers. We have found that mutations in the EGFR pathway differentially have an impact on signaling and metabolic pathways in cancer cells in a mutation- and tissue-selective manner. For example, although signaling and metabolic profiles of breast tumors with PIK3CA or AKT1 mutations are, as expected, highly similar, they display markedly different, sometimes even opposite, profiles to those with ERBB2 or EGFR amplifications. On the other hand, although low-grade gliomas and glioblastomas, both brain cancers, driven by EGFR amplifications are highly functionally similar, their functional footprints are significantly different from lung and breast tumors driven by EGFR or ERBB2. Overall, these observations argue that, contrary to expectations, the mechanisms of tumorigenicity associated with mutations in different genes along the same pathway, or in the same gene across different tissues, may be highly different. We present evidence that oncogenic functional footprints in cancer cell lines have significantly diverged from those in tumor tissues, which potentially explains the discrepancy of our findings with the current knowledge. Nevertheless, our analyses reveal a common inflammatory response signature in EGFR-driven human cancers of different tissue origins. Our results may have implications in the design of therapeutic strategies in cancers driven by these oncogenes. PMID- 24166507 TI - Human papillomavirus type 16 E7 perturbs DREAM to promote cellular proliferation and mitotic gene expression. AB - The study of the small DNA tumor viruses continues to provide valuable new insights into oncogenesis and fundamental biological processes. Although much has already been revealed about how the human papillomaviruses (HPVs) can transform cells and contribute to cervical and oropharyngeal cancer, there clearly is much more to learn. In this issue of Oncogene, Pang et al., doi:10.1038/onc.2013.426, demonstrate that the high-risk HPV16 E7 oncogene can promote cellular proliferation by interacting with the DREAM (DP, RB-like, E2F and MuvB) complex at two distinct phases of the cell cycle. Consistent with earlier work, HPV16 E7 can bind to the retinoblastoma tumor suppressor (RB) family member p130 (RBL2) protein and promote its proteasome-mediated destruction thereby disrupting the DREAM complex and can prevent exit from the cell cycle into quiescence. In addition, they demonstrate that HPV16 E7 can bind to MuvB core complex in association with BMYB and FOXM1 and activate gene expression during the G2 and M phase of the cell cycle. Thus, HPV16 E7 acts to prevent exit from the cell cycle entry and promotes mitotic proliferation and may account for the high levels of FOXM1 often observed in poor-risk cervical cancers. PMID- 24166509 TI - MicroRNA-106b-5p boosts glioma tumorigensis by targeting multiple tumor suppressor genes. AB - Aberrant expression of microRNAs (miRNAs) has been implicated in cancer initiation and progression. However, little is known about the potential role of miRNAs in glioma tumorigenesis. In this study, we found that miRNA-106b-5p was significantly upregulated in glioma tumor samples and cell lines compared with normal brain tissues, and its expression level correlated with the pathological grading. Overexpression of miR-106b-5p in glioma tumor cells significantly promoted cell proliferation, although inhibited cell apoptosis in vitro and in vivo. In contrast, knockdown of miR-106b-5p significantly inhibited cell proliferation, although enhanced cell apoptosis. Mechanistic study revealed that two target genes, retinoblastoma-like 1 (RBL1) and RBL2, were involved in miR 106b-5p's regulation of cell proliferation and one target gene, caspase-8 (CASP8), mediated miR-106b-5p's regulation of apoptosis. We also investigated the function of the three targets in glioma tumorigenesis by RNA interference manipulation and demonstrated that knockdown of these target genes led to cell proliferation enhancement or cell apoptosis inhibition in vitro. More interestingly, the expression levels of these targets were significantly downregulated in glioma samples and knockdown of these targets in glioma cells inhibited the xenograft tumor formation in vivo. Moreover, we verified the regulation function of miR-106b-5p and its targets on cell proliferation and apoptosis of the primary cultured astrocytes isolated from glioma tumor samples and healthy controls. Collectively, our findings show the critical roles of miR 106b-5p and its targets, RBL1, RBL2 and CASP8, in glioma tumorigenesis and provide potential candidates for malignant glioma therapy. PMID- 24166510 TI - Meal replacement based on Human Ration modulates metabolic risk factors during body weight loss: a randomized controlled trial. AB - PURPOSE: A meal replacement may be an effective strategy in the management of obesity to increase antioxidant intake, attenuating oxidative stress and inflammation. In the present study, we investigated the efficacy of a new nutritional supplement to reduce metabolic risk parameters in obese women. METHODS: In a randomized controlled crossover study (2 * 2), 22 women (percentage body fat 40.52 +/- 3.75%; body mass index-BMI 28.72 +/- 2.87 kg/m2; 35.04 +/- 5.6 years old) were allocated into two treatments: hypocaloric diet and drink containing "Human Ration" (HR) consumption (CRHR), and hypocaloric diet and control drink consumption (CR). The study consisted of 2 periods of 5 weeks with 1 week of washout in two orders (CR -> CRHR and CRHR -> CR). Caloric restriction was 15%, based on estimated energy requirement. Anthropometric, clinical and metabolic risk parameters were assessed at baseline and at the end of each period. RESULTS: Some metabolic risk factors were favorably modulated in both interventions: reduction in body weight (CR -0.74 +/- 1.27 kg; p = 0.01; CRHR 0.77 +/- 1.3 kg; p = 0.02), body mass index (BMI) (CR -0.27 +/- 0.51 kg/m2; p = 0.02; CRHR -0.30 +/- 0.52 kg/m2; p = 0.01) and HOMA-IR (CR -0.35 +/- 0.82; p = 0.02, CRHR -0.41 +/- 0.83; p = 0.03). However, CRHR reduced waist circumference ( 2.54 +/- 2.74 cm; p < 0.01) and gynoid fat (-0.264 +/- 0.28 g; p < 0.01), and increased HDL-c levels (0.08 +/- 0.15 mmol/l; p = 0.04). CONCLUSION: Associated with hypocaloric diet, the intake of a nutritional supplement rich in phytochemicals as a breakfast substitute for 5 weeks had no additional effect on weight reduction than caloric restriction alone, but increased central lipolysis and improved the lipoprotein profile. PMID- 24166512 TI - Vascular beneficial effects of polyphenol-rich olive oil and reduced body iron stores. PMID- 24166511 TI - Comparative evaluation of cow beta-casein variants (A1/A2) consumption on Th2 mediated inflammatory response in mouse gut. AB - PURPOSE: Recently, apprehension has been raised regarding "A1/A2 hypothesis" suggesting relationship between consumption of A1 "like" variants of cow beta casein and various physiological disorders. The information available is based on either the human epidemiological data of milk consumption or in vitro trials on cell lines with beta-casomorphin peptides. The direct scientific evidence establishing the link between consumption of A1/A2 "like" milk and health is scanty. Thus, under present investigation, in vivo trials in mice were undertaken to study the effect of feeding three genetic variants (A1A1, A1A2 and A2A2) of cow beta-casein milk on gastrointestinal immune system as it is the first and foremost site of immunological interactions. METHODS: Animals were divided into four groups for feeding with basal diet (control) and beta-casein isolated from milk of genotyped (A1A1, A1A2 and A2A2) dairy animals, respectively. Gut immune response was analyzed by spectrophotometric assessment of MPO activity, quantitative sandwich ELISA of inflammatory cytokines (MCP-1 and IL-4), antibodies (total IgE, IgG, sIgA, IgG1 and IgG2a) and qRT-PCR of mRNA expression for toll-like receptors (TLR-2 and TLR-4). Histological enumeration of goblet cells, total leukocytes and IgA(+) cells was also carried out. RESULTS: It was observed that consumption of A1 "like" variants (A1A1 and A1A2) significantly increased (p < 0.01) the levels of MPO, MCP-1, IL-4, total IgE, IgG, IgG1, IgG2a and leukocyte infiltration in intestine. TLR-2 and TLR-4 mRNA expression was also up-regulated (p < 0.01) on administration of A1 "like" variants. However, no changes in sIgA, IgA(+) and goblet cell numbers were recorded on consumption of any of the beta-casein variants. CONCLUSION: It is reasonable to conclude that consumption of A1 "like" variants of beta-casein induced inflammatory response in gut by activating Th2 pathway as compared to A2A2 variants. The present study thus supports the purported deleterious impacts of consumption of A1 "like" variants of beta-casein and suggests possible aggravation of inflammatory response for etiology of various health disorders. PMID- 24166513 TI - Association between accumulation of allene oxide synthase activity and development of resistance against downy mildew disease of pearl millet. AB - The present study was aimed at understanding the possible association of allene oxide synthase (AOS), an enzyme implicated in the octadecanoid pathway during the pearl millet-downy mildew interaction. AOS 13-HPOT (13-hydroperoxy-9,11,15 octadecatrienoic acid) metabolizing activity assays assessed in various pearl millet cultivars with differential resistances against downy mildew revealed a positive correlation between cultivar resistance levels and AOS activities. Furthermore, the involvement of AOS in response to downy mildew was demonstrated by induction of AOS activity in both susceptible and resistant pearl millet cultivars during Sclerospora graminicola infection with higher induction observed in the resistant cultivar. Consistently, western blot analysis and tissue-blot immunoassay demonstrated the remarkable increase in AOS protein accumulation in the incompatible interaction. In addition, the tissue-blot immunoassay also showed the compartmentalization of AOS in the epidermis and vascular bundles of pearl millet seedlings. Expression analysis of a putative PgAOS1 gene revealed a marked difference in accumulation of PgAOS1 transcripts between contrasting plants, with pathogen-induced higher accumulation of the transcripts observed only in the resistant cultivar; a result which is in agreement with pathogen induced AOS level and activity, indicating that PgAOS1 plays an important role in regulation of AOS level and activity in pearl millet upon S. graminicola infection. Our findings suggest an important role for AOS in regulation of responses to downy mildew disease in pearl millet. The differential AOS activities can potentially be used for selection of new disease-resistant pearl millet varieties, and the identified AOS-encoding gene(s) as genetic resource for development of enhanced downy mildew-resistant cultivars. PMID- 24166514 TI - Complicated puzzle in cetuximab-based chemotherapy: skin toxicity and resection rate in patients with initially unresectable colorectal liver metastases. PMID- 24166515 TI - Reply to R. Brierley et al. PMID- 24166516 TI - Pleiotropic approach to graft-versus-host disease. PMID- 24166517 TI - Reply to U.R. Mansmann et al and M.-W. An et al. PMID- 24166519 TI - Total mesorectal neglect in the age of total mesorectal excision. PMID- 24166518 TI - Toward a NOTCH1/FBXW7/RAS/PTEN-based oncogenetic risk classification of adult T cell acute lymphoblastic leukemia: a Group for Research in Adult Acute Lymphoblastic Leukemia study. AB - PURPOSE: The Group for Research in Adult Acute Lymphoblastic Leukemia (GRAALL) recently reported a significantly better outcome in T-cell acute lymphoblastic leukemia (T-ALL) harboring NOTCH1 and/or FBXW7 (N/F) mutations compared with unmutated T-ALL. Despite this, one third of patients with N/F-mutated T-ALL experienced relapse. PATIENTS AND METHODS: In a series of 212 adult T-ALLs included in the multicenter randomized GRAALL-2003 and -2005 trials, we searched for additional N/K-RAS mutations and PTEN defects (mutations and gene deletion). RESULTS: N/F mutations were identified in 143 (67%) of 212 patients, and lack of N/F mutation was confirmed to be associated with a poor prognosis. K-RAS, N-RAS, and PTEN mutations/deletions were identified in three (1.6%) of 191, 17 (8.9%) of 191, and 21 (12%) of 175 patients, respectively. The favorable prognostic significance of N/F mutations was restricted to patients without RAS/PTEN abnormalities. These observations led us to propose a new T-ALL oncogenetic classifier defining low-risk patients as those with N/F mutation but no RAS/PTEN mutation (97 of 189 patients; 51%) and all other patients (49%; including 13% with N/F and RAS/PTEN mutations) as high-risk patients. In multivariable analysis, this oncogenetic classifier remained the only significant prognostic covariate (event-free survival: hazard ratio [HR], 3.2; 95% CI, 1.9 to 5.15; P < .001; and overall survival: HR, 3.2; 95% CI, 1.9 to 5.6; P < .001). CONCLUSION: These data demonstrate that the presence of N/F mutations in the absence of RAS or PTEN abnormalities predicts good outcome in almost 50% of adult T-ALL. Conversely, the absence of N/F or presence of RAS/PTEN alterations identifies the remaining cohort of patients with poor prognosis. PMID- 24166520 TI - Aspirin therapy for colorectal cancer with PIK3CA mutation: simply complex! PMID- 24166521 TI - On denying denial. PMID- 24166524 TI - Is fidaxomicin the drug of choice for treating Clostridium difficile-associated diarrhea in patients with cancer? PMID- 24166523 TI - Reply to M.R. Green et al. PMID- 24166522 TI - Cost effectiveness of primary pegfilgrastim prophylaxis in patients with breast cancer at risk of febrile neutropenia. AB - PURPOSE: Guidelines advise primary granulocyte colony-stimulating factor (G-CSF) prophylaxis during chemotherapy if risk of febrile neutropenia (FN) is more than 20%, but this comes with considerable costs. We investigated the incremental costs and effects between two treatment strategies of primary pegfilgrastim prophylaxis. METHODS: Our economic evaluation used a health care perspective and was based on a randomized study in patients with breast cancer with increased risk of FN, comparing primary G-CSF prophylaxis throughout all chemotherapy cycles (G-CSF 1-6 cycles) with prophylaxis during the first two cycles only (G CSF 1-2 cycles). Primary outcome was cost effectiveness expressed as costs per patient with episodes of FN prevented. RESULTS: The incidence of FN increased from 10% in the G-CSF 1 to 6 cycles study arm (eight of 84 patients) to 36% in the G-CSF 1 to 2 cycles study arm (30 of 83 patients), whereas the mean total costs decreased from ? 20,658 (95% CI, ? 20,049 to ? 21,247) to ? 17,168 (95% CI ? 16,239 to ? 18,029) per patient, respectively. Chemotherapy and G-CSF determined 80% of the total costs. As expected, FN-related costs were higher in the G-CSF 1 to 2 cycles arm. The incremental cost effectiveness ratio for the G CSF 1 to 6 cycles arm compared with the G-CSF 1 to 2 cycles arm was ? 13,112 per patient with episodes of FN prevented. CONCLUSION: We conclude that G-CSF prophylaxis throughout all chemotherapy cycles is more effective, but more costly, compared with prophylaxis limited to the first two cycles. Whether G-CSF prophylaxis throughout all chemotherapy cycles is considered cost effective depends on the willingness to pay per patient with episodes of FN prevented. PMID- 24166525 TI - Reply to Y. Sunakawa et al and P. Mroczkowski et al. PMID- 24166527 TI - When inoperable becomes operable? PMID- 24166526 TI - Practice patterns and long-term survival for early-stage rectal cancer. AB - PURPOSE: Standard of care treatment for most stage I rectal cancers is total mesorectal excision (TME). Given the morbidity associated with TME, local excision (LE) for early-stage rectal cancer has been explored. This study examines practice patterns and overall survival (OS) for early-stage rectal cancer. METHODS: All patients in the National Cancer Data Base diagnosed with rectal cancer from 1998 to 2010 were initially included. Use of LE versus proctectomy and use of adjuvant radiation therapy were compared over time. Adjusted Cox proportional hazards models were used to compare OS based on treatment. RESULTS: LE was used to treat 46.5% of patients with T1 and 16.8% with T2 tumors. Use of LE increased steadily over time (P < .001). LE was most commonly used for women, black patients, very old patients, those without private health insurance, those with well-differentiated tumors, and those with T1 tumors. Proctectomy was associated with higher rates of tumor-free surgical margins compared with LE (95% v 76%; P < .001). Adjuvant radiation therapy use decreased over time independent of surgical procedure or T stage. For T2N0 disease, patients treated with LE alone had significantly poorer adjusted OS than those treated with proctectomy alone or multimodality therapy. CONCLUSION: Guideline-concordant adoption of LE for treatment of low-risk stage I rectal cancer is increasing. However, use of LE is also increasing for higher-risk rectal cancers that do not meet guideline criteria for LE. Treatment with LE alone is associated with poorer long-term OS. Additional studies are warranted to understand the factors driving increased use of LE. PMID- 24166528 TI - Application of tumor measurement-based metrics in the real world. PMID- 24166530 TI - Conflicts of interest in editorials in high-impact journals. PMID- 24166531 TI - Methodologic diligence is needed to define and validate tumor-size response metrics to predict overall survival in first-line metastatic colorectal cancer. PMID- 24166529 TI - Sibling donor and recipient immune modulation with atorvastatin for the prophylaxis of acute graft-versus-host disease. AB - PURPOSE: Graft-versus-host disease (GVHD) is major cause of morbidity and mortality after allogeneic hematopoietic cell transplantation (HCT). Atorvastatin is a potent immunomodulatory agent that holds promise as a novel and safe agent for acute GVHD prophylaxis. PATIENTS AND METHODS: We conducted a phase II trial to evaluate the safety and efficacy of atorvastatin administration for GVHD prophylaxis in both adult donors and recipients of matched sibling allogeneic HCT. Atorvastatin (40 mg per day orally) was administered to sibling donors, starting 14 to 28 days before the anticipated first day of stem-cell collection. In HCT recipients (n = 30), GVHD prophylaxis consisted of tacrolimus, short course methotrexate, and atorvastatin (40 mg per day orally). RESULTS: Atorvastatin administration in healthy donors and recipients was not associated with any grade 3 to 4 adverse events. Cumulative incidence rates of grade 2 to 4 acute GVHD at days +100 and +180 were 3.3% (95% CI, 0.2% to 14.8%) and 11.1% (95% CI, 2.7% to 26.4%), respectively. One-year cumulative incidence of chronic GVHD was 52.3% (95% CI, 27.6% to 72.1%). Viral and fungal infections were infrequent. One-year cumulative incidences of nonrelapse mortality and relapse were 9.8% (95% CI, 1.4% to 28%) and 25.4% (95% CI, 10.9% to 42.9%), respectively. One-year overall survival and progression-free survival were 74% (95% CI, 58% to 96%) and 65% (95% CI, 48% to 87%), respectively. Compared with baseline, atorvastatin administration in sibling donors was associated with a trend toward increased mean plasma interleukin-10 concentrations (5.6 v 7.1 pg/mL; P = .06). CONCLUSION: A novel two-pronged strategy of atorvastatin administration in both donors and recipients of matched sibling allogeneic HCT seems to be a feasible, safe, and potentially effective strategy to prevent acute GVHD. PMID- 24166532 TI - Economic impact of childhood/adolescent ADHD in a European setting: the Netherlands as a reference case. AB - Attention-deficit/hyperactivity disorder (ADHD) is a highly prevalent psychiatric disorder in children/adolescents. This study reviews available European-based studies of ADHD-related costs and applies the findings to the Netherlands to estimate annual national costs for children/adolescents from a societal perspective. A systematic literature search was conducted for primary studies in Europe, published January 1, 1990 through April 23, 2013. Per-person cost estimates were converted to 2012 Euros and used to estimate annual national ADHD related costs based on the Dutch 2011 census, ADHD prevalence rates, family composition, and employment rates. Seven studies met the inclusion criteria. The average total ADHD-related costs ranged from ?9,860 to 14,483 per patient and annual national costs were between ?1,041 and ?1,529 million (M). The largest cost category was education (?648 M), representing 62 and 42 % of the low- and high-value overall national estimates, respectively. By comparison, ADHD patient healthcare costs ranged between ?84 M (8 %) and ?377 M (25 %), and social services costs were ?4.3 M (0.3-0.4 %). While the majority of the costs were incurred by ADHD patients themselves, ?161 M (11-15 %) was healthcare costs to family members that were attributable to having an ADHD child/adolescent. In addition, productivity losses of family members were ?143-?339 M (14-22 %). Despite uncertainties because of the small number of studies identified and the wide range in the national cost estimates, our results suggest that ADHD imposes a significant economic burden on multiple public sectors in Europe. The limited number of European-based studies examining the economic burden of ADHD highlights the need for more research in this area. PMID- 24166533 TI - Facial emotion recognition in adolescents with personality pathology. AB - It has been argued that a heightened emotional sensitivity interferes with the cognitive processing of facial emotion recognition and may explain the intensified emotional reactions to external emotional stimuli of adults with personality pathology, such as borderline personality disorder (BPD). This study examines if and how deviations in facial emotion recognition also occur in adolescents with personality pathology. Forty-two adolescents with personality pathology, 111 healthy adolescents and 28 psychiatric adolescents without personality pathology completed the Emotion Recognition Task, measuring their accuracy and sensitivity in recognizing positive and negative emotion expressions presented in several, morphed, expression intensities. Adolescents with personality pathology showed an enhanced recognition accuracy of facial emotion expressions compared to healthy adolescents and clients with various Axis-I psychiatric diagnoses. They were also more sensitive to less intensive expressions of emotions than clients with various Axis-I psychiatric diagnoses, but not more than healthy adolescents. As has been shown in research on adults with BPD, adolescents with personality pathology show enhanced facial emotion recognition. PMID- 24166534 TI - Electronic structure, adsorption geometry, and photoswitchability of azobenzene layers adsorbed on layered crystals. AB - Mono- and multilayers of the molecular photoswitch azobenzene were adsorbed on two layered transition-metal dichalcogenides, semiconducting HfS2 and metallic TiTe2, at temperatures of 80-120 K and investigated in situ using valence-band and core-level photoelectron spectroscopy as well as near-edge X-ray absorption fine structure spectroscopy. The spectroscopic results indicate similar growth modes on the two substrates. In the monolayer systems, the azobenzene molecules tend to lie flat on the surface with average tilt angles of <15 degrees , whereas the multilayer systems show a larger average tilt angle of 35-45 degrees , depending on substrate surface conditions. The chemical environment of azobenzene, as investigated by XPS, does not change significantly from mono- to multilayers suggesting weak adsorbate-substrate coupling for the molecular layer that forms the interface with the substrate. Irradiation with ultraviolet light with a wavelength of 365 nm leads to a partial rearrangement of the adsorbed azobenzene molecules with a trans-to-cis conversion of up to 35%. PMID- 24166537 TI - Electron transfer from the benzophenone triplet excited state directs the photochemical synthesis of gold nanoparticles. AB - The rarely recognized electron donating ability of the benzophenone triplet excited state provides an unusual route for the photochemical synthesis of gold nanoparticles. PMID- 24166538 TI - Water-soluble CdTe quantum dots as an anode interlayer for solution-processed near infrared polymer photodetectors. AB - Water-soluble cadmium telluride (CdTe) quantum dots (QDs) used as an anode interlayer in solution-processed near infrared (NIR) polymer photodetectors (PDs) were demonstrated. Polymer PDs incorporated with CdTe QDs as an anode interlayer exhibited 10-fold suppressed dark current density and analogous photocurrent density relative to poly(3,4-ethylenedioxythiophene):poly(styrenesulfonate) (PEDOT:PSS), which resulted in enhanced detectivities over 10(11) Jones in the spectral range from 350 nm to 900 nm. Moreover, with the substitution of PEDOT:PSS by CdTe QDs, the stability of unencapsulated NIR polymer PDs was extended up to 650 hours, which is more than 3 times longer than those with PEDOT:PSS as an anode interlayer. These results indicated that CdTe QDs can be utilized as a solution-processable alternative to PEDOT:PSS as an anode interlayer for high performance NIR polymer PDs. PMID- 24166536 TI - Within-person coupling of changes in cortisol, testosterone, and DHEA across the day in adolescents. AB - We comprehensively examined within-person and between-person associations between cortisol and DHEA and cortisol and testosterone across the day. Data are from a sample of 213 adolescents aged 11-16 (M = 13.7, SD = 1.5 years) from the Northeastern US who were oversampled for psychopathology symptoms. Six repeated measures of hormone levels across 3 days were used to test three specific questions of cortisol-DHEA and cortisol-testosterone associations within individuals (coupling) across the day, and one question of cortisol-DHEA and cortisol-testosterone diurnal slopes were associated between adolescents. Results consistently revealed positive cortisol-DHEA and cortisol-testosterone coupling across the day, often more pronounced in girls relative to boys. Cortisol and DHEA slopes were positively associated, whereas cortisol and testosterone were negatively associated between-adolescents. Findings suggest multiple mechanisms and highlight the multifaceted nature of associations of hormone changes during adolescence and importance of considering both axes for between- and within person aspects of neuroendocrine development. PMID- 24166539 TI - Effects of methylprednisolone on femoral bone marrow: age-dependent susceptibility. AB - PURPOSE: We aimed to test our primary hypothesis that the effects of methylprednisolone on bone marrow in chickens are age-sensitive and increase with prolonged treatment and our secondary hypothesis that the effects of methylprednisolone on bone marrow can have individual effects. METHODS: Sixteen control (group A) and 29 methylprednisolone-treated (group B) chickens were categorised by age: pubertal chicks (subgroups A1, B1), young hens (A2, B2), and adult hens (A3, B3). Histologic evaluation 12 to 50 weeks after the start of methylprednisolone treatment included fat cell proliferation, trabecular bone loss, necrosis of bone and marrow, and new bone formation in the femoral head, neck, and intertrochanteric area. RESULTS: There were significant differences between groups A1 and B1 in new bone formation in the femoral neck (P = 0.048) and fat cell proliferation in the femoral head (P = 0.008) and neck (P = 0.048). New bone formation in the femoral head was also significantly different (P = 0.023) between groups A2 and B2. No differences were noted between groups A3 and B3 (all P>0.05). Necrosis of bone and marrow was observed in four control and three methylprednisolone-treated chickens (P>0.05). Significant new bone formation and fat cell proliferation in pubertal and young chickens occurred 12 to 19 weeks after administration of high-dose methylprednisolone. CONCLUSIONS: Younger animals may be more susceptible to methylprednisolone, and responses to methylprednisolone in femoral marrow may vary among individuals. PMID- 24166540 TI - Does your SEM really tell the truth? How would you know? Part 2. AB - The scanning electron microscope (SEM) has gone through a tremendous evolution to become indispensable for many and diverse scientific and industrial applications. The improvements have significantly enriched and augmented the overall SEM performance and have made the instrument far easier to operate. But, the ease of operation also might lead, through operator complacency, to poor results. In addition, the user friendliness has seemingly reduced the need for thorough operator training for using these complex instruments. One might then conclude that the SEM is just a very expensive digital camera or another peripheral device for a computer. Hence, a person using the instrument may be lulled into thinking that all of the potential pitfalls have been eliminated and they believe everything they see on the micrograph is always correct. But, this may not be the case. An earlier paper (Part 1), discussed some of the potential issues related to signal generation in the SEM, instrument calibration, electron beam interactions and the need for physics-based modeling to understand the actual image formation mechanisms. All these were summed together in a discussion of how these issues effect measurements made with the instrument. This second paper discusses another major issue confronting the microscopist: electron-beam-induced specimen contamination. Over the years, NIST has done a great deal of research into the issue of sample contamination and its removal and elimination and some of this work is reviewed and discussed here. PMID- 24166541 TI - Military service, war, and families: considerations for child development, prevention and intervention, and public health policy--Part 2. PMID- 24166542 TI - Seven members of the (1->3)-beta-glucanase gene family in barley (Hordeum vulgare) are clustered on the long arm of chromosome 3 (3HL). AB - Members of the (1->3)-beta-glucan glucanohydrolase (EC 3.2.1.39) gene family have been mapped on the barley genome using three doubled haploid populations and seven wheat-barley addition lines. Specific probes or polymerase chain reaction (PCR) primers were generated for the seven barley (1->3)-beta-glucanase genes for which cDNA or genomic clones are currently available. The seven genes are all located on the long arm of chromosome 3 (3HL), and genes encoding isoenzymes GI, GII, GIII, GIV, GV and GVII (ABG2) are clustered in a region less than 20 cM in length. The region is flanked by the RFLP marker MWG2099 on the proximal side and the Barley Yellow Mosaic Virus (BYMV) resistance gene ym4 at the distal end. The gene encoding isoenzyme GVI lies approximately 50 cM outside this cluster, towards the centromere. With the exception of the gene encoding isoenzyme GIV, all of the (1->3)-beta-glucanase genes are represented by single copies on the barley genome. The probe for the isoenzyme GIV gene hybridized with four DNA bands during Southern blot analysis, only one of which could be incorporated into the consensus linkage map. PMID- 24166543 TI - Influence of the female flowering environment on autumn frost-hardiness of Picea abies progenies. AB - Two experiments were designed to test possible effects of photoperiod and temperature during microsporogensis to anthesis on early autumn frost-hardiness of Picea abies progenies. Pollen lots were produced in phytotron rooms and used in crosses in a seed orchard. No biologically important differences in progeny performance were evident either between high and low temperature or between long and short-day treatments, and no significant interaction between photoperiod and temperature was found. In a third experiment, however, an effect of the environment during female flowering was obtained. Crosses performed in early spring (March) inside a heated greenhouse (short day, high temperature) produced progenies which were less hardy than their full-sibs reproduced from crosses indoors (long day, high temperature) and outdoors (long day, low temperature) in May. The most hardy siblings originated from the late-spring outdoor crosses. These results indicate that some stages in reproduction during female flowering, such as female meiosis, pollen tube growth, syngamy, early embryogenesis and embryo competition, may be sensitive to temperature and/or photoperiodic signals which can be transmitted to the progeny. We suspect that the altered performance of the progenies could be due to an activation of a regulatory mechanism affecting the expression of genes controlling adaptive traits. Both the present and earlier results have implications for the genetic interpretation of provenance differences in Norway spruce. PMID- 24166544 TI - RAPD markers linked to the Vf gene for scab resistance in apple. AB - Scab (Venturia inaequalis) is one of the most harmful diseases of apple, significantly affecting world apple production. The identification and early selection of resistant genotypes by molecular markers would greatly improve breeding strategies. Bulked segregant analysis was chosen for the identification of RAPD markers linked to the Vf scab resistant gene. Five different RAPD markers, derived from the wild species Malus floribunda. 821, were identified, and their genetic distance from Vf gene was estimated. The markers OPAM192200 and OPAL07580 were found to be very closely linked to the Vf gene. This result was indirectly confirmed by the analysis of resistant genotypes collected from various breeding programmes. Except for cv 'Murray', which carries the Vm gene, all these resistant genotypes showed the markers OPAM192200 and OPAL07580. PMID- 24166545 TI - The genetic and molecular characterization of pollen-derived plant lines from octoploid triticale x wheat hybrids. AB - Six doubled-haploid (DH) lines, derived by anther culture from octoploid triticale x wheat hybrids, were characterized using cytological, biochemical and molecular techniques. Lines varied in their wheat and rye genome composition, and were either wheat-rye chromosome multiple addition lines or had spontaneous substitutions and/or wheat-rye translocations. Most of the lines contained a pair of 4R chromosomes, whereas 1R or 7R were present in others. The results are similar to those previously obtained with hexaploid triticale x wheat crosses and indicate that it is possible to produce alien (wheat/rye) addition, substitution, and translocation lines directly from the anther culture of intergeneric hybrids. PMID- 24166546 TI - Comparative mapping in F2?3 and F 6?7 generations of quantitative trait loci for grain yield and yield components in maize. AB - This study was conducted to compare maize quantitative trait loci (QTL) detection for grain yield and yield components in F2?3 and F6?7 recombinant inbred (RI) lines from the same population. One hundred and eighty-six F6?7 RIs from a Mo17*H99 population were grown in a replicated field experiment and analyzed at 101 loci detected by restriction fragment length polymorphisms (RFLPs). Single factor analysis of variance was conducted for each locus-trait combination to identify QTL. For grain yield, 6 QTL were detected accounting for 22% of the phenotypic variation. A total of 63 QTL were identified for the seven grain yield components with alleles from both parents contributing to increased trait values. Several genetic regions were associated with more than one trait, indicating possible linked and/or pleiotropic effects. In a comparison with 150 F2?3 lines from the same population, the same genetic regions and parental effects were detected across generations despite being evaluated under diverse environmental conditions. Some of the QTL detected in the F2?3 seem to be dissected into multiple, linked QTL in the F6?7 generation, indicating better genetic resolution for QTL detection with RIs. Also, genetic effects at QTL are smaller in the F6?7 generation for all traits. PMID- 24166547 TI - A chalcone synthase/stilbene synthase DNA probe for conifers. AB - A probe for chalcone synthase (CHS) was generated by PCR using chalcone synthase conserved sequences. The cloned PCR product has high similarity to both chalcone synthase and stilbene synthase sequences. The probe was used to examine the organization of chalcone synthase and stilbene synthase genes in Abies procera, Pinus lambertiana, P. monticola, Picea glauca, P. sitchensis, Pseudostuga menziesii, Taxus brevifolia, and Thuja plicata. A large number of hybridizing bands were found in all species except T. plicata which did not cross hybridize. The hybridization patterns are highly polymorphic between the species and are also polymorphic within several of them. PMID- 24166548 TI - High level of genetic differentiation for allelic richness among populations of the argan tree [Argania spinosa (L.) Skeels] endemic to Morocco. AB - Genetic diversity at nine isozyme loci was surveyed in an endangered tree species, the argan tree, endemic to south-western Morocco. The species is highly diverse (3.6 alleles/locus) with populations strongly differentiated from each other (F ST=0.25). This example is used to illustrate a method for standardizing measures of allelic richness in samples of unequal sample sizes, which was developed for the estimation of the number of species and relies on the technique of rarefaction. In addition, it is shown that the measure of subdivision, theta ST, obtained when allelic richness is used in place ofh (Nei's index of diversity), is much larger than the F ST [e.g. theta ST(40)=0.52, where (40) indicates the specified sample used to estimate the allelic richness]. This suggests that rare alleles (which strongly influence measures of allelic richness) have a more scattered distribution than more frequent ones, a result which raises special conservation issues for the argan tree. PMID- 24166549 TI - Evidence for RAPD heteroduplex formation in cranberry: implications for pedigree and genetic-relatedness studies and a source of co-dominant RAPD markers. AB - Silver-stained random amplified polymorphic DNA (ssRAPD) markers have been identified that are always jointly present or absent in the ssRAPD profiles of cranberry varieties. On the basis of segregation data and the ability to re create these "associated ssRAPDs" through the intermixing of amplified DNA from individuals lacking them, five of the six pairs of associated ssRAPDs analyzed were shown to be consistent with heteroduplex molecules. Heteroduplexes are "hybrid"" double-stranded DNAs that are formed following the polymerase chain reaction (PCR) amplification of two DNA segments that have a high degree of homology to one another, yet differ in their nucleotide sequences as a result of base pair deletions, additions, or substitutions. Three of the five putative heteroduplex systems identified are consistent with a one locus, two-allele heteroduplex model. The remaining two systems appeared to be multi-allelic, involving interactions among three and four alleles, respectively. RAPD heteroduplex formation has the potential to confound genetic relatedness and pedigree studies. Heterozygous individuals exhibit heteroduplex RAPDs not seen in either of the two homozygote classes. Genetic estimates under such a circumstance would "inflate" the differences between the heterozygote and the homozygote classes. Heteroduplex formation is also a mechanism for the presence of non parental RAPDs in progeny of parents homozygous for alternate alleles. While this class of molecular markers can confound RAPD analyses, they also offer a source of co-dominant RAPD markers, which are of value in genetic relatedness estimates and as markers for studying breeding behavior. PMID- 24166550 TI - The role of irradiation dose and DNA content of somatic hybrid calli in producing asymmetric plants between an interspecific tomato hybrid and eggplant. AB - Highly asymmetric somatic hybrid plants were obtained by PEG/DMSO fusion of gamma irradiated mesophyll protoplasts of the kanamycin-resistant (KmR(+)) interspecific hybrid Lycopersicon esculentum x L. pennellii (EP) with mesophyll protoplasts of Solanum melongena (eggplant, E). Elimination of the EP chromosomes was obtained by irradiating the donor genome with different doses of gamma rays (100, 250, 500, 750 and 1000 Gy). The selection of somatic hybrid calli was based on kanamycin resistance; EP and E protoplasts did not divide due to the irradiation treatment and sensitivity to kanamycin, respectively. KmR(+) calli were recovered following all irradiation doses of donor EP protoplasts. The hybrid nature of the recovered calli was confirmed by PCR amplification of the NptII gene, RAPD patterns and Southern hybridizations using potato ribosomal DNA and pTHG2 probes. Ploidy levels of calli confirmed as hybrid were further analyzed by flow cytometry. Such analyses revealed that the vast majority of hybrid calli that did not regenerate shoots were 5-9n polyploids. The three asymmetric somatic hybrid plants obtained were regenerated only from callus with a ploidy level close to 4n, and such calli occurred only when the donor EP had been exposed to 100 Gy. The amount of DNA in somatic hybrid calli, from 100-Gy exposure, was found by dot blot hybridization with the species-specific probe, pTHG2, to be equivalent with 3.1-25.8% of the tomato genome. Thus, DNA contained in 3.8-13.2 average-size tomato chromosomes was present in these hybrid calli. The asymmetric somatic hybrid plants had the eggplant morphology and were regenerated from one hybrid callus that contained an amount of tomato DNA equivalent to 6.29 average-size tomato chromosomes. PMID- 24166551 TI - The Yd2 gene for barley yellow dwarf virus resistance maps close to the centromere on the long arm of barley chromosome 3. AB - Barley yellow dwarf luteovirus (BYDV) causes serious yield losses in all cereals worldwide. The Yd2 gene from a number of Ethiopian barleys (Hordeum vulgare L.) has been the most effective means of providing resistance against BYDV in cultivated barley. Isolation of the Yd2 gene will enable characterisation of the molecular basis of the Yd2-BYDV interaction. This paper describes the first stage in a project to isolate the gene: the construction of a detailed linkage map of the Yd2 region. The map encompasses 27.6 centiMorgans (cM) of chromosome 3 and contains 19 RFLPs, 2 morphological marker loci, the centromere and Yd2. In the mapping population of 106 F2 individuals, Yd2 perfectly cosegregated with the RFLP loci Xwg889 and XYlp, which were located on the long arm, 0.5 cM from the centromere. The two morphological marker loci, uzu dwarfand white stripe j, both mapped distal to Yd2. The protein product of the gene at the XYlp locus will provide a convenient assay for the selection of Yd2 during the breeding of BYDV resistant barley varieties. PMID- 24166552 TI - Inheritance and linkage relationships of isozyme and morphological loci in cucumber (Cucumis sativus L.). AB - Twenty-one polymorphic and 17 monomorphic cucumber (Cucumis sativus L.) isozyme loci were identified in 15 enzyme systems. Seven of the polymorphic loci (Ak-2, Ak-3, Fdp-1, Fdp-2, Mpi-1, Pep-gl, and Skdh) had not been described previously. Segregation in F2 and BC families for isozyme and morphological loci demonstrated agreement with the expected 1?2?1 and 1?1 segregation ratio (P<0.01). Nine morphological markers were found to be linked to isozyme loci and were integrated to form a map containing four linkage groups spanning 584 cM with a mean linkage distance of approximately 19 cM. Linkage groups (A to D) contain the following loci in genetic order: A psl, Pep-la, B, Per, dm, Pgm, Mpi-1, Idh, Ar, Fdp-1, Ak 2, Pgd-1, Mpi-2 and gl; B lh, Mdh-2, Pep-gl, Pgd-2, Fdp-2, Ccu, Mdh-3, Ak-3, ll, de, F and Mdh-1, and Gr; C cor, Gpi, and Skdh; D Tu and ss. This study detected four new linkages between morphological markers (dm-psl, de-ll, ll-F, and de-F) and confirmed previously reported linkages, dm-Ar and Tu-ss. The isozyme/morphological map constructed in this study led to a more comprehensive understanding of the genetic relationships between several economically important traits. PMID- 24166553 TI - Inheritance of resistance to the root-knot nematode Meloidogyne arenaria in Myrobalan plum. AB - The inheritance of resistance of the self-incompatible Myrobalan plum Prunus cerasifera to the root-knot nematode Meloidogyne arenaria was studied using first a diallel cross between five parents of variable host suitability (including two highly resistant clones P.1079 and P.2175, a moderate host P.2032, a good host P.2646 and an excellent host P.16.5), followed by the G2 crosses P.16.5 * (P.2646 * P.1079) and P.2646 * (P.16.5 * P.1079). A total of 355 G1 and 72 G2 clones obtained from hard-wood cuttings sampled from trees in the field experimental design, then rooted in the nursery and inoculated individually in containers (5 10 replicates per clone) under greenhouse conditions, were evaluated for their host suitability based on a 0-5 gall-index rating under a high and durable inoculum pressure of the nematode. In the crosses involving the resistant P.1079 and P.2175 and the hosts P.2646 and P.16.5: (1) all of the G1 crosses of P.1079 were resistant while the G2 crosses segregated 1 resistant to 1 host, (2) the G1 crosses between P.2175 and either P.2646 or P.16.5 segregated 1 resistant to 1 host, and (3) all of the G1 progeny between P.2646 and P.16.5 were host. These results indicate that resistance is conferred by a single major dominant resistance gene (homozygous) in P.1079, and the same, or an allelic or a different, major dominant gene (heterozygous) in P.2175, and that P.2646 and P.16.5 are recessive for this (these) major resistance gene(s). As expected according to the hypothesis of a recessive genotype for P.2032, all of its hybrids with P.1079 were resistant, all of its hybrids with P.2646 and P.16.5 were host, and its hybrids with P.2175 segregated for resistance. Nevertheless, the 3?2 segregation ratio of these latter hybrids suggests that clones bearing the P.2175 gene would have a selective advantage. Both resistance genes are completely dominant and confer a non-host behaviour that totally prevents the multiplication of the nematode. This is the first reported evidence of major nematode resistance genes towards M. arenaria in a species of the subgenus Prunophora in the genus Prunus. The symbols Ma1 for the P.2175 gene and Ma2 for the P.1079 gene are proposed. PMID- 24166554 TI - R6 and R7 alleles of potato conferring race-specific resistance to Phytophthora infestans (Mont.) de Bary identified genetic loci clustering with the R3 locus on chromosome XI. AB - In potato, 11 resistance alleles (R1-R11) are known which confer race-specific resistance to the fungus Phytophthora infestans. R1 has been mapped previously to potato chromosome V and R3 to chromosome XI. Here we report on the localization of the R6 and R7 alleles on the genetic map of potato. Differential resistant strains of tetraploid Solanum tuberosum, clones MaR6 and MaR7, were used as parental plants for the parthenogenetic induction and selection of diploid genotypes containing the R6 or the R7 resistance allele to P. infestans. One resistant dihaploid from MaR7 could be used directly as a parent to produce diploid F1 progeny suitable for phenotypic and RFLP analysis. MaR6 did not produce useful dihaploids directly. After crossing MaR6 with a tetraploid susceptible genotype, resistant F1 clones were selected. The resistant genotypes were then used as parents for the induction of dihaploids. Six dihaploids bearing R6 were identified that could be crossed with a diploid susceptible genotype. Two diploid F1 populations, segregating for R6 and R7, respectively, were analysed with RFLP markers known to be linked with previously identified R genes. Markers linked with R3 were found also to be linked with R6 and R7. The resistance alleles R6 and R7 mapped to a similar distal position on chromosome XI as the R3 allele. PMID- 24166555 TI - Effects of pollen selection on progeny vigor in a Cucurbita pepo x C. texana hybrid. AB - We examined the effects of pollen selection for rapid pollen-tube growth on progeny vigor. First, we crossed a wild gourd (Cucurbita texana) to a cultivated zucchini (Cucurbita pepo cv 'Black Beauty') to produce an F1 and then an F2 generation. Half of the F1 seeds were produced by depositing small loads of C. texana pollen onto the stigmas of C. pepo. These small pollen loads were insufficient to produce a full complement of seeds and, consequently, both the fast- and the slow-growing pollen tubes were permitted to achieve fertilization. An F2 generation was then produced by depositing small loads of F1 pollen onto stigmas of F1 plants. The F2 seeds resulting from two generations of small pollen loads are termed the non-selected line because there was little or no selection for pollen-tube growth rate on these plants. The other half of the F1 and F2 seeds were produced by depositing large pollen loads (>10 000 pollen grains) onto stigmas and then allowing only the first 1% or so of the pollen tubes that entered the ovary to fertilize the ovules. We did this by excising the styles at the ovary at 12-15 h after pollination. The resulting F2 seeds are termed 'the selected line' because they were produced by two generations of selection for only the fastest growing pollen tubes. Small pollen loads from the F2plants, both the selected and the non-selected lines, were then deposited onto stigmas of different C. pepo flowers, and the vigor of the resulting seeds was compared under greenhouse and field conditions. The results showed that the seeds fertilized by pollen from the selected line had greater vegetative vigor as seedlings and greater flower and fruit production as mature plants than the seeds fertilized by pollen from the non-selected line. This study demonstrates that selection for fast pollen-tube growth (selection on the microgametophyte) leads to a correlated increase in sporophyte (progeny) vigor. PMID- 24166556 TI - Selection of monosomic addition plants in offspring families using repetitive DNA probes in Beta L. AB - The distribution of two repetitive DNA probes Sat-121 and PB6-4, specific for the section Procumbentes of the genus Beta, was tested in 16 B. patellaris monosomic addition families using a dot-blot hybridization procedure. All monosomic additions were accurately distinguished from diploid sib plants with both DNA probes. The probe PB6-4, with the strongest signal after hybridization, was selected for rapid screening of an extensive number of putative monosomic additions in B. patellaris or B. procumbens addition families using a squash-blot hybridization procedure. The probe PB6-4 detected 118 monosomic additions in 640 plants (18.4%) in eight different B. procumbens addition families. The addition family with chromosome 4 of B. procumbens was semi-lethal and could not be tested. The distribution of PB6-4 in B. patellaris addition families was confirmed in 63 addition families using the squash-blot procedure. In 4580 plants of these addition families, 628 individual monosomic additions (13.7%) were found. The relationship of the morphological characteristics of monosomic addition plants to the results of the squash-blot hybridization (plants with signal) using probe PB6-4 is quite rigorous but not complete. The correlation between plants with a signal and chromosome number (2n=19) is complete. These results indicate that sequences present on PB6-4 are probably present on all chromosomes of B. patellaris and B. procumbens. The possibility of utilizing the sequence information of Sat-121 for a PCR-based assay to screen for putative monosomic addition plants was also investigated as an alternative to chromosome counting. The DNA-amplification profiles using the primers REP and REP.INV clearly distinguished monosomic addition plants from their diploid sibs. PMID- 24166557 TI - Mutations at the Asc locus of tomato confer resistance to the fungal pathogen Alternaria alternata f. sp. lycopersici. AB - The fungal pathogen Alternaria alternata f. sp. lycopersici produces host selective AAL-toxins that cause Alternaria stem canker in tomato. Susceptibility to the disease is based on the relative sensitivity of the host to the AAL-toxins and is controlled by the Asc locus on chromosome 3L. Chemical mutagenesis was employed to study the genetic basis of sensitivity to AAL-toxins and susceptibility to fungal infection. Following the treatment of seeds of a susceptible line with ethyl methanesulphonate (EMS), resistant M2 mutants were obtained. Most plants with induced resistances showed toxin-sensitivity responses that were comparable to those of resistant control lines carrying the Asc locus. In addition, genetic analysis of the mutagenised plants indicated that the mutations occurred at the Asc locus. Furthermore, novel mutants were identified that were insensitive to the AAL-toxins at the seedling stage but toxin-sensitive and susceptible to fungal infection at mature stages. No AAL-toxin-insensitive insertion mutants were identified following a transposon mutagenesis procedure. Molecular mechanisms involved in host defence against A a. lycopersici are discussed. PMID- 24166558 TI - Identification of quantitative trait loci under drought conditions in tropical maize. 1. Flowering parameters and the anthesis-silking interval. AB - Drought is an important climatic phenomenon which, after soil infertility, ranks as the second most severe limitation to maize production in developing countries. When drought stress occurs just before or during the flowering period, a delay in silking is observed, resulting in an increase in the length of the anthesis silking interval (ASI) and in a decrease in grain yield. Selection for reduced ASI in tropical open-pollinated varieties has been shown to be correlated with improved yields under drought stress. Since efficient selection for drought tolerance requires carefully managed experimental conditions, molecular markers were used to identify the genomic segments responsible for the expression of ASI, with the final aim of developing marker-assisted selection (MAS) strategies. An F2population of 234 individuals was genotyped at 142 loci and F3 families were evaluated in the field under several water regimes for male flowering (MFLW), male sterility (STER), female flowering (FFLW) and ASI. The genetic variance of ASI increased as a function of the stress intensity, and the broad-sense heritabilites of MFLW, FFLW and ASI were high under stress conditions, being 86%, 82% and 78%, respectively. Putative quantitative trait loci (QTLs) involved in the expression of MFLW and/or FFLW under drought were detected on chromosomes 1, 2, 4, 5, 8, 9 and 10, accounting for around 48% of the phenotypic variance for both traits. For ASI, six putative QTLs were identified under drought on chromosomes 1, 2, 5, 6, 8 and 10, and together accounted for approximately 47% of the phenotypic variance. Under water stress conditions, four QTLs were common for the expression of MFLW and FFLW, one for the expression of ASI and MFLW, and four for the expression of ASI and FFLW. The number of common QTLs for two traits was related to the level of linear correlation between these two traits. Segregation for ASI was found to be transgressive with the drought-susceptible parent contributing alleles for reduced ASI (4 days) at two QTL positions. Alleles contributed by the resistant line at the other four QTLs were responsible for a 7 day reduction of ASI. These four QTLs represented around 9% of the linkage map, and were stable over years and stress levels. It is argued that MAS based on ASI QTLs should be a powerful tool for improving drought tolerance of tropical maize inbred lines. PMID- 24166559 TI - Transmission of hepatitis C from a midwife to a patient through non-exposure prone procedures. AB - A woman developed acute hepatitis C (HCV) infection 2 months after delivering her baby at a London Hospital. The other patients who had been on the unit at the same time all had negative HCV serology antenatally. Testing of the healthcare workers who had been involved in this patient's care revealed that one of the midwives who only worked on the postnatal unit was chronically infected with the same viral genotype. Sequencing and phylogenetic analysis revealed close identity between the viruses from the two individuals. Although, the midwife had only performed non-exposure prone procedures including venepuncture and cannulation, our findings indicate that transmission of the virus had occurred from the healthcare worker to the patient. The potential implications of this case within the setting of national policy on blood borne viruses and healthcare workers are discussed. PMID- 24166560 TI - Effect of lipoic acid and alpha-glyceryl-phosphoryl-choline on astroglial cell proliferation and differentiation in primary culture. AB - Lipoic acid plays a crucial role as antioxidant and metabolic component of enzymes involved in glucose metabolism of different cell types. Choline alphoscerate (alpha-glyceryl-phosphoryl-choline [alphaGPC]) is a semisynthetic derivative of phosphatidylcholines representing, among acetilcholine precursors, a cholinergic drug. In the present study, we evaluated the expression of some proliferation and differentiation markers in 15 or 21 DIV astrocyte cultures treated with 50 MUM (+)lipoic acid or (+/-)lipoic acid and/or 10 mM alphaGPC for 24 hr. In addition, we evaluated the possible genoprotective effect by analysis of DNA status detected by alkaline comet assay. The addition of single drugs [(+)lipoic acid, (+/-)lipoic acid, or alphaGPC] induced an "upward modulation" of the expression of biomarkers used in our study. On the contrary, the cotreatment with either (+)lipoic acid + alphaGPC or (+/-)lipoic + alphaGPC surprisingly showed no significant modification or even a downregulation of the above mentioned biomarkers. This latter finding demonstrated no additional effect after the cotreatment with both drugs with respect to the single treatments alone. Further studies are necessary to clarify the specific mechanism evoked by the processing of these neuroprotective agents in our in vitro models. Finally, these preliminary findings may represent a good tool with which to clarify the antioxidant and metabolic roles played by lipoic acid in proliferating and differentiating astroglial cell cultures, during an interactive cross-talk between glial and neuronal cells, after brain lesions or damage correlated with oxidative stress that may occur in some degenerative diseases. PMID- 24166561 TI - Factors affecting the occurrence of symptomatic intracerebral haemorrhage after intravenous thrombolysis depending on the haemorrhage definition. AB - BACKGROUND AND PURPOSE: Symptomatic intracerebral haemorrhage (sICH) remains the most feared complication of systemic thrombolysis in patients with ischaemic stroke. The aim of the study was to analyze the impact of different factors on the occurrence of sICH, depending on definition used. MATERIAL AND METHODS: We retrospectively evaluated the influence of several factors on the occurrence of sICH (according to definitions used in ECASS2, SITS-MOST and NINDS studies) in 200 patients treated with systemic thrombolysis from 2006 to 2011. Multivariate analysis of impact of individual variables on the occurrence of haemorrhagic transformation (HT) and parenchymal haemorrhage type 2 (PH2) were performed. RESULTS: Haemorrhagic transformation occurred in 35 cases (17.5%). SICH was found in 10 cases according to ECASS2, in 7 cases according to SITS and in 13 cases according to NINDS. Older age was related to higher risk of sICH, regardless which definition was used (ECASS2: p = 0.014, SITS-MOST: p = 0.048, NINDS: p = 0.008), and female sex was related to higher risk of sICH according to NINDS and ECASS2 definition (p = 0.002 and p = 0.04, respectively). Blood glucose level and high NIHSS score (> 14 pts) were found as risk factor of sICH in ECASS2 definition (p = 0.044 and p = 0.03, respectively). In multivariate logistic regression higher NIHSS scores were associated with HT independent of age, gender and glucose level (p = 0.012). Multivariate analysis showed no impact of age, gender, severity of stroke and glucose level on presence of PH2. CONCLUSIONS: Definition of sICH can determine variables that are related to a high risk of this complication. In our study most factors correlated with sICH using the ECASS2 definition. PMID- 24166562 TI - No effects of anodal transcranial direct stimulation on language abilities in early rehabilitation of post-stroke aphasic patients. AB - BACKGROUND AND PURPOSE: Recent research suggests that an increased level of stroke-affected left hemisphere cortical (especially frontal) excitability is associated with better language improvement in aphasic patients. Anodal transcranial direct current stimulation (A-tDCS), increasing cortical activity, may facilitate perilesional left hemisphere recruitment to subserve language processing and enhance effects of behavioural therapy. The aim of the study (randomized, double-blind, sham-controlled) was to evaluate the effectiveness of repeated A-tDCS over Broca area as a strategy to enhance aphasia recovery during early post-stroke rehabilitation. MATERIAL AND METHODS: Thirty-seven participants with moderate or severe aphasia were randomized to receive 15 consecutive daily sessions of A-tDCS (1 mA, 10 min; experimental group, n = 18) or sham stimulation (1 mA, 25 s; control group, n = 19) followed by language therapy. Effects of tDCS were assessed using the Boston Diagnostic Aphasia Examination, performed before and after the rehabilitation, and three months later. RESULTS: The results did not confirm a positive impact of repeated A-tDCS, preceding language therapy, on language abilities in our patients. Although both groups improved after the therapy, there were no statistically significant differences between groups in either short-term or long-term tDCS effects. Effect sizes for the experimental group, at post-treatment and the 3-month follow-up, were slightly higher than in controls but insufficient to infer any beneficial influence of the applied intervention. CONCLUSIONS: The findings do not support A-tDCS functional benefits during early rehabilitation of post-stroke aphasia. Further research is needed to explore the effectiveness of this kind of neuromodulation. PMID- 24166563 TI - Causes and consequences of falls in Parkinson disease patients in a prospective study. AB - BACKGROUND AND PURPOSE: Falls are common events in Parkinson disease (PD) but only a few prospective studies have focused on causes and consequences of falls in PD patients. The aim of the study was prospective analysis of direct causes and consequences of falls in PD patients in comparison to the control group. MATERIAL AND METHODS: One hundred PD patients and 55 age-matched controls were enrolled in the study. The diagnostic workup in all patients included neurological examination, Unified Parkinson's Disease Rating Scale, magnetic resonance imaging, electroencephalography, ultrasonography, otolaryngological, ophthalmological and autonomic function examination. During 12 months of follow up, falls were registered in both groups, direct causes were classified according to the St. Louis and Olanow classification, and consequences were established. RESULTS: Falls occurred in 54% of PD patients and in 18% of control subjects. Analysis of direct causes of falls revealed that sudden falls were the most common (31%), followed by episodes of freezing and festination (19.6%), neurological and sensory disturbances (mostly vertigo) (12%), environmental factors (12%), postural instability (11%), orthostatic hypotension (4%), and severe dyskinesia (3.6%); 6.19% of falls were unclassified; 22% of patients had the same etiology of subsequent falls. In PD patients, intrinsic factors were dominant, whereas in the control group intrinsic and extrinsic factors occurred with the same frequency. Every third fall intensified fear of walking. 34% of falls caused injuries; among them bruises of body parts other than the head were most frequent. CONCLUSIONS: Intrinsic factors are the most common causes of falls in PD. Every third fall intensifies fear of walking and causes injuries. PMID- 24166564 TI - The incidence and risk factors of falls in Parkinson disease: prospective study. AB - BACKGROUND AND PURPOSE: Although Parkinson disease (PD) patients suffer falls more frequently than other old people, only a few studies have focused on identifying the specific risk factors for falls in PD patients. The aim of this study was to assess the incidence and risk factors of falls in a prospective study in comparison to a control group. MATERIAL AND METHODS: One hundred patients with PD were recruited to the study along with 55 gender- and age matched healthy controls. Both groups were examined twice; the second examination took place one year after the first one. Examination of the PD group included: medical history including falls, neurological examination, assessment of the severity of parkinsonism [Unified Parkinson's Disease Rating Scale (UPDRS), Schwab and England scale (S and E), Hoehn and Yahr scale (H and Y), Mini-Mental State Examination (MMSE)], Hamilton scale and quality of life scales (SF-36, EQ 5D) and Freezing of Gait Questionnaire (FOG-Q). In both groups falls were recorded over the 12 months. Frequent fallers are defined as having more than 3 falls a year. RESULTS: Over the year falls occurred in 54% of PD patients and 18% of controls. In a prospective study 28% of PD patients fell more frequently than in retrospective analysis. Frequent fallers were found in 20% of patients and in 7% of controls. Fallers showed higher scores in UPDRS, H and Y, S and E, MMSE, and Hamilton scale than non-fallers. Independent risk factors for falls were: age, previously reported falls and higher score in the FOG-Q. CONCLUSIONS: Falls in PD patients occurred three times more frequently than in controls. Independent risk factors for falls were: high score in FOG-Q, older age and presence of falls in medical history. PMID- 24166565 TI - Magnetic resonance spectroscopy in intracranial tumours of glial origin. AB - BACKGROUND AND PURPOSE: To determine in vivo magnetic resonance spectroscopy (MRS) characteristics of intracranial glial tumours and to assess MRS reliability in glioma grading and discrimination between different histopathological types of tumours. MATERIAL AND METHODS: Analysis of spectra of 26 patients with glioblastomas, 6 with fibrillary astrocytomas, 4 with anaplastic astrocytomas, 2 with pilocytic astrocytoma, 3 with oligodendrogliomas, 3 with anaplastic oligodendrogliomas and 17 control spectra taken from healthy hemispheres. RESULTS: All tumours' metabolite ratios, except for Cho/Cr in fibrillary astrocytomas (p = 0.06), were statistically significantly different from the control. The tumours showed decreased Naa and Cr contents and a high Cho signal. The Lac-Lip signal was high in grade III astrocytomas and glioblastomas. Reports that Cho/Cr ratio increases with glioma's grade whereas Naa/Cr decreases were not confirmed. Anaplastic astrocytomas compared to grade II astrocytomas had a statistically significantly greater mI/Cr ratio (p = 0.02). In pilocytic astrocytomas the Naa/Cr value (2.58 +/- 0.39) was greater, whilst the Cho/Naa ratio was lower (2.14 +/- 0.64) than in the other astrocytomas. The specific feature of oligodendrogliomas was the presence of glutamate/glutamine peak Glx. However, this peak was absent in two out of three anaplastic oligodendrogliomas. Characteristically, the latter tumours had a high Lac-Lip signal. CONCLUSIONS: MRS in vivo cannot be used as a reliable method for glioma grading. The method is useful in discrimination between WHO grade I and WHO grade II astrocytomas as well as oligodendrogliomas from other gliomas. PMID- 24166566 TI - The influence of the menstrual cycle on the result of brain examination with hydrogen magnetic resonance spectroscopy - a pilot study. AB - BACKGROUND AND PURPOSE: Hydrogen magnetic resonance spectroscopy (1HMRS) is nowadays one of the basic tools for noninvasive brain metabolism assessment. The study focuses on the important problem of the influence of hormone fluctuation during the menstrual cycle on brain metabolism, assessed by 1HMRS for clinical diagnostics. MATERIAL AND METHODS: In 11 healthy regularly menstruating women, 1HMRS was performed at the start (phase I), in the middle (phase II) and at the end (phase III) of the menstrual cycle. The relative concentration ratios of 12 brain metabolites in every woman in all cycle phases were examined, in 6 different volumes of interest (VOIs). Finally, statistically significant differences in relative metabolite ratios between the phases examined in given locations were sought. RESULTS: Statistically significant relations between menstrual cycle phases and relative ratios of 4 metabolites - Lac/Cr, NAA/Cr, Glx1/Cr and Glx2/Cr - in different brain locations were found. In all locations, mean NAA/Cr ratios were greater in phase I compared to the other phases. A similar relationship was found for Glx1/Cr ratio in one location (left occipital lobe). For Lac/Cr and Glx2/Cr ratios, a higher mean ratio value was obtained in phase II compared to phases I and III in the right occipital lobe and left basal ganglia, respectively. CONCLUSIONS: Menstrual cycle phase should be considered in planning a date and interpretation of 1HMRS examination, performed for the verification of a disease manifesting as brain metabolite disturbances in the 1HMRS spectrum. PMID- 24166567 TI - Surgical management of posterior petrous meningiomas. AB - BACKGROUND AND PURPOSE: The aim of the study is to present our experience in the surgical treatment of posterior petrous meningiomas in regard to clinical presentation, surgical anatomy, complications and long-term functional postoperative results. MATERIAL AND METHODS: A series of 48 consecutive patients operated on for posterior petrous meningiomas at the authors' institution between 2002 and 2011 is reported. The main symptom on first admission was hypoacusis, impairment of the fifth cranial nerve and cerebellar ataxia. The tumour was found to be attached to the premeatal dura in 46%, the inframeatal dura in 29% and the postmeatal dura in 25% of cases. Tumour resection was categorized as grade I in 16 patients, grade II in 29 patients, grade III in 1 patient and grade IV in 2 patients, according to the Simpson classification system. The petrosal approach and retrosigmoid approach were suitable for posterior petrous meningiomas. RESULTS: Postoperative facial nerve dysfunction appeared in 8 and further deteriorated in 2 patients. Hearing function deteriorated after surgery in 8 and improved in 2 cases. Perioperative death occurred in two patients. Tumour recurrence was observed in two patients, and both underwent a second operation and postoperative stereotactic radiotherapy. CONCLUSIONS: Surgical treatment of posterior petrous meningiomas has become increasingly safe but these tumours still remain a surgical challenge because of the relatively high incidence of permanent complications associated with their removal. The site of displacement of the cranial nerves depending on the dural origin of the tumour has the most influence on the related difficulties in its removal. PMID- 24166568 TI - Results of endovascular treatment of aneurysms depending on their size, volume and coil packing density. AB - BACKGROUND AND PURPOSE: In contrast to neurosurgery, which is more efficient, endovascular treatment (EVT) is less invasive. The main purpose of EVT is complete occlusion of the aneurysm and protection from subarachnoid haemorrhage. Accurate measurements of the aneurysm (size, volume) obtained using a 3D digital subtraction angiography (DSA) workstation can assist in the proper assessment of coil packing density (CPD), which affects possible distant recanalization. The main disadvantage of endovascular treatment of intracranial aneurysms compared to neurosurgery is the high recurrence rate. We evaluated the results of endovascular treatment of aneurysms depending on their size, volume and coil packing density. MATERIAL AND METHODS: Thirty-five patients with intracranial aneurysms underwent endovascular embolization with bare platinum coils. Three dimensional DSA was used to evaluate aneurysms' morphology. Eighteen patients underwent 3D DSA follow-up 6-45 months after treatment. Initial and follow-up results of embolization were assessed with the Raymond-Montreal scale. The impact of aneurysms' morphology, volume and initial CPD on endovascular treatment was evaluated. RESULTS: Among 35 patients, complete initial embolization was achieved in 74%. Mean initial aneurysm volume in 3D DSA was 0.517 mL and decreased significantly after embolization. Initial CPD varied from 74% to 2% depending on aneurysm diameter (12.1% for aneurysms >= 10 mm, 22.5% for aneurysms < 10 mm). Results of embolization on the Raymond-Montreal scale significantly depended on aneurysms' CPD. Aneurysms' recanalization rate on 3D DSA follow-up was 36%, with complete recanalization in 3.3%. CONCLUSIONS: We can achieve a better outcome if size and volume of the aneurysm sac is smaller and if CPD is higher. PMID- 24166569 TI - [Apomorphine in advanced Parkinson disease]. AB - Apomorphine is the most potent dopamine receptor agonist and its symptomatic effectiveness is comparable to levodopa. Subcutaneous apomorphine is rapidly and completely absorbed. Plasma peak concentrations are achieved after 5-15 minutes and onset of clinical effect is within 20 minutes. Apomorphine intermittent subcutaneous injections are effective as rescue therapy for unpredictable off periods in advanced Parkinson disease (PD). More often apomorphine is administered as a subcutaneous infusion which secures the continuous dopaminergic stimulation. The benefit on 'off' periods is consistent across all studies, but dyskinesia improvement is not so obvious. Two infusion therapies (apomorphine and intraduodenal levodopa) and deep brain stimulation (DBS) are effective in advanced PD patients with untreatable motor complications. Apomorphine infusions should be considered in patients unable to undergo DBS because of cognitive impairment and neurosurgical contraindications. PMID- 24166570 TI - [Need for creating Polish registry of multiple sclerosis patients]. AB - Multiple sclerosis (MS) is the most common cause of neurological disability of young people. It is estimated that 40 000-60 000 people in the country suffer from MS, and approximately 2000 new cases are diagnosed annually. These are, however, estimated data and require verification by nation-wide research. Results published so far concern only certain regions of Poland. It is also vital to precisely describe the needs of patients in terms of immunomodulating treatment and to perform detailed pharmacoeconomical analysis. In order to estimate basic epidemiological parameters there is a need of creating, in imitation of many other countries, a national register of MS patients which would concentrate all assets concerning MS around this project. The article presented the most important of American and European databases and explained the basis of the Polish register of MS patients, which is already functioning in one of the regions. PMID- 24166571 TI - Nemaline myopathy in a newborn infant: a rare muscle disorder. AB - Nemaline myopathy (NM) is a genetically and clinically heterogeneous muscle disorder, defined by the presence of characteristic nemaline bodies on muscle biopsy. The disease has a wide spectrum of phenotypes, ranging from forms with neonatal onset and fatal outcome to asymptomatic forms. The neonatal form is severe and usually fatal. The clinical variability, with differing age of onset and severity of symptoms makes the diagnosis difficult during infancy. There is no curative treatment. L-tyrosine may prevent aspiration by reducing pharyngeal secretions and drooling. Most of the patients die from respiratory and cardiac failure. This article discusses a newborn infant who presented with generalized weakness and respiratory failure. Partial response to L-tyrosine treatment was noted. The case is worth presenting to remind clinicians of congenital myopathies in the differential diagnosis of floppy infant during neonatal period and to emphasize the importance of muscle biopsy in diagnosis. PMID- 24166572 TI - Idiopathic trigeminal sensory neuropathy. A case report. AB - Idiopathic trigeminal sensory neuropathy is a rare clinical condition characterized by sensory disturbances on the face. Its symptoms may be permanent or temporary and a wide variety of diagnostic procedures is usually required to establish the diagnosis. Frequently, it is the first manifestation of a systemic disorder. In the majority of cases causal treatment is not possible, even though patients with trigeminal sensory neuropathy should be carefully monitored by physicians. PMID- 24166573 TI - Acute focal dystonia induced by a tricyclic antidepressant in a patient with Wilson disease: a case report. AB - The authors present the case of a 19-year-old patient with Wilson disease (WD) who developed symptoms of acute focal dystonia of the left hand (a 'starfish' hand presentation) shortly after treatment with the tricyclic antidepressant clomipramine. The diagnosis of WD was made 8 months earlier based on abnormal copper metabolism parameters and was confirmed by genetic testing. Initially, the patient presented with akathisia, sialorrhea, oromandibular dystonia (occasionally grimacing) and slight dysarthria. The patient's symptoms diminished after treatment with d-penicillamine was initiated. No further deterioration was observed after copper-chelating therapy was started. The authors diagnosed acute focal dystonia induced by clomipramine. Botulinum toxin and intensive rehabilitation was initiated; complete regression of hand dystonia was observed. Based on the case, the authors suggest that care should be exercised with regard to starting medications that could potentially impact the extrapyramidal system in WD patients. PMID- 24166574 TI - Synthesizing lessons learned from get with the guidelines: the value of disease based registries in improving quality and outcomes. PMID- 24166576 TI - DHAP-dependent aldolases from (hyper)thermophiles: biochemistry and applications. AB - Generating new carbon-carbon (C-C) bonds in an enantioselective way is one of the big challenges in organic synthesis. Aldolases are a natural tool for stereoselective C-C bond formation in a green and sustainable way. This review will focus on thermophilic aldolases in general and on dihydroxyacetone phosphate dependent aldolases in particular. Biochemical properties and applications for synthesis of rare sugars and carbohydrates will be discussed. PMID- 24166575 TI - Secondary prevention of atherosclerotic cardiovascular disease in older adults: a scientific statement from the American Heart Association. PMID- 24166577 TI - Time-resolved angiography using inflow subtraction (TRAILS). AB - PURPOSE: A novel pseudo-continuous arterial spin labeling based angiographic method called Time-Resolved Angiography using InfLow Subtraction is introduced and used to acquire time-resolved whole-head angiographic data sets in healthy volunteers in a clinical feasible scan time of less than 5 min. METHODS: Using this new method, in conjunction with a sliding window reconstruction, a temporal resolution of 7.2 ms with a low temporal footprint of 432 ms can be achieved. RESULTS: Excellent vessel delineation compared to a time-of-flight MRA was demonstrated. Normal variations of the vascular system including the Circle of Willis (CoW) were identified using Time-Resolved Angiography Using Inflow Subtraction. Signal intensities were measured in various vascular segments to quantify the blood transit time. CONCLUSION: In this feasibility study, we showed that Time-Resolved Angiography using InfLow Subtraction can be used to acquire hemodynamic information of the whole head in healthy volunteers with a high temporal and spatial resolution. Further studies in patients that suffer from vascular diseases to explore various flow patterns including longer transit time are needed. PMID- 24166578 TI - Distinct physiological and developmental properties of hippocampal CA2 subfield revealed by using anti-Purkinje cell protein 4 (PCP4) immunostaining. AB - The hippocampal CA2 subfield was initially identified by Lorente de No as an anatomically distinct region based on its cytoarchitectural features. Although there is an enormous body of literature on other hippocampal subfields (CA1 and CA3), relatively little is known about the physiological and developmental properties of CA2. Here we report identification of the CA2 region in the mouse by immunostaining with a Purkinje cell protein 4 (PCP4) antibody, which effectively delineates CA3/CA2 and CA2/CA1 borders and agrees well with previous cytoarchitectural definitions of CA2. The PCP4 immunostaining-delineated CA2 neurons have distinguishable differences in cell morphology, physiology, and synaptic circuit connections compared with distal CA3 and proximal CA1 regions. The average somatic sizes of excitatory cells differ across CA1-3, with the smallest to largest somatic size being CA1 LEW) are also evident in prepubescence (early adolescence). To assess this possibility, adult (Experiment 1) and prepubertal (Experiment 2) F344 and LEW rats were assessed for their ability to acquire morphine-induced taste avoidance (0, 3.2, 10, or 18 mg/kg) in a modified taste avoidance procedure. In each experiment, rats of both strains were given repeated pairings of saccharin and morphine followed by a final two-bottle avoidance test. Adult and prepubertal F344 subjects displayed a more rapid acquisition of the avoidance response as well as stronger suppression of consumption than their LEW counterparts. These data suggest the strains differ in their sensitivity to the aversive effects of morphine and that this differential sensitivity is evident early in development and is developmentally stable. The basis for these strain differences in morphine induced avoidance was discussed. PMID- 24166593 TI - In young men sperm telomere length is related to sperm number and parental age. AB - STUDY QUESTION: What are the relationships between telomere lengths in leukocytes and sperm, sperm count and parents' age at conception in a group of apparently healthy subjects of the same age? SUMMARY ANSWER: Sperm telomere length (STL) is related to sperm count, it is lower in oligozoospermic than in normozoospermic men and it is directly related to parents' age at conception. WHAT IS KNOWN ALREADY: Leukocyte telomere length (LTL) decreases with age but STL increases and offspring of older fathers tend to have longer leukocyte telomeres. Only one study analyzed STL in relation to male fertility, and reported shorter telomeres in infertile versus fertile men. No data have been reported on STL in relation to parents' age at conception. STUDY DESIGN, SIZE, DURATION: Prospective study conducted from January to December 2012 of 18-19-year-old high school students. PARTICIPANTS/MATERIALS, SETTING AND METHODS: The volunteers were 81 apparently healthy subjects, including 61 with normozoospermia and 20 with idiopathic oligozoospermia. Leukocyte and sperm telomere length were measured by real-time PCR. Data were analyzed for determining the relationships between LTL, STL, sperm count and parents' age at conception. MAIN RESULTS AND THE ROLE OF CHANCE: Sperm and leukocyte telomere length were strongly correlated, but STL was significantly longer. A significant positive correlation between STL and total sperm number was found. STL was significantly lower in oligozoospermic than in normozoospermic men. Finally, we found a significant positive relationship between maternal age and both leukocyte and sperm telomere length and a significant positive relation between paternal age and STL in the offspring. The relative contributions of mothers' and fathers' ages to their offspring's telomere length could not be determined because of the high correlation between paternal and maternal ages. LIMITATIONS AND REASONS FOR CAUTION: Although consistent with previous findings, this is the first study on telomere length in oligo- and normozoospermic men and included a relatively low number of subjects. Our study was also restricted to young (18-19 year old) men, so future studies should determine whether our findings can be generalized to men at ages typically encountered at fertility centers. Future studies should also try to determine the possible effect of abstinence time and frequency of ejaculation with STL. WIDER IMPLICATIONS OF THE FINDINGS: Our study sheds new light on the association between STL and sperm count and on the inheritance of telomere length (in leukocytes and sperm) in relation to the parents' age at conception. Additional studies are needed to confirm these observations, to clarify if the association between shorter STL and damaged spermatogenesis represents a pathophysiological link, and to determine the effect on offspring telomere length of assisted reproduction techniques performed on couples of advanced age or where the man is oligozoospermic. STUDY FUNDING/COMPETING INTEREST(S): This work was supported by the Italian Ministry of University and Research (grant no. 2009AMPA9C to C.F.) and Padova University (grant 2010 to A.D.R.). The authors have no competing interests to declare. PMID- 24166594 TI - Modified natural cycle versus controlled ovarian hyperstimulation IVF: a cost effectiveness evaluation of three simulated treatment scenarios. AB - STUDY QUESTION: Can modified natural cycle IVF or ICSI (MNC) be a cost-effective alternative for controlled ovarian hyperstimulation IVF or ICSI (COH)? SUMMARY ANSWER: The comparison of simulated scenarios indicates that a strategy of three to six cycles of MNC with minimized medication is a cost-effective alternative for one cycle of COH with strict application of single embryo transfer (SET). WHAT IS KNOWN ALREADY: MNC is cheaper per cycle than COH but also less effective in terms of live birth rate (LBR). However, strict application of SET in COH cycles reduces effectiveness and up to three MNC cycles can be performed at the same costs as one COH cycle. STUDY DESIGN, SIZE, DURATION: The cost-effectiveness of MNC versus COH was evaluated in three simulated treatment scenarios: three cycles of MNC versus one cycle of COH with SET or double embryo transfer (DET) and subsequent transfer of cryopreserved embryos (Scenario 1); six cycles of MNC versus one cycle of COH with strictly SET and subsequent transfer of cryopreserved embryos (Scenario 2); six cycles of MNC with minimized medication (hCG ovulation trigger only) versus one cycle of COH with SET or DET and subsequent transfer of cryopreserved embryos (Scenario 3). We used baseline data obtained from two retrospective cohorts of consecutive patients (2005-2008) undergoing MNC in the University Medical Center Groningen (n = 499, maximum six cycles per patient) or their first COH cycle with subsequent transfer of cryopreserved embryos in the Academic Medical Center Amsterdam (n = 392). PARTICIPANTS/MATERIALS, SETTING, METHODS: Data from 1994 MNC cycles (958 MNC-IVF and 1036 MNC-ICSI) and 392 fresh COH cycles (one per patient, 196 COH-IVF and 196 COH-ICSI) with subsequent transfer of cryopreserved embryos (n = 72 and n = 94 in MNC and COH cycles, respectively) in ovulatory, subfertile women <36 years of age served as baseline for the three simulated scenarios. To compare the scenarios, the incremental cost-effectiveness ratio (ICER) was calculated, defined as the ratio of the difference in IVF costs up to 6 weeks postpartum to the difference in LBR. Live birth was the primary outcome measure and was defined as the birth of at least one living child after a gestation of >=25 weeks. MAIN RESULTS AND THE ROLE OF CHANCE: In the baseline data, MNC was not cost-effective, as COH dominated MNC with a higher cumulative LBR (27.0 versus 24.0%) and lower cost per patient (?3694 versus ?5254). The simulations showed that in scenario 1 three instead of six cycles lowered the costs of MNC to below the level of COH (?3390 versus ?3694, respectively), but also lowered the LBR per patient (from 24.0 to 16.2%, respectively); Scenario 2: COH with strict SET was less effective than six cycles MNC (LBR 17.5 versus 24.0%, respectively), but also less expensive per patient (?2908) than MNC (?5254); Scenario 3: improved the cost-effectiveness of MNC but COH still dominated MNC when medication was minimized in terms of costs, i.e. ?855 difference in favor of COH and 3% difference in LBR in favor of COH (ICER: ?855/-3.0%). LIMITATIONS, REASONS FOR CAUTION: Owing to the retrospective nature of the study, the analyses required some assumptions, for example regarding the costs of pregnancy and delivery, which had to be based on the literature rather than on individual data. Furthermore, costs of IVF treatment were based on tariffs and not on actual costs. Although this may limit the external generalizability of the results, the limitations will influence both treatments equally, and would therefore not bias the comparison of MNC versus COH. WIDER IMPLICATIONS OF THE FINDINGS: The combined results suggest that MNC with minimized medication might be a cost-effective alternative for COH with strict SET. The scenarios reflect realistic alternatives for daily clinical practice. A preference for MNC depends on the willingness to trade off effectiveness in terms of LBR against the benefits of a milder stimulation regimen, including a very low rate of multiple pregnancies and hyperstimulation syndrome and ensuing lower costs per live birth. STUDY FUNDING/COMPETING INTEREST(S): The study was supported by research grants from Merck Serono and Ferring Pharmaceuticals. The authors declare no conflicts of interest. TRIAL REGISTRATION NUMBER: Not applicable. PMID- 24166595 TI - Follicular fluid from infertile women with mild endometriosis may compromise the meiotic spindles of bovine metaphase II oocytes. AB - STUDY QUESTION: What is the potential impact of follicular fluid (FF) from infertile women with mild endometriosis (ME) on oocyte quality, especially on nuclear maturation and the meiotic spindle? SUMMARY ANSWER: FF from infertile women with ME may compromise nuclear maturation and the meiotic spindles of in vitro matured bovine oocytes. WHAT IS KNOWN ALREADY: Controversial studies have suggested that impaired oocyte quality may be involved in the pathogenesis of endometriosis-related infertility. Moreover, some studies have demonstrated alterations in the composition of FF from infertile women with endometriosis. However, to date no study has evaluated the effect of FF from infertile women with ME on the genesis of meiotic oocyte anomalies. STUDY DESIGN, SIZE, DURATION: We performed an experimental study. Samples of FF were obtained from February 2009 to February 2011 from 22 infertile women, 11 with ME and 11 with tubal or male factors of infertility (control group), who underwent ovarian stimulation for ICSI at our university IVF Unit. From March 2011 to February 2012 we performed in vitro maturation (IVM) experiments using immature bovine oocytes as described below. PARTICIPANTS/MATERIALS, SETTING, METHODS: FF free of blood and containing a mature oocyte was obtained from 22 infertile women during oocyte retrieval for ICSI. Immature bovine oocytes underwent IVM in the absence of FF (No-FF) and in the presence of four concentrations (1, 5, 10 and 15%) of FF from infertile women without endometriosis (C-FF) and with ME (ME-FF). Eleven replicates were performed, each one using FF from a control patient and a patient with ME. Each FF sample was used in only one experiment. After 22-24 h of IVM, oocytes were denuded, fixed and immunostained for morphological visualization of microtubules and chromatin by confocal microscopy. MAIN RESULTS AND THE ROLE OF CHANCE: A total of 1324 cumulus-oocyte complexes were matured in vitro. Of these, 1128 were fixed and 1048 were analyzed by confocal microscopy. The percentage of meiotically normal oocytes was significantly higher for oocytes that underwent IVM in the absence of FF (No-FF; 76.5%) and in the presence of 1% (80.9%), 5% (76.6%), 10% (75%) and 15% (76.2%) C-FF than in oocytes that underwent IVM in the presence of 1% (44.4%), 5% (36.7%), 10% (45.5%) and 15% (51.2%) ME-FF (P < 0.01). No differences were observed among FF concentrations within each group. When the four concentrations from each group were pooled, the number of oocytes in metaphase I stage was significantly higher in the ME-FF (50 oocytes) than in the C-FF (29 oocytes) group and the percentage of meiotic abnormalities was significantly higher when oocytes were matured with ME-FF (55.8%) than with C-FF (23.1%), P < 0.01. LIMITATIONS, REASONS FOR CAUTION: Owing to the strict selection criteria for FF donors, this study had a small sample size (11 cases and 11 controls), and thus further investigations using a large cohort of patients are needed to confirm these results. In addition, data obtained from studies using animal models may not necessarily be extrapolated to humans and studies evaluating in vivo matured oocytes from infertile women with ME are important to confirm our results. WIDER IMPLICATIONS OF THE FINDINGS: Our results open new insights into the pathogenic mechanisms of infertility related to mild endometriosis, suggesting that FF from infertile women with mild endometriosis may be involved in the worsening of oocyte quality of these women. STUDY FUNDING/COMPETING INTEREST(S): This study was supported by the National Council for Scientific and Technological Development (CNPq), Brazil. The authors declare no conflicts of interest. PMID- 24166596 TI - Rhythm outcomes after catheter ablation of atrial fibrillation. Clinical implication of biomarkers. AB - Atrial fibrillation (AF) occurs as the result of numerous complex physiological processes in the atria leading to AF promotion and maintenance. Improved diagnostic techniques have identified various biomarkers which may play an important role in the prediction of AF related outcomes (cardio- and cerebrovascular events, as well as mortality and rhythm outcomes). Biomarkers refer to 'biological markers' and biomarkers in blood, urine as well as imaging marker (eg, dimensions (left atrial diameter and volume), anatomical features (left appendage and pulmonary vein anatomy), and physiological pattern (LAA flow velocity)) may play important role(s) as clinically important indices in relation to outcomes after different therapeutic strategies. However, the main domain in the biomarker field has focused on blood-based biomarkers, which are widely used to predict therapeutic success regarding underlying pathophysiological mechanism, such as inflammation, fibrosis, endothelial damage. This review provides an update of the role of clinically relevant biomarkers in AF, with particular focus on AF rhythm outcomes. PMID- 24166597 TI - Glucose transport by epithelia prepared from harvested enterocytes. AB - Transformed and cultured cell lines have significant shortcomings for investigating the characteristics and responses of native villus enterocytes in situ. Interpretations of results from intact tissues are complicated by the presence of underlying tissues and the crypt compartment. We describe a simple, novel, and reproducible method for preparing functional epithelia using differentiated enterocytes harvested from the small intestine upper villus of adult mice and preterm pigs with and without necrotizing enterocolitis. Concentrative, rheogenic glucose uptake was used as an indicator of epithelial function and was demonstrated by cellular accumulation of tracer (14)C D-glucose and Ussing chamber based short-circuit currents. Assessment of the epithelia by light and immunofluorescent microscopy revealed the harvested enterocytes remain differentiated and establish cell-cell connections to form polarized epithelia with distinct apical and basolateral domains. As with intact tissues, the epithelia exhibit glucose induced short-circuit currents that are increased by exposure to adenosine and adenosine 5'-monophosphate (AMP) and decreased by phloridzin to inhibit the apical glucose transporter SGLT-1. Similarly, accumulation of (14)C D-glucose by the epithelia was inhibited by phloridzin, but not phloretin, and was stimulated by pre-exposure to AMP and adenosine, apparently by a microtubule-based mechanism that is disrupted by nocodazole, with the magnitudes of responses to adenosine, forskolin, and health status exceeding those we have measured using intact tissues. Our findings indicate that epithelia prepared from harvested enterocytes provide an alternative approach for comparative studies of the characteristics of nutrient transport by the upper villus epithelium and the responses to different conditions and stimuli. PMID- 24166598 TI - Salt ions and related parameters affect PEI-DNA particle size and transfection efficiency in Chinese hamster ovary cells. AB - Transfection efficiency is directly associated with the expression level and quantity of recombinant protein after the transient transfection of animal cells. The transfection process can be influenced by many still-unknown factors, so it is valuable to study the precise mechanism and explore these factors in gene delivery. Polyethylenimine (PEI) is considered to have high transfection efficiency and endosome-disrupting capacity. Here we aimed to investigate optimal conditions for transfection efficiency by setting different parameters, including salt ion concentration, DNA/PEI ratio, and incubation time. We examined the PEI DNA particle size using a Malvern particle size analyzer and assessed the transfection efficiency using flow cytometry in Chinese hamster ovary-S cells. Salt ions, higher amounts of PEI tended to improve the aggregation of PEI-DNA particles and the particle size of PEI-DNA complexes and the transfection efficiency were increased. Besides, the particle size was also found to benefit from longer incubation time. However, the transfection efficiency increased to maximum of 68.92 % at an incubation time of 10 min, but decreased significantly thereafter to 23.71 %, when incubating for 120 min (P < 0.05). Besides, PEI-DNA complexes formed in salt-free condition were unstable. Our results suggest DNA and PEI incubated in 300 mM NaCl at a ratio of 1:4 for 10 min could achieve the optimal transfection efficiency. Our results might provide guidance for the optimization of transfection efficiency and the industrial production of recombinant proteins. PMID- 24166599 TI - Preparation of andrographolide-loaded solid lipid nanoparticles and their in vitro and in vivo evaluations: characteristics, release, absorption, transports, pharmacokinetics, and antihyperlipidemic activity. AB - Andrographolide (AND) is one of diterpenoids separated from Andrographis paniculata with a wide spectrum of biological activities of being anti inflammatory, anticancer, hepatoprotective, and antihyperlipidemic. But its poor water solubility and instability resulted in lower bioavailability and seriously limited its pharmacological function. In this study, AND-loaded solid lipid nanoparticles (AND-SLNs) were prepared by a high-pressure homogenization method and presented as spherically shaped under transmission electron microscopy with an average diameter of 286.1 nm and zeta potential of -20.8 mV. The average drug entrapment efficiency and drug loading were 91.00% and 3.49%, respectively. The results indicated that the lower bioavailability of AND is not only because of the poor solubility but also owing to its metabolic instability in intestinal segments. Furthermore, the transport mechanism of AND in Caco-2 cell model is complex in which an active transport carrier (P-glycoprotein) is involved in. The bioavailability and antihyperlipidemic activity of AND were improved by AND-SLNs by increasing the solubility and stability of AND in the intestine and by changing its transport mode in Caco-2 cell. The bioavailability of AND was increased to 241% by AND-SLNs as compared with AND suspension. AND-SLNs would be a promising drug-delivery system to enhance the oral absorption and bioavailability of AND. PMID- 24166600 TI - High nuclear phosphorylated extracellular signal-regulated kinase expression associated with poor differentiation, larger tumor size, and an advanced stage of breast cancer. AB - Extracellular signal-regulated kinase (ERK1/2) is implicated in the malignant behavior of breast cancer cells. However, previous clinical-pathological studies have shown that expression of activated/phosphorylated ERK1/2 is not associated with enhanced proliferation and invasion of mammary carcinomas. ERK1/2 is expressed in the cytoplasm, and activated/phosphorylated ERK1/2 translocates to the nucleus. The aim of this study is to evaluate nuclear phosphorylated ERK1/2 as a biomarker for breast cancer prognosis. The clinical-pathological relation of cytoplasmic/nuclear phosphorylated ERK1/2 was analyzed in 105 surgically resected breast cancer specimens by immunohistochemistry with tissue microarray. The results showed that non-neoplastic breast tissue mainly showed faint phosphorylated ERK1/2 staining. No statistically significant association was found between the level of cytoplasmic phosphorylated ERK1/2 expression and the clinical features of the disease. High nuclear phosphorylated ERK1/2 expression was associated with high grade (poor differentiation, p = = 0.010), high T status (larger tumor size, p = 0.033), and an advanced stage (p = 0.018) of the disease. Thus, nuclear phosphorylated ERK1/2 is associated with enhanced proliferation and invasion of mammary carcinomas and may be a biomarker for breast cancer prognosis and the determination of therapeutic strategies. PMID- 24166601 TI - Lymph node micrometastases of adenocarcinoma located in gastroesophagal junction. AB - BACKGROUND: The aim of this study was to evaluate the presence of micrometastases (MM) and tumor cell microinvolvement (TCM) in regional lymph nodes of patients with gastroesophageal junction adenocarcinoma. MATERIAL AND METHODS: 61 patients with adenocarcinoma (stage N0) were included in this study. Lymph nodes removed during surgery were examined using mixed monoclonal antibodies against pan cytokeratins (AE1/AE3). Micrometastases was defined as single neoplastic cells or infiltration with diameter below 0.5 mm but not involving the interstitium. RESULTS: Micrometastases were found in 2 cases with adenocarcinoma type I and 4 cases with type III. Tumor cell microinvolvement was found in 2 cases of either adenocarcinoma type I or type III (according to Siewert's classification). Presence of MM did not influence survival rate. CONCLUSIONS: Despite no influence of MM presence on survival rate, MM came from adenocarcinoma type III more frequently. The presence of MM proved lack of homogeneity in the group of N0 stage and makes evaluation advantageous. PMID- 24166602 TI - Frequency of ERG-positive prostate carcinoma in Polands. AB - Prostatic carcinoma (PC) is one of the most frequent cancers in men. Molecular pathogenesis of PC remains poorly understood. Translocations involving ERG were found to be the single most frequent genetic event. A strong correlation exists between this translocation and ERG positivity on immunohistochemistry. The rate of ERG positivity and its relationship with other clinicopathological parameters differ between populations and between studies; in particular, there are few data on ERG-positive PC in Eastern Europeans. In the present study, tissue microarrays of unselected PC cases were constructed and standard immunohistochemistry for ERG performed. The results were compared with the basic pathologic prognostic parameters. The group under study consisted of 113 cases; 52 (46.02%) were positive for ERG. The positive cases showed a slightly higher Gleason score (median 6 vs. 7). The majority of ERG-positive cases showed nerve bundle invasion and were also less likely to be prostate confined than negative ones. In conclusion, the frequency of ERG-positive PC in our series is similar to Western populations, and they show some unfavorable prognostic features. PMID- 24166603 TI - The immunohistochemical expression of CD24 and CD171 adhesion molecules in borderline ovarian tumors. AB - CD24 and CD171 are cell adhesion proteins, which have been shown to be overexpressed in several carcinomas and to be associated with a poor clinical outcome. Our aim was to determine the expression of these two adhesion molecules in ovarian borderline neoplasms. We investigated 50 ovarian borderline tumors (serous, mucinous and endometrioid) as well as 29 benign cystadenomas and 25 carcinomas, which were used as controls. Paraffin sections were stained immunohistochemically for CD24 and CD171, and their expression was recorded in a semi-quantitative manner. In normal epithelium and benign ovarian cystadenomas both the CD24 and CD171 expression was negative to low, while their expression was significantly increased in borderline and malignant ovarian tumors. High grade carcinomas, and carcinomas with metastases to the omentum presented considerably higher CD24 expression than low-grade carcinomas, and carcinomas without metastases. In addition, a few borderline and many malignant tumors presented cytoplasmic CD24 immunoreactivity, whereas all benign and most borderline tumors showed apical localization of this molecule. In conclusion, borderline tumors and carcinomas of the ovary present increased expression of CD24 and CD171 in relation to their benign counterparts, as is the case in malignant tumors of other organs. Change of staining pattern of CD24 (apical to cytoplasmic) apparently relates to a more aggressive phenotype. PMID- 24166604 TI - Association of Thr241Met polymorphism of XRCC3 gene with risk of colorectal cancer in the Polish population. AB - DNA double strand breaks (DSBs) are the most dangerous lesions which can lead to carcinogenesis. Homologous recombination (HR) is an important pathway responsible for maintaining genome integrity through repair of DSBs. Single nucleotide polymorphism (SNP) is an essential source of genetic variation whose presence in genes involved in HR may have a crucial role in modulation of DNA repair capacity. This case-control study was designed to evaluate the influence of XRCC3 gene Thr241Met polymorphism on CRC risk and progression among Polish population. Genotyping was performed by RFLP-PCR (restriction length fragment polymorphism). The subject of our study was consist of 194 patients with CRC and 204 cancer-free individuals who were age and sex-matched as a control group. Obtained genotype distributions in controls as well as patients fit to the Hardy-Weinberg expectations. Odd ratio analysis indicates diminished risk for heterozygous model and Met allele. Comparison of patients with noninvasive and advanced stage of CRC did not imply any statistical significance. Our results suggest that Thr241Met XRCC3 gene polymorphism might be regarded as CRC potential molecular marker. Nevertheless, that hypothesis needs to be confirmed by subsequent studies. PMID- 24166605 TI - Role of polymorphism of methyltetrahydrofolate-homocysteine methyltransferase (MTR) A2756G and breast cancer risk. AB - Breast cancer (BC) is one of the most common causes of death among women, and second in Iran. The objectives of this study were to determine the frequency of methyltetrahydrofolate-homocysteine methyltransferase (MTR) 2756 gene polymorphism in patients with breast cancer. For the first time, we evaluated these polymorphisms and effects on the breast cancer risk association in an Iranian sporadic population-based case-control study of 282 breast cancer cases and 310 controls using a PCR-RFLP-based assay. Analyses of affected and controls show that homozygote genotype MTR 2756 AA has the highest frequency in both groups (33.3 in patients). Genotype MTR 2756 GG was the highest risk factor in our population [AG/GG odds ratio, 0.329 (95% CI: 0.146-0.741) p = 0.006, AA/AG, OR, 2.316, 95% CI: 1.509-3.555, p = 0.001, AA/GG odds ratio, 0.761 (95% CI: 0.363 1.595) p = 0.297]. There was a significant association of breast cancer risk with MTR 2756 GG and AA polymorphism. PMID- 24166606 TI - Memantine - neuroprotective drug in aging brain. AB - Aging is the process of progressive accumulation of changes over time, which is additionally connected with increasing susceptibility to some diseases and ultimately leads to death. Aging is associated mainly with loss of permanent cells, e.g. in heart, skeletal muscle and brain. During aging neurons die mainly in the apoptotic way. Apoptosis can be divided into three phases: initiation, execution and degradation. During the execution phase activation of specific enzymes, caspases, is observed. These enzymes are responsible for initiation of the death machinery. Caspase-9 is connected with the internal pathway of apoptosis, which begins at the mitochondrium in response to apoptotic stimulants, such as free radicals, UV radiation or chemotherapeutics. Before the executive phase starts, cytochrome c leaks from the mitochondrium to the cytoplasm, where it joins to the protein Apaf-1 and procaspase-9 and forms a complex called the apoptosome. Then procaspase-9 is converted by autolysis to caspase-9, which subsequently activates procaspase-3 to the active form which ultimately leads to apoptosis. Immunohistochemical analysis demonstrated a small decrease in caspase 9 and caspase-3 activation during normal aging and an increase in this process after application of stress factors. Also increased apoptosis in the cerebrum after administration of a drug for Alzheimer disease, memantine, to aging rats was observed. Taken together, the results obtained in this study seem to confirm the neuroprotective effect of memantine on increasing levels of cells with active caspase-3 and active caspase-9. It probably improves caspase-dependent apoptosis in the aging brain. PMID- 24166607 TI - The antioxidant role of N-acetylcysteine on the testicular remote injury after skeletal muscle ischemia and reperfusion in rats. AB - t is known that ischemia reperfusion causes remote organ injury as well as local injury. The aim of this study was to investigate whether N-acetylcysteine has a protective effect against testicular injury after skeletal muscle ischemia reperfusion. Twenty male Wistar rats were allocated to two groups: ischemia reperfusion (control group) and ischemia reperfusion + N-acetylcysteine (treatment group). All animals underwent 2 h of ischemia by occlusion of the femoral artery and 24 h of reperfusion. Rats in treatment group received N acetylcysteine (150 mg/kg IV) before the reperfusion period. After the reperfusion period, testes were removed for histopathological and biochemical studies. The blood samples were collected for evaluation of serum malondialdehyde (MDA) and nitric oxide (NO) production levels. The MDA levels in testes homogenates were found to be significantly decreased in treatment group (p < 0.05). Treatment of N-acetylcysteine significantly decreased serum MDA and NO levels compared to the control group (p < 0.05). In the control group, tissues showed histological changes. Histopathologically, there was a significant difference (p < 0.05) between two groups. According to histological and biochemical findings, we conclude that N-acetylcysteine has preventive effects in the testicular injury after skeletal muscle ischemia reperfusion. PMID- 24166608 TI - Primary mucoepidermoid carcinoma of the breast: a case report with immunohistochemical analysis and comparison with salivary gland mucoepidermoid carcinomas. AB - Mucoepidermoid carcinomas in mammary glands represent 0.3% of all breast tumors. Features of salivary gland mucoepidermoid carcinoma have been used in studies concerning mucoepidermoid carcinomas of the breast because both share similar morphologic and molecular features. We report a case of primary mucoepidermoid carcinoma of the breast with an immunohistochemistry staining panel. We verified that MUC5AC occurs in more than 50% of high-grade tumors, and MUC1 correlates with shorter disease-free survival. The comparative analysis of mucin profiles may provide further insights into the clinical behavior of these tumors. PMID- 24166610 TI - Co-existence of intramuscular spindle cell lipoma with an intramuscular ordinary lipoma:report of a case. AB - Spindle cell lipoma is a relatively rare adipocytic neoplasm, which usually occurs in the posterior neck, shoulder or upper back of male patients aged 45-65 years. We report here an unusual coexistence of ordinary and spindle cell lipoma. The patient presented with a painless mass in the area of the right scapula. Imaging was suggestive of a lipomatous mass, possibly liposarcoma. Histological examination revealed the concurrent existence of an intramuscular spindle cell lipoma and an ordinary lipoma. In the literature there are only fourteen cases of intramuscular spindle cell lipoma and only in four cases there was a coexisting mature lipoma. As exclusion of malignancy remains clinicians main concern,diagnosis and treatment of deep seated lipomatous tumors remains challenging. PMID- 24166609 TI - Solid-pseudopapillary neoplasm of the pancreas - comparisons between magnetic resonance and histological findings. AB - Solid-pseudopapillary neoplasm is a rare pancreatic tumor typically observed in young adults. A new case of the tumor was diagnosed in a 22-year-old woman. An abnormal mass connected with the pancreatic body was found on ultrasound and computed tomography. Magnetic resonance revealed weak homogeneous contrast enhancement and a low ADC value (0.824 mm/s2; b1000). Primary radiological diagnosis suggested a solid pancreatic neoplasm, which was confirmed during histopathological assessment after resection of the pancreatic body with preservation of the spleen and normal drainage through the main pancreatic duct. Histological appearance of the solid-pseudopapillary neoplasm corresponded with its radiological morphology. PMID- 24166611 TI - Brown bowel syndrome (intestinal lipofuscinosis) - a case report and review of the literature. AB - Brown bowel syndrome (BBS) is a very rare condition occurring in association with malabsorption syndromes. It is characterised by deposition of granular, brown pigment (lipofuscin or ceroid) in intestinal smooth muscles. Rarely BBS can be complicated by distention of any segment of the bowel. We present a case of BBS associated with massive dilation of first loop of the small intestine and moderate dilation of the sigmoid colon with functional intestinal disturbances requiring surgical intervention in an 11-year-old boy. PMID- 24166617 TI - Establishment of molecular markers and linkage groups in two F2 populations of Upland cotton. AB - Two F2 populations of cotton (Gossypium hirsutum L.) from the crosses of HS46 x MARCABUCAG8US-1-88 (MAR) and HS46 x Pee Dee 5363 (PD5363) were characterized for restriction fragment length polymorphisms (RFLPs) using DNA probes. Seventy-three probe/enzyme combinations were used in the HS46 x MAR population analysis, which resulted in 42 informative polymorphic fragments. These 42 moleclar markers represented 26 polymorphic loci, which consisted of 15 codominant and 11 dominant (+/-) genotypes. Chi-square analyses of these loci fit expected genotypic ratios of 1?2?1 and 3?1, respectively An analysis of these loci with the MAPMAKER program resulted in the establishment of four linkage groups A, B, C, and D with 4,2,2, and 2 loci, respectively, as well as 16 unlinked loci. Six probe-enzyme combinations were assayed on the HS46 x PD5363 population, which resulted in 11 informative polymorphic fragments. These 11 fragments represented 6 polymorphic loci, 1 dominant (+/-) and 5 codominant genotypes. The MAPMAKER analysis of these loci yielded 2 linked loci. Thus, a total of 53 polymorphic fragments and 32 polymorphic loci, representing five linkage groups, were identified among the two families. PMID- 24166616 TI - Mantle cell lymphoma with a unique pattern of CD5 expression: a case report with review of the literatures. AB - Mantle cell lymphoma (MCL) is a unique subtype of B-cell non-Hodgkin's lymphoma characterized by chromosomal translocation t(11;14)(q13;q32), positive CD5, and nuclear cyclin D1 overexpression with unfavorable prognosis. We report herein a case of MCL in a 73-year-old male diagnosed with diffuse large B-cell lymphoma (ileal tumor) at another hospital, who subsequently relapsed with CD5-negative MCL. At the 1st relapse, he developed neck lymph node swelling, of which biopsy showed proliferation of atypical large pleomorphic cells with CD5-negativity by both immunohistochemistry and flow cytometry. At the 2nd relapse, he again developed an ileal tumor, of which biopsy showed positivity for CD5, CD20, and cyclin D1. In MCL, CD5-negative expression has sometimes been reported as having pleomorphic and blastoid variants. The present case was also histologically the pleomorphic type, but the CD5 expression changed from negative at the onset and the 1st relapse to positive at the 2nd relapse. This is a rare and interesting case because of the different expression of CD5 at all stage. This phenomenon made the diagnosis of MCL difficult. PMID- 24166615 TI - Reduced C9orf72 gene expression in c9FTD/ALS is caused by histone trimethylation, an epigenetic event detectable in blood. AB - Individuals carrying (GGGGCC) expanded repeats in the C9orf72 gene represent a significant portion of patients suffering from amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Elucidating how these expanded repeats cause "c9FTD/ALS" has since become an important goal of the field. Toward this end, we sought to investigate whether epigenetic changes are responsible for the decrease in C9orf72 expression levels observed in c9FTD/ALS patients. We obtained brain tissue from ten c9FTD/ALS individuals, nine FTD/ALS cases without a C9orf72 repeat expansion, and nine disease control participants, and generated fibroblastoid cell lines from seven C9orf72 expanded repeat carriers and seven participants carrying normal alleles. Chromatin immunoprecipitation using antibodies for histone H3 and H4 trimethylated at lysines 9 (H3K9), 27 (H3K27), 79 (H3K79), and 20 (H4K20) revealed that these trimethylated residues bind strongly to C9orf72 expanded repeats in brain tissue, but not to non-pathogenic repeats. Our finding that C9orf72 mRNA levels are reduced in the frontal cortices and cerebella of c9FTD/ALS patients is consistent with trimethylation of these histone residues, an event known to repress gene expression. Moreover, treating repeat carrier-derived fibroblasts with 5-aza-2-deoxycytidine, a DNA and histone demethylating agent, not only decreased C9orf72 binding to trimethylated histone residues, but also increased C9orf72 mRNA expression. Our results provide compelling evidence that trimethylation of lysine residues within histones H3 and H4 is a novel mechanism involved in reducing C9orf72 mRNA expression in expanded repeat carriers. Of importance, we show that mutant C9orf72 binding to trimethylated H3K9 and H3K27 is detectable in blood of c9FTD/ALS patients. Confirming these exciting results using blood from a larger cohort of patients may establish this novel epigenetic event as a biomarker for c9FTD/ALS. PMID- 24166618 TI - RFLP mapping of QTLs for yield and related characters in rice (Oryza sativa L.). AB - Quantitative triat loci (QTLs) for yield and related traits in rice were mapped based on RFLP maps from two indica/indica F2 populations, Tesanai 2/CB and Waiyin 2/CB. In Tesanai 2/CB, 14 intervals carrying QTLs for eight traits were detected, including 3 for grain weight per plant (GWT), 2 for number of panicles per plant (NP), 2 for number of grains per panicle (NG), 1 for total number of spikelets per panicle (TNS), 1 for spikelet fertility (SF), 3 for 1000-grain weight (TGWT), 1 for spikelet density (SD), and 1 for number of first branches per main panicle. The 3 QTLs for GWT were located on chromosomes 1, 2, and 4, with 1 in each chromosome. The additive effect of the single locus ranged from 2.0 g to 9.1 g. A major gene (np4) for NP was detected on chromosome 4 within the interval of RG143 RG214, about 4cM for RG143, and this locus explained 26.1% of the observed phenotypic variance for NP. The paternal allele of this locus was responsible for reduced panicles per plant (3 panicles per plant). In another population, Waiyin 2/CB, 12 intervals containing QTLs for six of the above-mentioned traits were detected, including 3 for GWT, 2 for each of NP, TNS, TGWT and SD, 1 for SF. Three QTLs for GWT were located on chromosome 1, 4, and 5, respectively. The additive effect of the single locus for GWT ranged from 6.7 g to 8.8 g, while the dominance effect was 1.7-11.5 g. QTL mapping in two populations with a common male parent is compared and discussed. PMID- 24166619 TI - Wheat phylogeny determined by RFLP analysis of nuclear DNA. 3. Intra- and interspecific variations of five Aegilops Sitopsis species. AB - The level of intra- and interspecific variations on nuclear DNA in five Aegilops species of the Sitopsis section were investigated using restriction fragment length polymorphism (RFLP) analysis. A total of 18 accessions, i.e. 7 of Ae. speltoides, 3 of Ae. longissima, 2 of Ae. searsii, 3 of Ae. sharonensis and 3 of Ae. bicornis, were used. One accession each of Triticum aestivum, T. durum, T. urartu and Ae. squarrosa was included as reference material. Five enzymes and 20 probes were used. Among the five Sitopsis species studied, Ae. speltoides had the largest intraspecific variation (pi=0.061), which was as high as the interspecific variation observed among the other four species. The section Sitopsis was divided into two distinct groups: one containing only Ae. speltoides and the other, Ae. longissima, Ae. searsii, Ae. sharonensis and Ae. bicornis. This grouping by RFLP analysis is in agreement with the taxonomical classification of the subsections. PMID- 24166620 TI - QTL analysis of horticultural traits differentiating the cultivated tomato from the closely related species Lycopersicon pimpinellifolium. AB - Molecular markers were used to map and characterize quantitative trait loci (QTLs) for several characters of agronomic and biological importance in an interspecific backcross of tomato. The parents of the cross were an elite processing inbred Lycopersicon esculentum cv 'M82-1-7' and the closely related red-fruited wild species L. pimpinellifolium (LA1589). A total of 257 BC1 plants were grown under field conditions in Ithaca, New York and scored for 19 quantitative traits. A genetic linkage map was constructed for the same population using 115 RFLP, 3 RAPD and 2 morphological markers that spanned 1,279 cM of the tomato genome with an average interval length of 10.7 cM. A minimum of 54 putatively significant QTLs (P<0.001; LOD> 2.4) were detected for all characters with a range of 1-7 QTLs detected per character. Of the total 54 QTLs 11% had alleles with effects opposite to those predicted by the parental phenotypes. The percentage of phenotypic variation associated with single QTLs ranged from 4% to 47%. Multilocus analysis showed that the cumulative action of all QTLs detected for each trait accounted for 12-59% of the phenotypic variation. The difference in fruit weight was controlled largely by a single major QTL (fw2.2). Digenic epistasis was not evident. Several regions of the genome (including the region near sp on chromosome 6) showed effects on more than one trait. Implications for variety improvement and inferences about the domestication of the cultivated tomato are discussed. PMID- 24166621 TI - Mapping of a QTL for oleic acid concentration in spring turnip rape (Brassica rapa ssp. oleifera). AB - Bulk segregant analysis was used to search for RAPD (random amplified polymorphic DNA) markers linked to gene(s) affecting oleic acid concentration in an F2 population from the Brassica rapa ssp. oleifera cross Jo4002 x a high oleic acid individual from line Jo4072. Eight primers (=8 markers) out of 104 discriminated the 'high' and 'low' bulks consisting of extreme individuals from the oleic acid distribution. These markers were analysed throughout the entire F2 population, and their association with oleic acid was studied using both interval mapping and ANOVA analysis. Six of the markers mapped to one linkage group. A quantitative trait locus (QTL) affecting oleic acid concentration was found to reside within this linkage group with a LOD score >15. The most suitable marker for oleic acid content is OPH-17, a codominant marker close (<4cM) to the QTL. The mean seed oleic acid content in the F2 individuals carrying the larger allele of this marker was 80.14+/-9.76%; in individuals with the smaller allele, 54.53+/-6.83%; in the heterozygotes, 65.47+/-8.15%. To increase reproducibility, the RAPD marker was converted into a SCAR (sequence characterized amplied region) marker with specific primers. Marker OPH-17 can be used to select spring turnip rape individuals with the desired oleic acid content. PMID- 24166622 TI - Genetic analysis of RFLPs, GATA microsatellites and RAPDs in a cross between L. esculentum and L. pimpinellifolium. AB - A population of 257 BC1 plants was developed from a cross between an elite processing line of tomato (Lycopersicon esculentum cv'M82-1-7') and the closely related wild species L. pimpinellifolium (LA1589). The population was used to construct a genetic linkage map suitable for quantitative trait locus (QTL) analysis to be conducted in different backcross generations. The map comprises 115 RFLP, 3 RAPD and 2 morphological markers that span 1279 cM of the tomato genome with an average distance between markers of 10.7 cM. This map is comparable in length to that of the highdensity RFLP map derived from a L. esculentum x L. pennellii F2 population. The order of the markers in the two maps is also in good agreement, however there are considerable differences in the distribution of recombination along the chromosomes. The segregation of six GATA containing loci and 47 RAPD markers was also analyzed in subsets of the population. All of the microsatellite loci and 35 (75%) of the RAPDs mapped to clusters associated with centromeric regions. PMID- 24166623 TI - Exclusion probabilities for pedigree testing farm animals. AB - Pedigree testing, using genetic markers, may be undertaken for a variety of situations, of which the classical paternity testing is only one. This has not always been made clear in the literature. Exclusion probabilities associated with various testing situations, including the use of autosomal or X-linked codominant marker systems with any number of alleles, are presented. These formulae can be used to determine the appropriate exclusion probability for the situation being investigated. One such situation is where sire groups of progeny are to be verified without knowledge of the dams' genotypes, in which case the classical paternity exclusion probability is too high, and if used may result in an optimistic declaration about the progeny that have not been excluded. On the other hand, if mating pairs are known then incorrect progeny can be excluded at a higher rate than suggested by paternity exclusion calculations. The formulae also assist in determining the usefulness of X-linked markers, particularly if the pedigree checks involve progeny of only one sex. A system of notation that is useful for the algebraic manipulation of genetic probabilities, including exclusion probabilities as presented here, is also given. PMID- 24166624 TI - DNA methylation and expression of NPT II in transgenic petunias and progeny. AB - The expression and inheritance of the NPT II (neomycin phosphotransferase II) gene was studied in four transgenic petunia (Petunia hybrida Vilm.) plants and their progeny. The four transgenic plants, each of which had more than one site of insertion, were different from each other in the level of foreign gene expression. Transmission of one or more NPT II alleles to progeny as deteceted by DNA hybridization did not lead to consistant or predictable patterns of NPT II expression. All transgenic plants and their progeny displaying NPT II enzyme activity contained unmethylated SstII (methylation-sensitive restriction enzyme) sites in the nopaline synthase (NOS) promoter (controlling NPT II gene transcription); whereas, 13 of 17 plants which contained the NPT II gene and which showed no NPT II activity had methylated SstII sites. Two progeny of 1 transgenic plant appeared to have some unmethylated SstII sites, but no NPT II enzyme activity was found in leaf tissue samples. DNA methylation of the SstII site in the NOS promoter is strongly correlated with a decrease in NPT II gene expression in transgenic petunia plants and their progeny. However, DNA methylation alone could not account for the variability seen in NPT II gene expression. PMID- 24166625 TI - Behaviour of chromosomes in anaphase cells in embryogenic callus cultures of maize (Zea mays L.). AB - Mitotic anaphase cells of highly friable and embryogenic calluses which had been induced from immature embryos of two inbred lines of maize that have contrasting levels of heterochromatic knobs were analysed for the presence of abnormalities 3, 6, 9 and 12 months after the initiation of culture. A total of 500 typical anaphases was scored at each time point, and various aberrations, such as delay in the separation of sister chromatides, chromosome bridges (single, double and multiple) and chromosome fragments, were revealed to occur extensively in the cultures of both genotypes. Preparations after C-banding revealed that primary breakages often occurred inside knobs or at junction regions between the euchromatin and the heterochromatin of the knobs. Figures characterized by the delayed separation of sister chromatids, which originated preferentially at the knob level and was considered to be an initial event in the development of breakages, were observed at constant frequencies throughout the experiment. Increasing numbers of aberrant cells were detected with time, mainly due to the accumulation of cells with chromosome bridges and fragments. Several mitotic figures suggested the occurrence of breakagefusion-bridge cycles that were initiated by broken chromosomes. The overall frequencies of aberrant cells were similar for both genotypes, despite the differences in knob composition. However, callus cultures induced from the genotype having the higher level of knobs had more aberrant cells with abnormalities that involved several chromosomes, such as multiple bridges and multiple fragments. PMID- 24166626 TI - Genetic localization of four genes for nematode (Heterodera schachtii Schm.) resistance in sugar beet (Beta vulgaris L.). AB - Sugar beet (Beta vulgaris L.) is highly susceptible to the beet cyst nematode (Heterodera schachtii Schm.). Three resistance genes originating from the wild beets B. procumbens (Hs1 (pro-1)) and B. webbiana (Hs1 (web-1), Hs2 (web-7)) have been transferred to sugar beet via species hybridization. We describe the genetic localization of the nematode resistance genes in four different sugar beet lines using segregating F2 populations and RFLP markers from our current sugar beet linkage map. The mapping studies yielded a surprising result. Although the four parental lines carrying the wild beet translocations were not related to each other, the four genes mapped to the same locus in sugar beet independent of the original translocation event. Close linkage (0-4.6 cM) was found with marker loci at one end of linkage group IV. In two populations, RFLP loci showed segregation distortion due to gametic selection. For the first time, the non-randomness of the translocation process promoting gene transfer from the wild beet to the sugar beet is demonstrated. The data suggest that the resistance genes were incorporated into the sugar beet chromosomes by non-allelic homologous recombination. The finding that the different resistance genes are allelic will have major implications on future attempts to breed sugar beet combining the different resistance genes. PMID- 24166627 TI - Application of a canonical transformation to detection of quantitative trait loci with the aid of genetic markers in a multi-trait experiment. AB - Effects of individual quantitative trait loci (QTLs) can be isolated with the aid of linked genetic markers. Most studies have analyzed each marker or pair of linked markers separately for each trait included in the analysis. Thus, the number of contrasts tested can be quite large. The experimentwise type-I error can be readily derived from the nominal type-I error if all contrasts are statistically independent, but different traits are generally correlated. A new set of uncorrelated traits can be derived by application of a canonical transformation. The total number of effective traits will generally be less than the original set. An example is presented for DNA microsatellite D21S4, which is used as a marker for milk production traits of Israeli dairy cattle. This locus had significant effects on milk and protein production but not on fat. It had a significant effect on only one of the canonical variables that was highly correlated with both milk and protein, and this variable explained 82% of the total variance. Thus, it can be concluded that a single QTL is affecting both traits. The effects on the original traits could be derived by a reverse transformation of the effects on the canonical variable. PMID- 24166628 TI - Cloning and analysis of a 6.8-kb rDNA intergenic spacer region of the European ash (Fraxinus excelsior L.). AB - The 6.8-kb rDNA intergenic spacer region of F. excelsior was isolated from a CsCl/actinomycin-D gradient and cloned into pUC18 for further characterization. We observed the presence of subrepeats delimited by HaeIII enzyme sites. These subrepeats were sub-cloned and 11 clones were sequenced. These corresponded to subrepeated elements of either 32 bp or 41 bp that shared a 23-bp common sequence in the 5' end. Within each family of subrepeats, the percentage of common nucleotides was 84.4% for the 5 32-bp subrepeats and 67.4% for the 640-bp subrepeats. Non-repeated HaeIII fragments of 450 bp and 650 bp were also sub cloned. To compare homology at the IGS region between the rDNA spacers of F. excelsior and the three related species (F. oxyphylla, F. americana, F. ornus), we conducted Southern hybridization analyses using each member of the 32-bp and 40-bp subrepeat families and the unique 450-bp and 650-bp fragments as probes. These analyses indicated that (1) the American ash is more genetically distant from the other three species that the latter are from each other and (2) F. oxyphylla and F. excelsior are more closely related to each other than to F. ornus. PMID- 24166629 TI - Molecular phylogeny and DNA amplification fingerprinting of Petunia taxa. AB - The relationship of five species of Petunia and ten cultivars of the cultivated petunia, Petunia x hybrida, were investigated using DNA-amplification fingerprinting (DAF). Reproducible banding profiles were obtained from P. parodii and P. axillaris DNA from different seed sources. In contrast, other petunias such as P. inflata, P. violacea and P. integrifolia produced variable fingerprints when different plants were examined. However, representative profiles of the variable Petunia taxa were obtained by bulking the leaf tissue from ten different individual plants. Each of ten octamer primers revealed polymorphic loci between taxa. Among a total of 201 bands produced, 146 (73%) loci were polymorphic and distinguished all species and cultivars. Phenetic and cluster analysis using DAF markers separated P. axillaris from P. parodii and distinguished between the violet-flowered species, P. inflata, P. violacea, and P. integrifolia. P. parodii grouped together with the monophyletic set of the ten cultivars of P. x hybrida examined, indicating that it had made a major contribution to the development of these cultivars. Cultivars were distributed within the dendograms by flower color. The results demonstrated the utility of DAF in establishing relationships among closely related species and cultivars of Petunia. PMID- 24166630 TI - Colchicine-mediated chromosome doubling during anther culture of maize (Zea mays L.). AB - Efficient methods of chromosome doubling are critical for the production of microspore-derived, doubled-haploid (=DH) plants, especially if, as in maize anther culture, spontaneous chromosome doubling occurs infrequently. In the present study, colchicine (5-1000 mg/l) was added to the induction medium and maize anthers were incubated in the colchicine-containing medium for different durations (1-7 days). In order to improve overall anther culture response, the culture temperature was adjusted to 14 degrees C during the first 7 days. Colchicine applied at low concentration, i.e. 5 mg/l (7 days), or for short duration, i.e. 1-3 days (250 mg/l), showed beneficial effects on the formation of embryolike structures (=ES) and thus led to increased plant production, but was comparatively ineffective regarding chromosome doubling. Optimal doubling effects were observed when anthers had been exposed to culture medium containing 250 and 1000 mg/l of colchicine (7 days); in these treatments the doubling index (=DI), defined as the quotient of the number of DH plants and the number of totally regenerated plants in a specific treatment, rose to 0.56 and 0.53, respectively, compared to 0.20 in the untreated control. However, colchicine administered at concentrations higher than 250 mg/l seemed to be detrimental to general plant production; thus, in spite of a high DI, the overall DH plant production was even lower than in the control treatment. Maximum DH plant production for three different genotypes was accomplished with culture medium containing 250 mg/l of colchicine (7 days). With the best-responding genotype (ETH-M 36) a DH plant production of 9.9 DH plants/100 anthers was accomplished, i.e. a 7-fold increase compared to the non-treated anthers. This is the first report on efficient chromosome doubling in anther culture by subjecting anthers to colchicinecontaining induction medium during a post-plating cold treatment. Chromosome doubling as described here becomes an integral part of the maize anther culture protocol and thus represents a rapid and economical way to produce DH plants. PMID- 24166631 TI - Comparative genetic mapping between duplicated segments on maize chromosomes 3 and 8 and homoeologous regions in sorghum and sugarcane. AB - Comparative mapping within maize, sorghum and sugarcane has previously revealed the existence of syntenic regions between the crops. In the present study, mapping on the sorghum genome of a set of probes previously located on the maize and sugarcane maps allow a detailed analysis of the relationship between maize chromosomes 3 and 8 and sorghum and sugarcane homoeologous regions. Of 49 loci revealed by 46 (4 sugarcane and 42 maize) polymorphic probes in sorghum, 42 were linked and were assigned to linkage groups G (28), E (10) and I (4). On the basis of common probes, a complete co-linearity is observed between sorghum linkage group G and the two sugarcane linkage groups II and III. The comparison between the consensus sorghum/sugarcane map (G/II/III) and the maps of maize chromosomes 3 and 8 reveals a series of linkage blocks within which gene orders are conserved. These blocks are interspersed with non-homoeologous regions corresponding to the central part of the two maize chromosomes and have been reshuffled, resulting in several inversions in maize compared to sorghum and sugarcane. The results emphasize the fact that duplication will considerably complicate precise comparative mapping at the whole genome scale between maize and other Poaceae. PMID- 24166632 TI - Molecular characterization of the fate of transgenes in transformed wheat (Triticum aestivum L.). AB - Molecular analysis of the transgenes bar and gus was carried out over successive generations in six independent transgenic lines of wheat, until the plants attained homozygosity. Data on expression and integration of the transgenes is presented. Five of the lines were found to be stably transformed, duly transferring the transgenes to the next generation. The copy number of the transgenes varied from one to five in the different lines. One line was unstable, first losing expression of and then eliminating both the transgenes in R3 plants. Although the gus gene was detected in all the lines, GUS expression had been lost in R2 plants of all but one line. Rearrangement of transgene sequences was observed, but it had no effect on gene expression. All the stable lines were found to segregate for transgene activity in a Mendelian fashion. PMID- 24166633 TI - Correlations between low-temperature tolerance of anther donor clones of potato and the production of anther-derived embryos and calli at low temperatures. AB - The main purpose of this study was to investigate whether the degree of tolerance to low non-freezing temperatures of immature microspores in anther culture was correlated to the degree of low-temperature tolerance, measured by chlorophyll fluorescene, in the anther donor clone. Anther cultures of six tetraploids and eight dihaploids, derived from anther cultures of clone 199.13, were incubated at 10, 15, 20, 25 or 30 degrees C respectively. The embryo and callus production were determined and subsequently two quotients/clone, designated "temperature related embryo and callus production," were established. The quotients were defined as embryo and callus production at 10 or 15 degrees C divided by the embryo and callus production, for the individuals clone, at the optimal temperature (20 or 25 degrees C) for the same production. These quotients were thereafter correlated to the low-temperature tolerances of the anther donors. The tetraploid and dihaploid group were treated separately and significant positive correlations were found in both cases. This indicates that tolerance to low temperatures is expressed in the anther donor plant as well as in the microspores grown in anther culture. It is suggested that in vitro selection through anther culture may be a useful tool for breeding for increased tolerance to low temperatures in potato. PMID- 24166634 TI - Identification and mapping on chromosome 9 of RAPD markers linked to Sw-5 in tomato by bulked segregant analysis. AB - Bulked segregant analysis was used to identify random amplified polymorphic DNA (RAPD) markers linked to the Sw-5 gene for resistance to tomato spotted wilt virus (TSWV) in tomato. Using two pools of phenotyped individuals from one segregating population, we identified four RAPD markers linked to the gene of interest. Two of these appeared tightly linked to Sw-5, whereas another, linked in repulsion phase, enabled the identification of heterozygous and susceptible plants. After linkage analysis of an F2 population, the RAPD markers were shown to be linked to Sw-5 within a distance of 10.5 cM. One of the RAPD markers close to Sw-5 was used to develop a SCAR (sequence characterized amplified region) marker. Another RAPD marker was stabilized into a pseudo-SCAR marker by enhancing the specificity of its primer sequence without cloning and sequencing. RAPD markers were mapped to chromosome 9 on the RFLP tomato map developed by Tanksley et al. (1992). The analysis of 13 F3 families and eight BC2 populations segregating for resistance to TSWV confirmed the linkage of the RAPD markers found. These markers are presently being used in marker-assisted plant breeding. PMID- 24166635 TI - Allozyme variation in populations, full-sib families and selfed lines in Betula pendula Roth. AB - Changes in genetic variability in populations (stand origins), full-sib (FS) families and three generations of selfed lines of Betula pendula were observed based on 15 allozyme loci. Growth vigour, measured as stem volume, and its relationship with heterozygosity was studied to determine the effect of inbreeding. Pooled FS families showed a higher percentage of polymorphic loci (P) and allelic numbers per locus (A) than those of natural populations, but no difference in heterozygosity. There was no difference in allozyme variability between fast-and slow-growing family groups, and heterozygosity was not correlated with stem volume among FS families. Allozyme variability was significantly decreased in advancing generations of selfing, and the further the selfing generation, the lower the heterozygosity and the slower the growth. Observed heterozygosity after advancing generations of inbreeding was increasingly higher than expected, indicating overdominance effects or, alternatively, selection against deleterious homozygotes. PMID- 24166636 TI - A putative major gene for rust resistance linked with a RFLP marker in sugarcane cultivar 'R570'. AB - Inheritance of resistance to rust was investigated in the self progeny of the sugarcane cultivar 'R570' also used to build a RFLP genetic map. Resistance was evaluated through both field and controlled greenhouse trials. A clear-cut 3 (resistant) ? 1 (susceptible) segregation indicative of a probable dominant resistant gene was observed. This is the first documented report of a monogenic inheritance for disease resistance in sugarcane. This gene was found linked at 10 cM with an RFLP marker revealed by probe CDSR29. Other minor factors involved in the resistance were also detected. PMID- 24166637 TI - Tomato chromosome 6: a high resolution map of the long arm and construction of a composite integrated marker-order map. AB - Integration of molecular and classical genetic maps is an essential requirement for marker-assisted breeding, quantitative trait locus mapping and map-based cloning. With respects to tomato, such maps are only available for the top part of chromosome 1, for chromosome 3 and for the short arm and the centromere proximal part of the long arm of chromosome 6. Employing an L. esculentum line carrying an L. hirsutum introgression we constructed an integrated linkage map for the telomere proximal part of the long arm of tomato chromosome 6, thereby completing the integrated map published previously. With an average map distance of only 0.6 cM the map provides detailed information on the relative position of molecular markers and several traits of economical importance, such as the fruit color marker B. Furthermore, two additional crosses using lines containing L. pennellii introgressions were performed to address the question as to how the recombination frequency in a marked interval on the long arm of chromosome 6 is affected by introgressed segments from different origins. It is concluded that recombination is not merely affected by the local level of homology but also by surrounding sequences. Combination of all the linkage data generated in various crosses described in this and other studies enabled the construction of the first integrated map of an entire tomato chromosome. This map carries 42 loci and shows the position of 15 classical genes relative to 59 molecular markers. PMID- 24166638 TI - RFLP mapping of the dwarfing (Ddw1) and hairy peduncle (Hp) genes on chromosome 5 of rye (Secale cereale L.). AB - An F2 population was established for mapping the two dominant genes for dwarfness (Ddw1) and hairy peduncle (Hp) on chromosome 5R. The location of both genes was shown to be on the segment of chromosome 5RL which was ancestrally translocated and is homoeologous to Triticeae 4L. Hp cosegregated with the wheat gDNA probe WG199, localised in wheat on chromosomes 5AL, 4BL and 4DL. No segregation was observed between the traits hairy peduncle and hairy leaf sheath. The locus for Ddw1 was found to map distally to Hp/Xwg199 but proximal to the isozyme marker beta-amy-R1. The genetical distances were 5.6 cM between Hp/Xwg199 and Ddw1 and ll.ScM between Ddw1 and beta-amy-R1, respectively. The map position of Ddw1 suggests that it is homoeologous to the wheat dominant dwarfing gene Rht12, present on chromosome 5AL and linked to beta-amy-A1. PMID- 24166640 TI - Can the spread of agriculture in Europe be followed by tracing the spread of the weed Silene latifolia. A RAPD study. AB - On the basis of gene frequency data of three flavone glycosylating genes, populations of the agricultural weed Silene latifolia (Caryophyllaceae) in Europe can be divided into two chemical races: an eastern and a western race. Morphological data also show a clear east-west division. When the two datasets are combined at least nine different geographical races can be distinguished using cluster analysis. Because these observations are hard to explain by selection, it has been proposed that these different races probably originated as a consequence of migration during the spread of agriculture over Europe in the past. To discriminate between selection and genetic drift many more selectively neutral easy-to-score characters are needed. In order to test whether random amplified polymorphic DNAs (RAPDs) might be suitable for this purpose, we performed a small-scale RAPD analysis on 16 geographical different populations. Using Jaccard's coefficient of similarity, we calculated genetic distances by pair-wise comparisons of both unique and shared amplification products, and a dendrogram was subsequently constructed using an unweighted pair-group method with arithmetical averages (UPGMA). On the basis of the dendrogram two clusters were discerned that clearly coincide with the aforementioned east-west division in populations. As there has been little or no artificial selection on this weed, its migration routes may be a good reflection of the different geographical routes agriculture has taken. We propose that a phylogenetic analysis of RAPD data of many more populations may provide additional information on the spread of agriculture over Europe. PMID- 24166639 TI - Microsatellite analysis of relationships within cultivated potato (Solanum tuberosum). AB - The potential of microsatellite markers for use in genetical studies in potato (Solanum tuberosum) was evaluated. Database searches revealed that microsatellite sequences were present in the non-coding regions of 24 potato genes. Twenty-two sets of primers were designed and products successfully amplified using 19 primer pairs. These were tested against a panel of 18 tetraploid potato cultivars. Four pairs of primers designed to amplify microsatellites from tomato were also used. Seven (including 2 of the tomato sequences) failed to reveal any variation in the accessions tested. Sixteen primer pairs did reveal polymorphism, detecting between 2 and 19 alleles at each locus. Of these, 3 gave rise to complex band patterns, suggesting that multiple polymorphic loci were being amplified using a single primer pair. Heterozygosity values ranged from 0.408 to 0.921. Phenetic analysis of the derived information allowed a dendrogram to be constructed depicting the relationships between the 18 potato cultivars. The potential of microsatellite markers for genetic analysis and satutory applications in potato is discussed in the context of these results. Furthermore, the potential of 'crossspecies amplification' is highlighted as an additional source of microsatellite markers for genetic research in potato. PMID- 24166641 TI - Genetic relationships in Lens species and parentage determination of their interspecific hybrids using RAPD markers. AB - Broadening of the genetic base and systematic exploitation of heterosis in cultivated lentils requires reliable information on genetic diversity in the germplasm. The ability of random amplified polymorphic DNA (RAPD) to distinguish among different taxa of Lens was evaluated for several geographically dispersed accessions/cultivars of four diploid Lens species. This study was carried out to assess whether RAPD data can provide additional evidence about the origin of the cultivated lentil and to measure genetic variability in lentil germplasm. Three cultivars of Lens culinaris ssp. culinaris, including one microsperma, and two macrosperma types, and four wild species (L. culinaris ssp. orientalis, L. odemensis and L. nigricans) were evaluated for genetic variability using a set of 1 11-mer and 14 random 10-mer primers. One hundred and fifty-eight reproducible and scorable DNA bands were observed from these primers. Genetic distances between each of the accessions were calculated from simple matching coefficients. Split decomposition analysis of the RAPD data allowed construction of an unrooted tree. This study revealed that (1) the level of intraspecific genetic variation in cultivated lentils is narrower than that in some wild species. (2) L. culinaris ssp. orientalis is the most likely candidate as a progenitor of the cultivated species, (3) L. nigricans accession W6 3222 (unknown) and L. c. ssp. orientalis W6 3244 (Turkey) can be reclassified as species of L. odemensis and (4) transmission of genetic material in Lens interspecific hybrids is genotypically specific, as identified by the RAPD markers in our study. PMID- 24166642 TI - Analysis of genetic effects on nutrient quality traits in indica rice. AB - Nine cytoplasmic male-sterile lines and five restorer lines were used in an incomplete diallel cross to analyze seed effects, cytoplasmic effects, and maternal gene effects on nutrient quality traits of indica rice (Oryza sauva L.). The results indicated that nutrient quality traits were controlled by cytoplasmic and maternal effects as well as by seed direct effects. Maternal effects for lysine content (LC), lysine index (LI), and the ratio of lysine content to protein content (RLP) were more important than seed direct effects, while protein content (PC) and protein index (PI) were mainly affected by seed direct effects. Cytoplasmic effects accounted for 2.41-20.80% of the total genetic variation and were significant for all nutrient quality traits. Additive genetic effects were much more important than dominance effects for all of the traits studied, so that selection could be applied for these traits in early generations. PMID- 24166643 TI - High frequncies of fertilization and embryo formation in hexaploid wheat x Tripsacum dactyloides crosses. AB - The Hexaploid wheat variety Fukuho was crossed with Tripsacum dactyloides (2n=4x=72). The total fertilization frequencies for the egg cell, polar nuclei, and both, were 58.3%, 26.8% and 58.9% of the 168 ovaries examined. However, the fertilization frequency of single polar nuclei was much lower at only 0.6%. The total frequency of fertilization was higher than that in wheat x maize crosses. A total of 49 hexaploid wheat varieties, including Hope carrying the dominant genes Kr1 and Kr2, were crossed with T. dactyloides, and most gave embryos. The embryoformation frequencies ranged from 0.5% to 59.0%. A higher frequency of 32.0% embryo formation was obtained following pollination of the variety Hope. In comparison with embryo formation in wheat x maize crosses the difference of embryo-formation frequencies between the two crosses was significant. The results of high frequencies of fertilization and embryo formation in wheat x T. dactyloides crosses indicated that the Kr genes are as inactive in wheat x T. dactyloides, as they are in wheat x maize crosses, and also that the efficiency of fertilization and embryo formation is higher in wheat x T. dactyloides than in what x maize crosses. The potential of wheat x T. dactyloides crosses for wheat haploid production and wheat improvement is discussed. PMID- 24166644 TI - Species-specific evolution of telomeric and rDNA repeats in the tobacco composite genome. AB - In order to investigate possible interactions between parental genomes in the composite genome of Nicotiana tabacum we have analyzed the organization of telomeric (TTTAGGG)n and ribosomal gene (rDNA) repeats in the progenitor genomes Nicotiana sylvestris and Nicotiana tomentosiformis or Nicotiana otophora. Telomeric arrays in the Nicotiana species tested are heterogeneous in length ranging from 20 to 200 kb in N. sylvestris, from 20 to 50 kb in N. tomentosiformis, from 15 to 100kb in N. otophora, and from 40 to 160kb in N. tabacum. The patterns of rDNA repeats (18S, 5.8S, 25S RNA) appeared to be highly homogeneous and speciesspecific; no parental rDNA units corresponding to N. sylvestris, N. tomentosiformis or N. otophora were found in the genome of N. tabacum by Southern hybridization. The results provide evidence for a species specific evolution of telomeric and ribosomal repeats in the tobacco composite genome. PMID- 24166646 TI - The impact of atrial natriuretic peptide on anxiety, stress and craving in patients with alcohol dependence. AB - AIMS: Atrial natriuretic peptide (ANP) is well known to modulate fluid and electrolyte homeostasis but also to counter-regulate hypothalamic-pituitary adrenal (HPA) axis activity. Correspondingly, recent studies suggest an important role of ANP in the neurobiology of anxiety. Preclinical and clinical data now provide evidence for an involvement of ANP in the pathophysiology of addictive behavior. The present study aims to elucidate the effects of ANP on alcohol dependent patients' anxiety, perceived stress and craving during alcohol withdrawal. METHODS: A sample of 59 alcohol-dependent inpatients was included in the analysis. A blood sample was taken at day 14 of detoxification in order to assess the concentrations of ANP and cortisol in plasma. In parallel, we assessed patients' alcohol craving, using the Obsessive Compulsive Drinking Scale, as well as anxiety (State-Trait Anxiety Inventory). Patients' stress levels were assessed using the Perceived Stress Scale. RESULTS: We found a significant negative association between patients' ANP plasma concentrations and anxiety, craving for alcohol and perceived stress. Regression analyses suggest that ANP is a significant predictor both for patients' perceived stress and for the severity of anxiety during early abstinence. The association of patients' ANP plasma levels and craving is suggested to be mediated by perceived stress. CONCLUSION: Our results suggest that the association of patients' ANP plasma levels and craving is mediated by their perceived stress. For this reason, intranasal application of ANP may prove to be a new avenue for the treatment of alcohol dependence in patients exhibiting high levels of perceived stress. PMID- 24166648 TI - Diazobenzene-containing conjugated polymers as dark quenchers. AB - The synthesis and photophysical characterization of new conjugated polymers (CPs) with alternating phenylethynylene and diazobenzene (azo-PPE) units were reported, which showed broadened absorption and no measurable fluorescence. Quenching studies showed that azo-PPEs displayed high efficiency over a wide wavelength range. PMID- 24166645 TI - A GABRA2 variant is associated with increased stimulation and 'high' following alcohol administration. AB - AIMS: Variation in genes encoding GABAA receptor subunits has been implicated in the risk of alcohol dependence (AD). We sought to replicate and extend previous findings of a moderating effect of single nucleotide polymorphisms (SNPs) in GABRA2 (which encodes the GABAA alpha-2 subunit) on the subjective effects of alcohol by examining SNPs in this and the adjacent GABRG1 gene on chromosome 4. METHODS: Fifty-two European-Americans (22 males, 28 light drinkers and 24 heavy drinkers) completed 3 laboratory sessions, during which they drank low-dose, high dose, or placebo alcohol prior to undergoing periodic assessments of stimulation, sedation and drug enjoyment. We genotyped subjects for three SNPs previously associated with AD: rs279858 in GABRA2, and rs7654165 and rs6447493 in GABRG1. RESULTS: Two SNPs were associated with altered stimulatory effects of alcohol as measured on the Biphasic Alcohol Effects Scale, (rs279858: P = 0.0046; rs6447493: P = 0.0023); both effects were in the opposite direction of previous findings. Carriers of the rs279858 C allele experienced greater stimulation from alcohol. Further inspection of the rs6447493 interaction did not support a pharmacogenetic effect. The effects of rs279858 (but not the other two SNPs) on items from a secondary outcome measure, the Drug Effects Questionnaire (DEQ), were significant. Higher ratings by individuals with the C allele were observed on the DEQ items 'feel the alcohol effect' (P < 0.001), 'like the alcohol effect' (P < 0.001) and feel 'high' (P < 0.001). CONCLUSION: We did not find that the GABRG1 SNPs rs7654165 and rs6447493 moderated the effects of alcohol. Greater stimulatory and euphoric effects of alcohol in carriers of the rs279858 C allele may, in part, explain the previously reported association of this allele with AD. PMID- 24166649 TI - First observation of rich lamellar structures formed by a single-tailed amphiphilic ionic liquid in aqueous solutions. AB - It was found for the first time that rich lamellar structures are formed by a single-tailed amphiphilic ionic liquid (IL), 1-dodecyl-3-methylimidazolium beta naphthalene sulfonate ([C12mim][Nsa]), in aqueous solutions without any additives. With increasing IL concentration, spontaneous transition from micelles to unilamellar and multilamellar vesicles, planar bilayers, and then to lamellar liquid crystals occurs. PMID- 24166656 TI - Three-dimensional assembly of single-layered MoS(2). AB - Assembly of single layers: Three-dimensional assembly of single-layered MoS2 is achieved on a large scale via a solution method. The as-prepared tubular architectures have tunable size and mesopores in the shell, which are desirable for applications. As a example, they exhibit excellent lithium storage properties and are highly active for hydrodesulfurization of thiophene resulting from their structural advantages. PMID- 24166657 TI - Spontaneous cerebrospinal fluid effusion of the temporal bone: repair, audiological outcomes, and obesity. AB - OBJECTIVES/HYPOTHESIS: Spontaneous occurrence of otogenic cerebrospinal fluid (CSF) effusion is now far more prevalent than causes related to infections, prior surgeries, or trauma-trends that may be increasing because of higher rates of obesity and improved diagnostic awareness. In our patient cohort with spontaneous CSF effusion, we report its association with obesity and audiological findings before and after surgery. STUDY DESIGN: Retrospective study. METHODS: In our 45 patients (46 ears) with CSF effusion (with or without lateral skull base meningoencephaloceles), we report clinical data, imaging studies, audiogram results, operative techniques, and recurrence rates. Causes included 33 spontaneous, 10 due to chronic otitis media, one iatrogenic, and one traumatic. RESULTS: Body mass index (BMI) averaged 35 overall (37 for spontaneous type and 32 for nonspontaneous type). Surgical repair of skull base defect was performed using three middle fossa approaches, 24 combined transmastoid/middle fossa, and 19 transmastoid alone. Overall recurrence of CSF leaks was 6.5%. Thirty patients had audiograms available. Sensorineural hearing loss occurred in 10% of patients. Air-bone gap improved by >= 15 dB in 20% of patients and worsened by >= 15 dB in 6.7% of patients. CONCLUSION: Patients with spontaneous CSF effusion had a BMI higher than in the nonspontaneous group, but the difference was not statistically significant. However, the dramatic trend toward spontaneous CSF effusion heightens the need for clinician's acumen for diagnosis, particularly in overweight/obese patients. Our audiological outcomes confirm the efficacy of surgical approaches in correcting conductive hearing loss and preserving bone conduction, although hearing loss is a risk during surgical repair. LEVEL OF EVIDENCE: 4. Laryngoscope, 124:1204-1208, 2014. PMID- 24166658 TI - Hybrid nanotube-graphene junctions: spin degeneracy breaking and tunable electronic structure. AB - Hybrid carbon nanostructures have attracted enormous interest due to their structural stability and unique physical properties. Geometric and physical properties of a carbon nanotube (CNT)-graphene nanoribbon (GNR) hybrid system were investigated via first-principles density functional theory (DFT) calculations. The nanotube-graphene junction (NTGJ), where the GNR directly links to the CNT by covalent bonds, shows novel electronic dependence on the structural parameters of the building-blocks, such as chirality, nanotube diameter and width of the nanoribbon. For an armchair NTGJ, a small band gap opens up representing asymmetrical spin-up and spin-down bands. However, zig-zag NTGJ shows direct semi conducting characteristics with a tunable band gap ranging from zero to 0.6 eV. Interestingly, the value of the band gap follows the specific width and diameter dependent oscillations, namely the 3p - 1 principle. Transition-state results reveal the formation of NTGJs is exothermic and has a low energy-barrier. In addition, nanotube-graphene-nanotube junctions or namely dumbbell NTGJs were also studied, which exhibits similar properties with single NTGJ. PMID- 24166660 TI - Immunity and the burden of herpes zoster. AB - The burden of herpes zoster may be related to patients' immunity, although this has not been studied extensively. This hypothesis was tested in a matched case control study of patients with herpes zoster who sought treatment at one of seven university hospitals in Korea from January 1, 2007, to December 31, 2010. Patients diagnosed with herpes zoster were placed into three groups based on their immune status: severely immunocompromised, mild-to-moderately immunocompromised, and normal immunity. Each patient in the severely immunocompromised group was matched with one patient in the mild-to-moderately immunocompromised group and one patient in the normal immunity group in the same hospital based on age, sex, and date of herpes zoster onset. A total of 582 patients with herpes zoster were included in the analysis: 194 in each of the three groups. Patients in the severely immunocompromised group had the highest herpes zoster-related hospitalization rate as compared to patients in the mild-to moderately immunocompromised and normal immune groups (P < 0.01). The length of hospital stay and herpes zoster-related medical cost increased significantly with the deterioration of patients' immunity (P < 0.01, respectively). Cutaneous complications occurred more frequently in the severely immunocompromised group than in the other two groups (P < 0.01). An increase in herpes zoster burden was observed as the patients' immunity decreased. Therefore, effective measures are necessary to prevent herpes zoster and reduce its burden in severely immunocompromised patients. PMID- 24166659 TI - Assessing medication adherence: options to consider. AB - BACKGROUND: Adherence to chronic therapy is a key determinant of patient health outcomes in chronic disease. However, only about 50 % of patients adhere to chronic therapy. One of the challenges in promoting adherence is having an accurate understanding of adherence rates and the factors that contribute to non adherence. There are many measures available to assess patient medication adherence. AIM OF THE REVIEW: This review aims to present the commonly used indirect methods available for measuring medication adherence in routine healthcare and research studies. METHOD: A literature review on medication adherence measures in patient populations with chronic conditions taking chronic medications was conducted through Medline (2003-2013). A complementary manual search of references cited in the retrieved studies was performed in order to identify any additional studies. RESULTS: Of the 238 initial Medline search results, 57 full texts were retrieved. Forty-seven articles were included as a result of the manual search. Adherence measures identified were: self-report (reported in 50 publications), electronic measures (33), pharmacy refills and claims data (26) and pill counts (25). Patient self-report, electronic measures, pharmacy refill and claims data were the most commonly used measures of adherence in research, routine practice, epidemiological and intervention studies. These methods, and their strengths and limitations have been described in this paper. CONCLUSION: A multitude of indirect measures of adherence exist in the literature, however, there is no "gold" standard for measuring adherence to medications. Triangulation of methods increases the validity and reliability of the adherence data collected. To strengthen the adherence data collected and allow for comparison of data, future research and practice interventions should use an internationally accepted, operational standardized definition of medication adherence and clearly describe the medication adherence methods used. PMID- 24166661 TI - Protein function annotation by local binding site surface similarity. AB - Hundreds of protein crystal structures exist for proteins whose function cannot be confidently determined from sequence similarity. Surflex-PSIM, a previously reported surface-based protein similarity algorithm, provides an alternative method for hypothesizing function for such proteins. The method now supports fully automatic binding site detection and is fast enough to screen comprehensive databases of protein binding sites. The binding site detection methodology was validated on apo/holo cognate protein pairs, correctly identifying 91% of ligand binding sites in holo structures and 88% in apo structures where corresponding sites existed. For correctly detected apo binding sites, the cognate holo site was the most similar binding site 87% of the time. PSIM was used to screen a set of proteins that had poorly characterized functions at the time of crystallization, but were later biochemically annotated. Using a fully automated protocol, this set of 8 proteins was screened against ~60,000 ligand binding sites from the PDB. PSIM correctly identified functional matches that predated query protein biochemical annotation for five out of the eight query proteins. A panel of 12 currently unannotated proteins was also screened, resulting in a large number of statistically significant binding site matches, some of which suggest likely functions for the poorly characterized proteins. PMID- 24166662 TI - Clostridium butyricum MIYAIRI 588 improves high-fat diet-induced non-alcoholic fatty liver disease in rats. AB - BACKGROUND/AIMS: Non-alcoholic fatty liver disease (NAFLD) has become a common liver disease, as its prevalence has increased markedly in recent decades. The aim of the present study was to examine the improving effect of Clostridium butyricum MIYAIRI 588 (CBM588), a probiotic in clinical use for antibiotic associated diarrhea, against high-fat diet (HFD)-induced fatty liver in rats. METHODS: After feeding HFD or HFD coated with CBM588 (HFD-CBM) for 12 weeks, we evaluated the hepatic mRNA levels related to lipid metabolism, and then assessed the hepatic protein levels of several transcription factors regulating these lipogenic gene expressions. RESULTS: The HFD-CBM group had decreased accumulation of lipid droplets in the liver compared with the HFD group. The HFD-CBM group had significantly decreased diacylglycerol acyltransferase (DGAT) 2 mRNA in the liver compared with the HFD group, whereas DGAT1 mRNA did not change between the HFD group and the HFD-CBM group. Moreover, the HFD-CBM group had significantly increased hepatic mRNA regulating cholesterol catabolism enzymes and excretion transporters. Correspondingly, the HFD-CBM588 groups had increased hepatic protein levels of peroxisome proliferator-activated receptor alpha/gamma and liver X receptor alpha compared with the HFD group. The HFD-CBM group had accelerated excretion of total bile acid and non-esterified fatty acid in the feces. CONCLUSIONS: CBM588 intake may have novel potential for improving NAFLD. PMID- 24166663 TI - High serum vaspin concentrations in patients with ulcerative colitis. AB - BACKGROUND: Adipocytokines are associated with energy homeostasis and mediate various immune responses and inflammatory processes. Vaspin is a novel adipocytokine that is thought to exhibit anti-inflammatory effects. AIM: We aimed to evaluate serum vaspin levels in inflammatory bowel disease (IBD) and determine its possible associations with the course and to clarify its intestinal localization. METHODS: Serum samples were obtained from patients with Crohn's disease (CD; n = 30) and ulcerative colitis (UC; n = 33) and from healthy volunteers (controls; n = 26). Enzyme-linked immunosorbent assays were performed for all patients. Vaspin immunohistochemical staining was performed for intestines affected with IBD. RESULTS: Serum vaspin concentrations were significantly higher in patients with UC than in patients with CD and controls (422.9 +/- 361.9 vs. 163.4 +/- 116.2 vs. 147.5 +/- 89.4 pg/mL, respectively; P < 0.01). There was no difference in the serum vaspin concentrations between the patients with CD and controls. There was also no difference in the serum vaspin concentrations between the patients with active IBD and those with inactive IBD. However, the serum vaspin concentrations of most patients with UC increased after remission induction. Vaspin was expressed in the adipocytes of the mesenteric adipose tissues but not in the epithelial or inflammatory cells of large intestines of the patients with IBD. CONCLUSIONS: Serum vaspin concentrations are elevated in patients with UC and increase further after remission induction, suggesting that vaspin may aid the auxiliary diagnosis of UC and may be useful for assessing disease activity in patients. PMID- 24166664 TI - For patients with primary achalasia the clinical success of pneumatic balloon dilatation can be predicted from the residual fraction of radionuclide during esophageal transit scintigraphy. AB - BACKGROUND: Esophageal transit scintigraphy (ETS) and esophagography have long been used to evaluate patients with achalasia. The objectives of our study were to evaluate the efficacy of endoscopic pneumatic dilatation (EPD) as treatment for Koreans with achalasia and to determine which findings from ETS and esophagography predict successful treatment of achalasia. METHODS: Patients with achalasia who were treated by EPD between April 2002 and January 2012 were recruited. We defined the success of EPD as 6 months or more of clinical remission without symptoms or a decrease in the Eckardt scores by at least two points and a total Eckardt score not exceeding 3. We reviewed the percentage of maximum scintigraphic activity retained in the esophagus at 30 s (R 30) and the post-PD rate of reduction of R 30 ((Pre R 30 - Post R 30)/Pre R 30 * 100) by ETS. Possible predictive factors determined by ETS and esophagography were analyzed. RESULTS: Our study included 53 eligible patients. The median symptom score (Eckardt score) was 5 (4-8). R 30 and T 1/2 were, respectively, 61.8 % and 38.5 min before EPD and 20 % and 4.19 min after EPD. Successful EPD was achieved for 40 of 53 (75.47 %) patients. Age (>=40, p = 0.027) and post-PD rate of reduction of R 30 (>20 %, p = 0.003) were best prognostic indicators of clinical success. There were no perforations related to EPD. CONCLUSION: Older age and a post-PD rate of reduction of R 30 were strongly associated with better outcomes. Examination with ETS before and after EPD can be used to objectively assess a patient's short-term response to EPD. PMID- 24166665 TI - Correlation of MR elastography with morphometric quantification of liver fibrosis (Fibro-C-Index) in chronic hepatitis B. AB - PURPOSE: We evaluated the correlation of MR Elastography (MRE) with morphometric assessment of liver fibrosis in chronic hepatitis B (CHB). METHODS: Thirty-two patients with CHB underwent both MRE and a liver biopsy within a 6-month interval. MRE was performed using standard MRE sequence on a 1.5 Tesla clinical scanner. The liver stiffness (LS) was measured on automatically generated stiffness maps. Morphometric quantification of fibrosis of liver biopsies was performed using a semi-automated image analysis program and expressed as percentage area (Fibro-C-Index). Correlations between MRE, Fibro-C-Index, and histologic fibrosis stages were evaluated. Receiver operating curve (ROC) analysis of MRE and Fibro-C-index for differentiating fibrosis (>=F1), significant fibrosis (>=F2), advanced fibrosis (>=F3), and cirrhosis (F4) was performed. RESULTS: MRE showed excellent correlation with both Fibro-C-Index (r = 0.78, 95% confidence interval [CI], 0.59-0.88, P < 0.001) and histologic staging (rho = 0.87, 95% CI, 0.72-0.94, P < 0.0001). Significant differences in MRE (P = 0.0001) and Fibro-C-Index (P = 0.003) among different stages of liver fibrosis was found. MRE and Fibro-C-Index had similar accuracies for differentiating fibrosis stages: >=F1 (0.87 versus 0.81, P = 0.6), >=F2 (0.95 versus 0.94, P = 0.78), >=F3 (0.98 versus 0.96, P = 0.76), and F4 (1.00 versus 0.92, P = 0.10). CONCLUSION: MRE is an excellent noninvasive indicator of liver fibrosis burden in CHB. PMID- 24166666 TI - New oral anticoagulants and the risk of intracranial hemorrhage: traditional and Bayesian meta-analysis and mixed treatment comparison of randomized trials of new oral anticoagulants in atrial fibrillation. AB - IMPORTANCE: Randomized studies have shown a decreased risk of intracranial hemorrhage (ICH) with use of novel oral anticoagulants (NOACs). However, it is unclear whether the magnitude of benefit is similar for all NOACs currently available. OBJECTIVE: To perform a systematic review and meta-analysis to quantitatively assess the rates of ICH within the framework of both conventional and Bayesian statistics. DATA SOURCES: The MEDLINE, CENTRAL, CINAHL, and EBSCO databases, supplemented with conference abstracts, were searched up to December 1, 2012, with no language restriction. STUDY SELECTION: Randomized trials comparing NOACs vs a comparator and reporting on ICH events. DATA EXTRACTION AND SYNTHESIS: The NOACs were pooled to perform a comparison with all comparators and among themselves in both traditional frequentist and Bayesian random-effects models using vague priors and Markov chain Monte Carlo simulation with Gibbs sampling, calculating pooled odds ratios and associated 95% confidence intervals as well as numbers needed to treat and 95% credible intervals for the Bayesian analysis. MAIN OUTCOMES AND MEASURES: Intracranial hemorrhage events associated with NOACs in comparison with comparators, expressed as odds ratios. RESULTS: Six studies (1 administering dabigatran etexilate mesylate, 2 administering rivaroxaban, and 3 administering apixaban) enrolling a total of 57,491 patients were included for analysis. The NOACs significantly reduced the risk of ICH against all comparators (odds ratio = 0.49; 95% CI, 0.36-0.65). Each of the 3 drugs reduced the risk of ICH, with Bayesian indirect comparison analysis not revealing a significant credible difference between the specific medications. CONCLUSIONS AND RELEVANCE: Novel oral anticoagulants are uniformly associated with an overall reduced risk of ICH when used for stroke prevention in atrial fibrillation. Any of the currently available NOACs can be considered first line for patients at high risk for ICH. PMID- 24166667 TI - Identification of unknown impurity of azelaic acid in liposomal formulation assessed by HPLC-ELSD, GC-FID, and GC-MS. AB - The identification of new contaminants is critical in the development of new medicinal products. Many impurities, such as pentanedioic acid, hexanedioic acid, heptanedioic acid, octanedioic acid, decanedioic acid, undecanedioic acid, dodecanedioic acid, tridecanedioic acid, and tetradecanedioic acid, have been identified in samples of azelaic acid. The aim of this study was to identify impurities observed during the stability tests of a new liposomal dosage form of azelaic acid that is composed of phosphatidylcholine and a mixture of ethyl alcohol and water, using high-performance liquid chromatography with evaporative light-scattering detector (HPLC-ELSD), gas chromatography-flame ionisation detection (GC-FID), and gas chromatography-mass spectrometry (GC-MS) methods. During the research and development of a new liposomal formulation of azelaic acid, we developed a method for determining the contamination of azelaic acid using HPLC-ELSD. During our analytical tests, we identified a previously unknown impurity of a liposomal preparation of azelaic acid that appeared in the liposomal formulation of azelaic acid during preliminary stability studies. The procedure led to the conclusion that the impurity was caused by the reaction of azelaic acid with one of the excipients that was applied in the product. The impurity was finally identified as an ethyl monoester of azelaic acid. The identification procedure of this compound was carried out in a series of experiments comparing the chromatograms that were obtained via the following chromatographic methods: HPLC-ELSD, GC-FID, and GC-MS. The final identification of the compound was carried out by GC with MS. PMID- 24166668 TI - Preparation and pharmacokinetic study of aprepitant-sulfobutyl ether-beta cyclodextrin complex. AB - Aprepitant (APR), a neurokinin 1 receptor antagonist, is an approved treatment for chemotherapy-induced nausea and vomiting and for post-operative nausea and vomiting. However, it has poor water solubility. This study was performed to optimize the capsule formulation of an inclusion complex of APR with sulfobutyl ether-beta-cyclodextrin (SBE-beta-CD), and to evaluate its water solubility, dissolution rate, and bioavailability. The complex was prepared through the saturated-aqueous solution method and then characterized by Fourier transform infrared spectroscopy, x-ray powder diffraction, and differential scanning calorimetry. Subsequently, a pharmacokinetic study was performed using liquid chromatography-tandem mass spectrometry. Emend, which features an innovative formulation that incorporates drug nanoparticles with high bioavailability, was used as a reference for comparison with the optimized formulation. As a result, the dissolution rates and extent of release of the test formulation in various media were enhanced relative to those of Emend. The bioavailability of the drug complex was comparable to that of Emend. In summary, the SBE-beta-CD complexation could provide a practical and cost-effective option for enhancing the solubility and bioavailability of APR according to our research. PMID- 24166669 TI - Caffeic acid inhibits organic anion transporters OAT1 and OAT3 in rat kidney. AB - BACKGROUND: Some food components influence drug elimination. Previously, we found that caffeic acid, present in coffee, fruits, and vegetables, strongly inhibited human homologs of organic anion transporters (OATs) OAT1 and OAT3, which are responsible for renal tubular secretion of anionic drugs. In this study, we examined the effect of caffeic acid on drug transport by OAT1 and OAT3 in the rat kidney. METHODS: The inhibitory effect of caffeic acid on rat OAT1 and OAT3 was assessed by drug uptake experiment using Xenopus laevis oocytes. Urinary excretion of phenolsulfonphthalein (PSP), a diagnostic agent secreted by renal OATs, was examined in rats, and the influence of caffeic acid was evaluated. RESULTS: Expression of rat OAT1 (rOAT1) and rOAT3 stimulated uptake of their typical substrates, p-aminohippurate and estrone sulfate, respectively, into oocytes, and caffeic acid inhibited them dose dependently. After intravenous injection of PSP in rats, 42.7% of the dose was excreted into urine up to 60 min, and the simultaneous administration of caffeic acid reduced it to 32.0%. CONCLUSIONS: These findings show that caffeic acid inhibits OAT1 and OAT3 in the rat kidney. PMID- 24166670 TI - Unexpected interaction between CYP3A4 and BI 11634: is BI 11634 interacting with CYP3A4 similar to nifedipine? AB - BACKGROUND: Interactions between cytochrome P450 3A4 (CYP3A4) and its substrates are complex with multiple binding sites within the active site. BI 11634 is a factor Xa inhibitor in drug development and its interaction with CYP3A4 was evaluated. METHODS: Reaction phenotyping studies were conducted to determine human isoform(s) of cytochrome P450 responsible for BI 11634 metabolism using recombinant CYPs and specific chemical inhibitors. Metabolite identification and quantitation were performed for incubations of [14C]BI 11634 with human liver microsomes (HLMs) or recombinant CYP3A4 (rCYP3A4) using a high-performance liquid chromatography-mass spectrometry-radiomatic detector. Inhibition of the CYP3A4 mediated metabolism of BI 11634 by quinidine was further evaluated. RESULTS: From the reaction phenotyping studies, it was shown that the metabolism of BI 11634 in HLM was inhibited by ketoconazole and quinidine, well-accepted specific inhibitors of CYP3A4 and CYP2D6, respectively. In contrast, BI 11634 metabolism was exclusively mediated by rCYP3A4. Additional studies confirmed that BI 11634 was metabolized by CYP3A4 to form one major metabolite and this reaction was inhibited by quinidine with a Ki of 7 uM. CONCLUSIONS: These data indicated that BI 11634 may interact with CYP3A4 similar to nifedipine. CYP3A4 substrates have been categorized into three subgroups, including a stand-alone subgroup for dihydropyridine calcium channel blockers such as nifedipine and felodipine. In addition, this study emphasizes the importance of using rCYP in conjunction with approaches relying on inhibition when conducting CYP450 reaction phenotyping studies, as one single method may generate misleading results. The specificity of quinidine as a CYP2D6 inhibitor is questionable as it can also significantly inhibit CYP3A4-mediated metabolism of some compounds. PMID- 24166671 TI - Pregnane X receptor (PXR)--a contributor to the diabetes epidemic? AB - Pregnane X receptor (PXR), a ligand-activated nuclear receptor, was originally identified as a regulator of drug and bile acid metabolism. Studies in experimental animals and humans within the last decade have revealed PXR as a regulator of energy metabolism repressing gluconeogenesis and hepatic lipid oxidation. The most recent in vivo studies demonstrate that PXR activation has a detrimental role in the regulation of glucose metabolism. The prevalence of many PXR agonists in low concentrations in our environments as well as the PXR activating properties of numerous commonly used medications and herbal remedies may have unanticipated health effects. It could be speculated that, due to its dual role as a xenosensor and a regulator of energy metabolism, PXR, in concert with a mixture of PXR agonists in the environment, contributes to the present-day type 2 diabetes epidemic. With this hypothesis in mind, we review the current literature on PXR as a regulator of glucose and hepatic lipid metabolism and the association of exposure to PXR agonists with diabetes susceptibility. PMID- 24166673 TI - Comparison of an enzymatic assay with liquid chromatography-pulsed amperometric detection for the determination of lactulose and mannitol in urine of healthy subjects and patients with active celiac disease. PMID- 24166672 TI - Increased plasma arginase activity in human sepsis: association with increased circulating neutrophils. AB - BACKGROUND: The pathophysiology of sepsis is incompletely understood. Impaired bioavailability of L-arginine, the substrate for NO synthesis, is linked to sepsis severity, and plasma arginase has been linked to hypoargininemia in other disease states. Circulating neutrophils are increased in sepsis and constitutively express arginase. We investigated whether plasma arginase activity is increased in human sepsis and whether this is associated with neutrophil numbers and activation. METHODS: We used HPLC and a radiometric assay to evaluate plasma amino acid concentrations and plasma arginase activity. The relationships between plasma arginase activity, neutrophil count, neutrophil activity and plasma L-arginine and arginine metabolites were evaluated in 44 sepsis patients and 25 controls. RESULTS: Plasma arginase activity was increased in sepsis patients, correlated with neutrophil count (r=0.44; p=0.003), but was independent of sepsis severity (SOFA or APACHE II score). Plasma HNP1-3 correlated with neutrophil count (r=0.31; p=0.04), was elevated in shock (median 180 ng/mL vs. 83 ng/mL sepsis without shock, p=0.0006) and correlated with SOFA score. Sepsis patients with high neutrophil counts had significantly higher plasma HNP1-3 and arginase activity and lower plasma L-arginine concentrations than those with lower neutrophil counts and controls. CONCLUSIONS: Plasma arginase activity, potentially derived in part from neutrophil activation, is elevated in sepsis, and may contribute to impaired bioavailability of L-arginine in sepsis. PMID- 24166674 TI - Identification of an 18 bp deletion in the TWIST1 gene by CO-amplification at lower denaturation temperature-PCR (COLD-PCR) for non-invasive prenatal diagnosis of craniosynostosis: first case report. AB - BACKGROUND: Non-invasive prenatal diagnosis has found application in a limited number of genetic diseases due to the difficulty in detecting a few copies of fetal mutated sequences in the presence of a large excess of wild-type maternal alleles, even in the case of single-base mutations. METHODS: We developed conditions for the enrichment of fetal mutated alleles in maternal plasma based on CO-amplification at lower denaturation temperature-PCR (COLD-PCR). In particular, we applied a full COLD-PCR protocol to the identification of a p.A87_G92del mutation in the TWIST1 gene causing craniosynostosis in a couple at risk for the disease. RESULTS: The use of the COLD-PCR protocol coupled with direct sequencing enabled correct identification of the fetal paternally inherited mutated allele, in accordance with the result obtained on DNA extracted from chorionic villi. CONCLUSIONS: COLD-PCR proved to be a simple and powerful tool for the identification of minority mutated alleles even in the case of a moderately large deletion (18 bp) and confirmed to be very suitable for non invasive prenatal diagnosis of a variety of genetic diseases. PMID- 24166675 TI - To the editor: TIGIT versus CD226: hegemony or coexistence? PMID- 24166676 TI - Urodynamic studies for management of urinary incontinence in children and adults. AB - BACKGROUND: Urodynamic tests are used to investigate people who have urinary incontinence or other urinary symptoms in order to make a definitive, objective diagnosis. The aim is to help select the treatment most likely to be successful. The investigations are invasive and time consuming. OBJECTIVES: The objective of this review was to determine if treatment according to a urodynamic-based diagnosis, compared to treatment based on history and examination, led to more effective clinical care of people with urinary incontinence and better clinical outcomes.The intention was to test the following hypotheses in predefined subgroups of people with incontinence:(i) urodynamic investigations improve the clinical outcomes;(ii) urodynamic investigations alter clinical decision making;(iii) one type of urodynamic test is better than another in improving the outcomes of management of incontinence or influencing clinical decisions, or both. SEARCH METHODS: We searched the Cochrane Incontinence Group Specialised Register, which contains trials identified from the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE and MEDLINE In-Process, handsearching of journals and conference proceedings (searched 19 February 2013), and the reference lists of relevant articles. SELECTION CRITERIA: Randomised and quasi randomised trials comparing clinical outcomes in groups of people who were and were not investigated using urodynamics, or comparing one type of urodynamic test against another were included. Trials were excluded if they did not report clinical outcomes. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed trial quality and extracted data. MAIN RESULTS: Eight trials involving around 1100 people were included but data were only available for 1036 women in seven trials, of whom 526 received urodynamics. There was some evidence of risk of bias. The four deaths and 12 dropouts in the control arm of one trial were unexplained.There was significant evidence that the tests did change clinical decision making. Women in the urodynamic arms of three trials were more likely to have their management changed (proportion with change in management compared with the control arm 17% versus 3%, risk ratio (RR) 5.07, 95% CI 1.87 to 13.74), although there was statistical heterogeneity. There was evidence from two trials that women treated after urodynamic investigations were more likely to receive drugs (RR 2.09, 95% CI 1.32 to 3.31). On the other hand, in five trials women undergoing treatment following urodynamic investigation were not more likely to undergo surgery (RR 0.99, 95% CI 0.88 to 1.12).There was no statistically significant difference however in the number of women with urinary incontinence if they received treatment guided by urodynamics (37%) compared with those whose treatment was based on history and clinical findings alone (36%) (for example, RR for the number with incontinence after the first year 1.02, 95% CI 0.86 to 1.21). It was calculated that the number of women needed to treat was 100 women (95% CI 86 to 114 women) undergoing urodynamics to prevent one extra individual being incontinent at one year.One trial reported adverse effects and no significant difference was found (RR 1.10, 95% CI 0.81 to 1.50). AUTHORS' CONCLUSIONS: While urodynamic tests did change clinical decision making, there was some evidence that this did not result in better outcomes in terms of a difference in urinary incontinence rates after treatment. There was no evidence about their use in men, children, or people with neurological diseases. Larger definitive trials are needed in which people are randomly allocated to management according to urodynamic findings or to management based on history and clinical examination to determine if performance of urodynamics results in higher continence rates after treatment. PMID- 24166678 TI - Use of contact pressure-sensitive surfaces as an indicator of graft tension in medial patellofemoral ligament reconstruction. AB - BACKGROUND: No previous description has been made about an objective method to test the graft resistance in MPFL reconstruction intraoperatively. In our study, we aimed to obtain intraoperative objective data about the graft resistance using contact pressure-sensitive surfaces and measuring pressure formed under the graft. MATERIALS AND METHODS: In 2012, double-layered contact pressure-sensitive Fuji Prescale Film bands were placed under MPFL in 15 fresh-frozen high above knee amputates (Group 1) and under graft in 10 patients who underwent MPFL reconstruction (Group 2). Measured values at different flexion angles were compared between and in groups. RESULTS: Statistical analysis was performed by Student's t test. It has been found that the pressure under the graft was higher in patients having reconstruction as compared to the pressure under natural MPFL. Decreasing pressure values were observed with increasing flexion angles in both groups. CONCLUSION: Contact pressure-sensitive surfaces provided objective data when placed under the graft in natural MPFL and during surgery. Therefore, they may be used as an objective marker providing information about graft resistance. PMID- 24166680 TI - Peritoneal debulking/intraperitoneal chemotherapy-non-sarcoma. AB - The combination of cytoreductive surgery (CRS) and intraperitoneal chemotherapy (IPC) is widely practiced for appendiceal, colorectal, gastric, and ovarian cancers with isolated peritoneal metastasis as well as for primary peritoneal cancer. The aim of this report is to explain the rationale and available techniques for CRS and IPC, and to highlight disease-specific considerations that should be taken into account when evaluating potential candidates for CRS and IPC. PMID- 24166681 TI - Optical manipulation of charged microparticles in polar fluids. AB - In this study, we report a systematic study of the response of a charged microparticle confined in an optical trap and driven by electric fields. The particle is embedded in a polar fluid, hence, the role of ions and counterions forming a double layer around the electrodes and the particle surface itself has been taken into account. We analyze two different cases: (i) electrodes energized by a step-wise voltage (DC mode) and (ii) electrodes driven by a sinusoidal voltage (AC mode). The experimental outcomes are analyzed in terms of a model that combines the electric response of the electrolytic cell and the motion of the trapped particle. In particular, for the DC mode we analyze the transient particle motion and correlate it with the electric current flowing in the cell. For the AC mode, the stochastic and deterministic motion of the trapped particle is analyzed either in the frequency domain (power spectral density, PSD) or in the time domain (autocorrelation function). Moreover, we will show how these different approaches (DC and AC modes) allow us, assuming predictable the applied electric field (here generated by plane parallel electrodes), to provide accurate estimation (3%) of the net charge carried by the microparticle. Vice versa, we also demonstrate how, once predetermined the charge, the trapped particle acts as a sensitive probe to reveal locally electric fields generated by arbitrary electrode geometries (in this work, wire-tip geometry). PMID- 24166683 TI - Short-term neonatal outcomes in diamniotic twin pregnancies delivered after 32 weeks and indications of late preterm deliveries. AB - OBJECTIVE: We sought to compare neonatal outcomes in twin pregnancies following moderately preterm birth (MPTB), late preterm birth (LPTB), and term birth and determine the indications of LPTB. STUDY DESIGN: We performed a retrospective cohort study. MPTB was defined as delivery between 32(0/7) and 33(6/7) weeks and LPTB between 34(0/7) and 36(6/7) weeks. The composite neonatal adverse respiratory outcome was defined as respiratory distress syndrome and/or bronchopulmonary dysplasia. The composite neonatal adverse nonrespiratory outcome included early onset culture-proven sepsis, necrotizing enterocolitis, retinopathy of prematurity, intraventricular hemorrhage, or periventricular leukomalacia. LPTB cases were categorized as spontaneous (noniatrogenic), evidence-based iatrogenic, and non-evidence-based (NEB) iatrogenic. RESULTS: Of the 747 twin deliveries during the study period, 453 sets met the inclusion criteria with 22.7% (n = 145) MPTB, 32.1% (n = 206) LPTB, and 15.9% (n = 102) term births. Compared with term neonates, the composite neonatal adverse respiratory outcome was increased following MPTB (relative risk [RR] 24; 95% confidence interval [CI] 3.0 to 193.6) and LPTB (RR 13.7; 95% CI 1.8 to 101.8). Compared with term neonates, the composite neonatal adverse nonrespiratory outcome was increased following MPTB (RR 22.3; 95% CI 3.9 to 127.8) and LPTB (RR 5.5; 95% CI 1.1 to 27.6). Spontaneous delivery of LPTB was 63.6% (n = 131/206) and the rate of iatrogenic delivery was 36.4% (n = 75/206). The majority, 66.6% (n = 50/75), of these iatrogenic deliveries were deemed NEB, giving a total of 24.2% (50/206) NEB deliveries in LPTB group. CONCLUSION: Our data demonstrate a high rate of late preterm birth among twin pregnancies, with over half of nonspontaneous early deliveries due to NEB indications. Although our morbidity data will be helpful to providers in counseling patients, our finding of high NEB indications underscores the need for systematic evaluation of indications for delivery in LPTB twin deliveries. Furthermore, this may lead to more effective LPTB rate reduction efforts. PMID- 24166684 TI - Downregulation of UBE2Q1 is associated with neuronal apoptosis in rat brain cortex following traumatic brain injury. AB - Aberrant functionality of the ubiquitin proteasome system (UPS) has been implicated in the pathology of various neurological disorders. Although it has been reported that the expressions of various UPS components were altered significantly following traumatic brain injury (TBI), detailed information on the subject remains largely unclear. In the study, using microarray assay, we identified a gene encoding ubiquitin-conjugating enzyme E2Q1 (UBE2Q1) that was significantly downregulated during TBI. Western blot and immunohistochemical analyses verified the reduced expression of UBE2Q1 in ipsilateral brain cortex adjacent to the lesion site compared with the contralateral and sham-operated ones. Double-immunofluorescence staining indicated that UBE2Q1 was expressed mainly in the nucleus of neurons, with a minority in astrocytes in normal cortex. In addition, we observed a remarkable reduction in the number of UBE2Q1-positive neurons following brain trauma. Furthermore, we showed that TBI resulted in a significant increase in the levels of p53, bax, p21 and active caspase 3 in brain cortex, which was correlated with decreased expression of UBE2Q1. We also found that knockdown of UBE2Q1 apparently increased the level of p53, whereas overexpressing UBE2Q1 attenuated cellular p53 level in PC12 neuronal cells. Accordingly, interference with UBE2Q1 augmented H2O2-induced apoptosis of PC12 cells. Taken together, our findings indicate that UBE2Q1 might play an important role in the neuropathological process of TBI through modulating p53 signaling. PMID- 24166685 TI - A developing world perspective on homicide and personality disorder. AB - High rates of psychotic disorder among special populations of homicide offenders, females, youth and the mentally disordered, have received much investigation. Personality disorder, especially antisocial personality disorder, augments the relative risk ratio of violence, especially in combination with substance use disorder. Few studies of these correlates of violence and especially homicide have been reported in low- and medium-income countries (LMIC). Using the structured clinical interview for DSM diagnosis (SCID), personality disorders were identified in a cross sectional study involving 546 homicide offenders in Jimma prison, Ethiopia. Predictors of personality disorder were determined using multivariate analysis of various demographic and clinical variables, for example, age, psychiatric history and substance use. Out of the 316 offenders who completed the SCID, only 16% fulfilled DSM IV criteria for personality disorder. The rationale for killing, self-defence, anger and revenge (52% of offenders), planning involved in offending (50%) and reasonably high level of relationship functioning (57% married) were different from most data from the high-income countries. Diagnostically relevant cultural factors in LMIC, not in play in high income countries, may explain the differences in personality disorders similar to other mental disorders and the underlying mediators of homicide. PMID- 24166682 TI - Evaluation of the antitumor activity of dacomitinib in models of human bladder cancer. AB - Members of the human epidermal growth factor receptor (HER) family play a significant role in bladder cancer progression and may underlie the development of chemotherapy resistance. Dacomitinib is an irreversible tyrosine kinase inhibitor with structural specificity for the catalytic domains of epidermal growth factor receptor (EGFR), HER2 and HER4 that has exhibited vigorous efficacy against other solid tumors. We evaluated the antitumor activity of dacomitinib in human bladder cancer cell lines expressing varying levels of HER family receptors. These cell lines also were established as bladder cancer xenografts in nonobese diabetic/severe combined immunodeficiency (NOD/SCID) mice to assess dacomitinib activity in vivo. Significant cytotoxic and cytostatic effects were noted in cells expressing elevated levels of the dacomitinib target receptors with apoptosis and cell cycle arrest being the predominant mechanisms of antitumor activity. Cells expressing lower levels of HER receptors were much less sensitive to dacomitinib. Interestingly, dacomitinib was more active than either trastuzumab or cetuximab in vitro, and exhibited increased growth inhibition of bladder tumor xenografts compared with lapatinib. Pharmacodynamic effects of dacomitinib included decreased E-cadherin (E-cad) expression, reduction of EGFR and extracellular signal-regulated kinase (ERK) phosphorylation and reduced mitotic count. Dacomitinib also inhibited tumor growth in a chemotherapy resistant xenograft and, when combined with chemotherapy in a sensitive xenograft, exhibited superior antitumor effects compared with individual treatments. Evaluation in xenograft-bearing mice revealed that this combination was broadly feasible and well tolerated. In conclusion, dacomitinib exhibited pronounced activity both as a single agent and when combined with chemotherapy in human bladder cancer models. Further investigation of dacomitinib in the preclinical and clinical trial settings is being pursued. PMID- 24166686 TI - Philemon and Baucis, Diogenes and syllogomania, Wischnewski and hypothermia- gastric mucosal lesions in partially mummified bodies. AB - We present a case of two brothers who died simultaneously, where their deaths could be considered to be a form of a Philemon and Baucis death; they also showed signs of Diogenes syndrome and syllogomania. The two brothers had been living in a socially isolated state and had not left their flat for months. They were found dead during the winter, in a flat with no heating. Taking the poor condition of the flat into consideration, it can be assumed that a draught existed and, therefore, the bodies were exposed to convection, that is, ventilation and low humidity, which is what caused partial mummification to the exposed areas of the body. The exact cause of death could not be determined due to the postmortem changes; however, there was very little to point to homicide or suicide as the manner of death. Despite these postmortem changes, the Wischnewski spots remained clearly visible, whose presence, in addition to the overall circumstances of the case, indicate that hypothermia could be a possible or at least contributing cause of death in both cases. PMID- 24166687 TI - Estimation of time since death from electrolyte, glucose and calcium analysis of postmortem vitreous humour in semi-arid climate. AB - Estimating time since death (TSD) with fair accuracy from postmortem changes still remains an important but difficult task to be performed by every autopsy surgeon in medicolegal scenario. The aim of the present study was to estimate TSD from electrolyte analysis of postmortem vitreous humour collected from samples under semi-arid climate. Vitreous humour was collected from 210 dead bodies brought to University College of Medical Sciences and Guru Teg Bahadur Hospital, Delhi, during the period of November 2010 to April 2012. The vitreous samples were analysed for sodium, potassium, calcium, chloride and glucose. The results showed a significant positive relationship between TSD and potassium (r = 0.841, p = 0.000) and a weak negative relationship between TSD and sodium (r = -0.137, p = 0.048) and glucose (r = -0.241, p = 0.000), whereas no significant relationship could be established between TSD and calcium (r = 0.055, p = 0.429) and chloride (r = 0.075, p = 0.11). PMID- 24166688 TI - Can immunohistochemistry quantification of Cathepsin-D be useful in the differential diagnosis between vital and post-mortem wounds in humans? AB - Markers of skin wound vitality and the research methodology used for their determination are still matters of debate in forensic pathology. Cathepsin-D, a lysosomal enzyme, is the most expressed cathepsin in human skin, and although it seems to have the necessary requirements to be utilized as a vitality marker, past research has provided no definitive and clear response on its potential usefulness. Immunohistochemistry with monoclonal antibodies and image analysis has been employed to detect and quantify the expression of Cathepsin-D in human skin wounds. We analyzed skin fragments obtained from 20 living individuals (group A) and 20 persons deceased from natural causes (group B). For each case, five skin fragments were withdrawn at 0', 5', 10', 30', and 90' after abdominal incision. Once the samples were formalin-fixed and paraffin-embedded, we analyzed the expression of Cathepsin-D through the quantification of the immunohistochemistry signal by image analysis. Immunoreactivity was displayed in Pixels of positive area measured by image analysis and converted in micrometer squares. The average levels of Cathepsin-D were higher in group B than in group A, except in three cases which showed a lower expression, with a statistically significant difference of Cathepsin-D expression between the two groups (p < 0.0001). Group B showed unvaried levels among the progressive samples and group A revealed an increasing predominant trend at 30'. Due to the high levels of expression of Cathepsin-D found in the post-mortem injuries, our study definitively excludes any usefulness of immunohistochemistry quantification of this enzyme in the differentiation between vital and post-mortem injuries. PMID- 24166689 TI - Fatal hemothorax due to homicidal blunt trauma to carotid artery in the neck. AB - A 30-year-old man was found dead in a pool of blood inside his office room in the morning. Autopsy revealed a small contusion at the lower anterior part of neck, laceration on the left common carotid artery, hemothorax and a laceration over the nose with underlying fracture. On investigation, it was found that on the previous night the victim had been assaulted by his domestic help with an iron rod over head and neck. The blunt trauma to the neck resulted in laceration on the left common carotid artery and subsequently bled, causing fatal hemothorax. The authors report this case owing to the rarity of such patterns of injury leading to fatal outcomes, which may be overlooked due to the simple nature of external injuries. PMID- 24166690 TI - A study of elderly unnatural deaths in medico-legal autopsies at Lucknow locality. AB - The main aim of this study was to determine the causes and epidemiological aspects of unnatural deaths in the elderly. Data were collected on 4405 male and female victims of unnatural deaths aged 50 years or more from the total number of 21,235 autopsies performed in King George's Medical University, Lucknow, India over a 5-year period, from 2008 to 2012. There were 3165 male victims and 1240 female victims. Unnatural deaths were higher in rural (64%) than in urban (37%) areas. Accidental deaths were the most common manner of unnatural deaths (59%), followed by suicidal deaths (34%) and homicidal deaths (7%). Traumas were the most common cause of unnatural death (77.3%), followed by undetermined causes (16.6%) and toxicological causes (6.1%). The most common causes of traumatic deaths were blunt head injuries (34%) followed by stab in the chest (6%), burn (16%), blunt injuries in abdomen and chest (10%), firearm injuries in the head and trunk (9%), strangulation (3%), stab in the abdomen (4%), smothering (4%), cut throat (3%), throttling (1%) and hanging (10%). Carbamate poisoning was the most common cause of toxicological deaths (44%) followed by organophosphorous poisoning (33%), ethyl alcohol poisoning (12%), barbiturate poisoning (3%) and zinc phosphide poisoning (8%). PMID- 24166691 TI - The future for forensic science. PMID- 24166692 TI - Is cartilage conduction classified into air or bone conduction? AB - OBJECTIVES/HYPOTHESIS: The aim of this study was to establish the sound transmission characteristics of cartilage conduction proposed by Hosoi (2004), which is available by a vibration signal delivered to the aural cartilage from a transducer. STUDY DESIGN: Experimental study. METHOD: Eight volunteers with normal hearing participated. Thresholds at frequencies of 0.5, 1, 2, and 4 kHz for air conduction, bone, and cartilage conductions were measured with and without an earplug. The sound pressure levels on the eardrum at the threshold estimated with a Head and Torso Simulator were compared between air and cartilage conductions. The force levels calibrated with an artificial mastoid at the threshold were compared between bone and cartilage conductions. RESULTS: The difference in the estimated sound pressure levels on the eardrum at the thresholds between air and cartilage conductions were within 10 dB. In contrast, the force levels at the thresholds for cartilage conduction were remarkably lower than those for bone conduction. These findings suggested that sounds were probably transmitted via the eardrum for cartilage conduction. The threshold shifts by an earplug showed no significant difference between bone and cartilage conductions at 0.5 kHz. At 1 and 2 kHz, the threshold-shifts increased significantly in the order of bone, cartilage, and air conductions. These results suggested that airborne sound induced by the vibration of the cartilaginous portion of the ear canal played a significant role in sound transmission for cartilage conduction. CONCLUSIONS: Cartilage conduction has different characteristics from conventional air and bone conductions. PMID- 24166693 TI - Comparison of the Dutch and English versions of the Carolinas Comfort Scale: a specific quality-of-life questionnaire for abdominal hernia repairs with mesh. AB - PURPOSE: Repair of abdominal wall hernias with mesh is one of the most common procedures in general surgery. The introduction of hernia repair with mesh has lowered recurrence rates and shifted the focus to quality of life after surgery, raising the need for a specific tool measuring quality of life. The Carolinas Comfort Scale (CCS) is a questionnaire designed specifically for patients having hernia repair with mesh. The aim of this study is to validate the Dutch CCS and to compare it to the generic short form-36 (SF-36). METHODS: The CCS questionnaire was translated into Dutch. Patients undergoing mesh hernia repair between April 2010 and December 2011 completed the CCS, the SF-36 and four questions comparing these two questionnaires in the first week after surgery. After 3 weeks, the CCS was repeated. Correlations between the two surveys were calculated using the Spearman's rank correlation test with a 95 % confidence interval to determine validity. RESULTS: The response rate was 60.3 % (100/168). The CCS showed excellent reliability with a Cronbach's alpha of 0.948. Significant correlation existed between the CCS and the domains physical functioning, bodily pain, role-physical, vitality and social functioning of the SF-36. Seventy-nine percent of the patients preferred the CCS to the SF-36, and 83 % considered the CCS a better reflection of their quality of life after hernia repair with mesh. CONCLUSION: The Dutch CCS appears a valid and clinically relevant tool for assessing quality of life after repair of abdominal wall hernia with mesh. PMID- 24166694 TI - Segmental zoster abdominal paresis/paralysis, zoster pseudohernia or zoster lumbar hernia? PMID- 24166695 TI - Elevated risk for invasive meningococcal disease among persons with HIV. AB - BACKGROUND: An association between HIV and invasive meningococcal disease (IMD) has been suggested by several previous studies but has not been fully described in the era of highly active antiretroviral therapy in the United States. OBJECTIVE: To estimate the risk for IMD and death in people living with HIV/AIDS (PLWHA) in New York City (NYC) and the contribution of CD4(+) cell count and viral load (VL) to IMD risk. DESIGN: Comparison of the incidence rate of IMD among PLWHA with that among HIV-uninfected persons. Surveillance data on IMD for patients aged 15 to 64 years from 2000 to 2011 were matched to death and HIV registries to calculate IMD risk and case-fatality ratios. A subset of PLWHA who had a CD4(+) cell count and VL measurement near the time of their IMD infection was included in age-matched case-control analyses to assess HIV markers and IMD risk. SETTING: Retrospective cohort from communicable disease surveillance. PATIENTS: 265 persons aged 15 to 64 years with IMD during 2000 to 2011. MEASUREMENTS: Meningococcal and HIV data abstracted from surveillance and registry databases, including CD4(+) cell counts and VL. RESULTS: The average annual incidence rate of IMD was 0.39 cases per 100 000 persons. The relative risk for IMD among PLWHA in NYC during 2000 to 2011 was 10.0 (95% CI, 7.2 to 14.1). Among PLWHA, patients with IMD were 5.3 times (CI, 1.4 to 20.4 times) as likely as age-matched control patients to have CD4(+) counts less than 0.200 * 10(9) cells/L. LIMITATION: Missing data on smoking status and comorbidity. CONCLUSION: People living with HIV/AIDS in NYC are at increased risk for IMD. Cost-effectiveness and vaccine efficacy studies are needed to evaluate the value of a national recommendation for routine meningococcal vaccination of PLWHA. PRIMARY FUNDING SOURCE: New York City Tax Levy. PMID- 24166701 TI - Electrochemical properties of graphene flakes as an air cathode material for Li O2 batteries in an ether-based electrolyte. AB - We employed graphene flakes as an air-cathode material for Li-O2 batteries and investigated their electrochemical properties in the dimethyl ether electrolyte. Graphene flakes were prepared by microwave-assisted reduction of graphene oxide, and their electrochemical properties were compared with those of Ketjen Black and carbon nanotubes. The catalytic effect of the prepared graphene flake-air cathode was demonstrated using cyclic voltammetry and discharge-charge testing performed under a limited discharge capacity. The catalytic effect of graphene flakes was also supported by morphological and spectroscopic analysis of the discharge charge products formed on the graphene surface. Scanning electron microscopy, X ray diffraction, and Fourier-transform infrared spectroscopy revealed that Li2O2, Li2O, and Li2CO3 were the main discharge products on all carbon-air cathode surfaces. Raman spectroscopy revealed that LiRCO3 was additionally formed on Ketjen Black and carbon nanotubes during the first discharge; however, its formation was not observed on the graphene flakes. The catalytic effect of the graphene flakes and the absence of LiRCO3 in the discharge product could explain the higher Coulombic efficiency in the discharge-charge tests. PMID- 24166696 TI - Strategies for developing prediction models from genome-wide association studies. AB - Genome-wide association studies (GWASs) have identified hundreds of single nucleotide polymorphisms (SNPs) associated with complex human diseases. However, risk prediction models based on them have limited discriminatory accuracy. It has been suggested that including many such SNPs can improve predictive performance. Here, we studied various aspects of model building to improve discriminatory accuracy, as measured by the area under the receiver operating characteristic curve (AUC), including: (1) How well does a one-phase procedure that selects SNPs and estimates odds ratios on the same data perform? (2) How should training data be allocated between SNP selection (Phase 1) and estimation (Phase 2) in a two phase procedure? (3) Should SNP selection be based on P-value thresholding or ranking P-values? (4) How many SNPs should be selected? and (5) Is multivariate estimation preferred to univariate estimation in the presence of linkage disequilibrium (LD)? We used realistic estimates of the distributions of genetic effect sizes, allele frequencies, and LD patterns based on GWAS data for Crohn's disease and prostate cancer. Theory and simulations were used to estimate AUC. Empirical risk models based on 10,000 cases and controls had considerably lower AUC than theoretically achievable. The most critical aspect of prediction model building was initial SNP selection. The single-phase procedure achieved higher AUC than the two-phase procedure. Multivariate estimation did not perform as well as univariate (marginal) estimation. For complex diseases and samples of 10,000 or fewer cases and controls, one should limit the number of SNPs to tens or hundreds. PMID- 24166702 TI - Mapping the intramolecular signal transduction of G-protein coupled receptors. AB - G-protein coupled receptors (GPCRs), a major gatekeeper of extracellular signals on plasma membrane, are unarguably one of the most important therapeutic targets. Given the recent discoveries of allosteric modulations, an allosteric wiring diagram of intramolecular signal transductions would be of great use to glean the mechanism of receptor regulation. Here, by evaluating betweenness centrality (CB ) of each residue, we calculate maps of information flow in GPCRs and identify key residues for signal transductions and their pathways. Compared with preexisting approaches, the allosteric hotspots that our CB -based analysis detects for A2 A adenosine receptor (A2 A AR) and bovine rhodopsin are better correlated with biochemical data. In particular, our analysis outperforms other methods in locating the rotameric microswitches, which are generally deemed critical for mediating orthosteric signaling in class A GPCRs. For A2 A AR, the inter-residue cross-correlation map, calculated using equilibrium structural ensemble from molecular dynamics simulations, reveals that strong signals of long range transmembrane communications exist only in the agonist-bound state. A seemingly subtle variation in structure, found in different GPCR subtypes or imparted by agonist bindings or a point mutation at an allosteric site, can lead to a drastic difference in the map of signaling pathways and protein activity. The signaling map of GPCRs provides valuable insights into allosteric modulations as well as reliable identifications of orthosteric signaling pathways. PMID- 24166703 TI - Comorbid anxiety disorders alter the association between cardiovascular diseases and depression: the German National Health Interview and Examination Survey. AB - PURPOSE: This study aims to examine whether specific anxiety disorder comorbidity alters the purported association between depression and specific cardiovascular diseases (CVDs). METHODS: In 4,181 representative German participants of the general population, 12-month prevalence of psychiatric disorders was assessed through the Composite International Diagnostic Interview and CVDs by physician verified diagnosis. Adjusting for conventional risk factors logistic regression analyzed the association between CVDs (peripheral vascular disease (PVD), hypertension, cerebrovascular disease and heart disease) and combinations of comorbidity between depression and anxiety disorder types (panic disorder, specific phobia, social phobia and generalized anxiety). RESULTS: There were 770 cases of hypertension (18.4 %), 763 cases of cerebrovascular disease (18.2 %), 748 cases of PVD (17.9 %), and 1,087 cases of CVD (26.0 %). In adjusted analyses phobia comorbid with depression was associated with cerebrovascular disease (odds ratio (OR) 1.61; 95 % confidence interval (CI) 1.04-2.50) as was panic disorder (OR 2.89; 95 % CI 1.47-5.69). PVD was significantly associated with panic disorder (adjusted OR 2.97; 95 % CI 1.55-5.69). Panic disorder was associated with CVDs (adjusted OR 2.28; 95 % CI 1.09-4.77) as was phobia (adjusted OR 1.35; 95 % CI 1.04-1.78). CONCLUSIONS: Classification of anxiety and depression according to comorbidity groups showed discrete effects for panic disorder and specific phobia with CVDs, independent from covariates and depression. PMID- 24166704 TI - Anterior chamber angle evaluation with ultrasound biomicroscopy and optical coherence tomography in eyes implanted with a Crystalens. AB - This study employs optical coherence tomography (OCT) and ultrasound biomicroscopy (UBM) imaging as well as optical aberrometry to examine correlations between the anterior chamber angle aperture and visual acuity for near vision as well as coma along the horizontal and vertical axes in eyes implanted with an accommodative intraocular lens (Crystalens). A retrospective comparative consecutive case series of 22 eyes of 11 patients (5 males) uneventfully implanted with a Crystalens. Eyes with signs of posterior capsular opacification were excluded. All eyes were examined with 40 MHz UBM (Ellex Eyecubed) and spectral-domain OCT (Zeiss Visante). The angle aperture along the horizontal and vertical meridians was recorded based on the software of the systems. The coma root mean square (RMS) scores for the horizontal and vertical meridians were also recorded with the iTrace aberrometer. The anterior chamber angle was significantly wider along the horizontal axis compared with the vertical axis by UBM (46.37 degrees and 44.20 degrees , respectively) and by OCT (46.79 degrees and 43.58 degrees , respectively) (p = 0.02 in both cases, paired samples t test). The correlations between the logMAR-converted Jaeger near vision score and the horizontal or vertical angle apertures was not statistically significant. Horizontal coma RMS was significantly inversely correlated with the horizontal angle aperture (r = -0.45, p = 0.03 and r = -0.39, p = 0.04 by OCT and UBM, respectively). Measurement of the horizontal angle aperture by the modalities used may represent an anatomical and clinical predictor of the optical aberrations induced by the Crystalens. PMID- 24166705 TI - Secondary membrane formation after cataract surgery with primary intraocular lens implantation in children. AB - To evaluate the risk factors for secondary membrane (SM) formation after congenital cataract surgery with intraocular lens (IOL) implantation. A retrospective non-interventional comparative study. Thirty-nine patients (63 eyes) aged 1-135 months. The study included patients who underwent cataract extraction and primary IOL implantation between 1994 and 2001 at the University Hospital. The postoperative follow-up was 6-24 months. Thirty-three eyes received a poly(methyl methacrylate) (PMMA) IOL without square edges, 29 eyes received a hydrophobic acrylic IOL with truncated square edges (AcrySof), and there was no data for IOL type in one eye. Thirty-nine eyes had primary posterior capsulotomy (PPC) and anterior vitrectomy (AV) and in 24 eyes the posterior capsule was left intact. Cox proportional hazard regression analysis was performed to identify significant risk factors for SM formation, and Wilcoxon test to evaluate the difference in time from surgery to SM formation. SM developed in 24 eyes (38 %)- 58 % of eyes with an intact posterior capsule and 26 % of eyes having PPC and AV, 42 % of eyes with a PMMA IOL, and 34 % of eyes with an AcrySof lens. In multivariate Cox regression analysis intraoperative PPC and AV (P = 0.02) and AcrySof lens implantation (P = 0.097) were associated with decreased postoperative incidence of SM formation. Median time until SM development was 2.9 months with PMMA IOLs (range 1-17 months) and 6 months with AcrySof lenses (range 1-21.8 months) (P = 0.037). Posterior capsule management as well as IOL design and material influence the incidence and the timing of SM formation after primary IOL implantation in children. PMID- 24166707 TI - Phase transformation synthesis of novel Ag(2)O/Ag(2)CO(3) heterostructures with high visible light efficiency in photocatalytic degradation of pollutants. AB - Coreshell-like Ag2 O/Ag2 CO3 nanoheterostructures with tailored interface are fabricated by a facile, low-cost and one-step phase transformation method. The unique bandgap structure of the Ag2 O/Ag2 CO3 exhibits high separation efficiency of photogenerated electrons and holes, which effectively protects the Ag2 CO3 semiconductor to avoid its photoreduction and gives rise to high activity and stability in degradation of the typical water pollutants. PMID- 24166706 TI - The role of primary pharmacological therapy in acromegaly. AB - BACKGROUND AND OBJECTIVES: Primary pharmacological therapy may be the only viable treatment option for many patients with acromegaly, especially those presenting with advanced disease with large inoperable tumors. Long-acting somatostatin analogs are currently the first-line treatment of choice in this setting, where they provide biochemical control and reduce tumor size in a significant proportion of patients. We herein present a brief overview of the role of primary pharmacological therapy in the treatment of acromegaly within the context of Latin America and support this with a representative case study. CASE DESCRIPTION: A 20 year old male presented with clinical and biochemical evidence of acromegaly. The glucose-suppressed growth hormone (GH) was 5.3 MUg/L, his insulin-like growth factor-1(IGF-1) was 3.5 times the ULN and serum prolactin greater than 4,000 MUg/L. Pituitary MRI revealed a large and invasive mass, extending superiorly into the optic chiasm and laterally into the left cavernous sinus. He was treated with a combination of octreotide and cabergoline with remarkable clinical improvement, normalization of GH and IGF-1 values and striking shrinkage of the adenoma. CONCLUSION: This case illustrates how effective the pharmacological therapy of acromegaly can be and yet at the same time, raises several important issues such as the need for life-long treatment with costly medications such as the somatostatin analogs. Access to these agents may be limited in regions where resources are restricted and clinicians face challenges in order to make the most efficient use of available options. PMID- 24166708 TI - Protective effects of Pogostemon cablin Bentham water extract on inflammatory cytokine expression in TNBS-induced colitis in rats. AB - In inflammatory bowel disease (IBD), colon epithelial cells express a variety of inflammatory mediators, including chemokines, which perpetuate inflammatory response. In the current study, we report that water extract of Pogostemon cablin Bentham aerial parts (PCW), which has traditionally been used for treatment of the common cold and infectious disease, suppressed colon inflammation. Treatment with PCW resulted in effective inhibition of tumor necrosis factor (TNF)-alpha induced adhesion of monocytes to HT-29 human colonic epithelial cells. In a trinitrobenzene sulfonic acid (TNBS)-induced rat model of IBD, PCW suppressed clinical signs of colitis, including weight loss, colon tissue myeloperoxidase activity, a marker for inflammatory cell infiltration, and cyclooxygenase-2 expression in a dose-dependent manner. In addition, PCW suppressed TNBS-induced mRNA expression of IL-8, MCP-1, and IL-6 in rat colon. The nuclear level of NF kappaB in TNBS-treated rat colon and NF-kappaB luciferase reporter gene activity in TNF-alpha-treated HT-29 cells were significantly inhibited by PCW. Taken together, the results of this study suggest that PCW suppressed colon inflammation via suppression of NF-kappaB-dependent expression of pro inflammatory cytokines. PMID- 24166709 TI - Two new meroterpenoids produced by the endophytic fungus Penicillium sp. SXH-65. AB - Two new meroterpenoids, arisugacins I (1) and J (2), together with five known meroterpenoids including arisugacin B (3), arisugacin F (4), arisugacin G (5), territrem B (6) and territrem C (7) were isolated from an endophytic fungus Penicillium sp. SXH-65. Their structures were determined by extensive spectroscopic experiments and comparison with literature data. Their cytotoxicities were evaluated against Hela, HL-60 and K562 cell lines, and only 3 and 4 exhibited weak cytotoxicities against Hela, HL-60 and K562 cell lines with IC50 values ranging from 24 to 60 MUM. PMID- 24166710 TI - The early monocytic response to cytomegalovirus infection is MyD88 dependent but occurs independently of common inflammatory cytokine signals. AB - Cytomegalovirus latently infects myeloid cells; however, the acute effects of the virus on this cell subset are poorly characterised. We demonstrate that systemic cytomegalovirus infection induced rapid activation of monocytes in the bone marrow, characterised by upregulation of CD69, CD11c, Ly6C and M-CSF receptor. Activated bone marrow monocytes were more sensitive to M-CSF and less sensitive to granulocyte-monocyte colony stimulating factor in vitro, resulting in the generation of more macrophages and fewer dendritic cells, respectively. Monocyte activation was also observed in the periphery and resulted in significant accumulation of monocytes in the spleen. MyD88 expression was required within the haematopoietic compartment to initiate monocyte activation and recruitment. However, monocytes lacking MyD88 were activated and recruited in the presence of MyD88-sufficient cells in mixed bone marrow chimeras, indicating that once initiated, the process was MyD88 independent. Interestingly, we found that monocyte activation occurred in the absence of the common inflammatory cytokines, namely type I interferons (IFNs), IL-6, TNF-alpha and IL-1 as well as the NLRP3 inflammasome adaptor protein, ASC. We also excluded a role for the chemokine-like protein MCK-2 (m131/129) expressed by murine CMV. Taken together, these results challenge the notion that a single inflammatory cytokine mediates activation and recruitment of monocytes in response to infection. PMID- 24166711 TI - Prevention program at construction worksites aimed at improving health and work ability is cost-saving to the employer: results from an RCT. AB - BACKGROUND: To prolong sustainable healthy working lives of construction workers, a prevention program was developed which aimed to improve the health and work ability of construction workers. The objective of this study was to analyze the cost-effectiveness and financial return from the employers' perspective of this program. METHODS: A total of 293 workers in 15 departments were randomized to the intervention (n = 8 departments) or control group (n = 7). Data on work ability and health were collected using questionnaires. Sick leave data were obtained from the companies. Both the cost-effectiveness analyses and return on investment analyses were performed. RESULTS: After 12 months, the absenteeism costs were significantly lower in the intervention group than in the control group. At 12 month follow-up, no significant differences were found with respect to the primary outcomes (work ability, mental and physical health status) and secondary outcomes (musculoskeletal symptoms), meaning that the intervention was not cost effective in comparison with the control group. The net-benefit was ?641 per worker, and the intervention generated a positive financial return to the employer. CONCLUSION: The intervention in the present study was cost-saving to the employer due to reduced sickness absenteeism costs in the intervention group compared with the control group. However, the intervention cannot be regarded as cost-effective as no significant effects were found for work ability and health. PMID- 24166712 TI - MIP-1alpha/CCL3-mediated maintenance of leukemia-initiating cells in the initiation process of chronic myeloid leukemia. AB - In the initiation process of chronic myeloid leukemia (CML), a small number of transformed leukemia-initiating cells (LICs) coexist with a large number of normal hematopoietic cells, gradually increasing thereafter and eventually predominating in the hematopoietic space. However, the interaction between LICs and normal hematopoietic cells at the early phase has not been clearly delineated because of the lack of a suitable experimental model. In this study, we succeeded in causing a marked leukocytosis resembling CML from restricted foci of LICs in the normal hematopoietic system by direct transplantation of BCR-ABL gene transduced LICs into the bone marrow (BM) cavity of nonirradiated mice. Herein, we observed that BCR-ABL(+)lineage(-)c-kit(-) immature leukemia cells produced high levels of an inflammatory chemokine, MIP-1alpha/CCL3, which promoted the development of CML. Conversely, ablation of the CCL3 gene in LICs dramatically inhibited the development of CML and concomitantly reduced recurrence after the cessation of a short-term tyrosine kinase inhibitor treatment. Finally, normal hematopoietic stem/progenitor cells can directly impede the maintenance of LICs in BM in the absence of CCL3 signal. PMID- 24166713 TI - Dual leucine zipper kinase is required for excitotoxicity-induced neuronal degeneration. AB - Excessive glutamate signaling is thought to underlie neurodegeneration in multiple contexts, yet the pro-degenerative signaling pathways downstream of glutamate receptor activation are not well defined. We show that dual leucine zipper kinase (DLK) is essential for excitotoxicity-induced degeneration of neurons in vivo. In mature neurons, DLK is present in the synapse and interacts with multiple known postsynaptic density proteins including the scaffolding protein PSD-95. To examine DLK function in the adult, DLK-inducible knockout mice were generated through Tamoxifen-induced activation of Cre-ERT in mice containing a floxed DLK allele, which circumvents the neonatal lethality associated with germline deletion. DLK-inducible knockouts displayed a modest increase in basal synaptic transmission but had an attenuation of the JNK/c-Jun stress response pathway activation and significantly reduced neuronal degeneration after kainic acid-induced seizures. Together, these data demonstrate that DLK is a critical upstream regulator of JNK-mediated neurodegeneration downstream of glutamate receptor hyper-activation and represents an attractive target for the treatment of indications where excitotoxicity is a primary driver of neuronal loss. PMID- 24166714 TI - The skin is an important bulwark of acquired immunity against intestinal helminths. AB - Once animals have experienced a helminthic infection, they often show stronger protective immunity against subsequent infections. Although helminthic infections are well known to elicit Th2-type immune responses, it remains ill-defined where and how acquired protection is executed. Here we show that skin-invading larvae of the intestinal helminth Nippostrongylus brasiliensis are surrounded by skin infiltrating cells and are prevented from migrating out of infected skin during the second but not the first infection. B cell- or IgE receptor FcepsilonRI deficient mice showed impaired larval trapping in the skin. Selective ablation of basophils, but not mast cells, abolished the larval trapping, leading to increased worm burden in the lung and hence severe lung injury. Skin-infiltrating basophils produced IL-4 that in turn promoted the generation of M2-type macrophages, leading to the larval trapping in the skin through arginase-1 production. Basophils had no apparent contribution to worm expulsion from the intestine. This study thus reveals a novel mode of acquired antihelminth immunity, in which IgE-armed basophils mediate skin trapping of larvae, thereby limiting lung injury caused by larval migration. PMID- 24166717 TI - Learning a new language: moving countries and changing subjects. PMID- 24166715 TI - On-site education of VEGF-recruited monocytes improves their performance as angiogenic and arteriogenic accessory cells. AB - Adult neovascularization relies on the recruitment of monocytes to the target organ or tumor and functioning therein as a paracrine accessory. The exact origins of the recruited monocytes and the mechanisms underlying their plasticity remain unclear. Using a VEGF-based transgenic system in which genetically tagged monocytes are conditionally summoned to the liver as part of a VEGF-initiated angiogenic program, we show that these recruited cells are derived from the abundant pool of circulating Ly6C(hi) monocytes. Remarkably, however, upon arrival at the VEGF-induced organ, but not the naive organ, monocytes undergo multiple phenotypic and functional changes, endowing them with enhanced proangiogenic capabilities and, importantly, with a markedly increased capacity to remodel existing small vessels into larger conduits. Notably, monocytes do not differentiate into long-lived macrophages, but rather appear as transient accessory cells. Results from transfers of presorted subpopulations and a novel tandem transfer strategy ruled out selective recruitment of a dedicated preexisting subpopulation or onsite selection, thereby reinforcing active reprogramming as the underlying mechanism for improved performance. Collectively, this study uncovered a novel function of VEGF, namely, on-site education of recruited "standard" monocytes to become angiogenic and arteriogenic professional cells, a finding that may also lend itself for a better design of angiogenic therapies. PMID- 24166716 TI - Non-corticosteroid immunosuppressive medications for steroid-sensitive nephrotic syndrome in children. AB - BACKGROUND: About 80% to 90% of children with steroid-sensitive nephrotic syndrome (SSNS) have relapses. Of these children, around half relapse frequently, and are at risk of adverse effects from corticosteroids. Non-corticosteroid immunosuppressive medications are used to prolong periods of remission in these children; however, these medications have significant potential adverse effects. Currently, there is no consensus about the most appropriate second line agent in children who are steroid sensitive, but who continue to relapse. This is the third update of a review first published in 2001 and updated in 2005 and 2008. OBJECTIVES: To evaluate the benefits and harms of non-corticosteroid immunosuppressive medications in relapsing SSNS in children. SEARCH METHODS: For this update we searched the Cochrane Renal Group's Specialised Register to June 2013. SELECTION CRITERIA: Randomised controlled trials (RCTs) or quasi-RCTs were included if they compared non-corticosteroid immunosuppressive medications with placebo, prednisone or no treatment, different non-corticosteroid immunosuppressive medications and different doses, durations or routes of administration of the same non-corticosteroid immunosuppressive medication. DATA COLLECTION AND ANALYSIS: Two authors independently assessed the risk of bias of the included studies and extracted data. Statistical analyses were performed using a random-effects model and results expressed as risk ratio (RR) or mean difference (MD) with 95% confidence intervals (CI). MAIN RESULTS: We identified 32 studies (1443 children) of which one study is still ongoing. In the 31 studies with data, risk of bias assessment indicated that 11 (37%) and 16 (53%) studies were at low risk of bias for sequence generation and allocation concealment respectively. Six (29%) studies were at low risk of performance and detection bias. Twenty seven (87%) and 19 (60%) studies were at low risk of incomplete and selective reporting respectively. Alkylating agents (cyclophosphamide and chlorambucil) significantly reduced the risk of relapse at six to 12 months (RR 0.43, 95% CI 0.31 to 0.60) and 12 to 24 months (RR 0.20, 95% CI 0.09 to 0.46) compared with prednisone alone. There was no significant difference in relapse risk at two years between chlorambucil and cyclophosphamide (RR 1.31, 95% CI 0.80 to 2.13). There was no significant difference at one year between intravenous and oral cyclophosphamide (RR 0.99, 95% CI 0.76 to 1.29). Cyclosporin was as effective as cyclophosphamide (RR 1.07, 95% CI 0.48 to 2.35) and chlorambucil (RR 0.82, 95% CI 0.44 to 1.53) at the end of therapy while levamisole (RR 0.47, 95% CI 0.24 to 0.89) was more effective than steroids alone. However the effects of cyclosporin and levamisole were not sustained once treatment was stopped. In one small study cyclosporin significantly reduced the relapse rate compared with mycophenolate mofetil (MD 0.75, 95% CI 0.01 to 1.49). Limited data from a cross over study suggested that cyclosporin was more effective than mycophenolate mofetil in maintaining remission. In steroid- and cyclosporin-dependent disease, rituximab significantly reduced the risk of relapse at three months compared with conventional therapy. Mizoribine and azathioprine were no more effective than placebo or prednisone alone in maintaining remission. AUTHORS' CONCLUSIONS: Eight week courses of cyclophosphamide or chlorambucil and prolonged courses of cyclosporin and levamisole reduce the risk of relapse in children with relapsing SSNS compared with corticosteroids alone. Limited data indicate that mycophenolate mofetil and rituximab are valuable additional medications for relapsing SSNS. However clinically important differences in efficacy are possible and further comparative studies are still needed. PMID- 24166718 TI - Angiotensin II type 2 receptor regulates the development of pancreatic endocrine cells in mouse embryos. AB - BACKGROUND: We previously identified a local renin-angiotensin system (RAS) regulating the differentiation of an isolated population of human pancreatic progenitor cells. Major RAS components that regulate organogenesis have been also described in embryos; however, it is not known whether a local RAS is present in the fetal pancreas. We now hypothesize that angiotensin II type 1 (AT1 ) and type 2 (AT2 ) receptors are expressed in mouse embryonic pancreas and involved in regulating endocrine cell development. RESULTS: Differential expression of AT1 and AT2 receptors was observed in the mouse pancreata in late embryogenesis. Systemic AT2 , but not AT1 , receptor blockade during the second transition in pancreatic development (from embryonic day 12.0 onward) reduced the beta-cell to alpha-cell ratio of the neonate islets, impaired their insulin secretory function and the glucose tolerance of the pups. Studies with pancreas explants ex vivo revealed regulation by AT2 receptors of the differentiation of pancreatic progenitors into insulin-producing cells and of the proliferation of the differentiated cell, actions that did not result from reduced angiogenesis as a secondary effect of AT2 receptor antagonism. CONCLUSIONS: These data revealed an AT2 receptor-mediated mechanism regulating pancreatic endocrine cell development in vivo. PMID- 24166719 TI - Psoriasis, electrocardiographic characteristics, and incidence of atrial fibrillation. AB - Psoriasis patients have an increased incidence of cardiovascular disease. Atrial fibrillation is the most common cardiac arrhythmia and is associated with increased morbidity and risk of stroke. In this study, we assessed the association between psoriasis, electrocardiographic characteristics, and incident atrial fibrillation. Two cohorts were studied to address this question. First, the electrocardiograms of 169 subjects with psoriasis and coronary heart disease were reviewed and matched to patients without psoriasis. The Framingham risk score for atrial fibrillation was calculated to predict incident atrial fibrillation. Second, a larger cohort of 2,078 patients with psoriasis was matched to 6,234 patients without psoriasis. In the first group, psoriasis patients had no significantly different electrocardiographic characteristics, but a trend towards a decreased predicted incidence of atrial fibrillation using the Framingham risk score (12.8 vs. 14.6 % over a 10-year period, P = 0.06), suggesting that patients with psoriasis do not have a higher prevalence of risk factors for atrial fibrillation based on established risk scores. In the second group, the 5-year incidence of atrial fibrillation among patients with psoriasis was 2.5, vs. 3.3 % for matched controls (P = 0.4). The rates of atrial fibrillation per 1,000 person-years ranged from 4.8 events/1,000 person-years for mild psoriasis to 5.4 for patients with moderate/severe psoriasis. On multivariable analysis, there remained no association between mild psoriasis (adjusted HR 1.32, 95 % CI 0.91-1.89) or moderate-to-severe psoriasis (adjusted HR 1.27, 95 % CI 0.54-3.03) and incident atrial fibrillation. PMID- 24166720 TI - Neuroprotective effect of apigenin in rats after contusive spinal cord injury. AB - Apigenin, a common plant flavonoid, has been extensively studied and showed a wide variety of beneficial effects. The aim of this study was to determine the therapeutic efficacy of starting apigenin treatment 3 day after spinal cord injury (SCI) in rat and to investigate the underlying mechanism. SCI was induced using the modified weight-drop method in Sprague-Dawley rats. The SCI animals were randomly assigned to five groups: sham control group, SCI model group, the methylprednisolone sodium succinate (MPSS) group, the 10 mg/kg apigenin treatment group and the 20 mg/kg apigenin treatment group. First, neuronal function after SCI was evaluated with Basso Beattie Bresnahan locomotor rating scale (BBB) and the result showed that injured animals treated with apigenin showed a significant increase in BBB scores. To explore the underlying mechanism, antioxidative effect of apigenin was assessed by measuring malondialdehyde (MDA), superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) activities after SCI. Apigenin treatment reversed the decrease of SOD and GSH-Px activity, and the increase of MDA level caused by SCI, suggesting its antioxidative role in response to the injury. In addition, apigenin treatment decreased serum interleukin-1beta, tumor necrosis factor-alpha and intercellular adhesion molecule-1 release after SCI, suggesting an anti-inflammatory effect of apigenin. Finally, apigenin treatment affected the expression level of apoptosis-related gene Bax, Bcl-2 and caspase-3, which indicated its antiapoptosis role after SCI. Our data suggest that apigenin significantly promotes the recovery of rat neuronal function after SCI, which is associated with its antioxidative, anti-inflammatory and antiapoptotic properties. PMID- 24166721 TI - Determination of heavy metal (Zn, Pb, Cd and Cr) concentration in benthic fauna tissues collected from the southeast Caspian Sea, Iran. AB - The aim of the present study was to determine zinc (Zn), chromium (Cr), cadmium (Cd) and lead (Pb) content of benthic fauna in the southeast coast of the Caspian Sea, where the major fish restocking programs are conducted. Seasonal sampling was performed in three sampling sites: north Miankaleh (NM), south Miankaleh (SM) and Gharesoo coast (GC). Results showed that sampling sites, sampling seasons and sampling sites * sampling seasons interaction had a significant effect on the heavy metal levels (p < 0.05). The yearly heavy metal concentration order was as follows: Zn > Pb > Cd > Cr. Yearly Pb levels of the NM site were significantly higher than the other sites. Also, yearly Cr levels of the SM site were significantly higher than site GC. Comparison of the benthos heavy metal levels with the available reference values suggests that the benthos tissues might be highly polluted which can intoxicate the fish feeding on them. PMID- 24166722 TI - Concentrations of essential and non-essential toxic trace elements in wild boar (Sus Scrofa L., 1758) tissues from southern Turkey. AB - Wild animals, including wild boars, are suitable for use as bioindicators. The aim of this study was to evaluate the concentrations of selected essential (Co, Cu, Fe, Se, Zn) and non-essential (As, Cd, Pb) potentially toxic trace elements in various tissues (hair and hoof) of wild boars hunted in the vicinity of Antalya province in Turkey, in relation to hunting seasons. Concentrations in mg/kg on dry weight basis were determined as 0.37 +/- 0.27 mg/kg for As, 0.05 +/- 0.04 mg/kg for Cd, 0.24 +/- 0.33 mg/kg for Co, 4.84 +/- 2.48 mg/kg for Cu, 289.94 +/- 165.26 mg/kg for Fe, 8.71 +/- 15.68 mg/kg for Pb, 0.24 +/- 0.10 mg/kg for Se, and 28.99 +/- 21.41 mg/kg for Zn in the hair samples; and as 0.11 +/- 0.04 mg/kg for As, 0.01 +/- 0.04 mg/kg for Cd, 0.01 +/- 0.01 mg/kg for Co, 1.03 +/- 0.25 mg/kg for Cu, 56.88 +/- 18.68 mg/kg for Fe, 0.30 +/- 0.18 mg/kg for Pb, 0.11 +/- 0.05 mg/kg for Se, and 17.91 +/- 10.98 mg/kg for Zn in the hoof samples. PMID- 24166723 TI - Paradoxical vocal fold motion disorder in the elite athlete: experience at a large division I university. AB - OBJECTIVES/HYPOTHESIS: To review our experience at a large division I university with the diagnosis and management of paradoxical vocal fold motion disorder (PVFMD) in elite athletes. STUDY DESIGN: A single institution retrospective review and cohort analysis. METHODS: All elite athletes (division I collegiate athletes, triathletes, and marathon runners) with a diagnosis of PVFMD were identified. All patients underwent flexible fiberoptic laryngoscopy (FFL) to confirm the diagnosis of PVFMD. The type of PVFMD therapy was identified and efficacy of treatment was graded based on symptom resolution. RESULTS: Forty-six consecutive athletes with PVFMD were identified. A total of 30/46 (65%) were division 1 collegiate athletes and 16/46 (35%) were triathletes or marathon runners. In comparison to a nonathlete PVFMD cohort, athletes were less likely to present with a history of reflux (P < 0.01), psychiatric diagnosis (P < 0.01), dysphonia (P < 0.01), cough (P = 0.02), or dysphagia (P < 0.01). The use of postexertion FFL provided additional diagnostic information in 11 (24%) patients. Laryngeal control therapy (LCT) was recommended for 45/46. A total of 36/45 attended at least one LCT session and 25 (69%) reported improvement of symptoms. Additionally, biofeedback, practice-observed therapy, and thyroarytenoid muscle botulinum toxin injection were required in three, two, and two patients, respectively. CONCLUSION: The addition of postexertion FFL improves the sensitivity to detect PVFMD in athletes. PVFMD in athletes responds well to LCT. However, biofeedback, practice-observed therapy, and botulinum toxin injection may be required for those patients with an inadequate response to therapy. LEVEL OF EVIDENCE: 4. PMID- 24166724 TI - Billing code algorithms to identify cases of peripheral artery disease from administrative data. AB - OBJECTIVE: To construct and validate billing code algorithms for identifying patients with peripheral arterial disease (PAD). METHODS: We extracted all encounters and line item details including PAD-related billing codes at Mayo Clinic Rochester, Minnesota, between July 1, 1997 and June 30, 2008; 22 712 patients evaluated in the vascular laboratory were divided into training and validation sets. Multiple logistic regression analysis was used to create an integer code score from the training dataset, and this was tested in the validation set. We applied a model-based code algorithm to patients evaluated in the vascular laboratory and compared this with a simpler algorithm (presence of at least one of the ICD-9 PAD codes 440.20-440.29). We also applied both algorithms to a community-based sample (n=4420), followed by a manual review. RESULTS: The logistic regression model performed well in both training and validation datasets (c statistic=0.91). In patients evaluated in the vascular laboratory, the model-based code algorithm provided better negative predictive value. The simpler algorithm was reasonably accurate for identification of PAD status, with lesser sensitivity and greater specificity. In the community-based sample, the sensitivity (38.7% vs 68.0%) of the simpler algorithm was much lower, whereas the specificity (92.0% vs 87.6%) was higher than the model-based algorithm. CONCLUSIONS: A model-based billing code algorithm had reasonable accuracy in identifying PAD cases from the community, and in patients referred to the non-invasive vascular laboratory. The simpler algorithm had reasonable accuracy for identification of PAD in patients referred to the vascular laboratory but was significantly less sensitive in a community-based sample. PMID- 24166725 TI - Overrides of medication-related clinical decision support alerts in outpatients. AB - BACKGROUND: Electronic prescribing is increasingly used, in part because of government incentives for its use. Many of its benefits come from clinical decision support (CDS), but often too many alerts are displayed, resulting in alert fatigue. OBJECTIVE: To characterize the override rates for medication related CDS alerts in the outpatient setting, the reasons cited for overrides at the time of prescribing, and the appropriateness of overrides. METHODS: We measured CDS alert override rates and the coded reasons for overrides cited by providers at the time of prescribing. Our primary outcome was the rate of CDS alert overrides; our secondary outcomes were the rate of overrides by alert type, reasons cited for overrides at the time of prescribing, and override appropriateness for a subset of 600 alert overrides. Through detailed chart reviews of alert override cases, and selective literature review, we developed appropriateness criteria for each alert type, which were modified iteratively as necessary until consensus was reached on all criteria. RESULTS: We reviewed 157,483 CDS alerts (7.9% alert rate) on 2,004,069 medication orders during the study period. 82,889 (52.6%) of alerts were overridden. The most common alerts were duplicate drug (33.1%), patient allergy (16.8%), and drug-drug interactions (15.8%). The most likely alerts to be overridden were formulary substitutions (85.0%), age-based recommendations (79.0%), renal recommendations (78.0%), and patient allergies (77.4%). An average of 53% of overrides were classified as appropriate, and rates of appropriateness varied by alert type (p<0.0001) from 12% for renal recommendations to 92% for patient allergies. DISCUSSION: About half of CDS alerts were overridden by providers and about half of the overrides were classified as appropriate, but the likelihood of overriding an alert varied widely by alert type. Refinement of these alerts has the potential to improve the relevance of alerts and reduce alert fatigue. PMID- 24166726 TI - Impact of HCV treatment and depressive symptoms on adherence to HAART among HIV HCV-coinfected patients: results from the ANRS-CO13-HEPAVIH cohort. AB - BACKGROUND: The additional burden of HCV infection in HIV-HCV-coinfected individuals may have some consequences on adherence to HAART. Few studies have explored the pattern of correlates of non-adherence to HAART while simultaneously considering the impact of HCV treatment and depressive symptoms on adherence to HAART. We used longitudinal data to assess factors associated with non-adherence to HAART. METHODS: The French national prospective cohort ANRS-CO13-HEPAVIH is a multicentrer cohort, which recruited 1,175 HIV-HCV-coinfected patients in 17 hospital outpatient units delivering HIV and HCV care in France between October 2006 and June 2008. For this analysis, we selected participants on HAART with self-reported data for adherence to HAART (n=727 patients, 1,190 visits). Data were collected using self-administered questionnaires and medical records. A mixed logistic regression model based on an exchangeable correlation matrix was used to identify factors associated with non-adherence to HAART. RESULTS: Patients reported non-adherence to HAART in 808 (68%) of the 1,190 visits. Four variables remained associated with non-adherence to HAART after multivariate analysis: hazardous alcohol consumption, cocaine use and depressive symptoms, regardless of whether treatment for depression was being received. Finally, patients being treated for HCV infection were less likely to be non-adherent to HAART. CONCLUSIONS: Besides the problem of polydrug use, two other dimensions deserve special attention when considering adherence to HAART in HIV-HCV coinfected patients. Access to HCV treatment should be encouraged as well adequate treatment for depression in this population to improve adherence and response to HAART. PMID- 24166727 TI - Systematic review of nutrient intake and growth in children with multiple IgE mediated food allergies. AB - BACKGROUND: Food allergies affect up to 8% of American children. The current recommended treatment for food allergies is strict elimination of the allergens from the diet. Dietary elimination of nutrient-dense foods may result in inadequate nutrient intake and impaired growth. The purpose of this review was to critically analyze available research on the effect of an elimination diet on nutrient intake and growth in children with multiple food allergies. METHODS: A systematic review of the literature was conducted and a workgroup was established to critically analyze each relevant article. The findings were summarized and a conclusion was generated. RESULTS: Six studies were analyzed. One study found that children with food allergies are more likely to be malnourished than children without food allergies. Three studies found that children with multiple food allergies were shorter than children with 1 food allergy. Four studies assessed nutrient intake of children with multiple food allergies, but the inclusion and comparison criteria were different in each of the studies and the findings were conflicting. One study found that children with food allergies who did not receive nutrition counseling were more likely to have inadequate intake of calcium and vitamin D. CONCLUSION: Children with multiple food allergies have a higher risk of impaired growth and may have a higher risk of inadequate nutrient intake than children without food allergies. Until more research is available, we recommend monitoring of nutrition and growth of children with multiple food allergies to prevent possible nutrient deficiencies and to optimize growth. PMID- 24166729 TI - [Evaluation of a structured smoking cessation program for primary care medicine]. AB - BACKGROUND: Despite the fact that 9 of 10 general practitioners in Germany believe that smoking cessation is an important topic structured programs are only rarely offered to patients. Beside a lack of time and missing reimbursement, physician's limited treatment skills are frequent reasons for this observation. Therefore we aimed to develop a structured, easy to learn and time-effective smoking cessation program for the general practice. Evidence based treatment elements were combined and standardized by a step by step treatment guideline. METHODS: In a non-interventional observation we tested the program's integration in the daily routines of physicians, the rate of continuous tobacco abstinence after 12 weeks and both patient's and physician's satisfaction with the program and the medication. RESULTS: 44 physicians participated in the study. 184 patients were observed over a mean period of 12.8 weeks and were treated with an individually adapted nicotine replacement therapy for 10 weeks. At the end of treatment (12.1 weeks after the target quit date) 48.4% of the patients reported continuous abstinence. The combination of structured counseling with nicotine substitution in this program was easily implemented in doctor's practice, induced a high user satisfaction and a long usage of medication. The encouraging abstinence rate could have been influenced by selecting highly motivated patients, by offering structured and regular consultations at fixed intervals over the first weeks and by the treatment with the individually adapted nicotine substitution. CONCLUSION: This study shows an easy way to implement an individual and structured smoking cessation therapy in primary care medicine in Germany. Nevertheless, the results should be confirmed in larger cohorts and on a higher methodological level. PMID- 24166728 TI - Impact of factors affecting the residual tumor size diagnosed by MRI following neoadjuvant chemotherapy in comparison to pathology. AB - BACKGROUND AND OBJECTIVES: To investigate accuracy of magnetic resonance imaging (MRI) for measuring residual tumor size in breast cancer patients receiving neoadjuvant chemotherapy (NAC). METHODS: Ninety-eight patients were studied. Several MRI were performed during NAC for response monitoring, and the residual tumor size was measured on last MRI after completing NAC. Covariates, including age, tumor characteristics, biomarkers, NAC regimens, MRI scanners, and time from last MRI to operation, were analyzed. Univariate and Multivariate linear regression models were used to determine the predictive value of these covariates for MRI-pathology size discrepancy as the outcome measure. RESULTS: The mean (+/ SD) of the absolute difference between MRI and pathological residual tumor size was 1.0 +/- 2.0 cm (range, 0-14 cm). Univariate regression analysis showed tumor type, morphology, HR status, HER2 status, and MRI scanner (1.5 T or 3.0 T) were significantly associated with MRI-pathology size discrepancy (all P < 0.05). Multivariate regression analyses demonstrated that only tumor type, tumor morphology, and biomarker status considering both HR and HER-2 were independent predictors (P = 0.0014, 0.0032, and 0.0286, respectively). CONCLUSION: The accuracy of MRI in evaluating residual tumor size depends on tumor type, morphology, and biomarker status. The information may be considered in surgical planning for NAC patients. PMID- 24166730 TI - Inhibition of inducible nitric oxide synthase-derived nitric oxide as a therapeutical target for acute pancreatitis induced by secretory phospholipase A2. AB - BACKGROUND: Nitric oxide is a key signalling molecule in the pathogenesis of inflammation, but its role in acute pancreatitis and related abdominal pain induced by secretory phospholipase A2 (sPLA2 ) from Crotalus durissus terrificus (Cdt) venom has not been investigated. METHODS: Male Wistar rats were i.v. injected with L-NAME (20 mg/kg), aminoguanidine (AG, 50 mg/kg), 7-nitroindazole (7-NI, 10 mg/kg) or vehicle 10 min before or 60 min after the injection of sPLA2 (300 MUg/kg) into the common bile duct. After 4 h of sPLA2 injection, abdominal hyperalgesia and inflammation were assessed in addition to serum amylase, nitrite/nitrate (NOx), pancreas lipoperoxidation and 3-nitrotyrosine (3-NT) contents. RESULTS: sPLA2 -induced acute pancreatitis, related abdominal hyperalgesia, hyperamylasemia and increased concentration of NOx were not correlated with lipoperoxidation or increased 3-NT in the pancreas. Pretreatment with all the nitric oxide synthase (NOS) inhibitors significantly reduced abdominal mechanical hyperalgesia, but only iNOS blockade by AG suppressed pancreas oedema and serum NOx increase. The therapeutic approach with all the NOS inhibitors produced a similar reduction pattern of the abdominal hyperalgesia, but AG treatment also inhibited serum hyperamylasemia and NOx concentrations and pancreatic myeloperoxidase. The nNOS blockade by 7-NI treatment also inhibited myeloperoxidase activity in both pancreas and lung. CONCLUSIONS: Therapeutic blockade of iNOS or nNOS provides benefits in terms of inhibition of the acute pancreatitis-related abdominal hyperalgesia, while iNOS inhibition also ameliorates the inflammatory cell influx to the pancreas and reduces the resultant hyperamylasemia and NOx levels, thus representing alternative pharmacological strategies for treatment of clinical pancreatitis associated with increased PLA2 . PMID- 24166731 TI - GEE-based SNP set association test for continuous and discrete traits in family based association studies. AB - Family-based genetic association studies of related individuals provide opportunities to detect genetic variants that complement studies of unrelated individuals. Most statistical methods for family association studies for common variants are single marker based, which test one SNP a time. In this paper, we consider testing the effect of an SNP set, e.g., SNPs in a gene, in family studies, for both continuous and discrete traits. Specifically, we propose a generalized estimating equations (GEEs) based kernel association test, a variance component based testing method, to test for the association between a phenotype and multiple variants in an SNP set jointly using family samples. The proposed approach allows for both continuous and discrete traits, where the correlation among family members is taken into account through the use of an empirical covariance estimator. We derive the theoretical distribution of the proposed statistic under the null and develop analytical methods to calculate the P values. We also propose an efficient resampling method for correcting for small sample size bias in family studies. The proposed method allows for easily incorporating covariates and SNP-SNP interactions. Simulation studies show that the proposed method properly controls for type I error rates under both random and ascertained sampling schemes in family studies. We demonstrate through simulation studies that our approach has superior performance for association mapping compared to the single marker based minimum P-value GEE test for an SNP set effect over a range of scenarios. We illustrate the application of the proposed method using data from the Cleveland Family GWAS Study. PMID- 24166733 TI - Baicalein attenuates astroglial activation in the 1-methyl-4-phenyl-1,2,3,4 tetrahydropyridine-induced Parkinson's disease model by downregulating the activations of nuclear factor-kappaB, ERK, and JNK. AB - In Parkinson's disease (PD), neuroinflammation plays a critical role in the neurodegenerative process. Furthermore, activated microglia and astrocytes, responsible for activated immune response in the central nervous system, are found in regions associated with dopaminergic neuronal death. The flavonoid baicalein is known to have antibacterial, antiviral, and antiinflammatory activities. In the present study, the neuroprotective effects of baicalein were examined in a murine 1-methyl-4-phenyl-1,2,3,4-tetrahydropyridine (MPTP) model of PD. Low doses of baicalein improved motor ability and prevented dopaminergic neuron loss caused by MPTP. In addition, microglial and astrocyte activations were reduced in PD mice pretreated with baicalein. Further study of primary astrocytes revealed that baicalein suppressed the 1-methyl-4-phenylpyridine induced nuclear translocation of nuclear factor-kappaB and reduced the activations of JNK and ERK, suggesting that the neuroprotective effects of baicalein in our PD model were due to attenuated astrocyte activation. The findings of this study indicate that baicalein could be useful for the treatment of PD and other neuroinflammation-related neurodegenerative diseases. PMID- 24166732 TI - Mushroom hunting by using bioinformatics: application of a predictive framework facilitates the selective identification of sesquiterpene synthases in basidiomycota. AB - The Basidiomycota fungi represent a diverse source of natural products, particularly the sesquiterpenoids. Recently, genome sequencing, genome mining, and the subsequent discovery of a suite of sesquiterpene synthases in Omphalotus olearius was described. A predictive framework was developed to facilitate the discovery of sesquiterpene synthases in Basidiomycota. Phylogenetic analyses indicated a conservation of both sequence and initial cyclization mechanisms used. Here, the first robust application of this predictive framework is reported. It was used to selectively identify sesquiterpene synthases that follow 1,6-, 1,10-, and 1,11-cyclization mechanisms in the crust fungus Stereum hirsutum. The successful identification and characterization of a 1,6- and a 1,10 cyclizing sesquiterpene synthase, as well as three 1,11-cyclizing Delta(6) protoilludene synthases, is described. This study verifies the accuracy and utility of the predictive framework as a roadmap for the discovery of specific sesquiterpene synthases from Basidiomycota, and thus represents an important step forward in natural product discovery. PMID- 24166734 TI - Embryonic expression of the transforming growth factor beta ligand and receptor genes in chicken. AB - BACKGROUND: Transforming growth factor-beta (TGFbeta) signaling regulates a myriad of biological processes during embryogenesis, in the adult, and during the manifestation of disease. TGFbeta signaling is propagated through one of three TGFbeta ligands interacting with Type I and Type II receptors, and Type III co receptors. Although TGFbeta signaling is regulated partly by the combinatorial expression patterns of TGFbeta receptors and ligands, a comprehensive gene expression analysis has not been published. RESULTS: Here we report the embryonic mRNA expression patterns in chicken embryos of the canonical TGFbeta ligands (TGFB1, TGFB2, and TGFB3) and receptors (TGFBR1, TGFBR2, TGFBR3), plus the Activin A receptor, type 1 (ACVR1) and co receptor Endoglin (ENG) that also transduce TGFbeta signaling. CONCLUSIONS: TGFB ligands and receptors show dynamic and frequently overlapping expression patterns in numerous embryonic cell layers and structures. Integrating expression information identifies combinations of ligands and receptors that are involved in specific developmental processes including somitogenesis, cardiogenesis and vasculogenesis. PMID- 24166735 TI - Silver ion promoted, Pd(II)-catalyzed arylation of arenes with a free amine as directing group in aqueous medium. AB - Palladium(II)-catalyzed arylation of arenes with aryl boronic acids and a free amine as directing group in aqueous medium has been developed. High reactivity and chemoselectivity for the formation of carbon-carbon bonds were achieved by the use of soluble silver salts. The addition of water is crucial to improve the arylation yield. PMID- 24166736 TI - Lipoxin A4 modulates adaptive immunity by decreasing memory B-cell responses via an ALX/FPR2-dependent mechanism. AB - Specialized proresolving mediators are endogenous bioactive lipid molecules that play a fundamental role in the regulation of inflammation and its resolution. Lipoxins and other specialized proresolving mediators have been identified in important immunological tissues including bone marrow, spleen, and blood. Lipoxins regulate functions of the innate immune system including the promotion of monocyte recruitment and increase macrophage phagocytosis of apoptotic neutrophils. A major knowledge gap is whether lipoxins influence adaptive immune cells. Here, we analyzed the actions of lipoxin A4 (LXA4) and its receptor ALX/FPR2 on human and mouse B cells. LXA4 decreased IgM and IgG production on activated human B cells through ALX/FPR2-dependent signaling, which downregulated NF-kappaB p65 nuclear translocation. LXA4 also inhibited human memory B-cell antibody production and proliferation, but not naive B-cell function. Lastly, LXA4 decreased antigen-specific antibody production in an OVA immunization mouse model. To our knowledge, this is the first description of the actions of lipoxins on human B cells, demonstrating a link between resolution signals and adaptive immunity. Regulating antibody production is crucial to prevent unwanted inflammation. Harnessing the ability of lipoxins to decrease memory B-cell antibody production can be beneficial to threat inflammatory and autoimmune disorders. PMID- 24166737 TI - Chikungunya emergency in China: microevolution and genetic analysis for a local outbreak. AB - A small-scale local chikungunya outbreak occurred in a Guangdong village of southern China in October 2010. The five chikungunya viruses (CHIKV) isolated from the epidemic and three other imported cases obtained from the same period were sequenced and analyzed for phylogenesis. The results demonstrated that all of the eight sequences were clustered in the Eastern, Central, Southern, and African group. However, the local strains and imported isolates showed different sequence variations. A226V in E1 gene and V264A in E2 gene were detected in all three imported isolates, the unique substitutions S250P in E1 gene and H313Y in E2 genes could be observed in four of the five local strains. These significant variations might be some of the causes for the outbreak. It would be an important event for CHIKV to have mutated adaption to the local mosquitoes in China, Aedes albopictus and Aedes aegypti. PMID- 24166739 TI - Antibacterial activity of silver: the role of hydrodynamic particle size at nanoscale. AB - Silver shows the highest antimicrobial activities amongst all metals. It is better than many first line antibiotics. The antimicrobial properties of silver can be tuned by altering its physical and surface properties. Researchers have demonstrated enhancement in the antibacterial properties of silver with decreasing particle size from bulk to nano. In the present article, we study the effect of particle size of silver at nanoscale on their antimicrobial properties. Two samples of silver nanoparticles (SNPs) of same physical size (~8 nm) but different hydrodynamic size (59 and 83 nm) are prepared by chemical reduction of AgNO3 with oleylamine followed by phase transfer with triblock copolymer Pluronic F-127. Their antimicrobial properties are investigated by microdilution method against clinically important strains of gram positive (S. aureus and B. megaterium) and gram negative (P. vulgaris and S. sonnei) bacteria. Nearly 38-50% enhancement in the antibacterial action of SNPs was observed when their hydrodynamic size was reduced to 59 nm from 83 nm. It has been observed that the antibacterial action of SNPs was governed by their hydrodynamic size and not by their crystallite and physical size. The phenomenological model was also proposed which makes an attempt to explain the microscopic mechanism responsible for the size dependent antibacterial activities of silver. PMID- 24166738 TI - Genetic data generated from virus-host complexes obtained by membrane co immobilization are equivalent to data obtained from tangential filtrate virus concentrates and virus cultures. AB - The sieving and immobilization of virus-host complexes using impact filtration (aka membrane co-immobilization or MCI) is a novel approach to the study of plankton viruses. One of the most interesting characteristics of the method is the possibility of generating data on potential viral hosts without the need of culturing hosts cells. MCI has demonstrated to be useful for studying viruses of picoalgae, but studies comparing data generated by MCI to data obtained by other techniques are lacking. In this work, Ostreococcus virus (OV) and Ostreococcus sp. sequences generated from virus-host complexes obtained by MCI were compared to sequences obtained from tangential filtration (TF) concentrates and virus cultures (VC). Statistical parsimony, phylogenetic analyses, pairwise distance comparisons, and analysis of molecular variance showed that the viral and host sequences obtained by the three methods were highly related to each other, indicating that MCI, TF, and VC produce equivalent results. Minor differences were observed among viral sequences obtained from VC and TF concentrates as well as among host sequences generated from VC and MCI. As discussed in the body of the paper, the divergence observed for cultured cells could be due to selective pressures exerted by culture conditions, whereas the correlate observed for the corresponding viral sequences could obey to a hitchhiking effect. PMID- 24166740 TI - Parkinson's disease and occupation: differences in associations by case identification method suggest referral bias. AB - METHODS: We used a population-based sample of 403 Parkinson's disease cases and 405 controls to examine risks by occupation. Results were compared to a previous clinic-based analysis. RESULTS: With censoring of jobs held within 10 years of diagnosis, the following had significantly or strongly increased risks: social science, law and library jobs (OR = 1.8); farming and horticulture jobs (OR = 2.0); gas station jobs (OR = 2.6); and welders (OR = 3.0). The following had significantly decreased risks: management and administration jobs (OR = 0.70); and other health care jobs (OR = 0.44). CONCLUSIONS: These results were consistent with other findings for social science and farming occupations. Risks for teaching, medicine and health occupations were not elevated, unlike our previous clinic-based study. This underscores the value of population-based over clinic-based samples. Occupational studies may be particularly susceptible to referral bias because social networks may spread preferentially via jobs. PMID- 24166741 TI - Influenza vaccines in immunosuppressed adults with cancer. AB - BACKGROUND: Immunosuppressed cancer patients are at increased risk of serious influenza-related complications. Guidelines, therefore, recommend influenza vaccination for these patients. However, data on vaccine effectiveness in this population is lacking, and the value of vaccination in this population remains unclear. OBJECTIVES: To assess the effectiveness of influenza vaccine in immunosuppressed adults with malignancies. The primary review outcome is all cause mortality, preferably at the end of the influenza season. Influenza-like illness (ILI, a clinical definition), confirmed influenza, pneumonia, any hospitalization and influenza-related mortality were defined as secondary outcomes. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE and LILACS databases up to August 2013. We searched the following conference proceedings: ICAAC, ECCMID, IDSA (infectious disease conferences), ASH, ASBMT, EBMT (hematological), and ASCO (oncological) between the years 2006 to 2010. In addition, we scanned the references of all identified studies and pertinent reviews. We searched the websites of the manufacturers of influenza vaccine. Finally, we searched for ongoing or unpublished trials in clinical trial registry databases using the website. SELECTION CRITERIA: Randomized controlled trials (RCTs), prospective and retrospective cohort studies and case-control studies were considered, comparing inactivated influenza vaccines versus placebo, no vaccination or a different vaccine, in adults (16 years and over) with cancer. We considered solid malignancies treated with chemotherapy, haematological cancer patients treated or not treated with chemotherapy, cancer patients post-autologous (up to six months after transplantation) or allogeneic (at any time) hematopoietic stem cell transplantation. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed the risk of bias and extracted data from included studies adhering to Cochrane methodology. Meta-analysis could not be performed because of different outcome and denominator definitions in the included studies. MAIN RESULTS: We identified four studies: one RCT and three observational studies, including 2124 participants. One study reported results in person-years while the other three reported per person. The studies were performed between 1993 and 2012 and included adults with haematological diseases (two studies), patients following bone marrow transplantation (one study) and solid malignancies (three studies). Only two observational studies reported all-cause mortality; one showing an adjusted hazard ratio (HR) of 0.88 (95% CI 0.77 to 0.99) for death with vaccination and the other reporting an odds ratio (OR) of 0.43 (95% CI 0.26 to 0.71). The RCT reported a statistically significant reduction in ILI with vaccination, while no difference was observed in one observational study. Confirmed influenza rates were lower with vaccination in the three observational studies, the difference reaching statistical significance in one. Pneumonia was observed significantly less frequently with vaccination in one observational study, but no difference was detected in another or in the RCT. The RCT showed a reduction in hospitalizations following vaccination, while an observational study found no difference. No life-threatening or persistent adverse effects from vaccination were reported. The strength of evidence is limited by the low number of included studies and by their low methodological quality (high risk of bias). AUTHORS' CONCLUSIONS: Observational data suggests a lower mortality with influenza vaccination. Infection-related outcomes were lower or similar with influenza vaccination. The strength of evidence is limited by the small number of studies and by the fact that only one was a RCT. Influenza vaccination is safe and the evidence, although weak, is in favour of vaccinating adults with cancer receiving chemotherapy. PMID- 24166742 TI - Flunarizine in the prophylaxis of migrainous vertigo: a randomized controlled trial. AB - Migrainous vertigo is a common cause of dizziness presenting to an otorhinolaryngology/otoneurology clinic. Although it causes a substantial burden to the individual and society there are no randomized controlled trails on prophylactic medication for this condition. Flunarizine, a calcium channel blocker has been used effectively in both migraine and vestibular conditions. This randomized control trial was undertaken in a tertiary academic referral center to evaluate the efficacy of flunarizine in patients with migrainous vertigo when compared to non-specific vestibular treatment of betahistine and vestibular exercises. The effect of flunarizine on two particularly disabling symptoms of vertigo and headache was studied. A total of 48 patients who were diagnosed with definitive migrainous vertigo completed the study of 12 weeks duration. Patients in arm A received 10-mg flunarizine daily along with betahistine 16 mg and paracetamol 1 gm during episodes, and arm B received only betahistine and paracetamol during episodes. Symptom scores were noted at the start of the study and at the end of 12 weeks. Analysis of the frequency of vertiginous episodes showed a significant difference between arm A and arm B (p = 0.010) and improvement in severity of vertigo between the two groups (p = 0.046). Headache frequency and severity did not improve to a significant degree in arm A as compared to arm B. The main side effects were weight gain and somnolence and this was not significantly different between the two groups. Flunarizine (10 mg) is effective in patients with migrainous vertigo who suffer from considerable vestibular symptoms. PMID- 24166743 TI - Suitability of digoxin as a P-glycoprotein probe: implications of other transporters on sensitivity and specificity. AB - The study of transporter-mediated drug-drug interactions (DDI) requires use of appropriate probes to reflect transporter function. Digoxin is often used as a probe in DDI studies involving P-glycoprotein (P-gp) and is recommended by FDA for this purpose, despite several lingering questions regarding suitability of digoxin as P-gp probe. This review aims to critically evaluate use of digoxin as a probe for P-gp-mediated clinical DDI studies, with focus on sensitivity and specificity of digoxin for P-gp. Although previous reviews have evaluated digoxin transport by P-gp, the purpose of the current review is to critically evaluate such literature in light of newly evolving literature suggesting digoxin transport by non-P-gp transporters. PMID- 24166744 TI - Monitoring the morphology development of polymer-monolithic stationary phases by thermal analysis. AB - Thermal analysis and SEM were employed to gain insights in the different stages of morphology development and the thermal properties of polymer-monolithic stationary phases. The studied system was a thermally initiated free-radical copolymerization reaction at 70 degrees C of styrene and divinylbenzene in the presence of tetrahydrofuran and 1-decanol. The key events in the early stages of morphology development are initiation, chain growth, branching, and cyclization, leading to microgel particles. Interparticle reactions through pendant vinyl groups lead to the formation of microgel clusters. The rapid increase in molecular weight and cross-link density of the microgel clusters causes a reaction-induced phase separation, and the formation of a macroscopic network of interconnected globules was observed (macrogelation) at around 45 min. After 3 h or 65% conversion, a space-filling macroporous monolithic network was observed. Afterwards, mainly growth of existing globules takes place, reducing the macropore size. The porogen ratio affects the timing of the reaction-induced phase separation, strongly influencing the morphology of the polymer material. The use of a mixture of divinylbenzene isomers yielded a monolithic material that is less cross-linked at the surface compared to the central part of the polymer backbone due to copolymerization-composition drift. The less cross-linked outer layer starts devitrifying at 100 degrees C. PMID- 24166745 TI - Insecticidal activities of Cunninghamia konishii Hayata against Formosan subterranean termite, Coptotermes formosanus (Isoptera: Rhinotermitidae). AB - BACKGROUND: Formosan subterranean termite, Coptotermes formosanus Shiraki (Isoptera: Rhinotermitidae), is a major urban pests in many countries throughout the world. In an attempt to find natural products that could be employed in the effective and environmentally friendly control of the termite, this study investigates, for the first time, the insecticidal activities of the wood and leaf essential oils and ethanolic extracts from Cunninghamia konishii Hayata against C. formosanus according to direct contact application. RESULTS: Wood and leaf essential oils and wood ethanolic extract showed the excellent antitermitic activities. Among the four fractions of wood ethanolic extract, the hexane soluble fraction showed the strongest antitermitic activities. In addition, beta elemol and alpha-cadinol showed excellent inhibitory action against C. formosanus. CONCLUSION: The results clearly reveal that the wood and leaf essential oils and ethanolic extract from C. konishii, and their effective constituents, served as potential, eco-friendly termite-control agents. PMID- 24166746 TI - Relationship of serum isoflavone, insulin and adiponectin levels with breast cancer risk. AB - BACKGROUND: Obesity is one of the well-known risk factors of breast cancer. Accumulating evidence suggests that adiponectin, an obesity-related hormone, is inversely associated with breast cancer risk, particularly in postmenopausal women. Obesity is also associated with high levels of insulin. In addition, studies have suggested that the soy isoflavones present in the traditional Japanese diet have been associated with decreased risk of breast cancer. However, there is no study that has assessed associations between serum levels of isoflavones, insulin, adiponectin and the risk of breast cancer all together with menopausal status. METHODS: In a case-control study of 63 histologically confirmed breast cancer patients and 76 controls, serum isoflavone, insulin, and high-molecular-weight (HMW) adiponectin levels and breast cancer risk were examined for their association with breast cancer risk after adjustment for various risk factors. RESULTS: Women in the highest tertile of serum HMW adiponectin levels were associated with a statistically significant decreased risk for breast cancer compared with women in the lowest tertile [odds ratio (OR), 0.09; 95 % confidence interval (CI) 0.03-0.33]. This association was observed in postmenopausal women (OR 0.06; 95 % CI 0.01-0.28), but not in premenopausal women. The observed associations were independent of possible effects of insulin, body mass index, and known risk factors for breast cancer. Serum isoflavones and insulin levels were not associated with breast cancer risk. CONCLUSIONS: This study suggests that high serum HMW adiponectin levels are significantly associated with a decreased risk for breast cancer. Our result support the hypothesis that serum adiponectin may act as a potential biomarker for breast cancer. PMID- 24166747 TI - Biomimetic autonomous robot inspired by the Cyanea capillata (Cyro). AB - A biomimetic robot inspired by Cyanea capillata, termed as 'Cyro', was developed to meet the functional demands of underwater surveillance in defense and civilian applications. The vehicle was designed to mimic the morphology and swimming mechanism of the natural counterpart. The body of the vehicle consists of a rigid support structure with linear DC motors which actuate eight mechanical arms. The mechanical arms in conjunction with artificial mesoglea create the hydrodynamic force required for propulsion. The full vehicle measures 170 cm in diameter and has a total mass of 76 kg. An analytical model of the mechanical arm kinematics was developed. The analytical and experimental bell kinematics were analyzed and compared to the C. capillata. Cyro was found to reach the water surface untethered and autonomously from a depth of 182 cm in five actuation cycles. It achieved an average velocity of 8.47 cm s(-1) while consuming an average power of 70 W. A two-axis thrust stand was developed to calculate the thrust directly from a single bell segment yielding an average thrust of 27.9 N for the whole vehicle. Steady state velocity during Cyro's swimming test was not reached but the measured performance during its last swim cycle resulted in a cost of transport of 10.9 J (kg ? m)(-1) and total efficiency of 0.03. PMID- 24166748 TI - Isolated hepatic perfusion for metastatic melanoma. AB - Unresectable hepatic metastases from melanoma present a challenge to the physician. Although there have been advances in systemic therapies for patients with metastatic cutaneous melanoma to the liver, the overall prognosis is poor and is worse in patients with metastatic ocular melanoma. Isolated hepatic perfusion, open or percutaneous, allows high doses of cytotoxic chemotherapy to be delivered directly to the liver while minimizing systemic exposure, and has emerged as a viable treatment options for these complex patients. PMID- 24166749 TI - Angiogenic factors in diagnosis, management, and research in preeclampsia. PMID- 24166750 TI - Histone deacetylase 4 controls neointimal hyperplasia via stimulating proliferation and migration of vascular smooth muscle cells. AB - Histone deacetylases (HDACs) are transcriptional coregulators. Recently, we demonstrated that HDAC4, one of class IIa family members, promotes reactive oxygen species-dependent vascular smooth muscle inflammation and mediates development of hypertension in spontaneously hypertensive rats. Pathogenesis of hypertension is, in part, modulated by vascular structural remodeling via proliferation and migration of vascular smooth muscle cells (SMCs). Thus, we examined whether HDAC4 controls SMC proliferation and migration. In rat mesenteric arterial SMCs, small interfering RNA against HDAC4 inhibited platelet derived growth factor (PDGF)-BB-induced SMC proliferation as determined by a cell counting and bromodeoxyuridine incorporation assay as well as migration as determined by Boyden chamber assay. Expression and activity of HDAC4 were increased by PDGF-BB. HDAC4 small interfering RNA inhibited phosphorylation of p38 mitogen-activated protein kinase and heat shock protein 27 and expression of cyclin D1 as measured by Western blotting. HDAC4 small interfering RNA also inhibited PDGF-BB-induced reactive oxygen species production as measured fluorometrically using 2', 7'-dichlorofluorescein diacetate and nicotinamide adenine dinucleotide phosphate oxidase activity as measured by lucigenin assay. A Ca(2+)/calmodulin-dependent protein kinase II inhibitor, KN93, inhibited PDGF-BB induced SMC proliferation and migration as well as phosphorylation of HDAC4. In vivo, a class IIa HDACs inhibitor, MC1568 prevented neointimal hyperplasia in mice carotid ligation model. MC1568 also prevented increased activation of HDAC4 in the neointimal lesions. The present results for the first time demonstrate that HDAC4 controls PDGF-BB-induced SMC proliferation and migration through activation of p38 mitogen-activated protein kinase/heat shock protein 27 signals via reactive oxygen species generation in a Ca(2+)/calmodulin-dependent protein kinase-dependent manner, which may lead to the neointimal hyperplasia in vivo. PMID- 24166751 TI - New gestational phase-specific cutoff values for the use of the soluble fms-like tyrosine kinase-1/placental growth factor ratio as a diagnostic test for preeclampsia. AB - To establish gestational phase adapted cutoffs for the use of the soluble fms like tyrosine kinase-1 (sFlt-1)/placental growth factor (PlGF) ratio as a diagnostic tool for preeclampsia in the clinical setting, a multicenter case control study including a total of 1149 patients was performed. We report normal values of sFlt-1, PlGF, and the sFlt-1/PlGF ratio based on the analysis of a total of 877 patients with uneventful pregnancy outcome. A total of 234 patients with preeclampsia and a matched cohort consisting of 468 patients with normal pregnancy outcome were compared, and sFlt-1 and PlGF were measured on an automated platform. Separate cutoffs for the sFlt-1/PlGF ratio were determined for the early (20+0-33+6 weeks) and the late gestational phase (34+0 weeks delivery). For each of the 2 gestational phases, 2 independent cutoffs framing an equivocal zone were determined: the first cutoff with focus on high sensitivity, and the second focusing on high specificity. Between 20+0 and 33+6 weeks, the cutoffs at <=33 and >=85 resulted in a sensitivity/specificity of 95%/94% and 88%/99.5%, respectively. An sFlt-1/PlGF ratio of <=33 had the lowest likelihood of a negative test (0.05; 95% confidence interval, 0.02-0.13), whereas values >=85 had the highest likelihood of a positive test (176; 95% confidence interval, 24.88-1245). After 34+0 weeks, the cutoffs at <=33 and >=110 yielded a sensitivity/specificity of 89.6%/73.1% and 58.2%/95.5%, respectively. The approach to use multiple cutoffs for the early and late gestational phase enhances the diagnostic accuracy of the sFlt-1/PlGF ratio as a diagnostic tool for preeclampsia. PMID- 24166752 TI - Transient neonatal high oxygen exposure leads to early adult cardiac dysfunction, remodeling, and activation of the renin-angiotensin system. AB - Perinatal conditions (such as preterm birth) can affect adult health and disease, particularly the cardiovascular system. Transient neonatal high O(2) exposure in rat in adulthood (a model of preterm birth-related complications) leads to elevated blood pressure, vascular rigidity, and dysfunction with renin angiotensin system activation. We postulate that neonatal hyperoxic stress also affects myocardial structure, function, and expression of renin-angiotensin system components. Sprague-Dawley pups were kept with their mother in 80% O(2) or in room air (control) from days 3 to 10 of life. Left ventricular function was assessed in 4-, 7-, 12-week-old (echocardiography) and in 16-week-old (intraventricular catheterization) male O(2)-exposed versus control rats. At 16 weeks, hearts from O(2)-exposed rats showed cardiomyocyte hypertrophy, enhanced fibrosis, and increased expression of transforming growth factor-beta1, senescence-associated proteins p53 and Rb, upregulation of angiotensin II type 1 (AT1) receptor expression (protein and AT1a/b mRNA), and downregulation of AT2 receptors. At 4 weeks (before blood pressure increase), the expression of cardiomyocyte surface area, fibrosis, p53, and AT1b was significantly increased and AT2 decreased in O(2)-exposed animals. After 4 weeks of continuous angiotensin II infusion (starting at 12 weeks), O(2)-exposed rats developed severe heart failure, with impaired myocardial mechanical properties compared with saline-infused rats. Transient neonatal O(2) exposure in rats leads to left ventricular hypertrophy, fibrosis and dysfunction, and increased susceptibility to heart failure under pressure overload. These results are relevant to the growing population of individuals born preterm who may be at higher risk of cardiac dysfunction when faced with increased peripheral resistance associated with hypertension, vascular diseases, and aging. PMID- 24166753 TI - Loss of the eukaryotic initiation factor 2alpha kinase general control nonderepressible 2 protects mice from pressure overload-induced congestive heart failure without affecting ventricular hypertrophy. AB - In response to several stresses, including nutrient deprivation, general control nonderepressible 2 kinase (GCN2) attenuates mRNA translation by phosphorylating eukaryotic initiation factor 2alpha(Ser51). Energy starvation is known to exacerbate congestive heart failure, and eukaryotic initiation factor 2alpha(Ser51) phosphorylation is increased in the failing heart. However, the effect of GCN2 during the evolution of congestive heart failure has not been tested. In this study, we examined the influence of GCN2 expression in response to a cardiac stress by inducing chronic pressure overload with transverse aortic constriction in wild-type and GCN2 knockout mice. Under basal conditions, GCN2 knockout mice had normal left ventricular structure and function, but after transverse aortic constriction, they demonstrated less contractile dysfunction, less increase in lung weight, less increase in lung inflammation and vascular remodeling, and less myocardial apoptosis and fibrosis compared with wild-type mice, despite an equivalent degree of left ventricular hypertrophy. As expected, GCN2 knockout attenuated transverse aortic constriction-induced cardiac eukaryotic initiation factor 2alpha(Ser51) phosphorylation and preserved sarcoplasmic reticulum Ca(2+) ATPase expression compared with wild-type mice. Interestingly, the expression of the antiapoptotic protein Bcl-2 was significantly elevated in GCN2 knockout hearts, whereas in isolated neonatal cardiomyocytes, selective knockdown of GCN2 increased Bcl-2 protein expression and enhanced myocyte resistance to an apoptotic stress. Collectively, our data support the notion that GCN2 impairs the ventricular adaptation to chronic pressure overload by reducing Bcl-2 expression and increasing cardiomyocyte susceptibility to apoptotic stimuli. Our findings suggest that strategies to reduce GCN2 activity in cardiac tissue may be a novel approach to attenuate congestive heart failure development. PMID- 24166754 TI - Of risks and ratios: the usefulness of angiogenic balance for diagnosing preeclampsia at different gestational ages. PMID- 24166755 TI - Imaging early signaling events in T lymphocytes with fluorescent biosensors. AB - Many recent advances in our understanding of T lymphocyte functions in adaptive immunity are derived from sophisticated imaging techniques used to visualize T lymphocyte behavior in vitro and in vivo. A current challenge is to couple such imaging techniques with methods that will allow researchers to visualize signaling phenomenon at the single-cell level. Fluorescent biosensors, either synthetic or genetically encoded, are emerging as important tools for revealing the spatio-temporal regulation of intracellular biochemical events, such as specific enzyme activities or fluctuations in metabolites. In this review, we revisit the development of fluorescent Ca(2+) sensors with which the first experiments visualizing T lymphocyte activation at the single-cell were performed, and which have since become routine tools in immunology. We then examine a number of examples of how fluorescence resonance energy transfer (FRET) based biosensors have been developed and applied to T lymphocyte migration, adhesion and T-cell receptor (TCR)-mediated signal transduction. These include the study of small GTPases such as RhoA, Rac and Rap1, the tyrosine kinases Lck and ZAP-70, and metabolites such as cAMP and Ca(2+) . Future development and use of biosensors should allow immunologists to reconcile the vast wealth of existing biochemical data concerning T-cell functions with the power of dynamic live-cell imaging. PMID- 24166756 TI - Evidence for multiple stressor interactions and effects on coral reefs. AB - Concern is growing about the potential effects of interacting multiple stressors, especially as the global climate changes. We provide a comprehensive review of multiple stressor interactions in coral reef ecosystems, which are widely considered to be one of the most sensitive ecosystems to global change. First, we synthesized coral reef studies that examined interactions of two or more stressors, highlighting stressor interactions (where one stressor directly influences another) and potentially synergistic effects on response variables (where two stressors interact to produce an effect that is greater than purely additive). For stressor-stressor interactions, we found 176 studies that examined at least 2 of the 13 stressors of interest. Applying network analysis to analyze relationships between stressors, we found that pathogens were exacerbated by more costressors than any other stressor, with ca. 78% of studies reporting an enhancing effect by another stressor. Sedimentation, storms, and water temperature directly affected the largest number of other stressors. Pathogens, nutrients, and crown-of-thorns starfish were the most-influenced stressors. We found 187 studies that examined the effects of two or more stressors on a third dependent variable. The interaction of irradiance and temperature on corals has been the subject of more research (62 studies, 33% of the total) than any other combination of stressors, with many studies reporting a synergistic effect on coral symbiont photosynthetic performance (n = 19). Second, we performed a quantitative meta-analysis of existing literature on this most-studied interaction (irradiance and temperature). We found that the mean effect size of combined treatments was statistically indistinguishable from a purely additive interaction, although it should be noted that the sample size was relatively small (n = 26). Overall, although in aggregate a large body of literature examines stressor effects on coral reefs and coral organisms, considerable gaps remain for numerous stressor interactions and effects, and insufficient quantitative evidence exists to suggest that the prevailing type of stressor interaction is synergistic. PMID- 24166757 TI - Characterization of N-demethyllincosamide methyltransferases LmbJ and CcbJ. AB - Chemical diversity: Two SAM-dependent N-methyltransferases-LmbJ from the biosynthesis of the antibiotic lincomycin and CcbJ from celesticetin biosynthesis have been characterized and compared. Both tested enzymes form multimers and are able to utilize N-demethyllincomycin, the natural substrate of LmbJ, with comparable efficiency. PMID- 24166758 TI - Identifying rare variants with optimal depth of coverage and cost-effective overlapping pool sequencing. AB - Genome-wide association studies have identified hundreds of genetic variants associated with complex diseases although most variants identified so far explain only a small proportion of heritability, suggesting that rare variants are responsible for missing heritability. Identification of rare variants through large-scale resequencing becomes increasing important but still prohibitively expensive despite the rapid decline in the sequencing costs. Nevertheless, group testing based overlapping pool sequencing in which pooled rather than individual samples are sequenced will greatly reduces the efforts of sample preparation as well as the costs to screen for rare variants. Here, we proposed an overlapping pool sequencing to screen rare variants with optimal sequencing depth and a corresponding cost model. We formulated a model to compute the optimal depth for sufficient observations of variants in pooled sequencing. Utilizing shifted transversal design algorithm, appropriate parameters for overlapping pool sequencing could be selected to minimize cost and guarantee accuracy. Due to the mixing constraint and high depth for pooled sequencing, results showed that it was more cost-effective to divide a large population into smaller blocks which were tested using optimized strategies independently. Finally, we conducted an experiment to screen variant carriers with frequency equaled 1%. With simulated pools and publicly available human exome sequencing data, the experiment achieved 99.93% accuracy. Utilizing overlapping pool sequencing, the cost for screening variant carriers with frequency equaled 1% in 200 diploid individuals dropped to at least 66% at which target sequencing region was set to 30 Mb. PMID- 24166759 TI - A radical process towards the development of transition-metal-free aromatic carbon-carbon bond-forming reactions. AB - Transition-metal-free cross-coupling reactions have been a hot topic in recent years. With the aid of a radical initiator, a number of unactivated arene C-H bonds can be directly arylated/functionalized by using aryl halides through homolytic aromatic substitution. Commercially available or specially designed promoters (e.g. diamines, diols, and amino alcohols) have been used to make this synthetically attractive method viable. This protocol offers an inexpensive, yet efficient route to aromatic C-C bond formations since transition metal catalysts and impurities can be avoided by using this reaction system. In this article, we focus on the significance of the reaction conditions (e.g. bases and promoters), which allow this type of reaction to proceed smoothly. Substrate scope limitations and challenges, as well as mechanistic discussion are also included. PMID- 24166760 TI - Investigation of safety, tolerability, pharmacokinetics, and pharmacodynamics of single and multiple doses of a long-acting alpha-MSH analog in healthy overweight and obese subjects. AB - MC4-NN2-0453 is a novel, long-acting, selective, melanocortin-4-receptor agonist developed for treatment of obesity. This first-human-dose, randomized, double blind, placebo-controlled trial investigated the safety, tolerability, pharmacokinetics, and pharmacodynamics of single and multiple doses of MC4-NN2 0453 in overweight to obese but otherwise healthy subjects. The trial included a single-dose part of ascending subcutaneous 0.03-1.50 mg/kg doses in overweight to obese but otherwise healthy men, and a multiple-dose part of ascending subcutaneous 0.75-3.0 mg/day doses in obese but otherwise healthy men/women. The single-dose part included 7 cohorts of 8 subjects, randomized 6:2 to active drug/placebo; the multiple-dose part included 4 cohorts of 20 subjects, randomized 16:4 to active drug/placebo. MC4-NN2-0453 was well tolerated and raised no safety concerns except for nonserious skin-related adverse events, this along with lack of weight loss effect led to premature termination of the trial. Headache, sexual-arousal disturbance, and penile erection were also reported. Single-dose pharmacokinetics showed dose-linearity and dose-proportionality. Maximum plasma concentration was observed after 50-100 hours, which then declined with a of approximately 250 hours. Plasma concentration reached steady state after 4 weeks for 0.75 and 1.5 mg/day multiple-dose cohorts, and the was similar to single dose. There were no significant pharmacodynamic effects, including effect on body weight. PMID- 24166761 TI - Quality control method for commercially available wild Jujube leaf tea based on HPLC characteristic fingerprint analysis of flavonoid compounds. AB - Flavonoids are the main active components of natural medicinal plants with many physiological functions. In this study, an HPLC fingerprinting method based on the distribution and relative amount of 11 bioactive flavonoids was established for the quality evaluation of commercially available wild Jujube leaf tea (JLT) from China. Separation of the crude flavonoid extract was achieved on a column filled with C18 material with a high carbon content. The flavonoids in wild JLT were identified based on UV spectroscopy and accurate mass measurements by TOF MS. Twenty-one batches of practical samples collected from different habitats were analyzed by using the developed HPLC method to construct the HPLC characteristic fingerprint of wild JLT. Then, combined with clustering and similarity analyses, the HPLC characteristic fingerprint was used for the authentication and quality evaluation of commercial wild JLT. Results indicated that the proposed HPLC characteristic fingerprint reflected the inherent characteristics of wild JLT collected from different regions. Authenticity identification and quality control of commercially available wild Jujube tea were achieved based on the HPLC characteristic fingerprint analysis. This new approach to bioactive component profiling provided a promising reference method for the quality evaluation of commercial wild flower and plant tea. PMID- 24166762 TI - Urine concentrations of oral salbutamol in samples collected after intense exercise in endurance athletes. AB - Our objective was to investigate urine concentrations of 8 mg oral salbutamol in samples collected after intense exercise in endurance athletes. Nine male endurance athletes with a VO2max of 70.2 +/- 5.9 mL/min/kg (mean +/- SD) took part in the study. Two hours after administration of 8 mg oral salbutamol, subjects performed submaximal exercise for 15 min followed by two, 2-min exercise bouts at an intensity corresponding to 110% of VO2max and a bout to exhaustion at same intensity. Urine samples were collected 4, 8, and 12 h following administration of salbutamol. Samples were analyzed by the Norwegian World Anti doping Agency (WADA) laboratory. Adjustment of urine concentrations of salbutamol to a urine specific gravity (USG) of 1.020 g/mL was compared with no adjustment according to WADA's technical documents. We observed greater (P = 0.01) urine concentrations of salbutamol 4 h after administration when samples were adjusted to a USG of 1.020 g/mL compared with no adjustment (3089 +/- 911 vs. 1918 +/- 1081 ng/mL). With the current urine decision limit of 1200 ng/mL for salbutamol on WADA's 2013 list of prohibited substances, fewer false negative urine samples were observed when adjusted to a USG of 1.020 g/mL compared with no adjustment. In conclusion, adjustment of urine samples to a USG of 1.020 g/mL decreases risk of false negative doping tests after administration of oral salbutamol. Adjusting urine samples for USG might be useful when evaluating urine concentrations of salbutamol in doping cases. PMID- 24166763 TI - Workplace mistreatment and sickness absenteeism from work: results from the 2010 National Health Interview survey. AB - OBJECTIVE: This study examined the association between workplace mistreatment and occurrence, duration, and costs of sickness absenteeism. METHODS: We used the 2010 National Health Interview Survey and considered 13,807 employed adult respondents. We used a zero-inflated negative binomial (zinb) model to examine the association between exposure to workplace mistreatment and the occurrence and number of workdays missed due to illness/injury in the preceding 12 months. RESULTS: In 2010, 7.6% of US workers employed at the time of the survey reported having been mistreated at their workplace. Both occurrence and duration of sickness absence were higher for mistreated than for non-mistreated workers. The zinb results showed that being mistreated was associated with a 42% increase in the number of missed workdays, controlling for covariates. The marginal effect analysis showed that lost workdays differed by 2.45 days between mistreated and non-mistreated workers. This implies that workplace mistreatment was associated with $4.1 billion, or 5.5%, of sickness absenteeism costs in 2010. CONCLUSIONS: Workplace mistreatment is associated with sickness absence in the United States. While a causal relationship could not be established due to the cross-sectional design of the study, this study reveals the economic importance of developing workplace mistreatment prevention strategies. PMID- 24166764 TI - Secretory ranalexin produced in recombinant Pichia pastoris exhibits additive or synergistic bactericidal activity when used in combination with polymyxin B or linezolid against multi-drug resistant bacteria. AB - Ranalexin, a cationic peptide from frogs, is a potent therapeutic antimicrobial peptide (AMP). Its limited availability is an obstacle for a wider application. A high-level production of AMPs via bioengineering is possible but remains a challenging task. In the current study, we investigated the potential antibacterial properties of recombinant ranalexin, expressed in the yeast Pichia pastoris. A 78-bp DNA fragment encoding the mature ranalexin peptide with a 6-His tag on its C-terminus was designed using the preferred codon usage of P. pastoris. The gene was inserted into pPICZaA and transformed into competent cells of P. pastoris strain KM71. The yield of secretory ranalexin reached up to ~6 mg/L culture. Time-kill curve analysis of ranalexin against both Escherichia coli and methicillin-resistant Staphylococcus aureus (MRSA) demonstrated a concentration- dependent rapid bactericidal activity. In checkerboard assays, the combinations of ranalexin with the established antibiotics polymyxin B or linezolid reduced the MIC additively in most tested bacteria. Time-kill assays indicated a significant synergism in E. coli and MRSA when ranalexin was used in combination with antibiotics, even at concentrations of 1/4 MIC or 1/2 MIC of ranalexin, respectively. Thus we propose that secretory ranalexin produced in P. pastoris could be a useful tool to unravel ranalexin's biological function and for use in future in vivo studies against multi- resistant bacterial infections. PMID- 24166766 TI - Immunity at the barriers. PMID- 24166765 TI - Hormones and diet, but not body weight, control hypothalamic microglial activity. AB - The arcuate nucleus (ARC) of the hypothalamus plays a key role in sensing metabolic feedback and regulating energy homeostasis. Recent studies revealed activation of microglia in mice with high-fat diet (HFD)-induced obesity (DIO), suggesting a potential pathophysiological role for inflammatory processes within the hypothalamus. To further investigate the metabolic causes and molecular underpinnings of such glial activation, we analyzed the microglial activity in wild-type (WT), monogenic obese ob/ob (leptin deficient), db/db (leptin-receptor mutation), and Type-4 melanocortin receptor knockout (MC4R KO) mice on either a HFD or on standardized chow (SC) diet. Following HFD exposure, we observed a significant increase in the total number of ARC microglia, immunoreactivity of ionized calcium binding adaptor molecule 1 (iba1-ir), cluster of differentiation 68 (CD68-ir), and ramification of microglial processes. The ob/ob mice had significantly less iba1-ir and ramifications. Leptin replacement rescued these phenomena. The db/db mice had similar iba1-ir comparable with WT mice but had significantly lower CD68-ir and more ramifications than WT mice. After 2 weeks of HFD, ob/ob mice showed an increase of iba1-ir, and db/db mice showed increase of CD68-ir. Obese MC4R KO mice fed a SC diet had comparable iba1-ir and CD68-ir with WT mice but had significantly more ramifications than WT mice. Intriguingly, treatment of DIO mice with glucagon-like peptide-1 receptor agonists reduced microglial activation independent of body weight. Our results show that diet type, adipokines, and gut signals, but not body weight, affect the presence and activity levels of hypothalamic microglia in obesity. PMID- 24166767 TI - Oxidative stress response of Beauveria bassiana to Bordeaux mixture and its influence on fungus growth and development. AB - BACKGROUND: Chemical fungicides used to manage plant diseases may negatively affect beneficial fungi such as entomopathogens. In this study, the participation of the antioxidative system in the entomopathogenic fungus Beauveria bassiana exposed to the copper-based Bordeaux mixture fungicide and its relation with fungus growth and development were examined. The fungus was grown in submerged culture containing Bordeaux mixture at the recommended dose. Within the first 24 h of elicitation, the vegetative growth, germination, sporulation and activity of amylase and laccase and the antioxidative enzymes catalase (CAT) and superoxide dismutase (SOD), as well as the production of hydrogen peroxide (H2 O2 ), were evaluated. RESULTS: Bordeaux mixture inhibited B. bassiana germination (between 65 and 88%) and sporulation (between 15 and 57%) and significantly increased laccase production (>=130%), especially within the first 4 h of fungus exposure. By contrast, the mycelial growth was found to be less affected by the fungicide. These effects were accompanied with a significant increase in H2 O2 levels in fungal cells, as well as in SOD activity, but not in CAT, showing clear signs of increased oxidative stress. CONCLUSION: The effect of Bordeaux mixture on B. bassiana development was probably due to the toxicity of the copper ion itself, and it also induced an oxidative state in fungal cells. PMID- 24166768 TI - Macrophage responses to a Zr-based bulk metallic glass. AB - Bulk metallic glasses (BMGs) are considered to be a competitive candidate of biomedical materials, owing to their appealing mechanical properties and high thermal processability. Based on the established biosafety of the Zr-based BMGs, macrophage responses to (Zr55 Al10 Ni5 Cu30)99 Y1 (atomic percent) BMG were investigated in the present study, in comparison with Ti-6Al-4V alloy. The adhesion of RAW 264.7 macrophages to both alloys was found to be mediated by protein adsorption. The Zr-based BMG is capable of supporting regular adhesion and proliferation of macrophages, indicating its good biocompatibility, which agrees with previous findings using other mammalian cells. A lower degree of morphological activation was revealed on Zr-based BMG substrates than on Ti-6Al 4V substrates, which is evidenced by smaller spreading areas and less ruffling on cell surfaces. Smaller amount of proinflammatory cytokine, tumor necrosis factor alpha, was secreted by macrophages cultured on Zr-based BMGs, which further confirms the lower level of inflammation induced by BMG than by Ti alloys. PMID- 24166769 TI - Blood proteins strongly reduce the mobility of artificial self-propelled micromotors. AB - Autonomous self-propelled catalytic microjets are envisaged as an important technology in biomedical applications, including drug delivery, micro/nanosurgery, and active dynamic bioassays. The direct in vivo application of these microjets, specifically in blood, is however impeded by insufficient knowledge on the in vivo viability of the technique. This study highlights the effect of blood proteins on the viability of the microjets. The presence of blood proteins, including serum albumin and gamma-globulins at physiological concentrations, has been found to dramatically reduce the viability of the microjets. The reduction of viability has been measured in terms of a lower number of active microjets and a decrease in the velocity of propulsion. It is clear from this study that in order for microjets to function in biomedical applications, different modes of propulsion besides platinum-catalyzed oxygen bubble ejection must be employed. These findings have serious implications for the biomedical applications of catalytic microjets. PMID- 24166771 TI - The primate vaginal microbiome: comparative context and implications for human health and disease. AB - The primate body hosts trillions of microbes. Interactions between primate hosts and these microbes profoundly affect primate physiology, reproduction, health, survival, and ultimately, evolution. It is increasingly clear that primate health cannot be understood fully without knowledge of host-microbial interactions. Our goals here are to review what is known about microbiomes of the female reproductive tract and to explore several factors that influence variation within individuals, as well as within and between primate species. Much of our knowledge of microbial variation derives from studies of humans, and from microbes located in nonreproductive regions (e.g., the gut). We review work suggesting that the vaginal microbiota affects female health, fecundity, and pregnancy outcomes, demonstrating the selective potential for these agents. We explore the factors that correlate with microbial variation within species. Initial colonization by microbes depends on the manner of birth; most microbial variation is structured by estrogen levels that change with age (i.e., at puberty and menopause) and through the menstrual cycle. Microbial communities vary by location within the vagina and can depend on the sampling methods used (e.g., swab, lavage, or pap smear). Interindividual differences also exist, and while this variation is not completely understood, evidence points more to differences in estrogen levels, rather than differences in external physical environment. When comparing across species, reproductive-age humans show distinct microbial communities, generally dominated by Lactobacillus, unlike other primates. We develop evolutionary hypotheses to explain the marked differences in microbial communities. While much remains to be done to test these hypotheses, we argue that the ample variation in primate mating and reproductive behavior offers excellent opportunities to evaluate host-microbe coevolution and adaptation. PMID- 24166770 TI - Characterization of the respiration-induced yeast mitochondrial permeability transition pore. AB - When isolated mitochondria from the yeast Saccharomyces cerevisiae oxidize respiratory substrates in the absence of phosphate and ADP, the yeast mitochondrial unselective channel, also called the yeast permeability transition pore (yPTP), opens in the inner membrane, dissipating the electrochemical gradient. ATP also induces yPTP opening. yPTP opening allows mannitol transport into isolated mitochondria of laboratory yeast strains, but mannitol is not readily permeable through the yPTP in an industrial yeast strain, Yeast Foam. The presence of oligomycin, an inhibitor of ATP synthase, allowed for respiration induced mannitol permeability in mitochondria from this strain. Potassium (K+) had varied effects on the respiration-induced yPTP, depending on the concentration of the respiratory substrate added. At low respiratory substrate concentrations K+ inhibited respiration-induced yPTP opening, while at high substrate concentrations this effect diminished. However, at the high respiratory substrate concentrations, the presence of K+ partially prevented phosphate inhibition of yPTP opening. Phosphate was found to inhibit respiration-induced yPTP opening by binding a site on the matrix space side of the inner membrane in addition to its known inhibitory effect of donating protons to the matrix space to prevent the pH change necessary for yPTP opening. The respiration-induced yPTP was also inhibited by NAD, Mg2+, NH4 + or the oxyanion vanadate polymerized to decavanadate. The results demonstrate similar effectors of the respiration induced yPTP as those previously described for the ATP-induced yPTP and reconcile previous strain-dependent differences in yPTP solute selectivity. PMID- 24166772 TI - Continuous flow nanoparticle concentration using alternating current electroosmotic flow. AB - Achieving real-time detection of environmental pathogens such as viruses and bacterial spores requires detectors with both rapid action and a suitable detection threshold. However, most biosensors have detection limits of an order of magnitude or more above the potential infection threshold, limiting their usefulness. This can be improved through the use of automated sample preparation techniques such as preconcentration. In this paper, we describe the use of AC electroosmosis to concentrate nanoparticles from a continuous flow. Electrodes at an optimized angle across a flow cell, and energized by a 1 kHz signal, were used to push nanoparticles to one side of a flow cell, and to extract the resulting stream with a high particle concentration from that side of the flow cell. A simple model of the behavior of particles in the flow cell has been developed, which shows good agreement with experimental results. The method indicates potential for higher concentration factors through cascading devices. PMID- 24166773 TI - Expression of microRNA-218 in human pancreatic ductal adenocarcinoma and its correlation with tumor progression and patient survival. AB - BACKGROUND: Our aim was to analyze clinicopathologic and prognostic values of microRNA (miR)-218 in pancreatic ductal adenocarcinima (PDAC). METHODS: TaqMan quantitative RT-PCR was used to determine the expression of miR-218 in human PDAC cells and tissue samples. The association of miR-218 expression with clinicopathologic variables was analyzed. Kaplan-Meier survival analysis was performed to analyze the association of miR-218 expression with recurrence-free survival or overall survival of patients. Univariate and multivariate Cox regression analyses were performed. RESULTS: The relative level of miR-218 in PDAC cells was significantly lower than that in normal human pancreatic duct epithelial cell line. Also, the mean level of miR-218 in PDAC tissues was significantly lower than that in normal pancreatic tissues. Statistical analyses indicated that low miR-218 expression was closely associated with poor tumor differentiation, advanced tumor stage, higher incidence of lymph node metastasis, and tumor recurrence. Kaplan-Meier survival analyses showed that patients with low miR-218 expression had lower recurrence-free and overall survival than those with high miR-218 expression. Univariate and multivariate Cox regression analyses showed that miR-218 might be an independent prognostic factor. CONCLUSION: Reduced miR-218 in PDAC tissues was correlated with tumor progression, and might be an independent poor prognostic factor for patients. PMID- 24166774 TI - A fresh look at livestock greenhouse gas emissions and mitigation potential in Europe. PMID- 24166776 TI - Bio-inspired swing leg control for spring-mass robots running on ground with unexpected height disturbance. AB - We proposed three swing leg control policies for spring-mass running robots, inspired by experimental data from our recent collaborative work on ground running birds. Previous investigations suggest that animals may prioritize injury avoidance and/or efficiency as their objective function during running rather than maintaining limit-cycle stability. Therefore, in this study we targeted structural capacity (maximum leg force to avoid damage) and efficiency as the main goals for our control policies, since these objective functions are crucial to reduce motor size and structure weight. Each proposed policy controls the leg angle as a function of time during flight phase such that its objective function during the subsequent stance phase is regulated. The three objective functions that are regulated in the control policies are (i) the leg peak force, (ii) the axial impulse, and (iii) the leg actuator work. It should be noted that each control policy regulates one single objective function. Surprisingly, all three swing leg control policies result in nearly identical subsequent stance phase dynamics. This implies that the implementation of any of the proposed control policies would satisfy both goals (damage avoidance and efficiency) at once. Furthermore, all three control policies require a surprisingly simple leg angle adjustment: leg retraction with constant angular acceleration. PMID- 24166775 TI - Tracheomalacia is associated with lower FEV1 and Pseudomonas acquisition in children with CF. AB - BACKGROUND: Tracheomalacia (TM) occurs in approximately 1 in 2,100 children. Because the trachea develops abnormally in animal models of cystic fibrosis (CF), we hypothesized this may also occur in children with CF, increasing their risk of TM. PURPOSE: To examine the prevalence and clinical consequences of TM in children with CF. METHODS: We studied children with CF born between 1995 and 2012. TM was defined as dynamic collapse of the trachea, and the severity was recorded as described in the chart. The effect of TM on patient outcomes, including FEV1 , CT changes, and acquisition of CF pathogens, was assessed using a longitudinal patient dataset. RESULTS: Eighty-nine percent of children with CF had at least one bronchoscopy (n = 97/109). Fifteen percent of these children had TM described in any bronchoscopy report (n = 15/97). Of the patients with TM, eight had meconium ileus (P = 0.003) and all were pancreatic insufficient. Pseudomonas aeruginosa infection occurred 1.3 years earlier among children with TM (P = 0.01). Starting FEV1 values by age 8 were diminished by over 18% of predicted for patients with TM. Life-threatening episodes of airway obstruction occurred in 3 of 15 patients with CF and TM, including one leading to death. Gender, prematurity, and hepatic disease were not associated with TM. No difference was observed in the frequency of bronchiectasis. CONCLUSIONS: TM is significantly more common in infants and children with CF than in the general population and is associated with airway obstruction and earlier Pseudomonas acquisition. PMID- 24166777 TI - p40 (DeltaNp63) is more specific than p63 and cytokeratin 5 in identifying squamous cell carcinoma of bronchopulmonary origin: a review and comparative analysis. AB - The therapeutic options now available for pulmonary squamous cell carcinoma (SQCC) and adenocarcinoma (ADC) are very different. The increasing demand to make a diagnosis on minimal tissue, ancillary techniques such as immunohistochemistry (IHC) are need to be highly sensitive and specific. The IHC marker p40 (DeltaNp63) is a truncated isoform of p63 that is a promising IHC marker for SQCC. In this study, we have compared the specificity of p40(DeltaNp63) IHC with p63 and cytokeratin 5 (CK5) on fine-needle aspiration (FNA) cell blocks (CB). Thirty cases of pulmonary SQCC and 30 cases of pulmonary ADC with CB were selected. IHC for p40(DeltaNp63), p63, and CK5 were performed on all paraffin embedded CB serial sections. All cases (n = 30) of SQCC stained positive for p40(DeltaNp63). All cases of bronchopulmonary ADC were negative for both p40(DeltaNp63) and CK5. Six cases (20%) of bronchopulmonary ADC demonstrated nuclear staining for p63 in at least 10% of malignant cells. Our data support p40(DeltaNp63) to be more sensitive and specific and possess a greater positive and negative predictive value for SQCC in comparison to p63. This study also documents that p40(DeltaNp63) does not stain ADC, which p63 does in 20% of the cases. We also found that p40(DeltaNp63) shows a greater sensitivity and negative predictive value when compared to CK5. In paucicellular CB the increased indices p40(DeltaNp63) provides may be extremely helpful in confirming the diagnosis of SQCC, which may have significant therapeutic implications. PMID- 24166778 TI - Myeloid-derived suppressor cells are key players in the resolution of inflammation during a model of acute infection. AB - Myeloid-derived suppressor cells (MDSCs) are key players in the immune suppressive network. During acute infection with the causative agent of Chagas disease, Trypanosoma cruzi, BALB/c mice show less inflammation and better survival than C57BL/6 (B6) mice. In this comparative study, we found a higher number of MDSCs in the spleens and livers of infected BALB/c mice compared with infected B6 mice. An analysis of the two major MDSCs subsets revealed a greater number of granulocytic cells in the spleens and livers of BALB/c mice when compared with that in B6 mice. Moreover, splenic MDSCs purified from infected BALB/c mice inhibited ConA-induced splenocyte proliferation. Mechanistic studies demonstrated that ROS and nitric oxide were involved in the suppressive activity of MDSCs, with a higher number of infected CD8(+) T cells suffering surface nitration compared to uninfected controls. An upregulation of NADPH oxidase p47 phox subunit and p-STAT3 occurred in MDSCs and infected IL-6 KO mice showed less recruitment of MDSCs and impaired survival. Remarkably, in vivo depletion of MDSCs led to increased production of IL-6, IFN-gamma, and a Th17 response with very high parasitemia and mortality. These findings demonstrate a new facet of MDSCs as crucial regulators of inflammation during T. cruzi infection. PMID- 24166779 TI - The cell membrane is the main target of resveratrol as shown by interdisciplinary biomolecular/cellular and biophysical approaches. AB - One of the research lines developed in our laboratory is focused on the study of the bioactivity of natural substances. Resveratrol (RV) is a polyphenol nonflavonoid compound present in a number of plant species but mainly in the berries of the red grape Vitis vinifera. The powerful antioxidant action of this molecule is well documented. In this work we evaluated the effects of this substance by adopting diverse experimental strategies. In particular, we studied the effects on cell vitality and cycle by MTT and cytofluorimetric assays. In addition, we explored the action of RV on the cell membrane by a well consolidated biophysical approach: electrorotation. This technique allows assessment of the structure/function of the cell membrane. The results presented here demonstrate that RV shows a modest effect on the biological properties of the cell in terms of cytotoxicity and cell cycle alterations. On the contrary, a significant effect on the membrane structure/function was observed, consisting of an enhanced intramembrane ion transport. The implications and interpretation of these membrane alterations are discussed. PMID- 24166780 TI - Highly sialylated recombinant human erythropoietin production in large-scale perfusion bioreactor utilizing CHO-gmt4 (JW152) with restored GnT I function. AB - Therapeutic glycoprotein drugs require a high degree of sialylation of their N glycans for a better circulatory half-life that results in greater efficacy. It has been demonstrated that Chinese hamster ovary (CHO) glycosylation mutants lacking N-acetylglucosaminyltransferase I (GnT I), when restored by introduction of a functional GnT I, produced highly sialylated erythropoietin (EPO). We have now further engineered one of such mutants, JW152, by inactivating the dihydrofolate reductase (DHFR) gene to allow for the amplification of the EPO gene with methotrexate (MTX). Several MTX-amplified clones maintained the ability to produce highly sialylated EPO and one was selected for culture in a perfusion bioreactor that is used in an existing industrial EPO-production bioprocess. Extensive characterization of the EPO produced was performed using total sialic quantification, HPAEC-PAD and MALDI-TOF MS analyses. Our results demonstrated that the EPO produced by the mutant line exhibits superior sialylation compared to the commercially used EPO-producing CHO clone cultured under the same conditions. Therefore, this mutant has the industrial potential for producing highly sialylated recombinant EPO and potentially other recombinant glycoprotein therapeutics. PMID- 24166781 TI - Time-resolved in-situ observation of starch polysaccharide degradation pathways. AB - Analytical challenges in the direct time-resolved observation of starch metabolism have been addressed by using optimized multidimensional NMR experiments. Starch provides the main source of human dietary energy intake and is a raw material for beverage and renewable fuel production. Use of direct in situ observations of starch remodeling pathways could facilitate our understanding and control of processes of biotechnological, medical, and environmental relevance. Processes involving starch synthesis or degradation are difficult to monitor directly in aqueous solution, however, because starch consists of glucopyranosyl homopolymers that are built up from and degraded into structurally similar fragments that yield only small signal dispersion in optical and NMR spectroscopy. By focusing on acetal groups only, (1) H,(13) C HSQC experiments sampling narrow spectral windows in the highly resolved (13) C dimension have been employed in order to observe the amylopectin cleavage pathway in real time with a temporal resolution of 150 s. Quantifiable signals for more than 15 molecular species emerging during starch fragmentation by human saliva have been resolved and tracked over time in this manner. Altered accumulation of intermediates in the digestion of amylopectin in the presence of black tea acting as an effector have been monitored. PMID- 24166785 TI - A simple, one-tube assay for the simultaneous detection and diagnosis of ten Australian poultry Eimeria. AB - Coccidiosis is a costly worldwide enteric disease of chickens caused by parasites of the genus Eimeria. At present, there are seven described species that occur globally and a further three undescribed, operational taxonomic units (OTUs X, Y, and Z) that are known to infect chickens from Australia. Species of Eimeria have both overlapping morphology and pathology and frequently occur as mixed-species infections. This makes definitive diagnosis with currently available tests difficult and, to date, there is no test for the detection of the three OTUs. This paper describes the development of a PCR-based assay that is capable of detecting all ten species of Eimeria, including OTUs X, Y, and Z in field samples. The assay is based on a single set of generic primers that amplifies a single diagnostic fragment from the mitochondrial genome of each species. This one-tube assay is simple, low-cost, and has the capacity to be high throughput. It will therefore be of great benefit to the poultry industry for Eimeria detection and control, and the confirmation of identity and purity of vaccine strains. PMID- 24166784 TI - X-linked sideroblastic anemia due to ALAS2 intron 1 enhancer element GATA-binding site mutations. AB - X-linked sideroblastic anemia (XLSA) is the most common form of congenital sideroblastic anemia. In affected males, it is uniformly associated with partial loss-of-function missense mutations in the erythroid-specific heme biosynthesis protein 5-aminolevulinate synthase 2 (ALAS2). Here, we report five families with XLSA owing to mutations in a GATA transcription factor binding site located in a transcriptional enhancer element in intron 1 of the ALAS2 gene. As such, this study defines a new class of mutations that should be evaluated in patients undergoing genetic testing for a suspected diagnosis of XLSA. PMID- 24166786 TI - Determination of free formaldehyde in vaccines and biological samples using solid phase microextraction coupled to GC-MS. AB - A headspace solid-phase microextraction method coupled to GC-MS was successfully developed for the trace determination of formaldehyde in veterinary bacterial and human vaccines, and diphtheria-tetanus antigen. The formaldehyde was derivatized by means of the Hantzsch reaction prior to extraction and subsequent determination. Three different types of solid-phase microextraction fibers, polar, and nonpolar poly(dimethylsiloxane) and polyethylene glycol were prepared by using a sol-gel technique. The effects of different parameters such as type of fiber coating, extraction time and temperature, desorption conditions, agitation rate, and salt effect were investigated. Under the optimized conditions, the detection limit of the method was 979 ng/L using the selected ion-monitoring mode. The interday and intraday precisions of the developed method under the optimized conditions were below 13%, and the method shows linearity in the range of 1.75-800 MUg/L with a correlation coefficient of 0.9963. The optimized method was applied to the determination of formaldehyde from some biological products. The results were satisfactory compared to the standard method. PMID- 24166787 TI - Workplace drug testing and alcohol policy in Italy; there is still a long way to go. AB - The effectiveness of workplace drug testing (WDT) in Italy has recently been questioned, while very little is known about the real consumption of alcoholic beverages among workers performing hazardous jobs, such as professional drivers (PDs). The aim of this study is to investigate the modality and frequency of WDT execution and of alcohol consumption in the above category. Anonymous questionnaires were used to collect information. Four hundred and ninety-seven questionnaires were collected; 50.1% declared that they know well in advance when they will be subjected to screening tests for drugs, while 19.5% claimed they have never been subjected to such a test. The greater the number of employees in a company, the greater the likelihood that the tests are performed with a genuinely surprise effect [odds ratio (OR) 2.41, 5.39 and 9.07, respectively, for businesses with 5-14 employees, 15-50 and more than 50, compared with companies with less than 5 employees, p < 0.01]. Twenty-one point four percent declared they drink alcoholic beverages during working hours or work breaks. This attitude is positively correlated with driver seniority [OR 1.07, 95% confidence interval (CI) 1.03-1.11 p < 0.01] and is more common in those who operate on mainly international routes (OR 3.34 CI 1.30-8.59 p < 0.01) and only occasionally consume meals in restaurants (OR 4.27, CI 1.19-15.42 p < 0.05). Fifteen percent of the participants have an AUDIT C score >= 5. In conclusion WDT is largely ineffective, particularly in small businesses. The high percentage of PDs who claim to drink during working hours and who are hazardous drinkers requires a further strengthening of prevention strategies in this area. PMID- 24166788 TI - A new proposal for greenhouse gas emissions responsibility allocation: best available technologies approach. AB - In recent years, several methodologies have been developed for the quantification of greenhouse gas (GHG) emissions. However, determining who is responsible for these emissions is also quite challenging. The most common approach is to assign emissions to the producer (based on the Kyoto Protocol), but proposals also exist for its allocation to the consumer (based on an ecological footprint perspective) and for a hybrid approach called shared responsibility. In this study, the existing proposals and standards regarding the allocation of GHG emissions responsibilities are analyzed, focusing on their main advantages and problems. A new model of shared responsibility that overcomes some of the existing problems is also proposed. This model is based on applying the best available technologies (BATs). This new approach allocates the responsibility between the producers and the final consumers based on the real capacity of each agent to reduce emissions. The proposed approach is demonstrated using a simple case study of a 4-step life cycle of ammonia nitrate (AN) fertilizer production. The proposed model has the characteristics that the standards and publications for assignment of GHG emissions responsibilities demand. This study presents a new way to assign responsibilities that pushes all the actors in the production chain, including consumers, to reduce pollution. PMID- 24166789 TI - Intraperitoneal chemotherapy: rationale, applications, and limitations. AB - Intraperitoneal chemotherapy, involving the administration of certain chemotherapeutic agents directly to the intraperitoneal cavity, was developed as a novel therapeutic strategy early in the 1950s. Intraperitoneal administration of chemotherapy results in higher intraperitoneal concentration of the cytotoxic medications and minimal systemic exposure than observed with intravenous administration, which in turn may increase the efficacy of these agents with substantial reduction in systemic toxicity. Intraperitoneal chemotherapy was used successfully in peritoneal surface malignancies, including malignant peritoneal mesothelioma, pseudomyxoma peritonei, malignant ascites, sarcomatosis, and peritoneal carcinomatosis from gastrointestinal and ovarian cancers. Pharmacists may play a major role in optimizing intraperitoneal chemotherapy through verification of chemotherapy order for proper doses, dilution, preparation, and administration. Moreover, pharmacists are medication experts who can provide other health care professionals with the necessary drug information. Despite the local application of chemotherapy, intraperitoneal chemotherapy is not free of systemic side effects and can be associated with serious complications. The benefits of intraperitoneal chemotherapy should be weighed against its potential harm to maximize efficacy and to minimize morbidity and mortality as much as possible. The aim of this article is to review the current available literature regarding the safety and efficacy of intraperitoneal chemotherapy in cancer treatment. PMID- 24166790 TI - Job stress and work-related musculoskeletal symptoms among intensive care unit nurses: a comparison between job demand-control and effort-reward imbalance models. AB - BACKGROUND: The aims of this study were to compare job demand-control (JDC) and effort-reward imbalance (ERI) models in examining the association of job stress with work-related musculoskeletal symptoms and to evaluate the utility of a combined model. METHODS: This study analyzed cross-sectional survey data obtained from a nationwide random sample of 304 intensive-care unit (ICU) nurses. Demographic and job factors were controlled in the analyses using logistic regression. RESULTS: Both JDC and ERI variables had strong and statistically significant associations with work-related musculoskeletal symptoms. Effort reward imbalance had stronger associations than job strain or iso-strain with musculoskeletal symptoms. Effort-reward imbalance alone showed similar or stronger associations with musculoskeletal symptoms compared to combined variables of the JDC and ERI models. CONCLUSIONS: The ERI model appears to capture the magnitude of the musculoskeletal health risk among nurses associated with job stress at least as well and possibly better than the JDC model. Our findings suggest that combining the two models provides little gain compared to using effort-reward imbalance only. PMID- 24166791 TI - Splitting headache (off). PMID- 24166792 TI - Association of low baseline levels of erythrocyte folate with treatment nonresponse at three months in rheumatoid arthritis patients receiving methotrexate. AB - OBJECTIVE: To investigate whether baseline concentrations of one-carbon metabolism biomarkers are associated with treatment nonresponse and adverse events in rheumatoid arthritis (RA) patients receiving methotrexate (MTX). METHODS: A prospective derivation cohort (n = 285) and validation cohort (n = 102) of RA patients receiving MTX were studied. Concentrations of plasma homocysteine, serum vitamin B12 , serum folate, erythrocyte vitamin B6 , and erythrocyte folate were determined at baseline and after 3 months of treatment. Nonresponse after 3 months was assessed using the Disease Activity Score in 28 joints (DAS28) and the European League Against Rheumatism (EULAR) response criteria. Adverse events at 3 months were assessed using biochemical parameters and health status questionnaires. Analyses were corrected for baseline DAS28, age, sex, MTX dose, comedications, and presence of the methylenetetrahydrofolate reductase 677TT genotype. RESULTS: In the derivation cohort, the mean DAS28 scores at baseline and 3 months were 4.94 and 3.12, respectively, and 78% of patients experienced adverse events. This was similar between the 2 cohorts, despite a lower MTX dose in the validation cohort. Patients with lower levels of erythrocyte folate at baseline had a higher DAS28 at 3 months in both the derivation cohort (beta = -0.15, P = 0.037) and the validation cohort (beta = 0.20, P = 0.048). In line with these results, lower baseline erythrocyte folate levels were linearly associated with a 3-month DAS28 of >3.2 in both cohorts (derivation cohort, P = 0.049; validation cohort, P = 0.021) and with nonresponse according to the EULAR criteria (derivation cohort, P = 0.066; validation cohort, P = 0.027). None of the other biomarkers (levels at baseline or changes over 3 months) were associated with the DAS28 or treatment nonresponse. Baseline levels of the biomarkers and changes in levels after 3 months were not associated with incidence of adverse events. CONCLUSION: A low baseline concentration of erythrocyte folate is associated with high disease activity and nonresponse at 3 months after the start of MTX treatment and could be used in prediction models for MTX outcome. None of the investigated one-carbon metabolism biomarkers were associated with incidence of adverse events at 3 months. PMID- 24166794 TI - Clinically significant renal involvement in primary Sjogren's syndrome: clinical presentation and outcome. AB - OBJECTIVE: To estimate the prevalence and investigate the clinical features and the outcome of clinically significant renal involvement in a large cohort of patients with primary Sjogren's syndrome (SS). METHODS: Among 715 patients who met the American-European Consensus Group criteria for primary SS, those with clinically significant renal involvement were identified and their clinical and immunologic features were recorded. The prognosis in patients with primary SS with renal involvement was assessed by the clinical appearance of any of the following major outcomes: death, hemodialysis, chronic renal failure (CRF), and lymphoma. Kaplan-Meier analysis was applied to compare death rates between patients without and those with renal involvement. RESULTS: Thirty-five patients with primary SS (4.9%) had clinically significant renal involvement, representing a total followup time after renal diagnosis of 252.2 person-years. Thirteen patients (37.1%) had interstitial nephritis alone, 17 patients (48.6%) had glomerulonephritis (GN) alone, and 5 patients (14.3%) had both entities. Nine patients died (25.7%), 11 developed CRF (including 4 requiring chronic hemodialysis) (31.4%), and 9 developed lymphoma (25.7%). The overall 5-year survival rate was 85%. Kaplan-Meier analysis showed statistically significant reduced survival for patients with primary SS with renal involvement compared to those without renal involvement (P < 0.0001 by log rank test), with GN patients displaying increased mortality. Eight of 9 reported deaths (89%) and 8 of 9 lymphomas (89%) were observed among patients with GN. CONCLUSION: The long-term prognosis varies for patients with primary SS who have clinically significant renal involvement. Patients with interstitial nephritis display a favorable prognosis, while patients with GN are at high risk of developing lymphoma and have poor survival. PMID- 24166793 TI - Headache in systemic lupus erythematosus: results from a prospective, international inception cohort study. AB - OBJECTIVE: To examine the frequency and characteristics of headaches and their association with global disease activity and health-related quality of life (HRQOL) in patients with systemic lupus erythematosus (SLE). METHODS: A disease inception cohort was assessed annually for headache (5 types) and 18 other neuropsychiatric (NP) events. Global disease activity scores (SLE Disease Activity Index 2000 [SLEDAI-2K]), damage scores (Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index [SDI]), and Short Form 36 (SF-36) mental and physical component summary scores were collected. Time to first headache and associations with SF-36 scores were analyzed using Cox proportional hazards and linear regression models with generalized estimating equations. RESULTS: Among the 1,732 SLE patients enrolled, 89.3% were female and 48.3% were white. The mean +/- SD age was 34.6 +/- 13.4 years, duration of disease was 5.6 +/- 5.2 months, and length of followup was 3.8 +/- 3.1 years. At enrollment, 17.8% of patients had headache (migraine [60.7%], tension [38.6%], intractable nonspecific [7.1%], cluster [2.6%], and intracranial hypertension [1.0%]). The prevalence of headache increased to 58% after 10 years. Only 1.5% of patients had lupus headache, as identified in the SLEDAI-2K. In addition, headache was associated with other NP events attributed to either SLE or non-SLE causes. There was no association of headache with SLEDAI-2K scores (without the lupus headache variable), SDI scores, use of corticosteroids, use of antimalarials, use of immunosuppressive medications, or specific autoantibodies. SF-36 mental component scores were lower in patients with headache compared with those without headache (mean +/- SD 42.5 +/- 12.2 versus 47.8 +/- 11.3; P < 0.001), and similar differences in physical component scores were seen (38.0 +/- 11.0 in those with headache versus 42.6 +/- 11.4 in those without headache; P < 0.001). In 56.1% of patients, the headaches resolved over followup. CONCLUSION: Headache is frequent in SLE, but overall, it is not associated with global disease activity or specific autoantibodies. Although headaches are associated with a lower HRQOL, the majority of headaches resolve over time, independent of lupus-specific therapies. PMID- 24166797 TI - Method of continuous variations: applications of job plots to the study of molecular associations in organometallic chemistry. AB - Applications of the method of continuous variations (MCV or the Method of Job) to problems of interest to organometallic chemists are described. MCV provides qualitative and quantitative insights into the stoichiometries underlying association of m molecules of A and n molecules of B to form A(m)B(n) . Applications to complex ensembles probe associations that form metal clusters and aggregates. Job plots in which reaction rates are monitored provide relative stoichiometries in rate-limiting transition structures. In a specialized variant, ligand- or solvent-dependent reaction rates are dissected into contributions in both the ground states and transition states, which affords insights into the full reaction coordinate from a single Job plot. Gaps in the literature are identified and critiqued. PMID- 24166798 TI - Disparities in assessments of asthma control between children, parents, and physicians. AB - OBJECTIVE: Assessment of asthma control in children by physicians, patients and their parents was compared, assuming parents may underestimate symptoms in asthmatic children and exploring whether physicians tend to agree with them. DESIGN: Asthma control perception was assessed in 4- to 11-year-old asthmatic children and their parents, using C-ACT, during 2011-2012. Pediatric pulmonologists used GINA guidelines for their assessment; pediatricians, not having spirometry, used the information given in addition to physical examination. The C-ACT scores given by the children and their parents were further analyzed separately, and compared with their physicians' assessment. Statistical methods, which also measured possible influence of different variables, included kappa, Chi-square, linear-by-linear association, McNemar test and logistic regression. PATIENT SELECTION: The study comprised 354 parents and children aged 4-11 years with moderate-severe asthma; 129 (36.4%) were treated by 23 pediatricians; 225 (63.6%) by 11 pediatric pulmonologists. RESULTS: The C-ACT was generally found valid in assessing asthma control (P < 0.001; kappa 0.529; CI 0.441, 0.617) and showed that in 229/354 (53%) of children the asthma was uncontrolled. Nevertheless, of the 229 children who indicated their asthma was uncontrolled, 124 (54.1%) of their parents (kappa 0.245; CI 0.15, 0.34) and 96 (41.9%) of their physicians believed it to be controlled (kappa 0.331; 0.24, 0.43). Comparing the physician-child discordance vis-a-vis the parents, the significant difference was when 96/229 children (41.9%) and 34/126 parents (27.0%) indicated the asthma was uncontrolled while the physician determined it controlled (OR 1.95; 1.19, 3.24). There were no significant differences between pediatric pulmonologists and pediatricians. CONCLUSIONS: In addition to increasing awareness of parents to symptoms in their asthmatic children, physicians should question the child appropriately, as well as using the children's responses to C-ACT as an information source for properly assessing asthma control. PMID- 24166799 TI - The embryogenesis of the tick Rhipicephalus (Boophilus) microplus: the establishment of a new chelicerate model system. AB - Chelicerates, which include spiders, ticks, mites, scorpions, and horseshoe crabs, are members of the phylum Arthropoda. In recent years, several molecular experimental studies of chelicerates have examined the embryology of spiders; however, the embryology of other groups, such as ticks (Acari: Parasitiformes), has been largely neglected. Ticks and mites are believed to constitute a monophyletic group, the Acari. Due to their blood-sucking activities, ticks are also known to be vectors of several diseases. In this study, we analyzed the embryonic development of the cattle tick, Rhipicephalus (Boophilus) microplus (Acari: Ixodidae). First, we developed an embryonic staging system consisting of 14 embryonic stages. Second, histological analysis and antibody staining unexpectedly revealed the presence of a population of tick cells with similar characteristics to the spider cumulus. Cumulus cell populations also exist in other chelicerates; these cells are responsible for the breaking of radial symmetry through bone morphogenetic protein signaling. Third, it was determined that the posterior (opisthosomal) embryonic region of R. microplus is segmented. Finally, we identified the presence of a transient ventral midline furrow and the formation and regression of a fourth leg pair; these features may be regarded as hallmarks of late tick embryogenesis. Importantly, most of the aforementioned features are absent from mite embryos, suggesting that mites and ticks do not constitute a monophyletic group or that mites have lost these features. Taken together, our findings provide fundamental common ground for improving knowledge regarding tick embryonic development, thereby facilitating the establishment of a new chelicerate model system. PMID- 24166801 TI - Direct observation of the binding mode of the phosphonate anchor to nanosized polyoxotitanate clusters. AB - The structures of three newly synthesized phosphonate-substituted polyoxotitanates are reported. The Ti/O core of [Ti4O(OEt)12(PhenylPO3)] (1) is the building block for two larger phosphonate-substituted nanoclusters, [Ti25O26(OEt)36(PhenylPO3)6] (2) and [Ti26O26(OEt)39(PhenylPO3)6]Br (3). All compounds exhibit a not previously recognized triply bridging binding mode of the phosphonate anchor with short connecting Ti-O bonds, the average of which is 2.010(7) A. Comparison with previously reported work suggests that the binding mode of the phosphonate anchor is strongly dependent on the structure of the underlying substrate. PMID- 24166803 TI - Inhibition of chondrocyte and synovial cell death after exposure to commonly used anesthetics: chondrocyte apoptosis after anesthetics. AB - BACKGROUND: An intra-articular injection of local anesthetics is a common procedure for diagnostic and therapeutic purposes. It has been shown that these agents are toxic to articular cartilage and synovial tissue in a dose- and time dependent fashion, and in some cases, they may lead to postarthroscopic glenohumeral chondrolysis (PAGCL). However, the role of apoptosis in cell death is still unclear, and the potential role of apoptosis inhibition in minimizing chondrocyte and synovial cell death has not been reported. PURPOSE: (1) To quantify the degree of apoptotic cell death in chondrocytes and synovial cells exposed to local anesthetics, and (2) to determine whether caspase inhibition could reduce cell death. STUDY DESIGN: Controlled laboratory study. METHODS: Human chondrocytes and synovial cells were expanded in vitro and exposed to normal saline, 0.5% bupivacaine, 0.5% ropivacaine, 1% lidocaine, or 1:1000 epinephrine for 90 minutes. Apoptosis was then detected at 1, 3, 5, and 7 days after exposure using terminal deoxynucleotidyl transferase (TdT)-mediated dUTP nick-end labeling (TUNEL) and immunohistochemistry. Apoptosis was then inhibited using the pan-caspase inhibitor z-vad-fmk. Results were normalized to normal saline controls and analyzed by generalized regression models and pairwise confidence intervals. RESULTS: Analysis of cumulative chondrocyte apoptosis relative to controls after anesthetic exposure demonstrated more than 60% cell death with 0.5% bupivacaine and 1:1000 epinephrine. The greatest chondroprotective effect of caspase inhibition occurred with 0.5% ropivacaine. Similarly, in synovial cells, epinephrine was also very cytotoxic; however, 1% lidocaine induced the most apoptosis. Synovial cells exposed to 0.5% ropivacaine were again most sensitive to protective caspase inhibition. CONCLUSION: Local anesthetics induce chondrocyte and synovial cell apoptosis in a time-dependent fashion, with peak apoptosis occurring 5 days after exposure. Both chondrocytes and synovial cells are most sensitive to caspase inhibition after exposure to 0.5% ropivacaine. CLINICAL RELEVANCE: Apoptosis inhibition may be an effective strategy in minimizing chondrocyte and synovial cell death after exposure to anesthetics. Further investigation is clinically warranted. PMID- 24166804 TI - Clinical outcomes after cell-seeded autologous chondrocyte implantation of the knee: when can success or failure be predicted? AB - BACKGROUND: Autologous chondrocyte implantation (ACI) has been associated with satisfying results. Still, it remains unclear when success or failure after ACI can be estimated. PURPOSE: To evaluate the clinical outcomes of cell-seeded collagen matrix-supported ACI (ACI-Cs) for the treatment of cartilage defects of the knee at 36 months and to determine a time point after ACI-Cs at which success or failure can be estimated. STUDY DESIGN: Cohort study; Level of evidence, 3. METHODS: A total of 80 patients with isolated full-thickness cartilage defects of the knee joint treated with ACI-Cs were prospectively assessed before surgery as well as postoperatively by use of the International Knee Documentation Committee (IKDC) score and Lysholm knee score. RESULTS: Preoperative IKDC and Lysholm scores increased from 49.6 and 59.5, respectively, to 79.1 and 83.5, respectively, at 36 months. Only half the patients (46.6%) with poor IKDC scores (ie, <70) at 6 months postoperatively showed continued poor or fair scores at 36 months' follow-up. The probability of poor scores at 36 months after surgery further increased to 0.61 and 0.81, respectively, when scores were persistent at 12 and 24 months. All 3 patients (100%) with good IKDC scores (ie, 81-90) at 6 months after surgery showed constant or even improved scores at 36 months' follow up. Ninety-one percent of patients with good and excellent scores at 12 months and 83% of patients with good and excellent scores at 24 months (a total of 23 and 37 patients, respectively) were able to maintain these scores at 36 months' follow-up. Similar results were obtained for the Lysholm score. CONCLUSION: With regard to the improvements in functional outcomes after ACI-Cs at 36 months after surgery, the technique described here appears to lead to satisfying and stable clinical results. This study helps the treating physician to predict the likeliness of further clinical improvements or constant unsatisfactory results after ACI. In patients with good/excellent scores shortly after surgery, deterioration of the knee's condition is rarely found. For patients with poor and fair postoperative scores, clinical outcomes are more difficult to predict, especially during the first year after the procedure. PMID- 24166802 TI - Chemoselective immobilization of proteins by microcontact printing and bio orthogonal click reactions. AB - Herein, a combination of microcontact printing of functionalized alkanethiols and site-specific modification of proteins is utilized to chemoselectively immobilize proteins onto gold surfaces, either by oxime- or copper-catalyzed alkyne-azide click chemistry. Two molecules capable of click reactions were synthesized, an aminooxy-functionalized alkanethiol and an azide-functionalized alkanethiol, and self-assembled monolayer (SAM) formation on gold was confirmed by IR spectroscopy. The alkanethiols were then individually patterned onto gold surfaces by microcontact printing. Site-specifically modified proteins-horse heart myoglobin (HHMb) containing an N-terminal alpha-oxoamide and a red fluorescent protein (mCherry-CVIA) with a C-terminal alkyne-were immobilized by incubation onto respective stamped functionalized alkanethiol patterns. Pattern formation was confirmed by fluorescence microscopy. PMID- 24166800 TI - High mobility group box protein-1 promotes cerebral edema after traumatic brain injury via activation of toll-like receptor 4. AB - Traumatic brain injury (TBI) is a major cause of mortality and morbidity worldwide. Cerebral edema, a life-threatening medical complication, contributes to elevated intracranial pressure (ICP) and a poor clinical prognosis after TBI. Unfortunately, treatment options to reduce post-traumatic edema remain suboptimal, due in part, to a dearth of viable therapeutic targets. Herein, we tested the hypothesis that cerebral innate immune responses contribute to edema development after TBI. Our results demonstrate that high-mobility group box protein 1 (HMGB1) was released from necrotic neurons via a NR2B-mediated mechanism. HMGB1 was clinically associated with elevated ICP in patients and functionally promoted cerebral edema after TBI in mice. The detrimental effects of HMGB1 were mediated, at least in part, via activation of microglial toll-like receptor 4 (TLR4) and the subsequent expression of the astrocytic water channel, aquaporin-4 (AQP4). Genetic or pharmacological (VGX-1027) TLR4 inhibition attenuated the neuroinflammatory response and limited post-traumatic edema with a delayed, clinically implementable therapeutic window. Human and rodent tissue culture studies further defined the cellular mechanisms demonstrating neuronal HMGB1 initiates the microglial release of interleukin-6 (IL-6) in a TLR4 dependent mechanism. In turn, microglial IL-6 increased the astrocytic expression of AQP4. Taken together, these data implicate microglia as key mediators of post traumatic brain edema and suggest HMGB1-TLR4 signaling promotes neurovascular dysfunction after TBI. PMID- 24166805 TI - Comparative proteomic analysis of different Toxoplasma gondii genotypes by two dimensional fluorescence difference gel electrophoresis combined with mass spectrometry. AB - Toxoplasma gondii is a protozoan parasite infecting almost all warm-blooded animals and humans. There are three infective stages of T. gondii: the tachyzoites, the bradyzoites, and the oocysts. The tachyzoite is a rapidly multiplying stage and the main pathogenic factor. In North America and Europe, T. gondii is consisted of four major clonal lineages (namely Types I, II, III, and Type 12). In this study, we explored the proteomic profiles of different genotypes (Type I-RH strain, Type II-PRU strain, Type II-TgQHO strain, and ToxoDB 9-TgC7 strain) of T. gondii tachyzoites by using 2D DIGE combined with MALDI-TOF MS. Totally, 110 differentially abundant protein spots were selected. Of these, 98 spots corresponding to 56 proteins from T. gondii were successfully identified. These included surface antigen (SAG1), heat shock protein 70 (Hsp 70), disulfide isomerase, coronin, heat shock protein 60 (Hsp 60), pyruvate kinase, receptor for activated C kinase 1, and peroxiredoxin. Gene ontology enrichment analysis revealed that most of the differentially abundant proteins were involved in biological regulation, metabolic process, response to stress, binding, antioxidant activity, and transporter activity. According to the KEGG metabolic pathway maps of T. gondii, some identified proteins were involved in the glycolytic/gluconeogenesis pathway. The present study identified differentially abundant proteins among different genotypes of T. gondii and these findings have implications for the better understanding of the phenotypic differences among the examined T. gondii genotypes, which in turn may contribute to the better control of toxoplasmosis. PMID- 24166806 TI - Quadrupedal bounding with a segmented flexible torso: passive stability and feedback control. AB - In this paper, the implications of torso flexibility on the dynamics of quadrupedal running are examined in a template setting. In the same vein with the spring loaded inverted pendulum, a reductive sagittal-plane model with a segmented flexible torso and compliant legs is introduced to capture the dynamics of bounding in the presence of torso flexibility via a minimum number of variables and parameters. Numerical return map studies of the system in dimensionless setting reveal that a large variety of cyclic bounding motions can be realized passively, through the natural interaction of the model with its environment. Despite the simplicity of the model, the resulting motions correspond to torso bending movements that resemble those in galloping mammals without explicit reliance on the fine structural and morphological details. Furthermore, for certain combinations of the system parameters--in particular the torso and leg relative stiffness--self-stable bounding motions emerge. The implications of the existence of such self-stable bounding orbits to control design are also discussed and a hybrid control law is derived that is capable of stabilizing the system as it encounters significantly large disturbances using only a single actuator located at the torso joint. PMID- 24166807 TI - Osteocytes: regulating the mineral reserves? PMID- 24166808 TI - Rapid on-site evaluation of EUS-FNA by cytopathologist: an experience of a tertiary hospital. AB - Endoscopic ultrasound-guided-fine-needle aspiration (EUS-FNA) is the preferred modality nowadays for the cytological diagnosis of various mediastinal and gastrointestinal lesions. Onsite cytopathology interpretation is not available in most centers. The objective of this study is to assess whether rapid on-site evaluation (ROSE) by cytopathologist of the tissue samples improves the diagnostic accuracy of EUS-FNA. This study is a retrospective review of all 646 patients undergoing EUS-FNA between January 2009 and October 2012 in our hospital. Patients in group I had cytology slides prepared by an endoscopy nurse. Patients in group II had cytology slides prepared, stained and assessed for adequacy of tissue sampling by a cytopathologist onsite. The adequacy of the samples and the final cytopathological diagnosis (definitely positive, definitely negative, inconclusive, or inadequate) was compared between the two groups. A total of 425 EUS-FNA procedures were performed in 375 patients in group I and 271 EUS-FNA procedures in 271 patients in group II. The mean of needle passes in group I was 3.12 passes per patient and 3.24 passes in group II. The difference in the number of needle passes was not statistically significant (P = 0.30). The final diagnosis was definite in 64.8% in group I compared with 97.7 % in group II (P = 0.001). The percentage of inconclusive and inadequate diagnoses was 5.6% and 29.3%, respectively in group I and 0% and 2.3% in group II (P = 0.001). In conclusion, ROSE by cytopathologist and interpretation significantly improves the diagnostic yield of EUS-FNA. PMID- 24166809 TI - Seeing the wood for the trees: a minimal reference phylogeny for the human Y chromosome. AB - During the last few decades, a wealth of studies dedicated to the human Y chromosome and its DNA variation, in particular Y-chromosome single-nucleotide polymorphisms (Y-SNPs), has led to the construction of a well-established Y chromosome phylogeny. Since the recent advent of new sequencing technologies, the discovery of additional Y-SNPs is exploding and their continuous incorporation in the phylogenetic tree is leading to an ever higher resolution. However, the large and increasing amount of information included in the "complete" Y-chromosome phylogeny, which now already includes many thousands of identified Y-SNPs, can be overwhelming and complicates its understanding as well as the task of selecting suitable markers for genotyping purposes in evolutionary, demographic, anthropological, genealogical, medical, and forensic studies. As a solution, we introduce a concise reference phylogeny whereby we do not aim to provide an exhaustive tree that includes all known Y-SNPs but, rather, a quite stable reference tree aiming for optimal global discrimination capacity based on a strongly reduced set that includes only the most resolving Y-SNPs. Furthermore, with this reference tree, we wish to propose a common standard for Y-marker as well as Y-haplogroup nomenclature. The current version of our tree is based on a core set of 417 branch-defining Y-SNPs and is available online at http://www.phylotree.org/Y. PMID- 24166810 TI - The Perlman syndrome: familial renal dysplasia with Wilms tumor, fetal gigantism and multiple congenital anomalies. 1984. AB - INTRODUCTION: The ensuing paper by Professor Giovanni Neri and colleagues was originally published in 1984, American Journal of Medical Genetics 19:195-207. The original article described a new family with a condition that the authors designated as the Perlman syndrome. This disorder, while uncommon, is an important multiple congenital anomaly and dysplasia syndrome; the causative gene was recently identified. This paper is a seminal work and is graciously republished by Wiley-Blackwell in the Special Festschrift issue honoring Professor Neri. We describe a familial syndrome of renal dysplasia, Wilms tumor, hyperplasia of the endocrine pancreas, fetal gigantism, multiple congenital anomalies and mental retardation. This condition was previously described by Perlman et al. [1973, 1975] and we propose to call it the "Perlman syndrome." It appears to be transmitted as an autosomal recessive trait. The possible relationships between dysplasia, neoplasia and malformation are discussed. PMID- 24166811 TI - Simpson-Golabi-Behmel syndrome: an X-linked encephalo-tropho-schisis syndrome. 1988. AB - INTRODUCTION: The following paper by Professor GiovanniNeri and colleagues was originally published in 1988, American Journal of Medical Genetics 30:287-299. This paper represented a seminal work at the time of publication as it not only reported a new family with a disorder that had been called the "gigantism dysplasia syndrome", but also suggested naming the condition the Simpson-Golabi Behmel syndrome. This eponym has clearly stood "the test of time", and that designation is now widely accepted. This paper is graciously republished by Wiley Blackwell in the Special Festschrift issue honoring Professor Neri. We report on another family with the so-called "gigantism-dysplasia syndrome", an X-linked condition characterized by pre-and postnatal overgrowth, characteristic face with apparent coarseness, dysplastic changes in several tissues, and mild intellectual impairment. This condition has been called the Golabi-Rosen syndrome; however, we agree that is the same entity as that described, in a milder form, by Simpson et al. in 1975 and by Behmel et al. in 1984. Therefore, we suggest that this entity be designated the Simpson-Golabi-Behmel syndrome. The manifestations in affected individuals suggest that this condition represents an X-linked encephalo-tropho schisis syndrome. PMID- 24166812 TI - My memories of Dr. Giovanni Neri. PMID- 24166813 TI - My memories of Professor Giovanni Neri: the cardiofaciocutaneous syndrome (CFC). PMID- 24166814 TI - Malformations among the X-linked intellectual disability syndromes. AB - Malformations are significant contributions to childhood mortality and disability. Their co-occurrence with intellectual disability may compound the health burden, requiring additional evaluation and management measures. Overall, malformations of greater or lesser severity occur in at least some cases of almost half of the 153 XLID syndromes. Genitourinary abnormalities are most common, but tend to contribute little or no health burden and occur in only a minority of cases of a given XLID syndrome. Some malformations (e.g., lissencephaly, hydranencephaly, long bone deficiency, renal agenesis/dysplasia) are not amenable to medical or surgical intervention; others (e.g., hydrocephaly, facial clefting, cardiac malformations, hypospadias) may be substantially corrected. PMID- 24166815 TI - Annals of morphology. Atavisms: phylogenetic Lazarus? AB - Dedication: with highest respect and affection to Prof. Giovanni Neri on the eve of his official administrative retirement as Chair of the Institute of Medical Genetics of the Universita Cattolica of Rome for leadership in medical genetics and medical science and friendship for decades. The concept "atavism," reversion, throwback, Ruckschlag remains an epistemological challenge in biology; unwise or implausible over-interpretation of a given structure as such has led some to almost total skepticism as to its existence. Originating in botany in the 18th century it became applied to zoology (and humans) with increasing frequency over the last two centuries such that the very concept became widely discredited. Presently, atavisms have acquired a new life and reconsideration given certain reasonable criteria, including: Homology of structure of the postulated atavism to that of ancestral fossils or collateral species with plausible soft tissue reconstructions taking into account relationships of parts, obvious sites of origin and insertion of muscles, vascular channels, etc. Most parsimonious, plausible phylogenetic assumptions. Evident rudimentary or vestigial anatomical state in prior generations or in morphogenesis of a given organism. Developmental instability in prior generations, that is, some closely related species facultatively with or without the trait. Genetic identity or phylogenomic similarity inferred in ancestors and corroborated in more or less closely related species. Fluctuating asymmetry may be the basis for the striking evolutionary diversification and common atavisms in limbs; however, strong selection and developmental constraints would make atavisms in, for example, cardiac or CNS development less likely. Thus, purported atavisms must be examined critically in light of the above criteria. PMID- 24166816 TI - RUSH and CRUSH: a rapid and conditional RNA interference method in mice. AB - RNA interference (RNAi) is a powerful approach to phenocopy mutations in many organisms. Gold standard conventional knock-out mouse technology is labor- and time-intensive; however, off-target effects may confound transgenic RNAi approaches. Here, we describe a rapid method for conditional and reversible gene silencing in RNAi transgenic mouse models and embryonic stem (ES) cells. RUSH and CRUSH RNAi vectors were designed for reversible or conditional knockdown, respectively, demonstrated using targeted replacement in an engineered ROSA26(lacZ) ES cell line and wildtype V6.5 ES cells. RUSH was validated by reversible knockdown of Dnmt1 in vitro. Conditional mouse model production using CRUSH was expedited by deriving ES cell lines from Cre transgenic mouse strains (nestin, cTnnT, and Isl1) and generating all-ES G0 transgenic founders by tetraploid complementation. A control CRUSH(GFP) RNAi mouse strain showed quantitative knockdown of GFP fluorescence as observed in compound CRUSH(GFP) , Ds-Red Cre-reporter transgenic mice, and confirmed by Western blotting. The capability to turn RUSH and CRUSH alleles off or on using Cre recombinase enables this method to rapidly address questions of tissue-specificity and cell autonomy of gene function in development. PMID- 24166817 TI - Masked polycythemia vera diagnosed according to WHO and BCSH classification. AB - Polycythemia vera (PV) is currently diagnosed by the World Health Organization (WHO) criteria regarding hemoglobin (HB) levels and JAK2V617F and related mutations or by the British Committee for Standards in Haematology (BCSH) guidelines predominantly based on hematocrit (HCT) values (>52% in men and >48% in women) in JAK2 mutated patients. We examined clinical features at diagnosis and outcome in 397 mutated PV patients showing a bone marrow (BM) morphology conforming with the WHO descriptions but including also cases with a HB level <18.5 g/dL in males (range 16.0-18.4) and <16.5 g/dL in females (range 15.0 16.4). These patients were regarded as masked PV (mPV) comprising 140 (35%) cases of our cohort. A comparison with the BCSH criteria based on HCT levels revealed a decrease of mPV patients to 59 (15%). In both classification systems, mPV patients were more males, presented more frequently with higher platelet counts, and increased BM reticulin fibrosis. A worsening of overall survival was documented in mPV patients in comparison with overt PV following the WHO (P = 0.011) as well as the BCSH (P = 0.0019) criteria. Risk factors for inferior survival in mPV were age >65 years and white blood cell count >15 * 10(9) /L. Without these risk factors mPV patients had the same survival as overt PV suggesting that a fraction of patients with HB lower than that required for WHO diagnosis should still be considered as overt PV. This study has established the existence of mPV by two different classification systems based on either HB or HCT threshold values. PMID- 24166818 TI - Characterization of the pyrolysis products of methiopropamine. AB - 1-(Thien-2-yl)-2-methylaminopropane (methiopropamine, MPA), appeared as a 'legal high' in late 2010. It is structurally similar to methamphetamine, with a thiophene ring replacing the benzene moiety. Methiopropamine reportedly retains the pharmacological properties of amphetamine stimulants, but it does not fall under existing drug laws in the USA and Ireland. The objective of this research was to identify the pyrolysis products formed under conditions that mimic those used by recreational drugs users. Thirteen pyrolysis products were identified and ten were confirmed by comparison to synthesized standards. Methods for synthesizing the standards as well as an alternative method for the synthesis of methiopropamine were developed. The MPA pyrolysis products are formed through N dealkylation, N-alkylation, N-formylation, beta-carbon oxidation, beta-carbon oxidation/N-alkylation, amine elimination and carbon-carbon bond cleavage. Two pyrazine isomers also formed. Some of these products have the potential to be psychoactive while others are potentially toxic. PMID- 24166819 TI - Green chromatographic fingerprinting: an environmentally friendly approach for the development of separation methods for fingerprinting complex matrices. AB - A chromatographic fingerprint is a comprehensive method that reveals the distinctive pattern of peaks across the chromatogram for a given sample. It is considered an effective strategy to assess the identity and quality of herbal materials, as well as for the control of the quality of their derived products. HPLC is the most employed technique for these purposes and it is used routinely for quality control in industry. Hence, its impact on the environment should not be neglected. This work provides a rational and generic procedure to qualitatively fingerprint complex matrices. Resource- and time-saving experimental designs were selected; an alternative safer organic solvent was tested and a time-saving and innovative response entitled the green chromatographic fingerprinting response was developed and employed. This procedure was applied in the development of chromatographic fingerprints for extracts of Bauhinia forficata and Casearia sylvestris. Moreover, the response proposed here can be combined with a complementary metric available in the literature to compare methods using different solvents. According to this, the chromatographic fingerprints developed here using ethanol as the organic solvent provided a performance better than that of reference methods in which more harmful acetonitrile or methanol were employed. PMID- 24166820 TI - CHO cell culture longevity and recombinant protein yield are enhanced by depletion of miR-7 activity via sponge decoy vectors. AB - Improving the efficiency of recombinant protein production by CHO cells is highly desirable as more complex proteins (MAbs, fusion proteins, blood/clotting factors, etc.) go into development and come onto the market. Previous reports have shown that microRNA (miRNA)-7 overexpression arrests the growth of CHO cells and that its depletion increases the proliferation of various cell types. In this study we generated stable CHO clones that overexpressed a miR-7-specific decoy transcript (sponge) downstream of a green fluorescent protein reporter gene. The miR-7 sponge efficiently diverted miR-7 away from its endogenous targets as exemplified by the increased expression of CDC7. Although the sponge effectively sequestered miR-7, it also appeared to protect the bound miRNA sequence from degradation in the cell, as exemplified by the apparent increase in mature miR-7 levels without any change in primary transcription. Phenotypically, CHO clones with sequestered miR-7 displayed improved maximum cell density (40%), significantly improved viability and an almost two-fold increase in yield of secreted protein in a fed-batch culture. These findings demonstrate that miRNA sponge transcripts could potentially be used in cell line development projects to generate producer clones that grow to higher densities and last longer in the bioreactor - thereby improving product yield. PMID- 24166821 TI - Crystal and electronic structure of the lithium-rich silver silicide Li12Ag(1 x)Si4 (x=0.15). PMID- 24166822 TI - Asthma-predictive-index, bronchial-challenge, sputum eosinophils in acutely wheezing preschoolers. AB - BACKGROUND: Most preschoolers with viral wheezing exacerbations are not atopic. AIM: To test in a prospective controlled trial whether wheezing preschoolers presenting to the ED are different from the above in three different domains defining asthma: the atopic characteristics based on stringent asthma predictive index (S-API), the characteristics of bronchial hyper-responsiveness (BHR), and airway inflammation. METHODS: The S-API was prospectively collected in 41 preschoolers (age 31.9 +/- 17.4 months, range; 1-6 years) presenting to the ED with acute wheezing and compared to healthy preschoolers (n = 109) from our community (community control group). Thirty out of the 41 recruited preschoolers performed two sets of bronchial challenge tests (BCT)-(methacholine and adenosine) within 3 weeks and following 3 months of the acute event and compared to 30 consecutive ambulatory preschoolers, who performed BCT for diagnostic workup in our laboratory (ambulatory control group). On presentation, induced sputum (IS) was obtained from 22 of the 41 children. OUTCOMES: Primary: S-API, secondary: BCTs characteristics and percent eosinophils in IS. RESULTS: Significantly more wheezing preschoolers were S-API positive compared with the community control group: 20/41 (48.7%) versus 15/109 (13.7%, P < 0.001). All methacholine-BCTs-30/30 (100%) were positive compared with 13/14 (92.8%) in the ambulatory control group (P = 0.32). However, 23/27 (85.2%) were adenosine-BCT positive versus 3/17 (17.5%) in the ambulatory control group (P < 0.001). Diagnostic IS success rate was 18/22 (81.8%). Unexpectedly, 9/18 (50.0%) showed eosinophilia in the IS. CONCLUSIONS: Wheezing preschoolers presenting to the ED is a unique population with significantly higher rate of positive S-API and adenosine-BCT compared with controls and frequently (50%) express eosinophilic airway inflammation. PMID- 24166823 TI - Olfactory ensheathing cells, but not Schwann cells, proliferate and migrate extensively within moderately X-irradiated juvenile rat brain. AB - Olfactory ensheathing cells (OECs) and Schwann cells (SCs) share many characteristics, including the ability to promote neuronal repair when transplanted directly into spinal cord lesions, but poor survival and migration when transplanted into intact adult spinal cord. Interestingly, transplanted OECs, but not SCs, migrate extensively within the X-irradiated (40 Gy) adult rat spinal cord, suggesting distinct responses to environmental cues [Lankford et al., (2008) GLIA 56:1664-1678]. In this study, GFP-expressing OECs and SCs were transplanted into juvenile rat brains (hippocampus) subjected to a moderate radiation dose (16 Gy). As in the adult spinal cord, OECs, but not SCs, migrated extensively within the irradiated juvenile rat brain. Unbiased stereology revealed that the number of OECs observed within irradiated rat brains three weeks after transplantation was as much as 20 times greater than the number of cells transplanted, and the cells distributed extensively within the brain. In conjunction with the OEC dispersion, the number of activated microglia in OEC transplanted irradiated brains was reduced. Unlike in the intact adult spinal cord, both OECs and SCs showed some, but limited, migration within nonirradiated rat brains, suggesting that the developing brain may be a more permissive environment for cell migration than the adult CNS. These results show that OECs display unique migratory, proliferative, and microglia interaction properties as compared with SCs when transplanted into the moderately X-irradiated brain. PMID- 24166824 TI - A comparison of computer-generated and naturally occurring foraging patterns in route-network-constrained spider monkeys. AB - The attribution of goal-directed behavior to observations of primate foraging and ranging requires that simpler explanations for observed behavior patterns be eliminated. Computer-generated simulations of non-goal-directed foraging behavior can be used as null models for higher complexity cognitive foraging, and can provide quantifiable data against which to compare the observed behavioral patterns in wild primates. In this paper, we compare the results of two variations of computer simulated null models with observed foraging behavior of wild spider monkeys (Ateles belzebuth). One model simulates monkeys searching using a modified random-walk model in which monkeys alternate 100-m steps with turn angles derived from observed behavior. The second model constrains travel to an observed route system derived from observations of wild spider monkeys. Simulated monkeys in each model searched among increasing densities of feeding trees ranging from 10 to 1,000. We compared travel distance, travel directness, and accuracy of starting direction for each feeding tree discovered for the two models. We then compared these results with those derived from observations of wild spider monkeys. Route-model monkeys traveled shorter distances and more directly to feeding trees than did randomly foraging monkeys, and discovered trees in the direction they started more often. Observed spider monkeys outperformed simulated monkeys from both models in all variables, allowing us to reject the null hypothesis that observed foraging and ranging behavior could be explained by non-goal-directed travel. PMID- 24166825 TI - Controlling and predicting crystal shapes: the case of urea. PMID- 24166826 TI - Capillary electrophoresis separation of the desamino degradation products of oxytocin. AB - Oxytocin (OT) is an endogenous and therapeutic hormone necessary for maternal health. It is also the subject of fast growing research in the field of behavioral science. This article describes a rapid CE method using UV detection at 214 nm for the determination of the deamidation products of OT. Deamidation is the most common degradation pathway of peptides and proteins and can lead to reduced therapeutic efficiency of biopharmaceuticals. To achieve a separation of the seven structurally similar desamino peptides from OT, 11 mM sulfobutyl ether beta-CD and 10% v/v MeOH were added to a BGE of 50 mM phosphate buffer at pH 6.0. The assay is linear within <=5-100 MUM for all species with a total analysis time of 12 min. The method was then applied to monitor the heat-stress degradation of OT at 70 degrees C, where all seven desamino species were observed over a 96 h period. PMID- 24166827 TI - Relationship between wingbeat frequency and resonant frequency of the wing in insects. AB - In this study, we experimentally studied the relationship between wingbeat frequency and resonant frequency of 30 individuals of eight insect species from five orders: Odonata (Sympetrum flaveolum), Lepidoptera (Pieris rapae, Plusia gamma and Ochlodes), Hymenoptera (Xylocopa pubescens and Bombus rupestric), Hemiptera (Tibicen linnei) and Coleoptera (Allomyrina dichotoma). The wingbeat frequency of free-flying insects was measured using a high-speed camera while the natural frequency was determined using a laser displacement sensor along with a Bruel and Kjaer fast Fourier transform analyzer based on the base excitation method. The results showed that the wingbeat frequency was related to body mass (m) and forewing area (Af), following the proportionality f ~ m(1/2)/Af, while the natural frequency was significantly correlated with area density (f0 ~ mw/Af, mw is the wing mass). In addition, from the comparison of wingbeat frequency to natural frequency, the ratio between wingbeat frequency and natural frequency was found to be, in general, between 0.13 and 0.67 for the insects flapping at a lower wingbeat frequency (less than 100 Hz) and higher than 1.22 for the insects flapping at a higher wingbeat frequency (higher than 100 Hz). These results suggest that wingbeat frequency does not have a strong relation with resonance frequency: in other words, insects have not been evolved sufficiently to flap at their wings' structural resonant frequency. This contradicts the general conclusion of other reports--that insects flap at their wings' resonant frequency to take advantage of passive deformation to save energy. PMID- 24166828 TI - Impaired response inhibition is associated with self-reported symptoms of depression, anxiety, and ADHD in female FMR1 premutation carriers. AB - Fragile X Mental Retardation 1 (FMR1) premutation carriers (PM-carriers) have a defective trinucleotide expansion on the FMR1 gene that is associated with continuum of neuropsychological and mental disorders. Currently, little is known about the distinct subcomponents of executive function potentially impaired in female PM-carriers, and there have been no investigations into associations between executive function and incidences of mental disorders. A total of 35 female PM-carriers confirmed by Asuragen triple primed PCR DNA testing and 35 age and intelligence-matched controls completed tests of executive function (i.e., response inhibition and working memory) and self-reported on social anxiety, depression, and ADHD predominantly inattentive (ADHD-PI) symptoms. Compared to controls, PM-carriers were significantly elevated on self-reported social anxiety and ADHD-PI symptoms. Irrespective of mental symptoms, female PM-carries performed significantly worse than controls on a response inhibition test, and further investigations revealed significant correlations between executive function performance and self-reported symptoms of anxiety, depression and ADHD PI. Critically, among PM-carriers with good executive function performance, no women exceeded threshold markers for probable caseness of mental disorder. However, rates of probable caseness were elevated in those with average performance (response inhibition: social anxiety: 41.7%; depression: 20%; ADHD: 44.4%; working memory: social anxiety: 27.3%; depression: 9.1%; ADHD: 18.2%) and highly elevated for those with poor executive function performance (response inhibition: social anxiety: 58.3%; depression: 80%; ADHD: 55.6%; working memory: social anxiety: 100%; depression: 50%; ADHD: 83.3%). These data suggest that subtle executive dysfunction may be a useful neuropsychological indicator for a range of mental disorders previously reported in female PM-carriers. PMID- 24166829 TI - Mutations and polymorphisms in the human argininosuccinate lyase (ASL) gene. AB - Argininosuccinate lyase deficiency (ASLD) is caused by a defect of the urea cycle enzyme argininosuccinate lyase (ASL) encoded by the ASL gene. Patients often present early after birth with hyperammonemia but can also manifest outside the neonatal period mainly triggered by excessive protein catabolism. Clinical courses comprise asymptomatic individuals who only excrete the biochemical marker, argininosuccinic acid, in urine, and patients who succumb to their first hyperammonemic decompensation. Some patients without any hyperammonemia develop severe neurological disease. Here, we are providing an update on the molecular basis of ASLD by collecting all published (n = 67) as well as novel mutations (n = 67) of the ASL gene. We compile data on all 160 different genotypes ever identified in 223 ASLD patients, including clinical courses whenever available. Finally, we are presenting structural considerations focusing on the relevance of mutations for ASL homotetramer formation. ASLD can be considered as a panethnic disease with only single founder mutations identified in the Finnish (c.299T>C, p.Ile100Thr) and Arab (c.1060C>T, p.Gln354*) population. Most mutations are private with only few genotypes recurring in unrelated patients. The majority of mutations are missense changes including some with more frequent occurrence such as p.Arg12Gln, p.Ile100Thr, p.Val178Met, p.Arg186Trp, p.Glu189Gly, p.Gln286Arg, and p.Arg385Cys. PMID- 24166830 TI - Chromophore-linked substrate (CLS405): probing metallo-beta-lactamase activity and inhibition. AB - Serine- and metallo-beta-lactamases present a threat to the clinical use of nearly all beta-lactam antibiotics, including penicillins, cephalosporins, and carbapenems. Efforts to develop metallo-beta-lactamase (MBL) inhibitors require suitable screening platforms to allow the rapid determination of beta-lactamase activity and efficient inhibition. Unfortunately, the platforms currently available are not ideal for this purpose. Further progress in MBL inhibitor identification requires inexpensive and widely applicable assays. Herein the identification of an inexpensive and stable chromogenic substrate suitable for use in assays of clinically relevant MBLs is described. (6R,7R)-3-((4 Nitrophenoxy)methyl)-8-oxo-7-(2-phenylacetamido)-5-thia-1-azabicyclo[4.2.0]oct-2 ene-2-carboxylic acid 5,5-dioxide (CLS405) was synthesised in a three-step protocol. CLS405 was then characterised spectroscopically, and its stability and kinetic properties evaluated. With a Deltalambdamax value of 100 nm between the parent and hydrolysis product, a higher analytical accuracy is possible with CLS405 than with commonly used chromogenic substrates. The use of CLS405 in assays was validated by MBL activity measurements and inhibitor screening that resulted in the identification of N-hydroxythiazoles as new inhibitor scaffolds for MBLs. Further evaluation of the identified N-hydroxythiazoles against a panel of clinically relevant MBLs showed that they possess inhibitory activities in the mid- to low-micromolar range. The findings of this study provide both a useful tool compound for further inhibitor identification, and novel scaffolds for the design of improved MBL inhibitors with potential as antibiotics against resistant strains of bacteria. PMID- 24166831 TI - Identification of a molecular target of a novel fungal metabolite, pyrrolizilactone, by phenotypic profiling systems. AB - In the course of screening our microbial metabolite fraction library, we identified a novel pyrrolizidinone compound, pyrrolizilactone. In this study, we report the identification and characterization of a molecular target for pyrrolizilactone by using two phenotypic profiling systems. Cell morphology-based profiling analysis using an imaging cytometer (MorphoBase) classified pyrrolizilactone as a proteasome inhibitor. Consistently, proteome-based profiling analysis using 2D difference gel electrophoresis (DIGE; ChemProteoBase) also demonstrated that pyrrolizilactone is associated with proteasome inhibition. On the basis of these predictions, we determined that pyrrolizilactone is a novel type of proteasome inhibitor inhibiting the trypsin-like activity of the proteasome. PMID- 24166833 TI - Biophysical approaches for investigation of the cytoskeleton. A special issue stemming from research presented at the 2012 ECF meeting: a FEBS/EMBO workshop lecture course in Pecs, Hungary. PMID- 24166832 TI - Phase II trial of biweekly gemcitabine and paclitaxel with recurrent or metastatic squamous cell carcinoma of the head and neck: Southwest Oncology Group study S0329. AB - BACKGROUND: A phase I study and an institutional pilot study in patients with metastatic/recurrent squamous cell carcinoma of the head and neck (SCCHN) utilizing biweekly gemcitabine and paclitaxel (GEMTAX), showed an overall response rate of 53%. 1 This phase II trial was conducted to determine the feasibility, tolerability, and efficacy of this combination. METHODS: Patients with metastatic/recurrent SCCHN were treated with gemcitabine (3000 mg/m2) and paclitaxel (150 mg/m2) on days 1 and 15 of every 28-day cycle. RESULTS: In 57 patients with measurable disease, median progression-free survival (PFS) was 4 months and median overall survival (OS) was 8 months. Overall response rate of 28% and disease stabilization in 19% were seen. There were no treatment-related deaths with grade 3/4 hematologic toxicity seen in 20% of the patients. CONCLUSION: Biweekly GEMTAX is feasible, well tolerated, and demonstrated reasonable efficacy. This may be an alternative for patients who are not candidates for platinum-based chemotherapy. PMID- 24166834 TI - Chromosomal translocations and karyotype complexity in chronic lymphocytic leukemia: a systematic reappraisal of classic cytogenetic data. AB - The significance of chromosomal translocations (CTRAs) and karyotype complexity (KC) in chronic lymphocytic leukemia (CLL) remains uncertain. To gain insight into these issues, we evaluated a series of 1001 CLL cases with reliable classic cytogenetic data obtained within 6 months from diagnosis before any treatment. Overall, 320 cases were found to carry >= 1 CTRAs. The most frequent chromosome breakpoints were 13q, followed by 14q, 18q, 17q, and 17p; notably, CTRAs involving chromosome 13q showed a wide spectrum of translocation partners. KC (>= 3 aberrations) was detected in 157 cases and significantly (P < 0.005) associated with unmutated IGHV genes and aberrations of chromosome 17p. Furthermore, it was identified as an independent prognostic factor for shorter time-to-first treatment. CTRAs were assigned to two categories (i) CTRAs present in the context of KC, often with involvement of chromosome 17p aberrations, occurring mostly in CLL with unmutated IGHV genes; in such cases, we found that KC rather than the presence of CTRAs per se negatively impacts on survival; (ii) CTRAs in cases without KC, having limited if any impact on survival. On this evidence, we propose that all CTRAs in CLL are not equivalent but rather develop by different processes and are associated with distinct clonal behavior. PMID- 24166836 TI - Announcing two new features of the American Journal of Primatology. PMID- 24166837 TI - A dinuclear ruthenium(II) complex as a one- and two-photon luminescent probe for biological Cu(2+) detection. AB - A new dinuclear Ru(II) polypyridyl complex, [(bpy)2 Ru(H2 bpip)Ru(bpy)2 ](4+) (RuH2 bpip, bpy=2,2-bipyridine, H2 bpip=2,6-pyridyl(imidazo[4,5 f][1,10]phenanthroline), was developed to act as a one- and two-photon luminescent probe for biological Cu(2+) detection. This Ru(II) complex shows a significant two-photon absorption cross section (400 GM) and displays a remarkable one- and two-photon luminescence switch in the presence of Cu(2+) ions. Importantly, RuH2 bpip can selectively recognise Cu(2+) in aqueous media in the presence of other abundant cellular cations (such as Na(+) , K(+) , Mg(2+) , and Ca(2+) ), trace metal ions in organisms (such as Zn(2+) , Ag(+) , Fe(3+) , Fe(2+) , Ni(2+) , Mn(2+) , and Co(2+) ), prevalent toxic metal ions in the environment (such as Cd(2+) , Hg(2+) , and Cr(3+) ), and amino acids, with high sensitivity (detection limit<=3.33*10(-8) M) and a rapid response time (<=15 s). The biological applications of RuH2 bpip were also evaluated and it was found to exhibit low cytotoxicity, good water solubility, and membrane permeability; RuH2 bpip was, therefore, employed as a sensing probe for the detection of Cu(2+) in living cells and zebrafish. PMID- 24166838 TI - Adolescence: challenges and responses. PMID- 24166835 TI - Role of TGF-beta in a mouse model of high turnover renal osteodystrophy. AB - Altered bone turnover is a key pathologic feature of chronic kidney disease mineral and bone disorder (CKD-MBD). Expression of TGF-beta1, a known regulator of bone turnover, is increased in bone biopsies from individuals with CKD. Similarly, TGF-beta1 mRNA and downstream signaling is increased in bones from jck mice, a model of high-turnover renal osteodystrophy. A neutralizing anti-TGF-beta antibody (1D11) was used to explore TGF-beta's role in renal osteodystrophy. 1D11 administration to jck significantly attenuated elevated serum osteocalcin and type I collagen C-telopeptides. Histomorphometric analysis indicated that 1D11 administration increased bone volume and suppressed the elevated bone turnover in a dose-dependent manner. These effects were associated with reductions in osteoblast and osteoclast surface areas. Micro-computed tomography (uCT) confirmed the observed increase in trabecular bone volume and demonstrated improvements in trabecular architecture and increased cortical thickness. 1D11 administration was associated with significant reductions in expression of osteoblast marker genes (Runx2, alkaline phosphatase, osteocalcin) and the osteoclast marker gene, Trap5. Importantly, in this model, 1D11 did not improve kidney function or reduce serum parathyroid hormone (PTH) levels, indicating that 1D11 effects on bone are independent of changes in renal or parathyroid function. 1D11 also significantly attenuated high-turnover bone disease in the adenine induced uremic rat model. Antibody administration was associated with a reduction in pSMAD2/SMAD2 in bone but not bone marrow as assessed by quantitative immunoblot analysis. Immunostaining revealed pSMAD staining in osteoblasts and osteocytes but not osteoclasts, suggesting 1D11 effects on osteoclasts may be indirect. Immunoblot and whole genome mRNA expression analysis confirmed our previous observation that repression of Wnt/beta-catenin expression in bone is correlated with increased osteoclast activity in jck mice and bone biopsies from CKD patients. Furthermore, our data suggest that elevated TGF-beta may contribute to the pathogenesis of high-turnover disease partially through inhibition of beta catenin signaling. PMID- 24166839 TI - The PTEN inhibitor bisperoxovanadium enhances myelination by amplifying IGF-1 signaling in rat and human oligodendrocyte progenitors. AB - Oligodendrocytes (OLGs) produce and maintain myelin in the central nervous system (CNS). In the demyelinating autoimmune disease multiple sclerosis, OLGs are damaged and those remaining fail to fully remyelinate CNS lesions. Therefore, current therapies directed to restrain the inflammation process with approaches that protect and reconstitute oligodendrocyte density would be essential to pave the way of myelin repair. A critical signal for oligodendrocytes is insulin-like growth factor-1 (IGF-1), which promotes their development and ultimately myelin formation. PTEN inhibits the phosphoinositide 3-kinase (PI3K)/Akt signaling, a convergence downstream pathway for growth factors such as IGF-1. In this report, we temporarily inhibited PTEN activity by treating rat and human oligodendrocyte progenitors (OLPs) cultured alone or with dorsal root ganglion neurons (DRGNs) with bisperoxovanadium (phen). Our findings show that phen potentiates IGF-1 actions by increasing proliferation of OLPs in a concentration-dependent manner, and caused a sustained and time-dependent activation of the main pathways: PI3K/Akt/mammalian target of rapamycin (mTOR) and MEK/ERK. At low concentrations, IGF-1 and phen stimulated the differentiation of rat and human OLPs. Concordantly, the PTEN inhibitor together with IGF-1 robustly augmented myelin basic protein accumulation in rat newborn and human fetal OLGs co-cultured with DRGNs in a longer timeframe by promoting the elaboration of organized myelinated fibers as evidenced by confocal microscopy. Thus, our results suggest that a transient suppression of a potential barrier for myelination in combination with other therapeutic approaches including growth factors may be promising to improve the functional recovery of CNS injuries. PMID- 24166840 TI - Microcalorimetric measurements of the solvent contribution to the entropy changes upon electrochemical lithium bulk deposition. PMID- 24166844 TI - Direct amidation from alcohols and amines through a tandem oxidation process catalyzed by heterogeneous-polymer-incarcerated gold nanoparticles under aerobic conditions. AB - We describe herein a highly elegant and suitable synthesis of amide products from alcohols and amines through a tandem oxidation process that uses molecular oxygen as a terminal oxidant. Carbon-black-stabilized polymer-incarcerated gold (PICB Au) or gold/cobalt (PICB-Au/Co) nanoparticles were employed as an efficient heterogeneous catalyst depending on alcohol reactivity and generated only water as the major co-product of the reaction. A wide scope of substrate applicability was shown with 42 examples. The catalysts could be recovered and reused without loss of activity by using a simple operation. PMID- 24166841 TI - Copper-assisted click reactions for activity-based proteomics: fine-tuned ligands and refined conditions extend the scope of application. AB - Copper-catalysed alkyne-azide 1,3-dipolar cycloaddition (CuAAC) is the predominantly used bioconjugation method in the field of activity-based protein profiling (ABPP). Several limitations, however, including conversion efficiency, protein denaturation and buffer compatibility, restrict the scope of established procedures. We introduce an ABPP customised click methodology based on refined CuAAC conditions together with new accelerating copper ligands. A screen of several triazole compounds revealed the cationic quaternary {3-[4-({bis[(1-tert butyl-1H-1,2,3-triazol-4-yl)methyl]amino}methyl)-1H-1,2,3-triazol-1 yl]propyl}trimethylammonium trifluoroacetate (TABTA) to be a superior ligand. TABTA exhibited excellent in vitro conjugation kinetics and optimal ABPP labelling activity while almost exclusively preserving the native protein fold. The application of this CuAAC-promoting system is amenable to existing protocols with minimal perturbations and is even compatible with previously unusable buffer systems such as Tris?HCl. PMID- 24166845 TI - Differing associations of BMI and body fat with asthma and lung function in children. AB - BACKGROUND: Current evidence suggests that in children there is a significant, albeit weak, association between asthma and obesity. Studies generally use body mass index (BMI) in evaluating body adiposity, but there are limitations to its use. METHOD: Children from a population-based study attending follow-up (age 11 years) were weighed, measured and had percent body (PBF) and truncal (PTF) fat assessed using bioelectrical impedance. They were skin prick tested and completed spirometry. Parents completed a validated respiratory questionnaire. Children were defined as normal or overweight according to BMI and PBF cut-offs. We tested the association between these adiposity markers with wheeze, asthma, atopy, and lung-function. RESULTS: Six hundred forty-six children (339 male) completed follow-up. BMI z-score, PBF, and PTF were all positively associated with current wheeze (odds ratio [95% CI]: 1.27 [1.03, 1.57], P = 0.03; 1.05 [1.00, 1.09], P = 0.03; 1.04 [1.00, 1.08], P = 0.04, respectively). Similar trends were seen with asthma. However, when examining girls and boys separately, significant positive associations were found with PBF and PTF and asthma but only in girls (gender interaction P = 0.06 and 0.04, respectively). Associations between being overweight and wheezing and asthma were stronger when overweight was defined by PBF (P = 0.007, 0.03) than BMI (P > 0.05). Higher BMI was significantly associated with an increase in FEV(1) and FVC, but only in girls. Conversely, increasing body fat (PBF and PTF) was associated with reduced FEV(1) and FVC, but only in boys. No associations between adiposity and atopy were found. CONCLUSION: All adiposity measures were associated with wheeze, asthma, and lung function. However, BMI and PBF did not have the same effects and girls and boys appear to be affected differently. PMID- 24166847 TI - Clinicopathologic predictors of recurrence and overall survival in adenoid cystic carcinoma of the head and neck: a single institutional experience at a tertiary care center. AB - BACKGROUND: The purpose of this study was to determine factors that impact recurrence and long-term survival of head and neck adenoid cystic carcinoma (ACC). METHODS: We conducted a retrospective review of 87 patients with head and neck ACC who were evaluated between 1992 and 2009. Staining for Ki-67, p53, alpha estrogen receptor (alphaER), and progesterone receptor (PR) was performed. RESULTS: Forty men (46%) and 47 women (54%) were included in this study. Median follow-up for patients was 98 months. Five-year recurrence-free and overall survival (OS) rates were 56% and 81%, respectively. Ki-67 and p53 expression was observed in 5 (6%) and 2 (2%) patients, respectively. alphaER and PR were all negative. The most important determinants of disease-free survival (DFS) were perineural invasion (PNI; p = .001) and female sex (p = .027). Disease site (major vs minor salivary gland) was the only predictor of worse OS on multivariate analysis. CONCLUSION: Perineural invasion, female sex, and disease site were the most consistent predictors of poor outcome in head and neck ACC. PMID- 24166846 TI - A homozygous PDE6D mutation in Joubert syndrome impairs targeting of farnesylated INPP5E protein to the primary cilium. AB - Joubert syndrome (JS) is characterized by a distinctive cerebellar structural defect, namely the << molar tooth sign >>. JS is genetically heterogeneous, involving 20 genes identified to date, which are all required for cilia biogenesis and/or function. In a consanguineous family with JS associated with optic nerve coloboma, kidney hypoplasia, and polydactyly, combined exome sequencing and mapping identified a homozygous splice-site mutation in PDE6D, encoding a prenyl-binding protein. We found that pde6d depletion in zebrafish leads to renal and retinal developmental anomalies and wild-type but not mutant PDE6D is able to rescue this phenotype. Proteomic analysis identified INPP5E, whose mutations also lead to JS or mental retardation, obesity, congenital retinal dystrophy, and micropenis syndromes, as novel prenyl-dependent cargo of PDE6D. Mutant PDE6D shows reduced binding to INPP5E, which fails to localize to primary cilia in patient fibroblasts and tissues. Furthermore, mutant PDE6D is unable to bind to GTP-bound ARL3, which acts as a cargo-release factor for PDE6D bound INPP5E. Altogether, these results indicate that PDE6D is required for INPP5E ciliary targeting and suggest a broader role for PDE6D in targeting other prenylated proteins to the cilia. This study identifies PDE6D as a novel JS disease gene and provides the first evidence of prenyl-binding-dependent trafficking in ciliopathies. PMID- 24166848 TI - Application of an efficient strategy based on liquid-liquid extraction, high speed counter-current chromatography, and preparative HPLC for the rapid enrichment, separation, and purification of four anthraquinones from Rheum tanguticum. AB - This study presents an efficient strategy based on liquid-liquid extraction, high speed counter-current chromatography, and preparative HPLC for the rapid enrichment, separation, and purification of four anthraquinones from Rheum tanguticum. A new solvent system composed of petroleum ether/ethyl acetate/water (4:2:1, v/v/v) was developed for the liquid-liquid extraction of the crude extract from R. tanguticum. As a result, emodin, aloe-emodin, physcion, and chrysophanol were greatly enriched in the organic layer. In addition, an efficient method was successfully established to separate and purify the above anthraquinones by high-speed counter-current chromatography and preparative HPLC. This study supplies a new alternative method for the rapid enrichment, separation, and purification of emodin, aloe-emodin, physcione, and chrysophanol. PMID- 24166849 TI - Burrowing behaviour of robotic bivalves with synthetic morphologies. AB - Several bivalve species burrow into sandy sediments to reach their living position. There are many hypotheses concerning the functional morphology of the bivalve shell for burrowing. Observational studies are limited and often qualitative and should be complemented by a synthetic approach mimicking the burrowing process using a robotic emulation. In this paper we present a simple mechatronic set-up to mimic the burrowing behaviour of bivalves. As environment we used water and quartz sand contained in a glass tank. Bivalve shells were mathematically modelled on the computer and then materialized using a 3D printer. The burrowing motion of the shells was induced by two external linear motors. Preliminary experiments did not expose any artefacts introduced to the burrowing process by the set-up. We tested effects of shell size, shape and surface sculpturing on the burrowing performance. Neither the typical bivalve shape nor surface sculpture did have a clear positive effect on burrowing depth in the performed experiments. We argue that the presented method is a valid and promising approach to investigate the functional morphology of bivalve shells and should be improved and extended in future studies. In contrast to the observation of living bivalves, our approach offers complete control over the parameters defining shell morphology and motion pattern. The technical set-up allows the systematic variation of all parameters to quantify their effects. The major drawback of the built set-up was that the reliability and significance of the results was limited by the lack of an optimal technique to standardize the sediment state before experiments. PMID- 24166851 TI - Variability is the law of life. PMID- 24166850 TI - Specific macrothrombocytopenia/hemolytic anemia associated with sitosterolemia. AB - Sitosterolemia (phytosterolemia) is a rare inherited sterol storage disorder, characterized by significantly elevated plasma levels of plant sterols. The clinical features of sitosterolemia are xanthomas, premature atherosclerosis, arthritis, and, occasionally, liver function impair and hematologic abnormalities. This disorder is caused by mutations of ABCG5/ABCG8 genes. We report here the clinical, laboratory, and molecular genetic features of 13 patients with sitosterolemia from eight unrelated families who had specific hematologic problems of macrothrombocytopenia, hemolytic anemia, and splenomegaly besides the major clinical manifestations. The peripheral blood films showed some unique features: large platelets surrounded by a circle of vacuoles, and various abnormal erythrocyte shapes, especially stomatocyte. According to these distinct changes of blood cell morphology, we identified two sitosterolemia patients who lacked the classical clinical phenomena. All the patients had been misdiagnosed with immune thrombocytopenia (ITP), Evans syndrome, or secondary ITP with delay being 28.8 years between symptom onset and correct diagnosis. These results indicate that sitosterolemia is certainly not as rare as originally thought. The phenomena of macrothrombocytopenia/hemolysis might represent a new platelet disorder. Plasma plant sterols and ABCG5/ABCG8 genes should be analyzed when such hematologic abnormalities are unexplained. PMID- 24166852 TI - Spatial foraging in free ranging bearded sakis: traveling salesmen or Levy Walkers? AB - According to optimal foraging theory and most current models of primate socioecology, primate foraging involves a series of decisions concerning when is the most optimal time to leave a food patch, how to travel to the next patch in an efficient manner, and how to minimize the time and distance traveled to all patches throughout the course of the day. In this study, I assess how bearded sakis solve these challenges by presenting data on their patch use, distance minimization, and by comparing their movements with non-deterministic foraging patterns. The study group, composed of 38 +/- 15 individuals, fed significantly longer in higher quality patches (quality defined by patch size and productivity) and in those that contained ripe fruit pulp. However, group size was not a significant predictor of patch occupancy. Bearded sakis traveled relatively directly between food patches, sometimes over distances > 300 m. In addition, they chose the optimal daily path among all patches visited on 9 of 17 occasions, and on average traveled only 21% more than the least distance route. Bearded saki step lengths were consistent with a Brownian rather than a Levy Walk pattern while waiting times were consistent with a Levy pattern. However, the distribution of their turning angles indicated a high degree of directional persistence between patches. These results suggest that bearded sakis exploit food patches that are randomly distributed spatially but heterogenous in patch quality. They appear to encode the locations of high quality food patches and minimize travel between them, despite opportunistically feeding from more abundant and randomly distributed, lower quality patches en route. PMID- 24166853 TI - The bright side of stress-induced eating: eating more when stressed but less when pleased. AB - Previous research suggests that approximately 40% to 50% of the population increase food consumption under stressful conditions. The prevailing view is that eating in response to stress is a type of maladaptive self-regulation. Past research has concentrated mainly on the negative effects of social stress on eating. We propose that positive social experiences may also modulate eating behavior. In the present study, participants were assigned to social-exclusion, neutral, and social-inclusion conditions. In a subsequent bogus taste test, the amount of ice cream eaten and habitual stress-related eating were measured. After being socially excluded, people who habitually eat more in response to stress (stress hyperphagics) ate significantly more than people who habitually eat less in response to stress (stress hypophagics). Conversely, after being socially included, stress hyperphagics ate significantly less than stress hypophagics. The present findings provide the first evidence for complementary adjustments of food consumption across positive and negative situations. Implications of these findings for the relationship of stress and body weight are discussed. PMID- 24166854 TI - Trust in me: trustworthy others are seen as more physically similar to the self. PMID- 24166855 TI - The morning morality effect: the influence of time of day on unethical behavior. AB - Are people more moral in the morning than in the afternoon? We propose that the normal, unremarkable experiences associated with everyday living can deplete one's capacity to resist moral temptations. In a series of four experiments, both undergraduate students and a sample of U.S. adults engaged in less unethical behavior (e.g., less lying and cheating) on tasks performed in the morning than on the same tasks performed in the afternoon. This morning morality effect was mediated by decreases in moral awareness and self-control in the afternoon. Furthermore, the effect of time of day on unethical behavior was found to be stronger for people with a lower propensity to morally disengage. These findings highlight a simple yet pervasive factor (i.e., the time of day) that has important implications for moral behavior. PMID- 24166856 TI - Look here, eye movements play a functional role in memory retrieval. AB - Research on episodic memory has established that spontaneous eye movements occur to spaces associated with retrieved information even if those spaces are blank at the time of retrieval. Although it has been claimed that such looks to "nothing" can function as facilitatory retrieval cues, there is currently no conclusive evidence for such an effect. In the present study, we addressed this fundamental issue using four direct eye manipulations in the retrieval phase of an episodic memory task: (a) free viewing on a blank screen, (b) maintaining central fixation, (c) looking inside a square congruent with the location of the to-be recalled objects, and (d) looking inside a square incongruent with the location of the to-be-recalled objects. Our results provide novel evidence of an active and facilitatory role of gaze position during memory retrieval and demonstrate that memory for the spatial relationship between objects is more readily affected than memory for intrinsic object features. PMID- 24166857 TI - Saccades toward the target are planned as sequences rather than as single steps. AB - To find a target during visual search, observers often need to make multiple eye movements, which results in a scan path. It is an open question whether the saccade destinations in scan paths are planned ahead. In the two experiments reported here, we investigated this question by focusing on the observer's ability to deviate from potentially planned paths. In the first experiment, the stimulus configuration could change during the initial saccade. We found that the observer's ability to deviate from potentially planned paths crucially depended on whether altered configurations could be processed with sufficient rapidity. In a follow-up experiment, we asked whether planned paths can include more than two saccade destinations. Investigating the influence of potentially planned paths on a secondary task demonstrated that planned paths can include at least three saccade destinations. Together, these experiments provide the first evidence of scan-path planning in visual search. PMID- 24166858 TI - Dynamic microparticle manipulation with an electroosmotic flow gradient in low frequency alternating current dielectrophoresis. AB - In this study, the potential of low-frequency AC insulator-based DEP (iDEP) was explored for the separation of polystyrene microparticles and yeast cells. An EOF gradient was generated by employing an asymmetrical, 20 Hz AC electrical signal in an iDEP device consisting of a microchannel with diamond-shaped insulating posts. Two types of samples were analyzed, the first sample contained three types of polystyrene particles with different diameters (0.5, 1.0, and 2.0 MUm) and the second sample contained two types of polystyrene particles (1.0 and 2 MUm) and yeast cells (6.3 MUm). This particular scheme uses a tapered AC signal that allows for all particles to be trapped and concentrated at the insulating post array, as the signal becomes asymmetrical (more positive), particles are selectively released. The smallest particles in each sample were released first, since they require greater dielectrophoretic forces to remain trapped. The largest particles in each sample were released last, when the applied signal became cyclical. A dielectropherogram, which is analogous to a chromatogram, was obtained for each sample, demonstrating successful separation of the particles by showing "peaks" of the released particles. These separations were achieved at lower applied potentials than those reported in previous studies that used solely direct current electrical voltages. Additionally, mathematical modeling with COMSOL Multiphysics was carried out to estimate the magnitude of the dielectrophoretic and EOF forces acting on the particles considering the low frequency, asymmetrical AC signal used in the experiments. The results demonstrated the potential of low-frequency AC-iDEP systems for handling and separating complex mixtures of microparticles and biological cells. PMID- 24166859 TI - Immunocytochemical detection of mycobacterial antigen in extrapulmonary tuberculosis. AB - The aim of the study is to determine whether immunostaining for mycobacterial antigen can contribute to the cytological diagnosis of extrapulmonary tuberculosis (EPTB). The study was carried out on aspirated material of lymph nodes, and other accessible sites, from 65 patients with clinical diagnosis of tuberculosis (TB). Twenty patients, diagnosed by fine-needle aspiration, with non tuberculous granulomas served as controls. The diagnosis of TB was based on the demonstration of acid-fast bacilli (AFB), culture positivity for Mycobacterium tuberculosis (M. tuberculosis), or response to treatment with standard anti tubercular therapy. Immunostaining was done using polyclonal antibody to mycobacteria. AFB positivity by Ziehl Neelsen (ZN) staining was 21%, 65.38%, and 68% respectively in Pattern 1 (granulomas alone), in Pattern 2 (granulomas with necrosis), and in Pattern 3 (necrosis alone). Overall AFB positivity was 56.92%. Twenty-eight of 65 cases were negative for AFB on direct smear. Culture was positive in 46% (13/28). Sensitivity and specificity of immunostaining were 96.92% (63/65) and 95%, respectively. Immunoreactivity was seen in 26 (92.8%) of 28 cases which were negative by ZN staining. Except in the case of leprosy, in which cross reactivity was seen, there was no immunoreactivity in the control group. Immunocytochemistry (ICC) had high sensitivity (96.2%) and specificity (95%) in the diagnosis of EPTB. ICC may be a useful adjunct to evaluation of cytomorphology and ZN staining. PMID- 24166860 TI - Ethical considerations surrounding survival benefit-based liver allocation. AB - The disparity between the demand for and supply of donor livers has continued to grow over the last 2 decades, and this has placed greater weight on the need for efficient and effective liver allocation. Although the use of extended criteria donors has shown great potential, it remains unregulated. A survival benefit based model was recently proposed to answer calls to increase efficiency and reduce futile transplants. However, it was previously determined that the current allocation system was not in need of modification and that instead geographic disparities should be addressed. In contrast, we believe that there is a significant need to replace the current allocation system and complement efforts to improve donor liver distribution. We illustrate this need first by identifying major ethical concerns shaping liver allocation and then by using these concerns to identify strengths and shortcomings of the Model for End-Stage Liver Disease/Pediatric End-Stage Liver Disease system and a survival benefit-based model. The latter model is a promising means of improving liver allocation: it incorporates a greater number of ethical principles, uses a sophisticated statistical model to increase efficiency and reduce waste, minimizes bias, and parallels developments in the allocation of other organs. However, it remains limited in its posttransplant predictive accuracy and may raise potential issues regarding informed consent. In addition, the proposed model fails to include quality-of-life concerns and prioritize younger patients. We feel that it is time to take the next steps toward better liver allocation not only through reductions in geographic disparities but also through the adoption of a model better equipped to balance the many ethical concerns shaping organ allocation. Thus, we support the development of a similar model with suggested amendments. PMID- 24166866 TI - Vitamin D does not increase calcium absorption in young women: a randomized clinical trial. AB - It is commonly said that vitamin D should be used to increase calcium absorption. We tested this statement in a dose-response study of vitamin D on calcium absorption. A total of 198 white and African American women, aged 25 to 45 years, with vitamin D insufficiency, serum 25-hydroxyvitamin D (25OHD) <20 ng/mL, were randomized in a double-blind study to vitamin D3 400, 800, 1600, 2400 IU, or placebo. A calcium supplement was given to increase mean calcium intake at baseline from 706 mg/d to 1031 mg/d. Calcium absorption was measured at baseline and after 12 months using a single isotope method with radiocalcium45 and 100 mg of calcium. Mean baseline serum 25OHD was 13.4 ng/mL (33.5 nmol/L) and increased to 40 ng/mL (100 nmol/L) on the highest dose of 2400 IU. Using a multivariate regression analysis with significant predictors, baseline absorption, calcium intake, and weight, there was no increase in 12-month calcium absorption compared with baseline on any dose of vitamin D in either whites or African Americans. There was no significant relationship between 12-month calcium absorption and final serum 25OHD. In an analysis of calcium absorption and serum 25OHD at baseline, serum 25OHD levels were divided into groups: 0 to 5, 6 to 10, 11 to 15, or 16 to 20 ng/mL. There was no evidence of a threshold decrease in calcium absorption or serum 1,25 dihydroxyvitamin D (1,25(OH)2 D) amongst the lowest groups. Vitamin D doses up to 2400 IU daily did not increase calcium absorption. No threshold level of serum 25OHD for calcium absorption was found at baseline or in the longitudinal study, suggesting that active transport of calcium is saturated at very low serum 25OHD levels <5 ng/mL. There is no need to recommend vitamin D for increasing calcium absorption in normal subjects. Very efficient calcium absorption at very low levels of serum 25OHD explains why people do not develop osteomalacia provided that dietary intakes of calcium and phosphorus are adequate. PMID- 24166861 TI - Site-specific basal body duplication in Chlamydomonas. AB - Correct centriole/basal body positioning is required for numerous biological processes, yet how the cell establishes this positioning is poorly understood. Analysis of centriolar/basal body duplication provides a key to understanding basal body positioning and function. Chlamydomonas basal bodies contain structural features that enable specific triplet microtubules to be specified. Electron tomography of cultures enriched in mitotic cells allowed us to follow basal body duplication and identify a specific triplet at which duplication occurs. Probasal bodies elongate in prophase, assemble transitional fibers (TF) and are segregated with a mature basal body near the poles of the mitotic spindle. A ring of nine-singlet microtubules is initiated at metaphase, orthogonal to triplet eight. At telophase/cytokinesis, triplet microtubule blades assemble first at the distal end, rather than at the proximal cartwheel. The cartwheel undergoes significant changes in length during duplication, which provides further support for its scaffolding role. The uni1-1 mutant contains short basal bodies with reduced or absent TF and defective transition zones, suggesting that the UNI1 gene product is important for coordinated probasal body elongation and maturation. We suggest that this site-specific basal body duplication ensures the correct positioning of the basal body to generate landmarks for intracellular patterning in the next generation. PMID- 24166867 TI - Improved synthesis of cyclic tertiary allylic alcohols by asymmetric 1,2-addition of AlMe3 to enones. AB - The development of an improved protocol for the enantioselective Rh(I) /binap catalysed 1,2-addition of AlMe3 to cyclic enones is reported. (31)P NMR analysis of the reaction revealed that the catalyst in its resting state is a chloride bridged dimer. This insight led to the use of AgBF4 as an additive for in situ activation of the dimeric precatalyst. Thus, the catalyst loading can now be reduced to only 1 mol% with respect to rhodium. Various 5-7-membered cyclic enones can be transformed into tertiary allylic alcohols with excellent levels of enantioselectivity and high yields. The obtained products are versatile synthetic building blocks, shown by a highly enantioselective formal total synthesis of the pheromone (-)-frontalin as well as formation of a bicyclic lactone that has the core structure of the natural flavour component "wine lactone". PMID- 24166869 TI - The role of oxidative debris on graphene oxide films. AB - We study the effect of oxidative impurities on the properties of graphene oxide and on the graphene oxide Langmuir-Blodgett films (LB). The starting material was grupo Antolin nanofibers (GANF) and the oxidation process was a modified Hummers method to obtain highly oxidized graphene oxide. The purification procedure reported in this work eliminated oxidative impurities decreasing the thickness of the nanoplatelets. The purified material thus obtained presents an oxidation degree similar to that achieved by chemical reduction of the graphite oxide. The purified and non-purified graphene oxides were deposited onto silicon by means of a Langmuir-Blodgett (LB) methodology. The morphology of the LB films was analyzed by field emission scanning microscopy (FE-SEM) and micro-Raman spectroscopy. Our results show that the LB films built by transferring Langmuir monolayers at the liquid-expanded state of the purified material are constituted by close-packed and non-overlapped nanoplatelets. The isotherms of the Langmuir monolayer precursor of the LB films were interpreted according to the Volmer's model. PMID- 24166868 TI - AgOTf-catalyzed electrophilic cyclization of triynols with NXS: rapid synthesis of densely trisubstituted naphthalenes and quinolines. AB - A silver triflate-catalyzed electrophilic cyclization reaction of acyclic triynols with NXS (X=I, Br) under mild conditions is reported. Three reactive functional groups, such as a carbonyl group, an alkyne group, and a halogen, could be selectively installed at the C1, C2, and C3 positions to obtain the naphthalene and quinoline products, respectively. The obtained densely trisubstituted products could be further transformed into more complex aromatic products by manipulating the alkynyl moiety and the other two functional groups as synthons. PMID- 24166870 TI - Palladium(II)-catalyzed intramolecular hydroamination of 1,3-dienes to give homoallylic amines. PMID- 24166871 TI - Physiological correlates of pulmonary function in children with cystic fibrosis. AB - RATIONALE: Although peak aerobic capacity (VO(2peak)) has been linked to outcome in patients with cystic fibrosis (CF), measuring is time consuming, and requires expensive equipment and expertise that is not readily available in all centers. Other fitness parameters such as peak anaerobic power, measures of power and strength may be simpler to deliver in the clinic. The relationship between these measures and established outcomes such as forced expiratory volume in one second (FEV(1)) and peak aerobic power (VO(2peak)) in CF remains unclear. Therefore we evaluated (a) aerobic fitness, (b) anaerobic fitness, and (c) upper and lower body muscle strength to determine their relationship to FEV(1) and VO(2peak) in children with CF. METHODS: Eighty-two patients (7-18 years) with CF (40 female) from the CF clinic at The Hospital for Sick Children in Toronto performed a maximal incremental cycling test to exhaustion. Anaerobic power (W) for 10 and 30 sec cycling trials as well as vertical jump (VJ) and hand grip strength (HG) were compared to FEV(1) and VO(2peak). RESULTS: Absolute VO(2peak) (R(2) = 0.16, P < 0.001), anaerobic power (R(2) = 0.21, P < 0.001), and hand grip strength (R(2) = 0.10, P = 0.003) were significantly correlated to lung function whereas measures of explosive lower body strength (VJ) were not. Anaerobic power (R(2) = 0.16, P = 0.001) and hand grip strength (R(2) = 0.08, P = 0.01) were related to VO(2peak). Vertical jump was correlated with VO(2peak) (R(2) = 0.29, P < 0.001) but not FEV(1). CONCLUSIONS: Simple fitness tests such as hand grip strength and anaerobic cycle tests may be useful indicators of lung health and fitness. PMID- 24166872 TI - Time trends in T3 to T4 laryngeal cancer: a population-based long-term analysis. AB - BACKGROUND: A decline in laryngectomies and survival in laryngeal cancer has been reported, especially among patients with advanced tumors. METHODS: Of 1058 patients with laryngeal cancer diagnosed from 1978 to 2007 in the Uppsala-Orebro region in Sweden, 263 T3 to T4 tumors treated with curative intent were studied retrospectively. Two time periods were defined, 1978 to 1992 and 1993 to 2007. RESULTS: Glottic tumors decreased constituting 68.6% of cases in 1978 to 1992 and 47.9% in 1993 to 2007. Laryngectomies were performed in 38.8% and 34.5% in the corresponding time periods. The use of laryngectomy was not strongly prognostic. A decline in overall survival (OS) over time could only be identified for the first year of follow-up. Chemotherapy was only used in a minority of cases. CONCLUSION: The marked decrease of glottic site may mark a shift in etiology. Laryngectomy was not strongly associated with improved survival. The absence of improved survival calls for intensified research. PMID- 24166873 TI - Emerging role of microRNAs in cancer and cancer stem cells. AB - Cancer stem cells (CSCs), or cancer cells with stem cell properties, represent a small fraction of tumor bulk and are thought to be responsible for tumor formation and metastasis. However, the mechanisms of how CSCs are generated and regulated at the molecular level are poorly understood. Recent progress has highlighted the significance of microRNAs (miRNAs) in cancer progression and CSC function. The function and dysfunction of miRNAs in the development of cancer and CSCs have become a burgeoning area of intense research. A new finding has elucidated a mechanism of antagonistic miRNA crosstalk whereby one miRNA can inhibit another miRNA in regulating CSCs. Herein we make this short review to summarize the current understanding of the regulatory mechanisms of miRNAs in cancer and CSCs and discuss the implications of targeting CSCs for cancer therapeutics. PMID- 24166874 TI - Analysis of reactive oxygen species, Ca2+ , and Hsp70 in the gill and mantle of clams Ruditapes philippinarum exposed in cadmium. AB - In this study, the probes 2',7'-dichlorofluorescein diacetate (H2 DCF-DA) and Fluo-3 AM were used to investigate the instantaneous change of reactive oxygen species (ROS) and Ca(2+) in the gill and mantle of clams Ruditapes philippinarum exposed in 0.05 mg L(-1) Cd(2+) with the laser-scanning confocal microscopy. The results indicated that Ca(2+) level was declined in the gill and slightly increased in the mantle. The level of ROS was declined in the gill, while the oscillation of ROS level was observed in the mantle. These data revealed that Ca(2+) could stimulate mitochondrial activity and enhance the respiratory chain in the gill and mantle. In addition, the expression of Hsp70 was increased in the gill and mantle of clams exposed in 0.05 mg L(-1) Cd(2+) . The change of Ca(2+) and ROS level affected the expression of Hsp70 in the gill and mantle. An appropriate method was established to analyze the effects of Cd(2+) on ROS, Ca(2+) , and Hsp70 in the gill and mantle of clams with confocal microscopy. Both confocal microscopy and chemical fluorescent are valuable tools for measurement of time-dependent intracellular ROS and Ca(2+) signals. PMID- 24166875 TI - GPU-based acceleration of computations in nonlinear finite element deformation analysis. AB - The physics of deformation for biological soft-tissue is best described by nonlinear continuum mechanics-based models, which then can be discretized by the FEM for a numerical solution. However, computational complexity of such models have limited their use in applications requiring real-time or fast response. In this work, we propose a graphic processing unit-based implementation of the FEM using implicit time integration for dynamic nonlinear deformation analysis. This is the most general formulation of the deformation analysis. It is valid for large deformations and strains and can account for material nonlinearities. The data-parallel nature and the intense arithmetic computations of nonlinear FEM equations make it particularly suitable for implementation on a parallel computing platform such as graphic processing unit. In this work, we present and compare two different designs based on the matrix-free and conventional preconditioned conjugate gradients algorithms for solving the FEM equations arising in deformation analysis. The speedup achieved with the proposed parallel implementations of the algorithms will be instrumental in the development of advanced surgical simulators and medical image registration methods involving soft-tissue deformation. PMID- 24166876 TI - Estimating the elastic properties of few-layer graphene from the free-standing indentation response. AB - Using molecular mechanics simulations, the elastic properties of multi-layer graphene (MLG) are investigated; this includes both the linear analysis based on the indentation load-displacement relationship and the nonlinear analysis based on the strain energy. The elastic properties of graphene layers in MLG are similar to each other and also quite close to those of monolayer graphene. The van der Waals (VDW) interaction between graphene layers (interlayer interaction) will create a difference between the indenter tip displacement and the deviation of MLG in indentation, which will cause an overestimation of the elastic modulus of MLG based on classic indentation analysis. This overestimation can be as high as 20%. In addition, the interlayer interaction will significantly affect the nonlinear elastic behavior of MLG in free-standing indentation. With an increase in the number of layers of MLG, the second-order elastic stiffness of MLG is very sensitive to the indentation loading range, and the third-order nonlinear elastic constant is significantly increased. PMID- 24166877 TI - Friends of Physiology: an interview with Clara Franzini-Armstrong and Clay Armstrong. PMID- 24166879 TI - A six-year experience with anal cytology in women with HPV in the lower genital tract: utility, limitations, and clinical correlation. AB - This study assessed the utility and limitations of anal cytology as a screening method for women infected with human papilloma virus (HPV) in the lower genital tract. Furthermore, this study aimed to establish risk factors for pathological anal cytology/biopsy findings, the prevalence of anatomopathological lesions associated with positive anal brushings, and the frequency of concomitant lesions of the lower genital tract. A cross-sectional, retrospective, descriptive study in 207 women with HPV-associated lesions of the lower genital tract and 25 women with immunosuppression was carried out. Anal cytology, high resolution anoscopy, and biopsy of suspicious lesions were performed. In total, 232 anal brushings were performed: 184 (79.3%) were negative, 24 (10.34%) showed atypical squamous cells of undeterminated significance, 18 (7.7%) showed low-grade squamous intraepithelial lesions, and 6 (2.6%) showed high-grade squamous intraepithelial lesion. Cytohistological correlation was obtained for 70 cases. The sensitivity of anal cytology in detecting intraepithelial lesions was 70%, whereas the specificity was 93%. The sensitivity of the method for detecting high-grade lesions (84%) was higher, than that for detecting low-grade lesions (66%). The most frequently associated pathology was vulvar lesion. It is important to perform anal brushings in women who have had lower genital tract biopsies for HPV associated lesions due to the high prevalence of anal lesions in such patients. Anal cytology is useful for detecting high-grade lesions but the sensitivity for detecting low-grade lesions is low. It is of the utmost importance to perform high-resolution anoscopy and biopsy in women with suspicious lesions in order to confirm the pathology. PMID- 24166880 TI - A method for evaluating the use of fluorescent dyes to track proliferation in cell lines by dye dilution. AB - Labeling nonquiescent cells with carboxyfluorescein succinimidyl ester (CFSE) like dyes gives rise to a population width exceeding the threshold for resolving division peaks by flow cytometry. Width is a function of biological heterogeneity plus extrinsic and intrinsic error sources associated with the measurement process. Optimal cytometer performance minimizes extrinsic error, but reducing intrinsic error to the point of facilitating peak resolution requires careful fluorochrome selection and fluorescent cell sorting. In this study, we labeled the Jurkat and A549 cell lines with CFSE, CellTraceViolet (CTV), and eFluor 670 proliferation dye (EPD) to test if we could resolve division peaks in culture after reducing the labeled input widths by cell sorting. Reanalysis of the sorted populations to ascertain the level of reduction achieved always led to widths exceeding the gated limits due to the contribution of errors. Measuring detector specific extrinsic error by sorting uniform fluorescent particles with similar spectral properties to the tracking dyes allowed us to determine the intrinsic error for each dye and cell type using a simple mathematical approach. We found that cell intrinsic error ultimately dictated whether we could resolve division peaks, and that as this increased, the required sort gate width to resolve any division peaks decreased to the point whereby issues with yield made A549 unsuitable for this approach. Finally, attempts to improve yields by setting two concurrent sort gates on the fluorescence distribution enriched for cells in different stages of the cell cycle that had nonequivalent proliferative properties in culture and thus should be practiced with caution. PMID- 24166878 TI - Structural basis of ion permeation gating in Slo2.1 K+ channels. AB - The activation gate of ion channels controls the transmembrane flux of permeant ions. In voltage-gated K(+) channels, the aperture formed by the S6 bundle crossing can widen to open or narrow to close the ion permeation pathway, whereas the selectivity filter gates ion flux in cyclic-nucleotide gated (CNG) and Slo1 channels. Here we explore the structural basis of the activation gate for Slo2.1, a weakly voltage-dependent K(+) channel that is activated by intracellular Na(+) and Cl(-). Slo2.1 channels were heterologously expressed in Xenopus laevis oocytes and activated by elevated [NaCl]i or extracellular application of niflumic acid. In contrast to other voltage-gated channels, Slo2.1 was blocked by verapamil in an activation-independent manner, implying that the S6 bundle crossing does not gate the access of verapamil to its central cavity binding site. The structural basis of Slo2.1 activation was probed by Ala scanning mutagenesis of the S6 segment and by mutation of selected residues in the pore helix and S5 segment. Mutation to Ala of three S6 residues caused reduced trafficking of channels to the cell surface and partial (K256A, I263A, Q273A) or complete loss (E275A) of channel function. P271A Slo2.1 channels trafficked normally, but were nonfunctional. Further mutagenesis and intragenic rescue by second site mutations suggest that Pro271 and Glu275 maintain the inner pore in an open configuration by preventing formation of a tight S6 bundle crossing. Mutation of several residues in S6 and S5 predicted by homology modeling to contact residues in the pore helix induced a gain of channel function. Substitution of the pore helix residue Phe240 with polar residues induced constitutive channel activation. Together these findings suggest that (1) the selectivity filter and not the bundle crossing gates ion permeation and (2) dynamic coupling between the pore helix and the S5 and S6 segments mediates Slo2.1 channel activation. PMID- 24166881 TI - Management of synchronous vascular and ductal anomalies in living donor liver transplantation for hepatic epithelioid hemangioendothelioma. PMID- 24166882 TI - Re: Clinical significance of first-trimester chorionic bumps: a matched case control study. Y. Sana, A. Appiah, A. Davison, K. H. Nicolaides, J. Johns and J. A. Ross. Ultrasound Obstet Gynecol 2013; 42: 585-589. PMID- 24166883 TI - Re: Prenatal identification of invasive placentation using ultrasound: systematic review and meta-analysis. F. D'Antonio, C. Iacovella and A. Bhide. Ultrasound Obstet Gynecol 2013; 42: 509-517. PMID- 24166884 TI - Re: assessing repeatability of 3D Doppler indices obtained by static 3D and STIC power Doppler: a combined in-vivo/in-vitro flow phantom study. PMID- 24166885 TI - Increased heterogeneity of bone matrix mineralization in pediatric patients prone to fractures: a biopsy study. AB - Idiopathic osteoporosis (IOP) in children is characterized by fragility fractures and/or low bone mineral density in otherwise healthy individuals. The aim of the present work was to measure bone mineralization density distribution (BMDD) based on quantitative backscattered electron imaging (qBEI) in children with suspected IOP. Entire cross-sectional areas of transiliac bone biopsy samples from children (n = 24, 17 boys; aged 6.7-16.6 years) with a history of fractures (n = 14 with at least one vertebral fracture) were analyzed for cancellous (Cn) and cortical (Ct) BMDD. Outcomes were compared with normal reference BMDD data and correlated with the patients' clinical characteristics and bone histomorphometry findings. The subjects had similar average degree but significantly higher heterogeneity of mineralization in both Cn and Ct bone (Cn.CaWidth +23%, Ct.CaWidth +15%, p < 0.001 and p = 0.002, respectively), together with higher percentages of low mineralized cancellous (Cn.CaLow +35%, p < 0.001) and highly mineralized cortical bone areas (Ct.CaHigh +82%, p = 0.032). Ct.CaWidth and Ct.CaLow were positively correlated with mineralizing surface per bone surface (MS/BS; a primary histomorphometric determinant of bone formation) and with serum bone turnover markers (all p < 0.05). The correlations of the mineralization heterogeneity with histomorphometric and serum bone turnover indices suggest that an enhanced variation in bone turnover/formation contributes to the increased heterogeneity of mineralization. However, it remains unclear whether the latter is cause for, or the response to the increased bone fragility in these children with suspected IOP. PMID- 24166886 TI - Super-resolution microscopy: going live and going fast. AB - Super-resolution microscopy is increasingly becoming an important tool for biological research, providing valuable information at the nanometer-length scales inside cells and tissues. In the past decade numerous technological advancements have transformed super-resolution microscopes into powerful tools of discovery. While the first super-resolution images took several hours to acquire, recent progress has led to tremendous improvement in acquisition speed, enabling researchers to probe dynamic processes in living cells with unprecedented spatiotemporal resolution. This minireview focuses on the recent developments in live-cell super-resolution microscopy and its biological applications. PMID- 24166887 TI - Case of partial vertical laryngectomy with vocal cord reconstruction using a thyroid gland flap. AB - BACKGROUND: To preserve laryngeal function in early-stage laryngeal cancer, chemotherapy and radiotherapy are performed more often than surgery as initial treatment. However, in recurrent cases, complex salvage surgery is often required as patients who received aggressive chemoradiotherapy are susceptible to postoperative complications. We report here salvage therapy that preserved laryngeal function in a recurrent case. METHODS: A 52-year-old man with recurrent laryngeal cancer (rT2N0M0) after chemoradiotherapy and followed by induction chemotherapy underwent partial vertical laryngectomy and right vocal cord reconstruction with a thyroid flap. RESULTS: Laryngeal functions were successfully preserved and the patient was discharged 2 months after surgery. CONCLUSION: The number of salvage surgeries performed after high-dose chemotherapy and radiation is expected to increase in the future. A thyroid gland flap promises to be an effective treatment option for vocal cord reconstruction especially for patients at high risk of postchemoradiotherapy complications. PMID- 24166888 TI - Stereospecific biosynthesis of beta-methyltryptophan from (L)-tryptophan features a stereochemical switch. AB - Make the switch: The three-enzyme cassette MarG/H/I is responsible for stereospecific biosynthesis of beta-methyltryptophan from L-tryptophan (1). MarG/I convert 1 into (2S,3R)-beta-methyltryptophan, while MarG/I combined with MarH convert 1 into (2S,3S)-beta-methyltryptophan. MarH serves as a stereochemical switch by catalyzing the stereoinversion of the beta-stereocenter. PMID- 24166889 TI - Differential DNA methylation profiles of infants exposed to maternal asthma during pregnancy. AB - BACKGROUND: Asthma is a complex disease that involves both genetic factors and environmental exposures. Aberrant epigenetic modifications, such as DNA methylation, may be important in asthma development. Fetal exposure to maternal asthma during critical periods of in utero development may lead to epigenetic alterations that predispose infants to a greater risk of developing asthma themselves. We investigated alterations in the DNA methylation profile of peripheral blood from infants exposed to maternal asthma during pregnancy. METHODS: Peripheral blood was collected from 12-month-old infants born to women with (n = 25) and without (n = 15) doctor diagnosed asthma during pregnancy. Genomic DNA was extracted, bisulfite converted, and hybridized to Infinium Methylation 27 arrays (Illumina), containing over27,000 CpGs from 14,495 genes. CpG loci in only autosomal genes were classified as differentially methylated at the 99% level (P < 0.01, |DiffScore| > 22 and delta beta >0.06). RESULTS: There were 70 CpG loci, corresponding to 67 genes that were significantly differentially methylated. Twelve CpG loci (11 genes) showed greater than 10% comparative difference in DNA methylation, including hyper-methylated loci of FAM181A, MRI1, PIWIL1, CHFR, DEFA1, MRPL28, AURKA, and hypo-methylated loci of NALP1L5, MAP8KIP3, ACAT2, and PM20D1 in maternal asthma. Methylation of MAPK8IP3 was significantly negatively correlated with maternal blood eosinophils (r = 0.38; P = 0.022), maternal eNO (r = -0.44; P = 0.005), and maternal serum total IgE (r = -0.39, P = 0.015). Methylation of AURKA negatively correlated with maternal hemoglobin (r = -0.43; P = 0.008), infants height (r = -0.51; P < 0.001) and weight (r = -0.36; P = 0.021). Methylation of PM20D1 was lower in infants born to mothers with asthma on inhaled corticosteroid treatment. Methylation of PM20D1 was lower and MRI1 was higher in infants born to atopic mothers without asthma. CONCLUSIONS: In an Australian study population, exposure to maternal asthma during pregnancy is associated with differential methylation profiles of infants' peripheral blood DNA, which may act as risk factors for future asthma development. PMID- 24166890 TI - Impact of continued medical therapy in patients with refractory chronic rhinosinusitis. AB - BACKGROUND: Patients with refractory chronic rhinosinusitis (RCRS) have persistent symptoms despite best medical therapy. Some evidence suggests continued medical therapy (CMT) is appropriate for patients with RCRS. The primary objective of this study was to evaluate the clinical impact of CMT in patients with RCRS who have significant reductions in baseline disease-specific quality of life (QoL) and would be considered candidates for endoscopic sinus surgery (ESS). METHODS: A prospective longitudinal observational study was undertaken between August 2011 and June 2013. INCLUSION CRITERIA: age >18 years, CRS defined by American Academy of Otolaryngology (AAO) adult sinusitis guidelines, failed medical therapy (defined by a 3-month minimum of topical intranasal steroid, minimum 7-day course of systemic corticosteroid, +/- 2-week course of broad spectrum systemic antibiotic), and elected ESS. Primary outcomes were change in disease-specific QoL and endoscopic scores between enrolment and immediately prior to ESS. Secondary outcomes included medication consumption and work days missed. RESULTS: A total of 31 patients were enrolled. Following CMT for a mean of 7.1 months, there was an absolute worsening in mean 22-item Sino Nasal Outcomes Test (SNOT-22) score between baseline and preoperative follow-up, 57.6 to 66.1, respectively (p = 0.006). There was a significant worsening of mean endoscopic score between baseline and preoperative follow-up, 6.9 to 7.7, respectively (p = 0.002). There was an increase in budesonide irrigations along with a reduction in use of topical nasal steroid sprays prior to ESS. Patients experienced a mean increase of 3.6 work days lost while receiving CMT (p = 0.023). CONCLUSION: Results from this study suggest that patients with RCRS who have significant reductions in baseline disease-specific QoL do not experience clinical improvement while receiving CMT. PMID- 24166891 TI - Comparative study of children and adolescents referred for eating disorder treatment at a specialist tertiary setting. AB - OBJECTIVE: To examine child and adolescent differences in the clinical presentation of eating disorders (EDs) at referral to a specialist pediatric program. METHOD: This study compared cognitive, behavioral, and physical and medical features of children (<= 12 years) and adolescents (13-18 years) with EDs presenting to a state-wide specialist pediatric ED service over two decades (N = 656; 8-18 years; 94% female). RESULTS: Significant differences were found between the groups. Children were more commonly male (p < .001), had lower eating pathology scores (p < .001), were less likely to binge eat (p = .02), purge (p < .001) or exercise for shape and weight control (p < .001), and lost weight at a faster rate than adolescents (p = .009), whereas adolescents were more likely to present with bulimia nervosa spectrum disorders (p = .004). Children and adolescents did not differ significantly on mean body mass index z-score, percentage of body weight lost, or indicators of medical compromise (p > .05). DISCUSSION: The clinical presentation of EDs differs among children and adolescents, with eating pathology and behavioral symptoms less prominent among children. Frontline health professionals require knowledge of these differences to assist with early detection, diagnosis, and prognosis. PMID- 24166892 TI - DNA-PKcs associates with PLK1 and is involved in proper chromosome segregation and cytokinesis. AB - Accurate mitotic regulation is as important as intrinsic DNA repair for maintaining genomic stability. It is believed that these two cellular mechanisms are interconnected with DNA damage. DNA-PKcs is a critical component of the non homologous end-joining pathway of DNA double-stranded break repair, and it was recently discovered to be involved in mitotic processing. However, the underlying mechanism of DNA-PKcs action in mitotic control is unknown. Here, we demonstrated that depletion of DNA-PKcs led to the dysregulation of mitotic progression in response to DNA damage, which eventually resulted in multiple failures, including failure to segregate sister chromatids and failure to complete cytokinesis, with daughter cells becoming fused again. The depletion of DNA-PKcs resulted in a notable failure of cytokinesis, with a high incidence of multinucleated cells. There were also cytoplasmic bridges containing DNA that continuously connected the daughter cells after DNA damage was induced. Phosphorylated DNA-PKcs (T2609) colocalizes with PLK1 throughout mitosis, including at the centrosomes from prophase to anaphase and at the kinetochores from prometaphase to metaphase, with accumulation at the midbody during cytokinesis. Importantly, DNA-PKcs was found to associate with PLK1 in the mitotic phase, and the depletion of DNA-PKcs resulted in the overexpression of PLK1 due to increased protein stability. However, deficiency in DNA-PKcs attenuated the recruitment of phosphorylated PLK1 to the midbody but not to the kinetochores and centrosomes. Our results demonstrate the functional association of DNA-PKcs with PLK1, especially in chromosomal segregation and cytokinesis control. PMID- 24166894 TI - Charge carriers and small-polaron migration as the origin of intrinsic dielectric anomalies in multiferroic TbMnO3 polycrystals. AB - Temperature-dependent and frequency-dependent dielectric investigations have been performed in TbMnO3 polycrystals sintered in either oxidative or reductive atmospheres. The results revealed the occurrence of two dielectric anomalies above 100 K, which are caused by the thermal activation of charge carriers and their motion in grain cores and grain boundaries. The temperature dependence of the bulk dc conductivity was also analysed and indicates that charge carriers move between inequivalent sites according to a variable-range-hopping mechanism. Also, a strong correlation between dielectric properties and crystalline structure was observed. Furthermore, a low-temperature dielectric relaxation, commonly reported in rare-earth manganite crystals, was observed in both samples. This relaxation follows the empirical Cole-Cole model and was attributed to small polaron tunnelling. Polaron motion was observed to be affected by the magnetic transitions, structural properties and intrinsic anisotropies in TbMnO3. It is also worth mentioning that the dielectric anomaly due to motion of charge carriers in grain boundaries is the only one of extrinsic origin, while the anomalies related to carrier motion in grain cores and small-polaron tunnelling are intrinsic to TbMnO3. PMID- 24166893 TI - Effects of calcium and vitamin D3 on transforming growth factors in rectal mucosa of sporadic colorectal adenoma patients: a randomized controlled trial. AB - Transforming growth factor alpha (TGFalpha) and TGFbeta1 are growth-promoting and -inhibiting autocrine/paracrine growth factors, respectively, that may (1) affect risk for colorectal cancer and (2) be modifiable by anti-proliferative exposures. The effects of supplemental calcium and vitamin D3 on these two markers in the normal-appearing colorectal mucosa in humans are unknown. We conducted a pilot, randomized, double-blind, placebo-controlled, 2 * 2 factorial clinical trial (n = 92; 23/treatment group) of calcium 2 g and/or vitamin D3 800 IU/d versus placebo over 6 mo. TGFalpha and TGFbeta1 expression was measured in biopsies of normal appearing rectal mucosa using automated immunohistochemistry and quantitative image analysis at baseline and 6-mo follow-up. In the calcium, vitamin D3 , and calcium plus vitamin D3 groups relative to the placebo group (1) the mean overall expression of TGFbeta1 increased by 14% (P= 0.25), 19% (P = 0.17), and 22% (P = 0.09); (2) the ratio of TGFalpha expression in the upper 40% (differentiation zone) to that in the lower 60 (proliferation zone) of the crypts decreased by 34% (P = 0.11), 31% (P = 0.22), and 26% (P = 0.33); and (3) the TGFalpha/TGFbeta1 ratio in the upper 40% of the crypts decreased by 28% (P = 0.09), 14% (P = 0.41), and 22% (P = 0.24), respectively. These preliminary results, although not statistically significant, suggest that supplemental calcium and vitamin D3 may increase TGFbeta1 expression and shift TGFalpha expression downward from the differentiation to the proliferation zone in the crypts in the normal-appearing colorectal mucosa of sporadic colorectal adenoma patients, and support further investigation in a larger clinical trial. PMID- 24166895 TI - Can liver transplantation provide the statistical cure? AB - Liver transplantation (LT) represents the only chance of long-term survival for patients with end-stage liver disease. When the mortality rate for transplant patients returns to the same level as that for the general population, they can be considered statistically cured. However, cure models in the setting of LT have never been applied. Data from 1371 adult patients undergoing LT for the first time between January 1999 and December 2012 at 2 Italian centers were reviewed in order to establish probabilities of being cured by LT. A parametric Weibull model was applied to compare the mortality rate after LT to the rate expected for the general population (matched by sex and age). The observed 3-, 5-, and 10-year overall survival rates after LT were 77.8%, 73.3%, and 65.6%, respectively, and they did not differ between the 2 centers (P = 0.37). The cure fraction for the entire study population was 63.4% (95% confidence interval = 52.6%-72.0%), and the time to cure was 10 years with a 90% confidence level. The best cure fraction was observed for younger recipients without hepatitis C virus (HCV) who had favorable donor-recipient matches, that is, low Donor Model for End-Stage Liver Disease (D-MELD) scores (90.1%); conversely, the lowest probability was observed for elderly HCV recipients with high D-MELD scores (34.6%). The time to cure was 6.22 years for non-HCV patients and 14.78 years for HCV patients. The median survival time for uncured patients was 2.29 years. Among uncured recipients, the longest survival time was observed for younger patients (7.31 years). In conclusion, we provide here a new clinical measure for LT suggesting that survival after transplantation can approximate that of the general population and provide a statistical cure. PMID- 24166896 TI - Fine-needle aspiration cytology of primary renal angiosarcoma with histopathologic and immunocytochemical correlation: a case report. AB - Primary renal angiosarcoma is an extremely rare neoplasm, with fewer than 28 cases reported thus far in the English literature. We report for the first time the cytomorphology and immunocytochemistry of this tumor in liquid-based (ThinPrep) fine-needle aspiration (FNA) samples in correlation with the conventional cytologic and histopathologic findings. Conventional smears showed pleomorphic tumor cells focally arranged in structures suggesting anastomosing vascular channels, while ThinPrep smears were less cellular with fewer and smaller tumor cells arranged in clusters or rosette-like formations. Immunocytochemical staining demonstrated positive results for vimentin, CD31, and CD34 and negative staining for epithelial markers, thus supporting the diagnosis of a mesenchymal tumor of vascular origin. The diagnosis of primary renal angiosarcoma was established after histopathologic evaluation of a metastatic liver nodule. The cytological differential diagnosis of this neoplasm and the utility of the ThinPrep method as a diagnostic adjunct to conventional FNA cytology are further discussed. PMID- 24166897 TI - Commentary. PMID- 24166898 TI - Darkening of white hair following levodopa therapy in a patient with Parkinson's disease. PMID- 24166899 TI - Unified Huntington's disease rating scale for advanced patients: validation and follow-up study. AB - The Unified Huntington's Disease Rating Scale (UHDRS) adequately measures decline in patients at early and moderate stages of Huntington's disease (HD). In advanced patients, floor effects hamper the evaluation, thus calling for an adjusted scale. We designed the UHDRS-For Advanced Patients (UHDRS-FAP), in order to improve longitudinal assessment of patients at advanced disease stage. Sixty nine patients with a Total Functional Capacity (TFC) <= 5 were recruited in France and in the Netherlands. Among them, 45 patients were followed longitudinally (mean 1.6 +/- 1.2 years) with the UHDRS-FAP; 30 were also assessed with the UHDRS. Cross-sectional analyses evaluated psychometric properties and interrater reliability of the scale. Longitudinal analyses evaluated the sensitivity to decline compared to the UHDRS. Internal consistency was higher for motor and cognitive scores than for somatic and behavioral scores (0.84, 0.91, 0.70, and 0.49, respectively). Interrater reliability was >= 0.88 in all scores. The somatic score, specific to the UHDRS-FAP, declined over time, as well as motor and cognitive performance with both scales. Although performance with the 2 scales correlated, the UHDRS-FAP appeared more sensitive to change and was the only scale that detected decline in patients with a TFC <= 1. Neither scale detected a significant decline in behavioral scores. The UHDRS-FAP is reliable and more sensitive to change than the original UHDRS for cognitive and motor domains. It offers items relevant for daily care. Behavioral scores tended to decline but this may reflect the decline in the communicative abilities of the patients. PMID- 24166902 TI - Conjunctival melanomas harbor BRAF and NRAS mutations--Letter. PMID- 24166904 TI - The context of blood vessels and response to VEGF-targeted therapy. AB - Although therapy directed against VEGF has produced clinical benefit, an understanding of responsive tumor characteristics is lacking. Blood vessel location relative to tumor cells and stromal factors may influence tumor susceptibility to VEGF-targeted therapy. Clinical validation of this potential biomarker is needed to influence clinical practice. PMID- 24166903 TI - Phase I safety, pharmacokinetic, and pharmacodynamic study of SAR245408 (XL147), an oral pan-class I PI3K inhibitor, in patients with advanced solid tumors. AB - PURPOSE: SAR245408 is a pan-class I phosphoinositide 3-kinase (PI3K) inhibitor. This phase I study determined the maximum tolerated dose (MTD) of two dosing schedules [first 21 days of a 28-day period (21/7) and continuous once-daily dosing (CDD)], pharmacokinetic and pharmacodynamic profiles, and preliminary efficacy. EXPERIMENTAL DESIGN: Patients with refractory advanced solid malignancies were treated with SAR245408 using a 3 + 3 design. Pharmacokinetic parameters were determined after single and repeated doses. Pharmacodynamic effects were evaluated in plasma, hair sheath cells, and skin and tumor biopsies. RESULTS: Sixty-nine patients were enrolled. The MTD of both schedules was 600 mg; dose-limiting toxicities were maculopapular rash and hypersensitivity reaction. The most frequent drug-related adverse events included dermatologic toxicities, diarrhea, nausea, and decreased appetite. Plasma pharmacokinetics showed a median time to maximum concentration of 8 to 22 hours, mean terminal elimination half life of 70 to 88 hours, and 5- to 13-fold accumulation after daily dosing (first cycle). Steady-state concentration was reached between days 15 and 21, and exposure was dose-proportional with doses up to 400 mg. SAR245408 inhibited the PI3K pathway (~40%-80% reduction in phosphorylation of AKT, PRAS40, 4EBP1, and S6 in tumor and surrogate tissues) and, unexpectedly, also inhibited the MEK/ERK pathway. A partial response was seen in one patient with advanced non-small cell lung cancer. Eight patients were progression-free at 6 months. Pharmacodynamic and clinical activity were observed irrespective of tumor PI3K pathway molecular alterations. CONCLUSIONS: SAR245408 was tolerable at doses associated with PI3K pathway inhibition. The recommended phase II dose of the capsule formulation is 600 mg administered orally with CDD. PMID- 24166905 TI - Deep molecular response in chronic myeloid leukemia: the new goal of therapy? AB - Chronic myeloid leukemia (CML) is caused by formation of the BCR-ABL1 fusion protein. Tyrosine kinase inhibitors (TKI) that target BCR-ABL1 are now the standard of care for patients with CML. Molecular monitoring of residual BCR-ABL1 mRNA transcripts, typically performed using real-time quantitative PCR, has improved treatment management, particularly for patients with CML in chronic phase. Major molecular response (MMR; i.e., a >=3-log reduction in BCR-ABL1 transcript levels) is used in current treatment guidelines to assess prognosis. Recent evidence suggests that deeper molecular responses (>=4-log reductions in BCR-ABL1 transcript levels), particularly when attained early during treatment, may have even better correlation with long-term outcomes, including survival and disease progression. Furthermore, achieving deep molecular response is a requirement for entering trials evaluating treatment-free remission (TFR). In this review, we discuss the evolving definition of minimal residual disease and the various levels of molecular response under evaluation in current clinical studies. In addition, the available clinical data on achieving MMR and deeper levels of molecular response with TKI therapy, the prognostic value of deep molecular response, and factors that may predict a patient's ability to achieve and sustain a deep molecular response on TKI therapy are also discussed. Available data from TFR studies are addressed. We discuss current knowledge of the ideal conditions for attempting treatment discontinuation, factors predictive of molecular relapse, when TKI therapy should be restarted, and which therapeutic strategies (when administered in the first-line setting and beyond) are expected to best enable successful TFR. PMID- 24166907 TI - The role of protein kinase CK2 in glioblastoma development. AB - Glioblastoma is the most prevalent and malignant primary brain tumor in adults, and its response to current therapies is limited. Protein kinase CK2 is overexpressed in glioblastoma and regulates glioblastoma cell survival, proliferation, and migration and brain tumorigenesis. Targeting CK2 for glioblastoma treatment may benefit patients with glioblastoma. PMID- 24166908 TI - Stressing the development of small molecules targeting HSP90. AB - Inhibitors of the molecular chaperone HSP90 have been in clinical development as anticancer agents since 1999. Recent clinical studies, including the work of Saif and colleagues in this issue of Clinical Cancer Research, demonstrate that significant progress has been made in overcoming the obstacles preventing regulatory approval. PMID- 24166906 TI - Comprehensive biomarker analysis and final efficacy results of sorafenib in the BATTLE trial. AB - PURPOSE: To report the clinical efficacy of sorafenib and to evaluate biomarkers associated with sorafenib clinical benefit in the BATTLE (Biomarker-Integrated Approaches of Targeted Therapy for Lung Cancer Elimination) program. PATIENTS AND METHODS: Patients with previously treated non-small cell lung cancer (NSCLC) received sorafenib until progression or unacceptable toxicity. Eight-week disease control rate (DCR), progression-free survival (PFS), and overall survival (OS) were assessed. Prespecified biomarkers included K-RAS, EGFR, and B-RAF mutations, and EGFR gene copy number. Gene expression profiles from NSCLC cell lines and patient tumor biopsies with wild-type EGFR were used to develop a sorafenib sensitivity signature (SSS). RESULTS: A total of 105 patients were eligible and randomized to receive sorafenib. Among 98 patients evaluable for eight-week DCR, the observed DCR was 58.2%. The median PFS and OS were 2.83 [95% confidence interval (CI), 2.04-3.58] and 8.48 months (95% CI, 5.78-10.97), respectively. Eight-week DCR was higher in patients with wild-type EGFR than patients with EGFR mutation (P = 0.012), and in patients with EGFR gene copy number gain (FISH positive) versus patients FISH-negative (P = 0.048). In wild-type EGFR tumors, the SSS was associated with improved PFS (median PFS 3.61 months in high SSS vs. 1.84 months in low SSS; P = 0.026) but not with eight-week DCR. Increased expression of fibroblast growth factor-1, NF-kappaB, and hypoxia pathways were identified potential drivers of sorafenib resistance. CONCLUSION: Sorafenib demonstrates clinical activity in NSCLC, especially with wild-type EGFR. SSS was associated with improved PFS. These data identify subgroups that may derive clinical benefit from sorafenib and merit investigation in future trials. PMID- 24166909 TI - Targeting metabolic scavenging in pancreatic cancer. AB - Pancreatic tumor metabolism is rewired to facilitate survival and growth in a nutrient-depleted environment. This leads to a unique dependence on metabolic recycling and scavenging pathways, including NAD salvage. Targeting this pathway in pancreatic cancer disrupts metabolic homeostasis and impairs tumor growth. PMID- 24166910 TI - Comparative efficacy of bisphosphonates in metastatic breast and prostate cancer and multiple myeloma: a mixed-treatment meta-analysis. AB - PURPOSE: A mixed-treatment comparison (MTC) was undertaken to compare the efficacy of zoledronic acid, clodronate, pamidronate, and ibandronate (i.v. and oral) in patients with skeletal-related events (SRE) secondary to metastatic breast and prostate cancer and multiple myeloma. EXPERIMENTAL DESIGN: Studies of bisphosphonates in the three malignancies were identified and SRE data were extracted. Outcomes from the MTC were expressed as the annual SRE rate and as the mean likelihood (probability) ratio for the rate of SREs during treatment with zoledronic acid compared with the other bisphosphonates. RESULTS: A total of 17 studies were identified (7 breast, 3 prostate, and 7 multiple myeloma). Data were available for all bisphosphonates in breast cancer; no data were available for ibandronate (oral or i.v.) in prostate cancer or for oral ibandronate in multiple myeloma. The SRE rates in breast cancer were 1.60 for zoledronic acid, 1.67 for oral ibandronate (excess SRE rate, 4%), 1.70 for i.v. ibandronate (6%), 2.07 for pamidronate (29%), and 2.29 for clodronate (42%). In prostate cancer, the SRE rates were 0.83 for zoledronic acid, 1.11 for clodronate (35%), and 1.41 for pamidronate (71%). In multiple myeloma, the SRE rates were 1.43 for zoledronic acid, 1.64 for pamidronate (15%), 1.90 for clodronate (33%), and 2.49 for i.v. ibandronate (75%). CONCLUSIONS: Zoledronic acid seems to be the most efficacious bisphosphonate for reducing the risk of SREs in patients with cancer of the breast or prostate and those with multiple myeloma. PMID- 24166911 TI - Molecular pathways: transcription factories and chromosomal translocations. AB - The mammalian nucleus is a highly complex structure that carries out a diverse range of functions such as DNA replication, cell division, RNA processing, and nuclear export/import. Many of these activities occur at discrete subcompartments that intersect with specific regions of the genome. Over the past few decades, evidence has accumulated to suggest that RNA transcription also occurs in specialized sites, called transcription factories, that may influence how the genome is organized. There may be certain efficiency benefits to cluster transcriptional activity in this way. However, the clustering of genes at transcription factories may have consequences for genome stability, and increase the susceptibility to recurrent chromosomal translocations that lead to cancer. The relationships between genome organization, transcription, and chromosomal translocation formation will have important implications in understanding the causes of therapy-related cancers. PMID- 24166912 TI - CD137 as a biomarker for tumor-reactive T cells: finding gold in the desert. AB - Although human cancer is often surrounded by immune cells, only a small number are tumor-reactive T cells that recognize the tumor antigens and are able to eliminate the cancer cells. Ye and colleagues now found that many of these tumor reactive T cells are marked by expressing CD137, a T-cell costimulatory receptor. PMID- 24166913 TI - Oxford and the Savannah: can the hippo provide an explanation for Peto's paradox? AB - Peto's paradox is the counterintuitive finding that increasing body mass and thereby cell number does not correlate with an increase in cancer incidence across different species. The Hippo signaling pathway is an evolutionarily conserved system that determines organ size by regulating apoptosis and cell proliferation. It also affects cell growth by microRNA-29 (miR-29)-mediated cross talk to the mTOR signaling pathway. Whether these pathways that decide organ size could explain this paradox merits consideration. Inactivation of most genes of the Hippo pathway in Drosophila melanogaster genetic screens causes excessive tissue-specific growth of developing tissues. Altered Hippo pathway activity is frequently found in diverse tumor types, but mutations of component pathway genes are rare. Most Hippo pathway components are encoded by tumor suppressor genes (TSG), but an exception is the downstream effector gene called YAP. Activity of the Hippo pathway causes deactivating phosphorylation of YES-associated protein (YAP) with nuclear exclusion. YAP can also be phosphorylated at a second site, S127, by AKT. YAP induces the expression of genes responsible for proliferation and suppression of apoptosis. Resolving Peto's paradox may serendipitously provide new insights into the biology and treatment of cancer. This article considers Hippo signaling and Peto's paradox in the context of TSG-oncogene computed models. Interspecies differences in dietary composition, metabolic rates, and anabolic processes are also discussed in the context of Hippo-mTOR signaling. The metabolically important LKB1-AMPK (liver kinase B1-AMP activated protein kinase) signaling axis that suppresses the mTOR pathway is also considered. PMID- 24166916 TI - Issue highlights--Cytometry part B November 2013. PMID- 24166914 TI - Anticipating the clinical use of prognostic gene expression-based tests for colon cancer stage II and III: is Godot finally arriving? AB - PURPOSE: According to current recommendations for adjuvant treatment, patients with colon cancer stage II are not routinely offered chemotherapy, unless considered to have a high risk of relapse based on specific clinicopathological parameters. Following these criteria, it is challenging to identify the subgroup of patients that will benefit the most from adjuvant treatment. Contrarily, patients with colon cancer stage III are routinely offered chemotherapy, but due to expected adverse effects and frailty, elderly patients are often excluded from standard protocols. Colon cancer is a disease of the elderly and accordingly, there is a large subgroup of patients for which guidelines for adjuvant treatment remain less clear. In these two clinical settings, improved risk stratification has great potential impact on patient care, anticipating that high-risk patients will benefit from chemotherapy. However, microsatellite instability is the only molecular prognostic marker recommended for clinical use. EXPERIMENTAL DESIGN: In this perspective, we provide an updated view on the status and clinical potential of the many proposed prognostic gene expression-based tests for colon cancer stage II and III. RESULTS: The main limitation for clinical implementation is lack of prospective validation. For patients with stage II, highly promising tests have been identified and clinical trials are ongoing. For elderly patients with stage III, the value of such tests has received less focus, but promising early results have been shown. CONCLUSION: Although awaiting results from prospective trials, improved risk assessment for patients with stage II and III is likely to be achieved in the foreseeable future. PMID- 24166917 TI - Motion of Li(+) in nanoengineered LiBH(4) and LiBH(4):Al(2)O(3) comparison with the microcrystalline form. AB - The introduction of structural disorder and large volume fractions of different kinds of interfaces enables the manipulation of ion dynamics in solids. Variable temperature solid-state NMR relaxometry is highly useful to study Li(+) jump processes. If carried out as a function of frequency, the resulting NMR relaxation rates also contain information on the dimensionality (1D, 2D, or 3D) of the diffusion process. Recently, NMR relaxometry has revealed the 2D nature of Li hopping in LiBH4 , and thus this hydride is an interesting ion conductor for further diffusion studies on the spatially confined motion of Li spins. Here, nanocrystalline LiBH4 and the two-phase analogue LiBH4 :Al2 O3 , which are prepared by ball milling, serve as interesting model systems to track the changes in NMR relaxation rates with respect to coarse-grained, thermodynamically stable LiBH4 . This reveals that interface (nano)engineering influences the hexagonal-to orthorhombic phase transition and thus alters the ion-transport properties of Li in one- and two-phase LiBH4 towards higher diffusivities at lower temperatures. PMID- 24166918 TI - Introduction to special issue. PMID- 24166919 TI - The contributions of Jeanne Altmann. PMID- 24166920 TI - Contributions of Sarah Blaffer Hrdy. PMID- 24166921 TI - The evolution of the patterning of human lactation: a comparative perspective. AB - Some four decades ago, Jeanne Altmann started her detailed field studies of baboon mothers and their infants with a focus on the behavioral ecology of maternal reproductive investment. Around the same time, Sarah Hrdy studied langur mothers and their infants, focusing on the influence of the social environment on a female's reproductive options and decisions. Their pioneering work has inspired many subsequent studies of female primate reproduction in its natural context and shaped our own work on primate mothers. PMID- 24166922 TI - A practical guide to the study of social relationships. AB - Behavioral ecologists have devoted considerable effort to identifying the sources of variation in individual reproductive success. Much of this work has focused on the characteristics of individuals, such as their sex and rank. However, many animals live in stable social groups and the fitness of individuals depends at least in part on the outcome of their interactions with other group members. For example, in many primate species, high dominance rank enhances access to resources and reproductive success. The ability to acquire and maintain high rank often depends on the availability and effectiveness of coalitionary support. Allies may be cultivated and coalitions may be reinforced by affiliative interactions such as grooming, food sharing, and tolerance. These findings suggest that if we want to understand the selective pressures that shape the social behavior of primates, it will be profitable to broaden our focus from the characteristics of individuals to the properties of the relationships that they form with others. The goal of this paper is to discuss a set of methods that can be used to quantify the properties of social relationships. PMID- 24166923 TI - Reproductive suppression in female primates: a review. AB - Reproductive performance is the currency of evolution. All things being equal, an organism should reproduce as often as possible. The puzzling questions in evolutionary biology, therefore, are not how and why an organism does reproduce, but rather how and why an organism does not reproduce. It is difficult to understand why any individual, particularly a female, might forestall reproduction when one of the biggest limitations for female mammalian reproduction is time (that is, reproductive lifespan). The answer, now widely cited throughout behavioral ecology is quite simple: Reproductive suppression can be an adaptive strategy. PMID- 24166924 TI - The Impact of male reproductive skew on kin structure and sociality in multi-male groups. AB - Patterns of within-group relatedness are expected to affect the prospects for cooperation among group members through kin selection. It has long been established that dispersal patterns determine the availability of kin and there is ample evidence of matrilineal kin biases in social behavior across primate species. However, in 1979, Jeanne Altmann(1) suggested that mating patterns also influence the structure of within-group relatedness; high male reproductive skew and the frequent replacement of breeding males leads to relatively high levels of paternal relatedness and age-structured paternal sibships within groups. As a consequence of frequent replacement of breeding males, relatedness among offspring of a given female will be reduced to the half- rather than full-sibling level. Depending on the number of sires and degree of relatedness among mothers, members of the same birth cohort may be as closely related as maternal siblings. If animals are able to recognize their paternal kin and exhibit biases in favor of them, this may influence the distribution of cooperation and the intensity of competition within groups of primates. Here, I summarize the evidence that serves as the basis for Altmann's predictions and review evidence regarding whether or not the availability of paternal kin also leads to paternal kin bias among primates. PMID- 24166925 TI - Cooperation and conflict between women in the family. AB - Here I review recent research on reproductive conflict between females in families and how it influences their reproductive behaviour. Kin selection can favor cooperation between parent and offspring, siblings, or unrelated co residents who share interests in other family members such as grand-offspring. However, these are also the individuals most likely to be sharing resources, and so conflict can also emerge. While substantial interest has arisen in evolutionary anthropology, especially over the last two decades, in the possibility of cooperative breeding in humans, less attention has been paid to reproductive conflict among female kin. Communal breeding in animals is generally understood as emerging from competition over the resources needed to breed. Competition for household resources is a problem that also faces human families. Models suggest that in some circumstances, inclusive fitness can be maximized by sharing reproduction rather than harming relatives by fighting with them, even if the shares that emerge are not equal. Thus, competition and cooperation turn out to be strongly related to each other. Reproductive competition within and between families may have underpinned the biological evolution of fertility patterns (such as menopause) and the cultural evolution of marriage, residence, and inheritance norms (such as late male marriage or primogeniture), which can enhance cooperation and minimize the observed incidence of such conflicts. PMID- 24166926 TI - Choosy but not chaste: multiple mating in human females. AB - When Charles Darwin set out to relate his theory of evolution by natural selection to humans he discovered that a complementary explanation was needed to properly understand the great variation seen in human behavior. The resulting work, The Descent of Man and Selection in Relation to Sex, laid out the defining principles and evidence of sexual selection. In brief, this work is best known for illuminating the typically male strategy of intrasexual competition and the typically female response of intersexual choice. While these sexual stereotypes were first laid out by Darwin, they grew in importance when, years later, A. J. Bateman, in a careful study of Drosophila mating strategies, noted that multiple mating appeared to provide great benefit to male reproductive success, but to have no such effect on females. As a result, female choice soon became synonymous with being coy, and only males were thought to gain from promiscuous behavior. However, the last thirty years of research have served to question much of the traditional wisdom about sex differences proposed by Darwin and Bateman, illuminating the many ways that women (and females more generally) can and do engage in multiple mating. PMID- 24166927 TI - Tracheobronchomalacia in infants: the use of non-breath held 3D CT bronchoscopy. AB - OBJECTIVE: To evaluate the use of a non-breath held 3D-CT-bronchoscopy in detecting tracheobronchomalacia in infants. METHODS: The study was based on 17 infants who received both bronchoscopy and 3D-CT-bronchoscopy within 1 week at our institution. 3D-CT-bronchoscopy consisted of an axial-enhanced-chest-scan and a 3D-volume-external rendering (VR) image of the airways and was scanned with a consciously sedated non-breath held protocol, using a 64-channel-multidetecter-CT scanner. VR images were classified by two radiologists as normal, luminal narrowing or complete obliteration. All patients were confirmed with bronchoscopy and the sensitivity, specificity, negative predictive value (NPV), positive predictive value (PPV) was calculated. RESULTS: Ten (M:F1/47:3, mean 1 month) out of 17 infants were confirmed of tracheobronchomalacia. The sensitivity was <75% in detecting laryngomalacia, tracheomalacia and bronchomalacia. However, the specificity and NPV were higher than 75% for laryngomalacia, tracheomalacia and bronchomalacia and the PPV was 100% in laryngomalacia and tracheomalacia. False positive cases included secretion plugging, extrinsic compression and foreign body, which were distinguishable in axial scans. The effective radiation dose was 0.73_0.49mSv. CONCLUSION: A volume rendering image of the airways can be used to evaluate tracheobronchomalacia and stenosis in infants. Although, non-breath held MDCT is not recommended for screening airway lesions, narrowing of the larynx, and trachea and patency of the bronchus are reliable findings. PMID- 24166929 TI - Effect of hyperbaric oxygen therapy on a murine squamous cell carcinoma model. AB - BACKGROUND: Hyperbaric oxygen (HBO) therapy is sometimes used to assist in wound healing after major head and neck cancer surgery. However, there is concern that HBO treatments might enhance the growth of any residual microscopic disease. This was studied in a mouse model of squamous cell carcinoma (SCC). METHODS: SCC VII/SF tumor cells were cultured, and then injected (3 * 10(3) cells) into C3H/HeJ mice in 5 groups: subcutaneous (SQ) control (n = 13), SQ-immediate (n = 12), SQ-delayed (n = 13), tail vein control (n = 8), and tail vein immediate (n = 9). The 3 experimental groups were subjected to HBO therapy, 2.4 atm for 90 minutes, 5 days per week for 4 weeks, starting on postinjection day 3 ("immediate") or 10 ("delayed"). Tumors in the SQ mice were measured 3 times per week. Lung metastases in the tail vein mice were counted at necropsy. RESULTS: At postimplantation day 28, when the immediate group completed its HBO therapy, the tumor volume in the SQ-immediate group was 49.1% higher than the control group, and the SQ-delayed group was 105.1% higher than controls (p < .05). Two weeks later, the SQ-immediate group and SQ-delayed group tumor volumes were still significantly higher than controls, but the difference was smaller (18.4% and 43.8%, respectively; p < .05 only for the delayed group). The tail vein groups had similar numbers of lung metastases, with a mean of 8.7 metastases in the control group and 9.0 metastases in the HBO group (not significant [NS]). CONCLUSION: This study suggests that HBO therapy does accelerate the growth of microscopic foci of SCCs. This finding differs from some earlier studies and warrants further study. PMID- 24166928 TI - The Yersinia enterocolitica Ysa type III secretion system is expressed during infections both in vitro and in vivo. AB - Yersinia enterocolitica biovar 1B maintains two type III secretion systems (T3SS) that are involved in pathogenesis, the plasmid encoded Ysc T3SS and the chromosomally encoded Ysa T3SS. In vitro, the Ysa T3SS has been shown to be expressed only at 26 degrees C in a high-nutrient medium containing an exceptionally high concentration of salt - an artificial condition that provides no clear insight on the nature of signal that Y. enterocolitica responds to in a host. However, previous research has indicated that the Ysa system plays a role in the colonization of gastrointestinal tissues of mice. In this study, a series of Ysa promoter fusions to green fluorescent protein gene (gfp) were created to analyze the expression of this T3SS during infection. Using reporter strains, infections were carried out in vitro using HeLa cells and in vivo using the mouse model of yersiniosis. Expression of green fluorescent protein (GFP) was measured from the promoters of yspP (encoding a secreted effector protein) and orf6 (encoding a structural component of the T3SS apparatus) in vitro and in vivo. During the infection of HeLa cells GFP intensity was measured by fluorescence microscopy, while during murine infections GFP expression in tissues was measured by flow cytometry. These approaches, combined with quantification of yspP mRNA transcripts by quantitative reverse transcriptase-polymerase chain reaction (qRT PCR), demonstrate that the Ysa system is expressed in vitro in a contact dependent manner, and is expressed in vivo during infection of mice. PMID- 24166931 TI - The sorting test of the D-KEFS in current and weight restored anorexia nervosa patients. AB - OBJECTIVE: Efforts have been made to characterize executive functions (EF) in anorexia nervosa (AN) both in the acute stage of the illness and after weight gain, yet many questions remain. The question of verbal versus visuo-perceptual stimuli in this regard has not been adequately addressed. The aim of this study is to further examine EF in women with past and present AN and to compare their performances in verbal and visual modalities with women who have never suffered from an eating disorder. METHOD: Thirty-five underweight AN patients, 33 weight restored patients symptom-free for at least 2 years, and 48 healthy female controls completed the Delis-Kaplan Executive Function System Sorting Test, so as to evaluate their EF. RESULTS: No differences were observed between the scores of women with current and past AN. Both groups scored lower than controls on most test variables. However, while in the visuo-perceptual domain the performance of the AN groups was worse than that of controls, in the verbal domain they performed similarly to them. DISCUSSION: Women with a past or present diagnosis of AN show difficulties in visuo-perceptual EF, whereas verbal EF seem to be preserved. There may be a dissociation between verbal and visuo-perceptual EF that persists after weight restoration. PMID- 24166932 TI - Superconducting pairing and the pseudogap in the nematic dynamical stripe phase of La2-xSrxCuO4. AB - Fully absorption coefficient corrected Raman spectra were obtained in La2 xSrxCuO4. The B1g spectra have a Fleury-Loudon type two-magnon peak (resonant term) whose energy decreases from 3180 cm(-1) (394 meV) to 440 cm(-1) (55 meV) on increasing the carrier density from x = 0 to 0.25, while the B2g spectra have a 1000-3500 cm(-1) (124-434 meV) hump (hill) whose lower-edge energy increases from x = 0 to 0.115 and then stays constant to x = 0.25. The B2g hump is assigned to the electronic scattering (non-resonant term) of the spectral function with magnetic self-energy. The completely different carrier density dependence arises from anisotropic magnetic excitations of spin-charge stripes. The B1g spectra were assigned to the sum of k ? and k? stripe excitations and the B2g spectra to k? stripe excitations according to the calculation by Seibold and Lorenzana (2006 Phys. Rev. B 73 144515). The k ? and k? stripe excitations in fluctuating spin charge stripes were separately detected for the first time. The appearance of only k? stripe excitations in the electronic scattering arises from the charge hopping perpendicular to the stripe. This is the same direction as the Burgers vector of the edge dislocation in metal. The successive charge hopping in the Burgers vector direction across the charge stripes may cause Cooper pairs as predicted by Zaanen et al (2004 Ann. Phys. 310 181). Indeed, this is supported by the experimental fact that the superconducting coherent length coincides with the inter-charge stripe distance in the wide carrier density range. The one directional charge hopping perpendicular to the stripe causes the flat Fermi surface and the pseudogap near (pi,0) and (0,pi), but the states around (pi/2,pi/2) cannot be produced. The low-energy Raman scattering disclosed that the electronic states at the Fermi arc around (pi/2,pi/2) are coupled to the A1g soft phonon of the tetragonal-orthorhombic phase transition. This suggests that the Fermi arc is produced by the electron-phonon interaction. All the present Raman data suggest that Cooper pairs are formed at moving edge dislocations of dynamical charge stripes. PMID- 24166930 TI - Genetic variant rs16430 6bp > 0bp at the microRNA-binding site in TYMS and risk of sporadic breast cancer risk in non-Hispanic white women aged <= 55 years. AB - Thymidylate synthase (TYMS) is involved in the folate metabolism and provision of nucleotides needed for DNA synthesis and repair. Thus, functional genetic variants in TYMS may alter cancer risk. In the study, we evaluated associations of three germline variants (rs2790 A > G, rs16430 6 bp > 0 bp, and rs1059394 C > T) in the predicted miRNA-binding sites of TYMS with risk of sporadic breast cancer in non-Hispanic white women aged <= 55. We found that carriers of the rs16430 0 bp variant allele had an increased risk of breast cancer [adjusted odd ratio (OR) = 1.37, 95% confidence interval (CI): 1.08-1.73; P = 0.010], compared with carriers of the 6 bp/6 bp genotype. This increased risk was more evident in older subjects (OR = 1.47, 95% CI = 1.06-2.03, P = 0.022), never smokers (OR = 1.67, 95% CI = 1.23-2.25, P < 0.001), never drinkers (OR = 1.44, 95% CI = 1.01 2.05, P = 0.043), and estrogen receptor-positive patients (OR = 1.46, 95% CI = 1.11-1.92, P = 0.006), regardless of tumor stages. The results are consistent with the functional analyses of rs16430 as previously reported, which showed that the 0 bp allele had a decrease in both luciferase activity by ~ 70% and mRNA levels by ~ 50% compared with the 6bp allele. Additionally, the rs16430 variant was predicted to influence the binding activity of miR-561. Taken together, these findings indicate that the TYMS rs16430 may contribute to the etiology of sporadic breast cancer in non-Hispanic white women aged <= 55 yr. Further validation in large population-based or cohort studies is needed. PMID- 24166933 TI - Chelator-free synthesis of a dual-modality PET/MRI agent. PMID- 24166935 TI - Subclassification of "atypia of undetermined significance" in thyroid fine-needle aspirates. AB - To identify the subtypes of atypia of undetermined significance (AUS) that confers a different magnitude for the risk of malignancy (RM), thyroid fine needle aspiration (FNA) cases carrying a diagnosis of "atypical follicular cells" or "follicular lesion" with surgical pathology followup were included in this study. The direct smears of the aspirates were rereviewed and subclassified into four subgroups based on cytomorphology: AUS cannot exclude follicular neoplasm (AUS-FN), AUS cannot exclude Hurthle cell neoplasm (AUS-HCN), AUS cannot exclude papillary carcinoma (AUS-PTC) and AUS, not otherwise specified (AUS-NOS). Based on the followup histopathologic findings, RM not including papillary microcarcinoma (PMC), RM including PMC and the risk of neoplasm (RN) were calculated for each of the four AUS subgroups. A total of 138 AUS cases were subclassified into AUS-NOS (48), AUS-PTC (41), AUS-FN (32), and AUS-HCN (17). RM not including PMC was 32% for AUS-PTC (P < 0.001), 25% for AUS-FN, 8% for AUS NOS, 0% for AUS-HCN, and 18% for all AUS cases. RM including PMC was 54% for AUS PTC (P < 0.001), 34% for AUS-FN, 19% for AUS-NOS, 18% for AUS-HCN, and 33% for all AUS cases. RN was 63% for AUS-PTC (P = 0.05), 81% for AUS-FN (P < 0.01), AUS HCN 53%, AUS-NOS 44% and 59% for all cases. In our study, subclassification enabled us to further divide AUS cases into high- and low-risk groups. The high risk group includes AUS-PTC with a significantly higher risk of malignancy and AUS-FN with a significantly higher risks of neoplasm. AUS-HCN and AUS-NOS subgroups demonstrate a lower risk of malignancy of <10%. PMID- 24166936 TI - Nanoparticle impacts show high-ionic-strength citrate avoids aggregation of silver nanoparticles. AB - Quantitative analytical detection and sizing of silver nanoparticles is achieved by applying the new electrochemical method nanoparticle coulometry. For the first time, tri-sodium citrate is used as both an electrolyte and a nanoparticle stabilizing agent, allowing the individual particles to be addressed. PMID- 24166934 TI - Prospects on strategies for therapeutically targeting oncogenic regulatory factors by small-molecule agents. AB - Although the Human Genome Project has raised much hope for the identification of druggable genetic targets for cancer and other diseases, this genetic target based approach has not improved productivity in drug discovery over the traditional approach. Analyses of known human target proteins of currently marketed drugs reveal that these drugs target only a limited number of proteins as compared to the whole proteome. In contrast to genome-based targets, mechanistic targets are derived from empirical research, at cellular or molecular levels, in disease models and/or in patients, thereby enabling the exploration of a greater number of druggable targets beyond the genome and epigenome. The paradigm shift has made a tremendous headway in developing new therapeutic agents targeting different clinically relevant mechanisms/pathways in cancer cells. In this Prospects article, we provide an overview of potential drug targets related to the following four emerging areas: (1) tumor metabolism (the Warburg effect), (2) dysregulated protein turnover (E3 ubiquitin ligases), (3) protein-protein interactions, and (4) unique DNA high-order structures and protein-DNA interactions. Nonetheless, considering the genetic and phenotypic heterogeneities that characterize cancer cells, the development of drug resistance in cancer cells by adapting signaling circuitry to take advantage of redundant pathways or feedback/crosstalk systems is possible. This "phenotypic adaptation" underlies the rationale of using therapeutic combinations of these targeted agents with cytotoxic drugs. PMID- 24166937 TI - Time to improve and recover from depressive symptoms and interpersonal problems in a clinical trial. AB - Results from an earlier clinical trial comparing narrative therapy with cognitive behavioural therapy (Lopes et al., 2013) suggested that narrative therapy is efficacious for depression. However, there were significant differences in symptom reduction on the Beck Depression Inventory-II, favouring cognitive behavioural therapy, if dropouts were included in the analysis, suggesting that time to recovery or improvement would differ in both treatments. Contrarily, results showed that treatment assignment was not a predictor for differential effect. Using a survival analytic approach, it was found that four sessions were necessary for 50% improvement and 16 sessions for 50% recovery. Additionally, depressive symptoms changes occurred significantly faster than interpersonal changes, again regardless of treatment assignment. These results support previous findings of the dose-response literature and of the phase model of change, with the advantage of being specific to psychotherapy with depressive clients. PMID- 24166938 TI - Distinctive patterns of naive/memory subset distribution and cytokine expression in CD4 T lymphocytes in ZAP-70 B-chronic lymphocytic patients. AB - BACKGROUND: ZAP-70 upregulation in B chronic lymphocytic leukemia (B-CLL) cells is a recognized marker of poor prognosis in these patients; the biological basis of this differential clinical outcome nonetheless remains unknown. ZAP-70 overexpression is considered a surrogate marker of a B-CLL cell subset. To test whether the differential biological characteristics of these patients also include the T helper population, we studied naive, non-terminated memory (NTEM), terminated memory (TEM) and central memory (CM) cells, and cytokine expression by CD4 T lymphocytes from ZAP-70(+) and ZAP-70(-) B-CLL patients. METHODS: Expression of CD3, CD8, CD45RA, CD27, and CD28 antigens and intracytoplasmic cytokine production (IFNgamma, IL-2, IL-4, IL-10, and TNFalpha) were assessed simultaneously by nine-color flow-cytometry in peripheral blood lymphocytes from B-CLL patients. B cell ZAP-70 expression in B-CLL cells was also analyzed by flow cytometry. RESULTS: Compared to ZAP-70(-) B-CLL patients, ZAP-70(+) B-CLL patients showed 1) significant reduction in the naive T helper subset and expansion of NTEM and TEM subsets, 2) a decrease in the percentage of activated CD4 T lymphocytes expressing IFNgamma, TNFalpha, and IL-2, and 3) an increase in the percentage of CD4 T lymphocytes expressing IL-4 or IL-10. CONCLUSIONS: In conclusion, in early stage B-CLL patients, ZAP-70 upregulation is associated with distinct patterns of activation/differentiation stage subset distribution and of cytokine expression in CD4 T lymphocytes. PMID- 24166939 TI - Effects of dietary induced weight loss on exercise-induced bronchoconstriction in overweight and obese children. AB - RATIONALE: Previous studies showed that obesity in asthmatic children is associated with more severe exercise-induced bronchoconstriction (EIB), compared with non-obese asthmatic children. This study investigates the effect of weight loss on EIB in overweight and obese asthmatic children. METHODS: In this intervention study, children aged 8-18 years with EIB and moderate to severe overweight, followed a diet based on healthy daily intake for 6 weeks. Before and after the diet period they underwent an exercise challenge test in cold air. Primary outcome was change in exercise-induced fall in FEV1 and relation between weight loss and EIB. Secondary outcomes were changes in recovery of FEV1 ("area under the curve"; AUC), fraction of exhaled nitric oxide (FeNO) and scores of the Pediatric Asthma Quality of Life Questionnaire (PAQLQ) and Asthma Control Questionnaire (ACQ). RESULTS: Twenty children completed the study. After the diet period, weight, and body mass index (BMI) were significantly reduced (changes respectively -2.6% and -1.5 kg/m(2), P < 0.01). There was a significant improvement of the percentage exercise-induced fall in FEV1 (30.6% vs. 21.8%, P < 0.01), AUC and PAQLQ score. The reduction in BMI z-score was significantly related to the reduction in the percentage exercise-induced fall in FEV1 in children that lost weight (r = 0.53, P = 0.03). There were no changes in FeNO and ACQ. CONCLUSIONS: Dietary induced weight loss in overweight and obese asthmatic children leads to significant reduction in severity of EIB and improvement of the quality of life. The reduction in BMI z-score is significantly related to the improvement of EIB. PMID- 24166940 TI - Commentary. PMID- 24166941 TI - Training cognitive flexibility in patients with anorexia nervosa: a pilot randomized controlled trial of cognitive remediation therapy. AB - OBJECTIVE: Inefficient cognitive flexibility is considered a neurocognitive trait marker involved in the development and maintenance of anorexia nervosa (AN). Cognitive Remediation Therapy (CRT) is a specific treatment targeting this cognitive style. The aim of this study was to investigate the feasibility and efficacy (by estimating the effect size) of specifically tailored CRT for AN, compared to non-specific cognitive training. METHOD: A prospective, randomized controlled, superiority pilot trial was conducted. Forty women with AN receiving treatment as usual (TAU) were randomized to receive either CRT or non-specific neurocognitive therapy (NNT) as an add-on. Both conditions comprised 30 sessions of computer-assisted (21 sessions) and face-to-face (9 sessions) training over a 3-week period. CRT focused specifically on cognitive flexibility. NNT was comprised of tasks designed to improve attention and memory. The primary outcome was performance on a neuropsychological post-treatment assessment of cognitive set-shifting. RESULTS: Data available from 25 treatment completers were analyzed. Participants in the CRT condition outperformed participants in the NNT condition in cognitive set-shifting at the end of the treatment (p = 0.027; between-groups effect size d = 0.62). Participants in both conditions showed high treatment acceptance. DISCUSSION: This study confirms the feasibility of CRT for AN, and provides a first estimate of the effect size that can be achieved using CRT for AN. Furthermore, the present findings corroborate that neurocognitive training for AN should be tailored to the specific cognitive inefficiencies of this patient group. PMID- 24166943 TI - The 'harsh and the hassle' of science and the slide to irreproducibility: a concern that must be addressed by investigators and journals. PMID- 24166942 TI - Relationship between onset of hypocalcemic symptoms and the recovery time from transient hypocalcemia after total thyroidectomy. AB - BACKGROUND: The purpose of this study was to examine whether the time required for recovery from transient hypoparathyroidism is correlated with the onset of hypocalcemic symptoms in patients with total thyroidectomy. METHODS: Medical records of 54 patients were retrospectively reviewed. The correlation between the onset of hypocalcemic symptoms and the recovery time were compared for all patients divided into 3 groups based on first appearance of hypocalcemic symptoms; group 1, onset within 24 hours; group 2, onset at 24 to 48 hours; and group 3, onset >48 hours. RESULTS: There was a negative correlation between onset and recovery times (p < .001). Serum parathyroid hormone levels 1 year after surgery were significantly lower in group 1 than in groups 2 or 3 (p < .001). CONCLUSION: Recovery time can be predicted by time of onset of hypocalcemic symptoms and signs. Earlier onset leads to longer recovery times. PMID- 24166944 TI - Scientific journals' responsibility in shaping public health policy. PMID- 24166945 TI - Policy decisions on endocrine disruptors should be based on science across disciplines: a response to Dietrich et al. PMID- 24166946 TI - Proteomic analysis for Type I interferon antagonism of Japanese encephalitis virus NS5 protein. AB - Japanese encephalitis virus (JEV) nonstructural protein 5 (NS5) exhibits a Type I interferon (IFN) antagonistic function. This study characterizes Type I IFN antagonism mechanism of NS5 protein, using proteomic approach. In human neuroblastoma cells, NS5 expression would suppress IFNbeta-induced responses, for example, expression of IFN-stimulated genes PKR and OAS as well as STAT1 nuclear translocation and phosphorylation. Proteomic analysis showed JEV NS5 downregulating calreticulin, while upregulating cyclophilin A, HSP 60 and stress induced-phosphoprotein 1. Gene silence of calreticulin raised intracellular Ca(2+) levels while inhibiting nuclear translocalization of STAT1 and NFAT-1 in response to IFNbeta, thus, indicating calreticulin downregulation linked with Type I IFN antagonism of JEV NS5 via activation of Ca(2+) /calicineurin. Calcineurin inhibitor cyclosporin A attenuated NS5-mediated inhibition of IFNbeta induced responses, for example, IFN-sensitive response element driven luciferase, STAT1-dependent PKR mRNA expression, as well as phosphorylation and nuclear translocation of STAT1. Transfection with calcineurin (vs. control) siRNA enhanced nuclear translocalization of STAT1 and upregulated PKR expression in NS5 expressing cells in response to IFNbeta. Results prove Ca(2+) , calreticulin, and calcineurin involvement in STAT1-mediated signaling as well as a key role of JEV NS5 in Type I IFN antagonism. This study offers insights into the molecular mechanism of Type I interferon antagonism by JEV NS5. PMID- 24166947 TI - The relationship between work-related rumination and evening and morning salivary cortisol secretion. AB - The perseverative cognition hypothesis suggests that worry/ruminative thinking prolongs stress-related physiological activation. This study explored the association of work-related rumination with salivary cortisol sampled at 10 pm and the cortisol awakening response (CAR) the following morning. On a mid-week evening, 108 school teachers completed a small diary about their work-related thoughts and gave a saliva cortisol sample at 10 pm. The following morning, they gave four additional saliva samples: at awakening and at 15, 30 and 45 min after awakening, along with a rating of their anticipatory thoughts about work. The CAR was calculated as the percentage increase in cortisol secretion from awakening to 30 min, and the sample was divided at their respective medians to classify participants into low and high rumination groups. Cortisol secretion was found to be significantly greater in the high compared with the low ruminators at 10 pm, and this effect was not related to leisure activities or work patterns during the evening. For the morning measures, high ruminators demonstrated a flattened CAR relative to the low ruminators, and this effect appeared to be associated with sleep disturbance during the night. Ruminating about work-related issues is associated with cortisol secretion, and our findings support the perseverative cognition hypothesis. PMID- 24166948 TI - Increased age is associated with epigenetic and structural changes in chromatin from neuronal nuclei. AB - Chromatin organization has been considered to play a major role on aging, by regulating DNA accessibility to transcription and repair machinery. Such organization can be modulated by epigenetic events, such as DNA methylation and histone post-translational modifications. Since changes on gene expression profiles have been described in aged neurons, our aim was to study the age dependent relationship between structural and epigenetic alterations on chromatin of cortical neurons from mice. For this purpose, isolated neuronal nuclei from mice of two ages were studied by image analysis after cytochemistry, or assessed for chromatin accessibility by enzymatic digestion. Additionally, two epigenetic marks, for open and for densely packed chromatin fibers were quantified. Results indicate epigenetically driven alterations on chromatin organization of cortical neurons with advancing age, whose fibers seem to undergo redistribution and unpackaging. Since increased transcriptional activity is not characteristic of aged neurons, these loosened chromatin fibers may be associated with impaired genome stability, as well as with increased accessibility of repair machinery to a life span damaged DNA. PMID- 24166949 TI - HLA class II (DR0401) molecules induce Foxp3+ regulatory T cell suppression of B cells in Plasmodium yoelii strain 17XNL malaria. AB - Unlike human malaria parasites that induce persistent infection, some rodent malaria parasites, like Plasmodium yoelii strain 17XNL (Py17XNL), induce a transient (self-curing) malaria infection. Cooperation between CD4 T cells and B cells to produce antibodies is thought to be critical for clearance of Py17XNL parasites from the blood, with major histocompatibility complex (MHC) class II molecules being required for activation of CD4 T cells. In order to better understand the correspondence between murine malaria models and human malaria, and in particular the role of MHC (HLA) class II molecules, we studied the ability of humanized mice expressing human HLA class II molecules to clear Py17XNL infection. We showed that humanized mice expressing HLA-DR4 (DR0401) molecules and lacking mouse MHC class II molecules (EA(0)) have impaired production of specific antibodies to Py17XNL and cannot cure the infection. In contrast, mice expressing HLA-DR4 (DR0402), HLA-DQ6 (DQ0601), HLA-DQ8 (DQ0302), or HLA-DR3 (DR0301) molecules in an EA(0) background were able to elicit specific antibodies and self-cure the infection. In a series of experiments, we determined that the inability of humanized DR0401.EA(0) mice to elicit specific antibodies was due to expansion and activation of regulatory CD4(+) Foxp3(+) T cells (Tregs) that suppressed B cells to secrete antibodies through cell-cell interactions. Treg depletion allowed the DR0401.EA(0) mice to elicit specific antibodies and self-cure the infection. Our results demonstrated a differential role of MHC (HLA) class II molecules in supporting antibody responses to Py17XNL malaria and revealed a new mechanism by which malaria parasites stimulate B cell suppressogenic Tregs that prevent clearance of infection. PMID- 24166950 TI - Characteristic age distribution of Plasmodium vivax infections after malaria elimination on Aneityum Island, Vanuatu. AB - Resurgence is a major concern after malaria elimination. After the initiation of the elimination program on Aneityum Island in 1991, microscopy showed that Plasmodium falciparum disappeared immediately, whereas P. vivax disappeared from 1996 onward, until P. vivax cases were reported in January 2002. By conducting malariometric surveys of the entire population of Aneityum, we investigated the age distribution of individuals with parasites during this epidemic in the context of antimalarial antibody levels and parasite antigen diversity. In July 2002, P. vivax infections were detected by microscopy in 22/759 individuals: 20/298 born after the beginning of the elimination program in 1991, 2/126 born between 1982 and 1991, and none of 335 born before 1982. PCR increased the number of infections detected to 77, distributed among all age groups. Prevalences were 12.1%, 16.7%, and 6.0%, respectively (P < 0.001). In November, a similar age pattern was found, but with fewer infections: 6/746 and 39/741 individuals were found to be infected by microscopy and PCR, respectively. The frequencies of antibody responses to P. vivax were significantly higher in individuals born before 1991 than in younger age groups and were similar to those on Malakula Island, an area of endemicity. Remarkably low antigen diversity (h, 0.15) of P. vivax infections was observed on Aneityum compared with the other islands (h, 0.89 to 1.0). A P. vivax resurgence was observed among children and teenagers on Aneityum, an age distribution similar to those before elimination and on islands where P. vivax is endemic, suggesting that in the absence of significant exposure, immunity may persist, limiting infection levels in adults. The limited parasite gene pool on islands may contribute to this protection. PMID- 24166951 TI - Serogroup-specific interaction of Neisseria meningitidis capsular polysaccharide with host cell microtubules and effects on tubulin polymerization. AB - We have previously shown that during late stages of the infectious process, serogroup B meningococci (MenB) are able to escape the phagosome of in vitro infected human epithelial cells. They then multiply in the cytosolic environment and spread intracellularly and to surrounding cells by exploiting the microtubule cytoskeleton, as suggested by results of infections in the presence of microtubule inhibitors and evidence of nanotubes connecting neighboring cells. In this study, by using microtubule binding assays with purified microtubule asters and bundles and microtubule bundles synthesized in vitro, we demonstrate that the MenB capsule directly mediates the interaction between bacteria and microtubules. The direct interaction between the microtubules and the MenB capsular polysaccharide was confirmed by coimmunoprecipitation experiments. Unexpectedly, serogroup C meningococci (MenC), which have a capsular polysaccharide that differs from that of MenB only by its anomeric linkage, alpha(2->9) instead of alpha(2->8), were not able to interact with the microtubules, and the lack of interaction was not due to capsular polysaccharide O-acetylation that takes place in most MenC strains but not in MenB strains. Moreover, we demonstrate that the MenB capsular polysaccharide inhibits tubulin polymerization in vitro. Thus, at variance with MenC, MenB may interfere with microtubule dynamics during cell infection. PMID- 24166952 TI - Candida albicans airway exposure primes the lung innate immune response against Pseudomonas aeruginosa infection through innate lymphoid cell recruitment and interleukin-22-associated mucosal response. AB - Pseudomonas aeruginosa and Candida albicans are two pathogens frequently encountered in the intensive care unit microbial community. We have demonstrated that C. albicans airway exposure protected against P. aeruginosa-induced lung injury. The goal of the present study was to characterize the cellular and molecular mechanisms associated with C. albicans-induced protection. Airway exposure by C. albicans led to the recruitment and activation of natural killer cells, innate lymphoid cells (ILCs), macrophages, and dendritic cells. This recruitment was associated with the secretion of interleukin-22 (IL-22), whose neutralization abolished C. albicans-induced protection. We identified, by flow cytometry, ILCs as the only cellular source of IL-22. Depletion of ILCs by anti CD90.2 antibodies was associated with a decreased IL-22 secretion and impaired survival after P. aeruginosa challenge. Our results demonstrate that the production of IL-22, mainly by ILCs, is a major and inducible step in protection against P. aeruginosa-induced lung injury. This cytokine may represent a clinical target in Pseudomonas aeruginosa-induced lung injury. PMID- 24166953 TI - Limited role of nuclear receptor Nur77 in Escherichia coli-induced peritonitis. AB - Nuclear receptor Nur77 (NR4A1, TR3, or NGFI-B) has been shown to play an anti inflammatory role in macrophages, which have a crucial function in defense against peritonitis. The function of Nur77 in Escherichia coli-induced peritoneal sepsis has not yet been investigated. Wild-type and Nur77-knockout mice were inoculated with E. coli, and bacterial outgrowth, cell recruitment, cytokine profiles, and tissue damage were investigated. We found only a minor transient decrease in bacterial loads in lung and liver of Nur77-knockout compared to wild type mice at 14 h postinfection, yet no changes were found in the peritoneal lavage fluid or blood. No differences in inflammatory cytokine levels or neutrophil/macrophage numbers were observed, and bacterial loads were equal in wild-type and Nur77-knockout mice at 20 h postinfection in all body compartments tested. Also, isolated peritoneal macrophages did not show any differences in cytokine expression patterns in response to E. coli. In endothelial cells, Nur77 strongly downregulated both protein and mRNA expression of claudin-5, VE cadherin, occludin, ZO-1, and beta-catenin, and accordingly, these genes were upregulated in lungs of Nur77-deficient mice. Functional permeability tests pointed toward a strong role for Nur77 in endothelial barrier function. Indeed, tissue damage in E. coli-induced peritonitis was notably modulated by Nur77; liver necrosis and plasma aspartate aminotransferase (ASAT)/alanine aminotransferase (ALAT) levels were lower in Nur77-knockout mice. These data suggest that Nur77 does not play a role in the host response to E. coli in the peritoneal and blood compartments. However, Nur77 does modulate bacterial influx into the organs via increased vascular permeability, thereby aggravating distant organ damage. PMID- 24166954 TI - Response of extraintestinal pathogenic Escherichia coli to human serum reveals a protective role for Rcs-regulated exopolysaccharide colanic acid. AB - Extraintestinal Escherichia coli (ExPEC) organisms are the leading cause of Gram negative bacterial bloodstream infections. These bacteria adapt to survival in the bloodstream through expression of factors involved in scavenging of nutrients and resisting the killing activity of serum. In this study, the transcriptional response of a prototypic ExPEC strain (CFT073) to human serum was investigated. Resistance of CFT073 to the bactericidal properties of serum involved increased expression of envelope stress regulators, including CpxR, sigmaE, and RcsB. Many of the upregulated genes induced by active serum were regulated by the Rcs two component system. This system is triggered by envelope stress such as changes to cell wall integrity. RcsB-mediated serum resistance was conferred through induction of the exopolysaccharide colanic acid. Production of this exopolysaccharide may be protective while cell wall damage caused by serum components is repaired. PMID- 24166955 TI - Human lung tissue explants reveal novel interactions during Legionella pneumophila infections. AB - Histological and clinical investigations describe late stages of Legionnaires' disease but cannot characterize early events of human infection. Cellular or rodent infection models lack the complexity of tissue or have nonhuman backgrounds. Therefore, we developed and applied a novel model for Legionella pneumophila infection comprising living human lung tissue. We stimulated lung explants with L. pneumophila strains and outer membrane vesicles (OMVs) to analyze tissue damage, bacterial replication, and localization as well as the transcriptional response of infected tissue. Interestingly, we found that extracellular adhesion of L. pneumophila to the entire alveolar lining precedes bacterial invasion and replication in recruited macrophages. In contrast, OMVs predominantly bound to alveolar macrophages. Specific damage to septa and epithelia increased over 48 h and was stronger in wild-type-infected and OMV treated samples than in samples infected with the replication-deficient, type IVB secretion-deficient DotA(-) strain. Transcriptome analysis of lung tissue explants revealed a differential regulation of 2,499 genes after infection. The transcriptional response included the upregulation of uteroglobin and the downregulation of the macrophage receptor with collagenous structure (MARCO). Immunohistochemistry confirmed the downregulation of MARCO at sites of pathogen induced tissue destruction. Neither host factor has ever been described in the context of L. pneumophila infections. This work demonstrates that the tissue explant model reproduces realistic features of Legionnaires' disease and reveals new functions for bacterial OMVs during infection. Our model allows us to characterize early steps of human infection which otherwise are not feasible for investigations. PMID- 24166956 TI - Importance of bacillithiol in the oxidative stress response of Staphylococcus aureus. AB - In Staphylococcus aureus, the low-molecular-weight thiol called bacillithiol (BSH), together with cognate S-transferases, is believed to be the counterpart to the glutathione system of other organisms. To explore the physiological role of BSH in S. aureus, we constructed mutants with the deletion of bshA (sa1291), which encodes the glycosyltransferase that catalyzes the first step of BSH biosynthesis, and fosB (sa2124), which encodes a BSH-S-transferase that confers fosfomycin resistance, in several S. aureus strains, including clinical isolates. Mutation of fosB or bshA caused a 16- to 60-fold reduction in fosfomycin resistance in these S. aureus strains. High-pressure liquid chromatography analysis, which quantified thiol extracts, revealed some variability in the amounts of BSH present across S. aureus strains. Deletion of fosB led to a decrease in BSH levels. The fosB and bshA mutants of strain COL and a USA300 isolate, upon further characterization, were found to be sensitive to H2O2 and exhibited decreased NADPH levels compared with those in the isogenic parents. Microarray analyses of COL and the isogenic bshA mutant revealed increased expression of genes involved in staphyloxanthin synthesis in the bshA mutant relative to that in COL under thiol stress conditions. However, the bshA mutant of COL demonstrated decreased survival compared to that of the parent in human whole-blood survival assays; likewise, the naturally BSH-deficient strain SH1000 survived less well than its BSH-producing isogenic counterpart. Thus, the survival of S. aureus under oxidative stress is facilitated by BSH, possibly via a FosB-mediated mechanism, independently of its capability to produce staphyloxanthin. PMID- 24166957 TI - Role of leptin-mediated colonic inflammation in defense against Clostridium difficile colitis. AB - The role of leptin in the mucosal immune response to Clostridium difficile colitis, a leading cause of nosocomial infection, was studied in humans and in a murine model. Previously, a mutation in the receptor for leptin (LEPR) was shown to be associated with susceptibility to infectious colitis and liver abscess due to Entamoeba histolytica as well as to bacterial peritonitis. Here we discovered that European Americans homozygous for the same LEPR Q223R mutation (rs1137101), known to result in decreased STAT3 signaling, were at increased risk of C. difficile infection (odds ratio, 3.03; P = 0.015). The mechanism of increased susceptibility was studied in a murine model. Mice lacking a functional leptin receptor (db/db) had decreased clearance of C. difficile from the gut lumen and diminished inflammation. Mutation of tyrosine 1138 in the intracellular domain of LepRb that mediates signaling through the STAT3/SOCS3 pathway also resulted in decreased mucosal chemokine and cell recruitment. Collectively, these data support a protective mucosal immune function for leptin in C. difficile colitis partially mediated by a leptin-STAT3 inflammatory pathway that is defective in the LEPR Q223R mutation. Identification of the role of leptin in protection from C. difficile offers the potential for host-directed therapy and demonstrates a connection between metabolism and immunity. PMID- 24166958 TI - Maternal infection with Schistosoma japonicum induces a profibrotic response in neonates. AB - The global burden of schistosomiasis is significant, with fibrosis a major associated morbidity and the primary cause of mortality. We have previously shown that schistosomiasis during pregnancy upregulates proinflammatory cytokines in the cord blood. In this study, we extend these findings to include a large panel of fibrosis-associated markers. We developed a multiplex bead-based assay to measure the levels of 35 proteins associated with fibrosis. Cord blood from 109 neonates born to mothers residing in an area of Schistosoma japonicum endemicity was assessed for these molecules. Ten mediators were elevated in the cord blood from schistosome-infected pregnancies, including insulin-like growth factor 1 (IGF-1), tumor growth factor beta1 (TGF-beta1), connective tissue growth factor (CTGF), procollagen I carboxy-terminal propeptide (PICP), amino-telopeptide of type 1 collagen (ICTP), collagen VI, desmosine, matrix metalloproteinase 2 (MMP 2), tissue inhibitor of metalloproteinases 1 (TIMP-1), and TIMP-4. Many of these were also positively correlated with preterm birth (PICP, ICTP, MMP-2, TGF-beta1, desmosine, CTGF, TIMP-1). In addition, birth weight was 168 g lower for infants with detectable levels of CTGF than for those with CTGF levels below the level of detection. Maternal schistosomiasis results in upregulation of fibrosis associated proteins in the cord blood of the neonate, a subset of which are also associated with adverse birth outcomes. As the first report of fibrosis associated molecules altered in the newborn of infected mothers, this study has broad implications for the health of the fetus, stretching from gestation to adulthood. PMID- 24166959 TI - Deficiency of the myeloid differentiation primary response molecule MyD88 leads to an early and rapid development of Helicobacter-induced gastric malignancy. AB - Approximately 50% of the world's population is infected with Helicobacter pylori, leading to chronic inflammation, which increases the risk for gastric adenocarcinoma. MyD88 is a key adaptor molecule in inflammatory pathways involved in interleukin 1 (IL-1)/IL-18/Toll-like receptor signaling and has been shown to have divergent effects in carcinogenesis. The role of MyD88 in Helicobacter induced gastric malignancy is unknown. Using a mouse model of Helicobacter induced gastric cancer, we assessed the role of MyD88 in cancer development by evaluating gastric histopathology, apoptosis, proliferation, and cytokine expression. Infection of MyD88-deficient (Myd88(-/-)) mice with Helicobacter resulted in early and rapid advancement to gastric dysplasia as early as 25 weeks postinfection. The progression of Helicobacter-induced disease to precancerous and cancerous lesions in the absence of MyD88 signaling was accompanied by increased gastric epithelial apoptosis and proliferation. In addition, inflammatory cytokines, including tumor necrosis factor alpha (TNF-alpha), gamma interferon (IFN-gamma), IL-6, and IL-1beta were highly expressed in association with the development of gastric dysplasia. These data suggest that MyD88 signaling retards development and progression to cancer during Helicobacter infection. This is the first study to show evidence of MyD88 protection in an infection-driven inflammation-associated cancer model. PMID- 24166961 TI - Influenza vaccines and guillain-barre syndrome: the continuing question. AB - Influenza is a global public health problem, with complications of seasonal influenza resulting in thousands of deaths and substantial morbidity worldwide. Periodically, particularly virulent viral strains emerge, resulting in more infections and fatalities (e.g., influenza A [H1N1] virus and influenza A/H5N1, "bird flu"). Influenza infection may be prevented or mitigated by vaccination; seasonal vaccine is highly effective in reducing clinical illness and limiting viral spread through respiratory droplets. PMID- 24166962 TI - Harmonization of European neurology education: the junior doctor's perspective. AB - The objective of this article, written by executives of the European Association of Young Neurologists and Trainees (EAYNT), is to illustrate the status quo of neurology training in Europe and give an outlook on ongoing efforts and prospects for junior neurologists. The European Union is an economic and political union that currently encompasses 27 member states with more than 500 million inhabitants (or 7.3% of the world population) (interested readers are referred to http://en.wikipedia.org/wiki/European_Union). Countries of the European Union act as a single market with free movement of citizens, goods, services, and finances. As a consequence, a diploma and postgraduate training obtained in one EU country will be automatically recognized by all other EU member states. At the Lisbon European Council in March 2000, the Heads of State or Government signed a treaty that expresses their ambition of making Europe "the most competitive and dynamic knowledge-based economy in the world, capable of sustainable economic growth with more and better jobs and greater social cohesion" (www.en.wikipedia.org/wiki/Lisbon_Strategy). More than 1.6 million physicians in all the different medical specialties are represented by the European Union of Medical Specialists (UEMS). The UEMS was founded in 1958 and the objectives include the study, promotion, and harmonization of the highest level of training of medical specialists, medical practice, and health care within the European Union. The European Board of Neurology (UEMS-EBN; www.uems-neuroboard.org) is in charge of the implementation of the UEMS policy regarding neurology. PMID- 24166960 TI - Ferric uptake regulator-dependent antinitrosative defenses in Salmonella enterica serovar Typhimurium pathogenesis. AB - Herein we report an important role for the ferric uptake regulator (Fur) in the resistance of Salmonella enterica serovar Typhimurium to the reactive nitrogen species produced by inducible nitric oxide (NO) synthase in an NRAMP1(r) murine model of acute systemic infection. The expression of fur protected Salmonella grown under normoxic and hypoxic conditions against the bacteriostatic activity of NO. The hypersusceptibility of fur-deficient Salmonella to the cytotoxic actions of NO coincides with a marked repression of respiratory activity and the reduced ability of the bacteria to detoxify NO. A fur mutant Salmonella strain contained reduced levels of the terminal quinol oxidases of the electron transport chain. Addition of the heme precursor delta-aminolevulinic acid restored the cytochrome content, respiratory activity, NO consumption, and wild type growth in bacteria undergoing nitrosative stress. The innate antinitrosative defenses regulated by Fur added to the adaptive response associated with the NO detoxifying activity of the flavohemoprotein Hmp. Our investigations indicate that, in addition to playing a critical role in iron homeostasis, Fur is an important antinitrosative determinant of Salmonella pathogenesis. PMID- 24166963 TI - The pivotal sign of CANVAS. AB - A 75-year-old woman complained about insecure gait since age 55. Clinical examination revealed signs of cerebellar ataxia, bilateral vestibulopathy, and peripheral sensory impairment. Sensory nerve action potentials were absent. The visually enhanced vestibulo-ocular reflex (VVOR) was impaired (video on the Neurology((r)) Web site at www.neurology.org, figure 1) and the diagnosis of cerebellar ataxia (figure 2) with neuropathy and bilateral vestibular areflexia syndrome (CANVAS) was made.(1) CANVAS is considered to be a recessive disorder with a mean age at onset of 60 years.(2) VVOR impairment is its characteristic clinical sign.(2) It can only be elicited if both smooth-pursuit eye movements and the vestibulo-ocular reflex are deficient. Normally, both are redundant at low head velocities.(2.) PMID- 24166965 TI - Ultrasound as the first choice for peripheral nerve imaging? PMID- 24166964 TI - Pearls & Oy-sters: ictal syncope in a patient with temporal lobe epilepsy. PMID- 24166967 TI - Mystery case: a young boy with myoclonic jerks. AB - A 16-year-old right-handed boy presented for consultation for recent development of seizures. He is the product of a normal pregnancy and delivery without a history of developmental delay, head trauma, or family history of epilepsy. A year and a half prior to our consultation, the patient noted that his hand would suddenly jerk across the page while writing in his morning classes. Stress would exacerbate the jerks. Six months later, after staying up late the previous night, the patient awoke early and began to play on the computer when both of his hands suddenly jerked multiple times. He then fell over and began seizing. His mother witnessed tonic contraction of his body followed by clonic activity. He was brought by ambulance to the nearest hospital where a CT head was reported normal. PMID- 24166968 TI - Teaching neuroimages: neurocysticercosis with subretinal cyst. AB - A 30-year-old woman presented with headache and diminution of vision of 2 weeks' duration. Visual acuity was finger counting at 1 meter in the right eye. Fundus examination showed a subretinal cyst (figure 1A). Neurologic examination was normal. Neuroimaging revealed neurocysticercosis (figure 2A). Ultrasound orbit showed subretinal cysticercosis (figure 2B). The patient was started on steroids and laser photocoagulation was recommended. PMID- 24166969 TI - Teaching neuroimages: microvascular decompression of the optic nerve. AB - Vascular compression is a known cause of cranial nerve dysfunction in a variety of disease states including trigeminal neuralgia, hemifacial spasm, and hypoglossal neuralgia.(1,2.) PMID- 24166970 TI - Childhood absence epilepsy: poor attention is more than seizures. AB - Dr. Masur and colleagues(1) from the Childhood Absence Epilepsy Study Group tried to answer a few important questions regarding childhood absence epilepsy (CAE) in their article "Pretreatment cognitive deficits and treatment effects on attention in childhood absence epilepsy." First, they wanted to know whether children with absence epilepsy have any problems with thinking before starting medications. If the children have problems with thinking, the authors wanted to identify the specific types of thinking problems the children have. The authors also wanted to assess what effect seizure medications have on attention in these children. In principle, medications could improve or worsen attention. The possible effects of medication on attention may or may not depend on whether the medications control the seizures. PMID- 24166971 TI - Uterine cervical ectopy during reproductive age: cytological and microbiological findings. AB - Cervical ectopy is common in adolescents, pregnant women, and those taking high doses of estrogen-containing contraceptives. The majority of cases have spontaneous reversion, but some cases can be persistent. Studies suggested that the adequacy of a Pap smear could be affected and there is an increased risk cervical infections. This study is a cross-sectional study conducted from December 2009 to February 2011 with 457 women with cervical ectopy and 736 without ectopy. Cervical samples were collected in vials for analysis by ThinPrep cytology (Hologic, Marlborough, MA). The Mann-Whitney test and Fisher's exact test (95% CI) were applied. The study was approved by the ethics committee of the Federal University of Ceara. The mean ages of the study group and control group were 28.7 (+/-14.8) and 33.6 (+/-7.5) years old, respectively (P < 0.0001). Negative diagnosis for malignancy and intraepithelial lesion was present in 399 (87%) cases and 705 (96%) in the study and control groups, respectively (P < 0.0001). Shift in the flora suggestive of bacterial vaginosis (BV) was observed more frequently in the study group: 74 (16.2%) than in the control group: 86(11.7%) (P = 0.017). The differences among the other morphotypes showed no significance. The smears were atypical in 12.7% (58/457) of the patients from the study group and in 4.2% (31/736) in the control group (P < 0.001; RR = 3 [2.033 4.712]). The association between ectopy and inflammatory cytology, the presence of the shift in the flora suggestive of BV and cytological atypia is evident. PMID- 24166972 TI - A single-electrode based triboelectric nanogenerator as self-powered tracking system. AB - A newly designed triboelectric nanogenerator (TENG) is demonstrated based on a contact-separation process between an Al foil and a finite size polyamide (PA) film. The working mechanism is based on charge transfer between the Al foil and ground. A 4*4 matrix of TENG array can be used for tracking motion by recording the output voltages signals in real-time to form a pressure map. PMID- 24166973 TI - Cutting edge: feed-forward activation of phospholipase Cgamma2 via C2 domain mediated binding to SLP65. AB - Ag-mediated B cell stimulation relies on phospholipase Cgamma2 (PLCgamma2) for Ca(2+) mobilization. Enzymatic activity of PLCgamma2 is triggered upon Src homology 2 domain-mediated binding to the tyrosine-phosphorylated adaptor SLP65. However, SLP65 phosphorylation outlasts the elevation of cytosolic Ca(2+) concentration suggesting additional levels of PLCgamma2 regulation. We show in this article that the functionality of the PLCgamma2/SLP65 complex is controlled by the weakly characterized C2 domain of PLCgamma2. Usually C2 domains bind membrane lipids, but that of PLCgamma2 docks in a Ca(2+)-regulated manner to a distinct phosphotyrosine of SLP65. Hence, early Ca(2+) fluxing provides feed forward signal amplification by promoting anchoring of the PLCgamma2 C2 domain to phospho-SLP65. As the cellular Ca(2+) resources become exhausted, the concomitant decline of Ca(2+) dampens the C2-phosphotyrosine interaction so that PLCgamma2 activation terminates despite sustained SLP65 phosphorylation. PMID- 24166974 TI - Sialylation of Campylobacter jejuni endotoxin promotes dendritic cell-mediated B cell responses through CD14-dependent production of IFN-beta and TNF-alpha. AB - Campylobacter jejuni is the most common bacterial cause of human gastroenteritis and often precedes development of Guillain-Barre syndrome (GBS), a life threatening paralytic disease. The incorporation of the carbohydrate sialic acid into C. jejuni lipooligosaccharides (LOS) is associated with increased severity of gastroenteritis and with induction of GBS; however, the underlying mechanisms remain completely unknown. In this study, we demonstrate that sialic acids in C. jejuni endotoxin enhance the rapid production of IFN-beta and TNF-alpha by human dendritic cells (DCs). Using neutralizing Abs and receptors it was shown that these DC-derived cytokines promote the proliferation of human mucosal B cells in a T cell-independent manner. The production of both IFN-beta and TNF-alpha by DCs in response to LOS requires CD14, and the amplified response of DCs to sialylated C. jejuni LOS is CD14 dependent. Together, these results indicate that sialylation of C. jejuni LOS increases DC activation and promotes subsequent B cell responses through CD14-driven production of IFN-beta and TNF-alpha. This enhanced DC/B cell response may explain the increased pathogenicity of sialylated C. jejuni and may be key to the initiation of B cell-mediated autoimmunity in GBS. PMID- 24166975 TI - Cutting edge: IL-25 elicits innate lymphoid type 2 and type II NKT cells that regulate obesity in mice. AB - The cellular composition of visceral adipose tissue (VAT) and release of cytokines by such cells within VAT has been implicated in regulating obesity and metabolic homeostasis. We show the importance of IL-25-responsive innate cells, which release the Th2 cytokine IL-13, in regulating weight and glucose homeostasis in mouse models of diet-induced obesity. Treating obese mice with IL 25 induces weight loss and improves glucose tolerance, and is associated with increased infiltration of innate lymphoid type 2 cells (ILC2), type I and type II NKT cells, eosinophils, and alternatively activated macrophages into the VAT. By depleting ILC2 in obese Rag1(-/-) mice, we observe exacerbated weight gain and glucose intolerance. Conversely, transferring ILC2 or type I or type II NKT cells into obese mice induces transient weight loss and stabilizes glucose homeostasis. Our data identify a mechanism whereby IL-25 eliciting IL-13-producing innate cells regulates inflammation in adipose tissue and prevents diet-induced obesity. PMID- 24166978 TI - Manifestation of long-range ordered state in layered VX2 (X = Cl, Br, I) systems. AB - We report the first-principles based density functional investigation of correlated magnetic behavior for the layered VX2 (X = Cl, Br, I) system both in bulk and monolayer forms. The bulk system stabilizes in the Neel 120 degrees spin structure with the onset of long-range order at a very low temperature. However, a monolayer of the same system results in a two-dimensional long-range ordered spin-gel configuration in the a-b plane. The occurrence of this two dimensional non-collinear long-range order for such hexagonal systems with honeycomb topology may provide an additional feature for controlling the use of such materials in magnetic memory devices. PMID- 24166976 TI - Posttranscriptional gene regulation of IL-17 by the RNA-binding protein HuR is required for initiation of experimental autoimmune encephalomyelitis. AB - IL-17 is a proinflammatory cytokine produced by activated Th17 cells and other immune cells. IL-17-producing Th17 cells are major contributors to chronic inflammatory and autoimmune diseases, such as multiple sclerosis, rheumatoid arthritis, and inflammatory bowel disease. Although the transcriptional regulation of Th17 cells is well understood, the posttranscriptional regulation of IL-17 gene expression remains unknown. The RNA-binding protein HuR positively regulates the stability of many target mRNAs via binding the AU-rich elements present in the 3' untranslated region of many inflammatory cytokines including IL 4, IL-13, and TNF-alpha. However, the regulation of IL-17 expression by HuR has not been established. CD4(+) Th17 cells from HuR knockout mice had decreased IL 17 steady-state mRNA and protein levels compared with wild-type Th17 cells, as well as decreases in frequency of IL-17(+) cells. Moreover, we demonstrated that HuR directly binds to the IL-17 mRNA 3' untranslated region by using RNA immunoprecipitation and biotin pulldown assays. In addition, the knockout of HuR decreased cellular proliferation of CD4(+) T cells. Mice with adoptively transferred HuR KO Th17 cells had delayed initiation and reduced disease severity in the onset of experimental autoimmune encephalomyelitis compared with wild-type Th17 cells. Our results reveal a HuR-induced posttranscriptional regulatory mechanism of Th17 differentiation that influences IL-17 expression. These findings may provide novel therapeutic targets for the treatment of Th17-mediated autoimmune neuroinflammation. PMID- 24166977 TI - Unique features of naive CD8+ T cell activation by IL-2. AB - IL-2 has a pervasive influence on the immune system and dictates the survival and differentiation of multiple T cell subsets, including CD4 regulatory T cells, CD4 Th cells, and CD8 memory cells. IL-2 is synthesized by T cells during the early stages of the immune response and promotes T cell expansion and effector cell generation after initial activation via TCR signaling. Based on studies with activated T cell lines maintained in vitro, IL-2 is known to activate multiple signaling pathways that show considerable overlap with the pathways elicited via the TCR. In this paper, we have examined IL-2 signaling under TCR-independent conditions, namely by culturing purified resting naive CD8 T cells with IL-2 in the absence of Ag or APC. Under these conditions, we show in this study that IL-2 elicits a unique pattern of signaling associated with strong lymphocyte-specific protein tyrosine kinase/JAK3-dependent activation of the PI3K/AKT pathway with little or no involvement of STAT5, NF-kappaB, or the calcineurin/NFAT pathways. Such signaling induces marked proliferation associated with rapid and selective expression of eomesodermin but not T-bet and differentiation into long-lived central memory cells after adoptive transfer. PMID- 24166979 TI - Gas-phase spectroscopy of ferric heme-NO complexes. AB - Weakly bound complexes between ferric heme cations and NO were synthesised in the gas phase from ion-molecule reactions, and their absorption measured based on photodissociation yields. The Soret band, which serves as an important marker band for heme-protein spectroscopy, is maximal at 357+/-5 nm and significantly blue-shifted compared to ferric heme nitrosyl proteins (maxima between 408 and 422 nm). This is in stark contrast to the Q-band absorption where the protein microenvironment is nearly innocent in perturbing the electronic structure of the porphyrin macrocycle. Photodissociation is primarily through loss of NO. In contrast to the Q-band region, two-photon absorption was seen in the Soret band despite NO loss only requiring ~1 eV. A model based on intersystem crossing to a long-lived triplet state where a barrier has to be surmounted is suggested. Finally, we summarise the measured absorption maxima of heme and its complexes with amino acids and NO. PMID- 24166980 TI - Direct synthesis of hydrogen peroxide from hydrogen and oxygen by using a water soluble iridium complex and flavin mononucleotide. AB - H2 , O2 to H2 O2 : The direct synthesis of hydrogen peroxide from hydrogen and oxygen in water has been made possible by using an iridium(III) complex, [Ir(III) (Cp*)(4-(1H-pyrazol-1-yl-kappaN(2) )benzoic acid-kappaC(3) )(H2 O)]2 SO4 , and flavin mononucleotide. This method gives hydrogen peroxide with a high turnover number (847) and yield (19.2 %) under normal pressure and at room temperature. PMID- 24166982 TI - Residual disease in AML, a target that can move in more than one direction. PMID- 24166981 TI - The role of sympathetic and parasympathetic nerve systems on the smooth muscle of rat seminal vesicles - experimental results and speculation for physiological implication on ejaculation. AB - Ejaculation is a process involving sympathetic and parasympathetic effects during different stages - emission and ejection. Some conditions of ejaculation dysfunction are associated with autonomic nerves. However, the exact effects of autonomic nerves on ejaculation are not well defined. Autonomic agonists induce different recorded trace patterns of seminal vesicular contraction. The different traces contain different components of phasic and tonic contraction, which may have physiological implications. In this study, we examined isolated rat seminal vesicle (SV) contraction by phenylephrine (PE), acetylcholine, and their respective antagonists and then speculated upon physiological roles of sympathetic and parasympathetic nerves on SV during ejaculation. We found that PE and Ach both achieved good contraction of rat SV. Compared to alpha1b for sympathetic and M1, M2 for parasympathetic receptors, alpha1a and M3 are the relatively dominant subtypes on rat SV. Adrenergic and cholinergic agonists cause different trace patterns of SV contraction. We speculated that the sympathetic effect is dominant during emission to squeeze seminal fluid out and that the parasympathetic effect is dominant during ejection to provide an anti-reflux effect on the ejaculatory duct. PMID- 24166983 TI - Clinical and pathological impact of VHL, PBRM1, BAP1, SETD2, KDM6A, and JARID1c in clear cell renal cell carcinoma. AB - VHL is mutated in the majority of patients with clear cell renal cell carcinoma (ccRCC), with conflicting clinical relevance. Recent studies have identified recurrent mutations in histone modifying and chromatin remodeling genes, including BAP1, PBRM1, SETD2, KDM6A, and JARID1c. Current evidence suggests that BAP1 mutations are associated with aggressive disease. The clinical significance of the remaining genes is unknown. In this study, targeted sequencing of VHL and JARID1c (entire genes) and coding regions of BAP1, PBRM1, SETD2, and KDM6A was performed on 132 ccRCCs and matched normal tissues. Associations between mutations and clinical and pathological outcomes were interrogated. Inactivation of VHL (coding mutation or promoter methylation) was seen in 75% of ccRCCs. Somatic noncoding VHL alterations were identified in 29% of ccRCCs and may be associated with improved overall survival. BAP1 (11%), PBRM1 (33%), SETD2 (16%), JARID1c (4%), and KDM6A (3%) mutations were identified. BAP1-mutated tumors were associated with metastatic disease at presentation (P = 0.023), advanced clinical stage (P = 0.042) and a trend towards shorter recurrence free survival (P = 0.059) when compared with tumors exclusively mutated for PBRM1. Our results support those of recent publications pointing towards a role for BAP1 and PBRM1 mutations in risk stratifying ccRCCs. Further investigation of noncoding alterations in VHL is warranted. PMID- 24166984 TI - Driving and off-road impairments underlying failure on road testing in Parkinson's disease. AB - Parkinson's disease (PD) affects driving ability. We aimed to determine the most critical impairments in specific road skills and in clinical characteristics leading to failure on a road test in PD. In this cross-sectional study, certified driving assessment experts evaluated specific driving skills in 104 active, licensed drivers with PD using a standardized, on-road checklist and issued a global decision of pass/fail. Participants also completed an off-road evaluation assessing demographic features, disease characteristics, motor function, vision, and cognition. The most important driving skills and off-road predictors of the pass/fail outcome were identified using multivariate stepwise regression analyses. Eighty-six (65%) passed and 36 (35%) failed the on-road driving evaluation. Persons who failed performed worse on all on-road items. When adjusted for age and gender, poor performances on lateral positioning at low speed, speed adaptations at high speed, and left turning maneuvers yielded the best model that determined the pass/fail decision (R(2) = 0.56). The fail group performed poorer on all motor, visual, and cognitive tests. Measures of visual scanning, motor severity, PD subtype, visual acuity, executive functions, and divided attention were independent predictors of pass/fail decisions in the multivariate model (R(2) = 0.60). Our study demonstrated that failure on a road test in PD is determined by impairments in specific driving skills and associated with deficits in motor, visual, executive, and visuospatial functions. These findings point to specific driving and off-road impairments that can be targeted in multimodal rehabilitation programs for drivers with PD. PMID- 24166985 TI - Epigenetic changes in gene expression for drug-metabolizing enzymes and transporters. AB - Individual differences in drug response can be caused by genetic and epigenetic variability and disease determinants. Pharmacoepigenetics is a new field that studies the expression changes in pharmacogenes without changes in DNA sequences. Epigenetic control mechanisms are associated with DNA methylation, histone modification, small noncoding RNAs, and nucleosome remodeling. Researchers are actively attempting to identify epigenetic mechanisms for controlling the expression of enzymes and transporters affecting the metabolism and disposition of drugs. Current evidence suggests that epigenetic changes play a major role in cytochrome P450 enzyme expression, major transporter function, and in interactions with nuclear receptors. A thorough understanding of pharmacoepigenetics provides insight into new approaches to drug discovery and development, provides an understanding of previously observed actions of older drugs, and provides a pathway by which epigenetics can be harnessed to provide better patient-specific therapy. PMID- 24166986 TI - Uncertain diagnosis after newborn screening for cystic fibrosis: An ethics-based approach to a clinical dilemma. AB - There is uncertainty about the diagnosis of cystic fibrosis after newborn screening (NBS) for some babies, either because of an intermediate sweat chloride test or inconclusive gene mutation analysis. There is considerable difficulty knowing how best to manage these babies, some of whom will develop cystic fibrosis, but many not. This article offers an ethics-based approach to this clinical dilemma that should be helpful to clinicians managing the baby with an uncertain diagnosis of cystic fibrosis after NBS. PMID- 24166987 TI - Molecular interaction networks for the analysis of human disease: utility, limitations, and considerations. AB - High-throughput '-omics' data can be combined with large-scale molecular interaction networks, for example, protein-protein interaction networks, to provide a unique framework for the investigation of human molecular biology. Interest in these integrative '-omics' methods is growing rapidly because of their potential to understand complexity and association with disease; such approaches have a focus on associations between phenotype and "network-type." The potential of this research is enticing, yet there remain a series of important considerations. Here, we discuss interaction data selection, data quality, the relative merits of using data from large high-throughput studies versus a meta database of smaller literature-curated studies, and possible issues of sociological or inspection bias in interaction data. Other work underway, especially international consortia to establish data formats, quality standards and address data redundancy, and the improvements these efforts are making to the field, is also evaluated. We present options for researchers intending to use large-scale molecular interaction networks as a functional context for protein or gene expression data, including microRNAs, especially in the context of human disease. PMID- 24166989 TI - The optimal duration of frequency-volume charts related to compliance and reliability. AB - AIMS: To assess Frequency-volume charts (FVCs) for the yield of additional recorded days and the ideal duration of recording related to compliance and reliability. METHODS: Of 500 consecutive urologic outpatients willing to complete a 7-day FVC, 378 FVCs were evaluable. During seven consecutive days every voiding time and volume were recorded. Missed entries were indicated with a coded letter, thereby assessing the true frequency and compliance. Reliability is the agreement of the day-to-day FVC parameters with the 7-day FVC pattern. Single-day reliability was assessed and used in the Spearman-Brown formula. RESULTS: FVCs of 228 male and 150 females were evaluated. Mean age was 55.2 years (standard deviation [SD]: 16.2 years), and mean 24-hr urine production was 1,856 ml (SD: 828 ml). The percentage of patients with complete FVCs decreased from 78% on day 2 to 58% on day 7, and dropped below 70% after 4 days. Single-day reliability was r = 0.63 for nocturnal urine production, r = 0.72 for 24-hr urine production, and r = 0.80 for mean voided volume. At 5 days, reliability of 90% was achieved for all parameters. CONCLUSIONS: With each additional day, FVCs showed a decrease in compliance and an increase in reliability. At day 3, reliability of 80% was achieved for all FVC parameters, but compliance dropped to 73%. Beyond 5 days, the yield of additional recorded days was limited. We advocate an FVC duration of 3 days, but the duration may be shortened or extended depending on the goal of the FVC. PMID- 24166988 TI - Initial testing (stage 1) of the topoisomerase II inhibitor pixantrone, by the pediatric preclinical testing program. AB - Pixantrone, a novel aza-anthracenedione with cytotoxic activity, was tested against the PPTP in vitro panel (3.0 nM to 30.0 MUM) and against a limited panel of PPTP Wilms tumors and sarcomas (7.5 mg/kg) administered intravenously using an every 4 day * 3 schedule. In vitro pixantrone showed a median relative IC50 value of 54 nM (range <3 nM to 1.03 MUM). In vivo pixantrone induced significant differences in EFS distribution compared to controls in two of eight solid tumor xenografts at dose levels relevant to human drug exposure. A complete response was observed for one Wilms tumor xenograft. PMID- 24166990 TI - Using DNA to design plasmonic metamaterials with tunable optical properties. PMID- 24166991 TI - MEAT SCIENCE AND MUSCLE BIOLOGY SYMPOSIUM--mechanism of growth hormone stimulation of skeletal muscle growth in cattle. AB - Growth hormone, also called somatotropin (ST), is a polypeptide hormone produced by the anterior pituitary. The major functions of GH include stimulating bone and skeletal muscle growth, lipolysis, milk production, and expression of the IGF-I gene in the liver. Based on these functions, recombinant bovine ST (bST) and recombinant porcine ST (pST) have been used to improve milk production in dairy cows and lean tissue growth in pigs, respectively. However, despite these applications, the mechanisms of action of GH are not fully understood. Indeed, there has been a lot of controversy over the role of liver-derived circulating IGF-I and locally produced IGF-I in mediating the growth-stimulatory effect of GH during the last 15 yr. It is in this context that we have conducted studies to further understand how GH stimulates skeletal muscle growth in cattle. Our results do not support a role of skeletal muscle-derived IGF-I in GH-stimulated skeletal muscle growth in cattle. Our results indicate that GH stimulates skeletal muscle growth in cattle, in part, by stimulating protein synthesis in muscle through a GH receptor-mediated, IGF-I-independent mechanism. In this review, besides discussing these results, we also argue that liver-derived circulating IGF-I should be still considered as the major mechanism that mediates the growth-stimulatory effect of GH on skeletal muscle in cattle and other domestic animals. PMID- 24166992 TI - Nutrient database for sorghum distillers dried grains with solubles from ethanol plants in the Western Plains Region and their effects on nursery pig performance. AB - Samples of sorghum distillers dried grains with solubles (DDGS) were collected and analyzed to establish a nutrient database and evaluate the quality and consistency between and within 5 ethanol plants in Kansas and Texas. Each sample (n = 21) was analyzed for AA, DM, CP, crude fiber, crude fat, ash, NDF, ADF, trace minerals, and starch. Mean values (DM basis) were 0.88% Lys, 10.49% crude fat, 34.21% CP, and 4,722 kcal/kg GE. The standard deviations among sorghum DDGS plants were similar to those within plants for most nutrients. Results of these analyses were used to formulate diets for 2 nursery trials. The 2 experiments were conducted to determine the effects of adding sorghum DDGS (29.0% CP and 7.2% crude fat) to corn- or sorghum-based diets on nursery pig growth performance. In Exp. 1, 360 nursery barrows (6.8 kg and 26 d of age) were used in a 34-d study. Pigs were allotted to 1 of 8 dietary treatments with 5 pigs per pen and 9 pens per treatment. Treatments were arranged in a 2 * 4 factorial with main effects of grain source (corn vs. sorghum) and sorghum DDGS (0, 15, 30, or 45%). Diets were formulated to 1.30 and 1.25% standardized ileal digestible (SID) Lys in phases 1 and 2, respectively, but were not balanced for energy. Overall, there were no differences among pigs fed sorghum- or corn-based diets for ADG and ADFI; however, as sorghum DDGS increased from 0 to 45% of the diet, ADG decreased (linear, P < 0.01). There was a DDGS * grain source interaction (linear, P < 0.04) observed for G:F. In corn-based diets, pigs fed increasing sorghum DDGS had relatively similar G:F. However, in pigs fed sorghum-based diets, G:F was best for those fed 0% DDGS but was decreased in pigs fed 15, 30, or 45% sorghum DDGS. In Exp. 2, 180 nursery pigs (10.7 kg and 38 d of age) were used in a 21-d study with 6 pigs per pen and 5 pens per treatment. Treatments were arranged in a 2 * 3 factorial with main effects of grain source (corn vs. sorghum) and DDGS (0 vs. 30% corn or sorghum DDGS). Diets were formulated to 1.27% SID Lys and were not balanced for energy. Overall, there were no differences in ADG among pigs fed sorghum- or corn-based diets as well as no differences among pigs fed sorghum or corn DDGS. Pigs fed diets with 30% DDGS gained less (P < 0.03) than pigs fed basal diets. These results indicate sorghum can be a suitable replacement for corn in nursery pig diets, but increasing sorghum DDGS decreased ADG. PMID- 24166993 TI - MEAT SCIENCE AND MUSCLE BIOLOGY SYMPOSIUM--role of satellite cells in anabolic steroid-induced muscle growth in feedlot steers. AB - Both androgenic and estrogenic steroids are widely used as growth promoters in feedlot steers because they significantly enhance feed efficiency, rate of gain, and muscle growth. However, despite their widespread use relatively little is known about the biological mechanism by which androgenic and estrogenic steroids enhance rate and efficiency of muscle growth in cattle. Treatment of feedlot steers with a combined estradiol (E2) and trenbolone acetate (TBA) implant results in an increased number of muscle satellite cells, increased expression of IGF-1 mRNA in muscle tissue, and increased levels of circulating IGF-1. Similarly, treatment of bovine satellite cell (BSC) cultures with either TBA or E2 results in increased expression of IGF-1 mRNA, increased rates of proliferation and protein synthesis, and decreased rates of protein degradation. Effects of E2 on BSC are mediated at least in part through the classical E2 receptor, estrogen receptor-alpha (ESR1), the IGF-1 receptor (IGFR1), and the G protein-coupled estrogen receptor-1 (GPER-1), formerly known as G protein-coupled receptor-30 (GPR30). The effects of TBA appear to be primarily mediated through the androgen receptor. Based on current research results, it is becoming clear that anabolic steroid-enhanced bovine muscle growth involves a complex interaction of numerous pathways and receptors. Consequently, additional in vivo and in vitro studies are necessary to understand the mechanisms involved in this complex process. The fundamental information generated by this research will help in developing future, safe, and effective strategies to increase rate and efficiency of muscle growth in beef cattle. PMID- 24166994 TI - Lentiviral modification of enriched populations of bovine male gonocytes. AB - Undifferentiated germ cells have the capacity to develop into sperm capable of fertilizing oocytes and contributing genetic material to subsequent generations. The most primitive prepubertal undifferentiated germ cells include gonocytes and undifferentiated spermatogonia, including spermatogonial stem cells (SSC). Gonocytes, present in the testis at birth, differentiate into SSC, which maintain spermatogenesis for the remainder of the male's life. Because of their capacity to contribute to lifelong spermatogenesis, undifferentiated germ cells are attractive targets for genetic modification to produce transgenic animals, including cattle. To maximize the efficiency of genetic modification of bovine gonocytes and SSC, effective enrichment techniques need to be developed. Selection of bovine gonocytes using differential plating was improved 8-fold (P < 0.001) when using a combination of extracellular matrix proteins, including laminin, fibronectin, collagen type IV, and gelatin, compared to using laminin and gelatin alone. Selected cells labeled with PKH26 formed colonies of donor derived germ cells after transplantation into recipient mouse testes, indicating putative stem cell function. Significantly more colonies (P < 0.001) per 1 * 10(5) viable transplanted cells were formed from isolated nonadherent cells (203 +/- 23.2) compared to adherent (20 +/- 2.7) or Percoll (45.5 +/- 4.5) selected cells. After selection, some gonocytes were transduced using a lentiviral vector containing the transgene for the enhanced green fluorescent protein. Transduction efficiency was 17%. Collectively, these data demonstrate effective methods for the selection and genetic modification of bovine undifferentiated germ cells. PMID- 24166996 TI - Effects of ractopamine hydrochloride and zilpaterol hydrochloride supplementation on longissimus muscle shear force and sensory attributes of beef steers. AB - Effect of ractopamine hydrochloride (RH) and zilpaterol hydrochloride (ZH) on LM shear force and sensory attributes was determined using pens (n = 40) British * Continental crossbred steers randomly allocated to one of the following treatments: control; RH fed at 200 (RH 200) or 300 mg * steer(-1) * d(-1) (RH 300), or 400 mg * steer(-1) * d(-1) (RH 400) top-dressed for the final 30 d of feeding; or ZH fed at 7.5 mg/kg, beginning 23 d before slaughter with a 3-d withdrawal. Two replicates (pens) per treatment were represented in four blocks. Eighteen carcasses per pen were randomly selected and one 5-cm LM sample was removed from both carcass sides to be used for shear force and sensory evaluation. Samples were aged for 14 d, frozen at -28.8 degrees C, and cut into 2.5-cm steaks. All steaks were cooked to an internal temperature of 71.1 degrees C before being evaluated for Warner-Bratzler shear force (WBSF), slice shear force (SSF), or being fed to trained sensory panelists. Increasing dose and potency of beta-agonist increased WBSF by 4 to 17% and SSF by 5 to 24% (P < 0.05). Steaks from steers fed ZH had higher WBSF and SSF values compared with all other treatments (P < 0.05), whereas steaks from controls and steers fed RH 200 were not different (P > 0.05). Probability of steaks failing to meet shear force standards to be certified tender (WBSF <4.4 kg, SSF < 20 kg) was increased from an initial probability of <0.06 in steaks from steers in the control treatment to 0.10 to 0.20 in steers fed RH 400 or ZH (P < 0.05). No difference was detected in panel ratings for overall tenderness of steaks from steers fed RH 200 compared with controls (P > 0.05). Steaks from steers fed RH 300 and RH 400 were comparable for all sensory attributes; however, both RH 300 and RH 400 were rated lower for overall tenderness than controls (P < 0.05). Panelists failed to detect differences in overall tenderness of steaks from steers fed RH 400 and ZH (P < 0.05). Panelists detected no difference in flavor profile or juiciness among treatments (P > 0.05). Results from this study indicated beta-agonists negatively affected beef tenderness and these effects may be more noticeable in steers supplemented with ZH and higher doses of RH. PMID- 24166998 TI - Effects of feeding diets containing highly peroxidized distillers dried grains with solubles and increasing vitamin E levels to wean-finish pigs on growth performance, carcass characteristics, and pork fat composition. AB - Lipid peroxidation in animal feed can negatively affect growth performance and meat quality. Weanling pigs (n = 432; BW = 6.6 +/- 0.4 kg) were used to evaluate the effects of feeding peroxidized distillers dried grains with solubles (DDGS) with 3 levels of vitamin E (alpha-tocopheryl acetate) on growth performance, carcass composition, fatty acid composition of pork fat, and lipid peroxidation in LM. The DDGS source used in this study contained the highest thiobarbituric acid reactive substances (TBARS) value, peroxide value, and total S content (5.2 ng malondialdehyde/mg oil, 84.1 mEq/kg oil, and 0.95%, respectively) among 30 DDGS sources sampled. Pens within blocks were assigned randomly to 1 of 6 diets in a 2 * 3 factorial arrangement of treatments with 8 pens per treatment and 9 pigs per pen. Pigs were fed a corn-soybean meal (CON) or 30% peroxidized DDGS (Ox DDGS) diets with 3 levels of vitamin E: none supplemented (No-E), NRC (1X-E), or 10X NRC (10X-E). Compared to CON, inclusion of 30% Ox-DDGS in diets reduced (P < 0.001) final BW (110 vs. 107 kg), overall ADG (0.76 vs. 0.74 kg/d), and G:F (0.39 vs. 0.37). Increasing dietary vitamin E concentrations improved G:F (P = 0.03) of pigs fed 10X-E and 1X-E vs. No-E diets (0.39 and 0.39 vs. 0.38, respectively). Hot carcass weight, dressing percentage, backfat depth, and LM area were reduced (P < 0.01) in pigs fed Ox-DDGS compared to CON, but percentage of fat-free carcass lean was not affected. Feeding Ox-DDGS increased (P < 0.001) PUFA concentration, particularly linoleic acid (P < 0.001), and iodine value (P < 0.001) in belly fat and backfat compared to pigs fed CON. Dietary vitamin E levels did not affect fatty acid profiles in belly or back fat. Loin muscle TBARS were measured to determine the lipid peroxidation level in pork loins. Although pigs were fed a Ox-DDGS source in this study, TBARS in LM were similar between Ox DDGS and CON treatments. There was no interaction between Ox-DDGS and dietary vitamin E concentration in LM TBARS. Alpha-tocopherol concentration in LM was greater (P < 0.001) in 10X-E than No-E or 1X-E dietary treatments. Compared to CON, feeding Ox-DDGS increased alpha-tocopherol concentration in LM of pigs fed No-E (1.0 vs. 3.1 mg/kg; P = 0.005) but not in those fed 1X-E or 10X-E. These results indicate that feeding diets containing 30% Ox-DDGS to wean-finish pigs may negatively affect growth performance, but supplementation of additional vitamin E in the diet did not counteract these effects. PMID- 24166999 TI - North American Beef Tenderness Survey 2011-2012: benchmarking tenderness and sample shipping procedures. AB - Fifty-four stores in 30 U.S. cities were sampled from June 2011 through May 2012 to benchmark beef tenderness at retail, as assessed by Warner-Bratzler shear force (WBSF). Top loin (Longissimus dorsi; n = 980) and sirloin (Gluteus medius and Biceps femoris; n = 860) steaks were collected at random (Quality Grade and brand) and shipped via overnight delivery to Colorado State University. From June 2011 through November 2011, North American Beef Tenderness Survey (NABTS) Period 1, samples were shipped fresh and then frozen. Mean WBSF values during Period 1 were 2.9 and 3.5 kg for top loin and sirloin steaks, respectively. Frequencies of steaks classified as tough (WBSF >= 4.4 kg) were 8.6% and 17.7% for top loin and sirloin steaks, respectively. When shipped fresh, a disproportionately high frequency (16.9%) of top loin steaks had WBSF <= 2.0 kg, representing a deviation from previous works. Two trials were conducted to assess the effect of freezing, retail display, and shipping on WBSF and slice shear force (SSF) of beef top loin steaks. Freezing, retail display, and shipment reduced WBSF by 0.4, 0.3, and 0.0 kg during Trial 1, and by 0.4, 0.3, and 0.1 kg during Trial 2. Slice shear force was lower (P < 0.05) in steaks exposed to shipping conditions during Trial 1; however, this difference was not observed in Trial 2. Shipping decreased the frequency of steaks categorized as tough (SSF >= 20.0 kg) from 11.1 to 5.7% and from 30.5 to 28.6%, during Trial 1 and 2, respectively. During Trial 1, WBSF indicated that shipping increased incidence of tough samples from 0.0 to 3.8%, but this trend was reversed during Trial 2 when shipping reduced incidence of tough samples from 13.0 to 5.6%. Coefficients of variation for treatment effects suggested variance remained unchanged (+/- 2.0%), with respect to shear force values. However, mean values were reduced as a result of shipping conditions. These findings dictated a change in NABTS protocol from December 2011 through May 2012 (Period 2), during which time samples were shipped frozen. Mean WBSF values were 3.4 and 4.0 kg for top loin and sirloin samples, respectively. Frequencies of steaks classified as tough were 14% and 23.5% for top loin and sirloin steaks, respectively. These findings suggest that freezing samples before shipment may influence shear force of steaks collected at the retail level. These data should be considered when evaluating beef tenderness surveys and in the design of future works. PMID- 24167000 TI - Effect of using frozen-thawed boar sperm differing in post-thaw motility in the first and second inseminations on pregnancy establishment, litter size, and fetal paternity in relation to time of ovulation. AB - Frozen-thawed boar sperm (FTS) has reduced motility and viability compared to cooled semen. Motility of FTS is related to in vitro and in vivo fertility, but this effect has not been determined in relation to the timing of ovulation. To test the effect of variable FTS motility in a multiple-AI system, ejaculates from 38 boars were collected and frozen in 0.5-mL straws. Upon thawing, samples were classified (mean +/- SEM) by motility as poor (P, 20.2% +/- 1.1%), moderate (M, 31.3% +/- 0.9%), or good (G, 43.5% +/- 0.8%). In replicates, mature gilts were synchronized and checked for estrus at 12-h intervals and assigned (n = 207) to receive 4.0 billion total sperm in each AI at 24 and 36 h after onset of estrus using the treatments: 1) P and M (P-M), 2) M and P (M-P), 3) G and M (G-M), and 4) M and G (M-G). For each treatment combination, a set of 3 boars was randomly selected within motility class for their allelic distinction with M sperm from a single boar represented across all treatments and sires used in both first and second inseminations. The insemination to ovulation interval (IOI) was determined using ultrasound every 12 h. Reproductive tracts were collected at approximately d 32 after AI. Treatment did not interact with IOI (P > 0.10) and did not affect (P > 0.10) pregnancy rate (57%, 67%, 71%, 76% +/- 7.2%, pooled SEM) or total number of fetuses (9.2, 9.1, 9.5, 10.0 +/- 0.8) for P-M, M-P, G-M, and M-G treatments, respectively. Treatment did affect (P < 0.05) the number of fetuses sired from the first AI (3.1, 7.2, 6.4, 6.3 +/- 1.2) and second AI (5.7, 2.6, 3.0, 3.6 +/- 0.9) for the P-M, M-P, G-M, and M-G treatments, respectively. The IOI also influenced (P < 0.05) the proportion of offspring sired by the second AI (30.0%, 57.7%, 51.3%, 18.3% +/- 6.5%), as well as the number of fetuses sired by each AI. These results indicate FTS motility had no effect on pregnancy rate or litter size but did affect the number of fetuses sired from the first and second inseminations. The first AI appears to sire most of the litter except when P sperm was used. Number of fetuses sired was reduced when P sperm was used in either insemination compared to M, although no difference was evident between M and G. Fetal paternity appears to be a more sensitive marker for identifying the effects of sperm quality and IOI in a multiple-AI system with use of FTS. These results suggest that use of semen of various qualities can be used in combinations to aid in pregnancy establishment and contribute to litter size. PMID- 24167001 TI - Nutrient digestibility of lentil and regular- and low-oligosaccharide, micronized full-fat soybean fed to grower pigs. AB - A study was conducted to determine the standardized ileal digestibility (SID) of AA and calculate the NE value for regular-oligosaccharide, micronized full-fat soybean (R-MFFSB), low-oligosaccharide, micronized full-fat soybean (LO-MFFSB), lentil, and enzymatically hydrolyzed casein (EHC) for growing pigs. Six ileal cannulated barrows (31.4 kg BW) were fed 6 diets in a 6 * 6 Latin square. Five diets were cornstarch based, containing either soybean meal (SBM), R-MFFSB, LO MFFSB, or EHC as sole protein source or N free. The sixth diet contained lentil as sole protein and energy source. The SID of AA for diets was calculated using the N-free diet. Digestibility of AA in feedstuffs was determined by the direct method. Energy digestibility in SBM, R-MFFSB, and LO-MFFSB was determined by difference from the N-free diet whereas energy digestibility in lentil was determined by the direct method. On DM basis, SBM, R-MFFSB, LO-MFFSB, and lentil contained 52, 43, 43, and 27% CP, 8, 12, 14, and 16% NDF, and 1.8, 19, 21, and 1.6% ether extract, respectively. The SID of Lys for SBM was greater (P < 0.05) than that for R-MFFSB or LO-MFFSB (76 vs. 79 and 79%). The SID of other indispensable AA (except Trp) for SBM was also greater (P < 0.05) than that for R MFFSB or LO-MFFSB. The R-MFFSB and LO-MFFSB were similar in SID of AA. The SID of Lys for lentil (81%) was lower (P < 0.05) than that for SBM with a similar trend for SID of other indispensable AA except for Met and Thr whose SID was similar to SBM. The SID of AA for EHC ranged from 98 to 112%. The SBM had a lower (P < 0.05) NE value than R-MFFSB or LO-MFFSB (2.63 vs. 2.95 and 3.00 Mcal/kg DM). Lentil and SBM were similar in NE value (2.60 vs. 2.63 Mcal/kg DM). In conclusion, R-MFFSB and LO-MFFSB were similar in energy and AA value for pigs. Lentil had lower SID of AA than SBM. However, lentil and SBM were similar in NE value; therefore, lentil can serve as alternative pulse feedstuff for pigs. The AA in EHC were mostly completely digested indicating that EHC can be fed to estimate ileal endogenous AA losses. PMID- 24167002 TI - Feasibility study: phospho-specific flow cytometry enabling rapid functional analysis of bone marrow samples from patients with multiple myeloma. AB - Background: Multiple myeloma (MM) is an incurable cancer accounting for about 2% of cancer deaths. Its diagnosis is based on a combination of criteria, which are not always easily measurable. Flow cytometry now allows multiplex analysis of intracellular signaling at the single cell level. We investigated the feasibility of using intracellular protein phosphorylation analysis by flow cytometry on primary plasma cells from bone marrow and its usefulness in MM diagnosis. Methods: Cells from frozen bone marrow of five MM patients and four normal donors were stimulated with LPS, IL-6, IL-21, IFN? and TNF?. Cells were stained by fluorescent cell barcoding to allow multiplex analysis. Staining with antibodies against phosphorylated NFkB-p65, Stat1, Stat3 and p38 were used to identify cellular responses following stimulation. Results: Activation profile of MM and normal plasma cells have been established. MM cells showed heterogeneous response profiles while normal cells responses were homogeneous between donors. We also noticed that many MM samples seemed to show elevated basal level of Stat3 phosphorylation. These results suggest that different response profiles in primary MM cells might correspond to different subtypes of the disease. Thus, we provide an example of how these results may be used as a criterion for MM subtypes classification. Conclusions: We demonstrate that flow cytometry can be used to study signaling pathways in primary MM cells. The heterogeneity observed in MM cells from different patients can prove valuable for MM characterization and represents an interesting avenue for future research in MM diagnosis. (c) 2013 Clinical Cytometry Society. PMID- 24167003 TI - Tube-in-tube reactor as a useful tool for homo- and heterogeneous olefin metathesis under continuous flow mode. AB - A tube-in-tube reactor was successfully applied in homo- and heterogeneous olefin metathesis reactions under continuous flow mode. It was shown that the efficient removal of ethylene facilitated by connection of the reactor with a vacuum pump significantly improves the outcome of metathesis reactions. The beneficial aspects of this approach are most apparent in reactions performed at low concentration, such as macrocyclization reactions. The established system allows achievement of both improved yield and selectivity, and is ideal for industrial applications. PMID- 24167004 TI - Assessment of reproducibility in depletion and enrichment workflows for plasma proteomics using label-free quantitative data-independent LC-MS. AB - Quantitation in plasma-based proteomics necessitates the reproducible removal of highly abundant proteins to enable the less abundant proteins to be visible to the mass spectrometer. We have evaluated immunodepletion (proteoprep20) and enrichment (Bio-Rad beads), as the current predominant approaches. Label-free analysis offers an opportunity to estimate the effectiveness of this approach without incorporating chemical labels. Human plasma samples were used to quantitatively assess the reproducibility of these two methods using nano-LC-data independent acquisition MS. We have selected 18 candidate proteins and a comparison of both methodologies showed that both of the methods were reproducible and fell below 20% residual SD. With the same candidate proteins, individual inter-day variability for the samples was also processed, allowing us to monitor instrument reproducibility. Overall, a total of 131 proteins were identified by both methods with 272 proteins identified by enrichment and 200 identified by immunodepletion. Reproducibility of measurements of the amount of protein in the processed sample for individual proteins is within analytically acceptable standards for both methodologies. This enables both methods to be used for biomarker studies. However, when sample is limited, enrichment is not suitable as larger volumes (>1.0 mL) are required. In experiments where sample is not limited then a greater number of proteins can be reliably identified using enrichment. PMID- 24167005 TI - Draft genomes of 12 host-adapted and environmental isolates of Pseudomonas aeruginosa and their positions in the core genome phylogeny. AB - Pseudomonas aeruginosa is a Gram-negative opportunistic pathogen particularly associated with the inherited disease cystic fibrosis (CF). Pseudomonas aeruginosa is well known to have a large and adaptable genome that enables it to colonise a wide range of ecological niches. Here, we have used a comparative genomics approach to identify changes that occur during infection of the CF lung. We used the mucoid phenotype as an obvious marker of host adaptation and compared these genomes to analyse SNPs, indels and islands within near-isogenic pairs. To commence the correction of the natural bias towards clinical isolates in genomics studies and to widen our understanding of the genomic diversity of P. aeruginosa, we included four environmental isolates in our analysis. Our data suggest that genome plasticity plays an important role in chronic infection and that the strains sequenced in this study are representative of the two major phylogenetic groups as determined by core genome SNP analysis. PMID- 24167007 TI - Inconclusive or erroneous fine-needle aspirates of breast with adequate and representative material: a cytologic/histologic study. AB - Adequately cellular and representative fine-needle aspirates (FNAs) of breast have a high diagnostic accuracy. There is, however, a recognized category designated as "gray zone" where a definitive diagnosis cannot be reached. We reviewed our experience in this category to identify useful diagnostic parameters. Twenty-four such FNAs with surgical follow-up were retrieved from AUBMC files (2003-2009). Cytology slides were reviewed blindly. All cases were females, 29-73 years. There were three erroneous and 21 inconclusive diagnoses. The majority (15) was invasive adenocarcinomas: two cribriform, four tubular, one lobular, and eight not otherwise specified. The remaining cases were papillary and fibroepithelial tumors (three each), ductal carcinoma in situ, cribriform (two), and one adenomyoepithelioma (AME). Useful diagnostic features included: (1) Biphasic cell population with focal nuclear atypia and intranuclear and cytoplasmic vacuolar inclusions (AME). (2) Complex clusters of epithelial cells with cribriform architecture (cribriform carcinoma). (3) Rigid tubular epithelial structures with abrupt change in diameter, ending in pointed tips with abnormal branching (tubular carcinoma). (4) Cellular stromal fragments (fibroepithelial tumors). (5) Papillary fibrovascular cores, columnar cells, and three-dimensional papillary epithelial fragments (papillary tumors). Myoepithelial cells classically described in benign aspirates were not always a discriminatory factor. The "gray zone" in breast FNA is usually due to overlapping cytologic features of some benign and malignant lesions. Useful distinguishing cytologic features are described. PMID- 24167006 TI - Comparative modeling of proteins: a method for engaging students' interest in bioinformatics tools. AB - The huge increase in data being produced in the genomic era has produced a need to incorporate computers into the research process. Sequence generation, its subsequent storage, interpretation, and analysis are now entirely computer dependent tasks. Universities from all over the world have been challenged to seek a way of encouraging students to incorporate computational and bioinformatics skills since undergraduation in order to understand biological processes. The aim of this article is to report the experience of awakening students' interest in bioinformatics tools during a course focused on comparative modeling of proteins. The authors start by giving a full description of the course environmental context and students' backgrounds. Then they detail each class and present a general overview of the protein modeling protocol. The positive and negative aspects of the course are also reported, and some of the results generated in class and in projects outside the classroom are discussed. In the last section of the article, general perspectives about the course from students' point of view are given. This work can serve as a guide for professors who teach subjects for which bioinformatics tools are useful and for universities that plan to incorporate bioinformatics into the curriculum. PMID- 24167008 TI - Stakeholder views on pharmacogenomic testing. AB - Pharmacogenomics has an important role in the evolution of personalized medicine, and its widespread uptake may ultimately depend on the interests and perspectives of key players in health care. Our aim was to summarize studies on stakeholder perspectives and attitudes toward pharmacogenomic testing. Thus, we conducted a review of original research studies that reported stakeholder views on pharmacogenomic testing using a structured approach in PubMed, International Pharmaceutical Abstracts, Cumulative Index to Nursing and Allied Health Literature, and EMBASE. A standardized data abstraction form was developed that included stakeholder group of interest-patients, general public, providers, and payers. Stakeholder views regarding barriers to pharmacogenetic implementation were organized into the following themes: ancillary information-related, clinical, economic, educational, ethical or legal, medical mistrust, and practicality. Of 34 studies that met our inclusion criteria, 37 perspectives were reported (15 on providers, 9 on the general public, 9 on patients, and 4 on payers). The most common topics that arose in studies of providers related to clinical usefulness of genetic data (n=11) and educational needs (n=11). Among the general public, the most common concerns were medical mistrust (n=5), insufficient education (n=5), and practicality (n=5). The most prevalent issues from the patient perspective were ethical or legal (n=6) and economic (n=5) issues. Among payers, leading issues were practicality (n=4) and clinical usefulness (n=3). There was overlap in the topics and concerns across stakeholder perspectives, including lack of knowledge about pharmacogenomic testing. Views on issues related to privacy, cost, and test result dissemination varied by stakeholder perspective. Limited research had been conducted in underrepresented groups. Efforts to address the issues raised by stakeholders may facilitate the implementation of pharmacogenomic testing into clinical practice. PMID- 24167009 TI - Beyond here be dragons: SIBO in Parkinson's disease. PMID- 24167010 TI - Validation of the Urogenital Distress Inventory (UDI-6) and Incontinence Impact Questionnaire (IIQ-7) in a Dutch population. AB - AIMS: The Urogenital Distress Inventory (UDI-6) and Incontinence Impact Questionnaire (IIQ-7) assess symptom distress and the impact on daily life of urinary incontinence. The UDI-6 has not been validated before in males. Our aim was to validate the UDI-6 and IIQ-7 in Dutch men and women. METHODS: The translation to Dutch followed standardized procedures. We validated the IIQ-7 with and without an additional gender-neutral item (IIQ-SF). Adults with urinary incontinence for at least 3 months, completed the measures at inclusion; 1-week after inclusion to evaluate the test-retest reproducibility; and 6 months after inclusion with the addition of the RAND-36 health transition item to assess responsiveness and interpretability. To assess the discriminate ability, a reference population was enrolled. To assess construct validity, the urodynamic diagnosis was used. RESULTS: Questionnaire data of 160 patients were analyzed. Patients reported more symptoms and bother than the reference population (P < 0.001). The internal consistency was good in the IIQ-SF baseline scores (Cronbach's alphas 0.86-0.92), though moderate in the UDI-6 (Cronbach's alphas 0.44-0.66). Both measures showed good reproducibility at the test-retest (Intraclass Correlations Coefficients 0.75-0.85). Construct was adequate with 75% confirmed hypotheses of urodynamic data with measure scores. The measures were responsive after treatment with smaller measurement errors than the minimal important change. No floor or ceiling effects were observed in baseline data. CONCLUSIONS: The Dutch UDI-6 and IIQ-7 are reliable, valid, and responsive instruments for assessing symptom distress of urinary incontinence and its impact on daily life in both men and women. PMID- 24167011 TI - Burnout in inpatient-based versus outpatient-based physicians: a systematic review and meta-analysis. AB - BACKGROUND: Burnout is a syndrome affecting the entirety of work life and characterized by cynicism, detachment, and inefficacy. Despite longstanding concerns about burnout in hospital medicine, few data about burnout in hospitalists have been published. PURPOSE: A systematic review of the literature on burnout in inpatient-based and outpatient-based physicians worldwide was undertaken to determine whether inpatient physicians experience more burnout than outpatient physicians. DATA SOURCES: Five medical databases were searched for relevant terms with no language restrictions. Authors were contacted for unpublished data and clarification of the practice location of study subjects. STUDY SELECTION: Two investigators independently reviewed each article. Included studies provided a measure of burnout in inpatient and/or outpatient nontrainee physicians. DATA EXTRACTION: Fifty-four studies met inclusion criteria, 15 of which provided direct comparisons of inpatient and outpatient physicians. Twenty eight studies used the same burnout measure and therefore were amenable to statistical analysis. DATA SYNTHESIS: Outpatient physicians reported more emotional exhaustion than inpatient physicians. No statistically significant differences in depersonalization or personal accomplishment were found. Further comparisons were limited by the heterogeneity of instruments used to measure burnout and the lack of available information about practice location in many studies. CONCLUSIONS: The existing literature does not support the widely held belief that burnout is more frequent in hospitalists than outpatient physicians. Better comparative studies of hospitalist burnout are needed. PMID- 24167012 TI - Graphene oxide nanoribbon as hole extraction layer to enhance efficiency and stability of polymer solar cells. AB - Graphene oxide nanoribbons for efficient and stable polymer solar cells are discussed. With controllable bandgap, good solubility and film forming property, graphene oxide nanoribbons serve as a new class of excellent hole extraction materials for efficient and stable polymer solar cells outperforming their counterparts based on conventional hole extraction materials, including PEDOT:PSS. PMID- 24167017 TI - Factors contributing to high ThinPrep(r) Pap test unsatisfactory rates in an academic medical center laboratory. AB - Specimen adequacy is a key component in the cytologic evaluation of cervical Pap tests. At our institution, yearly unsatisfactory rates continue to be high, placing our laboratory in the 95th percentile for CAP benchmark data for unsatisfactory Pap test rates. Using the 2001 Bethesda System criteria, unsatisfactory Pap test rates were calculated over a ten year period (January 2002 to December 2011) and contributing factors were analyzed. Of the 124,457 ThinPrep Pap tests performed, 4,163 (3.3%) were unsatisfactory for evaluation, the majority (90%) due to too few squamous epithelial cells. Peri/postmenopausal women and those who had received radiation/chemotherapy had the highest unsatisfactory rates; 55% and 25%, respectively. Higher unsatisfactory Pap test rates are related to the patient population served. Defined, reproducible adequacy criteria need to be defined for Pap tests from patients in certain clinical conditions. PMID- 24167016 TI - Changes in taste perception and eating behavior after bariatric surgery-induced weight loss in women. AB - OBJECTIVE: Roux-en-Y gastric bypass (RYGB) surgery causes greater weight loss than laparoscopic adjustable gastric banding (LAGB). We tested the hypothesis that RYGB has weight loss-independent effects on taste perception, which influence eating behavior and contribute to the greater weight loss. METHODS: Subjects were studied before and after ~20% weight loss induced by RYGB (n = 17) or LAGB (n = 10). The following have been evaluated: taste sensitivity for sweet, salty and savory stimuli, sucrose and monosodium glutamate (MSG) preferences, sweetness palatability, eating behavior, and expression of taste-related genes in biopsies of fungiform papillae. RESULTS: Weight loss induced by both procedures caused the same decrease in: preferred sucrose concentration (-12 +/- 10%), perceived sweetness of sucrose (-7 +/- 5%), cravings for sweets and fast-foods ( 22 +/- 5%), influence of emotions (-27 +/- 5%), and external food cues (-30 +/- 4%) on eating behavior, and expression of alpha-gustducin in fungiform papillae (all P values <0.05). RYGB, but not LAGB, shifted sweetness palatability from pleasant to unpleasant when repetitively tasting sucrose (P = 0.05). Neither procedure affected taste detection thresholds nor MSG preferences. CONCLUSIONS: LAGB and RYGB cause similar alterations in eating behaviors, when weight loss is matched. These changes in eating behavior were not associated with changes in taste sensitivity, suggesting other, as yet unknown, mechanisms are involved. PMID- 24167018 TI - De novo generation of singlet oxygen and ammine ligands by photoactivation of a platinum anticancer complex. AB - Worth the excitement: Highly reactive oxygen and nitrogen species are generated by photoactivation of the anticancer platinum(IV) complex trans,trans,trans [Pt(N3 )2 (OH)2 (MA)(Py)] (MA=methylamine, Py=pyridine). Singlet oxygen is formed from the hydroxido ligands and not from dissolved oxygen, and ammine ligands are products from the conversion of azido ligands to nitrenes. Both processes can induce oxidation of guanine. PMID- 24167019 TI - Omalizumab therapy for allergic bronchopulmonary aspergillosis in children with cystic fibrosis: a synthesis of published evidence. AB - Allergic bronchopulmonary aspergillosis (ABPA) complicating cystic fibrosis (CF) is treated with corticosteroids. Since elevated IgE is a cardinal abnormality, anti-IgE has been used sporadically as adjuvant treatment. In eight case reports, 13 children with CF and ABPA received anti-IgE resulting in improved FEV1 , fewer respiratory symptoms and decreased corticosteroid use. PMID- 24167020 TI - Interactions and chemical transformations of coronene inside and outside carbon nanotubes. AB - By exposing flat and curved carbon surfaces to coronene, a variety of van der Waals hybrid heterostructures are prepared, including coronene encapsulated in carbon nanotubes, and coronene and dicoronylene adsorbed on nanotubes or graphite via pi-pi interactions. The structure of the final product is determined by the temperature of the experiment and the curvature of the carbon surface. While at temperatures below and close to the sublimation point of coronene, nanotubes with suitable diameters are filled with single coronene molecules, at higher temperatures additional dimerization and oligomerization of coronene occurs on the surface of carbon nanotubes. The fact that dicoronylene and possible higher oligomers are formed at lower temperatures than expected for vapor-phase polymerization indicates the active role of the carbon surface used primarily as template. Removal of adsorbed species from the nanotube surface is of utmost importance for reliable characterization of encapsulated molecules: it is demonstrated that the green fluorescence attributed previously to encapsulated coronene is instead caused by dicoronylene adsorbed on the surface which can be solubilized and removed using surfactants. After removing most of the adsorbed layer, a combination of Raman spectroscopy and transmission electron microscopy was employed to follow the transformation dynamics of coronene molecules inside nanotubes. PMID- 24167021 TI - Subclinical inflammation during third trimester of pregnancy was not associated with markers of the metabolic syndrome in young adult offspring. AB - OBJECTIVE: Growing evidence indicates that the metabolic syndrome (MS) is rooted in adverse exposures during fetal life. The aim of this study was to assess the possible associations between biomarkers of inflammation during third trimester of pregnancy and markers of MS in adult offspring. METHODS: High-sensitive C reactive protein (CRP), tumor necrosis factor-alpha (TNF-alpha), interleukin 1beta (IL-1beta) and interleuki-6 (IL-6) were measured in serum samples obtained in gestational week 30. Offspring were clinically examined at age 20 years. Analyses based on 439 mother-offspring dyads were adjusted for maternal smoking during pregnancy, height, prepregnancy body mass index (BMI), education, and offspring's sex. Offspring MS markers included waist circumference, BMI, blood pressure, HOMA insulin resistance, and plasma levels of fasting glucose, triglycerides, cholesterol fractions, insulin, and leptin. RESULTS: The median level was 2.8 (interquartile range = 3.3) ug/ml for CRP, for TNF-alpha: 5.7 (3.2) pg/ml, for IL-1beta: 0.5 (0.4) pg/ml, and for IL-6: 1.1 (0.7) pg/ml. Concentrations were not significantly associated with MS markers in the offspring. The results remained essentially unchanged after correction for potential confounding. CONCLUSION: Markers for subclinical inflammation in third trimester in healthy women were not associated with components of MS in their adult offspring. PMID- 24167022 TI - A case of choreoathetosis due to glutaric aciduria type 1. PMID- 24167023 TI - 99mTc-mercaptoacetyltriglycine camera-based measurement of renal clearance: should the result be normalized for body surface area? AB - Testing the rate of creatinine clearance by measuring the level of creatinine in the blood and in a 24-h urine collection is a common method of evaluating renal function. The result is routinely normalized for body surface area (BSA). Alternatively, renal clearance can be measured by (99m)Tc mercaptoacetyltriglycine (MAG3) renal imaging without the need for urine collection. Frequently, the (99m)Tc-MAG3 camera-based result is also normalized for BSA. METHODS: I evaluated the need for BSA normalization of renal clearance measurements in (99m)Tc-MAG3 imaging studies from both a conceptual and a mathematic point of view. Both approaches involved analyzing the effect of patient size, that is, BSA, on the factors blood volume, renal blood flow, and amount of test substance present in the blood in the creatinine clearance method compared with the (99m)Tc-MAG3 camera-based method. RESULTS: Both the conceptual and the mathematic analyses were consistent with a significant difference between the creatinine and (99m)Tc-MAG3 approaches to measuring renal clearance. Larger patients have larger kidneys, greater renal blood flow, higher renal clearances, larger blood volumes, more muscle mass, and higher BSAs than smaller patients. However, the concentration of creatinine in the blood of patients of any size with normal renal function is similar because the amount of creatinine released into the blood varies with patient muscle mass, which varies with blood volume. Because normalization for BSA is needed for creatinine clearance, a single reference range can be used for all patients. In the case of measurement of renal clearance with (99m)Tc-MAG3 imaging (assuming a constant dose), the concentration of tracer in the blood will vary inversely with patient size because blood volume varies with patient size. Thus, as patient size increases, the blood concentration of tracer will go down and compensate for the increase in renal blood flow and renal clearance, and conversely. Consequently, the (99m)Tc-MAG3 renal imaging study is self-correcting for BSA and no additional correction is needed. CONCLUSION: A conceptual and mathematic analysis suggests that, although normalization for BSA is necessary in the measurement of renal clearance by the standard creatinine clearance test, such normalization is inappropriate in the (99m)Tc-MAG3 camera-based imaging study because the (99m)Tc-MAG3 method is inherently self-normalizing for BSA. PMID- 24167024 TI - Marginal structural models for skewed outcomes: identifying causal relationships in health care utilization. AB - Evaluating the impacts of clinical or policy interventions on health care utilization requires addressing methodological challenges for causal inference while also analyzing highly skewed data. We examine the impact of registering with a Family Medicine Group, an integrated primary care model in Quebec, on hospitalization and emergency department visits using propensity scores to adjust for baseline characteristics and marginal structural models to account for time varying exposures. We also evaluate the performance of different marginal structural generalized linear models in the presence of highly skewed data and conduct a simulation study to determine the robustness of alternative generalized linear models to distributional model mis-specification. Although the simulations found that the zero-inflated Poisson likelihood performed the best overall, the negative binomial likelihood gave the best fit for both outcomes in the real dataset. Our results suggest that registration to a Family Medicine Group for all 3 years caused a small reduction in the number of emergency room visits and no significant change in the number of hospitalizations in the final year. PMID- 24167025 TI - Expression of p53 in imprint smears of endometrial carcinoma. AB - The aims of this study were to determine the expression of p53 protein in endometrial adenocarcinomas (as a potential prognostic indicator before treatment) as well as normal endometrium in imprint smears and to correlate the results with clinicopathologic parameters of primary untreated endometrial cancer patients. Two hundred fifty five patients were evaluated with endometrial imprint cytology during a 29-month period. Endometrial samples freshly resected from women who underwent total abdominal hysterectomy were studied. One hundred twenty six patients had endometrial carcinoma and 129 cases were diagnosed as normal endometrium. The expression of p53 was assessed by immunocytochemistry. Positive staining was correlated with increased surgical-pathological stage, histological grade and lymph node metastases. High expression of p53 staining was significantly more frequent in histological type II than type I endometrial adenocarcinoma. High-grade endometrial carcinoma had higher proportions and stronger intensity compared with low-grade carcinoma. Negative immunostain for p53 protein was found in proliferative, secretory, and atrophic endometrium. Immunocytochemical findings from p53 stain, in addition to cytomorphologic features, appeared to be useful in the diagnosis and in the postoperative prognosis of endometrial carcinoma in endometrial cytology, especially if combined with other markers. High p53 expression correlates with morphologic features of aggressiveness and the expression pattern of p53 correspond to the expected cyclic/atrophic pattern in normal endometrium. PMID- 24167026 TI - The role of Homer1c in metabotropic glutamate receptor-dependent long-term potentiation. AB - Group I metabotropic glutamate receptors (mGluR1/5) play a role in synaptic plasticity and they demonstrate direct interactions with the neuronal Homer1c protein. We have previously shown that Homer1c can restore the plasticity deficits in Homer1 knockout mice (H1-KO). Here, we investigated the role of Homer1c in mGluR-dependent synaptic plasticity in wild-type mice, H1-KO, and H1 KO mice overexpressing Homer1c (KO+H1c). We used a form of plasticity induced by activation of mGluR1/5 that transforms short-term potentiaion (STP) induced by a subthreshold theta burst stimulation into long-term potentiation (LTP). We have shown that although acute hippocampal slices from wild-type animals can induce LTP using this stimulation protocol, H1-KO only show STP. Gene delivery of Homer1c into the hippocampus of H1-KO mice rescued LTP to wild-type levels. This form of synaptic plasticity was dependent on mGluR5 but not mGluR1 activation both in wild-type mice and in KO+H1c. mGluR1/5-dependent LTP was blocked with inhibitors of the MEK-ERK and PI3K-mTOR pathways in KO+H1c mice. Moreover, blocking Homer1c-mGluR5 interactions prevented the maintenance of LTP in acute hippocampal slices from KO+H1c. These data indicate that Homer1c-mGluR5 interactions are necessary for mGluR-dependent LTP, and that mGluR1/5-dependent LTP involves PI3K and ERK activation. PMID- 24167027 TI - Carbon nanotube - reduced graphene oxide composites for thermal energy harvesting applications. AB - By controlling the SWNT-rGO electrode composition and thickness to attain the appropriate porosity and tortuosity, the electroactive surface area is maximized while rapid diffusion of the electrolyte through the electrode is maintained. This leads to an increase in exchange current density between the electrode and electrolyte which results in enhanced thermocell performance. PMID- 24167029 TI - Robotic revisional bariatric surgery: a comparative study with laparoscopic and open surgery. AB - BACKGROUND: Revisional bariatric procedures (RBP) can be technically challenging. While robotics might provide help for complex procedures, the study aim was to report our experience with robotic RBP. METHODS: From March 2000 to June 2013, 60 consecutive RBP (11 robotic, 21 laparoscopic, 28 open) have been prospectively entered into a dedicated database and reviewed retrospectively. Outcomes have been compared between the three approaches. RESULTS: The robotic group had fewer complications (0 vs. 14.3% for laparoscopy, vs. 10.7% for open; P > 0.05), but took longer than the other approaches (352 vs. 270 vs. 250 minutes respectively; P < 0.05). There were fewer conversions in the robotic group (0 vs. 14.3% for laparoscopy; P > 0.05), and a significantly shorter hospital stay (6 vs. 8 vs. 9 days, respectively). CONCLUSIONS: Robotic RBP is feasible and safe, but at the price of a longer operative time. The exact role of robotics remains yet to be defined for this indication in larger studies. PMID- 24167028 TI - Effect of botulinum toxin A on urothelial-release of ATP and expression of SNARE targets within the urothelium. AB - AIMS: Botulinum neurotoxin serotype A (BoNT/A) has emerged as an effective treatment of urinary bladder overactivity. Intravesical lipotoxin (BoNT/A delivery using liposomes), which may target the urothelium, is effective in blocking acetic acid induced hyperactivity in animals. The objective of this study was to assess the possible site of toxin action within the urothelium. METHODS: We examined expression of the toxin receptor (SV2) and its cleavage targets (SNAP-25 and SNAP-23) within urothelium as well as effects of the toxin on mechanically evoked release of ATP from cultured rat urothelial cells. ATP release was measured using the luciferin-luciferase assay; we examined expression of SNAP-23 and -25 in urothelial cells and mucosa of rat and human bladders. RESULTS: BoNT/A (1.5 U; 1-3 hr) blocked hypotonic evoked release of urothelial ATP, without affecting morphology. The expression of protein targets for BoNT/A binding (SV2) was detected in human and rat bladder mucosa and catalytic action (SNAP-23, -25) in urothelial cells and mucosa (differed in intensity) from rat and human bladder. Incubation of cultured (rat) urothelial cells with BoNT/A decreased expression levels of both SNAP-23 (44%) and SNAP-25 (80%). CONCLUSIONS: Our findings reveal that the bladder urothelium expresses the intracellular targets and the binding protein for cellular uptake of BoNT/A; and that the toxin is able to suppress the levels of these targets as well as hypotonic-evoked ATP release. These data raise the possibility that intravesical treatment with BoNT/A suppresses bladder reflex and sensory mechanisms by affecting a number of urothelial functions including release of transmitters. PMID- 24167030 TI - Significance of atypia in pancreatic and bile duct brushings: follow-up analysis of the categories atypical and suspicious for malignancy. AB - Brushing cytology is frequently utilized for the investigation of pancreatic and biliary strictures but is associated with low diagnostic sensitivity. The Papanicolaou Society of Cytopathology has presented a system for diagnostic classification which includes the categories benign, atypical, suspicious for malignancy and malignant. We studied a series of 216 pancreatic and biliary brushings with either histologic follow-up or a minimum of 6 months clinical follow-up to determine outcomes for the diagnostic categories ("benign," "atypical, favor reactive," "atypical, not otherwise specified," "atypical, suspicious" and "malignant"). Eighty-six of the 216 (39.8%) were designated "atypical" with 10 of these designated as "atypical favor reactive." Forty-five were called "atypical not otherwise specified" and 31 were interpreted as "atypical suspicious for malignancy." On follow-up, 2 of 10 (20%) "atypical favor reactive" were eventually associated with a malignant diagnosis and 23 of 31 (74.2%) "atypical, suspicious for malignancy" demonstrated a malignant outcome. The remaining 45 brushings in the "atypical" category were "atypical not otherwise specified," and 62% of these were associated with malignancy on follow up. Stratification of the "atypical" category into "atypical favor reactive," "atypical, not otherwise specified" and "atypical, suspicious for malignancy" improves diagnostic accuracy. The "atypical suspicious for malignancy" category has a follow-up similar to the "malignant" category while the "atypical favor reactive" category is associated with a clinical outcome similar to that of the "benign" category. PMID- 24167031 TI - Proteomic analysis reveals tanshinone IIA enhances apoptosis of advanced cervix carcinoma CaSki cells through mitochondria intrinsic and endoplasmic reticulum stress pathways. AB - Cervix cancer is the second most common cancer among women worldwide, whereas paclitaxel, the first line chemotherapeutic drug used to treat cervical cancer, shows low chemosensitivity on the advanced cervical cancer cell line. Tanshinone IIA (Tan IIA) exhibited strong growth inhibitory effect on CaSki cells (IC50 = 5.51 MUM) through promoting caspase cascades with concomitant upregulating the phosphorylation of p38 and JNK signaling. Comprehensive proteomics revealed the global protein changes and the network analysis implied that Tan IIA treatment would activate ER stress pathways that finally lead to apoptotic cell death. Moreover, ER stress inhibitor could alleviate Tan IIA caused cell growth inhibition and ameliorate C/EBP-homologous protein as well as apoptosis signal regulating kinase 1 mediated cell death. The therapeutic interventions targeting the mitochondrial-related apoptosis and ER stress responses might be promising strategies to conquer paclitaxel resistance. PMID- 24167032 TI - S2 fluorescence dynamics of meso-aryl-substituted subporphyrins. PMID- 24167033 TI - Are parents following the recommendations for keeping children younger than 2 years rear facing during motor vehicle travel? AB - PURPOSE: Between 2007 and 2012 there have been several recommendations that infants and toddlers ride in a car safety seat (CSS) rear facing until 2 years of age. This study reports the effect of these recommendations on the observed direction of travel for infants and toddlers transported in motor vehicles between 2007 and 2012. METHODS: This is an observational, cross-sectional survey of drivers transporting children collected at 25 convenience locations selected in Indiana during summer 2007 through 2012. Observations were conducted by Certified Child Passenger Safety Technicians. As drivers completed a written survey, the Certified Child Passenger Safety Technician recorded the vehicle seating location, type of restraint, CSS direction and use of the CSS harness or safety belt as appropriate, and demographic data. The infant and toddler's age and weight were collected. Data from 2007 through 2012 for ages birth through 23 months were compared in order to determine if recommendations impacted observed direction of travel. RESULTS: During the study period, the percent of infants and toddlers (birth through 23 months) observed rear facing in a motor vehicle varied from 44.2% (2007) to 59.1% (2012). For infants (birth through 11 months) observed rear facing, it was 85.1% (2009) to 91.6% (2012). The percent of toddlers (12 months through 23 months) observed rear facing ranged from 3.3% (2008) to 18.2% (2012). CONCLUSIONS: During the study period, the proportion of toddlers rear facing increased approximately 15% (p=0.03). Counselling by primary care providers should continue and be strengthened to increase parent and caregiver awareness of the latest child passenger safety recommendations. PMID- 24167034 TI - Assessing the accuracy of the International Classification of Diseases codes to identify abusive head trauma: a feasibility study. AB - OBJECTIVE: To assess the accuracy of an International Classification of Diseases (ICD) code-based operational case definition for abusive head trauma (AHT). METHODS: Subjects were children <5 years of age evaluated for AHT by a hospital based Child Protection Team (CPT) at a tertiary care paediatric hospital with a completely electronic medical record (EMR) system. Subjects were designated as non-AHT traumatic brain injury (TBI) or AHT based on whether the CPT determined that the injuries were due to AHT. The sensitivity and specificity of the ICD based definition were calculated. RESULTS: There were 223 children evaluated for AHT: 117 AHT and 106 non-AHT TBI. The sensitivity and specificity of the ICD based operational case definition were 92% (95% CI 85.8 to 96.2) and 96% (95% CI 92.3 to 99.7), respectively. All errors in sensitivity and three of the four specificity errors were due to coder error; one specificity error was a physician error. CONCLUSIONS: In a paediatric tertiary care hospital with an EMR system, the accuracy of an ICD-based case definition for AHT was high. Additional studies are needed to assess the accuracy of this definition in all types of hospitals in which children with AHT are cared for. PMID- 24167035 TI - Timing of adjuvant radiotherapy and treatment outcome in childhood ependymoma. AB - BACKGROUND: Several trials incorporating adjuvant focal RT for treatment of young children with ependymoma have demonstrated improved survival with acceptable adverse effects. The optimal timing of RT administration is, however, unknown. PROCEDURE: A retrospective review of territory-wide database was performed to identify pediatric patients with ependymoma diagnosed between 1995 and 2011. OS and EFS were compared between patients receiving upfront RT (<150 days of diagnosis), delayed RT (>=150 days of diagnosis), or no RT. RESULTS: Thirty-one patients with intracranial ependymoma were identified. Median age was 3.5 years and 14 (45%) were male. Primary tumor was supratentorial in 10 (32%) and infratentorial in 21 (68%). All patients underwent initial surgery, with gross total resection (GTR) in 27 (87%). Twelve (39%) received upfront RT, 10 (32%) had delayed RT and 9 (29%) had no RT. During the study period, there were 11 relapses (35%) and 10 deaths (32%). Five-year OS was 69.9% and 5yr-EFS was 49.3%. In univariate analysis, GTR led to improved OS (P < 0.001) and EFS (P = 0.004); superior OS and EFS was observed in patients who received RT when compared with those without (P = 0.018 and 0.011, respectively). Upfront RT also resulted in better OS and EFS than delayed RT (P = 0.049 and 0.014, respectively). No significant effect on survival was observed with age, sex, tumor location, RT dosage, and protocol used. In multivariate analysis, GTR significantly improved OS (P = 0.002) and EFS (P = 0.004). CONCLUSIONS: Our results support the early initiation of adjuvant RT in the multi-modal management of pediatric ependymomas. PMID- 24167036 TI - Association of body mass index and waist circumference with successful aging. AB - OBJECTIVE: The prediction of successful aging by midlife body mass index (BMI) and waist circumference (WC) was examined. METHODS: BMI/WC were assessed in 4869 persons (mean age 51.2, range 42-63 in 1991/1993) and survival and successful aging (alive, no chronic disease at age >60 years, not in the worst age- and sex standardized quintile of cognitive, physical, respiratory,cardiovascular, and mental health) ascertained over a 16-year follow-up, analyzed using logistic regression adjusted for sociodemographic factors and health behaviors. RESULTS: 507 participants died, 1008 met the criteria for successful aging. Those with BMI >= 30 kg/m(2) had lower odds of successful aging (odds ratio or OR) = 0.37; 95% confidence interval or CI: 0.27, 0.50) and survival (OR = 0.55; 95% CI: 0.41, 0.74) compared to BMI between 18.5 and 25 kg/m(2) . Those with a large WC (>=102/88 cm in men/women) had lower odds of successful aging (OR = 0.41; 95% CI: 0.31, 0.54) and survival (OR = 0.57; 95% CI: 0.44, 0.73) compared with those with a small waist (<94/80 cm in men/women). Analysis with finer categories showed lower odds of successful aging starting at BMI >= 23.5 kg/m(2) and WC 82/68 cm in men/women. CONCLUSIONS: Optimal midlife BMI and WC for successful aging might be substantially below the current thresholds used to define obesity. PMID- 24167037 TI - A case of mucoepidermoid carcinoma of the bronchus presented with hydropneumothorax in a child. AB - Mucoepidermoid carcinoma is a rare pulmonary neoplasm seen in the pediatric population. We report a low grade mucoepidermoid carcinoma in a 12-year-old boy who presented with spontaneous pneumothorax. PMID- 24167039 TI - Protein carbonylation and muscle function in COPD and other conditions. AB - Skeletal muscle, the most abundant tissue in mammals, is essential for any activity in life. Muscle dysfunction is a common systemic manifestation in highly prevalent conditions such as chronic obstructive pulmonary disease (COPD), cancer cachexia, and sepsis. It has a significant impact on exercise tolerance, thus worsening the patients' quality of life and survival. Among several factors, oxidative stress is a major player in the etiology of skeletal muscle dysfunction associated with those conditions. Whereas low levels of oxidants are absolutely required for normal cell adaptation, high levels of reactive oxygen species (ROS) alter the function and structure of molecules such as proteins, DNA, and lipids. Specifically, protein carbonylation, a common variety of protein oxidation, was shown to alter the function of key enzymes and structural proteins involved in muscle contractile performance. Moreover, increased levels of ROS may also activate proteolytic systems, thus leading to enhanced protein breakdown in several models. In the current review, the specific modifications induced by carbonylation in protein structure and function in muscles have been described. Furthermore, the potential role of ROS in the activation of proteolytic systems in skeletal muscles is also discussed. The review summarizes the effects of protein carbonylation on muscles in several models and conditions such as COPD, disuse muscle atrophy, cancer cachexia, sepsis, and aging. Future research should focus on the elucidation of the specific protein sites modified by ROS in these muscles using redox proteomics analyses and on the assessment of the consequent alterations in protein function and stability. PMID- 24167040 TI - Ultrasound guided fine needle aspiration biopsy: the new challenges and opportunities for cytopathologists. PMID- 24167038 TI - PINK1 heterozygous mutations induce subtle alterations in dopamine-dependent synaptic plasticity. AB - Homozygous or compound heterozygous mutations in the phosphatase and tensin homolog-induced putative kinase 1 (PINK1) gene are causative of autosomal recessive, early onset Parkinson's disease. Single heterozygous mutations have been detected repeatedly both in a subset of patients and in unaffected individuals, and the significance of these mutations has long been debated. Several neurophysiological studies from non-manifesting PINK1 heterozygotes have demonstrated the existence of neural plasticity abnormalities, indicating the presence of specific endophenotypic traits in the heterozygous state. We performed a functional analysis of corticostriatal synaptic plasticity in heterozygous PINK1 knockout (PINK1(+/-) ) mice using a multidisciplinary approach and observed that, despite normal motor behavior, repetitive activation of cortical inputs to striatal neurons failed to induce long-term potentiation (LTP), whereas long-term depression was normal. Although nigral dopaminergic neurons exhibited normal morphological and electrophysiological properties with normal responses to dopamine receptor activation, a significantly lower dopamine release was measured in the striatum of PINK1(+/-) mice compared with control mice, suggesting that a decrease in stimulus-evoked dopamine overflow acts as a major determinant for the LTP deficit. Accordingly, pharmacological agents capable of increasing the availability of dopamine in the synaptic cleft restored normal LTP in heterozygous mice. Moreover, monoamine oxidase B inhibitors rescued physiological LTP and normal dopamine release. Our results provide novel evidence for striatal plasticity abnormalities, even in the heterozygous disease state. These alterations might be considered an endophenotype to this monogenic form of Parkinson's disease and a valid tool with which to characterize early disease stage and design possible disease-modifying therapies. PMID- 24167041 TI - Interface-induced modulation of charge and polarization in thin film Fe(3)O(4). AB - Charge and polarization modulations in Fe3 O4 are controlled by taking advantage of interfacial strain effects. The feasibility of oxidation state control by strain modification is demonstrated and it is shown that this approach offers a stable configuration at room temperature. Direct evidence of how a local strain field changes the atomic coordination and introduces atomic displacements leading to polarization of Fe ions is presented. PMID- 24167042 TI - The treatment of dystonic tremor: a systematic review. AB - Tremor is one of the clinical manifestations of dystonia; however, there are no specific therapeutic trials evaluating the efficacy of treatments for dystonic tremor (DT), tremor associated with dystonia or primary writing tremor (PWT). We systematically reviewed the literature available up to July 2013 on the treatment of these tremors and retrieved the data of 487 patients published in 43 papers detailing the effects of given interventions on tremor severity. Treatment outcome was highly variable, depending on the specific type of intervention and tremor distribution. No specifically designed studies were available for the treatment of tremor associated with dystonia. As for the other tremors, drug efficacy was generally disappointing and a moderate effect was only found with anticholinergics, tetrabenazine, clonazepam, beta-blockers and primidone; levodopa was only efficacious on tremor due to dopa-responsive dystonia. The largest amount of data was available for botulinum toxin injections, which provided a marked improvement, particularly for the management of axial tremors (head or vocal cords). In refractory DTs, deep brain stimulation of several targets was attempted. Deep brain stimulation of globus pallidus internus, thalamus or subthalamic area led to a marked improvement of dystonic axial or appendicular tremors in most cases refractory to other treatments. Few other non invasive treatments, for example, orthotic device in PWT, have been used with anecdotal success. In conclusion, considering the lack of good-quality studies, future randomised controlled trials are needed. In absence of evidence-based guidelines, we propose an algorithm for the treatment of DT based on currently available data. PMID- 24167043 TI - Contributions of human hippocampal subfields to spatial and temporal pattern separation. AB - We sought to explore the roles of the hippocampal subregions and adjacent medial temporal lobe regions in pattern separation and any differential contributions based on sequential or spatial information. Young adults performed an incidental encoding task on a sequence of four objects presented on the screen in one of eight locations while we collected high-resolution functional MRI brain scans. We employed five trials of interest: first presentations, exact repetitions, lures in which the same objects were repeated in different locations (spatial lures), lures in which the same objects were presented in a different sequential order (sequential lures), and lures in which both the spatial location and sequence were changed (both lures). We found no evidence for spatial or sequential specialization in the hippocampal subfields, consistent with the hypothesis that the dentate gyrus acts as a universal pattern separator. Likewise, we did not observe specialization for the perirhinal or parahippocampal cortices for spatial or sequential information, though both regions show evidence for associative processing in this task. PMID- 24167044 TI - Assessment of adrenocortical and gonadal hormones in male spider monkeys (Ateles geoffroyi) following capture, restraint and anesthesia. AB - The spider monkey (SM) (Ateles geoffroyi) a New World primate species native to Mexican forests, has become endangered in the wild due to environmental perturbations. Little is known about adrenal function and its relationship to reproduction in this species. Our objectives were to assess serum glucocorticoid (GC), mineralocorticoid (MC) and testosterone concentrations in captive SM and evaluate adrenal and testicular responses to potentially stressful animal handling procedures. Seven adult males, housed in a single mixed gender group in an off-exhibit enclosure at the University Park were captured for anesthesia every 2 months over a 1-year period. Blood samples were collected from each male at three time points: (1) ~5-10 min after ketamine injection in the outdoor enclosure; (2) ~2 hr later following animal transport to the laboratory and immediately after tiletamine-zolazepam injection; and (3) ~20-30 min following the second anesthetic injection. Serum samples were frozen and later analyzed for cortisol, corticosterone, aldosterone and testosterone via radioimmunoassay. Cortisol was the primary GC detected in SM serum with much higher mean concentrations than for corticosterone. Capture, restraint and anesthesia resulted in significant increases in both cortisol and corticosterone concentrations. Whereas aldosterone concentrations were unchanged by animal handling procedures, testosterone concentrations significantly declined under anesthesia over time. In summary, these results provide data for the main adrenocortical hormones in male SM and characterize their acute adrenal responses to potentially stressful handling and anesthesia procedures. Our findings also suggest an interaction between acute increases in corticosteroids and decreased concentrations of serum testosterone. PMID- 24167045 TI - A chemical perspective on transcriptional fidelity: dominant contributions of sugar integrity revealed by unlocked nucleic acids. AB - Transcription unlocked: A synthetic chemical biology approach involving unlocked nucleic acids was used to dissect the contribution of sugar backbone integrity to the RNA Polymerase II (Pol II) transcription process. An unexpected dominant role for sugar-ring integrity in Pol II transcriptional efficiency and fidelity was revealed. PMID- 24167046 TI - Onchocercoma-cytological diagnosis. PMID- 24167047 TI - Finding your way back: wires, loops, needles and balloons. PMID- 24167048 TI - Drug-eluting stents for ostial coronary stenoses: perspectives on the horizon. PMID- 24167049 TI - A new surrogate to assess distal left main bifurcating lesions? PMID- 24167050 TI - Self-expanding stents: another tool in the armamentarium for treating bifurcation lesions? PMID- 24167051 TI - Acute thrombotic occlusion or intramural hematoma: only IVUS can tell for sure. PMID- 24167052 TI - Ready for anything: the value of anticipation, prevention, and early treatment of complications during chronic total occlusion interventions. PMID- 24167053 TI - Small is beautiful but fragile and hazardous in the cath lab. PMID- 24167054 TI - Hybrid use of Melody valve: the best of both worlds? PMID- 24167055 TI - Alcohol ablation in the younger HCM heart: is there an age limit? PMID- 24167056 TI - Proteomic strategy for probing complementary lethality of kinase inhibitors against pancreatic cancer. AB - In the present study, proteomic analysis was performed to discover combinational molecular targets for therapy and chemoresistance by comparing differential protein expression from Panc-1 cells treated with FDA-approved drugs such as sunitinib, imatinib mesylate, dasatinib, and PD184352. A total of 4041 proteins were identified in the combined data from all of the treatment groups by nano electrospray ultra-performance LC and MS/MS analysis. Most of the proteins with significant changes are involved in apoptosis, cytoskeletal remodeling, and epithelial-to-mesenchymal transition. These processes are associated with increased chemoresistance and progression of pancreatic cancer. Among the differentially expressed proteins, heme oxygenase-1 (HO-1) was found in the sunitinib and imatinib mesylate treatment groups, which possibly acts as a specific target for synthetic lethality in combinational treatment. HO-1 was found to play a key role in sensitizing the chemoresistant Panc-1 cell line to drug therapy. Viability was significantly decreased in Panc-1 cells cotreated with sunitinib and imatinib mesylate at low doses, compared to those treated with sunitinib or imatinib mesylate alone. The results suggest that induction of chemosensitization by manipulating specific molecular targets can potentiate synergistic chemotherapeutic effects at lower, better tolerated doses, and in turn reduce the toxicity of multidrug treatment of pancreatic cancer. PMID- 24167058 TI - Dynamically doped white light emitting tandem devices. AB - Solution-processed, salt-containing, blue and orange light-emitting layers lead to efficient white light-emitting devices when arranged in a tandem configuration separated by a thin metal layer. PMID- 24167057 TI - Mass spectrometry and 3-nitrotyrosine: strategies, controversies, and our current perspective. AB - Reactive-nitrogen species (RNS) such as peroxynitrite (ONOO(-)), that is, the reaction product of nitric oxide ((*)NO) and superoxide (O2(-*)), nitryl chloride (NO2Cl) and (*)NO2 react with the activated aromatic ring of tyrosine to form 3 nitrotyrosine. This modification, which has been known for more than a century, occurs to both the free form of the amino acid (i.e., soluble/free tyrosine) and to tyrosine residues covalently bound within the backbone of peptides and proteins. Nitration of tyrosine is thought to be of biological significance and has been linked to health and disease, but determining its role has proved challenging. Several key questions have been the focus of much of the research activity: (a) to what extent is free/soluble tyrosine nitrated in biological tissues and fluids, and (b) are there specific site(s) of nitration within peptides/proteins and to what extent (i.e., stoichiometry) does this modification occur? These issues have been addressed in a wide range of sample types (e.g., blood, urine, CSF, exhaled breath condensate and various tissues) and a diverse array of physiological/pathophysiological scenarios. The accurate determination of nitrated tyrosine is, however, a stumbling block. Despite extensive study, the extent to which nitration occurs in vivo, the specificity of the nitration reaction, and its importance in health and disease, remain unclear. In this review, we highlight the analytical challenges and discuss the approaches adopted to address them. Mass spectrometry, in combination with either gas chromatography (GC-MS, GC-MS/MS) or liquid chromatography (LC-MS/MS), has played the central role in the analysis of 3-nitrotyrosine and tyrosine-nitrated biological macromolecules. We discuss its unique attributes and highlight the role of stable isotope labeled 3-nitrotyrosine analogs in both accurate quantification, and in helping to define the biological relevance of tyrosine nitration. We show that the application of sophisticated mass spectrometric techniques is advantageous if not essential, but that this alone is by no means a guarantee of accurate findings. We discuss the important analytical challenges in quantifying 3 nitrotyrosine, possible workarounds, and we attempt to make sense of the disparate findings that have been reported so far. PMID- 24167059 TI - A randomized, double-blind, placebo-controlled clinical trial of megestrol acetate as an appetite stimulant in children with weight loss due to cancer and/or cancer therapy. AB - BACKGROUND: Megestrol acetate (MA) is an appetite stimulant with efficacy in promoting weight gain in adults with cancer-associated anorexia-cachexia. Studies documenting MA efficacy in children, however, are limited. We present the first randomized, double-blind, placebo-controlled clinical trial of MA versus placebo in children with cancer and weight loss. METHODS: Subjects <18 years of age with weight loss (minimum 5% from highest previous weight; or %ideal body weight <90%) due to cancer and/or cancer therapy were randomized to either MA (7.5 mg/kg/day) or placebo for a planned study duration of 90 days. Primary outcome was the difference between groups in mean percent weight change from beginning to end of the study period. Secondary outcomes included effects on anthropometrics, body composition, need for tube feeding or parenteral nutrition, and toxicities. RESULTS: Twenty-six patients were randomly assigned (13 MA, 13 placebo). The MA group experienced a mean weight gain of +19.7% compared to a mean weight loss of 1.2% in the placebo group, for a difference of +20.9% (95%CI: +11.3% to +30.5%, P = 0.003) in favor of MA over placebo. MA subjects experienced significant increases in weight for age z-scores, body mass index z-scores, and mid upper arm circumference compared to placebo. DXA scanning suggested disproportionate increases in fat accrual. Adrenal suppression was the main toxicity of MA. CONCLUSION: In children with high-risk malignancies, MA resulted in significant increases in mean percent weight change compared to placebo. Further studies of MA should be pursued to better delineate the effect on nutritional status. PMID- 24167060 TI - Spatial discrimination deficits as a function of mnemonic interference in aged adults with and without memory impairment. AB - It is well established that aging is associated with declines in episodic memory. In recent years, an emphasis has emerged on the development of behavioral tasks and the identification of biomarkers that are predictive of cognitive decline in healthy as well as pathological aging. Here, we describe a memory task designed to assess the accuracy of discrimination ability for the locations of objects. Object locations were initially encoded incidentally, and appeared in a single space against a 5 * 7 grid. During retrieval, subjects viewed repeated object location pairings, displacements of 1, 2, 3, or 4 grid spaces, and maximal corner to-opposite-corner displacements. Subjects were tasked with judging objects in this second viewing as having retained their original location, or having moved. Performance on a task such as this is thought to rely on the capacity of the individual to perform hippocampus-mediated pattern separation. We report a performance deficit associated with a physically healthy aged group compared to young adults specific to trials with low mnemonic interference. Additionally, for aged adults, performance on the task was correlated with performance on the delayed recall portion of the Rey Auditory Verbal Learning Test (RAVLT), a neuropsychological test sensitive to hippocampal dysfunction. In line with prior work, dividing the aged group into unimpaired and impaired subgroups based on RAVLT Delayed Recall scores yielded clearly distinguishable patterns of performance, with the former subgroup performing comparably to young adults, and the latter subgroup showing generally impaired memory performance even with minimal interference. This study builds on existing tasks used in the field, and contributes a novel paradigm for differentiation of healthy from possible pathological aging, and may thus provide an avenue for early detection of age related cognitive decline. PMID- 24167061 TI - Limitations of using same-hospital readmission metrics. AB - OBJECTIVE: To quantify the limitations associated with restricting readmission metrics to same-hospital only readmission. DESIGN: Using 2000-2009 California Office of Statewide Health Planning and Development Patient Discharge Data Nonpublic file, we identified the proportion of 7-, 15- and 30-day readmissions occurring to the same hospital as the initial admission using All-cause Readmission (ACR) and 3M Corporation Potentially Preventable Readmissions (PPR) Metric. We examined the correlation between performance using same and different hospital readmission, the percent of hospitals remaining in the extreme deciles when utilizing different metrics, agreement in identifying outliers and differences in longitudinal performance. Using logistic regression, we examined the factors associated with admission to the same hospital. RESULTS: 68% of 30 day ACR and 70% of 30-day PPR occurred to the same hospital. Abdominopelvic procedures had higher proportions of same-hospital readmissions (87.4-88.9%), cardiac surgery had lower (72.5-74.9%) and medical DRGs were lower than surgical DRGs (67.1 vs. 71.1%). Correlation and agreement in identifying high- and low performing hospitals was weak to moderate, except for 7-day metrics where agreement was stronger (r = 0.23-0.80, Kappa = 0.38-0.76). Agreement for within hospital significant (P < 0.05) longitudinal change was weak (Kappa = 0.05-0.11). Beyond all patient refined-diagnostic related groups, payer was the most predictive factor with Medicare and MediCal patients having a higher likelihood of same-hospital readmission (OR 1.62, 1.73). CONCLUSIONS: Same-hospital readmission metrics are limited for all tested applications. Caution should be used when conducting research, quality improvement or comparative applications that do not account for readmissions to other hospitals. PMID- 24167062 TI - Cytologic features in vitreous preparations of patients with suspicion of intraocular lymphoma. AB - Intraocular lymphoma may occur, primarily with or without overt parenchymal CNS lymphoma or secondarily from a variety of other lymphomas. The diagnosis is frequently based on cytologic features and/or a limited panel of ancillary techniques. Twenty-seven cytology samples from the vitreous preparations of 20 patients with clinical suspicion or histopathologic diagnoses of lymphoma were retrospectively reviewed (2007-2011). Floaters and decreased visual acuity were the most common ocular symptoms. Sixteen (of 20) patients had at least one cytology that was "positive" or "suspicious" for lymphoma (F = 10; M = 6, median age = 71 years, range = 52-82). Involvement was limited to the eye in half of the cases (n = 8). Seven patients had CNS involvement, and three had systemic lymphoma. Cytologic specimens were classified as large B cell lymphoma (LBCL) (n = 13), suspicious for LBCL (n = 5), atypical/negative (n = 5), and consistent with NK-T cell lymphoma (n = 1). Three cytologic samples were acellular. Cytologic findings included increased cellularity (high n = 7, moderate n = 7), large to medium (n = 19) cell size, marked nuclear irregularities (n = 12), frequent apoptosis (n = 7), lymphoglandular bodies (n = 12), and necrosis (n = 12). Easily identifiable mitotic figures were present in two cases. CD20 immunocytochemistry performed in 15 cases with available cell blocks/destained cytospins preparations, was confirmatory in 8 cases. Cytologic evaluation of intraocular lymphoma is possible in vitreous specimens. Extraocular involvement was not present in half of the cases. The most useful cytologic features include increased cellularity, necrosis, and nuclear enlargement. Ancillary immunocytochemical studies are useful and support the morphologic impression in a subset of cases. PMID- 24167063 TI - Interpretive conundrums when practice doesn't always make perfect. PMID- 24167065 TI - Effect of pressure on the stability of G-quadruplex DNA: thermodynamics under crowding conditions. AB - Under pressure: A DNA G-quadruplex was unfolded under high pressure, but crowding conditions repressed this effect owing to enthalpic contributions. Volumetric analysis showed that ethylene glycol or poly(ethylene glycol) decreased the volume change of the transition by more than fourfold owing to the alteration of the number and/or radii of hydrating water molecules. PMID- 24167064 TI - Reshaping the transcriptional frontier: epigenetics and somatic cell nuclear transfer. AB - Somatic-cell nuclear transfer (SCNT) experiments have paved the way to the field of cellular reprogramming. The demonstrated ability to clone over 20 different species to date has proven that the technology is robust but very inefficient, and is prone to developmental anomalies. Yet, the offspring from cloned animals exhibit none of the abnormalities of their parents, suggesting the low efficiency and high developmental mortality are epigenetic in origin. The epigenetic barriers to reprogramming somatic cells into a totipotent embryo capable of developing into a viable offspring are significant and varied. Despite their intimate relationship, chromatin structure and transcription are often not uniformly reprogramed after nuclear transfer, and many cloned embryos develop gene expression profiles that are hybrids between the donor cell and an embryonic blastomere. Recent advances in cellular reprogramming suggest that alteration of donor-cell chromatin structure towards that found in an normal embryo is actually the rate-limiting step in successful development of SCNT embryos. Here we review the literature relevant to the transformation of a somatic-cell nucleus into an embryo capable of full-term development. Interestingly, while resetting somatic transcription and associated epigenetic marks are absolutely required for development of SCNT embryos, life does not demand perfection. PMID- 24167066 TI - Transformation of ferulic acid to vanillin using a fed-batch solid-liquid two phase partitioning bioreactor. AB - Amycolatopsis sp. ATCC 39116 (formerly Streptomyces setonii) has shown promising results in converting ferulic acid (trans-4-hydroxy-3-methoxycinnamic acid; substrate), which can be derived from natural plant wastes, to vanillin (4 hydroxy-3-methoxybenzaldehyde). After exploring the influence of adding vanillin at different times during the growth cycle on cell growth and transformation performance of this strain and demonstrating the inhibitory effect of vanillin, a solid-liquid two-phase partitioning bioreactor (TPPB) system was used as an in situ product removal technique to enhance transformation productivity by this strain. The thermoplastic polymer Hytrel((r)) G4078W was found to have superior partitioning capacity for vanillin with a partition coefficient of 12 and a low affinity for the substrate. A 3-L working volume solid-liquid fed-batch TPPB mode, using 300 g Hytrel G4078W as the sequestering phase, produced a final vanillin concentration of 19.5 g/L. The overall productivity of this reactor system was 450 mg/L. h, among the highest reported in literature. Vanillin was easily and quantitatively recovered from the polymers mostly by single stage extraction into methanol or other organic solvents used in food industry, simultaneously regenerating polymer beads for reuse. A polymer-liquid two phase bioreactor was again confirmed to easily outperform single phase systems that feature inhibitory or easily further degraded substrates/products. This enhancement strategy might reasonably be expected in the production of other flavor and fragrance compounds obtained by biotransformations. PMID- 24167067 TI - Divergence of water balance mechanisms and acclimation potential in body color morphs of Drosophila ananassae. AB - Drosophila ananassae is a desiccation sensitive species, but the physiological basis of its abundance in the drier subtropical areas is largely unknown. We tested the hypothesis whether body color morphs of D. ananassae differ in the mechanistic basis of water conservation as well as desiccation acclimation potential, consistent with their distribution under dry or wet habitats. We observed reduced rate of water loss consistent with the greater desiccation potential of dark morph as compared with light morph, despite lack of quantitative differences in cuticular lipid mass between them. Dark morph evidenced greater wet and dry mass (~1.17-fold) as well as higher hemolymph content (~1.70-fold) and (~17%) dehydration tolerance to sustain longer survival under desiccation stress (LT50 17.5 hr) as compared with light morph (LT50 4.3 hr). We found significant differences in the storage of energy metabolites in the body color morphs of D. ananassae, that is, carbohydrate content was significantly higher (~0.18 mg/mg dry mass) in the dark morph as compared to light morph, but greater (~0.05 mg/mg dry mass) body lipid content was evident in the light morph. Under desiccation stress, dark and light morphs utilized mainly carbohydrates but also lipids to a lesser extent. However, the rate of utilization of energy metabolites did not vary between dark and light morphs. Further, the dark morph consumed higher energy content derived from carbohydrates under desiccation stress as compared with the light morph. Finally, we found contrasting patterns of acclimation to desiccation stress in the two body color morphs, that is, increase in desiccation survival (4.7 hr), as well as in dehydration tolerance (~6%) due to acclimation of the dark morph but no such effects were observed in the light morph. Thus, divergence in water balance mechanisms as well as acclimation potential reflects evolved physiological adaptations of the dark morph under drier but of the light morph to wet climatic conditions. PMID- 24167069 TI - Pulmonary marginal zone B-cell lymphoma of MALT type: a cytological report with emphasis on the usefulness of detection of lymphoepithelial lesion. PMID- 24167068 TI - Joint instability and cartilage compression in a mouse model of posttraumatic osteoarthritis. AB - Joint instability and cartilage trauma have been previously studied and identified as key mediators in the development of posttraumatic osteoarthritis (PTOA). The purpose of this study was to use an in vivo model to compare the effect of joint instability, caused by the rupture of the anterior cruciate ligament (ACL), versus cartilage compression. In this study, mice were subjected to cyclical axial loads of twelve Newtons (N) for 240 cycles or until the ACL ruptured. One and eight weeks after this procedure, knees were sectioned coronally and evaluated for osteoarthritis by histology. Using a scoring scale established by [Pritzker K, Gay S, Jimenez S, et al. (2006): Osteoarthritis Cartilage 14:13-29], the articular cartilage across each surface was scored and combined to produce a total degeneration score. The ACL-ruptured group had a significantly greater total degeneration score than either control or compression treated joints at 1 and 8 weeks. Additionally, only sections from ACL-ruptured knees consistently showed synovitis after 1 week and osteophyte formation after 8 weeks. Thus, it appears using that ACL rupture consistently creates a severe osteoarthritis phenotype, while axial cartilage compression alone does not appear to be an appropriate method of inducing PTOA in vivo. PMID- 24167070 TI - Body composition in paediatric intestinal failure patients receiving long-term parenteral nutrition. AB - OBJECTIVE: Outcome of children with intestinal failure (IF) has improved on treatment with parenteral nutrition (PN). The effects of PN and IF on body composition (BC) are unknown. The aim was to review BC in PN-treated children and those weaned off and to compare with reference data. DESIGN: Children on long term/home PN underwent measurement of regional fat mass (FM) and lean mass (LM) using dual energy X-ray absorptiometry. Underlying diseases were intestinal enteropathy, n=15, short bowel syndrome (SBS), n=8 and intestinal dysmotility, n=11. PN duration was median 10 years. Fat Mass Index (FMI) and Lean Mass Index (LMI) were compared in children with and without intestinal inflammation, steroid treatment and according to PN dependency. RESULTS: 34 children aged 5-20 years were studied. They were short, mean height SD score (SDS) -1.8 (p<0.001) and light (mean weight SDS -0.86, p<0.001) with high body mass index (BMI) SDS: mean 0.4 (p=0.04) and low Limb LMI SDS -0.9 (p<0.001). Children with SBS had low FMI SDS -0.8 (p=0.01). BC did not significantly differ between diagnostic groups or with steroid treatment. Patients with intestinal inflammation (n=20) had higher BMI SDS than those without, p=0.007. Totally, PN-dependent children, n=11 had higher BMI SDS, p=0.004, total body FMI SDS, p=0.008 and trunk FMI SDS, p=0.001 compared with patients partially dependent and off PN. CONCLUSIONS: Significantly low limb LM was seen in all patient groups with high FM in children on total PN. Children with IF requiring PN treatment >27 days may benefit from BC monitoring and PN adjustment according to results in order to maximise linear growth and health in later life. PMID- 24167071 TI - Swaddling and hip dysplasia: an orthopaedic perspective. PMID- 24167072 TI - Proteomics analysis of UV-irradiated Lonicera japonica Thunb. with bioactive metabolites enhancement. AB - A previous study showed that the contents of caffeoylquinic acids and iridoids, the major bioactive components in the postharvest Lonicera japonica Thunb., were induced by enhanced ultraviolet (UV)-A or UV-B irradiation. To clarify the UV responsive key enzymes in the bioactive metabolites biosynthetic pathway and the related plant defense mechanism in L. japonica, 2DE in combination with MALDI TOF/TOF MS was employed. Seventy-five out of 196 differential proteins were positively identified. Based on the functions, these proteins were grouped into nine categories, covering a wide range of molecular processes including the secondary metabolites (caffeoylquinic acids and iridoids) biosynthetic-related proteins, photosynthesis, carbohydrate and energy metabolism, stress, DNA, transport-related proteins, lipid metabolism, amino acid metabolism, cell wall. Of note is the increasing expression of 1-deoxy-d-xylulose 5-phosphate reductoisomerase and 5-enol-pyruvylshikimate-phosphate synthase, which was crucial to supply more precursor for the secondary metabolites including caffeoylquinic acids and iridoids. Thus, this study provides both the clues at the protein level for the increase of the two bioactive components upon UV irradiation and the profile of UV-responsive proteins in L. japonica. PMID- 24167073 TI - Pcid2 inactivates developmental genes in human and mouse embryonic stem cells to sustain their pluripotency by modulation of EID1 stability. AB - Self-renewal and differentiation are the hallmarks of embryonic stem cells (ESCs). However, it is largely unknown about how the pluripotency is regulated. Here we demonstrate that Pcid2 is required for the maintenance of self-renewal both in mouse and human ESCs. Pcid2 plays a critical role in suppression of ESC differentiation. Pcid2 deficiency causes early embryonic lethality before the blastocyst stage. Pcid2 associates with EID1 and is present in the CBP/p300-EID1 complex in the ESCs. We show that MDM2 is an E3 ligase for K48-linked EID1 ubiquitination for its degradation. For the maintenance of self-renewal, Pcid2 binds to EID1 to impede the association with MDM2. Then EID1 is not degraded to sustain its stability to block the HAT activity of CBP/p300, leading to suppression of the developmental gene expression. Collectively, Pcid2 is present in the CBP/p300-EID1 complex to control the switch balance of mouse and human ESCs through modulation of EID1 degradation. PMID- 24167078 TI - A prospective intravascular ultrasound investigation of the necessity for and efficacy of postdilation beyond nominal diameter of 3 current generation DES platforms for the percutaneous treatment of the left main coronary artery. AB - OBJECTIVES: To define the size of the left mainstem coronary artery (LMS) in the Northern Irish population and investigate the clinical feasibility, safety, and efficacy of post dilation beyond nominal diameter of current generation Drug eluting stent (DES) when treating the LMS. BACKGROUND: There is no prospective data examining the need, feasibility, and safety of over-expansion of current generation DES beyond nominal diameter. METHODS: Patients with flow-limiting coronary atheroma requiring IVUS assessment of the LMS were recruited. Standardized measurements of the distal LMS were made. Subsequently, patients requiring post dilation of current generation DES within the LMS were entered into a PCI registry. RESULTS: Overall, 125 patients were recruited into the initial study. Mean cross-sectional area (CSA) of the distal LMS was 22.6 mm(2) (SD +/- 5.4 mm(2) ). Mean maximal vessel diameter was 5.7 mm (SD +/- 0.7 mm). Increasing plaque burden was associated with reduced CSA (P < 0.001). In 31 consecutive patients undergoing IVUS guided PCI of the LMS with 5.5 and 6.0 mm balloon catheters, mean maximal stent diameters were >5.0 mm with the Biomatrix Flex 9 crown and Promus Element Large vessel platforms. No intraprocedural complications occurred. Mean follow up was 13.4 months. Clinical restenosis rate was 3.2%, with 2 deaths unrelated to index procedure. CONCLUSIONS: The majority of patients with angiographic coronary atheroma have a mean LMS diameter of >4 mm indicating the requirement for post dilation beyond nominal diameter all of current generation DES in almost all patients when treating the LMS. This is achievable with current DES platforms with no intraprocedural complication. Clinical follow up indicates excellent short-term efficacy. PMID- 24167079 TI - Think twice: misleading food-induced respiratory symptoms in children with food allergy. AB - Reported food-related symptoms of patients may sometimes be misleading. A correct delineation of food-induced symptoms is often difficult and various differential diagnoses have to be considered. We report on two cases of food-induced, predominantly respiratory symptoms (in one case life-threatening) in children with food allergy. First, a two-year-old boy with no history of allergies and suspected foreign body aspiration which was finally diagnosed as an anaphylactic reaction to fish, and secondly a six-year-old girl with multiple food allergies and allergic asthma who during an electively performed oral food challenge developed severe respiratory distress, drop in blood pressure, and asphyxia not due to an anaphylactic reaction but due to choking on an unnoticed sweet. These two cases represent challenging, life-threatening symptom constellations involving food-induced reactions in food allergic children, reminding us to question first impressions. PMID- 24167080 TI - Preclinical SPECT/CT imaging of alphavbeta6 integrins for molecular stratification of idiopathic pulmonary fibrosis. AB - Transforming growth factor beta activation by the alphavbeta6 integrin is central to the pathogenesis of idiopathic pulmonary fibrosis. Expression of the alphavbeta6 integrin is increased in fibrotic lung tissue and is a promising therapeutic target for treatment of the disease. Currently, measurement of alphavbeta6 integrin levels in the lung requires immunohistochemical analysis of biopsy samples. This procedure is clinically impractical for many patients with pulmonary fibrosis, and a noninvasive strategy for measuring alphavbeta6 integrin levels in the lungs is urgently required to facilitate monitoring of disease progression and therapeutic responses. METHODS: Using a murine model of bleomycin induced lung injury, we assessed the binding of intravenously administered (111)In-labeled alphavbeta6-specific (diethylenetriamine pentaacetate-tetra [DTPA]-A20FMDV2) or control (DTPA-A20FMDVran) peptide by nanoSPECT/CT imaging. Development of fibrosis was assessed by lung hydroxyproline content, and alphavbeta6 protein and itgb6 messenger RNA were measured in the lungs. RESULTS: Maximal binding of (111)In-labeled A20FMDV2 peptide to alphavbeta6 integrins was detected in the lungs 1 h after intravenous administration. No significant binding was detected in mice injected with control peptide. Integrin binding was increased in the lungs of bleomycin-, compared with saline-, exposed mice and was attenuated by pretreatment with alphavbeta6-blocking antibodies. Levels of (111)In-labeled A20FMDV2 peptide correlated positively with hydroxyproline, alphavbeta6 protein, and itgb6 messenger RNA levels. CONCLUSION: We have developed a highly sensitive, quantifiable, and noninvasive technique for measuring alphavbeta6 integrin levels within the lung. Measurement of alphavbeta6 integrins by SPECT/CT scanning has the potential for use in stratifying therapy for patients with pulmonary fibrosis. PMID- 24167081 TI - (18)F-FDOPA PET for differentiating recurrent or progressive brain metastatic tumors from late or delayed radiation injury after radiation treatment. AB - Brain metastases are frequently treated with radiation. It is critical to distinguish recurrent or progressive brain metastases (RPBM) from late or delayed radiation injury (LDRI). The purpose of this study was to examine the diagnostic accuracy as well as the prognostic power of 6-(18)F-fluoro-l-dopa ((18)F-FDOPA) PET for differentiating RPBM from LDRI. METHODS: Thirty-two patients who had 83 previously irradiated brain metastases and who underwent (18)F-FDOPA PET because of an MR imaging-based suggestion of RPBM were studied retrospectively. PET studies were analyzed semiquantitatively (lesion-to-striatum and lesion-to-normal brain tissue ratios based on both maximum and mean standardized uptake values) and visually (4-point scale). The diagnostic accuracy of PET was verified by histopathologic analysis (n = 9) or clinical follow-up (n = 74) on a lesion-by lesion basis. Receiver operating characteristic curve analysis was used to identify the best diagnostic indices. The power of (18)F-FDOPA PET to predict disease progression was evaluated with the Kaplan-Meier and Cox regression methods. RESULTS: The best overall accuracy was achieved by visual scoring, with which a score of 2 or more (lesion uptake greater than or equal to striatum uptake) resulted in a sensitivity of 81.3% and a specificity of 84.3%. Semiquantitative (18)F-FDOPA PET uptake indices based on lesion-to-normal brain tissue ratios were significantly higher for RPBM than for LDRI. Among the various predictors tested, (18)F-FDOPA PET was the strongest predictor of tumor progression (hazard ratio, 6.26; P < 0.001), and the lesion-to-normal brain tissue ratio or visual score was the best discriminator. The mean time to progression was 4.6 times longer for lesions with negative (18)F-FDOPA PET results than for lesions with positive (18)F-FDOPA PET results (76.5 vs. 16.7 mo; P < 0.001). (18)F-FDOPA PET findings tended to predict overall survival. CONCLUSION: Metabolic imaging with (18)F-FDOPA PET was useful for differentiating RPBM from LDRI. Semiquantitative indices, particularly lesion-to-normal uptake ratios, could be used. A visual score comparing tumor (18)F-FDOPA uptake and striatum (18)F-FDOPA uptake provided the highest sensitivity and specificity and was predictive of disease progression. PMID- 24167082 TI - Highly stretchable piezoelectric-pyroelectric hybrid nanogenerator. AB - A highly stretchable hybrid nanogenerator has been developed using a micro patterned piezoelectric polymer P(VDF-TrFE), PDMS-CNT composite, and graphene nanosheets. Mechanical and thermal energies are simultaneously harvested from a single cell of the device. The hybrid nanogenerator exhibits high robustness behavior even after 30% stretching and generates very stable piezoelectric and pyroelectric power outputs due to micro-pattern designing. PMID- 24167083 TI - Comparison of diagnostic accuracy between CellprepPlus(r) and ThinPrep(r) liquid based preparations in effusion cytology. AB - Liquid-based cytology (LBC) is being increasingly used for body fluid specimens and has improved diagnostic accuracy when compared to conventional smears. We compared the diagnostic accuracy and cellular morphologic features between CellprepPlus(r) LBC and ThinPrep(r) LBC in effusion cytology. One hundred and eighty body fluid specimens, consisting of 119 pleural fluid specimens, 59 peritoneal fluid specimens, and 2 pericardial fluid specimens, were obtained from 166 patients. Equal volumes of body fluid from each specimen were used in the CellprepPlus(r) and ThinPrep(r) preparations. Sensitivity, specificity, and positive and negative predictive values were evaluated. In addition, we selected 16 specimens from patients with metastatic adenocarcinoma, confirmed them by both LBC preparations, and measured the size of the nucleus in the tumor cells in these specimens. The sensitivity of the CellprepPlus(r) and ThinPrep(r) methods was 73.1% and 50.0%, respectively. The specificity and positive predictive values were 100% for both LBC methods, and the negative predictive values of the CellprepPlus(r) and ThinPrep(r) methods were 90.9% and 83.3%, respectively. The average nuclear size of the tumor cells was calculated as 20.87 MUm using the CellprepPlus(r) method and 15.08 MUm using the ThinPrep(r) method (P < 0.05). The CellprepPlus(r) method provided better diagnostic accuracy of effusion cytology compared to the ThinPrep(r) method and revealed the characteristic morphological features of tumor cells, including large and hypochromatic nuclei, prominent nucleoli, distinct nuclear membranes, and high cellularity. PMID- 24167084 TI - Fixation effect of SurePath preservative fluids using epidermal growth factor receptor mutation-specific antibodies for immunocytochemistry. AB - BACKGROUND: Cytological diagnosis of respiratory disease has become important, not only for histological typing using immunocytochemistry (ICC) but also for molecular DNA analysis of cytological material. The aim of this study was to investigate the fixation effect of SurePath preservative fluids. METHODS: Human lung cancer PC9 and 11-18 cell lines, and lung adenocarcinoma cells in pleural effusion, were fixed in CytoRich Blue, CytoRich Red, 15% neutral-buffered formalin, and 95% ethanol, respectively. PC9 and 11-18 cell lines were examined by ICC with epidermal growth factor receptor (EGFR) mutation-specific antibodies, the EGFR mutation DNA assay, and fluorescence in situ hybridization. The effect of antigenic storage time was investigated in lung adenocarcinoma cells in pleural effusion by ICC using the lung cancer detection markers. RESULTS: PC9 and 11-18 cell lines in formalin-based fixatives showed strong staining of EGFR mutation-specific antibodies and lung cancer detection markers by ICC as compared with ethanol-based fixatives. DNA preservation with CytoRich Blue and CytoRich Red was superior to that achieved with 95% ethanol and 15% neutral-buffered formalin fixatives, whereas EGFR mutations by DNA assay and EGFR gene amplification by fluorescence in situ hybridization were successfully identified in all fixative samples. Although cytoplasmic antigens maintained high expression levels, expression levels in nuclear antigens fell as storage time increased. CONCLUSIONS: These results indicate that CytoRich Red is not only suitable for ICC with EGFR mutation-specific antibodies, but also for DNA analysis of cytological material, and is useful in molecular testing of lung cancer, for which various types of analyses will be needed in future. PMID- 24167085 TI - Quality of life impacts on 16-year survival of an older ethnically diverse cohort. AB - OBJECTIVE: The objective of this study is to examine the prediction of mortality, over 16 years, by the domains and domain elements underlying generic measures of quality of life (QoL). METHODS: The method used was an analysis of mortality in an older (65 + years) representative sample (N = 2130) of a multicultural community in North Manhattan. Five conventional QoL domains were measured by in home, rater-administered, and computer-assisted questionnaire: depressed mood, pain, self-perceived health, and function and social relationships. RESULTS: Some domain scales that qualitatively express distress, such as depressed mood and widespread pain, significantly predicted lower mortality (were protective) and felt isolation trended in that direction, whereas domains indicating quantitative limitations such as impairment of functioning in daily tasks, stair climbing, as well as social disengagements and lack of support network significantly predicted higher mortality. Domain elements also mattered; contrary to their domain predictions, increased mortality was predicted by the domain elements of somatic symptoms of depression. Self-perceived poor health reflected the predictive (higher mortality) direction of the limitations cluster. CONCLUSIONS: The internal complexity of QoL is underscored by differential impacts of domains and elements on mortality. Clinical implications include setting distress domains as important clinical goals, whereas strengthening limiting domains could result in lengthening life and secondarily relieving distress. The relative weighting of these goals could be derived from patient preferences and clinical efficacy. Fundamental implications lie in the interaction between the person's qualitative evaluations of choices and the quantitative building of desired choices for a better QoL. PMID- 24167086 TI - Fed-batch synthesis of galacto-oligosaccharides with Aspergillus oryzae beta galactosidase using optimal control strategy. AB - Fed-batch synthesis of galacto-oligosaccharides (GOS) from lactose with beta galactosidase from Aspergillus oryzae was evaluated experimentally and reaction yield was maximized via optimal control technique. The optimal lactose and enzyme feed flow rate profiles were determined using a model for GOS synthesis previously reported by the authors. Experimentally it was found that fed-batch synthesis allowed an increase on the maximum total GOS concentration from 115 (batch synthesis) to 218 g L(-1) as consequence of the increase in total sugars concentration from 40 to 58% w/w. Such high concentration of total sugars was not attainable in batch operation because of the low solubility of lactose at the reaction temperature (40 degrees C). Simulations predicted a GOS yield of 32.5 g g(-1) in fed-batch synthesis under optimal conditions, while experimentally the same yield as in batch synthesis was obtained (28 g g(-1) ). Besides, an enrichment of total oligosaccharides in GOS with a high polymerization degree (GOS-5 and GOS-6) was observed in the fed-batch synthesis. Experimental profiles for all sugars were similar to the ones predicted by simulation, which supports the use of this methodology for the optimization of GOS synthesis. PMID- 24167087 TI - Sex-related differences in neuromuscular control: Implications for injury mechanisms or healthy stabilisation strategies? AB - Sex-related differences in neuromuscular activation have been previously identified and are thought to be an underlying contributor to the ACL injury mechanism. During dynamic tasks evaluating the role of muscle action as it relates to joint stability is difficult since individual muscle contributions to force generation are confounded by biomechanical factors of movement. The purpose of this study was to examine sex-related differences in knee muscle action during a weight-bearing isometric exercise and identify the stabilising role of these muscles. Healthy young adults stood with their dominant leg in a boot fixed to a force platform. A force matching protocol required participants to modulate normalised ground reaction forces in various combinations of anterior-posterior, medial-lateral loads while maintaining a constant joint position. Normalised electromyographic data of eight muscles crossing the knee joint were displayed in polar plots. Patterns were quantified with an orientation analysis and mean activation magnitudes were computed. Females demonstrated symmetrical activation patterns with significantly greater activation in the rectus femoris (p = 0.037), lateral gastrocnemius (p = 0.012), and tensor fascia lata (p = 0.005) compared to males. High between-subject reliability (ICC = 0.772-0.977) was observed across groups suggesting we have identified fundamental sex-related differences in knee joint stabilisation strategies. PMID- 24167088 TI - Disparities in pediatric oncology patient education and linguistic resources: results of a national survey of pediatric oncologists. AB - BACKGROUND: Extensive patient and family education is required at the time of a new diagnosis of pediatric cancer yet little data exist regarding the availability and linguistic competency of new cancer diagnosis education provided by pediatric oncology institutions. PROCEDURE: Using the American Society of Pediatric Hematology/Oncology (ASPHO) membership list, a web-based survey was conducted among a cohort of pediatric oncologists to determine pediatric oncologists' assessment of institutional resources for new cancer diagnosis education and the availability of linguistically appropriate education. RESULTS: Of 1,294 ASPHO members sent email survey invitations, 573 (44.3%) responded with 429 meeting eligibility criteria. Oncologists at academic institutions reported their institutions had more availability of resources for new diagnosis education compared with those from non-academic institutions (mean 78.6 vs. 74.3; 0 [not at all]-100 [well equipped]; P = 0.05). The mean score increased with volume of new cancer diagnoses/year: small (<75) = 73.4; medium (75-149) = 76.7; large (>150) = 84.5 (P < 0.001). Oncologists at large volume institutions reported more availability of an established patient education protocol (50.8% vs. 38.1%, P < 0.001) and increased use of dedicated non-physician staff (79.9% vs. 66.1%, P = 0.02), but less use of websites for patient education (17.2% vs. 33.3%, P = 0.001). Availability of linguistically appropriate education improved with increasing institution size: small (76.4), medium (82.3), and large (84.0) patient volume (P < 0.011). CONCLUSION: According to pediatric oncologists, a disparity in educational and linguistic resources for new pediatric cancer diagnosis education exists depending on institution type and size. PMID- 24167089 TI - Small RNA regulation of reproductive function. AB - Post-transcriptional gene regulation is one mechanism that occurs "above the genome," allowing the cells of an organism to have dramatically different phenotypes and functions. Non-coding ribonucleic acid (ncRNA) molecules regulate transcript and protein abundance above the level of transcription, and appear to play substantial roles in regulation of reproductive tissues. Three primary classes of small ncRNA are microRNA (miRNA), endogenous small interfering RNA (endo-siRNA), and PIWI-interacting RNA (piRNA). These RNA classes have similarities and clear distinctions between their biogenesis and in the interacting protein machinery that facilitate their effects on cellular phenotype. Characterization of the expression and importance of the critical components for the biogenesis of each class in different tissues is continuously contributing a better understanding of each of these RNA classes in different reproductive cell types. Here, we discuss the expression and potential roles of miRNA, endo-siRNA, and piRNA in reproduction from germ-cell development to pregnancy establishment and placental function. Additionally, the potential contribution of RNA binding proteins, long ncRNAs, and the more recently discovered circular RNAs (circRNAs) in relation to small RNA function is discussed. PMID- 24167090 TI - The human oligodendrocyte proteome. AB - Myelination of the CNS is performed by oligodendrocytes (OLs), which have been implicated in brain disorders, such as multiple sclerosis and schizophrenia. We have used the human oligodendroglial cell line MO3.13 to establish an OL reference proteome database. Proteins were prefractionationated by SDS-PAGE and after in-gel digestion subjected to nanoflow LC-MS analysis. Approximately 11 600 unique peptides were identified and, after stringent filtering, resulted in 2290 proteins representing nine distinct biological processes and various molecular classes and functions. OL-specific proteins, such as myelin basic protein (MBP) and 2',3'-cyclic nucleotide 3'-phosphodiesterase (CNP), as well as other proteins involved in multiple sclerosis and schizophrenia were also identified and are discussed. Proteins of this dataset have also been classified according to their chromosomal origin for providing useful data to the Chromosome-centric Human Proteome Project (C-HPP). Given the importance of OLs in the etiology of demyelinating and oligodendrogial disorders, the MO3.13 proteome database is a valuable data resource. The MS proteomics data have been deposited to the ProteomeXchange with identifier PXD000263 (http://proteomecentral.proteomexchange.org/dataset/PXD000263). PMID- 24167091 TI - Intracellular reactive oxygen species mark and influence the megakaryocyte erythrocyte progenitor fate of common myeloid progenitors. AB - While most studies regarding reactive oxygen species (ROS) focus on their deleterious biological effects, a growing body of evidence indicates the importance of ROS as critical mediators of several signaling pathways, including those involved in hematopoiesis. In this study, we show the critical role of ROS in lineage decision of myeloid progenitors. In megakaryocyte-erythrocyte progenitor cells (MEP), intracellular ROS levels were found to be as low as those in hematopoietic stem cells (HSC). In contrast, remarkably high intracellular ROS levels were observed in granulocyte-monocyte progenitor cells. Intracellular ROS levels in common myeloid progenitors (CMP) were inversely correlated with their MEP differentiation potential. Moreover, gene set enrichment analysis revealed that ROS-low CMP showed gene expression patterns similar to those of MEP, indicating that intracellular ROS levels mark the fate of CMP. In in vitro assays, ROS significantly suppressed the generation of MEP and the formation of megakaryocyte-erythrocyte colonies from CMP. In ROS-high CMP, expression of colony-stimulating factor one receptor (CSF1R) was highly upregulated, and its surface expression correlated with their granulocyte-monocyte differentiation potential. Furthermore, ROS was found to induce the expression of CSF1R mRNA in a leukemia cell line. These data provide novel insights into the relationship between ROS and the hematopoietic differentiation system. PMID- 24167092 TI - Novel mitral clipping technique overcoming extreme atrial dilatation. AB - The mitral clipping technique is emerging as a promising new treatment option for severe mitral regurgitation. The device was designed and assessed in intermediate risk populations, which is in contrast to the real world, where most patients are deemed to be at very high risk for open heart surgery. The cardiac anatomy of these patients often challenges the freedom grades of the current mitral clip device. In this case presentation, we describe a novel technique overcoming extreme atrial dilation in a patient with severe mitral regurgitation despite previous implantation of two mitral clips. Based on a low/anterior trans-septal puncture, this procedure relied on a counter clock-wise 90 degrees turn of the steerable sheath and alignment of the clip delivery system to the mitral valve, thereby gaining additional longitudinal freedom. This resulted in the successful implantation of two additional clips with achievement of a mild to moderate mitral regurgitation without relevant gradient and dramatic and sustained clinical improvement of the patient. PMID- 24167093 TI - Visible-light photocatalytic conversion of carbon monoxide to methane by nickel(II) oxide. AB - Solar Fuels: Different n- and p-type semiconductors have been investigated for sustainable solar fuel production. p-Type semiconductors, such as NiO, Fe3 O4 , Co3 O4 , and CuO, are able to reduce carbon monoxide by water or hydrogen to methane. The highest CH4 yield achieved was 17.26 mmol of CH4 per gram of catalyst using NiO in an excess of H2 . PMID- 24167094 TI - Morphing metal-polymer janus particles. AB - The direct deformation and shape recovery of micron-sized polystyrene particles via nanoimprint lithography is reported. The recovery of the programmed PS particles can be utilized to create a range of smart Janus particles with contrasting properties in conductivity and topography, by use of metal-layer constrained recovery. PMID- 24167097 TI - The role of farm operational and rural environments as potential risk factors for pediatric asthma in rural Saskatchewan. AB - BACKGROUND: Researchers have historically reported that farm children have a lower prevalence of asthma compared to more urban children. Potential explanations include theories surrounding differences in personal factors, access to health care, engagement in health risk behaviors, and differences in the environment. OBJECTIVE: The aims of this study were to: (1) confirm whether the prevalence of asthma varies between farm and small town status among children living in Saskatchewan; (2) identify risk and protective factors for asthma, and use this information to infer which of the above theories is most explanatory for any observed geographic variations in pediatric asthma. METHODS: Rural students (N = 2383, 42% participation rate) from the province of Saskatchewan participated in a 2011 cross-sectional study. Parents completed a survey that included questions about location of residence, respiratory symptoms, potential risk factors for respiratory disease, and exposures to farm activities. Multiple logistic regression was used to examine relations between respiratory outcomes (asthma, wheeze) with farm type and farm activities, while accounting for factors that may underlie such relations. RESULTS: Asthma and wheeze prevalence did not differ by residential status. Living on a grain farm (OR = 0.64, 95% CI = 0.43 0.96), cleaning or playing in pens (OR = 0.69, 95% CI = 0.46-1.02), filling grain bins (OR = 0.56, 95% CI = 0.32-0.96), and riding horses (OR = 0.65, 95% CI = 0.40 1.05) were protective factors for ever diagnosis with asthma. CONCLUSIONS: We identified a number of risk and protective factors for asthma and associated wheeze. This suggests the need to focus on specific environmental explanations to better understand previously observed associations between farm residential status and asthma. PMID- 24167098 TI - Are physicians' prescribing decisions sensitive to drug prices? Evidence from a free-antibiotics program. AB - This paper investigates whether patient-level factors, in particular cost considerations, affect the physicians' prescribing decisions. In the context of a natural experiment, we examine the effect of the first US commercial free antibiotics program on retail antibiotic sales. We find an overall increase in antibiotic prescriptions under the program and substitutions to covered antibiotics from not-covered antibiotics. The shift away from not-covered antibiotics, particularly from those without covered equivalents, indicates a change in the physicians' prescribing decisions. We locate stronger program effects in low-income areas. Our findings, robust to a variety of specifications, are in contrast with previous literature. PMID- 24167099 TI - Iodamoeba butschlii in an anal pap test confirmed by iodine stain. AB - We report the finding of Iodamoeba butschlii amebic cysts on a liquid-based anal Pap smear from an HIV-positive male. Iodine staining of the smear confirmed the diagnosis. It is important to distinguish I. butschlii from pathogenic ameobae and other organisms seen on anal Pap smears. PMID- 24167100 TI - Poly(ethylene glycol) grafting to poly(ether imide) membranes: influence on protein adsorption and thrombocyte adhesion. AB - The chain length and end groups of linear PEG grafted on smooth surfaces is known to influence protein adsorption and thrombocyte adhesion. Here, it is explored whether established structure function relationships can be transferred to application relevant, rough surfaces. Functionalization of poly(ether imide) (PEI) membranes by grafting with monoamino PEG of different chain lengths (Mn =1 kDa or 10 kDa) and end groups (methoxy or hydroxyl) is proven by spectroscopy, changes of surface hydrophilicity, and surface shielding effects. The surface functionalization does lead to reduction of adsorption of BSA, but not of fibrinogen. The thrombocyte adhesion is increased compared to untreated PEI surfaces. Conclusively, rough instead of smooth polymer or gold surfaces should be investigated as relevant models. PMID- 24167103 TI - Viral clearance by flow-through mode ion exchange columns and membrane adsorbers. AB - Anion exchange (AEX) is a common downstream purification operation for biotechnology products manufactured in cell culture such as therapeutic monoclonal antibodies (mAbs) and Fc-fusion proteins. We present a head-to-head comparison of the viral clearance efficiency of AEX adsorbers and column chromatography using the same process fluids and comparable run conditions. We also present overall trends from the CDER viral clearance database. In our comparison of multiple brands of resins and adsorbers, clearance of three model viruses (PPV, X-MuLV, and PR772) was largely comparable, with some exceptions which may reflect run conditions that had not been optimized on a resin/membrane specific basis. PMID- 24167104 TI - Neuropathic pain in patients with sickle cell disease. AB - BACKGROUND: Despite the suggestion of a neuropathic component to sickle cell disease (SCD) pain, there are minimal data on the systematic assessment of neuropathic pain in patients with SCD. Neuropathic pain is defined as pain primarily initiated by dysfunction of the peripheral or central nervous system. PROCEDURE: In a cross-sectional study, we used the painDETECT questionnaire, a one-page validated neuropathic pain screening tool, to determine the presence of neuropathic pain in patients with SCD and to evaluate the relationship between neuropathic pain, age, and gender. We hypothesized that 20% of patients with SCD will experience neuropathic pain and that neuropathic pain will be associated with older age and female gender. The completed painDETECT questionnaire yields a total score between 0 and 38 (>= 19 = definite neuropathic pain, 13-18 = probable neuropathic pain, <= 12 = no neuropathic pain). Scores >= 13 were designated as having evidence of neuropathic pain. RESULTS: A total of 56 patients participated. Median age was 20.3 years and 77% were female. We found 37% of patients had evidence of neuropathic pain. Age was positively correlated with total score (r = 0.43; P = 0.001) suggesting older patients experience more neuropathic pain. Females had higher mean total scores (13 vs. 8.4; P = 0.04). Significantly more patients with neuropathic pain were taking hydroxyurea (90% vs. 59%; P = 0.015). Despite 37% of patients experiencing neuropathic pain, only 5% were taking a neuropathic pain drug. CONCLUSIONS: Neuropathic pain exists in SCD. Valid screening tools can identify patients that would benefit from existing and future neuropathic pain therapies and could determine the impact of these therapies. PMID- 24167105 TI - Total synthesis and structural revision of the alkaloid incargranine B. PMID- 24167106 TI - trans-10, cis-12 conjugated linoleic acid enhances in vitro maturation of porcine oocytes. AB - The aim of this study was to determine the effects of trans-10, cis-12 conjugated linoleic acid (t10c12 CLA) supplementation on oocyte maturation and embryo development in pigs. Compared with the control, supplementation of 50 uM t10c12 CLA to in vitro maturation (IVM) medium significantly increased the proportion of oocytes at the metaphase-II (MII) stage and subsequent parthenogenetic embryo development in terms of cleavage rate, blastocyst formation rate, and cell numbers in blastocysts. The t10c12 CLA-treated oocytes resumed meiotic maturation and progressed to the MII stage significantly faster than those of control. The expression of phosphorylated mitogen-activated protein kinase 3/1 (p-MAPK3/1) and cyclooxygenase-2 (COX2) in cumulus oocyte complexes (COCs) at 5, 10, and 22 hr of IVM were significantly increased in the t10c12 CLA-treatment group. The level of p-MAPK3/1 in t10c12 CLA-treated MII oocytes was also higher (P < 0.05) than that of control. Moreover, t10c12 CLA supplementation partially overcame the negative effects of U0126 on cumulus expansion and nuclear maturation, and completely recovered COX2 protein levels in the presence of U0126. Treatment of COCs with NS398 also significantly suppressed cumulus expansion and nuclear maturation, which was overcome by t10c12 CLA. Yet, this simulatory effect of t10c12 CLA was blocked in the presence of both U0126 and NS398. The t10c12 CLA treatment significantly reduced reactive oxygen species level and increased glutathione concentrations in MII oocyte. In conclusion, supplementation of t10c12 CLA during porcine oocyte maturation exerts its beneficial effects on nuclear and cytoplasmic maturation, which contributes to enhancing subsequent embryo development. PMID- 24167107 TI - Separation of five oligostilbenes from Vitis amurensis by flow-rate gradient high performance counter-current chromatography. AB - A rapid and efficient high-performance counter-current chromatography (HPCCC) method was developed to separate five oligostilbenes from the roots of Vitis amurensis. An n-hexane/ethyl acetate/methanol/water system (4:8:4:10, v/v/v/v) was selected as an optimal two-phase solvent system of which the upper phase was used as the stationary phase and the lower phase was used as the mobile one. Partition coefficient values for the target compounds under these optimized conditions were 0.28 (1, ampleosin A), 7.12 (2, (+)-g-viniferin), 2.26 (3, vitisin A), 5.38 (4, wilsonol C), and 11.23 (5, vitisin B). Flow-rate gradient HPCCC (4 mL/min in 0-70 min, 8 mL/min in 70-250 min) was applied to isolate the target compounds in as high purity as possible within the shortest possible run time. Under these conditions, ampelopsin A (12.1 mg), (+)-g-viniferin (10.4 mg), vitisin A (2.8 mg), wilsonol C (3.2 mg), and vitisin B (37 mg) were isolated with >95% purity from 150 mg of enriched oligostilbene extract. Although the KD of the last eluted compound, vitisin B (KD = 11.23), was relatively large, it was eluted in 115-145 min using the two-phase solvent system. This study shows that HPCCC is an efficient tool for the isolation and purification of natural products. PMID- 24167108 TI - Complex robotic-enhanced percutaneous coronary intervention. AB - A remote-controlled, robotic system was developed to address procedural challenges and occupational hazards associated with traditional percutaneous coronary intervention (PCI). The PRECISE (Percutaneous Robotically Enhanced Coronary Intervention) Study demonstrated the safety and feasibility of the robotic system. We report four cases of complex coronary interventions demonstrating the capabilities of robotic-enhanced PCI to treat multilesion, multivessel coronary disease, saphenous venous graft disease, and an ST-elevation myocardial infarction. The robotic system offers enhanced visibility, precise measurement, accurate stent positioning, improved ergonomics, and superior operator protection from radiation. PMID- 24167109 TI - An investigation of association between chronic musculoskeletal pain and cardiovascular disease in the Health Survey for England (2008). AB - BACKGROUND: Chronic musculoskeletal pain (CMP) may be associated with cardiovascular disease (CVD). This study aimed to investigate the association between CMP and CVD, and the contribution of physical activity and sedentary behaviour to any association. METHODS: We performed a secondary analysis of 3332 middle-aged (45-64 years) and 2022 older (65+ years) adults included in the Health Survey for England (2008). The survey contained self-reported physical activity/sedentary behaviour data. Objectively measured physical activity/sedentary behaviour using accelerometry (ActigraphTM) was also available for a subset of the middle-aged (n = 715) and older (n = 492) participants. Logistic regression examined the association between CMP and CVD adjusted for self-reported and objectively measured physical activity, sedentary behaviour and a range of other CVD risk factors. RESULTS: There was a higher prevalence of CVD in those with CMP for both the middle-aged (22.5% vs. 13.5%) and the older (46.8% vs. 28.2%) adults (p < 0.001). After adjusting for CVD risk factors, older adults with CMP were significantly more likely to have CVD {odds ratio [95% confidence interval (CI)] 1.828 (1.452, 2.300); p < 0.001}. A similar non-significant trend was shown for the middle-aged adults [odds ratio (95% CI) 1.271 (0.975, 1.656); p = 0.076]. Neither self-reported nor objectively measured physical activity (or sedentary behaviour) had any meaningful effect on the association between CMP and CVD. CONCLUSIONS: CMP is associated with an increased risk of CVD and the association is stronger in older adults. Neither physical activity nor sedentary behaviour contributed to this relationship. Longitudinal studies are warranted to better understand the relationship between CVD and CMP. PMID- 24167110 TI - Significant increase of salivary testosterone levels after single therapeutic transdermal administration of testosterone: suitability as a potential screening parameter in doping control. AB - The legally defensible proof of the abuse of endogenous steroids in sports is currently based on carbon isotope ratio mass spectrometry (IRMS), i.e. a comparison between (13)C/(12)C ratios of diagnostic precursors and metabolites of testosterone. The application of this technique requires a chromatographic baseline separation of respective steroids prior to IRMS detection and hence laborious sample pre-processing of the urinary steroid extracts including clean up by solid-phase extraction and/or liquid chromatography. Consequently, an efficient pre-selection of suspicious control urine samples is essential for appropriate follow up confirmation by IRMS and effective doping control. Two single transdermal administration studies of testosterone (50 mg Testogel(r) and Testopatch(r) at 3.8 mg in 16 h, respectively) were conducted and resulting profiles of salivary testosterone and urinary steroid profiles and corresponding carbon isotope ratios were determined. Conventional doping control markers (testosterone/epitestosterone ratio, threshold concentrations of androsterone, etiocholanolone, or androstanediols) did not approach or exceed critical thresholds. In contrast to these moderate variations, the testosterone concentration in oral fluid increased from basal values (30-142 pg/mg) to peak concentrations above 1000 pg/mg. It is likely that this significant increase in oral fluid is due to a pulsatile elevation of free (protein unbound) circulating testosterone after transdermal administration and may be assumed to represent a more diagnostic marker for transdermal testosterone administration. PMID- 24167112 TI - To count or not to count deaths: reranking effects in health distribution evaluation. AB - Populations' structures and sizes can be a result of healthcare policy decisions. We use a two-period theoretical framework and a dynamic microsimulation model to examine the consequences of this assertion on the appraisal of alternative health policy options. Results show that standard welfare-in-health measures are sensitive to changes in populations' sizes, in that taking into account the (virtual) existence of the dead can alter the ranking of policy options. Disregarding differences in the survivals induced by alternative policies can bias programmes' ranking in favour of less live-saving policies. The paper alerts on the risk of policy misranking by the use of ex-post cross-sectional analyses, neglecting deaths occurring in the past as well as counterfactual deaths in alternative policy scenarios. PMID- 24167111 TI - B-type natriuretic peptide inhibits angiotensin II-induced proliferation and migration of pulmonary arterial smooth muscle cells. AB - Pulmonary vascular remodeling, characterized by disordered proliferation and migration of pulmonary arterial smooth muscle cells (PASMCs), is a pathognomonic feature of pulmonary arterial hypertension. Thus, pharmacologic strategy targeting on anti-proliferation and anti-migration of PASMCs may have therapeutic implications for PAH. Here we investigated the effects and underlying mechanisms of B-type natriuretic peptide (BNP) on angiotensin II (Ang II)-induced proliferation and migration of PASMCs. Proliferation and migration of PASMCs cultured from Wistar rats were induced by Ang II, with or without BNP treatment. In addition, potential underlying mechanisms including cell cycle progression, Ca(2+) overload, reactive oxygen species (ROS) production, signal transduction of MAPK and Akt, and the cGMP/PKG pathway were examined. We found that BNP inhibited Ang II-induced PASMCs proliferation and migration dose dependently. BNP could also arrest the cell cycle progression in the G0/G1-phase. In addition, BNP attenuated intracellular calcium overload caused by Ang II. Moreover, Ang II induced ROS production was mitigated by BNP, with associated down-regulation of NAD(P)H oxidase 1 (Nox1) and reduced mitochondrial ROS production. Finally, Ang II-activated MAPKs and Akt were also counteracted by BNP. Of note, all these effects of BNP were abolished by a PKG inhibitor (Rp-8-Br-PET-cGMPS). In conclusion, BNP inhibits Ang II-induced PASMCs proliferation and migration. These effects are potentially mediated by decreased calcium influx, reduced ROS production by Nox1 and mitochondria, and down-regulation of MAPK and Akt signal transduction, through the cGMP/PKG pathway. Therefore, this study implicates that BNP may have a therapeutic role in pulmonary vascular remodeling. PMID- 24167113 TI - The evolutionary ecology of symbiont-conferred resistance to parasitoids in aphids. AB - Aphids may harbor a wide variety of facultative bacterial endosymbionts. These symbionts are transmitted maternally with high fidelity and they show horizontal transmission as well, albeit at rates too low to enable infectious spread. Such symbionts need to provide a net fitness benefit to their hosts to persist and spread. Several symbionts have achieved this by evolving the ability to protect their hosts against parasitoids. Reviewing empirical work and some models, I explore the evolutionary ecology of symbiont-conferred resistance to parasitoids in order to understand how defensive symbiont frequencies are maintained at the intermediate levels observed in aphid populations. I further show that defensive symbionts alter the reciprocal selection between aphids and parasitoids by augmenting the heritable variation for resistance, by increasing the genetic specificity of the host-parasitoid interaction, and by inducing environment dependent trade-offs. These effects are conducive to very dynamic, symbiont mediated coevolution that is driven by frequency-dependent selection. Finally I argue that defensive symbionts represent a problem for biological control of pest aphids, and I propose to mitigate this problem by exploiting the parasitoids' demonstrated ability to rapidly evolve counteradaptations to symbiont-conferred resistance. PMID- 24167114 TI - Clarification and capture of high-concentration refold pools for E. coli-based therapeutics using expanded bed adsorption chromatography. AB - Expanded bed adsorption (EBA) chromatography was investigated for clarification and capture of high-concentration refold pools of Escherichia coli-based therapeutics. Refolding of denatured inclusion bodies (IBs) at high protein concentration significantly improved product throughput; however, direct filtration of the refold materials became very challenging because of high content of protein precipitates formed during refolding. In addition, irreversible protein precipitation caused by high local concentration was encountered in packed bed capture during cation exchange chromatography elution, which limited column loading capacity and capture step productivity. In this study, the two issues are addressed in one unit operation by using EBA. Specifically, EBA can handle feed streams with significant amount of particles and precipitates, which eliminated the need for refold pool clarification through filtration. The relatively broad EBA elution profile is particularly suitable for proteins of low solubility and can effectively avoid product loss previously associated with on-column precipitation during capture. As the EBA resin (RHOBUST((r)) FastLine SP IEX) used here has unique properties, it can be operated at high linear velocity (800-1,600 cm/h), while achieving a selectivity and impurity clearance largely comparable to the packed bed resin of the same ligand chemistry (SP Sepharose FF). Furthermore, the filtration of the EBA elution pool is easily manageable within facility capability. Overall, this study demonstrates that the EBA process helps debottleneck the purification of high turbidity refold pools by removing precipitates and concurrently capturing the product, which can be applied to other E. coli-based therapeutics that also requires refolding of IBs. PMID- 24167115 TI - Clear cell chondrosarcoma: Cytologic findings in six cases. AB - Clear cell chondrosarcoma (CCCS) is a rare variant of chondrosarcoma characterized, in most instances, by indolent behavior and a long interval to progression of disease. CCCS commonly occurs in adult individuals and has a proclivity for the epiphysis of long bones, although it has been reported in other sites. This lesion is difficult to diagnose preoperatively. Factors contributing to difficulty in recognizing this lesion include its relative scarcity as well as its tendency to be confused with other lesions on imaging studies. In the following, we report six cases of CCCS initially diagnosed by fine needle aspiration and/or touch preparations of needle biopsy samples. The cytologic features identified include large, plasmacytoid cells with foamy cytoplasm as well as extracellular chondroid type matrix material. Definitive diagnosis was made in each case by recognizing the "clear cell" nature of the tumor on cell block material. PMID- 24167117 TI - The organization of innovation--the history of an obsession. PMID- 24167116 TI - Numerical modeling of susceptibility-related MR signal dephasing with vessel size measurement: phantom validation at 3T. AB - PURPOSE: MRI is used to obtain quantitative oxygenation and blood volume information from the susceptibility-related MR signal dephasing induced by blood vessels. However, analytical models that fit the MR signal are usually not accurate over the range of small blood vessels. Moreover, recent studies have demonstrated limitations in the simultaneous assessment of oxygenation and blood volume. In this study, a multiparametric MRI framework that aims to measure vessel radii in addition to magnetic susceptibility and volume fraction was introduced. METHODS: The protocol consisted of gradient-echo sampling of the spin echo, diffusion, T2, and B0 acquisitions. After correction steps, the data were postprocessed with a versatile numerical model of the MR signal. An important analytical model was implemented for comparison. The approach was validated in phantoms with coiling strings as proxy for blood vessels. RESULTS: The feasibility of the vessel radius measurement is demonstrated. The numerical model shows an improved accuracy compared with the analytical approach. However, both methods overestimate the radius. The simultaneous measurement of the magnetic susceptibility and the volume fraction remains challenging. CONCLUSION: The results suggest that this approach could be interesting in vivo to better characterize the microvasculature without contrast agent. PMID- 24167118 TI - Post-infection activities of fungicides against Cercospora arachidicola of peanut (Arachis hypogaea). AB - BACKGROUND: Despite strong indirect evidence of post-infection activity by a selection of systemic fungicides against Cercospora arachidicola, the causal organism of early leaf spot of peanut, direct post-infection activities in this pathosystem have yet to be reported in detail. This study was conducted to describe the activities of pyraclostrobin, penthiopyrad and prothioconazole on early leaf spot when each fungicide was applied after pathogen penetration began and throughout the incubation period. RESULTS: Most C. arachidicola penetration events occurred between 3 and 5 days after inoculation (dai), and the mean incubation period was 11.8 dai. Post-infection activities of the systemic fungicides were similar for all dependent variables measured. Systemic fungicides reduced lesion density compared with the non-treated control when applied at 3, 5 and 7 dai, and disease severity was >60% less for leaves treated with a systemic fungicide at all application dates (3, 5, 7, 9, 11 and 13 dai). CONCLUSIONS: Pyraclostrobin, penthiopyrad and prothioconazole showed similar systemic mobility within peanut leaves and activities against C. arachidicola, and appear to completely arrest the development of the pathogen at least 2 days post penetration, and limit pathogen colonization even when applications occur after symptom onset. PMID- 24167119 TI - Neuronal differences between chronic low back pain and depression regarding long term habituation to pain. AB - BACKGROUND: Longitudinal studies of experimental pain are rare and little is known about the differences regarding sensitization and habituation over longer periods in patients with chronic pain or depression compared with controls. METHODS: We used a standardized longitudinal painful heat paradigm that was designed to induce long-term habituation in 19 patients with chronic low back pain (CLBP), 21 patients with depression (DEP) and 21 healthy participants (controls) over a time course of eight consecutive days. We applied functional magnetic resonance imaging on the first and last day of this period and after 3 months. RESULTS: Although the pain paradigm was standardized, patients with DEP exhibited significantly higher pain thresholds and a trend to higher pain ratings and, in functional imaging, showed less activation of the operculum and the secondary somatosensory cortex (S2) as compared to patients with CLBP and controls. Conversely, patients with CLBP showed increased activation in the anterior insula and parietal operculum as compared to patients with DEP and controls. Within session, all participants sensitized to pain, which was associated with higher activation levels in the thalamus, amygdala, midcingulate cortex, and sensory and motor areas. However, patients with depression showed significantly less activation in midbrain and brainstem areas. CONCLUSION: Given that pain and depression potentiate each other clinically, our data suggest that this may involve different cortical pain areas. PMID- 24167120 TI - Pediatricians' attitudes and costs of bronchiolitis in the emergency department: a prospective multicentre study. AB - BACKGROUND: How pediatricians manage bronchiolitis and the derived total costs (direct and indirect) in the emergency department (ED) have not been fully characterized. The aim of the present study is to calculate those costs in a European country. METHODS: A prospective and observational study, including 10 EDs of tertiary hospitals throughout Spain and during the bronchiolitis season 2010-2011, was performed. Every ED recruited children on random days of the week (3 days per week; always including one non-working day per every week). Recruitment aimed at a total sample size of 600 children. Direct (diagnostic procedures, time spent in the ED and medication) and indirect costs (work hours lost by parents, babysitting, travels, and meals) were collected. Comparisons between bronchiolitis caused by respiratory syncytial virus (RSV) and non-RSV bronchiolitis, as well as costs across severity categories were performed with the Kruskal-Wallis test. A multiple regression model was built to assess the influence of several of the studied factors on the total costs, including a RSV positive test and episode severity as independent variables; and gender, age, attending nursery school, preterm birth, low birth weight, smoker mother during pregnancy, and current smoker father as covariates. RESULTS: From the 664 recruited children, direct mean costs were ?213.2 +/- 91.8 and indirect ones were ?35.9 +/- 55.3; the total costs being ?249.2 +/- 122.9. Costs were significantly higher in children positive to RSV and rose with increased severity. Those associations were maintained in the multiple regression analysis. CONCLUSIONS: Although relatively low at the individual level (?249.2, mean total cost) the costs for just the ED expenses of bronchiolitis in Spain would add up to about ?20 million per year. PMID- 24167121 TI - An automated sample preparation for detection of 72 doping-related substances. AB - Automation of sample preparation procedures in a doping control laboratory is of great interest due to the large number of samples that have to be analyzed, especially in large events where a high throughput protocol is required to process samples over 24 h. The automation of such protocols requires specific equipment capable of carrying out the diverse mechanical tasks required for accomplishing these analytical methodologies, which include pipetting, shaking, heating, or crimping. An automated sample preparation procedure for the determination of doping-related substances by gas chromatography-mass spectrometry (GC-MS) and gas chromatography-tandem mass spectrometry (GC-MS/MS) analysis, including enzymatic hydrolysis, liquid-phase extraction and derivatization steps, was developed by using an automated liquid handling system. This paper presents a description of the equipment, together with the validation data for 72 doping-related compounds including extraction efficiency, evaluation of carry-over, interferences, and robustness. Validation was approached as a comparison between the results obtained using the manual protocol and the transferred automated one. The described methodology can be applied for sample preparation in routine anti-doping analysis with high sample throughput and suitable performance. PMID- 24167122 TI - Analysis of transcriptomes of three orb-web spider species reveals gene profiles involved in silk and toxin. AB - As an ancient arthropod with a history of 390 million years, spiders evolved numerous morphological forms resulting from adaptation to different environments. The venom and silk of spiders, which have promising commercial applications in agriculture, medicine and engineering fields, are of special interests to researchers. However, little is known about their genomic components, which hinders not only understanding spider biology but also utilizing their valuable genes. Here we report on deep sequenced and de novo assembled transcriptomes of three orb-web spider species, Gasteracantha arcuata, Nasoonaria sinensis and Gasteracantha hasselti which are distributed in tropical forests of south China. With Illumina paired-end RNA-seq technology, 54 871, 101 855 and 75 455 unigenes for the three spider species were obtained, respectively, among which 9 300, 10 001 and 10 494 unique genes are annotated, respectively. From these annotated unigenes, we comprehensively analyzed silk and toxin gene components and structures for the three spider species. Our study provides valuable transcriptome data for three spider species which previously lacked any genetic/genomic data. The results have laid the first fundamental genomic basis for exploiting gene resources from these spiders. PMID- 24167123 TI - Cationic solid lipid nanoparticles with cholesterol-mediated surface layer for transporting saquinavir to the brain. AB - Cholesterol-mediated cationic solid lipid nanoparticles (CSLNs) were formulated with esterquat 1 (EQ 1) and stearylamine as positively charged external layers on hydrophobic internal cores of cacao butter. These CSLNs were employed to deliver saquinavir (SQV) to the brain. The permeability of SQV across the blood-brain barrier (BBB) using SQV-loaded CSLNs (SQV-CSLNs) was estimated with an in vitro model of a monolayer of human brain-microvascular endothelial cells (HBMECs) regulated by human astrocytes. The results revealed that the average diameter of SQV-CSLNs diminished when the weight percentage of cholesterol and EQ 1 increased. The morphological images indicated a uniform size of SQV-CSLNs with compact lipid structure. In addition, an increasing weight percentage of cholesterol and EQ 1 enhanced the zeta potential of SQV-CSLNs. The fluorescent staining demonstrated that HBMECs could internalize SQV-CSLNs. An increase in the weight percentage of cholesterol and EQ 1 also promoted the uptake of SQV-CSLNs by HBMECs. Moreover, a high content of cholesterol and EQ 1 in SQV-CSLNs increased the BBB permeability of SQV. The cholesterol-mediated SQV-CSLNs can be an efficacious drug delivery system for brain-targeting delivery of antiviral agents. PMID- 24167124 TI - Effective down-regulation of signal transducer and activator of transcription 3 (STAT3) by polyplexes of siRNA and lipid-substituted polyethyleneimine for sensitization of breast tumor cells to conventional chemotherapy. AB - Signal transducer and activator of transcription 3 (STAT3) is a transcription factor that plays a major role in the development of resistance to conventional anti-cancer drugs in many types of cancer, when constitutively activated. Inhibition of STAT3 is considered as a promising strategy for inhibition of tumor growth and overcoming the drug resistance manifested. In this study, the capability of STAT3 knockdown by lipid substituted low molecular weight (2 kDa) polyethyleneimine (PEI2) complexes of STAT3-siRNA was assessed. The efficiency of PEI/STAT3-siRNA polyplexes in the induction of STAT3 associated cell death in wild type and drug-resistant MDA-MB-435 breast cancer cells as monotherapy and upon combination with chemotherapeutic agents, doxorubicin and paclitaxel, was also investigated. Our results identified linoleic acid-substituted (PEI-LA) polymer as the most efficient carrier among different lipid substituted PEI2 for siRNA delivery, leading to most STAT3 associated loss of cell viability in MDA-MB 435 cells. STAT3-siRNA delivery by the PEI-LA polymer resulted in efficient down regulation of STAT3 at both mRNA and protein levels. Furthermore, pre-treatment of cancer cells with STAT3-siRNA formulation increased the cytotoxic effect of doxorubicin and paclitaxel in both wild type and drug resistant MDA-MB-435 cells. The results of this study point to the potential of PEI-LA polyplexes of STAT3 siRNA as inhibitors of STAT3 expression in breast tumor cells. The results also demonstrate an improved efficacy for chemotherapeutic drugs in combination with lipid-substituted low molecular weight PEI-LA/STAT3-siRNA complexes in comparison to drug therapy alone. PMID- 24167125 TI - Diagnostic value of B-RAF(V600E) in difficult-to-diagnose thyroid nodules using fine-needle aspiration: systematic review and meta-analysis. AB - Fine-needle aspiration (FNA) is routinely used in the preoperative evaluation of thyroid nodules. However, approximately 5-20% of thyroid nodules are considered indeterminate or suspicious cases that do not meet clinical standards. The B RAF(V600E) mutation has been reported in FNA specimens. We conducted a systematic review to evaluate the diagnostic value of testing for B-RAF(V600E) in thyroid nodules that are difficult to diagnose by FNA. A systematic literature search was performed from January 1, 2002 to June 30, 2012. Articles were obtained by searching two electronic databases (MEDLINE and EMBASE), hand searching selected journals, and contacting authors. Article quality was assessed using the Quality Assessment of Diagnostic Accuracy Studies (QUADAS) tool. Sensitivity, specificity, and other measures of accuracy were pooled using random effects models. Summary receiver operating characteristic (SROC) curves were used to summarize overall diagnostic accuracy. A total of 16 studies incorporating 1131 patients were included in a meta-analysis on diagnostic accuracy of B-RAF(V600E) tests. Pooled sensitivity was 0.60 (95% confidence interval [CI]: 0.556-0.634), pooled specificity was 0.99 (95% CI 0.976-0.997), and the area under the curve of the SROC curve was 0.8376. Q index value was 0.7696. Our data suggest a potentially useful adjunct to evaluating thyroid nodules that are difficult to diagnose. The B-RAF(V600E) test has a high positive predictive value and could help clinicians formulate a more individualized treatment schedule. When supplemented with other noninvasive test methods, the B-RAF(V600E) test could be a powerful adjunct with extensive clinical applications. PMID- 24167126 TI - [Progress in TcpC research]. AB - TcpC is a homolog of the Toll/interleukin-1 receptor (TIR) domain and is secreted by uropathogenic E. coli strain CFT073. TcpC can bind to MyD88, hereby exerting inhibitory effects on macrophages. TcpC represents an important virulence factor that promotes bacterial survival and pathogenicity. TcpC plays a critical role in urinary tract infection, particularly in the pathogenesis of pyelonephritis. In this review,the progress and prospects in TcpC research are discussed. PMID- 24167127 TI - [TcpC induces apoptosis of macrophages through promoting ROS production]. AB - OBJECTIVE: To investigate the effects of Toll/interleukin 1 receptor domain containing protein(TcpC)on macrophages and its mechanisms. METHODS: Murine macrophage J774A cells were co-cultured with TcpC producing wild type E. coli strain CFT073 (TcpC(wt)) or tcpc gene-deleted CFT073 mutant (TcpC(mut)) in Transwell system, respectively. Apoptosis of J774A cells co-cultured with TcpC(wt) or TcpC(mut) was analyzed by Annexin/PI double staining. The levels of reactive oxygen species (ROS) in J774A cells were determined by DCFH-DA staining after treatment with TcpC(wt) or TcpC(mut) at 6 h, 12 h,24 h or 36 h. After the ROS was scavenged by N-acetylcysteine (NAC), the changes of J774A cell apoptosis were also examined. The expression of caspase-3 in J774A cells co-cultured with TcpC(wt) or TcpC(mut) in the presence or absence of 0.1 mmol NAC was detected by Western blot. RESULTS: J774A cells co-cultured with TcpC(wt) for 24 h or 36 h showed significantly increased apoptosis (27.39% +/- 4.05% and 28.45% +/- 4.55%,respectively) when compared to control group (7.96% +/- 1.63% and 10.55% +/ 1.44%,P<0.01) or TcpC(mut) group (11.45% +/- 2.77% and 19.26%+/- 2.89%,P<0.01). Levels of ROS in J774A cells treated with TcpC(wt) for 24 h (108.8 +/- 9.73) or 36 h (100.3 +/- 10.11) were significantly higher than those in control group (56.8 +/- 4.11 and 52.8 +/- 4.42,P<0.01) or TcpC(mut) (69.7 +/- 5.66 and 62.6 +/- 4.56, P < 0.01). The pro-apoptotic effects of TcpC(wt) on J774A cells were reversed by 0.1 or 1 mMol NAC treatment. Expression of caspase-3 in J774A cells co-cultured with TcpC(wt) (0.43 +/- 0.04) decreased significantly when compared to control group (0.75 +/- 0.08,P<0.05) or TcpC(mut) group (0.80 +/- 0.12,P<0.05). However,total caspase-3 expression was restored in J774A cells co cultured with TcpC(wt) in the presence of 0.1 mmol NAC (0.80 +/- 0.09). CONCLUSION: TcpC can promote ROS production in macrophages,hereby inducing macrophage apoptosis. PMID- 24167128 TI - [TcpC induces apoptosis of human vascular endothelial cells and its mechanisms]. AB - OBJECTIVE: To investigate the effects of TcpC on human umbilical vascular endothelial cells (HUVECs) and its mechanisms. METHODS: HUVECs were co-cultured with TcpC secreting wild-type E. coli strain CFT073 (TcpC(wt)) or tcpc gene deleted CFT073 mutant strain (TcpC(mut)) in transwell system,respectively. Apoptosis of HUVECs was analyzed by Annexin-V/PI double staining. Mitochondrial membrane depolarization was detected by JC-1 staining. Expression of apoptosis related proteins in HUVECs was determined by Western blot. RESULTS: HUVECs showed morphological changes after co-cultured with TcpC(wt) for 24 h: the cells became detached and cell debris increased,and cell number was also decreased when compared to HUVECs co-cultured with TcpC(mut). The apoptosis of HUVEC cells co cultured with TcpC(wt) for 24 h significantly increased,compared to that of control group and TcpC(mut) group (60.1% 9.7% compared with 9.0% 1.3% and 16.9% 0.4%,respectively, P<0.05); meanwhile the mitochondrial depolarization of HUVECs co-cultured with TcpC(wt) was significantly increased,compared to that in control and TcpC(mut) groups (64.5% 0.9% compared with 14.5% 2.1% and 15.6% 3.3%, respectively,P<0.05). Cleavage of PARP and inhibition of Mcl-1 and XIAP expression were seen in HUVECs co-cultured with TcpC(wt),but not in groups of control and TcpC(mut). CONCLUSION: TcpC secreted from CFT073 can induce apoptosis of HUVECs through mitochondrial pathway, in which PARP is cleaved and Mcl-1 and XIAP expressions are inhibited. PMID- 24167129 TI - [CCL21-CD40L fusion gene induce augmented antitumor activity in colon cancer]. AB - OBJECTIVE: To investigate the anti-tumor activity of CCL21-exCD40L eukaryotic expression vector. METHODS: CCL21-exCD40L fusion gene were constructed by overlap PCR connecting CCL21 and exCD40L through a flexible linker (Gly3Ser)4, and then was cloned into expression vector pcDNA3.1(+). pcDNA3.1(+)/CCL21 and pcDNA3.1(+)/exCD were constructed as negative control. Wsestern blot was used to identify the fusion protein. CHO cells was transfected with pcDNA3.1(+)/CCL21 exCD, pcDNA3.1(+)/CCL21 and pcDNA3.1(+), respectively. The chemotatic function of the expressed product was detected by Transwell method and its anti-tumor activity was tested with vivo transfection. RESULTS: Gene sequencing and restrictive digestion proved the successful construction of pcDNA3.1(+)/CCL21 exCD40L,and its expression was conformed by western blot. The transfectant supernantes of pcDNA3.1(+)/CCL21-exCD40 group had a significant chmotactic function to DCs, of which the cell numbers passing through the film was 14.95 times of blank control every high power microscope visual field. After tumor orthotoic injection of plasmid carrying fusion gene in Balb/c mouse, the tumor mass reduced remarkablely, and all the mouse in fusion gene group survived after 4 weeks. CONCLUSION: CCL21-exCD40L fusion protein had a remarkable function to DCs and it can inhibit tumor growth and prolong the mouse survival time, which is more effective than all control group. PMID- 24167130 TI - [Pro-apoptotic effects of luteolin on hepatoma HepG2 cells]. AB - OBJECTIVE: To investigate the effect of luteolin on cell growth and apoptosis of HepG2 cells in vitro. METHODS: Cultured HepG2,HL60,A549 and LO2 cells were treated with luteolin for different doses (0 MUg/ml,2.5 MUg/ml,10 MUg/ml and 20 MUg/ml) and varied times (0 h,24 h,48 h and 72 h). Cell viability was measured with MTT assay and IC50 was calculated. The reactive oxygen species (ROS) levels in HepG2 cells treated with luteolin for 6 h and 12 h were measured with flow cytometry. Cell apoptosis of HepG2 cells treated with luteolin for 24h was examined with flow cytometry and Annexin V-FITC/PI. Expression levels of apoptosis pathway proteins (p53,ASPP2 and iASPP) in HepG2 cells were detected with western blot and the dose and time-effect was analyzed. RESULTS: Luteolin effectively inhibited tumor cell proliferation in a dose-and time-dependent manner,and the inhibition rates of 20 MUg/ml Luteolin for 72 h were 39.34%,62.90%,57.57% and 62.90% to LO2,HepG2, HL60 and A549 cells,respectively. The intracellular ROS level was decreased in HepG2 cells by 13.88% and 41.11% after being treated with luteolin for 6 h and 12 h,respectively. The apoptosis rate of HepG2 cells treated with luteolin for 24 h was 14.43%,and western blot showed that luteolin reduced the expression level of iASPP by 77.07% and up regulated the expression of p53 by 179.37% and ASPP2 by 725.02% in HepG2 cells treated with luteolin for 12 h. CONCLUSION: Luteolin has ant-proliferative and pro-apoptotic activity on hepatoma HepG2 cells, which is associated with the altered expression of pro-apoptotic factors and decreased ROS level in HepG2 cells. PMID- 24167131 TI - [Preparation of anti-B7-H4 monoclonal antibody to investigate B7-H4 expression in pancreatic cancer]. AB - OBJECTIVE: To prepare a monoclonal antibody (mAb) against extracellular domain of B7-H4 and to investigate the expression of B7-H4 in pancreatic cancer tissue with the prepared mAb. METHODS: Balb/c mice were immunized with 3T3-B7-H4 cells and the splenic cells of the immunized mice were fused with Sp2/0 myeloma cells by conventional hybridoma techniques. An indirect ELISA method using 3T3-B7-H4 lysate as antigen was established to screen antibody-producing hybridoma cell lines. Western blott, immunoprecipitation (IP), and immunohistochemistry (IHC) were applied to characterize the mAb. Immunohistochemical staining was used to detect the expression of B7-H4 in human pancreatic cancer tissue. The correlation of B3-H4 expressions and pathological features of pancreatic cancer was analyzed. RESULTS: A hybridoma cell line secreting mAb against B7-H4 was obtained. The subclass of this mAb was IgM, and the light chain was Kappa. Western blot and IP showed that the mAb specifically recognized B7-H4. IHC staining revealed that the mAb stained in a predominantly diffuse plasmalemmal or cytoplasmic pattern when applied to certain tumor tissues. The B7-H4 was diffusely expressed in the cytoplasma and/or membrane of pancreatic cancer tissue, which was much higher than that expressed in normal pancreatic tissue (4.00 +/- 1.44 compared with 1.12 +/- 0.78, P +/- 0.01). The expression of B7-H4 was higher in pancreatic cancer tissues with higher pathological grade or with lymph node metastasis as compared with that in pancreatic cancer tissues with lower grade or with no lymph mode metastasis (6.10 +/- 0.72 compared with 3.55 +/- 1.12,P<0.01: 6.14 +/- 0.66 compared with 3.70 +/- 1.25,P<0.01). The expression level of B7-H4 was not related to patients'age and gender. CONCLUSION: Monoclonal antibody against B7-H4 with high activity and specificity has been prepared successfully. The expression of B7-H4 in pancreatic cancer tissue is up-regulated,which is closely related to the tumor grade and lymph node metastasis in pancreatic cancer. PMID- 24167132 TI - [Expression of PCNA, C-fos and Bax proteins in human embryonic tongue tissues]. AB - OBJECTIVE: To investigate of proliferating cell nuclear antigen (PCNA), C-fos and Bax proteins in human embryonic tongue tissue of different developmental stages. METHODS: Immunohistochemistry was used to detect the expressions of PCNA, C-fos and Bax proteins in embryonic tongue tissues of fetuses with 2, 3 and 4 month gestational age (n=16). One-way ANOVA and LSD-t test were employed to compare the number of positive expression cells in tongue tissues of fetuses with different gestational age. RESULTS: In the fetuses at 2, 3 and 4 months of gestation, the numbers of PCNA-positive cells in tongue epithelial tissues were 20.20 +/- 7.13, 39.10 +/- 13.44 and 26.00 +/- 9.02, respectively; those in tongue muscle and fiber tissues were 17.20 +/- 8.99, 22.30 +/- 6.57 and 32.40 +/- 14.72, respectively. In fetuses at 2 month of gestation, no C-fos-positive cells were found in tongue tissues; while at 3 and 4 months of gestation, the numbers of C fos-positive cells in the tongue epithelial layers were 25.10 +/- 7.91, 17.40 +/- 2.80; those in tongue muscle and fiber tissues were 24.50 +/- 4.67 and 28.00 +/- 7.75, respectively. Only weak positive expression of Bax protein was observed in the third month of gestation in embryonic tongue tissues. A significant difference was noted in PCNA expression in tongue epithelial layers, the muscle and fiber tissues (P<0.01 and P<0.05) among 3 embryonic periods. A significant difference was found in C-fos expression in tongue epithelial layers (P<0.01), but not in tongue muscle and fiber tissues (P>0.05) among 3 periods. CONCLUSION: Dynamic changes were seen in PCNA and C-fos expressions in embryonic tongue tissues in different gestational ages of fetus, indicating these two proteins may participate in regulation of the development and differentiation of tongue tissues in human embryos and fetuses. PMID- 24167133 TI - [Effects of sub-micro emulsion composition on cellular disposition of incorporated lipophilic drug]. AB - OBJECTIVE: To investigate the effects of sub-micro emulsion composition on cellular uptake and disposition of incorporated lipophilic drug. METHODS: Sub micro emulsions containing 10 % oil, 1.2 % lecithin and 2.25 % glycerol were prepared, and the fluorescent agent coumarin 6 was used as a model drug. The effects of oil types, co-surfactants and cationic lipid on uptake and elimination kinetics of 6-coumarin in HeLa cells were studied. The uptake mechanism of sub micro emulsions was further investigated. RESULTS: Oil type and Tweens had no influence on the cellular uptake. Modifications of surfactants with Span series increased the cellular influx, among which Span 20 with hydrophilic-lipophilic balance (HLB) value of 8.6 was the best enhancer. The intracellular drug level reached up to (46.09 +/- 1.98)ng/MUg protein which had significant difference with control group [(38.54 +/- 0.34)ng/MUg protein]. The positively charged emulsions significantly increased the uptake rate constant and elimination rate constant which were 4 times and 1.5 times of those in anionic groups, respectively. The uptake enhancement was also observed in cationic emulsions, cellular concentrations at plateau were (42.73 +/- 0.84)ng/MUg protein, which was about 3 times of that in anionic emulsions [(15.71 +/- 0.74)ng/MUg protein], when extracellular drug concentration kept at 100 ng/ml. Cationic emulsions delivered the payload mainly by direct drug transfer to contacted cells, while the negative ones depended on both drug passive diffusion and clathrin-mediated endocytosis of drug containing oil droplets which accounted for 20% of the intracellular drug. CONCLUSION: Interfacial characteristic of sub-micro emulsions such as co surfactants HLB as well as zeta potentials can influence lipophilic drug both in cellular uptake and elimination. PMID- 24167134 TI - [Characteristics of microsomal phase II metabolic enzymes in mouse embryonic stem cell-derived liver tissue]. AB - OBJECTIVE: To investigate the characteristics of phase II metabolic enzymes in mouse embryonic stem (ES) cell-derived liver tissue. METHODS: Mature hepatocytes were differentiated from embryonic stem cells in cultured mouse embryoid bodies (EB) at d18. Western blot was used to detect the expression of uridine 5' diphosphate glucronosyl transferase (UGT1a1,UGT1a6) and microsomal glutathione S transferases 1(mGST1) during the differentiation course.The derived liver tissue was incubated with UDPGA and 7-HFC,the formation of 7-HFC glucuronide was detected by HPLC to examine the total activities of UGT1a1 and UGT1a6. Furthermore, the microsomes were incubated with CDNB and GSH,and the mGST1 activity was measured by spectrometry. RESULTS: An increase tendency of UGT1a1 expression was noticed during the differentiation course. UGT1a6 and mGST1 were not detected in the earlier stage until d18 of differentiation. The metabolic activity of mGST1 in the derived hepatocytes was 7.65 nmol/min/mg on d18. CONCLUSION: The ES cell-derived liver tissue possesses partial metabolic function of phase II enzymes on d18 of differentiation,which might be used as a model for in vitro research on hepatic pathophysiology and phase II drug metabolism. PMID- 24167135 TI - [PP2 enhances intercellular communication of gap junction in breast cancer Hs578T cells]. AB - OBJECTIVE: To investigate the effect of Src kinase inhibitor PP2 on intercellular communication of gap junction in breast cancer cells. METHODS: Cultured breast cancer Hs578T cells were treated with various concentrations of pp2 (0,1,2,4,8,16,32 MUmol/L) for 24h. Cell growth was determined by MTT assay; dye spread in Hs578T cells was measured by Parachute assay; and the expression of Src kinase in Hs578T cells was detected by Western blot. RESULTS: MTT assay showed that the survive rate of Hs578T cells treated with PP2 (1 ? 8 MUmol/L) was 98% +/ 3% ? 94 % +/- 4%. Parachute assay showed that compared to control group the standard normalized dye spread rates of Hs578T cells treated with 1,2,4 and 8 MUmol/L PP2 were 1.60 +/- 0.08,2.00 +/- 0.05,2.20 +/- 0.05 and 2.70 +/- 0.09,respectively (all P<0.01). Moreover,compared to control group at the same time points,the standard normalized dye spread of Hs578T cells treated with 8 MUmol/L PP2 for 6,12 and 24 h were 1.4 +/- 0.05,1.7 +/- 0.06,and 2.2 +/- 0.07,respectively (all P<0.01). Western blot showed that the expression ratios of Src kinase/beta-actin of Hs578T cells treated with 1,2,4 and 8 MUmol/L PP2 for 24 h were 0.93 +/- 0.02,0.70 +/- 0.09,0.66 +/- 0.09 and 0.36 +/- 0.10,which were significantly inhibited compared with control group (P<0.05 or 0.01). And the expression ratio of Src kinase/beta-actin of Hs578T cells treated with 8 MUmol/L PP2 for 6,12 and 24h was 0.82 +/- 0.03,0.66 +/- 0.08 and 0.59 +/-0.09, which were all inhibited significantly compared to control group (P<0.01). CONCLUSION: PP2 enhances the gap junction function in breast cancer Hs578T cells, which is probably related to the inhibition of Src kinase. PMID- 24167136 TI - [Effect of Helicobacter pylori lipopolysaccharide on expression of Gli and Ptch-1 proteins in sonic hedgehog signaling pathway of gastric mucosa GES-1 cells]. AB - OBJECTIVE: To investigate the effect of Helicobacter Pylori lipopolysaccharide (Hp-LPS) on expression of Gli and Ptch-1 proteins in sonic hedgehog (Shh) signaling pathway of gastric mucosa GES-1 cells. METHODS: The LPS was extracted from Hp by hot phenol water method, and then the concentration of LPS was detected by the kinetic turbidimetric assay. GES-1 cells were stimulated by different concentrations of Hp-LPS (0, 1, 10, 20, 30 and 40 MUg/ml). The inhibition rates of cell growth were measured by MTT assay after treated with Hp LPS for 24 h. The expression of Gli and Ptch-1 proteins were determined by Western Blot. RESULTS: MTT assay showed that the inhibition rates of GES-1 cell growth after treatment by different concentrations of Hp-LPS (1, 10, 20, 30 and 40MUg/ml) were 25.8% +/- 2.7%, 34.2% +/- 3.1 %, 46.3% 3.4%, 60.8% +/- 2.1% and 82.9% +/- 2.8% respectively (r=0.985, P<0.001). Western blot showed that the expressions of Gli and Ptch-1 proteins were decreased after Hp-LPS treatment (0, 1, 10, 20, 30 and 40 MUg/ml): the relative expression values of Gli were 1.286 +/ 0.180, 0.963 +/- 0.067, 0.850 +/- 0.085, 0.566 +/- 0.058, 0.549 +/- 0.056 and 0.377 +/- 0.047, respectively (r=-0.945, P<0.001); those of Ptch-1 were 1.688 +/- 0.088, 1.466 +/- 0.061, 1.170 +/- 0.065, 1.042 +/- 0.064, 0.648 +/- 0.057 and 0.482 +/- 0.074, respectively (r=-0.985, P<0.001). CONCLUSION: Hp-LPS can decrease the related protein expression of Shh signaling pathway, which indicates that Hp may interfere with the function of Shh signaling pathway in gastric mucosa via the effect of its LPS. PMID- 24167137 TI - [Effect of renal sympathetic denervation on left ventricular hypertrophy and inflammatory factors in spontaneously hypertensive rats]. AB - OBJECTIVE: To investigate the effect of renal sympathetic denervation on left ventricular hypertrophy and inflammatory factors in spontaneously hypertensive rats. METHODS: Thirty six spontaneously hypertensive rats (SHR) were divided into 3 groups with 12 animals in each group: SHR control group,operation group and sham operation group. Bilateral renal sympathectomy or sham operation were performed in operation and sham groups,respectively; another 12 WKY rats served as normal controls. The blood pressure and body weight were examined weekly. The animals were sacrificed at w1 and w6, rat hearts were collected and left ventricular mass index (LVMI) was calculated. The expression of TLR4,TNF-alpha and IL-6 in heart tissue were detected by immunohistochemistry and Western blot. RESULTS: The systolic blood pressure [(201.67 +/- 11.09) mmHg compared with (140.0 +/- 10.86)mmHg,P<0.05],diastolic blood pressure [(144.50 +/- 10.48)mmHg compared with (78.50 +/- 7.32)mmHg,P<0.05], LVMI (2.44 +/- 0.05 compared with 1.93 +/- 0.05,P<0.05),the expression of TLR4 (0.298 +/- 0.004 compared with 0.126 +/- 0.004, P<0.05), NF-kappaB (0.249 +/- 0.006 compared with 0.195 +/- 0.005, P<0.05),TNF-alpha(0.323 +/- 0.004 compared with 0.146 +/- 0.004,P <0.05), IL-6 (0.283 +/- 0.005 compared with 0.207 +/- 0.006, P<0.05) in SHR control group were significantly higher than those in WKY group. Compared to sham operation group,the systolic blood pressure (157.30 +/- 9.35 compared with 197.30 +/- 11.5, P<0.05),diastolic blood pressure (112.50 +/- 6.25 compared with 146.80 +/- 7.6, P<0.05),LVMI (2.32 +/- 0.04 compared with 2.57 +/- 0.09, P<0.05, TLR4 (0.198 +/- 0.006 compared with 0.317 +/- 0.008, P<0.05), NF-kappaB (0.208 +/- 0.006 compared with 0.332 +/- 0.007, P<0.05), TNF-alpha(0.27 +/- 0.009 compared with 0.375 +/- 0.004,P<0.05), IL-6 (0.218 +/- 0.004 compared with 0.376 +/- 0.009, P<0.05) in operation group were all decreased at w1 after sympathectomy. Six weeks after the operation,there were no significant differences in systolic blood pressure (197.50 +/- 12.13 compared with 208.83 +/- 10.23,P>0.05) and diastolic blood pressure (150.33 +/- 7.74 compared with 151.50 +/- 8.22, P>0.05) between denervated and sham-operated SHRs; however,the LVMI (2.46 +/- 0.07 compared with 2.81 +/- 0.05,P<0.05) and the expression of TLR4(0.301 +/- 0.009 compared with 0.567 +/- 0.006, P<0.05), NF-kappaB (0.251 +/- 0.004 compared with 0.476 +/- 0.009,P<0.05),TNF-alpha(0.324 +/- 0.005 compared with 0.535 +/- 0.006, P<0.05,IL 6 (0.285 +/- 0.009 compared with 0.549 +/- 0.007, P<0.05) in operation group were still significantly lower than those in sham operation group. CONCLUSION: Renal sympathetic denervation can significantly delay the progression of LVH in SHR, which may associated with lowering blood pressure and decreasing expression of TLR4, NF-kappaB,TNF-alpha, IL-6 in myocardial tissue. PMID- 24167138 TI - [Extract of Herba Siegesbeckiae on mouse rheumatoid arthritis induced by anthrogen-CIA monoclonal antibody]. AB - OBJECTIVE: To investigate the anti-inflammatory effect of Herba Siegesbeckiae extracts on mouse rheumatoid arthritis induced by arthrogen-CIA monoclonal antibody. METHODS: The rheumatoid arthritis was induced by arthrogen-CIA arthritogenic monoclonal antibody in mice. The sandwich enzyme-linked immunosorbent assay was used to determine the concentration of IL-1betain mouse serum,and the content of IL-6,IL-17 and MMP-3 in supernatant of tissue homogenate of hind limb below the stifle of mice. One-way ANOVA was used for data analysis. RESULTS: The toe swelling was attenuated in Siegesbeckiae group than that in model group [(0.218 +/- 0.0307)cm(3) compared with (0.2545 +/- 0.0179)cm(3), P<0.05]. The serum IL-1beta level in Siegesbeckiae group was lower than that in model group [(63.74 +/- 21.74)pg/ml compared with (104.96 +/- 31.22)pg/ml, P<0.01]. The contents of IL-6, IL-17 and MMP-3 in tissue supernatants of Siegesbeckiae group were all lower than those of model group [(171.10 +/- 48.35)pg/ml compared with (249.64 +/- 75.08)pg/ml, P<0.05; (115.42 +/- 56.52)pg/ml compared with (208.40 +/- 88.54)pg/ml, P<0.05;(3660.31 +/- 1680.99) pg/ml compared with (5420.79 +/- 1201.43)pg/ml, P<0.05, respectively]. CONCLUSION: The extract of Herba Siegesbeckiae has anti-inflammatory effect on mouse rheumatoid arthritis induced by mixed arthrogen monoclonal antibody. PMID- 24167139 TI - [Effects of Corbrin Shugan capsule on dimethylnitrosamine-induced hepatic fibrosis in rats]. AB - OBJECTIVE: To investigate the effects of Corbrin Shugan capsule on dimethylnitrosamine (DMN)-induced hepatic fibrosis in rats. METHODS: Hepatic fibrosis was induced by DMN in AD rats. The serum concentrations of III pro collagen (III PC),laminin (LN) and tissue inhibitor of metalloproteinase-1(TIMP 1) were determined with ELISA. The concentration of albumin (ALB) in sera and the content of hydroxyproline (Hyp) in liver tissues were determined with chemical colorimetric and HPLC, respectively. The fibrosis area was measured with Motic Med 6.0 digital medical image analysis system. RESULTS: Compared to model group the high-dose (450 mg kg(-1)),mid-dose (270 mg kg(-1)) and low-dose (90 mg kg( 1)) groups of Corbrin Shugan capsule had significantly lower serum content of III PC [34.46 +/- 13.95),(36.15 +/- 9.46), and (40.58 +/- 7.72)ng ml(-1) compared with (49.38 +/- 10.95)ng ml(-1),P<0.05 or P<0.01],TIMP-1 [(16.65 +/- 4.24),(16.66 +/- 4.34),and (18.99 +/- 6.05)ng ml(-1) compared with (30.84 +/- 14.48)ng ml(-1), P<0.05 or P<0.01], LN [(12.94 +/- 4.29), (12.96 +/- 3.21),and (15.32 +/- 8.00)ng ml(-1) compared with (30.22 +/- 17.00)ng ml(-1),P<0.05 or P<0.01] and smaller hepatic fibrosis area [(0.02240 +/- 0.01337), (0.02176 +/- 0.01460) and (0.02384 +/- 0.01405)MUm(2) compared with vs (0.03929 +/- 0.01732)MUm2, P<0.05 or P<0.01]; the high-dose and mid-dose groups of Corbrin Shugan capsule had significantly lower content of Hyp in liver tissues [(0.77 +/- 0.09) and (0.81 +/- 0.09)MUg MUmg(-1) compared with (1.06 +/- 0.33)MUg mg(-1),P<0.05 or P<0.01]; and the high dose group of Corbrin Shugan capsule significantly increased the content of ALB in sera [(34.02 +/- 4.17)g L(-1) compared with (30.25 +/- 4.21)g L(-1),P<0.05]. CONCLUSION: Corbrin Shugan capsule is effective in treatment of DMN-induced hepatic fibrosis in rats. PMID- 24167140 TI - [MAPK p38 pathway may be involved in renal function improvement in chronic renal failure rats treated with Jianpi Qinghua decoction]. AB - OBJECTIVE: To investigate the involvement of MAPK p38 pathway in treatment of chronic renal failure with Jianpi Qinghua Decoction in rats. METHODS: Forty SPF SD rats were divided into sham group (n=10),model group (n=10), Jianpi Qinghua group (n=10) and losartan group (n=10). Rat chronic renal failure was induced by 5/6 nephrectomy (Platt method) in model, Jianpi Qinghua and losartan groups, and rats in sham group received sham operation. Jianpi Qinghua decoction (3.9 g 200 g(-1)) or losartan (3.3 g 200 g(-1)) daily were administrated by gavage in Jianpi Qinghua and losartan groups for 60 days, respectively, Rats in sham and model groups were orally administered with saline of the same volume. The serum levels of creatinine and urea nitrogen were measured by biochemical method, the expression of MAPK p38 was detected by Western Blot,and renal pathological changes were observed with hematoxylin-eosin staining. RESULTS: Compared to model group,serum creatinine levels after 60d in Jianpi Qinghua and losartan groups were decreased significantly (42.67 +/- 5.98 or 40.90 +/- 5.07 compared with 60.90 +/- 9.54, both P<0.01), the expression of MAPK p38 was significantly down regulated (0.555 +/- 0.004 or 0.587 +/- 0.045 compared with 0.930 +/- 0.265,both P<0.01) and serum urea nitrogen was also decreased (8.56 +/- 0.75 or 7.97 +/- 0.86 compared with 8.62 +/- 0.62,both P<0.05). The renal pathology in the model group presented glomerular mesangial proliferation,hyperplasia of glomenrulus mesangial cells and interstitial inflammation. Those pathological changes were attenuated significantly in Jianpi Qinghua and losartan groups. CONCLUSION: Jianpi Qinghua Decoctions can improve the renal function and renal pathological changes in a rat with chronic renal failure, which may be associated with down regulation of MAPK p38 immune inflammatory pathways. PMID- 24167141 TI - [Two-dimensional ultrasound speckle tracking imaging in detection of myocardial torsion for patients with chronic pulmonary heart disease]. AB - OBJECTIVE: To evaluate the application of two-dimensional ultrasound speckle tracking imaging (STI) in assessment of myocardial torsion and left ventricular function for patients with chronic pulmonary heart disease (CPHD). METHODS: Thirty six patients with CPHD and 38 normal subjects were enrolled in the study,and STI examinations were performed. The left ventricular short-axis views (mitral level,apical level) were observed,the rotation angles of the standardized time point were measured at each short-axis views and the corresponding left ventricular torsion angles were calculated. Simultaneously, the basal rotation peak, apical rotation peak, left ventricular twist peak, end-systolic basal rotation value, end-systolic apical rotation value and end-systolic left ventricular twist value were recorded. The correlations of left ventricular ejection fraction (LVEF) with left ventricular torsion peak, end-systolic left ventricular twist value in patients were analyzed. RESULTS: Compared to normal controls, the basal rotation peak, apical rotation peak, left ventricular twist peak, end-systolic basal rotation value, end-systolic apical rotation value and end-systolic left ventricular twist value were significantly lower (P<0.01) in CPHD patients. The LVEF was highly correlated with left ventricular twist peak and end-systolic left ventricular twist value in CPHD patients (r=0.967, 0.952,P<0.001). CONCLUSION: STI is sensitive to detect left ventricular myocardial torsion change; left ventricular torsion peak and end-systolic left ventricular twist value can be used to assess the left ventricular function in patients with CPHD. PMID- 24167142 TI - [Bone alkaline phosphatase and N-MID osteocalcin in monitoring of osteoporosis treatment with recombinant human parathyroid hormone 1-34]. AB - OBJECTIVE: To evaluate the application of bone turnover markers bone alkaline phosphatase (BALP) and N-MID osteocalcin (N-MID) in monitoring of osteoporosis treatment with recombined parathyroid hormone 1-34 (rhPTH1-34). METHODS: The bone mineral density (BMD) of the lumbar spine L2-L4 and the proximal femur were examined by dual energy X-ray absorptiometry (DXA) before and 6 and 12 months after rhPTH 1-34 treatment. Meanwhile, serum levels of BALP and N-MID were detected by electro-chemiluminescence assay. RESULTS: Six months after rhPTH 1-34 treatment, the BMD of proximal femur remained unchanged, and the BMD of the lumbar L2-L4 spine increased from 0.753 g/cm(2) to 0.781 g/cm(2) (P<0.05); while serum levels of N-MID increased from 15.46 ng/ml to 27.07 ng/ml(P<0.01), BALP from 14.05 MUg/ml to 24.31 MUg/ml(P<0.01). Twelve months after drug administration, no significant changes were observed in BMD of proximal femur, and the BMD of the lumbar spine L2-L4 increased from 0.753 g/cm(2) to 0.807 g/cm(2)(P<0.01) while serum levels of N-MID and BALP increased from 15.46 ng/ml and 14.05MUg/ml to 49.38 ng/ml and 33.99 MUg/ml, respectively (both P<0.01). CONCLUSION: Serum levels of BALP and N-MID are more sensitive than BMD. Combination of two methods may provide better indicators for monitoring of osteoporosis treatment. PMID- 24167143 TI - [The roles of glutamate in sleep and wakefulness]. AB - Glutamate as an excitatory neurotransmitter in the central nervous system, participate in initiation and maintaining of sleep and wakefulness. The paper presents an overview of the research progress of glutamate in the regulation of sleep and wakefulness, especially focuses on its role in the brainstem, lateral hypothalamus and basal forebrain. Glutamate in the brain stem regulates the brain activity and maintains muscle tone during the wakefulness, as well as adjusts the electroencephalograph (EEG) in rapid eye movement phase and leads to muscle weakness. Glutamate in the lateral hypothalamus participates in the lateral hypothalamic arousal system by activating orexins neurons. The basal forebrain glutamatergic neurons take part in EEG synchronization and cause the decrease of sleep. Finally,The glutamatergic neurons of the cerebral cortex is not just a target of the arousal system, but itself contribute to regulation of arousal. Meantime, the glutamatergic neurons can regulate sleep stages through interaction with other types of neurons, which forms a complex sleep-wake regulation network in the brain. These indicate that the switches between different phases of sleep and wakefulness have different neuronal circuits.So we also reviewed the neuronal circuits and mechanisms that glutamate may be involved in. This review will help us to get a better understanding of the roles of glutamate in sleep and wakefulness. PMID- 24167144 TI - [Crosstalk between canonical TGF-beta/Smad and Wnt/beta-catenin signaling pathway]. AB - TGF-beta signaling pathway plays a central role in the signaling networks that control the growth, differentiation of the cell, and the initiation of fibrosis and cancer. Wnt signaling pathway is critical for the embryonic development and the invasion and migration of cancer cells. TGF-beta signaling and Wnt signaling, both of which play an important role in regulating embryonic development, fibrotic disease and tumor progression, have a close relationship. Researches find several typical cross points between these two signaling systems, such as Smad, Axin, Dvl and beta-catenin. In this review, we focus on the crosstalk between TGF-beta signaling and Wnt signaling through these typical factors, intending to better understand the process of fibrosis and tumor progression. PMID- 24167145 TI - Micromotor-based high-yielding fast oxidative detoxification of chemical threats. PMID- 24167146 TI - Synthesis and insecticidal activities of novel pyrazole oxime ether derivatives with different substituted pyridyl rings. AB - BACKGROUND: Pyrazole oxime ether derivatives with different substituted pyridyl rings represent new types of compounds that possess good insecticidal and acarcidal activity against Aphis laburni Kaltenbach and Tetranychus cinnabarinus. RESULTS: In total, 82 novel pyrazole oxime ether derivatives were synthesized and identified by (1) H NMR, elemental analysis or high-resolution mass spectrometry, and their insecticidal and acarcidal activities were tested against A. laburni Kaltenbach and T. cinnabarinus. Bioassays showed that at a 200 mg L(-1) dosage, one-third of the compounds displayed high insecticidal activity against A. laburni Kaltenbach (> 90%), whereas most of of the compound II series exhibited excellent acarcidal activity against T. cinnabarinus (> 92%). Most compound II series exhibited good activity in both insecticidal and acarcidal tests. In addition, at a low concentration of 10 mg L(-1) , the insecticidal activity of compounds IB9 and IE4 exceeded 90%, and the acarcidal activity of compounds IIB1 and IIB2 was >= 95%. CONCLUSION: Structure-activity relationships were also examined. Results suggested that the tert-butoxycarbonyl group, as well as the position between tert-butoxycarbonyl and the atom N of the pyridyl ring, were essential to obtaining the acarcidal activity of the title compounds. PMID- 24167147 TI - Osteoblast response to nanocrystalline calcium hydroxyapatite depends on carbonate content. AB - Normal bone mineral is a carbonated-apatite, but there are limited data on the effect of mineral containing carbonate on cell response. We characterized surface chemical compositions of three experimental carbonated hydroxyapatite (CO3(2-) HA) substrates and investigated their effect on osteoblast differentiation. Carbonate was incorporated into the hydroxyapatite powders while phosphate and hydroxyl groups were shown to be reduced by analyzing the chemical composition of the substrate surfaces. CO3(2-) HA powders with increasing carbonate concentrations designated as C1 (3.88%), C2 (4.85%), and C3 (5.82%) were molded, pressed, and fired into 14 mm discs. We observed that calcium phosphate ratios increased monotonically with increasing carbonate content, whereas differentiation of MG63 cells decreased. CO3(2-) HA surfaces also affected factor production. Addition of carbonate caused a 70% reduction in osteoprotegerin (OPG) compared to cultures on pure HA, but the effect of carbonate was not dose dependent. Low carbonate content reduced VEGF-A by 80%, but higher levels of carbonate reversed this effect in a concentration dependent manner, with the C3 VEFG-A levels approximately twice that of C1 levels. These observations collectively indicate that bone cells are sensitive to carbonate content in bone mineral and the effects of carbonate substitution vary with the outcome being measured. Overall, this study provides a preliminary understanding of how carbonate substitution within hydroxyapatite modulates cellular behavior. PMID- 24167148 TI - Cannibalism in the pea aphid, Acyrthosiphon pisum. AB - Previous observations of cannibalism have been made in the aphid Acyrthosiphon pisum (L.): this article seeks to quantify factors contributing to such behaviors. We observed and quantified the responses of a number of clones and life stages to varying levels of starvation, in the form of increasingly desiccated Vica faba L. plants (receiving 50, 25, or 10 mL every second day) or a complete absence of host plant. We found that, while the longest incidences of cannibalism are carried out by juveniles (F = 3.45, P = 0.019, df = 3) and targeted at adults, the starvation treatments had the most significant effect on the prevalence of cannibalism in mature A. pisum (F = 2.24, P = 0.025, df = 9). Furthermore, there was no difference between the prevalence or duration of cannibalistic activities within and between different clones (P >= 0.05 in all cases), though juveniles were more likely to target unrelated aphids (V = 6 112, P = 0.011), and spent more time feeding on aphids from the same culture (V = 6 062, P = 0.018). PMID- 24167149 TI - DART-MS for rapid, preliminary screening of urine for DMAA. AB - Dimethylamylamine (DMAA) is a sympathomimetic amine found in weight-loss/workout supplements or used as an appetite suppressant. DMAA is a stimulant that is banned by the World Anti-Doping Agency (WADA). Adverse health effects as well as fatalities have been implicated with its use. Direct analysis in real time mass spectrometry (DART-MS) is an ambient ionization method that was employed to rapidly identify the presence of DMAA in various samples without any extraction or preparations whatsoever. DMAA was first identified in supplements, sampled directly in their solid forms. Furthermore, DMAA was detected directly in urine over 48 h as a means of indicating recent abuse of the substance. DART-MS analysis is instantaneous, and coupled with the high mass accuracy associated with the time-of-flight mass analyzer, results in unequivocal identification of the presence of DMAA. These features demonstrate DART-MS as an attractive potential alternative screening method for the presence of drugs and medications or for toxicological investigations. PMID- 24167150 TI - Atropisomeric chiral dienes in asymmetric catalysis: C(2) -symmetric (Z,Z)-2,3 bis[1-(diphenylphosphinyl)ethylidene]tetralin as a highly active Lewis base organocatalyst. AB - Diene catalysts with a twist: The title C2 -symmetric tetralin-fused 1,3 butadiene derivative is atropisomeric and can be resolved into the two helical enantiomers. The optically pure compound showed excellent enantioselectivity as well as unusually high catalytic activity as a chiral Lewis basic organocatalyst in the asymmetric allylation of various aldehydes with beta-substituted allyltrichlorosilanes. PMID- 24167151 TI - Polymorphism of the rs1800896 IL10 promoter gene protects children from post bronchiolitis asthma. AB - Viral bronchiolitis is a major cause of hospitalization in infancy, with increased asthma risk in later childhood. However, the principal mechanisms behind post-bronchiolitic asthma have remained unclear. Previously, different cytokine polymorphisms have been associated with asthma occurrence, but no previous follow-up study has investigated cytokine polymorphisms in relation to post-bronchiolitic asthma. We hypothesized that former bronchiolitis patients with cytokine gene variants associating with Th2 cell up-regulation are at asthma risk at preschool age. Our emphasis was in IL10 rs1800896, since IL-10 has an important role in immune tolerance, and lower production of IL-10 has been associated with Th2-type immunology, and accordingly, with increased asthma risk. IL10 rs1800896, IFNG rs2430561, and IL18 rs1872387 polymorphims and their associations with asthma and allergy were studied in 135 preschool-aged children hospitalized for bronchiolitis at age 0-6 months. Parents were interviewed to record asthma and allergy from infancy to present. At age 6.4 years (mean), asthma was present in 17(12.6%), atopic eczema in 47(34.8%) and allergic rhinitis in 36(26.7%) children. IL10 rs1800896 SNP associated significantly with asthma; only 1/32 (3.1%) of those with G/G genotype had asthma (P = 0.04). In logistic regression adjusted for gender, age and atopy, the carriage of allele A (rs1800896) was a significant risk factor for preschool asthma. IFNG rs2430561 or IL18 rs1872387 SNP's had no associations with asthma or allergy. In conclusion, IL10 rs1800896 SNP was significantly associated with preschool asthma after severe lower respiratory tract infection in early infancy. PMID- 24167152 TI - Early weaning PCB 95 exposure alters the neonatal endocrine system: thyroid adipokine dysfunction. AB - Polychlorinated biphenyls (PCBs) are persistent environmental pollutants that can severely disrupt the endocrine system. In the present study, early-weaned male rats were administered a single dose of 2,3,6-2',5'-pentachlorinated biphenyl (PCB 95; 32 mg/kg per day, by i.p. injection) for two consecutive days (postnatal days (PNDs) 15 and 16) and killed 24 and 48 h after the administration of the last dose. Compared with the control group, administration of PCB 95 induced a reduction (P<0.01) in serum concentrations of thyroxine, triiodothyronine, and GH and an increase (P<0.01) in the serum concentration of TSH at PNDs 17 and 18. These conspicuous perturbations led to some histopathological deterioration in the thyroid gland characterized by follicular degeneration, edema, fibrosis, hemorrhage, luminal obliteration, and hypertrophy with reduced colloidal contents at PND 18. The dyshormonogenesis and thyroid dysgenesis may be attributed to the elevation of DNA fragmentation at PNDs 17 and 18. Furthermore, this hypothyroid state revealed higher (P<0.01) serum concentrations of leptin, adiponectin, and tumor necrosis factor and lower (P<0.01) serum concentrations of IGF1 and insulin at both PNDs compared with the control group. Interestingly, the body weight of the neonates in the PCB 95 group exhibited severe decreases throughout the experimental period in relation to that of the control group. These results imply that PCB 95 may act as a disruptor of the developmental hypothalamic-pituitary thyroid axis. Hypothyroidism caused by PCB 95 may impair the adipokine axis, fat metabolism, and in general postnatal development. Thus, further studies need to be carried out to understand this concept. PMID- 24167153 TI - Silica coating of the pore walls of a microporous polycaprolactone membrane to be used in bone tissue engineering. AB - Polycaprolactone/silica microporous hybrid membranes were produced in two steps: A microporous polycaprolactone membrane with an interconnected porosity of 80% was obtained via a freeze extraction procedure, then silica was formed by a sol gel reaction inside the micropores using tetraethyl orthosilicate, TEOS, as silica precursor. It is shown that silica forms a thin coating layer homogeneously distributed over the pore walls when sol-gel reaction is catalyzed by hydrochloric acid, while it forms submicron spherical particles when using basic catalyzer. Some physical properties and the viability and osteoblastic differentiation of bone marrow rat mesenchymal stem cells cultured on pure and hybrid membranes were studied. PMID- 24167154 TI - Obesity negatively impacts lung function in children and adolescents. AB - OBJECTIVES: To investigate the relationship between weight status (body mass index [BMI] percentile and BMI z-score) and lung volumes in healthy children and adolescents. HYPOTHESES: We hypothesized that: (a) there would be a significant inverse relationship between age- and sex-specific BMI distribution and functional residual capacity (FRC), and expiratory reserve volume (ERV), respectively; and (b) obese children would have significantly reduced FRC and ERV compared to their non-obese peers. METHODS: The medical records of all individuals who successfully performed pulmonary function testing between 2000 and 2007 at two university children's hospitals were reviewed. Participants were excluded if they had cardiopulmonary, neuromuscular, or chest wall disease. RESULTS: Of 1,469 record reviewed, 327 subjects met study criteria. Percent predicted ERV was lowest in the obese group (P < 0.001) while residual volume (RV) was lowest in the overweight and obese groups (P < 0.001). Underweight participants had a lower percent predicted forced vital capacity (FVC) (P = 0.027) and vital capacity (VC; P = 0.039). Obese participants had the lowest FEV1 /FVC (P < 0.001). A positive linear relationship existed between BMI z-score and percent predicted FVC, VC, and diffusing capacity of carbon monoxide (DLCO ). A negative linear relationship was found between BMI z-score and percent predicted FRC, ERV, RV, and absolute FEV1 /FVC. CONCLUSIONS: Our results show that increasing weight status in children and adolescents is associated with a general reduction in lung volume measurements, which may reflect impaired lung function, increased respiratory symptoms, and decreased functional status. PMID- 24167156 TI - AllergenFP: allergenicity prediction by descriptor fingerprints. AB - MOTIVATION: Allergenicity, like antigenicity and immunogenicity, is a property encoded linearly and non-linearly, and therefore the alignment-based approaches are not able to identify this property unambiguously. A novel alignment-free descriptor-based fingerprint approach is presented here and applied to identify allergens and non-allergens. The approach was implemented into a four step algorithm. Initially, the protein sequences are described by amino acid principal properties as hydrophobicity, size, relative abundance, helix and beta-strand forming propensities. Then, the generated strings of different length are converted into vectors with equal length by auto- and cross-covariance (ACC). The vectors were transformed into binary fingerprints and compared in terms of Tanimoto coefficient. RESULTS: The approach was applied to a set of 2427 known allergens and 2427 non-allergens and identified correctly 88% of them with Matthews correlation coefficient of 0.759. The descriptor fingerprint approach presented here is universal. It could be applied for any classification problem in computational biology. The set of E-descriptors is able to capture the main structural and physicochemical properties of amino acids building the proteins. The ACC transformation overcomes the main problem in the alignment-based comparative studies arising from the different length of the aligned protein sequences. The conversion of protein ACC values into binary descriptor fingerprints allows similarity search and classification. AVAILABILITY AND IMPLEMENTATION: The algorithm described in the present study was implemented in a specially designed Web site, named AllergenFP (FP stands for FingerPrint). AllergenFP is written in Python, with GIU in HTML. It is freely accessible at http://ddg-pharmfac.net/Allergen FP. CONTACT: idoytchinova@pharmfac.net or ivanbangov@shu-bg.net. PMID- 24167155 TI - Telling metabolic stories to explore metabolomics data: a case study on the yeast response to cadmium exposure. AB - MOTIVATION: The increasing availability of metabolomics data enables to better understand the metabolic processes involved in the immediate response of an organism to environmental changes and stress. The data usually come in the form of a list of metabolites whose concentrations significantly changed under some conditions, and are thus not easy to interpret without being able to precisely visualize how such metabolites are interconnected. RESULTS: We present a method that enables to organize the data from any metabolomics experiment into metabolic stories. Each story corresponds to a possible scenario explaining the flow of matter between the metabolites of interest. These scenarios may then be ranked in different ways depending on which interpretation one wishes to emphasize for the causal link between two affected metabolites: enzyme activation, enzyme inhibition or domino effect on the concentration changes of substrates and products. Equally probable stories under any selected ranking scheme can be further grouped into a single anthology that summarizes, in a unique subnetwork, all equivalently plausible alternative stories. An anthology is simply a union of such stories. We detail an application of the method to the response of yeast to cadmium exposure. We use this system as a proof of concept for our method, and we show that we are able to find a story that reproduces very well the current knowledge about the yeast response to cadmium. We further show that this response is mostly based on enzyme activation. We also provide a framework for exploring the alternative pathways or side effects this local response is expected to have in the rest of the network. We discuss several interpretations for the changes we see, and we suggest hypotheses that could in principle be experimentally tested. Noticeably, our method requires simple input data and could be used in a wide variety of applications. AVAILABILITY AND IMPLEMENTATION: The code for the method presented in this article is available at http://gobbolino.gforge.inria.fr. PMID- 24167157 TI - Fast protein fragment similarity scoring using a Binet-Cauchy kernel. AB - MOTIVATION: Meaningful scores to assess protein structure similarity are essential to decipher protein structure and sequence evolution. The mining of the increasing number of protein structures requires fast and accurate similarity measures with statistical significance. Whereas numerous approaches have been proposed for protein domains as a whole, the focus is progressively moving to a more local level of structure analysis for which similarity measurement still remains without any satisfactory answer. RESULTS: We introduce a new score based on Binet-Cauchy kernel. It is normalized and bounded between 1-maximal similarity that implies exactly the same conformations for protein fragments-and -1-mirror image conformations, the unrelated conformations having a null mean score. This allows for the search of both similar and mirror conformations. In addition, such score addresses two major issue of the widely used root mean square deviation (RMSD). First, it achieves length independent statistics even for short fragments. Second, it shows better performance in the discrimination of medium range RMSD values. Being simpler and faster to compute than the RMSD, it also provides the means for large-scale mining of protein structures. AVAILABILITY AND IMPLEMENTATION: The computer software implementing the score is available at http://bioserv.rpbs.univ-paris-diderot.fr/BCscore/ CONTACT: frederic.guyon@univ paris-diderot.fr SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 24167158 TI - Direction pathway analysis of large-scale proteomics data reveals novel features of the insulin action pathway. AB - MOTIVATION: With the advancement of high-throughput techniques, large-scale profiling of biological systems with multiple experimental perturbations is becoming more prevalent. Pathway analysis incorporates prior biological knowledge to analyze genes/proteins in groups in a biological context. However, the hypotheses under investigation are often confined to a 1D space (i.e. up, down, either or mixed regulation). Here, we develop direction pathway analysis (DPA), which can be applied to test hypothesis in a high-dimensional space for identifying pathways that display distinct responses across multiple perturbations. RESULTS: Our DPA approach allows for the identification of pathways that display distinct responses across multiple perturbations. To demonstrate the utility and effectiveness, we evaluated DPA under various simulated scenarios and applied it to study insulin action in adipocytes. A major action of insulin in adipocytes is to regulate the movement of proteins from the interior to the cell surface membrane. Quantitative mass spectrometry-based proteomics was used to study this process on a large-scale. The combined dataset comprises four separate treatments. By applying DPA, we identified that several insulin responsive pathways in the plasma membrane trafficking are only partially dependent on the insulin-regulated kinase Akt. We subsequently validated our findings through targeted analysis of key proteins from these pathways using immunoblotting and live cell microscopy. Our results demonstrate that DPA can be applied to dissect pathway networks testing diverse hypotheses and integrating multiple experimental perturbations. AVAILABILITY AND IMPLEMENTATION: The R package 'directPA' is distributed from CRAN under GNU General Public License (GPL)-3 and can be downloaded from: http://cran.r project.org/web/packages/directPA/index.html CONTACT: jean.yang@sydney.edu.au SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 24167159 TI - Respiratory viruses are associated with common respiratory pathogens in cystic fibrosis. AB - OBJECTIVES: Test the hypothesis that the link between respiratory viruses and pulmonary exacerbation in cystic fibrosis (CF) reflects increased frequency or severity of lower airways infection. STUDY DESIGN: Molecular respiratory viral panels (RVPs), cell counts, and quantitative bacterial cultures were assessed in 235 bronchoalveolar lavage fluid (BALF) samples from 138 children with CF. Relationships among the data were analyzed using multivariate methods. RESULTS: RVPs were positive in 67 (28.5%) BALF samples from 52 (37.7%) patients, with rhinovirus/enterovirus most common (82.4% of RVP+). RVP+ patients were younger (5.4 years, IQR 3.0-9.7 vs. 8.0 years, IQR 3.5-12.9; P < 0.01), more likely to have respiratory symptoms (74.6% vs. 55.2%, P < 0.01), and had higher BALF percent neutrophils (70.5%, IQR 46-85% vs. 59.3%, IQR 34-77%; P < 0.05). Percent predicted FEV1 at bronchoscopy was diminished from baseline in both groups, but recovered in the RVP- (90.2 +/- 22.2% vs. 89.6 +/- 19.7%, P = 0.62) but not the RVP+ subjects (95.7 +/- 21.1% vs. 89.1 +/- 18.0%, P < 0.05). RVP status did not alter recovery rates of typical CF respiratory pathogens including Staphylococcus aureus (44.8% vs. 42.9%) and Pseudomonas aeruginosa (25.4% vs. 25.6%). However, common respiratory pathogens (Haemophilus species, Moraxella species, and Streptococcus pneumoniae) were recovered more frequently from RVP+ samples independent of age (OR 3.6, 95% CI 1.8-7.5, P < 0.001). CONCLUSIONS: Respiratory viruses were frequently detected in BALF from CF patients and associated with markers of disease severity. Respiratory viruses did not impact frequency or severity of infection with typical CF pathogens, but rates of infection with common respiratory pathogens were increased. This finding may have treatment implications. PMID- 24167160 TI - AMPK and FoxO1 regulate catalase expression in hypoxic pulmonary arterial smooth muscle. AB - BACKGROUND: Hypoxia and reactive oxygen species (ROS) including H(2)O(2) play major roles in triggering and progression of pulmonary vascular remodeling in persistent pulmonary hypertension. Catalase (CAT), the major endogenous enzyme scavenging H(2)O(2), is regulated in a tissue- and context-specific manner. OBJECTIVE: To investigate mechanisms by which hypoxia and H(2)O(2) regulate catalase expression, and the role of AMPK-FoxO pathway, in neonatal porcine pulmonary artery smooth muscle (PASMC). DESIGN/METHODS: PASMC were grown in hypoxia (10% O(2)) or normoxia (21% O(2)) for 72 hr. We measured catalase activity and lipid peroxidation; CAT, FoxO1, and FoxO3a expression by qPCR; protein contents of CAT, FoxOs, p-AMPK, p-AKT, p-JNK, p-ERK1/2 in whole lysates, and FoxOs in nuclear extracts, by immunoblot; and FoxO-1 nuclear localization by immunocytochemistry, quantified by laser scanning cytometry. RESULTS: Hypoxia upregulated CAT transcription, content and activity, by increasing CAT transcription factors FoxO1 and FoxO3a mRNA, and promoting nuclear translocation of FoxO1. However, lipid peroxidation increased in hypoxic PASMC. Among candidate FoxO regulatory kinases, hypoxia activated AMPK, and decreased p-Akt and ERK1/2. AMPK activation increased FoxO1 (total and nuclear) and CAT, while AMPK inhibition inhibited FoxO1 and CAT, but not FoxO3a. Exogenous H(2)O(2) decreased p-AMPK and increased p-AKT in hypoxic PASMC. This decreased active FoxO1, and reduced mRNA and protein content of CAT. Hypoxic induction of CAT, AKT inhibition (LY294002), or addition of PEG-catalase partly ameliorated the H(2)O(2) -mediated loss of nuclear FoxO1. CONCLUSIONS: Hypoxia induces catalase expression, though this adaptation is insufficient to protect PASMC from hypoxia-induced lipid peroxidation. This occurs via hypoxic activation of AMPK, which promotes nuclear FoxO1 and thus catalase expression. Exogenous ROS may downregulate cellular antioxidant defenses; H(2)O(2) activates survival factor Akt, decreasing nuclear FoxO1 and thus catalase. PMID- 24167161 TI - Mechanisms underlying the influence of saliency on value-based decisions. AB - Objects in the environment differ in their low-level perceptual properties (e.g., how easily a fruit can be recognized) as well as in their subjective value (how tasty it is). We studied the influence of visual salience on value-based decisions using a two alternative forced choice task, in which human subjects rapidly chose items from a visual display. All targets were equally easy to detect. Nevertheless, both value and salience strongly affected choices made and reaction times. We analyzed the neuronal mechanisms underlying these behavioral effects using stochastic accumulator models, allowing us to characterize not only the averages of reaction times but their full distributions. Independent models without interaction between the possible choices failed to reproduce the observed choice behavior, while models with mutual inhibition between alternative choices produced much better results. Mutual inhibition thus is an important feature of the decision mechanism. Value influenced the amount of accumulation in all models. In contrast, increased salience could either lead to an earlier start (onset model) or to a higher rate (speed model) of accumulation. Both models explained the data from the choice trials equally well. However, salience also affected reaction times in no-choice trials in which only one item was present, as well as error trials. Only the onset model could explain the observed reaction time distributions of error trials and no-choice trials. In contrast, the speed model could not, irrespective of whether the rate increase resulted from more frequent accumulated quanta or from larger quanta. Visual salience thus likely provides an advantage in the onset, not in the processing speed, of value-based decision making. PMID- 24167162 TI - Motion-direction specificity for adaptation-induced duration compression depends on temporal frequency. AB - Adapting to a 20 Hz oscillating grating reduces the apparent duration of a 10 Hz drifting grating displayed subsequently in the same location as the adaptor. The effect is orientation-independent as it remains once the adaptor is rotated 90 degrees relative to the tests (Johnston, Arnold, & Nishida, 2006). However, it was shown that, for random dots moving at 3 degrees /s, duration compression follows adaptation only when the adaptor and test drift in the same direction, and it disappears when they drift in opposite directions (Curran & Benton, 2012). Here, we explored the relationship between the relative motion direction of adaptor and test and the strength of duration compression for a wider range of speeds and for narrow-band stimuli (temporal frequencies between 3 and 18 Hz). We first measured perceived temporal frequency for the same stimuli after adaptation, and we used these estimates to match the apparent rate of the adapted and unadapted tests in the duration task. We found that, whereas at 3 Hz the effect of adaptation in the opposite direction on duration is marginal, at higher frequencies there is substantial duration compression in the opposite direction. These results indicate that there may be two contributions to apparent duration compression: a cortical contribution sensitive to orientation and motion direction at a wide range of temporal frequencies and a direction-independent subcortical contribution, which is revealed at higher frequencies. However, while direction specificity implies cortical involvement, subcortical orientation dependency and the influence of feedback to subcortical areas should not be ignored. PMID- 24167163 TI - The ventriloquist in periphery: impact of eccentricity-related reliability on audio-visual localization. AB - The relative reliability of separate sensory estimates influences the way they are merged into a unified percept. We investigated how eccentricity-related changes in reliability of auditory and visual stimuli influence their integration across the entire frontal space. First, we surprisingly found that despite a strong decrease in auditory and visual unisensory localization abilities in periphery, the redundancy gain resulting from the congruent presentation of audio visual targets was not affected by stimuli eccentricity. This result therefore contrasts with the common prediction that a reduction in sensory reliability necessarily induces an enhanced integrative gain. Second, we demonstrate that the visual capture of sounds observed with spatially incongruent audio-visual targets (ventriloquist effect) steadily decreases with eccentricity, paralleling a lowering of the relative reliability of unimodal visual over unimodal auditory stimuli in periphery. Moreover, at all eccentricities, the ventriloquist effect positively correlated with a weighted combination of the spatial resolution obtained in unisensory conditions. These findings support and extend the view that the localization of audio-visual stimuli relies on an optimal combination of auditory and visual information according to their respective spatial reliability. All together, these results evidence that the external spatial coordinates of multisensory events relative to an observer's body (e.g., eyes' or head's position) influence how this information is merged, and therefore determine the perceptual outcome. PMID- 24167165 TI - Influenza-associated pediatric deaths in the United States, 2004-2012. AB - BACKGROUND: Influenza-associated deaths in children occur annually. We describe the epidemiology of influenza-associated pediatric deaths from the 2004-2005 through the 2011-2012 influenza seasons. METHODS: Deaths in children <18 years of age with laboratory-confirmed influenza virus infection were reported to the Centers for Disease Control and Prevention by using a standard case report form to collect data on demographic characteristics, medical conditions, clinical course, and laboratory results. Characteristics of children with no high-risk medical conditions were compared with those of children with high-risk medical conditions. RESULTS: From October 2004 through September 2012, 830 pediatric influenza-associated deaths were reported. The median age was 7 years (interquartile range: 1-12 years). Thirty-five percent of children died before hospital admission. Of 794 children with a known medical history, 43% had no high risk medical conditions, 33% had neurologic disorders, and 12% had genetic or chromosomal disorders. Children without high-risk medical conditions were more likely to die before hospital admission (relative risk: 1.9; 95% confidence interval: 1.6-2.4) and within 3 days of symptom onset (relative risk: 1.6; 95% confidence interval: 1.3-2.0) than those with high-risk medical conditions. CONCLUSIONS: Influenza can be fatal in children with and without high-risk medical conditions. These findings highlight the importance of recommendations that all children should receive annual influenza vaccination to prevent influenza, and children who are hospitalized, who have severe illness, or who are at high risk of complications (age <2 years or with medical conditions) should receive antiviral treatment as early as possible. PMID- 24167167 TI - Conflicts between religious or spiritual beliefs and pediatric care: informed refusal, exemptions, and public funding. AB - Although respect for parents' decision-making authority is an important principle, pediatricians should report suspected cases of medical neglect, and the state should, at times, intervene to require medical treatment of children. Some parents' reasons for refusing medical treatment are based on their religious or spiritual beliefs. In cases in which treatment is likely to prevent death or serious disability or relieve severe pain, children's health and future autonomy should be protected. Because religious exemptions to child abuse and neglect laws do not equally protect all children and may harm some children by causing confusion about the duty to provide medical treatment, these exemptions should be repealed. Furthermore, public health care funds should not cover alternative unproven religious or spiritual healing practices. Such payments may inappropriately legitimize these practices as appropriate medical treatment. PMID- 24167166 TI - Nonmedical prescription opioid and sedative use among adolescents in the emergency department. AB - OBJECTIVES: Nonmedical prescription opiate use (NPOU) and nonmedical prescription sedative use (NPSU) are serious public health concerns. The objectives of this study were to determine the prevalence and emergency department (ED) visit characteristics and other correlates associated with past-year NPOU and NPSU among adolescents and young adults using the ED. METHODS: Participants aged 14 to 20 presenting to the ED at the University of Michigan Medical Center between September 2010 and September 2011 were systematically recruited. A computerized self-report screening survey with validated items measuring past-year NPOU, NPSU, substance use, and violence was delivered to participants, and a retrospective chart review was performed. RESULTS: Of the 2135 participants (86.0% response rate), 222 (10.4%) reported either NPOU or NPSU. Among the 185 (8.7%) participants that reported NPOU, 14.6% had a current home prescription for an opioid and among the 115 (5.4%) with NPSU, 12.3% had a current home prescription for a sedative. After controlling for demographics (age, gender, race, public assistance), correlates of NPOU or NPSU included other substance use, and drinking and driving or riding with a drinking driver. Additional correlates of NPOU included receiving an intravenous opioid in the ED and for NPSU, dating violence, presenting to the ED for a noninjury complaint, and previous ED visit in the past year. CONCLUSIONS: Nearly 1 in 10 young people who use the ED for care report NPOU or NPSU, and only 12.3% and 14.6% report having current home prescriptions for sedatives and opioids. The ED represents a key location for screening and intervention efforts. PMID- 24167169 TI - Fetal growth and childhood cancer: a population-based study. AB - OBJECTIVE: The etiology of childhood cancers is largely unknown. Studies have suggested that birth characteristics may be associated with risk. Our goal was to evaluate the risk of childhood cancers in relation to fetal growth. METHODS: We conducted a case-control study nested within Nordic birth registries. The study included cancer cases diagnosed in Denmark, Finland, Norway, and Sweden among children born from 1967 to 2010 and up to 10 matched controls per case, totaling 17,698 cases and 172,422 controls. Odds ratios (ORs) and 95% confidence intervals (95% CIs) were derived from conditional logistic regression. RESULTS: Risks of all childhood cancers increased with increasing birth weight (P trend <= .001). Risks of acute lymphoid leukemia and Wilms tumor were elevated when birth weight was >4000 g and of central nervous system tumors when birth weight was >4500 g. Newborns large for gestational age were at increased risk of Wilms tumor (OR: 2.1 [95% CI: 1.2-3.6]) and connective/soft tissue tumors (OR: 2.1 [95% CI: 1.1-4.4]). In contrast, the risk of acute myeloid leukemia was increased among children born small for gestational age (OR: 1.8 [95% CI: 1.1-3.1]). Children diagnosed with central nervous system tumors at <1 year of age had elevated risk with increasing head circumference (P trend < .001). Those with head circumference >39 cm had the highest risk (OR: 4.7 [95% CI: 2.5-8.7]). CONCLUSIONS: In this large, Nordic population-based study, increased risks for several childhood tumors were associated with measures of fetal growth, supporting the hypothesis that tumorigenesis manifesting in childhood is initiated in utero. PMID- 24167170 TI - Narrow vs broad-spectrum antimicrobial therapy for children hospitalized with pneumonia. AB - BACKGROUND: The 2011 Pediatric Infectious Diseases Society/Infectious Diseases Society of America community-acquired pneumonia (CAP) guideline recommends narrow spectrum antimicrobial therapy for most children hospitalized with CAP. However, few studies have assessed the effectiveness of this strategy. METHODS: Using data from 43 children's hospitals, we conducted a retrospective cohort study to compare outcomes and resource utilization among children hospitalized with CAP between 2005 and 2011 receiving either parenteral ampicillin/penicillin (narrow spectrum) or ceftriaxone/cefotaxime (broad spectrum). Children with complex chronic conditions, interhospital transfers, recent hospitalization, or the occurrence of any of the following during the first 2 calendar days of hospitalization were excluded: pleural drainage procedure, admission to intensive care, mechanical ventilation, death, or hospital discharge. RESULTS: Overall, 13,954 children received broad-spectrum therapy (89.7%) and 1610 received narrow spectrum therapy (10.3%). The median length of stay was 3 days (interquartile range 3-4) in the broad- and narrow-spectrum therapy groups (adjusted difference 0.12 days, 95% confidence interval [CI]: -0.02 to 0.26). One hundred fifty-six children (1.1%) receiving broad-spectrum therapy and 13 children (0.8%) receiving narrow-spectrum therapy were admitted to intensive care (adjusted odds ratio 0.85, 95% CI: 0.27 to 2.73). Readmission occurred for 321 children (2.3%) receiving broad-spectrum therapy and 39 children (2.4%) receiving narrow-spectrum therapy (adjusted odds ratio 0.85, 95% CI: 0.45 to 1.63). Median costs for the hospitalization were $3992 and $4375 (adjusted difference -$14.4, 95% CI: -177.1 to 148.3). CONCLUSIONS: Clinical outcomes and costs for children hospitalized with CAP are not different when treatment is with narrow- compared with broad spectrum therapy. PMID- 24167172 TI - Maternal prenatal weight gain and autism spectrum disorders. AB - BACKGROUND: The rising population of individuals identified with an autism spectrum disorder (ASD) calls for further investigation of its underlying etiology. A disturbance in the fetal steroid hormone environment may be a mechanism in which environmental and genetic risk factors interact. The mother, fetus, and placenta collectively create the fetal steroid environment. Prepregnancy BMI and pregnancy weight gain have served as markers for fetal steroid hormone exposure in other disease states. This study's objective is to determine whether prepregnancy BMI and pregnancy weight gain are associated with increased ASD risk across study designs and cohorts while controlling for important confounding variables. METHODS: A population-based Utah ASD cohort (n = 128) was ascertained in a 3-county surveillance area and gender- and age-matched to 10,920 control subjects. A second, research-based ASD cohort of Utah children (n = 288) and their unaffected siblings (n = 493) were ascertained through participation in an ASD genetics study. Prenatal variables were obtained from birth certificate records. RESULTS: ASD risk was significantly associated with pregnancy weight gain (adjusted odds ratio = 1.10, 95% confidence interval: 1.03 to 1.17; adjusted odds ratio = 1.17, 95% confidence interval: 1.01 to 1.35 for each 5 pounds of weight gained), but not prepregnancy BMI, in population and research-based cohorts, respectively. When analyses were restricted to ASD cases with normal IQ, these associations remained significant. CONCLUSIONS: ASD risk associated with a modest yet consistent increase in pregnancy weight gain suggests that pregnancy weight gain may serve as an important marker for autism's underlying gestational etiology. This justifies an investigation into phenomena that link pregnancy weight gain and ASD independent of prepregnancy BMI. PMID- 24167173 TI - Association of hospital and provider types on sickle cell disease outcomes. AB - OBJECTIVES: Adolescents and young adults (A/YA) with sickle cell disease (SCD) are hospitalized in both children's and general hospitals. We determined the effect of hospital type and provider specialty on outcomes of hospitalized A/YA with SCD and acute chest syndrome (ACS). METHODS: This retrospective cohort study used the 2007-2009 Premier Database, a large multi-institutional database, to identify 1476 patients ages 16 to 25 years with 2299 admissions with SCD and ACS discharged from 256 US hospitals from 2007 to 2009. Multilevel logistic regression and zero-truncated negative binomial regression were performed after adjustment for patient demographic, clinical, and hospital characteristics to test the association of hospital type and provider specialty on death, endotracheal intubation, simple or exchange transfusion, length of stay (LOS), and 30-day readmission. RESULTS: Of all admissions, 14 died and 45% were intubated. General hospitals had 13 deaths and were associated with higher intubation rates (predicted probability [PP], 48% [95% confidence interval (CI), 43%-52%]) and longer LOS (predicted mean LOS, 7.6 days [95% CI, 7.2-7.9]) compared with children's hospitals (PP of intubation, 24% [95% CI, 5%-42%]; and predicted mean LOS, 6.8 days [95% CI, 5.6-5.8]). There was no difference by hospital type or provider specialty in PP of simple or exchange transfusion, or 30-day readmission. CONCLUSIONS: General hospitals carry higher intubation risks for A/YA with SCD and ACS compared with children's hospitals. We need to better understand the drivers of these differences, including the role of staff expertise, hospital volume, and quality of ongoing SCD care. PMID- 24167177 TI - Bronchoscopy with N-acetylcysteine lavage in severe respiratory failure from pertussis infection. AB - Pertussis is an illness that causes significant morbidity and mortality, especially in infants younger than 3 months old. In the most severe cases, it can cause pneumonia, respiratory failure, acute respiratory distress syndrome, pulmonary hypertension, and death. There are reports of using rescue extracorporeal membrane oxygenation (ECMO) as a rescue therapy. However, the mortality of ECMO with pertussis is higher than with other causes of pediatric respiratory failure. We report here the case of a 2-month-old boy with severe respiratory failure and pulmonary hypertension who satisfied ECMO criteria but was successfully treated with repeated bronchoscopy with instillation of N acetylcysteine. Our patient's respiratory failure was refractory to multiple therapies that have shown benefit in pediatric hypoxemic respiratory failure, including open lung strategies, prone positioning, intratracheal surfactant, and inhaled nitric oxide. Although pulmonary hypertension is a key factor in most cases of fatal pertussis, the adverse effects of hyperinflation and air leaks were more important in this patient's clinical course. Because bronchiolar obstruction from inflammatory, mucous, and airway epithelial debris can be seen in severe pertussis, a regimen of repeated therapeutic bronchoscopy was initiated, and thick, inspissated secretions were retrieved. The patient's airway obstruction gradually resolved, and he eventually recovered with minimal sequelae. PMID- 24167175 TI - Cognitive-behavioral therapy for anxiety in children with high-functioning autism: a meta-analysis. AB - BACKGROUND: Anxiety is a common and impairing problem in children and adolescents with autism spectrum disorder (ASD). There is emerging evidence that cognitive behavioral therapy (CBT) could reduce anxiety in children with high-functioning ASD. OBJECTIVE: To systematically review the evidence of using CBT to treat anxiety in children and adolescents with ASD. Methods for this review were registered with PROSPERO (CRD42012002722). METHODS: We included randomized controlled trials published in English in peer-reviewed journals comparing CBT with another treatment, no treatment control, or waitlist control. Two authors independently screened 396 records obtained from database searches and hand searched relevant journals. Two authors independently extracted and reconciled all data used in analyses from study reports. RESULTS: Eight studies involving 469 participants (252 treatment, 217 comparison) met our inclusion criteria and were included in meta-analyses. Overall effect sizes for clinician- and parent rated outcome measures of anxiety across all studies were d = 1.19 and d = 1.21, respectively. Five studies that included child self-report yielded an average d = 0.68 across self-reported anxiety. CONCLUSIONS: Parent ratings and clinician ratings of anxiety are sensitive to detecting treatment change with CBT for anxiety relative to waitlist and treatment-as-usual control conditions in children with high-functioning ASD. Clinical studies are needed to evaluate CBT for anxiety against attention control conditions in samples of children with ASD that are well characterized with regard to ASD diagnosis and co-occurring anxiety symptoms. PMID- 24167179 TI - Fundamental movement skill interventions in youth: a systematic review and meta analysis. AB - BACKGROUND: Fundamental movement skill (FMS) proficiency is positively associated with physical activity and fitness levels. The objective of this study was to systematically review evidence for the benefits of FMS interventions targeting youth. METHODS: A search with no date restrictions was conducted across 7 databases. Studies included any school-, home-, or community-based intervention for typically developing youth with clear intent to improve FMS proficiency and that reported statistical analysis of FMS competence at both preintervention and at least 1 other postintervention time point. Study designs included randomized controlled trials (RCTs) using experimental and quasi-experimental designs and single group pre-post trials. Risk of bias was independently assessed by 2 reviewers. RESULTS: Twenty-two articles (6 RCTs, 13 quasi-experimental trials, 3 pre-post trials) describing 19 interventions were included. All but 1 intervention were evaluated in primary/elementary schools. All studies reported significant intervention effects for >= 1 FMS. Meta-analyses revealed large effect sizes for overall gross motor proficiency (standardized mean difference [SMD] = 1.42, 95% confidence interval [CI] 0.68-2.16, Z = 3.77, P < .0002) and locomotor skill competency (SMD = 1.42, 95% CI 0.56-2.27, Z = 3.25, P = .001). A medium effect size for object control skill competency was observed (SMD = 0.63, 95% CI 0.28-0.98, Z = 3.53, P = .0004). Many studies scored poorly for risk of bias items. CONCLUSIONS: School- and community-based programs that include developmentally appropriate FMS learning experiences delivered by physical education specialists or highly trained classroom teachers significantly improve FMS proficiency in youth. PMID- 24167181 TI - Hypospadias and residential proximity to pesticide applications. AB - BACKGROUND: Experimental evidence suggests pesticides may be associated with hypospadias. OBJECTIVE: Examine the association of hypospadias with residential proximity to commercial agricultural pesticide applications. METHODS: The study population included male infants born from 1991 to 2004 to mothers residing in 8 California counties. Cases (n = 690) were ascertained by the California Birth Defects Monitoring Program; controls were selected randomly from the birth population (n = 2195). We determined early pregnancy exposure to pesticide applications within a 500-m radius of mother's residential address, using detailed data on applications and land use. Associations with exposures to physicochemical groups of pesticides and specific chemicals were assessed using logistic regression adjusted for maternal race or ethnicity and age and infant birth year. RESULTS: Forty-one percent of cases and controls were classified as exposed to 57 chemical groups and 292 chemicals. Despite >500 statistical comparisons, there were few elevated odds ratios with confidence intervals that excluded 1 for chemical groups or specific chemicals. Those that did were for monochlorophenoxy acid or ester herbicides; the insecticides aldicarb, dimethoate, phorate, and petroleum oils; and adjuvant polyoxyethylene sorbitol among all cases; 2,6-dinitroaniline herbicides, the herbicide oxyfluorfen, and the fungicide copper sulfate among mild cases; and chloroacetanilide herbicides, polyalkyloxy compounds used as adjuvants, the insecticides aldicarb and acephate, and the adjuvant nonyl-phenoxy-poly(ethylene oxy)ethanol among moderate and severe cases. Odds ratios ranged from 1.9 to 2.9. CONCLUSIONS: Most pesticides were not associated with elevated hypospadias risk. For the few that were associated, results should be interpreted with caution until replicated in other study populations. PMID- 24167182 TI - Image-guided volumetric modulated arc therapy for breast cancer: a feasibility study and plan comparison with three-dimensional conformal and intensity modulated radiotherapy. AB - OBJECTIVE: To test the feasibility of volumetric modulated arc therapy (VMAT) in breast cancer and to compare it with three-dimensional conformal radiotherapy (3D CRT) as conventional tangential field radiotheraphy (conTFRT). METHODS: 12 patients (Stage I, 8: 6 left breast cancer and 2 right breast cancer; Stage II, 4: 2 on each side). Three plans were calculated for each case after breast conserving surgery. Breast was treated with 50 Gy in four patients with supraclavicular lymph node inclusion, and in eight patients without the node inclusion. Multiple indices and dose parameters were measured. RESULTS: V95% was not achieved by any modality. Heterogeneity index: 0.16 (VMAT), 0.13 [intensity modulated radiotherapy (IMRT)] and 0.14 (conTFRT). Conformity index: 1.06 (VMAT), 1.15 (IMRT) and 1.69 (conTFRT). For both indices, IMRT was more effective than VMAT (p=0.009, p=0.002). Dmean and V20 for ipsilateral lung were lower for IMRT than VMAT (p=0.0001, p=0.003). Dmean, V2 and V5 of contralateral lung were lower for IMRT than VMAT (p>0.0001, p=0.005). Mean dose and V5 to the heart were lower for IMRT than for VMAT (p=0.015, p=0.002). CONCLUSION: The hypothesis of equivalence of VMAT to IMRT was not confirmed for planning target volume parameter or dose distribution to organs at risk. VMAT was inferior to IMRT and 3D-CRT with regard to dose distribution to organs at risk, especially at the low dose level. ADVANCES IN KNOWLEDGE: New technology VMAT is not superior to IMRT or conventional radiotherapy in breast cancer in any aspect. PMID- 24167184 TI - Differences in breast density assessment using mammography, tomosynthesis and MRI and their implications for practice. PMID- 24167183 TI - Clinical-dosimetric relationship between lacrimal gland dose and ocular toxicity after intensity-modulated radiotherapy for sinonasal tumours. AB - OBJECTIVE: To characterise the relationship between lacrimal gland dose and ocular toxicity among patients treated by intensity-modulated radiotherapy (IMRT) for sinonasal tumours. METHODS: 40 patients with cancers involving the nasal cavity and paranasal sinuses were treated with IMRT to a median dose of 66.0 Gy. Toxicity was scored using the Radiation Therapy Oncology Group morbidity criteria based on conjunctivitis, corneal ulceration and keratitis. The paired lacrimal glands were contoured as organs at risk, and the mean dose, maximum dose, V10, V20 and V30 were determined. Statistical analysis was performed using logistic regression and the Akaike information criterion (AIC). RESULTS: The maximum and mean dose to the ipsilateral lacrimal gland were 19.2 Gy (range, 1.4-75.4 Gy) and 14.5 Gy (range, 11.1-67.8 Gy), respectively. The mean V10, V20 and V30 values were 50%, 25% and 17%, respectively. The incidence of acute and late Grade 3+ toxicities was 23% and 19%, respectively. Based on logistic regression and AIC, the maximum dose to the ipsilateral lacrimal gland was identified as a more significant predictor of acute toxicity (AIC, 53.89) and late toxicity (AIC, 32.94) than the mean dose (AIC, 56.13 and 33.83, respectively). The V20 was identified as the most significant predictor of late toxicity (AIC, 26.81). CONCLUSION: A dose-response relationship between maximum dose to the lacrimal gland and ocular toxicity was established. Our data suggesting a threshold relationship may be useful in establishing dosimetric guidelines for IMRT planning that may decrease the risk of acute and late lacrimal toxicities in the future. ADVANCES IN KNOWLEDGE: A threshold relationship between radiation dose to the lacrimal gland and ocular toxicity was demonstrated, which may aid in treatment planning and reducing the morbidity of radiotherapy for sinonasal tumours. PMID- 24167186 TI - A 12-cm mass with no symptoms and unremarkable laboratory results. PMID- 24167187 TI - Commentary. PMID- 24167188 TI - Commentary. PMID- 24167185 TI - "Dazed and diffused": making sense of diffusion abnormalities in neurologic pathologies. AB - To review diffusion abnormalities seen in diffusion-weighted MRI in neurological pathologies. We examine the clinical significance of the abnormalities in a broad spectrum of neurological diseases and highlight our current understanding of their causes. Diffusion abnormalities seen on diffusion-weighted MRI can play an important role in the diagnosis and follow-up of a broad spectrum of neurological diseases. A thorough understanding of the appearance and significance of these abnormalities is critical in patient management. PMID- 24167189 TI - Abdominal pain and increased CA19-9. PMID- 24167190 TI - A test in development. PMID- 24167191 TI - Clinical case conference--an alliteration. PMID- 24167193 TI - Andreas Vesalius: his science, teaching, and exceptional books. PMID- 24167194 TI - The importance of non-exercise physical activity for cardiovascular health and longevity. AB - BACKGROUND: Sedentary time is increasing in all societies and results in limited non-exercise physical activity (NEPA) of daily life. The importance of low NEPA for cardiovascular health and longevity is limited, especially in elderly. AIM: To examine the association between NEPA and cardiovascular health at baseline as well as the risk of a first cardiovascular disease (CVD) event and total mortality after 12.5 years. STUDY DESIGN: Cohort study. MATERIAL AND METHODS: Every third 60-year-old man and woman in Stockholm County was invited to a health screening study; 4232 individuals participated (78% response rate). At baseline, NEPA and exercise habits were assessed from a self-administrated questionnaire and cardiovascular health was established through physical examinations and laboratory tests. The participants were followed for an average of 12.5 years for the assessment of CVD events and mortality. RESULTS: At baseline, high NEPA was, regardless of regular exercise and compared with low NEPA, associated with more preferable waist circumference, high-density lipoprotein cholesterol and triglycerides in both sexes and with lower insulin, glucose and fibrinogen levels in men. Moreover, the occurrence of the metabolic syndrome was significantly lower in those with higher NEPA levels in non-exercising and regularly exercising individuals. Furthermore, reporting a high NEPA level, compared with low, was associated with a lower risk of a first CVD event (HR=0.73; 95% CI 0.57 to 0.94) and lower all-cause mortality (0.70; 0.53 to 0.98). CONCLUSIONS: A generally active daily life was, regardless of exercising regularly or not, associated with cardiovascular health and longevity in older adults. PMID- 24167195 TI - A DNMT3A mutation common in AML exhibits dominant-negative effects in murine ES cells. AB - Somatic heterozygous mutations of the DNA methyltransferase gene DNMT3A occur frequently in acute myeloid leukemia and other hematological malignancies, with the majority (~60%) of mutations affecting a single amino acid, Arg882 (R882), in the catalytic domain. Although the mutations impair DNMT3A catalytic activity in vitro, their effects on DNA methylation in cells have not been explored. Here, we show that exogenously expressed mouse Dnmt3a proteins harboring the corresponding R878 mutations largely fail to mediate DNA methylation in murine embryonic stem (ES) cells but are capable of interacting with wild-type Dnmt3a and Dnmt3b. Coexpression of the Dnmt3a R878H (histidine) mutant protein results in inhibition of the ability of wild-type Dnmt3a and Dnmt3b to methylate DNA in murine ES cells. Furthermore, expression of Dnmt3a R878H in ES cells containing endogenous Dnmt3a or Dnmt3b induces hypomethylation. These results suggest that the DNMT3A R882 mutations, in addition to being hypomorphic, have dominant-negative effects. PMID- 24167197 TI - Surgeon who operated without insurance is suspended. PMID- 24167196 TI - Pharmacologic increase in HIF1alpha enhances hematopoietic stem and progenitor homing and engraftment. AB - Hematopoietic stem cell (HSC) transplantation is a lifesaving therapy for a number of immunologic disorders. For effective transplant, HSCs must traffic from the peripheral blood to supportive bone marrow niches. We previously showed that HSC trafficking can be enhanced by ex vivo treatment of hematopoietic grafts with 16-16 dimethyl prostaglandin E2 (dmPGE2). While exploring regulatory molecules involved in dmPGE2 enhancement, we found that transiently increasing the transcription factor hypoxia-inducible factor 1-alpha (HIF1alpha) is required for dmPGE2-enhanced CXCR4 upregulation and enhanced migration and homing of stem and progenitor cells and that pharmacologic manipulation of HIF1alpha is also capable of enhancing homing and engraftment. We also now identify the specific hypoxia response element required for CXCR4 upregulation. These data define a precise mechanism through which ex vivo pulse treatment with dmPGE2 enhances the function of hematopoietic stem and progenitor cells; these data also define a role for hypoxia and HIF1alpha in enhancement of hematopoietic transplantation. PMID- 24167198 TI - Short- and long-term associations between widowhood and mortality in the United States: longitudinal analyses. AB - BACKGROUND: Past research shows that spousal death results in elevated mortality risk for the surviving spouse. However, most prior studies have inadequately controlled for socioeconomic status (SES), and it is unclear whether this 'widowhood effect' persists over time. METHODS: Health and Retirement Study participants aged 50+ years and married in 1998 (n = 12 316) were followed through 2008 for widowhood status and mortality (2912 deaths). Discrete-time survival analysis was used to compare mortality for the widowed versus the married. RESULTS: Odds of mortality during the first 3 months post-widowhood were significantly higher than in the continuously married (odds ratio (OR) for men = 1.87, 95% CI: 1.27, 2.75; OR for women = 1.47, 95% CI: 0.96, 2.24) in models adjusted for age, gender, race and baseline SES (education, household wealth and household income), behavioral risk factors and co-morbidities. Twelve months following bereavement, men experienced borderline elevated mortality (OR = 1.16, 95% CI: 1.00, 1.35), whereas women did not (OR = 1.07, 95% CI: 0.90, 1.28), though the gender difference was non-significant. CONCLUSION: The 'widowhood effect' was not fully explained by adjusting for pre-widowhood SES and particularly elevated within the first few months after widowhood. These associations did not differ by sex. PMID- 24167199 TI - Enabling patients with respiratory symptoms to access chest X-rays on demand: the experience of the walk-in service in Corby, UK. AB - BACKGROUND: UK clinical guidance for lung cancer (NICE 141) includes pathways for chest X-rays (CXRs). Many patients fulfilling the criteria do not receive one, either because they do not consult their doctor or because their doctor does not refer them. The town of Corby, UK, has particularly high incidence and mortality rates for lung cancer and was chosen as a pilot site for a new, patient-requested X-ray service. METHODS: The number of community-initiated CXRs were compared before and after the introduction of the service and between similar geographical areas. Clinical data and patient questionnaires were analysed for those attending the service. RESULTS: There was a 63% increase in the total number of community initiated CXRs in Corby for the year following the introduction of the service, compared with the year before. This was statistically greater than in surrounding geographical areas. Corby General Practitioners also requested 47% more CXRs than in the previous year. CONCLUSIONS: The implementation of the service was associated with a significant increase in the numbers of clinically indicated CXRs in an area of high lung cancer incidence and mortality. The service attracted a clinically appropriate population. The numbers of cancers detected were in line with statistical expectations. PMID- 24167200 TI - An adult with a neck lump. AB - A 40 year old man presents with a 1 cm tender soft swelling in the lateral neck region. This developed seven days after the onset of a tonsillitis episode that has now resolved. He has a 20 pack-year smoking history and consumes minimal alcohol. Examination is otherwise normal. PMID- 24167201 TI - India has a problem with palm oil. PMID- 24167202 TI - Act now to fight chronic procrastination disorder. PMID- 24167203 TI - Is closure of patent foramen ovale to prevent ischaemic stroke ever justified? PMID- 24167204 TI - The rise and further rise of concierge medicine. PMID- 24167205 TI - Government's choice to chair Monitor drops out after MPs reject his appointment. PMID- 24167206 TI - We might get a lot from a province-wide colon screening program, but maybe not peace of mind. PMID- 24167207 TI - CIHR cuts grants for in-depth health journalism to focus on social media. PMID- 24167209 TI - Changes ahead for Medical Council of Canada qualifying exams. PMID- 24167208 TI - Incidence of neurologic death among patients with brain injury: a cohort study in a Canadian health region. AB - BACKGROUND: Hospital mortality has decreased over time for critically ill patients with various forms of brain injury. We hypothesized that the proportion of patients who progress to neurologic death may have also decreased. METHODS: We performed a prospective cohort study involving consecutive adult patients with traumatic brain injury, subarachnoid hemorrhage, intracerebral hemorrhage or anoxic brain injury admitted to regional intensive care units in southern Alberta over a 10.5-year period. We used multivariable logistic regression to adjust for patient age and score on the Glasgow Coma Scale at admission, and to assess whether the proportion of patients who progress to neurologic death has changed over time. RESULTS: The cohort consisted of 2788 patients. The proportion of patients who progressed to neurologic death was 8.1% at the start of the study period, and the adjusted odds of progressing to neurologic death decreased over the study period (odds ratio [OR] per yr 0.92, 95% confidence interval [CI] 0.87 0.98, p = 0.006). This change was most pronounced among patients with traumatic brain injury (OR per yr 0.87, 95% CI 0.78-0.96, p = 0.005); there was no change among patients with anoxic injury (OR per yr 0.96, 95% CI 0.85-1.09, p = 0.6). A review of the medical records suggests that missed cases of neurologic death were rare (<= 0.5% of deaths). INTERPRETATION: The proportion of patients with brain injury who progress to neurologic death has decreased over time, especially among those with head trauma. This finding may reflect positive developments in the prevention and care of brain injury. However, organ donation after neurologic death represents the major source of organs for transplantation. Thus, these findings may help explain the relatively stagnant rates of deceased organ donation in some regions of Canada, which in turn has important implications for the care of patients with end-stage organ failure. PMID- 24167210 TI - Canada-EU trade agreement expected to increase drug costs. PMID- 24167212 TI - Access to patient services lacking: National Physician Survey. PMID- 24167214 TI - Intrapartum care of the HIV-positive woman. PMID- 24167215 TI - Health Canada to improve drug recall process. PMID- 24167216 TI - Unusual venous thrombosis in a 35-year-old man. PMID- 24167217 TI - Advocating for equality for preterm infants. PMID- 24167218 TI - Obama promises to fix flawed health insurance website. PMID- 24167219 TI - Indian Supreme Court rejects bid for panel to be established to regulate soft drinks. PMID- 24167220 TI - Selective inhibition of cytochrome P450 2D6 by Sarpogrelate and its active metabolite, M-1, in human liver microsomes. AB - The present study was performed to evaluate the in vitro inhibitory potential of sarpogrelate and its active metabolite, M-1, on the activities of nine human cytochrome (CYP) isoforms. Using a cocktail assay, the effects of sarpogrelate on nine CYP isoforms and M-1 were measured by specific marker reactions in human liver microsomes. Sarpogrelate potently and selectively inhibited CYP2D6-mediated dextromethorphan O-demethylation with an IC50 (Ki) value of 3.05 MUM (1.24 MUM), in a competitive manner. M-1 also markedly inhibited CYP2D6 activity; its inhibitory effect with an IC50 (Ki) value of 0.201 MUM (0.120 MUM) was more potent than that of sarpogrelate, and was similarly potent as quinidine (Ki, 0.129 MUM), a well-known typical CYP2D6 inhibitor. In addition, sarpogrelate and M-1 strongly inhibited both CYP2D6-catalyzed bufuralol 1'-hydroxylation and metoprolol alpha-hydroxylation activities. However, sarpogrelate and M-1 showed no apparent inhibition of the other following eight CYPs: CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2E1, or CYP3A4/5. Upon 30-minute preincubation of human liver microsomes with sarpogrelate or M-1 in the presence of NADPH, no obvious shift in IC50 was observed in terms of inhibition of the nine CYP activities, suggesting that sarpogrelate and M-1 are not time-dependent inactivators. Sarpogrelate strongly inhibited the activity of CYP2D6 at clinically relevant concentrations in human liver microsomes. These observations suggest that sarpogrelate could have an effect on the metabolic clearance of drugs possessing CYP2D6-catalyzed metabolism as a major clearance pathway, thereby eliciting pharmacokinetic drug-drug interactions. PMID- 24167221 TI - Over 60% of US adolescents have experienced a potentially traumatic event, almost 8% of whom have associated PTSD. PMID- 24167222 TI - A cellular memory mechanism aids overload hypertrophy in muscle long after an episodic exposure to anabolic steroids. AB - Previous strength training with or without the use of anabolic steroids facilitates subsequent re-acquisition of muscle mass even after long intervening periods of inactivity. Based on in vivo and ex vivo microscopy we here propose a cellular memory mechanism residing in the muscle cells. Female mice were treated with testosterone propionate for 14 days, inducing a 66% increase in the number of myonuclei and a 77% increase in fibre cross-sectional area. Three weeks after removing the drug, fibre size was decreased to the same level as in sham treated animals, but the number of nuclei remained elevated for at least 3 months (>10% of the mouse lifespan). At this time, when the myonuclei-rich muscles were exposed to overload-exercise for 6 days, the fibre cross-sectional area increased by 31% while control muscles did not grow significantly. We suggest that the lasting, elevated number of myonuclei constitutes a cellular memory facilitating subsequent muscle overload hypertrophy. Our findings might have consequences for the exclusion time of doping offenders. Since the ability to generate new myonuclei is impaired in the elderly our data also invites speculation that it might be beneficial to perform strength training when young in order to benefit in senescence. PMID- 24167223 TI - Exercise counteracts the effects of short-term overfeeding and reduced physical activity independent of energy imbalance in healthy young men. AB - Physical activity can affect many aspects of metabolism but it is unclear to what extent this relies on manipulation of energy balance. Twenty-six active men age 25 +/- 7 years (mean +/- SD) were randomly assigned either to consume 50% more energy than normal by over-consuming their habitual diet for 7 days whilst simultaneously restricting their physical activity below 4000 steps day(-1) to induce an energy surplus (SUR group; n = 14) or to the same regimen but with 45 min of daily treadmill running at 70% of maximum oxygen uptake (SUR+EX group; n = 12). Critically, the SUR+EX group received additional dietary energy intake to account for the energy expended by exercise, thus maintaining a matched energy surplus. At baseline and follow-up, fasted blood samples and abdominal subcutaneous adipose tissue biopsies were obtained and oral glucose tolerance tests conducted. Insulinaemic responses to a standard glucose load increased 2 fold from baseline to follow-up in the SUR group (17 +/- 16 nmol (120 min) l(-1); P = 0.002) whereas there was no change in the SUR+EX group (1 +/- 6 nmol (120 min) l(-1)). Seven of 17 genes within adipose tissue were differentially expressed in the SUR group; expression of SREBP-1c, FAS and GLUT4 was significantly up-regulated and expression of PDK4, IRS2, HSL and visfatin was significantly down-regulated (P <= 0.05). The pAMPK/AMPK protein ratio in adipose tissue was significantly down-regulated in the SUR group (P = 0.005). Vigorous intensity exercise counteracted most of the effects of short-term overfeeding and under-activity at the whole-body level and in adipose tissue, even in the face of a standardised energy surplus. PMID- 24167224 TI - Cellular properties and chemosensory responses of the human carotid body. AB - The carotid body (CB) is the major peripheral arterial chemoreceptor in mammals that mediates the acute hyperventilatory response to hypoxia. The CB grows in response to sustained hypoxia and also participates in acclimatisation to chronic hypoxaemia. Knowledge of CB physiology at the cellular level has increased considerably in recent times thanks to studies performed on lower mammals, and rodents in particular. However, the functional characteristics of human CB cells remain practically unknown. Herein, we use tissue slices or enzymatically dispersed cells to determine the characteristics of human CB cells. The adult human CB parenchyma contains clusters of chemosensitive glomus (type I) and sustentacular (type II) cells as well as nestin-positive progenitor cells. This organ also expresses high levels of the dopaminotrophic glial cell line-derived neurotrophic factor (GDNF). We found that GDNF production and the number of progenitor and glomus cells were preserved in the CBs of human subjects of advanced age. Moreover, glomus cells exhibited voltage-dependent Na(+), Ca(2+) and K(+) currents that were qualitatively similar to those reported in lower mammals. These cells responded to hypoxia with an external Ca(2+)-dependent increase of cytosolic Ca(2+) and quantal catecholamine secretion, as reported for other mammalian species. Interestingly, human glomus cells are also responsive to hypoglycaemia and together these two stimuli can potentiate each other's effects. The chemosensory responses of glomus cells are also preserved at an advanced age. These new data on the cellular and molecular physiology of the CB pave the way for future pathophysiological studies involving this organ in humans. PMID- 24167225 TI - Physiological roles of glucocorticoids during early embryonic development of the zebrafish (Danio rerio). AB - While glucocorticoids (GCs) are known to be present in the zebrafish embryo, little is known about their physiological roles at this stage. We hypothesised that GCs play key roles in stress response, hatching and swim activity during early development. To test this, whole embryo cortisol (WEC) and corticosteroid related genes were measured in embryos from 6 to 120 h post fertilisation (hpf) by enzyme linked immunosorbent assay (ELISA) and quantitative real-time polymerase chain reaction (qRT-PCR). Stress response was assessed by change in WEC following stirring, hypoxia or brief electrical impulses applied to the bathing water. The impact of pharmacological and molecular GC manipulation on the stress response, spontaneous hatching and swim activity at different stages of development was also assessed. WEC levels demonstrated a biphasic pattern during development with a decrease from 0 to 36 hpf followed by a progressive increase towards 120 hpf. This was accompanied by a significant and sustained increase in the expression of genes encoding cyp11b1 (GC biosynthesis), hsd11b2 (GC metabolism) and gr (GC receptor) from 48 to 120 hpf. Metyrapone (Met), an inhibitor of 11beta-hydroxylase (encoded by cyp11b1), and cyp11b1 morpholino (Mo) knockdown significantly reduced basal and stress-induced WEC levels at 72 and 120 hpf but not at 24 hpf. Spontaneous hatching and swim activity were significantly affected by manipulation of GC action from approximately 48 hpf onwards. We have identified a number of key roles of GCs in zebrafish embryos contributing to adaptive physiological responses under adverse conditions. The ability to alter GC action in the zebrafish embryo also highlights its potential value for GC research. PMID- 24167228 TI - Development of pre-deployment primary healthcare training for Combat Medical Technicians. AB - INTRODUCTION: To develop and run a primary healthcare (PHC) refresher package to address the range of clinical presentations to Combat Medical Technicians (CMTs) on deployment and improve their confidence and capability in providing PHC for Op Herrick 18, with particular regard to the first month of deployment. METHODS: A regimental level, two-and-a-half day refresher package was developed following analysis of PHC conditions most likely to be seen on Op HERRICK 18. It consisted of lectures and skill stations with written and case-based assessment phases to demonstrate effective and safe use of CMT clinical protocols on simulated patients. Internal feedback assessed the CMT's subjective understanding of each individual section. A qualitative questionnaire was used to retrospectively evaluate the package after 1 month of deployment. RESULTS: Immediate feedback showed that the refresher training was well received. Following the first month of deployment, CMTs who had attended the PHC refresher package felt more confident in managing PHC patients and felt they had received training for the majority of PHC conditions witnessed during their deployment in comparison with CMTs who had not. DISCUSSION: By delivering a training package acceptable to the majority of medics, we have increased the confidence and capability of CMTs in delivering PHC within the context of their protocols and prepared them for their first month of deployment. It suggests that PHC delivery can be improved by such a package and consideration should be given to formalising this into a military training qualification. PMID- 24167226 TI - Down-regulation of CaV1.2 channels during hypertension: how fewer CaV1.2 channels allow more Ca(2+) into hypertensive arterial smooth muscle. AB - Hypertension is a clinical syndrome characterized by increased arterial tone. Although the mechanisms are varied, the generally accepted view is that increased CaV1.2 channel function is a common feature of this pathological condition. Here, we investigated the mechanisms underlying vascular dysfunction in a mouse model of genetic hypertension. Contrary to expectation, we found that whole-cell CaV1.2 currents (ICa) were lower in hypertensive (BPH line) than normotensive (BPN line) myocytes. However, local CaV1.2 sparklet activity was higher in BPH cells, suggesting that the relatively low ICa in these cells was produced by a few hyperactive CaV1.2 channels. Furthermore, our data suggest that while the lower expression of the pore-forming alpha1c subunit of CaV1.2 currents underlies the lower ICa in BPH myocytes, the increased sparklet activity was due to a different composition in the auxiliary subunits of the CaV1.2 complexes. ICa currents in BPN cells were produced by channels composed of alpha1c/alpha2delta/beta3 subunits, while in BPH myocytes currents were probably generated by the opening of channels formed by alpha1c/alpha2delta/beta2 subunits. In addition, Ca(2+) sparks evoked large conductance, Ca(2+)-activated K(+) (BK) currents of lower magnitude in BPH than in BPN myocytes, because BK channels were less sensitive to Ca(2+). Our data are consistent with a model in which a decrease in the global number of CaV1.2 currents coexist with the existence of a subpopulation of highly active channels that dominate the resting Ca(2+) influx. The decrease in BK channel activity makes the hyperpolarizing brake ineffective and leads BPH myocytes to a more contracted resting state. PMID- 24167229 TI - Conversational and narrative speaking in adolescents: examining the use of complex syntax. AB - PURPOSE: Few tools are available to examine the narrative speaking ability of adolescents. Hence, the authors designed a new narrative task and sought to determine whether it would elicit a higher level of syntactic complexity than a conversational task in adolescents with typical language development. METHOD: Forty adolescents (Mage = 14;0 [years;months]; 20 boys and 20 girls) were individually interviewed. Each adolescent participated in a standard conversational task followed by a narrative task that involved listening to fables and retelling the stories. It was predicted that the narrative task would elicit a higher level of syntactic complexity than the conversational task because fables, although superficially simple stories, express rather sophisticated meanings. RESULTS: The narrative task elicited greater syntactic complexity than the conversational task as measured by mean length of C-unit and clausal density. Additionally, the 2 syntactic measures, mean length of C-unit and clausal density, were closely associated on both tasks. CONCLUSION: Fables can elicit a high level of syntactic complexity in adolescents with typical language development. Future studies are needed to build a normative database using fables. PMID- 24167230 TI - Increase in speech recognition due to linguistic mismatch between target and masker speech: monolingual and simultaneous bilingual performance. AB - PURPOSE: To examine whether improved speech recognition during linguistically mismatched target-masker experiments is due to linguistic unfamiliarity of the masker speech or linguistic dissimilarity between the target and masker speech. METHOD: Monolingual English speakers (n = 20) and English-Greek simultaneous bilinguals (n = 20) listened to English sentences in the presence of competing English and Greek speech. Data were analyzed using mixed-effects regression models to determine differences in English recogition performance between the 2 groups and 2 masker conditions. RESULTS: Results indicated that English sentence recognition for monolinguals and simultaneous English-Greek bilinguals improved when the masker speech changed from competing English to competing Greek speech. CONCLUSION: The improvement in speech recognition that has been observed for linguistically mismatched target-masker experiments cannot be simply explained by the masker language being linguistically unknown or unfamiliar to the listeners. Listeners can improve their speech recognition in linguistically mismatched target-masker experiments even when the listener is able to obtain meaningful linguistic information from the masker speech. PMID- 24167231 TI - Videofluoroscopic investigation of body position on articulatory positioning. AB - PURPOSE: To quantitatively examine the effects of body position on the positioning of the epiglottis, tongue, and velum at rest and during speech. METHOD: Videofluoroscopic data were obtained from 12 healthy adults in the supine and upright positions at rest and during speech while the participants produced 12 VCV sequences. The effects of body position, target sounds, and adjacent sounds on structural positioning and vowel formant structure were investigated. RESULTS: Velar retropositioning in the supine position was the most consistent pattern observed at rest. During speech, all structures, with varying degrees of adjustment, appeared to work against the gravitational pull, resulting in no significant narrowing in the oro- and nasopharyngeal regions while in the supine position. Minimal differences in the formant data between the body positions were also observed. Overall, structural positioning was significantly dependent on the target and adjacent sounds regardless of body position. CONCLUSIONS: The present study demonstrated that structural positioning in response to gravity varied across individuals based on the type of activities being performed. With varying degrees of positional adjustment across different structures, fairly consistent articulatory positioning in the anterior-posterior dimension was maintained in different body positions during speech. PMID- 24167232 TI - Barium versus nonbarium stimuli: differences in taste intensity, chemesthesis, and swallowing behavior in healthy adult women. AB - PURPOSE: The authors examined the impact of barium on the perceived taste intensity of 7 different liquid tastant stimuli and the modulatory effect that these differences in perceived taste intensity have on swallowing behaviors. METHOD: Participants were 80 healthy women, stratified by age group (<40; >60) and genetic taste status (supertasters; nontasters). Perceived taste intensity and chemesthetic properties (fizziness; burning-stinging) were rated for 7 tastant solutions (each prepared with and without barium) using the general Labeled Magnitude Scale. Tongue-palate pressures and submental surface electromyography (sEMG) were simultaneously measured during swallowing of these same randomized liquids. Path analysis differentiated the effects of stimulus, genetic taste status, age, barium condition, taste intensity, and an effortful saliva swallow strength covariate on swallowing. RESULTS: Barium stimuli were rated as having reduced taste intensity compared with nonbarium stimuli. Barium also dampened fizziness but did not influence burning-stinging sensation. The amplitudes of tongue-palate pressure or submental sEMG did not differ when swallowing barium versus nonbarium stimuli. CONCLUSIONS: Despite impacting taste intensity, the addition of barium to liquid stimuli does not appear to alter behavioral parameters of swallowing. Barium solutions can be considered to elicit behaviors that are similar to those used with nonbarium liquids outside the assessment situation. PMID- 24167233 TI - Objective quantification of pre- and postphonosurgery vocal fold vibratory characteristics using high-speed videoendoscopy and a harmonic waveform model. AB - PURPOSE: The model-based quantitative analysis of high-speed videoendoscopy (HSV) data at a low frame rate of 2,000 frames per second was assessed for its clinical adequacy. Stepwise regression was employed to evaluate the HSV parameters using harmonic models and their relationships to the Voice Handicap Index (VHI). Also, the model-based HSV parameters were compared with those using conventional analysis techniques. METHOD: Eight pairs of HSV recordings of vocal folds before and after surgery for benign lesions were investigated. Five glottal area waveform features-fundamental frequency (F0), open quotient (OQ), speed index (SI), relative glottal gap (RGG), and harmonics-to-noise ratio (HNR)-were measured using model-based and conventional approaches. The statistical analyses were conducted on the mean (M) and standard deviation (SD) of the feature measurements over 1 s during sustained phonation. RESULTS: Two model-based HSV parameters, OQ M (rho = .67) and HNR M (rho = -.56), were selected and explained 55% of the VHI variation. The conventional techniques yielded a regression model with OQ SD (rho = -.60) and F0 SD (rho = .44), explaining 61% of the VHI variation. CONCLUSIONS: Although the selected model-based HSV parameters explained less variation in the VHI than the conventionally computed HSV parameters, the behaviors of the model-based parameters were more consistent with expectations and theory than the conventional analysis techniques. PMID- 24167234 TI - Language impairment from 4 to 12 years: prediction and etiology. AB - PURPOSE: The authors of this article examined the etiology of developmental language impairment (LI) at 4 and 12 years of age, as well as the relationship between the 2. METHOD: Phenotypic and quantitative genetic analyses using longitudinal data from the Twins Early Development Study (Oliver & Plomin, 2007) were conducted. A total of 2,923 pairs of twins (1,075 monozygotic [MZ]; 975 dizygotic same sex [DZss]; and 873 dizygotic opposite sex [DZos]) provided data at 4 and 12 years. At 4 years, (a) psychometric LI was defined on the basis of a low parent-reported expressive vocabulary score (-1.25 SDs; 226 MZ and 115 DZss probands for genetic analysis); and (b) parent referral was defined as having seen a medical professional or speech-language pathologist following parental concern (112 MZ and 104 DZss probands). The 12-year language measure was a composite of 4 web-administered receptive language tests. RESULTS: (a) Psychometric LI at 4 years is more predictive than parent referral of poor language performance at age 12 years, and (b) parent referral is substantially and significantly more heritable than psychometric LI. CONCLUSIONS: Parents' concern about their child's language development seems to be the marker of a more heritable disorder than poor expressive language skills alone. However, the language difficulties that arouse parental concern in preschool children, although more heritable, are not predictive of language difficulties in early adolescence. Rather, poor expressive language skills at age 4 years, psychometrically defined, are a better predictor than parent referral of continuing language difficulties at age 12 years. PMID- 24167235 TI - Perceptual learning of acoustic noise by individuals with dyslexia. AB - PURPOSE: A phonological deficit is thought to affect most individuals with developmental dyslexia. The present study addresses whether the phonological deficit is caused by difficulties with perceptual learning of fine acoustic details. METHOD: A demanding test of nonverbal auditory memory, "noise learning," was administered to both adults with dyslexia and control adult participants. On each trial, listeners had to decide whether a stimulus was a 1-s noise token or 2 abutting presentations of the same 0.5-s noise token (repeated noise). Without the listener's knowledge, the exact same noise tokens were presented over many trials. An improved ability to perform the task for such "reference" noises reflects learning of their acoustic details. RESULTS: Listeners with dyslexia did not differ from controls in any aspect of the task, qualitatively or quantitatively. They required the same amount of training to achieve discrimination of repeated from nonrepeated noises, and they learned the reference noises as often and as rapidly as the control group. However, they did show all the hallmarks of dyslexia, including a well-characterized phonological deficit. CONCLUSION: The data did not support the hypothesis that deficits in basic auditory processing or nonverbal learning and memory are the cause of the phonological deficit in dyslexia. PMID- 24167236 TI - Influence of embedded fibers and an epithelium layer on the glottal closure pattern in a physical vocal fold model. AB - PURPOSE The purpose of this study was to explore the possible structural and material property features that may facilitate complete glottal closure in an otherwise isotropic physical vocal fold model. METHOD Seven vocal fold models with different structural features were used in this study. An isotropic model was used as the baseline model, and other models were modified from the baseline model by either embedding fibers aligned along the anterior-posterior direction in the body or cover layer, adding a stiffer outer layer simulating the epithelium layer, or a combination of the 2 features. Phonation tests were performed with both aerodynamic and acoustic measurements and high-speed imaging of vocal fold vibration. RESULTS Compared with the isotropic one-layer model, the presence of a stiffer epithelium layer led to complete glottal closure along the anterior-posterior direction and strong excitation of high-order harmonics in the resulting acoustic spectra. Similar improvements were observed with fibers embedded in the cover layer, but to a lesser degree. The presence of fibers in the body layer did not yield noticeable improvements in glottal closure or harmonic excitation. CONCLUSION This study shows that the presence of collagen and elastin fibers and the epithelium layer may play a critical role in achieving complete glottal closure. PMID- 24167237 TI - Coordination of gaze and speech in communication between children with hearing impairment and normal-hearing peers. AB - PURPOSE: To investigate gaze behavior during communication between children with hearing impairment (HI) and normal-hearing (NH) peers. METHOD: Ten HI-NH and 10 NH-NH dyads performed a referential communication task requiring description of faces. During task performance, eye movements and speech were tracked. Using verbal event (questions, statements, back channeling, and silence) as the predictor variable, group characteristics in gaze behavior were expressed with Kaplan-Meier survival functions (estimating time to gaze-to-partner) and odds ratios (comparing number of verbal events with and without gaze-to-partner). Analyses compared the listeners in each dyad (HI: n = 10, mean age = 12;6 years, mean better ear pure-tone average = 33.0 dB HL; NH: n = 10, mean age = 13;7 years). RESULTS: Log-rank tests revealed significant group differences in survival distributions for all verbal events, reflecting a higher probability of gaze to the partner's face for participants with HI. Expressed as odds ratios (OR), participants with HI displayed greater odds for gaze-to-partner (ORs ranging between 1.2 and 2.1) during all verbal events. CONCLUSIONS: The results show an increased probability for listeners with HI to gaze at the speaker's face in association with verbal events. Several explanations for the finding are possible, and implications for further research are discussed. PMID- 24167239 TI - Growth of finiteness in the third year of life: replication and predictive validity. AB - PURPOSE: The authors of this study investigated the validity of tense and agreement productivity (TAP) scoring in diverse sentence frames obtained during conversational language sampling as an alternative measure of finiteness for use with young children. METHOD: Longitudinal language samples were used to model TAP growth from 21 to 30 months of age for 37 typically developing toddlers. Empirical Bayes (EB) linear and quadratic growth coefficients and child sex were then used to predict elicited grammar composite scores on the Test of Early Grammatical Impairment (TEGI; Rice & Wexler, 2001) at 36 months. RESULTS: A random-effects quadratic model with no intercept best characterized TAP growth, replicating the findings of Rispoli, Hadley, and Holt (2009). The combined regression model was significant, with the 3 variables accounting for 55.5% of the variance in the TEGI composite scores. CONCLUSION: These findings establish TAP growth as a valid metric of finiteness in the 3rd year of life. Developmental and theoretical implications are discussed. PMID- 24167238 TI - Late language emergence in 24-month-old twins: heritable and increased risk for late language emergence in twins. AB - PURPOSE: This study investigated the etiology of late language emergence (LLE) in 24-month-old twins, considering possible twinning, zygosity, gender, and heritability effects for vocabulary and grammar phenotypes. METHOD: A population based sample of 473 twin pairs participated. Multilevel modeling estimated means and variances of vocabulary and grammar phenotypes, controlling for familiality. Heritability was estimated with DeFries-Fulker regression and variance components models to determine effects of heritability, shared environment, and nonshared environment. RESULTS: Twins had lower average language scores than norms for single-born children, with lower average performance for monozygotic than dizygotic twins and for boys than girls, although gender and zygosity did not interact. Gender did not predict LLE. Significant heritability was detected for vocabulary (0.26) and grammar phenotypes (0.52 and 0.43 for boys and girls, respectively) in the full sample and in the sample selected for LLE (0.42 and 0.44). LLE and the appearance of Word Combinations were also significantly heritable (0.22-0.23). CONCLUSIONS: The findings revealed an increased likelihood of LLE in twin toddlers compared with single-born children that is modulated by zygosity and gender differences. Heritability estimates are consistent with previous research for vocabulary and add further suggestion of heritable differences in early grammar acquisition. PMID- 24167240 TI - Effect of 24 hours of sleep deprivation on auditory and linguistic perception: a comparison among young controls, sleep-deprived participants, dyslexic readers, and aging adults. AB - PURPOSE: To test the effects of 24 hr of sleep deprivation on auditory and linguistic perception and to assess the magnitude of this effect by comparing such performance with that of aging adults on speech perception and with that of dyslexic readers on phonological awareness. METHOD: Fifty-five sleep-deprived young adults were compared with 29 aging adults (older than 60 years) and with 18 young controls on auditory temporal order judgment (TOJ) and on speech perception tasks (Experiment 1). The sleep deprived were also compared with 51 dyslexic readers and with the young controls on TOJ and phonological awareness tasks (One Minute Test for Pseudowords, Phoneme Deletion, Pig Latin, and Spoonerism; Experiment 2). RESULTS: Sleep deprivation resulted in longer TOJ thresholds, poorer speech perception, and poorer nonword reading compared with controls. The TOJ thresholds of the sleep deprived were comparable to those of the aging adults, but their pattern of speech performance differed. They also performed better on TOJ and phonological awareness than dyslexic readers. CONCLUSIONS: A variety of linguistic skills are affected by sleep deprivation. The comparison of sleep-deprived individuals with other groups with known difficulties in these linguistic skills might suggest that different groups exhibit common difficulties. PMID- 24167241 TI - Impact of prematurity on language skills at school age. AB - PURPOSE: The existing literature on language outcomes in children born prematurely focuses almost exclusively on standardized test scores rather than discourse-level abilities. The authors of this study looked longitudinally at school-age language outcomes and potential moderating variables for a group of twins born prematurely versus a control group of twins born at full term, analyzing both standardized test results and language sample data from the population-based Western Reserve Reading Project (WRRP; Petrill, Deater-Deckard, Thompson, DeThorne, & Schatschneider, 2006). METHOD: Fifty-seven children born prematurely, at <=32 weeks or <1,500 g, were compared with 57 children born at full term and were matched for age, gender, race, and parental education. Data included discourse-level language samples and standardized test results, collected at average ages 7, 8, and 10 years. The language samples were analyzed to yield a number of semantic and syntactic measures that were consolidated via factor analysis. RESULTS: Regression models showed significant differences between the 2 groups for standardized test results, although the mean score for both groups fell in the normal range. For the discourse-level language measures, however, differences never reached statistical significance. Parental education was significantly associated with improved standardized test scores. CONCLUSIONS: These findings suggest that in the absence of frank neurological impairment, sophisticated semantic and syntactic skills may be relatively intact in the discourse-level language of children born prematurely. Implications for assessment, particularly the potential role of attention and executive function in standardized testing tasks, are reviewed. PMID- 24167242 TI - Effects of speech practice on fast mapping in monolingual and bilingual speakers. AB - PURPOSE: This study examines the effects of the levels of speech practice on fast mapping in monolingual and bilingual speakers. METHOD: Participants were 30 English-speaking monolingual and 30 Spanish-English bilingual young adults. Each participant was randomly assigned to 1 of 3 practice conditions prior to the fast mapping task: (a) intensive speech practice, (b) moderate speech practice, or (c) no practice. In a fast-mapping experiment, each participant was briefly exposed to novel objects and their corresponding novel words. Participants' knowledge of the target novel words was assessed immediately after the exposures. RESULTS: There were significant effects of speech practice on fast mapping for both monolingual and bilingual adults. It is important to note that participants' language experience also played a role in their fast-mapping performance. CONCLUSION: The findings suggest that speech practice, interacting with language experience, facilitates the processes for fast mapping. PMID- 24167243 TI - Processing of phonological variation in children with hearing loss: compensation for English place assimilation in connected speech. AB - PURPOSE: In this study, the authors explored phonological processing in connected speech in children with hearing loss. Specifically, the authors investigated these children's sensitivity to English place assimilation, by which alveolar consonants like t and n can adapt to following sounds (e.g., the word ten can be realized as tem in the phrase ten pounds). METHOD: Twenty-seven 4- to 8-year-old children with moderate to profound hearing impairments, using hearing aids (n = 10) or cochlear implants (n = 17), and 19 children with normal hearing participated. They were asked to choose between pictures of familiar (e.g., pen) and unfamiliar objects (e.g., astrolabe) after hearing t- and n-final words in sentences. Standard pronunciations (Can you find the pen dear?) and assimilated forms in correct (... pem please?) and incorrect contexts (... pem dear?) were presented. RESULTS: As expected, the children with normal hearing chose the familiar object more often for standard forms and correct assimilations than for incorrect assimilations. Thus, they are sensitive to word-final place changes and compensate for assimilation. However, the children with hearing impairment demonstrated reduced sensitivity to word-final place changes, and no compensation for assimilation. Restricted analyses revealed that children with hearing aids who showed good perceptual skills compensated for assimilation in plosives only. PMID- 24167244 TI - Clostridium difficile toxin B-induced necrosis is mediated by the host epithelial cell NADPH oxidase complex. AB - Clostridium difficile infection (CDI) is a leading cause of health care associated diarrhea and has increased in incidence and severity over the last decade. Pathogenesis is mediated by two toxins, TcdA and TcdB, which cause fluid secretion, inflammation, and necrosis of the colonic mucosa. TcdB is a potent cytotoxin capable of inducing enzyme-independent necrosis in both cells and tissue. In this study, we show that TcdB-induced cell death depends on assembly of the host epithelial cell NADPH oxidase (NOX) complex and the production of reactive oxygen species (ROS). Treating cells with siRNAs directed against key components of the NOX complex, chemical inhibitors of NOX function, or molecules that scavenge superoxide or ROS confers protection against toxin challenge. To test the hypothesis that chemical inhibition of TcdB-induced cytotoxicity can protect against TcdB-induced tissue damage, we treated colonic explants with diphenyleneiodonium (DPI), a flavoenzyme inhibitor, or N-acetylcysteine (NAC), an antioxidant. TcdB-induced ROS production in colonic tissue was inhibited with DPI, and both DPI and NAC conferred protection against TcdB-induced tissue damage. The efficacy of DPI and NAC provides proof of concept that chemical attenuation of ROS could serve as a viable strategy for protecting the colonic mucosa of patients with CDI. PMID- 24167245 TI - Differential expression of olfactory genes in the southern house mosquito and insights into unique odorant receptor gene isoforms. AB - The southern house mosquito, Culex quinquefasciatus, has one of the most acute and eclectic olfactory systems of all mosquito species hitherto studied. Here, we used Illumina sequencing to identify olfactory genes expressed predominantly in antenna, mosquito's main olfactory organ. Less than 50% of the trimmed reads generated by high-quality libraries aligned to a transcript, but approximately 70% of them aligned to the genome. Differential expression analysis, which was validated by quantitative real-time PCR on a subset of genes, showed that approximately half of the 48 odorant-binding protein genes were enriched in antennae, with the other half being predominantly expressed in legs. Similar patterns were observed with chemosensory proteins, "plus-C" odorant-binding proteins, and sensory neuron membrane proteins. Transcripts for as many as 43 ionotropic receptors were enriched in female antennae, thus making the ionotropic receptor family the largest of antennae-rich olfactory genes, second only to odorant receptor (OR) genes. As many as 177 OR genes have been identified, including 36 unique transcripts. The unique OR genes differed from previously annotated ORs in internal sequences, splice variants, and extended N or C terminus. One of the previously unknown transcripts was validated by cloning and functional expression. When challenged with a large panel of physiologically relevant compounds, CquiOR95b responded in a dose-dependent manner to ethyl 2 phenylacteate, which was demonstrated to repel Culex mosquitoes, and secondarily to citronellal, a known insect repellent. This transcriptome study led to identification of key molecular components and a repellent for the southern house mosquito. PMID- 24167246 TI - Keratins as the main component for the mechanical integrity of keratinocytes. AB - Keratins are major components of the epithelial cytoskeleton and are believed to play a vital role for mechanical integrity at the cellular and tissue level. Keratinocytes as the main cell type of the epidermis express a differentiation specific set of type I and type II keratins forming a stable network and are major contributors of keratinocyte mechanical properties. However, owing to compensatory keratin expression, the overall contribution of keratins to cell mechanics was difficult to examine in vivo on deletion of single keratin genes. To overcome this problem, we used keratinocytes lacking all keratins. The mechanical properties of these cells were analyzed by atomic force microscopy (AFM) and magnetic tweezers experiments. We found a strong and highly significant softening of keratin-deficient keratinocytes when analyzed by AFM on the cell body and above the nucleus. Magnetic tweezers experiments fully confirmed these results showing, in addition, high viscous contributions to magnetic bead displacement in keratin-lacking cells. Keratin loss neither affected actin or microtubule networks nor their overall protein concentration. Furthermore, depolymerization of actin preserves cell softening in the absence of keratin. On reexpression of the sole basal epidermal keratin pair K5/14, the keratin filament network was reestablished, and mechanical properties were restored almost to WT levels in both experimental setups. The data presented here demonstrate the importance of keratin filaments for mechanical resilience of keratinocytes and indicate that expression of a single keratin pair is sufficient for almost complete reconstitution of their mechanical properties. PMID- 24167247 TI - First-person action experience reveals sensitivity to action efficiency in prereaching infants. AB - Do infants learn to interpret others' actions through their own experience producing goal-directed action, or does some knowledge of others' actions precede first-person experience? Several studies report that motor experience enhances action understanding, but the nature of this effect is not well understood. The present research investigates what is learned during early motoric production, and it tests whether knowledge of goal-directed actions, including an assumption that actors maximize efficiency given environmental constraints, exists before experience producing such actions. Three-month-old infants (who cannot yet effectively reach for and grasp objects) were given novel experience retrieving objects that rested on a surface with no barriers. They were then shown an actor reaching for an object over a barrier and tested for sensitivity to the efficiency of the action. These infants showed heightened attention when the agent reached inefficiently for a goal object; in contrast, infants who lacked successful reaching experience did not differentiate between direct and indirect reaches. Given that the infants could reach directly for objects during training and were given no opportunity to update their actions based on environmental constraints, the training experience itself is unlikely to have provided a basis for learning about action efficiency. We suggest that infants apply a general assumption of efficient action as soon as they have sufficient information (possibly derived from their own action experience) to identify an agent's goal in a given instance. PMID- 24167248 TI - Polynucleobacter necessarius, a model for genome reduction in both free-living and symbiotic bacteria. AB - We present the complete genomic sequence of the essential symbiont Polynucleobacter necessarius (Betaproteobacteria), which is a valuable case study for several reasons. First, it is hosted by a ciliated protist, Euplotes; bacterial symbionts of ciliates are still poorly known because of a lack of extensive molecular data. Second, the single species P. necessarius contains both symbiotic and free-living strains, allowing for a comparison between closely related organisms with different ecologies. Third, free-living P. necessarius strains are exceptional by themselves because of their small genome size, reduced metabolic flexibility, and high worldwide abundance in freshwater systems. We provide a comparative analysis of P. necessarius metabolism and explore the peculiar features of a genome reduction that occurred on an already streamlined genome. We compare this unusual system with current hypotheses for genome erosion in symbionts and free-living bacteria, propose modifications to the presently accepted model, and discuss the potential consequences of translesion DNA polymerase loss. PMID- 24167249 TI - Endocannabinoid anandamide mediates hypoxic pulmonary vasoconstriction. AB - Endocannabinoids are important regulators of organ homeostasis. Although their role in systemic vasculature has been extensively studied, their impact on pulmonary vessels remains less clear. Herein, we show that the endocannabinoid anandamide (AEA) is a key mediator of hypoxic pulmonary vasoconstriction (HPV) via fatty acid amide hydrolase (FAAH)-dependent metabolites. This is underscored by the prominent vasoconstrictive effect of AEA on pulmonary arteries and strongly reduced HPV in FAAH(-/-) mice and wild-type mice upon pharmacological treatment with FAAH inhibitor URB597. In addition, mass spectrometry measurements revealed a clear increase of AEA and the FAAH-dependent metabolite arachidonic acid in hypoxic lungs of wild-type mice. We have identified pulmonary vascular smooth muscle cells as the source responsible for hypoxia-induced AEA generation. Moreover, either FAAH(-/-) mice or wild-type mice treated with FAAH inhibitor URB597 are protected against hypoxia-induced pulmonary hypertension and the concomitant vascular remodeling in the lung. Thus, the AEA/FAAH pathway is an important mediator of HPV and is involved in the generation of pulmonary hypertension. PMID- 24167250 TI - Odd-skipped related-1 controls neural crest chondrogenesis during tongue development. AB - The tongue is a critical element of the feeding system in tetrapod animals for their successful adaptation to terrestrial life. Whereas the oral part of the mammalian tongue contains soft tissues only, the avian tongue has an internal skeleton extending to the anterior tip. The mechanisms underlying the evolutionary divergence in tongue skeleton formation are completely unknown. We show here that the odd-skipped related-1 (Osr1) transcription factor is expressed throughout the neural crest-derived tongue mesenchyme in mouse, but not in chick, embryos during early tongue morphogenesis. Neural crest-specific inactivation of Osr1 resulted in formation of an ectopic cartilage in the mouse tongue, reminiscent in shape and developmental ontogeny of the anterior tongue cartilage in chick. SRY-box containing gene-9 (Sox9), the master regulator of chondrogenesis, is widely expressed in the nascent tongue mesenchyme at the onset of tongue morphogenesis but its expression is dramatically down-regulated concomitant with activation of Osr1 expression in the developing mouse tongue. In Osr1 mutant mouse embryos, expression of Sox9 persisted in the developing tongue mesenchyme where chondrogenesis is subsequently activated to form the ectopic cartilage. Furthermore, we show that Osr1 binds to the Sox9 gene promoter and that overexpression of Osr1 suppressed expression of endogenous Sox9 mRNAs and Sox9 promoter-driven reporter. These data indicate that Osr1 normally prevents chondrogenesis in the mammalian tongue through repression of Sox9 expression and suggest that changes in regulation of Osr1 expression in the neural crest-derived tongue mesenchyme underlie the evolutionary divergence of birds from other vertebrates in tongue morphogenesis. PMID- 24167251 TI - Ctr2 regulates biogenesis of a cleaved form of mammalian Ctr1 metal transporter lacking the copper- and cisplatin-binding ecto-domain. AB - Copper is an essential catalytic cofactor for enzymatic activities that drive a range of metabolic biochemistry including mitochondrial electron transport, iron mobilization, and peptide hormone maturation. Copper dysregulation is associated with fatal infantile disease, liver, and cardiac dysfunction, neuropathy, and anemia. Here we report that mammals regulate systemic copper acquisition and intracellular mobilization via cleavage of the copper-binding ecto-domain of the copper transporter 1 (Ctr1). Although full-length Ctr1 is critical to drive efficient copper import across the plasma membrane, cleavage of the ecto-domain is required for Ctr1 to mobilize endosomal copper stores. The biogenesis of the truncated form of Ctr1 requires the structurally related, previously enigmatic copper transporter 2 (Ctr2). Ctr2(-/-) mice are defective in accumulation of truncated Ctr1 and exhibit increased tissue copper levels, and X-ray fluorescence microscopy demonstrates that copper accumulates as intracellular foci. These studies identify a key regulatory mechanism for mammalian copper transport through Ctr2-dependent accumulation of a Ctr1 variant lacking the copper- and cisplatin-binding ecto-domain. PMID- 24167252 TI - GATA-1 regulates the generation and function of basophils. AB - Developmental processes of hematopoietic cells are orchestrated by transcriptional networks. GATA-1, the founding member of the GATA family of transcription factors, has been demonstrated to play crucial roles in the differentiation of erythroid cells, magakaryocytes, eosinophils, and mast cells. However, the role of GATA-1 in basophils remains elusive. Here we show that basophils abundantly express Gata1 mRNAs, and that siRNA-mediated knockdown of Gata1 resulted in impaired production of IL-4 by basophils in response to the stimulation with IgE plus antigens. DeltadblGATA mice that carry the mutated Gata1 promoter and are widely used for functional analysis of eosinophils owing to their selective loss of eosinophils showed a decreased number of basophils with reduced expression of Gata1 mRNAs. The number of basophil progenitors in bone marrow was reduced in these mice, and the generation of basophils from their bone marrow cells in culture with IL-3 or thymic stromal lymphopoietin was impaired. DeltadblGATA basophils responded poorly ex vivo to stimulation with IgE plus antigens compared with wild-type basophils as assessed by degranulation and production of IL-4 and IL-6. Moreover, DeltadblGATA mice showed impaired responses in basophil-mediated protective immunity against intestinal helminth infection. Thus, DeltadblGATA mice showed numerical and functional aberrancy in basophils in addition to the known deficiency of eosinophils. Our findings demonstrate that GATA-1 plays a key role in the generation and function of basophils and underscore the need for careful distinction of the cell lineage responsible for each phenotype observed in DeltadblGATA mice. PMID- 24167253 TI - Large-scale detection of in vivo transcription errors. AB - Accurate transmission and expression of genetic information are crucial for the survival of all living organisms. Recently, the coupling of mutation accumulation experiments and next-generation sequencing has greatly expanded our knowledge of the genomic mutation rate in both prokaryotes and eukaryotes. However, because of their transient nature, transcription errors have proven extremely difficult to quantify, and current estimates of transcription fidelity are derived from artificial constructs applied to just a few organisms. Here we report a unique cDNA library preparation technique that allows error detection in natural transcripts at the transcriptome-wide level. Application of this method to the model organism Caenorhabditis elegans revealed a base misincorporation rate in mRNAs of ~4 * 10(-6) per site, with a very biased molecular spectrum. Because the proposed method is readily applicable to other organisms, this innovation provides unique opportunities for studying the incidence of transcription errors across the tree of life. PMID- 24167254 TI - Electrolytic synthesis of aqueous aluminum nanoclusters and in situ characterization by femtosecond Raman spectroscopy and computations. AB - The selective synthesis and in situ characterization of aqueous Al-containing clusters is a long-standing challenge. We report a newly developed integrated platform that combines (i) a selective, atom-economical, step-economical, scalable synthesis of Al-containing nanoclusters in water via precision electrolysis with strict pH control and (ii) an improved femtosecond stimulated Raman spectroscopic method covering a broad spectral range of ca. 350-1,400 cm( 1) with high sensitivity, aided by ab initio computations, to elucidate Al aqueous cluster structures and formation mechanisms in real time. Using this platform, a unique view of flat [Al13(MU3-OH)6(MU2-OH)18(H2O)24](NO3)15 nanocluster formation is observed in water, in which three distinct reaction stages are identified. The initial stage involves the formation of an [Al7(MU3 OH)6(MU2-OH)6(H2O)12](9+) cluster core as an important intermediate toward the flat Al13 aqueous cluster. PMID- 24167255 TI - Detection and mapping of 5-methylcytosine and 5-hydroxymethylcytosine with nanopore MspA. AB - Precise and efficient mapping of epigenetic markers on DNA may become an important clinical tool for prediction and identification of ailments. Methylated CpG sites are involved in gene expression and are biomarkers for diseases such as cancer. Here, we use the engineered biological protein pore Mycobacterium smegmatis porin A (MspA) to detect and map 5-methylcytosine and 5 hydroxymethylcytosine within single strands of DNA. In this unique single molecule tool, a phi29 DNA polymerase draws ssDNA through the pore in single nucleotide steps, and the ion current through the pore is recorded. Comparing current levels generated with DNA containing methylated CpG sites to current levels obtained with unmethylated copies of the DNA reveals the precise location of methylated CpG sites. Hydroxymethylation is distinct from methylation and can also be mapped. With a single read, the detection efficiency in a quasirandom DNA strand is 97.5 +/- 0.7% for methylation and 97 +/- 0.9% for hydroxymethylation. PMID- 24167256 TI - Lipoatrophy and severe metabolic disturbance in mice with fat-specific deletion of PPARgamma. AB - Adipose tissue is an important metabolic organ, the dysfunction of which is associated with the development of obesity, diabetes mellitus, and cardiovascular disease. The nuclear receptor peroxisome proliferator-activated receptor gamma (PPARgamma) is considered the master regulator of adipocyte differentiation and function. Although its cell-autonomous role in adipogenesis has been clearly demonstrated in cell culture, previous fat-specific knockouts of the murine PPARgamma gene did not demonstrate a dramatic phenotype in vivo. Here, using Adipoq-Cre mice to drive adipose-specific recombination, we report a unique fat specific PPARgamma knockout (PPARgamma FKO) mouse model with almost no visible brown and white adipose tissue at age 3 mo. As a consequence, PPARgamma FKO mice had hugely enlarged pancreatic islets, massive fatty livers, and dramatically elevated levels of blood glucose and serum insulin accompanied by extreme insulin resistance. PPARgamma FKO mice also exhibited delayed hair coat formation associated with absence of dermal fat, disrupted mammary gland development with loss of mammary fat pads, and high bone mass with loss of bone marrow fat, indicating the critical roles of adipose PPARgamma in these tissues. Together, our data reveal the necessity of fat PPARgamma in adipose formation, whole-body metabolic homeostasis, and normal development of fat-containing tissues. PMID- 24167257 TI - Substrate protein switches GroE chaperonins from asymmetric to symmetric cycling by catalyzing nucleotide exchange. AB - The complex kinetics of Pi and ADP release by the chaperonin GroEL/GroES is influenced by the presence of unfolded substrate protein (SP). Without SP, the kinetics of Pi release are described by four phases: a "lag," a "burst" of ATP hydrolysis by the nascent cis ring, a "delay" caused by ADP release from the nascent trans ring, and steady-state ATP hydrolysis. The release of Pi precedes the release of ADP. The rate-determining step of the asymmetric cycle is the release of ADP from the trans ring of the GroEL-GroES1 "bullet" complex that is, consequently, the predominant species. In the asymmetric cycle, the two rings of GroEL function alternately, 180 degrees out of phase. In the presence of SP, a change in the kinetic mechanism occurs. With SP present, the kinetics of ADP release are also described by four phases: a lag, a "surge" of ADP release attributable to SP-induced ADP/ATP exchange, and a "pause" during which symmetrical "football" particles are formed, followed by steady-state ATP hydrolysis. SP catalyzes ADP/ATP exchange on the trans ring. Now ADP release precedes the release of Pi, and the rate-determining step of the symmetric cycle becomes the hydrolysis of ATP by the symmetric GroEL-GroES2 football complex that is, consequently, the predominant species. A FRET-based analysis confirms that asymmetric GroEL-GroES1 bullets predominate in the absence of SP, whereas symmetric GroEL-GroES2 footballs predominate in the presence of SP. This evidence suggests that symmetrical football particles are the folding functional form of the chaperonin machine in vivo. PMID- 24167258 TI - Regulation of bone remodeling by vasopressin explains the bone loss in hyponatremia. AB - Although hyponatremia is known to be associated with osteoporosis and a high fracture risk, the mechanism through which bone loss ensues has remained unclear. As hyponatremic patients have elevated circulating arginine-vasopressin (AVP) levels, we examined whether AVP can affect the skeleton directly as yet another component of the pituitary-bone axis. Here, we report that the two Avp receptors, Avpr1alpha and Avpr2, coupled to Erk activation, are expressed in osteoblasts and osteoclasts. AVP injected into wild-type mice enhanced and reduced, respectively, the formation of bone-resorbing osteoclasts and bone-forming osteoblasts. Conversely, the exposure of osteoblast precursors to Avpr1alpha or Avpr2 antagonists, namely SR49059 or ADAM, increased osteoblastogenesis, as did the genetic deletion of Avpr1alpha. In contrast, osteoclast formation and bone resorption were both reduced in Avpr1alpha(-/-) cultures. This process increased bone formation and reduced resorption resulted in a profound enhancement of bone mass in Avpr1alpha(-/-) mice and in wild-type mice injected with SR49059. Collectively, the data not only establish a primary role for Avp signaling in bone mass regulation, but also call for further studies on the skeletal actions of Avpr inhibitors used commonly in hyponatremic patients. PMID- 24167259 TI - Global meta-analysis reveals no net change in local-scale plant biodiversity over time. AB - Global biodiversity is in decline. This is of concern for aesthetic and ethical reasons, but possibly also for practical reasons, as suggested by experimental studies, mostly with plants, showing that biodiversity reductions in small study plots can lead to compromised ecosystem function. However, inferring that ecosystem functions will decline due to biodiversity loss in the real world rests on the untested assumption that such loss is actually occurring at these small scales in nature. Using a global database of 168 published studies and >16,000 nonexperimental, local-scale vegetation plots, we show that mean temporal change in species diversity over periods of 5-261 y is not different from zero, with increases at least as likely as declines over time. Sites influenced primarily by plant species' invasions showed a tendency for declines in species richness, whereas sites undergoing postdisturbance succession showed increases in richness over time. Other distinctions among studies had little influence on temporal richness trends. Although maximizing diversity is likely important for maintaining ecosystem function in intensely managed systems such as restored grasslands or tree plantations, the clear lack of any general tendency for plant biodiversity to decline at small scales in nature directly contradicts the key assumption linking experimental results to ecosystem function as a motivation for biodiversity conservation in nature. How often real world changes in the diversity and composition of plant communities at the local scale cause ecosystem function to deteriorate, or actually to improve, remains unknown and is in critical need of further study. PMID- 24167260 TI - Error rates for nanopore discrimination among cytosine, methylcytosine, and hydroxymethylcytosine along individual DNA strands. AB - Cytosine, 5-methylcytosine, and 5-hydroxymethylcytosine were identified during translocation of single DNA template strands through a modified Mycobacterium smegmatis porin A (M2MspA) nanopore under control of phi29 DNA polymerase. This identification was based on three consecutive ionic current states that correspond to passage of modified or unmodified CG dinucleotides and their immediate neighbors through the nanopore limiting aperture. To establish quality scores for these calls, we examined ~3,300 translocation events for 48 distinct DNA constructs. Each experiment analyzed a mixture of cytosine-, 5-methylcytosine , and 5-hydroxymethylcytosine-bearing DNA strands that contained a marker that independently established the correct cytosine methylation status at the target CG of each molecule tested. To calculate error rates for these calls, we established decision boundaries using a variety of machine-learning methods. These error rates depended upon the identity of the bases immediately 5' and 3' of the targeted CG dinucleotide, and ranged from 1.7% to 12.2% for a single-pass read. We estimate that Q40 values (0.01% error rates) for methylation status calls could be achieved by reading single molecules 5-19 times depending upon sequence context. PMID- 24167261 TI - Transplantation of human islets without immunosuppression. AB - Transplantation of pancreatic islets is emerging as a successful treatment for type-1 diabetes. Its current stringent restriction to patients with critical metabolic lability is justified by the long-term need for immunosuppression and a persistent shortage of donor organs. We developed an oxygenated chamber system composed of immune-isolating alginate and polymembrane covers that allows for survival and function of islets without immunosuppression. A patient with type-1 diabetes received a transplanted chamber and was followed for 10 mo. Persistent graft function in this chamber system was demonstrated, with regulated insulin secretion and preservation of islet morphology and function without any immunosuppressive therapy. This approach may allow for future widespread application of cell-based therapies. PMID- 24167262 TI - Fibrinogen-specific antibody induces abdominal aortic aneurysm in mice through complement lectin pathway activation. AB - Abdominal aortic aneurysm (AAA) is a common vascular disease associated with high mortality rate due to progressive enlargement and eventual rupture. There is currently no established therapy known to alter the rate of aneurysmal expansion. Thus, understanding the processes that initiate and sustain aneurysmal growth is pivotal for the development of medical therapies aimed at halting disease progression. Using an elastase-induced AAA mouse model that recapitulates key features of human AAA, we previously reported that a natural IgG antibody directs alternative pathway complement activation and initiates the inflammatory process that culminates in aneurysmal development. The target of this natural antibody, however, was unknown. Herein we identify a natural IgG that binds to fibrinogen deposited in elastase-perfused aortic tissues, activates the complement lectin pathway (LP), and induces AAA. Moreover, we establish that alterations in the glycosylation patterns of this antibody critically affect its ability to activate the LP in vivo. We find that LP activation precedes the alternative pathway and absence of the LP complement protein mannan-binding lectin abrogates elastase induced AAA. In human AAA tissues the mouse anti-fibrinogen antibody recognizes epitopes that localize to the same areas that stain positively for mannan-binding lectin, which suggests that the complement LP is engaged in humans as well. Lastly, we demonstrate that circulating antibodies in a subset of AAA patients react against fibrinogen or fibrinogen-associated epitopes in human aneurysmal tissues. Our findings support the concept that an autoimmune process directed at aortic wall self-antigens may play a central role in the immunopathogenesis of AAA. PMID- 24167263 TI - High-performance, low-voltage electroosmotic pumps with molecularly thin silicon nanomembranes. AB - We have developed electroosmotic pumps (EOPs) fabricated from 15-nm-thick porous nanocrystalline silicon (pnc-Si) membranes. Ultrathin pnc-Si membranes enable high electroosmotic flow per unit voltage. We demonstrate that electroosmosis theory compares well with the observed pnc-Si flow rates. We attribute the high flow rates to high electrical fields present across the 15-nm span of the membrane. Surface modifications, such as plasma oxidation or silanization, can influence the electroosmotic flow rates through pnc-Si membranes by alteration of the zeta potential of the material. A prototype EOP that uses pnc-Si membranes and Ag/AgCl electrodes was shown to pump microliter per minute-range flow through a 0.5-mm-diameter capillary tubing with as low as 250 mV of applied voltage. This silicon-based platform enables straightforward integration of low-voltage, on chip EOPs into portable microfluidic devices with low back pressures. PMID- 24167264 TI - Purified TMEM16A is sufficient to form Ca2+-activated Cl- channels. AB - Ca(2+)-activated Cl(-) channels (CaCCs) are key regulators of numerous physiological functions, ranging from electrolyte secretion in airway epithelia to cellular excitability in sensory neurons and muscle fibers. Recently, TMEM16A (ANO1) and -B were shown to be critical components of CaCCs. It is still unknown whether they are also sufficient to form functional CaCCs, or whether association with other subunits is required. Recent reports suggest that the Ca(2+) sensitivity of TMEM16A is mediated by its association with calmodulin, suggesting that functional CaCCs are heteromultimers. To test whether TMEM16A is necessary and sufficient to form functional CaCCs, we expressed, purified, and reconstituted human TMEM16A. The purified protein mediates Ca(2+)-dependent Cl(-) transport with submicromolar sensitivity to Ca(2+), consistent with what is seen in patch-clamp experiments. The channel is synergistically gated by Ca(2+) and voltage, so that opening is promoted by depolarizing potentials. Mutating two conserved glutamates in the TM6-7 intracellular loop selectively abolishes the Ca(2+) dependence of reconstituted TMEM16A, in a manner similar to what was reported for the heterologously expressed channel. Well-characterized CaCC blockers inhibit Cl(-) transport with Kis comparable to those measured for native and heterologously expressed CaCCs. Finally, direct physical interactions between calmodulin and TMEM16A could not be detected in copurification experiments or in functional assays. Our results demonstrate that purified TMEM16A is necessary and sufficient to recapitulate the biophysical and pharmacological properties of native and heterologously expressed CaCCs. Our results also show that association of TMEM16A with other proteins, such as calmodulin, is not required for function. PMID- 24167266 TI - Chronic exposure to arsenic in drinking water can lead to resistance to antimonial drugs in a mouse model of visceral leishmaniasis. AB - The Indian subcontinent is the only region where arsenic contamination of drinking water coexists with widespread resistance to antimonial drugs that are used to treat the parasitic disease visceral leishmaniasis. We have previously proposed that selection for parasite resistance within visceral leishmaniasis patients who have been exposed to trivalent arsenic results in cross-resistance to the related metalloid antimony, present in the pentavalent state as a complex in drugs such as sodium stibogluconate (Pentostam) and meglumine antimonate (Glucantime). To test this hypothesis, Leishmania donovani was serially passaged in mice exposed to arsenic in drinking water at environmentally relevant levels (10 or 100 ppm). Arsenic accumulation in organs and other tissues was proportional to the level of exposure and similar to that previously reported in human liver biopsies. After five monthly passages in mice exposed to arsenic, isolated parasites were found to be completely refractory to 500 MUg . mL(-1) Pentostam compared with the control passage group (38.5 MUg . mL(-1)) cultured in vitro in mouse peritoneal macrophages. Reassessment of resistant parasites following further passage for 4 mo in mice without arsenic exposure showed that resistance was stable. Treatment of infected mice with Pentostam confirmed that resistance observed in vitro also occurred in vivo. We conclude that arsenic contamination may have played a significant role in the development of Leishmania antimonial resistance in Bihar because inadequate treatment with antimonial drugs is not exclusive to India, whereas widespread antimonial resistance is. PMID- 24167265 TI - Developmental origins of the world's largest flowers, Rafflesiaceae. AB - Rafflesiaceae, which produce the world's largest flowers, have captivated the attention of biologists for nearly two centuries. Despite their fame, however, the developmental nature of the floral organs in these giants has remained a mystery. Most members of the family have a large floral chamber defined by a diaphragm. The diaphragm encloses the reproductive organs where pollination by carrion flies occurs. In lieu of a functional genetic system to investigate floral development in these highly specialized holoparasites, we used comparative studies of structure, development, and gene-expression patterns to investigate the homology of their floral organs. Our results surprisingly demonstrate that the otherwise similar floral chambers in two Rafflesiaceae subclades, Rafflesia and Sapria, are constructed very differently. In Rafflesia, the diaphragm is derived from the petal whorl. In contrast, in Sapria it is derived from elaboration of a unique ring structure located between the perianth and the stamen whorl, which, although developed to varying degrees among the genera, appears to be a synapomorphy of the Rafflesiaceae. Thus, the characteristic features that define the floral chamber in these closely related genera are not homologous. These differences refute the prevailing hypothesis that similarities between Sapria and Rafflesia are ancestral in the family. Instead, our data indicate that Rafflesia-like and Sapria-like floral chambers represent two distinct derivations of this morphology. The developmental repatterning we identified in Rafflesia, in particular, may have provided architectural reinforcement, which permitted the explosive growth in floral diameter that has arisen secondarily within this subclade. PMID- 24167267 TI - Yeast metabolic and signaling genes are required for heat-shock survival and have little overlap with the heat-induced genes. AB - Genome-wide gene-expression studies have shown that hundreds of yeast genes are induced or repressed transiently by changes in temperature; many are annotated to stress response on this basis. To obtain a genome-scale assessment of which genes are functionally important for innate and/or acquired thermotolerance, we combined the use of a barcoded pool of ~4,800 nonessential, prototrophic Saccharomyces cerevisiae deletion strains with Illumina-based deep-sequencing technology. As reported in other recent studies that have used deletion mutants to study stress responses, we observed that gene deletions resulting in the highest thermosensitivity generally are not the same as those transcriptionally induced in response to heat stress. Functional analysis of identified genes revealed that metabolism, cellular signaling, and chromatin regulation play roles in regulating thermotolerance and in acquired thermotolerance. However, for most of the genes identified, the molecular mechanism behind this action remains unclear. In fact, a large fraction of identified genes are annotated as having unknown functions, further underscoring our incomplete understanding of the response to heat shock. We suggest that survival after heat shock depends on a small number of genes that function in assessing the metabolic health of the cell and/or regulate its growth in a changing environment. PMID- 24167268 TI - Pulvinar neurons reveal neurobiological evidence of past selection for rapid detection of snakes. AB - Snakes and their relationships with humans and other primates have attracted broad attention from multiple fields of study, but not, surprisingly, from neuroscience, despite the involvement of the visual system and strong behavioral and physiological evidence that humans and other primates can detect snakes faster than innocuous objects. Here, we report the existence of neurons in the primate medial and dorsolateral pulvinar that respond selectively to visual images of snakes. Compared with three other categories of stimuli (monkey faces, monkey hands, and geometrical shapes), snakes elicited the strongest, fastest responses, and the responses were not reduced by low spatial filtering. These findings integrate neuroscience with evolutionary biology, anthropology, psychology, herpetology, and primatology by identifying a neurobiological basis for primates' heightened visual sensitivity to snakes, and adding a crucial component to the growing evolutionary perspective that snakes have long shaped our primate lineage. PMID- 24167269 TI - A universal strategy for visually guided landing. AB - Landing is a challenging aspect of flight because, to land safely, speed must be decreased to a value close to zero at touchdown. The mechanisms by which animals achieve this remain unclear. When landing on horizontal surfaces, honey bees control their speed by holding constant the rate of front-to-back image motion (optic flow) generated by the surface as they reduce altitude. As inclination increases, however, this simple pattern of optic flow becomes increasingly complex. How do honey bees control speed when landing on surfaces that have different orientations? To answer this, we analyze the trajectories of honey bees landing on a vertical surface that produces various patterns of motion. We find that landing honey bees control their speed by holding the rate of expansion of the image constant. We then test and confirm this hypothesis rigorously by analyzing landings when the apparent rate of expansion generated by the surface is manipulated artificially. This strategy ensures that speed is reduced, gradually and automatically, as the surface is approached. We then develop a mathematical model of this strategy and show that it can effectively be used to guide smooth landings on surfaces of any orientation, including horizontal surfaces. This biological strategy for guiding landings does not require knowledge about either the distance to the surface or the speed at which it is approached. The simplicity and generality of this landing strategy suggests that it is likely to be exploited by other flying animals and makes it ideal for implementation in the guidance systems of flying robots. PMID- 24167270 TI - Gating of the proton-gated ion channel from Gloeobacter violaceus at pH 4 as revealed by X-ray crystallography. AB - Cryoelectron microscopy and X-ray crystallography have recently been used to generate structural models that likely represent the unliganded closed-channel conformation and the fully liganded open-channel conformation of different members of the nicotinic-receptor superfamily. To characterize the structure of the closed-channel conformation in its liganded state, we identified a number of positions in the loop between transmembrane segments 2 (M2) and 3 (M3) of a proton-gated ortholog from the bacterium Gloeobacter violaceus (GLIC) where mutations to alanine reduce the liganded-gating equilibrium constant, and solved the crystal structures of two such mutants (T25'A and Y27'A) at pH ~4.0. At the level of backbone atoms, the liganded closed-channel model presented here differs from the liganded open-channel structure of GLIC in the pre-M1 linker, the M3-M4 loop, and much more prominently, in the extracellular half of the pore lining, where the more pronounced tilt of the closed-channel M2 alpha-helices toward the pore's long axis narrows the permeation pathway. On the other hand, no differences between the liganded closed-channel and open-channel models could be detected at the level of the extracellular domain, where conformational changes are expected to underlie the low-to-high proton-affinity switch that drives gating of proton-bound channels. Thus, the liganded closed-channel model is nearly indistinguishable from the recently described "locally closed" structure. However, because cross-linking strategies (which could have stabilized unstable conformations) and mutations involving ionizable side chains (which could have affected proton-gated channel activation) were purposely avoided, we favor the notion that this structure represents one of the end states of liganded gating rather than an unstable intermediate. PMID- 24167271 TI - Quantitative selection and parallel characterization of aptamers. AB - Aptamers are promising affinity reagents that are potentially well suited for high-throughput discovery, as they are chemically synthesized and discovered via completely in vitro selection processes. Recent advancements in selection, sequencing, and the use of modified bases have improved aptamer quality, but the overall process of aptamer generation remains laborious and low-throughput. This is because binding characterization remains a critical bottleneck, wherein the affinity and specificity of each candidate aptamer are measured individually in a serial manner. To accelerate aptamer discovery, we devised the Quantitative Parallel Aptamer Selection System (QPASS), which integrates microfluidic selection and next-generation sequencing with in situ-synthesized aptamer arrays, enabling simultaneous measurement of affinity and specificity for thousands of candidate aptamers in parallel. After using QPASS to select aptamers for the human cancer biomarker angiopoietin-2 (Ang2), we in situ synthesized arrays of the selected sequences and obtained equilibrium dissociation constants (Kd) for every aptamer in parallel. We thereby identified over a dozen high-affinity Ang2 aptamers, with Kd as low as 20.5 +/- 7.3 nM. The same arrays enabled us to quantify binding specificity for these aptamers in parallel by comparing relative binding of differentially labeled target and nontarget proteins, and by measuring their binding affinity directly in complex samples such as undiluted serum. Finally, we show that QPASS offers a compelling avenue for exploring structure function relationships for large numbers of aptamers in parallel by coupling array-based affinity measurements with next-generation sequencing data to identify nucleotides and motifs within the aptamer that critically affect Ang2 binding. PMID- 24167272 TI - Prevention of inflammation-mediated bone loss in murine and canine periodontal disease via recruitment of regulatory lymphocytes. AB - The hallmark of periodontal disease is the progressive destruction of gingival soft tissue and alveolar bone, which is initiated by inflammation in response to an invasive and persistent bacterial insult. In recent years, it has become apparent that this tissue destruction is associated with a decrease in local regulatory processes, including a decrease of forkhead box P3-expressing regulatory lymphocytes. Accordingly, we developed a controlled release system capable of generating a steady release of a known chemoattractant for regulatory lymphocytes, C-C motif chemokine ligand 22 (CCL22), composed of a degradable polymer with a proven track record of clinical translation, poly(lactic-co glycolic) acid. We have previously shown that this sustained presentation of CCL22 from a point source effectively recruits regulatory T cells (Tregs) to the site of injection. Following administration of the Treg-recruiting formulation to the gingivae in murine experimental periodontitis, we observed increases in hallmark Treg-associated anti-inflammatory molecules, a decrease of proinflammatory cytokines, and a marked reduction in alveolar bone resorption. Furthermore, application of the Treg-recruiting formulation (fabricated with human CCL22) in ligature-induced periodontitis in beagle dogs leads to reduced clinical measures of inflammation and less alveolar bone loss under severe inflammatory conditions in the presence of a diverse periodontopathogen milieu. PMID- 24167273 TI - Enduring legacy of a toxic fan via episodic redistribution of California gold mining debris. AB - The interrelationships between hydrologically driven evolution of legacy landscapes downstream of major mining districts and the contamination of lowland ecosystems are poorly understood over centennial time scales. Here, we demonstrate within piedmont valleys of California's Sierra Nevada, through new and historical data supported by modeling, that anthropogenic fans produced by 19th century gold mining comprise an episodically persistent source of sediment adsorbed Hg to lowlands. Within the enormous, iconic Yuba Fan, we highlight (i) an apparent shift in the relative processes of fan evolution from gradual vertical channel entrenchment to punctuated lateral erosion of fan terraces, thus enabling entrainment of large volumes of Hg-laden sediment during individual floods, and (ii) systematic intrafan redistribution and downstream progradation of fan sediment into the Central Valley, triggered by terrace erosion during increasingly long, 10-y flood events. Each major flood apparently erodes stored sediment and delivers to sensitive lowlands the equivalent of ~10-30% of the entire postmining Sierran Hg mass so far conveyed to the San Francisco Bay-Delta (SFBD). This process of protracted but episodic erosion of legacy sediment and associated Hg is likely to persist for >10(4) y. It creates, within an immense swath of river corridor well upstream of the SFBD, new contaminated floodplain surfaces primed for Hg methylation and augments/replenishes potential Hg sources to the SFBD. Anticipation, prediction, and management of toxic sediment delivery, and corresponding risks to lowland ecology and human society globally, depend on the morphodynamic stage of anthropogenic fan evolution, synergistically coupled to changing frequency of and duration extreme floods. PMID- 24167274 TI - Keratins significantly contribute to cell stiffness and impact invasive behavior. AB - Cell motility and cell shape adaptations are crucial during wound healing, inflammation, and malignant progression. These processes require the remodeling of the keratin cytoskeleton to facilitate cell-cell and cell-matrix adhesion. However, the role of keratins for biomechanical properties and invasion of epithelial cells is only partially understood. In this study, we address this issue in murine keratinocytes lacking all keratins on genome engineering. In contrast to predictions, keratin-free cells show about 60% higher cell deformability even for small deformations. This response is compared with the less pronounced softening effects for actin depolymerization induced via latrunculin A. To relate these findings with functional consequences, we use invasion and 3D growth assays. These experiments reveal higher invasiveness of keratin-free cells. Reexpression of a small amount of the keratin pair K5/K14 in keratin-free cells reverses the above phenotype for the invasion but does not with respect to cell deformability. Our data show a unique role of keratins as major players of cell stiffness, influencing invasion with implications for epidermal homeostasis and pathogenesis. This study supports the view that down regulation of keratins observed during epithelial-mesenchymal transition directly contributes to the migratory and invasive behavior of tumor cells. PMID- 24167275 TI - Cyclic diguanosine monophosphate represses bacterial flagella synthesis by interacting with the Walker A motif of the enhancer-binding protein FleQ. AB - The transcription factor FleQ is a bacterial AAA+ ATPase enhancer-binding protein that is the master activator of flagella gene expression in the opportunistic bacterial pathogen Pseudomonas aeruginosa. Homologs of FleQ are present in all Pseudomonas species and in many polarly flagellated gamma proteobacteria. Cyclic diguanosine monophosphate (c-di-GMP) is a second messenger that controls the transition between planktonic and biofilm modes of growth in bacteria in response to diverse environmental signals. C-di-GMP binds to FleQ to dampen its activity, causing down-regulation of flagella gene expression. This action is potentiated in the simultaneous presence of another protein, FleN. We explored the effect of c-di-GMP and FleN on the ATPase activity of FleQ and found that a relatively low concentration of c-di-GMP competitively inhibited FleQ ATPase activity, suggesting that c-di-GMP competes with ATP for binding to the Walker A motif of FleQ. Confirming this, a FleQ Walker A motif mutant failed to bind c-di-GMP. FleN, whose gene is regulated by FleQ, also inhibited FleQ ATPase activity, and FleQ ATPase activity was much more inhibited by c-di-GMP in the presence of FleN than in its absence. These results indicate that FleN and c-di-GMP cooperate to inhibit FleQ activity and, by extension, flagella synthesis in P. aeruginosa. The Walker A motif of FleQ is perfectly conserved, opening up the possibility that other AAA+ ATPases may respond to c-di-GMP. PMID- 24167276 TI - A neuropeptide speeds circadian entrainment by reducing intercellular synchrony. AB - Shift work or transmeridian travel can desynchronize the body's circadian rhythms from local light-dark cycles. The mammalian suprachiasmatic nucleus (SCN) generates and entrains daily rhythms in physiology and behavior. Paradoxically, we found that vasoactive intestinal polypeptide (VIP), a neuropeptide implicated in synchrony among SCN cells, can also desynchronize them. The degree and duration of desynchronization among SCN neurons depended on both the phase and the dose of VIP. A model of the SCN consisting of coupled stochastic cells predicted both the phase- and the dose-dependent response to VIP and that the transient phase desynchronization, or "phase tumbling", could arise from intrinsic, stochastic noise in small populations of key molecules (notably, Period mRNA near its daily minimum). The model also predicted that phase tumbling following brief VIP treatment would accelerate entrainment to shifted environmental cycles. We tested this using a prepulse of VIP during the day before a shift in either a light cycle in vivo or a temperature cycle in vitro. Although VIP during the day does not shift circadian rhythms, the VIP pretreatment approximately halved the time required for mice to reentrain to an 8 h shifted light schedule and for SCN cultures to reentrain to a 10-h shifted temperature cycle. We conclude that VIP below 100 nM synchronizes SCN cells and above 100 nM reduces synchrony in the SCN. We show that exploiting these mechanisms that transiently reduce cellular synchrony before a large shift in the schedule of daily environmental cues has the potential to reduce jet lag. PMID- 24167277 TI - Combining two strategies to improve perfusion and drug delivery in solid tumors. AB - Blood perfusion in tumors can be significantly lower than that in the surrounding normal tissue owing to the leakiness and/or compression of tumor blood vessels. Impaired perfusion reduces oxygen supply and results in a hypoxic microenvironment. Hypoxia promotes tumor progression and immunosuppression, and enhances the invasive and metastatic potential of cancer cells. Furthermore, poor perfusion lowers the delivery of systemically administered drugs. Therapeutic strategies to improve perfusion include reduction in vascular permeability by vascular normalization and vascular decompression by alleviating physical forces (solid stress) inside tumors. Both strategies have shown promise, but guidelines on how to use these strategies optimally are lacking. To this end, we developed a mathematical model to guide the optimal use of these strategies. The model accounts for vascular, transvascular, and interstitial fluid and drug transport as well as the diameter and permeability of tumor vessels. Model simulations reveal an optimal perfusion region when vessels are uncompressed, but not very leaky. Within this region, intratumoral distribution of drugs is optimized, particularly for drugs 10 nm in diameter or smaller and of low binding affinity. Therefore, treatments should modify vessel diameter and/or permeability such that perfusion is optimal. Vascular normalization is more effective for hyperpermeable but largely uncompressed vessels (e.g., glioblastomas), whereas solid stress alleviation is more beneficial for compressed but less-permeable vessels (e.g., pancreatic ductal adenocarcinomas). In the case of tumors with hyperpermeable and compressed vessels (e.g., subset of mammary carcinomas), the two strategies need to be combined for improved treatment outcomes. PMID- 24167278 TI - Gata3/Ruvbl2 complex regulates T helper 2 cell proliferation via repression of Cdkn2c expression. AB - GATA-binding protein 3 (Gata3) controls the differentiation of naive CD4 T cells into T helper 2 (Th2) cells by induction of chromatin remodeling of the Th2 cytokine gene loci, direct transactivation of Il5 and Il13 genes, and inhibition of Ifng. Gata3 also facilitates Th2 cell proliferation via additional mechanisms that are far less well understood. We herein found that Gata3 associates with RuvB-like protein 2 (Ruvbl2) and represses the expression of a CDK inhibitor, cyclin-dependent kinase inhibitor 2c (Cdkn2c) to facilitate the proliferation of Th2 cells. Gata3 directly bound to the Cdkn2c locus in an Ruvbl2-dependent manner. The defect in the proliferation of Gata3-deficient Th2 cells is rescued by the knockdown of Cdkn2c, indicating that Cdkn2c is a key molecule involved in the Gata3-mediated induction of Th2 cell proliferation. Ruvbl2-knockdown Th2 cells showed decreased antigen-induced expansion and caused less airway inflammation in vivo. We therefore have identified a functional Gata3/Ruvbl2 complex that regulates the proliferation of differentiating Th2 cells through the repression of a CDK inhibitor, Cdkn2c. PMID- 24167279 TI - Symmetric GroEL:GroES2 complexes are the protein-folding functional form of the chaperonin nanomachine. AB - Using calibrated FRET, we show that the simultaneous occupancy of both rings of GroEL by ATP and GroES occurs, leading to the rapid formation of symmetric GroEL:GroES2 "football" particles regardless of the presence or absence of substrate protein (SP). In the absence of SP, these symmetric particles revert to asymmetric GroEL:GroES1 "bullet" particles. The breakage of GroES symmetry requires the stochastic hydrolysis of ATP and the breakage of nucleotide symmetry. These asymmetric particles are both persistent and dynamic; they turnover via the asymmetric cycle. When challenged with SP, however, they revert to symmetric particles within a second. In the presence of SP, the symmetric particles are also persistent and dynamic. They turn over via the symmetric cycle. Under these conditions, the stochastic hydrolysis of ATP and the breakage of nucleotide symmetry also occur within the ensemble of particles. However, on account of SP-catalyzed ADP/ATP exchange, GroES symmetry is rapidly restored. The residence time of both GroES and SP on functional GroEL is reduced to ~1 s, enabling many more iterations than was previously believed possible, consistent with the iterative annealing mechanism. This result is inconsistent with currently accepted models. Using a foldable SP, we show that as the SP folds to the native state and the population of unfolded SP declines, the population of symmetric particles reverts to asymmetric particles in parallel, a result that is consistent with the former being the folding functional form. PMID- 24167281 TI - Elevated rates of gold mining in the Amazon revealed through high-resolution monitoring. AB - Gold mining has rapidly increased in western Amazonia, but the rates and ecological impacts of mining remain poorly known and potentially underestimated. We combined field surveys, airborne mapping, and high-resolution satellite imaging to assess road- and river-based gold mining in the Madre de Dios region of the Peruvian Amazon from 1999 to 2012. In this period, the geographic extent of gold mining increased 400%. The average annual rate of forest loss as a result of gold mining tripled in 2008 following the global economic recession, closely associated with increased gold prices. Small clandestine operations now comprise more than half of all gold mining activities throughout the region. These rates of gold mining are far higher than previous estimates that were based on traditional satellite mapping techniques. Our results prove that gold mining is growing more rapidly than previously thought, and that high-resolution monitoring approaches are required to accurately quantify human impacts on tropical forests. PMID- 24167280 TI - Sleeping Beauty mutagenesis in a mouse medulloblastoma model defines networks that discriminate between human molecular subgroups. AB - The Sleeping Beauty (SB) transposon mutagenesis screen is a powerful tool to facilitate the discovery of cancer genes that drive tumorigenesis in mouse models. In this study, we sought to identify genes that functionally cooperate with sonic hedgehog signaling to initiate medulloblastoma (MB), a tumor of the cerebellum. By combining SB mutagenesis with Patched1 heterozygous mice (Ptch1(lacZ/+)), we observed an increased frequency of MB and decreased tumor free survival compared with Ptch1(lacZ/+) controls. From an analysis of 85 tumors, we identified 77 common insertion sites that map to 56 genes potentially driving increased tumorigenesis. The common insertion site genes identified in the mutagenesis screen were mapped to human orthologs, which were used to select probes and corresponding expression data from an independent set of previously described human MB samples, and surprisingly were capable of accurately clustering known molecular subgroups of MB, thereby defining common regulatory networks underlying all forms of MB irrespective of subgroup. We performed a network analysis to discover the likely mechanisms of action of subnetworks and used an in vivo model to confirm a role for a highly ranked candidate gene, Nfia, in promoting MB formation. Our analysis implicates candidate cancer genes in the deregulation of apoptosis and translational elongation, and reveals a strong signature of transcriptional regulation that will have broad impact on expression programs in MB. These networks provide functional insights into the complex biology of human MB and identify potential avenues for intervention common to all clinical subgroups. PMID- 24167283 TI - Electronic structure of carbon dioxide under pressure and insights into the molecular-to-nonmolecular transition. AB - Knowledge of the high-pressure behavior of carbon dioxide (CO2), an important planetary material found in Venus, Earth, and Mars, is vital to the study of the evolution and dynamics of the planetary interiors as well as to the fundamental understanding of the C-O bonding and interaction between the molecules. Recent studies have revealed a number of crystalline polymorphs (CO2-I to -VII) and an amorphous phase under high pressure-temperature conditions. Nevertheless, the reported phase stability field and transition pressures at room temperature are poorly defined, especially for the amorphous phase. Here we shed light on the successive pressure-induced local structural changes and the molecular-to nonmolecular transition of CO2 at room temperature by performing an in situ study of the local electronic structure using X-ray Raman scattering, aided by first principle exciton calculations. We show that the transition from CO2-I to CO2-III was initiated at around 7.4 GPa, and completed at about 17 GPa. The present study also shows that at ~37 GPa, molecular CO2 starts to polymerize to an extended structure with fourfold coordinated carbon and minor CO3 and CO-like species. The observed pressure is more than 10 GPa below previously reported. The disappearance of the minority species at 63(+/- 3) GPa suggests that a previously unknown phase transition within the nonmolecular phase of CO2 has occurred. PMID- 24167282 TI - Mind wandering away from pain dynamically engages antinociceptive and default mode brain networks. AB - Human minds often wander away from their immediate sensory environment. It remains unknown whether such mind wandering is unsystematic or whether it lawfully relates to an individual's tendency to attend to salient stimuli such as pain and their associated brain structure/function. Studies of pain-cognition interactions typically examine explicit manipulation of attention rather than spontaneous mind wandering. Here we sought to better represent natural fluctuations in pain in daily life, so we assessed behavioral and neural aspects of spontaneous disengagement of attention from pain. We found that an individual's tendency to attend to pain related to the disruptive effect of pain on his or her cognitive task performance. Next, we linked behavioral findings to neural networks with strikingly convergent evidence from functional magnetic resonance imaging during pain coupled with thought probes of mind wandering, dynamic resting state activity fluctuations, and diffusion MRI. We found that (i) pain-induced default mode network (DMN) deactivations were attenuated during mind wandering away from pain; (ii) functional connectivity fluctuations between the DMN and periaqueductal gray (PAG) dynamically tracked spontaneous attention away from pain; and (iii) across individuals, stronger PAG-DMN structural connectivity and more dynamic resting state PAG-DMN functional connectivity were associated with the tendency to mind wander away from pain. These data demonstrate that individual tendencies to mind wander away from pain, in the absence of explicit manipulation, are subserved by functional and structural connectivity within and between default mode and antinociceptive descending modulation networks. PMID- 24167284 TI - Enhanced fatigue endurance of metallic glasses through a staircase-like fracture mechanism. AB - Bulk-metallic glasses (BMGs) are now candidate materials for structural applications due to their exceptional strength and toughness. However, their fatigue resistance can be poor and inconsistent, severely limiting their potential as reliable structural materials. As fatigue limits are invariably governed by the local arrest of microscopically small cracks at microstructural features, the lack of microstructure in monolithic glasses, often coupled with other factors, such as the ease of crack formation in shear bands or a high susceptibility to corrosion, can lead to low fatigue limits (some ~1/20 of their tensile strengths) and highly variable fatigue lives. BMG-matrix composites can provide a solution here as their duplex microstructures can arrest shear bands at a second phase to prevent cracks from exceeding critical size; under these conditions, fatigue limits become comparable with those of crystalline alloys. Here, we report on a Pd-based glass that similarly has high fatigue resistance but without a second phase. This monolithic glass displays high intrinsic toughness from extensive shear-band proliferation with cavitation and cracking effectively obstructed. We find that this property can further promote fatigue resistance through extrinsic crack-tip shielding, a mechanism well known in crystalline metals but not previously reported in BMGs, whereby cyclically loaded cracks propagate in a highly "zig-zag" manner, creating a rough "staircase-like" profile. The resulting crack-surface contact (roughness-induced crack closure) elevates fatigue properties to those comparable to crystalline alloys, and the accompanying plasticity helps to reduce flaw sensitivity in the glass, thereby promoting structural reliability. PMID- 24167285 TI - Hypermutability and error catastrophe due to defects in ribonucleotide reductase. AB - The enzyme ribonucleotide reductase (RNR) plays a critical role in the production of deoxynucleoside-5'-triphosphates (dNTPs), the building blocks for DNA synthesis and replication. The levels of the cellular dNTPs are tightly controlled, in large part through allosteric control of RNR. One important reason for controlling the dNTPs relates to their ability to affect the fidelity of DNA replication and, hence, the cellular mutation rate. We have previously isolated a set of mutants of Escherichia coli RNR that are characterized by altered dNTP pools and increased mutation rates (mutator mutants). Here, we show that one particular set of RNR mutants, carrying alterations at the enzyme's allosteric specificity site, is characterized by relatively modest dNTP pool deviations but exceptionally strong mutator phenotypes, when measured in a mutational forward assay (>1,000-fold increases). We provide evidence indicating that this high mutability is due to a saturation of the DNA mismatch repair system, leading to hypermutability and error catastrophe. The results indicate that, surprisingly, even modest deviations of the cellular dNTP pools, particularly when the pool deviations promote particular types of replication errors, can have dramatic consequences for mutation rates. PMID- 24167286 TI - Designing DNA-grafted particles that self-assemble into desired crystalline structures using the genetic algorithm. AB - In conventional research, colloidal particles grafted with single-stranded DNA are allowed to self-assemble, and then the resulting crystal structures are determined. Although this Edisonian approach is useful for a posteriori understanding of the factors governing assembly, it does not allow one to a priori design ssDNA-grafted colloids that will assemble into desired structures. Here we address precisely this design issue, and present an experimentally validated evolutionary optimization methodology that is not only able to reproduce the original phase diagram detailing regions of known crystals, but is also able to elucidate several previously unobserved structures. Although experimental validation of these structures requires further work, our early success encourages us to propose that this genetic algorithm-based methodology is a promising and rational materials-design paradigm with broad potential applications. PMID- 24167287 TI - Microclimate moderates plant responses to macroclimate warming. AB - Recent global warming is acting across marine, freshwater, and terrestrial ecosystems to favor species adapted to warmer conditions and/or reduce the abundance of cold-adapted organisms (i.e., "thermophilization" of communities). Lack of community responses to increased temperature, however, has also been reported for several taxa and regions, suggesting that "climatic lags" may be frequent. Here we show that microclimatic effects brought about by forest canopy closure can buffer biotic responses to macroclimate warming, thus explaining an apparent climatic lag. Using data from 1,409 vegetation plots in European and North American temperate forests, each surveyed at least twice over an interval of 12-67 y, we document significant thermophilization of ground-layer plant communities. These changes reflect concurrent declines in species adapted to cooler conditions and increases in species adapted to warmer conditions. However, thermophilization, particularly the increase of warm-adapted species, is attenuated in forests whose canopies have become denser, probably reflecting cooler growing-season ground temperatures via increased shading. As standing stocks of trees have increased in many temperate forests in recent decades, local microclimatic effects may commonly be moderating the impacts of macroclimate warming on forest understories. Conversely, increases in harvesting woody biomass -e.g., for bioenergy--may open forest canopies and accelerate thermophilization of temperate forest biodiversity. PMID- 24167289 TI - Sulfur isotope homogeneity of oceanic DMSP and DMS. AB - Oceanic emissions of volatile dimethyl sulfide (DMS) represent the largest natural source of biogenic sulfur to the global atmosphere, where it mediates aerosol dynamics. To constrain the contribution of oceanic DMS to aerosols we established the sulfur isotope ratios ((34)S/(32)S ratio, delta(34)S) of DMS and its precursor, dimethylsulfoniopropionate (DMSP), in a range of marine environments. In view of the low oceanic concentrations of DMS/P, we applied a unique method for the analysis of delta(34)S at the picomole level in individual compounds. Surface water DMSP collected from six different ocean provinces revealed a remarkable consistency in delta(34)S values ranging between +18.9 and +20.30/00. Sulfur isotope composition of DMS analyzed in freshly collected seawater was similar to delta(34)S of DMSP, showing that the in situ fractionation between these species is small (<+10/00). Based on volatilization experiments, emission of DMS to the atmosphere results in a relatively small fractionation (-0.5 +/- 0.20/00) compared with the seawater DMS pool. Because delta(34)S values of oceanic DMS closely reflect that of DMSP, we conclude that the homogenous delta(34)S of DMSP at the ocean surface represents the delta(34)S of DMS emitted to the atmosphere, within +10/00. The delta(34)S of oceanic DMS flux to the atmosphere is thus relatively constant and distinct from anthropogenic sources of atmospheric sulfate, thereby enabling estimation of the DMS contribution to aerosols. PMID- 24167288 TI - Cell responses only partially shape cell-to-cell variations in protein abundances in Escherichia coli chemotaxis. AB - Cell-to-cell variations in protein abundance in clonal cell populations are ubiquitous in living systems. Because protein composition determines responses in individual cells, it stands to reason that the variations themselves are subject to selective pressures. However, the functional role of these cell-to-cell differences is not well understood. One way to tackle questions regarding relationships between form and function is to perturb the form (e.g., change the protein abundances) and observe the resulting changes in some function. Here, we take on the form-function relationship from the inverse perspective, asking instead what specific constraints on cell-to-cell variations in protein abundance are imposed by a given functional phenotype. We develop a maximum entropy-based approach to posing questions of this type and illustrate the method by application to the well-characterized chemotactic response in Escherichia coli. We find that full determination of observed cell-to-cell variations in protein abundances is not inherent in chemotaxis itself but, in fact, appears to be jointly imposed by the chemotaxis program in conjunction with other factors (e.g., the protein synthesis machinery and/or additional nonchemotactic cell functions, such as cell metabolism). These results illustrate the power of maximum entropy as a tool for the investigation of relationships between biological form and function. PMID- 24167290 TI - Frontalin pheromone biosynthesis in the mountain pine beetle, Dendroctonus ponderosae, and the role of isoprenyl diphosphate synthases. AB - The mountain pine beetle (Dendroctonus ponderosae Hopkins) is the most destructive pest of western North American pine forests. Adult males produce frontalin, an eight-carbon antiaggregation pheromone, via the mevalonate pathway, as part of several pheromones that initiate and modulate the mass attack of host trees. Frontalin acts as a pheromone, attractant, or kairomone in most Dendroctonus species, other insects, and even elephants. 6-Methylhept-6-en-2-one, a frontalin precursor, is hypothesized to originate from 10-carbon geranyl diphosphate (GPP), 15-carbon farnesyl diphosphate (FPP), or 20-carbon geranylgeranyl diphosphate (GGPP) via a dioxygenase- or cytochrome P450-mediated carbon-carbon bond cleavage. To investigate the role of isoprenyl diphosphate synthases in pheromone biosynthesis, we characterized a bifunctional GPP/FPP synthase and a GGPP synthase in the mountain pine beetle. The ratio of GPP to FPP produced by the GPP/FPP synthase was highly dependent on the ratio of the substrates isopentenyl diphosphate and dimethylallyl diphosphate used in the assay. Transcript levels in various tissues and life stages suggested that GGPP rather than GPP or FPP is used as a precursor to frontalin. Reduction of transcript levels by RNA interference of the isoprenyl diphosphate synthases identified GGPP synthase as having the largest effect on frontalin production, suggesting that frontalin is derived from a 20-carbon isoprenoid precursor rather than from the 10- or 15-carbon precursors. PMID- 24167291 TI - Epstein-Barr virus nuclear antigen leader protein localizes to promoters and enhancers with cell transcription factors and EBNA2. AB - Epstein-Barr virus (EBV) nuclear antigens EBNALP (LP) and EBNA2 (E2) are coexpressed in EBV-infected B lymphocytes and are critical for lymphoblastoid cell line outgrowth. LP removes NCOR and RBPJ repressive complexes from promoters, enhancers, and matrix-associated deacetylase bodies, whereas E2 activates transcription from distal enhancers. LP ChIP-seq analyses identified 19,224 LP sites of which ~50% were +/- 2 kb of a transcriptional start site. LP sites were enriched for B-cell transcription factors (TFs), YY1, SP1, PAX5, BATF, IRF4, ETS1, RAD21, PU.1, CTCF, RBPJ, ZNF143, SMC3, NFkappaB, TBLR, and EBF. E2 sites were also highly enriched for LP-associated cell TFs and were more highly occupied by RBPJ and EBF. LP sites were highly marked by H3K4me3, H3K27ac, H2Az, H3K9ac, RNAPII, and P300, indicative of activated transcription. LP sites were 29% colocalized with E2 (LP/E2). LP/E2 sites were more similar to LP than to E2 sites in associated cell TFs, RNAPII, P300, and histone H3K4me3, H3K9ac, H3K27ac, and H2Az occupancy, and were more highly transcribed than LP or E2 sites. Gene affected by CTCF and LP cooccupancy were more highly expressed than genes affected by CTCF alone. LP was at myc enhancers and promoters and of MYC regulated ccnd2, 23 med complex components, and MYC regulated cell survival genes, igf2r and bcl2. These data implicate LP and associated TFs and DNA looping factors CTCF, RAD21, SMC3, and YY1/INO80 chromatin-remodeling complexes in repressor depletion and gene activation necessary for lymphoblastoid cell line growth and survival. PMID- 24167292 TI - Grammatical morphology as a source of early number word meanings. AB - How does cross-linguistic variation in linguistic structure affect children's acquisition of early number word meanings? We tested this question by investigating number word learning in two unrelated languages that feature a tripartite singular-dual-plural distinction: Slovenian and Saudi Arabic. We found that learning dual morphology affects children's acquisition of the number word two in both languages, relative to English. Children who knew the meaning of two were surprisingly frequent in the dual languages, relative to English. Furthermore, Slovenian children were faster to learn two than children learning English, despite being less-competent counters. Finally, in both Slovenian and Saudi Arabic, comprehension of the dual was correlated with knowledge of two and higher number words. PMID- 24167293 TI - Intracellular Shigella remodels its LPS to dampen the innate immune recognition and evade inflammasome activation. AB - LPS is a potent bacterial effector triggering the activation of the innate immune system following binding with the complex CD14, myeloid differentiation protein 2, and Toll-like receptor 4. The LPS of the enteropathogen Shigella flexneri is a hexa-acylated isoform possessing an optimal inflammatory activity. Symptoms of shigellosis are produced by severe inflammation caused by the invasion process of Shigella in colonic and rectal mucosa. Here we addressed the question of the role played by the Shigella LPS in eliciting a dysregulated inflammatory response of the host. We unveil that (i) Shigella is able to modify the LPS composition, e.g., the lipid A and core domains, during proliferation within epithelial cells; (ii) the LPS of intracellular bacteria (iLPS) and that of bacteria grown in laboratory medium differ in the number of acyl chains in lipid A, with iLPS being the hypoacylated; (iii) the immunopotential of iLPS is dramatically lower than that of bacteria grown in laboratory medium; (iv) both LPS forms mainly signal through the Toll-like receptor 4/myeloid differentiation primary response gene 88 pathway; (v) iLPS down-regulates the inflammasome-mediated release of IL-1beta in Shigella-infected macrophages; and (vi) iLPS exhibits a reduced capacity to prime polymorfonuclear cells for an oxidative burst. We propose a working model whereby the two forms of LPS might govern different steps of the invasive process of Shigella. In the first phases, the bacteria, decorated with hypoacylated LPS, are able to lower the immune system surveillance, whereas, in the late phases, shigellae harboring immunopotent LPS are fully recognized by the immune system, which can then successfully resolve the infection. PMID- 24167294 TI - Enhancing tumor cell response to chemotherapy through nanoparticle-mediated codelivery of siRNA and cisplatin prodrug. AB - Cisplatin and other DNA-damaging chemotherapeutics are widely used to treat a broad spectrum of malignancies. However, their application is limited by both intrinsic and acquired chemoresistance. Most mutations that result from DNA damage are the consequence of error-prone translesion DNA synthesis, which could be responsible for the acquired resistance against DNA-damaging agents. Recent studies have shown that the suppression of crucial gene products (e.g., REV1, REV3L) involved in the error-prone translesion DNA synthesis pathway can sensitize intrinsically resistant tumors to chemotherapy and reduce the frequency of acquired drug resistance of relapsed tumors. In this context, combining conventional DNA-damaging chemotherapy with siRNA-based therapeutics represents a promising strategy for treating patients with malignancies. To this end, we developed a versatile nanoparticle (NP) platform to deliver a cisplatin prodrug and REV1/REV3L-specific siRNAs simultaneously to the same tumor cells. NPs are formulated through self-assembly of a biodegradable poly(lactide-coglycolide)-b poly(ethylene glycol) diblock copolymer and a self-synthesized cationic lipid. We demonstrated the potency of the siRNA-containing NPs to knock down target genes efficiently both in vitro and in vivo. The therapeutic efficacy of NPs containing both cisplatin prodrug and REV1/REV3L-specific siRNAs was further investigated in vitro and in vivo. Quantitative real-time PCR results showed that the NPs exhibited a significant and sustained suppression of both genes in tumors for up to 3 d after a single dose. Administering these NPs revealed a synergistic effect on tumor inhibition in a human Lymph Node Carcinoma of the Prostate xenograft mouse model that was strikingly more effective than platinum monotherapy. PMID- 24167295 TI - Conformational selection and adaptation to ligand binding in T4 lysozyme cavity mutants. AB - The studies presented here explore the relationship between protein packing and molecular flexibility using ligand-binding cavity mutants of T4 lysozyme. Although previously reported crystal structures of the mutants investigated show single conformations that are similar to the WT protein, site-directed spin labeling in solution reveals additional conformational substates in equilibrium exchange with a WT-like population. Remarkably, binding of ligands, including the general anesthetic halothane shifts the population to the WT-like state, consistent with a conformational selection model of ligand binding, but structural adaptation to the ligand is also apparent in one mutant. Distance mapping with double electron-electron resonance spectroscopy and the absence of ligand binding suggest that the new substates induced by the cavity-creating mutations represent alternate packing modes in which the protein fills or partially fills the cavity with side chains, including the spin label in one case; external ligands compete with the side chains for the cavity space, stabilizing the WT conformation. The results have implications for mechanisms of anesthesia, the response of proteins to hydrostatic pressure, and protein engineering. PMID- 24167296 TI - Immunosignatures can predict vaccine efficacy. AB - The development of new vaccines would be greatly facilitated by having effective methods to predict vaccine performance. Such methods could also be helpful in monitoring individual vaccine responses to existing vaccines. We have developed "immunosignaturing" as a simple, comprehensive, chip-based method to display the antibody diversity in an individual on peptide arrays. Here we examined whether this technology could be used to develop correlates for predicting vaccine effectiveness. By using a mouse influenza infection, we show that the immunosignaturing of a natural infection can be used to discriminate a protective from nonprotective vaccine. Further, we demonstrate that an immunosignature can determine which mice receiving the same vaccine will survive. Finally, we show that the peptides comprising the correlate signatures of protection can be used to identify possible epitopes in the influenza virus proteome that are correlates of protection. PMID- 24167297 TI - Viroporin activity of the JC polyomavirus is regulated by interactions with the adaptor protein complex 3. AB - Viroporins, which are encoded by a wide range of animal viruses, oligomerize in host cell membranes and form hydrophilic pores that can disrupt a number of physiological properties of the cell. Little is known about the relationship between host cell proteins and viroporin activity. The human JC polyomavirus (JCV) is the causative agent of progressive multifocal leukoencephalopathy. The JCV-encoded agnoprotein, which is essential for viral replication, has been shown to act as a viroporin. Here we demonstrate that the JCV agnoprotein specifically interacts with adaptor protein complex 3 through its delta subunit. This interaction interrupts adaptor protein complex 3-mediated vesicular trafficking with suppression of the targeting of the protein to the lysosomal degradation pathway and instead permits the transport of agnoprotein to the cell surface with resulting membrane permeabilization. The findings demonstrate a previously undescribed paradigm in virus-host interactions allowing the host to regulate viroporin activity and suggest that the viroporins of other viruses may also be highly regulated by specific interactions with host cell proteins. PMID- 24167298 TI - High-speed laser microsurgery of alert fruit flies for fluorescence imaging of neural activity. AB - Intravital microscopy is a key means of monitoring cellular function in live organisms, but surgical preparation of a live animal for microscopy often is time consuming, requires considerable skill, and limits experimental throughput. Here we introduce a spatially precise (<1-um edge precision), high-speed (<1 s), largely automated, and economical protocol for microsurgical preparation of live animals for optical imaging. Using a 193-nm pulsed excimer laser and the fruit fly as a model, we created observation windows (12- to 350-um diameters) in the exoskeleton. Through these windows we used two-photon microscopy to image odor evoked Ca(2+) signaling in projection neuron dendrites of the antennal lobe and Kenyon cells of the mushroom body. The impact of a laser-cut window on fly health appears to be substantially less than that of conventional manual dissection, for our imaging durations of up to 18 h were ~5-20 times longer than prior in vivo microscopy studies of hand-dissected flies. This improvement will facilitate studies of numerous questions in neuroscience, such as those regarding neuronal plasticity or learning and memory. As a control, we used phototaxis as an exemplary complex behavior in flies and found that laser microsurgery is sufficiently gentle to leave it intact. To demonstrate that our techniques are applicable to other species, we created microsurgical openings in nematodes, ants, and the mouse cranium. In conjunction with emerging robotic methods for handling and mounting flies or other small organisms, our rapid, precisely controllable, and highly repeatable microsurgical techniques should enable automated, high-throughput preparation of live animals for optical experimentation. PMID- 24167299 TI - Introduction to chemistry and applications in nature of mass independent isotope effects special feature. AB - Stable isotope ratio variations are regulated by physical and chemical laws. These rules depend on a relation with mass differences between isotopes. New classes of isotope variation effects that deviate from mass dependent laws, termed mass independent isotope effects, were discovered in 1983 and have a wide range of applications in basic chemistry and nature. In this special edition, new applications of these effects to physical chemistry, solar system origin models, terrestrial atmospheric and biogenic evolution, polar paleo climatology, snowball earth geology, and present day atmospheric sciences are presented. PMID- 24167302 TI - The 'one animal in all creation about which man knows the least'. PMID- 24167300 TI - Characterization of the Staphylococcal enterotoxin A: Vbeta receptor interaction using human receptor fragments engineered for high affinity. AB - Staphylococcal food poisoning is a gastrointestinal disorder caused by the consumption of food containing Staphylococcal enterotoxins. Staphylococcal enterotoxin A (SEA) is the most common enterotoxin recovered from food poisoning outbreaks in the USA. In addition to its enteric activity, SEA also acts as a potent superantigen through stimulation of T cells, although less is known about its interactions than the superantigens SEB, SEC and toxic shock syndrome toxin 1. To understand more about SEA:receptor interactions, and to develop toxin detection systems for use in food testing, we engineered various SEA-binding receptor mutants. The extracellular domain of the receptor, a variable region of the beta chain (Vbeta22) of the T-cell receptor, was engineered for stability as a soluble protein and for high affinity, using yeast-display technology. The highest affinity mutant was shown to bind SEA with a Kd value of 4 nM. This was a 25 000-fold improvement in affinity compared with the wild-type receptor, which bound to SEA with low affinity (Kd value of 100 uM), similar to other superantigen:Vbeta interactions. The SEA:Vbeta interface was centered around residues within the complementarity determining region 2 loop. The engineered receptor was specific for SEA, in that it did not bind to two other closely related enterotoxins SEE or SED, providing information on the SEA residues possibly involved in the interaction. The specificity and affinity of these high affinity Vbeta proteins also provide useful agents for the design of more sensitive and specific systems for SEA detection. PMID- 24167303 TI - Female competition and aggression: interdisciplinary perspectives. AB - This paper introduces a Theme Issue combining interdisciplinary perspectives in the study of female competition and aggression. Despite a history of being largely overlooked, evidence is now accumulating for the widespread evolutionary significance of female competition. Here, we provide a synthesis of contributions to this Theme Issue on humans and other vertebrates, and highlight directions for future research. Females compete for resources needed to survive and reproduce, and for preferred mates. Although female aggression takes diverse forms, under most circumstances relatively low-risk competitive strategies are favoured, most probably due to constraints of offspring production and care. In social species, dominance relationships and threats of punishment can resolve social conflict without resort to direct aggression, and coalitions or alliances may reduce risk of retaliation. Consistent with these trends, indirect aggression is a low cost but effective form of competition among young women. Costs are also minimized by flexibility in expression of competitive traits, with aggressive behaviour and competitive signalling tailored to social and ecological conditions. Future research on female competition and the proximate mediators of female aggression will be greatly enhanced by opportunities for interdisciplinary exchange, as evidenced by contributions to this Theme Issue. PMID- 24167304 TI - Social competition and selection in males and females. AB - During the latter half of the last century, evidence of reproductive competition between males and male selection by females led to the development of a stereotypical view of sex differences that characterized males as competitive and aggressive, and females as passive and choosy, which is currently being revised. Here, we compare social competition and its consequences for selection in males and females and argue that similar selection processes operate in both sexes and that contrasts between the sexes are quantitative rather than qualitative. We suggest that classifications of selection based on distinction between the form of competition or the components of fitness that are involved introduce unnecessary complexities and that the most useful approach in understanding the evolution and distribution of differences and similarities between the sexes is to compare the operation of selection in males and females in different reproductive systems. PMID- 24167305 TI - Intra-sexual selection in cooperative mammals and birds: why are females not bigger and better armed? AB - In cooperatively breeding mammals and birds, intra-sexual reproductive competition among females may often render variance in reproductive success higher among females than males, leading to the prediction that intra-sexual selection in such species may have yielded the differential exaggeration of competitive traits among females. However, evidence to date suggests that female biased reproductive variance in such species is rarely accompanied by female biased sexual dimorphisms. We illustrate the problem with data from wild Damaraland mole-rat, Fukomys damarensis, societies: the variance in lifetime reproductive success among females appears to be higher than that among males, yet males grow faster, are much heavier as adults and sport larger skulls and incisors (the weapons used for fighting) for their body lengths than females, suggesting that intra-sexual selection has nevertheless acted more strongly on the competitive traits of males. We then consider potentially general mechanisms that could explain these disparities by tempering the relative intensity of selection for competitive trait exaggeration among females in cooperative breeders. Key among these may be interactions with kin selection that could nevertheless render the variance in inclusive fitness lower among females than males, and fundamental aspects of the reproductive biology of females that may leave reproductive conflict among females more readily resolved without overt physical contests. PMID- 24167306 TI - Resolving social conflict among females without overt aggression. AB - Members of animal societies compete over resources and reproduction, but the extent to which such conflicts of interest are resolved peacefully (without recourse to costly or wasteful acts of aggression) varies widely. Here, we describe two theoretical mechanisms that can help to understand variation in the incidence of overt behavioural conflict: (i) destruction competition and (ii) the use of threats. The two mechanisms make different assumptions about the degree to which competitors are socially sensitive (responsive to real-time changes in the behaviour of their social partners). In each case, we discuss how the model assumptions relate to biological reality and highlight the genetic, ecological and informational factors that are likely to promote peaceful conflict resolution, drawing on empirical examples. We suggest that, relative to males, reproductive conflict among females may be more frequently resolved peacefully through threats of punishment, rather than overt acts of punishment, because (i) offspring are more costly to produce for females and (ii) reproduction is more difficult to conceal. The main need now is for empirical work to test whether the mechanisms described here can indeed explain how social conflict can be resolved without overt aggression. PMID- 24167307 TI - Female competition in chimpanzees. AB - Female chimpanzees exhibit exceptionally slow rates of reproduction and raise their offspring without direct paternal care. Therefore, their reproductive success depends critically on long-term access to high-quality food resources over a long lifespan. Chimpanzee communities contain multiple adult males, multiple adult females and their offspring. Because males are philopatric and jointly defend the community range while most females transfer to new communities before breeding, adult females are typically surrounded by unrelated competitors. Communities are fission-fusion societies in which individuals spend time alone or in fluid subgroups, whose size depends mostly on the abundance and distribution of food. To varying extents in different populations, females avoid direct competition by foraging alone or in small groups in distinct, but overlapping core areas within the community range to which they show high fidelity. Although rates of aggression are low, females compete for space and access to food. High rank correlates with high reproductive success, and high-ranking females win direct contests for food and gain preferential access to resource-rich sites. Females are aggressive to immigrant females and even kill the newborn infants of community members. The intensity of such aggression correlates with population density. These patterns are compared to those in other species, including humans. PMID- 24167308 TI - The evolutionary psychology of women's aggression. AB - Evolutionary researchers have identified age, operational sex ratio and high variance in male resources as factors that intensify female competition. These are discussed in relation to escalated intrasexual competition for men and their resources between young women in deprived neighbourhoods. For these women, fighting is not seen as antithetical to cultural conceptions of femininity, and female weakness is disparaged. Nonetheless, even where competitive pressures are high, young women's aggression is less injurious and frequent than young men's. From an evolutionary perspective, I argue that the intensity of female aggression is constrained by the greater centrality of mothers, rather than fathers, to offspring survival. This selection pressure is realized psychologically through a lower threshold for fear among women. Neuropsychological evidence is not yet conclusive but suggests that women show heightened amygdala reactivity to threatening stimuli, may be better able to exert prefrontal cortical control over emotional behaviour and may consciously register fear more strongly via anterior cingulate activity. The impact of testosterone and oxytocin on the neural circuitry of emotion is also considered. PMID- 24167309 TI - The development of human female competition: allies and adversaries. AB - Throughout their lives, women provide for their own and their children's and grandchildren's needs and thus must minimize their risk of incurring physical harm. Alliances with individuals who will assist them in attaining these goals increase their probability of survival and reproductive success. High status in the community enhances access to physical resources and valuable allies. Kin, a mate, and affines share a mother's genetic interests, whereas unrelated women constitute primary competitors. From early childhood onwards, girls compete using strategies that minimize the risk of retaliation and reduce the strength of other girls. Girls' competitive strategies include avoiding direct interference with another girl's goals, disguising competition, competing overtly only from a position of high status in the community, enforcing equality within the female community and socially excluding other girls. PMID- 24167310 TI - Do human females use indirect aggression as an intrasexual competition strategy? AB - Indirect aggression includes behaviours such as criticizing a competitor's appearance, spreading rumours about a person's sexual behaviour and social exclusion. Human females have a particular proclivity for using indirect aggression, which is typically directed at other females, especially attractive and sexually available females, in the context of intrasexual competition for mates. Indirect aggression is an effective intrasexual competition strategy. It is associated with a diminished willingness to compete on the part of victims and with greater dating and sexual behaviour among those who perpetrate the aggression. PMID- 24167311 TI - Reproductive competition between females in the matrilineal Mosuo of southwestern China. AB - The matrilineal Mosuo of southwestern China live in communal households where brothers and sisters of three generations live together (duolocal residence), and men visit their wives, who reside elsewhere, only at night in 'visiting' marriages. Here we show that these communally breeding sisters are in reproductive conflict, in the sense that they share the resources needed to reproduce. We analyse determinants of reproductive success in females and males, and show that co-resident female kin are in competition; the more female kin reside in the household, the more reproductive success is reduced. Male reproductive success, however, is not determined by the kin in his natal household; duolocal males are not in reproductive conflict with their siblings. Competition with female cousins can be worse than that between sisters. We also find that female work on the farm (which is the main communal resource) is not equal. We use a 'tug-of-war' model of reproductive skew generated by incomplete control, to model the patterns of effort put into competition between sisters and cousins. The model predicts that more dominant (older) sisters will put less effort into reproductive conflict than will less dominant (younger) sisters; but younger sisters will also have lower reproductive success because they are less efficient at gaining access to the shared resource. Both predictions are consistent with our data. Younger sisters work less in the fields than do older sisters, which may represent a form of conflict or may be because their average relatedness to the household is lower than that of their more fertile older sisters. PMID- 24167312 TI - Wake up and smell the conflict: odour signals in female competition. AB - Odour signals used in competitive and aggressive interactions between males are well studied in the context of sexual selection. By contrast, relatively little is known about comparable signals used by females, despite current interest in the evolution of female ornaments and weaponry. Available evidence suggests that odour signals are important in competitive interactions between female mammals, with reductions or reversals of male-biased sexual dimorphism in signalling where female competition is intense. Scent marking is often associated with conflict between females over access to resources or reproductive opportunities. Female scent marks may therefore provide reliable signals of competitive ability that could be used both by competitors and potential mates. Consistent with this hypothesis, we report that aggressive behaviour of female house mice is correlated with the amount of major urinary protein (MUP) excreted in their urine, a polymorphic set of proteins that are used in scent mark signalling. Under semi-natural conditions, females with high MUP output are more likely to produce offspring sired by males that have high reproductive success, and less likely to produce offspring by multiple different sires, suggesting that females with strong MUP signals are monopolized by males of particularly high quality. We conclude that odour signals are worthy of more detailed investigation as mediators of female competition. PMID- 24167313 TI - Proximate perspectives on the evolution of female aggression: good for the gander, good for the goose? AB - Female-female aggression often functions in competition over reproductive or social benefits, but the proximate mechanisms of this apparently adaptive behaviour are not well understood. The sex steroid hormone testosterone (T) and its metabolites are well-established mediators of male-male aggression, and several lines of evidence suggest that T-mediated mechanisms may apply to females as well. However, a key question is whether mechanisms of female aggression primarily reflect correlated evolutionary responses to selection acting on males, or whether direct selection acting on females has made modifications to these mechanisms that are adaptive in light of female life history. Here, I examine the degree to which female aggression is mediated at the level of T production, target tissue sensitivity to T, or downstream genomic responses in order to test the hypothesis that selection favours mechanisms that facilitate female aggression while minimizing the costs of systemically elevated T. I draw heavily from avian systems, including the dark-eyed junco (Junco hyemalis), as well as other organisms in which these mechanisms have been well studied from an evolutionary/ecological perspective in both sexes. Findings reveal that the sexes share many behavioural and hormonal mechanisms, though several patterns also suggest sex-specific adaptation. I argue that greater attention to multiple levels of analysis-from hormone to receptor to gene network, including analyses of individual variation that represents the raw material of evolutionary change will be a fruitful path for understanding mechanisms of behavioural regulation and intersexual coevolution. PMID- 24167314 TI - The influence of androgenic steroid hormones on female aggression in 'atypical' mammals. AB - Dimorphism on dominance and agonistic behaviour in mammals tends to be strongly biased toward males. In this review, we focus on a select few species of mammals in which females are as or more aggressive than males, and/or are dominant to males, and explore the role of androgenic hormones in mediating this important difference. While the data are not as clear-cut as those published on traditional laboratory mammals, our review highlights important endocrine substrates for both organizational and activational influences of steroids on female aggressive behaviour. We highlight areas in which further observations and experiments are crucial, especially the potential facilitative effects of androgens on female aggression. Finally, new and innovative techniques, including molecular genetics and receptor pharmacology, portend important insights into the ways in which androgenic hormones regulate aggressive behaviour in 'atypical' female mammals. PMID- 24167315 TI - Maternal aggression in rodents: brain oxytocin and vasopressin mediate pup defence. AB - The most significant social behaviour of the lactating mother is maternal behaviour, which comprises maternal care and maternal aggression (MA). The latter is a protective behaviour of the mother serving to defend the offspring against a potentially dangerous intruder. The extent to which the mother shows aggressive behaviour depends on extrinsic and intrinsic factors, as we have learned from studies in laboratory rodents. Among the extrinsic factors are the pups' presence and age, as well as the intruders' sex and age. With respect to intrinsic factors, the mothers' innate anxiety and the prosocial brain neuropeptides oxytocin (OXT) and arginine vasopressin (AVP) play important roles. While OXT is well known as a maternal neuropeptide, AVP has only recently been described in this context. The increased activities of these neuropeptides in lactation are the result of remarkable brain adaptations peripartum and are a prerequisite for the mother to become maternal. Consequently, OXT and AVP are significantly involved in mediating the fine-tuned regulation of MA depending on the brain regions. Importantly, both neuropeptides are also modulators of anxiety, which determines the extent of MA. This review provides a detailed overview of the role of OXT and AVP in MA and the link to anxiety. PMID- 24167316 TI - Decellularized feeders: an optimized method for culturing pluripotent cells. AB - Pluripotent cells such as human embryonic stem cells and human induced pluripotent stem cells are useful in the field of regenerative medicine because they can proliferate indefinitely and differentiate into all cell types. However, a limiting factor for maintaining and propagating stem cells is the need for inactivated fibroblasts as a growth matrix, since these may potentially cause cross-contamination. In this study, we aimed to maintain stem cells on the extracellular matrix (ECM) of either nonirradiated or gamma-irradiated fibroblasts. It has been demonstrated that the ECM contains factors and proteins vital for the adhesion, proliferation, and differentiation of pluripotent cells. In order to preserve the ECM, the cell layers of the fibroblasts were decellularized by treatment with 0.05% sodium dodecyl sulfate (SDS), which resulted in an absence of DNA as compared with conventional feeder culture. However, SDS treatment did not cause a detectable change in the ECM architecture and integrity. Furthermore, immunohistochemistry demonstrated that expressions of major ECM proteins, such as fibronectin, collagen, and laminin, remained unaltered. The human pluripotent cells cultured on this decellularized matrix maintained gene expression of the pluripotency markers NANOG and OCT4 and had the potency to differentiate to three germ layers. The in vitro culture system shown here has an excellent potential since the main allogeneic components (i.e., DNA of the feeder cells) are removed. It is also a technically easy, fast, safe, and cheap method for maintaining a refined feeder-free stem cell culture for further cell differentiation studies. PMID- 24167317 TI - Genetically modified neural stem cells for a local and sustained delivery of neuroprotective factors to the dystrophic mouse retina. AB - A continuous intraocular delivery of neurotrophic factors (NFs) is being explored as a strategy to rescue photoreceptor cells and visual functions in degenerative retinal disorders that are currently untreatable. To establish a cell-based intraocular delivery system for a sustained administration of NFs to the dystrophic mouse retina, we used a polycistronic lentiviral vector to genetically modify adherently cultivated murine neural stem (NS) cells. The vector concurrently encoded a gene of interest, a reporter gene, and a resistance gene and thus facilitated the selection, cloning, and in vivo tracking of the modified cells. To evaluate whether modified NS cells permit delivery of functionally relevant quantities of NFs to the dystrophic mouse retina, we expressed a secretable variant of ciliary neurotrophic factor (CNTF) in NS cells and grafted the cells into the vitreous space of Pde6b(rd1) and Pde6b(rd10) mice, two animal models of retinitis pigmentosa. In both mouse lines, grafted cells attached to the retina and lens, where they differentiated into astrocytes and some neurons. Adverse effects of the transplanted cells on the morphology of host retinas were not observed. Importantly, the CNTF-secreting NS cells significantly attenuated photoreceptor degeneration in both mutant mouse lines. The neuroprotective effect was significantly more pronounced when clonally derived NS cell lines selected for high expression levels of CNTF were grafted into Pde6b(rd1) mice. Intravitreal transplantations of modified NS cells may thus represent a useful method for preclinical studies aimed at evaluating the therapeutic potential of a cell-based intraocular delivery of NFs in mouse models of photoreceptor degeneration. PMID- 24167318 TI - Zinc finger nuclease-expressing baculoviral vectors mediate targeted genome integration of reprogramming factor genes to facilitate the generation of human induced pluripotent stem cells. AB - Integrative gene transfer using retroviruses to express reprogramming factors displays high efficiency in generating induced pluripotent stem cells (iPSCs), but the value of the method is limited because of the concern over mutagenesis associated with random insertion of transgenes. Site-specific integration into a preselected locus by engineered zinc-finger nuclease (ZFN) technology provides a potential way to overcome the problem. Here, we report the successful reprogramming of human fibroblasts into a state of pluripotency by baculoviral transduction-mediated, site-specific integration of OKSM (Oct3/4, Klf4, Sox2, and c-myc) transcription factor genes into the AAVS1 locus in human chromosome 19. Two nonintegrative baculoviral vectors were used for cotransduction, one expressing ZFNs and another as a donor vector encoding the four transcription factors. iPSC colonies were obtained at a high efficiency of 12% (the mean value of eight individual experiments). All characterized iPSC clones carried the transgenic cassette only at the ZFN-specified AAVS1 locus. We further demonstrated that when the donor cassette was flanked by heterospecific loxP sequences, the reprogramming genes in iPSCs could be replaced by another transgene using a baculoviral vector-based Cre recombinase-mediated cassette exchange system, thereby producing iPSCs free of exogenous reprogramming factors. Although the use of nonintegrating methods to generate iPSCs is rapidly becoming a standard approach, methods based on site-specific integration of reprogramming factor genes as reported here hold the potential for efficient generation of genetically amenable iPSCs suitable for future gene therapy applications. PMID- 24167319 TI - Mouse embryonic stem cells established in physiological-glucose media express the high KM Glut2 glucose transporter expressed by normal embryos. AB - Glut2 is one of the facilitative glucose transporters expressed by preimplantation and early postimplantation embryos. Glut2 is important for survival before embryonic day 10.5. The Glut2 KM (~16 mmol/liter) is significantly higher than physiologic glucose concentrations (~5.5 mmol/liter), suggesting that Glut2 normally performs some essential function other than glucose transport. Nevertheless, Glut2 efficiently transports glucose when extracellular glucose concentrations are above the Glut2 KM. Media containing 25 mmol/liter glucose are widely used to establish and propagate embryonic stem cells (ESCs). Glut2-mediated glucose uptake by embryos induces oxidative stress and can cause embryo cell death. Here we tested the hypothesis that low-glucose embryonic stem cells (LG-ESCs) isolated in physiological-glucose (5.5 mmol/liter) media express a functional Glut2 glucose transporter. LG-ESCs were compared with conventional D3 ESCs that had been cultured only in high-glucose media. LG-ESCs expressed Glut2 mRNA and protein at much higher levels than D3 ESCs, and 2 deoxyglucose transport by LG-ESCs, but not D3 ESCs, exhibited high Michaelis Menten kinetics. Glucose at 25 mmol/liter induced oxidative stress in LG-ESCs and inhibited expression of Pax3, an embryo gene that is inhibited by hyperglycemia, in neuronal precursors derived from LG-ESCs. These effects were not observed in D3 ESCs. These findings demonstrate that ESCs isolated in physiological-glucose media retain a functional Glut2 transporter that is expressed by embryos. These cells are better suited to the study of metabolic regulation characteristic of the early embryo and may be advantageous for therapeutic applications. PMID- 24167322 TI - Quantified ADC histogram analysis: a new method for differentiating mass-forming focal pancreatitis from pancreatic cancer. AB - BACKGROUND: As their prognosis and management are different, differentiation of mass-forming focal pancreatitis (FP) from pancreatic adenocarcinoma (PC) is important. However, the similar clinical presentations and imaging features of these conditions, along with inconclusive biopsy results can make such differentiation difficult. PURPOSE: To determine whether apparent diffusion coefficient (ADC) histogram analysis can discriminate between a normal pancreas, FP, and PC. MATERIAL AND METHODS: In a retrospective study, 25 PC patients, 14 FP patients, and 25 subjects with a normal pancreas underwent breath-hold diffusion weighted imaging (DWI) on a 3.0 T magnetic resonance (MR) scanner. Regions of interest (ROIs) were drawn on the normal pancreases and on the entire focal lesions of both PC and FP. The ADC value was averaged from the lowest to 10th, 30th, 50th, and 100th percentile of the histogram (i.e. ADC10, ADC30, ADC50, and ADC100, respectively), and the results were analyzed statistically. RESULTS: There were no significant differences among the head, body, and tail of normal pancreases for any of the mean ADC values (P > 0.05). ADC10, ADC30, and ADC50 values demonstrated significant differences between lesion and non-lesion areas of both PC (P < 0.05) and FP (P < 0.05). Differences in lesion areas between PC and FP were found with ADC50 and ADC100 values (P < 0.05), and helped differentiate a normal pancreas from FP and PC, and FP from PC. CONCLUSION: Quantified ADC histogram can specifically reflect tissue heterogeneity and help differentiate a normal pancreas from FP and PC. PMID- 24167320 TI - Concise review: stem/progenitor cells for renal tissue repair: current knowledge and perspectives. AB - The kidney is a specialized low-regenerative organ with several different types of cellular lineages; however, the identity of renal stem/progenitor cells with nephrogenic potential and their preferred niche(s) are largely unknown and debated. Most of the therapeutic approaches to kidney regeneration are based on administration of cells proven to enhance intrinsic reparative capabilities of the kidney. Endogenous or exogenous cells of different sources were tested in rodent models of ischemia-reperfusion, acute kidney injury, or chronic disease. The translation to clinics is at the moment focused on the role of mesenchymal stem cells. In addition, bioproducts from stem/progenitor cells, such as extracellular vesicles, are likely a new promising approach for reprogramming resident cells. This concise review reports the current knowledge about resident or exogenous stem/progenitor populations and their derived bioproducts demonstrating therapeutic effects in kidney regeneration upon injury. In addition, possible approaches to nephrogenesis and organ generation using organoids, decellularized kidneys, and blastocyst complementation are surveyed. PMID- 24167321 TI - Neural stem cell-mediated delivery of irinotecan-activating carboxylesterases to glioma: implications for clinical use. AB - CPT-11 (irinotecan) has been investigated as a treatment for malignant brain tumors. However, limitations of CPT-11 therapy include low levels of the drug entering brain tumor sites and systemic toxicities associated with higher doses. Neural stem cells (NSCs) offer a novel way to overcome these obstacles because of their inherent tumor tropism and ability to cross the blood-brain barrier, which enables them to selectively target brain tumor sites. Carboxylesterases (CEs) are enzymes that can convert the prodrug CPT-11 (irinotecan) to its active metabolite SN-38, a potent topoisomerase I inhibitor. We have adenovirally transduced an established clonal human NSC line (HB1.F3.CD) to express a rabbit carboxylesterase (rCE) or a modified human CE (hCE1m6), which are more effective at converting CPT-11 to SN-38 than endogenous human CE. We hypothesized that NSC mediated CE/CPT-11 therapy would allow tumor-localized production of SN-38 and significantly increase the therapeutic efficacy of irinotecan. Here, we report that transduced NSCs transiently expressed high levels of active CE enzymes, retained their tumor-tropic properties, and mediated an increase in the cytotoxicity of CPT-11 toward glioma cells. CE-expressing NSCs (NSC.CEs), whether administered intracranially or intravenously, delivered CE to orthotopic human glioma xenografts in mice. NSC-delivered CE catalyzed conversion of CPT-11 to SN 38 locally at tumor sites. These studies demonstrate the feasibility of NSC mediated delivery of CE to glioma and lay the foundation for translational studies of this therapeutic paradigm to improve clinical outcome and quality of life in patients with malignant brain tumors. PMID- 24167323 TI - Optical coherence tomography-based corneal power measurement and intraocular lens power calculation following laser vision correction (an American Ophthalmological Society thesis). AB - PURPOSE: To use optical coherence tomography (OCT) to measure corneal power and improve the selection of intraocular lens (IOL) power in cataract surgeries after laser vision correction. METHODS: Patients with previous myopic laser vision corrections were enrolled in this prospective study from two eye centers. Corneal thickness and power were measured by Fourier-domain OCT. Axial length, anterior chamber depth, and automated keratometry were measured by a partial coherence interferometer. An OCT-based IOL formula was developed. The mean absolute error of the OCT-based formula in predicting postoperative refraction was compared to two regression-based IOL formulae for eyes with previous laser vision correction. RESULTS: Forty-six eyes of 46 patients all had uncomplicated cataract surgery with monofocal IOL implantation. The mean arithmetic prediction error of postoperative refraction was 0.05 +/- 0.65 diopter (D) for the OCT formula, 0.14 +/- 0.83 D for the Haigis-L formula, and 0.24 +/- 0.82 D for the no-history Shammas-PL formula. The mean absolute error was 0.50 D for OCT compared to a mean absolute error of 0.67 D for Haigis-L and 0.67 D for Shammas-PL. The adjusted mean absolute error (average prediction error removed) was 0.49 D for OCT, 0.65 D for Haigis-L (P=.031), and 0.62 D for Shammas-PL (P=.044). For OCT, 61% of the eyes were within 0.5 D of prediction error, whereas 46% were within 0.5 D for both Haigis-L and Shammas-PL (P=.034). CONCLUSIONS: The predictive accuracy of OCT-based IOL power calculation was better than Haigis-L and Shammas-PL formulas in eyes after laser vision correction. PMID- 24167324 TI - The blue arc entoptic phenomenon in glaucoma (an American ophthalmological thesis). AB - PURPOSE: To determine whether the blue arc entoptic phenomenon, a positive visual response originating from the retina with a shape that conforms to the topology of the nerve fiber layer, is depressed in glaucoma. METHODS: We recruited a cross sectional, nonconsecutive sample of 202 patients from a single institution in a prospective manner. Subjects underwent full ophthalmic examination, including standard automated perimetry (Humphrey Visual Field 24-2) or frequency doubling technology (Screening C 20-5) perimetry. Eligible patients viewed computer generated stimuli under conditions chosen to optimize perception of the blue arcs. Unmasked testers instructed patients to report whether they were able to perceive blue arcs but did not reveal what response was expected. We created multivariable logistic regression models to ascertain the demographic and clinical parameters associated with perceiving the blue arcs. RESULTS: In multivariable analyses, each 0.1 unit increase in cup-disc ratio was associated with 36% reduced likelihood of perceiving the blue arcs (odds ratio [OR] = 0.66 [95% confidence interval (CI): 0.53-0.83], P<.001). A smaller mean defect was associated with an increased likelihood of perceiving the blue arcs (OR=1.79 [95% CI: 1.40-2.28]); P<.001), while larger pattern standard deviation (OR=0.72 [95% CI: 0.57-0.91]; P=.005) and abnormal glaucoma hemifield test (OR=0.25 [0.10 0.65]; P=.006) were associated with a reduced likelihood of perceiving them. Older age and media opacity were also associated with an inability to perceive the blue arcs. CONCLUSION: In this study, the inability to perceive the blue arcs correlated with structural and functional features associated with glaucoma, although older age and media opacity were also predictors of this entoptic response. PMID- 24167325 TI - Cost-effectiveness of bevacizumab and ranibizumab for newly diagnosed neovascular macular degeneration (an American Ophthalmological Society thesis). AB - PURPOSE: To determine the most cost-effective treatment for patients with newly diagnosed neovascular macular degeneration: monthly or as-needed bevacizumab injections, or monthly or as-needed ranibizumab injections. METHODS: Using a Markov model with a 20-year time horizon, we compared the incremental cost effectiveness of treating a hypothetical cohort of 80-year-old patients with newly diagnosed neovascular macular degeneration using monthly bevacizumab, as needed bevacizumab, monthly ranibizumab, or as-needed ranibizumab. Data came from the Comparison of Age-Related Macular Degeneration Treatment Trial (CATT), the Medicare Fee Schedules, and the medical literature. RESULTS: Compared with as needed bevacizumab, the incremental cost-effectiveness ratio of monthly bevacizumab is $242,357 per quality-adjusted life year (QALY). Monthly ranibizumab gains an additional 0.02 QALYs vs monthly bevacizumab at an incremental cost-effectiveness ratio of more than $10 million per QALY. As-needed ranibizumab was dominated by monthly bevacizumab. In sensitivity analyses assuming a willingness to pay of $100,000 per QALY, the annual risk of serious vascular events would have to be at least 2.5 times higher with bevacizumab than that observed in the CATT trial for as-needed ranibizumab to have an incremental cost-effectiveness ratio of <$100,000 per QALY. In another sensitivity analysis, even if every patient receiving bevacizumab experienced declining vision by one category (eg, from 20/25-20/40 to 20/50-20/80) after 2 years but all patients receiving ranibizumab retained their vision level, as-needed ranibizumab would have an incremental cost-effectiveness ratio of $97,340 per QALY. CONCLUSION: Even after considering the potential for differences in risks of serious adverse events and therapeutic effectiveness, bevacizumab confers considerably greater value than ranibizumab for the treatment of neovascular macular degeneration. PMID- 24167329 TI - Critical review and validation of the concept of Ama. PMID- 24167326 TI - Evaluation of electronic health record implementation in ophthalmology at an academic medical center (an American Ophthalmological Society thesis). AB - PURPOSE: To evaluate three measures related to electronic health record (EHR) implementation: clinical volume, time requirements, and nature of clinical documentation. Comparison is made to baseline paper documentation. METHODS: An academic ophthalmology department implemented an EHR in 2006. A study population was defined of faculty providers who worked the 5 months before and after implementation. Clinical volumes, as well as time length for each patient encounter, were collected from the EHR reporting system. To directly compare time requirements, two faculty providers who utilized both paper and EHR systems completed time-motion logs to record the number of patients, clinic time, and nonclinic time to complete documentation. Faculty providers and databases were queried to identify patient records containing both paper and EHR notes, from which three cases were identified to illustrate representative documentation differences. RESULTS: Twenty-three faculty providers completed 120,490 clinical encounters during a 3-year study period. Compared to baseline clinical volume from 3 months pre-implementation, the post-implementation volume was 88% in quarter 1, 93% in year 1, 97% in year 2, and 97% in year 3. Among all encounters, 75% were completed within 1.7 days after beginning documentation. The mean total time per patient was 6.8 minutes longer with EHR than paper (P<.01). EHR documentation involved greater reliance on textual interpretation of clinical findings, whereas paper notes used more graphical representations, and EHR notes were longer and included automatically generated text. CONCLUSION: This EHR implementation was associated with increased documentation time, little or no increase in clinical volume, and changes in the nature of ophthalmic documentation. PMID- 24167327 TI - The spectrum of optic disc ischemia in patients younger than 50 years (an Amercian Ophthalmological Society thesis). AB - PURPOSE: To identify the spectrum of clinical and fluorescein angiographic features of optic disc ischemia in patients younger than 50 years. METHODS: This retrospective comparative case series from a university consultative neuro ophthalmology practice consisted of two phases. The first compared 108 cases of nonarteritic anterior ischemic optic neuropathy in patients younger than 50 years (NAIONy) to a cohort of 108 cases in patients 50 years or older (NAIONo). Predisposing risk factors, fluorescein angiographic features, and clinical course were compared. In the second phase, 12 cases of diabetic papillopathy under age 50 were assessed by fluorescein angiographic criteria for evidence of optic disc ischemia and compared to patients with NAIONy. RESULTS: NAIONy comprised 108 (12.7%) of 848 NAION cases reviewed. Chronic renal failure with dialysis and migraine were more common in NAIONy. Fellow eye involvement rate was significantly higher for NAIONy patients (46/108, 42.6%) than for NAIONo patients (32/108, 29.6%). Fluorescein angiographic features of ischemia were documented in 44 (81.5%) of 54 eyes studied. In one case, these features were documented in pre NAION edema. Diabetic papillopathy demonstrated delayed filling consistent with ischemia in 7 of 10 (70.0%), without significant visual field loss. CONCLUSIONS: Ischemic optic neuropathy in patients younger than 50 years is not rare. Fellow eye involvement is more frequent in younger patients. Fluorescein angiography confirmation of impaired perfusion in multiple syndromes of optic neuropathy corroborates a spectrum of optic disc ischemia ranging from perfusion delay without visual loss to severely impaired perfusion and visual loss and incorporates optic neuropathies previously considered nonischemic. PMID- 24167328 TI - Sphenoid sinus expansion: a radiographic sign of intracranial hypotension and the sunken eyes, sagging brain syndrome (an American Ophthalmological Society thesis). AB - PURPOSE: To test the hypothesis that in patient with sunken eyes, sagging brain syndrome, bone remodeling is not limited to the orbits. Volumetric analysis of the sphenoid sinus is performed in this study. METHODS: In this university-based retrospective case-control study, the dimensions of the sphenoid sinus were measured in four patients (2 males, 2 females; mean age 26.3 years, range 16-38 years) out of five individuals identified with sunken eyes, sagging brain syndrome. Three measurements were taken: the distance between the orbital apices, the posterior extension of the sphenoid sinus posterior to the orbital apices, and the maximal horizontal width. The mean of each was determined and compared to that of the control group (5 males, 5 females; mean age 35.6 years, range 23-45 years). RESULTS: Posterior extension and width of the sphenoid sinus were markedly larger in the enophthalmic patients than in the control group: posterior extension (26.3 +/- 4.1 mm vs 13.4 +/- 6.3 mm, P=.0015, Student's t test), width (39.2 +/- 8.7 mm vs 25.1 +/- 6.9 mm, P=.0035, Student's t test). Mean distance between the orbital apices was slightly greater (36.3 +/- 1.7 mm vs 34.1 +/- 2.1 mm, P=.047, Student's t test). CONCLUSIONS: Skull remodeling occurring in association with intracranial hypotension after ventriculoperitoneal shunting is not limited to the orbits. In this study we have demonstrated expansion of the sphenoid sinus. This finding adds to our knowledge and understanding of the scope of the sunken eyes, sagging brain syndrome and elucidates a clinically useful radiographic sign. PMID- 24167330 TI - Estimation of salivary and tongue coating pH on chewing household herbal leaves: A randomized controlled trial. AB - OBJECTIVES: The purpose of the study was to evaluate saliva and tongue coating pH and also to assess the degree of tongue coating in healthy subjects before and after chewing herbal leaves (tulsi, mint, and curry leaf). MATERIALS AND METHODS: A double-blind, randomized, concurrent, parallel-group study was conducted among 60 volunteer subjects, who were randomly assigned into three groups of 20 each (tulsi, mint, and curry leaf) and were asked to chew five to six fresh leaves of the respective plants twice daily for 7 days. Salivary and tongue coating pH were measured by a digital pH meter and color pH indicators. Data were analyzed statistically using repeated measure analysis of variance and Student's t-test. RESULTS: Mean salivary pH values showed an increase immediately and 30 min after chewing the herbal leaves. A significant difference (P < 0.01) was observed between mint and curry leaf groups immediately after chewing and between tulsi and curry leaf groups (P < 0.05) 30 min after chewing the leaves. Tongue coating pH showed an increase toward alkalinity in all the groups. The assessment of tongue coating showed an increase in scores among tulsi and curry leaf groups, but this difference was not statistically significant. CONCLUSION: Chewing traditional medicinal plant leaves can be considered as safe, effective, and economical alternate options for maintaining good oral health. PMID- 24167331 TI - Sexual dysfunction (Krcchra Vyavaya) in obesity (Sthaulya): Validation by an observational study. AB - OBJECTIVE: The present study intends to evaluate the relationship between Sthaulya (obesity) and Krcchra Vyavaya (sexual dysfunction) with respect to different phases of sexual intercourse through a single-centered, observational study in male patients of obesity. MATERIALS AND METHODS: The study involved 33 obese males from the outpatient department of the Institution whose sexual functioning was assessed using an International Index of Erectile Function questionnaire, which was meant to assess five specific areas of sexual functioning. RESULTS: A varying degree of sexual dysfunction was observed in four out of five areas of sexual functioning viz. erectile function (P < 0.02), orgasmic function (P < 0.02), sexual desire (P < 0.08), and overall satisfaction (P < 0.000) in obese individuals. Statistically significant dysfunction was not observed in intercourse satisfaction. CONCLUSIONS: Varying degree of sexual dysfunction is present in obese males, suggesting that obesity has a possible role in reducing the quality of sexual functioning in males as indicated in the classical ayurvedic literature. PMID- 24167332 TI - Nigella sativa extract affects conditioned place preference induced by morphine in rats. AB - OBJECTIVE: Neuroprotective, antioxidant, anticonvulsant, and analgesic effects of Nigella sativa (NS) have been previously shown. The interaction of NS with opioid system has also been reported. In the present study, the effects of NS hydro alcoholic extract on the acquisition and expression of morphine-induced conditioned place preference (CPP) in rats were evaluated. MATERIALS AND METHODS: CPP was induced by injection of morphine (5 mg/kg, i.p.) on three consecutive days in compartment A of the CPP apparatus. Injection of NS extract (200 and 400 mg/kg, i.p.) 60 min before morphine administration on the conditioning days and 60 min before the post-conditioning phase was done for the evaluation of acquisition and expression effects, respectively. Conditioning effect of NS extract was also evaluated by injection of extract (200 or 400 mg/kg, i.p.) in the conditioning phase, instead of morphine in different groups. The difference in time which the animals spent in compartment A on the day before conditioning and the days after conditioning was determined and compared between groups. RESULTS: The time spent by the rats in compartment A in the morphine group was greater than that in the saline group (P < 0.01). Both doses of NS extract decreased acquisition of morphine-induced CPP (P < 0.01 and P < 0.001), but had no significant effect on the expression of morphine CPP. Higher dose of the extract (400 mg) showed a significant conditioning effect which was comparable to the effect of morphine. CONCLUSION: The results of the present study showed that the hydro-alcoholic extract of NS has conditioning effect. It also decreased acquisition, but had no significant effect on the expression of morphine CPP. PMID- 24167333 TI - Comparison of effect of Gayatri Mantra and Poem Chanting on Digit Letter Substitution Task. AB - CONTEXT: Attention is one of the components to enhance academic excellence. Traditional techniques were included in Indian schools to develop mental faculties with a view to add value to the latter. AIM: The aim was to evaluate the effects of Gayatri mantra (GM) chanting on attention as measured by digit letter substitution task (DLST). SETTINGS AND DESIGN: School setting and self as control study design. MATERIALS AND METHODS: Subjects consisted of 60 school students included (boys = 30 and girls = 30) in the age range of 12-14 years, who were trained for chanting GM for 5 days. They were assessed on DLST immediately before and after two sessions (i) GM chanting (10 min) and (ii) Poem line (PL) chanting with an equal duration (10 min). Fifty percent of participants performed GM chanting and remaining on the PL recitation on day 6. The orders of the sessions were reversed on day 7. STATISTICAL ANALYSIS USED: Repeated measure analysis of variance with Bonferroni adjustment used. RESULTS: Both sessions showed significant improvement in the total and net score of DLST. The magnitude of net score improvement was greater after GM (21.67%) compared to PL (4.85%). Female group had found better performance following GM compared to PL chanting. CONCLUSIONS: Both GM and PL led to improvement in performance, as assessed by DLST. But the influence of GM had significantly higher than PL in net score of female group. PMID- 24167334 TI - Immunomodulatory activity of Amalaki Rasayana: An experimental evaluation. AB - BACKGROUND: Ayurvedic system of medicine holds a number of drugs that improves the immunity. Amalaki (Emblica officinalis) is one such drug. Researches with crude extracts of Amalaki have proven the antioxidant and immunomodulatory activities. But, works on Amalaki Rasayana are not found reported. AIMS: Considering this, two samples of Amalaki Rasayana (AR7 and AR21) were studied to evaluate comparative immunomodulatory activity against the cyclophosphamide immunosuppression in rats. MATERIALS AND METHODS: Test drugs were prepared by following classical guidelines. Wistar strain albino rats of either sex were used in the study. STATISTICAL ANALYSIS: For comparison of data from cyclophosphamide control group with remaining cyclophosphamide plus test drug administered groups one way ANOVA with Dunnett's multiple t-test (DMTT) was employed. RESULTS AND CONCLUSIONS: Amalaki Rasayana possesses significant immunostimulant activity and moderate cytoprotective activity. AR21 was found to have better activity profile in terms of both immunostimulant as well as cytoprotective activity. PMID- 24167335 TI - Ethnozoology of the Karbis of Assam, India: Use of ichthyofauna in traditional health-care practices. AB - BACKGROUND: Traditional or folk medicine is still prevalent among the Karbis as means of primary health-care. Traditional medicine is not only a source of healing, but the practice is also an important part of their religion and culture. AIM: The aim of the present study is to discuss the use of ichthyofauna in traditional health-care practices among the Karbis and other ethnic tribes of Karbi Anglong district, Assam. SETTING AND DESIGN: Field study was undertaken from March 2011 to June 2012. A total of 75 informants were selected from 27 villages and the selection was based on their recognition as having sound knowledge relating to health-care practices. MATERIALS AND METHODS: Information was collected following both unstructured and structured interview methods, group discussions and personal observation. Fish used in health-care practices were collected with the help of local guides and identified using available literatures. RESULTS: The present study has recorded use of 14 species belonging 7 families in the treatment of 25 disease conditions. Traditional health-care practices of the Karbis include both local and oral applications and rituals to cure diseases. Use of fish to cure mental depression like symptoms locally referred as nihu kachingtung is prevalent until today. Studies among the Dimasa and Thadou tribes also revealed the use of fish in traditional medicine as therapies against different ailments, but do not use fish in rituals. CONCLUSION: Study on fish-based zootherapy could be a viable option for discovery of new compounds with therapeutic potentials. However, the attitude of the present generation towards traditional medicine as being unscientific and acculturation are the main causes of decline of such practice in the Karbis. Destructive fishing practices by poisoning water bodies with synthetic chemicals pose serious threats to aquatic fauna in the hill streams. PMID- 24167336 TI - Role of Sadyo Vamana in dental abscess (danta arbuda). AB - Sadyo Vamana is a type of purificatory measure mentioned in Ayurveda, which to expel the pus and morbid factors present in a dental abscess without opening it. However, Sadyo Vamana's role in fever and pus filled dental abscess has not been reported so far. I report a case of dental abscess with fever. A 24-year-old male patient with a pus filled dental abscess. His fever and dental abscess didn't respond to antibiotic and analgesic treatment for 10 days. The patient was given Sadyo Vamana (instant therapeutic emesis) to expel the accumulated pus in dental abscess without opening it. The patient got complete relief from fever and dental abscess after Sadyo Vamana. The patient not gave internal medication. PMID- 24167337 TI - Pharmacognostic and phytochemical studies on Ficus Microcarpa L. fil. AB - BACKGROUND: Ficus microcarpa L. fil. (Syn: Ficus retusa) (Moraceae) is well-known traditional medicinal plant. The bark is used for diverse health ailments in traditional and folklore remedies. AIMS: The present study was undertaken to lay down pharmacognostical and phytochemical standards. MATERIALS AND METHODS: Pharmacognostic studies on fresh, dried and powdered bark was carried out to determine it's morphological, anatomical, and phytochemical diagnostic features. Furthermore, major phytoconstituents were identified from the extracts with the help of high performance liquid chromatography (HPLC) study. RESULTS: The morphology showed to be soft, brittle, rough, shallow vertical, irregularly oriented fissures, curved surface; with splintering, laminated fracture. Microscopically F. microcarpa showed all general characteristics of bark with some distinct differentiation. The phellem is thin and even, phelloderm few cell and rectangular and followed by smaller sclerides, the phloem rays are broad, multi-serrate and showed the scattered bundles of sclerides. The fluorescence and physicochemical standards for bark were established. HPLC analysis showed the predominant presence of therapeutically important phytoconstituents such as oleanolic, betulinic acid, lupeol, beta-sitosterol, catechin, and gallic acid. CONCLUSION: The bark of F. microcarpa considered equivalent to other Ficus species, such as Ficus virens, Ficus infectoria, Ficus arnottiana, Ficus lacor, and Ficus talboti. However, there is no pharmacognostical and phytochemical reports on F. microcarpa to authenticate and differentiate it from similar species. Present work has described pharmacognostical and phytochemical characteristics of F. microcarpa and diagnostic features to differentiate it. PMID- 24167338 TI - Antiulcer activity of Amlapitta Mishran suspension in rats: A pilot study. AB - CONTEXT: Amlapitta Mishran suspension is a poly herbal ayurvedic formulation, which has been traditionally used for acidity and gastric ulcers. AIM: The aim of this study is to evaluate the antiulcer activity of Amlapitta Mishran on non steroidal anti-inflammatory drugs (NSAID's) -induced ulcers in the rat model. SUBJECTS AND METHODS: The antiulcer activity of Amlapitta Mishran was investigated on indomethacin (100 mg/kg) NSAID's induced ulcers in rats. Effect of two different doses of Amlapitta Mishran was studied by calculating the total number of ulcers, ulcer index and percentage inhibition. STATISTICAL ANALYSIS USED: Data was analyzed by the Student's t-test (P < 0.05). RESULTS: Amlapitta Mishran treated rats have shown significant (P < 0.0001) decrease in the total number of ulcers and ulcer index and significant increase in % inhibition of ulcers as compared with positive control group. CONCLUSION: The results indicate that Amlapitta Mishran has showed a dose dependent antiulcer activity in experimental animals and confirms ayurvedic use of Amlapitta Mishran in gastric ulcers. PMID- 24167339 TI - Capacity building of AYUSH practitioners to study the feasibility of their involvement in non-communicable disease prevention and control. AB - BACKGROUND: Sharing of public health knowledge and skills by professionals in allopathic system of medicine with Ayurveda, Yoga, and Naturopathy, Unani, Siddha and Homeopathy (AYUSH) professionals in India has always been considered as part of integrating the health system in India. But till date, a curriculum has not been framed for follow-up. MATERIALS AND METHODS: A training course was developed for AYUSH professionals in India on the public health principles for the prevention and control of non-communicable diseases (NCDs). Three course chairs interacted with international and national public health and AYUSH experts, and the curriculum for a 3-month course was developed. RESULTS: The curriculum comprised interactive lectures, problem-based exercise, field visits, and research protocol development. A total of four participants, nominated by the World Health Organization, India, were trained during the course, with significant (P = 0.00) improvement in knowledge from 53.2 to 80.0 points. CONCLUSION: A novel and feasible public health course for complementary and alternative medicine professionals on the public health principles for NCDs' prevention and control is needed to bridge the demand gap for public health professionals in India. PMID- 24167340 TI - Ayurvedic Point, translating tradition into modernity. PMID- 24167341 TI - Quality control for Tamra (copper) Bhasma. PMID- 24167343 TI - Biomarkers for psychiatric disorders: where are we standing? PMID- 24167344 TI - Biomarkers in schizophrenia: a brief conceptual consideration. AB - Biomarkers have been sought after in the field of schizophrenia research for decades. In this paper, we discuss some of the concepts around developing biomarkers in an effort to understand why the use of biomarkers for schizophrenia has not been realized. In particular, we address the following 4 questions. Why would we need a diagnostic biomarker for schizophrenia? How is a biomarker typically defined and how does that influence the discovery of biomarkers in schizophrenia? What is the best use of biomarkers in schizophrenia? Do any biomarkers for schizophrenia currently exist? Thus, while we suggest that no biomarker currently exists for schizophrenia, the heterogeneity associated with schizophrenia will most likely need to be taken into account which will result in multiple biomarkers that identify the multiple underlying pathophysiological processes involved in schizophrenia. Therefore, much additional work will be required prior to obtaining any well-established biomarkers for schizophrenia. PMID- 24167345 TI - Coding and noncoding gene expression biomarkers in mood disorders and schizophrenia. AB - Mood disorders and schizophrenia are common and complex disorders with consistent evidence of genetic and environmental influences on predisposition. It is generally believed that the consequences of disease, gene expression, and allelic heterogeneity may be partly the explanation for the variability observed in treatment response. Correspondingly, while effective treatments are available for some patients, approximately half of the patients fail to respond to current neuropsychiatric treatments. A number of peripheral gene expression studies have been conducted to understand these brain-based disorders and mechanisms of treatment response with the aim of identifying suitable biomarkers and perhaps subgroups of patients based upon molecular fingerprint. In this review, we summarize the results from blood-derived gene expression studies implemented with the aim of discovering biomarkers for treatment response and classification of disorders. We include data from a biomarker study conducted in first-episode subjects with schizophrenia, where the results provide insight into possible individual biological differences that predict antipsychotic response. It is concluded that, while peripheral studies of expression are generating valuable results in pathways involving immune regulation and response, larger studies are required which hopefully will lead to robust biomarkers for treatment response and perhaps underlying variations relevant to these complex disorders. PMID- 24167346 TI - Biomarkers predicting antidepressant treatment response: how can we advance the field? AB - Major depression, affecting an estimated 350 million people worldwide, poses a serious social and economic threat to modern societies. There are currently two major problems calling for innovative research approaches, namely, the absence of biomarkers predicting antidepressant response and the lack of conceptually novel antidepressant compounds. Both, biomarker predicting a priori whether an individual patient will respond to the treatment of choice as well as an early distinction of responders and nonresponders during antidepressant therapy can have a significant impact on improving this situation. Biosignatures predicting antidepressant response a priori or early in treatment would enable an evidence based decision making on available treatment options. However, research to date does not identify any biologic or genetic predictors of sufficient clinical utility to inform the selection of specific antidepressant compound for an individual patient. In this review, we propose an optimized translational research strategy to overcome some of the major limitations in biomarker discovery. We are confident that early transfer and integration of data between both species, ideally leading to mutual supportive evidence from both preclinical and clinical studies, are most suitable to address some of the obstacles of current depression research. PMID- 24167347 TI - Peripheral biomarkers in animal models of major depressive disorder. AB - Investigations of preclinical biomarkers for major depressive disorder (MDD) encompass the quantification of proteins, peptides, mRNAs, or small molecules in blood or urine of animal models. Most studies aim at characterising the animal model by including the assessment of analytes or hormones affected in depressive patients. The ultimate objective is to validate the model to better understand the neurobiological basis of MDD. Stress hormones or inflammation-related analytes associated with MDD are frequently measured. In contrast, other investigators evaluate peripheral analytes in preclinical models to translate the results in clinical settings afterwards. Large-scale, hypothesis-free studies are performed in MDD models to identify candidate biomarkers. Other studies wish to propose new targets for drug discovery. Animal models endowed with predictive validity are investigated, and the assessment of peripheral analytes, such as stress hormones or immune molecules, is comprised to increase the confidence in the target. Finally, since the mechanism of action of antidepressants is incompletely understood, studies investigating molecular alterations associated with antidepressant treatment may include peripheral analyte levels. In conclusion, preclinical biomarker studies aid the identification of new candidate analytes to be tested in clinical trials. They also increase our understanding of MDD pathophysiology and help to identify new pharmacological targets. PMID- 24167348 TI - Biomarkers in posttraumatic stress disorder: overview and implications for future research. AB - PTSD can develop in the aftermath of traumatic incidents like combat, sexual abuse, or life threatening accidents. Unfortunately, there are still no biomarkers for this debilitating anxiety disorder in clinical use. Anyhow, there are numerous studies describing potential PTSD biomarkers, some of which might progress to the point of practical use in the future. Here, we outline and comment on some of the most prominent findings on potential imaging, psychological, endocrine, and molecular PTSD biomarkers and classify them into risk, disease, and therapy markers. Since for most of these potential PTSD markers a causal role in PTSD has been demonstrated or at least postulated, this review also gives an overview on the current state of research on PTSD pathobiology. PMID- 24167350 TI - Early complication in sickle cell anemia children due to A(TA)nTAA polymorphism at the promoter of UGT1A1 gene. AB - AIM: To determine the implication of the polymorphism, namely, A(TA)nTAA of UGT1A1 in lithogenesis for the first time in Tunisia among sickle cell anemia (SCA) children patients. MATERIAL AND METHODS: Our study was performed in 2010 and it involved 76 subjects chosen as control group characterized with normal hemoglobin status and presence of cholelithiasis and 102 SCA pediatric patients among whom 52 have cholelithiasis. We analyzed the polymorphism A(TA)nTAA at the UGT1A1 promoter and the relationships between the various A(TA)nTAA genotypes and alleles and bilirubin levels and occurrence of cholelithiasis. RESULTS AND DISCUSSION: The repartition of genotypes found according to serum bilirubin level shows a significant association between genotypes carrying variant (TA)7 and hyperbilirubinemia (P < 0.05). We demonstrated the association of two genotypes with gallstones formation among SCA children patients: (TA)7/(TA)7 and (TA)7/(TA)8 with P = 8.1 * 10-8 and P = 0.01, respectively. (TA)7 and (TA)8 allele variants act as a risk factor for early gallstones formation in SCA patients with P = 5.8 * 10-9 and P = 0.01, respectively. As for the control group only the genotype (TA)7/(TA)7 presented a risk factor for gallstones formation. CONCLUSION: The novelty of this report is that it is the first time that a similar study was made on the Tunisian children sickle cell population and that the results show a clear association of (TA)7 variant in early gallstones formation in Tunisian SCA children. Interestingly our findings highlighted the association of (TA)8 variant as well, which was not found in previous studies. PMID- 24167349 TI - Current progress and challenges in the search for autism biomarkers. AB - Autism spectrum disorders (ASD) encompass a range of neurodevelopmental conditions that are clinically and etiologically very heterogeneous. ASD is currently diagnosed entirely on behavioral criteria, but intensive research efforts are focused on identifying biological markers for disease risk and early diagnosis. Here, we discuss recent progress toward identifying biological markers for ASD and highlight specific challenges as well as ethical aspects of translating ASD biomarker research into the clinic. PMID- 24167351 TI - HLA markers for poor prognosis in systemic sclerosis Brazilian patients. AB - OBJECTIVES: The aim of this study was to evaluate human leukocyte antigen (HLA) involvement in the disease expression and poor prognostic clinical features (pulmonary fibrosis and pulmonary arterial hypertension) in patients diagnosed with systemic sclerosis (SSc) in a multiethnic population. METHODS: SSc patients followed up between 2008 and 2011 were included, and clinical data were obtained through records review. Molecular HLA typing was performed (polymerase chain reaction amplification technique using specific primer sequences). The statistical analysis involved Fisher's exact test and Pearson's corrected chi square test. P (values) <= 0.05 were considered significant. The delta method was used to estimate the variance of the prevalence ratio (PR). RESULTS: A total of 141 patients (120 women and 21 men) with SSc were studied, including 33.3% with diffuse cutaneous SSc (dcSSc), 62.4% with limited cutaneous SSc (lcSSc), and 4.3% with sine scleroderma. Pulmonary fibrosis was present in 61 patients (43.3%), and the HLA-A*30 and DQB1*04 alleles were related to susceptibility. In contrast, the HLA-DRB1*01 and DQB1*05 alleles were protective. Pulmonary arterial hypertension was diagnosed in 19 patients (13.5%) and was associated with HLA-B*35 and C*04; in contrast, C*03 seemed to be protective. CONCLUSIONS: Our current study documents the association of some classes I and II HLA alleles with the most severe clinical manifestations in a multiethnic case series. Our findings differed slightly from the previous data in other populations. PMID- 24167352 TI - Markers of increased cardiovascular risk in postmenopausal women: focus on oxidized-LDL and HDL subpopulations. AB - OBJECTIVE: To evaluate the effect of gender and menopause in cardiovascular risk (CVR) in a healthy population based on both classical and nontraditional markers. METHODS: 56 men and 68 women (48 pre- and 20 postmenopause) were enrolled in the study. The following markers were analyzed: blood pressure (BP), body mass index (BMI), waist circumference (WC), glucose, total cholesterol (total-c), triglycerides (TGs), low-density lipoprotein cholesterol (LDL-c), oxidized-LDL (Ox-LDL), HDL-c and subpopulations, paraoxonase-1 activity, hsCRP, uric acid, tumor necrosis factor alpha (TNF- alpha ), adiponectin, vascular endothelial growth factor (VEGF), and intercellular adhesion molecular 1 (ICAM1). RESULTS: Relative to the women, men present significantly increased BMI, WC, BP, glucose, total-c, TGs, LDL-c, Ox-LDL, uric acid, and TNF- alpha and reduced adiponectin and total and large HDL-c. The protective profile of women is lost after menopause with a significantly increased BMI, WC, BP, glucose, LDL-c, Ox-LDL, hsCRP, and VEGF and decreased total and large HDL-c. Significant correlations were found in women population and in postmenopausal women between Ox-LDL and total, large, and small HDL-c and between TNF- alpha and total, large, and small HDL-c, LDL-c, and Ox-LDL. CONCLUSIONS: Men present higher CVR than women who lost protection after menopause, evidenced by nontraditional markers, including Ox-LDL and HDL subpopulations. PMID- 24167353 TI - Reduced paraoxonase 1 activity as a marker for severe coronary artery disease. AB - Paraoxonase-1 (PON1), a high-density-lipoprotein- (HDL-) associated enzyme, has the potential to protect against atherogenesis. We examine the relationships between plasma PON1 activity and the progression of atherosclerosis as well as coronary artery disease (CAD). Fasting blood samples were collected from female apolipoprotein E-deficient (apoE(-/-)) mice and 149 patients undergoing coronary angiography for the biochemical parameters measurement. The severity of CAD was defined using angiographic Gensini score (GSS). Compared to 3-month-old apoE(-/-) mice, aged mice had significantly lower PON1 activity, which is negatively correlated with the size of atherosclerotic lesion and plasma interleukin-6 (IL 6) and tumor necrosis factor alpha (TNF- alpha ) levels. In study patients, PON1 activity was correlated with age, sex, and HDL-cholesterol, apolipoprotein AI, and high-sensitivity C-reactive protein (hs-CRP) levels and was significantly lower in CAD group than that in non-CAD control group. Interestingly, PON1 activity in severe CAD group (GSS > 40) was further significantly reduced compared to those in mild and moderate subgroups (GSS <= 40) (P < 0.01). There is a significant correlation between PON1 activity and the severity of CAD as assessed by GSS (r = -0.393, P < 0.001). PON1 activity may be a potential biomarker for the severity of CAD. PMID- 24167354 TI - Relationship between acute phase proteins and serum fatty acid composition in morbidly obese patients. AB - BACKGROUND: Obesity is considered a low-grade inflammatory state and has been associated with increased acute phase proteins as well as changes in serum fatty acids. Few studies have assessed associations between acute phase proteins and serum fatty acids in morbidly obese patients. OBJECTIVE: To investigate the relationship between acute phase proteins (C-Reactive Protein, Orosomucoid, and Albumin) and serum fatty acids in morbidly obese patients. METHODS: Twenty-two morbidly obese patients were enrolled in this study. Biochemical and clinical data were obtained before bariatric surgery, and fatty acids measured in preoperative serum. RESULTS: Orosomucoid was negatively correlated with lauric acid (P = 0.027) and eicosapentaenoic acid (EPA) (P = 0.037) and positively with arachidonic acid (AA) (P = 0.035), AA/EPA ratio (P = 0.005), and n-6/n-3 polyunsaturated fatty acids ratio (P = 0.035). C-Reactive Protein (CRP) was negatively correlated with lauric acid (P = 0.048), and both CRP and CRP/Albumin ratio were negatively correlated with margaric acid (P = 0.010, P = 0.008, resp.). Albumin was positively correlated with EPA (P = 0.027) and margaric acid (P = 0.008). Other correlations were not statistically significant. CONCLUSION: Our findings suggest that serum fatty acids are linked to acute phase proteins in morbidly obese patients. PMID- 24167355 TI - mRNA expression of MMP-28 (Epilysin) in gingival tissues of chronic and aggressive periodontitis patients: a reverse transcriptase PCR study. AB - BACKGROUND AND OBJECTIVES: Matrix metalloproteinases degrade extracellular membrane and also release bioactive fragments and growth factors, thus influencing fundamental biological and pathological processes. Epilysin (MMP-28) differs from most other MMPs as it is expressed in a number of normal tissues, suggestive of functions in tissue homeostasis. The aim of the present study was to quantitatively evaluate and compare the mRNA expression of epilysin (MMP-28) in gingival tissues of healthy patients and of patients affected by chronic or aggressive periodontitis. METHODS: A total of 60 subjects, 20 periodontally healthy subjects, 20 with chronic periodontitis, and 20 with aggressive periodontitis, were included in this study. Periodontal status was evaluated by measuring gingival index, probing depth and clinical attachment level. mRNA expression of MMP-28 was determined by quantitative real-time reverse transcriptase polymerase chain reaction (RT-PCR) in gingival tissue samples collected. RESULTS: Relative quantification of mRNA expression of MMP-28 was highest in healthy tissues (RQ = 0.97) when compared to subjects with chronic periodontitis (RQ = 0.37) and aggressive periodontitis (RQ = 0.23), but the difference was not statistically significant. CONCLUSION: mRNA expression of MMP 28 was highest in healthy tissues when compared to diseased periodontal tissues suggesting that MMP-28 could act as a biomarker for periodontal health. PMID- 24167356 TI - Comparison of the diagnostic accuracy of the MSLN gene products, mesothelin and megakaryocyte potentiating factor, as biomarkers for mesothelioma in pleural effusions and serum. AB - The MSLN gene products, soluble mesothelin and megakaryocyte potentiating factor (MPF), are being investigated as biomarkers for the asbestos-related cancer malignant mesothelioma (MM). Pleural fluid biomarkers of MM can be elevated when serum levels remain normal. The aim of this study was to determine if this was true for MPF and to compare levels of mesothelin. Biomarker concentrations were compared in 66 MM patients, 39 patients with other malignancies, 37 with benign disease, 18 asbestos-exposed healthy individuals, and 53 patients with chronic kidney disease. In pleural effusions, MPF and soluble mesothelin concentrations were both significantly elevated in MM patients relative to controls. No significant difference between the area under the receiver operator curve (AUC) for MPF (0.945 +/- 0.02) and mesothelin (0.928 +/- 0.03) when distinguishing MM from all other causes of effusion was observed. MPF and mesothelin serum concentrations were highly correlated and of equivalent diagnostic accuracy with AUCs of 0.813 +/- 0.04 and 0.829 +/- 0.03, respectively. Serum levels of both markers increased with decreasing kidney function. In conclusion, MPF is elevated in the pleural effusions of MM patients similar to that of mesothelin. Mesothelin and MPF convey equivalent diagnostic information for distinguishing MM from other diseases in pleural effusions as well as serum. PMID- 24167357 TI - COMT-Val158Met-polymorphism is not a risk factor for acute kidney injury after cardiac surgery. AB - BACKGROUND: Cardiac surgery-associated acute kidney injury (CSA-AKI) depicts a major complication after cardiac surgery using cardiopulmonary bypass (CPB). OBJECTIVE: CSA-AKI has clearly been linked to increased perioperative morbidity and mortality. Dysregulations of vasomotor tone are assumed to be causal for CSA AKI. While catechol-O-methyltransferase (COMT) is involved in metabolizing catecholamines, a single-nucleotide polymorphism (SNP) in the COMT gene leads to different enzyme activities according to genotype. Pilot studies found associations between those COMT genotypes and CSA-AKI. METHODS: We prospectively included 1741 patients undergoing elective cardiac surgery using cardiopulmonary bypass (CPB). Patients were genotyped for COMT-Val158Met-(G/A) polymorphism (rs4680). RESULTS: Demographic characteristics and procedural data revealed no significant differences between genotypes. No association between COMT genotypes and the RIFLE criteria could be detected. A multiple linear regression analysis for postoperative creatinine increase revealed highly significant associations for aortic cross-clamp time (P < 0.001), CPB time (P < 0.001), norepinephrine (P < 0.001), and age (P < 0.001). No associations were found for COMT genotypes or baseline creatinine. With an R (2) = 0.39 and a sample size of 1741, the observed power of the regression analysis was >99%. CONCLUSIONS: Based on our results, we can rule out an association between the COMT-Val158Met-(G/A) polymorphism and the appearance of CSA-AKI. PMID- 24167358 TI - Plasma levels of soluble receptor for advanced glycation end products and coronary atherosclerosis: possible correlation with clinical presentation. AB - Receptor for Advanced Glycation End-products (RAGE) is a multi-ligand receptor ubiquitous present on epithelial, neuronal, vascular and inflammatory cells, usually expressed at low levels in homeostasis and to increased degrees at sites of stress or injury. The aim of the present study was to evaluate sRAGE plasma levels in patients with Acute Coronary Syndrome (ACS) and to assess its diagnostic efficacy in identification of patients with acute events. Plasma levels of sRAGE were determined in 860 patients with Coronary Artery Disease (CAD): 530 patients presented stable angina and 330 were observed during acute ischemic event (147 with unstable angina and 183 with myocardial infarction). sRAGE plasma levels were significantly lower in patients with ACS than in patients with stable angina: [median 584 pg/mL (IQR: 266-851 pg/mL) in MI patients, median 769 pg/mL (IQR: 394-987 pg/mL) in patients with unstable angina, median 834 pg/mL (IQR 630-1005 pg/mL) in patients with stable angina; P < 0.001]. sRAGE levels did not differ among ACS patients stratified by the extent of coronary artery disease. In conclusion, this study confirm the role of sRAGE in activation and progression of inflammatory process and suggests the possibility that sRAGE can be considered an indicator of destabilization of vulnerable plaque. PMID- 24167359 TI - Role of SH levels and markers of immune response in the stroke. AB - BACKGROUND: Sulfhydryl groups (SH) are considered a key factor in redox sensitive reaction of plasma, and their modification could be considered an expression of abnormal generation of oxygen free radicals. METHODS: Fifty consecutive patients with acute brain stroke were enclosed in this study. The plasma concentrations of SH groups were correlated to cytokines (IL-1b, IL-6, IL-8, TNF- alpha ), plasma chitotriosidase (Chit), metalloprotease (MMP2-9), intercellular adhesion molecule 1 (ICAM-1). RESULTS: The results demonstrated a significant reduction of SH groups within 24 hours from the onset of an acute ischemic stroke, a reduction of plasma IL-1b, IL-6, and IL-8, and an increase of Chit and TNF- alpha in relation to the stroke severity. CONCLUSION: The observation of an intense microenvironment activation that follows the stroke and the correlation between SH levels and markers of immune response suggest that, especially in stroke, is necessary to maintain the redox function to prevent the brain damage. The reduced SH levels represent an attempt to neutralize the abnormal generation of free radicals. Since the reperfusion of brain after ischemic event represents a severe oxidative stress, which must be corrected by regeneration of redox sensitive function, pharmacological intervention could be beneficial in this setting. PMID- 24167360 TI - Glycophenotype evaluation in cutaneous tumors using lectins labeled with acridinium ester. AB - BACKGROUND: Tumor cells show alterations in their glycosylation patterns when compared to normal cells. Lectins can be used to evaluate these glycocode changes. Chemiluminescence assay is an effective technique for quantitative analysis of proteins, nucleic acids, and carbohydrates due to its high sensitivity, specificity, and rapid testing. OBJECTIVE: To use histochemiluminescence based on lectin conjugated to acridinium ester (AE) for the investigation of glycophenotype changes in cutaneous tumors. METHODS: Concanavalin A (Con A), Peanut agglutinin (PNA), Ulex europaeus agglutinin-I (UEA I), and Maackia amurensis agglutinin (MAA) were conjugated to acridinium ester. Biopsies of cutaneous tumors and normal skin were incubated with the lectins-AE, and chemiluminescence was quantified and expressed as Relative Light Units (RLU). Results. Actinic keratosis (AK), keratoacanthoma (KA), squamous cell carcinoma (SCC), and basal cell carcinoma (BCC) showed lower expression of alpha -D glucose/mannose and alpha -L-fucose residues compared to normal tissue. Cutaneous tumors displayed higher expression of Gal- beta (1-3)-GalNAc residues than normal tissue. AK and SCC exhibited higher expression of Neu5Ac- alpha (2,3)Gal residues than normal epidermis. KA and BCC showed equivalent RLU values compared to normal tissue. CONCLUSIONS: Lectin histochemiluminescence allowed quantitative assessment of the carbohydrate expression in cutaneous tissues, contributing to eliminate the subjectivity of conventional techniques used in the histopathological diagnosis. PMID- 24167361 TI - Plasma gamma-glutamyltransferase is strongly determined by acylation stimulating protein levels independent of insulin resistance in patients with acute coronary syndrome. AB - BACKGROUND: Steatosis is a manifestation of the metabolic syndrome often associated with release of liver enzymes and inflammatory adipocytokines linked to cardiovascular risk. Gamma-glutamyltransferase (GGT) is one sensitive liver marker recently identified as an independent cardiovascular risk factor. Mechanisms involved in enhanced hepatic lipogenesis causing steatosis are not yet identified and are usually linked to insulin resistance (IR). Acylation stimulating protein (ASP), a potent lipogenic factor, was recently shown to increase in patients with steatosis and was implicated in its pathogenesis. AIM: To investigate the association of plasma ASP levels with liver and metabolic risk markers in acute coronary syndrome (ACS) patients. METHODS: 28 patients and 30 healthy controls were recruited. Their anthropometrics, lipid profile, liver markers, insulin, and ASP levels were measured. RESULTS: In the patients, ASP, liver, and metabolic risk markers were markedly higher than in the controls. ASP strongly predicted GGT levels (B = 0.75, P < 0.0001), followed by triglycerides (B = 0.403, P = 0.017), together determining 57.6% variation in GGT levels. Insulin and IR correlated with metabolic risk components but not with liver enzymes. CONCLUSION: The strong association of ASP with GGT in ACS patients suggests that ASP, independent of IR, may contribute to a vicious cycle of hepatic lipogenic stimulation and GGT release promoting atherogenesis. PMID- 24167362 TI - Positive ALDH1A3 and negative GPX3 expressions are biomarkers for poor prognosis of gallbladder cancer. AB - BACKGROUND: Gallbladder cancers (GBCs) are highly aggressive cancers with high mortality. However, biological markers for the progression and prognosis of GBC are currently unavailable in the clinic. OBJECTIVE: To identify biomarkers for predicting GBC metastasis and prognosis. METHODS: We examined ALDH1A3 and GPX3 expressions in 46 squamous cell/adenosquamous carcinomas (SC/ASC) and 80 adenocarcinomas (AC) by using immunohistochemistry. RESULTS: Positive ALDH1A3 and negative GPX3 expressions were significantly associated with lymph node metastasis and invasion of SC/ASCs and ACs. Univariate Kaplan-Meier analysis showed that either positive ALDH1A3 (P < 0.001) or negative GPX3 (P < 0.001) expression significantly correlated with decreased overall survival in both SC/ASC and AC patients. Multivariate Cox regression analysis showed that positive ALDH1A3 expression or negative GPX3 expression was an independent poor-prognostic predictor in both SC/ASC and AC patients. CONCLUSIONS: Our study suggested that positive ALDH1A3 and negative GPX3 expressions are closely associated with clinical pathological behaviors and poor prognosis of gallbladder cancer. PMID- 24167363 TI - Assessment of endothelial dysfunction: the role of symmetrical dimethylarginine and proinflammatory markers in chronic kidney disease and renal transplant recipients. AB - OBJECTIVES: The study was designed to evaluate associations between symmetric dimethylarginine (SDMA), inflammation, and superoxide anion (O2?-) with endothelial function and to determine their potential for screening of endothelial dysfunction in patients with chronic kidney disease (CKD) and renal transplant (RT) recipients. MATERIALS AND METHODS: We included 64 CKD and 52 RT patients. Patients were stratified according to brachial artery flow-mediated dilation (FMD). RESULTS: Logistic regression analysis showed that high SDMA and high sensitive C-reactive protein (hs-CRP) were associated with impaired FMD in CKD and RT patients, after adjustment for glomerular filtration rate. The ability of inflammation, SDMA, and O2?- to detect impaired FMD was investigated by receiving operative characteristic analysis. Hs-CRP (area under the curves (AUC) = 0.754, P < 0.001), IL-6 (AUC = 0.699, P = 0.002), and SDMA (AUC = 0.689, P = 0.007) had the highest ability to detect impaired FMD. SDMA in combination with inflammatory parameters and/or O2?- had better screening performance than SDMA alone. CONCLUSIONS: Our results indicate a strong predictable association between hs-CRP, SDMA, and endothelial dysfunction in CKD patients and RT recipients. The individual marker that showed the strongest discriminative ability for endothelial dysfunction is hs-CRP, but its usefulness as a discriminatory marker for efficient diagnosis of endothelial dysfunction should be examined in prospective studies. PMID- 24167364 TI - Genetic analysis of PARK2 and PINK1 genes in Brazilian patients with early-onset Parkinson's disease. AB - Parkinson's disease is the second most frequent neurodegenerative disorder in the world, affecting 1-2% of individuals over the age of 65. The etiology of Parkinson's disease is complex, with the involvement of gene-environment interactions. Although it is considered a disease of late manifestation, early onset forms of parkinsonism contribute to 5-10% of all cases. In the present study, we screened mutations in coding regions of PARK2 and PINK1 genes in 136 unrelated Brazilian patients with early-onset Parkinson's disease through automatic sequencing. We identified six missense variants in PARK2 gene: one known pathogenic mutation, two variants of uncertain role, and three nonpathogenic changes. No pathogenic mutation was identified in PINK1 gene, only benign polymorphisms. All putative pathogenic variants found in this study were in heterozygous state. Our data show that PARK2 point mutations are more common in Brazilian early-onset Parkinson's disease patients (2.9%) than PINK1 missense variants (0%), corroborating other studies worldwide. PMID- 24167365 TI - Multivariate path analysis of serum 25-hydroxyvitamin D concentration, inflammation, and risk of type 2 diabetes mellitus. AB - BACKGROUND AND AIMS: Despite growing interest in the protective role that vitamin D may have in health outcomes, little research has examined the mechanisms underlying this role. This study aimed to test two hypotheses: (1) serum 25 hydroxyvitamin D [25(OH)D] is inversely associated with type 2 diabetes mellitus (T2DM) and elevated hemoglobin A1c; (2) these associations are mediated by serum C-reactive protein (CRP). METHODS: Participants aged 20 and older in 2001-2006 National Health and Nutrition Examination Surveys (n = 8,655) with measures of serum 25(OH)D, CRP, hemoglobin A1c, and other important covariates were included in the present study. Logistic regression and path analysis methods were applied to test the study hypotheses. RESULTS: Decreased serum 25(OH)D concentration was significantly associated with increased odds of T2DM. In males, an estimated 14.9% of the association between 25(OH)D and hemoglobin A1c was mediated by serum CRP. However, this mediation effect was not observed in females. CONCLUSION: Using a nationally representative sample, the present study extends previous research and provides new evidence that the effect of decreased serum vitamin D concentration on T2DM may proceed through increased systemic inflammation in males. Longitudinal studies and randomized control trials are needed to confirm the present findings. PMID- 24167366 TI - Overexpression of FXYD-3 is involved in the tumorigenesis and development of esophageal squamous cell carcinoma. AB - OBJECTIVE: To investigate the association of FXYD-3 expression with clinicopathological variables and PINCH in patients with ESCC. PATIENTS AND METHODS: Expression of FXYD-3 protein was immunohistochemically examined in normal esophageal mucous (n = 20) and ESCC (n = 64). RESULTS: Expression of FXYD 3 in the cytoplasm markedly increased from normal esophageal epithelial cells to primary ESCC (P = 0.001). The expression of FXYD-3 was correlated with TNM stages and depth of tumor invasion. Furthermore, the cases with lymph node metastasis tended to show a higher frequency of positive expression than those without metastasis (P = 0.086), and FXYD-3 expression tended to be positively related to the expression of PINCH (P = 0.063). Moreover, the cases positive for both proteins had the highest frequency of lymph node metastasis (P = 0.001). However, FXYD-3 expression was not correlated with patient's gender (P = 0.847), age (P = 0.876), tumor location (P = 0.279), size (P = 0.771), grade of differentiation (P = 0.279), and survival (P = 0.113). CONCLUSION: Overexpression of FXYD-3 in the cytoplasm may play an important role in the tumorigenesis and development in the human ESCC, particularly in combination with PINCH expression. PMID- 24167367 TI - Serum interleukin-15 levels are associated with severity of pain in patients with knee osteoarthritis. AB - BACKGROUND: Inflammation plays a crucial role in the development and progression of osteoarthritis (OA). Interleukin-15 (IL-15) is a well-known proinflammatory cytokine. OBJECTIVE: We aimed at evaluating the relationship between serum IL-15 levels and the severity of pain as well as radiographic progression in patients with knee OA. METHODS: Two hundred and twenty-six OA patients and 106 controls were enrolled in this study. The symptomatic/radiological severity of OA was assessed by the Western Ontario McMaster University Osteoarthritis Index- (WOMAC )pain scores/Kellgren-Lawrence (KL) grading system. Serum IL-15 levels were measured by enzyme-linked immunosorbent assay (ELISA). RESULTS: Serum IL-15 levels were significantly higher in OA patients compared with controls. Serum IL 15 levels were independently and positively correlated with WOMAC-pain scores but not KL grades in OA patients. CONCLUSIONS: We demonstrated that increased serum IL-15 levels were independently correlated with self-reported greater pain in knee OA patients. These results suggest that IL-15 might play a crucial role in the pathogenesis of OA related pain and therapeutic interventions by blocking IL 15 signaling pathways to delay the degenerative process of OA related pain which warrants further investigations. PMID- 24167368 TI - AGR2 predicts tamoxifen resistance in postmenopausal breast cancer patients. AB - Endocrine resistance is a significant problem in breast cancer treatment. Thus identification and validation of novel resistance determinants is important to improve treatment efficacy and patient outcome. In our work, AGR2 expression was determined by qRT-PCR in Tru-Cut needle biopsies from tamoxifen-treated postmenopausal breast cancer patients. Our results showed inversed association of AGR2 mRNA levels with primary treatment response (P = 0.0011) and progression free survival (P = 0.0366) in 61 ER-positive breast carcinomas. As shown by our experimental and clinical evaluations, elevated AGR2 expression predicts decreased efficacy of tamoxifen treatment. From this perspective, AGR2 is a potential predictive biomarker enabling selection of an optimal algorithm for adjuvant hormonal therapy in postmenopausal ER-positive breast cancer patients. PMID- 24167369 TI - Increased RCAS1 expression is associated with advanced histopathological stage and poor prognosis in patients with gastric adenocarcinoma. AB - BACKGROUND: The receptor-binding cancer antigen expressed on SiSo cells (RCAS1) is a human tumor-associated antigen that has been considered to play a crucial role in tumor progression by enabling cancer cells to evade immune surveillance. The present study aimed to evaluate the clinical significance of the RCAS1 expression in gastric adenocarcinoma. MATERIAL AND METHODS: RCAS1 protein expression was assessed immunohistochemically on 54 gastric adenocarcinoma tissue samples and was analyzed in relation to clinicopathological parameters, tumor proliferative capacity, and patients' survival. RESULTS: Enhanced RCAS1 expression levels were significantly associated with advanced histopathological stage and presence of organ metastasis (P = 0.0084 and P = 0.0327). Gastric cancer patients with elevated RCAS1 expression levels showed significantly shorter survival times compared to those with low RCAS1 expression (log-rank test, P = 0.0168). In multivariate analysis, histopathological stage and grade of differentiation as well as the RCAS1 expression were identified as independent prognostic factors (Cox regression analysis, P = 0.0204, P = 0.0035, and P = 0.0081). CONCLUSIONS: Our data support the evidence that RCAS1 upregulation may contribute to gastric malignant progression, representing a useful biomarker to predict the biological behaviour and prognosis in gastric neoplasia. PMID- 24167370 TI - Immune activation and viral replication after vaccination with an influenza A H1N1 2009 vaccine in HIV-infected children receiving antiretroviral therapy. AB - Immunization with a pandemic influenza A H1N1 2009 was recommended for HIV infected patients. However, there is limited information concerning the impact of immunization with this vaccine on immune activation and HIV viral replication. In this study, 45 HIV-infected children and adolescents receiving antiretroviral therapy were immunized with a 2-dose series of nonadjuvated monovalent influenza A H1N1 2009 vaccine upon enrollment and approximately 1 month later. Immunogenicity was determined by haemagglutination inhibition assay. The level of immune activation was determined by identification of CD38 and HLA-DR on CD8+ T cells. Patients were divided into 2 groups which include patients who had an undetectable HIV viral load (HIV detectable group) and patients who show virological failure (HIV nondetectable group). The results showed seroconversion rate of 55.2% in HIV nondetectable group, whereas 31.3% was found in HIV detectable group. Both groups of patients showed no major increase in immune activation after immunization. Interestingly, a decrease in the frequency of CD8+ T cells that coexpressed CD38 and HLA-DR was observed after immunization in both groups of patients. We suggested that immunization with influenza A H1N1 2009 vaccine can induce immune response to the pandemic virus without major impact on HIV viral replication and immune activation. PMID- 24167371 TI - CagA-positive Helicobacter pylori infection and reduced sperm motility, vitality, and normal morphology. AB - Helicobacter pylori (HP) infection, particularly when caused by strains expressing CagA, may be considered a concomitant cause of male and female reduced fertility. This study explored, in 87 HP-infected males, the relationship between infection by CagA-positive HP strains and sperm parameters. HP infection and CagA status were determined by ELISA and Western blotting; semen analysis was performed following WHO guidelines. The amino acid sequence of human enzymes involved in glycolysis and oxidative metabolism were "blasted" with peptides expressed by HP J99. Thirty-seven patients (42.5%) were seropositive for CagA. Sperm motility (18% versus 32%; P < 0.01), sperm vitality (35% versus 48%; P < 0.01) and the percentage of sperm with normal forms (18% versus 22%; P < 0.05) in the CagA-positive group were significantly reduced versus those in the CagA negative group. All the considered enzymes showed partial linear homology with HP peptides, but four enzymes aligned with four different segments of the same cag island protein. We hypothesize a relationship between infection by strains expressing CagA and decreased sperm quality. Potentially increased systemic levels of inflammatory cytokines that occur in infection by CagA-positive strains and autoimmune phenomena that involve molecular mimicry could explain the pathogenetic mechanism of alterations observed. PMID- 24167372 TI - Inflammatory cytokines and the risk of cardiovascular complications in type 2 diabetes. AB - This study evaluates peripheral blood T lymphocyte expression of inflammatory and proinflammatory cytokines as well as T regulatory (Treg) (FOXP3+CD25+CD4+) cells in type 2 diabetes (T2DM). Participants included 40 T2DM and 30 healthy control subjects. Twenty-four patients had no complications while 16 were afflicted with coronary heart disease (CHD). Relative to healthy subjects, all T2DM patients showed a significant increase in expression of CD4+IFN- Y +, CD4+TNF- alpha +, and CD4+IL-8+ T cells (P < 0.001) as well as CD4+IL-6+, CD4+IL-1 beta +, and IL 17+ T cells (P < 0.05) while the ratios of Treg/Th1(CD4+IFN- Y +) and Treg/Th 17(CD4+IL-17+) cells were significantly decreased (P < 0.05 and P < 0.01). T2DM patients with CHD showed a significant increase in CD4+IFN- Y +, CD4+TNF- alpha +, and CD4+IL-17+ T cells and a significant decrease in Treg/Th1 and Treg/IL-17 cells compared to T2DM patients without CHD (P < 0.05). In CHD-afflicted T2DM, HbA1c correlated positively with CD4+IFN- Y + T cells (P < 0.01), HDL correlated negatively with each of CD4+IL-8+ T cells and CD4+IL-17+ T cells (P < 0.05), and LDL correlated positively with CD4+IL-1 beta + T cells (P < 0.05). Conclusion. This study shows that hyperglycemia and dyslipidemia correlate with increased inflammatory cytokine expression and suggests the involvement of T cells in the development of diabetes and its complications. PMID- 24167373 TI - Association of IL-4-590 C>T and IL-13-1112 C>T gene polymorphisms with the susceptibility to type 2 diabetes mellitus. AB - BACKGROUND: The goal of the study is to investigate the association of IL-4-590 and IL-13-1112 genetic polymorphisms with type 2 diabetes mellitus (T2DM) in Egyptian patients. SUBJECTS AND METHODS: The study included 135 cases with T2DM and 75 healthy unrelated age-matched controls from the same locality of Egypt. DNA was extracted and processed by the ARMS-PCR technique for characterization of genetic variants of IL-4-590 C>T and IL-13-1112 C>T polymorphisms. RESULTS: Egyptian cases with T2DM showed a lower frequency of the IL-4-590 CC homozygous genotype compared to controls (10.4% versus 43.48%) with a higher CT heterozygous genotype (85.2% versus 47.8%). Similarly, cases showed a lower frequency of the IL-13-1112 CC genotype (20.7% versus 56.8%) with a higher frequency of the heterozygous IL-13-1112 CT genotype (76.3% versus 41.3%). Both polymorphisms showed significantly positive associations with T2DM in the dominant, codominant, and overdominant models of inheritance. On the other hand, comparing genotypes of subgroups related to gender, positive family history, and positive consanguinity showed a nonsignificant difference (P > 0.05). CONCLUSION: Heterozygous genotypes (IL-4-590 CT and IL-13-1112 CT) could be considered as risk factors, while the homozygous wild types (-590 CC and -1112 CC) might be considered protective to T2DM. PMID- 24167374 TI - Serum paraoxonase 1 activity is associated with fatty acid composition of high density lipoprotein. AB - INTRODUCTION: Cardioprotective effect of high density lipoprotein (HDL) is, in part, dependent on its related enzyme, paraoxonase 1 (PON1). Fatty acid composition of HDL could affect its size and structure. On the other hand, PON1 activity is directly related to the structure of HDL. This study was designed to investigate the association between serum PON1 activity and fatty acid composition of HDL in healthy men. METHODS: One hundred and forty healthy men participated in this research. HDL was separated by sequential ultracentrifugation, and its fatty acid composition was analyzed by gas chromatography. PON1 activity was measured spectrophotometrically using paraxon as substrate. RESULTS: Serum PON1 activity was directly correlated with the amount of stearic acid and dihomo-gamma-linolenic acid (DGLA). PON1/HDL-C was directly correlated with the amount of miristic acid, stearic acid, and DGLA and was inversely correlated with total amount of omega 6 fatty acids of HDL. CONCLUSION: The fatty acid composition of HDL could affect the activity of its associated enzyme, PON1. As dietary fats are the major determinants of serum lipids and lipoprotein composition, consuming some special dietary fatty acids may improve the activity of PON1 and thereby have beneficial effects on health. PMID- 24167375 TI - Increased glutamate and homocysteine and decreased glutamine levels in autism: a review and strategies for future studies of amino acids in autism. AB - There are many reports about the significant roles of some amino acids in neurobiology and treatment of autism. This is a critical review of amino acids levels in autism. No published review article about the level of amino acids in autism was found. The levels of glutamate and homocystein are increased in autism while the levels of glutamine and tryptophan are decreased. Findings regarding the plasma levels of taurine and lysine are controversial. The urinary levels of homocysteine and essential amino acids in both the untreated and treated autistic children are significantly less than those in the controls. The current literature suffers from many methodological shortcomings which needed to be considered in future studies. Some of them are age, gender, developmental level, autism symptoms severity, type of autism spectrum disorders, medical comorbidities, intelligent quotient, diet, concomitant medications, body mass index, and technical method of assessment of amino acids. PMID- 24167376 TI - Association between angiotensin II type 1 receptor polymorphism and sudden cardiac death in myocardial infarction. AB - OBJECTIVE: The renin-angiotensin system is involved in the pathogenesis of coronary artery disease and myocardial infarction (MI). Angiotensin II (Ang II) has many adverse effects such as vasoconstriction and vascular remodeling, and these actions are mediated by the angiotensin II type 1 receptor (AT1R). PATIENTS AND METHODS: A total of 1376 patients were recruited from January 2010 to April 2012. The study group consisted of 749 patients with ACS (317 females and 432 males) and of 627 healthy controls. RESULTS: The ACS patients demonstrated a lower proportion of AA genotypes and AC genotypes but higher proportions of CC genotypes than the control population. The AT1R CC genotype conferred a 2.76-fold higher risk of MI compared with the genotype AC and AA. In addition, the CC genotype was also associated with a 4.08 times higher risk of left anterior descending artery infarction and a 3.07 times higher risk of anterior wall infarction. We also found that the CC genotype was independently associated with sudden cardiac death. IN SUMMARY: This study demonstrated that the AT1R CC genotype is an independent risk factor for ACS incidence, and this genotype is associated with a greater ACS severity and greater risk of sudden cardiac death. PMID- 24167377 TI - Fecal S100A12 in healthy infants and children. AB - BACKGROUND AND AIMS: Fecal S100A12 is shown to be a useful noninvasive marker of gut inflammation. However, the studies to date have not characterised the patterns of expression in healthy young children. This study aimed to determine S100A12 levels in infants and children without symptoms of underlying gut disease. METHODS: Stool samples were collected from healthy infants (<12 months) and children without gastrointestinal symptoms. Faecal S100A12 was measured by immunoassay. RESULTS: Fifty-six children were recruited. Serial samples were obtained from seven term infants over the first 6 months of life. Single samples were obtained from 49 healthy children ranging from 0.16 to 13.8 years of age. Median S100A12 levels were 0.5 mg/kg (ranging from 0.39 to 25) in the healthy children, with high values (>10 mg/kg) in five infants only. There was no variation between gender. Median S100A12 levels in healthy infants remained below the established normal cut-off from birth to six months of age. CONCLUSION: S100A12 levels in well infants and children are almost exclusively lower than the standard cut-off. Transiently higher levels may be seen in early infancy. An elevated level of S100A12 in children older than 12 months of age is likely to represent organic gut disease. PMID- 24167378 TI - Levels of circulating microparticles in lung cancer patients and possible prognostic value. AB - BACKGROUND: Endothelial-derived microparticles (EDMPs) and platelet-derived microparticles (PDMPs) have been reported to be increasing in various diseases including malignant diseases. Here, we investigated whether these MPs may be useful biomarkers for predicting lung cancer (LC) disease status, cell type, or metastasis. METHODS AND RESULTS: One hundred and thirty LC patients were prospectively enrolled into the study between April 2011 and February 2012. Flow cytometric analysis demonstrated that the circulating levels of platelet-derived activated MPs (PDAc-MPs), platelet-derived apoptotic MPs (PDAp-MPs), endothelial derived activated MPs (EDAc-MPs), and endothelial-derived apoptotic MPs (EDAp MPs) were significantly higher in LC patients than in 30 age- and gender-matched normal control subjects (all P < 0.05). Additionally, circulating level of PDAc MPs was significantly lower (P = 0.031), whereas the circulating levels of the other three biomarkers did not differ (all P > 0.1) in early stage versus late stage LC patients. Furthermore, the circulating levels of the four types of MPs did not differ among patients with different disease statuses (i.e., disease controlled, disease progression, and disease without treatment, i.e., fresh case) (all P > 0.2) or between patients with or without LC metastasis (all P > 0.5). Moreover, only the circulating level of EDAp-MPs was significantly associated with the different cell types (i.e., squamous cell carcinoma, adenocarcinoma, and small cell carcinoma) of LC (P = 0.045). CONCLUSION: Circulating MP levels are significantly increased in LC patients as compared with normal subjects. Among the MPs, only an increased level of EDAp-MPs was significantly associated with different LC cell types. PMID- 24167379 TI - Mycobacterial dormancy regulon protein Rv2623 as a novel biomarker for the diagnosis of latent and active tuberculous meningitis. AB - The present study was designed to investigate Rv2623 antigen, a major dormancy regulon protein of Mycobacterium tuberculosis (MTB) in CSF of suspected latent and active tuberculous meningitis (TBM) patients. A total of 100 CSF samples from TBM (n = 31), suspected latent TBM (n = 22), and suitable noninfectious control subjects (n = 47) were collected and evaluated for Rv2623 antigen level using ELISA protocol. A significantly high (P < 0.05) mean absorbance was observed in samples of suspected latent TBM and active TBM patients as compared to non-TBM control patients. However, no significant difference in Rv2623 level was observed between suspected latent TBM and TBM patients. Our preliminary findings suggest that Rv2623 may be useful as a potential biomarker for the diagnosis of the latent as well as active TBM infection. Futher evaluation of this biomarker in large number of samples is therefore needed to confirm the result. PMID- 24167381 TI - The importance of proper citation of references in biomedical articles. AB - In scientific circles, the reference is the information that is necessary to the reader in identifying and finding used sources. The basic rule when listing the sources used is that references must be accurate, complete and should be consistently applied. On the other hand, quoting implies verbatim written or verbal repetition of parts of the text or words written by others that can be checked in original. Authors of every new scientific article need to explain how their study or research fits with previous one in the same or similar fields. A typical article in the health sciences refers to approximately 20-30 other articles published in peer reviewed journals, cite once or hundreds times. Citations typically appear in two formats: a) as in-text citations where the sources of information are briefly identified in the text; or b) in the reference list at the end of the publication (book chapter, manuscript, article, etc.) that provides full bibliographic information for each source. Group of publishers met in Vancouver in 1978 and decided to prescribe uniform technical propositions for publication. Adopted in the 1979 by the National Library of Medicine in Bethesda, then the International Committee of Medical Journals Editors (ICMJE), whose review in 1982 entered the official application by 300 international biomedical journals. Authors writing articles for publication in biomedical publications used predominantly citation styles: Vancouver style, Harward style, PubMed style, ICMJE, APA, etc. The paper gives examples of all of these styles of citation to the authors in order to facilitate their applications. Also in this paper is given the review about the problem of plagiarism which becomes more common in the writing of scientific and technical articles in biomedicine. PMID- 24167380 TI - Serum anti-CCNY autoantibody is an independent prognosis indicator for postoperative patients with early-stage nonsmall-cell lung carcinoma. AB - Cyclin Y (CCNY) is a novel cyclin and almost nothing is known about its role in human cancers. To investigate the clinical significance of serum anti-CCNY autoantibodies in nonsmall-cell lung carcinoma (NSCLC), the serum levels of CCNY protein in 264 patients with NSCLC, 103 patients with tuberculosis, and 89 healthy controls were analyzed by immunohistochemistry. The result shows that, compared with normal lung tissues, the NSCLC tissues contained higher levels of CCNY protein. The levels of anti-CCNY autoantibodies were higher in the sera of the patients with NSCLC than in the sera of the healthy controls (P < 0.001) or the patients with tuberculosis (P = 0.027). Moreover, in a Cox regression analysis, anti-CCNY autoantibody was an independent factor that predicted poor prognosis for postoperative patients with early-stage NSCLC (P = 0.026) as well as for those with distant metastasis (P = 0.012). Our data indicated that Anti CCNY autoantibody may be useful as a latent tumor marker to facilitate diagnosis and may represent a novel prognostic indicator for patients with early stage NSCLC. PMID- 24167382 TI - At what level of collective equipoise does a randomized clinical trial become ethical for the members of institutional review board/ethical committees? AB - BACKGROUND: The conduct of a randomized controlled trial (RCT) is deemed ethical only if we are in state of "equipoise" as to which treatment would be most beneficial for the patients. Individual equipoise applies to an individual clinician or a member of ethical, institutional review board (IRB), whilst collective equipoise refers to the profession as a whole. It is argued that physicians are not bound by the equipoise but their actions are directed by the confines of the expert opinion. Experts can agree or disagree in various proportions on the merit of a given treatment. Hence, the collective equipoise will be often incomplete. In turn, the opinions of content expert in the field of the proposed trial influence the IRB members' decision regarding trial approval. METHODS: We conducted a survey of IRB members at University of South Florida and the IRB members attending the bioethics conference organized in Clearwater, Florida, USA. The survey was made available as hard copy (paper based) and included six hypothetical scenarios outlining clinical trials targeted at measuring the collective equipoise. We defined the collective equipoise as the situation when survey participants were equally split (50:50) in their decision regarding whether a proposed clinical trial would be ethical to conduct. The opinion of 100 experts in the field expressed as proportion of experts favoring treatment A vs. B in each of the five scenarios was made available to the participants. RESULTS: The response rate of our survey was 33% (71/218). Fifty percent of the IRB members would approve an RCT addressing the efficacy of two drugs for the management of headache even if 80% of experts favor one treatment over another (median: 80%; third quartile: 80%). Similarly, half of participating IRB members would approve the study when the median distribution of equipoise among experts was 70% (70 in favor of treatment A vs. 30 in favor of treatment B) for treatment of leukemia, 60% for treatment of geriatric patients and 70% for treatment of newborns. Half of IRB members would approve the study when the median distribution of equipoise among experts was 70% for treatment for leukemia in dogs and 85% for leukemia in rats (and 25% of IRB members would approve such a study even if 100% of experts favors one treatment over another). None of the demographic features of respondents affected collective equipoise. CONCLUSIONS: This is the first study assessing collective equipoise among ethical committee/IRB members. Our study findings show that IRB members perceived that conduct of a trial enrolling humans is unethical when the equipoise level is beyond 80% (80:20 distribution of uncertainty). IRB members require a higher level of equipoise when it comes to testing a new drug in humans than in animals. A relatively high level of equipoise is needed for IRB members to be comfortable to approve trials involving life-threatening situations, children and elderly patients. PMID- 24167383 TI - Sickness Impact Profile (SIP) Score, a Good Alternative Instrument for Measuring Quality of Life in Patients with Ileal Urinary Diversions. AB - OBJECTIVE: To determine the effectiveness of the use of the SIP score and the quality of life impairment in patients with ileal conduit and orthotropic ileal derivations by Hautmann and AbolEnein/Ghoneim. METHODS: Prospectively evaluated 146 patients in different age groups. In 66 patients ileal conduit derivation was performed, in 20 patients orthotropic derivation using Hautman technique was recorded and in 20 of them AbolEnein/Ghoneim was used. Prior to examining patients with urinary diversions, 40 patients with minor urological symptoms not requiring any active treatment, were surveyed in order to validate SIP score. Six months after the operation, all patients with urinary diversions filled the SIP score questionnaire. RESULTS: Using Crombach's Alpha equation the high reliability of SIP questionnaire was proven. Average scale value was 0,93. Using descriptive statistics mean values of all categories and dimensions of the SIP questionnaire of examined patients were determined, calculated according to the questionnaire manual being converted to percentage. Total value of SIP score for the ileal conduit group was 34,76% and in orthotropic derivation 18,52% respectively. For Hautmann procedure total SIP score was 18,35% and for AbolEnein/Ghoneim 18,7%. In the control group total SIP score was 9%. The most influential dimensions on the total score of ileal conduit were physical and psycho-social, while independent dimension did not significantly influent total SIP score. CONCLUSION: Taking into consideration the lack of questionnaires on quality of life for urinary derivations, SIP score as a general disease influence to the quality of life questionnaire represents a reliable alternative for objectification and quantification of the quality of life upon urinary derivation. According to this instrument, orthotropic derivations provide significantly better quality of life compared to ileal conduit. PMID- 24167384 TI - Colonoscopic Polypectomies and Recommendations on the Colonoscopy Follow-up Intervals Depending on Endoscopic and Histopathological Findings. AB - THE AIM: To show histopathological diagnoses after colonoscopic polypectomy in the University Hospital Center (KBC) Split with recommendations on further follow up colonoscopy depending on the endoscopic and histological findings. PATIENTS AND METHODS: The study included 2842 patients who underwent colonoscopy in a two year period (2008-2009), followed by a detailed analysis of 350 patients in which one or more polyps were simultaneously removed and 163 patients who were only sampled for histological analysis. Patients from the National Program for Colorectal Cancer Prevention and patients in which colonoscopy is indicated as part of daily outpatient or inpatient treatment were included as well. RESULTS: During 2008 and 2009 in KBC Split, out of a total of 2842 colonoscopies, 350 patients underwent colonoscopic polypectomy, whereby 618 polyps were removed (1-8 polyps in individual patients), while in 163 patients only biopsy specimens were sampled. Out of the total of 557 polyps sent for histological analysis, 236 were hyperplastic (42%), 193 were identified as tubular adenoma (35%), 84 were tubulovillous (15%), 18 villous (3%), 9 were adenocarcinoma (2%) and other 17 (3%). In 35 (15.4%) polyps high-grade dysplasia was found. The largest number of nonpolypectomized changes confirmed the presence of adenocarcinoma (76-47%), adenomas and hyperplastic polyps were 37 (22%) and regular findings 23 (14%). Mucosal high-grade dysplasia was demonstrated in 35 (23.1%) biopsied changes. CONCLUSION: Colonoscopies with polypectomy decreased the risk of the formation of colorectal cancer in these patients almost to the level of risk in patients who have not even had a polyp during colonoscopy. Arguably the best method of prevention and early detection of colorectal cancer are already widely established national programs. The next qualitative level is constantly improving the quality of colonoscopy with clear criteria and the establishment of a body to evaluate the performers and the equipment, and making recommendations on the colonoscopy follow-up intervals depending on endoscopic and histopathological findings of patients who for any reason underwent colonoscopy. PMID- 24167385 TI - Therapeutic ultrasound and pain in degenerative diseases of musculoskeletal system. AB - INTRODUCTION: Therapeutic ultrasound is a physical modality which is constantly expanding range of indications. Analgesic effect of ultrasound is still under discussion. Regardless the extensive application of pulsed ultrasound of low intensity, continuous ultrasound has a better analgesis effect, which is explained by its mechanism of action. AIMS: The main research objective of this study was to determine the effect of continuous ultrasound to pain caused by degenerative diseases of the musculoskeletal system in the intensity and duration of ultrasound treatment. Other objectives are entailed determining the correlation between the degree of pain reduction with: location of pain, age, gender and body mass index (BMI). MATERIAL AND METHODS: The study included 68 patients with chronic pain localized in the region of the spine or major joints of the extremities, depending on the localization of the degenerative changes. Patients are divided into two groups. The first group was treated with 10 applications of continuous ultrasound with frequency of 1 MHz, intensity 0.4 W/cm2 for 8 minutes, and the other group with 10 applications of ultrasound with frequency of 1 MHz, intensity 0.8 W/cm 2 for 4 minutes. RESULTS AND DISCUSSION: Pain intensity was assessed before and after ultrasound therapy performed by subjective visual analogue scale (VAS) for pain, numbered from 0-10, where 0 is the rating for the state of no pain, and 10 grades for severe pain. The average VAS improvement in the first group was 3.97, and 4.74 in second one. The results of F (1.66) = 2.93, p = 0.09 analysis of variance showed no significance difference between the average improvement of two groups. Correlation between the degree of pain reduction showed significance only with BMI, or that higher BMI is associated with a lower degree of pain reduction. The results of this study showed that application of continuous ultrasound in patients with chronic pain, caused by degenerative changes in the musculoskeletal system, led to a significant reduction in pain. Different intensity and duration of ultrasound application showed no significant effect on the degree of pain reduction. Body mass index showed significant negative correlation with the degree of pain reduction, but age, gender and location of pain did not show significant correlation. PMID- 24167386 TI - The Effect of Educational Intervention on Medical Diagnosis Recording among Residents. AB - INTRODUCTION: Studies indicate that using interventions including education may improve medical record documentation and decrease incomplete files. Since physicians play a crucial role in medical record documentation, the researchers intend to examine the effect of educational intervention on physicians' performance and knowledge about principles of medical diagnosis recording among residents in Hormozgan University of Medical Sciences(HUMS). METHODS: This quasi experimental study was conducted in 2010 on 40 specialty residents (from internal medicine, obstetrics and gynecology, pediatrics, anesthesiology and surgery specialties) in Hormozgan University of Medical Sciences. During a workshop, guidelines for recording diagnostic information related to given specialty were taught. Before and after the intervention, five medical records from each resident were selected to assess physician performance about chart documentation. Using a questionnaire, physicians' knowledge was investigated before and after intervention. Data were analyzed through one-way ANOVA test. RESULTS: Change in physicians' knowledge before and after education was not statistically significant (p = 0.15). Residents' behavior did not have statistically significant changes during three phases of the study. CONCLUSION: Diversity of related factors which contributes to the quality of documentation compels portfolio of strategies to enhance medical charting. Employing combination of best practice efforts including educating physicians from the beginning of internship and applying targeted strategy focus on problematic areas and existing gap may enhance physicians' behavior about chart documentation. PMID- 24167387 TI - External Evaluation of Four Hospitals According to Patient-centred Care Standards. AB - INTRODUCTION: Hospital accreditation is a multi-factorial issue. The aim of the current study was to accredit social security organization and university hospitals (that certificated by ISO 9001-2008) in Isfahan, the second largest city of Iran, based on Joint Commission International (JCI) accreditation standards. METHODS: Accreditation of four hospitals was evaluated and compared in a cross-sectional study. Seven checklists were driven from patient-centered JCI accreditation standards to cover indices of access of patients to care and continuity of care (ACC), patients and families rights (PFR), patients and families education (PFE), assessment of patients (AOP), care of patients (COP), analgesic and surgical care (ASC), and medication management and use (MMU). They were filled out by seven inspectors. The findings were analyzed by SPSS 14 (SPSS Inc., Chicago, IL). RESULTS: Beheshti and Zahra hospitals demonstrated the lowest and the highest mean levels preparation, respectively (60 vs. 68.5 percent, respectively). Also, Beheshti hospital revealed the lowest prepared levels in AOP, ASC, MMU and PFE among all evaluated hospitals; the corresponding mean amounts of preparation were 68, 82.5, 56 and 42 percent, respectively. Whereas Zahra hospital showed the highest prepared levels in AOP, COP, MMU and PFE among all evaluated hospitals; the mean amounts of preparation were 82, 61.5, 84 and 57 percent, respectively. No significant difference was found among the four hospitals in any of the seven indices. DISCUSSION: The four evaluated hospitals were not fully prepared to present the best possible patient-centered care system. PMID- 24167388 TI - The use of information sources by faculty members of babol university of medical sciences: a case study from iran. AB - INTRODUCTION: This study seeks to determine the expertise, use, and satisfaction of faculty members of Babol University of Medical Sciences, using the provided online information services by the university. METHODS: This study is descriptive and analytical survey and the information gathering was through the questionnaireand the samples, based on the random of Kerjesi and Morgan Table sample size determination that was selected through stratified sampling proportionately to the size of the departments which summed up to 155 of which 113 responded to the mailed questionnaire. RESULTS: The results of the study show that among the various data sources such as books, journals and internet, faculty members have more undemandingand convenient access to the Internet compared to other resources use, however, half of the information needs of faculty members, 57 (50.4 percent) are provided by the printed books;and the databases available to the University and used by faculty members are PubMed with 76.1% and Science direct with 53.1% and Iranmedex with 46.9%.Only 17% of faculty members have the absolute contentment of the Internet information services,and more than half of the respondents (58.4%) expressed the low speed of Internet service as their major reason for their dissatisfaction of the provided services. PRACTICAL IMPLICATIONS: Use and Satisfaction of Internet-Based Information Services of Faculty Members. DISCUSSION: Using the Internet to provide the needed information with an index of 46%is a significant issue. The results of the study show that among the various data sources such as books, journals and internet, faculty members have more undemandingand convenient access to the Internet and their access to printed books was really hard and limited, although the internet was more convenient to acquire information, most of the information needs of faculty members are provided by the printed books based on what they expressed. The study showed that the use and acquaintance of the sample of the information databases is very lowand only a few of them have the full satisfaction of the provided Internet information services and the main foremost reason for this major dissatisfaction is the low-speed Internet services at the University. PMID- 24167389 TI - Intensive care information system impacts. AB - INTRODUCTION: Today, intensive care needs to be increased with a prospect of an aging population and socioeconomic factors influencing health intervention, but there are some problems in the intensive care environments, it is essential to resolve. The intensive Care information system has the potential to solve many of ICU problems. The objective of the review was to establish the impact of intensive care information systems on the practitioners practice, patient outcomes and ICU performance. METHODS: Scientific databases and electronic journal citations was searched to identify articles that discussed the impacts of intensive care information system on the practices, patient outcomes and ICU performance. A total of 22 articles discussing ICIS outcomes was included in this study from 609 articles initially obtained from the searches. RESULTS: Pooling data across studies, we found that the median impact of ICIS on information management was 48.7%. The median impact of ICIS on user' outcomes was 36.4%, impact on saving tips by 24%, clinical decision support by a mean of 22.7%, clinical outcomes improved by a mean of 18.6%, and researches improved by 18%. CONCLUSION: The functionalities of ICIS are growing day by day and new functionalities are available with every major release. Better adoption of ICIS by the intensive care environments emphasizes the opportunity of better intensive care services through patient oriented intensive care clinical information systems. There is an immense need for developing guidelines for standardizing ICIS to to maximize the power of ICISs and to integrate with HISs. This will enable intensivists to use the systems in a more meaningful way for better patient care. This study provides a better understanding and greater insight into the effectiveness of ICIS in improving patient care and reducing health care expenses. PMID- 24167390 TI - Prevalence of Non-drug Poisoning in Patients Admitted to Hospitals of Mazandaran University of Medical Sciences, 2010-2011. AB - INTRODUCTION: Every year million people have poisoning. Most of them will duo to severity of complications. Identifying the pattern of poisoning will help to prevent of them. Because of the non-medicine substance have a wide variety range and easily is used among people, so the aim of this study was to determine frequency of non-medicinal poisoning according to 10th revision of International Classification of Diseases (ICD-10) in hospitalized patient. METHOD: This is a descriptive cross section study. The medical records of inpatient hospitalized in hospitals of Mazandaran University of Medical Sciences during 2010-2011 were reviewed. The ICD-10 codes for retrieval patient records were T51-T65 which was included alcohol, organic solvent, halogen derivatives, corrosive substance, detergent, metals, inorganic substance, carbon monoxide, gases, fumes and vapors, pesticide, noxious substance has eaten as seafood, noxious substance has eaten as food, unspecified substances. The data were analyzed with SPSS and descriptive and X2 statistics. RESULTS: Of the 1546 in patient with diagnosed poisoning, the 581(37.5%) were non medicine poisoning. Median of age 29+/-17 years, 231(51.6%) female, 300(51.6%) are intentional, and the most material were insecticide276 (47.5%), sting 96(16.3%) and alcohol 76(13%) and organic solvent 40 cases and the 38(95%) of them was children. CONCLUSION: According the result of this study the most cause of poisoning was insecticides. Preventive program for all the groups are suggested and for intentional self-harms and suicide attempted the program of consultation is necessary. PMID- 24167391 TI - Proposed model for Iranian national system of registration of allergy and asthma. AB - INTRODUCTION: Asthma and allergies in addition to demanding social costs-the economic community, one of the major causes of morbidity and mortality in the world is considered. In the last decade in Iran despite the positive developments in many areas of health records into categories based asthma and allergy international standards, less attention has been paid. Improving the quality of care system, identifying groups at risk of asthma and allergies, control plan, prevention and assessment of asthma and allergies due to possible that when allergy and asthma information registration system and create the complete and timely data to be collected. Considering now an efficient national system of registration allergy and asthma that can meet the health needs can no need for this study was felt. MATERIALS AND METHODS: This study, study-the comparison was done in the years 2010-2011. In this research, using library resources, information networks and consultations with experts inside the country gathered on the main axis and branches of national registration system, asthma and allergies in American countries-Australia and England were examined and given economic conditions, cultural and geographical themes for our records system, the axes were proposed objectives, structure, data elements, standard registration process? Data and classification systems are given. RESULTS: The proposed model for national registration system, asthma and allergies in the country is shown in a table. In this table the proposed system based on six main "targets", "structure", "data elements", "data collection process," "registration criteria" and "classification system" is designed. CONCLUSION: The results and recommendations to the International Institute for asthma and allergies, reduction in low registers, and can increase the quality of the proposed model, including advantages in comparison with the existing system of the country noted. PMID- 24167392 TI - Validity of magnetic resonance imaging in knee injuries. AB - INTRODUCTION: Knee injuries are common in athletes, recreationists, and other people in their everyday activities. OBJECTIVE: The study is aimed at establishing the validity of clinical findings, MRI and diagnostic arthroscopy of the knee in ACL, PCL, medial or lateral ligament lesions. METHODS: The prospective research involved 63 inpatients at the Traumatology Clinic in Banja Luka- Nis between 1 January 2011 and 1 June 2012. RESULTS: When clinically examining the ACL and based on the calculated post-test probability amounting to (LR+) = 0.8017, we conclude that there is a considerable probability (80.17%) that a patient with an arthroscopically diagnosed ACL lesion will have the same lesion diagnosed by MRI. The post-test probability following the clinical examination of the medial meniscus and amounting to (LR+) = 0.6943 suggests that there is a considerable probability (69.43%) that an arthroscopically diagnosed lesion of the medial meniscus will also be diagnosed by MRI. On the basis of the clinical examination of the lateral meniscus in the examined sample and calculated post-test probability amounting to (LR+) = 0.6346, we conclude that there is a considerable difference (63.46%) between the diagnostic arthroscopy and MRI of lateral meniscus lesions. CONCLUSION: Arthroscopic examination of the knee is a more valuable method than diagnosis by MRI and clinical examination for detecting lesions of the ACL, PCL, medial and lateral meniscus. PMID- 24167393 TI - P300 wave changes in patients with multiple sclerosis. AB - INTRODUCTION: In patients with multiple sclerosis among other symptoms occur cognitive dysfunctions, which can be shown by P300 wave changes. GOAL: The aim of this study was to demonstrate that patients with multiple sclerosis have reduced amplitude and prolonged latency, longer than 300 +/- 10 ms. METHODS: The study included group of patients with multiple sclerosis and control group. After reviewing the medical records both groups of 14 participants were subjected to the same testing procedures auditory cognitive potentials (P300). RESULTS: We have shown that patients with multiple sclerosis don't have prolonged P300 target stimulus latency, but they have a longer P300 frequent stimulus latency for 18 ms. From 14 patients seven had a pathological P300 target stimulus amplitude, and even 12 patient had pathological P300 frequent stimulus amplitude. CONCLUSION: People with multiple sclerosis have altered P300 which indicates the presence of cognitive dysfunction in these patients. PMID- 24167394 TI - Diagnostic Capabilities of 64 Slice CT Coronography Compared to Classic in Coronary Disease Detection. AB - INTRODUCTION: Cardiovascular disease, among which the most common is coronary disease of the hearth are the main cause of death at middle aged persons in the majority of European countries. Percent of cardiovascular disease in overall mortality among our population is even more than 50%. Up to 55 years of live myocardial infarction is by 5-6 times more common among men, and up to age of 75 years that difference decreases to 2.5 times. GOAL: The goal of this study is to determine the diagnostic value of 64 slices computerized tomography in detection of coronary disease compared to classic, invasive coronography. MATERIAL AND METHODS: Study included 50 patients, of both genders, at average age of 60 years. Patients underwent CT coronography as well as classic coronography. RESULTS: Our research prove that the sensitivity of MSCT coronography 92% with positive predictive value of 86%. Mayor difference was in the analysis of CX artery in the evaluation of significant and non-significant stenosis in application of these two methods. During the analysis of LAD and RCA artery there was no statistically significant difference in findings of these two methods. CONCLUSION: CT coronography is non-invasive, comfortable and reliable method in coronary disease diagnostics. Thanks to its high sensitivity and PPV it enables reliable exclusion of coronary disease and takes significant place in a cardiovascular diseases diagnostic algorithm. PMID- 24167395 TI - Comparison of 3D CRT and IMRT Tratment Plans. AB - Plans of patients with prostate tumor have been studied. These patients have been scanned in the CT simulator and the images have been sent to the Focal, the system where the doctor delineates the tumor and the organs at risk. After that in the treatment planning system XiO there are created for the same patients three dimensional conformal and intensity modulated radiotherapy treatment plans. The planes are compared according to the dose volume histograms. It is observed that the plans with IMRT technique conform better the isodoses to the planning target volume and protect more the organs at risk, but the time needed to create such plans and to control it is higher than 3D CRT. So it necessary to decide in which patients to do one or the other technique depending on the full dose given to PTV and time consuming in genereral. PMID- 24167396 TI - Primary fibro sarcoma of the heart. AB - Primary malignant heart tumors represent rare entities where fibro sarcoma represents about 3% of all. Introducing the patient: A 15 years old patient with cardiac insufficiency (heart failure) symptoms, such as weakness, cyanosis, palpitations and breathing difficulties; enlargement of upper mediastinum and pleural effusion. Through echocardiography a pericardial effusion and intracavitary thrombus in atrium was diagnosed. With computed tomography is diagnosed a tumoral mass in right atrium which is also spread in the right ventricle of the heart. Tumor is completely removed; pat histology result showed primary fibro sarcoma of the heart. At that time no metastasis was found. Conclusion. Primary malignant heart tumors may manifest like cardiac insufficiency or like systemic diseases. Fibrosarcomas are rare and have bad prognosis. On average patients can live around six months after initial symptoms appeared and diagnosis of the tumor was done. In the case of cardiac insufficiency with differential diagnosis we should also think of heart tumors, which could certainly be proved for or eliminated by echocardiography. PMID- 24167397 TI - Hb H Interference on Measurement Of HbA1c With Ion-Exchange HPLC. AB - In this article, an interference caused by hemoglobin H (Hb H), during the measurement of hemoglobin A1c (HbA1c) with ion exchange high pressure liquid chromatography (HPLC) method, was presented in blood sample of a 20-year-old male patient. HbA1c measurement was performed with Agilent 1200 HPLC system using a commercial Recipe HbA1c ion-exchange column. Hemoglobin electrophoresis was performed with Interlab G26 agarose electrophoresis automated compact system. HbA1c level was 18.2% and HbA0 level was 81.5% with ion-exchange HPLC method. Patient's fasting serum glucose was assessed before HbA1c measurement and the result was 165 mg/dL (9.16 mmol/L). On the other hand, the result of HbA0 was 87.9%, Hb H was 10.8% and Hb A2 was 1.3% with electrophoresis. Whole blood test values were within reference ranges except MCV. MCV value was 79.6 fL. It is important to keep in mind that HbA1c level might be considered falsely high with ion-exchange HPLC method because of Hb H containing sample. PMID- 24167398 TI - New medical education system: implementation of informatic technology and holistic approach concept. PMID- 24167399 TI - Non-insertional tendinopathy of the subscapularis. AB - PURPOSE: (1) Describe a previously unreported finding involving the intra articular portion of the subscapularis, the Conrad lesion. (2) Describe a novel classification system for the spectrum of non-insertional tendinopathy of the subscapularis. (3) Report the outcomes of surgical treatment of this spectrum of pathology. MATERIALS AND METHODS: Outcomes of 34 patients (23 males and 11 females, mean age 60.5 +/- 7.5) with non-insertional tendinopathy of the subscapularis treated arthroscopically were retrospectively reviewed. All patients had anterior shoulder pain with no weakness during belly-press testing and no subscapularis footprint involvement on magnetic resonance imaging. All patients were managed with subscapularis tendon debridement and side-to-side repair along with treatment of concomitant pathology. RESULTS: Seven patients had a Type I lesion (so-called Conrad lesion) - a nodule on the leading edge of the subscapularis. Eighteen patients had a Type II lesion - a visible split tear with degeneration in the upper 1/2 of the intra-articular tendon. Nine patients had a Type III lesion - more extensive splitting in the tendon with advanced tendon degeneration. At a mean follow-up of 24 months, 97% of patients were completely satisfied. Significant improvements were seen in forward elevation (152 +/- 12 degrees to 172 +/- 5 degrees , P < 0.001) and visual analog scale pain scores (5.9 +/- 1.7-0.6 +/- 1.0, P < 0.001). Internal rotation strength and external rotation motion at the side were maintained. ASES scores averaged 95.4 +/- 7.4, disabilities of arm, shoulder and hand scores averaged 6.19 +/- 9.8, Western Ontario Rotator Cuff scores averaged 91.7 +/- 9.3 and the average University of California at Los Angeles score was 33.1 +/- 2.4. CONCLUSIONS: We present a previously unreported finding of the subscapularis, the Conrad lesion, along with a novel classification system for non-insertional tendinopathy of the subscapularis. Arthroscopic treatment of this spectrum of tendinopathy along with concomitant shoulder pathology eliminated pain and improved patient outcomes without detrimental effects. LEVEL OF EVIDENCE: IV, Retrospective Case Series. PMID- 24167400 TI - Results of the repair of acute rotator cuff tears is not influenced by tear retraction. AB - PURPOSE: This study evaluated retraction in the setting of acute rotator cuff tears and determined its effects on patient outcomes and tendon repair integrity. MATERIALS AND METHODS: A total of 22 patients had surgery within 6 weeks or less from the time of injury. Fifteen of these patients were prospectively followed at a minimum of 2 years; average 40.5 months (range 24-69). Pre-operative objective and subjective outcomes were compared. Tendon repair integrity was assessed with ultrasound at a minimum of 1 year from surgery. The population was stratified into Group 1 (8 patients) with minimal intra-operative medial tendon retraction to the mid-line level of the humeral head and Group 2 (7 patients) with a large medial tendon retraction to the glenohumeral joint or greater. RESULTS: The average time to surgery from the onset of symptoms was 27 days (range, 6-42). Post-operative motion increased significantly for external rotation and forward elevation, 77% of patients were pain free, 80% were completely satisfied, and 100% would have the surgery again. Group 1 (small retraction) versus Group 2 (large retraction) showed that post-operative pain levels, satisfaction, range of motion, strength, subjective shoulder value (95.4% vs. 92.3%), Constant Score (80.8 vs. 78.1), and American Society of Shoulder and Elbow Surgeons (96.2 vs. 93.5) scores were not statistically different. Ultrasound showed a tendon repair integrity rate of 87%. 2 patients who did have a re-tear were in Group 2, yet had comparative outcomes. CONCLUSION: In acute rotator cuff tears, equal patient satisfaction, pain scores, range of motion, strength, and outcome measures should be expected with surgical repair despite the level of retraction. LEVEL OF EVIDENCE: Therapeutic level IV. PMID- 24167401 TI - Thermal damage during humeral reaming in total shoulder resurfacing. AB - INTRODUCTION: Total shoulder resurfacing (TSR) provides a reliable solution for the treatment of glenohumeral arthritis. It confers a number of advantages over traditional joint replacement with stemmed humeral components, in terms of bone preservation and improved joint kinematics. This study aimed to determine if humeral reaming instruments produce a thermal insult to subchondral bone during TSR. PATIENTS AND METHODS: This was tested in vivo on 13 patients (8 with rheumatoid arthritis and 5 with osteoarthritis) with a single reaming system and in vitro with three different humeral reaming systems on saw bone models. Real time infrared thermal video imaging was used to assess the temperatures generated. RESULTS: Synthes (Epoca) instruments generated average temperatures of 40.7 degrees C (SD 0.9 degrees C) in the rheumatoid group and 56.5 degrees C (SD 0.87 degrees C) in the osteoarthritis group (P = 0.001). Irrigation with room temperature saline cooled the humeral head to 30 degrees C (SD 1.2 degrees C). Saw bone analysis generated temperatures of 58.2 degrees C (SD 0.79 degrees C) in the Synthes (Epoca) 59.9 degrees C (SD 0.81 degrees C) in Biomet (Copeland) and 58.4 degrees C (SD 0.88 degrees C) in the Depuy Conservative Anatomic Prosthesis (CAP) reamers (P = 0.12). CONCLUSION: Humeral reaming with power driven instruments generates considerable temperatures both in vivo and in vitro. This paper demonstrates that a significant thermal effect beyond the 47 degrees C threshold needed to induce osteonecrosis is observed with humeral reamers, with little variation seen between manufacturers. Irrigation with room temperature saline cools the reamed bone to physiological levels and should be performed regularly during this step in TSR. PMID- 24167402 TI - Relationship between the functional outcomes and radiological results of conservatively treated displaced proximal humerus fractures in the elderly: A prospective study. AB - PURPOSE: The purpose of this prospective study is to investigate the relationship between the functional outcome and the radiographic results of conservatively treated two-, three- and four-part proximal humeral fractures in patients aged over 65 years. MATERIALS AND METHODS: The study comprised 29 prospectively followed cases aged over 65 years who presented with displaced proximal humerus fracture between 2009 and 2011. The fractures were classified according to the Neer classification and all met the displacement criteria described by Neer. Standard physical therapy program was applied. Patients were evaluated clinically using Constant shoulder score, quick form of disabilities of arm, shoulder and hand score and visual analog scale. At the final follow-up, humeral head position in the coronal plane was assessed with neck-shaft angle. Any complication was recorded during the treatment period. Correlation between the functional outcomes and final radiologic results were statistically analyzed. RESULTS: Data were analyzed from 29 cases (21 female, 8 male) with a mean age was 78 +/- 8.6 years (range 65-93 years). The mean follow-up period was 18.2 +/- 4.07 months (range 12 26 months). Functional results were significantly related with initial fragmentation. However, there was no correlation between the functional outcomes and the final geometry of the humeral head. Despite the union occurred with deformity, the functional outcome were satisfactory. CONCLUSION: The results of this study show that initial fragmentation has a negative effect on the functional results. However, the changed position of the humeral head on coronal plane does not affect the final functional results. PMID- 24167403 TI - Total shoulder arthroplasty versus hemiarthroplasty for glenohumeral arthritis: A systematic review of the literature at long-term follow-up. AB - INTRODUCTION: The optimal surgical treatment of end-stage primary glenohumeral osteoarthritis remains controversial. The objective of this article is to systematically review the current available literature to formulate evidence based guidelines for treatment of this pathology with an arthroplasty. MATERIALS AND METHODS: A systematic literature search was performed to identify all articles from 1990 onward that presented data concerning treatment of glenohumeral arthritis with total shoulder arthroplasty (TSA) or head arthroplasty (HA) with a minimal follow-up of 7 years. The most relevant electronic databases were searched. RESULTS: After applying the inclusion and exclusion criteria, we identified 18 studies (of the initial 832 hits). The search included a total of 1,958 patients (HA: 316 and TSA: 1,642) with 2,111 shoulders (HA: 328 + TSA: 1,783). The revision rate for any reason in the HA group (13%) was higher than in the TSA group (7%) (P < 0.001). There was a trend of a higher complication rate (of any kind) in the TSA group (12%) when compared with the HA group (8%) (P = 0.065). The weighted mean improvement in anteflexion, exorotation and abduction were respectively 33 degrees , 15 degrees and 31 degrees in the HA group and were respectively 56 degrees , 21 degrees and 48 degrees in the TSA group. Mean decrease in pain scores was 4.2 in the HA and 5.5 in the TSA group. CONCLUSION: Finally, we conclude that TSA results in less need for revision surgery, but has a trend to result in more complications. The conclusions of this review should be interpreted with caution as only Level IV studies could be included. LEVEL OF EVIDENCE: IV. PMID- 24167404 TI - Lipoma arborescens associated with osseous/chondroid differentiation in subdeltoid bursa. AB - Lipoma arborescens (LA) is a rare benign lesion of unknown etiology. It is characterized histologically by villous proliferation of the synovial membrane and diffuse replacement of the subsynovial tissue by mature fat cells. This condition affects the knee joint most commonly. Cases involving other locations including glenohumeral joint,[1] hip,[2] elbow,[3] hand[4] and ankle[5] have been rarely described. Involvement of the subdeltoid bursa has also been reported, but to date no case has described LA with osseous/chondroid differentiation of this bursa. Another significant finding in our case was the coexistence of LA with intermuscular lipoma, SLAP lesion and labral cyst. PMID- 24167405 TI - Arthroscopically assisted Latarjet procedure: A new surgical approach for accurate coracoid graft placement and compression. AB - The Latarjet procedure is a confirmed method for the treatment of shoulder instability in the presence of bone loss. It is a challenging procedure for which a key point is the correct placement of the coracoid graft onto the glenoid neck. We here present our technique for an athroscopically assisted Latarjet procedure with a new drill guide, permitting an accurate and reproducible positioning of the coracoid graft, with optimal compression of the graft onto the glenoid neck due to the perfect position of the screws: perpendicular to the graft and the glenoid neck and parallel between them. PMID- 24167406 TI - An uncommon complication following synthetic ligament reconstruction of the acromioclavicular joint. PMID- 24167407 TI - Arthroscopic assisted removal of screws from proximal humeral locking plates. PMID- 24167408 TI - Neuronal autophagy and neurodevelopmental disorders. AB - Neurodevelopmental disorders include a wide range of diseases such as autism spectrum disorders and mental retardation. Mutations in several genes that regulate neural development and synapse function have been identified in neurodevelopmental disorders. Interestingly, some affected genes and pathways in these diseases are associated with the autophagy pathway. Autophagy is a complex, bulky degradative process that involves the sequestration of cellular proteins, RNA, lipids, and cellular organelles into lysosomes. Despite recent progress in elucidating the genetics and molecular pathogenesis of these disorders, little is known about the pathogenic mechanisms and autophagy-related pathways involved in common neurodevelopmental disorders. Therefore, in this review, we focus on the current understanding of neuronal autophagy as well as recent findings on genetics and the roles of autophagy pathway in common neurodevelopmental disorders. PMID- 24167409 TI - Brain-Region Specific Apoptosis Triggered by Eph/ephrin Signaling. AB - Eph receptors and their ligands, ephrins, are abundantly expressed in neuroepithelial cells of the early embryonic brain. Overstimulation of Eph signaling in vivo increases apoptotic cell death of neuroepithelial cells, whereas null mutation of the Eph gene leads to the development of a larger brain during embryogenesis. Thus, it appears that Eph-ephrin signaling plays a role in regulating apoptotic cell death of neuroepithelial cells, thereby influencing brain size during embryonic development. Interestingly, Eph-ephrin signaling is bi-directional, with forward signaling from ephrin- to Eph-expressing cells and reverse signaling from Eph- to ephrin-expressing cells. However, it is not clear whether this forward or reverse signaling plays a role in regulating the size of the neuroepithelial cell population during early brain development. Also, Eph receptors and their corresponding ligands are mutually exclusive in their expression domains, and they encounter each other only at interfaces between their expression domains. This expression pattern may be a critical mechanism for preventing overstimulation of Eph-ephrin signaling. Nevertheless, Eph receptors are co-expressed with their corresponding ligands in certain brain regions. Recently, two studies demonstrated that brain region-specific apoptosis may be triggered by the overlapping expression of Eph and ephrin, a theme that will be explored in this mini-review. PMID- 24167410 TI - Physiological and pathological significance of dynamin-related protein 1 (drp1) dependent mitochondrial fission in the nervous system. AB - Mitochondria are essential for proper neuronal morphogenesis and functions, as they are the major source of energy for neural development. The dynamic morphology of mitochondria determines the key functions of mitochondria. Several regulatory proteins such as dynamin-related protein 1 (Drp1) are required to maintain mitochondrial morphology via a balance between continuous fusion and fission. Activity of Drp1, a key regulator in mitochondrial fission, is modulated by multiple post-translation modifications and receptor interactions. In addition, numerous researches have revealed that the regulation of Drp1 activity and mitochondrial dynamics is closely associated with several neurodegenerative diseases such as Alzheimer's and Parkinson's diseases. In this article, we concisely review the recent findings about the biological importance of Drp1 mediated mitochondrial fission in neurons under physiological and pathological conditions. PMID- 24167411 TI - In-vivo Optical Measurement of Neural Activity in the Brain. AB - The optical neural recording techniques are promising tools in recent years. Compared to the traditional electrophysiological recording, the optical means offer several advantages including no inclusion of electrical noise, simultaneous imaging of a large number of neurons, or selective recording from genetically targeted neurons. Overall the optical neural recording technique comprises the intrinsic and the extrinsic optical recordings. The methods for intrinsic neural recording employ the change of optical properties in brains such as blood flow/oxygenation, cellular volume change, or refractive index change without addition of external indicators. Those properties can be detected using various optical techniques including laser Doppler flowmetry (LDF), near-infrared (NIR) spectrometer, functional optical coherence tomography (fOCT), and surface plasmon resonance (SPR). The extrinsic monitoring techniques use fluorescence signals reflecting neuronal activity via chemical or genetic modification of the neuronal cells. Two most popular activity-dependent fluorescent probes, calcium indicators and voltage-sensitive fluorescent proteins will be examined in this review. The principles, the instrumentations and in vivo applications of those optical signal measurements are described. PMID- 24167412 TI - Promise of neurorestoration and mitochondrial biogenesis in Parkinson's disease with multi target drugs: an alternative to stem cell therapy. AB - There is an unmet need in progressive neurodegenerative diseases such as Parkinson's and Alzheimer's diseases. The present therapeutics for these diseases at best is symptomatic and is not able to delay disease or possess disease modifying activity. Thus an approach to drug design should be made to slow or halt progressive course of a neurological disorder by interfering with a disease specific pathogenetic process. This would entail the ability of the drug to protect neurons by blocking the common pathway for neuronal injury and cell death and the ability to promote regeneration of neurons and restoration of neuronal function. We have now developed a number of multi target drugs which possess neuroprotective, and neurorestorative activity as well as being able to active PGC-1alpha (peroxisome proliferator-activated receptor gamma coactivator-1alpha), SIRT1 (NAD-dependent deacetylase protein) and NTF (mitochondrial transcription factor) that are intimately associated with mitochondrial biogenesis. PMID- 24167414 TI - 4-hydroxy-2(E)-Nonenal facilitates NMDA-Induced Neurotoxicity via Triggering Mitochondrial Permeability Transition Pore Opening and Mitochondrial Calcium Overload. AB - N-methyl-D-aspartate (NMDA) receptor-mediated excitotoxicity is one of the major causes for neuronal cell death during cerebral ischemic insult. Previously, we reported that the final product of lipid membrane peroxidation 4-hydroxy-2E nonenal (HNE) synergistically increased NMDA receptor-mediated excitotoxicity (J Neurochem., 2006). In this study, we investigated the mechanism involved in the synergistic neuronal cell death induced by co-treatment with HNE and NMDA. Although neither HNE (1 uM) nor NMDA (2 uM) alone induced the death of cortical neurons, simultaneous treatment of neuronal cells with HNE and NMDA synergistically evoked the death of the cells. However, the synergistic effect on neuronal death was observed only in the presence of calcium. HNE neither increased the cytosolic calcium level ([Ca(2+)]i) nor altered the NMDA-induced intracellular calcium influx. However, HNE together with NMDA elevated the mitochondrial calcium level and depolarized the mitochondrial transmembrane potential. Furthermore, HNE evoked damage of isolated mitochondria at the cytosolic calcium level (200 nM), which is maximally induced by 2 uM NMDA. Consistently, ATP was depleted in neurons when treated with both HNE and NMDA together. Ciclopirox, a potent inhibitor of mitochondrial permeability transition pore opening (Br. J. Pharmacol., 2005), largely prevented the synergistic damage of mitochondria and death of cortical neurons. Therefore, although low concentrations of HNE and NMDA cannot individually induce neuronal cell death, they can evoke the neuronal cell death by synergistically accelerating mitochondrial dysfunction. PMID- 24167415 TI - Apoptotic Effects of Melandryum firmum Root Extracts in Human SH-SY5Y Neuroblastoma Cells. AB - Melandryum firmum is a biennial plant that has been used in traditional medicine for treatment of bacterial and fungal infection. Here, we investigated molecular mechanisms underlying apoptotic effects of Melandryum firmum root extract (MFRE) in neuroblastoma cells, since the effect of this natural compound on cancer cells has not been fully clarified. The root extract of M. firmum reduced cell proliferation, as revealed by cell viability assay. However, MFRE-treated cells exhibited morphological changes including cell rounding, neurite retraction and membrane blebbing. These alterations of cellular shape suggest this morphological change might be due to the apoptosis which shows fragmented DNA. In addition, MFRE up-regulated the pro-apoptotic protein Bax and down-regulated the anti apoptotic protein Bcl-2 and Mcl-1, which also finally activated cleaved caspase-3 in a dose-dependent manner, as determined by western blot analyses. Together, these findings demonstrate that apoptotic and cytotoxic effects of MFRE on SH SY5Y cells are mediated by intrinsic mitochondria-mediated caspase pathway and that this natural extract might be effective as an anticancer agent for neuroblastoma malignancies. PMID- 24167416 TI - Beneficial Effect of Vitamin E in Rotenone Induced Model of PD: Behavioural, Neurochemical and Biochemical Study. AB - Parkinson's disease (PD) a neurodegenerative disorder for which no preventive or long-term effective treatment strategies are available. Epidemiologic studies have failed to identify specific environmental, dietary or lifestyle risk factors for PD. However, oxidative stress in the SN is the most broadly accepted hypothesis for the etiopathology of PD. The Symptoms do not appear until there is a decline of striatal dopamine levels by 80% making it difficult to have early therapeutic interventions. Thus, the present experiment was designed to track down the sequential changes starting from the initiation of motor dysfunction and associated biochemical abnormality in rotenone based PD model. The study also evaluated the neuroprotective efficacy of vitamin E. Rats were treated with rotenone 2 mg/kg b.wt (s.c.) for 35 days. The level of dopamine decreased by 70~80% which was in turn reflected by marked deterioration in motor function such as (Total locomotor activity and catalepsy). Along with these the level of GSH and SOD declined significantly which was associated with elevated lipid peroxidation levels as much as by 60%.Vitamin E co-administration at a dose of 100 I.U/kg b.wt (i.m.) ameliorated rotenone induced changes in motor functions i.e Total locomotor activity and Catalepsy at the end of 5(th) week. Further, vitamin E supplementation significantly decreased lipid peroxidation and improved associated biochemical parameters i.e SOD and GSH level. Most interestingly the changes appeared as early as 3(rd) week suggesting that supplementation of vitamin E right at the beginning should be neuroprotective in PD. PMID- 24167417 TI - Cocaine-induced behavioral sensitization in mice: effects of microinjection of dopamine d2 receptor antagonist into the nucleus accumbens. AB - To determine the role of dopamine D2 receptor (D2R) in the nucleus accumbens (NAc) core in cocaine-induced behavioral sensitization, D2R antagonist, raclopride was bilaterally microinjected (2.5 or 5 nmol) into the NAc core of WT and D2R(-/-) mice and the initiation and expression phase of cocaine-mediated locomotor sensitization were analyzed. WT and D2R knockout (D2R(-/-)) mice received bilateral injections of either saline, or raclopride at the NAc core 30 min before each of five daily repeated injections of saline or cocaine (15 mg/kg i.p.). Following 2 weeks of withdrawal after repeated exposure to cocaine, the animals were pre-treated with an intra-accumbal injection of vehicle or raclopride before receiving a systemic cocaine challenge for the expression of sensitization. Animals which had been microinjected raclopride into NAc core displayed the enhancement of cocaine-induced behavioral response for the initiation but also for the expression of sensitization in WT as well as in D2R( /-) mice, which was thus unaltered as compared to vehicle-injected control group. These results suggest that D2R in NAc core is not involved in cocaine-induced behavioral sensitization. PMID- 24167418 TI - A case of thyrotoxic myopathy with extreme type 2 fiber predominance. AB - In hyperthyroidism, many patients had neuromuscular symptoms and clinical weakness correlated with free thyroxine (T4) concentrations. The common clinical symptoms of chronic thyrotoxic myopathy were characterized by progressive weakness in proximal muscles and atrophy. A 55-year old woman was visited our hospital with two years of progressive weakness of both legs. Physical examination showed diffuse enlargement of the thyroid gland, muscle atrophy and tachycardia. Motor examination showed proximal weakness in both legs. Serum creatine phosphokinase was normal and electromyography showed a myopathic pattern. Serum thyroxine (T4) was greatly increased and serum thyroid stimulating hormone was very low. Muscle biopsy showed mild atrophic change and type 2 fiber predominance. The patient's symptoms were improved during treatment with methimazole. Herein we report a case of thyrotoxic myopathy with extreme type 2 fiber predominance histologically. PMID- 24167413 TI - The neural basis of optimism and pessimism. AB - Our survival and wellness require a balance between optimism and pessimism. Undue pessimism makes life miserable; however, excessive optimism can lead to dangerously risky behaviors. A review and synthesis of the literature on the neurophysiology subserving these two worldviews suggests that optimism and pessimism are differentially associated with the two cerebral hemispheres. High self-esteem, a cheerful attitude that tends to look at the positive aspects of a given situation, as well as an optimistic belief in a bright future are associated with physiological activity in the left-hemisphere (LH). In contrast, a gloomy viewpoint, an inclination to focus on the negative part and exaggerate its significance, low self-esteem as well as a pessimistic view on what the future holds are interlinked with neurophysiological processes in the right hemisphere (RH). This hemispheric asymmetry in mediating optimistic and pessimistic outlooks is rooted in several biological and functional differences between the two hemispheres. The RH mediation of a watchful and inhibitive mode weaves a sense of insecurity that generates and supports pessimistic thought patterns. Conversely, the LH mediation of an active mode and the positive feedback it receives through its motor dexterity breed a sense of confidence in one's ability to manage life's challenges, and optimism about the future. PMID- 24167419 TI - Two new species and a new subgenus of toothed Brachyhypopomus electric knifefishes (Gymnotiformes, Hypopomidae) from the central Amazon and considerations pertaining to the evolution of a monophasic electric organ discharge. AB - We describe two new, closely related species of toothed Brachyhypopomus (Hypopomidae: Gymnotiformes: Teleostei) from the central Amazon basin and create a new subgenus for them. Odontohypopomus, new subgenus of Brachyhypopomus, is diagnosed by (1) small teeth present on premaxillae; (2) medialmost two branchiostegal rays thin with blades oriented more vertically than remaining three rays; (3) background color in life (and to lesser extent in preservation) distinctly yellowish with head and sides peppered with small, widely spaced, very dark brown stellate chromatophores that greatly contrast with light background coloration; (4) a dark blotch or bar of subcutaneous pigment below the eye; (5) electric organ discharge waveform of very long duration (head-positive phase approx. 2 milliseconds or longer, head-negative phase shorter or absent) and slow pulse repetition rate (3-16 Hz). The type species of the new subgenus, Brachyhypopomus (Odontohypopomus) walteri sp. n., is diagnosed by the following additional character states: (1) subcutaneous dark pigment at base of orbit particularly prominent, (2) body semi-translucent and nearly bright yellow background coloration in life, (3) a biphasic electric organ discharge (EOD) waveform of very long duration (between 3.5 and 4 milliseconds at 25 degrees C) with head-positive first phase significantly longer than second head-negative phase in both sexes. Brachyhypopomus (Odontohypopomus) bennetti sp. n. is diagnosed by two character states in addition to those used to diagnose the subgenus Odontohypopomus: (1) a deep electric organ, visible as large semi transparent area, occupying approximately 14-17% body depth directly posterior to the abdominal cavity in combination with a short, but deep, caudal filament, and (2) a monophasic, head-positive EOD waveform, approximately 2.1 milliseconds in duration in both sexes. These are the only described rhamphichthyoid gymnotiforms with oral teeth, and Brachyhypopomus bennetti is the first Brachyhypopomus reported to have a monophasic (head-positive) EOD waveform. Unlike biphasic species, the waveform of its EOD is largely unaffected by tail damage from predators. Such injuries are common among specimens in our collections. This species' preference for floating meadow habitat along the major channels of the Amazon River basin may put it at particularly high risk of predation and "tail grazing." PMID- 24167420 TI - Intraspecific variation in the turtle barnacle, Cylindrolepas sinica Ren, 1980 (Cirripedia, Thoracica, Coronuloidea), with brief notes on habitat selectivity. AB - Specimens of the turtle barnacle Cylindrolepas sinica Ren, 1980 were collected from sea turtles in Japanese waters. The specimens were hexagonal in shape and were found burrowing into the sea turtle plastron. Specimens were dissected and the hard and soft parts were compared with the original description. PMID- 24167421 TI - Plutella australiana (Lepidoptera, Plutellidae), an overlooked diamondback moth revealed by DNA barcodes. AB - The genus Plutella was thought to be represented in Australia by a single introduced species, Plutella xylostella (Linnaeus), the diamondback moth. Its status as a major pest of cruciferous crops, and the difficulty in developing control strategies has motivated broad-ranging studies on its biology. Prior genetic work has generally supported the conclusion that populations of this migratory species are connected by substantial gene flow. However, the present study reveals the presence of two genetically divergent lineages of this taxonin Australia. One shows close genetic and morphological similarity with the nearly cosmopolitan Plutella xylostella. The second lineage possesses a similar external morphology, but marked sequence divergence in the barcode region of the cytochrome c oxidase I gene, coupled with clear differences in genitalia. As a consequence, members of this lineage are described as a new species, Plutella australiana Landry & Hebert, which is broadly distributed in the eastern half of Australia. PMID- 24167422 TI - Review of Canadian species of the genus Dinaraea Thomson, with descriptions of six new species (Coleoptera, Staphylinidae, Aleocharinae, Athetini). AB - Twelve species of the genus Dinaraea Thomson are recognized in the Nearctic region, ten of which occur in Canada, all east of the Rocky Mountains. Six species are herein described as new to science: Dinaraea bicornis Klimaszewski & Webster, sp. n.; Dinaraea curtipenis Klimaszewski & Webster, sp. n.; Dinaraea longipenis Klimaszewski & Webster, sp. n.; Dinaraea quadricornis Klimaszewski & Webster, sp. n.; Dinaraea worki Klimaszewski & Jacobs, sp. n.; and Dinaraea piceana Klimaszewski & Jacobs, sp. n. Four formerly described species are confirmed in Canada: Dinaraea angustula (Thomson), Dinaraea backusensis Klimaszewski & Brunke, Dinaraea borealis Lohse, and Dinaraea pacei Klimaszewki & Langor. The previously unknown male of Dinaraea borealis Lohse and female of Dinaraea backusensis are described. All species are illustrated with colour habitus images and black and white images of the median lobe of the aedeagus and spermatheca, and tergite VIII and sternite VIII of both sexes. New habitat and distribution data are presented and a key to all Nearctic species of the genus is provided. PMID- 24167423 TI - The most frequent psychiatric disorders registered at day hospital of psychiatric clinic in sarajevo during 2006-2007. AB - CONFLICT OF INTEREST: NONE DECLARED Day Hospital is an alternative to inpatient treatment as a transition from hospital to outpatient type of treatment, especially for those patients who cannot quickly return to the family, and patients who are unable to leave the usual social contacts so to them the hospitalization will pose a great mental risk. The aim of the research is to determine the structure of psychiatric morbidity, as well as demographic features and duration of hospitalization in patients treated at a Day Hospital of Psychiatric Clinic in Sarajevo during the period 2006-2007. The survey is conducted at the Psychiatric Clinic, Clinical Center of Sarajevo University as retrospective, based on observations of certain variables (gender, age, hospitalization duration), and the number of diagnosis. The results of the research show that the total number of registered patients in the observed period is 400. During the two year study there were more female (61.3%) than male patients (38.7%). Also, during the two years of research, most of those were with one diagnosis. The average hospitalization duration was 45 days, and the most often hospitalization duration was from 1 to 3 months. During both years, mostly present was the population in age group 46 to 65 years, followed by age group 26 to 44 years. Leading diseases during both years of research were from the group F30-F39, and the most common co-morbid diseases from groups: F30-F39, F40-F49 and F60-F69. We can conclude that Day Hospital has great significance in the mental health prevention. Daily structured program provides hospital diagnosis, treatment and rehabilitation of persons of both genders from different age groups and with diverse psychopathology. PMID- 24167424 TI - A framework for a competency based medical curriculum in saudi arabia. AB - BACKGROUND: We recently adopted a competency based curriculum based on the CanMEDs model. This shift required the cross-mapping of all key CanMEDs competencies with the competencies for higher education in Saudi Arabia as per the Saudi National Commission for Academic Accreditation & Assessment (NCAAA) guidelines. OBJECTIVES: To formulate competencies for our curriculum and to create a framework aligned with NCAAA, CanMEDs and Saudi Meds. METHODS: After finalization of program outcomes, the program goals were cross-mapped with CanMEDs and Saudi Meds competencies and then the CanMEDs competencies were reverse mapped with our outcomes. Finally benchmarking of outcomes with the programs of the Universities of Manitoba and Toronto was done. RESULTS: We were able to cross-map and match major outcomes of our program with both the CanMEDs and the Saudi Meds frameworks, ensuring that the outcomes are in line with NCAAA, CanMEDs and Saud Meds. Also, our program objectives were bench marked with two of the Canadian medical schools. CONCLUSION: We propose that our framework can be a model for other universities in Saudi Arabia to consider when shifting to a competency based curriculum. PMID- 24167425 TI - Clostridium difficile infection in hospitalized patients at university clinical center tuzla, bosnia and herzegovina: a 4 year experience. AB - INTRODUCTION: Clostridium difficile (C. difficile) is currently the leading cause of healthcare-associated diarrhea, but almost nothing is known about the extent of C. difficile infection (CDI) in Bosnia and Herzegovina. GOAL: We aimed to retrospectively analyze CDI in hospitalized patients at University Clinical Center (UCC) Tuzla, Bosnia and Herzegovina from January 2009 through June 2012. METHODS: We analyzed all patients (except children ages 0-2), diagnosed with CDI based on anamnestic and epidemiological, clinical picture and microbiological tests (proof of toxins in the stool by enzyme-linked immunosorbent assay). RESULTS: From a total of 989 patients tested for C. difficile toxin (60.2 per 10,000 inpatient days) 347 (35.08%) were positives. The mean incidence rate of CDI was 2.23 per 10,000 inpatient days (range 1.32-2.87). Annual rates of hospitalization were 15.68 per 10,000 admissions (range 8.99-20.35). Most patients had a previously identified risk profile of old age, comorbidity and recent use of antibiotics. 41/276 (14.86%) patients had died, and 11/41 (26.82%) were CDI-associated deaths. Complicated CDI were registered in 53/276 (19.21%) patients, and recurrent infections in 65/276 (23.55%). CONCLUSION: Our data suggest that CDI is largely present in our setting which represents a serious problem and points to the importance of international surveillance, detection and control of CDI. PMID- 24167426 TI - Predictors and effective factors on quality of life among Iranian patients with rheumatoid arthritis. AB - INTRODUCTION: Rheumatoid arthritis is a chronic autoimmune disorder that leads to joint swelling, stiffness, pain and progressive joint destruction. It is a common disease with prevalence of 1% worldwide that affecting all aspects of patients' lives. Therefore, this study was conducted to summarize and provide a clear view of quality of life among the patients in Iran through a literature review. METHODS: This study was conducted as a literature review over article published between 2000 to 2013, by using data bases comprise of Google scholar, Science Direct, Pubmed, IRANDOC, SID, Medlib, Magiran and by key words: "quality of life", "rheumatoid arthritis", "Iran" and their Persian equivalents. Finally 2065 articles assessed and according to the aim of the study are 11 studies synthesized. Extracted results first were summarized in Extraction Table, and then analyzed manually. RESULTS: In reviewed articles rheumatoid arthritis patients' quality of life was measured by using five different tools, the most important one of them was SF36 questionnaire. Among eight dimensions of SF36 questionnaire, the highest mean according included articles result was social functioning with average score of 63.4 and the lowest for physical limitation (physical role functioning) with score of 43. Overall, mean of eight dimensions was 52.47. The most important factors affecting quality of life were disease severity and pain, depression, income, educational, occupational status, married status, sign of disease, fatigue, anxiety and disease activity scores. CONCLUSION: The results of the study showed relatively low quality of life of rheumatoid arthritis patients in Iran. Empowering patients by participating them in service delivery process and decision making can improves quality of life and in this regard health care provider must be focused on patient self-care abilities and reinforcing this factor by training them. PMID- 24167427 TI - Prevalence of dental caries in the municipality gorazde during the period 2007 2012. AB - INTRODUCTION: Dental caries today, regardless of known multi causal etiology of the disease and the possibility of its effective prevention still represents the most widespread disease of our civilization, which affects about 95% of our population. It affects all populations and age groups and is a disease that is very difficult to completely eradicate due to a complex interaction of biological factors, eating habits, social status Etc. GOAL: Goal is to report the prevalence of dental caries, DMFT-index and DMFT index in the first and seventh grades of grammar school in the municipality Gorazde during the last six years. MATERIAL AND METHODS: Children, which have yet to enroll in school and in the seventh grade children, have required medical examinations. A total of 1198 first grade and 1666 seventh-grade students are included. To determine the prevalence of dental caries DMFT was used. Examinations are carried out in accordance with the methodology and criteria of the WHO, by a dental mirror and dental probe. RESULTS: The prevalence of dental caries is extremely high as well as the values of DMFT index in the first and seventh grades in the municipality Gorazde. CONCLUSION: In practice it is necessary to introduce prevention programs for pregnant women, toddlers, preschool and school-aged children with a wider use of the mass media. PMID- 24167428 TI - Allopurinol effect on values of lipid profile fractions in hyperuricemic patients diagnosed with metabolic syndrome. AB - SUBJECT: The concentration of serum uric acid (SUA) is one of the potential markers of cardiovascular and cerebrovascular diseases, as well as some other severe diseases. In this pharmacological - clinical study we evaluated allopurinol effect on certain values of lipid profile fractions in hyperuricemic patients diagnosed with metabolic syndrome that had pronounced cardiovascular problems, also with diagnosed hypertension. METHODS: Research sample comprised 40 clinically treated hyperuricemic patients of both sexes, different ages, classified into several subgroups according to the disease diagnoses. The methods used in the study included: assay analysis, statistical and comparative methods. All clinical measurements were performed with standard IFCC methods on suitable biochemical analyzers. RESULTS: Study established that after the first three months of allopurinol use, there was statistically significant difference in the average value of uric acid compared to the patients' initial state. During the next three months of therapy no further statistically significant difference in average values of uric acid (p = 0,936) was detected, meaning that the desirable effects of drug use were achieved. Simultaneously, the values of triglycerides, cholesterol and LDL fractions in test subjects increased significantly (p > 0,05). The values of HDL fractions increased after three month therapy with allopurinol, but later their value remained constant. Atherogenic index increased significantly after three and six months of therapy, therewith retaining at upper limit of reference value. CONCLUSION: The study results confirmed the primary hypothesis, which was that the allopurinol use affects the values of lipid profile fractions in hyperuricemic patients. PMID- 24167429 TI - Hyperhomocysteinemia and of Methylenetetrahydrofolate Reductase (C677T) Genetic Polymorphism in Patients with Deep Vein Thrombosis. AB - AIM: To determine the concentration of total plasma homocysteine (tHcy) as well as different genotypes of methylenetetrahydrofolate reductase MTHFR (C677T) in healthy subjects and patients with deep vein thrombosis (DVT). MATERIAL AND METHODS: The investigation comprised a total of 160 subjects divided in two main groups: 80 healthy subjects (control group) and 80 patients with deep vein thrombosis. Concentration of tHcy was determined by spectrophotometric cyclic enzymatic method and mutation of MTHFR (C677T) gene was examined by polymerase chain reaction according to Schneider. RESULTS: The results obtained for plasma tHcy in the control group were 11.62+/-3.43 MUmol/L, while tHcy level was significantly higher in patients with deep vein thrombosis as compared to the control group, 15.19+/-3.63 MUmol/L (r<0.001). The analysis of the results has shown that MTHFR (C677T) genetic polymorphism was responsible for mild to moderate hyperhomocysteinemia in the majority of subjects. CONCLUSION: The level of tHcy in the examined patients was significantly higher in comparison with the control group. Multiple regression analysis has shown that tHcy level in CT and TT genotypes of MTHFR (C677T) was statistically higher in comparison with CC genotype of MTHFR (C677T) in both, the control group and the DVT patients. PMID- 24167430 TI - Midwifery errors: a descriptive study in isfahan forensic medicine general department. AB - GOAL: In this paper we will identify the frequency and reasons of midwives errors in patient claims referred to Isfahan legal medicine center during 5 past years. METHODS: It is a cross - sectional study. The population of the study consisted of all patients claims from midwifery staffs occupied in hospitals, clinics and other healthcare centers from 2007-20012. The data were collected by a checklist. The data were analyzed by SPSS. RESULT: Results shown 41 claims (5.8%) of 708 claims were from midwives. In 43.9% of cases, midwives were convicted. In 38.9% cases negligence and in 44.4% cases, carelessness of governmental rules such as premature induction of labor were the main reasons of midwives malpractice. The 35-40 age groups had the most frequency with 31.7%. In 85.4% cases, midwives services were served in hospitals and in 12.2% cases; these services were served in home-health. CONCLUSION: With attention to importance of midwifery, the practitioners of this occupation should be informed of medical laws and regulations, crimes and infractions, blood money law, abortion laws and other legal materials. PMID- 24167431 TI - Life Satisfaction and Risk-taking Behavior in Secondary Schools Adolescents. AB - INTRODUCTION: Life satisfaction involves cognitive component that allows evaluation of the life and accomplishments of life, and emotional component that includes an evaluation of emotions and mood that followed these accomplishments. GOAL: To examine the life satisfaction of young people who attend secondary school, examine the level of satisfaction with life according to sex, to academic achievement, the presence of siblings and to examine the relationship between levels of life satisfaction and risk-taking behaviors. RESULTS AND DISCUSSION: The results showed that there was no relationship between life satisfaction and preferences of delinquency, as well as life satisfaction and achieved academic success. The results confirmed the relationship between life satisfaction and sex as well as the relationship between life satisfaction and the presence of siblings in the family. PMID- 24167432 TI - Chateter-associated Urinary Tract Infections in Adults. AB - INTRODUCTION: Hospital-acquired Urinary tract infections make 35% of all the hospital-acquired infections, and about 80% of them are related to the catheterization of the urinary bladder. PURPOSE: To determine clinical characteristics and dominant etiologic factors of Urinary Tract Infections associated with urinary catheter (C-UTIs). METHODS: Determined clinical characteristics of C-UTIs were prospectively analyzed on 38 hospitalized patients in the Clinic for Infectious Diseases at the University Clinical Centre Tuzla, from January 1(st) 2011 to December 31(st) 2011. The control group constituted of 200 patients with community-acquired Urinary Tract Infections (Co-UTIs) hospitalized in the same period. RESULTS: It was registered on 22 (57.89%) of symptomatic infections, 14 (36.84%) asymptomatic bacteriuria and 2 (5.26%) other C-UTIs. Dominant etiologic factors were: E. coli, caused 14 (36.84%), Extended Spectrum Beta-lactamase producing (ESBL) Klebsiella pneumoniae 7 (18.42%), Enterococcus faecium and Candida spp. 3 (7.89%) of C-UTIs. E. coli was significantly most common etiologic factor of C-UTIs in younger women (p=0.04). E. coli from C-UTIS showed significantly higher resistance to antimicrobial drugs. Inadequate antimicrobial therapy was significantly more common prescribed to patients from C-UTIs. Lethal outcome was significantly most common associated with certain clinical and laboratory findings. CONCLUSION: Initial antimicrobial therapy of those serious infections should be based on data from those research. PMID- 24167433 TI - Maxillofacial fractures: twenty years of study in the department of maxillofacial surgery in kosovo. AB - THE AIM: The aim of this study was to analyze maxillofacial region fractures during the past 20 years in the Department of Maxillofacial Surgery in Prishtina. METHODS: We have analyzed the histories of all patients with trauma who were hospitalized in the Department of Maxillofacial Surgery in Prishtina since the opening of the clinic in 1983 through 2005. Narrowing the subject of our research, we concentrated on fractures of the maxillofacial region treated at the Clinic of Maxillofacial Surgery for the period 2001-2005. We have analyzed those fractures and compared them with the period from 1983 to 2005 only when it was reasonable. RESULTS: During this period, 1,945 patients were treated for trauma in the maxillofacial region by the Department of Maxillofacial Surgery. This group included 19.8% females and 80.2% males. The largest age group were those between 20 and 20 years of age. Causes of trauma for both periods were predominantly traffic accidents; however, during the period 2001-2005, interpersonal conflicts were increasingly the cause of fractures. CONCLUSION: Interpersonal conflict as a cause of maxillofacial trauma has risen in recent years. With this increase the methods of treating fractures in this region are also changing. PMID- 24167434 TI - Comparative study of ezetimibe and atorvastatin alone and in combination on lipid profile in rats. AB - INTRODUCTION: Coronary heart disease and hyperlipidemia is a global problem in today's world. A large number of people suffer from hypertension, atherosclerosis and all these has strong association with the hyperlipidemia. There are many drugs for the treatment of hyperlipidemia, but statins are most commonly used. But, with high dose of statins, the side effect is also there which restricts its use in high dose. Ezetimibe is a comparatively new drug for the treatment of hyperlipidemia having lesser adverse effect as compared to statin. This study has been planned to find out the comparative efficacy of Ezetimibe and Atorvastatin alone and in combination on the lipid profile in rats. METHODOLOGY: This study was conducted in SCB Medical College, Cuttack. 60 rats were fed on atherogenic diet. These were divided in six groups having ten rats in each group and followed for 12 weeks. Group I received only atherogenic diet. All other groups received drugs after four weeks. Group II received Ezetimibe 1mg/kg, Group III received Ezetimibe 2mg/kg, Group IV received Atorvastatin 4mg/kg, Group V received Atorvastatin 8mg/kg and Group VI received Atorvastatin 4mg/kg and Ezetimibe 1mg/kg. Blood lipid profile measured at zero week, four weeks and 12 weeks. RESULTS: All the lipid profile parameters improved significantly with treatment groups as compared with control group. There was no significant difference in the level of different lipid parameters between Group V (Atorvastatin 8mg/kg) and Group VI (Atorvastatin 4mg/kg and Ezetimibe 1mg/kg). CONCLUSION: High dose of Atorvastatin is associated with more adverse effect. The efficacy of high dose of Atorvastatin is comparable to combination of low dose Atorvastatin with Ezetimibe. This combination has lesser side effects. So, this can be a good alternative. PMID- 24167435 TI - Comparative analysis of smoking influence on periodontal tissue in subjects with periodontal disease. AB - THE AIM OF THE STUDY: The aim of the study was clinical and cytological examination of gingival changes in smokers and non-smokers. Further, specific goals of this study were health promotion in patient, particularly in smokers. METHODS: The anamnesis was taken and clinical examination was conducted on the patients who came on Dental Clinic. During the clinical examination, plaque index (Pl)(16), gingival index Loe-Silness (Gi) and the community periodontal index of treatment needs (CPITN)(17) were done. After diagnosis was established, participants divided into group I -smokers, and group II - non-smokers. The gingival smears were taken for cytological analysis, dried on air, and stained by haematoxylin-eosin method. RESULTS: The values of gingival index (GI)- Loe Silness and periodontal index (CPITN) were higher in the group of smokers, but plaque index was also higher with statistically significant difference of their values between examined group, with maximum level of significance (p<0,001). The size of nucleus (area, Ferret's diameter and perimeter) was higher in the group of smokers, but differences were not statistically significant. In the group of non-smokers density of nucleus was higher than in non-smokers group, but difference was not statistically significant. CONCLUSION: The values of examined indices showed higher values in smokers group. This finding could show that the level of oral hygiene is higher in the non smokers group. The size of nucleus (area, Ferret's diameter and perimeter) was higher in the group of smokers, but differences were not statistically significant. Teamwork of many different speciality experts is required for better periodontal health of smokers. PMID- 24167436 TI - Depression, anxiety and somatization in women with war missing family members. AB - INTRODUCTION: During the war circumstances, women and children are exposed to multiple traumatic experiences, one of which is an violent disappearance of a family member. GOAL: The aim of this research was to establish the presence of symptoms of depression, anxiety and somatization in women in Bosnia and Herzegovina who have sought their war missing family members for 15 to 18 years. SUBJECTS AND METHODS: The research was based on a sample of 120 women with war missing family member and 40 women without a war missing family member as a control group. For assessment of depression, anxiety and symptoms of somatization the self-rating Beck Depression Inventory (BDI), Hamilton Anxiety Rating Scale (HAM-A), Somatic Symptoms Index (SSI) questionnaire and a general questionnaire on the sociodemographic data and data on war missing family members were used. RESULTS: A significantly higher intensity of symptoms of depression (p<0.001), anxiety (p<0.001) and somatization (p = 0.013) was present in women with, in comparison to women without a missing family member. In comparison of the kinship with the missing family members, statistically significantly higher intensity of symptoms of depression, anxiety and somatization was in women with a missing child (p<0.001) in comparison to other missing family members. CONCLUSION: A prolonged period of seeking, waiting and uncertainty of what happened in the war with the missing family member presents for those women a prolonged suffering manifested through depression, anxiety and symptoms of somatization. PMID- 24167437 TI - Efficacy of physical therapy in the treatment of gonarthrosis in physically burdened working men. AB - INTRODUCTION: Gonarthrosis is most frequently defined as the change involving damage of the articular cartilage of the knee joint, emergence of abnormal knee tissue, reactive changes in synovial membrane, and pathological synovial fluid. The site of initial damage most often remains unknown. Goal of the research. THE GOAL: The goal of this research is to demonstrate the efficacy of individual physical therapy during the medical treatment for gonarthrosis in the working population engaged in physical labour, and to compare the state of pain and mobility before and after the treatment. SUBJECTS AND RESEARCH METHODS: The research encompassed 30 subjects diagnosed with gonarthrosis, and it was conducted in the Institute of Occupational Health and Sports Medicine of the Zenica-Doboj Canton. On the basis of the applied physical treatments, we divided the subjects into control group and treatment group. All the subjects were treated during 21 days. RESULTS AND CONCLUSIONS: In the largest number of subjects in both groups gonarthrosis occurred primarily as a consequence of knee joint trauma, and then because of weight and physical strain. Of the total number of subjects covered by this research, 9 subjects in control and 8 in treatment group had gonarthrosis of their right knee. 4 subjects in the control and 5 in the treatment group had gonarthrosis of the left knee, while 2 subjects from each group had gonarthrosis on both knees. By the analysis of clinical symptoms of gonarthrosis prior to the treatment, it was found that all the subjects from both groups had pain symptom, in 13 subjects from the control and 14 subjects from the treatment group limited range of motion was established, while 8 subjects from control and 9 subjects from treatment group had swelling in the joint area. The condition of the subjects prior to the treatment was analyzed by means of pain scale, and it was found that both groups experienced moderate level of pain before the treatment. After the 21st day of treatment, the pain intensity was again measured in the subjects that underwent combined physical and medication treatments. In the subjects from the control group that also underwent electrotherapy, the average pain scale value amounted to 2,33+/-1,34 after treatment, whereas in the subjects that underwent magnetotherapy and combined physical and medication treatments the pain scale amounted to 0,73+/-0,38. The ANOVA test showed that there is a statistically significant difference in the pain scale before and after the treatment, and also that the improvement in the clinical picture and reduction of pain occurred in both groups of subjects. PMID- 24167438 TI - Patients perception of community pharmacist in bosnia and herzegovina. AB - Community pharmacists play a significant role in patient/disease management and perception by patients is increasingly important. A self-administered questionnaire was developed consisted of sociodemographic part and 15 questions. Patients have a positive overall perception of community pharmacists that is comparable to most studies in Europe. Community pharmacists' beyond dispensing drugs play a significant role in patient and disease management. This role of the pharmacist is performed through pharmaceutical care. Patient's opinion is increasingly considered to be a useful component in the determination of care outcomes and consumer satisfaction is an integral component of the quality of primary health care. For the purpose of this study we developed self-administered questionnaire consisted of sociodemographic part, and 15 questions. Survey has been conducted in 10 pharmacies. Results are presented in tables and figures and descriptive statistics has been used. We found that patients in Bosnia and Herzegovina have a positive overall perception of community pharmacists and of the services offered from community pharmacies that is comparable to most studies in Europe, but there is still room for improvement of relationships and pharmaceutical services. PMID- 24167439 TI - Frequency of blood pressure measuring according to the degree of working population education in canton sarajevo. AB - INTRODUCTION: Hypertension (high blood pressure) is one of the most widely spread modern diseases and one of the leading risk factors for heart and blood vessel diseases, particularly stroke and coronary heart disease. The prevalence of hypertension is about 25% in adults. Many studies show that blood pressure tends to have lower values among people with higher education levels. GOAL: To determine the frequency of measurement and control of blood pressure in relation to the level of education of the active working population of the Sarajevo Canton. MATERIAL AND METHODS: The study was conducted on 443 subjects randomly selected from the categories of the active working population of the Sarajevo Canton. The study was conducted at the Center for Heart, Clinical Center University of Sarajevo University through the project "Prevention of risk factors for cardiovascular disease in the active working population of the Sarajevo Canton". Respondents were at age in range from 18-65 years, who have voluntarily joined the study. RESULTS: Of 443 (100%) of the respondents 153 (34.5%) were males compared to females whose participation in the sample was 290 (65.5%). Regarding the structure of respondents, the majority of them 213 (48.1%) graduated faculty, 142 (32, 1%) graduated secondary vocational schools and 66 (14.9%) with a higher degree, with the lowest number with completed grammar school (1.4%) and secondary school (0.5%). Blood pressure never measure 16 (3.6%) of respondents, which is not insignificant number, more than 5 years ago 23 (5.2%), within last 1-5 years 90 (20.3%), in the past 12 months 88 (19.9% ) and 226 (51%) measured the blood pressure in the past 6 months. Blood pressure never controlled 4.33% of respondents with secondary or higher education and 2.82% of the respondents with university education. Chi-square test showed a difference between education and the prevalence of blood pressure, chi2=7.812; DF=8; p=0.045. CONCLUSION: Monitoring of blood pressure and frequent measurement can in large number prevent progression of hypertension, which can often remain unnoticed if the blood pressure is not measured regularly. Lower levels of education may be associated with lower socioeconomic status of healthy subjects, as well as the low level of health education, which may be factors that contribute to improper diet, lack of physical activity, smoking, so indirectly affect the occurrence of the disease. Education can be a potential risk factor for high blood pressure during their lifetime and thus the risk factor for other cardiovascular diseases. PMID- 24167440 TI - Barriers to implement Electronic Health Records (EHRs). AB - INTRODUCTION: During the past 20 years, with huge advances in information technology and particularly in the areas of health, various forms of electronic records have been studied, analyzed, designed or implemented. An Electronic Health Records (EHRs) is defined as digitally stored healthcare information throughout an individual's lifetime with the purpose of supporting continuity of care, education, and research. The EHRs may include such things as observations, laboratory tests, medical images, treatments, therapies; drugs administered, patient identifying information, legal permissions, and so on. Despite of the potential benefits of electronic health records, implement of this project facing with barriers and restriction ,that the most of these limitations are cost constraints, technical limitations, standardization limits, attitudinal constraints-behavior of individuals and organizational constraints. AIM: The aim of this study was to express the main barriers to implement EHRs. METHODS: This study was unsystematic-review study. The literature was searched on main barriers to implement EHRs with the help of library, books, conference proceedings, data bank, and also searches engines available at Google, Google scholar. For our searches, we employed the following keywords and their combinations: Electronic health record, implement, obstacle, and information technology in the searching areas of title, keywords, abstract, and full text. RESULTS AND DISCUSSION: In this study, more than 43 articles and reports were collected and 32 of them were selected based on their relevancy. Many studies indicate that the most important factor than other limitations to implement the EHR are resistance to change. PMID- 24167441 TI - Stressful Life Events and Relapse Among Formerly Alcohol Dependent Adults. AB - We examined associations between stressful life events and relapse among adults in the United States with at least 1 year of remission from DSM-IV alcohol dependence. The sample consisted of individuals in remission from alcohol dependence at the Wave 1 interview (2001-2002) for the National Epidemiologic Survey on Alcohol and Related Conditions (NESARC) who also participated in a Wave 2 interview (2004-2005; N 1,707). Associations between stressful life events, demographic variables, = and the binary outcome of alcohol dependence relapse were examined with multiple logistic regression models. After adjustment for potential confounders, respondents who were divorced or separated in the year preceding the baseline assessment (Wave 1) were over two times more likely (OR = 2.32; CI = 1.01-5.34) to have relapsed 3 years later (Wave 2), compared to those not experiencing a divorce/separation in the 12 months prior to Wave 1. No other stressful life event was associated with relapse. Findings suggest that formerly alcohol dependent adults are at increased risk for relapse following divorce/separation. These results highlight the need for social work practitioners to consider the possibility of relapse following a divorce when one or both partners have a history of alcohol dependence. PMID- 24167442 TI - A critical role for the hippocampus in the valuation of imagined outcomes. AB - Many choice situations require imagining potential outcomes, a capacity that was shown to involve memory brain regions such as the hippocampus. We reasoned that the quality of hippocampus-mediated simulation might therefore condition the subjective value assigned to imagined outcomes. We developed a novel paradigm to assess the impact of hippocampus structure and function on the propensity to favor imagined outcomes in the context of intertemporal choices. The ecological condition opposed immediate options presented as pictures (hence directly observable) to delayed options presented as texts (hence requiring mental stimulation). To avoid confounding simulation process with delay discounting, we compared this ecological condition to control conditions using the same temporal labels while keeping constant the presentation mode. Behavioral data showed that participants who imagined future options with greater details rated them as more likeable. Functional MRI data confirmed that hippocampus activity could account for subjects assigning higher values to simulated options. Structural MRI data suggested that grey matter density was a significant predictor of hippocampus activation, and therefore of the propensity to favor simulated options. Conversely, patients with hippocampus atrophy due to Alzheimer's disease, but not patients with Fronto-Temporal Dementia, were less inclined to favor options that required mental simulation. We conclude that hippocampus-mediated simulation plays a critical role in providing the motivation to pursue goals that are not present to our senses. PMID- 24167444 TI - The open access movement grows up: taking stock of a revolution. PMID- 24167443 TI - Coevolution and the effects of climate change on interacting species. AB - BACKGROUND: Recent studies suggest that environmental changes may tip the balance between interacting species, leading to the extinction of one or more species. While it is recognized that evolution will play a role in determining how environmental changes directly affect species, the interactions among species force us to consider the coevolutionary responses of species to environmental changes. METHODOLOGY/PRINCIPLE FINDINGS: We use simple models of competition, predation, and mutualism to organize and synthesize the ways coevolution modifies species interactions when climatic changes favor one species over another. In cases where species have conflicting interests (i.e., selection for increased interspecific interaction strength on one species is detrimental to the other), we show that coevolution reduces the effects of climate change, leading to smaller changes in abundances and reduced chances of extinction. Conversely, when species have nonconflicting interests (i.e., selection for increased interspecific interaction strength on one species benefits the other), coevolution increases the effects of climate change. CONCLUSIONS/SIGNIFICANCE: Coevolution sets up feedback loops that either dampen or amplify the effect of environmental change on species abundances depending on whether coevolution has conflicting or nonconflicting effects on species interactions. Thus, gaining a better understanding of the coevolutionary processes between interacting species is critical for understanding how communities respond to a changing climate. We suggest experimental methods to determine which types of coevolution (conflicting or nonconflicting) drive species interactions, which should lead to better understanding of the effects of coevolution on species adaptation. Conducting these experiments across environmental gradients will test our predictions of the effects of environmental change and coevolution on ecological communities. PMID- 24167445 TI - What can article-level metrics do for you? AB - Article-level metrics (ALMs) provide a wide range of metrics about the uptake of an individual journal article by the scientific community after publication. They include citations, usage statistics, discussions in online comments and social media, social bookmarking, and recommendations. In this essay, we describe why article-level metrics are an important extension of traditional citation-based journal metrics and provide a number of example from ALM data collected for PLOS Biology. PMID- 24167446 TI - Collection overview: ten years of wonderful open access science. AB - To mark our tenth Anniversary at PLOS Biology, we are launching a special, celebratory Tenth Anniversary PLOS Biology Collection which showcases 10 specially selected PLOS Biology research articles drawn from a decade of publishing excellent science. It also features newly commissioned articles, including thought-provoking pieces on the Open Access movement (past and present), on article-level metrics, and on the history of the Public Library of Science. Each research article highlighted in the collection is also accompanied by a PLOS Biologue blog post to extend the impact of these remarkable studies to the widest possible audience. PMID- 24167447 TI - A lot can happen in a decade. PMID- 24167448 TI - Architecting the future of research communication: building the models and analytics for an open access future. PMID- 24167450 TI - Modelling the strategic use of antiretroviral therapy for the treatment and prevention of HIV. AB - Nathan Ford and Gottfried Hirnschall reflect on recent research by Jan Hontelez and colleagues published in this week's PLOS Medicine. The authors argue that the future HIV modeling efforts should focus on helping programs make choices about which interventions need to be prioritized in order to achieve the levels of enrollment and retention in care required to maximize the prevention benefit of ART. Please see later in the article for the Editors' Summary. PMID- 24167449 TI - Elimination of HIV in South Africa through expanded access to antiretroviral therapy: a model comparison study. AB - BACKGROUND: Expanded access to antiretroviral therapy (ART) using universal test and treat (UTT) has been suggested as a strategy to eliminate HIV in South Africa within 7 y based on an influential mathematical modeling study. However, the underlying deterministic model was criticized widely, and other modeling studies did not always confirm the study's finding. The objective of our study is to better understand the implications of different model structures and assumptions, so as to arrive at the best possible predictions of the long-term impact of UTT and the possibility of elimination of HIV. METHODS AND FINDINGS: We developed nine structurally different mathematical models of the South African HIV epidemic in a stepwise approach of increasing complexity and realism. The simplest model resembles the initial deterministic model, while the most comprehensive model is the stochastic microsimulation model STDSIM, which includes sexual networks and HIV stages with different degrees of infectiousness. We defined UTT as annual screening and immediate ART for all HIV-infected adults, starting at 13% in January 2012 and scaled up to 90% coverage by January 2019. All models predict elimination, yet those that capture more processes underlying the HIV transmission dynamics predict elimination at a later point in time, after 20 to 25 y. Importantly, the most comprehensive model predicts that the current strategy of ART at CD4 count <=350 cells/ul will also lead to elimination, albeit 10 y later compared to UTT. Still, UTT remains cost-effective, as many additional life-years would be saved. The study's major limitations are that elimination was defined as incidence below 1/1,000 person-years rather than 0% prevalence, and drug resistance was not modeled. CONCLUSIONS: Our results confirm previous predictions that the HIV epidemic in South Africa can be eliminated through universal testing and immediate treatment at 90% coverage. However, more realistic models show that elimination is likely to occur at a much later point in time than the initial model suggested. Also, UTT is a cost-effective intervention, but less cost-effective than previously predicted because the current South African ART treatment policy alone could already drive HIV into elimination. Please see later in the article for the Editors' Summary. PMID- 24167451 TI - Diagnostic accuracy of quantitative PCR (Xpert MTB/RIF) for tuberculous meningitis in a high burden setting: a prospective study. AB - BACKGROUND: Tuberculous meningitis (TBM) is difficult to diagnose promptly. The utility of the Xpert MTB/RIF test for the diagnosis of TBM remains unclear, and the effect of host- and sample-related factors on test performance is unknown. This study sought to evaluate the sensitivity and specificity of Xpert MTB/RIF for the diagnosis of TBM. METHODS AND FINDINGS: 235 South-African patients with a meningeal-like illness were categorised as having definite (culture or Amplicor PCR positive), probable (anti-TBM treatment initiated but microbiological confirmation lacking), or non-TBM. Xpert MTB/RIF accuracy was evaluated using 1 ml of uncentrifuged and, when available, 3 ml of centrifuged cerebrospinal fluid (CSF). To evaluate the incremental value of MTB/RIF over a clinically based diagnosis, test accuracy was compared to a clinical score (CS) derived using basic clinical and laboratory information. Of 204 evaluable patients (of whom 87% were HIV-infected), 59 had definite TBM, 64 probable TBM, and 81 non-TBM. Overall sensitivity and specificity (95% CI) were 62% (48%-75%) and 95% (87%-99%), respectively. The sensitivity of Xpert MTB/RIF was significantly better than that of smear microscopy (62% versus 12%; p = 0.001) and significantly better than that of the CS (62% versus 30%; p = 0.001; C statistic 85% [79%-92%]). Xpert MTB/RIF sensitivity was higher when centrifuged versus uncentrifuged samples were used (82% [62%-94%] versus 47% [31%-61%]; p = 0.004). The combination of CS and Xpert MTB/RIF (Xpert MTB/RIF performed if CS<8) performed as well as Xpert MTB/RIF alone but with a ~10% reduction in test usage. This overall pattern of results remained unchanged when the definite and probable TBM groups were combined. Xpert MTB/RIF was not useful in identifying TBM among HIV-uninfected individuals, although the sample was small. There was no evidence of PCR inhibition, and the limit of detection was ~80 colony forming units per millilitre. Study limitations included a predominantly HIV-infected cohort and the limited number of culture-positive CSF samples. CONCLUSIONS: Xpert MTB/RIF may be a good rule-in test for the diagnosis of TBM in HIV-infected individuals from a tuberculosis-endemic setting, particularly when a centrifuged CSF pellet is used. Further studies are required to confirm these findings in different settings. Please see later in the article for the Editors' Summary. PMID- 24167452 TI - Utility of the Xpert MTB/RIF assay for diagnosis of tuberculous meningitis. AB - David Boulware discusses the challenges of diagnosing tuberculous meningitis and the implications of the study by Patel and colleagues using the Xpert MTB/RIF assay for diagnosis. Please see later in the article for the Editors' Summary. PMID- 24167454 TI - A transcriptional signature for active TB: have we found the needle in the haystack? AB - Adithya Cattamanchi and colleagues reflect on recent research by Michael Levin and coworkers into the use of whole blood mRNA expression signatures to detect tuberculosis. The authors highlight challenges faced in getting this promising technology into clinics in low-resource settings. Please see later in the article for the Editors' Summary. PMID- 24167453 TI - Detection of tuberculosis in HIV-infected and -uninfected African adults using whole blood RNA expression signatures: a case-control study. AB - BACKGROUND: A major impediment to tuberculosis control in Africa is the difficulty in diagnosing active tuberculosis (TB), particularly in the context of HIV infection. We hypothesized that a unique host blood RNA transcriptional signature would distinguish TB from other diseases (OD) in HIV-infected and uninfected patients, and that this could be the basis of a simple diagnostic test. METHODS AND FINDINGS: Adult case-control cohorts were established in South Africa and Malawi of HIV-infected or -uninfected individuals consisting of 584 patients with either TB (confirmed by culture of Mycobacterium tuberculosis [M.TB] from sputum or tissue sample in a patient under investigation for TB), OD (i.e., TB was considered in the differential diagnosis but then excluded), or healthy individuals with latent TB infection (LTBI). Individuals were randomized into training (80%) and test (20%) cohorts. Blood transcriptional profiles were assessed and minimal sets of significantly differentially expressed transcripts distinguishing TB from LTBI and OD were identified in the training cohort. A 27 transcript signature distinguished TB from LTBI and a 44 transcript signature distinguished TB from OD. To evaluate our signatures, we used a novel computational method to calculate a disease risk score (DRS) for each patient. The classification based on this score was first evaluated in the test cohort, and then validated in an independent publically available dataset (GSE19491). In our test cohort, the DRS classified TB from LTBI (sensitivity 95%, 95% CI [87 100]; specificity 90%, 95% CI [80-97]) and TB from OD (sensitivity 93%, 95% CI [83-100]; specificity 88%, 95% CI [74-97]). In the independent validation cohort, TB patients were distinguished both from LTBI individuals (sensitivity 95%, 95% CI [85-100]; specificity 94%, 95% CI [84-100]) and OD patients (sensitivity 100%, 95% CI [100-100]; specificity 96%, 95% CI [93-100]). Limitations of our study include the use of only culture confirmed TB patients, and the potential that TB may have been misdiagnosed in a small proportion of OD patients despite the extensive clinical investigation used to assign each patient to their diagnostic group. CONCLUSIONS: In our study, blood transcriptional signatures distinguished TB from other conditions prevalent in HIV-infected and -uninfected African adults. Our DRS, based on these signatures, could be developed as a test for TB suitable for use in HIV endemic countries. Further evaluation of the performance of the signatures and DRS in prospective populations of patients with symptoms consistent with TB will be needed to define their clinical value under operational conditions. Please see later in the article for the Editors' Summary. PMID- 24167455 TI - Integrated care pilot in north-west London: a mixed methods evaluation. AB - INTRODUCTION: This paper provides the results of a year-long evaluation of a large-scale integrated care pilot in north-west London. The pilot aimed to integrate care across primary, acute, community, mental health and social care for people with diabetes and/or those aged 75+ through care planning, multidisciplinary case reviews, information sharing and project management support. METHODS: The evaluation team conducted qualitative studies of change at organisational, clinician and patient levels (using interviews, focus groups and a survey); and quantitative analysis of change in service use and patient-level clinical outcomes (using patient-level datasets and a matched control study). RESULTS: The pilot had successfully engaged provider organisations, created a shared strategic vision and established governance structures. However, the engagement of clinicians was variable and there was no evidence to date of significant reductions in emergency admissions. There was some evidence of changes in care processes. CONCLUSION: Although the pilot has demonstrated the beginnings of large-scale change, it remains in the early stages and faces significant challenges as it seeks to become sustainable for the longer term. It is critical that National Health Service managers and clinicians have realistic expectations of what can be achieved in a relatively short period of time. PMID- 24167456 TI - The management of cardiovascular disease in the Netherlands: analysis of different programmes. AB - BACKGROUND: Disease management programmes are increasingly used to improve the efficacy and effectiveness of chronic care delivery. But, disease management programme development and implementation is a complex undertaking that requires effective decision-making. Choices made in the earliest phases of programme development are crucial, as they ultimately impact costs, outcomes and sustainability. METHODS: To increase our understanding of the choices that primary healthcare practices face when implementing such programmes and to stimulate successful implementation and sustainability, we compared the early implementation of eight cardiovascular disease management programmes initiated and managed by healthcare practices in various regions of the Netherlands. Using a mixed-methods design, we identified differences in and challenges to programme implementation in terms of context, patient characteristics, disease management level, healthcare utilisation costs, development costs and health-related quality of life. RESULTS: Shifting to a multidisciplinary, patient-centred care pathway approach to disease management is demanding for organisations, professionals and patients, and is especially vulnerable when sustainable change is the goal. Funding is an important barrier to sustainable implementation of cardiovascular disease management programmes, although development costs of the individual programmes varied considerably in relation to the length of the development period. The large number of professionals involved in combination with duration of programme development was the largest cost drivers. While Information and Communication Technology systems to support the new care pathways did not directly contribute to higher costs, delays in implementation indirectly did. CONCLUSIONS: Developing and implementing cardiovascular disease management programmes is time-consuming and challenging. Multidisciplinary, patient-centred care demands multifaceted changes in routine care. As care pathways become more complex, they also become more expensive. Better preparedness and training can prevent unnecessary delays during the implementation period and are crucial to reducing costs. PMID- 24167457 TI - Examining intersectoral integration for malaria control programmes in an urban and a rural district in Ghana: a multinomial multilevel analysis. AB - BACKGROUND: Intersectoral integration is acknowledged to be essential for improving provision of health care and outcomes, yet it remains one of the main primary health care strategic challenges. Although this is well articulated in the literature, the factors that explain differentials in levels of intersectoral integration have not been systematically studied, particularly in low and middle income countries. In this study, we examine the levels and determinants of intersectoral integration amongst institutions engaged in malaria control programmes in an urban (Kumasi Metropolitan) district and a rural (Ahafo Ano South) district in Ghana. METHODS: Interviews were conducted with representatives of 32 institutions engaged in promoting malaria prevention and control. The averaging technique proposed by Brown et al. and a two-level multinomial multilevel ordinal logistic regression were used to examine the levels of integration and the factors that explain the differentials. RESULTS: The results show high disparity in levels of integration amongst institutions in the two districts. Integration was higher in the rural district compared to the urban district. The multivariate analysis revealed that the district effect explained 25% of the variations in integration. The type of institution, level of focus on malaria and source of funding are important predictors of intersectoral integration. CONCLUSION: Although not causal, integrated malaria control programmes could be important for improving malaria-related health outcomes in less developed regions as evident from the rapid decline in malaria fatality rates observed in the Ahafo Ano South district. Harmonisation of programmes should be encouraged amongst institutions and the public and private sectors should be motivated to work in partnership. PMID- 24167458 TI - Obstacles to continuity of care in young mental health service users' pathways - an explorative study. AB - BACKGROUND: Users of mental health services often move between different primary and specialised health and care services, depending on their current condition, and this often leads to fragmentation of care. The aim of this study was to map care pathways in the case of young adult mental health service users and to identify key obstacles to continuity of care. METHOD: Quarterly semi-structured interviews were performed with nine young adults with mental health difficulties, following their pathways in and out of different services in the course of a year. RESULTS: Key obstacles to continuity of care included the mental health system's lack of access to treatment, lack of integration between different specialist services, lack of progress in care and inadequate coordination tools such as 'Individual Plan' and case conferences that did not prevent fragmented care pathways. CONCLUSIONS: Continuity of care should be more explicitly linked to aspirations for development and progress in the users' care pathways, and how service providers can cooperate with users to actually develop and make progress. Coordination tools such as case conferences and 'individual plans' should be upgraded to this end and utilised to the utmost. This may be the most effective way to counteract the system obstacles. PMID- 24167459 TI - Late breaking chromosomes. PMID- 24167460 TI - Mutations in the VEGFR3 signaling pathway explain 36% of familial lymphedema. AB - Lymphedema is caused by dysfunction of lymphatic vessels, leading to disabling swelling that occurs mostly on the extremities. Lymphedema can be either primary (congenital) or secondary (acquired). Familial primary lymphedema commonly segregates in an autosomal dominant or recessive manner. It can also occur in combination with other clinical features. Nine mutated genes have been identified in different isolated or syndromic forms of lymphedema. However, the prevalence of primary lymphedema that can be explained by these genetic alterations is unknown. In this study, we investigated 7 of these putative genes. We screened 78 index patients from families with inherited lymphedema for mutations in FLT4, GJC2, FOXC2, SOX18, GATA2, CCBE1, and PTPN14. Altogether, we discovered 28 mutations explaining 36% of the cases. Additionally, 149 patients with sporadic primary lymphedema were screened for FLT4, FOXC2, SOX18, CCBE1, and PTPN14. Twelve mutations were found that explain 8% of the cases. Still unidentified is the genetic cause of primary lymphedema in 64% of patients with a family history and 92% of sporadic cases. Identification of those genes is important for understanding of etiopathogenesis, stratification of treatments and generation of disease models. Interestingly, most of the proteins that are encoded by the genes mutated in primary lymphedema seem to act in a single functional pathway involving VEGFR3 signaling. This underscores the important role this pathway plays in lymphatic development and function and suggests that the unknown genes also have a role. PMID- 24167461 TI - Array-CGH Analysis Suggests Genetic Heterogeneity in Rhombencephalosynapsis. AB - Rhombencephalosynapsis is an uncommon, but increasingly recognized, cerebellar malformation defined as vermian agenesis with fusion of the hemispheres. The embryologic and genetic mechanisms involved are still unknown, and to date, no animal models are available. In the present study, we used Agilent oligonucleotide arrays in a large series of 57 affected patients to detect candidate genes. Four different unbalanced rearrangements were detected: a 16p11.2 deletion, a 14q12q21.2 deletion, an unbalanced translocation t(2p;10q), and a 16p13.11 microdeletion containing 2 candidate genes. These genes were further investigated by sequencing and in situ hybridization. This first microarray screening of a rhombencephalosynapsis series suggests that there may be heterogeneous genetic causes. PMID- 24167462 TI - FTO and INSIG2 Genotyping Combined with Metabolic and Anthropometric Phenotyping of Morbidly Obese Patients. AB - Obesity is a major health problem worldwide. Associations of obesity with common variants of the fat mass- and obesity-associated gene (FTO) and insulin-induced gene 2 (INSIG2) have been reported in various studies. We aimed to further investigate the association of 2 single nucleotide polymorphisms (SNPs), rs9939609 in FTO and rs7566605 in INSIG2, with body mass index (BMI) and other anthropometric and metabolic parameters in subjects with morbid obesity (BMI >=40). SNPs rs9939609 and rs7566605 were genotyped in 124 unrelated morbidly obese patients (mean BMI = 50, range 40.1-77.1) from Mainz, Germany, and in 253 normal controls without a history of morbid obesity. Metabolic and anthropometric parameters were analyzed in 109 of the 124 patients, and associations with the genotype data were examined. The high-risk AA genotype for FTO rs9939609 was observed in 32.3% of patients versus 15.8% of controls (p = 0.0004) and was associated with an increased obesity risk [odds ratio (OR) = 2.54, 95% confidence interval (CI) = 1.53-4.21]. The intermediate-risk AT genotype was found in patients and controls at similar frequencies (48.4 vs. 48.6%, OR = 0.99). The low risk TT genotype for rs9939609 was found in 19.4% of patients (35.5% of controls; p = 0.0013) and was associated with a decreased risk for morbid obesity (OR = 0.43, CI = 0.26-0.73). In contrast, INSIG2 rs7566605 showed no association with obesity in our patients. Evaluation of metabolic data indicated associations between the high-risk FTO genotype (rs9939609_AA) and increased levels of serum glutamic oxaloacetic transaminase (GOT) and between the high-risk INSIG2 genotype (rs7566605_CC) and lower waist-to-hip ratio and lower hemoglobin A1c (HbA1c) levels. Our results confirm an association of the FTO SNP with extreme obesity. However, we found no association of the potential obesity risk allele of INSIG2 in our sample and thus cannot confirm an association of the INSIG2 CC genotype with obesity. We identified an association between the high-risk FTO genotype (rs9939609_AA) and higher GOT levels, which could possibly reflect the increased frequency of nonalcoholic steatohepatitis with obesity. We also detected associations of the high-risk INSIG2 genotype (rs7566605_CC) with lower waist-to hip ratios and lower HbA1c levels, which may indicate amelioration of impaired glucose tolerance and type 2 diabetes for patients with this genotype after bariatric surgery. PMID- 24167463 TI - Interstitial deletions at 6q14.1q15 associated with developmental delay and a marfanoid phenotype. AB - There are a number of reports of interstitial deletions of the long arm of chromosome 6 that have developmental delay and obesity suggesting that this is a distinct phenotype almost like Prader-Willi syndrome. Here we report a patient with a similar deletion but a strikingly different phenotype, one more in keeping with Marfan syndrome, although he does not fulfil the criteria for that syndrome. Array comparative genomic hybridization was performed to investigate a patient with a striking phenotype. This revealed an interstitial deletion of 6q14.1q15. Parental FISH studies were normal, indicating that this is a de novo deletion. Our patient has a completely different phenotype compared to other patients reported to have similar deletions. The common feature is developmental delay, but the body features are quite different in that our patient is tall, strikingly thin with pectus excavatum, scoliosis, skin striae, arachnodactyly, pes planus, cataracts, and a high-arched palate. This contrasts with other patients who have a similar deletion but have short stature and obesity. 6q14.1q15 interstitial deletions can have a very variable phenotype and do not necessarily conform to a clinical recognizable microdeletion syndrome caused by haploinsufficiency of dosage-sensitive genes in that region as proposed by others. PMID- 24167464 TI - Delineation of a de novo 7q21.3q31.1 Deletion by CGH-SNP Arrays in a Girl with Multiple Congenital Anomalies Including Severe Glaucoma. AB - In this study, we present a female patient with a constitutional de novo deletion in 7q21.3q31.1 as determined by G-banding and CGH-SNP arrays. She exhibited, among other features, psychomotor retardation, congenital severe bilateral glaucoma, a cleft palate, and heart defect. Microarray assay disclosed a deleted 12.5-Mb region roughly 88 kb downstream the ectrodactyly critical region; thus, the patient's final karyotype was 46,XX.arr 7q21.3q31.1(96,742,140-109,246,085)*1 dn. This girl represents the fourth patient described so far with congenital glaucoma and a deletion encompassing or overlapping the 7q21.3q31.1 region, and confirms the presence of a locus or loci related to such a clinical feature. According to our results, the proneness to ocular defects secondary to 7q intermediate deletions could be caused by co-deletion of TAC1, HBP1, and a small cluster of cytochrome P450 genes (subfamily 3A). This conclusion is supported by their functional roles and expression locations as well as because TAC1 is related to the functional pathway of the MYOC gene whose mutations are linked to glaucoma. Moreover, given that this girl is clinically reminiscent of several phenotypes related to diverse deletions within 7q21q32, our results and observations offer a general overview of the gene content of deletions/phenotypes overlapping 7q21.3q31.1 and confirm that loci distal to DLX genes including the CUX1 gene and potential regulatory elements downstream from DLX5 are unrelated to ectrodactyly. PMID- 24167465 TI - Cognitive deficit, learning difficulties, severe behavioral abnormalities and healed cleft lip in a patient with a 1.2-mb distal microduplication at 22q11.2. AB - The 22q11.2 duplication syndrome has been recently characterized as a new entity with features overlapping the 22q11.2 deletion syndrome. Most 22q11.2 duplications represent reciprocal events of the typical 3-Mb deletions extending between low copy repeat (LCR) 22-A and LCR22-D. It has been suggested that the clinical manifestations observed in patients with 22q11.2 microduplications may range from milder phenotypes to multiple severe defects, and this variability could be responsible for many undetected cases. Here, we report on a patient with a 1.2-Mb microduplication at 22q11.2 spanning LCR22-F and LCR22-H which harbor the SMARCB1 and SNRPD3 genes. The patient presented healed cleft lip, mild facial dysmorphism, cognitive deficit, and delayed language development associated with severe behavioral problems including learning difficulties and aggressive behavior. PMID- 24167466 TI - Complex phenotype associated with 17q21.31 microdeletion. AB - We report on a patient carrying a 17q21.31 microdeletion and exhibiting many common syndrome features, together with other clinical signs which have rarely or never been described to date. The detected 695-kb 17q21.31 deletion is larger than in most previously reported cases but is still probably the result of recombination between flanking low-copy repeats. Due to the complexity of the patient's clinical condition, together with the presence of 3 previously unreported symptoms, namely chronic anemia, cervical vertebrae arthrosis and vertebrae fusion, this case is an important addition to the existing knowledge about the 17q21.31 microdeletion syndrome. PMID- 24167467 TI - Otocephaly-Dysgnathia Complex: Description of Four Cases and Confirmation of the Role of OTX2. AB - Otocephaly-dysgnathia complex is characterized by mandibular hypo- or aplasia, ear abnormalities, microstomia, and microglossia. Mutations in the orthodenticle homeobox 2 (OTX2) and paired related homeobox 1 (PRRX1) genes have recently been identified in some cases. We screened 4 otocephalic cases for these 2 genes and identified OTX2 mutations in 2 of them, thus confirming OTX2 is implicated in otocephaly. No PRRX1 mutation was identified. Interestingly, ocular involvement is not a constant feature in otocephalic cases with an OTX2 mutation. In one case, the mutation was inherited from a microphthalmic mother. The mechanism underlying this intrafamilial phenotypic variability remains unclear, but other genetic factors are likely to be necessary for the manifestation of the otocephalic phenotype. PMID- 24167468 TI - Pyrrhic victories: the need for social status drives costly competitive behavior. AB - Competitive behavior is commonly defined as the decision to maximize one's payoffs relative to others. We argue instead that competitive drive derives from a desire for social status. We make use of a multi-player auction task in which subjects knowingly incur financial losses for the sake of winning auctions. First, we show that overbidding is increased when the task includes members of a rival out-group, suggesting that social identity is an important mediator of competitiveness. In addition, we show that the extent that individuals are willing to incur losses is related to affective responses to social comparisons but not to monetary outcomes. Second, we show that basal levels of testosterone predict overbidding, and that this effect of testosterone is mediated by affective responses to social comparisons. Based on these findings, we argue that competitive behavior should be conceptualized in terms of social motivations as opposed to just relative monetary payoffs. PMID- 24167469 TI - Reconstructing for joint angles on the shoulder and elbow from non-invasive electroencephalographic signals through electromyography. AB - In this study, first the cortical activities over 2240 vertexes on the brain were estimated from 64 channels electroencephalography (EEG) signals using the Hierarchical Bayesian estimation while 5 subjects did continuous arm reaching movements. From the estimated cortical activities, a sparse linear regression method selected only useful features in reconstructing the electromyography (EMG) signals and estimated the EMG signals of 9 arm muscles. Then, a modular artificial neural network was used to estimate four joint angles from the estimated EMG signals of 9 muscles: one for movement control and the other for posture control. The estimated joint angles using this method have the correlation coefficient (CC) of 0.807 (+/-0.10) and the normalized root-mean square error (nRMSE) of 0.176 (+/-0.29) with the actual joint angles. PMID- 24167470 TI - The FMRP regulon: from targets to disease convergence. AB - The fragile X mental retardation protein (FMRP) is an RNA-binding protein that regulates mRNA metabolism. FMRP has been largely studied in the brain, where the absence of this protein leads to fragile X syndrome, the most frequent form of inherited intellectual disability. Since the identification of the FMRP gene in 1991, many studies have primarily focused on understanding the function/s of this protein. Hundreds of potential FMRP mRNA targets and several interacting proteins have been identified. Here, we report the identification of FMRP mRNA targets in the mammalian brain that support the key role of this protein during brain development and in regulating synaptic plasticity. We compared the genes from databases and genome-wide association studies with the brain FMRP transcriptome, and identified several FMRP mRNA targets associated with autism spectrum disorders, mood disorders and schizophrenia, showing a potential common pathway/s for these apparently different disorders. PMID- 24167472 TI - MicroRNA-431 regulates axon regeneration in mature sensory neurons by targeting the Wnt antagonist Kremen1. AB - MicroRNAs (miRNAs) are small, non-coding RNAs that function as key post transcriptional regulators in neural development, brain function, and neurological diseases. Growing evidence indicates that miRNAs are also important mediators of nerve regeneration, however, the affected signaling mechanisms are not clearly understood. In the present study, we show that nerve injury-induced miR-431 stimulates regenerative axon growth by silencing Kremen1, an antagonist of Wnt/beta-catenin signaling. Both the gain-of-function of miR-431 and knockdown of Kremen1 significantly enhance axon outgrowth in murine dorsal root ganglion neuronal cultures. Using cross-linking with AGO-2 immunoprecipitation, and 3' untranslated region (UTR) luciferase reporter assay we demonstrate miR-431 direct interaction on the 3'-UTR of Kremen1 mRNA. Together, our results identify miR-431 as an important regulator of axonal regeneration and a promising therapeutic target. PMID- 24167471 TI - Stem cell therapy to protect and repair the developing brain: a review of mechanisms of action of cord blood and amnion epithelial derived cells. AB - In the research, clinical, and wider community there is great interest in the use of stem cells to reduce the progression, or indeed repair brain injury. Perinatal brain injury may result from acute or chronic insults sustained during fetal development, during the process of birth, or in the newborn period. The most readily identifiable outcome of perinatal brain injury is cerebral palsy, however, this is just one consequence in a spectrum of mild to severe neurological deficits. As we review, there are now clinical trials taking place worldwide targeting cerebral palsy with stem cell therapies. It will likely be many years before strong evidence-based results emerge from these trials. With such trials underway, it is both appropriate and timely to address the physiological basis for the efficacy of stem-like cells in preventing damage to, or regenerating, the newborn brain. Appropriate experimental animal models are best placed to deliver this information. Cell availability, the potential for immunological rejection, ethical, and logistical considerations, together with the propensity for native cells to form teratomas, make it unlikely that embryonic or fetal stem cells will be practical. Fortunately, these issues do not pertain to the use of human amnion epithelial cells (hAECs), or umbilical cord blood (UCB) stem cells that are readily and economically obtained from the placenta and umbilical cord discarded at birth. These cells have the potential for transplantation to the newborn where brain injury is diagnosed or even suspected. We will explore the novel characteristics of hAECs and undifferentiated UCB cells, as well as UCB-derived endothelial progenitor cells (EPCs) and mesenchymal stem cells (MSCs), and how immunomodulation and anti inflammatory properties are principal mechanisms of action that are common to these cells, and which in turn may ameliorate the cerebral hypoxia and inflammation that are final pathways in the pathogenesis of perinatal brain injury. PMID- 24167473 TI - When is Sirt1 activity bad for dying neurons? AB - Sirt1, the class III histone deacetylase, is generally associated with increased life span and with a pro-survival effect in neurons stressed by pathological factors. Recent work, however, suggests that Sirt1 silencing could also promote neuronal survival. A possible reason suggested is Sirt1 silencing enhanced expression of both IGF-1 and IGF-1 receptor, signaling from which promotes survival. This work adds to the small but steady stream of findings that are diametrically opposite to the overwhelmingly large amount of evidence supporting a beneficial effect of sustaining or enhancing Sirt1 activity in neuronal injuries and diseases. We attempt to reconcile this discrepancy below by noting evidence that elevated Sirt1 levels and/or activity may not help, and could even adversely exacerbates demise, during events of acute neuronal damage or death. However, sustained Sirt1 activation will be beneficial in situations of chronic and long-term sub-lethal stresses, and the status of IGF-1 signaling may influence Sirt1 action in a context dependent manner. PMID- 24167474 TI - Erratum: A new in vivo model of pantothenate kinase-associated neurodegeneration reveals a surprising role for transcriptional regulation in pathogenesis. AB - [This corrects the article on p. 146 in vol. 7, PMID: 24058333.]. PMID- 24167477 TI - Memory formation for trace fear conditioning requires ubiquitin-proteasome mediated protein degradation in the prefrontal cortex. AB - The cellular mechanisms supporting plasticity during memory consolidation have been a subject of considerable interest. De novo protein and mRNA synthesis in several brain areas are critical, and more recently protein degradation, mediated by the ubiquitin-proteasome system (UPS), has been shown to be important. Previous work clearly establishes a relationship between protein synthesis and protein degradation in the amygdala, but it is unclear whether cortical mechanisms of memory consolidation are similar to those in the amygdala. Recent work demonstrating a critical role for prefrontal cortex (PFC) in the acquisition and consolidation of fear memory allows us to address this question. Here we use a PFC-dependent fear conditioning protocol to determine whether UPS mediated protein degradation is necessary for memory consolidation in PFC. Groups of rats were trained with auditory delay or trace fear conditioning and sacrificed 60 min after training. PFC tissue was then analyzed to quantify the amount of polyubiquibated protein. Other animals were trained with similar procedures but were infused with either a proteasome inhibitor (clasto-lactacystin beta-lactone) or a translation inhibitor (anisomycin) in the PFC immediately after training. Our results show increased UPS-mediated protein degradation in the PFC following trace but not delay fear conditioning. Additionally, post-training proteasome or translation inhibition significantly impaired trace but not delay fear memory when tested the next day. Our results further support the idea that the PFC is critical for trace but not delay fear conditioning and highlight the role of UPS mediated degradation as critical for synaptic plasticity. PMID- 24167475 TI - Pathophysiological power of improper tonic GABA(A) conductances in mature and immature models. AB - High-affinity extrasynaptic gamma-aminobutyric acid A (GABA(A)) receptors are tonically activated by low and consistent levels of ambient GABA, mediating chronic inhibition against neuronal excitability (tonic inhibition) and the modulation of neural development. Synaptic (phasic) inhibition is spatially and temporally precise compared with tonic inhibition, which provides blunt yet strong integral inhibitory force by shunting electrical signaling. Although effects of acute modification of tonic inhibition are known, its pathophysiological significance remains unclear because homeostatic regulation of neuronal excitability can compensate for long-term deficit of extrasynaptic GABA(A) receptor activation. Nevertheless, tonic inhibition is of great interest for its pathophysiological involvement in central nervous system (CNS) diseases and thus as a therapeutic target. Together with the development of experimental models for various pathological states, recent evidence demonstrates such pathological involvements of tonic inhibition in neuronal dysfunction. This review focuses on the recent progress of tonic activation of GABA(A) conductance on the development and pathology of the CNS. Findings indicate that neuronal function in various brain regions are exacerbated with a gain or loss of function of tonic inhibition by GABA spillover. Disturbance of tonic GABA(A) conductance mediated by non-synaptic ambient GABA may result in brain mal-development. Therefore, various pathological states (epilepsy, motor dysfunctions, psychiatric disorders, and neurodevelopmental disorders) may be partly attributable to abnormal tonic GABA(A) conductances. Thus, the tone of tonic conductance and level of ambient GABA may be precisely tuned to maintain the regular function and development of the CNS. Therefore, receptor expression and factors for regulating the ambient GABA concentration are highlighted to gain a deeper understanding of pathology and therapeutic strategy for CNS diseases. PMID- 24167478 TI - Variable delay-to-signal: a fast paradigm for assessment of aspects of impulsivity in rats. AB - Testing impulsive behavior in rodents is challenging and labor-intensive. We developed a new behavioral paradigm-the Variable Delay-to-Signal (VDS) test-that provides rapid and simultaneous assessment of response and decision impulsivity in rodents. Presentation of a light at variable delays signals the permission for action (nose poke) contingent with a reward. 2 blocks of 25 trials at 3 s delay flank a block of 70 trials in which light is presented with randomly selected 6 or 12 s delays. Exposure to such large delays boosts the rate of premature responses when the delay drops to 3 s in the final block, an effect that is blunted by an acute methamphetamine challenge and that correlates with the delay discounting (DD) paradigm (choice impulsivity). Finally, as expected, treatment with the NMDA antagonist MK-801 caused a generalized response increase in all VDS blocks. The pharmacological validation, particularly with methamphetamine which has a well established dual effect on response and decision impulsivity, and the correlations between the impulsive behavior in the DD and VDS paradigms, suggests that the later is able to provide, in a single session, a multi-dimensional assessment of impulsive behavior. PMID- 24167476 TI - The nucleus accumbens as a nexus between values and goals in goal-directed behavior: a review and a new hypothesis. AB - Goal-directed behavior is a fundamental means by which animals can flexibly solve the challenges posed by variable external and internal conditions. Recently, the processes and brain mechanisms underlying such behavior have been extensively studied from behavioral, neuroscientific and computational perspectives. This research has highlighted the processes underlying goal-directed behavior and associated brain systems including prefrontal cortex, basal ganglia and, in particular therein, the nucleus accumbens (NAcc). This paper focusses on one particular process at the core of goal-directed behavior: how motivational value is assigned to goals on the basis of internal states and environmental stimuli, and how this supports goal selection processes. Various biological and computational accounts have been given of this problem and of related multiple neural and behavior phenomena, but we still lack an integrated hypothesis on the generation and use of value for goal selection. This paper proposes an hypothesis that aims to solve this problem and is based on this key elements: (a) amygdala and hippocampus establish the motivational value of stimuli and goals; (b) prefrontal cortex encodes various types of action outcomes; (c) NAcc integrates different sources of value, representing them in terms of a common currency with the aid of dopamine, and thereby plays a major role in selecting action outcomes within prefrontal cortex. The "goals" pursued by the organism are the outcomes selected by these processes. The hypothesis is developed in the context of a critical review of relevant biological and computational literature which offer it support. The paper shows how the hypothesis has the potential to integrate existing interpretations of motivational value and goal selection. PMID- 24167479 TI - Consumption of glucose drinks slows sensorimotor processing: double-blind placebo controlled studies with the Eriksen flanker task. AB - Modulations of blood glucose concentration (BGC) in the normal range are known to facilitate performance in memory and other cognitive tasks but few studies have investigated the effects of BGC variations on complex sensorimotor task so far. The present study aimed to examine glucose effects with the Eriksen flanker task. This task was chosen because it can dissociate between the effects of BGC on sensorimotor processing and cognitive control by assessing congruency effects. In two linked double-blind placebo-controlled experiments BGC was elevated within the normal BGC range (4-7 mmol/l) by approx. 1.5 mmol/l with glucose drinks and compared to a placebo drink condition while a flanker task with either strong or weak stimulus-response (SR) mapping was performed. Modulation of the performance in the flanker task by glucose was linked to the strength of the SR mapping but not congruency effects. Under weak SR mapping, reaction times (RTs) were slowed in the glucose condition compared to placebo while error rates remained unchanged, whereas cognitive control was not affected by glucose. When SR mapping was strong, no differences were found between glucose and placebo. Enhanced glucose levels differentially affect behavior. Whereas the literature mainly reports facilitating characteristics of enhanced glucose levels in the normal range, the present study shows that higher glucose levels can slow RTs. This suggests that glucose does not have a uniform effect on cognition and that it might be differential depending on the cognitive domain. PMID- 24167480 TI - Exploring the subjective experience of the "rubber hand" illusion. AB - Despite the fact that the rubber hand illusion (RHI) is an experimental paradigm that has been widely used in the last 14 years to investigate different aspects of the sense of bodily self, very few studies have sought to investigate the subjective nature of the experience that the RHI evokes. The present study investigates the phenomenology of the RHI through a specific elicitation method. More particularly, this study aims at assessing whether the conditions usually used as control in the RHI have an impact in the sense of body ownership and at determining whether there are different stages in the emergence of the illusion. The results indicate that far from being "all or nothing," the illusion induced by the RHI protocol involves nuances in the type of perceptual changes that it creates. These perceptual changes affect not only the participants' perception of the rubber hand but also the perception of their real hand. In addition, perceptual effects may vary greatly between participants and, importantly, they evolve over time. PMID- 24167481 TI - A clinical case study of a psychoanalytic psychotherapy monitored with functional neuroimaging. AB - This case study describes 1 year of the psychoanalytic psychotherapy using clinical data, a standardized instrument of the psychotherapeutic process (Psychotherapy process Q-Set, PQS), and functional neuroimaging (fMRI). A female dysthymic patient with narcissistic traits was assessed at monthly intervals (12 sessions). In the fMRI scans, which took place immediately after therapy hours, the patient looked at pictures of attachment-relevant scenes (from the Adult Attachment Projective Picture System, AAP) divided into two groups: those accompanied by a neutral description, and those accompanied by a description tailored to core conflicts of the patient as assessed in the AAP. Clinically, this patient presented defense mechanisms that influenced the relationship with the therapist and that was characterized by fluctuations of mood that lasted whole days, following a pattern that remained stable during the year of the study. The two modes of functioning associated with the mood shifts strongly affected the interaction with the therapist, whose quality varied accordingly ("easy" and "difficult" hours). The PQS analysis showed the association of "easy" hours with the topic of the involvement in significant relationships and of "difficult hours" with self-distancing, a defensive maneuver common in narcissistic personality structures. In the fMRI data, the modes of functioning visible in the therapy hours were significantly associated with modulation of the signal elicited by personalized attachment-related scenes in the posterior cingulate (p = 0.017 cluster-level, whole-volume corrected). This region has been associated in previous studies to self-distancing from negatively valenced pictures presented during the scan. The present study may provide evidence of the possible involvement of this brain area in spontaneously enacted self-distancing defensive strategies, which may be of relevance in resistant reactions in the course of a psychoanalytic psychotherapy. PMID- 24167482 TI - The reasoning criminal vs. Homer Simpson: conceptual challenges for crime science. AB - A recent disciplinary offshoot of criminology, crime science (CS) defines itself as "the application of science to the control of crime." One of its stated ambitions is to act as a cross-disciplinary linchpin in the domain of crime reduction. Despite many practical successes, notably in the area of situational crime prevention (SCP), CS has yet to achieve a commensurate level of academic visibility. The case is made that the growth of CS is stifled by its reliance on a model of decision-making, the Rational Choice Perspective (RCP), which is inimical to the integration of knowledge and insights from the behavioral, cognitive and neurosciences (CBNs). Examples of salient developments in the CBNs are provided, as regards notably multiple-system perspectives of decision-making and approaches to person-environment interaction. Short and long-term benefits of integration for CS are briefly outlined. PMID- 24167483 TI - Effects of weak transcranial alternating current stimulation on brain activity-a review of known mechanisms from animal studies. AB - Rhythmic neuronal activity is ubiquitous in the human brain. These rhythms originate from a variety of different network mechanisms, which give rise to a wide-ranging spectrum of oscillation frequencies. In the last few years an increasing number of clinical research studies have explored transcranial alternating current stimulation (tACS) with weak current as a tool for affecting brain function. The premise of these interventions is that tACS will interact with ongoing brain oscillations. However, the exact mechanisms by which weak currents could affect neuronal oscillations at different frequency bands are not well known and this, in turn, limits the rational optimization of human experiments. Here we review the available in vitro and in vivo animal studies that attempt to provide mechanistic explanations. The findings can be summarized into a few generic principles, such as periodic modulation of excitability, shifts in spike timing, modulation of firing rate, and shifts in the balance of excitation and inhibition. These effects result from weak but simultaneous polarization of a large number of neurons. Whether this can lead to an entrainment or a modulation of brain oscillations, or whether AC currents have no effect at all, depends entirely on the specific dynamic that gives rise to the different brain rhythms, as discussed here for slow wave oscillations (~1 Hz) and gamma oscillations (~30 Hz). We conclude with suggestions for further experiments to investigate the role of AC stimulation for other physiologically relevant brain rhythms. PMID- 24167484 TI - Inhibition among olfactory receptor neurons. AB - Often assumed to be epiphenomena of a cell's activity, extracellular currents and resulting potential changes are increasingly recognized to influence the function of other cells in the vicinity. Experimental evidence shows that even small electric fields can modulate spike timing in neurons. Moreover, when neurons are brought close together experimentally or in pathological conditions, activity in one neuron can excite its neighbors. Inhibitory ephaptic mechanisms, however, may depend on more specialized coupling among cells. Recent studies in the Drosophila olfactory system have shown that excitation of a sensory neuron can inhibit its neighbor, and it was speculated that this interaction was ephaptic. Here we give an overview of ephaptic interactions that effect changes in spike timing, excitation or inhibition in diverse systems with potential relevance to human neuroscience. We examine the mechanism of the inhibitory interaction in the Drosophila system and that of the well-studied ephaptic inhibition of the Mauthner cell in more detail. We note that both current towards and current away from the local extracellular environment of a neuron can inhibit it, but the mechanism depends on the specific architecture of each system. PMID- 24167485 TI - Training of ultra-fast speech comprehension induces functional reorganization of the central-visual system in late-blind humans. AB - Individuals suffering from vision loss of a peripheral origin may learn to understand spoken language at a rate of up to about 22 syllables (syl) per seconds (s)-exceeding by far the maximum performance level of untrained listeners (ca. 8 syl/s). Previous findings indicate the central-visual system to contribute to the processing of accelerated speech in blind subjects. As an extension, the present training study addresses the issue whether acquisition of ultra-fast (18 syl/s) speech perception skills induces de novo central-visual hemodynamic activation in late-blind participants. Furthermore, we asked to what extent subjects with normal or residual vision can improve understanding of accelerated verbal utterances by means of specific training measures. To these ends, functional magnetic resonance imaging (fMRI) was performed while subjects were listening to forward and reversed sentence utterances of moderately fast and ultra-fast syllable rates (8 or 18 syl/s) prior to and after a training period of ca. 6 months. Four of six participants showed-independently from residual visual functions-considerable enhancement of ultra-fast speech perception (about 70% points correctly repeated words) whereas behavioral performance did not change in the two remaining participants. Only subjects with very low visual acuity displayed training-induced hemodynamic activation of the central-visual system. By contrast, participants with moderately impaired or even normal visual acuity showed, instead, increased right-hemispheric frontal or bilateral anterior temporal lobe responses after training. All subjects with significant training effects displayed a concomitant increase of hemodynamic activation of left hemispheric SMA. In spite of similar behavioral performance, trained "experts" appear to use distinct strategies of ultra-fast speech processing depending on whether the occipital cortex is still deployed for visual processing. PMID- 24167486 TI - Does the motor cortex differentiate between linguistic symbols and scribbles? PMID- 24167487 TI - Statistical evaluation of synchronous spike patterns extracted by frequent item set mining. AB - We recently proposed frequent itemset mining (FIM) as a method to perform an optimized search for patterns of synchronous spikes (item sets) in massively parallel spike trains. This search outputs the occurrence count (support) of individual patterns that are not trivially explained by the counts of any superset (closed frequent item sets). The number of patterns found by FIM makes direct statistical tests infeasible due to severe multiple testing. To overcome this issue, we proposed to test the significance not of individual patterns, but instead of their signatures, defined as the pairs of pattern size z and support c. Here, we derive in detail a statistical test for the significance of the signatures under the null hypothesis of full independence (pattern spectrum filtering, PSF) by means of surrogate data. As a result, injected spike patterns that mimic assembly activity are well detected, yielding a low false negative rate. However, this approach is prone to additionally classify patterns resulting from chance overlap of real assembly activity and background spiking as significant. These patterns represent false positives with respect to the null hypothesis of having one assembly of given signature embedded in otherwise independent spiking activity. We propose the additional method of pattern set reduction (PSR) to remove these false positives by conditional filtering. By employing stochastic simulations of parallel spike trains with correlated activity in form of injected spike synchrony in subsets of the neurons, we demonstrate for a range of parameter settings that the analysis scheme composed of FIM, PSF and PSR allows to reliably detect active assemblies in massively parallel spike trains. PMID- 24167488 TI - Design principles of the sparse coding network and the role of "sister cells" in the olfactory system of Drosophila. AB - Sensory systems face the challenge to represent sensory inputs in a way to allow easy readout of sensory information by higher brain areas. In the olfactory system of the fly drosopohila melanogaster, projection neurons (PNs) of the antennal lobe (AL) convert a dense activation of glomeruli into a sparse, high dimensional firing pattern of Kenyon cells (KCs) in the mushroom body (MB). Here we investigate the design principles of the olfactory system of drosophila in regard to the capabilities to discriminate odor quality from the MB representation and its robustness to different types of noise. We focus on understanding the role of highly correlated homotypic projection neurons ("sister cells") found in the glomeruli of flies. These cells are coupled by gap-junctions and receive almost identical sensory inputs, but target randomly different KCs in MB. We show that sister cells might play a crucial role in increasing the robustness of the MB odor representation to noise. Computationally, sister cells thus might help the system to improve the generalization capabilities in face of noise without impairing the discriminability of odor quality at the same time. PMID- 24167489 TI - Role of movement in long-term basal ganglia changes: implications for abnormal motor responses. AB - Abnormal involuntary movements (AIMs) and dyskinesias elicited by drugs that stimulate dopamine receptors in the basal ganglia are a major issue in the management of Parkinson's disease (PD). Preclinical studies in dopamine denervated animals have contributed to the modeling of these abnormal movements, but the precise neurochemical and functional mechanisms underlying these untoward effects are still elusive. It has recently been suggested that the performance of movement may itself promote the later emergence of drug-induced motor complications, by favoring the generation of aberrant motor memories in the dopamine-denervated basal ganglia. Our recent results from hemiparkinsonian rats subjected to the priming model of dopaminergic stimulation are in agreement with this. These results demonstrate that early performance of movement is crucial for the manifestation of sensitized rotational behavior, indicative of an abnormal motor response, and neurochemical modifications in selected striatal neurons following a dopaminergic challenge. Building on this evidence, this paper discusses the possible role of movement performance in drug-induced motor complications, with a look at the implications for PD management. PMID- 24167490 TI - Neural Schematics as a unified formal graphical representation of large-scale Neural Network Structures. AB - One of the major outcomes of neuroscientific research are models of Neural Network Structures (NNSs). Descriptions of these models usually consist of a non standardized mixture of text, figures, and other means of visual information communication in print media. However, as neuroscience is an interdisciplinary domain by nature, a standardized way of consistently representing models of NNSs is required. While generic descriptions of such models in textual form have recently been developed, a formalized way of schematically expressing them does not exist to date. Hence, in this paper we present Neural Schematics as a concept inspired by similar approaches from other disciplines for a generic two dimensional representation of said structures. After introducing NNSs in general, a set of current visualizations of models of NNSs is reviewed and analyzed for what information they convey and how their elements are rendered. This analysis then allows for the definition of general items and symbols to consistently represent these models as Neural Schematics on a two dimensional plane. We will illustrate the possibilities an agreed upon standard can yield on sampled diagrams transformed into Neural Schematics and an example application for the design and modeling of large-scale NNSs. PMID- 24167491 TI - Targeting peripheral opioid receptors to promote analgesic and anti-inflammatory actions. AB - Mechanisms of endogenous pain control are significant. Increasing studies have clearly produced evidence for the clinical usefulness of opioids in peripheral analgesia. The immune system uses mechanisms of cell migration not only to fight pathogens but also to control pain and inflammation within injured tissue. It has been demonstrated that peripheral inflammatory pain can be effectively controlled by an interaction of immune cell-derived opioid peptides with opioid receptors on peripheral sensory nerve terminals. Experimental and clinical studies have clearly shown that activation of peripheral opioid receptors with exogenous opioid agonists and endogenous opioid peptides are able to produce significant analgesic and anti-inflammatory effects, without central opioid mediated side effects (e.g., respiratory depression, sedation, tolerance, dependence). This article will focus on the role of opioids in peripheral inflammatory conditions and the clinical implications of targeting peripheral opioid receptors. PMID- 24167492 TI - Integrated approach for smart implantable cardioverter defibrillator (ICD) device with real time ECG monitoring: use of flexible sensors for localized arrhythmia sensing and stimulation. AB - Arrhythmias are the most common cause of death associated with sudden death and are common in US and worldwide. Cardiac resynchronization therapy (CRT), evolving from pacemakers and development of implantable cardioverter defibrillator (ICD), has been adopted for therapeutic use and demonstrated benefits in patients over the years due to its design and intricate functionality. Recent research has been focused on significant design improvement and efforts are dedicated toward device size reduction, weight and functionality in commercially available ICD's since its invention in the 1960's. Commercially available CRT-D has shown advancement on both clinical and technical side. However, improved focus is required on the device miniaturization, technologically supported and integrated wireless based system for real time heart monitoring electrocardiogram (ECG). In the present report a concise overview for the state-of-the art technology in ICDs and avenues for future development are presented. A unique perspective is also included for ICD device miniaturization and integration of flexible sensing array. Sensor array integration along with its capabilities for identifying localized arrhythmia detection and targeted stimulation for enhancing ICD device capabilities is reviewed. PMID- 24167493 TI - 5 years after the Kahn's etiquette-based medicine: a brief checklist proposal for a functional second meeting with the patient. PMID- 24167494 TI - Imposed visual feedback delay of an action changes mass perception based on the sensory prediction error. AB - While performing an action, the timing of when the sensory feedback is given can be used to establish the causal link between the action and its consequence. It has been shown that delaying the visual feedback while carrying an object makes people feel the mass of the object to be greater, suggesting that the feedback timing can also impact the perceived quality of an external object. In this study, we investigated the origin of the feedback timing information that influences the mass perception of the external object. Participants made a straight reaching movement while holding a manipulandum. The movement of the manipulandum was presented as a cursor movement on a monitor. In Experiment 1, various delays were imposed between the actual trajectory and the cursor movement. The participants' perceived mass of the manipulandum significantly increased as the delay increased to 400 ms, but this gain did not reach significance when the delay was 800 ms. This suggests the existence of a temporal tuning mechanism for incorporating the visual feedback into the perception of mass. In Experiment 2, we examined whether the increased mass perception during the visual delay was due to the prediction error of the visual consequence of an action or to the actual delay of the feedback itself. After the participants adapted to the feedback delay, the perceived mass of the object became lighter than before, indicating that updating the temporal prediction model for the visual consequence diminishes the overestimation of the object's mass. We propose that the misattribution of the visual delay into mass perception is induced by the sensorimotor prediction error, possibly when the amount of delay (error) is within the range that can reasonably include the consequence of an action. PMID- 24167495 TI - Facing off with Scylla and Charybdis: a comparison of scalar, partial, and the novel possibility of approximate measurement invariance. AB - Measurement invariance (MI) is a pre-requisite for comparing latent variable scores across groups. The current paper introduces the concept of approximate MI building on the work of Muthen and Asparouhov and their application of Bayesian Structural Equation Modeling (BSEM) in the software Mplus. They showed that with BSEM exact zeros constraints can be replaced with approximate zeros to allow for minimal steps away from strict MI, still yielding a well-fitting model. This new opportunity enables researchers to make explicit trade-offs between the degree of MI on the one hand, and the degree of model fit on the other. Throughout the paper we discuss the topic of approximate MI, followed by an empirical illustration where the test for MI fails, but where allowing for approximate MI results in a well-fitting model. Using simulated data, we investigate in which situations approximate MI can be applied and when it leads to unbiased results. Both our empirical illustration and the simulation study show approximate MI outperforms full or partial MI In detecting/recovering the true latent mean difference when there are (many) small differences in the intercepts and factor loadings across groups. In the discussion we provide a step-by-step guide in which situation what type of MI is preferred. Our paper provides a first step in the new research area of (partial) approximate MI and shows that it can be a good alternative when strict MI leads to a badly fitting model and when partial MI cannot be applied. PMID- 24167496 TI - Witnessing hateful people in pain modulates brain activity in regions associated with physical pain and reward. AB - How does witnessing a hateful person in pain compare to witnessing a likable person in pain? The current study compared the brain bases for how we perceive likable people in pain with those of viewing hateful people in pain. While social bonds are built through sharing the plight and pain of others in the name of empathy, viewing a hateful person in pain also has many potential ramifications. In this functional Magnetic Resonance Imaging (fMRI) study, Caucasian Jewish male participants viewed videos of (1) disliked, hateful, anti-Semitic individuals, and (2) liked, non-hateful, tolerant individuals in pain. The results showed that, compared with viewing liked people, viewing hateful people in pain elicited increased responses in regions associated with observation of physical pain (the insular cortex, the anterior cingulate cortex (ACC), and the somatosensory cortex), reward processing (the striatum), and frontal regions associated with emotion regulation. Functional connectivity analyses revealed connections between seed regions in the left ACC and right insular cortex with reward regions, the amygdala, and frontal regions associated with emotion regulation. These data indicate that regions of the brain active while viewing someone in pain may be more active in response to the danger or threat posed by witnessing the pain of a hateful individual more so than the desire to empathize with a likable person's pain. PMID- 24167497 TI - A taste for words and sounds: a case of lexical-gustatory and sound-gustatory synesthesia. AB - Gustatory forms of synesthesia involve the automatic and consistent experience of tastes that are triggered by non-taste related inducers. We present a case of lexical-gustatory and sound-gustatory synesthesia within one individual, SC. Most words and a subset of non-linguistic sounds induce the experience of taste, smell and physical sensations for SC. SC's lexical-gustatory associations were significantly more consistent than those of a group of controls. We tested for effects of presentation modality (visual vs. auditory), taste-related congruency, and synesthetic inducer-concurrent direction using a priming task. SC's performance did not differ significantly from a trained control group. We used functional magnetic resonance imaging to investigate the neural correlates of SC's synesthetic experiences by comparing her brain activation to the literature on brain networks related to language, music, and sound processing, in addition to synesthesia. Words that induced a strong taste were contrasted to words that induced weak-to-no tastes ("tasty" vs. "tasteless" words). Brain activation was also measured during passive listening to music and environmental sounds. Brain activation patterns showed evidence that two regions are implicated in SC's synesthetic experience of taste and smell: the left anterior insula and left superior parietal lobe. Anterior insula activation may reflect the synesthetic taste experience. The superior parietal lobe is proposed to be involved in binding sensory information across sub-types of synesthetes. We conclude that SC's synesthesia is genuine and reflected in her brain activation. The type of inducer (visual-lexical, auditory-lexical, and non-lexical auditory stimuli) could be differentiated based on patterns of brain activity. PMID- 24167498 TI - Developmental changes in the association between approximate number representations and addition skills in elementary school children. AB - The approximate number system (ANS) is assumingly related to mathematical learning but evidence supporting this assumption is mixed. The inconsistent findings might be attributed to the fact that different measures have been used to assess the ANS and mathematical skills. Moreover, associations between the performance on a measure of the ANS and mathematical skills may be discontinuous, i.e., stronger for children with lower math scores than for children with higher math scores, and may change with age. The aim of the present study was to examine the development of the ANS and arithmetic skills in elementary school children and to investigate how the relationship between the ANS and arithmetic skills develops. Individual markers of children's ANS (internal Weber fractions and mean reaction times in a non-symbolic numerical comparison task) and addition skills were assessed in their first year of school and 1 year later. Children showed improvements in addition performance and in the internal Weber fractions, whereas mean reaction times in the non-symbolic numerical comparison task did not change significantly. While children's addition performance was associated with the internal Weber fractions in the first year, it was associated with mean reaction times in the non-symbolic numerical comparison task in the second year. These associations were not found to be discontinuous and could not be explained by individual differences in reasoning, processing speed, or inhibitory control. The present study extends previous findings by demonstrating that addition performance is associated with different markers of the ANS in the course of development. PMID- 24167499 TI - Brain responses to odor mixtures with sub-threshold components. AB - Although most odorants we encounter in daily life are mixtures of several chemical substances, we still lack significant information on how we perceive and how the brain processes mixtures of odorants. We aimed to investigate the processing of odor mixtures using behavioral measures and functional magnetic resonance imaging (fMRI). The odor mixture contained a target odor (ambroxan) in a concentration at which it could be perceived by half of the subjects (sensitive group); the other half could not perceive the odor (insensitive group). In line with previous findings on multi-component odor mixtures, both groups of subjects were not able to distinguish a complex odor mixture containing or not containing the target odor. However, sensitive subjects had stronger activations than insensitive subjects in chemosensory processing areas such as the insula when exposed to the mixture containing the target odor. Furthermore, the sensitive group exhibited larger brain activations when presented with the odor mixture containing the target odor compared to the odor mixture without the target odor; this difference was smaller, though present for the insensitive group. In conclusion, we show that a target odor presented within a mixture of odors can influence brain activations although on a psychophysical level subjects are not able to distinguish the mixture with and without the target. On the practical side these results suggest that the addition of a certain compound to a mixture of odors may not be detected on a cognitive level; however, this additional odor may significantly change the cerebral processing of this mixture. In this context, FMRI offers unique possibilities to look at the subliminal effects of odors. PMID- 24167500 TI - Multiple Aspects of Gene Dysregulation in Huntington's Disease. AB - Huntington's Disease (HD) is a genetic neurodegenerative disease caused by a CAG expansion in the gene encoding Huntingtin (Htt). It is characterized by chorea, cognitive, and psychiatric disorders. The most affected brain region is the striatum, and the clinical symptoms are directly correlated to the rate of striatal degeneration. The wild-type Htt is a ubiquitous protein and its deletion is lethal. Mutated (expanded) Htt produces excitotoxicity, mitochondrial dysfunctions, axonal transport deficit, altered proteasome activity, and gene dysregulation. Transcriptional dysregulation occurs at early neuropathological stages in HD patients. Multiple genes are dysregulated, with overlaps of altered transcripts between mouse models of HD and patient brains. Nuclear localization of Exp-Htt interferes with transcription factors, co-activators, and proteins of the transcriptional machinery. Another key mechanism described so far, is an alteration of cytoplasmic retention of the transcriptional repressor REST, which is normally associated with wild-type Htt. As such, Exp-Htt causes alteration of transcription of multiple genes involved in neuronal survival, plasticity, signaling, and mitochondrial biogenesis and respiration. Besides these transcriptional dysregulations, Exp-Htt affects the chromatin structure through altered post-translational modifications (PTM) of histones and methylation of DNA. Multiple alterations of histone PTM are described, including acetylation, methylation, ubiquitylation, polyamination, and phosphorylation. Exp-Htt also affects the expression and regulation of non-coding microRNAs (miRNAs). First multiple neural miRNAs are controlled by REST, and dysregulated in HD, with concomitant de-repression of downstream mRNA targets. Second, Exp-Htt protein or RNA may also play a major role in the processing of miRNAs and hence pathogenesis. These pleiotropic effects of Exp-Htt on gene expression may represent seminal deleterious effects in the pathogenesis of HD. PMID- 24167501 TI - How the prohormone theory solved two important controversies in hormonal and neural Peptide biosynthesis. AB - This Prohormone Theory was simultaneously proposed in 1967 by two independent groups using two different approaches and two experimental models. Donald Steiner, in elegant pulse-chase experiments, proposed the existence of proinsulin when he observed that a human insulinoma was producing higher MW forms of immunoreactive insulin, subsequently transformed into insulin-like material (1). Simultaneously and independently, Michel Chretien, based on amino acid sequence homologies between three pituitary peptides, beta-lipotropic hormone (beta-LPH), gamma-LPH, and beta-melanocyte-stimulating hormone (beta-MSH), concluded that active peptide hormones are derived from endoproteolytic cleavages of inactive precursors, apparently at pairs of basic amino acids (2). One year later, Donald Chance confirmed that the cleavage sites in proinsulin were also made of paired basic amino acids (3). This novel paradigm solved two major controversies on the biosynthesis of both insulin and neuropeptides. This short review describes how. PMID- 24167502 TI - Contribution of the Local RAS to Hematopoietic Function: A Novel Therapeutic Target. AB - The renin-angiotensin system (RAS) has long been a known endocrine system that is involved in regulation of blood pressure and fluid balance. Over the last two decades, evidence has accrued that shows that there are local RAS that can affect cellular activity, tissue injury, and tissue regeneration. There are locally active ligand peptides, mediators, receptors, and signaling pathways of the RAS in the bone marrow (BM). This system is fundamentally involved and controls the essential steps of primitive and definitive blood-cell production. Hematopoiesis, erythropoiesis, myelopoiesis, thrombopoiesis, formation of monocytic and lymphocytic lineages, as well as stromal elements are regulated by the local BM RAS. The expression of a local BM RAS has been shown in very early, primitive embryonic hematopoiesis. Angiotensin-converting enzyme (ACE-1, CD143) is expressed on the surface of hemangioblasts and isolation of the CD143 positive cells allows for recovery of all hemangioblast activity, the first endothelial and hematopoietic cells, forming the marrow cavity in the embryo. CD143 expression also marks long-term blood-forming CD34+ BM cells. Expression of receptors of the RAS is modified in the BM with cellular maturation and by injury. Ligation of the receptors of the RAS has been shown to modify the status of the BM resulting in accelerated hematopoiesis after injury. The aim of the present review is to outline the known functions of the local BM RAS within the context of primitive and definitive hematopoiesis as well as modification of BM recovery by administration of exogenous ligands of the RAS. Targeting the actions of local RAS molecules could represent a valuable therapeutic option for the management of BM recovery after injury as well as neoplastic disorders. PMID- 24167503 TI - APECED: A Paradigm of Complex Interactions between Genetic Background and Susceptibility Factors. AB - Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) is a rare autosomal recessive disease, caused by mutations of a single gene named Autoimmune regulator gene (AIRE) which results in a failure of T-cell tolerance. Central tolerance takes place within the thymus and represents the mechanism by which potentially auto-reactive T-cells are eliminated through the negative selection process. The expression of tissue-specific antigens (TSAs) by medullary thymic epithelial cells (mTECs) in the thymus is a key process in the central tolerance and is driven by the protein encoded by AIRE gene, the transcription factor autoimmune regulator (AIRE). A failure in this process caused by AIRE mutations is thought to be responsible of the systemic autoimmune reactions of APECED. APECED is characterized by several autoimmune endocrine and non-endocrine manifestations and the phenotype is often complex. Although APECED is the paradigm of a monogenic autoimmune disorder, it is characterized by a wide variability of the clinical expression even between siblings with the same genotype, thus implying that additional mechanisms, other than the failure of Aire function, are involved in the pathogenesis of the disease. Unraveling open issues of the molecular basis of APECED, will help improve diagnosis, management, and therapeutical strategies of this complex disease. PMID- 24167504 TI - The control of the specificity of CD4 T cell responses: thresholds, breakpoints, and ceilings. AB - It has been known for over 25 years that CD4 T cell responses are restricted to a finite number of peptide epitopes within pathogens or protein vaccines. These selected peptide epitopes are termed "immunodominant." Other peptides within the antigen that can bind to host MHC molecules and recruit CD4 T cells as single peptides are termed "cryptic" because they fail to induce responses when expressed in complex proteins or when in competition with other peptides during the immune response. In the last decade, our laboratory has evaluated the mechanisms that underlie the preferential specificity of CD4 T cells and have discovered that both intracellular events within antigen presenting cells, particular selective DM editing, and intercellular regulatory pathways, involving IFN-gamma, indoleamine 2,3-dioxygenase, and regulatory T cells, play a role in selecting the final peptide specificity of CD4 T cells. In this review, we summarize our findings, discuss the implications of this work on responses to pathogens and vaccines and speculate on the logic of these regulatory events. PMID- 24167506 TI - Descendant root volume varies as a function of root type: estimation of root biomass lost during uprooting in Pinus pinaster. AB - Root systems of woody plants generally display a strong relationship between the cross-sectional area or cross-sectional diameter (CSD) of a root and the dry weight of biomass (DWd) or root volume (Vd) that has grown (i.e., is descendent) from a point. Specification of this relationship allows one to quantify root architectural patterns and estimate the amount of material lost when root systems are extracted from the soil. However, specifications of this relationship generally do not account for the fact that root systems are comprised of multiple types of roots. We assessed whether the relationship between CSD and Vd varies as a function of root type. Additionally, we sought to identify a more accurate and time-efficient method for estimating missing root volume than is currently available. We used a database that described the 3D root architecture of Pinus pinaster root systems (5, 12, or 19 years) from a stand in southwest France. We determined the relationship between CSD and Vd for 10,000 root segments from intact root branches. Models were specified that did and did not account for root type. The relationships were then applied to the diameters of 11,000 broken root ends to estimate the volume of missing roots. CSD was nearly linearly related to the square root of Vd, but the slope of the curve varied greatly as a function of root type. Sinkers and deep roots tapered rapidly, as they were limited by available soil depth. Distal shallow roots tapered gradually, as they were less limited spatially. We estimated that younger trees lost an average of 17% of root volume when excavated, while older trees lost 4%. Missing volumes were smallest in the central parts of root systems and largest in distal shallow roots. The slopes of the curves for each root type are synthetic parameters that account for differentiation due to genetics, soil properties, or mechanical stimuli. Accounting for this differentiation is critical to estimating root loss accurately. PMID- 24167507 TI - MASCP gator: an overview of the Arabidopsis proteomic aggregation portal. AB - A key challenge in the area of bioinformatics in the coming decades is the ability to manage the wealth of information that is being generated from the variety of high throughput methodologies currently being undertaken in laboratories across the world. While these approaches have made available large volumes of data to the research community, less attention has been given to the problem of how to intuitively present the data to enable greater biological insights. Recently, an attempt was made to tackle this problem in the area of Arabidopsis proteomics. The model plant has been the target of countless proteomics surveys producing an exhaustive array of data and online repositories. The MASCP Gator is an aggregation portal for proteomic data currently being produced by the community and unites a large collection of specialized resources to a single portal (http://gator.masc-proteomics.org/). Here we describe the latest additions, upgrades and features to this resource further expanding its role into protein modifications and genome sequence variations. PMID- 24167509 TI - Rose bush leaf and internode expansion dynamics: analysis and development of a model capturing interplant variability. AB - Rose bush architecture, among other factors, such as plant health, determines plant visual quality. The commercial product is the individual plant and interplant variability may be high within a crop. Thus, both mean plant architecture and interplant variability should be studied. Expansion is an important feature of architecture, but it has been little studied at the level of individual organs in rose bushes. We investigated the expansion kinetics of primary shoot organs, to develop a model reproducing the organ expansion of real crops from non-destructive input variables. We took interplant variability in expansion kinetics and the model's ability to simulate this variability into account. Changes in leaflet and internode dimensions over thermal time were recorded for primary shoot expansion, on 83 plants from three crops grown in different climatic conditions and densities. An empirical model was developed, to reproduce organ expansion kinetics for individual plants of a real crop of rose bush primary shoots. Leaflet or internode length was simulated as a logistic function of thermal time. The model was evaluated by cross-validation. We found that differences in leaflet or internode expansion kinetics between phytomer positions and between plants at a given phytomer position were due mostly to large differences in time of organ expansion and expansion rate, rather than differences in expansion duration. Thus, in the model, the parameters linked to expansion duration were predicted by values common to all plants, whereas variability in final size and organ expansion time was captured by input data. The model accurately simulated leaflet and internode expansion for individual plants (RMSEP = 7.3 and 10.2% of final length, respectively). Thus, this study defines the measurements required to simulate expansion and provides the first model simulating organ expansion in rosebush to capture interplant variability. PMID- 24167508 TI - Two-way plant mediated interactions between root-associated microbes and insects: from ecology to mechanisms. AB - Plants are members of complex communities and function as a link between above- and below-ground organisms. Associations between plants and soil-borne microbes commonly occur and have often been found beneficial for plant fitness. Root associated microbes may trigger physiological changes in the host plant that influence interactions between plants and aboveground insects at several trophic levels. Aboveground, plants are under continuous attack by insect herbivores and mount multiple responses that also have systemic effects on belowground microbes. Until recently, both ecological and mechanistic studies have mostly focused on exploring these below- and above-ground interactions using simplified systems involving both single microbe and herbivore species, which is far from the naturally occurring interactions. Increasing the complexity of the systems studied is required to increase our understanding of microbe-plant-insect interactions and to gain more benefit from the use of non-pathogenic microbes in agriculture. In this review, we explore how colonization by either single non pathogenic microbe species or a community of such microbes belowground affects plant growth and defense and how this affects the interactions of plants with aboveground insects at different trophic levels. Moreover, we review how plant responses to foliar herbivory by insects belonging to different feeding guilds affect interactions of plants with non-pathogenic soil-borne microbes. The role of phytohormones in coordinating plant growth, plant defenses against foliar herbivores while simultaneously establishing associations with non-pathogenic soil microbes is discussed. PMID- 24167511 TI - Retraction: Influence of ATP-binding cassette transporters in root exudation of phytoalexins, signals, and in disease resistance. PMID- 24167510 TI - "Breath figures" on leaf surfaces-formation and effects of microscopic leaf wetness. AB - "Microscopic leaf wetness" means minute amounts of persistent liquid water on leaf surfaces which are invisible to the naked eye. The water is mainly maintained by transpired water vapor condensing onto the leaf surface and to attached leaf surface particles. With an estimated average thickness of less than 1 MUm, microscopic leaf wetness is about two orders of magnitude thinner than morning dewfall. The most important physical processes which reduce the saturation vapor pressure and promote condensation are cuticular absorption and the deliquescence of hygroscopic leaf surface particles. Deliquescent salts form highly concentrated solutions. Depending on the type and concentration of the dissolved ions, the physicochemical properties of microscopic leaf wetness can be considerably different from those of pure water. Microscopic leaf wetness can form continuous thin layers on hydrophobic leaf surfaces and in specific cases can act similar to surfactants, enabling a strong potential influence on the foliar exchange of ions. Microscopic leaf wetness can also enhance the dissolution, the emission, and the reaction of specific atmospheric trace gases e.g., ammonia, SO2, or ozone, leading to a strong potential role for microscopic leaf wetness in plant/atmosphere interaction. Due to its difficult detection, there is little knowledge about the occurrence and the properties of microscopic leaf wetness. However, based on the existing evidence and on physicochemical reasoning it can be hypothesized that microscopic leaf wetness occurs on almost any plant worldwide and often permanently, and that it significantly influences the exchange processes of the leaf surface with its neighboring compartments, i.e., the plant interior and the atmosphere. The omission of microscopic water in general leaf wetness concepts has caused far-reaching, misleading conclusions in the past. PMID- 24167505 TI - Host Factors and HIV-1 Replication: Clinical Evidence and Potential Therapeutic Approaches. AB - HIV and human defense mechanisms have co-evolved to counteract each other. In the process of infection, HIV takes advantage of cellular machinery and blocks the action of the host restriction factors (RF). A small subset of HIV+ individuals control HIV infection and progression to AIDS in the absence of treatment. These individuals known as long-term non-progressors (LNTPs) exhibit genetic and immunological characteristics that confer upon them an efficient resistance to infection and/or disease progression. The identification of some of these host factors led to the development of therapeutic approaches that attempted to mimic the natural control of HIV infection. Some of these approaches are currently being tested in clinical trials. While there are many genes which carry mutations and polymorphisms associated with non-progression, this review will be specifically focused on HIV host RF including both the main chemokine receptors and chemokines as well as intracellular RF including, APOBEC, TRIM, tetherin, and SAMHD1. The understanding of molecular profiles and mechanisms present in LTNPs should provide new insights to control HIV infection and contribute to the development of novel therapies against AIDS. PMID- 24167512 TI - Initially Nondiagnosed Fabry's Disease when Electron Microscopy Is Lacking: The Continuing Story of Focal and Segmental Glomerulosclerosis. AB - Focal and segmental glomerulosclerosis is classified as either primary or secondary. We present a patient with a past history of biopsy-proven focal and segmental glomerulosclerosis. Despite initial response to dual blockade and steroids, proteinuria raised when steroids were decreased. After the patient was restarted on steroids, proteinuria did not improve. Another biopsy confirmed the previous diagnosis but suggested Fabry's disease, later confirmed by electron microscopy, alpha-galactosidase A serum and leukocyte deficiency as well as genetic studies. Proteinuria decreased when agalsidase beta was prescribed in parallel with steroid tapering, increased with steroid discontinuation and improved with meprednisone administration. This report highlights the relevance of electron microscopy in kidney biopsy. In glomerulosclerosis, despite specific treatment, secondary hemodynamic and immunologic pathways may contribute to the development of proteinuria and accelerate the renal disease progression due to the primary disease. We discuss possible pathophysiologic pathways involved in proteinuria in Fabry's disease according to the biopsy and the therapeutic response. PMID- 24167513 TI - Disseminated mucormycosis in a patient with recent kidney transplantation: a case report and review of the literature. AB - Mucormycosis is an invasive fungal infection commonly seen in diabetics and immunocompromised patients. We report a case of disseminated mucormycosis in a 47 year-old diabetic male who underwent deceased donor renal allograft transplantation about 5 weeks prior to presentation. Our patient presented with increasing fatigue, diarrhea and oligoanuria and was found to have significant acute kidney injury. Doppler ultrasound of the allograft revealed segmental decreased renal perfusion in the upper pole of the allograft with moderate hydronephrosis. Nephrostomy tube placement yielded minimal urine output. An allograft biopsy showed diffuse C4d-positive staining and fungal hyphae suggestive of Mucor infection. Computed tomography (CT) imaging revealed a right upper lobe mass, a small hypodensity in the liver and normal findings in the head. Despite prompt management including discontinuation of immunosuppression, amphotericin B and allograft nephrectomy, the patient had a rapid decompensation, developed respiratory failure requiring intubation, hypotension and supraventricular tachycardia with multiple new areas of hypoattenuation on head CT - all of which ultimately resulted in his death. A review of the literature revealed that mucormycosis is a relatively rare disease with a cumulative 12 month incidence rate of 0.07% in solid organ transplant recipients. Disseminated disease was found in about 23% of cases, with a mortality rate of 96%. PMID- 24167514 TI - A case of arteriovenous fistula after renal biopsy in an IgA nephropathy patient with macroscopic hematuria. AB - Macroscopic hematuria is a common symptom in IgA nephropathy and is also one of the most frequent complications after a percutaneous renal biopsy. Here, we describe a patient with IgA nephropathy and recurrent macroscopic hematuria who developed an arteriovenous fistula after renal biopsy. PMID- 24167515 TI - A case of malignancy-associated cryoglobulinemia. AB - We present a case of type 1 cryoglobulinemia with an underlying hematological malignancy. Unusually, the entire unifying diagnosis was made on the basis of the renal biopsy. Initially, serum cryoglobulin was not identified; repeat samples were positive. It is important to note that there is a significant false-negative rate with laboratory testing for cryoglobulin, due, at least in part, to the specific conditions required for collection and processing. With that in mind, in all cases with strong clinical or histological evidence of cryoglobulin but negative testing, carefully repeated samples should be sent. PMID- 24167517 TI - Rosuvastatin-induced acute interstitial nephritis. AB - We report a case of acute interstitial nephritis (AIN), most likely induced by rosuvastatin, in an 83-year-old male patient. The patient underwent angioplasty of the left internal carotid artery, after which he began a regimen of rosuvastatin (20 mg/day). After 3 weeks the patient was admitted to our unit for acute renal failure with mild proteinuria with negligible urinary sediment. A left kidney biopsy showed dense interstitial infiltrates, mainly composed of lymphocytes with evident tubulitis. Rosuvastatin withdrawal plus prednisolone (1 mg/kg/day) treatment, which was slowly tapered over a period of 4 weeks, allowed for a complete recovery of renal function. To our knowledge, this is the first case report of rosuvastatin-induced AIN. Acute renal failure is associated with a clear increase in morbidity, length of hospital stay and mortality. Moreover, since statins are among the most widely prescribed drugs in Western countries, we think that the risk of AIN should be taken into account as a possible side effect of rosuvastatin. PMID- 24167516 TI - Delayed progression to dialysis with early and intensive management of predialysis chronic kidney disease: a case-based approach. AB - In addition to hypertension and diabetes, disorders in mineral metabolism and bone disease (e.g. affecting phosphorus, calcium, parathyroid hormone, and vitamin D) are common complications of chronic kidney disease (CKD) and contribute to morbidity and mortality. Consequently, CKD requires multifactorial treatment to slow CKD progression and avoid end-stage renal disease. CKD progression and treatment outcomes are monitored by measuring the estimated glomerular filtration rate (eGFR), which decreases by 2-12 ml/min/1.73 m(2) per year depending on the stage of CKD and comorbidities, such as diabetes. This paper presents representative case studies illustrating the delay and reversal of CKD progression with comprehensive, individualized treatment regimens, including non-calcium phosphate binders, antihypertensives, lipid-lowering drugs, calcimimetics, and other drugs as required, to treat each component of CKD including CKD-mineral and bone disorder. Four patients are included, with an average age of 70-81 years and CKD stage 3 or 4 accompanied by various comorbidities, most notably diabetes and hypertension. The range of treatment and follow-up durations was 6-7 years. In each case, there was evidence of slowing or prevention of CKD progression, according to eGFR and serum creatinine, regardless of the patient's age or CKD stage. Despite a baseline eGFR of <20 ml/min/1.73 m(2) in 1 female patient, after 6 years of follow-up, her eGFR had stabilized and was maintained at >15 ml/min/1.73 m(2). These observations reinforce the value of early nephrology referral and comprehensive management of CKD and underlying conditions (hypertension and diabetes) beginning at eGFR <60 ml/min/1.73 m(2). PMID- 24167518 TI - A potential new biological marker of the biological age. PMID- 24167520 TI - Future prospects of Qiliqiangxin on heart failure: epigenetic regulation of regeneration. PMID- 24167519 TI - EBV finds a polycomb-mediated, epigenetic solution to the problem of oncogenic stress responses triggered by infection. AB - Viruses that establish a persistent infection, involving intracellular latency, commonly stimulate cellular DNA synthesis and sometimes cell division early after infection. However, most cells of metazoans have evolved "fail-safe" responses that normally monitor unscheduled DNA synthesis and prevent cell proliferation when, for instance, cell proto-oncogenes are "activated" by mutation, amplification, or chromosomal rearrangements. These cell intrinsic defense mechanisms that reduce the risk of neoplasia and cancer are collectively called oncogenic stress responses (OSRs). Mechanisms include the activation of tumor suppressor genes and the so-called DNA damage response that together trigger pathways leading to cell cycle arrest (e.g., cell senescence) or complete elimination of cells (e.g., apoptosis). It is not surprising that viruses that can induce cellular DNA synthesis and cell division have the capacity to trigger OSR, nor is it surprising that these viruses have evolved countermeasures for inactivating or bypassing OSR. The main focus of this review is how the human tumor-associated Epstein-Barr virus manipulates the host polycomb group protein system to control - by epigenetic repression of transcription - key components of the OSR during the transformation of normal human B cells into permanent cell lines. PMID- 24167521 TI - TNF-Alpha Inhibitors for Chronic Urticaria: Experience in 20 Patients. AB - Patients with severe chronic urticaria may not respond to antihistamines, and other systemic treatment options may either be ineffective or associated with unacceptable side effects. We present data on efficacy and safety of adalimumab and etanercept in 20 adult patients with chronic urticaria. Twelve (60%) patients obtained complete or almost complete resolution of urticaria after onset of therapy with either adalimumab or etanercept. Further three patients (15%) experienced partial response. Duration of treatment ranged between 2 and 39 months. Those responding completely or almost completely had a durable response with a mean of 11 months. Six patients (30%) experienced side effects and five patients had mild recurrent upper respiratory infections, whereas one patient experienced severe CNS toxicity that could be related to treatment with TNF-alpha inhibitor. Adalimumab and etanercept may be effective and relatively safe treatment options in a significant proportion of patients with chronic urticaria who do not respond sufficiently to high-dose antihistamines or in whom standard immunosuppressive drugs are ineffective or associated with unacceptable side effects. PMID- 24167522 TI - The subjective understanding of guideline recommendations and of the risks of the side effects of medication. PMID- 24167523 TI - Study of perceptions of the extent to which guideline recommendations are binding: a survey of commonly used terminology. AB - BACKGROUND: Doctors are more likely to implement guidelines in their everyday practice if the recommendations contained in them are understandable. So far, there has been little standardization in the wording of guideline recommendations. It would be important to know how certain terms are understood by guideline users. In this study, doctors were asked in a survey about what they considered to be the level of obligation carried by various formulations that are commonly used in guidelines to recommend particular courses of action. METHODS: An online survey of physicians (mostly dermatologists) was carried out in which they were asked to rate, on a visual analog scale, what they perceived to be the level of obligation of various common formulations for guideline recommendations. RESULTS: The terms "muss" (must) and "darf nicht" (must not) were interpreted as being maximally binding. The two closely related German words "soll" (shall) and "sollte" (should) were considered highly binding, as were negative formulations such as "wird nicht empfohlen" (is not recommended). The perceived level of obligation of "soll" did not differ from that of "sollte" to any detectable extent, nor was there any detectable distinction between the various negative formulations studied. Formulations with the words "wird empfohlen" (is recommended), "kann empfohlen werden" (can be recommended), or other "kann" (can) expressions were considered to be only mildly or moderately binding. In general, there was marked variation in the perceived level of obligation of formulations located in the low and middle ranges. CONCLUSION: These findings suggest that guideline users do not necessarily perceive recommendation strengths as the guideline authors intended. It might be better if positive recommendations came in only two different strengths, while a single recommendation strength might suffice for negative ones. Further studies should shed more light on this question. PMID- 24167524 TI - Comprehension of the description of side effects in drug information leaflets: a survey of doctors, pharmacists and lawyers. AB - BACKGROUND: The German Federal Institute for Drugs and Medical Devices (Bundesinstitut fur Arzneimittel und Medizinprodukte, BfArM) states that it uses standardized terms to describe the probabilities of side effects in drug information leaflets. It is unclear, however, whether these terms are actually understood correctly by doctors, pharmacists, and lawyers. METHODS: A total of 1000 doctors, pharmacists, and lawyers were questioned by mail, and 60.4% of the questionnaires were filled out and returned. In the absence of any particular, potentially suggestive context, the respondents were asked to give a numerical interpretation of each of 20 verbal expressions of probability. Side effects were the subject of a hypothetical physician-patient case scenario. The respondents were also asked to give percentages that they felt corresponded to the terms "common," "uncommon," and "rare." The values obtained were compared with the intended values of the BfArM. RESULTS: The results obtained from the three professional groups resembled each other but stood in marked contrast to the BfArM definitions. With respect to side effects, the pharmacists matched the BfArM definitions most closely (5.8% "common," 1.9% "uncommon" and "rare"), followed by the physicians (3.5%, 0.3%, 0.9%) and the lawyers (0.7%, 0%, 0.7%). When the context of the side effects was not mentioned, the degree of agreement was much lower. CONCLUSION: Statements about the frequency of side effects are found in all drug information leaflets. Only a small minority of the respondents correctly stated the meaning of terms that are used to describe the frequency of occurrence of side effects, even though they routinely have to convey probabilities of side effects in the course of their professional duties. It can be concluded that the BfArM definitions of these terms do not, in general, correspond to their meanings in ordinary language. PMID- 24167525 TI - Adverse drug events in older patients admitted as an emergency: the role of potentially inappropriate medication in elderly people (PRISCUS). Study design. PMID- 24167526 TI - In reply. PMID- 24167527 TI - Klinefelter syndrome: the commonest form of hypogonadism, but often overlooked or untreated. Psychological and neurological problems. PMID- 24167528 TI - Klinefelter syndrome: the commonest form of hypogonadism, but often overlooked or untreated. Cardiological disorders. PMID- 24167529 TI - In reply. PMID- 24167530 TI - One-year evaluation of a neonatal screening program for cystic fibrosis in Switzerland. Problems. PMID- 24167531 TI - In reply. PMID- 24167532 TI - Health in the long-term unemployed. Higher risk of obesity. PMID- 24167533 TI - In reply. PMID- 24167534 TI - Clinical performance of a new biomimetic double network material. AB - BACKGROUND: The development of ceramics during the last years was overwhelming. However, the focus was laid on the hardness and the strength of the restorative materials, resulting in high antagonistic tooth wear. This is critical for patients with bruxism. OBJECTIVES: The purpose of this study was to evaluate the clinical performance of the new double hybrid material for non-invasive treatment approaches. MATERIAL AND METHODS: The new approach of the material tested, was to modify ceramics to create a biomimetic material that has similar physical properties like dentin and enamel and is still as strong as conventional ceramics. RESULTS: The produced crowns had a thickness ranging from 0.5 to 1.5 mm. To evaluate the clinical performance and durability of the crowns, the patient was examined half a year later. The crowns were still intact and soft tissues appeared healthy and this was achieved without any loss of tooth structure. CONCLUSIONS: The material can be milled to thin layers, but is still strong enough to prevent cracks which are stopped by the interpenetrating polymer within the network. Depending on the clinical situation, minimally- up to non invasive restorations can be milled. CLINICAL RELEVANCE: Dentistry aims in preservation of tooth structure. Patients suffering from loss of tooth structure (dental erosion, Amelogenesis imperfecta) or even young patients could benefit from minimally-invasive crowns. Due to a Vickers hardness between dentin and enamel, antagonistic tooth wear is very low. This might be interesting for treating patients with bruxism. PMID- 24167535 TI - Long term water storage deteriorates bonding of composite resin to alumina and zirconia short communication. AB - Objective of this study was to evaluate the effects of long term water storage and ageing on the bond strength of resin composite cement to yttria-stabilized zirconium dioxide (zirconia) and dialuminium trioxide (alumina). Substrate specimens of alumina and zirconia were air particle abraded with dialuminium trioxide before priming and application of composite resin. Priming was made with gamma metharyloxy-trimethoxysilane or acryloxypropyl-trimethoxysilane monomer after which the intermediate dimethacrylate resin was applied and photopolymerized. This was followed by curing particulate composite resin cement (Relyx ARC) to the substrate as a resin stub. The ageing methods of the specimens (n=6) were: (1) they stored four years in 37+/-1oC distilled water, (2) thermocycled 8000 times between 55+/-1oC and 5+/-1oC, (3) stored first in water for four years and then thermocycled. Specimens which were stored dry, were used as controls. Bonding of composite resin was measured by shear-bond strength test set-up. Both thermocycling and long-term water storage decreased significantly shear bond strength values compared to the control group (from the level of 20 MPa to 5 MPa) regardless of the used primer or the type of the substrate. Combination of four years water storage and thermocyling reduced the bond strength even more, to the level of two to three megapascals. In can be concluded that water storage and thermocycling itselves, and especially combination of water storage and thermocycling can cause considerable reduction in the bond strength of composite resin cement to alumina and zirconia. PMID- 24167536 TI - The effect of surface roughness on repair bond strength of light-curing composite resin to polymer composite substrate. AB - OBJECTIVE: The purpose of this study was to analyze the shear bond strength of a new composite resin to polymer-based composite substrates using various surface roughnesses and two kinds of polymer matrices. MATERIALS AND METHODS: Particulate filler composite resin with cross-linked polymer matrix and fiber-reinforced composite with semi-interpenetrating polymer matrix were used as bonding substrates after being ground to different roughnesses. Substrates were aged in water for one week before bonding to new resin composites. Twelve specimens in the substrate groups were ground with grinding papers of four grits; 320, 800, 1200 and 2400. RESULTS: Corresponding values of surface roughness (Ra) varied from 0.09 to 0.40 for the particulate filler composite resin and 0.07 to 0.96 for the fiber-reinforced composite resin. Characteristic shear bond strength between the new resin and particulate filler composite resin was highest (27.8 MPa) with the roughest surface (Weibull modulus: 2.085). Fiber-reinforced composite showed the highest bond strength (20.8 MPa) with the smoothest surface (Weibull modulus: 4.713). CONCLUSIONS: We concluded that surface roughness did not increase the bonding of new resin to the substrate of IPN based fiber-reinforced composite, whereas the roughness contributed to bonding the new resin to the particulate filler composite resin with a cross-linked polymer matrix. PMID- 24167537 TI - Vocation, friendship and resilience: a study exploring nursing student and staff views on retention and attrition. AB - INTRODUCTION: There is international concern about retention of student nurses on undergraduate programmes. United Kingdom Higher Education Institutions are monitored on their attrition statistics and can be penalised financially, so they have an incentive to help students remain on their programmes beyond their moral duty to ensure students receive the best possible educational experience. AIMS: to understand students' and staff concerns about programmes and placements as part of developing our retention strategies. DESIGN: This study reports qualitative data on retention and attrition collected as part of an action research study. SETTING: One University School of Nursing and Midwifery in the South West of England. PARTICIPANTS: Staff, current third year and ex-student nurses from the adult field. METHODS: Data were collected in focus groups, both face-to face and virtual, and individual telephone interviews. These were transcribed and subjected to qualitative content analysis. RESULTS: FOUR THEMES EMERGED: Academic support, Placements and mentors, Stresses and the reality of nursing life, and Dreams for a better programme. CONCLUSIONS: The themes Academic support, Placements and mentors and Stresses and the reality of nursing life, resonate with international literature. Dreams for a better programme included smaller group learning. Vocation, friendship and resilience seem instrumental in retaining students, and Higher Education Institutions should work to facilitate these. 'Vocation' has been overlooked in the retention discussions, and working more actively to foster vocation and belongingness could be important. PMID- 24167538 TI - Discharge planning in chronic conditions: an evidence-based analysis. AB - BACKGROUND: Chronically ill people experience frequent changes in health status accompanied by multiple transitions between care settings and care providers. Discharge planning provides support services, follow-up activities, and other interventions that span pre-hospital discharge to post-hospital settings. OBJECTIVE: To determine if discharge planning is effective at reducing health resource utilization and improving patient outcomes compared with standard care alone. DATA SOURCES: A standard systematic literature search was conducted for studies published from January 1, 2004, until December 13, 2011. REVIEW METHODS: Reports, randomized controlled trials, systematic reviews, and meta-analyses with 1 month or more of follow-up and limited to specified chronic conditions were examined. Outcomes included mortality/survival, readmissions and emergency department (ED) visits, hospital length of stay (LOS), health-related quality of life (HRQOL), and patient satisfaction. RESULTS: One meta-analysis compared individualized discharge planning to usual care and found a significant reduction in readmissions favouring individualized discharge planning. A second meta analysis compared comprehensive discharge planning with postdischarge support to usual care. There was a significant reduction in readmissions favouring discharge planning with postdischarge support. However, there was significant statistical heterogeneity. For both meta-analyses there was a nonsignificant reduction in mortality between the study arms. LIMITATIONS: There was difficulty in distinguishing the relative contribution of each element within the terms "discharge planning" and "postdischarge support." For most studies, "usual care" was not explicitly described. CONCLUSIONS: Compared with usual care, there was moderate quality evidence that individualized discharge planning is more effective at reducing readmissions or hospital LOS but not mortality, and very low quality evidence that it is more effective at improving HRQOL or patient satisfaction. Compared with usual care, there was low quality evidence that the discharge planning plus postdischarge support is more effective at reducing readmissions but not more effective at reducing hospital LOS or mortality. There was very low quality evidence that it is more effective at improving HRQOL or patient satisfaction. PMID- 24167539 TI - In-home care for optimizing chronic disease management in the community: an evidence-based analysis. AB - BACKGROUND: The emerging attention on in-home care in Canada assumes that chronic disease management will be optimized if it takes place in the community as opposed to the health care setting. Both the patient and the health care system will benefit, the latter in terms of cost savings. OBJECTIVES: To compare the effectiveness of care delivered in the home (i.e., in-home care) with no home care or with usual care/care received outside of the home (e.g., health care setting). DATA SOURCES: A literature search was performed on January 25, 2012, using OVID MEDLINE, OVID MEDLINE In-Process and Other Non-Indexed Citations, OVID EMBASE, EBSCO Cumulative Index to Nursing & Allied Health Literature (CINAHL), the Wiley Cochrane Library, and the Centre for Reviews and Dissemination database, for studies published from January 1, 2006, until January 25, 2012. REVIEW METHODS: An evidence-based analysis examined whether there is a difference in mortality, hospital utilization, health-related quality of life (HRQOL), functional status, and disease-specific clinical measures for in-home care compared with no home care for heart failure, atrial fibrillation, coronary artery disease, stroke, chronic obstructive pulmonary disease, diabetes, chronic wounds, and chronic disease / multimorbidity. Data was abstracted and analyzed in a pooled analysis using Review Manager. When needed, subgroup analysis was performed to address heterogeneity. The quality of evidence was assessed by GRADE. RESULTS: The systematic literature search identified 1,277 citations from which 12 randomized controlled trials met the study criteria. Based on these, a 12% reduced risk for in-home care was shown for the outcome measure of combined events including all-cause mortality and hospitalizations (relative risk [RR]: 0.88; 95% CI: 0.80-0.97). Patients receiving in-home care had an average of 1 less unplanned hospitalization (mean difference [MD]: -1.03; 95% CI: -1.53 to 0.53) and an average of 1 less emergency department (ED) visit (MD: -1.32; 95% CI: -1.87 to -0.77). A beneficial effect of in-home care was also shown on activities of daily living (MD: -0.14; 95% CI: -0.27 to -0.01), including less difficulty dressing above the waist or below the waist, grooming, bathing/showering, toileting, and feeding. These results were based on moderate quality of evidence. Additional beneficial effects of in-home care were shown for HRQOL although this was based on low quality of evidence. LIMITATIONS: Different characterization of outcome measures across studies prevented the inclusion of all eligible studies for analysis. CONCLUSIONS: In summary, education-based in home care is effective at improving outcomes of patients with a range of heart disease severity when delivered by nurses during a single home visit or on an ongoing basis. In-home visits by occupational therapists and physical therapists targeting modification of tasks and the home environment improved functional activities for community-living adults with chronic disease. PMID- 24167540 TI - Continuity of care to optimize chronic disease management in the community setting: an evidence-based analysis. AB - BACKGROUND: This evidence-based analysis reviews relational and management continuity of care. Relational continuity refers to the duration and quality of the relationship between the care provider and the patient. Management continuity ensures that patients receive coherent, complementary, and timely care. There are 4 components of continuity of care: duration, density, dispersion, and sequence. OBJECTIVE: The objective of this evidence-based analysis was to determine if continuity of care is associated with decreased health resource utilization, improved patient outcomes, and patient satisfaction. DATA SOURCES: MEDLINE, EMBASE, CINAHL, the Cochrane Library, and the Centre for Reviews and Dissemination database were searched for studies on continuity of care and chronic disease published from January 2002 until December 2011. REVIEW METHODS: Systematic reviews, randomized controlled trials, and observational studies were eligible if they assessed continuity of care in adults and reported health resource utilization, patient outcomes, or patient satisfaction. RESULTS: Eight systematic reviews and 13 observational studies were identified. The reviews concluded that there is an association between continuity of care and outcomes; however, the literature base is weak. The observational studies found that higher continuity of care was frequently associated with fewer hospitalizations and emergency department visits. Three systematic reviews reported that higher continuity of care is associated with improved patient satisfaction, especially among patients with chronic conditions. LIMITATIONS: Most of the studies were retrospective cross-sectional studies of large administrative databases. The databases do not capture information on trust and confidence in the provider, which is a critical component of relational continuity of care. The definitions for the selection of patients from the databases varied across studies. CONCLUSIONS: There is low quality evidence that: Higher continuity of care is associated with decreased health service utilization.There is insufficient evidence on the relationship of continuity of care with disease-specific outcomes.There is an association between high continuity of care and patient satisfaction, particularly among patients with chronic diseases. PMID- 24167542 TI - Interior-point methods for estimating seasonal parameters in discrete-time infectious disease models. AB - Infectious diseases remain a significant health concern around the world. Mathematical modeling of these diseases can help us understand their dynamics and develop more effective control strategies. In this work, we show the capabilities of interior-point methods and nonlinear programming (NLP) formulations to efficiently estimate parameters in multiple discrete-time disease models using measles case count data from three cities. These models include multiplicative measurement noise and incorporate seasonality into multiple model parameters. Our results show that nearly identical patterns are estimated even when assuming seasonality in different model parameters, and that these patterns show strong correlation to school term holidays across very different social settings and holiday schedules. We show that interior-point methods provide a fast and flexible approach to parameterizing models that can be an alternative to more computationally intensive methods. PMID- 24167543 TI - Proteomic analysis of the low mutation rate of diploid male gametes induced by colchicine in Ginkgo biloba L. AB - Colchicine treatment of G. biloba microsporocytes results in a low mutation rate in the diploid (2n) male gamete. The mutation rate is significantly lower as compared to other tree species and impedes the breeding of new economic varieties. Proteomic analysis was done to identify the proteins that influence the process of 2n gamete formation in G. biloba. The microsporangia of G. biloba were treated with colchicine solution for 48 h and the proteins were analyzed using 2-D gel electrophoresis and compared to protein profiles of untreated microsporangia. A total of 66 proteins showed difference in expression levels. Twenty-seven of these proteins were identified by mass spectrometry. Among the 27 proteins, 14 were found to be up-regulated and the rest 13 were down-regulated. The identified proteins belonged to five different functional classes: ATP generation, transport and carbohydrate metabolism; protein metabolism; ROS scavenging and detoxifying enzymes; cell wall remodeling and metabolism; transcription, cell cycle and signal transduction. The identification of these differentially expressed proteins and their function could help in analysing the mechanism of lower mutation rate of diploid male gamete when the microsporangium of G. biloba was induced by colchicine. PMID- 24167544 TI - Transient Inhibition of FGFR2b-ligands signaling leads to irreversible loss of cellular beta-catenin organization and signaling in AER during mouse limb development. AB - The vertebrate limbs develop through coordinated series of inductive, growth and patterning events. Fibroblast Growth Factor receptor 2b (FGFR2b) signaling controls the induction of the Apical Ectodermal Ridge (AER) but its putative roles in limb outgrowth and patterning, as well as in AER morphology and cell behavior have remained unclear. We have investigated these roles through graded and reversible expression of soluble dominant-negative FGFR2b molecules at various times during mouse limb development, using a doxycycline/transactivator/tet(O)-responsive system. Transient attenuation (<= 24 hours) of FGFR2b-ligands signaling at E8.5, prior to limb bud induction, leads mostly to the loss or truncation of proximal skeletal elements with less severe impact on distal elements. Attenuation from E9.5 onwards, however, has an irreversible effect on the stability of the AER, resulting in a progressive loss of distal limb skeletal elements. The primary consequences of FGFR2b-ligands attenuation is a transient loss of cell adhesion and down-regulation of P63, beta1-integrin and E-cadherin, and a permanent loss of cellular beta-catenin organization and WNT signaling within the AER. Combined, these effects lead to the progressive transformation of the AER cells from pluristratified to squamous epithelial-like cells within 24 hours of doxycycline administration. These findings show that FGFR2b-ligands signaling has critical stage-specific roles in maintaining the AER during limb development. PMID- 24167545 TI - Association between serum ferritin and osteocalcin as a potential mechanism explaining the iron-induced insulin resistance. AB - BACKGROUND: Increased iron stores are associated with increased risk of type 2 diabetes, however, the mechanisms underlying these associations are poorly understood. Because a reduction of circulating osteocalcin levels after iron overload have been demonstrated in cell cultures, and osteocalcin is related to glucose and insulin metabolism, the iron-induced osteocalcin reductions could contribute to explain the role of iron metabolism in the development of type 2 diabetes mellitus. OBJECTIVE: To analyzed the associations between serum total and uncarboxylated osteocalcin and adiponectin concentrations with serum ferritin and soluble transferrin receptor (sTfR) in elderly subjects. DESIGN: We evaluated a total of 423 subjects from the PREDIMED cohort in a population-based cross sectional analysis. Extensive clinical, nutritional and laboratory measurements, including total and uncarboxylated osteocalcin, adiponectin, ferritin and sTfR were recorded. RESULTS: Serum ferritin was positively correlated with increased glucose and insulin circulating levels but also with HOMA-IR, and was inversely associated with total osteocalcin and adiponectin. A regression analysis revealed that serum ferritin and transferrin receptor levels were significantly associated with a decrease in total and uncarboxylated osteocalcin. Serum sTfR levels were associated with lower uncarboxylated osteocalcin levels in the whole-study subjects and remained significant only in the IFG (impaired fasting glucose) individuals. CONCLUSIONS: We described, for the first time, an inverse association between serum ferritin and sTfR with osteocalcin and extend previous results on adiponectin, thus supporting that factors related to iron metabolism could contribute to the insulin resistance and the development of type 2 diabetes mellitus. TRIAL REGISTRATION: Controlled-Trials.com ISRCTN35739639 . PMID- 24167546 TI - Systolic peak detection in acceleration photoplethysmograms measured from emergency responders in tropical conditions. AB - Photoplethysmogram (PPG) monitoring is not only essential for critically ill patients in hospitals or at home, but also for those undergoing exercise testing. However, processing PPG signals measured after exercise is challenging, especially if the environment is hot and humid. In this paper, we propose a novel algorithm that can detect systolic peaks under challenging conditions, as in the case of emergency responders in tropical conditions. Accurate systolic-peak detection is an important first step for the analysis of heart rate variability. Algorithms based on local maxima-minima, first-derivative, and slope sum are evaluated, and a new algorithm is introduced to improve the detection rate. With 40 healthy subjects, the new algorithm demonstrates the highest overall detection accuracy (99.84% sensitivity, 99.89% positive predictivity). Existing algorithms, such as Billauer's, Li's and Zong's, have comparable although lower accuracy. However, the proposed algorithm presents an advantage for real-time applications by avoiding human intervention in threshold determination. For best performance, we show that a combination of two event-related moving averages with an offset threshold has an advantage in detecting systolic peaks, even in heat-stressed PPG signals. PMID- 24167547 TI - Evaluation [corrected] of the "Iceberg Phenomenon" in Johne's disease through mathematical modelling. AB - Johne's disease (JD) is a chronic, enteric disease in ruminants caused by Mycobacterium avium subsp. paratuberculosis (MAP). Disease progression follows four distinct stages: silent, subclinical, clinical and advanced. Available diagnostic tests have poor sensitivity and cannot detect early stages of the infection; as a result, only animals in the clinical and advanced stages, which represent the tip of the 'iceberg', are identified through testing. The Iceberg Phenomenon is then applied to provide estimates for JD prevalence. For one animal in the advanced stage, it is assumed that there are one to two in the clinical stage, four to eight in the subclinical stage, and ten to fourteen in the silent stage. These ratios, however, are based on little evidence. To evaluate the ratios, we developed a deterministic ordinary differential equation model of JD transmission and disease progression dynamics. When duration periods associated with the natural course of the disease progression are used, the above ratios do not hold. The ratios used to estimate JD prevalence need to be further investigated. PMID- 24167548 TI - Ultradeep 16S rRNA sequencing analysis of geographically similar but diverse unexplored marine samples reveal varied bacterial community composition. AB - BACKGROUND: Bacterial community composition in the marine environment differs from one geographical location to another. Reports that delineate the bacterial diversity of different marine samples from geographically similar location are limited. The present study aims to understand whether the bacterial community compositions from different marine samples harbour similar bacterial diversity since these are geographically related to each other. METHODS AND PRINCIPAL FINDINGS: In the present study, 16S rRNA deep sequencing analysis targeting V3 region was performed using Illumina bar coded sequencing. A total of 22.44 million paired end reads were obtained from the metagenomic DNA of Marine sediment, Rhizosphere sediment, Seawater and the epibacterial DNA of Seaweed and Seagrass. Diversity index analysis revealed that Marine sediment has the highest bacterial diversity and the least bacterial diversity was observed in Rhizosphere sediment. Proteobacteria, Actinobacteria and Bacteroidetes were the dominant taxa present in all the marine samples. Nearly 62-71% of rare species were identified in all the samples and most of these rare species were unique to a particular sample. Further taxonomic assignment at the phylum and genus level revealed that the bacterial community compositions differ among the samples. CONCLUSION: This is the first report that supports the fact that, bacterial community composition is specific for specific samples irrespective of its similar geographical location. Existence of specific bacterial community for each sample may drive overall difference in bacterial structural composition of each sample. Further studies like whole metagenomic sequencing will throw more insights to the key stone players and its interconnecting metabolic pathways. In addition, this is one of the very few reports that depicts the unexplored bacterial diversity of marine samples (Marine sediment, Rhizosphere sediment, Seawater) and the host associated marine samples (Seaweed and Seagrass) at higher depths from uncharacterised coastal region of Palk Bay, India using next generation sequencing technology. PMID- 24167549 TI - A molecular evolution approach to study the roles of tropomyosin in fission yeast. AB - Tropomyosin, a coiled-coil protein that binds along the length of the actin filament, is a universal regulator of the actin cytoskeleton. We have taken a bioinformatics/proteomic approach to studying structure-function relationships in this protein. The presence of a single, essential tropomyosin gene, cdc8, in fission yeast, Schizosaccharomyces pombe, enables a systems-based approach to define the residues that are important for cellular functions. Using molecular evolution methodologies we identified the most conserved residues and related them to the coiled coil structure. Mutants in which one or more of 21 of the most conserved surface residues was mutated to Ala were tested for the ability to rescue growth of a temperature-sensitive cdc8 mutant when overexpressed at the restrictive temperature. Based on altered morphology of the septum and actin cytoskeleton, we selected three sets of mutations for construction of mutant cdc8 strains using marker reconstitution mutagenesis and analysis of recombinant protein in vitro: D16A.K30A, V114S.E117A.H118A and R121A.D131A.E138A. The mutations have sequence-specific effects on cellular morphology including cell length, organization of cytoskeletal structures (actin patches, actin cables and contractile rings), and in vitro actin affinity, lending credence to the proteomic approach introduced here. We propose that bioinformatics is a valid analysis tool for defining structure-function relationships in conserved proteins in this model organism. PMID- 24167551 TI - GRAPES: a software for parallel searching on biological graphs targeting multi core architectures. AB - Biological applications, from genomics to ecology, deal with graphs that represents the structure of interactions. Analyzing such data requires searching for subgraphs in collections of graphs. This task is computationally expensive. Even though multicore architectures, from commodity computers to more advanced symmetric multiprocessing (SMP), offer scalable computing power, currently published software implementations for indexing and graph matching are fundamentally sequential. As a consequence, such software implementations (i) do not fully exploit available parallel computing power and (ii) they do not scale with respect to the size of graphs in the database. We present GRAPES, software for parallel searching on databases of large biological graphs. GRAPES implements a parallel version of well-established graph searching algorithms, and introduces new strategies which naturally lead to a faster parallel searching system especially for large graphs. GRAPES decomposes graphs into subcomponents that can be efficiently searched in parallel. We show the performance of GRAPES on representative biological datasets containing antiviral chemical compounds, DNA, RNA, proteins, protein contact maps and protein interactions networks. PMID- 24167550 TI - Natural killer T cells in advanced melanoma patients treated with tremelimumab. AB - A significant barrier to effective immune clearance of cancer is loss of antitumor cytotoxic T cell activity. Antibodies to block pro apoptotic/downmodulatory signals to T cells are currently being tested. Because invariant natural killer T cells (iNKT) can regulate the balance of Th1/Th2 cellular immune responses, we characterized the frequencies of circulating iNKT cell subsets in 21 patients with melanoma who received the anti-CTLA4 monoclonal antibody tremelimumab alone and 8 patients who received the antibody in combination with MART-126-35 peptide-pulsed dendritic cells (MART-1/DC). Blood T cell phenotypes and functionality were characterized by flow cytometry before and after treatment. iNKT cells exhibited the central memory phenotype and showed polyfunctional cytokine production. In the combination treatment group, high frequencies of pro-inflammatory Th1 iNKT CD8(+) cells correlated with positive clinical responses. These results indicate that iNKT cells play a critical role in regulating effective antitumor T cell activity. PMID- 24167552 TI - Quantitative changes in the sleep EEG at moderate altitude (1630 m and 2590 m). AB - BACKGROUND: Previous studies have observed an altitude-dependent increase in central apneas and a shift towards lighter sleep at altitudes >4000 m. Whether altitude-dependent changes in the sleep EEG are also prevalent at moderate altitudes of 1600 m and 2600 m remains largely unknown. Furthermore, the relationship between sleep EEG variables and central apneas and oxygen saturation are of great interest to understand the impact of hypoxia at moderate altitude on sleep. METHODS: Fourty-four healthy men (mean age 25.0 +/- 5.5 years) underwent polysomnographic recordings during a baseline night at 490 m and four consecutive nights at 1630 m and 2590 m (two nights each) in a randomized cross-over design. RESULTS: Comparison of sleep EEG power density spectra of frontal (F3A2) and central (C3A2) derivations at altitudes compared to baseline revealed that slow wave activity (SWA, 0.8-4.6 Hz) in non-REM sleep was reduced in an altitude dependent manner (~4% at 1630 m and 15% at 2590 m), while theta activity (4.6-8 Hz) was reduced only at the highest altitude (10% at 2590 m). In addition, spindle peak height and frequency showed a modest increase in the second night at 2590 m. SWA and theta activity were also reduced in REM sleep. Correlations between spectral power and central apnea/hypopnea index (AHI), oxygen desaturation index (ODI), and oxygen saturation revealed that distinct frequency bands were correlated with oxygen saturation (6.4-8 Hz and 13-14.4 Hz) and breathing variables (AHI, ODI; 0.8-4.6 Hz). CONCLUSIONS: The correlation between SWA and AHI/ODI suggests that respiratory disturbances contribute to the reduction in SWA at altitude. Since SWA is a marker of sleep homeostasis, this might be indicative of an inability to efficiently dissipate sleep pressure. PMID- 24167553 TI - Functional analysis of deep intronic SNP rs13438494 in intron 24 of PCLO gene. AB - The single nucleotide polymorphism (SNP) rs13438494 in intron 24 of PCLO was significantly associated with bipolar disorder in a meta-analysis of genome-wide association studies. In this study, we performed functional minigene analysis and bioinformatics prediction of splicing regulatory sequences to characterize the deep intronic SNP rs13438494. We constructed minigenes with A and C alleles containing exon 24, intron 24, and exon 25 of PCLO to assess the genetic effect of rs13438494 on splicing. We found that the C allele of rs13438494 reduces the splicing efficiency of the PCLO minigene. In addition, prediction analysis of enhancer/silencer motifs using the Human Splice Finder web tool indicated that rs13438494 induces the abrogation or creation of such binding sites. Our results indicate that rs13438494 alters splicing efficiency by creating or disrupting a splicing motif, which functions by binding of splicing regulatory proteins, and may ultimately result in bipolar disorder in affected people. PMID- 24167555 TI - Long-term environmental correlates of invasion by Lantana camara (Verbenaceae) in a seasonally dry tropical forest. AB - Invasive species, local plant communities and invaded ecosystems change over space and time. Quantifying this change may lead to a better understanding of the ecology and the effective management of invasive species. We used data on density of the highly invasive shrub Lantana camara (lantana) for the period 1990-2008 from a 50 ha permanent plot in a seasonally dry tropical forest of Mudumalai in southern India. We used a cumulative link mixed-effects regression approach to model the transition of lantana from one qualitative density state to another as a function of biotic factors such as indicators of competition from local species (lantana itself, perennial grasses, invasive Chromolaena odorata, the native shrub Helicteres isora and basal area of native trees) and abiotic factors such as fire frequency, inter-annual variability of rainfall and relative soil moisture. The density of lantana increased substantially during the study period. Lantana density was negatively associated with the density of H. isora, positively associated with basal area of native trees, but not affected by the presence of grasses or other invasive species. In the absence of fire, lantana density increased with increasing rainfall. When fires occurred, transitions to higher densities occurred at low rainfall values. In drier regions, lantana changed from low to high density as rainfall increased while in wetter regions of the plot, lantana persisted in the dense category irrespective of rainfall. Lantana seems to effectively utilize resources distributed in space and time to its advantage, thus outcompeting local species and maintaining a population that is not yet self-limiting. High-risk areas and years could potentially be identified based on inferences from this study for facilitating management of lantana in tropical dry forests. PMID- 24167554 TI - MicroRNA profiling in prostate cancer--the diagnostic potential of urinary miR 205 and miR-214. AB - Prostate cancer (PCa) is the most common type of cancer in men in the United States, which disproportionately affects African American descents. While metastasis is the most common cause of death among PCa patients, no specific markers have been assigned to severity and ethnic biasness of the disease. MicroRNAs represent a promising new class of biomarkers owing to their inherent stability and resilience. In the present study, we investigated potential miRNAs that can be used as biomarkers and/or therapeutic targets and can provide insight into the severity and ethnic biasness of PCa. PCR array was performed in FFPE PCa tissues (5 Caucasian American and 5 African American) and selected differentially expressed miRNAs were validated by qRT-PCR, in 40 (15 CA and 25 AA) paired PCa and adjacent normal tissues. Significantly deregulated miRNAs were also analyzed in urine samples to explore their potential as non-invasive biomarker for PCa. Out of 8 miRNAs selected for validation from PCR array data, miR-205 (p<0.0001), mir-214 (p<0.0001), miR-221(p<0.001) and miR-99b (p<0.0001) were significantly downregulated in PCa tissues. ROC curve shows that all four miRNAs successfully discriminated between PCa and adjacent normal tissues. MiR-99b showed significant down regulation (p<0.01) in AA PCa tissues as compared to CA PCa tissues and might be related to the aggressiveness associated with AA population. In urine, miR-205 (p<0.05) and miR-214 (p<0.05) were significantly downregulated in PCa patients and can discriminate PCa patients from healthy individuals with 89% sensitivity and 80% specificity. In conclusion, present study showed that miR-205 and miR-214 are downregulated in PCa and may serve as potential non-invasive molecular biomarker for PCa. PMID- 24167556 TI - High cryptic diversity across the global range of the migratory planktonic copepods Pleuromamma piseki and P. gracilis. AB - Although holoplankton are ocean drifters and exhibit high dispersal potential, a number of studies on single species are finding highly divergent genetic clades. These cryptic species complexes are important to discover and describe, as identification of common marine species is fundamental to understanding ecosystem dynamics. Here we investigate the global diversity within Pleuromamma piseki and P. gracilis, two dominant members of the migratory zooplankton assemblage in subtropical and tropical waters worldwide. Using DNA sequence data from the mitochondrial gene cytochrome c oxidase subunit II (mtCOII) from 522 specimens collected across the Pacific, Atlantic and Indian Oceans, we discover twelve well resolved genetically distinct clades in this species complex (Bayesian posterior probabilities >0.7; 6.3-17% genetic divergence between clades). The morphologically described species P. piseki and P. gracilis did not form monophyletic groups, rather they were distributed throughout the phylogeny and sometimes co-occurred within well-resolved clades: this result suggests that morphological characters currently used for taxonomic identification of P. gracilis and P. piseki may be inaccurate as indicators of species' boundaries. Cryptic clades within the species complex ranged from being common to rare, and from cosmopolitan to highly restricted in distribution across the global ocean. These novel lineages appear to be ecologically divergent, with distinct biogeographic distributions across varied pelagic habitats. We hypothesize that these mtDNA lineages are distinct species and suggest that resolving their systematic status is important, given the ecological significance of the genus Pleuromamma in subtropical-tropical waters worldwide. PMID- 24167557 TI - Spatial structure facilitates cooperation in a social dilemma: empirical evidence from a bacterial community. AB - Cooperative organisms are ubiquitous in nature, despite their vulnerability to exploitation by cheaters. Although numerous theoretical studies suggest that spatial structure is critical for cooperation to persist, the spatial ecology of microbial cooperation remains largely unexplored experimentally. By tracking the community dynamics of cooperating (rpoS wild-type) and cheating (rpoS mutant) Escherichia coli in well-mixed flasks and microfabricated habitats, we demonstrate that spatial structure stabilizes coexistence between wild-type and mutant and thus facilitates cooperator maintenance. We develop a method to interpret our experimental results in the context of game theory, and show that the game wild-type and mutant bacteria play in an unstructured environment changes markedly over time, and eventually obeys a prisoner's dilemma leading to cheater dominance. In contrast, when wild-type and mutant E. coli co-inhabit a spatially-structured habitat, cooperators and cheaters coexist at intermediate frequencies. Our findings show that even in microhabitats lacking patchiness or spatial heterogeneities in resource availability, surface growth allows cells to form multi-cellular aggregates, yielding a self-structured community in which cooperators persist. PMID- 24167559 TI - Digital language death. AB - Of the approximately 7,000 languages spoken today, some 2,500 are generally considered endangered. Here we argue that this consensus figure vastly underestimates the danger of digital language death, in that less than 5% of all languages can still ascend to the digital realm. We present evidence of a massive die-off caused by the digital divide. PMID- 24167558 TI - G-CSF prevents progression of diabetic nephropathy in rat. AB - BACKGROUND: The protective effects of granulocyte colony-stimulating factor (G CSF) have been demonstrated in a variety of renal disease models. However, the influence of G-CSF on diabetic nephropathy (DN) remains to be examined. In this study, we investigated the effect of G-CSF on DN and its possible mechanisms in a rat model. METHODS: Otsuka Long-Evans Tokushima Fatty (OLETF) rats with early DN were administered G-CSF or saline intraperitoneally. Urine albumin creatinine ratio (UACR), creatinine clearance, mesangial matrix expansion, glomerular basement membrane (GBM) thickness, and podocyte foot process width (FPW) were measured. The levels of interleukin (IL)-1beta, transforming growth factor (TGF) beta1, and type IV collagen genes expression in kidney tissue were also evaluated. To elucidate the mechanisms underlying G-CSF effects, we also assessed the expression of G-CSF receptor (G-CSFR) in glomeruli as well as mobilization of bone marrow (BM) cells to glomeruli using sex-mismatched BM transplantation. RESULTS: After four weeks of treatment, UACR was lower in the G-CSF treatment group than in the saline group (p<0.05), as were mesangial matrix expansion, GBM thickness, and FPW (p<0.05). In addition, the expression of TGF-beta1 and type IV collagen and IL-1beta levels was lower in the G-CSF treatment group (p<0.05). G CSFR was not present in glomerular cells, and G-CSF treatment increased the number of BM-derived cells in glomeruli (p<0.05). CONCLUSIONS: G-CSF can prevent the progression of DN in OLETF rats and its effects may be due to mobilization of BM cells rather than being a direct effect. PMID- 24167560 TI - Sagittal abdominal diameter is an independent predictor of all-cause and cardiovascular mortality in incident peritoneal dialysis patients. AB - BACKGROUNDS AND AIMS: Visceral fat has a crucial role in the development and progression of cardiovascular disease, the major cause of death in end-stage renal disease (ESRD). Although sagittal abdominal diameter (SAD), as an index of visceral fat, significantly correlated with mortality in the general population, the impact of SAD on clinical outcomes has never been explored in ESRD patients. Therefore, we sought to elucidate the prognostic value of SAD in incident peritoneal dialysis (PD) patients. METHODS: We prospectively determined SAD by lateral abdominal X-ray at PD initiation, and evaluated the association of SAD with all-cause and cardiovascular mortality in 418 incident PD patients. RESULTS: The mean SAD was 24.5 +/- 4.3 cm, and during a mean follow-up of 39.4 months, 97 patients (23.2%) died, and 49.4% of them died due to cardiovascular disease. SAD was a significant independent predictor of all-cause [3rd versus 1st tertile, HR (hazard ratio): 3.333, 95% CI (confidence interval): 1.514-7.388, P = 0.01; per 1 cm increase, HR: 1.071, 95% CI: 1.005-1.141, P = 0.03] and cardiovascular mortality (3rd versus 1st tertile, HR: 8.021, 95% CI: 1.994-32.273, P = 0.01; per 1 cm increase, HR: 1.106, 95% CI: 1.007-1.214, P = 0.03). Multivariate fractional polynomial analysis also showed that all-cause and cardiovascular mortality risk increased steadily with higher SAD values. In addition, SAD provided higher predictive value for all-cause (AUC: 0.691 vs. 0.547, P<0.001) and cardiovascular mortality (AUC: 0.644 vs. 0.483, P<0.001) than body mass index (BMI). Subgroup analysis revealed higher SAD (>= 24.2 cm) was significantly associated with all cause mortality in men, women, younger patients (<65 years), and patients with lower BMI (<22.3 kg/m(2)). CONCLUSIONS: SAD determined by lateral abdominal X-ray at PD initiation was a significant independent predictor of all-cause and cardiovascular mortality in incident PD patients. Estimating visceral fat by SAD could be useful to stratify mortality risk in these patients. PMID- 24167561 TI - Histones-mediated lymphocyte apoptosis during sepsis is dependent on p38 phosphorylation and mitochondrial permeability transition. AB - Lymphocyte apoptosis is one reason for immunoparalysis seen in sepsis, although the triggers are unknown. We hypothesized that molecules in plasma, which are up regulated during sepsis, may be responsible for this. In this study, peripheral lymphocyte apoptosis caused by extracellular histones was confirmed both in mouse and human primary lymphocytes, in which histones induced lymphocyte apoptosis dose-dependently and time-dependently. To identify which intracellular signal pathways were activated, phosphorylation of various mitogen-activated protein kinases (MAPKs) were evaluated during this process, and p38 inhibitor (SB203580) was used to confirm the role of p38 in lymphocyte apoptosis induced by histones. To investigate the mitochondrial injury during these processes, we analyzed Bcl2 degradation and Rhodamine 123 to assess mitochondrial-membrane stability, via cyclosporin A as an inhibitor for mitochondrial permeability transition (MPT). Then, caspase 3 activation was also checked by western-blotting. We found that p38 phosphorylation, mitochondrial injury and caspase 3 activation occurred dose dependently in histones-mediated lymphocyte apoptosis. We also observed that p38 inhibitor SB203580 decreased lymphocyte apoptotic ratio by 49% (P<0.05), and inhibition of MPT protected lymphocytes from apoptosis. Furthermore, to investigate whether histones are responsible for lymphocyte apoptosis, various concentrations of histone H4 neutralization antibodies were co-cultured with human primary lymphocytes and plasma from cecal ligation and puncture (CLP) mice or sham mice. The results showed that H4 neutralization antibody dose-dependently blocked lymphocyte apoptosis caused by septic plasma in vitro. These data demonstrate for the first time that extracellular histones, especially H4, play a vital role in lymphocyte apoptosis during sepsis which is dependent on p38 phosphorylation and mitochondrial permeability transition. Neutralizing H4 can inhibit lymphocyte apoptosis, indicating that it could be a potential target in clinical interventions for sepsis associated immunoparalysis. PMID- 24167562 TI - Stable isotope and signature fatty acid analyses suggest reef manta rays feed on demersal zooplankton. AB - Assessing the trophic role and interaction of an animal is key to understanding its general ecology and dynamics. Conventional techniques used to elucidate diet, such as stomach content analysis, are not suitable for large threatened marine species. Non-lethal sampling combined with biochemical methods provides a practical alternative for investigating the feeding ecology of these species. Stable isotope and signature fatty acid analyses of muscle tissue were used for the first time to examine assimilated diet of the reef manta ray Manta alfredi, and were compared with different zooplankton functional groups (i.e. near-surface zooplankton collected during manta ray feeding events and non-feeding periods, epipelagic zooplankton, demersal zooplankton and several different zooplankton taxa). Stable isotope delta(15)N values confirmed that the reef manta ray is a secondary consumer. This species had relatively high levels of docosahexaenoic acid (DHA) indicating a flagellate-based food source in the diet, which likely reflects feeding on DHA-rich near-surface and epipelagic zooplankton. However, high levels of omega6 polyunsaturated fatty acids and slightly enriched delta(13)C values in reef manta ray tissue suggest that they do not feed solely on pelagic zooplankton, but rather obtain part of their diet from another origin. The closest match was with demersal zooplankton, suggesting it is an important component of the reef manta ray diet. The ability to feed on demersal zooplankton is likely linked to the horizontal and vertical movement patterns of this giant planktivore. These new insights into the habitat use and feeding ecology of the reef manta ray will assist in the effective evaluation of its conservation needs. PMID- 24167563 TI - The influence of sex, stroke and distance on the lactate characteristics in high performance swimming. AB - BACKGROUND: In order to achieve world-class performances, regular performance diagnostics is required as an essential prerequisite for guiding high performance sport. In high performance swimming, the lactate performance diagnostic is an important instrument in testing the sport specific endurance capacity. Although the role of lactate as a signaling molecule, fuel and a gluconeogenic substrate is accepted, lactate parameters are discussed concerning stability, explanatory power and interpretability. METHODS: We calculated the individual anaerobic threshold (IAT) of Bunc using the swimming-specific lactate threshold test by Pansold. RESULTS: The cross-sectional analysis (ANOVA) of n = 398 high performance swimmers showed significant effects for sex, stroke and distance on the IAT, the percentage of personal best time on the IAT (% of PB on IAT) and maximal lactate values (max. bLA). For the freestyle events the IAT decreased, % of PB on IAT and max. bLA increased from 100 to 400 m significantly in men and women. Women showed significantly higher % of PB on IAT with descriptive lower IAT in 7 of 8 analyzed events. Men showed significantly higher max. bLA in 5 of 8 events. In the second step, the analysis of 1902 data sets of these 398 athletes with a multi-level analysis (MLA) showed also significant effects for sex, swimming distance and stroke. For initial status and development over time, the effect sizes for the variables distance and sex were medium to large, whereas for stroke there were no or small effect sizes. DISCUSSION: These significant results suggest that lactate tests in swimming specifically have to consider the lactate affecting factors sex and distance under consideration of the time period between measurements. Anthropometrical factors and the physiology of women are possible explanations for the relative better performance for lower lactate concentrations compared to men. PMID- 24167565 TI - Dominant functional group effects on the invasion resistance at different resource levels. AB - BACKGROUND: Functional group composition may affect invasion in two ways the effect of abundance, i.e. dominance of functional group; and the effect of traits, i.e. identity of functional groups. However, few studies have focused on the role of abundance of functional group on invasion resistance. Moreover, how resource availability influences the role of the dominant functional group in invasion resistance is even less understood. METHODOLOGY/PRINCIPAL FINDINGS: In this experiment, we established experimental pots using four different functional groups (annual grass, perennial grass, deciduous shrub or arbor and evergreen shrub or arbor), and the dominant functional group was manipulated. These experimental pots were respectively constructed at different soil nitrogen levels (control and fertilized). After one year of growth, we added seeds of 20 different species (five species per functional group) to the experimental pots. Fertilization significantly increased the overall invasion success, while dominant functional group had little effect on overall invasion success. When invaders were grouped into functional groups, invaders generally had lower success in pots dominated by the same functional group in the control pots. However, individual invaders of the same functional group exhibited different invasion patterns. Fertilization generally increased success of invaders in pots dominated by the same than by another functional group. However, fertilization led to great differences for individual invaders. CONCLUSIONS/SIGNIFICANCE: The results showed that the dominant functional group, independent of functional group identity, had a significant effect on the composition of invaders. We suggest that the limiting similarity hypothesis may be applicable at the functional group level, and limiting similarity may have a limited role for individual invaders as shown by the inconsistent effects of dominant functional group and fertilization. PMID- 24167564 TI - LRRK2 affects vesicle trafficking, neurotransmitter extracellular level and membrane receptor localization. AB - The leucine-rich repeat kinase 2 (LRRK2) gene was found to play a role in the pathogenesis of both familial and sporadic Parkinson's disease (PD). LRRK2 encodes a large multi-domain protein that is expressed in different tissues. To date, the physiological and pathological functions of LRRK2 are not clearly defined. In this study we have explored the role of LRRK2 in controlling vesicle trafficking in different cellular or animal models and using various readouts. In neuronal cells, the presence of LRRK2(G2019S) pathological mutant determines increased extracellular dopamine levels either under basal conditions or upon nicotine stimulation. Moreover, mutant LRRK2 affects the levels of dopamine receptor D1 on the membrane surface in neuronal cells or animal models. Ultrastructural analysis of PC12-derived cells expressing mutant LRRK2(G2019S) shows an altered intracellular vesicle distribution. Taken together, our results point to the key role of LRRK2 to control vesicle trafficking in neuronal cells. PMID- 24167566 TI - Production of factor VIII by human liver sinusoidal endothelial cells transplanted in immunodeficient uPA mice. AB - Liver sinusoidal endothelial cells (LSECs) form a semi-permeable barrier between parenchymal hepatocytes and the blood. LSECs participate in liver metabolism, clearance of pathological agents, immunological responses, architectural maintenance of the liver and synthesis of growth factors and cytokines. LSECs also play an important role in coagulation through the synthesis of Factor VIII (FVIII). Herein, we phenotypically define human LSECs isolated from fetal liver using flow cytometry and immunofluorescence microscopy. Isolated LSECs were cultured and shown to express endothelial markers and markers specific for the LSEC lineage. LSECs were also shown to engraft the liver when human fetal liver cells were transplanted into immunodeficient mice with liver specific expression of the urokinase-type plasminogen activator (uPA) transgene (uPA-NOG mice). Engrafted cells expressed human Factor VIII at levels approaching those found in human plasma. We also demonstrate engraftment of adult LSECs, as well as hepatocytes, transplanted into uPA-NOG mice. We propose that overexpression of uPA provides beneficial conditions for LSEC engraftment due to elevated expression of the angiogenic cytokine, vascular endothelial growth factor. This work provides a detailed characterization of human midgestation LSECs, thereby providing the means for their purification and culture based on their expression of CD14 and CD32 as well as a lack of CD45 expression. The uPA-NOG mouse is shown to be a permissive host for human LSECs and adult hepatocytes, but not fetal hepatoblasts. Thus, these mice provide a useful model system to study these cell types in vivo. Demonstration of human FVIII production by transplanted LSECs encourages further pursuit of LSEC transplantation as a cellular therapy for the treatment of hemophilia A. PMID- 24167567 TI - Thiopental inhibits global protein synthesis by repression of eukaryotic elongation factor 2 and protects from hypoxic neuronal cell death. AB - Ischemic and traumatic brain injury is associated with increased risk for death and disability. The inhibition of penumbral tissue damage has been recognized as a target for therapeutic intervention, because cellular injury evolves progressively upon ATP-depletion and loss of ion homeostasis. In patients, thiopental is used to treat refractory intracranial hypertension by reducing intracranial pressure and cerebral metabolic demands; however, therapeutic benefits of thiopental-treatment are controversially discussed. In the present study we identified fundamental neuroprotective molecular mechanisms mediated by thiopental. Here we show that thiopental inhibits global protein synthesis, which preserves the intracellular energy metabolite content in oxygen-deprived human neuronal SK-N-SH cells or primary mouse cortical neurons and thus ameliorates hypoxic cell damage. Sensitivity to hypoxic damage was restored by pharmacologic repression of eukaryotic elongation factor 2 kinase. Translational inhibition was mediated by calcium influx, activation of the AMP-activated protein kinase, and inhibitory phosphorylation of eukaryotic elongation factor 2. Our results explain the reduction of cerebral metabolic demands during thiopental treatment. Cycloheximide also protected neurons from hypoxic cell death, indicating that translational inhibitors may generally reduce secondary brain injury. In conclusion our study demonstrates that therapeutic inhibition of global protein synthesis protects neurons from hypoxic damage by preserving energy balance in oxygen-deprived cells. Molecular evidence for thiopental-mediated neuroprotection favours a positive clinical evaluation of barbiturate treatment. The chemical structure of thiopental could represent a pharmacologically relevant scaffold for the development of new organ-protective compounds to ameliorate tissue damage when oxygen availability is limited. PMID- 24167568 TI - Inhibition of CIN85-mediated invasion by a novel SH3 domain binding motif in the lysyl oxidase propeptide. AB - The lysyl oxidase gene inhibits Ras signaling in transformed fibroblasts and breast cancer cells. Its activity was mapped to the 162 amino acid propeptide domain (LOX-PP) of the lysyl oxidase precursor protein. LOX-PP inhibited the Her 2/Ras signaling axis in breast cancer cells, and reduced the Her-2-driven breast tumor burden in a xenograft model. Since its mechanism of action is largely unknown, co-affinity-purification/mass spectrometry was performed and the "Cbl interacting protein of 85-kDa" (CIN85) identified as an associating protein. CIN85 is an SH3-containing adapter protein that is overexpressed in invasive breast cancers. The CIN85 SH3 domains interact with c-Cbl, an E3 ubiquitin ligase, via an unconventional PxxxPR ligand sequence, with the highest affinity displayed by the SH3-B domain. Interaction with CIN85 recruits c-Cbl to the AMAP1 complex where its ubiquitination activity is necessary for cancer cells to develop an invasive phenotype and to degrade the matrix. Direct interaction of LOX-PP with CIN85 was confirmed using co-immunoprecipitation analysis of lysates from breast cancer cells and of purified expressed proteins. CIN85 interaction with c-Cbl was reduced by LOX-PP. Domain specific CIN85 regions and deletion mutants of LOX-PP were prepared and used to map the sites of interaction to the SH3-B domain of CIN85 and to an epitope encompassing amino acids 111 to 116 of LOX-PP. Specific LOX-PP point mutant proteins P111A and R116A failed to interact with CIN85 or to compete for CIN85 binding with c-Cbl. Structural modeling identified a new atypical PxpxxRh SH3-binding motif in this region of LOX-PP. The LOX-PP interaction with CIN85 was shown to reduce the invasive phenotype of breast cancer cells, including their ability to degrade the surrounding extracellular matrix and for Matrigel outgrowth. Thus, LOX-PP interacts with CIN85 via a novel SH3-binding motif and this association reduces CIN85-promoted invasion by breast cancer cells. PMID- 24167569 TI - Motor imagery cognitive network after left ischemic stroke: study of the patients during mental rotation task. AB - Although motor imagery could improve motor rehabilitation, the detailed neural mechanisms of motor imagery cognitive process of stroke patients, particularly from functional network perspective, remain unclear. This study investigated functional brain network properties in each cognitive sub-stage of motor imagery of stroke patients with ischemic lesion in left hemisphere to reveal the impact of stroke on the cognition of motor imagery. Both stroke patients and control subjects participated in mental rotation task, which includes three cognitive sub stages: visual stimulus perception, mental rotation and response cognitive process. Event-related electroencephalograph was recorded and interdependence between two different cortical areas was assessed by phase synchronization. Both global and nodal properties of functional networks in three sub-stages were statistically analyzed. Phase synchronization of stroke patients significantly reduced in mental rotation sub-stage. Longer characteristic path length and smaller global clustering coefficient of functional network were observed in patients in mental rotation sub-stage which implied the impaired segregation and integration. Larger nodal clustering coefficient and betweenness in contralesional occipitoparietal and frontal area respectively were observed in patients in all sub-stages. In addition, patients also showed smaller betweenness in ipsilesional central-parietal area in response sub-stage. The compensatory effects on local connectedness and centrality indicated the neuroplasticity in contralesional hemisphere. The functional brain networks of stroke patients demonstrated significant alterations and compensatory effects during motor imagery. PMID- 24167570 TI - Policing in nonhuman primates: partial interventions serve a prosocial conflict management function in rhesus macaques. AB - Studies of prosocial policing in nonhuman societies traditionally focus on impartial interventions because of an underlying assumption that partial support implies a direct benefit to the intervener, thereby negating the potential for being prosocial in maintaining social stability for the benefit of the group. However, certain types of partial interventions have significant potential to be prosocial in controlling conflict, e.g. support of non-kin subordinates. Here, we propose a policing support hypothesis that some types of agonistic support serve a prosocial policing function that maintains group stability. Using seven large captive groups of rhesus macaques, we investigated the relationship between intervention type and group-level costs and benefits (rates of trauma, severe aggression, social relocation) and individual level costs and benefits (preferential sex-dyad targeting, dominance ambiguity reduction, access to mates, and return aggression). Our results show that impartial interventions and support of subordinate non-kin represent prosocial policing as both (1) were negatively associated with group-level rates of trauma and severe aggression, respectively, (2) showed no potential to confer individual dominance benefits, (3) when performed outside the mating season, they did not increase chances of mating with the beneficiary, and (4) were low-cost for the highest-ranking interveners. We recommend expanding the definition of 'policing' in nonhumans to include these 'policing support interventions'. PMID- 24167571 TI - The trypanosome Pumilio domain protein PUF5. AB - PUF proteins are a conserved family of RNA binding proteins found in all eukaryotes examined so far. This study focussed on PUF5, one of 11 PUF family members encoded in the Trypanosoma brucei genome. Native PUF5 is present at less than 50000 molecules per cell in both bloodstream and procyclic form trypanosomes. C-terminally myc-tagged PUF5 was mainly found in the cytoplasm and could be cross-linked to RNA. PUF5 knockdown by RNA interference had no effect on the growth of bloodstream forms. Procyclic forms lacking PUF5 grew normally, but expression of PUF5 bearing a 21 kDa tandem affinity purification tag inhibited growth. Knockdown of PUF5 did not have any effect on the ability of trypanosomes to differentiate from the mammalian to the insect form of the parasite. PMID- 24167572 TI - Double-stranded RNA mycovirus infection of Aspergillus fumigatus is not dependent on the genetic make-up of the host. AB - Aspergillus fumigatus is a fungus that causes opportunistic infections in immunocompromised patients, with high morbidity and mortality. In its turn, A. fumigatus can become infected with mycoviruses. Most mycoviruses have a dsRNA genome and can cause fungal hypovirulence. For that reason, mycoviruses could theoretically be used as therapeutic tools to combat fungal infections. We determined if a certain genetic make-up of A. fumigatus was associated with the presence of mycoviruses in 86 clinical A. fumigatus isolates. Mycovirus screening was performed by isolating dsRNA from mycelial cultures using a Trizol/Chloroform method. The genetic relatedness of dsRNA infected A. fumigatus was determined by cell surface protein (CSP) typing and determination of the mating type. Sixteen (18.6%) of the 86 clinical A. fumigatus isolates contained dsRNA. The A. fumigatus collection could be divided into 11 different CSP types. DsRNA infected A. fumigatus isolates had similar CSP types as non-infected isolates. In both cases, the CSP types t01, t02, t03 and t04 were the most prevalent and the distribution comparable to the CSP types observed in other Dutch collections. Mating types MAT1-1 and MAT1-2 were evenly distributed among all A. fumigatus strains, regardless of CSP type. No difference was observed in mycovirus infections between MAT1-1 and MAT1-2 isolates. DsRNA mycovirus infections in A. fumigatus are not related to either CSP or mating type and therefore represent an interesting future therapeutic tool to combat fungal infections. PMID- 24167573 TI - Powerful haplotype-based Hardy-Weinberg equilibrium tests for tightly linked loci. AB - Recently, there have been many case-control studies proposed to test for association between haplotypes and disease, which require the Hardy-Weinberg equilibrium (HWE) assumption of haplotype frequencies. As such, haplotype inference of unphased genotypes and development of haplotype-based HWE tests are crucial prior to fine mapping. The goodness-of-fit test is a frequently-used method to test for HWE for multiple tightly-linked loci. However, its degrees of freedom dramatically increase with the increase of the number of loci, which may lack the test power. Therefore, in this paper, to improve the test power for haplotype-based HWE, we first write out two likelihood functions of the observed data based on the Niu's model (NM) and inbreeding model (IM), respectively, which can cause the departure from HWE. Then, we use two expectation-maximization algorithms and one expectation-conditional-maximization algorithm to estimate the model parameters under the HWE, IM and NM models, respectively. Finally, we propose the likelihood ratio tests LRT[Formula: see text] and LRT[Formula: see text] for haplotype-based HWE under the NM and IM models, respectively. We simulate the HWE, Niu's, inbreeding and population stratification models to assess the validity and compare the performance of these two LRT tests. The simulation results show that both of the tests control the type I error rates well in testing for haplotype-based HWE. If the NM model is true, then LRT[Formula: see text] is more powerful. While, if the true model is the IM model, then LRT[Formula: see text] has better performance in power. Under the population stratification model, LRT[Formula: see text] is still more powerful. To this end, LRT[Formula: see text] is generally recommended. Application of the proposed methods to a rheumatoid arthritis data set further illustrates their utility for real data analysis. PMID- 24167574 TI - A single vaccination with an improved nonspreading Rift Valley fever virus vaccine provides sterile immunity in lambs. AB - Rift Valley fever virus (RVFV) is an important pathogen that affects ruminants and humans. Recently we developed a vaccine based on nonspreading RVFV (NSR) and showed that a single vaccination with this vaccine protects lambs from viremia and clinical signs. However, low levels of viral RNA were detected in the blood of vaccinated lambs shortly after challenge infection. These low levels of virus, when present in a pregnant ewe, could potentially infect the highly susceptible fetus. We therefore aimed to further improve the efficacy of the NSR vaccine. Here we report the expression of Gn, the major immunogenic protein of the virus, from the NSR genome. The resulting NSR-Gn vaccine was shown to elicit superior CD8 and CD4-restricted memory responses and improved virus neutralization titers in mice. A dose titration study in lambs revealed that the highest vaccination dose of 10(6.3) TCID50/ml protected all lambs from clinical signs and viremia. The lambs developed neutralizing antibodies within three weeks after vaccination and no anamnestic responses were observed following challenge. The combined results suggest that sterile immunity was achieved by a single vaccination with the NSR-Gn vaccine. PMID- 24167575 TI - Comparative transcriptional profiling of 3 murine models of SLE nephritis reveals both unique and shared regulatory networks. AB - OBJECTIVE: To define shared and unique features of SLE nephritis in mouse models of proliferative and glomerulosclerotic renal disease. METHODS: Perfused kidneys from NZB/W F1, NZW/BXSB and NZM2410 mice were harvested before and after nephritis onset. Affymetrix based gene expression profiles of kidney RNA were analyzed using Genomatix Pathway Systems and Ingenuity Pathway Analysis software. Gene expression patterns were confirmed using real-time PCR. RESULTS: 955, 1168 and 755 genes were regulated in the kidneys of nephritic NZB/W F1, NZM2410 and NZW/BXSB mice respectively. 263 genes were regulated concordantly in all three strains reflecting immune cell infiltration, endothelial cell activation, complement activation, cytokine signaling, tissue remodeling and hypoxia. STAT3 was the top associated transcription factor, having a binding site in the gene promoter of 60/263 regulated genes. The two strains with proliferative nephritis shared a macrophage/DC infiltration and activation signature. NZB/W and NZM2410 mice shared a mitochondrial dysfunction signature. Dominant T cell and plasma cell signatures in NZB/W mice reflected lymphoid aggregates; this was the only strain with regulatory T cell infiltrates. NZW/BXSB mice manifested tubular regeneration and NZM2410 mice had the most metabolic stress and manifested loss of nephrin, indicating podocyte loss. CONCLUSIONS: These findings identify shared inflammatory mechanisms of SLE nephritis that can be therapeutically targeted. Nevertheless, the heterogeneity of effector mechanisms suggests that individualized therapy might need to be based on biopsy findings. Some common mechanisms are shared with non-immune-mediated renal diseases, suggesting that strategies to prevent tissue hypoxia and remodeling may be useful in SLE nephritis. PMID- 24167576 TI - Potent antiproliferative cembrenoids accumulate in tobacco upon infection with Rhodococcus fascians and trigger unusual microtubule dynamics in human glioblastoma cells. AB - AIMS: Though plant metabolic changes are known to occur during interactions with bacteria, these were rarely challenged for pharmacologically active compounds suitable for further drug development. Here, the occurrence of specific chemicals with antiproliferative activity against human cancer cell lines was evidenced in hyperplasia (leafy galls) induced when plants interact with particular phytopathogens, such as the Actinomycete Rhodococcus fascians. METHODS: We examined leafy galls fraction F3.1.1 on cell proliferation, cell division and cytoskeletal disorganization of human cancer cell lines using time-lapse videomicroscopy imaging, combined with flow cytometry and immunofluorescence analysis. We determined the F3.1.1-fraction composition by gas chromatography coupled to mass spectrometry. RESULTS: The leafy galls induced on tobacco by R. fascians yielded fraction F3.1.1 which inhibited proliferation of glioblastoma U373 cells with an IC50 of 4.5 ug/mL, F.3.1.1 was shown to increase cell division duration, cause nuclear morphological deformations and cell enlargement, and, at higher concentrations, karyokinesis defects leading to polyploidization and apoptosis. F3.1.1 consisted of a mixture of isomers belonging to the cembrenoids. The cellular defects induced by F3.1.1 were caused by a peculiar cytoskeletal disorganization, with the occurrence of fragmented tubulin and strongly organized microtubule aggregates within the same cell. Colchicine, paclitaxel, and cembrene also affected U373 cell proliferation and karyokinesis, but the induced microtubule rearrangement was very different from that provoked by F3.1.1. Altogether our data indicate that the cembrenoid isomers in F3.1.1 have a unique mode of action and are able to simultaneously modulate microtubule polymerization and stability. PMID- 24167578 TI - Glycolytic metabolites are critical modulators of oocyte maturation and viability. AB - The maturation of an oocyte into an egg is a key step in preparation for fertilization. In Xenopus, oocyte maturation is independent of transcription, being regulated at the level of translation and post-translational modifications of proteins. To identify factors involved in the maturation process we used two dimensional differential gel electrophoresis to compare the proteome of oocytes and eggs. Protein abundance changes were observed in multiple cellular pathways during oocyte maturation. Most prominent was a general reduction in abundance of enzymes in the glycolytic pathway. Injection into oocytes of the glycolytic intermediates glyceraldehyde-3-phosphate, phosphoenolpyruvate and glucose-6 phosphate prevented oocyte maturation. Instead, these metabolites stimulated ROS production and subsequent apoptosis of the oocyte. In contrast, all other metabolites tested had no effect on oocyte maturation and did not induce apoptosis. These data suggest that a subset of glycolytic metabolites have the capacity to regulate oocyte viability. PMID- 24167577 TI - Isozyme-specific ligands for O-acetylserine sulfhydrylase, a novel antibiotic target. AB - The last step of cysteine biosynthesis in bacteria and plants is catalyzed by O acetylserine sulfhydrylase. In bacteria, two isozymes, O-acetylserine sulfhydrylase-A and O-acetylserine sulfhydrylase-B, have been identified that share similar binding sites, although the respective specific functions are still debated. O-acetylserine sulfhydrylase plays a key role in the adaptation of bacteria to the host environment, in the defense mechanisms to oxidative stress and in antibiotic resistance. Because mammals synthesize cysteine from methionine and lack O-acetylserine sulfhydrylase, the enzyme is a potential target for antimicrobials. With this aim, we first identified potential inhibitors of the two isozymes via a ligand- and structure-based in silico screening of a subset of the ZINC library using FLAP. The binding affinities of the most promising candidates were measured in vitro on purified O-acetylserine sulfhydrylase-A and O-acetylserine sulfhydrylase-B from Salmonella typhimurium by a direct method that exploits the change in the cofactor fluorescence. Two molecules were identified with dissociation constants of 3.7 and 33 uM for O-acetylserine sulfhydrylase-A and O-acetylserine sulfhydrylase-B, respectively. Because GRID analysis of the two isoenzymes indicates the presence of a few common pharmacophoric features, cross binding titrations were carried out. It was found that the best binder for O-acetylserine sulfhydrylase-B exhibits a dissociation constant of 29 uM for O-acetylserine sulfhydrylase-A, thus displaying a limited selectivity, whereas the best binder for O-acetylserine sulfhydrylase-A exhibits a dissociation constant of 50 uM for O-acetylserine sulfhydrylase-B and is thus 8 fold selective towards the former isozyme. Therefore, isoform-specific and isoform-independent ligands allow to either selectively target the isozyme that predominantly supports bacteria during infection and long-term survival or to completely block bacterial cysteine biosynthesis. PMID- 24167579 TI - Serum metabolomics of slow vs. rapid motor progression Parkinson's disease: a pilot study. AB - Progression of Parkinson's disease (PD) is highly variable, indicating that differences between slow and rapid progression forms could provide valuable information for improved early detection and management. Unfortunately, this represents a complex problem due to the heterogeneous nature of humans in regards to demographic characteristics, genetics, diet, environmental exposures and health behaviors. In this pilot study, we employed high resolution mass spectrometry-based metabolic profiling to investigate the metabolic signatures of slow versus rapidly progressing PD present in human serum. Archival serum samples from PD patients obtained within 3 years of disease onset were analyzed via dual chromatography-high resolution mass spectrometry, with data extraction by xMSanalyzer and used to predict rapid or slow motor progression of these patients during follow-up. Statistical analyses, such as false discovery rate analysis and partial least squares discriminant analysis, yielded a list of statistically significant metabolic features and further investigation revealed potential biomarkers. In particular, N8-acetyl spermidine was found to be significantly elevated in the rapid progressors compared to both control subjects and slow progressors. Our exploratory data indicate that a fast motor progression disease phenotype can be distinguished early in disease using high resolution mass spectrometry-based metabolic profiling and that altered polyamine metabolism may be a predictive marker of rapidly progressing PD. PMID- 24167580 TI - Efficient knockin mouse generation by ssDNA oligonucleotides and zinc-finger nuclease assisted homologous recombination in zygotes. AB - The generation of specific mutant animal models is critical for functional analysis of human genes. The conventional gene targeting approach in embryonic stem cells (ESCs) by homologous recombination is however laborious, slow, expensive, and limited to species with functional ESCs. It is therefore a long sought goal to develop an efficient and simple alternative gene targeting strategy. Here we demonstrate that, by combining an efficient ZFN pair and ssODN, a restriction site and a loxP site were successfully introduced into a specific genomic locus. A targeting efficiency up to 22.22% was achieved by coinciding the insertion site and the ZFN cleavage site isogenic and keeping the length of the homology arms equal and isogenic to the endogenous target locus. Furthermore, we determine that ZFN and ssODN-assisted HR is ssODN homology arm length dependent. We further show that mutant alleles generated by ZFN and ssODN-assisted HR can be transmitted through the germline successfully. This study establishes an efficient gene targeting strategy by ZFN and ssODN-assisted HR in mouse zygotes, and provides a potential avenue for genome engineering in animal species without functional ES cell lines. PMID- 24167581 TI - Predictors of beta-blocker intolerance and mortality in patients after acute coronary syndrome. AB - PURPOSE: To investigate the predictors of intolerance to beta-blockers treatment and the 6-month mortality in hospitalized patients with acute coronary syndrome (ACS). METHODS: This was a single-center, prospective, and longitudinal study including 370 consecutive ACS patients in Killip class I or II. BBs were prescribed according to international guidelines and withdrawn if intolerance occurred. The study was approved by the institutional ethics committee of our university. STATISTICS: the clinical parameters evaluated at admission, and the related intolerance to BBs and death at 6 months were analyzed using logistic regression (p<0.05)in PATIENTS. RESULTS: BB intolerance was observed in 84 patients and was associated with no prior use of statins (OR: 2.16, 95%CI: 1.26 3.69, p= 0.005) and Killip class II (OR: 2.5, 95%CI: 1.30-4.75, p=0.004) in the model adjusted for age, sex, blood pressure, and renal function. There was no association with ST-segment alteration or left anterior descending coronary artery plaque. Intolerance to BB was associated with the greatest risk of death (OR: 4.5, 95%CI: 2.15-9.40, p<0.001). CONCLUSIONS: After ACS, intolerance to BBs in the first 48 h of admission was associated to non previous use of statin and Killip class II and had a high risk of death within 6 months. PMID- 24167582 TI - Heat shock transcription factor 1-deficiency attenuates overloading-associated hypertrophy of mouse soleus muscle. AB - Hypertrophic stimuli, such as mechanical stress and overloading, induce stress response, which is mediated by heat shock transcription factor 1 (HSF1), and up regulate heat shock proteins (HSPs) in mammalian skeletal muscles. Therefore, HSF1-associated stress response may play a key role in loading-associated skeletal muscle hypertrophy. The purpose of this study was to investigate the effects of HSF1-deficiency on skeletal muscle hypertrophy caused by overloading. Functional overloading on the left soleus was performed by cutting the distal tendons of gastrocnemius and plantaris muscles for 4 weeks. The right muscle served as the control. Soleus muscles from both hindlimbs were dissected 2 and 4 weeks after the operation. Hypertrophy of soleus muscle in HSF1-null mice was partially inhibited, compared with that in wild-type (C57BL/6J) mice. Absence of HSF1 partially attenuated the increase of muscle wet weight and fiber cross sectional area of overloaded soleus muscle. Population of Pax7-positive muscle satellite cells in HSF1-null mice was significantly less than that in wild-type mice following 2 weeks of overloading (p<0.05). Significant up-regulations of interleukin (IL)-1beta and tumor necrosis factor mRNAs were observed in HSF1 null, but not in wild-type, mice following 2 weeks of overloading. Overloading related increases of IL-6 and AFT3 mRNA expressions seen after 2 weeks of overloading tended to decrease after 4 weeks in both types of mice. In HSF1-null mice, however, the significant overloading-related increase in the expression of IL-6, not ATF3, mRNA was noted even at 4th week. Inhibition of muscle hypertrophy might be attributed to the greater and prolonged enhancement of IL-6 expression. HSF1 and/or HSF1-mediated stress response may, in part, play a key role in loading-induced skeletal muscle hypertrophy. PMID- 24167584 TI - Exposure of wild boar to Mycobacterium tuberculosis complex in France since 2000 is consistent with the distribution of bovine tuberculosis outbreaks in cattle. AB - The Eurasian wild boar (Sus scrofa) is increasingly considered as a relevant actor in the epidemiology of animal tuberculosis (TB). Therefore, monitoring TB in wild boar becomes a key tool for establishing comprehensive control schemes for this disease. To estimate the exposure of free living wild boar to Mycobacterium tuberculosis complex (MTC) in France, a bovine-purified protein derivative based ELISA was used to test 2,080 archived serum samples of hunter harvested animals in 58 French "departements". Two cut-off values were used for diagnostic interpretation: 0.2, recommended by the manufacturer (specificity: 96.43%; sensitivity: 72.6%), and 0.5 (specificity: 100%; sensitivity: 64%). During the same period, at the 0.2 cut-off, global true seroprevalence was 5.9% (IC95%: 4.3%-7.7%) and 76% of the sampled "departements" had seropositive wild boar, including seven cattle TB-free "departements. At the 0.5 cut-off, global true seroprevalence was 2.2% (IC95%: 1.5-3.2) and positive wild boar belonged to 21% of the "departements". All but one of these positive "departements" had reported at least one cattle TB outbreak since 2000. A good consistence between seropositive wild boar and TB outbreaks in cattle was found, especially at the 0.5 cut-off value (the mean distance to the nearest cattle TB outbreak was 13 km and 27 km for seropositive and seronegative wild boar, respectively; P<0.05). The use of an ELISA to detect MTC antibodies in wild boar has permitted the description of the geographic distribution of MTC contact in wild boar in France. Our results suggest that the ELISA could be used as a first screening tool to conduct TB surveillance in wild boar at a population level. High-risk wild boar populations (e.g. overabundant) could be tested and if identified positive by ELISA they should be surveyed in detail by combining pathology and culture. PMID- 24167583 TI - Central role of cellular senescence in TSLP-induced airway remodeling in asthma. AB - BACKGROUND: Airway remodeling is a repair process that occurs after injury resulting in increased airway hyper-responsiveness in asthma. Thymic stromal lymphopoietin (TSLP), a vital cytokine, plays a critical role in orchestrating, perpetuating and amplifying the inflammatory response in asthma. TSLP is also a critical factor in airway remodeling in asthma. OBJECTIVES: To examine the role of TSLP-induced cellular senescence in airway remodeling of asthma in vitro and in vivo. METHODS: Cellular senescence and airway remodeling were examined in lung specimens from patients with asthma using immunohischemical analysis. Both small molecule and shRNA approaches that target the senescent signaling pathways were used to explore the role of cellular senescence in TSLP-induced airway remodeling in vitro. Senescence-Associated beta-galactosidase (SA-beta-Gal) staining, and BrdU assays were used to detect cellular senescence. In addition, the Stat3 targeted inhibitor, WP1066, was evaluated in an asthma mouse model to determine if inhibiting cellular senescence influences airway remodeling in asthma. RESULTS: Activation of cellular senescence as evidenced by checkpoint activation and cell cycle arrest was detected in airway epithelia samples from patients with asthma. Furthermore, TSLP-induced cellular senescence was required for airway remodeling in vitro. In addition, a mouse asthma model indicates that inhibiting cellular senescence blocks airway remodeling and relieves airway resistance. CONCLUSION: TSLP stimulation can induce cellular senescence during airway remodeling in asthma. Inhibiting the signaling pathways of cellular senescence overcomes TSLP-induced airway remodeling. PMID- 24167587 TI - Monosaccharide-responsive phenylboronate-polyol cell scaffolds for cell sheet and tissue engineering applications. AB - Analyte-responsive smart polymeric materials are of great interest and have been actively investigated in the field of regenerative medicine. Phenylboronate containing copolymers form gels with polyols under alkaline conditions. Monosaccharides, by virtue of their higher affinity towards boronate, can displace polyols and solubilize such gels. In the present study, we investigate the possibility of utilizing phenylboronate-polyol interactions at physiological pH in order to develop monosaccharide-responsive degradable scaffold materials for systems dealing with cells and tissues. Amine assisted phenylboronate-polyol interactions were employed to develop novel hydrogel and cryogel scaffolds at neutral pH. The scaffolds displayed monosaccharide inducible gel-sol phase transformability. In vitro cell culture studies demonstrated the ability of scaffolds to support cell adhesion, viability and proliferation. Fructose induced gel degradation is used to recover cells cultured on the hydrogels. The cryogels displayed open macroporous structure and superior mechanical properties. These novel phase transformable phenylboronate-polyol based scaffolds displayed a great potential for various cell sheet and tissue engineering applications. Their monosaccharide responsiveness at physiological pH is very useful and can be utilized in the fields of cell immobilization, spheroid culture, saccharide recognition and analyte-responsive drug delivery. PMID- 24167586 TI - Lifelong expression of apolipoprotein D in the human brainstem: correlation with reduced age-related neurodegeneration. AB - The lipocalin apolipoprotein D (Apo D) is upregulated in peripheral nerves following injury and in regions of the central nervous system, such as the cerebral cortex, hippocampus, and cerebellum, during aging and progression of certain neurological diseases. In contrast, few studies have examined Apo D expression in the brainstem, a region necessary for survival and generally less prone to age-related degeneration. We measured Apo D expression in whole human brainstem lysates by slot-blot and at higher spatial resolution by quantitative immunohistochemistry in eleven brainstem nuclei (the 4 nuclei of the vestibular nuclear complex, inferior olive, hypoglossal nucleus, oculomotor nucleus, facial motor nucleus, nucleus of the solitary tract, dorsal motor nucleus of the vagus nerve, and Roller's nucleus). In contrast to cortex, hippocampus, and cerebellum, apolipoprotein D was highly expressed in brainstem tissue from subjects (N = 26, 32-96 years of age) with no history of neurological disease, and expression showed little variation with age. Expression was significantly stronger in somatomotor nuclei (hypoglossal, oculomotor, facial) than visceromotor or sensory nuclei. Both neurons and glia expressed Apo D, particularly neurons with larger somata and glia in the periphery of these brainstem centers. Immunostaining was strongest in the neuronal perinuclear region and absent in the nucleus. We propose that strong brainstem expression of Apo D throughout adult life contributes to resistance against neurodegenerative disease and age-related degeneration, possibly by preventing oxidative stress and ensuing lipid peroxidation. PMID- 24167585 TI - KLF15 is a molecular link between endoplasmic reticulum stress and insulin resistance. AB - Obesity places major demands on the protein folding capacity of the endoplasmic reticulum (ER), resulting in ER stress, a condition that promotes hepatic insulin resistance and steatosis. Here we identify the transcription factor, Kruppel-like factor 15 (KLF15), as an essential mediator of ER stress-induced insulin resistance in the liver. Mice with a targeted deletion of KLF15 exhibit increased hepatic ER stress, inflammation, and JNK activation compared to WT mice; however, KLF15 (-/-) mice are protected against hepatic insulin resistance and fatty liver under high-fat feeding conditions and in response to pharmacological induction of ER stress. The mammalian target of rapamycin complex 1 (mTORC1), a key regulator of cellular energy homeostasis, has been shown to cooperate with ER stress signaling pathways to promote hepatic insulin resistance and lipid accumulation. We find that the uncoupling of ER stress and insulin resistance in KLF15 (-/-) liver is associated with the maintenance of a low energy state characterized by decreased mTORC1 activity, increased AMPK phosphorylation and PGC-1alpha expression and activation of autophagy, an intracellular degradation process that enhances hepatic insulin sensitivity. Furthermore, in primary hepatocytes, KLF15 deficiency markedly inhibits activation of mTORC1 by amino acids and insulin, suggesting a mechanism by which KLF15 controls mTORC1-mediated insulin resistance. This study establishes KLF15 as an important molecular link between ER stress and insulin action. PMID- 24167588 TI - Learning auditory space: generalization and long-term effects. AB - BACKGROUND: Previous findings have shown that humans can learn to localize with altered auditory space cues. Here we analyze such learning processes and their effects up to one month on both localization accuracy and sound externalization. Subjects were trained and retested, focusing on the effects of stimulus type in learning, stimulus type in localization, stimulus position, previous experience, externalization levels, and time. METHOD: We trained listeners in azimuth and elevation discrimination in two experiments. Half participated in the azimuth experiment first and half in the elevation first. In each experiment, half were trained in speech sounds and half in white noise. Retests were performed at several time intervals: just after training and one hour, one day, one week and one month later. In a control condition, we tested the effect of systematic retesting over time with post-tests only after training and either one day, one week, or one month later. RESULTS: With training all participants lowered their localization errors. This benefit was still present one month after training. Participants were more accurate in the second training phase, revealing an effect of previous experience on a different task. Training with white noise led to better results than training with speech sounds. Moreover, the training benefit generalized to untrained stimulus-position pairs. Throughout the post-tests externalization levels increased. In the control condition the long-term localization improvement was not lower without additional contact with the trained sounds, but externalization levels were lower. CONCLUSION: Our findings suggest that humans adapt easily to altered auditory space cues and that such adaptation spreads to untrained positions and sound types. We propose that such learning depends on all available cues, but each cue type might be learned and retrieved differently. The process of localization learning is global, not limited to stimulus-position pairs, and it differs from externalization processes. PMID- 24167589 TI - Experimental design-based functional mining and characterization of high throughput sequencing data in the sequence read archive. AB - High-throughput sequencing technology, also called next-generation sequencing (NGS), has the potential to revolutionize the whole process of genome sequencing, transcriptomics, and epigenetics. Sequencing data is captured in a public primary data archive, the Sequence Read Archive (SRA). As of January 2013, data from more than 14,000 projects have been submitted to SRA, which is double that of the previous year. Researchers can download raw sequence data from SRA website to perform further analyses and to compare with their own data. However, it is extremely difficult to search entries and download raw sequences of interests with SRA because the data structure is complicated, and experimental conditions along with raw sequences are partly described in natural language. Additionally, some sequences are of inconsistent quality because anyone can submit sequencing data to SRA with no quality check. Therefore, as a criterion of data quality, we focused on SRA entries that were cited in journal articles. We extracted SRA IDs and PubMed IDs (PMIDs) from SRA and full-text versions of journal articles and retrieved 2748 SRA ID-PMID pairs. We constructed a publication list referring to SRA entries. Since, one of the main themes of -omics analyses is clarification of disease mechanisms, we also characterized SRA entries by disease keywords, according to the Medical Subject Headings (MeSH) extracted from articles assigned to each SRA entry. We obtained 989 SRA ID-MeSH disease term pairs, and constructed a disease list referring to SRA data. We previously developed feature profiles of diseases in a system called "Gendoo". We generated hyperlinks between diseases extracted from SRA and the feature profiles of it. The developed project, publication and disease lists resulting from this study are available at our web service, called "DBCLS SRA" (http://sra.dbcls.jp/). This service will improve accessibility to high-quality data from SRA. PMID- 24167590 TI - Regional brain atrophy and functional connectivity changes related to fatigue in multiple sclerosis. AB - Fatigue is one of the most frequent symptoms in multiple sclerosis (MS), and recent studies have described a relationship between the sensorimotor cortex and its afferent and efferent pathways as a substrate of fatigue. The objectives of this study were to assess the neural correlates of fatigue in MS through gray matter (GM) and white matter (WM) atrophy, and resting state functional connectivity (rs-FC) of the sensorimotor network (SMN). Eighteen healthy controls (HCs) and 60 relapsing-remitting patients were assessed with the Fatigue Severity Scale (FSS). Patients were classified as fatigued (F) or nonfatigued (NF). We investigated GM and WM atrophy using voxel-based morphometry, and rs-FC changes with a seed-based method and independent component analysis (ICA). F patients showed extended GM and WM atrophy focused on areas related to the SMN. High FSS scores were associated with reductions of WM in the supplementary motor area. Seed analysis of GM atrophy in the SMN showed that HCs presented increased rs-FC between the primary motor and somatosensory cortices while patients with high FSS scores were associated with decreased rs-FC between the supplementary motor area and associative somatosensory cortex. ICA results showed that NF patients presented higher rs-FC in the primary motor cortex compared to HCs and in the premotor cortex compared to F patients. Atrophy reduced functional connectivity in SMN pathways and MS patients consequently experienced high levels of fatigue. On the contrary, NF patients experienced high synchronization in this network that could be interpreted as a compensatory mechanism to reduce fatigue sensation. PMID- 24167591 TI - An indole alkaloid from a tribal folklore inhibits immediate early event in HSV-2 infected cells with therapeutic efficacy in vaginally infected mice. AB - Herpes genitalis, caused by HSV-2, is an incurable genital ulcerative disease transmitted by sexual intercourse. The virus establishes life-long latency in sacral root ganglia and reported to have synergistic relationship with HIV-1 transmission. Till date no effective vaccine is available, while the existing therapy frequently yielded drug resistance, toxicity and treatment failure. Thus, there is a pressing need for non-nucleotide antiviral agent from traditional source. Based on ethnomedicinal use we have isolated a compound 7-methoxy-1 methyl-4,9-dihydro-3H-pyrido[3,4-b]indole (HM) from the traditional herb Ophiorrhiza nicobarica Balkr, and evaluated its efficacy on isolates of HSV-2 in vitro and in vivo. The cytotoxicity (CC50), effective concentrations (EC50) and the mode of action of HM was determined by MTT, plaque reduction, time-of addition, immunofluorescence (IFA), Western blot, qRT-PCR, EMSA, supershift and co-immunoprecipitation assays; while the in vivo toxicity and efficacy was evaluated in BALB/c mice. The results revealed that HM possesses significant anti HSV-2 activity with EC50 of 1.1-2.8 ug/ml, and selectivity index of >20. The time kinetics and IFA demonstrated that HM dose dependently inhibited 50-99% of HSV-2 infection at 1.5-5.0 ug/ml at 2-4 h post-infection. Further, HM was unable to inhibit viral attachment or penetration and had no synergistic interaction with acyclovir. Moreover, Western blot and qRT-PCR assays demonstrated that HM suppressed viral IE gene expression, while the EMSA and co-immunoprecipitation studies showed that HM interfered with the recruitment of LSD-1 by HCF-1. The in vivo studies revealed that HM at its virucidal concentration was nontoxic and reduced virus yield in the brain of HSV-2 infected mice in a concentration dependent manner, compared to vaginal tissues. Thus, our results suggest that HM can serve as a prototype to develop non-nucleotide antiviral lead targeting the viral IE transcription for the management of HSV-2 infections. PMID- 24167592 TI - Methylglyoxal evokes pain by stimulating TRPA1. AB - Diabetic neuropathy is a severe complication of long-standing diabetes and one of the major etiologies of neuropathic pain. Diabetes is associated with an increased formation of reactive oxygen species and the electrophilic dicarbonyl compound methylglyoxal (MG). Here we show that MG stimulates heterologously expressed TRPA1 in CHO cells and natively expressed TRPA1 in MDCK cells and DRG neurons. MG evokes [Ca(2+)]i-responses in TRPA1 expressing DRG neurons but is without effect in neurons cultured from Trpa1(-/-) mice. Consistent with a direct, intracellular action, we show that methylglyoxal is significantly more potent as a TRPA1 agonist when applied to the intracellular face of excised membrane patches than to intact cells. Local intraplantar administration of MG evokes a pain response in Trpa1(+/+) but not in Trpa1(-/-) mice. Furthermore, persistently increased MG levels achieved by two weeks pharmacological inhibition of glyoxalase-1 (GLO-1), the rate-limiting enzyme responsible for detoxification of MG, evokes a progressive and marked thermal (cold and heat) and mechanical hypersensitivity in wildtype but not in Trpa1(-/-) mice. Our results thus demonstrate that TRPA1 is required both for the acute pain response evoked by topical MG and for the long-lasting pronociceptive effects associated with elevated MG in vivo. In contrast to our observations in DRG neurons, MG evokes indistinguishable [Ca(2+)]i-responses in pancreatic beta-cells cultured from Trpa1(+/+) and Trpa1(-/-) mice. In vivo, the TRPA1 antagonist HC030031 impairs glucose clearance in the glucose tolerance test both in Trpa1(+/+) and Trpa1(-/-) mice, indicating a non-TRPA1 mediated effect and suggesting that results obtained with this compound should be interpreted with caution. Our results show that TRPA1 is the principal target for MG in sensory neurons but not in pancreatic beta-cells and that activation of TRPA1 by MG produces a painful neuropathy with the behavioral hallmarks of diabetic neuropathy. PMID- 24167593 TI - Crouching tiger, hidden trouble: urban sources of Aedes albopictus (Diptera: Culicidae) refractory to source-reduction. AB - Our ultimate objective is to design cost-effective control strategies for Aedes albopictus, the Asian tiger mosquito, an important urban nuisance and disease vector that expanded worldwide during the last 40 years. We conducted mosquito larval surveys from May through October 2009 in the City of Trenton, New Jersey, USA, while performing intensive monthly source-reduction campaigns that involved removing, emptying, or treating all accessible containers with larvicides and pupicides. We examined patterns of occurrence of Ae. albopictus and Culex pipiens, another urban mosquito, among different container types by comparing observed and expected number of positive containers of each type. Expected use was based on the relative frequency of each container type in the environment. Aedes albopictus larvae and pupae were found significantly more often than expected in medium volumes of water in buckets and plant saucers but were rarely collected in small volumes of water found in trash items such as discarded cups and cans. They were also absent from large volumes of water such as in abandoned swimming pools and catch basins, although we consistently collected Cx. pipiens from those habitats. The frequency of Ae. albopictus in tires indicated rapid and extensive use of these ubiquitous urban containers. Standard larval-based indices did not correlate with adult catches in BG-Sentinel traps, but when based only on Ae. albopictus key containers (buckets, plant saucers, equipment with pockets of water, and tires) they did. Although we found that only 1.2% of the 20,039 water holding containers examined contained immature Ae. albopictus (5.3% if only key containers were counted), adult populations were still above nuisance action thresholds six times during the 2009 mosquito season. We conclude that in urban New Jersey, effective source reduction for Ae. albopictus control will require scrupulous and repeated cleaning or treatment of everyday use containers and extensive homeowner collaboration. PMID- 24167594 TI - Colitis promotes adaptation of an intestinal nematode: a Heligmosomoides polygyrus mouse model system. AB - The precise mechanism of the very effective therapeutic effect of gastrointestinal nematodes on some autoimmune diseases is not clearly understood and is currently being intensively investigated. Treatment with living helminths has been initiated to reverse intestinal immune-mediated diseases in humans. However, little attention has been paid to the phenotype of nematodes in the IBD affected gut and the consequences of nematode adaptation. In the present study, exposure of Heligmosomoides polygyrus larvae to the changed cytokine milieu of the intestine during colitis reduced inflammation in an experimental model of dextran sulphate sodium (DSS)- induced colitis, but increased nematode establishment in the moderate-responder BALB/c mouse strain. We used mass spectrometry in combination with two-dimensional Western blotting to determine changes in protein expression and changes in nematode antigens recognized by IgG1 in mice with colitis. We show that nematode larvae immunogenicity is changed by colitis as soon as 6 days post-infection; IgG1 did not recognize highly conserved proteins Lev-11 (isoform 1 of tropomyosin alpha1 chain), actin-4 isoform or FTT-2 isoform a (14-3-3 family) protein. These results indicate that changes in the small intestine provoked by colitis directly influence the nematode proteome. The unrecognized proteins seem to be key antigenic epitopes able to induce protective immune responses. The proteome changes were associated with weak immune recognition and increased larval adaptation and worm growth, altered localization in the intestine and increased survival of males but reduced worm fecundity. In this report, the mechanisms influencing nematode survival and the consequences of changed immunogenicity that reflect the immune response at the site colonized by the parasite in mice with colitis are described. The results are relevant to the use of live parasites to ameliorate IBD. PMID- 24167595 TI - The effect of sugar-free versus sugar-sweetened beverages on satiety, liking and wanting: an 18 month randomized double-blind trial in children. AB - BACKGROUND: Substituting sugar-free for sugar-sweetened beverages reduces weight gain. A possible explanation is that sugar-containing and sugar-free beverages cause the same degree of satiety. However, this has not been tested in long-term trials. METHODS: We randomized 203 children aged 7-11 years to receive 250 mL per day of an artificially sweetened sugar-free beverage or a similarly looking and tasting sugar-sweetened beverage. We measured satiety on a 5-point scale by questionnaire at 0, 6, 12 and 18 months. We calculated the change in satiety from before intake to 1 minute after intake and 15 minutes after intake. We then calculated the odds ratio that satiety increased by 1 point in the sugar-group versus the sugar-free group. We also investigated how much the children liked and wanted the beverages. RESULTS: 146 children or 72% completed the study. We found no statistically significant difference in satiety between the sugar-free and sugar-sweetened group; the adjusted odds ratio for a 1 point increase in satiety in the sugar group versus the sugar-free group was 0.77 at 1 minute (95% confidence interval, 0.46 to 1.29), and 1.44 at 15 minutes after intake (95% CI, 0.86 to 2.40). The sugar-group liked and wanted their beverage slightly more than the sugar-free group, adjusted odds ratio 1.63 (95% CI 1.05 to 2.54) and 1.65 (95% CI 1.07 to 2.55), respectively. CONCLUSIONS: Sugar-sweetened and sugar-free beverages produced similar satiety. Therefore when children are given sugar-free instead of sugar-containing drinks they might not make up the missing calories from other sources. This may explain our previous observation that children in the sugar-free group accumulated less body fat than those in the sugar group. TRIAL REGISTRATION: ClinicalTrials.gov NCT00893529 http://clinicaltrials.gov/show/NCT00893529. PMID- 24167596 TI - Bupleurum polysaccharides attenuates lipopolysaccharide-induced inflammation via modulating Toll-like receptor 4 signaling. AB - BACKGROUND: Bupleurum polysaccharides (BPs), isolated from Bupleurum smithii var. parvifolium, possesses immunomodulatory activity, particularly on inflammation. Bacterial endotoxin lipopolysaccharide (LPS) triggers innate immune responses through Toll-like receptor 4 (TLR4) on host cell membrane. The present study was performed to evaluate whether the therapeutic efficacy of BPs on suppression of LPS's pathogenecity could be associated with the modulating of TLR4 signaling pathway. METHODOLOGY/PRINCIPAL FINDINGS: LPS stimulated expression and activation of factors in the TLR4 signaling system, including TLR4, CD14, IRAK4, TRAF6, NF kappaB, and JNK, determined using immunocytochemical and/or Western blot assays. BPs significantly inhibited these effects of LPS. LPS increased pro-inflammatory cytokines (TNF-alpha, IL-6, IL-1beta, IL-12p40, and IFN-beta) and NO production, evaluated using ELISA and Griess reaction assays, respectively. BPs antagonized these effects of LPS. Interestingly, BPs alone augmented secretion of some pro inflammatory cytokines of non-LPS stimulated macrophages and enhanced phagocytic activity towards fluorescent E.coli bioparticles. In a rat model of acute lung injury (ALI) with pulmonary hemorrhage and inflammation, BPs ameliorated lung injuries and suppressed TLR4 expression. SIGNIFICANCE: The therapeutic properties of BPs in alleviating inflammatory diseases could be attributed to its inhibitory effect on LPS-mediated TLR4 signaling. PMID- 24167597 TI - Evaluating predictive pharmacogenetic signatures of adverse events in colorectal cancer patients treated with fluoropyrimidines. AB - The potential clinical utility of genetic markers associated with response to fluoropyrimidine treatment in colorectal cancer patients remains controversial despite extensive study. Our aim was to test the clinical validity of both novel and previously identified markers of adverse events in a broad clinical setting. We have conducted an observational pharmacogenetic study of early adverse events in a cohort study of 254 colorectal cancer patients treated with 5-fluorouracil or capecitabine. Sixteen variants of nine key folate (pharmacodynamic) and drug metabolising (pharmacokinetic) enzymes have been analysed as individual markers and/or signatures of markers. We found a significant association between TYMP S471L (rs11479) and early dose modifications and/or severe adverse events (adjusted OR = 2.02 [1.03; 4.00], p = 0.042, adjusted OR = 2.70 [1.23; 5.92], p = 0.01 respectively). There was also a significant association between these phenotypes and a signature of DPYD mutations (Adjusted OR = 3.96 [1.17; 13.33], p = 0.03, adjusted OR = 6.76 [1.99; 22.96], p = 0.002 respectively). We did not identify any significant associations between the individual candidate pharmacodynamic markers and toxicity. If a predictive test for early adverse events analysed the TYMP and DPYD variants as a signature, the sensitivity would be 45.5 %, with a positive predictive value of just 33.9 % and thus poor clinical validity. Most studies to date have been under-powered to consider multiple pharmacokinetic and pharmacodynamic variants simultaneously but this and similar individualised data sets could be pooled in meta-analyses to resolve uncertainties about the potential clinical utility of these markers. PMID- 24167598 TI - M2 macrophages activate WNT signaling pathway in epithelial cells: relevance in ulcerative colitis. AB - Macrophages, which exhibit great plasticity, are important components of the inflamed tissue and constitute an essential element of regenerative responses. Epithelial Wnt signalling is involved in mechanisms of proliferation and differentiation and expression of Wnt ligands by macrophages has been reported. We aim to determine whether the macrophage phenotype determines the expression of Wnt ligands, the influence of the macrophage phenotype in epithelial activation of Wnt signalling and the relevance of this pathway in ulcerative colitis. Human monocyte-derived macrophages and U937-derived macrophages were polarized towards M1 or M2 phenotypes and the expression of Wnt1 and Wnt3a was analyzed by qPCR. The effects of macrophages and the role of Wnt1 were analyzed on the expression of beta-catenin, Tcf-4, c-Myc and markers of cell differentiation in a co-culture system with Caco-2 cells. Immunohistochemical staining of CD68, CD206, CD86, Wnt1, beta-catenin and c-Myc were evaluated in the damaged and non-damaged mucosa of patients with UC. We also determined the mRNA expression of Lgr5 and c-Myc by qPCR and protein levels of beta-catenin by western blot. Results show that M2, and no M1, activated the Wnt signaling pathway in co-culture epithelial cells through Wnt1 which impaired enterocyte differentiation. A significant increase in the number of CD206+ macrophages was observed in the damaged mucosa of chronic vs newly diagnosed patients. CD206 immunostaining co-localized with Wnt1 in the mucosa and these cells were associated with activation of canonical Wnt signalling pathway in epithelial cells and diminution of alkaline phosphatase activity. Our results show that M2 macrophages, and not M1, activate Wnt signalling pathways and decrease enterocyte differentiation in co-cultured epithelial cells. In the mucosa of UC patients, M2 macrophages increase with chronicity and are associated with activation of epithelial Wnt signalling and diminution in enterocyte differentiation. PMID- 24167599 TI - Identification of novel amelogenin-binding proteins by proteomics analysis. AB - Emdogain (enamel matrix derivative, EMD) is well recognized in periodontology. It is used in periodontal surgery to regenerate cementum, periodontal ligament, and alveolar bone. However, the precise molecular mechanisms underlying periodontal regeneration are still unclear. In this study, we investigated the proteins bound to amelogenin, which are suggested to play a pivotal role in promoting periodontal tissue regeneration. To identify new molecules that interact with amelogenin and are involved in osteoblast activation, we employed coupling affinity chromatography with proteomic analysis in fractionated SaOS-2 osteoblastic cell lysate. In SaOS-2 cells, many of the amelogenin-interacting proteins in the cytoplasm were mainly cytoskeletal proteins and several chaperone molecules of heat shock protein 70 (HSP70) family. On the other hand, the proteomic profiles of amelogenin-interacting proteins in the membrane fraction of the cell extracts were quite different from those of the cytosolic-fraction. They were mainly endoplasmic reticulum (ER)-associated proteins, with lesser quantities of mitochondrial proteins and nucleoprotein. Among the identified amelogenin-interacting proteins, we validated the biological interaction of amelogenin with glucose-regulated protein 78 (Grp78/Bip), which was identified in both cytosolic and membrane-enriched fractions. Confocal co-localization experiment strongly suggested that Grp78/Bip could be an amelogenin receptor candidate. Further biological evaluations were examined by Grp78/Bip knockdown analysis with and without amelogenin. Within the limits of the present study, the interaction of amelogenin with Grp78/Bip contributed to cell proliferation, rather than correlate with the osteogenic differentiation in SaOS-2 cells. Although the biological significance of other interactions are not yet explored, these findings suggest that the differential effects of amelogenin-derived osteoblast activation could be of potential clinical significance for understanding the cellular and molecular bases of amelogenin-induced periodontal tissue regeneration. PMID- 24167600 TI - Collecting duct carcinomas represent a unique tumor entity based on genetic alterations. AB - Collecting duct carcinoma (CDC) is a rare renal neoplasm that is associated with poor prognosis due to its highly aggressive course and limited response to immuno or chemotherapy. Histologically, CDC is defined as a subtype of renal cell carcinomas, but in some cases, it is difficult to differentiate from urothelial carcinomas (UC). Therefore the aim of this study was to determine genetic alterations of CDC in comparison to that of urothelial carcinomas of the upper urinary tract (UUT-UC) to clarify the histological origin of this rare tumor entity. Twenty-nine CDC samples were obtained from seven different German centers and compared with twenty-six urothelial carcinomas of the upper urinary tract. Comparative genomic hybridization (CGH) was used to investigate the genetic composition of patients' tumors and allowed the detection of losses and gains of DNA copy numbers throughout the entire genome. The clinical data were correlated with CGH results. CGH analysis of CDC revealed DNA aberrations in many chromosomes. DNA losses were more frequently observed than gains, while high level amplifications were not detected. The mean frequency of CDC chromosomal aberrations (4.9/case) was slightly lower than that in UUT-UC (5.4/case). Recurrent CDC DNA losses occurred at 8p (n=9/29), 16p (9/29), 1p (n=7/29) and 9p (n=7/29), and gains occurred in 13q (n=9/29). In contrast to CDC, the most frequently detected UUT-UC DNA aberration was a loss at 9q (n=13/26). DNA losses at 9q, 13q and 8q as well as gains at 8p showed significant variations in UUT-UC compared to CDC. There was no correlation between the patients' clinical course and the presence or absence of these recurrent genetic alterations. CDCs are characterized by a different genetic pattern compared to UUT-UC. Regarding the published data on renal cell carcinoma, we conclude that CDC appears to be a unique entity among kidney carcinomas. PMID- 24167601 TI - Association of follicle-stimulating hormone receptor polymorphisms with ovarian response in Chinese women: a prospective clinical study. AB - BACKGROUND: Follicular stimulating hormone (FSH) is a glycoprotein and widely used for the treatment of infertility; FSH action is mediated by FSH receptor (FSHR), SNPs of which determine the ovarian response. Two polymorphisms of the FSHR gene were identified, which caused a change of threonine (T) to alanine (A) at position 307 and asparagine (N) to serine(S) at position 680. Both polymorphic sites give rise to three discrete variants of the FSHR: TT, TA, and AA for position 307; NN, NS, and SS for position 680. METHODOLOGY/PRINCIPAL FINDINGS: 450 Chinese women were recruited in an assisted reproductive technology program from October 2011 to March 2012. FSHR polymorphisms at the positions 307 and 680 were examined by PCR-RFLP. Serum FSH and estradiol level, FSH amount, ovarian response and pregnancy rate were recorded during treatment. The basal FSH levels were higher in AA [7.38 +/- 2.07 vs 6.34 +/- 1.75, 6.63 +/- 1.94, P<0.05, 95% CI (6.75, 8.01)] and SS [7.51 +/- 2.01 vs 6.31 +/- 1.75, 6.66 +/- 1.96, P<0.05, 95% CI (6.88, 8.15)] compared to other genotypes respectively; the days for ovulation induction was slightly longer in AA and SS. Women with AA and SS have higher rates of poor response compared to carriers of other genotypes (P<0.05). Furthermore, there is a nearly complete linkage between these two polymorphisms in Chinese women (D'=0.95, r(2)=0.84). CONCLUSIONS/SIGNIFICANCE: In Chinese women receiving ART, the subjects with AA and SS genotypes have higher basal FSH levels, and these genotypes are associated with an increased risk of poor response. Our data suggested that the personalized FSH therapy may be applied according to patient's genetic background in clinical settings. The linkage suggested that the polymorphisms of Thr307Ala and Asn680Ser may be used as TAG SNP markers for analysis of potential genotyping in ART. PMID- 24167602 TI - A fast and cost-effective method for identifying a polymorphism of interleukin 28B related to hepatitis C. AB - Approximately 170 million people are chronic carriers of hepatitis C virus (HCV). Patients with chronic hepatitis C are currently treated with pegylated interferon and ribavirin (PEG-IFN/RBV). A genome-wide association with PEG-IFN/RBV treatment response and a single nucleotide polymorphism (rs12979860) has been identified near the interleukin 28B gene that encodes interferon-lambda-3. In this paper, we describe an innovative, fast, and low-cost multiplex polymerase chain reaction with confronting two-pair primers that detects the rs12979860 polymorphism. The assay is internally controlled and does not require the use of restriction endonucleases or special equipment. Moreover, the assay decreases costs, being about 40% cheaper than direct sequencing methods. PMID- 24167603 TI - Label-free detection of insulin and glucagon within human islets of Langerhans using Raman spectroscopy. AB - Intrahepatic transplantation of donor islets of Langerhans is a promising therapy for patients with type 1 diabetes. It is of critical importance to accurately monitor islet quality before transplantation, which is currently done by standard histological methods that are performed off-line and require extensive sample preparation. As an alternative, we propose Raman spectroscopy which is a non destructive and label-free technique that allows continuous real-time monitoring of the tissue to study biological changes as they occur. By performing Raman spectroscopic measurements on purified insulin and glucagon, we showed that the 520 cm(-1) band assigned to disulfide bridges in insulin, and the 1552 cm(-1) band assigned to tryptophan in glucagon are mutually exclusive and could therefore be used as indirect markers for the label-free distinction between both hormones. High-resolution hyperspectral Raman imaging for these bands showed the distribution of disulfide bridges and tryptophan at sub-micrometer scale, which correlated with the location of insulin and glucagon as revealed by conventional immunohistochemistry. As a measure for this correlation, quantitative analysis was performed comparing the Raman images with the fluorescence images, resulting in Dice coefficients (ranging between 0 and 1) of 0.36 for insulin and 0.19 for glucagon. Although the use of separate microscope systems with different spatial resolution and the use of indirect Raman markers cause some image mismatch, our findings indicate that Raman bands for disulfide bridges and tryptophan can be used as distinctive markers for the label-free detection of insulin and glucagon in human islets of Langerhans. PMID- 24167604 TI - Improved glucose control and reduced body weight in rodents with dual mechanism of action peptide hybrids. AB - Combination therapy is being increasingly used as a treatment paradigm for metabolic diseases such as diabetes and obesity. In the peptide therapeutics realm, recent work has highlighted the therapeutic potential of chimeric peptides that act on two distinct receptors, thereby harnessing parallel complementary mechanisms to induce additive or synergistic benefit compared to monotherapy. Here, we extend this hypothesis by linking a known anti-diabetic peptide with an anti-obesity peptide into a novel peptide hybrid, which we termed a phybrid. We report on the synthesis and biological activity of two such phybrids (AC164204 and AC164209), comprised of a glucagon-like peptide-1 receptor (GLP1-R) agonist, and exenatide analog, AC3082, covalently linked to a second generation amylin analog, davalintide. Both molecules acted as full agonists at their cognate receptors in vitro, albeit with reduced potency at the calcitonin receptor indicating slightly perturbed amylin agonism. In obese diabetic Lep(ob)/Lep (ob) mice sustained infusion of AC164204 and AC164209 reduced glucose and glycated haemoglobin (HbA1c) equivalently but induced greater weight loss relative to exenatide administration alone. Weight loss was similar to that induced by combined administration of exenatide and davalintide. In diet-induced obese rats, both phybrids dose-dependently reduced food intake and body weight to a greater extent than exenatide or davalintide alone, and equal to co-infusion of exenatide and davalintide. Phybrid-mediated and exenatide + davalintide-mediated weight loss was associated with reduced adiposity and preservation of lean mass. These data are the first to provide in vivo proof-of-concept for multi-pathway targeting in metabolic disease via a peptide hybrid, demonstrating that this approach is as effective as co-administration of individual peptides. PMID- 24167605 TI - Psychological and social factors associated with late pregnancy iron deficiency anaemia in rural Viet Nam: a population-based prospective study. AB - OBJECTIVES: The aim of this study was to examine the relationships between psychological and social factors and late pregnancy IDA among pregnant women in rural Viet Nam. METHODS: Pregnant women from 50 randomly-selected communes within Ha Nam province were recruited and assessed at 12 - 20 weeks gestation (Wave 1, W1). They were followed up in the last trimester (Wave 2, W2). IDA was defined as Haemoglobin < 11 g/dL and serum ferritin < 15 ng/mL. Symptoms of Common Mental Disorders (CMD) were assessed by the Edinburgh Postnatal Depression Scale-Vietnam (EPDS-V). Persistent antenatal CMD was defined as having an EPDS-V score >= 4 in both W1 and W2. Hypothesis models were tested by Structural Equation Modeling analyses. RESULTS: A total of 378 women provided complete data at both W1 and W2. The incidence risk of IDA in the third trimester was 13.2% (95% confidence interval (CI): 9.8-16.7). Persistent CMD was found in 16.9% (95% CI: 13.1-20.7) pregnant women and predicted by intimate partner violence, fear of other family members, experience of childhood abuse, coincidental life adversity, and having a preference for the sex of the baby. There was a significant pathway from persistent CMD to IDA in late pregnancy via the length of time that iron supplements had been taken. Receiving advice to take iron supplements and higher household wealth index were indirectly related to lower risk of late pregnancy IDA. Early pregnancy IDA and being multi-parous also contributed to late pregnancy IDA. CONCLUSIONS: Antenatal IDA and CMD are prevalent public health problems among women in Viet Nam. The link between them suggests that while direct recommendations to use iron supplements are important, the social factors associated with common mental disorders should be addressed in antenatal care in order to improve the health of pregnant women and their infants. PMID- 24167606 TI - Local properties of vigilance states: EMD analysis of EEG signals during sleep waking states of freely moving rats. AB - Understanding the inherent dynamics of the EEG associated to sleep-waking can provide insights into its basic neural regulation. By characterizing the local properties of the EEG using power spectrum, empirical mode decomposition (EMD) and Hilbert-spectral analysis, we can examine the dynamics over a range of time scales. We analyzed rat EEG during wake, NREMS and REMS using these methods. The average instantaneous phase, power spectral density (PSD) of intrinsic mode functions (IMFs) and the energy content in various frequency bands show characteristic changes in each of the vigilance states. The 2nd and 7th IMFs show changes in PSD for wake and REMS, suggesting that those modes may carry wake- and REMS-associated cognitive, conscious and behavior-specific information of an individual even though the EEG may appear similar. The energy content in theta2 (6 Hz-9 Hz) band of the 1st IMF for REMS is larger than that of wake. The decrease in the phase function of IMFs from wake to REMS to NREMS indicates decrease of the mean frequency in these states, respectively. The rate of information processing in waking state is more in the time scale described by the first three IMFs than in REMS state. However, for IMF5-IMF7, the rate is more for REMS than that for wake. We obtained Hilbert-Huang spectral entropy, which is a suitable measure of information processing in each of these state-specific EEG. It is possible to evaluate the complex dynamics of the EEG in each of the vigilance states by applying measures based on EMD and Hilbert-transform. Our results suggest that the EMD based nonlinear measures of the EEG can provide useful estimates of the information possessed by various oscillations associated with the vigilance states. Further, the EMD-based spectral measures may have implications in understanding anatamo-physiological correlates of sleep-waking behavior and clinical diagnosis of sleep-pathology. PMID- 24167607 TI - GmSAL1 hydrolyzes inositol-1,4,5-trisphosphate and regulates stomatal closure in detached leaves and ion compartmentalization in plant cells. AB - Inositol polyphosphatases are important regulators since they control the catabolism of phosphoinositol derivatives, which are often signaling molecules for cellular processes. Here we report on the characterization of one of their members in soybean, GmSAL1. In contrast to the substrate specificity of its Arabidopsis homologues (AtSAL1 and AtSAL2), GmSAL1 only hydrolyzes inositol-1,4,5 trisphosphate (IP3) but not inositol-1,3,4-trisphosphate or inositol-1,4 bisphosphate.The ectopic expression of GmSAL1 in transgenic Arabidopsis thaliana led to a reduction in IP3 signals, which was inferred from the reduction in the cytoplasmic signals of the in vivo biomarker pleckstrin homology domain-green florescent protein fusion protein and the suppression of abscisic acid-induced stomatal closure. At the cellular level, the ectopic expression of GmSAL1 in transgenic BY-2 cells enhanced vacuolar Na(+) compartmentalization and therefore could partially alleviate salinity stress. PMID- 24167608 TI - Molecular characterization of Msp2/P44 of Anaplasma phagocytophilum isolated from infected patients and Haemaphysalis longicornis in Laizhou Bay, Shandong Province, China. AB - Molecular characterization of the MSP2/P44 protein of Anaplasma phagocytophilum may determine not only if the bacterium is capable of invading hosts but also whether it generates antigenic variation for the purpose of escaping the host immune response, resulting in various pathologic injuries and serious clinical outcomes. Chinese anaplasmosis patients usually present with serious manifestations, and the fatality rate is as high as 26.5%. In this study, we amplified, cloned and sequenced the msp2/p44 genes of three Chinese A. phagocytophilum isolates from Laizhou Bay, Shandong Province, where human granulocytic anaplasmosis (HGA) patients present severe clinical manifestations, and analyzed their genetic characterization and structural features. We also compared them with the HZ and Webster A. phagocytophilum strains. The sequences for both strains are available in GenBank. Analyses indicated that Chinese A. phagocytophilum isolates were significantly different from the HZ and Webster strains in terms of nucleotide sequences, amino acid sequences and protein secondary and tertiary structures. Moreover, the number of immunologic B-cell epitopes (19) of the MSP2 protein of the Chinese isolates was higher than that of the A. phagocytophilum strains HZ (16) and Webster (9). This genetic diversity of the MSP2/P44 protein of Chinese A. phagocytophilum isolates might be relevant and might have serious clinical outcomes. This observation could provide a clue to further understand the pathogenesis of Chinese A. phagocytophilum. PMID- 24167609 TI - Nicorandil in patients with acute myocardial infarction undergoing primary percutaneous coronary intervention: a systematic review and meta-analysis. AB - BACKGROUND: Nicorandil, as an adjunctive therapy with primary percutaneous coronary intervention (PCI), had controversial benefits in cardioprotection in patients with acute myocardial infarction (AMI). METHODS AND RESULTS: We performed a systematic review of randomized controlled trials (RCTs) comparing treatment with nicorandil prior to reperfusion therapy with control (placebo or no nicorandil) in patients who suffered from AMI and performed primary PCI. PubMed, EMBASE and CENTRAL databases and other sources were searched without language and publication restriction. 14 trials involving 1680 patients were included into this meta-analysis. Nicorandil significantly reduced the incidence of thrombolysis in myocardial infarction (TIMI) flow grade <= 2 (risk ratio [RR], 0.57; 95% confidence interval [CI]: 0.42 to 0.79), the Timi frame count (TFC) (mean difference [MD], -5.19; 95% CI: -7.13 to -3.26), increased left ventricular ejection fraction (LVEF) (%) (MD, 3.08; 95% CI: 0.79 to 5.36), and reduced the incidence of ventricular arrhythmia (RR, 0.53; 95% CI: 0.37 to 0.76) and congestive heart failure (CHF) (RR, 0.41; 95% CI: 0.22 to 0.75). No difference in the pear creatine kinase (CK) value (MD, -290.19; 95% CI: -793.75 to 213.36) or cardiac death (RR, 0.39; 95% CI: 0.09 to 1.67) was observed. CONCLUSIONS: Nicorandil prior to reperfusion is associated with improvement of coronary reflow as well as suppression of ventricular arrhythmia, and further improves left ventricular function in patients who suffered from AMI and underwent primary PCI. But the definite clinical benefits of nicorandil were not found, which may be due to the small sample size of the selected studies. PMID- 24167610 TI - Abnormal movement preparation in task-specific focal hand dystonia. AB - Electrophysiological and behavioral studies in primary dystonia suggest abnormalities during movement preparation, but this crucial phase preceding movement onset has not yet been studied specifically with functional magnetic resonance imaging (fMRI). To identify abnormalities in brain activation during movement preparation, we used event-related fMRI to analyze behaviorally unimpaired sequential finger movements in 18 patients with task-specific focal hand dystonia (FHD) and 18 healthy subjects. Patients and controls executed self initiated or externally cued prelearnt four-digit sequential movements using either right or left hands. In FHD patients, motor performance of the sequential finger task was not associated with task-related dystonic posturing and their activation levels during motor execution were highly comparable with controls. On the other hand reduced activation was observed during movement preparation in the FHD patients in left premotor cortex / precentral gyrus for all conditions, and for self-initiation additionally in supplementary motor area, left mid-insula and anterior putamen, independent of effector side. Findings argue for abnormalities of early stages of motor control in FHD, manifesting during movement preparation. Since deficits map to regions involved in the coding of motor programs, we propose that task-specific dystonia is characterized by abnormalities during recruitment of motor programs: these do not manifest at the behavioral level during simple automated movements, however, errors in motor programs of complex movements established by extensive practice (a core feature of FHD), trigger the inappropriate movement patterns observed in task-specific dystonia. PMID- 24167612 TI - Gene expression of desaturase (FADS1 and FADS2) and Elongase (ELOVL5) enzymes in peripheral blood: association with polyunsaturated fatty acid levels and atopic eczema in 4-year-old children. AB - BACKGROUND: It is unknown if changes in the gene expression of the desaturase and elongase enzymes are associated with abnormal n-6 long chain polyunsaturated fatty acid (LC-PUFA) levels in children with atopic eczema (AE). We analyzed whether mRNA-expression of genes encoding key enzymes of LC-PUFA synthesis (FADS1, FADS2 and ELOVL5) is associated with circulating LC-PUFA levels and risk of AE in 4-year-old children. METHODS: AE (n=20) and non-AE (n=104) children participating in the Sabadell cohort within the INfancia y Medio Ambiente (INMA) Project were included in the present study. RT-PCR with TaqMan Low-Density Array cards was used to measure the mRNA-expression of FADS1, FADS2 and ELOVL5. LC-PUFA levels were measured by fast gas chromatography in plasma phospholipids. The relationship of gene expression with LC-PUFA levels and enzyme activities was evaluated by Pearson's rank correlation coefficient, and logistic regression models were used to study its association with risk of developing AE. RESULTS: Children with AE had lower levels of several n-6 PUFA members, dihomo-gamma linolenic (DGLA) and arachidonic (AA) acids. mRNA-expression levels of FADS1 and 2 strongly correlated with DGLA levels and with D6D activity. FADS2 and ELOVL5 mRNA-expression levels were significantly lower in AE than in non-AE children ( 40.30% and -20.36%; respectively), but no differences were found for FADS1. CONCLUSIONS AND SIGNIFICANCE: Changes in the mRNA-expression levels of FADS1 and 2 directly affect blood DGLA levels and D6D activity. This study suggests that lower mRNA-expressions of FADS2 and ELOVL5 are associated with higher risk of atopic eczema in young children. PMID- 24167611 TI - 5-HTT deficiency affects neuroplasticity and increases stress sensitivity resulting in altered spatial learning performance in the Morris water maze but not in the Barnes maze. AB - The purpose of this study was to evaluate whether spatial hippocampus-dependent learning is affected by the serotonergic system and stress. Therefore, 5-HTT knockout (-/-), heterozygous (+/-) and wildtype (+/+) mice were subjected to the Barnes maze (BM) and the Morris water maze (WM), the latter being discussed as more aversive. Additionally, immediate early gene (IEG) expression, hippocampal adult neurogenesis (aN), and blood plasma corticosterone were analyzed. While the performance of 5-HTT-/- mice in the BM was undistinguishable from both other genotypes, they performed worse in the WM. However, in the course of the repeated WM trials 5-HTT-/- mice advanced to wildtype level. The experience of a single trial of either the WM or the BM resulted in increased plasma corticosterone levels in all genotypes. After several trials 5-HTT-/- mice exhibited higher corticosterone concentrations compared with both other genotypes in both tests. Corticosterone levels were highest in 5-HTT-/- mice tested in the WM indicating greater aversiveness of the WM and a greater stress sensitivity of 5-HTT deficient mice. Quantitative immunohistochemistry in the hippocampus revealed increased cell counts positive for the IEG products cFos and Arc as well as for proliferation marker Ki67 and immature neuron marker NeuroD in 5-HTT-/- mice compared to 5-HTT+/+ mice, irrespective of the test. Most differences were found in the suprapyramidal blade of the dentate gyrus of the septal hippocampus. Ki67 immunohistochemistry revealed a genotype x environment interaction with 5-HTT genotype differences in naive controls and WM experience exclusively yielding more Ki67-positive cells in 5-HTT+/+ mice. Moreover, in 5-HTT-/- mice we demonstrate that learning performance correlates with the extent of aN. Overall, higher baseline IEG expression and increased an in the hippocampus of 5-HTT-/- mice together with increased stress sensitivity may constitute the neurobiological correlate of raised alertness, possibly impeding optimal learning performance in the more stressful WM. PMID- 24167613 TI - Macrophage migration inhibitory factor and stearoyl-CoA desaturase 1: potential prognostic markers for soft tissue sarcomas based on bioinformatics analyses. AB - The diagnosis and treatment of soft tissue sarcomas (STSs) has been particularly difficult, because STSs are a group of highly heterogeneous tumors in terms of histopathology, histological grade, and primary site. Recent advances in genome technologies have provided an excellent opportunity to determine the complete biological characteristics of neoplastic tissues, resulting in improved diagnosis, treatment selection, and investigation of therapeutic targets. We had previously developed a novel bioinformatics method for marker gene selection and applied this method to gene expression data from STS patients. This previous analysis revealed that the extracted gene combination of macrophage migration inhibitory factor (MIF) and stearoyl-CoA desaturase 1 (SCD1) is an effective diagnostic marker to discriminate between subtypes of STSs with highly different outcomes. In the present study, we hypothesize that the combination of MIF and SCD1 is also a prognostic marker for the overall outcome of STSs. To prove this hypothesis, we first analyzed microarray data from 88 STS patients and their outcomes. Our results show that the survival rates for MIF- and SCD1-positive groups were lower than those for negative groups, and the p values of the log rank test are 0.0146 and 0.00606, respectively. In addition, survival rates are more significantly different (p = 0.000116) between groups that are double positive and double-negative for MIF and SCD1. Furthermore, in vitro cell growth inhibition experiments by MIF and SCD1 inhibitors support the hypothesis. These results suggest that the gene set is useful as a prognostic marker associated with tumor progression. PMID- 24167614 TI - Triple negative breast tumors in African-American and Hispanic/Latina women are high in CD44+, low in CD24+, and have loss of PTEN. AB - BACKGROUND: African-American women have higher mortality from breast cancer than other ethnic groups. The association between poor survival and differences with tumor phenotypes is not well understood. The purpose of this study is to assess the clinical significance of (1) Stem cell-like markers CD44 and CD24; (2) PI3K/Akt pathway associated targets PTEN, activation of Akt, and FOXO1; and (3) the Insulin-like growth factor-1 (IGF-I) and IGF binding protein-3 (IGFBP3) in different breast cancer subtypes, and compare the differences between African American and Hispanic/Latina women who have similar social-economic-status. METHODS: A total of N=318 African-American and Hispanic/Latina women, with clinically-annotated information within the inclusion criteria were included. Formalin fixed paraffin embedded tissues from these patients were tested for the different markers using immunohistochemistry techniques. Kaplan-Meier survival curves and Cox-regression analyses were used to assess Relative Risk and Disease Free-Survival (DFS). RESULTS: The triple-negative-breast-cancer (TNBC) receptor subtype was more prevalent among premenopausal women, and the Hormonal Receptor (HR) positive subtype was most common overall. TNBC tumors were more likely to have loss of PTEN, express high Ki67, and have increased CD44+/CD24- expression. TNBC was also associated with higher plasma-IGF-I levels. HR-/HER2+ tumors showed high pAkt, decreased FOXO1, and high CD24+ expression. The loss of PTEN impacted DFS significantly in African Americans, but not in Hispanics/Latinas after adjusted for treatment and other tumor pathological factors. The CD44+/CD24- and CD24+/CD44- phenotypes decreased DFS, but were not independent predictors for DFS. HER2-positive and TNBC type of cancers continued to exhibit significant decrease in DFS after adjusting for the selected biomarkers and treatment. CONCLUSIONS: TNBC incidence is high among African-American and Hispanic/Latino women residing in South Los Angeles. Our study also shows for the first time that TNBC was significantly associated with PTEN loss, high Ki67 and the CD44+/CD24- phenotype. The loss of PTEN impacts DFS significantly in African Americans. PMID- 24167615 TI - Evidence for a retroviral insertion in TRPM1 as the cause of congenital stationary night blindness and leopard complex spotting in the horse. AB - Leopard complex spotting is a group of white spotting patterns in horses caused by an incompletely dominant gene (LP) where homozygotes (LP/LP) are also affected with congenital stationary night blindness. Previous studies implicated Transient Receptor Potential Cation Channel, Subfamily M, Member 1 (TRPM1) as the best candidate gene for both CSNB and LP. RNA-Seq data pinpointed a 1378 bp insertion in intron 1 of TRPM1 as the potential cause. This insertion, a long terminal repeat (LTR) of an endogenous retrovirus, was completely associated with LP, testing 511 horses (chi(2)=1022.00, p<<0.0005), and CSNB, testing 43 horses (chi(2)=43, p<<0.0005). The LTR was shown to disrupt TRPM1 transcription by premature poly-adenylation. Furthermore, while deleterious transposable element insertions should be quickly selected against the identification of this insertion in three ancient DNA samples suggests it has been maintained in the horse gene pool for at least 17,000 years. This study represents the first description of an LTR insertion being associated with both a pigmentation phenotype and an eye disorder. PMID- 24167616 TI - Improving the quality of maternal and neonatal care: the role of standard based participatory assessments. AB - BACKGROUND: Gaps in quality of care are seriously affecting maternal and neonatal health globally but reports of successful quality improvement cycles implemented at large scale are scanty. We report the results of a nation-wide program to improve quality of maternal and neonatal hospital care in a lower-middle income country focusing on the role played by standard-based participatory assessments. METHODS: Improvements in the quality of maternal and neonatal care following an action-oriented participatory assessment of 19 areas covering the whole continuum from admission to discharge were measured after an average period of 10 months in four busy referral maternity hospitals in Uzbekistan. Information was collected by a multidisciplinary national team with international supervision through visit to hospital services, examination of medical records, direct observation of cases and interviews with staff and mothers. Scores (range 0 to 3) attributed to over 400 items and combined in average scores for each area were compared with the baseline assessment. RESULTS: Between the first and the second assessment, all four hospitals improved their overall score by an average 0.7 points out of 3 (range 0.4 to 1), i.e. by 22%. The improvements occurred in all main areas of care and were greater in the care of normal labor and delivery (+0.9), monitoring, infection control and mother and baby friendly care (+0.8) the role of the participatory action-oriented approach in determining the observed changes was estimated crucial in 6 out of 19 areas and contributory in other 8. Ongoing implementation of referral system and new classification of neonatal deaths impede the improved process of care to be reflected in current statistics. CONCLUSIONS: Important improvements in the quality of hospital care provided to mothers and newborn babies can be achieved through a standard-based action oriented and participatory assessment and reassessment process. PMID- 24167617 TI - Geniposide regulates glucose-stimulated insulin secretion possibly through controlling glucose metabolism in INS-1 cells. AB - Glucose-stimulated insulin secretion (GSIS) is essential to the control of metabolic fuel homeostasis. The impairment of GSIS is a key element of beta-cell failure and one of causes of type 2 diabetes mellitus (T2DM). Although the KATP channel-dependent mechanism of GSIS has been broadly accepted for several decades, it does not fully describe the effects of glucose on insulin secretion. Emerging evidence has suggested that other mechanisms are involved. The present study demonstrated that geniposide enhanced GSIS in response to the stimulation of low or moderately high concentrations of glucose, and promoted glucose uptake and intracellular ATP levels in INS-1 cells. However, in the presence of a high concentration of glucose, geniposide exerted a contrary role on both GSIS and glucose uptake and metabolism. Furthermore, geniposide improved the impairment of GSIS in INS-1 cells challenged with a high concentration of glucose. Further experiments showed that geniposide modulated pyruvate carboxylase expression and the production of intermediates of glucose metabolism. The data collectively suggest that geniposide has potential to prevent or improve the impairment of insulin secretion in beta-cells challenged with high concentrations of glucose, likely through pyruvate carboxylase mediated glucose metabolism in beta-cells. PMID- 24167619 TI - Electrophysiological characteristics of a SCN5A voltage sensors mutation R1629Q associated with Brugada syndrome. AB - Brugada syndrome (BrS) is an inherited arrhythmogenic syndrome leading to sudden cardiac death, partially associated with autosomal dominant mutations in SCN5A, which encodes the cardiac sodium channel alpha-subunit (Nav1.5). To date some SCN5A mutations related with BrS have been identified in voltage sensor of Nav1.5. Here, we describe a dominant missense mutation (R1629Q) localized in the fourth segment of domain IV region (DIV-S4) in a Chinese Han family. The mutation was identified by direct sequencing of SCN5A from the proband's DNA. Co expression of Wild-type (WT) or R1629Q Nav1.5 channel and hbeta1 subunit were achieved in human embryonic kidney cells by transient transfection. Sodium currents were recorded using whole cell patch-clamp protocols. No significant changes between WT and R1629Q currents were observed in current density or steady state activation. However, hyperpolarized shift of steady-state inactivation curve was identified in cells expressing R1629Q channel (WT: V1/2 = -81.1 +/- 1.3 mV, n = 13; R1629Q: V1/2 = -101.7 +/- 1.2 mV, n = 18). Moreover, R1629Q channel showed enhanced intermediate inactivation and prolonged recovery time from inactivation. In summary, this study reveals that R1629Q mutation causes a distinct loss-of-function of the channel due to alter its electrophysiological characteristics, and facilitates our understanding of biophysical mechanisms of BrS. PMID- 24167618 TI - Periostin deficiency increases bone damage and impairs injury response to fatigue loading in adult mice. AB - Bone damage removal and callus formation in response to fatigue loading are essential to prevent fractures. Periostin (Postn) is a matricellular protein that mediates adaptive response of cortical bone to loading. Whether and how periostin influences damage and the injury response to fatigue remains unknown. We investigated the skeletal response of Postn(-/-) and Postn(+/+) mice after fatigue stimulus by axial compression of their tibia. In Postn(+/+) mice, cracks number and surface (CsNb, CsS) increased 1h after fatigue, with a decrease in strength compared to non-fatigued tibia. At 15 days, CsNb had started to decline, while CtTV and CtBV increased in fatigued vs non-fatigued tibia, reflecting a woven bone response that was present in 75% of the fatigued bones. Cortical porosity and remodelling also prominently increased in the fatigued tibia of Postn(+/+) mice. At 30 days, paralleling a continuous removal of cortical damage, strength of the fatigued tibia was similar to the non-fatigue tibia. In Postn(-/ ) mice, cracks were detectable even in the absence of fatigue, while the amount of collagen crosslinks and tissue hardness was decreased compared to Postn(+/+). Fatigue significantly increased CsNb and CsS in Postn(-/-), but was not associated with changes in CtTV and CtBV, as only 16% of the fatigued bones formed some woven bone. Cortical porosity and remodelling did not increase either after fatigue in Postn(-/-), and the level of damage remained high even after 30 days. As a result, strength remained compromised in Postn(-/-) mice. Contrary to Postn(+/+), which osteocytic lacunae showed a change in the degree of anisotropy (DA) after fatigue, Postn(-/-) showed no DA change. Hence periostin appears to influence bone materials properties, damage accumulation and repair, including local modeling/remodeling processes in response to fatigue. These observations suggest that the level of periostin expression could influence the propensity to fatigue fractures. PMID- 24167620 TI - Efficient immortalization of primary nasopharyngeal epithelial cells for EBV infection study. AB - Nasopharyngeal carcinoma (NPC) is common among southern Chinese including the ethnic Cantonese population living in Hong Kong. Epstein-Barr virus (EBV) infection is detected in all undifferentiated type of NPC in this endemic region. Establishment of stable and latent EBV infection in premalignant nasopharyngeal epithelial cells is an early event in NPC development and may contribute to its pathogenesis. Immortalized primary nasopharyngeal epithelial cells represent an important tool for investigation of EBV infection and its tumorigenic potential in this special type of epithelial cells. However, the limited availability and small sizes of nasopharyngeal biopsies have seriously restricted the establishment of primary nasopharyngeal epithelial cells for immortalization. A reliable and effective method to immortalize primary nasopharyngeal epithelial cells will provide unrestricted materials for EBV infection studies. An earlier study has reported that Bmi-1 expression could immortalize primary nasopharyngeal epithelial cells. However, its efficiency and actions in immortalization have not been fully characterized. Our studies showed that Bmi-1 expression alone has limited ability to immortalize primary nasopharyngeal epithelial cells and additional events are often required for its immortalization action. We have identified some of the key events associated with the immortalization of primary nasopharyngeal epithelial cells. Efficient immortalization of nasopharyngeal epithelial cells could be reproducibly and efficiently achieved by the combined actions of Bmi-1 expression, activation of telomerase and silencing of p16 gene. Activation of MAPK signaling and gene expression downstream of Bmi-1 were detected in the immortalized nasopharyngeal epithelial cells and may play a role in immortalization. Furthermore, these newly immortalized nasopharyngeal epithelial cells are susceptible to EBV infection and supported a type II latent EBV infection program characteristic of EBV-infected nasopharyngeal carcinoma. The establishment of an efficient method to immortalize primary nasopharyngeal epithelial cells will facilitate the investigation into the role of EBV infection in pathogenesis of nasopharyngeal carcinoma. PMID- 24167621 TI - Epidemiology of Staphylococcus aureus bacteraemia at a tertiary children's hospital in Cape Town, South Africa. AB - BACKGROUND: Staphylococcus aureus is an important pathogen in paediatric patients with bloodstream infections. The epidemiology of S. aureus bacteraemia, however, has not been well documented in children in South Africa. METHODS: A retrospective study was conducted at a children's hospital in Cape Town, South Africa, to investigate the epidemiology of S. aureus bacteraemia from 2007-2011. The incidence, clinical presentation, risk factors, management and outcomes of methicillin sensitive S. aureus (MSSA) and methicillin resistant S. aureus (MRSA) bacteraemia were compared. RESULTS: Over the five year study period, 365 episodes of S. aureus bacteraemia were identified. The annual incidence was 3.28 cases per 1000 hospital admissions. MRSA was responsible for 26% of S. aureus bacteraemia and 72% of nosocomial infections. Only six possible cases of community-acquired MRSA infections were described. MSSA bacteraemia was more likely to present as pulmonary and bone or joint infections, while bacteraemia without a source was the most common presentation with MRSA. Infants, children with malnutrition, and residents of long-term care facilities were at highest risk for MRSA bacteraemia. The overall case fatality rate for S. aureus bacteraemia was 8.8% over five years, with MRSA being the only significant risk factor for mortality. CONCLUSION: The incidence of S. aureus bacteraemia and MRSA bacteraemia in children has remained stable over the past five years. MRSA is a predominantly nosocomial pathogen in children with S. aureus bacteraemia in Cape Town, South Africa. PMID- 24167622 TI - Genotype-specific vs. cross-reactive host immunity against a macroparasite. AB - Vertebrate hosts often defend themselves against several co-infecting parasite genotypes simultaneously. This has important implications for the ecological dynamics and the evolution of host defence systems and parasite strategies. For example, it can drive the specificity of the adaptive immune system towards high genotype-specificity or cross-reactivity against several parasite genotypes depending on the sequence and probability of re-infections. However, to date, there is very little evidence on these interactions outside mammalian disease literature. In this study we asked whether genotype-specific or cross-reactive responses dominate in the adaptive immune system of a fish host towards a common macroparasite. In other words, we investigated if the infection success of a parasite genotype is influenced by the immunization genotype. We reciprocally immunized and re-exposed rainbow trout (Oncorhynchus mykiss) to a range of genotypes of the trematode eye fluke Diplostomum pseudospathaceum, and measured infection success of the parasite. We found that the infection success of the parasite genotypes in the re-exposure did not depend on the immunization genotype. While immunization reduced average infection success by 31%, the reduction was not larger against the initial immunization genotype. Our results suggest significant cross-reactivity, which may be advantageous for the host in genetically diverse re-exposures and have significant evolutionary implications for parasite strategies. Overall, our study is among the first to demonstrate cross-reactivity of adaptive immunity against genetically diverse macroparasites with complex life cycles. PMID- 24167623 TI - Evaluating true BCI communication rate through mutual information and language models. AB - Brain-computer interface (BCI) systems are a promising means for restoring communication to patients suffering from "locked-in" syndrome. Research to improve system performance primarily focuses on means to overcome the low signal to noise ratio of electroencephalogric (EEG) recordings. However, the literature and methods are difficult to compare due to the array of evaluation metrics and assumptions underlying them, including that: 1) all characters are equally probable, 2) character selection is memoryless, and 3) errors occur completely at random. The standardization of evaluation metrics that more accurately reflect the amount of information contained in BCI language output is critical to make progress. We present a mutual information-based metric that incorporates prior information and a model of systematic errors. The parameters of a system used in one study were re-optimized, showing that the metric used in optimization significantly affects the parameter values chosen and the resulting system performance. The results of 11 BCI communication studies were then evaluated using different metrics, including those previously used in BCI literature and the newly advocated metric. Six studies' results varied based on the metric used for evaluation and the proposed metric produced results that differed from those originally published in two of the studies. Standardizing metrics to accurately reflect the rate of information transmission is critical to properly evaluate and compare BCI communication systems and advance the field in an unbiased manner. PMID- 24167624 TI - Reprogramming of round spermatids by the germinal vesicle cytoplasm in mice. AB - The birthrate following round spermatid injection (ROSI) remains low in current and evidence suggests that factors in the germinal vesicle (GV) cytoplasm and certain substances in the GV such as the nucleolus might be responsible for genomic reprogramming and embryonic development. However, little is known whether the reprogramming factors in GV oocyte cytoplasm and/or nucleolus in GV are beneficial to the reprogramming of round spermatids and development of ROSI embryos. Here, round spermatids were treated with GV cytolysates and injected this round spermatid alone or co-injected with GV oocyte nucleolus into mature metaphase II oocytes. Subsequent embryonic development was assessed morphologically and by Oct4 expression in blastocysts. There was no significant difference between experimental groups at the zygote to four-cell development stages. Blastocysts derived from oocytes which were injected with cytolysate treated-round spermatid alone or co-injected with nucleoli injection yielded 63.6% and 70.3% high quality embryos, respectively; comparable to blastocysts derived by intracytoplasmic sperm injection (ICSI), but higher than these oocytes which were co-injected with lysis buffer-treated round spermatids and nucleoli or injected with the lysis buffer-treated round spermatids alone. Furthermore, the proportion of live offspring resulting from oocytes which were co-injected with cytolysate treated-round spermatids and nucleoli or injected with cytolysate treated-round spermatids alone was higher than those were injected with lysis buffer treated-round spermaids, but comparable with the ICSI group. Our results demonstrate that factors from the GV cytoplasm improve round spermatid reprogramming, and while injection of the extra nucleolus does not obviously improve reprogramming its potential contribution, although which cannot be definitively excluded. Thus, some reprogramming factors are evidently present in GV oocyte cytoplasm and could significantly facilitate ROSI technology, while the nucleolus in GV seems also having a potential to improve reprogramming of round spermatids. PMID- 24167625 TI - The interactive effects of transgenically overexpressed 1Ax1 with various HMW-GS combinations on dough quality by introgression of exogenous subunits into an elite Chinese Wheat variety. AB - Seed storage proteins in wheat endosperm, particularly high-molecular-weight glutenin subunits (HMW-GS), are primary determinants of dough properties, and affect both end-use quality and grain utilization of wheat (Triticum aestivum L). In order to investigate the interactive effects between the transgenically overexpressed 1Ax1 subunit with different HMW-GS on dough quality traits, we developed a set of 8 introgression lines (ILs) overexpressing the transgenic HMW glutenin subunit 1Ax1 by introgression of this transgene from transgenic line B102-1-2/1 into an elite Chinese wheat variety Chuanmai107 (C107), using conventional crossing and backcrossing breeding technique. The donor C107 strain lacks 1Ax1 but contains the HMW-GS pairs 1Dx2+1Dy12 and 1Bx7+1By9. The resultant ILs showed robust and stable expression of 1Ax1 even after five generations of self-pollination, and crossing/backcrossing three times. In addition, overexpression of 1Ax1 was compensated by the endogenous gluten proteins. All ILs exhibited superior agronomic performance when compared to the transgenic parent line, B102-1-2/1. Mixograph results demonstrated that overexpressed 1Ax1 significantly improved dough strength, resistance to extension and over-mixing tolerance, in the targeted wheat cultivar C107. Further, comparisons among the ILs showed the interactive effects of endogenous subunits on dough properties when 1Ax1 was overexpressed: subunit pair 17+18 contributed to increased over mixing tolerance of the dough; expression of the Glu-D1 allele maintained an appropriate balance between x-type and y-type subunits and thereby improved dough quality. It is consistent with ILs C4 (HMW-GS are 1, 17+18, 2+12) had the highest gluten index and Zeleny sedimentation value. This study demonstrates that wheat quality could be improved by using transgenic wheat overexpressing HMW-GS and the feasibility of using such transgenic lines in wheat quality breeding programs. PMID- 24167626 TI - Sensitivity of the green alga Pediastrum duplex Meyen to allelochemicals is strain-specific and not related to co-occurrence with allelopathic macrophytes. AB - Interspecific differences in the response of microalgae to stress have numerous ecological implications. However, little is known of intraspecific sensitivities and the potential role of local genetic adaptation of populations. We compared the allelochemical sensitivity of 23 Pediastrum duplex Meyen strains, a common component of the freshwater phytoplankton. In order to test for local genetic adaptation, strains were isolated from water bodies with and without the allelopathically-active submerged macrophyte Myriophyllum. Strains were assigned to P. duplex on the basis of cell shape and colony morphology and only P. duplex strains that belonged to the same lineage in an ITS rDNA phylogeny were used. Inhibition of strain growth rates and maximum quantum yields of photosystem II were measured after exposure to tannic acid (TA) and co-culture with Myriophyllum spicatum. Growth rate inhibition varied over one order of magnitude between the P. duplex strains. There was no correlation between the presence of Myriophyllum in the source location and the sensitivity of the strains to TA or the presence of Myriophyllum, suggesting that at least strong unidirectional local adaptation to Myriophyllum had not taken place in the studied water bodies. The maximum quantum yield of photosystem II of TA exposed algae decreased, whereas the yield of algae exposed to M. spicatum was slightly higher than that of the controls. The ranking of P. duplex strain sensitivities differed between the types of exposure (single additions of TA versus co-existence with M. spicatum) and the parameter measured (growth rate versus maximum quantum yield), emphasizing the importance of measuring multiple traits when analysing strain-specific sensitivities towards allelochemicals. The observation that sensitivities to allelochemicals vary widely among strains of a single freshwater algal species should be taken into account if evaluating ecological consequences of allelopathic interactions. PMID- 24167627 TI - Pistil starch reserves at anthesis correlate with final flower fate in avocado (Persea americana). AB - A common observation in different plant species is a massive abscission of flowers and fruitlets even after adequate pollination, but little is known as to the reason for this drop. Previous research has shown the importance of nutritive reserves accumulated in the flower on fertilization success and initial fruit development but direct evidence has been elusive. Avocado (Persea americana) is an extreme case of a species with a very low fruit to flower ratio. In this work, the implications of starch content in the avocado flower on the subsequent fruit set are explored. Firstly, starch content in individual ovaries was analysed from two populations of flowers with a different fruit set capacity showing that the flowers from the population that resulted in a higher percentage of fruit set contained significantly more starch. Secondly, in a different set of flowers, the style of each flower was excised one day after pollination, once the pollen tubes had reached the base of the style, and individually fixed for starch content analysis under the microscope once the fate of its corresponding ovary (that remained in the tree) was known. A high variability in starch content in the style was found among flowers, with some flowers having starch content up to 1,000 times higher than others, and the flowers that successfully developed into fruits presented significantly higher starch content in the style at anthesis than those that abscised. The relationship between starch content in the ovary and the capacity of set of the flower together with the correlation found between the starch content in the style and the fate of the ovary support the hypothesis that the carbohydrate reserves accumulated in the flower at anthesis are related to subsequent abscission or retention of the developing fruit. PMID- 24167628 TI - Contribution of soft substrates to malignancy and tumor suppression during colon cancer cell division. AB - In colon cancer, a highly aggressive disease, progression through the malignant sequence is accompanied by increasingly numerous chromosomal rearrangements. To colonize target organs, invasive cells cross several tissues of various elastic moduli. Whether soft tissue increases malignancy or in contrast limits invasive colon cell spreading remains an open question. Using polyelectrolyte multilayer films mimicking microenvironments of various elastic moduli, we revealed that human SW480 colon cancer cells displayed increasing frequency in chromosomal segregation abnormalities when cultured on substrates with decreasing stiffness. Our results show that, although decreasing stiffness correlates with increased cell lethality, a significant proportion of SW480 cancer cells did escape from the very soft substrates, even when bearing abnormal chromosome segregation, achieve mitosis and undergo a new cycle of replication in contrast to human colonic HCoEpiC cells which died on soft substrates. This observation opens the possibility that the ability of cancer cells to overcome defects in chromosome segregation on very soft substrates could contribute to increasing chromosomal rearrangements and tumor cell aggressiveness. PMID- 24167629 TI - Identification of novel viruses using VirusHunter--an automated data analysis pipeline. AB - Quick and accurate identification of microbial pathogens is essential for both diagnosis and response to emerging infectious diseases. The advent of next generation sequencing technology offers an unprecedented platform for rapid sequencing-based identification of novel viruses. We have developed a customized bioinformatics data analysis pipeline, VirusHunter, for the analysis of Roche/454 and other long read Next generation sequencing platform data. To illustrate the utility of VirusHunter, we performed Roche/454 GS FLX titanium sequencing on two unclassified virus isolates from the World Reference Center for Emerging Viruses and Arboviruses (WRCEVA). VirusHunter identified sequences derived from a novel bunyavirus and a novel reovirus in the two samples respectively. Further sequence analysis demonstrated that the viruses were novel members of the Phlebovirus and Orbivirus genera. Both Phlebovirus and Orbivirus genera include many economic important viruses or serious human pathogens. PMID- 24167630 TI - Differential effects of genistein on prostate cancer cells depend on mutational status of the androgen receptor. AB - Blocking the androgen receptor (AR) activity is the main goal of therapies for advanced prostate cancer (PCa). However, relapse with a more aggressive, hormone refractory PCa arises, which harbors restored AR activity. One mechanism of such reactivation occurs through acquisition of AR mutations that enable its activation by various steroidal and non-steroidal structures. Thus, natural and chemical compounds that contribute to inappropriate (androgen-independent) activation of the AR become an area of intensive research. Here, we demonstrate that genistein, a soy phytoestrogen binds to both the wild and the Thr877Ala (T877A) mutant types of AR competitively with androgen, nevertheless, it exerts a pleiotropic effect on PCa cell proliferation and AR activity depending on the mutational status of the AR. Genistein inhibited, in a dose-dependent way, cell proliferation and AR nuclear localization and expression in LAPC-4 cells that have wild AR. However, in LNCaP cells that express the T877A mutant AR, genistein induced a biphasic effect where physiological doses (0.5-5 umol/L) stimulated cell growth and increased AR expression and transcriptional activity, and higher doses induced inhibitory effects. Similar biphasic results were achieved in PC-3 cells transfected with AR mutants; T877A, W741C and H874Y. These findings suggest that genistein, at physiological concentrations, potentially act as an agonist and activate the mutant AR that can be present in advanced PCa after androgen ablation therapy. PMID- 24167631 TI - Klf1, a C2H2 zinc finger-transcription factor, is required for cell wall maintenance during long-term quiescence in differentiated G0 phase. AB - Fission yeast, Schizoaccharomyces pombe, is a model for studying cellular quiescence. Shifting to a medium that lacks a nitrogen-source induces proliferative cells to enter long-term G0 quiescence. Klf1 is a Kruppel-like transcription factor with a 7-amino acid Cys2His2-type zinc finger motif. The deletion mutant, ?klf1, normally divides in vegetative medium, but proliferation is not restored after long-term G0 quiescence. Cell biologic, transcriptomic, and metabolomic analyses revealed a unique phenotype of the ?klf1 mutant in quiescence. Mutant cells had diminished transcripts related to signaling molecules for switching to differentiation; however, proliferative metabolites for cell-wall assembly and antioxidants had significantly increased. Further, the size of ?klf1 cells increased markedly during quiescence due to the aberrant accumulation of Calcofluor-positive, chitin-like materials beneath the cell wall. After 4 weeks of quiescence, reversible proliferation ability was lost, but metabolism was maintained. Klf1 thus plays a role in G0 phase longevity by enhancing the differentiation signal and suppressing metabolism for growth. If Klf1 is lost, S. pombe fails to maintain a constant cell size and normal cell morphology during quiescence. PMID- 24167632 TI - Complexation and sequestration of BMP-2 from an ECM mimetic hyaluronan gel for improved bone formation. AB - Bone morphogenetic protein-2 (BMP-2) is considered a promising adjuvant for the treatment of skeletal non-union and spinal fusion. However, BMP-2 delivery in a conventional collagen scaffold necessitates a high dose to achieve an efficacious outcome. To lower its effective dose, we precomplexed BMP-2 with the glycosaminoglycans (GAGs) dermatan sulfate (DS) or heparin (HP), prior to loading it into a hyaluronic acid (HA) hydrogel. In vitro release studies showed that BMP 2 precomplexed with DS or HP had a prolonged delivery compared to without GAG. BMP-2-DS complexes achieved a slightly faster release in the first 24 h than HP; however, both delivered BMP-2 for an equal duration. Analysis of the kinetic interaction between BMP-2 and DS or HP showed that HP had approximately 10 times higher affinity for BMP-2 than DS, yet it equally stabilized the protein, as determined by alkaline phosphatase activity. Ectopic bone formation assays at subcutaneous sites in rats demonstrated that HA hydrogel-delivered BMP-2 precomplexed with GAG induced twice the volume of bone compared with BMP-2 delivered uncomplexed to GAG. PMID- 24167633 TI - Evaluation and validation of reference genes for normalization of quantitative real-time PCR based gene expression studies in peanut. AB - The quantitative real-time PCR (qPCR) based techniques have become essential for gene expression studies and high-throughput molecular characterization of transgenic events. Normalizing to reference gene in relative quantification make results from qPCR more reliable when compared to absolute quantification, but requires robust reference genes. Since, ideal reference gene should be species specific, no single internal control gene is universal for use as a reference gene across various plant developmental stages and diverse growth conditions. Here, we present validation studies of multiple stably expressed reference genes in cultivated peanut with minimal variations in temporal and spatial expression when subjected to various biotic and abiotic stresses. Stability in the expression of eight candidate reference genes including ADH3, ACT11, ATPsyn, CYP2, ELF1B, G6PD, LEC and UBC1 was compared in diverse peanut plant samples. The samples were categorized into distinct experimental sets to check the suitability of candidate genes for accurate and reliable normalization of gene expression using qPCR. Stability in expression of the references genes in eight sets of samples was determined by geNorm and NormFinder methods. While three candidate reference genes including ADH3, G6PD and ELF1B were identified to be stably expressed across experiments, LEC was observed to be the least stable, and hence must be avoided for gene expression studies in peanut. Inclusion of the former two genes gave sufficiently reliable results; nonetheless, the addition of the third reference gene ELF1B may be potentially better in a diverse set of tissue samples of peanut. PMID- 24167634 TI - Gefitinib inhibits invasive phenotype and epithelial-mesenchymal transition in drug-resistant NSCLC cells with MET amplification. AB - Despite the initial response, all patients with epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer (NSCLC) eventually develop acquired resistance to EGFR tyrosine kinase inhibitors (TKIs). The EGFR-T790M secondary mutation is responsible for half of acquired resistance cases, while MET amplification has been associated with acquired resistance in about 5-15% of NSCLCs. Clinical findings indicate the retained addiction of resistant tumors on EGFR signaling. Therefore, we evaluated the molecular mechanisms supporting the therapeutic potential of gefitinib maintenance in the HCC827 GR5 NSCLC cell line harbouring MET amplification as acquired resistance mechanism. We demonstrated that resistant cells can proliferate and survive regardless of the presence of gefitinib, whereas the absence of the drug significantly enhanced cell migration and invasion. Moreover, the continuous exposure to gefitinib prevented the epithelial-mesenchymal transition (EMT) with increased E-cadherin expression and down-regulation of vimentin and N-cadherin. Importantly, the inhibition of cellular migration was correlated with the suppression of EGFR-dependent Src, STAT5 and p38 signaling as assessed by a specific kinase array, western blot analysis and silencing functional studies. On the contrary, the lack of effect of gefitinib on EGFR phosphorylation in the H1975 cells (EGFR-T790M) correlated with the absence of effects on cell migration and invasion. In conclusion, our findings suggest that certain EGFR-mutated patients may still benefit from a second-line therapy including gefitinib based on the specific mechanism underlying tumor cell resistance. PMID- 24167635 TI - Coastal habitats as surrogates for taxonomic, functional and trophic structures of benthic faunal communities. AB - Due to human impact, there is extensive degradation and loss of marine habitats, which calls for measures that incorporate taxonomic as well as functional and trophic aspects of biodiversity. Since such data is less easily quantifiable in nature, the use of habitats as surrogates or proxies for biodiversity is on the rise in marine conservation and management. However, there is a critical gap in knowledge of whether pre-defined habitat units adequately represent the functional and trophic structure of communities. We also lack comparisons of different measures of community structure in terms of both between- (beta) and within-habitat (alpha) variability when accounting for species densities. Thus, we evaluated a priori defined coastal habitats as surrogates for traditional taxonomic, functional and trophic zoobenthic community structure. We focused on four habitats (bare sand, canopy-forming algae, seagrass above- and belowground), all easily delineated in nature and defined through classification systems. We analyzed uni- and multivariate data on species and trait diversity as well as stable isotope ratios of benthic macrofauna. A good fit between habitat types and taxonomic and functional structure was found, although habitats were more similar functionally. This was attributed to within-habitat heterogeneity so when habitat divisions matched the taxonomic structure, only bare sand was functionally distinct. The pre-defined habitats did not meet the variability of trophic structure, which also proved to differentiate on a smaller spatial scale. The quantification of trophic structure using species density only identified an epi- and an infaunal unit. To summarize the results we present a conceptual model illustrating the match between pre-defined habitat types and the taxonomic, functional and trophic community structure. Our results show the importance of including functional and trophic aspects more comprehensively in marine management and spatial planning. PMID- 24167636 TI - Normal development in mice over-expressing the intracellular domain of DLL1 argues against reverse signaling by DLL1 in vivo. AB - The Notch signaling pathway mediates the direct communication between adjacent cells and regulates multiple developmental processes. Interaction of the Notch receptor with its ligands induces the liberation of the intracellular portion of Notch (NICD) referred to as regulated intramembraneous proteolysis (RIP). NICD translocates to the nucleus, and by complexing with the DNA binding protein RBPjkappa and other cofactors activates transcription of bHLH genes. RIP-like processing of various mammalian Notch ligands (DLL1, JAG1 and JAG2) and the translocation of their intracellular domains (ICDs) to the nucleus has also been observed. These observations together with effects of over-expressed ligand ICDs in cultured cells on cell proliferation, differentiation, and Notch activity and target gene expression have led to the idea that the intracellular domains of Notch ligands have signaling functions. To test this hypothesis in vivo we have generated ES cells and transgenic mice that constitutively express various versions of the intracellular domain of mouse DLL1. In contrast to other cell lines, expression of DICDs in ES cells did not block proliferation or stimulate neuronal differentiation. Embryos with ubiquitous DICD expression developed to term without any apparent phenotype and grew up to viable and fertile adults. Early Notch-dependent processes or expression of selected Notch target genes were unaltered in transgenic embryos. In addition, we show that mouse DICD enters the nucleus inefficiently. Collectively, our results argue against a signaling activity of the intracellular domain of DLL1 in mouse embryos in vivo. PMID- 24167637 TI - The PhysioFlow thoracic impedancemeter is not valid for the measurements of cardiac hemodynamic parameters in chronic anemic patients. AB - The aim of the present study was to test the validity of the transthoracic electrical bioimpedance method PhysioFlow(r) to measure stroke volume in patients with chronic anemia. Stroke volume index (SVI), as well as cardiac index (CI) obtained by transthoracic electrical bioimpedance method and doppler echocardiography were compared in healthy subjects (n = 25) and patients with chronic anemia (i.e. mainly with sickle cell anemia; n = 32), at rest. While doppler echocardiography was able to detect difference in SVI between the two populations, the Physioflow(r) failed to detect any difference. Bland & Altman analyses have demonstrated no interchangeability between the two methods to assess CI and SVI in anemic patients and healthy subjects. While doppler echocardiography displayed a good concordance for SVI results with those obtained in the literature for anemic patients, the Physioflow(r) did not. Finally, in contrast to doppler echocardiography: 1) the CI obtained with the Physioflow(r) was not correlated with the hemoglobin level and 2) the stroke volume determined by the Physioflow(r) was highly influenced by body surface area. In conclusion, our findings indicate that the Physioflow(r) device is inaccurate for the measurement of SVI and CI in patients with chronic anemia and has a poor accuracy for the measurement of these parameters in African healthy subjects. PMID- 24167638 TI - Adeno-associated virus mediated delivery of a non-membrane targeted human soluble CD59 attenuates some aspects of diabetic retinopathy in mice. AB - Diabetic retinopathy is the leading cause of visual dysfunction in working adults and is attributed to retinal vascular and neural cell damage. Recent studies have described elevated levels of membrane attack complex (MAC) and reduced levels of membrane associated complement regulators including CD55 and CD59 in the retina of diabetic retinopathy patients as well as in animal models of this disease. We have previously described the development of a soluble membrane-independent form of CD59 (sCD59) that when delivered via a gene therapy approach using an adeno associated virus vector (AAV2/8-sCD59) to the eyes of mice, can block MAC deposition and choroidal neovascularization. Here, we examine AAV2/8-sCD59 mediated attenuation of MAC deposition and ensuing complement mediated damage to the retina of mice following streptozotocin (STZ) induced diabetes. We observed a 60% reduction in leakage of retinal blood vessels in diabetic eyes pre-injected with AAV2/8-sCD59 relative to negative control virus injected diabetic eyes. AAV2/8-sCD59 injected eyes also exhibited protection from non-perfusion of retinal blood vessels. In addition, a 200% reduction in retinal ganglion cell apoptosis and a 40% reduction in MAC deposition were documented in diabetic eyes pre-injected with AAV2/8-sCD59 relative to diabetic eyes pre-injected with the control virus. This is the first study characterizing a viral gene therapy intervention that targets MAC in a model of diabetic retinopathy. Use of AAV2/8 sCD59 warrants further exploration as a potential therapy for advanced stages of diabetic retinopathy. PMID- 24167640 TI - Updates on Psoriasis and Cutaneous Oncology: Proceedings from the 2013 MauiDerm Meeting. PMID- 24167641 TI - Bone marrow necrosis - initial presentation in sickle cell anemia. AB - PATIENT: Male, 20 FINAL DIAGNOSIS: Sickle cell anemia Symptoms: Bone marrow necrosis * bone pain * fever * hepatomegaly * icterus * splenomegaly * weakness MEDICATION: - Clinical Procedure: - Specialty: Hematology. OBJECTIVE: Unusual clinical course. BACKGROUND: In sickle cell disease, bone involvement is the commonest clinical presentation in the acute as well as chronic setting presenting as painful vaso-occlusive crisis and avascular necrosis, respectively. Other complications include bone marrow necrosis and infarction. CASE REPORT: We report a case of a 20-year-old male who was referred for bone marrow evaluation due to symptoms of fever, weakness, and repeated episodes of bone pains. Bone trephine biopsy revealed multiple areas of central necrosis surrounded by fibroblasts. CONCLUSIONS: Recognition of necrosis through bone trephine biopsy is important for early initiation of therapy. PMID- 24167642 TI - A case with unusual stroke and fulminant outcome in a Hispanic male. AB - PATIENT: Male, 42 FINAL DIAGNOSIS: Moyamoya disease (MMD) Symptoms: Aphasia * concentration difficulty * dysarthria * personality change MEDICATION: - Clinical Procedure: - Specialty: Radiology. OBJECTIVE: Rare disease. BACKGROUND: Moyamoya disease (MMD) was first described in 1957 as "hypoplasia of the bilateral internal carotid arteries." The characteristic appearance of the associated network of abnormally dilated collateral vessels on angiography was later likened to "something hazy, like a puff of cigarette smoke," which, in Japanese, is Moyamoya. This paper describes the fulminant course of the disease in a Hispanic male involving the corpus callosum. CASE REPORT: A 42-year-old Hispanic male with progressive aphasia, slow mentation, and sudden onset of sensorimotor symptoms with gait disturbance was found to have multiple intracranial supratentorial infarcts of variable stages of evolution involving, but not limited to, the anterior corpus callosum, followed by rapid development of further infarcts. Angiography demonstrated right ACA occlusion, left supraclinoid ICA occlusion with a Moyamoya pattern of collateralization, and diffuse arteriopathy. A fulminant course ensued and the patient did not survive the acute phase of ischemic disease. CONCLUSIONS: Moyamoya disease may rarely present in North American Hispanic males, with advanced atypical clinical and imaging features involving the anterior corpus callosum and having a fulminant course. PMID- 24167643 TI - A new era of neurologic practice, the need to shift the residency training paradigm, and the importance of hospitalist neurology. PMID- 24167644 TI - Systematic review of teleneurology: neurohospitalist neurology. AB - The use of 2-way audiovisual telemedicine technology for the delivery of acute stroke care is well established in the literature and is a growing practice. The use of such technology for neurologic consultation outside the cerebrovascular specialty has been reported to a variable extent across most disciplines within the field of neurology, including that of the neurohospitalist medicine. A systematic review of these reports is lacking. Hence, the main purpose of this study was to conduct a systematic review of the literature on teleneurologic consultation in hospital neurology. The databases Ovid MEDLINE, EMBASE, PsychINFO, CINAHL, and Cochrane were used as data sources and were searched with key words "teleneurology" and its numerous synonyms and cognates. These key words were cross-referenced with subspecialties of neurology. The studies were included for further review only if the title or the abstract indicated that the study made use of 2-way audiovisual communication to address a neurologic indication. This search yielded 6625 abstracts. By consensus between the 2 investigators, 688 publications met the criteria for inclusion and further review. Four of those citations directly pertained to the inpatient hospital neurologic consultation. Each of the 4 relevant articles was scored with a novel rubric scoring functionality, application, technology, and evaluation phase. A subspecialty category score was calculated by averaging those scores. The use of 2-way audiovisual technology for general neurologic consultation of hospital inpatients, beyond stroke-related care, is promising, but the evidence supporting its routine use is weak. Further studies on reliability, validity, safety, efficacy, and cost-effectiveness are encouraged. PMID- 24167645 TI - Diffusion-weighted imaging in acute hyperammonemic encephalopathy. AB - Magnetic resonance imaging (MRI) findings associated with chronic liver disease are characterized by cerebral atrophy and bilateral, symmetric hyperintensities of the globus pallidus on T1-weighted images without corresponding signal intensities in T2-weighted images. Recently, distinct MRI changes of acute hepatic encephalopathy have been described which may be misinterpreted given their resemblance to hypoxic-ischemic injury imaging changes as well as their limited description in the neurologic literature. We describe 3 cases of acute hyperammonemic encephalopathy primarily characterized by restricted diffusion involving the insular and cingulate cortices and thalamus bilaterally. PMID- 24167646 TI - Resolution of acute onset hemichorea-hemiballismus after treatment with intravenous tissue plasminogen activator. AB - Hyperkinetic movement disorders are uncommon after acute ischemic stroke. Since these movement disorders are rarely the initial manifestation of acute cerebral ischemia, their presence may result in diagnostic uncertainty or it may inappropriately delay intravenous thrombolytic therapy for ischemic stroke. Hemichorea-hemiballism (HC-HB) is one of the more frequently encountered hyperkinetic movement disorders occurring in conjunction with stroke. Although HC HB may result from a stroke mimic, the acute onset should prompt rapid evaluation and consideration for the presence of stroke along with its time-dependent therapies including recombinant tissue plasminogen activator (rtPA). In this article, we describe a case of a patient with acute cerebral ischemia presenting clinically with HC-HB, who was given intravenous rtPA therapy despite an initially negative, early diffusion-weighted magnetic resonance imaging (MRI). Follow-up brain MRI performed 24 hours after the initiation of thrombolytic therapy confirmed acute infarction in the contralateral striatum. The patient had near-complete resolution of her HC-HB on discharge and had no complications related to the administration of intravenous rtPA. PMID- 24167647 TI - Inpatient falls: defining the problem and identifying possible solutions. Part I: an evidence-based review. AB - In this 2 part series, analysis of the risk stratification tools that are available, definition for the scope of the problem, and potential solutions through a review of the literature are presented. A systematic review was used to identify articles for risk stratification and interventions. Three risk stratification systems are discussed, St Thomas's Risk Assessment Tool in Falling Elderly Inpatients, Morse Fall Scale, and the Hendrich Fall Risk Model. Of these scoring systems, the Hendrich Fall Risk Model is the easiest to use and score. Predominantly, multifactorial interventions are used to prevent patient falls. Education and rehabilitation are common themes in studies with statistically significant results. The second article presents a guide to implementing a quality improvement project around hospital falls. A 10-step approach to Plan-Do Study-Act (PDSA) cycles is described. Specific examples of problems and analysis are easily applicable to any institution. Furthermore, the sustainability of interventions and targeting new areas for improvement is discussed. Although specific to falls in the hospitalized patient, the goal is to present a stepwise approach which is broadly applicable to other areas requiring quality improvement. PMID- 24167648 TI - Intravascular catheter-related bloodstream infection. AB - Intravascular catheters required for the care of many hospitalized patients can give rise to bloodstream infection, a complication of care that has occurred most frequently in intensive care unit (ICU) settings. Elucidation of the pathogenesis of catheter-related bloodstream infections (CRBSIs) has guided development of effective diagnostic, management, and prevention strategies. When CRBSIs occur in the ICU, physicians must be prepared to recognize and treat them. Prevention of these infections requires careful attention to optimal catheter selection, insertion and maintenance, and to removal of catheters when they are no longer needed. This review provides a succinct summary of the epidemiology, pathogenesis, and microbiology of CRBSIs and a review of current guidance for the diagnosis, management, and prevention of these infections. PMID- 24167650 TI - Indirect carotid-cavernous fistula presenting with unilateral ptosis, limitation of extraocular movements, proptosis, and conjunctival injection. PMID- 24167649 TI - Neurological complications of solid organ transplantation. AB - Solid organ transplantation (SOT) is the preferred treatment for an expanding range of conditions whose successful therapy has produced a growing population of chronically immunosuppressed patients with potential neurological problems. While the spectrum of neurological complications varies with the type of organ transplanted, the indication for the procedure, and the intensity of long-term required immunosuppression, major neurological complications occur with all SOT types. The second part of this 2-part article on transplantation neurology reviews central and peripheral nervous system problems associated with SOT with clinical and neuroimaging examples from the authors' institutional experience. Particular emphasis is given to conditions acquired from the donated organ or tissue, problems specific to types of organs transplanted and drug therapy related complications likely to be encountered by hospitalists. Neurologically important syndromes such as immune reconstitution inflammatory syndrome (IRIS), posterior reversible encephalopathy syndrome (PRES), and posttransplantation lymphoproliferative disorder (PTLD) are readdressed in the context of SOT. PMID- 24167651 TI - The reversible corpus callosum splenium lesion associated with hypoglycemic encephalopathy. PMID- 24167652 TI - An 80-year-old woman with left-sided headache and diplopia. PMID- 24167653 TI - Overexpression of HGF Promotes HBV-Induced Hepatocellular Carcinoma Progression and Is an Effective Indicator for Met-Targeting Therapy. AB - Hepatitis B virus (HBV) is a well-known cause of hepatocellular carcinoma (HCC), but the regulators effectively driving virus production and HCC progression remain unclear. By using genetically engineered mouse models, we show that overexpression of hepatocyte growth factor (HGF) accelerated HCC progression, supporting the genomic analysis that an up-regulated HGF signature is associated with poor prognosis in HBV-positive HCC patients. We show that for both liver regeneration and spontaneous HCC development there is an inclusive requirement for MET expression, and when HGF induces autocrine activation the tumor displays sensitivity to a small-molecule Met inhibitor. Our results demonstrate that HGF is a driver of HBV-induced HCC progression and may serve as an effective biomarker for Met-targeted therapy. MET inhibitors are entering clinical trials against cancer, and our data provide a molecular basis for targeting the Met pathway in hepatitis B-induced HCC. PMID- 24167654 TI - Extracellular Vesicle-Mediated Transfer of a Novel Long Noncoding RNA TUC339: A Mechanism of Intercellular Signaling in Human Hepatocellular Cancer. AB - Although the expression of long noncoding RNA (lncRNA) is altered in hepatocellular cancer (HCC), their biological effects are poorly defined. We have identified lncRNA with highly conserved sequences, ultraconserved lncRNA (ucRNA) that are transcribed and altered in expression in HCC. Extracellular vesicles, such as exosomes and microvesicles, are released from tumor cells and can transfer biologically active proteins and RNA across cells. We sought to identify the role of vesicle-mediated transfer of ucRNA as a mechanism by which these novel lncRNA could influence intercellular signaling with potential for environmental modulation of tumor cell behavior. HCC-derived extracellular vesicles could be isolated from cells in culture and taken up by adjacent cells. The expression of several ucRNA was dramatically altered within extracellular vesicles compared to that in donor cells. The most highly significantly expressed ucRNA in HCC cell-derived extracellular vesicles was cloned and identified as a 1,198-bp ucRNA, termed TUC339. TUC339 was functionally implicated in modulating tumor cell growth and adhesion. Suppression of TUC339 by siRNA reduced HCC cell proliferation, clonogenic growth, and growth in soft agar. Thus, intercellular transfer of TUC339 represents a unique signaling mechanism by which tumor cells can promote HCC growth and spread. These findings expand the potential roles of ucRNA in HCC, support the existence of selective mechanisms for lncRNA export from cells, and implicate extracellular vesicle-mediated transfer of lncRNA as a mechanism by which tumor cells can modulate their local cellular environment. Intercellular transfer of functionally active RNA molecules by extracellular vesicles provides a mechanism that enables cells to exert genetic influences on other cells within the microenvironment. PMID- 24167655 TI - RABL6A Promotes Oxaliplatin Resistance in Tumor Cells and Is a New Marker of Survival for Resected Pancreatic Ductal Adenocarcinoma Patients. AB - Pancreatic ductal adenocarcinoma (PDAC) is characterized by early recurrence following pancreatectomy, rapid progression, and chemoresistance. Novel prognostic and predictive biomarkers are urgently needed to both stratify patients for clinical trials and select patients for adjuvant therapy regimens. This study sought to determine the biological significance of RABL6A (RAB, member RAS oncogene family-like protein 6 isoform A), a novel pancreatic protein, in PDAC. Analyses of RABL6A protein expression in PDAC specimens from 73 patients who underwent pancreatic resection showed that RABL6A levels are altered in 74% of tumors relative to adjacent benign ductal epithelium. Undetectable RABL6A expression, found in 7% (5/73) of patients, correlated with improved overall survival (range 41 to 118 months with 3/5 patients still living), while patients with RABL6A expression had a worse outcome (range 3.3 to 100 months, median survival 20.3 months) (P = 0.0134). In agreement with those findings, RABL6A expression was increased in pancreatic cancer cell lines compared to normal pancreatic epithelial cells, and its knockdown inhibited pancreatic cancer cell proliferation and induced apoptosis. Moreover, RABL6A depletion selectively sensitized cells to oxaliplatin-induced arrest and death. This work reveals that RABL6A promotes the proliferation, survival, and oxaliplatin resistance of PDAC cells, whereas its loss is associated with extended survival in patients with resected PDAC. Such data suggest RABL6A is a novel biomarker of PDAC and potential target for anticancer therapy. PMID- 24167656 TI - MicroRNA 203 Modulates Glioma Cell Migration via Robo1/ERK/MMP-9 Signaling. AB - Glioblastoma (GBM) is the most common and malignant primary adult brain cancer. Allelic deletion on chromosome 14q plays an important role in the pathogenesis of GBM, and this site was thought to harbor multiple tumor suppressor genes associated with GBM, a region that also encodes microRNA-203 (miR-203). In this study, we sought to identify the role of miR-203 as a tumor suppressor in the pathogenesis of GBM. We analyzed the miR-203 expression data of GBM patients in 10 normal and 495 tumor tissue samples derived from The Cancer Genome Atlas data set. Quantitative real-time PCR and in situ hybridization in 10 high-grade GBM and 10 low-grade anaplastic astrocytoma tumor samples showed decreased levels of miR-203 expression in anaplastic astrocytoma and GBM tissues and cell lines. Exogenous expression of miR-203 using a plasmid expressing miR-203 precursor (pmiR-203) suppressed glioma cell proliferation, migration, and invasion. We determined that one relevant target of miR-203 was Robo1, given that miR-203 expression decreased mRNA and protein levels as determined by RT-PCR and Western blot analysis. Moreover, cotransfection experiments using a luciferase-based transcription reporter assay have shown direct regulation of Robo1 by miR-203. We also show that Robo1 mediates miR-203 mediated antimigratory functions as up regulation of Robo1 abrogates miR-203 mediated antimigratory effects. We also show that miR-203 expression suppressed ERK phosphorylation and MMP-9 expression in glioma cells. Furthermore, we demonstrate that miR-203 inhibits migration of the glioma cells by disrupting the Robo1/ERK/MMP-9 signaling axis. Taken together, these studies demonstrate that up-regulation of Robo1 in response to the decrease in miR-203 in glioma cells is responsible for glioma tumor cell migration and invasion. PMID- 24167657 TI - A novel cutaneous Fatty Acid-binding protein-related signaling pathway leading to malignant progression in prostate cancer cells. AB - Cutaneous fatty acid-binding protein (C-FABP), a cancer promoter and metastasis inducer, is overexpressed in the majority of prostatic carcinomas. Investigation of molecular mechanisms involved in tumor-promoting activity of C-FABP has established that there is a fatty acid-initiated signaling pathway leading to malignant progression of prostatic cancer cells. Increased C-FABP expression plays an important role in this novel signaling pathway. Thus, when C-FABP expression is increased, excessive amounts of fatty acids are transported into the nucleus where they act as signaling molecules to stimulate their nuclear receptor peroxisome proliferator-activated receptor gamma (PPARgamma). The activated PPARgamma then modulates the expression of its downstream target regulatory genes, which eventually lead to enhanced tumor expansion and aggressiveness caused by an overgrowth of cells with reduced apoptosis and an increased angiogenesis. PMID- 24167658 TI - CRK SH3N Domain Diminishes Cell Invasiveness of Non-Small Cell Lung Cancer. AB - CRK (c-Crk) as an adaptor protein is involved in several oncogenic signal transduction pathways, conveying oncogenic signals to its downstream effectors and thereby affecting multiple cellular processes including proliferation, differentiation, and migration. For example, we have observed that CRK expression and phosphorylation influence the invasiveness of non-small cell lung cancer (NSCLC) cells. To intervene in CRK signaling pathway, we examined whether CRK protein domains can be used as therapeutic tools to interrupt CRK signaling, thus influencing the biological behavior of NSCLC cells. For this purpose, Src Homology domains of CRK-I (i.e., SH2 and SH3N domains) were overexpressed in H157, Rh2, and A549 cells. CRK-SH3N domain expression induced epithelial morphology in H157 cells and enhanced epithelial morphology of A549 and Rh2 cells as compared to cells transfected with CRK-SH2 domain or empty vector. In addition, CRK-SH3N domain expression significantly decreased the motility and invasiveness of A549 and H157 cells. Furthermore, CRK-SH3N domain expression disrupted the interaction of CRK-II with DOCK180. In summary, these data provide evidence that the CRK-SH3N domain can be used to influence the malignant phenotype of NSCLC cells and also reduce the metastatic potential of these cells. PMID- 24167659 TI - Design and Synthesis of Potent Bivalent Peptide Agonists Targeting the EphA2 Receptor. AB - Designing potent and selective peptides and small molecules that target Eph receptor tyrosine kinases remains a challenge and new strategies are needed for developing novel and potent ligands for these receptors. In this study, we performed a structure-activity relationship study of a previously identified 12 amino acid-long peptide, SWL, by alanine scanning to identify residues important for receptor binding. To further enhance and optimize the receptor binding affinity of the SWL peptide, we applied the concept of bivalent ligand design to synthesize several SWL-derived dimeric peptides as novel ligands capable of binding simultaneously to two EphA2 receptor molecules. The dimeric peptides possess higher receptor binding affinity than the original monomeric SWL peptide, consistent with bivalent binding. The most potent dimeric peptide, a SWL dimer with a 6 carbon linker, has about 13 fold increased potency compared to SWL. Furthermore, similar to SWL, the dimeric peptide is an agonist and can promote EphA2 tyrosine phosphorylation (activation) in cultured cells. PMID- 24167661 TI - Squamous cell carcinoma antigen in cervical cancer and beyond. PMID- 24167660 TI - Herpesviruses: latency and reactivation - viral strategies and host response. AB - Eight members of the Herpesviridae family commonly infect humans, and close to 100% of the adult population is infected with at least one of these. The five that cause the most health concerns are: herpes simplex virus (HSV) type 1 and 2, Epstein-Barr virus (EBV), cytomegalovirus (CMV), and varicella zoster virus (VZV). In addition, there are human herpes virus (HHV) types 6-8. The review starts by introducing possible viral strategies in general. The particular biology and host relationship of the various human herpesviruses, including their pathology, are examined subsequently. Factors that contribute to the maintenance of latency and reactivation of viral replication are discussed. There will be special reference to how these viruses exploit and contribute to pathology in the oral cavity. Reactivation does not necessarily imply clinical symptoms, as reflected in the asymptomatic shedding of EBV and CMV from oral mucosa. The immune response and the level of viral output are both important to the consequences experienced. PMID- 24167662 TI - Staging of ovarian cancer: time to subdivide more? PMID- 24167663 TI - Potential opportunities to reduce cervical cancer by addressing risk factors other than HPV. AB - Cervical cancer is the most common cancer in developing world and 80% of global burden is reported from these nations. Human papillomavirus along with poverty, illiteracy/lower education level and standards, multi-parity, tobacco, malnutrition and poor genital hygiene may act synergistically to cause cervical cancer. Risk factor of cervical cancer may in itself be the reason for non viability of cervical cancer vaccine program in this part of the world. Interventions to address these risk factors in addition to vaccination of girls before their sexual debut may hold promises of reducing the morbidity and mortality of female genital cancers. PMID- 24167664 TI - Incidence of cervical, endometrial, and ovarian cancer in Korea, 1999-2010. AB - OBJECTIVE: To investigate the recent incidence of and trends in cervical, endometrial, and ovarian cancer in Korean females. METHODS: Data from the Korea Central Cancer Registry between 1999 and 2010 were analyzed. Age-standardized rates (ASRs) and annual percent changes (APCs) were calculated. RESULTS: THE ABSOLUTE INCIDENCE RATES OF THE THREE MAJOR GYNECOLOGIC CANCERS INCREASED: 6,394 in 1999 to 7,454 in 2010. The ASR for gynecologic cancer was 23.7 per 100,000 in 1999 and decreased to 21.0 in 2010 (APC, -1.1%; 95% confidence interval [CI], 1.53 to -0.70) due to a definitive decrease in the incidence of cervical cancer (APC, -4.3%). Endometrial cancer has been definitively increasing (APC, 6.9% during 1999-2010), especially in females <30 years old (APC, 11.2%) and in females >=80 years old (APC, 9.5%). The incidence of ovarian cancer is increasing gradually (APC, 1.5%). CONCLUSION: ASRs and APC for gynecologic cancers overall are decreasing due to the decrease in the incidence of cervical cancer. However, the incidence of endometrial and ovarian cancer has been increasing. PMID- 24167665 TI - Learning curve analysis of robot-assisted radical hysterectomy for cervical cancer: initial experience at a single institution. AB - OBJECTIVE: The aim of this study was to evaluate the learning curve and perioperative outcomes of robot-assisted laparoscopic procedure for cervical cancer. METHODS: A series of 65 cases of robot-assisted laparoscopic radical hysterectomies with bilateral pelvic lymph node dissection for early stage cervical cancer were included. Demographic data and various perioperative parameters including docking time, console time, and total operative time were reviewed from the prospectively collected database. Console time was set as a surrogate marker for surgical competency, in addition to surgical outcomes. The learning curve was evaluated using cumulative summation method. RESULTS: The mean operative time was 190 minutes (range, 117 to 350 minutes). Two unique phases of the learning curve were derived using cumulative summation analysis; phase 1 (the initial learning curve of 28 cases), and phase 2 (the improvement phase of subsequent cases in which more challenging cases were managed). Docking and console times were significantly decreased after the first 28 cases compared with the latter cases (5 minutes vs. 4 minutes for docking time, 160 minutes vs. 134 minutes for console time; p<0.001 and p<0.001, respectively). There was a significant reduction in blood loss during operation (225 mL vs. 100 mL, p<0.001) and early postoperative complication rates (28% vs. 8.1%, p=0.003) in phase 2. No conversion to laparotomy occurred. CONCLUSION: Improvement of surgical performance in robot-assisted surgery for cervical cancer can be achieved after 28 cases. The two phases identified by cumulative summation analysis showed significant reduction in operative time, blood loss, and complication rates in the latter phase of learning curve. PMID- 24167666 TI - Posttreatment cut-off levels of squamous cell carcinoma antigen as a prognostic factor in patients with locally advanced cervical cancer treated with radiotherapy. AB - OBJECTIVE: The aim of the present study was to assess prognostic factors for patients with locally advanced cervical cancer treated with radiotherapy as the primary treatment and to assess the posttreatment cut-off levels of squamous cell carcinoma antigen (SCC-Ag) to predict three-year overall survival (OS) rates. METHODS: One hundred and twenty-eight patients with cervical squamous cell carcinoma (International Federation of Gynecology and Obstetrics [FIGO] stage IIB IVA) treated using radiotherapy or concurrent chemoradiotherapy were identified. Of these patients, 116 who had SCC-Ag levels >1.5 ng/mL prior to treatment were analyzed retrospectively. RESULTS: Median age was 68 years (range, 27 to 79 years). The complete response rate was 70.7% and the three-year OS rate was 61.1%. The median levels of pretreatment and posttreatment SCC-Ag were 11.5 ng/mL (range, 1.6 to 310.0 ng/mL) and 0.9 ng/mL (range, 0.4 to 41.0 ng/mL), respectively. Multivariate analysis showed that pretreatment anemia (p=0.041), pelvic lymph node metastasis (p=0.016) and posttreatment SCC-Ag levels (p=0.001) were independent prognostic factors for three-year OS. The SCC-Ag level cut-off point for three-year OS rates, calculated using a receiver operating characteristic curve, was 1.15 ng/mL (sensitivity, 80.0%; specificity, 74.0%). CONCLUSION: Pretreatment anemia and pelvic lymph node metastasis are poor prognostic factors in locally advanced cervical cancer. Furthermore, posttreatment SCC-Ag levels <1.15 ng/mL predicted better three-year OS rates. PMID- 24167667 TI - Utility of serum squamous cell carcinoma antigen levels at the time of recurrent cervical cancer diagnosis in determining the optimal treatment choice. AB - OBJECTIVE: To investigate the utility of serum squamous cell carcinoma antigen (SCC-Ag) levels upon the diagnosis of recurrent cervical cancer for decision making in patient management. METHODS: Clinical records from 167 cervical cancer patients who developed recurrence between April 1996 and September 2010 were reviewed. A Cox proportional hazards regression model was used to investigate the prognostic significance of serum SCC-Ag levels at the time of recurrence. The effects of various salvage treatments on survival outcomes of recurrent cervical cancer were examined with respect to serum SCC-Ag levels. RESULTS: Serum SCC-Ag levels were elevated (>2.0 ng/mL) in 125 patients (75%) when recurrence was diagnosed. These patients exhibited significantly shorter postrecurrence survival than those with normal SCC-Ag levels (log-rank; p=0.033). Multivariate analyses revealed that an elevated serum SCC-Ag level was an independent prognostic factor for poor postrecurrence survival. In patients with SCC-Ag levels <14.0 ng/mL, radiotherapy or surgery resulted in improved survival compared with chemotherapy or supportive care. In contrast, in patients with SCC-Ag levels of >=14.0 ng/mL, salvage treatment with radiotherapy had only a minimal impact on postrecurrence survival. CONCLUSION: The serum SCC-Ag level measured when cervical cancer recurrence is diagnosed can be useful for deciding upon the appropriate salvage treatment. PMID- 24167668 TI - Clinical outcome of 31 patients with primary malignant melanoma of the vagina. AB - OBJECTIVE: To investigate the clinical characteristics of and prognostic factors for primary malignant melanoma of the vagina. METHODS: Clinical data from 31 patients treated for primary malignant melanoma of the vagina at the Sun Yat-sen University Cancer Center between March 1970 and June 2005 were retrospectively analyzed. RESULTS: The median age was 58 years (range, 18 to 73 years), and the main symptoms reported were vaginal bleeding and vaginal discharge. Most tumors were of the nodular type and classified as stage I according to International Federation of Gynecology and Obstetrics staging criteria. Surgery was performed on 22 patients, chemotherapy was administered to 7 patients, and immunotherapy was administered to 19 patients. Recurrent tumors developed in 11 patients (35.5%) during a median follow-up period of 20.2 months (range, 1 month to 18 years). The 5-year overall survival rate was 32.3%. Univariate analysis revealed that macroscopic tumor growth and the treatment method significantly affected survival outcome (p=0.039 and p<0.001, respectively), whereas the radicality of surgery did not (p=0.296). Multivariate analysis revealed that macroscopic tumor growth (hazard ratio [HR], 4.1; 95% confidence interval [CI], 1.4 to 12.1; p=0.010) and treatment method (HR, 0.3; 95% CI, 0.1 to 0.9; p=0.025) were independent prognostic factors for overall survival. CONCLUSION: Patients with primary vaginal melanoma have a poor prognosis. Macroscopic tumor growth and treatment method are prognostic factors for primary malignant melanoma of the vagina. PMID- 24167669 TI - Serum leptin, adiponectin and endometrial cancer risk in Chinese women. AB - OBJECTIVE: To investigate the relationship between serum concentrations of leptin or adiponectin, and endometrial carcinoma in Chinese women. METHODS: We conducted a case-control study of a total of 516 Chinese women to detect the relationships between serum concentrations of leptin or adiponectin, and endometrial carcinoma in Chinese women. The study subject constituted 206 cases of endometrial cancer and 310 normal controls. RESULTS: Patients with endometrial carcinoma had higher serum leptin concentrations than controls (28.8+/-2.2 ug/L vs. 19.8+/-1.4 ug/L; p<0.001). The adiponectin levels in patients were lower than in controls with borderline statistical significance (2,330.7+/-180.5 ug/L vs. 2,583.9+/-147.2 ug/L; p=0.078). Logistic regression analysis confirmed the associations between leptin or adiponectin, and endometrial carcinoma after adjustment for age, body mass index, fasting insulin, serum glucose, cholesterol, triglycerides, and high density lipoprotein cholesterol (odds ratio for the top tertile vs. the bottom tertile: leptin 2.05; 95% confidence interval [CI], 1.28 to 3.29; p<0.001; adiponectin 0.52; 95% CI, 0.32 to 0.83; p<0.001). CONCLUSION: Increased leptin or decreased adiponectin levels are associated with endometrial carcinoma. PMID- 24167670 TI - Trends in incidence and survival outcome of epithelial ovarian cancer: 30-year national population-based registry in Taiwan. AB - OBJECTIVE: To investigate the changes of incidence and prognosis of epithelial ovarian cancer in thirty years in Taiwan. METHODS: The databases of women with epithelial ovarian cancer during the period from 1979 to 2008 were retrieved from the National Cancer Registration System of Taiwan. The incidence and prognosis of these patients were analyzed. RESULTS: Totally 9,491 patients were included in the study. The age-adjusted incidences of epithelial ovarian cancer were 1.01, 1.37, 2.37, 3.24, 4.18, and 6.33 per 100,000 person-years, respectively, in every 5-year period from 1979 to 2008. The age-specific incidence rates increased especially in serous, endometrioid and clear cell carcinoma, and the age of diagnosis decreased from sixty to fifty years old in the three decades. Patients with mucinous, endometrioid, or clear cell carcinoma had better long-term survival than patients with serous carcinoma (log rank test, p<0.001). Patients with undifferentiated carcinoma or carcinosarcoma had poorer survival than those with serous carcinoma (log rank test, p<0.001). The mortality risk of age at diagnosis of 30-39 was significantly higher than that of age of 70 years or more (test for trend, p<0.001). The mortality risk decreased from the period of 1996 1999 (hazard ratio [HR], 0.90; p=0.054) to the period after 2000 (HR, 0.74; p<0.001) as compared with that from the period of 1991-1995. CONCLUSION: An increasing incidence and decreasing age of diagnosis in epithelial ovarian cancer patients were noted. Histological type, age of diagnosis, and treatment period were important prognostic factors for epithelial ovarian carcinoma. PMID- 24167671 TI - Improvements to the FIGO staging for ovarian cancer: reconsideration of lymphatic spread and intraoperative tumor rupture. AB - OBJECTIVE: To evaluate the improvement in prognosis prediction with reassignment of International Federation of Gynecology and Obstetrics (FIGO) stages for ovarian carcinoma. METHODS: This was a retrospective study of patients with epithelial ovarian, fallopian tube, and primary peritoneal cancers. Sub-staging criteria used in stage reassignment were defined as follows: surgical spillage (IC1), capsule rupture before surgery or tumor on the surface (IC2), and positive cytology results (IC3); microscopic (IIB1) and macroscopic (IIB2) pelvic spread; microscopic extrapelvic spread (IIIA1) and retroperitoneal lymph node (LN) metastasis without extrapelvic spread (IIIA2); and supraclavicular LN metastasis (IVA) and other distant metastasis (IVB). Survival outcomes associated with the current and reassigned stages were compared. RESULTS: Overall, 870 patients were eligible for analysis. The median follow-up period was 45 months (range, 0 to 263 months). The 5-year overall survival rates (5YSRs) according to the current staging were 93.5% (IA), 82.5% (IC), 75.0% (IIB), 74.5% (IIC), 57.5% (IIIA), 54.0% (IIIB), 38.5% (IIIC), and 33.0% (IV). The 5YSRs of patients with IC1, IC2, and IC3 after sub-staging were 92.0%, 85.0%, and 71.0%, respectively (p=0.004). Patients who were reassigned to stage IIIA2 had a better 5YSR than those with extrapelvic tumors >2 cm (66.3% vs. 35.8%; p=0.005). Additionally, patients with newly assigned stage IVA disease had a significantly better 5YSR than those with stage IVB disease (52.0% vs. 28.0%; p=0.015). CONCLUSION: The modified FIGO staging for ovarian carcinoma appears superior to the current staging for discriminating survival outcomes of patients with surgical spillage, retroperitoneal LN metastasis without extrapelvic peritoneal involvement, or distant metastasis to supraclavicular LNs. PMID- 24167672 TI - Feasibility, acceptability and preferences for intraperitoneal chemotherapy with paclitaxel and cisplatin after optimal debulking surgery for ovarian and related cancers: an ANZGOG study. AB - OBJECTIVE: Intraperitoneal (IP) chemotherapy in women with optimally debulked stage III ovarian cancer has been reported to prolong overall survival, but has not been widely adopted due to concerns about its toxicity, inconvenience and acceptability to patients. The purposes of this study were to determine the regimen's feasibility, adverse events, catheter-related complications, progression-free survival, health-related quality of life (HRQL), and patients' preferences for IP versus intravenous (IV) chemotherapy. METHODS: We conducted a single arm, multi-center study of IP chemotherapy with IV paclitaxel 135 mg/m(2) (D1) over 3 hours, IP cisplatin 75 mg/m(2) (D2), and IP paclitaxel 60 mg/m(2) (D8) for 6 cycles in women with optimally debulked stage III ovarian or related cancers. RESULTS: Thirty-eight eligible patients were recruited from 12 sites between July 2007 and December 2009. Seventy-one percent (n=27) completed at least 4 cycles and 63% (n=24) completed all 6 cycles. Grade 3 or 4 adverse events included nausea (n=2), vomiting (n=2), abdominal pain (n=2), and diarrhea (n=1), but not febrile neutropenia, neurotoxicity, or nephropathy. There were no treatment-related deaths. Catheter-related complications were the most frequent cause of early discontinuation of treatment (16 patients, 21%). Apart from neurotoxicity HRQL which worsened over time, HRQL was stable or improved with time. Most patients (>=50%) judged moderate benefits (e.g., an extra 6 months survival time or a 5% improvement in survival rates) necessary to make IP chemotherapy worthwhile. CONCLUSION: IP chemotherapy was feasible, tolerable, and most participants considered moderate survival benefits sufficient to warrant the adverse effects and inconvenience. PMID- 24167673 TI - The correlates of unemployment and its association with quality of life in cervical cancer survivors. AB - OBJECTIVE: Little is known regarding cervical cancer survivors' employment status, which represents social integration of cancer survivors as a pivotal domain of long-term quality of life. The goal of this study was to assess the correlates of unemployment and evaluate the impact on the comprehensive quality of life in cervical cancer survivors. METHODS: We enrolled 858 cervical cancer survivors from the gynecologic oncology departments of multi-centers in Korea. Factors associated with unemployment were identified using multivariate logistic regression analyses. We assessed different health-related quality of life domains with multivariate-adjusted least-square means between cervical cancer survivors who currently work and do not. RESULTS: After diagnosis and treatment, the percentage of unemployed survivors increased from 50.6% to 72.8%. Lower income (adjusted odds ratio [aOR], 1.97; 95% confidence interval [CI], 1.38 to 2.81), medical aid (aOR, 1.58; 95% CI, 1.05 to 2.38), two or more comorbidities (aOR, 1.80; 95% CI, 1.12 to 2.90), current alcohol drinkers (aOR, 2.33; 95% CI, 1.54 to 3.52), and employed at the time of diagnosis (aOR, 10.72; 95% CI, 7.10 to 16.16) were significantly associated with unemployment. Non-working groups showed significant differences with respect to physical functioning, role functioning, depression, and existential well-being. CONCLUSION: The proportion of unemployed cervical cancer survivors seems to increase, with low-income status and the presence of medical aid negatively being associated with employment, in addition to other comorbidities and previous working status. Effort should be made to secure the financial status of cervical cancer survivors. PMID- 24167675 TI - Management of cervical cancer patients with isolated para-aortic lymph node metastases. PMID- 24167676 TI - Editorial. PMID- 24167674 TI - The roles of ARID1A in gynecologic cancer. AB - One of the exciting findings in recent cancer genome studies is the discovery of somatic mutations in several chromatin remodeling genes. These studies not only illuminate the emerging roles of chromatin remodeling in the pathogenesis of human cancer but also provide molecular genetic basis of aberrant epigenomic regulation as one of the key mechanisms driving cancer development. This is because chromatin remodeling influences a variety of DNA activities such as replication, transcription, repair, methylation, and recombination. Among the mutated chromatin remodeling genes reported, ARID1A is frequently mutated in a variety of human cancers, especially in endometrium-related neoplasms including ovarian clear cell carcinoma, ovarian endometrioid carcinomas, and uterine endometrioid carcinomas, all of which arise from endometrial epithelium. This review will summarize the recent advances in studying the roles of ARID1A mutations in gynecologic cancers with special emphasis on how this new knowledge will further extend our understanding of the pathogenesis of endometrium-related carcinomas. PMID- 24167677 TI - A 12-week nursing support programme for carers of children and adolescents in the UK with attention deficit hyperactivity disorder prescribed atomoxetine. AB - INTRODUCTION: Patient support programmes are assuming greater importance in the UK in many therapeutic areas, mostly with the aim of improving adherence to medication and many being provided by the pharmaceutical industry. Atomoxetine is a noradrenaline reuptake inhibitor for the treatment of attention deficit hyperactivity disorder that has recently demonstrated incremental efficacy for at least 12 weeks. Issues of adherence may be predicted over this initial period particularly if adverse events are reported. The Strattera Support Service was initiated in 2006 ( funded by Eli Lilly) to provide advice, initially through telephone contact, by trained nurses during the first 12 weeks of atomoxetine therapy and is offered to carers of patients diagnosed with ADHD after atomoxetine has been prescribed. The aim of this pilot service evaluation is to assess discontinuation rates and compare them with historical control data. METHODS: Data from patients in the service who initiated atomoxetine between 1 January 2009 and 31 March 2010 were analysed to provide a pilot service evaluation. Continuation rates of patients in the service who were taking atomoxetine at week 12 were assessed and compared with historical control data. RESULTS: Between 1 January 2009 and 31 March 2010, 346 patients (300 male patients) enrolled in the programme and commenced treatment with atomoxetine. The mean age of patients was 10.5 years. At 12 weeks, 33 (9.5%) patients had discontinued treatment; continuation rates were similar regardless of age and sex. Discontinuation rates of 39% are reported from historical control data. CONCLUSIONS: Preliminary data from a 12-week atomoxetine patient support programme are supportive that discontinuation rates may be lower than historically expected. Further service evaluations of this programme may be required. PMID- 24167678 TI - Cost-effectiveness of ethyl-eicosapentaenoic acid in the treatment of bipolar disorder. AB - BACKGROUND: This study develops an economic model to evaluate the cost effectiveness of ethyl-eicosapentaenoic acid (ethyl-EPA) as an adjunct treatment of bipolar I disorder. METHODS: A 1-year Markov model is used incorporating three health states: euthymic, manic and depressive. The model was populated using outcomes from a clinical trial on clinical efficacy and other published literature. RESULTS: The incremental cost-effectiveness ratio (ICER) per quality adjusted life year (QALY) of ethyl-EPA in comparison with placebo was estimated to be -L2,782 in 2008/09 prices, the negative ICER indicating ethyl-EPA to be a more effective and less costly treatment option than placebo in terms of cost savings of other resource use. CONCLUSIONS: The sensitivity analysis indicated that the results were robust. Future research covering a longer time period using broader costs of the disease will be required to consolidate these findings. PMID- 24167679 TI - Clozapine treatment of patients with refractory schizophrenia, concurrent dengue infection and hematological abnormalities: three case reports. AB - BACKGROUND: Dengue is a febrile illness that is most common in tropical areas but is recognized worldwide as one of the most important arbovirus diseases of humans. This febrile illness generally has a course with mild alterations in white blood cell count, but there are also rare cases of severe neutropenia or agranulocytosis during dengue infection. Clozapine (CLZ) remains the most effective treatment for schizophrenia, but because of its poor side effect profile, in particular due to the increased risk of neutropenia and agranulocytosis, it is generally used for patients whose condition responds poorly to other antipsychotics. METHODS: We report three cases of dengue infection in patients with refractory schizophrenia who were using CLZ, and we discuss the implications of this infection on the continuation of CLZ treatment in these patients. RESULTS: Of these three cases with dengue infection and co occurence of CLZ use, the first would be classified as severe neutropenia and the second as moderate leucopenia; the last case had a white blood cell (WBC) count inside the normal range, and had no need to change his antipsychotic. The first and the second patient presented a worsening in their schizophrenic psychopathologies, after CLZ withdrawal, evolving into catatonic states, that were reverted after the careful reintroduction of CLZ. DISCUSSION: It is very likely that during dengue epidemics many patients with schizophrenia and using CLZ have their treatment permanently discontinued given WBC count concerns, causing relapse of symptoms of schizophrenia and impairment of quality of life of these patients.This is the first report of neutropenia cases among CLZ-treated patients during dengue infection that describes the withdrawal of CLZ and its successful readministration. PMID- 24167680 TI - Patients' and clinicians' attitude towards long-acting depot antipsychotics in subjects with a first episode of psychosis. AB - OBJECTIVES: The acceptance and use of long-acting depot antipsychotics has been shown to be influenced by the attitudes of patients and clinicians. Depot treatment rates are low across countries and especially patients with first episode psychosis are rarely treated with depot medication. The aim of this article was to review the literature on patients' and clinicians' attitudes towards long-acting depot antipsychotics in subjects with first-episode psychosis. METHODS: A systematic search of Medline, Embase, PsycINF and Google Scholar was conducted. Studies were included if they reported original data describing patients' and clinicians' attitudes towards long-acting depot antipsychotic in subjects with first-episode psychosis. RESULTS: Six studies out of a total of 503 articles met the inclusion criteria. Four studies conveyed a negative and two a positive opinion of clinicians toward depot medication. No systematic study directly addressed the attitude of patients with first-episode psychosis. Psychiatrists frequently presume that patients with first-episode psychosis would not accept depot medication and that depots are mostly eligible for chronic patients. CONCLUSIONS: Full information of all patients especially those with first episode psychosis in a therapeutic relationship that includes shared decision-making processes could reduce the negative image and stigmatization attached to depots. PMID- 24167683 TI - Editorial. PMID- 24167682 TI - Ziprasidone for obsessive compulsive disorder in schizophrenia. PMID- 24167681 TI - Acute and chronic cognitive effects of levodopa and dopamine agonists on patients with Parkinson's disease: a review. AB - The spatiotemporal progression of dopamine depletion in Parkinson's disease (PD) provides a special model for assessing dopaminergic effects on neural systems with differential baseline dopamine levels. This study aims at reviewing cognitive effects of dopaminergic stimulation in PD. While considering dopaminergic drugs (levodopa or dopamine agonists), temporal intervals (acute or chronic) and cognitive domains, we found that empirical evidence was almost focused on acute effects of levodopa on executive functions. The paucity of empirical evidence suggests that no meaningful conclusions can be actually drawn and further research is needed in relation to: (1) other cognitive domains; (2) the acute cognitive effects of dopamine agonists, as compared with levodopa; (3) possible differences between cognitive effects of different dopamine agonists; (4) the cognitive effects of chronic dopaminergic therapies. The latter issue is of particular clinical interest considering that many PD patients present a mild cognitive impairment: is this cognitive feature worsened or improved by the prolonged dopaminergic therapy? In addition to the potential risk of inducing dyskinesia and behavioral side effects such as impulse control disorders, also cognitive effects of prolonged dopaminergic treatments should be taken in account by clinicians in order to anticipate or to delay their prescription to PD patients. PMID- 24167684 TI - Clinical efficacy and changes in the dosages of concomitantly used psychotropic drugs in memantine therapy in Alzheimer's disease with behavioral and psychological symptoms on dementia. AB - OBJECTIVE: We investigated the clinical efficacy and changes in the dosages of concomitantly used psychotropic drugs in memantine therapy in Alzheimer's disease (AD) with behavioral and psychological symptoms on dementia (BPSD). METHODS: The subjects were 38 inpatients who had been diagnosed with AD according to the Diagnostic and Statistical Manual of Mental Disorders, fourth edition (DSM-IV). The outcome measures assessed were BPSD and cognitive function. BPSD was assessed using the neuropsychiatric inventory (NPI) and cognitive function was assessed using the mini-mental examination (MMSE). The changes in the dosages of concomitant psychotropic drugs were also assessed. RESULTS: SIGNIFICANT DECREASES WERE FOUND IN THE MEMANTINE THERAPY GROUP IN THE FOLLOWING NPI TOTAL SCORE AND FIVE NPI SUBSCALES: delusions, hallucinations, agitation, irritability, and aberrant motor behavior, but no significant differences were seen between the memantine therapy group and the control group. Furthermore, the memantine therapy group allowed the dosage of the psychotropic drugs to be significantly reduced compared with the control group. CONCLUSION: The results of this study suggest that the administration of memantine to patients with AD with BPSD may afford superior efficacy and may also make it possible to reduce the risperidone equivalent dose, the diazepam equivalent dose and the dosage of the psychotropic drugs. PMID- 24167685 TI - Plasma quetiapine in relation to prescribed dose and other factors: data from a therapeutic drug monitoring service, 2000-2011. AB - OBJECTIVE: Suggested predose plasma quetiapine target ranges for effective therapy in schizophrenia lie between 50 and 500 ug/l. We aimed to examine data from a quetiapine therapeutic drug monitoring (TDM) service to assess the plasma quetiapine concentrations attained at specified doses in clinical practice. METHOD: We studied TDM data from patients given immediate-release quetiapine in the period 2000-2011. RESULTS: There were 946 samples from 487 patients (257 males, age at time of first sample, median [range] 34 [14-87] years, and 230 females, age at time of first sample, median [range] 38 [10-92] years). The plasma quetiapine concentration was <50 and <100 ug/l in 30% and 50% of samples, respectively (no quetiapine detected in 9% of samples). The relationship between dose and plasma quetiapine was poor. The mean (95% confidence interval [CI]) quetiapine dose was higher (t = 3.6, df = 446, p <0.01) in males versus females (641 [600-1240] and 548 [600-943] mg/day, respectively), although there was no difference in median dose (600 mg/day) or in the mean (95% CI) plasma quetiapine concentrations attained. Smoking habit had no discernible effect on plasma quetiapine concentration. CONCLUSIONS: There was a poor relationship between dose and plasma quetiapine concentration in this study, as found by others. This is probably because of the short plasma half-life of the drug, at least in part. Nevertheless, quetiapine TDM can help assess adherence and measurement of quetiapine metabolites, notably N-desalkylquetiapine, as well as quetiapine itself may enhance the value of quetiapine TDM in future. PMID- 24167686 TI - Sleep architecture in ziprasidone-treated bipolar depression: a pilot study. AB - OBJECTIVES: This study investigated the effect of ziprasidone augmentation therapy on sleep architecture in bipolar depression. METHODS: We conducted a double-blind, randomized, placebo-controlled clinical pilot trial of ziprasidone versus placebo in Diagnostic and Statistical Manual of Mental Disorders, fourth edition bipolar disorder with current major depressive episode. The effects during acute (2-5 days) and continuation treatment (28-31 days) were measured. Main outcomes were sleep architecture variables including rapid eye movement sleep (REM) and slow wave sleep (SWS) measured by polysomnography. Secondary outcomes included subjective sleep quality measures and illness severity measures including the 17-item Hamilton Depression Rating Scale (HAMD-17), Montgomery Asberg Depression Rating Scale (MADRS), Hamilton Anxiety Rating Scale (HAMA) and Clinical Global Illness Severity (CGI-S) scores. RESULTS: The completer analysis comprised of 14 patients (ziprasidone, N = 8 and placebo, N = 6). Latency to REM, duration of SWS, duration of stage 2 sleep, total sleep time, onset to sleep latency, number of awakenings and overall sleep efficiency significantly improved in ziprasidone-treated participants over placebo. CGI-S and HAMA scores also significantly improved. No significant difference between treatment groups was seen on the HAMD-17, MADRS or in self-reported sleep quality. Increase in SWS duration significantly correlated with improvement in CGI-S, however, this finding did not withstand Bonferroni correction. CONCLUSION: Adjunctive ziprasidone treatment alters sleep architecture in patients with bipolar depression, which may partially explain its mechanism of action and merits further investigation. PMID- 24167687 TI - A review of the suitability of duloxetine and venlafaxine for use in patients with depression in primary care with a focus on cardiovascular safety, suicide and mortality due to antidepressant overdose. AB - Depression and anxiety disorders are among the most common disorders treated by general practitioners (GPs) in the UK. Since both disorders are associated with a significantly increased risk of suicide, including with antidepressant overdose, the safety of antidepressants in overdose is of paramount importance. Numerous updates relating to antidepressant safety have been issued by regulators in the UK which may have eroded GP confidence in antidepressants. Venlafaxine, a serotonin nor adrenaline reuptake inhibitor (SNRI) had primary care prescribing restrictions placed on it in 2004 due to concerns about cardiotoxicity and mortality in overdose. Although a review of the evidence led to a reversal of the majority of restrictions in 2006, evidence suggests GPs may still be cautious in their prescribing of venlafaxine and possibly other SNRI antidepressants for patients with depression and anxiety disorders. This paper reviews the evidence pertaining to the safety of SNRI antidepressants from a perspective of cardiovascular safety and overdose. The currently available evidence suggests a marginally higher toxicity of venlafaxine in overdose compared with another SNRI duloxetine and the selective serotonin reuptake inhibitors (SSRIs), although this may be related to differential patterns of prescribing in high-risk patients. Based on this review SNRIs have a positive risk benefit profile in the treatment of depression and generalized anxiety disorder in primary care, especially as second-line agents to SSRIs. PMID- 24167689 TI - Prolactinoma-associated obesity treated with bupropion and methylphenidate. PMID- 24167690 TI - Editorial. PMID- 24167688 TI - Lithium: the pharmacodynamic actions of the amazing ion. AB - Lithium has been used for the treatment of mood disorders for over 60 years, yet the exact mechanisms by which it exerts its therapeutic effects remain unclear. Two enzymatic chains or pathways emerge as targets for lithium: inositol monophosphatase within the phosphatidylinositol signalling pathway and the protein kinase glycogen synthase kinase 3. Lithium inhibits these enzymes through displacing the normal cofactor magnesium, a vital regulator of numerous signalling pathways. Here we provide an overview of evidence, supporting a role for the inhibition of glycogen synthase kinase 3 and inositol monophosphatase in the pharmacodynamic actions of lithium. We also explore how inhibition of these enzymes by lithium can lead to downstream effects of clinical relevance, both for mood disorders and neurodegenerative diseases. Establishing a better understanding of lithium's mechanisms of action may allow the development of more effective and more tolerable pharmacological agents for the treatment of a range of mental illnesses, and provide clearer insight into the pathophysiology of such disorders. PMID- 24167691 TI - Clinical trial in the treatment of 80 Iranian patients with major depression disorder by the combination of omega 3 fatty acid and a selective serotonin reuptake inhibitor. AB - OBJECTIVES: Bipolar disorder type I is a disturbing psychiatric syndrome, which is treated by mood-stabilizing medications, psychosocial intervention and electroconvulsive therapy. As supplementation with omega 3 has been considered effective in the treatment of many diseases especially mental disorders, this study aimed at evaluating the effect of omega 3 with fluvoxamine compared with fluvoxamine alone in the treatment of the deep depression phase in bipolar patients type I. METHODS: A total of 80 patients in this clinical trial study were selected using a randomized controlled trial in two case and control groups by a psychiatrist. The case group took fluvoxamine and omega 3 tablets and the control group took only fluvoxamine. Patients completed the Hamilton Depression Rating Scale and demographic questionnaire at the beginning of the study and after 2, 4, 8 and 12 weeks. RESULTS: The mean scores in the Hamilton Depression Rating Scale in both groups under study after 2, 4, 8, 12 weeks decreased. Statistics showed a significant difference in scores in both groups before the treatment and after mentioned weeks. CONCLUSIONS: Since research findings showed the effectiveness of omega 3 and its harmlessness, it is suggested that omega 3 can be prescribed with other antidepressant medications. PMID- 24167692 TI - Long-term remission in schizophrenia and schizoaffective disorder: results from the risperidone long-acting injectable versus quetiapine relapse prevention trial (ConstaTRE). AB - OBJECTIVE: The objective of this study was to report the long-term remission results from the ConstaTRE relapse prevention trial, in which clinically stable adults with schizophrenia or schizoaffective disorder treated with oral risperidone, olanzapine, or oral conventional antipsychotics were randomized to risperidone long-acting injectable (RLAI) or oral quetiapine, dosed according to package-insert recommendations. METHODS: In the ConstaTRE trial, efficacy and tolerability were recorded for up to 24 months. This post hoc analysis presents remission data, defined, according to the Schizophrenia Working Group criteria, as achieving and maintaining eight core symptoms of schizophrenia that are mild or less over 6 months. Additional secondary outcome measures are also presented. RESULTS: A total of 710 patients were randomized to RLAI (n = 355) or quetiapine (n = 355). Mean mode +/- standard deviation (SD) drug doses were RLAI 33 +/- 10 mg every 2 weeks and quetiapine 413 +/- 159 mg daily. Full remission was achieved by 51.1% of patients with RLAI and 39.3% with quetiapine (p = 0.003). Mean +/- SD of full remission durations were not significantly different with RLAI (540 +/- 181 days) and quetiapine (508 +/- 188 days). Overall tolerability was similar between treatment groups. CONCLUSIONS: Among stable patients with schizophrenia or schizoaffective disorder, remission was more likely after switching to RLAI than quetiapine. PMID- 24167693 TI - Medication adherence in schizophrenia: factors influencing adherence and consequences of nonadherence, a systematic literature review. AB - BACKGROUND: Nonadherence to medication is a recognized problem and may be the most challenging aspect of treatment. METHODS: We performed a systematic review of factors that influence adherence and the consequences of nonadherence to the patient, healthcare system and society, in patients with schizophrenia. Particular attention was given to the effect of nonadherence on hospitalization rates, as a key driver of increased costs of care. A qualitative systematic literature review was conducted using a broad search strategy using disease and adherence terms. Due to the large number of abstracts identified, article selection was based on studies with larger sample sizes published after 2001. Thirty-seven full papers were included: 15 studies on drivers and 22 on consequences, of which 12 assessed the link between nonadherence and hospitalization. RESULTS: Key drivers of nonadherence included lack of insight, medication beliefs and substance abuse. Key consequences of nonadherence included greater risk of relapse, hospitalization and suicide. Factors positively related to adherence were a good therapeutic relationship with physician and perception of benefits of medication. The most frequently reported driver and consequence were lack of insight and greater risk of hospitalization respectively. CONCLUSIONS: Improving adherence in schizophrenia may have a considerable positive impact on patients and society. This can be achieved by focusing on the identified multitude of factors driving nonadherence. PMID- 24167694 TI - Methadone, QTc interval prolongation and torsade de pointes: Case reports offer the best understanding of this problem. AB - We reviewed the literature and found 31 adult cases and 1 newborn case of methadone-associated QTc interval prolongation and/or torsade de pointes (TdP). Parametric statistics may not be useful in studying this issue because methadone associated TdP is a very rare event and, hence, "an extreme outlier" consistent with scalable randomness. We may have to rely upon narrative medicine in the form of case reports with all its limitations and hazards to provide our best understanding. We report risk factors for methadone-associated QTc interval prolongation and TdP based on review of published case reports. We believe both drug manufacturers and the FDA would better serve our patients and inform clinicians if they more readily reported drug-induced outliers such as methadone associated TdP using a case report format. PMID- 24167696 TI - Psychosis during treatment with isotretinoin. PMID- 24167695 TI - Off-licence prescribing and regulation in psychiatry: current challenges require a new model of governance. AB - The growing worldwide use of pharmaceuticals is managed in some countries by a regulatory system which sharply divides legal use into licensed and unlicensed categories. We examine how for the range of psychotropics this simultaneously restricts the possible benefits to patients, prescribers and producers in some domains, while failing to manage the risks in others. A more flexible system, which shares at an earlier stage experience and evidence on benefits and risks in patients, previously marginalized on the grounds of age, diagnosis or comorbidity, would aid the development of safer, more effective 'real-world prescribing'. Practical recommendations are made for a new model of research and prescribing governance, to enable more effective repurposing of these treatments. PMID- 24167697 TI - The emergence of obsessive compulsive and compulsive buying symptomatology after acute stress and short-term use of ribavirin: case reports. PMID- 24167698 TI - Contribution of methotrexate in precipitation of manic episode in bipolar affective disorder explored: a case report. AB - Bipolar affective disorder is characterized by recurring episodes of mania with or without, but commonly with, episodes of depression. It usually begins in adolescence and can cause enduring and substantial impairment if left untreated. It needs a long-term treatment with mood stabilizers to prevent relapses. Elevated or depressed mood relapses can be either primary or secondary. However, primary mood relapses can occur without a significant precipitating factor, more often tending to occur following stressful life events or discontinuation of mood stabilizer medications. Secondary mood relapses can be caused by many conditions, such as physical illnesses, substance misuse and medications. When a mental illness coexists with another physical illness and the treatment of one complicates the other, it adds complexity to the selection of appropriate pharmacological regime for either condition. In this paper, the authors present a case of bipolar affective disorder who had two episodes of mania likely precipitated by methotrexate, which were reversed by the withdrawal of the offending drug (methotrexate). To the best of the authors' knowledge, to date there have been no published reports in the literature in which methotrexate, an immunosuppressive and a cytotoxic drug, precipitated a manic episode in a patient with bipolar affective disorder. PMID- 24167699 TI - Editorial - october 2013. PMID- 24167700 TI - Impact of active monitoring on lithium management in Norfolk. AB - BACKGROUND: Lithium has been used in the fields of rheumatology and psychiatry since the 1800s and it is now generally considered to be a gold standard treatment for bipolar disorders. However, lithium is known to have significant side effects and requires close serum level monitoring to ensure levels remain within the therapeutic range to minimize the risk of serious adverse effects or toxicity. This article reviews the monitoring of lithium and reports on the implementation of a regional lithium register and database within Norfolk. METHODS: Recorded blood results from the Norfolk lithium database were extracted for the first full year of operation across the region, 2005/6, and from the most recent full year 2011/12. The number of lithium monitoring tests, U&Es and thyroid function tests conducted on all people registered on the database were compared between the two sample years. RESULTS: In 2005/6 there were a significant number of people not receiving the recommended number of four or more serum lithium test per year (68.3%) and the majority of people had two or three tests (62%). By 2011/12 this had noticeably increased with the majority of patients having four or more tests per year (68.5%) and the number having only two or three tests reducing dramatically (26.4%). CONCLUSION: Improved rates of lithium testing and monitoring have been demonstrated since the introduction of the Norfolk database helping to achieve national targets. Consequently, the chances of adverse events from insufficient monitoring have been minimized. PMID- 24167701 TI - Continuing clozapine with granulocyte colony-stimulating factor in patients with neutropenia. AB - BACKGROUND: The current guidelines dictate that clozapine should be stopped following the emergence of neutropenia. Various alternative approaches have been tried in the past, among them one rarely used alternative being to continue treatment with clozapine with coprescription of granulocyte colony-stimulating factor (G-CSF). AIM AND METHOD: In this case series we aim to describe the treatment and progress of a number of patients in a secure psychiatric hospital in the UK. These patients were restarted on clozapine in combination with G-CSF, in spite of previous neutropenia associated with clozapine treatment. DISCUSSION AND CONCLUSION: We hope that this case series will raise the profile of a potentially effective alternative to discontinuing clozapine after neutropenia. PMID- 24167702 TI - Clozapine for self-injurious behavior in individuals with borderline personality disorder. AB - Prior reports suggest that clozapine can markedly reduce aggression and self injurious behavior in patients with borderline personality disorder (BPD). We present a series of four patients with BPD and persistent self-injurious behavior treated with clozapine at a state psychiatric hospital. After treatment with clozapine these patients ceased self-injurious behaviors and aggression, and no longer required intensive levels of observation or restrictive procedures. All were successfully discharged from the hospital soon after initiation of clozapine. Clozapine appears to be efficacious in the management of chronic suicidality, self-injurious behaviors and aggression in patients with severe BPD. PMID- 24167703 TI - Life-threatening haematemesis associated with clozapine: a case report and literature review. AB - Clozapine is regarded as a second-line and in some cases last-line antipsychotic known for its common life-threatening side effects, such as agranulocytosis, constipation and cardiomyopathies, but rarely haematemesis. We report a case of severe haemetemesis in a chronic schizophrenic patient managed with clozapine. The patient was a 46-year-old male being managed for chronic schizophrenia with treatment resistance who developed sudden severe haematemesis following commencement of clozapine for 6 weeks. The patient had 1.1 l of blood transfusion. The relevant literature is reviewed. Clozapine can be associated with a life-threatening haematemesis. Psychiatrists and other medical specialists need to be alert to the fatality of clozapine-induced haematemesis in the treatment of psychiatric disorders. PMID- 24167705 TI - A therapeutic interaction between cimetidine and clozapine: case study and review of the literature. PMID- 24167706 TI - Treatment of clozapine-induced priapism by goserline acetate injection. AB - Clozapine (Denzapine) is a treatment for resistant schizophrenia. Among the serious but rare side effects of clozapine are agranulocytosis and priapism. We hereby present the case of a 30-year-old man with a diagnosis of schizophrenia who has spent nearly 12 years of his adult life on various psychiatric in-patient units including open wards, secure units, psychiatric intensive care units and rehab wards. Diagnosed at the age of 15, he only responded to clozapine at the age of 18. Whilst being on clozapine he developed priapism in June 2010 and needed emergency surgical treatment in the form of surgical decompression. He again responded only to clozapine and fortunately he did not redevelop priapism; however, he was readmitted in February 2011 due to relapse, and he remained resistant to other antipsychotics. He was rechallenged with clozapine and recovered, but unfortunately redeveloped priapism which required emergency surgical and medical intervention (goserline acetate and tinzaperin injection). In order to relieve the recurrent priapism, he agreed to continue clozapine and goserline acetate injection. This decision was made by the patient in a compos mentis state. As far as we are aware, this is the first time goserline acetate has been reported as a successful treatment for clozapine-induced priapism. PMID- 24167704 TI - Possible mechanisms for the skeletal effects of antipsychotics in children and adolescents. AB - The increasing use of antipsychotics (APs) to treat pediatric psychiatric conditions has led to concerns over the long-term tolerability of these drugs. While the risk of cardiometabolic abnormalities has received most of the attention, preclinical and clinical studies provide preliminary evidence that APs can adversely impact bone metabolism. This would be most concerning in children and adolescents as suboptimal bone accrual during development may lead to increased fracture risk later in life. However, the potential mechanisms of action through which APs may impact bone turnover and, consequently, bone mineral content are not clear. Emerging data suggest that the skeletal effects of APs are complex, with APs directly and indirectly impacting bone cells through modulation of multiple signaling pathways, including those involving dopamine D2, serotonin, adrenergic, and prolactin receptors, as well as by affecting gonadotropins. Determining the action of APs on skeletal development is further complicated by polypharmacy. In children and adolescents, APs are frequently coprescribed with psychostimulants and selective serotonin reuptake inhibitors, which have also been linked to changes in bone metabolism. This review discusses the mechanisms by which APs may influence bone metabolism. Also covered are preclinical and pediatric findings concerning the impact of APs on bone turnover. However, the dearth of clinical information despite the potential public health significance of this issue underscores the need for further studies. The review ends with a call for clinicians to be vigilant about promoting optimal overall health in chronically ill youth with psychopathology, particularly when pharmacotherapy is unavoidable. PMID- 24167707 TI - Dynamic relationship of the epithelium and mesenchyme during salivary gland initiation: the role of Fgf10. AB - Salivary glands provide an excellent model for the study of epithelial mesenchymal interactions. We have looked at the interactions involved in the early initiation and development of murine salivary glands using classic recombination experiments and knockout mice. We show that salivary gland epithelium, at thickening and initial bud stages, is able to direct salivary gland development in non-gland pharyngeal arch mesenchyme at early stages. The early salivary gland epithelium is therefore able to induce gland development in non-gland tissue. This ability later shifts to the mesenchyme, with non-gland epithelium, such as from the limb bud, able to form a branching gland when combined with pseudoglandular stage gland mesenchyme. This shift appears to involve Fgf signalling, with signals from the epithelium inducing Fgf10 in the mesenchyme. Fgf10 then signals back to the epithelium to direct gland down-growth and bud development. These experiments highlight the importance of epithelial mesenchymal signalling in gland initiation, controlling where, when and how many salivary glands form. PMID- 24167708 TI - The role of Tal2 and Tal1 in the differentiation of midbrain GABAergic neuron precursors. AB - Midbrain- and hindbrain-derived GABAergic interneurons are critical for regulation of sleep, respiratory, sensory-motor and motivational processes, and they are implicated in human neurological disorders. However, the precise mechanisms that underlie generation of GABAergic neuron diversity in the midbrain hindbrain region are poorly understood. Here, we show unique and overlapping requirements for the related bHLH proteins Tal1 and Tal2 in GABAergic neurogenesis in the midbrain. We show that Tal2 and Tal1 are specifically and sequentially activated during midbrain GABAergic neurogenesis. Similar to Gata2, a post-mitotic selector of the midbrain GABAergic neuron identity, Tal2 expression is activated very early during GABAergic neuron differentiation. Although the expression of Tal2 and Gata2 genes are independent of each other, Tal2 is important for normal midbrain GABAergic neurogenesis, possibly as a partner of Gata2. In the absence of Tal2, the majority of midbrain GABAergic neurons switch to a glutamatergic-like phenotype. In contrast, Tal1 expression is activated in a Gata2 and Tal2 dependent fashion in the more mature midbrain GABAergic neuron precursors, but Tal1 alone is not required for GABAergic neuron differentiation from the midbrain neuroepithelium. However, inactivation of both Tal2 and Tal1 in the developing midbrain suggests that the two factors co-operate to guide GABAergic neuron differentiation in a specific ventro-lateral midbrain domain. The observed similarities and differences between Tal1/Tal2 and Gata2 mutants suggest both co-operative and unique roles for these factors in determination of midbrain GABAergic neuron identities. PMID- 24167709 TI - Mff functions with Pex11pbeta and DLP1 in peroxisomal fission. AB - PEROXISOMAL DIVISION COMPRISES THREE STEPS: elongation, constriction, and fission. Translocation of dynamin-like protein 1 (DLP1), a member of the large GTPase family, from the cytosol to peroxisomes is a prerequisite for membrane fission; however, the molecular machinery for peroxisomal targeting of DLP1 remains unclear. This study investigated whether mitochondrial fission factor (Mff), which targets DLP1 to mitochondria, may also recruit DLP1 to peroxisomes. Results show that endogenous Mff is localized to peroxisomes, especially at the membrane-constricted regions of elongated peroxisomes, in addition to mitochondria. Knockdown of MFF abrogates the fission stage of peroxisomal division and is associated with failure to recruit DLP1 to peroxisomes, while ectopic expression of MFF increases the peroxisomal targeting of DLP1. Co expression of MFF and PEX11beta, the latter being a key player in peroxisomal elongation, increases peroxisome abundance. Overexpression of MFF also increases the interaction between DLP1 and Pex11pbeta, which knockdown of MFF, but not Fis1, abolishes. Moreover, results show that Pex11pbeta interacts with Mff in a DLP1-dependent manner. In conclusion, Mff contributes to the peroxisomal targeting of DLP1 and plays a key role in the fission of the peroxisomal membrane by acting in concert with Pex11pbeta and DLP1. PMID- 24167710 TI - The nucleus of endothelial cell as a sensor of blood flow direction. AB - Hemodynamic shear stresses cause endothelial cells (ECs) to polarize in the plane of the flow. Paradoxically, under strong shear flows, ECs disassemble their primary cilia, common sensors of shear, and thus must use an alternative mechanism of sensing the strength and direction of flow. In our experiments in microfluidic perfusion chambers, confluent ECs developed planar cell polarity at a rate proportional to the shear stress. The location of Golgi apparatus and microtubule organizing center was biased to the upstream side of the nucleus, i.e. the ECs polarized against the flow. These in vitro results agreed with observations in murine blood vessels, where EC polarization against the flow was stronger in high flow arteries than in veins. Once established, flow-induced polarization persisted over long time intervals without external shear. Transient destabilization of acto-myosin cytoskeleton by inhibition of myosin II or depolymerization of actin promoted polarization of EC against the flow, indicating that an intact acto-myosin cytoskeleton resists flow-induced polarization. These results suggested that polarization was induced by mechanical displacement of EC nuclei downstream under the hydrodynamic drag. This hypothesis was confirmed by the observation that acute application of a large hydrodynamic force to ECs resulted in an immediate downstream displacement of nuclei and was sufficient to induce persistent polarization. Taken together, our data indicate that ECs can sense the direction and strength of blood flow through the hydrodynamic drag applied to their nuclei. PMID- 24167711 TI - Ethanol exposure disrupts extraembryonic microtubule cytoskeleton and embryonic blastomere cell adhesion, producing epiboly and gastrulation defects. AB - Fetal alcohol spectrum disorder (FASD) occurs when pregnant mothers consume alcohol, causing embryonic ethanol exposure and characteristic birth defects that include craniofacial, neural and cardiac defects. Gastrulation is a particularly sensitive developmental stage for teratogen exposure, and zebrafish is an outstanding model to study gastrulation and FASD. Epiboly (spreading blastomere cells over the yolk cell), prechordal plate migration and convergence/extension cell movements are sensitive to early ethanol exposure. Here, experiments are presented that characterize mechanisms of ethanol toxicity on epiboly and gastrulation. Epiboly mechanisms include blastomere radial intercalation cell movements and yolk cell microtubule cytoskeleton pulling the embryo to the vegetal pole. Both of these processes were disrupted by ethanol exposure. Ethanol effects on cell migration also indicated that cell adhesion was affected, which was confirmed by cell aggregation assays. E-cadherin cell adhesion molecule expression was not affected by ethanol exposure, but E-cadherin distribution, which controls epiboly and gastrulation, was changed. E-cadherin was redistributed into cytoplasmic aggregates in blastomeres and dramatically redistributed in the extraembryonic yolk cell. Gene expression microarray analysis was used to identify potential causative factors for early development defects, and expression of the cell adhesion molecule protocadherin-18a (pcdh18a), which controls epiboly, was significantly reduced in ethanol exposed embryos. Injecting pcdh18a synthetic mRNA in ethanol treated embryos partially rescued epiboly cell movements, including enveloping layer cell shape changes. Together, data show that epiboly and gastrulation defects induced by ethanol are multifactorial, and include yolk cell (extraembryonic tissue) microtubule cytoskeleton disruption and blastomere adhesion defects, in part caused by reduced pcdh18a expression. PMID- 24167712 TI - FancJ regulates interstrand crosslinker induced centrosome amplification through the activation of polo-like kinase 1. AB - DNA damage response (DDR) and the centrosome cycle are two of the most critical processes for maintaining a stable genome in animals. Sporadic evidence suggests a connection between these two processes. Here, we report our findings that six Fanconi Anemia (FA) proteins, including FancI and FancJ, localize to the centrosome. Intriguingly, we found that the localization of FancJ to the mother centrosome is stimulated by a DNA interstrand crosslinker, Mitomycin C (MMC). We further show that, in addition to its role in interstrand crosslinking (ICL) repair, FancJ also regulates the normal centrosome cycle as well as ICL induced centrosome amplification by activating the polo-like kinase 1 (PLK1). We have uncovered a novel function of FancJ in centrosome biogenesis and established centrosome amplification as an integral part of the ICL response. PMID- 24167713 TI - A new look at the Dynamic Similarity Hypothesis: the importance of swing phase. AB - The Dynamic Similarity Hypothesis (DSH) suggests that when animals of different size walk at similar Froude numbers (equal ratios of inertial and gravitational forces) they will use similar size-corrected gaits. This application of similarity theory to animal biomechanics has contributed to fundamental insights in the mechanics and evolution of a diverse set of locomotor systems. However, despite its popularity, many mammals fail to walk with dynamically similar stride lengths, a key element of gait that determines spontaneous speed and energy costs. Here, we show that the applicability of the DSH is dependent on the inertial forces examined. In general, the inertial forces are thought to be the centripetal force of the inverted pendulum model of stance phase, determined by the length of the limb. If instead we model inertial forces as the centripetal force of the limb acting as a suspended pendulum during swing phase (determined by limb center of mass position), the DSH for stride length variation is fully supported. Thus, the DSH shows that inter-specific differences in spatial kinematics are tied to the evolution of limb mass distribution patterns. Selection may act on morphology to produce a given stride length, or alternatively, stride length may be a "spandrel" of selection acting on limb mass distribution. PMID- 24167714 TI - Cell-cycle dependent localization of MELK and its new partner RACK1 in epithelial versus mesenchyme-like cells in Xenopus embryo. AB - Maternal Embryonic Leucine zipper Kinase (MELK) was recently shown to be involved in cell division of Xenopus embryo epithelial cells. The cytokinetic furrow of these cells ingresses asymmetrically and is developmentally regulated. Two subpopulations of xMELK, the mMELK (for "mitotic" xMELK) and iMELK ("interphase" xMELK), which differ in their spatial and temporal regulation, are detected in Xenopus embryo. How cells regulate these two xMELK populations is unknown. In this study we show that, in epithelial cells, xMELK is present at a higher concentration at the apical junctional complex, in contrast to mesenchyme-like cells, which have uniform distribution of cortical MELK. Interestingly, mMELK and iMELK also differ by their requirements towards cell-cell contacts to establish their proper cortical localization both in epithelial and mesenchyme-like cells. Receptor for Activated protein Kinase C (RACK1), which we identified as an xMELK partner, co-localizes with xMELK at the tight junction. Moreover, a truncated RACK1 construct interferes with iMELK localization at cell-cell contacts. Collectively, our results suggest that iMELK and RACK1 are present in the same complex and that RACK1 is involved in the specific recruitment of iMELK at the apical junctional complex in epithelial cells of Xenopus embryos. PMID- 24167715 TI - Single cell lineage analysis of mouse embryonic stem cells at the exit from pluripotency. AB - Understanding how interactions between extracellular signalling pathways and transcription factor networks influence cellular decision making will be crucial for understanding mammalian embryogenesis and for generating specialised cell types in vitro. To this end, pluripotent mouse Embryonic Stem (mES) cells have proven to be a useful model system. However, understanding how transcription factors and signalling pathways affect decisions made by individual cells is confounded by the fact that measurements are generally made on groups of cells, whilst individual mES cells differentiate at different rates and towards different lineages, even in conditions that favour a particular lineage. Here we have used single-cell measurements of transcription factor expression and Wnt/beta-catenin signalling activity to investigate their effects on lineage commitment decisions made by individual cells. We find that pluripotent mES cells exhibit differing degrees of heterogeneity in their expression of important regulators from pluripotency, depending on the signalling environment to which they are exposed. As mES cells differentiate, downregulation of Nanog and Oct4 primes cells for neural commitment, whilst loss of Sox2 expression primes cells for primitive streak commitment. Furthermore, we find that Wnt signalling acts through Nanog to direct cells towards a primitive streak fate, but that transcriptionally active beta-catenin is associated with both neural and primitive streak commitment. These observations confirm and extend previous suggestions that pluripotency genes influence lineage commitment and demonstrate how their dynamic expression affects the direction of lineage commitment, whilst illustrating two ways in which the Wnt signalling pathway acts on this network during cell fate assignment. PMID- 24167716 TI - Significant modulation of the hepatic proteome induced by exposure to low temperature in Xenopus laevis. AB - The African clawed frog, Xenopus laevis, is an ectothermic vertebrate that can survive at low environmental temperatures. To gain insight into the molecular events induced by low body temperature, liver proteins were evaluated at the standard laboratory rearing temperature (22 degrees C, control) and a low environmental temperature (5 degrees C, cold exposure). Using nano-flow liquid chromatography coupled with tandem mass spectrometry, we identified 58 proteins that differed in abundance. A subsequent Gene Ontology analysis revealed that the tyrosine and phenylalanine catabolic processes were modulated by cold exposure, which resulted in decreases in hepatic tyrosine and phenylalanine, respectively. Similarly, levels of pyruvate kinase and enolase, which are involved in glycolysis and glycogen synthesis, were also decreased, whereas levels of glycogen phosphorylase, which participates in glycogenolysis, were increased. Therefore, we measured metabolites in the respective pathways and found that levels of hepatic glycogen and glucose were decreased. Although the liver was under oxidative stress because of iron accumulation caused by hepatic erythrocyte destruction, the hepatic NADPH/NADP ratio was not changed. Thus, glycogen is probably utilized mainly for NADPH supply rather than for energy or glucose production. In conclusion, X. laevis responds to low body temperature by modulating its hepatic proteome, which results in altered carbohydrate metabolism. PMID- 24167717 TI - The class I-specific HDAC inhibitor MS-275 modulates the differentiation potential of mouse embryonic stem cells. AB - Exploitation of embryonic stem cells (ESC) for therapeutic use and biomedical applications is severely hampered by the risk of teratocarcinoma formation. Here, we performed a screen of selected epi-modulating compounds and demonstrate that a transient exposure of mouse ESC to MS-275 (Entinostat), a class I histone deacetylase inhibitor (HDAC), modulates differentiation and prevents teratocarcinoma formation. Morphological and molecular data indicate that MS-275 primed ESCs are committed towards neural differentiation, which is supported by transcriptome analyses. Interestingly, in vitro withdrawal of MS-275 reverses the primed cells to the pluripotent state. In vivo, MS275-primed ES cells injected into recipient mice give only rise to benign teratomas but not teratocarcinomas with prevalence of neural-derived structures. In agreement, MS-275-primed ESC are unable to colonize blastocysts. These findings provide evidence that a transient alteration of acetylation alters the ESC fate. PMID- 24167718 TI - A gene regulation network controlled by Celf1 protein-rbpj mRNA interaction in Xenopus somite segmentation. AB - Somite segmentation is impaired in Xenopus celf1 morphant embryos. The Celf1 RNA binding protein targets bound mRNAs for rapid degradation, and antisense approaches demonstrated that segmentation defects in celf1 morphants were due to a derepression of rbpj mRNA. Rbpj protein is a key player of Notch signalling. Because segmentation involves complex cross-talk between several signalling pathways, we analysed how rbpj derepression impacted these pathways. We found that rbpj derepression stimulated the Notch pathway. Notch positively controlled the expression of cyp26a, which encodes a retinoic acid (RA)-degrading enzyme. Thus, rbpj derepression led to cyp26a overexpression and RA attenuation. It also repressed fgf8, consistent with an inhibition of FGF signalling. Pharmacological inhibition of the FGF pathway repressed cyp26a, but rbpj derepression was sufficient to restore cyp26a expression. Hence, while it was known that the FGF pathway antagonized RA signalling through expression of cyp26a, our results suggest that Rbpj mediates this antagonism. Furthermore, they show that the post transcriptional repression exerted by Celf1 on rbpj mRNA is required to keep cyp26a expression under the control of FGF signalling. We conclude that rbpj repression by Celf1 is important to couple the FGF and RA pathways in Xenopus segmentation. PMID- 24167719 TI - Selection of autophagy or apoptosis in cells exposed to ER-stress depends on ATF4 expression pattern with or without CHOP expression. AB - Cells exposed to ER-stress undergo the Unfolded Protein Response (UPR) to avoid apoptosis, but may also activate autophagy. However, the signal for selection of one of these two protective responses is unknown. To clarify the key switch between autophagy and apoptosis, we examined the correlation of UPR-related signals with autophagy and/or apoptosis inductions in HepG2 cells exposed to three ER-stress inducers (NaF, tunicamycin, and thapsigargin) with time, including the effect of small interfering RNA on the cell responses. Thapsigargin induced ER-stress caused only apoptosis after ~2 hr with Ire1 phosphorylation, and Grp78, ATF4, and CHOP expressions. On the other hand, NaF- and tunicamycin induced ER-stress caused only autophagy in the early stage by ~8 hr with ATF4 expression and without CHOP expression. ATF4-siRNA completely inhibited the autophagy induced by NaF or tunicamycin with suppressed ATF4 protein and mRNA expressions, and also inhibited apoptosis by thapsigargin with suppression of both ATF4 and CHOP. CHOP-siRNA had no effect on autophagy activation by NaF and tunicamycin. On the other hand, CHOP-siRNA activated autophagy in thapsigargin induced ER-stress with significant ATF4 expression, and suppressed apoptosis with CHOP suppression. These results showed that ATF4 is the key signal for autophagy induced by ER-stress, and that autophagy is switched to apoptosis by subsequent CHOP upregulation, suggesting that the changeover switch between autophagy and apoptosis is located between ATF4 to CHOP in the PERK pathway. PMID- 24167720 TI - Human spermatozoa: revelations on the road to conception. AB - Human spermatozoa are highly complex specialized cells designed to survive a long and perilous journey from the site of insemination to the upper reaches of the female reproductive tract where fertilization occurs. During this journey, these cells have to run the gauntlet laid down by the female immune system and time their physiological maturation so that as soon as an egg appears in the Fallopian tube, they are equipped to recognize this cell and participate in a remarkable cascade of cellular interactions culminating in fertilization. Despite their high level of specialization, human spermatozoa are notoriously inadequate and appear to be major contributors to the poor fertility that characterizes our species. Defective spermatozoa are also known to have a major impact on the progress of pregnancy and the health trajectory of the offspring, resulting in paternally mediated increases in miscarriage rate and a range of diseases in the progeny, including dominant genetic diseases and cancer. The causes of defective sperm function are complex and involve both genetic and environmental impacts, as well as paternal age. Where genetic factors are involved, there is a concern that the widespread use of assisted conception technologies will serve to enhance the retention of poor fertility genes in the population such that the more we use assisted reproductive technologies in one generation the more we shall need them in the next. These observations may have important implications for the health and well-being of children and for the provision of reproductive healthcare services for future generations. PMID- 24167721 TI - B lymphocyte antigen receptor signaling: initiation, amplification, and regulation. AB - B lymphocytes and their differentiated daughters are charged with responding to the myriad pathogens in our environment and production of protective antibodies. A sample of the protective antibody produced by each clone is utilized as a component of the cell's antigen receptor (BCR). Transmembrane signals generated upon antigen binding to this receptor provide the primary directive for the cell's subsequent response. In this report, we discuss recent progress and current controversy regarding B cell receptor signal initiation, transduction and regulation. PMID- 24167722 TI - Stimulated nuclear import by beta-like importins. AB - Classic nuclear shuttling is mediated by an importin-alpha?beta heterodimer that binds to cargoes containing a nuclear localization signal, and shuttles most nuclear proteins immediately after their translation. Aside from this canonical mechanism, kariopheryn-betas or beta-like importins operate by binding to non canonical nuclear localization signals to mediate translocation without the assistance of importin-alpha. The mechanism by which these components operate is much less understood and is currently under investigation. Recently, several beta like importins have been implicated in the stimulated nuclear translocation of signaling proteins. Here, we propose that this group of importins might be responsible for the swift nuclear shuttling of many proteins following various stimuli. PMID- 24167723 TI - Intensive risk factor control in stroke prevention. AB - Stroke prevention is an urgent priority because of the aging of the population and the steep association of age and risk of stroke. Direct costs of stroke are expected to more than double in the US between 2012 and 2030. By getting everything right, patients can reduce the risk of stroke by 80% or more; however, getting everything right is a tall order. Roughly in order of importance, this requires smoking cessation, maintenance of a healthy weight, a Cretan Mediterranean diet, blood pressure control, lipid-lowering drugs, appropriate use of antiplatelet agents and anticoagulants, and appropriate carotid endarterectomy and stenting. A new approach called "treating arteries instead of targeting risk factors" appears promising but requires validation in randomized trials. PMID- 24167724 TI - Major advances in managing community-acquired pneumonia. AB - This article is a non-systematic review of selected recent publications in community-acquired pneumonia, including a comparison of various guidelines. Risk stratification of patients has recently been advanced by the addition of several useful biomarkers. The issue of single versus dual antibiotic treatment remains controversial and awaits a conclusive randomized controlled trial. However, in the meantime, there is a working consensus that more severe patients should receive dual therapy. PMID- 24167725 TI - Research advances in esophageal diseases: bench to bedside. AB - Over the last year, significant steps have been made toward understanding the pathogenesis of esophageal diseases and translating this knowledge to clinical practice. Gastroesophageal reflux disease (GERD) is the most common outpatient diagnosis in gastroenterology and has a high prevalence in the general population. As many as 40% of patients with GERD have incomplete response to medical therapy, and the pathophysiological mechanisms underlying lack of response are now better understood. Novel medical and minimally invasive interventions are available to optimize management of GERD. Esophageal cancer, regardless of the histological subtype, has among the worst survival statistics among all malignancies. Taking advantage of technological advances in genome sequencing, the mutational spectra in esophageal cancer are now emerging, offering novel avenues for targeted therapies. Early diagnosis is another strand for improving survival. While genome-wide association studies are providing insights into genetic susceptibility, novel approaches to early detection of cancer are being devised through the use of biomarkers applied to esophageal samples and as part of imaging technologies. Dysmotility and eosinophilic esophagitis are the differential diagnoses in patients with dysphagia. New pathophysiological classifications have improved the management of motility disorders. Meanwhile, exciting progress has been made in the endoscopic management of these conditions. Eosinophilic esophagitis is still a relatively new entity, and the pathogenesis remains poorly understood. However, it is now clear that an allergic reaction to food plays an important role, and dietary interventions as well as biologic agents to block the inflammatory cascade are novel, promising fields of clinical research. PMID- 24167727 TI - The Associations between Pain Sensitivity and Knee Muscle Strength in Healthy Volunteers: A Cross-Sectional Study. AB - Objectives. To investigate associations between muscle strength and pain sensitivity among healthy volunteers and associations between different pain sensitivity measures. Methods. Twenty-eight healthy volunteers (21 females) participated. Pressure pain thresholds (PPTs) were obtained from 1) computer controlled pressure algometry on the vastus lateralis and deltoid muscles and on the infrapatellar fat pad and 2) computerized cuff pressure algometry applied on the lower leg. Deep-tissue pain sensitivity (intensity and duration) was assessed by hypertonic saline injections into the vastus lateralis, deltoid, and infrapatellar fat pad. Quadriceps and hamstring muscle strength was assessed isometrically at 60-degree knee flexion using a dynamometer. Associations between pain sensitivity and muscle strength were investigated using multiple regressions including age, gender, and body mass index as covariates. Results. Knee extension strength was associated with computer-controlled PPT on the vastus lateralis muscle. Computer-controlled PPTs were significantly correlated between sites (r > 0.72) and with cuff PPT (r > 0.4). Saline induced pain intensity and duration were correlated between sites (r > 0.39) and with all PPTs (r < -0.41). Conclusions. Pressure pain thresholds at the vastus lateralis are positively associated with knee extensor muscle strength. Different pain sensitivity assessment methods are generally correlated. The cuff PPT and evoked infrapatellar pain seem to reflect the general pain sensitivity. This trial is registered with ClinicalTrials.gov: NCT01351558. PMID- 24167726 TI - Cdc48: a swiss army knife of cell biology. AB - Cdc48 (also called VCP and p97) is an abundant protein that plays essential regulatory functions in a broad array of cellular processes. Working with various cofactors, Cdc48 utilizes its ATPase activity to promote the assembly and disassembly of protein complexes. Here, we review key biological functions and regulation of Cdc48 in ubiquitin-related events. Given the broad employment of Cdc48 in cell biology and its intimate ties to human diseases (e.g., amyotrophic lateral sclerosis), studies of Cdc48 will bring significant insights into the mechanism and function of ubiquitin in health and diseases. PMID- 24167728 TI - The Relationship between Marital Status and Psychological Resilience in Chronic Pain. AB - We examined the relationship between marital status and a 2-stage model of pain related effect, consisting of pain unpleasantness and suffering. We studied 1914 chronic pain patients using multivariate analysis of covariance (MANCOVA) to clarify whether marital status was a determinant factor in the emotional or ideational suffering associated with chronic pain after controlling for pain sensation intensity, age, and ethnicity. Marital status was unrelated to immediate unpleasantness (P = 0.08). We found a strong association with emotional suffering (P < 0.0001) but not with negative illness beliefs (P = 0.44). Interestingly, widowed subjects experienced significantly less frustration, fear, and anger than all other groups (married, divorced, separated, or single). A final MANCOVA including sex as a covariate revealed that the emotional response to pain was the same for both widow and widower. Only those individuals whose spouse died experienced less emotional turmoil in the face of a condition threatening their lifestyle. These data suggest that after experiencing the death of a spouse, an individual may derive some "emotional inoculation" against future lifestyle threat. PMID- 24167730 TI - Tubercular Ascites Simulating Ovarian Hyperstimulation Syndrome following In Vitro Fertilization and Embryo Transfer Pregnancy. AB - Ovarian hyperstimulation syndrome (OHSS) is a known complication of using ovulation induction drugs in assisted reproductive techniques. Its incidence and severity vary. Tuberculosis is a very common disease in the developing world, and ascites is one of its sequelae. The newer aids in diagnosing tuberculosis include measuring levels of Adenosine DeAminase (ADA) in the third-space fluids or serum. This case report is from a tertiary care center, reflecting how tubercular ascites simulated OHSS, and the right diagnosis was made and managed. This is being presented due to its rarity. PMID- 24167729 TI - Opioid therapy pharmacogenomics for noncancer pain: efficacy, adverse events, and costs. AB - Chronic non-cancer pain is a debilitating condition associated with high individual and societal costs. While opioid treatment for pain has been available for centuries, it is associated with high variability in outcome, and a considerable proportion of patients is unable to attain relief from symptoms while suffering adverse events and developing medication dependence. We performed a review of the efficacy of pharmacogenomic markers and their abilities to predict adverse events, dependence, and associated economic costs, focusing on two genes: OPRM1 and CYP2D6. Data sources were articles indexed by PubMed on or before August 6, 2013. Articles were first selected after review of their titles and abstracts, and full papers were read to confirm eligibility. Initially, fifty two articles were identified. Of these, 17 were relevant to biological actions of pharmacogenomic markers and their effect on therapeutic efficacy, 16 to adverse events, 15 to opioid dependence, and eight to economic costs. In conclusion, increasing costs of opioid therapy have made the advances in pharmacogenomics an attractive solution to personalize care with unclear repercussions related to the impact on costs, morbidity, and outcomes. This intersection of pharmacoeconomics and pharmacogenomics presents a unique platform to further examine current advances in clinical medicine and their utility in cost-effective treatment of chronic pain. PMID- 24167731 TI - The impact of centralization of obstetric care resources in Japan on the perinatal mortality rate. AB - Objective. We investigated the effects of the centralization of obstetricians and obstetric care facilities on the perinatal mortality rate in Japan. Methods. We used the Gini coefficient as an index to represent the centralization of obstetricians and obstetric care facilities. The Gini coefficients were calculated for the number of obstetricians and obstetric care facilities of 47 prefectures using secondary medical care zones as units. To measure the effects of the centralization of obstetricians and obstetric care facilities on the outcomes (perinatal mortality rates), we performed multiple regression analysis using the perinatal mortality rate as the dependent variable. Results. Obstetric care facilities were more evenly distributed than obstetricians. The perinatal mortality rate was found to be significantly negatively correlated with the number of obstetricians per capita and the Gini coefficient of obstetric care facilities. The latter had a slightly stronger effect on the perinatal mortality rate. Conclusion. The centralization of obstetric care facilities can improve the perinatal mortality rate, even when increasing the number of obstetricians is difficult. PMID- 24167732 TI - Virological investigation of avian influenza virus on postglacial species of phasianidae and tetraonidae in the italian alps. AB - Land-based birds, belonging to Galliformes order are considered to be potential intermediaries in the emergence of new strains of influenza A viruses (AIVs), but the viral circulation in these birds remains largely unknown. To gain insights into the circulation of AIV in the wild Galliformes populations in Italian Alps, we conducted a virological survey on rock partridge (Alectoris graeca saxatilis) belonging to Phasianidae family and on tetraonids including rock ptarmigan (Lagopus mutus helveticus) and black grouse (Tetrao tetrix tetrix). In 2003 and 2004, during the hunting seasons, 79 wild Galliformes, categorised into age and sex classes, were hunted in the Sondrio Province (Central Alps). Cloacal swabs were collected from 11 rock partridges and from 68 tetraonids including 23 alpine rock ptarmigans and 45 black grouses. We tested cloacal swabs by a high sensitive reverse transcription- (RT-) PCR detecting the matrix gene of AIV. No AIV was detected in the investigated samples, thus, suggesting the lack of AIV circulation in these relict populations in the study period. In terms of threatened species conservation, during wildlife management activities, it is very important to exclude the introduction of AIV-carrier birds in shared territories, a fact representing a health risk for these populations. PMID- 24167733 TI - Physiological parameters of endurance horses pre- compared to post-race, correlated with performance: a two race study from scandinavia. AB - Few studies have investigated the physiological parameters of endurance horses in Scandinavia. Hence, this two race study has focused on the effects of endurance racing in terms of equine clinicopathological blood parameters, heart score, and fluid use. Race A involved 15 horses (120 km). Two pre- and one post-race blood samples were taken, body condition score was assessed in triplicate pre-race, and an ECG was used to determine heart score. Race B involved 16 horses (65-120 km). One pre- and two post-race blood samples were taken. For both races, horse data as well as fluid intake estimates and cooling water were noted. Race A showed that blood haematocrit, albumin, sodium, and triglycerides increased significantly with endurance racing, whilst chloride, glucose, iron, and potassium decreased significantly. In race B, blood creatinine, cholesterol, and inorganic phosphate continued to increase significantly during the first post race sampling period compared to pre-race levels, whilst iron, which decreased significantly during the race, increased significantly over the two post-race sampling periods. It is concluded that whilst no correlation between heart score and speed was observed, a significant correlation exists between experience and changes in blood parameters with endurance racing and between fluid intake and average speed. PMID- 24167734 TI - Targeted versus Universal Neonatal Hearing Screening in a Single Egyptian Center. AB - Aim. To compare targeted neonatal hearing screening (TNHS) and universal neonatal hearing screening (UNHS) since many developing countries, including Egypt, implement selective screening for high-risk neonates. Methods. 150 neonates were assessed; 50 full terms consecutively admitted to the well-baby nursery and 100 neonates consecutively admitted to neonatal intensive care unit (NICU), Ain Shams University. Patients were further subdivided into high-risk group which included 50 neonates with multiple risk factors for hearing loss and low risk group which included 50 neonates with only one risk factor. Transient evoked otoacoustic emissions (TEOAEs) were used for hearing screening. Auditory brain response (ABR) was performed 3 months later for failed TEOAEs. Results. The most frequent risk factor was consanguinity (46%). In the well-baby population, 16% failed TEOAEs. In the NICU, 30% of the low risk and 38% of the high risk groups failed TEOAEs. Regarding ABR, failed results were 12%, 10%, and 8% in the high-risk, low-risk, and healthy groups, respectively. Conclusion. The use of TNHS would have missed 8% of neonates from the well-baby group who actually had PCHL (permanent congenital hearing loss). The use of UNHS would identify all cases with PCHL, allowing for early intervention and follow-up. PMID- 24167735 TI - Effects of thyroid hormone analogue and a leukotrienes pathway-blocker on reperfusion injury attenuation after heart transplantation. AB - Background. Global myocardial ischemia reperfusion injury after heart transplantation is believed to impair graft function and aggravate both acute and chronic rejection episodes. Objectives. To assess the possible protective potential of MK-886 and 3,5-diiodothyropropionic acid DITPA against global myocardial ischemia reperfusion injury after heart transplantation. Materials and Methods. Adult albino rats were randomized into 6 groups as follows: group I sham group; group II, control group; groups III and IV, control vehicles (1,2); group V, MK-886 treated group. Donor rats received MK-886 30 min before transplantation, and the same dose was repeated for recipients upon reperfusion; in group VI, DITPA treated group, donors and recipients rats were pretreated with DITPA for 7 days before transplantation. Results. Both MK-886 and DITPA significantly counteract the increase in the levels of cardiac TNF- alpha , IL-1 beta , and ICAM-1 and plasma level of cTnI (P < 0.05). Morphologic analysis showed that both MK-886 and DITPA markedly improved (P < 0.05) the severity of cardiac injury in the heterotopically transplanted rats. Conclusions. The results of our study reveal that both MK-886 and DITPA may ameliorate global myocardial ischemia reperfusion injury after heart transplantation via interfering with inflammatory pathway. PMID- 24167736 TI - Anticonvulsant Effect of Antiaris toxicaria (Pers.) Lesch. (Moraceae) Aqueous Extract in Rodents. AB - Antiaris toxicaria (Moraceae) was evaluated for anticonvulsant activity in rodents. Animal models used include maximal electroshock test (MEST); pentylenetetrazole-induced (PTZ) convulsions; picrotoxin-induced (PCT) convulsions; strychnine- (STR-) and 4-aminopyridine-induced convulsions. Increase in latency to seizures as well as reduction in duration and frequency of seizures indicated anticonvulsant activity. The extract was more effective in all models used except the maximal electroshock test and strychnine-induced convulsions. Antiaris toxicaria aqueous extract (200, 400, and 800 mg kg(-1)) significantly (P < 0.05 - 0.01) shortened the duration of convulsions in PTZ- and PCT-induced seizures. Delay in the onset of convulsions in the two tests was significant (P < 0.001). Reduction in the frequency of seizures was also significant (P < 0.05 - 0.001) in both tests. Antiaris further delayed the onset of seizures in 4 aminopyridine model while producing 75% protection against death in mice. Diazepam (0.1, 0.3, and 1 mg kg(-1)), carbamazepine (3, 10, and 30 mg kg(-1)), and sodium valproate (100-400 mg kg(-1)) were used as reference anticonvulsant drugs for various models. Flumazenil blocked the effect of the extract in the PTZ test significantly suggesting that Antiaris toxicaria may be acting by enhancing the effects of the GABAergic system. Antiaris toxicaria aqueous extract therefore possesses anticonvulsant activity. PMID- 24167737 TI - Therapeutic Effect of Ficus lacor Aerial Roots of Various Fractions on Adjuvant Induced Arthritic Rats. AB - The present study was carried out to evaluate antiarthritic potential and phytochemical screening of various extracts of Ficus lacor aerial roots. The antiarthritic activity was evaluated by adjuvant-induced arthritis at the dose of 50 and 100 mg/kg body weight and the standard drug used was indomethacin. The extracts administered in higher doses reduced the lesions to a greater extent showing a dose-dependent decrease in lesions comparable with standard drug indomethacin. The extracts of FLPE and FLET showed significant increase in body weight as compared to arthritic control group as well as an increase in liver weight, a decrease in liver weight, and an increase in spleen weight in arthritis control. The extracts of FLPE and FLET showed significant decrease in WBC count, increase in hemoglobin contents, and RBC count as compared to control group. FLEA and FLCF were not able to produce a significant effect. There was significant reduction in production of IL-1 and TNF- alpha level between model group and control group in serum. In conclusion, we demonstrate that, at 100 mg/kg body weight, doses of FLPE and PLET extracts were highly effective in preventing and suppressing the development of adjuvant-induced arthritis. PMID- 24167738 TI - Protective nature of mangiferin on oxidative stress and antioxidant status in tissues of streptozotocin-induced diabetic rats. AB - Oxidative stress plays an important role in the progression of diabetes complications. The aim of the present study was to investigate the beneficial effect of oral administration of mangiferin in streptozotocin (STZ)-induced diabetic rats by measuring the oxidative indicators in liver and kidney as well as the ameliorative properties. Administration of mangiferin to diabetic rats significantly decreased blood glucose and increased plasma insulin levels. The activities of antioxidant enzymes superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPx) and level of reduced glutathione (GSH) were significantly (P < 0.05) decreased while increases in the levels of lipidperoxidation (LPO) markers were observed in liver and kidney tissues of diabetic control rats as compared to normal control rats. Oral treatment with mangiferin (40 mg/kg b.wt/day) for a period of 30 days showed significant ameliorative effects on all the biochemical and oxidative parameters studied. Diabetic rats treated with mangiferin restored almost normal architecture of liver and kidney tissues, which was confirmed by histopathological examination. These results indicated that mangiferin has potential ameliorative effects in addition to its antidiabetic effect in experimentally induced diabetic rats. PMID- 24167740 TI - Common carotid artery occlusion: a case series. AB - Subjects and Methods. We analysed 5000 cerebrovascular ultrasound records. A total of 0.4% of the patients had common carotid artery occlusion (CCAO). Results. The mean age was 59.8 +/- 14.2 years, and the male/female ratio was 2.33. The most frequent risk factors were hypertension, ischaemic heart disease, dyslipidemia, diabetes mellitus, and smoking. Right-sided and left-sided CCAO occurred in 65% and 30% of the cases, respectively, and bilateral occlusion was detected in one case (5%). Patent bifurcation was observed in 10 cases of CCAO in which the anterograde flow in the ICA was maintained from the external carotid artery with reversed flow. In two of the cases, the occluded CCA was hypoplastic. The aetiology of CCAO in the majority of cases was the atherosclerosis (15 cases). The male/female ratio was higher in the patients with occluded distal vessels, and the short-term outcome was poorer. Only two cases from this series underwent revascularisation surgery. Spontaneous recanalisation was observed in one case. Conclusions. The most frequent cause of CCAO was atherosclerosis. The outcome is improved in the cases with patent distal vessels, and spontaneous recanalisation is possible. Treatment methods have not been standardised. Surgical revascularisation is possible in cases of patent distal vessels, but the indications are debatable. PMID- 24167739 TI - Antiallergic and Antiarthritic Effects of Stem Bark Extract of Glyphaea brevis (Spreng) Monachino (Tiliaceae) in Murine Models. AB - Background. Various parts of Glyphaea brevis (Spreng) Monachino (Tiliaceae) find a use in traditional medicine in the treatment of pain and oedema among others. This study evaluates the anti-inflammatory, antiallergic, and antiarthritic effects of a 70% (v/v) aqueous ethanol extract of the stem bark of Glyphaea brevis in murine models. Materials and Methods. The effect of the aqueous ethanol extract of Glyphaea brevis extract (GBE) was assessed on the maximal and total oedema responses in the carrageenan-induced paw oedema in mice to evaluate the acute anti-inflammatory actions of the extract. Systemic anaphylaxis was induced with compound 48/80 and survival rates monitored for 1 h in mice with prior treatment with GBE to assess the anti-allergic action of the extract. The indirect antihistamine effect of GBE was evaluated on clonidine-induced catalepsy. Rat adjuvant-induced arthritis model was used to study GBE's antiarthritic action. Results. GBE significantly suppressed the mean maximal swelling and the total paw swellings over 6 h in the carrageenan-induced paw oedema when administered either prophylactically or therapeutically. GBE dose dependently increased the time for compound 48/80-induced mortality. Administered either prophylactically or therapeutically, GBE inhibited clonidine-induced catalepsy while it had no effect on haloperidol-induced catalepsy. GBE caused a significant dose-dependent suppression of Freund's adjuvant-induced arthritis. Conclusion. Glyphaea brevis inhibits the in vivo degranulation of mast cells and thereby suppress allergy. In addition it exhibits anti-inflammatory action and attenuates Freund's adjuvant-induced arthritis. The results of this work contribute to validate the traditional use of Glyphaea brevis in the management of inflammatory disorders. PMID- 24167741 TI - Association of intracranial aneurysms with meningiomas, pituitary adenomas, and gliomas: review of possible interrelationships. AB - Asymptomatic intracranial abnormalities are increasingly becoming a focus of attention with the utilization of high-resolution imaging. The concurrence of tumor and aneurysm has been described, largely, by case reports and single surgeon experiences. Recent papers have outlined the ethics of incidental findings and possible treatment algorithms. Incidental finding of an aneurysm occurs most commonly in patients with meningiomas, pituitary adenomas, and gliomas. Such an association may explain the mechanisms of aneurysm formation, growth, and rupture in acromegalic patients; however, insufficient data are available to link aneurysm with either glioma or meningioma. PMID- 24167742 TI - Radiographic parameters in predicting outcome of patients with hepatocellular carcinoma treated with yttrium-90 microsphere radioembolization. AB - Background. In patients with hepatocellular carcinoma, selection criteria for transarterial hepatic selective internal radiotherapy are imprecise. Additionally, radiographic parameters to predict outcome of transarterial hepatic selective internal radiotherapy have not been fully characterized. Patients and methods. Computed tomography (CT) scans of 23 patients with unresectable primary hepatocellular carcinoma before and after transarterial hepatic selective internal radiotherapy with yttrium-90 microspheres were retrospectively reviewed. Selected radiographic parameters were evaluated and correlated with progression free survival and overall survival. Response to treatment was assessed with Response RECIST 1.1 and Morphology, Attenuation, Size, and Structure (MASS) criteria. Results. On the post-SIRT CT, 68% of tumors demonstrated decreased size (median decrease of 0.8 cm, P = 0.3); 64% had decreased attenuation (median decrease 5.7 HU, P = 0.06), and 48% demonstrated increased tumor necrosis (P < 0.001). RECIST-defined partial response was seen in 10% patients, stable disease in 80%, and 10% had disease progression. Median progression-free survival was 3.9 months (range, 3.3 to 7.3), and median overall survival was 11.2 months (7.1 to 31.1). Pretreatment lower hepatopulmonary shunt fraction, central hypervascularity, and well-defined tumor margins were associated with improved progression-free survival. Conclusion. In patients with unresectable hepatocellular carcinoma, pretreatment CT parameters may predict favorable response to SIRT and improve patient selection. PMID- 24167744 TI - The predictive value of cystatin C in monitoring of B non-hodgkin lymphomas: relation to biochemical and clinical parameters. AB - The predictive value of cystatin C as a marker of course of the disease has been evaluated. Fifty-two pairs of serum samples of patients with B non-Hodgkin lymphoma have been collected at the time of diagnosis and before fourth cycle of chemotherapy. The levels of cystatin C, CRP, beta 2M, LDH, and IL-6 in samples have been measured, and clinical parameters of course of the disease (B symptoms, clinical stage, patients' age, and IPI) have been noted. In total patient's group cystatin C levels correlated with beta 2M and IPI. In aggressive lymphomas, the inhibitor levels correlated with clinical stage of disease and were significantly higher in patients with elevated LDH activity. In aggressive nodal lymphomas its levels correlated with beta 2M, IPI, and clinical stage of disease. The cystatin C level was significantly increased in total group of patients over 60 years old, while in particular types of lymphoma, no statistical significance has been obtained. Our results indicate that cystatin C should be taken into consideration in disease monitoring. However, we expect that the disease-free and overall survival analysis will give the definitive answer about the reliability of cystatin C as an indicator of course of aggressive lymphomas. PMID- 24167743 TI - From radical mastectomy to breast-conserving therapy and oncoplastic breast surgery: a narrative review comparing oncological result, cosmetic outcome, quality of life, and health economy. AB - Surgical management of breast cancer has evolved considerably over the last two decades. There has been a major shift toward less-invasive local treatments, from radical mastectomy to breast-conserving therapy (BCT) and oncoplastic breast surgery (OBS). In order to investigate the efficacy of each of the three abovementioned methods, a literature review was conducted for measurable outcomes including local recurrence, survival, cosmetic outcome, quality of life (QOL), and health economy. From the point of view of oncological result, there is no difference between mastectomy and BCT in local recurrence rate and survival. Long term results for OBS are not available. The items assessed in the QOL sound a better score for OBS in comparison with mastectomy or BCT. OBS is also associated with a better cosmetic outcome. Although having low income seems to be associated with lower BCT and OBS utilization, prognosis of breast cancer is worse in these women as well. Thus, health economy is the matter that should be studied seriously. OBS is an innovative, progressive, and complicated subspeciality that lacks published randomized clinical trials comparing surgical techniques and objective measures of outcome, especially from oncologic and health economy points of view. PMID- 24167745 TI - Evaluation of the benefit of routine intraoperative frozen section analysis of sentinel lymph nodes in breast cancer. AB - Aims. Intraoperative analysis of the sentinel lymph node (SLN) by frozen section (FS) allows for immediate axillary lymph node dissection (ALND) in case of metastatic disease in patients with breast cancer. The aim of this study is to evaluate the benefit of intraoperative FS, with regard to false negative rate (FNR) and influence on operation time. Materials and Methods. Intraoperative analysis of the SLN by FS was performed on 628 patients between January 2005 and October 2009. Patients were retrospectively studied. Results. FS accurately predicted axillary status in 525 patients (83.6%). There were 78 true positive findings (12.4%), of which there are 66 macrometastases (84.6%), 2 false positive findings (0.3%), and 101 false negative findings (16.1%), of which there are 65 micrometastases and isolated tumour cells (64.4%) resulting in an FNR of 56.4%. Additional operation time of a secondary ALND after wide local excision and SLNB is 17 minutes, in case of ablative surgery 35 minutes. The SLN was negative in 449 patients (71.5%), making their scheduled operation time unnecessary. Conclusions. FS was associated with a high false negative rate (FNR) in our population, and the use of telepathology caused an increase in this rate. Only 12.4% of the patients benefited from intraoperative FS, as secondary ALND could be avoided, so FS may be indicated for a selected group of patients. PMID- 24167746 TI - Beyond the limits of oxygen: effects of hypoxia in a hormone-independent prostate cancer cell line. AB - Prostate cancer (PCa) has a high incidence worldwide. One of the major causes of PCa resistance is intratumoral hypoxia. In solid tumors, hypoxia is strongly associated with malignant progression and resistance to therapy, which is an indicator of poor prognosis. The antiproliferative effect and induced death caused by doxorubicin, epirubicin, cisplatin, and flutamide in a hormone independent PCa cell line will be evaluated. The hypoxia effect on drug resistance to these drugs, as well as cell proliferation and migration, will be also analyzed. All drugs induced an antiproliferative effect and also cell death in the cell line under study. Hypoxia made the cells more resistant to all drugs. Moreover, our results reveal that long time cell exposure to hypoxia decreases cellular proliferation and migration. Hypoxia can influence cellular resistance, proliferation, and migration. This study shows that hypoxia may be a key factor in the regulation of PCa. PMID- 24167747 TI - Inhibition of Nitric Oxide Synthase by L-NAME Promotes Cisplatin-Induced Nephrotoxicity in Male Rats. AB - Objective. Nitric oxide (NO) has numerous important functions in the kidney. The role of NO in cisplatin (CP)-induced nephrotoxicity is not completely understood. This study was designed to determine the role of NO synthase inhibitor (L-NAME) on the severity of CP-induced nephrotoxicity in rats. Methods. Sixty four male (M) and female (F) Wistar rats were randomly divided into eight groups. The sham groups (group 1, male, n = 6 and group 2, female, n = 6) received saline. Groups 3 (male, n = 8) and 4 (female, n = 8) were treated with L-NAME (4 mg/kg, i.p.), and groups 5 (male, n = 8) and 6 (female, n = 8) received CP (3 mg/kg) for 7 days. Groups 7 (male, n = 8) and 8 (female, n = 8) were treated with L-NAME and CP for 7 days. Results. The CP-alone treated rats showed weight loss and increase in serum levels of blood urea nitrogen (BUN) and creatinine (Cr). Coadministration of L-NAME and CP did not improve weight loss, and it increased the levels of BUN and Cr in male but not in female rats (P < 0.05). CP alone increased kidney damage significantly (P < 0.05 ), however, the damage induced by combination of CP and L-NAME was gender-related. Conclusion. NOS inhibition by L NAME increased CP-induced nephrotoxicity, which was gender-related. PMID- 24167748 TI - Anti-yo associated paraneoplastic cerebellar degeneration in a man with large cell cancer of the lung. AB - Purkinje cell cytoplasmic antibody type 1 (PCA-1), or anti-Yo, is the most frequently detected autoantibody in paraneoplastic cerebellar degeneration (PCD). The vast majority of cases of anti-Yo PCD, however, occur in females over 60 years old and are associated with gynecologic tumors. Only 10 cases have been reported in males, and only 2 were associated with cancer of the lung. Here we describe the youngest known case of PCA-1 positive PCD in a male, whose lung tumor was undetectable even on FDG-PET. PMID- 24167749 TI - Vulvar malignancy in neurofibromatosis syndrome. AB - Type 1 neurofibromatosis (NF1) is a dominantly inherited neurologic disorder that affects primarily the skin, bones, and peripheral nervous system. It may be associated with a variety of clinical manifestations including cafe-au-lait spots, skinfold freckling, Lisch nodules, and visceral neurofibromas. Individuals affected by NF1 harbor an increased risk for both benign and malignant tumors. Malignant transformation is usually observed in the form of neurosarcoma. Rarely, NF1 affects the genital tract, and isolated vulvar localization is extremely rare. Here is reported a rare case of a solitary neurosarcoma of the vulva in a 43-year-old woman affected by NF1 syndrome treated with surgical excision. The purpose of this case is to underline the possibility of association between NF1 and genital tract sarcoma and to suggest an accurate evaluation of rapid growth vulvar mass in this setting. PMID- 24167750 TI - Imaging Comparison between (18) F-FDG-PET/CT and (18) F-Flouroethyl Choline PET/CT in Rare Case of Thymus Carcinoma Exhibiting a Positive Choline Uptake. AB - It is of great value by using PET imaging in oncology to recognize any atypical uptake not related to the underlying disease. That helps in avoiding the false positive finding and may contribute in extending the application range of used radiopharmaceuticals in further disorders. It is well known that radiolabeled choline is an essential PET tracer used currently in prostate cancer. The physiological choline distribution was described. Nevertheless there is still a lack of studies, which describe this distribution in young patients; given that the radiolabeled choline is generally being used in the field of prostate cancer. Whether the thymus exhibits normally a positive choline uptake or not is still unknown. In particular, it is known that the lymphocytes express high affinity of choline transporter and enzymes involving its metabolism. Some cases of thymus carcinoma exhibiting a positive choline had been reported in the literature, however, mostly using (11)C-choline. We report a rare case of metastatic thymic carcinoma detected incidentally using (18)F-choline-PET in a 78-year-old male patient referred with elevation of prostate specific antigen. Moreover we present a comparison pattern with (18)F-FDG-PET modality, in which (18)F-choline-PET was turned out to be superior in tumor delineation. PMID- 24167751 TI - Extraosseous intra-articular osteochondroma. AB - Background. Conventional osteochondromas are common bone lesions developing in the metaphyseal region of growing skeleton. Marginal excision is the treatment of choice for such tumours. Extraosseous cartilaginous tumours are rare and their biological potential is poorly characterized. Case Presentation. A-52-year old woman presented with 3-year history of fullness and dull pain and inability to flex her left knee, sit cross-legged, or squat. Clinical and imaging studies revealed a nodular mineralised mass in the anterior portion of the knee displacing the patellar tendon laterally. Excision biopsy confirmed the diagnosis of extraosseous osteochondroma-like soft tissue mass. There is no recurrence at two-year followup. Conclusion. An integrated clinicopathological diagnosis helps to clarify the nature of extraosseous cartilaginous tumour that can arise at an unusual anatomic site. Complete surgical excision is the treatment of choice. PMID- 24167752 TI - Immediate cementless hemiarthroplasty for severe destructive glenohumeral tuberculous arthritis. AB - The glenohumeral joint tuberculosis (TB) is rare as compared with other joints. Plaster immobilization, arthrodesis, and resection arthroplasty have been proposed as the additional treatments with anti-TB medications in severe destructive arthritis. To our knowledge, however, the surgical treatment with shoulder arthroplasty has never been reported. We present two cases of active TB with unsalvageable glenohumeral joint. The cementless hemishoulder arthroplasties were performed immediately following the radical debridement. Anti-TB medications were given for 12 months after the surgery. Postoperatively, the patients were satisfied with the rapid symptomatic relief and significant functional recovery. With the follow-up period of 5 years, the operative results were still satisfactory and the reactivation of the infection was not detected. PMID- 24167753 TI - Diagnostic Modalities of Precancerous and Cancerous Cervical Lesions with Special Emphasis on CD31 Angiogenesis Factor as a Marker. AB - Objectives. To evaluate the role of angiogenesis tumor marker CD31 in the detection of precancerous and cancerous cervical lesions and to compare its efficacy with colposcopy and histopathology. Materials and Methods. 230 patients with a suspicious looking cervix and an abnormal Pap smear attending the Outpatient Department of Obstetrics and Gynaecology of GSVM Medical College were subjected to a colposcopic examination. 180 patients with suspected colposcopic findings were subjected to a colposcopic directed biopsy. Biopsy tissues were sent for histopathological examination out of which 50 biopsied samples were sent for immunostaining of CD-31. Statistical analysis was done. Results. Comparison of microvessel density (MVD) count by haematoxylin and eosin staining (HE) and immunostaining of CD31 in preinvasive group were 4.012 +/- 2.57 and 5.44 +/- 2.21, respectively, and in invasive group were 9.18 +/- 2.32 and 12.82 +/- 4.07, respectively, which showed that MVD was higher by CD31 both in preinvasive and invasive group, and it was statistically significant. Conclusion. Angiogenesis is a marker of tumor progression, and CD31 fixes up vessel better as compared to HE, so aggressiveness of the tumor can be better predicted by MVD-CD31 as compared to MVD-HE. PMID- 24167755 TI - Frayar, D.C., Ervin, R.B. Caloric intake from fast food among adults: United States, 2007-2010. NCHS Data Brief, No. 114, February 2013. Hyattsville, MD: National Center for Health Statistics, 2013. PMID- 24167756 TI - Let's Talk About Sex: A Diary Investigation of Couples' Intimacy Conflicts in the Home. AB - Although intimacy plays a central role in our closest relationships, we know surprisingly little about how couples handle intimacy conflicts in their daily lives. We utilized 100 married couples' diary reports of 748 instances of naturalistic marital conflict to test whether intimacy as a topic was associated with other conflict topics; conflict characteristics, such as recurrence and significance; and spouses' constructive, angry, and depressive conflict expressions. Results from dyadic hierarchical linear modeling revealed that intimacy issues were not likely to be discussed along with other topics (e.g., children, finances). Results also indicated that intimacy conflicts were likely to be recurrent and held relatively high levels of current and long-term importance to the relationship. Husbands and wives generally handled intimacy conflicts in constructive ways (e.g., expressed problem solving and positive emotions). However, husbands' depression symptoms emerged as a potent moderator of how intimacy conflicts were handled: Among couples that included a husband with higher levels of depression symptoms, discussing intimacy in conflict in the home was associated with greater use of angry expressions and depressive expressions by both husbands and wives. The current findings enhance understanding of intimacy conflicts in naturalistic contexts and offer clinical treatment implications and future research directions. PMID- 24167757 TI - Construction of a Reactive Diblock Copolymer, Polyphosphoester-block-Poly(L lactide), as a Versatile Framework for Functional Materials that are Capable of Full Degradation and Nanoscopic Assembly Formation. AB - The development of a diblock copolymer, polyphosphoester-block-poly(L-lactide), which has potential for being fully-degradable and biocompatible, was achieved by one-pot sequential ring-opening polymerizations (ROPs) of two cyclic monomers: alkyne-functionalized phospholane and L-lactide (LLA). A kinetic study of the polymerization in each step was investigated in a detailed manner by nuclear magnetic resonance (NMR) spectroscopy and gel permeation chromatography (GPC), revealing living/controlled characteristics with narrow molecular weight distributions and a linear increase of molecular weights vs. monomer conversion and time. Subsequently, photo-induced thiol-yne "click" reactions with small molecule thiols bearing either carboxylic acid or amino groups afforded amphiphilic diblock copolymers with carboxylate or amino side-chain functionalities along the polyphosphoester segment of the diblock copolymer backbone. Finally, direct dissolution of the two different types of amphiphilic diblock copolymers in aqueous solutions yielded well-defined spherical micelles with corresponding negative or positive surface charges, respectively, as confirmed by transmission electron microscopy (TEM), dynamic light scattering (DLS) and zeta potential analyses. PMID- 24167758 TI - Novel function of STAT1 in breast cancer. AB - In the past, the transcription factor STAT1 was considered as a tumor suppressor. We have recently discovered that STAT1 in malignant cells favors breast cancer progression as it stimulates immunosuppressive effects mediated by myeloid derived suppressor cells (MDSCs). Inhibiting STAT1 activity offers a promising therapeutic approach against advanced breast cancer. PMID- 24167759 TI - Immunological consequences of selective BRAF inhibitors in malignant melanoma: Neutralization of myeloid-derived suppressor cells. AB - Myeloid-derived suppressor cells (MDSC) potently repress antitumor immunity. The amount of MDSC in the blood of melanoma patients declines in response to vemurafenib, an inhibitor of oncogenic BRAF signaling that abrogates the ability of malignant cells to induce MDSC. This suggests that vemurafenib may be used in combination with various immunotherapeutic agents for the induction of long lasting tumor regression. PMID- 24167754 TI - Pentraxins: structure, function, and role in inflammation. AB - The pentraxins are an ancient family of proteins with a unique architecture found as far back in evolution as the Horseshoe crab. In humans the two members of this family are C-reactive protein and serum amyloid P. Pentraxins are defined by their sequence homology, their pentameric structure and their calcium-dependent binding to their ligands. Pentraxins function as soluble pattern recognition molecules and one of the earliest and most important roles for these proteins is host defense primarily against pathogenic bacteria. They function as opsonins for pathogens through activation of the complement pathway and through binding to Fc gamma receptors. Pentraxins also recognize membrane phospholipids and nuclear components exposed on or released by damaged cells. CRP has a specific interaction with small nuclear ribonucleoproteins whereas SAP is a major recognition molecule for DNA, two nuclear autoantigens. Studies in autoimmune and inflammatory disease models suggest that pentraxins interact with macrophage Fc receptors to regulate the inflammatory response. Because CRP is a strong acute phase reactant it is widely used as a marker of inflammation and infection. PMID- 24167760 TI - HDAC inhibitors and their potential applications to glioblastoma therapy. AB - Natural killer (NK) cells are integral components of the antitumor immune response. The downregulation of ligands for NK-cell stimulatory receptors represents a strategy whereby glioblastoma cells can evade NK-cell attacks. Histone deacetylase inhibitors can stimulate the (re)expression of these ligands, driving cytotoxic responses against glioblastoma cells that efficiently inhibit tumor growth. PMID- 24167761 TI - Arming NK cells with enhanced antitumor activity: CARs and beyond. AB - Natural killer (NK) cells hold great promise for adoptive cancer immunotherapy. The antitumor activity of NK cells can be enhanced by the transgene driven expression of chimeric antigen receptors that facilitate the selective recognition and killing of malignant cells. Recent data from our laboratory suggest that NK cells may similarly be "armed" against neoplastic cells by the expression of cancer-specific granzyme B-containing fusion proteins that are released as soluble factors upon NK-cell activation. PMID- 24167762 TI - Immunological profiling as a means to invigorate personalized cancer therapy. AB - Immunotherapy has taken off but has not yet reached its cruising altitude and is certainly far from its final destination. Identifying the unique immunological profile of individual cancer patients will provide critical clues for the design of optimal strategies that rectify tumor-induced immune imbalances. PMID- 24167763 TI - The many flavors of tumor-associated B cells. AB - Little is known on the role of distinct B-cell subtypes in human malignancies. We have recently performed a multiplex characterization of B cells in patient derived tumor-associated tissues, documenting the activation and antigen-driven differentiation of B cells in metastatic lymph nodes and neoplastic lesions. Here we discuss the role of B lymphocytes as antigen-presenting cells and catalysts of T cell-based immunotherapies in view of these findings. PMID- 24167764 TI - Improved immunogenicity of fusions between ethanol-treated cancer cells and dendritic cells exposed to dual TLR stimulation. AB - Tumor-derived transforming growth factor beta1 (TGFbeta1) generally abrogates the immunogenicity of dendritic cells (DCs) fused to whole cancer cells. We have recently revealed that ethanol-treated neoplastic cells fused to DCs exposed to 2 Toll-like receptor agonists efficiently induce cytotoxic T lymphocytes via TGFbeta1 blockade and the production of interleukin-12. PMID- 24167765 TI - Microsatellite instability in hematological malignancies: Hypermutation vs. immune control-who is challenging who? AB - The genome of colorectal carcinomas displaying pronounced microsatellite instability codes for an extraordinarily high number of mutated proteins that elicit tumor-specific cellular immune responses. We have recently demonstrated that leukemic cells are also vulnerable to T cells specific for tumor-associated antigens produced in the context of microsatellite instability. This finding extends our understanding of secondary and therapy-related leukemogenesis, linking it to the mutual interaction between immune control and escape. PMID- 24167766 TI - The "spin" doctors. PMID- 24167767 TI - Perceptions of health equity and subjective social status among baccalaureate nursing students engaged in service-learning activities in Hawai'i. AB - The purpose of this study was to measure undergraduate students' knowledge of social determinants of health, health equity, and subjective social status (SSS). A cross-sectional semi-structured survey was administered to 68 racially/ethnically diverse freshman students enrolled in a baccalaureate nursing program in O'ahu, Hawai'i. Students ranked the impact of 13 issues on Hawai'i residents' health and described how well the health care system addressed these issues. A 10-rung ladder was used to rank SSS; students marked an "X" on the ladder rung where they stand in society and explained what they would need to "move up or down" the ladder. The students identified three key issues that adversely impact health: substance abuse, diet/nutrition, and cancer. Sixty-nine percent of students stated that social determinants of health impact Hawai'i residents' health either "quite a bit" or "very much", while only 31% felt that the health care system adequately addressed these determinants. Students who ranked high on the ladder (rungs 6-10) cited family as the reason. The students who ranked low on the ladder (rungs 3-5) credited their position to lack of money. Students' perceptions of social determinants of health and health equity align with findings from public health studies in Hawai'i. These concepts were integrated into the 4-year nursing school curricula and findings inform future research and service-based learning activities conducted by the students. While findings presented here focus on nursing students in Hawai'i, this educational innovation could be replicated with students in other undergraduate health sciences programs. PMID- 24167768 TI - Intubation methods by novice intubators in a manikin model. AB - Tracheal Intubation is an important yet difficult skill to learn with many possible methods and techniques. Direct laryngoscopy is the standard method of tracheal intubation, but several instruments have been shown to be less difficult and have better performance characteristics than the traditional direct method. We compared 4 different intubation methods performed by novice intubators on manikins: conventional direct laryngoscopy, video laryngoscopy, Airtraq(r) laryngoscopy, and fiberoptic laryngoscopy. In addition, we attempted to find a correlation between playing videogames and intubation times in novice intubators. Video laryngoscopy had the best results for both our normal and difficult airway (cervical spine immobilization) manikin scenarios. When video was compared to direct in the normal airway scenario, it had a significantly higher success rate (100% vs 83% P=.02) and shorter intubation times (29.1 +/- 27.4 sec vs 45.9 +/- 39.5 sec, P=.03). In the difficult airway scenario video laryngoscopy maintained a significantly higher success rate (91% vs 71% P=0.04) and likelihood of success (3.2 +/- 1.0 95%CI [2.9-3.5] vs 2.4 +/- 0.9 95%CI [2.1-2.7]) when compared to direct laryngoscopy. Participants also reported significantly higher rates of self-confidence (3.5 +/- 0.6 95%CI [3.3-3.7]) and ease of use (1.5 +/- 0.7 95%CI [1.3-1.8]) with video laryngoscopy compared to all other methods. We found no correlation between videogame playing and intubation methods. PMID- 24167769 TI - Treatment of overactive bladder syndrome with urethral calibration in women. AB - Our objective was to determine whether urethral calibration with Walther's urethral sounds may be an effective treatment for overactive bladder syndrome. The diagnosis of overactive bladder syndrome is a clinical one based on the presence of urgency, with or without urge incontinence, and is usually accompanied by frequency and nocturia in the absence of obvious pathologic or metabolic disease. These symptoms exert a profound effect on the quality of life. Pharmacologic treatment is generally used to relieve symptoms, however anticholinergic medications may be associated with several undesirable side effects. There are case reports of symptom relief following a relatively quick and simple office procedure known as urethral dilation. It is hypothesized that this may be an effective treatment for the symptoms of overactive bladder. Women with clinical symptoms of overactive bladder were evaluated. Eighty-eight women were randomized to either urethral calibration (Treatment), or placebo (Control) treatment. Women's clinical outcomes at two and eight weeks were assessed and compared between the two treatment arms. Eight weeks after treatment, 31.1% (n=14) of women who underwent urethral calibration were responsive to the treatment versus 9.3% (n=4) of the Control group. Also, 51.1% (n=23) of women within the Treatment group showed at least a partial response versus 20.9% (n=9) of the Control group. Our conclusion is that Urethral calibration significantly improves the symptoms of overactive bladder when compared to placebo and may be an effective alternative treatment method. PMID- 24167770 TI - Five years after the Hawai'i smoke-free law: tourism and hospitality economic indicators appear unharmed. AB - Opponents of Hawai'i's smoke-free law argued that such a law would lead to a decrease in tourism. The purpose of this study is to determine if there is evidence of an adverse impact of Hawai'i's smoke-free law on tourism utilizing data obtained from Hawai'i's Department of Business, Economic Development & Tourism website for tourists from the United States. Descriptive statistics were reported before and after the law and linear regression was used to assess the relationship between the implementation of the law and changes in indicators of tourism while adjusting for underlying economic factors. The most pronounced fluctuations observed with all tourism indicators occurred around the time the US entered the recession (December 2007), with steady increases following the end of the US recession. While controlling for economic and seasonal trends, the presence of the smoke-free law was associated with an increase in arrivals (beta= 42847.9; 95% CI: 16303.3, 69392.5), accommodation employees (beta= 969.0; 95% CI: 351.1, 1586.8) and food services & beverage places employees (beta=3390.8; 95% CI: 2326.9, 4454.7). Fluctuations in tourism indicators are likely to be associated with greater economic forces, such as decreasing GDP and consumer confidence in the United States and greater global economic trends, rather than the smoke-free law. PMID- 24167771 TI - Medical school hotline: Enhancing problem-based learning with technology: the introduction of iPads into the John A. Burns School of Medicine Curriculum. PMID- 24167772 TI - Insights in public health: It takes a Hui to raise a child: a case for peer-to peer support for child abuse prevention. PMID- 24167773 TI - University of Hawai'i Cancer Center Connection: Improving public health across the Pacific: a retrospective of the 2012 Pacific Global Health Conference. PMID- 24167775 TI - Examining the Relationship Between Soda Consumption and Eating Disorder Pathology. AB - OBJECTIVE: This study aimed to compare diet soda drinkers, regular soda drinkers, and individuals who do not regularly consume soda on clinically significant eating disorder psychopathology, including binge eating, overeating, and purging. METHOD: Participants (n=2077) were adult community volunteers who completed an online survey that included the Eating Disorder Examination Questionnaire and questions regarding binge eating behaviors, purging, current weight status, and the type and frequency of soda beverages consumed. RESULTS: Diet soda drinkers (34%, n=706) reported significantly higher levels of eating, shape, and weight concerns than regular soda drinkers (22%, n=465), who in turn reported higher levels on these variables than non-soda drinkers (44%, n=906). Diet soda drinkers were more likely to report binge eating and purging than regular soda drinkers, who were more likely to report these behaviors than non-soda drinkers. Consumption of any soda was positively associated with higher BMI, though individuals who consumed regular soda reported significantly higher BMI than diet soda drinkers, who in turn reported higher weight than those who do not consume soda regularly. CONCLUSIONS: Individuals who consume soda regularly reported higher BMI and more eating psychopathology than those who do not consume soda. These findings extend previous research demonstrating positive associations between soda consumption and weight. PMID- 24167776 TI - Structural differences between C-terminal regions of tropomyosin isoforms. AB - Tropomyosins are actin-binding regulatory proteins which overlap end-to-end along the filament. High resolution structures of the overlap regions were determined for muscle and non-muscle tropomyosins in the absence of actin. Conformations of the junction regions bound to actin are unknown. In this work, orientation of the overlap on actin alone and on actin-myosin complex was evaluated by measuring FRET distances between a donor (AEDANS) attached to tropomyosin and an acceptor (DABMI) bound to actin's Cys374. Donor was attached to the Cys residue introduced by site-directed mutagenesis near the C-terminal half of the overlap. The recombinant alpha-tropomyosin isoforms used in this study - skeletal muscle skTM, non-muscle TM2 and TM5a, and chimeric TM1b9a had various amino acid sequences of the N- and C-termini involved in the end-to-end overlap. The donor-acceptor distances calculated for each isoform varied between 36.4 A and 48.1 A. Rigor binding of myosin S1 increased the apparent FRET distances of skTM and TM2, but decreased the distances separating TM5a and TM1b9a from actin. The results show that isoform-specific sequences of the end-to-end overlaps determine orientations and dynamics of tropomyosin isoforms on actin. This can be important for specificity of tropomyosin in the regulation of actin filament diverse functions. PMID- 24167777 TI - Ontogeny in the tube-crested dinosaur Parasaurolophus (Hadrosauridae) and heterochrony in hadrosaurids. AB - The tube-crested hadrosaurid dinosaur Parasaurolophus is remarkable for its unusual cranial ornamentation, but little is known about its growth and development, particularly relative to well-documented ontogenetic series for lambeosaurin hadrosaurids (such as Corythosaurus, Lambeosaurus, and Hypacrosaurus). The skull and skeleton of a juvenile Parasaurolophus from the late Campanian-aged (~75.5 Ma) Kaiparowits Formation of southern Utah, USA, represents the smallest and most complete specimen yet described for this taxon. The individual was approximately 2.5 m in body length (~25% maximum adult body length) at death, with a skull measuring 246 mm long and a femur 329 mm long. A histological section of the tibia shows well-vascularized, woven and parallel fibered primary cortical bone typical of juvenile ornithopods. The histological section revealed no lines of arrested growth or annuli, suggesting the animal may have still been in its first year at the time of death. Impressions of the upper rhamphotheca are preserved in association with the skull, showing that the soft tissue component for the beak extended for some distance beyond the limits of the oral margin of the premaxilla. In marked contrast with the lengthy tube-like crest in adult Parasaurolophus, the crest of the juvenile specimen is low and hemicircular in profile, with an open premaxilla-nasal fontanelle. Unlike juvenile lambeosaurins, the nasal passages occupy nearly the entirety of the crest in juvenile Parasaurolophus. Furthermore, Parasaurolophus initiated development of the crest at less than 25% maximum skull size, contrasting with 50% of maximum skull size in hadrosaurs such as Corythosaurus. This early development may correspond with the larger and more derived form of the crest in Parasaurolophus, as well as the close relationship between the crest and the respiratory system. In general, ornithischian dinosaurs formed bony cranial ornamentation at a relatively younger age and smaller size than seen in extant birds. This may reflect, at least in part, that ornithischians probably reached sexual maturity prior to somatic maturity, whereas birds become reproductively mature after reaching adult size. PMID- 24167778 TI - Citations and the h index of soil researchers and journals in the Web of Science, Scopus, and Google Scholar. AB - Citation metrics and h indices differ using different bibliometric databases. We compiled the number of publications, number of citations, h index and year since the first publication from 340 soil researchers from all over the world. On average, Google Scholar has the highest h index, number of publications and citations per researcher, and the Web of Science the lowest. The number of papers in Google Scholar is on average 2.3 times higher and the number of citations is 1.9 times higher compared to the data in the Web of Science. Scopus metrics are slightly higher than that of the Web of Science. The h index in Google Scholar is on average 1.4 times larger than Web of Science, and the h index in Scopus is on average 1.1 times larger than Web of Science. Over time, the metrics increase in all three databases but fastest in Google Scholar. The h index of an individual soil scientist is about 0.7 times the number of years since his/her first publication. There is a large difference between the number of citations, number of publications and the h index using the three databases. From this analysis it can be concluded that the choice of the database affects widely-used citation and evaluation metrics but that bibliometric transfer functions exist to relate the metrics from these three databases. We also investigated the relationship between journal's impact factor and Google Scholar's h5-index. The h5-index is a better measure of a journal's citation than the 2 or 5 year window impact factor. PMID- 24167779 TI - Gooseneck barnacles (Lepas spp.) ingest microplastic debris in the North Pacific Subtropical Gyre. AB - Substantial quantities of small plastic particles, termed "microplastic," have been found in many areas of the world ocean, and have accumulated in particularly high densities on the surface of the subtropical gyres. While plastic debris has been documented on the surface of the North Pacific Subtropical Gyre (NPSG) since the early 1970s, the ecological implications remain poorly understood. Organisms associated with floating objects, termed the "rafting assemblage," are an important component of the NPSG ecosystem. These objects are often dominated by abundant and fast-growing gooseneck barnacles (Lepas spp.), which predate on plankton and larval fishes at the sea surface. To assess the potential effects of microplastic on the rafting community, we examined the gastrointestinal tracts of 385 barnacles collected from the NPSG for evidence of plastic ingestion. We found that 33.5% of the barnacles had plastic particles present in their gastrointestinal tract, ranging from one plastic particle to a maximum of 30 particles. Particle ingestion was positively correlated to capitulum length, and no blockage of the stomach or intestines was observed. The majority of ingested plastic was polyethylene, with polypropylene and polystyrene also present. Our results suggest that barnacle ingestion of microplastic is relatively common, with unknown trophic impacts on the rafting community and the NPSG ecosystem. PMID- 24167780 TI - Protein signatures using electrostatic molecular surfaces in harmonic space. AB - We developed a novel method based on the Fourier analysis of protein molecular surfaces to speed up the analysis of the vast structural data generated in the post-genomic era. This method computes the power spectrum of surfaces of the molecular electrostatic potential, whose three-dimensional coordinates have been either experimentally or theoretically determined. Thus we achieve a reduction of the initial three-dimensional information on the molecular surface to the one dimensional information on pairs of points at a fixed scale apart. Consequently, the similarity search in our method is computationally less demanding and significantly faster than shape comparison methods. As proof of principle, we applied our method to a training set of viral proteins that are involved in major diseases such as Hepatitis C, Dengue fever, Yellow fever, Bovine viral diarrhea and West Nile fever. The training set contains proteins of four different protein families, as well as a mammalian representative enzyme. We found that the power spectrum successfully assigns a unique signature to each protein included in our training set, thus providing a direct probe of functional similarity among proteins. The results agree with established biological data from conventional structural biochemistry analyses. PMID- 24167781 TI - Analysis of close associations of uropod-associated proteins in human T-cells using the proximity ligation assay. AB - We have shown previously that the raft-associated proteins flotillin-1 and -2 are rapidly recruited to the uropods of chemoattractant-stimulated human neutrophils and T-cells and are involved in cell polarization. Other proteins such as the adhesion receptor PSGL-1, the actin-membrane linker proteins ezrin/radixin/moesin (ERM) and the signaling enzyme phosphatidylinositol-4-phosphate 5-kinase type Igamma90 (PIPKIgamma90) also accumulate in the T-cell uropod. Using the in situ proximity ligation assay (PLA) we now have investigated putative close associations of these proteins in human freshly isolated T-cells before and after chemokine addition. The PLA allows in situ subcellular localization of close proximity of endogenous proteins at single-molecule resolution in fixed cells. It allows detection also of weaker and transient complexes that would not be revealed with co-immunoprecipitation approaches. We previously provided evidence for heterodimer formation of tagged flotillin-1 and -2 in T-cells before and after chemokine addition using fluorescence resonance energy transfer (FRET). We now confirm these findings using PLA for the endogenous flotillins in fixed human T-cells. Moreover, in agreement with the literature, our PLA findings confirm a close association of endogenous PSGL-1 and ERM proteins both in resting and chemokine-activated human T-cells. In addition, we provide novel evidence using the PLA for close associations of endogenous activated ERM proteins with PIPKIgamma90 and of endogenous flotillins with PSGL-1 in human T-cells, before and after chemokine addition. Our findings suggest that preformed clusters of these proteins coalesce in the uropod upon cell stimulation. PMID- 24167782 TI - PhyBin: binning trees by topology. AB - A major goal of many evolutionary analyses is to determine the true evolutionary history of an organism. Molecular methods that rely on the phylogenetic signal generated by a few to a handful of loci can be used to approximate the evolution of the entire organism but fall short of providing a global, genome-wide, perspective on evolutionary processes. Indeed, individual genes in a genome may have different evolutionary histories. Therefore, it is informative to analyze the number and kind of phylogenetic topologies found within an orthologous set of genes across a genome. Here we present PhyBin: a flexible program for clustering gene trees based on topological structure. PhyBin can generate bins of topologies corresponding to exactly identical trees or can utilize Robinson-Fould's distance matrices to generate clusters of similar trees, using a user-defined threshold. Additionally, PhyBin allows the user to adjust for potential noise in the dataset (as may be produced when comparing very closely related organisms) by pre processing trees to collapse very short branches or those nodes not meeting a defined bootstrap threshold. As a test case, we generated individual trees based on an orthologous gene set from 10 Wolbachia species across four different supergroups (A-D) and utilized PhyBin to categorize the complete set of topologies produced from this dataset. Using this approach, we were able to show that although a single topology generally dominated the analysis, confirming the separation of the supergroups, many genes supported alternative evolutionary histories. Because PhyBin's output provides the user with lists of gene trees in each topological cluster, it can be used to explore potential reasons for discrepancies between phylogenies including homoplasies, long-branch attraction, or horizontal gene transfer events. PMID- 24167783 TI - Development and evaluation of a novel biodegradable sustained release microsphere formulation of paclitaxel intended to treat breast cancer. AB - OBJECTIVE: The objective of this study was to develop a novel 1 month depot paclitaxel (PTX) microspheres that give a sustained and complete drug release. MATERIALS AND METHODS: PTX loaded microspheres were prepared by o/w emulsion solvent evaporation technique using the blends of poly(lactic-co-glycolic acid) (PLGA) 75/25, polycaprolactone 14,000 and polycaprolactone 80,000. Fourier transform infrared spectroscopy was used to investigate drug excipient compatibility. Compatible blends were used to prepare F1-F6 microspheres, the process was characterised and the optimum formulation was selected based on the release. Optimised formulation was characterised for solid state of the drug using the differential scanning calorimetry (DSC) studies, surface morphology using the scanning electron microscopy (SEM), in vivo drug release, in vitro in vivo correlation (IVIVC) and anticancer activity. Anticancer activity of release medium was determined using the cell viability assay in Michigan Cancer Foundation (MCF-7) cell line. RESULTS: Blend of PLGA with polycaprolactone (Mwt 14,000) at a ratio of 1:1 (F5) resulted in complete release of the drug in a time frame of 30 days. F5 was considered as the optimised formulation. Incomplete release of the drug resulted from other formulations. The surface of the optimised formulation was smooth and the drug changed its solid state upon fabrication. The formulation also resulted in 1-month drug release in vivo. The released drug from F5 demonstrated anticancer activity for 1-month. Cell viability was reduced drastically with the release medium from F5 formulation. A 100% IVIVC was obtained with F5 formulation suggesting the authenticity of in vitro release, in vivo release and the use of the formulation in breast cancer. CONCLUSIONS: From our study, it was concluded that with careful selection of different polymers and their combinations, PTX 1 month depot formulation with 100% drug release and that can be used in breast cancer was developed. PMID- 24167784 TI - Development and characterization of gelatin based nanoparticles for targeted delivery of zidovudine. AB - INTRODUCTION: The present work was aimed at development and evaluation of zidovudin (AZT) loaded gelatin nanoparticles (GNPs) by simple desolvation method and further couple it with mannose. MATERIAL AND METHODS: Total seven batches of GNPs (A1-A7) were formulated by changing the concentration of polymer gelatin. Various parameters such as particle size, polydispersity index, zeta potential, % entrapment efficiency and in-vitro drug release of plain and mannosylated gelatin nanoparticles (M-GNPs) were studied. RESULTS: Scanning electron microscopy (SEM) studies revealed that the average particle size of GNPs and M-GNPs were found to be 394 +/- 3.21 and 797.2 +/- 2.89 nm respectively (optimised batch A3). It was interesting to note that the average particle size of M-GNPs was more due to anchored mannose, whereas drug entrapment was lesser compared to plain GNPs. Studies have showed drug loading for GNPs and M-GNPs to be 66.56% and 58.85% respectively. Zeta potential studies demonstrated little reduction in solution stability of M-GNPs compared to GNPs. In-vitro drug release studies showed almost 80% release (bimodal) up to 24 h, following Korsmeyer-Peppas release kinetics model (GNPs, r = 0.9760; M-GNPs, r = 0.9712). CONCLUSIONS: Hence, it can be concluded that, development of GNPs and M-GNPs will pave the way for reticuloendothelial system uptake of AZT; thus, achieving targeted delivery, selectivity and reduction in associated side effect reduction in acquired immuno defficiency syndrome. PMID- 24167785 TI - Synthesis characterization and in vitro drug release from acrylamide and sodium alginate based superporous hydrogel devices. AB - OBJECTIVE: Present investigation was aimed at developing gastroretentive superporous hydrogels (SPHs) having desired mechanical characteristics with sustained release. MATERIALS AND METHODS: The acrylamide based SPHs of various generations (1(st), 2(nd) and 3(rd)) were synthesized by gas blowing technique. The prepared SPHs were evaluated for swelling, mechanical strength studies and scanning electron microscopy studies. Verapamil hydrochloride was loaded into selected SPHs by aqueous drug loading method and characterized via Fourier transform infrared spectroscopy (FTIR), X-ray diffraction (X-RD), differential scanning calorimetry (DSC), nuclear magnetic resonance (NMR) and in vitro drug release studies. RESULTS: SPHs of third generation were observed to have desired mechanical strength with sufficient swelling properties. Integrity of the drug was maintained in hydrogel polymeric network as indicated by FTIR, X-RD, and DSC and NMR studies. Initially, fast drug release (up to 60%) was observed in 30 min in formulation batches containing pure drug only (A, C and E), which was further sustained untill 24 h. DISCUSSION: The increase in mechanical strength was due to the chemical cross-linking of secondary polymer in hydrogel network. The initial burst release was due to the presence of free drug at the surface and later sustained drug release was due to diffusion of entrapped drug in polymeric network. Significant decrease in drug release was observed by the addition of hydroxypropyl methyl cellulose. CONCLUSION: SPH interpenetrating networks with fast swelling and sufficient mechanical strength were prepared, which can be potentially exploited for designing gastroretentive drug delivery devices. PMID- 24167786 TI - Development and optimization of enteric coated mucoadhesive microspheres of duloxetine hydrochloride using 3(2) full factorial design. AB - BACKGROUND: Microspheres constitute an important part of oral drug delivery system by virtue of their small size and efficient carrier capacity. However, the success of these microspheres is limited due to their short residence time at the site of absorption. OBJECTIVE: The objective of the present study was to formulate and systematically evaluate in vitro performance of enteric coated mucoadhesive microspheres of duloxetine hydrochloride (DLX), an acid labile drug. MATERIALS AND METHODS: DLX microspheres were prepared by simple emulsification phase separation technique using chitosan as carrier and glutaraldehyde as a cross-linking agent. Microspheres prepared were coated with eudragit L-100 using an oil-in-oil solvent evaporation method. Eudragit L-100was used as enteric coating polymer with the aim to release the drug in small intestine The microspheres prepared were characterized by particle size, entrapment efficiency, swelling index (SI), mucoadhesion time, in vitro drug release and surface morphology. A 3(2) full factorial design was employed to study the effect of independent variables polymer-to-drug ratio (X1) and stirring speed (X2) on dependent variables, particle size, entrapment efficiency, SI, in vitro mucoadhesion and drug release up to 24 h (t24). RESULTS: Microspheres formed were discrete, spherical and free flowing. The microspheres exhibited good mucoadhesive property and also showed high percentage entrapment efficiency. The microspheres were able to sustain the drug release up to 24 h. CONCLUSION: Thus, the prepared enteric coated mucoadhesive microspheres may prove to be a potential controlled release formulation of DLX for oral administration. PMID- 24167787 TI - Design of sustained release pellets of ferrous fumarate using cow ghee as hot melt coating agent. AB - INTRODUCTION: The objective of the present study was to design ferrous fumarate (FF) sustained release (SR) pellets using of cow ghee (CG) as an important hot melt coating (HMC) agent. MATERIALS AND METHODS: The pellets were coated by HMC technique using CG and ethyl cellulose composition by conventional coating pan without the use of spray system. FF formulated as pellets and characterized with regard to the drug content and physico-chemical properties. Stability studies were carried out on the optimized formulation for a period of 6 months at 40 +/- 2 degrees C and 75 +/- 5% relative humidity. RESULTS: Pellets with good surface morphology and smooth texture confirmed by stereo micrographs. HMC is easy, efficient, rapid and simple method since virtually no agglomeration seen during coating. In-vitro release from pellets at a given level of coating and for present pellet size was dependent upon the physico-chemical property of the drug and mostly aqueous solubility of the drug. The selection of optimized FF formulation was confirmed by comparing percent cumulative drug release with theoretical release profile. Formulation F2 had difference factor (f 1) and similarity factor (f 2) values was found to be 5 and 66 respectively. F2 showed SR of drug for 8 h with cumulative per cent release of 98.03 +/- 4.49%. Release kinetics indicates approximately zero order release pattern. HMC pellets were stable during the course of stability study. CONCLUSIONS: By means of HMC using CG and ethyl cellulose, SR pellets containing FF were successfully prepared. PMID- 24167788 TI - Comparative evaluation of single and bilayered lamotrigine floating tablets. AB - AIM: The purpose of this study was to prepare lamotrigine (LM) bilayered and single layered floating tablets and to compare their release profiles. MATERIALS AND METHODS: LM floating tablets were prepared by direct compression method. Drug, hydroxy propyl methyl cellulose K4M, lactose monohydrate and polyvinylpyrrolidone K30 constitute controlled release layer components and floating layer components includes polymers and sodium bicarbonate. The prepared tablets were evaluated for physicochemical parameters such as hardness, friability, weight variation, thickness, floating lag time (FLT), floating time, in vitro buoyancy study, in vitro release studies. The drug-polymer interaction was studied by fourier transform infrared and differential scanning calorimetry. RESULTS AND DISCUSSION: The FLT of all the formulations were within the prescribed limits (<3 min). When ethyl cellulose was used as floating layer component, tablets showed good buoyancy effect but eroded within 6-8 h. Hence it was replaced with hydroxypropyl cellulose -M hydrophilic polymer, which showed good FLT and floating duration for 16 h. Formulation LFC4 was found to be optimized with dissolution profile of zero order kinetics showing fickian diffusion. A comparative study of bilayered and single layered tablets of LM showed a highest similarity factor of 83.03, difference factor of 2.74 and t-test (P < 0.05) indicates that there is no significant difference between them. CONCLUSION: Though bilayered tablet possess many advantages, single layered tablet would be economical, cost-effective and reproducible for large scale production in the industry. However, the results of present study demonstrated that the in vitro development of bilayered gastro retentive floating tablets with controlled drug release profile for LM is feasible. PMID- 24167789 TI - Ethyl cellulose and hydroxypropyl methyl cellulose buoyant microspheres of metoprolol succinate: Influence of pH modifiers. AB - INTRODUCTION: Incorporation of pH modifier has been the usual strategy employed to enhance the dissolution of weakly basic drug from floating microspheres. Microspheres prepared using a combination of both ethyl cellulose (EC) and hydroxypropyl methylcellulose (HPMC) which shows highest release were utilize to investigate the effect of fumaric acid (FA), citric acid (CA), ascorbic acid (AA) and tartaric acid (TA) (all 5-20% w/w) incorporation on metoprolol succinate (MS) release. MATERIALS AND METHODS: EC, HPMC alone or in combination were used to prepare microspheres that floated in simulated gastric fluid and evaluated for a percent yield, drug entrapment, percent buoyancy and drug release. The higher drug release in combination (MS:HPMC:EC, 1:1:2) was selected for the evaluation of influence of pH modifiers on MS release. CA (5-20% w/w), AA (5-20% w/w), FA (5 20% w/w) and TA (5-20% w/w) were added and evaluated for drug release. Present investigation is directed to develop floating drug delivery system of MS by solvent evaporation technique. RESULTS: The microspheres of MS:HPMC:EC (1:1:2) exhibited the highest entrapment (74.36 +/- 2.18). The best percentage yield was obtained at MS:HPMC (1:1) (83.96 +/- 1.50) and combination of MS:HPMC:EC (1:1:2) (79.23 +/- 1.63). CONCLUSION: MS release from the prepared microspheres was influenced by changing MS-polymer, MS-polymer-polymer ratio and pH modifier. Although significant increment in MS release was observed with CA (20% w/w), TA (20% w/w) and AA (20% w/w), addition of 20% w/w FA demonstrated more pronounced and significant increase in drug entrapment as well as release from MS:HPMC:EC (1:1:2) buoyant microspheres. PMID- 24167790 TI - Relation between left atrial enlargement and stroke subtypes in acute ischemic stroke patients. AB - OBJECTIVE: Increased atrial size is frequently seen in ischemic stroke patients in clinical practice. There is controversy about whether left atrial enlargement (LAE) should be regarded as a risk factor for cerebral infarction. We investigated the association between indexed left atrial volume (LAVI) and conventional stroke risk factors as well as stroke subtypes in acute ischemic stroke patients. METHODS: One hundred eighty two acute cerebral infarction patients were included in this study. Brain magnetic resonance imaging and transthoracic echocardiography were done for all patients within 30 days of diagnosis of acute cerebral infarction. Echocardiographic LAE was identified when LAVI was more than 27 mL/m(2). Stroke subtypes were classified by the Trial of Org 10171 in acute stroke treatment classification. RESULTS: There were significant differences between subjects with normal and increased LAVI in prevalence of stroke risk factors including atrial fibrillation (p = 0.001), hypertension (p = 0.000), valvular heart disease (p = 0.011) and previous stroke (p = 0.031). An increased LAVI was associated with cardioembolic subtype with an adjusted odds ratio was 6.749 (p = 0.002) compared with small vessel disease. CONCLUSION: Increased LAVI was more prevalent in those who had cardiovascular risk factors, such as atrial fibrillation, hypertension, valvular heart disease and history of previous stroke. LAE influenced most patients in all subtypes of ischemic stroke but was most prevalent in the cardioembolic stroke subtype. Increased LAVI might be a risk factor of cerebral infarction, especially in patients with cardioembolic stroke subtype. PMID- 24167791 TI - Endovascular mechanical thrombectomy in basilar artery occlusion: initial experience. AB - OBJECTIVE: This study was conducted to assess the efficacy and safety of endovascular mechanical thrombectomy (EMT) for patients diagnosed with basilar artery (BA) occlusion. MATERIALS AND METHODS: We retrospectively analyzed clinical and imaging data of 16 patients diagnosed with BA occlusion who were treated with endovascular intervention from July 2012 to February 2013. Direct suction using the Penumbra system and thrombus retrieval by the Solitaire stent were the main endovascular techniques used to restore BA flow. The outcomes were evaluated based on rate of angiographic recanalization, rate of improvement of National Institutes of Health Stroke Scale (NIHSS) score, rate of modified Rankin Scale (mRS) at discharge and after 3 months, and rate of cerebral hemorrhagic complications. Successful recanalization was defined as achieving Thrombolysis In Cerebral Infarction (TICI) of II or III. RESULTS: Sixteen patients received thrombectomy. The mean age was 67.8 +/- 11 years and the mean NIHSS score was 12.3 +/- 8.2. Eight patients treated within 6 hours of symptom onset were grouped as A and the other 8 patients treated beyond 6 hours (range, 6-120) were grouped as B. Successful recanalization was met in six patients (75%) for group A and 7 (87.5%) for group B. Favorable outcome occurred in 4 patients (50%) for group A and 5 (62.5%) for group B. CONCLUSION: Our study supports the effectiveness and safety of endovascular mechanical thrombectomy in treating BA occlusion even 6 hours after symptom onset. PMID- 24167792 TI - The anatomy of the superficial temporal artery in adult koreans using 3 dimensional computed tomographic angiogram: clinical research. AB - OBJECTIVE: The increased use of bypass surgery in the treatment of ischemic cerebrovascular diseases requires a better understanding of the superficial temporal artery (STA) anatomy. This study is to describe the gross anatomy of STA in adult Korean population with respect to cranial surgery and to provide basic anatomic data for bypass surgery. METHODS: The study evaluated retrospectively 35 patients who visited the neurosurgery department at a single institution. For each patient, both the left and right STA (70 vessels) were evaluated by a 3 dimensional computed tomographic angiogramfor diameter and anatomic relationships to external landmarks. RESULTS: Of 70 STAs, 69 had a bifurcation. Among these, 57 (82.6%) were above the superior margin of the zygomatic arch. The STA bifurcation was 53.2 +/- 5.9 mm posterior to the keyhole, 9.5 +/- 5.3 mm anterior to the posterior margin of condylar process of the mandible, and 21.7 +/- 15.8 mm superior to the superior margin of the zygomatic arch. The inner diameter of the STA was 1.8 +/- 0.5 mm at the superior margin of the zygomatic arch, and 1.4 +/- 0.4 mm and 1.4 +/- 0.5 mm for frontal and parietal branches, respectively. The 75.7% of frontal and 66.7% of parietal branches were suitable for microvascular anastomosis. CONCLUSION: This present study demonstrated the STA in Korean adults, which may benefit the clinician in dealing with the surgical procedures related to this STA. PMID- 24167793 TI - Association between the daily temperature range and occurrence of spontaneous intracerebral hemorrhage. AB - OBJECTIVE: We have observed, anecdotally, that the incidence of primary spontaneous intracerebral hemorrhage (sICH), as well as spontaneous subarachnoid hemorrhage, varies in accordance with seasonality and meteorological conditions. This retrospective single-hospital-based study aimed to determine the seasonality of sICH and the associations, if any, between the occurrence of sICH and meteorological parameters in Incheon city, which is a northwestern area of South Korea. METHODS: Electronic hospital data on 708 consecutive patients admitted with primary sICH from January 2008 to December 2010 was reviewed. Traumatic and various secondary forms of ICHs were excluded. Average monthly admission numbers of sICH were analyzed, in relation with the local temperature, atmospheric pressure, humidity, and daily temperature range data. The relationships between the daily values of each parameter and daily admission numbers of sICH were investigated using a combination of correlation and time-series analyses. RESULTS: No seasonal trend was observed in sICH-related admissions during the study period. Furthermore, no statistically significant correlation was detected between the daily sICH admission numbers and the meteorological parameters of temperature, atmospheric pressure and humidity. The daily temperature range tended to correlate with the number of daily sICH-related admissions (p = 0.097). CONCLUSION: This study represents a comprehensive investigation of the association between various meteorological parameters and occurrence of spontaneous ICH. The results suggest that the daily temperature range may influence the risk of sICH. PMID- 24167794 TI - Clinical and Angiographic Outcomes of Wide-necked Aneurysms Treated with the Solitaire AB Stent. AB - OBJECTIVE: This study investigated the clinical and angiographic outcomes of treatment with stent-assisted coil embolization using the Solitaire AB stents for wide-necked intracranial aneurysms. METHODS: From October 2010 to December 2011, 22 patients with aneurysms were treated with the Solitaire AB stent. One patient with a dissecting aneurysm was excluded, thus 21 patients with 21 wide-necked saccular aneurysms were included in this study. The technical success rate, procedure-related complications, initial and follow-up angiographic results, and clinical outcomes were retrospectively collected. RESULTS: THE LOCATIONS OF ANEURYSMS WERE AS FOLLOWS: paraclinoid in 14, distal internal carotid artery in 4, and vertebral artery in 3 patients. All aneurysms were unruptured and less than 10 mm-sized. The mean dome-to-neck ratio of the aneurysms was 1.00 (range: 0.45-1.81). The mean follow-up duration was 12.1 (7-15) months after the initial procedure. The technical success rate was 21 (95.5%) of 22 patients with aneurysms. Fortunately, there were no procedure-related complications. Follow-up angiography showed that the rate of complete occlusion was 57.1%, neck remnants 38.1%, and incomplete occlusion 4.8%. CONCLUSION: We suggest that using Solitaire AB stent is technically feasible and safe in the stent-assisted coil embolization for wide-necked saccular intracranial aneurysms. To evaluate the long-term effects of this stent, further follow-up angiography is needed. PMID- 24167795 TI - Two indices affecting the directions of the sylvian fissure dissection in middle cerebral artery bifurcation aneurysms. AB - OBJECTIVE: This study proposes more objective methods for deciding the appropriate direction of the sylvian fissure dissection during surgical clipping in middle cerebral artery (MCA) bifurcation aneurysms. METHODS: We reviewed data of 36 consecutive patients with MCA bifurcation aneurysms. We measured 2 indices preoperatively on 3-dimensional computed tomography angiography (3D-CTA). Analysis of the calculated data allowed us to select the appropriate direction of sylvian fissure dissection for ease of proximal control of M1. Statistically, Mann-Whitney test was used. RESULTS: We classified subjects into 2 groups based on the technical level of M1 exposure during surgical clipping. When it was difficult to expose M1, subjects were assigned to Group I, and Group II were subjects in whom M1 exposure was easy. The mean difference between the distances extending from the limbus sphenoidale (LS) line to the internal carotid artery bifurcation and extending from the LS line to the MCA bifurcation was 1.00 +/- 0.42 mm in group I and 4.39 +/- 2.14 mm in group II. The mean M1 angle was 9.36 +/- 3.73 degrees in the group I and 34.05 +/- 16.71 degrees in the group II (M1 slope gap p < 0.05, M1 angle p < 0.05). CONCLUSION: We have found an objective method for preoperatively verifying ease of exposure of M1 artery during surgical clipping. Therefore, we suggest use of the preoperative M1 slope gap and M1 angle as indicators in 3D-CTA selecting the direction of sylvian fissure dissection for easy proximal control of M1. PMID- 24167796 TI - The role of adiponectin in secondary inflammatory reaction in cerebral ischemia. AB - OBJECTIVE: In this study, we investigate the role of adiponectin in the interaction between leukocytes and endothelium in the secondary inflammatory reaction of cerebral ischemia. METHODS: Adiponectin knock-out mice group (APN-KO) (n = 8) and wild-type mice group (WT) (n = 8) were prepared. Each group was sub divided into 2 groups by reperfusion time. One-hour middle cerebral artery occlusion and reperfusion were induced using the intraluminal filament technique. At 6 and 12 hours after the occlusion, the mice were placed on a stereotactic frame to perform craniotomy in the left parietal area. After craniotomy, a straight pial venule was selected as a target vessel. With the fluorescence intravital microscope, the number of rolling leukocytes and leukocytes that adhered to endothelium were counted and documented at 6 and 12 hours after the reperfusion. RESULTS: At 6 and 12 hours after the reperfusion, more rolling leukocyte and leukocyte adhesion were observed in the APN-KO mice than in the WT mice. The difference in leukocyte numbers between the APN-KO and WT mice was found to be statistically significant (p = 0.029) by Mann-Whitney U-test. CONCLUSION: We found that adiponectin inhibits the interaction between the endothelium and leukocytes in cerebral ischemia-reperfusion. Therefore adiponectin might prevent the secondary insult caused by the inflammation reaction. PMID- 24167797 TI - Pterional-subolfactory Approach for Treatment of High Positioned Anterior Communicating Artery Aneurysms. AB - OBJECTIVE: The purpose of this study is to compare the surgical outcomes of pterional-subolfactory approach for the high positioned anterior communicating artery (ACoA) aneurysm with the conventional pterional approach. METHODS: Between February 2005 and December 2012, 463 ACoA aneurysms were surgically treated in our institution. Forty eight high positioned ACoA aneurysms were treated with pterional-subolfactory or conventional pterional approach. High positioned ACoA aneurysms were defined as aneurysms located higher than 10 mm above the anterior clinoid process. Pterional-subolfactory approach is a procedure including dissection of olfactory tract and resection of the gyrus rectus inferior and medial to the olfactory tract. Thirty-four of the 48 cases were treated with pterional-subolfactory approach and 14 were treated conventionally. RESULTS: There were 2 postoperative cerebral infarction with the conventional pterional approach, but none with the pterional-subolfactory approach group (p = 0.026). Postoperative digital subtraction angiography revealed significant remnant aneurysm in the conventional pterional approach group. All patients with unruptured aneurysms had good clinical outcomes with Glasgow outcome score of 5. Among ruptured ACoA aneurysm patients, 2 patients with conventional pterional approach had postoperative cerebral infarctions but permanent neurologic deficit was found in only 1 patient. Three patients treated with the pterional subolfactory approach, who had preoperative ruptured aneurysms had poor clinical outcomes. The mean operation time for the conventional pterional approach was 58 minutes longer than for the pterional-subolfactory approach (p = 0.001). CONCLUSION: We concluded that pterional-subolfactory approach is highly preferable for cases of high positioned ACoA aneurysm, giving a wide and effective operation view. PMID- 24167798 TI - Single-session Coil Embolization of Multiple Intracranial Aneurysms. AB - OBJECTIVE: There is no clear treatment strategy for the management of multiple intracranial aneurysms because of variable anatomical distribution, difficult identification of the aneurysm ruptured, and poor overall outcomes. The purpose of this study was to assess the efficacy and safety of single-session coil embolization for multiple intracranial aneurysms. METHODS: Between September 2008 and December 2012, 209 aneurysms in 117 patients were treated at our institute. Twenty eight among the 117 patients had multiple aneurysms with a total of 71, and 60 of the 71 aneurysms underwent coil embolization in a single-session. RESULTS: A total of 60 aneurysms were treated with a single-session coil embolization, of which the most frequent locations were in the posterior communicating artery, followed by the middle cerebral artery. Immediate post embolization angiographies showed total occlusion in 49 (81.7%) aneurysms, remnant neck in 6 (10%), and body-filling in 5 (8.3%). Procedure-related complications had developed in 2 (3.3%) of the 60 embolized aneurysms: an asymptomatic thromboembolic event, and a partial coil protrusion without a subsequent thromboembolic complication. CONCLUSION: With careful evaluation of individual aneurysm characteristics and configuration, multiple intracranial aneurysms previously thought to require multimodality therapy can be safely treated in a single-session coil embolization. PMID- 24167799 TI - Thirteen-year Experience of 44 Patients with Adult Hemorrhagic Moyamoya Disease from a Single Institution: Clinical Analysis by Management Modality. AB - Our objective was a retrospective assessment of the management modalities that provided the most beneficial treatment in hemorrhagic moyamoya disease during the last 13 years at our institution. The clinical results of 44 patients with hemorrhagic moyamoya disease were investigated, comparing revascularization surgery (direct, indirect, and combined bypass) or conservative treatment. Angiographic features, rebleeding, and clinical outcome were investigated. Six of the 35 patients (17.1%) with revascularization surgery experienced rebleeding, as did 4 of 9 patients (44.4%) with conservative treatment. However, patients who underwent bypass surgery had a lower chance of rebleeding. No significant difference in chance of rebleeding was observed between bypass surgery and non surgery groups (p > 0.05). Cerebral angiography performed after bypass surgery showed that for achieving good postoperative revascularization, direct and combined bypass methods were much more effective (p < 0.05). While the risk of rebleeding in the revascularization group was generally lower than in the conservative treatment group, there was no statistically significant difference between treatment modalities and conservative treatment. Although statistical significance was not attained, direct and combined bypass may reduce the risk of hemorrhage more effectively than indirect bypass. PMID- 24167800 TI - Comparative Results of the Patients with Intracerebral and Intra-sylvian Hematoma in Ruptured Middle Cerebral Artery Aneurysms. AB - OBJECTIVE: To clarify the prognosis of the patients with intra-sylvian hematoma (ISH) and intracerebral hematoma (ICH) in ruptured middle cerebral artery (MCA) aneurysms. METHODS: We categorized hematoma into ISH and ICH by the presence of intra-hematomal contrast enhancing vessel (IHCEV) on computed tomography angiography (CTA). Forty-four ruptured MCA aneurysm patients with ICH or ISH were grouped by the grading system proposed by the authors in our previous study. We investigated the relevance of the following factors: patient's age, gender, Hunt Hess grade, Glasgow outcome scale (GOS) and changes in Glasgow coma scale (GCS) between pre-operation and 7 days after operation. RESULTS: There were no significant differences statistically in age, gender, Hunt-Hess grade, and GOS between the ISH and ICH groups. In their peri-operative GCS change, the ICH group showed greater improvement compared to the ISH group (p = 0.0391). The hematoma grade had a significant relevance with the patients' GOS. CONCLUSION: Although there were no significant statistic differences in the GOS of the 2 hematoma groups, there were prominent improvements of post-operative GCS in the ICH group. Unlike in the ISH group, effective removal of hematoma was possible in most patients of the ICH group. Thus although there is no difference in the prognosis of the 2 groups, early surgical evacuation of hematoma seems to be effective in improving the short-term GCS score in peri-operative period. PMID- 24167801 TI - Clinical and radiological spectrum of posterior reversible encephalopathy syndrome. AB - OBJECTIVE: Symptoms of posterior reversible encephalopathy syndrome (PRES) include headache, altered mental status, visual disturbances, and seizures. Typical radiological features include edema of the parieto-occipital lobes. The purpose of this study is to review the clinical and radiological findings in patients diagnosed with PRES. METHODS: All patients diagnosed with PRES between January 2006 and December 2012 were retrospectively included in this study. We reviewed demographic and clinical characteristics, and radiological findings. RESULTS: We identified 16 patients with PRES. The most common clinical presentation was seizure (n = 12, 75%). Clinical recovery occurred in all patients within days (mean, 5.7 +/- 4.6 days). Comorbid conditions included hypertension (n = 4, 25%), cytotoxic medications (n = 3, 18.8%), sepsis (n = 4, 25%), malignancy (n = 4, 25%), subarachnoid hemorrhage (n = 1, 6.3%), autoimmune disorders (n = 1, 6.3%) and eclampsia (n = 1, 6.3%). The most commonly involved location was the parieto-occipital lobe (n = 13, 81.3%). Atypical radiological findings included significant basal ganglia involvement in 4 episodes; brainstem in 3, cerebellum in 2, and thalamus in 3. Eleven patients (68.8%) underwent diffusion-weighted imaging and apparent diffusion coefficient mapping. Of those, 9 patients (81.8%) had hypo- or isointensity on diffusion-weighted imaging. On the apparent diffusion coefficient map, 10 patients (90.9%) had hyperintensity, and the other had normal values. CONCLUSION: We suggest that PRES may occur in patients with complex systemic conditions. The prognosis of PRES is usually benign. Physicians should be aware of certain atypical radiological findings to avoid a delayed diagnosis of PRES, as delayed diagnosis and treatment can result in permanent neurological sequlae. PMID- 24167802 TI - The outcomes of spontaneous intracerebral hemorrhage in young adults - a clinical study. AB - OBJECTIVE: Spontaneous intracerebral hemorrhage (ICH) in young adults is rare. The purpose of this study was to investigate causes, sites and other factors affecting the prognosis of ICH in young adults aged <= 40 years. METHODS: We reviewed 39 consecutive patients diagnosed with spontaneous ICH between January 2001 and June 2012. Patients with primary subarachnoid hemorrhage, previously diagnosed brain tumor bleeding, or vascular malformation were excluded. We analyzed the differences in prognostic factors such as hemorrhage location and vascular structural etiology. The outcome was measured using the Glasgow outcome scale (GOS), and a good outcome was defined as a score of 4 or more. RESULTS: We retrospectively evaluated 39 patients (mean age, 33 years; SD = 6.4, range 17 to 40 years). The most common structural etiology was arteriovenous malformation. A statistically significantly higher proportion of patients with good outcomes had a lower initial systolic blood pressure (SBP <= 160 mmHg, p = 0.036), a higher initial Glasgow coma scale (GCS) (9 or more, p = 0.034), lower cholesterol levels (< 200 mg/dl, p = 0.036), and smoking history (at discharge, p = 0.008; 6 months after discharge, p = 0.019). CONCLUSION: In this study, cryptogenic ICH was the leading cause of spontaneous ICH. A GCS score of 9 or more on admission, a lower serum cholesterol level (< 200 mg/dl), and a lower SBP (< 160 mmHg) predicted a good outcome. PMID- 24167803 TI - Distal subclavian artery occlusion causing multiple cerebral infarcts consequence of retrograde flow of a thrombus? AB - Intracranial embolization usually arises from the heart, a vertebrobasilar artery, a carotid artery, or the aorta, but rarely from the distal subclavian artery upstream of an embolus. We report on a patient who experienced left shoulder and forearm pain with weak blood pressure and pulse followed by concurrent onset of left hemiplegia. This case is a rare example of multiple cerebral embolic infarctions, which developed as a complication of distal subclavian artery thrombosis possibly associated with protein S deficiency. PMID- 24167804 TI - Vertebrobasilar occlusion presenting as sudden isolated bilateral sensorineural hearing loss: case report. AB - Isolated bilateral deafness is a rare but possible symptom of vertebrobasilar ischemia, primarily due to occlusion of the anterior inferior cerebellar arteries or their branch, the internal auditory artery. We reported on uncommon case of sudden bilateral sensorineural hearing loss without typical neurological symptoms resulting from vertebrobasilar ischemia. We performed the available examinations, including otoscopy, laboratory tests, and pure tone audiogram, however we were not able to identify the cause of bilateral sensorineural hearing loss. Brain magnetic resonance image showed the cerebellar infarction of the posterior inferior cerebellar artery territory. Brain magnetic resonance angiography showed bilateral vertebral and basilar artery occlusion. We suggest vertebrobasilar ischemia as a cause of sudden isolated deafness. PMID- 24167805 TI - The difference of each angiographic finding after multiple stent according to stent type in bilateral vertebral artery dissection. AB - We report a case of spontaneous bilateral intracranial vertebral artery dissecting aneurysms with subarachnoid hemorrhage. One dissecting lesion was treated with a coronary balloon-mounted stent (BMS) technique; however, due to differences in access route tortuosity, the other lesion was treated with a self expandable stent (SES) technique. After 2 months, the angiographic outcome showed complete healing of the dissected segment on the side that was treated with BMS; in contrast, the dissection lesion appeared to be re-growing on the side that was treated with SES. Complete treatment of the aggravated lesion was achieved by additional deployment of BMSs. Therefore, we have provided a discussion of the possible reasons for this difference in outcome according to the stent type. PMID- 24167807 TI - Microsurgical extraction of a malfunctioned pipeline embolization device following complete deployment. AB - The Pipeline Embolization Device (PED) is an effective treatment approach for complex intracranial aneurysms. Intraprocedural complications during PED deployment are seldom reported. We report a rare complication of a PED malfunction identified immediately following complete deployment during endovascular treatment of a giant middle cerebral artery (MCA) bifurcation aneurysm. After multiple failed attempts at endovascular retrieval of the malfunctioned PED, the patient was taken for microsurgical extraction due to accumulation of thrombus on the proximal unopened portion of the stent and widespread distal dissemination of emboli. After removing the PED from the vessel lumen and resecting the giant aneurysm, we could not reanastamose the proximal MCA to the distal segment. The management of PED malfunction is poorly understood. While removal of an incompletely deployed PED may be undertaken with limited adverse effects, retrieval of a fully deployed PED is associated with a much higher risk of morbidity. Until larger case series of such complications better define the risks and benefits of endovascular or microsurgical retrieval of malfunctioned PEDs, the management of these rare intraprocedural complications will be based on the unique aspects of each individual case and the expertise of the treating neurointerventionalist. PMID- 24167806 TI - Ruptured mycotic aneurysm of the distal middle cerebral artery manifesting as subacute subdural hematoma. AB - Mycotic aneurysms are rare inflammatory neurovascular lesions. Ruptured mycotic aneurysm manifesting as subdural hematoma is extremely rare. A 72-year-old male patient was admitted to our hospital with headache and drowsiness. Computer tomography (CT) of brain and CT angiography revealed subdural hematoma and an aneurysm located at the M4 segment of the left middle cerebral artery (MCA). Cerebral angiogram revealed 2 aneurysms; one located at the left distal MCA and the other at the bifurcation of left MCA. Laboratory studies showed leukocytosis and elevated inflammatory factors. The patent was treated with antibiotic therapy for 4 weeks. The follow-up CT and cerebral angiography showed that the mycotic aneurysm was completely resolved, and the patient was nearly free of symptoms. PMID- 24167808 TI - Idiopathic lenticulostriate artery pseudoaneurysm protruding into the lateral ventricle: a case report. AB - We report a rare case of an idiopathic pseudoaneurysm causing intraventricular hemorrhage (IVH). A 28-year-old man presented with sudden onset of severe headache. He underwent external ventricular drainage for an isolated IVH in the right lateral ventricle. Digital subtraction angiography (DSA) revealed that the aneurysm (7.5*4.5 mm) arose from the distal part of the medial lenticulostriate artery. Following removal of the external ventricular drainage catheter, the aneurysm decreased in size (4.0*2.3 mm). However, follow-up DSA revealed a slightly enlarged aneurysm (4.2*3.2 mm) with morphologic change. The aneurysm was clipped via the interhemispheric transcallosal approach, but postoperative DSA revealed a residual aneurysm sac beside the clips. Given the risk of rebleeding, a second operation was planned for complete resection of the aneurysm. After revised craniotomy and careful dissection of the caudate nucleus, the aneurysm sac was completely resected. Histopathological examination revealed that the aneurysm was a pseudoaneurysm. The patient recovered without any neurological sequel and was discharged. To the best of our knowledge, this is the first reported case of an idiopathic lenticulostriate artery pseudoaneurysm protruding into the right lateral ventricle and causing an IVH that was successfully treated with microsurgical resection. PMID- 24167809 TI - Intraosseous arteriovenous malformation of the sphenoid bone presenting with orbital symptoms mimicking cavernous sinus dural arteriovenous fistula: a case report. AB - Intraosseous arteriovenous malformation (AVM) in the craniofacial region is rare. When it occurs, it is predominantly located in the mandible and maxilla. We encountered a 43-year-old woman with Klippel-Trenaunay syndrome affecting the right lower extremity who presented with a left orbital chemosis and proptosis mimicking the cavernous sinus dural arteriovenous fistula. Computed tomography angiography revealed an intraosseous AVM of the sphenoid bone. The patient's symptoms were completely relieved after embolization with Onyx. We report an extremely rare case of intraosseous AVM involving the sphenoid bone, associated with Klippel-Trenaunay syndrome. PMID- 24167810 TI - Giant cystic cerebral cavernous malformation with multiple calcification - case report. AB - Cerebral cavernous malformation with giant cysts is rare and literature descriptions of its clinical features are few. In this case study, the authors describe the clinical symptoms, radiological findings, and pathological diagnosis of cerebral cavernous malformations with giant cysts, reviewing the relevant literature to clearly differentiate this from other disease entities. The authors present a case of a 19-year-old male with a giant cystic cavernous malformation, who was referred to the division of neurosurgery due to right sided motor weakness (grade II/II). Imaging revealed a large homogenous cystic mass, 7.2*4.6*6 cm in size, in the left fronto-parietal lobe and basal ganglia. The mass had an intra-cystic lesion, abutting the basal portion of the mass. The initial diagnosis considered this mass a glioma or infection. A left frontal craniotomy was performed, followed by a transcortical approach to resect the mass. Total removal was accomplished without post-operative complications. An open biopsy and a histopathological exam diagnosed the mass as a giant cystic cavernous malformation. Imaging appearances of giant cavernous malformations may vary. The clinical features, radiological features, and management of giant cavernous malformations are described based on pertinent literature review. PMID- 24167811 TI - The pterional approach and extradural anterior clinoidectomy to clip paraclinoid aneurysms. AB - OBJECTIVE: The surgical clipping of paraclinoid segment internal carotid artery aneurysms is considered difficult because of the complex anatomical location and important neighboring structures. Our experiences of pterional craniotomy and extradural anterior clinoidectomy (EAC) to clip paraclinoid aneurysms are reported herein. METHODS: We present two patients with paraclinoid aneurysms who underwent surgical clipping using pterional craniotomy and EAC. The clinical results and operative techniques were reviewed from the patients' medical records. RESULTS: EAC improves the surgical field in the suprasellar and periclinoid regions. Clinically, a good outcome was obtained in both cases. No surgical complications directly resulting from the EAC were observed. CONCLUSION: Favorable surgical results can be obtained with pterional craniotomy and EAC for the clipping of paraclinoid aneurysms. EAC is advocated for the clipping of paraclinoid aneurysms. PMID- 24167812 TI - Clinical evaluation and cost-effectiveness analysis of serum tumor markers in lung cancer. AB - The detection of serum tumor markers is valuable for the early diagnosis of lung cancer. Tumor markers are frequently used for the management of cancer patients. However, single markers are less efficient but marker combinations increase the cost, which is troublesome for clinics. To find an optimal serum marker combination panel that benefits the patients and the medical management system as well, four routine lung cancer serum markers (SCCA, NSE, CEA, and CYFRA21-1) were evaluated individually and in combination. Meanwhile, the costs and effects of these markers in clinical practice in China were assessed by cost-effectiveness analysis. As expected, combinations of these tumor markers improved their sensitivity for lung cancer and different combination panels had their own usefulness. NSE + CEA + CYFRA21-1 was the optimal combination panel with highest Youden's index (0.64), higher sensitivity (75.76%), and specificity (88.57%), which can aid the clinical diagnosis of lung cancer. Nevertheless, the most cost effective combination was SCCA + CEA, which can be used to screen the high-risk group. PMID- 24167813 TI - Biological pretreatment of rubberwood with Ceriporiopsis subvermispora for enzymatic hydrolysis and bioethanol production. AB - Rubberwood (Hevea brasiliensis), a potential raw material for bioethanol production due to its high cellulose content, was used as a novel feedstock for enzymatic hydrolysis and bioethanol production using biological pretreatment. To improve ethanol production, rubberwood was pretreated with white rot fungus Ceriporiopsis subvermispora to increase fermentation efficiency. The effects of particle size of rubberwood (1 mm, 0.5 mm, and 0.25 mm) and pretreatment time on the biological pretreatment were first determined by chemical analysis and X-ray diffraction and their best condition obtained with 1 mm particle size and 90 days pretreatment. Further morphological study on rubberwood with 1 mm particle size pretreated by fungus was performed by FT-IR spectra analysis and SEM observation and the result indicated the ability of this fungus for pretreatment. A study on enzymatic hydrolysis resulted in an increased sugar yield of 27.67% as compared with untreated rubberwood (2.88%). The maximum ethanol concentration and yield were 17.9 g/L and 53% yield, respectively, after 120 hours. The results obtained demonstrate that rubberwood pretreated by C. subvermispora can be used as an alternative material for the enzymatic hydrolysis and bioethanol production. PMID- 24167814 TI - Leptin increases blood pressure and markers of endothelial activation during pregnancy in rats. AB - Raised leptin levels have been reported in the placentae and serum of women with elevated blood pressure and proteinuria during pregnancy. The role of leptin in this however remains unknown. This study investigates the effect of leptin administration on systolic blood pressure (SBP) and proteinuria and serum markers of endothelial activation during pregnancy in Sprague Dawley rats. From day 1 of pregnancy, 24 rats were randomised into those given either saline (group 1) or leptin at 60 or 120 MU g/kg/body weight/day (groups 2 and 3 resp.). SBP was measured every 5 days and 24-h urinary protein was measured at days 0 and 20 of pregnancy. Animals were euthanised on day 20 of pregnancy, and serum was collected for estimation of E-selectin and ICAM-1. Compared to group 1, SBP during the latter part of the pregnancy was significantly higher in the leptin treated group (P < 0.01). Urinary protein excretion, serum E-selectin, and ICAM-1 were significantly higher in leptin-treated rats (P < 0.05). It seems that leptin administration to normotensive Sprague Dawley rats during pregnancy significantly increases SBP, urinary protein excretion, and markers of endothelial activation. However, further studies are required to examine the underlying mechanism responsible for this and its relevance to preeclampsia in humans. PMID- 24167815 TI - Outbreak of hepatitis A in a nursery school. AB - In a background of very low incidence of hepatitis A HA in the last decade (annual average of 1.8 cases per 100,000 inhabitants) we describe an outbreak of HA which evolved in Mallorca between May and August 2010, whose main focus was a nursery school where more cases were parents and other young relatives of the children of the institution. Thirty-four cases were defined as outbreak cases. Ten were children of the nursery or their siblings and 22 adults (3 staff members of the nursery and 19 relatives; median age 33 years). The first detected cases were children of the same class. There were 2 adults with haematological complications, though not severe. All children, nursery staff members, parents, and siblings of the cases of the first affected class were immediately offered HA vaccination, but only 43.3% eligible individuals accepted it. None of the cases had been vaccinated. The outbreak spread mostly from asymptomatic children to young adults, showing the changes in HA pattern. That is of great concern as the risk of severe illness rises with age. This incident shows the need to implement new HA vaccination policies in outbreak control. This was later carried out. PMID- 24167816 TI - A quartz enhanced photo-acoustic gas sensor based on a custom tuning fork and a terahertz quantum cascade laser. AB - An innovative quartz enhanced photoacoustic (QEPAS) gas sensing system operating in the THz spectral range and employing a custom quartz tuning fork (QTF) is described. The QTF dimensions are 3.3 cm * 0.4 cm * 0.8 cm, with the two prongs spaced by ~800 MUm. To test our sensor we used a quantum cascade laser as the light source and selected a methanol rotational absorption line at 131.054 cm(-1) (~3.93 THz), with line-strength S = 4.28 * 10(-21) cm mol(-1). The sensor was operated at 10 Torr pressure on the first flexion QTF resonance frequency of 4245 Hz. The corresponding Q-factor was 74 760. Stepwise concentration measurements were performed to verify the linearity of the QEPAS signal as a function of the methanol concentration. The achieved sensitivity of the system is 7 parts per million in 4 seconds, corresponding to a QEPAS normalized noise-equivalent absorption of 2 * 10(-10) W cm(-1) Hz(-1/2), comparable with the best result of mid-IR QEPAS systems. PMID- 24167817 TI - What's in a name? That which we call a "provider". PMID- 24167819 TI - Comparison of endoscopic versus 3D CT derived airway measurements. AB - OBJECTIVES/HYPOTHESIS: To understand: 1) how endoscopic airway measurements compare to three-dimensional (3D) CT derived measurements; 2) where each technique is potentially useful; and 3) where each has limitations. STUDY DESIGN: Compare airway diameters and cross-sectional areas from endoscopic images and CT derived 3D reconstructions. METHODS: Videobronchoscopy was performed and recorded on an adult-sized commercially available airway mannequin. At various levels, cross-sectional areas were measured from still video frames using a referent placed via the biopsy port. A 3D reconstruction was generated from a high resolution CT of the mannequin; planar sections were cut at similar cross sectional levels; and cross-sectional areas were obtained. RESULTS: At three levels of mechanically generated tracheal stricture, the differences between the endoscopic measurement and CT-derived cross-sectional area were 1%, 0%, and 7% (1.8, 0.8, and 14 mm2). At the vocal folds, the difference was 9% (7.8 mm2). The tip of the epiglottis and width of the epiglottis differed by 27% and 10% (18.73 mm2, 0.40 mm). The airway measurements at the base of tongue, minimal cross sectional area of the pharynx, and choana differed by 26%, 36%, and 30% (101.40 mm2, 36.67 mm2, 122.71 mm2). CONCLUSIONS: Endoscopy is an effective tool for obtaining airway measurements compared with 3D reconstructions derived from CT. Concordance is best in geometrically simple areas where the entire cross-section measured is visible within one field of view (trachea, round; vocal folds, triangular) versus geometrically complex areas that encompass more than one field of view (i.e. pharynx, choana). PMID- 24167818 TI - A role for anti-BP180 autoantibodies in chronic rhinosinusitis. AB - OBJECTIVES/HYPOTHESIS: Chronic Rhinosinusitis (CRS) is accompanied by evidence of a vigorous adaptive immune response, and emerging studies demonstrate that some nasal polyps manifest a polyclonal autoantibody response. We previously found that antibodies against BP180, a component of the hemidesmosome complex and the dominant epitope in autoimmune bullous pemphigoid, were found at elevated levels in nasal polyp tissue. Given the critical role of hemidesmosomes in maintaining epithelial integrity, we sought to investigate the distribution of BP180 in nasal tissue and evaluate for evidence of systemic autoimmunity against this antigen in CRS. STUDY DESIGN: Case-control experimental study. METHODS: The expression and distribution of BP180 in cultured nasal epithelial cells and normal nasal tissue were confirmed using real-time polymerase chain reaction (PCR), Western immunoblotting, immunofluorescence and immunohistochemistry. Sera were collected from three groups: control, CRSsNP, and CRSwNP. A commercially available ELISA was utilized to compare anti-BP180 autoantibody levels in sera. RESULTS: BP180 is expressed in nasal epithelium, but is not confined to the basement membrane as it is in human skin. In cultured nasal epithelial cells, confocal immunofluorescence showed a punctate distribution of BP180 along the basal surface, consistent with its distribution in epithelial keratinocytes. There are significantly higher levels of circulating nonpathologic anti-BP180 autoantibodies in CRS patients compared with normal controls (P <0.05). CONCLUSIONS: BP180 is more widely expressed in nasal epithelium versus skin, although it appears to play a similar role in the formation of hemidesmosomes along the basement membrane. Further investigations are ongoing to characterize the pathogenicity of the anti epithelial antibody response in CRS. PMID- 24167820 TI - Prognostic significance of HIF-1a, CA-IX, and OPN in T1-T2 laryngeal carcinoma treated with radiotherapy. AB - OBJECTIVES/HYPOTHESIS: To examine the prognostic value of hypoxia inducible factor HIF-1a, CA-IX, and OPN on clinical outcome in patients with T1-T2 supraglottic laryngeal squamous cell carcinoma (LSCC) treated with primarily radiotherapy (RT). STUDY DESIGN: Retrospective cohort study. METHODS: Tumor tissue sections of 60 patients with T1-T2 supraglottic LSCC treated with primarily radiotherapy were assessed immunohistochemically for expression of HIF 1a, CA-IX, and OPN. The relationship of protein expression and classical clinical parameters with clinical outcome was studied, using Cox regression and Kaplan Meier survival analyses. RESULTS: Neither HIF-1a nor CA-IX was of prognostic significance toward local control or overall survival in T1-T2 supraglottic LSCC. Cox regression survival analysis showed no relation between HIF-1a or CA-IX expression and local control (HR [hazard ratio] 1.07, CI [95% confidence interval] 0.29-3.87; HR 0.34, CI 0.04-2.58). Furthermore, OPN expression was not associated with local control (HR 1.37, CI 0.45-4.17) and overall survival (HR 0.99, CI 0.44-2.21). Our earlier findings in T1-T2 glottic LSCC (Schrijvers et al., 2008) could not be confirmed. CONCLUSION: The absence of prognostic significance for HIF-1a and CA-IX toward local control in supraglottic LSCC, unlike glottic LSCC, suggests that supraglottic LSCC might represent another biological entity. PMID- 24167821 TI - Awake versus drug-induced sleep endoscopy: evaluation of airway obstruction in obstructive sleep apnea/hypopnoea syndrome. AB - OBJECTIVES/HYPOTHESIS: To compare the degree and patterns of upper airway obstruction, as detected by endoscopy with Muller's maneuver versus drug-induced sleep endoscopy (DISE). METHODS: Sixty-six patients (60 males and 6 females), with a mean age of 49.59 +/- 13.04 years, underwent videonasal-pharyngo laryngoscopy to asses anatomy and dynamic behavior of upper airways during the Muller's maneuver awake, and during DISE by Propofol with boluses refracted technique. RESULTS: In the majority of our patients, we detected an obstruction due to nasal septal deviation (91%) and turbinate hypertrophy (100%). The pattern of the obstruction caused by the soft palate and the tongue base was similar in DISE and Muller's maneuver, whereas the registered degree was significantly higher in DISE. Concerning the larynx, 22.7% of patients showed an involvement of the epiglottis during sedation that was not assessable during wakefulness. CONCLUSIONS: DISE is a simple additional tool to plan surgical treatment in patients with OSAHS, and in our hands has proven to be more accurate and precise than endoscopy with Muller's maneuver. PMID- 24167822 TI - Combining J-edited and correlation spectroscopies within a multi-dimensional spatial frequency encoding: toward fully resolved 1H NMR spectra. AB - J-resolved at a glance: Passive coupling refocusing-COSY experiments based on a frequency encoding of the sample along two directions of space are presented. It allows various spin evolutions to be triggered in different parts of the sample in a selective and fully controlled manner. This yields 2D spectra in which the whole proton network appears as a series of fully resolved and straightforwardly assignable doublets, triplets or quartets (see figure). PMID- 24167823 TI - Tertiary amines as synthetic equivalents of vinyl cations: zinc bromide promoted coupling of propargylamines with alpha-isocyanoacetamides to give 2,4,5 trisubstituted oxazoles initiated by an internal redox process. AB - Crabee interrupted: Propargylamines 1 react with alpha-isocyanoacetamides 2 in the presence of zinc bromide to afford vinyl oxazoles 3. The transformation, wherein the propargylamine acts as a vinyl cation synthetic equivalent, involves a domino sequence incorporating a 1,5-hydride shift, intermolecular trapping/cyclization, and a 1,6-elimination (see scheme). PMID- 24167824 TI - Mesoporous core-shell Fenton nanocatalyst: a mild, operationally simple approach to the synthesis of adipic acid. AB - Mesoporous nanoparticles composed of gamma-Al2O3 cores and alpha-Fe2O3 shells were synthesized in aqueous medium. The surface charge of gamma-Al2O3 helps to form the core-shell nanocrystals. The core-shell structure and formation mechanism have been investigated by wide-angle XRD, energy-dispersive X-ray spectroscopy, and elemental mapping by ultrahigh-resolution (UHR) TEM and X-ray photoelectron spectroscopy. The N2 adsorption-desorption isotherm of this core shell materials, which is of type IV, is characteristic of a mesoporous material having a BET surface area of 385 m2 g(-1) and an average pore size of about 3.2 nm. The SEM images revealed that the mesoporosity in this core-shell material is due to self-aggregation of tiny spherical nanocrystals with sizes of about 15-20 nm. Diffuse-reflectance UV/Vis spectra, elemental mapping by UHRTEM, and wide angle XRD patterns indicate that the materials are composed of aluminum oxide cores and iron oxide shells. These Al2O3@Fe2O3 core-shell nanoparticles act as a heterogeneous Fenton nanocatalyst in the presence of hydrogen peroxide, and show high catalytic efficiency for the one-pot conversion of cyclohexanone to adipic acid in water. The heterogeneous nature of the catalyst was confirmed by a hot filtration test and analysis of the reaction mixture by atomic absorption spectroscopy. The kinetics of the reaction was monitored by gas chromatography and 1H NMR spectroscopy. The new core-shell catalyst remained in a separate solid phase, which could easily be removed from the reaction mixture by simple filtration and the catalyst reused efficiently. PMID- 24167825 TI - Extending the Arabidopsis flowering paradigm to a mass flowering phenomenon in the tropics. AB - Flowering time is a critical life history trait, one that is shaped by evolution to maximize fecundity, reproductive success and fitness (Amasino 2010). This is especially true of annual plants where the cycle of floral initiation, pollination and seed production occur at regular intervals to ensure the survival of the species. In long-lived perennials, however, flowering can be an intermittent phenomenon and thus a challenge to understand. In this issue of Molecular Ecology, Kobayashi et al. (2013) tackle this particular challenge by applying modern-day molecular techniques to the 'spectacular and mysterious' mass flowering that takes places in mixed dipterocarp forests of South-East Asia. Here, amidst an almost unimaginable diversity of forbs, shrubs and trees, these authors used next-generation sequencing technology to characterize what they refer to as the 'ecological transcriptome' in an attempt to glimpse into the functional genomic reprogramming of Shorea beccariana at pre- and postflowering developmental transitions. They encountered many of the challenges that are often underappreciated yet typical for tropical ecological research including sample collection within a ~40-m high tree canopy, unpredictable flowering intervals and determining the most appropriate preflowering state for sampling. Despite these challenges, the authors were able to integrate gene ontology relationships with gene-clustering algorithms and environmental data to support the hypothesis that drought is a key trigger for flowering in S. beccariana. The cloning and transgenic expression of selected S. beccariana genes to corroborate presumed protein function is a key feature of their work and seldom applied within an ecological framework. As illustrated by Kobayashi et al. (2013), the inclusion of molecular biology, genomics and bioinformatics has the potential to shed light on long-standing questions of ecological concern. PMID- 24167826 TI - Looking ahead: the WHIMS-Young study. PMID- 24167827 TI - Sugary foods and gynecological cancer risk. PMID- 24167828 TI - Measuring vulvovaginal symptoms in postmenopausal women. PMID- 24167829 TI - Differences in mortality between oophorectomy and ovarian conservation. PMID- 24167830 TI - Author's reply: To PMID 23456733. PMID- 24167831 TI - Retraction. The occurrence of bleaching stripe disease in Gracilaria corticata and controlling of the disease using quorum quenching approach. PMID- 24167832 TI - Retraction. PMID- 24167833 TI - An upper gastrointestinal ulcer still bleeding after endoscopy: what comes next? AB - INTRODUCTION: Recurrent bleeding from an upper gastrointestinal ulcer when endoscopy fails is a reason for radiological or surgical treatment, both of which have their advantages and disadvantages. CASE: Based on a patient with recurrent gastrointestinal bleeding, we reviewed the available evidence regarding the efficacy and safety of surgical treatment and embolisation, respectively. DISCUSSION: Transarterial embolisation (TAE) and surgical treatment are both options for recurrent gastrointestinal bleeding when endoscopy fails. Both therapies have serious complications and a risk of rebleeding. Choosing the therapy depends on the capability of the patient to tolerate haemodynamic instability, resuscitation and hypotension. CONCLUSION: Choosing between TAE and surgery depends a great deal on the case presented, haemodynamic stability and the skills and tools available at that moment. PMID- 24167834 TI - Reply: To PMID 23231740. PMID- 24167835 TI - Europe offers example for approving biosimilars. PMID- 24167836 TI - Esophageal cancer rates drop for blacks. PMID- 24167837 TI - Oncology drug shortages drive cost of care up. PMID- 24167838 TI - Millions more will deal with atrial fibrillation. PMID- 24167839 TI - ACOG guidance on early-term deliveries. PMID- 24167840 TI - Addressing substance use in primary care. AB - Problematic use of alcohol, tobacco, and other drugs, including prescription medications, contributes to increased risk for injury, illness, suffering, and premature death across the lifespan. Nurse practitioners can positively impact the health of patients, their families, and communities by addressing substance use and related disorders in primary care settings. PMID- 24167841 TI - WHO releases guidance on mental health care after trauma. New clinical protocol and guidelines to enable effective mental health care for adults and children exposed to trauma and loss. PMID- 24167842 TI - Breastfeeding: Only 1 in 5 countries fully implement WHO's Infant Formula Code. PMID- 24167843 TI - [Antibacterial activity for clinical isolates from pediatric patients of clavulanic acid/amoxicillin (1: 14) -outcomes of special drug use investigation on antibacterial activity (annual changes)]. AB - As a special drug use investigation, we monitored and assessed trends in antibacterial activity of clavulanic acid/amoxicillin (1:14) (hereafter, "CVA/AMPC (1:14)") and other antimicrobial agents for clinical isolates from pediatric patients with otitis media or respiratory, skin, and urinary tract infections. Against Streptococcus pneumoniae, Haemophilus influenzae, Moraxella catarrhalis isolated and identified from otorrhea, epipharynx and rhinorrhea of pediatric patients with otitis media, the MIC90s of CVA/AMPC (1:14) in five years between 2006-2010 were 1 microg/mL for S. pneumoniae and 8 microg/mL for H. influenzae and 0.25-0.5microg/mL for M catarrhalis. The changes of MIC90s of CVA/AMPC (1:14) for penicillin-resistant S. pneumoniae (PRSP) and beta-lactamase non-producing H. influenzae were two times, and no decrease in drug susceptibility was found in the period of the present investigation. In addition, the MIC changes of other antimicrobial agents for these three organisms were approximately two to four times as well. Against organisms isolated and identified from pus, sputum, pharynx, skin and urine of pediatric patients with respiratory, skin, and urinary tract infections, the MIC90s of CVA/AMPC (1:14) in four years between 2008-2011 were 1 microg/mL for S. pneumoniae, < or =0.06microg/mL for penicillin susceptible S. pneumoniae (PSSP) without any change, 0.5-1 microg/mL for penicillin intermediate resistant S. pneumoniae (PISP) with a twofold change and 1 microg/mL for PRSP with no change. The MIC90s of CVA/AMPC (1:14) were 2-8 microg/mL for S. aureus with a fourfold change, 2 microg/mL for methicillin-sensitive S. aureus without any change, 4-8 microg/mL for H. influenzae with a twofold change. Against beta-lactamase non-producing H. influenzae, MIC90s of CVA/AMPC (1:14) were 1 microg/mL for beta-lactamase negative ampicillin susceptible (BLNAS), 8 microg/mL for beta-lactamase negative ampicillin resistant (BLNAR), showing no change. Neither Streptococcus pyogenes or Klebsiella pneumoniae demonstrated any change and M. catarrhalis and Escherichia coli showed twofold changes of MIC90s of CVA/AMPC (1: 14). In the present investigation conducted to monitor annual changes in antibacterial activity intended for pediatric patients with otitis media or other infections, there was no significant change in antibacterial activity of CVA/AMPC (1: 14). PMID- 24167844 TI - Population pharmacokinetics of itraconazole in Japanese patients with invasive fungal peritonitis. AB - Severely ill patients are frequently at risk of developing fungal infection. Itraconazole (ITCZ), a triazole antifungal agent, is used for the treatment of candidiasis, aspergillosis, cryptococcosis. Correlation of pharmacokinetic and pharmacodynamic (PK-PD) parameters with the in vivo bactericidal action of antimicrobial agents has progressed markedly in recent years. However, the optimal dosage of antifungal agents based on PK-PD properties has not been clearly established. In this study, we performed a population pharmacokinetic analysis of ITCZ after infusion or oral administration of ITCZ in Japanese 51 patients with fungal infections. The population pharmacokinetic analysis was performed using NONMEM software. The population mean clearance (CL; liter/h) was estimated as 5.15-0.0673 x(Age-62) L/h, the population mean volume of distribution (V; liter) was determined as 878L and the bioavailability (F) was determined as 0.665. PMID- 24167845 TI - [Search for bioactive natural products having effects on signaling pathways from mainly microbial sources]. PMID- 24167846 TI - [New and future treatments for neurological disorders--knowledge essential to daily clinics and future prospects. editorial: global contribution of medical innovation in Japan]. PMID- 24167847 TI - [New and future treatments for neurological disorders--knowledge essential to daily clinics and future prospects. Topics: 1. Topics of headache treatment]. PMID- 24167848 TI - [New and future treatments for neurological disorders--knowledge essential to daily clinics and future prospects. Topics: 2. Dementia]. PMID- 24167849 TI - [New and future treatments for neurological disorders--knowledge essential to daily clinics and future prospects. Topics: 3. Cerebrovascular disease; 1) Treatment for acute phase of stroke]. PMID- 24167850 TI - [New and future treatments for neurological disorders--knowledge essential to daily clinics and future prospects. Topics: 3. Cerebrovascular disease: 2) Prevention of stroke recurrence and therapeutic strategies for residual symptoms]. PMID- 24167851 TI - [New and future treatments for neurological disorders--knowledge essential to daily clinics and future prospects. Topics: 4. Parkinson's disease: progress in the medical treatment]. PMID- 24167852 TI - [New and future treatments for neurological disorders--knowledge essential to daily clinics and future prospects. Topics: 5. Epilepsy]. PMID- 24167853 TI - [New and future treatments for neurological disorders--knowledge essential to daily clinics and future prospects. Topics: 6. Malignant brain tumor]. PMID- 24167854 TI - [New and future treatments for neurological disorders--knowledge essential to daily clinics and future prospects. Topics: 7. Encephalitis and prion disease]. PMID- 24167855 TI - [New and future treatments for neurological disorders--knowledge essential to daily clinics and future prospects. Topics: 8. Guillain-Barre syndrome and chronic inflammatory demyelinating polyneuropathy]. PMID- 24167856 TI - [New and future treatments for neurological disorders--knowledge essential to daily clinics and future prospects. Topics: 9. Therapeutic progress in multiple sclerosis and neuromyelitis optica]. PMID- 24167857 TI - [New and future treatments for neurological disorders--knowledge essential to daily clinics and future prospects. Topics: 10. Amyotrophic lateral sclerosis]. PMID- 24167858 TI - [New and future treatments for neurological disorders--knowledge essential to daily clinics and future prospects. Topics: 11. Myopathy]. PMID- 24167859 TI - [New and future treatments for neurological disorders--knowledge essential to daily clinics and future prospects. Topics: 12. Myasthenia]. PMID- 24167860 TI - [New and future treatments for neurological disorders--knowledge essential to daily clinics and future prospects. Topics: 13. Treatment of neuropathic pain]. PMID- 24167861 TI - [New and future treatments for neurological disorders--knowledge essential to daily clinics and future prospects. Topics: 14. The drug development of orphan drug]. PMID- 24167862 TI - [New and future treatments for neurological disorders--knowledge essential to daily clinics and future prospects. Topics: 15. Therapeutic application of iPS cells]. PMID- 24167863 TI - [Discussion meeting on globalization of medicine and daily clinical practice]. PMID- 24167864 TI - [Case report; familial occurrence of cat-scratch disease diagnosed by PCR of lymph node aspirate]. PMID- 24167865 TI - [Case report: focal adenocarcinoma arising from sessile serrated adenoma/polyp with intestinal spirochetosis, report of a case]. PMID- 24167866 TI - [Case report; a case of massive bleeding from jejunal diverticula completely treated by double balloon endoscopy]. PMID- 24167867 TI - [Case report; a case of minocycline-induced polyarteritis nodosa with fever, arthralgia, and erythema on bilateral lower extremities]. PMID- 24167868 TI - [Case report; a case of anti-glutamate receptor antibody positive limbic encephalitis with positive various autoantibodies]. PMID- 24167869 TI - [The cutting-edge of medicine; diagnosis and treatments of autoimmune encephalitis]. PMID- 24167870 TI - [The cutting-edge of medicine; present status and future perspective of ventricular assist device treatment]. PMID- 24167871 TI - [The cutting-edge of medicine; new therapeutic targets for renal senescence]. PMID- 24167872 TI - [Series: for attending physicians; seeking to understand the diversity of medicine; understanding human error: viewpoints for reviewing medical malpractice]. PMID- 24167873 TI - [Series: Clinical study from Japan and its reflections; introduction of a randomized, double-blind, controlled, comparative trial of formula food in visceral fat obesity: FLAVO study]. PMID- 24167875 TI - [The artemisinin derivatives must be in France the first-line treatment of all P. falciparum malaria cases simple or severe]. PMID- 24167874 TI - [Inert, you said inert?]. PMID- 24167876 TI - [Cerebrospinal fluid fistula]. PMID- 24167877 TI - [The market drift of the hearing aid industry]. PMID- 24167878 TI - [New methods for exploration of the small intestine]. AB - For ten years, a lot of advances have been achieved for the morphological exploration of the small intestine as well as with CT and MR enterography than with wireless capsule endoscopy. These investigations have renewed the approaches of different diseases that can affect the small intestine: tumors, especially sub mucosal tumors (CT enterography), iron-deficiency anemia (capsule endoscopy) and follow-up of patients with Crohn's disease of the small intestine (MR enterography). Balloon enteroscopy may then allow therapeutic approach when needed (treatment of bleeding angiodysplasia). PMID- 24167879 TI - [Cancers of the oral and genital mucosa]. AB - Squamous cell carcinomas account for over 90 % of cancers of the oral cavity in France. Alcohol and tobacco are the main risk factors. Delay in diagnosis is unfortunately frequent. The management of the cancer is based on surgery, possibly associated to radiation therapy and chemotherapy. The survival rate at 5 years does not exceed 30-40%. We hope to see a decrease in the number of oral cancer thanks to the development of preventive medicine (alcohol and tobacco cessation and early detection of potentially malignant lesions). Vulvar squamous cell carcinoma is a rare disease which traditionally affect elderly woman but continues to rise in incidence especially in younger women. There are at least 2 forms of genital squamous cell carcinoma. The most common form is found on older women arising in a background of lichen sclerosus and the second is associated with "high risk" human papillomavirus infection affecting younger women. A biopsy is usually required for diagnosis. Attempts to reduce genital cancer must focus on treating precursor lesions, namely lichen sclerosus and HPV-related intraepithelial neoplasia (VIN and PIN). Most genital cancer occur on undiagnosed or untreated lichens sclerosus, vulvar inspection when women attend for their cervical smears or seeking about significance of any chronic genital symptom by a clinical examination. PMID- 24167880 TI - [Chagas disease: when to think of it in France?]. AB - The chronic Chagas disease, which is dumb in approximately 2/3 of the cases, is present from now on all the continents, with local prevalence which is a function of the age, the origin and the importance of the immigration from South and Central America. The European, North American, Japanese or Australian general practitioner can be thus confronted with this disease in a half-dozen of circumstances which we tried to define while calling back way the characteristic main things of the disease, the way it evolves, the laboratory tests which allow to detect it and the problems which puts its treatment. PMID- 24167882 TI - [Social networks in 10 lessons: # 7 Citeulike: social bookmarking references]. PMID- 24167881 TI - [Cold agglutinin disease]. PMID- 24167883 TI - [Chronic hepatitis C: untreated patients should be well monitored]. PMID- 24167884 TI - [AINS-IPP coprescription: don't forget to renew!]. PMID- 24167885 TI - [Beware of statins toxicity reinforced by certain macrolides]. PMID- 24167886 TI - [Obstructive sleep apnea: snoring is not very predictive if it is IMC<30]. PMID- 24167887 TI - [Not Available]. PMID- 24167888 TI - [Not Available]. PMID- 24167889 TI - [Not Available]. PMID- 24167890 TI - [Not Available]. PMID- 24167891 TI - [Stroke in young adult]. PMID- 24167892 TI - [Epidemiology and prognosis of stroke in young adults]. AB - Stroke in young adults is not rare since one in ten stroke patients are less than 55 years old, and incidence is 20 to 35/100000 per year at this age. This incidence increased over the last past years because of the rise in the prevalence of diabetes, obesity, and marijuana abuse, and still a high prevalence of smoking. This latter risk factor is the most frequent and accounts for more than one half of young stroke patients. Even though both survival and functional outcome of young stroke patients are better than those observed in older patients, socioeconomic and quality of life consequences make this disease a main objective for practitioners who should identify individuals at risk and apply preventive strategies. PMID- 24167893 TI - [Etiological workup for cerebral infarction in young adults]. AB - identifying the cause of ischemic stroke in young adults is of major importance to prevent stroke recurrence. However, given the wide variety of potential underlying causes, the etiological workup of stroke in young adults requires a different approach from that in the elderly The purpose of this article is to provide a sequential diagnostic workup in order to optimize the yield of diagnostic tests, and to reduce their cost and risks for the patient. The first line screening mainly includes contemporary MRI of the brain and its vessels, and cardiac investigations which will assess the most frequent causes of stroke in this age group: arterial dissection and cardioembolism. The second line screening should be guided by context and clinical suspicion: lumbar puncture and immunological tests in case of angeitis suspicion; lumbar puncture, blood culture and serologies in case of infectious context; antiphospholipid syndrome, Holter ECG, transoesophageal echocardiography, HIV and syphilis serologies in absence of context. Finally, the third line screening may include more invasive tests such as angiography and leptomeningeal biopsy in case of angeitis suspicion or genetic analyses. Despite such a comprehensive workup, about one third of cases will remain unexplained, leading to the diagnosis of idiopathic ischemic stroke. PMID- 24167894 TI - [Stroke during the pregnancy and the puerperium]. PMID- 24167895 TI - [Cervical and intracranial artery dissections]. AB - Cervical and intracranial artery dissections result from the occurrence of an intramural hematoma. Arterial dissection is one of the main causes of ischemic stroke in young adults. Pathophysiology remains misunderstood but probably results from the association of a triggering environmental factor with an underlying arteriopathy. Usually, headache or neck pain, sometimes associated with local signs (e.g., Horner's sign) occurs after a trivial trauma, followed some hours or days later by cerebral infarct. Diagnosis may be confirmed by CT scan or MRI with angiogram. In the absence of randomized studies, acute treatment of cervical artery dissection is based on antithrombotics. IV thrombolysis is recommended in acute stroke. Outcome is favorable in most cases, related to infarct severity. Recurrences are very rare. PMID- 24167896 TI - [Fibromuscular dysplasia of arteries]. PMID- 24167897 TI - [Cerebral venous thrombosis]. AB - Cerebral venous thrombosis represents less than 1 % of all strokes, usually affecting young women, probably because of hormonal factors. The most common symptom is headache, with or without focal neurological findings such as deficits or seizures. Brain MRI is the gold standard for diagnosis. Anticoagulation should be initiated as soon as possible, followed by vitamin K antagonists, for at least 3 months. Predisposing causes and risk factors for cerebral venous thrombosis are multiple. Prognosis is good and recurrence rate is low. PMID- 24167898 TI - [Subarachnoid hemorrhage in young patients]. AB - Subarachnoid hemorrhage (SAH) accounts for 5 % of strokes with a high rate of death and morbidity. It occurs in young patients, often hypertensive and smoking. Patients usually present with sudden headache. Initial clinical evaluation uses a prognosis grading scale including level of consciousness and motor deficit on admission (WFNS scale). Unenhanced CT brain imaging demonstrates the SHA together with evaluation of the initial blood amount, predictive of the occurrence of cerebral vasospasm that may lead to delayed cerebral ischemia. After referral to a multidisciplinary center with neurovascular expertise, MR, CT and/or catheter angiography detects the ruptured aneurysm, the cause of SAH in 85 % of cases. Since rebleeding is an imminent danger, occlusion of the aneurysm should be performed, as soon as possible and within the first 72 heures, either by an endovascular or microsurgical approach. Medical management includes early detection of hydrocephalus and cerebral vasospasm is a devastating complication inducing death and functional impairment. Prevention strategies remain limited and include maintenance of normovolemia and calcium antagonists such as nimodipine. Treatment of cerebral vasospasm associates maintenance of cerebral perfusion and more invasive techniques such as chemical or mechanical angioplasty. PMID- 24167899 TI - [Intracerebral haemorrhage in young adults]. AB - In Western countries, less than 5 % of strokes occur in adults less than 50 years. Most of these strokes are cerebral infarctions, but 10 to 30 % are intracerebral hemorrhages (ICH). The causes of ICH in young adults are wider than in the elderly. Vascular malformations and lipohyalinosis of small vessels weakened by hypertension constitute the most frequent causes. Management of ICH is an emergency and these patients should be hospitalized in specialized units. Compared to cerebral infarction the prognosis of patients with ICH is poor with a risk of death between 40 % and 50 % during the first year. Survivors are left with severe disability in 20 % of cases. The risk of recurrence of ICH in young adults depends of the underlying cause. PMID- 24167900 TI - [When to replace the vitamin K antagonists by new anticoagulants?]. AB - New oral anticoagulants (dabigatran, rivaroxaban, apixaban) have as main advantage an easier use (fixed dose therapy, no laboratory monitoring). Switching from vitamine K antagonists (VKA) to new oral anticoagulant is tempting. The indication of dabigatran and rivaroxaban for the prevention of stroke and systemic embolism in nonvalvular atrial fibrillation, and the indication of rivaroxaban for the treatment of deep-vein thrombosis and for the long-term prevention of venous thromboembolism are based from large, randomized trials. New oral anticoagulant should not be used to prevent stroke or major thromboembolic events in patients with mechanical prosthetic heart valve. It is recommended switching from VKA to new oral anticoagulant only if it is difficult to maintain a therapeutic INR Non-adherence to VKA therapy should not justify the switch to a new oral anticoagulant. PMID- 24167901 TI - [New direct oral anticoagulants and venous thromboprophylaxis]. AB - The new direct oral anticoagulants currently available are dabigatran, rivaroxaban and apixaban. These three drugs have been labeled in France for the prevention of venous thromboembolism after elective orthopaedic surgery including total hip or knee arthroplastly. Rivaroxaban is also labeled for the secondary prevention of thrombosis recurrence following an initial acute event. Pharmacologic properties of these drugs are reminded as well as the results of the main studies having conducted to their approval. PMID- 24167902 TI - [New anticoagulants in the treatment of venous thromboembolism]. AB - Anticoagulant therapy is the cornerstone of treatment of venous thromboembolism (VTE). The treatment needs rapid initial anticoagulaton to minimize the risk of thrombus extension and fata pulmonary embolism, followed by an extended anticoagulation, aimed at preventing recurrent VTE. Till very recently, immediate anticoagulation can only be achieved with parenteral agents, such as heparin, low molecular-weight heparin, or fondaparinux. Extended treatment usually involves the administration of vitamin K antagonists, such as warfarin. Emerging direct oral anticoagulants have the potential to streamline VTE treatment. These agents include oral anticoagulants that target thrombin or factor Xa. This article reviews the characteristics of these agents, describes the results of clinical trials in venous thromboembolic disease and outlines their strengths and weakness. PMID- 24167903 TI - [A sober medicine (better care at lower cost)]. PMID- 24167904 TI - [Muco-cutaneous allergies in child and adult. Urticaria. Atopic and contact dermatitis]. PMID- 24167905 TI - [Psychiatric treatment without consent]. PMID- 24167906 TI - [Palliative care in pediatrics and neonatology]. PMID- 24167907 TI - [Pain in children: sedation and analgesia]. PMID- 24167908 TI - [Medical recollections. Francois Magendie, creator of the pharmacology, inspirer of Claude Bernard's researches]. PMID- 24167909 TI - Situational analysis and expert evaluation of the nutrition and health status of infants and young children in five countries in sub-Saharan Africa. AB - BACKGROUND: The poor feeding practices of pregnant women, infants, and young children contribute to the burden of malnutrition and subsequently to childhood morbidity and mortality in sub-Saharan Africa. Gaining insight into the nutritional and health status of infants and young children will help to focus future nutrition programs and actions. OBJECTIVE: To assess the nutrition and health status of infants and young children in five sub-Saharan African countries: Ivory Coast, Senegal, Cameroon, Kenya, and Nigeria. METHODS: Published and gray literature was critically reviewed and enriched with the views of local experts from academia, hospitals, and institutions to assess infants' and children's diet and health in the five sub-Saharan African countries. Subsequently, the Africa Nutriday Conference was held in Senegal in November 2011 to further discuss key challenges, action plans, and recommendations for future research. RESULTS: This review highlighted the need for education of parents and healthcare professionals in order to increase their knowledge of breastfeeding, vaccination programs, and over- and undernutrition. An integrated health and nutrition surveillance is needed both to identify micronutrient deficiencies and to recognize early signs of overweight. These data will help to adapt nutrition education and food fortification programs to the target populations. CONCLUSIONS: Different countries in sub-Saharan Africa face similar nutrition and health issues and are currently not sharing best practices, nutrition programs, and scientific studies optimally. There is a need for closer collaboration among scientists within and between countries. PMID- 24167910 TI - Nutritional impact of highly pathogenic avian influenza in Kenya. AB - BACKGROUND: Outbreaks of highly pathogenic avian influenza (HPAI) (virus type H5N1) have led to extensive bird culling and other control measures throughout the world, with implications especially for the livelihoods of the poor. There is limited empirical evidence for the impact of HPAI on poultry consumption and nutrition of vulnerable populations. OBJECTIVE: To test the effect of reduced per capita poultry consumption at the household level due to an HPAI event on anthropometric measurements of children. METHODS: This study used data from the Kenya Integrated Household Budget Survey (KIHBS) 2004/05 to characterize the nutritional status of young children 6 to 36 months of age, household dietary diversity (number of food groups consumed), and determinants of anthropometric outcomes, including z-scores for height-for-age (HAZ), weight-for-age (WAZ), and weight-for-height (WHZ). Propensity score matching (PSM) was applied to ascertain the nutritional impacts of reduced poultry consumption arising from an HPAI event. RESULTS: Thirty-four percent of the children were stunted (HAZ < -2 SD), 16% were underweight (WAZ < -2 SD), and 8% were wasted (WHZ < -2 SD), with the highest prevalences in the Coast, Eastern, North Eastern, Nyanza, and Rift Valley provinces. On average, households reported consuming food from 2.5 +/- 1.3 food groups per week. Consistently significant determinants of anthropometric outcomes in these children were child's age, child's sex, household level of education, and various income and wealth determinants. PSM demonstrated that a reduction of consumption of poultry meat and eggs due to HPAI infection would increase the prevalence of stunting by 3.9 percentage points (Average Treatment Effect on the Treated (ATT), p = .06), increase the prevalence of underweight by 5 percentage points, and reduce WAZ by 0.16 (ATT, p = .03). CONCLUSIONS: Through the household dietary diversity and consumption pathways, HPAI could have nutrition-related consequences with public health significance. In the event of HPAI, action may be needed to protect the nutrition of young children 6 to 36 months of age. PMID- 24167911 TI - Are school feeding programs in low-income settings sustainable? Insights on the costs of school feeding compared with investments in primary education. AB - BACKGROUND: School feeding programs are ubiquitous. Benchmarking expenditures for school feeding is an important component of program accountability and sustainability. OBJECTIVE: To analyze the costs of school feeding and the cost relative to education expenditure and other measures of economic growth. METHODS: Data on the costs of school feeding were collected from multiple sources, including United Nations databases, gray literature, and published reviews. Relationships between costs of school feeding, costs of education, and GDP per capita were analyzed through standard linear regression. RESULTS: Data on costs of school feeding were obtained for 74 countries, including 12 high-income, 40 middle-income, and 22 in low-income countries. School feeding programs were found to cost US$173 per child per year, ranging from US$54 in low-income countries to US$693 in high-income countries. In high-income countries, school feeding costs per capita were on average equivalent to 11% of the per capita investments in primary education, compared with 19% in middle-income countries and 68% in low income countries. In middle- and low-income countries, school feeding programs covered on average 18% and 13% of the children enrolled in primary school, respectively. The total budget for school feeding in low-income countries was found to be on average 11% of the estimated total primary school education budget, compared to 4% in middle-income countries. CONCLUSIONS: School feeding investments are targeted in low- and middle-income settings, reaching only a portion of primary schoolchildren, with total costs only a fraction of the overall investment in education. As countries get richer, school feeding costs become a much smaller proportion of education costs. The findings of this study provide an updated framework for benchmarking school feeding programs. PMID- 24167912 TI - Relative costs of 24-hour recall and Household Consumption and Expenditures Surveys for nutrition analysis. AB - BACKGROUND: The technical and resource demands of the most precise dietary assessment methods, 24-hour recall and observed-weighed food records, have proven impractical for most low- and middle-income countries, leaving nutrition policymakers with a woefully inadequate evidence base and compromising nutrition program effectiveness. OBJECTIVE: To better understand the relative costs of informing food and nutrition policy-making using two different data sources: 24 hour recall survey data and Household Consumption and Expenditures Survey (HCES) data. METHODS: A comparative analysis of the costs of designing, implementing, and analyzing a 24-hour recall survey and the cost of secondary analysis of HCES data. RESULTS: The cost of conducting a 24-hour recall survey with a sample of the size typical of HCES would be roughly 75 times higher than the cost of analyzing the HCES data. CONCLUSIONS: Although the 24-hour recall method is undoubtedly more precise, it has become self-evident that the practical choice for most countries is not between these two surveys, but between having data from less precise, but much more readily available and affordable HCES or having no nationally representative data. In the light of growing concerns about inappropriate fortification policies developed without data, there is an urgent need to begin working to strengthen HCES to provide more precise food and nutrition data. The best way forward is not likely to rest with one data source or another, but with the development of an eclectic approach that exploits the strengths and weaknesses of alternative surveys and uses them to complement one another. PMID- 24167913 TI - Control of iodine-deficiency disorders following universal salt iodization in Shenzhen, China, 1997-2011. AB - BACKGROUND: Since universal salt iodization (USI) was implemented in Shenzhen, China, in 1996, evaluation of the time trend of USI to indicate the control of iodine-deficiency disorders has not been performed. OBJECTIVE: To assess the time trend of median urinary iodine and total goiter rates from 1997 to 2011. METHODS: Probability-proportionate-to-size sampling was employed in the surveillance of iodine-deficiency disorders, for which schoolchildren aged 8 to 10 years were randomly selected from five districts of the city during each iodine-deficiency disorders survey. Urinary iodine content and thyroid size were measured by ammonium persulfate oxidation and B ultrasound, respectively. RESULTS: The coverage of iodized salt increased from 73.2% in 1997 to more than 90% in 2011. The median urinary iodine of children aged 8 to 10 years varied between 207.1 and 278.8 microg/L; these levels were above the urinary iodine level in 1995. The proportion of urine samples with iodine content above 300 microg/L was 45.6% in 1997 and decreased to 20.8% in 2011, indicating excessive consumption of iodine by the children. The goiter rate among children dropped from 10.8% in 1997 to 1.3% in 2011; both values were lower than the goiter rate in 1995, indicating that the spread of endemic goiter was under control. CONCLUSIONS: Preliminary elimination of iodine-deficiency disorders was achieved by USI in Shenzhen. Nevertheless, some problems still existed, such as over-iodization. To clarify the causes of excessive urinary iodine content, the various sources of iodine from the diet need to be investigated in the future. PMID- 24167914 TI - Sustainability and scaling-up analysis of community-based management of acute malnutrition: lessons learned from Burkina Faso. AB - BACKGROUND: Community-based management of acute malnutrition (CMAM) is an effective strategy frequently implemented by nongovernmental organizations, but handing CMAM over to national health systems and scaling it up remains a great challenge. OBJECTIVE: To highlight the challenges to sustainability and scalability of a CMAM program in Burkina Faso. METHODS: We conducted a review of program reports to evaluate program performance and conducted individual interviews with key informants (health system fieldworkers and officials and program staff members) and focus group discussions with beneficiaries (mothers whose children were attending the program, community volunteers, and village leaders) to analyze the required conditions for scaling up using ExpandNet recommendations. RESULTS: The program coverage rate was 90% among children under 5 years of age in the 180 intervention villages. Between June 2007 and December 2010, 19,009 cases of acute malnutrition (AM) among children under 5 years of age were treated, of which 4,308 (22.7%) were cases of severe acute malnutrition (SAM). The recovery rate was 89.4% for moderate acute malnutrition (MAM) and 86.5% for SAM. The case-fatality rate was 2.8% for MAM and 4.2% for SAM. The default rate was 7% for all cases. The prevalence of SAM decreased between 2008 and 2009 from 5.4% to 1.8%. Barriers to sustainability and scaling up were underlined: management by external personnel from the health system, no financial support for the scaling-up process, insufficient national advocacy, and nonsustainable activities (e.g., free care). CONCLUSIONS: The CMAM program was effective, but the handover conditions and scaling-up requirements were unsatisfactory. We identified poor integration into the health system, lack of resources, and insufficient advocacy. PMID- 24167915 TI - Can iron supplementation be reconciled with benefits and risks in areas hyperendemic for malaria? AB - Malaria is associated with about a million fatalities annually, largely among young children in zones of intense malarial transmission. The last thing needed would be measures that might increase the severity of clinical malaria. Thus, the finding in a field trial on Pemba Island, Tanzania, that routine oral iron supplementation produced adverse effects in iron-sufficient subjects had a ripple effect throughout the international public health community; it has effectively paralyzed efforts to redress iron-deficiency anemia in malaria-endemic regions. From a Hippocratic perspective, we consider the de facto moratorium on oral supplementation in such circumstance as a prudent interim measure. Public health programs to combat iron-deficiency anemia cannot be denied indefinitely to malaria-endemic populations, but the universal campaigns of iron provision cannot simply resume in the manner of the past. Contemporary biological and epidemiological understanding of the coevolution of humans and their pathogens should be able to provide guidance within the context of the essential and harmful aspects of iron. From these evolutionary standpoints, we identify a series of unresolved dilemmas. Toward a way forward, we highlight the pros and cons, as well as possible directions toward short-term strengthening, within three domains: tailored oral iron compounds, iron administration targeted only to iron-deficient individuals through screening, and prudent use of antimalarial prophylaxis. Although the tension between the essentiality of iron for humans and its role in pathogen virulence looms through every consideration, this recognition is a starting point toward the weighing of appropriate options balancing benefits and safety. PMID- 24167917 TI - Service evaluation and improvement methods. PMID- 24167918 TI - Assessing obstetric patient experience: a SERVQUAL questionnaire. AB - PURPOSE: Across health services, there is a drive to respond to patient feedback and to incorporate their views into service improvement. The SERVQUAL method has been used in several clinical settings to quantify whether services meet patient expectations. However, work has been limited in the obstetric population. This paper seeks to address these issues. DESIGN/METHODOLOGY/APPROACH: This study used an adapted SERVQUAL questionnaire to assess a reconfigured antenatal clinic service. The most important care aspects, as rated by patients, were used to construct the SERVQUAL questions. The questionnaire was administered to eligible women in two parts. The first was completed before their first hospital antenatal appointment and the second either at home (a postal-chasing exercise) or while waiting for their next appointment. Only fully completed questionnaires (both parts) were analysed. FINDINGS: Service strengths included staff politeness, patient respect and privacy. Areas for improvement included hand cleanliness, women's involvement in decision making and communicating risk. However, the low variability in patient responses makes concrete conclusions difficult and methodological issues complicate evaluating hand cleanliness. The new antenatal clinic service received low negative weighted and un-weighted overall scores. The SERVQUAL measure was developed from patient feedback and used to further improve services. PRACTICAL IMPLICATIONS: The SERVQUAL-based measure allowed an internal evaluation of patient experience and highlighted areas for improvement. However, without validation, the questionnaire cannot be used as an outcome measure and variation between published SERVQUAL questionnaires makes comparisons difficult. This highlights an important balance in patient evaluation measures--between locally responsive and externally comparable. ORIGINALITY/VALUE: The SERVQUAL approach allows healthcare teams to evaluate patient experience, while accounting for variation in their expectations and priorities. The study highlights several areas that are important to obstetric patients, where expectation scores are high. However, the similar means and small samples left little difference between excellence and room for improvement. PMID- 24167916 TI - Implications of acquired environmental enteric dysfunction for growth and stunting in infants and children living in low- and middle-income countries. AB - Changes in small bowel function early in infancy in developing countries are increasingly being demonstrated, probably accompanied by altered mucosal architecture in most individuals, including reduced enterocyte mass and evidence of immune activation and inflammation in the mucosa. These alterations appear to be the result of factors of uncertain nature in the environment, and may be a cause of growth faltering and stunting in young children. For these reasons, this constellation of findings is being referred to as environmental enteropathy, or as we propose herein, environmental enteric dysfunction. If the causes were known and effective interventions were available, strategies and policies to intervene at--or possibly before--birth could be developed and promoted in order to prevent subsequent malnutrition and recurrent infection, which are known to interact in a cyclical and synergistic manner in a downward clinical course often ending in death. Resources would be mobilized and applied differently, and the emphasis would change from treatment to prevention. In order to move in this highly desired direction, investments in research will be required to establish the criteria to assess environmental enteric dysfunction, determine its predictive value for growth faltering and stunting, identify the causes, and propose and test potential interventions. The concepts and tools are available. What is required is the decision to move forward along this pathway to better health for infants and children in low-income countries. PMID- 24167919 TI - Using the Plan-Do-Study-Act model: Pacesetters experiences. AB - PURPOSE: This article aims to analytically review the Plan-Do-Study-Act (PDSA) model used in the Pacesetters national programme evaluation. DESIGN/METHODOLOGY/APPROACH: The evaluation team's two-fold role is outlined: supporting project teams to develop PDSA plans and collect evaluation data. Four case studies are used to show the PDSA model's application and effect in a participatory action learning approach. Despite limitations, it is clear that all four case studies illustrate the PDSA model's potential benefits in a participatory evaluation approach, which involves public and patients. FINDINGS: The model's effectiveness is premised on several enabling factors such as: teams appreciating the model; a climate that values all learning and open to re planning; engaging any external evaluators whose role is clearly communicated to all project stakeholders in a timely fashion. PRACTICAL IMPLICATIONS: There are clear intentions to promote evidence-based commissioning in the UK that values patient and public involvement. The PDSA model has the potential to test and implement changes in real work-place settings and to involve the public in evaluation. ORIGINALITY/VALUE: Case study analysis identifies new reflections on the PDSA model's use to support innovative NHS practice development with public involvement in a participatory approach. PMID- 24167920 TI - Six Sigma in healthcare delivery. AB - PURPOSE: The purpose of this paper is to conduct a comprehensive review and assessment of the extant Six Sigma healthcare literature, focusing on: application, process changes initiated and outcomes, including improvements in process metrics, cost and revenue. DESIGN/METHODOLOGY/APPROACH: Data were obtained from an extensive literature search. Healthcare Six Sigma applications were categorized by functional area and department, key process metric, cost savings and revenue generation (if any) and other key implementation characteristics. FINDINGS: Several inpatient care areas have seen most applications, including admission, discharge, medication administration, operating room (OR), cardiac and intensive care. About 42.1 percent of the applications have error rate as their driving metric, with the remainder focusing on process time (38 percent) and productivity (18.9 percent). While 67 percent had initial improvement in the key process metric, only 10 percent reported sustained improvement. Only 28 percent reported cost savings and 8 percent offered revenue enhancement. These results do not favorably assess Six Sigma's overall effectiveness and the value it offers healthcare. Results are based on reported applications. Future research can include directly surveying healthcare organizations to provide additional data for assessment. PRACTICAL IMPLICATIONS: Future application should emphasize obtaining improvements that lead to significant and sustainable value. Healthcare staff can use the results to target promising areas. ORIGINALITY/VALUE: This article comprehensively assesses Six Sigma healthcare applications and impact. PMID- 24167921 TI - Quality improvement training: experiences of frontline staff. AB - PURPOSE: Healthcare organizations have employed numerous strategies to promote quality improvement (QI) initiatives, yet little is known about their effectiveness. In 2008, staff in one organization developed an in-house QI training program designed for frontline managers and staff and this article aims to report employee perspectives. DESIGN/METHODOLOGY/APPROACH: Qualitative interviews were conducted with 22 course participants to examine satisfaction, self-assessed change in proficiency and ability to successfully engage with QI initiatives. Sampling bias may have occurred as the participants volunteered for the study and they may not represent all course participants. Recall bias is also possible since most interviews took place one year after the course was completed to assess long-term impact. Respondents were asked to self-rate their pre- and post-course knowledge and skill, which may not represent what was actually learned. FINDINGS: Informants reported that the course expanded their QI knowledge and skills, and that supervisor support for the course was essential for success. Additionally, the course QI project provided participants with an opportunity to translate theory into practice, which has the potential to influence patient outcomes. PRACTICAL IMPLICATIONS: Several lessons for future QI training can be gleaned from this evaluation, including respondent opinions that it is challenging to offer one program when participants have different QI knowledge levels before the course begins, that "booster sessions" or refresher classes after the course ends would be helpful and that supervisor support was critical to successful QI-initiative implementation. ORIGINALITY/VALUE: This study conducts in-depth interviews with QI course participants to elicit staff feedback on program structure and effectiveness. These findings can be used by QI educators to disseminate more effective training programs. PMID- 24167922 TI - Clinical quality improvement: eliminating unplanned extubation in the CCU. AB - PURPOSE: This article aims to explore coronary care unit (CCU) extubation structures, processes and outcomes. There were 13 unplanned-extubation cases (UE) among 251 intubated patients (5.2 per cent) in a cardiologist-led CCU in 2008. Seven did not require re-intubation, implying possible earlier extubation. A quality improvement project was undertaken with a goal to eliminate CCU UE within 12 months. DESIGN/METHODOLOGY/APPROACH: Using the clinical practice improvement (CPI) method, the most significant root causes were missing sedation/analgesia protocol, no ventilator weaning protocol and absent respiratory therapist during the CCU morning rounds. Non-physician directed sedation/analgesia and ventilation weaning protocols were created and put on trial in Plan-Do-Study-Act cycles before formal implementation. Arrangements were made to allocate a respiratory therapist to the CCU daily for morning rounds. FINDINGS: For 12 months after fully implementing the interventions, UE incidence dropped from 5.2 per cent to 0.9 per cent (p = 0.006). There were no adverse outcomes, re-intubation and/or readmission to CCU within 48 hours. PRACTICAL IMPLICATIONS: Through a multi disciplinary CPI approach, adopting non-physician directed protocols has successfully streamlined and improved airway management in mechanically ventilated patients in a cardiologist-led CCU. ORIGINALITY/VALUE: There is little published data on improving intubated patient care in cardiologist-led CCUs. Previous studies centered on intensive care units managed by critical care specialists. PMID- 24167923 TI - Nurses' understandings of suitable footwear for older people. AB - PURPOSE: The purpose of this paper is to gain insight into nurses' understandings of what constitutes suitable footwear for older people in care homes. DESIGN/METHODOLOGY/APPROACH: An exploratory descriptive qualitative survey was carried out of 20 registered nurses employed in six Scottish care homes for older people. Data were collected using a semi-structured questionnaire that included five open-ended questions. Content analysis was used to theme footwear perceptions. FINDINGS: Participants had several views about what encompasses safe footwear; some were erroneous. The link between inappropriate footwear and falls was recognised by 80 per cent of respondents, but some were unclear about the features that effect or inhibit safety. No UK or international standardised guidelines were identified that advise nurses about appropriate footwear for older people. PRACTICAL IMPLICATIONS: It is unknown whether respondents represent the nurse population because findings are restricted by a small sample size. Nonetheless, the group showed variable understanding of what constitutes safe footwear for older people and links with fall prevention. Improved nurse education about what comprises safe footwear and the links with falls prevention in older people is required. Structured guidelines to direct nurse educators about what to teach student nurses about appropriate footwear for older people may work towards reducing falls. ORIGINALITY/VALUE: No guidelines to direct nurses about appropriate footwear for older people in care homes have been written. Key points have been developed. PMID- 24167925 TI - [IMAJ--the reflection of medical research in Israel 2012-2013]. PMID- 24167924 TI - Risk segmentation in Chilean social health insurance. AB - PURPOSE: The objective of this study is to identify how risk and social variables are likely to be impacted by an increase in private sector participation in health insurance provision. The study focuses on the Chilean health insurance industry, traditionally dominated by the public sector. DESIGN/METHODOLOGY/APPROACH: Predictive risk modelling is conducted using a database containing over 250,000 health insurance policy records provided by the Superintendence of Health of Chile. FINDINGS: Although perceived with suspicion in some circles, risk segmentation serves as a rational approach to risk management from a resource perspective. The variables that have considerable impact on insurance claims include the number of dependents, gender, wages and the duration a claimant has been a customer. PRACTICAL IMPLICATIONS: As shown in the case study, to ensure that social benefits are realised, increased private sector participation in health insurance must be augmented by regulatory oversight and vigilance. ORIGINALITY/VALUE: As it is clear that a "community rated" health insurance provision philosophy impacts on insurance firm's ability to charge "market" prices for insurance provision, the authors explore whether risk segmentation is a feasible means of predicting insurance claim behaviour in Chile's private health insurance industry. PMID- 24167926 TI - [Patient dissatisfaction following prolonged stay in the post-anesthesia care unit due to unavailable ward bed in a tertiary hospital]. AB - OBJECTIVES: The present study aimed to evaluate subjective reactions of post surgery and anesthesia patients who stay in post-anesthesia care units (PACU) longer than necessary medically, due to administrative causes. METHODS: We interviewed consenting postoperative patients during an 18-month period. All patients who remained in the PACU twice our obligatory PACU length of stay (> 4 hours) due to lack of an available bed in the appropriate hospital ward, were interviewed at the time of discharge. The study group consisted of those who remained > 4 hours after surgery and a control group of patients who were discharged within 4 hours. The questions were chosen from different sources, including generic and condition-specific questionnaires. RESULTS: A total of 67 patients stayed > 4 hours and 63 < 4 hours. The overall mean PACU length of stay for the former was 14.23 +/- 5.77 hours (range 1.5-30 hours). No significant differences were found between the groups in terms of age, gender, surgical time or postoperative pain visual analogue scale. Irritability due to lack of independence were statistically higher, and satisfaction rates were lower in patients who stayed > 12 hours compared to those who were discharged after 4-12 hours (P < 0.05). CONCLUSIONS: Overcrowded wards may lead to significant delays in discharge from the PACU. Prolonged stay in the PACU requires attention, both from the administrative and the medical standpoints, because it may irritate the patient. Patients' irate behavior may distract the medical staff from effectively performing their duties and interferes with optimal medical care in the PACU. PMID- 24167927 TI - [Detection of wooden rod in pleural and peritoneal cavities during forensic autopsy]. AB - INTRODUCTION: A rare event of fatal sexual assault by the insertion of a wooden rod through the anus to the upper chest is reported. Examination of the body at the scene did not raise any suspicion of assault while the subsequent autopsy revealed findings that changed the assessment of the cause of death and the circumstances. CASE HISTORY: The body of a 57 years old man with a history of psychiatric illness was found in his room. At autopsy a round wooden rod which was inserted through the anus was found in the peritoneal and pleural cavities. In addition, signs of manual pressure were detected on the neck and trunk, and on the head and extremities signs of blunt trauma were observed. DISCUSSION: In patients affected by mental disorders it is difficult to distinguish between self inflicted anal injuries and injuries sustained during an attack. Detection of damage to other areas of the body (such as the neck) assist in determining the nature of the assault. SUMMARY: This case demonstrates the need for a full autopsy in every case of death under unclear circumstances, especially when a limited examination of the body can't determine the type of death (natural, accident, suicide or homicide). PMID- 24167928 TI - [Simulation-based intervention to improve anesthesiology residents communication with families of critically ill patients--preliminary prospective evaluation]. AB - BACKGROUND: Although effective communication with families of critically ill patients is a vital component of quality care, training in this field is neglected. AIMS: The article aims to validate communication skills training program for anesthesiology residents in the intensive care set up. METHODS: Ten anesthesia residents, following 3 months of Intensive Care Unit (ICU) rotation, had 4 hours of lectures and one day simulation-based communication skills training with families of critically ill patients. Participants completed an attitude questionnaire over 3 time periods--before training [t1], immediately following training (t2) and three months following training (t3). The participants' communication skills were assessed by two blinded independent observers using the SEGUE framework while performing a simulation-based scenario at t1 and t3. RESULTS: Seven participants finished the study protocol. Participants ndicated communication importance as 3.68 +/- 0.58 (t1), 4.05 +/- 0.59 (t2), 4.13 +/- 0.64 (t3); their communication ability as 3.09 +/- 0.90 (t1), 3.70 +/- 0.80 (t2), 3.57 +/- 0.64 (t3); the contribution of lecture to communication 3.04 +/- 0.43 (t1), 3.83 +/- 0.39 (t2), 3.87 +/- 0.51 (t3), and contribution of simulation training to communication 3.00 +/- 0.71 (t1), 4.04 +/- 0.52 (t2), 3.84 +/- 0.31 (t3). The differences did not reach statistical significance. Objective assessment of the communication skills using the SEGUE framework indicated that 6/7 participants improved their communication skills, with communication ability before training at 2.66 +/- 0.83 and 1 month following training it was 3.38 +/- 0.78 (p = 0.09). CONCLUSIONS: This preliminary study demonstrates the value of communication skills training in the intensive care environment. PMID- 24167929 TI - [Occupational asthma--the case of bakers' asthma]. AB - Occupational asthma (OA) is the most common of all occupational lung diseases in industrialized countries and its prevalence has been rising steadily. It is estimated that occupational factors account for one out of six cases of adult asthmatic patients causing significant morbidity, disability and costs. Due to its high prevalence and substantial health and socio-economic impacts OA represents a significant public health concern. OA can be divided into allergic and non allergic asthma. Allergic OA is further divided into IgE mediated and non IgE mediated. Baker's asthma (BA), is the leading cause of IgE mediated OA caused by high molecular weight antgens in industrialized countries. Innovations in the baking industry during the last few decades have led to the introduction of new allergens inducing OA. OA is potentially preventable, through early diagnosis and exposure cessation interventions. Thus, clinicians should consider the occupational history in every adult patient presenting with newly diagnosed asthma. PMID- 24167930 TI - [Lycopene and tomatoes--their effect on prevention of prostatic cancer]. AB - Prostate cancer is one of the most common types of cancer and it is the second most common cause of cancer-related death among men in the western world. Microscopic prostate cancer was found in up to 30% of men as early as 20-40 years old of age. Lycopene is a lipid soluble carotenoid molecule. It is found in high concentration in red fruit and vegetables. Lycopene has a significant anti oxidative activity. There is laboratory evidence that explain it's function as an inhibitor of various tumors as well as epidemiological evidence that shows that lycopene-rich foods reduce the incidence of a few types of cancer and especially prostate cancer. This paper reviews the evidence that explain lycopene activity, its biological effect and availability and its effect on the prevention of prostate cancer. PMID- 24167931 TI - [SOCS--suppressor of cytokine signaling proteins and their role in the pathogenesis of allergic and autoimmune disorders]. AB - Cytokines play a major role in the innate and the adaptive immune responses. Since cytokines are very powerful messengers, several regulatory systems (in all levels: production, secretion, effect on target) control their action in order to prevent overstimulation of cytokines. Recently, a negative feedback of cytokine activity in the target cell, namely suppressor of cytokine signaling (SOCS) was defined. This regulatory system consist of 8 proteins (CIS.SOCS 1-7) n which each one of them specifically regulates one or more cytokines. Malfunction of the SOCS proteins may lead to unregulated activity of cytokines which may lead to the development of allergic and autoimmune disorders. PMID- 24167932 TI - [Genital ulcers--what's new?]. AB - The most common infectious causes of genital ulcers are herpes simplex virus and syphilis. However, mixed infections can occur and genital ulcer may increase the risk of acquiring human immunodeficiency virus. Although the history and physical examination can narrow the differential diagnosis, there is a need for initial routine laboratory testing for the most common pathogens that includes: for syphilis: serologic screening and dark field examination of the lesion; for herpes simplex virus: serology, vial culture and/or polymerase chain reaction. Human immunodeficiency testing is mandatory. Recently, some clinical laboratories adapted the reverse screening algorithm for syphilis (initial treponemal test, and, if positive, followed by non-treponemal test) that may potentially lead to overtreatment. Early and prompt therapy may decrease the risk of transmission of the infectious agent to others. This article reviews the infectious pathogens causing genital ulcers, their unique clinical manifestation, diagnosis and treatment. PMID- 24167933 TI - [Epilepsy in pregnancy]. AB - Most women with epilepsy will need to continue antiepileptic drugs prior to and during pregnancy. Pre-conception counseling should be available to all wormen with epilepsy who are considering pregnancy, and should address obstetrical complications, change in seizure frequency, and adverse pregnancy outcome. Supplementation with folic acid. 0.4-5 mg/day, is recommended for all women with epilepsy of childbearing potential, especially 3 months prior to conception and throughout the first trimester. It is advisable to obtain serum drug concentrations before pregnancy, when seizure control is optimal, in order to establish a baseline. Serum concentration should be performed each trimester among patients with good seizure control, and monthly in patients with complicated epilepsy, breakthrough seizures, significant side effects, and those treated with lamotrigine or oxcarbazepine. The incidence of major congenital malformations in offspring of women treated with antiepileptic drugs has ranged from 4 to 10%, corresponding to a two-fold increase from the expected incidence in the general population. Malformation rates are higher with valproate, lower with carbamazepine and lamotrigine, and dose-effect relationship has been shown for teratogenicity especially with valproate. An expert morphological assessment, targeted at the neural axis, heart and face, should be performed at 11-13 weeks and 18-22 weeks. There is generally no contraindication to breast feeding among mothers with epilepsy, but further studies are needed to establish the safety of newer antiepileptic drugs. PMID- 24167934 TI - [HIV testing: the medical laboratory role in HIV diagnosis and monitoring]. AB - Diagnosis of HIV infection is performed via enzyme immunoassay (EIA), an assay based on screening for antibodies against HIV. Confirmation of diagnosis is performed by Western-Blot, a more specific assay directed at a number of viral proteins for which antibodies exist. Routine follow-up of HIV-infected individuals includes measurement of CD4 cell count to evaluate the immune status, of viral load to assess virus replication, and of changes in the viral genome to characterize resistance to drugs and tropism. In addition, absence of the HLA B*57:01 allele is verified before prescription of abacavir, and drug levels of protease-inhibitors are determined in treatment-failing individuals after ruling out other causes of failure. Rapid diagnosis and regular follow-up improve the quality of life of patients and extend their life expectancy, also helping to control the spread of the epidemic at the national level. PMID- 24167935 TI - [Elite controllers and the mechanisms behind spontaneous control of HIV]. AB - Elite controlllers (EC) are a unique and rare group of HIV-positive patients who control viral replication to undetectable levels in the absence of antiretroviral treatment. They tend to maintain stable CD4 count, and do not progress to AIDS. While the mechanisms underlying elite control are currently under intensive investigation, research has revealed that a set of host genetic and acquired factors, as well as specific viral characteristics, contribute to viral containment. One of the central genetic markers consistently associated with control is specific class I HLA molecules, especially HLA-B5701, highlighting the role of potent cytotoxic T cell responses in eliminating HIV-infected cells and restricting the viral reservoir. A significant contribution was also attributed to T helper cells, regulatory T cells and several cell subsets of the innate immune system including natural killer (NK) cells. Studies characterizing viruses from EC found inconsistent results showing both highly mutated viruses with reduced fitness, and virulent, fully replication-competent viruses, leaving open the question of host-mediated control versus intrinsic viral attenuation as the cause for extremely low viral reservoirs in elite controllers. Further understanding of the mechanisms behind spontaneous control of HIV infection is imperative, and might prove important for efforts to develop a prophylactic and therapeutic HIV vaccine. PMID- 24167936 TI - [Leber's hereditary optic neuropathy]. AB - Lebers hereditary optic neuropathy (LHON) is a maternally inherited disease characterized by subacute severe visual loss in both eyes, which usually manifests in young adulthood. The disease has maternal inheritance due to mitochondrial DNA mutation. The final diagnosis is genetic. There is still no proven treatment, but there is significant progress in developments on the genetics of the disease to reach gene therapy. In this article we review the latest literature relevant to this disease. PMID- 24167937 TI - [Use of hypnosis in the treatment of combat post traumatic stress disorder (PTSD)]. AB - Clinical reports and observations going back almost two centuries consistently indicate that hypnotherapy is an effective modality for the treatment of post traumatic stress disorder (PTSD). Pierre Janet was the first clinician to describe the successful initiation of stepwise hypnotic techniques in PTSD symptom reduction. Hypnotherapy may accelerate the formation of a therapeutic alliance and contribute to a positive treatment outcome. Hypnotic techniques may be valuable for patients with PTSD who exhibit symptoms such as anxiety, dissociation, widespread somatoform pain complaints and sleep disturbances. Hypnotic techniques may also facilitate the arduous tasks of working through traumatic memories, increasing coping skills, and promoting a sense of competency. In this review we will present guidelines for the stepwise implementation of hypnotherapy in PTSD. Since most data regarding the use of hypnotherapy in PTSD has been gathered from uncontrolled clinical observations, methodologically sound research demonstrating the efficacy of hypnotic techniques in PTSD is required for hypnotherapy to be officially added to the therapeutic armamentarium for this disorder. PMID- 24167938 TI - [The beginnings of orthopedic surgery in Israel]. AB - In early mandatory Israel, orthopedics was mainly conservative, The first modern orthopedic surgeon was Ernst Spira from Czechoslovakia who established an orthopedic service at the Beilinson Hospital in Petah Tikva and left in 1948 to establish the Orthopedic Department and the Rehabilitation Center in Tel Hashomer, which treated the War of Independence casualties including amputees and victims of spinal cord injuries. A second orthopedic department was opened in Tel Hashomer by Shmuel Weissman who left in 1961 to open the Orthopedic Department at the Ichilov hospital in Tel Aviv. Shmuel Weissman became the first Chairman of Orthopedic Surgery at the Tel Aviv University medical school. In 1955, Myer Makin opened a modern orthopedic department in the Hadassah Hospital in Jerusalem and the Alyn Hospital for crippled children. In 1951, Assaf Harofeh Hospital opened the Department of Orthopedic Surgery headed by Anatol Axer who specialized in the treatment and rehabilitation of polio patients. The majority of the second generation of orthopedic department directors was trained by these four surgeons. Major developments in the 1960s and 1970s were the introduction of the AO system revolutionizing fracture treatment from conservative to operative treatment, the advent of total hip and knee replacements, Harrington instrumentation in spinal surgery and arthroscopy were major advances in orthopedic patient care brought to Israel by the aforementioned second generation of orthopedic surgeons. Hand surgery became an independent subspecialty of orthopedics and was lead by the internationally renowned hand surgeon, Isidore Kessler. PMID- 24167939 TI - [Orbital tumors treated at the University Hospital Otolaryngology Clinic in Krakow between 1997 and 2011]. AB - The main aim of the study was to establish the frequency of orbital tumor occurrence in the patients of the University Hospital Otolaryngology Clinic in Krakow as well as to analyze the clinical features, location in the orbit and to identify the group of patients with the highest risk of orbital tumor. The authors retrospectively analyzed 46 patients (29 women and 17 men) between the ages of 23 and 87. This group of patients was compared to a group of 80 patients who were surgically treated at the same clinic 10 years ago and to a group of 70 patients treated 15 years ago. We established that the tumors localized in the orbit were mainly benign. A variety of histological types of tumors arises in the orbit but it was significant that inflammatory pseudotumors were the most common cases in all three groups of patients treated in our clinic now, about 10 and about 15 years ago. Referring to the group of patients at the highest risk, we established that orbital tumors are definitely most common in women than men. It has turned out to be statistically significant that benign tumors were most common in younger patients and malignant in older people. That suggests the conclusion that being female is a risk factor for orbital tumors and age is a risk factor for them being malignant. Comparing different approaches for the resection of orbital tumors, we established that the lateral orbitotomy provides access to orbital tumors in the most common locations (intraconal and in the top corner of the orbit). Malignant and extensive tumors have to be treated by orbital exenteration. PMID- 24167940 TI - [Evaluation of the impact of symptomatic gastroesophageal reflux disease on the result of surgical treatment with the use of endoscopic techniques and postoperative pharmacological treatment in patients with chronic sinusitis]. AB - It is estimated that in Europe 10% of adults suffer from chronic sinusitis. Chronic sinusitis can be caused by many different diseases that share chronic inflammation of the sinuses as a common symptom. Rhinitis can be caused by stomach acid coming up from the stomach into the esophagus, which successively can result in chronic sinusitis. The current gold standard for diagnosing GERD is -bothersome for the patient--24 h esophageal pH monitoring. This method can be unpleasant for the patients, which makes it less acceptable. Because of that the criteria for symptomatic GERD were made an alternative diagnostic way. We acknowledge that the presence of heartburn and stomach acid coming up from the stomach into the esophagus at least once a week can be diagnosed as symptomatic GERD. The aim of the study is the assessment of the frequency of symptomatic GERD in patients operated because of chronic sinusitis and impact of symptomatic GERD on the follow-up treatment up to 12 months after endoscopic nasal surgery. The authors analysed 144 patients operated at the JUCM Otolaryngological Clinic in Krakow between 2011 and 2013 because of sinusitis. The inclusion criteria were: diagnosed chronic sinusitis, indications for endoscopic sinus surgery, and a written consent for the research. Each patient was examined laryngologically and surveyed. Patients were divided into two groups: with and without symptomatic GERD. We analysed the symptoms in patients treated for sinusitis with or without GERD before, between 3 and 6 as well as in the 12th month after endonasal surgery. Moreover, we analysed the intensity of the global symptoms (expressed in the VAS scale) and separately for each of the 13 symptoms of chronic sinusitis (expressed on a scale 0 - 3). We established that 33 out of the 144 patients (22.9%) qualified for the first survey reported the symptoms of GERD. In the second survey, which was conducted between 3 and 6 month after ESS, 24 out of 119 (20%) people reported the symptoms and in the third survey, which took place in the 12th month after ESS, 14 out of 52 patients reported symptomatic GERD. The intensity of global symptoms rated in the VAS scale in patients with chronic sinusitis during the first survey was 7.8 and in the second and third survey the intensity was 4.2 and 4.3 respectively. But in patients without any symptoms they were 7.4, 2.8, 3.2. We also analysed 13 symptoms of chronic sinusitis rated on a scale 0 - 3. The result of the research was that in patients with symptomatic GERD, even after FESS and the appropriate follow-up, we can still suspect such symptoms as streaming the fluid over the back side of the throat, cough, pain or the feeling of fullness in the ear, headache or halitosis. We should take it under consideration during qualification for the surgery as well as predicting the results of the treatment. Further research is required to state if and how different methods and procedures used in case of patients with symptomatic GERD can reduce the uncomfortable influence of this disease on the effects of chronic sinusitis treatment. PMID- 24167941 TI - [The relationship between serum soluble apoptosis marker (sTRAIL) concentration and nutritional parameters in hemodialyzed patients]. AB - TRAIL (TNF-related apoptosis-inducing ligand) acts as a soluble cytokine interacting with transmembrane receptors belonging to the TNF-receptor family. TRAIL can activate both apoptotic and anti-apoptotic signals. Lower levels of serum sTRAIL were inversely associated with a higher risk of all-cause mortality in CKD population. A strong association between malnutrition, inflammation and atherosclerosis, have been observed in CKD patients. The aim of the study was to investigate the relationship between sTRAIL and nutritional markers and adipose tissue metabolism indices in patients on maintenance hemodialysis. The study was performed in group of 76 patients (36 female and 40 male) of average age 60 +/- 12 years on hemodialysis (74.8 +/- 58.0 months). sTRAIL, leptin and adiponectin were determined by ELISA, BMI based on Quetelet formula and serum albumin level using colorimetric bromokrezol green method. The following values of studied parameters were obtained: sTRAIL = 959.6 +/- 204.0 pg/ml, BMI = 24.5 +/- 4.8, leptin = 36.42 +/- 57.94 ng/ml, adiponectin = 17.55 +/- 10.52 microg/ml, leptin/ adiponectin (x10(-3)) = 2.1 +/- 4.5 and albumin = 38.5 +/- 4.5 g/l. sTRAIL correlate negatively with adiponectin and positively with the remaining studied parameters: BMI, albumin, leptin and leptin/adiponectin ratio. CONCLUSION: The observed interrelations between sTRAIL and nutritional parameters as well as studied adipokines may indicate the modulating role of sTRAIL in metabolic regulation. PMID- 24167942 TI - [Factors influencing on the prevalence frequency of infectious skin changes of bacterial and fungal origin in patients after kidney transplantation]. AB - Infective skin changes are frequent complications in patients after kidney transplantation receiving immunosuppressive therapy. The aim of the study was to evaluate factors influencing on frequency and type of skin infections of bacterial and fungal origin in patients after kidney transplantation. The study was performed in 486 patients, 296 male (60.9%) and 190 female (39.1%) aged 46.1 +/- 13.1 years (18-74 years) 74.3 +/- 52.1 months after kidney transplantation remain mainly on triple immunosupresive therapy. Type, size and localization of skin changes revealed during dermatological evaluation were described according age, sex, and applied immunosuppression. The obtained results were analyzed based on t-Student's, Mann-Whitney's, chi-square and Fisher tests. It was shown that fungal infective skin changes in patients after kidney transplantation are more frequent in older population (48.4 +/- 11.8 vs. 45.2 +/- 13.4 years; p < 0.017). The significant differences concern interdigitale mycoses 49.7 +/- 11.1 vs. 45.4 +/- 13.3 years; p < 0.009, nail mycoses 51.5 +/- 10.4 vs. 45.5 +/- 13.2 years; p < 0,004 and foot mycoses 51.8 +/- 10.7 vs. 45.5 +/- 13.2 years; p < 0.0005. In male more frequent as compare with female were also fungal infections (30.7% vs. 18.4%; p < 0.002) including pityriasis versicolor 37.0% vs. 9.5%; p < 0.016 and interdigitale mycoses 18.6% vs. 9.0%; p < 0.004. CONCLUSIONS: Infective skin changes frequency in patients after kidney transplantation on immunosuppressive therapy depends on advanced age, male sex, and applied immunosuppressive therapy. PMID- 24167943 TI - [Evaluation of trigger finger operative treatment and quality of life improvement with PEM (Patient Evaluation Measure) questionnaire]. AB - One of the most frequent couse of pain and function impairment of the hand is trigger finger. The treatment of this desease can be conservative or operative. The aim of this study was the evaluation of operative treatment and improvement of the quality of life after the procedure with PEM questionnaire. There were 50 patient included into evaluation, all of them were treated in Second Department of Surgery of the Jagiellonian University Medical College between 2008 and 2010. Patients evaluated the function of their hand before surgery and then 3 months and a year after the procedure. There were also the assessment of treatment satisfaction. We analised the results and observed significant improvement of hand function after the surgery and very high satisfaction with the treatment. CONCLUSIONS: 1. Surgery is a very effective treatment method of trigger finger. 2. It is quite simple procedure and followed by very few complications. 3. It allows to significantly improve hand function and early return to work. 4. It can be performed in the outpatient clinic, which considerably reduces the costs of treatment. PMID- 24167944 TI - Neurofeedback therapy in patients with acute and chronic pain syndromes- literature review and own experience. AB - Pain management is based mainly on pharmacotherapy which has many limitations. Non-pharmacological techniques, like neurofeedback (EEG-biofeedback) are alternative methods of pain treatment. Data from literature confirm high efficacy of neurofeedback in pain syndromes treatment, chronic and acute as well. Neurofeedback plays an important role in management of post stroke, post traumatic headaches and in primary headaches like tension type headaches or migraine. Literature review and own experience indicate importance of number and frequency of performed neurofeedback trainings on treatment effectiveness. Satisfactory results have already been observed after 30 trainings however usually 40-60 training have to be performed. Effectiveness of such therapy in pain syndromes is usually good or less often acceptable (50% reduction of headaches). Children with tension type headaches (differently than adults) need reminder therapy every 6-12 months, otherwise recurrence of headaches is observed. Based on our own experience neurofeedback therapy seems to play role in neuropathic pain and cancer pain management. PMID- 24167945 TI - [Homocysteine and its role in pathogenesis of Parkinson's disease and other neurodegenerative disorders]. AB - Homocysteine (Hcy) has recently become the focus of interest in the research on Parkinson's disease (PD) and other neurodegenarative disorders. Chronic treatment with levodopa (LD), considered the standard treatment for PD, leads to an increase in homocysteine concentration in serum and cerebro-spinal fluid. Independently from this effect, homocysteine is also regarded as a marker of neurodegenerative disorders. Main interest was focused on hyperhomocysteinemia (hHcy) as the potential risk factor for atheromatosis. Subsequently, its role in neuropsychiatric diseases, e.g. depression, mild cognitive impairment and dementia was investigated. The potential pathogenic role of Hcy in peripheral neuropathy in patients with PD that are treated with LD is an interesting hypothesis but the literature is scarce. Confirmation of this association may lead to introduction of preventive therapies, e.g. administration of vitamin B and inhibitors of catechol-O-methyl transferase (COMT) that may decrease the Hcy blood concentrations. PMID- 24167946 TI - [Coping with chronic somatic disease according to the concept of psychological stress]. AB - The article presents the problem of coping with chronic disease according to the concept of psychological stress. The Lazarus and Folkman theory in which stress is regarded as a relational concept, the importance of cognitive assessment and functions of coping with disease are described. The attention is paid to the illness perception and its impact on the behavioral and emotional processes. The most known tools for stress assessment and coping with stress and current research directions are shown. PMID- 24167947 TI - [Treatment of depression in patients with epilepsy]. AB - Depression is one of the most frequent comorbid psychiatric disorders in epilepsy. Comorbid depression in epilepsy affects negatively health-related quality of life, increases the risk for suicide and costs of medical care when compared to patients without depression. Unfortunately, affective disorders are underrecognized, and appropriate treatment is infrequent. The purpose of this article is to review strategies used in the pharmacologic treatment of depression in patients with epilepsy, choice of antidepressants, effects of antidepressants on seizure threshold, pharmacokinetic interactions between antidepressant drugs and antiepileptic drugs and psychotropic properties of antiepileptic drugs. PMID- 24167948 TI - [Introduction to human genome sequencing in diagnostics]. AB - The increasing efficiency of genetic analyzers together with the decreasing price of DNA sequencing per single nucleotide read, makes the method of individual genomes sequencing more available for diagnostic laboratories. Nowadays genome sequencing applications are predominantly used for research purposes but in nearest future we will be using them in routine patient evaluation as we are using analytic approaches based on Sanger method now. New generation sequencing is a tool which gives the researchers excellent possibilities for the realization of personalized medicine assumptions. However, before we will be able to make full use of it, there are still some questions to be answered, as for example who should perform the analysis, interpret results and finally who should be responsible for data management. PMID- 24167949 TI - [Natriuretic peptides. History of discovery, chemical structure, mechanism of action and the removal routes. Basis of diagnostic and therapeutic use]. AB - Natriuretic peptides (NP) are the group of proteins synthesized and secreted by the mammalian heart. All the NP are synthesized from prohormones and have 17 amino acid cyclic structures containing two cysteine residues linked by internal disulphide bond. They are characterized by a wide range of actions, mainly through their membrane receptors. The NP regulate the water and electrolyte balance, blood pressure through their diuretic, natriuretic, and relaxating the vascular smooth muscles effects. They also affect the endocrine system and the nervous system. The neurohormonal regulation of blood circulation results are mainly based on antagonism with renin--angiotensin--aldosterone system. The NP representatives are: atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP), C-type natriuretic peptide (CNP), urodilatine and (DNP) Dendroaspis natriuretic peptide, not found in the human body. According to the guidelines of the European Society of Cardiology determination of NT-proBNP level have found a use in the diagnosis of acute and chronic heart failure, risk stratification in acute coronary syndromes and pulmonary embolism. There are reports found in the literature, that demonstrate the usefulness of NT-proBNP determination in valvular, atrial fibrillation, and syncopes. Recombinant human ANP--Carperitid and BNP--Nesiritid, have already found a use in the adjunctive therapy of dyspnea in acute heart failure. PMID- 24167950 TI - [Modern methods of surgical treatment of hallux valgus deformity]. AB - Hallux valgus is the most common deformity of the foot, affecting 2-4% of the population. The disease is mostly genetic, but there are also exogenous factors. Conservative treatment for the use of orthotics is usually ineffective and only surgery leads to a complete cure. The indications for surgery are pain and/or problems with shoe choosing. AP and lateral foot standing X-ray film is necessary for the proper qualifications. Depending on the size of the hallux valgus angle (HVA) and intermetatarsal angle (IMA) deformations are divided into mild, moderate, advanced and severe. In addition, we assess congruency of the first metatarsophalangeal joint (MTP I). Depending on the degree of deformation and the ascertained pathology we combine different procedures, such as: bunionectomy with medial capsulorrhaphy, osteotomy of basal phalanx of the great toe, distal, midshaft or proximal osteotomy of the first metatarsal, double osteotomy of the first metatarsal, MTP I joint arthrodesis and arthrodesis of medial cuneiform first metatarsal I joint. In non-congruent MTP I joint we usually perform lateral release. In some indications we also use arthroplasty and minimally invasive techniques. Only the proper qualification for surgery provides a good clinical effect. PMID- 24167951 TI - [Atypical case of teenager fatal poisoning by butane as a result of gas for lighters inhalation against his will]. AB - Inhalatomania with volatile organic compounds is a still present phenomenon among Polish young adolescents. Conscious, voluntary exposition on such substances may result in serious health consequences, including sudden death in the course of acute intoxication. In this paper, atypical case of death of 16-year-old teenager as a result of complications of physically forced inhalation of gas for lighters is presented. According to testimonies of witnesses, the container was placed in the mouth of victim and the gas was introduced directly to his throat. Autopsy revealed small damage of tooth with corresponding bruising of lower lip; brain and lung oedma; single bruisings in the upper respiratory tract and subpleural. Chemical-toxicological analysis of blood, brain and lung samples taken during autopsy revealed in all of them the presence of n-butan--a component of gas for lighters (the greatest in brain and lung tissues). Additionally, in blood the presence of carboxyhemoglobin (COHb) in concentration 7% was confirmed. Based on the results of analyses, acute intoxication with n-butan was estimated as a cause of death; however the key role played the information obtained during the investigation. This case shows, that deaths resulting from gas for lighters inhalation may be a consequence of forced exposition--against victim's will. So medical staff should always check, if on the body of patient there are any signs of physical constraint (the presence of bruisings in the area of viscerocranium and oral cavity, teeth damages, etc.). PMID- 24167952 TI - [Emil Michalowski Member of the founding Committee of the Polish Urological Society. Biographical note]. PMID- 24167953 TI - Changes in food caused by deep fat frying--a review. AB - Deep-fat frying is widely used in food industries because of its low cost and high demand, since it produces convenient food of high acceptability. The process is based on the oil-food interaction at high temperatures, which cooks and dehydrates the food, leading to physical and chemical changes, such as starch gelatinization, protein denaturation, flavoring and color production via Maillard reaction. Some food and oil compounds are lost in the frying process, and potentially toxic compounds are developed in the oxidized oil. Although widely studied, many of these compounds have not been fully identified. The purpose of this study was to review literature findings on changes in food caused by the frying process. PMID- 24167954 TI - [Impact of risk factors for osteoporosis on bone mineral density in perimenopausal women of the City of Queretaro, Mexico]. AB - It is essential to evaluate osteoporosis risk factors, mainly the modifiable, like the lifestyle, in Mexican women in order to prevent it, since it is a serious public health problem. We studied 805 women (35-55 years old) in the City of Queretaro, Mexico. We obtained: personal data, family history, habits, such as smoking, alcohol, caffeine (coffee and soft drink of cola) and physical activity. Participants complete the questionnaire on 19 risk factors for osteoporosis (International Osteoporosis Foundation) one of them with risk. We evaluated: body mass index (BMI), cardiovascular risk and corporal complexion. Bone densitometry was performed in two diagnostic regions: lumbar spine and total hip and participants were classified as normal bone mass density (BMD), low BMD and osteoporosis. The prevalence of osteoporosis was 7% and of low BMD was 34%, predominantly in the lumbar region and in those with menopause. In osteoporotic women, the age was higher (51 years) and 85% menopausal women, also lower values of weight, height, BMI, waist circumference and hip than women with normal bone mass density. The significantly modifiable risk factors were: low weight, smoking and consumption of soft drink of cola with 6,5, 1,2 and 1,4 (odds ratio), respectively (p < 0.05). The significantly non-modifiable risk factors were: menopause (surgical), history of fracture and risk. It is concluded that within the modifiable risk factors for the prevention ofosteoporosis, those with the greatest impact were low weight, cigarette and soft drink of cola. PMID- 24167955 TI - Prevention of liver steatosis through fish oil supplementation: correlation of oxidative stress with insulin resistance and liver fatty acid content. AB - Non-alcoholic fatty liver disease (NAFLD) is triggered by a nutritional-metabolic alteration characterized by triacylglicerides acumulation, insulin resistance (IR), oxidative stress and depletion of polyunsaturated fatty acid (PUFA). The n 3 PUFA, such as eicosapentaenoic (EPA) and docosahexaenoic (DHA) acids, would be hepatoprotective against the development of NAFLD by stimulating lipolysis and inhibit lipogenesis. So, fish oil supplementation (EPA + DHA) prevents HFD induced NAFLD. In this context, the aim of this study is to evaluate the correlation between liver oxidative stress with IR and levels of PUFA in supplemented mice. Male mice C57BL/6J (n = 9) were fed for 12th week: a) control diet (20% protein, 70% carbohydrate, 10% lipids), b) control diet and fish oil supplementation (200 mg EPA+DHA/kg/day), c) high fat diet (20% protein, 20% carbohydrate, 60% lipids), and d) high fat diet and fish oil supplementation. Liver steatosis (histology), insulin resistance (HOMA), liver oxidative stress (GSH/GSSG, carbonyl protein and 8-isoprostanes) and liver fatty acid content were evaluated. The significant decrease in liver oxidative stress parameters (p < 0.05, ANOVA followed by Newman Keuls test) were correlated (Pearson test) with HOMA and levels of PUFA, along with the hepatoprotection observed. It concludes that prevention of NAFLD by supplementation with fish oil (EPA+DHA) is dependent of the prevention of liver oxidative stress, IR and PUFA depletion. PMID- 24167956 TI - [Effect of a nutrition education intervention on consumption of fruits, vegetables and fish in families of prescholers and scholers]. AB - The objective of this study was to assess the impact of a nutrition education intervention on fruits, vegetables and fish consumption in pre-school and school age children families, through a three months education intervention with a pre post evaluation in 27 intervened families and 32 controls from public schools in Santiago, Chile. A food-frequency questionnaire on fruits, vegetables and fish, and a survey on food and nutrition knowledge, attitudes and practices were applied to children and their parents. The intervention consisted in six 90 minutes cooking workshops, including the utilization of videos and photovoice for those who cooked in the families. Results showed a significant more consumption of fruits, vegetables and fish in the intervened than in the control group (test de Kolmogorov-Smirnov, test de Wilcoxon, p < 0.05). Comparing pre-post consumption by group, significance differences were for the intervened group in all cases. (test de Wilcoxon for paired samples, p < 0.05). In parents, fruit consumption increased 135.8 g, vegetables 19.5 g, and fish 10,2 g per day. In children, the increase in fruits was 92.1 g, vegetables 65.9, and fish 5.2 g per day. All the intervened families (n = 22) introduced a significant healthy food improvement at home. Results showed that it is possible to change food habits in families with the implementation of a nutrition education intervention including cooking workshops, videos and photovoice. PMID- 24167957 TI - [Macronutrients in mature milk of teenagers and adult mothers]. AB - This is a comparative, prospective and non-experimental study that evaluated the level of macronutrients in teenage mothers'mature breastmilk. The sample was represented by mature milk of 52 healthy and eutrophic mothers, divided in two groups: A n = 24 constituted by adolescent mothers's milk among 10 and 18 years and B n = 28 formed by adult mothers's milk among 19 and 35 years who accompanied their children 1-6 months of age hospitalized, from august 2009 to august 2010. The samples were analyzed to determine concentrations of carbohydrates, lipids and proteins. The maternal characteristics of group A and B respectively were: mestizo ethnicity 59.4% and 39.9%, average BMI: were 23.55 +/- 1.01 kg/m2 and 24.2 +/- 0.38 kg/m2. Primiparous were 87.5% in A and 35.7% in B. Age of children aged 1-2 months was 66.6% (A) 71.4% (B). Maternal age: group A 75% had between 16 and 18 years and group B 28.5% were between 19 and 21 years. About macronutrient concentrations, median protein level in A was 1.8 +/- 0.7 g/100 ml and 1.9 +/- 0.7 g/100 ml for B median fat concentration in teenage group was 3.8 +/- 1.5 g/100 ml and in adults 3.9 +/- 1.3 g/100 ml. Median carbohydrates level in teenage was 6.8 +/- 0.8 g/100 ml and in B Group was 6.6 +/- 0.9 g/100 ml, being non statistically significative in all three cases. The macronutrient concentrations and energetic value in teenage mothers's mature breastmilk were similar than the adult mother's milk. PMID- 24167958 TI - [Analysis of the microbiological quality and potential presence of Listeria monocytogenes in custard apple (Annona muricata), mango (Mangifera indica) and passion fruit (Passiflora edulis) pulps from Costa Rica]. AB - The objective of this work was to determine some of the indicators associated to shelf life, hygiene, process and storage conditions for some of custard apple, mango and passion fruit pulps distributed by the main supermarket chains of the Metropolitan Area of San Jose, Costa Rica, as well as to examine the potential presence of Listeria monocytogenes in them. Sixty fruit pulp samples were analyzed. Tests included pH determination, total aerobic plate count, yeasts and mold count, lactic bacteria count, total and fecal most probable number and the presence/absence of Listeria monocytogenes in 25 g of the product. Fruit pulp's pH ranged between 3,1 and 3,9, and the microbiological counts obtained were relatively low except for one industry. None of the samples analyzed presented total or fecal coliforms. The presence of Listeria monocytogenes was confirmed in three samples, all of them coming from industry C. Low microbiological counts obtained may be due to the addition of preserving substances and to the pasteurization of some of the products; lack of these two elements may allow the presence of dangerous bacteria such as Listeria monocytogenes. PMID- 24167959 TI - Viability of probiotic Lactobacillus casei in yoghurt: defining the best processing step to its addition. AB - Probiotics are live microorganisms capable of producing beneficial effects on its host when consumed in adequate amounts. To exert these effects, foods must contain probiotic microorganisms in populations above 10(6) CFU/g or mL throughout its shelf life. One of the strategies to ensure high population of probiotics in fermented milk is to add them during or after the fermentation process separately from the starter cultures. The objective of this study was to investigate the behavior of the probiotic microorganism Lactobacillus casei added to yoghurt in different stages of production. Yoghurts with L. casei were produced at different stages: before addition of starter (Streptococcus salivarius subsp. thermophilus and Lactobacillus delbrueckii subsp. bulgaricus), added together with this culture and at the end of fermentation. Yoghurt without probiotic added was produced as a control. The products were stored at 4 degrees C and analyzed after 1, 7, 14 and 21 days of storage. In these periods, the populations ofprobiotic and starter cultures were enumerated and the parameters pH and acidity were analyzed. The results were evaluated using analysis of variance and Tukey's test, both at 5% significance level. L. casei remained viable in populations of more than 10(8) CFU / g during 21 days of storage, which is suitable to define the formulations as probiotics. When the different stages of the addition of probiotics in yoghurts were evaluated there was no statistical difference between the formulations (p < 0.05) for populations of L. casei except for the first day of storage. PMID- 24167960 TI - Iron bioavailability in Wistar rats fed with fortified rice by Ultra Rice technology with or without addition of yacon flour (Smallanthus sonchifolius). AB - This study aimed to evaluate iron (Fe) bioavailability in Wistar rats fed with rice fortified with micronized ferric pyrophosphate (FP) by Ultra Rice (UR) technology with or without addition of yacon flour as a source of 7.5% of fructooligosaccharides (FOS). Diets were supplied with 12 mg iron/kg from the following sources: ferrous sulfate (FS - control diet), fortified rice with micronized ferric pyrophosphate (Ultra Rice) (UR diet), ferrous sulfate + yacon flour (FS + Y diet) or Ultra Rice + yacon flour (UR + Y diet). Blood samples were collected at the end of depletion and repletion stages for determination of hemoglobin concentration and calculation of the relative biological value (RBV). Also, the content of short chain fatty acids (SCFA) (acetic, propionic and butyric acids) from animals' stools and caecum weight were determined. The UR diet showed high iron bioavailability (RBV = 84.7%). However, the addition of yacon flour in the diet containing fortified rice (UR + Y diet) decreased RBV (63.1%) significantly below the other three groups (p < 0.05). Groups that received yacon flour showed higher acetic acid values compared to those who did not. In conclusion, fortified UR with micronized ferric pyrophosphate showed high iron bioavailability but the addition of yacon flour at 7.5% FOS reduced iron bioavailability despite increased caecum weight and SCFA concentration. PMID- 24167961 TI - [Fatty acid variation in yellowfin tuna, spotted weakfish and Florida pompano when submitted to six cooking techniques]. AB - The aim of the present study was to analyze the effect of six cooking techniques (steamed, foiled, foiled with banana leaf, baked, microwave-cooked and light frying) in the fatty acid content of Thunnus albacore (yellowfin tuna), Cynoscionnebulosus (spotted weakfish) and Trachinotuscarolinus (Florida pompano). After cooking the fish fillets, fatty acid analyses were performed using gas chromatography. Total lipids increased in all cooking techniques in tunaand spotted weakfish. Saturated fatty acids of tuna and spotted weakfish increased in three cooking techniques, while in Florida pompano only gas oven raised their content. Lightly frying generated the highest content of n-3 in tuna and spotted weakfish, and the lowest in Florida pompano, specie that presented less variation. In tuna fish, the most recommended cooking techniques are foiled with aluminum and microwave oven; for spotted weakfish, foiled with banana leaf; while Florida pompano can be prepared using all cooking methods except gas oven. This information is useful to enrich data from chemical composition tables, in which concentrations are usually presented in raw food. PMID- 24167962 TI - Antioxidant capacity, phenolic acids and caffeine contents of some commercial coffees available on the Romanian market. AB - In the present study a simple and highly sensitive RP-HPLC method has been established for simultaneous determination of chlorogenic acid, caffeic acid, vanillic acid and caffeine in coffee samples. The method has been applied to eight different coffees available on the Romanian market which were previously analysed concerning the total polyphenols content and antioxidant capacity. Reduction of the DPPH radical was used to determine the antioxidant capacity of the coffee extracts while the total polyphenols content was determined by spectrophotometry (Folin Ciocalteu's method). The total polyphenols content ranged from 1.98 g GAE/100 g to 4.19 g GAE/100 g while the caffeine content ranged from 1.89 g/100 g to 3.05 g/100 g. A large variability was observed in chlorogenic acid content of the investigated coffee samples which ranged between 0.6 and 2.32 g/100 g. PMID- 24167963 TI - [Descriptive phenomenological study: visual perception metamorphosis precedes schizophrenic onset]. AB - In this study, descriptive phenomenological analysis was performed on visual perception metamorphosis of 24 people with schizophrenia not taking antipsychotics. There have been various statements from patients on this matter, and we categorized them into 9 groups and examined them. The results suggest that these phenomena could be understood as dysfunction of the autonomic nervous system, a decrease of loss of eye movement, and dysfunction of convergence, such as: 1) wearing thick-lensed glasses, 2) a stabilized retinal image, and 3) a stereogram. These phenomena also occur in healthy individuals under certain conditions; therefore, the results revealed commonalities between healthy individuals and schizophrenic patients. Moreover, the accessory oculomotor nucleus (Edinger-Westphal), superior colliculus, and midbrain are individually considered to cause these phenomena as part of the central nervous system. Although the aim of this study is not to discuss the localization of these phenomena, the area from the midbrain to basal ganglion is a lower system than the cerebrum, which is inconsistent with recent studies on the psychopathology of schizophrenia viewing it as a defect of the cerebrum. PMID- 24167964 TI - [Survey regarding mental health conditions of high school students and attitudes of students and their teachers toward students' mental health issues]. AB - We administered a self-reporting questionnaire survey regarding the mental health conditions of high school students and attitudes of students and their teachers toward students' mental health issues. In addition, we discussed the requirements for high school students' mental health support system. The subjects were 3,312 students and 208 teachers in four Shizuoka prefectural public high schools in 2009. University Personality Inventory (UPI) is usually conducted to assess university students' mental state and is a questionnaire that high school students can answer easily. Therefore, we adopted UPI for this survey. UPI was composed of 56 unhealthy and 4 healthy condition items. High school students completed the UPI and determined the sum of unhealthy condition items; a higher score indicated a poorer mental health status. The average UPI score of all students (n = 3,312) was 12.7 points, and that of females (n = 1,217)was 15.2 points, which was significantly higher than the 11.3 points of males (n = 2,095). Those with scores > or = 30 points (7.5%), which was more than half of the maximum score, were designated as the High Score (HS) group and considered to have poor mental health. Those with scores of > or = 40 (1.4%) seemed to have very poor mental health, and there was concern that they may be suffering from psychosis. Our observations indicated that HS students were likely to avoid seeking help regarding mental health issues, which was especially true for male HS students. The majority of students chose their friends and parents as advisers, but HS students were significantly more likely to choose advisers who were engaged in jobs related to medical work. Students in both the HS and non-HS groups who did not wish to consult anyone else about their mental conditions wanted to be approached by those around them. High school teachers hesitated to intervene with mentally disturbed students and attempted to resolve problems within the school. Thus, it appears necessary for families, school teachers, and psychiatrists to build closer relations with each other to promote mental health among high school students. PMID- 24167965 TI - [Recent topics in neurophysiological studies of patients with schizophrenia]. AB - It has been suggested that psychotic symptoms of schizophrenia are associated with brain dysfunction at least to some extent. This article overviewed hot topics in neurophysiological studies of patients with schizophrenia. Moreover, it focused on recent findings in electroencephalography and magnetoencephalography. First, the author introduced auditory mismatch negativities (MMN), auditory P300, face N170, and gamma band neural oscillations. Findings of MMN and P300 supported schizophrenia being characterized by brain dysfunctions, some of which occur before full symptom onset and some progress in the 1-2 years after onset. In addition, neurophysiological indices for social dysfunction may lead to new preventive approaches. Finally, neural oscillations are possible translational paradigms, since they can be recorded from animals, healthy subjects, and patients with schizophrenia. To understand the pathophysiology of schizophrenia, neurophysiological efforts are important. PMID- 24167966 TI - [Characteristics of single event-related cerebral hemodynamics during verbal task in emotionally charged state measured by multi-channel near-infrared spectroscopy (NIRS) in patients with schizophrenia: comparison with healthy subjects]. AB - Neared infrared spectroscopy (NIRS) is one of the recently developed methodologies which can measure cerebral blood volumes to determine the blood hemoglobin (Hb) concentration simultaneously at multiple points with marked time resolution. Monitoring the changes in the Hb concentration yields site-specific readings on blood flow and, thus, on neural activities. The aim of this study was to examine the characteristics of a single event-related oxyhemoglobin concentration [oxy-Hb] changes in patients with schizophrenia using multi-channel NIRS during a word generation task, Japanese 'Shiritori', and single-word generation task in an emotionally charged state induced by three facial expressions of "crying", "neutral", and "smiling" babies' photographs. Thirty four patients with schizophrenia and 34 age-matched healthy controls participated in the present study after giving consent. In healthy controls, [oxy-Hb] changes when viewing the "crying" baby's photograph were significantly larger than when viewing the "smiling" baby's photograph. On the other hand, in patients with schizophrenia, [oxy-Hb] changes when viewing the "smiling" baby's photograph were significantly larger than when viewing the "crying" baby's photograph. These results suggest that cautions/execution functions in patients with schizophrenia during the single event word "Shiritori" task measured by multi-channel NIRS were impaired. It was also suggested that, in patients with schizophrenia, the affective reaction influenced by each photograph may be different from healthy controls (mismatch). Multi-channel NIRS can be a useful tool for research and clinical purposes in psychiatry. PMID- 24167967 TI - [Clinical status and outcome biomarkers in schizophrenia: a review for near infrared spectroscopy studies]. AB - Neuroimaging technologies have seen enormous progress during the past two decades, and are now able to provide detailed illustrations of brain structure and activity. As a result, our understanding of the pathophysiology of mental illnesses such as schizophrenia has expanded, and potential clinical applications are becoming apparent. Unlike most physical illnesses, mental illnesses often lack objective markers, and this is one of the reasons why some patients and their family members experience difficulty in understanding symptoms and disabilities. In some cases, this leads to delays in patients seeking treatment, discontinuation of treatment, and relapse. If biological markers can be utilized as aids in differential diagnosis, selection of treatment options, and assessment of severity and treatment response in clinical settings, they may lead to improved treatment quality and clinical outcomes. Near-infrared spectroscopy (NIRS) is a functional neuroimaging technique that may be a candidate for clinical application in psychiatry. Advantages of NIRS include: 1) its non invasive nature, with no harmful impact resulting from repeated measurement, even in infants; 2) high temporal resolution (> 10 Hz); 3) compact size, enabling easy movement; and 4) no required restraint position: people undergoing testing may take a natural position, such as sitting or standing, and may converse and perform manual tasks during measurement. Previous NIRS studies have revealed different characteristic waveform patterns during verbal fluency tasks among patients with major depression, bipolar disorder, and schizophrenia, which led to government approval in 2009 as an "advanced medical technology to aid in the differential diagnosis of depressive symptoms." This was the first approval in the field of psychiatry in Japan. Future NIRS studies will focus more on clinical applications, and multi-site studies are needed to assess the impact of non illness factors such as age, sex, and head size, in addition to factors related to illness, including differences in sub-type diagnosis, severity of symptoms, and treatment. It is hoped that findings will support the development of new biomarkers that will facilitate differential diagnosis, better understanding of present conditions and prognosis, and decisions regarding treatment options. PMID- 24167968 TI - [Progress in MRI studies of the schizophrenia spectrum]. AB - Morphologic brain imaging studies using magnetic resonance imaging (MRI) have demonstrated gray matter reduction in the frontal and temporolimbic-paralimbic regions in schizophrenia. Although the causes as well as timing and course of these morphologic changes remain elusive, these changes might at least partly reflect early neurodevelopmental abnormalities. On the other hand, longitudinal MRI studies suggest that patients with schizophrenia and other psychoses also show progressive brain morphologic changes during the transition period as well as initial period after the onset of florid psychosis. Recently, increasing evidence based on MRI findings in individuals at risk of developing psychosis (at risk mental state: ARMS) suggests that ARMS subjects who subsequently develop psychosis show baseline brain changes, which could be at least partly predictive of later transition. In this article, we review recent findings in ARMS and our own neuroimaging findings regarding the schizophrenia spectrum. We also refer to remaining issues to be addressed before applying these neuroimaging research findings in a clinical setting. PMID- 24167969 TI - [Connectivity analyses of white matters in schizophrenia]. AB - Investigation of brain morphology in schizophrenia has improved by the advance of magnetic resonance imaging (MRI). Recently, pathology of white matter has been extensively investigated from the viewpoint of disconnection hypotheses of schizophrenia. Diffusion tensor imaging (DTI) technique enables us to evaluate the integrity of white matter tracts, using indices including fractional anisotropy (FA). The authors revealed that the integrity of white matter is decreased in widespread regions, compared with healthy controls. The mean FA value of the whole white matter skeleton was significantly lower and correlated with global mean cortical thicknesses in schizophrenia. And in the regional level, the mean FA value of the right thalamo-orbitofrontal pathway was significantly lower and correlated with the thicknesses of the right frontal polar and lateral orbitofrontal cortices in schizophrenia. The corresponding correlation was not found in healthy subjects. These findings, corroborating recent molecular genetic and post-mortem findings, suggest the intertwined nature of gray and white matter pathology of schizophrenia. PMID- 24167971 TI - ["Please let my colleagues concentrate on their job": a plea from a professor of gastroenterological surgery]. PMID- 24167970 TI - [Review of placebo effect and re-evaluation of psychotherapy focusing on depressive disorders]. AB - It is well known that based on the findings of double-blind studies of antidepressants, placebos have an unexpected positive effect on depression. Neuroimaging studies comparing the effect of antidepressants and placebos by means of PET revealed that both placebo and fluoxetine treatment induced regional metabolic increases in such areas as the prefrontal and posterior cingulate, and metabolic decreases in such areas as the subgenual and thalamus. It is indicated that placebos have a similar pharmacological effect as antidepressants (Mayberg et al., 2002). This biological finding strongly suggests that when a patient takes an antidepressant administered by a doctor, and the treatment is effective, a placebo effect is always implicitly appended to any pharmacological effect of the medicine. In other words, the overall curative effect by administration of antidepressants can be schematically expressed as follows: Overall curative effect by antidepressant = Effect specific to pharmacotherapy + Placebo effect. In this case, the placebo effect is based on the patient's expectation and hope of recovery that is working consciously, preconsciously, and unconsciously; it is an essential condition that the patient has confidence and an expectation that the medicine will work. Such linguistic elements and subjective factors help to correct the metabolism of the cranial nerve system that was changed by depression, and thus encourages a cycle of resilience to restore the system to its former healthy state. This mechanism can be considered to operate as a top down system. As easily inferred from the fact that the placebo effect is made up of a linguistic element and an emotional element found in the doctor-patient relationship, the formation of the doctor-patient relationship itself can be considered to be by tacit consent effective as a kind of psychotherapy. A brief look at the recent biological studies on the placebo effect lends support to the possibility that even one word spoken by a physician to a patient may bring about an effect that corrects any neurotic malfunction inside the brain. This paper indicates that non-pharmacotherapy such as psychotherapy or psychological and social support may have a similar effect to the administration of actual medicines that directly work on neurotransmitters in the brain. PMID- 24167972 TI - [Establishment of committee on preparing a guideline for cadaver usage for education and research in clinical medicine]. PMID- 24167973 TI - [Up-to-date scientific evidence on Kampo for surgeons]. PMID- 24167974 TI - [Effectiveness and motion mechanism of Taikencyuto in the perioperative period]. AB - Taikencyuto (TJ-100) is a Japanese herbal (Kampo) medicine that contains Zanthouxylum and piperitum, Zingiber officinale, Panax ginseng, and Saccharum granorum. TJ-100 enhances intestinal motility, is thought to promote acetylcholine and motilin release, and is a vanilloid receptor. Furthermore, TJ 100 increases intestinal blood flow and works as an antiinflammatory and anticytokine agent by producing calcitonin gene-related peptide and adrenomedullin. TJ-100 is considered to be useful for promoting intestinal motility and preventing ileus during the perioperative period. Further studies must be performed to confirm its usefulness in perioperative care. PMID- 24167975 TI - [Effects of rikkunshito on postoperative anorexia]. AB - Rikkunshito is a traditional Japanese medicine used to treat a variety of gastrointestinal symptoms. In several previous studies, it was demonstrated that rikkunshito stimulates gastrointestinal movement, accelerates gastric emptying, and promotes gastric adaptive relaxation. Clinically, it is known that rikkunshito attenuates dyspeptic symptoms, appetite loss, and gastroesophageal reflux after gastrointestinal surgery and in chemotherapy-induced nausea and anorexia. A recent study has demonstrated that rikkunshito affects the appetite enhancing hormone ghrelin. Rikkunshito was also reported to increase plasma ghrelin levels and to enhance the action of ghrelin. Rikkunshito may alleviate dyspeptic symptoms after gastrointestinal surgery through its prokinetic effects and ghrelin. PMID- 24167976 TI - [Effects of a Kampo medicine on postoperative infection]. AB - We studied the effects of preoperative administration of Hochuekkito (TJ-41) on the host response of patients undergoing gastrectomy or colectomy in a prospective, randomized, multicenter clinical trial. Forty-eight patients were randomized into two groups: one received 7.5 g/day of TJ-41 for 7 days before surgery (n = 22); and the other served as the control group (n = 26). The body temperature and pulse rate in patients in the TJ41 group were significantly better controlled during the study compared with those in the control group. The concentration of serum cortisol on the first postoperative day in the TJ-41 group was also significantly lower compared with that in the control group. These results clearly indicate that the preoperative administration of TJ-41 may ameliorate an excessive postoperative inflammatory response and prolonged immunosuppressed state, resulting in fewer postoperative infectious complications. PMID- 24167977 TI - [Kampo medicine in the pediatric surgical field]. AB - Kampo medicine has been used for over 4,000 years. Recently, some Kampo formulas have been prescribed for postoperative pediatric patients with gastrointestinal anomalies and disease. However, it has been only 30 years since Kampo medicine has been widely used in the pediatric surgical field. Some of the principal Kampo formulas used for daily treatment in the pediatric surgical field are: Rikkunshito and Bukuryouin-Gou-Hangekoubokuto for patients after upper gastrointestinal surgery; Daikenchuto for patients after colorectal surgery; Inchinkoto for postoperative patients with biliary atresia; and Hainosankyuto for periproctal abscess. Kampo formulas according to the postoperative condition are reviewed from the viewpoint of evidence-based medicine, our experience, and experiments. The results of the Kampo treatments listed above were superior to the results when a Kampo formula was not administered in pediatric patients postoperatively. PMID- 24167978 TI - [Kampo medicine for the treatment of adverse effects caused by anticancer drugs]. AB - In contrast to conventional single-target drugs, multicomponent Kampo medicines are designed to achieve therapeutic effects through multiple drug targets. This article discusses recent advances in mechanistic studies and the clinical effects of eight representative Kampo formulations (Rikkunshito, Hangeshashinto, Daikenchuto, Goshajinkigan, Yokukansan, and the tonics Hochuekkito, Juzentaihoto, and Ninjinyoeito) for the treatment of adverse effects caused by anticancer drugs such as anorexia, oral mucositis, diarrhea, neurotoxicity, abnormal behavior, malaise, weakness, and thrombocytopenia, which Western pharmaceuticals fail to address adequately. PMID- 24167979 TI - [Beneficial effects of preoperative administration of Inchinkoto in patients undergoing major hepatectomy]. AB - Inchinkoto (ICKT) is one of the most commonly used herbal medicines and is a hepatoprotective agent. Among the numerous chemical compounds included in ICKT, geniposide is the most abundant component. After oral intake, geniposide is converted into the active metabolite genipin by intestinal bacteria and absorbed in the portal circulation. The biological properties of ICKT and its major active ingredient genipin have been studied in numerous experiments using cells and animals. ICKT or genipin administration exerts a choleretic effect through upregulation of multidrug resistance-associated protein 2 in hepatocytes. ICKT also exerts antiapoptoic activity by inhibiting the transforming growth factor beta 1- or tumor necrosis factor alpha-dependent signaling pathway. The excessive inflammatory response induced by various forms of hepatic stress is also attenuated by ICKT preadministration. Proinflammatory cytokine-induced upregulation of inducible nitric oxide synthase is strongly attenuated by ICKT in both in vivo and in vitro experiments. Moreover, ICKT enhances antioxidant enzymes in the liver under oxidative stress. These experimental results clearly indicate the effects of ICKT on hepatic stress. To date, however, clinical data on the benefits of ICKT for liver disease are very rare. To extend the clinical applications of ICKT in humans, it is crucial to design and perform a rigorous clinical trial. In this review article, recent evidence relating to the hepatoprotective effects of ICKT in the field of basic and clinical science is summarized and discussed. PMID- 24167980 TI - [Current status and future perspective of cancer immunotherapy]. PMID- 24167981 TI - [Current status and future perspective of cancer immunotherapy--basic understanding of tumor immunology]. PMID- 24167982 TI - [What we can learn from a case of medical malpractice--compensation was awarded to the plaintiff for the pain and suffering that resulted from the defendent's failure to provide a full explanation of the cutting-edge treatment, regardless of whether the advanced procedure was indicated for the plaintiff's condition]. PMID- 24167983 TI - [Lobectomy with pulmonary angioplasty]. PMID- 24167984 TI - [The consciousness research about the business expanding of nurse in pediatric cardiology]. PMID- 24167985 TI - [Present status and problems of a female gastrointestinal surgeon working at acute care hospital while raising a preschool child]. PMID- 24167986 TI - [Endoscopic reconstruction skull base using pedicled nasoseptal flap and its anatomy measurement]. AB - OBJECTIVE: The harvesting procedures on cadaver heads and a radioanatomic study of measuring dimensions of skull base by endoscopic endonasal approach were performed. The measurements could do help to design the nasoseptal mucoperiosteum and improve the rate of repair success. METHOD: The surgical procedures were demonstrated on cadaver heads specimens. Then 20 adult CT scans of sinus and skull base were calculated by workstations. The dimensions of three different skull base (the defect of anterior skull base/cribriform plate approach, sellar region/planum sphenoidale region and clivus region) of maximum areas, length and width, were measured. And with these data the nasoseptal flap were designed for providing enough area to cover the defect. The distance from the projection of sphenopalatine foramen to related area of skull base were plused for obtaining desired the length of nasoseptal flap. RESULT: The mean length from the projection of sphenopalatine to the anterior skull base, planum/sella area and clivus were 49.56 mm, 57.47 and 67.19 mm, respectively. The means of areas of anterior dural defect, transsellar defect and panclivectomy were 16.13 cm2, 14.03 cm2 and 13.12 cm2, respectively. The average length of the nasoseptal flap ranged between 64.71-65.93 mm, the width ranged between 28.57-30.95 mm with an average area of 22.95 cm2. CONCLUSION: One side of nasal septal flap can provide enough area to reconstruct the anterior skull base and planum/sella area. In some cases, the flap can not completely cover the area of clivus region because of the limitation of its length. PMID- 24167987 TI - [Trans-sphenoid sinus-clivus endoscopic management of petrous apex cholesterol granuloma]. AB - OBJECTIVE: To explore the endoscopic management of petrous apex cholesterol granuloma through trans-sphenoid sinus-clivus approach. METHOD: One case of right side petrous apex cholesterol granuloma were undertaken surgical treatment through trans-sphenoid sinus-clivus approach, then the possibility of any other approach and their advantages and disadvantages were analyzed. RESULT: The operation was success without any complications. Patient's hearing was recovered and tinnitus vanished. The patient was discharge from hospital at the third day after operation, and followed up for four month without recurrence. CONCLUSION: Trans-sphenoid sinus clivus endoscopic management of petrous apex cholesterol granuloma is effective and safe. The operators can monitor internal carotid artery then to access to the diseased region with reducing risk. PMID- 24167988 TI - [Two surgical approaches for treating post-traumatic external nasal deformity and nasal septal deviation]. AB - OBJECTIVE: To investigate the nasal functional reconstructive methods for post traumatic external nasal deformity and nasal septal deviation, and to evaluate the efficacy of surgical treatment. METHOD: (1) Twelve patients with C-type external nasal deviation were choose undertaking L-shaped incision of the interface of left nasal septal skin and mucosa as well as bilateral inter cartilaginous incision using endoscopy which named close group; (2) 5 patients with S-type and 10 patients with side-skew-type external nasal deviation patients were choose undertaking trans-columella inversed-V incision as well as bilateral infra-cartilaginous incision viewing directly which named open group. Both of the groups undertook nasal septal reconstruction surgery and rhinoplasty with autologous nasal septal cartilage grafts. RESULT: During the follow-up period, both groups were satisfied with the functional and aesthetic outcome, while with no recurrence of symptoms and complications. No significant differences were found between the two groups. CONCLUSION: Autologous nasal septal cartilage and bone are the best filling grafts for cosmetic rhinoplasty. Rhinoplasty with simultaneous nasal septum surgery can reconstruct nasal function and appearance. PMID- 24167989 TI - [Clinical analysis and review of 8 cases with sinonasal neuroendocrine carcinoma]. AB - OBJECTIVE: To study the diagnosis, treatment and prognosis of sinonasal neuroendocrine carcinoma. METHOD: Eight patients with sinonasal neuroendocrine carcinoma from February 2009 to February 2012 were retrospectively analyzed and the related literatures were reviewed. RESULT: There were seven males and one female. Three cases were treated by surgery only, one case received surgery followed by radiotherapy, and four cases were treated by combined treatment (surgery followed by radiotherapy and chemotherapy). There were three patients with a primary tumor originating from the maxillary sinus, two cases died after 8 and 14 months, another patient was survived in 10 months of follow-up, and the carcinomas did not recur. There were five patients with primary neuroendocrine carcinoma from the nasal cavity, one patient recurred after the surgery and after radiotherapy, the patient did not recur after 20 months of follow-up, and the other four patients did not recur, in 13, 20, 27 and 28 months of follow-up. CONCLUSION: Neuroendocrine carcinomas of the sinuses are rare malignant tumors. Neuroendocrine carcinomas cases with the lesions at different sites differ in the clinical manifestations and prognosis, pathology, immunocytochemistry and electron microscopy, It should be differentiated from poorly differentiated squamous carcinoma melanoma, olfactory nerve blastoma and neurospongioma. The key to improve the survival rate of the disease is early accurate diagnosis and combined treatment. PMID- 24167990 TI - [Clinical analysis of nasal mucosa contact headache]. AB - OBJECTIVE: To investigate the efficacy of nasal mucosa contact point headache with the treatment of endoscopic sinus surgery. METHOD: Clinical data of 75 cases with nasal mucosa contact point headache treated in our department from Jan 2008 to Nov 2011 were retrospectively analyzed. These patients were performed with endoscopic sinus surgery. RESULT: All patients were followed up for more than six months. They all achieved significant efficacy and no complications occurred. CONCLUSION: Nasal mucosa contact point headache and primary headache had different clinical features and different treatment. Misdiagnosis were easily made if not being carefully analyzed. Three lines tension relaxing septorhinoplasty combined with nasal bone fracture correction can achieve satisfactory curative effect and can effectively prevent the occurrence of complications. Therefore, it is necessary to strengthen the awareness of this disease. Nasal structure abnormality is the main reason of nasal mucosa contact point headache. The implementation of individualized nasal endoscopic sinus surgery can achieve satisfactory curative effect. PMID- 24167991 TI - [Diagnosis and treatment of the complex fracture of the maxillary and nasal bone]. AB - OBJECTIVE: To explore the effect of surgical treatment for compound fracture of nasal bone and frontal process of maxilla with endoscopy and small local incision. METHOD: Twenty-two cases with compound fracture of nasal bone and frontal process of maxilla were treated with surgery, and the postoperative effect were analysed. RESULT: Twenty-two cases healed well. CONCLUSION: CT scan and 3D reconstruction before operation can help the diagnosis. Corresponding incision and assisted endoscopy can make good surgical field and achieve surgical success. Rigid internal fixation is also the key for surgical success. PMID- 24167992 TI - [Comparation of low-temperature plasm radiofrequency and high-intensity focused ultrasound therapy on allergic rhinitis patients with nasal septal deviation]. AB - OBJECTIVE: To compare the therapeutic effects of low-temperature plasm radiofrequency and high-intensity focused ultrasound in treatment of perennial allergic rhinitis (PAR) complicated with nasal septum deviation. METHOD: A total of 224 cases of identified PAR who treated in our hospital were randomly divided into 2 matched groups: low-temperature plasm radiofrequency group (n = 140) and high-intensity focused ultrasound group (n = 84). The therapeutic affection were evaluated by clinical symptoms controlled counting-scores. Inferior turbinate mucosa were collected and examined pathologically before and at 15 days and 6 months after the therapy. RESULT: The follow-up data indicated the effective rate in 15 days was 97.1% in high-intensity focused ultrasound group, and 90.4% in low temperature plasm radiofrequency group, in 6 months was 90.7% and 85.4% respectively. CONCLUSION: The treatment of high-intensity focused ultrasound in PAR is minimally invasive and safe with reliable efficacy. PMID- 24167993 TI - [Clinical research of transoral endoscopic adenoidectomy on the treatment of the adenoid hypertrophy children with chronic sinusitis]. AB - OBJECTIVE: To determine the clinical value of transoral endoscopic adenoidectomy for the pediatric sinusitis. METHOD: Patients with chronic sinusitis and adenoid hypertrophy were divided into two group by undertaken with or without adenoidectomy, the operation group with 43 cases and the control group with 40 cases. Evaluation was performed in pretherapy and after 3 months therapy. Evaluation index included symptom scale for nasal obstruction and rhinorrhea, endoscopy score and CT score for chronic sinusitis. RESULT: There was a positive correlation (0.38) between the adenoid size and the symptom of nasal obstruction (P < 0.01). But there were no correlation between the adenoid size and the other index scores (P > 0.05). Whether in the operation group or the control group, all index scores in pretherapy were higher than in post-therapy (P < 0.05). After 3 month therapy, all index scores in the operation group were lower than the control group (P < 0.01). The decreased amplitude of all index scores in the the operation group were higher than the control group (P < 0.01). CONCLUSION: Adenoidectomy combined with topical nasal treatment is one effective method for the pediatric sinusitis. Adenoidectomy play an important role in the treatment of pediatric rhinosinusitis. PMID- 24167994 TI - [Radiofrequency coblation of tongue channeling for supine position associated obstructive sleep apnea]. AB - OBJECTIVE: To assess the effect of low-temperature radiofrequency coblation of tongue Channeling for supine position associated OSAHS. METHOD: One thousand and three hundred eighty one patients with OSAHS were examined and treated with radiofrequency coblation of tongue channeling. Polysomnography was performed before and one year after the surgery. Visual analogue scale was performed to assess the postoperative function of speech and swallowing, Scores of quality of life and sleepiness scale to evaluate the effectiveness of the surgery. RESULT: One year after the surgery, the patients were obviously relieved with sleep snoring, arousal and daytime sleepiness symptoms as swallowing and speech function was not affected. AHI with supine position was reduced by an average of 27.1 times/h and the minimum postoperative O2 saturation was significantly increased. SF-36 health questionnaire survey showed that social function and mental health dimension scores were significantly higher than the preoperative. CONCLUSION: Radiofrequency coblation of tongue channeling is an applicable method of therapy for patients who have sleep apnea that is more marked in the supine position. PMID- 24167995 TI - [Screening and mass spectrometry analysis of differentially expressed proteins of plasm between laryngocarcinoma and healthy individuals]. AB - OBJECTIVE: To compare and analyze the expression difference of proteins between laryngocarcinoma and healthy individuals to search for protein biomarkers that may be detected in plasm of laryngocarcinoma patients. METHOD: Pooled plasm from 6 laryngocarcinoma patients and 6 healthy individuals as controls were collected. Two-dimensional gel electrophoresis (2-DE) was used to isolate the total proteins, and the differential protein spots were identified by MALDI-TOF/TOF mass spectrometer, and then the biological information of the proteins was analyzed. RESULT: Twenty differential expressed protein spots with more than 1.5 fold between the laryngocarcinoma and healthy individuals were selected, and there were 8 proteins upregulated and 12 proteins downregulated among these proteins. After identifying by MALDI-TOF/TOF, compared with healthy controls, the spots that were L1, C-reactive protein, haptoglobin, ceruloplasmin; the spots that were downregulated were: Serotransferrin, alpha-2-HS-glycoprotein, fibrinogen gamma chain, haptoglobin related protein, Ig lambda-1 chain C regions, Ig kappa chain C region, apolipoprotein A-I, transthyretin, apolipoprotein C-III. CONCLUSION: Compared with laryngocarcinoma and healthy individuals, the plasm proteins profile showed differently. The proteins of differential expressed are expected to be the specific plasm biomarkers for laryngocarcinoma patients. PMID- 24167996 TI - [Electrocochleographic findings in recurrent idiopathic sudden sensorineural hearing loss]. PMID- 24167997 TI - [Expression of IL-17 in laryngeal squamous cell carcinoma tissues and the clinical significance]. AB - OBJECTIVE: To investigate the expression of interleukin 17 in laryngeal squamous cell carcinoma tissues, and to evaluate the value of interleukin-17 in the biological behavior and prognosis of laryngeal squamous cell carcinoma. METHOD: Expressions of IL-17 were analyzed in 71 laryngeal squamous cell carcinoma samples and 21 cases of adjacent tissues of carcinoma as control by immunohistochemistry. RESULT: The expression of IL-17 in laryngeal squamous cell carcinoma tissues was obviously higher than that in adjacent tissues (P < 0.05). The expression of IL-17 was associated with tumor T staging, tumor differentiation, regional lymph node metastasis, distant metastasis and recurrence (P < 0.05). Log-rank test showed that the prognosis of patients was related to the primary tumor site, tumor stage, regional lymph node metastasis, distant metastasis and IL-17 expression (P < 0.05), While Cox multiple factors analysis showed that IL-17 was not an independent prognostic factors. CONCLUSION: The expression of IL-17 may be the vital index in laryngeal squamous cell carcinoma, and it can provide some theoretical basis for the anti-tumor immunotherapy for laryngeal squamous cell carcinoma. PMID- 24167998 TI - [Diagnosis and treatment of fungal ball rhino-sinusitis]. AB - OBJECTIVE: To explore the diagnosis and treatment of the fungal ball rhino sinusitis. METHOD: The clinical data of 128 cases with the fungal ball rhino sinusitis in our hospital between September 2005 and January 2012 were retrospectively analyzed. All patients were accepted nasal endoscopic surgery and followed up after surgery. The diagnosis were confirmed by postoperative pathological examination. RESULT: The sinus of all patients epithelialized after the surgery from fourth to ninth weeks, one case recurred eight months later. CONCLUSION: Sinus CT scan and nasal endoscopy were very important to the diagnosis of the fungal ball rhino-sinusitis, and nasal endoscopic surgery is the most important treatment method to fungal ball rhino-sinusitis. PMID- 24167999 TI - [Preliminary study on treatment of lingual tonsil hypertrophy by endoscopic assisted coblation]. AB - OBJECTIVE: To investigate the feasibility and safety of lingual tonsil excision by endoscopic assisted coblation. METHOD: Twenty seven cases with lingual tonsil hypertrophy were recruited in this study. Preoperative fibrolaryngoscope and CT and (or) MRI examination of the base of the tongue, lingual tonsil was removed by 70 degrees nasal endoscopy-assisted plasma radiofrequency after nasotracheal intubation. The tongue wound healing and post-operative bleeding were observed after operation, the advantages of the endoscopic-assisted plasma radiofrequency on lingual tonsil removal were analyzed, and its feasibility and safety were summarized. RESULT: During the surgery the base of the tongue and epiglottis had satisfaction exposure in the same operative field. No complications happened in the surgery and endotracheal tube was plucked safely after operation. There was no primary bleeding, and the number of secondary bleeding were 4 cases, accounting for 14.81% (4/27), respectively occurred on the sixth, seventh, tenth and twelfth day with the amount of bleeding of 30-70 ml. The bleeding were cured after conservative treatment or re-application applicating of radiofrequency; 27 patients had no taste disturbance, and they were followed up for 6-30 months without recurrence. CONCLUSION: Lingual tonsil excision by nasal endoscopic assisted coblation has enough exposure, complete resection and low recurrence rate. Stopping bleeding should be attentioned to prevent postoperative bleeding. PMID- 24168000 TI - [Clinical application on nasal septum continuous mattress suture after septoplasty]. PMID- 24168001 TI - [Application of hemostasis with balloon tamponade used in the emergency treatment of nasal hemorrhage]. PMID- 24168002 TI - [Treatment of endoscopic surgery on 26 cases with nasal septum benign tumor]. PMID- 24168003 TI - [Bilateral solitary fungus balls sphenoid sinus]. AB - Diagnosis of sphenoid sinus disease is very difficult because the location of sinus is deep and hidden within the skull and the symptoms of sphenoiditis are nonspecific. However, thanks to new technologies in imaging (CT and MRI) and nasal endoscopy, the literature on sphenoid sinus fungus ball have been published more. But all of the SSFB which have been reported are isolated or unilateral. We reported one rare case of bilateral sphenoid sinus fungus balls. This patient was treated in our department. Headache was the only symptom in this case. The patient was treated by sphenoidotomy via endoscopic approach and removal both of the lesions. No recurrence was found after 6-months follow-up. PMID- 24168004 TI - [One case of big nasopharynx granulation caused by postnasal packing]. AB - In April of this year, one patient was under left posterior nostril packing treatment with gauze balls as his left nostril bleeding. 3 days later the balls were removed. Soon after, he had foreign body sensation in his throat and the discomfort was increasingly severe. Under electronic laryngoscopy a big neoplasm like nasopharynx granulation was discovered and therefore resected when he was in general anesthesia. Under light microscope, it was found out that the neoplasm had fibrogenesis, angiogenesis, infiltration and interstitial osteoporosis edema. In pathological diagnosis, it was nasopharyngeal inflammatory granulation tissue. PMID- 24168005 TI - [The clinical classification systems and surgical methods for nasal inverted papilloma]. AB - Nasal inverted papilloma (NIP) is one primary benign lesion that occurs in the nasal cavity and paranasal sinuses. In this paper, several clinical classifications of NIP were summarized. The most important classification, which was developed by Krouse in 2000, and endoscopic technique was applied to treat NIP in different Surgical methods. PMID- 24168006 TI - Loop-forming method: new method for endoscopic insertion tube shaft rotation. PMID- 24168007 TI - A familial case of Muenke syndrome. Diverse expressivity of the FGFR3 Pro252Arg mutation--case report and review of the literature. AB - Muenke is a fibroblast growth factor receptor 3 (FGFR-3)-associated syndrome, which was first described in late 1990 s. Muenke syndrome is an autosomal dominant disorder characterized mainly by coronal suture craniosynostosis, hearing impairment and intellectual disability. The syndrome is defined molecularly by a unique point mutation c.749C > G in exon 7 of the FGFR3 gene which results to an amino acid substitution p.Pro250Arg of the protein product. Despite the fact that the mutation rate at this nucleotide is one of the most frequently described in human genome, few Muenke familial case reports are published in current literature. We describe individuals among three generations of a Greek family who are carriers of the same mutation. Medical record and physical examination of family members present a wide spectrum of clinical manifestations. In particular, a 38-year-old woman and her father appear milder clinical findings regarding craniofacial characteristics compared to her uncle and newborn female child. This familial case illustrates the variable expressivity of Muenke syndrome in association with an identical gene mutation. PMID- 24168008 TI - Relaxation of surface tension in the liquid-solid interfaces of Lennard-Jones liquids. AB - We have established the surface tension relaxation time in the liquid-solid interfaces of Lennard-Jones (LJ) liquids by means of direct measurements in molecular dynamics (MD) simulations. The main result is that the relaxation time is found to be almost independent of the molecular structures and viscosity of the liquids (at 70-fold change) used in our study and lies in such a range that in slow hydrodynamic motion the interfaces are expected to be at equilibrium. The implications of our results for the modeling of dynamic wetting processes and interpretation of dynamic contact angle data are discussed. PMID- 24168010 TI - Small cell carcinoma of the urinary bladder: a contemporary review with a special focus on bladder-sparing treatments. AB - Small cell carcinoma of the urinary bladder (SCCUB) is a rare and aggressive disease. To date, no standard treatment has been proposed due to the lack of prospective studies resulting from the rarity of this disease. Recently published studies of relatively large patient cohorts, however, have shed some light on the management of SCCUB patients. In this article, the authors review the epidemiology, pathogenesis, diagnosis and treatment (based on disease stage), and they then discuss the optimal therapeutic strategy for SCCUB patients, particularly for those with limited, locoregional disease. The authors conclude that multidisciplinary approaches are needed for the optimal management of this aggressive disease. The authors also discuss bladder-sparing approaches for SCCUB patients, compared to those for conventional bladder urothelial carcinoma patients. PMID- 24168009 TI - Intramural leoimyoma without endometrial cavity distortion may negatively affect the ICSI - ET outcome. AB - BACKGROUND: To assess the impact of intramural fibroids on the intracytoplasmic sperm injection-embryo transfer (ICSI-ET) cycle outcome, when there is no compression of the endometrial cavity. METHODS: In this retrospective, matched control study, the ICSI-ET outcome of sixty-two patients (Group I) with intramural fibroid (mean diameter <7 cm) and normal endometrial cavity demonstrated by office hysteroscopy was compared with matched-control group of patients (n = 301) with no fibroid (Group II). The diagnosis of fibroids was done by transvaginal ultrasonography. RESULTS: The mean age in fibroid group was 32.66 +/- 5.30 while this figure was 32.95 +/- 3.98 in control group. The clinical pregnancy rate was significantly lower in the fibroid group although fibroids not distorting the uterine cavity (25.8% vs. 39.9%, p = 0.04). In fibroid group the implantation rate was significantly lower than control group (20.97 +/- 37.93 vs.32.89 +/- 43.18%, p = 0.04). However, spontaneous abortion rate was higher in fibroid group but it did not reach the significant level (12.5% vs. 9.2%, p > 0.05). CONCLUSION: Women having intramural leiomyomas not encroaching on the uterine cavity have unfavorable ICSI/ET outcomes comparable to those of women without such leiomyomas. Therefore, myomectomy may be a good option for such patients with intramural fibroids even they do not have any endometrial distortion. PMID- 24168012 TI - Disorder influenced absorption line shapes of a chromophore coupled to two-level systems. AB - We have carried out a theoretical and numerical study of disorder-induced changes in the absorption line shape of a chromophore embedded in a host matrix. The stochastic sudden jump model is employed wherein the host matrix molecules are treated as noninteracting two-level systems (TLSs) occupying points on a three dimensional lattice with randomly oriented dipole moments. By systematically controlling the degree of positional disorder (alpha) attributed to them, a perfectly crystalline (alpha = 0) or a glassy environment (alpha = 1) or a combination of the two is obtained. The interaction between the chromophore and the TLSs is assumed to be of the dipole-dipole form. With an increase in alpha, the broadening of the absorption line shape was found to follow a power-law behavior. More importantly, it is revealed in the long-time limit that the resultant line shape is Gaussian in the absence of disorder but transforms to Lorentzian for a completely disordered environment. For an arbitrarily intermediate value of alpha, the resultant line shape can be approximately fitted by a linear combination of Gaussian and Lorentzian components. The Lorentzian profile for the disordered medium is attributed to the chomophore-TLS pairs with vanishingly small separation between them. PMID- 24168011 TI - An overview of the British Columbia Glomerulonephritis network and registry: integrating knowledge generation and translation within a single framework. AB - BACKGROUND: Glomerulonephritis (GN) is a group of rare kidney diseases with a substantial health burden and high risk of progression to end-stage renal disease. Research in GN has been limited by poor availability of large comprehensive registries. Substantial variations in access to and administration of treatment and outcomes in GN have been described. Leveraging provincial resources and existing infrastructure, the British Columbia (BC) GN Network is an initiative which serves to combine research and clinical care objectives. The goal of the BC GN Network is to coordinate and improve health care, including robust data capture, on all patients with GN in BC, a Canadian province of over 4.6 million people. This provincial initiative will serve as a model for Canadian or other national and international endeavours. DESCRIPTION: The BC Provincial Renal Agency (BCPRA) is the provincial governmental agency responsible for health delivery for all kidney patients in BC. The BC GN Network has been created by the BCPRA to ensure high quality and equitable access to care for all patients with GN and is a platform for evidence based clinical care programs and associated health policy. All patients with biopsy-proven GN are registered at the time of kidney biopsy into the BCPRA provincial database of kidney disease patients, forming the BC GN Registry. Thereafter, all laboratory results and renal related outcomes are captured automatically. Histology data and core clinical variables are entered into the database. Additional linkages between the GN Registry and administrative databases ensure robust capture of medications, hospital admissions, health care utilization, comorbidities, cancer and cardiac outcomes, and vital statistics. CONCLUSIONS: The BC GN Network and Registry is a unique model in that it combines robust data capture, data linkages, and health care delivery and evaluation into one integrated system. This model utilizes existing health infrastructure to prospectively capture population level data on patients with GN, producing a rich dataset capable of real-time identification and evaluation of GN health policy initiatives, of supporting observational cohort studies and health services research in GN, and of facilitating patient recruitment into GN clinical trials. PMID- 24168013 TI - A new medical treatment with botulinum toxin in persistent genital arousal disorder: successful treatment of two cases. AB - Persistent genital arousal disorder is described in a spontaneous, persistent, and uncontrollable genital arousal in women, with or without orgasm or genital engorgement, unrelated to any feelings of sexual desire. This study aimed to argue that application of Botulinum toxin in the periclitoral region in order to block the dorsal nerve of the clitoris might decrease symptoms of persistent genital arousal disorder. The authors presented 2 cases, in which application of Botulinum toxin resulted in improvement of the symptoms of persistent genital arousal disorder. Botulinum toxin type A treatment protocol is seen as a promising application for the persistent genital arousal disorder. However, further controlled studies in large samples are needed. PMID- 24168014 TI - Equipment for ground ambulances. PMID- 24168015 TI - Next-generation sequencing for the genetic screening of phaeochromcytomas and paragangliomas: riding the new wave, but with caution. PMID- 24168017 TI - Synthesis of indole substituted twistenediones from a 2-quinonyl boronic acid. AB - Indole substituted twistane-like derivatives resulted in a reaction between 3,5 dimethyl-2-quinonyl boronic acid and 2-alkenyl indoles. Their MCPBA oxidation gave 6/6/9 caged systems. Boronic acid acts as a temporal promoter allowing a site-selective conjugate addition of the heteroaromatic system to the methyl substituted C-3 quinone carbon, giving an intermediate diene which is regioselectively trapped by intramolecular [4 + 2] cycloaddition. PMID- 24168016 TI - The kiwi fruit peptide kissper displays anti-inflammatory and anti-oxidant effects in in-vitro and ex-vivo human intestinal models. AB - Literature reports describe kiwi fruit as a food with significant effects on human health, including anti-oxidant and anti-inflammatory activity. Fresh fruit or raw kiwi fruit extracts have been used so far to investigate these effects, but the molecule(s) responsible for these health-promoting activities have not yet been identified. Kissper is a kiwi fruit peptide displaying pore-forming activity in synthetic lipid bilayers, the composition of which is similar to that found in intestinal cells. The objective of this study was to investigate the kissper influence on intestinal inflammation using cultured cells and ex-vivo tissues from healthy subjects and Crohn's disease (CD) patients. The anti-oxidant and anti-inflammatory properties of kissper were tested on Caco-2 cells and on the colonic mucosa from 23 patients with CD, by challenging with the lipopolysaccharide from Escherichia coli (EC-LPS) and monitoring the appropriate markers by Western blot and immunofluorescence. EC-LPS challenge determined an increase in the intracellular concentration of calcium and reactive oxygen species (ROS). The peptide kissper was highly effective in preventing the increase of LPS-induced ROS levels in both the Caco-2 cells and CD colonic mucosa. Moreover, it controls the calcium increase, p65-nuclear factor (NF)-kB induction and transglutaminase 2 (TG2) activation inflammatory response in Caco-2 cells and CD colonic mucosa. Kissper efficiently counteracts the oxidative stress and inflammatory response in valuable model systems consisting of intestinal cells and CD colonic mucosa. This study reports the first evidence supporting a possible correlation between some beneficial effects of kiwi fruit and a specific protein molecule rather than generic nutrients. PMID- 24168018 TI - Cross-cultural adaptation of the Female Genital Self-Image Scale (FGSIS) in Iranian female college students. AB - The aim of the present study was to investigate the psychometric properties of a translated and culturally adapted Iranian version of the Female Genital Self Image Scale (FGSIS-I) in a sample of college women. Further, the relationship between women's self-image, body appreciation, sexual functioning, and gynecological exam behavior was explored. A sample of 1,877 female students from five different universities across Qazvin and Tehran completed the Female Sexual Function Index (FSFI), the Body Appreciation Scale (BAS), the Rosenberg Self Esteem Scale (RSES), the FGSIS-I, and a gynecological exam behavior questionnaire. Good to excellent internal consistency reliability, test-retest reliability, and convergent and construct validity were found. Exploratory factor analysis (EFA) and confirmatory factor analysis (CFA) both provided a two-factor structure for the FGSIS-I. The validity of the FGSIS-I in predicting gynecological exam behavior of college women was tested using structural equation modeling (SEM). The final model accounted for 33% of the variance in gynecological exam behavior (p < 0.01). In conclusion, the FGSIS-I was found to be a highly valid and reliable instrument to assess female genital self-image in Iranian women. PMID- 24168019 TI - Working with young people: evaluation of an education resource for medical trainees. AB - AIM: Many health professionals report interest in consulting more effectively with young people but have unmet training needs. We set out to evaluate a teaching resource in adolescent health and medicine that was designed for Australian trainees in specialist medicine. METHODS: Thirty-two paediatric and adult trainees of the Royal Australasian College of Physicians completed a pre evaluation questionnaire to assess attitudes and confidence in working with young people. They were then provided with a training resource and, 6 weeks later, completed a post-evaluation questionnaire. Repeated-measures anovas were used to assess changes in attitudes, self-reported knowledge and confidence by trainee type. chi(2) -tests were used to compare variation in the use of and opinions about the resource. RESULTS: Trainees' awareness of the health issues that affect young people, confidence in working with young people and confidence in their knowledge greatly improved after using the resource. Beforehand, adult medicine trainees scored lower than paediatric trainees. A relatively higher rate of improvement resulted in similar scores between trainee types after using the resource, which was rated equally highly by the different groups of trainees. CONCLUSIONS: As a result of significant gains in the confidence of specialist medicine trainees after access to the resource, it will now be made available for Australian trainees in specialist medicine. PMID- 24168021 TI - Gold-catalyzed tandem reactions of methylenecyclopropanes and vinylidenecyclopropanes. AB - Gold catalysis is often the key step in the synthesis of natural products, and is a powerful tool for tandem or domino reaction processes. Both gold salts and complexes are among the most powerful soft Lewis acids for electrophilic activation of carbon-carbon multiple bonds toward a variety of nucleophiles. The core of these reactions relies on the interaction between gold catalysts and pi bonds of alkenes, alkynes, and allenes. Activation of functional groups by gold complexes provides a useful and important method for facilitating many different organic transformations with high atom efficiency. Although they are highly strained, methylenecyclopropanes (MCPs) and vinylidenecyclopropanes (VDCPs) are readily accessible molecules that have served as useful building blocks in organic synthesis. Because of their unique structural and electronic properties, significant developments have been made in the presence of transition metal catalysts such as nickel, rhodium, palladium, and ruthenium during the past decades. However, less attention has been paid to the gold-catalyzed chemistry of MCPs and VDCPs. In this Account, we describe gold-catalyzed chemical transformations of MCPs and VDCPs developed both in our laboratory and by other researchers. Chemists have demonstrated that MCPs and VDCPs have amphiphilic properties. When MCPs or VDCPs are activated by a gold catalyst, subsequent nucleophilic attack by other reagents or ring-opening (ring-expansion) of the cyclopropane moiety will occur. However, the C-C double bonds of MCPs and VDCPs can also serve as nucleophilic reagents while more electrophilic reagents are present and activated by gold catalyst, and then further cascade reactions take place as triggered by the release of ring strain of cyclopropane. Based on this strategy, both our group and others have found some interesting gold-catalyzed transformations in recent years. These transformations of MCPs and VDCPs can produce a variety of polycyclic and heterocyclic structures, containing different sized skeletons. Moreover, we have carried out some isotopic labeling experiments and computational studies for mechanistic investigation. These reactions always give the desired products with high level control of chemo-, regio-, and diastereoselectivities, making them highly valuable for the synthesis of natural products and to the pharmaceutical industry and medicine in general. PMID- 24168020 TI - Functional and differential proteomic analyses to identify platelet derived factors affecting ex vivo expansion of mesenchymal stromal cells. AB - BACKGROUND: Multilineage differentiation, immunomodulation and secretion of trophic factors render mesenchymal stromal cells (MSC) highly attractive for clinical application. Human platelet derivatives such as pooled human platelet lysate (pHPL) and thrombin-activated platelet releasate in plasma (tPRP) have been introduced as alternatives to fetal bovine serum (FBS) to achieve GMP compliance. However, whereas both pHPL and tPRP support similar proliferation kinetics of lipoaspirate-derived MSC (LA-MSC), only pHPL significantly accelerates bone marrow-derived MSC (BM-MSC) expansion. To identify functionally bioactive factors affecting ex vivo MSC expansion, a differential proteomic approach was performed and identified candidate proteins were evaluated within a bioassay. RESULTS: Two dimensional difference gel electrophoresis (2D-DIGE), MALDI-TOF analyses and complementary Western blotting revealed 20 differential protein species. 14 candidate proteins occured at higher concentrations in pHPL compared to tPRP and 6 at higher concentrations in tPRP. The candidate proteins fibrinogen and apolipoprotein A1 differentially affected LA- and BM-MSC proliferation.In a second set of experiments, reference cytokines known to foster proliferation in FBS were tested for their effects in the human supplements. Interestingly although these cytokines promoted proliferation in FBS, they failed to do so when added to the humanized system. CONCLUSIONS: The differential proteomic approach identified novel platelet derived factors differentially acting on human MSC proliferation. Complementary testing of reference cytokines revealed a lack of stimulation in the human supplements compared to FBS. The data describe a new coherent approach to combine proteomic technologies with functional testing to develop novel, humanized, GMP-compliant conditions for MSC expansion. PMID- 24168022 TI - Patient perspectives on care received at community acupuncture clinics: a qualitative thematic analysis. AB - BACKGROUND: Community acupuncture is a recent innovation in acupuncture service delivery in the U.S. that aims to improve access to care through low-cost treatments in group-based settings. Patients at community acupuncture clinics represent a broader socioeconomic spectrum and receive more frequent treatments compared to acupuncture users nationwide. As a relatively new model of acupuncture in the U.S., little is known about the experiences of patients at community acupuncture clinics and whether quality of care is compromised through this high-volume model. The aim of this study was to assess patients' perspectives on the care received through community acupuncture clinics. METHODS: The investigators conducted qualitative, thematic analysis of written comments from an observational, cross-sectional survey of clients of the Working Class Acupuncture clinics in Portland, Oregon. The survey included an open-ended question for respondents to share comments about their experiences with community acupuncture. Comments were received from 265 community acupuncture patients. RESULTS: Qualitative analysis of written comments identified two primary themes that elucidate patients' perspectives on quality of care: 1) aspects of health care delivery unique to community acupuncture, and 2) patient engagement in health care. Patients identified unique aspects of community acupuncture, including structures that facilitate access, processes that make treatments more comfortable and effective and holistic outcomes including physical improvements, enhanced quality of life, and empowerment. The group setting, community-based locations, and low cost were highlighted as aspects of this model that allow patients to access acupuncture. CONCLUSIONS: Patients' perspectives on the values and experiences unique to community acupuncture offer insights on the quality of care received in these settings. The group setting, community-based locations, and low cost of this model potentially reduce access barriers for those who might not otherwise consider using acupuncture. In addition, the community acupuncture model may offer individuals the opportunity for increased frequency of treatments, which raises pertinent questions about the dose-response relationship of acupuncture and health outcomes. This study provides preliminary data for future evaluations of the quality and effectiveness of community acupuncture. Future studies should include the perspectives of patients who initiated, and subsequently, discontinued community acupuncture treatment. PMID- 24168025 TI - Topographic Keratoconus is not Rare in an Iranian population: the Tehran Eye Study. AB - PURPOSE: To determine the prevalence of topographic keratoconus in an Iranian population, selected from Tehran districts 1 to 4. METHODS: In a cross-sectional study, samples were selected from four districts of Tehran through stratified cluster sampling. Participants underwent ophthalmic and optometric examinations and Orbscan topography maps were acquired from 442 people. Based on Orbscan topography maps, cases of keratoconus were categorized. RESULTS: In the study sample, 263 people (61.7%) were female, and the participants' mean age was 40.8 +/- 17.1 years (range 14-81 years). Age- and sex-standardized prevalence of keratoconus was 3.3% (95% confidence interval, CI, 0.1-5.5%. The standardized prevalence of bilateral keratoconus was 1.8% (95% CI 0.2-3.5). The age standardized prevalence of keratoconus was 3.9% and 2.6% in men and women, respectively (p = 0.341). The prevalence of keratoconus was 0.8% in the 14-29 year-old age group and 7.5% in those >= 60 years; the prevalence of keratoconus significantly increased with age (odds ratio, OR, 1.05, 95% CI 1.01-1.08). The prevalence of keratoconus was 2.5% (95% CI 0.5-4.6) in the Persian ethnic group and 7.9% (95% CI 1.6-15.7) among non-Persians (p = 0.063 and OR 3.33). CONCLUSIONS: This study provides the first population-based estimate of the prevalence of keratoconus in Iran. The prevalence of topographic keratoconus was high among citizens of Tehran districts 1 to 4. To confirm the hypothesis of a high rate of keratoconus in Iran, more extensive studies are needed which would examine the role of genetics and the environment. PMID- 24168026 TI - Temporoparietal scalp keloid: an unusual occurrence. PMID- 24168028 TI - Developing a new perspective to study the health of survivors of Sichuan earthquakes in China: a study on the effect of post-earthquake rescue policies on survivors' health-related quality of life. AB - BACKGROUND: Sichuan is a province in China with an extensive history of earthquakes. Recent earthquakes, including the Lushan earthquake in 2013, have resulted in thousands of people losing their homes and their families. However, there is a research gap on the efficiency of government support policies. Therefore, this study develops a new perspective to study the health of earthquake survivors, based on the effect of post-earthquake rescue policies on health-related quality of life (HRQOL) of survivors of the Sichuan earthquake. METHODS: This study uses data from a survey conducted in five hard-hit counties (Wenchuan, Qingchuan, Mianzhu, Lushan, and Dujiangyan) in Sichuan in 2013. A total of 2,000 questionnaires were distributed, and 1,672 were returned; the response rate was 83.6%. RESULTS: Results of the rescue policies scale and Medical Outcomes Study Short Form 36 (SF-36) scale passed the reliability test. The confirmatory factor analysis model showed that the physical component summary (PCS) directly affected the mental component summary (MCS). The results of structural equation model regarding the effects of rescue policies on HRQOL showed that the path coefficients of six policies (education, orphans, employment, poverty, legal, and social rescue policies) to the PCS of survivors were all positive and passed the test of significance. Finally, although only the path coefficient of the educational rescue policy to the MCS of survivors was positive and passed the test of significance, the other five policies affected the MCS indirectly through the PCS. CONCLUSIONS: The general HRQOL of survivors is not ideal; the survivors showed a low satisfaction with the post-earthquake rescue policies. Further, the six post-earthquake rescue policies significantly improved the HRQOL of survivors and directly affected the promotion of the PCS of survivors. Aside from the educational rescue policy, all other policies affected the MCS indirectly through the PCS. This finding indicates relatively large differences in the effects of different post-earthquake rescue policies on the HRQOL of survivors. PMID- 24168027 TI - The prevalence of hypertension and abnormal kidney function in children with sickle cell disease -a cross sectional review. AB - BACKGROUND: Renal disease is a known contributor to mortality in adults with sickle cell disease (SCD) and renal abnormalities are evident in childhood. Hyperfiltration (evidenced by elevated glomerular filtration rate, GFR) occurs in children with SCD early in disease. However, the incidence of low GFR (<90 ml/min/1.73 m(2)) suggestive of chronic kidney disease (CKD), is not well established. The prevalence of hypertension is also not well known. The goal of this study was to determine the prevalence of hypertension and CKD in a cohort of children with SCD. METHODS: We performed a retrospective chart review of patients followed at the Rainbow Babies and Children's Sickle Cell Disease Clinic who were seen during routine follow up visits. Inclusion criteria were all patients ages 3 18. Exclusion criteria included recent (within 2 weeks) hospitalization and/or episode of acute chest, pain crises, febrile illness or red blood cell transfusion. Data collected included serum creatinine, blood pressure and history of sickle cell complications (acute chest syndrome, stroke or stroke risk). Estimated GFR (eGFR) was calculated using the updated Schwartz creatinine-based estimating formula. Analysis examined the associations among eGFR, blood pressure and sickle cell complications. The Institutional Review Board at University Hospitals Case Medical Center approved this study. RESULTS: A total of 48 children had complete data available. Mean eGFR was 140 mL/min/1.73 m(2) +/- 34.9 (range 71.9-404.2 mL/min/1.73 m(2)). Four patients (8.3%) had eGFRs < 90 mL/min/1.73 m(2), 35 patients (72.9%) had eGFRs > 120 mL/min/1.73 m(2) and 9 patients (18.8%) had eGFRs in the normal range. Eight patients (16.7%) had evidence of elevated blood pressures (pre-hypertension or hypertension). There was no correlation between eGFR and age, and no association of eGFR with acute chest or stroke risk. CONCLUSION: In this SCD cohort, we identified abnormally low eGFR (suggestive of early CKD) in 8.3% of patients and elevated blood pressure in 16.7%. These findings are in contrast to other published studies that show primarily normal or elevated GFR and the absence of or minimal hypertension. These findings indicate that elevated blood pressure and decreased eGFR are not uncommon in children with SCD, and should be more rigorously studied. PMID- 24168029 TI - Intermetatarsal coalition: a delayed complication of hallux valgus surgery. PMID- 24168031 TI - DNA extraction from long-term stored urine. AB - BACKGROUND: Traditionally, for DNA analyses, DNA is recovered from buffy coats. Since DNA in urine has been reported to deteriorate quickly, this option is often not considered. To complete our DNA database in patients with ANCA-associated vasculitis, we aimed to extract DNA from stored urine. METHODS: Urine was stored at the time of kidney biopsy from patients included in our regional kidney biopsy database, who had given informed consent for further study. Urine was subsequently filtered, dialyzed, concentrated and freeze dried and finally resolubilized and centrifuged. DNA was extracted using the high pure PCR template preparation kit (Roche Diagnostics). Next, concentration and purity were determined by Nanodrop analysis and by Quant-iT analysis. RESULTS: One hundred and eighty-one patients with ANCA-associated vasculitis were included. Of 114 patients (63%), DNA was available. From 53 of the remaining 67 patients, stored urine was available. Of the 53 samples that were processed, 46 (86.8%) yielded DNA with a mean concentration of 258.7 ng/MUL (range 33.2-529) with a mean purity ratio of 1.81 (lambda 260/280). CONCLUSION: DNA extraction from fresh urine has been described before, yielding DNA usable for PCR analysis in healthy subjects. Storage of fresh urine at 4 degrees C or lower temperatures results in significant degradation of the DNA, making recovery of DNA more difficult with longer periods of storage. In the current study, we demonstrated that DNA could be retrieved from subsequently filtered, dialyzed, concentrated and freeze dried urine that was stored at room temperature. In addition, we demonstrated that this DNA could be used for PCR analysis. This method is useful when no other material from these patients is available. PMID- 24168030 TI - Differential requirement for Dab2 in the development of embryonic and extra embryonic tissues. AB - BACKGROUND: Disabled-2 (Dab2) is an endocytic adaptor protein involved in clathrin-mediated endocytosis and cargo trafficking. Since its expression is lost in several cancer types, Dab2 has been suggested to be a tumor suppressor. In vitro studies indicate that Dab2 establishes epithelial cell polarity and organization by directing endocytic trafficking of membrane glycoproteins. Dab2 also modulates cellular signaling pathways by mediating the endocytosis and recycling of surface receptors and associated signaling components. Previously, two independent gene knockout studies have been reported, with some discrepancies in the observed embryonic phenotypes. To further clarify the in vivo roles of Dab2 in development and physiology, we designed a new floxed allele to delete dab2 gene. RESULTS: The constitutive dab2 deleted embryos showed a spectrum in the degree of endoderm disorganization in E5.5 and no mutant embryos persisted at E9.5. However, the mice were grossly normal when dab2 deletion was restricted to the embryo proper and the gene was retained in extraembryonic tissues using Meox2 Cre and Sox2-Cre. Adult Dab2-deficient mice had a small but statistically significant increase in serum cholesterol levels. CONCLUSION: The study of the new dab2 mutant allele in embryos and embryoid bodies confirms a role for Dab2 in extraembryonic endoderm development and epithelial organization. Experimental results with embryoid bodies suggest that additional endocytic adaptors such as Arh and Numb could partially compensate for Dab2 loss. Conditional deletion indicates that Dab2 is dispensable for organ development, when the vast majority of the embryonic cells are dab2 null. However, Dab2 has a physiological role in the endocytosis of lipoproteins and cholesterol metabolism. PMID- 24168032 TI - The effects of CA IX catalysis products within tumor microenvironment. AB - Solid tumors are composed of both cancer cells and various types of accessory cells, mainly fibroblasts, that collectively compose the so called tumor microenvironment. Cancer-associated fibroblasts have been described to actively participate in cancer progression by establishing a cytokine-mediated as well as metabolic crosstalk with cancer cells. In the present paper we show that activated human fibroblasts are able to boost tumor cells proliferation and that this effect is greatly dependent on stromal carbonic anhydrase IX (CA IX) activity. In fact fibroblasts show a strong upregulation of CA IX expression upon activation by cancer cells, while CA IX products, protons and bicarbonate, exert differential effects on cancer cells proliferation. While acidification of extracellular pH, a typical condition of rapidly growing solid tumors, is detrimental for tumor cells proliferation, bicarbonate, through its organication, supplies cancer cells with intermediates useful to sustain their high proliferation rate. Here we propose a new kind of fibroblasts/tumor cells crosstalk within tumor microenvironment, mediated by stromal CA IX products, aimed to favor cancer cells growth, opening new perspectives on CA IX role in tumor microenvironment. PMID- 24168033 TI - Rapid evolution of cooperation in group-living animals. AB - BACKGROUND: It is often assumed that evolution takes place on very large timescales. Countering this assumption, rapid evolutionary dynamics are increasingly documented in biological systems, e.g. in the context of predator prey interactions, species coexistence and invasion. It has also been shown that rapid evolution can facilitate the evolution of cooperation. In this context often evolutionary dynamics influence population dynamics, but in spatial models rapid evolutionary dynamics also emerge with constant population sizes. Currently it is not clear how well these spatial models apply to species in which individuals are not embedded in fixed spatial structures. To address this issue we employ an agent-based model of group living individuals. We investigate how positive assortment between cooperators and defectors and pay-off differences between cooperators and defectors depend on the occurrence of evolutionary dynamics. RESULTS: We find that positive assortment and pay-off differences between cooperators and defectors differ when comparing scenarios with and without selection, which indicates that rapid evolutionary dynamics are occurring in the selection scenarios. Specifically, rapid evolution occurs because changes in positive assortment feed back on evolutionary dynamics, which crucially impacts the evolution of cooperation. At high frequencies of cooperators these feedback dynamics increase positive assortment facilitating the evolution of cooperation. In contrast, at low frequencies of cooperators rapid evolutionary dynamics lead to a decrease in assortment, which acts against the evolution of cooperation. The contrasting dynamics at low and high frequencies of cooperators create positive frequency-dependent selection. CONCLUSIONS: Rapid evolutionary dynamics can influence the evolution of cooperation in group-living species and lead to positive frequency-dependent selection even if population size and maximum group-size are not affected by evolutionary dynamics. Rapid evolutionary dynamics can emerge in this case because sufficiently strong selective pressures allow evolutionary and demographic dynamics, and consequently also feedback between assortment and evolution, to occur on the same timescale. In particular, emerging positive frequency-dependent selection could be an important explanation for differences in cooperative behaviors among different species with similar population structures such as humans and chimpanzees. PMID- 24168034 TI - Segmental arterial mediolysis of left gastric artery: a case report and review of pathology. AB - BACKGROUND: Segmental arterial mediolysis (SAM) is a rare non inflammatory vascular disease that can present with massive haemorrhage, which may lead to death without prompt surgical intervention. CASE PRESENTATION: A 60 years old Aboriginal female presented with life threatening, spontaneous intra-abdominal bleeding requiring an emergency laparotomy. The source of bleeding was found to be ruptured left gastric artery. A total gastrectomy was performed as a damage control procedure. A staged Roux-en-Y oesophago-jejunostomy with Hunt Lawrence pouch reconstruction was undertaken thirty six hours later. Histopathological findings revealed evidence of non-inflammatory segmental vascular damage with microaneurysm, consistent with segmental arterial mediolysis. CONCLUSION: Prompt resuscitation and surgical intervention can decrease the morbidity and mortality in this rare clinical entity. PMID- 24168035 TI - Genotoxic and mutagenic effects of diflubenzuron, an insect growth regulator, on mice. AB - This study assessed the genotoxic and mutagenic potential of diflubenzuron (DFB) insecticide in mice. Mice were divided into five groups: group I: negative control; group II: positive control; group III: 0.3 mg/kg of DFB; group IV: 1 mg/kg of DFB; group V: 3 mg/kg DFB. Peripheral blood was collected for the comet assay and the micronucleus (MN) test. DFB increased incidence of comet formation at all doses tested. A rise in the frequency of MN in mouse peripheral blood was observed 24, 48, and 72 h postexposure at all doses tested. Data demonstrate that DFB exerts genotoxic and mutagenic effects in a dose-dependent manner. PMID- 24168036 TI - Occupational exposure to particulate matter and respiratory symptoms in Portuguese swine barn workers. AB - Certain environmental conditions in animal and plant production have been associated with increased frequency in respiratory illnesses, including asthma, chronic bronchitis, and hypersensitivity pneumonitis, in farmers occupationally exposed in swine production. The aim of this study was to characterize particulate matter (PM) contamination in seven Portuguese swine farms and determine the existence of clinical symptoms associated with asthma and other allergy diseases, utilizing the European Community Respiratory Health Survey questionnaire. Environmental assessments were performed with portable direct reading equipment, and PM contamination including five different sizes (PM0.5, PM1.0, PM2.5, PM5.0, PM10) was determined. The distribution of particle size showed the same trend in all swine farms, with high concentrations of particles with PM5 and PM10. Results from the questionnaire indicated a trend such that subjects with diagnosis of asthma were exposed to higher concentrations of PM with larger size (PM2.5, PM5, and PM10) while subjects with sneezing, runny nose, or stuffy nose without a cold or flu were exposed to higher concentrations of PM with smaller size (PM0.5 and PM1). Data indicate that inhalation of PM in swine farm workers is associated with increased frequency of respiratory illnesses. PMID- 24168037 TI - Developmental abnormalities in chicken embryos exposed to N-nitrosoatrazine. AB - Nitrate and atrazine (ATR) occur in combination in some drinking-water supplies and might react to form N-nitrosoatrazine (NNAT), which is reportedly more toxic than nitrate, nitrite, or ATR. Current evidence from population-based studies indicates that exposure to nitrate, nitrite, and nitrosatable compounds increases the risk of congenital defects and/or rate of embryo lethality. To test the hypothesis that NNAT induces malformations during embryogenesis, chicken embryos were examined for lethality and developmental abnormalities after treating fertilized eggs with 0.06-3.63 MUg NNAT. After 5 d of incubation (Hamburger and Hamilton stage 27), 90% of embryos in NNAT-treated eggs were alive, of which 23% were malformed. Malformations included heart and neural-tube defects, caudal regression, gastroschisis, microphthalmia, anophthalmia, and craniofacial hypoplasia. The findings from this investigation suggest further studies are needed to determine the mechanisms underlying NNAT-induced embryotoxicity. PMID- 24168038 TI - Effects of prepubertal exposure to silver nanoparticles on reproductive parameters in adult male Wistar rats. AB - The incidence of male reproductive pathologies, such as hypospadias, cryptorchidism, testicular cancer, and low sperm production in adulthood, is increasing and may be related to exposure to environmental contaminants. The silver nanoparticles (AgNP) are a new class of chemical compounds commonly used in both medical and nonmedical settings, and they affect development of spermatogonial stem cells in vitro. The aim of this study was to examine the adverse productive toxic effects of AgNPs in male Wistar rats exposed during the prepubertal period and sacrificed at postnatal day (PND) 53 and PND90. Growth was assessed by daily weighing. The progress of puberty in the rats was measured by preputial separation, while spermatogenesis was assayed by (1) measuring the sperm count in testes and epididymis and (2) examining the morphology and morphometry of seminiferous epithelium using stereological analysis. In addition, testosterone and estradiol levels were assayed by radioimmunoassay. The weight of the animals at PND90 did not change markedly, but growth was less in the group treated with AgNP at 50 MUg/kg from PND34 to PND53. AgNP exposure produced a delay in puberty in both treated groups. Decreased sperm reserves in the epididymis and diminished sperm transit time were observed at PND53, while a reduction in sperm production occurred at PND90. The morphology of the seminiferous epithelium was markedly altered. Data demonstrated that prepubertal exposure to AgNP altered reproductive development in prepubertal male Wistar rats, as evidenced by impairment in spermatogenesis and a lower sperm count in adulthood. PMID- 24168039 TI - Effects of chronic low-dose cadmium exposure on selected biochemical and antioxidant parameters in rats. AB - The effects of long-term (1 yr) exposure to low doses of cadmium (Cd) dissolved in drinking water on selected biochemical and antioxidant parameters were studied in Wistar rats. Rats were divided into four groups: male control group (C-m), female control group (C-f), male Cd-exposed group (Cd-m), and female Cd-exposed group (Cd-f). Cd groups were exposed to Cd dissolved in drinking water (cadmium dichloride 4.8 mg CdCl2/L, i.e., 2.5 mg Cd/L, 500-fold of maximal allowable concentration for potable water). The experiment was terminated on d 370. In all groups, biochemical parameters (total protein [TP], albumin, alanine aminotransferase, aspartate aminotransferase, glucose, cholesterol, triacylglycerols, urea, and creatinine) and antioxidant parameters (glutathione peroxidase, superoxide dismutase, and total antioxidant capacity) were measured in the blood. Total protein and albumin concentrations were decreased significantly in the Cd-m group. Other biochemical parameters did not change in Cd groups compared to control groups. Superoxide dismutase fell significantly in both male and female Cd-exposed groups. Activity of glutathione peroxidase was markedly lower in Cd-exposed groups. Total antioxidant capacity increased significantly in Cd-f group. These results suggest that chronic low-dose oral Cd exposure induces oxidative stress. PMID- 24168041 TI - Fitness and competitive ability of Botrytis cinerea field isolates with dual resistance to SDHI and QoI fungicides, associated with several sdhB and the cytb G143A mutations. AB - Respiration inhibitors such as the succinate dehydrogenase inhibitors (SDHIs) and the quinone outside inhibitors (QoIs) are fungicide classes with increasing relevance in gray mold control. However, recent studies have shown that dual resistance to both fungicide classes is a common trait in Botrytis cinerea populations from several hosts throughout the world. Resistance of B. cinerea to SDHIs is associated with several mutations in the sdhB, sdhC, and sdhD genes, while resistance to QoIs, in most cases, is associated with the G143A mutation in the cytb gene. The objective of the current study was to investigate the fitness and the competitive ability of B. cinerea field strains possessing one of the H272Y/R/L, N230I, or P225F sdhB substitutions and the G143A mutation of cytb. Fitness parameters measured were (i) mycelial growth and conidia germination in vitro, (ii) aggressiveness and sporulation capacity in vivo, (iii) sclerotia production in vitro and sclerotia viability under different storage conditions, and (iv) sensitivity to oxidative stress imposed by diquat treatments. The competitive ability of the resistant isolates was measured in the absence and presence of the SDHI fungicides boscalid and fluopyram selection pressure. The measurements of individual fitness components showed that the H272R/G143A isolates had the lower differences compared with the sensitive isolates. In contrast, the groups of H272Y/L/G143A, N230I/G143A, and P225F/G143A isolates showed reduced fitness values compared with the sensitive isolates. Isolates possessing only the cytb G143A substitution did not show any fitness cost. The competition experiments showed that, in the absence of fungicide selection pressure, after four disease cycles on apple fruit, the sensitive isolates dominated in the population in all the mixtures tested. In contrast, when the competition experiment was conducted under the selection pressure of boscalid, a gradual decrease in the frequency of sensitive isolates was observed, whereas the frequency of H272L and P225F isolates was increased. When the competition experiment was conducted in the presence of fluopyram, the sensitive isolates were eliminated even after the first disease cycle and the P225F mutants dominated in the population. Such results suggest that the sdhB mutations may have adverse effects on the mutants. The observed dominance of sensitive isolates in the competition experiments conducted in the absence of fungicides suggest that the application of SDHIs in alternation schemes may delay the selection or reduce the frequency of SDHI-resistant mutants. PMID- 24168042 TI - Summer heat and low soil organic matter influence severity of hazelnut Cytospora canker. AB - Cytospora canker, caused by the fungus Cytospora corylicola, is present in hazelnut production areas worldwide. The disease is widespread throughout the main production areas of Italy. The causal agent is considered to be a secondary invader of damaged tissue that attacks mainly stressed plants. However, little is known of disease severity and stress factors that predispose plants to infection. In particular, the role of pedoclimatic factors was investigated. Direct survey indicated that disease severity varied across several study sites. Geostatistics showed a strong positive correlation between disease severity index and summer heat (r = 0.80 and 0.91 for July and August, respectively) and strong negative correlation between disease severity index and soil organic matter (r = -0.78). A moderate positive correlation between disease severity index and magnesium/potassium ratio (r = 0.58) and moderate negative correlations between disease severity index and total soil nitrogen (r = -0.53), thermal shock (r = 0.46), and rainfall (r = -0.53) were determined. No significant correlation between disease severity index and soil aluminum (r = -0.35), soil pH (r = 0.01), and plant age (r = -0.38) was found. PMID- 24168044 TI - QTL mapping of fruit rot resistance to the plant pathogen Phytophthora capsici in a recombinant inbred line Capsicum annuum population. AB - Phytophthora capsici is an important pepper (Capsicum annuum) pathogen causing fruit and root rot, and foliar blight in field and greenhouse production. Previously, an F6 recombinant inbred line population was evaluated for fruit rot susceptibility. Continuous variation among lines and partial and isolate-specific resistance were found. In this study, Phytophthora fruit rot resistance was mapped in the same F6 population between Criollo del Morelos 334 (CM334), a landrace from Mexico, and 'Early Jalapeno' using a high-density genetic map. Isolate-specific resistance was mapped independently in 63 of the lines evaluated and the two parents. Heritability of the resistance for each isolate at 3 and 5 days postinoculation (dpi) was high (h(2) = 0.63 to 0.68 and 0.74 to 0.83, respectively). Significant additive and epistatic quantitative trait loci (QTL) were identified for resistance to isolates OP97 and 13709 (3 and 5 dpi) and 12889 (3 dpi only). Mapping of fruit traits showed potential linkage with few disease resistance QTL. The partial fruit rot resistance from CM334 suggests that this may not be an ideal source for fruit rot resistance in pepper. PMID- 24168043 TI - Genetic diversity of Grapevine virus A in Washington and California vineyards. AB - Grapevine virus A (GVA; genus Vitivirus, family Betaflexiviridae) has been implicated with the Kober stem grooving disorder of the rugose wood disease complex. In this study, 26 isolates of GVA recovered from wine grape (Vitis vinifera) cultivars from California and Washington were analyzed for their genetic diversity. An analysis of a portion of the RNA-dependent RNA polymerase (RdRp) and complete coat protein (CP) sequences revealed intra- and inter-isolate sequence diversity. Our results indicated that both RdRp and CP are under strong negative selection based on the normalized values for the ratio of nonsynonymous substitutions per nonsynonymous site to synonymous substitutions per synonymous site. A global phylogenetic analysis of CP sequences revealed segregation of virus isolates into four major clades with no geographic clustering. In contrast, the RdRp-based phylogenetic tree indicated segregation of GVA isolates from California and Washington into six clades, independent of geographic origin or cultivar. Phylogenetic network coupled with recombination analyses showed putative recombination events in both RdRp and CP sequence data sets, with more of these events located in the CP sequence. The preponderance of divergent variants of GVA co-replicating within individual grapevines could increase viral genotypic complexity with implications for phylogenetic analysis and evolutionary history of the virus. The knowledge of genetic diversity of GVA generated in this study will provide a foundation for elucidating the epidemiological characteristics of virus populations at different scales and implementing appropriate management strategies for minimizing the spread of genetic variants of the virus by vectors and via planting materials supplied to nurseries and grape growers. PMID- 24168045 TI - Toxigenic capacity and trichothecene production by Fusarium graminearum isolates from Argentina and their relationship with aggressiveness and fungal expansion in the wheat spike. AB - At least 20 epidemics of Fusarium head blight (FHB) of wheat have been registered in the last 50 years in Argentina, with variable intensity. Damage induced by the disease is further aggravated by the presence of mycotoxins in affected grains that may cause health problems to humans and animals. The trichothecene chemotype was analyzed for 112 isolates of Fusarium graminearum from Argentina by polymerase chain reaction and two field trials were conducted to study the aggressiveness of a subsample of 14 representative isolates and to analyze deoxynivalenol (DON) production in planta and in vitro. All isolates belonged to the 15-acetyl-DON chemotype. Significant differences were observed in both the symptom severity induced in wheat spikes and the in vivo DON production, and a close correlation was found between these two variables. However, in vitro toxigenic potential was not correlated with the capacity of F. graminearum isolates to produce DON under natural conditions. The progress of infection in the rachis of inoculated wheat spikes was analyzed and the pathogen presence verified in both symptomatic and symptomless spikes. Even isolates with a limited capacity to induce symptoms were able to colonize the vascular tissue and to produce considerable amounts of DON in planta. PMID- 24168046 TI - Shade tree spatial structure and pod production explain frosty pod rot intensity in cacao agroforests, Costa Rica. AB - Vegetation composition and plant spatial structure affect disease intensity through resource and microclimatic variation effects. The aim of this study was to evaluate the independent effect and relative importance of host composition and plant spatial structure variables in explaining disease intensity at the plot scale. For that purpose, frosty pod rot intensity, a disease caused by Moniliophthora roreri on cacao pods, was monitored in 36 cacao agroforests in Costa Rica in order to assess the vegetation composition and spatial structure variables conducive to the disease. Hierarchical partitioning was used to identify the most causal factors. Firstly, pod production, cacao tree density and shade tree spatial structure had significant independent effects on disease intensity. In our case study, the amount of susceptible tissue was the most relevant host composition variable for explaining disease intensity by resource dilution. Indeed, cacao tree density probably affected disease intensity more by the creation of self-shading rather than by host dilution. Lastly, only regularly distributed forest trees, and not aggregated or randomly distributed forest trees, reduced disease intensity in comparison to plots with a low forest tree density. A regular spatial structure is probably crucial to the creation of moderate and uniform shade as recommended for frosty pod rot management. As pod production is an important service expected from these agroforests, shade tree spatial structure may be a lever for integrated management of frosty pod rot in cacao agroforests. PMID- 24168047 TI - Uncovering the links between diet and the incidence of bowel cancer. PMID- 24168049 TI - Expert review: an update in current and developing intravesical therapies for non muscle-invasive bladder cancer. AB - Non-muscle-invasive bladder cancer is a highly prevalent disease and recurrences, after initial therapy, are common. Consequently, the healthcare costs for non muscle-invasive bladder cancer are high. Despite a primary adequate response to adjuvant intravesical treatment, many patients suffer from recurrences, and some even from progression. To date, cystectomy remains the only option for those non responding patients with high risk of recurrence and progression. Mainly because outcome after progression, in this group, is poor. Therefore, new intravesical therapies are needed. Moreover, new accurate and individual parameters, to distinguish responder from non-responders, will provide additional benefit in clinical decision-making. In this review, current diagnostics and therapies will be discussed. In addition, we will elucidate developing therapies in non-muscle invasive bladder cancer. PMID- 24168050 TI - Molecular pathways and potential therapeutic targets in glioblastoma multiforme. AB - Glioblastoma multiforme (GBM) is the most common primary brain malignancy. The current standard of therapy consists of surgical resection followed by concurrent chemoradiotherapy with temozolomide. Despite steady advances in all therapeutic modalities, clinical improvements have been slow and the prognosis remains poor. Utilizing powerful large-scale molecular techniques, several key pathways implicated in gliomagenesis have recently been identified and confirmed. These represent potential therapeutic targets, and by developing novel methods to specifically manipulate these pathways, we may achieve a meaningful and substantial improvement in the way we treat GBM. Here, we present and discuss the current status of research into the molecular pathways and potential therapeutic targets in GBM. PMID- 24168051 TI - Biology in prevention and treatment of brain metastases. AB - Brain metastases are common in cancer patients, may significantly diminish neurocognitive function and quality of life and carry a poor prognosis. Brain metastases differ from metastases in other organs such as liver, lung, lymph nodes and bone, both from a pathobiological and from a clinical perspective. Despite the high incidence of brain metastases, only relatively few studies aiming at better understanding of their pathobiology have been performed in the past. However, recently druggable targets have been identified in brain metastases of several tumor types and novel treatment approaches are becoming a feasible option for selected patients. In addition, scientific advances are elucidating some fundamental aspects of brain metastasis formation and may lead to effective strategies of drug-mediated prevention of metastatic brain invasion or inhibition of intracerebral outgrowth. PMID- 24168052 TI - Clinical trial transparency: an assessment of the disclosure of results of company-sponsored trials associated with new medicines approved recently in Europe. AB - BACKGROUND: Previous studies have raised concerns around the transparency and disclosure rates of clinical trial results on clinical trial registries and in the scientific literature. The objective of this study was to assess the timely disclosure in the public domain of results of company-sponsored clinical trials related to all new medicines approved by the European Medicines Agency (EMA) over a recent 3 year period. METHODS: The study surveyed various publicly available information sources for both clinical trial registration and disclosure of results (including clinical trial registries, the International Federation of Pharmaceutical Manufacturers and Associations [IFPMA] Clinical Trials Portal, EMA European Public Assessment Reports and PubMed), searched from 27 December 2012 to 31 January 2013. The study covered all 53 new medicines (except vaccines and fixed-dose combinations) approved for marketing by 34 pharmaceutical companies by the EMA in 2009, 2010 and 2011. It included all completed company-sponsored clinical trials conducted in patients and recorded on a clinical trial registry and/or included in an EPAR. OUTCOME MEASURE AND RESULTS: The main outcome measure was the proportion of trials for which results had been disclosed on a registry or in the scientific literature either within 12 months of the later of either first regulatory approval or trial completion, or by 31 January 2013 (end of survey). Of the completed clinical trials associated with all 53 new medicines approved by the EMA between 2009 and 2011, 77% had results disclosed within 12 months. By 31 January 2013, this had increased to 89%. Rates of results disclosure within 12 months were 71%, 81% and 86% for new medicines approved in 2009, 2010 and 2011 respectively. Disclosure increased to 86%, 93% and 91% respectively by 31 January 2013. Although this was a purely quantitative study which did not aim to assess the content of disclosure against any specific requirements, limitations relating to a number of difficulties in finding all relevant data from multiple sources in the public domain were captured. CONCLUSIONS: Results of over three-quarters of all company-sponsored clinical trials related to new medicines recently approved by the EMA were disclosed within a year of completion or regulatory approval, and almost 90% were disclosed by 31 January 2013, suggesting transparency is now better than has sometimes been reported previously. PMID- 24168053 TI - A gestational ketogenic diet alters maternal metabolic status as well as offspring physiological growth and brain structure in the neonatal mouse. AB - BACKGROUND: The use of the ketogenic diet (KD) among women of child-bearing age has been increasing, leading to increased interest in identifying the diet's suitability during gestation. To date, no studies have thoroughly investigated the effect of a gestational KD on offspring growth. Since ketones have been reported to play a role in cerebral lipid and myelin synthesis, it is particularly important to investigate the diet's impact on brain anatomy of the offspring. METHODS: To fill this knowledge gap we imaged CD-1 mouse neonates whose mothers were fed either a standard diet (SD) or a KD prior to and during gestation. Images were collected at postnatal (P) 11.5 and 21.5 using Magnetic Resonance Imaging (MRI). Maternal metabolic status was also tracked during lactation, by following their body weight, blood glucose, ketone, cholesterol, and triglyceride concentrations. RESULTS: The KD dams exhibit a significant reduction in maternal fertility and litter size, as well as a high risk of developing fatal ketoacidosis by mid-lactation. To increase survival of the KD dams and offspring, fostering of P2.5 pups (from both KD and SD litters) by SD foster dams was carried out. This resulted in stabilization of blood ketones of the KD dams, and aversion of the fatal ketoacidosis. We also note a slower and smaller weight loss for the KD compared with the SD dams. The average fostered KD pup exhibits retarded growth by P21.5 compared with the average fostered SD pup. An anatomical comparison of their brains further revealed significant structural differences at P11.5, and particularly at P21.5. The KD brain shows a relative bilateral decrease in the cortex, fimbria, hippocampus, corpus callosum and lateral ventricle, but a relative volumetric enlargement of the hypothalamus and medulla. CONCLUSION: A gestational ketogenic diet deleteriously affects maternal fertility and increases susceptibility to fatal ketoacidosis during lactation. Prenatal and early postnatal exposure to a ketogenic diet also results in significant alterations to neonatal brain structure, and results in retarded physiological growth. These alterations could be accompanied by functional and behavioural changes in later postnatal life. PMID- 24168054 TI - Early pregnancy exposure to feto-toxic medications among out-patients in Malawi. AB - OBJECTIVES: To estimate the proportion of women in early pregnancy prescribed potentially feto-toxic medications at an out-patient clinic in Malawi. METHODS: Over six-months the number of women of child-bearing age attending out-patient clinics and prescribed medicines at Mitundu Community Hospital was derived from the hospital's registry and pharmacy records. Women prescribed potentially feto toxic medicines (using Food and Drug Administration classifications) by medical assessments were subsequently interviewed and pregnancy tested. Exposure to potentially feto-toxic medications was estimated and differences between pregnant and non-pregnant women were described. RESULTS: Of 8970 female outpatients, 1012 (11.3%; 95% CI: 10.6% to 12%) were prescribed potentially feto-toxic medicines. After excluding 740 as unlikely to be pregnant, 209 women had negative pregnancy tests and 63 were confirmed as pregnant, representing one in 16 of women prescribed contraindicated medicines or between 2.8% and 3.5% of all women attending in early pregnancy. Most medicines were FDA rated C or D. Only 152 (55.9%) of these women had been asked about pregnancy and prescribing practices did not discriminate between pregnant and non-pregnant patients. CONCLUSIONS: Assessment and prescribing practices for women attending out-patient clinics who might be in early pregnancy were inadequate, increasing the risk of exposure to potentially feto-toxic medicines. PMID- 24168055 TI - Risky sexual behavior among young adult Latinas: are acculturation and religiosity protective? AB - A sexual health disparity exists among U.S. Latinas, who have rates of sexually transmitted infections (STIs) that are more than double their peers. Previous research has identified acculturation and religiosity as key social determinants of sexual health, but such findings have been inconsistent, with some researchers identifying protective benefits and other researchers noting increased risk. The purpose of this study was to explain how intrinsic and extrinsic religiosity as well as acculturation predict risky sexual behavior using Structural Equation Modeling of a nationally representative sample of self-identified Latinas (N=1,168) from the National Longitudinal Survey of Adolescent Health. Results indicated that intrinsic religiosity and acculturation assert protective effects while extrinsic religiosity increases risk. Recommendations for policy, intervention, and future research are offered. PMID- 24168056 TI - Insufficient radiofrequency ablation promotes epithelial-mesenchymal transition of hepatocellular carcinoma cells through Akt and ERK signaling pathways. AB - BACKGROUND: Residual tumor progression after insufficient radiofrequency ablation (RFA) has been recently reported. However, whether epithelial-mesenchymal transition (EMT), which is a key process that drives cancer metastasis, is involved in the tumor progression after insufficient RFA is not well understood. METHODS: Human hepatocellular carcinoma (HCC) cell lines SMMC7721 and Huh7 were used. Insufficient RFA was simulated using a water bath (47 degrees C 5 min, 10 min, 15 min, 20 min and 25 min gradually). MTT assay was used to evaluate the proliferation of HCC cells in vitro. Migration and invasion of HCC cells were determined by transwell assay. The molecular changes in HCC cells after insufficient RFA were evaluated by western blot. LY294002 and PD98059 were used to treat HCC cells. An ectopic nude mice model and a tail vein metastatic assay were used to evaluate the growth and metastatic potential of SMMC7721 cells in vivo after insufficient RFA. RESULTS: SMMC7721 and Huh7 cells after insufficient RFA (named as SMMC7721-H and Huh7-H respectively) exhibited enhanced proliferation, migration and invasion (6.4% and 23.6%, 33.2% and 66.1%, and 44.1% and 57.4% increase respectively) in vitro. Molecular changes of EMT were observed in SMMC7721-H and Huh7-H cells. LY294002 and PD98059 inhibited the EMT of SMMC7721-H and Huh7-H cells. SMMC7721-H cells also exhibited larger tumor size (1440.8+/-250.3 mm3 versus 1048.56+/-227.6 mm3) and more lung metastasis (97.4% increase) than SMMC7721 cells in vivo. Higher expression of PCNA, N-cadherin and MMP-2 and MMP-9, was also observed in SMMC7721-H tumors. CONCLUSIONS: Insufficient RFA could directly promote the invasiveness and metastasis of HCC cells. Insufficient RFA may promote the EMT of HCC cells through Akt and ERK signaling pathways. PMID- 24168058 TI - Association of the gonadotrophin-regulated testicular RNA helicase gene polymorphism with human male infertility. AB - Gonadotrophin-regulated testicular RNA helicase (GRTH) plays an important role in RNA functions including nuclear transcription, pre-mRNA splicing and it regulates the translation of specific genes required for the progression of spermatogenesis. In this study, we analysed the association of GRTH gene IVS6+55G/T and c.852C/T polymorphisms with human male infertility. The study showed c.852 T allele was associated with an increased risk of male infertility (OR: 3.16, P = 0.008), whereas IVS6+55G/T allele conferred no risk. In Indian population, this is the first report on association of GRTH gene SNP polymorphism and male infertility and it underscores the significance of GRTH genotypes in modulating the risk of male infertility. PMID- 24168057 TI - Lack of host gut microbiota alters immune responses and intestinal granuloma formation during schistosomiasis. AB - Fatalities from schistosome infections arise due to granulomatous, immune mediated responses to eggs that become trapped in host tissues. Schistosome specific immune responses are characterized by initial T helper type 1 (Th1) responses and our previous studies demonstrated that myeloid differentiation primary response gene 88 (Myd88)-deficient mice failed to initiate such responses in vivo. Paradoxically, schistosomal antigens fail to stimulate innate cells to release proinflammatory cytokines in vitro. Since Schistosoma mansoni infection is an intestinal disease, we hypothesized that commensal bacteria could act as bystander activators of the intestinal innate immune system to instigate Th1 responses. Using a broad spectrum of orally administered antibiotics and anti mycotics we analysed schistosome-infected mice that were simultaneously depleted of gut bacteria. After depletion there was significantly less inflammation in the intestine, which was accompanied by decreased intestinal granuloma development. In contrast, liver pathology remained unaltered. In addition, schistosome specific immune responses were skewed and faecal egg excretion was diminished. This study demonstrates that host microbiota can act as a third partner in instigating helminth-specific immune responses. PMID- 24168059 TI - A rare presentation of malignant melanoma with acute hepatic and consecutive multisystem organ failure. PMID- 24168061 TI - Genetic variation, linkage mapping of QTL and correlation studies for yield, root, and agronomic traits for aerobic adaptation. AB - BACKGROUND: Water scarcity and drought have seriously threatened traditional rice cultivation practices in several parts of the world, including India. Aerobic rice that uses significantly less water than traditional flooded systems has emerged as a promising water-saving technology. The identification of QTL conferring improved aerobic adaptation may facilitate the development of high yielding aerobic rice varieties. In this study, experiments were conducted for mapping QTL for yield, root-related traits, and agronomic traits under aerobic conditions using HKR47 * MAS26 and MASARB25 * Pusa Basmati 1460 F2:3 mapping populations. RESULTS: A total of 35 QTL associated with 14 traits were mapped on chromosomes 1, 2, 5, 6, 8, 9, and 11 in MASARB25 x Pusa Basmati 1460 and 14 QTL associated with 9 traits were mapped on chromosomes 1, 2, 8, 9, 10, 11, and 12 in HKR47 * MAS26. Two QTL (qGY8.1 with an R2 value of 34.0% and qGY2.1 with an R2 value of 22.8%) and one QTL (qGY2.2 with an R2 value of 43.2%) were identified for grain yield under aerobic conditions in the mapping populations MASARB25 * Pusa Basmati 1460 and HKR47 * MAS26, respectively.A number of breeding lines with higher yield per plant, root length, dry biomass, length-breadth ratio, and with Pusa Basmati 1460-specific alleles in a homozygous or heterozygous condition at the BAD2 locus were identified that will serve as novel material for the selection of stable aerobic Basmati rice breeding lines. CONCLUSIONS: Our results identified positive correlation between some of the root traits and yield under aerobic conditions, indicating the role of root traits for improving yield under aerobic situations possibly through improved water and nutrient uptake. Co localization of QTL for yield, root traits, and yield-related agronomic traits indicates that the identified QTL may be immediately exploited in marker-assisted breeding to develop novel high-yielding aerobic rice varieties. PMID- 24168060 TI - Interleukin-6 induces malignant transformation of rat mesenchymal stem cells in association with enhanced signaling of signal transducer and activator of transcription 3. AB - Mesenchymal stem cells (MSCs) have the potential to be the source for cell-based therapies. However, MSCs can undergo malignant transformation in a tumor microenvironment where a high level of interleukin (IL)-6 is present. In this study, we investigated the role of IL-6 and signal transducer and activator of transcription 3 (STAT3) signaling in malignant transformation of MSCs. Rat MSCs were isolated and indirectly cocultured with C6 glioma cells. Coculture of MSCs with astrocytes was used as a control. After 7 days of culture, the cells were assessed for malignant transformation using MTT assay and immunofluorescence staining. The levels of hepatocyte growth factor, IL-6, and basic fibroblast growth factor, and the expression of STAT3 and soluble IL-6 receptor in the cultured cells and conditioned media were measured using RT-PCR, ELISA, and Western blot analysis. The expression levels of STAT3 downstream targets, CyclinD1 and Bcl-xl, were determined as well. Our data showed that almost all of the MSCs became phenotypically malignant after indirect coculture with glioma cells, which was confirmed by tumor formation assays when these cells were injected into nude mice. The expression of IL-6 was significantly increased in MSCs cocultured with glioma cells, which was associated with significantly increased expressions of soluble IL-6 receptor, transmembrane glycoprotein GP130, STAT3, phosphorylated STAT3, CyclinD1, and Bcl-xl. Similar results were obtained when the MSCs were treated with IL-6. Treatment of the cocultured MSCs and glioma cells with STA-21, to block the constitutive STAT3 signaling, reduced the risk of MSC tumor-like transformation in the tumor microenvironment. These data suggest that IL-6 plays a critical role in malignant transformation of rat MSCs, which is associated with an enhancement of the STAT3 signaling pathway in the tumor microenvironment. PMID- 24168062 TI - Dorso-ventral buccal mucosal graft for treating gunshot bulbar urethral damage. PMID- 24168063 TI - Casual sexual relationships and mental health in adolescence and emerging adulthood. AB - Casual sexual relationships are relatively common in emerging adulthood. Yet the mental health implications of engaging in these relationships are unclear; past research has found negative associations, positive associations, or no association with mental health. In addition, little research has accounted for mental health status prior to entering casual sexual relationships. Using data from the National Longitudinal Study of Adolescent Health (N = 12,401), we measured mental health prior to engaging in casual sexual relationships and subsequent mental health after engaging in these relationships. We found that suicidal ideation and depressive symptoms in adolescence were associated with entrance into casual sexual relationships in emerging adulthood. Furthermore, casual sexual relationships were associated with an increased likelihood of reporting suicidal ideation in emerging adulthood. PMID- 24168064 TI - The practice of defensive medicine among hospital doctors in the United Kingdom. AB - BACKGROUND: Defensive medicine is defined as a doctor's deviation from standard practice to reduce or prevent complaints or criticism. The objectives of this study were to assess the prevalence of the practice of defensive medicine in the UK among hospital doctors and the factors affecting it. METHODS: A quantitative study was designed, with a detailed seventeen point questionnaire. Defensive medicine practice was assessed and tested against four factors age, gender, specialty and grade. Three hundred hospital doctors from three UK hospitals received the questionnaire. RESULTS: Two hundred and four (68%) out of 300 hospital doctors responded to the survey. Seventy eight percent reported practicing one form or another of defensive medicine. Ordering unnecessary tests is the commonest form of defensive medicine reported by 59% of the respondents. This is followed by unnecessary referral to other specialties (55%). While only 9% of the sampled doctors would refuse to treat high risk patients, double this number would avoid high risks procedures all together (21%). A linear regression module has shown that only senior grade was associated with less practice of defensive medicine. CONCLUSION: Defensive medical practice is common among the doctors who responded to the survey. Senior grade is associated with less practice of defensive medicine. PMID- 24168065 TI - Species difference in the inhibitory potentials of non-steroidal anti inflammatory drugs on the hepatic sulfation and glucuronidation of bioactive flavonoids: differential observations among common inhibition parameters. AB - 1. This study elucidated the species differences between rats and humans in the inhibitory potential of drugs against sulfation and glucuronidation, and whether such differences depend on the inhibition parameter adopted. 2. With 14 non steroidal anti-inflammatory drugs (NSAIDs) as model inhibitors and three flavanoids baicalein, wogonin and oroxylin A as model substrates, three common inhibition parameters percentage of control, IC50 and Ki were determined in rat liver cytosols (RLCs), human liver cytosols (HLCs), rat liver microsomes (RLMs) and human liver microsomes (HLMs). The closeness of the inhibition parameters from rat liver preparations to that from human liver preparations was analyzed by geometric mean fold error (GMFE) and statistical comparisons. 3. The percentage of control in RLC/RLM was not significantly different from that in HLC/HLM, with a GMFE of 0.85 (RLC-HLC) and 1.03 (RLM-HLM); whereas the IC50 and Ki in RLC/RLM were significantly different from that in HLC/HLM. The trend of difference was consistent between IC50 and Ki, where these parameters in RLC and RLM underestimated (GMFE <0.5) and overestimated (GMFE >2) that in HLC and HLM, respectively. 4. In conclusion, the inhibitory potentials of NSAIDs against sulfation and glucuronidation in rats and humans were different and depended on the adopted inhibition parameters. PMID- 24168067 TI - High-pressure combinatorial process integrating hot isostatic pressing. AB - A high-pressure combinatorial process integrating hot isostatic pressing (HIP) was developed by providing a reaction vessel with a high-pressure tightness based on a commercial flange. The reaction vessel can be used up to 200 MPa and 500 degrees C under HIP processing condition. Preparation of spinel-type MgAl2O4 from Mg(OH)2, Al(OH)3 and AlOOH was performed using the reaction vessel under 200 MPa and 500 degrees C as demonstration. The entire powder library was characterized using powder X-ray diffraction patterns, and the single phase of spinel-type MgAl2O4 was obtained from Mg(OH)2+Al(OH)3. These assessments corresponded with previously published data. PMID- 24168068 TI - Nephrotoxic medication exposure in very low birth weight infants. AB - OBJECTIVE: To quantify exposure to potentially nephrotoxic medications among very low birth weight (VLBW) infants and determine the relationship of nephrotoxic medication exposure to acute kidney injury (AKI) in this vulnerable population. METHODS: We reviewed 107 VLBW infants who survived to discharge from April 2011 to March 2012 and measured exposure to the following nephrotoxic medications: acyclovir, amikacin, amphotericin B, gentamicin, ibuprofen, indomethacin, iohexol, tobramycin and vancomycin. Acute kidney injury was determined by the KDIGO guidelines. RESULTS: Exposure to >= 1 nephrotoxic medication occurred in 87% of infants. The most common exposures were gentamicin (86%), indomethacin (43%) and vancomycin (25%). There was an inverse linear relationship between birth weight and nephrotoxic medications received per day (R(2) = 0.169, p < 0.001). Infants with AKI received more nephrotoxic medications per day than those who did not (0.24 versus 0.15; p = 0.003). CONCLUSIONS: VLBW infants are frequently exposed to nephrotoxic medications, receiving approximately two weeks of nephrotoxic medications before discharge or 1 for every 6 d of hospitalization. The greatest exposure occurred among the smallest, most immature infants and those who experienced AKI. PMID- 24168069 TI - Combination therapy for Gram-negative bacteria: what is the evidence? AB - The treatment of infections caused by multidrug-resistant Gram-negative bacteria is challenging given the limited options for effective therapy. Combination therapy has garnered great interest recently, with the goals of ensuring appropriate therapy with at least one active agent, and achieving synergistic activity among the anti-microbials used. In this review, we evaluate the data supporting the use of combination therapy against Pseudomonas aeruginosa, carbapenem-resistant Enterobacteriaceae, Acinetobacter species and Stenotrophomonas maltophilia. Various regimens have been tried with promising results; however, the data are mostly derived from in vitro synergy studies. While these reports suggest an advantage of combination therapy over monotherapy, clinical data are scarce, and are comprised of retrospective and a few prospective observational studies. Well-designed randomized trials are needed to better elucidate the efficacy of the various combination regimens. Until then, this review offers a critical appraisal of the published literature and provides recommendations based on the available evidence. PMID- 24168070 TI - Dilated iris vasculature in the setting of the neonatal hypoxic encephelopathy. AB - The differential diagnosis of dilated iris vasculature in a neonate includes retinopathy of prematurity with anterior segment plus disease, persistent fetal vasculature, intrauterine cocaine exposure, maternal diabetes, and other pathologies associated with iris neovascularization and ischemia seen in adult populations, such as central retinal vein occlusions, ocular ischemic syndrome, and chronic retinal detachment. We present neonatal hypoxic ischemic encephalopathy as a new etiology of dilated iris vasculature in a male baby who suffered a large in-utero brain vasculature insult three weeks prior to delivery but with normal fundi, no risk factors for retinopathy of prematurity (normal birth weight, and gestational age), and no other explanatory etiologies. The mechanism of the dilated iris vasculature is likely also ischemic and therefore its presence likely portends a poor prognosis. We recommend that the neonatologist evaluate for this sign for this reason and consult ophthalmology to ensure its correct etiology. PMID- 24168071 TI - Colorimetric and luminescent sensors for chloride: hydrogen bonding vs deprotonation. AB - The synthesis and photophysical properties of four squaramide based fluorescent anion sensors (1-4) are described. These luminescent compounds showed selectivity for Cl(-) over various other anions with concomitant changes in both their UV/visible and fluorescence properties upon Cl(-) addition, attributed to initial H-bonding followed by NH deprotonation in the presence of excess Cl(-), signaled by a color change. The nature of the electron withdrawing aryl substituents is directly related to the H-bonding ability/acidity of the squaramide protons and can be used to tune the deprotonation behavior. PMID- 24168072 TI - Optical characterization of chemistry in shocked nitromethane with time-dependent density functional theory. AB - We compute the optical properties of the liquid-phase energetic material nitromethane (CH3NO2) for the first 100 ps behind the front of a simulated shock at 6.5 km/s, close to the experimentally observed detonation shock speed of the material. We utilize molecular dynamics trajectories computed using the multiscale shock technique (MSST) for time-resolved optical spectrum calculations based on both linear response time-dependent DFT (TDDFT) and the Kubo-Greenwood formula with Kohn-Sham DFT wave functions. We find that the TDDFT method predicts an optical conductivity 25-35% lower than the Kubo-Greenwood calculation and provides better agreement with the experimentally measured index of refraction of unreacted nitromethane. We investigate the influence of electronic temperature on the Kubo-Greenwood spectra and find no significant effect at optical wavelengths. In both Kubo-Greenwood and TDDFT, the spectra evolve nonmonotonically in time as shock-induced chemistry takes place. We attribute the time-resolved absorption at optical wavelengths to time-dependent populations of molecular decomposition products, including NO, CNO, CNOH, H2O, and larger molecules. These calculations offer direction for guiding and interpreting ultrafast optical measurements on reactive materials. PMID- 24168073 TI - Assessing excellence in translational cancer research: a consensus based framework. AB - BACKGROUND: It takes several years on average to translate basic research findings into clinical research and eventually deliver patient benefits. An expert-based excellence assessment can help improve this process by: identifying high performing Comprehensive Cancer Centres; best practices in translational cancer research; improving the quality and efficiency of the translational cancer research process. This can help build networks of excellent Centres by aiding focused partnerships. In this paper we report on a consensus building exercise that was undertaken to construct an excellence assessment framework for translational cancer research in Europe. METHODS: We used mixed methods to reach consensus: a systematic review of existing translational research models critically appraised for suitability in performance assessment of Cancer Centres; a survey among European stakeholders (researchers, clinicians, patient representatives and managers) to score a list of potential excellence criteria, a focus group with selected representatives of survey participants to review and rescore the excellence criteria; an expert group meeting to refine the list; an open validation round with stakeholders and a critical review of the emerging framework by an independent body: a committee formed by the European Academy of Cancer Sciences. RESULTS: The resulting excellence assessment framework has 18 criteria categorized in 6 themes. Each criterion has a number of questions/sub criteria. Stakeholders favoured using qualitative excellence criteria to evaluate the translational research "process" rather than quantitative criteria or judging only the outputs. Examples of criteria include checking if the Centre has mechanisms that can be rated as excellent for: involvement of basic researchers and clinicians in translational research (quality of supervision and incentives provided to clinicians to do a PhD in translational research) and well designed clinical trials based on ground-breaking concepts (innovative patient stratification, substantial fraction of phase I/II trials, investigator-initiated trials). Critically, the framework supports reduced bureaucracy by building on existing European evaluation systems. CONCLUSIONS: The excellence framework is the product of an intense stakeholder consensus building exercise. It will be piloted during an expert peer review/site visit of at least three European Comprehensive Cancer Centres. The findings regarding content, governance and implementation can have relevance for other clinical and research fields. PMID- 24168074 TI - Goal Management Training improves everyday executive functioning for persons with spina bifida: self-and informant reports six months post-training. AB - Executive dysfunction accounts for significant disability for many patients with spina bifida (SB), thus indicating the need for effective interventions aimed at improving executive functioning in this population. Goal Management TrainingTM (GMT) is a cognitive rehabilitation approach that targets disorganised behaviour resulting from executive dysfunction, and has received empirical support in studies of other patient groups. The purpose of this study was to determine if GMT would lead to perceived improved executive functioning in the daily lives of patients with SB, as evidenced by reduced report of dysexecutive problems in daily life on self- and informant questionnaires. Thirty-eight adults with SB were included in this randomised controlled trial (RCT). Inclusion was based upon the presence of executive functioning complaints. Experimental subjects (n = 24) received 21 hours of GMT, with efficacy of GMT being compared to results of subjects in a wait-list condition (n = 14). All subjects were assessed at baseline, post-intervention, and at six-month follow-up. Self-report measures indicated that the GMT group's everyday executive functioning improved significantly after training, lasting at least 6 months post-treatment. There were no significant effects on informant-report questionnaires. Overall, these findings indicate that executive difficulties in everyday life can be ameliorated for individuals with congenital brain dysfunction. PMID- 24168075 TI - Using Twitter for breast cancer prevention: an analysis of breast cancer awareness month. AB - BACKGROUND: One in eight women will develop breast cancer in her lifetime. The best-known awareness event is breast cancer awareness month (BCAM). BCAM month outreach efforts have been associated with increased media coverage, screening mammography and online information searching. Traditional mass media coverage has been enhanced by social media. However, there is a dearth of literature about how social media is used during awareness-related events. The purpose of this research was to understand how Twitter is being used during BCAM. METHODS: This was a cross-sectional, descriptive study. We collected breast cancer- related tweets from 26 September - 12 November 2012, using Twitter's application programming interface. We classified Twitter users into organizations, individuals, and celebrities; each tweet was classified as an original or a retweet, and inclusion of a mention, meaning a reference to another Twitter user with @username. Statistical methods included ANOVA and chi square. For content analysis, we used computational linguistics techniques, specifically the MALLET implementation of the unsupervised topic modeling algorithm Latent Dirichlet Allocation. RESULTS: There were 1,351,823 tweets by 797,827 unique users. Tweets spiked dramatically the first few days then tapered off. There was an average of 1.69 tweets per user. The majority of users were individuals. Nearly all of the tweets were original. Organizations and celebrities posted more often than individuals. On average celebrities made far more impressions; they were also retweeted more often and their tweets were more likely to include mentions. Individuals were more likely to direct a tweet to a specific person. Organizations and celebrities emphasized fundraisers, early detection, and diagnoses while individuals tweeted about wearing pink. CONCLUSIONS: Tweeting about breast cancer was a singular event. The majority of tweets did not promote any specific preventive behavior. Twitter is being used mostly as a one-way communication tool. To expand the reach of the message and maximize the potential for word-of-mouth marketing using Twitter, organizations need a strategic communications plan to ensure on-going social media conversations. Organizations may consider collaborating with individuals and celebrities in these conversations. Social media communication strategies that emphasize fundraising for breast cancer research seem particularly appropriate. PMID- 24168076 TI - Boundary slip of superoleophilic, oleophobic, and superoleophobic surfaces immersed in deionized water, hexadecane, and ethylene glycol. AB - The boundary slip condition is an important property, and its existence can reduce fluid drag in micro/nanofluidic systems. The boundary slip on various surfaces immersed in water and various electrolytes has been widely studied. For the surfaces immersed in oil, the boundary slip on superoleophilic and oleophilic surfaces has been studied, but there is no data on oleophobic and superoleophobic surfaces. In this paper, experiments are carried out to study electrostatic force and boundary slip on superoleophilic, oleophobic, and superoleophobic surfaces immersed in deionized (DI) water, hexadecane, and ethylene glycol. In addition, the surface charge density of the samples immersed in DI water is quantified. Results show that the electrostatic force and the absolute value of the surface charge density of an octadecyltrichlorosilane surface are larger than that of a polystyrene surface, and the electrostatic force and the absolute value of surface charge density of a superoleophilic surface are larger than that of oleophobic and superoleophobic surfaces. For the same liquid, the larger contact angle leads to a larger slip length at the solid-liquid interface. For the same surface, the larger liquid viscosity leads to a larger slip length. The relevant mechanisms are discussed in this paper. PMID- 24168077 TI - A randomized saline-controlled trial of NASHA hyaluronic acid for knee osteoarthritis. AB - OBJECTIVE: NASHA hyaluronic acid is administered as a single intra-articular injection to treat the symptoms of osteoarthritis (OA). In a previous trial, post hoc analysis indicated that NASHA provides significantly greater pain relief than saline in patients with OA confined to the study knee. We aimed to evaluate the safety and efficacy of NASHA in patients with unilateral knee OA. RESEARCH DESIGN AND METHODS: This was a randomized, double-blind, saline-controlled trial. All patients had knee OA confirmed by American College of Rheumatology criteria and a WOMAC pain score of 7-17 in the study knee, but no pain in the previous 3 months in the non-study knee. Treatment comprised a single intra-articular injection of NASHA or saline control. The follow-up period was 6 weeks. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov NCT01806207. MAIN OUTCOME MEASURES: The primary efficacy endpoint was the responder rate, defined as the percentage of patients with >=40% improvement from baseline in WOMAC pain score and an absolute improvement of >=5 points. RESULTS: A total of 218 patients received study treatment (NASHA: 108, saline: 110). In the main intention-to-treat (ITT) analysis, no statistically significant difference in responder rate was found between the two groups at 6 weeks (NASHA: 30.6%; saline: 26.4%). A post-hoc subgroup analysis of patients without clinical effusion in the study knee at baseline showed a significantly higher 6 week responder rate with NASHA than with saline: 40.6% versus 19.7% (p = 0.0084). A total of 68 adverse events were reported among 44 patients in the NASHA group, compared with 69 adverse events among 44 patients in the saline group. The main weakness of the study was the short, 6 week follow-up duration. In addition, image guidance was not used to ensure injection as intended into the intra-articular space. CONCLUSIONS: Single injection NASHA was well tolerated and, although there was no significant benefit versus saline control in the primary analysis, post-hoc analysis showed a statistically significant improvement in pain relief at 6 weeks among patients without clinical effusion at baseline. PMID- 24168078 TI - Prevalence of community-acquired methicillin-resistant Staphylococcus aureus and antibiotic resistance in patients with atopic dermatitis in Porto Alegre, Brazil. AB - BACKGROUND: Atopic dermatitis (AD) is a skin manifestation of atopy caused by hyperreactivity to various antigens. Studies have shown that 60-100% of patients with this condition present with colonization by Staphylococcus aureus. Given increasing rates of antimicrobial resistance, the sensitivity to antimicrobials of S. aureus colonizing atopic patients has been investigated. Cross-sectional studies worldwide suggest that the prevalence of methicillin-resistant S. aureus infection (MRSA) in the AD population varies from 0% to 30.8%. OBJECTIVES: The objectives of this study were to determinate the prevalence of S. aureus and MRSA in patients with AD in two dermatologic centers in Porto Alegre, Brazil. METHODS: A total of 91 patients with AD attending two dermatologic centers in Porto Alegre were enrolled in this study from December 2009 to July 2011. Two skin swabs were taken from each patient, one from the nares and the other from a non-infected eczematous skin lesion. The swabs were sent to the laboratory, where standard procedures to isolate bacteria and identify S. aureus, antimicrobial resistance, and sensitivity patterns were carried out. The severity of AD was defined using the Eczema Area and Severity Index (EASI). RESULTS: Of the 91 patients sampled, 67 (73.6%) patients were found to be positive for S. aureus colonization. Nasal swabs were positive in 55 (60.4%) patients, lesional swabs in 44 (48.4%) patients, and both lesional and nasal swabs were positive in 32 (35.2%) patients. Patients with positive swabs had a higher mean +/- standard deviation EASI score [mean (9.1 +/- 8.8)] compared with patients with negative swabs (3.9 +/- 3.6) (P = 0.002). None of the 91 patients showed any evidence of MRSA infection. Overall, nearly 32% of the S. aureus isolated from nasal swabs and 36.40% of the S. aureus isolated from lesional swabs was resistant to erythromycin. CONCLUSIONS: The results of this study confirm a high rate of S. aureus colonization in pediatric patients with AD and indicate a relevant association between colonization and high EASI score. No MRSA was found in cultures from this sample of patients in southern Brazil. Nearly one-third of isolates were identified as resistant to erythromycin, an antibiotic that is commonly used in pediatric patients. PMID- 24168079 TI - High dose droperidol and QT prolongation: analysis of continuous 12-lead recordings. AB - AIMS: To investigate the QT interval after high dose droperidol using continuous 12-lead Holter recordings. METHODS: This was a prospective study of patients given droperidol with a continuous Holter recording. Patients were recruited from the DORM II study which included patients with aggression presenting to the emergency department. Patients initially received 10 mg droperidol as part of a standardized sedation protocol. An additional 10 mg dose was given after 15 min if required and further doses at the clinical toxicologist's discretion. Continuous 12-lead Holter recordings were obtained for 2-24 h utilizing high resolution digital recordings with automated QT interval measurement. Electrocardiograms were extracted hourly from Holter recordings. The QT interval was plotted against heart rate (HR) on the QT nomogram to determine if it was abnormal. QTc F (Fridericia's HR correction) was calculated and >500 ms was defined as abnormal. RESULTS: Forty-six patients had Holter recordings after 10 40 mg droperidol and 316 QT-HR pairs were included. There were 32 abnormal QT measurements in four patients, three given 10 mg and one 20 mg. In three of the four patients QTc F >500 ms but only in one taking methadone was the timing of QTc F >500 ms consistent with droperidol dosing. Of the three other patients, one took amphetamines, one still had QT prolongation 24 h after droperidol and one took a lamotrigine overdose. No patient given >30 mg had a prolonged QT. There were no arrhythmias. CONCLUSION: QT prolongation was observed with high dose droperidol. However, there was little evidence supporting droperidol being the cause and QT prolongation was more likely due to pre-existing conditions or other drugs. PMID- 24168080 TI - A recombinant human hyaluronidase sustained release gel for the treatment of post surgical edema. AB - BACKGROUND: Edema commonly accompanies surgical procedures and when excessive, can adversely affect surgical outcomes. The skin extracellular matrix, including one of its primary components, hyaluronan (HA), is a significant barrier to effective drainage of accumulated edematous fluid. Recombinant human hyaluronidase (rHuPH20) is a human hyaluronidase that acts transiently and locally to depolymerize HA. A non-liposomal gel formulation that provides a sustained release of rHuPH20 was tested in vivo in a preclinical murine model of acquired lymphedema. METHODS: Lymphedemic mice were injected 24 hours before surgery, and at 2 and 12 days following surgery with rHuPH20 sustained release gel (PH20 SR gel). Quantitative assessment of treatment response indicated that a single dose of PH20 SR gel resulted in accelerated resolution and reduced severity of post-surgical edema as compared to the gel vehicle (control). RESULTS: Statistically significant enzymatic degradation of HA was demonstrated up to 5 mm from the injection site, and histological analysis confirmed removal of HA up to 72 hours following PH20 SR gel administration. CONCLUSIONS: These results demonstrate sustained hyaluronidase enzymatic activity that promotes diffusion of accumulated post-surgical edematous fluid, suggesting that PH20 SR gel may be a useful adjuvant in promoting postoperative edema resolution. PMID- 24168082 TI - Evaluation of interspecimen trypsin digestion efficiency prior to multiple reaction monitoring-based absolute protein quantification with native protein calibrators. AB - Implementation of quantitative clinical chemistry proteomics (qCCP) requires targeted proteomics approaches, usually involving bottom-up multiple reaction monitoring-mass spectrometry (MRM-MS) with stable-isotope labeled standard (SIS) peptides, to move toward more accurate measurements. Two aspects of qCCP that deserve special attention are (1) proper calibration and (2) the assurance of consistent digestion. Here, we describe the evaluation of tryptic digestion efficiency by monitoring various signature peptides, missed cleavages, and modifications during proteolysis of apolipoprotein A-I and B in normo- and hypertriglyceridemic specimens. Absolute quantification of apolipoprotein A-I and B was performed by LC-MRM-MS with SIS peptide internal standards at two time points (4 and 20 h), using three native protein calibrators. Comparison with an immunoturbidimetric assay revealed recoveries of 99.4 +/- 6.5% for apolipoprotein A-I and 102.6 +/- 7.2% for apolipoprotein B after 4 h of trypsin digestion. Protein recoveries after 20 h trypsin incubation equaled 95.9 +/- 6.9% and 106.0 +/- 10.0% for apolipoproteins A-I and B, respectively. In conclusion, the use of metrologically traceable, native protein calibrators looks promising for accurate quantification of apolipoprotein A-I and B. Selection of rapidly formed peptides, that is, with no or minor missed cleavages, and the use of short trypsin incubation times for these efficiently cleaved peptides are likely to further reduce the variability introduced by trypsin digestion and to improve the traceability of test results to reach the desirable analytical performance for clinical chemistry application. PMID- 24168083 TI - Annual report of the Australian National Enterovirus Reference Laboratory 2010 2011. AB - Australia conducts clinical surveillance for cases of polio-like illness in children in accordance with the World Health Organization (WHO) recommended surveillance criteria for acute flaccid paralysis (AFP). AFP cases are ascertained either by clinicians notifying the Australian Paediatric Surveillance Unit or designated nurses enrolling cases as part of the Paediatric Active Enhanced Disease Surveillance system at four sentinel tertiary paediatric hospitals. The National Enterovirus Reference Laboratory (NERL), formerly the National Poliovirus Reference Laboratory, is accredited by the World Health Organization (WHO) for the testing of faecal specimens from cases of AFP and operates as a Poliovirus Regional Reference Laboratory for the Western Pacific Region. In 2010 and 2011, for the 3rd and 4th consecutive years, Australia met the WHO AFP surveillance performance indicator. This is indicative of a sensitive surveillance system capable of detecting an imported case of polio in children. However, the faecal collection rate for the virological investigation of AFP cases was below the WHO surveillance performance indicator in both years and represented a gap in Australia's polio surveillance. Enterovirus and environmental surveillance were established in Australia as virological surveillance to complement the clinical surveillance schemes. No poliovirus was detected by the clinical or virological surveillance schemes in 2010 or 2011 and Australia maintained its polio-free status. India was declared polio-free in January 2012, a significant step towards global polio eradication, leaving Afghanistan, Nigeria and Pakistan as the remaining countries endemic for wild poliovirus. PMID- 24168081 TI - Clinical significance of macrophage heterogeneity in human malignant tumors. AB - The fact that various immune cells, including macrophages, can be found in tumor tissue has long been known. With the recent introduction of the novel concept of macrophage differentiation into a classically activated phenotype (M1) and an alternatively activated phenotype (M2), the role of tumor-associated macrophages (TAMs) is gradually beginning to be elucidated. Specifically, in human malignant tumors, TAMs that have differentiated into M2 macrophages act as "protumoral macrophages" and contribute to the progression of disease. Based on recent basic and preclinical research, TAMs that have differentiated into protumoral or M2 macrophages are believed to be intimately involved in the angiogenesis, immunosuppression, and activation of tumor cells. In this paper, we specifically discuss both the role of TAMs in human malignant tumors and the cell-cell interactions between TAMs and tumor cells. PMID- 24168084 TI - Surveillance for Creutzfeldt-Jakob disease in Australia: update to December 2012. AB - Nation-wide surveillance for transmissible spongiform encephalopathies including Creutzfeldt-Jakob disease (CJD) is undertaken by the Australian National Creutzfeldt-Jakob disease Registry (ANCJDR), based at the University of Melbourne. Surveillance has been undertaken since 1993. During this period the unit has evolved and adapted to changes in surveillance practices and requirements, the emergence of new disease subtypes, improvements in diagnostic capabilities and the overall heightened awareness and understanding of CJD and other transmissible spongiform encephalopathies in the health care setting. In 2012, routine surveillance continued. This brief report provides an update on the surveillance data collected by the ANCJDR prospectively from 1993 to December 2012, and retrospectively to 1970. It also highlights the recent release of the revised Australian CJD Infection Control Guidelines. PMID- 24168085 TI - Australian trachoma surveillance annual report, 2011. AB - Australia remains the only developed country to have endemic trachoma in some regions. Endemic levels of trachoma in Australia are found predominantly in remote and very remote Aboriginal communities. Data are collected from Aboriginal communities designated at risk for endemic trachoma (defined as a prevalence of 5% or greater among children) in the Northern Territory, South Australia and Western Australia. This report presents data collected in 2011. The World Health Organization (WHO) grading criteria were used to diagnose cases of trachoma in Aboriginal children with jurisdictions focusing screening activities on the 5-9 year age group. The prevalence of trachoma within a community was used to guide appropriate treatment strategies as a public health response. Aboriginal adults aged 40 years or older were screened for trichiasis. Population screening coverage for trichiasis in 2011 was 9% with a prevalence of 2% in those adults screened. Trachoma screening coverage of the estimated populationof children aged 5-9 years in at-risk communities was 65%. Trachoma prevalence among children aged 5-9 years who were screened was 7%. Of the communities screened, 47% were found to have no cases of active trachoma and 40% were found to have endemic levels. Treatment was required in 80 at-risk communities screened. Treatment coverage of active cases and their contacts varied between jurisdictions, ranging from 53% to 98%. This report provides evidence of increasing coverage of trachoma screening and control activities. In the Northern Territory and Western Australia, there is also evidence of a decline in the prevalence of infection that may be attributable to an improvement in control activities. Despite these apparent advances, trachoma prevalence remains at endemic levels in many communities in remote Australia. Continued efforts are required to ensure that Australia remains on track to reach the goal of elimination by 2020 or sooner. PMID- 24168086 TI - Supplementary report: surveillance of adverse events following immunisation among children aged less than seven years in Australia, 1 January to 30 June 2012. PMID- 24168087 TI - Assessing the threat of chikungunya virus emergence in Australia. AB - BACKGROUND: Chikungunya virus (CHIKV) is a major threat to Australia given the distribution of competent vectors, and the large number of travellers returning from endemic regions. We describe current knowledge of CHIKV importations into Australia, and quantify reported viraemic cases, with the aim of facilitating the formulation of public health policy and ensuring maintenance of blood safety. METHODS: Cases reported to the National Notifiable Disease Surveillance System (NNDSS) from 2002 to 2012 were analysed by place, month of acquisition, and place of residence. Rates of chikungunya importation were estimated based on reported cases and on the numbers of short-term movements. RESULTS: Between 2002 and 2012, there were 168 cases of chikungunya virus (CHIKV) imported into Australia. Victoria and New South Wales had the largest number of notifications. The main sources were Indonesia, India and Malaysia. The number of cases increased from 2008 to reach a peak in 2010 (n=64; 40%). Although Indonesia accounted for the majority of CHIKV notifications in Australia, travel from India had the highest CHIKV importation rate (number of imported cases per 100,000 travellers). CONCLUSIONS: The Australian population is increasingly at risk from CHIKV. Arrivals from endemic countries have increased concurrently with vector incursions via imported goods, as well as via local movement from the Torres Strait to North Queensland ports. An outbreak of CHIKV could have a significant impact on health, the safety of the blood supply and on tourism. Case and vector surveillance as well as population health responses are crucial for minimising any potential impact of CHIKV establishment in Australia. PMID- 24168088 TI - An outbreak of staphylococcal food poisoning in a commercially catered buffet. AB - Staphylococcal food poisoning is a common cause of foodborne illness. In Australia, since 2000, approximately 30% of foodborne Staphylococcus aureus outbreaks reported to OzFoodNet have been associated with foods prepared by commercial caterers. We conducted a retrospective cohort analysis of an outbreak of gastrointestinal illness among participants of an elite sporting event during which 22 individuals became ill after eating a commercially catered buffet dinner in June 2012. All recalled eating fried rice which had been intended for lunch service earlier that day and 20 of the 22 reported eating chicken stir-fry. Though no food samples were available for analysis, laboratory analysis conducted on four faecal specimens resulted in S. aureus being cultured from one specimen and S. aureus enterotoxin detected in another. The known epidemiology of staphylococcal food poisoning suggests a food contaminated by an infected food handler which was subject to temperature abuse may have caused the outbreak. As S. aureus foodborne outbreaks are often underreported, this investigation is a valuable contribution to the evidence-base and understanding of foodborne illness due to S. aureus and staphylococcal enterotoxin. PMID- 24168089 TI - Review of Australia's polio surveillance. AB - With eradication almost within reach, the importance of detecting every poliomyelitis case has taken on additional significance. The selected surveillance strategy must be effective and efficient. A review of polio surveillance in Australia was conducted to consider whether current strategies were optimal. Document review and semi-structured key informant interviews were used to conduct the review. Interviews were recorded, transcribed and thematically analysed. The review was an iterative process with feedback on the findings sought from interviewees. Since Western Pacific Regional polio elimination status was certified, one imported adult case was detected in 2007 in Australia, with no evidence of further transmission, and no Australian paediatric cases identified. Respondents reported that: it was not possible to prevent importations; paediatric cases were more likely to be identified than adult cases; and there may be a low level of suspicion among clinicians. Case detection and outbreak mitigation were considered key reasons to undertake polio surveillance. While Australia has not achieved one of the key World Health Organization (WHO) surveillance targets, this did not compromise Australias polio free status. Identified issues with polio surveillance were the potential for an importation with high attendant investigation and containment costs, low stool sample collection rates, and the opportunity to improve safeguards around the importation and laboratory storage of biological samples containing poliovirus. The review found strong support for ongoing polio surveillance, particularly to detect imported cases and to demonstrate commitment to maintaining a polio-free region. Existing polio surveillance strategies were considered appropriate for Australia. PMID- 24168090 TI - Adolescent school-based vaccination in Australia. AB - Adolescents have become an increasingly prominent target group for vaccination in Australia and other developed countries. Over the past decade, voluntary school based vaccination programs have evolved to become the primary method of delivering adolescent vaccines funded under Australia's National Immunisation Program (NIP). These programs operate at a state and territory level and offer NIP vaccines to adolescents in specific school grades using local teams of trained vaccine providers. This paper summarises the current operation of voluntary school-based vaccination programs in Australia. Information was obtained through a literature review, semi-structured interviews with those managing and implementing school-based vaccination programs in each jurisdiction and a review of program resources. Available coverage data was obtained from each state or territory. Vaccines are delivered at the school, during school hours, and typically target late primary or early secondary school grades. Written parental consent is required for any vaccine to be administered. Operation of the programs is influenced by various factors at the school and provider level. Despite variability in program implementation, collection and analysis of coverage data, comparable coverage has been achieved across all states and territories. Coverage is higher than that reported by other countries where adolescent vaccines are mandated for school entry or available only through community vaccination providers. Voluntary school-based vaccination programs are an established mechanism for the delivery of adolescent vaccines in Australia and vaccines offered will continue to evolve in light of national recommendations. Current gaps in evidence include a detailed understanding of the influence of procedural factors on uptake, the best ways to maximise consent form return and, standardisation of coverage data reporting. PMID- 24168091 TI - A history of adolescent school based vaccination in Australia. AB - As adolescents have become an increasingly prominent target group for vaccination, school-based vaccination has emerged as an efficient and effective method of delivering nationally recommended vaccines to this often hard to reach group. School-based delivery of vaccines has occurred in Australia for over 80 years and has demonstrated advantages over primary care delivery for this part of the population. In the last decade school-based vaccination programs have become routine practice across all Australian states and territories. Using existing records and the recollection of experts we have compiled a history of school based vaccination in Australia, primarily focusing on adolescents. PMID- 24168092 TI - National tuberculosis advisory committee 2012 committee report. PMID- 24168093 TI - Annual report of the Australian National Enterovirus Reference Laboratory 2012. AB - In 2012 no cases of poliomyelitis were reported through clinical surveillance in Australia, and poliovirus was not detected through virological surveillance. Australia conducts surveillance for cases of acute flaccid paralysis (AFP) in children less than 15 years as the main mechanism to monitor its polio-free status in accordance with World Health Organization (WHO) recommendations. Cases of AFP in children are notified to the Australian Paediatric Surveillance Unit or the Paediatric Active Enhanced Disease Surveillance System. In 2012 Australia reported 1.2 non-polio AFP cases per 100,000 children, meeting the WHO performance criterion for a sensitive system for the fifth year in a row. However the faecal specimen collection rate from AFP cases was 29%, which was well below the WHO target of 80%. Virological surveillance for poliovirus consists of two components. Firstly, the Enterovirus Reference Laboratory Network of Australia (ERLNA) reports on the typing of enteroviruses detected in or isolated from clinical specimens. Secondly, environmental surveillance is conducted at sentinel sites. These surveillance systems are co-ordinated by the National Enterovirus Reference Laboratory (NERL). PMID- 24168094 TI - Dietary intake of vegetables, fruits, and meats/beans as potential risk factors of acute myeloid leukemia: a Texas case-control study. AB - Diet has been identified as a risk factor for some cancers, but its role in adult de novo acute myeloid leukemia (AML) is unclear. This study was conducted at the University of Texas MD Anderson Cancer Center to evaluate associations between consumption of vegetables, fruits, and meats with AML risk among Texas residents. All participants, 323 adult de novo AML cases and 380 frequency-matched controls, completed demographic and food frequency questionnaires. Overall, AML risk was significantly decreased among those who consumed the most dark green vegetables, seafood, and nuts/seeds; and it was significantly increased among greatest consumers of red meat. Among men, AML risk was lowest among those whose consumption was in the highest quartile for fruits [odds ratio (OR) = 0.25, 95% confidence interval (CI) = 0.10-0.69], poultry (OR = 0.28, 95%CI = 0.10-0.78), and seafood (OR = 0.39, 95%CI = 0.16-0.96) compared to those in the lowest. Among women, risk was lowest among those whose consumption was in the highest quartile of dark-green vegetables (OR = 0.28, 95%CI = 0.12-.68), orange vegetables (OR = 0.40, 95%CI = 0.17-.96) and nuts/beans (OR = 0.26, 95%CI = 0.11-0.60). Based on these findings, interventions can be developed to modify intake of specific dietary components to reduce cancer risk. PMID- 24168095 TI - Isolation of human genomic DNA for genetic analysis from premature neonates: a comparison between newborn dried blood spots, whole blood and umbilical cord tissue. AB - BACKGROUND: Genotyping requires biological sample collection that must be reliable, convenient and acceptable for patients and clinicians. Finding the most optimal procedure of sample collection for premature neonates who have a very limited blood volume is a particular challenge. The aim of the current study was to evaluate the use of umbilical cord (UC) tissue and newborn dried blood spot (DBS)-extracted genomic DNA (gDNA) as an alternative to venous blood-derived gDNA from premature neonates for molecular genetic analysis.All samples were obtained from premature newborn infants between 24-32 weeks of gestation. Paired blood and UC samples were collected from 31 study participants. gDNA was extracted from ethylenediaminetetraacetic acid (EDTA) anticoagulant-treated blood samples (~500 MUl) and newborn DBSs (n = 723) using QIAamp DNA Micro kit (Qiagen Ltd., Crawley, UK); and from UC using Qiagen DNAeasy Blood and Tissue kit (Qiagen Ltd., Crawley, UK). gDNA was quantified and purity confirmed by measuring the A260:A280 ratio. PCR amplification and pyrosequencing was carried out to determine suitability of the gDNA for molecular genetic analysis. Minor allele frequency of two unrelated single nucleotide polymorphisms (SNPs) was calculated using the entire cohort. RESULTS: Both whole blood samples and UC tissue provided good quality and yield of gDNA, which was considerably less from newborn DBS. The gDNA purity was also reduced after 3 years of storage of the newborn DBS. PCR amplification of three unrelated genes resulted in clear products in all whole blood and UC samples and 86%-100% of newborn DBS. Genotyping using pyrosequencing showed 100% concordance in the paired UC and whole blood samples. Minor allele frequencies of the two SNPs indicated that no maternal gDNA contamination occurred in the genotyping of the UC samples. CONCLUSIONS: gDNAs from all three sources are suitable for standard PCR and pyrosequencing assays. Given that UC provide good quality and quantity gDNA with 100% concordance in the genetic analysis with whole blood, it can replace blood sampling from premature infants. This is likely to reduce the stress and potential side effects associated with invasive sample collection and thus, greatly facilitate participant recruitment for genetic studies. PMID- 24168096 TI - Anterior segment applications of in vivo confocal microscopy. AB - PURPOSE: To review the current literature on in vivo confocal microscopy anterior segment applications (cornea, conjunctiva, and glaucoma) and discuss its advantages in different pathological conditions. METHODS: Review of selected relevant literature on in vivo confocal microscopy and its different applications. RESULTS: In vivo confocal microscopy can be used to visualize most layers of the cornea and conjunctiva, providing excellent resolution. In the past, it was mainly utilized as a research tool; lately there seems to be an increasing interest for clinical applications; confocal microscopy aids the diagnosis and follow-up of many anterior segment disorders, such as corneal dystrophies, corneal and conjunctival inflammatory and neoplastic diseases, glaucoma patients, and assessment of surgical procedures. CONCLUSION: In vivo confocal microscopy is an important addition to the ophthalmic diagnostic tools with several anterior segment applications. Its clinical applications are being continuously explored and are quickly expanding to cover many new pathological aspects. PMID- 24168097 TI - Clinical applications of attenuated MVA poxvirus strain. AB - The highly attenuated poxvirus strain modified vaccinia virus Ankara (MVA) has reached maturity as a vector delivery system and as a vaccine candidate against a broad spectrum of diseases. This has been largely recognized from research on virus-host cell interactions and immunological studies in pre-clinical and clinical trials. This review addresses the studies of MVA vectors used in phase I/II clinical trials, with the aim to provide the main findings obtained on their behavior when tested against relevant human diseases and cancer and also highlights the strategies currently implemented to improve the MVA immunogenicity. The authors assess that MVA vectors are progressing as strong vaccine candidates either alone or when administered in combination with other vectors. PMID- 24168100 TI - Exploitation of dual character of CN moiety in the synthesis of uniquely decorated 3H-pyrroles: a rare observation. AB - This is the first report of an innovative, one-pot, organocatalyzed, multicomponent synthesis of 3H-pyrroles from ketones, thiols, and malononitrile in ecofriendly solvent water. The approach to 3H-pyrroles presented herein offers, for the first time, an unprecedented coupling which leads to the construction of the nitrogen containing ring without starting from any amine moiety. In this context, cyanide-based multicomponent reactions involving the dual nature of the CN moiety has blossomed in an unprecedented way. PMID- 24168099 TI - Emergency endoscopy for acute gastrointestinal bleeding: prognostic value of endoscopic hemostasis and the AIMS65 score in Japanese patients. AB - BACKGROUND AND AIM: To evaluate the prognostic factors, including risk scores (Glasgow-Blatchford score and AIMS65) in patients with acute upper or lower gastrointestinal bleeding. METHODS: The medical records of patients who had undergone emergency gastrointestinal endoscopy for suspected gastrointestinal bleeding during the past 5 years were retrospectively analyzed. RESULTS: A total of 232 endoscopies (130 esophagogastroduodenoscopies, 102 colonoscopies) for 192 patients met the inclusion criteria. Median age was 66 years, and 64% of patients were males. Endoscopy identified causes for bleeding in 173 patients (post endoscopic interventions for neoplastic lesions in 36 cases, colonic diverticula in 34, gastroduodenal ulcers in 29, gastric erosions in 15, vascular ectasia in 14, post-biopsy bleeding in 13, malignant tumors in 10, inflammatory conditions in nine, esophagogastric varices in five, Mallory-Weiss tears in four, nasalbleeding in three, and injury by swallowed blister pack in one), whereas the source of bleeding remained obscure in 19 patients. Blood transfusion was given in 97 patients (51%), and 97 (51%) underwent endoscopic hemostasis. During the follow-up period, 49 patients (26%) experienced rebleeding, seven of whom were treated by interventional radiology. Thirty-nine patients (20%) died as a result of various diseases. The probabilities of overall survival (OS) after 3 and 5 years were 71% and 67%, respectively. Cox multivariate analysis revealed blood transfusion, co-existing malignancy, absence of endoscopic hemostasis, and high AIMS65 score to be independent prognostic factors for poor OS. CONCLUSION: The AIMS65 score is useful for predicting the prognosis of patients with acute gastrointestinal bleeding. PMID- 24168101 TI - HCl accommodation, dissociation, and propensity for the surface of water. AB - A new reactive and polarizable molecular model was developed to describe HCl dissociation in liquid water and used to investigate HCl behavior at the air water interface. It was found that the mechanism of HCl accommodation at the air water interface began with its hydrogen pointing toward the water as it approached from the air. This was followed by dissociation into a contact ion pair once solvated at the air-water interface with the hydronium oriented more toward the air than the chloride on average. In comparison with NaCl, HCl showed some similar behavior in that its contact ion pair was stabilized at the air water interface in comparison with the bulk. However, dissociated HCl had a greater propensity for the air-water interface than NaCl due to the fact that the hydronium ion was more surface active than sodium. PMID- 24168098 TI - Transcriptome interrogation of human myometrium identifies differentially expressed sense-antisense pairs of protein-coding and long non-coding RNA genes in spontaneous labor at term. AB - OBJECTIVE: To identify differentially expressed long non-coding RNA (lncRNA) genes in human myometrium in women with spontaneous labor at term. MATERIALS AND METHODS: Myometrium was obtained from women undergoing cesarean deliveries who were not in labor (n = 19) and women in spontaneous labor at term (n = 20). RNA was extracted and profiled using an Illumina(r) microarray platform. We have used computational approaches to bound the extent of long non-coding RNA representation on this platform, and to identify co-differentially expressed and correlated pairs of long non-coding RNA genes and protein-coding genes sharing the same genomic loci. RESULTS: We identified co-differential expression and correlation at two genomic loci that contain coding-lncRNA gene pairs: SOCS2 AK054607 and LMCD1-NR_024065 in women in spontaneous labor at term. This co differential expression and correlation was validated by qRT-PCR, an experimental method completely independent of the microarray analysis. Intriguingly, one of the two lncRNA genes differentially expressed in term labor had a key genomic structure element, a splice site, that lacked evolutionary conservation beyond primates. CONCLUSIONS: We provide, for the first time, evidence for coordinated differential expression and correlation of cis-encoded antisense lncRNAs and protein-coding genes with known as well as novel roles in pregnancy in the myometrium of women in spontaneous labor at term. PMID- 24168102 TI - Nonexercise physical activity and inflammatory and oxidative stress markers in women. AB - BACKGROUND: Leisure time exercise has been linked to lower circulating levels of inflammatory markers. Few studies have examined the association of nonexercise physical activity with markers of inflammation and oxidative stress. METHODS: This cross-sectional analysis included 1005 Chinese women aged 40-70 years. Usual physical activity was assessed through in-person interviews using a validated physical activity questionnaire. Plasma proinflammatory cytokines and urinary F2 isoprostanes were measured. Multivariable linear models were used to evaluate the association of inflammatory and oxidative stress markers with nonexercise physical activity and its major components. RESULTS: Nonexercise physical activity accounted for 93.8% of overall physical activity energy expenditure. Levels of nonexercise physical activity were inversely associated with circulating concentrations of interleukin (IL)-6 (Ptrend=0.004), IL-1beta (Ptrend=0.03) and tumor necrosis factor-alpha (TNF-alpha) (Ptrend=0.01). Multivariable-adjusted concentrations of these cytokines were 28.2% for IL-6, 22.1% for IL-1beta, and 15.9% for TNF-alpha lower in the highest quartile of nonexercise physical activity compared with the lowest quartile. Similar inverse associations were found for two major components of nonexercise physical activity, walking and biking for transportation, and household activity. No significant associations were observed between nonexercise physical activity and oxidative stress markers. CONCLUSION: Daily nonexercise physical activity is associated with lower levels of systemic inflammation. This finding may have important public health implications because this type of activity is the main contributor to overall physical activity among middle-aged and elderly women. PMID- 24168103 TI - Relationship of phasic left atrial volume and emptying function to left ventricular filling pressure: a cardiovascular magnetic resonance study. AB - BACKGROUND: Left atrial volume (LAV) and emptying fraction (LAEF) are phasic during cardiac cycle. Their relationships to left ventricular end diastolic pressure (LVEDP) have not been fully defined. METHODS: Forty one patients undergoing clinically indicated left heart catheterization were recruited for same day cardiovascular magnetic resonance (CMR). LAV and LAEF were assessed in cine images using biplane area and length method. Three phasic LAV was assessed at LV end systole (LAV(max)), LV end diastole (LAV(min)) and late LV diastole prior to LA contraction (LAV(ac)). LAEF was assessed as global LAEF (LAEF(Total)), passive (LAEF(Passive)) and active LAEF (LAEF(Contractile)). The relationships of phasic LAV and LAEF to LVEDP were assessed using Receiver operating characteristic comparing areas under the curves (AUC). RESULTS: The mean age of the patients was 59 years. A history of heart failure was present in 16 (39%) with NYHA functional class III or IV in 8 (20%) patients. Average LV ejection fraction was 49 +/- 16% ranging from 10% to 74% and LVEDP by catheterization 14 +/- 8 mmHg ranging from 4 mmHg to 32 mmHg. LAV(min) had the strongest association with LVEDP elevation (>12 mmHg) (AUC 0.765, p = 0.002), as compared to LAV(max) (AUC 0.677, p = 0.074) and LAV(ac) (AUC 0.735, p = 0.008). Among three phasic LAEF assessed, LAEF(Total) had the closest association with LVEDP elevation (AUC 0.780, p = 0.001), followed by LAEF(Contractile) (AUC 0.698, p = 0.022) and LAEF(Passive) (AUC 0.656, p = 0.077). CONCLUSIONS: Increased LAV(min) and decreased LAEF(Total) have the best performance in identifying elevated LVEDP among three phasic LAV and LAEF analyzed. Future studies should further characterize LA phasic indices in clinical outcomes. PMID- 24168105 TI - Cutaneous botryomycosis caused by Staphylococcus aureus in a patient with diabetes. PMID- 24168104 TI - Clinical management patterns and treatment outcomes in patients with non-small cell lung cancer (NSCLC) across Europe: EPICLIN-Lung study. AB - BACKGROUND: Throughout Europe, physicians face similar challenges in non-small cell lung cancer (NSCLC) management, but comprehensive international information on usual clinical practice is lacking so the burden of NSCLC is not fully understood. METHODS: This multinational, multicentre, non-interventional study (NCT00831909) was conducted in eight European countries. Patients with confirmed NSCLC were consecutively enrolled from January to March 2009 and followed for 12 months or until death. Information was collected on patient and disease characteristics, diagnosis and treatment patterns, and clinical outcomes. Spontaneously reported adverse events (AEs) were also recorded. RESULTS: Data were available for 3508 patients. Most patients (77.5%) were male, median (range) age was 65.0 years (21.6-90.7), the majority of patients had a World Health Organization performance status of <=1 (74.7%), and 10.8% were never smokers. The most prevalent histologies were adenocarcinoma (43.8%) and squamous-cell carcinoma (29.4%). Most patients presented with advanced disease (11.6% with stage IIIA, 18.7% with stage IIIB, 48.6% with stage IV). In stage IV disease, median progression-free survival and overall survival (months) by first-line treatment cluster were platinum regimens: 6.5, 10.8; non-platinum regimens: 4.3, 8.5; regimens with bevacizumab 8.7, 12.9; investigational regimens: 5.6, 10.8; best supportive care: 5.4, 6.6. The most frequently reported severe (Common Terminology Criteria for Adverse Events v3.0>2) AEs were blood/bone marrow (16.0%) and pulmonary/upper respiratory (7.8%). Key limitations of this study related to its non-interventional nature and wide regional focus; for example, achieving a representative sample of the overall NSCLC population, variation in recruitment between countries, and data based on information from medical records derived from routine visits. CONCLUSIONS: The Epidemiological Study to Describe NSCLC Clinical Management Pattern in Europe-Lung (EPICLIN-Lung) study provides new insights into the descriptive patterns and clinical management strategies for NSCLC across Europe, and how they affect patient outcomes. PMID- 24168106 TI - Large gas containing hepatic abscess following transarterial chemoembolization. PMID- 24168107 TI - Effect of mushroom diet on pharmacokinetics of gabapentin in healthy Chinese subjects. AB - AIMS: This study evaluated the pharmacokinetics of gabapentin in Chinese subjects who received a diet rich in shiitake mushrooms. Shiitake mushrooms have been shown to contain high amount of ergothioneine. In vitro studies have shown that OCTN1-mediated secretion of gabapentin is trans-stimulated by ergothioneine. This study also investigated the concentrations of ergothioneine in plasma at baseline and following mushroom consumption. METHODS: Ten healthy male subjects were recruited and received a diet containing no mushrooms (treatment A) or a high mushroom diet (treatment B; after at least a 7 day washout period) 1 day prior to administration of a single oral dose of gabapentin 600 mg. RESULTS: Ingestion of shiitake mushrooms produced significant increases in plasma ergothioneine concentrations that were sustained for more than 48 h. A statistically significant but modest increase in the renal clearance (CLR ) of gabapentin occurred after intake of the mushroom diet (91.1 +/- 25.1 vs. 76.9 +/- 20.6 ml min(-1) , P = 0.031). No significant changes in AUC(0,tlast ) of gabapentin were observed (P = 0.726). Creatinine clearance did not correlate with CLR of gabapentin at baseline (treatment A). After ingestion of the mushroom diet, creatinine clearance accounted for 65.3% of the variance in CLR of gabapentin. CONCLUSIONS: These data suggest that diet-drug pharmacokinetic interactions may occur during co-exposure to gabapentin and mushroom constituents. However, as it does not affect the AUC(0,tlast ) of gabapentin, it may not have clinically important consequences. Shiitake mushrooms can also be used as a source of ergothioneine for future clinical studies. PMID- 24168108 TI - Effectiveness of experiential life skills coaching for youth with a disability. AB - AIMS: There is little empirical evidence about the effectiveness of life skills programs in preparing youth with disabilities for successful participation in adult life. This retrospective study examined the effectiveness of an experiential life skills coaching intervention. METHODS: Using Goal Attainment Scaling (GAS) and the Canadian Occupational Performance Measure (COPM) as outcome measures, we compared the effectiveness of group-based and one-to-one interventions on goal attainment, and explored whether this was affected by gender or goal domain. RESULTS: We found that goal attainment was statistically and clinically significant for all genders and intervention formats. No differences in goal attainment were found between group and one-to-one interventions. CONCLUSIONS: These results provide evidence for the effectiveness of goal-focused, community-based experiential life skills interventions to support skill development in youth with a disability and help them prepare for transition to adult life. PMID- 24168109 TI - Diabetes care and service access among elderly Vietnamese with type 2 diabetes. AB - BACKGROUND: Vietnamese patients are disproportionately represented in type 2 diabetes mellitus statistics and also incur high rates of diabetes complications. This situation is compounded by limited access to health care. The aim of this project was to gain a deeper understanding of the difficulties Vietnamese patients experience when accessing services and managing their type 2 diabetes mellitus, and to identify factors that are important in promoting health service use. METHODS: Three focus groups with 15 Vietnamese participants with type 2 diabetes mellitus, 60 to >70 years of age, were conducted in Vietnamese. Open ended questions were used and focussed on experiences of living with diabetes and access to healthcare services in the Inner Northwest Melbourne region. Audio recordings were transcribed and then translated into English. Data were analysed using a thematic analysis framework. RESULTS: Findings indicate four main themes, which together provide some insight into the experiences of living with diabetes and accessing ongoing care and support, for elderly Vietnamese with type 2 diabetes. Themes included: (1) the value of being healthy; (2) controlling diabetes; (3) staying healthy; and (4) improving services and information access. CONCLUSIONS: Participants in this study were encouraged to adhere to diabetes self-management principles, based largely on a fear of medical complications. Important aspects of healthcare access were identified as; being treated with respect, having their questions answered and having access to interpreters and information in Vietnamese. Attention to these details is likely to lead to improved access to healthcare services and ultimately to improve glycemic control and overall health status for this community. PMID- 24168111 TI - An investigation into the anticancer effects and mechanism of action of hop beta acid lupulone and its natural and synthetic derivatives in prostate cancer cells. AB - Lupulone, a beta-acid derived from hop extracts has been shown to exhibit antibacterial and anticancer activity. In this study we investigated the anticancer potency of lupulone and its novel derivatives and their mechanism of action on prostate cancer cells. Cell viability was determined using the MTT assay, and the ELISA approach was used to investigate induction of apoptosis. Immunoblot analysis was carried out to determine activation and regulation of proteins associated with cell death. Screening of natural and new lupulone derivatives for their anticancer activity demonstrated that one (lupulone derivative 1h) displayed stronger anticancer activity than lupulone itself on PC3 and DU145 prostate cancer cells. We further found that lupulone derivatives induced caspase-dependent apoptosis that is associated with activation of caspases 8, 9, and 3. Furthermore, caspase 8 inhibitor Z-IETD-fmk reduced cell death induced by lupulone derivatives, suggesting that apoptosis is mediated by caspase 8. Finally, we found that lupulone and its synthetic derivatives also increased formation of LC3II suggesting that autophagy is also implicated in prostate cancer cell death. The new lupulone derivatives induce caspase-dependent apoptosis and autophagy in prostate cancer cells and appear to be good candidates for further preclinical studies of prostate cancer treatment. PMID- 24168110 TI - Increased expression of system large amino acid transporter (LAT)-1 mRNA is associated with invasive potential and unfavorable prognosis of human clear cell renal cell carcinoma. AB - BACKGROUND: The system L amino acid transporter (LAT) has an important role in the transport of various amino acids, and there have been reports about the relation of this system to cancer. Although LATs are highly expressed in the kidneys, little is known about their influence on human renal cancer. METHODS: To clarify the role of LATs in human clear cell renal cell carcinoma (RCC), we investigated the expression of mRNAs for LAT1, LAT2, LAT3, LAT4, and 4F2hc in clear cell RCC tissues. The mRNAs of these five genes were analyzed by the real time reverse transcription polymerase chain reaction in matched sets of tumor and non-tumor tissues obtained at operation from 82 Japanese patients with clear cell RCC. We also measured phosphorylated S6 ribosomal protein (Ser-235/236) proteins levels in 18 paired tumor and non-tumor tissues of the patients by Western blotting. RESULTS: Expression of LAT1 mRNA was significantly increased in tumor tissue compared with non-tumor tissue, while expression of LAT2 and LAT3 mRNAs was reduced. There was no difference in the expression of LAT4 and 4F2hc mRNAs between tumor and non-tumor tissues. Increased expression of LAT1 mRNA was associated with less differentiated tumors, local invasion, microscopic vascular invasion, and metastasis. Kaplan-Meier survival analysis showed that a higher serum LAT1 mRNA level was associated with a shorter overall survival time. Phosphorylated S6 ribosomal protein levels were associated with metastatic potential. LAT1 mRNA levels positively correlated with phosphorylated S6 ribosomal protein proteins levels in primary tumors. CONCLUSIONS: These findings suggest that LAT1 mRNA is related to the invasive and progressive potential of clear cell RCC. PMID- 24168113 TI - Capillary malformation-arteriovenous malformation: a clinical review of 45 patients. AB - BACKGROUND: Capillary malformation-arteriovenous malformation (CM-AVM) is a recently described autosomal dominant disorder that results from mutations in RASA1. It has been initially described as multiple CMs affecting several members of the same family, associated with fast-flow malformations in at least one family member. OBJECTIVE: To report and analyze clinical data on 45 patients with CM-AVM assessed at the Department of Pediatric Dermatology, Ramos Mejia Hospital (Buenos Aires, Argentina). METHOD: Retrospective clinical review of all the patients clinically diagnosed as having CM-AVM over a period of eight years. RESULTS: Forty-five patients were recorded (24 females and 21 males). The age ranged from one month to 44 years. In 36 patients, the stains were congenital; progressive acquired lesions were observed in 39. Family history was positive in 32 subjects. Well defined, round to oval, pink-purple or reddish-brown macules were found in all the patients; pinpoint red lesions with a pale halo were found in nine cases. The macules were warmer than normal skin in 15 cases and surrounded by a white halo in 26 cases. Three subjects presented associated overgrowth, lymphatic malformation was present in one case, retinal vascular lesion in one patient, and isolated port wine stain in two cases. Three patients also had infantile hemangioma. We had no cases of fast-flow vascular malformation or combined vascular syndromes. CONCLUSIONS: CM-AVM is a heterogeneous disorder with phenotypic variability, from fast-flow malformation, limb enlargement, or Parkes Weber syndrome to multiple CMs without internal involvement. PMID- 24168112 TI - Novel anti-tumor mechanism of galanin receptor type 2 in head and neck squamous cell carcinoma cells. AB - Galanin and its receptors, GALR1 and GALR2, are known tumor suppressors and potential therapeutic targets in head and neck squamous cell carcinoma (HNSCC). Previously, we demonstrated that, in GALR1-expressing HNSCC cells, the addition of galanin suppressed tumor proliferation via upregulation of ERK1/2 and cyclin dependent kinase inhibitors, whereas, in GALR2-expressing cells, the addition of galanin not only suppressed proliferation, but also induced apoptosis. In this study, we first transduced HEp-2 and KB cell lines using a recombinant adeno associated virus (rAAV)-green fluorescent protein (GFP) vector and confirmed a high GFP expression rate (>90%) in both cell lines at the standard vector dose. Next, we demonstrated that GALR2 expression in the presence of galanin suppressed cell viability to 40-60% after 72 h in both cell lines. Additionally, the annexin V-positive rate and sub-G0/G1 phase population were significantly elevated in HEp 2 cells (mock vs GALR2: 12.3 vs 25.0% (P < 0.01) and 9.1 vs 32.0% (P < 0.05), respectively) after 48 h. These changes were also observed in KB cells, although to a lesser extent. Furthermore, in HEp-2 cells, GALR2-mediated apoptosis was caspase-independent, involving downregulation of ERK1/2, followed by induction of the pro-apoptotic Bcl-2 protein, Bim. These results illustrate that transient GALR2 expression in the presence of galanin induces apoptosis via diverse pathways and serves as a platform for suicide gene therapy against HNSCC. PMID- 24168115 TI - Evaluation of short stature in children. AB - Normal growth in children is a reflection of general health and is the result of a complex interaction between genetic, nutritional, and hormonal factors. From conception through infancy, growth is mostly driven by maternal nutrition and the in utero environment. Genetic factors, growth and thyroid hormones, ghrelin, and sex steroids have a more prominent influence later. Normal growth is not linear; it is marked by periods of growth spurts, particularly during puberty, separated by periods of slow or immeasurable growth. There is often a period of growth deceleration observed before the onset of puberty, with maximal pubertal growth spurts occurring at Tanner stage III for girls and Tanner stage IV for boys. This is caused primarily by the combined effect of the increased amplitude of growth hormone pulses and sex steroids. Short stature (SS), which is the subject of this review, is defined as a length or height more than 2 standard deviations below the mean for age and gender, which corresponds to a percentile below 2.5%. Taking a thorough patient history and completing a comprehensive physical examination are some of the most important diagnostic tools for pediatricians to use in the diagnosis of SS, and in making appropriate referrals as needed. PMID- 24168116 TI - Diagnosis and treatment of adolescent idiopathic scoliosis. AB - Scoliosis is defined as a lateral curvature of the spine greater than 10 degrees on radiography that is typically associated with trunk rotation. The three major types of scoliosis are congenital, idiopathic, and neuromuscular. Idiopathic scoliosis is divided into three subcategories based on the age of onset. Infantile idiopathic scoliosis affects patients younger than 3 years, juvenile idiopathic scoliosis appears in children between 3 and 10 years, and adolescent idiopathic scoliosis (AIS) occurs in skeletally immature patients older than 10 years. AIS is the most common form of idiopathic scoliosis. Approximately 2% to 4% of children aged 10 to 16 years have some degree of spinal curvature. Although some researchers view routine screening for AIS as controversial, well-child examinations and sports physicals are an optimal time to evaluate for AIS in the clinical setting. In 2008, the American Academy of Orthopaedic Surgeons, the Scoliosis Research Society, the Pediatric Orthopaedic Society of North America, and the American Academy of Pediatrics convened a task force to review the issues related to scoliosis screening and issued an information statement concluding that although screening has limitations, the potential benefits that patients with idiopathic scoliosis receive from early treatment can be substantial. Recommendations are now that females are screened twice, at age 10 and 12 years, and males once at age 13 or 14 years. Screening during routine well-child examinations and/or school-based evaluations will help identify patients who need ongoing monitoring. The evaluation of curvatures in conjunction with the level of skeletal maturity will help to guide the management of the curvature. PMID- 24168114 TI - Arginine modifications by methylglyoxal: discovery in a recombinant monoclonal antibody and contribution to acidic species. AB - Heterogeneity is common among protein therapeutics. For example, the so-called acidic species (charge variants) are typically observed when recombinant monoclonal antibodies (mAbs) are analyzed by weak-cation exchange chromatography (WCX). Several protein post-translational modifications have been established as contributors but still cannot completely account for all heterogeneity. As reported herein, an unexpected modification by methylglyoxal (MGO) was identified, for the first time, in a recombinant monoclonal antibody expressed in Chinese hamster ovary (CHO) cells. Modifications of arginine residues by methylglyoxal lead to two adducts (dihydroxyimidazolidine and hydroimidazolone) with increases of molecular weights of 72 and 54 Da, respectively. In addition, the modification by methylglyoxal causes the antibody to elute earlier in the weak cation exchange chromatogram. Consequently, the extent to which an antibody was modified at multiple sites corresponds to the degree of shift in elution time. Furthermore, cell culture parameters also affected the extent of modifications by methylglyoxal, a highly reactive metabolite that can be generated from glucose or lipids or other metabolic pathways. Our findings again highlight the impact that cell culture conditions can have on the product quality of recombinant protein pharmaceuticals. PMID- 24168117 TI - Musculoskeletal screening: developmental dysplasia of the hip. AB - Developmental dysplasia of the hip (DDH) is common because it is present in 1 of 100 newborns. Failure to diagnose DDH and treat in infancy can result in significant long-term disability. Early diagnosis can be accomplished through a quick but careful physical examination of all newborns. Further selective screening by ultrasound is indicated for those children with risk factors for DDH, which include family history, breech presentation, and unstable hip examination at the initial newborn examination. Continued examination of the hip at all routine well-child checkups is mandatory through the first year of life because late presenting DDH may occur. Treatment with a Pavlik harness is not typically instituted in the neonate because many unstable hips stabilize without intervention, but it is indicated in children older than 2 weeks with hip instability. Ultrasound screening for infants with risk factors for DDH is recommended at age 6 weeks. Pavlik harness treatment for children with unstable hips or significant dysplasia on ultrasound is continued until the hips stabilize and show concentric reduction on imaging. With time, diagnosis and treatment evolve to accommodate the growing child. Infants who fail to respond to nonoperative management may require more extensive interventions. At any time when treatment is initiated, a DDH specialist should be involved in the patient's care. If DDH is recognized early, treatment is less invasive, and long-term effects are minimized. PMID- 24168118 TI - Skeletal trauma in child abuse. AB - Fractures and other skeletal injuries are common in childhood. Most are the result of falls, motor vehicle accidents, and other forms of accidental trauma. However, skeletal trauma is present in a significant number of abused children. Age and developmental abilities are key components in raising clinical suspicion for child abuse. Children who are unable to provide their own history because of age or developmental delay require increased attention. Younger children are more likely to have abusive fractures, whereas accidental fractures increase with age and developmental abilities. The consequences of missing abuse are high because children returned to their homes without intervention are likely to face further abuse and have an increased mortality risk. Because of the potentially high cost of undiagnosed child abuse, diagnosis of a skeletal injury is incomplete without diagnosing its etiology. All health providers for children should be able to recognize patterns of skeletal injury secondary to abusive trauma and understand the process for initiating Child Protective Services (CPS) investigations when necessary. Although they can occur accidentally, fractures in nonmobile children should always increase the clinician's concern for abusive trauma. In light of the significant consequences for children when abuse is missed by a primary care provider, abuse should be on the differential diagnosis for all presenting childhood injuries. PMID- 24168119 TI - Protect our kids! PMID- 24168121 TI - Infant stress and maternal depression. PMID- 24168122 TI - A 16-year-old girl with amenorrhea. PMID- 24168123 TI - Nasolabial rings and things. PMID- 24168124 TI - An arresting sickle cell disease complication. PMID- 24168125 TI - Musculoskeletal screening in children. PMID- 24168126 TI - Innovations in pediatric surgery. PMID- 24168128 TI - A conversation with David G. Nichols, MD, MBA. Interview by Stanford T. Shulman. PMID- 24168129 TI - Economic evaluations of hepatitis A vaccination in middle-income countries. AB - Economic evaluations of hepatitis A vaccination are important to assist national and international policy makers in different jurisdictions on making effective decisions. Up to now, a comprehensive review of the potential health and economic benefits on hepatitis A vaccination in middle-income countries (MICs) has not been performed yet. In this study, we reviewed the literature on the cost effectiveness of hepatitis A vaccination in MICs. Most of the studies confirmed that hepatitis A vaccination was cost effective or even cost saving under certain conditions. We found that vaccine price, medical costs, incidence and discount rate were the most influential parameters on the sensitivity analyses. Vaccine price has been shown as a barrier for MICs in implementing universal vaccination of hepatitis A. Given their relatively limited financial resources, implementation of single-dose vaccination could be considered. Despite our findings, we argue that further economic evaluations in MICs are still required in the near future. PMID- 24168130 TI - Launching and evolving a robotic cystectomy service by developing your 'FORTE'. PMID- 24168131 TI - A study of shape optimization on the metallic nanoparticles for thin-film solar cells. AB - The shape of metallic nanoparticles used to enhance the performance of thin-film solar cells is described by Gielis' superformula and optimized by an evolutionary algorithm. As a result, we have found a lens-like nanoparticle capable of improving the short circuit current density to 19.93 mA/cm2. Compared with a two scale nanospherical configuration recently reported to synthesize the merits of large and small spheres into a single structure, the optimized nanoparticle enables the solar cell to achieve a further 7.75% improvement in the current density and is much more fabrication friendly due to its simple shape and tolerance to geometrical distortions. PMID- 24168132 TI - Transparency and public accountability on the use of non-human primates as laboratory animals needs actions, as well as words. PMID- 24168133 TI - Development of a vessel organ culture system: characterisation of the method and implications for the reduction of animal experiments. AB - In the field of cardiovascular research, the pig is considered to be an excellent animal model of human diseases. It is well-known that primary cultures of endothelial cells (ECs) are a powerful tool for the study of vascular physiology and pathology, and, according to the principles of the Three Rs, their use results in a substantial reduction in the numbers of experimental animals required. However, a limitation of EC culture is that the cells are not in their physiological context. Here, we describe and characterise a method for the culture of porcine vessels that overcomes the limitation of EC cultures, with the advantage of reducing the number of animals used for research purposes. The organ cultures were set-up by using an aortic cylinder obtained from the arteries of control pigs sacrificed for other experimental purposes. In order to characterise the method, vascular endothelial growth factor (VEGF) secretion, matrix metalloproteinase (MMP) activation and the vessel's structural features were evaluated during organ culture. These analyses confirm that the culture of aortic cylinder lumen, in a medium specific for ECs, results in a stable system in terms of VEGF and MMP secretion. The ECs do not undergo cell division during the organ culture, which is also the case in vivo, if no stimulation occurs. Overall, we show that this novel system closely resembles the in vivo context. Importantly, porcine aortas can be collected from either veterinary surgeries or slaughterhouses, without having to sacrifice animals specifically for the purposes of this type of research. PMID- 24168134 TI - Ethical review of projects involving non-human primates funded under the European Union's 7th Research Framework Programme. AB - Internet searches were performed on projects involving non-human primates ('primates') funded under the European Union (EU) 7th Research Framework Programme (FP7), to determine how project proposals are assessed from an ethical point of view. Due to the incompleteness of the information publicly available, the types and severity of the experiments could not be determined with certainty, although in some projects the level of harm was considered to be 'severe'. Information was scarce regarding the numbers of primates, their sourcing, housing, care and fate, or the application of the Three Rs within projects. Project grant holders and the relevant Commission officer were consulted about their experiences with the FP7 ethics review process. Overall, it was seen as meaningful and beneficial, but some concerns were also noted. Ethical follow-up during project performance and upon completion was recognised as a valuable tool in ensuring that animal welfare requirements were adequately addressed. Based upon the outcome of the survey, recommendations are presented on how to strengthen the ethical review process under the upcoming Framework Programme 'Horizon 2020', while adequately taking into account the specific requirements of Directive 2010/63/EU, with the aim of limiting the harms inflicted on the animals and the numbers used, and ultimately, replacing the use of primates altogether. PMID- 24168135 TI - An opportunity to refocus on the 'humane' in experimental endpoints: moving beyond Directive 2010/63/EU. AB - Humane endpoints are a core refinement concept in animal experimentation. This paper identifies an urgent requirement for individuals and institutions to refocus on humane endpoints as part of the transposition of Directive 2010/63/EU into the national laws of the Member States, and to go beyond their legal construction when setting new guidance or applying humane endpoints in practice. It will be argued that requirements for humane endpoints within the Directive appear not to promote recent advances in best practice, but seem reliant on a narrow and potentially outdated definition of the term. We describe progress that has been made in encouraging change in the construction and application of humane endpoints, and suggest that Directive 2010/63/EU does not sufficiently acknowledge the conceptual complexity of this refinement strategy. For example, a useful development representing recent consensual views of best practice has been proposed by an EU consortium (in 2012). A complex approach to humane endpoints may place additional demands on institutions and raise challenges that would, unfortunately, not need to be overcome in order to remain within the Directive's current requirements regarding humane endpoints. We argue that there is now a need for a practical tool to help structure appropriate ethical reflection during research planning and experimentation, in order to facilitate best practice in the application of this important refinement concept. PMID- 24168136 TI - Statistics of Scientific Procedures on Living Animals 2012: another increase in experimentation - genetically-altered animals dominate again. AB - The Annual Statistics of Scientific Procedures on Living Animals Great Britain 2012 reveal that the level of animal experimentation in Great Britain continues to rise, with just over 4.1 million procedures being started in that year. Despite the previous year's indication that the dominance of the production and use of genetically-altered (GA, i.e. genetically-modified animals plus animals with harmful genetic defects) animal might be abating, it returned with a vengeance in 2012. Breeding increased from 43% to 48% of all procedures, and GA animals were involved in 59% of all the procedures. Indeed, if the breeding of these animals were removed from the statistics, the total number of procedures would actually decline by 2%. In order to honour their pledge to reduce animal use in science, the Coalition Government will have to address this issue. The general trends in the species used, and the numbers and types of procedures, are also reviewed. Finally, forthcoming changes to the statistics are discussed. PMID- 24168137 TI - Laboratory animal ethics course planning in Iran. PMID- 24168138 TI - The Three Rs in India. PMID- 24168139 TI - Laboratory animal welfare and the Three Rs in Korea. PMID- 24168140 TI - The current status of laboratory animal ethics in South Africa. PMID- 24168141 TI - 6. Replacement. PMID- 24168142 TI - A deconstruction of gambling task performance among HIV+ individuals: the differential contributions of problem solving and risk taking. AB - This study sought to deconstruct gambling task (GT) performance among HIV+ individuals (N = 143) and is intended to capture other cognitive features of task performance (i.e., problem solving and strategy preference). Consistent with our hypotheses, cluster analysis identified three GT groups: a safe/advantageous (AS) strategy group, a risky/disadvantageous (RS) strategy group, and a novel third group who failed to develop a strategy (NS). The NS group performed worst on global neuropsychological performance, processing speed, and executive function. Our results support a novel measure of GT task performance and suggest that failure to develop/implement a strategy reflects cognitive dysfunction. PMID- 24168143 TI - Probing functional polymorphisms in the dengue vector, Aedes aegypti. AB - BACKGROUND: Dengue is the most prevalent arboviral disease world-wide and its primary vector is the mosquito Aedes aegypti. The current lack of commercially available vaccines makes control of vector populations the only effective strategy to prevent dengue transmission. Aedes aegypti geographic populations exhibit great variability in insecticide resistance and susceptibility to dengue infection. The characterization of single nucleotide polymorphisms (SNPs) as molecular markers to study quantitatively this variation is needed greatly because this species has a low abundance of microsatellite markers and limited known restriction fragments length polymorphisms (RFLPs) and single-strand conformation polymorphism (SSCP) markers. RESULTS: We used RNA-seq to characterize SNPs in three Ae. aegypti strains, including the Liverpool (LVP) strain, from which the current genome annotation is derived. We identified 131,764 unique genome locations with at least one alternative nucleotide to what is reported in the reference annotation. These comprised changes in both open reading frames (ORFs) and untranslated regions (UTRs) of transcripts. An in depth look at sequence variation in immunity genes revealed that those associated with autophagy, MD2-like receptors and Peptidoglycan Recognition Proteins had more sequence variation in their 3'UTRs than mutations associated with non-synonymous changes. This supports the conclusion that these genes had maintained their functional specificity while being adapted to different regulatory domains. In contrast, a number of peroxidases, serpins and Clip-domain serine proteases exhibited conservation of putative UTR regulatory sequences while displaying diversification of the ORFs. Transcriptome evidence also was found for ~2500 novel transcriptional units (NTUs) not annotated in the reference genome. CONCLUSIONS: The transcriptome-wide assessment of within and inter-strain polymorphisms in Ae. aegypti adds considerably to the number of molecular markers available for genetic studies in this mosquito. Additionally, data supporting NTU discovery emphasizes the need for continuous amendments of the reference genome annotation. PMID- 24168144 TI - Elevated alpha-methyl-gamma-hydroxy-1,N2-propano-2'-deoxyguanosine levels in urinary samples from individuals exposed to urban air pollution. AB - Acetaldehyde and crotonaldehyde are genotoxic aldehydes present in tobacco smoke and vehicle exhaust. The reaction of these aldehydes with 2'-deoxyguanosine in DNA produces alpha-methyl-gamma-hydroxy-1,N(2)-propano-2'-deoxyguanosine (1,N(2) propanodGuo). Online HPLC-tandem mass spectrometry was utilized to accurately quantify 1,N(2)-propanodGuo in human urinary samples from 47 residents of Sao Paulo City (SP) and 35 residents of the rural municipality of Sao Joao da Boa Vista (SJBV) in the state of Sao Paulo. Significantly higher 1,N(2)-propanodGuo levels were found in the samples from SP donors than in samples from SJBV donors. Our results provide the first evidence that elevated levels of 1,N(2)-propanodGuo in urinary samples may be correlated with urban air pollution. PMID- 24168146 TI - Giant neobladder stone. PMID- 24168147 TI - Stereochemical assignment of the fungal metabolites pestalotiopsones D and E through enantiopure synthesis. AB - The pestalotiopsones are fungal metabolites isolated from an endophytic fungus Pestalotiopsis sp. found in the mangrove Rhizophora mucronata, used in traditional Chinese medicine to treat symptoms of dysentery. The absolute configurations of pestalotiopsones D (4) and E (5) were elucidated through total synthesis of both the R and S enantiomers, allowing for the assignment of the stereochemistry of the natural compounds as the (+)-S enantiomers. The key steps include homologation of a substituted benzoic acid to the appropriate phenylacetate derivative using Birch reductive alkylation, an oxa-Michael cyclization induced by microwave irradiation to form the chromanone substructure, and an IBX-mediated dehydrogenation yielding the chromone skeleton. Assessment of the synthetic compounds against clinical pathogens was performed. PMID- 24168148 TI - Elderly cancer patients in the 3rd millenium: between hope and reality. Introduction. PMID- 24168149 TI - Medical treatment of elderly patients with breast cancer. AB - We performed a bibliographic electronic search of MEDLINE and Cochrane databases on breast cancer in the elderly. In the adjuvant setting aromatase inhibitors are more effective than tamoxifen with an acceptable profile of toxicity. In aged, poorer risk, patients adjuvant chemotherapy is feasible but organ function and comorbidities have to be considered. Adjuvant trastuzumab is also an option for the treatment of Her2 positive aged breast cancer. Neoadjuvant chemotherapy +/- HER2-targeted treatment is today a possible treatment for triple negative and HER2-positive disease, respectively. Older women are more likely than younger women to present with more advanced breast cancer. Hormone therapy is the treatment of choice for older women with hormone receptor positive metastatic breast cancer until they develop resistance. When appropriate, polychemotherapy may be employed but unfortunately we have a lack of data on this matter. However, because fit women older than 70 years of age have similar results with chemotherapy as their younger counterparts most oncologists tend to propose this option to their patients. Trastuzumab has proven to be effective and well tolerated in elderly patients (older than 60-70 years), but caution is needed due to the risk of heart failure. Recently, an all-oral combination of capecitabine and vinorelbine demonstrated good acitivity and tolerability profile in patients older than 70 years. Nab-paclitaxel has shown a safer and more active profile compared with the q3w taxanes in such population. There is, therefore, an urgent need to study anticancer agents in the elderly within large randomized controlled trials. PMID- 24168150 TI - Treatment approaches in elderly patients with head and neck cancer. AB - Integration of geriatric assessment into cancer clinical practice is strongly needed in squamous cell carcinoma of the head and neck (SCCHN) due to the frequent discrepancy between chronologic and biologic age. Comprehensive Geriatric Assessment (CGA) is a multidimensional assessment tool that examines age-related domains. These parameters can be well assessed by easier tests such as Activity Daily Living and Instrumental Activity Daily Living for functional status; Charlson Comorbidity Index for comorbidity; Mini Mental State examination for cognitive status; Mini Nutritional Assessment for nutritional status; Beers criteria for concomitant drug assumption. Early stage SCCHN is usually treated with either surgery or radiation therapy. Age is not an exclusion criteria for both modalities, but elderly patients have a higher complication rate. Patients with locally advanced SCCHN are preferably treated with concomitant cisplatin radiotherapy, but the impact of chemotherapy on survival is lower with increasing patient age. The combination of cetuximab and radiation therapy can be a suitable option in elderly patients with locally advanced SCCHN. However, also in this group of patients, survival benefit is lower in elderly patients. Chemotherapy represents the mainstay of treatment in recurrent/metastatic SCCHN. However, elderly patients can receive more toxicity. Myelosuppression, diarrhea, mucositis, nephrotoxicity and neurotoxicity have to be early diagnosed and adequately treated. The initial approach for screening elderly SCCHN patients may benefit from relatively easy tests such as Vulnerable Elders Survey 13 (VES-13), which can screen patients who are to undergo full CGA. PMID- 24168151 TI - Hematopoietic growth factors support in the elderly cancer patients treated with antiblastic chemotherapy. AB - The 60% of tumors affected patients >65years of age and the future previsions are considering an amount of 70% after 2030. Elderly Patients presents multiple comorbidity, polipharmacy, and disability. Geriatric assessment helps physicians to take the best therapeutic decisions. Clinical conditions influence efficacy and tolerability of chemotherapy. Prophylactic use of G-CSF after chemotherapy lowers the rate and length of severe neutropenia , and decreases the episodes of febrile neutropenia. Anemia is a hematologic condition associated with ageing , but is frequently associated to concomitant chronic disease. Stem cells display increasing resistance to erythropoietin in the elderly patients and this is connected with the onset of pro-inflammatory cytokines characteristic of this age . Anemia is a common adverse event in cancer patients receiving chemotherapy. Several of the symptoms associated with anemia, such as fatigue, syncope, palpitations and dyspnea, reduce patient activity and have a profound effect on the quality of life [QOL]. Considering the unfit or frail status of elderly patient the at home use of peg-filgrastim and weekly or three weekly erythropoietin administration could be preferred for this setting of patients that lack of specialized nursing care or facilities. Further studies, considering the several differences in health organizations in vary countries, could be held to state the real impact of the biosimilars in comparison to the long acting originators in the reduction of costs in this group of patients. PMID- 24168153 TI - Simple relationship between oxidation state and electron affinity in gas-phase metal-oxo complexes. AB - The photoelectron spectra of WO3H(-) and WO2F(-) are presented and analyzed in the context of a series of previous similar measurements on MO(y)(-) (M = Mo, W; y = 0-3), MO4H(-) and AlMOy(-) (y <= 4) complexes. The electronic structures of the WO3H and WO2F anion and neutral complexes were investigated using the B3LYP hybrid density functional method. The spectra of WO3H(-), WO2F(-), and previously measured AlWO3(-) photoelectron spectra show that the corresponding neutrals, in which the transition metal centers are all in a +5 oxidation state, have comparable electron affinities. In addition, the electron affinities fit the general trend of monotonically increasing electron affinity with oxidation state, in spite of the WO3H(-), WO2F(-), and AlWO3(-) having closed shell ground states, suggesting that the oxidation state of the metal atom has more influence than shell closing on the electron affinity of these transition metal-oxo complexes. Results of DFT calculations suggest that the neutrals are pyramidal and the anions are planar. However, the barriers for inversion on the neutral surface are low, and attempts to generate simple Franck-Condon simulations based on simple normal coordinate displacement, ignoring the effects of inversion, are inadequate. PMID- 24168152 TI - Human disposition, metabolism and excretion of etamicastat, a reversible, peripherally selective dopamine beta-hydroxylase inhibitor. AB - AIMS: Etamicastat is a reversible dopamine-beta-hydroxylase inhibitor that decreases noradrenaline levels in sympathetically innervated tissues and slows down sympathetic nervous system drive. In this study, the disposition, metabolism and excretion of etamicastat were evaluated following [(14)C]-etamicastat dosing. METHODS: Healthy Caucasian males (n = 4) were enrolled in this single-dose, open label study. Subjects were administered 600 mg of unlabelled etamicastat and 98 uCi weighing 0.623 mg [(14)C]-etamicastat. Blood samples, urine and faeces were collected to characterize the disposition, excretion and metabolites of etamicastat. RESULTS: Eleven days after administration, 94.0% of the administered radioactivity had been excreted; 33.3 and 58.5% of the administered dose was found in the faeces and urine, respectively. Renal excretion of unchanged etamicastat and its N-acetylated metabolite (BIA 5-961) accounted for 20.0 and 10.7% of the dose, respectively. Etamicastat and BIA 5-961 accounted for most of the circulating radioactivity, with a BIA 5-961/etamicastat ratio that was highly variable both for the maximal plasma concentration (19.68-226.28%) and for the area under the plasma concentration-time curve from time zero to the last sampling time at which the concentration was above the limit of quantification (15.82- 281.71%). Alongside N-acetylation, metabolism of etamicastat also occurs through oxidative deamination of the aminoethyl moiety, alkyl oxidation, desulfation and glucuronidation. CONCLUSIONS: Etamicastat is rapidly absorbed, primarily excreted via urine, and its biotransformation occurs mainly via N acetylation (N-acetyltransferase type 2), although glucuronidation, oxidation, oxidative deamination and desulfation also take place. PMID- 24168154 TI - Influence of day length and temperature on the content of health-related compounds in broccoli (Brassica oleracea L. var. italica). AB - Vegetables grown at different latitudes are exposed to various temperatures and day lengths, which can affect the content of health- and sensory-related compounds in broccoli florets. A 2 * 2 factorial experiment was conducted under controlled growth conditions, with contrasting temperatures (15/9 and 21/15 degrees C) and day lengths (12 and 24 h), to investigate the effect on glucosinolates, vitamin C, flavonols, and soluble sugars. Aliphatic glucosinolates, quercetin, and kaempferol were at their highest levels at high temperatures combined with a 12 h day. Levels of total glucosinolates, d-glucose, and d-fructose were elevated by high temperatures. Conversely, the content of vitamin C was highest with a 12 h day length combined with 15/9 degrees C. Our results indicate that temperature and day length influence the contents of health related compounds in broccoli florets in a complex way, suggesting no general superiority of any of the contrasting growth conditions. PMID- 24168155 TI - Some features of the developmental uterus in human fetuses. AB - Proper development of each component of the reproductive tract is imperative for successful natural reproduction. The aim was to investigate some morphological features of the fetal uterus in early phases of its development. The uteruses of 65 fetuses of different gestational age were included and each of them was measured in three dimensions: uterine length (UL), uterine width (BC) and the antero-posterior (sagittal) thickness of the uterine fundus (FT) using ImageJ computer program. It was observed that the most intense fetal uterus growth occurred between seventh and eighth month of gestational age (between week 25 and 31). The most intense rate of uterine growth had UL and it showed steeper growth curve from the fourth month of gestational age. The values of UL, BC, FT showed statistically highly positive Pearson's linear correlation with values of CRL, and GA, and among themselves. The strongest correlation was between UL and gestational age. Contrary to proved rising linear trends of UL/FT and UL/BC, BC/FT performed linear trend of decline. However, two divergent linear trends, one ascending (UL/FT), and other declining (BC/FT) have similar descent in values during the early gestational age, from week 12 to 15. Fetal uteruses did not grow at the same rate by all three measured dimensions, and each of measured dimensions has noticeable standard deviations during gestational periods, even with a resolution of a week, suggesting individuality of each human development/growth even during prenatal life. PMID- 24168156 TI - Serum leptin, adiponectin, and resistin among adult patients with acanthosis nigricans: correlations with insulin resistance and risk factors for cardiovascular disease. AB - BACKGROUND: Acanthosis nigricans (AN) is linked to obesity and insulin resistance. Major adipokines such as leptin, adiponectin, and resistin are known to be dysregulated in obesity and are key players in the pathogenesis of metabolic syndrome. OBJECTIVES: This study was conducted to assess serum levels of the major adipokines leptin, adiponectin, and resistin, and to study their correlations with the state of insulin resistance and other risk factors for cardiovascular disease (CVD) among AN patients. METHODS: A total of 115 adult subjects were included in the study; 52 of these had benign acquired AN, and 63 (control subjects) were without AN. Thirty-three of the control group were obese, and 30 were healthy subjects of normal weight. Body mass index (BMI), blood pressure, lipid profile, fasting blood glucose, fasting insulin, serum leptin, adiponectin, and resistin were assessed in all subjects. RESULTS: We found significant differences between AN patients and obese controls in serum levels of leptin (30.02 +/- 15.14 ng/ml vs. 21.07 +/- 7.92 ng/ml; P = 0.002), adiponectin (5.55 +/- 2.89 MUg/l vs. 9.02 +/- 2.33 MUg/ml; P = 0.00001), and resistin (20.88 +/- 3.97 ng/ml vs. 16.82 +/- 4.36 ng/ml; P = 0.00003). Significant positive correlations were found between serum leptin and homeostasis model assessment (HOMA) value, insulin, glucose, BMI, cholesterol, and low-density lipoprotein. There were also significant negative correlations between adiponectin and HOMA value, insulin, BMI, cholesterol, and leptin among AN patients. CONCLUSIONS: Acanthosis nigricans is a likely forerunner of the finding of metabolic syndrome. High serum leptin and resistin and low serum adiponectin may increase the risk for CVD among AN patients. PMID- 24168157 TI - Glaucoma in an eye with situs inversus of the optic disc. AB - Situs inversus of the optic disc is a congenital abnormality characterized by dysversion of the optic nerve head and surrounding retinal vessels. Here, we report the retinal nerve fiber layer (RNFL) characteristics of eyes with situs inversus of the optic discs with and without glaucoma, as imaged using spectral domain optical coherence tomography (OCT). OCT findings of an eye with situs inversus of optic disc and uveitic glaucoma revealed abnormal RNFL thinning. After six months of treatment, progressive RNFL thinning in the superior-nasal and inferior-nasal areas was found. The fellow eye with situs inversus of the optic disc without glaucoma showed a thicker nasal RNFL, a thinner temporal RNFL, and more nasally located RNFL peak locations compared with normative database. RNFL thickness characteristics in eyes with situs inversus of the optic discs, presented here, should be considered when assessing glaucoma in eyes with this abnormality. PMID- 24168158 TI - Preparation and Ni-doping effect of nanosized truncated octahedral LiCoMnO(4) as cathode materials for 5 V li-ion batteries. AB - LiCoMnO4 with nanosized truncated octahedral structure was prepared via a modified sol-gel route. The single-crystalline subunits grew completely without serious agglomeration. The growth mechanism was discussed in detail. The sample was tested as cathode materials for 5 V Li-ion batteries. Ni doping was also investigated to decrease the content of Mn(3+) ions and the Mn dissolution, and then the decomposition of electrolyte was inhibited on the cathode surface. LiCo0.9Ni0.1MnO4 exhibited enhanced cyclic stability compared with the pristine LiCoMnO4. PMID- 24168159 TI - Considering quality of care for young adults with diabetes in Ireland. AB - BACKGROUND: Research on the quality of diabetes care provided to young adults with Type 1 diabetes is lacking. This study investigates perceptions of quality of care for young adults with Type 1 diabetes (23-30 years old) living in the Republic of Ireland. METHODS: Thirty-five young adults with Type 1 diabetes (twenty-nine women, six men) and thirteen healthcare professionals (ten diabetes nurse specialists, three consultant Endocrinologists) were recruited. All study participants completed semi-structured interviews that explored their perspectives on the quality of diabetes services in Ireland. Interviews were analyzed using standard qualitative thematic analysis techniques. RESULTS: Most interviewees identified problems with Irish diabetes services for young adults. Healthcare services were often characterised by long waiting times, inadequate continuity of care, overreliance on junior doctors and inadequate professional patient interaction times. Many rural and non-specialist services lacked funding for diabetes education programmes, diabetes nurse specialists, insulin pumps or for psychological support, though these services are important components of quality Type 1 diabetes healthcare. Allied health services such as psychology, podiatry and dietician services appeared to be underfunded in many parts of the country. While Irish diabetes services lacked funding prior to the recession, the economic decline in Ireland, and the subsequent austerity imposed on the Irish health service as a result of that decline, appears to have additional negative consequences. Despite these difficulties, a number of specialist healthcare services for young adults with diabetes seemed to be providing excellent quality of care. Although young adults and professionals identified many of the same problems with Irish diabetes services, professionals appeared to be more critical of diabetes services than young adults. Young adults generally expressed high levels of satisfaction with services, even where they noted that aspects of those services were sub-optimal. CONCLUSION: Good quality care appears to be unequally distributed throughout Ireland. National austerity measures appear to be negatively impacting health services for young adults with diabetes. There is a need for more Endocrinologist and diabetes nurse specialist posts to be funded in Ireland, as well as allied health professional posts. PMID- 24168160 TI - Anticarcinogenic effects of the ethanolic extract of Salix aegyptiaca in colon cancer cells: involvement of Akt/PKB and MAPK pathways. AB - The bark from Salix species of plants has been traditionally consumed for its antiinflammatory properties. Because inflammation frequently accompanies the progress of colorectal cancer (CRC), we have evaluated the anticancer properties of the ethanolic extract from the bark (EEB) of S. aegyptiaca, a Salix species endogenous to the Middle East, using HCT-116 and HT29 CRC cell lines. Fresh bark from S. aegyptiaca was extracted with ethanol, fractionated by solvent-solvent partitioning and the fractions were analyzed by tandem mass spectrometry. Catechin, catechol, and salicin were the most abundant constituents of the extract. Interestingly, EEB showed the highest anticancer effect in the colon cancer cells followed by its fractions in ethyl acetate and water, with catechin, catechol, and salicin showing the least efficacy. EEB could strongly reduce the proliferation of the cancer cells, but not of CCD-18Co, normal colon fibroblast cell line. Accompanying this was cell cycle arrest at G1/S independent of DNA damage in the cancer cells, induction of apoptosis through a p53 dependent pathway and an inhibition of PI3K/Akt and MAP Kinase pathways at levels comparable to known commercial inhibitors. We propose that the combination of the polyphenols and flavonoids in EEB contributes toward its potent anticarcinogenic effects. [Supplementary materials are available for this article. Go to the publisher's online edition of Nutrition and Cancer for the following free supplemental resource(s): Supplementary Figure 1 and Supplementary Figure 2.]. PMID- 24168161 TI - Radiation-induced telomere length variations in normal and in Nijmegen Breakage Syndrome cells. AB - PURPOSE: The meiotic recombination protein 11 (MRE11), radiation sensitive 50 (RAD50) and nibrin (NBN) are members of the MRE11/RAD50/NBN (MRN) complex which plays a fundamental role in the double-strand break damage response, including DNA damage sensing, signalling and repair after exposure to ionizing radiations. In addition the MRN complex is involved in the mechanisms regulating telomere length maintenance. Based on our previous results indicating that, in contrast to X-rays, high linear energy transfer (LET) radiations were able to elongate telomeres, we investigated the behavior of cells mutated in components of the MRN complex after exposure either to 62 MeV carbon-ions (50 keV/MUm, at cell surface) or X-rays. MATERIALS AND METHODS: Epstein Barr Virus (EBV)-transformed lymphoblastoid cell lines (LCL) established from normal, heterozygous for the NBN gene, homozygous for either mutant/deleted NBN, RAD50 or ataxia telangiectasia mutated (ATM) genes were irradiated with 4 Gy, with telomere length being evaluated 24 h later or in time course-experiments up to 15 days later. The induction of telomeric sister chromatid exchanges (T-SCE) was measured as a hallmark of homologous directed recombinational repair. RESULTS: NBN and RAD50 mutated cells failed to elongate telomeres that instead occurred in the remaining cell lines as a response only to high-LET irradiation. Also, a kinetic study with 0.5-4 Gy up to 15 days from irradiation confirmed that NBN gene was indispensable for telomere elongation. Furthermore, such an elongation, was accompanied by an increased frequency of sister chromatid exchanges at telomeres (T-SCE). In contrast, the induction of genomic sister chromatid exchanges (G-SCE) occurred for carbon-ions irrespective of NBN gene status. CONCLUSIONS: We speculate that the MRN is necessary to process a subclass of high-LET radiation-induced complex DNA damage through a recombinational-repair mediated mechanism which in turn is responsible for telomere elongation. PMID- 24168162 TI - Mental health screening tools in correctional institutions: a systematic review. AB - BACKGROUND: Past studies have identified poor rates of detection of mental illness among inmates. Consequently, mental health screening is a common feature to various correctional mental health strategies and best practice guidelines. However, there is little guidance to support the selection of an appropriate tool. This systematic review compared the sensitivity and specificity of mental health screening tools among adult jail or prison populations. METHODS: A systematic review of MEDLINE and PsycINFO up to 2011, with additional studies identified from a search of reference lists. Only studies involving adult jail or prison populations, with an independent measure of mental illness, were included. Studies in forensic settings to determine fitness to stand trial or criminal responsibility were excluded. Twenty-four studies met all inclusion and exclusion criteria for the review. All articles were coded by two independent authors. Study quality was coded by the lead author. RESULTS: Twenty-two screening tools were identified. Only six tools have replication studies: the Brief Jail Mental Health Screen (BJMHS), the Correctional Mental Health Screen for Men (CMHS-M), the Correctional Mental Health Screen for Women (CMHS-W), the England Mental Health Screen (EMHS), the Jail Screening Assessment Tool (JSAT), and the Referral Decision Scale (RDS). A descriptive summary is provided in lieu of use of meta analytic techniques due to the lack of replication studies and methodological variations across studies. CONCLUSIONS: The BJMHS, CMHS-M, CMHS-W, EMHS and JSAT appear to be the most promising tools. Future research should consider important contextual factors in the implementation of a screening tool that have received little attention. Randomized or quasi-randomized trials are recommended to evaluate the effectiveness of screening to improve the detection of mental illness compared to standard practices. PMID- 24168163 TI - Downregulation of erythroid differentiation regulator 1 as a novel marker of skin tumors. AB - BACKGROUND: Erythroid differentiation regulator 1 is decreased in malignant melanoma. However, the expression of erythroid differentiation regulator 1 has not been reported in normal epidermis, vessel, nerve, dermal adnexae, and various skin tumors. METHODS: To investigate the expression of erythroid differentiation regulator 1 in normal skin and various skin tumors, immunohistochemical analysis of normal skin, epidermal tumors, sebaceous tumors, and eccrine tumors was performed. The image analysis was quantitatively performed using HistoQuant(TM) software. RESULTS: Erythroid differentiation regulator 1 was strongly expressed in the nuclei of normal epidermis, sebaceous gland, eccrine gland, vessel, and nerve. Expression of erythroid differentiation regulator 1 was weak in seborrheic keratosis, sebaceous hyperplasia, and eccrine spiradenoma. Erythroid differentiation regulator 1 was rarely observed in malignant skin tumors, including squamous cell carcinoma, basal cell carcinoma, malignant melanoma, sebaceous carcinoma, and eccrine porocarcinoma. CONCLUSIONS: The expression of erythroid differentiation regulator 1 was negatively correlated with the malignant potential in various skin tumors. The results support the role of erythroid differentiation regulator 1 in cutaneous carcinogenesis and indicate its potential as a novel marker of skin tumors. PMID- 24168164 TI - Identification of dyes on single textile fibers by HPLC-DAD-MS. AB - An HPLC-DAD-MS method is described to analyze textile dyes in different dye classes (reactive, basic, acid, direct, disperse). The described method is sensitive enough to analyze single fibers with a length of a few millimeters or less, which makes it suitable for forensic analyses. The current paper describes the information content of the acquired data as well as the results of a validation study, in which the repeatability, specificity, and limit of detection of the method were assessed by repeated measurements of nine different dyes in the mentioned dye classes. The mass accuracy (deviation generally <2 ppm) and absorbance spectra were found to be highly stable in several measurements over a period of 8 weeks. Deviation in retention times were observed and attributed to small experimental effects and a precolumn blockage. The results show that dye analysis is possible for most fibers with a minimum length of one or a few millimeters. PMID- 24168165 TI - NRD1, which encodes nardilysin protein, promotes esophageal cancer cell invasion through induction of MMP2 and MMP3 expression. AB - Esophageal squamous cell carcinoma (ESCC) is one of the most common malignancies worldwide. In the present study, to identify novel prognostic markers or therapeutic targets for ESCC, we reviewed a list of genes with upregulated expression in ESCC compared with normal esophagus, as identified by our serial analysis of gene expression (SAGE) analysis. We focused on the NRD1 gene, which encodes the nardilysin protein. Quantitative reverse transcription-polymerase chain reaction (qRT-PCR) in 34 ESCC tissue samples revealed that mRNA expression of NRD1 was upregulated in 56% of ESCC tissue samples. Immunohistochemical analysis of nardilysin in 109 ESCC tissue samples demonstrated that 43 (39%) ESCC cases were positive for nardilysin. Nardilysin-positive ESCC cases were more advanced in terms of T classification (P = 0.0007), N classification (P = 0.0164), and tumor stage (P < 0.0001) than nardilysin-negative ESCC cases. Furthermore, nardilysin expression was significantly associated with poorer prognosis (P = 0.0258). Univariate and multivariate analyses revealed that nardilysin expression is an independent prognostic classifier of patients with ESCC. The invasiveness of NRD1-knockdown TE1 and TE5 esophageal cancer cell lines was less than that of the negative control siRNA-transfected cell lines. Expression of MMP2 and MMP3 mRNA was significantly lower in NRD1-knockdown TE5 cells than in negative control siRNA-transfected cells. These results suggest that nardilysin is involved in tumor progression, and is an independent prognostic classifier in patients with ESCC. PMID- 24168166 TI - Clinical development of candidate HIV vaccines: different problems for different vaccines. AB - Realization of individual and public health benefit from an HIV vaccine requires clinical testing to demonstrate efficacy. To facilitate clinical testing, preclinical HIV vaccine developers should consider the realities of clinical practice and the conduct of clinical trials in product design. There are several essentially different approaches to prophylactic HIV vaccine design: (1) induce immunity that allows infection but reduces initial peak viremia and viral load set point; (2) induce immunity that allows infection but controls viremia to below the level of detection; (3) induce immunity that allows infection but promotes viral clearance before disease (classic vaccine approach); (4) induce "sterilizing immunity" that prevents acquisition of infection. Each approach presents different challenges for clinical product development. Current clinical trial practices and evolving treatment standards may make it infeasible to perform an efficacy trial of a preventive vaccine that only modestly reduces viremia. A vaccine that promotes control of viremia to below the level of detection is testable but will require extended follow-up to determine how long virus control persists; once control is lost boosting with the same vaccine may not be useful. A vaccine that permits infection but promotes subsequent complete clearance of the virus from the body will require the development and validation of an effective assay for virus clearance. A vaccine that prevents acquisition of infection is the most straightforward to test in the clinic, but escalating costs require more attention by vaccine developers to understanding how the vaccine works and the breadth of protection. All types of vaccine require attention to effect size to ensure adequate powering of efficacy trials. PMID- 24168167 TI - Compound headedness in the mental lexicon: an event-related potential study. AB - Compound words in Romance languages may have the head either in the initial or in the final position. In the present event-related potential (ERP) study, we address the hypothesis that Italian compounds are processed differently according to their head position and that this is mostly due to the perceived change in the canonical order of syntactic elements. Compound stimuli (head-initial, head final, or exocentric) were visually displayed in two presentation modes, as whole words or separated into their constituents, in the context of a lexical decision task. Behavioural results showed an increased split cost in head-final and exocentric compounds as compared to head-initial compounds. ERP results showed an enhanced left anterior negativity (LAN) for head-final and exocentric compounds as compared to head-initial compounds, regardless of the presentation mode. Results suggest that the analogy with syntactic order may influence the internal structure of a compound and, as a consequence, its processing, but other characteristics (such as the grammatical properties of constituents) may affect the processing itself. PMID- 24168168 TI - Effect of nanoparticles on heat capacity of nanofluids based on molten salts as PCM for thermal energy storage. AB - In this study, different nanofluids with phase change behavior were developed by mixing a molten salt base fluid (selected as phase change material) with nanoparticles using the direct-synthesis method. The thermal properties of the nanofluids obtained were investigated. These nanofluids can be used in concentrating solar plants with a reduction of storage material if an improvement in the specific heat is achieved. The base salt mixture was a NaNO3-KNO3 (60:40 ratio) binary salt. The nanoparticles used were silica (SiO2), alumina (Al2O3), titania (TiO2), and a mix of silica-alumina (SiO2-Al2O3). Three weight fractions were evaluated: 0.5, 1.0, and 1.5 wt.%. Each nanofluid was prepared in water solution, sonicated, and evaporated. Measurements on thermophysical properties were performed by differential scanning calorimetry analysis and the dispersion of the nanoparticles was analyzed by scanning electron microscopy (SEM). The results obtained show that the addition of 1.0 wt.% of nanoparticles to the base salt increases the specific heat of 15% to 57% in the solid phase and of 1% to 22% in the liquid phase. In particular, this research shows that the addition of silica-alumina nanoparticles has a significant potential for enhancing the thermal storage characteristics of the NaNO3-KNO3 binary salt. These results deviated from the predictions of the theoretical model used. SEM suggests a greater interaction between these nanoparticles and the salt. PMID- 24168169 TI - Sacral neuromodulation is an effective option for non-obstructive urinary retention in men with cerebral palsy. PMID- 24168171 TI - Nucleophile-catalyzed, facile, and highly selective C-H activation of fluoroform with Pd(II). AB - Exceedingly facile (23 degrees C) and chemoselective H-CF3 activation with [(dppp)Pd(Ph)(OH)] in the presence of a Lewis base promoter such as n-Bu3P leads to Pd-CF3 bond formation in nearly quantitative yield. A combined experimental and computational study points to a new mechanism that involves H-bonding Pd O(H)...H-CF3 and nucleophilic attack of the promoter on the metal, followed by a push-pull-type collapse of the resultant five-coordinate Pd(II) intermediate via a polar transition state. PMID- 24168170 TI - Loss of WSTF results in spontaneous fluctuations of heterochromatin formation and resolution, combined with substantial changes to gene expression. AB - BACKGROUND: Williams syndrome transcription factor (WSTF) is a multifaceted protein that is involved in several nuclear processes, including replication, transcription, and the DNA damage response. WSTF participates in a chromatin remodeling complex with the ISWI ATPase, SNF2H, and is thought to contribute to the maintenance of heterochromatin, including at the human inactive X chromosome (Xi). WSTF is encoded by BAZ1B, and is one of twenty-eight genes that are hemizygously deleted in the genetic disorder Williams-Beuren syndrome (WBS). RESULTS: To explore the function of WSTF, we performed zinc finger nuclease assisted targeting of the BAZ1B gene and isolated several independent knockout clones in human cells. Our results show that, while heterochromatin at the Xi is unaltered, new inappropriate areas of heterochromatin spontaneously form and resolve throughout the nucleus, appearing as large DAPI-dense staining blocks, defined by histone H3 lysine-9 trimethylation and association of the proteins heterochromatin protein 1 and structural maintenance of chromosomes flexible hinge domain containing 1. In three independent mutants, the expression of a large number of genes were impacted, both up and down, by WSTF loss. CONCLUSIONS: Given the inappropriate appearance of regions of heterochromatin in BAZ1B knockout cells, it is evident that WSTF performs a critical role in maintaining chromatin and transcriptional states, a property that is likely compromised by WSTF haploinsufficiency in WBS patients. PMID- 24168173 TI - Intermolecular interaction in the NH3-H2 and H2O-H2 complexes by molecular beam scattering experiments: the role of charge transfer. AB - New molecular beam scattering experiments are reported for the ammonia-hydrogen system recording with unprecedented resolution "glory" quantum interferences in the total cross sections. Direct comparison with the analogous water-hydrogen complex, investigated under the same experimental conditions, highlights relevant differences in the intermolecular interaction affecting the observables. Analysis of the electronic charge displacement accompanying formation of both complexes, calculated using very accurate ab initio methods, helps to rationalize the experimental findings and unveils the selective and crucial role of charge transfer in driving water interactions and formation of a weak hydrogen bond. PMID- 24168172 TI - Effective palliation of obstructive jaundice due to colorectal cancer liver metastasis. PMID- 24168174 TI - Rapid screening of fatty acid alkyl esters in olive oils by time domain reflectometry. AB - The main aim of the present research is to assess the possibility of quickly screening fatty acid alkyl esters (FAAE) in olive oils using time domain reflectometry (TDR) and partial least-squares (PLS) multivariate statistical analysis. Eighteen virgin olive oil samples with fatty acid alkyl ester contents and fatty acid ethyl ester/methyl ester ratios (FAEE/FAME) ranging from 3 to 100 mg kg(-1) and from 0.3 to 2.6, respectively, were submitted to tests with time domain resolution of 1 ps. The results obtained in test set validation demonstrated that this new and fast analytical approach is able to predict FAME, FAEE, and FAME + FAEE contents with R(2) values of 0.905, 0.923, and 0.927, respectively. Further measurements on mixtures between olive oil and FAAE standards confirmed that the prediction is based on a direct influence of fatty acid alkyl esters on the TDR signal. The suggested technique appeared potentially suitable for monitoring one of the most important quality attribute of the olive oil in the extraction process. PMID- 24168175 TI - Customized weight curves for Spanish fetuses and newborns. AB - OBJECTIVES: To construct a model of customized birthweight curves for use in a Spanish population. MATERIALS AND METHODS: Data of 20 331 newborns were used to construct a customized birthweight model. Multiple regression analysis was performed with newborn weight as the dependent variable and gestational age (GA), sex and maternal (M) weight, height, parity and ethnic origin as the independent variables. Using the new model, 27,507 newborns were classified as adequate for GA (AGA), large for GA (LGA) or small for GA (SGA). The results were compared with those of other customized and non-customized models. RESULTS: The resulting formula for the calculation of optimal neonatal weight was: Optimum weight (g) = 3289.681 + 135.413*GA40-14.063*GA40(2)-0.838*GA40(3) + 113.889 (if multiparous) + 165.560 (if origin = Asia) + 161.550 (South America) + 67.927 (rest of Europe) +109.265 (North Africa) + 9.392*Maternal-Height + 4.856*Maternal-Weight 0.098*Maternal-Weight(2) + 0.001*Maternal-Weight(3) + 67.188*Sex + GA40*(6.890*Sex + 9.032 (If multiparous) +0.006*Maternal-Height(3) + 0.260*Maternal-Weight) + GA40(2) (-0.378*Maternal-Height - 0.008*Maternal Height(2)) + GA40(3) (-0.032*Maternal-Height). Weight percentiles were obtained from standard data using optimum weight variation coefficient. Agreement between our customized model and other Spanish models was "good" (kappa = 0.717 and kappa = 0.736; p < 0.001). CONCLUSIONS: Our model is comparable to other Spanish models, but offers the advantage of being customized, updated and freely available on the web. The 30.6% of infants classified as SGA using our model would be considered as AGA following a non-customized model. PMID- 24168176 TI - Effect of gamma-irradiation on gene expression of heat shock proteins in the foodborne pathogen Escherichia coli O157:H7. AB - PURPOSE: The expression levels of seven genes (clpB, dnaK, groES, grpE, htpG, htpX and ibpB) encoding heat shock proteins (HSP) in Escherichia coli O157:H7 (E. coli) gamma irradiated was investigated. Timing impact of post-irradiated RNA extraction on the expression levels of these seven genes was also studied at a dose damaging the bacterial cells (0.4 kGy). METHODS: Bacterial samples were gamma-irradiated at 0.4 kGy and at a lethal dose of 1.3 kGy. RNA was extracted at 0 min post irradiation for both irradiation doses and at 15, 30, 60, 90 or 120 min post-irradiation at the dose damaging the cells. Quantification of the gene expression was performed using quantitative real-time polymerase chain reaction (q-RT-PCR). RESULTS: The expression of genes encoding HSP was a very dynamic process evolving rapidly when E. coli cells were irradiated at 0.4 kGy. Notably, groES, grpE and ibpB were more up- regulated at 1.3 kGy than those at 0.4 kGy. CONCLUSIONS: For the seven genes studied there were more damaged proteins during irradiation at the lethal dose and this dose causes increased expression in HSP which contributes to damage reparation. Expression patterns of genes encoding HSP in E. coli treated by gamma-irradiation are different from those treated by heat shock. PMID- 24168177 TI - Scabies community prevalence and mass drug administration in two Fijian villages. AB - BACKGROUND: Scabies has been estimated to affect approximately 300 million people worldwide each year. Scabies rates are high and pose a significant public health problem in Fiji. Community-based comparison treatment trials have not been undertaken. We estimated scabies prevalence and compared the efficacy and tolerability of mass drug administration (MDA) of benzyl benzoate lotion (BB) or oral ivermectin (IVM) in two villages in Fiji. METHODS: A prospective MDA trial was undertaken in two Fijian villages, comparing three daily applications of BB with single dose IVM or permethrin cream for those aged under two years. The therapies were offered to all community members regardless of the presence of scabies or its symptoms. The difference in prevalence was measured before and after the intervention and absolute risk reduction (ARR) and relative risk (RR) calculated. RESULTS: In the BB group, there were 572 eligible participants, of whom 435 (76%) enrolled and 201 (46%) returned for follow-up. In the IVM group, there were 667 eligible participants, of whom 325 (49%) enrolled and 126 (39%) returned. Scabies prevalence was lower after the intervention in both groups. It fell from 37.9 to 20.0% (ARR 18.0%; RR 0.52) in the BB group and from 23.7 to 9.5% (ARR 14.2%; RR 0.40) in the IVM group. CONCLUSIONS: Our study provides proof of principle that MDA for scabies can reduce scabies prevalence at the community level, and that there was no significant difference in this trial between BB and oral IVM. PMID- 24168178 TI - Diagnosis of malignant hypertension with ocular examination: a child case. AB - A 12-year-old female patient was admitted to our clinic complaining about low vision. Bilateral optic disc edema, macular star, and preretinal hemorrhages were found in fundoscopic examination. In fundus fluorescein angiography, massive leakage in the late phase was seen in the optic nerve head and macular area. These findings were compatible with high-grade hypertensive retinopathy. The patient consulted with pediatrics and a diagnosis of vesicourethral reflux and malignant hypertension was made. PMID- 24168179 TI - Distinguishing the histological and radiological features of cystic lung disease in Birt-Hogg-Dube syndrome from those of tobacco-related spontaneous pneumothorax. AB - AIMS: Birt-Hogg-Dube syndrome (BHD) is a rare autosomal dominantly inherited genodermatosis that predisposes to cystic lung disease, leading to spontaneous pneumothoraces. This retrospective analysis of five BHD cases (two men, three women) compared lung histology and computed tomography (CT) imaging to a matched cohort of non-BHD patients with spontaneous pneumothoraces (SPN). METHODS AND RESULTS: Lung was sampled during pleurodesis to resect bullae. Recurrent pneumothoraces was seen in two patients. Fourteen sets of histological slides (seven in each group) and 10 CT scans (five in each group) were reviewed. CT scans in BHD showed multiple cysts with a basal predominance and intraparenchymal/peribronchial distribution. On histological examination, BHD lungs showed punch-out cysts with no inflammation, and lacked subpleural fibroelastotic scars and smoking changes. In contrast, all SPN cases showed respiratory bronchiolitis and subpleural fibroelastotic scars. CONCLUSIONS: This study emphasizes the importance of smoking history and topography of the lesions in assessing cystic lung disease. Pathologists need to remain alert to the possibility of BHD in the setting of recurrent pneumothoraces in a non-smoker, in particular in a woman, at any age, and should take part in a multidisciplinary approach to the diagnosis of cystic lung disease to obtain clinical and CT scan details. PMID- 24168180 TI - Downregulation of PTEN expression in psoriatic lesions. AB - BACKGROUND: Considerable studies showed that tumor suppressor phosphatase and tensin homolog (PTEN) deleted on chromosome 10 is a major tumor suppressor, which inhibits cell proliferation through inactivation of the PI3 kinase (PI3K)/Akt signal pathway. In many human tumors, there is loss of function or mutations in PTEN. In our previous study, it was found that Akt activity in psoriatic lesions increased compared with that in normal controls. However, the expression of PTEN and the correlation between PTEN and PI3K/Akt have not been investigated in patients with psoriasis. MATERIALS AND METHODS: Skin tissue samples were obtained from 18 patients with psoriasis and 19 healthy controls. The expressions of PTEN were measured with quantitative real-time polymerase chain reaction (RT-PCR) assay, Western blotting, and immunohistochemistry. RESULTS: Quantitative RT-PCR analysis demonstrated that the mRNA levels of PTEN in psoriatic lesions were decreased in comparison with that in normal skin. Western blotting and immunohistochemistry analysis of PTEN showed that PTEN protein was lowly expressed in psoriatic lesions compared with that in normal controls, which suggested that the reduction of PTEN mRNA expression leads to decreased PTEN protein levels. CONCLUSIONS: The downregulation of PTEN expressions may play a role in the overactivation of the PI3K/Akt pathway in psoriatic lesions and correlate with the hyperproliferation of psoriatic keratinocytes. PMID- 24168181 TI - Single-molecule observation of long jumps in polymer adsorption. AB - Single-molecule fluorescence imaging of adsorption onto initially bare surfaces shows that polymer chains need not localize immediately after arrival. In a system optimized to present limited adsorption sites (quartz surface to which polyethylene glycol (PEG) chains adsorb from aqueous solution at pH 8.2), we find that some chains diffuse back into bulk solution and readsorb at some distance away, sometimes multiple times before they either localize at a stable position or diffuse away into bulk solution. This mechanism of surface diffusion is considerably more rapid than the classical model in which adsorbed polymers crawl on surfaces while the entire molecule remains adsorbed, suggesting the conceptual generality of a recent report ( Phys. Rev. Lett. 2013 , 110 , 256101 ) but in a new experimental system and with comparison of different chain lengths. We find the trajectories with jumps to follow a truncated Levy distribution of step size with limiting slope -2.5, consistent with a well-defined, rapid surface diffusion coefficient over the times we observe. The broad waiting time distribution appears to reflect that polymer chains possess a broad distribution of bound fraction: the smaller the bound fraction of a given chain, the shorter the surface residence time before executing the next surface jump. PMID- 24168182 TI - Fabrication of a new hydrous Zr(IV) oxide-based nanocomposite for enhanced Pb(II) and Cd(II) removal from waters. AB - To overcome the technical bottleneck of fine hydrated Zr(IV) oxide particles in environmental remediation, we irreversibly impregnated nanosized hydrated Zr(IV) oxide inside a commercial cation exchange resin D-001 and obtained a new nanocomposite NZP. NZP exhibited efficient removal of lead and cadmium ions in a pH range of 2-6, where no Zr(IV) leaching was detected from NZP. As compared to D 001, NZP showed more preferable adsorption toward both toxic metals from the background Ca(II) solution at greater levels. The synthetic Pb(II) or Cd(II) solution containing other ubiquitous metal ions was employed as the feeding influent for column adsorption, and the results indicated that the treatable volume of NZP is around 3-4 times that of D-001 before reaching the breakthrough point set according to the effluent discharge standard of China. With respect to Pb(II) removal from an acidic mining effluent, the treatable volume of NZP was 13 times higher than that of D-001. The exhausted NZP could be effectively regenerated by HNO3-Ca(NO3)2 binary solution for repeated use without any significant capacity loss. The superior performance of NZP was attributed to the Donnan membrane effect exerted by the host D-001 as well as the impregnated HZO nanoparticles of specific interaction toward toxic metals, as confirmed by the comparative isothermal adsorption and X-ray photoelectron spectroscopic study. PMID- 24168183 TI - Decoding the knots of initiation of oncogenic epithelial-mesenchymal transition in tumor progression. AB - Oncogenic epithelial-mesenchymal transition (oncEMT) plays important roles in the genesis of cancer stem cells (CSCs), malignant tumor initiation and progression, cancer metastasis, and drug resistance. Although the role of oncEMT in tumorigenesis has recently been extensively studied, the initiation of oncEMT is not clearly understood, and its mechanisms of action are still unknown. Emerging evidence suggests that oncEMT is a complex process, which involves multiple endogenous and exogenous factors. Overexpression of several oncogenes and reprogramming factors in precancerous and cancerous cells, including Ras, Myc, Bmi-1, Oct4, Nanog, Slug, Twist, Zeb1, and Zeb2, may initiate oncEMT and tumorigenesis. Defects in key tumor suppressors, such as p53, PTEN, CCN6 protein, and p21 also are associated with oncEMT. MicroRNA (miRNA) may also play a role in the oncEMT. Furthermore, exogenous factors, including chemical carcinogens, viruses, radiation, hypoxia, and acidic microenvironment, can drive oncEMT. Moreover, various growth factors derived from either malignant tumor cells or tumor-associated non-tumor cells in the cancer microenvironment can promote oncEMT. Together, the endogenous and exogenous factors, as well as a hostile cancer microenvironment, initiate the oncEMT program through diverse signaling pathways and networks. However, the dynamic process of initiating oncEMT and the mechanisms are still incompletely understood. Further characterization of the dynamics and mechanisms of the oncEMT will provide new insights into oncogenesis, as well as identify specific oncEMT markers and targets for early diagnosis of cancer and novel anti-cancer drug discovery. PMID- 24168185 TI - Epigenetic regulation of epithelial to mesenchymal transition. AB - Epithelial-mesenchymal transition (EMT) is a vital process implemented in embryo development, organ fibrosis, and cancer metastasis. Several transcription factors and signaling pathways impinge on the transcriptional program of the cell, leading to the change of cell phenotype without alteration of genotype. Accumulating evidence suggests that epigenetic mechanisms play important roles in inducing EMT and orchestrating the heredity and reversibility of EMT. In this review, we discuss how DNA methylation, histone modifications, and microRNAs (miRNAs) act in a concerted manner to regulate EMT. 'Epigenetic therapies' inhibitors of DNA methyltransferases and histone deacetylases as well as microRNAs are emerging as promising agents for cancer intervention. PMID- 24168184 TI - Regulation of EMT by KLF4 in gastrointestinal cancer. AB - Gastrointestinal (GI) cancer is characterized by its aggressiveness, but the underlying mechanism is not fully understood. Studies reveal that epithelial to mesenchymal transition (EMT), which is regulated by a series of transcription factors and signaling pathways, is strongly associated with GI cancer cell proliferation, invasion and metastasis. Importantly, EMT is a product of crosstalk between signaling pathways. Kruppel-like factor 4 (KLF4), a zinc finger type transcription factor, is decreased or lost in most GI cancers. By transcriptionally regulating its downstream target genes, KLF4 plays important roles of GI cancer tumorigenesis, proliferation and differentiation. In this review, we focus on the mechanism of KLF4 in GI cancer EMT, and demonstrate that through crosstalk with TGF-beta, Notch, and Wnt signaling pathways, KLF4 negatively regulates EMT of GI cancers. Finally, we indicate the challenging new frontiers for KLF4 which contributes to better understanding of the mechanism of GI cancer aggressiveness. PMID- 24168187 TI - Regulation of EMT by Notch signaling pathway in tumor progression. AB - Notch signaling pathway has been reported to play critical roles in the development and progression of human cancers because Notch signaling pathway is critically involved in many cellular processes including cell proliferation, survival, apoptosis, migration, invasion, angiogenesis, and metastasis. Emerging evidence suggests that Notch regulates EMT (Epithelial-to-Mesenchymal Transition), leading to tumor invasion and metastasis. Thus, this mini-review is focused on discussing the novel role of Notch signaling pathway in the regulation of EMT. Moreover, we summarized that Notch signaling pathway could be down regulated by its inhibitors or natural compounds, resulting in the reversal of EMT to MET (Mesenchymal-to-Epithelial Transition), which could be a promising strategy for achieving better treatment outcome in patients diagnosed with cancer. PMID- 24168189 TI - MicroRNAs as critical regulators involved in regulating epithelial- mesenchymal transition. AB - The epithelial-mesenchymal transition (EMT) is a fundamental biological process that is involved in normal embryogenesis, would healing, and tissue repair, as well as numerous pathologies, including organ fibrosis, malignant transformation, and cancer progression. Both transcriptional and post-transcriptional regulatory mechanisms contribute to a complex and tightly controlled regulatory network during the EMT process, and a growing body of evidence now demonstrates that microRNAs (miRNAs) are crucial regulators of this network. miRNAs are a class of small non-coding RNAs that regulate gene expression through translational repression or mRNA degradation. A set of miRNAs have been discovered that have the potential to target multiple components of the signaling pathways and downstream effectors of the EMT. Our understanding of the roles that miRNAs play during the EMT process suggests that these miRNAs may eventually serve as novel biomarkers and therapeutic targets for various EMT-based pathological conditions. This review summarizes the current knowledge concerning how miRNAs mechanistically regulate the EMT and discusses the specific roles that miRNAs play in three EMT subtypes. We hope that a more comprehensive understanding of the functions of miRNAs in the EMT process will lead to the rapid development of novel diagnostic techniques and molecular-based strategies for controlling EMT. PMID- 24168186 TI - The Role of Snail in EMT and Tumorigenesis. AB - Epithelial-mesenchymal transition (EMT) is a highly conserved process in which polarized, immobile epithelial cells lose tight junctions, associated adherence, and become migratory mesenchymal cells. Several transcription factors, including the Snail/Slug family, Twist, deltaEF1/ZEB1, SIP1/ZEB2 and E12/E47 respond to microenvironmental stimuli and function as molecular switches for the EMT program. Snail is a zinc-finger transcriptional repressor controlling EMT during embryogenesis and tumor progression. Through its N-terminal SNAG domain, Snail interacts with several corepressors and epigenetic remodeling complexes to repress specific target genes, such as the E-cadherin gene (CDH1). An integrated and complex signaling network, including the RTKs, TGF-beta, Notch, Wnt, TNF alpha, and BMPs pathways, activates Snail, thereby inducing EMT. Snail expression correlates with the tumor grade, nodal metastasis of many types of tumor and predicts a poor outcome in patients with metastatic cancer. Emerging evidences indicate that Snail causes a metabolic reprogramming, bestows tumor cells with cancer stem cell-like traits, and additionally, promotes drug resistance, tumor recurrence and metastasis. Despite many new and exciting developments, several challenges remain to be addressed in order to understand more thoroughly the role of Snail in metastasis. Additional investigations are required to disclose the contribution of microenvironmental factors on tumor progression. This information will lead to a comprehensive understanding of Snail in cancer and will provide us with novel approaches for preventing and treating metastatic cancers. PMID- 24168188 TI - Emerging role of mucins in epithelial to mesenchymal transition. AB - Epithelial to mesenchymal transition (EMT) is an important and complex phenomenon that determines the aggressiveness of cancer cells. The morphological transformation of cancerous cells is accompanied by various cellular processes such as alterations in cell-cell adhesion, cell matrix degradation, down regulation of epithelial marker Ecadherin and upregulation of mesenchymal markers N-cadherin and Vimentin. Besides these markers several other important tumor antigens/mucins are also involved in the EMT process. Mainly high molecular weight glycoproteins such as mucin molecules (MUC1, MUC4 and MUC16) play a major role in the cellular transformation and signaling alteration in EMT process. In addition to these factors, EMT may be an essential process triggering the emergence or expansion of the CSC population, which slowly results in the initiation of tumor at metastatic sites. Furthermore, mucins have been demonstrated to be involved in the EMT process and also in the enrichment of cancer stem cell population. Mucin mediated EMT is very complex since the key components of tumor microenvironment are also regulating mucin molecules. In this review, we have discussed all the aforementioned factors and their mechanistic involvement for EMT process. PMID- 24168191 TI - Roles of epithelial-mesenchymal transition in cancer drug resistance. AB - Overcoming intrinsic and acquired drug resistance is a major challenge in treating cancer. Poor responses to drug treatment can result in metastasis, cancer dissemination and death. Recently, the epithelial-mesenchymal transition (EMT) has been found to play a critical role in cancer drug resistance, but the nature of this intrinsic link remains unclear. This review summarizes recent advances in the understanding of drug resistance and focuses especially on the association between EMT and drug resistance. We discuss the roles of EMT in regulating drug resistance across different types of cancer, focusing simultaneously on the molecular mechanisms and potential pathways involved in the regulation of drug resistance by EMT. In addition, we discuss potential therapeutic strategies to target EMT to reverse drug resistance. PMID- 24168190 TI - Regulation of mesenchymal phenotype by MicroRNAs in cancer. AB - Epithelial-mesenchymal transition (EMT) is a developmental process that converts epithelial cells into migratory and invasive cells. This process also plays an important role in cancer progression and metastasis by enabling tumor cells to leave primary sites. EMT is regulated by complex transcription networks and post transcriptional modulators. MicroRNAs are single-stranded non-coding RNAs that represent a novel class of gene regulators. It has been shown that microRNAs are critical regulators of EMT process. The molecular mechanisms of EMT modulation by microRNAs include the suppression of transcription factors that directly regulate EMT and the down-regulation of cellular genes and pathways that are indirectly involved in EMT process. The expressions of microRNAs that control EMT process are dysregulated in cancer. In this review, we summarize the recent progress of microRNAs in EMT regulation. PMID- 24168192 TI - Unveiling the role of nuclear transport in epithelial-to-mesenchymal transition. AB - Epithelial-to-Mesenchymal transition (EMT) is a phenomenon in which cancer cells loose their polarity, undergo morphological changes from epithelial to mesenchymal thereby achieving plasticity that confers an invasive and metastatic behavior. A large number of signaling molecules (Wnt/beta-Catenin, TGF-beta, notch, EGF, HGF and hypoxia) have been implicated in the EMT process. The EMT signaling molecules are localized either extracellularly, in the cytosol, or in the nucleus. The Wnt, TGF-beta, notch, EGF and HGF signaling initiates from receptors on the cell surface through the cytoplasm and ultimately to the cell's nucleus where the signaling cascade leads to the expression of EMT genes. No matter what the source is, the ultimate effector molecules from each one of these signaling pathways need to reach cell nucleus, aligning on DNA in a sequence specific manner and initiating the transcription of EMT promoting genes. In essence cellular transport, particularly the nuclear transport that is regulated by specialized proteins called Karyopherins, in a way controls the majority of EMT promoting pathways either directly or indirectly. Nevertheless, there have been no attempts to understand the consequence of alterations in the nuclear transport machinery that is often times aberrantly expressed in cancer, on EMT development. This review poses important questions on the role of nuclear transporters (Importins and Exportins) in the development of EMT and provides an in depth understanding of the underappreciated cellular transport based regulation of EMT signaling molecules and also discusses the possibility of targeting the nuclear import and export proteins to rein in EMT. PMID- 24168193 TI - Emerging roles of epithelial-to-mesenchymal transition in tumorigenesis. PMID- 24168194 TI - Dietary patterns and stomach cancer: a meta-analysis. AB - Investigation of the relationship between dietary patterns and some chronic diseases becomes appealing in nutrition epidemiology. Many studies reported potential associations between different dietary patterns and the risk of stomach cancer, however, a consistent perspective hasn't been established to date. Herein, we carried this meta-analysis to identify the associations between different dietary patterns and the risk of stomach cancer. A total of 23 studies met the inclusion criteria and were included in this meta-analysis. A decreased risk of stomach cancer was shown for the highest compared with the lowest category of a "healthy" dietary pattern [odds ratio (OR) = 0.69; confidence interval (CI): 0.53, 0.89; P = 0.005). There were evidence of the increased risk of stomach cancer in the highest compared with the lowest categories of Western style pattern (OR = 1.59; CI: 1.25, 2.04; P = 0.0002) and alcohol-drinking pattern (OR = 1.37; CI: 1.11, 1.70; P = 0.004). The results of this meta-analysis indicate that healthy dietary pattern may decrease the risk of stomach cancer, whereas Western-style and alcohol-drinking dietary patterns may increase the risk of stomach cancer. PMID- 24168195 TI - Relationship between left ventricular geometry and soluble ST2 in a cohort of hypertensive patients. AB - Left ventricular (LV) hypertrophy (LVH) is classified according to geometric pattern into 4 types: concentric hypertrophy, eccentric hypertrophy, concentric remodeling, and normal geometry. Prevalence of death and cardiovascular complications associated with hypertension depend on the geometric pattern. Although soluble ST2 levels, a novel cardiac biomarker of mechanical strain is increased in hypertension, the relationship with hypertensive LV geometric patterns has not been studied. The authors investigated the relationship between soluble ST2 levels and LV geometric patterns in a cohort of hypertensive patients. LVH was considered present when echocardiographic LV mass index exceeded 49.2 g/m(2.7) in men and 46.2 g/m(2.7) in women. Patients with concentric hypertrophy had higher soluble ST2 levels compared with patients with normal geometry (20.4+/-8.4 ng/mL vs 14.3+/-5.4 ng/mL, P<.002). Therefore, soluble ST2 level is not only affected by hypertensive LV, but may be a future biomarker in differentiating concentric hypertrophy from normal geometry in hypertension. PMID- 24168196 TI - Culture-specific familiarity equally mediates action representations across cultures. AB - Previous studies have shown that we need to distinguish between means and end information about actions. It is unclear how these two subtypes of action information relate to each other with theoretical accounts postulating the superiority of end over means information and others linking separate means and end routes of processing to actions of differential meaningfulness. Action meaningfulness or familiarity differs between cultures. In a cross-cultural setting, we investigated how action familiarity influences recognition memory for means and end information. Object directed actions of differential familiarity were presented to Chinese and German participants. Action familiarity modulated the representation of means and end information in both cultures in the same way, although the effects were based on different stimulus sets. Our results suggest that, in the representation of actions in memory, end information is superordinate to means information. This effect is independent of culture whereas action familiarity is not. PMID- 24168197 TI - Auditory temporal-regularity processing correlates with language and literacy skill in early adulthood. AB - This work tests the hypothesis that language skill depends on the ability to incorporate streams of sound into an accurate temporal framework. We tested the ability of young English-speaking adults to process single time intervals and rhythmic sequences of such intervals, hypothesized to be relevant to the analysis of the temporal structure of language. The data implicate a specific role for the ability to process beat-based temporal regularities in phonological language and literacy skill. PMID- 24168198 TI - N400 incongruity effect in an episodic memory task reveals different strategies for handling irrelevant contextual information for Japanese than European Canadians. AB - East Asians/Asian Americans show a greater N400 effect due to semantic incongruity between foreground objects and background contexts than European Americans (Goto, Ando, Huang, Yee, & Lewis, 2010). Using analytic attention instructions, we asked Japanese and European Canadians to judge, and later, remember, target animals that were paired with task-irrelevant original (congruent), or novel (incongruent) contexts. We asked: (1) whether the N400 also shows an episodic incongruity effect, due to retrieved contexts conflicting with later-shown novel contexts; and (2) whether the incongruity effect would be more related to performance for Japanese, who have been shown to have more difficulty ignoring such contextual information. Both groups exhibited episodic incongruity effects on the N400, with Japanese showing more typical N400 topographies. However, incongruent-trial accuracy was related to reduction of N400s only for the Japanese. Thus, we found that the N400 can reflect episodic incongruity which poses a greater challenge to Japanese than European Canadians. PMID- 24168200 TI - Relationship of cognitive reserve and APOE status to the emergence of clinical symptoms in preclinical Alzheimer's disease. AB - The APOE epsilon4 allele increases the risk of developing Alzheimer's disease, whereas the APOE epsilon2 allele reduces risk. We examined whether cognitive reserve (CR), as measured by an index consisting of education, reading, and vocabulary, modifies these associations. CR was measured at baseline in 257 cognitively normal individuals (mean age 57.2 years) who have been followed for up to 17 years (mean follow-up = 9.2 years). Cox regression models showed that CR and APOE epsilon4 independently affected the risk of progressing from normal cognition to onset of clinical symptoms: CR reduced risk by about 50% in both epsilon4 carriers and non-carriers, while epsilon4 increased risk by about 150%. In contrast, APOE epsilon2 interacted with CR, such that CR was more protective in epsilon2 carriers than non-carriers. This suggests that individuals with an epsilon2 genotype may disproportionately benefit from lifetime experiences that enhance cognition. PMID- 24168201 TI - The interaction between language and visual spatial attention systems in grammatical gender processing. An N2pc study. AB - This ERP study employed an N2pc paradigm to investigate possible functional interactions between mechanisms of visual spatial attention and grammatical gender processing. Previous studies showed that the N2pc, an attention-related ERP component, can be modulated by lexical-semantic variables. However, it remains to be seen whether the N2pc can be affected by grammatical features as well. To test this, we conducted an N2pc study with Italian word pairs whose grammatical gender either agreed or disagreed. Participants read a centrally presented noun followed by an adjective in a lateralized position during a gender agreement task. Between 170 and 310ms, the N2pc was elicited contralaterally to the adjective position with a left-lateralized effect of the agreement manipulation. These results suggest that this component could be influenced by grammatical features, supporting a functional interaction between processes mediating visual spatial attention and agreement computation. PMID- 24168199 TI - The entorhinal cortex and neurotrophin signaling in Alzheimer's disease and other disorders. AB - A major problem in the field of neurodegeneration is the basis of selective vulnerability of subsets of neurons to disease. In aging, Alzheimer's disease (AD), and other disorders such as temporal lobe epilepsy, the superficial layers of the entorhinal cortex (EC) are an area of selective vulnerability. In AD, it has been suggested that the degeneration of these neurons may play a role in causing the disease because it occurs at an early stage. Therefore, it is important to define the distinctive characteristics of the EC that make this region particularly vulnerable. It has been shown that neurotrophins such as brain-derived neurotrophic factor (BDNF) are critical to the maintenance of the cortical neurons in the adult brain, and specifically the EC. Here we review the circuitry, distinctive functions, and neurotrophin-dependence of the EC that are relevant to its vulnerability. We also suggest that a protein that is critical to the actions of BDNF, the ARMS/Kidins220 scaffold protein, plays an important role in neurotrophic support of the EC. PMID- 24168202 TI - Role of working memory in transformation of visual and motor representations for use in mental simulation. AB - This study examined the role of visual working memory when transforming visual representations to motor representations in the context of motor imagery. Participants viewed randomized number sequences of three, four, and five digits, and then reproduced the sequence by finger tapping using motor imagery or actually executing the movements; movement duration was recorded. One group viewed the stimulus for three seconds and responded immediately, while the second group had a three-second view followed by a three-second blank screen delay before responding. As expected, delay group times were longer with each condition and digit load. Whereas correlations between imagined and executed actions (temporal congruency) were significant in a positive direction for both groups, interestingly, the delay group's values were significantly stronger. That outcome prompts speculation that delay influenced the congruency between motor representation and actual execution. PMID- 24168203 TI - The effect of manipulability and religion on the multisensory integration of objects in peripersonal space. AB - In this study participants were required to respond to vibrotactile stimuli applied to the hand while ignoring visual distractors superimposed on pictures representing Christian, Hindu, or profane objects that were categorized as manipulable or non-manipulable. Overall, participants responded slower when the visual distractor appeared at an incongruent location with respect to the vibrotactile stimulus, which is known as the crossmodal congruency effect (i.e., CCE). The CCE was modulated by the type of object involved (i.e., Christian, Hindu, or Profane), the object manipulability (i.e., manipulable vs. non manipulable) and the religious background of the participant (i.e., Christian, Hindu, or non-religious). The finding that both object manipulability, the religious significance of the object, and the religious background of the participant have a combined effect on multisensory integration suggests important interactions between low-level body-object integration and the symbolic extension of the self. PMID- 24168204 TI - My face, my heart: cultural differences in integrated bodily self-awareness. AB - Body-awareness is produced by an integration of both interoceptive and exteroceptive bodily signals. However, previous investigations into cultural differences in bodily self-awareness have only studied these two aspects in isolation. We investigated the interaction between interoceptive and exteroceptive self-processing in East Asian and Western participants. During an interoceptive awareness task, self-face observation improved performance of those with initially low awareness in the Western group, but did not benefit the East Asian participants. These results suggest that the integrated, coherent experience of the body differs between East Asian and Western cultures. For Western participants, viewing one's own face may activate a bodily self-awareness which enhances processing of other bodily information, such as interoceptive signals. Instead, for East Asian individuals, the external appearance of the self may activate higher-level, social aspects of self-identity, reflecting the importance of the sociocultural construct of "face" in East Asian cultures. PMID- 24168206 TI - Editorial Comment from Dr Schiavina et al. to Cystectomy and urinary diversion as management of treatment-refractory benign disease: the impact of preoperative urological conditions on perioperative outcomes. PMID- 24168205 TI - Self-construal priming modulates pain perception: event-related potential evidence. AB - We investigated whether and how temporary shifts in self-construals modulate neural correlates of pain perception. Event-related potentials (ERPs) to painful and non-painful electrical stimulations were recorded from adults after being primed with independent and interdependent self-construals. Electrical stimulations to the left hand elicited two negative components (N60 and N130) over the frontal /central regions and two positive components (P90 and P300) over the central/parietal regions with larger amplitudes over the right rather than the left hemispheres. Painful vs. non-painful stimulations enlarged P90, N130, and P300 amplitudes. Independent vs. interdependent self-construal priming induced larger N130 amplitudes to painful stimulations but did not affect the N130 amplitudes to non-painful stimulations. The self-construal priming effect on the P300 amplitudes to painful stimulation positively correlated with self reported interdependence. Our ERP results suggest that temporary shifts in self construals affect pain perception by modulating the neural activities engaged in early somatosensory and late evaluation processing of physical pain. PMID- 24168207 TI - Don't miss it: a rare case of multifocal necrotizing fasciitis. PMID- 24168208 TI - Effectiveness of an organized colorectal cancer screening program on increasing adherence in asymptomatic average-risk Canadians. AB - BACKGROUND: Colorectal cancer (CRC) is the third most commonly diagnosed cancer and second highest cause of cancer-related mortality in Canada. Despite the availability of screening services and establishment of guidelines, utilization of colorectal cancer screening in Canada remains low. In 2008, the province of Ontario launched ColonCancerCheck, an organized colorectal cancer screening program aimed at increasing CRC screening adherence. In this study, we adopt a quasi-experimental approach to estimate and describe the impact of ColonCancerCheck on screening behavior in the asymptomatic average risk population. METHODS: Annual screening rates from the target population were estimated using five cycles of the Canadian Community Health Survey, a cross sectional nationally representative survey of health status, healthcare use, and determinants of health in the Canadian population. We used a difference-in differences design to measure the overall impact of ColonCancerCheck on past-year fecal occult blood testing (FOBT) and endoscopy in Ontario relative to the rest of Canada. Several verification tests validated the suitability of our model specification. RESULTS: The difference-in-differences analysis shows that ColonCancerCheck increased FOBT screening in the average risk population by 5.2 percentage points (95% CI [3.2, 7.2]), an increase of 33% relative to pre-program screening rates. The program had no observed effect on endoscopy screening and we found no evidence that ColonCancerCheck differentially altered the screening practices of population sub-groups. CONCLUSIONS: Our findings suggest ColonCancerCheck has been successful at increasing use of FOBT in the asymptomatic average risk population. PMID- 24168210 TI - Coordination and hydrolysis of plutonium ions in aqueous solution using Car Parrinello molecular dynamics free energy simulations. AB - Car-Parrinello molecular dynamics (CPMD) simulations have been used to examine the hydration structures, coordination energetics, and the first hydrolysis constants of Pu(3+), Pu(4+), PuO2(+), and PuO2(2+) ions in aqueous solution at 300 K. The coordination numbers and structural properties of the first shell of these ions are in good agreement with available experimental estimates. The hexavalent PuO2(2+) species is coordinated to five aquo ligands while the pentavalent PuO2(+) complex is coordinated to four aquo ligands. The Pu(3+) and Pu(4+) ions are both coordinated to eight water molecules. The first hydrolysis constants obtained for Pu(3+) and PuO2(2+) are 6.65 and 5.70, respectively, all within 0.3 pH unit of the experimental values (6.90 and 5.50, respectively). The hydrolysis constant of Pu(4+), 0.17, disagrees with the value of -0.60 in the most recent update of the Nuclear Energy Agency Thermochemical Database (NEA-TDB) but supports recent experimental findings. The hydrolysis constant of PuO2(+), 9.51, supports the experimental results of Bennett et al. [Radiochim. Acta 1992, 56, 15]. A correlation between the pKa of the first hydrolysis reaction and the effective charge of the plutonium center was found. PMID- 24168209 TI - Air trapping and airflow obstruction in newborn cystic fibrosis piglets. AB - RATIONALE: Air trapping and airflow obstruction are being increasingly identified in infants with cystic fibrosis. These findings are commonly attributed to airway infection, inflammation, and mucus buildup. OBJECTIVES: To learn if air trapping and airflow obstruction are present before the onset of airway infection and inflammation in cystic fibrosis. METHODS: On the day they are born, piglets with cystic fibrosis lack airway infection and inflammation. Therefore, we used newborn wild-type piglets and piglets with cystic fibrosis to assess air trapping, airway size, and lung volume with inspiratory and expiratory X-ray computed tomography scans. Micro-computed tomography scanning was used to assess more distal airway sizes. Airway resistance was determined with a mechanical ventilator. Mean linear intercept and alveolar surface area were determined using stereologic methods. MEASUREMENTS AND MAIN RESULTS: On the day they were born, piglets with cystic fibrosis exhibited air trapping more frequently than wild type piglets (75% vs. 12.5%, respectively). Moreover, newborn piglets with cystic fibrosis had increased airway resistance that was accompanied by luminal size reduction in the trachea, mainstem bronchi, and proximal airways. In contrast, mean linear intercept length, alveolar surface area, and lung volume were similar between both genotypes. CONCLUSIONS: The presence of air trapping, airflow obstruction, and airway size reduction in newborn piglets with cystic fibrosis before the onset of airway infection, inflammation, and mucus accumulation indicates that cystic fibrosis impacts airway development. Our findings suggest that early airflow obstruction and air trapping in infants with cystic fibrosis might, in part, be caused by congenital airway abnormalities. PMID- 24168211 TI - HIV-associated tuberculosis: relationship between disease severity and the sensitivity of new sputum-based and urine-based diagnostic assays. AB - BACKGROUND: Reducing mortality from HIV-associated tuberculosis (TB) requires diagnostic tools that are rapid and have high sensitivity among patients with poor prognosis. We determined the relationship between disease severity and the sensitivity of new sputum-based and urine-based diagnostic assays. METHODS: Consecutive ambulatory patients enrolling for antiretroviral treatment in South Africa were screened for TB regardless of symptoms using diagnostic assays prospectively applied to sputum (fluorescence smear microscopy, Xpert MTB/RIF and liquid culture (reference standard)) and retrospectively applied to stored urine samples (Determine TB-LAM and Xpert MTB/RIF). Assay sensitivities were calculated stratified according to pre-defined indices of disease severity: CD4 count, symptom intensity, serum C-reactive protein (CRP), hemoglobin concentration and vital status at 90 days. RESULTS: Sputum culture-positive TB was diagnosed in 15% (89/602) of patients screened and data from 86 patients were analyzed (median CD4 count, 131 cells/MUL) including 6 (7%) who died. The sensitivity of sputum microscopy was 26.7% overall and varied relatively little with disease severity. In marked contrast, the sensitivities of urine-based and sputum-based diagnosis using Determine TB-LAM and Xpert MTB/RIF assays were substantially greater in sub groups with poorer prognosis. Rapid diagnosis from sputum and/or urine samples was possible in >80% of patients in sub-groups with poor prognosis as defined by either CD4 counts <100 cells/MUL, advanced symptoms, CRP concentrations >200 mg/L or hemoglobin <8.0 g/dl. Retrospective testing of urine samples with Determine TB LAM correctly identified all those with TB who died. CONCLUSIONS: The sensitivities of Xpert MTB/RIF and Determine TB-LAM for HIV-associated TB were highest among HIV-infected patients with the most advanced disease and poorest prognostic characteristics. These data provide strong justification for large scale intervention studies that assess the impact on survival of screening using these new sputum-based and urine-based diagnostic approaches. PMID- 24168213 TI - Effect of roscovitine on intracellular calcium dynamics: differential enantioselective responses. AB - Cyclin-dependent kinases (CDKs) inhibitors have emerged as interesting therapeutic candidates. Of these, (S)-roscovitine has been proposed as potential neuroprotective molecule for stroke while (R)-roscovitine is currently entering phase II clinical trials against cancers and phase I clinical tests against glomerulonephritis. In addition, (R)-roscovitine has been suggested as potential antihypertensive and anti-inflammatory drug. Dysfunction of intracellular calcium balance is a common denominator of these diseases, and the two roscovitine enantiomers (S and R) are known to modulate calcium voltage channel activity differentially. Here, we provide a detailed description of short- and long-term responses of roscovitine on intracellular calcium handling in renal epithelial cells. Short-term exposure to (S)-roscovitine induced a cytosolic calcium peak, which was abolished after stores depletion with cyclopiazonic acid (CPA). Instead, (R)-roscovitine caused a calcium peak followed by a small calcium plateau. Cytosolic calcium response was prevented after stores depletion. Bafilomycin, a selective vacuolar H(+)-ATPase inhibitor, abolished the small calcium plateau. Long-term exposure to (R)-roscovitine significantly reduced the basal calcium level compared to control and (S)-roscovitine treated cells. However, both enantiomers increased calcium accumulation in the endoplasmic reticulum (ER). Consistently, cells treated with (R)-roscovitine showed a significant increase in SERCA activity, whereas (S)-roscovitine incubation resulted in a reduced PMCA expression. We also found a tonic decreased ability to release calcium from the ER, likely via IP3 signaling, under treatment with (S)- or (R)-roscovitine. Together our data revealed that (S)-roscovitine and (R) roscovitine exert distinct enantiospecific effects on intracellular calcium signaling in renal epithelial cells. This distinct pharmacological profile can be relevant for roscovitine clinical use. PMID- 24168212 TI - mRNA-Seq and microarray development for the Grooved Carpet shell clam, Ruditapes decussatus: a functional approach to unravel host-parasite interaction. AB - BACKGROUND: The Grooved Carpet shell clam Ruditapes decussatus is the autochthonous European clam and the most appreciated from a gastronomic and economic point of view. The production is in decline due to several factors such as Perkinsiosis and habitat invasion and competition by the introduced exotic species, the manila clam Ruditapes philippinarum. After we sequenced R. decussatus transcriptome we have designed an oligo microarray capable of contributing to provide some clues on molecular response of the clam to Perkinsiosis. RESULTS: A database consisting of 41,119 unique transcripts was constructed, of which 12,479 (30.3%) were annotated by similarity. An oligo-DNA microarray platform was then designed and applied to profile gene expression in R. decussatus heavily infected by Perkinsus olseni. Functional annotation of differentially expressed genes between those two conditionswas performed by gene set enrichment analysis. As expected, microarrays unveil genes related with stress/infectious agents such as hydrolases, proteases and others. The extensive role of innate immune system was also analyzed and effect of parasitosis upon expression of important molecules such as lectins reviewed. CONCLUSIONS: This study represents a first attempt to characterize Ruditapes decussatus transcriptome, an important marine resource for the European aquaculture. The trancriptome sequencing and consequent annotation will increase the available tools and resources for this specie, introducing the possibility of high throughput experiments such as microarrays analysis. In this specific case microarray approach was used to unveil some important aspects of host-parasite interaction between the Carpet shell clam and Perkinsus, two non-model species, highlighting some genes associated with this interaction. Ample information was obtained to identify biological processes significantly enriched among differentially expressed genes in Perkinsus infected versus non-infected gills. An overview on the genes related with the immune system on R. decussatus transcriptome is also reported. PMID- 24168214 TI - Unilateral uveitis with vitreous haze following zoledronic Acid therapy for osteoporosis. AB - Zoledronic acid is widely used in the treatment of osteoporosis and other bone diseases. However, patients may experience adverse effects involving the anterior segment of the eye following intravenous infusion. This paper reports a rare case of uveitis involving the vitreous cavity following the intravenous administration of zoledronic acid. PMID- 24168215 TI - New phenanthrene glycosides from Dioscorea opposita. AB - Two new phenanthrene glycosides, dioscopposide A and dioscopposide B (1 and 2), were isolated from the rhizomes of Dioscorea opposita. Their structures were determined primarily on the basis of 1D and 2D NMR techniques, MS studies, and chemical methods. All the isolates were evaluated for their inhibitory effects on the lipopolysaccharide-induced nitric oxide production using murine macrophage RAW 264.7 cells. The IC50 values of dioscopposide A and dioscopposide B were 5.8 and 7.2 MUM, respectively. PMID- 24168216 TI - How we learn to make decisions: rapid propagation of reinforcement learning prediction errors in humans. AB - Our ability to make decisions is predicated upon our knowledge of the outcomes of the actions available to us. Reinforcement learning theory posits that actions followed by a reward or punishment acquire value through the computation of prediction errors-discrepancies between the predicted and the actual reward. A multitude of neuroimaging studies have demonstrated that rewards and punishments evoke neural responses that appear to reflect reinforcement learning prediction errors [e.g., Krigolson, O. E., Pierce, L. J., Holroyd, C. B., & Tanaka, J. W. Learning to become an expert: Reinforcement learning and the acquisition of perceptual expertise. Journal of Cognitive Neuroscience, 21, 1833-1840, 2009; Bayer, H. M., & Glimcher, P. W. Midbrain dopamine neurons encode a quantitative reward prediction error signal. Neuron, 47, 129-141, 2005; O'Doherty, J. P. Reward representations and reward-related learning in the human brain: Insights from neuroimaging. Current Opinion in Neurobiology, 14, 769-776, 2004; Holroyd, C. B., & Coles, M. G. H. The neural basis of human error processing: Reinforcement learning, dopamine, and the error-related negativity. Psychological Review, 109, 679-709, 2002]. Here, we used the brain ERP technique to demonstrate that not only do rewards elicit a neural response akin to a prediction error but also that this signal rapidly diminished and propagated to the time of choice presentation with learning. Specifically, in a simple, learnable gambling task, we show that novel rewards elicited a feedback error-related negativity that rapidly decreased in amplitude with learning. Furthermore, we demonstrate the existence of a reward positivity at choice presentation, a previously unreported ERP component that has a similar timing and topography as the feedback error related negativity that increased in amplitude with learning. The pattern of results we observed mirrored the output of a computational model that we implemented to compute reward prediction errors and the changes in amplitude of these prediction errors at the time of choice presentation and reward delivery. Our results provide further support that the computations that underlie human learning and decision-making follow reinforcement learning principles. PMID- 24168217 TI - Discriminating taxonomic categories and domains in mental simulations of concepts of varying concreteness. AB - Most studies of conceptual knowledge in the brain focus on a narrow range of concrete conceptual categories, rely on the researchers' intuitions about which object belongs to these categories, and assume a broadly taxonomic organization of knowledge. In this fMRI study, we focus on concepts with a variety of concreteness levels; we use a state of the art lexical resource (WordNet 3.1) as the source for a relatively large number of category distinctions and compare a taxonomic style of organization with a domain-based model (an example domain is Law). Participants mentally simulated situations associated with concepts when cued by text stimuli. Using multivariate pattern analysis, we find evidence that all Taxonomic categories and Domains can be distinguished from fMRI data and also observe a clear concreteness effect: Tools and Locations can be reliably predicted for unseen participants, but less concrete categories (e.g., Attributes, Communications, Events, Social Roles) can only be reliably discriminated within participants. A second concreteness effect relates to the interaction of Domain and Taxonomic category membership: Domain (e.g., relation to Law vs. Music) can be better predicted for less concrete categories. We repeated the analysis within anatomical regions, observing discrimination between all/most categories in the left mid occipital and left mid temporal gyri, and more specialized discrimination for concrete categories Tool and Location in the left precentral and fusiform gyri, respectively. Highly concrete/abstract Taxonomic categories and Domain were segregated in frontal regions. We conclude that both Taxonomic and Domain class distinctions are relevant for interpreting neural structuring of concrete and abstract concepts. PMID- 24168218 TI - The reconstruction of choice value in the brain: a look into the size of consideration sets and their affective consequences. AB - It has been proposed that choice utility exhibits an inverted U-shape as a function of the number of options in the choice set. However, most researchers have so far only focused on the "physically extant" number of options in the set while disregarding the more important psychological factor, the "subjective" number of options worth considering to choose-that is, the size of the consideration set. To explore this previously ignored aspect, we examined how variations in the size of a consideration set can produce different affective consequences after making choices and investigated the underlying neural mechanism using fMRI. After rating their preferences for art posters, participants made a choice from a presented set and then reported on their level of satisfaction with their choice and the level of difficulty experienced in choosing it. Our behavioral results demonstrated that enlarged assortment set can lead to greater choice satisfaction only when increases in both consideration set size and preference contrast are involved. Moreover, choice difficulty is determined based on the size of an individual's consideration set rather than on the size of the assortment set, and it decreases linearly as a function of the level of contrast among alternatives. The neuroimaging analysis of choice-making revealed that subjective consideration set size was encoded in the striatum, the dACC, and the insula. In addition, the striatum also represented variations in choice satisfaction resulting from alterations in the size of consideration sets, whereas a common neural specificity for choice difficulty and consideration set size was shown in the dACC. These results have theoretical and practical importance in that it is one of the first studies investigating the influence of the psychological attributes of choice sets on the value-based decision-making process. PMID- 24168220 TI - Spontaneous mentalizing predicts the fundamental attribution error. AB - When explaining the reasons for others' behavior, perceivers often overemphasize underlying dispositions and personality traits over the power of the situation, a tendency known as the fundamental attribution error. One possibility is that this bias results from the spontaneous processing of others' mental states, such as their momentary feelings or more enduring personality characteristics. Here, we use fMRI to test this hypothesis. Participants read a series of stories that described a target's ambiguous behavior in response to a specific social situation and later judged whether that act was attributable to the target's internal dispositions or to external situational factors. Neural regions consistently associated with mental state inference-especially, the medial pFC strongly predicted whether participants later made dispositional attributions. These results suggest that the spontaneous engagement of mentalizing may underlie the biased tendency to attribute behavior to dispositional over situational forces. PMID- 24168219 TI - Learning to read an alphabet of human faces produces left-lateralized training effects in the fusiform gyrus. AB - Numerous functional neuroimaging studies have shown that most orthographic stimuli, such as printed English words, produce a left-lateralized response within the fusiform gyrus (FG) at a characteristic location termed the visual word form area (VWFA). We developed an experimental alphabet (FaceFont) comprising 35 face-phoneme pairs to disentangle phonological and perceptual influences on the lateralization of orthographic processing within the FG. Using functional imaging, we found that a region in the vicinity of the VWFA responded to FaceFont words more strongly in trained versus untrained participants, whereas no differences were observed in the right FG. The trained response magnitudes in the left FG region correlated with behavioral reading performance, providing strong evidence that the neural tissue recruited by training supported the newly acquired reading skill. These results indicate that the left lateralization of the orthographic processing is not restricted to stimuli with particular visual perceptual features. Instead, lateralization may occur because the anatomical projections in the vicinity of the VWFA provide a unique interconnection between the visual system and left-lateralized language areas involved in the representation of speech. PMID- 24168221 TI - When three is not some: on the pragmatics of numerals. AB - Both numerals and quantifiers (like some) have more than one possible interpretation (i.e., weak and strong interpretations). Some studies have found similar behavior for numerals and quantifiers, whereas others have shown critical differences. It is, therefore, debated whether they are processed in the same way. A previous fMRI investigation showed that the left inferior frontal gyrus is linked to the computation of the strong interpretation of quantifiers (derived by a scalar implicature) and that the left middle frontal gyrus and the medial frontal gyrus are linked to processing the mismatch between the strong interpretation of quantifiers and the context in which they are presented. In the current study, we attempted to characterize the similarities and differences between numbers and quantifiers by examining brain activation patterns related to the processing of numerals in these brain regions. When numbers were presented in a mismatch context (i.e., where their strong interpretation did not match the context), they elicited brain activations similar to those previously observed with quantifiers in the same context type. Conversely, in a match context (i.e., where both interpretations of the scalar item matched the context), numbers elicited a different activation pattern than the one observed with quantifiers: Left inferior frontal gyrus activations in response to the match condition showed decrease for numbers (but not for quantifiers). Our results support previous findings suggesting that, although they share some features, numbers and quantifiers are processed differently. We discuss our results in light of various theoretical approaches linked to the representation of numerals. PMID- 24168222 TI - Metrical rhythm implicitly orients attention in time as indexed by improved target detection and left inferior parietal activation. AB - When we direct attentional resources to a certain point in time, expectation and preparedness is heightened and behavior is, as a result, more efficient. This future-oriented attending can be guided either voluntarily, by externally defined cues, or implicitly, by perceived temporal regularities. Inspired by dynamic attending theory, our aim was to study the extent to which metrical structure, with its beats of greater or lesser relative strength, modulates attention implicitly over time and to uncover the neural circuits underlying this process of dynamic attending. We used fMRI to investigate whether auditory meter generated temporal expectancies and, consequently, how it affected processing of auditory and visual targets. Participants listened to a continuous auditory metrical sequence and pressed a button whenever an auditory or visual target was presented. The independent variable was the time of target presentation with respect to the metrical structure of the sequence. Participants' RTs to targets occurring on strong metrical positions were significantly faster than responses to events falling on weak metrical positions. Events falling on strong beats were accompanied by increased activation of the left inferior parietal cortex, a region crucial for orienting attention in time, and, by greater functional connectivity between the left inferior parietal cortex and the visual and auditory cortices, the SMA and the cerebellum. These results support the predictions of the dynamic attending theory that metrical structure with its relative strong and weak beats modulates attentional resources over time and, in turn, affects the functioning of both perceptual and motor preparatory systems. PMID- 24168224 TI - Multiple aspects of neural activity during reaching preparation in the medial posterior parietal area V6A. AB - The posterior parietal cortex is involved in the visuomotor transformations occurring during arm-reaching movements. The medial posterior parietal area V6A has been shown to be implicated in reaching execution, but its role in reaching preparation has not been sufficiently investigated. Here, we addressed this issue exploring the neural correlates of reaching preparation in V6A. Neural activity of single cells during the instructed delay period of a foveated Reaching task was compared with the activity in the same delay period during a Detection task. In this latter task, animals fixated the target but, instead of performing an arm reaching movement, they responded with a button release to the go signal. Targets were allocated in different positions in 3-D space. We found three types of neurons: cells where delay activity was equally spatially tuned in the two tasks (Gaze cells), cells spatially tuned only during reaching preparation (Set cells), and cells influenced by both gaze and reaching preparation signals (Gaze/Set cells). In cells influenced by reaching preparation, the delay activity in the Reaching task could be higher or lower compared with the Detection task. All the Set cells and a minority of Gaze/Set cells were more active during reaching preparation. Most cells modulated by movement preparation were also modulated with a congruent spatial tuning during movement execution. Present results highlight the convergence of visuospatial information, reach planning and reach execution signals on V6A, and indicate that visuospatial processing and movement execution have a larger influence on V6A activity than the encoding of reach plans. PMID- 24168223 TI - Resting state correlates of subdimensions of anxious affect. AB - Resting state fMRI may help identify markers of risk for affective disorder. Given the comorbidity of anxiety and depressive disorders and the heterogeneity of these disorders as defined by DSM, an important challenge is to identify alterations in resting state brain connectivity uniquely associated with distinct profiles of negative affect. The current study aimed to address this by identifying differences in brain connectivity specifically linked to cognitive and physiological profiles of anxiety, controlling for depressed affect. We adopted a two-stage multivariate approach. Hierarchical clustering was used to independently identify dimensions of negative affective style and resting state brain networks. Combining the clustering results, we examined individual differences in resting state connectivity uniquely associated with subdimensions of anxious affect, controlling for depressed affect. Physiological and cognitive subdimensions of anxious affect were identified. Physiological anxiety was associated with widespread alterations in insula connectivity, including decreased connectivity between insula subregions and between the insula and other medial frontal and subcortical networks. This is consistent with the insula facilitating communication between medial frontal and subcortical regions to enable control of physiological affective states. Meanwhile, increased connectivity within a frontoparietal-posterior cingulate cortex-precunous network was specifically associated with cognitive anxiety, potentially reflecting increased spontaneous negative cognition (e.g., worry). These findings suggest that physiological and cognitive anxiety comprise subdimensions of anxiety related affect and reveal associated alterations in brain connectivity. PMID- 24168227 TI - Ag nanoparticle embedded TiO(2) composite nanorod arrays fabricated by oblique angle deposition: toward plasmonic photocatalysis. AB - Using a unique oblique angle co-deposition technique, well-aligned arrays of Ag nanoparticle embedded TiO2 composite nanorods have been fabricated with different concentrations of Ag. The structural, optical, and photocatalytic properties of the composite nanostructures are investigated using a variety of experimental techniques and compared with those of pure TiO2 nanorods fabricated similarly. Ag nanoparticles are formed in the composite nanorods, which increase the visible light absorbance due to localized surface plasmon resonance. The Ag concentrations and the annealing conditions are found to affect the size and the density of Ag nanoparticles and their optical properties. The Ag nanoparticle embedded TiO2 nanostructures exhibit enhanced photocatalytic activity compared to pure TiO2 under visible- or UV-light illumination. Ag plays different roles in assisting the photocatalysis with different light sources. Ag can be excited and can inject electrons to TiO2, working as an electron donor under visible light. While under UV illumination, Ag acts as an electron acceptor to trap the photogenerated electrons in TiO2. Due to the opposite electron transfer direction under UV and visible light, the presence of Ag may not result in a greater enhancement in the photocatalytic performance. PMID- 24168225 TI - Association of the Hermansky-Pudlak syndrome type 4 (HPS4) gene variants with cognitive function in patients with schizophrenia and healthy subjects. AB - BACKGROUND: The Hermansky-Pudlak Syndrome Type 4 (HPS4) gene, which encodes a subunit protein of the biogenesis of lysosome-related organelles complex (BLOC) 3, which is involved in late endosomal trafficking, is associated with schizophrenia; however, its clinical relevance in schizophrenia remains unknown. The purpose of the present study was to investigate whether HPS4 is associated with cognitive functions in patients with schizophrenia and healthy controls and with the clinical profiles of patients with schizophrenia. METHODS: We investigated the association of variants of HPS4 with clinical symptoms and cognitive function in Japanese patients with schizophrenia (n = 240) and age matched healthy control subjects (n = 240) with single nucleotide polymorphisms (SNP)- or haplotype-based linear regression. We analyzed five tagging SNPs (rs4822724, rs61276843, rs9608491, rs713998, and rs2014410) of HPS4 and 2-5 locus haplotypes of these five SNPs. The cognitive functions of patients and healthy subjects were evaluated with the Brief Assessment of Cognition in Schizophrenia, Japanese-language version, and the patients were assessed for their symptomatology with the Positive and Negative Symptom Scale (PANSS). RESULTS: In patients with schizophrenia, rs713998 was significantly associated with executive function under the dominant genetic model (P = 0.0073). In healthy subjects, there was a significant association between working memory and two individual SNPs under the recessive model (rs9608491: P = 0.001; rs713998: P = 0.0065) and two haplotypes (rs9608491-713998: P = 0.0025; rs61276843-9608491-713998: P = 0.0064). No significant association was found between HPS4 SNPs and PANSS scores or premorbid IQ, as measured by the Japanese version of the National Adult Reading Test. CONCLUSIONS: These findings suggested the involvement of HPS4 in the working memory of healthy subjects and in the executive function deficits in schizophrenia. PMID- 24168228 TI - Nuclear expression of CDK4 correlates with disease progression and poor prognosis in human nasopharyngeal carcinoma. AB - AIMS: The purpose of this study was to examine the correlation between nuclear expression of cyclin-dependent kinase 4 (CDK4) and clinicopathological data in nasopharyngeal carcinoma (NPC), including patient survival. METHODS AND RESULTS: Using real-time PCR and immunohistochemistry, the expression of CDK4 was examined in NPC and nasopharyngeal (NP) tissues. We observed that mRNA expression of CDK4 was elevated significantly in NPC tissues compared to NP tissues. Further, we found that CDK4 protein was expressed in both the nucleus and cytoplasm. Nuclear expression of CDK4 was correlated positively with clinical stage (P = 0.048), but not associated with other clinical features. Patients with tumours showing nuclear expression of CDK4 had poorer overall survival rates than those without nuclear tumour expression of CDK4. Nuclear expression of CDK4 was associated inversely with survival time for NPC patients in stages T1-2, stages N2-3 and clinical stages III-IV, and after treatment with radiotherapy or chemotherapy. Nuclear expression of CDK4 was an independent and unfavourable prognostic factor for patients with NPC. CONCLUSIONS: Our findings suggest that nuclear expression of CDK4 is a potential marker for the progression and poor prognosis of NPC. PMID- 24168229 TI - Non-recombinant display of the B subunit of the heat labile toxin of Escherichia coli on wild type and mutant spores of Bacillus subtilis. AB - BACKGROUND: Mucosal infections are a major global health problem and it is generally accepted that mucosal vaccination strategies, able to block infection at their entry site, would be preferable with respect to other prevention approaches. However, there are still relatively few mucosal vaccines available, mainly because of the lack of efficient delivery systems and of mucosal adjuvants. Recombinant bacterial spores displaying a heterologous antigen have been shown to induce protective immune responses and, therefore, proposed as a mucosal delivery system. A non-recombinant approach has been recently developed and tested to display antigens and enzymes. RESULTS: We report that the binding subunit of the heat-labile toxin (LTB) of Escherichia coli efficiently adsorbed on the surface of Bacillus subtilis spores. When nasally administered to groups of mice, spore-adsorbed LTB was able to induce a specific immune response with the production of serum IgG, fecal sIgA and of IFN-gamma in spleen and mesenteric lymph nodes (MLN) of the immunized animals. Dot blotting experiments showed that the non-recombinant approach was more efficient than the recombinant system in displaying LTB and that the efficiency of display could be further increased by using mutant spores with an altered surface. In addition, immunofluorescence microscopy experiments showed that only when displayed on the spore surface by the non-recombinant approach LTB was found in its native, pentameric form. CONCLUSION: Our results indicate that non-recombinant spores displaying LTB pentamers can be administered by the nasal route to induce a Th1-biased, specific immune response. Mutant spores with an altered coat are more efficient than wild type spores in adsorbing the antigen, allowing the use of a reduced number of spores in immunization procedures. Efficiency of display, ability to display the native form of the antigen and to induce a specific immune response propose this non-recombinant delivery system as a powerful mucosal vaccine delivery approach. PMID- 24168231 TI - Structural elucidation of lignin polymers of Eucalyptus chips during organosolv pretreatment and extended delignification. AB - Effective delignification of lignocelluloses is a very important to guarantee the economic feasibility of organosolv-based biorefinery. Eucalyptus chips were successively subjected to organosolv pretreatment (AEOP) and extended delignification (ED) process in the present study. The effects of delignification processes were scientifically evaluated by component analysis, SEM, and CP-MAS NMR techniques. It was found that the integrated process of organosolv pretreatment and subsequent delignification resulted in an effective delignification. The fundamental chemistry of the lignin obtained after these processes was thoroughly investigated by FT-IR, multidimensional NMR ((31)P-, (13)C-, and 2D-HSQC NMR), and GPC techniques. It was observed that an extensive cleavage of aryl ether linkages, ethoxylation, and some condensation reactions occurred in AEOP process, while alpha-oxidation mainly took place in alkaline hydrogen peroxide (AHP) process. It is believed that better understanding the fundamental chemistry of lignin facilitates the optimization of the delignification process. More importantly, well-defined of lignin polymers will facilitate their value-added applications in current and future biorefineries. PMID- 24168232 TI - Pathological upgrading and upstaging of patients eligible for active surveillance according to currently used protocols. AB - OBJECTIVES: To investigate the ability of six contemporary active surveillance protocols to appropriately select active surveillance candidates among Korean men who underwent radical prostatectomy. METHODS: Between January 2001 and December 2011, 1968 patients underwent radical prostatectomy for prostate cancer at Samsung Medical Center, Seoul, Korea. Patients met the criteria for active surveillance according to six currently used criteria, including those from the Johns Hopkins Hospital, the University of Toronto, the University of California at San Francisco, the Prospective Prostate Cancer Research International Active Surveillance, the University of Miami and the Memorial Sloan-Kettering Cancer Center. The rates of Gleason score upgrading, upstaging and misclassification at final pathology were assessed. RESULTS: Among 1006 assessable patients, the percentage of men eligible for active surveillance varied from 13.5% to 38.5%, depending on the criteria used. The rates of upgrading ranged from 41.6% to 50.6%. Extracapsular extension was reported in 4.1% to 8.5% of patients, whereas seminal vesicle invasion was reported in 0.5% to 1.6% of patients. The upstaging rates according to the six active surveillance criteria varied from 4.5% to 9.3%, and the rates of misclassification varied from 44.5% to 54.8%. CONCLUSIONS: Currently available active surveillance criteria might not be suitable in Korean patients with prostate cancer, as they have a high likelihood of underestimating cancer. PMID- 24168233 TI - In vitro evaluation of S-(+)-ibuprofen as drug candidate for intra-articular drug delivery system. AB - Intra-articular drug delivery systems (DDSs) are envisaged as interesting alternative to locally release non-steroidal anti-inflammatory drugs (NSAIDs) such as ibuprofen to reduce pain in patients with osteoarthritis. The present study examines the efficacy of S-(+)-ibuprofen on cartilage degradation as drug candidate for DDS loading. Humeral cartilage and joint capsule explants were collected from healthy sheep shoulder joints and they were cultured in mono- or in co-culture for 13 days with LPS in combination with S-(+)-ibuprofen at 50 uM and 1 mM. S-(+)-ibuprofen (50 uM) blocked prostaglandins production in LPS activated explants but did not reduce cartilage degradation. By contrast, 1 mM S (+)-ibuprofen treatment of cartilage explants reduced nitric oxide synthesis by 51% (p = 0.0072), proteoglycans degradation by 35% (p = 0.0114) and expression of serum amyloid protein - the main protein induced upon LPS challenge - by 44% (p < 0.0001). On contrary, in presence of synovial membrane, the protective effects of S-(+)-ibuprofen on cartilage damages were significantly diminished. At 1mM, S-(+) ibuprofen reduced the cell lysis during culture of cartilage and joint capsule either in mono- or in co-culture. This study performed on sheep explants shows that 1 mM S-(+)-ibuprofen inhibited cartilage degradation via a mechanism independent of cyclooxygenase inhibition. Reduction of prostaglandins synthesis at 50 uM in all treatment groups and reduction of cartilage degradation observed at 1 mM suggest that S-(+)-ibuprofen could be considered as a promising drug candidate for the loading of intra-articular DDS. PMID- 24168234 TI - Oral bioavailability and intestinal absorption of candesartan cilexetil: role of naringin as P-glycoprotein inhibitor. AB - OBJECTIVE: The aim of the study is to explore the pharmacokinetic behavior of candesartan solid dispersions prepared by different pharmaceutical interventions using P-gp inhibitor in rabbits to validate the effectiveness of naringin as a pharmaceutical excipient in enhancing the oral delivery of lipophilic candesartan cilexetil. METHODS: Male albino rabbits (1-1.5 kg) were orally administered pure CAN suspensions and various candesartan solid dispersions (10 mg/kg) with and without naringin (15 mg/kg) and blood samples were collected at specified time points. CAN plasma samples were measured using HPLC. KEY FINDINGS: After oral dosing of pure CAN suspension, the mean AUC0-8 h was found to be 0.14 +/- 0.09 MUgh/ml which was increased significantly, i.e. 0.52 +/- 0.13 MUgh/ml with freeze dried solid dispersions in the presence of naringin (p < 0.01). Similarly, the mean Cmax of pure CAN suspension increased from 35.81 +/- 0.13 MUg/ml (without naringin) to 112.23 +/- 0.13 MUg/ml (freeze-dried solid dispersions with naringin) (p < 0.01). A 3.7-folds increase in apparent bioavailability was noticed with freeze-dried solid dispersions with naringin as compared to free CAN suspension administered alone. CONCLUSION: These results are quite stimulating for further development of a clinically useful oral formulation of candesartan cilexetil based on P-gp inhibition using naringin, a natural flavonoid as a pharmaceutical excipient. PMID- 24168235 TI - A comprehensive and quantitative analysis of the major specificities in rabbit antithymocyte globulin preparations. AB - Antithymocyte globulin (ATG) preparations are used for treatment and prevention of graft rejection episodes, graft versus host disease and aplastic anemia. The immunomodulatory and immuosuppressive properties of ATGs are mediated by their interaction with a large variety of antigens expressed on immune and nonimmune cell populations. We have conducted a comprehensive analysis on antibody specificities contained in rabbit ATGs in clinical use, ATG-Fresenius (ATG-F) and Thymoglobulin (THG). We have used retroviral expression cloning to identify novel ATG antigens and demonstrate that together with ATG antigens described earlier, these molecules account for the majority of ATG antibodies directed to human cells. Moreover, we have employed cell lines engineered to express antigens at high levels to quantify the antibodies directed to each ATG antigen. We have used cell lines expressing the T cell receptor complex, CD2 and CD28 to remove antibodies to these antigens from ATG preparations and demonstrate that this treatment abrogated the ability of ATGs to induce activation and forkhead box P3 expression in T cells. Comprehensive information and differences on the antigens targeted by ATG-F and THG as well as novel approaches to assess their functional properties are the basis for a better understanding of their immunomodulatory capacities and might eventually translate into improved ATG-based regimen. PMID- 24168236 TI - Whole-brain irradiation increases NREM sleep and hypothalamic expression of IL 1beta in rats. AB - PURPOSE: Although it has mainly been described qualitatively, whole brain irradiation induces somnolence in patients with malignant diseases. Therefore, we used a rat model to quantify the effects of irradiation of healthy brain tissue on both sleep-wake patterns and the expression of the pro-inflammatory cytokine interleukin-1beta (IL-1beta), which is known to induce sleep. MATERIALS AND METHODS: Different groups were examined at three time points after irradiation (1 day, 30 days and 60 days). Polysomnographic recordings were performed on each rat before and after total cranial irradiation (12 Gy). IL-1beta protein levels in several brain regions were assessed by enzyme-linked immunosorbent assays, and site-specific immunoreactivity was observed by immunofluorescence. RESULTS: We found that both non-rapid eye movement sleep and IL-1beta protein expression in the hypothalamus increased 30 days after irradiation. CONCLUSIONS: Whole brain irradiation increases sleep in our rat model, and this finding is similar to qualitative reports from patients. Because IL-1beta has been proposed as a sleep promoting molecule, we propose that the polysomnographic results may be attributable, at least in part, to the delayed overexpression of IL-1beta in the hypothalamus. PMID- 24168238 TI - A novel method for high throughput lipophilicity determination by microscale shake flask and liquid chromatography tandem mass spectrometry. AB - Modern small molecule drug design requires the optimization of not only the binding characteristics of the molecule but also its physicochemical properties for ADMET performance. A key physical property is lipophilicity and medicinal chemists need rapid access to high quality data in order to drive their decision making. Traditionally lipophilicity (log D) measurements are performed with a shake flask method and UV determination. This method suffers from low sensitivity and is not easily converted to a high throughput format. Over the past decade, several groups have taken different approaches to improve this assay, including replacing the shake flask method with one that utilizes reverse phase HPLC. Here we describe a new microscale shake flask method that utilizes UPLC-MS/MS to achieve increased throughput, sensitivity and accuracy. Approaches for assessing data quality are also described. This platform technology only requires micrograms of compound and is routinely used by most small molecule drug discovery project teams at Genentech. PMID- 24168237 TI - Red meat-derived heterocyclic amines increase risk of colon cancer: a population based case-control study. AB - Formation of mutagenic heterocyclic amines (HCAs) and polycyclic aromatic hydrocarbons (PAHs) is one pathway believed to drive the association of colon cancer with meat consumption. Limited data exist on the associations of individual HCAs and PAHs in red or white meat with colon cancer. Analyzing data from a validated meat preparation questionnaire completed by 1062 incident colon cancer cases and 1645 population controls from an ongoing case-control study, risks of colon cancer were estimated using unconditional logistic regression models, comparing the fourth to the first quartile of mutagen estimates derived from a CHARRED based food frequency questionnaire. Total dietary intake of 2 amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx) [adjusted odds ratio (aOR) = 1.87, 95% confidence interval (CI) = 1.44-2.44, P(trend) < 0.0001], 2-amino-3,4,8 trimethylimidazo[4,5-f]quinoxaline (DiMeIQx) (aOR = 1.68, 95% CI = 1.29-2.17, P(trend) = 0.001) and meat-derived mutagenic activity (aOR = 1.77, 95% CI = 1.36 2.30, P(trend) < 0.0001) were statistically significantly associated with colon cancer risk. Meat type specific analyses revealed statistically significant associations for red meat-derived MeIQx, DiMeIQx, and mutagenic activity but not for the same mutagens derived from white meat. Our study adds evidence supporting red meat-derived, but not white-meat derived HCAs and PAHs, as an important pathway for environmental colon cancer carcinogenesis. PMID- 24168239 TI - Unusual H-type aggregation of coumarin-481 dye in polar organic solvents. AB - Coumarin-481 (C481) dye shows intriguing time-resolved (TR) fluorescence behavior in polar organic solvents of both protic and aprotic nature, namely, ethanol (EtOH) and acetonitrile (ACN), demonstrating the presence of multiple emitting species in the solution. Following concentration-dependent and wavelength dependent TR fluorescence measurements and the time-resolved emission spectra (TRES) and time-resolved area-normalized emission spectra (TRANES) subsequently constructed using wavelength dependent decay parameters, we convincingly conclude that in the studied solvents a part of the dissolved dye undergoes H-type of aggregation, even at a very low dye concentration. This is quite an unusual finding because the dye C481 apparently shows reasonably good solubility in these organic solvents. As the TR measurements indicate, major contribution in the fluorescence decays is due to monomeric dye, having reasonably short lifetime (~0.64-0.68 ns), which is in accordance with the conversion of fluorescent intramolecular charge transfer (ICT) state to nonfluorescent twisted intramolecular charge transfer (TICT) state suggested for the dye in high polarity solvents, causing an efficient nonradiative deexcitation. The minor contributions arising from the aggregated dyes show its clear presence in the decays at the blue edge of the emission spectra and have relatively longer lifetimes (~1.2-5.2 ns) because the steric hindrance caused by the stacked dyes resists the ICT to TICT conversion. Aggregation of C481 dye as observed in the present study in polar organic solvents is an intriguing finding, as the dye is a widely used fluorescent probe for various photochemical studies, where overlooking such aggregation can mislead the observed results. PMID- 24168241 TI - On the functional nature of the N400: Contrasting effects related to visual word recognition and contextual semantic integration. AB - Electrical scalp recordings revealed the brain's sensitivity to both lexical properties of words and their contextual fit with a previous sentence context around 400 ms after word presentation. The so-called N400 component has been suggested to reflect the cost either of target word recognition or of a postlexical process for integrating word meaning into a context. In a sentence comprehension study, we manipulated the potential interference exerted in visual word recognition by target words' orthographic neighbors and the semantic constraints induced by the context in one and the same experiment. Neighbor frequency modulated the N400 only in low-constraint contexts; in high-constraint contexts the largely suppressed N400 did not show this neighbor interference effect. Furthermore, the earlier onset of the ERP effect (about 100 ms) induced by the contextual manipulation compared to the neighbor manipulation suggests distinct neurocognitive processes affecting the N400 component in an interactive manner. PMID- 24168242 TI - Neural correlates of visual extinction or awareness in a series of patients with right temporoparietal damage. AB - Patients with visual extinction following right-hemisphere damage can typically detect left visual field stimulation when it is presented in isolation, but tend to miss this when it is paired with competing concurrent right visual stimulation. Some single-case studies have provided preliminary evidence that right visual cortex may show residual activation for contralesional, extinguished visual stimuli. Here we go beyond prior work by using individual retinotopic mapping and online eye-tracking during fMRI to study activity in stimulus responsive retinotopic visual cortex for a case series of four extinction patients. We found consistent activation of retinotopic right visual cortex for bilateral visual stimulation that resulted in left extinction. This residual unconscious activation included areas V1 to V3 and was not due to inadvertent eye movements. We also provide further evidence for the emerging view that awareness may require activity of frontal and parietal regions well beyond visual cortex. PMID- 24168243 TI - Hemispheric processing in bilinguals: The role of shared meanings across languages and sentential constraint. AB - In monolinguals, the right hemisphere plays a key role when readers process multiple meanings of ambiguous words and when text weakly leads to a specific outcome (i.e., is weakly constrained). However, currently little is known about the influence of word meanings and sentential constraint in the hemispheres of bilinguals. Using a divided visual field paradigm, we investigated how cognates, interlingual homographs, and control words (within strongly and weakly constrained sentences) influence hemispheric processing in bilinguals. In the current study, both languages showed facilitation in the right hemisphere, whereas only the language currently in use showed facilitation in the left hemisphere. In addition, bilinguals (unlike monolinguals) processed strongly constrained targets more quickly than weakly constrained targets in both hemispheres. Thus, bilinguals and monolinguals process shared meanings of words similarly in the right hemisphere, but process sentential constraint differently in the hemispheres. PMID- 24168240 TI - Scolopendra subspinipes mutilans attenuates neuroinflammation in symptomatic hSOD1(G93A) mice. AB - BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a progressive, adult-onset neurodegenerative disorder characterized by selective motor neuron death in the spinal cord, brainstem, and motor cortex. Neuroinflammation is one of several pathological causes of degenerating motor neurons and is induced by activated microglial cells and astrocytes in ALS.Scolopendra subspinipes mutilans (SSM) is utilized in traditional Chinese and Korean medicine for the treatment of a variety of diseases, such as cancer, apoplexy, and epilepsy. However, the mechanisms underlying the effects of SSM are currently unclear, even though SSM increases immune and antibiotic activity. METHODS: To determine the effects of SSM on symptomatic hSOD1G93A transgenic mice, SSM (2.5 MUl/g) was injected bilaterally at the Zusanli (ST36) acupoint three times per week for two weeks. The effects of SSM treatment on anti-neuroinflammation in the brainstem and spinal cord of hSOD1G93A mice were assessed via Nissl and Fluoro-Jade B (FJB) staining, and immunohistochemistry using Iba-1, CD14, HO1, and NQO1 proteins was evaluated by Western blotting. RESULTS: In this study, we investigated whether SSM affects neuroinflammation in the spinal cord of symptomatic hSOD1G93A transgenic mice. We found that SSM treatment attenuated the loss of motor neurons and reduced the activation of microglial cells and astrocytes. Furthermore, we demonstrated that SSM administration in this animal model of ALS suppressed oxidative stress in the brainstem and spinal cord by 1.6- and 1.8-fold, respectively. CONCLUSIONS: Our findings suggest that SSM, which has previously been used in complementary and alternative medicine (CAM), might also be considered as an anti-neuroinflammatory therapy for neurodegenerative diseases. PMID- 24168244 TI - An early stage of conceptual combination: Superimposition of constituent concepts in left anterolateral temporal lobe. AB - Conceptual combination is an essential cognitive process, yet little is known about its neural correlates. In the present study, a categorization task was used to evoke patterns of neural activation for complex concepts (e.g., young man) as well as their constituents (e.g., young, man). A functional region of interest (fROI) within left anterolateral temporal lobe was identified as a possible site of conceptual combination. In this region, the superimposition of activity for constituent concepts reliably predicted the activation pattern for the complex concept built from those constituents. PMID- 24168245 TI - Do we have independent visual streams for perception and action? AB - The perception-action model proposes that vision-for-perception and vision-for action are based on anatomically distinct and functionally independent streams within the visual cortex. This idea can account for diverse experimental findings, and has been hugely influential over the past two decades. The model itself comprises a set of core contrasts between the functional properties of the two visual streams. We critically review the evidence for these contrasts, arguing that each of them has either been refuted or found limited empirical support. We suggest that the perception-action model captures some broad patterns of functional localization, but that the specializations of the two streams are relative, not absolute. The ubiquity and extent of inter-stream interactions suggest that we should reject the idea that the ventral and dorsal streams are functionally independent processing pathways. PMID- 24168246 TI - Dissociations of perception and action do not automatically imply independent visual processing streams. AB - Abstract Since the publication of Milner and Goodale's perception-action model of visual processing, there has been a general tendency to attribute any dissociation in the performance of perceptual and action tasks to a difference in the abilities and limitations of the ventral and dorsal visual streams. However, behavioral dissociations do not necessarily imply different underlying neural systems. In particular, there is a class of illusions, brought about by distortions of the observer's egocentric reference frame, that can cause perception-action dissociations without requiring or implying the existence of separate visual processing streams. PMID- 24168247 TI - Computation in the dorsal and ventral stream. AB - Abstract I argue that the evidence described by Schenk and McIntosh warrants the search for a new approach to the function of the dorsal and ventral visual streams rather than merely recasting the model in terms of relative specialization. In this regard, it may be profitable to think in terms of the computations carried out by the two visual streams. The effects of memory provide one source of information concerning the distinctive nature of these computations. PMID- 24168248 TI - Ventral and dorsal streams as modality-independent phenomena. AB - Abstract Interest in ventral and dorsal streams is not limited to vision, and the functionality of similar pathways in other domains has also been considered. Auditory dual pathway models share many conceptual and empirical concerns with those put forward for vision, including the absolute vs. relative, localized vs. distributed, and exact nature of functionality of the two streams. Despite their problems, dual pathway hypotheses provide broad frameworks with which to consider cortical architecture across the senses. PMID- 24168249 TI - Two visual streams: Interconnections do not imply duplication of function. AB - Abstract Schenk and McIntosh (S&M) provide a useful review of the perception action model (PAM), highlighting some of the gaps that need to be filled, and counteracting the erroneous belief held by some that the PAM implies two mutually independent streams. Although we agree with S&M's contention that the functional independence of the two streams has been overestimated, we reject their speculation that "the specializations proposed may be relative rather than absolute." We argue that the contributions made by the two streams are quite distinct, and that establishing how they work together is the key to a full understanding of visually guided behavior. PMID- 24168250 TI - Is the visual dorsal stream really very visual after all? AB - Abstract The perception-action model (PAM) provides a misleading account of the core function of the dorsal stream: which is the integration of sensory signals to create dynamic representations of corporeal and extrapersonal space. Recent evidence suggests that the parietal-occipital cortex plays a key role in integrating multimodal spatial signals that relate to the direction of gaze and the direction of reaching movements. I suggest that a core deficit of the 'dorsal' stream-optic ataxia-arises because of an inability to simultaneously represent different multimodal spatial representations. PMID- 24168251 TI - Vision for action is not veridical. AB - Abstract We agree with Schenk and McIntosh that the human brain can better be described in terms of task-specific functional networks than in terms of a division between (dorsal) egocentric vision for action and (ventral) viewpoint independent vision for perception. However, by concentrating on the lack of experimental support for the latter division, the authors neglect an important reason for postulating that there is a separate vision-for-action system: needing veridical metric information to guide one's actions. We argue that considering this reason would support the authors' conclusion because the visual information that guides our actions does not have to be veridical. PMID- 24168252 TI - Dorsal stream areas process action semantics. AB - Abstract Evidence from recent studies investigating the functional and neural mechanisms supporting action semantics, i.e., the knowledge of how to use objects in a functionally appropriate manner, suggests that semantic processing for action is not restricted to high-level perceptual processing in the ventral stream but is directly associated with activation in dorsal areas, i.e., the motor system, and motor performance. These findings argue for a distributed and interactive account of action semantics and against functionally independent processing in dorsal and ventral stream areas. PMID- 24168253 TI - Reply to commentaries. AB - In our review, we argued that the ubiquity and extent of inter-stream interactions suggests that the ventral and dorsal visual streams are not functionally independent processing pathways. Most commentaries agreed with our conclusions. However, the notion that the specializations of the two streams are relative, not absolute, was criticised. We address this and other challenges. We conclude that, while the perception-action model works well as a high-level description of the functional organization of the visual cortex, it does not account for the complex interplay between perception and sensorimotor control revealed by a finer-grain analysis. PMID- 24168255 TI - Role of hepatitis C virus substitutions and interleukin-28B polymorphism on response to peginterferon plus ribavirin in a prospective study of response guided therapy. AB - Recent studies have indicated that amino acid (aa) substitutions in the core region and NS5A interferon sensitivity-determining region (ISDR) of hepatitis C virus (HCV) as well as genetic polymorphisms in the interleukin-28B (IL-28B) locus affect the outcome of interferon (IFN)-based therapies. We aimed to investigate the role of these factors on response to peginterferon plus ribavirin in a prospective study of response-guided therapy. The aa sequences in core region and ISDR and rs12979860 genotypes were analysed in 115 HCV-1 patients. The treatment was 24 weeks for patients achieving a rapid virological response (RVR), 48 weeks for those with an early virological response (EVR) and early terminated in those without an EVR. A sustained virological response (SVR) was achieved in 82% of 34 RVR patients, 45% of 74 EVR patients and 0% of seven non-EVR patients. Logistic regression analysis showed that ISDR mutation (>=2) [odds ratio(OR): 6.024], double core 70/91 mutations (OR: 0.136), and platelet counts>=15*10(4) /MUL (OR: 3.119) were independent pretreatment factors associated with SVR. Apart from rs12979860 CC genotype, low viral load and ISDR mutation (>=2) were significant factors predictive of RVR. Combination of rs12979860 genotype and baseline viral characteristics (viral load and core/ISDR mutations) could predict RVR and SVR with positive predictive value of 100% and 91%, and negative predictive value of 80% and 54%, respectively. In conclusion, pretreatment screening rs12979860 genotype and aa substitutions in the core region and ISDR could help identifying patients who are good candidates for peginterferon plus ribavirin therapy. PMID- 24168256 TI - Evolution of fibrosis during HCV recurrence after liver transplantation- influence of IL-28B SNP and response to peg-IFN and ribavirin treatment. AB - The IL-28 gene is associated with sustained viral response (SVR) after treatment with peg-IFN and ribavirin in liver transplant recipients with chronic hepatitis C genotype 1 infection. We analysed the importance of recipient and donor IL-28B genotype for response to treatment and fibrosis progression in 54 liver transplant recipients. Fibrosis stage (F) was defined as mild when F<=2 and severe when F>=3 in a liver biopsy or according to liver elasticity analysis. We found a significantly lower prevalence of IL-28B SNP CC in the recipients (22%) than in the donors (67%), P<0.0001. SVR was seen in 61% of the recipients with mild and 27% with severe fibrosis pretreatment, P=0.01. Recipients with IL-28 CC and non-CC had mild fibrosis in 64% and 38% prior to treatment, P=0.13. At follow up, after treatment, significantly more recipients with CC had mild fibrosis than non-CC recipients (75% versus 32%, P=0.0072), and all with CC and SVR had mild fibrosis. The strongest baseline factor predicting SVR was genotype. Hence, 13/19 (68%) genotype non-1 patients reached SVR versus only 9/35 (26%) genotype 1 patients, P=0.0022. In summary, we found that liver transplant recipients with IL 28B CC tended to have less advanced fibrosis prior to and significantly less after SOC treatment and that all recipients with IL-28B CC who achieved SVR had mild fibrosis at follow-up. A significantly higher SVR rate was achieved in recipients with mild than severe fibrosis pretreatment and with genotype non-1 than 1 infection. Our findings indicate that treatment for post-transplant HCV recurrence should be offered before advanced fibrosis is seen in the recipient. PMID- 24168257 TI - Evolutionary dynamics of hepatitis C virus NS3 protease domain during and following treatment with narlaprevir, a potent NS3 protease inhibitor. AB - Narlaprevir, a hepatitis C virus (HCV) NS3/4A serine protease inhibitor, has demonstrated robust antiviral activity in a placebo-controlled phase 1 study. To study evolutionary dynamics of resistant variants, the NS3 protease sequence was clonally analysed in thirty-two HCV genotype 1-infected patients following treatment with narlaprevir. Narlaprevir monotherapy was administered for one week (period 1) followed by narlaprevir/pegylated interferon-alpha-2b combination therapy with or without ritonavir (period 2) during two weeks, interrupted by a washout period of one month. Thereafter, all patients initiated pegylated interferon-alpha-2b/ribavirin combination therapy. Longitudinal clonal analysis was performed in those patients with NS3 mutations. After narlaprevir re exposure, resistance-associated mutations at position V36, T54, R155 and A156 were detected in five patients in >95% of the clones. Narlaprevir retreatment resulted in a 2.58 and 5.06 log10 IU/mL viral load decline in patients with and without mutations, respectively (P=<0.01). After treatment, resistant variants were replaced with wild-type virus within 2-24 weeks in three patients. However, the R155K mutation was still observed 3.1 years after narlaprevir dosing in two patients in 5% and 45% of the viral population. Resistant variants could be detected early during treatment with narlaprevir. A slower viral load decline was observed in those patients with resistance-associated mutations detectable by direct population sequencing. These mutations disappeared within six months following treatment with the exception of R155K mutation, which persisted in two patients. PMID- 24168254 TI - The new paradigm of hepatitis C therapy: integration of oral therapies into best practices. AB - Emerging data indicate that all-oral antiviral treatments for chronic hepatitis C virus (HCV) will become a reality in the near future. In replacing interferon based therapies, all-oral regimens are expected to be more tolerable, more effective, shorter in duration and simpler to administer. Coinciding with new treatment options are novel methodologies for disease screening and staging, which create the possibility of more timely care and treatment. Assessments of histologic damage typically are performed using liver biopsy, yet noninvasive assessments of histologic damage have become the norm in some European countries and are becoming more widespread in the United States. Also in place are new Centers for Disease Control and Prevention (CDC) initiatives to simplify testing, improve provider and patient awareness and expand recommendations for HCV screening beyond risk-based strategies. Issued in 2012, the CDC recommendations aim to increase HCV testing among those with the greatest HCV burden in the United States by recommending one-time testing for all persons born during 1945 1965. In 2013, the United States Preventive Services Task Force adopted similar recommendations for risk-based and birth-cohort-based testing. Taken together, the developments in screening, diagnosis and treatment will likely increase demand for therapy and stimulate a shift in delivery of care related to chronic HCV, with increased involvement of primary care and infectious disease specialists. Yet even in this new era of therapy, barriers to curing patients of HCV will exist. Overcoming such barriers will require novel, integrative strategies and investment of resources at local, regional and national levels. PMID- 24168258 TI - Who is more likely to respond to dual treatment with pegylated-interferon and ribavirin for chronic hepatitis C? A gender-oriented analysis. AB - We assessed, in real-life practice, viral, demographic, genetic and metabolic factors influencing the sustained virologic response (SVR), with a gender oriented analysis, in patients with chronic hepatitis C virus (HCV) treated with pegylated interferon and ribavirin. Six hundred and seventy naive patients were treated with dual therapy and evaluated by gender and HCV genotype. Associations between baseline variables and SVR were assessed by multivariate logistic regression analysis. Among 362 genotype 1 patients, SVR was achieved in 158 patients (44%), and SVR was independently associated with age less than 50 years (OR 2.12; 95% CI 1.09-4.30; P=0.039) and C/C genotype rs12979860 SNP (OR 2.83; 1.19-6.74; P=0.002) in 163 females, while absence of visceral obesity (OR 2.491; 1.131-5.487; P=0.023), HCV-RNA lower than 400,000 IU/mL (OR 2.66; 1.273-5.558; P=0.009) and C/C genotype rs12979860 SNP (OR 4.969; 2.401-10.283; P<0.001) were independently associated with SVR in 199 males. Combining favourable baseline variables, the probability of obtaining SVR ranged from 27.6% to 84.2% in females, and from 14.3% to 85.7% in males. The rate of SVR was 81.1% in 175 genotype 2 patients, and 69% in 100 genotype 3 patients. Rapid virologic response was the only valid predictor of SVR regardless of other features. In conclusions, in the setting of HCV genotype 1, chronic hepatitis, combining rapid virologic response and predictive factors, which are different for females and males, allows clinicians to single out a group of patients whose likelihood of SVR exceeds 80%. For these patients, triple therapy with first-generation protease inhibitors may be unwarranted. PMID- 24168259 TI - Hepatitis B vaccination with or without hepatitis B immunoglobulin at birth to babies born of HBsAg-positive mothers prevents overt HBV transmission but may not prevent occult HBV infection in babies: a randomized controlled trial. AB - Vertical transmission of Hepatitis B virus HBV can result in a state of chronic HBV infection and its complications. HBV vaccination with or without hepatitis B immunoglobulin (HBIG) prevents transmission of overt infection to the babies. However, whether it also prevents occult HBV infection in babies is not known. Consecutive pregnant women of any gestation found to be HBsAg positive were followed till delivery, and their babies were included in the study. Immediately after delivery, babies were randomized to receive either HBIG or placebo in addition to recombinant HBV vaccine (at 0, 6, 10 and 14 weeks). The primary end point of the study, assessed at 18 weeks of age, was remaining free of any HBV infection (either overt or occult) plus the development of adequate immune response to vaccine. The babies were further followed up for a median of 2 years of age to determine their eventual outcome. Risk factors for HBV transmission and for poor immune response in babies were studied. Of the 283 eligible babies, 259 were included in the trial and randomized to receive either HBIG (n=128) or placebo (n=131) in addition to recombinant HBV vaccine. Of the 222 of 259 (86%) babies who completed 18 weeks of follow-up, only 62/222 (28%) reached primary end point. Of the remaining, 6/222 (3%) developed overt HBV infection, 142/222 (64%) developed occult HBV infection, and 12/222 (5%) had no HBV infection but had poor immune response. All 6 overt infections occurred in the placebo group (P=0.030), while occult HBV infections were more common in the HBIG group (76/106 [72%] vs. 66/116 [57%]; P=0.025). This may be due to the immune pressure of HBIG. There was no significant difference between the two groups in frequency of babies developing poor immune response or those achieving primary end-point. The final outcome of these babies at 24 months of age was as follows: overt HBV infection 4%, occult HBV infection 42%, no HBV infection but poor immune response 8% and no HBV infection with good immune response 28%. Women who were anti-HBe positive were a low-risk group, and their babies were most likely to remain free of HBV infection (occult or overt) and had good immune response to the vaccine. Maternal HBeAg-positive status and negativity for anti-HBe predicted not only overt but also any infection (both overt and occult) in babies. In addition, high maternal HBV DNA and treatment with vaccine alone were significant factors for overt HBV infection in babies. The current practice of administration of vaccine with HBIG at birth to babies born of HBsAg-positive mothers is not effective in preventing occult HBV infection in babies, which may be up to 40%. Because the most important risk factors for mother-to-baby transmission of HBV infection are the replicative status and high HBV DNA level in mothers; it will be worthwhile investigating the role of antivirals and HBIG administration during pregnancy to prevent mother-to-child transmission of HBV infection. PMID- 24168260 TI - Angiotensin-converting enzyme 2/angiotensin-(1-7)/Mas axis protects against lung fibrosis by inhibiting the MAPK/NF-kappaB pathway. AB - Accumulating evidence has demonstrated that up-regulation of the angiotensin (Ang)-converting enzyme (ACE)/AngII/AngII type 1 receptor (AT1R) axis aggravates pulmonary fibrosis. The recently discovered ACE2/Ang-(1-7)/Mas axis, which counteracts the activity of the ACE/AngII/AT1R axis, has been shown to protect against pulmonary fibrosis. However, the mechanisms by which ACE2 and Ang-(1-7) attenuate pulmonary fibrosis remain unclear. We hypothesized that up-regulation of the ACE2/Ang-(1-7)/Mas axis protects against bleomycin (BLM)-induced pulmonary fibrosis by inhibiting the mitogen-activated protein kinase (MAPK)/NF-kappaB pathway. In vivo, Ang-(1-7) was continuously infused into Wistar rats that had received BLM or AngII. In vitro, human fetal lung-1 cells were pretreated with compounds that block the activities of AT1R, Mas (A-779), and MAPKs before exposure to AngII or Ang-(1-7). The human fetal lung-1 cells were infected with lentivirus-mediated ACE2 before exposure to AngII. In vivo, Ang-(1-7) prevented BLM-induced lung fibrosis and AngII-induced lung inflammation by inhibiting the MAPK phosphorylation and NF-kappaB signaling cascades. However, exogenous Ang-(1 7) alone clearly promoted lung inflammation. In vitro, Ang-(1-7) and lentivirus mediated ACE2 inhibited the AngII-induced MAPK/NF-kappaB pathway, thereby attenuating inflammation and alpha-collagen I production, which could be reversed by the Mas inhibitor, A-779. Ang-(1-7) inhibited AngII-induced lung fibroblast apoptotic resistance via inhibition of the MAPK/NF-kappaB pathway and activation of the BCL-2-associated X protein/caspase-dependent mitochondrial apoptotic pathway. Ang-(1-7) alone markedly stimulated extracellular signal-regulated protein kinase 1/2 phosphorylation and the NF-kappaB cascade. Up-regulation of the ACE2/Ang-(1-7)/Mas axis protected against pulmonary fibrosis by inhibiting the MAPK/NF-kappaB pathway. However, close attention should be paid to the proinflammatory effects of Ang-(1-7). PMID- 24168261 TI - En coup de sabre morphea treated with hyaluronic acid filler. Report of a case and review of the literature. PMID- 24168263 TI - Millipede burn masquerading as trash foot in a paediatric patient. PMID- 24168262 TI - Characterization and transcript profiling of the pectin methylesterase (PME) and pectin methylesterase inhibitor (PMEI) gene families in flax (Linum usitatissimum). AB - BACKGROUND: Pectin methylesterases (PMEs) catalyze the demethylesterification of homogalacturonans in the cell wall; their activity is regulated in part by pectin methylesterase inhibitors (PMEIs). PME activity may result in either rigidification or loosening of the cell wall, depending on the mode of demethylesterification. The activity of PMEs in the middle lamella is expected to affect intrusive elongation of phloem fibers, and their adhesion to adjacent cells. Length and extractability of phloem fibers are qualities important for their industrial uses in textiles and composites. As only three flax PMEs had been previously described, we were motivated to characterize the PME and PMEI gene families of flax. RESULTS: We identified 105 putative flax PMEs (LuPMEs) and 95 putative PMEIs (LuPMEIs) within the whole-genome assembly. We found experimental evidence for the transcription of 77/105 LuPMEs and 83/95 LuPMEIs, and surveyed the transcript abundance of these in 12 different tissues and stages of development. Six major monophyletic groups of LuPMEs could be defined based on the inferred relationships of flax genes and their presumed orthologs from other species. We searched the LuPMEs and LuPMEIs for conserved residues previously reported to be important for their tertiary structure and function. In the LuPMEs, the most highly conserved residues were catalytic residues while in the LuPMEIs, cysteines forming disulfude bridges between helices alpha2 and alpha3 were most highly conserved. In general, the conservation of critical residues was higher in the genes with evidence of transcript expression than in those for which no expression was detected. CONCLUSIONS: The LuPMEs and LuPMEIs comprise large families with complex patterns of transcript expression and a wide range of physical characteristics. We observed that multiple PMEs and PMEIs are expressed in partially overlapping domains, indicative of several genes acting redundantly during most processes. The potential for functional redundancy was highlighted also by the phylogenetic analyses. We were able to identify a subset of PME and PMEIs that appeared particularly relevant to fiber development, which may provide a basis for the improvement of key traits in industrial feedstocks and a better understanding of the physiological roles of PMEs and PMEIs in general. PMID- 24168264 TI - Human umbilical cord blood-derived CD34-positive endothelial progenitor cells stimulate osteoblastic differentiation of cultured human periosteal-derived osteoblasts. AB - The aim of this study was to examine the effects of human umbilical cord blood derived CD34-positive endothelial progenitor cells (CD34+ EPCs) on osteoblastic differentiation of cultured human periosteal-derived osteoblasts (POs). CD34+ cells from human umbilical cord blood were sorted to purify more EPCs in characterization. These sorted cells showed CD31, VE-cadherin, and KDR expression as well as CD34 expression and formed typical tubes in Matrigel. These sorted cells were referred to as human cord blood-derived CD34+ EPCs. In in vivo bone formation using a miniature pig model, the newly formed bone was clearly examined in defects filled with polydioxanone/pluronic F127 (PDO/Pluronic F127) scaffolds containing either human umbilical cord blood-derived CD34+ EPCs and POs or human umbilical vein endothelial cells (HUVEC) and POs; however, the new bone had the greatest density in the defect treated with CD34+ EPCs and POs. Osteoblastic phenotypes of cultured human POs using ALP activity and von Kossa staining were also more clearly found in CD34+ EPC-conditioned medium than CD34-negative (CD34 ) cell-conditioned medium, whereas HUVEC-conditioned medium had an intermediate effect. PCR array for common cytokines and growth factors showed that the secretion of interleukin (IL)-1beta was significantly higher in CD34+ EPCs than in HUVEC, followed by level in CD34- cells. In addition, IL-1beta also potently and dose dependently increased ALP activity and mineralization of POs in culture. These results suggest that human umbilical cord blood-derived CD34+ EPCs stimulates osteoblastic differentiation of cultured human POs. The functional role of human umbilical cord blood-derived CD34+ EPCs in increasing the osteogenic phenotypes of cultured human POs may depend on IL-1beta secreted from human umbilical cord blood-derived CD34+ EPCs. PMID- 24168265 TI - Children's perceptions about falls and their prevention: a qualitative study from a rural setting in Bangladesh. AB - BACKGROUND: Childhood falls is a major public health problem in Bangladesh. In depth understanding of the situation by the target groups and their families is necessary for successful development, implementation and evaluation of any intervention. The study aimed at knowing the views of Bangladeshi rural children about childhood falls and their suggestions for prevention. METHODS: Children of 10-17 were selected purposely from 4 villages of Sherpur Sadar upazila (sub district), Sherpur district of Bangladesh. Six focus group discussions and ten in depth interviews were conducted during July-August 2010 for this study. Gender and education of the participants were considered. Major themes were identified, coded and categorized from content analysis. RESULTS: Participants stated that young children (<5 years of age) and boys appeared to be the main victims of falls and majority of these injuries occurred in and around the households. Boys commonly fall from the tree around their premises and high places. Girls usually fall when they remain busy in household chores and playing with friends around their premises. Participants also mentioned that children mostly sustained injury when they are unsupervised. Supervision, public awareness and putting barriers (e.g. door barrier, putting pillow and use net around the bed etc.) were suggested as the preventive measures. CONCLUSION: Findings of this study could be considered as part of knowledge-base in designing interventions to address childhood falls. PMID- 24168266 TI - New triterpenoid saponins from the flowers of Pueraria thomsonii. AB - Two new oleanane-type triterpenoid saponins, kakkasaponin II (1) and kakkasaponin III (2), were isolated from the methanol extract of the flowers of Pueraria thomsonii (Leguminosae), together with seven known oleanane-type triterpenoid saponins, phaseoside IV (3), sophoradiol monoglucuronide (4), kakkasaponin I (5), kaikasaponin III (6), soyasaponin I (7), soyasaponin III (8), and soyasaponin IV (9). The structures of 1 and 2 were elucidated by spectroscopic methods including IR, ESI-TOF-MS, and 1D and 2D NMR experiments. PMID- 24168268 TI - Polyoxometalate-reduced graphene oxide hybrid catalyst: synthesis, structure, and electrochemical properties. AB - The deposition of polyoxometalate (POM) on chemically reduced graphene oxide sheets was carried out through electron transfer interaction and electrostatic interaction between POM and graphene sheets to make a heterogeneous catalyst in aqueous media. Well dispersed individual phosphomolybdic acid (PMo) clusters were observed by electron microscopy and atomic force microscopy measurements. The interaction between polyoxometalate and the graphene sheet was confirmed by using various spectroscopic methods such as FT-IR, UV-vis, and Raman. The UV-visible, IR, and cyclic voltammetry results revealed alteration of the electronic structure of deposited PMo as a result of strong interaction with the graphene oxide surface. Electrochemical properties of the PMo-rGO catalyst were investigated in an aqueous acidic electrolyte. The hybrid catalyst showed enhanced electro-oxidation of nitrite compared with pure homogeneous PMo and rGO. PMID- 24168267 TI - In vitro selection of shape-changing DNA nanostructures capable of binding induced cargo release. AB - Many biological systems employ allosteric regulatory mechanisms, which offer a powerful means of directly linking a specific binding event to a wide spectrum of molecular functionalities. There is considerable interest in generating synthetic allosteric regulators that can perform useful molecular functions for applications in diagnostics, imaging and targeted therapies, but generating such molecules through either rational design or directed evolution has proven exceptionally challenging. To address this need, we present an in vitro selection strategy for generating conformation-switching DNA nanostructures that selectively release a small-molecule payload in response to binding of a specific trigger molecule. As an exemplar, we have generated a DNA nanostructure that hybridizes with a separate 'cargo strand' containing an abasic site. This abasic site stably sequesters a fluorescent cargo molecule in an inactive state until the DNA nanostructure encounters an ATP trigger molecule. This ATP trigger causes the nanostructure to release the cargo strand, thereby liberating the fluorescent payload and generating a detectable fluorescent readout. Our DNA nanostructure is highly sensitive, with an EC50 of 30 MUM, and highly specific, releasing its payload in response to ATP but not to other chemically similar nucleotide triphosphates. We believe that this selection approach could be generalized to generate synthetic nanostructures capable of selective and controlled release of other small-molecule cargos in response to a variety of triggers, for both research and clinical applications. PMID- 24168269 TI - FPGS rs1544105 polymorphism is associated with treatment outcome in pediatric B cell precursor acute lymphoblastic leukemia. AB - BACKGROUND: Folypolyglutamate synthase (FPGS) catalyzes the polyglutamation of folates and antifolates, such as methotrexate (MTX), to produce highly active metabolites. FPGS tag SNP rs1544105C > T is located in the gene promoter. The aim of the present study was to investigate the impact of rs1544105 polymorphism on the treatment outcome in pediatric B-cell precursor acute lymphoblastic leukemia (BCP-ALL). METHODS: This study enrolled 164 children with BCP-ALL. We genotyped the FPGS SNP rs1544105, and analyzed the associations between its genotypes and treatment outcome. We also examined FPGS mRNA levels by real-time PCR in 64 of the 164 children, and investigated the function of this polymorphism on gene expression. RESULTS: We found significantly poor relapse-free survival (RFS) (p = 0.010) and poor event-free survival (EFS) (p = 0.046) in carriers of CC genotype. Multivariable Cox regression analyses adjusted for possible confounding variables showed that, relative to the CT + TT genotypes, the CC genotype was an independent prognostic factor for poor RFS (hazard ratio [HR], 4.992.; 95% CI, 1.550-16.078; p = 0.007). No association was found between any toxicity and rs1544105 polymorphism. Quantitative PCR results showed that individuals with the T allele had lower levels of FPGS transcripts. CONCLUSIONS: Our study indicates that FPGS rs1544105C > T polymorphism might influence FPGS expression and affect treatment outcome in BCP-ALL patients. PMID- 24168270 TI - Orthogonal assembly of a designed ankyrin repeat protein-cytotoxin conjugate with a clickable serum albumin module for half-life extension. AB - The generation of drug conjugates for safe and effective tumor targeting requires binding proteins tolerant to functionalization by rational engineering. Here, we show that Designed Ankyrin Repeat Proteins (DARPins), a novel class of binding proteins not derived from antibodies, can be used as building blocks for facile orthogonal assembly of bioconjugates for tumor targeting with tailored properties. DARPin Ec1, which targets the Epithelial Cell Adhesion Molecule (EpCAM), was genetically modified with a C-terminal cysteine for conjugation of the small molecule cytotoxin monomethylauristatin F (MMAF). In addition, it was N terminally functionalized by metabolic introduction of the non-natural amino acid azidohomoalanine to enable linkage of site-specifically dibenzocyclooctyne modified mouse serum albumin (MSA) for half-life extension using Cu(I)-free click chemistry. The conjugate MSA-Ec1-MMAF was assembled to obtain high yields of a pure and stable drug conjugate as confirmed by various analytical methods and in functional assays. The orthogonality of the assembly led to a defined reaction product and preserved the functional properties of all modules, including EpCAM specific binding and internalization, FcRn binding mediated by MSA, and cytotoxic potency. Linkage of MMAF to the DARPin increased receptor-specific uptake of the drug while decreasing nonspecific uptake, and further coupling of the conjugate to MSA enhanced this effect. In mice, albumin conjugation increased the serum half-life from 11 min to 17.4 h, resulting in a more than 22-fold increase in the area-under-the-curve (AUC). Our data demonstrate the promise of the DARPin format for facile modular assembly of drug conjugates with improved pharmacokinetic performance for tumor targeting. PMID- 24168271 TI - Augmentation of 5-lipoxygenase activity and expression during dengue serotype-2 infection. AB - BACKGROUND: Leukotriene B4, a 5-lipoxygenase product of arachidonic acid with potent chemotactic effects on neutrophils, has not been assessed in dengue patients. In this study, plasma leukotriene B4 and serum high-sensitivity C reactive protein levels were determined in adult patients during the febrile, convalescent and defervescent stages of dengue serotype-2 (DENV-2) infection, and compared with those of age-matched healthy and non-dengue febrile subjects. In vitro studies were performed to examine the effects of live and heat-inactivated DENV-2 on the activities and expression of 5-lipoxygenase in human neutrophils. RESULTS: Plasma leukotriene B4 was elevated during the febrile stages of dengue infection compared to levels during convalescence and in study controls. Plasma leukotriene B4 also correlated with serum high-sensitivity C-reactive protein in dengue patients (febrile, r = 0.91, p < 0.001; defervescence, r = 0.87, p < 0.001; convalescence, r = 0.87, p < 0.001). Exposure of human neutrophils to DENV 2 resulted in a significant rise in leukotriene B4; the extent of increase, however, did not differ between exposure to live and heat-inactivated DENV-2. Pre incubation of either live or heat-inactivated DENV-2 resulted in reduced leukotriene B4 release by neutrophils, indicating that contact with dengue antigens (and not replication) triggers the neutrophil response. Production of leukotriene B4 was associated with an increase in 5-lipoxygenase expression in human neutrophils; addition of MK886 (a 5-lipoxygenase activating protein inhibitor) attenuated further increase in leukotriene B4 production. CONCLUSION: These findings provide important clinical and mechanistic data on the involvement of 5-lipoxygenase and its metabolites in dengue infection. Further studies are needed to elucidate the therapeutic implications of these findings. PMID- 24168273 TI - On the role of episodic future simulation in encoding of prospective memories. AB - Simulating future events is dependent on a similar neural circuitry to that which supports retrieving contextual information about past events. The current study examined two novel predictions from recently reported episodic future simulation studies. Prospective memory is broadly defined as the usage of episodic memory processes to encode and retrieve intentions at some appropriate moment in the future. The results from two experiments are consistent with the idea that episodic future simulation is an important component of encoding prospective memories (i.e., forming intentions for the future). Furthermore, the results necessitate further neuroscientific investigations of encoding prospective memories and additionally suggest that current theories of prospective memory need to be updated to fully account for our ability to encode, retrieve, and fulfill intentions for the future. PMID- 24168272 TI - Transcriptome analysis of chicken kidney tissues following coronavirus avian infectious bronchitis virus infection. AB - BACKGROUND: Infectious bronchitis virus (IBV), a prototype of the Coronaviridae family, is an economically important causative agent of infectious bronchitis in chickens and causes an acute and highly contagious upper respiratory tract infections that may lead to nephritis. However, the molecular antiviral mechanisms of chickens to IBV infection remain poorly understood. In this study, we conducted global gene expression profiling of chicken kidney tissue after nephropathogenic IBV infection to better understand the interactions between host and virus. RESULTS: IBV infection contributed to differential expression of 1777 genes, of which 876 were up-regulated and 901 down-regulated in the kidney compared to those of control chickens and 103 associated with immune and inflammatory responses may play important roles in the host defense response during IBV infection. Twelve of the altered immune-related genes were confirmed by real-time RT-PCR. Gene ontology category, KEGG pathway, and gene interaction networks (STRING analysis) were analyzed to identify relationships among differentially expressed genes involved in signal transduction, cell adhesion, immune responses, apoptosis regulation, positive regulation of the I-kappaB kinase/NF-kappaB cascade and response to cytokine stimulus. Most of these genes were related and formed a large network, in which IL6, STAT1, MYD88, IRF1 and NFKB2 were key genes. CONCLUSIONS: Our results provided comprehensive knowledge regarding the host transcriptional response to IBV infection in chicken kidney tissues, thereby providing insight into IBV pathogenesis, particularly the involvement of innate immune pathway genes associated with IBV infection. PMID- 24168274 TI - Hemispheric differences for enhancement and suppression mechanisms during story comprehension. AB - Although readers are able to follow the goals of a character in a story, little is currently known about the underlying enhancement and suppression mechanisms that occur in each cerebral hemisphere. In this study, participants read texts that mentioned a goal of a character, which was later followed by information related to the original goal, a new goal, or unrelated information. Participants then performed a lexical decision task to original-goal-related targets, which were presented to either the left visual field-right hemisphere or the right visual field-left hemisphere. When the original goal was repeated, facilitation was greater in the right hemisphere than the left hemisphere. When a new goal was introduced, the left hemisphere exhibited decreased facilitation for the original goal information. The current findings suggest that two separable mechanisms (i.e., enhancement and suppression), located in different hemispheres, may be involved when readers process goals during narrative text comprehension. PMID- 24168275 TI - Time and numerosity estimation are independent: Behavioral evidence for two different systems using a conflict paradigm. AB - Walsh ( 2003 ) proposed that time and numerical estimation are processed by one generalized magnitude system located mainly in the parietal cortex. According to this perspective, if the time and numerosity share the same mechanism, then interference effects should be observed when the two dimensions are put in conflict. In this study, 16 volunteers were required to listen to 25 audio files, differing in duration and number of tones, in two tasks: One required estimating the duration of the stimulus; the other required estimating the number of tones. For example, the same duration may contain 11, 13, 15, 17 or 19 tones, and 11 tones could last for 5, 7, 9, 11 or 13 s. Results show that estimates of duration were unaffected by the number of tones, and estimates of numerosity were unaffected by duration: This is incompatible with time and numerosity being processed by the same mechanism. Theoretical implications are discussed. PMID- 24168276 TI - Multiple attentional control settings influence late attentional selection but do not provide an early attentional filter. AB - When one is responding to targets containing a specific feature, non-predictive peripheral cues that share this feature lead to faster responses to the target, while cues that do not contain the target feature effectively are ignored, providing evidence for the role of attentional control settings (ACSs) in the contingent capture hypothesis. It is unclear, however, at what stage of processing multiple ACSs are implemented. We took advantage of the excellent temporal resolution of electroencephalography to demonstrate that the maintenance of multiple ACSs influences later stages of attentional selection rather than providing an early attentional filter. N2pc analyses for cues and targets revealed a similar degree of spatial capture for any peripheral cue, regardless of control settings, with target P3s reflecting the application of the ACS color contingencies. PMID- 24168277 TI - The neural basis of disturbed efference copy mechanism in patients with schizophrenia. AB - Core psychopathological symptoms in patients with schizophrenia suggest that their sense of self may be disturbed. A disturbance in predictive motor mechanisms may be the cause of such symptoms. Ten patients with schizophrenia and ten healthy right-handed control subjects opened and closed their hand. This movement was filmed with an MRI compatible video camera and projected online onto a monitor. BOLD contrast was measured with fMRI. The temporal delay between movement and feedback was parametrically varied. Participants judged whether or not there was a delay. Patients were less sensitive to these delays than a matched control group. Comparing neural activation between the two groups showed a reduced attenuation of movement-sensitive perceptual areas in patients with increasing delay and a higher activation in the putamen in controls. The results provide further evidence that impaired efference copy mechanisms may contribute to the pathogenesis of schizophrenia and its first rank symptoms. PMID- 24168278 TI - The role of the left inferior frontal gyrus in episodic encoding of faces: An interference study by repetitive transcranial magnetic stimulation. AB - Despite extensive research on face recognition, only a few studies have examined the integration of perceptual features with semantic, biographical, and episodic information. In order to address this issue, we used repetitive transcranial magnetic stimulation (rTMS) to target the left inferior frontal gyrus (IFG) and the left occipital face area (OFA) during a face recognition task. rTMS was delivered during the encoding of "context" faces (i.e., linked to an occupation, e.g., "lawyer") and "no-context" faces (i.e., linked to a nonword pattern, e.g., "xxxx"). Subjects were then asked to perform a recognition memory task. Accuracy at retrieval showed a mild decrease after left OFA stimulation, whereas rTMS over the left IFG drastically compromised memory performance selectively for no context faces. On the other hand, absence of rTMS interference on context faces might be due either to the fact that pairing an occupation to a face makes the memory trace stronger, therefore less susceptible to rTMS interference, or to a different functional specificity of the left IFG subregions. PMID- 24168279 TI - Abstract relational categories, graded persistence, and prefrontal cortical representation. AB - Human behavior is characterized by creativity, flexibility, and adaptability. Psychologists have argued that this is a result of analogical reasoning processes. Neuroimaging studies point to PFC as a critical component of a larger network; however, it remains unclear how the brain accomplishes analogical reasoning. This paper presents a theory of prefrontal cortical function that attempts to explain the neural mechanisms of analogical processing in the context of the broader theoretical and empirical work on PFC. Specifically, the current paper proposes that neurons in PFC are particularly sensitive to relationship information, and that they develop response preferences for relationship information that increases in abstractness and complexity along the posterior anterior axis. Further, this theory posits that representation formation in PFC is driven by fronto-striatal circuits and that the persistence of these representations is determined by environmental consequences such that the longer the representation predicts reward or punishment, the longer the representation lasts. Finally, it is suggested that because analogy has been proposed as a core cognitive process, underlying many other interesting cognitive phenomena such as learning, creativity, and decision-making, it could serve as a useful tool for studying PFC function in general. PMID- 24168280 TI - Analogical reasoning: An incremental or insightful process? What cognitive and cortical evidence suggests. AB - Abstract The step-by-step, incremental nature of analogical reasoning can be questioned, since analogy making appears to be an insight-like process. This alternative view of analogical thinking can be integrated in Speed's model, even though the alleged role played by dopaminergic subcortical circuits needs further supporting evidence. PMID- 24168281 TI - Development of reasoning: Behavioral evidence to support reinforcement over cognitive control accounts. AB - Abstract Speed's theory makes two predictions for the development of analogical reasoning. Firstly, young children should not be able to reason analogically due to an undeveloped PFC neural network. Secondly, category knowledge enables the reinforcement of structural features over surface features, and thus the development of sophisticated, analogical, reasoning. We outline existing studies that support these predictions and highlight some critical remaining issues. Specifically, we argue that the development of inhibition must be directly compared alongside the development of reasoning strategies in order to support Speed's account. PMID- 24168282 TI - Are all analogies created equal? Prefrontal cortical functioning may predict types of analogical reasoning. AB - Abstract The proposed theory can account for analogies based on learned relationships between elements in the source and target domains. However, its explanatory power regarding the discovery of new relationships during analogical reasoning is limited. We offer an alternative perspective for the role of PFC in analogical thought that may better address different types of analogical mappings. PMID- 24168283 TI - Does the PFC model of analogy account for decision making, problem solving, reasoning, flexibility, adaptability, and even creativity? AB - Abstract From everyday cognition to scientific discovery, analogical processes play an important role: bringing connection, integration, and interrelation of information. Recently, a PFC model of analogy has been proposed to explain many cognitive processes and integrate general functional properties of PFC. We argue here that analogical processes do not suffice to explain the cognitive processes and functions of PFC. Moreover the model does not satisfactorily integrate specific explanatory mechanisms required for the different processes involved. Its relevance would be improved if fewer cognitive phenomena were considered and more specific predictions and explanations about those processes were stated. PMID- 24168284 TI - What role for the anterior cingulate in analogical reasoning? AB - Abstract While prefrontal and frontal cortex of the brain are well documented to mediate many executive functions, including creativity, flexibility, and adaptability, the anterior cingulate cortex (ACC) is known to be involved in error detection and conflict resolution, and is crucial to reward-based learning. A case is made for the notion that any neural model of analogical reasoning must incorporate the critical (and specialized) contributions of the ACC. PMID- 24168285 TI - The neurophysiology of magnitude: One example of extraction analogies. AB - Abstract Brain mapping for analogical information seems based on extraction of similarity on various levels, including perceptual similarity, abstract conceptual dimensions, and goals. Given the utility of analogical inferences on quantities that would extract covariance of time, space, and numbers, we discuss here the processing of time, space, and quantity as an example of the process of extraction of analogical information. This view is supported by evidence documenting common activation of the prefrontal cortex (PFC) in the processing of all of these magnitudes. PMID- 24168286 TI - Architecture of PFC supports analogy, but PFC is not an analogy machine. AB - In the preceding discussion paper, I proposed a theory of prefrontal cortical organization that was fundamentally intended to address the question: How does prefrontal cortex (PFC) support the various functions for which it seems to be selectively recruited? In so doing, I chose to focus on a particular function, analogy, that seems to have been largely ignored in the theoretical treatments of PFC, but that does underlie many other cognitive functions (Hofstadter, 2001 ; Holyoak & Thagard, 1997 ). At its core, this paper was intended to use analogy as a foundation for exploring one possibility for prefrontal function in general, although it is easy to see how the analogy-specific interpretation arises (as in the comment by Ibanez). In an attempt to address this more foundational question, this response will step away from analogy as a focus, and will address first the various comments from the perspective of the initial motivation for developing this theory, and then specific issues raised by the commentators. PMID- 24168288 TI - Psychoacoustic analyses of cochlear mechanisms in tinnitus patients with normal auditory thresholds. AB - OBJECTIVE: Tinnitus is often related to auditory dysfunction. We hypothesised that, among individuals with normal auditory thresholds, the mechanism of frequency selectivity might differ between subjects with and without tinnitus. Our objective was to identify any differences between normal-hearing individuals with tinnitus and those without in terms of psychophysical tuning curves (PTCs) and threshold-equalising noise (TEN) test results. DESIGN: We determined PTCs and performed the TEN test. STUDY SAMPLE: We evaluated 57 individuals, 16 with bilateral tinnitus (tinnitus-group) and 41 without tinnitus (control-group). RESULTS: We found significant differences between tinnitus and control groups regarding the following: 2 kHz PTCs obtained in noise at 6 and 8 kHz; 4 kHz PTCs obtained in noise at 2 and 8 kHz; and 6 and 8 kHz PTCs obtained in noise at 2 and 3 kHz. The TEN test revealed differences between groups in terms of auditory thresholds, which were significantly higher in the tinnitus group. In addition, none of the individuals in the tinnitus group were found to have dead regions in the cochlea. CONCLUSIONS: Despite having normal auditory thresholds, individuals with tinnitus have auditory patterns that differ significantly from those seen in individuals without tinnitus, such differences being suggestive of cochlear impairment. PMID- 24168289 TI - Synthesis of 3-alkylbenzoxazolones from N-alkyl-N-arylhydroxylamines by contiguous O-trichloroacetylation, trichloroacetoxy ortho-shift, and cyclization sequence. AB - Benzoxazolone pharmacophore is present in clinical pharmaceuticals, drug candidates, and many compounds having a wide spectrum of biological activities. The methods available for the synthesis of benzoxazolones have limited diversity due to problems in accessibility and air-sensitivity of diversely substituted o aminophenols from which they are generally prepared by cyclocarbonylation with phosgene or its equivalents. The present paper describes a mild method for the synthesis of 3-alkylbenzoxazolones from easily accessible and air-stable nitroarenes. Nitroarenes were converted to N-alkyl-N-arylhydroxylamines in two steps involving partial reduction to arylhydroxylamines followed by selective N alkylation. Treatment of N-alkyl-N-arylhydroxylamines with trichloroacetyl chloride and triethylamine afforded 3-alkylbenzoxazolones generally in good yields through an uninterrupted three-step sequence involving O trichloroacetylation, N->C(ortho) trichloroacetoxy shift, and cyclization in a single pot at ambient temperatures. The present method is mild, wide in scope, economical, and regioselective. Many sensitive groups like alkyl and aryl esters, amide, cyano, and the carbon-carbon double bond survive the reaction. PMID- 24168290 TI - Sunitinib-related interstitial pneumonia after treatment with temsirolimus: a case of possible recall phenomenon. AB - A 55-year-old Japanese man was admitted to Oita University Hospital (Oita, Japan) for pyrexia, malaise and dyspnea, and abnormal shadows on chest radiographs. He had started receiving sunitinib (37.5 mg a day for 3 weeks, followed by a 3-week break before beginning the next dosing cycle) for metastatic renal cell carcinoma after the improvement of temsirolimus-induced interstitial pneumonia. Sunitinib is a multiple tyrosine kinase receptor inhibitor approved for the treatment of metastatic renal cell carcinoma, and the most common clinical adverse effects of sunitinib are diarrhea, mucositis, stomatitis, hypertension, rashes and altered taste. We herein report a rare case of sunitinib-related interstitial pneumonia after treatment with temsirolimus for metastatic renal cell carcinoma. This case suggests the possibility of recall phenomenon of drug-induced pneumonia during the administration of additional chemotherapy. PMID- 24168291 TI - Sensory improvement of leprosy peripheral neuropathy in patients treated with perineural injection of platelet-rich plasma. AB - BACKGROUND: Leprosy (Hansen's disease) is a chronic granulomatous infection caused by Mycobacterium leprae with peripheral neuropathy as cutaneous and neurological manifestations. Peripheral nerve regeneration may be stimulated by vascular endothelial growth factor and other growth factors (GFs) that have important roles in extracellular matrix regeneration. All of those GFs can be found in platelet-rich plasma (PRP) preparation. The effect of PRP injection in leprosy peripheral neuropathy has never been reported. MATERIALS AND METHODS: A double-blind, randomized, control clinical trial was conducted among 60 patients with leprosy peripheral neuropathy. They were randomized to receive either a 1-ml injection of PRP as treatment or a 1-ml injection of platelet-poor plasma (PPP) as control. Skin sensibilities were measured by two-point discrimination test (TPDT) and visual analog scale (VAS), which were taken before and two weeks after treatment. RESULTS: Perineural injection of PRP was shown to be significantly more effective than PPP (P < 0.05) either in VAS or TPDT measurements. In both groups, the patients had a tingling sensation at the time of injection that disappeared shortly after. CONCLUSION: This study shows that perineural PRP injection could promote improvement of peripheral neuropathy sensibility in patients with leprosy. More research is needed to better determine the effects of PRP in nerve regeneration. PMID- 24168292 TI - Antibody discovery: sourcing of monoclonal antibody variable domains. AB - Historically, antibody variable domains for therapeutic antibodies have been sourced primarily from the mouse IgG repertoire, and typically either chimerized or humanized. More recently, human antibodies from transgenic mice producing human IgG, phage display libraries, and directly from human B lymphocytes have been used more broadly as sources of antibody variable domains for therapeutic antibodies. Of the total 36 antibodies approved by major maket regulatory agencies, the variable domain sequences of 26 originate from the mouse. Of these, four are marketed as murine antibodies (of which one is a mouse-rat hybrid IgG antibody), six are mouse-human chimeric antibodies, and 16 are humanized. Ten marketed antibodies have originated from human antibody genes, three isolated from phage libraries of human antibody genes and seven from transgenic mice producing human antibodies. Five antibodies currently in clinical trials have been sourced from camelids, as well as two from non-human primates, one from rat, and one from rabbit. Additional sources of antibody variable domains that may soon find their way into the clinic are potential antibodies from sharks and chickens. Finally, the various methods for retrieval of antibodies from humans, mouse and other sources, including various display technologies and amplification directly from B cells, are described. PMID- 24168293 TI - Spectrophotometric and chromatographic assessment of contributions of carotenoids and chlorophylls to the total antioxidant capacities of plant foods. AB - Carotenoids and chlorophylls are photosynthetic compounds and also efficient antioxidants. This study aims to identify and quantify carotenoids and chlorophylls in some vegetables (carrot, tomato, spinach), to measure the total antioxidant capacity (TAC) of these samples with two spectrophotometric methods, to correlate TAC data with carotenoid structure, and to compare the TAC results with HPLC findings. Separation of the individual antioxidant pigments was achieved on a C30 column using a developed gradient elution program involving methanol-acetonitrile (50:50, v/v) with 0.1% (v/v) triethylamine (TEA) (A) and acetone (B) mobile phases. Total antioxidant capacities of the acetone extracts of studied samples, in trolox and beta-carotene equivalents, were in the order: spinach > tomato > carrot by both CUPRAC and ABTS methods. CUPRAC responded favorably to both chlorophylls a and b. The TAC calculated with aid of combined HPLC-spectrophotometry was very close to the spectrophotometric value (93-108%) for real samples and synthetic mixtures. PMID- 24168295 TI - Sexuality in older adults: changing misconceptions. PMID- 24168294 TI - The adapter proteins of TLRs, TRIF and MYD88, are upregulated in depressed individuals. AB - BACKGROUND AND AIMS: TRIF and MYD88 are intracellular adaptor proteins for TLR signaling, and altered expression of these molecules can lead to defective or unregulated immune responses. Furthermore, previous studies revealed that depression may alter immune responses, but its mechanisms of action are unclear yet. There is a possibility that immunity and depression are linked through molecules such as TRIF and MYD88, thus, the aim of this study was to evaluate the mRNA levels of TRIF and MYD88 in the PBMCs isolated from depressed medical students. MATERIAL AND METHODS: The current study examined 38 depressed medical students studying in Iran and 43 healthy students from the same cohort as a control group. The mRNA levels of TRIF and MYD88 were examined in parallel with a housekeeping gene using real-time PCR. RESULTS: Our results demonstrated that expression of TRIF and MYD88 were significantly elevated in PBMCs isolated from depressed patients when compared to healthy subjects. CONCLUSIONS: Based on the current results, it seems that chronic inflammation in depressed patients correlates to the over expression of TRIF and MYD88 genes. Our results show a possible link between the reported increases of chronic inflammation in depressed individuals with unbalanced expression of genes that regulate immunity. PMID- 24168298 TI - Improving medication management for older adult clients residing in long-term care facilities. PMID- 24168301 TI - Effects of lidocaine administration via continuous rate infusion on the minimum alveolar concentration of isoflurane in New Zealand White rabbits (Oryctolagus cuniculus). AB - OBJECTIVE: To evaluate the effect of a continuous rate infusion (CRI) of lidocaine on the minimum alveolar concentration (MAC) of isoflurane in rabbits. ANIMALS: Five 12-month-old female New Zealand White rabbits (Oryctolagus cuniculus). PROCEDURES: Rabbits were anesthetized with isoflurane. Baseline isoflurane MAC was determined by use of the tail clamp technique. A loading dose of lidocaine (2.0 mg/kg, IV) was administered followed by a CRI of lidocaine at 50 MUg/kg/min. After 30 minutes, isoflurane MAC was determined. Another loading dose was administered, and the lidocaine CRI then was increased to 100 MUg/kg/min. After 30 minutes, isoflurane MAC was determined again. Plasma samples were obtained for lidocaine analysis after each MAC determination. RESULTS: Baseline isoflurane MAC was 2.09%, which was similar to previously reported values in this species. Lidocaine CRI at 50 and 100 MUg/kg/min induced significant reductions in MAC. The 50 MUg/kg/min CRI resulted in a mean plasma lidocaine concentration of 0.654 MUg/mL and reduction of MAC by 10.5%. The 100 MUg/kg/min CRI of lidocaine resulted in a mean plasma concentration of 1.578 MUg/mL and reduction of MAC by 21.7%. Lidocaine also induced significant decreases in arterial blood pressure and heart rate. All cardiopulmonary variables were within reference ranges for rabbits anesthetized with inhalation anesthetics. No adverse effects were detected; all rabbits had an uncomplicated recovery from anesthesia. CONCLUSIONS AND CLINICAL RELEVANCE: Lidocaine administered as a CRI at 50 and 100 MUg/kg/min decreased isoflurane MAC in rabbits. The IV administration of lidocaine may be a useful adjunct in anesthesia of rabbits. PMID- 24168302 TI - Computed tomographic evaluation to determine efficacy of euthanasia of yearling feedlot cattle by use of various firearm-ammunition combinations. AB - OBJECTIVE: To evaluate with CT the efficacy of various combinations of firearms and ammunitions to penetrate and disrupt the brain tissue of cadaveric heads of feedlot steers. SAMPLE: 42 fresh cadaveric heads of 12- to 18-month-old Bos taurus steers. PROCEDURES: For each of 7 combinations of firearms and ammunitions (.22-caliber rifle firing a long rifle 30-grain plated lead solid- or hollow point round, .223-caliber carbine firing a 50-grain ballistic-tip round, 9-mm pistol firing a 124-grain total metal jacket round, .45-caliber automatic Colt pistol [ACP] firing a 230-grain full metal jacket round, and 12-gauge shotgun firing a 2.75-inch 1.25-ounce No. 4 birdshot shell or a 1-ounce rifled slug), 6 cadaveric heads were shot at an identical distance (3 m), angle, and anatomic location. Heads were scanned with third-generation CT, and images were evaluated to determine extent of penetration, projectile fragmentation, cranial fracture, and likelihood of instantaneous death (>= 30% destruction of brain tissue or a brainstem lesion). RESULTS-41 of 42 skulls were penetrated by the projectile. Instantaneous death was considered a likely consequence for 83% (25/30) of heads shot with a rifle-fired .22-caliber solid-point round, pistol-fired .45-caliber ACP round, carbine-fired .223-caliber round, and shotgun-fired birdshot and slug. Of the 18 heads shot with pistol-fired 9-mm and .45-caliber ACP rounds and rifle fired .22-caliber hollow-point rounds, only 6 had brainstem lesions. CONCLUSIONS AND CLINICAL RELEVANCE-Results suggested that gunshots delivered by all firearm ammunition combinations except rifle-fired .22-caliber hollow-point rounds and pistol-fired 9-mm rounds were viable options for euthanasia of feedlot cattle. PMID- 24168303 TI - Evaluation of a rapid pressor response test in healthy cats. AB - OBJECTIVE: To evaluate angiotensin I and angiotensin II rapid pressor response tests in healthy cats. ANIMALS: 6 purpose-bred sexually intact male cats. PROCEDURES: Telemetric blood pressure (BP) implants were placed in all cats. After 2 weeks, cats were anesthetized for challenge with exogenous angiotensin I or angiotensin II. Continuous direct arterial BP was recorded during and immediately after IV administration of boluses of angiotensin I or angiotensin II at increasing doses. Blood pressure responses were evaluated for change in systolic BP (SBP), change in diastolic BP (DBP), and rate of increase of SBP by 4 observers. RESULTS: Following IV angiotensin I and angiotensin II administration, transient, dose-dependent increases in BP (mean +/- SEM change in SBP, 25.7 +/- 5.2 and 45.0 +/- 9.1; change in DBP, 23.4 +/- 4.7 mm Hg and 36.4 +/- 7.8 mm Hg; for 100 ng of angiotensin I/kg and angiotensin II/kg, respectively) and rate of increase of SBP were detected. At angiotensin I and II doses < 2.0 ng/kg, minimal responses were detected, with greater responses at doses ranging from 20 to 1,000 ng/kg. A significant effect of observer was not found. No adverse effects were observed. CONCLUSIONS AND CLINICAL RELEVANCE: The rapid pressor response test elicited dose-dependent, transient increases in SBP and DBP. The test has potential as a means of objectively evaluating the efficacy of various modifiers of the renin-angiotensin-aldosterone system in cats. Ranges of response values are provided for reference in future studies. PMID- 24168304 TI - Association between subcutaneous fat thickness measured on thoracic radiographs and body condition score in dogs. AB - OBJECTIVE: To determine whether subcutaneous fat thickness measured on thoracic radiographs was associated with body condition score (BCS) in dogs. Animals-87 client-owned dogs (41 males and 46 females) with a median age of 10.0 years (range, 1 to 16 years) and median weight of 20.3 kg (range, 3.1 to 58.0 kg). PROCEDURES: Age, sex, body weight, and breed were recorded. Body condition scores (scale from 1 to 9) and muscle condition scores were assigned by a single investigator. Subcutaneous fat thickness was measured at the level of the eighth rib head on a dorsoventral or ventrodorsal radiographic view of the thorax by a single investigator. Ratios of subcutaneous fat thickness to the width of the midbody of T8 on the ventrodorsal or dorsoventral radiographic view (T8 ratio) and to the length of the midbody of T4 on a right lateral radiographic view (T4 ratio) were calculated and compared with BCS by means of the Spearman correlation method. RESULTS: Median BCS was 6 (range, 1 to 9), and all muscle condition scores were represented. There were significant correlations between BCS and T4 ratio (r = 0.86) and between BCS and T8 ratio (r = 0.84). CONCLUSIONS AND CLINICAL RELEVANCE: Results indicated that in this population, there was a significant association between BCS and subcutaneous fat thickness measured on thoracic radiographs. Findings suggested that measuring subcutaneous fat thickness could aid in the retrospective assignment of BCS in studies involving dogs in which BCS was not recorded in the medical record. PMID- 24168305 TI - Evaluation of the use of atropine sulfate, a combination of butylscopolammonium bromide and metamizole sodium, and flunixin meglumine to ameliorate clinical adverse effects of imidocarb dipropionate in horses. AB - OBJECTIVE: To evaluate the ability of atropine sulfate, butylscopolammonium bromide combined with metamizole sodium, and flunixin meglumine to ameliorate the clinical adverse effects of imidocarb dipropionate in horses. ANIMALS: 28 horses with piroplasmosis. PROCEDURES: 28 horses were randomly assigned to 4 equal groups according to the pretreatment administered. Fifteen minutes before administration of 2.4 mg of imidocarb dipropionate/kg IM, horses in the first group were pretreated with 0.02 mg of atropine sulfate/kg IV, the second group with a combination of 0.2 mg of butylscopolammonium bromide/kg IV and 25 mg of metamizole sodium/kg IV, the third group with 1.1 mg of flunixin meglumine/kg IV, and the fourth (control) group with 1 mL of saline (0.9% NaCl) solution/50 kg IV. Physical examination, including evaluation of rectal temperature, heart and respiratory rates, capillary refill time, mucous membrane color, hydration status, abdominal sounds, signs of abdominal pain, salivation, diarrhea, and number of defecations, was performed. RESULTS: Imidocarb dipropionate use in the control group was associated with serious adverse effects including signs of abdominal pain (4/7 horses) and diarrhea (2/7). Horses pretreated with atropine had no diarrhea, but 6 had signs of abdominal pain. Only 1 horse that received butylscopolammonium-metamizole pretreatment had signs of abdominal pain and 3 had diarrhea, which was numerically but not significantly different than the control group. Of horses pretreated with flunixin, 3 had signs of abdominal pain and 3 had diarrhea. CONCLUSIONS AND CLINICAL RELEVANCE: A combination of butylscopolammonium bromide and metamizole sodium may be useful to ameliorate the adverse effects of imidocarb dipropionate in horses, although group size was small and significant differences from the control group were not found. PMID- 24168306 TI - Anti-glucagon-like peptide-1 immunoreactivity in samples of blood and ileum obtained from neonatal and adult alpacas. AB - OBJECTIVE: To compare numbers of L cells in intestinal samples and blood concentrations of glucagon-like peptide (GLP)-1 between neonatal and mature alpacas. SAMPLE: Intestinal samples from carcasses of 4 suckling crias and 4 postweaning alpacas for immunohistochemical analysis and blood samples from 32 suckling crias and 19 healthy adult alpacas for an ELISA. PROCEDURES: Immunohistochemical staining was conducted in accordance with Oregon State University Veterinary Diagnostic Laboratory standard procedures with a rabbit polyclonal anti-GLP-1 primary antibody. Stained cells with staining results in ileal tissue were counted in 20 fields by 2 investigators, and the mean value was calculated. For quantification of GLP-1 concentrations, blood samples were collected into tubes containing a dipeptidyl peptidase-4 inhibitor. Plasma samples were tested in duplicate with a commercial GLP-1 ELISA validated for use in alpacas. RESULTS: Counts of stained cells (mean +/- SD, 50 +/- 18 cells) and plasma GLP-1 concentrations (median, 0.086 ng/mL; interquartile range, 0.061 to 0.144 ng/mL) were higher for suckling alpacas than for postsuckling alpacas (stained cells, 26 +/- 4 cells; plasma GLP-1 concentration, median, 0.034 ng/mL; interquartile range, 0.015 to 0.048 ng/mL). CONCLUSIONS AND CLINICAL RELEVANCE: Older alpacas had lower numbers of L cells in intestinal tissues and lower blood concentrations of GLP-1 than those in neonates. These findings suggested that there may be a decrease in the contribution of GLP-1 to insulin production in adult alpacas, compared with the contribution in neonates. PMID- 24168307 TI - Effect of dexamethasone or synthetic ACTH administration on endogenous ACTH concentrations in healthy dogs. AB - OBJECTIVE: To determine the effects of dexamethasone or synthetic ACTH administration on endogenous ACTH concentrations in healthy dogs. ANIMALS: 10 healthy neutered dogs. PROCEDURES: Each dog received dexamethasone (0.01 mg/kg), synthetic ACTH (5 MUg/kg), or saline (0.9% NaCl) solution (0.5 mL) IV at intervals of >= 30 days. Plasma endogenous ACTH concentrations were measured before (baseline; time 0) and 1, 8, 12, and 24 hours after drug administration; serum cortisol concentrations were measured before and 1 hour after synthetic ACTH and saline solution administration and 8 hours after dexamethasone administration. RESULTS: Analysis of serum cortisol concentrations confirmed effects of drug administration. Dexamethasone significantly decreased the endogenous ACTH concentration from the baseline value at both 8 and 12 hours. Synthetic ACTH administration significantly decreased the endogenous ACTH concentration from the baseline value at 8 hours. Saline solution administration had no significant effect on endogenous ACTH concentration. CONCLUSIONS AND CLINICAL RELEVANCE: Dexamethasone and synthetic ACTH administered IV at doses used routinely during testing for hyperadrenocorticism caused significant but transient reductions of endogenous ACTH concentrations in healthy dogs. Thus, a 2 hour washout period following ACTH stimulation testing before collection of samples for measurement of the endogenous ACTH concentration may be insufficient. Although this effect has not been verified in dogs with hyperadrenocorticism, these data suggested that samples for measurement of endogenous ACTH concentrations should be obtained before or > 8 hours after initiation of an ACTH stimulation test or before or > 12 hours after the start of a low-dose dexamethasone suppression test. PMID- 24168309 TI - Localization of the cutaneus trunci muscle reflex in horses. AB - OBJECTIVE: To determine the magnitude and location of skin movement attributable to the cutaneus trunci muscle reflex in response to localized stimulation of the skin of the dorsolateral aspect of the thoracic wall in horses. ANIMALS: 8 horses. PROCEDURES: A grid of 56 reflective markers was applied to the lateral aspect of the body wall of each horse; markers were placed at 10-cm intervals in 7 rows and 8 columns. A motion analysis system with 10 infrared cameras was used to track movements of the markers in response to tactile stimulation of the dorsolateral aspect of the thoracic wall at the levels of T6, T11, and T16. Marker movement data determined after skin stimulation were used to create a skin deformation gradient tensor field, which was analyzed with custom software. RESULTS: The sites of maximal skin deformation were located close to the stimulation sites; the centers of the twitch responses were located a mean distance of 7.7 to 12.8 cm ventral and between 6.6 cm cranial and 3.1 cm caudal to the stimulation sites. CONCLUSIONS AND CLINICAL RELEVANCE: Findings of this study may have implications for assessment of nerve conduction velocities of the cutaneus trunci muscle reflex and may enhance understanding of the responses of horses to placement of tack or other equipment on skin over the cutaneus trunci muscles. PMID- 24168308 TI - Genetic variability and in vitro transcriptional permissibility of primary ovine beta-retrovirus promoter isolates. AB - OBJECTIVE: To assess genomic sequence conservation and variation in the proviral promoter of enzootic nasal tumor virus (ENTV) and Jaagsiekte sheep retrovirus (JSRV) in tissue samples from 3 sheep with nasal adenocarcinoma associated with ENTV and 3 sheep with pulmonary adenocarcinoma associated with JSRV and to identify a cell culture system that supports transcriptional activity of the ENTV and JSRV viral promoters. ANIMALS: 6 adult sheep. PROCEDURES: Standard PCR procedures for detection of the ENTV and JSRV long terminal repeat (LTR) promoter region were performed on samples from the 3 nasal adenocarcinomas and 3 pulmonary adenocarcinomas, respectively. The LTRs were cloned into shuttle vectors, amplified, sequenced, and analyzed. The cloned LTR regions were transferred into reporter plasmids and multiple human and ruminant cell lines, and primary cells were transfected with the promoter-reporter plasmids. The viral promoter activity was evaluated by use of an in vitro beta-galactosidase reporter assay. RESULTS: Each isolate had a unique nucleotide sequence. Single nucleotide polymorphisms were the most common LTR mutation and rarely occurred at transcription factor binding sites. Relative to ENTV, the JSRV promoter isolates had a conserved 66-bp U3 insertion, including the lung-specific transcription factor HNF-3beta binding site. Among the cell lines used, human embryonic kidney (293T) and goat synovial membrane cells supported promoter transcription. CONCLUSIONS AND CLINICAL RELEVANCE: The LTRs of ENTV and JSRV have extensive blocks of sequence conservation. Human 293T and goat synovial membrane cell lines may be suitable in vitro cell culture systems for further research of viral promoter functions. PMID- 24168310 TI - Effects of advanced age on whole-body protein synthesis and skeletal muscle mechanistic target of rapamycin signaling in horses. AB - OBJECTIVE: To determine the effects of advanced age on whole-body protein synthesis and activation of the mechanistic target of rapamycin (mTOR) signaling pathway in skeletal muscle of horses. ANIMALS: Six 22- to 26-year-old (aged) and six 7- to 14-year-old (mature) horses. PROCEDURES: Whole-body protein synthesis was measured with a 2-hour primed constant infusion of (13)C sodium bicarbonate, followed by a 4-hour primed constant infusion of 1-(13)C phenylalanine. After the infusions, a biopsy specimen was obtained from a gluteus medius muscle and activation of protein kinase B (Akt), p70 riboprotein S6 kinase (S6K1), riboprotein S6 (rpS6), and eukaryotic initiation factor 4E binding protein 1 (4EBP1) was determined with western immunoblot analysis. For all horses, inflammatory cytokine expression in muscle and blood samples was measured with quantitative real-time PCR analysis. RESULTS: Advanced age had no effect on whole body protein synthesis or the phosphorylation of Akt, rpS6, and 4EBP1; however, muscle specimens of aged horses had 42% lower phosphorylation of S6K1 than did those of mature horses. Aged and mature horses had similar inflammatory cytokine expression in muscle and blood samples. CONCLUSIONS AND CLINICAL RELEVANCE: The lower S6K1 activation for aged horses, compared with that for mature horses, could be indicative of low rates of muscle protein synthesis in aged horses. However, advanced age had no effect on any other indicators of whole-body or muscle protein synthesis or on measures of systemic or muscle inflammation, which suggested that protein metabolism and subsequently requirements may not differ between healthy mature and aged horses. PMID- 24168311 TI - Assessment of biometric tools for quantitative gait analysis in Holstein calves. AB - OBJECTIVE: To assess biometric tools for gait analysis in healthy calves by use of pressure mat sensors, a handheld algometer, and serial circumferential measurements of selected joints. ANIMALS: 20 six- to eight-week-old healthy male Holstein calves. PROCEDURES: Calves were evaluated over a 4-day period. Gait analysis was performed by training calves to walk over a pressure-sensitive mat, which recorded quantitative measurements. An algometer was applied perpendicular to each joint until an aversion response was observed or a preset limit of 50 N/cm(2) was obtained. Circumference measurements of the carpal and tarsal joints were obtained by the application of a flexible measuring tape to defined areas of each limb. Variability between joint circumference measurements and pressure mat variables were analyzed with a standard least squares means model. Algometer measurements were dichotomized, and logistic regression was used to assess the probability that a calf reacted to algometer-applied pressure. RESULTS: 1 calf was removed from the study because of lameness. Mean carpal and tarsal joint circumference measurements were reliable and consistent among calves. Algometry results suggested that healthy calves were more sensitive to pressure applied to the elbow and stifle joints, compared with pressure applied to the carpal, tarsal, and metacarpophalangeal or metatarsophalangeal joints. Pressure mat variables of stance time and stride velocity varied greatly among calves, whereas impulse and maximum forces varied little. CONCLUSIONS AND CLINICAL RELEVANCE: Findings can serve as reference points for other studies and be used for comparison with results for calves with lameness or altered gaits. PMID- 24168312 TI - Pharmacokinetics, bioavailability, and hemodynamic effects of trazodone after intravenous and oral administration of a single dose to dogs. AB - OBJECTIVE: To determine the pharmacokinetics and hemodynamic effects of trazodone after IV and oral administration in dogs and bioavailability after oral administration. ANIMALS: 6 adult Beagles. PROCEDURES: Dogs received trazodone HCl (8 mg/kg) orally and IV in a randomized controlled crossover design. Blood samples were collected at various times after administration. Heart rates and indirectly measured blood pressures of dogs and plasma concentrations and pharmacokinetics of trazodone were determined. RESULTS: Following IV administration, the mean +/- SD elimination half-life, apparent volume of distribution, and plasma total body clearance were 169 +/- 53 minutes, 2.53 +/- 0.47 L/kg, and 11.15 +/- 3.56 mL/min/kg, respectively. Following oral administration, the mean +/- SD elimination half-life and absolute bioavailability were 166 +/- 47 minutes and 84.6 +/- 13.2%, respectively. Maximum plasma concentration following oral administration was 1.3 +/- 0.5 MU/mL, and time to maximum plasma concentration was 445 +/- 271 minutes. After IV administration, all dogs immediately developed transient tachycardia (184.3 +/- 8.0 beats/min), and 3 of 6 dogs developed aggression. Increase in heart rate was significantly associated with increase in plasma drug concentration following IV administration. CONCLUSIONS AND CLINICAL RELEVANCE: Results of this study indicated oral administration of trazodone resulted in acceptable absolute bioavailability, with substantial variability in time to maximum plasma concentration. Individualized approaches in dosing intervals may be necessary for dogs receiving oral trazodone. An orally administered dose of 8 mg/kg was well tolerated in dogs; IV administration of a dose of 8 mg/kg caused substantial adverse effects, including tachycardia and behavior disinhibition. PMID- 24168313 TI - Induction and disappearance of gammaH2AX foci and formation of micronuclei after exposure of human lymphocytes to 60Co gamma-rays and p(66)+ Be(40) neutrons. AB - PURPOSE: To investigate both the formation of micronuclei (MN) and the induction and subsequent loss of phosphorylated histone H2AX foci (gammaH2AX foci) after in vitro exposure of human lymphocytes to either (60)Co gamma-rays or p(66)+ Be(40) neutrons. MATERIALS AND METHODS: MN dose response (DR) curves were obtained by exposing isolated lymphocytes of 10 different donors to doses ranging from 0-4 Gy gamma-rays or 0-2 Gy neutrons. Also, gammaH2AX foci DR curves were obtained following exposure to doses ranging from 0-0.5 Gy of either gamma-rays or neutrons. Foci kinetics for lymphocytes for a single donor exposed to 0.5 Gy gamma-rays or neutrons were studied up to 24 hours post-irradiation. RESULTS: Micronuclei yields following neutron exposure were consistently higher compared to that from (60)Co gamma-rays. All MN yields were over-dispersed compared to a Poisson distribution. Over-dispersion was higher after neutron irradiation for all doses > 0.1 Gy. Up to 4 hours post-irradiation lower yields of neutron induced gammaH2AX foci were observed. Between 4 and 24 hours the numbers of foci from neutrons were consistently higher than that from gamma-rays. The half-live of foci disappearance is only marginally longer for neutrons compared to that from gamma-rays. Foci formations were more likely to be over-dispersed for neutron irradiations. CONCLUSION: Although neutrons are more effective to induce MN, the absolute number of induced gammaH2AX foci are less at first compared to gamma-rays. With time neutron-induced foci are more persistent. These findings are helpful for using gammaH2AX foci in biodosimetry and to understand the repair of neutron-induced cellular damage. PMID- 24168315 TI - Triboelectric nanogenerator built on suspended 3D spiral structure as vibration and positioning sensor and wave energy harvester. AB - An unstable mechanical structure that can self-balance when perturbed is a superior choice for vibration energy harvesting and vibration detection. In this work, a suspended 3D spiral structure is integrated with a triboelectric nanogenerator (TENG) for energy harvesting and sensor applications. The newly designed vertical contact-separation mode TENG has a wide working bandwidth of 30 Hz in low-frequency range with a maximum output power density of 2.76 W/m(2) on a load of 6 MOmega. The position of an in-plane vibration source was identified by placing TENGs at multiple positions as multichannel, self-powered active sensors, and the location of the vibration source was determined with an error less than 6%. The magnitude of the vibration is also measured by the output voltage and current signal of the TENG. By integrating the TENG inside a buoy ball, wave energy harvesting at water surface has been demonstrated and used for lighting illumination light, which shows great potential applications in marine science and environmental/infrastructure monitoring. PMID- 24168314 TI - Long-term characterization of axon regeneration and matrix changes using multiple channel bridges for spinal cord regeneration. AB - Spinal cord injury (SCI) results in loss of sensory and motor function below the level of injury and has limited available therapies. The host response to SCI is typified by limited endogenous repair, and biomaterial bridges offer the potential to alter the microenvironment to promote regeneration. Porous multiple channel bridges implanted into the injury provide stability to limit secondary damage and support cell infiltration that limits cavity formation. At the same time, the channels provide a path that physically directs axon growth across the injury. Using a rat spinal cord hemisection injury model, we investigated the dynamics of axon growth, myelination, and scar formation within and around the bridge in vivo for 6 months, at which time the bridge has fully degraded. Axons grew into and through the channels, and the density increased overtime, resulting in the greatest axon density at 6 months postimplantation, despite complete degradation of the bridge by that time point. Furthermore, the persistence of these axons contrasts with reports of axonal dieback in other models and is consistent with axon stability resulting from some degree of connectivity. Immunostaining of axons revealed both motor and sensory origins of the axons found in the channels of the bridge. Extensive myelination was observed throughout the bridge at 6 months, with centrally located and peripheral channels seemingly myelinated by oligodendrocytes and Schwann cells, respectively. Chondroitin sulfate proteoglycan deposition was restricted to the edges of the bridge, was greatest at 1 week, and significantly decreased by 6 weeks. The dynamics of collagen I and IV, laminin, and fibronectin deposition varied with time. These studies demonstrate that the bridge structure can support substantial long-term axon growth and myelination with limited scar formation. PMID- 24168316 TI - A public private partnership to fight against malaria along the Chad-Cameroon pipeline corridor: I. Baseline data on socio-anthropological aspects, knowledge, attitudes and practices of the population concerning malaria. AB - BACKGROUND: Malaria is ranked as the major public health problem in Cameroon, representing 50% of illness in less than five year old children, 40-45% of medical consultation and 40% of the annual home income spent on health. The Cameroon Oil Transportation Company (COTCO) that exploits the Chad-Cameroon pipeline in Cameroon territory, initiated in 2010, a public private partnership project to control malaria along the pipeline corridor. A research component was included in the project so as to guide and evaluate the control measures applied in this pipeline corridor. This study presents the baseline socio-anthropological data as well as the knowledge, attitudes and practices of the local population concerning malaria, its transmission, management and prevention. METHODS: A descriptive cross-sectional survey was undertaken in four sentinel sites (one site per ecological zone) along the Chad-Cameroon pipeline corridor. Three structured questionnaires were used for the survey. Two of them were addressed to the heads of households (one for census and the other to collect information concerning the characteristics of houses and living conditions in households as well as their knowledge, attitudes and practices concerning malaria). The last questionnaire was used to collect information on malaria management and prevention. It was addressed to women who had delivered a living child within the past three years. Interviewers were recruited from each village and trained for two consecutive days on how to fill the different questionnaires. All data were analysed at 5% significant level using Epi-Info, SPSS and Cs PRO 4.0 STATA. Values of p <= 0.05 were considered statistically significant. RESULTS: Interviews were conducted in 2597 households (Bipindi 399, Belabo 835, in Meidougou 820 and Dompta 543). Whatever the study site, 50% of the heads of household were workers of the agro-pastoral sector. Most of the heads of household were men (average 77.4% for men and 22.6% for females). The walls of households were mostly made-up of earth blocks and access to media was low. There were significant differences between mean ages and educational level of the heads of household. Significant differences were also observed between the characteristics of houses and the sites located in the southern regions (Bipindi and Belabo) and those located in the northern regions (Meidougou and Dompta). The later household heads were younger and less educated than those in the other regions.In most of the study sites, paracetamol was cited as the first intention drug for malaria treatment, followed by chloroquine, a banned drug. More than half of the households studied had a correct knowledge of malaria and its mode of transmission: 120/155 (77.1%) in Bipindi, 244/323 (74.5%) in Belabo, 171/235 (72.8%) in Meidougou and 118/218 (54.1%) in Dompta. Fever and headache were the malaria signs/symptoms most often cited by the households. An important percentage of pregnant women did not take any malaria prophylaxis during their last pregnancy (up to 43.4% in Belabo). CONCLUSION: In all the study sites, there were conditions that indicated the all year round transmission of malaria (characteristics of houses and limited access to media making sensitization campaigns difficult). In general, most households had a good knowledge of malaria and its mode of transmission. However, malaria treatment drugs were most often inappropriate. In this study, recommendations were made in order to guide the implementation of control measures. PMID- 24168317 TI - Remote glucose monitoring in cAMP setting reduces the risk of prolonged nocturnal hypoglycemia. AB - OBJECTIVE: This study tested the feasibility and effectiveness of remote continuous glucose monitoring (CGM) in a diabetes camp setting. SUBJECTS AND METHODS: Twenty campers (7-21 years old) with type 1 diabetes were enrolled at each of three camp sessions lasting 5-6 days. On alternating nights, 10 campers were randomized to usual wear of a Dexcom (San Diego, CA) G4TM PLATINUM CGM system, and 10 were randomized to remote monitoring with the Dexcom G4 PLATINUM communicating with the Diabetes Assistant, a cell phone platform, to allow wireless transmission of CGM values. Up to 15 individual graphs and sensor values could be displayed on a single remote monitor or portable tablet. An alarm was triggered for values <70 mg/dL, and treatment was given for meter-confirmed hypoglycemia. The primary end point was to decrease the duration of hypoglycemic episodes <50 mg/dL. RESULTS: There were 320 nights of CGM data and 197 hypoglycemic events. Of the remote monitoring alarms, 79% were true (meter reading of <70 mg/dL). With remote monitoring, 100% of alarms were responded to, whereas without remote monitoring only 54% of alarms were responded to. The median duration of hypoglycemic events <70 mg/dL was 35 min without remote monitoring and 30 min with remote monitoring (P=0.078). Remote monitoring significantly decreased prolonged hypoglycemic events, eliminating all events <50 mg/dL lasting longer than 30 min as well as all events <70 mg/dL lasting more than 2 h. CONCLUSIONS: Remote monitoring is feasible at diabetes camps and effective in reducing the risk of prolonged nocturnal hypoglycemia. This technology will facilitate forthcoming studies to evaluate the efficacy of automated closed-loop systems in the camp setting. PMID- 24168318 TI - Pseudoaneurysm of the anterior tibial artery after ankle arthroscopy. PMID- 24168319 TI - Monolithic composites of silica aerogels by reactive supercritical deposition of hydroxy-terminated poly(dimethylsiloxane). AB - Monolithic composites of silica aerogels with hydroxyl-terminated poly(dimethylsiloxane) (PDMS(OH)) were developed with a novel reactive supercritical deposition technique. The method involves dissolution of PDMS(OH) in supercritical CO2 (scCO2) and then exposure of the aerogel samples to this single phase mixture of PDMS(OH)-CO2. The demixing pressures of the PDMS(OH)-CO2 binary mixtures determined in this study indicated that PDMS(OH) forms miscible mixtures with CO2 at a wide composition range at easily accessible pressures. Upon supercritical deposition, the polymer molecules were discovered to react with the hydroxyl groups on the silica aerogel surface and form a conformal coating on the surface. The chemical attachment of the polymer molecules on the aerogel surface were verified by prolonged extraction with pure scCO2, simultaneous deposition with superhydrophobic and hydrophilic silica aerogel samples and ATR-FTIR analysis. All of the deposited silica aerogel samples were obtained as monoliths and retained their transparency up to around 30 wt % of mass uptake. PDMS(OH) molecules were found to penetrate all the way to the center of the monoliths and were distributed homogenously throughout the cylindrical aerogel samples. Polymer loadings as high as 75.4 wt % of the aerogel mass could be attained. It was shown that the polymer uptake increases with increasing exposure time, as well as the initial polymer concentration in the vessel. PMID- 24168320 TI - Does environmental robustness play a role in fluctuating environments? AB - Fluctuating environments are expected to select for individuals that have highest geometric fitness over the experienced environments. This leads to the prediction that genetically determined environmental robustness in fitness, and average fitness across environments should be positively genetically correlated to fitness in fluctuating environments. Because quantitative genetic experiments resolving these predictions are missing, we used a full-sib, half-sib breeding design to estimate genetic variance for egg-to-adult viability in Drosophila melanogaster exposed to two constant or fluctuating temperatures that were above the species' optimum temperature, during development. Viability in two constant environments (25 degrees C or 30 degrees C) was used to estimate breeding values for environmental robustness of viability (i.e., reaction norm slope) and overall viability (reaction norm elevation). These breeding values were regressed against breeding values of viability at two different fluctuating temperatures (with a mean of 25 degrees C or 30 degrees C). Our results based on genetic correlations show that average egg-to-adult viability across different constant thermal environments, and not the environmental robustness, was the most important factor for explaining the fitness in fluctuating thermal environments. Our results suggest that the role of environmental robustness in adapting to fluctuating environments might be smaller than anticipated. PMID- 24168321 TI - Improving the sweeping efficiency of permanganate into low permeable zones to treat TCE: experimental results and model development. AB - The residual buildup and treatment of dissolved contaminants in low permeable zones (LPZs) is a particularly challenging issue for injection-based remedial treatments. Our objective was to improve the sweeping efficiency of permanganate into LPZs to treat dissolved-phase TCE. This was accomplished by conducting transport experiments that quantified the ability of xanthan-MnO4(-) solutions to penetrate and cover (i.e., sweep) an LPZ that was surrounded by transmissive sands. By incorporating the non-Newtonian fluid xanthan with MnO4(-), penetration of MnO4(-) into the LPZ improved dramatically and sweeping efficiency reached 100% in fewer pore volumes. To quantify how xanthan improved TCE removal, we spiked the LPZ and surrounding sands with (14)C-lableled TCE and used a multistep flooding procedure that quantified the mass of (14)C-TCE oxidized and bypassed during treatment. Results showed that TCE mass removal was 1.4 times greater in experiments where xanthan was employed. Combining xanthan with MnO4(-) also reduced the mass of TCE in the LPZ that was potentially available for rebound. By coupling a multiple species reactive transport model with the Brinkman equation for non-Newtonian flow, the simulated amount of (14)C-TCE oxidized during transport matched experimental results. These observations support the use of xanthan as a means of enhancing MnO4(-) delivery into LPZs for the treatment of dissolved-phase TCE. PMID- 24168322 TI - Salt and cocrystals of sildenafil with dicarboxylic acids: solubility and pharmacokinetic advantage of the glutarate salt. AB - Sildenafil is a drug used to treat erectile dysfunction and pulmonary arterial hypertension. Because of poor aqueous solubility of the drug, the citrate salt, with improved solubility and pharmacokinetics, has been marketed. However, the citrate salt requires an hour to reach its peak plasma concentration. Thus, to improve solubility and bioavailability characteristics, cocrystals and salts of the drug have been prepared by treating aliphatic dicarboxylic acids with sildenafil; the N-methylated piperazine of the drug molecule interacts with the carboxyl group of the acid to form a heterosynthon. Salts are formed with oxalic and fumaric acid; salt monoanions are formed with succinic and glutaric acid. Sildenafil forms cocrystals with longer chain dicarboxylic acids such as adipic, pimelic, suberic, and sebacic acids. Auxiliary stabilization via C-H...O interactions is also present in these cocrystals and salts. Solubility experiments of sildenafil cocrystal/salts were carried out in 0.1N HCl aqueous medium and compared with the solubility of the citrate salt. The glutarate salt and pimelic acid cocrystal dissolve faster than the citrate salt in a two hour dissolution experiment. The glutarate salt exhibits improved solubility (3.2 fold) compared to the citrate salt in water. Solubilities of the binary salts follow an inverse correlation with their melting points, while the solubilities of the cocrystals follow solubilities of the coformer. Pharmacokinetic studies on rats showed that the glutarate salt exhibits doubled plasma AUC values in a single dose within an hour compared to the citrate salt. The high solubility of glutaric acid, in part originating from the strained conformation of the molecule and its high permeability, may be the reason for higher plasma levels of the drug. PMID- 24168324 TI - Cytochrome P450 isoforms are differently up-regulated in aflatoxin B1-exposed human lymphocytes and monocytes. AB - CONTEXT: Aflatoxins (AFs) are highly hazardous mycotoxins with potent carcinogenic, mutagenic and immune disregulatory properties. Cytochrome P450 (CYP) isoforms are central for enhanced AFB1 toxicity in situ. It remains to be seen whether and how these AFB1 activators work in human leukocytes. OBJECTIVE: To investigate the involvement of CYP isoforms in AFB1 toxicity of circulating mononuclear cells, we examined the impact of environmentally relevant levels of AFB1 on lymphocytes and monocytes. MATERIALS AND METHODS: Very low and moderate doses of AFB1 with/without CYP inducers on transcription of key CYP isoforms and toll-like receptor 4 (TLR4) were examined in human lymphocytes, monocytes and HepG2 cells; cell cycle distribution and viability were also analyzed in AFB1 exposed lymphocytes and monocytes. RESULTS: Only CYP1A1, CYP1B1, CYP3A4, CYP3A5 and CYP3A7 expressed in lymphocytes and monocytes. TLR4 much more expressed in monocytes than in lymphocytes, but HepG2 showed little TLR4 transcription. While CYP1A1, CYP1B1 and CYP3A4 were highly induced by AFB1 in monocytes, in lymphocytes only CYP1A1 was induced. Among CYP1A1, CYP1B1 and CYP3A4 only CYP1A1 responded to low and moderate levels of AFB1. Enhanced transcripts of CYPs by AFB1 yielded little synergies on TLR4 transcription in lymphocytes and monocytes. Cell cycle arrest and necrosis were also detected in AFB1-exposed lymphocytes and monocytes. CONCLUSIONS: Our novel findings indicate that AFB1 more intensively stimulates CYP genes expression in monocytes than in lymphocytes. Mechanistically, this could explain a more pronounced immunotoxicity of AFB1 in myeloid than in lymphoid lineage cells in vitro/situ/vivo. PMID- 24168323 TI - Sub-microscopic gametocyte carriage in febrile children living in different areas of Gabon. AB - BACKGROUND: Considering malaria prevalence declines in parts of sub-Saharan Africa, such as Gabon, identification of the human infectious reservoir is important for successful malaria control. Microscopic and sub-microscopic parasites contribute to malaria transmission. The aim of the present study was to evaluate the proportion of microscopic and sub-microscopic gametocyte carriers among febrile patients in two different areas of Gabon. METHODS: Samples from febrile children aged less than 11 years old were collected from February 2008 to January 2009 at two health centres of Gabon. Patients were screened for the presence of asexual Plasmodium falciparum parasites. Gametocyte carriage was determined by microscopy and QT-NASBA. RESULTS: Gametocytes were detected in 5.3% (n = 16/304) of children by microscopy compared to 45.7% (n = 139/304) by QT Nasba. Sub-microscopic gametocyte carriage (ie microscopy negative and QT-Nasba positive) was found in 89.2% (n = 124/139) of patients. Among patients with microscopically detected trophozoites, the proportion of sub-microscopic gametocyte (SMG) carriers was 58.4% (n = 118/202) and 6% in samples from children with negative slides (p < 0.01). In Oyem, where malaria prevalence is three-fold higher than in Owendo, SMG carriage was more frequent (49.0% vs 32.6% in Owendo; p < 0.01). CONCLUSION: Sub-microscopic gametocytaemia is common among Gabonese febrile children. They might strongly contribute to maintain malaria transmission. However, further analysis of sub-microscopic parasite carriage among asymptomatic individuals will be helpful to better characterize malaria transmission. PMID- 24168325 TI - A study on glabellar wrinkle patterns in Koreans. AB - BACKGROUND: Botulinum toxin is a well-established treatment for dynamic glabellar lines. The glabella is in fact, the most common site for botulinum toxin injection in Asians. Previous studies have identified five glabellar contraction patterns according to the predominance of eyebrow approximation, depression or elevation. Unfortunately, the authors found the former classification somewhat confusing. OBJECTIVE: To identify and classify glabellar wrinkle patterns in Koreans for a better treatment approach. We also aimed to provide an Asian consensus recommendation for the individual wrinkle pattern. METHODS: A retrospective photographic analysis of 139 Korean patients who received botulinum toxin for the first time to treat glabellar wrinkles was conducted. The wrinkle patterns were identified and classified by a panel of experienced Korean dermatologists, based on the prevalence of perpendicular and transverse glabellar lines, the nasal wrinkles and the forehead wrinkles. The panel also convened to develop a clinical consensus on the individual wrinkle pattern in Asians. RESULTS: Five patterns were identified: (1) 'U', (2) '11', (3) 'X', (4) 'pi (Phi)' and (5) 'I'. The classification method allowed indentifying the most important muscles in each wrinkle pattern. The consensus recommendation addressed the most heavily used muscles to receive higher doses and to be injected into a larger number of sites. Those less solicited muscles were left untreated or received lower doses, allowing for more effective and natural results. CONCLUSION: Interpersonal differences in facial animation exist among Koreans. We hope our simple glabellar wrinkles classification enables a more accurate, individualized treatment with botulinum toxin in Asians. PMID- 24168326 TI - Successful treatment with rituximab and mycophenolate mofetil of refractory autoimmune hemolytic anemia post-hematopoietic stem cell transplant for dyskeratosis congenita due to TINF2 mutation. AB - AIHA following allogeneic HSCT is appearing more frequently in the literature. It occurs as a result of donor cell-derived antibodies targeting donor red cell antigens. Little guidance exists on the management of such patients, particularly in the pediatric setting. First-line conventional treatment is corticosteroids and/or immunoglobulin therapy with monoclonal antibody therapy reserved for treatment failure. We report our experience of a child refractory to immunoglobulin and steroid therapy who required several infusions of rituximab and immunomodulatory therapy to obtain a clinically significant response. PMID- 24168328 TI - Emotion processing in Parkinson's disease: an EEG spectral power study. AB - OBJECTIVE: Although an emotional deficit is a common finding in Parkinson's disease (PD), its neurobiological mechanism on emotion recognition is still unknown. This study examined the emotion processing deficits in PD patients using electroencephalogram (EEG) signals in response to multimodal stimuli. METHOD: EEG signals were investigated on both positive and negative emotions in 14 PD patients and 14 aged-matched normal controls (NCs). The relative power (i.e., ratio of EEG signal power in each frequency band compared to the total EEG power) was computed over three brain regions: the anterior (AF3, F7, F3, F4, F8 and AF4), central (FC5 and FC6) and posterior (T7, P7, O1, O2, P8 and T8) regions for theta (4-8 Hz), alpha (8-13 Hz), beta (13-30 Hz) and gamma (30-60 Hz) frequency sub-bands, respectively. RESULTS: Behaviorally, PD patients showed decreased performance in classifying emotional stimuli as measured by subjective ratings. EEG power at theta, alpha, beta, and gamma bands in all regions were significantly different between the NC and PD groups during both the emotional tasks, with p-values less than 0.05. Furthermore, an increase of relative spectral powers in the theta and gamma bands and a decrease of relative powers in the alpha and beta bands were observed for PD patients compared with NCs during emotional information processing. CONCLUSION: The results suggest the possibility of the existence of a distinctive neurobiological substrate of PD patients during emotional information processing. Also, these distributed spectral powers in different frequency bands might provide meaningful information about emotional processing in PD patients. PMID- 24168327 TI - High-level expression of sugar inducible gene2 (HSI2) is a negative regulator of drought stress tolerance in Arabidopsis. AB - BACKGROUND: HIGH-LEVEL EXPRESSION OF SUGAR INDUCIBLE GENE2 (HSI2), also known as VAL1, is a B3 domain transcriptional repressor that acts redundantly with its closest relative, HSI2-LIKE1 (HSL1), to suppress the seed maturation program following germination. Mutant hsi2 hsl1 seedlings are arrested early in development and differentially express a number of abiotic stress-related genes. To test the potential requirement for HSI2 during abiotic stress, hsi2 single mutants and plants overexpressing HSI2 were subjected to simulated drought stress by withholding watering, and characterized through physiological, metabolic and gene expression studies. RESULTS: The hsi2 mutants demonstrated reduced wilting and maintained higher relative water content than wild-type after withholding watering, while the overexpressing lines displayed the opposite phenotype. The hsi2 mutant displayed lower constitutive and ABA-induced stomatal conductance than wild-type and accumulated lower levels of ABA metabolites and several osmolytes and osmoprotectants following water withdrawal. Microarray comparisons between wild-type and the hsi2 mutant revealed that steady-state levels of numerous stress-induced genes were up-regulated in the mutant in the absence of stress but down-regulated at visible wilting. Plants with altered levels of HSI2 responded to exogenous application of ABA and a long-lived ABA analog, but the hsi2 mutant did not show altered expression of several ABA-responsive or ABA signalling genes 4 hr after application. CONCLUSIONS: These results implicate HSI2 as a negative regulator of drought stress response in Arabidopsis, acting, at least in part, by regulating transpirational water loss. Metabolic and global transcript profiling comparisons of the hsi2 mutant and wild-type plants do not support a model whereby the greater drought tolerance observed in the hsi2 mutant is conferred by the accumulation of known osmolytes and osmoprotectants. Instead, data are consistent with mutants experiencing a relatively milder dehydration stress following water withdrawal. PMID- 24168329 TI - Microbial transformation of acetyl-11-keto-boswellic acid by Cunninghamella elegans. AB - Microbial biotransformation of acetyl-11-keto-boswellic acid by Cunninghamella elegans AS 3.1207 was carried out, and totally four transformed products were isolated. On the basis of the extensive spectral data, their structures were characterized as 7beta-hydroxy-11-keto-boswellic acid (1), 7beta,30-dihydroxy-11 keto-boswellic acid (2), 7beta,16alpha-dihydroxy-3-acetyl-11-keto-boswellic acid (3), and 7beta,15alpha,21beta-trihydroxy-3-acetyl-11-keto-boswellic acid (4), respectively. Among them, products 1 and 2 are the new compounds. PMID- 24168331 TI - The cognitive neuroscience of consciousness. AB - The past decade has seen an explosion of interest in the neural mechanisms underlying consciousness. Experimental approaches from cognitive neuroscience that emphasize converging evidence from multiple methodologies have changed our understanding of how conscious mental states are associated with patterns of brain activity. In this special issue of Cognitive Neuroscience, we bring together five new empirical contributions to this literature plus a new theoretical discussion paper and associated peer commentaries. PMID- 24168330 TI - Diabetes in Argentina: cost and management of diabetes and its complications and challenges for health policy. AB - BACKGROUND: Diabetes is an expensive disease in Argentina as well as worldwide, and its prevalence is continuously rising affecting the quality of life of people with the disease and their life expectancy. It also imposes a heavy burden to the national health care budget and on the economy in the form of productivity losses. AIMS: To review and discuss a) the reported evidence on diabetes prevalence, the degree of control, the cost of care and outcomes, b) available strategies to decrease the health and economic disease burden, and c) how the disease fits in the Argentinian health care system and policy. Finally, to propose evidence-based policy options to reduce the burden of diabetes, both from an epidemiological as well as an economic perspective, on the Argentinian society. The evidence presented is expected to help the local authorities to develop and implement effective diabetes care programmes. METHODOLOGY: A comprehensive literature review was performed using databases such as MEDLINE, EMBASE and LILACS (Latin American and Caribbean Health Sciences). Literature published from 1980 to 2011 was included. This information was complemented with grey literature, including data from national and provincial official sources, personal communications and contacts with health authorities and diabetes experts in Argentina. RESULTS: Overall diabetes prevalence increased from 8.4% in 2005 to 9.6% 2009 at national level. In 2009, diabetes was the seventh leading cause of death with a mortality rate of 19.2 per 100,000 inhabitants, and it accounted for 1,328,802 DALYs lost in the adult population, mainly affecting women aged over fifty. The per capita hospitalisation cost for people with diabetes was significantly higher than for people without the disease, US$ 1,628 vs. US$ 833 in 2004. Evidence shows that implementation of combined educative interventions improved quality of care and outcomes, decreased treatment costs and optimised the use of economic resources. CONCLUSIONS: Based on the evidence reviewed, we believe that the implementation of structured health care programmes including diabetes education at every level, could improve quality of care as well as its clinical, metabolic and economic outcomes. If implemented across the country, these programmes could decrease the disease burden and optimise the use of human and economic resources. PMID- 24168332 TI - Biased figure-ground assignment affects conscious object recognition in spatial neglect. AB - Unilateral spatial neglect is a disorder of attention and spatial representation, in which early visual processes such as figure-ground segmentation have been assumed to be largely intact. There is evidence, however, that the spatial attention bias underlying neglect can bias the segmentation of a figural region from its background. Relatively few studies have explicitly examined the effect of spatial neglect on processing the figures that result from such scene segmentation. Here, we show that a neglect patient's bias in figure-ground segmentation directly influences his conscious recognition of these figures. By varying the relative salience of figural and background regions in static, two dimensional displays, we show that competition between elements in such displays can modulate a neglect patient's ability to recognise parsed figures in a scene. The findings provide insight into the interaction between scene segmentation, explicit object recognition, and attention. PMID- 24168333 TI - Theta-burst transcranial magnetic stimulation to the prefrontal cortex impairs metacognitive visual awareness. AB - We used a recently developed protocol of transcranial magnetic stimulation (TMS), theta-burst stimulation, to bilaterally depress activity in the dorsolateral prefrontal cortex as subjects performed a visual discrimination task. We found that TMS impaired subjects' ability to discriminate between correct and incorrect stimulus judgments. Specifically, after TMS subjects reported lower visibility levels for correctly identified stimuli, as if they were less fully aware of the quality of their visual information processing. A signal detection theory analysis confirmed that the results reflect a change in metacognitive sensitivity, not just response bias. The effect was specific to metacognition; TMS did not change stimulus discrimination performance, ruling out alternative explanations such as TMS impairing visual attention. Together these results suggest that activations in the prefrontal cortex in brain imaging experiments on visual awareness are not epiphenomena, but rather may reflect a critical metacognitive process. PMID- 24168334 TI - Feeling in control of your footsteps: Conscious gait monitoring and the auditory consequences of footsteps. AB - A fundamental aspect of the "I" of conscious experience is that the self is experienced as a single coherent representation of the entire, spatially situated body. The purpose of the present study was to investigate agency for the entire body. We provided participants with performance-related auditory cues and induced online sensorimotor conflicts in free walking conditions investigating the limits of human consciousness in moving agents. We show that the control of full-body locomotion and the building of a conscious experience of it are at least partially distinct brain processes. The comparable effects on agency using audio motor and visuo-motor cues as found in the present and previous agency work may reflect common supramodal mechanisms in conscious action monitoring. Our data may help to refine the scientific criteria of selfhood and are of relevance for the investigation of neurological and psychiatric patients with disturbance of selfhood. PMID- 24168335 TI - Disorders of consciousness: Moving from passive to resting state and active paradigms. AB - Following coma, some patients will recover wakefulness without signs of consciousness (i.e., vegetative state) or may show nonreflexive movements but with no ability for functional communication (i.e., minimally conscious state). Currently, there remains a high rate of misdiagnosis of the vegetative state. The increasing use of fMRI and EEG tools permits the clinical characterization of these patients to be improved. We first discuss "resting metabolism" and "passive activation" paradigms, used in neuroimaging and evoked potential studies, which merely identify neural activation reflecting "automatic" processing-that is, occurring without the patient's willful intervention. Secondly, we present an alternative approach consisting of instructing subjects to imagine well-defined sensory-motor or cognitive-mental actions. This strategy reflects volitional neural activation and, hence, witnesses awareness. Finally, we present results on blood-oxgen-level-dependent "default mode network"/resting state studies that might be a promising tool in the diagnosis of these challenging patients. PMID- 24168336 TI - How neuroscience will change our view on consciousness. AB - Is there consciousness in machines? Or in animals? What happens to consciousness when we are asleep, or in vegetative state? These are just a few examples of the many questions about consciousness that are troubling scientists and laypersons alike. Moreover, these questions share a striking feature: They seem to have been around forever, yet neither science nor philosophy has been able to provide an answer. Why is that? In my view, the main reason is that the study of consciousness is dominated by what we know from introspection and behavior. This has fooled us into thinking that we know what we are conscious of. The scientific equivalent of this is Global Workspace theory. But in fact we don't know what we are conscious of, as I will explain from a simple experiment in visual perception. Once we acknowledge that, it is clear that we need other evidence about the presence or absence of a conscious sensation than introspection or behavior. Assuming the brain has something to do with it, I will demonstrate how arguments from neuroscience, together with theoretical and ontological arguments, can help us resolve what the exact nature of our conscious sensation is. It turns out that we see much more than we think, and that Global Workspace theory is all about access but not about seeing. The exercise is an example of how neuroscience will move us away from psychological intuitions about consciousness, and hence depict a notion of consciousness that may go against our deepest conviction: "My consciousness is mine, and mine alone." It's not. PMID- 24168337 TI - Stage 3 and what we see. AB - Abstract In his article, Lamme provides a neurotheoretical argument that recurrent processing (RP) produces the phenomenological sensations that form the contents of our conscious experiences. Importantly, he argues that this processing includes local intra-areal (i.e., horizontal connections) as well as local inter-areal feedback (i.e., from higher level sensory areas to lower level ones) interactions that occur within the sensory cortices. This has direct implications for what the contents of these experiences may be and the role that neuroscience can play in identifying them. PMID- 24168338 TI - Consciousness minus retrospective mental time travel. AB - Abstract In this paper we apply the concept of mental time travel to introduce the basic features of full-blown conscious experiences (encapsulation in mental models and recollection). We discuss the perspective that Lamme's 'Level 3' experiences can be considered as part of the scope of phenomenological consciousness, in relation to which we emphasize the necessity to consider the different degrees of consciousness and how a particular situation compares to the conscious experiences present in resting states of wakefulness. PMID- 24168339 TI - Explaining seeing? Disentangling qualia from perceptual organization. AB - Abstract Visual perception and integration seem to play an essential role in our conscious phenomenology. Relatively local neural processing of reentrant nature may explain several visual integration processes (feature binding or figure ground segregation, object recognition, inference, competition), even without attention or cognitive control. Based on the above statements, should the neural signatures of visual integration (via reentrant process) be non-reportable phenomenological qualia? We argue that qualia are not required to understand this perceptual organization. PMID- 24168340 TI - How consciousness will change our view on neuroscience. AB - Abstract Victor Lamme proposed that the study of consciousness should not be based on introspection. Nevertheless, Lamme understands consciousness as a subjective phenomenon, and introspection as the way in which we acquire knowledge about consciousness. This makes the task to find introspective-free methods to study consciousness difficult. Lamme attempts to make progress by introducing "neural arguments," but fails to show how such arguments are independent of introspective methods which seem necessary in order to decide how any neural process relates to mental phenomena. This commentary paper thus aims to show that our understanding of neural correlates is shaped by introspection. PMID- 24168341 TI - Electrophysiological evidence for phenomenal consciousness. AB - Abstract Recent evidence from event-related brain potentials (ERPs) lends support to two central theses in Lamme's theory. The earliest ERP correlate of visual consciousness appears over posterior visual cortex around 100-200 ms after stimulus onset. Its scalp topography and time window are consistent with recurrent processing in the visual cortex. This electrophysiological correlate of visual consciousness is mostly independent of later ERPs reflecting selective attention and working memory functions. Overall, the ERP evidence supports the view that phenomenal consciousness of a visual stimulus emerges earlier than access consciousness, and that attention and awareness are served by distinct neural processes. PMID- 24168342 TI - Neural theories need to account for, not discount, introspection and behavior. AB - Abstract A satisfying neuroscience of consciousness must account for phenomenological properties in terms of neural properties. While pursuing this project may challenge our intuitions about what we are conscious of, evidence from behavior and introspection should not be discounted. All three lines of evidence need to be integrated in order to naturalize phenomenal experience. PMID- 24168343 TI - Localized phenomenology: A recurrent debate. AB - Abstract The neuroscience carried out by Lamme and colleagues is fascinating and important. But his case for localised phenomenology rests on a flawed understanding of rival theories and a misguided view of introspective report. PMID- 24168344 TI - Experiencing more complexity than we can tell. AB - Abstract The notion of unreportable conscious contents is misguidedly premised on the idea that access necessarily follows phenomenal representation. We suggest instead that conscious experience should be viewed as a constructive, dynamical process that involves representational redescription: The brain continuously and unconsciously performs signal detection on its own representations, so developing an understanding of itself that subtends conscious experience. Cases where phenomenality seems to overflow access are thus illusory and depend on interactions between task instructions and stimulus complexity. We support this perspective through recent evidence suggesting that properly graded, qualitative subjective reports appear to be exhaustive in revealing conscious knowledge. PMID- 24168345 TI - Is recurrent processing necessary and/or sufficient for consciousness? AB - Abstract Abstract While we agree with Lamme's general framework, we are not so convinced by his mapping between psychological concepts with their underlying neuronal mechanisms. Specifically, we doubt if recurrent processing is either necessary or sufficient for consciousness. A gist of a scene may be consciously perceived by purely feedforward, without recurrent, processing. Neurophysiological studies of perceptual suppression show recurrent processing in visual cortex for consciously invisible objects. While the neuronal correlates of attention and consciousness remain to be clarified, we agree with Lamme that these two processes are independent, evinced by our recent demonstration of opposing effects of attention and consciousness. PMID- 24168346 TI - What introspection has to offer, and where its limits lie. AB - A proper science of consciousness combines all the available evidence - either coming from introspection, behavior, neuroscience or theory - in such a way that a 'best of all worlds' perspective is attained. Introspection shows us that qualia are all about perceptual organization. Neuroscience can then tell us where and when perceptual organization occurs, and whether this is independent of attention, access or report. Access, no matter in what guise it comes, remains ill-suited to explain where, when and how qualia emerge. PMID- 24168347 TI - The effect of condoms on penile vibrotactile sensitivity thresholds in young, heterosexual men. AB - INTRODUCTION: Investigating the ways in which barrier methods such as condoms may affect penile sensory thresholds has potential relevance to the development of interventions in men who experience negative effects of condoms on sexual response and sensation. A quantitative, psychophysiological investigation examining the degree to which sensations are altered by condoms has, to date, not been conducted. AIM: The objective of this study was to examine penile vibrotactile sensitivity thresholds in both flaccid and erect penises with and without a condom while comparing men who do and those who do not report condom associated erection problems (CAEP). METHODS: Penile vibrotactile sensitivity thresholds were assessed among a total of 141 young, heterosexual men using biothesiometry. An incremental two-step staircase method was used and repeated three times for each of four conditions. Intra-class correlation coefficients (ICCs) were calculated for all vibratory assessments. Penile vibratory thresholds were compared using a mixed-model analysis of variance. MAIN OUTCOME MEASURES: Penile vibrotactile sensitivity thresholds with and without a condom, erectile function measured by International Index of Erectile Function Questionnaire, and self-reported degree of erection. RESULTS: Significant main effects of condoms (yes/no) and erection (yes/no) were found. No main or interaction effects of CAEP were found. Condoms were associated with higher penile vibrotactile sensitivity thresholds (F[1,124] = 17.11, P < 0.001). Penile vibrotactile thresholds were higher with an erect penis than with a flaccid penis (F[1,124] = 4.21, P = 0.042). CONCLUSION: The current study demonstrates the feasibility of measuring penile vibratory thresholds with and without a condom in both erect and flaccid experimental conditions. As might be expected, condoms increased penile vibrotactile sensitivity thresholds. Interestingly, erections were associated with the highest thresholds. Thus, this study was the first to document that erect penises are less sensitive to vibrotactile stimulation than flaccid penises. PMID- 24168348 TI - Metal-free [3 + 2 + 1]/[2 + 2 + 1] biscyclization: stereospecific construction with concomitant functionalization of indolizin-5(1H)-one. AB - A metal-free [3 + 2 + 1]/[2 + 2 + 1] biscyclization strategy has been developed for the stereospecific construction with concomitant derivation of biologically significant indolizin-5(1H)-ones from simple and commercial starting materials. The transformations are notable because they can yield five new sigma bonds and six stereocenters including a quaternary carbon center in a single operation. PMID- 24168349 TI - Specialized pediatric palliative home care: a prospective evaluation. AB - OBJECTIVES: In Germany since 2007 children with advanced life-limiting diseases are eligible for Pediatric Palliative Home Care (PPHC), which is provided by newly established specialized PPHC teams. The objective of this study was to evaluate the acceptance and effectiveness of PPHC as perceived by the parents. METHODS: Parents of children treated by the PPHC team based at the Munich University Hospital were eligible for this prospective nonrandomized study. The main topics of the two surveys (before and after involvement of the PPHC team) were the assessment of symptom control and quality of life (QoL) in children; and the parents' satisfaction with care, burden of patient care (Hausliche Pflegeskala, home care scale, HPS), anxiety and depression (Hospital Anxiety and Depression Scale, HADS), and QoL (Quality of Life in Life-Threatening Illness Family Carer Version, QOLLTI-F). RESULTS: Of 43 families newly admitted to PPHC between April 2011 and June 2012, 40 were included in the study. The median interval between the first and second interview was 8.0 weeks. The involvement of the PPHC team led to a significant improvement of children's symptoms and QoL (P<0.001) as perceived by the parents; and the parents' own QoL and burden relief significantly increased (QOLLTI-F, P<0.001; 7-point change on a 10-point scale), while their psychological distress and burden significantly decreased (HADS, P<0.001; HPS, P<0.001). CONCLUSIONS: The involvement of specialized PPHC appears to lead to a substantial improvement in QoL of children and their parents, as experienced by the parents, and to lower the burden of home care for the parents of severely ill children. PMID- 24168350 TI - Australian survey of current practice and guideline use in adult cancer pain assessment and management: perspectives of palliative care physicians. AB - BACKGROUND: Cancer pain continues to be undertreated, despite the availability of evidence-based guidelines. The Australian National Pain Strategy identified establishment of systems and guidelines to adequately manage cancer pain as a high priority. OBJECTIVES: This study aimed to identify barriers and facilitators to adult cancer pain assessment and management as perceived by Australian health professionals; establish the perceived need for new Australian guidelines and implementation strategies; identify which guidelines are used; and identify barriers and facilitators to guideline use. This article focuses on the perceptions of responding palliative care physicians. DESIGN: A cross-sectional survey was administered online. PARTICIPANTS: Invitations were circulated via peak bodies and clinical leaders. Comments were coded independently by two researchers. RESULTS: Ninety-two palliative care physicians responded to the survey; 39% of the national total. The majority reported barriers to pain management, including insufficient access to nonpharmacologic interventions, poor coordination between services, and management challenges posed by comorbidities. Forty-five percent reported using pain guidelines, most commonly the Australian Therapeutic Guidelines-Palliative Care. Respondents were largely supportive of the development of new Australian guidelines and implementation strategies, in particular any offering advice on specific cases of cancer pain (e.g., neuropathic), patient self-management resources, assessment of patient priorities, and disciplinary roles. CONCLUSION: Barriers to evidence-based practice identified by our survey might be addressed via strategies to support decision making and coordination of care (e.g., a clinical pathway). Particular attention should be paid to promoting access to nonpharmacologic interventions and patient education, and improving referral and care coordination. PMID- 24168351 TI - Isolation and identification of phenolic compounds accumulated in brown rice grains ripened under high air temperature. AB - This study aimed to examine the compounds increasing or decreasing in concentration in brown rice grains ripened under high air temperature during ripening using a heat-tolerant cultivar Fusaotome, a heat-intolerant cultivar Hatsuboshi, and an intermediate cultivar Koshihikari. 6-O-Feruloylsucrose (1), 3',6-di-O-sinapoylsucrose (2), 3'-O-sinapoyl-6-O-feruloylsucrose (3), 3',6-di-O feruloylsucrose (4), cycloartenyl ferulate (5), and 24-methylenecycloartanyl ferulate (6) were isolated from the extracts of brown rice grains. The structures of the isolated compounds (1-6) were elucidated on the basis of spectroscopic analyses. The mean concentrations of compounds 2, 3, and 6 in the grains ripened under high air temperature were markedly higher than those ripened under normal air temperature. In contrast, the mean concentration of compound 5 in the grains ripened under high air temperature was markedly lower than those ripened under normal air temperature. Thus, compounds 2, 3, 5, and 6 constitute potential biomarkers of heat stress in the cultivars used. The mean concentrations of compound 4 in the grains of Fusaotome were the highest in all cultivars. In contrast, the mean concentration of compound 5 in the grains of Fusaotome was the lowest. Therefore, the unique composition of heat-tolerant Fusaotome combines a high concentration of compound 4 with a low concentration of compound 5. PMID- 24168352 TI - Widespread decreased expression of immune function genes in human peripheral blood following radiation exposure. AB - We report a large-scale reduced expression of genes in pathways related to cell type specific immunity functions that emerges from microarray analysis 48 h after ex vivo gamma-ray irradiation (0, 0.5, 2, 5, 8 Gy) of human peripheral blood from five donors. This response is similar to that seen in patients at 24 h after the start of total-body irradiation and strengthens the rationale for the ex vivo model as an adjunct to human in vivo studies. The most marked response was in genes associated with natural killer (NK) cell immune functions, reflecting a relative loss of NK cells from the population. T- and B-cell mediated immunity genes were also significantly represented in the radiation response. Combined with our previous studies, a single gene expression signature was able to predict radiation dose range with 97% accuracy at times from 6-48 h after exposure. Gene expression signatures that may report on the loss or functional deactivation of blood cell subpopulations after radiation exposure may be particularly useful both for triage biodosimetry and for monitoring the effect of radiation mitigating treatments. PMID- 24168354 TI - Worming their way into shape: toroidal formations in micellar solutions. AB - We report the formation of nanostructured toroidal micellar bundles (nTMB) from a semidilute wormlike micellar solution, evidenced by both cryogenic-electron microscopy and transmission electron microscopy images. Our strategy for creating nTMB involves a two-step protocol consisting of a simple prestraining process followed by flow through a microfluidic device containing an array of microposts, producing strain rates in the wormlike micelles on the order of 10(5) s(-1). In combination with microfluidic confinement, these unusually large strain rates allow for the formation of stable nTMB. Electron microscopy images reveal a variety of nTMB morphologies and provide the size distribution of the nTMB. Small angle neutron scattering indicates the underlying microstructural transition from wormlike micelles to nTMB. We also show that other flow-induced approaches such as sonication can induce and control the emergence of onion-like and nTMB structures, which may provide a useful tool for nanotemplating. PMID- 24168355 TI - Cibacron blue immobilized poly(glycidyl-methacrylate) nanobeads for albumin removal in proteome studies. AB - A new approach to albumin removal for proteome studies involving human plasma samples was presented with dye affinity poly glycidyl methacrylate (PGMA) nanobeads in an average size of 45 nm. The specific surface area of PGMA nanobeads was calculated as 2616 m(2)/g. Cibacron Blue F3GA (CB) was immobilized onto PGMA nanobeads as dye ligand, and CB immobilized PGMA (CB-PGMA) nanobeads were characterized by a serial processing. Albumin depletion efficiency of CB PGMA nanobeads was investigated in human plasma sample and confirmed by two dimensional gel electrophoresis. PMID- 24168356 TI - Hallermann-Streiff syndrome with cutaneous manifestations. PMID- 24168358 TI - Circumportal pancreas: rarely seen often missed. PMID- 24168359 TI - An integrative technique based on synergistic coremoval and sequential recovery of copper and tetracycline with dual-functional chelating resin: roles of amine and carboxyl groups. AB - A novel chelating resin (R-AC) bearing dual-functional groups (amino and carboxyl groups) was self-synthesized and it showed superior properties on synergistic coremoval of Cu(II) and tetracycline (TC) to commercial resins (amine, carboxyl, and hydrophobic types), which was deeply investigated by equilibrium and kinetic tests in binary, preloading, and saline systems. The adsorption of TC on R-AC was markedly enhanced when coexisted with Cu(II), up to 13 times of that in sole system, whereas Cu(II) uptake seldom decreased in the copresence of TC. Decomplexing-bridging, which included [Cu-TC] decomplexing and [R-Cu] bridging for TC, was demonstrated as the leading mechanism for the synergistic coremoval of Cu(II) and TC. Carboxyl groups of R-AC played a dominant role in decomplexing of [Cu-TC] complex and releasing free TC. Cu(II) coordinated with amine groups of R-AC was further proved to participate in bridging interaction with free TC, and the bridging stoichiometric ratio ([NH-Cu]: TC) possibly was 2:1. About 96.9% of TC and 99.3% of Cu could be sequentially recovered with dilute NaOH followed by HCl. Considering stable application for five cycles in simulated and practical wastewater, R-AC shows great potential in green and simple coremoval of antibiotic and heavy metal ions. PMID- 24168360 TI - Polymeric nanocarriers for magnetic targeted drug delivery: preparation, characterization, and in vitro and in vivo evaluation. AB - In this paper the preparation of magnetic nanocarriers (MNCs), containing superparamagnetic domains, is reported, useful as potential magnetically targeted drug delivery systems. The preparation of MNCs was performed by using the PHEA-IB p(BMA) graft copolymer as coating material through the homogenization-solvent evaporation method. Magnetic and nonmagnetic nanocarriers containing flutamide (FLU-MNCs) were prepared. The prepared nanocarriers have been exhaustively characterized by dynamic light scattering (DLS), transmission electron microscopy (TEM), and magnetic measurements. Biological evaluation was performed by in vitro cytotoxicity and cell uptake tests and in vivo biodistribution studies. Magnetic nanocarriers showed dimensions of about 300 nm with a narrow size distribution, an amount of loaded FLU of 20% (w/w), and a superparamagnetic behavior. Cell culture experiments performed on prostate cancer cell line LNCaP demonstrated the cytotoxic effect of FLU-MNCs. In vivo biodistribution studies carried out by the application of an external magnetic field in rats demonstrated the effect of the external magnet on modifying the biodistribution of FLU-MNCs. FLU-MNCs resulted efficiently internalized by tumor cells and susceptible to magnetic targeting by application of an external magnetic field. The proposed nanocarriers can represent a very promising approach to obtain an efficient magnetically targeted anticancer drug delivery system. PMID- 24168362 TI - Editorial: molecular targeting for development of novel therapeutic strategies in brain diseases: myth or reality?). PMID- 24168363 TI - Mitochondrial neuroprotection in traumatic brain injury: rationale and therapeutic strategies. AB - Traumatic brain injury (TBI) is still the worldwide, leading cause of mortality and morbidity in young adults. The prognosis of TBI patients is strongly affected by secondary brain damage including mitochondrial dysfunctions. In many basic and clinical studies, mitochondrial dysfunctions, including the opening of mitochondrial permeability transition (mPT) pore, and treatments including cyclosporine A (CsA) have been studied. These evidences suggest an important role for mitochondria as therapeutic targets for neuroprotection after TBI. This review summarizes the data about normal and pathological mitochondrial function after TBI, TBI pathobiology relating to mitochondrial dysfunction and therapeutic strategies including drug treatment. This review also mentioned about glucose, lactate, and pyruvate metabolisms in TBI, including the "astrocyte-neuron lactate shuttle (ANLS)" hypothesis. Mitochondrial pathophysiology in TBI is still unclear. Thus, the pharmacological treatment in TBI patient is still challenging. This review could help further understanding of this topic. Hopefully, this could help further development and innovation for drug therapies in TBI. PMID- 24168364 TI - Positive allosteric modulators (PAMs) of metabotropic glutamate receptor 5 (mGluR5) attenuate microglial activation. AB - Traumatic brain injury causes progressive neurodegeneration associated with chronic microglial activation. Recent studies show that neurodegeneration and neuroinflammation after traumatic brain injury can be inhibited as late as one month in animals by the activation of the metabotropic glutamate receptor 5 in microglia using (RS)-2-chloro-5- hydroxy-phenylglycine. However, the therapeutic potential of this agonist is limited due to its relatively weak potency and brain permeability. To address such concerns, we evaluated the anti-inflammatory activities of several positive allosteric modulators using various in vitro assays, and found that 3,3'-difluorobenzaldazine, 3-cyano-N-(1,3-diphenyl-1H pyrazol- 5-yl)benzamide and 4-nitro-N-(1-(2-fluorophenyl)-3-phenyl-1H-pyrazol-5 yl)benzamide showed significantly improved potency which makes them potential lead compounds for further development of positive allosteric modulators for the treatment of traumatic brain injury. PMID- 24168361 TI - Biomaterial strategies for stem cell maintenance during in vitro expansion. AB - Stem cells, having the potential for self-renewal and multilineage differentiation, are the building blocks for tissue/organ regeneration. Stem cells can be isolated from various sources but are, in general, available in too small numbers to be used directly for clinical purpose without intermediate expansion procedures in vitro. Although this in vitro expansion of undifferentiated stem cells is necessary, stem cells typically diminish their ability to self-renew and proliferate during passaging. Consequently, maintaining the stemness of stem cells has been recognized as a major challenge in stem cell based research. This review focuses on the latest developments in maintaining the self-renewal ability of stem cells during in vitro expansion by biomaterial strategies. Further, this review highlights what should be the focus for future studies using stem cells for regenerative applications. PMID- 24168365 TI - Involvement of the mitochondrial benzodiazepine receptor in traumatic brain injury: therapeutic implications. AB - Traumatic brain injuries represent the leading cause of death and morbidity in young adults in western countries, and are responsible for a major social and economical burden. For decades, the mainstay of neurotrauma management has been represented by control of post-traumatic edema. With the emergence of a better understanding of the underlying cellular mechanisms responsible for the generation of secondary brain damage, the hope for the "magic bullet" has prompted the development of novel drugs that have repeatedly failed to significantly improve outcome of head-injured patients. During the past decade, mitochondrial functional and structural impairment has emerged as a pivotal event in the pathway of cell to secondary death. Extensive research has identified a vast range of deleterious signals that are generated and integrated at the mitochondrial level resulting in impairment of major mitochondrial functions such as calcium homeostasis, free radicals generation and detoxification, energy production and neurosteroidogenesis. Mitochondria have therefore emerged as a potential therapeutic target. Within the spectrum of major mitochondrial structural components, the 18 kDa translocator protein (TSPO) has shown important and relevant functions such as steroid synthesis and modulation of the mitochondrial permeability transition that may substantially affect the fate of injured cells. This review summarizes the potential therapeutic implications of TSPO modulation in traumatic brain injury in the view of the current knowledge on this intriguing mitochondrial complex. PMID- 24168366 TI - Subcellular injuries in Alzheimer's disease. AB - Alzheimer's disease (AD) is the most common form of dementia occurring in the elderly. Several hypotheses have been proposed to explain the pathophysiology of AD, including amyloidogenesis, disruption of calcium homeostasis, energetic failure, induction of oxidative stress, and hyperphosphorylation of tau protein. This review examines associations between cellular and subcellular injuries, neurodegeneration, and cell death in experimental models, clinical symptoms, and autopsy reports of AD to identify the subcellular events leading to disease onset and progression. The order in which these events occur is discussed. The first injuries reported in AD are subcellular and occur at the Golgi apparatus before any beta-amyloid proteins deposit in the Golgi and endosomes. This is followed by lysosomal alterations and the inability of cells to clear beta-amyloid. The next stage reveals functional changes and modifications in hippocampal synaptic transmission before structural changes are observed at the cellular level. Subsequently, an extensive intracellular inflammatory process develops in neurons and astrocytes. This inflammatory reaction begins in the nucleus, endoplasmic reticulum, endosomes and mitochondria, and is thought to lead to neurodegeneration and cell death. Finally, the neuroinflammatory response of chronically activated microglia escalates the neurodegeneration and cell death. Identifying the detailed sequence of subcellular events induced by the primum movens defect in AD may lead to the identification of novel drug targets for the treatment of the disease. PMID- 24168367 TI - Novel approach to the role of NMDA receptors in traumatic brain injury. AB - For more than two decades the intensive research effort on the role of NMDA receptors (NMDAR) in traumatic brain injury (TBI) and cerebral ischemia (stroke) was led by the observations that extracellular concentrations of glutamate and aspartate are elevated after the insult and play a major role in brain pathologies. Indeed, NMDAR antagonists were shown to improve post-injury recovery in animal models and subsequently, large scale placebo-controlled clinical trials in TBI and stroke were performed with NMDAR antagonists. However, all these trials have demonstrated either no benefit or even deleterious effects. The discrepancy between the animal and human studies prompted us to investigate the temporal changes of the NMDAR after brain insult in TBI and stroke mouse models. We found that the early hyperactivation of the NMDAR is followed by loss of functional NMDAR which persists for weeks. Such dynamic changes could well explain the discrepancies between the preclinical and clinical experience as well as suggest alternative modes of treatment, namely, activation, rather than blockade of the NMDAR in the sub-acute period after TBI and stroke. Stimulation of the glycine modulatory site of the glycine/NMDAR by the partial agonist Dcycloserine (DCS) when given at least 24 hrs after TBI or stroke was shown to improve recovery of neurobehavioral and cognitive functions. It was also shown to restore impaired hippocampal Long-Term potentiation (LTP) and induce expression of Brain Derived-Neurotrophic Factor (BDNF) in a TBI model and to improve somatosensory and cognitive function in a stroke model. Experiments to optimize the DCS treatment paradigm showed that similar benefits were demonstrated in TBI mice whether the drug was given as a single injection at 24 or 72 hrs post injury, or as double (24 and 48 hrs) or triple (24, 48 and 72 hrs) doses. Interestingly, beneficial effects of DCS were reported in a range of animal models of human diseases as well as in several clinical indications thought to involve disruptions in NMDAR function, such as drug addiction, post-traumatic stress disorder, Parkinson's disease, aging and psychiatric disorders. As DCS has a good safety profile, and is already in use in humans in several different indications, and based on studies with DCS in the mouse TBI model, a multi-center prospective randomized controlled clinical trial, aiming to assess the effect of a single dose of DCS on cognitive outcome in patients with moderate TBI has recently begun. PMID- 24168368 TI - alpha-Synuclein ubiquitination and novel therapeutic targets for Parkinson's disease. AB - Accumulation of alpha-synuclein is key to the pathogenesis of Parkinson's disease (PD), though the exact mechanisms involved in its toxicity are still subject to debate. Increased alpha-synuclein expression or reduced degradation may play a role in the proteotoxicity observed in PD. Here we review the mechanisms of alpha synuclein ubiquitination by different E3 ubiquitin-ligases, and its degradation via the proteasome, autophagy and lysosomes. Activators of alpha- synuclein ubiquitination and degradation pathways represent a plausible strategy to decrease alpha-synuclein burden in the disease. Nevertheless, since proteasomes and autophagy might be impaired in the disease, and because proteolytic impairment causes the accumulation of monoubiquitinated alpha-synuclein and the formation of toxic inclusions, compounds that promote alpha-synuclein monoubiquitination should be used in concert with compounds that boost these proteolytic pathways. This combined approach may therefore ease the accumulation of alpha-synuclein in PD and may represent a promising new avenue for the development of novel treatments for the disease. PMID- 24168369 TI - Concentration-dependent bimodal effect of specific 18 kDa translocator protein (TSPO) ligands on cell death processes induced by ammonium chloride: potential implications for neuropathological effects due to hyperammonemia. AB - The role of the 18-kDa Translocator Protein (TSPO) in cell death induced by NH4Cl (1-50 mM) for 24-72 hours to human glioblastoma U118MG cells was investigated. Cell death was already observed after 48 hours of treatment with NH4Cl at 5 mM. Dose and time-responses curves indicated that 15 mM of NH4Cl applied for 72 hours was the optimal condition for our viability assays. For example, 72 hours of 15 mM of NH4Cl caused a 50.3% increase in propidium iodide uptake, and lactate dehydrogenase release was 41.2% of the positive control, indicating significant increases in cell death. Furthermore, compared to vehicle control, these experimental conditions resulted in a significant decrease of 44.9% of the mitochondrial activity, a 62.3% increase in incidence of collapse of mitochondrial membrane potential, and an increase of 49.0% of cardiolipin peroxidation. In addition, a significant 4.3 fold increase in the maximal binding capacity (Bmax) of TSPO was found in NH4Cl-exposed cells. Surprisingly, western blot analysis and real-time PCR did not demonstrate changes in TSPO expression. We also found that neither NH4Cl nor glutamine (a metabolic product of enhanced NH4Cl levels) inhibited binding of the TSPO ligand [(3)H]PK 11195. Interestingly, we observed a bimodal effect of the TSPO ligands PK 11195, Ro5-4864, and FGIN-1 27 on the toxicity of NH4Cl; such that 1-100 nM concentrations of TSPO ligands were protective, while concentrations above 1 MUM enhanced NH4Cl-induced cell death processes. In conclusion, TSPO takes part in a bimodal way in the lethal effects induced by NH4Cl in glial type cells. PMID- 24168371 TI - Melatonin prevents pancreatic beta-cell loss due to glucotoxicity: the relationship between oxidative stress and endoplasmic reticulum stress. AB - Prolonged hyperglycemia results in pancreatic beta-cell dysfunction and apoptosis, referred to as glucotoxicity. Although both oxidative and endoplasmic reticulum (ER) stresses have been implicated as major causative mechanisms of beta-cell glucotoxicity, the reciprocal importance between the two remains to be elucidated. The aim of this study was to evaluate the differential effect of oxidative stress and ER stress on beta-cell glucotoxicity, by employing melatonin which has free radical-scavenging and antioxidant properties. As expected, in beta-cells exposed to prolonged high glucose levels, cell viability and glucose stimulated insulin secretion (GSIS) were significantly impaired. Melatonin treatment markedly attenuated cellular apoptosis by scavenging reactive oxygen species via its plasmalemmal receptor-independent increase in antioxidant enzyme activity. However, treatments with antioxidants alone were insufficient to recover the impaired GSIS. Interestingly, 4-phenylbutyric acid (4-PBA), a chemical chaperone that attenuate ER stress by stabilizing protein structure, alleviated the impaired GSIS, but not apoptosis, suggesting that glucotoxicity induces oxidative and ER stress independently. We found that cotreatment of glucotoxic beta-cells with melatonin and 4-PBA dramatically improved both their survival and insulin secretion. Taken together, these results suggest that ER stress may be the more critical mechanism for prolonged high-glucose-induced GSIS impairment, whereas oxidative stress appears to be more critical for the impaired beta-cell viability. Therefore, combinatorial therapy of melatonin with an ER stress modifier may help recover pancreatic beta-cells under glucotoxic conditions in type 2 diabetes. PMID- 24168370 TI - Ex vivo tetramer staining and cell surface phenotyping for early activation markers CD38 and HLA-DR to enumerate and characterize malaria antigen-specific CD8+ T-cells induced in human volunteers immunized with a Plasmodium falciparum adenovirus-vectored malaria vaccine expressing AMA1. AB - BACKGROUND: Malaria is responsible for up to a 600,000 deaths per year; conveying an urgent need for the development of a malaria vaccine. Studies with whole sporozoite vaccines in mice and non-human primates have shown that sporozoite induced CD8+ T cells targeting liver stage antigens can mediate sterile protection. There is a need for a direct method to identify and phenotype malaria vaccine-induced CD8+ T cells in humans. METHODS: Fluorochrome-labelled tetramers consisting of appropriate MHC class I molecules in complex with predicted binding peptides derived from Plasmodium falciparum AMA-1 were used to label ex vivo AMA 1 epitope specific CD8+ T cells from research subjects responding strongly to immunization with the NMRC-M3V-Ad-PfCA (adenovirus-vectored) malaria vaccine. The identification of these CD8+ T cells on the basis of their expression of early activation markers was also investigated. RESULTS: Analyses by flow cytometry demonstrated that two of the six tetramers tested: TLDEMRHFY: HLA-A*01:01 and NEVVVKEEY: HLA-B*18:01, labelled tetramer-specific CD8+ T cells from two HLA A*01:01 volunteers and one HLA-B*18:01 volunteer, respectively. By contrast, post immune CD8+ T cells from all six of the immunized volunteers exhibited enhanced expression of the CD38 and HLA-DRhi early activation markers. For the three volunteers with positive tetramer staining, the early activation phenotype positive cells included essentially all of the tetramer positive, malaria epitope specific CD8+ T cells suggesting that the early activation phenotype could identify all malaria vaccine-induced CD8+ T cells without prior knowledge of their exact epitope specificity. CONCLUSIONS: The results demonstrated that class I tetramers can identify ex vivo malaria vaccine antigen-specific CD8+ T cells and could therefore be used to determine their frequency, cell surface phenotype and transcription factor usage. The results also demonstrated that vaccine antigen-specific CD8+ T cells could be identified by activation markers without prior knowledge of their antigen-specificity, using a subunit vaccine for proof of-concept. Whether, whole parasite or adjuvanted protein vaccines will also induce {CD38 and HLA-DRhi}+ CD8+ T cell populations reflective of the antigen specific response will the subject of future investigations. PMID- 24168372 TI - Golden berry juice attenuates the severity of hepatorenal injury. AB - The aim of the present work is to investigate the potential of Physalis peruviana fruits as a hepatorenal protective agent against carbon tetrachloride (CCl4) induced hepatic and renal fibrosis. The phytochemical screening test revealed the presence of alkaloids, free withanolides, glycowithanolides, and flavonoids. Acute toxicity study (500, 1000, and 1500 mg/kg body weight) revealed extract safety. The biological evaluation was conducted on different animal groups: control, control treated with fruit, CCl4 group, CCl4 treated with fruit, and CCl4 treated with silymarin drug. The evaluation was done through measuring oxidative stress markers: malondialdehyde (MDA), superoxide dismutase (SOD), and nitric oxide (NO). Liver function indices such as aspartate and alanine aminotransferases (AST & ALT), alkaline phosphatase (ALP), gamma glutamyl transferase (GGT), bilirubin, and total protein were estimated. Kidney disorder biomarkers such as creatinine, urea, and serum protein were also evaluated. Treatment improved all the investigated parameters, and the histopathological analysis confirmed our results. In conclusion, Physalis peruviana fruit succeeded to protect liver and kidney against fibrosis. Further studies are needed to identify the molecules responsible for its pharmacological application. PMID- 24168373 TI - Observer ratings of neighborhoods: comparison of two methods. AB - BACKGROUND: Although neighborhood characteristics have important relationships with health outcomes, direct observation involves imperfect measurement. The African American Health (AAH) study included two observer neighborhood rating systems (5-item Krause and 18-item AAH Neighborhood Assessment Scale [NAS]), initially fielded at two different waves. Good measurement characteristics were previously shown for both, but there was more rater variability than desired. In 2010 both measures were re-fielded together, with enhanced training and field methods implemented to decrease rater variability while maintaining psychometric properties. METHODS: AAH included a poor inner city and more heterogeneous suburban areas. Four interviewers rated 483 blocks, with 120 randomly-selected blocks rated by two interviewers. We conducted confirmatory factor analysis of scales and tested the Krause (5-20 points), AAH 18-item NAS (0-28 points), and a previous 7-item and new 5-item versions of the NAS (0-17 points, 0-11 points). Retest reliability for items (kappa) and scales (Intraclass Correlation Coefficient [ICC]) were calculated overall and among pre-specified subgroups. Linear regression assessed interviewer effects on total scale scores and assessed concurrent validity on lung and lower body functions. Mismeasurement effects on self-rated health were also assessed. RESULTS: Scale scores were better in the suburbs than in the inner city. ICC was poor for the Krause scale (ICC=0.19), but improved if the retests occurred within 10 days (ICC=0.49). The 7- and 5-item NAS scales had better ICCs (0.56 and 0.62, respectively), and were higher (0.71 and 0.73) within 10 days. Rater variability for the Kraus and 5- and 7-item NAS scales was 1-3 points (compared to the supervising rater). Concurrent validity was modest, with residents living in worse neighborhood conditions having worse function. Unadjusted estimates were biased towards the null compared with measurement-error corrected estimates. CONCLUSIONS: Enhanced field protocols and rater training did not improve measurement quality. Specifically, retest reliability and interviewer variability remained problematic. Measurement error partially reduced, but did not eliminate concurrent validity, suggesting there are robust associations between neighborhood characteristics and health outcomes. We conclude that the 5-item AAH NAS has sufficient reliability and validity for further use. Additional research on the measurement properties of environmental rating methods is encouraged. PMID- 24168374 TI - Prognosis of AKI in malignant diseases with and without sepsis. AB - BACKGROUND: AKI significantly worsens prognosis of hospitalized patients. This is particularly the case in patients with sepsis. The risk for aquiring sepsis is significantly increased in malignant diseases. Aim of the present retrospective study was to analyze outcomes of tumor patients with sepsis and AKI. METHODS: One thousand and seventeen patients, treated at the ICU of the Department of Nephrology and Rheumatology of the University Hospital Gottingen from 2009 to 2011 were retrospectively analyzed for mortality, sepsis, AKI, need for renal replacement therapy (dialysis) and malignancies. RESULTS: AKI occurred significantly more frequent in septic than in non-septic patients and in tumor as oposed to non-tumor patients. Mortaliy rates were higher in the respective latter groups. Mortality increased even further if patients suffered from a malignant disease with sepsis and AKI. Mortality rates peaked if dialysis treatment became mandatory. In non-solid tumors 100% of the patients died if they suffered drom sepsis and AKI. This was not the case in solid malignancies (mortality rate 56%). CONCLUSIONS: We conclude that prognosis of tumor patients with AKI and sepsis is very poor. Mortality increases to almost 70% if diaylsis therapy is initiated. Non-solid tumors are associated with a 100% mortality if sepsis and AKI conincide. PMID- 24168375 TI - Re-starting a neural race: anti-saccade correction. AB - In the anti-saccade task, a subject must make a saccadic eye movement in the opposite direction from a suddenly-presented visual target. This sets up a conflict between the natural tendency to make a pro-saccade towards the target and the required anti-saccade. Consequently there is a tendency to make errors, usually corrected by a second movement in the correct anti-saccade direction. In a previous paper, we showed that a very simple model, with racing LATER (Linear Approach to Threshold at Ergodic Rate) units for the pro- and anti-directions, and a stop unit that inhibits the impending error response, could account precisely for the detailed distributions of reaction times both for correct and error responses. However, the occurrence and timing of these final corrections have not been studied. We propose a novel mechanism: the decision race re-starts after an error. Here we describe measurements of all the responses in an anti saccade task, including corrections, in a group of human volunteers, and show that the timing of the corrections themselves can be predicted by the same model with one additional assumption, that initiation of an incorrect pro-saccade also resets and initiates a corrective anti-saccade. No extra parameters are needed to predict this complex aspect of behaviour, adding weight to our proposal that we correct our mistakes by re-starting a neural decision race. The concept of re starting a decision race is potentially exciting because it implies that neural processing of one decision can influence the next, and may be a fruitful way of understanding the complex behaviour underlying sequential decisions. PMID- 24168376 TI - Cognitive Neuroscience: What? Another journal? AB - Yes, another journal! The field of cognitive neuroscience continues to grow and mature, and it is important that publishing outlets continue to grow and mature in order to support the increasing volume of high-quality research. However, it is our intention that Cognitive Neuroscience will offer something genuinely different in terms of content and publishing standards. This editorial sets out the ethos behind the journal and presents some publishing statistics on our first year. PMID- 24168377 TI - Multimodal temporal perception deficits in a patient with left spatial neglect. AB - We examined multisecond time estimation (up to 60 s) for visual and auditory events in a patient with left spatial neglect (RR), who grossly underestimated all durations in all tasks. In contrast, healthy controls and a patient with left hemisphere damage (HW) demonstrated accurate estimates of the same durations. These findings add to a growing body of literature suggesting that neglect cannot be understood simply in terms of a bias in orienting attention to one side of space. In addition, these data suggest that the right hemisphere parietal cortex may be important for the perception of time across multiple modalities. PMID- 24168378 TI - Requirements at retrieval modulate subsequent memory effects: An event-related potential study. AB - Neural indices of memory formation can be acquired by contrasting activity during study for items that are remembered or forgotten on a subsequent memory test. These "subsequent memory" effects vary with the stimulus types that are encoded, how they are encoded, the correspondences between study and test materials, and the time intervals between study and test phases. We investigated whether event related potential (ERP) subsequent memory effects also vary with the content people must retrieve. Participants saw words on the left/right side of fixation, and made a drawing difficulty or pleasantness judgment to each. In separate test phases, participants were asked to remember study screen location, or which task judgment had been made. The ERP subsequent memory effects from these two tasks were functionally distinct, demonstrating for the first time that ERP subsequent memory effects dissociate according to what people are trying to retrieve. PMID- 24168379 TI - Preschoolers' mental rotation of letters: Sex differences in hemispheric asymmetry. AB - Adults' mental rotation performance has been found to produce one of the largest sex differences in cognition accompanied by sex differences in functional cerebral asymmetry. In this study sex differences in mental rotation of letters were investigated with children as young as five years. Based on the electrophysiological brain correlates of mental rotation, we observed a bilateral brain activity for preschool girls whereas the preschool boys' brain activity was clearly lateralized towards the right hemisphere if and only if mental rotation was needed to solve the task. At the same time, we did not find any sex differences in mental rotation speed or accuracy. Thus, sex differences in functional hemispheric asymmetry during mental rotation do not require hormonal changes that occur during puberty. PMID- 24168380 TI - Overclaiming and the medial prefrontal cortex: A transcranial magnetic stimulation study. AB - The tendency to claim more knowledge than one actually has is common and well documented; however, little research has focused on the neural mechanisms that underlie this phenomenon. The goal of the present study was to investigate the cortical correlates of overclaiming. Transcranial magnetic stimulation (TMS) was delivered to the medial prefrontal cortex (MPFC), supplementary motor area, and precuneus during the presentation of a series of words that participants were told made up a cultural IQ test. However, participants were not informed that 50% of the words were actually fabricated. False claiming was reduced following MPFC TMS. Furthermore, reaction time decreases following MPFC TMS indicated that participants engaged in less reflection during the task, suggesting a potential reduction in social monitoring of behavior. PMID- 24168381 TI - Enhanced brain connectivity in math-gifted adolescents: An fMRI study using mental rotation. AB - Mathematical giftedness is a form of intelligence related to enhanced mathematical reasoning that can be tested using a variety of numerical and spatial tasks. A number of neurobiological mechanisms related to exceptional mathematical reasoning ability have been postulated, including enhanced brain connectivity. We aimed to further investigate this possibility by comparing a group of mathematically gifted adolescents with an average math ability control group performing mental rotation of complex three-dimensional block figures. Functional magnetic resonance imaging (fMRI) data were collected and differences in intrahemispheric and interhemispheric connectivity between the groups were assessed using structural equation modeling (SEM). The math-gifted showed heightened intrahemispheric frontoparietal connectivity, as well as enhanced interhemispheric frontal connectivity between the dorsolateral prefrontal and premotor cortex. These enhanced connectivity patterns are consistent with previous studies linking increased activation of the frontal and parietal regions with high fluid intelligence, and may be a unique neural characteristic of the mathematically gifted brain. PMID- 24168382 TI - The right time and the left time: Spatial associations of temporal cues affect target detection in right brain-damaged patients. AB - Humans map timewords such as "yesterday" or "future" onto a mental timeline that holds temporally earlier events on the left side of space and temporally later events on the right side. The perception of time and spatial mapping both are partially subserved by right temporo-parietal brain regions. We tested stroke patients with right-hemisphere lesions on a spatio-temporal cueing task to see whether spatial associations of noninformative temporal cues would elicit the same cognitive deficits as do typical stimulus-driven exogenous cues. While our right brain-damaged patients were able to maintain a mental timeline with words referring to the past sitting to the left and words referring to the future sitting to the right, we also observed that the typical deficit in disengaging from incongruently cued locations persists for noninformative cues that are mapped onto a mental spatial continuum. PMID- 24168384 TI - Purification and modeling amphipathic alpha helical antimicrobial peptides from skin secretions of Euphlyctis cyanophlyctis. AB - Antimicrobial peptides as ancient immune system are found in almost all types of living organisms. Amphibian's skin is an important source of bioactive peptides with strong antibacterial, antiviral, and antitumor properties. They have important role in inducing apoptosis as well as cancer therapy in vitro. In this study, we extracted and purified antimicrobial peptides from skin secretions of Euphlyctis cyanophlyctis and named them brevinin-Eu and cyanophlyctin beta. They showed favorable antibacterial properties on both Gram-positive and Gram-negative bacteria with ignorable hemolytic activity of <1.9% and 0.7% at very high concentrations of brevinin-Eu and cyanophlyctin beta, respectively. For antibacterial activity and MIC determination, two Gram-positive (Staphylococcus aureus PTCC1431 and B. cereus PTCC1247) and two Gram-negative bacteria (Escherichia coli HP101BA 7601c and Klebsiella pneumoniae PTCC1388) were assayed. MIC values of extracted peptides demonstrated that they can inhibit bacterial growth at very low concentration (17 and 12 MUg/mL) for brevinin-Eu and cyanophlyctin beta, respectively. Structural prediction suggested that the brevinin-Eu can efficiently bind and destroy bacterial membrane, but cyanophlyctin beta uses a diverse mode of action. PMID- 24168385 TI - New sesquiterpenoid derivatives from Solanum lyratum and their cytotoxicities. AB - Three new sesquiterpenoid isopropylidene derivatives, named solajiangxins H and I (1 and 2) and 7-hydroxylsolajiangxin I (3), were isolated from the whole plant of Solanum lyratum. Their structures were elucidated on the basis of integrated spectroscopic techniques, mainly HR-FAB-MS, 1D NMR, and 2D NMR ((1)H-(1)H COSY, HMQC, HMBC, and NOESY). In vitro, compounds 1-3 were found to show significant cytotoxicity against three cancer cells (P-388, HONE-1, and HT-29), and gave IC50 values in the range of 3.2-7.7 MUM. PMID- 24168387 TI - Very late relapse of PTLD 10 yr after allogeneic HSCT and nine yr after stopping immunosuppressive therapy. AB - We present a very late onset relapse of PTLD 10 yr after allogeneic HSCT in a patient in third remission for ALL, nine yr after the first episode of PTLD. The recipient was conditioned with fractionated TBI 12 Gy, cyclophosphamide, and horse ATG. The first episode of PTLD with a large retroperitoneal tumor occurred one yr after transplantation; a residual tumor infiltrating spleen and colon was resected one yr later. Due to continual pathological signals in liver and lungs, persistent fever, and an M-component in peripheral blood, a new course of four rituximab doses was given, after which the fever settled, the PET scan normalized, and the M-component disappeared. Without any ongoing immunosuppressive therapy, PTLD relapsed nine yr later with large intra-abdominal lymph node masses causing ureteric obstruction with bilateral hydronephrosis. Pathological features were identical to the primary PTLD tumor: EBV related, of donor origin, positive for CD138 and CD79 alpha, but negative for CD20 and CD19. The transcription factor PAX5 was negative but BOB1 and OCT2 were positive, consistent with plasmablastic lymphoma. The relapse was successfully treated with a combination of low dose chemotherapy and rituximab. Five yr after end of treatment, the girl has moderately reduced renal function but otherwise remains well without evidence of disease. PMID- 24168386 TI - Identification of B-cell epitopes in an antigen for inducing specific class of antibodies. AB - BACKGROUND: In the past, numerous methods have been developed for predicting antigenic regions or B-cell epitopes that can induce B-cell response. To the best of authors' knowledge, no method has been developed for predicting B-cell epitopes that can induce a specific class of antibody (e.g., IgA, IgG) except allergenic epitopes (IgE). In this study, an attempt has been made to understand the relation between primary sequence of epitopes and the class of antibodies generated. RESULTS: The dataset used in this study has been derived from Immune Epitope Database and consists of 14725 B-cell epitopes that include 11981 IgG, 2341 IgE, 403 IgA specific epitopes and 22835 non-B-cell epitopes. In order to understand the preference of residues or motifs in these epitopes, we computed and compared amino acid and dipeptide composition of IgG, IgE, IgA inducing epitopes and non-B-cell epitopes. Differences in composition profiles of different classes of epitopes were observed, and few residues were found to be preferred. Based on these observations, we developed models for predicting antibody class-specific B-cell epitopes using various features like amino acid composition, dipeptide composition, and binary profiles. Among these, dipeptide composition-based support vector machine model achieved maximum Matthews correlation coefficient of 0.44, 0.70 and 0.45 for IgG, IgE and IgA specific epitopes respectively. All models were developed on experimentally validated non redundant dataset and evaluated using five-fold cross validation. In addition, the performance of dipeptide-based model was also evaluated on independent dataset. CONCLUSION: Present study utilizes the amino acid sequence information for predicting the tendencies of antigens to induce different classes of antibodies. For the first time, in silico models have been developed for predicting B-cell epitopes, which can induce specific class of antibodies. A web service called IgPred has been developed to serve the scientific community. This server will be useful for researchers working in the field of subunit/epitope/peptide-based vaccines and immunotherapy (http://crdd.osdd.net/raghava/igpred/). PMID- 24168388 TI - Association between APOE epsilon 4 allele and postoperative cognitive dysfunction: a meta-analysis. AB - BACKGROUND: Carriers of the apolipoprotein E epsilon 4 allele (APOEepsilon4) may be at increased risk of postoperative cognitive dysfunction (POCD), but this association has not been reported consistently. We conducted a meta-analysis to derive a more precise conclusion. METHODS: The PubMed, EBSCO and EMBASE databases were searched for eligible studies published in English before March 2013. The association between APOEepsilon4 and POCD was expressed by the odds ratio (OR) with 95% confidence interval (CI). Funnel plots were constructed and publication bias assessed by Egger's test. RESULTS: Nine studies encompassing 1063 APOEepsilon4 carriers and 2983 noncarriers were included. At about 1-week postsurgery, a significant association between APOEepsilon4 and POCD was found (OR 1.83, 95% CI: 1.18-2.85), but the association was no longer significant after removing one large study (OR 1.35, 95% CI: 0.92-1.97). Stratified analysis of cardiac/vascular surgery patients also yielded no significant correlation (OR 1.62, 95% CI: 0.80-3.28). One to three months postsurgery, neither the overall analysis (OR 1.56, 95% CI: 0.87-2.81) nor the stratified analysis of cardiac/vascular surgery patients (OR 3.33, 95% CI: 0.55-20.22) indicated a significant correlation. APOEepsilon4 was also not correlated with POCD at 1-year postsurgery (OR 1.15, 95% CI: 0.71-1.86). No evidence of publication bias was revealed by Egger's test. CONCLUSIONS: The APOEepsilon4 allele was associated with a significantly increased POCD risk about 1-week postsurgery, but the association depended on one large study. No association was found 1-3 months and 1-year postsurgery. PMID- 24168389 TI - Extraction, stability, and separation of betalains from Opuntia joconostle cv. using response surface methodology. AB - Betalains were extracted and analyzed from Opuntia joconostle (the prickly pear known as xoconostle in Mexico). For the extraction, two solvent systems were used, methanol/water and ethanol/water. A three-variable Box-Behnken statistical design was used for extraction: solvent concentration (0-80%, v/v), temperature (5-30 degrees C), and treatment time (10-30 min). The extraction and stability of betalains from xoconostle were studied using response surface methodology (RSM). Techniques such as UV-vis, column chromatography, and HPLC were employed for the separation and analysis of the main pigments present in the extracts. Maximum pigment concentration (92 mg/100 g of fruit) was obtained at a temperature of 15 degrees C and a time of 10 min for methanol/water (20:80), whereas maximum stability of the pigment was observed at pH 5 and a temperature of 25 degrees C. HPLC chromatograms showed the main betalains of the xoconostle characterized were betalain, betanidin, and isobetalain. PMID- 24168390 TI - beta-Amyloid amorphous aggregates induced by the small natural molecule ferulic acid. AB - There is an emerging interest in small natural molecules for their potential therapeutic use in neurodegenerative disorders like Alzheimer's disease (AD). Ferulic acid (FA), an antioxidant phenolic compound present in fruit and vegetables, has been proposed as an inhibitor of beta amyloid (Abeta) pathological aggregation. Using fluorescence and Fourier transform infrared spectroscopy, electrophoresis techniques, chromatographic analysis, and confocal microscopy, we investigated the effects of FA in the early stages of Abeta fibrillogenesis in vitro. Our results show that FA interacts promptly with Abeta monomers/oligomers, interfering since the beginning with its self-assembly and finally forming amorphous aggregates more prone to destabilization. These findings highlight the molecular basis underlying FA antiamyloidogenic activity in AD. PMID- 24168391 TI - Stroke-coordination and symmetry of elite backstroke swimmers using a comparison between net drag force and timing protocols. AB - Stroke-coordination and symmetry influence the force fluctuations within any net drag force profile. The aim of this study was to analyse elite (FINA points 938) backstroke swimmers stroke-coordination using an instantaneous net drag force and timing protocols using a symmetry index tool. Ten male and nine female elite backstroke swimmers completed three maximum speed trials and five maximum speed net drag force swimming trials. Net drag force was measured using an assisted motorised dynamometer device. Each trial was filmed using three genlocked 50 Hz cameras, synchronised to the net drag force output from the force-platform. This methodology enabled the comparison of stroke-coordination timing symmetry index to net drag force symmetry index. The timing symmetry index and net drag force symmetry index yielded different results, the timing reflects the stroke coordination, whilst the force index identified the effectiveness of the stroke. The only variable that was significantly different when comparing left and right stroke patterns was the location of minimum net drag forces. Conversely, gender influenced the location of maximum net drag force. Relationship analysis identified that location of maximum net drag force production was the only variable to correlate with speed within this cohort. Backstroke arm coordination was minimally influenced by gender. PMID- 24168394 TI - Acquired generalized lipodystrophy associated with peripheral T cell lymphoma with cutaneous infiltration. PMID- 24168393 TI - Temperature-controlled encapsulation and release of an active enzyme in the cavity of a self-assembled DNA nanocage. AB - We demonstrate temperature-controlled encapsulation and release of the enzyme horseradish peroxidase using a preassembled and covalently closed three dimensional DNA cage structure as a controllable encapsulation device. The utilized cage structure was covalently closed and composed of 12 double-stranded B-DNA helices that constituted the edges of the structure. The double stranded helices were interrupted by short single-stranded thymidine linkers constituting the cage corners except for one, which was composed by four 32 nucleotide long stretches of DNA with a sequence that allowed them to fold into hairpin structures. As demonstrated by gel-electrophoretic and fluorophore-quenching experiments this design imposed a temperature-controlled conformational transition capability to the structure, which allowed entrance or release of an enzyme cargo at 37 degrees C while ensuring retainment of the cargo in the central cavity of the cage at 4 degrees C. The entrapped enzyme was catalytically active inside the DNA cage and was able to convert substrate molecules penetrating the apertures in the DNA lattice that surrounded the central cavity of the cage. PMID- 24168396 TI - Genetic variation in CD36, HBA, NOS3 and VCAM1 is associated with chronic haemolysis level in sickle cell anaemia: a longitudinal study. AB - Chronic haemolysis stands out as one of the hallmarks of sickle cell anaemia, a clinically heterogeneous autosomal recessive monogenic anaemia. However, the genetic architecture of this sub-phenotype is still poorly understood. Here, we report the results of an association study between haemolysis biomarkers (serum LDH, total bilirubin and reticulocyte count) and the inheritance of 41 genetic variants of ten candidate genes in a series of 99 paediatric SS patients (median current age of 9.9 yr) followed up in two general hospitals in Greater Lisboa area (median follow-up per patient of 5.0 yr). Although in a large number of tests a seemingly significant (i.e. P < 0.05) association was observed, the following ones were confirmed upon correction for multiple comparisons: (i) an increased serum LDH level was associated with haplotype 7 within VCAM1 gene; (ii) a lower total bilirubin was associated with the 3.7-kb deletion at HBA gene, rs2070744_T allele at NOS3 gene, and haplotype 9 within VCAM1 promoter; and (iii) a diminished reticulocyte count was associated with the 3.7-kb deletion at HBA, whereas an increased count was associated with rs1984112_G allele at CD36 gene. On the whole, our findings suggest a complex genetic architecture for the sickle cell anaemia haemolysis process involving multiple pathways, namely control of vascular cell adhesion, NO synthesis and erythrocyte volume and haemoglobinisation. PMID- 24168397 TI - Insights on the interactions of chitosan with phospholipid vesicles. Part I: Effect of polymer deprotonation. AB - Interactions between the polysaccharide chitosan and negatively charged phospholipid liposomes were studied as a function of compositional and environmental conditions. Using isothermal titration calorimetry, different levels of deprotonation of chitosan in acidic solutions were attained with titration of the fully protonated polymer at pH 4.48 into solutions with increasing pH. The process was found to be highly endothermic. We then examined the interaction of the polymer with vesicles in solutions of different pH. Even when partially deprotonated, the chitosan chains retain their affinity to the negatively charged liposomes. However, the stronger adsorption results in lower organization of the chains over the membrane. PMID- 24168395 TI - Three-dimensional aggregates of mesenchymal stem cells: cellular mechanisms, biological properties, and applications. AB - Mesenchymal stem cells (MSCs) are primary candidates in cell therapy and tissue engineering and are being tested in clinical trials for a wide range of diseases. Originally isolated and expanded as plastic adherent cells, MSCs have intriguing properties of in vitro self-assembly into three-dimensional (3D) aggregates reminiscent of skeletal condensation in vivo. Recent studies have shown that MSC 3D aggregation improved a range of biological properties, including multilineage potential, secretion of therapeutic factors, and resistance against ischemic condition. Hence, the formation of 3D MSC aggregates has been explored as a novel strategy to improve cell delivery, functional activation, and in vivo retention to enhance therapeutic outcomes. This article summarizes recent reports of MSC aggregate self-assembly, characterization of biological properties, and their applications in preclinical models. The cellular and molecular mechanisms underlying MSC aggregate formation and functional activation are discussed, and the areas that warrant further investigation are highlighted. These analyses are combined to provide perspectives for identifying the controlling mechanisms and refining the methods of aggregate fabrication and expansion for clinical applications. PMID- 24168398 TI - Organocatalytic conjugate addition of nitroalkanes to 3-ylidene oxindoles: a stereocontrolled diversity oriented route to oxindole derivatives. AB - An efficient and highly enantioselective Michael addition of nitroalkanes to 3 ylidene oxindoles is described, mediated by thiourea-based bifunctional organocatalysts. The stereochemistry at C(alpha) and C(beta) centers is perfectly controlled, and the intermediate C-3 enolate is trapped with a second Michael acceptor. The developed one-pot three-component consecutive reactions generate up to four contiguous stereocenters, including the C-3 all-carbon quaternary center, in a perfectly defined configuration. The conversion of the beta-nitro oxindole into the corresponding beta-amino derivative discloses synthetically useful transformations, exploitable to generate pharmaceutically attractive molecular targets. PMID- 24168399 TI - Faecolith arising from jejunal diverticulosis: an unusual cause of small bowel obstruction in the virgin abdomen. PMID- 24168401 TI - The relationship of vertical skeletofacial morphology to oropharyngeal airway shape using cone beam computed tomography: possible implications for airway restriction. AB - OBJECTIVE: To determine if the shape of the oropharyngeal airway is related to the vertical morphology of the skeletofacial complex, including the hyoid bone. MATERIALS AND METHODS: Cone beam computed tomography scans from 50 pretreatment adult orthodontic records were used to obtain skeletal and airway measurements. Linear regression statistics were used to compare soft tissue variables to hard tissue predictor variables. RESULTS: Transverse airway widening was significantly increased when the distance between the hyoid and vertebrae was reduced; when the three-dimensional (3D) facial axis angle decreased (became more vertical); when the 3D mandibular plane angle increased; when the width of the hyoid increased, or when the calculated length of the geniohyoid decreased. CONCLUSIONS: A laterally elliptical airway-found when the face is more vertical and when the hyoid is closer to the cervical vertebrae-is hypothetically more resistant to collapse. Patients with a retrognathic, skeletal deep bite and a rounded oropharynx should be identified and corrected early to prevent potential airway problems. PMID- 24168400 TI - The long non-coding RNA ERIC is regulated by E2F and modulates the cellular response to DNA damage. AB - BACKGROUND: The human genome encodes thousands of unique long non-coding RNAs (lncRNAs), and these transcripts are emerging as critical regulators of gene expression and cell fate. However, the transcriptional regulation of their expression is not fully understood. The pivotal transcription factor E2F1 which can induce both proliferation and cell death, is a critical downstream target of the tumor suppressor, RB. The retinoblastoma pathway is often inactivated in human tumors resulting in deregulated E2F activity. RESULTS: Here, we report that lncRNA XLOC 006942, which we named ERIC, is regulated by E2F1 and, most probably, also E2F3. We show that expression levels of ERIC were elevated upon activation of exogenous E2F1, E2F3 or endogenous E2Fs. Moreover, knockdown of either E2F1 or E2F3 reduced ERIC levels and endogenous E2F1 binds ERIC's promoter. Expression of ERIC was cell cycle regulated and peaked in G1 in an E2F1-dependent manner. Inhibition of ERIC expression increased E2F1-mediated apoptosis, suggesting that E2F1 and ERIC constitute a negative feedback loop that modulates E2F1 activity. Furthermore, ERIC levels were increased following DNA damage by the chemotherapeutic drug Etoposide, and inhibition of ERIC expression enhanced Etoposide -induced apoptosis. CONCLUSIONS: Our data identify ERIC as a novel lncRNA that is transcriptionally regulated by E2Fs, and restricts apoptosis induced by E2F1, as well as by DNA damage. PMID- 24168402 TI - The effect of water storage on the bending properties of esthetic, fiber reinforced composite orthodontic archwires. AB - OBJECTIVE: To study the effect of water storage on the bending properties of fiber-reinforced composite archwires and compare it to nickel-titanium (NiTi), stainless steel (SS), and beta-titanium archwires. MATERIALS AND METHODS: Align A, B, and C and TorQ A and B composite wires from BioMers Products, 0.014-, 0.016, and 0.018-inch, and 0.019*0.025-inch NiTi, 0.016-inch SS, and 0.019*0.025 inch beta-titanium archwires were tested (n=10/type/size/condition). A 20-mm segment was cut from each end of the archwire; one end was then stored in water at 37 degrees C for 30 days, while the other was stored dry. The segments were tested using three-point bending to a maximum deflection of 3.1 mm with force monitored during loading (activation) and unloading (deactivation). Statistical analysis was completed via two-way analysis of variance with wire and condition (dry and water-stored) as factors. RESULTS: In terms of stiffness and force delivery during activation, in general: beta-titanium was >TorQ B>TorQ A>0.019*0.025-inch NiTi and 0.016-inch SS>Align C>0.018-inch NiTi>Align B>0.016 inch NiTi>Align A>0.014-inch NiTi. Water exposure was detrimental to the larger translucent wires (Align B and C, TorQ A and B) because they were more likely to craze during bending, resulting in decreased forces applied at a given deflection. Align A and the alloy wires were not significantly (P>.05) affected by water storage. Overall, the alloy wires possessed more consistent force values compared to the composite wires. CONCLUSION: Environmental conditions are more likely to affect fiber-reinforced composite archwires compared to alloy wires. PMID- 24168403 TI - Thermomechanical properties of lignin-based electrospun nanofibers and films reinforced with cellulose nanocrystals: a dynamic mechanical and nanoindentation study. AB - We produced defect-free electrospun fibers from aqueous dispersions of lignin, poly(vinyl alcohol) (PVA), and cellulose nanocrystals (CNCs), which were used as reinforcing nanoparticles. The thermomechanical performance of the lignin-based electrospun fibers and the spin-coated thin films was improved when they were embedded with CNCs. Isochronal dynamic mechanical analysis (DMA) was used to assess the viscoelastic properties of the lignin:PVA electrospun fiber mats loaded with CNCs. DMA revealed that alpha relaxation processes became less prominent with an increased lignin content, an effect that correlated with the loss tangent (tan delta = E"/E') and alpha peak (Tg) that shifted to higher temperatures. This can be ascribed to the restraint of the segmental motion of PVA in the amorphous regions caused by strong intermolecular interactions. The reinforcing effect and high humidity stability attained by addition of CNCs (5, 10, or 15 wt %) in the multicomponent fiber mats were revealed. Nanoindentation was performed to assess the elastic modulus and hardness of as-prepared and cross section surfaces of spin-coated lignin:PVA (75:25) films loaded with CNC. The properties of the two surfaces differed, and only the trend in cross-section elastic modulus correlated with DMA results. After addition of 5 wt % CNCs, both the DMA and nanoindentation elastic modulus remained constant, while after addition of 15 wt % CNCs, both increased substantially. An indentation size effect was observed in the nanoindentation hardness, and the results provided insight into the effect of addition of CNCs on the microphysical processes controlling the yield behavior in the composites. PMID- 24168404 TI - Isolation of bioactive phytoconstituent from Alpinia galanga L. with anti hyperlipidemic activity. AB - The present study was undertaken to explore the antihyperlipidemic effect of ethanolic extract of rhizomes of Alpinia galanga L. and its chloroform fraction in Triton-induced hyperlipidemic rats. Bioactivity guided fractionation was followed by chromatographic studies. Flash chromatography was done for the most active fraction resulting in the isolation of 5-(hydroxymethyl) furfural. Animals were administered with i.p. injection of Triton WR 1339 at dose of 400 mg/kg body weight. After 24 hr of Triton administration, the ethanolic extract and its fraction were administered orally at doses of 200 and 400 mg/kg body weight in rats. The treatment was continued for 5 days with a view to see the effect on lipid profile. Serum samples were subjected to biochemical analysis. The study dose dependently inhibited the total cholesterol (TC), triglycerides (TG), low density lipoprotein (LDL) level, and significantly increased high-density lipoprotein (HDL) level. Phytochemical screening revealed the presence of tannins, coumarins, flavanoids, sterols, and glycosides. Phytochemical investigation of the chloroform fraction of A. galanga L. resulted in the isolation of 5-(hydroxymethyl) furfural. UV lambdamax was found to be 276 nm for the isolated component. Acute treatment caused a stimulatory effect on the HDL level and inhibition in TC and TG elevation induced by triton. PMID- 24168405 TI - Targeting proinsulin-reactive CD8+ T cells: a new direction for type 1 diabetes treatment. PMID- 24168406 TI - Looking for the best target for biologic treatment of spondyloarthritis. PMID- 24168408 TI - Is urine mRNA analysis a useful tool in the detection of acute rejection? AB - Suthanthiran et al. have correlated the mRNA of more than 4000 urine samples in a blinded fashion with the result of kidney biopsies after transplantation. This was the first study which used mRNA evaluation on a broad scale to investigate acute rejection. This study established an algorithm of different markers which was highly predictive for the outcome of the biopsy retrospectively. The study is highly relevant to the field, but as other studies needs to be validated in a prospective design testing whether the algorithm suggested indeed predicts the result of the biopsy. In the near future, a method such as used in this study could be applied to patients after transplantation as an early follow-up marker. PMID- 24168409 TI - A possible turning point in the hematopoietic stem cell gene therapy for primary immunodeficiency diseases? Lentiviral vectors could take the place of retroviral vectors. AB - Wiskott-Aldrich syndrome (WAS), an X-linked primary immunodeficiency disease (PID) with unique and characteristic features, had been considered to be a good candidate for gene therapy. In 2010, hematopoietic stem cell (HSC) gene therapy, using a retroviral vector, was performed for WAS patients; however, concerns remain regarding the long-term safety of this therapy as several patients with PID developed myeloproliferative diseases due to insertional mutagenesis related to HSC gene therapy using retroviral vectors. Aiuti et al. first reported HSC gene therapy for WAS using a lentiviral vector and compared the safety and efficacy of the two therapies in the context of the same disease background. They undertook a detailed study of the vector integration sites and concluded that lentiviral HSC gene therapy was safer than retroviral gene therapy. PMID- 24168410 TI - A case for antibiotic perturbation of the microbiota leading to allergy development. AB - The use of antibiotics to treat pathogenic bacterial infections has been one of the greatest contributions to human health, yet antibiotic use also perturbs the communities of commensal and symbiotic bacteria that reside in the intestine of mammals. The microbiota are critical for normal immune development and for maintaining intestinal homeostasis, and disruption of the microbiota has been linked to the emergence of allergic disease both in humans and in animal models. The evidence and mechanisms for antibiotic-mediated disruptions leading to the onset of allergic disease at mucosal surfaces is discussed, as well as the future challenges for the field. A more complete understanding of the mechanisms by which the intestinal microbiota modulate allergic disease development will allow for interventions to counter the potentially adverse effects of antibiotic treatment on the microbiota. PMID- 24168411 TI - Immunology of stiff person syndrome and other GAD-associated neurological disorders. AB - Antibodies against glutamic acid decarboxylase (GAD), the rate-limiting enzyme for the synthesis of GABA, are associated with an array of distinct, mostly autoimmune, neurological conditions. In all associated syndromes, namely stiff person syndrome, cerebellar ataxia, epilepsy, limbic encephalitis or abnormal eye movements, anti-GAD antibodies are detected at high titers and play a fundamental role in diagnosis, but do not correlate with disease severity, diversity of symptomatology or response to therapies. Despite considerable efforts, including in vitro (enzymatic assays) and in vivo (animal models) systems, the pathogenicity of anti-GAD antibodies has not been unequivocally proven for any specific condition. The search for the responsible autoantigen has revealed a few other antigenic targets, particularly for SPS, localized in the pre- or post synaptic inhibitory neuronal synapses. Cumulative clinical and laboratory evidence indicates that anti-GAD and related antibodies define a novel group of syndromes, collectively known as 'hyperexcitability disorders'. PMID- 24168412 TI - Neutrophils and emerging targets for treatment in chronic obstructive pulmonary disease. AB - Chronic obstructive pulmonary disease (COPD) is characterized by a decreased airflow due to airway narrowing that, once it occurs, is not fully reversible. The disease usually is progressive and associated with an enhanced inflammatory response in the lungs after exposure to noxious particles or gases. After removal of the noxious particles, the inflammation can continue in a self-sustaining manner. It has been established that improper activation of neutrophils lies at the core of the pathology. This paper provides an overview of the mechanisms by which neutrophils can induce the pulmonary damage of COPD. As the pathogenesis of COPD is slowly being unraveled, new points of intervention are discovered, some of which with promising results. PMID- 24168413 TI - The interaction between autoimmune diseases and fibromyalgia: risk, disease course and management. AB - Fibromyalgia (FM) is a common non-autoimmune rheumatologic disease with a wide range of symptoms that worsen the clinical status of patients. Several authors have tried to identify a putative autoimmune biomarker but, unfortunately, without positive results. Moreover, the altered pain perception characteristic of FM patients is similar in other autoimmune rheumatologic and non-rheumatologic diseases, in fact the pain in FM is not strictly tied to an organic disease, the perception and the severity of it are comparable with those of autoimmune conditions, for example, the polymyalgia rheumatica. In this review, we focus on the FM comorbidities, especially related to autoimmune rheumatologic and non rheumatologic conditions. PMID- 24168414 TI - Current status of systemic sclerosis biomarkers: applications for diagnosis, management and drug development. AB - Systemic sclerosis (SSc) is a clinically heterogeneous orphan disease of unknown etiology and no effective therapy. It is characterized by protean manifestations, an unpredictable disease course and variable outcomes. Clinical manifestations reflect underlying autoimmunity, small vessel vasculopathy and progressive multi organ fibrosis. Predicting disease progression, pattern and severity of complications and response to therapy in SSc remain major challenges both for the management of patients and for the development of effective disease-modifying therapies. This review summarizes contemporary understanding of novel and emerging biomarkers for SSc. We focus on the development of new classification criteria, the utility of SSc-specific autoantibodies as diagnostic and prognostic markers, and on biomarkers for skin and lung involvement. Finally, we review genome-wide expression analysis as a tool to predict therapeutic responses. We anticipate that the development, validation and application of these biomarkers, singly or more likely in combination, will have a transformative impact in SSc, informing early diagnosis, classification and management, as well as the design, execution and interpretation of clinical trials of novel therapeutic agents. PMID- 24168415 TI - Association of cytokine/costimulatory molecule polymorphism and allograft rejection: a comparative review. AB - One reason for genetic variations among human individuals is SNP which may confer diverse disease susceptibility or resistance in a population. Genetic variations in a key immunoregulatory agent can manifest various immunological responses, such as graft rejection. In fact, the outcome of organ transplantation can be impacted by several genetic causes including polymorphisms in genes encoding cytokines and costimulatory molecules in the donor or recipient. Thus, it can be helpful to contemplate the SNPs relating to these immunological determinants in order to achieve an improved transplantation therapy. PMID- 24168416 TI - Paroxysmal nocturnal hemoglobinuria and the age of therapeutic complement inhibition. AB - Paroxysmal nocturnal hemoglobinuria (PNH) is a rare disease of hematopoietic stem cells due to a mutation in the PIG-A gene leading to a deficiency of GPI-anchored proteins. Lack of two specific GPI-anchored proteins, CD55 and CD59, leads to uncontrolled complement activation that result in both intravascular and extravascular hemolysis. Free hemoglobin leads to nitric oxide depletion that mediates the pathophysiology of some of the common clinical signs of PNH. Clinical symptoms of PNH include evidence of hemolytic anemia, bone marrow failure, smooth muscle dystonias and thromboses. Treatment options for patients with PNH include bone marrow transplantation, a therapy associated with high morbidity and mortality, or treatment with the complement inhibitor eculizumab. Eculizumab is a first-in-class anti-complement drug that in PNH has been shown to block complement-mediated hemolysis, reduce transfusion dependency, reduce thromboembolic complications and improve the quality of life (QoL) of patients. PMID- 24168417 TI - Immunodiscordant responses to HAART--mechanisms and consequences. AB - A relevant fraction of HIV-1-infected individuals (ranging from 15 to 30%) presenting virologically successful highly active antiretroviral therapy fail to recover CD4 T-cell counts. These individuals, called immunodiscordant or immunological nonresponders, are at increased risk of clinical progression and death. Although older age, lower nadir CD4 T-cell count and HCV co-infection are some of clinical predictive factors, immunological mechanisms rely on impaired thymic production and accumulation of apoptosis-prone CD4 T cells. Indeed, immunodiscordant individuals may show increased tissue fibrosis and damage of gut associated lymphoid tissue that results in higher hyperactivation, inflammation and immunosenescence, altered Treg/Th17 ratio and increased T-cell death. A better knowledge of the final pathogenic mechanism and factors influencing CD4 T cell recovery will help to select the optimal therapeutic strategies for them. PMID- 24168418 TI - Giant mesenteric hemangioma of cavernous and venous mixed type: a rare case report. AB - BACKGROUND: Although vascular tumours are one of the most common soft tissue neoplasms, those occurring in the gastrointestinal system are rare and cases involving mesentery are even further rare. Herein, we reported a rare case of giant hemangioma in mesentery of the small bowel. CASE PRESENTATION: A 5-year-old girl was admitted to the emergency room with abdominal pain and vomit for two days. Ultrasonography and computed tomography showed a giant solid-cystic abdominal mass, preferring diagnosis of teratoma. A large neoplasm in the mesentery of the small bowel was found in the surgical exploration, which was then resected with the partial bowel. A brown honeycomb mass in size 16 cm*8 cm*5 cm was observed to adhere to the small bowel, and diagnosed as hemangioma of cavernous and venous mixed type in final pathology. CONCLUSION: The mesenteric hemangioma is extremely rare and the variable imaging tests are non-specific, thus the diagnosis is rarely made before surgery and usually established by histopathological investigation after surgery. So the mesenteric hemangioma is supposed to be differentiated in abdominal mass, either in adults or children. Complete surgical resection is the optimal treatment. PMID- 24168419 TI - Effect of chain elongation on biological properties of the toxin paralysin beta alanyl-tyrosine. AB - In hemolymph of insect species, compounds with remarkable properties for pharmaceutical industry are present. At the first line, there were found compounds of low molecular mass, less than 1 kDa. One of such compounds, beta alanyl-tyrosine (252 Da), was isolated from larval hemolymph of some species of holometabolous insects (e.g. Neobellieria bullata). Its paralytic activity and antimicrobial properties were described until now. In this study, we present the effect of elongation of beta-alanyl-tyrosine by repeating of this motive on the biological and physical properties of prepared analogues. For assessment of antimicrobial properties of these new compounds strains of Gram-positive, Gram negative bacteria and fungi were used, we also followed the haemolytic activity and toxic effect on human cell culture HepG2. On the base of ECD spectroscopy measurement, subsequent molecular modelling and known secondary structure of original beta-alanyl-tyrosine dipeptide, the secondary structures of repeating sequences of beta-AY were specified. The repeating structures of beta-alanyl tyrosine show increase in antimicrobial activity; for Escherichia coli, Staphylococcus aureus and Pseudomonas aeruginosa, minimal inhibitory concentration was decreased from 30 to 15 mM for 2xbeta-AY, 0.4 mM for 4xbeta-AY and 0.25 mM for 6xbeta-AY. PMID- 24168420 TI - Time is more than a sensory feature: Attending to duration triggers specific anticipatory activity. AB - Time processing requires the estimation of events' duration per se, but also seems to trigger attentional and memory processes. To isolate attentional processes, we investigated neural correlates of anticipatory attention when estimating stimulus duration. Magneto-encephalographic (MEG) activity was recorded in fourteen healthy right-handed volunteers, who were cued to attend to either the duration or the intensity of a visual stimulus. We report an increase of gamma-band oscillations over right fronto-central and parietal regions when subjects are prompted to attend to duration, which is not present when subjects are cued to attend to intensity. Cue-related alpha power decreases over occipito parietal regions were similar in the two conditions. Our results support the hypothesis that the right fronto-parietal network observed repeatedly in time estimation imaging studies is indeed involved in attentional control rather than stimulus processing. Moreover, they underline the supramodal property of time dimension that goes beyond purely perceptive features. PMID- 24168421 TI - Experimentally induced social inclusion influences behavior on trust games. AB - Being socially excluded is profoundly distressing. It is unknown whether exclusion renders victims vulnerable to manipulation or whether excluded individuals become more cautious about being exploited by, and less trusting of, the person who excluded them. We investigated this by testing how much participants trust people who have socially included or excluded them. Inclusion and exclusion were manipulated using Cyberball (a virtual ball game) and, after playing Cyberball, participants played trust games. In a Reputation group participants played trust games with players from Cyberball; in the No Reputation group, participants played with strangers. Inclusion/exclusion manipulation interacted with Group such that participants in the Reputation group trusted individuals who included them more than those who excluded them, whereas inclusion/exclusion made no difference to trust in the No-Reputation group. Our findings suggest that exclusion does not increase gullibility, but that reputation is transferred from a social to an economic setting so that social inclusion increases trust. PMID- 24168422 TI - On the taste of "Bouba" and "Kiki": An exploration of word-food associations in neurologically normal participants. AB - We investigated whether there are reliable crossmodal associations between foods/flavours and words in neurologically normal individuals. Participants were given a range of foods to taste, and had to rate each one along a number of dimensions. These included scales anchored with the words "takete/maluma" and "bouba/kiki". The results highlight the existence of robust crossmodal associations between complex foods/flavours and words in normal (i.e., nonsynesthetic) individuals. For example, crisps (potato chips) and cranberry sauce are rated as being more "takete" than brie cheese, while mint chocolate is rated as more "kiki" than regular chocolate. On the basis of these results, we suggest that our brains can extract supramodal/conceptual properties from foods/flavours (just as has been demonstrated previously using auditory and visual stimuli) and meaningfully match them crossmodally. The possibility that this process is based on the global Gestalt of a food rather than on any specific sensory qualities is also discussed. PMID- 24168423 TI - Modulation of somatosensory perception by motor intention. AB - The intention to execute a movement can modulate our perception of sensory events; however, theoretical accounts of these effects, and also empirical data, are often contradictory. We investigated how perception of a somatosensory stimulus differed according to whether it was delivered to a limb being prepared for movement or to a nonmoving limb. Our results demonstrate that individuals perceive a somatosensory stimulus delivered to the "moving" limb as occurring significantly later than when an identical stimulus is delivered to a "nonmoving" limb. Furthermore, human brain imaging (fMRI) analyses demonstrate that this modulation is accompanied by a significant decrease in BOLD signal in the right parietal operculum (SII) for stimuli delivered to the moving limb. These results indicate that during movement preparation a network of premotor brain areas may facilitate movement execution by attenuating the processing of behaviorally irrelevant signals within higher-order secondary somatosensory (SII) areas. PMID- 24168424 TI - Direct risk standardisation: a new method for comparing casemix adjusted event rates using complex models. AB - BACKGROUND: Comparison of outcomes between populations or centres may be confounded by any casemix differences and standardisation is carried out to avoid this. However, when the casemix adjustment models are large and complex, direct standardisation has been described as "practically impossible", and indirect standardisation may lead to unfair comparisons. We propose a new method of directly standardising for risk rather than standardising for casemix which overcomes these problems. METHODS: Using a casemix model which is the same model as would be used in indirect standardisation, the risk in individuals is estimated. Risk categories are defined, and event rates in each category for each centre to be compared are calculated. A weighted sum of the risk category specific event rates is then calculated. We have illustrated this method using data on 6 million admissions to 146 hospitals in England in 2007/8 and an existing model with over 5000 casemix combinations, and a second dataset of 18,668 adult emergency admissions to 9 centres in the UK and overseas and a published model with over 20,000 casemix combinations and a continuous covariate. RESULTS: Substantial differences between conventional directly casemix standardised rates and rates from direct risk standardisation (DRS) were found. Results based on DRS were very similar to Standardised Mortality Ratios (SMRs) obtained from indirect standardisation, with similar standard errors. CONCLUSIONS: Direct risk standardisation using our proposed method is as straightforward as using conventional direct or indirect standardisation, always enables fair comparisons of performance to be made, can use continuous casemix covariates, and was found in our examples to have similar standard errors to the SMR. It should be preferred when there is a risk that conventional direct or indirect standardisation will lead to unfair comparisons. PMID- 24168425 TI - Prevalence of impaired fasting glucose and analysis of related factors in Taiwanese adolescents. AB - OBJECTIVE: To determine the prevalence of impaired fasting glucose (IFG) in Taiwanese adolescents and important related variables. SUBJECTS AND METHODS: This analysis was based on the Nutrition and Health Survey in Taiwan (NAHSIT) data during 2010 and 2011. The original study was a cross-sectional and national representative survey. A total of 1949 subjects (965 males and 984 females) aged 11-20 years participated. Research tools consisted of questionnaires, anthropometry parameters, and blood biochemical indicators. The acquired data were analyzed using descriptive and inferential statistics. RESULTS: The prevalence of IFG in Taiwanese adolescents was 22% (a fasting glucose level between 100 and 125 mg/dL is considered abnormal). Factors that significantly affected IFG levels included sex, age, quality of family dietary environment, overweight, obesity, and the number of cardio-metabolic risk factors. CONCLUSION: The prevalence of IFG in Taiwanese adolescents is a public health issue that should not be ignored. The prevalence may be reduced by adjusting lifestyles. Healthy family environments should be encouraged and appropriate healthy lifestyle counseling plans offered specifically to male adolescents with overweight, obesity, and cardio-metabolic risk factors. PMID- 24168426 TI - Conversion of alpha-chitin substrates with varying particle size and crystallinity reveals substrate preferences of the chitinases and lytic polysaccharide monooxygenase of Serratia marcescens. AB - Industrial depolymerization of chitinous biomass generally requires numerous steps and the use of deleterious substances. Enzymatic methods provide an alternative, but fundamental knowledge that could direct potential development of industrial enzyme cocktails is scarce. We have studied the contribution of monocomponent chitinases (ChiA, -B, and -C) and the lytic polysaccharide monooxygenase (LPMO) from Serratia marcescens on depolymerization of alpha-chitin substrates with varying particle size and crystallinity that were generated using a converge mill. For all chitinases activity was positively correlated to a decline in particle size and crystallinity. Especially ChiC, the only nonprocessive endochitinase from the S. marcescens chitinolytic machinery, benefited from mechanical pretreatment. Combining the chitinases revealed clear synergies for all substrates tested. CBP21, the chitin-active LPMO from S. marcescens, increased solubilization of substrates with high degrees of crystallinity when combined with each of the three chitinases, but this synergy was reduced upon decline in crystallinity. PMID- 24168427 TI - Target dIsease-Guided placEbo-contRolled (TIGER) design: a novel method for clinical trials of acupuncture. AB - BACKGROUND: At present, the design of an ideal placebo control in acupuncture studies challenges researchers. Previously devised sham acupuncture techniques have reported various imperfections; therefore, the specific effects of acupuncture cannot be accurately examined in clinical trials primarily because of interferences from the placebo effects. METHOD: Guided by evidence-based medicine (EBM) theories, we have made an initial attempt to establish a set of control methods for use in acupuncture studies, which is named the target disease-guided placebo-controlled (TIGER) design. In a trial using the TIGER design, participants suffering simultaneously from a predefined target disease and a pseudo target disease will be recruited and randomized to receive identical acupuncture intervention measures. As a result, the interventions not only appear the same but also produce the same stimulations in both groups. The patients in the treatment group will be informed of the actual target disease that the treatment aims for, whereas patients in the control group will be informed that the treatment is for the pseudotarget disease. It is speculated that no psychological response will be aroused in the control group. During data analysis, changes in the outcome measures of the patients in the control groupreveal the real therapeutic effect of acupuncture, and those of patients in the treatment group show both the real and placebo acupuncture effect. In this article, we explain how to put this design into use in a planned randomized clinical trial of acupuncture for the treatment of migraine. RESULTS: This approach can eliminate the acupuncture placebo effect in the control group that may confound trial results. It is possible to observe the specific and placebo effects of acupuncture for the target disease separately using the TIGER design. CONCLUSIONS: The proposed TIGER design has limitations. It is designed for clinical studies focusing on the specific effects of acupuncture, and it needs to be tested and verified for practicality and feasibility in various clinical research settings. PMID- 24168428 TI - Physiological demands of women's rugby union: time-motion analysis and heart rate response. AB - The aim of this study was to determine the physical demands of women's rugby union match play using time-motion analysis and heart rate (HR) response. Thirty eight premier club level female rugby players, ages 18-34 years were videotaped and HRs monitored for a full match. Performances were coded into 12 different movement categories: 5 speeds of locomotion (standing, walking, jogging, striding, sprinting), 4 forms of intensive non-running exertion (ruck/maul/tackle, pack down, scrum, lift) and 3 discrete activities (kick, jump, open field tackle). The main results revealed that backs spend significantly more time sprinting and walking whereas forwards spend more time in intensive non running exertion and jogging. Forwards also had a significantly higher total work frequency compared to the backs, but a higher total rest frequency compared to the backs. In terms of HR responses, forwards displayed higher mean HRs throughout the match and more time above 80% of their maximum HR than backs. In summary, women's rugby union is characterised by intermittent bursts of high intensity activity, where forwards and backs have similar anaerobic energy demands, but different specific match demands. PMID- 24168429 TI - A comparison of toxicant-induced succession for five antifouling compounds on marine periphyton in SWIFT microcosms. AB - Five antifouling biocides, chlorothalonile, dichlofluanide, medetomidine, tolylfluanide, and zinc pyrithione, were evaluated regarding their effect on the composition of the periphyton community and the subsequent toxicant-induced succession (TIS). The periphyton communities were exposed in a semi-static setting for 96 h using a SWIFT microcosm. As a measure of community composition, pigment profiles from the exposed communities were used as effect indicators and compared with unexposed parts of the same community using the Bray-Curtis dissimilarity index. Chlorothalonile caused changes in the community starting at 85 MUg l(-1) while dichlofluanide had no effect even at the highest concentrations used, 810 MUg l(-1). The related substance tolylfluanide only affected the community composition at 2700 MUg l(-1). Medetomidine had a different response curve with a small effect on the community composition at 0.8 MUg l(-1) which then disappeared only to reappear at 240 MUg l(-1). Zinc pyrithione had the largest effect on the periphyton community with changes starting at 10 MUg l(-1) and no detectable pigments at 100 MUg l(-1). The changes in the community composition for the five substances were also compared using multidimensional scaling. When all substances were analyzed and plotted together, chlorothalonile, dichlofluanide, medetomidine, and tolylfluanide showed surprisingly similar effects compared to zinc pyrithione that gave very different TIS. However, when only chlorothalonile, dichlofluanide, and tolylfluanide were plotted together, clear differences in TIS between the three toxicants were revealed. Dichlofluanide only induced small effects, while concentration dependent TIS trajectories for chlorothalonile and tolylfluanide took off in opposite directions indicating very different responses of the periphyton communities. This study demonstrates that substances with a similar chemical structure and mechanisms of action can have different effects on the community composition. With the exception of zinc pyrithione, none of the recorded effect levels were at concentrations reported from marine environments so far. PMID- 24168431 TI - The role of different structural motifs in the ultrafast dynamics of second generation protein stains. AB - Engineering the properties of fluorescent probes through modifications of the fluorophore structure has become a subject of interest in recent times. By doing this, the photophysical and photochemical properties of the modified fluorophore can be understood and this can guide the design and synthesis of better fluorophores for use in biotechnology. In this work, the electronic spectra and fluorescence decay kinetics of four analogues of the fluorescent natural product epicocconone were investigated. Epicocconone is unique in that the native state is weakly green fluorescent, whereas the enamine formed reversibly with proteins is highly emissive in the red. It was found that the ultrafast dynamics of the analogues depends profoundly on the H-bonding effect of solvents and solvent viscosity though solvent polarity also plays a role. Comparing the steady state and time-resolved data, the weak fluorescence of epicocconone in its native state is most likely due to the photoisomerization of the hydrocarbon side chain, while the keto enol moiety also has a role to play in determining the fluorescence quantum yield. This understanding is expected to aid the design of better protein stains from the same family. PMID- 24168432 TI - Origin of indirect optical transitions in few-layer MoS2, WS2, and WSe2. AB - It has been well-established that single layer MX2 (M = Mo, W and X = S, Se) are direct gap semiconductors with band edges coinciding at the K point in contrast to their indirect gap multilayer counterparts. In few-layer MX2, there are two valleys along the Gamma-K line with similar energy. There is little understanding on which of the two valleys forms the conduction band minimum (CBM) in this thickness regime. We investigate the conduction band valley structure in few layer MX2 by examining the temperature-dependent shift of indirect exciton photoluminescence peak. Highly anisotropic thermal expansion of the lattice and the corresponding evolution of the band structure result in a distinct peak shift for indirect transitions involving the K and Lambda (midpoint along Gamma-K) valleys. We identify the origin of the indirect emission and concurrently determine the relative energy of these valleys. PMID- 24168430 TI - Human monoclonal Fab and human plasma antibodies to carbamyl-epitopes cross-react with malondialdehyde-adducts. AB - Oxidized low-density lipoprotein (OxLDL) plays a crucial role in the development of atherosclerosis. Carbamylated LDL has been suggested to promote atherogenesis in patients with chronic kidney disease. Here we observed that plasma IgG and IgM antibodies to carbamylated epitopes were associated with IgG and IgM antibodies to oxidation-specific epitopes (rho = 0.65-0.86, P < 0.001) in healthy adults, suggesting a cross-reaction between antibodies recognizing carbamyl-epitopes and malondialdehyde (MDA)/malondialdehyde acetaldehyde (MAA) -adducts. We used a phage display technique to clone a human Fab antibody that bound to carbamylated LDL and other carbamylated proteins. Anti-carbamyl-Fab (Fab106) cross-reacted with oxidation-specific epitopes, especially with MDA-LDL and MAA-LDL. We showed that Fab106 bound to apoptotic Jurkat cells known to contain these oxidation specific epitopes, and the binding was competed with soluble carbamylated and MDA /MAA-modified LDL and BSA. In addition, Fab106 was able to block the uptake of carbamyl-LDL and MDA-LDL by macrophages and stained mouse atherosclerotic lesions. The observed cross-reaction between carbamylated and MDA-/MAA-modified LDL and its contribution to enhanced atherogenesis in uraemic patients require further investigation. PMID- 24168433 TI - Angiogenesis is increased in advanced haemophilic joint disease and characterised by normal pericyte coverage. AB - BACKGROUND: Repeated intra-articular bleedings in patients with haemophilia results in a crippling arthropathy for which no specific treatment is currently available. Recent studies have shown that neoangiogenesis is involved in the pathologic process. The aim of this study was to determine whether angiogenesis is dysregulated in haemophilic joint disease (HJD). METHODS: Synovial tissue and synovial fluid were collected from patients with severe haemophilia undergoing knee or hip replacement and from a control group consisting of non-haemophilic patients undergoing diagnostic procedures. In a second set of patients, blood samples were collected in patients with mild, moderate and severe haemophilia A when free from current bleeding. Analysis of microvascular density, vascular endothelial growth factor (VEGF) expression and pericyte coverage was performed by immunofluorescence. Analyses of VEGF concentrations in plasma, platelet lysates and synovial fluid were performed by ELISA. RESULTS: Microvascular density and VEGF expression were significantly increased in synovial tissue from haemophilic patients compared with controls (P = 0.005 and P = 0.02, respectively). There was no difference in pericyte coverage of synovial vessels or levels of VEGF in plasma, platelet lysates or synovial fluid. CONCLUSIONS: Angiogenesis observed as synovial microvascular density, and VEGF expression is increased in HJD. As pericyte coverage was similar in synovial vessels from haemophilic and non-haemophilic patients, we assume that the vessels were mature, suggesting that the rate of new vessel formation is low in the chronic phase of haemophilic joint disease. PMID- 24168435 TI - Insights on the interactions of chitosan with phospholipid vesicles. Part II: Membrane stiffening and pore formation. AB - The interactions between the polysaccharide chitosan and phospholipids are studied using giant unilamellar vesicles (GUVs). We explore both bare GUVs incubated in chitosan solution post vesicle formation and GUVs prepared using a reverse-phase method where the polymer is adsorbed on both sides of the membrane leaflet. The fluctuations of the vesicle membrane are significantly reduced in the presence of chitosan as characterized by the bending rigidity, which increases with chitosan concentration denoting physical restrictions imposed to the bilayer as a consequence of the interaction with the polysaccharide. In the absence of chitosan, the rigidity of the bare phosphatidylcholine vesicles is also observed to increase (about 3-fold) upon the incorporation of a small fraction (10 mol %) of phosphatidylglycerol. Pore formation caused by chitosan is evidenced by loss of optical contrast of the giant vesicles denoting exchange between internal and external solutions through the pores. Our study provides evidence for the potential of chitosan to affect the bilayer permeability and to disrupt negatively charged membranes as well as to promote adhesiveness of vesicles on glass surfaces. PMID- 24168436 TI - Megaseminal vesicles in adult polycystic kidney disease. PMID- 24168437 TI - Can more than one incremental cycling test be performed within one day? AB - Changes in performance parameters over four consecutive maximal incremental cycling tests were investigated to determine how many tests can be performed within one single day without negatively affecting performance. Sixteen male and female subjects (eight trained (T): 25 +/- 3 yr, BMI 22.6 +/- 2.5 kg.m(-2), maximal power output (P(max)) 4.6 +/- 0.5 W.kg(-1); eight untrained (UT): 27 +/- 3 yr, BMI 22.3 +/- 1.2 kg.m(-2), P(max) 2.9 +/- 0.3 W.kg(-1)) performed four successive maximal incremental cycling tests separated by 1.5 h of passive rest. Individual energy requirements were covered by standardised meals between trials. Maximal oxygen uptake (VO(2max)) remained unchanged over the four tests in both groups (P = 0.20 and P = 0.33, respectively). P(max) did not change in the T group (P = 0.32), but decreased from the third test in the UT group (P < 0.01). Heart rate responses to submaximal exercise were elevated from the third test in the T group and from the second test in the UT group (P < 0.05). The increase in blood lactate shifted rightward over the four tests in both groups (P < 0.001 and P < 0.01, respectively). Exercise-induced net increases in epinephrine and norepinephrine were not different between the tests in either group (P >= 0.15). If VO(2max) is the main parameter of interest, trained and untrained individuals can perform at least four maximal incremental cycling tests per day. However, because other parameters changed after the first and second test, respectively, no more than one test per day should be performed if parameters other than VO(2max) are the prime focus. PMID- 24168438 TI - Vitamin D and the metabolic syndrome. AB - Vitamin D is essential in bone mineralization and calcium homeostasis, and an increasing body of evidence suggests that vitamin D may be important for maintaining extraskeletal health, including having beneficial effects on cardiometabolic outcomes. Vitamin D deficiency is widespread, but the role of vitamin D in the metabolic syndrome is not fully elucidated. In this review we summarize data from observational studies and randomized controlled trials on the relation between vitamin D and the metabolic syndrome and its components. A large number of observational studies suggest a relationship between low levels of 25(OH)D and the metabolic syndrome or its individual clinical features. Randomized controlled trials of vitamin D supplementation addressing aspects of the metabolic syndrome have yielded inconsistent results, and many studies suffer from methodological limitations. There is an urgent need for large, well-designed randomized controlled trials with relevant endpoints. Until definitive results from such studies are available, caution should be taken towards the use of vitamin D-supplementation for disorders other than musculoskeletal system. New molecular biological techniques elucidating the interaction between the active vitamin D derivatives and target genes represent a promising approach to more precise knowledge about new biomedical function, which also might shed light on the complex metabolic syndrome. PMID- 24168439 TI - Editorial: nutritional therapy in metabolic syndrome. PMID- 24168441 TI - Inflammation, oxidative stress and metabolic syndrome: dietary modulation. AB - The metabolic syndrome (MetS) is a cluster of risk factors for the development of cardiovascular disease and type 2 diabetes mellitus. These risk factors include raised blood pressure, dyslipidemia (raised triglycerides and lowered high density lipoprotein cholesterol), raised fasting glucose, and central obesity. MetS has become a serious public health and clinical problem whose prevalence and incidence are increasing along with the worldwide rise in rates of obesity and sedentary lifestyles. A number of studies have shown that MetS is associated with a state of low-grade inflammation, characterized by abnormal pro-inflammatory cytokine production, increased acute-phase reactants, and activation of a network of inflammatory signalling pathways. Moreover, MetS has also been linked to oxidative stress, a consequence of a reduction in the antioxidant systems and an increase in the production of reactive oxygen species. Nevertheless, agreement exists that dietary intervention may modulate the pro-inflammatory state and lessen oxidative stress related to MetS, thereby decreasing the cardiovascular risk. In this review we address the current available evidence regarding dietary modulation of inflammation and oxidative stress associated with MetS. PMID- 24168443 TI - Diet and metabolic syndrome: an overview. AB - The metabolic syndrome (MetS) is a complex multifactorial disorder and its incidence is on the increase worldwide. Due to the definitive link between obesity and the MetS weight loss strategies are of prime importance in halting the spread of MetS. Numerous epidemiological studies provide evidence linking dietary patterns to incidence of MetS symptoms. As a consequence of the epidemiology studies, dietary intervention studies which analyse the effects of supplementing diets with particular nutrients of interest on the symptoms of the MetS have been conducted. Evidence has shown that lifestyle intervention comprising changes in dietary intake and physical activity leads to an improved metabolic profile both in the presence or absence of weight loss thus highlighting the importance of a multi-faceted approach in combating MetS. Nutritional therapy research is not focused solely on reducing energy intake and manipulating macronutrient intake but is investigating the role of functional foods or bioactive components of food. Such bioactives which target weight maintenance and /or insulin sensitivity may have a potentially positive effect on the symptoms of the MetS. However the efficacy of different functional nutrients needs to be further defined and clearly demonstrated. PMID- 24168442 TI - Dietary regulation of glucose metabolism in metabolic syndrome. AB - Diet and lifestyle are major modifiable determinants of inflammation, hypertension, atherogenic dyslipidemia, glucose metabolism and central obesity and should be targeted for the prevention and treatment of the metabolic syndrome. As insulin resistance, raised fasting and postprandial insulin levels, impaired carbohydrate tolerance and, ultimately, diabetes (all components of the metabolic syndrome) have been related to increased cardiovascular risk, in this report we review the potential role that individual nutrients, foods/food groups, and dietary patterns play in insulin sensitivity and secretion in the management of metabolic syndrome. We also discuss the effect of diet alone on inflammation and the homeostatic control of glucose, regardless of the effect of exercise and weight loss. PMID- 24168444 TI - Relevance of postprandial lipemia in metabolic syndrome. AB - Metabolic Syndrome (MetS) is a complex disorder defined by the aggregation of interconnected cardiometabolic risk factors which increase the risk of diabetes mellitus type 2 and cardiovascular disease (CVD). MetS is currently a matter of concern and it will continue to be in the future, since there is likely to be a dramatic increase in its prevalence, and subjects with MetS will have an increased risk of mortality, mainly through CVD. Moreover, the implications on the global health burden and the worldwide epidemic of this complex disorder will impact greatly on socioeconomic cost. MetS is therefore a matter of serious concern and we need to understand its etiology in order to improve strategies of treatment and prevention. In this regard, postprandial lipemia has increased in importance over the last few years as it has been demonstrated to influence the development of atherosclerosis. In addition, in modern times, fasting is not the typical physiological state of humans; in fact, they spend most of the time in the postprandial state. However, although it is obvious that postprandial lipemia is present in conditions of obesity, little is known about the relevance of postprandial lipemia in MetS. In the current review, we will explore some aspects of postprandial lipemia which could be of interest for understanding the pathogenesis of this complex disorder and which may help us advance towards more personalized nutrition. PMID- 24168445 TI - Hemostatic factors and the metabolic syndrome. AB - Metabolic syndrome (MetS) is associated with increased risk of both atherothrombotic cardiovascular events and venous thromboembolism. The pro thrombotic potential of MetS, may explain this association. In this review we discuss the relationship of MetS with hemostasis focusing on endothelial function, platelet activity, coagulation, fibrinolysis and hemorheologic markers. Endothelial-dependent vasodilatation is impaired in MetS. This is mostly mediated by a reduced expression of vasodilators (nitric oxide and prostacyclin) with a concomitant increase of vasoconstrictors (endothelin- 1, angiotensin II and thromboxane A2). Platelet activity is enhanced in MetS. A cross-talk between activated endothelium and platelets results in a pro-thrombotic vicious cycle. Enhanced coagulation together with impaired fibrinolysis is also present in MetS. This is mirrored by high fibrinogen and plasminogen activator inhibitor-1 levels. Endothelial dysfunction, expressed by high von Willebrand factor and tissue plasminogen factor levels, also contributes to this abnormality. Whole blood and plasma viscosity is increased in MetS. Lifestyle intervention can improve the MetS-related pro-thrombotic state. These measures include weight reduction and improved composition of the diet. A Mediterranean-style diet rich in olive oil, as a source of monounsaturated fat, and low saturated fat consumption may also be beneficial. PMID- 24168446 TI - Adipobiology for novel therapeutic approaches in metabolic syndrome. AB - Obesity is dramatically increasing virtually worldwide, which has been linked to the rising prevalence of metabolic syndrome. Excess fat accumulation causes severe alterations in adipose tissue function. Actually, adipose tissue is now recognized as a major endocrine and secretory organ that releases a wide variety of signaling molecules (hormones, growth factors, cytokines, chemokines, etc.), the adipokines, which play central roles in the regulation of energy metabolism and homeostasis, immunity and inflammation. In addition, adipose tissue is no longer regarded as a passive lipid storage site but as a highly dynamic energy depot which stores excess energy during periods of positive energy balance and mobilizes it in periods of nutrient deficiency in a tightly regulated manner. Altered lipid release and adipokine production and signaling, as occurs in obesity, are linked to insulin resistance and the associated comorbidities of metabolic syndrome (dyslipidemia, hypertension), which confer an increased risk for the development of type 2 diabetes and cardiovascular disease. Here we summarize current knowledge on adipose tissue and review the contribution of novel techniques and experimental approaches in adipobiology to the identification of novel biomarkers and potential targets for dietary or pharmacological intervention to prevent and treat adipose tissue-associated diseases. PMID- 24168447 TI - Nutrigenetics, metabolic syndrome risk and personalized nutrition. AB - The metabolic syndrome (MetS) is a constellation of metabolic risk factors reflecting overnutrition and sedentary lifestyle and its increasing prevalence is reaching epidemic proportions. The importance of MetS lies in its close association with the risk of cardiometabolic disease. In this scenario, the principal goals of pharmacological therapy for these patients are to achieve and maintain an optimal cardiometabolic control, including lipids, blood glucose and blood pressure; in order to prevent and treat potential complications. Moreover nutrition has commonly been accepted as a cornerstone of treatment for MetS, with the expectation that an appropriate intake of energy and nutrients will improve its control. However the question arises as to whether dietary therapy may require a more personalised approach. In this regard improvements in genetic analysis have enhanced our understanding of the role of genetics in this dietrelated condition. In this review we will present recent data highlighting the importance of gene-nutrient interactions in the context of MetS risk. PMID- 24168448 TI - Evaluation of biochars and activated carbons for in situ remediation of sediments impacted with organics, mercury, and methylmercury. AB - In situ amendment of activated carbon (AC) to sediments can effectively reduce the bioavailability of hydrophobic organic contaminants. While biochars have been suggested as low-cost and sustainable alternatives to ACs, there are few comparative sorption data especially for mercury (Hg) and methylmercury (MeHg) at the low porewater concentrations in sediments. Here we compare the ability of a wide range of commercially available and laboratory synthesized ACs and biochars to sorb PAHs, PCBs, DDTs, inorganic Hg, and MeHg at environmentally relevant concentrations. Compared to natural organic matter, sorption capacity for most organic compounds was at least 1-2 orders of magnitude higher for unactivated biochars and 3-4 orders of magnitude higher for ACs which translated to sediment porewater PCB concentration reductions of 18-80% for unactivated biochars, and >99% for ACs with 5% by weight amendment to sediment. Steam activated carbons were more effective than biochars in Hg sorption and translated to modeled porewater Hg reduction in the range of 94-98% for sediments with low native Kd and 31-73% for sediments with high native Kd values for Hg. Unactivated biochars were as effective as the steam activated carbons for MeHg sorption. Predicted reductions of porewater MeHg were 73-92% for sediments with low native Kd and 57 86% for sediment with high native K(d). ACs with high surface areas therefore are likely to be effective in reducing porewater concentrations of organics, Hg, and MeHg in impacted sediments. Unactivated biochars had limited effectiveness for organics and Hg but can be considered when MeHg exposure is the primary concern. PMID- 24168449 TI - Differential serum levels of eosinophilic eotaxins in primary sclerosing cholangitis, primary biliary cirrhosis, and autoimmune hepatitis. AB - To investigate pathogenic mechanisms of primary sclerosing cholangitis (PSC), primary biliary cirrhosis (PBC), and autoimmune hepatitis (AIH), serum levels of 26 chemokines and cytokines were determined and compared with patients with chronic hepatitis C or in healthy controls. The chemokine eotaxin-3 (E3; CCL26), which recruits eosinophils to sites of inflammation, was found to be highly elevated in all PSC, PBC, and AIH patients compared with HCV patients and healthy controls. Eotaxin-1 (E1; CCL11), another eosinophil-specific chemokine, was elevated in PSC but reduced in PBC and AIH, while the macrophage-derived chemokine (MDC; CCL22) was lower in all PSC, PBC, and AIH patients compared with HCV patients and controls. By incorporating levels of the interleukin (IL)-15 into a diagnostic algorithm, PSC, PBC, and AIH patients could each be differentiated with good sensitivity and specificity. These findings represent the first study to compare the level of serum cytokine/chemokine levels among these related autoimmune-like liver diseases. Furthermore, our data indicate that the measurement of serum E3, E1, CCL22, and IL-15 levels can aid in the diagnosis of these clinically challenging diseases and shed light on the potential pathogenic mechanisms underlying these diseases. By suggesting a potential role for an allergic phenomenon involving eosinophils, which may define them as liver specific allergic diseases, this may open up potential new therapeutic avenues by abrogating the action of these disease-associated immune modulators. PMID- 24168451 TI - Hemodynamic monitoring in the cardiac intensive care unit. AB - Hemodynamic monitoring is central to the management of critically ill patients in the cardiac intensive care unit (CICU). The goals of hemodynamic monitoring are to anticipate threats and complications before they arise, to gauge the effectiveness of interventions, and to avoid progression to a decompensated shock state. Although there are numerous modalities of hemodynamic monitoring in the CICU, discordance exists between assessments based on physical exam and standard hemodynamic parameters and those based on measurements of cardiac output. This article will review both the standard and advanced hemodynamic monitoring strategies employed in the CICU. PMID- 24168450 TI - IL-18 expression results in a recombinant vaccinia virus that is highly attenuated and immunogenic. AB - Interferon-gamma (IFN-gamma) is an attenuating factor for vaccinia virus (VACV), decreasing its virulence in vivo by more than a million fold. It is also a highly effective adjuvant when administered at the time of immunization with protein antigens. However, recombinant VACV (rVACV) vaccines expressing IFN-gamma do not induce enhanced immune responses. It is possible that the IFN-gamma expressed by rVACVs induces both an antiviral state and increased immunological clearance, thus resulting in decreased levels of antigen expression due to reduced viral replication and spread. We conjectured that delaying expression of IFN-gamma would result in enhanced production of antigens by rVACVs thus resulting in increased immune responses to foreign antigens. Interleukin (IL)-18, also known as IFN-gamma inducing factor, is a cytokine that induces T and NK cells to produce IFN-gamma. In this study, we demonstrated that an rVACV expressing bioactive murine IL-18 replicated to low but detectable levels in vivo, unlike an rVACV expressing IFN-gamma. Moreover, the rVACV expressing IL-18 was significantly attenuated in both immunocompromised and immunocompetent mice. This attenuation was dependent on IFN-gamma, as IL-18 expression failed to attenuate VACV in IFN-gamma knock-out mice. Cytotoxic T-cell (CTL) and anamnestic antibody responses were slightly increased in animals vaccinated with the rVACV expressing IL-18. Thus, induction of IFN-gamma because of IL-18 expression resulted in an rVACV that replicated to low but detectable levels in vivo, yet elicited slightly better CTL and anamnestic humoral immune responses. PMID- 24168454 TI - Quantum chemical study of B(C6F5)3-catalyzed hydrosilylation of carbonyl group. AB - The hydrosilylation reaction of a carbonyl group catalyzed by tris(pentafluorophenyl)borane, B(C6F5)3, is investigated by using the DFT method. M06-2X level calculations suggest the presence of a stable complex between trimethylsilane and B(C6F5)3. The attack of the carbonyl group in acetone from the back side of the Si-H bond prompts the abstraction of the hydride ion by B(C6F5)3. This reaction path is lower in free energy than the conventional carbonyl-activation path via a four-membered cyclic transition state. The silane activation mechanism is supported in this case, in agreement with experimental results reported by Piers and by Oestreich. The calculations show, on the other hand, that the silane-activation mechanism does not apply to the reaction catalyzed by BF3. This difference in mechanisms arises from a stronger electrophilicity of the boron center in B(C6F5)3 than in BF3 toward a hydride ion, as demonstrated by an analysis of reactive orbitals. Attractions between the silane part and the fluorine atoms at the ortho positions of C6F5 groups in the Lewis acid assist the path by making up for the destabilization of the reacting system that is caused by the distortion of the B(C6F5)3 framework in forming a bond with the hydrogen of silane. PMID- 24168453 TI - Effect of n-3 and n-6 unsaturated fatty acids on prostate cancer (PC-3) and prostate epithelial (RWPE-1) cells in vitro. AB - Prostate cancer (PCa) is one of the leading causes of death in the elderly men. Polyunsaturated fatty acids (PUFAs) regulate proliferation of cancer cells. In the present study, we evaluated the effect of various PUFAs on the proliferation and survival of human prostate cancer (PC-3) and human prostate epithelial (RWPE 1) cells in vitro.LA, GLA, AA, ALA, EPA and DHA (linoleic acid, gamma-linolenic acid, arachidonic acid, alpha-linolenic acid, eicosapentaenoic acid and docosahexaenoic acid respectively) when tested at 50, 100, 150, and 200 MUM inhibited proliferation of RWPE-1 and PC-3 cells, except that lower concentrations of LA (25 MUM) and GLA (5, 10 MUM) promoted proliferation. Though all fatty acids tested produced changes in the production of interleukin-6 (IL 6), tumor necrosis factor-alpha (TNF-alpha), lipoxin A4 and free radical generation by RWPE-1 and PC-3 cells, there were significant differences in their ability to do so. As expected, supplementation of various n-3 and n-6 fatty acids to RWPE-1 and PC-3 cells enhanced the content of the added fatty acids and their long-chain metabolites in these cells. In contrast to previous results, we did not find any direct correlation between inhibition of cell proliferation induced by various fatty acids and free radical generation. These results suggest that polyunsaturated fatty acids suppress proliferation of normal and tumor cells by a variety of mechanisms that may partly depend on the type(s) of cell(s) being tested and the way these fatty acids are handled by the cells. Hence, it is suggested that more deeper and comprehensive studies are needed to understand the actions of fatty acids on the growth of normal and tumor cells. PMID- 24168452 TI - Selective modulation of autophagy, innate immunity, and adaptive immunity by small molecules. AB - Autophagy is an evolutionarily conserved catabolic process that directs cytoplasmic proteins, organelles and microbes to lysosomes for degradation. Autophagy acts at the intersection of pathways involved in cellular stress, host defense, and modulation of inflammatory and immune responses; however, the details of how the autophagy network intersects with these processes remain largely undefined. Given the role of autophagy in several human diseases, it is important to determine the extent to which modulators of autophagy also modify inflammatory or immune pathways and whether it is possible to modulate a subset of these pathways selectively. Here, we identify small-molecule inducers of basal autophagy (including several FDA-approved drugs) and characterize their effects on IL-1beta production, autophagic engulfment and killing of intracellular bacteria, and development of Treg, TH17, and TH1 subsets from naive T cells. Autophagy inducers with distinct, selective activity profiles were identified that reveal the functional architecture of connections between autophagy, and innate and adaptive immunity. In macrophages from mice bearing a conditional deletion of the essential autophagy gene Atg16L1, the small molecules inhibit IL 1beta production to varying degrees suggesting that individual compounds may possess both autophagy-dependent and autophagy-independent activity on immune pathways. The small molecule autophagy inducers constitute useful probes to test the contributions of autophagy-related pathways in diseases marked by impaired autophagy or elevated IL-1beta and to test novel therapeutic hypotheses. PMID- 24168455 TI - EIF2AK3 mutations in South Indian children with permanent neonatal diabetes mellitus associated with Wolcott-Rallison syndrome. AB - OBJECTIVE: This study describes the clinical and genetic evaluation of permanent neonatal diabetes due to Wolcott-Rallison syndrome (WRS) in south Indian consanguineous families. We aimed to evaluate the genetic basis of the disease in eight children with WRS from five South Indian families. PATIENTS AND METHODS: We studied eight children who presented with permanent neonatal diabetes from five South Indian families. Follow up clinical evaluation revealed features (like liver disease, skeletal dysplasia, and thyroid dysfunction) suggestive of WRS. All the coding exons along with splice sites of KCNJ11, ABCC8, INS, GCK and EIF2AK3 genes were sequenced in all the probands. RESULTS: Two novel homozygous mutations (Trp658Ser, c.3150+1G>T) and one known homozygous mutation (Arg1065*, c.3193C>T) in EIF2AK3 gene were identified in children with WRS. Mutation Arg1065*was identified in four children. CONCLUSIONS: Our results in these families show that the mutations in homozygous state are likely to be causative. We suggest the screening for EIF2AK3 gene mutations as WRS is now recognized as the most frequent cause of neonatal diabetes in children with consanguineous parents. As the mode of inheritance is recessive, screening for genetic mutations becomes important to aid in risk prediction and clinical management. PMID- 24168456 TI - Pregnancy outcome of five patients with renal amyloidosis regarding familial Mediterranean fever. AB - Familial Mediterranean fever (FMF) is an autosomal recessive disease affecting mainly patients of the Mediterranean basin and its major complication is the development of renal AA amyloidosis. On the other hand pregnancy with amyloidosis is not common; nevertheless, amyloidosis will complicate pregnancies also with the underlying disease and may cause terrible perinatal morbidities and mortalities. We report here the cases of five pregnant women and their pregnancy outcomes, who have been diagnosed with FMF complicated by renal amyloidosis. In the five cases, we observed that increased pregnancy complication such as small for gestational age, intrauterine growth restriction, preeclampsia and preterm birth. PMID- 24168458 TI - Granuloma annulare as a possible new adverse effect of topiramate. AB - BACKGROUND: Granuloma annulare (GA) is a relatively common, self-limiting condition that can be associated with disorders such as diabetes mellitus, malignancy, and thyroid disease, and with the use of some drugs. Topiramate is approved for the prevention of migraine. Its adverse effects include somnolence, fatigue, paresthesia, anorexia and weight loss, and other abnormalities. OBJECTIVES: We report a 50-year-old woman in whom topiramate at 50 mg/d was initiated in January 2010. CASE REPORT: One month after starting topiramate, the patient presented with painless nodules on the left ankle, which later spread to the left leg. Histopathology of a punch biopsy revealed lymphohistiocytic infiltrate, collagen degeneration, and mucin deposition, all of which are characteristic of GA. Two weeks after the discontinuation of topiramate, the lesion resolved. Two years later, the patient resumed topiramate. Two weeks later, a new GA appeared in the same area and disappeared within a few weeks of discontinuation of the drug. CONCLUSIONS: Associations between the use of topiramate and a GA-like reaction have been reported in recent years. Based on the present case, it would appear that an actual association between GA and topiramate is possible given that: (i) the GA appeared only after the initiation of topiramate; (ii) the GA resolved after the discontinuation of topiramate; (iii) the GA reappeared with the resumption of topiramate in the same area and with the same characteristics as previously; and (iv) the lesion healed after topiramate was suspended. PMID- 24168457 TI - Hematological and hepatic effects of vascular epidermal growth factor (VEGF) used to stimulate hair growth in an animal model. AB - BACKGROUND: Alopecia areata is the hair loss usually reversible, in sharply defined areas. The treatment of alopecia using growth factors shows interesting activity in promoting hair growth. In this concept, VEGF (vascular endothelial growth factor) is a marker of angiogenesis, stimulating hair growth by facilitating the supply of nutrients to the hair follicle, increasing follicular diameter. The aim of this study was the evaluation of a topical gel enriched with VEGF liposomes on the hair growth stimulation and its toxicological aspects. METHODS: Mesocricetus auratus were randomly divided into three groups. Control group was treated with Aristoflex(r) gel, 1% group with the same gel but added 1% VEGF and 3% group with 3% VEGF. Biochemical, hematological and histological analyses were done. RESULTS: At the end of the experiment (15th day of VEGF treatment) efficacy was determined macroscopically by hair density dermatoscopy analysis, and microscopically by hair diameter analysis. They both demonstrated that hair of the VEGF group increased faster and thicker than control. On the other hand, biochemical and hematological results had shown that VEGF was not 100% inert. CONCLUSIONS: VEGF increased hair follicle area, but more studies are necessary to confirm its toxicity. PMID- 24168459 TI - New directions for EJCC. PMID- 24168461 TI - Poly(amidoamine) dendrimer complexes as a platform for gene delivery. AB - INTRODUCTION: Gene therapy is one of the most effective ways to treat major infectious diseases, cancer and genetic disorders. It is based on several viral and non-viral systems for nucleic acid delivery. The number of clinical trials based on application of non-viral drug and gene delivery systems is rapidly increasing. AREAS COVERED: This review discusses and summarizes recent advances in poly(amidoamine) dendrimers as effective gene carriers in vitro and in vivo, and their advantages and disadvantages relative to viral vectors and other non viral systems (liposomes, linear polymers) are considered. EXPERT OPINION: In this regard, dendrimers are non-immunogenic and have the highest efficiency of transfection among other non-viral systems, and none of the drawbacks characteristic for viral systems. The toxicity of dendrimers both in vitro and in vivo is an important question that has been addressed on many occasions. Several non-toxic and efficient multifunctional dendrimer-based conjugates for gene delivery, along with modifications to improve transfection efficiency while decreasing cytotoxicity, are discussed. Twelve paradigms that affected the development of dendrimer-based gene delivery are described. The conclusion is that dendrimers are promising candidates for gene delivery, but this is just the beginning and further studies are required before using them in human gene therapy. PMID- 24168460 TI - Electroacupuncture at Jing-jiaji points for neck pain caused by cervical spondylosis: a study protocol for a randomized controlled pilot trial. AB - BACKGROUND: Neck pain caused by cervical spondylosis (CS) has become one of the most common health problems around the world. Electroacupuncture (EA) has been employed to relieve CS neck pain, but there is limited clinical evidence for its effectiveness. METHODS/DESIGN: This study consists of a randomized controlled trial (RCT) with two parallel arms: an acupuncture group and an EA group. Both groups will receive acupuncture at Jing-jiaji points for 30 minutes each time, for five sessions per week for a total of 20 sessions during this four-week period. In addition, the EA group will be connected with EA apparatus. The following outcome measurements will be used in examination of subjects: the Northwick Park Neck Pain Questionnaire (NPQ), McGill Pain Questionnaire (MPQ), and Short-Form 36 (SF-36) scale. All these outcomes will be examined at the start of the study, at the end of the second week, at four weeks after randomization, and one and three months after treatment cessation respectively. DISCUSSION: This study aims to assess the efficacy of EA, compared with acupuncture intervention at Jing-jiaji points for the CS neck pain. TRIAL REGISTRATION: Chinese Clinical Trials Register: ChiCTR-TRC-13003422. PMID- 24168462 TI - Milk and rice. AB - The following short article is an account of Israeli nurses caring for Syrian wounded. These wounded are shuffled across the Syrian border into Israeli hospitals. Until today and including today, we are considered 'enemy countries' with no diplomatic relations and fire arms pointing at each other. Six months ago when the Syrian wounded started trickling into our hospitals, the nurses did not know how to react and stood on shaky ground. The casualties were admitted directly into the intensive care units and emergency rooms without knowledge of mechanism of injury, date or circumstances of injury, and alone with no family support. We were told not to communicate with them. However, that request was quickly overlooked and relationships developed. The following report is that of one of the bedside nurses in an Israeli border hospital and her experience of caring for a Syrian casualty. PMID- 24168463 TI - Enhancement of the thermal polarization of water via heat flux and dipole moment dynamic correlations. AB - It has been recently shown that liquid water polarizes as a response to a temperature gradient. This polarization effect can be significant for temperature gradients that can be achieved at micro and nanoscales. In this paper we investigate the dependence of the polarization response of liquid and supercritical water at different thermodynamic conditions using both equilibrium and nonequilibrium molecular dynamics simulations for the extended point charge water model. We find that the thermal polarization features a nonmonotonic behavior with temperature, reaching a maximum response at specific thermodynamic states. We show that the thermal polarization is maximized when the density of states of the heat flux and dipole moment correlation functions feature the strongest overlap. The librational modes of water are shown to play an important role in determining this behavior as well as the heat transport mechanism in water. The librational frequencies show a significant dependence with temperature and pressure. This dependence provides a microscopic mechanism to explain the observed maximization of the thermal-polarization effect. Our work provides new microscopic insights on the mechanism determining the orientation of polar fluids under thermal gradients, as well as new strategies to maximize their orientation by manipulating the dynamic correlations between the heat flux and the sample dipole moment. PMID- 24168465 TI - Effects of a nurse-based case management compared to usual care among aged patients with myocardial infarction: results from the randomized controlled KORINNA study. AB - BACKGROUND: Transition from hospital to home is a critical period for older persons with acute myocardial infarction (AMI). Home-based secondary prevention programs led by nurses have been proposed to facilitate the patients' adjustment to AMI after discharge. The objective of this study was to evaluate the effects of a nurse-based case management for elderly patients discharged after an AMI from a tertiary care hospital. METHODS: In a single-centre randomized two-armed parallel group trial of patients aged 65 years and older hospitalized with an AMI between September 2008 and May 2010 in the Hospital of Augsburg, Germany, patients were randomly assigned to a case management or a control group receiving usual care. The case-management intervention consisted of a nurse-based follow-up for one year including home visits and telephone calls. Key elements of the intervention were to detect problems or risks and to give advice regarding a wide range of aspects of disease management (e.g. nutrition, medication). Primary study endpoint was time to first unplanned readmission or death. Block randomization per telephone call to a biostatistical center, where the randomization list was kept, was performed. Persons who assessed one-year outcomes and validated readmission data were blinded. Statistical analysis was based on the intention-to-treat approach and included Cox Proportional Hazards models. RESULTS: Three hundred forty patients were allocated to receive case management (n=168) or usual care (n=172). The analysis is based on 329 patients (intervention group: n=161; control group: n=168). Of these, 62% were men, mean age was 75.4 years, and 47.1% had at least either diabetes or chronic heart failure as a major comorbidity. The mean follow-up time for the intervention group was 273.6 days, and for the control group it was 320.6 days. During one year, in the intervention group there were 57 first unplanned readmissions and 5 deaths, while the control group had 75 first unplanned readmissions and 3 deaths. With respect to the endpoint there was no significant effect of the case management program after one year (Hazard Ratio 1.01, 95% confidence interval 0.72-1.41). This was also the case among subgroups according to sex, diabetes, living alone, and comorbidities. CONCLUSIONS: A nurse-based management among elderly patients with AMI had no significant influence on the rate of first unplanned readmissions or death during a one-year follow-up. A possible long-term influence should be investigated by further studies. CLINICAL TRIAL REGISTRATION: ISRCTN02893746. PMID- 24168466 TI - Simply mixed commercial red phosphorus and carbon nanotube composite with exceptionally reversible sodium-ion storage. AB - Recently, sodium ion batteries (SIBs) have been given intense attention because they are the most promising alternative to lithium ion batteries for application in renewable power stations and smart grid, owing to their low cost, their abundant natural resources, and the similar chemistry of sodium and lithium. Elemental phosphorus (P) is the most promising anode materials for SIBs with the highest theoretical capacity of 2596 mA h g(-1), but the commercially available red phosphorus cannot react with Na reversibly. Here, we report that simply hand grinding commercial microsized red phosphorus and carbon nanotubes (CNTs) can deliver a reversible capacity of 1675 mA h g(-1) for sodium ion batteries (SIBs), with capacity retention of 76.6% over 10 cycles. Our results suggest that the simply mixed commercial red phosphorus and CNTs would be a promising anode candidate for SIBs with a high capacity and low cost. PMID- 24168469 TI - Friction between solids and adsorbed fluids is spatially distributed at the nanoscale. AB - The widespread developments in the use of nanomaterials in catalysis, adsorption, and nanofluidics present significant new challenges in achieving optimal adsorbed fluid flow characteristics. Here we demonstrate, using molecular dynamics simulations of nanoconfined fluids, that at nanoscales, fluid-solid friction is not restricted to a sharp interface as is commonly assumed; instead it is distributed over the whole adsorbed fluid phase, and is strongest in an interfacial region that is not negligible in comparison to the system size. Our simulations yield position-dependent dynamical fluid-solid friction coefficients, and lead to a modification of conventional hydrodynamics, incorporating distributed momentum loss in the fluid due to fluid-solid interaction. The results demonstrate that the usual concepts of slip length or interfacial friction coefficient are meaningful only for uniform fluids, and lose their significance for adsorbates in nanospaces, which are intrinsically inhomogeneous. We show that static friction coefficients, based on equilibrium density distributions, follow the same spatial dependence as the dynamical coefficients. These results open up possibilities for tailoring nanomaterials and surfaces to engineer low friction pathways for adsorbed fluid flow by tuning the potential energy landscape. PMID- 24168468 TI - Supplementary motor area activation is impaired in severe traumatic brain injury parkinsonism. AB - A high percentage of survivors of severe traumatic brain injury present diffuse axonal injury and extrapyramidal symptoms. The association between diffuse cerebral damage and parkinsonian symptoms is probably because of the interruption of nigro-striato-frontal pathways. While functional magnetic resonance imaging (fMRI) has been widely used to investigate parkinsonism in idiopathic Parkinson disease, little is known about functional brain modifications related to post traumatic parkinsonism (PTP). The aim of this study is to assess cerebral activity of the action-related network in patients with PTP comparing these patients to matched healthy controls. In the fMRI scanner, we proposed to 12 PTP patients and 12 healthy control participants a continuum of tasks involving action-related word production, mental simulation of action, and miming of action triggered by external stimuli such as drawings of objects. Patients with PTP showed a main effect similar to that of healthy controls in all the tasks. Direct comparison revealed hypoactivation of areas in the action-related network in patients with PTP for all the tasks. During the mime of action, which involved actual movement, the hypoactivation was localized to the motor network. Our results suggest that patients with PTP showed a cerebral reorganization for motor tasks in agreement with the cerebral reorganization observed in idiopathic Parkinson disease. For patients with PTP, supplementary motor area impairment seems to play a central role in parkinsonism, in line with the brain reorganization of action-related tasks. PMID- 24168467 TI - Participation of glutamate-333 of the D1 polypeptide in the ligation of the Mn4CaO5 cluster in photosystem II. AB - In the 1.9 A structural model of photosystem II (PDB: 3ARC), the amino acid residue Glu333 of the D1 polypeptide coordinates to the oxygen-evolving Mn4CaO5 cluster. This residue appears to be highly significant in that it bridges the two Mn ions (Mn(B3) and the "dangling" Mn(A4)) that are also bridged by the oxygen atom O5. This oxygen atom has been proposed to be derived from one of two substrate water molecules and to become incorporated into the product dioxygen molecule during the final step in the catalytic cycle. In addition, the backbone nitrogen of D1-Glu333 interacts directly with a nearby Cl- atom. To further explore the influence of this structurally unique residue on the properties of the Mn4CaO5 cluster, the D1-E333Q mutant of the cyanobacterium Synechocystis sp. PCC 6803 was characterized with a variety of biophysical and spectroscopic methods, including polarography, EPR, X-ray absorption, and FTIR difference spectroscopy. The kinetics of oxygen release in the mutant were essentially unchanged from those in wild-type. In addition, the oxygen flash yields exhibited normal period-four oscillations having normal S state parameters, although the yields were lower, indicative of the mutant's lower steady-state dioxygen evolution rate of approximately 30% compared to that of the wild-type. The S1 state Mn-XANES and Mn-EXAFS and S2 state multiline EPR signals of purified D1 E333Q PSII core complexes closely resembled those of wild-type, aside from having lower amplitudes. The S(n+1)-minus-S(n) FTIR difference spectra showed only minor alterations to the carbonyl, amide, and carboxylate stretching regions. However, the mutation eliminated a negative peak at 3663 cm-1 in the weakly H-bonding O-H stretching region of the S2-minus-S1 FTIR difference spectrum and caused an approximately 9 cm-1 downshift of the negative feature in this region of the S1 minus-S0 FTIR difference spectrum. We conclude that fully functional Mn4CaO5 clusters assemble in the presence of the D1-E333Q mutation but that the mutation decreases the yield of assembled clusters and alters the H-bonding properties of one or more water molecules or hydroxide groups that are located on or near the Mn4CaO5 cluster and that either deprotonate or form stronger hydrogen bonds during the S0 to S1 and S1 to S2 transitions. PMID- 24168470 TI - Simultaneous bilateral sleeve fracture of the patellae in a preadolescent athlete. PMID- 24168472 TI - Impact of the motion and visual complexity of the background on players' performance in video game-like displays. AB - The visual interfaces of virtual environments such as video games often show scenes where objects are superimposed on a moving background. Three experiments were designed to better understand the impact of the complexity and/or overall motion of two types of visual backgrounds often used in video games on the detection and use of superimposed, stationary items. The impact of background complexity and motion was assessed during two typical video game tasks: a relatively complex visual search task and a classic, less demanding shooting task. Background motion impaired participants' performance only when they performed the shooting game task, and only when the simplest of the two backgrounds was used. In contrast, and independently of background motion, performance on both tasks was impaired when the complexity of the background increased. Eye movement recordings demonstrated that most of the findings reflected the impact of low-level features of the two backgrounds on gaze control. PMID- 24168471 TI - Self-rated quality of life of city-dwelling elderly people benefitting from social help: results of a cross-sectional study. AB - BACKGROUND: The percentage of people aged 65 or older living in Poland is 13.6%, but 17.2% in Lodz. The aim of the study was to identify factors correlating with the self-rated quality of life of elderly inhabitants of cities applying for social help, on the basis of a cross-sectional study. METHODS: The study was conducted in Lodz, a large Polish city, between September 2011 and February 2012 in a group of people applying for help in the Municipal Social Welfare Centre. Four hundred and sixty-six respondents aged 65 or older were included in the study. The tool used in the study was an interview questionnaire. The respondents answered questions on their demographic situation, living conditions, financial, health and social situation. The authors also applied the WHOQOL-BREF Questionnaire, the Activities of Daily Living Scale (ADL) and the Geriatric Depression Scale (GSOD). For statistical purposes, the authors used single- and multiple-factor regression and the Statistica 9.0 Program. The results were presented as an odds ratio (OR) with a 95% confidence interval (CI); the adopted significance level was p < 0.05. The authors applied the Pearson's x(2) test in order to evaluate the structure of the studied group and the subpopulation, who were aged 65 or older and using social help, throughout the city. RESULTS: Logistic regression confirmed that a high quality of life depends on the following variables: university education (OR = 2.31; p<0.05), an income which is sufficient to live (OR = 1.63; p<0.05), no heart palpitations (OR = 2.32; p<0.05), stable blood pressure (OR = 2.32; p<0.05), no headaches (OR = 1.55; p<0.05), no pain in the chest (OR = 1.51; p<0.01), no shortness of breath (OR = 1.51; p<0.01), no tiredness (OR = 2.08; p<0.05), a score on the Geriatric Depression Scale pointing to a lack of suspected depression (OR = 9.88; p<0.001 if the person does not suffer from depression and OR = 6.33; p<0.001 if there is uncertain depression) as well as not using nursing services, a score on the ADL Scale confirming the person's fitness and participation in family gatherings. CONCLUSIONS: A subjective evaluation of the quality of life of the elderly depends on many factors. An identification of these factors might be helpful in implementing steps aimed at improving the quality of life of elderly people who, as a consequence, will need less social help: particularly nursing services. PMID- 24168474 TI - Purification and physicochemical characterization of a trypsin inhibitor from Cassia absus Linn. AB - A thermotolerant protein with trypsin inhibitory activity designated as CaTI was purified to homogeneity from seeds of Cassia absus. Gel filtration chromatography and SDS-PAGE analysis showed the apparent molecular mass of ~20 kDa. Partial internal sequences indicate that CaTI belongs to Kunitz-inhibitor family. CaTI inhibits the bovine trypsin in 1:1 molar ratio and exhibited a competitive-type inhibitory activity with Ki = 5.6 x 10(-9) M. The inhibitory activity was retained over a broad pH range (2-12). Thermal stability study showed that it is stable up to 80 degrees C and inhibition activity reduced at and above 90 degrees C which might be due to the presence of predominantly beta-sheets revealed by the CD study. The proteolysis studies of CaTI exhibited strong resistance to proteolysis by different proteases tested. The studies show that CaTI can be used as potential candidates for the development of the transgenic plant against the microbes and insect pests. PMID- 24168475 TI - Defect structure, phase separation, and electrical properties of nonstoichiometric tetragonal tungsten bronze Ba(0.5-x)TaO(3-x). AB - New insight into the defect chemistry of the tetragonal tungsten bronze (TTB) Ba(0.5-x)TaO(3-x) is established here, which is shown to adapt to a continuous and extensive range of both cationic and anionic defect stoichiometries. The highly nonstoichiometric TTB Ba(0.5-x)TaO(3-x) (x = 0.25-0.325) compositions are stabilized via the interpolation of Ba(2+) cations and (TaO)(3+) groups into pentagonal tunnels, forming distinct Ba chains and alternate Ta-O rows in the pentagonal tunnels along the c axis. The slightly nonstoichiometric Ba(0.5 x)TaO(3-x) (x = 0-0.1) compositions incorporate framework oxygen and tunnel cation deficiencies in the TTB structure. These two mechanisms result in phase separation within the 0.1< x < 0.25 nonstoichiometric range, resulting in two closely related (TaO)(3+)-containing and (TaO)(3+)-free TTB phases. The highly nonstoichiometric (TaO)(3+)-containing phase exhibits Ba(2+) cationic migration. The incorporation of (TaO)(3+) units into the pentagonal tunnel and the local relaxation of the octahedral framework around the (TaO)(3+) units are revealed by diffraction data analysis and are shown to affect the transport and polarization properties of these compositions. PMID- 24168476 TI - Altogether now: Activating interdependent self-construal induces hypermotor resonance. AB - Nonconscious mimicry (NCM) has been widely studied but the mechanisms underlying it remain unspecified. One possibility is that NCM is mediated by motor resonance (MR). If so, factors that moderate NCM may affect MR. Priming interdependent self construal (InterSC) increases NCM. We measured MR in a cued-response task using electromyography (EMG) while participants squeezed a rubber ball hard or softly in response to colored words. Words were superimposed on videos depicting hard or soft squeezes. Words primed InterSC or independent self-construal (IndSC). When observed squeezes were incongruent with word color, reaction time (RT) slowed and EMG activity was modulated. These effects were greater for InterSC primes than IndSC primes. Participants who failed to notice any difference in the actions in the videos also showed the effect. Activating InterSC causes MR processes to become hypersensitive to observed actions, even in the absence of awareness of what the action was. PMID- 24168478 TI - The footprints of a wandering mind: Further examination of the time course of an attentional lapse. AB - Recently, understanding the sequence of events that precedes an attentional lapse has become an important question in cognitive neuroscience. To examine the processes which lead to such errors, participants performed a simple go/no-go task used for measuring attentional failure. To study the role of internal distraction, the participants' tendency to daydreaming was assessed via a questionnaire. Principal components analysis (PCA) was used to decompose the response time (RT) course into the underlying components. Analysis identified three components that made up 54% of the data collected. One factor indicated the overall magnitude of the RT in a given block. This factor showed a significant negative weighting prior to an error. A second factor indicating that RT shifted from slow to fast was also identified. The parity of this factor was predictive of error for individuals high on daydreaming, indicating that errors in individuals with a rich, imaginative mental life showed a shift from slow to fast responding prior to an attentional lapse. This analysis provides further evidence that attentional lapses can result from events that took place many seconds before the mistake and that the elements of the default mode may be involved in these lapses. PMID- 24168477 TI - Corticospinal excitability modulation to hand muscles during the observation of appropriate versus inappropriate actions. AB - Transcranial magnetic stimulation (TMS) studies have shown that the observation of an action causes subliminal activation within the motor system. However, the issue of whether such an effect is modulated by the match between the observed action and that the observer would have exhibited if acting under similar circumstances remains unclear. We address this issue by recording motor potentials evoked by single-pulse TMS from the first dorsal interosseous (FDI) and abductor digiti minimi (ADM) muscles during the observation of video-clips representing prehensile actions towards small or large objects. In a separate behavioral study, participants were asked to evaluate which type of grasp would be the most appropriate for the tested objects. The TMS data revealed a selective motor facilitation during the observation of movements recruiting the targeted digits. We contend that, in action observation tasks, the human corticospinal system mediating action observation effects codes merely for the visual aspects of the observed action. PMID- 24168479 TI - Mirror-touch synaesthesia: A case of faulty self-modelling and insula abnormality. AB - Abstract This commentary describes an additional line of evidence related to the suggestion that mechanisms of social perception facilitate the development of a perceptual model of one's own mind. Drawing on findings from mirror-touch synaesthesia, we highlight the importance of the insula in distinguishing between the perceptions of one's own experience versus someone else's. PMID- 24168480 TI - Functions of consciousness. AB - Abstract Evolutionary theory indicates that consciousness has a function, if it is complex enough to be supported by genetically guided brain structures. Otherwise there would be no selective pressure against degrading it. Hints about its function come from word priming studies, where conscious awareness of a prime allows it to be avoided according to instructions. Consciousness, then, allows behavior to be driven by internal plans rather than primed contingencies from the momentary environment. Since consciousness is normally tested by memory of events, its mechanism may be a form of working memory. PMID- 24168481 TI - Should damage to the machinery of social perception damage perception? AB - Abstract We argue that Graziano and Kastner are mistaken to claim that neglect favors their self-directed social perception account of consciousness. For the latter should not predict that neglect would result from damage to mechanisms of social perception. Neglect is better explained in terms of damage to attentional mechanisms. PMID- 24168482 TI - Consciousness is for sharing. AB - Abstract I welcome the idea that consciousness, rather than being private, has a crucial role in understanding other minds. However, I believe that the critical mechanism underlying consciousness is meta-cognition; the ability to reflect upon and report mental states, whether our own or those of others. This allows us to share experiences and create a more accurate picture of the world. PMID- 24168483 TI - Hybrid Social Cognitive Models, Meta-Consciousness, and representations. AB - Abstract Hybrid social cognitive models, based not only on simulation, are desirable, especially in complex scenarios. It is unclear, however, which neural systems support non simulative processes. Furthermore, the proposal that consciousness is a form of representation of attention, while novel, relies on a traditional concept of representation. Recent findings suggest an ontological priority of representations, where the representation and the thing being represented are not distinct at all. PMID- 24168484 TI - Autism and perception of awareness in self and others: Two sides of the same coin or dissociated abilities? AB - Abstract Graziano and Kastner propose a theoretical framework suggesting that the same cognitive machinery underlies computation and inferences concerning (the content of) awareness in others as underlies the perception of the contents of our own awareness. We draw from this hypothesis a strong prediction: Individuals who have deficiencies in one of these abilities must also be impaired in the other. We discuss evidence supporting this prediction from the literature on autism spectrum disorder, but also discuss tentative evidence for a possible dissociation between these two abilities. We conclude that these lines of evidence form crucial empirical tests of the theory. PMID- 24168485 TI - Not all information is created equal. AB - Abstract Granziano & Kastner's account of consciousness as a process based on knowledge of what others are attending to does explain conscious access to spatial location. However, it fails to account for consciousness of the many object attributes that an external observer cannot infer from the subject's gaze. PMID- 24168487 TI - Bodily self-consciousness, and the primacy of self related signals such as the 1(st) person perspective and self-location. AB - Abstract G&K provide a new and interesting perspective on consciousness, by arguing that consciousness is a product of social perception. Based on the overlap between the neural mechanisms underlying spatial awareness of other people and oneself, out-of-body experiences (OBEs), and social perception the authors argue that consciousness is based on the brain signals that represent other people and their spatial awareness. Although we generally welcome the authors efforts, we (1) would like to emphasize that consciousness has two distinct spatial aspects, namely self-location and first-person perspective, (2) cite evidence about distinct developmental and brain mechanisms concerning first- versus third-person perceptions and cogitations and (3) argue for a primacy of multisensory own body perception over social perception and awareness as a neurobiological foundation of consciousness. PMID- 24168486 TI - Stimulus independence, social cognition and consciousness. AB - Abstract A consensus emerging from neuroscience is that certain brain regions show activity correlated with stimulus independent (e.g. private) conscious thought and yet are also implicated in public social processes. The fact that systems supporting social processing also exhibit activity with no obvious perceptual referent, can be seen as support for the framework suggested by Graziano and Kerber (this volume) once it is recognized that the property of stimulus independence is also an important feature of consciousness. Understanding the social basis behind private stimulus independent thought, therefore, may provide an important assessment of the validity of the Graziano and Kerber hypothesis. PMID- 24168488 TI - Awareness as a perceptual model of attention. AB - We proposed a theory of consciousness in which the machinery for social perception constructs awareness, and awareness is a perceptual model of the process of attention. One can attribute awareness to others or to oneself. Awareness of X is the brain's perceptual metaphor for the deep attentive processing of X. A set of ten comments on our hypothesis are included in this issue. Each comment raises specific points some of which directly challenge the hypothesis. Here we respond to these specific points and challenges. PMID- 24168489 TI - Substantial skeletal muscle loss occurs during only 5 days of disuse. AB - AIM: The impact of disuse on the loss of skeletal muscle mass and strength has been well documented. Given that most studies have investigated muscle atrophy after more than 2 weeks of disuse, few data are available on the impact of shorter periods of disuse. We assessed the impact of 5 and 14 days of disuse on skeletal muscle mass, strength and associated intramuscular molecular signalling responses. METHODS: Twenty-four healthy, young (23 +/- 1 year) males were subjected to either 5 (n = 12) or 14 (n = 12) days of one-legged knee immobilization using a full leg cast. Before and immediately after the immobilization period, quadriceps muscle cross-sectional area (CSA), leg lean mass and muscle strength were assessed, and biopsies were collected from the vastus lateralis. RESULTS: Quadriceps muscle CSA declined from baseline by 3.5 +/ 0.5 (P < 0.0001) and 8.4 +/- 2.8% (P < 0.001), leg lean mass was reduced by 1.4 +/- 0.7 (P = 0.07) and 3.1 +/- 0.7% (P < 0.01) and strength was decreased by 9.0 +/- 2.3 (P < 0.0001) and 22.9 +/- 2.6% (P < 0.001) following 5 and 14 days of immobilization respectively. Muscle myostatin mRNA expression doubled following immobilization (P < 0.05) in both groups, while the myostatin precursor isoform protein content decreased after 14 days only (P < 0.05). Muscle MAFBx mRNA expression increased from baseline by a similar magnitude following either 5 or 14 days of disuse, whereas MuRF1 mRNA expression had increased significantly only after 5 days. CONCLUSION: We conclude that even short periods of muscle disuse can cause substantial loss of skeletal muscle mass and strength and are accompanied by an early catabolic molecular signalling response. PMID- 24168492 TI - A prospective, multi-institutional diagnostic trial to determine pathologist accuracy in estimation of percentage of malignant cells. AB - CONTEXT: The fraction of malignant cells in tumor tissue submitted for tests of genetic alterations is a critical variable in testing accuracy. That fraction is currently determined by pathologist visual estimation of the percentage of malignant cells. Inaccuracy could lead to a false-negative test result. OBJECTIVE: To describe a prospective, multi-institutional study to determine pathologist estimation accuracy. DESIGN: Ten *20 magnification images of hematoxylin-eosin-stained colon tissue specimens were sent as an educational component of the College of American Pathologists KRAS-B 2011 Survey. Data from 194 labs were analyzed and compared to a criterion standard with comprehensive manual nuclear counts. RESULTS: Survey responses indicated low interlaboratory precision of pathologist estimation, but mean estimates were fairly accurate. A total of 5 of the 10 cases assessed showed more than 10% of respondents overestimating in a manner that could lead to false-negative test results. CONCLUSIONS: The significance of estimation errors resulting in molecular testing failures with implications for patient care is unknown, but the current study suggests false-negative test results may occur. PMID- 24168493 TI - Room for improvement: initial experience with anal cytology: observations from the College of American Pathologists interlaboratory comparison program in nongynecologic cytology. AB - CONTEXT: Anal cytology is being used more frequently for anal cancer screening, yet many cytologists are unfamiliar with it. OBJECTIVE: To describe the performance of anal cytology in the College of American Pathologists' Interlaboratory Comparison Program in Non-Gynecologic Cytology (CAP NGC) educational slide program during a 6-year time span, from 2006 to 2011, using participant responses (pathologist, cytotechnologist, and laboratory). DESIGN: Concordance rates for the target diagnosis and general category for each slide challenge were analyzed. Four main factors were included in the analysis: (1) general category or specific responses, (2) program year from 2006 to 2011, (3) participant type (pathologist, cytotechnologist, or overall laboratory), and (4) preparation type (liquid-based or conventional). RESULTS: Participants most frequently correctly classified negative for intraepithelial lesion or malignancy, low-grade squamous intraepithelial lesion, and herpes simplex virus infection, with concordance rates of 78.8%, 85%, and 80.2%, respectively. Performance on challenges with target diagnoses of high-grade squamous intraepithelial lesion (HSIL), squamous cell carcinoma, and ameba was poor, with concordance rates of 57.1%, 56.2%, and 41.5%, respectively. Significant improvement during the 6 years was seen in the concordance rates of participants' responses for low-grade squamous intraepithelial lesion challenges but not for HSIL. There was no significant difference in performance by slide preparation type. CONCLUSIONS: The poor performance on anal cytology in the CAP NGC program, especially with regard to correct identification of HSIL and squamous cell carcinoma, indicates that there is a need for continued education about anal cytology. PMID- 24168494 TI - Implementation of the Bethesda System for Reporting Thyroid Cytopathology: observations from the 2011 thyroid supplemental questionnaire of the College of American Pathologists. AB - CONTEXT: Although information about the Bethesda System for Reporting Thyroid Cytopathology (TBSRTC) has been widely disseminated since its inception in 2007, the extent of its implementation and impact on daily practice has not been formally evaluated. OBJECTIVES: To assess the extent of uptake of TBSRTC across pathology laboratories and to evaluate its impact on daily practice by collating participant responses to the 2011 supplemental thyroid questionnaire of the College of American Pathologists. DESIGN: A questionnaire was designed to gather information about various aspects of TBSRTC and mailed in June 2011 to 2063 laboratories participating in the College of American Pathologists cytopathology interlaboratory comparison program. The participating laboratories' answers were collated and summarized. RESULTS: Seven hundred and seventy-seven laboratories (37.6%) returned the survey. Although 60.9% (n = 451) and 17.1% (n = 127) of laboratories reported using TBSRTC or planning to use it in the near future, respectively, 22% (n = 163) had no plans to implement TBSRTC. Of the latter, 32% (n = 70) stated that they were unaware of this classification system. The majority (78.3%, n = 343) of the laboratories used TBSRTC as published in the Thyroid Bethesda System atlas, whereas 21.7% (n = 95) used it with minor modifications. Most reported that the use of TBSRTC had caused either no change (n = 67, 15.2%) or only minor changes (n = 353, 80.2%) in the terminology and diagnostic criteria previously used in their laboratories. CONCLUSIONS: According to the collected data, TBSRTC is generally well implemented in pathology laboratories. However, because approximately a third of those not using this terminology are not aware of it, additional educational efforts regarding TBSRTC are warranted. PMID- 24168495 TI - Histologic and immunohistochemical analyses of endometrial carcinomas: experiences from endometrial biopsies in 358 consultation cases. AB - CONTEXT: Uterine serous carcinoma is biologically more aggressive than the endometrioid carcinoma. Because uterine serous carcinoma has a high propensity for lymphovascular invasion and intraperitoneal and extra-abdominal spread, accurate diagnosis of this tumor type in endometrial biopsies/curettings is critical for appropriate clinical management. OBJECTIVE: To share our experience in the evaluation of endometrial biopsy specimens in type I and type II endometrial adenocarcinoma. DESIGN: We retrospectively reviewed 358 biopsies containing endometrial carcinoma during a recent 3 year period of our consultation records. In cases in which our interpretation differed from the submitting diagnosis, a panel of immunostains was performed. The performance characteristics of each antibody in our panel was calculated in this group of challenging cases. RESULTS: Among the endometrial carcinomas we examined, a diagnosis of type I carcinoma accounted for 91% of cases (327 of 358) and type II carcinoma for 9% of cases (31 of 358); 41 cases (11.5%) were ambiguous or discordant (differing from submitted diagnoses and reviewed) based on histology alone. All 41 ambiguous and discordant cases were further evaluated with a battery of immunohistochemical markers. Of the 41 cases, 36 (88%) were ultimately classified (10 cases [24%] were endometrioid carcinoma; 18 cases [44%] were uterine serous carcinoma; 8 cases [20%] resulted in various other outcomes) and 5 cases (12%) remained indeterminate. CONCLUSIONS: Making the distinction between type I and II endometrial carcinoma remains a common problem in general practice. Although no one biomarker provides excellent statistical performance, a panel of immunohistochemical markers is often useful in difficult cases. PMID- 24168496 TI - BerEp4, cytokeratin 14, and cytokeratin 17 immunohistochemical staining aid in differentiation of basaloid squamous cell carcinoma from basal cell carcinoma with squamous metaplasia. AB - CONTEXT: Basaloid squamous cell carcinoma (bSCC) is an uncommon variant of squamous cell carcinoma, which may overlap histologically with basal cell carcinoma with squamous metaplasia (BCCm). OBJECTIVE: To aid in the differentiation of these neoplasms using immunohistochemical staining because of the worse prognosis associated with bSCC. DESIGN: Using immunohistochemical techniques, we investigated BerEp4, cytokeratin 17 (CK17), and cytokeratin 14 (CK14) protein expression in 25 cases of bSCC (8 cutaneous [32%], 12 aerodigestive tract [48%], and 5 lymph node metastases [20%]) and 43 cases of BCCm (39 cutaneous [91%], and 4 metastases [9%]). An immunoreactivity score was assigned using the percentage of tumor cells staining and the pattern of expression. Interobserver agreement for 2 independent pathologists was assessed using a kappa coefficient. RESULTS: The mean percentage of staining was significantly higher in BCCm, compared with bSCC (BerEp4, P = .006; CK17, P < .001; CK14, P < .001; unpaired t test), with 58% of BCCm cases (25 of 43) displaying diffuse staining for all markers, and nearly all (98%; 42 of 43) displaying diffuse staining for CK17 and CK14. In contrast, no bSCC cases (0%) displayed diffuse staining for all 3 markers, and only 8% (2 of 25) displayed diffuse staining for CK17 and CK14. High interobserver agreement was determined. CONCLUSIONS: BerEp4 alone is unreliable for differentiation between BCCm and bSCC, and the addition of either CK14 or CK17 will augment the sensitivity and negative predictive value of BerEp4 staining in BCCm and bSCC diagnosis. PMID- 24168497 TI - Lack of standards for the detection of melanoma in sentinel lymph nodes: a survey and recommendations. AB - CONTEXT: Detection of microscopic melanoma metastases in sentinel lymph nodes drives clinical care; patients without metastases are observed, and patients with metastases are offered completion lymphadenectomy and adjuvant therapy. OBJECTIVE: We sought to determine common elements in currently used analytic platforms for sentinel lymph nodes in melanoma patients. DESIGN: An electronic survey was distributed to 83 cancer centers in North America. RESULTS: Seventeen responses (20%) were received. The number of sentinel lymph node mapping procedures for melanoma ranged from less than 11 to more than 100 patients per year, with 72% of institutions mapping more than 50 melanoma patients a year. Uniform practices included (1) processing all of the lymph node tissue rather than submitting representative sections and (2) use of immunohistochemical stains if no tumor was identified on the hematoxylin-eosin-stained sections. Significant variability existed regarding the method of sectioning lymph nodes at grossing and in the histology laboratory; most bisected nodes longitudinally (94%) and performed deeper levels into the block (67%), but these were not uniform practices. S-100 was the most commonly used immunohistochemical stain (78%), followed by Melan-A (56%), MART-1 (50%), HMB-45 (44%), tyrosinase (33%), MiTF (11%), and pan-melanoma (6%). CONCLUSIONS: There is a need for a standardized platform for detecting melanoma in sentinel lymph nodes. Current practices by a majority of laboratories and findings in the reported literature support the following: histologic evaluation of all lymph node tissue, use of immunohistochemical stains, bisecting lymph nodes longitudinally, and performing deeper levels into the tissue block. PMID- 24168498 TI - Utility of flow cytometry of cerebrospinal fluid as a screening tool in the diagnosis of central nervous system lymphoma. AB - CONTEXT: Experiences at our institution show that flow cytometry analysis (FCA) has become routine clinical practice in the workup of patients with altered mental status, even if risk factors are low. OBJECTIVE: To assess diagnostic accuracy of combined FCA and cytology in the diagnosis of central nervous system lymphoma in an unselected patient population with neurologic symptoms, including patients with no history of lymphoma or suspicious radiology. DESIGN: Between 2001 and 2011, cerebrospinal fluid was submitted from 373 patients for lymphoma screening by FCA. The medical records were reviewed for patient symptomatology, history of malignancy, brain imaging, FCA results, cytology results, brain biopsy, and clinical follow-up. RESULTS: A lymphoid malignancy was detected by FCA in 4% of cases. A positive diagnosis was more likely in patients with either a history of hematologic malignancy and/or a suspicious radiology result (P = .009). All patients with no history of lymphoma and no suspicious radiology (n = 102) had negative cytology, and none had a correspondingly positive FCA result. The positive and negative predictive values of combined cytology and FCA in the patients with history of lymphoma and/or abnormal imaging results were 92% and 89%, respectively, when compared with open brain tissue biopsy, and 89% and 86%, respectively, when compared with clinical follow-up. When low-risk patients were included, the positive predictive value remained at 92%, but the negative predictive value dropped to 52% with the open brain biopsy as the reference, and values did not change significantly for the group with clinical follow-up. CONCLUSIONS: Concurrent FCA and cytology are most useful in the appropriate clinical setting, and we propose a triage algorithm for how FCA on cerebrospinal fluid is best used. PMID- 24168500 TI - Should "indeterminate" diagnoses be used for thyroid fine-needle aspirates of nodules smaller than 1 cm? AB - CONTEXT: The Bethesda System for thyroid fine-needle aspirates does not account for the size of the lesion that is aspirated. OBJECTIVE: To determine whether the size of the lesion would be helpful in order to reduce indeterminate thyroid aspirations. DESIGN: We correlated the results of all thyroid aspirations and surgical resection for the last 16 years at our institutions. RESULTS: A total of 9080 cases were aspirated and 1393 resections were performed. Of those resected, a total of 236 (17%) were classified as atypical follicular cells of undetermined significance, and 256 (18%) were classified as suspicious for a follicular/Hurthle cell neoplasm. A total of 52 incidental papillary carcinomas were identified in these indeterminate cases at resection (52 of 492; 11%). Thirty-seven (16%) atypical follicular cells of undetermined significance cases and 21 (8%) suspicious for a follicular/Hurthle cell neoplasm cases were for nodules smaller than 1 cm in diameter. When cases subtyped as atypical, a papillary carcinoma cannot be ruled out, were removed (13 cases), the remaining 24 and 21 aspirates identified 3 tumors each (13% and 14%), all papillary carcinomas. Together, the incidence of identified carcinomas was not significantly different than that of incidental carcinomas (13% versus 11%, P = .48). The rate of identified carcinomas was significantly less than for similar indeterminate cases smaller than 1 cm (excluding cases of atypical, papillary carcinoma cannot be ruled out) (88 of 330 cases; 27%; P = .05). CONCLUSIONS: For nodules smaller than 1 cm in our series, indeterminate aspirates without features of papillary carcinomas have the same risk of malignancy as benign aspirates. PMID- 24168499 TI - The expression of PTEN is associated with improved prognosis in patients with ampullary adenocarcinoma after pancreaticoduodenectomy. AB - CONTEXT: Phosphatase and tensin homolog (PTEN) is one of the most frequently inactivated tumor suppressor genes in sporadic cancers. Somatic mutations of PTEN occur in many tumors including those of the gastrointestinal and hepatobiliary tracts. Loss of PTEN expression is associated with poor prognosis in patients with metastatic colonic adenocarcinoma, gastroesophageal junction adenocarcinoma, gastric adenocarcinoma, and pancreatic ductal adenocarcinoma. OBJECTIVE: To study the expression of PTEN and its significance in ampullary adenocarcinoma (AA). DESIGN: We constructed tissue microarrays by using archival tissue from 92 patients (55 males, 37 females; median age, 63 years; age range, 37 to 87 years) with previously untreated AA who underwent pancreaticoduodenectomy at our institution. PTEN expression was evaluated by immunohistochemistry, scored semiquantitatively (based on staining intensity and percentage positive tumor cells), and correlated with clinicopathologic features and survival. RESULTS: Of 92 cases, 23 (25.0%) were PTEN negative. Loss of PTEN expression correlated with lymph node metastasis (P = .004), advanced American Joint Committee on Cancer (AJCC) stage (P = .02), and higher frequency of recurrence (P = .03). Patients with PTEN-negative tumors had shorter disease-free survival (DFS, mean: 89.0 +/- 20.8 months) and overall survival (OS, mean: 93.1 +/- 19.1 months) than those with PTEN-positive tumors (DFS, mean: 161.4 +/- 11.7 months, P = .01; OS, mean: 175.4 +/- 11.0 months, P = .001). In multivariate analyses, PTEN expression was a prognostic factor for both DFS and OS, independent of AJCC stage, lymph node status, pathologic tumor (pT) stage, and differentiation. CONCLUSIONS: Loss of PTEN expression is associated with poor DFS and OS in patients with AA after curative surgery. PTEN expression may be used as a prognostic marker for patients with resected AA. PMID- 24168501 TI - Patterns in immunohistochemical usage in extended core prostate biopsies: comparisons among genitourinary pathologists and nongenitourinary pathologists. AB - CONTEXT: Immunohistochemical (IHC) stains have known utility in prostate biopsies and are widely used to augment routine staining in difficult cases. Patterns in IHC utilization and differences based on pathologist training and experience is understudied in the peer-reviewed literature. OBJECTIVES: To compare the rates of IHC usage between specialized (genitourinary; [GU]) and nonspecialized (non-GU) pathologists in extended core prostate biopsies (ECPBs) and the effects of diagnosis; and in cancer cases Gleason grade, disease extent, and perineural invasion on the rate. DESIGN: Consecutive ECPBs from 2009-2011 were identified and billing data were used to determine the number of biopsies and IHC stains per case. Diagnoses were mapped and in cancer cases, Gleason grade, extent of disease, and perineural invasion were recorded. Pathologists were classified as GU or non-GU on the basis of training and experience. RESULTS: A total of 618 ECPBs were included in the study. Genitourinary pathologists ordered significantly fewer IHC tests per case and per biopsy than non-GU pathologists. The rate of ordering was most disparate for biopsies of cancerous and benign lesions. For biopsies of cancerous lesions, high-grade cancer, bilateral disease, and perineural invasion decreased the rate of ordering in both groups. In cancer cases, GU pathologists ordered significantly fewer stain tests for highest Gleason grade of 3 + 3 = 6, for patients with focal disease and for patients with multiple positive bilateral cores. The effect of the various predictors on IHC ordering rates was similar in both groups. CONCLUSIONS: Genitourinary pathologists ordered significantly fewer IHC stain tests than non-GU pathologists in ECPBs. Guidelines to define when IHC workup is necessary and not necessary may be helpful to guide workups. PMID- 24168502 TI - Reference intervals of reticulated platelets and other platelet parameters and their associations. AB - CONTEXT: Reticulated platelets are platelets recently released from the bone marrow, and they can serve as a noninvasive indicator of recent megakaryopoietic activity. Widespread clinical use has been hampered by laborious methods and lack of standardization. Recently, a fully automated method was released on the Abbott CELL-DYN Sapphire hematology analyzer. OBJECTIVE: To establish reference ranges for reticulated platelets. Secondary aims were to investigate associations between reticulated platelets and other platelet parameters like mean platelet volume, plateletcrit, and platelet distribution width. DESIGN: Reticulated platelets and other platelet parameters were measured in an unselected cohort of 8089 subjects visiting a primary health care laboratory. The reticulated platelet data were analyzed using the Bhattacharya technique. In addition, a nonparametric method was used in selected subjects with normal platelet counts for providing reference ranges. RESULTS: Reticulated platelets ranged from 0.4% to 6.0% or from 1 to 18 * 10(3)/MUL. Reticulated platelets increased significantly with the subjects' age. Statistically, males had slightly higher values than females, but the differences were negligible. Reticulated platelets were positively correlated with platelet count and negatively with mean platelet volume. CONCLUSIONS: Reference ranges have been established for reticulated platelets as measured on the CELL-DYN Sapphire hematology analyzer. There were no relevant differences between the sexes, but there was a clear effect of age. An individual's reticulated platelets are associated with the platelet count as well as mean platelet volume. PMID- 24168503 TI - Use of an automated coagulation analyzer to perform heparin neutralization with polybrene in blood samples for routine coagulation testing: practical, rapid, and inexpensive. AB - CONTEXT: Heparin contamination in blood samples may cause false prolongation of activated partial thromboplastin time (aPTT) and prothrombin time results. Polybrene can neutralize heparin, but it affects coagulation by itself. OBJECTIVES: To determine the optimal concentration of polybrene to neutralize heparin, to determine the suitable sequence of reagents for the neutralization method performed on the analyzer at the same time as prothrombin time and aPTT testing, and to detect the heparin contamination in blood samples for coagulation tests in our hospital using this method. DESIGN: Various concentrations of heparin were added to 10 normal and 76 abnormal plasma samples to study the efficacy of polybrene. Two programs of reagent sequencing for aPTT with polybrene performed on the analyzer were tested. Samples suspected of heparin contamination according to our criteria were selected for neutralization during a 3-month period. RESULTS: The optimal final concentration of polybrene was 25 MUg/mL. Polybrene should be added after the aPTT reagent to minimize its interference effect. Even though results of prothrombin time and aPTT after neutralization did not equal those before the spike of heparin, the differences might not be clinically significant. Eighty-one of 4921 samples (1.6%) were selected for aPTT with the neutralization method, and the detection rate of heparin contamination was 84% (68 of 81), giving an overall incidence of 1.4% (68 of 4921). CONCLUSIONS: This method is inexpensive and can be performed rapidly with prothrombin time and aPTT on the automated analyzer, which makes it easy to practice with no need for extra plasma volumes. PMID- 24168504 TI - Histopathologic diagnosis of pediatric neoplasms: a review of international consultations. AB - CONTEXT: Correct histopathologic diagnosis is fundamental to defining proper treatment and improving outcomes in children with malignancies. The Department of Pathology at St. Jude Children's Research Hospital (SJCRH) has collaborated with SJCRH International Outreach Program partner sites to improve the accuracy of histopathologic diagnoses in countries with limited resources. Pathologists at SJCRH provide review and evaluation of cases that are considered difficult or complex. OBJECTIVES: To determine the quality of pathology diagnosis and to identify areas for improvement in our international partner sites, we retrospectively analyzed all the international cases that were submitted for review. A comparison of our data with selected reports of surgical pathology error rates published in the medical literature was performed. DESIGN: From January 2009 through December 2011, SJCRH received 763 cases submitted by international pathologists from 37 countries for histopathologic review and evaluation. Of 763 cases reviewed, 705 (92.4%) met the criteria for inclusion in this study. Rates of concordance between the submitted diagnoses and SJCRH reviewed diagnoses were analyzed. RESULTS: Overall concordance, minor disagreement, and major disagreement rates between submitted diagnoses and SJCRH reviewed diagnoses were 430 (61.0%), 98 (13.9%), and 177 (25.1%) of the cases, respectively. Major disagreement rates ranged from 13.7% to 37.1% among studied countries. CONCLUSIONS: The major disagreement rate between referring international sites and SJCRH was substantially higher than the major disagreement rate among US institutions. Lack of the availability of immunohistochemistry and the training of pathologists in the diagnosis of pediatric neoplasms may have contributed to the discrepancies. PMID- 24168505 TI - The utility of the BIOMED-2 primers in the detection of 2 clonal, B lymphoproliferative disorders simultaneously involving the same site. AB - CONTEXT: Molecular tests for clonality performed on atypical lymphoid lesions may yield abnormal results because of the coexistence of monoclonal B lymphocytosis or monoclonal gammopathy of undetermined significance in the sample investigated. OBJECTIVE: To investigate the ability of the BIOMED-2 sets of primers to identify 2 clonal populations in the same formalin-fixed, paraffin-embedded tissue sample. Design.-Ten cases with 2 B-lymphoproliferative disorders at the same site were analyzed using 5 BIOMED-2 primer sets (IGH FR1, FR2, FR3, IGK VJ, and IGK VKde). RESULTS: All 10 cases (100%) showed at least 1 clone; 8 of 10 cases (80%) had 2 clones with at least 1 primer set, and the 2 clones were shown by 4 or 5 primer sets in none of the cases (0%), by 3 sets in 1 of 10 cases (10%), by 2 sets in 4 of 10 cases (40%), and by 1 set in 3 of 10 cases (30%). The most effective set was IGH FR2, detecting 4 of 10 biclonal cases (40%). The IGK VJ and IGK VKde each showed 2 clones in 3 of 10 cases (30% each). The least effective sets were IGH FR1 and FR3, with 2 of 10 cases (20%) each, with IGH FR1 being the least useful. CONCLUSIONS: The BIOMED-2 primers are effective in the detection of 2 clonal populations in the same sample. PMID- 24168506 TI - Review of estrogen receptor, progesterone receptor, and HER-2/neu immunohistochemistry impacts on treatment for a small subset of breast cancer patients transferring care to another institution. AB - CONTEXT: Estrogen receptor (ER), progesterone receptor (PR), and HER-2/neu studies are variably submitted for pathology review but are influential in treatment choices for breast cancer patients seeking second opinion or transferring care. OBJECTIVE: To determine the frequency of interinstitutional discordance for the interpretation of ER/PR and HER-2/neu immunohistochemical slides and assess the resulting clinical significance. DESIGN: One thousand one hundred thirty-nine ER, 1111 PR, and 663 HER-2/neu immunohistochemistry stains from 1139 cases were reviewed at contributing and referral centers and compared for concordance and clinical impact of discordance. RESULTS: Interinstitutional concordance for individual stains was excellent (ER: kappa = 0.93; PR: kappa = 0.90; HER-2/neu: kappa = 0.93). One hundred four (9.1%) had interinstitutional discordance in 1 or more stains; however, the majority of the discordance was clinically insignificant. Seven patients (0.6%) had a clinically significant change in treatment recommendation based on review and 2 (0.2%) had interpretation changes that would likely have resulted in treatment change had they not already completed therapy. Two patients (0.2%) had change in treatment despite concordant interpretations. CONCLUSIONS: Overall, there was excellent interinstitutional concordance for pathology review of ER, PR, and HER-2/neu immunohistochemistry stains. However, a small but significant number of patients (0.8%) received potential benefit from review, justifying inclusion of these slides along with other pathology slides to be reviewed for all breast cancer patients being seen at another institution who have not yet completed hormonal and/or chemotherapy. PMID- 24168507 TI - Thyroid fine-needle aspiration reporting rates and outcomes before and after Bethesda implementation within a combined academic and community hospital system. AB - CONTEXT: The current study compares data from our hospital system before and after the 2008 implementation of the Bethesda System for Reporting Thyroid Cytology (BSRTC). OBJECTIVE: To show the effects the BSRTC has had on the reporting rates and outcomes for thyroid lesions. DESIGN: A search for thyroid fine-needle aspiration biopsies (FNABs) was performed for 2002-2005 (before BSRTC) and 2009-2011 (after BSRTC). Diagnostic outcomes were reviewed for cases with available follow-up. RESULTS: For 2002-2005, cytology reports for 3302 thyroid FNABs were reviewed, and 309 (9.4%) were classified as suspicious. For 2009-2011, cytology reports for 3432 thyroid FNABs were reviewed; 72 (2.1%) were classified as "atypia of undetermined significance or follicular lesion of undetermined significance" (AUS/FLUS), and 142 (4.1%) were classified as suspicious. Follow-up material was available for 31 AUS/FLUS cases (43.0%), and 6 of these cases (19%) were malignant. Follow-up material was available for 60 cases (42.3%) classified as suspicious, and 23 of these cases (38%) were malignant. CONCLUSIONS: The AUS/FLUS rate of 2.1% at our institution is at the lower range of the <7% recommended by the BSRTC, and our rate of 19% for risk of malignancy for AUS/FLUS is slightly above the BSRTC recommendation of 5% to 15%. Implementation of the BSRTC did not significantly affect our institution's reporting rates, most likely because an essentially similar classification system was employed before implementation of the BSRTC. PMID- 24168508 TI - Immunostaining for rapid diagnosis of acute promyelocytic leukemia with the tetramethylrhodamine-5-isothiocyanate-conjugated anti-promyelocytic leukemia monoclonal antibody PG-M3. AB - CONTEXT: Anti-promyelocytic leukemia (PML) immunofluorescence staining is a known diagnostic tool for rapid diagnosis of acute promyelocytic leukemia (APL). OBJECTIVE: We describe our methods using the recently developed, commercially available, tetramethylrhodamine-5-isothiocyanate-labeled PG-M3 anti-PML antibody for APL testing. DESIGN: Immunofluorescence staining with the tetramethylrhodamine-5-isothiocyanate-labeled PG-M3 antibody was used to detect PML-RARA in bone marrow aspirate and/or peripheral blood smears from 30 patients with acute leukemia. The results were compared with those of concurrent testing with our in-house polyclonal anti-PML antibody and with established tests. RESULTS: All APL cases showed a positive (fine/microgranular) immunofluorescence staining pattern, whereas non-APL cases showed a negative (chunky/macrogranular) pattern. These results, which were available within 2 hours, were validated by testing with the polyclonal anti-PML antibody and with established cytogenetic and molecular testing methods. CONCLUSIONS: We validated the utility of the tetramethylrhodamine-5-isothiocyanate-labeled anti-PML antibody PG-M3 for the diagnosis of APL. Our results indicate that immunofluorescence staining with this antibody is a rapid and reliable method for the diagnosis of APL. PMID- 24168509 TI - Decreased expressions of Toll-like receptor 9 and its signaling molecules in chronic hepatitis B virus-infected patients. AB - CONTEXT: Toll-like receptors (TLRs) play crucial roles in immune responses, especially innate immunity, against viral infections. Toll-like receptor 9 recognizes intracellular viral double-strand DNA, which leads to the activation of nuclear factor B (NF-kappaB) through the myeloid differentiation primary response 88 (MYD88) pathway. Defects in the expression of TLR9 and its signaling molecules may cause attenuated immune responses against hepatitis B virus. OBJECTIVE: To determine expression levels of TLR9 messenger RNA along with MYD88, interleukin 1 receptor-associated kinase 1 (IRAK1), tumor necrosis factor receptor-associated factor 6 (TRAF6), and NF-kappaB in the peripheral blood mononuclear cells obtained from chronic hepatitis B virus (CHB)-infected patients. DESIGN: In this study, 60 CHB patients and 60 healthy controls were recruited and the expression of TLR9 and its downstream signaling molecules was examined by real-time polymerase chain reaction techniques using beta-actin as a housekeeping gene. RESULTS: Our results showed that expression of TLR9, MYD88, IRAK1, TRAF6, and NF-kappaB in peripheral blood mononuclear cells of CHB patients was significantly decreased in comparison with healthy controls. CONCLUSIONS: According to our results, it appears that CHB patients are unable to appropriately express genes in the TLR9 pathway, which may impede immune responses against hepatitis B virus infection. These results suggest a mechanism that may partially explain the fact that immune responses are disrupted in CHB patients. PMID- 24168510 TI - Primary clear cell sarcoma of the tongue. AB - Clear cell sarcoma shares features with melanoma, but frequently shows EWSR1 rearrangements. It is an aggressive tumor typically occurring in the soft tissues of the extremities, with a gastrointestinal variant with less consistent melanocytic differentiation. It is extremely rare in the head and neck region, with no reported cases in the oral cavity. We report a case of an 82-year-old woman with a clear cell sarcoma arising in the tongue, with cervical lymph node metastases. Histologically, the tumor showed some features of gastrointestinal clear cell sarcoma. No osteoclast-type giant cells were present. The tumor cells were positive for S100 protein and negative for other melanocytic markers. Fluorescence in situ hybridization showed rearrangements of EWSR1 and ATF1. This case expands the spectrum of clear cell sarcoma with a gastrointestinal-like variant in a novel site, emphasizing the need to consider it as a differential diagnosis to melanoma in mucosal sites. PMID- 24168511 TI - Pulmonary hemorrhage with capillaritis secondary to mycophenolate mofetil in a heart-transplant patient. AB - Immunosuppressive drugs are an integral part of therapy in organ transplantation. However, they are not without side effects, and although rare, these agents should be considered in the differential diagnosis of pulmonary complications in patients receiving transplants. We present a case of a patient who developed acute respiratory failure 7 days after orthotopic heart transplantation and who had been on both mycophenolate mofetil (MMF) and tacrolimus agents. Lung biopsy revealed features of pulmonary hemorrhage with capillaritis. Considered as a possible etiology, MMF was withdrawn. There was immediate improvement of the patient's symptoms. The temporal relationship between MMF exposure and onset of pulmonary symptoms in the absence of other possible etiologies strongly suggests a causal relationship. Previously published reports of pulmonary toxicity from MMF included interstitial fibrosis. To the best of our knowledge, this is the first reported case of pulmonary hemorrhage with capillaritis because of administration of MMF. PMID- 24168512 TI - Pleomorphic lobular carcinoma of the breast: a morphologically and clinically distinct variant of lobular carcinoma. AB - Pleomorphic lobular carcinoma is an uncommon variant of lobular carcinoma, characterized by significant cytologic atypia that contrasts with the low pleomorphism of classical lobular carcinoma. It accounts for approximately 1% of all epithelial breast malignancies. In addition to its pleomorphism, it is characterized by aggressive behavior and shortened patient survival. Although the morphologic features of pleomorphic lobular carcinoma are well described, it often eludes accurate pathologic characterization. Some controversy surrounds the pathogenesis of pleomorphic lobular carcinoma; however, it is now considered a well-defined variant of invasive lobular carcinoma. Pleomorphic lobular carcinoma shares molecular alterations with classical lobular carcinoma, such as alterations in the gene CDH1 on chromosome band 16q22 that results in changes in E-cadherin protein function. The aggressive biology of pleomorphic lobular carcinoma relates to the acquisition of genetic alterations typical of high-grade ductal carcinoma, such as overexpression of HER2/neu and c-myc. PMID- 24168513 TI - Inhibition effect of small interfering RNA of connective tissue growth factor on the expression of extracellular matrix molecules in cultured human renal proximal tubular cells. AB - OBJECTIVE: In this study, we investigated the effect of small interfering RNA (siRNA) of connective tissue growth factor (CTGF) by pRetro-Super (PRS) retrovirus vector on the expression of CTGF and related extracellular matrix molecules in human renal proximal tubular cells (HKCs) induced by high glucose, to provide help for renal tubulointerstitial fibrosis therapy. METHODS: HKCs were exposed to d-glucose to observe their dose and time effect, while the mannitol as osmotic control. Retrovirus producing CTGF siRNA were constructed from the inverted oligonucleotides and transferred into packaging cell line PT67 with lipofectamine, and the virus supernatant was used to infect HKC. The expression of CTGF, fibronectin (FN) and collagen-type I (col1) were measured by semi quantitative RT-PCR and Western blot. RESULTS: In response to high glucose, CTGF expression in HKCs was increased in a dose- and time-dependent manner, whereas the increase did not occur in the osmotic control. Introduction of PRS-CTGF-siRNA resulted in the significant reduction of CTGF, FN, col1 mRNA (p < 0.01, respectively) and CTGF, col1 protein (p < 0.05, respectively) expression, while PRS void vector group did not have these effects (p > 0.05). CONCLUSIONS: CTGF siRNA therapy can effectively reduce the levels of CTGF, FN and col1 induced by high glucose in cultured HKCs, which suggested that it may be a potential therapeutic strategy to prevent the renal interstitial fibrosis in the future. PMID- 24168514 TI - Low-dose oral isotretinoin versus topical retinoic acid for photoaging: a randomized, comparative study. AB - BACKGROUND: Oral isotretinoin (ISO) is the only drug which promotes prolonged remission or cure of severe acne. It also has other properties, supporting its use for non-acne indications. Retinoic acid (RA) is gold standard treatment for photoaging. ISO for photoaging treatment was reported in non-controlled trials as alternative to RA, which causes skin irritation. OBJECTIVE: To compare clinical, histological, and immunohistochemical effects of low-dose ISO and 0.05% topical RA to treat photoaging. METHODS: Randomized, comparative, evaluator-blinded, single-center study. Twenty-four healthy, Caucasian, 50 to 75-year-old men and women (menopausal or sterilized) with advanced photoaging were included. Twelve subjects received ISO, 20 mg/day, and 12 subjects were treated with RA cream, for six months; both treatments were administered every other day, and moisturizer and sunscreen were also used. Outcome measures included patient assessments, blinded photographic evaluations, Life Quality Index, histological (HE, Verhoeff) and immunohistochemical (p53, collagen type I) evaluations, adverse events, liver function, lipid profile, and blood count. Statistical analysis with generalized estimating equations and repeated measures ANOVA tests was used. RESULTS: Eleven subjects in each group completed the study. Patient and photographic assessments showed overall improvement in skin appearance. Quality-of-life scores were reduced for all subjects. Histological analysis revealed corneal layer diminution, epidermal thickness increase, and elastosis reduction. Immunohistochemical findings revealed significant epidermal p53 reduction and dermal collagen 1 increase. No differences were found between groups; laboratory tests showed no significant alterations. CONCLUSION: Despite being safe and effective, low-dose ISO was not superior to 0.05% RA for advanced photoaging treatment. PMID- 24168515 TI - Dihydrogen phosphate as a hydrogen-bonding donor element: anion receptors based on acylhydrazone. AB - Chromogenic anion receptors based on acylhydrazone are designed and synthesized. UV-vis and (1)H NMR titration showed that receptors 1 and 2 are selective receptors for dihydrogen phosphate (H2PO4(-)). Both showed strong association constants with H2PO4(-) even in polar solvents. Receptor 1 was found to recognize H2PO4(-) through three types of hydrogen-bonding (H-bonding) donors: indole N-H, amide N-H, and imine C-H hydrogens. However, receptor 2 seemed to sense H2PO4(-) through two types of H-bonding donors. Despite this seemingly different number of H-bonding elements, the binding constants of receptors 1 and 2 with H2PO4(-) were almost equal. To understand this puzzling result, we investigated the binding poses of complexes using density functional theory. The proposed 2.H2PO4(-) complex structure revealed another possible H-bonding element involving an aromatic nitrogen acting as a H-bonding acceptor. To confirm this, we synthesized receptor 3, which is devoid of this nitrogen. The binding constant of receptor 3 for H2PO4(-) was 2 orders of magnitude lower than those of receptors 1 and 2. This decreased binding affinity strongly supports the existence of a N(aromatic)...H-O(phosphate) interaction. These results provide a rare opportunity to identify H2PO4(-) acting as a H-bonding donor during an anion recognition event. PMID- 24168516 TI - Improving activity and enantioselectivity of lipase via immobilization on macroporous resin for resolution of racemic 1- phenylethanol in non-aqueous medium. AB - BACKGROUND: Burkholderia cepacia lipase (BCL) has been proved to be capable of resolution reactions. However, its free form usually exhibits low stability, bad resistance and no reusability, which restrict its further industrial applications. Therefore, it is of great importance to improve the catalytic performance of free lipase in non-aqueous medium. RESULTS: In this work, macroporous resin NKA (MPR-NKA) was utilized as support for lipase immobilization. Racemic transesterification of 1-phenylethanol with vinyl acetate was chosen as model reaction. Compared with its free form, the enzyme activity and enantioselectivity (ees) of the immobilized lipase have been significantly enhanced. The immobilized BCL exhibited a satisfactory thermostability over a wide range of temperature (from 10 to 65 degrees C) and an excellent catalytic efficiency. After being used for more than 30 successive batches, the immobilized lipase still kept most of its activity. In comparison with other immobilized lipases, the immobilized BCL also exhibits better catalytic efficiency, which indicates a significant potential in industrial applications. CONCLUSION: The results of this study have proved that MPR-NKA was an excellent support for immobilization of lipase via the methods of N2 adsorption-desorption, scanning electron microscopy (SEM), energy dispersive spectroscopy (EDS) and Fourier transform-infrared spectroscopy (FT-IR). The improvement of enzyme activity and ees for the immobilized lipase was closely correlated with the alteration of its secondary structure. This information may contribute to a better understanding of the mechanism of immobilization and enzymatic biotransformation in non-aqueous medium. PMID- 24168517 TI - Numerical implementation of constitutive model for arterial layers with distributed collagen fibre orientations. AB - Several constitutive models have been proposed for the description of mechanical behaviour of soft tissues containing collagen fibres. Some of the commonly used approaches accounting for the dispersion of fibre orientations are based on the summation of (mechanical) contributions of differently oriented fibre families. This leads to the need of numerical integration on the sphere surface, and the related numerical consumption is the main disadvantage of this category of constitutive models. The paper is focused on the comparison of various numerical integration methods applied to a specific constitutive model applicable for arterial walls. Robustness and efficiency of several integration rules were tested with respect to application in finite element (FE) codes. Among all the analysed numerical integration rules, the best results were reached by Lebedev quadrature; the related parameters for the specific constitutive model are presented in the paper. The results were implemented into the commercial FE code ANSYS via user subroutines, and their applicability was demonstrated by an example of FE simulation with non-homogenous stress field. PMID- 24168518 TI - The more the better - polyandry and genetic similarity are positively linked to reproductive success in a natural population of terrestrial salamanders (Salamandra salamandra). AB - Although classically thought to be rare, female polyandry is widespread and may entail significant fitness benefits. If females store sperm over extended periods of time, the consequences of polyandry will depend on the pattern of sperm storage, and some of the potential benefits of polyandry can only be realized if sperm from different males is mixed. Our study aimed to determine patterns and consequences of polyandry in an amphibian species, the fire salamander, under fully natural conditions. Fire salamanders are ideal study objects, because mating, fertilization and larval deposition are temporally decoupled, females store sperm for several months, and larvae are deposited in the order of fertilization. Based on 18 microsatellite loci, we conducted paternity analysis of 24 female-offspring arrays with, in total, over 600 larvae fertilized under complete natural conditions. More than one-third of females were polyandrous and up to four males were found as sires. Our data clearly show that sperm from multiple males is mixed in the female's spermatheca. Nevertheless, paternity is biased, and the most successful male sires on average 70% of the larvae, suggesting a 'topping off' mechanism with first-male precedence. Female reproductive success increased with the number of sires, most probably because multiple mating ensured high fertilization success. In contrast, offspring number was unaffected by female condition and genetic characteristics, but surprisingly, it increased with the degree of genetic relatedness between females and their sires. Sires of polyandrous females tended to be genetically similar to each other, indicating a role for active female choice. PMID- 24168520 TI - Solvent sensitivity of protein unfolding: dynamical study of chicken villin headpiece subdomain in water-ethanol binary mixture. AB - We carry out a series of long atomistic molecular dynamics simulations to study the unfolding of a small protein, chicken villin headpiece (HP-36), in water ethanol (EtOH) binary mixture. The prime objective of this work is to explore the sensitivity of protein unfolding dynamics toward increasing concentration of the cosolvent and unravel essential features of intermediates formed in search of a dynamical pathway toward unfolding. In water-ethanol binary mixtures, HP-36 is found to unfold partially, under ambient conditions, that otherwise requires temperature as high as ~600 K to denature in pure aqueous solvent. However, an interesting course of pathway is observed to be followed in the process, guided by the formation of unique intermediates. The first step of unfolding is essentially the separation of the cluster formed by three hydrophobic (phenylalanine) residues, namely, Phe-7, Phe-11, and Phe-18, which constitute the hydrophobic core, thereby initiating melting of helix-2 of the protein. The initial steps are similar to temperature-induced unfolding as well as chemical unfolding using DMSO as cosolvent. Subsequent unfolding steps follow a unique path. As water-ethanol shows composition-dependent anomalies, so do the details of unfolding dynamics. With an increase in cosolvent concentration, different partially unfolded intermediates are found to be formed. This is reflected in a remarkable nonmonotonic composition dependence of several order parameters, including fraction of native contacts and protein-solvent interaction energy. The emergence of such partially unfolded states can be attributed to the preferential solvation of the hydrophobic residues by the ethyl groups of ethanol. We further quantify the local dynamics of unfolding by using a Marcus-type theory. PMID- 24168521 TI - Chemically stable multilayered covalent organic nanosheets from covalent organic frameworks via mechanical delamination. AB - A series of five thermally and chemically stable functionalized covalent organic frameworks (COFs), namely, TpPa-NO2, TpPa-F4, TpBD-(NO2)2, TpBD-Me2, and TpBD (OMe)2 were synthesized by employing the solvothermal aldehyde-amine Schiff base condensation reaction. In order to complete the series, previously reported TpPa 1, TpPa-2, and TpBD have also been synthesized, and altogether, eight COFs were fully characterized through powder X-ray diffraction (PXRD), Fourier transform IR (FT-IR) spectroscopy, (13)C solid-state NMR spectroscopy, and thermogravimetric analysis. These COFs are crystalline, permanently porous, and stable in boiling water, acid (9 N HCl), and base (3 N NaOH). The synthesized COFs (all eight) were successfully delaminated using a simple, safe, and environmentally friendly mechanical grinding route to transform into covalent organic nanosheets (CONs) and were well characterized via transmission electron microscopy and atomic force microscopy. Further PXRD and FT-IR analyses confirm that these CONs retain their structural integrity throughout the delamination process and also remain stable in aqueous, acidic, and basic media like the parent COFs. These exfoliated CONs have graphene-like layered morphology (delaminated layers), unlike the COFs from which they were synthesized. PMID- 24168523 TI - Long-time-scale interaction dynamics between a model antimicrobial peptide and giant unilamellar vesicles. AB - The interaction dynamics between a lytic peptide and a biomembrane was studied using time-lapse fluorescence lifetime imaging microscopy. The model membrane was 1,2-dipalmitoyl-sn-glycero-3-phosphochloine giant unilamellar vesicles (GUVs), and the peptide was the K14 derivative of melittin, to which the polarity sensitive fluorescent probe AlexaFluor 430 was grafted. The interaction of the peptide with the GUVs resulted in a progressive quenching of the fluorescence lifetime over a period of minutes. From previous photophysics characterization of the peptide, we were able to deconvolve the contribution of three distinct peptide states to the lifetime trajectory and use this data to develop a kinetics model for the interaction process. It was found that the peptide-membrane interaction was well described by a two-step mechanism: peptide monomer adsorption followed by membrane surface migration, assembly, and insertion to form membrane pores. There was an equilibrium exchange between pore and surface monomers at all lipid/peptide (L/P) concentration ratios, suggesting that the fully inserted phase was reached, even at low peptide concentrations. In contrast to previous studies, there was no evidence of critical behavior; irrespective of L/P ratio, lytic pores were the dominant peptide state at equilibrium and were formed even at very low peptide concentrations. We suggest that this behavior is seen in GUVs because their low curvature means low Laplace pressure. Membrane elasticity is therefore relatively ineffective at damping the thermal fluctuations of lipid molecules that lead to random molecular-level lipid protrusions and membrane undulations. The transient local membrane deformations that result from these thermal fluctuations create the conditions necessary for facile peptide insertion. PMID- 24168522 TI - Does EEG-neurofeedback improve neurocognitive functioning in children with attention-deficit/hyperactivity disorder? A systematic review and a double-blind placebo-controlled study. AB - BACKGROUND: The number of placebo-controlled randomized studies relating to EEG neurofeedback and its effect on neurocognition in attention deficient/hyperactivity disorder (ADHD) is limited. For this reason, a double blind, randomized, placebo-controlled study was designed to assess the effects of EEG-neurofeedback on neurocognitive functioning in children with ADHD, and a systematic review on this topic was performed. METHODS: Forty-one children (8-15 years) with a DSM-IV-TR diagnosis of ADHD were randomly allocated to EEG neurofeedback or placebo-neurofeedback treatment for 30 sessions, twice a week. Children were stratified by age, electrophysiological state of arousal, and medication use. Neurocognitive tests of attention, executive functioning, working memory, and time processing were administered before and after treatment. Researchers, teachers, children and their parents, with the exception of the neurofeedback-therapist, were all blind to treatment assignment. Outcome measures were the changes in neurocognitive performance before and after treatment. CLINICAL TRIAL REGISTRATION: www.clinicaltrials.gov: NCT00723684. RESULTS: No significant treatment effect on any of the neurocognitive variables was found. A systematic review of the current literature also did not find any systematic beneficial effect of EEG-neurofeedback on neurocognitive functioning. CONCLUSION: Overall, the existing literature and this study fail to support any benefit of neurofeedback on neurocognitive functioning in ADHD, possibly due to small sample sizes and other study limitations. PMID- 24168524 TI - Asymptomatic carotid blunt cerebrovascular injury: a new screening criterion. PMID- 24168526 TI - Splenic marginal zone lymphoma: disease features and management. AB - Splenic marginal zone lymphoma (SMZL) is a lymphoma recognized as a distinct entity in the WHO classification of the lymphoid tumors. SMZL probably results from the expansion of a marginal zone B-cell driven by persistent antigen stimulation. SMZL is clinically and biologically heterogeneous. The SMZL Working Group has published guidelines for the diagnosis, workup and treatment of SMZL. There are no standard criteria to initiate treatment. A policy of watch and wait in asymptomatic patients is recommended. In symptomatic patients, data from retrospective studies suggest that rituximab with or without chemotherapy is the best strategy for SMZL. It is uncertain which is the optimal type of chemotherapy and whether patients may benefit from splenectomy prior chemoimmunotherapy. In the future, we may see progress with agents targeting known molecular lesions in SMZL. PMID- 24168525 TI - A study of two generic health-related quality of life questionnaires--Nottingham Health Profile and Short-Form 36 Health Survey--and of coping in patients with sensory hyperreactivity. AB - BACKGROUND: Sensory hyperreactivity (SHR) is one explanation for airway symptoms induced by chemicals and scents. Little is known about health-related quality of life (HRQOL) and coping, in this group of patients. A study was done in patients with SHR to (1) compare the Nottingham Health Profile (NHP) and the Short-Form 36 Health Survey (SF-36) in regard to their suitability, validity, reliability, and acceptability; (2) evaluate how the patients cope with the illness; (3) assess whether there are differences between women and men with respect to HRQOL and coping; and (4) assess whether there are differences between patients and normative data with respect to HRQOL and coping. METHODS: A total of 115 patients (91 women) with SHR were asked to answer five questionnaires: a study-specific questionnaire, the Chemical Sensitivity Scale for Sensory Hyperreactivity (CSS SHR), the NHP, the SF-36, and the Jalowiec Coping Scale-60. RESULTS: Eighty-three patients (72%; 70 women) completed all questionnaires. The SF-36 scores were less skewed and more homogeneously distributed and showed fewer floor and ceiling effects than the NHP scores. The SF-36 was also discriminated better between patients with high and low CSS-SHR scores. The reliability standard for both questionnaires was satisfactory. There were no gender differences in HRQOL. Patients with SHR had significantly lower HRQOL scores than the normative data in comparable domains of the NHP and the SF-36: emotional reactions/mental health, energy/vitality, physical mobility/functioning, and pain/bodily pain. In social isolation/functioning, the results were different; the NHP scores were similar to the normative data and the SF-36 scores were lower. The most commonly used coping styles were optimistic, self-reliant, and confrontational. Women used optimistic coping more than men. Compared with the normative group, patients with SHR used confrontational and optimistic coping more and emotive coping less. CONCLUSIONS: The current findings showed that both the NHP and the SF-36 were reliable instruments; but the results suggest that the SF-36 is a more sensitive instrument than the NHP for elucidating HRQOL in patients with SHR. Patients with SHR experienced a poor HRQOL and they followed the Western tradition of preferring problem-focused coping strategies to palliative and emotive strategies. PMID- 24168527 TI - Cognitive neuroscience of bodily representations: Psychological processes and neural mechanisms. AB - The past decade has seen increasing interest within the cognitive neuroscience community in understanding the psychological processes involved in representing the body, and in learning how these processes may be implemented within the brain. This special issue of Cognitive Neuroscience presents six new empirical papers that contribute to this rapidly developing literature, together with two theoretical discussion papers that are accompanied by peer commentaries. PMID- 24168528 TI - Combined effects of attention and inversion on event-related potentials to human bodies and faces. AB - We investigated effects of attentional load and inversion on event-related potentials to body or face distractors. Participants performed demanding (high load) or less demanding (low load) unrelated letter-search tasks. Bodies and faces were intact (Experiment 1) or without heads or eyes (Experiment 2). We measured prominent P100, N170, and late occipito-temporal negative (LNC) components. N170 to bodies had smaller and more anterior maxima than faces. N170 to intact bodies and faces was increased by inversion, relatively independently of load. Inversion effects were dramatically reduced for headless bodies, and even reversed for eyeless faces. Load effects were most prominent in LNC, with enhanced negativity under low load. We suggest that N170 reflects mandatory, category-specific initial distractor encoding in body- or face-sensitive cortical areas, a process which may depend on interactive encoding of hierarchical cues (bodies, heads, eyes). By contrast, LNC mainly reflects residual capacity allocated to extended processing of task-irrelevant distractors. PMID- 24168529 TI - The influence of body-ownership cues on tactile sensitivity. AB - To some extent the bodies of others and one's own body are represented differently in the human brain. This study investigates how these different body representations are used during tactile perception. Two types of cues--purely visual cues (pictures of hands) and multisensory cues (equivalent to the rubber hand illusion paradigm)--were used to control whether a seen hand was one's own hand or somebody else's hand. We found that viewing one's own hand improves nonspatial tactile discrimination of supra-threshold stimuli, but attenuates tactile detection performance. Furthermore, when multisensory information signals that the viewed hand is not one's own hand, tactile nonspatial performance seems to be generally sensitized as compared to not viewing a hand. Such body-ownership specific modulations were present only when multisensory cues signaled body ownership. PMID- 24168530 TI - Imagined paralysis impairs embodied spatial transformations. AB - Recent studies showed that motor deficits and limb amputations selectively impair mental rotation of respective body parts. This is due to modifications in the body schema, which plays a pivotal role in bodily related mental spatial transformations. In the present study, we investigated whether imagined paralysis could affect mental transformations in healthy participants. Participants were required to make leg laterality judgments of imitable and non-imitable body postures that were presented at different orientations. Mental spatial transformation of imitable body posture relies on emulation processes, a mechanism through which the posture is covertly imitated by the observer. Imagined paralysis selectively impaired mental transformation of imitable body postures. These results reflect an inability to fully emulate stimulus postures, suggesting a modulation in the body schema. Our results show that the body schema incorporates top-down information about motoric constraints which can influence embodied cognition in healthy participants. PMID- 24168531 TI - Differential effects of perceived hand location on the disruption of embodiment by apparent physical encroachment of the limb. AB - while much is known about the processes underlying the embodiment of non corporeal objects, less research has been conducted to explore the mechanisms that prevent embodiment. The current study investigates the effect of violation of the human body template on embodiment of fake limbs by appearing to encroach the fake limb with a solid object. Encroachment of the limb disrupted embodiment, but only when the limb was far from the body. When the encroached limb was close to the body, it was not disembodied despite such clear violations of knowledge related to the body. The representation of the limb in the body schema was similarly robust to near-hand violations, suggesting that competing representations of the limb that are close to the body are preferred to those that are far from the body. PMID- 24168532 TI - Proprioceptive drift without illusions of ownership for rotated hands in the "rubber hand illusion" paradigm. AB - The rubber hand illusion is one reliable way to experimentally manipulate the experience of body ownership. However, debate continues about the necessary and sufficient conditions eliciting the illusion. We measured proprioceptive drift and the subjective experience (via questionnaire) while manipulating two variables that have been suggested to affect the intensity of the illusion. First, the rubber hand was positioned either in a posturally congruent position, or rotated by 180 degrees . Second, either the anatomically same rubber hand was used, or an anatomically incongruent one. We found in two independent experiments that a rubber hand rotated by 180 degrees leads to increased proprioceptive drift during synchronous visuo-tactile stroking, although it does not lead to feelings of ownership (as measured by questionnaire). This dissociation between drift and ownership suggests that proprioceptive drift is not necessarily a valid proxy for the illusion when using hands rotated by 180 degrees . PMID- 24168533 TI - Disownership and disembodiment of the real limb without visuoproprioceptive mismatch. AB - The brain is able to sustain multiple bodily representations, and it is still unclear whether real body parts can be disembodied during the embodiment of fake or illusory body parts. The current experiment attempted to disembody the real hand without the visuoproprioceptive mismatch thought to compromise disembodiment in the rubber hand illusion by providing asynchronous feedback of the hand viewed in its actual location. Participants disowned their real hand and claimed ownership of a synchronous fake hand as measured by ownership questionnaires and skin conductance responses to perceived threat. In contrast, the body schema, as indexed by manual pointing, was only mildly affected, further supporting the distinction between bodily representations. Conflicts in time were more disruptive than conflicts in space for body ownership, while the effect was less so for body schema, schema being more affected by the proximity of vision and proprioception. PMID- 24168534 TI - The role of occipitotemporal body-selective regions in person perception. AB - The visual appearance of others' bodies is a powerful source of information about the people around us. This information is implicit in the stimulus and must be extracted and made explicit by the coordination of activity in multiple cortical areas. Here we consider the contribution to this process of two strongly body selective occipitotemporal regions identified in human neuroimaging experiments: the extrastriate body area (EBA) and the fusiform body area (FBA). We address the evidence and arguments behind numerous recent proposals that EBA and FBA build explicit representations of identity, emotion, body movements, or goal-directed actions from the visual appearance of bodies, and also explore the contribution of these regions to motor control. We argue that the current evidence does not support a model in which EBA and FBA directly perform any of these higher-level functions. Instead, we argue that these regions comprise populations of neurons that encode fine details of the shape and posture of the bodies of people in the current percept. In doing so, they provide a powerful but cognitively unelaborated perceptual framework that allows other cortical systems to exploit the rich, socially relevant information that is conveyed by the body. PMID- 24168535 TI - Do body-part concepts depend on the EBA/FBA? AB - Abstract Downing and Peelen argue that the EBA/FBA represent body-part shapes in a highly schematic manner that is independent of personal identity, emotional expression, movement pattern, and action goal, and that cuts across visual and haptic modalities. According to the grounded cognition framework, these properties make the EBA/FBA suitable for processing body-part shapes not only for perceptual purposes but also for conceptual purposes. Any account of the neural substrates of body-part concepts must, however, accommodate significant cross linguistic diversity in this semantic domain. Hence, an alternative possibility is that the shape components of body-part concepts depend on areas adjacent to the EBA/FBA. PMID- 24168536 TI - Adaptation studies suggest interactive feedback shapes responses in occipitotemporal regions. AB - Abstract Downing and Peelen portray the EBA and FBA as a largely impenetrable system, passing on visual signals to other cortical areas where high-level information is extracted. They suggest that the influence of other regions on EBA and FBA is primarily limited to changes in attentional modulation. In the following commentary, this proposal is evaluated within the context of a predictive coding framework. Recent evidence is discussed indicating that fMRI adaptation effects in occipitotemporal cortex, including EBA and FBA, are consistent with the influence of higher-level modulation, suggesting that responses in these regions are shaped through the interactive feedback of a hierarchical network. PMID- 24168537 TI - Human body perception and higher-level person perception are dissociated in early development. AB - Abstract Developmental data support the proposal that human body perceptual processing is distinct from other aspects of person perception. Infants are sensitive to human bodily motion and attribute goals to human arm movements before they demonstrate recognition of human body structure. The developmental data suggest the possibility of bidirectional linkages between EBA- and FBA mediated representations and these higher-level elements of person perception. PMID- 24168538 TI - No two are the same: Body shape is part of identifying others. AB - Abstract Downing and Peelen argue for a clear distinction between body and identity representation, with the former performed by EBA and FBA, and the latter performed elsewhere in the brain. Under a predictive coding account, we argue that this separation is unnecessary: Representing bodies is part of representing identity. While neurons in EBA and FBA may only code for body shape and posture, we propose that they are a part of a reciprocally connected cortical network that functions to minimize prediction error when making identity inferences. We propose a novel way to test the hypothesis that EBA and FBA are critically involved in person identification. PMID- 24168539 TI - When perception and attention collide: Neural processing in EBA and FBA. AB - Abstract In their timely review, Downing and Peelen differentiate between neural systems dedicated to body perception and body-based person inferences. Rather than supporting their view of these operations as largely separate mental and neural entities, we emphasize reasons to favor a stronger notion of co dependency. PMID- 24168540 TI - The extrastriate body area (EBA): One structure, multiple functions? AB - Abstract Downing and Peelen argue that the extrastriate body area (EBA) creates an unelaborated visual repre- sentation of the human body, but is not implicated in any higher-order computational process. We believe that this reflects an outdated view of brain function, in which neural regions are informationally encapsulated modules with fixed computational properties. In contrast, there is mounting evidence that functional properties may not be fixed but may be dependent on the context in which the region is recruited. We will illustrate this by taking a closer look at a visual area of which the properties are potentially even simpler: the primary visual cortex. PMID- 24168541 TI - Functional and epiphenomenal modulation of neural activity in body-selective visual areas. AB - Abstract Although attention may play a major role in explaining EBA/FBA activation during high-order, body-related tasks, it is important to establish the functional significance of top-down modulation in different tasks. While neuroimaging studies documented the functional and anatomical specificity of EBA/FBA activation during body form perception, repetitive transcranial magnetic stimulation (rTMS) and brain-lesion studies provided causative evidence that activity in EBA is essential for processing morphological details of body parts. Local processing of body shapes in EBA might contribute to the representation of high-order body attributes, including person identity and body esthetics, which probably rely on a widespread network of different interconnected areas. PMID- 24168542 TI - Faces and bodies in the brain. AB - Abstract The discovery of face-sensitive and body-sensitive regions in the extrastriate human cortex has raised the problem of the relations of these areas to face and body knowledge and their role in person identification. In this commentary, I point to some as yet unexplored aspects of these cortical regions, including their status as proper anatomo-functional areas, the role of body appearance in the recognition of persons, and the development of body-related and face-related areas in sighted and congenitally blind individuals. PMID- 24168544 TI - The urge for self and species preservation. AB - Besides sneezing, yawning, and scratching, other types of more complex behaviors can be considered urges for action, in that they are both compelling and can be overtly inhibited. Many behaviors increasing the survival rate of self and species have this instinctual (although not compulsory) nature. We feel a terrible urge to catch a newborn falling from a table, although we could choose not to do so. The hypothesis is advanced that both insula and cingulate cortex participate in social behaviors such as contagious yawning, laughing, and crying, but are not necessarily involved in the urge to cough, for example. PMID- 24168543 TI - How might occipitotemporal body-selective regions interact with other brain areas to support person perception? AB - We argued in our Discussion Paper for the view that the main functional role of occipitotemporal body-selective regions is to make explicit, via patterns of activity, the shape and posture of perceived bodies, rather than directly representing higher-order person attributes. Much of the commentary was on the question of how activity in other brain areas interacts with activity in EBA and FBA. In this reply, we emphasize that our claims do not imply that EBA and FBA are cognitively impenetrable modules that are driven only by bottom-up input from earlier visual regions. Instead, it is likely that these regions interact heavily with other brain regions, and that their activity is shaped--in limited ways--by both feed-forward and feedback connections. In the context of such large-scale networks, EBA and FBA activity will be most effective at conveying detailed information about the shape and posture of bodies in the current percept. PMID- 24168545 TI - Similarities and differences between normal urges and the urge to tic. AB - Abstract Investigations into the neurobiological substrates underlying urge are important for developing better understanding and treatment for impulse-control disorders. We characterize the phenomenon based on normal bodily (interoceptive) urges. Features include the following: a preceding awareness of an uncomfortable bodily sensation, a sense of urgency that action must be taken, rising distress when action is delayed, a temporary (e.g., a few minutes in length) ability to suppress or manifest the action voluntarily, subsequent relief once action is taken, association with an action that is necessary to survival. We compare and contrast these characteristics with those described by Tourette syndrome patients as the urge to tic, and highlight several unknowns which merit further investigation. PMID- 24168546 TI - The role of consciousness in the urge-for-action. AB - Abstract A neuroanatomical model of urge-for-action phenomena has been proposed based on the "motivation-for-action" network (e.g., insula and mid-cingulate cortex). Notwithstanding the sound evidence presented regarding the functional and anatomical correlates of this model, the nature of the relationship between urges and conscious awareness remains to be addressed. Moreover, this model does not seem to explain (1) how a conscious access threshold is reached, and (2) the way in which the urges are related to more general contents of consciousness. PMID- 24168547 TI - Urges, inhibition, and voluntary action. AB - Abstract It is constitutive of the notion of an urge that it must precede the action it urges. For the duration of an urge to be non-zero, some process must keep the action being urged in check. Urges therefore inevitably involve inhibition of action, and perhaps conflict between action and inaction. In any event, they cannot form a critical part of the phenomenology that many argue must precede voluntary action, for if they play any part at all, it is only in situations where the action is to some degree inhibited. PMID- 24168548 TI - Unaware urges? Let's not complicate matters further. AB - Abstract The model put forward for the neuroanatomical basis of urges-for-action is compelling. The arguments based on meta-analyses of existing neuroimaging data are elegant and convincing. However, I am not convinced by the suggestion that there are conscious urges and urges that remain unaware. In my view, awareness is a defining feature of an urge. PMID- 24168549 TI - My urge, my tic - a missing link between urges and tic inhibition. AB - Abstract Despite the fact that premonitory urges precede most tics in patients with Gilles de la Tourette syndrome (GTS), the voluntariness of tic elicitation and its suppressibility as a response to these urges still remains unclear. Moreover, there are no systematic studies examining the association between urge intensity and the ability to suppress tics. As shown by behavioral, neurophysiological, and imaging data, sensorimotor networks in GTS exhibit altered patterns of organization modulated through interactions with frontomesial networks of volitional inhibition. PMID- 24168550 TI - An urge to act or an urge to suppress? AB - Abstract There is no doubt that there exist urges to act, but are these really the cause of the action or is an urge a shorthand term to describe the effort involved in suppressing an action that is triggered automatically by some other process? PMID- 24168551 TI - Resolving confusions about urges and intentions. AB - In our article we considered the nature and the functional anatomy of "urges-for action," both in the context of everyday behaviors such as yawning, swallowing, and micturition, and in relation to clinical disorders in which the urge-for action is considered pathological (e.g., Tourette syndrome), and we argued for a key role for the insular and cingulate cortices in experiencing the urge-for action. Here we seek to address some of the key points raised within several of the interesting commentaries on, and challenges to, our paper. PMID- 24168553 TI - Pulsed EPR study of amino acid and tetrahydropterin binding in a tyrosine hydroxylase nitric oxide complex: evidence for substrate rearrangements in the formation of the oxygen-reactive complex. AB - Tyrosine hydroxylase is a nonheme iron enzyme found in the nervous system that catalyzes the hydroxylation of tyrosine to form l-3,4-dihydroxyphenylalanine, the rate-limiting step in the biosynthesis of the catecholamine neurotransmitters. Catalysis requires the binding of three substrates: tyrosine, tetrahydrobiopterin, and molecular oxygen. We have used nitric oxide as an O2 surrogate to poise Fe(II) at the catalytic site in an S = 3/2, {FeNO}7 form amenable to EPR spectroscopy. 2H-electron spin echo envelope modulation was then used to measure the distance and orientation of specifically deuterated substrate tyrosine and cofactor 6-methyltetrahydropterin with respect to the magnetic axes of the {FeNO}7 paramagnetic center. Our results show that the addition of tyrosine triggers a conformational change in the enzyme that reduces the distance from the {FeNO}7 center to the closest deuteron on 6,7-2H-6 methyltetrahydropterin from >5.9 A to 4.4 +/- 0.2 A. Conversely, the addition of 6-methyltetrahydropterin to enzyme samples treated with 3,5-2H-tyrosine resulted in reorientation of the magnetic axes of the S = 3/2, {FeNO}7 center with respect to the deuterated substrate. Taken together, these results show that the coordination of both substrate and cofactor direct the coordination of NO to Fe(II) at the active site. Parallel studies of a quaternary complex of an uncoupled tyrosine hydroxylase variant, E332A, show no change in the hyperfine coupling to substrate tyrosine and cofactor 6-methyltetrahydropterin. Our results are discussed in the context of previous spectroscopic and X-ray crystallographic studies done on tyrosine hydroxylase and phenylalanine hydroxylase. PMID- 24168555 TI - Propagating nanocavity-enhanced rapid crystallization of silicon thin films. AB - We demonstrate a mechanism of solid-phase crystallization (SPC) enabled by nanoscale cavities formed at the interface between an hydrogenated amorphous silicon film and embedded 30 to 40 nm Si nanocrystals. The nanocavities, 10 to 25 nm across, have the unique property of an internal surface that is part amorphous and part crystalline, enabling capillarity-driven diffusion from the amorphous to the crystalline domain. The nanocavities propagate rapidly through the amorphous phase, up to five times faster than the SPC growth rate, while "pulling behind" a crystalline tail. Using transmission electron microscopy it is shown that twin boundaries exposed on the crystalline surface accelerate crystal growth and influence the direction of nanocavity propagation. PMID- 24168554 TI - Cross-sectional associations between prevalent vertebral fracture and pulmonary function in the sixth Tromso study. AB - BACKGROUND: Persons with vertebral fracture may have reduced pulmonary function, but this association has not been much studied. The aim of this cross-sectional study was therefore to examine the relationship between vertebral fracture and pulmonary function in a general, elderly population. METHODS: Vertebral morphometry was used for vertebral fracture assessment in 2132 elderly men (n = 892) and women (n = 1240) aged 55 to 87 years in the population-based Tromso Study 2007-08. Pulmonary function was examined by spirometry. Pulmonary function was expressed as FVC% predicted, FEV1% predicted, and FEV1/FVC% predicted values, adjusted FVC, FEV1, and FEV1/FVC, and obstructive and restrictive ventilatory impairment. Vertebral fracture was classified according to appearance, number, severity, and location of fractures. Associations were analyzed using general linear and logistic models. RESULTS: FVC% predicted and FEV1% predicted values were not associated with vertebral fracture (P > 0.05), whereas FEV1/FVC% predicted ratio was associated with both prevalent fracture, number of fractures, severity of fractures, and fracture site in men (P < 0.05), but not in women. When FVC, FEV1, and FEV1/FVC values were adjusted for multiple covariates, we found no significant association with vertebral fracture. Obstructive and restrictive ventilatory impairment was not associated with prevalent vertebral fracture. CONCLUSIONS: In conclusion, this study did not confirm any clinically relevant associations between prevalent vertebral fracture and ventilatory impairment in elderly individuals. PMID- 24168556 TI - Pursue or shoot? Effects of exercise-induced fatigue on the transition from running to rifle shooting in a pursuit task. AB - To investigate to what degree exercise-induced fatigue influences behavioural choices, participants' transition from running to rifle shooting in a pursue-and shoot task was assessed. Participants ran on a treadmill and chased a target in a virtual environment and were free to choose when to stop the treadmill and shoot at the target. Fatigue increased progressively throughout the 20-minute test. Results indicated that shooting accuracy was not affected by fatigue. However, the distance to the target at which participants decided to shoot showed a U shaped relationship with fatigue, R(2) = 0.884, p = 0.013. At low fatigue levels (ratings of perceived exertion [RPE] < 6.5), the distance to the target at which participants shot decreased, whereas at higher fatigue levels (RPE > 6.5) shooting distance increased again. At high levels of fatigue, participants stopped running sooner, aimed at the target longer and shot less often. Findings indicate that physiological parameters influence not only perception but also actual transitions between different actions. PMID- 24168557 TI - Structural insights into the small G-protein Arl13B and implications for Joubert syndrome. AB - Ciliopathies are human diseases arising from defects in primary or motile cilia. The small G-protein Arl13B (ADP-ribosylation factor-like 13B) localizes to microtubule doublets of the ciliary axoneme and is mutated in Joubert syndrome. Its GDP/GTP mechanistic cycle and the effect of its mutations in patients with Joubert syndrome remain elusive. In the present study we applied high resolution structural and biochemical approaches to study Arl13B. The crystal structure of Chlamydomonas rheinhardtii Arl13B, comprising the G-domain and part of its unique C-terminus, revealed an incomplete active site, and together with biochemical data the present study accounts for the absence of intrinsic GTP hydrolysis by this protein. The structure shows that the residues representing patient mutations R79Q and R200C are involved in stabilizing important intramolecular interactions. Our studies suggest that Arg79 is crucial for the GDP/GTP conformational change by stabilizing the large two-residue register shift typical for Arf (ADP-ribosylation factor) and Arl subfamily proteins. A corresponding mutation in Arl3 induces considerable defects in effector and GAP (GTPase activating protein) binding, suggesting a loss of Arl13B function in patients with Joubert syndrome. PMID- 24168558 TI - Perinatal common mental disorders and child survival in Ethiopia. AB - AIMS: The study aims to evaluate the impact of perinatal common mental disorders (CMDs) on child mortality up to 3.5 years in a demographic surveillance site at Butajira, Ethiopia. METHODS: One thousand sixty-five eligible women were assessed for CMD in the third trimester of pregnancy and at 2 months post-delivery using the Self-Reporting Questionnaire. We derived a four-level categorical exposure variable for the course of perinatal CMD. The outcome measure was child death recorded from 1 month after the postnatal assessment up to 3.5 years. Potential confounders and mediators were evaluated. RESULTS: The cumulative child mortality rates were 62.6/1000 at 1 year and 82.5/1000 at 3.5 years, respectively. Exposure to perinatal CMD did not significantly affect child survival at 3.5 years, with results showing fully adjusted hazard ratio (HR) and 95% confidence interval (95% CI) of 1.85 (0.43, 7.88) for CMD in pregnancy only, 1.47 (0.14, 15.66) for CMD in postnatal period only and 0.41 (0.02, 7.38) for persistent CMD (both in pregnancy and postnatal). Only using soap less frequently than daily (HR 5.67, 95% CI 1.58 20.30) and episode of malaria in pregnancy (HR 5.02, 95% CI 2.15-11.72) were associated with child mortality in multivariable analysis. CONCLUSIONS: Maternal health, health behaviours and family structure appear to be the most important factors affecting post-neonatal child mortality in this Ethiopian birth cohort, with little evidence for an effect of maternal perinatal CMD. PMID- 24168559 TI - Treatment of refractory melasma with combination of topical 5% magnesium ascorbyl phosphate and fluorescent pulsed light in Asian patients. AB - BACKGROUND: Melasma is an acquired disorder of hypermelanosis of great psychosocial concern. The treatments with various conventional therapies are often unsatisfactory. Lasers and light sources have been used to treat pigmented lesions, but in Asian skin with higher melanin content, such treatments may be challenging. OBJECTIVES: To determine the effectiveness of treating melasma with a combination of topical 5% magnesium ascorbyl phosphate (MAP) and fluorescent pulsed light (FPL). MATERIALS AND METHODS: Patients of skin types III-V with refractory melasma were treated for 12 weeks with topical application of 5% MAP and three sessions of FPL (570-950 nm) at 3, 6, and 9 weeks (fluence 12-14 J/cm(2) , pulse width 15 ms, and spot size 3 cm(2) ). They were followed up for another 12 weeks to assess the persistence of treatment benefit. Digital photographs of the patients were taken at each visit. Treatment efficacy was determined by calculating mean melasma area and severity index (MASI) at the beginning and then at weeks 6, 12, and 24. The subjective assessment was done by comparing pre-treatment and post-treatment photographs by an independent observer and self-assessment by patients using four-point scoring scale (1, poor, 2, fair, 3, good, and 4, excellent). RESULTS: Sixty-five patients completed the study. The baseline mean MASI score of 14.80 decreased to 4.53 at the 12th week (end of treatment) and 6.35 at the 24th week (end of follow-up). The overall regression of mean MASI at these end-points was 69.3% and 57% (P < 0.01). The pre- and post treatment photographic evaluation by independent observer and patients' self assessment at the 12th week showed good to excellent response (scores 3 and 4) in 52.3% and 44.6% cases, respectively. No significant adverse effects of treatment were noted. CONCLUSION: Combination of 5% MAP with FPL is effective, well tolerated, and safe in treating refractory melasma in Asian patients but for persistent improvement, maintenance treatments would be required. PMID- 24168560 TI - The loss of NHS Direct is an attack on nursing. PMID- 24168573 TI - March 2014 closure of NHS Direct leaves staff uncertain over future. PMID- 24168578 TI - Liverpool Care Pathway: dying to know what will happen next. PMID- 24168584 TI - Urinary incontinence. PMID- 24168585 TI - Intimacy after cancer. AB - To mark Breast Awareness Month, Macmillan Cancer Support has released results of research into the effect the disease has on women's sex lives. Nurses can support women by listening to their concerns, discussing issue raised and 'normalising' these sensitive conversations. PMID- 24168586 TI - A brighter future. AB - Women entering prison often have serious physical and mental health problems and history of substance misuse. More healthcare resources are needed but services are improving, with some female offenders now attending rehabilitation courses in the community. PMID- 24168587 TI - Stay strong - but how? AB - Resilience is one of the attributes nurses need if they are to deliver quality care successfully in an ever more demanding environment. But how does resilience enhance a healthcare setting and the wellbeing of patients, and is it a personal trait or something that can be taught? PMID- 24168600 TI - The church, not the NHS, should be funding hospital chaplains. PMID- 24168601 TI - It will cost us all more to keep warm, but we are still stuck with frozen pay. PMID- 24168602 TI - School nurses sidelined by the latest proposals for teachers. PMID- 24168604 TI - Help the nursing and midwifery council to shape revalidation. PMID- 24168605 TI - We need nurse consultants for their voice and leadership. PMID- 24168610 TI - Identifying individuals who might benefit from genetic services and information. AB - This is the second in a series of articles on genetics. This article focuses on competency 1 of the revised framework for genetics/genomics for nurses. The authors discuss the importance of nurses identifying individuals who may benefit from genetic services. Recording a family history and drawing a family tree are useful skills that will help to identify these individuals and inform the healthcare team. The article explains when to refer individuals to genetic services and what they may expect from these referrals. PMID- 24168611 TI - Hospice transfer for patients at the end of life: part 2. AB - This is the second in a series of two articles on improving end of life care for terminally ill patients in a medical assessment unit. Through joint working between staff in a district general hospital and staff at a hospice, a new service was developed offering patients who are at the end of life and being cared for in the medical assessment unit the opportunity to be transferred to the hospice for palliative care instead of acute interventions. This article uses an ethical framework to examine the ethical, legal and practical considerations involved in developing the new service. PMID- 24168612 TI - Improving care and quality of life for patients with lung cancer. AB - Lung cancer is the most common cancer worldwide and is associated with significant morbidity and mortality. In recent years, there have been important developments in the techniques used to diagnose lung cancer and in the treatment options available, allowing more people to be given anti-cancer treatment with the aim of increasing survival rates. This article provides an overview of lung cancer, including epidemiology, risk factors, diagnosis and treatment. It aims to provide healthcare professionals with information to improve care delivery and patients' quality of life. PMID- 24168613 TI - Diabetic neuropathy. PMID- 24168614 TI - All in a day's work. PMID- 24168615 TI - Rewards of bereavement care. PMID- 24168617 TI - Breach of race equality duties. PMID- 24168619 TI - Coping in a crisis. PMID- 24168618 TI - Keeping up with developments. PMID- 24168620 TI - The stereochemistry and dynamics of the introduction of hydrogen atoms onto FeMo co, the active site of nitrogenase. AB - The catalyzed hydrogenations effected at the active site FeMo-co of nitrogenase have been proposed to involve serial supply of the required multiple protons along a proton wire terminating at sulfur atom S3B of FeMo-co. In conjunction with serial electron transfer to FeMo-co, these protons become H atoms, and then are able to migrate from S3B to other Fe and S atoms of FeMo-co, and to transfer to bound substrate and intermediates. This general model, which can account for all reactions of nitrogenase, involves a preparatory stage in which each incoming H atom is required to move from the proton delivery side of S3B to the opposite migration side of S3B. This report examines the mechanism of this reconfiguration of S3B-H, finding four stable configurations in which S3B-H has pyramidal trigonal coordination, with one elongated Fe-S3B interaction. The transition states and energies for reconfiguration are described. Pseudotetrahedral four coordination and planar-trigonal coordination for S3B-H are less stable than pyramidal-trigonal coordination. Results are presented for FeMo-co with one, two, three, and four H atoms (the E1H1, E2H2, E3H3, and E4H4 Thorneley-Lowe stages), and the general principles are defined, for application in the various chemical mechanisms of nitrogenase. PMID- 24168622 TI - Fluorogenic, two-photon-triggered photoclick chemistry in live mammalian cells. AB - The tetrazole-based photoclick chemistry has provided a powerful tool to image proteins in live cells. To extend photoclick chemistry to living organisms with improved spatiotemporal control, here we report the design of naphthalene-based tetrazoles that can be efficiently activated by two-photon excitation with a 700 nm femtosecond pulsed laser. A water-soluble, cell-permeable naphthalene-based tetrazole was identified that reacts with acrylamide with the effective two photon cross-section for the cycloaddition reaction determined to be 3.8 GM. Furthermore, the use of this naphthalene-tetrazole for real-time, spatially controlled imaging of microtubules in live mammalian cells via the fluorogenic, two-photon-triggered photoclick chemistry was demonstrated. PMID- 24168624 TI - Evidence of surfactant protein A and D expression decrement and their localizations in human prostate adenocarcinomas. AB - AIM: Surfactant proteins (SP-A and SP-D) were originally described in the lung; however, they are also present in the prostate. Purpose of this study, therefore, was to determine how surfactant proteins are altered in prostate adenocarcinomas (PCa) and find out any connection exists between their expressions and their staining patterns, prostate-specific antigen (PSA) values, Gleason score, age, tumor volume and tumor, node, metastases (TNM) clinical stage. METHODS: Thirty five tissue samples were obtained during radical prostatectomy. All specimens were classified to three groups based on the Gleason score <7, 7 and Gleason score >7. Surfactant proteins' expressions were tested by immunohistochemical and Western blotting methods. RESULTS: Immunoreactivity was detected in the cytoplasm from both basal cells and secretory epithelial cells in malignant and non malignant areas. About 80% of the malignant basal cells were characterized as either weak or strong while non-malignant epithelial cells demonstrated strong immunoreactivity for SP-A. Also malignant (81.8%) and non-malignant cells (90.6%) were characterized as either weak or strong for SP-D. Decrement of SP-A and SP-D immunostaining tended to associate with an increasing Gleason score (p > 0.05, p < 0.05), tumor volume (p < 0.05, p > 0.05) and age (p > 0.05, p > 0.05). There was a strong positive correlation between Gleason score and tumor volume (p < 0.01). Also, either none or weak SP-A and SP-D immunoreactivity was observed specimens with Gleason score 7 or higher. SP-A and SP-D reacted with 34 kDa (SP A) and 43 kDa (SP-D) immunoreactive single bands were decreased in tumor tissues. CONCLUSIONS: The development of prostate cancer may be related to decreased level of surfactant protein A and D. PMID- 24168623 TI - Reconciling in vivo and in silico key biological parameters of Pseudomonas putida KT2440 during growth on glucose under carbon-limited condition. AB - BACKGROUND: Genome scale metabolic reconstructions are developed to efficiently engineer biocatalysts and bioprocesses based on a rational approach. However, in most reconstructions, due to the lack of appropriate measurements, experimentally determined growth parameters are simply taken from literature including other organisms, which reduces the usefulness and suitability of these models. Pseudomonas putida KT2440 is an outstanding biocatalyst given its versatile metabolism, its ability to generate sufficient energy and turnover of NADH and NAD. To apply this strain optimally in industrial production, a previously developed genome-scale metabolic model (iJP815) was experimentally assessed and streamlined to enable accurate predictions of the outcome of metabolic engineering approaches. RESULTS: To substantially improve the accuracy of the genome scale model (iJP815), continuous bioreactor cultures on a mineral medium with glucose as a sole carbon source were carried out at different dilution rates, which covered pulling analysis of the macromolecular composition of the biomass. Besides, the maximum biomass yield (on substrate) of 0.397 gDCW . gglc 1, the maintenance coefficient of 0.037 gglc . gDCW-1 . h-1 and the maximum specific growth rate of 0.59 h-1 were determined. Only the DNA fraction increased with the specific growth rate. This resulted in reliable estimation for the Growth-Associated Maintenance (GAM) of 85 mmolATP . gDCW-1 and the Non Growth Associated Maintenance (NGAM) of 3.96 mmolATP . gDCW-1 . h-1. Both values were found significantly different from previous assignment as a consequence of a lower yield and higher maintenance coefficient than originally assumed. Contrasting already published 13C flux measurements and the improved model allowed for constraining the solution space, by eliminating futile cycles. Furthermore, the model predictions were compared with transcriptomic data at overall good consistency, which helped to identify missing links. CONCLUSIONS: By careful interpretation of growth stoichiometry and kinetics when grown in the presence of glucose, this work reports on an accurate genome scale metabolic model of Pseudomonas putida, providing a solid basis for its use in designing superior strains for biocatalysis. By consideration of substrate specific variation in stoichiometry and kinetics, it can be extended to other substrates and new mutants. PMID- 24168626 TI - Genome size increases in recently diverged hornwort clades. AB - As our knowledge of plant genome size estimates continues to grow, one group has continually been neglected: the hornworts. Hornworts (Anthocerotophyta) have been traditionally grouped with liverworts and mosses because they share a haploid dominant life cycle; however, recent molecular studies place hornworts as the sister lineage to extant tracheophytes. Given the scarcity of information regarding the DNA content of hornworts, our objective was to estimate the 1C value for a range of hornwort species within a phylogenetic context. Using flow cytometry, we estimated genome size for 36 samples representing 24 species. This accounts for roughly 10% of known hornwort species. Haploid genome sizes (1C value) ranged from 160 Mbp or 0.16 pg (Leiosporoceros dussii) to 719 Mbp or 0.73 pg (Nothoceros endiviifolius). The average 1C-value was 261 +/- 104 Mbp (0.27 +/- 0.11 pg). Ancestral reconstruction of genome size on a hornwort phylogeny suggests a small ancestral genome size and revealed increases in genome size in the most recently divergent clades. Much more work is needed to understand DNA content variation in this phylogenetically important group, but this work has significantly increased our knowledge of genome size variation in hornworts. PMID- 24168627 TI - Insights into the dynamics of genome size and chromosome evolution in the early diverging angiosperm lineage Nymphaeales (water lilies). AB - Nymphaeales are the most species-rich lineage of the earliest diverging angiosperms known as the ANA grade (Amborellales, Nymphaeales, Austrobaileyales), and they have received considerable attention from morphological, physiological, and ecological perspectives. Although phylogenetic relationships between these three lineages of angiosperms are mainly well resolved, insights at the whole genome level are still limited because of a dearth of information. To address this, genome sizes and chromosome numbers in 34 taxa, comprising 28 species were estimated and analysed together with previously published data to provide an overview of genome size and chromosome diversity in Nymphaeales. Overall, genome sizes were shown to vary 10-fold and chromosome numbers and ploidy levels ranged from 2n = 2x = 18 to 2n = 16x = ~224. Distinct patterns of genome diversity were apparent, reflecting the differential incidence of polyploidy, changes in repetitive DNA content, and chromosome rearrangements within and between genera. Using model-based approaches, ancestral genome size and basic chromosome numbers were reconstructed to provide insights into the dynamics of genome size and chromosome number evolution. Finally, by combining additional data from Amborellales and Austrobaileyales, a comprehensive overview of genome sizes and chromosome numbers in these early diverging angiosperms is presented. PMID- 24168625 TI - Isolation of equine multipotent mesenchymal stromal cells by enzymatic tissue digestion or explant technique: comparison of cellular properties. AB - BACKGROUND: The treatment of tendon lesions with multipotent mesenchymal stromal cells (MSCs) is widely used in equine medicine. Cell sources of MSCs include bone marrow, as well as solid tissues such as adipose tissue. MSCs can be isolated from these solid tissues either by enzymatic digestion or by explant technique. However, the different preparation techniques may potentially influence the properties of the isolated MSCs. Therefore, the aim of this study was to investigate and compare the effects of these two different methods used to isolate MSCs from solid tissues.Equine adipose tissue, tendon and umbilical cord matrix served as solid tissue sources of MSCs with different stiffness and density. Subsequent to tissue harvest, MSCs were isolated either by enzymatic digestion with collagenase or by explant technique. Cell yield, growth, differentiation potential and tendon marker expression were analysed. RESULTS: At first passage, the MSC yield was significantly higher in enzymatically digested tissue samples than in explanted tissue samples, despite a shorter period of time in primary culture. Further analysis of cell proliferation, migration and differentiation revealed no significant differences between MSCs isolated by enzymatic digestion and MSCs isolated by explant technique. Interestingly, analysis of gene expression of tendon markers revealed a significantly higher expression level of scleraxis in MSCs isolated by enzymatic digestion. CONCLUSIONS: Both isolation techniques are feasible methods for successful isolation of MSCs from solid tissues, with no major effects on cellular proliferation, migration or differentiation characteristics. However, higher MSC yields were achieved in a shorter period of time by collagenase digestion, which is advantageous for the therapeutic use of MSCs. Moreover, based on the higher level of expression of scleraxis in MSCs isolated by enzymatic digestion, these cells might be a better choice when attempting tendon regeneration. PMID- 24168628 TI - A first exploration of genome size diversity in sponges. AB - The phyla known as early-branching lineages of animals have become the subject of increasing interest from the perspectives of genomics and evolutionary biology. Unfortunately, data on even the most fundamental properties of their genomes, such as genome size, remain very scarce. In this study, genome size estimates are reported for 75 species of sponges (phylum Porifera) representing 33 families and 12 orders, marking the first large survey of genome size diversity for an early branching phylum. Sponge genome sizes averaged around 0.2 pg but exhibited a 17 fold range overall (0.04-0.63 pg). In addition, the results of comparisons of two methods of genome size quantification (flow cytometry and Feulgen image analysis densitometry) are presented, thereby facilitating future work on these animals. Some particularly promising avenues for future investigation are highlighted. PMID- 24168629 TI - Patterns of genome size diversity in bats (order Chiroptera). AB - Despite being a group of particular interest in considering relationships between genome size and metabolic parameters, bats have not been well studied from this perspective. This study presents new estimates for 121 "microbat" species from 12 families and complements a previous study on members of the family Pteropodidae ("megabats"). The results confirm that diversity in genome size in bats is very limited even compared with other mammals, varying approximately 2-fold from 1.63 pg in Lophostoma carrikeri to 3.17 pg in Rhinopoma hardwickii and averaging only 2.35 pg +/- 0.02 SE (versus 3.5 pg overall for mammals). However, contrary to some other vertebrate groups, and perhaps owing to the narrow range observed, genome size correlations were not apparent with any chromosomal, physiological, flight-related, developmental, or ecological characteristics within the order Chiroptera. Genome size is positively correlated with measures of body size in bats, though the strength of the relationships differs between pteropodids ("megabats") and nonpteropodids ("microbats"). PMID- 24168630 TI - Heterochromatin and genome size in Drosophila. PMID- 24168634 TI - Genome size evolution: patterns, mechanisms, and methodological advances. PMID- 24168635 TI - Morphological enhancement of microscopy mineral image using opening- and closing based toggle operator. AB - To enhance unclear microscopy mineral images, an algorithm based on toggle operator using opening and closing is proposed in this paper. Firstly, the specified toggle operator using opening and closing through designing the selection rules is analysed. Secondly, after importing the multiscale theory into the specified toggle operator, useful mineral image features, especially the mineral details, are extracted using the multiscale theory-based toggle operator. Finally, the mineral image is enhanced through the strategy of enlarging the contrast between the extracted bright and dark image features. Experimental results on different types of mineral images verified that the proposed algorithm could effectively enhance mineral images and performed better than some other algorithms. The enhanced mineral image is clear and contains rich mineral details, whereas the grey scale distribution of the original mineral image is appropriately maintained. This would be useful for the further mineral analysis. Therefore, the proposed algorithm could be widely used for image-based mineral applications. PMID- 24168636 TI - Influence of environmental humidity on organization and molecular dynamics of heteromacrocyclic assemblies. AB - 1D and 2D NMR study, Car-Parrinello molecular dynamics, as well as classical molecular dynamics were employed to investigate three derivatives of benzodiazacoronands (achiral compounds which are able to form single crystals with a planar chirality) with intention to explain all subtle effects important during their preorganization, the step anticipating formation of crystals. The experimental study was carried out in two solvents: chloroform and DMSO either containing traces of water (commercial samples) or carefully dried over molecular sieves. Both methods revealed that environmental humidity has a dramatic influence on topology of solute-solvent interactions. Damping of the macrocycle dynamics by its diverse types of interactions with water molecules was shown by computational means. In the most spectacular experiment, we have proved that in chloroform-d during the low temperature measurements traces of water dramatically change the spectral pattern, leading to isochronous NMR signals of the AB spin system of benzodiazacoronand. The temperature of isochronous point (TIP) strongly depends on the benzodiazacoronand/water (BW) ratio. This observation opens a pathway to a new strategy based on variable temperature crystallizations and fitting of BW ratio with hope to optimize conditions for formation of chiral crystals. PMID- 24168637 TI - Thermoreversible nanogel shuttle between ionic liquid and aqueous phases. AB - We describe a nanogel that can reversibly shuttle between a hydrophobic ionic liquid (IL) phase and an aqueous phase in response to temperature changes. A thermosensitive diblock copolymer, consisting of poly(ethylene oxide) (PEO) as the first segment and a random copolymer of N-isopropylacrylamide (NIPAm) and N acryloyloxysuccinimide (NAS) as the second segment, was prepared as a nanogel precursor using anionic ring-opening polymerization of EO followed by reversible addition-fragmentation chain-transfer (RAFT) polymerization of NIPAm and NAS. After the micellization of the diblock copolymer in an aqueous solution upon heating to temperatures higher than the lower critical solution temperature (LCST) of the second segment, a coupling reaction of the NAS group of the P(NIPAm r-NAS) core with ethylenediamine gave a nanogel with a well-solvated PEO corona. The nanogel exhibited contrasting thermosensitivities in the aqueous and IL phases. Dynamic light scattering measurements revealed that the nanogel exhibited LCST phase behavior (low-temperature-swollen/high-temperature-shrunken) in the aqueous phase and the opposite upper critical solution temperature (UCST) phase behavior (high-temperature-swollen/low-temperature-shrunken) in hydrophobic ILs. The nanogel favored the aqueous phase at low temperatures and the IL phase at high temperatures because of the solubility changes in the PEO corona. Upon increasing the temperature, the nanogel underwent a swollen-to-shrunken phase change in the aqueous phase, a transfer from the aqueous phase to the IL phase, and a shrunken-to-swollen phase change in the IL phase. These processes were thermally reversible, which made the round-trip shuttling of the nanogel between the aqueous and IL phases possible. PMID- 24168638 TI - Physical activity, sedentary behavior and total wellness changes among sedentary adults: a 4-week randomized controlled trial. AB - BACKGROUND: The construct of total wellness includes a holistic approach to the body, mind and spirit components of life. While the health benefits of reducing sedentary behavior and increasing physical activity are well documented, little is known about the influence on total wellness of an internet-based physical activity monitor designed to help people to achieve higher physical activity levels. PURPOSE: The purpose of this four-week, personal activity monitor-based intervention program was to reduce sedentary behavior and increase physical activity levels in daily living for sedentary adults and to determine if these changes would also be associated with improvement in total wellness. METHODS: Twenty-two men and 11 women (27 years +/- 4.0) were randomly assigned to either an intervention (n = 18) or control group (n = 15). The intervention group interacted with an online personal activity monitor (Gruve SolutionTM) designed to reduce sedentary time and increase physical activity during activities of daily living. The control group did not interact with the monitor, as they were asked to follow their normal daily physical activities and sedentary behavior routines. The Wellness Evaluation of Lifestyle (WEL) inventory was used to assess total wellness. Sedentary time, light, walking, moderate and vigorous intensity physical activities were assessed for both intervention and control groups at baseline and at week-4 by the 7-day Sedentary and Light Intensity Physical Activity Log (7-day SLIPA Log) and the International Physical Activity Questionnaire (IPAQ). RESULTS: Significant increases in pre-post total wellness scores (from 64% +/- 5.7 to 75% +/- 8.5) (t(17) = -6.5, p < 0.001) were observed in the intervention group by the end of week four. Intervention participants decreased their sedentary time (21%, 2.3 hours/day) and increased their light (36.7%, 2.5 hours/day), walking (65%, 1057 MET-min/week), moderate (67%, 455 MET min/week) and vigorous intensity (60%, 442 MET-min/week) physical activity (all p < 0.001). No significant differences for total wellness were observed between the groups at baseline and no pre-post significant differences were observed for any outcome variable in the control group. CONCLUSION: Total wellness is improved when sedentary, but sufficiently physically active adults, reduce sedentary time and increase physical activity levels (i.e. light, waking, moderate and vigorous). PMID- 24168639 TI - Commensals, probiotics and pathogens in the Caenorhabditis elegans model. AB - Caenorhabditis elegans is a useful model host for a wide variety of microorganisms that have implications for human health. Recent surveys of mammalian and metazoan microbiota demonstrate the often profound effects of gut commensal bacteria on host lifespan, health and development. Work using C. elegans has revealed the surprising extent to which bacterial metabolism can interact with host pathways with examples from Escherichia coli folate metabolism and Bacillus subtilis nitric oxide synthesis. The C. elegans model has also shed light on the mechanisms by which probiotic bacteria influence lifespan. PMID- 24168640 TI - Healthcare costs among patients with chronic constipation: a retrospective claims analysis in a commercially insured population. AB - OBJECTIVE: To evaluate total annual all-cause, gastrointestinal-related, and symptom-related healthcare costs among chronic constipation (CC) patients and estimate incremental all-cause healthcare costs of CC patients relative to matched controls. METHODS: Patients aged >=18 years with continuous medical and pharmacy benefit eligibility in 2010 were identified from the HealthCore Integrated Research Database. CC patients had >=2 medical claims for constipation (ICD-9-CM code 564.0x) >=90 days apart or >=1 medical claim for constipation plus >=1 constipation-related pharmacy claim >=90 days apart, and no medical claims for irritable bowel syndrome (IBS). Sub-groups with and without abdominal symptoms were classified according to the presence/absence of abdominal pain (ICD 9-CM code 789.0x) and bloating (ICD-9-CM code 787.3x). Controls without claims for constipation, abdominal pain, bloating, or IBS or constipation-related prescriptions were randomly selected and matched 1:1 with CC patients on age, gender, health plan region, and plan type. Generalized linear models with bootstrapping evaluated incremental all-cause costs attributable to CC, adjusting for demographics and comorbidities. RESULTS: Overall, 14,854 patients (n = 7427 each in CC and control groups) were identified (mean age = 59 years; 75.4% female). Mean annual all-cause costs for CC patients were $11,991 (2010 USD), with nearly half (44.8%) attributable to outpatient services, including physician office visits and other outpatient services (10.0% and 34.8%, respectively). GI related costs comprised 33.7% of total all-cause costs. Symptom-related costs accounted for 10.5%, primarily driven by costs of other outpatient services (50.6%). Adjusted incremental all-cause costs associated with CC were $3508 per patient per year ($4446 for CC with abdominal symptoms; $2783 for CC without abdominal symptoms), of which 81.0% were from medical services. Incremental cost estimates may be over- or under-estimated due to classification based on claims. CONCLUSIONS: CC imposes a substantial burden in direct healthcare costs in a commercially insured population, mainly attributable to greater use of medical services. PMID- 24168641 TI - Transfusion immunomodulation from a clinical perspective: an update. AB - Accumulated evidence demonstrates that allogeneic blood transfusions have clinically significant effects on the recipient's immune system. This transfusion immunomodulation effect is associated with an increased rate of cancer recurrence (uncertain causality) and post-operative infection (established causality). The exact mechanisms of transfusion immunomodulation are still unknown. Data suggests that transfusion immunomodulation is a biologic effect strongly associated with the infusion of allogeneic leukocytes. Soluble mediators that accumulate in transfused red cells and platelets during storage are also possible causes of post-transfusion complications. Some approaches can mitigate these effects. Most important is adopting more conservative transfusion practices. Leukoreduction (proven) and plasma depletion (proposed) are other methods to significantly reduce transfusion immunomodulation and its clinical sequela. PMID- 24168642 TI - Isotropic bicelles stabilize the juxtamembrane region of the influenza M2 protein for solution NMR studies. AB - The protein M2 from influenza is a tetrameric membrane protein with several roles in the viral life cycle. The transmembrane helix (TMH) of M2 has proton channel activity that is required for unpackaging the viral genome. Additionally a C terminal juxtamembrane region includes an amphipathic helix (APH) important for virus budding and scission. The APH interacts with membranes and is required for M2 localization to the site of viral budding. As a step toward obtaining high resolution information on the structure and lipid interactions of the M2 APH, we sought to develop a fast tumbling bicelle system, which would make studies of M2 in a membrane-like environment by solution NMR possible. Since M2 is highly sensitive to the solubilizing environment, an M2 construct containing the APH was studied under micelle and bicelle conditions while maintaining the same detergent and lipid headgroup chemistry to facilitate interpretation of the spectroscopic results. The sequence from a human H1N1 "swine flu" isolate was used to design an M2 construct (swM2) similar in amino acid sequence to currently circulating viruses. Comparison of swM2 solubilized in either the diacyl detergent 1,2 dihexanoyl-sn-glycero-3-phosphocholine (DHPC) or a mixture of DHPC and the lipid 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC) (q = 0.4) indicated that the largest changes were a decrease in helicity at the N-terminus of the TMH and a decrease in dynamics for the juxtamembrane linker residues connecting the TMH and the APH. Whereas the linker region is very dynamic and the amide protons are rapidly exchanged with water protons in micelles, the dynamics and water exchange are largely suppressed in the presence of lipid. Chemical shift changes and relaxation measurements were consistent with an overall stabilization of the linker region, with only modest changes in conformation or environment of the APH itself. Such changes are consistent with differences observed in structures of M2 in lipid bilayers and detergent micelles, indicating that the bicelle system provides a more membrane-like environment. PMID- 24168644 TI - The role of the temporal lobe in contextual sentence integration: A single-pulse transcranial magnetic stimulation study. AB - Neuroimaging studies have shown the left temporal lobe to be important for contextual sentence integration. This study used single-pulse transcranial magnetic stimulation (TMS) to establish stronger causal evidence for the role of this brain region and also explored the involvement of the same cortical region in the right hemisphere (RH). In a semantic decision task, sentences with different cloze probability endings (highly expected, unexpected, and semantically anomalous) were presented to 59 participants. Single-pulse TMS was applied to the left or the right posterior temporal lobe. Vertex stimulation served as a baseline. Left temporal stimulation decelerated responses to expected and unexpected endings in a sentence-integration task. RH stimulation did not affect the responses. These results support the causal role of the left temporal lobe in semantic integration. Single-pulse TMS can contribute to a better understanding of language organization at a sentence level. PMID- 24168643 TI - Carbapenemase-producing Pseudomonas aeruginosa from central Greece: molecular epidemiology and genetic analysis of class I integrons. AB - BACKGROUND: Multidrug-resistant Pseudomonas aeruginosa is a serious challenge for antimicrobial therapy of nosocomial infections, as it possesses several mechanisms of antimicrobial resistance. In Central Greece, a sudden increase of infections caused by carbapenem-resistant P. aeruginosa was observed during 2011, indicating the need for further analysis. METHODS: Five-hundred and sixty-eight P. aeruginosa isolates were collected consecutively during an 8-month period in 2011 from inpatients treated in three hospitals in the Thessaly region (1,000,000 habitants) of Greece. Carbapenem-resistant P. aeruginosa (n = 284) were characterized by antimicrobial susceptibility testing and beta-lactamase content, and the genetic relatedness of carbapenemase-producing isolates was assessed by BOX-PCR, multilocus sequence typing, and eBURST analysis. Mapping of the class I integrons of Verona integron-encoded metallo-beta-lactamase (VIM)-carrying isolates was also performed, and clinical data of the VIM producers were reviewed. RESULTS: Eighty (14.1%) out of the 568 P. aeruginosa isolates recovered from clinical specimens were VIM producers. Multilocus sequence typing revealed high prevalence of the international clones ST111 and ST235 among blaVIM-2- and blaVIM-4-positive isolates, respectively. blaVIM-17 was identified in an isolate of a novel sequence type (ST1457). blaVIM gene cassettes were carried by five distinct class I integrons, including two novel ones. CONCLUSIONS: Since the first report of VIM-producing P. aeruginosa in 2000, this microorganism still remains among the most prevalent multidrug resistant pathogens in Greece. The spread of VIM-producers belonging to the most common international clones (ST111 and ST235), the spread of integrons of divergent structures, and the emergence of novel integrons underscore their ongoing evolution. PMID- 24168645 TI - Prominent reflexive eye-movement orienting associated with deafness. AB - Profound deafness affects orienting of visual attention. Until now, research focused exclusively on covert attentional orienting, neglecting whether overt oculomotor behavior may also change in deaf people. Here we used the pro- and anti-saccade task to examine the relative contribution of reflexive and voluntary eye-movement control in profoundly deaf and hearing individuals. We observed a behavioral facilitation in reflexive compared to voluntary eye movements, indexed by faster saccade latencies and smaller error rates in pro- than anti-saccade trials, which was substantially larger in deaf than hearing participants. This provides the first evidence of plastic changes related to deafness in overt oculomotor behavior, and constitutes an ecologically relevant parallel to the modulations attributed to deafness in covert attention orienting. Our findings also have implications for designers of real and virtual environments for deaf people and reveal that experiments on deaf visual abilities must not ignore the prominent reflexive eye-movement orienting in this sensory-deprived population. PMID- 24168646 TI - Visual memory and visual mental imagery recruit common control and sensory regions of the brain. AB - Separate lines of research have shown that visual memory and visual mental imagery are mediated by frontal-parietal control regions and can rely on occipital-temporal sensory regions of the brain. We used fMRI to assess the degree to which visual memory and visual mental imagery rely on the same neural substrates. During the familiarization/study phase, participants studied drawings of objects. During the test phase, words corresponding to old and new objects were presented. In the memory test, participants responded "remember," "know," or "new." In the imagery test, participants responded "high vividness," "moderate vividness," or "low vividness." Visual memory (old-remember) and visual imagery (old-high vividness) were commonly associated with activity in frontal-parietal control regions and occipital-temporal sensory regions. In addition, visual memory produced greater activity than visual imagery in parietal and occipital temporal regions. The present results suggest that visual memory and visual imagery rely on highly similar--but not identical--cognitive processes. PMID- 24168647 TI - Grapheme-color and tone-color synesthesia is associated with structural brain changes in visual regions implicated in color, form, and motion. AB - Synesthesia is a rare condition in which stimulation in one modality leads to a secondary experience in another sensory modality. Varying accounts attribute the condition to either neuroanatomical differences between the synesthetes and non synesthetes or functional differences in how sensory brain regions interact. This study employed voxel-based morphometry to examine whether synesthetes who experience both grapheme-color and tone-color synesthesia as their evoked sensation show neuroanatomical differences in gray matter volume compared to non synesthetes. We observed that synesthetes showed an increase in gray matter volume in left posterior fusiform gyrus (FG), but a concomitant decrease in anterior regions of left FG and left MT/V5. These findings imply that synesthesia for color is linked to neuroanatomical changes between adjacent regions of the visual system. PMID- 24168649 TI - An early category-specific neural response for the perception of both places and faces. AB - Rapid and accurate recognition of faces and places is crucial in everyday life. Magnetoencephalography (MEG) studies have demonstrated that the human visual system can categorize an incoming visual stimulus as a face within 100 ms, as reflected by the M100. No similar, early, place-specific MEG component has been described, somewhat surprisingly, as there is behavioral evidence for rapid visual categorization of places. The current study aimed to explore the existence, as well as the spatio-temporal dynamics, of a place-selective MEG component. MEG activity was recorded while 10 participants were presented with pairs of face and place stimuli. Our results show that the perception of places generates a category-specific MEG component (M100p), which occurs just as early as that seen for faces. Our findings suggest that early visual categorization within cortical areas does not occur exclusively for faces, but instead may be a more general phenomenon. PMID- 24168648 TI - Opposite effects of perceptual and working memory load on perceptual filling-in of an artificial scotoma. AB - A target presented on a background of dynamic noise disappears from awareness after a few seconds of maintained peripheral viewing. Whereas the effects of bottom-up factors in such filling-in are well documented, the roles of different top-down functions remain relatively unexplored. Here, we investigated the roles of attention and working memory (WM) by manipulating load in concurrent tasks while participants reported filling-in of a peripheral target. In Experiment 1, increasing perceptual load reduced the probability of filling-in and increased the latency of its occurrence. In Experiment 2, increasing WM load shortened the time before filling-in occurred--the opposite effect to increasing perceptual load. These results demonstrate that different top-down functions may have dissociable effects on filling-in. PMID- 24168650 TI - Rapid decision-making under risk. AB - Impulsivity is often characterized by rapid decisions under risk, but most current tests of decision-making do not impose time pressures on participants' choices. Here we introduce a new traffic lights test which requires people to choose whether to program a risky, early eye movement before a traffic light turns green (earning them high rewards or a penalty) or wait for the green light before responding to obtain a small reward instead. Young participants demonstrated bimodal responses: an early, high-risk and a later, low-risk set of choices. By contrast, elderly people invariably waited for the green light and showed little risk-taking. Performance could be modeled as a race between two rise-to-threshold decision processes, one triggered by the green light and the other initiated before it. The test provides a useful measure of rapid decision making under risk, with the potential to reveal how this process alters with aging or in patient groups. PMID- 24168654 TI - Microstructure versus flaw: mechanisms of failure and strength in nanostructures. AB - Understanding failure in nanomaterials is critical for the design of reliable structural materials and small-scale devices with nanoscale components. No consensus exists on the effect of flaws on fracture at the nanoscale, but proposed theories include nanoscale flaw tolerance and maintaining macroscopic fracture relationships at the nanoscale with scarce experimental support. We explore fracture in nanomaterials using nanocrystalline Pt nanocylinders with prefabricated surface notches created using a "paused" electroplating method. In situ scanning electron microscopy (SEM) tension tests demonstrate that the majority of these samples failed at the notches, but that tensile failure strength is independent of whether failure occurred at or away from the flaw. Molecular dynamics simulations verify these findings and show that local plasticity is able to reduce stress concentration ahead of the notch to levels comparable with the strengths of microstructural features (e.g., grain boundaries). Thus, failure occurs at the stress concentration with the highest local stress whether this is at the notch or a microstructural feature. PMID- 24168655 TI - Estimating autozygosity from high-throughput information: effects of SNP density and genotyping errors. AB - BACKGROUND: Runs of homozygosity are long, uninterrupted stretches of homozygous genotypes that enable reliable estimation of levels of inbreeding (i.e., autozygosity) based on high-throughput, chip-based single nucleotide polymorphism (SNP) genotypes. While the theoretical definition of runs of homozygosity is straightforward, their empirical identification depends on the type of SNP chip used to obtain the data and on a number of factors, including the number of heterozygous calls allowed to account for genotyping errors. We analyzed how SNP chip density and genotyping errors affect estimates of autozygosity based on runs of homozygosity in three cattle populations, using genotype data from an SNP chip with 777,972 SNPs and a 50 k chip. RESULTS: Data from the 50 k chip led to overestimation of the number of runs of homozygosity that are shorter than 4 Mb, since the analysis could not identify heterozygous SNPs that were present on the denser chip. Conversely, data from the denser chip led to underestimation of the number of runs of homozygosity that were longer than 8 Mb, unless the presence of a small number of heterozygous SNP genotypes was allowed within a run of homozygosity. CONCLUSIONS: We have shown that SNP chip density and genotyping errors introduce patterns of bias in the estimation of autozygosity based on runs of homozygosity. SNP chips with 50,000 to 60,000 markers are frequently available for livestock species and their information leads to a conservative prediction of autozygosity from runs of homozygosity longer than 4 Mb. Not allowing heterozygous SNP genotypes to be present in a homozygosity run, as has been advocated for human populations, is not adequate for livestock populations because they have much higher levels of autozygosity and therefore longer runs of homozygosity. When allowing a small number of heterozygous calls, current software does not differentiate between situations where these calls are adjacent and therefore indicative of an actual break of the run versus those where they are scattered across the length of the homozygous segment. Simple graphical tests that are used in this paper are a current, yet tedious solution. PMID- 24168656 TI - microRNA-122 down-regulation may play a role in severe myocardial fibrosis in human aortic stenosis through TGF-beta1 up-regulation. AB - miRNAs (microRNAs) have been shown to play a role in myocardial fibrosis. The present study was designed to analyse whether alterations in miRNA expression contribute to the progression of myocardial fibrosis in AS (aortic valve stenosis) patients through up-regulation of the pro-fibrotic factor TGF-beta1 (transforming growth factor-beta type 1). Endomyocardial biopsies were obtained from 28 patients with severe AS, and from the necropsies of 10 control subjects. AS patients presented increased myocardial CVF (collagen volume fraction) and TGF beta1 compared with the controls, these parameters being correlated in all patients. Patients were divided into two groups by cluster analysis according to their CVF: SF (severe fibrosis; CVF >15%; n=15) and non-SF (CVF <=15%; n=13). TGF beta1 was increased in patients with SF compared with those with non-SF. To analyse the involvement of miRNAs in SF, the miRNA expression profile of 10 patients (four with non-SF and six with SF) was analysed showing that 99 miRNAs were down-regulated and 19 up-regulated in the SF patients compared with the non SF patients. Those miRNAs potentially targeting TGF-beta1 were validated by real time RT (reverse transcription)-PCR in the whole test population, corroborating that miR-122 and miR-18b were down-regulated in patients with SF compared with those with non-SF and the control subjects. Additionally, miR-122 was inversely correlated with the CVF, TGF-beta1 and the TGF-beta1-regulated PCPE-1 (procollagen C-terminal proteinase enhancer-1) in all patients. Experiments in human fibroblasts demonstrated that miR-122 targets and inhibits TGF-beta1. In conclusion, for the first time we show that myocardial down-regulation of miR-122 might be involved in myocardial fibrosis in AS patients, probably through TGF beta1 up-regulation. PMID- 24168658 TI - Microsurgical management of bronchogenic cysts in the thalamus: an illustrative case and literature review. AB - Intracranial bronchogenic cysts are extremely rare. This is the first reported case of a bronchogenic cyst arising from the thalamus. Complete microsurgical resection was undertaken. A literature review was conducted to explore the etiologies, diagnostic approaches, and therapeutic strategies for this type of rare disease. PMID- 24168659 TI - Cauda equina syndrome: findings on perineal examination. PMID- 24168660 TI - Cardiac cavernous haemangioma: diagnosis and treatment. PMID- 24168661 TI - Energetic and dynamic aspects of the affinity maturation process: characterizing improved variants from the bevacizumab antibody with molecular simulations. AB - Antibody affinity maturation is one of the fundamental processes of immune defense against invading pathogens. From the biological point of view, the clonal selection hypothesis represents the most accepted mechanism to explain how mutations increasing the affinity for target antigens are introduced and selected in antibody molecules. However, understanding at the molecular level how protein modifications, such as point mutation, can modify and modulate the affinity of an antibody for its antigen is still a major open issue in molecular biology. In this paper, we address various aspects of this problem by analyzing and comparing atomistic simulations of 17 variants of the bevacizumab antibody, all directed against the common target protein VEGF-A. In particular, we examine MD-based descriptors of the internal energetics and dynamics of mutated antibodies and their possible correlations with experimentally determined affinities for the antigens. Our results show that affinity improvement is correlated with a variation of the internal stabilization energy of the antibody molecule when bound to the antigen, compensated by the variation in the interaction energy between the antigen and the antibody, paralleled by an overall modulation of internal coordination within the antibody molecular structure. A possible model of the mechanism of rigidification and of the main residues involved is proposed. Overall, our results can help in understanding the molecular determinants of antigen recognition and have implications in the rational design of new antibodies with optimized affinities. PMID- 24168662 TI - Incorporation of trinuclear lanthanide(III) hydroxo bridged clusters in macrocyclic frameworks. AB - A cluster of lanthanide(III) or yttrium(III) ions, Ln3(MU3-OH)2, (Ln(III) = Nd(III), Sm(III), Eu(III), Gd(III), Tb(III), Dy(III), Yb(III), or Y(III)) can be bound in the center of a chiral macrocyclic amines H3L1(R), H3L1(S), and H3L2(S) obtained in a reduction of a 3 + 3 condensation product of (1R,2R)- or (1S,2S) 1,2-diaminocyclohexane and 2,6-diformyl-4-methylphenol or 2,6-diformyl-4 tertbutylphenol. X-ray crystal structures of the Nd(III), Sm(III), Gd(III), Dy(III), and Y(III) complexes reveal trinuclear complexes with Ln(III) ions bridged by the phenolate oxygen atoms of the macrocycle as well as by MU3-hydroxo bridges. In the case of the Nd(III) ion, another complex form can be obtained, whose X-ray crystal structure reveals two trinuclear macrocyclic units additionally bridged by hydroxide anions, corresponding to a [Ln3(MU3-OH)]2(MU2 OH)2 cluster encapsulated by two macrocycles. The formation of trinuclear complexes is confirmed additionally by (1)H NMR, electrospray ionization mass spectrometry (ESI MS), and elemental analyses. Titrations of free macrocycles with Sm(III) or Y(III) salts and KOH also indicate that a trinuclear complex is formed in solution. On the other hand, analogous titrations with La(III) salt indicate that this kind of complex is not formed even with the excess of La(III) salt. The magnetic data for the trinuclear Gd(III) indicate weak antiferromagnetic coupling (J = -0.17 cm(-1)) between the Gd(III) ions. For the trinuclear Dy(III) and Tb(III) complexes the chi(M)T vs T plots indicate a more complicated dependence, resulting from the combination of thermal depopulation of mJ sublevels, magnetic anisotropy, and possibly weak antiferromagnetic and ferromagnetic interactions. PMID- 24168663 TI - Rare case of primary cutaneous mucormycosis of the hand caused by Rhizopus microsporus in an immunocompetent patient. AB - BACKGROUND: Primary cutaneous mucormycosis is a very uncommon manifestation occurring most often in diabetics or following trauma. METHODS AND RESULTS: We herein present a case of primary cutaneous mucormycosis of the hand caused by Rhizopus microsporus in an immunocompetent patient. CONCLUSION: This is the second such reported case in the literature. PMID- 24168664 TI - Classification of stevia sweeteners in soft drinks using liquid chromatography and time-of-flight mass spectrometry. AB - The aim of this study was to develop a comprehensive analytical method for the characterisation of stevia sweeteners in soft drinks. By using LC and time-of flight MS, we detected 30 steviol glycosides from nine stevia sweeteners. The mass spectral data of these compounds were applied to the analysis to determine steviol glycosides in nine soft drinks. On the basis of chromatographic data and principal-component analysis, these soft drinks were classified into three groups, and the soft drinks of each group, respectively, contained high rebaudioside A extract, normal stevia extract or alfa-glucosyltransferase-treated stevia extract. PMID- 24168665 TI - In vitro anti-mycobacterial activity of selected medicinal plants against Mycobacterium tuberculosis and Mycobacterium bovis strains. AB - BACKGROUND: Tuberculosis (TB) is a global burden with one -third of the world's population infected with the pathogen Mycobacterium tuberculosis complex and annually 1.4 million deaths occur due to the disease. This high incidence of infection and the increased rate of multi-drug resistant and extensively-drug resistant strains of the organism further complicated the problem of TB control and have called for an urgent need to develop new anti-TB drugs from plants. In this study, the in vitro activity of root of Calpurnia aurea, seeds of Ocimum basilicum, leaves of Artemisia abyssinica, Croton macrostachyus, and Eucalyptus camaldulensis were evaluated against M. tuberculosis and M. bovis strains. METHODS: Five Ethiopian medicinal plants, root of Calpurnia aurea, seeds of Ocimum basilicum, leaves of Artemisia abyssinica, Croton macrostachyus, and Eucalyptus camaldulensis used locally for the management of TB. They were investigated for in vitro antimycobacterial activity against M. tuberculosis and M. bovis strains. 80% methanolic extracts of the plant materials were obtained by maceration. The antimycobacterial activity was determined using 96 wells of microplate with the help of visual Resazurin Microtiter Assay. RESULTS: The crude 80% methanolic extracts of the root of C. aurea, seeds of O. basilicum, and leaves of A. abyssinica, C. macrostachyus, and E. camaldulensis had anti mycobacterial activity with minimum inhibitory concentration (MIC) ranging from 6.25-100 MUg/mL. The MIC of 80% methanol extracts in the order mentioned above ranged 25-100 MUg/ml and 12.5-75 MUg/mL, 25-100 MUg/mL and 25-50 MUg/mL, 6.25-50 MUg/mL and 12.5-50 MUg/mL, 12.5-100 MUg/mL and 18.25-50 MUg/mL and 6.25-50 MUg/mL and 12.5-50 MUg/mL, respectively for M. tuberculosis and M. bovis strains. CONCLUSIONS: The results support the local use of these plants in the treatment of TB and it is suggested that these plants may have therapeutic value in the treatment of TB. However, further investigations are needed on isolating chemical constituents responsible for eliciting the observed activity in these plants. PMID- 24168666 TI - Live cell chemical profiling of temporal redox dynamics in a photoautotrophic cyanobacterium. AB - Protein reduction-oxidation (redox) modification is an important mechanism that allows microorganisms to sense environmental changes and initiate cellular responses. We have developed a quantitative chemical probe approach for live cell labeling and imaging of proteins that are sensitive to redox modifications. We utilize this in vivo strategy to identify 176 proteins undergoing ~5-10-fold dynamic redox change in response to nutrient limitation and subsequent replenishment in the photoautotrophic cyanobacterium Synechococcus sp. PCC 7002. We detect redox changes in as little as 30 s after nutrient perturbation and oscillations in reduction and oxidation for 60 min following the perturbation. Many of the proteins undergoing dynamic redox transformations participate in the major components for the production (photosystems and electron transport chains) or consumption (Calvin-Benson cycle and protein synthesis) of reductant and/or energy in photosynthetic organisms. Thus, our in vivo approach reveals new redox susceptible proteins and validates those previously identified in vitro. PMID- 24168667 TI - Exploring scale-up, spread, and sustainability: an instrumental case study tracing an innovation to enhance dysphagia care. AB - BACKGROUND: Adoption, adaptation, scale-up, spread, and sustainability are ill defined, undertheorised, and little-researched implementation science concepts. An instrumental case study will track the adoption and adaptation, or not, of a locally developed innovation about dysphagia as a patient safety issue. The case study will examine a conceptual framework with a continuum of spread comprising hierarchical control or 'making it happen', participatory adaptation or 'help it happen', and facilitated evolution or 'let it happen'. METHODS: This case study is a prospective, longitudinal design using mixed methods. The fifteen-month (October 2012 to December 2013) instrumental case study is set in large, healthcare organisation in England. The innovation refers to introducing a nationally recognised, inter-disciplinary dysphagia competency framework to guide workforce development about fundamental aspects of care. Adoption and adaptation will be examined at an organisational level and along two, contrasting care pathways: stroke and fractured neck of femur. A number of educational interventions will be deployed, including training a cadre of trainers to cascade the essentials of dysphagia management and developing a Dysphagia Toolkit as a learning resource. Mixed methods will be used to investigate scale-up, spread, and sustainability in acute and community settings. A purposive sample of senior managers and clinical leaders will be interviewed to identify path dependency or the context specific particularities of implementation. A pre- and post evaluation, using mealtime observations and a survey, will investigate the learning effect on staff adherence to patient specific dysphagia recommendations and attitudes towards dysphagia, respectively. Official documents and an ethnographic field journal allow critical junctures, temporal aspects and confounding factors to be explored. DISCUSSION: Researching spread and sustainability presents methodological and practical challenges. These include fidelity, adaptation latitude, time, and organisational changes. An instrumental case study will allow these confounding factors to be tracked over time and in place. The case study is underpinned by, and will test a conceptual framework about spread, to explore theoretical generalizability. PMID- 24168668 TI - Miniature inverted-repeat transposable elements: discovery, distribution, and activity. AB - Eukaryotic organisms have dynamic genomes, with transposable elements (TEs) as a major contributing factor. Although the large autonomous TEs can significantly shape genomic structures during evolution, genomes often harbor more miniature nonautonomous TEs that can infest genomic niches where large TEs are rare. In spite of their cut-and-paste transposition mechanisms that do not inherently favor copy number increase, miniature inverted-repeat transposable elements (MITEs) are abundant in eukaryotic genomes and exist in high copy numbers. Based on the large number of MITE families revealed in previous studies, accurate annotation of MITEs, particularly in newly sequenced genomes, will identify more genomes highly rich in these elements. Novel families identified from these analyses, together with the currently known families, will further deepen our understanding of the origins, transposase sources, and dramatic amplification of these elements. PMID- 24168669 TI - Assembly and comparative analysis of transposable elements from low coverage genomic sequence data in Asparagales. AB - The research field of comparative genomics is moving from a focus on genes to a more holistic view including the repetitive complement. This study aimed to characterize relative proportions of the repetitive fraction of large, complex genomes in a nonmodel system. The monocotyledonous plant order Asparagales (onion, asparagus, agave) comprises some of the largest angiosperm genomes and represents variation in both genome size and structure (karyotype). Anonymous, low coverage, single-end Illumina data from 11 exemplar Asparagales taxa were assembled using a de novo method. Resulting contigs were annotated using a reference library of available monocot repetitive sequences. Mapping reads to contigs provided rough estimates of relative proportions of each type of transposon in the nuclear genome. The results were parsed into general repeat types and synthesized with genome size estimates and a phylogenetic context to describe the pattern of transposable element evolution among these lineages. The major finding is that although some lineages in Asparagales exhibit conservation in repeat proportions, there is generally wide variation in types and frequency of repeats. This approach is an appropriate first step in characterizing repeats in evolutionary lineages with a paucity of genomic resources. PMID- 24168670 TI - Isolation and characterization of novel Ty1-copia-like retrotransposons from lily. AB - Species of the genus Lilium are well known for their large genomes. Although expansion of noncoding repeated DNA is believed to account for this genome size, retroelement del Ty3-gypsy is the only one described so far in the genus Lilium. We isolated Ty1-copia elements from Lilium longiflorum and named them LIREs (lily retrotransposons). The long terminal repeats, primer binding site, and polypurine tract sequences are highly similar among the LIRE elements, indicating that they are in the same lineage. Although the protein-coding regions were highly decayed, the sequence motifs of the integrase, reverse transcriptase, and RNase H domains were identifiable as belonging to the order of Ty1-copia elements. Phylogenetic analysis and primer binding site sequences revealed that these elements belonged to the Ale lineage among the six lineages of plant Ty1-copia elements. Base substitutions in the long terminal repeats estimated that the integration times of the LIRE Ty1-copia elements were between 0.7 and 5.5 mya. In situ hybridization showed that the LIRE elements were present in all the chromosomes of L. longiflorum and L. lancifolium, but absent in centromeres, telomeres, and 45S rRNA sites in both species. The LIRE elements were present very abundantly in species of the genus Lilium, but absent in other genera of the family Liliaceae, implying that the LIRE elements might have contributed to the expansion of the genome in the genus Lilium. PMID- 24168671 TI - Sizing up arthropod genomes: an evaluation of the impact of environmental variation on genome size estimates by flow cytometry and the use of qPCR as a method of estimation. AB - A study was undertaken to evaluate both a pre-existing method and a newly proposed approach for the estimation of nuclear genome sizes in arthropods. First, concerns regarding the reliability of the well-established method of flow cytometry relating to impacts of rearing conditions on genome size estimates were examined. Contrary to previous reports, a more carefully controlled test found negligible environmental effects on genome size estimates in the fly Drosophila melanogaster. Second, a more recently touted method based on quantitative real time PCR (qPCR) was examined in terms of ease of use, efficiency, and (most importantly) accuracy using four test species: the flies Drosophila melanogaster and Musca domestica and the beetles Tribolium castaneum and Dendroctonus ponderosa. The results of this analysis demonstrated that qPCR has the tendency to produce substantially different genome size estimates from other established techniques while also being far less efficient than existing methods. PMID- 24168672 TI - Larger Daphnia at lower temperature: a role for cell size and genome configuration? AB - Experiments with Daphnia magna and Daphnia pulex raised at 10 and 20 degrees C yielded larger adult size at the lower temperature. This must reflect increased cell size, increased cell numbers, or a combination of both. As it is difficult to achieve good estimates on cell size in crustaceans, we, therefore, measured nucleus and genome size using flow cytometry at 10 and 20 degrees C. DNA was stained with propidium iodide, ethidium bromide, and DAPI. Both nucleus and genome size estimates were elevated at 10 degrees C compared with 20 degrees C, suggesting that larger body size at low temperature could partly be accredited to an enlarged nucleus and thus cell size. Confocal microscopy observations confirmed the staining properties of fluorochromes. As differences in nucleotide numbers in response of growth temperature within a life span is unlikely, these results seem accredited to changed DNA-fluorochrome binding properties, presumably reflecting increased DNA condensation at low temperature. This implies that genome size comparisons may be impacted by ambient temperature in ectotherms. It also suggests that temperature-induced structural changes in the genome could affect cell size and for some species even body size. PMID- 24168673 TI - A novel application of ecological analyses to assess transposable element distributions in the genome of the domestic cow, Bos taurus. AB - Transposable elements (TEs) are among the most abundant components of many eukaryotic genomes. Efforts to explain TE abundance, as well as TE diversity among genomes, have led some researchers to draw an analogy between genomic and ecological processes. Adopting this perspective, we conducted an analysis of the cow (Bos taurus) genome using techniques developed by community ecologists to determine whether environmental factors influence community composition. Specifically, each chromosome within the Bos taurus genome was treated as a "linear transect", and a multivariate redundancy analysis (RDA) was used to identify large-scale spatial patterns in TE communities associated with 10 TE families. The position of each TE community on the chromosome accounted for ~50% of the variation along the chromosome "transect". Multivariate analysis further revealed an effect of gene density on TE communities that is influenced by several other factors in the (genomic) environment, including chromosome length and TE density. The results of this analysis demonstrate that ecological methods can be applied successfully to help answer genomic questions. PMID- 24168676 TI - Aliphatic/aromatic systems under irradiation: influence of the irradiation temperature and of the molecular organization. AB - With the aim of understanding the electronic excitation, charge or reactive species transfers occurring during irradiation, we studied the role of the aromatic content on ethylene/styrene random copolymers (PES) and on cyclohexane/benzene glasses (amorphous organic solids). Radiation-induced modifications were monitored in situ, at the molecular level, using Fourier transform infrared spectroscopy (FTIR). Irradiations were performed under a vacuum, and thanks to in situ measurements, oxidation was avoided. We followed both the C?C bond creation in the aliphatic moiety and the destruction of the aromatic moiety. The influence of the irradiation temperature was investigated by irradiating samples at room temperature and at 11 K. At such a low temperature, long-range migration hardly occurs and its influence is considerably reduced or could even vanish. Therefore, low temperature irradiation gives insight on the relative influence of reactive species transport and electronic excitation and charge transport. We found that the effect of lowering the PES irradiation temperature from room temperature to 11 K is small, indicating a minor role for the reactive species transport. Moreover, the two chosen systems allow the examination of the relative magnitude of intra- and intermolecular transfers. We demonstrate that, under conditions where reactive species are almost frozen, intermolecular transfers are very efficient. PMID- 24168677 TI - Effect of pro-inflammatory cytokine (IFN-gamma +874, IL-18-137 G/C,-607 C/A) genes in relation to risk of vesico-ureteral reflux. AB - AIM: The aim this work is to estimate whether genetic polymorphisms of +874 of IFN-gamma and -137 G/C,-607 C/A of IL-18 genes are implicated in the development of VUR, because a vast literature indicates that genetic variations play a significant role in the pathogenesis of VUR. MATERIALS AND METHODS: The PCR single specific primer (SSP) and amplification refractory mutation system (ARMS) were applied for analyzing the polymorphic sites of -137 G/C,-607 C/A of IL-18 and +874 of IFN-gamma genes in 110 healthy controls and 124 VUR children. RESULTS: A significant relationship was found between AT and combined AT + TT genotypes of IFN-gamma and highly increased risk of VUR (OR = 4.2, 95% CI, 2.00 9.24; p < 0.0001: OR = 4.00, 95% CI, 1.90-8.70, p < 0.0001, respectively). On the other hand, the genotype frequency of IL18-137 G/C indicated a significant assessment of the decrease risk of VUR for GC and GC + CC genotypes (OR = 0.53, 95% CI, 0.3-0.9; p = 0.02: OR = 0.53, 95% CI, 0.3-0.92 p = 0.01, respectively). No significant association was found between -607 C/A polymorphism of IL-18 and UVR. CONCLUSION: To the author's best knowledge, this is the first data regarding polymorphism of IFN-gamma (+874) cytokine genes that highly increased the risk of VUR. To confirm the presented data, further studies should be done in different populations with a larger sample size. PMID- 24168678 TI - The risk of CNS involvement in aggressive lymphomas in the rituximab era. AB - The risk of CNS dissemination and CNS prophylaxis strategies in aggressive non Hodgkin lymphoma (NHL) is still debated. CNS dissemination is a rare but fatal event. A CNS prophylaxis is common for Burkitt and B-cell lymphoblastic lymphoma; however, in other NHLs, prophylactic treatments are not systematically warranted. Current risk models showed low sensitivity in predicting CNS involvement, implying overtreatment in roughly 70% of high-risk patients. Risk models in the rituximab era were modulated for the detection of occult CNS disease at diagnosis using flow cytometry. The optimal regimen for CNS prophylaxis in aggressive lymphoma patients has not been established thus far and should be modulated at different levels of 'intensity' such as standard intrathecal chemotherapy, 'active' intrathecal chemotherapy with liposomal cytarabine or more aggressive systemic treatment with high doses of drugs having good CNS bioavailability reserved for patients who are truly at high risk of CNS dissemination. PMID- 24168679 TI - De novo determination of the crystal structure of a large drug molecule by crystal structure prediction-based powder NMR crystallography. AB - The crystal structure of form 4 of the drug 4-[4-(2-adamantylcarbamoyl)-5-tert butyl-pyrazol-1-yl]benzoic acid is determined using a protocol for NMR powder crystallography at natural isotopic abundance combining solid-state (1)H NMR spectroscopy, crystal structure prediction, and density functional theory chemical shift calculations. This is the first example of NMR crystal structure determination for a molecular compound of previously unknown structure, and at 422 g/mol this is the largest compound to which this method has been applied so far. PMID- 24168681 TI - Keeping the theory in measurement. PMID- 24168680 TI - The CONSORT Patient-Reported Outcome (PRO) extension: implications for clinical trials and practice. AB - To inform clinical guidelines and patient care we need high quality evidence on the relative benefits and harms of intervention. Patient reported outcome (PRO) data from clinical trials can "empower patients to make decisions based on their values" and "level the playing field between physician and patient". While clinicians have a good understanding of the concept of health-related quality of life and other PROs, evidence suggests that many do not feel comfortable in using the data from trials to inform discussions with patients and clinical practice. This may in part reflect concerns over the integrity of the data and difficulties in interpreting the results arising from poor reporting.The new CONSORT PRO extension aims to improve the reporting of PROs in trials to facilitate the use of results to inform clinical practice and health policy. While the CONSORT PRO extension is an important first step in the process, we need broader engagement with the guidance to facilitate optimal reporting and maximize use of PRO data in a clinical setting. Endorsement by journal editors, authors and peer reviewers are crucial steps. Improved design, implementation and transparent reporting of PROs in clinical trials are necessary to provide high quality evidence to inform evidence synthesis and clinical practice guidelines. PMID- 24168682 TI - Chronic care model: a framework for experiential learning during clinical rotation. PMID- 24168683 TI - Using quick response codes to facilitate self-directed learning in a nursing skills laboratory. PMID- 24168686 TI - Statement of retraction. Temporal preparation accelerates visual processing: evidence from event-related brain potentials. PMID- 24168684 TI - Standard role for a conserved aspartate or more direct involvement in deglycosylation? An ONIOM and MD investigation of adenine-DNA glycosylase. AB - 8-Oxoguanine (OG) is one of the most frequently occurring forms of DNA damage and is particularly deleterious since it forms a stable Hoogsteen base pair with adenine (A). The repair of an OG:A mispair is initiated by adenine-DNA glycosylase (MutY), which hydrolyzes the sugar-nucleobase bond of the adenine residue before the lesion is processed by other proteins. MutY has been proposed to use a two-part chemical step involving protonation of the adenine nucleobase, followed by SN1 hydrolysis of the glycosidic bond. However, differences between a recent (fluorine recognition complex, denoted as the FLRC) crystal structure and the structure on which most mechanistic conclusions have been based to date (namely, the lesion recognition complex or LRC) raise questions regarding the mechanism used by MutY and the discrete role of various active-site residues. The present work uses both molecular dynamics (MD) and quantum mechanical (ONIOM) models to compare the active-site conformational dynamics in the two crystal structures, which suggests that only the understudied FLRC leads to a catalytically competent reactant. Indeed, all previous computational studies on MutY have been initiated from the LRC structure. Subsequently, for the first time, various mechanisms are examined with detailed ONIOM(M06-2X:PM6) reaction potential energy surfaces (PES) based on the FLRC structure, which significantly extends the mechanistic picture. Specifically, our work reveals that the reaction proceeds through a different route than the commonly accepted mechanism and the catalytic function of various active-site residues (Geobacillus stearothermophilus numbering). Specifically, contrary to proposals based on the LRC, E43 is determined to solely be involved in the initial adenine protonation step and not the deglycosylation reaction as the general base. Additionally, a novel catalytic role is proposed for Y126, whereby this residue plays a significant role in stabilizing the highly charged active site, primarily through interactions with E43. More importantly, D144 is found to explicitly catalyze the nucleobase dissociation step through partial nucleophilic attack. Although this is a more direct role than previously proposed for any other DNA glycosylase, comparison to previous work on other glycosylases justifies the larger contribution in the case of MutY and allows us to propose a unified role for the conserved Asp/Glu in the DNA glycosylases, as well as other enzymes that catalyze nucleotide deglycosylation reactions. PMID- 24168688 TI - Effects of transcranial direct-current stimulation (tDCS) of the dorsolateral prefrontal cortex (DLPFC) during a mixed-gambling risky decision-making task. AB - Previous studies have led to hypothesizing that right DLPFC activity is related to risk propensity, but the generality of this relationship remains unclear. Here, we experimentally modulated DLPFC activity in 47 healthy, female volunteers during a risky decision-making task, where monetary gambles defined by potential win, loss, and outcome probability were evaluated in the absence of feedback and uncertainty. Three participant groups, receiving left anodal/right cathodal, right anodal/left cathodal, and sham tDCS, were compared. Overall, participants performed the task well above chance level and were significantly risk averse, but tDCS did not affect task performance or risk propensity. However, right anodal/left cathodal tDCS significantly elevated response confidence, independently of accept/reject response. Our results suggest that the relationship between DLPFC activity and risk propensity may not be universally valid for all task types and requires further characterization. Enhancing right and attenuating left DLPFC activity boosts subjective confidence, with potential implications for understanding pathological gambling. PMID- 24168689 TI - Intelligence and the brain: A model-based approach. AB - Various biological correlates of general intelligence (g) have been reported. Despite this, however, the relationship between neurological measurements and g is not fully clear. We use structural equation modeling to model the relationship between behavioral Wechsler Adult Intelligence Scale (WAIS) estimates of g and neurological measurements (voxel-based morphometry and diffusion tensor imaging of eight regions of interest). We discuss psychometric models that explicate the relationship between g and the brain in a manner in line with the scientific study of g. Fitting the proposed models to the data, we find that a MIMIC model (for multiple indicators, multiple causes), where the contributions of different brain regions to a unidimensional g are estimated separately, provides the best fit against the data. PMID- 24168690 TI - The visual P2 is attenuated for attended objects near the hands. AB - Vision is altered when people place their hands near the object they are observing. To investigate the neural processes underlying this effect, we measured electroencephalographic visual-evoked potentials (VEPs) elicited by reversing checkerboards, while participants' hands either surrounded the visual display or rested at their sides. We found the P2 component was attenuated for hand-proximal stimuli, but only when participants attended to the location of the checkerboard. In Experiment 1, participants performed an attention-demanding color-change task that was presented centrally, and the P2 component was attenuated for central, but not peripheral, checkerboards. In Experiment 2, participants performed the attention task in the periphery, and the P2 was attenuated for peripheral, but not central, checkerboards. These results suggest that hand-proximal stimuli benefit from enhanced selective attention at later stages of perceptual processing. The effect only occurs for objects at task relevant locations, however, even when task-irrelevant locations are physically closer to the hands. PMID- 24168691 TI - Having to identify a target reduces antisaccade latencies in mixed saccadic paradigms: A top-down effect released by tonic prefrontal activation? AB - Instructing participants to "identify a target" dramatically reduces saccadic reaction times in prosaccade tasks (PS). However, it has been recently shown that this effect disappears in antisaccade tasks (AS). The instruction effect observed in PS may result from top-down processes, mediated by pathways connecting the prefrontal cortex (PFC) to the superior colliculus. In AS, the PFC's prior involvement is in competition with the instruction process, annulling its effect. This study aims to discover whether the instruction effect persists in mixed paradigms. According to Dyckman's fMRI study (2007), the difficulty of mixed tasks leads to PFC involvement. The antisaccade-related PFC activation observed on comparison of blocked AS and PS therefore disappears when the two are compared in mixed paradigms. However, we continued to observe the instruction effect for both PS and AS. We therefore posit different types of PFC activation: phasic during blocked AS, and tonic during mixed saccadic experiments. PMID- 24168692 TI - Voluntary switching between identities in dissociative identity disorder: A functional MRI case study. AB - Patients who suffer from dissociative identity disorder present unique scientific and clinical challenges for psychology and psychiatry. We have been fortunate in working with a patient who-while undergoing functional MRI-can switch rapidly and voluntarily between her main personality (a middle-aged, high-functioning woman) and an alternate personality (a 4-6-year-old girl). A unique task was designed to isolate the processes occurring during the switches between these personalities. Data are from two imaging sessions, conducted months apart, each showing the same activated areas during switches between these personalities. The activated areas include the following: the primary sensory and motor cortex, likely associated with characteristic facial movements made during switching; the nucleus accumbens bilaterally, possibly associated with aspects of reward connected with switching; and prefrontal sites, presumably associated with the executive control involved in the switching of personalities. PMID- 24168693 TI - Reach trajectories reveal delayed processing of low spatial frequency faces in developmental prosopagnosia. AB - Developmental prosopagnosia (DP) is characterized by a selective deficit in face recognition despite normal cognitive and neurological functioning. Previous research has established configural processing deficits in DP subjects. Low spatial frequency (LSF) information subserves configural face processing. Using hybrid stimuli, here we examined the evolution of perceptual dynamics and integration of LSF information by DP subjects while they pointed to high spatial frequency (HSF) face targets. Permutation analysis revealed a 230-ms delay in LSF processing by DP subjects as compared to controls. This delayed processing is likely to contribute to the difficulties associated with face recognition in DP subjects and is reflective of their alleged reliance on local rather than global features in face perception. These results suggest that quick and efficient processing of LSF information is critical for the development of normal face perception. PMID- 24168694 TI - Gustatory cortical lesions affect motivation for snack foods. AB - Most neuropsychological research using food as a reward uses single-bid auctions. We wished to determine whether focal brain lesions would affect the ability and motivation to win snack food items in a computerized auction allowing multiple bids. This allowed us to assess participants' abilities under more complex conditions. We enrolled 154 male penetrating traumatic brain injury (pTBI) veterans, mean age 58, from the Vietnam Head Injury Study registry, and 53 male uninjured veterans, mean age 59. We used voxel-based lesion symptom mapping (VLSM) to identify effects of brain lesions on the ability to win items and on participants' answers to statements regarding their level of motivation and evaluation of how well they performed. Number of items won was not significantly associated with any lesions; however, lesions in gustatory cortex (GC) affected motivation and self-evaluation. Our findings provide further evidence of the primary GC's role in motivation for food and drink. PMID- 24168696 TI - The natural alternative: protozoa as cellular models for Legionella infection. AB - The severe pneumonia known as Legionnaires' disease occurs following infection by the Gram-negative bacterium Legionella pneumophila. Normally resident in fresh water sources, Legionella are subject to predation by eukaryotic phagocytes such as amoeba and ciliates. To counter this, L. pneumophila has evolved a complex system of effector proteins which allow the bacteria to hijack the phagocytic vacuole, hiding and replicating within their erstwhile killers. These same mechanisms allow L. pneumophila to hijack another phagocyte, lung-based macrophages, which thus avoids a vital part of the immune system and leads to infection. The course of infection can be divided into five main categories: pathogen uptake, formation of the replication-permissive vacuole, intracellular replication, host cell response, and bacterial exit. L. pneumophila effector proteins target every stage of this process, interacting with secretory, endosomal, lysosomal, retrograde and autophagy pathways, as well as with mitochondria. Each of these steps can be studied in protozoa or mammalian cells, and the knowledge gained can be readily applied to human pathogenicity. Here we describe the manner whereby L. pneumophila infects host protozoa, the various techniques which are available to analyse these processes and the implications of this model for Legionella virulence and the pathogenesis of Legionnaires' disease. PMID- 24168698 TI - Microwave-assisted solvothermal synthesis and optical properties of tagged MIL 140A metal-organic frameworks. AB - A series of tagged MIL-140A-R frameworks have been synthesized using a microwave assisted solvothermal method. Compared with their UiO-66-R polymorphs, the absorption energies in the MIL-140A-R series (R = NH2, NO2, Br, Cl, and F) are extended toward the visible region because of the spatial arrangement of the linkers. PMID- 24168695 TI - The discovery and identification of a candidate proteomic biomarker of active tuberculosis. AB - BACKGROUND: Noninvasive and convenient biomarkers for early diagnosis of tuberculosis (TB) remain an urgent need. The aim of this study was to discover and identify potential biomarkers specific for TB. METHODS: The surface-enhanced laser desorption ionization time of flight mass spectrometry (SELDI-TOF MS) combined with weak cation exchange (WCX) magnetic beads was used to screen serum samples from 180 cases of TB and 211 control subjects. A classification model was established by Biomarker Pattern Software (BPS). Candidate protein biomarkers were purified by reverse phase-high performance liquid chromatography (RP-HPLC), identified by MALDI-TOF MS, LC-MS/MS and validated using enzyme-linked immunosorbent assay (ELISA). RESULTS: A total of 35 discriminating m/z peaks were detected that were related to TB (P < 0.01). The model of biomarkers based on the four biomarkers (2554.6, 4824.4, 5325.7, and 8606.8 Da) was established which could distinguish TB from controls with the sensitivity of 83.3% and the specificity of 84.2%. The candidate biomarker with m/z of 2554.6 Da was found to be up-regulated in TB patients, and was identified as a fragment of fibrinogen, alpha polypeptide isoform alpha-E preproprotein. Analysis in 22 patients with TB showed increased fibrinogen degradation product (FDP) (5,005 +/- 1,297 vs. 4,010 +/- 1,181 ng/mL, P < 0.05) and in 142 patients showed elevated plasma fibrinogen levels. CONCLUSIONS: A diagnostic model for TB with high sensitivity and specificity was developed using mass spectrometry combined with magnetic beads. Fibrinogen was identified as a potential biomarker for TB and showed diagnostic values in clinical application. PMID- 24168697 TI - Antibacterial and anti-inflammatory effects of Syzygium jambos L. (Alston) and isolated compounds on acne vulgaris. AB - BACKGROUND: Acne vulgaris is a chronic skin disorder leading to inflammation as a result of the production of reactive oxygen species due to the active involvement of Propionibacterium acnes (P. acnes) in the infection site of the skin. The current study was designed to assess the potential of the leaf extract of Syzygium jambos L. (Alston) and its compounds for antibacterial and anti inflammatory activity against the pathogenic P. acnes. METHODS: The broth dilution method was used to assess the antibacterial activity. The cytotoxicity investigation on mouse melanocyte (B16-F10) and human leukemic monocyte lymphoma (U937) cells was done using sodium 3'-[1-(phenyl amino-carbonyl)-3,4-tetrazolium] bis-[4-methoxy-6-nitrobenzene sulfonic acid hydrate (XTT) reagent. The non-toxic concentrations of the samples was investigated for the suppression of cytokines interleukin 8 (IL 8) and tumour necrosis factor (TNF alpha) by testing the supernatants in the co-culture of the human U937 cells and heat killed P. acnes using enzyme immunoassay kits (ELISA). The statistical analysis was done using the Graph Pad Prism 4 program. RESULTS: Bioassay guided isolation of ethanol extract of the leaves of S. jambos led to the isolation of three known compounds namely; squalene, an anacardic acid analogue and ursolic acid which are reported for the first time from this plant. The ethanol extract of S. jambos and one of the isolated compound namely, anacardic acid analogue were able to inhibit the growth of P. acnes with a noteworthy minimum inhibitory concentration (MIC) value of 31.3 and 7.9 MUg/ml, respectively. The ethanol extract and three commercially acquired compounds namely; myricetin, myricitrin, gallic acid exhibited significant antioxidant activity with fifty percent inhibitory concentration (IC50) ranging between 0.8-1.9 MUg/ml which was comparable to that of vitamin C, the reference antioxidant agent. The plant extract, compounds ursolic acid and myricitrin (commercially acquired) significantly inhibited the release of inflammatory cytokines IL 8 and TNF alpha by suppressing them by 74 - 99%. TEM micrographs showed the lethal effects of selected samples against P. acnes. CONCLUSIONS: The interesting antibacterial, antioxidant and anti-inflammatory effects of S. jambos shown in the present study warrant its further investigation in clinical studies for a possible alternative anti-acne agent. PMID- 24168699 TI - Stretching single polymer chains of donor-acceptor foldamers: toward the quantitative study on the extent of folding. AB - Single-molecule force spectroscopy has proven to be an efficient tool for the quantitative characterization of flexible foldamers on the single-molecule level in this study. The extent of folding has been estimated quantitatively for the first time to the best of our knowledge, which is crucial for a better understanding of the "folding-process" on single-molecule level. Therefore, this study may provide a guidance to regulate folding for realizing rational control over the functions of bulk materials. PMID- 24168700 TI - Detection of quantitative trait loci in Bos indicus and Bos taurus cattle using genome-wide association studies. AB - BACKGROUND: The apparent effect of a single nucleotide polymorphism (SNP) on phenotype depends on the linkage disequilibrium (LD) between the SNP and a quantitative trait locus (QTL). However, the phase of LD between a SNP and a QTL may differ between Bos indicus and Bos taurus because they diverged at least one hundred thousand years ago. Here, we test the hypothesis that the apparent effect of a SNP on a quantitative trait depends on whether the SNP allele is inherited from a Bos taurus or Bos indicus ancestor. METHODS: Phenotype data on one or more traits and SNP genotype data for 10 181 cattle from Bos taurus, Bos indicus and composite breeds were used. All animals had genotypes for 729 068 SNPs (real or imputed). Chromosome segments were classified as originating from B. indicus or B. taurus on the basis of the haplotype of SNP alleles they contained. Consequently, SNP alleles were classified according to their sub-species origin. Three models were used for the association study: (1) conventional GWAS (genome wide association study), fitting a single SNP effect regardless of subspecies origin, (2) interaction GWAS, fitting an interaction between SNP and subspecies origin, and (3) best variable GWAS, fitting the most significant combination of SNP and sub-species origin. RESULTS: Fitting an interaction between SNP and subspecies origin resulted in more significant SNPs (i.e. more power) than a conventional GWAS. Thus, the effect of a SNP depends on the subspecies that the allele originates from. Also, most QTL segregated in only one subspecies, suggesting that many mutations that affect the traits studied occurred after divergence of the subspecies or the mutation became fixed or was lost in one of the subspecies. CONCLUSIONS: The results imply that GWAS and genomic selection could gain power by distinguishing SNP alleles based on their subspecies origin, and that only few QTL segregate in both B. indicus and B. taurus cattle. Thus, the QTL that segregate in current populations likely resulted from mutations that occurred in one of the subspecies and can have both positive and negative effects on the traits. There was no evidence that selection has increased the frequency of alleles that increase body weight. PMID- 24168701 TI - On giant's shoulders: an interview with Masatoshi Takeichi (RIKEN Center for Developmental Biology, Kobe). PMID- 24168702 TI - Uncorrected refractive error and presbyopia among junior high school teachers in Jakarta, Indonesia. AB - PURPOSE: To report on the frequency of observed refractive and accommodative errors among junior high school teachers in Jakarta, Indonesia, who participated in a Helen Keller International screening, refraction and spectacle distribution program. METHODS: A total of 965 teachers from 19 schools were eligible for screening; those with uncorrected distance visual acuity (VA) <= 6/12-3 and teachers >= 35 years old with uncorrected end-point print size >Jaeger (J) 6 were referred. Autorefraction and subjective refraction were performed for teachers with confirmed decreased VA. Refractive error was considered present if sphere <= 0.75 diopters (D), sphere >=+0.25D or cylinder <=-0.50 D resulted in >= 2 lines of improvement in VA. Presbyopia was considered present if an end-point print size >J6 improved by >= 1 optotype with the use of a lens >=+1.00 D. RESULTS: Overall, 866 teachers were screened (89.7% of those eligible) with complete screening data available for 858 (99.0%), among whom 762 failed screening. Distance refraction data were available for 666 of 762 (87.4%) and near refraction data for 520 of 686 (75.8%) teachers who failed screening. Of those screened, 76.2 +/- 9.0% of teachers had refractive and/or accommodative error and 57.1 +/- 7.6% had uncorrected refractive and/or accommodative error. Overall and uncorrected distance refractive error affected 44.2 +/- 3.7% and 36.0 +/- 3.6%, respectively; overall and uncorrected presbyopia affected 66.4 +/- 8.1% and 41.0 +/- 6.6%, respectively. CONCLUSION: As defined in this program, refractive and accommodative errors were common among teachers in Jakarta. PMID- 24168703 TI - Is glycosylated haemoglobin associated with psychosocial stress in non-diabetic 6 year-olds? AB - AIM: Glycosylated haemoglobin (HbA1c), a marker of diabetic glycemic control, is associated with chronic psychosocial stress in non-diabetic adults. This study aimed to determine whether HbA1c also acts as a biomarker of psychosocial stress in healthy 6-year-olds. METHODS: DESIGN AND PARTICIPANTS: Eligible participants were 326 children recruited from 6 socio-economically diverse areas in Melbourne, Australia, who took part in an earlier randomised trial for sleep problems at age 7 months. At 6 years, they participated in a follow-up assessment. OUTCOME: HbA1c collected by finger-prick. Exposures (collected simultaneously): proxy measures of child stress including: (i) child mental health; (ii) maternal mental health (depression, anxiety, stress), negative life events in the preceding year, life stresses and coping; and (iii) family socioeconomic status and financial stress. ANALYSES: linear regressions, adjusted for original randomisation status and clustering. RESULTS: Sixty percent (134/225) of children retained at 6 years provided HbA1c data, which ranged from 3.9%-5.8% (SD 0.3%). No child or family variable was associated with HbA1c. Of the maternal variables, only anxiety predicted HbA1c (adjusted difference per point increase: -0.01, 95% CI: -0.003 to 0.02, P = 0.01); this association was in the opposite direction to that hypothesised and clinically insignificant. CONCLUSION: HbA1c was not associated with psychosocial stress in healthy 6-year-olds. This suggests that any link between HbA1c and psychosocial stress emerges after this age, and that HbA1c is unlikely to be a reliable biomarker for stress in early childhood or over the transition to school. PMID- 24168705 TI - Efficient edit distance with duplications and contractions. AB - : We propose three algorithms for string edit distance with duplications and contractions. These include an efficient general algorithm and two improvements which apply under certain constraints on the cost function. The new algorithms solve a more general problem variant and obtain better time complexities with respect to previous algorithms. Our general algorithm is based on min-plus multiplication of square matrices and has time and space complexities of O (|Sigma|MP (n)) and O (|Sigma|n2), respectively, where |Sigma| is the alphabet size, n is the length of the strings, and MP (n) is the time bound for the computation of min-plus matrix multiplication of two n * n matrices (currently, MP(n)=On3log3lognlog2n due to an algorithm by Chan).For integer cost functions, the running time is further improved to O|Sigma|n3log2n. In addition, this variant of the algorithm is online, in the sense that the input strings may be given letter by letter, and its time complexity bounds the processing time of the first n given letters. This acceleration is based on our efficient matrix-vector min-plus multiplication algorithm, intended for matrices and vectors for which differences between adjacent entries are from a finite integer interval D. Choosing a constant 1log|D|n30, respectively (lowest K(D) = 0.1-0.3 nM for both inhibitors). This shows, for the first time in a direct binding assay with the two-domain enzyme, the existence of two binding modes of the pharmacological inhibitors, presumably with the two ACE domains. The BPP-11b-ACE binding curves were complex but showed a predominant interaction with K(D) in the nanomolar range. The caseinopeptides, known to inhibit ACE with an IC50 of 4.3 MUM, bound to ACE with K(D) = 3-4 MUM. Mapping of the F(174)ALPQY(179) binding site on ACE by sequential binding studies using captopril or BPP-11b indicated that it bound to (or near) the two active sites of ACE, in agreement with the stoichiometry of 2 determined from data fitting. Our results provide a detailed characterization of ACE-inhibitor binding modes and validate SPR for predicting the inhibitory potential of new compounds. PMID- 24168711 TI - Primary perineal hernia: a differential diagnosis for Bartholin's cyst in women. PMID- 24168710 TI - Doppler spectral waveform parameters at neurovascular bundle vessels in patients with prostate biopsy. AB - INTRODUCTION AND OBJECTIVES: There is a need to improve prescreening determination of prostate cancer to better select patients who need biopsy. Such a strategy properly implemented, will decrease the number of negative biopsies for prostate cancer and in turn better balance the risks and morbidity for patients recommended for biopsy. The aim of study is to investigate Doppler spectral waveform parameters of neurovascular bundle (NVB) vessels and determine differences between benign and malignant pathologies. PATIENTS AND METHODS: We performed a prospective analysis involving 292 patients who received prostate biopsy for elevated prostate-specific antigen (PSA) values or abnormal digital rectal examination, as well as 174 patients with symptomatic benign prostatic hyperplasia. Doppler spectral waveform (DSW) parameters (peak-systolic velocity [PSV], end-diastolic velocity [EDV], and resistive index [RI]) were measured at bilateral NVB vessels through Doppler transrectal ultrasound at the right lateral decubitus position, compared, and analyzed among patients with benign versus malignant histology for each side. RESULTS: Overall, both PSV and EDV at malignant sides were significantly higher than those at benign sides, as well as lower RI (all p-values <0.05, unpaired t-test). In subgroup analysis with 93 patients of serum PSA between 10 and 20 ng/mL and 56 patients with one-side malignancy, higher EDV and lower RI were significantly associated with malignancies (all p<0.05). The values of PSV and EDV rather than RI might be influenced by the patients' position and RI by the prostate volume. CONCLUSIONS: In this study, DSW parameters (mainly EDV and RI) at NVB vessels were significantly associated with prostate cancer, particularly in patients with serum PSA of 10-20 ng/mL. It should be in caution that the patients' position and prostate volume may influence the Doppler signal as demonstrated in the current study. These findings can provide more diagnostic information before prostate biopsy. PMID- 24168712 TI - CKD is associated with recurrent ischemia but not with hemorrhagic transformation in acute ischemic stroke patients. AB - BACKGROUND: We investigated the associations of Recurrent Ischemic Stroke (RIS) and Hemorrhagic Transformation (HT) with CKD in acute ischemic stroke patients. METHOD: The subjects were 160 patients, divided into two groups: with eGFR <60 mL/min/1.73 m2 (CKD), with eGFR >=60 mL/min/1.73 m2 (without CKD). RESULTS: Subjects having DM (p = 0.018), CKD (p = 0.025) and treated with ACEI/ARB (p = 0.039) revealed association with RIS. Regression analysis disclosed only CKD (p = 0.04). Carotid artery stenosis (p = 0.030) and serum calcium levels (p = 0.013) showed significant association with HT. CONCLUSION: Our results disclosed that CKD could be a risk factor for RIS. There is no relation between CKD and HT. PMID- 24168713 TI - Clinical features of young children referred for impairing temper outbursts. AB - OBJECTIVE: In light of the current controversy about whether severe temper outbursts are diagnostic of mania in young children, we conducted a study to characterize such children, focusing on mania and other mood disorders, emotion regulation, and parental psychiatric history. METHODS: Study participants included 51 5-9-year-old children with frequent, impairing outbursts (probands) and 24 non-referred controls without outbursts. Parents completed a lifetime clinical interview about their child, and rated their child's current mood and behavior. Teachers completed a behavior rating scale. To assess emotion regulation, children were administered the Balloons Game, which assesses emotion expressivity in response to frustration, under demands of high and low regulation. Parental lifetime diagnoses were ascertained in blind clinical interviews. RESULTS: No child had bipolar disorder, bipolar disorder not otherwise specified (NOS), or major depression (MDD). The most prevalent disorder was oppositional defiant disorder (88.2%), followed by attention deficit/hyperactivity disorder (74.5%), anxiety disorders (49.0%), and non-MDD depressive disorders (33.3%). Eleven probands (21.6%) met criteria for severe mood dysregulation. During the Balloons Game, when there were no demands for self regulation, children with severe outbursts showed reduced positive expressivity, and also showed significant deficits in controlling negative facial expressions when asked to do so. Anxiety disorders were the only diagnoses significantly elevated in probands' mothers. CONCLUSIONS: Overall, young children with severe temper outbursts do not present with bipolar disorder. Rather, disruptive behavior disorders with anxiety and depressive mood are common. In children with severe outbursts, deficits in regulating emotional facial expressions may reflect deficits controlling negative affect. This work represents a first step towards elucidating mechanisms underlying severe outbursts in young children. PMID- 24168714 TI - Sodium valproate may be a treatment for sleep bruxism. PMID- 24168715 TI - Effect of OROS methylphenidate on encopresis in children with attention deficit/hyperactivity disorder. AB - OBJECTIVES: Although encopresis shows a high rate of comorbidity in patients with attention-deficit/hyperactivity disorder (ADHD), the etiologic origin of this relationship and the effect of ADHD drugs on encopresis are unclear. In this chart review, we explored the effect of OROS long-acting methylphenidate (MPH) treatment on encopresis in children with ADHD. We also evaluated the relationship between the clinical variables of ADHD and encopresis. METHODS: The sample consisted of 21 children and adolescents (20 boys and 1 girl) with encopresis and coexisting ADHD 7-15 years of age. Their clinical characteristics and baseline (visit 1) and end of the second months' (visit 2) Conners' Parent Rating Scale (CPRS) subscores were recorded. Retrospective clinician determinations were made using the Clinical Global Impressions-Severity subscale (CGI-S) for encopresis severity and the Clinical Global Impressions-Improvement subscale (CGI-I) for encopresis response. RESULTS: According to the CGI-I, 14 subjects (71.4 %) showed much or very much improvement in their encopresis at the second visit. All of the CPRS scores showed a significant reduction during the second visit. No association was found between the CGI-I score and the changes in any of the CPRS scores. Baseline oppositional defiant disorder (ODD) and conduct disorder (CD) scores were correlated with the CGI-S score; however, no association was found between core ADHD symptom severity and the CGI-S score. With regard to the encopresis outcome, the baseline CD score was negatively correlated with the CGI I score, and the baseline ODD score was prone to show a negative correlation with the CGI-I score. CONCLUSIONS: These results suggest that coexisting behavioral problems may be a vulnerability factor based on the severity of encopresis, and that MPH treatment may have a positive effect on encopresis in children and adolescents with ADHD. PMID- 24168716 TI - Abnormalities in whole-brain functional connectivity observed in treatment-naive post-traumatic stress disorder patients following an earthquake. AB - BACKGROUND: Convergent studies have highlighted the dysfunction of the amygdala, prefrontal cortex and hippocampus in post-traumatic stress disorder (PTSD). However, only a few studies have investigated the functional connectivity between brain regions in PTSD patients during the resting state, which may improve our understanding of the neuropathophysiology of PTSD. The aim of this study was to investigate patterns of whole-brain functional connectivity in treatment-naive PTSD patients without co-morbid conditions who experienced the 8.0-magnitude earthquake in the Sichuan province of China. METHOD: A total of 72 PTSD patients and 86 trauma-exposed non-PTSD controls participated in the resting-state functional magnetic resonance imaging study. All these subjects were recruited from the disaster zone of the 2008 Sichuan earthquake. Functional connectivities between 90 paired brain regions in PTSD patients were compared with those in trauma-exposed non-PTSD controls. Furthermore, Pearson correlation analysis was performed between significantly abnormal connectivities in PTSD patients and their clinician-administered PTSD scale (CAPS) scores. RESULTS: Compared with non PTSD controls, PTSD patients showed weaker positive connectivities between the middle prefrontal cortex (mPFC) and the amygdala, hippocampus, parahippocampal gyrus and rectus, as well as between the inferior orbitofrontal cortex and the hippocampus. In addition, PTSD patients showed stronger negative connectivity between the posterior cingulate cortex (PCC) and the insula. The CAPS scores in PTSD patients correlated negatively with the connectivity between the amygdala and the mPFC. CONCLUSIONS: PTSD patients showed abnormalities in whole-brain functional connectivity, primarily affecting the connectivities between the mPFC and limbic system, and connectivity between the PCC and insula. PMID- 24168717 TI - RAMSY: ratio analysis of mass spectrometry to improve compound identification. AB - The complexity of biological samples poses a major challenge for reliable compound identification in mass spectrometry (MS). The presence of interfering compounds that cause additional peaks in the spectrum can make interpretation and assignment difficult. To overcome this issue, new approaches are needed to reduce complexity and simplify spectral interpretation. Recently, focused on unknown metabolite identification, we presented a new approach, RANSY (ratio analysis of nuclear magnetic resonance spectroscopy; Anal. Chem. 2011, 83, 7616-7623), which extracts the (1)H signals related to the same metabolite based on peak intensity ratios. On the basis of this concept, we present the ratio analysis of mass spectrometry (RAMSY) method, which facilitates improved compound identification in complex MS spectra. RAMSY works on the principle that, under a given set of experimental conditions, the abundance/intensity ratios between the mass fragments from the same metabolite are relatively constant. Therefore, the quotients of average peak ratios and their standard deviations, generated using a small set of MS spectra from the same ion chromatogram, efficiently allow the statistical recovery of the metabolite peaks and facilitate reliable identification. RAMSY was applied to both gas chromatography/MS and liquid chromatography tandem MS (LC-MS/MS) data to demonstrate its utility. The performance of RAMSY is typically better than the results from correlation methods. RAMSY promises to improve unknown metabolite identification for MS users in metabolomics or other fields. PMID- 24168718 TI - Prevalence of unintended pregnancy and its associated factors among sexually active never-married youth in Shanghai. AB - AIMS: This study was conducted to determine the prevalence and the associated factors for unintended pregnancy among never-married sexually active youth (15-24 years old) in Shanghai. METHODS: Using a probability sample (n = 765, including 502 males and 263 females) from 2006, we estimated prevalence of unintended pregnancy involvement for females and males by demographic factors and its associations with contextual and behavioural factors, guided by a social ecological framework. RESULTS: Weighted proportion analyses estimated that 13.8% of females and 17.7% of males had been involved in an unintended pregnancy, and 99.0% and 90.5% of such pregnancies were reported to have ended in abortion by females and males, respectively. Controlling for sexual behaviour factors and residence history, multivariate hazard analyses with Weibull functions found increased hazard among older female youth (19-21 vs. 15-18 years old) but decreased hazard among older male youth (15-18 vs. 19-21/22-24 years old) as compared with the younger groups. Parallel analyses of unintended pregnancy's associations with contextual factors by sex also suggested that female unintended pregnancy involvement was more likely to be associated with family factors (family living arrangements and maternal education), while unintended pregnancy involvement among males was only associated with school factors (school climate and sex education on pregnancy) and perceived neighbourhood contraceptive services access. CONCLUSIONS: Sexually active and never-married youth are at considerable risk of unintended pregnancy and abortion in Shanghai. Age- and sex specific strategies will be needed if China is going to be successful in addressing unintended pregnancy. PMID- 24168719 TI - Efficacy of very low-dose prostaglandin E1 in duct-dependent congenital heart disease. AB - AIM: The present study aims to define the lowest effective prostaglandin E1 dose in patients with inadequacy of pulmonary blood flow and/or intracardiac blood mixing and those with inadequate systemic blood flow. METHODS: Patients with inadequacy of both pulmonary blood flow and/or blood mixing (Group 1) and those with inadequate systemic blood flow (Group 2) were retrospectively evaluated in two separate groups with regard to the prostaglandin E1 starting dose given in the referring facility, the lowest and the highest dose administered in our centre, treatment duration, adverse effects, and administered treatment. RESULTS: No difference between the groups could be detected with respect to sex or birth weight (p=0.95 and 0.42, respectively). Group 1 and Group 2 were statistically similar in aspect of prostaglandin treatment duration (9.73+/-0.81 days versus 11.6+/-1.05 days, p=0.064). When compared with Group 2, the initial, maintenance and lowest efficient doses of prostaglandin E1 treatment were significantly lower and the titrated dose of prostaglandin E1 was significantly higher in Group 1 (p=0.001 for each). CONCLUSION: Our findings indicate that the infusion of prostaglandin at a very low dose (0.003-0.005 mcg/kg/minute) is sufficient to maintain the patency of the ductus arteriosus. A higher dose of prostaglandin E1 may be necessary in patients with inadequate systemic blood flow. PMID- 24168720 TI - In situ imaging of Cu2O under reducing conditions: formation of metallic fronts by mass transfer. AB - Active catalytic sites have traditionally been analyzed based on static representations of surface structures and characterization of materials before or after reactions. We show here by a combination of in situ microscopy and spectroscopy techniques that, in the presence of reactants, an oxide catalyst's chemical state and morphology are dynamically modified. The reduction of Cu2O films is studied under ambient pressures (AP) of CO. The use of complementary techniques allows us to identify intermediate surface oxide phases and determine how reaction fronts propagate across the surface by massive mass transfer of Cu atoms released during the reduction of the oxide phase in the presence of CO. High resolution in situ imaging by AP scanning tunneling microscopy (AP-STM) shows that the reduction of the oxide films is initiated at defects both on step edges and the center of oxide terraces. PMID- 24168721 TI - A pilot project to improve access to telepsychotherapy at rural clinics. AB - BACKGROUND: The U.S. Department of Veterans Affairs (VA) has pioneered telemental health (TMH) with over 500,000 TMH encounters over the past decade. VA community based outpatient clinics were established to improve accessibility of mental healthcare for rural Veterans. Despite these clinics clinics and increased availability of TMH, many rural Veterans have difficulty receiving mental healthcare, particularly psychotherapy. MATERIALS AND METHODS: Twelve therapists participated in a pilot project using TMH technologies to improve mental healthcare service delivery to rural Veterans treated at six community clinics. Therapists completed online training, and study staff communicated with them monthly and clinical leaders every other month. Therapists completed two questionnaires: before training and 10 months later. This article describes barriers and facilitators to the implementation of the project, as well as therapists' knowledge, confidence, and motivation regarding TMH. RESULTS: Two clinicians were offering telepsychotherapy after 10 months. At all six sites, unanticipated organizational constraints and administrative barriers delayed implementation; establishing organizational practices and therapists' motivation helped facilitate the process. Adopters of the project reported more positive views of the modality and did not worry about staffing, a concern of nonadopters. CONCLUSIONS: Despite barriers to implementation, lessons learned from this pilot project have led to improvements and changes in TMH processes. Results from the pilot showed that therapists providing telepsychotherapy had increased confidence, knowledge, and motivation. As TMH continues to expand, formalized decision-making with clinical leaders regarding project goals, better matching of therapists with this modality, and assessment of medical center and clinic readiness are recommended. PMID- 24168722 TI - Sensitivity analysis for critical control points determination and uncertainty analysis to link FSO and process criteria: application to Listeria monocytogenes in soft cheese made from pasteurized milk. AB - Microbiological food safety is an important economic and health issue in the context of globalization and presents food business operators with new challenges in providing safe foods. The hazard analysis and critical control point approach involve identifying the main steps in food processing and the physical and chemical parameters that have an impact on the safety of foods. In the risk-based approach, as defined in the Codex Alimentarius, controlling these parameters in such a way that the final products meet a food safety objective (FSO), fixed by the competent authorities, is a big challenge and of great interest to the food business operators. Process risk models, issued from the quantitative microbiological risk assessment framework, provide useful tools in this respect. We propose a methodology, called multivariate factor mapping (MFM), for establishing a link between process parameters and compliance with a FSO. For a stochastic and dynamic process risk model of Listeriamonocytogenes in soft cheese made from pasteurized milk with many uncertain inputs, multivariate sensitivity analysis and MFM are combined to (i) identify the critical control points (CCPs) for L.monocytogenes throughout the food chain and (ii) compute the critical limits of the most influential process parameters, located at the CCPs, with regard to the specific process implemented in the model. Due to certain forms of interaction among parameters, the results show some new possibilities for the management of microbiological hazards when a FSO is specified. PMID- 24168723 TI - Ser1333 phosphorylation indicates ROCKI activation. AB - BACKGROUND: Two isoforms of Rho-associated protein kinase (ROCK), ROCKI and ROCKII, play a pivotal role in regulation of cytoskeleton and are involved in multiple cellular processes in mammalian cells. Knockout mice experiments have indicated that the functions of ROCKI and II are probably non-redundant in physiology. However, it is difficult to differentiate the activation status of ROCKI and ROCKII in biological samples. Previously, we have identified phosphorylation site of ROCKII at Ser1366 residue sensitive to ROCK inhibition. We further investigated the activity-dependent phosphorylation site in ROCKI to establish the reagents that can be used to detect their individual activation. RESULTS: The phosphorylation site of ROCKI sensitive to its inhibition was identified to be the Ser1333 residue. The ROCKI pSer1333-specific antibody does not cross-react with phosphorylated ROCKII. The extent of S1333 phosphorylation of ROCKI correlates with myosin II light chain phosphorylation in cells in response to RhoA stimulation. CONCLUSIONS: Active ROCKI is phosphorylated at Ser1333 site. Antibodies that recognize phospho-Ser1333 of ROCKI and phospho S1366 residues of ROCKII offer a means to discriminate their individual active status in cells and tissues. PMID- 24168724 TI - The clinical, operational, and financial worlds of neonatal palliative care: A focused ethnography. AB - OBJECTIVE: Due to multiple issues, integrated interdisciplinary palliative care teams in a neonatal intensive care unit (NICU) may be difficult to access, sometimes fail to be implemented, or provide inconsistent or poorly coordinated care. When implementing an effective institution-specific neonatal palliative care program, it is critical to include stakeholders from the clinical, operational, and financial worlds of healthcare. In this study, researchers sought to gain a multidisciplinary perspective into issues that may impact the implementation of a formal neonatal palliative care program at a tertiary regional academic medical center. METHOD: In this focused ethnography, the primary researcher conducted semistructured interviews that explored the perspectives of healthcare administrators, finance officers, and clinicians about neonatal palliative care. The perspectives of 39 study participants informed the identification of institutional, financial, and clinical issues that impact the implementation of neonatal palliative care services at the medical center and the planning process for a formal palliative care program on behalf of neonates and their families. RESULTS: Healthcare professionals described experiences that influenced their views on neonatal palliative care. Key themes included: (a) uniqueness of neonatal palliative care, (b) communication and conflict among providers, (c) policy and protocol discrepancies, and (d) lack of administrative support. SIGNIFICANCE OF RESULTS: The present study highlighted several areas that are challenging in the provision of neonatal palliative care. Our findings underscored the importance of recognizing and procuring resources needed simultaneously from the clinical, operational, and financial worlds in order to implement and sustain a successful neonatal palliative care program. PMID- 24168725 TI - Studies on metal-organic frameworks of Cu(II) with isophthalate linkers for hydrogen storage. AB - Hydrogen (H2) is a promising alternative energy carrier because of its environmental benefits, high energy density, and abundance. However, development of a practical storage system to enable the "Hydrogen Economy" remains a huge challenge. Metal-organic frameworks (MOFs) are an important class of crystalline coordination polymers constructed by bridging metal centers with organic linkers. MOFs show promise for H2 storage owing to their high surface area and tuneable properties. In this Account, we summarize our research on novel porous materials with enhanced H2 storage properties and describe frameworks derived from 3,5 substituted dicarboxylates (isophthalates) that serve as versatile molecular building blocks for the construction of a range of interesting coordination polymers with Cu(II) ions. We synthesized a series of materials by connecting linear tetracarboxylate linkers to {Cu(II)2} paddlewheel moieties. These materials exhibit high structural stability and permanent porosity. Varying the organic linker modulates the pore size, geometry, and functionality to control the overall H2 adsorption. Our top-performing material in this series has a H2 storage capacity of 77.8 mg g(-1) at 77 K, 60 bar. H2 adsorption at low, medium, and high pressures correlates with the isosteric heat of adsorption, surface area, and pore volume, respectively. Another series, using tribranched C3 symmetric hexacarboxylate ligands with Cu(II), gives highly porous (3,24) connected frameworks incorporating {Cu(II)2} paddlewheels. Increasing the length of the hexacarboxylate struts directly tunes the porosity of the resultant material from micro- to mesoporosity. These materials show exceptionally high H2 uptakes owing to their high surface area and pore volume. The first member of this family reported adsorbs 111 mg g(-1) of H2, or 55.9 g L(-1), at 77 K, 77 bar, while at 77 K, 1 bar, the material adsorbs 2.3 wt % H2. We and others have since achieved enhanced H2 adsorption in these frameworks using combinations of polyphenyl groups linked by alkynes. The maximum storage achieved for one of the enhanced materials is 164 mg g(-1) at 77 K, 70 bar, but because of its low density, its volumetric capacity is only 45.7 g L(-1). We attribute the significant adsorption of H2 at low pressures to the arrangement of the {Cu24(isophthalate)24} cuboctahedral cages within the polyhedral structure. Free metal coordination positions are the first binding sites for D2, and these frameworks have two types of Cu(II) centers, one with its vacant site pointing into the cuboctahedral cage and another pointing externally. D2 molecules bind first at the former position and then at the external open metal sites. Design of ligands and complexes is key for enhancing and maximizing H2 storage, and although current materials operate at 77 K, research continues to explore routes to high capacity H2 storage materials that can function at higher temperatures. PMID- 24168727 TI - Oxidative aromatic coupling of meso-arylamino-porphyrins. AB - Strategic placement of the bis-arylamino group at the meso-position of porphyrins allowed fusion of these two moieties via aromatic dehydrogenation. By placing two di(naphthalene-2-yl)amine or bis(3,5-dimethoxyphenyl)amine groups at positions 5 and 15 of the porphyrin, the oxidative aromatic coupling was directed toward closing one six-membered ring. The extension of the porphyrin chromophore leads to significant change in linear optical properties, such as a bathochromic shift of absorption and broadening of the Q-band. PMID- 24168726 TI - Birth order and myopia. AB - PURPOSE: An association between birth order and reduced unaided vision (a surrogate for myopia) has been observed previously. We examined the association between birth order and myopia directly in four subject groups. METHODS: Subject groups were participants in (1) the Avon Longitudinal Study of Parents and Children (ALSPAC; UK; age 15 years; N = 4401), (2) the Singapore Cohort Study of Risk Factors for Myopia (SCORM; Singapore; age 13 years; N = 1959), (3) the Raine Eye Health Study (REHS; Australia; age 20 years; N = 1344), and (4) Israeli Defense Force Pre-recruitment Candidates (IDFC; Israel; age 16-22 years; N = 888,277). The main outcome was odds ratios (OR) for myopia in first-born versus non-first-born individuals after adjusting for potential risk factors. RESULTS: The prevalence of myopia was numerically higher in first-born versus non-first born individuals in all study groups, but the strength of evidence varied widely. Adjusted ORs (95% confidence intervals, CIs) were: ALSPAC, 1.31 (1.05-1.64); SCORM, 1.25 (0.89-1.77); REHS, 1.18 (0.90-1.55); and IDFC, 1.04 (1.03-1.06). In the large IDFC sample, the effect size was greater (a) for the first-born versus fourth- or higher-born comparison than for the first-born versus second/third born comparison (p < 0.001) and (b) with increasing myopia severity (p < 0.001). CONCLUSIONS: Across all studies, the increased risk of myopia in first-born individuals was low (OR < 1.3). Indeed, only the studies with >4000 participants provided strong statistical support for the association. The available evidence suggested the relationship was independent of established risk factors such as time outdoors/reading, and thus may arise through a different causal mechanism. PMID- 24168728 TI - Calretinin-immunoreactive mucosal innervation in very short-segment Hirschsprung disease: a potentially misleading observation. AB - Absent calretinin-immunoreactive (CRir) mucosal innervation in aganglionic rectal biopsies is considered a useful diagnostic finding for Hirschsprung disease. Analysis of a series of rectosigmoid resections from patients with short-segment (>2-cm aganglionic, n = 9) and very short-segment (<=2-cm aganglionic, n = 9) Hirschsprung disease demonstrates that CRir mucosal nerves extend into the proximal 1-2 cm of aganglionic bowel, where their presence in distal rectal biopsies could complicate diagnosis of very short-segment disease. Indeed, retrospective analysis of preoperative, aganglionic, distal rectal biopsies from 4 of 9 patients with very short-segment Hirschsprung disease revealed CRir mucosal innervation. Accurate diagnosis was possible based on generous histopathological submucosal sampling to exclude ganglion cells and the presence of abundant large-caliber submucosal nerves (more than 4 nerves >30 um thick/*200 field or more than 2 nerves >40 um thick/*200 field). Absent CRir mucosal innervation supports the diagnosis of Hirschsprung disease, but the presence of CRir mucosal nerves does not exclude aganglionosis, especially in distal rectal biopsies from patients with very short-segment Hirschsprung disease. PMID- 24168729 TI - Current knowledge of the human sperm proteome. AB - The knowledge of the mature sperm proteome is undoubtedly the basis for understanding sperm function, the mechanisms responsible for fertilization, the reasons for infertility and possible treatments. The methods of sperm protein extraction depend mainly on the proteins of interest and the protein separation techniques that will be employed. The isolation of the membrane proteins appears to be most problematic step. Nevertheless, two-dimensional electrophoresis and mass spectrometry have become the main techniques used in human sperm protein analysis. We outline the present techniques used to examine the sperm proteome and data generated from studies on the human sperm and different types of male infertility. We present the most characteristic proteins that are involved in sperm function. Their value as biomarkers for diagnosis and treatment of infertility would require further validation. We focus on selected and critical studies of the human sperm proteome to present our subjective view of this fast moving field. PMID- 24168730 TI - Rheumatoid nodules in the thyroid bed following total thyroidectomy: a case report. AB - INTRODUCTION: Rheumatoid nodules occur in 30 percent of patients with active rheumatoid arthritis. Common sites include the buttocks or the extensor surface of the forearm, with one group documenting their presence in the thyrohyoid membrane. To the best of our knowledge, rheumatoid nodules have not been described in the thyroid bed. CASE PRESENTATION: We present the case of a 46-year old Caucasian woman with active rheumatoid arthritis and Hashimoto's thyroiditis who presented with compressive neck symptoms. An ultrasound scan revealed that both lobes of her thyroid were enlarged. The right lobe measured 7.9*3.4*3.3cm and the left 8.3*3.3*3.1cm. A solitary 1.0*0.6*0.8cm nodule was seen in the right lower lobe. Her thyroid-stimulating hormone level was 4.22uU/mL (0.34 to 5.60). A total thyroidectomy was performed due to her symptoms and the possible growth of a nodule when on levothyroxine. A postoperative ultrasound scan showed no remaining thyroid tissue. The pathology revealed several small neoplasms ranging from a well-encapsulated adenoma to highly atypical follicular and papillary Hurthle cell lesions in the setting of Hashimoto's thyroiditis. Low-dose radioactive iodine (33.4mCi) was given. Four months later, our patient complained of a feeling of fullness in her neck. A solid nodule of mixed echogenicity (5.6*3.3*2.3cm) was seen in the right level VI of the neck, and solid tissue of mixed echogenicity (2.9*2.3*1.7cm) on the left. Following repeat surgery, the pathology from the right specimen showed Hashimoto's thyroiditis. The left specimen had areas of granuloma formation with fibrinoid necrosis and palisading histiocytes, consistent with the histology of rheumatoid nodules. No evidence of malignancy was seen. The patient continues to do well and remains disease-free. CONCLUSIONS: Rheumatoid nodules have not been reported in the thyroid bed. Their pathogenesis is not clear. Postoperative release of tumor necrosis factor alpha and local vascular damage may have triggered the nodule formation in this case. Rheumatoid nodules must be kept in the differential diagnosis of an enlarging thyroid in the setting of active rheumatoid arthritis. A fine-needle aspiration biopsy may show granuloma formation and be the most cost-effective initial diagnostic step, especially if there is a concern for malignancy. Early identification of these nodules will help decrease morbidity from unnecessary interventions and result in treatment that is both timely and appropriate. PMID- 24168731 TI - A journal for and with health promotion practitioners and researchers. PMID- 24168732 TI - Australian children lack the basic movement skills to be active and healthy. PMID- 24168733 TI - Booze barns: fuelling hazardous drinking in Australia? PMID- 24168734 TI - Pressing need for more evidence to guide efforts to address substance use among young Indigenous Australians. AB - ISSUE ADDRESSED: There are no systematic reviews available to guide the delivery of programs to prevent or address substance misuse among young Indigenous Australians METHODS: A search was conducted for peer-reviewed journal articles published between 1990 and 2011 that evaluated interventions targeting young Indigenous Australians (aged 8-25 years) with the primary aim of reducing substance use. A comprehensive search was conducted of electronic databases (Cochrane, DRUG, Embase, Informit, Medline, Nursing and Allied Health, PreMedline and PsychInfo). Retrieved manuscripts were analysed using a narrative synthesis methodology. RESULTS: Eight published studies were found. Nearly all had major methodological limitations. Of the four projects that reported reductions in substance use, two included recreational or cultural activities and had strong community support, and one included supply control combined with employment opportunities. Two programs that provided education alone did not show changes in substance use. CONCLUSIONS: Increased systematic evaluation of efforts to prevent and treat substance use among young Indigenous Australians is needed. So what? The limited data support multiprong interventions, designed with community input, to protect young Indigenous people against substance misuse, rather than simple facts-based education. However, more research is needed. PMID- 24168735 TI - Providing health information for culturally and linguistically diverse women: priorities and preferences of new migrants and refugees. AB - ISSUES ADDRESSED: Preferences for topics and means of access to health information among newly arrived, culturally and linguistically diverse women in Perth, Western Australia, were explored. METHODS: A mixed-methods approach was adopted. Qualitative material obtained from focus groups and interviews with 22 service providers and 26 migrant women was used to develop a questionnaire, which was then administered to 268 newly arrived migrant and refugee women from 50 countries. Participants' information and support priorities were ascertained from a ranking exercise conducted in a non-threatening context. Responses of migrant and refugee women were compared quantitatively. RESULTS: Women's top priorities for information and support included employment advice, as well as information regarding mental health issues, women's health, exercise and nutrition, family violence and alcohol and other drug issues. Their preferred methods for receiving information were interactive talks or presentations, with written material support. Audiovisual and Web-based material were also considered useful. There were differences between refugee women's and other migrants' preferences for means of receiving information and topics of most concern. DISCUSSION: The use of a non-threatening ranking process encouraged women to prioritise sensitive topics, such as family violence, and revealed a need for such topics to be incorporated within general health information presentations. Internet-based technologies are becoming increasingly important methods for disseminating information to migrant women. SO WHAT? Differences between migrant and refugee women's priority health issues and their preferred methods for receiving information highlight the desirability of tailoring information to particular groups. Although advice on employment pathways and mental health concerns were top priorities, the study revealed a need for more discussion on other sensitive topics, such as family violence and alcohol-related issues, and that ideally these should be incorporated into general information sessions to destigmatise attendance The increasing relevance of computer technology and social media for information dissemination was also of note. PMID- 24168736 TI - Effective recruitment and retention strategies in community health programs. AB - ISSUE ADDRESSED: The aim of this project was to identify effective recruitment and retention strategies used by health-promotion organisations that focus on increasing physical activity and improving nutrition within the local community. METHODS: Semistructured telephone or face-to-face interviews with 25 key informants from stakeholder organisations were conducted. Key informants discussed strategies used by their organisation to effectively recruit and retain participants into community-based healthy eating and/or physical activity programs. Transcribed data were analysed with NVivo software. RESULTS: Effective recruitment strategies included word of mouth, links with organisations, dissemination of printed materials, media, referrals, cross-promotion of programs and face-to-face methods. Effective retention strategies included encouraging a sense of community ownership, social opportunities, recruiting a suitable leader and offering flexibility and support. Fees and support for recruiting and retaining participants was also identified. CONCLUSION: This study provides novel insights to a greatly under researched topic in the field of health promotion. There are two key take-home messages from the present study that are applicable to health practitioners as well as developers and deliverers of community health promotion programs: (1) it is imperative that all community health organisations report on the effectiveness of their recruitment and retention, both successes and failures; and (2) there is a clear need to tailor the recruitment and retention approach to the target population and the setting the program is occurring in. SO WHAT? These findings provide important insights for the development of future community-based healthy eating and physical activity programs. PMID- 24168737 TI - Community-based efforts to prevent obesity: Australia-wide survey of projects. AB - ISSUES ADDRESSED: Community-based programs that affect healthy environments and policies have emerged as an effective response to high obesity levels in populations. Apart from limited individual reports, little is currently known about these programs, limiting the potential to provide effective support, to promote effective practice, prevent adverse outcomes and disseminate intervention results and experience. The aim of the present study was to identify the size and reach of current community-based obesity prevention projects in Australia and to examine their characteristics, program features (e.g. intervention setting), capacity and approach to obesity prevention. METHODS: Detailed survey completed by representatives from community-based obesity prevention initiatives in Australia. RESULTS: There was wide variation in funding, capacity and approach to obesity prevention among the 78 participating projects. Median annual funding was Au$94900 (range Au$2500-$4.46 million). The most common intervention settings were schools (39%). Forty per cent of programs focused on a population group of >=50000 people. A large proportion of respondents felt that they did not have sufficient resources or staff training to achieve project objectives. CONCLUSION: Community-based projects currently represent a very large investment by both government and non-government sectors for the prevention of obesity. Existing projects are diverse in size and scope, and reach large segments of the population. Further work is needed to identify the full extent of existing community actions and to monitor their reach and future 'scale up' to ensure that future activities aim for effective integration into systems, policies and environments. SO WHAT? Community-based programs make a substantial contribution to the prevention of obesity and promotion of healthy lifestyles in Australia. A risk of the current intervention landscape is that effective approaches may go unrecognised due to lack of effective evaluations or limitations in program design, duration or size. Policy makers and researchers must recognise the potential contribution of these initiatives, to both public health and knowledge generation, and provide support for strong evaluation and sustainable intervention designs. PMID- 24168738 TI - Would you Find Thirty online? Website use in a Western Australian physical activity campaign. AB - ISSUE ADDRESSED: Mass media campaigns have used a range of traditional media (television, radio and print) to communicate health messages. In the past decade the Internet has added to these traditional methods with Web 2.0, smart phone technology and interactive media. 'Find Thirty every day((r))', a Western Australia population-wide mass media campaign delivered over 2 years, used a combination of traditional mass media, a website, online resources and banner advertising. The aim of the present study is to describe the use of the Find Thirty every day((r)) website during the campaign media activities of May 2008 June 2010. METHODS: Cross-sectional self-reported survey data were collected from a random sample of adults using a computer-assisted telephone interview over the period February-March 2010. Objective online analytical measures of unique visits to the Find Thirty every day((r)) website were collected between June 2008 and June 2010. RESULTS: Monthly visitors to the Find Thirty every day((r)) website increased from 3193 in 2009 to 4374 in 2010. During the last two media waves (October 2009 and February 2010), site visits were 5388 and 5272 per month, respectively. CONCLUSION: The impact of the Find Thirty every day((r)) website was a positive outcome, considering the minimal online presence. SO WHAT? Health communication campaign planners should maximise the potential synergy of traditional mass media and new social media in future campaigns. Accordingly, a multidisciplinary approach that includes communication researchers, experts in information systems and a creative team experienced in online environments will need to be the way forward. PMID- 24168739 TI - Reliability and validity of the International Physical Activity Questionnaire Short Form for older adults in Vietnam. AB - ISSUES ADDRESSED: The International Physical Activity Questionnaire (IPAQ) was developed as a global standard questionnaire to monitor physical activity across diverse populations. In Vietnam, the IPAQ-Short Form (SF) has only been tested for reliability and validity among adolescents. The present study determined test retest reliability and criterion validity of the IPAQ-SF for older Vietnamese adults aged 60-75 years. METHODS: In all, 197 participants were recruited from the community. Subjects were requested to wear a pedometer, record daily steps and list all physical activities in a log-book for 7 consecutive days. Those who completed the requirements were interviewed using the IPAQ-SF (IPAQ1). A repeated interview was arranged 3 days later (IPAQ2). RESULTS: The final sample consisted of 150 participants (75 men, 75 women) with mean (+/- s.d.) age of 66.8+/-5.1 years. The intraclass correlation coefficients between IPAQ1 and IPAQ2 exceeded 0.80 for all physical activity domains and sitting, indicating good reliability. However, fair to weak validity was evident between IPAQ1 measures and activity log and pedometer readings, with Spearman correlations of 0.46 and 0.20, respectively. CONCLUSIONS: The Vietnamese translated version of IPAQ-SF appears to be a reliable and reasonably valid instrument to assess and monitor habitual physical activity for older adults in Vietnam. SO WHAT? The IPAQ-SF could provide useful physical activity data to evaluate the effectiveness of health promotion intervention programs and for international comparison purposes. PMID- 24168740 TI - The Torres Indigenous Hip Hop Project: evaluating the use of performing arts as a medium for sexual health promotion. AB - ISSUE ADDRESSED: The Torres Indigenous Hip Hop Project (the Project) was conducted in the Torres and Northern Peninsula Area of Queensland during early 2010. This paper provides a critical analysis of project outcomes and identifies criteria that may form a suitable framework for the assessment of proposals for sexual health promotion using performing arts-based approaches in Aboriginal and Torres Strait Islander settings. METHODS: A case study method was used. The first phase of analysis assessed whether project objectives were met using data collected during project planning and implementation. The second phase used these findings, augmented by interviews with key personnel, to respond to the question 'How could this be done better?'. RESULTS: The Project required significant human and organisational implementation support. The project was successful in facilitating event-specific community mobilisation. It raised awareness of sexual health disadvantage and engaged effectively with the target group. It laid important groundwork to progress school-based and community mechanisms to address regional youth disadvantage. Against these benefits are issues of opportunity cost and the need for ongoing resources to capitalise on the opportunities created. CONCLUSIONS: With substantial support and planning, such approaches can play an important role in engaging young people and bridging the gap between clinical interventions and improvements in health deriving from community-driven strategies. SO WHAT? This paper contributes to existing literature by identifying key elements of an effective approach to using performing arts in sexual health promotion in Aboriginal and Torres Strait Islander settings. It also provides guidance when consideration is being given to investment in resource-intensive health promotion initiatives. PMID- 24168741 TI - The advertised diet: an examination of the extent and nature of food advertising on Australian television. AB - ISSUES ADDRESSED: The aim of the present study was to describe food advertising and expenditure on Australian television, and to conduct an audit to assess what proportion of food and beverage television advertisements was consistent with dietary recommendations. METHODS: Data were acquired from a national media monitoring company for advertisements broadcast in five major Australian cities from 1 September 2010 to 31 October 2010. Content analysis was undertaken on these advertisements and the advertised foods were assessed against the Australian Guide to Healthy Eating. The data also included advertising expenditures. RESULTS: Most advertised foods were non-core foods (63%), with few advertisements for fruits and vegetables (6%). Advertisements for non-core foods were significantly more frequent during prime time viewing periods (71% vs 60%; P<0.01). High levels of advertising for fast food (28%) and non-core beverages (24%) were recorded. CONCLUSIONS: The present study found that the foods advertised during the data-collection period were inconsistent with the recommended diet. There are clear areas for policy concern given that the majority of recorded advertisements were for foods classified as 'occasional foods', there were low levels of advertising for fruit and vegetables, and there were no social marketing messages to support healthy eating. SO WHAT? The findings of the study suggest that there is an urgent need for more comprehensive regulation of food advertising in Australia. PMID- 24168742 TI - Smoking mull: a grounded theory model on the dynamics of combined tobacco and cannabis use among adult men. AB - ISSUE ADDRESSED: Australians' use of cannabis has been increasing. Over a third of Australians (35.4%) have used cannabis at some time in their lives and 10.3% are recent users. Almost two-thirds of cannabis users combine cannabis with tobacco. The aim of this study was to understand the process of mulling - smoking tobacco and cannabis together - using a grounded theory approach. METHODS: Twenty one in-depth semistructured interviews were conducted with men aged 25-34 and living on the North Coast of New South Wales. Interviews explored participants' smoking practices, histories and cessation attempts. RESULTS: A model describing mulling behaviour and the dynamics of smoking cannabis and tobacco was developed. It provides an explanatory framework that demonstrates the flexibility in smoking practices, including substance substitution - participants changed the type of cannabis they smoked, the amount of tobacco they mixed with it and the devices they used to smoke according to the situations they were in and the effects sought. CONCLUSION: Understanding these dynamic smoking practices and the importance of situations and effects, as well as the specific role of tobacco in mulling, may allow health workers to design more relevant and appropriate interventions. SO WHAT? Combining tobacco with cannabis is the most common way of smoking cannabis in Australia. However, tobacco cessation programmes rarely address cannabis use. Further research to develop evidence-based approaches for mull use would improve cessation outcomes. PMID- 24168743 TI - Communicating endometriosis with young women to decrease diagnosis time. AB - ISSUES ADDRESSED: Endometriosis is estimated to affect approximately 10% of women. Although early detection may enhance health outcomes and fertility, there is a recognised diagnostic delay of 6.7 years. There are limited data on ways to discuss endometriosis with young women. The aims of the present study were to determine what young women know about endometriosis, what young women want to know about endometriosis and how this is best communicated to promote early detection. METHODS: Women aged 16-25 years were invited to complete an online survey that was advertised via Facebook, email, Twitter and flyers at high schools and a university. RESULTS: In all, 131 women responded to the survey. Fifty-two percent of participants had heard of endometriosis, 89% thought teenagers should be educated about endometriosis and 78% thought that young men should also be educated about the condition. Favoured sources for obtaining information were schools (40%), the Internet (22%) and magazines (13%). Participants were most comfortable talking to a doctor (75%), parent (59%) or friend (51%). Participants primarily wanted to know about the disease, its symptoms, risk factors and treatment. Many participants' descriptions of endometriosis were vague or inaccurate. CONCLUSIONS: The results of the present study indicate that young women are keen to learn about endometriosis, particularly its symptoms. Preferential sources of information appear to be schools or the Internet, and young women appear more comfortable talking to doctors. SO WHAT? To promote early detection of endometriosis, health promotion activities should direct their information towards sources that young women prefer. PMID- 24168744 TI - Review of Australian childhood obesity research funding 2010-2013. PMID- 24168745 TI - Community concern about the sale of high-caffeine drinks to children under 12 years of age: Western Australia population survey results. PMID- 24168746 TI - The fly-in, fly out debate: what happens to the communities? PMID- 24168747 TI - Evaluation of a multilingual oral health DVD for newly arrived refugees. PMID- 24168750 TI - The application of virtual microscopy in a dermatopathology educational setting: assessment of attitudes among dermatopathologists. AB - OBJECTIVES: Whole-slide imaging with virtual microscopy is increasingly used as a tool in resident education and training, board certification and maintenance of certification examinations, and diagnostic evaluation. The objective of this study was to determine attitudes toward virtual microscopy compared with traditional glass slide microscopy during a continuing medical education dermatopathology workshop. METHODS: Twenty-three board-certified, practicing or retired dermatopathologists were given 26 "advanced" cases to review using both virtual microscopy and traditional glass slides. Diagnostic accuracy was not assessed because of the complexity of the cases. Participants were surveyed on: (i) their previous experience with digital imaging; (ii) the quality, ease of use, and speed of slide review; and (iii) overall attitudes toward digital and traditional review. RESULTS: Equal proportions of participants did and did not have prior experience with digital imaging of histopathologic specimens. Most participants preferred to use both virtual microscopy and traditional microscopy together. The quality of glass slides was rated as better than that of digital images, but virtual microscopy achieved higher ratings for ease of navigation and overall satisfaction. CONCLUSIONS: Virtual microscopy is a useful tool for dermatopathology workshops. Specifically, dermatopathologists with and without prior digital slide review experience responded favorably to viewing slides on a computer monitor. Overall satisfaction was high, and the majority of participants indicated that they would use virtual microscopy in the future. These results show a trend toward the acceptance of digital slide review, which supports the inevitable expansion of this practice in an increasingly digitized world. PMID- 24168752 TI - Interplay of experiment and theory: determination of an accurate equilibrium structure of 1-methyluracil by the gas electron diffraction method and coupled cluster computations. AB - As far as fundamental knowledge is concerned, the methyl derivatives of uracil can be considered as the simplest objects for studying the structural effects due to the substitution in the pyrimidyne nucleobases. From this point of view, 1 methyluracil is of special importance in biochemistry because uracil attaches ribose in ribonucleic acid (RNA) just precisely at the N1 atom. The semi experimental equilibrium structure (r(e)(se)) of 1-methyluracil has been determined for the first time by the gas electron diffraction (GED) method taking into account rovibrational corrections to the thermal-average internuclear distances calculated with harmonic and anharmonic (cubic) MP2/cc-pVTZ force constants with consideration of the methyl torsion as a large-amplitude motion. For the first time, the structure of the molecule has been optimized by the very time-consuming coupled-cluster method with single and double excitations and perturbative treatment of connected triples using the correlation-consistent polarized weighted core-valence triple-zeta basis set with all electrons being correlated (CCSD(T)(all)/cc-pwCVTZ) and extrapolated to the complete basis set (CBS) with the help of the MP2 calculations. Small differences between similar bond lengths of equilibrium configurations were assumed in the GED analysis at the CCSD(T)(all)/CBS values. A remarkable agreement between the semi-experimental and computed equilibrium structures points out the high accuracy of both the GED determination and the coupled-cluster computations. The effect of methylation on the structure of uracil has been analyzed. PMID- 24168753 TI - Cognitive impairment in depression: a systematic review and meta-analysis. AB - BACKGROUND: This review aimed to address the question of whether cognitive impairment should be considered a core feature of depression that may be a valuable target for treatment. METHOD: We conducted a systematic review and meta analysis of cognitive function, assessed with a single neuropsychological test battery, the Cambridge Neuropsychological Test Automated Battery (CANTAB), in patients with depression during symptomatic and remitted states. Inclusion of studies comparing patients remitted from depression and controls enabled us to investigate whether cognitive impairment persists beyond episodes of low mood in depression. RESULTS: Our meta-analysis revealed significant moderate cognitive deficits in executive function, memory and attention in patients with depression relative to controls (Cohen's d effect sizes ranging from -0.34 to -0.65). Significant moderate deficits in executive function and attention (Cohen's d ranging from -0.52 to -0.61) and non-significant small/moderate deficits in memory (Cohen's d ranging from -0.22 to -0.54) were found to persist in patients whose depressive symptoms had remitted, indicating that cognitive impairment occurs separately from episodes of low mood in depression. CONCLUSIONS: Both low mood and cognitive impairment are associated with poor psychosocial functioning. Therefore, we argue that remediation of cognitive impairment and alleviation of depressive symptoms each play an important role in improving outcome for patients with depression. In conclusion, this systematic review and meta-analysis demonstrates that cognitive impairment represents a core feature of depression that cannot be considered an epiphenomenon that is entirely secondary to symptoms of low mood and that may be a valuable target for future interventions. PMID- 24168754 TI - Social support may buffer the effect of intrafamilial stressors on preschool children's television viewing time in low-income families. AB - BACKGROUND: Excessive television (TV) viewing in preschool children has been linked to negative outcomes during childhood, including childhood obesity. In a sample of low-income families, this study examined associations between intrafamilial factors and preschool children's TV-viewing time and the moderating effect of social support from nonfamily members on this association. METHODS: In 2010, 129 mothers/female guardians of 2- to 5-year-old children enrolled at five Head Start centers in Rensselaer County, New York, completed a self-report survey. The survey assessed child TV-viewing time (including TV, DVDs, and videos) and intrafamilial risk factors, including maternal perceived stress, depressive symptoms, TV viewing, leisure-time physical activity (inactivity), and family functioning. Social support from nonfamily members (nonfamily social support) was also measured and examined as an effect modifier. RESULTS: Children watched TV an average of 160 minutes per day. Moderate depressive symptoms (Personal Health Questionnaire depression scale scores >=10), higher perceived stress, poorer family functioning, and higher maternal TV-viewing were significantly and independently associated with greater minutes of child TV viewing, controlling for covariates. In all instances, nonfamily social support moderated these associations, such that negative experiences within the family environment were linked with higher child TV-viewing time under conditions of low nonfamily social support, but not high nonfamily support. CONCLUSIONS: Social support from nonfamily members may buffer potentially negative effects of intrafamilial factors on preschool children's TV-viewing time. PMID- 24168755 TI - Externally predictive quantitative modeling of supercooled liquid vapor pressure of polychlorinated-naphthalenes through electron-correlation based quantum mechanical descriptors. AB - For predicting physico-chemical properties related to environmental fate of molecules, quantitative structure-property relationships (QSPRs) are valuable tools in environmental chemistry. For developing a QSPR, molecular descriptors computed through quantum-mechanical methods are generally employed. The accuracy of a quantum-mechanical method, however, rests on the amount of electron correlation estimated by the method. In this work, single-descriptor QSPRs for supercooled liquid vapor pressure of chloronaphthalenes and polychlorinated naphthalenes are developed using molecular descriptors based on the electron correlation contribution of the quantum-mechanical descriptor. The quantum mechanical descriptors for which the electron-correlation contribution is analyzed include total-energy, mean polarizability, dipole moment, frontier orbital (HOMO/LUMO) energy, and density-functional theory (DFT) based descriptors, namely, absolute electronegativity, chemical hardness, and electrophilicity index. A total of 40 single-descriptor QSPRs were developed using molecular descriptors computed with advanced semi-empirical (SE) methods, namely, RM1, PM7, and ab intio methods, namely, Hartree-Fock and DFT. The developed QSPRs are validated using state-of-the-art external validation procedures employing an external prediction set. From the comparison of external predictivity of the models, it is observed that the single-descriptor QSPRs developed using total energy and correlation energy are found to be far more robust and predictive than those developed using commonly employed descriptors such as HOMO/LUMO energy and dipole moment. The work proposes that if real external predictivity of a QSPR model is desired to be explored, particularly, in terms of intra-molecular interactions, correlation-energy serves as a more appropriate descriptor than the polarizability. However, for developing QSPRs, computationally inexpensive advanced SE methods such as PM7 can be more reliable than the expensive ab inito methods. PMID- 24168757 TI - Cardiac diagnoses, procedures, and healthcare utilisation in inpatients with Ellis-van Creveld syndrome. AB - INTRODUCTION: Ellis-van Creveld syndrome is a rare condition associated with a very high incidence of congenital malformations of the heart. Prior reports have suggested increased morbidity and mortality following surgery for congenital malformations of the heart in patients with Ellis-van Creveld syndrome. MATERIALS AND METHODS: The Pediatric Health Information System database, an administrative database containing data from 43 free-standing paediatric hospitals in North America, was queried to search for patients with the diagnostic code for Ellis van Creveld syndrome between 2004 and 2011. Those patients who underwent cardiac procedures were compared with those who did not with respect to measures of healthcare utilisation. RESULTS: A total of 138 admissions occurred in 93 patients with Ellis-van Creveld syndrome during the study period. Of these, 74% had an underlying diagnosis of congenital malformations of the heart. Half of the patients in the sample underwent a cardiac surgical or interventional catheterisation procedure. Patients who underwent a cardiac procedure had a longer hospital length of stay, higher incidence of intensive care unit admission, and higher total and per day hospital charges than patients who did not undergo cardiac surgery during admission. CONCLUSIONS: In a large group of inpatients with Ellis-van Creveld syndrome, the prevalence of congenital malformations of the heart was similar to that reported in prior studies. Cardiac surgical and interventional procedures appear to drive a substantial portion of healthcare utilisation in these patients. PMID- 24168751 TI - Molecules that mimic apolipoprotein A-I: potential agents for treating atherosclerosis. AB - Certain amphipathic alpha-helical peptides can functionally mimic many of the properties of full-length apolipoproteins, thereby offering an approach to modulate high-density lipoprotein (HDL) for combating atherosclerosis. In this Perspective, we summarize the key findings and advances over the past 25 years in the development of peptides that mimic apolipoproteins, especially apolipoprotein A-I (apoA-I). This assemblage of information provides a reasonably clear picture of the state of the art in the apolipoprotein mimetic field, an appreciation of the potential for such agents in pharmacotherapy, and a sense of the opportunities for optimizing the functional properties of HDL. PMID- 24168756 TI - Fluticasone impact on airway dendritic cells in smokers: a randomized controlled trial. AB - BACKGROUND: Myeloid Dendritic cells are key drivers of inflammation in smoke related lung diseases, whereas plasmacytoid DCs play a crucial role in the defense against infections. Effects of inhaled corticosteroids (ICS) on airway DCs in smokers are unknown. METHODS: In this randomized, double-blind, placebo controlled clinical trial, 45 active cigarette smokers inhaled placebo, fluticasone or fluticasone plus salmeterol twice daily for 4 weeks. Bronchoalveolar lavage fluid DCs were analyzed using four-color flow cytometry before and after the inhalation period. In addition, fluticasone effects were tested on T-cell proliferation in co-cultures with blood myeloid DCs from smokers. RESULTS: Inhalation of fluticasone plus salmeterol, but not fluticasone alone or placebo, reduced endobronchial concentrations of myeloid DCs (median decrease: 24%), macrophages (median decrease: 26%) and neutrophils (median decrease: 76%). In contrast, fluticasone reduced plasmacytoid DC concentrations independently of salmeterol. There were no changes in the expression of function associated surface molecules on myeloid DC (such as CD1a, Langerin, BDCA-1, CD83 or CCR5) in all groups after treatment. Fluticasone (either alone or in combination with salmeterol) suppressed T-cell proliferation in co-cultures with blood myeloid DCs from smokers. CONCLUSIONS: Resistance to ICS monotherapy in smokers might in part be due to lacking effects on airway myeloid DCs, whereas the increased risk for infections during ICS therapy could be attributable to a reduction in plasmacytoid DCs. Combination therapy of fluticasone with salmeterol is associated with a reduction in airway myeloid DCs, but also airway macrophages and neutrophils. TRIAL REGISTRATION: Registered at ClinicalTrials.gov (identifier: NCT00908362) and the European Clinical Trial Database, EudraCT (identifier: 2009-009459-40). PMID- 24168758 TI - Ruptured gastric stromal tumour into gastric lumen with an abscess. PMID- 24168759 TI - Equine-associated maxillofacial injuries: retrospective 5-year analysis. AB - We explored the relation between the causes of facial injuries in equestrians and the presence or absence of associated injuries. Over a 5-year period we retrospectively reviewed all patients who presented to the John Hunter Hospital, New South Wales, with facial injuries that had resulted from activity with horses. We analysed the rates of hard and soft tissue injuries, and of associated injuries by sex and mechanism. A total of 85 patients were included (50 female and 35 male) with an age range of 2-88 years. There was a significant difference in the rate of maxillofacial and associated injuries when groups were analysed for sex and mechanism of injury. Facial injuries caused by falling from a horse were more often associated with other injuries in men than in women (p<0.05), and men were 4 times more likely to present with associated injuries than women (OR 3.9; 95% CI 1.1 to 14) We also found significant differences in the rates of facial fracture. Women who had been kicked by a horse were more likely to sustain bony injuries than men (p<0.05). Our data confirm the association between kicks and facial fracture, and this may provide an impetus for the development of appropriate protective equipment. Patients who sustain facial injuries when falling from a horse often present with associated injuries and this has practical implications for clinicians involved in their management. PMID- 24168760 TI - Retinal fiber layer thickness in children with thalessemia major and iron deficiency anemia. AB - PURPOSE: We aimed to measure peripapillary retinal nerve fiber layer (RNFL) thickness in children with thalassemia major (tha-major), children with iron deficiency anemia (IDA), and children in a healthy control group. MATERIALS AND METHODS: A total of 47 children with tha-major and 22 children with IDA were selected from two pediatric hematology outpatient clinics as our experimental groups, while 35 healthy children were randomly selected from a primary school to act as a control group. After a complete eye examination was conducted and intraocular pressure measurements were obtained, RNFL measurements were performed using optical coherence tomography, and the information was recorded for statistical analysis. RESULTS: The mean age of the participants was 9.65 +/- 4.13 years in the tha-major group, 9.14 +/- 2.53 years in the IDA group, and 9.13 +/- 3.29 years in the control group, respectively, with no statistically significant difference among the three groups (p > 0.05). Mean peripapillary RNFL thickness was 119.38 +/- 35.49 microns in the tha-major group, 184.00 +/- 31.14 microns in the IDA group, and 187.73 +/- 27.36 microns in the control group. It was significantly thinner in all quadrants in the tha-major group vs. the other two groups (p < 0.01), and in only the inferior quadrant in the IDA group (p < 0.05). Average RNLF thickness correlated positively with mean hemoglobin value (r = 0.488; p < 0.001) and negatively with mean ferritin level (r = -0.544; p < 0.001), but no correlations with mean number of transfusions and mean visual acuity were observed (p > 0.05). CONCLUSION: The study revealed that peripapillary RNFL is thinner in tha-major in all quadrants and in only the inferior quadrant in IDA. Thinning of the RNLF correlated with hemoglobin value and ferritin level, but not with number of transfusions and visual acuity. PMID- 24168761 TI - Operational rules for the implementation of INN prescribing. AB - PURPOSE: The aim is to describe the process, principles and results of the International Nonproprietary Name (INN) prescribing project in Belgium. The purpose of this project was to operationalize electronic INN prescribing for outpatient care in daily medical practice and to develop a factual database which can be used in electronic INN prescribing applications. METHODS: The operationalization process consisted of three phases: (1) expert consultation, (2) review by regulatory authorities and (3) test phase with stakeholders and end users. RESULTS: The INN prescribing project resulted into (1) operational rules for electronic INN prescribing and (2) a reference database to be implemented in commercial medical software. The operational rules for electronic INN prescribing define valid INN groups as sets of equivalent medicinal products, described by three elements: the therapeutic moiety (the active part of the therapeutic ingredient) or combination of therapeutic moieties, the strength (with standardized denominators), and the method of administration (with simplified but standardized options). The operational rules also define two categories of exemptions for INN prescribing: INN groups where the first choice of treatment should be continued throughout the therapy period (NO SWITCH) and medicinal product groups not suitable for INN prescribing (NO INN). The reference database is the result of the virtual classification of the Belgian therapeutic arsenal into INN groups, according to the operational rules. CONCLUSIONS: Defining the operational rules for INN prescribing for and with different stakeholders was a difficult yet feasible assignment. The INN prescribing project resulted into explicit operational rules and a reference database. The Belgian experience may provide important information for other countries planning to operationalize or refine electronic INN prescribing. It can also be used for a thorough evaluation of the impact of the new concept of INN prescribing on daily practice and on medical education. PMID- 24168762 TI - The relationship between the timing of a palliative care consult and utilization outcomes for ventilator-assisted intensive care unit patients. AB - OBJECTIVE: Given the great number of chronic care patients facing the end of life and the challenges of critical care delivery, there has been emerging evidence supporting the benefit of palliative care in the intensive care unit (ICU). We studied the relationship between the timing of a palliative care consult (PCC) and two utilization outcomes - length of stay (LOS) and pharmacy costs - in ventilator-assisted ICU patients. METHOD: A retrospective chart review was conducted (N = 90). Summed pharmacy costs were compared using a paired t test before and after PCC. Spearman correlations were performed between days to PCC and ICU LOS, ventilator days, and days to death following ventilator discontinuation. RESULTS: Number of days from admission to PCC was correlated with total days on ventilator (rho = 0.685, p < 0.0001) and total ICU LOS (rho = 0.654, p < 0.0001). Number of days to PCC was correlated with pre-PCC total medication costs (rho = 0.539, p < 0.0001). Median medication costs were significantly reduced after the PCC (p < 0.0001), from $230.96 to 30.62. Median medication costs decreased for all categories except for analgesics, antiemetics, and opioids. The number of patients receiving opioid infusion increased (37 vs. 90%) after PCC (p < 0.0001). SIGNIFICANCE OF RESULTS: Earlier timing for PCC in the ICU is associated with a lower LOS through quicker mechanical ventilation (MV) withdrawal, presenting a unique opportunity to both decrease costs and improve patient care. PMID- 24168763 TI - Therapeutic targeting of erbB3 with MM-121/SAR256212 enhances antitumor activity of paclitaxel against erbB2-overexpressing breast cancer. AB - INTRODUCTION: Elevated expression of erbB3 rendered erbB2-overexpressing breast cancer cells resistant to paclitaxel via PI-3 K/Akt-dependent upregulation of Survivin. It is unclear whether an erbB3-targeted therapy may abrogate erbB2 mediated paclitaxel resistance in breast cancer. Here, we study the antitumor activity of an anti-erbB3 antibody MM-121/SAR256212 in combination with paclitaxel against erbB2-overexpressing breast cancer. METHODS: Cell growth assays were used to determine cell viability. Cells undergoing apoptosis were quantified by a specific apoptotic ELISA. Western blot analyses were performed to assess the protein expression and activation. Lentiviral vector containing shRNA was used to specifically knockdown Survivin. Tumor xenografts were established by inoculation of BT474-HR20 cells into nude mice. The tumor-bearing mice were treated with paclitaxel and/or MM-121/SAR256212 to determine whether the antibody (Ab) enhances paclitaxel's antitumor activity. Immunohistochemistry was carried out to study the combinatorial effects on tumor cell proliferation and induction of apoptosis in vivo. RESULTS: MM-121 significantly facilitated paclitaxel mediated anti-proliferative/anti-survival effects on SKBR3 cells transfected with a control vector or erbB3 cDNA. It specifically downregulated Survivin associated with inactivation of erbB2, erbB3, and Akt. MM-121 enhances paclitaxel-induced poly(ADP-ribose) polymerase (PARP) cleavage, activation of caspase-8 and -3, and apoptosis in both paclitaxel-sensitive and -resistant cells. Specific knockdown of Survivin in the trastuzumab-resistant BT474-HR20 cells dramatically enhanced paclitaxel-induced apoptosis, suggesting that increased Survivin caused a cross resistance to paclitaxel. Furthermore, the studies using a tumor xenograft model established from BT474-HR20 cells revealed that either MM-121 (10 mg/kg) or low dose (7.5 mg/kg) paclitaxel had no effect on tumor growth, their combinations significantly inhibited tumor growth in vivo. Immunohistochemical analysis showed that the combinations of MM-121 and paclitaxel significantly reduced the cells with positive staining for Ki-67 and Survivin, and increased the cells with cleaved caspase-3. CONCLUSIONS: The combinations of MM-121 and paclitaxel not only inhibit tumor cell proliferation, but also promote erbB2-overexpressing breast cancer cells to undergo apoptosis via downregulation of Survivin in vitro and in vivo, suggesting that inactivation of erbB3 with MM-121 enhances paclitaxel-mediated antitumor activity against erbB2-overexpressing breast cancers. Our data supports further exploration of the combinatorial regimens consisting of MM-121 and paclitaxel in breast cancer patients with erbB2 overexpressing tumors, particularly those resistant to paclitaxel. PMID- 24168764 TI - Modulation of distinct asthmatic phenotypes in mice by dose-dependent inhalation of microbial products. AB - BACKGROUND: Humans with asthma display considerable heterogeneity with regard to T helper (Th) 2-associated eosinophilic and Th17-associated neutrophilic inflammation, but the impact of the environment on these different forms of asthma is poorly understood. OBJECTIVE: We studied the nature and longevity of asthma-like responses triggered by inhalation of allergen together with environmentally relevant doses of inhaled lipopolysaccharide (LPS). METHODS: Ovalbumin (OVA) was instilled into the airways of mice together with a wide range of LPS doses. Following a single OVA challenge, or multiple challenges, animals were assessed for pulmonary cytokine production, airway inflammation, and airway hyperresponsiveness (AHR). RESULTS: Mice instilled with OVA together with very low doses (<=10-3 MUg) of LPS displayed modest amounts of Th2 cytokines, with associated airway eosinophilia and AHR after a single challenge, and these responses were sustained after multiple OVA challenges. When the higher but still environmentally relevant dose of 10-1 MUg LPS was used, mice initially displayed similar Th2 responses, as well as Th17-associated neutrophilia. After multiple OVA challenges, however, the 10-1 MUg LPS animals also accumulated large numbers of allergen-specific T regulatory (Treg) cells with high levels of inducible co stimulatory molecule (ICOS). As a result, asthma-like features in these mice were shorter-lived than in mice sensitized using lower doses of LPS. CONCLUSIONS: The nature and longevity of Th2, Th17, and Treg immune responses to inhaled allergen are dependent on the quantity of LPS inhaled at the time of allergic sensitization. These findings might account in part for the heterogeneity of inflammatory infiltrates seen in lungs of asthmatics. PMID- 24168765 TI - Endothelial function state following repair of cyanotic congenital heart diseases. AB - BACKGROUND: Repairing cyanotic congenital heart disease may be associated with preserving endothelial function. The present study aimed to evaluate vascular endothelial function in patients with repaired cyanotic congenital heart disease. METHODS: In a case-control study conducted in 2012 in Isfahan, Iran, 42 consecutive patients aged <35 years who had suffered from different types of cyanotic congenital heart disease and had undergone complete repair of their congenital heart defect were assessed in regard to their endothelial function state by measuring flow-mediated dilatation and other cardiac function indices. They were paired with 42 sex- and age-matched healthy controls. RESULTS: The mean flow-mediated dilatation was lower in patients with repaired cyanotic congenital heart disease than in the controls [6.14+/-2.78 versus 8.16+/-1.49 respectively (p<0.001)]. Significant adverse correlations were found between flow-mediated dilatation, age, and body mass indexes, in those who underwent repair surgery. In addition, flow-mediated dilatation had a positive association with the shortening fraction, ejection fraction, and tricuspid annular plane systolic excursion value, and it was also inversely associated with carotid intima-media thickness and the myocardial performance index. The mean of the flow-mediated dilatation was significantly higher in the group with tetralogy of Fallot along with complete repair before the age of 2.5 years and also in those patients with total anomalous pulmonary venous connection or transposition of the great arteries repaired with an arterial switch operation before 6 months of age, compared with the other two subgroups. This includes patients with a tetralogy of Fallot defect repaired after 4 years of age and those with complex cyanotic congenital heart disease that was repaired after 2.5 years of age (mean age at repair 9+/-6.1 years). CONCLUSION: Early repair of a cyanotic defect can result in the protection of vascular endothelial function and prevent the occurrence of vascular accidents at an older age. PMID- 24168766 TI - A transition metal carbonyl probe for use in a highly specific and sensitive SERS based assay for glucose. AB - A triosmium carbonyl cluster-boronic acid conjugate is used as a secondary carbohydrate probe in a SERS-based assay. The assay does not require conjugation of the metal carbonyl probe to a SERS-active species, and it utilizes the CO stretching vibrations of the metal carbonyl, which lies in a silent region of the SERS spectrum (1800-2200 cm(-1)), for quantification. High selectivity for glucose over fructose and galactose is obtained, and a human urine sample doped with glucose is detected accurately. PMID- 24168768 TI - Nodular fasciitis after parathyroidectomy. PMID- 24168769 TI - [OdA TPA--Organization for the working world of Swiss veterinary practice assistants]. PMID- 24168767 TI - Characterisation of exacerbation risk and exacerbator phenotypes in the POET-COPD trial. AB - BACKGROUND: Data examining the characteristics of patients with frequent exacerbations of chronic obstructive pulmonary disease (COPD) and associated hospitalisations and mortality are scarce. METHODS: Post-hoc analysis of the Prevention Of Exacerbations with Tiotropium in COPD (POET-COPD) trial, targeting exacerbations as the primary endpoint. Patients were classified as non-, infrequent, and frequent exacerbators (0, 1, or >= 2 exacerbations during study treatment), irrespective of study treatment. A multivariate Cox regression model assessed the effect of covariates on time to first exacerbation. RESULTS: In total, 7376 patients were included in the analysis: 63.5% non-exacerbators, 22.9% infrequent, 13.6% frequent exacerbators. Factors significantly associated with exacerbation risk were age, sex, body mass index, COPD duration and severity, smoking history, baseline inhaled corticosteroid use, and preceding antibiotic or systemic corticosteroid courses. Frequent exacerbators had greater severity and duration of COPD, received more pulmonary medication, and >= 2 systemic corticosteroid or antibiotic courses in the preceding year, and were more likely to be female and ex-smokers. The small proportion of frequent exacerbators (13.6%) accounted for 56.6% of exacerbation-related hospitalisations, which, overall, were associated with a three-fold increase in mortality. CONCLUSION: The frequent exacerbator phenotype was closely associated with exacerbation-related hospitalisations, and exacerbation-related hospitalisations were associated with poorer survival. TRIAL REGISTRATION: NCT00563381; Study identifier: BI 205.389. PMID- 24168770 TI - [Castration in the bull calf and ram lamb]. AB - This paper aims to provide an overview of the accepted techniques of pain relief and castration and guidelines of how to best perform these painful interventions in an animal-friendly way under Swiss conditions. Calves should be castrated at the age of 14 days or less, at least 10 minutes after local anesthesia with lidocaine, applying a single rubber ring. Concurrently, a NSAID should be administered intravenously (ketoprofen, 3 mg/kg of bodyweight) and Tetanus-serum subcutaneously (off label use). If possible, ketoprofen(4.5 mg/kg BW) should be orally administered for 3 - 5 days postoperatively. At 10 days after applying the rubber ring, the dried-off scrotum including the rubber ring should be removed with a clean knife or a scalpel. Local anesthesia is not necessary for this procedure. Ram lambs should be castrated at the age of 14 days or less, at least 10 minutes after local anesthesia with lidocaine, applying a rubber ring. The toxic dose of 4 mg lidocaine/kg BW (corresponds to 1 ml lidocaine 2 % per lamb of 5 kg BW) should not be exceeded. Concurrently, a NSAID (off label use) and Tetanus-serum should be administered systemically. Immunization against GnRH represents an animal-friendly and economically feasible alternative to rubber ring castration. With two immunizations at an interval of 3 - 4 weeks testicular development can be inhibited for at least 3 months and the onset of puberty clearly delayed. However, a specific vaccine for use in ruminants is currently registered neither in Switzerland nor in Europe. PMID- 24168772 TI - Malignant peripheral nerve sheath tumour in the nasopharynx of a cow. AB - This case describes the findings in a Swiss Braunvieh cow with a malignant peripheral nerve sheath tumour (MPNST) in the nasopharynx. The major clinical signs were mixed dyspnoea with inspiratory and expiratory noises. Radiographic views of the head revealed an irregular mass with soft-tissue density in the nasopharynx originating from the dorsal pharynx and occupying and restricting the pharyngeal cavity. Endoscopic examination showed a lobulated mass obstructing almost the entire lumen of the aboral nasal passages and nasopharynx. Postmortem examination revealed a lobulated mass in the choanae with a broad attachment to the dorsal pharynx and histologically a soft tissue sarcoma with tumour cells positive for the S-100 and p75NTR (neurotrophin receptor) proteins and negative for CNPase. Electron microscopic examination showed few structures that indicated that the tumour originated from Schwann cells. PMID- 24168771 TI - [Vigilance for veterinary medicinal products: reports of adverse reactions in the year 2012]. AB - 197 adverse reactions of Swissmedic-authorized veterinary medicinal products were reported during the year 2012 (2011: 167). Species and drug classes remain unchanged over the years: most of the reports related to reactions following the use of antiparasitic products (37.6 %), antiinfectives (15.7 %) or non-steroidal antiinflammatory drugs (11.7 %) in companion animals (94 dogs and 53 cats) followed by cattle/calves (29). Additionally, 45 cases transmitted by the Swiss Toxicological Information Centre in Zurich were processed. We discuss a paradoxical reaction under the potential influence of acepromazine as well as a modified protocol for treating permethrin intoxication in cats. Finally, the vaccinovigilance program received 95 declarations following the application of various vaccines, mainly to dogs or cats. PMID- 24168773 TI - [Blood vessel anomalities in the oral cavity of two calves]. AB - Two calves were presented with a congenital mass in the rostral mandibular gingiva. In both cases the masses relapsed after surgical removal. Histologically, the two masses were composed of irregularly arranged vascular cavities, embedded in loosely arranged stroma and alcian-blue PAS positive ground substance. Radiologically, a destruction of the alveolar cavity was recognized in both cases, which was in case 1 histologically compatible with bone resorption and remodeling associated with the infiltration of abundant granulation tissue. A literature survey revealed that no consistent criteria for a correct classification for vascular tumours exists, resulting in the fact that comparable lesions were named differently in the past. We therefore propose to classify such lesions as congential vascular malformation until distinct morphological, immunohistochemical and molecular genetic analysis criteria will exist. PMID- 24168776 TI - Development of plasma cell myeloma in a B-cell chronic lymphocytic leukemia patient with chromosome 12 trisomy. AB - BACKGROUND: Cancer development results from the progressive accumulation of genomic abnormalities that culminate in the neoplastic phenotype. Cytogenetic alterations, mutations and rearrangements may be considered as molecular legacy which trace the clonal history of the disease. Concomitant tumors are reported and they may derive from a common or divergent founder clone. B-cell chronic lymphocytic leukemia (B-CLL) and plasma cell myeloma (PCM) are both mature B-cell neoplasms, and their concomitancy, albeit rare, is documented. CASE PRESENTATION: Here, we described a patient with prior B-CLL with secondary development of PCM. Cytogenetic and multi parametric flow cytometry analyses were performed. The B CLL population presented chromosome 12 trisomy, unlikely the arisen PCM population. CONCLUSION: The close follow up of B-CLL patients is important for early intervention in case of development of other malignancy, such as myeloma. Our observation suggests these two diseases may have arisen from different clones. We understand that the investigation of clonal origin may provide important information regarding therapeutic decisions, and should be considered in concomitant neoplasm. PMID- 24168777 TI - Crusted erythematous plaques over scalp with hair palisades. PMID- 24168778 TI - Nonparaphilic hypersexual behavior and depressive symptoms: a meta-analytic review of the literature. AB - Research on nonparaphilic hypersexual behavior and its associated characteristics has increased in recent years. In the present article, the authors review the literature on the relation between nonparaphilic hypersexual behavior and depressive symptoms. There was a moderate, positive relation between nonparaphilic hypersexual behavior and depressive symptoms (r =.34). This relation was similar across gender, sexual orientation, and age. The authors discuss the implications for researchers and clinicians working with hypersexual individuals. Future research should work to elucidate the causal direction of the relation between nonparaphilic hypersexual behavior and depressive symptoms. The authors encourage clinicians who work with hypersexual patients to assess them for depressive symptoms and consider treatment options that address concurrent depressive symptoms. PMID- 24168780 TI - Antioxidant effects of ryegrass phenolics in lamb liver and plasma. AB - Sixteen lambs were divided into two groups and fed two different diets. Eight lambs were stall-fed with a concentrate-based diet (C), and the remaining eight lambs were allowed to graze on Lolium perenne (G). The antioxidant status was measured in the liver and plasma samples before and after solid-phase extraction (SPE) to probe the antioxidant effects that grass phenolic compounds may have conferred onto the animal tissues. The liver and plasma samples from grass-fed lambs displayed a greater antioxidant capacity than the tissues from C lamb group, but only if samples had not been passed through SPE cartridges. Finally, the feed and animal tissues, which had been purified by SPE, were analysed by liquid chromatography combined with mass spectrometry (LC???MS) to identify phenolic compounds present in L. perenne and to evaluate the results from the antioxidant assays. It would appear that the improvement of the antioxidant capacity of lamb liver and plasma from lambs fed ryegrass was not related to the direct transfer of phenolic compounds from grass to the animal tissues. PMID- 24168779 TI - Childhood maltreatment, juvenile disorders and adult post-traumatic stress disorder: a prospective investigation. AB - BACKGROUND: We examine prospectively the influence of two separate but potentially inter-related factors in the etiology of post-traumatic stress disorder (PTSD): childhood maltreatment as conferring a susceptibility to the PTSD response to adult trauma and juvenile disorders as precursors of adult PTSD. METHOD: The Dunedin Multidisciplinary Health and Development Study (DMHDS) is a birth cohort (n = 1037) from the general population of New Zealand's South Island, with multiple assessments up to age 38 years. DSM-IV PTSD was assessed among participants exposed to trauma at ages 26-38. Complete data were available on 928 participants. RESULTS: Severe maltreatment in the first decade of life, experienced by 8.5% of the sample, was associated significantly with the risk of PTSD among those exposed to adult trauma [odds ratio (OR) 2.64, 95% confidence interval (CI) 1.16-6.01], compared to no maltreatment. Moderate maltreatment, experienced by 27.2%, was not associated significantly with that risk (OR 1.55, 95% CI 0.85-2.85). However, the two estimates did not differ significantly from one another. Juvenile disorders (ages 11-15), experienced by 35% of the sample, independent of childhood maltreatment, were associated significantly with the risk of PTSD response to adult trauma (OR 2.35, 95% CI 1.32-4.18). CONCLUSIONS: Severe maltreatment is associated with risk of PTSD response to adult trauma, compared to no maltreatment, and juvenile disorders, independent of earlier maltreatment, are associated with that risk. The role of moderate maltreatment remains unresolved. Larger longitudinal studies are needed to assess the impact of moderate maltreatment, experienced by the majority of adult trauma victims with a history of maltreatment. PMID- 24168781 TI - What can England's NHS learn from Canterbury New Zealand? PMID- 24168782 TI - Randomized controlled trials in pediatric critical care: a scoping review. AB - INTRODUCTION: Evidence from randomized controlled trials (RCTs) is required to guide treatment of critically ill children, but the number of RCTs available is limited and the publications are often difficult to find. The objectives of this review were to systematically identify RCTs in pediatric critical care and describe their methods and reporting. METHODS: We searched MEDLINE, EMBASE, LILACS and CENTRAL (from inception to April 16, 2013) and reference lists of included RCTs and relevant systematic reviews. We included published RCTs administering any intervention to children in a pediatric ICU. We excluded trials conducted in neonatal ICUs, those enrolling exclusively preterm infants, and individual patient crossover trials. Pairs of reviewers independently screened studies for eligibility, assessed risk of bias, and abstracted data. Discrepancies were resolved by consensus. RESULTS: We included 248 RCTs: 45 (18%) were multicentered and 14 (6%) were multinational. Trials most frequently enrolled both medical and surgical patients (43%) but postoperative cardiac surgery was the single largest population studied (19%). The most frequently evaluated types of intervention were medications (63%), devices (11%) and nutrition (8%). Laboratory or physiological measurements were the most frequent type of primary outcomes (18%). Half of these trials (50%) reported blinding. Of the 107 (43%) trials that reported an a priori sample size, 34 (32%) were stopped early. The median number of children randomized per trial was 49 and ranged from 6 to 4,947. The frequency of RCT publications increased at a mean rate of 0.7 RCTs per year (P<0.001) from 1 to 20 trials per year. CONCLUSIONS: This scoping review identified the available RCTs in pediatric critical care and made them accessible to clinicians and researchers (http://epicc.mcmaster.ca). Most focused on medications and intermediate or surrogate outcomes, were single-centered and were conducted in North America and Western Europe. The results of this review underscore the need for trials with rigorous methodology, appropriate outcome measures, and improved quality of reporting to ensure that high quality evidence exists to support clinical decision-making in this vulnerable population. PMID- 24168783 TI - An increase of VEGF plasma levels is associated with restenosis of drug-eluting stents. AB - AIMS: Drug-eluting stents (DES) reduce late lumen loss compared to bare metal stents but were not able to eradicate in-stent restenosis (ISR) fully. Vascular endothelial growth factor (VEGF) may inhibit late lumen loss through accelerated reendothelialisation, but may also promote neointima formation by proinflammatory effects. The aim of this study was to evaluate whether endogenous plasma levels of VEGF are associated with development of ISR after implantation of DES. METHODS AND RESULTS: We studied 85 patients who were treated with 159 DES. VEGF plasma levels were determined before and 24 hours after PCI. During the eight-month follow-up period, two patients (2.4%) died of cardiovascular causes and 12 patients (14.5% of patients, 7.6% of stents) developed angiographic ISR. Basal VEGF plasma levels were not different in patients with and without ISR at follow up. In contrast to patients without ISR, VEGF increased significantly upon PCI in patients with ISR (p<0.005). Patients with a decrease of VEGF after PCI had a restenosis rate of 2.4% compared to a restenosis rate of 26.2% in patients with an increase of VEGF after the procedure (p<0.05). This was independent from clinical and angiographic risk factors. CONCLUSIONS: Basal plasma levels of VEGF are not associated with the development of ISR. However, an increase of VEGF after PCI is associated with a dramatically increased ISR rate after implantation of DES. PMID- 24168784 TI - Association between earthquake events and cholera outbreaks: a cross-country 15 year longitudinal analysis. AB - INTRODUCTION: Large earthquakes can cause population displacement, critical sanitation infrastructure damage, and increased threats to water resources, potentially predisposing populations to waterborne disease epidemics such as cholera. Problem The risk of cholera outbreaks after earthquake disasters remains uncertain. A cross-country analysis of World Health Organization (WHO) cholera data that would contribute to this discussion has yet to be published. METHODS: A cross-country longitudinal analysis was conducted among 63 low- and middle-income countries from 1995-2009. The association between earthquake disasters of various effect sizes and a relative spike in cholera rates for a given country was assessed utilizing fixed-effects logistic regression and adjusting for gross domestic product per capita, water and sanitation level, flooding events, percent urbanization, and under-five child mortality. Also, the association between large earthquakes and cholera rate increases of various degrees was assessed. RESULTS: Forty-eight of the 63 countries had at least one year with reported cholera infections during the 15-year study period. Thirty-six of these 48 countries had at least one earthquake disaster. In adjusted analyses, country-years with >=10,000 persons affected by an earthquake had 2.26 times increased odds (95 CI, 0.89-5.72, P = .08) of having a greater than average cholera rate that year compared to country-years having <10,000 individuals affected by an earthquake. The association between large earthquake disasters and cholera infections appeared to weaken as higher levels of cholera rate increases were tested. CONCLUSION: A trend of increased risk of greater than average cholera rates when more people were affected by an earthquake in a country-year was noted. However these findings did not reach statistical significance at traditional levels and may be due to chance. Frequent large-scale cholera outbreaks after earthquake disasters appeared to be relatively uncommon. PMID- 24168785 TI - Clinical utility of RD1, RD9 and hsp65 based PCR assay for the identification of BCG in vaccinated children. AB - BACKGROUND: Mycobacterium bovis Bacille Calmette-Guerin (BCG) vaccine is widely administered to prevent tuberculosis. Vaccine complications are rare. However, when BCG-related adverse reactions arise there is a need to rapidly and reliably identify BCG from other members of the Mycobacterium tuberculosis complex (TBC). PCR assays based on the detection of the regions of difference (RD), in particular RD1 and RD9, have been invaluable in the identification of BCG. Prior to this study, specimens were identified through HPLC analysis at a local reference laboratory taking up to 2 weeks for a result. We sought to expedite the identification process by validating a RD1, RD9 and hsp65 PCR assay for the identification and differentiation of BCG from TBC. FINDINGS: In last past 3 years, we validated the RD1, RD9 and hsp65 PCR assay for 16 mycobacterial isolates obtained from children who had experienced adverse reactions to BCG vaccination. In these cases, the clinician required a definitive identification of the isolate. The RD1 and RD9 PCR profiles indicated that all 16 isolates were BCG whilst amplification of the hsp65 target functioned as a PCR positive control. When tested against clinical M. tuberculosis (MTB), reference and non tuberculous mycobacteria the PCR assay demonstrated 100% sensitivity and specificity. CONCLUSIONS: The RD1, RD9 and hsp65 PCR assay is a useful tool for the rapid and reliable identification of BCG. Its ease of use has allowed it to be implemented in our clinical microbiology laboratory. PMID- 24168786 TI - Multi-component adjustable intraocular lenses: a new concept in pediatric cataract surgery. AB - PURPOSE: The multi-component intraocular lens (IOL) (IVO; SAS, Strasbourg, France) is a novel approach to the treatment of pediatric cataract. Because the refractive requirements for pediatric eyes often change over time, current IOL technology does not easily allow refractive adjustments after the primary surgical intervention. The multi-component IOL concept allows easy, surgical refractive adjustments to the initial surgical implantation at any postoperative time period. Thus, both surgical implantation and enhancement surgery have been successfully accomplished in adult patients. METHODS: A novel surgical approach to pediatric cataract surgery is described. At the time of the primary surgery, a two component IOL was implanted. At any postoperative time period, the front lens component, located in front of the capsular bag, could be easily surgically exchanged because the dioptric power requirements of the pediatric eye changed over time. RESULTS: Both primary and enhancement surgeries have been done in adult patients with good results. Implantations have occurred uneventfully in all cases with no intraoperative or postoperative complications. There was no statistically significant difference in the endothelial cell density, anterior chamber depth, and pachymetry readings preoperatively and 2 years postoperatively. There was no interlenticular fibrosis present. CONCLUSION: The multi-component IOL should provide a unique and greatly needed surgically adjustable approach to the treatment of pediatric cataract. PMID- 24168787 TI - Accuracy and reproducibility of cap thickness in small incision lenticule extraction. AB - PURPOSE: To evaluate the accuracy and reproducibility of cap thickness for small incision lenticule extraction (SMILE) with the VisuMax femtosecond laser (Carl Zeiss Meditec, Inc., Jena, Germany). METHODS: Artemis very high-frequency digital ultrasound (ArcScan Inc., Morrison, CO) measurements were obtained before and 3 months after SMILE in 70 eyes of 37 patients with intended cap thickness between 80 and 140 MUm. True cap thickness at the time of creation was calculated as the addition of the preoperative epithelial thickness and the postoperative stromal component of the flap and mapped for the central 5-mm diameter zone. Cap thickness accuracy was calculated as the difference between the mean and intended cap thickness. Reproducibility was evaluated as the cap thickness standard deviation between eyes. Accuracy and reproducibility of cap thickness were calculated for all eyes and grouped by intended cap thickness. Within-eye variation in cap thickness was calculated as the standard deviation of all data within the central 5-mm diameter zone. RESULTS: Mean cap thickness accuracy was between -2.3 and 6.5 MUm and was -0.7 MUm centrally (range: -11 to +14 MUm), including all eyes. Cap thickness reproducibility was 6 MUm or less for the majority of the central 5-mm diameter zone and was 4.4 MUm centrally. Cap thickness accuracy and reproducibility were similar for different intended cap thicknesses. Average within-eye variation in cap thickness was 4.3 MUm. CONCLUSIONS: SMILE cap thickness using the VisuMax femtosecond laser was found to be accurate and reproducible across the central 5-mm diameter zone for intended cap thicknesses over the range of 80 to 140 MUm. PMID- 24168788 TI - Safety profile of high-fluence corneal collagen cross-linking for progressive keratoconus: preliminary results from a prospective cohort study. AB - PURPOSE: To investigate the effect of high-fluence corneal collagen cross-linking (CXL) with riboflavin and ultraviolet-A in the management of progressive keratoconus. METHODS: Preliminary results from a prospective cohort study. Seven eyes from 7 patients with progressive keratoconus subjected to CXL were included. CXL was performed as a standard epithelium-off procedure, irradiating with high fluence settings (18 mW/cm(2) for 5 minutes). Endothelial cell density (ECD), speed of postoperative epithelial healing, maximal and average keratometric readings (Kmax and Kmean, respectively) of the anterior corneal surface, and corrected distance visual acuity (CDVA) were evaluated preoperatively and at 1 and 6 months after CXL. One-way analysis of variance was applied for statistical analysis. P values less than .05 were considered significant. RESULTS: ECD did not change significantly postoperatively and complete epithelial healing occurred in all eyes within 96 hours postoperatively. No morphological alterations in the corneal limbus were observed. Kmax, Kmean, and CDVA showed no significant changes at 1 and 6 months postoperatively. No complications were observed postoperatively. CONCLUSIONS: Although the preliminary results are not sufficient for a valid evaluation of the biomechanical effect and the overall safety profile of high-fluence CXL in vivo, they demonstrate that CXL at 18 mW/cm(2) for 5 minutes affects neither endothelial cell density nor the speed of epithelial healing, an indirect indicator of limbal stem cell function. PMID- 24168789 TI - Four-year visual, refractive, and contrast sensitivity outcomes after wavefront guided myopic LASIK using an advanced excimer laser platform. AB - PURPOSE: To evaluate the 4-year visual, refractive, and contrast sensitivity outcomes of wavefront-guided LASIK for the correction of low to moderate myopia using the VISX CustomVue technology (Abbott Medical Optics, Inc., Santa Ana, CA). METHODS: This was a prospective study including 255 consecutive eyes of 145 patients (age range: 19 to 55 years) with low to moderate myopia (mean spherical equivalent: -3.36 +/- 1.71 diopters [D]) undergoing laser refractive surgery. Wavefront-guided LASIK was performed in all eyes using the VISX STAR S4 IR excimer laser platform and the CustomVue procedure for the ablation profile design. Visual, refractive, and contrast sensitivity changes were evaluated during a 4-year follow-up period. RESULTS: Postoperative logMAR uncorrected distance visual acuity was 0.1 or better (20/25 Snellen) in 98.0% and 100% of eyes at 1 and 4 years, respectively. At 4 years postoperatively, mean spherical equivalent was reduced significantly to a mean value of -0.22 +/- 0.28 D (P < .01), with 97.3% of eyes with a spherical equivalent within +/-0.50 D. The astigmatic power vector component J0 of manifest refraction was also reduced significantly (P < .01). Postoperative logMAR corrected distance visual acuity was 0.0 or better (20/20 Snellen) in 96.1% and 98.8% of eyes at 1 and 4 years, respectively. Improvement in contrast sensitivity was observed in some spatial frequencies between 1 and 4 years postoperatively. No significant correlations were found between 4-year contrast sensitivity and corrected distance visual acuity (0.024 <= r <= -0.120, P >= .06). CONCLUSION: Wavefront-guided LASIK using the VISX CustomVue technology provides an effective and predictable correction of low to moderate myopia in the long term, preserving the patient's visual acuity and quality. PMID- 24168790 TI - Indications for and outcomes of tertiary referrals in refractive surgery. AB - PURPOSE: To review the spectrum of disease, symptomatology, and management offered to patients referred for a second opinion after refractive surgery. METHODS: A prospective cohort study was done on all patients referred from October 1, 2006, to September 30, 2011, to a tertiary eye clinic after refractive surgery of any kind (ie, corneal laser surgery, conductive keratoplasty, radial keratotomy, phakic implants, refractive lens exchanges, or any combination thereof). Data analysis was performed on all demographic and clinical aspects of this cohort, including the initial complaint, type of referral, number of complaints, procedure previously performed, diagnosis at our center, type of advice given, and rate and type of surgical intervention. RESULTS: One hundred thirty-one eyes (69 patients) were included. Corneal refractive surgery was performed in 82% (108 eyes), and 11% (14 eyes) were seen after phakic intraocular lens (PIOL) implantation and 7% (9 eyes) after refractive lens exchange. The most common diagnoses were tear film dysfunction (30 eyes, 23%), residual refractive error (25 eyes, 19%), and cataract (20 eyes, 15%). Most patients (42 patients, 61%) were treated conservatively. In 27 patients (39%), 36 eyes (28%) were managed surgically. Severe visual loss was seen in 1 eye. CONCLUSIONS: No major problems were found in most second opinions after refractive surgery referral. Dry eyes, small residual refractive error, or higher-order aberrations were the most common complaints. Surgical intervention was needed in 36 eyes (28%), almost half of which were cataract extractions. Severe visual loss was seen in 1 eye with a PIOL. There was no incidence of severe visual loss in keratorefractive and refractive lens exchange procedures. PMID- 24168791 TI - Stimulation with monochromatic green light during incubation alters satellite cell mitotic activity and gene expression in relation to embryonic and posthatch muscle growth of broiler chickens. AB - Previous studies showed that monochromatic green light stimuli during embryogenesis accelerated posthatch body weight (BW) and pectoral muscle growth of broilers. In this experiment, we further investigated the morphological and molecular basis of this phenomenon. Fertile broiler eggs (Arbor Acres, n=880) were pre-weighed and randomly assigned to 1 of the 2 incubation treatment groups: (1) dark condition (control group), and (2) monochromatic green light group (560 nm). The monochromatic lighting systems sourced from light-emitting diode lamps and were equalized at the intensity of 15 lx at eggshell level. The dark condition was set as a commercial control from day 1 until hatching. After hatch, 120 male 1-day-old chicks from each group were housed under incandescent white light with an intensity of 30 lx at bird-head level. No effects of light stimuli during embryogenesis on hatching time, hatchability, hatching weight and bird mortality during the feeding trial period were observed in the present study. Compared with the dark condition, the BW, pectoral muscle weight and myofiber cross-sectional areas were significantly greater on 7-day-old chicks incubated under green light. Green light also increased the satellite cell mitotic activity of pectoral muscle on 1- and 3-day-old birds. In addition, green light upregulated MyoD, myogenin and myostatin mRNA expression in late embryos and/ or newly hatched chicks. These data suggest that stimulation with monochromatic green light during incubation promote muscle growth by enhancing proliferation and differentiation of satellite cells in late embryonic and newly hatched stages. Higher expression of myostatin may ultimately help prevent excessive proliferation and differentiation of satellite cells in birds incubated under green light. PMID- 24168792 TI - Expression of stromal cell-derived factor-1 receptors CXCR4 and CXCR7 on circulating platelets of patients with acute coronary syndrome and association with left ventricular functional recovery. AB - BACKGROUND: Surface expression of stromal cell-derived factor-1 (SDF-1) on platelets is enhanced during ischaemic events and might play an important role in peripheral homing and myocardial repair. As SDF-1 effects are mediated through CXCR4/CXCR7, we investigated platelet expression of SDF-1/CXCR4/CXCR7 in patients with coronary artery disease (CAD). METHODS AND RESULTS: Expression of SDF-1, CXCR4, and CXCR7 in platelets was investigated by western blot analysis, immunofluorescence confocal microscopy, and flow cytometry among healthy subjects and patients with acute coronary syndrome (ACS) and stable CAD. In a cohort study, platelet surface expression of CXCR4, CXCR7, and SDF-1 was measured in 215 patients with symptomatic CAD (stable CAD = 112, ACS = 103) at the time of percutaneous coronary intervention. Course of left ventricular ejection fraction (LVEF) was followed up during intrahospital stay and at 3 months. Both CXCR4 and CXCR7 are surface expressed on human platelets and to a higher degree in CAD patients when compared with healthy controls. Platelet surface expression of CXCR7 but not CXCR4 was enhanced in patients with ACS when compared with patients with stable CAD (mean fluorescence intensity 17.8 vs. 15.3, P = 0.004 and 29.0 vs. 26.3, P = 0.122, respectively). CXCR4 and CXCR7 significantly correlated with their ligand SDF-1 on platelets (rho = 0.273, P < 0.001 and rho = 0.454, P < 0.001, respectively). Additionally, high CXCR7 expression above the median correlated with the absolute improvement of LVEF% after 5 days and 3 months (46.2, 49.8, 53.7; P = 0.003). CONCLUSION: These findings indicate that platelet surface expression of CXCR4 and CXCR7 might differentially contribute to SDF-1 mediated effects on regenerative mechanisms following ACS. Studies are warranted to further evaluate the regulatory mechanisms of CXCR4/-7 expression and its prognostic impact on CAD. PMID- 24168793 TI - Pulmonary hypertension related to congenital heart disease: a call for action. AB - Pulmonary arterial hypertension related to congenital heart disease (PAH-CHD) is a common type of pulmonary arterial hypertension (PAH). Despite this, little emphasis has been given to this group of patients until recently, when compared with idiopathic PAH. This is largely because of the complexity and the wide range of underlying cardiac anatomy and physiology, with a multitude of adaptive mechanisms not fully understood. Pulmonary arterial hypertension related to congenital heart disease is, therefore, best diagnosed and managed in centres specializing in both CHD and PAH, to avoid common pitfalls and old practices and to provide state-of-the-art care. We discuss the optimal management of PAH-CHD patients in a series of actions to be taken in order to optimize short- and long term outcome, based on current knowledge of the condition and the advent of targeted advanced therapies. PMID- 24168794 TI - Language and memory abilities of internationally adopted children from China: evidence for early age effects. AB - The goal of the present study was to examine if internationally adopted (IA) children from China (M = 10;8) adopted by French-speaking families exhibit lags in verbal memory in addition to lags in verbal abilities documented in previous studies (Gauthier & Genesee, 2011). Tests assessing verbal and non-verbal memory, language, non-verbal cognitive ability, and socio-emotional development were administered to thirty adoptees. Their results were compared to those of thirty non-adopted monolingual French-speaking children matched on age, gender, and socioeconomic status. The IA children scored significantly lower than the controls on language, verbal short-term memory, verbal working memory, and verbal long-term memory. No group differences were found on non-verbal memory, non verbal cognitive ability, and socio-emotional development, suggesting language specific difficulties. Despite extended exposure to French, adoptees may experience language difficulties due to limitations in verbal memory, possibly as a result of their delayed exposure to that language and/or attrition of the birth language. PMID- 24168795 TI - [Genetic testing in the fetus and child]. AB - New key technologies such as array-based molecular karyotyping and high throughput sequencing are currently introduced in pre- and postnatal diagnostic testing. These greatly improved genomic testing approaches are beginning to fundamentally change diagnostic strategies in the clinical setting. Molecular karyotyping in the fetus is now routinely performed in high risk situations or on parental request. It will replace the conventional microscopic approach in the near future. Non-invasive prenatal testing to exclude common trisomies is probably the most significant recent achievement and has the potential to dramatically reduce invasive testing. Multiple congenital malformations and intellectual disability (ID) occur in up to 3 % of the general population. A correct diagnosis at an early age is important for clinical management of the patients and for counselling the families with regard to recurrence risk. Conventional karyotyping has been replaced by molecular karyotyping (microarray analysis, Array-CGH), increasing the diagnostic yield up to 15 - 20 % in this population. This approach can be challenging with regard to interpretation of copy number variants of uncertain significance or variants with reduced penetrance. If the clinical assessment leads to the suspicion of a specific syndrome or a leading symptom like epilepsy or microcephaly is present, genetic testing might be directed towards single-gene analysis. However, increasing knowledge indicates that many of these conditions are genetically heterogeneous. The availability of next-generation sequencing techniques has led to the implementation of testing panels in the diagnostic setting, by which multiple genes are analyzed in parallel. This approach allows for increased diagnostic yield in monogenic disorders and defining of more detailed genoptype-phenotype correlations. In addition, whole-exome or whole-genome sequencing has led to the identification of the genetic basis of many known genetic disorders and to the identification and delineation of novel disorders thus allowing a diagnosis in more patients. Fulfilling the potential of the increasing number of options for genetic testing for accurate diagnosis requires close collaboration between clinical geneticists and paediatricians. PMID- 24168796 TI - [Screening and development of the child]. PMID- 24168797 TI - [Developmental disorders in preschool children: an interdisciplinary approach]. AB - Many children show developmental abnormalities in the first years of life. Thus, the primary care physician should know the procedures of developmental surveillance and screening and be informed about the further steps in the evaluation of children with developmental disorders. This article presents current developmental screening methods in primary care, defines the terminology of developmental disorders in young children, demonstrates the essential diagnostic procedures in developmentally impaired children and describes the interdisciplinary collaboration between physicians, psychologists, therapists and special needs educators. PMID- 24168798 TI - [Follow up care of the preterm infant]. AB - The birthrate of preterm infants in Switzerland has remained stable over the last few years with 7.3 % of all live births in 2011. Although outcome and survival have significantly improved in the last decades, morbidity and mortality of preterm infants are still challenging the health care system. Important sequelae especially of extreme preterm birth are bronchopulmonary dysplasia (BPD), impaired growth and neurodevelopmental delay. Respiratory problems following discharge are more common among preterm infants and include an increased risk of cough, wheeze and airway hyperresponsiveness leading to a higher re hospitalization rate in the first year of life compared to term infants. Routine vaccinations should be administered according to the chronological age. For very preterm infants an accelerated vaccination schedule is recommended. Respiratory Syncytial-Virus (RSV) immunoglobulin is available for infants with moderate and severe BPD. Growth and neurodevelopment of preterm infants should be closely monitored. In the first 24 months of life, interpretation of the findings should take the preterm birth into account and gestational age should be corrected accordingly. Preterm infants are at risk for neurodevelopmental impairment including vision and hearing. Early detection of neurodevelopmental problems and implementation of appropriate interventions can improve outcome. PMID- 24168800 TI - [Fever without a localizing source in infants]. AB - In this chapter we will give an overview over the most frequent etiologies of fever in infants in Switzerland, propose an algorithm to evaluate this children, and we will end up with a discussion on the value of additional laboratory parameters. Fever in infants and small children is a leading cause for parents to seek medical attention. The vast majority has a self limiting viral infection, but all the same, all infants need to be thoroughly evaluated. After this process, the treating physician has to decide, which child needs to be specifically treated or cared for, either to avoid overtreatment nor overlooking a serious infection. Because of a broader immunization coverage against bacterial infections, the epidemiology of invasive bacterial disease is changing. Additional laboratory work up is sometimes necessary, but has it's limitations. The interpretation of lab values must taken into account the changing prevalence of serious bacterial infections. Newer parameters (e. g. Procalcitonin) are upcoming, of which the importance is still debatable. Fever causes in this age other than infectious diseases will be alluded. PMID- 24168799 TI - [Pediatric emergencies -- the essential, briefly, for general practitioners]. AB - For general practitioners, emergency assessment of a critically ill or injured child can be difficult, as history is usually given by caregivers, physical examination may be challenging due to lack of cooperation and vital signs are potentially difficult to interpret because of age-related variations. The Pediatric Assessment Triangle (PAT) is a rapid and simple observational tool to standardize the initial assessment of children regardless of complaint or underlying diagnosis. It only uses visual and auditory clues, requires no equipment, and takes only seconds to perform. It allows clinicians to assess whether an urgent intervention is necessary or whether a more detailed history and physical examination may be done. Respiratory distress, gastro-enteritis with dehydration, febrile convulsions and traumatic brain injury constitute four common pediatric complaints that are encountered in a general practitioners consultation and will be discussed in some detail. PMID- 24168801 TI - [Obstructive air way disease in infants and children]. AB - Obstruktive airway disease in children are a heterogeneous entity of different age specific phenotypes. In infants and preschoolers, episodically occurring viral induced wheezing episodes are frequent and often transient. Approximately 10 % of children, however, develop a more chronic form of obstructive airway symptoms, often triggered by multiple factors such as viruses, pollutants and/or aeroallergens. The latter form, commonly referred as bronchial asthma, requires a different therapeutic approach using combined therapy with a preventive anti inflammatory therapy as well as additional bronchodilator therapy. Whereas purely viral induced forms of wheezing disorders require only bronchodilator therapy on demand. The current review provides strategies to clinically identify these various phenotypes and describes phenotype specific treatment recommendations based on national and international guidelines. PMID- 24168802 TI - [Failure to thrive in childhood]. AB - Failure to thrive is a state of malnutrition in a child due to inadequate caloric intake, inadequate caloric absorption, or excessive caloric expenditure. This all can lead to underweight and retarded growing, but also to a possible impairment of the immune system, as well as an impairment of the psychomotoric and cognitive development of a child. The aim of this article is to offer sound knowledge to the practising physician about definition, prevalence, etiology, diagnostic evaluation and therapy of failure to thrive. PMID- 24168803 TI - [The range of adolescent medicine]. AB - Adolescent medicine is situated "in between" and "on the borders of" different areas of medical specialisations: psychiatry, gynaecology, preventive medicine, paediatrics and internal medicine (and their respective subspecialties).The specificity of adolescent medicine is the evaluation of clinical situations with a particular consideration of the successive stages of the adolescent bio-psycho social development (puberty, identity construction, modifications of the relations to the peer-groups and the family). A special interest goes also to preventive aspects, especially concerning experimental and risk behaviours. The medical approach to adolescents requires a particular attention to psychosocial aspects when confronted with somatic complaints and inversely a good somatic evaluation in front of adolescents suffering from complexes psychosocial situations. PMID- 24168804 TI - [Options and limits in the treatment of overweight children and adolescents and their families in primary care]. AB - The general practitioner or pediatrician mostly is the first point of contact for overweight children and may recognize adiposity early enough in order to start therapy of obesity or comorbidity or to initiate measures of prevention. Interventions against overweight are most efficient before age 7 in terms of short-and long-term results and should not be delayed. As obesity requires care of the entire family, close or recurring contact with the overweight child and its family is important as well as the treatment nearby their residence. In preschoolers, targeting parents exclusively for obesity therapy is highly effective. Changing cherished habits and style of education is the biggest challenge to parents. Therefore, various techniques of treatment of alcohol or tobacco addiction can be used and recommendations for improvement of self-worth as well as healthy eating behavior and exercise are presented. First feasible objectives include modest lifestyle changes and reduction of comorbidities; if an extreme obesity with a BMI above 99.5th percentile or mental disorders are present or if it becomes apparent within the first 6 months that the patient cannot achieve his own goals for changes in lifestyle and body weight, a referral to a specialized center is indicated. There, a multi-professional treatment of the child and his family is performed in common by specialists for nutrition, exercise and psychology. Childhood obesity is a chronic disease that requires a very long-term treatment and usually persists into adulthood. PMID- 24168805 TI - A phase II study of pemetrexed in chemotherapy-naive elderly patients aged >= 75 years with advanced non-squamous non-small-cell lung cancer (HANSHIN Oncology Group 003). AB - OBJECTIVE: Pemetrexed has relatively mild toxicity and possibly can be administered long term to patients with non-small-cell lung cancer. We conducted a Phase II trial to evaluate the efficacy and safety of pemetrexed in chemotherapy-naive elderly patients with advanced non-squamous non-small-cell lung cancer. METHODS: In this multicenter Phase II trial, we recruited elderly patients with non-squamous non-small-cell lung cancer. Patients with previously untreated Stage IIIB or IV non-squamous non-small-cell lung cancer, >=75 years, Eastern Cooperative Oncology Group performance status 0-1 and adequate organ functions were eligible. Patients received pemetrexed (500 mg/m(2)) intravenously on Day 1 every 3 weeks until disease progression. The primary endpoint was objective response rate. RESULTS: Forty-seven patients were enrolled from August 2009 to July 2011, and 46 patients were eligible. The median age was 79 years (range 75-91 years), 57% were males, 37% had never smoked, 87% had adenocarcinoma, 74% had Stage IV and 33% had epidermal growth factor receptor tyrosine kinase-activating mutation. The median number of cycles was 4 (1-20). The objective response rate was 13.3% (95% confidence interval; 5.1-26.8%), the disease control rate was 66.7% (95% confidence interval 51.0-80.0%), the median progression-free survival was 4.9 months (95% confidence interval 3.0-6.1 months) and the median overall survival was 18.2 months (95% confidence interval 13.2 23.5 months). One Grade 5 infection (pneumonia) was observed. CONCLUSIONS: This study did not meet the primary endpoint. Pemetrexed monotherapy is not recommended in chemotherapy-naive elderly patients aged >=75 years with advanced non-squamous non-small-cell lung cancer. PMID- 24168806 TI - The primary extra-gastrointestinal stromal tumor of pleura: a case report and a literature review. AB - The gastrointestinal stromal tumor is the most common mesenchymal neoplasm of the gastrointestinal tract. The gastrointestinal stromal tumor universally expresses KIT and DOG-1 and frequently harbors oncogenic mutations in the KIT gene. While the gastrointestinal stromal tumor usually arises in the alimentary tract, it is rarely found in the extragastrointestinal area. When it is, it is called an extragastrointestinal stromal tumor. Although the pathogenesis, prognostic factors and outcomes of gastrointestinal stromal tumors are well known, those of extragastrointestinal stromal tumors have not been fully studied. We report, herein, a unique primary extragastrointestinal stromal tumor from the pleura in a 73-year-old woman who presented with pleural mass. The extragastrointestinal stromal tumor was surgically resected and confirmed by means of an immunohistochemical study and a molecular analysis. PMID- 24168807 TI - Efficacy and safety of selegiline transdermal system (STS) for the atypical subtype of major depressive disorder: pooled analysis of 5 short-term, placebo controlled trials. AB - OBJECTIVE: The objective of the present study is to investigate the efficacy and safety of the selegiline transdermal system (STS) in major depressive disorder (MDD) with atypical features. METHODS: This was a post-hoc analysis of 5 short term trials. The atypical subtype was defined as the presence of at least 1 item with a score of 2 or greater from items 22-26 on the 28-item Hamilton Depression Rating Scale (HAMD-28), and a maximum score of 1 point for items 6 (insomnia late), 12 (somatic symptoms, gastrointestinal), and 16 (loss of weight) to exclude vegetative features of melancholic depression. The mean changes of HAMD 28 total score from baseline to the endpoint (response rate defined as >=50% reduction in HAMD-28 scores and remission rate defined as <=10 HAMD-28 total score at the treatment endpoint) were compared between atypical and nonatypical groups. RESULTS: In this analysis, 352 subjects (STS = 168 vs placebo = 184) met the definition of atypical subtype at baseline. STS (n = 641) significantly decreased HAMD-28 total score compared with placebo (n = 648) from beginning to end of treatment (-10.7 +/- 9.3 vs -9.4 +/- 9.3; p = 0.014). STS showed comparable efficacy in patients with the atypical subtype compared with the nonatypical subtype for placebo-subtracted mean change in HAMD-28 total score ( 2.11 +/- 1.01 vs. -1.0 +/- 0.60; p = 0.34), odds ratio (OR) for response (1.41 vs 1.23, p = 0.62), and OR for remission (1.77 vs 1.18, p = 0.22). CONCLUSION: STS appears to be comparably efficacious and tolerable in atypical and nonatypical subtypes of MDD. Adequately powered, controlled, clinical trials are necessary to confirm our findings. PMID- 24168808 TI - Outcome and quality of life in patients with postoperative delirium during an ICU stay following major surgery. AB - INTRODUCTION: Delirium is an acute disturbance of consciousness and cognition that has been shown to be associated with poor outcomes, including increased mortality. We aimed to evaluate outcome after postoperative delirium in a cohort of surgical intensive care unit (SICU) patients. METHODS: This prospective study was conducted over a 10-month period in a SICU. Postoperative delirium was diagnosed in accordance with the Intensive Care Delirium Screening Checklist (ICDSC). The primary outcome was mortality at 6-month follow-up. Hospital mortality and becoming dependent were considered as secondary outcomes, on the basis of the evaluation of the patient's ability to undertake both personal and instrumental activities of daily living (ADL) before surgery and 6 months after discharge from the SICU. For each dichotomous outcome - hospital mortality, mortality at 6-month follow-up, and becoming dependent - a separate multiple logistic regression analysis was performed, which included delirium as an independent variable. Another outcome analyzed was changes in health-related quality of life, as determined using short-form 36 (SF-36), which was administered before and 6 months after discharge from the SICU. Additionally, for each SF-36 domain, a separate multiple linear regression model was used for each SF-36 domain, with changes in the SF-36 domain as a dependent variable and delirium as an independent variable. RESULTS: Of 775 SICU-admitted adults, 562 were enrolled in the study, of which 89 (16%) experienced postoperative delirium. Delirium was an independent risk factor for mortality at the 6-month follow-up (OR = 2.562, P <0.001) and also for hospital mortality (OR = 2.673, P <0.001). Delirium was also an independent risk factor for becoming dependent for personal ADL (P-ADL) after SICU discharge (OR = 2.188, P <0.046). Moreover, patients who experienced postoperative delirium showed a greater decline in SF-36 domains after discharge, particularly in physical function, vitality, and social function, as compared to patients without postoperative delirium. CONCLUSIONS: Postoperative delirium was an independent risk factor for 6-month follow-up mortality, hospital mortality, and becoming independent in P-ADL after SICU discharge. It was also significantly associated with a worsening in the quality of life after surgery. PMID- 24168809 TI - Semi-automatic segmentation of subcutaneous tumours from micro-computed tomography images. AB - This paper outlines the first attempt to segment the boundary of preclinical subcutaneous tumours, which are frequently used in cancer research, from micro computed tomography (microCT) image data. MicroCT images provide low tissue contrast, and the tumour-to-muscle interface is hard to determine, however faint features exist which enable the boundary to be located. These are used as the basis of our semi-automatic segmentation algorithm. Local phase feature detection is used to highlight the faint boundary features, and a level set-based active contour is used to generate smooth contours that fit the sparse boundary features. The algorithm is validated against manually drawn contours and micro positron emission tomography (microPET) images. When compared against manual expert segmentations, it was consistently able to segment at least 70% of the tumour region (n = 39) in both easy and difficult cases, and over a broad range of tumour volumes. When compared against tumour microPET data, it was able to capture over 80% of the functional microPET volume. Based on these results, we demonstrate the feasibility of subcutaneous tumour segmentation from microCT image data without the assistance of exogenous contrast agents. Our approach is a proof-of-concept that can be used as the foundation for further research, and to facilitate this, the code is open-source and available from www.setuvo.com. PMID- 24168810 TI - Speciation of the products of and establishing the role of water in the reaction of TNT with hydroxide and amines: structure, kinetics, and computational results. AB - The reaction of trinitrotoluene (TNT) with bases has been investigated by NMR and visible spectroscopy methods. Hydroxide ion was found to react in one of two ways, either by deprotonation of the methyl group or by nucleophilic attack on the aromatic ring to form a sigma adduct. The rate of each mode of reaction depends upon the polarity of the solvent. In tetrahydrofuran (THF), sigma adduct formation is rapid and the long-term equilibrium product is deprotonation of the methyl group. When the solvent is methanol (MeOH), the two reactions have similar rates and the sigma adduct becomes the majority product. Amines were found to be ineffective in directly deprotonating TNT or in forming sigma adducts. Rather, the amines react with ambient water to generate hydroxide ion, which then reacts with TNT. The solvent choice and water content are crucial to understanding the reactivity of bases with TNT. To assist in the interpretation of the experimental results, computational analysis was performed at the B3LYP/6-311+G**//HF/6 311+G** level to determine the thermodynamics of the reactions of TNT. The SM8 implicit solvation model was applied to converged geometries and suggested a strong solvation effect upon product formation. Thermodynamic analysis suggested a significant preference of alkoxide or hydroxide attack versus amine attack in any modeled dielectric, consistent with the experimental observations. PMID- 24168811 TI - Do assortative preferences contribute to assortative mating for adiposity? AB - Assortative mating for adiposity, whereby levels of adiposity in romantic partners tend to be positively correlated, has implications for population health due to the combined effects of partners' levels of adiposity on fertility and/or offspring health. Although assortative preferences for cues of adiposity, whereby leaner people are inherently more attracted to leaner individuals, have been proposed as a factor in assortative mating for adiposity, there have been no direct tests of this issue. Because of this, and because of recent work suggesting that facial cues of adiposity convey information about others' health that may be particularly important for mate preferences, we tested the contribution of assortative preferences for facial cues of adiposity to assortative mating for adiposity (assessed from body mass index, BMI) in a sample of romantic couples. Romantic partners' BMIs were positively correlated and this correlation was not due to the effects of age or relationship duration. However, although men and women with leaner partners showed stronger preferences for cues of low levels of adiposity, controlling for these preferences did not weaken the correlation between partners' BMIs. Indeed, own BMI and preferences were uncorrelated. These results suggest that assortative preferences for facial cues of adiposity contribute little (if at all) to assortative mating for adiposity. PMID- 24168812 TI - The effects of lumbo-pelvic postural taping on gait parameters in patients with lumbar spinal stenosis. AB - BACKGROUND: Altered gait patterns with lumbar-flexed posture threaten the quality of life in patients with lumbar spinal stenosis; however, few studies have developed management strategies to improve gait patterns and lumbo-pelvic posture. The present study investigated the effects of lumbo-pelvic postural taping on pelvic tilt, spatiotemporal gait parameters, and pain during walking in patients with lumbar spinal stenosis. METHODS: The pelvic tilt and gait parameters were assessed in 20 patients with lumbar spinal stenosis before sustained walking using a palpation meter and GAITRite system, respectively. Next, the participants were asked to walk on the ground for 20 min or until they complained of symptoms of neurogenic claudication. Pelvic tilt and gait parameters were measured immediately after the manifestation of neurogenic claudication followed by the application of lumbo-pelvic postural taping. The participants rated the pain intensity using a visual analog scale. Changes in dependent variables among the conditions were analyzed using a one-way repeated measures analysis of variance. FINDINGS: The results show a decreased pelvic anterior tilt, walking velocity, and step and stride lengths, as well as an increased base of support and pain after severe symptoms of neurogenic claudication (P<0.05). However, a greater pelvic anterior tilt, faster walking velocity with a longer step and stride length, and decreased base of support and pain were found after the application of postural taping (P<=0.001). INTERPRETATION: These findings suggest that lumbo-pelvic postural taping can provide beneficial management for improving gait patterns and lumbo-pelvic posture in patients with lumbar spinal stenosis. PMID- 24168813 TI - Antibodies attacking the brain: Is it time for a paradigm shift in psychiatric practice and service models? PMID- 24168814 TI - The autism spectrum disorder 'epidemic': Need for biopsychosocial formulation. PMID- 24168815 TI - Evaluation of the prevalence of severe hyperhomocysteinemia in adult patients with thrombosis who underwent screening for thrombophilia. AB - INTRODUCTION: Treatment with B-vitamins and betaine reduces the high risk of thrombosis in patients with homocystinuria, a metabolic syndrome that is characterized by severe hyperhomocysteinemia (HHcy). In contrast, there is no clear demonstration that B-vitamins reduce the risk of thrombosis in patients with mild HHcy: for this reason, many question the clinical utility of measuring total Hcy (tHcy) in patients with thrombosis. However, thrombosis may be the first clinical manifestation of homocystinuria in patients reaching adulthood without signs and symptoms of the syndrome. AIM: 1) to measure the prevalence of severe, previously undiagnosed, HHcy among patients with thrombosis 2) to profile these patients on the basis of their characteristics. METHODS: Six Italian Thrombosis Centers completed a first questionnaire, reporting tHcy levels in patients with thrombosis who underwent thrombophilia screening, and a second questionnaire, reporting the characteristics of patients with severe HHcy (tHcy>100MUmol/L). RESULTS: Of 19,678 cross-sectionally collected patients with thrombosis who underwent thrombophilia screening in the last 12.5years (median value, range 6-17), 38 had severe HHcy (0.2%). Their median age at diagnosis was 47years (range 19-83) and the median level of tHcy was 130MUmol/L (range 101 262). Venous thromboembolism (71%) was more frequent than arterial thromboembolism (26%); recurrent thrombosis occurred in 42% of cases. CONCLUSIONS: Measurement of tHcy in adult patients with thrombosis may reveal the presence of severe HHcy. Since treatment of patients with severe HHcy decreases the risk of thrombosis, measurement of tHcy in patients with thrombosis may prove clinically useful. PMID- 24168816 TI - [Foreign body aspiration. An occasional finding in patients with dementia?]. PMID- 24168817 TI - Abdominal ultrasound and medical education. AB - INTRODUCTION: Ultrasound is a very versatile diagnostic modality that permits real-time visualization of multiple internal organs. It is of invaluable help for the physical examination of the patients. AIM: To assess if ultrasound can be incorporated into medical education and if the students can perform a basic abdominal ultrasound examination without the necessity of a long period of training. METHODOLOGY: Twelve medical students were trained in basic abdominal ultrasound during a 15-h training program including a 5-h theoretical and practical course and supervised practice in 20 selected patients. Subsequently, we conducted an evaluation test that assessed the ability of students to obtain the ultrasound views and to detect various pathologies in five different patients. RESULTS: The students were able to correctly identify the abdominal views more than 90% of the times. This percentage was only lower (80%) in the right subcostal view to locate the gallbladder. The accuracy or global efficiency of the ultrasound for the diagnosis of relevant pathological findings of the patients was greater than 90% (91.1% gallstones, abdominal aortic aneurysm 100%; splenomegaly 98.3%, ascites 100%; dilated inferior vena cava 100%; acute urinary retention 100%). CONCLUSION: The ultrasound may be a feasible learning tool in medical education. Ultrasound can help students to improve the physical examination. PMID- 24168818 TI - Reliability of a modified motor unit number index (MUNIX) technique. AB - INTRODUCTION: The purpose of this study was to examine the relative and absolute between-day reliability of the motor unit number index (MUNIX). METHODS: Young, healthy adults (n=19) attended two testing sessions separated by 4-weeks where their maximal pinch-grip strength, MUNIX, and motor unit size index (MUSIX) were assessed in the abductor pollicis brevis muscle. Reliability was assessed by intraclass correlation coefficients (ICC), coefficient of variation (CV) and limits of agreement (LOA). RESULTS: No mean differences were observed for MUNIX or MUSIX. The CV for the MUNIX and MUSIX measures were between 13.5% and 17.5%. The ICC for both measures were moderate to moderately-high (0.73-0.76), The LOA for both indicated a homoscedastic relationship. DISCUSSION: Our findings indicate moderate to moderately-high reliability for both MUNIX and MUSIX. Future work is needed to ensure both measures are reliable in other muscles and cohorts, and further investigations are required to examine the validity of MUNIX. PMID- 24168820 TI - Design and evaluation of a simulation for pediatric dentistry in virtual worlds. AB - BACKGROUND: Three-dimensional virtual worlds are becoming very popular among educators in the medical field. Virtual clinics and patients are already used for case study and role play in both undergraduate and continuing education levels. Dental education can also take advantage of the virtual world's pedagogical features in order to give students the opportunity to interact with virtual patients (VPs) and practice in treatment planning. OBJECTIVE: The objective of this study was to design and evaluate a virtual patient as a supplemental teaching tool for pediatric dentistry. METHODS: A child VP, called Erietta, was created by utilizing the programming and building tools that online virtual worlds offer. The case is about an eight-year old girl visiting the dentist with her mother for the first time. Communication techniques such as Tell-Show-Do and parents' interference management were the basic elements of the educational scenario on which the VP was based. An evaluation of the simulation was made by 103 dental students in their fourth year of study. Two groups were formed: an experimental group which was exposed to the simulation (n=52) and a control group which did not receive the simulation (n=51). At the end, both groups were asked to complete a knowledge questionnaire and the results were compared. RESULTS: A statistically significant difference between the two groups was found by applying a t test for independent samples (P<.001), showing a positive learning effect from the VP. The majority of the participants evaluated the aspects of the simulation very positively while 69% (36/52) of the simulation group expressed their preference for using this module as an additional teaching tool. CONCLUSIONS: This study demonstrated that a pediatric dentistry VP built in a virtual world offers significant learning potential when used as a supplement to the traditional teaching techniques. PMID- 24168821 TI - Herd- and sow-related risk factors for lameness in organic and conventional sow herds. AB - Lameness in sows is an animal welfare problem which also presents an economic challenge to pig producers. Information about the prevalence of herd lameness in organic sows is relatively scarce. The first objective of this study was to establish the prevalence of lameness and to identify risk factors associated with sow lameness in Danish outdoor organic sow herds by analysing the association between risk factors at both sow and herd level using clinical records of lameness. A total of 1850 sows from nine organic herds were included in the study. Second, the study examined differences in the prevalence of sow lameness between outdoor organic and indoor conventional herds. An additional aim here was to identify risk factors associated with clinical records of sow lameness in Danish sow herds by analysing the association between risk factors with lameness at sow and herd level. One thousand and fifty four gestation sows from 44 indoor conventional and nine organic sow herds were included in this study. The nine organic herds were visited twice: once in summer/autumn 2011, and once in winter/spring 2012. In winter/spring 2011, a total of 44 indoor conventional herds were visited. Risk factors included in the study were clinical parameters and factors related to the production system. Sows were examined visually by one of four trained observers. The organic sows were assigned scores for lameness, body condition, hoof length, bursitis, abscesses and leg wounds, while the conventional sows were assigned scores for lameness, body condition and bursitis. A multivariable analysis was carried out by logistic regression with the herd and observer as random effects. The average herd lameness prevalence in gestation and lactation sows in organic herds was 11% in summer/autumn and 4.6% in winter/spring. 'Wounds, bursitis and abscess' on legs (OR=4.7, P<0.001) and body condition score >3 (OR=1.79, P=0.008) were associated with increased risk of lameness in Danish organic sow herds. Season (winter/spring v. summer/autumn) lowered the risk of lameness (OR=0.37, P<0.001). Average prevalence of lameness in gestation sow herds in winter/spring in conventional herds was 24.4%, and in organic herds it was 5.4%. An organic sow had a decreased risk of lameness (OR=0.28, P<0.001) as compared with a conventional sow. Bursitis was associated with increased risk of lameness (OR=2.08, P=0.002) regardless of the production system (i.e. whether the herd was organic or conventional). PMID- 24168822 TI - Bench-scale experiments for the development of a unified loop-mediated isothermal amplification (LAMP) assay for the in vitro diagnosis of Leishmania species' promastigotes. AB - We developed, in bench-scale experiments, a unified loop-mediated isothermal amplification (LAMP) assay for the detection of cutaneous, mucocutaneous and visceral leishmaniasis using DNA of cultivated promastigotes. Two primer sets for the LAMP assay were designed based on the 18S rRNA gene, and their sensitivity and specificity were tested and compared. Both of them were specific for Leishmania as the DNA of all ten Leishmania species tested was amplified, whereas the DNA of other parasites, including that of Trypanosoma, was not. The detection limit for primer set 1 ranged between 30 pg and 3.6 fg, depending on which Leishmania species tested. Primer set 2 showed high sensitivity, but was less sensitive than primer set 1. Our findings lead to the conclusion that the LAMP assay with primer set 1 is a promising and effective assay for the successful detection of a wide range of Leishmania infections using only a unified multiplex LAMP test. PMID- 24168823 TI - [Bardet-Biedl syndrome: diagnostic usefulness of exome sequencing]. PMID- 24168824 TI - [Rapunzel syndrome: laparoscopic treatment]. PMID- 24168825 TI - Cognitive control processes in paranoia: the impact of threat induction on strategic cognition and self-focused attention. AB - BACKGROUND: Current clinical models emphasize certain cognitive processes in the maintenance of distressing paranoia. While a number of these processes have been examined in detail, the role of strategic cognition and self-focused attention remain under-researched. AIMS: This study examined the deployment of cognitive strategies and self-focused attention in people with non-clinical paranoia. METHOD: An experimental design was used to examine the impact of a threat activation task on these processes, in participants with high and low non clinical paranoia. Twenty-eight people were recruited to each group, and completed measures of anxiety, paranoid cognition, strategic cognition and self focused attention. RESULTS: The threat activation task was effective in increasing anxiety in people with high and low non-clinical paranoia. The high paranoia group experienced more paranoid cognitions following threat activation. This group also reported greater use of thought suppression, punishment and worry, and less use of social control strategies when under threat. No differences were found between the groups on measures of self-focused attention. CONCLUSIONS: This study shows that the threat activation task increased anxiety in people with high non-clinical paranoia, leading to increased paranoid thinking. The use of strategic cognition following threat activation varied dependent on level of non-clinical paranoia. If these differences are replicated in clinical groups, the strategies may be implicated in the maintenance of distressing psychosis, and may therefore be a valuable target for therapeutic intervention. PMID- 24168827 TI - Parallel distribution of sexes within left and right uterine horns in Holstein dairy cows: evidence that the effect of side of pregnancy on sex ratio could be breed-specific in cattle. AB - Dissimilar distribution of male and female calves within left and right uterine horns has been observed in beef cows. A retrospective study was conducted to investigate the effect of side of pregnancy on secondary sex ratio in Holstein dairy cows. Data associated with sex of calves, side of pregnancy, sire, dam, parity number of dam, AI technician, season and year were retrieved from the database of a Holstein dairy farm. In total, data consisted of 6515 birth records from 3155 dams and 244 sires across years 2001-2010. Data were analyzed using logistic regression. There was no difference in proportion of male and female calves between left (52.9% and 47.1%, respectively) and right (53.2% and 46.8%, respectively) uterine horns (P>0.05). AI technician, year, season and parity of dam did not affect secondary sex ratio (P>0.05). Secondary sex ratio of left and right uterine horns, and consequently, overall secondary sex ratio (53.1%) were skewed toward males as compared with hypothetical secondary sex ratio of 50% (P<0.05). Incidence of right pregnancy (60.5%) was higher than hypothetical 50% incidence of right pregnancy. In conclusion, the present study revealed similar secondary sex ratio of calves between left and right uterine horns in Holstein dairy cows. PMID- 24168826 TI - Death after percutaneous dilatational tracheostomy: a systematic review and analysis of risk factors. AB - INTRODUCTION: Since the introduction and widespread acceptance of percutaneous techniques in the intensive care unit (ICU) setting, the number of critically ill patients undergoing tracheostomy has steadily increased. However, this procedure can be associated with major complications, including death. The purpose of this study is to estimate the incidence and analyze the causes of lethal complications due to percutaneous dilatational tracheostomy (PDT). METHODS: We analyzed cases of lethal outcome due to complications from PDT including cases published between 1985 and April 2013. A systematic literature search was performed and unpublished cases from our own departmental records were retrospectively analyzed. RESULTS: A total of 71 cases of lethal outcome following PDT were identified including 68 published cases and 3 of our own patients. The incidence of lethal complications was calculated to be 0.17%. Of the fatal complications, 31.0% occurred during the procedure and 49.3% within seven days of the procedure. The main causes of death were: hemorrhage (38.0%), airway complications (29.6%), tracheal perforation (15.5%), and pneumothorax (5.6%). We found specific risk factors for complications in 73.2% of patients, 25.4% of patients had more than one risk factor. Bronchoscopic guidance was used in only 46.5% of cases. CONCLUSIONS: According to this analysis, PDT-related death occurs in 1 out of 600 patients receiving a PDT. Careful patient selection, bronchoscopic guidance, and securing the tracheal cannula with sutures are likely to reduce complication rates. PMID- 24168828 TI - Comments on 'conservative management of diabetic foot osteomyelitis'. PMID- 24168829 TI - The influence of sex and age on the relationship between sleep duration and metabolic syndrome in Korean adults. AB - AIMS: To investigate the influence of sex and age on the relationship between sleep duration and metabolic syndrome in a nationally representative population. METHODS: We used data from the Korea National Health and Nutrition Examination Survey (2001-2010) and enrolled 24,511 participants aged 20-79 years. Sleep duration was categorized into five groups: <=5, 6, 7 (referent), 8, and >=9h/day. Age was categorized into three groups: younger (20-39y), middle-aged (40-59y), and older (60-79y). The association between sleep duration and metabolic syndrome was assessed in the total, separately in men and women, then in six groups based on sex and age. RESULTS: The prevalence of metabolic syndrome by sleep category demonstrated a U-shaped pattern in the total population. However, after adjusting for age, education, occupation, exercise, smoking, alcohol, and body mass index, the prevalence of metabolic syndrome increased in long sleepers (OR 1.31; 95% CI 1.14-1.51) but not in short sleepers (OR 1.00; 95% CI 0.89-1.11). The relationship between sleep duration and metabolic syndrome varied by sex and age long sleep (>=9h/day) was positively associated with metabolic syndrome only in younger (OR 2.13; 95% CI 1.38-3.28) and middle-aged (OR 1.63; 95% CI 1.21-2.21) women. Short sleep (<=5h/day) was not associated with metabolic syndrome in any sex and age groups. However, extremely short sleep (<=4h/day) was associated with metabolic syndrome in middle-aged men (OR 1.76, 95% CI 1.05-2.96). CONCLUSION: These data suggest that sex and age significantly modify the relationship between sleep duration and metabolic syndrome. PMID- 24168830 TI - Lack of transparency regarding collaboration with industry. PMID- 24168831 TI - Mycobacterial bone marrow infections at a medical centre in Taiwan, 2001-2009. AB - Mycobacterial bone marrow (BM) infection is the most common diagnosis established by BM examinations for fever of unknown origin. In this study, clinical features and outcomes of patients who fulfilled the criteria for BM infection due to Mycobacterium tuberculosis (MTB) and non-tuberculous mycobacteria (NTM) at a medical centre in Taiwan from 2001 to 2009 were investigated. The BM histopathological findings were also analysed. A total of 24 patients (16 men, eight women) with mycobacterial BM infections were found. Of these, nine (38%) were positive for human immunodeficiency virus (HIV) and six (25%) had no pre existing immunocompromised conditions. MTB isolates were obtained from 11 (46%) patients and NTM species were isolated from 10 (42%) patients, including M. avium complex (MAC, n = 7) and M. kansasii (n = 3). Patients with MTB infections were significantly older than those with NTM infections (60.5 vs. 47.7 years, P = 0.043) and were less likely to have a positive BM culture (45% vs. 100%, P = 0.012). The 90-day survival rates for MTB and NTM BM infections were 68% and 60%, respectively (P = 0.61). In addition, the presence of BM granulomas was significantly more common in patients with MTB BM infections than in those with NTM infections (82% vs. 30%, P = 0.030). In Taiwan, the importance of NTM was not inferior to MTB and besides MAC, M. kansasii might be an important pathogen in non-HIV-infected patients. The presence of BM granulomas and caseation provides valuable information regarding early treatment pending culture results. PMID- 24168832 TI - Towards improved hardware component attenuation correction in PET/MR hybrid imaging. AB - In positron emission tomography/computed tomography (PET/CT) hybrid imaging attenuation correction (AC) of the patient tissue and patient table is performed by converting the CT-based Hounsfield units (HU) to linear attenuation coefficients (LAC) of PET. When applied to the new field of hardware component AC in PET/magnetic resonance (MR) hybrid imaging, this conversion method may result in local overcorrection of PET activity values. The aim of this study thus was to optimize the conversion parameters for CT-based AC of hardware components in PET/MR. Systematic evaluation and optimization of the HU to LAC conversion parameters has been performed for the hardware component attenuation map (u-map) of a flexible radiofrequency (RF) coil used in PET/MR imaging. Furthermore, spatial misregistration of this RF coil to its u-map was simulated by shifting the u-map in different directions and the effect on PET quantification was evaluated. Measurements of a PET NEMA standard emission phantom were performed on an integrated hybrid PET/MR system. Various CT parameters were used to calculate different u-maps for the flexible RF coil and to evaluate the impact on the PET activity concentration. A 511 keV transmission scan of the local RF coil was used as standard of reference to adapt the slope of the conversion from HUs to LACs at 511 keV. The average underestimation of the PET activity concentration due to the non-attenuation corrected RF coil in place was calculated to be 5.0% in the overall phantom. When considering attenuation only in the upper volume of the phantom, the average difference to the reference scan without RF coil is 11.0%. When the PET/CT conversion is applied, an average overestimation of 3.1% (without extended CT scale) and 4.2% (with extended CT scale) is observed in the top volume of the NEMA phantom. Using the adapted conversion resulting from this study, the deviation in the top volume of the phantom is reduced to -0.5% and shows the lowest standard deviation inside the phantom in comparison to all other conversions. Simulation of a u-map misregistration shows acceptable results for shifts below 5 mm for the flexible surface RF coil. The adapted conversion from HUs to LAC at 511 keV within this study can improve hardware component AC in PET/MR hybrid imaging as shown for a flexible RF surface coil. Furthermore, these results have a direct impact on the improvement of the hardware component AC of the examined flexible RF coil in conjunction with position determination. PMID- 24168834 TI - The use of stoned olive cake and rolled linseed in the diet of intensively reared lambs: effect on the intramuscular fatty-acid composition. AB - The aim of the present study was to evaluate the effect of the inclusion of stoned olive cake and rolled linseed in a concentrate-based diet for lambs on the fatty-acid composition of polar and non-polar intramuscular lipids of the longissimus dorsi muscle. To achieve this objective, 32 Appenninica lambs were randomly distributed into four groups of eight lambs each and were fed conventional cereal-based concentrates (diet C); concentrates containing 20% on a dry matter (DM) basis of rolled linseed (diet L); concentrates containing 35% DM of stoned olive cake (diet OC); and concentrates containing both rolled linseed (10% DM) and stoned olive cake (17% DM; diet OCL). The concentrates were administered together with grass hay at a 20:80 forage:concentrate ratio. Growing performances and carcass traits were evaluated. The fatty-acid composition was analysed in the total intramuscular lipids, as well as in the polar and neutral lipids. The average feed intake and the growth performance of lambs were not affected by the dietary treatments, as a consequence of similar nutritional characteristics of the diets. The inclusion of rolled linseed in the L and OCL diets increased the content of C18:3 n-3 in intramuscular total lipids, which was threefold higher in meat from the L lambs and more than twofold higher in meat from the OCL lambs compared with the C and OC treatments. The n-6:n-3 ratio significantly decreased in the meat from lambs in the L and OCL groups, reaching values below 3. The L treatment resulted in the highest level of trans-18:1 fatty acids in the muscle. Regardless of the dietary treatment, the t10-18:1 was the major isomer, representing 55%, 45%, 49% and 45% of total trans-18:1 for C, L, OC and OCL treatments, respectively. Neutral lipids from the OC-fed lambs contained the highest amount of c9-18:1 (more than 36% of total fatty acids); however, the content of c9-18:1 did not differ between the OC and C lambs, suggesting an intensive biohydrogenation of dietary c9-18:1 in the case of OC treatment. The highest content of c9,t11-18:2 was detected in the intramuscular fat from the L fed lambs, followed by the OCL treatment. A similar trend was observed in the neutral lipid fraction and, to a lower extent, in the polar lipids. PMID- 24168833 TI - A mutation of the Col2a1 gene (G1170S) alters the transgenic murine phenotype and cartilage matrix homeostasis. AB - BACKGROUND/PURPOSE: Genomic studies have revealed that there is a significant association between a point mutation of the human Col2A1 gene (G1170S) and several hip disorders. The purpose of the study was to explore the phenotype and altered cartilage matrix homeostasis of transgenic mice carrying this mutated Col2a1 gene. METHODS: Wild-type and transgenic mice were used as the control and study groups, respectively. Body weight measurement, radiographic analysis, and histological analysis of the mice were carried out to describe differences between the wild-type and transgenic mice at different ages. Cartilage metabolism studies were also carried out, including an MTT assay of cellular proliferation and nitric oxide and glycosaminoglycan assays. Allelic expression levels of the mutant A allele and the normal G allele were established by TaqMan assay. Cytokine and protease gene expression were measured. RESULTS: Transgenic mice had a lower mean body weight, a deformed skeletal structure, and abnormal cartilage histomorphology. Chondrocyte proliferation was significantly compromised and this was linked to significantly higher NO secretion and less soluble glycosaminoglycan formation. TNF-alpha and IL-1beta gene expression was significantly upregulated, while MMP-13 gene expression was significantly downregulated. CONCLUSION: The mutant G1170S Col2a1 gene in mice clearly alters the transgenic murine phenotype and cartilage matrix homeostasis. PMID- 24168835 TI - Using goal-directed design to create a novel system for improving chronic illness care. AB - BACKGROUND: A learning health system enables patients, clinicians, and researchers to work together to choose care based on the best evidence, drive discovery as a natural outgrowth of patient care, and ensure innovation, quality, safety, and value in health care; all in a more real-time fashion. OBJECTIVE: Our paper describes how goal-directed design (GDD) methods were employed to understand the context and goals of potential participants in such a system as part of a design process to translate the concept of a learning health system into a prototype collaborative chronic care network (C3N), specifically for pediatric inflammatory bowel disease. METHODS: Thirty-six one-on-one in-depth interviews and observations were conducted with patients (10/36, 28%), caregivers (10/36, 28%), physicians/researchers (10/36, 28%), and nurses (6/36, 17%) from a pediatric gastroenterology center participating in the ImproveCareNow network. GDD methods were used to determine the context and goals of participants. These same methods were used in conjunction with idealized design process techniques to help determine characteristics of a learning health system for this pediatric health care ecology. Research was conducted in a clinic and, in the case of some patients and caregivers, at home. RESULTS: Thematic analysis revealed 3 parent child dyad personas (ie, representations of interviewees' behavior patterns, goals, skills, attitudes, and contextual information) that represented adaptation to a chronic illness over time. These were used as part of a design process to generate scenarios (potential interactions between personas and the learning health system under design) from which system requirements were derived. These scenarios in turn helped guide generation, prioritization, design, measurement, and implementation of approximately 100 prototype interventions consistent with the aim of C3N becoming a learning health network. CONCLUSIONS: GDD methods help ensure human goals and contexts inform the design of a network of health care interventions which reflect the shape and purpose of a C3N in pediatric chronic illness care. Developing online and in-person interventions according to well documented context and motivations of participants increases the likelihood that a C3N will enable all participants to act in ways that achieve their goals with grace and dignity. GDD methods complemented quality-improvement methods to generate prototypes consistent with clinical and research aims, as well as the goals of patient disease management. PMID- 24168837 TI - Computer-based programmed instruction did not improve the knowledge retention of medication instructions of individuals with type 2 diabetes mellitus. AB - PURPOSE: The purpose of this study was to investigate whether computer-based programmed instruction (CPI) with a dynamic avatar (DA) improves retention of medication information better than text (controls) or better than CPI with text (T-CPI), CPI with voice (V-CPI), or CPI with static avatar with text (SA-CPI). METHODS: Participants with type 2 diabetes mellitus were enrolled in a randomized controlled trial comparing TDS with CPI in 4 conditions (T-CPI, V-CPI, SA-CPI, and DA-CPI). CPI sequentially delivers segmented information in text or voice followed by a multiple-choice question. Immediately after the user selects an option, CPI delivers elaborated feedback. Satisfaction was measured immediately after the interventions, and medication knowledge was measured at 2 weeks. RESULTS: One-hundred fifty individuals (30 per group) with a mean age 62 years (standard deviation [SD] 7.99 years) participated. There were no baseline differences in race, body mass index, education, and health literacy. Medication knowledge retention at 2 weeks was not significantly different between the groups, df(4), F = 0.17, P = .95 (TDS, mean = 25.43, SD = 5.11; T-CPI, mean = 25.07, SD = 4.98; V-CPI, mean = 25.77, SD = 4.89; SA-CPI, mean = 25.83, SD = 5.31; and DA-CPI, mean = 24.93, SD = 6.25). Satisfaction scores were significantly lower for TDS, df(4), F = 3.11, P = .01. CONCLUSIONS: CPI did not improve medication knowledge retention at 2 weeks. CPI led to higher patient satisfaction compared with controls. PMID- 24168838 TI - How do peer coaches improve diabetes care for low-income patients?: a qualitative analysis. AB - PURPOSE: The purpose of the study was to explore the perspectives and roles of peer coaches, who are patients with diabetes trained to provide diabetes self management support (DSMS) to other patients. METHODS: A focus group and 17 qualitative semi-structured interviews were conducted with community-based peer coaches in San Francisco in order to better understand the process by which these coaches engaged with their patients. Transcripts were coded and analyzed using methods based on grounded theory to develop a theoretical model of peer coach roles. RESULTS: Peer coaches play 3 principal roles in providing DSMS: advisor, supporter, and role model. While working with patients, peer coaches had different approaches to setting emotional boundaries and to allocating responsibility for implementing health behavior changes. Peer coaches were more consistent in how they sought resources from providers. Peer coaches also became empowered to better manage their own diabetes. CONCLUSION: Peer coaches are a highly motivated potential workforce uniquely positioned to teach and empower patients by building trust through shared experiences. The variability in coaching styles suggests an inherent diversity among peer coaches that must be accounted for in future strategies for design, recruitment, training, and oversight of peer coaching programs. PMID- 24168836 TI - Digital photography as an educational food logging tool in obese patients with type 2 diabetes: lessons learned from a randomized, crossover pilot trial. AB - PURPOSE: The purpose of this pilot study is to investigate the utility of, and areas of refinement for, digital photography as an educational tool for food logging in obese patients with type 2 diabetes (T2DM). METHODS: Thirty-three patients aged 18 to 70 with T2DM, body mass index at least 30 kg/m(2), and A1C 7.5% to 9% were recruited from an endocrinology clinic and randomized to a week of food logging using a digital camera (DC) or paper diary (PD), crossing over for week 2. Patients then viewed a presentation about dietary effects on blood glucose, using patient DC and blood glucose entries. Outcomes of adherence (based on number of weekly entries), changes in mean blood glucose and frequency of blood glucose checks, and patient satisfaction were compared between methods. Patient feedback on the DC intervention and presentation was also analyzed. RESULTS: Thirty patients completed the study. Adherence was identical across methods. The mean difference in number of entries was not significant between methods. This difference increased and neared statistical significance (favoring DC) among patients who were adherent for at least 1 week (21 entries, with 2 entries per day for 5 of 7 days, n = 25). Mean blood glucose did not significantly decrease in either method. Patient satisfaction was similar between interventions. Feedback indicated concerns over photograph accuracy, forgetting to use the cameras, and embarrassment using them in public. CONCLUSION: Although the DC method was comparable to PD in adherence, blood glucose changes, and patient satisfaction in this pilot trial, patient feedback suggested specific areas of refinement to maximize utility of DC-based food logging as an educational tool in T2DM. PMID- 24168841 TI - Pretransplant mortality predictors in living and deceased donor liver transplantation. AB - BACKGROUND: Although there were some reports predicting postoperative morbidity and mortality in patients undergoing liver transplantation, most of them studied deceased-donor liver transplantation (DDLT). In this context, we performed this study to predict early mortality after liver transplantation from preoperative variables in both living-donor liver transplantation (LDLT) and DDLT. METHODS: We retrospectively reviewed the medical charts of 159 patients undergoing liver transplantation (LDLT, n = 103; DDLT, n = 56). Then, we identified the factors that independently predicted 30-day mortality using multivariable logistic regression models. RESULTS: The 30-day mortality and 1-year mortality for DDLT versus LDLT were 30% versus 6% and 39% versus 11%, respectively. In multivariate logistic regression analysis, pretransplant hepatic encephalopathy (odds ratio, 5.594; 95% confidence interval, 1.110-28.194; p = 0.037) in patients with DDLT and serum creatinine (odds ratio, 4.883; 95% confidence interval, 1.296-18.399; p = 0.019) in patients with LDLT were the independent risk factors for a composite of 30-day mortality. CONCLUSION: In conclusion, hepatic encephalopathy in DDLT and serum creatinine level in LDLT were the significant pretransplant variables that were related with early death after LT. PMID- 24168840 TI - Therapy contamination as a measure of therapist treatment adherence in a trial of cognitive behaviour therapy versus befriending for psychosis. AB - BACKGROUND: High quality randomized controlled trials (RCT) of psychotherapeutic interventions should ensure that the therapy being tested is what is actually delivered. However, contamination of one therapy into the other, a critical component of treatment adherence, is seldom measured in psychotherapy trials of psychosis. AIMS: The aim of the study was to determine whether a purpose-designed measure, the ACE Treatment Integrity Measure (ATIM) could detect therapy contaminations within a controlled trial of cognitive behavioural therapy (CBT) versus Befriending for first-episode psychosis and to compare the ATIM to a more traditional adherence measure, the Cognitive Therapy Scale (CTS). METHOD: Therapy sessions were audio-recorded and at least one therapy session from 53 of the 62 participants in the RCT was rated by an independent rater using the CTS and ATIM. RESULTS: Ninety-nine therapy sessions were rated. All Befriending sessions and all but three CBT sessions were correctly identified. The ATIM showed that 29 of the 99 (29%) sessions were contaminated by techniques from the other therapy. Within the CBT sessions, 19 of the 51 sessions (37%) were contaminated by one or more Befriending techniques. Of the Befriending sessions, 10 of 48 (21%) were contaminated by ACE techniques. The mean CTS score was higher in the CBT than the Befriending group. CONCLUSIONS: The ATIM was able to detect contaminations and revealed more meaningful, fine-grained analysis of what therapy techniques were being delivered and what contaminations occurred. The study highlights the benefit of employing purpose-designed measures that include contamination when assessing treatment adherence. PMID- 24168842 TI - IL23R polymorphisms influence phenotype and response to therapy in patients with ulcerative colitis. AB - OBJECTIVE: We aimed to identify the clinical and genetic [IL23 receptor (IL23R) single nucleotide polymorphisms (SNPs)] predictors of response to therapy in patients with ulcerative colitis. PATIENTS AND METHODS: A total of 174 patients with ulcerative colitis, 99 women and 75 men, were included. The mean age of the patients was 47+/-15 years and the mean disease duration was 11+/-9 years. The number of patients classified as responders (R) or nonresponders (NR) to several therapies was as follows: 110 R and 53 NR to mesalazine (5-ASA), 28 R and 20 NR to azathioprine (AZT), 18 R and 7 NR to infliximab. Clinical and demographic variables were recorded. A total of four SNPs were studied: IL23R G1142A, C2370A, G43045A, and G9T. Genotyping was performed by real-time PCR using Taqman probes. RESULTS: Older patients were more prone to respond to 5-ASA (P=0.004), whereas those with pancolitis were less likely to respond to such therapies (P=0.002). Patients with extraintestinal manifestations (EIMs) were less likely to respond to 5-ASA (P=0.001), AZT (P=0.03), and corticosteroids (P=0.06). Carriers of the mutant allele for IL23R SNPs had a significantly higher probability of developing EIMs (P<0.05), a higher probability of being refractory to 5-ASA (P<0.03), but a higher likelihood of responding to AZT (P=0.05). A significant synergism was observed between IL23R C2370A and EIMs with respect to nonresponse to 5-ASA (P=0.03). CONCLUSION: Besides extent of disease and age at disease onset, the presence of EIMs may be a marker of refractoriness to 5-ASA, corticosteroids, and AZT. IL23R SNPs are associated both with EIMs and with nonresponse to 5-ASA and corticosteroids. PMID- 24168843 TI - Length dependent loss of motor axons and altered motor unit properties in human diabetic polyneuropathy. AB - OBJECTIVE: To assess the number and properties of motor units in an upper and lower limb muscle (tibialis anterior [TA] and first dorsal interosseous [FDI]) in human diabetic polyneuropathy (DPN) using decomposition-based quantitative electromyography (DQEMG). METHODS: DQEMG protocols were performed in the TA and FDI of 12 patients with confirmed diabetes mellitus and associated DPN, as well as 12 age-matched control participants. Maximal dorsiflexion strength was also assessed using a dynamometer. RESULTS: In both muscles, patients with DPN had significantly reduced motor unit number estimates (MUNEs) (DeltaTA ~45%; DeltaFDI ~30%), compound muscle action potentials (CMAPs) (DeltaTA ~30%; DeltaFDI ~20%), and mean firing rates were reduced (DeltaTA ~15%; DeltaFDI ~15%) compared to controls (p<0.05). For the TA, patients with DPN had larger mean surface motor unit potentials (SMUPs) (DeltaTA ~40%; p<0.05), whereas in the FDI no differences were found (p>0.05). CONCLUSIONS: DPN may result in motor unit loss, remodeling, and altered firing rate patterns. The magnitude of changes in the neuromuscular properties of DPN patients are muscle dependent and reflect a length-dependent disease progression. SIGNIFICANCE: DQEMG may be a clinically useful technique in identifying the presence and severity of neuromuscular pathophysiology and tracking disease progression in DPN. PMID- 24168844 TI - Application of a disturbance-rejection controller for robotic-enhanced limb rehabilitation trainings. AB - The paper presents an application of a special case of an Active Disturbance Rejection Controller (ADRC) in governing a proper realization of basic limb rehabilitation trainings. The experimental study is performed on a model of a flexible joint manipulator, whose behavior resembles a real robotic rehabilitation device. The multidimensional character of the considered assisting mechanism makes it a nontrivial modeling and control problem. However, by the use of the ADRC approach, the modeling uncertainty in the plant is partially decoupled from the system, which increases the robustness of the whole control framework against both internal and external disturbances. PMID- 24168846 TI - [Homocysteine levels: measure or not?]. AB - An increase in the fasting plasma homocysteine concentration, even within the 'normal range', is a strong and independent predictor of cardiovascular risk. Low concentrations of specific B vitamins and decreased renal function are the most common causes of hyperhomocysteinaemia. Interventional trials with B vitamins showed a decrease in homocysteine levels, but no decrease in cardiovascular disease rates. There are several methodological concerns that preclude the drawing of definite conclusions from the trials; these include the fact that only very mild hyperhomocysteinaemia (>20 MUmol/l) was investigated and that possible detrimental effects of high doses of synthetic folic acid were not excluded. Screening for hyperhomocysteinaemia is only indicated in patients with severe premature vascular disease or with indications for an inherited disorder in homocysteine metabolism. Treatment of hyperhomocysteinaemia with moderately high doses of B vitamins should only be considered in severe premature vascular disease or if concentrations are greatly elevated. PMID- 24168847 TI - [CT colonography in daily practice]. AB - The sensitivity of computed tomography (CT) colonography for colorectal carcinoma and large polyps (>= 10 mm) is comparable with that of colonoscopy. Acceptance in symptomatic patients is higher than for colonoscopy. The accuracy of CT colonography for polyps of 6-9 mm, for flat polyps and in particular for polyps < 6 mm is lower than for colonoscopy. Indication for CT colonography depends on the a prior chance of finding something relevant, as colonoscopy is necessary in the case of relevant findings. CT colonography can be an alternative to colonoscopy in patients with symptoms consistent with colorectal cancer when colonoscopy is not possible or appears incomplete. It can be used as primary technique in older patients with comorbidity and low a prior chance of relevant findings. CT colonography is less appropriate for surveillance as the accuracy for flat polyps is lower. CT colonography is not suitable in hereditary syndromes due to the lower accuracy for polyps < 10 mm. CT colonography can be a good alternative in patients with irritable bowel syndrome in the case of a low suspicion of colorectal cancer. PMID- 24168848 TI - [Recurrent miscarriage turns out to be lung cancer]. AB - BACKGROUND: If a positive pregnancy test is followed by profuse vaginal bleeding, the diagnosis of miscarriage can generally be made. Sometimes, however, elevated hCG levels may be associated with a phantom pregnancy, which may be a paraneoplastic symptom. CASE DESCRIPTION: A 27-year-old woman was referred for a diagnosis after having experienced 3 consecutive miscarriages. The diagnostic workup could not identify an underlying cause. After 3 more biochemical miscarriages, the original diagnosis was called into question and extensive testing for ectopic hCG production was performed. It appeared that the false pregnancies were paraneoplastic symptoms of an hCG-producing non-small cell lung cancer. After a lobectomy, the hCG levels returned to normal and a spontaneous pregnancy and uncomplicated delivery followed. CONCLUSION: Phantom pregnancy as a paraneoplastic symptom is extremely rare, but should be considered in patients presenting with recurrent, non-objectifiable miscarriages. Careful documentation of the menstrual cycle is necessary for early detection of the condition. The fact is that vaginal bleeding after a positive pregnancy test can still be a normal menstruation. PMID- 24168850 TI - [Medical indications for laser therapy in dermatology]. AB - Laser therapy in dermatology is often associated with cosmetic procedures. However, nowadays laser therapy has become a treatment modality for many dermatological diseases. We present three cases of patients with different dermatological diseases that are highly therapy-resistant. The first case is a 19 year-old man with multiple angiofibromas in the face, who was treated with ablative laser therapy. We also administered ablative laser therapy to a 64-year old man with a big tumourous nose due to granuloma faciale, who had already tried multiple treatment options without result. Finally, a 69-year-old woman with extensive neurofibromas in the face, which had been considered untreatable, was successfully treated with ablative laser therapy. We would like to show the extensive therapeutical options of laser therapy for difficult-to-treat dermatological diseases. PMID- 24168851 TI - [A man with a swelling of his lower leg since 69 years]. AB - A 76-year-old man visited the Emergency Room because of pain of a progressive, swelling of his right lower leg that had developed 69 years ago after a posttraumatic compartment syndrome. We performed debridement on the necrotic, infected wound and made the diagnosis 'calcific myonecrosis'. PMID- 24168853 TI - We need to investigate whether racial discrimination explains differences in MRCGP exam results. PMID- 24168852 TI - Morphology and phylogeny of Bryophryoides ocellatus n. g., n. sp. (Ciliophora, Colpodea) from in situ soil percolates of Idaho, U.S.A. AB - We describe the morphology and 18S rDNA phylogeny of Bryophryoides ocellatus n. g., n. sp., a bryophryid ciliate inhabiting in situ soil percolates from Idaho, U.S.A. The new genus is distinguished from other bryophryid genera by a combination of the following features: (1) kreyellid (irregularly meshed) silverline pattern, (2) polymorphic adoral organelles in the preoral suture, (3) absence of vestibular kineties. In phylogenetic analyses, Bryophryoides ocellatus is most closely related to Bryophrya gemmea. The 18S rDNA sequence pairwise distance of 2% between these genera, while similar to that between many colpodidan species, exceeds that between some colpodidan genera (e.g. Mykophagophrys and Pseudoplatyophrya, 1.1%), further supporting establishment of the new genus. Topology hypothesis testing strongly supports the monophyly of the Colpodida including the bryophryids. Despite weak nodal support, tests of topology constraints narrowly reject the non-monophyly of the sequenced Bryophryidae (Bryophrya+Bryophryoides+Notoxoma). Likewise, the monophyletic origin of the sequenced Bryophryidae is indicated in the phylogenetic networks though with low support. PMID- 24168854 TI - Doppler-based renal resistance index for the detection of acute kidney injury and the non-invasive evaluation of paravalvular aortic regurgitation after transcatheter aortic valve implantation. AB - AIMS: Acute kidney injury (AKI) is a strong but rather late predictor of mortality after transcatheter aortic valve implantation (TAVI). Early clinically useful markers for the detection of AKI and prediction of outcome are needed in order to control and improve management of periprocedural complications after TAVI. The aim of our study was to assess the predictive value of the Doppler based renal resistance index (RRI), which correlates inversely with effective renal blood flow and creatinine clearance, for AKI in patients undergoing TAVI and to evaluate its association with paravalvular aortic regurgitation (PAR). METHODS AND RESULTS: TAVI was performed with the Medtronic CoreValve prosthesis in 132 consecutive high-risk patients (mean logistic EuroSCORE: 30.3+/-18.2%). RRI, serum creatinine and cystatin C level were determined before, and 4 hrs, 24 hrs, 48 hrs, 72 hrs, and 7 days after TAVI. AKI occurred in 32/132 patients (24.2%). While serum creatinine and cystatin C levels decreased at first after TAVI (also in most patients developing AKI), the RRI increased significantly immediately after the procedure from 0.79+/-0.09 to 0.87+/-0.12 in patients developing AKI (p=0.003). A RRI >0.85 predicted post-interventional AKI with a sensitivity of 58% and specificity of 86%, and was superior to the serum creatinine level (p<0.001). In addition, an elevated RRI was significantly related to haemodynamic changes after TAVI and was associated with the occurrence of moderate/severe PAR (p<0.001). CONCLUSIONS: Measurement of the Doppler-based RRI predicts risk for AKI and increased mortality rates at an early post procedural time point and is related to the occurrence of more-than-mild paravalvular aortic regurgitation after TAVI. PMID- 24168855 TI - NKG2D- and CD28-mediated costimulation regulate CD8+ T cell chemotaxis through different mechanisms: the role of Cdc42/N-WASp. AB - The activating receptor NKG2D is mainly expressed in NK cells and CD8(+) T cells. NKG2D and CD28 recruit the p85 subunit of PI3K to propagate their signals through the YXXM signaling motif. The function of CD28 as a costimulatory molecule is well-established in T cells. Ligation of NKG2D on T cells costimulates TCR signaling, although the intracellular signaling pathways triggered by the two receptors may not be identical. In this study, we analyzed the function of the NKG2D receptor in human CD8(+) T cell chemotaxis toward a CXCL12 gradient. We found that costimulation of the TCR together with CD28 or NKG2D impairs cell migration, although the signaling pathways responsible for this effect differ. Whereas the Rho GTPase Rac1 is activated upon TCR and costimulation via CD28 and NKG2D, the activity of Cdc42 is increased only upon CD3/NKG2D activation. Moreover, knockdown of N-WASp expression with siRNA rescues migration rates after NKG2D-mediated costimulation but not after CD3/CD28 activation. CD28- and NKG2D mediated costimulation induces cofilin activation by dephosphorylation. Inhibition of N-WASp by wiskostatin further decreases phosphorylation levels of cofilin, although this effect is especially severe upon CD3/NKG2D activation. Thus, our findings reveal new differences in the signaling pathways between CD28- and NKG2D-mediated costimulation in the regulation of cell chemotaxis in human CD8(+) T cells. PMID- 24168856 TI - Microdomains in the membrane landscape shape antigen-presenting cell function. AB - The plasma membrane of immune cells is a highly organized cell structure that is key to the initiation and regulation of innate and adaptive immune responses. It is well-established that immunoreceptors embedded in the plasma membrane have a nonrandom spatial distribution that is important for coupling to components of intracellular signaling cascades. In the last two decades, specialized membrane microdomains, including lipid rafts and TEMs, have been identified. These domains are preformed structures ("physical entities") that compartmentalize proteins, lipids, and signaling molecules into multimolecular assemblies. In APCs, different microdomains containing immunoreceptors (MHC proteins, PRRs, integrins, among others) have been reported that are imperative for efficient pathogen recognition, the formation of the immunological synapse, and subsequent T cell activation. In addition, recent work has demonstrated that tetraspanin microdomains and lipid rafts are involved in BCR signaling and B cell activation. Research into the molecular mechanisms underlying membrane domain formation is fundamental to a comprehensive understanding of membrane-proximal signaling and APC function. This review will also discuss the advances in the microscopy field for the visualization of the plasma membrane, as well as the recent progress in targeting microdomains as novel, therapeutic approach for infectious and malignant diseases. PMID- 24168857 TI - Hypoxia: how does the monocyte-macrophage system respond to changes in oxygen availability? AB - Hypoxia is an important feature of inflamed tissue, such as the RA joint. Activated monocytes/macrophages and endothelial cells play a pivotal role in the pathogenesis of RA, implicated in the mechanism of inflammation and erosion. During development, myeloid progenitor cells sequentially give rise to monoblasts, promonocytes, and monocytes that are released from the bone marrow into the bloodstream. After extravasation, monocytes differentiate into long lived, tissue-specific macrophages or DCs. The effect of different oxygen concentrations experienced by these cells during maturation represents a novel aspect of this developmental process. In inflamed joint tissue, the microvascular architecture is highly dysregulated; thus, efficiency of oxygen supply to the synovium is poor. Therefore, invading cells must adapt instantaneously to changes in the oxygen level of the microenvironment. Angiogenesis is an early event in the inflammatory joint, which is important in enabling activated monocytes to enter via endothelial cells by active recruitment to expand the synovium into a "pannus", resulting in cartilage degradation and bone destruction. The increased metabolic turnover of the expanding synovial pannus outpaces the dysfunctional vascular supply, resulting in hypoxia. The abnormal bioenergetics of the microenvironment further promotes synovial cell invasiveness. In RA, joint hypoxia represents a potential threat to cell function and survival. Notably, oxygen availability is a crucial parameter in the cellular energy metabolism, itself an important factor in determining the function of immune cells. PMID- 24168858 TI - Relations between white matter maturation and reaction time in childhood. AB - White matter matures with age and is important for the efficient transmission of neuronal signals. Consequently, white matter growth may underlie the development of cognitive processes important for learning, including the speed of information processing. To dissect the relationship between white matter structure and information processing speed, we administered a reaction time task (finger abduction in response to visual cue) to 27 typically developing, right-handed children aged 4 to 13. Magnetoencephalography and Diffusion Tensor Imaging were used to delineate white matter connections implicated in visual-motor information processing. Fractional anisotropy (FA) and radial diffusivity (RD) of the optic radiation in the left hemisphere, and FA and mean diffusivity (MD) of the optic radiation in the right hemisphere changed significantly with age. MD and RD decreased with age in the right inferior fronto-occipital fasciculus, and bilaterally in the cortico-spinal tracts. No age-related changes were evident in the inferior longitudinal fasciculus. FA of the cortico-spinal tract in the left hemisphere and MD of the inferior fronto-occipital fasciculus of the right hemisphere contributed uniquely beyond the effect of age in accounting for reaction time performance of the right hand. Our findings support the role of white matter maturation in the development of information processing speed. PMID- 24168860 TI - Source attribution of human campylobacteriosis in Denmark. AB - SUMMARY This study assesses the contribution of different sources of human campylobacteriosis in Denmark using two different source-attribution approaches. In total, 794 non-human isolates and 406 isolates from human cases (domestic, travel related, and cases with unknown travel history) were collected. Isolates were characterized by multilocus sequence typing, flaA typing and susceptibility to antibiotics. Both models used indicate that the major burden of human campylobacteriosis in Denmark originates from the domestic broiler chicken reservoir. The second most important reservoir was found to be cattle. The Asymmetric Island model attributed 52% [95% credibility interval (CrI) 37-67] to Danish chicken, 17% (95% CrI 3-33) to imported chicken, and 17% (95% CrI 7-28) to cattle. Similarly, the Campylobacter source-attribution model apportioned 38% (95% CrI 28-47) to Danish chicken, 14% (95% CrI 10-18) to imported chicken, and 16% (95% CrI 7-25) to cattle. The addition of flaA type as an extra discriminatory typing parameter did not change the attribution of cases markedly. PMID- 24168861 TI - Molecular localization techniques in the diagnosis and characterization of nonhuman primate infectious diseases. AB - Molecular localization techniques remain important diagnostic and research tools for the pathologist evaluating nonhuman primate tissues. In situ hybridization and immunohistochemistry protocols have been developed for many important pathogens of nonhuman primates, including RNA and DNA viruses, prions, and bacterial, protozoal, and fungal pathogens. Such techniques will remain critical in defining the impact and relevance of novel agents on animal health and disease. A comparative pathology perspective often provides valuable insight to the best strategy for reagent development and can also facilitate interpretation of molecular localization patterns. Such a perspective is grounded in a firm understanding of microbe-host pathobiology. This review summarizes current molecular localization protocols used in the diagnosis of selected primate infectious diseases. PMID- 24168862 TI - A comprehensive update on current fixation options for two-part proximal humerus fractures: a biomechanical investigation. AB - BACKGROUND: Recent advancements in implant technology offer updated options for surgical management that have been rapidly adopted into clinical practice. The objective of this study is to biomechanically test and compare the current fixation options available for surgical fixation of two-part proximal humerus fractures and establish load to failure and stiffness values. METHODS: Sixteen match-paired (32 total) fresh-frozen, cadaveric specimens were randomized to receive 1 of 4 fixation constructs following creation of an AO/OTA Type 11A3 (two part) proximal humerus fractures. Fixation constructs tested consisted of 3.5 mm fixed angle plate (3.5-FAP), 4.5 mm fixed angle plate (4.5-FAP), humeral intramedullary nail (IMN), and a humeral intramedullary nail with a fixed angle blade (IMN-FAB). Specimen bone density was measured to ensure no adequate, non osteoporotic bone. Constructs were tested for stiffness and ultimate load to failure and compared via one-way ANOVA analysis with subsequent post hoc Tukey HSD multiple group comparison statistical analysis. RESULTS: The IMN-FAB construct was significantly stiffer than the 3.5-FAP construct (123.8 vs. 23.9, p<0.0001), the 4.5-FAP construct (123.8 vs. 33.3, p<0.0001) and the IMN construct (123.8 vs. 60.1, p=0.005). The IMN-FAB construct reported a significantly higher load to failure than the 3.5-FAB construct (4667.3 N vs. 1756.9 N, p<0.0001), and the 4.5-FAP construct (4667.3 N vs. 2829.4 N, p=0.019, Table 2). The IMN construct had a significantly higher load to failure than the 3.5-FAP construct (3946.8 vs. 1756.9, p=0.001, Table 2). CONCLUSION: Biomechanical testing of modern fixation options for two-part proximal humerus fracture exhibited that the stiffest and highest load to failure construct was the IMN-FAB followed by the IMN, 3.5-FAP and then the 4.5-FAP constructs. However, prospective clinical trials with longer-term follow-up are required for definitive assessment of the ideal fixation construct for surgical management of two-part proximal humerus fractures. PMID- 24168863 TI - From the editor: trends in employee relations? PMID- 24168864 TI - Dress codes and appearance policies: challenges under federal legislation, part 1: title VII of the civil rights act and religion. AB - As more and more individuals choose to express themselves and their religious beliefs with headwear, jewelry, dress, tattoos, and body piercings and push the envelope on what is deemed appropriate in the workplace, employers have an increased need for creation and enforcement of reasonable dress codes and appearance policies. As with any employment policy or practice, an appearance policy must be implemented and enforced without regard to an individual's race, color, sex, national origin, religion, disability, age, or any other protected status. A policy governing dress and appearance based on the business needs of an employer that is applied fairly and consistently and does not have a disproportionate effect on any protected class will generally be upheld if challenged in court. By examining some of the more common legal challenges to dress codes and how courts have resolved the disputes, health care managers can avoid many potential problems. This article addresses the issue of religious discrimination focusing on dress and appearance and some of the court cases that provide guidance for employers. PMID- 24168865 TI - The organizational attraction of nursing graduates: using research to guide employer branding. AB - In the context of the global nursing shortage, only the most attractive employers are able to recruit a sufficient number of nurses to maintain high quality of care and ensure positive patient outcomes. It is important for health care organizations to align their practices and their employer marketing strategies with attraction factors important to nurses. This article presents the results of a survey of 666 nursing students graduating in the spring of 2009 in the Canadian province of Quebec. Hypotheses were tested using repeated-measures analysis of variance and post hoc tests. Consistent with hypotheses, the results showed that quality of care, type of work, compensation, and employer branding are organizational attraction factors that nursing graduates perceived as important, with quality of care being the most important one. These findings were later used by a Canadian university teaching hospital to optimize its employer branding and attraction strategy that resulted in an increase in the hiring of university trained nurses. Further research is needed to examine organizational attractiveness for new nurses over time, across generations, and within various cultural contexts. PMID- 24168866 TI - Massachusetts health care reform: is it working? AB - Before 2006, Massachusetts had more than 500 000 residents who lacked health insurance. Governor Mitt Romney enacted landmark legislation requiring all residents to obtain health insurance. Also, the legislation established a health insurance exchange for the purpose of broadening the choices of insurance plans made available to individuals in the state. The purpose of this research was to assess the Massachusetts health care reform in terms of access, cost, and sustainability. The methodology used was a literature review from 2006 to 2013; a total of 43 references were used. Health reform resulted in additional overall state spending of $2.42 billion on Medicaid for Massachusetts. Since the 2006 reform, 401 000 additional residents have obtained insurance. The number of Massachusetts residents who had access to health care increased substantially after the health care reform was enacted, to 98.1% of residents. The Massachusetts health care reform has not saved money for the state; its funding has been covered by Federal spending. However, reform has been sustained over time because of the high percentage of state residents who have supported the state mandate to obtain health care coverage. PMID- 24168867 TI - Emergency department utilization at a large regional hospital: a strategy for survivability. AB - This research effort provides a brief picture of the operational, patient, and financial patterns of the multiple emergency departments of a large hospital system located in the southeastern United States. The results are presented anonymously as a descriptive case study. A multifaceted strategy is presented to assist hospital leaders as they strive to ensure the survivability of their emergency departments in this era of high uncompensated care. PMID- 24168868 TI - Generational differences of the frontline nursing workforce in relation to job satisfaction: what does the literature reveal? AB - The job satisfaction of registered nurses has been found to be associated with retention, organizational commitment, workforce safety, and cost savings to health care organizations. Satisfaction of the workforce is vital because nursing turnover can be detrimental for a labor force that is growing older. However, the summation of the most important variables that are linked to job satisfaction has been difficult to discern in part because the workforce includes 3 main generations (ie, Baby Boomers, Gen Xers, and Millennials) with unique work values that drive their job satisfiers. This article provides a review of existing literature to examine the differences in variables that are linked to job satisfaction that exist between the generational cohorts. Differences in stress sources, need for work-life balance, and compensation are discussed. The knowledge about generationally driven variables that influence job satisfaction can help managers develop strategies to maintain a diverse nursing workforce. PMID- 24168869 TI - The evolution of retail clinics in the United States, 2006-2012. AB - In the recent decade, retail clinics have emerged to offer routine preventative and acute care services by nonphysician providers, with predictable wait times, more convenient venues, and posted prices. This article evaluates the evolution of retail clinics between 2006 and 2012 and examines the yearly openings and closings of clinics by location, owner, operator, and other important characteristics. The Merchant Medicine database was used. It is the only database of its kind that includes every retail clinic opening and closing since 2006. The data are collected on a monthly basis through operator self-report, telephone calls to operators, and monitoring of operator Web sites and articles in local newspapers. A growth period of 2006 through 2008 can be attributed to what was referred to at the time as a "land grab," in which competing operators sought to be the first to open in new markets. In 2008, with the start of the general economic recession, numerous clinics shut down during the slow spring and summer months and others closed altogether. The industry remains dominated by large retail pharmacy operators, and the involvement of hospital systems in retail clinic ownership is a recent and interesting phenomenon. An important question to address is the following: Will retail clinics remain as just a convenient way for busy insured patients to seek care afterhours and on weekends, or can they have a more significant impact in a primary care system on the brink of collapse? PMID- 24168871 TI - Performance management excellence among the Malcolm Baldrige National Quality Award Winners in Health Care. AB - When carefully constructed, performance management systems can help health care organizations direct their efforts toward strategic goals, high performance, and continuous improvement needed to ensure high-quality patient care and cost control. The effective management of performance is an integral component in hospital and health care systems that are recognized for excellence by the Malcolm Baldrige National Quality Award in Health Care. Using the framework in the 2011-2012 Health Care Criteria for Performance Excellence, this article identifies the best practices in performance management demonstrated by 15 Baldrige recipients. The results show that all of the recipients base their performance management systems on strategic goals, outcomes, or competencies that cascade from the organizational to the individual level. At the individual level, each hospital or health system reinforces the strategic direction with performance evaluations of leaders and employees, including the governing board, based on key outcomes and competencies. Leader evaluations consistently include feedback from internal and external stakeholders, creating a culture of information sharing and performance improvement. The hospitals or health care systems also align their reward systems to promote high performance by emphasizing merit and recognition for contributions. Best practices can provide a guide for leaders in other health systems in developing high-performance work systems. PMID- 24168872 TI - Developing a hospital-specific electronic inpatient fall surveillance program: phase 1. AB - Patient falls in hospitals continue to exist as a serious societal problem. The purpose of this study was to analyze nurses' perceptions of patient fall risk factors that may be used to develop an electronic patient decision support system to prevent patient falls. A survey was distributed to 150 nurses in a moderate size hospital system in Central Florida (200+ beds). Survey questions were developed to identify 3 fall risk factor categories: patient-centered, operational, and critical. Sixty-five surveys (43.3%) were returned. Descriptive statistics such as frequencies and percentages were calculated on all study variables. All participants indicated they were familiar with the circumstances that have contributed to falls or near-falls of patients. Findings included the majority of nurses perceived both patient-centered and operational factors increased the risks for patient falls, with pertinent results indicating a lack of appropriate ambulatory device (90.8%), low to very low nurse staffing levels (87.7%), and a history of a fall within the past year (73.8%) increased the risk for falls. The nurses' perceptions define a standard medical terminology that can be recorded in electronic progress notes and programmed to quickly link to additional sources of fall risk data (eg, laboratory work, medications) housed within the hospital's electronic health record. Further research is needed to assess the feasibility of an electronic health record-based system to prevent hospital falls using risk factors identified in this and other studies. PMID- 24168873 TI - The use of innovative advance directives programs in nursing homes. AB - End-of-life service providers continue to seek improved instruments for individuals to convey their last wishes. Two such instruments are Five Wishes and Physician Order for Life-Sustaining Treatment. This project explores the relationship of nursing home profit status and innovativeness to the use of these advance directive programs (ADPs). The specific aims of this study were to determine what other types of innovations are associated with the use of these ADPs and the differences in use by nursing home characteristics. Data for this project come from the 2004 National Nursing Home Survey (n = 949). The data were analyzed using 3 logistic regression models. The results revealed that quality-of life activities, having an in-house hospice, being a not-for-profit chain affiliated nursing home, or a for-profit freestanding nursing home were all associated with ADP. These results suggest that ADP use may be influenced by nursing home characteristics other than clinical services. PMID- 24168874 TI - Animal source foods have a positive impact on the primary school test scores of Kenyan schoolchildren in a cluster-randomised, controlled feeding intervention trial. AB - Micronutrient deficiencies and suboptimal energy intake are widespread in rural Kenya, with detrimental effects on child growth and development. Sporadic school feeding programmes rarely include animal source foods (ASF). In the present study, a cluster-randomised feeding trial was undertaken to determine the impact of snacks containing ASF on district-wide, end-term standardised school test scores and nutrient intake. A total of twelve primary schools were randomly assigned to one of three isoenergetic feeding groups (a local plant-based stew (githeri) with meat, githeri plus whole milk or githeri with added oil) or a control group receiving no intervention feeding. After the initial term that served as baseline, children were fed at school for five consecutive terms over two school years from 1999 to 2001. Longitudinal analysis was used controlling for average energy intake, school attendance, and baseline socio-economic status, age, sex and maternal literacy. Children in the Meat group showed significantly greater improvements in test scores than those in all the other groups, and the Milk group showed significantly greater improvements in test scores than the Plain Githeri (githeri+oil) and Control groups. Compared with the Control group, the Meat group showed significant improvements in test scores in Arithmetic, English, Kiembu, Kiswahili and Geography. The Milk group showed significant improvements compared with the Control group in test scores in English, Kiswahili, Geography and Science. Folate, Fe, available Fe, energy per body weight, vitamin B12, Zn and riboflavin intake were significant contributors to the change in test scores. The greater improvements in test scores of children receiving ASF indicate improved academic performance, which can result in greater academic achievement. PMID- 24168875 TI - Brain blood vessel segmentation using line-shaped profiles. AB - Segmentation of cerebral blood vessels is of great importance in diagnostic and clinical applications, especially for embolization of cerebral aneurysms and arteriovenous malformations (AVMs). In order to perform embolization of the AVM, the structural and geometric information of blood vessels from 3D images is of utmost importance. For this reason, the in-depth segmentation of cerebral blood vessels is usually done as a fusion of different segmentation techniques, often requiring extensive user interaction. In this paper we introduce the idea of line shaped profiling with an application to brain blood vessel and AVM segmentation, efficient both in terms of resolving details and in terms of computation time. Our method takes into account both local proximate and wider neighbourhood of the processed pixel, which makes it efficient for segmenting large blood vessel tree structures, as well as fine structures of the AVMs. Another advantage of our method is that it requires selection of only one parameter to perform segmentation, yielding very little user interaction. PMID- 24168877 TI - Improving discrimination in the grading of rat mammary tumors using two dimensional mapping of histopathological observations. AB - This work aims at characterizing rat mammary tumors induced by 7,12 dimethylbenz(a)anthracene (DMBA) and the respective malignancy potential, commonly graded with histopathology features grouped by intensity levels. Tumors were described over fourteen multiple ranged microscopic parameters and a comprehensive characterization of the histological patterns and their relation with tumor grade was carried out by principal component analysis (PCA). The number of histological patterns present on a tumor tends to correlate with malignant features. High grade tumors are characterized by the presence of several structural patterns, with cribriform prevalence and necrosis. The cribriform pattern correlates with grading, i.e., tumors having a higher predominance of the cribriform pattern are likely to be more malignant. The findings may represent a benchmark for similar characterization studies in other models. PMID- 24168878 TI - Going viral: adapting to pediatric surge during the H1N1 pandemic. AB - OBJECTIVES: The objective of this study was to assess hospital and emergency department (ED) pediatric surge strategies utilized during the 2009 H1N1 influenza pandemic as well as compliance with national guidelines. METHODS: Electronic survey was sent to a convenience sample of emergency physicians and nurses from US EDs with a pediatric volume of more than 10,000 annually. Survey questions assessed the participant's hospital baseline pandemic and surge preparedness, as well as strategies for ED surge and compliance with Centers for Disease Control and Prevention (CDC) guidelines for health care personal protection, patient testing, and treatment. RESULTS: The response rate was 54% (53/99). Preexisting pandemic influenza plans were absent in 44% of hospitals; however, 91% developed an influenza plan as a result of the pandemic. Twenty-four percent reported having a preexisting ED pandemic staffing model, and 36% had a preexisting alternate care site plan. Creation and/or modifications of existing plans for ED pandemic staffing (82%) and alternate care site plan (68%) were reported. Seventy-nine percent of institutions initially followed CDC guidelines for personal protection (use of N95 masks), of which 82% later revised their practices. Complete compliance with CDC guidelines was 60% for patient testing and 68% for patient treatment. CONCLUSIONS: Before the H1N1 pandemic, greater than 40% of the hospitals in our study did not have an influenza pandemic preparedness plan. Many had to modify their existing plans during the surge. Not all institutions fully complied with CDC guidelines. Data from this multicenter survey should assist clinical leaders to create more robust surge plans for children. PMID- 24168879 TI - Feasibility and acceptability of a pediatric emergency department alcohol prevention intervention for young adolescents. AB - OBJECTIVE: The objective of this study was to determine feasibility and acceptability of a brief pediatric emergency department (PED) prevention intervention to delay/prevent initiation of alcohol use in 12-to 14-year-olds. METHODS: Medically stable 12- to 14-year-olds presenting to the PED who were accompanied by a parent and who had not initiated alcohol use were eligible. Adolescent-parent dyads completed a computerized assessment and were randomized to either brief targeted prevention intervention (BPI) or enhanced standard care (ESC). Families randomized to BPI participated in a PED-based motivational interviewing and skill building-based session with a trained counselor. Parents randomized to BPI had telephone boosters at 1 and 3 months. Families randomized to ESC received standard care and adolescent substance use pamphlets. All dyads completed 6-month follow-up assessments to assess alcohol use-related outcomes. RESULTS: Two hundred twenty-eight families were approached: 122 were eligible and 104 were enrolled (85%). Mean youth age was 13 (SD, 0.83) years, 51% were female, and 90% of parents were females. Of the 104 enrolled, 5 withdrew; 99 (94%) completed the assessment battery in the PED in less than 30 minutes. All BPI dyads completed the counseling session in the PED. However, only 53% of BPI parents completed the booster telephone sessions. Brief targeted prevention intervention acceptability items were rated favorably (82%-100%) by both parents and adolescents. There were no differences between BPI and ESC on substance related outcomes, although the study was not adequately powered for this purpose because it was designed as a feasibility study. CONCLUSIONS: A BPI in the PED is both feasible and acceptable, but phone boosters proved less feasible. Larger samples and further study are needed to identify efficacy of the BPI in delaying onset of alcohol use in teens. PMID- 24168880 TI - Four-film X-ray series is more sensitive than 2-film for diagnosis of skull fractures in children. AB - OBJECTIVE: The objective of this study was to compare the sensitivity and specificity of 2- and 4-film x-ray series when interpreted by pediatric emergency medicine physicians in the diagnosis of skull fracture in children. METHODS: A noninferiority crossover study was performed. The skull radiographs of the 50 most recent cases of skull fracture for which a 4-film radiography series was available and 50 controls matched for age were reviewed. Two modules, containing a random sequence of 2- and 4-film series of each child, were constructed to have all children evaluated twice (once with 2 films and once with 4 films). Pediatric emergency physicians evaluated both modules 2 to 4 weeks apart. The interpretation of the 4-film series by a pediatric radiologist served as the criterion standard. The sensitivity and specificity of the 2-film versus the 4 film skull x-ray series, in the identification of fracture, were compared. RESULTS: Thirteen pediatric emergency physicians participated in the study. For sensitivity, the mean difference between the 2- and 4-view series was higher than the noninferiority margin of 0.055 with an absolute mean difference of 0.060 (4 view minus 2-view series) and a 1-sided 95% higher confidence limit of 0.099. However for specificity, the mean difference was within the margin with an absolute mean difference of 0.011 and a 1-sided 95% higher confidence limit of 0.033. CONCLUSIONS: For children sustaining a head trauma, the 2-film skull radiography series is not as sensitive as the 4-film series in the detection of fracture, when interpreted by pediatric emergency physicians. PMID- 24168881 TI - Pediatric left-without-being-seen patients: what happens to them after they leave the pediatric emergency department? AB - OBJECTIVES: The objective of this study was to evaluate what happens to the children who leave without being seen (LWBS) in an urban Pediatric Emergency Department (PED). METHODS: Patient advocates contacted families whose children LWBS in the PED via phone call and utilized a standardized questionnaire to interview them regarding medical care sought after leaving the PED. Questions asked included the following: Was further medical care sought by the family for the child? If so, where was the care obtained? Did the patient no longer require care? The family was also asked if the advocate could help make an appointment for medical care for the child. RESULTS: From April 2009 to September 2011, 3874 LWBS patients from the PED at the University of Chicago Comer Children's Hospital were called by patient advocates. Sixty-five percent (n = 2521) of these children's families were reached by phone. More than 50% of patients contacted sought medical care elsewhere, planned to seek care, or had scheduled an appointment for follow-up medical care. When contacted, 21% of the families felt that no further medical appointment/care was needed, and 23% refused assistance. CONCLUSIONS: Left-without-being-seen rates continued to be an ongoing issue for physicians in the PED. More than half of the contacted patients who LWBS were cared for elsewhere either on the day of the visit or later. This information obtained provides an initial look into understanding what happens to an urban PED patient population that leaves before receiving care in the PED. PMID- 24168882 TI - Predictive factors of hospitalization in children with acute asthma at a university emergency care unit. AB - OBJECTIVE: This study analyzed the factors that predicted the hospitalization of children with asthma following standardized treatment in emergency care unit (ECU). METHODS: This retrospective study examined data collected from the clinical records of children, 14 years or younger, who were diagnosed with asthma (often with bronchopneumonia, pneumonia, or other illnesses) and treated at the ECU of Santo Andre from January 2005 to December 2009. The following data were analyzed: month and year of care, child's age and sex, period of observation, and need for hospitalization. A pediatrician confirmed the clinical diagnoses of all participants. The children were first given clinical treatments and were then admitted to ECU for follow-up assessment. RESULTS: The number of hospital admissions was analyzed, and correlations were found with regard to this variable and child age (chi(2) = 166.9; P = 0.00001), the presence of associated illnesses (chi(2) = 63.8; P < 0.00001), and the observation period length (chi(2) = 11.4; P = 0.009). The number of hospital admissions was not correlated with child sex (chi(2) = 0.013; P = 0.9) or time of year (chi(2) = 15.8; P = 0.1). The 3-day observation period was not significant (P = 0.4) with regard to the remainder of the variables in the multiple logistic regression analysis. CONCLUSIONS: Age, mainly children younger than 1 year, the presence of associated illnesses, and the observation period length predicted the hospitalization of children with asthma following treatment in ECU. Sex and seasonality did not affect the need for hospitalization. PMID- 24168883 TI - Too attractive: the growing problem of magnet ingestions in children. AB - BACKGROUND: Small, powerful magnets are increasingly available in toys and other products and pose a health risk. Small spherical neodymium magnets marketed since 2008 are of particular concern. OBJECTIVE: The objective of this study was to determine the incidence, characteristics, and management of single and multiple magnet ingestions over time. METHODS: Magnet ingestion cases at a tertiary children's hospital were identified using radiology reports from June 2002 to December 2012. Cases were verified by chart and imaging review. Relative risk regressions were used to determine changes in the incidence of ingestions and interventions over time. RESULTS: Of 56 cases of magnet ingestion, 98% occurred in 2006 or later, and 57% involved multiple magnets. Median age was 8 years (range, 0-18 years). Overall, 21% of single and 88% of multiple ingestions had 2 or more imaging series obtained, whereas no single and 56.3% of multiple ingestions required intervention (25.0% endoscopy, 18.8% surgery, 12.5% both). Magnet ingestions increased in 2010 to 2012 compared with 2007 to 2009 (relative risk, 1.9; 95% confidence interval, 1.2-3.0). Small, spherical magnets likely from magnet sets comprised 27% of ingestions, all ingested 2010 or later: 86% involved multiple magnets, 50% of which required intervention. Excluding these cases, ingestions of other magnets did not increase in 2010 to 2012 compared with 2007 to 2009 (relative risk, 0.94; 95% confidence interval, 0.6-1.4). CONCLUSIONS: The incidence of pediatric magnet ingestions and subsequent interventions has increased over time. Multiple-magnet ingestions result in high utilization of radiological imaging and surgical interventions. Recent increases parallel the increased availability of small, spherical magnet sets. Young and at risk children should not have access to these and other small magnets. Improved regulation and magnet safety standards are needed. PMID- 24168884 TI - Interhospital transport of children with confirmed or suspected intussusception: experience at the New South Wales Newborn and Paediatric Emergency Transport Service over 10 years. AB - OBJECTIVE: The objective of this study was to compare medical and paramedic retrieval of children requiring interhospital transport with suspected or confirmed intussusception. METHODS: Cases of confirmed or suspected intussusception referred to the New South Wales Newborn and Paediatric Emergency Transport Service from January 2001 to August 2011 were identified retrospectively using the Newborn and Paediatric Emergency Transport Service database. Univariate analyses were used to compare patients transported by medical and paramedic escort teams, and multivariable logistic regression was used to determine independent predictors of the decision to use medical escort teams. RESULTS: Two hundred twenty-two cases were identified over the 10-year period. Paramedic escort teams were used in 48% of cases. There were no major complications recorded during retrieval by medical and paramedic escort teams. Only the presence of blood-stained stools (odds ratio, 1.9; 95% confidence interval, 0.93-3.86; P = 0.08) and increasing heart rate (odds ratio, 1.03; 95% confidence interval, 1.01-1.04; P = 0.002) were found to be predictors of the decision to use a medical escort retrieval team. No factors were found to be associated with increased medical intervention in the subgroup of patients transported by a medical escort team. CONCLUSIONS: Well children requiring interhospital transport for suspected or confirmed intussusception can be transported safely without a medical escort team if they have normal heart rates. PMID- 24168885 TI - Emergency department presentation of the pediatric systemic inflammatory response syndrome. AB - OBJECTIVES: The epidemiology of the systemic inflammatory response syndrome (SIRS) in children is poorly understood. We sought to determine national estimates of the incidence of pediatric SIRS and its corresponding clinical etiologies presenting to US emergency departments (EDs) using current definitions. METHODS: We analyzed ED visits by children younger than 18 years from 2007 to 2010 in the National Hospital Ambulatory Medical Care Survey. We used a Bayesian logical framework of prior probability distributions for white blood cell count result to make minimum, moderate, and maximum estimates for pediatric SIRS. RESULTS: Taking the minimum and maximum estimates as modified credible intervals, we report an overall incidence of pediatric SIRS presenting to the ED to be 21.7% (95% modified credible interval, 18.1%-25.4%). The national moderate estimate of pediatric ED visits presenting with SIRS was approximately 6.2 million per year. Children with SIRS and without SIRS had similar baseline characteristics, but SIRS patients were younger (2.9 vs 5.5 years; P < 0.0001), had higher triage acuity (emergent, 9.0 vs 6.3%; P < 0.0001), and were more often admitted (7.0 vs 2.4%; P < 0.0001) than children without SIRS. Based on the moderate estimate, infection was the most common (53%) associated etiology, followed by trauma (10%). Other traditional categories of SIRS were extremely rare. Of note, 35% of children with SIRS did not fall into any of the previously established categories. CONCLUSIONS: Pediatric SIRS is common; its associated clinical contexts include potentially dangerous etiologies; many cases of pediatric SIRS can be recognized in triage; and there is significant heterogeneity in the etiology of pediatric SIRS. PMID- 24168886 TI - Early clinical features and diagnosis of Dravet syndrome in 138 Chinese patients with SCN1A mutations. AB - OBJECTIVE: To summarize the early clinical features of Dravet syndrome (DS) patients with SCN1A gene mutations before the age of one. METHODS: SCN1A gene mutation screening was performed by PCR-DNA sequencing and multiple ligation dependent probe amplication (MLPA). The early clinical features of DS patients with SCN1A mutations were reviewed with attention to the seizures induced by fever and other precipitating factors before the first year of life. RESULTS: The clinical data of 138 DS patients with SCN1A gene mutations were reviewed. The median seizure onset age was 5.3 months. Ninety-nine patients (71.7%) experienced seizures with duration more than 15 min in the first year of life. Two or more seizures induced by fever within 24h or the same febrile illness were observed in 93 patients (67.4%). 111 patients (80.4%) had hemi-clonic and (or) focal seizures. Seizures had been triggered by fever of low degree (T<38 degrees C) in 62.3% (86/138) before the first year of life. Vaccine-related seizures were observed in 34.8% (48/138). Seizures in 22.5% (31/138) of patients were triggered by hot bath. Carbamazepine, oxcarbazepine, lamotrigine, phenobarbital and phenytoin showed either no effect or exacerbating the seizures in our group. CONCLUSION: The seizure onset age in DS patients was earlier than that was in common febrile seizures. When a baby exhibits two or more features of complex febrile seizures in the first year of life, a diagnosis of DS should be considered, and SCN1A gene mutation screening should be performed as early as possible. Early diagnosis of DS will help clinicians more effectively prescribe antiepileptic drugs for stronger prognosis. PMID- 24168887 TI - Why must NHS health checks be commissioned by local authorities? PMID- 24168888 TI - Fibroblast growth factor 23 (FGF23) gene polymorphism in children with Kawasaki syndrome (KS) and susceptibility to cardiac abnormalities. AB - BACKGROUND: Fibroblast Growth Factor (FGF) 23 influences endothelial integrity and few reports have studied the association between FGF23 and Kawasaki syndrome (KS), a childhood vasculitis displaying a high risk of subsequent cardiac abnormalities (CaA). AIM: To investigate the genetic variation in the FGF23 gene in a cohort of KS children and its association with serum FGF23 levels and eventual development of CaA, including both coronary artery dilatations and aneurysms. PATIENTS AND METHODS: 84 Italian KS children were recruited; 24/84 (28.6%) developed CaA. Each patient underwent evaluation of serum FGF23 levels and FGF23 genotype: the frequency of the c.212-37insC (rs3832879) polymorphism in intron 1 was examined and compared with sex, age at disease onset, fever duration, laboratory data, and occurrence of CaA. Univariate statistical analysis of categorical parameters was performed by the Pearson's Chi-square test or Fisher's exact test as appropriate. Parametric variables were assessed by Student's t-test for unpaired data. Independent predictors of disease were studied by a logistic regression model. RESULTS: 28/84 patients carried the FGF23 polymorphism (33.3%) and had higher serum FGF23 levels (p < 0.01). FGF23 polymorphism was significantly associated with CaA compared to wild type FGF23 children (respectively, p = 0.03 and p = 0.05). The comparison with demographical, clinical or laboratory data was not significant. CONCLUSIONS: The prevalent segregation of the c.212-37insC polymorphism in children with CaA advocates a possible functional FGF23 role in the predisposition to higher serum levels of FGF23 and potential occurrence of any coronary artery abnormalities in KS. PMID- 24168889 TI - Reducing social inequities in health in Norway: concerted action at state and local levels? AB - Norwegian national policies have been distinguished by their focus on equity, contributing to comprehensive policies to reduce the social inequities in health (SIH). The newly adopted Public health act, which aims at reducing the SIH, endorses these acknowledgements while highlighting the importance of municipalities as the key actors in public health. Municipal obligations include inter-sectoral policies for health, health impact assessments (HIA), and the development of local health overviews. Against the background of a system of local autonomy in Norway, this article illuminates whether, and how, municipal public health policies reflect national priorities. Our data are based on one qualitative study, combining document content analysis and expert interviews conducted in 2011, and one quantitative questionnaire sent to municipal chief administrative officers in 2011. Our findings indicate a divide between national and municipal public health strategies. Many municipalities focus on life-style and health-care related measures. Only few municipalities acknowledge the social determinants of health and have implemented HIA and health overviews. Arguing for the importance of concerted multi-level action to reduce the SIH, we need to better understand the gap between national and municipal approaches. We thus suggest further research to illuminate the challenges and success factors faced at local levels. PMID- 24168890 TI - Health promotion for unemployed jobseekers: new developments in Germany. AB - OBJECTIVES: The objective of the paper is to present findings from a health promotion programme for long-term unemployed older job seekers in Germany and to discuss conditions for successful linking health and employment promotion. METHODS: Implementation analysis: interviews with actors who implemented the programme and case studies of job centres where the programme took place. RESULTS: Health promotion with labour market programmes is possible, but requires (a) agreements and coordination between different branches of social security, (b) an enlargement of the dominant activation paradigm in labour market policy with a stronger emphasis on voluntary programme participation, (c) skills and competencies of the staff in job centres as well as an adapted work organization. CONCLUSIONS: Efforts to connect health and employment promotion and to induce the related social security's to cooperation are still in their infancy. Further practical steps as well as research and evaluation are necessary to bring these areas together. PMID- 24168892 TI - Sleep deprivation and obesity in shift workers in southern Brazil. AB - OBJECTIVE: The objective of our study was to explore the association between sleep deprivation and obesity among shift workers. DESIGN: A cross-sectional study was conducted. Obesity was defined as BMI >=30 kg/m2. Time of sleep was categorized as: >5 h of continuous sleep/d; <=5 h of continuous sleep/d with some additional rest (sleep deprivation level I); and <=5 h of continuous sleep/d without any additional rest (sleep deprivation level II). Sociodemographic, parental and behavioural variables were evaluated by means of a standardized pre tested questionnaire. Potential confounding factors were controlled for in the multivariable model. SETTING: A poultry-processing plant in southern Brazil. SUBJECTS: Nine hundred and five shift workers (63 % female). RESULTS: Obesity was more prevalent in the participants who were female, aged 40 years and older, who had less schooling and reported excess weight in both parents. Sleep deprivation levels I and II were associated with increased income, number of meals consumed throughout the day and nightshift work. All of the workers who exhibited a degree of sleep deprivation worked the night shift. After controlling for potential confounding factors, the prevalence ratios of obesity were 1.4 (95 % CI 0.8, 2.2) and 4.4 (95 % CI 2.4, 8.0) in the workers with sleep deprivation levels I and II, respectively, compared with the reference group. CONCLUSIONS: These results show a strong association between sleep deprivation and obesity in shift workers and that sleep deprivation may be a direct consequence of working at night. PMID- 24168893 TI - Eicosapentaenoic acid-enriched phosphatidylcholine isolated from Cucumaria frondosa exhibits anti-hyperglycemic effects via activating phosphoinositide 3 kinase/protein kinase B signal pathway. AB - Eicosapentaenoic acid-enriched phosphatidylcholine was isolated from the sea cucumber Cucumaria frondosa (Cucumaria-PC) and its effects on streptozotocin (STZ)-induced hyperglycemic rats were investigated. Male Sprague-Dawley rats were randomly divided into normal control, model control (STZ), low- and high-dose Cucumaria-PC groups (STZ + Cucumaria-PC at 25 and 75 mg/Kg.b.wt, intragastrically, respectively). Blood glucose, insulin, glycogen in liver and gastrocnemius were determined over 60 days. Insulin signaling in the rats' gastrocnemius was determined by reverse transcriptase-polymerase chain reaction (RT-PCR) and Western blotting. The results showed that Cucumaria-PC significantly decreased blood glucose level, increased insulin secretion and glycogen synthesis in diabetic rats. RT-PCR analysis revealed that Cucumaria-PC significantly promoted the expressions of glycometabolism-related genes of insulin receptor (IR), insulin receptor substrate-1 (IRS-1), phosphoinositide 3-kinase (PI3K), protein kinase B (PKB), and glucose transporter 4 (GLUT4) in gastrocnemius. Western blotting assay demonstrated that Cucumaria-PC remarkably enhanced the proteins abundance of IR-beta, PI3K, PKB, GLUT4, as well as phosphorylation of Tyr-IR-beta, p85-PI3K, Ser473-PKB (P < 0.05 and P < 0.01). These findings suggested that Cucumaria-PC exhibited significant anti-hyperglycemic activities through up-regulating PI3K/PKB signal pathway mediated by insulin. Nutritional supplementation with Cucumaria-PC, if validated for human studies, may offer an adjunctive therapy for diabetes mellitus. PMID- 24168894 TI - Dangerous liaison: successful percutaneous edge-to-edge mitral valve repair in patients with end-stage systolic heart failure can cause left ventricular thrombus formation. AB - AIMS: To evaluate the characteristics and clinical outcome of patients with new formation of left ventricular (LV) thrombus after percutaneous edge-to-edge mitral valve repair. METHODS AND RESULTS: Between 2009 and 2012 we intended to treat 150 patients with severe mitral regurgitation (MR) with percutaneous edge to-edge mitral valve repair in our centre. Post-procedural transthoracic echocardiographic examinations scheduled during the hospital stay revealed the new formation of LV thrombi in three out of 150 patients. All three patients suffered from end-stage systolic heart failure with a LV ejection fraction (LVEF) below 20% and were successfully treated in terms of MR reduction (reduction of at least two MR grades). No thrombus formation was observed in patients with a LVEF >20% treated in our centre (a total of 136 patients). The frequency of new LV thrombus formation in the cohort of patients with a LVEF <=20% treated in our centre was 21% (three out of 14 patients). CONCLUSIONS: New formation of LV thrombus was detected in patients with severely depressed LVEF (<=20%) after successful reduction of MR following percutaneous edge-to-edge mitral valve repair. This phenomenon could be a play of chance, but percutaneous edge-to-edge mitral valve repair using the MitraClip system is a new procedure. Special care is needed when performing new procedures, and the unexpected post-procedural finding of LV thrombus formation in approximately 20% in this cohort is worth reporting. PMID- 24168896 TI - Causal estimation of neural and overall baroreflex sensitivity in relation to carotid artery stiffness. AB - Continuous electrocardiogram, blood pressure and carotid artery ultrasound video were analyzed from 15 diabetics and 28 healthy controls. By using these measurements artery elasticity, overall baroreflex sensitivity (BRS) assessed between RR and systolic blood pressure variation, and neural BRS assessed between RR and artery diameter variation were estimated. In addition, BRS was estimated using traditional and causal methods which enable separation of feedforward and feedback variation. The aim of this study was to analyze overall and neural BRS in relation to artery stiffness and to validate the causal BRS estimation method in assessing these two types of BRS within the study population. The most significant difference between the healthy and diabetic groups (p < 0.0007) was found for the overall BRS estimated using the causal method. The difference between the groups was also significant for neural BRS (p < 0.0018). However neural BRS was normal in some old diabetics, which indicates normal functioning of autonomic nervous system (ANS), even though the elasticity in arteries of these subjects was reduced. The noncausal method overestimated neural BRS in low BRS values when compared to causal BRS. In conclusion, neural BRS estimated using the causal method is proposed as the best marker of ANS functioning. PMID- 24168897 TI - Association of climate variability and childhood diarrhoeal disease in rural Bangladesh, 2000-2006. AB - This study examined the effects of meteorological factors, particularly, extreme weather events, on the prevalence of childhood diarrhoeal disease in Matlab, Bangladesh. Logistic regression models were used to examine impacts of temperature, rainfall and the extreme weather factors (the number of hot days and days with heavy rainfall) on childhood diarrhoea from 2000 to 2006 at the bari (cluster of dwellings) level. The results showed that the increases in the number of hot days and days with heavy rainfall were associated with an increase in daily diarrhoea cases by 0.8-3.8% and 1-6.2%, respectively. The results from multivariable stepwise models showed that the extreme weather factors were still positively associated with childhood diarrhoea, while the associations for average temperature and rainfall could be negative after other variables were controlled. The findings showed that not only the intensity, but also the frequency of extreme weather events had significant effects on childhood diarrhoea. PMID- 24168898 TI - CAD/CAM glass ceramics for single-tooth implant crowns: a finite element analysis. AB - PURPOSE: To evaluate the load distribution of CAD/CAM mono-ceramic crowns supported with single-tooth implants in functional area. MATERIALS AND METHODS: A 3-dimensional numerical model of a soft tissue-level implant was constructed with cement-retained abutment to support glass ceramic machinable crown. Implant abutment complex and the retained crown were embedded in a O 1.5 * 1.5 cm geometric matrix for evaluation of mechanical behavior of mono-ceramic CAD/CAM aluminosilicate and leucite glass crown materials. Laterally positioned axial load of 300 N was applied on the crowns. Resulting principal stresses in the mono ceramic crowns were evaluated in relation to different glass ceramic materials. RESULTS: The highest compressive stresses were observed at the cervical region of the buccal aspect of the crowns and were 89.98 and 89.99 MPa, for aluminosilicate and leucite glass ceramics, respectively. The highest tensile stresses were observed at the collar of the lingual part of the crowns and were 24.54 and 25.39 MPa, respectively. CONCLUSION: Stresses induced upon 300 N static loading of CAD/CAM aluminosalicate and leucite glass ceramics are below the compressive strength of the materials. Impact loads may actuate the progress to end failure of mono-ceramic crowns supported by metallic implant abutments. PMID- 24168899 TI - Comparison of different cleaning procedures of implant drills using TC99. AB - PURPOSE: This study was carried out to evaluate implant drills' cleaning protocols efficiency as tested by the use of nuclear medicine. METHODS: Eighty one new drills of 2 different implant systems (Nobel Biocare and BioMet 3i) were selected as study samples. Six of these drills were used as positive control group, and the rest were contaminated with TC-labeled blood. The instruments were divided randomly into 5 groups (negative control group; group 1: immersion and brushing; group 2: immersion and brushing and then evaluation under magnifier; group 3: immersion and brushing and then ultrasonic cleaning for 15 minutes; and group 4: immersion and brushing and then ultrasonic cleaning for 30 minutes) so that every group contained equal number of each implant drills brand. Then the emitted gamma rays were counted by means of a gamma counter. RESULTS: Statistically significant differences were observed between the full cleaning protocol and ultrasonication group (P < 0.009). Immersion and brushing, and ultrasonic cleaning for 30 minutes before sterilization, were the most effective methods to remove contamination. CONCLUSIONS: Complete removal of biologic debris was not attained with any of the cleaning techniques used. It is recommended to use ultrasonic cleaner for 30 minutes after immersion and brushing to achieve the best results. PMID- 24168900 TI - Periimplant changes in different transplanted soft tissues around loaded endosseous implants in patients after oral tumor surgery. AB - PURPOSE: To examine periimplant reaction of transplanted soft tissues foreign to oral cavity when compared with local gingiva. METHODS: In 58 oral cancer patients, 210 dental implants were inserted mainly in the mandible after radical surgery and reconstruction. Ninety-six implants penetrated transplants (split skin, mucosal, platysma, pectoralis major, and intestinal) and were compared with 114 implants penetrating local gingiva. Prosthetic treatment consisted of telescopic or bar-retained overdentures or (in case of intestinal grafts) implant supported fixed prostheses. Follow-up lasted between 30 and 60 months. Plaque index, sulcus bleeding index, pocket probing depth, and width of vestibular-/oral attached mucosa were measured. RESULTS: Plaque index (before second year; P < 0.01) and pocket probing depth (after first year; P < 0.02-0.04) displayed significant differences with disadvantage for split skin grafts. Sulcus bleeding did not exceed index 1. Attached mucosa had no significant effect on periimplant health. CONCLUSION: Transplanted extraoral tissues behaved similarly when compared with local gingiva, showing no detrimental effect on periimplant health in oral cancer patients. Split skin and mucosal grafts had worst performance. PMID- 24168901 TI - Comparison of piezosurgery and conventional rotative instruments in direct sinus lifting. AB - OBJECTIVES: The purpose of this study was to compare the intraoperative and postoperative effects of Piezosurgery and conventional rotative instruments in direct sinus lifting procedure. PATIENTS AND METHODS: Twenty-three patients requiring direct sinus lifting were enrolled. The osteotomy and sinus membrane elevation were performed either with Piezosurgery tips or rotative diamond burs and manual membrane elevators. Time elapsed between bony window opening and completion of membrane elevation (duration), incidence of membrane perforation, visibility of the operation site, postoperative pain, swelling, sleeping, eating, phonetics, daily routine, and missed work as well as patient's expectation before and experience after the operation were evaluated. RESULTS: There was no significant difference between Piezosurgery and conventional groups regarding incidence of membrane perforation, duration, and operation site visibility as well as patient's expectation before and experience after the operation (P > 0.05). However, there were significantly more pain and swelling in the conventional group compared with the Piezosurgery group (P <= 0.05). CONCLUSION: Sinus lifting procedure performed with Piezosurgery causes less pain and swelling postoperatively compared with conventional technique. Patients' daily life activities and experience about the operation are not affected from the surgical technique. PMID- 24168902 TI - Bisphosphonate-related osteonecrosis of the jaw at a previously grafted sinus. AB - It had been frequently reported that surgical trauma by implant surgery can be related with the onset of bisphosphonate-related osteonecrosis of the jaw (BRONJ). Recently, a long-standing dental implant itself has also been reported to be a risk for the development of BRONJ. This article reports a case of development of BRONJ after long-term oral bisphosphonate (BP) administration and successful maxillary sinus augmentation with a xenograft and simultaneous dental implantation. Considering that the dental implant at the grafted sinus had been maintained successfully for a long period, the BRONJ in the present case was not related to surgical trauma but was regarded a spontaneous onset. The current case highlights the necessity of a long-term follow-up for BP patients with maxillary sinus augmentation for implant placement, even though the short-term progress after sinus surgery is normally uneventful. PMID- 24168903 TI - Rehabilitation with dental implants in microvascular iliac graft after solid ameloblastoma resection: a case report. AB - PURPOSE: Ameloblastoma is a true odontogenic tumor that is most frequently found in clinical practice. Osseous resection with clear margins is the recommended treatment followed by bone reconstruction, such as a vascularized graft. The use of osseointegrated dental implants for rehabilitation is advisable, as it allows the recovery of the masticatory function. MATERIALS AND METHODS: This case report includes 1 subject, a patient who presented with a large ameloblastoma treated by resection, a microvascular iliac graft, and dental implants. RESULTS: After 6 months of regular control, the patient exhibited perfect healing of both the soft tissues and bone graft. At the time of this report, the patient had undergone 36 months of clinical and radiographic follow-up and had not exhibited any sign of osseous loss, implant mobility, or tumor recurrence. CONCLUSIONS: The outcome of this case indicates that a microvascular graft and subsequent dental implantation is a good treatment plan that aids in a quick functional rehabilitation in ameloblastoma patients. PMID- 24168904 TI - Associations between dairy protein intake and body weight and risk markers of diabetes and CVD during weight maintenance. AB - Dairy products have previously been reported to be associated with beneficial effects on body weight and metabolic risk markers. Moreover, primary data from the Diet, Obesity and Genes (DiOGenes) study indicate a weight-maintaining effect of a high-protein-low-glycaemic index diet. The objective of the present study was to examine putative associations between consumption of dairy proteins and changes in body weight and metabolic risk markers after weight loss in obese and overweight adults. Results were based on secondary analyses of data obtained from overweight and obese adults who completed the DiOGenes study. The study consisted of an 8-week weight-loss phase and a 6-month weight-maintenance (WM) phase, where the subjects were given five different diets varying in protein content and glycaemic index. In the present study, data obtained from all the subjects were pooled. Dairy protein intake was estimated from 3 d dietary records at two time points (week 4 and week 26) during the WM phase. Body weight and metabolic risk markers were determined at baseline (week -9 to -11) and before and at the end of the WM phase (week 0 and week 26). Overall, no significant associations were found between consumption of dairy proteins and changes in body weight and metabolic risk markers. However, dairy protein intake tended to be negatively associated with body weight gain (P=0.08; beta=-0.17), but this was not persistent when controlled for total protein intake, which indicates that dairy protein adds no additional effect to the effect of total protein. Therefore, the present study does not report that dairy proteins are more favourable than other proteins for body weight regulation. PMID- 24168905 TI - Communication between coronary aneurysmal malformations and the left atrium. PMID- 24168906 TI - A spontaneously closed, acquired supravalvular Gerbode defect mimicking an unruptured sinus of Valsalva aneurysm. PMID- 24168907 TI - Non-tropical endomyocardial fibrosis associated with sarcoidosis. PMID- 24168908 TI - Unusual cause of acute coronary syndrome: dynamic coronary compression by an aortic pseudoaneurysm. PMID- 24168909 TI - Left atrial size and function by three-dimensional echocardiography to predict arrhythmia recurrence after first and repeated ablation of atrial fibrillation. AB - AIMS: Left atrial (LA) size has been related to the success of radiofrequency catheter ablation (RFCA) for atrial fibrillation (AF). However, potential predictors after a repeated procedure are unknown. We evaluate predictive factors related to successful AF ablation after a first and a repeated RFCA. METHODS AND RESULTS: A total of 154 patients with AF were treated with RFCA. LA size and function were assessed with three-dimensional echocardiography (3D Echo) before RFCA. The effectiveness of RFCA was evaluated after 6 months. Recurrence of the arrhythmia was defined as any documented (clinically or by 24-h Holter recording) atrial tachyarrhythmia lasting >30 s after 12 weeks following RFCA. Of 154 patients, 103 (67%) underwent a first ablation (Group 1) and 51 (33%) a repeated RFCA (Group 2). At follow-up, arrhythmias were eliminated in 56 of 103 (54%) patients after a first RFCA and in 20 of 51 (40%) after a repeated ablation. In Group I, hypertension and LA expansion index derived from 3D Echo were independent predictors of arrhythmia elimination. In Group 2, only age predicted persistence of sinus rhythm; and only in younger patients (<=54 year old), though 3D LA maximal volumes were significantly smaller in those without when compared with those with AF recurrences. CONCLUSION: A combination of the analysis of LA function with 3D Echo and clinical data predicts elimination of AF after a first ablation procedure for AF, beyond LA size. Among patients undergoing a repeated procedure, age and 3D echocardiographic LA maximum volume in younger patients predict the success of RFCA. PMID- 24168912 TI - Women who doctor shop for prescription drugs. AB - Doctor shopping is a term used to describe a form of diversion of prescription drugs when patients visit numerous prescribers to obtain controlled drugs for illicit use. Gender differences exist in regard to prescription drug abuse and methods of diversion. The purpose of this phenomenological study guided by the existential philosophy of Merleau-Ponty was to understand the lived experience of female doctor shoppers. Interviews were conducted with 14 women, which were recorded, transcribed, and analyzed. Included in the findings are figural aspects of the participants' experience of doctor shopping related to the existential grounds of world, time, body, and others. Four themes emerged from the data: (a) feeding the addiction, (b) networking with addicts, (c) playing the system, and (d) baiting the doctors. The findings suggest several measures that nurses can take to reduce the incidence of doctor shopping and to provide better care for female doctor shoppers. PMID- 24168911 TI - Nurses' perceptions of the factors which cause violence and aggression in the emergency department: a qualitative study. AB - There has been an increase in violence and aggression in emergency departments (EDs) in recent years. Among professional health care workers, nurses are more likely than other staff members to be involved in aggressive incidents with patients or relatives. This research study was undertaken to determine nurses' perceptions of the factors that cause violence and aggression in the ED. Using a qualitative approach, twelve nurses working in an Irish ED were interviewed. Thematic analysis of the interview data revealed that environmental and communication factors contributed to violence and aggression in the ED. Participants perceived waiting times and lack of communication as contributing factors to aggression, and triage was the area in the ED where aggression was most likely to occur. A number of key recommendations arise from the study findings and they all relate to communication. To address the aggression that may arise from waiting times, electronic boards indicating approximate waiting times may be useful. Also, information guides and videotapes on the patient's journey through the ED may be of benefit. Consideration to the appointment of a communication officer in the ED and communication training for ED staff is also recommended. PMID- 24168913 TI - Pemphigus herpetiformis with progression to pemphigus foliaceus: a case report. PMID- 24168914 TI - Can high-frequency skin ultrasound be used for the diagnosis and management of Basal cell carcinoma? PMID- 24168915 TI - Vascular endothelial growth factor inhibitor-induced hypertension: from pathophysiology to prevention and treatment based on long-acting nitric oxide donors. AB - Hypertension is the most common adverse effect of the inhibitors of vascular endothelial growth factor (VEGF) pathway-based therapy (VEGF pathway inhibitors therapy, VPI therapy) in cancer patients. VPI includes monoclonal antibodies against VEGF, tyrosine kinase inhibitors, VEGF Traps, and so-called aptamers that may become clinically relevant in the future. All of these substances inhibit the VEGF pathway, which in turn causes a decrease in nitric oxide (NO) and an increase in blood pressure, with the consequent development of hypertension and its final events (e.g., myocardial infarction or stroke). To our knowledge, there is no current study on how to provide an optimal therapy for patients on VPI therapy with hypertension. This review summarizes the roles of VEGF and NO in vessel biology, provides an overview of VPI agents, and suggests a potential treatment procedure for patients with VPI-induced hypertension. PMID- 24168916 TI - Association of ambulatory blood pressure and heart rate with advanced white matter lesions in ischemic stroke patients. AB - BACKGROUND: White matter lesions (WMLs) are a common finding in stroke patients, and the most important risk factors are old age and hypertension. Although many studies have described the association between WMLs and ambulatory blood pressure monitoring (ABPM) parameters in healthy subjects and hypertensive patients, little is known about the association in hypertensive ischemic stroke patients. METHODS: From July 2009 to June 2012, 169 consecutive hypertensive noncardioembolic ischemic stroke patients were recruited within 1 week of suffering a stroke, and ABPM was applied 1 or 2 weeks after stroke onset. The subjects were classified into 2 groups according to the presence of advanced WMLs, and their ABPM parameters were compared. Finally, multivariable logistic regression analyses were performed to investigate the independent relationships between WMLs and ABPM parameters. RESULTS: Seventy (41%) patients had advanced WMLs. In univariable analysis, higher 24-hour, awake, and asleep systolic blood pressure (SBP)/diastolic blood pressure levels and 24-hour pulse pressure were associated with advanced WMLs. However, circadian blood pressure parameters such as 24-hour BP variability, morning surge, and nocturnal dipping pattern were not associated with advanced WMLs. After adjustments, old age (odds ratio (OR) = 1.063; 95% confidence interval (CI) = 1.024-1.104; P = 0.002), high 24-hour SBP levels (OR = 1.055; 95% CI = 1.028-1.082; P < 0.001), and high 24-hour heart rate (OR = 1.041; 95% CI = 1.006-1.078; P = 0.023) were independently associated with advanced WMLs. CONCLUSIONS: In addition to old age and elevated 24-hour SBP, increased heart rate is associated with advanced WMLs in ischemic stroke patients. Heart rate deserves more attention in predicting advanced WMLs in those patients. PMID- 24168917 TI - Amlodipine increased endothelial nitric oxide and decreased nitroxidative stress disproportionately to blood pressure changes. AB - BACKGROUND: Clinical trials have shown that amlodipine reduces cardiovascular events at a rate that is not predicted by changes in brachial arterial pressure alone. These findings may be explained, in part, by the pleiotropic effects of amlodipine on endothelial cell (EC) function. In this study, we elucidated the effect of amlodipine on nitric oxide (NO) bioavailability and cytotoxic peroxynitrite (ONOO(-)) and blood pressure (BP). METHODS: Spontaneously hypertensive rats (SHRs) were treated with vehicle or amlodipine (5 mg/kg/day) for 8 weeks and compared with untreated, baseline rats. NO and ONOO(-) release from aortic and glomerular ECs were measured ex vivo using amperometric nanosensors following maximal stimulation with calcium ionophore. BP was measured using the tail-cuff method. RESULTS: As compared with baseline, vehicle treatment had reduced aortic endothelial NO release from 157 +/- 11 nM to 55 +/- 6 nM and increased ONOO(-) from 69 +/- 7 nM to 156 +/- 19 nM. The NO/ONOO(-) ratio, a comprehensive measurement of eNOS function, decreased from 2.3 +/- 0.3 to 0.3 +/- 0.1. Compared with vehicle, amlodipine treatment restored NO to 101 +/- 3 nM, decreased ONOO(-) to 50 +/- 4 nM, and increased the NO/ONOO(-) ratio to 2.0 +/- 0.2, a level similar to baseline. Similar changes were observed for glomerular ECs. Mean arterial blood pressure increased from 149 +/- 3 mm Hg (baseline) to 174 +/- 1 mm Hg (vehicle). Amlodipine slightly, but significantly, decreased mean arterial blood pressure to 167 +/- 3 mm Hg vs. vehicle treatment. CONCLUSIONS: Amlodipine increased NO bioavailability and decreased nitroxidative stress in SHRs with EC dysfunction disproportionately to BP changes. These direct, vascular effects of amlodipine on EC function may contribute to reduced risk for atherothrombotic events as observed in clinical trials. PMID- 24168919 TI - Pharmacogenetic-guided selection of warfarin versus novel oral anticoagulants for stroke prevention in patients with atrial fibrillation: a cost-effectiveness analysis. AB - OBJECTIVES: To compare clinical and economic outcomes of two anticoagulation therapy strategies, (i) pharmacogenetic-guided selection (PG-AC) of warfarin versus novel oral anticoagulants (NOACs), and (ii) usual anticoagulation care (usual AC) in patients with atrial fibrillation (AF), from the perspective of US healthcare payers. METHODS: A Markov model was used to simulate long-term outcomes in a hypothetical cohort of 65-year-old patients with newly diagnosed AF: (i) all usual AC patients received warfarin therapy, and (ii) all PG-AC patients were genotyped. Patients with normal warfarin sensitivity genotypes would receive warfarin. Patients with high or low warfarin sensitivity genotypes would receive NOAC. Model inputs were derived from clinical trials published in the literature. The outcome measure was incremental cost per quality-adjusted life-year (QALY) gained (ICER). RESULTS: PG-AC gained higher QALYs with higher cost (9.912 QALYs and USD94 396) when compared with usual AC (9.721 QALYs and USD93 853) in base-case analysis. The ICER of PG-AC was 2843 USD/QALY. The ICER of PG-AC would exceed 50 000 USD/QALY if the monthly cost of NOAC was more than USD285 or the risk of stroke with NOAC versus warfarin was more than 0.93. In 10 000 Monte Carlo simulations, PG-AC was cost-effective 96.4% of the time and usual AC was cost-effective 3.6% of the time. PG-AC was more costly than usual AC with a mean cost difference of USD1927 (95% confidence interval 1.877-1.977, P<0.001), and gained higher QALYs by 0.209 (95% confidence interval 0.208-0.210, P<0.001). CONCLUSION: Compared with warfarin therapy with time in therapeutic range of 60%, using genotype to triage AF patients to warfarin or NOAC appears to be highly cost-effective. PMID- 24168918 TI - Association of total protein intake with bone mineral density and bone loss in men and women from the Framingham Offspring Study. AB - OBJECTIVE: To examine (i) the association of percentage of total energy intake from protein (protein intake %) with bone mineral density (BMD, g/cm2) and bone loss at the femoral neck, trochanter and lumbar spine (L2-L4) and (ii) Ca as an effect modifier. SETTING: The Framingham Offspring Study. SUBJECTS: Men (n 1280) and women (n 1639) completed an FFQ in 1992-1995 or 1995-1998 and underwent baseline BMD measurement by dual-energy X-ray absorptiometry in 1996-2000. Men (n 495) and women (n 680) had follow-up BMD measured in 2002-2005. DESIGN: Cohort study using multivariable regression to examine the association of protein intake % with each BMD, adjusting for covariates. Statistical interaction between protein intake % and Ca (total, dietary, supplemental) intake was examined. RESULTS: The mean age at baseline was 61 (sd 9) years. In the cross-sectional analyses, protein intake % was positively associated with all BMD sites (P range: 0.02-0.04) in women but not in men. Significant interactions were observed with total Ca intake (<800 mg/d v. >=800 mg/d) in women at all bone sites (P range: 0.002-0.02). Upon stratification, protein intake % was positively associated with all BMD sites (P range: 0.04-0.10) in women with low Ca intakes but not in those with high Ca intakes. In the longitudinal analyses, in men, higher protein intake % was associated with more bone loss at the trochanter (P = 0.01) while no associations were seen in women, regardless of Ca intake. CONCLUSIONS: This suggests that greater protein intake benefits women especially those with lower Ca intakes. However, protein effects are not significant for short-term changes in bone density. Contrastingly, in men, higher protein intakes lead to greater bone loss at the trochanter. Longer follow-up is required to examine the impact of protein on bone loss. PMID- 24168920 TI - Introduction. The dual loop model in language and other modalities: an interdisciplinary approach. PMID- 24168921 TI - Consolidation therapy after concurrent radiochemotherapy? Still unclear who may potentially benefit! PMID- 24168923 TI - Changing management of head and neck cancer. PMID- 24168922 TI - The degree of microRNA-34b/c methylation in serum-circulating DNA is associated with malignant pleural mesothelioma. AB - OBJECTIVES: Malignant pleural mesothelioma (MPM) is an aggressive tumor with a poor prognosis. microRNA-34b/c (miR-34b/c), which plays an important role in the pathogenesis of MPM, is frequently downregulated by DNA methylation in approximately 90% of MPM cases. In this study, we estimated the degree of miR 34b/c methylation in serum-circulating DNA using a digital methylation specific PCR assay (MSP). MATERIALS AND METHODS: A real-time MSP assay was performed using the SYBR Green method. The melting temperature (Tm) of each PCR product was examined using a melting curve analysis. For a digital MSP assay, 40 wells were analyzed per sample. A total of 110 serum samples from 48 MPM cases, 21 benign asbestos pleurisy (BAP) cases, and 41 healthy volunteers (HVs) were examined. RESULTS: Positive range of Tm value for miR-34b/c methylation was defined as 77.71-78.79 degrees C which was the mean +/- 3 standard deviations of 40 wells of a positive control. The number of miR-34b/c methylated wells was counted per sample according to this criterion. The number of miR-34b/c methylated wells in MPM cases was significantly higher than that in BAP cases (P=0.03) or HVs (P<0.001). Advanced MPM cases tended to have higher number of miR-34b/c methylated wells than early MPM cases. Receiver-operating characteristic (ROC) curve analysis revealed that three number of miR-34b/c methylated wells per sample was the best cut-off of positivity of MPM with a 67% of sensitivity and a 77% specificity for prediction. The area under the ROC curve was 0.77. CONCLUSIONS: Our digital MSP assay can quantify miR-34b/c methylation in serum circulating DNA. The degree of miR-34b/c methylation in serum-circulating DNA is associated with MPM, suggesting that this approach might be useful for the establishment of a new detection system for MPM. PMID- 24168924 TI - Functional analysis of a lipolytic protein encoded in phytoplasma phage based genomic island. AB - Wall-less bacteria known as phytoplasmas are obligate transkingdom parasites and pathogens of plants and insect vectors. These unusual bacteria possess some of the smallest genomes known among pathogenic bacteria, and have never been successfully isolated in artificial culture. Disease symptoms induced by phytoplasmas in infected plants include abnormal growth and often severe yellowing of leaves, but mechanisms involved in phytoplasma parasitism and pathogenicity are little understood. A phage based genomic island (sequence variable mosaic, SVM) in the genome of Malaysian periwinkle yellows (MPY) phytoplasma harbors a gene encoding membrane-targeted proteins, including a putative phospholipase (PL), potentially important in pathogen-host interactions. Since some phytoplasmal disease symptoms could possibly be accounted for, at least in part, by damage and/or degradation of host cell membranes, we hypothesize that the MPY phytoplasma putative PL is an active enzyme. To test this hypothesis, functional analysis of the MPY putative pl gene-encoded protein was carried out in vitro after its expression in bacterial and yeast hosts. The results demonstrated that the heterologously expressed phytoplasmal putative PL is an active lipolytic enzyme and could possibly act as a pathogenicity factor in the plant, and/or insect, host. PMID- 24168925 TI - Rhizosphere competent microbial consortium mediates rapid changes in phenolic profiles in chickpea during Sclerotium rolfsii infection. AB - The present study was carried out with the aim of evaluating the effectiveness and potentiality of three compatible rhizosphere microbes, viz., fluorescent Pseudomonas aeruginosa (PHU094), Trichoderma harzianum (THU0816) and Mesorhizobium sp. (RL091), in promoting plant growth and mobilizing phenolic acid biosynthesis in chickpea under challenge of Sclerotium rolfsii. The microbes were applied as seed coating in different combinations in two experimental sets and the pathogen was inoculated after 25 days of sowing in one set. Results revealed that microbe application led to higher growth in chickpea particularly in the triple microbe combination compared to their individual treatments and control. Similarly, pathogen challenged plants accumulated higher amount of phenolic compounds both at the site of attack of the pathogen i.e. collar region as well as leaves compared to unchallenged plants. All the bioagents were found to trigger the level of phenolic compounds at collar region in varying degrees as compared to the healthy control (A). However, the most effective treatment was D7 (combined application of PHU094, THU0816 and RL091 with pathogen challenge) among all the treatments. Shikimic acid was maximally induced amongst all the phenolic compounds. In leaves also, the most effective treatment was D7 where shikimic acid, t-chlorogenic acid, ferulic acid, myricetin, quercetin and syringic acid were produced in higher amounts as compared to treatment B where the plants were challenged only with the pathogen. PMID- 24168926 TI - Accuracy and interobserver agreement between MR-non-expert radiologists and MR experts in reading MRI for suspected appendicitis. AB - OBJECTIVE: To compare accuracy and interobserver agreement between radiologists with limited experience in the evaluation of abdominal MRI (non-experts), and radiologists with longer MR reading experience (experts), in reading MRI in patients with suspected appendicitis. METHODS: MR imaging was performed in 223 adult patients with suspected appendicitis and read independently by two members of a team of eight MR-inexperienced radiologists, who were trained with 100 MR examinations previous to this study (non-expert reading). Expert reading was performed by two radiologists with a larger abdominal MR experience (>500 examinations) in consensus. A final diagnosis was assigned after three months based on all available information, except MRI findings. We estimated MRI sensitivity and specificity for appendicitis and for all urgent diagnoses separately. Interobserver agreement was evaluated using kappa statistics. RESULTS: Urgent diagnoses were assigned to 147 of 223 patients; 117 had appendicitis. Sensitivity for appendicitis was 0.89 by MR-non-expert radiologists and 0.97 in MR-expert reading (p=0.01). Specificity was 0.83 for MR-non-experts versus 0.93 for MR-expert reading (p=0.002). MR-experts and MR-non-experts agreed on appendicitis in 89% of cases (kappa 0.78). Accuracy in detecting urgent diagnoses was significantly lower in MR-non-experts compared to MR-expert reading: sensitivity 0.84 versus 0.95 (p<0.001) and specificity 0.71 versus 0.82 (p=0.03), respectively. Agreement on urgent diagnoses was 83% (kappa 0.63). CONCLUSION: MR-non-experts have sufficient sensitivity in reading MRI in patients with suspected appendicitis, with good agreement with MR-expert reading, but accuracy of MR-expert reading was higher. PMID- 24168927 TI - MRI of the SI joints commonly shows non-inflammatory disease in patients clinically suspected of sacroiliitis. AB - PURPOSE: To determine the prevalence of clinically relevant non-inflammatory disease on MRI of the sacroiliac (SI) joints in patients suspected of sacroiliitis. To assess the added value of axial imaging of the pelvis in these patients. METHODS: In a retrospective study of 691 patients undergoing MRI of the SI joints from January 2006 to December 2012 for inflammatory back pain the prevalence of sacroiliitis and non-inflammatory disease was recorded. RESULTS: In 285 (41%) patients MRI did not show any abnormal findings. In 36% of patients MRI features of sacroiliitis were present. Spinal degenerative changes were the most common non-inflammatory finding in 305 patients (44.1%) and consisted of disc degeneration in 222 (32%) patients, facet joint arthrosis in 58 (8.4%) patients and disc herniation in 25 (3.6%) patients. Hip joint disease in 44 (6.4%) patients, lumbosacral transitional anomaly in 41 (5.9%) patients, SI joint degenerative changes in 25 (3.6%) patients and diffuse idiopathic skeletal hyperostosis in 24 (3.5%) patients were also common. Osteitis condensans ilii in 17 (2.5%) patients, tumour in 11 (1.6%) patients, fracture in 8 (1.2%) patients, infection in 4 (0.6%) patients and acute spondylolysis in 2 patients (0.3%) were less frequently seen. CONCLUSION: Our study shows that non-inflammatory disease is more common than true sacroiliitis on MRI of the SI joints in patients with inflammatory type back pain. Axial pulse sequences may demonstrate unexpected findings that remain undetected if only coronal images are obtained. Clinical relevance statement:, MRI of the SI joints may demonstrate conditions that clinically mimic sacroiliitis. Axial imaging of the pelvis may help detect these unexpected findings. PMID- 24168928 TI - Adhesion properties of potentially probiotic Lactobacillus kefiri to gastrointestinal mucus. AB - We investigated the mucus-binding properties of aggregating and non-aggregating potentially probiotic strains of kefir-isolated Lactobacillus kefiri, using different substrates. All the strains were able to adhere to commercial gastric mucin (MUCIN) and extracted mucus from small intestine (SIM) and colon (CM). The extraction of surface proteins from bacteria using LiCl or NaOH significantly reduced the adhesion of three selected strains (CIDCA 8348, CIDCA 83115 and JCM 5818); although a significant proportion (up to 50%) of S-layer proteins were not completely eliminated after treatments. The surface (S-layer) protein extracts from all the strains of Lb. kefiri were capable of binding to MUCIN, SIM or CM, and no differences were observed among them. The addition of their own surface protein extract increased adhesion of CIDCA 8348 and 83115 to MUCIN and SIM, meanwhile no changes in adhesion were observed for JCM 5818. None of the seven sugars tested had the ability to inhibit the adhesion of whole bacteria to the three mucus extracts. Noteworthy, the degree of bacterial adhesion reached in the presence of their own surface protein (S-layer) extract decreased to basal levels in the presence of some sugars, suggesting an interaction between the added sugar and the surface proteins. In conclusion, the ability of these food-isolated bacteria to adhere to gastrointestinal mucus becomes an essential issue regarding the biotechnological potentiality of Lb. kefiri for the food industry. PMID- 24168929 TI - Physiological and psychological effects of walking on young males in urban parks in winter. AB - BACKGROUND: Interaction with nature has a relaxing effect on humans. Increasing attention has been focused on the therapeutic effects of urban green space; however, there is a lack of evidence-based field research. This study provided scientific evidence supporting the physiological and psychological effects of walking on young males in urban parks in winter. FINDINGS: Subjects (13 males aged 22.5 +/- 3.1 years) were instructed to walk predetermined 15-minute courses in an urban park (test) and in the city area (control). Heart rate and heart rate variability (HRV) were measured to assess physiological responses. The semantic differential (SD) method, Profile of Mood States (POMS), and State-Trait Anxiety Inventory (STAI) were used to determine psychological responses.Heart rate was significantly lower and the natural logarithm of the high frequency component of HRV was significantly higher when walking through the urban park than through the city area. The results of three questionnaires indicated that walking in the urban park improved mood and decreased negative feelings and anxiety. CONCLUSIONS: Physiological and psychological data from this field experiment provide important scientific evidence regarding the health benefits of walking in an urban park. The results support the premise that walking in an urban park has relaxing effects even in winter. PMID- 24168930 TI - The monetary value of diets consumed by British adults: an exploration into sociodemographic differences in individual-level diet costs. AB - OBJECTIVE: To describe the diet costs of adults in the National Diet and Nutrition Study (NDNS) and explore patterns in costs according to sociodemographic indicators. DESIGN: Cross-sectional diet diary information was matched to a database of food prices to assign a cost to each food or non alcoholic beverage consumed. Daily diet costs were calculated, as well as costs per 10 MJ to improve comparability across differing energy requirements. Costs were compared between categories of sociodemographic variables and health behaviours. Multivariable regression assessed the effects of each variable on diet costs after adjustment. SETTING: The NDNS is a rolling dietary survey, recruiting a representative UK sample each year. The study features data from 2008-2010. SUBJECTS: Adults aged 19 years or over were included. The sample consisted of 1014 participants. RESULTS: The geometric mean daily diet cost was L2.89 (95 % CI L2.81, L2.96). Energy intake and daily diet cost were strongly associated. The mean energy-adjusted cost was L4.09 (95 % CI L4.01, L4.18) per 10 MJ. Energy-adjusted costs differed significantly between many subgroups, including by sex and household income. Multivariable regression found significant effects of sex, qualifications and occupation (costs per 10 MJ only), as well as equivalized household income, BMI and fruit and vegetable consumption on diet costs. CONCLUSIONS: This is the first time that monetary costs have been applied to the diets of NDNS adults. The findings suggest that certain subgroups in the UK - for example those on lower incomes - consume diets of lower monetary value. Observed differences were mostly in the directions anticipated. PMID- 24168931 TI - Decrease of pulmonary hypertension impacts on prognosis after transcatheter aortic valve replacement. AB - AIMS: Transcatheter aortic valve replacement (TAVR) is established as a treatment strategy for patients with end-stage aortic stenosis, many of whom are suffering from severe pulmonary hypertension (PH). In cardiac surgery patients, PH is associated with less symptomatic improvement and increased late mortality. This study elucidates the impact of PH on outcome after TAVR. METHODS AND RESULTS: Pre and 90 days post-TAVR, pulmonary artery systolic pressure (PASP) was determined non-invasively by echocardiography in 353 patients undergoing TAVR. PH was classified as absent (<30 mmHg), mild-to-moderate (30-60 mmHg), and severe (>60 mmHg). Three hundred and fifty-three patients at high surgical risk, indicated by a logistic EuroSCORE of 26.6+/-16.5%, underwent TAVR. The severity of PH before TAVR was related to outcome with two-year mortality rates of 13.9%, 27.3%, and 48.4% for PASP <30 mmHg, 30-60 mmHg, and >60 mmHg, respectively (p=0.001). In patients with baseline PASP >60 mmHg, PASP decreased from 65.6+/-7.6 mmHg to 49.5+/-14.0 mmHg (p<0.001) at 90 days after TAVR. Patients with persistent severe PH had a worse prognosis than patients with a decrease of PASP below 60 mmHg (two year mortality rate: 50.0% vs. 18.6%; p=0.001). CONCLUSIONS: Severe pulmonary hypertension predicts adverse outcome after TAVR. Reduction of PASP after the procedure is associated with favourable prognosis. PMID- 24168933 TI - Linking brain imaging signals to visual perception. AB - The rapid advances in brain imaging technology over the past 20 years are affording new insights into cortical processing hierarchies in the human brain. These new data provide a complementary front in seeking to understand the links between perceptual and physiological states. Here we review some of the challenges associated with incorporating brain imaging data into such "linking hypotheses," highlighting some of the considerations needed in brain imaging data acquisition and analysis. We discuss work that has sought to link human brain imaging signals to existing electrophysiological data and opened up new opportunities in studying the neural basis of complex perceptual judgments. We consider a range of approaches when using human functional magnetic resonance imaging to identify brain circuits whose activity changes in a similar manner to perceptual judgments and illustrate these approaches by discussing work that has studied the neural basis of 3D perception and perceptual learning. Finally, we describe approaches that have sought to understand the information content of brain imaging data using machine learning and work that has integrated multimodal data to overcome the limitations associated with individual brain imaging approaches. Together these approaches provide an important route in seeking to understand the links between physiological and psychological states. PMID- 24168932 TI - A review of the distribution coefficients of trace elements in soils: influence of sorption system, element characteristics, and soil colloidal properties. AB - Knowledge about the behavior and reactions of separate soil components with trace elements (TEs) and their distribution coefficients (Kds) in soils is a key issue in assessing the mobility and retention of TEs. Thus, the fate of TEs and the toxic risk they pose depend crucially on their Kd in soil. This article reviews the Kd of TEs in soils as affected by the sorption system, element characteristics, and soil colloidal properties. The sorption mechanism, determining factors, favorable conditions, and competitive ions on the sorption and Kd of TEs are also discussed here. This review demonstrates that the Kd value of TEs does not only depend on inorganic and organic soil constituents, but also on the nature and characteristics of the elements involved as well as on their competition for sorption sites. The Kd value of TEs is mainly affected by individual or competitive sorption systems. Generally, the sorption in competitive systems is lower than in mono-metal sorption systems. More strongly sorbed elements, such as Pb and Cu, are less affected by competition than mobile elements, such as Cd, Ni, and Zn. The sorption preference exhibited by soils for elements over others may be due to: (i) the hydrolysis constant, (ii) the atomic weight, (iii) the ionic radius, and subsequently the hydrated radius, and (iv) its Misono softness value. Moreover, element concentrations in the test solution mainly affect the Kd values. Mostly, values of Kd decrease as the concentration of the included cation increases in the test solution. Additionally, the Kd of TEs is controlled by the sorption characteristics of soils, such as pH, clay minerals, soil organic matter, Fe and Mn oxides, and calcium carbonate. However, more research is required to verify the practical utilization of studying Kd of TEs in soils as a reliable indicator for assessing the remediation process of toxic metals in soils and waters. PMID- 24168934 TI - Effect of dietary inclusion of whole ear corn silage on stomach development and gastric mucosa integrity of heavy pigs at slaughter. AB - The effect of dietary inclusion of whole ear corn silage on stomach development and on the incidence of gastric lesions was studied in heavy pigs. Three groups of 14 castrated male pigs were fed a control cereal-based diet and two diets containing whole ear corn silage (15% or 30% DM) from 90 kg bodyweight to slaughter at 170 kg. The diets with whole ear corn silage increased the amount of neutral detergent fibre in the stomach contents, the weight of the organs and the area of the pyloric region. Follicular gastritis was significantly lower and gastritis less severe in pigs fed the whole ear corn silage diets than pigs fed the control diet. The inclusion of whole ear corn silage in the diet influenced the development of the stomach and reduced the incidence of gastritis in heavy pigs. PMID- 24168935 TI - The view from 30,000 feet. PMID- 24168936 TI - Ways to guarantee minority faculty will quit academic medicine. PMID- 24168937 TI - In reply to Rodriguez and Campbell. PMID- 24168938 TI - In support of medical student research. PMID- 24168939 TI - The importance of real-time feedback in undergraduate assessments. PMID- 24168941 TI - Artist's Statement: Road Trip Sky. PMID- 24168940 TI - "Moments of magic" require culture change. PMID- 24168942 TI - Learning together to practice together. PMID- 24168943 TI - Dr. Nurse, nurse doctor: blurring the lines of professional identity. PMID- 24168944 TI - Doctors and nurses through the patient's eyes. PMID- 24168945 TI - Toward mutuality and kinship in health care. PMID- 24168946 TI - What is a nurse? "A missioner of health". PMID- 24168948 TI - Working as a team to improve patient care in the intensive care unit. PMID- 24168947 TI - Medicine and nursing: parallel avenues to patient care. PMID- 24168949 TI - A new line of work. PMID- 24168950 TI - Medicine and the arts. That 2,000-yard stare by Tom Lea. Commentary. PMID- 24168952 TI - 2013 Humanism in Medicine Essay Contest: second place: caregiving as good doctoring. PMID- 24168953 TI - The heart of listening. PMID- 24168954 TI - AM last page: common evaluation designs in medical education I. PMID- 24168955 TI - A simple approach to obtain comparable Shigella sonnei MLVA results across laboratories. AB - Multilocus variable-number tandem repeat analysis (MLVA) is a promising subtyping tool to complement pulsed-field gel electrophoresis for discriminating closely related strains of some monomorphic organisms, including Shigella sonnei, which is one of the major foodborne pathogens. However, MLVA results are usually difficult to compare directly between laboratories, impeding the application of MLVA as a subtyping tool for disease surveillance and investigation of common outbreaks across regions or countries. It has long been a big challenge in seeking an approach that can be implemented to obtain comparable MLVA results across laboratories. By implementing a panel of calibration strains in each participating laboratory for data normalization, the MLVA results of 20 test strains were comparable even though some analytical conditions were different among the laboratories. This approach is simple, protocol independent, and easy to implement in every laboratory, and a small calibration set is sufficient to generate mathematical equations for accurate copy number conversion. PMID- 24168956 TI - Adjustment of therapy in rheumatoid arthritis on the basis of achievement of stable low disease activity with adalimumab plus methotrexate or methotrexate alone: the randomised controlled OPTIMA trial. AB - BACKGROUND: Biological agents offer good control of rheumatoid arthritis, but the long-term benefits of achieving low disease activity with a biological agent plus methotrexate or methotrexate alone are unclear. The OPTIMA trial assessed different treatment adjustment strategies in patients with early rheumatoid arthritis attaining (or not) stable low disease activity with adalimumab plus methotrexate or methotrexate monotherapy. METHODS: This trial was done at 161 sites worldwide. Patients with early (<1 year duration) rheumatoid arthritis naive to methotrexate were randomly allocated (by interactive voice response system, in a 1:1 ratio, block size four) to adalimumab (40 mg every other week) plus methotrexate (initiated at 7.5 mg/week, increased by 2.5 mg every 1-2 weeks to a maximum weekly dose of 20 mg by week 8) or placebo plus methotrexate for 26 weeks (period 1). Patients in the adalimumab plus methotrexate group who completed period 1 and achieved the stable low disease activity target (28-joint disease activity score with C-reactive protein [DAS28]<3.2 at weeks 22 and 26) were randomised to adalimumab-continuation or adalimumab-withdrawal for an additional 52 weeks (period 2). Patients achieving the target with initial methotrexate continued methotrexate-monotherapy. Inadequate responders were offered adalimumab plus methotrexate. All patients and investigators were masked to treatment allocation in period 1. During period 2, treatment reallocation of patients who achieved the target was masked to patients and investigators; patients who did not achieve the target remained masked to original randomisation, but were aware of the subsequent assignment. The primary endpoint was a composite measure of DAS28 of less than 3.2 at week 78 and radiographic non progression from baseline to week 78, compared between adalimumab-continuation and methotrexate-monotherapy. Adverse events were monitored throughout period 2. This trial is registered with ClinicalTrials.gov, number NCT00420927. FINDINGS: The study was done between Dec 28, 2006, and Aug 3, 2010. 1636 patients were assessed and 1032 were randomised in period 1 (515 to adalimumab plus methotrexate; 517 to placebo plus methotrexate). 466 patients in the adalimumab plus methotrexate group completed period 1; 207 achieved the stable low disease activity target, of whom 105 were rerandomised to adalimumab-continuation. 460 patients in the placebo plus methotrexate group completed period 1; 112 achieved the stable low disease activity target and continued methotrexate-monotherapy. 73 of 105 (70%) patients in the adalimumab-continuation group and 61 of 112 (54%) patients in the methotrexate-monotherapy group achieved the primary endpoint at week 78 (mean difference 15% [95% CI 2-28%], p=0.0225). Patients achieving the stable low disease activity target on adalimumab plus methotrexate who withdrew adalimumab mostly maintained their good responses. Overall, 706 of 926 patients in period 2 had an adverse event, of which 82 were deemed serious; however, distribution of adverse events did not differ between groups. INTERPRETATION: Treatment to a stable low disease activity target resulted in improved clinical, functional, and structural outcomes, with both adalimumab-continuation and methotrexate-monotherapy. However, a higher proportion of patients treated with initial adalimumab plus methotrexate achieved the low disease activity target compared with those initially treated with methotrexate alone. Outcomes were much the same whether adalimumab was continued or withdrawn in patients who initially responded to adalimumab plus methotrexate. FUNDING: AbbVie. PMID- 24168958 TI - Improved medical treatment in secondary prevention of stroke. PMID- 24168959 TI - Biological treatment in rheumatoid arthritis: when to stop? PMID- 24168960 TI - GPs may be the last port of call in suicide. PMID- 24168962 TI - The Bonebridge semi-implantable bone conduction hearing device: experience in an Asian patient. AB - For over three decades, bone conduction hearing aids have been changing the lives of patients with impaired hearing. The size, appearance and fitting discomfort of early generations of bone conduction hearing aids made them unpopular. The advent of bone-anchored hearing aids in the 1970s offered patients improved sound quality and fitting comfort, due to the application of osseointegration. However, the issue of post-operative peri-abutment pin tract wound infection persisted. The Bonebridge system incorporates the first active bone conduction device, and aims to resolve peri-abutment issues. Implantation of this system in an Asian patient is presented. PMID- 24168963 TI - MALDI-TOF mass spectrometry as a tool for differentiation of Bradyrhizobium species: application to the identification of Lupinus nodulating strains. AB - Genus Bradyrhizobium includes slow growing bacteria able to nodulate different legumes as well as species isolated from plant tumours. The slow growth presented by the members of this genus and the phylogenetic closeness of most of its species difficults their identification. In the present work we applied for the first time Matrix-Assisted Laser Desorption Ionization-Time-of-Flight Mass Spectrometry (MALDI-TOF MS) to the analysis of Bradyrhizobium species after the extension of MALDI Biotyper 2.0 database with the currently valid species of this genus. With this methodology it was possible to identify strains belonging to phylogenetically closely related species of genus Bradyrhizobium allowing the discrimination among species with rrs gene identities higher than 99%. The application of MALDI-TOF MS to strains isolated from nodules of different Lupinus species in diverse geographical locations allowed their correct identification when comparing with the results of rrs gene and ITS analyses. The nodulation of Lupinus gredensis, an endemic species of the west of Spain, by B. canariense supports the European origin of this species. PMID- 24168964 TI - Dendritic cells in tolerance and autoimmune diabetes. AB - Type 1 diabetes is a T cell mediated autoimmune disease where both central and peripheral mechanisms effect T cell tolerance induction. Dendritic cells (DCs) are key regulators of innate and adaptive immune responses. They significantly contribute to central and peripheral T cell tolerance and, following maturation, induce the activation and differentiation of naive T cells into effector and memory cells. DCs are also major actors in inflammation. Given these multiple effects on immune responses, DCs are suspected to contribute to autoimmune diseases. In this review we discuss how some specific features of DC may contribute to type 1 diabetes. PMID- 24168965 TI - Beyond the transcriptome: completion of act one of the Immunological Genome Project. AB - The Immunological Genome Consortium has generated a public resource (www.immgen.org) that provides a compendium of gene expression profiles of ~270 leukocyte subsets in the mouse. This effort established carefully standardized operating procedures that resulted in a transcriptional dataset of unprecedented comprehensiveness and quality. The findings have been detailed recently in a series of publications providing molecular insights into the development, heterogeneity, and/or function of these cellular lineages and distinct subpopulations. Here, we review the key findings of these studies, highlighting what has been gained and how the knowledge can be used to accelerate progress toward a comprehensive understanding of the immune system. PMID- 24168966 TI - Multicentric reticulohistiocytosis with extra-mammillary Paget's disease: a case report. AB - Multicentric reticulohistiocytosis (MRH) is a very rare systemic disease with variable phenotypic presentation and a high rate of misdiagnosis. Here we describe a patient with MRH and extra-mammillary Paget's disease (EMPD), a diagnosis that has not previously been described in the literature. PMID- 24168967 TI - miR-9 regulation of BRCA1 and ovarian cancer sensitivity to cisplatin and PARP inhibition. AB - BACKGROUND: Expression of BRCA1 is commonly decreased in sporadic ovarian cancer, and this is associated with platinum sensitivity and favorable prognosis. However, multiple mechanisms underlying low BRCA1 expression are not fully understood. METHODS: A bioinformatics-driven microRNA (miR) library screening was used to identify miRs that regulate BRCA1 expression. The effects of miR-9 on cisplatin (cDDP) and PARP inhibitor sensitivity were measured in ovarian cancer cells and C13* xenograft mice (n = 6 per group). The roles of miR-9 on prognosis were assessed in a cohort of ovarian cancer patients (n = 113) with Kaplan-Meier and Cox proportional hazards analyses. All statistical tests were two-sided. RESULTS: Reverse miR library screening revealed that miR-9 reduced the normalized luciferase activity to 60.3% (95% confidence interval [CI] = 52.0% to 68.5%; P < .001). miR-9 bound directly to the 3'-UTR of BRCA1 and downregulated BRCA1 expression in ovarian cancer cells. Treatment with miR-9 agomiR sensitized BRCA1 proficient C13* xenograft tumors to cisplatin and AG014699. In serous ovarian cancer, higher levels of miR-9 were inversely correlated with BRCA1 expression (Spearman rank correlation: R (2) = 0.379; P = .003). Patients with higher levels of miR-9 had better chemotherapy response, platinum sensitivity, and longer progression-free survival (PFS) (high vs low miR-9 expression: median PFS = 26.4 months, 95% CI = 13.8 to 39.0 months vs median PFS = 15.4 months, 95% CI = 6.8 to 23.9 months, P = .01). CONCLUSIONS: miR-9 mediates the downregulation of BRCA1 and impedes DNA damage repair in ovarian cancer. miR-9 may improve chemotherapeutic efficacy by increasing the sensitivity of cancer cells to DNA damage and may impact ovarian cancer therapy. PMID- 24168969 TI - Re: Risks of colorectal and other cancers after endometrial cancer for women with Lynch syndrome. PMID- 24168970 TI - Response. PMID- 24168968 TI - Germline genetic contributions to risk for esophageal adenocarcinoma, Barrett's esophagus, and gastroesophageal reflux. AB - BACKGROUND: Esophageal adenocarcinoma (EA) is an increasingly common cancer with poor survival. Barrett's esophagus (BE) is the main precursor to EA, and every year 0.12% to 0.5% of BE patients progress to EA. BE typically arises on a background of chronic gastroesophageal reflux (GERD), one of the risk factors for EA. METHODS: We used genome-wide association data to investigate the genetic architecture underlying GERD, BE, and EA. We applied a method to estimate the variance explained (array heritability, h(2)g) and the genetic correlation (rg) between GERD, BE, and EA by considering all single nucleotide polymorphisms (SNPs) simultaneously. We also estimated the polygenic overlap between GERD, BE, and EA using a prediction approach. All tests were two-sided, except in the case of variance-explained estimation where one-sided tests were used. RESULTS: We estimated a statistically significant genetic variance explained for BE (h(2)g = 35%; standard error [SE] = 6%; one-sided P = 1 * 10(-9)) and for EA (h(2)g = 25 %; SE = 5%; one-sided P = 2 * 10(-7)). The genetic correlation between BE and EA was found to be high (rg = 1.0; SE = 0.37). We also estimated a statistically significant polygenic overlap between BE and EA (one-sided P = 1 * 10(-6)), which suggests, together with the high genetic correlation, that shared genes underlie the development of BE and EA. Conversely, no statistically significant results were obtained for GERD. CONCLUSIONS: We have demonstrated that risk to BE and EA is influenced by many germline genetic variants of small effect and that shared polygenic effects contribute to risk of these two diseases. PMID- 24168971 TI - Enhanced tumor uptake and penetration of virotherapy using polymer stealthing and focused ultrasound. AB - BACKGROUND: Oncolytic viruses are among the most powerful and selective cancer therapeutics under development and are showing robust activity in clinical trials, particularly when administered directly into tumor nodules. However, their intravenous administration to treat metastatic disease has been stymied by unfavorable pharmacokinetics and inefficient accumulation in and penetration through tumors. METHODS: Adenovirus (Ad) was "stealthed" with a new N-(2 hydroxypropyl)methacrylamide polymer, and circulation kinetics were characterized in Balb/C SCID mice (n = 8 per group) bearing human ZR-75-1 xenograft tumors. Then, to noninvasively increase extravasation of the circulating polymer-coated Ad into the tumor, it was coinjected with gas microbubbles and the tumor was exposed to 0.5 MHz focused ultrasound at peak rarefactional pressure of 1.2 MPa. These ultrasound exposure conditions were designed to trigger inertial cavitation, an acoustic phenomenon that produces shock waves and can be remotely monitored in real-time. Groups were compared with Student t test or one-way analysis of variance with Tukey correction where groups were greater than two. All statistical tests were two-sided. RESULTS: Polymer-coating of Ad reduced hepatic sequestration, infection (>8000-fold; P < .001), and toxicity and improved circulation half-life (>50-fold; P = .001). Combination of polymer coated Ad, gas bubbles, and focused ultrasound enhanced tumor infection >30-fold; (4 * 10(6) photons/sec/cm(2); standard deviation = 3 * 10(6) with ultrasound vs 1.3 * 10(5); standard deviation = 1 * 10(5) without ultrasound; P = .03) and penetration, enabling kill of cells more than 100 microns from the nearest blood vessel. This led to substantial and statistically significant retardation of tumor growth and increased survival. CONCLUSIONS: Combining drug stealthing and ultrasound-induced cavitation may ultimately enhance the efficacy of a range of powerful therapeutics, thereby improving the treatment of metastatic cancer. PMID- 24168973 TI - Scarlet fever is caused by a limited number of Streptococcus pyogenes lineages and is associated with the exotoxin genes ssa, speA and speC. AB - BACKGROUND: Several outbreaks of scarlet fever caused by Streptococcus pyogenes were recently reported. Scarlet fever is historically considered a toxin-mediated disease, dependent on the production of the exotoxins SpeA and SpeC, but a strict association between scarlet fever and these exotoxins is not always detected. The aims of this study were to characterize the scarlet fever bacterial isolates recovered from patients in a Lisbon hospital and to identify any distinctive characteristics of such isolates. METHODS: We characterized a collection of 303 pharyngeal S. pyogenes collected between 2002 and 2008. One-hundred and one were isolated from scarlet fever patients and 202 were associated to a diagnosis of tonsillo-pharyngitis. Isolates were characterized by T and emm typing, pulsed field gel electrophoresis profiling and superantigen gene profiling. RESULTS: The diversity of the scarlet fever isolates was lower than that of the pharyngitis isolates. Specific lineages of emm87, emm4 and emm3 were overrepresented in scarlet fever isolates but only 1 pulsed field gel electrophoresis major lineage was significantly associated with scarlet fever. Multivariate analysis indicated associations of ssa, speA and speC with scarlet fever. CONCLUSIONS: In nonoutbreak conditions, scarlet fever is caused by a number of distinct genetic lineages. The lower diversity of these isolates and the association with specific exotoxin genes indicates that some lineages are more prone to cause this presentation than others even in nonoutbreak conditions. PMID- 24168972 TI - Can meteorological factors forecast asthma exacerbation in a paediatric population? AB - BACKGROUND: Asthma exacerbations attended in emergency departments show a marked seasonality in the paediatric age. This seasonal pattern can change from one population to another and the factors involved are poorly understood. OBJECTIVES: To evaluate the association between meteorological factors and schooling with asthma exacerbations in children attended in the paediatric emergency department of a district hospital. METHODS: We conducted a retrospective review of the medical records of children 5-14 years of age attended for asthma exacerbations during a 4-year period (2007-2011). Climatic data were obtained from a weather station located very close to the population studied. The number of asthma exacerbations was correlated to temperature, barometric pressure, relative humidity, rainfall, wind speed, wind distance, solar radiation, water vapour pressure and schooling, using regression analyses. RESULTS: During the study period, 371 children were attended for asthma exacerbations; median age was eight years (IQR: 6-11), and 59% were males. Asthma exacerbations showed a bimodal pattern with peaks in spring and summer. Maximum annual peak occurred in week 39, within 15 days from school beginning after the summer holidays. A regression model with mean temperature, water vapour pressure, relative humidity, maximum wind speed and schooling could explain 98.4% (p<0.001) of monthly asthma exacerbations. CONCLUSIONS: The combination of meteorological factors and schooling could predict asthma exacerbations in children attended in a paediatric emergency department. PMID- 24168975 TI - Unrecognized pediatric adult-type tuberculosis puts school contacts at risk. AB - Adolescents with an immigrant background who are from tuberculosis high-incidence regions were at highest risk to develop adult-type tuberculosis disease in a low incidence region during a 20-year period. If diagnosis and treatment were delayed up to 6 months, latent tuberculosis infection was detected in almost half of the affected individuals' school contacts. PMID- 24168976 TI - Impact of unlabeled French antibiotic guidelines on antibiotic prescriptions for acute respiratory tract infections in 7 Pediatric Emergency Departments, 2009 2012. AB - From November 2009 to October 2012, implementation of guidelines, unlabeled by the French Agency of Health Products, changed the categories of antibiotics prescribed for acute respiratory tract infections in 7 pediatric emergency departments. During the study, 36,413 acute respiratory tract infections-related antibiotic prescriptions were prescribed. Amoxicillin prescriptions rose from 30.0% to 84.7%, while amoxicillin-clavulanate and cefpodoxime prescriptions decreased to 10.2% and 2.5%, respectively. PMID- 24168957 TI - Aggressive medical treatment with or without stenting in high-risk patients with intracranial artery stenosis (SAMMPRIS): the final results of a randomised trial. AB - BACKGROUND: Early results of the Stenting and Aggressive Medical Management for Preventing Recurrent stroke in Intracranial Stenosis trial showed that, by 30 days, 33 (14.7%) of 224 patients in the stenting group and 13 (5.8%) of 227 patients in the medical group had died or had a stroke (percentages are product limit estimates), but provided insufficient data to establish whether stenting offered any longer-term benefit. Here we report the long-term outcome of patients in this trial. METHODS: We randomly assigned (1:1, stratified by centre with randomly permuted block sizes) 451 patients with recent transient ischaemic attack or stroke related to 70-99% stenosis of a major intracranial artery to aggressive medical management (antiplatelet therapy, intensive management of vascular risk factors, and a lifestyle-modification programme) or aggressive medical management plus stenting with the Wingspan stent. The primary endpoint was any of the following: stroke or death within 30 days after enrolment, ischaemic stroke in the territory of the qualifying artery beyond 30 days of enrolment, or stroke or death within 30 days after a revascularisation procedure of the qualifying lesion during follow-up. Primary endpoint analysis of between group differences with log-rank test was by intention to treat. This study is registered with ClinicalTrials.gov, number NCT 00576693. FINDINGS: During a median follow-up of 32.4 months, 34 (15%) of 227 patients in the medical group and 52 (23%) of 224 patients in the stenting group had a primary endpoint event. The cumulative probability of the primary endpoints was smaller in the medical group versus the percutaneous transluminal angioplasty and stenting (PTAS) group (p=0.0252). Beyond 30 days, 21 (10%) of 210 patients in the medical group and 19 (10%) of 191 patients in the stenting group had a primary endpoint. The absolute differences in the primary endpoint rates between the two groups were 7.1% at year 1 (95% CI 0.2 to 13.8%; p=0.0428), 6.5% at year 2 (-0.5 to 13.5%; p=0.07) and 9.0% at year 3 (1.5 to 16.5%; p=0.0193). The occurrence of the following adverse events was higher in the PTAS group than in the medical group: any stroke (59 [26%] of 224 patients vs 42 [19%] of 227 patients; p=0.0468) and major haemorrhage (29 [13%]of 224 patients vs 10 [4%] of 227 patients; p=0.0009). INTERPRETATION: The early benefit of aggressive medical management over stenting with the Wingspan stent for high-risk patients with intracranial stenosis persists over extended follow-up. Our findings lend support to the use of aggressive medical management rather than PTAS with the Wingspan system in high risk patients with atherosclerotic intracranial arterial stenosis. FUNDING: National Institute of Neurological Disorders and Stroke (NINDS) and others. PMID- 24168977 TI - Wheezing in children with pertussis associated with delayed pertussis diagnosis. AB - BACKGROUND: The classic clinical features of paroxysmal pertussis are often absent in older children and adults and after vaccination. The California pertussis epidemic of 2010 occurred in a highly vaccinated population. METHODS: All pediatric patients (0-18 years) with positive pertussis polymerase chain reaction from July to December 2010 were identified retrospectively from the Kaiser SCAL database. Information extracted by chart review included age at diagnosis, vaccine history, race, cough duration, number of clinic visits before diagnosis, presence of paroxysms, post-tussive emesis or wheezing, treatment for asthma during the course of illness and exposure to confirmed or suspected pertussis cases. RESULTS: Overall 501 pediatric patients (mean age = 8.4 years) with positive pertussis nasopharyngeal polymerase chain reaction were identified. Complete DTaP series and Tdap vaccine had been received by 93% and 38% of eligible patients, respectively. Paroxysms, post-tussive emesis and wheezing on physical examination were present in 34%, 30% and 8% of patients, respectively. Each was associated with a longer duration of symptoms at diagnosis. Wheezing was associated with a delay in diagnosis (60% requiring >1 clinic visit for diagnosis vs. 29% in the overall population, P < 0.0001). Documented exposures were associated with a more timely pertussis diagnosis (after 9.4 days vs. 14.5 days; P < 0.0001). CONCLUSIONS: Wheezing is present on examination of some patients with pertussis in a highly vaccinated pediatric population and appears to delay the diagnosis of pertussis. The presence of wheezing should not be used to exclude this diagnosis in children with chronic cough or other reasons to suspect pertussis. PMID- 24168978 TI - Short intensified treatment in children with drug-susceptible tuberculous meningitis. AB - BACKGROUND: The World Health Organization recommends 12-month treatment (2RHZE/10RH) for children with tuberculous meningitis (TBM). Studies evaluating length of antituberculous treatment for TBM report similar completion and relapse rates comparing 6-month treatment with 12-month treatment. METHODS: A prospective evaluation to determine whether short-course intensified treatment (6 RHZEth for HIV-infected and 9RHZEth for HIV-infected) is sufficient and safe in children with drug-susceptible TBM. RESULTS: Of 184 children with TBM, median age 58 months and 90 (49%) male, 98 children (53%) presented at stage II TBM, 64 (35%) at stage III TBM and only 22 (12%) at stage I TBM. Ninety (49%) children were treated at home after the first month of therapy; all others received their full treatment in hospital. The HIV prevalence was 14% (22/155 children tested). Anti TB drug-induced hepatotoxicity occurred in 5% (8 of 143 children tested), all tested negative for viral hepatitis; in all 8 cases, the original regimen was restarted without recurrence. After treatment completion, 147 (80%) children had a good outcome, 7 (3.8%) died. There was no difference in outcome between HIV infected and HIV-uninfected children who completed treatment (P = 0.986) nor between TBM-hydrocephalic children who were medically treated or shunted (P = 0.166). CONCLUSION: Short intensified treatment is safe and effective in both HIV infected and HIV-uninfected children with drug-susceptible TBM. PMID- 24168980 TI - Malnutrition: a risk factor for severe respiratory syncytial virus infection and hospitalization. AB - BACKGROUND: Longitudinal information examining the effect of poor infant growth on respiratory syncytial virus (RSV) severity is limited. Children hospitalized with RSV lower respiratory infection represent those at the severe end of the disease spectrum. METHODS: We followed up a cohort of 12,191 infants enrolled in a previous pneumococcal vaccine trial in Bohol, Philippines. Exposure measures were weight for age z-score at the first vaccination visit (median age 1.8 months) as well as the growth (the difference in weight for age z-score) between the first and third vaccination visits. The outcome was hospitalization with RSV lower respiratory infection. RESULTS: Children with a weight for age z-score <= 2 at their first vaccination visit had the highest rate of hospitalization with RSV lower respiratory infection, but this association was only evident in children whose mothers had >10 years of education (hazard ratio: 3.38; 95% confidence interval: 1.63-6.98). Children who had lower than median growth between their first and third vaccinations had a higher rate of RSV-associated hospitalization than those with growth above the median (hazard ratio: 1.34; 95% confidence interval: 1.02-1.76). CONCLUSIONS: Poor infant growth increases the risk for severe RSV infection leading to hospitalization. PMID- 24168981 TI - Prevalence of hepatitis E virus antibodies in children in Germany. AB - BACKGROUND: Since asymptomatic hepatitis E virus (HEV) infections particularly affect children, there is a need for studies to determine the HEV seroprevalence among infants, children and adolescents. METHODS: The prevalence of anti-HEV IgG antibodies was determined in sera taken in 2008-2010 from 1646 children aged 0-17 years living in Germany. Antibody testing was carried out using the enzyme-linked immunosorbent assay recomWell HEV IgG as well as the recomLine HEV IgG/IgM distributed by Mikrogen. Furthermore, the performance of MP Biomedicals enzyme linked immunosorbent assay HEV and the HEV-Ab enzyme-linked immunosorbent assay from Axiom was analyzed in comparison with the recomWell/recomLine test system using a defined subset of sera. RESULTS: In children, the overall prevalence of antibodies was 1.0%. Starting with the 5- to 6-year olds, there was a significant increase of HEV seroprevalence to 1.5% in the group of the 15- to 17-year olds. There was no statistically significant difference between seroprevalences of boys (1.2%) and girls (0.7%). Passively transmitted maternal antibodies persisted for about 3 months. The strength of agreement between the recomWell/recomLine system and the ELISAs from MP Biomedicals or Axiom varied between 0.229 and 0.542 and was calculated at 0.111 when the assays from MP Biomedicals and Axiom were compared. CONCLUSIONS: In Germany, only a very small number of HEV infections occur in children. Many infections occur in adults with increasing age. Because of considerable variations in assay accordance, there is an urgent need for standardization of HEV serology. PMID- 24168983 TI - Predictors of first recurrence of Clostridium difficile infections in children. AB - Little is known regarding the risk of recurrence of Clostridium difficile infection (CDI) in children. In a 9-year cohort, 12% of hospitalized children with CDI had recurrent disease. Receipt of concomitant antibiotics and community associated CDI were independently associated with recurrent disease in children hospitalized with CDI. Antibiotics administered for reasons other than treatment of CDI should be discontinued whenever possible. PMID- 24168982 TI - Comparative effectiveness of ceftriaxone in combination with a macrolide compared with ceftriaxone alone for pediatric patients hospitalized with community acquired pneumonia. AB - BACKGROUND: Guidelines for management of community-acquired pneumonia recommend empiric therapy with a macrolide and beta-lactam when infection with Mycoplasma pneumoniae is a significant consideration. Evidence to support this recommendation is limited. We sought to determine the effectiveness of ceftriaxone alone compared with ceftriaxone combined with a macrolide with respect to length of stay and total hospital costs. METHODS: We conducted a retrospective cohort study of children 1-17 years with pneumonia, using Poisson regression and propensity score analyses to assess associations between antibiotic and length of stay. Multivariable linear regression and propensity score analyses were used to assess log-treatment costs, adjusting for patient and hospital characteristics and initial tests and therapies. RESULTS: A total of 4701 children received combination therapy and 8892 received ceftriaxone alone. Among children 1-4 years of age, adjusted models revealed no significant difference in length of stay, with significantly higher costs in the combination therapy group [cost ratio: 1.08 (95% confidence interval: 1.05-1.11)]. Among children 5-17 years of age, children receiving combination therapy had a shorter length of stay [relative risk: 0.95 (95% confidence interval: 0.92-0.98)], with no significant difference in costs [cost ratio: 1.01 (95% confidence interval: 0.98-1.04)]. CONCLUSIONS: Combination therapy did not appear to benefit preschool children but was associated with higher costs. Among school-aged children, combination therapy was associated with a shorter length of stay without a significant impact on cost. Development of sensitive point-of-care diagnostic tests to identify children with M. pneumoniae infection may allow for more focused prescription of macrolides and enable comparative effectiveness studies of targeted provision of combination therapy. PMID- 24168984 TI - The role of coagulase-negative staphylococci in early onset sepsis in a large European cohort of very low birth weight infants. AB - BACKGROUND: Early Onset Sepsis (EOS) is associated with increased major morbidity and mortality rates among very low birth weight (VLBW) infants. The epidemiology is changing in response to evolving medical practice. The objective of the study was to evaluate EOS epidemiology, risk factors, mortality and major morbidity rates among VLBW infants within a European cohort. METHODS: Data from VLBW infants born from 2006 through 2009 was collected by neonatal units participating in the EuroNeoNet initiative. Univariate and multivariate analyses were performed to assess the independent association of EOS with VLBW infant's perinatal characteristics, morbidity and mortality rates. RESULTS: The cohort included 14,719 infants, 391 developed EOS (2.7%). The most common pathogen responsible for EOS was Gram-positive bacteria (53.9%). Coagulase-negative staphylococci (CoNS) were isolated in 22.5% of episodes. Antenatal steroids exposure, single gestation, very low gestational age and birth weight, low 5 minute Apgar score and delivery room resuscitation were independently associated with EOS. EOS was also associated with a longer hospital stay, increased risk of mortality [adjusted odd ratio (aOR): 2.4; 95% Confidence Interval (CI): 1.9-3.1], respiratory distress syndrome (OR: 1.4; 95% CI: 1.1-1.9), severe intraventricular haemorrhage (aOR: 2.1; 95%CI: 1.6-2.8) and severe retinopathy of prematurity (aOR: 5; 95% CI: 1.9-13.3). Morbidity and mortality rates of infants with EOS caused by CoNS were similar to those of infants with EOS caused by other pathogens. CONCLUSIONS: VLBW infants with EOS are at an increased risk of mortality and major morbidities. CoNS was a significant cause of sepsis, infants with CoNS were at a similarly high risk of complication of prematurity and mortality as those with EOS caused by other organisms. PMID- 24168985 TI - Delayed start of diphtheria, tetanus, acellular pertussis and inactivated polio vaccination in preterm and low birth weight infants in the Netherlands. AB - BACKGROUND: It is recommended that preterm (PT) and low birth weight infants be vaccinated according to standard guidelines. We studied the timeliness of the first diphtheria, tetanus, acellular pertussis and inactivated polio vaccination in the Netherlands, by gestational age (GA) and birth weight (BW). METHODS: We included all vaccinated children born during 2006-2010. Data from the national immunization register were used to determine the vaccination age and the proportion of timely vaccinated infants (<70 days). Results were compared between groups based on GA (extreme PT: <32, PT: 32-36, full term (FT): >=37 weeks) and BW. Characteristics associated with the timeliness of vaccination were studied by Cox regression analyses. RESULTS: The median vaccination age was lower with a higher GA/BW. The proportion of timely vaccinated infants was 66% for extreme PT, 76% for PT and 82% for FT infants. Similar results were seen by BW. Overall, the proportion of timely vaccinated infants increased from 2006 (77%) until 2010 (85%) and there were regional differences and differences by ethnicity. In extreme PT and PT infants, living in a very highly urbanized municipality and being light for GA were associated with less timely vaccination. Being vaccinated in a hospital was associated with a timelier vaccination in extreme PT infants. However, the reverse was seen for PT infants. CONCLUSIONS: In the Netherlands, PT and low birth weight infants were less often timely vaccinated than FT infants and were, therefore, at increased risk of vaccine-preventable infections. In FT infants, the timeliness of vaccination is better but could also be optimized. PMID- 24168986 TI - Formation of the first stars. AB - Understanding the formation of the first stars is one of the frontier topics in modern astrophysics and cosmology. Their emergence signalled the end of the cosmic dark ages, a few hundred million years after the Big Bang, leading to a fundamental transformation of the early Universe through the production of ionizing photons and the initial enrichment with heavy chemical elements. We here review the state of our knowledge, separating the well understood elements of our emerging picture from those where more work is required. Primordial star formation is unique in that its initial conditions can be directly inferred from the Lambda cold dark matter (LambdaCDM) model of cosmological structure formation. Combined with gas cooling that is mediated via molecular hydrogen, one can robustly identify the regions of primordial star formation, the so-called minihalos, having total masses of ~10(6) M? and collapsing at redshifts z ~ 20 30. Within this framework, a number of studies have defined a preliminary standard model, with the main result that the first stars were predominantly massive. This model has recently been modified to include a ubiquitous mode of fragmentation in the protostellar disks, such that the typical outcome of primordial star formation may be the formation of a binary or small multiple stellar system. We will also discuss extensions to this standard picture due to the presence of dynamically significant magnetic fields, of heating from self annihalating WIMP dark matter, or cosmic rays. We conclude by discussing possible strategies to empirically test our theoretical models. Foremost among them are predictions for the upcoming James Webb space telescope (JWST), to be launched ~2018, and for 'stellar archaeology', which probes the abundance pattern in the oldest, most-metal poor stars in our cosmic neighborhood, thereby constraining the nucleosynthesis inside the first supernovae. PMID- 24168987 TI - Quantitative annular dark field electron microscopy using single electron signals. AB - One of the difficulties in analyzing atomic resolution electron microscope images is that the sample thickness is usually unknown or has to be fitted from parameters that are not precisely known. An accurate measure of thickness, ideally on a column-by-column basis, parameter free, and with single atom accuracy, would be of great value for many applications, such as matching to simulations. Here we propose such a quantification method for annular dark field scanning transmission electron microscopy by using the single electron intensity level of the detector. This method has the advantage that we can routinely quantify annular dark field images operating at both low and high beam currents, and under high dynamic range conditions, which is useful for the quantification of ultra-thin or light-element materials. To facilitate atom counting at the atomic scale we use the mean intensity in an annular dark field image averaged over a primitive cell, with no free parameters to be fitted. To illustrate the potential of our method, we demonstrate counting the number of Al (or N) atoms in a wurtzite-type aluminum nitride single crystal at each primitive cell over the range of 3-99 atoms. PMID- 24168988 TI - Evaluation of congenital optic disc pits and optic disc colobomas by swept-source optical coherence tomography. AB - PURPOSE: To investigate the structural abnormalities of optic disc pits and colobomas by swept-source optical coherence tomography (OCT). METHODS: Sixteen eyes with congenital optic disc pits, and seven eyes with optic disc colobomas were studied. Papillary and peripapillary areas were examined with swept-source OCT. The entire course of the pit or cavity and the spatial relationship between pits and retrobulbar subarachnoid space (SAS) were examined. RESULTS: Optical coherence tomography images showed the entire course of the pits from their openings to the bottom in 12 eyes. Shape of optic disc pits varied from sharp triangular cavities to longitudinally oval according to the depth of the pits. In the other four eyes, the pit narrowed into a tunnel along the optic nerve. The entire area of the optic disc was observed in three of seven eyes with disc coloboma by OCT. In all of the eyes with optic disc pits, the lamina cribrosa was torn off of the peripapillary sclera at the site of the pits. In two cases with optic disc pits and one case with optic disc coloboma, Optical coherence tomography showed SAS immediately posterior to the highly reflective tissue lining the bottom of the excavation. The distance between the intraocular cavity and SAS in these three cases were 88, 126, and 133 MUm. CONCLUSIONS: Swept-source OCT is able to detect different kinds of abnormalities including shape of cavities, defect of lamina cribrosa, or distance to SAS in the excavated optic discs anomalies. PMID- 24168989 TI - The effects of 2% rebamipide ophthalmic solution on the tear functions and ocular surface of the superoxide dismutase-1 (sod1) knockout mice. AB - PURPOSE: To investigate the efficacy of 2% rebamipide ophthalmic solution on the tear functions and ocular surface status of the superoxide dismutase-1(Sod1(-/-)) mice. METHODS: Two percent Rebamipide ophthalmic solution was applied to 40-week old male Sod1(-/-) and wild-type (WT) mice four times a day for 2 weeks. We examined the cytokine concentrations in the tear fluid (by CytoBead assay), tear film break-up time, amount of tear production, and expressions of mucins 1, 4, and 5AC, by RT-PCR. We also performed vital staining of the ocular surface, PAS staining for muc5AC, and immunohistochemical stainings for 4-hydroxy-2-nonenal (4 HNE), 8-hydroxy-2'-deoxyguanosine (8-OHdG), in the conjunctiva to compare the results before and after rebamipide instillations. RESULTS: The tear functions and ocular surface epithelial damage scores were significantly worse in the Sod1( /-) than in the WT mice. Application of 2% rebamipide for 2 weeks significantly improved the tear film break-up time, the amount of tear production, and the corneal epithelial damage scores, which also significantly increased the conjunctival goblet cell density and muc5 mRNA expression, in the Sod1(-/-) mice. The mean IL-6, IL-17, TNF-alpha, and IFN-gamma levels in the tear fluid were reduced significantly along with a significant decrease in the density of cells positive for 4-HNE and 8-OHdG in the conjunctiva. CONCLUSIONS: Two percent Rebamipide ophthalmic solution significantly improved the tear stability and corneal epithelial damage, and enhanced the expression of muc5 mRNA on the ocular surface. We also observed anti-inflammatory effects in the tear film together with antioxidative effects in the conjunctiva, suggesting the efficacy of rebamipide in age-related dry eye disease attributable to SOD1 knockout. PMID- 24168991 TI - A new nanosecond UV laser at 355 nm: early results of corneal flap cutting in a rabbit model. AB - PURPOSE: A new 355 nm UV laser was used for corneal flap cutting in an animal model and tested for clinical and morphologic alterations. METHODS: Corneal flaps were created (Chinchilla Bastards; n = 25) with an UV nanosecond laser at 355 nm (150 kHz, pulse duration 850 ps, spot-size 1 MUm, spot spacing 6 * 6 MUm, side cut Deltaz 1 MUm; cutting depth 130 MUm) and pulse energies of 2.2 or 2.5 MUJ, respectively. Following slit-lamp examination, animals were killed at 6, 12, and 24 hours after treatment. Corneas were prepared for histology (hematoxylin and eosin [HE], TUNEL-assay) and evaluated statistically, followed by ultrastructural investigations. RESULTS: Laser treatment was tolerated well, flap lift was easier at 2.5 MUJ compared with 2.2 MUJ. Standard HE at 24 hours revealed intact epithelium in the horizontal cut, with similar increase in corneal thickness at both energies. Irrespective of energy levels, TUNEL assay revealed comparable numbers of apoptotic cells in the horizontal and vertical cut at 6, 12, and 24 hours, becoming detectable in the horizontal cut as an acellular stromal band at 24 hours. Ultrastructural analysis revealed regular morphology in the epi- and endothelium, while in the stroma, disorganized collagen lamellae were detectable representing the horizontal cut, again irrespective of energy levels applied. CONCLUSIONS: This new UV laser revealed no epi- nor endothelial damage at energies feasible for corneal flap cutting. Observed corneal swelling was lower compared with existing UV laser studies, albeit total energy applied here was much higher. Observed loss of stromal keratinocytes is comparable with available laser systems. Therefore, this new laser is suitable for refractive surgery, awaiting its test in a chronic environment. PMID- 24168990 TI - Hydrogen peroxide accumulation in the choroid during intermittent hypoxia increases risk of severe oxygen-induced retinopathy in neonatal rats. AB - PURPOSE: Extremely low gestational age neonates (ELGANs) requiring oxygen therapy often experience frequent episodes of intermittent hypoxia (IH) and are at high risk for severe retinopathy of prematurity (ROP). Using an established model for oxygen-induced retinopathy (OIR), we examined the hypothesis that there is a critical number of daily brief IH episodes which will result in irreversible retinal oxidative damage. METHODS: Newborn rats were exposed to increasing daily clustered IH episodes (12% O2 with 50% O2) from postnatal day (P) 0 to P7 or P0 to P14, or placed in room air (RA) until P21 following 7- or 14-day IH. RA littermates at P7, P14, and P21 served as controls. A group exposed to constant 50% O2 (CH) served as a second control. Blood gases, eye opening at P14, retinal, and choroidal oxidative stress and lipid peroxidation (8-isoPGF(2alpha)), oxidants (H2O2) and antioxidants (catalase and SOD), retinal pathology (adenosine diphosphatase (ADPase)-stained retinal flatmounts), and mitochondria-related genes were assessed. RESULTS: pO2 levels were higher with increasing IH episodes and remained elevated during the reoxygenation period. High SO2 levels were associated with most severe OIR. Levels of all measured biomarkers peaked with six IH episodes and decreased with 8 to 12 episodes. H2O2 accumulated in the choroid during the reoxygenation period with irreversible retinal damage. CONCLUSIONS: Our data suggest that six is the maximum number of IH episodes that the retina can sustain. Accumulation of H2O2 in the choroid may result in high levels being delivered to the entire retina, ultimately resulting in irreversible retinal oxidative damage. PMID- 24168992 TI - Comparison of factors associated with occludable angle between american Caucasians and ethnic Chinese. AB - PURPOSE: To determine if factors associated with gonioscopy-determined occludable angle among American Caucasians are similar to those found in ethnic Chinese. METHODS: This is a prospective cross-sectional study with 120 American Caucasian, 116 American Chinese, and 116 mainland Chinese subjects. All three groups were matched for sex and age (40-80 years). Gonioscopy was performed for each subject (occludable angles = posterior trabecular meshwork not visible for >=2 quadrants). Anterior segment optical coherence tomography and customized software was used to measure anterior segment biometry and iris parameters, including anterior chamber depth/width (ACD, ACW), lens vault (LV), and iris thickness/area/curvature. RESULTS: In both Chinese and Caucasians, eyes with occludable angles had smaller ACD and ACW, and larger LV and iris curvature than eyes with open angles (all P < 0.005). Chinese eyes had smaller ACD and ACW than Caucasian eyes (both P < 0.01) in the occludable angle cohort. Iris characteristics did not differ significantly between Chinese and Caucasians in the occludable angle cohort. Based on multivariate logistic regression, gonioscopy-determined occludable angle was significantly associated with LV, iris area, and sex (all P < 0.03) in Chinese; and with LV, ACD, iris thickness, age, and sex (all P < 0.04) in Caucasians. CONCLUSIONS: Several factors associated with occludable angle differed between Caucasians and Chinese, suggesting potentially different mechanisms in occludable angle development in the two racial groups. This is the first study to demonstrate that lens vault is an important anterior segment optical coherence tomography parameter in the screening for angle closure in Caucasians. In addition, iris thickness was a significant predictor for occludable angles in Caucasians but was not in ethnic Chinese. PMID- 24168994 TI - Effect of intravitreal injection of bevacizumab on optic nerve head leakage and retinal ganglion cell survival in a mouse model of optic nerve crush. AB - PURPOSE: To evaluate the effect of bevacizumab, a VEGF inhibitor, on optic nerve edema and retinal ganglion cell (RGC) loss in a mouse model of optic nerve crush (ONC). METHODS: Two hundred C57BL/6 wild-type mice were anesthetized. Right ONC was induced in 150 mice, of which half (n = 75) received an intravitreal injection of bevacizumab immediately thereafter and half (n = 75) did not. The remaining 50 received only bevacizumab. The left eyes served as a control. Findings were analyzed by fluorescein angiography (days 0, 1, 3), histologic and immunohistochemical tests (days 1, 3, 4, 21), and quantitative real-time PCR. RESULTS: Angiography revealed a reduction in postinjury disc leakage following bevacizumab injection (days 1, 3), confirmed with IgG staining. On PCR, expression of HO-1 and SOD-1 mRNA increased following ONC and further increased with bevacizumab. VEGF gene expression decreased following bevacizumab injection without ONC, remained at baseline after ONC, and increased slightly after ONC+bevacizumab. Histologically, there was a 38% RGC loss 21 days after ONC alone, which dropped to 14% with bevacizumab treatment; it was close to 15% with bevacizumab alone. Mean (SEM) microvascular perfusion in the optic nerve 4 days after ONC was significantly higher in the bevacizumab-treated (85% +/- 10%) than the vehicle-treated (33% +/- 13%) animals. CONCLUSIONS: Bevacizumab treatment following ONC induction exerts a protective effect, manifested by reduced optic nerve head edema. The underlying mechanism probably involves a lesser interruption of axonal transport. Reduced expression of antioxidative and ischemic genes may contribute to RGC preservation. PMID- 24168993 TI - The rat with oxygen-induced retinopathy is myopic with low retinal dopamine. AB - PURPOSE: Dopamine (DA) is a neurotransmitter implicated both in modulating neural retinal signals and in eye growth. Therefore, it may participate in the pathogenesis of the most common clinical sequelae of retinopathy of prematurity (ROP), visual dysfunction and myopia. Paradoxically, in ROP myopia the eye is usually small. The eye of the rat with oxygen-induced retinopathy (OIR) is characterized by retinal dysfunction and short axial length. There have been several investigations of the early maturation of DA in rat retina, but little at older ages, and not in the OIR rat. Therefore, DA, retinal function, and refractive state were investigated in the OIR rat. METHODS: In one set of rats, the development of dopaminergic (DAergic) networks was evaluated in retinal cross sections from rats aged 14 to 120 days using antibodies against tyrosine hydroxylase (TH, the rate-limiting enzyme in the biosynthesis of DA). In another set of rats, retinoscopy was used to evaluate spherical equivalent (SE), electoretinography (ERG) was used to evaluate retinal function, and high-pressure liquid chromatography (HPLC) was used to evaluate retinal contents of DA, its precursor levodopamine (DOPA), and its primary metabolite 3,4 dihydroxyphenylacetic acid (DOPAC). RESULTS: The normally rapid postnatal ramification of DAergic neurons was disrupted in OIR rats. Retinoscopy revealed that OIR rats were relatively myopic. In the same eyes, ERG confirmed retinal dysfunction in OIR. HPLC of those eyes' retinae confirmed low DA. Regression analysis indicated that DA metabolism (evaluated by the ratio of DOPAC to DA) was an important additional predictor of myopia beyond OIR. CONCLUSIONS: The OIR rat is the first known animal model of myopia in which the eye is smaller than normal. Dopamine may modulate, or fail to modulate, neural activity in the OIR eye, and thus contribute to this peculiar myopia. PMID- 24168995 TI - Axial length, retinal function, and oxygen consumption: a potential mechanism for a lower risk of diabetic retinopathy in longer eyes. AB - PURPOSE: To determine the relationship between axial length (AL), retinal function, and relative oxygen (O2) consumption to better understand the protective effect of axial elongation on diabetic retinopathy development. METHODS: Measurements of AL, multifocal electroretinogram (mfERG), and relative O2 consumption (difference between arteriolar and venular O2 saturation levels or A-V difference) were performed on 50 healthy individuals. The relationships between AL, mfERG amplitude, and A-V difference were analyzed using linear regression models. Path analysis was performed to determine the direct and indirect effects (via mfERG amplitude) of AL on A-V difference. RESULTS: mfERG P1 amplitude was positively associated with A-V difference (beta = 0.33; 95% confidence interval [CI]: 0.23-0.42). Increased AL was significantly associated with a decrease in A-V difference (beta = -1.08; 95% CI: -1.52 to -0.65) as well as a decrease in retinal function (beta = -3.14, 95% CI: -4.07 to -2.20). Path analysis models including AL (study factor), retinal function (intermediate variable), and A-V difference (outcome variable) showed that AL had little direct association with A-V difference (beta(p) = -0.002), while the indirect effect of AL on A-V difference via changes in retinal function were substantial (beta(p) = 0.51). CONCLUSIONS: In eyes with longer AL, the reduction in A-V difference is explained by the parallel reduction in retinal function. These findings suggest that longer eyes have decreased retinal function and O2 consumption, and thus are relatively less hypoxic in the presence of diabetes, which may partly explain the reduced risk of DR in these eyes. PMID- 24168996 TI - Association between retinal thickness of 64 sectors in posterior pole determined by optical coherence tomography and axial length and body height. AB - PURPOSE: We determined a significant correlation between the retinal thickness (RT) in 64 cells or sectors of the posterior pole, and the axial length (AL) and the body height (BH). METHODS: A prospective, observational cross-sectional study of 64 right eyes of 64 healthy volunteers (mean age, 26.0 +/- 4.5 years; range, 22-39 years). The RT within the central 24 degrees area was measured in the Spectralis spectral domain-optical coherence tomographic (SD-OCT) images. The correlations between the RT and the AL or the BH were determined by linear regression analyses. RESULTS: The mean +/- SD of the AL was 25.04 +/- 1.30 mm, and that of the BH was 167.2 +/- 8.5 cm. The RTs of the central four cells around the fovea were not significantly correlated with the AL. The RTs of 54 cells were significantly and negatively associated with the AL (r = -0.25 to -0.56, P < 0.05). In contrast, the RTs of the central to temporal eight cells were significantly and positively correlated with the BH (r = 0.26-0.37, P < 0.05). The RTs of 56 cells were not significantly correlated with the BH. CONCLUSIONS: The RT of the posterior retina, except in the fovea, decreased as AL elongated, and those of the central temporal areas were significantly correlated with the BH. Thus, the AL and BH must be considered when the RT is evaluated. The 64 sector analysis on OCT is useful to assess the detailed changes of RT affected by them. (http://www.umin.ac.jp/ctr/index.htm number, UMIN000007154.). PMID- 24168997 TI - Retinal arteriolar dilation to flicker light is reduced on short-term retesting. AB - PURPOSE: To investigate the impact of retesting frequency over a short period on flicker light-induced retinal vasodilation. METHODS: Twenty healthy participants were included. The retinal vascular response to flicker light stimulation was assessed three times (at baseline and after 5 and 30 minutes of rest [tests 1, 2, and 3, respectively]) in each participant using the Dynamic Vessel Analyzer. Relative dilations of selected arteriole and venule segments during flicker stimulation and resting diameters were measured automatically. The mean vessel dilations and resting diameters were compared using repeated-measures analysis of variance. RESULTS: Participants were young (mean [SD] age, 33.1 [5.7] years) and mostly female (70%). The mean (SD) maximum arteriolar dilations during flicker stimulation were 3.23% (2.06%), 2.44% (1.62%), and 3.36% (2.11%) in tests 1, 2, and 3, respectively. The mean (SD) venular dilations were 4.26% (1.28%), 3.81% (1.61%), and 4.43% (1.73%) in tests 1, 2, and 3, respectively. The mean arteriolar dilations were significantly different across the three tests (P < 0.001). Compared with test 1, arteriolar dilations were significantly reduced after 5 minutes (P = 0.008) but not 30 minutes (P = 0.437) of rest. No significant differences were found over time for the mean venular dilations (P = 0.128). Resting diameters of selected vessels were not significantly different between tests. CONCLUSIONS: Retinal arteriolar dilation during flicker stimulation is reduced on short-term retesting, without a significant change in baseline vessel diameter, indicating decreased responsiveness to the flicker stimulus. Researchers should allow at least 30 minutes between consecutive tests to minimize suppression of the flicker response. PMID- 24168998 TI - The cornea in classic type Ehlers-Danlos syndrome: macro- and microstructural changes. AB - PURPOSE: To analyze in vivo corneal morphology and ultrastructural features in patients with classic Ehlers-Danlos syndrome (EDS). METHODS: Fifty patients with classic EDS and 50 age- and sex-matched control subjects were studied. A clinical evaluation was made with the Ocular Surface Disease Index (OSDI) questionnaire and a complete ophthalmic examination, including assessment of the best-corrected visual acuity and refraction, slit-lamp biomicroscopy, tear break-up time, intraocular pressure, Schirmer test without topical anesthesia, and corneal diameter. Scheimpflug camera topography and in vivo confocal microscopy (IVCM) were used to investigate corneal morphology and corneal ultrastructural features respectively. RESULTS: Classic EDS patients, compared to controls, had thinner and steeper corneas (P < 0.001 and P < 0.05, respectively; independent samples t test). IVCM showed thinner stromas, lower keratocyte densities (P < 0.001), increased applanation-related stromal folds (P < 0.001; Mann-Whitney U test), and increased endothelial hyperreflective dots (P < 0.05) in these patients. The study group also had increased symptoms (OSDI score: P < 0.01, independent samples t-test) and signs (tear break-up time and Schirmer test: P < 0.001 and P < 0.05, respectively) of tear film dysfunction. CONCLUSIONS: Patients with classic EDS had macro- and microstructural changes of the cornea, which is a target tissue of the disease. These findings should be considered to optimize clinical management of these patients and to evaluate the opportunity of adding ocular findings to the classic EDS diagnostic criteria. PMID- 24168999 TI - Comparisons of choroidal thickness of normal eyes obtained by two different spectral-domain OCT instruments and one swept-source OCT instrument. AB - PURPOSE: We compared the subfoveal choroidal thickness (SFCT) measured on the images obtained by two spectral-domain optical coherence tomographic (SD-OCT) instruments and one swept-source OCT (SS-OCT) instrument. METHODS: A cross sectional, prospective noninterventional study was done in which SFCT was measured in the images obtained by two SD-OCT instruments; Heidelberg Spectralis OCT (Spectralis-SD-OCT) and Topcon 3D OCT-1000 Mark II (Topcon-SD-OCT). Images also were obtained with SS-OCT Atlantis DRI OCT-1 (DRI-SS-OCT). After manual segmentation, the measurements were made using the calipers embedded in each instrument. The intrarater, interrater, and intermachine agreements were assessed. RESULTS: We studied 35 subjects. The intrarater correlation coefficient (95% confidence interval) was 0.994 (0.988-0.994) for Spectralis-SD-OCT, 0.996 (0.993-0.998) for Topcon-SD-OCT, and 0.997 (0.991-0.998) for DRI-SS-OCT (P < 0.001). The interrater correlation coefficient was 0.995 (0.991-0.998) for Spectralis-SD-OCT, 0.995 (0.990-0.998) for Topcon-SD-OCT, and 0.996 (0.992-0.998) for DRI-SS-OCT (P < 0.001). The average SFCT was 273.2 MUm with Spectralis-SD OCT, 269.1 MUm with the Topcon-SD-OCT, and 280.5 MUm with DRI-SS-OCT. The intermachine correlation coefficient was 0.982 (0.964-0.991) for Spectralis-SD OCT versus Topcon-SD-OCT, 0.907 (0.815-0.953) for Topcon-SD-OCT versus DRI-SS OCT, and 0.911 (0.832-0.954) for DRI-SS-OCT versus Spectralis-SD-OCT (P < 0.001). The SFCT measured with DRI-SS-OCT was significantly thicker than that with Topcon SD-OCT, with a mean difference of 11.41 +/- 30.27 MUm (P = 0.032). CONCLUSIONS: In normal adult eyes, there was good reproducibility and repeatability of SFCT measurements obtained by the SD-OCT and SS-OCT instruments. However, the choroid measured with DRI-SS-OCT was thicker than that measured with both SD-OCT instruments, and, thus, the choroidal thickness should not be compared between the SD-OCT and SS-OCT instruments. (www.umin.ac.jp/ctr number, UMIN000011259.). PMID- 24169000 TI - Optical coherence tomography in the diagnosis of optic pathway gliomas. AB - PURPOSE: To compare visual function assessment, optic disc evaluation by indirect ophthalmoscopy, and retinal nerve fiber layer analysis by optical coherence tomography (OCT) for the screening of optic pathway gliomas in pediatric patients (2-15 years old) affected by neurofibromatosis type 1. METHODS: Fifty-seven consecutive patients with neurofibromatosis type 1 with recent (<6 months) orbital/brain magnetic resonance images (MRI) were included. Patients underwent visual function assessment (Hyvarinen symbols chart and/or Snellen charts) and optic disc evaluation by indirect ophthalmoscopy performed by experienced, masked pediatric ophthalmologists. Spectral domain OCT was performed to assess retinal nerve fiber layer. RESULTS: Fifteen of 57 enrolled patients (26%) were affected by MRI-proven optic pathway gliomas. Visual function assessment, optic disc evaluation, and retinal nerve fiber layer analysis by OCT were feasible in 84%, 95%, and 88% of patients, respectively. Visual function assessment, retinal nerve fiber layer analysis, and optic disc evaluation results correlated with the presence of optic pathway gliomas (P = 0.007, P < 0.0001, and P = 0.03, respectively). Specificity and negative predictive value of each test were statistically significant in detecting optic pathway glioma (P < 0.0001), whereas only retinal nerve fiber layers analysis reached statistically significant sensitivity and positive predictive value (P = 0.0386). CONCLUSIONS: Retinal nerve fiber layer analysis assessment using spectral domain OCT is superior to visual function assessment and optic disc evaluation as a clinical screening tool for optic pathway gliomas. PMID- 24169001 TI - Interaction of plant phenols with food macronutrients: characterisation and nutritional-physiological consequences. AB - Polyphenols are dietary constituents of plants associated with health-promoting effects. In the human diet, polyphenols are generally consumed in foods along with macronutrients. Because the health benefits of polyphenols are critically determined by their bioavailability, the effect of interactions between plant phenols and food macronutrients is a very important topic. In the present review, we summarise current knowledge, with a special focus on the in vitro and in vivo effects of food macronutrients on the bioavailability and bioactivity of polyphenols. The mechanisms of interactions between polyphenols and food macronutrients are also discussed. The evidence collected in the present review suggests that when plant phenols are consumed along with food macronutrients, the bioavailability and bioactivity of polyphenols can be significantly affected. The protein-polyphenol complexes can significantly change the plasma kinetics profile but do not affect the absorption of polyphenols. Carbohydrates can enhance the absorption and extend the time needed to reach a maximal plasma concentration of polyphenols, and fats can enhance the absorption and change the absorption kinetics of polyphenols. Moreover, as highlighted in the present review, not only a nutrient alone but also certain synergisms between food macronutrients have a significant effect on the bioavailability and biological activity of polyphenols. The review emphasises the need for formulations that optimise the bioavailability and in vivo activities of polyphenols. PMID- 24169002 TI - The use of MMP2 antibody-conjugated cationic microbubble to target the ischemic myocardium, enhance Timp3 gene transfection and improve cardiac function. AB - The objective of this study was to synthesize a cationic microbubble (CMB) conjugated with an antibody against matrix metalloproteinase 2 (CMBMMP2) to increase microbubble accumulation and gene transfection in the infarcted myocardium and to restore ventricular function following an ischemic insult. We previously reported that our CMBs enhanced the efficiency of gene transfection following ultrasound-targeted microbubble destruction (UTMD) in rodent hearts. Therefore, we conjugated a thiolated MMP2 antibody to the PEG chains on the CMB surface, which was verified by fluorescent microscopy. Rats underwent ischemia/reperfusion injury 3 days prior to UTMD delivery of the control or Timp3 plasmid. The CMBMMP2 improved microbubble accumulation in the infarct region, with 57% more contrast intensity compared to the non-conjugated CMB. UTMD mediated CMBMMP2 delivery of the Timp3 gene significantly increased TIMP3 protein levels in the infarct scar and border zone at 3 days post-UTMD compared to delivery by the non-conjugated CMB. Both MMP2 and MMP9 activity were reduced in the CMBMMP2Timp3 group, which resulted in smaller and thicker infarcts and improved cardiac function. UTMD therapy with this CMBMMP2 provides an efficient platform for the targeted delivery of factors intended to preserve ventricular structure and improve cardiac function after ischemic injury. PMID- 24169003 TI - Accelerating the clearance of mutant huntingtin protein aggregates through autophagy induction by europium hydroxide nanorods. AB - Autophagy is one of the well-known pathways to accelerate the clearance of protein aggregates, which contributes to the therapy of neurodegenerative diseases. Although there are numerous reports that demonstrate the induction of autophagy with small molecules including rapamycin, trehalose and lithium, however, there are few reports mentioning the clearance of aggregate-prone proteins through autophagy induction by nanoparticles. In the present article, we have demonstrated that europium hydroxide [Eu(III)(OH)3] nanorods can reduce huntingtin protein aggregation (EGFP-tagged huntingtin protein with 74 polyQ repeats), responsible for neurodegenerative diseases. Again, we have found that these nanorods induce authentic autophagy flux in different cell lines (Neuro 2a, PC12 and HeLa cells) through the expression of higher levels of characteristic autophagy marker protein LC3-II and degradation of selective autophagy substrate/cargo receptor p62/SQSTM1. Furthermore, depression of protein aggregation clearance through the autophagy blockade has also been observed by using specific inhibitors (wortmannin and chloroquine), indicating that autophagy is involved in the degradation of huntingtin protein aggregation. Since [Eu(III)(OH)3] nanorods can enhance the degradation of huntingtin protein aggregation via autophagy induction, we strongly believe that these nanorods would be useful for the development of therapeutic treatment strategies for various neurodegenerative diseases in near future using nanomedicine approach. PMID- 24169004 TI - Supramolecular adducts of squaraine and protein for noninvasive tumor imaging and photothermal therapy in vivo. AB - Extensive efforts have been devoted to the development of near-infrared (NIR) dye based imaging probes and/or photothermal agents for cancer theranostics in vivo. However, the intrinsic chemical instability and self-aggregation properties of NIR dyes in physiological condition limit their widely applications in the pre clinic study in living animals. Squaraine dyes are among the most promising NIR fluorophores with high absorption coefficiencies, bright fluorescence and photostability. By introducing dicyanovinyl groups into conventional squaraine (SQ) skeleton. These acceptor-substituted SQ dyes not only show superior NIR fluorescence properties (longer wavelength, higher quantum yield) but also exhibit more chemical robustness. In this work, we demonstrated highly stable and biocompatible supramolecular adducts of SQ and the natural carrier protein, i.e., bovine serum albumin (BSA) (SQ?BSA) for tumor targeted imaging and photothermal therapy in vivo. SQ was selectively bound to BSA hydrophobic domain via hydrophobic and hydrogen bonding interactions with up to 80-fold enhanced fluorescence intensity. By covalently conjugating target ligands to BSA, the SQ?BSA was capable of targeting tumor sites and allowed for monitoring the time dependent biodistribution of SQ?BSA, which consequently determined the protocol of photothermal therapy in vivo. We envision that this supramolecular strategy for selectively binding functional imaging agents and/or drugs into human serum albumin might potentially utilize in the preclinical and even clinic studies in the future. PMID- 24169005 TI - Usefulness of serial decline of kidney function to predict mortality and cardiovascular events in patients undergoing coronary angiography. AB - Chronic kidney disease increases cardiovascular risk and all-cause mortality. However, data on the predictive power of dynamic changes in kidney function are sparse. The aim of this research was to assess the predictive power of serial changes in kidney function on mortality and cardiovascular risk. Estimated glomerular filtration rate (eGFR) was calculated using the Chronic Kidney Disease Epidemiology Collaboration equation at baseline and at follow-up in a high-risk population of 619 consecutive patients who underwent coronary angiography. The population was stratified into 3 groups with respect to decreases in eGFR: stable kidney function (no decrease in eGFR) versus a mild decline (decrease in eGFR >0 but <4 ml/min/1.73 m(2) per year) and a rapid decline in kidney function (decrease in eGFR >=4 ml/min/1.73 m(2) per year). Mortality and nonfatal cardiovascular events were recorded over 4 years. Baseline coronary angiography revealed significant coronary stenoses (>=50%) in 368 patients (60%). Survival and event-free survival were significantly lower in patients with rapid decreases in eGFR compared with those with mild decreases (p <0.001 and p = 0.012, respectively) and stable kidney function (p <0.001 and p = 0.004, respectively). After multivariate adjustment in Cox regression analyses, the continuous variable decline in kidney function significantly predicted death (standardized adjusted hazard ratio 1.32, 95% confidence interval 1.03 to 1.70, p = 0.032) and the incidence of the composite end point death and nonfatal vascular events (hazard ratio 1.20, 95% confidence interval 1.01 to 1.43, p = 0.038). A 5 ml/min/1.73 m(2) decrease in eGFR independently conferred a 60% increase in mortality risk (p = 0.032). In conclusion, a rapid decline in kidney function is a powerful and independent new risk marker for death and vascular events. PMID- 24169006 TI - Target-attainment rates of low-density lipoprotein cholesterol using lipid lowering drugs one year after acute myocardial infarction in sweden. AB - The objective of this prospective cohort study was to describe real-life use of lipid-lowering drugs and low-density lipoprotein cholesterol (LDL-C) target attainment rates 1 year after acute myocardial infarction (AMI). LDL-C was recorded at hospital admission for AMI and at follow-up at 2 and 12 months after AMI in 17,236 patients in the Swedish heart registry, SWEDEHEART, from 2004 through 2009. Lipid-lowering treatments were identified using the Swedish Prescribed Drug Register. More than 90% of patients received statins after AMI. Simvastatin <=40 mg was used by 80% of patients at discharge and at 2 months and 68% at 1 year after AMI. Intensive statin therapy (LDL-C-lowering capacity >40%) was prescribed for 8.4%, 11.9%, and 12.2% at these time points, and combinations of statin/ezetimibe for 1.1%, 2.8%, and 5.0%, respectively. The LDL-C target of <2.5 mmol/L (97 mg/dl) was achieved in 74.5% of patients at 2 months and 72.3% at 12 months after AMI. Treatment was intensified for only 21.3% of patients with LDL-C above target at 2 months. In multivariate analysis, higher LDL-C levels at admission and at 2 months correlated to increased risk for under treatment at 12 months after AMI. In conclusion, statin treatment after AMI in Sweden has become standard, but titration to reach recommended LDL-C levels is still suboptimal. Strategies to further improve implementation of guidelines are needed. PMID- 24169007 TI - Usefulness of brachial artery flow-mediated dilation to predict long-term cardiovascular events in subjects without heart disease. AB - Endothelial dysfunction is considered an important prognostic factor in atherosclerosis. To determine the long-term association of brachial artery flow mediated dilation (FMD) and adverse cardiovascular (CV) events in healthy subjects, we prospectively assessed brachial FMD in 618 consecutive healthy subjects with no apparent heart disease, 387 men (63%), and mean age 54 +/- 11 years. After overnight fasting and discontinuation of all medications for >=12 hours, FMD was assessed using high-resolution linear array ultrasound. Subjects were divided into 2 groups: FMD <=11.3% (n = 309) and >11.3% (n = 309), where 11.3% is the median FMD, and were comparable regarding CV risk factors, lipoproteins, fasting glucose, C-reactive protein, concomitant medications, and Framingham 10-year risk score. In a mean clinical follow-up of 4.6 +/- 1.8 years, the composite CV events (all-cause mortality, nonfatal myocardial infarction, hospitalization for heart failure or angina pectoris, stroke, coronary artery bypass grafting, and percutaneous coronary interventions) were significantly more common in subjects with FMD <=11.3% rather than >11.3% (15.2% vs 1.2%, p = 0.0001, respectively). Univariate analysis demonstrated that the median FMD significantly predicted CV events (odds ratio 2.78, 95% CI 1.35 to 5.71, p <0.001). Multivariate analysis, controlling for traditional CV risk factors, demonstrated that median FMD was the best independent predictor of long-term CV adverse events (odds ratio 2.93, 95% CI 1.28 to 6.68, p <0.001). In conclusion, brachial artery median FMD independently predicts long-term adverse CV events in healthy subjects with no apparent heart disease in addition to those derived from traditional risk factor assessment. PMID- 24169008 TI - Impact of metabolic syndrome on the risk of cardiovascular disease mortality in the United States and in Japan. AB - The United States has a higher prevalence of metabolic syndrome (MS) and cardiovascular disease (CVD) mortality than Japan, but it is unknown how much of the difference in MS accounts for the mortality difference. The aim of this study was to examine the impact of MS on the excess CVD mortality in the United States compared with that in Japan. Data from the United States Third National Health and Nutrition Examination Survey (NHANES III; n = 12,561) and the Japanese National Integrated Project for Prospective Observation of Noncommunicable Disease and Its Trends in Aged (NIPPON DATA; n = 7,453) were analyzed. MS was defined as >=3 of 5 risk factors (obesity, high blood pressure, decreased high density lipoprotein cholesterol, elevated glycosylated hemoglobin, and elevated triglycerides). The results show that after a median of 13.8 years of follow-up in the United States, 1,683 patients died from CVD (11.75 per 1,000 person years), and after a median of 15 years of follow-up in Japan, 369 patients died from CVD (3.56 per 1,000 person-years). The age-adjusted prevalence of MS was 26.7% in the United States and 19.3% in Japan. Of 5 MS factors, obesity, high blood pressure, elevated triglycerides, and glycosylated hemoglobin in the United States, and high blood pressure and elevated glycosylated hemoglobin in Japan were significant risk factors for CVD mortality. Estimates of 13.3% and 44% of the excess CVD mortality for the United States could be explained by the higher prevalence of MS and MS plus baseline CVD history than in Japan. In conclusion, the present study is the first to quantitatively demonstrate that MS and MS plus baseline CVD history may significantly contribute to the explanation of excess CVD mortality in the United States compared with Japan. PMID- 24169009 TI - Treatment patterns and outcomes in patients undergoing percutaneous coronary intervention treated with prasugrel or clopidogrel (from the Swedish Coronary Angiography and Angioplasty Registry [SCAAR]). AB - Large real-world registry data are important for understanding the current use and outcomes of novel therapies. The aim of this study was to assess treatment patterns and outcomes in patients who underwent percutaneous coronary intervention (PCI) with prasugrel or clopidogrel. Consecutive patient data from the Swedish Coronary Angiography and Angioplasty Registry (SCAAR) for 2010 and 2011 were used. The study population consisted of all patients with acute coronary syndromes (ACS) and those without ACS who underwent PCI and were treated with prasugrel (with or without a clopidogrel loading dose) or solely with clopidogrel. Outcomes included were 30-day mortality and in-hospital bleeding. In 2010 and 2011, 23,994 patients were treated with clopidogrel during hospitalization for their first PCI during the study period, while 2,142 patients were treated with prasugrel. Prasugrel was mainly used in patients with ST segment elevation myocardial infarction. Hemorrhagic risk factors such as older age, female gender, and previous stroke were more common in the clopidogrel treated patients. However, Mehran bleeding risk scores were higher in prasugrel treated patients. In the ACS group, lower mortality was observed in the prasugrel group compared with the clopidogrel group. Mortality was comparable in patients who underwent elective angiography and PCI. In-hospital bleeding was lower in prasugrel-treated patients. In conclusion, in this real world population of patients who underwent urgent or elective PCI, prasugrel was used mainly in patients with ACS, while it was avoided in patients with characteristics indicating increased bleeding risk. Mortality and bleeding rates were lower with prasugrel than clopidogrel, probably because of patient selection. PMID- 24169010 TI - Comparison of procedural complications with versus without interventional cardiology fellows-in-training during contemporary percutaneous coronary intervention. AB - Despite increasing complexity of contemporary procedures at tertiary care hospitals, the relationship between interventional cardiology fellows-in-training (ICFITs) and complications of percutaneous coronary intervention (PCI) has not been reported. We compiled logbooks of 6 ICFITs at an academic hospital and evaluated patient and procedural characteristics of PCIs performed with and without presence of an ICFIT. The primary end point was the composite of all in hospital PCI complications defined by the American College of Cardiology's National Cardiovascular Data Registry: (1) catheterization laboratory events such as no-reflow and dissection/perforation, (2) general clinical events such as stroke or cardiogenic shock, (3) vascular and bleeding complications, and (4) miscellaneous complications such as peak troponin or creatinine levels. Logistic regression adjusted for differences in measured confounders between patients treated with and without presence of an ICFIT. All analyses were repeated after excluding PCI for ST-elevation myocardial infarction. Of 2,605 PCI procedures at the academic hospital between July 2007 and April 2010, an ICFIT was present for 1,638 procedures (63%). Despite having worse clinical and procedural characteristics, patients in the ICFIT group experienced similar rates of the composite end point (12.9% vs 14.5% without ICFIT, p = 0.27). Longer mean fluoroscopy times and greater number of stents were noted in the ICFIT group; however, hospital length of stay was shorter and no individual adverse events were increased in the ICFIT procedures. Presence of an ICFIT remained unrelated to the composite end point after multivariable adjustment (odds ratio 0.92, 95% confidence interval 0.71 to 1.20; p = 0.53), and findings were similar after excluding PCI for ST-elevation myocardial infarction. In conclusion, in contemporary practice at a large academic medical center, PCI complication rates were not adversely affected by the presence of an ICFIT. PMID- 24169011 TI - Usefulness of N-terminal pro-B-type natriuretic Peptide increase as a marker for cardiac arrhythmia in patients with syncope. AB - B-type natriuretic peptides (BNPs) have been investigated as biomarkers for risk stratification of patients with syncope. Their concentration can be influenced by age and co-morbidities. In the present study, we compared the change in N terminal pro-B-type natriuretic peptide (NT-proBNP) levels within 6 hours in patients with vasovagal and arrhythmic syncope to determine whether this change can predict arrhythmic syncope. Using a case-control design, 33 patients were enrolled. Of the 33 patients, 18 with arrhythmic syncope, as they underwent controlled ventricular tachycardia or ventricular fibrillation (VF) during device safety testing of an implantable cardioverter defibrillator implantation or battery replacement, were compared with 15 patients, who during a tilt-table test were diagnosed with vasovagal syncope (VS). For each patient, a blood sample for NT-proBNP evaluation was collected at baseline and 6 hours after the episode of ventricular tachycardia, VF, or VS. We calculated the percentage of increase in the 6-hour NT-proBNP concentration between the 2 groups using nonparametric techniques. We also calculated the area under a receiver operating characteristic curve with the 95% confidence intervals. The 6-hour change in the NT-proBNP concentrations between patients who had had an episode of ventricular tachycardia or VF and patients with VS was significantly different, with a median increase of 32% in the ventricular tachycardia or VF group versus 5% in the VS group (p <0.01). The area under a receiver operating characteristic curve to predict arrhythmic syncope was 0.8 (95% confidence interval 0.65 to 0.95). In conclusion, the results of the present study suggest that a 6-hour NT-proBNP increase might be able to predict arrhythmic syncope. Future work is needed to confirm these findings in undifferentiated emergency department patients who present with syncope. PMID- 24169013 TI - Automatic assessment of coronary artery calcium score from contrast-enhanced 256 row coronary computed tomography angiography. AB - The coronary artery calcium score (CS), an independent predictor of cardiovascular events, can be obtained from a stand-alone nonenhanced computed tomography (CT) scan (CSCT) or as an additional nonenhanced procedure before contrast-enhanced coronary CT angiography (CCTA). We evaluated the accuracy of a novel fully automatic tool for computing CS from the CCTA examination. One hundred thirty-six consecutive symptomatic patients (aged 59 +/- 11 years, 40% female) without known coronary artery disease who underwent both 256-row CSCT and CCTA were studied. Original scan reconstruction (slice thickness) was maintained (3 mm for CSCT and 0.67 mm for CCTA). CS was computed from CCTA by an automatic tool (COR Analyzer, rcadia Medical Imaging, Haifa, Israel) and compared with CS results obtained by standard assessment of nonenhanced CSCT (HeartBeat CS, Philips, Cleveland, Ohio). We also compared both methods for classification into 5 commonly used CS categories (0, 1 to 10, 11 to 100, 101 to 400, >400 Agatston units). All scans were of diagnostic quality. CS obtained by the COR Analyzer from CCTA classified 111 of 136 (82%) of patients into identical categories as CS by CSCT and 24 of remaining 25 into an adjacent category. Overall, CS values from CCTA showed high correlation with CS values from CSCT (Spearman rank correlation = 0.95, p <0.0001). In conclusion, CS values automatically computed from 256-row CCTA correlated highly with standard CS values obtained from nonenhanced CSCT. CS obtained directly from CCTA may obviate the need for an additional scan and attendant radiation. PMID- 24169012 TI - Relations of plasma total and high-molecular-weight adiponectin to new-onset heart failure in adults >=65 years of age (from the Cardiovascular Health study). AB - Adiponectin exhibits cardioprotective properties in experimental studies, but elevated levels have been linked to increased mortality in older adults and patients with chronic heart failure (HF). The adipokine's association with new onset HF remains less well defined. The aim of this study was to investigate the associations of total and high-molecular weight (HMW) adiponectin with incident HF (n = 780) and, in a subset, echocardiographic parameters in a community-based cohort of adults aged >=65 years. Total and HMW adiponectin were measured in 3,228 subjects without prevalent HF, atrial fibrillation or CVD. The relations of total and HMW adiponectin with HF were nonlinear, with significant associations observed only for concentrations greater than the median (12.4 and 6.2 mg/L, respectively). After adjustment for potential confounders, the hazard ratios per SD increment in total adiponectin were 0.93 (95% confidence interval 0.72 to 1.21) for concentrations less than the median and 1.25 (95% confidence interval 1.14 to 1.38) higher than the median. There was a suggestion of effect modification by body mass index, whereby the association appeared strongest in participants with lower body mass indexes. Consistent with the HF findings, higher adiponectin tended to be associated with left ventricular systolic dysfunction and left atrial enlargement. Results were similar for HMW adiponectin. In conclusion, total and HMW adiponectin showed comparable relations with incident HF in this older cohort, with a threshold effect of increasing risk occurring at their median concentrations. High levels of adiponectin may mark or mediate age-related processes that lead to HF in older adults. PMID- 24169014 TI - Usefulness of echocardiographically guided left ventricular lead placement for cardiac resynchronization therapy in patients with intermediate QRS width and non left bundle branch block morphology. AB - The current guidelines most strongly support cardiac resynchronization therapy (CRT) for patients with heart failure with a QRS width of >=150 ms and left bundle branch block (LBBB). Our objective was to assess the potential benefit of echocardiographically guided left ventricular (LV) lead positioning for patients with a QRS width <150 ms or non-LBBB as a substudy of the Speckle Tracking Assisted Resynchronization Therapy for Electrode Region (STARTER) prospective, randomized controlled trial. The STARTER trial randomized 187 patients with heart failure, a QRS of >=120 ms, and ejection fraction of <=35% to LV lead guided to the site of latest mechanical activation by speckle tracking radial strain versus routine implantation. The predefined primary end point was heart failure hospitalization or death within 2 years. This substudy included 151 CRT patients with matching echocardiographic and LV lead position data and complete follow-up data. Patients with a QRS width of 120 to 149 ms or non-LBBB and LV lead concordant or adjacent to the site of latest mechanical activation had favorable outcomes after CRT similar to those with LBBB or a QRS width of >=150 ms. In contrast, patients with a QRS of 120 to 149 ms or non-LBBB and remote LV leads had unfavorable outcomes (hazard ratio 5.45, 95% confidence interval 2.36 to 12.6, p <0.001, and hazard ratio 4.92, 95% confidence interval 2.12 to 11.39, p <0.001, respectively, with significant interaction after adjusting for baseline variables, p = 0.038 and p = 0.008). In conclusion, LV lead positioning with respect to the echocardiographic site of latest activation was significantly associated with more favorable clinical outcomes in patients with a QRS duration <150 ms and/or non-LBBB. Additional prospective study is warranted. PMID- 24169015 TI - Effect of type 2 diabetes mellitus on epicardial adipose tissue volume and coronary vasomotor function. AB - Patients with coronary artery disease and/or type 2 diabetes mellitus (DM) generally exhibit more epicardial adipose tissue (EAT) than healthy controls. Recently, it has been proposed that EAT affects vascular function and structure by secreting proinflammatory and vasoactive substances, thereby potentially contributing to the development of cardiovascular disease. In the present study, the interrelation of EAT, coronary vasomotor function, and coronary artery calcium was investigated in patients with and without DM, who were evaluated for coronary artery disease. Myocardial blood flow (MBF) was assessed at rest and during adenosine-induced hyperemia using [(15)O]-water positron emission tomography combined with computed tomography to quantify coronary artery calcium and EAT in 199 patients (46 with DM). In this cohort (mean age 58 +/- 10 years), the patients with DM had a greater body mass index, heart rate, and systolic blood pressure at rest (all p <0.05). Coronary artery calcium and the EAT volumes were comparable between those with and without DM. Both patient groups showed comparable MBF at rest and coronary vascular resistance. A lower hyperemic MBF and coronary flow reserve (CFR) and greater hyperemic coronary vascular resistance (all p <0.05) was observed in the patients with DM. A pooled analysis showed a positive association of EAT volume with hyperemic coronary vascular resistance but not with the MBF at rest, hyperemic MBF, or coronary vascular resistance at rest. In the group analysis, the EAT volume was inversely associated with hyperemic MBF (r = -0.16, p = 0.05) and CFR (r = -0.17, p = 0.04) and positively with hyperemic coronary vascular resistance (r = 0.26, p = 0.002) only in patients without DM. Multivariate regression analysis, adjusted for age, gender, and body mass index, showed an independent association between the EAT volume and hyperemic MBF (beta = -0.16, p = 0.02), CFR (beta = -0.16, p = 0.04), and hyperemic coronary vascular resistance (beta = 0.25, p <0.001) in the non-DM group. In conclusion, these results suggest a role for EAT in myocardial microvascular dysfunction; however, once DM has developed, other factors might be more dominant in contributing to impaired myocardial microvascular dysfunction. PMID- 24169016 TI - Comparison of two antiplatelet therapy strategies in patients undergoing transcatheter aortic valve implantation. AB - Dual antiplatelet therapy is commonly used in patients undergoing transcatheter aortic valve implantation (TAVI), but the optimal antiplatelet regimen is uncertain and remains to be determined. The objective of this study was to compare 2 strategies of antiplatelet therapy in patients undergoing TAVI. A strategy using monoantiplatelet therapy (group A, n = 164) was prospectively compared with a strategy using dual antiplatelet therapy (group B, n = 128) in 292 consecutive patients undergoing TAVI. The primary end point was a combination of mortality, major stroke, life-threatening bleeding (LTB), myocardial infarction, and major vascular complications at 30 days. All adverse events were adjudicated according to the Valve Academic Research Consortium. The primary end point occurred in 22 patients (13.4%) in the group A and in 30 patients (23.4%) in the group B (hazard ratio 0.51, 95% confidence interval 0.28 to 0.94, p = 0.026). LTB (3.7% vs 12.5%, p = 0.005) and major bleedings (2.4% vs 13.3%, p <0.0001) occurred less frequently in the group A, whereas the incidence of stroke (1.2% vs 4.7%, p = 0.14) and myocardial infarction (1.2% vs 0.8%, p = 1.0) was not significantly different between the 2 groups. The benefit of a strategy using mono versus dual antiplatelet therapy persisted after multivariate adjustment and propensity score analysis (hazard ratio 0.53, 95% confidence interval 0.28 to 0.95, p = 0.033). In conclusion, a strategy using mono versus dual antiplatelet therapy in patients undergoing TAVI reduces LTB and major bleedings without increasing the risk of stroke and myocardial infarction. The results of our study question the justification of dual antiplatelet therapy and require confirmation in a randomized trial. PMID- 24169017 TI - Presentation and revascularization patterns of patients admitted for acute coronary syndromes in France between 2004 and 2008 (from the National Observational Study of Diagnostic and Interventional Cardiac Catheterization [ONACI]). AB - Patients with acute coronary syndrome (ACS) comprise a heterogeneous group. Despite clear guidelines, the management of ACS in clinical practice is variable. We aimed to evaluate clinical characteristics and myocardial revascularization patterns of patients presenting with ACS from a large French nationwide registry. The National Observational Study of Diagnostic and Interventional Cardiac Catheterization is a multicenter registry including all interventional cardiology procedures performed since 2004. Patient demographics and co-morbidities, invasive parameters, treatment options, and procedural techniques were prospectively collected. The present study is focused on data collected between 2004 and 2008. Patients were recruited in 99 hospitals (55% in private clinics, 45% in public institutions). Over a 5-year period, 64,932 patients with ACS were included (mean age 65.7 +/- 13.3; 73% men, 31% ST-elevation myocardial infarction [STEMI]). Patients presenting with unstable angina pectoris and non-ST-elevation myocardial infarction weresimilar with regards to clinical presentation and coronary artery disease (CAD) extension. Overall, these patients were older, had a higher cardiovascular risk profile, and had more severe CAD compared with STEMI patients. In-hospital mortality during the first 24 hours was higher in STEMI patients. Patient's characteristics and CAD were highly dependent on the type of ACS. Patients with unstable angina/non-STEMI were older and had a more severe CAD. In-hospital complications were higher in STEMI patients. PMID- 24169018 TI - Giant coronary artery aneurysm after Takeuchi repair for anomalous left coronary artery from the pulmonary artery. AB - A 33-year-old woman with an anomalous left coronary artery arising from the pulmonary artery who had undergone Takeuchi repair at age 7 years presented for evaluation. The Takeuchi procedure creates an aortopulmonary window and an intrapulmonary tunnel that baffles the left coronary artery to the aorta. A mediastinal mass was identified as a giant aneurysm of the left coronary artery resulting in compression of the pulmonary artery and left upper pulmonary vein. The patient underwent open repair with patch closure at the aortic entrance of the left coronary Takeuchi repair and resection and evacuation of the aneurysm. A saphenous vein graft to the left anterior descending artery was performed. Postoperative echocardiography demonstrated normal left ventricular function. This is the first reported case of giant aneurysm formation after Takeuchi repair. The reported complications have included the development of pulmonary artery stenosis at the intrapulmonary baffle, baffle leak, decreased left ventricular function, and mitral regurgitation. In conclusion, late complications of the Takeuchi procedure are common, underscoring the importance of lifelong follow-up at a center with experience in treating coronary anomalies. PMID- 24169019 TI - Association between intraprocedural thrombotic events and adverse outcomes after primary percutaneous coronary intervention for ST-segment elevation myocardial infarction (a Harmonizing Outcomes With RevasculariZatiON and Stents in Acute Myocardial Infarction [HORIZONS-AMI] Substudy). AB - The present study sought to determine the extent to which adverse angiographic events encountered during percutaneous coronary intervention for ST-segment elevation myocardial infarction (STEMI) are associated with adverse clinical outcomes. Patients with STEMI represent a cohort at particularly high risk of intraprocedural thrombotic events (IPTEs). The overall frequency and implications of IPTEs occurring in patients with STEMI have not been systematically quantified in previous studies. A total of 3,163 patients undergoing primary percutaneous coronary intervention with stent implantation for STEMI in the Harmonizing Outcomes with RevasculariZatiON and Stents in Acute Myocardial Infarction (HORIZONS-AMI) trial underwent detailed frame-by-frame core laboratory angiographic analysis to assess IPTEs. The clinical outcomes at 30 days were compared between the patients with and without IPTEs. IPTEs, defined as the development of new or increasing thrombus, abrupt vessel closure, no reflow, slow reflow, and distal embolization at any point during the procedure, occurred in 386 patients (12.2%). The independent predictors of IPTE were thrombus at baseline, lesion length, and randomization to bivalirudin; the patients with IPTEs were also more likely to receive bailout glycoprotein IIb/IIIa inhibitors and unplanned thrombectomy. Compared with patients without IPTEs, the patients with IPTEs had higher 30-day rates of composite major adverse cardiovascular events (death, myocardial infarction, ischemic target vessel revascularization, and stroke; 7.8% vs 4.2%, p = 0.002), major bleeding not related to coronary artery bypass grafting (11.8% vs 6.5%, p <0.001), and all-cause death (4.2% vs 1.8%, p = 0.002). On multivariate analysis, IPTEs were independently associated with 30-day major adverse cardiovascular events, major bleeding, and death. In conclusion, the development of IPTEs in patients undergoing primary percutaneous coronary intervention for STEMI was associated with subsequent adverse outcomes, including major adverse cardiovascular events, major bleeding, and death. Additional studies of strategies to decrease the occurrence of IPTEs are warranted. PMID- 24169020 TI - Chronic pouchitis is associated with pouch polyp formation in patients with underlying ulcerative colitis. AB - BACKGROUND: Polypoid lesions can develop in ileal pouches. The risk factors associated with the development of pouch polyps have not been studied. AIM: To characterize clinical features, risk factors, and disease course of pouch polyp in a cohort of patients with underlying inflammatory bowel disease (IBD) from a subspecialty clinic. METHOD: A total of 1094 patients with restorative proctocolectomy and IPAA for IBD presenting to our Pouchitis Clinic from 2002 to 2010 were included. Demographic, clinical, and endoscopic variables were analyzed. RESULTS: The median durations from UC diagnosis to colectomy and from pouch creation to the last follow-up for the whole cohort were 6 (interquartile range [IQR]: 3-13) and 9years (IQR: 5-14), respectively. A total of 2472 surveillance and/or diagnostic pouchoscopies were performed for the cohort with a median follow-up of 5 (IQR: 2-6) years in the Pouchitis Clinic. The median number of pouchoscopies per patient was 2 (IQR: 1-3). Of the 1094 patients, 96 (8.8%) were found to have pouch polyps. The median size of the polyps was 1.2 (IQR: 1.0 2.0) cm. On histology, 93 patients (96.9%) had inflammatory-type polyps and 3 (3.1%) had polyps with low-grade dysplasia or indefinite for dysplasia. Multivariate logistic regression analysis demonstrated that chronic pouch inflammatory change was a risk factor for the development of pouch polyp with an odds ratio of 2.26 (95% confidence interval: 1.35-3.79; P=0.002). CONCLUSION: The majority of pouch polyps in patients with underlying UC were benign. Patients with concomitant chronic pouch inflammatory changes had an increased risk for developing pouch polyps. PMID- 24169021 TI - Predictors of recurrent stroke after percutaneous closure of patent foramen ovale. AB - AIMS: Closure of patent foramen ovale following presumed paradoxical embolic stroke remains controversial. The answer to the question as to whether cardiovascular risk factors (CVRF) impact on the recurrence of stroke in patients who have undergone PFO closure remains elusive so far. We aimed to investigate the potential impact of CVRF on the long-term rate of stroke/TIA recurrence in patients treated with an occluder following presumed paradoxical embolic stroke. METHODS AND RESULTS: 443 patients (mean age: 50.0+/-12.6 yrs, female: 206 [46.5%]) undergoing percutaneous PFO closure after presumed paradoxical embolic stroke were followed for a median time of 43.0 [interquartile range: 20.0-86.0] months. During the follow-up period a total of 22 (5.0%) strokes/TIAs and 17 (3.8%) deaths were observed. Cox regression analysis identified hypertension, age and the Essen stroke risk score as predictors of recurrent stroke/TIA. CONCLUSIONS: This study shows that, in patients with a prior presumed paradoxical embolic stroke, the risk for recurrent stroke/TIA after PFO closure is firmly linked to the presence of CVRF. PMID- 24169022 TI - Impact of training on pharmacists' counseling of patients starting antidepressant therapy. AB - OBJECTIVE: To measure the impact of a one-day depression-related training program on pharmacists' counseling of unannounced "mystery shoppers" (MS) starting antidepressant therapy. METHODS: Clustered RCT pharmacies; intervention group pharmacists received communication skills training related to depression (n=21); control pharmacists did not (n=19). Eight months after training, the 40 community pharmacies were visited by MS with a first prescription for antidepressants. The pharmacy interactions were recorded and analyzed using the Roter Interaction Analysis System (RIAS). Mann-Whitney U tests were used to evaluate the impact of training on pharmacy interactions and MS evaluations of the pharmacists' skills and attitudes. RESULTS: Interactions of intervention group pharmacists were significantly longer and consisted of more education and counseling statements about lifestyle and psychosocial concerns. Intervention group pharmacists asked more questions about medical condition and therapeutic regimen, as well as socioemotional concerns. MS gave more socioemotional information to intervention group pharmacists and were more positive in their assessment of these pharmacists' skills and attitudes (p values<0.05). CONCLUSION: Pharmacist training in depression care can positively affect the quality of patient care. PRACTICE IMPLICATIONS: Postgraduate training in depression related services is a worthwhile approach to improve the quality of pharmaceutical care. PMID- 24169023 TI - A 3-stage model of patient-centered communication for addressing cancer patients' emotional distress. AB - OBJECTIVE: To describe pathways through which clinicians can more effectively respond to patients' emotions in ways that contribute to betterment of the patient's health and well-being. METHODS: A representative review of literature on managing emotions in clinical consultations was conducted. RESULTS: A three stage, conceptual model for assisting clinicians to more effectively address the challenges of recognizing, exploring, and managing cancer patients' emotional distress in the clinical encounter was developed. To enhance and enact recognition of patients' emotions, clinicians can engage in mindfulness, self situational awareness, active listening, and facilitative communication. To enact exploration, clinicians can acknowledge and validate emotions and provide empathy. Finally, clinicians can provide information empathetically, identify therapeutic resources, and give referrals and interventions as needed to help lessen patients' emotional distress. CONCLUSION: This model serves as a framework for future research examining pathways that link clinicians' emotional cue recognition to patient-centered responses exploring a patient's emotional distress to therapeutic actions that contribute to improved psychological and emotional health. PRACTICAL IMPLICATIONS: Specific communicative and cognitive strategies are presented that can help clinicians better recognize a patient's emotional distress and respond in ways that have therapeutic value. PMID- 24169024 TI - Single-item or two-item literacy screener to predict the S-TOFHLA among adult hemodialysis patients. AB - OBJECTIVE: We compared single-item (SILS) and two-item (TILS) literacy screeners in predicting Short Test of Functional Health Literacy in Adults (S-TOFHLA) scores. METHODS: Adult hemodialysis patients completed SILS, which determines need for assistance when reading written medical information; TILS (last grade completed and self-reported reading ability); and S-TOFHLA. Receiver operator characteristic curves (ROC) and stratum specific likelihoods were calculated. RESULTS: Of 227 participants, median S-TOFHLA was 24 (IQR 15-34). 129 (55%) participants had adequate, 70 (30%) inadequate, and 37 (16%) marginal health literacy. SILS and TILS predicted S-TOFHLA scores equivalently. Test characteristics predicting inadequate health literacy were: SILS sensitivity for threshold >1, 54% (95%CI: 44, 64), for >2, 39% (29, 49) and specificity for >1, 73% (64, 80), for >2, 93% (87, 97), area under the ROC of 0.67 (0.60-0.74); TILS sensitivity for threshold >1, 72% (62, 80), for >2, 30% (21, 40) and specificity for >1, 54% (45, 63), for >2, 86% (79, 92), area under the ROC of 0.66 (0.59 0.73). CONCLUSION: SILS and TILS had similar test characteristics in predicting S TOFHLA. PRACTICE IMPLICATIONS: While a positive result on either test increases the likelihood that a patient has low health literacy, the SILS is easier to administer and score. PMID- 24169025 TI - Posterior orbital cellulitis: case report and literature review. AB - INTRODUCTION: It is rare for isolated sphenoid sinusitis to cause orbital cellulitis. We present a rare case of posterior orbital cellulitis, so caused, together with a review of the relevant literature. CASE REPORT: A 29-year-old woman presented with a 6-week history of progressive, unilateral, retro-orbital and periorbital right eye pain. On examination, the only finding was reduced visual acuity in the right eye. A computed tomography scan demonstrated right frontal and sphenoid sinus opacification. Sphenoidotomy and frontal sinus trephination were subsequently performed, following failure to respond to intravenous antibiotics. After surgery, the patient's vision returned to normal. CONCLUSION: Isolated sphenoid sinusitis is rare but can cause significant visual disturbance and permanent loss of vision. Vague symptoms unsupported by clinical signs at presentation are a feature of posterior orbital cellulitis. The presented case highlights the problem, and the need for a high index of clinical suspicion even in the absence of firm clinical signs, in order to prevent permanent visual loss. PMID- 24169026 TI - Pharmacological treatment of antipsychotic-induced dyslipidemia and hypertension. AB - Second-generation antipsychotics (SGAs) are associated with significant comorbid metabolic abnormalities. Adjunct medications may be prescribed to treat these metabolic side effects, but the evidence supporting this practice (especially for the management of antipsychotic-associated dyslipidemia and hypertension) is limited. The purpose of this review was to evaluate the effects of adjunct medications on triglyceride, total cholesterol, low-density lipoprotein, high density lipoprotein, and blood pressure levels in participants taking SGAs for psychosis. Studies were systematically searched and evaluated. Studies were included for review if participants were taking SGAs and if lipid and/or blood pressure levels were included as outcome measures. Statins, conventional lipid lowering agents, fluvoxamine, ramelteon, topiramate, valsartan, telmisartan, omega-3 fatty acids, metformin (including both immediate-release and extended release formulations), and a combination of metformin-sibutramine seemed to have beneficial effects on lipid levels. Valsartan, telmisartan, and topiramate appeared to be effective for controlling increases in blood pressure. The literature on adjunct medications for the treatment of antipsychotic-associated dyslipidemia and hypertension is not exhaustive, and long-term randomized controlled trials would offer valuable results. PMID- 24169028 TI - Assisted dying - nurse management of end of life for AL residents. PMID- 24169027 TI - Safety, tolerability, and efficacy of vortioxetine (Lu AA21004) in major depressive disorder: results of an open-label, flexible-dose, 52-week extension study. AB - Patients with major depressive disorder often experience relapse after responding to treatment; therefore, maintenance therapy with antidepressants is recommended for maintaining response or remission. This multicenter, open-label, flexible dose, 52-week extension study evaluated the long-term safety, tolerability, and maintenance of efficacy in study participants who had completed one of two randomized, double-blind, placebo-controlled, 8-week dose-ranging vortioxetine trials in study participants with major depressive disorder. At the open-label baseline, all study participants were switched to vortioxetine 5 mg/day for the first week, with subsequent dose adjustments from 2.5 to 10 mg/day on the basis of response and tolerability. Treatment with vortioxetine for 52 weeks was well tolerated, with no new safety signals identified. Among the 834 evaluable study participants, treatment-emergent adverse events were reported in 70.6%, with the most common in the combined (all doses) population of nausea (15.2%), headache (12.4%), nasopharyngitis (9.8%), diarrhea (7.2%), and dizziness (6.8%). The rate of adverse events related to sexual dysfunction was low and weight gain was minimal. Laboratory values, vital signs, ECGs, physical examinations, and Columbia-Suicide Severity Rating Scale results showed no trends of clinical concern. The change in the severity of depressive and anxiety symptoms was maintained throughout the study as reflected by a 24-item Hamilton Depression Scale total score of 8.2 at week 52 (from 17.6 at open-label baseline) in the observed case data set. PMID- 24169029 TI - Dipeptyl peptidase - 4 inhibitors in type 2 diabetes: cardiovascular risk reduction? PMID- 24169030 TI - Culture conditions for equine bone marrow mesenchymal stem cells and expression of key transcription factors during their differentiation into osteoblasts. AB - BACKGROUND: The use of equine bone marrow mesenchymal stem cells (BMSC) is a novel method to improve fracture healing in horses. However, additional research is needed to identify optimal culture conditions and to determine the mechanisms involved in regulating BMSC differentiation into osteoblasts. The objectives of the experiments were to determine: 1) if autologous or commercial serum is better for proliferation and differentiation of equine BMSC into osteoblasts, and 2) the expression of key transcription factors during the differentiation of equine BMSC into osteoblasts. Equine BMSC were isolated from the sterna of 3 horses, treated with purchased fetal bovine serum (FBS) or autologous horse serum (HS), and cell proliferation determined. To induce osteoblast differentiation, cells were incubated with L-ascorbic acid-2-phosphate and glycerol-2-phosphate in the presence or absence of human bone morphogenetic protein2 (BMP2), dexamethasone (DEX), or combination of the two. Alkaline phosphatase (ALP) activity, a marker of osteoblast differentiation, was determined by ELISA. Total RNA was isolated from differentiating BMSC between d 0 to 18 to determine expression of runt related transcription factor2 (Runx2), osterix (Osx), and T-box3 (Tbx3). Data were analyzed by ANOVA. RESULTS: Relative to control, FBS and HS increased cell number (133 +/- 5 and 116 +/- 5%, respectively; P < 0.001) and 5-bromo-2' deoxyuridine (BrdU) incorporation (167 +/- 6 and 120 +/- 6%, respectively; P < 0.001). Treatment with DEX increased ALP activity compared with control (1,638 +/ 38%; P < 0.001). In the absence and presence of Dex, BMP-2 did not alter ALP activity (P > 0.8). Runt-related transcription factor2 expression increased 3 fold (P < 0.001) by d 6 of culture. Osterix expression increased 9-fold (P < 0.05) by d 18 of culture. Expression of Tbx3 increased 1.8-fold at d 3 (P < 0.01); however expression was reduced 4-fold at d 18 (P < 0.01). CONCLUSIONS: Dexamethasone, but not BMP-2, is required for differentiation of equine BMSC into osteoblasts. In addition, expression of Runx2 and osterix increased and expression of Tbx3 is reduced during differentiation. PMID- 24169031 TI - Factors predicting sexual functioning in patients 3 months after surgical procedures for breast cancer: the role of the Sense of Coherence. AB - Women with breast cancer may have significant problems adjusting to the disease and therapy, due to the significant changes in body image and sexuality associated. The aim of this study was to 1) assess sexual functioning 3 months after surgical procedures for breast cancer, and 2) prospectively investigate the usefulness of a Sense of Coherence (SOC) and beauty treatment as predictors of sexual functioning. METHODS: One hundred women with breast cancer were randomly assigned to a group receiving beauty treatments during hospitalization or a control group. SOC subscales were assessed the day before surgery. Psychological distress and body image were assessed on day 6 after surgery and sexual functioning was assessed at three months. RESULTS: Patients with breast cancer seem to experience significant issues in sexual functioning 3 months after surgery. Half of them declared no sexual activity and 42% had no interest for sex. In terms of Sense of Coherence, only the perception that resources were available to face the disease (i.e. manageability) had a positive influence on sexual functioning. Beauty treatment was also associated, but the most statistically significant predictor of sexual functioning was a younger age. CONCLUSION: This study provides evidence that coping resources, and especially the perception that resources are available to face disease-related disturbances (i.e. manageability), have a positive influence on sexual functioning. Interventions aimed at improving patient perception of available resources might be useful to improve sexual functioning among patients with breast cancer. PMID- 24169032 TI - Simpson-Golabi-Behmel syndrome diagnosed by postmortem magnetic resonance imaging, restricted autopsy, and molecular genetics: a case report. PMID- 24169033 TI - Author's response. PMID- 24169034 TI - Hyperhomocysteinaemia is associated with biochemical hyperandrogenaemia in women with reproductive age. AB - OBJECTIVE: Hyperhomocysteinaemia is a well-established risk factor for cardiovascular disease. This study investigated the relationship between hyperhomocysteinaemia and factors related to polycystic ovary syndrome (PCOS). STUDY DESIGN: Case-control study. Three hundred and thirty-nine women were included; of these, 84 had hyperhomocysteinaemia (homocysteine>12.4 MUmol/l) and 255 had normal homocysteine levels. Homocysteine, high-sensitivity C-reactive protein, insulin resistance, metabolic disturbance and PCOS-related disturbance were evaluated. The clinical and biochemical characteristics of women with hyperhomocysteinaemia and normal homocysteine levels, including insulin resistance, metabolic disturbance and PCOS-related disturbance, were compared. RESULTS: Correlation was found between serum homocysteine level and serum total testosterone level and diastolic blood pressure. No correlation was found between serum homocysteine level and age, body mass index, insulin resistance and lipid profile. Women with hyperhomocysteinaemia had a significantly higher risk for biochemical hyperandrogenaemia and higher serum total testosterone levels than women with normal homocysteine levels. The prevalence rates of PCOS, oligo amenorrhoea, polycystic ovary morphology and metabolic disturbance did not differ between the two groups. The parameters of insulin resistance and lipid profiles were similar between the two groups, and signs of clinical hyperandrogenism (hirsutism and the modified Ferriman-Gallwey score) did not differ between the two groups. Logistic regression analysis found a significant association between hyperandrogenaemia and hyperhomocysteinaemia (odds ratio 2.24, 95% confidence interval 1.26-4.01). CONCLUSIONS: For women with PCOS, an elevated serum total testosterone level is the main factor associated with hyperhomocysteinaemia. The association between biochemical hyperandrogenism and hyperhomocysteinaemia may contribute to cardiovascular risk for women with PCOS. PMID- 24169035 TI - Inhibitory effects of androstenedione on endometrial cells: implications for poor reproductive outcome among women with androgen excess. AB - OBJECTIVE: Androstenedione (A4) is an androgen that can be metabolized by aromatase to estrone, but the effects of A4 on endometrial cell proliferation either as an androgen or via conversion to estrogens are unknown. The aim of this study was to investigate A4 effects on Ishikawa cells in culture. STUDY DESIGN: Ishikawa cells were treated with increasing concentrations of A4 (0-1000 pmol) for 4 days. Cell proliferation was measured by the (4,5-dimethylthiaxol-2-yi)-2,5 diphenyltetraxolium bromide (MTT) assay. Apoptosis was analyzed through Annexin V/propidium iodide (PI) staining and flow cytometry: 17beta-hydroxy steroid dehydrogenase type 1 (17beta-HSD1) and aromatase mRNA expression was measured by reverse transcription-polymerase chain reaction (RT-PCR). Western blotting was used to detect cell signaling expressions of Akt/MAPK. RESULTS: A4 treatment (1 nM) decreased cell proliferation and increased apoptosis, as demonstrated by MTT and flow cytometry or related gene expression. The cellular responses induced by A4 treatment were mediated by activation of the Akt and MAPK signaling pathway. Treatment had no effect on 17beta-HSD1 and aromatase expression. CONCLUSION: A4 treatment induced growth inhibition and apoptosis of Ishikawa cells through activation of the Akt/MAPK pathway. Effects of A4 on Ishikawa cells occurred in the absence of increased 17beta-HSD1 and aromatase expression. These results imply that women with excessive androgen, such as polycystic ovary syndrome, experience poor reproductive outcomes through androgen-regulated mechanisms. PMID- 24169036 TI - Protective effect of infliximab on ischemia/reperfusion injury in a rat ovary model: biochemical and histopathologic evaluation. AB - OBJECTIVE: The aim of this study was to investigate the effect of infliximab on experimentally induced ovarian ischemia/reperfusion injury (IRi). STUDY DESIGN: A total of 42 female rats were equally divided into 6 experimental groups; group 1: sham operation, group 2: 3-h ischemia, group 3 and 4: 3-h ischemia, 3-h reperfusion, group 5 and 6: 3-h ischemia, 24h reperfusion. In group 4 and group 6, 30 min before reperfusion, infliximab was administered intraperitoneally at a dose of 5mg/kg. Bilateral ovaries were removed for histopathologic and biochemical analysis. Serum MDA (sMDA), tissue MDA (tMDA), serum NO (sNO), tissue NO (tNO) and serum catalase concentrations were analyzed. Tissue damage of ovarian tissue was scored by histological examination. RESULTS: The infliximab administration significantly lowered the sNO, tNO and sMDA concentrations in group 4 compared to group 3 (p=0.041, p=0.025 and p=0.035, respectively). sNO, tNO and sMDA concentrations were also lower in group 6 when compared to group 5, but this differences were not significant (p>0.05). On the other hand, tMDA concentrations were lower in infliximab-applied groups when compared to ischemia/reperfusion groups (group 3 vs. 4 and 5 vs. 6) (p=0.045 and p=0.048, respectively). Moreover, histopathologic tissue damage scores in infliximab administration groups were significantly lower than in ischemia/reperfusion groups (p<0.001). CONCLUSION: Infliximab attenuates I/R-induced ovarian tissue injury in rats subjected to ischemia/reperfusion. PMID- 24169037 TI - The contribution of twins conceived by assisted reproduction technology to the very preterm birth rate: a population-based study. AB - OBJECTIVE: To assess the contribution of ART twins to the very preterm birth rate in Slovenia. STUDY DESIGN: In this retrospective population-based study we stratified by plurality and gestational age (<32 weeks vs >32 week) all deliveries >24 weeks in women who conceived by ART. We counted the frequencies of all ART liveborn twins among all liveborn infants and among all liveborn twins and frequencies in the subgroup of very preterm births. RESULTS: During the period 1987-2010, there were 13,293 twins (2.73%, range 1.93-3.62%, a nearly 2 fold increase from 1987 to 2010), 6939 infants born after ART (1.42%, range 0.03 2.62%, an 87-fold increase from 1987 to 2010), including 2317 (33.4%, range 14.28 44.83%, a 3-fold increase from 1987 to 2010) twins (0.47% of all deliveries). A total of 425 twin infants (0.99%, range: 1.07-1.2%, insignificant increase) were born at <32 weeks' gestation, including 261 after ART (61.4%, range 20-100%, 5 fold increase). Twins after ART born at <32 weeks comprised 0.05% of all births (range 0.004-0.11%) and increased 27-fold from 1987 to 2010. CONCLUSIONS: The incidence of twins after ART born at <32 weeks increased 27-fold from 1987 to 2010 and has not reduced from its peak incidence over the last decade. PMID- 24169038 TI - Multiscale gyrokinetics for rotating tokamak plasmas: fluctuations, transport and energy flows. AB - This paper presents a complete theoretical framework for studying turbulence and transport in rapidly rotating tokamak plasmas. The fundamental scale separations present in plasma turbulence are codified as an asymptotic expansion in the ratio epsilon = rhoi/alpha of the gyroradius to the equilibrium scale length. Proceeding order by order in this expansion, a set of coupled multiscale equations is developed. They describe an instantaneous equilibrium, the fluctuations driven by gradients in the equilibrium quantities, and the transport timescale evolution of mean profiles of these quantities driven by the interplay between the equilibrium and the fluctuations. The equilibrium distribution functions are local Maxwellians with each flux surface rotating toroidally as a rigid body. The magnetic equilibrium is obtained from the generalized Grad Shafranov equation for a rotating plasma, determining the magnetic flux function from the mean pressure and velocity profiles of the plasma. The slow (resistive timescale) evolution of the magnetic field is given by an evolution equation for the safety factor q. Large-scale deviations of the distribution function from a Maxwellian are given by neoclassical theory. The fluctuations are determined by the 'high-flow' gyrokinetic equation, from which we derive the governing principle for gyrokinetic turbulence in tokamaks: the conservation and local (in space) cascade of the free energy of the fluctuations (i.e. there is no turbulence spreading). Transport equations for the evolution of the mean density, temperature and flow velocity profiles are derived. These transport equations show how the neoclassical and fluctuating corrections to the equilibrium Maxwellian act back upon the mean profiles through fluxes and heating. The energy and entropy conservation laws for the mean profiles are derived from the transport equations. Total energy, thermal, kinetic and magnetic, is conserved and there is no net turbulent heating. Entropy is produced by the action of fluxes flattening gradients, Ohmic heating and the equilibration of interspecies temperature differences. This equilibration is found to include both turbulent and collisional contributions. Finally, this framework is condensed, in the low Mach-number limit, to a more concise set of equations suitable for numerical implementation. PMID- 24169039 TI - Separation and identification of underivatized plasma acylcarnitine isomers using liquid chromatography-tandem mass spectrometry for the differential diagnosis of organic acidemias and fatty acid oxidation defects. AB - A simple HPLC-MS/MS method has been established to separate and identify underivatized acylcarnitine isomers. Human plasma samples were deproteinized and concentrated. Acylcarnitines were separated on a reverse phase column and detected with triple quadrupole linear ion trap mass spectrometry. Deuterium labeled internal standards were used for quantitation. To identify acylcarnitines without pure standards, information-dependent acquisition linking to enhanced product ion scan mode was used. 112 acylcarnitines, including stereoisomers, were found in samples of patients. Dicarboxylic acylcarnitines, such as methylmalonylcarnitine and glutarylcarnitine, were detected with high sensitivity. Three stereoisomers of (R,S)2-methyl-3-hydroxy butyrylcarnitine were detected in samples of patients with beta-ketothiolase deficiency. Validation results revealed excellent precision and accuracy of the method. In general the within- and between-run coefficients of variation (CV%) were less than 15%, and recoveries were in the range of 92.7-117.5%. In addition, the reference intervals of acylcarnitines for children aged 3-day to13-year old were established. Using the new method and reference intervals, we have correctly diagnosed 49 patients with fatty acid oxidation defects or organic acidemias in 176 high-risk patients. PMID- 24169040 TI - Grafting the sol-gel based sorbents by diazonium salts: a novel approach toward unbreakable capillary microextraction. AB - The present work deals with a novel approach for grafting a sol-gel based sorbent, using diazonium salts for preparation of an unbreakable capillary microextraction (CME) device in on-line combination with high performance liquid chromatography (HPLC). The use of diazonium salts modifier allowed all types of metallic and non-metallic substrates to be used without any limitation. Substrates including copper, brass, stainless steel and polytetrafluoroethylene (PTFE) were chosen to be functionalized by chemical or electrochemical reduction of 4-amino phenyl acetic acid. Then, 3-(trimethoxysilyl)propylamine (3TMSPA) was selected as the precursor and the only reagent for preparation of the desired surface chemical bonded sorbent. The presence of chemical bond between substrate, diazonium salts and 3TMSPA is more probably responsible for thermal and solvent stability and long lifetime of the prepared sorbent. Characterization of the aryl group formation on the various substrates along with the prepared sorbents was thoroughly investigated by scanning electron microscopy (SEM), Fourier transform infrared spectroscopy (FTIR) and thermogravimetry analysis (TGA). Typically, one of the prepared sorbents, deposited on the inner surface of the copper tube, was selected for assessing the developed method. The CME device was used for on-line extraction of atrazine, ametryn and terbutryn, as model compounds, from the aquatic media. After extraction, the HPLC mobile phase was used for on-line desorption and elution of the extracted analytes from the CME loop, containing the grafted sol-gel based sorbent, through the HPLC column. Figures of merit of the developed method were also obtained in which the linearity for the analytes was in the range of 30-1000MUgL(-1). The value of LOD (S/N=3) for all analytes was 10MUgL(-1) and the RSD% values (n=5) were all below 9.4% at the 500MUgL(-1) level. Applicability of the developed method was examined by analyzing some real water samples in which the relative recovery percentage ranged from 75 to 95%. PMID- 24169041 TI - Synchronized gradient elution in capillary liquid chromatography. AB - The synchronization of injection valve operation and gradient elution in capillary liquid chromatography (cHPLC) is studied. Focus is placed on the cHPLC systems which rely on the splitting of a primary flow to provide the much smaller secondary flow required at the injection device and analytical column. Owing to the tiny secondary flow rates, synchronization is necessary to achieve proper optimization of gradient elution methods. Otherwise, there is a risk of having the analytes totally or partially eluted in the initial isocratic conditions, and there is no control on the actual gradient profile reaching the column. Synchronization is first achieved by switching back the valve to bypass after injection. This is important to save time, and to avoid the gradient slope to be reduced by mixing within the internal volume of the injector (a 47% of slope reduction, in the conditions used in this work). Valve switching to bypass should be produced immediately after the arrival of the end of the sample plug to the valve (tV). Fine system synchronization is further achieved by starting the gradient at the match time (tM), which is the time required to match the arrival of both the gradient front and the end of the sample plug to the valve, and therefore also to the column inlet. Synchronization of these two events requires starting the gradient either before or even after the injection, thus to prevent a late or an early arrival of the gradient front to the injection valve, respectively. Owing to their dependence with the backpressure, both tV and tM should be measured in the presence of the column at the initial gradient conditions. Simple experiments designed to measure tV and tM are described. With synchronization according to the techniques described in this work, control on the real gradient elution conditions at the column location is maintained, the analysis time is reduced and efficiency improves. The effects of synchronization are illustrated by injecting a mixture of alkylbenzenes. At 1MUL min(-1), valve switching to bypass reduced analysis time from ca. 36 to 12min (butylbenzene), and improved peak symmetry (from 2.00 to 0.94 for methylbenzene) and efficiency (the average apparent plate count increased approximately 60%). Synchronization according to the match time further improved efficiency (approximately, up to 120%). PMID- 24169042 TI - Continuous processing of recombinant proteins: Integration of inclusion body solubilization and refolding using simulated moving bed size exclusion chromatography with buffer recycling. AB - An integrated process which combines continuous inclusion body dissolution with NaOH and continuous matrix-assisted refolding based on closed-loop simulated moving bed size exclusion chromatography was designed and experimentally evaluated at laboratory scale. Inclusion bodies from N(pro) fusion pep6His and N(pro) fusion MCP1 from high cell density fermentation were continuously dissolved with NaOH, filtered and mixed with concentrated refolding buffer prior to refolding by size exclusion chromatography (SEC). This process enabled an isocratic operation of the simulated moving bed (SMB) system with a closed-loop set-up with refolding buffer as the desorbent buffer and buffer recycling by concentrating the raffinate using tangential flow filtration. With this continuous refolding process, we increased the refolding and cleavage yield of both model proteins by 10% compared to batch dilution refolding. Furthermore, more than 99% of the refolding buffer of the raffinate could be recycled which reduced the buffer consumption significantly. Based on the actual refolding data, we compared throughput, productivity, and buffer consumption between two batch dilution refolding processes - one using urea for IB dissolution, the other one using NaOH for IB dissolution - and our continuous refolding process. The higher complexity of the continuous refolding process was rewarded with higher throughput and productivity as well as significantly lower buffer consumption compared to the batch dilution refolding processes. PMID- 24169043 TI - Mitigation of chromatography adsorbent lot performance variability through control of buffer solution design space. AB - The separation of undesired product-related impurities often poses a challenge in the purification of protein therapeutic species. Product-related impurity species, which may consist of undesirable isoforms, aggregated, or misfolded variants of the desired monomeric form of the product, can be challenging to remove using preparatory scale chromatographic techniques. When using anion exchange chromatography to remove undesirable product-related impurities, the separation can be highly sensitive to relatively small changes in the chromatography operating conditions, including changes to buffer solution pH, buffer solution conductivity protein loading, and operating temperature. When performing difficult separations, slight changes to the chemical and physical properties of the anion exchange adsorbent lot may also impact the separation profile. Such lot-to-lot variability may not be readily measurable by the adsorbent manufacturer, since variability can be highly dependent on a specific protein separation. Consequently, manufacturers of chromatographic adsorbents may not be able to control adsorbent lot to lot variability tightly enough to prevent differences from occurring when performing difficult product-related separations at the preparatory scale. In such cases, it is desirable to design a chromatography step with a control strategy which accounts for adsorbent lot to lot variability in the separation performance. In order to avoid the undesired changes to process consistency and product quality, a proper adjustment of the column operating conditions can be implemented, based on the performance of each adsorbent lot or lot mixture. In this work, we describe how the adjustment of the column buffer solution composition can be used as a design space based-control strategy used to ensure consistent process performance and product quality are achieved for an anion exchange chromatography step susceptible to adsorbent lot to lot performance variability. In addition, a "use test" is described that can be employed to determine the optimal buffer solution compositions for different anion exchange adsorbent lots based on the retention volume of the therapeutic protein during a gradient elution. PMID- 24169044 TI - Spice/K2 drugs--more than innocent substitutes for marijuana. AB - Smokeable herbal mixtures containing synthetic agonists of cannabinoid receptors, known under brand names such as Spice, K2 and Kronic, represent a relatively new type of designer psychoactive drugs that has recently emerged on the recreational drug market. Although the Spice packages are labelled 'not for human consumption' or 'for aromatherapy only' and declared to be purely herbal, these herbal mixtures produce cannabis-like effects after smoking. This review surveys the current state of knowledge regarding the pharmacological properties of synthetic cannabimimetics and the prevalence and pattern of their use. Special emphasis is given to the negative consequences of using these products, including, among others, hallucinations, psychoses with delusions, seizures, cardiovascular symptoms and acute kidney injury. PMID- 24169045 TI - Effect of peripherally administered leptin antagonist on whole body metabolism and bone microarchitecture and biomechanical properties in the mouse. AB - Leptin's in vivo effect on the rodent skeleton depends on the model used and the mode of administration. Superactive mouse leptin antagonist (SMLA) was produced and then pegylated (PEG) to prolong and enhance its in vivo activity. We blocked leptin signaling by injecting this antagonist peripherally into normal mice at various time points and studied their metabolic and skeletal phenotypes. Subcutaneous PEG-SMLA injections into 4-wk-old female C57BL/6J mice increased weight gain and food consumption significantly after only 1 mo, and the effect lasted for the 3 mo of the experiment, proving its central inhibiting activity. Mice showed a significant increase in serum glucose, cholesterol, triglycerides, insulin, and HOMA-IR throughout the experiment. Quantification of gene expression in "metabolic" tissues also indicated the development of insulin resistance. Bone analyses revealed a significant increase in trabecular and cortical parameters measured in both the lumbar vertebrae and tibiae in PEG-SMLA-treated mice in the 1st and 3rd months as well as a significant increase in tibia biomechanical parameters. Interestingly, 30 days of treatment with the antagonist in older mice (aged 3 and 6 mo) affected body weight and eating behavior, just as they had in the 1-mo-old mice, but had no effect on bone parameters, suggesting that leptin's effect on bones, either directly or through its obesogenic effect, is dependent upon stage of skeletal development. This potent and reversible antagonist enabled us to study leptin's in vivo role in whole body and bone metabolism and holds potential for future therapeutic use in diseases involving leptin signaling. PMID- 24169047 TI - Epinephrine depletion exacerbates the fasting-induced protein breakdown in fast twitch skeletal muscles. AB - The physiological role of epinephrine in the regulation of skeletal muscle protein metabolism under fasting is unknown. We examined the effects of plasma epinephrine depletion, induced by adrenodemedullation (ADMX), on muscle protein metabolism in fed and 2-day-fasted rats. In fed rats, ADMX for 10 days reduced muscle mass, the cross-sectional area of extensor digitorum longus (EDL) muscle fibers, and the phosphorylation levels of Akt. In addition, ADMX led to a compensatory increase in muscle sympathetic activity, as estimated by the rate of norepinephrine turnover; this increase was accompanied by high rates of muscle protein synthesis. In fasted rats, ADMX exacerbated fasting-induced proteolysis in EDL but did not affect the low rates of protein synthesis. Accordingly, ADMX activated lysosomal proteolysis and further increased the activity of the ubiquitin (Ub)-proteasome system (UPS). Moreover, expression of the atrophy related Ub ligases atrogin-1 and MuRF1 and the autophagy-related genes LC3b and GABARAPl1 were upregulated in EDL muscles from ADMX-fasted rats compared with sham-fasted rats, and ADMX reduced cAMP levels and increased fasting-induced Akt dephosphorylation. Unlike that observed for EDL muscles, soleus muscle proteolysis and Akt phosphorylation levels were not affected by ADMX. In isolated EDL, epinephrine reduced the basal UPS activity and suppressed overall proteolysis and atrogin-1 and MuRF1 induction following fasting. These data suggest that epinephrine released from the adrenal medulla inhibits fasting induced protein breakdown in fast-twitch skeletal muscles, and these antiproteolytic effects on the UPS and lysosomal system are apparently mediated through a cAMP-Akt-dependent pathway, which suppresses ubiquitination and autophagy. PMID- 24169046 TI - Divergent compensatory responses to high-fat diet between C57BL6/J and C57BLKS/J inbred mouse strains. AB - Impaired glucose tolerance (IGT) and type 2 diabetes (T2DM) are polygenic disorders with complex pathophysiologies; recapitulating them with mouse models is challenging. Despite 70% genetic homology, C57BL/6J (BL6) and C57BLKS/J (BLKS) inbred mouse strains differ in response to diet- and genetic-induced obesity. We hypothesized these differences would yield insight into IGT and T2DM susceptibility and response to pharmacological therapies. To this end, male 8-wk old BL6 and BLKS mice were fed normal chow (18% kcal from fat), high-fat diet (HFD; 42% kcal from fat), or HFD supplemented with the PPARgamma agonist pioglitazone (PIO; 140 mg PIO/kg diet) for 16 wk. Assessments of body composition, glucose homeostasis, insulin production, and energy metabolism, as well as histological analyses of pancreata were undertaken. BL6 mice gained weight and adiposity in response to HFD, leading to peripheral insulin resistance that was met with increased beta-cell proliferation and insulin production. By contrast, BLKS mice responded to HFD by restricting food intake and increasing activity. These behavioral responses limited weight gain and protected against HFD-induced glucose intolerance, which in this strain was primarily due to beta cell dysfunction. PIO treatment did not affect HFD-induced weight gain in BL6 mice, and decreased visceral fat mass, whereas in BLKS mice PIO increased total fat mass without improving visceral fat mass. Differences in these responses to HFD and effects of PIO reflect divergent human responses to a Western lifestyle and underscore the careful consideration needed when choosing mouse models of diet-induced obesity and diabetes treatment. PMID- 24169048 TI - Agouti-related peptide plays a critical role in leptin's effects on female puberty and reproduction. AB - Deficient leptin signaling causes infertility via reduced activity of GnRH neurons, causing a hypogonadal state in both rodents and humans. Because GnRH neurons do not express leptin receptors, leptin's effect on GnRH neurons must be indirect. Neurons within the hypothalamic arcuate nucleus that coexpress AGRP and NPY are considered to be important intermediate neurons involved in leptin regulation of GnRH neurons. Previously, we reported that the absence of AGRP and haploinsufficiency of MC4R in leptin receptor mutant (Lepr(db/db)) females result in restoration of fertility and lactation despite the persistence of obesity and insulin resistance. The overarching hypothesis in the present study is that the absence or reduction of leptin's inhibition of AGRP/NPY neurons leads to suppression of GnRH release in cases of leptin signaling deficiency. Since TAC2 (NKB)-TAC3R signaling plays a role in puberty maturation and is modulated by metabolic status, the other aim of this study is to test whether TAC2/NKB neurons in ARC regulated by melanocortinergic signals herein affect leptin's action on puberty and reproduction. Our data showed that AGRP deficiency in Lepr(db/db) females restores normal timing of vaginal opening and estrous cycling, although uterine weight gain and mammary gland development are morphologically delayed. Nonetheless, Agrp(-/-) Lepr(db/db) females are fertile and sustain adequate nutrition of pups with lactation to weaning age. AGRP deficiency results in advanced vaginal opening in wild-type female mice. The postpubertal increase in hypothalamic TAC2 mRNA was not observed in Lepr(db/db) females, whereas AGRP deficiency restored it in Lepr(db/db) females. Additionally, MC4R activation with MTII induced FOS expression in TAC2 neurons, supporting the concept of melanocortinergic regulation of TAC2 neurons. These studies suggest that AGRP imposes an inhibitory effect on puberty and that TAC2 neurons may transmit melanocortinergic inhibition of GnRH neurons. PMID- 24169049 TI - PI3 kinase directly phosphorylates Akt1/2 at Ser473/474 in the insulin signal transduction pathway. AB - Insulin stimulated translocation of the glucose transporter GLUT4 from the cytosol to the plasma membrane in a concentration (1 nM-1 MUM)-dependent manner and increased glucose uptake in 3T3-L1 adipocytes. Insulin-induced GLUT4 translocation to the cell surface was prevented by the phosphoinositide 3 kinase (PI3K) inhibitor wortmannin, the 3-phosphoinositide-dependent protein kinase 1 (PDK1) inhibitor BX912 or the Akt1/2 inhibitor MK2206, and by knocking-down PI3K, PDK1 or Akt1/2. Insulin increased phosphorylation of Akt1/2 at Thr308/309 and Ser473/474, to activate Akt1/2, in the adipocytes. Insulin-induced phosphorylation of Akt1/2 was suppressed by wortmannin and knocking-down PI3K, while no significant inhibition of the phosphorylation was obtained with BX912 or knocking-down PDK1. In the cell-free Akt assay, PI3K phosphorylated Akt1 both at Thr308 and Ser473 and Akt2 at Ser474 alone. In contrast, PDK1 phosphorylates Akt1 at Thr308 and Akt2 at Thr309. The results of this study indicate that PI3K activates Akt1, independently of PDK1, and Akt2 by cooperating with PDK1 in the insulin signal transduction pathway linked to GLUT4 translocation. PMID- 24169050 TI - UII and UT in grouper: cloning and effects on the transcription of hormones related to growth control. AB - Urotensin II (UII) is a cyclic peptide that was originally extracted from the caudal neurosecretory system (CNSS) of fish. UII is well known to exhibit cardiovascular, ventilatory, and motor effects in vertebrates. Studies have reported that UII exerts mitogenic effects and can act as an autocrine/paracrine growth factor in mammals. However, similar information in fish is limited. In this study, the full-length cDNAs of UII and its receptor (UT) were cloned and characterized in the orange-spotted grouper. UII and UT were expressed ubiquitously in various tissues in grouper, and particularly high levels were observed in the CNSS, CNS, and ovary. A functional study showed that UT was coupled with intracellular Ca2+ mobilization in HEK293 cells. Studies carried out using i.p. injections of UII in grouper showed the following: i) in the hypothalamus, UII can significantly stimulate the mRNA expression of ghrh and simultaneously inhibit the mRNA expression of somatostatin 1 (ss1) and ss2 3 h after injection; ii) in the pituitary, UII also significantly induced the mRNA expression of gh 6 and 12 h after injection; and iii) in the liver, the mRNA expression levels of ghr1/ghr2 and igf1/igf2 were markedly increased 12 and 3 h after the i.p. injection of UII respectively. These results collectively indicate that the UII/UT system may play a role in the promotion of the growth of the orange-spotted grouper. PMID- 24169051 TI - Short-term follow-up of episodic wheeze and predictive factors for persistent wheeze. AB - Wheezing phenotypes may not be stable, and phenotype transitions may occur over time. This study investigates the natural course of episodic viral wheezing (EVW) and identifies the risk factors that predict persistence of wheezing through short-term follow-up. The medical records of children <3 years of age at hospital admission and classified as having EVW were retrospectively screened by two pediatric allergists. A total of 236 children were classified as having EVW between January 2010 and February 2011. The median follow-up period was 19.5 months. At the end of follow-up, wheezing persisted in 145 patients (61.4%) and changed to multiple-trigger wheeze in 37 patients (15.7%). Factors associated with persistent wheeze were age at initial wheezing <24 months, anti-inflammatory treatment at the time of diagnosis, history of severe episodic wheeze in the previous year, wheezing requiring systemic steroids in the previous year, frequent episodic wheeze, parental asthma, and a positive modified asthma predictive index (mAPI) for major criteria (each, p < 0.05). The logistic regression analysis revealed three independent risk factors: anti-inflammatory treatment at the time of diagnosis (p = 0.03), history of severe episodic wheeze in the previous year (p = 0.02), and a positive mAPI for major criteria (p = 0.02). The initial wheezing phenotype may vary over time. History of severe episodic wheeze in the previous year, anti-inflammatory treatment at the time of diagnosis, and a positive mAPI for major criteria predicts persistent wheeze at short-term follow-up. PMID- 24169052 TI - Effects of inhaled corticosteroids on the dual asthmatic response. AB - Bronchial asthma patients develop various asthmatic response types to allergen challenge, such as immediate asthmatic response (IAR), late asthmatic response (LAR), or dual asthmatic response (DAR), the latter being a combination of an early phase (IAR) and a late phase (LAR). This study was designed to investigate (1) the features of the DAR thus identifying it as either a genuine two-phase compact clinical entity or a simultaneous appearance of two independent asthmatic response types, IAR and LAR, and (2) the protective effects of inhaled budesonide (BUD) on the DAR. Two protection tests (PTs) with BUD and a placebo (PL), in a single dose of 800 micrograms, were performed on 48 DAR patients, divided into four groups. Each test consisted of two treatments, one given 30 minutes before and the other at 1, 2, 3, or 4 hours after the bronchial challenge with allergen. The study design was randomized, double-blind, double-dummy, placebo-matched, crossover. A single dose of inhaled BUD did not affect the early phase (IAR) when applied 30 minutes before the challenge (p > 0.2), whereas it significantly prevented the late phase (LAR) when administered either 30 minutes before (p < 0.001) or up to 4 hours after the allergen challenge (p < 0.05). The different protective effects of BUD on both of the phases of DAR would suggest that this response does not exist as a compact clinical entity, but it may be a manifestation of two independent simultaneous responses, IAR and LAR, because of different immunologic mechanisms. Inhaled corticosteroids in a single dose administered shortly before or up to 4 hours after the allergen exposure contribute significantly to the prevention of the LAR, whereas they are unable to affect the IAR. PMID- 24169053 TI - Hypersensitivity pneumonitis: the dug-well lung. AB - Hypersensitivity pneumonitis (HP), also known as extrinsic allergic alveolitis, is caused by a variety of environmental agents and may present as occult respiratory illness. HP represents a potentially curable subgroup of interstitial lung disease. This study was designed to examine a group of patients with HP due to a unique mechanism of environmental exposure. Five patients with HP were retrospectively identified, from our hospital records, admitted during the period of March 2007 to February 2011 with history of exposure to dug wells. The mode of exposure was specified as multiple entries into a dug well for different reasons. Other modes of exposure were considered as criteria of exclusion. All of the five patients had subacute HP based on available clinical, radiographic, immunologic, and supportive evidence and exposure. There were additional allergic bronchopulmonary aspergillosis-like features in one patient who did not have antecedent asthma. The evaluation of patient records indicated a fungal etiology. The air and soil from selected wells were tested for fungal organisms. Both settings grew Aspergillus as the predominant species. This novel mechanism of HP is labeled "dug-well lung" because the disease was attributed to exposure to dug wells. Lung disease may result from exposure to a dug well. Farmers or mechanics, climbing down these damp wells for a multitude of reasons, are prone to develop HP. The public health care personnel and farming community should be made aware of this potential occupation-related health hazard. PMID- 24169054 TI - Perspectives on allergic rhinitis and its treatment. PMID- 24169055 TI - Hypersensitivity to antihistamines. AB - Antihistamines are the cornerstone of allergy therapy and are not expected to cause hypersensitivity reactions. We describe two cases, one had urticaria to multiple anti-H1-preparations and the other had anaphylaxis to hydroxyzine. We also provide a review of the English literature on reported reactions regarding causative preparations and manifestations. The latter showed a wide range; most commonly urticaria/angioedema, contact dermatitis, anaphylaxis, and fixed drug eruption (FDE). Most reported cases were young to middle age adults, with apparent predilection to female subjects. The onset of reactions varied from a few minutes for anaphylaxis and urticaria/angioedema, several hours for maculopapular rashes, or longer for contact dermatitis and FDE. Almost all antihistamines have been reported as causing reactions; cetirizine was the most common oral preparation followed by its parent drug, hydroxyzine. Doxepin cream was the most commonly implicated topical preparation in causing contact dermatitis. A causal relationship is often difficult to recognize because the reaction may be similar to the disease being treated with that antihistamine preparation. Reactions to one preparation are likely to occur, but not always, to other members of the same class. Diagnosis is based on clinical suspicion and may be verified by challenge testing. Except for patch testing in contact dermatitis or fixed eruption, other tests have not shown optimal reliability. In most cases, challenge testing with multiple preparations would identify one or more preparations that can be tolerated. Although hypersensitivity to antihistamines seems to be very rare, awareness of the problem would reduce its misdiagnosis. PMID- 24169056 TI - Cross-reactivity and masqueraders in seafood reactions. AB - Confounding variables play a significant role in many adverse seafood reactions and a clear understanding of these factors is important in properly characterizing reactions associated with potential masqueraders and mimics. Although the medical literature is replete with reviews of seafood hypersensitivity and reports of cross-reactive and newly characterized allergens, there has not been a recent effort to provide an updated overview of the several processes that may lead clinicians to draw incorrect conclusions in evaluating reported reactions to seafood. Ranging from seafood intoxications to other nonallergic or complex seafood reactions, these events can easily be misconstrued as representing a seafood IgE-mediated allergy. Among these are the more familiar topics of cross-reactivity and scombroid intoxication, and those with a still evolving understanding such as ciguatera fish poisoning and Anisakis reactions. This article seeks to provide an accessible but comprehensive summary of the relevant information surrounding these confounders in assessing adverse reactions to seafood. Such knowledge may be instrumental in unraveling complex or otherwise unclear presentations and aid clinicians in accurately evaluating and managing patients with reported seafood reactions. PMID- 24169057 TI - A cross-sectional analysis of pet-specific immunoglobulin E sensitization and allergic symptomatology and household pet keeping in a birth cohort population. AB - It is unknown whether family members with detectable specific immunoglobulin E (sIgE) and/or allergic symptoms to pets are more or less likely to reside in a household with pets. We cross-sectionally investigated potential relationships between family members' allergic sensitization and symptoms to dogs and cats and current household pet-keeping practices, using birth cohort data. Blood samples taken from children enrolled in a birth cohort and their biological mothers and fathers, when the children were aged 18 years, were assessed for sIgE to dog and cat allergens. Interviews assessed subjects' self-reported pet exposure symptoms, current household pet-keeping practices, and socioeconomic characteristics. Overall, household dog or cat keeping was not associated with sIgE to these animals and/or self-reported allergic symptoms in the presence of these animals, even after controlling for factors such as education and household income. In subgroup analyses, current household dog keeping among dog-symptomatic teens (n = 40) was significantly lower than among teens who were not dog symptomatic (n = 289), at 48.8 and 61.1%, respectively (p = 0.036). Current household cat keeping was significantly lower among cat-symptomatic mothers (n = 27) compared with mothers who were not cat symptomatic (n = 120), at 24.3 and 37.0%, respectively (p = 0.015). However, when considering those who were both sensitized and reported symptoms, only the mother and cat-keeping associations persisted (p = 0.049). When cat-sensitized mothers report allergic symptoms to cats, these pets may be less likely to be kept in homes. Elevated dog and cat allergen sIgE does not appear to be associated with the keeping of these pets. PMID- 24169058 TI - Growth of preschool age children receiving daily inhaled corticosteroids. AB - Data on the effects of inhaled corticosteroid (ICS) on linear growth in children <5 years old are limited with conflicting results from existing studies. This study was designed to investigate growth effects of inhaled corticosteroid use in children <5 years of age treated for asthma with ICS administered through a valved holding chamber (VHC). A retrospective cohort study was performed of 145 children in three treatment groups: (1) metered-dose inhaler (MDI) containing ultrafine beclomethasone dipropionate (n = 62), (2) MDI containing fluticasone propionate (n = 32), and (3) oral montelukast sodium (n = 51). Children <5 years of age between 2000 and 2009 treated for asthma with one of the three drugs were included in the study. Linear mixed model analysis was used to examine and compare growth during sustained treatment with each of the three medications. The three treatment groups did not differ significantly in their effect on growth rates (p = 0.64). However, female subjects had significantly slower growth than male subjects (p = 0.017), and the addition of intranasal corticosteroids (INS; p = 0.013) and the presence of atopy (p = 0.015) had a significant negative effect on growth. In children <5 years of age receiving maintenance therapy for chronic asthma, low-to-medium doses of ultrafine beclomethasone or fluticasone administered through a VHC were not associated with growth inhibition compared with children receiving oral montelukast. A small but statistically significant decrease in growth was seen in subjects with positive skin testing to inhalant allergens in female subjects and in subjects receiving INS. PMID- 24169059 TI - Assessment of hereditary angioedema treatment risks. AB - Therapies used for hereditary angioedema (HAE) have been associated with adverse events to include thrombosis, emboli, hepatocellular carcinoma (HCC), exacerbation of attacks, and anaphylaxis. It is difficult to determine incidence of these adverse events from the literature. For this reason we surveyed multiple HAE physicians to determine the risk associated with therapies used in HAE. This study was designed to determine by survey the risk of thrombosis associated with C1-inhibitor (C1-INH), worsening attacks with fresh frozen plasma (FFP), and carcinoma secondary to androgens (mainly danazol). An Internet-based survey was sent to physicians internationally who treat patients with HAE. The survey queried physicians about their observations while treating HAE. Of the 66 physicians who participated in the survey, 37 had patients (856 patients) who were on C1-INH but only 4 (total of 5 patients) had patients on C1-INH who experienced an thromboembolic episode. Of the 17 patients on C1 esterase inhibitor and an indwelling catheter, 3 experienced an embolic, thrombosis, or thromboembolic event. The likelihood of an abnormal event when a patient is on a C1-INH is 5/856 (0.6%), compared with 3/17 (18%) with a central catheter. The incidence of HCC is rare. The incidence of adverse effects to FFP is greater than the literature suggests. Patients with HAE should avoid indwelling catheters, use FFP only when other therapies are unavailable, and use androgens with caution. Most importantly, adverse events to drugs should be reported so that the true incidence of adverse events can be determined. PMID- 24169060 TI - Changing the route of immunotherapy administration: an 18-year survey in pediatric patients with allergic rhinitis and asthma. AB - Immunotherapy can be administered either sublingually (sublingual immunotherapy [SLIT]) or subcutaneously (subcutaneous immunotherapy [SCIT]). The rate of route switching, required by patients, can provide an indirect evaluation of patients' preferences and adherence. The authors retrospectively reviewed patients' files over an 18-year period to quantify the changes in the route of administration. The clinical records of children referred for respiratory allergy between 1994 and 2011 and prescribed with SLIT or SCIT were reviewed. The specific causes of the shift from SLIT to SCIT and vice versa were always assessed, with a special attention to adverse events. The records of 4933 children (2289 male patients, aged 4-18 years) were reviewed. Six hundred forty-eight patients received SCIT and 4285 patients received SLIT. Of the 4285 SLIT patients, 340 (7.9%) shifted to SCIT, mainly with Parietaria judaica and grasses. The 85.8% of the changes were caused by a perceived low efficacy. None of the parents required the route change for side effects. Of the 648 patients initially treated with SCIT, 54 (8.3%) shifted to SLIT, 85% of them for local or systemic side effects, but none for poor efficacy. The rate of SCIT/SLIT changes is, overall, low and because of poor efficacy for SLIT and side effects for SCIT. PMID- 24169061 TI - Patient satisfaction with beclomethasone dipropionate nasal aerosol device with integrated dose counter during daily use. AB - Some patients with allergic rhinitis (AR) may prefer a "dry" intranasal corticosteroid aerosol to avoid certain sensory perceptions such as the "wet feeling in the nose" and the "dripping down the throat" associated with aqueous nasal sprays. A nonaqueous hydrofluoroalkane-propelled beclomethasone dipropionate (BDP) nasal aerosol with an established efficacy and safety profile was approved to treat the nasal symptoms associated with AR in adult and adolescent patients. This study was designed to evaluate ease of use and patient satisfaction with the BDP nasal aerosol device in patients with perennial AR (PAR). In this phase 3, randomized, double-blind, parallel-group, placebo controlled study, eligible patients (>=12 years of age) with PAR were randomly assigned to receive BDP nasal aerosol at 320 micrograms/day or placebo for 6 weeks. At the end of the treatment period, patients assessed device ease of use and satisfaction with the device using a questionnaire with a 5-point representative scale (not at all, not very, neither nor, somewhat, very [certain/easy/satisfactory]). Nearly all patients (89.7%) reported that the BDP nasal aerosol device with integrated dose counter was "very easy" or "somewhat easy" to use. The majority of patients (87.5%) also indicated that it was "very easy" or "somewhat easy" to tell when the device was empty, compared with only 42.3% who were "very certain" or "somewhat certain" of being able to tell when previously used aqueous nasal spray devices were empty. Overall, patient satisfaction with the BDP nasal aerosol device was high: 65.7% responded that they were "very satisfied" or "somewhat satisfied" and only 3.6% were "not satisfied at all" or "not very satisfied." These results indicate that the majority of patients considered the BDP nasal aerosol device easy to use and reported a high degree of satisfaction with the device compared with other nasal sprays they had used in the past. PMID- 24169062 TI - Beclomethasone dipropionate nasal aerosol with an integrated dose counter: functionality and performance. AB - Consistent medication delivery is critical for disease control including symptom management of allergic rhinitis (AR). Available aqueous intranasal corticosteroid devices lack an accurate dose (actuation) counter, which may lead patients to prematurely discard a unit or use a unit beyond its labeled number of actuations, therefore impacting patient adherence. Beclomethasone dipropionate (BDP) nasal aerosol, a nonaqueous hydrofluoroalkane formulation in a device with a novel integrated dose counter and an established efficacy/safety profile, was approved to treat AR-associated nasal symptoms in adolescent and adult patients. This study was designed to evaluate performance of the BDP nasal aerosol device with an integrated dose counter in perennial AR (PAR) patients. In a 6-week, double blind, placebo-controlled study in PAR patients (>=12 years), patients were randomized to receive once-daily BDP nasal aerosol at 320 micrograms or placebo. In addition to assessing the primary efficacy end point, patients evaluated the performance of the device and reliability, accuracy, and functionality of the dose counter. Concordance between daily patient-reported actuations and dose counter readings was assessed by classifying discrepancies into four categories: "fire not count," "count not fire," "count unknown fire," and "count up unknown fire." Analysis was performed for the total device completer population (n = 374), which included all randomized patients completing >=80% of actuations during the last 4 weeks of treatment. Low discrepancy rates were shown for all discrepancy categories. Of 41,891 patient-reported actuations, only 159 discrepancies (diary versus counter) were noted, resulting in an overall discrepancy rate of 0.38 per 100 actuations. The medically important discrepancy rate of "fire not count" was low (0.09 per 100 actuations). Overall, 79.1% of patients reported zero discrepancies, 9.4% reported one discrepancy, and 6.4% reported two discrepancies. These results showed the functionality and reliability of the BDP nasal aerosol device with an integrated dose counter in a clinical setting. (ClinicalTrials.gov identifier: NCT01134705.). PMID- 24169063 TI - A patient preference and satisfaction study of ciclesonide nasal aerosol and mometasone furoate aqueous nasal spray in patients with perennial allergic rhinitis. AB - Patients' preference and satisfaction with their nasal allergy medications may be influenced by their sensory attributes. This study evaluates patient preference and satisfaction with ciclesonide hydrofluoroalkane nasal aerosol (CIC-HFA) compared with mometasone furoate aqueous nasal spray (MFNS). Symptomatic subjects with perennial allergic rhinitis (PAR) were randomized to CIC-HFA at 74 micrograms or MFNS at 200 micrograms q.d. in an open-label, two-period, crossover study. Subject preference was recorded as total preference score (TPS; average of 17 individual preference items) at the end of treatment period 2, and satisfaction was assessed with a 76-item, self-administered instrument at baseline and at the end of each 2-week treatment period. The primary assessments were TPS and regimen attributes composite satisfaction score composed of two of nine satisfaction subscales: sensory impact (including medication running out of the nose, medication running down the throat, and impact on smell and taste) and regimen management (comprised of issues relating to dosing and ability to remember to take medication). Two hundred ninety-four subjects completed the study. A total of 68.1% of subjects preferred CIC-HFA (p < 0.0001 versus MFNS), with a mean TPS of 68.3 versus 31.7 for the MFNS group. The regimen attributes composite satisfaction score significantly (p < 0.0001 for each treatment period) favored CIC-HFA versus MFNS at the end of treatment period 1 (85.5 vs 77.6) and treatment period 2 (83.0 versus 73.5), respectively. In this study, subjects reported higher preference for and satisfaction with CIC-HFA compared with MFNS, suggesting significant differences in patient perception of attributes in favor of CIC-HFA. Clinical trial registration URL and registration number: www.clinicaltrials.gov/ct2/show/NCT01401465. PMID- 24169064 TI - Chronic bilateral pruritic arm dermatitis in a 61-year-old woman. AB - A 61-year-old woman presented to our Allergy/Immunology clinic for pruritic dermatitis of both arms since 2006. Initial symptoms included pruritus and burning dysesthesias of the upper extremities without a rash. Months later an excoriated, papular rash developed along the upper extremities. Cold compresses provided some relief, whereas sun exposure worsened symptoms. Over the years consultations with multiple dermatologists did not elicit a diagnosis, and symptoms did not improve after numerous trials of topical corticosteroids and systemic antihistamines. The differential diagnosis of pruritic rash is extensive; however, in the case of chronic pruritus without a primary rash other diagnoses should come to mind. Although pruritus is a hallmark of many atopic conditions, as allergists-immunologists it is important to remember that not all pruritus is atopic in nature. Prompt recognition and treatment of an occult process presenting primarily with pruritus will likely result in improved outcomes for the patient. PMID- 24169065 TI - For the patient. PMID- 24169066 TI - Regional fat distribution and cardiometabolic risk in healthy postmenopausal women. AB - BACKGROUND: Regional fat distribution is an important determinant of cardiometabolic risk after menopause. The aim of the present study was to investigate the association between indices of fat distribution obtained by Dual energy X-ray Absorptiometry (DXA) and representative cardiometabolic risk factors in a cohort of healthy postmenopausal women. METHODS: In this cross-sectional study, cardiometabolic risk factors were correlated with a variety of central and peripheral fat depots obtained by DXA, in a total of 150 postmenopausal women, free of diabetes and cardiovascular disease (age 54 +/- 7 years, BMI 29.6 +/- 5.8 kg/m(2), mean +/- 1 SD). RESULTS: After adjusting for age and total adiposity, DXA-derived indices of central and peripheral fat distribution displayed opposite associations (positive versus negative) with the examined cardiometabolic risk factors. In multivariate regression analysis, thoracic fat mass % was an independent predictor of blood pressure, HOMA index and triglycerides, abdominal fat mass % was an independent predictor of high sensitivity C-reactive protein, and abdominal-to-gluteofemoral fat ratio was an independent predictor of high density lipoprotein cholesterol. An index of peripheral fat distribution, gluteofemoral fat mass %, proved to be the most important determinant of metabolic syndrome (Odds Ratio 0.76, 95% confidence intervals 0.67-0.87, p<0.001), independent of total and central adiposity. CONCLUSION: DXA-derived indices of regional fat distribution such as thoracic, abdominal and gluteofemoral fat, correlate significantly with cardiometabolic risk factors in healthy postmenopausal women, and may serve as clinically useful tools for evaluating cardiometabolic risk after menopause. PMID- 24169068 TI - Magnetic resonance imaging of the liver: apparent diffusion coefficients from multiexponential analysis of b values greater than 50 s/mm2 do not respond to caloric intake despite increased portal-venous blood flow. AB - PURPOSE: The purpose of this study was to measure potential changes of the apparent diffusion coefficient (ADC) in diffusion-weighted imaging of the liver before and after caloric challenge in correlation to the induced changes in portal vein flow. MATERIALS AND METHODS: The study was approved by the local ethics committee. Each of 10 healthy volunteers underwent 4 measurements in a 1.5 T whole-body magnetic resonance scanner on 2 different days: a first scan after fasting for at least 8 hours and a second scan 30 minutes after intake of a standardized caloric either a protein- or carbohydrate-rich meal. Diffusion weighted spin-echo echo-planar magnetic resonance images were acquired at b values of 0, 50, 150, 250, 500, 750, and 1000 s/mm. In addition, portal vein flow was quantified with 2-dimensional phase-contrast imaging (velocity encoding parallel to flow direction, 60 cm/s). Mean ADC values for regions of interest in 3 different slices were measured from b50 to b250 and from b500 to b1000 images. RESULTS: Carbohydrate- and protein-rich food intake both resulted in a substantial increase in the portal vein flow (fasting state, 638.6 +/- 202.3 mL/min; after protein intake, 1322 +/- 266.8; after carbohydrate intake, 1767 +/- 421.6). The signal decay with increasingly strong diffusion weighting (b values from 0 to 1000 s/mm2) exhibited a triexponential characteristic, implying fast, intermediate, and slow-moving water-molecule proton-spin ensembles in the liver parenchyma. Mean ADC for high b values (b500-b1000) after fasting was 0.93 +/- 0.09 * 10 mm/s; that after protein intake, 0.93 +/- 0.11 * 10; and that after carbohydrate intake, 0.93 +/- 0.08 * 10. For intermediate b values (b50-b250), the signal-decay constants were 1.27 +/- 0.14 * 10 mm/s, 1.28 +/- 0.15 * 10, and 1.31 +/- 0.09 * 10, respectively. There was no statistically significant difference between fasting and caloric challenge. CONCLUSIONS: The postprandial increase in portal vein flow is not accompanied by a change of liver parenchymal ADC values. In clinical diffusion imaging, patients may be scanned without prescan food-intake preparations. To minimize interference of perfusion effects, liver-tissue molecular water diffusion should be quantified using high b values (>=500 s/mm) only. PMID- 24169067 TI - The MIXTA-like transcription factor MYB16 is a major regulator of cuticle formation in vegetative organs. AB - Cuticle secreted on the surface of the epidermis of aerial organs protects plants from the external environment. We recently found that Arabidopsis MIXTA-like R2R3 MYB family members MYB16 and MYB106 regulate cuticle formation in reproductive organs and trichomes. However, the artificial miRNA (amiRNA)-mediated knockdown plants showed no clear phenotypic abnormality in vegetative tissues. In this study, we used RNA interference (RNAi) targeting MYB16 to produce plants with reduced expression of both MYB16 and MYB106. The rosette leaves of RNAi plants showed more severe permeable cuticle phenotypes than the myb106 mutants expressing the MYB16 amiRNA in the previous study. The RNAi plants also showed reduced expression of cuticle biosynthesis genes LACERATA and ECERIFERUM1. By contrast, expression of a gain-of-function MYB16 construct induced over accumulation of waxy substances on leaves. These results suggest that MYB16 functions as a major regulator of cuticle formation in vegetative organs, in addition to its effect in reproductive organs and trichomes. PMID- 24169069 TI - Shear-wave elastographic features of breast cancers: comparison with mechanical elasticity and histopathologic characteristics. AB - OBJECTIVE: The objective of this study was to compare the quantitative and qualitative shear-wave elastographic (SWE) features of breast cancers with mechanical elasticity and histopathologic characteristics. MATERIALS AND METHODS: This prospective study was conducted with institutional review board approval, and written informed consent was obtained. Shear-wave elastography was performed for 30 invasive breast cancers in 30 women before surgery. The mechanical elasticity of a fresh breast tissue section, correlated with the ultrasound image, was measured using an indentation system. Quantitative (maximum, mean, minimum, and standard deviation of elasticity in kilopascals) and qualitative (color heterogeneity and presence of signal void areas in the mass) SWE features were compared with mechanical elasticity and histopathologic characteristics using the Pearson correlation coefficient and the Wilcoxon signed rank test. RESULTS: Maximum SWE values showed a moderate correlation with maximum mechanical elasticity (r = 0.530, P = 0.003). There were no significant differences between SWE values and mechanical elasticity in histologic grade I or II cancers (P = 0.268). However, SWE values were significantly higher than mechanical elasticity in histologic grade III cancers (P < 0.001), which have low amounts of fibrosis, high tumor cellularity, and intratumoral necrosis. In addition, color heterogeneity was correlated with intratumoral heterogeneity of mechanical elasticity (r = 0.469, P = 0.009). Signal void areas in the masses were present in 43% of breast cancers (13 of 30) and were correlated with dense collagen depositions (n = 11) or intratumoral necrosis (n = 2). CONCLUSIONS: Quantitative and qualitative SWE features reflect both the mechanical elasticity and histopathologic characteristics of breast cancers. PMID- 24169070 TI - Incidence of nephrogenic systemic fibrosis in patients undergoing dialysis after contrast-enhanced magnetic resonance imaging with gadolinium-based contrast agents: the Prospective Fibrose Nephrogenique Systemique study. AB - BACKGROUND: Nephrogenic systemic fibrosis (NSF) has been related to the use of gadolinium-based contrast agents (GBCAs) in patients undergoing dialysis. The Prospective Fibrose Nephrogenique Systemique study, a French prospective study supported by the French drug regulatory agency (Agence Nationale de Securite du Medicament) and the French Societies of Nephrology, Dermatology, and Radiology, aimed at determining the incidence of NSF in patients undergoing long-term dialysis. MATERIALS AND METHODS: Adult patients undergoing long-term dialysis receiving a magnetic resonance imaging (MRI) examination prescribed between January 15, 2009 and May 31, 2011, with or without GBCA were included. The methodology was based on a patient form intended to detect any dermatological event (DE) that may occur within 4 months after the examination. Further investigations were planned with their physicians if a DE was reported. RESULTS: A total of 571 patients were included. A total of 50.3% received GBCA. Among them, 93.4% received a macrocyclic GBCA, usually gadoteric acid (88.9%). All in all, 22 patients (3.9%) reported a DE. Dermatological diagnoses did not reveal any evidence of NSF. CONCLUSIONS: The incidence of NSF after a single dose of a macrocyclic GBCA is null in our sample of 268 patients undergoing dialysis (hemodialysis and peritoneal dialysis). This incidence is just lower than 0.5%. When contrast-enhanced MRI can be essential, or even decisive, to the diagnosis, these results are important and reassuring if physicians need to perform contrast enhanced MRI in patients undergoing dialysis. PMID- 24169071 TI - The effect of 8-weeks proprioceptive exercise program in postural sway and isokinetic strength of ankle sprains of Tunisian athletes. AB - OBJECTIVE: Our objective is to investigate the effects of proprioceptive exercises rehabilitation on isokinetic strength and postural balance in athletes with sprain ankle. MATERIALS AND METHODS: The ankles of 16 subjects were tested: eight in the functional instability (FI) group and eight non-injured (NI) subjects in the control group. Subjects were asked to take part in a testing session. The test order for the postural stability and isokinetic strength tests was randomized to avoid learning or fatigue effects. The testing session started with a 5-minute warm-up. Subjects were then instructed to perform several lower body flexibility exercises. The test procedure consisted in static assessments, where single-limb (right and left) stance postural stability was assessed. Three practice trials were allowed for each subject. The assessment quantifies postural sway velocity while the athlete stands calmly on one foot on the force plate, for each leg. They were asked to stand as still as possible for 30s, upper limbs along the body. The subjects were requested to maintain balance with eyes open and then with the eyes closed on the firm surface. The sway velocity (in degrees per second) is given for all trials. Subjects were allowed a 1-minute rest between tests. The regime of isokinetic evaluation of dorsi-plantar flexions is concentric, with three successive speeds: slow (30 degrees /s, reps 5), average (60 degrees /s, reps 10), and fast (120 degrees /s, reps 15), according to the protocol established by European Group for the development and the isokinetic research and the procedural guidelines. Relative moment of strength and times of acceleration and deceleration were calculated for each set of isokinetic testing repetitions per body side, muscle group and testing speed. RESULTS: The results of tests-retest and between both groups (injured vs. healthy) show that after eight weeks of proprioceptive work, significant increase of maximal strength, decrease in times of acceleration and deceleration at the level of plantar flexors and better stability of the injured limb at slow and average (P<0.05). For the healthy limb, improvements varying from 1 to 39% were obtained between test and retest on all the variables. However, these variations were not statistically significant. CONCLUSION: Proprioceptive training exercises can effectively stabilize an unstable ankle above for muscular and postural control. However, 8 weeks does not assess whether we have achieved maximum effect. In addition, we do not know to what extent these effects will continue over time. It would be interesting to later re-evaluate the athletes for the effect of this treatment, which is based on a proprioceptive training program on a year or more. PMID- 24169072 TI - Pulse wave amplitude reduction: a surrogate marker of micro-arousals associated with respiratory events occurring under non-invasive ventilation? AB - INTRODUCTION: Respiratory events occurring under non-invasive ventilation (NIV) may produce sleep fragmentation. Alternatives to polysomnography (PSG) should be validated for providing simple monitoring tools for patients treated at home with NIV. OBJECTIVES: To study the value of pulse wave amplitude (PWA) reduction as a surrogate marker of cortical micro-arousals associated with respiratory events occurring during NIV. METHODS: 27 PSG tracings under NIV recorded in 9 stable patients with Obesity Hypoventilation Syndrome (OHS), under 3 different ventilator modes (no back-up rate, low or high back-up rate) were analyzed. For all respiratory events (obstructive, central, or mixed event), the association with EEG-micro-arousals, PWA reduction of more than 30% and the presence of associated SpO2 desaturation >= 4% was recorded. RESULTS: 2474 respiratory events during NREM sleep were analyzed. 73.6% were associated with an EEG-MA, 91.4% with a >= 4% decrease in SpO2, and 74.9% with a significant PWA reduction. Sensitivity of PWA for the detection of an EEG-micro-arousal related to a respiratory event was 89.1% [95%CI: 76.7-95.3]. Positive predictive value (PPV) was 87.0% [95%CI: 75.0-94.0]. Sensitivity of PWA was highest in the S mode, compared to both other S/T modes, p = <0.001. Sensitivity of PWA was also higher for central and mixed events, compared to obstructive respiratory events, p = <0.05. CONCLUSIONS: PWA reduction is a sensitive marker with a high PPV for the detection of EEG-MA associated with respiratory events during NREM sleep in stable OHS patients treated by NIV. In this situation, PWA could be used to improve scoring of hypopneas and allow an appropriate assessment of sleep fragmentation related to respiratory events. PMID- 24169073 TI - Lung function and airway inflammation monitoring after hematopoietic stem cell transplantation. AB - BACKGROUND: Induced sputum is a non-invasive method to investigate airway inflammation, which has been used to assess pulmonary inflammatory diseases. However, this procedure has not been studied in the context of hematopoietic stem cell transplantation (HSCT). METHODS: We monitored lung function in 182 patients who underwent HSCT and measured airway inflammation by sputum induction in 80 of them. We prospectively measured FEV1, FVC, DLCO, KCO, TLC, RV, exhaled nitric oxide (FeNO) as well as sputum cell counts before and 3, 6, 12, 24 and 36 months after HSCT. RESULTS: For the whole cohort there was a progressive decrease in TLC, which was significant after 3 years (p < 0.01). By contrast, there was no change in other lung functions parameters or in FeNO. Baseline sputum analysis revealed increased neutrophil counts in patients {Median (IQR): 63% (38-79)} compared to healthy subjects matched for age {Median (IQR): 49% (17-67), p < 0.001} but there was no significant change in any type of sputum cell counts over the three years. When comparing myeloablative (MA) vs non-myeloablative (NMA) conditioning, falls in FEV1, FVC and DLCO, and rise in RV and sputum neutrophils were more pronounced over the first year of observation in those receiving MA. CONCLUSIONS: There was a progressive loss in lung function after HSCT, featuring a restrictive pattern. Myeloablative conditioning was associated with early rise of sputum neutrophils and greater alteration in lung function over the first year. PMID- 24169074 TI - 5-years APAP adherence in OSA patients--do first impressions matter? AB - BACKGROUND: Although continuous positive airway pressure (CPAP) is effective in treating obstructive sleep apnoea (OSA), inadequate adherence remains a major cause of treatment failure. This study aimed to determine long term adherence to auto adjusting-CPAP (APAP) and its influencing factors including the role of initial compliance. METHODS: Eighty-eight male patients with newly diagnosed moderate/severe OSA were included. After initiation of APAP treatment, patients had periodic follow-up appointments at 2 weeks, 6 months and then annually for at least 5 years. Patient's compliance to therapy was assessed in each appointment and predictors to treatment abandonment and poor compliance were evaluated. RESULTS: The studied population had a mean age of 53.8 years and mean apnoea hypopnoea index of 52.71/h. The mean time of follow-up was 5.2 (+/- 1.6) years, during that time 22 (25%) patients abandoned APAP, those who maintained treatment had good compliance to it since 94% of them used it more than 4 h/day for at least 70% of days. A significant negative association was found between age, % of days and mean time of APAP use on 12th day and 6th month and the risk of abandoning. APAP use lower than 33% and 57% of days at 12th day and 6th month, respectively had high specificity (~ 100%) to detect treatment abandonment. CONCLUSIONS: the majority of patients adheres to long term APAP treatment and has good compliance after 5-years of follow-up. Age and initial compliance (% days of use and mean hour/day) have the ability to predict future adherence, as soon as 12 days and 6 months after initiation. PMID- 24169075 TI - Kinetics of the use of cryopreserved autologous stem cell grafts: a GITMO-SIDEM survey. AB - BACKGROUND AIMS: Hematopoietic stem cell cryopreservation significantly contributed to autologous stem cell transplantation (ASCT). Cryopreserved stem cell units (SCU) are expected to be used soon after harvesting for most purposes, but, in a number of cases, they remain stored for some time, creating an increasing load for SCU depositories. Disposal policies vary widely in each center, and the existing guidelines are insufficient. METHODS: We conducted a survey of seven Gruppo Italiano Trapianto di Midollo Osseo centers to investigate the outcome of SCU harvested from January 2005 to December 2009 for ASCT. The data from 1603 collections were gathered, for a total of 5822 SCU. RESULTS: In our cohort, 79% of patients collected >5 * 106 CD34+ cells/kg, and 3.4% collected <2 * 106 CD34+ cells/kg. Up to 21% of all the patients and 42% of those with acute leukemia did not undergo reinfusion, and 37% of the cryopreserved SCU were excess, resulting from patients not reinfusing or partially reinfusing. Less than one-third of the excess SCU was disposed, and the major causes of disposal were death and, in a minority of cases, withdrawal of the indication for ASCT. In our analysis, very few first reinfusions occurred after 2 years, and those after 5 years were exceptional. Through the use of a multivariate analysis, we sought to identify the risk factors for collection non-use, independent of the centers' policies. Non-use of SCU was significantly associated with patients with acute leukemia, collections of <2 * 106 CD34/kg and lower age groups. CONCLUSIONS: These data serve as a valid basis to support rational recommendations for cost effective storage and disposal of SCU. PMID- 24169076 TI - C9orf72 repeat expansions are restricted to the ALS-FTD spectrum. AB - Expansion of a GGGGCC repeat (RE) in the C9orf72 gene has been recently reported as the main genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Given the growing evidence of genetic and clinicopathologic overlap among ALS, FTD, and other neurodegenerative diseases, we investigated the occurrence of RE in a subset of 9 patients with ALS-plus syndromes, including Parkinson's disease (PD), progressive supranuclear palsy (PSP), corticobasal syndrome (CBS), and multiple system atrophy. We identified RE in 2 ALS-plus individuals (22.2%) displaying PSP and CBS features. On the basis of this finding, we extended our analysis to a cohort composed of 190 PD, 103 CBS, 107 PSP, and 177 Alzheimer's disease cases. We did not identify any RE in these patients, indicating that C9orf72 is in all probability not involved in the pathogenesis of these disorders. However, the high frequency of C9orf72 RE in patients with ALS-plus syndromes suggests that, similar to ALS-FTD patients, individuals with combined motor neuron and extrapyramidal features should be screened for RE, independent of their family history. PMID- 24169077 TI - Transfemoral aortic valve replacement with the repositionable Lotus Valve System in high surgical risk patients: the REPRISE I study. AB - AIMS: To assess outcomes with a new fully repositionable and retrievable valve for transcatheter aortic valve replacement (TAVR). METHODS AND RESULTS: The Lotus Aortic Valve System is designed to facilitate precise positioning and minimise paravalvular regurgitation. REPRISE I enrolled symptomatic, high-surgical-risk patients with severe aortic stenosis. The primary endpoint (clinical procedural success) included successful implantation without major adverse cardiovascular or cerebrovascular events (MACCE). In all patients (N=11) the first Lotus Valve was successfully deployed. Partial resheathing to facilitate accurate placement was attempted and successfully performed in four patients; none required full retrieval. The primary endpoint was achieved in 9/11 with no in-hospital MACCE in 10/11. There was one major stroke; in another patient, discharge mean aortic gradient was 22 mmHg (above the primary endpoint threshold of 20 mmHg), but improved to 15 mmHg at 30 days. The cohort's mean aortic gradient decreased from 53.9+/-20.9 mmHg at baseline to 15.4+/-4.6 mmHg (p<0.001) at one year; valve area increased from 0.7+/-0.2 cm2 to 1.5+/-0.2 cm2 (p<0.001). Discharge paravalvular aortic regurgitation, adjudicated by an independent core laboratory, was mild (n=2), trivial (n=1), or absent (n=8). Four patients required a permanent pacemaker post-procedure. There were no deaths, myocardial infarctions or new strokes through one year. CONCLUSIONS: Initial results support proof-of-concept with the Lotus Valve for TAVR. PMID- 24169078 TI - The formation of secure new attachments by children who were maltreated: an observational study of adolescents in foster care. AB - Children who were maltreated and enter foster care are at risk for maladjustment and relationship disturbances with foster carers. A popular hypothesis is that prior attachment relationships with abusive birth parents are internalized and carried forward to impair the child's subsequent attachment relationships. However, the empirical base for this model is limited, especially in adolescence. We examined the attachment patterns of 62 adolescents with their birth parents and their foster parents; we compared them to a comparison sample of 50 adolescents in normal-risk families. Attachment was assessed using the Child Attachment Interview; adolescent-parent interaction quality was assessed from direct observation; disruptive behavior symptoms were assessed from multiple informants. Whereas nearly all of the adolescents in foster families exhibited insecure attachments to their birth mothers (90%) and birth fathers (100%), nearly one-half were classified as having a secure attachment with their foster mother (46%) and father (49%); rates of secure attachment toward foster parents did not differ significantly from the rate in comparison families. Within the foster care sample, attachment security to the foster mother was predicted from current observed relationship quality and the duration of current placement. In addition, attachment quality in foster adolescents was associated with fewer disruptive behavior symptoms, and this association was equally strong in foster and comparison families. Our findings demonstrate that there is substantial potential for maltreated children to change and develop subsequent secure attachments in adolescence. PMID- 24169079 TI - Clinical outcome of single porcelain-fused-to-zirconium dioxide crowns: a systematic review. AB - STATEMENT OF PROBLEM: The increasing demand by patients for esthetic and metal free restorations has driven the development of ceramic restorations with good esthetic and mechanical stability. Recent clinical studies have investigated the use of zirconium dioxide as a core material for complete crowns and computer aided-design/computer-aided-manufacturing fabricated restorations. PURPOSE: The aim of this systematic review was to evaluate the clinical survival rates of porcelain-fused-to-zirconia (PFZ) single crowns on anterior and posterior teeth and to compare them with metal ceramic (MC) crowns. MATERIAL AND METHODS: A systematic search was conducted with PubMed and manual research to identify literature written in English that refers to in vivo studies published from January 1, 1950 through July 1, 2011. Clinical trials that evaluated PFZ and MC single crowns on natural teeth were selected for further analysis. Titles and/or abstracts of articles identified through the electronic searches were reviewed and evaluated for appropriateness. In addition, a hand search of relevant dental journals was peformed, and reference lists of culled articles were screened to identify publications. RESULTS: The search resulted in a total of 488 initial matches. Nineteen studies with a total of 3621 crowns met the inclusion criteria. The survival rates of PFZ crowns (total 300) ranged from 92.7% to 100% for a follow-up time of 24 to 39 months, whereas those of MC crowns (total 3321) ranged from 70% to 100% for a follow-up time of 12 to 298 months. Studies that reported long-term results were found only for the MC crown group. CONCLUSIONS: The scientific clinical data available to compare PFZ and MC crowns are limited. The survival rates may well be influenced by the selection and appropriate use of the veneering ceramic, and, therefore, additional prospective long-term clinical trials are necessary to draw reliable conclusions. PMID- 24169080 TI - Color match of machinable lithium disilicate ceramics: effects of foundation restoration. AB - STATEMENT OF PROBLEM: Metal or white opaque foundation restorations may negatively affect the color of machinable lithium disilicate (MLD) ceramic restorations. PURPOSE: The purpose of this study was to evaluate the effects of ceramic thickness and foundation restoration materials on the color of MLD restorations. MATERIAL AND METHODS: Forty-five ceramic slices in 3 thicknesses (1.0 mm, 1.5 mm, 2.0 mm; 15 slices in each group) were made from low-translucency (LT) shade A1 IPS e.max CAD blocks. Resin cement (Multilink yellow) of 100-MUm cement thickness was bonded to 3 different foundation restoration materials: silver-palladium (Ag-Pd) (Albacast) alloy, Type III gold (Midas), and white opaque foundation resin (Paracore white) to make the cement-foundation blocks. After optically connecting each ceramic specimen to the cement-foundation block, the color of each laminated combination was measured with a portable spectrophotometer (Vita EasyShade Compact). The color differences (DeltaE) between the specimen assemblies and a control target block (a 12*14*14-mm crystalized shade A1 LT e.max CAD block) were calculated. Two-way ANOVA and general linear model were used to assess the effects of ceramic thickness, foundation materials, and their interactions to the resultant DeltaE (alpha=.05). Clinical significance was determined by comparing color differences to perceptibility and acceptability thresholds by using the t test (alpha=.05). RESULTS: Both ceramic thickness and foundation materials significantly affected the mean values of color difference (DeltaE) of MLD restorations (P<.001). The mean value of DeltaE decreased as the ceramic thickness increased. At a ceramic thickness of 1 mm, the color difference was above the clinically perceptible level (DeltaE>2.6) with the 3 tested foundation materials (P<.001). As for the foundation materials, the DeltaE was the lowest for Type III gold alloy, followed by Ag-Pd, then white opaque foundation resin. The color differences for Type III gold and a ceramic thickness of 1.5 or 2.0 mm were below the clinically perceptible level (DeltaE<2.6) (P<.001). For Ag-Pd alloy or white opaque foundation resin, the color differences were above the clinically perceptible level (DeltaE>2.6) (P<.001). Ag-Pd alloy reduced, the values of L* and b* parameters of MLD complexes, whereas the white opaque resin increased them. CONCLUSIONS: Based on the results of the study, the colors of MLD ceramic restorations were affected by both the ceramic thickness and foundation restoration materials. Increasing ceramic thickness improved the resultant shade matching. Ag-Pd alloy made the ceramic restorations darker and bluish, whereas white opaque foundation resin made restorations brighter and yellowish. PMID- 24169081 TI - Effects of tadalafil treatment on erectile function recovery following bilateral nerve-sparing radical prostatectomy: a randomised placebo-controlled study (REACTT). AB - BACKGROUND: The potential rehabilitative and protective effect of phosphodiesterase type 5 inhibitors (PDE5-Is) on penile function after nerve sparing radical prostatectomy (NSRP) remains unclear. OBJECTIVE: The primary objective was to compare the efficacy of tadalafil 5mg once daily and tadalafil 20mg on demand versus placebo taken over 9 mo in improving unassisted erectile function (EF) following NSRP, as measured by the proportion of patients achieving an International Index of Erectile Function-Erectile Function domain (IIEF-EF) score >= 22 after 6-wk drug-free washout (DFW). Secondary measures included IIEF EF, Sexual Encounter Profile question 3 (SEP-3), and penile length. DESIGN, SETTING, AND PARTICIPANTS: Randomised, double-blind, double-dummy, placebo controlled trial in men <= 68 yr of age with adenocarcinoma of the prostate (Gleason <= 7) and normal preoperative EF who underwent NSRP at 50 centres from nine European countries and Canada. INTERVENTIONS: 1:1:1 randomisation to 9 mo of treatment with tadalafil 5mg once daily, tadalafil 20mg on demand, or placebo followed by a 6-wk DFW and 3-mo open-label tadalafil once daily (all patients). OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Logistic regression, mixed-effects model for repeated measures, and analysis of covariance, adjusting for treatment, age, and country, were applied to IIEF-EF scores >= 22, SEP-3, and penile length. RESULTS AND LIMITATIONS: Four hundred twenty-three patients were randomised to tadalafil once daily (n=139), on demand (n=143), and placebo (n=141). The mean age was 57.9 yr of age (standard deviation: 5.58 yr); 20.9%, 16.9%, and 19.1% of patients in the tadalafil once daily, on demand, and placebo groups, respectively, achieved IIEF EF scores >= 22 after DFW; odds ratios for tadalafil once daily and on demand versus placebo were 1.1 (95% confidence interval [CI], 0.6-2.1; p=0.675) and 0.9 (95% CI, 0.5-1.7; p=0.704). At the end of double-blind treatment (EDT), least squares (LS) mean IIEF-EF score improvement significantly exceeded the minimally clinically important difference (MCID: DeltaIIEF-EF >= 4) in both tadalafil groups; for SEP-3 (MCID >= 23%), this was the case for tadalafil once daily only. Treatment effects versus placebo were significant for tadalafil once daily only (IIEF-EF: p=0.016; SEP-3: p=0.019). In all groups, IIEF EF and SEP-3 decreased during DFW but continued to improve during open-label treatment. At month 9 (EDT), penile length loss was significantly reduced versus placebo in the tadalafil once daily group only (LS mean difference 4.1mm; 95% CI, 0.4-7.8; p=0.032). CONCLUSIONS: Tadalafil once daily was most effective on drug assisted EF in men with erectile dysfunction following NSRP, and data suggest a potential role for tadalafil once daily provided early after surgery in contributing to the recovery of EF after prostatectomy and possibly protecting from penile structural changes. Unassisted EF was not improved after cessation of active therapy for 9 mo. TRIAL REGISTRATION: ClinicalTrials.gov identifier NCT01026818. PMID- 24169082 TI - Normative data for multisite quantitative ultrasound: the Canadian Multicenter Osteoporosis Study. AB - Multisite quantitative ultrasound (mQUS) machines are attractive tools for assessing fragility fracture risk as they are often portable, comparatively inexpensive, require little training for their use, and emit no ionizing radiation. The primary objective of this investigation was to generate an mQUS normative database of speed of sound (SOS, in m/s) measures from a large sample of randomly selected community-based individuals. mQUS (BeamMed Omnisense MultiSite Quantitative Ultrasound 7000 S) measurements were obtained and assessed at the distal radius, tibia, and phalanx. All analyses were made separately for men and women and for each anatomical site. Scatterplots (SOS vs age) identified 30-39 yr of age as periods of both maximal SOS and of relative stability for all 3 sites over the age span investigated (30-96 yr of age; 2948 women and 1176 men) and, thus, was used as the "reference" population. For cross-sectional comparison of trends over aging, a number of age groupings were created: 30-39, 40-49, 50 59, 60-69, 70-79, and 80+ yr. In general, there were decreases in SOS over increasing age groupings. The normative data generated can be used to compare a given patient's mQUS measurement with reference to a young, healthy population, assigning them a gender-appropriate T-score. PMID- 24169083 TI - Does the precision of dual-energy X-ray absorptiometry for bone mineral density differ by sex? AB - Given larger bone size in men, bone mineral density (BMD) precision might differ between sexes. This study compared dual-energy X-ray absorptiometry BMD precision of 3 International Society for Clinical Densitometry-certified technologists in older men and women. Each technologist scanned a cohort of 30 men and 30 women (total n = 180) by using a Lunar iDXA densitometer (GE Healthcare, Madison, WI). Each volunteer had 2 lumbar spine and bilateral hip scans with repositioning between examinations. BMD least significant change was calculated. Age and body mass index did not differ between men and women. Mean height and weight were greater in men, 174.6 cm +/- 6.9 and 81.6 kg +/- 11.1 respectively, (p < 0.0001) than in women, 161.5 cm +/- 5.9/69.1 kg +/- 14.2, respectively. Bone area was greater in men (p < 0.0001) at all sites. BMD least significant change was statistically better (p < 0.05) in women at the mean total femur (0.014 vs 0.018 g/cm(2)) and left femoral neck (0.025 vs 0.038 g/cm(2)), but not different at either total femur, the right femoral neck, or lumbar spine (all p > 0.05). In conclusion, statistically significant male/female differences in BMD precision were observed at the mean total femur and left femoral neck. Given the small magnitude of difference in g/cm(2) and inconsistent pattern, that is, no right femoral neck difference, there is virtually no clinical difference in BMD precision between sexes. These data do not support a need for sex-specific precision analyses. PMID- 24169084 TI - Necrotising otitis externa: clinical profile and management protocol. AB - BACKGROUND: Necrotising otitis externa, which is typically seen in elderly diabetics, is a severe infective disorder caused by Pseudomonas aeruginosa. There is lack of standard management policy for necrotising otitis externa, hence this study attempted to frame a protocol for management based on clinical parameters. METHOD: A retrospective study of 27 patients with necrotising otitis externa was conducted over 6 years in a tertiary care hospital. Data were analysed with regards to demographic characteristics, clinical features, investigations, staging and treatment modalities. RESULTS: Out of 27 patients, 26 were diabetics. The commonest organism isolated was P aeruginosa, which was sensitive to third generation cephalosporins and fluoroquinolones. Nine patients had cranial nerve involvement. Twelve of 15 patients treated with medical therapy recovered, as did 11 of 12 patients that underwent surgery. CONCLUSION: A high index of suspicion, early diagnosis and prompt intervention are key factors to decrease morbidity and mortality. Fluoroquinolones, third generation cephalosporins and surgical debridement are the mainstay of treatment. PMID- 24169085 TI - A novel acidic serine protease, ASPNJ inhibits proliferation, induces apoptosis and enhances chemo-susceptibility of acute promyelocytic leukemia cell. AB - Acidic serine protease (ASPNJ) purified from Neanthes japonica, is a fibrinolytic enzyme. Earthworm fibrinolytic enzyme has been recently reported with anti-tumor activity on human hepatoma cells. To investigate if ASPNJ play therapeutic effects on emergent blood cancer, acute promyelocytic leukemia (APL), we tested the effects of ASPNJ on APL cell line NB4. Our results showed that ASPNJ inhibited the growth of NB4 cells in a dose and time dependent manner. Cell apoptosis was induced by ASPNJ with obvious morphological changes. The sensitivity of cells to cytarabine and doxorubicin were greatly increased respectively by combination with ASPNJ. In contrast to inhibitory effects on NB4 cells, ASPNJ showed much less effect on normal human neutrophils survival. There were no effects of hemolysis and agglutination observed on normal human erythrocytes following ASPNJ treatment. Conclusively, our data suggest that ASPNJ may become a new candidate for leukemia therapeutic approaches. PMID- 24169086 TI - Genomic aberrations in anaplastic multiple myeloma: high frequency of 1q21(CKS1B) amplifications. AB - Anaplastic multiple myeloma (AMM) is a rare morphologic variant of MM with adverse prognosis. The underlying molecular cytogenetic abnormalities are poorly understood. We investigated 11 patients with AMM for myeloma associated cytogenetic aberrations and compared with 188 non-anaplastic MM using fluorescent in situ hybridization. Of the 11 AMM patients studied, 10 had CKS1B amplification, 5 hemizygous 17p(p53) deletions, 4 13q14 deletions, 4 t(4:14), and 2 had t(11:14). AMM was associated with significantly higher prevalence of CKS1B amplification (91% vs. 34%, p<0.001), 17p(p53) deletion (45% vs. 11%, p=0.006) and t(4,14) (36% vs. 14%, p=0.015) than non-anaplastic MM, which may have resulted in the genetic instability and more aggressive clinical course. PMID- 24169087 TI - Alcohol and immunology: Summary of the 2012 Alcohol and Immunology Research Interest Group (AIRIG) meeting. AB - On October 27, 2012, the 17th annual Alcohol and Immunology Research Interest Group (AIRIG) meeting was held at the Grand Wailea Hotel in Maui, Hawaii as a satellite meeting to the 2012 Society of Leukocyte Biology conference. This year's meeting focused on the influence of alcohol on signal transduction pathways in various disease and injury models. Three plenary sessions were held where invited speakers shared their research on alcohol-mediated alterations of cell signaling components, immune cell subsets, and inflammation. These studies suggested alcohol has a negative effect on cell signaling machinery and immune cell homeostasis, resulting in disease, disease progression, and increased mortality. Researchers also identified tissue-specific alcohol-linked elevations in markers of inflammation, including cold-shock proteins and microRNAs. Additionally, one study revealed the effects of alcohol on immune cell subsets in a model of allergic asthma. PMID- 24169088 TI - Inhibition of human alcohol and aldehyde dehydrogenases by acetaminophen: Assessment of the effects on first-pass metabolism of ethanol. AB - Acetaminophen is one of the most widely used over-the-counter analgesic, antipyretic medications. Use of acetaminophen and alcohol are commonly associated. Previous studies showed that acetaminophen might affect bioavailability of ethanol by inhibiting gastric alcohol dehydrogenase (ADH). However, potential inhibitions by acetaminophen of first-pass metabolism (FPM) of ethanol, catalyzed by the human ADH family and by relevant aldehyde dehydrogenase (ALDH) isozymes, remain undefined. ADH and ALDH both exhibit racially distinct allozymes and tissue-specific distribution of isozymes, and are principal enzymes responsible for ethanol metabolism in humans. In this study, we investigated acetaminophen inhibition of ethanol oxidation with recombinant human ADH1A, ADH1B1, ADH1B2, ADH1B3, ADH1C1, ADH1C2, ADH2, and ADH4, and inhibition of acetaldehyde oxidation with recombinant human ALDH1A1 and ALDH2. The investigations were done at near physiological pH 7.5 and with a cytoplasmic coenzyme concentration of 0.5 mM NAD(+). Acetaminophen acted as a noncompetitive inhibitor for ADH enzymes, with the slope inhibition constants (Kis) ranging from 0.90 mM (ADH2) to 20 mM (ADH1A), and the intercept inhibition constants (Kii) ranging from 1.4 mM (ADH1C allozymes) to 19 mM (ADH1A). Acetaminophen exhibited noncompetitive inhibition for ALDH2 (Kis = 3.0 mM and Kii = 2.2 mM), but competitive inhibition for ALDH1A1 (Kis = 0.96 mM). The metabolic interactions between acetaminophen and ethanol/acetaldehyde were assessed by computer simulation using inhibition equations and the determined kinetic constants. At therapeutic to subtoxic plasma levels of acetaminophen (i.e., 0.2-0.5 mM) and physiologically relevant concentrations of ethanol (10 mM) and acetaldehyde (10 MUm) in target tissues, acetaminophen could inhibit ADH1C allozymes (12-26%) and ADH2 (14-28%) in the liver and small intestine, ADH4 (15-31%) in the stomach, and ALDH1A1 (16-33%) and ALDH2 (8.3-19%) in all 3 tissues. The results suggest that inhibition by acetaminophen of hepatic and gastrointestinal FPM of ethanol through ADH and ALDH pathways might become significant at higher, subtoxic levels of acetaminophen. PMID- 24169091 TI - Safety climate, hardiness, and musculoskeletal complaints: a mediated moderation model. AB - This study explores the mechanisms linking the psychosocial characteristics of the workplace with employees' work-related musculoskeletal complaints. Poor safety climate perceptions represent a stressor that may elicit frustration, and subsequently, increase employees' reports of musculoskeletal discomforts. Results from an employee sample supported that when employees' perceived safety was considered a priority, they experienced less frustration and reported fewer work related upper body musculoskeletal symptoms. Psychological hardiness, a personality trait that is indicative of individuals' resilience and success in managing stressful circumstances, moderated these relationships. Interestingly, employees with high hardiness were more affected by poor safety climate. PMID- 24169089 TI - Developmental differences in EEG and sleep responses to acute ethanol administration and its withdrawal (hangover) in adolescent and adult Wistar rats. AB - Age-related differences in sensitivity to the acute effects of alcohol may play an important role in the increased risk for the development of alcoholism seen in teens that begin drinking at an early age. The present study evaluated the acute and protracted (hangover) effects of ethanol in adolescent (P33-P40) and adult (P100-P107) Wistar rats, using the cortical electroencephalogram (EEG). Six minutes of EEG was recorded during waking, 15 min after administration of 0, 1.5, or 3.0 g/kg ethanol, and for 3 h at 20 h post ethanol, during the rats' next sleep cycle. Significantly higher overall frontal and parietal cortical power was seen in a wide range of EEG frequencies in adolescent rats as compared to adult rats in their waking EEG. Acute administration of ethanol did not produce differences between adolescents and adults on behavioral measures of acute intoxication. However, it did produce a significantly less intense acute EEG response to ethanol in the theta frequencies in parietal cortex in the adolescents as compared to the adults. At 20 h following acute ethanol administration, during the rats' next sleep cycle, a decrease in slow-wave frequencies (1-4 Hz) was seen and the adolescent rats were found to display more reduction in the slow-wave frequencies than the adults did. The present study found that adolescent rats, as compared to adults, demonstrate low sensitivity to acute ethanol administration in the theta frequencies and more susceptibility to disruption of slow-wave sleep during hangover. These studies may lend support to the idea that these traits may contribute to increased risk for alcohol use disorders seen in adults who begin drinking in their early teenage years. PMID- 24169092 TI - Meeting the challenges of providing universal health coverage. PMID- 24169090 TI - Dietary antioxidants prevent alcohol-induced ciliary dysfunction. AB - Previously we have shown that chronic alcohol intake causes alcohol-induced ciliary dysfunction (AICD), leading to non-responsive airway cilia. AICD likely occurs through the downregulation of nitric oxide (NO) and cyclic nucleotide dependent kinases, protein kinase G (PKG) and protein kinase A (PKA). Studies by others have shown that dietary supplementation with the antioxidants N acetylcysteine (NAC) and procysteine prevent other alcohol-induced lung complications. This led us to hypothesize that dietary supplementation with NAC or procysteine prevents AICD. To test this hypothesis, C57BL/6 mice drank an alcohol/water solution (20% w/v) ad libitum for 6 weeks and were concurrently fed dietary supplements of either NAC or procysteine. Ciliary beat frequency (CBF) was measured in mice tracheas, and PKG/PKA responsiveness to beta-agonists and NOx levels were measured from bronchoalveolar lavage (BAL) fluid. Long-term alcohol drinking reduced CBF, PKG and PKA responsiveness to beta-agonists, and lung NOx levels in BAL fluid. In contrast, alcohol-drinking mice fed NAC or procysteine sustained ciliary function and PKG and PKA responsiveness to beta agonists. However, BAL NO levels remained low despite antioxidant supplementation. We also determined that removal of alcohol from the drinking water for as little as 1 week restored ciliary function, but not PKG and PKA responsiveness to beta-agonists. We conclude that dietary supplementation with NAC or procysteine protects against AICD. In addition, alcohol removal for 1 week restores cilia function independent of PKG and PKA activity. Our findings provide a rationale for the use of antioxidants to prevent damage to airway mucociliary functions in chronic alcohol-drinking individuals. PMID- 24169093 TI - A film festival for health. PMID- 24169094 TI - Health Research Authority outlines plans to improve transparency of UK clinical research. PMID- 24169095 TI - Effects of rhythmic exercise performed to music on the rheological properties of blood in women over 60 years of age. AB - The aim of this study was to analyze the effects of motor rehabilitation, in the form of rhythmic exercise to music, on the rheological characteristics of blood in older women. The study included 30 women (65-80 years of age), and the control group was comprised of 10 women of corresponding age. Women from the experimental group were subjected to a five-month rehabilitation program, in the form of rhythmic exercise performed to music (three 30-minute sessions per week); women from the control group were not involved in any regular physical activity. Blood samples from all the women were examined for hematological, rheological, and biochemical parameters prior to the study and five months thereafter. The rehabilitation program was reflected by a significant improvement of erythrocyte count and hematocrit. Furthermore, an improvement of erythrocyte deformability was observed by lower shear stress levels, while no significant changes were noted by the higher shear stress values. The rehabilitation resulted in a marked decrease of the aggregation amplitude while no significant changes were observed in aggregation index and total aggregation half-time. Additionally, the training regimen was reflected by a significant increase in the plasma viscosity, while no significant changes in fibrinogen levels were noted. PMID- 24169096 TI - The in vitro effects of sulfadoxine/pyrimethamine and artemether/lumefantrine on the viscoelasticity of erythrocyte membrane of healthy females. AB - Fansidar(r) (sulfadoxine/pyrimethamine) and Coartem(r) (artemether/lumefantrine) are drugs that destroy malarial parasites and also produce free radicals which cause hemolysis of malaria-parasitized erythrocytes. This study investigated the effect of these drugs on the viscoelasticity of erythrocytes of ten healthy female subjects using the BioProfiler. The concentration for each of the two drugs were determined based on the therapeutic dose as normal, half the therapeutic dose as low and double the therapeutic dose as high. For Fansidar(r), the concentrations were 0.15/0.01 mg/ml (low), 0.30/0.02 mg/ml (normal) and 0.60/0.04 mg/ml (high) based on the adult therapeutic dose of 1500/75 mg of sulfadoxine/pyrimethamine in the drug combination. For Coartem(r), the concentrations were 0.03/0.19 mg/ml (low), 0.06/0.38 mg/ml (normal) and 0.12/0.76 mg/ml (high) based on the adult therapeutic dose of 320/1920 mg of artermether/lumefantrine in the drug combination. There was a statistically significant (p < 0.05) decrease in viscosity, elasticity and relaxation time with Coartem(r) at normal and high doses. Fansidar(r) also showed significant (p < 0.05) reductions in these parameters only in the high dose. This suggests that Coartem(r) generated significant free radicals at normal and high doses, with Fansidar(r) only in the high dose, resulting in increased hemolysis and ultimately reduced viscoelasticity. PMID- 24169097 TI - Preliminary study of laser doppler perfusion signal by wavelet transform in patients with critical limb ischemia before and after revascularization. AB - The haemodynamics of skin microcirculation can be quantitatively evaluated by Laser Doppler Fluxmetry (LDF). LDF signal in human skin shows periodic oscillations. Spectral analysis by wavelet transform displays six characteristic frequency intervals (FI) from 0.005 to 2 Hz, related to distinct vascular structures activities: heart (0.6-2 Hz), sympathetic respiratory (0.145-0.6 Hz), myogenic (0.052-0.145 Hz), local sympathetic nerve (0.021-0.052 Hz) and endothelial cells NO dependent (0.0095-0.021 Hz) and NO independent (0.005-0.0095 Hz). The most advanced stage of peripheral arterial obstructive disease is the critical limb ischemia (CLI), which causes the reduction of blood perfusion threatening limb viability. Besides macrocirculatory alterations, many studies have shown microvascular misdistribution of skin blood flow as the main factor that leads patients to CLI. Revascularization can save limb and patient's life, too. In the present study, LDF signals have been recorded on the skin of the foot dorsum in 15 patients suffering from CLI. LDF signals have been analyzed before and after limb revascularization by means of the wavelet analysis. Significant changes in frequency distribution before and after limb revascularization have been detected: the median normalized values of spectral power increases for 49.8% (p = 0.0341) in the frequency range 0.050328-0.053707 Hz, whereas spectral power decreases for 77.1% (p = 0.0179) in the frequency range 0.018988-0.029284 Hz. We can conclude that changes in the frequency intervals occur after revascularization, shifting from a prevailing endothelial activity toward a prevailing sympathetic activity. PMID- 24169098 TI - The evaluation of plasma viscosity and endothelial dysfunction in smoking individuals. AB - BACKGROUND: Smoking is considered to be one the of risk factors effecting atherosclerosis which is associated the physical forces, biological and chemical stimuli occuring in vessel wall. The aim of this study is analysis of the biomechanical (plasma viscosity) and biochemical effect (nitric oxide, NOx; asymmetric dimethylarginine, ADMA) of smoking on endothelial function. METHODS: One hundred-twenty two individuals were divided into three groups according to their smoking status. Plasma viscosity was measured by Harkness Capillary Viscometer. Plasma NOx level was determined by enzymatic methods using commercial kits. ADMA concentration was determined by Elisa Plasma Assay and and physiologic spirometric and arterial gas parameters and pulmonary blood flow rate (PBFR) were measured. RESULTS: Viscosity variables of former smokers were significantly higher than those of non-smokers (p < 0.001). NOx levels were found to be statistically significantly higher when compared with current smokers and non smokers (p < 0.001), and former smokers and non-smokers (p < 0.05). There was a higher fibrinogen levels in current smokers (p < 0.05) than smokers. CONCLUSIONS: Smoking increases the plasma viscosity that may lead endothelial damage. Plasma viscosity plays an important role as a biophysical mechanical marker on the behalf of hemodynamics. Biochemical markers, NOx and ADMA may show this damage, however, we observed that plasma viscosity can be consistent with biochemical markers. Thus, plasma viscosity may be useful for diagnosis, treatment and follow up of the patients. PMID- 24169099 TI - Diagnostic and therapeutic challenges. PMID- 24169100 TI - Trends and factors related to outcomes for primary rhegmatogenous retinal detachment surgery in a large asian tertiary eye center. AB - PURPOSE: To describe trends and outcomes of vitreoretinal surgery for primary rhegmatogenous retinal detachment in a large Asian tertiary eye center. METHODS: Retrospective review of 1,530 eyes with primary retinal detachment between 2005 and 2011 managed at the Singapore National Eye Center by one of the following: scleral buckling (SB), pars plana vitrectomy (PPV), and combined SB and PPV (SB + PPV). Anatomical and functional outcomes were assessed. RESULTS: There was a trend toward PPV and PPV + SB as the primary reattachment procedure from 2005 to 2011. The primary anatomical success rate for PPV (78.6%) was worse than that for SB (88.8%) or SB + PPV (89.0%, P = 0.000). Final anatomical success rates were similar for all 3 procedures: SB 97.7%, PPV 95.2%, and SB + PPV 96.4%. Better functional success was achieved in the SB group (86.1%) than both the PPV (72.5%) and SB + PPV groups (77.5%, P = 0.000), partly attributable to the less complex nature of retinal detachments in the SB group. Older age and proliferative vitreoretinopathy were related to the poor functional outcomes in both phakic and pseudophakic eyes. CONCLUSION: There was an increasing trend toward PPV and PPV + SB as the primary retinal reattachment surgery from 2005 through to 2011. High rates of anatomical and functional outcomes were achieved with SB, PPV, and SB + PPV, proliferative vitreoretinopathy and older age were negatively correlated with the functional success in both phakic and pseudophakic eyes. PMID- 24169101 TI - Macular epiretinal brachytherapy in treated age-related macular degeneration (MERITAGE): month 24 safety and efficacy results. AB - PURPOSE: To evaluate the safety and efficacy of epimacular brachytherapy for the treatment of chronic, active neovascular age-related macular degeneration. METHODS: A prospective, multicenter, interventional noncontrolled clinical trial recruited 53 participants with previously treated neovascular age-related macular degeneration. Participants underwent pars plana vitrectomy with a single 24 Gray dose of epimacular brachytherapy, delivered using an intraocular cannula containing a Strontium 90/Yttrium 90 source that was positioned over the active lesion. Participants were retreated with ranibizumab, administered monthly as needed, using predefined retreatment criteria. Coprimary outcomes at 24 months were the proportion of participants losing <15 Early Treatment of Diabetic Retinopathy Study letters and mean number of ranibizumab retreatments. RESULTS: Over 24 months, 68.1% lost <15 letters with a mean of 8.7 ranibizumab retreatments. Mean change in visual acuity was -6.3 (standard deviation, 18.9) letters. There was one case of nonproliferative radiation retinopathy. CONCLUSION: The apparent reduction in ranibizumab retreatment was less evident in Year 2 than Year 1, with the moderate reduction in visual acuity extending into the second year. Although radiation retinopathy occurred in one case, it was not vision threatening and safety remained acceptable. PMID- 24169102 TI - Can spatial data substitute temporal data in phenological modelling? A survey using birch flowering. AB - In addition to the evaluation of long-term series, the analysis of spatial gradients, such as urbanization gradients, may be helpful in assessing phenological responses to global warming. But are phenological responses of birch (Betula pendula Roth) assessed by temperature variations comparable over time and space and can spatially calibrated models predict long-term phenological data adequately? We calibrated and tested linear regression models and the process based DORMPHOT model on phenological and temperature data sampled along an urbanization gradient in 2010 and 2011 in the German cities Munich and Ingolstadt (spatial data). Additionally, we analysed data from the German Meteorological Service for the period 1991-2010 (long-term data). The model comparison showed that the DORMPHOT model performed better than the linear model. Therefore, the importance of forcing and chilling sums as well as photoperiod, factors which were all considered in the DORMPHOT model, was evident. Models calibrated on spatial data produced good predictions of spatial data, but they were less adequate for predicting long-term data. Therefore, a time-for-space substitution might not always be appropriate. This finding was also confirmed by a comparison of temperature response rates. The rate of change in the spatial data (-4.4 days degrees C(-1)) did not match the changes observed in the long-term data (-1.9 days degrees C(-1)). Consequently, it is important not to generalize results derived from one specific study method, but their inherent methodological, spatial and temporal peculiarities have to be considered. PMID- 24169103 TI - Effects of nutrient optimization on intra-annual wood formation in Norway spruce. AB - In the Nordic countries, growth of Norway spruce (Picea abies (L.) Karst.) is generally limited by low availability of nutrients, especially nitrogen. Optimizing forest management requires better insight on how growth responds to the environmental conditions and their manipulation. The aim of this study was to analyse the effects of nutrient optimization on timing and the rate of tracheid formation of Norway spruce and to follow the differentiation of newly formed tracheids. The study was performed during two growing seasons in a long-term nutrient optimization experiment in northern Sweden, where all essential macro- and micronutrients were supplied in irrigation water every second day from mid June to mid-August. The control plots were without additional nutrients and water. Tracheid formation in the stem was monitored throughout the growing season by weekly sampling of microcores at breast height. The onset of xylogenesis occurred in early June, but in early summer there were no significant between treatment differences in the onset and relative rate of tracheid formation. In both treatments, the onset of secondary cell wall formation occurred in mid-June. The maximum rate of tracheid formation occurred close to the summer solstice and 50% of the tracheids had been accumulated in early July. Optimized nutrition resulted in the formation of ~50% more tracheids and delayed the cessation of tracheid formation, which extended the tracheid formation period by 20-50%, compared with control trees. The increased growth was mainly an effect of enhanced tracheid formation rate during the mid- and later-part of the growing season. In the second year, the increased growth rate also resulted in 11% wider tracheids. We conclude that the onset and rate of tracheid formation and differentiation during summer is primarily controlled by photoperiod, temperature and availability of nutrients, rather than supply of carbohydrates. PMID- 24169104 TI - Spring photosynthetic recovery of boreal Norway spruce under conditions of elevated [CO(2)] and air temperature. AB - Accumulated carbon uptake, apparent quantum yield (AQY) and light-saturated net CO2 assimilation (Asat) were used to assess the responses of photosynthesis to environmental conditions during spring for three consecutive years. Whole-tree chambers were used to expose 40-year-old field-grown Norway spruce trees in northern Sweden to an elevated atmospheric CO2 concentration, [CO2], of 700 MUmol CO2 mol(-1) (CE) and an air temperature (T) between 2.8 and 5.6 degrees C above ambient T (TE), during summer and winter. Net shoot CO2 exchange (Anet) was measured continuously on 1-year-old shoots and was used to calculate the accumulated carbon uptake and daily Asat and AQY. The accumulated carbon uptake, from 1 March to 30 June, was stimulated by 33, 44 and 61% when trees were exposed to CE, TE, and CE and TE combined, respectively. Air temperature strongly influenced the timing and extent of photosynthetic recovery expressed as AQY and Asat during the spring. Under elevated T (TE), the recovery of AQY and Asat commenced ~10 days earlier and the activity of these parameters was significantly higher throughout the recovery period. In the absence of frost events, the photosynthetic recovery period was less than a week. However, frost events during spring slowed recovery so that full recovery could take up to 60 days to complete. Elevated [CO2] stimulated AQY and Asat on average by ~10 and ~50%, respectively, throughout the recovery period, but had minimal or no effect on the onset and length of the photosynthetic recovery period during the spring. However, AQY, Asat and Anet all recovered at significantly higher T (average +2.2 degrees C) in TE than in TA, possibly caused by acclimation or by shorter days and lower light levels during the early part of the recovery in TE compared with TA. The results suggest that predicted future climate changes will cause prominent stimulation of photosynthetic CO2 uptake in boreal Norway spruce forest during spring, mainly caused by elevated T, but also elevated [CO2]. However, the effects of elevated T may not be linearly extrapolated to future warmer climates. PMID- 24169105 TI - The systemic administration of oleoylethanolamide exerts neuroprotection of the nigrostriatal system in experimental Parkinsonism. AB - Oleoylethanolamide (OEA) is an agonist of the peroxisome proliferator-activated receptor alpha (PPARalpha) and has been described to exhibit neuroprotective properties when administered locally in animal models of several neurological disorder models, including stroke and Parkinson's disease. However, there is little information regarding the effectiveness of systemic administration of OEA on Parkinson's disease. In the present study, OEA-mediated neuroprotection has been tested on in vivo and in vitro models of 6-hydroxydopamine (6-OH-DA)-induced degeneration. The in vivo model was based on the intrastriatal infusion of the neurotoxin 6-OH-DA, which generates Parkinsonian symptoms. Rats were treated 2 h before and after the 6-OH-DA treatment with systemic OEA (0.5, 1, and 5 mg/kg). The Parkinsonian symptoms were evaluated at 1 and 4 wk after the development of lesions. The functional status of the nigrostriatal system was studied through tyrosine-hydroxylase (TH) and hemeoxygenase-1 (HO-1, oxidation marker) immunostaining as well as by monitoring the synaptophysin content. In vitro cell cultures were also treated with OEA and 6-OH-DA. As expected, our results revealed 6-OH-DA induced neurotoxicity and behavioural deficits; however, these alterations were less severe in the animals treated with the highest dose of OEA (5 mg/kg). 6-OH-DA administration significantly reduced the striatal TH immunoreactivity (ir) density, synaptophysin expression, and the number of nigral TH-ir neurons. Moreover, 6-OH-DA enhanced striatal HO-1 content, which was blocked by OEA (5 mg/kg). In vitro, 0.5 and 1 MUM of OEA exerted significant neuroprotection on cultured nigral neurons. These effects were abolished after blocking PPARalpha with the selective antagonist GW6471. In conclusion, systemic OEA protects the nigrostriatal circuit from 6-OH-DA-induced neurotoxicity through a PPARalpha-dependent mechanism. PMID- 24169108 TI - An innovative professional practice model: adaptation of Carper's patterns of knowing, patterns of research, and Aristotle's intellectual virtues. AB - Professional practice models have emerged as the way hospital-based nursing expresses its consensus-derived philosophy. Magnet recognition influences this practice, while extant nursing theories continue the quest to bridge scholarship with practice. The innovative model presented in this article is an adaptation of Carper's patterns of knowing into a nursing meta-language of science, ethics, art, and advocacy. In this model, boundaries of the patterns of knowing blur and synchronous movement of values, patterns of research, and Aristotelian intellectual virtues blend. Patient and nurse in an intersubjective relationship share the end of human flourishing as the patient's narrative evolves and shared meaning of the ultimate good is actualized. PMID- 24169107 TI - Innovation in nursing: only radical change will do. PMID- 24169109 TI - The development and implementation of eSchoolCare: a novel health care support system for school nurses. AB - School-aged children with chronic conditions (CCC) are increasing in number and bring health needs into classrooms, with implications for learning. Changing technologies and complex care requirements for CCC have left school nurses, the primary health care professional in educational settings, seeking support and further training to provide quality care for CCC. This article describes the development and implementation of a Web-based program, eSchoolCare, designed to extend the expertise of professionals in an academic health care system to school nurses to improve CCC care. The eSchoolCare project serves as an exemplar of an innovative health care delivery support system. PMID- 24169111 TI - Using focus groups and social marketing to strengthen promotion of group prenatal care. AB - Centering Pregnancy, an innovative group model of prenatal care, shows promise to reduce persistent adverse maternal-infant outcomes and contain costs. Because this innovation requires systemwide change, clinics reported needing support enrolling women into groups and obtaining organizational buy-in. This study used the 3-step social marketing communication strategy to help clinic staff identify key customers and customer-specific barriers to adopting or supporting Centering Pregnancy. They developed targeted information to reduce barriers and built skills in communicating with different customers through role-playing. Findings provide practical information for others to use this communication strategy to improve implementation of Centering Pregnancy. PMID- 24169110 TI - Barriers to innovation: nurses' risk appraisal in using a new ethics screening and early intervention tool. AB - We developed and assessed feasibility of an Ethics Screening and Early Intervention Tool that identifies at-risk clinical situations and prompts early actions to mitigate conflict and moral distress. Despite intensive care unit and oncology nurses' reports of tool benefits, they noted some risk to themselves when initiating follow-up actions. The riskiest actions were discussing ethical concerns with physicians, calling for ethics consultation, and initiating patient conversations. When discussing why initiating action was risky, participants revealed themes such as "being the troublemaker" and "questioning myself." To improve patient care and teamwork, all members of the health care team need to feel safe in raising ethics-related questions. PMID- 24169112 TI - Self-management and representation of reality in photo stories. AB - The aim of study was to investigate whether the process of making photo stories in health care (the photo instrument) matches with requirements of self motivation in self-management programs. Although training and advice in self management were absent, the photo instrument shared important elements with self management: the call upon responsibility, the focus on concrete (visual) details of the life world, and the sharpened awareness of choices to make. Expressing one's views, prolonged reflection, a dialogue, and sharing of the photo stories are components that can be considered building stones for commitment to self representation of an illness story and a life beyond illness. PMID- 24169114 TI - Psychological changes and cognitive impairments in adolescent heavy drinkers. AB - AIMS: Adolescence is a developmental period characterized by increased risk taking behavior, including the initiation of alcohol and other substance use. In this brief review paper we describe psychological and cognitive constructs that are associated with heavy drinking during adolescence. These associations raise the question of causality: is alcohol somehow neurotoxic, or can we identify specific psychological and cognitive variables that serve as risk factors for the escalation of heavy drinking? METHODS: This narrative review summarizes results of recent prospective studies that focus on causal relationships between adolescents' alcohol use, and psychological changes and cognitive impairments. RESULTS: Psychological constructs such as elevated impulsivity and poor executive function are risk factors for alcohol involvement in youth. Furthermore heavy drinking during adolescence, particularly in a binge pattern, may exert neurotoxic effects and produce corresponding changes in executive function, perhaps setting the stage for the development of alcohol use disorders later on in life. CONCLUSION: Although the findings of the discussed studies shed light on the nature of the relationships between alcohol involvement and cognitive deficits, the question of cause and effect remains unanswered. The limitations of existing research and the need for well-powered prospective studies are highlighted. PMID- 24169113 TI - Information needed to support knowing the patient. AB - "Knowing the patient" is an essential element of nursing practice. Despite a key finding in prior studies, few scholars have directly inquired about the meaning of knowing the patient with nurses. We aimed to describe the meaning of knowing the patient and investigate how nurses obtain the information needed to support knowing the patient. A descriptive qualitative study was conducted with 12 nurses caring for pediatric patients on intensive care units. Nurses described knowing the patient as knowing clinical and personal information for individualized care. Verbal, paper-based, and electronic information sources were used to gather information needed to know the patient. The use of a paper-based supportive tool was the most valuable information source for nurses to know their patients. Future studies must further investigate the use of these paper-based tools and offer electronic solutions to support nurses in knowing their patients. PMID- 24169115 TI - Introduction. PMID- 24169116 TI - License for destruction: tumor-specific cytokine targeting. AB - Stroma is an integral part of solid tumors and plays a key role in growth promotion and immune suppression. Most current therapies focus on destroying tumors and/or abnormal vasculature. However, evidence is emerging that anticancer efficacy improves with vessel normalization rather than destruction. Specific targeting of cytokines into tumors provides proof-of-concept that tumor stroma is dynamic and can be remodeled to increase drug access and alleviate immune suppression. Changing the inflammatory milieu 'opens' tumors for therapy and thus provides a license for destruction. This involves reprogramming of paracrine signaling networks between multiple stromal components to break the vicious cycle of angiogenesis and immune suppression. With active immunotherapy rapidly moving into the clinic, local cytokine delivery emerges as an attractive adjuvant. PMID- 24169117 TI - Calcaneal chondrosarcoma: a case report. AB - Chondrosarcoma is a rare malignant cartilaginous tumour of the bone. It commonly occurs in the pelvis, scapula proximal femur, and shoulder girdle .We present a case of a woman in her 56 years of age with chondrosarcoma of the calcaneum-a rare lesion that accounts for 0.5-2.97% of all chondrosarcomas of other sites. Treatment for chondrosarcoma is generally wide surgical excision. Chemotherapy or radiation is not effective for most of these lesions. PMID- 24169118 TI - Description of the larva of Amblyomma calcaratum Neumann, 1899 (Acari: Ixodidae) by light and scanning electron microscopy. AB - The larval stage of Amblyomma calcaratum Neumann is described using optical and scanning electron microscopy. Unfed larvae were obtained from a colony of A. calcaratum originating from engorged females collected on Tamandua tetradactyla in the Jaragua Mountain (23 degrees 40'S, 45 degrees 44'W), Sao Paulo County, Brazil. Eleven larvae were prepared and mounted on slides and observed under a light microscope equipped with a drawing tube. Three specimens were prepared for SEM. Several morphological characters are described, including the chaetotaxy of the idiosoma, palpi, and Haller's organ, as well as morphological features of the idiosoma, gnathosoma, and legs of A. calcaratum larvae. In addition, topographical and numerical patterns of integumentary structures on the larval idiosoma are described using a recently proposed nomenclature. On the idiosoma, setaes, lyrifissures, small glands, and large wax glands were found. These structures were observed isolated or associated over the entire idiosoma, except on the scutum, which lacks large wax glands. The topographical and numerical patterns of integumentary structures of the A. calcaratum larva showed only minor differences when compared with patterns of other Amblyomma larvae; however, a few key features can be used to differentiate A. calcaratum from other members of this genus. PMID- 24169119 TI - Chronic HIV-infected patients show an impaired dendritic cells differentiation of bone marrow CD34+ cells. AB - HIV infection affects dendritic cells (DCs) number, maturation, and function although the cause remains largely unknown. Purified CD34+ hematopoietic progenitor cells (HPCs) obtained from bone marrow of chronic HIV-infected patients were investigated for the differentiative capability toward mature DCs. HIV, although not in active replication, was found able to impair CD34+ HPC differentiation into mature DCs. These results suggest that DCs impairment found in HIV-infected patients may be related to a failure by bone marrow CD34 HPCs to produce an adequate number of DCs. PMID- 24169120 TI - Safety, tolerability, and immunogenicity of repeated doses of dermavir, a candidate therapeutic HIV vaccine, in HIV-infected patients receiving combination antiretroviral therapy: results of the ACTG 5176 trial. AB - BACKGROUND: HIV-specific cellular immune responses are associated with control of viremia and delayed disease progression. An effective therapeutic vaccine could mimic these effects and reduce the need for continued antiretroviral therapy. DermaVir, a topically administered plasmid DNA-nanomedicine expressing HIV (CladeB) virus-like particles consisting of 15 antigens, induces predominantly central memory T-cell responses. METHODS: Treated HIV-infected adults (HIV RNA <50 and CD4 >350) were randomized to placebo or escalating DermaVir doses (0.1 or 0.4 mg of plasmid DNA at weeks 1, 7, and 13 in the low- and intermediate-dose groups and 0.8 mg at weeks 0, 1, 6, 7, 12, and 13 in the high-dose group), n = 5 6 evaluable subjects per group. Immunogenicity was assessed by a 12-day cultured interferon-gamma enzyme-linked immunosorbent spot assay at baseline and at weeks 9, 17, and 37 using 1 Tat/Rev and 3 overlapping Gag peptide pools (p17, p24, and p15). RESULTS: Groups were comparable at baseline. The study intervention was well tolerated, without dose-limiting toxicities. Most responses were highest at week 17 (4 weeks after last vaccination) when Gag p24 responses were significantly greater among intermediate-dose group compared with control subjects [median (IQR): 67,600 (5633-74,368) versus 1194 (9-1667)] net spot forming units per million cells, P = 0.032. In the intermediate-dose group, there was also a marginal Gag p15 response increase from baseline to week 17 [2859 (1867-56,933), P = 0.06], and this change was significantly greater than in the placebo group [0 (-713 to 297), P = 0.016]. CONCLUSIONS: DermaVir administration was associated with a trend toward greater HIV-specific, predominantly central memory T-cell responses. The intermediate DermaVir dose tended to show the greatest immunogenicity, consistent with previous studies in different HIV infected patient populations. PMID- 24169121 TI - Higher serum iron is associated with increased oxidant stress in HIV-infected men. AB - BACKGROUND: F2-isoprostanes (F2-IsoP) are oxidant stress biomarkers that are higher in HIV-infected women than men. We explored whether the effect of hemoglobin (Hgb), serum iron, or anemia on F2-IsoP is different between HIV infected women and men. METHODS: Plasma F2-IsoP were quantified by gas chromatography/mass spectrometry; clinical and laboratory data were collected at enrollment or from the medical record. Multivariable linear regression was used to assess associations between F2-IsoP and Hgb, anemia as a dichotomous variable, and serum iron with adjustment for age, sex, race, body mass index, CD4 lymphocyte count, self-reported current smoking status, and antiretroviral therapy. RESULTS: Compared with men, women had lower Hgb [median: 12.7 (interquartile range: 11.8-13.9) vs. 14.9 (13.7-15.8) g/dL, P < 0.001], lower iron levels [75 (47-97) vs. 90 (69-121) ug/dL, P = 0.004], more anemia (29% vs. 10%, P < 0.001), and higher levels of F2-IsoP [42 (32-62) vs. 36 (25-46) pg/mL, P < 0.001]. The relationship between iron and F2-IsoP differed significantly between men and women (interaction P = 0.02). Men had a 21% (95% confidence interval: 8 to 36) increase in F2-IsoP per interquartile increase in iron (P = 0.001), whereas no relationship was seen among women [-4% (-17 to 13, P = 0.65]. CONCLUSIONS: Although women have overall higher F2-IsoP than men, a relationship between circulating F2-IsoP and iron levels was observed in men but not in women with HIV infection. The association between female sex and higher F2-IsoP is not explained by iron or Hgb levels because the association persists when controlling for these factors. The role of iron in oxidant stress and sex-specific differences among HIV-infected individuals require further study. PMID- 24169123 TI - HIV treatment as prevention in a developed country setting: the current situation and future scenarios for Australia. AB - OBJECTIVE: We investigated the current success of early HIV detection in Australia and the likely effectiveness of Treatment as Prevention. METHODS: HIV diagnoses data from the Australian National HIV/AIDS Registry were analyzed for CD4 T-cell counts at diagnosis and for prior HIV testing. Mathematical modeling based on these data estimated future HIV prevalence and incidence under different scenarios of antiretroviral therapy (ART) usage. RESULTS: CD4 T-cell counts significantly decreased with age (P < 0.0001) for men who have sex with men (MSM) and women in all HIV diagnoses, and for diagnoses at primary HIV infection (P < 0.02). This decrease with age meant that >50% of MSM aged 29 years and older are diagnosed with a CD4 T-cell count <500 cells per cubic millimeters. Diagnosis during primary HIV infection has stabilized at 15% for MSM, with a lower percentage for older individuals (P = 0.002), but only 5% of women were diagnosed at this early stage. MSM older than 50 years were significantly less likely to have had an HIV test before diagnosis (P < 0.0001), whereas women of all ages at HIV diagnosis were less likely to have been tested than MSM. Mathematical modeling indicated that current levels of ART would see a continuing increase in HIV diagnoses among MSM. A 90% ART enrollment would result in an almost immediate decline in prevalence and would be cost effective in terms of person-years on ART by 2028. CONCLUSION: Treatment as Prevention would be an effective intervention in Australia and other developed countries. PMID- 24169124 TI - ESC Journals working together. PMID- 24169125 TI - Radiation - the double-edged sword of interventional procedures. PMID- 24169122 TI - Infant growth outcomes after maternal tenofovir disoproxil fumarate use during pregnancy. AB - OBJECTIVE: To determine whether maternal use of tenofovir disoproxil fumarate for treatment of HIV in pregnancy predicts fetal and infant growth. METHODS: The study population included HIV-uninfected live-born singleton infants of mothers enrolled in the International Maternal Pediatric Adolescent AIDS Clinical Trials Group protocol P1025 (born 2002-2011) in the United States and exposed in utero to a combined (triple or more) antiretroviral regimen. Infant weight at birth and 6 months was compared between infants exposed and unexposed to tenofovir in utero using 2-sample t test, chi test, and multivariable linear and logistic regression models, including demographic and maternal characteristics. RESULTS: Among 2025 infants with measured birth weight, there was no difference between those exposed (N = 630, 31%) versus unexposed to tenofovir in mean birth weight (2.75 vs. 2.77 kg, P = 0.64) or mean gestational age- and sex-adjusted birth weight z-score (WASZ) (0.14 vs. 0.14, P = 0.90). Among 1496 infants followed for 6 months, there was no difference in mean weight at 6 months between tenofovir-exposed (N = 457, 31%) and tenofovir-unexposed infants (7.64 vs. 7.59 kg, P = 0.52) or in mean WASZ (0.29 vs. 0.26, P = 0.61). Tenofovir exposure during the second/third trimester, relative to no exposure, significantly predicted underweight (WASZ < 5%) at age 6 months [odds ratio (95% confidence interval): 2.06 (1.01 to 3.95), P = 0.04]. Duration of tenofovir exposure did not predict neonatal or infant growth. CONCLUSIONS: By most measures, in utero exposure to tenofovir did not significantly predict infant birth weight or growth through 6 months of age. PMID- 24169126 TI - Cognitive performance in patients with resistant hypertension following renal sympathetic denervation. PMID- 24169128 TI - Innovation in technology and techniques for better patient care. PMID- 24169127 TI - The European Heart Journal and EuroIntervention: information and education in interventional cardiology. PMID- 24169129 TI - First-in-man report of a novel dedicated radiofrequency catheter for renal denervation via the transulnar approach. AB - Renal denervation (RDN) has been shown to be safe and efficacious in reducing blood pressure in patients with resistant hypertension. In the present study, we describe a first-in-man report of the Iberis renal denervation device in a patient who underwent two RDN procedures: one via the femoral artery and one via the transulnar approach. RDN was performed in the patient's right renal artery using an Iberis catheter via the transulnar approach, as the transfemoral or transradial arteries could not be approached due to their anatomic constraints. In summary, RDN via the transulnar approach is feasible and represents a technical alternative solution in certain patients. PMID- 24169130 TI - Novel use of NavX three-dimensional mapping to guide renal artery denervation. AB - AIMS: Renal artery denervation (RAD) is an effective treatment for resistant hypertension. The Navigation and Visualisation Technology (NavX) system creates three-dimensional (3-D) anatomical maps to guide catheter position and identify ablation sites. This first-in-human study assessed the utility of NavX 3-D mapping for RAD. METHODS AND RESULTS: Consecutive patients who underwent RAD using fluoroscopy alone (control group, n=8) were compared to NavX-guided RAD (NavX group, n=10). Where NavX was utilised, orthogonally located skin patches were applied to the torso for acquisition of 3-D geometry of each renal artery. Baseline clinical characteristics and renal artery anatomy were similar between groups. Median contrast dose was significantly higher in the control versus NavX group (123 ml versus 78 ml, p=0.016). Median radiation dose was significantly higher in the control versus NavX group (166 Gy cm2 versus 43 Gy cm2, p=0.034). Mean changes in systolic and diastolic BP at three-month follow-up were -22/-9 mmHg and -23/-11 mmHg in the control and NavX group, respectively (p=0.99). CONCLUSIONS: Use of NavX mapping as compared to standard renal artery denervation was found to correlate with a significant reduction in contrast load and radiation exposure. This study demonstrates both the feasibility and potential benefits of NavX 3-D mapping to guide renal artery denervation. PMID- 24169131 TI - Percutaneous sympathectomy of the renal arteries: the OneShot Renal Denervation System is not associated with significant vessel wall injury. AB - AIMS: Renal artery denervation (RADN) is an emerging technique for the treatment of resistant hypertension (RH). However, the use of the available systems has been associated with vascular injury, resulting in vasospasm and vessel wall thrombosis. The OneShot System (Covidien, San Jose, CA, USA) is an irrigated radiofrequency balloon designed to reduce vessel heating and injury during RADN. METHODS AND RESULTS: The aim of the present study was to evaluate the target vessel morphological features before and after renal ablation using the OneShot RADN system. In this prospective observational study, 12 renal arteries of patients underwent RADN using the OneShotTM RADN System. Pre-procedural and post procedural optical coherence tomography (OCT) pullbacks were performed and evaluated. No evidence for vasospasm, oedema or intraluminal thrombus formation was detected. Limited arterial dissections, after RADN, occurred in three renal arteries and did not require additional treatments. A sustained reduction of office blood pressure levels was observed over six months of follow-up in all the patients. CONCLUSIONS: This study demonstrates that, in a small patient population, RADN using the OneShot Renal Denervation System is not associated with arterial spasm or thrombus formation on the vessel wall. PMID- 24169132 TI - Anxiety, depression, quality of life and stress in patients with resistant hypertension before and after catheter-based renal sympathetic denervation. AB - AIMS: This study analysed quality of life (QoL), anxiety and depression, headache and stress tolerance in patients with resistant hypertension before and after renal denervation (RDN). METHODS AND RESULTS: RDN was performed in 119 patients (age 62 +/- 11 years, 55% male) with resistant hypertension (office blood pressure [BP] 165/91 +/- 22/15 mmHg), treated with 5.7 +/- 0.2 antihypertensive drugs. At baseline, at three and at six months after RDN, psychological status, intensity of headache and stress tolerance were documented. Stress was induced by a multitasking situation (Wiener Determination Task [DT]). Depression and anxiety (hospital anxiety and depression scale) and QoL (short form-12 health survey) were investigated. Intensity of headache was measured by visual analogous scale. Systolic and diastolic BP decreased by -20 +/- 2.4 and -10 +/- 1.4 mmHg, respectively, six months after RDN (p<0.0001). Patients showed more correct reactions (p<0.0001), fewer errors (p<0.05) and reacted faster (p<0.001) in the DT. Patients reported an improvement in QoL (p<0.05). Furthermore, anxiety (p<0.0001) and depression (p<0.0001) scores decreased. Intensity of headache decreased after RDN (p<0.01). CONCLUSIONS: RDN is associated with reduced anxiety and depression, intensity of headache and with improved QoL and stress tolerance in patients with resistant hypertension. PMID- 24169133 TI - Assessment of self-expanding nitinol stent deformation after chronic implantation into the femoropopliteal arteries. AB - AIMS: The purpose of this prospective clinical investigation was to quantify the degree and range of compressive and bending deformations sustained by self expanding nitinol stents when implanted into the femoropopliteal arteries of patients with symptomatic peripheral vascular disease (PVD). METHODS AND RESULTS: Twenty-three nitinol self-expanding stents (Absolute; Abbott Vascular, Santa Clara, CA, USA) with diameters ranging from 5-10 mm and lengths ranging from 40 100 mm were implanted in 19 lesions in 18 extremities of 17 patients. Two days following implantation, in vivo stent compression and bending were assessed by measurement of stent length and deflection angle via lateral view radiographs. The results showed that leg flexion was associated with significant stent bending; popliteal stents bent almost 90 degrees while SFA stents bent only minimally. Leg flexion was also associated with stent shortening (compression), the greatest amount being observed for stents implanted into the popliteal artery (popliteal 8.5% +/- 3.2%; SFA/prox pop 5.3% +/- 0.5%; SFA 3.1% +/- 1.8%). After a mean follow-up of 7.1 +/- 1.3 months, the degree of stent deformation during leg flexion was essentially unchanged as compared to immediate post-procedure levels. CONCLUSIONS: Indwelling nitinol stents are routinely bent and compressed during leg flexion, with most bending observed in stents implanted near the popliteal artery. The degree of deformation observed immediately after implantation appears to be predictive of the chronic state, as repeat measurements obtained after a mean of seven months were essentially unchanged from baseline. PMID- 24169134 TI - Beta radiation for renal nerve denervation: initial feasibility and safety. AB - AIMS: In small clinical trials, sympathetic renal denervation using radiofrequency (RF) energy shows promise in treating resistant hypertension. However, the RF procedure is lengthy and is associated with pain during ablation. Vascular brachytherapy, a proven treatment for in-stent restenosis, has the potential to cause nerve fibrosis. The purpose of the present study was to assess the safety and feasibility of renal artery brachytherapy for sympathetic renal denervation. METHODS AND RESULTS: A total of 10 normotensive domestic swine underwent vascular brachytherapy to left and right renal arteries using the Beta Cath 3.5 Fr delivery system at doses of 25 Gy (n=8) and 50 Gy (n=8) at 2 mm from the source centre. These groups were compared to untreated arteries that served as control (n=4). Follow-up obtained at one or two months included angiogram, intravascular ultrasound, and histopathology analysis. The vascular brachytherapy procedure was safe and no apparent angiographic or ultrasound injuries to the vessel were seen. Histology showed a varying degree of thermal injury more pronounced in the 50 Gy group. The majority of examined nerves showed some degree of injury; there was a dose-related effect on nerve injury severity. There were varying degrees of arteriolar changes in the examined sections, with most showing a 2-20% degree of endothelial cell loss. CONCLUSIONS: This initial feasibility and safety study of renal nerve denervation, mediated by low and intermediate beta-radiation dosages, indicates that this approach can cause nerve fibrosis while avoiding significant damage to the renal artery. PMID- 24169135 TI - A review of radiation exposures associated with radial cardiac catheterisation. AB - Transradial (TR) cardiac catheterisation is thought to be associated with an increased exposure to radiation compared with the traditional transfemoral (TF) access. This paper provides a review of current literature describing these reported associations. Although several studies have reported an increase in radiation exposure to both operator and patient with TR compared with TF access, others have reported findings suggesting no significant difference, even reporting decreased exposure with TR access. Ultimately, increased radiation exposure appears likely with TR access; however, in consideration of the many benefits associated with TR access, radiation exposure remains only one of many considerations when deciding between routes of access. PMID- 24169136 TI - Effectiveness of a lead cap in radiation protection of the head in the cardiac catheterisation laboratory. PMID- 24169137 TI - A novel lead attenuator to reduce operator exposure to scattered radiation in transradial coronary procedures. PMID- 24169138 TI - How should I treat acute left main coronary obstruction after transapical aortic valve implantation? PMID- 24169139 TI - Tools and techniques - statistics: analysis of continuous data using the t-test and ANOVA. PMID- 24169140 TI - Early valve failure in a first-in-man implant with an Edwards SAPIEN XT valve using the split sheath NovaFlex system in the treatment of a pulmonary conduit stenosis. PMID- 24169141 TI - Mislabelled table entries in ADVISE Registry by Petraco and colleagues. PMID- 24169142 TI - Renal denervation for resistant hypertension and new frontiers in interventional medicine: are we forgetting the patient? PMID- 24169143 TI - Improving pediatric hematology/oncology care in the emergency department. AB - PURPOSE: Pediatric hematology/oncology patients frequently use the emergency department (ED) for prompt care during potentially life-threatening events, such as sepsis and bleeding. One challenge of these visits is the unavailability of appropriate patient-specific medical information. Lack of information may result in ineffective ED visits for these patients with complex conditions. METHODS: A cross-sectional survey to determine ways to improve the care of pediatric hematology/oncology patients in the ED setting was conducted among parents at two affiliated pediatric hematology/oncology clinics. ED physicians in the catchment area of the clinic completed a separate survey. RESULTS: All physicians surveyed were confident in caring for pediatric patients in the ED; however, fewer were confident in caring for pediatric hematology/oncology patients. Physicians and parents reported that the patient's written medical history (physicians, 30%; parents, 33%), medication list (physicians, 28%; parents, 24%), on-call pediatric hematologist/oncologist contact information (physicians, 34%; parents, 31%), and needle size and gauge to access the patient's port (physicians, 8%; parents, 12%) would be valuable information to have when presenting to the ED. CONCLUSION: Parents were satisfied with ED care, but both physician and parent respondents thought additional information would be valuable to have available at the visit to help facilitate effective care. PMID- 24169144 TI - A totally recombinant human fibrin sealant. AB - BACKGROUND: Applications of plasma-derived human fibrin sealants (pdhFS) have been limited because of cost, limited supply of pathogen-screened plasma, the need for bioengineering improvements, and regulatory issues associated with federal approval. We describe a totally recombinant human fibrin sealant (rhFS), which may engender an abundant, safe, and cost-effective supply of efficacious fibrin sealant. MATERIALS AND METHODS: A first-generation rhFS made from recombinant human fibrinogen (rhFI; produced in the milk of transgenic cows), activated recombinant human factor XIII (rhFXIIIa; produced in yeast), and recombinant human thrombin (rhFIIa; purchased, made in animal cell culture) was formulated using thromboelastography (TEG). The hemostatic efficacy of rhFS versus commercial pdhFS was compared in a nonlethal porcine hepatic wedge excision model. RESULTS: The maximal clot strength of rhFS measured in vitro by TEG was not statistically different than that of pdhFS. TEG analysis also showed that the rhFS gained strength more quickly as reflected by a steeper alpha angle; however, the rhFS achieved this clot strength with a 5-fold lower factor I content than the pdhFS. When these fibrin sealants were studied in a porcine hepatic wedge excision model, the hemostatic scores of the rhFS were equivalent or better than that of the pdhFS. CONCLUSIONS: The bioengineered rhFS had equivalent or better hemostatic efficacy than the pdhFS in a nonlethal hemorrhage model, despite the factor I concentration in the rhFS being about one-fifth that in the pdhFS. Because the rhFS is amenable to large-scale production, the rhFS has the potential to be more economical and abundant than the pdhFS, while having a decreased risk of blood-borne pathogen transmission. PMID- 24169145 TI - Congenital cholesteatoma in siblings. AB - INTRODUCTION: The exact aetiology of congenital cholesteatoma, the less common form of this destructive disease, is still under debate. CASE REPORT: A two-year old boy was referred to paediatric otolaryngology with persistent, bloody, left sided otorrhoea refractory to oral and ototopical antibiotics. Prior to its onset at age 16 months, all ear examinations on the affected side were normal. Physical examination, imaging with computed tomography and eventual tympanomastoidectomy revealed extensive cholesteatoma. The extent of the disease, age at onset of symptoms and absence of otological disease before initial presentation suggested the diagnosis of congenital cholesteatoma. Review of the family history revealed that the patient's older brother had undergone tympanomastoidectomy for a small, well-encapsulated, mesotympanic congenital cholesteatoma at two years of age. DISCUSSION: This case joins a single, previous report describing congenital cholesteatoma in multiple family members, suggesting that in some cases, hereditary factors may play a role in the formation of the disease. PMID- 24169146 TI - Arthroscopic surgery of irreparable large or massive rotator cuff tears with low grade fatty degeneration of the infraspinatus: patch autograft procedure versus partial repair procedure. AB - PURPOSE: This study aimed to compare the arthroscopic patch graft procedure and partial repair for irreparable large or massive rotator cuff tears (RCTs) in shoulders with low-grade fatty degeneration of the infraspinatus (stage 1 or 2 according to Goutallier et al.) in terms of the functional and structural outcomes. METHODS: This study included 24 patients who underwent the patch graft procedure (group A) and 24 patients who underwent partial repair (group B) for irreparable large or massive RCTs. Clinical outcomes were evaluated at a mean of 35.5 months postoperatively in group A and 35.7 months in group B. RESULTS: The clinical findings were significantly improved at the final follow-up in both groups (P < .001). A significant difference was found between groups A and B in terms of postoperative Constant and American Shoulder and Elbow Surgeons scores (P = .001 and P = .021, respectively). There was a significant difference in the retear rate for the infraspinatus tendon (ISP) between the 2 groups (2 patients [8.3%] in group A v 10 patients [41.7%] in group B, P = .015). At the final follow-up, there was a significant difference in the affected side-versus unaffected side muscle strength ratios for abduction and external rotation between group A and group B (P < .001 for both). Shoulders with retears of the ISP showed significantly inferior clinical outcomes compared with those without retears (P < .001). CONCLUSIONS: In arthroscopic surgery for irreparable large or massive RCTs with low-grade fatty degeneration of the infraspinatus, the patch graft procedure showed an 8.3% retear rate for the repaired ISP with both improved clinical scores and recovery of muscle strength, whereas the partial repair had a retear rate of 41.7% (P = .015). LEVEL OF EVIDENCE: Level SH, retrospective comparative study. PMID- 24169149 TI - Current management and surgical outcomes of medically intractable epilepsy. AB - Epilepsy is one of the most common neurologic disorders in the world. While anti epileptic drugs (AEDs) are the mainstay of treatment in most cases, as many as one-third of patients will have a refractory form of disease indicating the need for a neurosurgical evaluation. Ever since the first half of the twentieth century, surgery has been a major treatment option for epilepsy, but the last 10 15 years in particular has seen several major advances. As shown in relatively recent studies, resection is more effective for medically intractable epilepsy (MIE) than AED treatment alone, which is why most clinicians now endorse a neurosurgical consultation after approximately two failed regimens of AEDs, ultimately leading to decreased healthcare costs and increased quality of life. Temporal lobe epilepsy (TLE) is the most common form of MIE and comprises about 80% of epilepsy surgeries with the majority of patients gaining complete seizure freedom. As the number of procedures and different approaches continues to grow, temporal lobectomy remains consistently focused on resection of mesial structures such as the amygdala, hippocampus, and parahippocampal gyrus while preserving as much of the neocortex as possible resulting in optimum seizure control with minimal neurological deficits. MIE originating outside the temporal lobe is also effectively treated with resection. Though not as successful as TLE surgery because of their frequent proximity to eloquent brain structures and more diffuse pathology, epileptogenic foci located extratemporally also benefit from resection. Favorable seizure outcome in each of these procedures has heavily relied on pre-operative imaging, especially since the massive surge in MRI technology just over 20 years ago. However, in the absence of visible lesions on MRI, recent improvements in secondary imaging modalities such as fluorodeoxyglucose positron emission computed tomography (FDG-PET) and single photon emission computed tomography (SPECT) have lead to progressively better long-term seizure outcomes by increasing the neurosurgeon's visualization of supposed non-lesional foci. Additionally, being historically viewed as a drastic surgical intervention for MIE, hemispherectomy has been extensively used quite successfully for diffuse epilepsies often found in pediatric patients. Although total anatomic hemispherectomy is not utilized as commonly today, it has given rise to current disconnective techniques such as hemispherotomy. Therefore, severe forms of hemispheric developmental epilepsy can now be surgically treated while substantially decreasing the amount of potential long-term complications resulting from cavitation of the brain following anatomical hemispherectomy. Despite the rapid pace at which we are gaining further knowledge about epilepsy and its surgical treatment, there remains a sizeable underutilization of such procedures. By reviewing the recent literature on resective treatment of MIE, we provide a recent up-date on epilepsy surgery while focusing on historical perspectives, techniques, prognostic indicators, outcomes, and complications associated with several different types of procedures. PMID- 24169147 TI - Effect of methylphenidate on attention in apathetic AD patients in a randomized, placebo-controlled trial. AB - BACKGROUND: Little is known about the effect of methylphenidate (MPH) on attention in Alzheimer's disease (AD). MPH has shown to improve apathy in AD, and both apathy and attention have been related to dopaminergic function. The goal was to investigate MPH effects on attention in AD and assess the relationship between attention and apathy responses. METHODS: MPH (10 mg PO twice daily) or placebo was administered for six weeks in a randomized, double-blind trial in mild-to-moderate AD outpatients with apathy (Neuropsychiatric Inventory (NPI) Apathy >= 4). Attention was measured with the Wechsler Adult Intelligence Scale- Digit Span (DS) subtest (DS forward, selective attention) and apathy with the Apathy Evaluation Scale (AES). A mixed effects linear regression estimated the difference in change from baseline between treatment groups, defined as delta (MPH (DS week 6-DS baseline)) - (placebo (DS week 6-DS baseline)). RESULTS: In 60 patients (37 females, age = 76 +/- 8, Mini-Mental State Examination (MMSE) = 20 +/- 5, NPI Apathy = 7 +/- 2), the change in DS forward (delta = 0.87 (95% CI: 0.06-1.68), p = 0.03) and DS total (delta = 1.01 (95% CI: 0.09-1.93), p = 0.03) favored MPH over placebo. Of 57 completers, 17 patients had improved apathy (>=3.3 points on the AES from baseline to end point) and 40 did not. There were no significant associations between AES and NPI Apathy with DS change scores in the MPH, placebo, AES responder, or non-responder groups. DS scores did not predict apathy response to MPH treatment. CONCLUSION: These results suggest MPH can improve attention and apathy in AD; however, the effects appear independent in this population. PMID- 24169150 TI - Preoperative spinal tumor embolization: an institutional experience with Onyx. AB - BACKGROUND: Preoperative embolization has the potential to decrease intraoperative blood loss and facilitate spinal cord decompression and tumor resection. OBJECTIVE: We report our institutional experience with the embolization of hypervascular extradural spinal tumors with Onyx as well as earlier embolic agents in a series of 28 patients. METHODS: A retrospective case review was conducted on patients undergoing preoperative transarterial embolization of a spinal tumor between 1995 and 2012 at our institution. RESULTS: Twenty-eight patients met the inclusion criteria, with a mean age of 60.6 years. Twenty-eight patients had metastatic tumors. In 14 (50%) patients the metastases were from renal cell carcinomas. Fifty-four vessels were embolized using PVA, NBCA, Onyx, coils, or embospheres. Sixteen patients were treated with Onyx, 6 patients with PVA, 3 patients with embospheres, 2 patients with NBCA, and 3 patients with a combination of embolic agents. The average decrease in tumor blush was 97.8% with Onyx versus 92.7% with the rest of the embolic agents (p=0.08). The estimated blood loss was 1616ml (range 350-5000ml). Blood loss was 750cm(3) on average with Onyx versus 1844 with the rest of the embolic agents (p=0.14). The mean length of stay was 16 days. The mortality rate was zero. Pre- and post-operative modified Rankin Score (mRS) did not differ significantly in the series (3.12 versus 3.10, respectively, p=0.9). CONCLUSION: In our experience, the use of transarterial tumor embolization as an adjunct for spinal surgery is a safe and feasible option. PMID- 24169152 TI - A high IL-4 production diplotype is associated with an increased risk but better prognosis of oral and pharyngeal carcinomas. AB - OBJECTIVE: Interleukin (IL)-4 is a key cytokine in humoral and adaptive immunity. This study aimed to evaluate the association of IL-4 genetic variants (-590C>T and VNTR in intron 3) with the risk and prognosis of oral and pharyngeal squamous cell carcinoma (OPSCC). DESIGN: A total of 1215 subjects, which included 623 healthy controls and 592 OPSCC cases (463 oral squamous cell carcinoma (OSCC) and 129 pharyngeal squamous cell carcinoma (PSCC) cases), were recruited. The genotypes were determined by TaqMan real-time assay and PCR-based assay. RESULTS: The IL-4 genotypes at locus -590C>T and intron 3 VNTR were not correlated with increased risk of OSCC, PSCC, and OPSCC, with the exception of early-stage OPSCC (at -590C>T: T/T vs. C/C+C/T, adjusted odds ratio (AOR)=1.42, 95% CI: 1.02-1.98; at intron 3 VNTR: RP1/RP1 vs. RP2/RP2+RP2/RP1, AOR=1.46, 95% CI: 1.05-2.04). Compared with other IL-4 diplotypes, the T,RP1/T,RP1 diplotype was associated with an increased risk of OPSCC (AOR=1.37, 95% CI: 1.03-1.81), particularly early stage OSCC (AOR=1.43, 95% CI: 1.02-2.00), PSCC (AOR=2.35, 95% CI: 1.06-5.19), and OPSCC (AOR=1.52, 95% CI: 1.10-2.11). Interactions between the IL-4 diplotype and the alcohol drinking status were found to contribute to the risk of early-stage OPSCC (p=0.024). In addition, the T,RP1/T,RP1 diplotype was correlated with better disease-specific survival (T,RP1/T,RP1 vs. other diplotypes, adjusted hazard ratio=0.70, 95% CI: 0.50-0.97). CONCLUSION: The T, RP1/T, RP1 diplotype of IL-4 was associated with an increased risk but favourable prognosis of OPSCC. PMID- 24169151 TI - Gynecomastia in MPS IIIA boys: related to treatment or precocious puberty? PMID- 24169153 TI - Changes in mandibular dimensions during the mediaeval to post-mediaeval transition in London: a possible response to decreased masticatory load. AB - OBJECTIVES: Biomechanical forces, such as those produced during mastication, are considered a primary agent in stimulating craniofacial growth and development. There appears to be a strong connection between the strength of the masticatory muscles and the dimensions of the craniofacial complex, with changes in biomechanical force and muscular strength influencing and altering the underlying bony tissues. This is markedly apparent in the mandible and it is possible to infer that changes to mandibular form are due in part to dietary changes. This study aims to investigate this idea by using an archaeological sample from a period that experienced important dietary changes as a result of the Industrial Revolution. DESIGN: 279 skeletons from the mediaeval and post-mediaeval periods in London were selected for analysis, and a detailed metric examination of each mandible was carried out. RESULTS: Males and females were analysed separately and statistically significant reductions were observed in nearly all post-mediaeval measurements. This effect was most pronounced in the areas of the mandible associated with masticatory muscles attachment, including the gonial angle, ramus height and width, bi-gonial breadth and bi-condylar breadth. CONCLUSIONS: These recorded changes in mandibular morphology of mediaeval and post-mediaeval Londoners are most likely the result of a shift in diet (and associated decrease in masticatory function) observed in the period surrounding the Industrial Revolution. PMID- 24169154 TI - Congenital portosystemic shunts in children: a new anatomical classification correlated with surgical strategy. AB - OBJECTIVE: To propose an anatomical classification of congenital portosystemic shunts (CPSs) correlating with conservative surgery. BACKGROUND: CPSs entail a risk of life-threatening complications because of poor portal inflow, which may be prevented or cured by their closure. Current classifications based on portal origin of the shunt are not helpful for planning conservative surgery. METHODS: Twenty-three patients who underwent at least 1 surgical procedure to close the CPSs were included in this retrospective study (1997-2012). We designed a classification according to the ending of the shunt in the caval system. We analyzed the results and outcomes of surgery according to this classification. RESULTS: Two patients had an extrahepatic portosystemic shunt, 17 had a portacaval shunt [subdivided in 5 end-to-side-like portal-caval, 7 side-to-side like portal-caval, and 5 H-shaped (H-type portal-caval)], 2 had portal-to-hepatic vein shunts (portohepatic), and 2 had a persistent ductus venosus. All extrahepatic portosystemic shunts, H-type portal-caval, portohepatic, and patent ductus venosus patients had a successful 1-stage ligation. All 5 end-to-side-like portal-caval patients had a threadlike intrahepatic portal venous system; a 2 stage complete closure was successfully achieved for 4 and a partial closure for 1. The first 2 side-to-side-like portal-caval patients had a successful 2-stage closure whereas the 5 others had a 1-stage longitudinal caval partition. All patients are alive and none needed a liver transplantation. CONCLUSIONS: Our classification correlates the anatomy of CPSs and the surgical strategy: outcomes are good provided end-to-side-like portal-caval shunts patients have a 2-stage closure, side-to-side portal-caval shunts patients have a 1-stage caval partition, and the others have a 1-stage ligation. PMID- 24169155 TI - Curative potential of surgical resection for locally recurrent rectal cancer. PMID- 24169156 TI - A marriage of databases produces knowledge offspring. PMID- 24169157 TI - Effect of postoperative complications on adjuvant chemotherapy use for stage III colon cancer. AB - OBJECTIVE: The National Quality Forum has endorsed a quality metric concerning the use of adjuvant chemotherapy administration in stage III colon cancer, yet a substantial treatment gap exists. Our objective was to evaluate the association of postoperative complications on the use of adjuvant therapy after colectomy for cancer. PATIENTS AND METHODS: Data from the American College of Surgeons National Surgical Quality Improvement Program and National Cancer Data Base were linked to augment cancer registry information with robust clinical data on comorbidities and postoperative complications (2006-2008). The association of complications on adjuvant chemotherapy use was assessed using hierarchical multivariable regression models. RESULTS: From 126 hospitals, 2368 patients underwent resection for stage III colon adenocarcinoma. Overall utilization of adjuvant chemotherapy was 63.2% (1497/2368). Of the 871 patients who did not receive chemotherapy, 652 met National Quality Forum exclusion criteria: death, severe comorbidity, refusal of care, advanced age (>=80 years), or prior malignancy. Of the remaining 219 patients, 19.1% (42/219) had 1 or more serious postoperative complications (eg, pneumonia, pulmonary failure). After accounting for the aforementioned potential explanations, the utilization rate was 87.2% (1497/1716). The strongest predictors of adjuvant chemotherapy omission were prolonged postoperative ventilation, renal failure, reintubation, and pneumonia (all Ps < 0.05). Superficial surgical site infection did not decrease adjuvant therapy receipt but delayed the time to its use by 3-fold. Serious complications increased time to chemotherapy by 65%. Abscess/anastomotic leak increased time to adjuvant chemotherapy by more than 5-fold. CONCLUSIONS: Serious postoperative complications explained nearly 20% of the adjuvant chemotherapy treatment gap for patients with stage III colon cancer. The use of clinical data remains important when judging provider performance. PMID- 24169160 TI - Do safety checklists improve teamwork and communication in the operating room? A systematic review. AB - OBJECTIVES: The aim of this systematic review was to assess the impact of surgical safety checklists on the quality of teamwork and communication in the operating room (OR). BACKGROUND: Safety checklists have been shown to impact positively on patient morbidity and mortality following surgery, but it is unclear whether this clinical improvement is related to an improvement in OR teamwork and communication. METHODS: A systematic search strategy of MEDLINE, EMBASE, PsycINFO, Google Scholar, and the Cochrane Database for Systematic Reviews was undertaken to obtain relevant articles. After de-duplication and the addition of limits, 315 articles were screened for inclusion by 2 researchers and all articles meeting a set of prespecified inclusion criteria were retained. Information regarding the type of checklist, study design, assessment tools used, outcomes, and study limitations was extracted. RESULTS: Twenty articles formed the basis of this systematic review. All articles described an empirical study relating to a case-specific safety checklist for surgery as the primary intervention, with some measure of change/improvement in teamwork and/or communication relating to its use. The methods for assessing teamwork and communication varied greatly, including surveys, observations, interviews, and 360 degrees assessments. The evidence suggests that safety checklists improve the perceived quality of OR teamwork and communication and reduce observable errors relating to poor team skills. This is likely to function through establishing an open platform for communication at the start of a procedure: encouraging the sharing of critical case-related information, promoting team coordination and decision making, flagging knowledge gaps, and enhancing team cohesion. However, the evidence would also suggest that when used suboptimally or when individuals have not bought in to the process, checklists may conversely have a negative impact on the function of the team. CONCLUSIONS: Safety checklists are beneficial for OR teamwork and communication and this may be one mechanism through which patient outcomes are improved. Future research should aim to further elucidate the relationship between how safety checklists are used and team skills in the OR using more consistent methodological approaches and utilizing validated measures of teamwork such that best practice guidelines can be established. PMID- 24169161 TI - Impact of preoperative local water-filtered infrared A irradiation on postoperative wound healing: a randomized patient- and observer-blinded controlled clinical trial. AB - OBJECTIVE: In addition to a preoperative antibiotic single-shot prophylaxis, we tested the impact of a one-time preoperative water-filtered infrared A irradiation (wIRA) on postoperative wound healing of patients. BACKGROUND: wIRA improves wound healing in postoperative settings. METHODS: A total of 400 consecutive patients undergoing gastrointestinal surgery were randomly assigned to the treatment group (A) or placebo group (B). We applied wIRA for 20 minutes while patients were prepared for surgery. Patients and observer were blinded to group assignment. Primary endpoints were surgical site infections (SSIs), wound healing, and rate and level of pain within 30 days after surgery. Primary efficacy analysis was carried out on the basis of an intention-to-treat (ITT) population and a full-analysis set (FAS). Missing values of primary outcome variables were considered as SSIs and maximum pain levels in the ITT analysis, respectively. RESULTS FAS: The incidence of SSI was 9 of 178 patients (5.1%) within group A compared with 22 of 182 (12.1%) within group B [P = 0.018; relative risk (RR) = 0.42; 95% CI: 0.18-0.93]. ITT: 32 of 200 (16%) SSIs occurred within group A and 39 of 200 (20%) within group B (P = 0.248) with an RR of 0.74 (95% CI: 0.43-1.28). The wIRA group showed lower postoperative pain at both the ITT (P = 0.092) and the FAS analysis (P = 0.045). CONCLUSIONS: This trial indicates a clinically relevant benefit of one-time application of preoperative wIRA as a supportive addition to prophylactic antibiotics. wIRA contributes to both reduced SSI rates and postoperative pain but also effectively decreases morbidity and related expenses in the health care system. PMID- 24169162 TI - The risk of perioperative bleeding in patients with chronic kidney disease: a systematic review and meta-analysis. AB - BACKGROUND: Worldwide, millions of patients with chronic kidney disease undergo surgery each year. Although chronic kidney disease increases the risk of bleeding in nonoperative settings, the risk of perioperative bleeding is less clear. We conducted a systematic review and meta-analysis to summarize existing information and quantify the risk of perioperative bleeding from chronic kidney disease. METHODS: We screened 9376 citations from multiple databases for cohort studies published between 1990 and 2011. Studies that met our inclusion criteria included patients undergoing any major surgery, with a sample size of at least 100 patients with chronic kidney disease (as defined by the primary study authors with an elevated preoperative serum creatinine value or a low estimated glomerular filtration rate). Their outcomes had to be compared with a reference group of at least 100 patients without chronic kidney disease. Our primary outcomes were (1) receipt of perioperative blood transfusions and (2) need for reoperation for reasons of bleeding. RESULTS: Twenty-three studies met our criteria for review (20 cardiac surgery, 3 non-cardiac surgery). Chronic kidney disease was associated with a greater risk of requiring blood transfusion (7 studies in cardiac surgery, totaling 22,718 patients) and weighted incidence in patients with normal kidney function was 53% and in chronic kidney disease was 73%; pooled odds ratio, 2.7 (95% confidence interval, 2.1-3.4). After adjustment for relevant factors, the association remained statistically significant in 4 studies. Chronic kidney disease was associated with more reoperation for reasons of bleeding (14 studies in cardiac surgery, totaling 569,715 patients) and weighted incidence in patients with normal kidney function was 2.4% and in chronic kidney disease was 2.7%; pooled odds ratio, 1.6 (95% confidence interval, 1.3-1.8). However, after adjustment for relevant factors (as done in 5 studies), the association was no longer statistically significant. CONCLUSIONS: Chronic kidney disease is associated with perioperative bleeding but not bleeding that required reoperation. Further studies should stage chronic kidney disease with the modern system, better define bleeding outcomes, and guide intervention to improve the safety of surgery in this at-risk population. PMID- 24169163 TI - Reduction of postoperative ileus by early enteral nutrition in patients undergoing major rectal surgery: prospective, randomized, controlled trial. AB - BACKGROUND: The current trend in postoperative nutrition is to promote a normal oral diet as early as possible. However, postoperative ileus is a frequent and common problem after major abdominal surgery. This study was designed to investigate whether early enteral nutrition (EEN), as a bridge to a normal diet, can reduce postoperative ileus. METHODS: Patients undergoing major rectal surgery for locally advanced primary or recurrent rectal carcinoma (after neoadjuvant (chemo)-radiation, with or without intraoperative radiotherapy) were randomly assigned to EEN (n = 61) or early parenteral nutrition (EPN, n = 62) in addition to an oral diet. Early nutrition was started 8 hours after surgery. Early parenteral nutrition was given as control nutrition to obtain caloric equivalence and minimize confounding. The primary endpoint was time to first defecation; secondary outcomes were morbidity, other ileus symptoms, and length of hospital stay. RESULTS: Baseline characteristics were similar for both groups. In intention-to-treat analysis, the time to first defecation was significantly shorter in the enteral nutrition arm than in the control arm (P = 0.04). Moreover, anastomotic leakage occurred significantly less frequently in the enteral group (1 patient) compared with parenteral supplementation (9 patients, P = 0.009). Mean length of stay in the enteral group was 13.4 +/- 2.2 days versus 16.7 +/- 2.3 days in the parenteral group (P = 0.007). CONCLUSIONS: Early enteral nutrition is safe and associated with significantly less ileus. Early enteral nutrition is associated with less anastomotic leakage in patients undergoing extensive rectal surgery. PMID- 24169164 TI - Introducing a novel and robust technique for determining lymph node status in colorectal cancer. AB - OBJECTIVE: This study aims to harness the potential of public gene expression repositories, to develop gene expression profiles that could accurately determine nodal status in colorectal cancer. BACKGROUND: Currently, techniques that determine lymph node positivity (before resection) have poor sensitivity and specificity. The ability to determine lymph node status, based on preoperative biopsies, would greatly assist in planning treatment in colorectal cancer. This is particularly relevant in polyp-detected cancers. METHODS: Public gene expression repositories were screened for experiments comparing metastatic and nonmetastatic colorectal cancer. A customized graphic user interface was developed to extract genes dysregulated across most identified studies (ie, consensus profiles). The utility of consensus profiles was tested by determining whether classifiers could be derived that determined nodal positivity or negativity. Consensus profiles-derived classifiers were tested on separate Affymetrix- and Illumina-based experiments, and collated outputs were compiled in summary receiver operator curve characteristic format, with area under the curve (AUC) reflecting accuracy. The association between classification and oncologic outcome was determined using an additional, independent data set. Final validation was conducted using the Ingenuity network-linkage environment. RESULTS: Four consensus profiles were generated from which classifiers were derived that accurately determined node positive and negative status (pooled AUC were 0.79 +/- 0.04 and 0.8 +/- 0.03 for nodal positivity and negativity, respectively). Overall AUC ranged from 0.73 to 0.86, demonstrating high accuracy across consensus profile type, classification technique, and array platform used. As consensus profile enabled classification of nodal status, survival outcomes could be compared for those predicted node negative or positive. Patterns of disease-free and overall survival were identical to those observed for standard histopathologic nodal status. Genes contained within consensus profiles were strongly linked to the metastatic process and included (among others) FYN, WNT5A, COL8A1, BMP, and SMAD family members. CONCLUSIONS: Microarray expression data available in public gene expression repositories can be harnessed to generate consensus profiles. The latter are a source of classifiers that have prognostic and predictive properties. PMID- 24169165 TI - Subpopulations of circulating cancer stem cell-like cells. PMID- 24169166 TI - Colorectal surgery in cirrhotic patients: the role of laparoscopy. PMID- 24169167 TI - Reply to letter: "Tumor regression after neoadjuvant chemotherapy in gastric carcinoma: are there really so few responders?". PMID- 24169168 TI - The presence of SDHB mutations should modify surgical indications for carotid body paragangliomas. AB - OBJECTIVE: The aim of this study was to determine whether the genetic background of the disease should be incorporated into treatment decision making. BACKGROUND: Carotid body paragangliomas are rare tumors that often affect patients with genetic mutations of the succinate dehydrogenase complex (SDHx). Despite growing evidence that germ line genetic mutations alter the aggressiveness of paragangliomas, treatment decisions are currently based only on clinical symptoms and tumor size in patients with carotid body paragangliomas. METHODS: Retrospective analysis of 34 patients with carotid body paragangliomas who underwent genetic testing and surgical treatment. Recurrence was defined by the return of locoregional disease and/or development of distant metastases. Clinical characteristics and genetic testing results were analyzed as predictors of patient outcomes. RESULTS: Thirty-four patients underwent 41 primary carotid body paraganglioma resections (median follow-up time of 42 months, range: 1-293). Overall survival was 91.2%. Twelve patients had germ line mutations in SDHB, 17 in SDHD, and 5 carried no known mutation. Surgical resection of larger tumors was associated with higher operative complications (odds ratio: 5.4, P = 0.05). Tumor size at resection was significantly smaller in patients with SDHB mutations than in patients with non-SDHB mutations (2.1 vs 3.3 cm, P = 0.02). Patients with a mutation in the SDHB gene also had significantly worse disease-free survival compared with patients without an SDHB gene mutation (P = 0.03). CONCLUSIONS: Mutations in the SDHB gene are associated with worse disease-free survival after resection in patients with carotid body paragangliomas despite earlier intervention. This suggests that a more aggressive surgical approach is warranted in patients with SDHB mutations. PMID- 24169169 TI - Laparoscopy within fast-track or within enhanced recovery after surgery? PMID- 24169170 TI - Frequency of lymph node metastasis in submucosal esophageal cancer. PMID- 24169171 TI - Reply to letter: "Surgical statistics: let's act fast and grasp the opportunity". PMID- 24169172 TI - The role of organ failure and infection in necrotizing pancreatitis: a prospective study. AB - OBJECTIVE: To clarify the roles of organ failure and infection in the outcome of necrotizing pancreatitis. BACKGROUND: Results of previous cohort studies that focused on the roles of infection and organ failure in acute pancreatitis are controversial. METHODS: In this study, we collected the medical records of 447 patients with necrotizing pancreatitis from January 2009 to June 2012. Data associated with organ failure and infection were analyzed. RESULTS: The overall mortality rate was 13% (58/447). Intervention was performed in 223 of 447 patients. Among these 223 patients, 134 were confirmed to be with infected necrosis by a positive culture. The mortality rate was 15% (13/89) in the sterile necrosis group and 18% (24/134) in the infected necrosis group (P = 0.52). A multivariate analysis of death predictors indicated that bacteremia (odds ratio [OR] = 2.76, 95% confidence interval [CI], 1.23-5.46, P < 0.001), age (OR = 1.07, 95% CI, 1.03-1.11, P < 0.001), American Society of Anesthesiologists class (OR = 3.56, 95% CI, 1.65-7.18, P = 0.001), persistent organ failure in the first week (OR = 16.72, 95% CI, 7.04-32.56, P < 0.001), and pancreatic necrosis (OR = 1.73, 95% CI, 1.14-2.98, P = 0.008) were significant factors. CONCLUSIONS: Among patients with necrotizing pancreatitis, the effects of organ failure on mortality are more critical than those of infection. Bacteremia, age, American Society of Anesthesiologists class, persistent organ failure in the first week, and pancreatic necrosis were identified as the predictors of mortality. PMID- 24169173 TI - Factors influencing readmission after pancreaticoduodenectomy: a multi institutional study of 1302 patients. PMID- 24169174 TI - Systematic review and meta-analysis of the role of routine colonic evaluation after radiologically confirmed acute diverticulitis. AB - OBJECTIVE: To determine the yield of colorectal cancer at routine colonic evaluation after radiologically proven acute diverticulitis. BACKGROUND: Acute diverticulitis accounts for 152,000 hospitalizations in the United States alone. Current guidelines recommend routine colonic evaluation after acute diverticulitis to confirm the diagnosis and exclude malignancy. However, research suggests that the yield of colorectal cancer after computed tomography-proven uncomplicated diverticulitis may be low. In the era of widespread computed tomographic scanning for diverticulitis, routine colonic evaluation after diverticulitis may represent a nonessential burden on health care resources. METHODS: The PubMed (MEDLINE), EMBASE, BIREME, CINAHL, and the Cochrane Library databases were searched. Original studies of colonic evaluation after proven acute diverticulitis were included. Meta-analysis of data from included studies was performed using a DerSimonian Laird random effect proportion analysis. RESULTS: Eleven studies from 7 countries were included in the analysis. Out of a pooled population of 1970 patients, cancer was found in 22. The pooled proportional estimate of malignancy was 1.6% (95% confidence interval [CI], 0.9% 2.8%). Of the 1497 patients with uncomplicated diverticulitis, cancer was found in 5 (proportional estimate of risk 0.7%; CI, 0.3%-1.4%). Of the 79 patients with complicated disease, cancer was found in 6 (proportion estimate of risk 10.8%; CI, 5.2%-21.0%). CONCLUSIONS: The risk of malignancy after a radiologically proven episode of acute uncomplicated diverticulitis is low. In the absence of other indications, routine colonoscopy may not be necessary. Patients with complicated diverticulitis still have a significant risk of colorectal cancer at subsequent colonic evaluation. PMID- 24169175 TI - A comparative study on comprehensive, objective outcomes of laparoscopic Heller myotomy with per-oral endoscopic myotomy (POEM) for achalasia. AB - OBJECTIVE: To compare symptomatic and objective outcomes between HM and POEM. BACKGROUND: The surgical gold standard for achalasia is laparoscopic Heller myotomy (HM) and partial fundoplication. Per-oral endoscopic myotomy (POEM) is a less invasive flexible endoscopic alternative. We compare their safety and efficacy. METHODS: Data on consecutive HMs and POEMs for achalasia from 2007 to 2012 were collected. PRIMARY OUTCOMES: swallowing function-1 and 6 months after surgery. SECONDARY OUTCOMES: operative time, complications, postoperative gastro esophageal reflux disease (GERD). RESULTS: There were 101 patients: 64 HMs (42% Toupet and 58% Dor fundoplications) and 37 POEMs. Presenting symptoms were comparable. Median operative time (149 vs 120 min, P < 0.001) and mean hospitalization (2.2 vs 1.1 days, P < 0.0001) were significantly higher for HMs. Postoperative morbidity was comparable. One-month Eckardt scores were significantly better for POEMs (1.8 vs 0.8, P < 0.0001). At 6 months, both groups had sustained similar improvements in their Eckardt scores (1.7 vs 1.2, P = 0.1).Both groups had significant improvements in postmyotomy lower esophageal sphincter profiles. Postmyotomy resting pressures were higher for POEMs than for HMs (16 vs 7.1 mm Hg, P = 0.006). Postmyotomy relaxation pressures and distal esophageal contraction amplitudes were not significantly different between groups. Routine postoperative 24-hour pH testing was obtained in 48% Hellers and 76% POEMs. Postoperatively, 39% of POEMs and 32% of HM had abnormal acid exposure (P = 0.7). CONCLUSIONS: POEM is an endoscopic therapy for achalasia with a shorter hospitalization than HM. Patient symptoms and esophageal physiology are improved equally with both procedures. Postoperative esophageal acid exposure is the same for both. The POEM is comparable with laparoscopic HM for safe and effective treatment of achalasia. PMID- 24169176 TI - Outcome analysis of a decade-long experience of isolated hepatic perfusion for unresectable liver metastases at a single institution. AB - OBJECTIVE: To evaluate outcomes of isolated hepatic perfusion (IHP) on isolated liver metastases (LMs). BACKGROUND: Isolated unresectable LMs are often the main determinant of overall survival (OS) for colorectal cancer (CRC) and other solid malignancies. We hypothesized that IHP can be performed safely and yield impressive responses for a variety of solid tumor pathology, using different perfusion agents. METHODS: Retrospective review of a prospectively collected database of patients undergoing IHP for unresectable solid tumor LM. RESULTS: Between 2003 and 2012, IHP was completed in 91 patients. Primary tumor pathology was CRC = 54, non-CRC = 37 (ocular/cutaneous melanoma = 32, cholangiocarcinoma = 3, appendiceal = 1, and breast = 1). IHP employed Melphalan (n = 69) (CRC = 32, non-CRC = 37), Oxaliplatin (n = 10) (CRC), or Oxaliplatin + 5FU (n = 12) (CRC). Hepatic arterial infusion (HAI) pumps were placed in all CRC patients. There were 3(3.3%) perioperative deaths. Response rates for CRC, melanoma, and cholangiocarcinoma were 68.2%, 57.1%, and 100% respectively. Response rates for CRC patients using 5FU + Oxaliplatin, Oxaliplatin, or Melphalan were 83.3%, 66.7%, and 60.9%, respectively. Median OS for the CRC patients (from IHP date) was 23 months (95% confidence interval: 15-28 months). On univariate analysis, receipt of HAI-FUDR (floxuridine) within 1 year of IHP was the only factor associated with improved OS (P = 0.043) in CRC patients. CONCLUSIONS: IHP results in excellent response rates for patients with unresectable liver metastasis from solid tumors. Improved local control for CRC patients undergoing IHP-HAI may improve survival. PMID- 24169177 TI - Defining optimum treatment of patients with pancreatic adenocarcinoma using regret-based decision curve analysis. AB - OBJECTIVE: To use regret decision theory methodology to assess three treatment strategies in pancreatic adenocarcinoma. BACKGROUND: Pancreatic adenocarcinoma is uniformly fatal without operative intervention. Resection can prolong survival in some patients; however, it is associated with significant morbidity and mortality. Regret theory serves as a novel framework linking both rationality and intuition to determine the optimal course for physicians facing difficult decisions related to treatment. METHODS: We used the Cox proportional hazards model to predict survival of patients with pancreatic adenocarcinoma and generated a decision model using regret-based decision curve analysis, which integrates both the patient's prognosis and the physician's preferences expressed in terms of regret associated with a certain action. A physician's treatment preferences are indicated by a threshold probability, which is the probability of death/survival at which the physician is uncertain whether or not to perform surgery. The analysis modeled 3 possible choices: perform surgery on all patients; never perform surgery; and act according to the prediction model. RESULTS: The records of 156 consecutive patients with pancreatic adenocarcinoma were retrospectively evaluated by a single surgeon at a tertiary referral center. Significant independent predictors of overall survival included preoperative stage [P = 0.005; 95% confidence interval (CI), 1.19-2.27], vitality (P < 0.001; 95% CI, 0.96-0.98), daily physical function (P < 0.001; 95% CI, 0.97-0.99), and pathological stage (P < 0.001; 95% CI, 3.06-16.05). Compared with the "always aggressive" or "always passive" surgical treatment strategies, the survival model was associated with the least amount of regret for a wide range of threshold probabilities. CONCLUSIONS: Regret-based decision curve analysis provides a novel perspective for making treatment-related decisions by incorporating the decision maker's preferences expressed as his or her estimates of benefits and harms associated with the treatment considered. PMID- 24169178 TI - Single-site robotic cholecystectomy in a broadly inclusive patient population: a prospective study. AB - OBJECTIVES: To describe our initial experience with single-site robotic cholecystectomy (SSRC) and its applicability to a broad segment of patients. BACKGROUND: At the initiation of our study, there were only 3 published reports on SSRC. These initial studies had limited inclusion criteria. We present our experience with the technical aspects and patient outcomes of SSRC in a broadly inclusive patient population. METHODS: Prospective cohort study from January 2012 to January 2013, in which 95 patients underwent SSRC. Procedural times, postoperative complications, delayed hospital discharges, and re-admissions were evaluated. RESULTS: Patients were predominantly female (71.6%) had mean age of 45.2 +/- 6.1 years and mean body mass index (BMI) of 30.1 +/- 7.1 kg/m. Overall, mean total operative time (TOT) for all patients (n = 95) was 88.63 +/- 32.0 (range: 49-220) minutes. SSRC was not completed in 8 (8.42%) patients: 6 conversions to laparoscopy, 1 conversion to open, and 1 aborted case. The group of patients who were able to complete SSRC (n = 87) had a mean TOT of 83.5 +/- 24.5 minutes and mean operative robotic time (RT) of 39.6 +/- 15.2 minutes. RT was longer in patients with intra-abdominal adhesions (P = 0.0139) and higher BMI (P = 0.03). A minority of patients required hospital admission (11.6%), readmission (6.3%), or reoperation (1.1%). No bile duct injury or death occurred. CONCLUSIONS: SSRC is safe and has a manageable learning curve. Patient factors, such as obesity, did not significantly affect conversion rates or TOTs. SSRC is a promising new technique, which can be offered to a wide array of patients. PMID- 24169179 TI - Improving our understanding of the surgical oncology workforce. AB - OBJECTIVE: This study characterizes the surgical oncology workforce as a baseline for future workforce projections. BACKGROUND: Measuring the capacity of the surgical oncology workforce is difficult due to the wide variety of surgeons who contribute to surgical cancer care. We hypothesize that the bulk of surgical oncology care is provided by general surgeons. METHODS: Using Medicare claims data linked to the North Carolina Central Cancer Registry, all patients 65 years or older who had a diagnosis of incident cancer of the bladder, breast, colon/rectum, esophagus, gallbladder, kidney, liver, lung, skin (melanoma-only), ovary, pancreas, prostate, small bowel, stomach, or uterus in 2005 and who underwent an extirpative procedure for cancer were identified. The proportion of procedures performed by different types of providers was examined. RESULTS: A total of 7759 patients underwent 16,734 extirpative surgical procedures. Excluding procedures for gynecologic/urologic malignancies, the proportion of procedures performed by general surgeons and surgical oncologists was 48% and 12%, respectively. Patients treated by general surgeons were more likely to be older, female, minority, and from areas of high poverty. For each tumor type, travel distances were shorter for patients treated by general surgeons than those treated by specialists. CONCLUSIONS: Workforce projections must account for the significant overlap in the scope of services delivered by providers of different specialties and for the large contribution of general surgeons to cancer care. Efforts to improve the quality of cancer care need to move beyond centralization and focus on educating the surgeons who are providing the bulk of oncology care. PMID- 24169180 TI - Reply to letter: "Laparoscopy within fast-track or within enhanced recovery after surgery?". PMID- 24169181 TI - Reply to letter: "Subpopulations of circulating cancer stem cell-like cells". PMID- 24169182 TI - Total Lesion Glycolysis in Early-stage Non-small Cell Lung Cancer: Proposal for an Alternative Dimensionless Volume-based Parameter. PMID- 24169183 TI - Reply to letter: "interdisciplinary teams for the comprehensive assessment and care of frail, older surgical patients". PMID- 24169184 TI - Saccadic eye movement metrics reflect surgical residents' fatigue. AB - OBJECTIVE: Little is known about the effects of surgical residents' fatigue on patient safety. We monitored surgical residents' fatigue levels during their call day using (1) eye movement metrics, (2) objective measures of laparoscopic surgical performance, and (3) subjective reports based on standardized questionnaires. BACKGROUND: Prior attempts to investigate the effects of fatigue on surgical performance have suffered from methodological limitations, including inconsistent definitions and lack of objective measures of fatigue, and nonstandardized measures of surgical performance. Recent research has shown that fatigue can affect the characteristics of saccadic (fast ballistic) eye movements in nonsurgical scenarios. Here we asked whether fatigue induced by time-on-duty (~24 hours) might affect saccadic metrics in surgical residents. Because saccadic velocity is not under voluntary control, a fatigue index based on saccadic velocity has the potential to provide an accurate and unbiased measure of the resident's fatigue level. METHODS: We measured the eye movements of members of the general surgery resident team at St. Joseph's Hospital and Medical Center (Phoenix, AZ) (6 males and 6 females), using a head-mounted video eye tracker (similar configuration to a surgical headlight), during the performance of 3 tasks: 2 simulated laparoscopic surgery tasks (peg transfer and precision cutting) and a guided saccade task, before and after their call day. Residents rated their perceived fatigue level every 3 hours throughout their 24-hour shift, using a standardized scale. RESULTS: Time-on-duty decreased saccadic velocity and increased subjective fatigue but did not affect laparoscopic performance. These results support the hypothesis that saccadic indices reflect graded changes in fatigue. They also indicate that fatigue due to prolonged time-on-duty does not result necessarily in medical error, highlighting the complicated relationship among continuity of care, patient safety, and fatigued providers. CONCLUSIONS: Our data show, for the first time, that saccadic velocity is a reliable indicator of the subjective fatigue of health care professionals during prolonged time-on duty. These findings have potential impacts for the development of neuroergonomic tools to detect fatigue among health professionals and in the specifications of future guidelines regarding residents' duty hours. PMID- 24169185 TI - Considering the fringe. PMID- 24169186 TI - Epidemiology of vascular injuries in modern wars. PMID- 24169187 TI - Infrahepatic inferior vena cava clamping for reduction of central venous pressure and blood loss during hepatic resection: a randomized controlled trial. PMID- 24169188 TI - Assessment of different bariatric surgeries in the treatment of obesity and insulin resistance in mice. PMID- 24169189 TI - Reply to letter: "Waiting time for breast cancer treatment". PMID- 24169190 TI - Is ambulatory laparoscopic Roux-en-Y gastric bypass associated with higher adverse events? AB - OBJECTIVE: To determine the impact of length of stay upon 30-day outcomes. BACKGROUND: It has been recommended the goal length of stay (LOS) after laparoscopic Roux-en-Y gastric bypass (LRYGB) should be 1 day to improve resource utilization. This study's aim was to assess LRYGB outcomes by LOS. METHODS: Data were obtained from the BOLD (Bariatric Outcomes Longitudinal Database) for 51,788 laparoscopic gastric bypass (LRYGB) procedures performed between 2007 and 2010. Logistic regression models were used to evaluate age, sex, race, body mass index, insurance status, comorbidities, and LOS as predictors for 30-day mortality, serious complications, and readmissions. RESULTS: Overall patient demographics were as follows: median age, 45 years; median body mass index, 46.3 kg/m; % female, 78.6; % white, 77.8; % private insurance, 86.2; and % comorbidities more than 5 (39.1%). Overall, 30-day outcomes included mortality, 0.1%; serious complications, 0.5%; and readmissions, 3.8%. median LOS was 2 days, and the distribution of LOS was as follows [n (%)]: 0 (1.0), 1 (18.4), 2 (59.0), 3 (17.5), and 4 (4.1). Using the median LOS 2 days as reference, the logistic regression analysis revealed that ambulatory LOS of was significantly associated with increased risk of 30-day mortality (odds ratio: 13.02; P < 0.0001) as was LOS 1 day (odds ratio: 2.02; P < 0.0552). For LOS of 0 day, there was a trend toward an increase in the rate of 30-day serious complications (odds ratio: 1.9; P < 0.16). There was no significant trend between LOS status and 30-day readmission rates. CONCLUSIONS: In this large, prospective, clinical database, LOS of 1 day or less for LRYGB patients was significantly associated with an increased risk of 30-day mortality and a trend toward increased risk of 30-day serious complications. PMID- 24169191 TI - Adherence with postdischarge venous thromboembolism chemoprophylaxis recommendations after colorectal cancer surgery among elderly Medicare beneficiaries. AB - OBJECTIVES: To assess national adherence with extended venous thromboembolism (VTE) chemoprophylaxis guideline recommendations after colorectal cancer surgery. BACKGROUND: Postoperative VTE remains a major cause of morbidity and mortality after abdominal cancer surgery. On the basis of the results from randomized controlled trials, since 2007, national guidelines have suggested that these patients be discharged on VTE chemoprophylaxis. METHODS: Medicare beneficiaries undergoing open colorectal cancer resections in 2008-2009 were identified using the Medicare Provider Analysis and Review data and limited to those who were enrolled and used Part D for their postoperative prescriptions. Postdischarge use of low-molecular-weight-heparin and other anticoagulants was assessed. RESULTS: A total of 5078 patients underwent open colorectal cancer surgery and met the inclusion criteria. Of these, 77% underwent colectomy and 23% underwent proctectomy. A prescription for an anticoagulant was filled immediately after discharge for 77 (1.5%) patients, and a low-molecular-weight-heparin for 60 (1.2%) patients. On multivariable analysis, patients were more likely to receive postdischarge VTE chemoprophylaxis if undergoing rectal cancer surgery [incidence rate ratio (IRR), 1.83; 95% confidence interval, 1.07-3.12; vs colon], if higher educational status (IRR, 2.20; 95% confidence interval, 1.23-3.95; vs low education), or if they had a higher Elixhauser comorbidity index (IRR, 1.13; 95% confidence interval, 1.01-1.25; vs lower index). CONCLUSIONS: Although VTE remains a major issue after abdominal cancer surgery, only 1.5% of Medicare beneficiaries undergoing colorectal cancer surgery received care consistent with established guidelines for postdischarge VTE chemoprophylaxis. Barriers to adherence must be elucidated to improve the quality of care for abdominal and pelvic cancer surgery patients. PMID- 24169192 TI - FK866, a visfatin inhibitor, protects against acute lung injury after intestinal ischemia-reperfusion in mice via NF-kappaB pathway. AB - OBJECTIVE: To determine whether administration of FK866, a competitive inhibitor of visfatin, attenuates acute lung injury induced by intestinal ischemia reperfusion (I/R). BACKGROUND: Acute lung injury, a frequent complication of intestinal I/R, is an inflammatory disorder of the lung, which is characterized by an overproduction of proinflammatory cytokines and increased permeability of the alveolar-capillary barrier, resulting in multiple organ dysfunction. Therefore, the development of novel and effective therapies for intestinal I/R is critical for the improvement of patient outcome. Visfatin, a 54-kDa secretory protein, is known as a proinflammatory cytokine and plays a deleterious role in inflammatory diseases. METHODS: Male C57BL/6J mice were subjected to intestinal I/R induced by occlusion of the superior mesenteric artery for 90 minutes, followed by reperfusion. During reperfusion period, mice were treated with vehicle or FK866 (10 mg/kg of body weight) by an intraperitoneal injection. The levels of visfatin, proinflammatory mediators, and other markers were assessed 4 hours after reperfusion. In addition, survival study was conducted in intestinal I/R mice with or without FK866 treatment. RESULTS: Plasma and lung visfatin protein levels were significantly increased after intestinal I/R. FK866 treatment significantly attenuated intestinal and lung injury by inhibiting proinflammatory cytokine production, cellular apoptosis, and NF-kappaB activation, hence improving survival rate. In vitro studies showed that macrophages treated with lipopolysaccharides upregulated visfatin expression, whereas FK866 inhibited proinflammatory cytokine production via modulation of the NF-kappaB pathway. CONCLUSIONS: Collectively, these findings implicate FK866 as a novel therapeutic compound for intestinal I/R-induced attenuates acute lung injury via modulation of innate immune functions. PMID- 24169193 TI - Reply to letter: "Concerning the article: assessment of different bariatric surgeries in the treatment of obesity and insulin resistance in mice". PMID- 24169194 TI - About the Rationale for Heating Oxaliplatin During HIPEC. PMID- 24169195 TI - Long-term follow-up of a randomized controlled trial of Lichtenstein's operation versus mesh plug repair for inguinal hernia. AB - OBJECTIVE: To compare long-term results of Lichtenstein's operation versus mesh plug repair for open inguinal hernia repair. BACKGROUND: The technique of best choice in open prosthetic inguinal hernia repair remains a subject of ongoing debate. METHODS: In this prospective, randomized controlled multicenter trial, patients with primary or recurrent inguinal hernias were randomized to undergo either Lichtenstein's operation or mesh plug repair. The primary endpoint was the long-term recurrence rate. Secondary endpoints included chronic pain, sensibility disorders, and reoperation rate. RESULTS: In total, 697 hernias in 594 patients were randomized (297 patients per group). At a median follow-up of 6.5 years, 528 (76%) operated hernias in 444 (75%) patients were clinically evaluated. The recurrence rate was similar in both groups [mesh plug: 21/268 hernias = 7.8%; Lichtenstein: 21/260 hernias = 8.1%; adjusted odds ratio (OR): 0.92; 95% confidence interval (CI): 0.51, 1.68; P = 0.795]. We did not find a significant difference for chronic pain (Visual Analog Scale score >3) (OR: 0.58; 95% CI: 0.31, 1.09; P = 0.088) and sensory testing (17% vs 20% of patients; OR: 0.53; 95% CI: 0.21, 1.37; P = 0.190) between the 2 groups. There were less reoperations in the mesh plug than in the Lichtenstein's operation group (OR: 0.43; 95% CI: 0.22, 0.85; P = 0.016). CONCLUSIONS: The long-term results of this trial indicate not enough evidence for differences in recurrence, chronic pain, and sensibility disorders between mesh plug repair and Lichtenstein's operation but a lower likelihood for reoperation for mesh plug repair. Estimates for all endpoints were statistically not significant or based on large CIs. CLINICAL TRIALS REGISTRATION: ClinicalTrials.gov Identifier: NCT01637818. PMID- 24169196 TI - Waiting time for breast cancer treatment. PMID- 24169197 TI - Lymph node ratio for gastric cancer: useful instrument or just an expedient to retrieve fewer lymph nodes? PMID- 24169198 TI - Multivisceral transplantation for diffuse portomesenteric thrombosis. PMID- 24169199 TI - [Post-cardiac arrest syndrome: a multiple organ disease]. PMID- 24169200 TI - [Hyperbaric oxygen therapy and inert gases in cerebral ischemia and traumatic brain injury]. AB - Cerebral ischemia is a common thread of acute cerebral lesions, whether vascular or traumatic origin. Hyperbaric oxygen (HBO) improves tissue oxygenation and may prevent impairment of reversible lesions. In experimental models of cerebral ischemia or traumatic brain injury, HBO has neuroprotective effects which are related to various mechanisms such as modulation of oxidative stress, neuro inflammation or cerebral and mitochondrial metabolism. However, results of clinical trials failed to prove any neuroprotective effects for cerebral ischemia and remained to be confirmed for traumatic brain injury despite preliminary encouraging results. The addition of inert gases to HBO sessions, especially argon or xenon which show neuroprotective experimental effects, may provide an additional improvement of cerebral lesions. Further multicentric studies with a strict methodology and a better targeted definition are required before drawing definitive conclusions about the efficiency of combined therapy with HBO and inert gases in acute cerebral lesions. PMID- 24169201 TI - Outpatient hemithyroidectomy. AB - Outpatient surgery consists of performing an elective surgical procedure in the context of a day-only admission. This type of management is the result of sociological changes and allows a reduction of the cost. Hemithyroidectomy is a well-defined surgical procedure with known complications. The authors assessed the feasibility, patient satisfaction and cost of outpatient hemithyroidectomy. MATERIAL AND METHODS: One hundred and forty-six hemithyroidectomies were performed between August 2011 and September 2012. Inclusion criteria for outpatient surgery were surgical, anaesthetic and patient-dependent. Exclusion criteria were related to the bleeding risk, socio-economic conditions and the patient's understanding of the procedure. Preoperative information and the modalities of anaesthesia, surgery, postoperative surveillance and follow-up were standardized. Patient satisfaction was evaluated by questionnaire and cost was evaluated on the basis of medical information department data. RESULTS: Forty patients were eligible and 34 patients agreed to outpatient surgery (M/F sex ratio: 1/4; mean age: 46 +/- 6.3 years), but only 32 operations were performed on an outpatient basis. Two conversions to conventional hospitalisation were required, one because of preoperative initiation of platelet anti-aggregants and the other because of nausea. One patient remained in hospital on the day after the operation because of severe asthenia and nausea. CONCLUSION: Patients were satisfied with this type of management and 100% of them reported that they would repeat the experience. The economy for our establishment was ?711 per patient. This procedure improves patient comfort without increasing the risks and allows a reduction of management costs. PMID- 24169202 TI - Aerobic production of succinate from arabinose by metabolically engineered Corynebacterium glutamicum. AB - Arabinose is considered as an ideal feedstock for the microbial production of value-added chemicals due to its abundance in hemicellulosic wastes. In this study, the araBAD operon from Escherichia coli was introduced into succinate producing Corynebacterium glutamicum, which enabled aerobic production of succinate using arabinose as sole carbon source. The engineered strain ZX1 (pXaraBAD, pEacsAgltA) produced 74.4 mM succinate with a yield of 0.58 mol (mol arabinose)(-1), which represented 69.9% of the theoretically maximal yield. Moreover, this strain produced 110.2 mM succinate using combined substrates of glucose and arabinose. To date, this is the highest succinate production under aerobic conditions in minimal medium. PMID- 24169203 TI - Introducing targeted reviews. PMID- 24169204 TI - The coping styles and health-related quality of life of South African patients with psychogenic nonepileptic seizures. AB - OBJECTIVE: The primary aim of this study was to explore a possible association between the coping styles and the health-related quality of life (HRQOL) of patients with psychogenic nonepileptic seizures (PNES) in the South African context. METHODS: Twenty-two patients with PNESs with confirmatory video-EEG were matched by age and gender with a healthy control group. Participants had to complete self-reported measures of HRQOL and coping strategies. Data analysis consisted of performing Pearson correlations, analysis of variances, and regression analysis. RESULTS: The results indicated that the HRQOL scores of the group with PNESs were significantly lower than the HRQOL scores of the healthy control group. The participants with PNESs utilized significantly more escape avoidance and distancing coping strategies in comparison to the healthy control group. The results also indicated that the avoidance coping strategies utilized by participants with PNESs had a significant negative effect on their HRQOL. CONCLUSIONS: The findings of this study provided greater insight into the coping strategies utilized by participants with PNESs, which have been identified as risk factors in PNESs. This is the first study of this nature of people with PNESs in South Africa. PMID- 24169205 TI - SUDEP: what do parents want to know? AB - PURPOSE: Our objective was to understand the range of parental views on whether and how to approach the issue of SUDEP with families, to clarify the optimal timing and formulation of the information, and to learn from parents the optimal counseling strategies in order to minimize the inherent emotional burden. METHODS: The principles of fundamental qualitative description were used to guide this descriptive and exploratory study of parental experiences and perceptions. Stratified purposeful sampling included parents (i) who lost children to SUDEP, (ii) of children with moderate to severe epilepsy, (iii) of children with mild epilepsy, and (iv) of children with new-onset epilepsy. Focus group and in-depth one-on-one interviews were conducted. The principles of directed content analysis were used to code and categorize the focus group and interview data. Key concepts from the interview guide were used as the first level of coding categories. Codes were subsequently collapsed into broader categories. RESULTS: There was full agreement, across both genders and regardless of seizure severity, that routine counseling about SUDEP should be provided by pediatric neurologists, during the appointment when the diagnosis of epilepsy is shared with parents, and with opportunities for short-term follow-up and discussions with clinical nurses or social workers. Parents described feeling overwhelmed, worried, and increasingly anxious when the risk of SUDEP was explained to them. Parents generally expressed a preference for receiving routine SUDEP counseling at the time of the diagnosis of epilepsy. Across all groups of parents, it was identified that SUDEP counseling should occur in a face-to-face interaction with the neurologist. In learning about SUDEP, parents expressed a need to be informed of the risk of SUDEP. There was group endorsement for receiving written information about SUDEP to reinforce the content shared by the neurologist. There was a consensus that it should be the parents' decision as to whether or not the child should be present at the meeting or when to inform the child about the risk of SUDEP. CONCLUSION: Participants in this study opined that all parents of children with epilepsy should receive routine SUDEP counseling and have access to ongoing professional support. Based on these findings, it is imperative for pediatric neurologists to refine their communication skills when counseling parents about SUDEP. PMID- 24169206 TI - Validation of the boronate sensor ContPY1 as a specific probe for fluorescent detection of hydrogen peroxide in plants. AB - Studying the implication of hydrogen peroxide in biological processes in plants remains a challenge due to the current shortcomings of H2O2-responsive probes. The use of ContPY1, a new fluorescent probe, which is highly selective and sensitive for H2O2, was investigated. To validate the use of ContPY1 on plants, we have generated protocols employing cells suspensions and leaves, and measured specifically H2O2 production by plants using spectrofluorometry and microscopy. PMID- 24169207 TI - Monitoring patient distress and related problems before and after hematopoietic stem cell transplantation. PMID- 24169208 TI - Mesenchymal stem cells ameliorate sepsis-associated acute kidney injury in mice. AB - OBJECTIVE: Significant progress has been made in critical care medicine during the past several decades. However, the mortality rate is still high in patients with sepsis, especially with acute kidney injury (AKI). Mesenchymal stem cells (MSCs) possess an ability to ameliorate renal injury from ischemia-reperfusion, but it is still unknown whether they have the ability to reduce sepsis-associated AKI. METHODS: Male C57BL/6 mice underwent cecal ligation and puncture operation to induce sepsis and then received either normal saline or MSCs (1 * 10 cells intravenously) 3 h after surgery. RESULTS: Within 24 h after cecal ligation and puncture operation, the septic mice developed kidney injury and exhibited a higher mortality. Treatment with MSCs decreased serum creatinine and blood urea nitrogen levels and improved recovery of tubular function. mRNA levels of interleukin 6 (IL-6), IL-17, tumor necrosis factor alpha, interferon gamma, CXCL1, CXCL2, CXCL5, CCL2, and CCL3 in kidney tissue were dramatically decreased after MSC treatment. Neutrophil infiltration in kidney and blood bacterial loads were attenuated after MSC injection. Moreover, mice treated with MSCs had a higher survival rate than the saline treatment group. Injected MSCs were mainly localized in the lungs, spleen, and abdominal cavity lymph node, but not in the kidneys. CONCLUSIONS: Treatment with MSCs can alleviate sepsis-associated AKI and improve survival in mice with polymicrobial sepsis. These effects may be mediated by the inhibition of IL-17 secretion and balance of the proinflammatory and anti inflammatory states. Mesenchymal stem cells may be a potential new therapeutic agent for the prevention or reduction of sepsis-associated AKI. PMID- 24169209 TI - Implementation and execution of military forward resuscitation programs. AB - Through necessity, military medicine has been the driver of medical innovation throughout history. The battlefield presents challenges, such as the requirement to provide care while under threat, resource limitation, and prolonged evacuation times, which must be overcome to improve casualty survival. Focus must also be placed on identifying the causes, and timing, of death within the battlefield. By doing so, military medical doctrine can be shaped, appropriate goals set, new concepts adopted, and relevant technologies investigated and implemented. The majority of battlefield casualties still die in the prehospital environment, before reaching a medical treatment facility, and hemorrhage remains the leading cause of potentially survivable death. Many countries have adopted policies that push damage control resuscitation forward into the prehospital setting, while understanding the need for timely medical evacuation. Although these policies vary according to country, the majority share many common principles. These include the need for early catastrophic hemorrhage control at point-of-wounding, judicious use of fluid resuscitation, use of blood products as far forward as possible, and early evacuation to a surgical facility. Some countries place medical providers with the ability, and resources, for advanced resuscitation with the forward fighting units (perhaps at company level), whereas others have established en route resuscitation capabilities. If we are to continue to improve battlefield casualty survival, we must continue to work together and learn from each other. We must also carry on working alongside our civilian colleagues so that the benefits of translational experience are not lost. This review describes several countries current military approaches to prehospital trauma care. These approaches, refined through a decade of experience, merit consideration for integration into civilian prehospital care practice. PMID- 24169212 TI - The loss of civility. PMID- 24169211 TI - Optimizing prostate cancer screening; prospective randomized controlled study of the role of PSA and PCA3 testing in a sequential manner in an opportunistic screening program. AB - OBJECTIVES: To reduce unnecessary biopsies (Bx) in an opportunistic screening programme of prostate cancer. MATERIAL AND METHODS: We perform a prospective evaluation of PCA3 as a second line biomarker in an opportunistic screening for prostate cancer (PCa). From September-2010 until September-2012, 2,366 men, aged 40-74 years and with >10 years life expectancy, were initially screened with PSA/digital rectal examination (DRE). Men with previous Bx or with recent urine infections were excluded. Men with abnormal DRE and/or PSA >3 ng/ml were submitted for PCA3. All men with PCA3 >= 35 underwent an initial biopsy (IBx) 12cores-. Men with PCA3 < 35 were randomized 1:1 to either IBx or observation. Re biopsy(16-18 cores) criteria were PSA increase >.5 ng/ml at 4-6 months or PSAv > .75 ng/ml/year. RESULTS: With median follow-up (FU) of 10.1 months, PCA3 was performed in 321/2366 men (13.57%), 289 at first visit and 32 during FU. All 110 PCA3+ men (34.3%) were biopsied and PCa was identified in 43 men in IBx (39.1%). In the randomized arm, 110 were observed and 101 underwent biopsy, finding 12 PCa (11.9%), showing a statistically significant reduction of PCa detection rate in this cohort (P<.001). Global PCa detection rates were 40.9% and 9.5% for the PCA3+ and PCA3- branches, respectively (P<.001). Area under the curve for PSA and PCA3 were .601 and .74, respectively. This is an ongoing prospective study limited by its short follow-up period and still limited enrolment. CONCLUSIONS: PCA3 as a second line biomarker within an opportunistic dual screening protocol, can potentially avoid 65.7% and 50.1% biopsies at first round and at median FU of 10.1 months, respectively, just missing around 3.2% of high grade PCa. PMID- 24169214 TI - Meet Katherine Chubbs, incoming president of ACEN. PMID- 24169210 TI - Hemostatic function of apheresis platelets stored at 4 degrees C and 22 degrees C. AB - INTRODUCTION: Platelet refrigeration decreases the risk of bacterial contamination and may preserve function better than standard-of-care room temperature (RT) storage. Benefits could include lower transfusion-related complications, decreased costs, improved hemostasis in acutely bleeding patients, and extended shelf life. In this study, we compared the effects of 22 degrees C and 4 degrees C storage on the functional and activation status of apheresis platelets. METHODS: Apheresis platelets (n = 5 per group) were stored for 5 days at 22 degrees C with agitation (RT) versus at 4 degrees C with agitation (4 degrees C + AG) and without (4 degrees C). Measurements included platelet counts, mean platelet volume, blood gas analytes, aggregation response, thromboelastography, thromboxane B2 and soluble CD40 ligand release, activation markers, and microparticle formation. RESULTS: Sample pH levels were within acceptable limits for storage products (pH 6.2-7.4). Platelet glucose metabolism (P < 0.05), aggregation response (adenosine diphosphate: RT 0; 4 degrees C + AG 5.0 +/- 0.8; 4 degrees C 5.6 +/- 0.9; P < 0.05), and clot strength (maximum amplitude: RT 58 +/- 2; 4 degrees C + AG 63 +/- 2; 4 degrees C 67 +/- 2; P < 0.05) were better preserved at 4 degrees C compared with RT storage. Refrigerated samples were more activated compared with RT (P < 0.05), although thromboxane B2 (P < 0.05) and soluble CD40 ligand release (P < 0.05) were higher at RT. Agitation did not improve the quality of 4 degrees C-stored samples. CONCLUSIONS: Apheresis platelets stored at 4 degrees C maintain more viable metabolic characteristics, are hemostatically more effective, and release fewer proinflammatory mediators than apheresis platelets stored at RT over 5 days. Given the superior bacteriologic safety of refrigerated products, these data suggest that cold-stored platelets may improve outcomes for acutely bleeding patients. PMID- 24169215 TI - The times they are a-changin'... Are we? PMID- 24169216 TI - A feeling of deja vu.... PMID- 24169217 TI - Emerging leaders and informatics. PMID- 24169218 TI - A value-added benefit of nurse practitioners in long-term care settings: increased nursing staff's ability to care for residents. AB - The number of people living longer is increasing, and those with physical or cognitive impairments may need admission into long-term care settings. In long term care there is a need to increase nursing staff's capacity to meet the care needs of residents, develop a team approach to providing care and provide opportunities for staff to improve their knowledge and skills. One approach to meet these needs has been to employ a nurse practitioner (NP). The purpose of this paper is to examine nursing staff's perceptions of how working with an NP affected their ability to provide care, function as a team and increase their knowledge and skill. Data used in this paper were obtained from nursing staff and managers who participated in focus groups that were part of case studies conducted in the second phase of a larger sequential, two-phase mixed-methods study. NPs used multiple approaches to increase staff knowledge and skills and improve quality of care. These findings describe the benefits of employing NPs in long-term care settings. PMID- 24169219 TI - Enablers and barriers to implementing bedside reporting: insights from nurses. AB - As part of efforts to improve patient safety, quality of care and patient- and family-centred care, there is a growing interest in moving away from traditional taped nursing reports or reporting at the nursing station to reporting at the bedside. Although a body of knowledge exists regarding what nurses view as benefits and challenges experienced in nurse-to-nurse bedside reporting, less is known about the perceptions of nurses who have experienced this change in reporting practice on their unit. In this context, a qualitative study using semi structured interviews was undertaken to explore nurses' perceptions of a newly implemented nurse-to-nurse bedside reporting practice at one acute care hospital. A total of 43 interviews were conducted on four units with seven nurses from respirology, 10 from obstetrics and gynecology, 10 from nephrology and 16 from general surgery. Data were analyzed using a directed content analysis approach. Three themes emerged that captured nurses' perceptions of the implementation of nurse-to-nurse bedside reporting: (a) being supported to change and embrace bedside reporting, (b) maintaining confidentiality and respecting patients' preferences and (c) experiencing challenges with bedside reporting. Our findings provide insight for other organizations in their efforts to change reporting practices. Specifically, there is a need for multi-pronged initiatives including leadership support, educational opportunities and ongoing monitoring and feedback mechanisms. Future research is required to examine how enablers can be leveraged and barriers mitigated or removed to ensure successful implementation and sustainability of nurse-to-nurse bedside reporting. PMID- 24169220 TI - Managerial span of control: a pilot study comparing departmental complexity and number of direct reports. AB - Nurse managers play pivotal roles in hospitals. However, restructuring has resulted in nurse managers having wider span of control and reduced visibility. The purpose of this pilot study was to compare two methods of measuring span of control: departmental complexity and number of direct reports. Forty-one nurse managers across nine hospitals completed The Ottawa Hospital Clinical Manager Span of Control Tool (TOH-SOC) and a demographic survey. A moderate positive relationship between number of direct reports and departmental complexity score was identified (r=.49, p=<.01). Intensive care departments were more likely to be classified differently, using departmental complexity compared to number of direct reports (54%). TOH-SOC is a reliable instrument (Cronbach's alpha = .838). Using departmental complexity rather than direct reports may more accurately reflect the full scope of nurse managers' responsibility. PMID- 24169221 TI - Interference of attention-deficit hyperactivity disorder in an older adult with a severe personality disorder and dermatillomania. AB - This case of a 65-year-old male with dermatillomania, diffuse anxiety symptoms, and avoidant personality disorder (PD) illustrates the interference of attention deficit hyperactivity disorder (ADHD) in the diagnostic process and during schema focused therapy. In conclusion, ADHD in older adults and interference with PD is a subject of clinical importance and worth further investigation. PMID- 24169222 TI - Parotid lymphoepithelial cysts in human immunodeficiency virus: a review. AB - BACKGROUND: Many patients with human immunodeficiency virus present with atypical features. Early indicators of human immunodeficiency virus are scarce and hence most affected patients are diagnosed in the later stages of the disease, which is associated with poor prognosis. Salivary gland disease usually develops before acquired immunodeficiency syndrome, and is sometimes the first manifestation of human immunodeficiency virus infection. Salivary gland lesions include benign lymphoepithelial cysts of the parotid gland, which are seen in 3-6 per cent of patients. Many of the reported lesions are diagnosed on routine examination. OBJECTIVE: This review aimed to highlight the association between parotid gland benign lymphoepithelial cyst and human immunodeficiency virus infection, in order to aid early diagnosis and management of the disease. CONCLUSION: Human immunodeficiency virus testing is recommended for patients with benign lymphoepithelial cysts, as this can often be the first indication of human immunodeficiency virus infection. Benign lymphoepithelial cysts are important diagnostic and prognostic indicators in human immunodeficiency virus infection. PMID- 24169223 TI - [Epidemiology and clinical features of bone metastases]. AB - The actual improvement of epidemiologic database collection concerning bone metastases of solid tumors allows us to better understand the seriousness of this evolution, its human, social and financial burden. A renewal of interest appeared with a better screening of the asymptomatic forms and by the therapeutic advances obtained by bone resorption inhibitors. They were developed in clinical trials with a specific and original methodology evaluating their efficacy on the skeletal-related events (SRE) (pain, fracture, spinal cord compression, pathologic fracture and hypercalcemia). It is a major concern for the clinician, whatever his specialization (medical oncology, radiotherapist, surgeon, supportive care expert), to recognize these SRE for an early diagnosis and treatment since they are, with the primary tumor, the most important prognostic factors for patient's survival. PMID- 24169224 TI - A case of homocystinuria due to CBS gene mutations revealed by cerebral venous thrombosis. AB - BACKGROUND: Homocystinuria caused by cystathionine beta synthase (CBS) deficiency is most often diagnosed in childhood and has a variable expressivity. The most frequent abnormalities include intellectual disability, ectopia lentis, myopia, skeletal abnormalities or thromboembolism. OBJECTIVE: To report a case of homocystinuria unraveled by cerebral venous thrombosis (CVT). OBSERVATION: A 17 year old female was admitted in our department of neurology for subacute headache and presented seizures in the emergency room. Cerebral imaging revealed CVT. Severe hyperhomocysteinemia was found and led to the diagnosis of homocystinuria due to composite heterozygous mutations in the CBS gene. Further investigations disclosed lens subluxation in association with myopia, mild scoliosis and osteopenia. The patient was treated by heparin followed by warfarin, vitamin therapy and dietary methionine restriction. Total homocysteine and methionine levels became normal in a few weeks and the patient had a complete recovery. CONCLUSION: In patients with CVT, plasma total homocysteine measurement as part of the etiologic work up may reveal severe hyperhomocysteinemia due to CBS or remethylation defects that require specific treatment and management including perhaps protein-restricted diet and/or vitamin therapy for life. PMID- 24169225 TI - First adult case of Helicobacter cinaedi meningitis. AB - Helicobacter cinaedi, a gram-negative spiral bacillus that inhabits the intestinal tracts of rodents and primates, is associated with gastroenteritis in humans. H. cinaedi infection has been commonly reported in immunocompromised individuals such as human immunodeficiency virus-infected patients, but rarely in immunocompetent individuals. Prior contact with animals has attracted attention as a possible source of H. cinaedi infection. We report a case of meningitis in an immunocompetent 34-year-old woman who had daily contact with a kitten for a month. She developed acute headaches, fevers, and chills. Neurological examination revealed neck stiffness and her cerebrospinal fluid (CSF) exhibited polymorphonuclear pleocytosis and a decreased concentration of glucose. Blood and CSF cultures were negative; however, the pathogen responsible for her condition was identified as H. cinaedi by polymerase chain reaction in CSF. This is the first adult case of meningitis caused by H. cinaedi. Thus, this bacillus should be considered a possible causative agent of bacterial meningitis in healthy adults. PMID- 24169226 TI - [Distal tibia peri-implant fracture with an intramedullary nail: a case report]. AB - Peri-implant fractures of the distal tibia after intramedullary nailing are rare. We present a case of a fracture of the distal tibia at the site of the distal interlocking screw. We found two cases reported in the world literature. There are no cases reported in the Spanish literature. PMID- 24169227 TI - [SECOT consensus on medial femorotibial osteoarthritis]. AB - A consensus, prepared by SECOT, is presented on the management of medial knee compartment osteoarthritis, in order to establish clinical criteria and recommendations directed at unifying the criteria in its management, dealing with the factors involved in the pathogenesis of medial femorotibial knee osteoarthritis, the usefulness of diagnostic imaging techniques, and the usefulness of arthroscopy. Conservative and surgical treatments are also analysed. The experts consulted showed a consensus (agreed or disagreed) in 65.8% of the items considered, leaving 14items where no consensus was found, which included the aetiopathogenesis of the osteoarthritis, the value of NMR in degenerative disease, the usefulness of COX-2 and the chondroprotective drugs, as well as on the ideal valgus tibial osteotomy technique. PMID- 24169229 TI - Inspecting the Inspector General's report on cataract surgery in the United States Veterans Health Administration. PMID- 24169230 TI - Examination of capsular bag-implanted intraocular lenses using an indirect contact lens during vitreous surgery. PMID- 24169231 TI - Correcting astigmatism with toric intraocular lenses: effect of posterior corneal astigmatism. AB - PURPOSE: To evaluate the impact of posterior corneal astigmatism on outcomes with toric intraocular lenses (IOLs). SETTING: Cullen Eye Institute, Baylor College of Medicine, Houston, Texas, USA. DESIGN: Case series. METHODS: Corneal astigmatism was measured using 5 devices before and 3 weeks after cataract surgery. Toric IOL alignment was recorded at surgery and at the slitlamp 3 weeks postoperatively. The actual corneal astigmatism was calculated based on refractive astigmatism 3 weeks postoperatively and the effective toric power calculated with the Holladay 2 formula. The prediction error was calculated as the difference between the astigmatism measured by each device and the actual corneal astigmatism. Vector analysis was used in all calculations. RESULTS: With the IOLMaster, Lenstar, Atlas, manual keratometer, and Galilei (combined Placido-dual Scheimpflug analyzer), the mean prediction errors (D) were, respectively, 0.59 @ 89.7, 0.48 @ 91.2, 0.51 @ 78.7, 0.62 @ 97.2, and 0.57 @ 93.9 for with-the-rule (WTR) astigmatism (60 to 120 degrees), and 0.17 @ 86.2, 0.23 @ 77.7, 0.23 @ 91.4, 0.41 @ 58.4, and 0.12 @ 7.3 for against-the-rule (ATR) astigmatism (0 to 30 degrees and 150 to 180 degrees). In the WTR eyes, there were significant WTR prediction errors (0.5 to 0.6 diopters [D]) by all devices. In ATR eyes, WTR prediction errors were 0.2 to 0.3 D by all devices except the Placido-dual Scheimpflug analyzer (all P<.05 with Bonferroni correction). CONCLUSIONS: Corneal astigmatism was overestimated in WTR by all devices and underestimated in ATR by all except the Placido-dual Scheimpflug analyzer. A new toric IOL nomogram is proposed. PMID- 24169232 TI - Design, synthesis and evaluation of 6-(4-((substituted-1H-1,2,3-triazol-4 yl)methyl)piperazin-1-yl)phenanthridine analogues as antimycobacterial agents. AB - Focus in this Letter is made to design and synthesize a series of nineteen new 6 (4-((substituted-1H-1,2,3-triazol-4-yl)methyl)piperazin-1-yl)phenanthridine analogues employing click chemistry and evaluated for their anti-tubercular activity against Mycobacterium tuberculosis H37Rv. Among the tested compounds, 7f and 7 j exhibited good activity (MIC = 3.125 MUg/mL), while 8a displayed excellent activity (MIC = 1.56 MUg/mL) against the growth of M. tuberculosis H37Rv. In addition, 7f, 7 j and 8a compounds were subjected to cytotoxic studies against mouse macrophage (RAW264.7) cell lines and the selectivity index values are >15 indicating suitability of compounds for further drug development. PMID- 24169233 TI - Structure-activity relationship studies of thalidomide analogs with a taxol-like mode of action. AB - Anti-microtubule agents such as paclitaxel and docetaxel have played an important role in the treatment of cancer for many years. Recently, a small molecule that has a taxol-like mode of action (5HPP-33) was reported. Herein, the detailed structure-activity relationship (SAR) studies of 5HPP-33 analogs that are substituted at the isoindole and phenyl rings are described. Bulky substitutions (such as di-isopropyl groups) on the phenyl ring result in the isoindole and phenyl rings being perpendicular to each other. It was found that this conformation is critical for anti-microtubule activity. These studies have provided valuable information, which will be helpful in the design of more potent analogs. PMID- 24169235 TI - Challenges, innovations, patient safety and quality: the past, present and future of regional anesthesia. PMID- 24169234 TI - 3',4'-Bis-difluoromethoxycinnamoylanthranilate (FT061): an orally-active antifibrotic agent that reduces albuminuria in a rat model of progressive diabetic nephropathy. AB - Cinnamoylanthranilates including tranilast have been identified as promising antifibrotics that can reduce fibrosis occurring in the kidney during diabetes, thereby delaying and/or preventing kidney dysfunction. Structure-activity relationships aimed at improving potency and metabolic stability have led to the discovery of FT061. This compound, which bears a bis-difluoromethoxy catechol, attenuates TGF-beta-stimulated production of collagen in cultured renal mesangial cells (approx 50% at 3 MUM). When dosed orally at 20mg/kg to male Sprague Dawley rats, FT061 exhibited a high bioavailability (73%), Cmax of 200 MUM and Tmax of 150 min, and a half-life of 5.4h. FT061 reduced albuminuria when orally dosed in rats at 200 mg kg/day in a late intervention study of a rat model of progressive diabetic nephropathy. PMID- 24169237 TI - Transthyretin stabilization by iododiflunisal promotes amyloid-beta peptide clearance, decreases its deposition, and ameliorates cognitive deficits in an Alzheimer's disease mouse model. AB - Alzheimer's disease (AD) is the most common form of dementia and now represents 50-70% of total dementia cases. Over the last two decades, transthyretin (TTR) has been associated with AD and, very recently, a novel concept of TTR stability has been established in vitro as a key factor in TTR/amyloid-beta (Abeta) interaction. Small compounds, TTR stabilizers (usually non-steroid anti inflammatory drugs), bind to the thyroxine (T4) central binding channel, increasing TTR tetrameric stability and TTR/Abeta interaction. In this work, we evaluated in vivo the effects of one of the TTR stabilizers identified as improving TTR/Abeta interaction, iododiflunisal (IDIF), in Abeta deposition and other AD features, using AbetaPPswe/PS1A246E transgenic mice, either carrying two or just one copy of the TTR gene (AD/TTR+/+ or AD/TTR+/-, respectively), available and characterized in our laboratory. The results showed that IDIF administered orally bound TTR in plasma and stabilized the protein, as assessed by T4 displacement assays, and was able to enter the brain as revealed by mass spectrometry analysis of cerebrospinal fluid. TTR levels, both in plasma and cerebrospinal fluid, were not altered. In AD/TTR+/- mice, IDIF administration resulted not only in decreased brain Abeta levels and deposition but also in improved cognitive function associated with the AD-like neuropathology in this mouse model, although no improvements were detectable in the AD/TTR+/+ animals. Further, in AD/TTR+/- mice, Abeta levels were reduced in plasma suggesting TTR promoted Abeta clearance from the brain and from the periphery. Taken together, these results strengthen the importance of TTR stability in the design of therapeutic drugs, highlighting the capacity of IDIF to be used in AD treatment to prevent and to slow the progression of the disease. PMID- 24169238 TI - White matter hyperintensities are positively associated with cortical thickness in Alzheimer's disease. AB - White matter hyperintensities are associated with an increased risk of Alzheimer's disease (AD). White matter hyperintensities are believed to disconnect brain areas. We examined the topographical association between white matter hyperintensities and cortical thickness in controls, mild cognitive impairment (MCI), and AD patients. We examined associations between white matter hyperintensities and cortical thickness among 18 older cognitively healthy participants, 18 amnestic MCI, and 17 mild AD patients. These associations were cluster-size corrected for multiple comparisons. In controls, a positive association between white matter hyperintensities and cortical thickness was found in lateral temporal gyri. In MCI patients, white matter hyperintensities were positively related to cortical thickness in frontal, temporal, and parietal areas. Positive associations between white matter hyperintensities and cortical thickness in AD patients were confined to parietal areas. The results of the interaction group by white matter hyperintensities on cortical thickness were consistent with the findings of positive associations in the parietal lobe for MCI and AD patients separately. In the frontal areas, controls and AD patients showed inverse associations between white matter hyperintensities and cortical thickness, while MCI patients still showed a positive association. These results suggest that a paradoxical relationship between white matter hyperintensities and cortical thickness could be a consequence of neuroinflammatory processes induced by AD-pathology and white matter hyperintensities. Alternatively, it might reflect a region-specific and disease-stage dependent compensatory hypertrophy in response to a compromised network. PMID- 24169239 TI - [Pay attention to nonmotor symptoms and electrophysiological diagnostic methods for the patients of multiple system atrophy]. PMID- 24169240 TI - [Comparative study on the diagnostic value of positron emission tomography and transcranial sonography in the diagnosis of Parkinson's disease]. AB - OBJECTIVE: To evaluate the consistency of dopamine transporter (DAT) positron emission tomography (PET) versus transcranial sonography (TCS) of Parkinson's disease (PD) patients. METHODS: A total of 53 clinically diagnosed idopathic PD patients from Beijing Tiantan Hospital underwent (11)C-CFT PET and transcranial sonography (TCS). Asymmetric reduced dopaminergic function was a positive result of PET while unilateral hyperechoic area larger than 0.2 cm2 a positive result of TCS. Kappa test was used to evaluate the consistency of two methods. RESULTS: Among them, 36 patients (67.92%) were TCS positive while 17 patients (32.08%) TCS negative. There were 48 patients (90.57%) with positive PET whereas PET was negative for 5 patients (9.43%). TCS and PET were both positive in 33 patients (62.26%) while 2 (3.77%) yielded a double negative result. As compared with the PET results, the sensitivity, specificity, positive predictive value and negative predictive value of TCS were 68.75%, 40%, 91.67% and 11.76% respectively. For Kappa test, Kappa = 0.042, P = 0.690, P > 0.05. It inferred a poor consistency. CONCLUSIONS: TCS has a high predictive value for PET positive PD patients. For clinically diagnosed PD patients, a positive TCS result highly predicts PD without DAT-PET. However a negative TCS result can not rule out the possibility of PD. DAT-PET needs to be performed for further confirmation. PMID- 24169241 TI - [Assessment of cognitive function, emotions and activities of daily living in patients with multiple system atrophy]. AB - OBJECTIVE: To explore the cognitive function, emotional status and activities of daily living in patients with multiple system atrophy (MSA). METHODS: Thirty-two MSA patients and 38 healthy controls from October 2009 to November 2012 were recruited from our hospital. Their cognitive function, emotional status and activities of daily living were assessed. Cognitive function was assessed by Montreal cognitive assessment (MoCA) and mini-mental state examination (MMSE); emotional status by self-rating depression scale (SDS) and self-rating anxiety scale (SAS); daily living and activities by activities of daily living scale (ADL). Data analysis was performed with SPSS 19.0. And the results were presented as the mean +/- standard deviation. Comparison of means was performed with independent sample t test. And Pearson's correlation test was used for correlation analysis. A P-value <0.05 was considered significant. RESULTS: Mild or moderate cognitive impairment was documented in 71.9% of MSA patients. The scores of MoCA and MMSE in the MSA group were significantly lower than those in the control group. And the scores of ADL, SDS and SAS in the MSA group were significantly higher than those in the control group (P < 0.05). MoCA subitems such as space/executive function, attention, abstraction, language and delayed memory of the MSA group were significantly lower than those of the control group (P < 0.05). A negative correlation existed between the scores of MoCA and MMSE with disease duration (P < 0.01). There was a positive correlation between the scores of SDS and SAS with ADL and disease duration (P < 0.05). And the relationship was significant between the scores of SDS and SAS (P < 0.01). A positive correlation existed between scores of ADL with disease duration (P < 0.05). CONCLUSION: MSA patients have certain degrees of cognitive impairment, emotion disorders and impaired ADL. Cognitive impairment in MSA patients may be more common than previously. Furthermore, the clinical features of cognitive impairment in these patients may have some clinical values for references. PMID- 24169242 TI - [Efficacy and safety of ropinirole in the treatment of Parkinson's disease: a multi-center, randomized, double-blind and bromocriptine-controlled trial]. AB - OBJECTIVE: To explore the efficacy and safety of ropinirole in the treatment of Parkinson's disease. METHODS: From November 2005 to April 2007, a total of 221 subjects from 7 hospitals of Beijing, Lanzhou and Wuhan participated in a 12-week multi-center, randomized, bromocriptine-controlled, double-blind, double-dummy and parallel-group trial. The efficacy of ropinirole was assessed with the unified Parkinson's disease rating scale (UPDRS) score, "off" time according to the patient's diary and the overall evolution of clinical efficacy. The safety was assessed on the basis of adverse events, blood pressure, pulse, laboratory measurement and electrocardiographic recordings. And the statistical analyses were performed with t, paired t, chi(2) and covariance tests. RESULTS: In the intent-to-treat population, the average UPDRSIII score decreased to (11 +/- 9) in ropinirole group and (11 +/- 10) in bromocriptine group while the UPDRSIIscore decreased to (4 +/- 4) and (3 +/- 5) respectively at Week 12 versus baseline. It showed that ropinirole was non-inferior to bromocriptine. The "off" time at Week 12 [(3.0 +/- 1.2)h, (3.8 +/- 1.6)h] versus baseline [(4.2 +/- 2.0)h, (4.4 +/- 1.7)h] decreased (t = 10.772, t = 5.746, P = 0.000) in ropinirole and bromocriptine groups. Ropinirole offered a better overall improvement rate (q = 7.241, P = 0.007). The adverse events occurring at a ratio of over 5% caused by ropinirole included orthostatic hypotension, nausea, dizziness, upper abdominal discomfort, insomnia and palpitation. No significant difference existed in the frequency of adverse events between two groups. CONCLUSIONS: Ropinirole is both effective and safe in the treatment of Chinese patients with Parkinson's disease. PMID- 24169243 TI - [Comparative study on diagnostic significance of urethral sphincter versus external anal sphincter electromyography in patients with multiple system atrophy]. AB - OBJECTIVE: To evaluate the diagnostic value of external anal sphincter electromyography (EAS-EMG) versus urethral sphincter electromyography (US-EMG) in patients with multiple system atrophy (MSA). METHODS: A total of 27 MSA patients were examined with EAS and US-EMG as treatment group while 28 non-MSA subjects as control group. Spontaneous activities during relaxation, mean duration & amplitude of motor unit potential (MUP), percentage of polyphasic and variations during strong contraction were recorded and analyzed statistically. RESULTS: There was significant difference in light contraction between MSA and non-MSA cases on both EAS-EMG and US-EMG (EAS-EMG, P < 0.001; US-EMG, P = 0.002) . Meanwhile, strong contraction and percentage of polyphasic showed significant differences between MSA and non-MSA cases on EAS-EMG only (strong contraction, P = 0.016; percentage of polyphasic, P = 0.004) . EAS-EMG showed more significant changes in neurogenic injury than US-EMG. CONCLUSIONS: US-EMG and EAS-EMG are valuable for the diagnosis of MSA. The differences of multiple parameters of EAS EMG were more significant than those of US-EMG for MSA cases. US-EMG may serve as a supplement of EAS-EMG in case of restriction. PMID- 24169244 TI - [Virus spectrum features of adult influenza-like fever in outpatients]. AB - OBJECTIVE: To analyze the results of detection on respiratory virus of influenza like illness ( ILI ) in Beijing from June 2010 to February 2012 and understand the virus spectrum of adult influenza-like fever. METHODS: A total of 502 swabs were collected and 279 throat swabs tested for 12 respiratory viruses with multiplex reverse transcription-polymerase chain reaction (RT-PCR). And 413 swabs were tested for pH1N1 by virus isolation influenza viruses. And the data were statistically analyzed. RESULTS: One or two viruses were detected in 26.9% (75/279) of the samples. Influenza A virus (FLU-A) accounted for 85.3% of positive samples and 22.9% (64/279) of ILI tested. The positive rate of other viruses was less than 3.0 %. The positive rates among the following subtypes were: 2.7% (11/413) for pH1N1, 2.4% (10/413) for H3 and 6.5% (27/413) for FLU-B. FLU-A was the predominant virus during the 2010-2011 influenza season and the positive rate peaked in January 2011 in Beijing and north China. FLU-B was the primary virus during the 2011-2012 influenza season and the positive rate peaked in January and February 2012. There was a significant reduction in the incidence of ILI in 2010 and 2011 when compared with 2009. During the 2009-2012 influenza seasons, the incidence peaked in December 2009, January 2011 and January and February 2012 in Beijing. CONCLUSIONS: Exposure to pH1N1 had no impact on typical influenza seasonal peaks. Influenza virus was the predominant virus of adult influenza-like fever cases after the pandemic period of influenza A (H1N1) 2009 and the positive rate peaked in January and February during the 2009-2012 influenza seasons. PMID- 24169245 TI - [Microcirculation characters in the elderly septic patients]. AB - OBJECTIVE: To explore the changes of sublingual microcirculation in elderly patients with severe sepsis/septic shock. METHODS: Twenty-three patients with sepsis, 10 patients without sepsis and 10 healthy elderly patients were enrolled. Sublingual microcirculation was evaluated by sidestream darkfield (SDF) imaging. And the 28-day mortality rates of all septic patients were recorded. RESULTS: Compared with the healthy group, all elderly patients had significant sublingual microcirculation dysfunctions. Compared with the severe septic and nonseptic patients, perfused vessel density (PDV) , proportion of perfused vessels (PPV) and microvascular flow index (MFI) of septic shocks were significantly lower. Compared with the severe septic patients, PDV, PPV and MFI instead of lactate and MAP of septic shocks were significantly lower from Day 1 to Day 3. The values of PDV, PPV, MFI and lactate but not MAP of the surviving septic patients were significantly higher than those of the deceased ones. CONCLUSIONS: The elderly patients with septic shock have severe sublingual microcirculatory alterations. And these abnormalities are more marked in septic shock patients. Nonsurvivors showed more severe alterations than survivors. Microcirculatory alterations may be measured to guide the therapy. PMID- 24169246 TI - [Three-dimensional flow perfusion culture enhances proliferation of human fetal osteoblasts in large scaffold with controlled architecture]. AB - OBJECTIVE: To demonstrate the feasibility and benefits of custom designed perfusion bioreactor in conjunction with well-defined three-dimensional (3D) environment for enhanced proliferation and homogeneous distribution of human fetal osteoblasts in large scaffold in vitro. METHODS: Large-scale beta tricalcium phosphate (beta-TCP) scaffolds with tightly controlled architectures were fabricated. And a custom designed perfusion bioreactor was developed. Human fetal osteoblasts were seeded onto the scaffolds, cultured for up to 16 days in static or flow perfusion conditions. At Days 4, 8 & 16 post-incubation, the proliferation and distribution of osteoblasts were determined by daily D-glucose consumption, cell viability (methyl thiazolyl tetrazolium (MTT) assay), histological evaluation and scanning electron microcopy (SEM). Sphere like structures observed in the SEM images were assessed by energy dispersive X-ray (EDX) analysis. RESULTS: In both static and perfusion cultures, the daily D glucose consumption increased with prolonged time. The daily D-glucose consumption was significantly higher in the perfusion culture than that in static culture (P < 0.05). The increased cell viability with time during the culture was similar to the daily D-glucose consumption under both conditions. There was much greater cell viability under flow perfusion culture compared to static culture (P < 0.05). Flow perfused constructs demonstrated improved cell proliferation and a homogeneous layer composed of cells and extracellular matrix in channels throughout the whole scaffold. However, the cells were biased to periphery in scaffolds culture statically. Sphere like structures present in the matrix were identified as calcium phosphate nodules via EDX analysis. CONCLUSIONS: Flow perfusion culture plus well-defined 3D interconnected channel environments enhances the proliferation and improve the distribution of human fetal osteoblasts in large scaffolds. Scaffolds with controlled architecture may be a potential tool of studying the fluid flow configuration and cell behavior inside scaffold in details. And human fetal osteoblasts can be used as a cell source in large bone graft research. PMID- 24169247 TI - [Surgical treatment of pulmonary tuberculosis complicated with aspergilloma]. AB - OBJECTIVE: To investigate the surgical indications of pulmonary tuberculosis complicated with aspergilloma , and to reduce postoperative complications. METHODS: From 1993 to 2010, a total of 51 surgically treated patients in pulmonary tuberculosis complicated with aspergilloma were analyzed retrospectively. The common surgical procedure performed was lobectomy(60.8%), followed by segmentectomy(15.7%), pneumonectomy(9.8%), wedge resection(9.8%). RESULTS: Postoperative non-fatal complications occurred in all patients, the complications (13 cases) included postoperative atelectasis(7.8%), bleeding(5.9%), bronchopleural fistula(5.9%), cardiac arrhythmia and heart failure(2.0%), incisional infection(2.0%). CONCLUSIONS: Surgical treatment of pulmonary tuberculosis complicated with aspergilloma is the most effective treatment; pulmonary resection is the treatment of choice when indicated. PMID- 24169248 TI - [Comparison of the efficacy of different types of laryngeal mask airways in patients undergoing laparoscopic gynecological surgery]. AB - OBJECTIVE: To compare the efficacy of laryngeal mask airway Supreme, ProSeal and I-gel in patients undergoing laparoscopic gynecological surgery. METHODS: From Jan 2010 to Sep 2012 in Beijing Hospital, approved by hospital ethics committee, ninety ASA IorII patients, aged 21-64 yr, weighing 45-90 kg, undergoing laparoscopic gynecological surgery, were randomized into 3 groups (n = 30 each): LMA Supreme group (group S), LMA ProSeal group (group P)and LMA I-gel group (group I). Mallampatti test was performed before operation for each case. Anesthesia was induced with target-controlled infusion. After the patients lost consciousness, rocuronium 0.6 mg/kg was given to facilitate the LMA insertion. LMA Supreme, LMA ProSeal and LMA I-gel were inserted in S, P and I groups respectively. A gastric tube was inserted through the drain tube of the LMA. The LMA placement time, the number of attempts of LMA insertion, the number of attempts of gastric tube placement, the airway sealing pressure, the parameters of ventilation, and complications (sore throat, odynophagia, hoarseness, regurgitation of gastric contents, LMA with adhesion of blood)were recorded. The fiberoptic laryngoscopy scores were assessed after LMA placement. The anesthesia time and recovery time were also recorded. RESULTS: There was no significant difference in the anesthesia time, recovery time, fiberoptic bronchoscopy scores among the three groups (P > 0.05). Parameters of ventilation in each group were normal. The success rates of LMA and gastric tube placement were 100% in each group. The airway sealing pressure in S, P and I groups were 25 +/- 5 cm H2O, 32 +/- 5 cm H2O, 30 +/- 6 cm H2O respectively, the airway sealing pressure was significantly higher in group P and group I, compare with group S (P < 0.05). The LMA placement time in S, P and I groups were 8 +/- 4s, 10 +/- 5s, 8 +/- 3s respectively, while the incidence of sore throat were 17%, 20%, 3%. The LMA placement time was significantly shorter and the incidence of sore throat was significantly lower in group I than in group P (P < 0.05). CONCLUSIONS: The three LMA can all be used effectively for gynecological laparoscopic surgery. LMA I-gel and LMA ProSeal can provide higher airway sealing pressure. LMA I-gel provides adequate ventilation during operation with fewer complications. PMID- 24169249 TI - [Clinical features and acid alpha-glucosidase gene mutation in 7 Chinese patients with glycogen storage disease type II]. AB - OBJECTIVE: To explore the clinical features and acid alpha-glucosidase (GAA) gene mutations of Chinese patients with glycogen storage disease typeII(GSDII). METHODS: Seven patients with GSDII were diagnosed by muscle pathology examination at Department of Neurology, Peking University First Hospital from 2003 to 2011. One patient with infant-onset presented development retardation, generalized muscle weakness, dyspnea, cardiomegaly and hepatomegaly. Six cases were of late onset ranging from 1 to 29 years. Their main clinical features included progressive muscle weakness. Two patients developed respiratory insufficiency. Increased serum creatine kinase was detected in all of them. Electromyography studies showed myopathic (n = 5) and neuropathic (n = 1) changes. Muscle biopsies showed basophilic vacuoles in muscle fibers containing a large amounts of glycogen on electron microscopy. GAA gene mutation was detected by direct sequencing of polymerase chain reaction (PCR) product. Novel mutations were screened in 100 normal controls. RESULTS: GAA gene mutations were found in all of them, including 10 point mutations and 1 frameshift deletion. Six mutations (p. P361L, p. P266S, p.R437C, p.R600C, p.W746S and p.W746*) have been reported before. And five novel mutations (p.R168Q, p.R168P, p.E521V, p.R594H and c.827_845del) were found in this study. None of these novel mutations were found in 100 normal controls except for p.R168Q mutation in two normal controls. p. P361L and p.W746* were detected in two unrelated GSDII patients while other mutations were carried by only one patient. CONCLUSIONS: In our study, we found several novel GAA mutations in Chinese patients with GSDII. No hot spot mutation of GAA gene existed in our patient group. However, p. P266S, p. P361L and p.R437C might be associated with late-onset GSDII. PMID- 24169250 TI - [Umbilicus metastasis in patients with epithelial ovarian cancer : clinical features of 21 patients]. AB - OBJECTIVE: To analyze the clinical features, treatments and prognosis of patients with Sister Mary Joseph's nodule of umbilicus (SMJN) from epithelial ovarian cancer (EOC) patients. METHODS: Among a total of 2642 pathologically diagnosed EOC cases, 21 cases with SMJN were histopathologically diagnosed and had an age range of 40-66 years at Sun Yat-sen University Cancer Center between January 1991 and January 2011. Their clinical data were retrospectively analyzed. RESULTS: The incidence of SMJN in EOC was 0.79 %. The 1, 2 and 5-year survival rates were 61.8%, 26.8% and 9.5% respectively. The diagnosis was confirmed via local excision biopsy, fine-needle aspiration biopsy or gross pathological diagnosis. Univariate analysis showed that patients with progressive disease or relapsing with umbilical metastasis after treatment had worse prognosis than those diagnosed at pre-treatment (22 vs 6 months, P < 0.01) . Patients with suboptimal cytoreductive surgery and/or less than 6 circles of chemotherapy or palliative treatment had worse prognosis than those with optional cytoreductive surgery during 6-8 circles of chemotherapy (21 vs. 4 months). Multivariate analysis showed that the time to diagnose and treatment regimen were independent predictors of survival (relative risk = 41.28, P < 0.01). CONCLUSIONS: SMJN is a rare manifestation of EOC. Improving the diagnostic vigilance, optimal debulking surgery plus regular chemotherapy and other new individualized postoperative treatments may arrest the progression of EOC and prolong patient survival. PMID- 24169251 TI - [Expression and significance of ACE2-Ang-(1-7)-Mas axis in the endometrium of patients with polycystic ovary syndrome]. AB - OBJECTIVE: To explore the expression of renin-angiotensin system component (ACE AngII-AT1/AT2 & ACE2-Ang-(1-7)-Mas) in endometrium of polycystic ovary syndrome (PCOS) patients and normal controls. METHODS: Thirty cases of normal endometrium in proliferative and secretory phases respectively were selected for the protein levels of AngII, AT1, AT2, ACE2, Ang-(1-7) and Mas through immunohistochemistry. And the specimens of proliferative endometrium from 15 PCOS patients and 15 normal controls respectively were prepared for the expressions of AT1, AT2, ACE2 and Mas mRNA through relative quantitative -polymerase chain reaction (RQ-PCR). The histological phases of endometria were confirmed by hematoxylin & eosin staining under microscope. RESULTS: The expressions of AngII, AT1R, AT2R, ACE2, Ang-(1-7) and Mas showed periodical changes in endometrium throughout normal menstrual cycles and shared a similar trend. The expression was more pronounced in epithelial cells than that in stromal cells while it was also more dramatic in secretory phase than proliferative phase; The mRNA expressions of AT1, AT2, ACE2 and MAS were higher in PCOS endometrium than those in normal controls. Statistically significant differences existed between two groups (P < 0.01). CONCLUSIONS: There is local existence of RAS in endometrium; Increased expressions of AT1 mRNA, AT2 mRNA, ACE2 mRNA and Mas mRNA in endometrium of PCOS may influence endometrial development and play a role in the pathological process of PCOS. PMID- 24169252 TI - [Short-segment fixation of thoracolumbar burst fractures using pedicle fixation at the level of fracture in patients with osteoporosis]. AB - OBJECTIVE: To evaluate the curative effect of short-segment transpedicular fixation plus vertebra fracture fixation for thoracolumbar burst fractures in patients with osteoporosis. METHODS: The clinical data of thoracolumbar burst fractures in 46 patients with osteoporosis, single segment fracture and neurological intactness were analyzed retrospectively from January 2008 to January 2012. There were 20 males and 26 females with a mean age of 64.5 (56-78) years. The mechanisms of injury were fall (n = 20), traffic accident (n = 12), high falling injury (n = 8) and heavy pound injury (n = 4). The involved vertebrae included T11 (n = 5); T12 (n = 17); L1 (n = 21); L2 (n = 3). Pedicle screw was inserted into injured vertebra and the height of collapsed vertebra fractures reduced with position and instrument. Visual analogue scale (VAS) and short form-36 scoring systems were used to evaluate pain level and quality of life. The height restoration and kyphotic correction rates of fracture level were measured radiologically. RESULTS: All patients underwent surgery safely without severe complications. The average follow-up period was 20.5 (9-48) months. There was significant difference (t = 20.057, P = 0.000; t = 24.287, P = 0.000) in VAS score between last follow-up (3.09 +/- 1.01) and post-operation (2.35 +/- 1.02) versus pre-operation (7.22 +/- 1.05) respectively. And also there was significant difference (P < 0.05) in SF-36 score between last follow-up (126.5 +/- 22.3) and post-operation (96.7 +/- 17.5). The Cobb angle was corrected to (5.6 +/- 1.9) degrees of post-operation and (7.8 +/- 3.3) degrees of last follow-up. The loss rate of vertebral was (4.8 +/- 5.2)% of post-operation and (7.6 +/- 2.9) % of last follow-up. There was no loosening or breakage of internal fixations. CONCLUSIONS: The approach of short-segment transpedicular fixation plus vertebra fracture fixation is both safe and effective to maintain reduction and reduce the rate of correction loss and instrument failure. PMID- 24169253 TI - [Role of the CX3CR1/ERK5 pathway in spinal microglia for the development of neuropathic pain]. AB - OBJECTIVE: To explore the role of spinal microglial CX3CR1/ERK5 pathway in the development of neuropathic pain. METHODS: The model of spinal nerve ligation (SNL) was established by ligating the L5 spinal nerve with 6-0 silk thread in male Sprague Dawley rats. The expression of activated ERK5 (p-ERK5) was examined by immunohistochemistry test. To detect the role of ERK5 in neuropathic pain, PWT and PWL were measured after an intrathecal knockdown of ERK5. For determining the regulating effect of CX3CL1/CX3CR1 on the activity of microglial ERK5, CX3CR1 was blocked by an intrathecal injection of anti-rat CX3CR1 antibody and the activity of spinal ERK5 tested. Then whether an intrathecal knockdown of ERK5 could reverse the effect of CX3CL1 on pain hypersensitivity and microglia activation was investigated. RESULTS: ERK5 was activated in spinal microglia after SNL compared to the sham group (61.75 +/- 11.52 vs 2.2 +/- 0.12; 58.01 +/- 10.45 vs 1.1 +/- 0.11) . The knockdown of ERK5 by an intrathecal injection of antisense oligonucleotides suppressed the mechanical (15.42 +/- 3.46 vs 22.73 +/- 3.21g; 13.63 +/- 2.88 vs. 21.42 +/- 4.12g) and thermal hyperalgesia (13.48 +/- 2.01) vs (18.05 +/- 3.71) s; (11.6 +/- 2.33) vs (17.73 +/- 1.42) s induced by nerve injury. The blockage of CX3CR1, a receptor of CX3CL1, significantly reduced the level of ERK5 activation following SNL (30.12 +/- 8.60) vs (58.25 +/- 11.5); (49.5 +/- 12.12) vs (35.51 +/- 3.74) (P < 0.05). In addition, the antisense knockdown of ERK5 reversed the CX3CL1-induced hyperalgesia and spinal microglia activation. CONCLUSIONS: CX3CL1/CX3CR1 regulates nerve injury-induced pain hypersensitivity through ERK5. PMID- 24169254 TI - [Relationship between Golgi apparatus and cell migration direction in vivo and in vitro]. AB - OBJECTIVE: To explore the relationship between Golgi apparatus and the direction of tumor cell migration in vivo and in vitro. METHODS: Cell migration assays were conducted with rat C6 glioma cells, human U251 and SNB19 glioma cells respectively. Then immunofluorescence was used to detect the position of Golgi apparatus in migrating cells. The percentage of cells with Golgi apparatus facing towards wound edge was calculated. Cell pseudopodium was stained with TRITC phalloidin and the relationship between Golgi apparatus and pseudopodium detected. Immunohistochemistry was used to reveal the Golgi apparatus in tumor tissue samples. And the percentage of cells with Golgi apparatus facing opposite to the necrotic zones was calculated. RESULTS: In cells located at wound edge, the Golgi apparatus was found facing towards the wound in the vast majority of cells (C6 83% +/- 6%, U251 80% +/- 7%, SNB19 82% +/- 6%). In U251 and SNB19 cells, the golgi apparatus was located in the same direction with cellular pseudopodium. Immunohistochemical staining showed that in cells located around the necrotic zone, the Golgi apparatus faced opposite to the necrotic zones in most cells (rat tissue samples 80% +/- 7%, human tissue samples 82% +/- 6%). CONCLUSIONS: The Golgi apparatus is closely correlated with cell migration and it may be considered as a direction indicator of cell migration. And it provides an important index for the study of tumor cell invasion both in vivo and in vitro. PMID- 24169256 TI - A novel computer test to assess driving-relevant cognitive functions--a pilot study. AB - BACKGROUND: The assessment of driving-relevant cognitive functions in older drivers is a difficult challenge as there is no clear-cut dividing line between normal cognition and impaired cognition and not all cognitive functions are equally important for driving. METHODS: To support decision makers, the Bern Cognitive Screening Test (BCST) for older drivers was designed. It is a computer assisted test battery assessing visuo-spatial attention, executive functions, eye hand coordination, distance judgment, and speed regulation. Here we compare the performance in BCST with the performance in paper and pencil cognitive screening tests and the performance in the driving simulator testing of 41 safe drivers (without crash history) and 14 unsafe drivers (with crash history). RESULTS: Safe drivers performed better than unsafe drivers in BCST (Mann-Whitney U test: U = 125.5; p = 0.001) and in the driving simulator (Student's t-test: t(44) = -2.64, p = 0.006). No clear group differences were found in paper and pencil screening tests (p > 0.05; ns). BCST was best at identifying older unsafe drivers (sensitivity 86%; specificity 61%) and was also better tolerated than the driving simulator test with fewer dropouts. CONCLUSIONS: BCST is more accurate than paper and pencil screening tests, and better tolerated than driving simulator testing when assessing driving-relevant cognition in older drivers. PMID- 24169255 TI - The future of uveitis treatment. AB - Uveitis is a heterogeneous collection of diseases with polygenic and environmental influences. This heterogeneity presents challenges in trial design and selection of end points. Despite the multitude of causes, therapeutics targeting common inflammatory pathways are effective in treating diverse forms of uveitis. These treatments, including corticosteroids and immunomodulatory agents, although often effective, can have untoward side effects, limiting their utility. The search for drugs with equal or improved efficacy that are safe is therefore paramount. A mechanism-based approach is most likely to yield the future breakthroughs in the treatment of uveitis. We review the literature and provide examples of the nuances of immune regulation and dysregulation that can be targeted for therapeutic benefit. As our understanding of the causes of uveitis grows we will learn how to better apply antibodies designed to block interaction between inflammatory cytokines and their receptors. T-lymphocyte activation can be targeted by blocking co-stimulatory pathways or inhibiting major histocompatibility complex protein interactions. Furthermore, intracellular downstream molecules from cytokine or other pathways can be inhibited using small molecule inhibitors, which have the benefit of being orally bioavailable. An emerging field is the lipid-mediated inflammatory and regulatory pathways. Alternatively, anti-inflammatory cytokines can be provided by administering recombinant protein, and intracellular "brakes" of inflammatory pathways can be introduced potentially by gene therapy. Novel approaches of delivering a therapeutic substance include, but are not limited to, the use of small interfering RNA, viral and nonviral gene therapy, and microparticle or viscous gel sustained-release drug-delivery platforms. PMID- 24169257 TI - Migrants' healthcare: who pays? PMID- 24169258 TI - 0.4% dimeticone spray, a novel physically acting household treatment for control of cat fleas. AB - The cat flea, Ctenocephalides felis, is the most important ectoparasite of cats and dogs worldwide as a cause of irritation and health problems. Most products to control these pests in the household environment rely upon a combination of neurotoxic insecticides and insect growth regulators to inhibit development of flea eggs and larvae into adults. However, some of these are affected by problems of insecticide resistance as well as public concerns about their potential for toxicity in domestic use. Heavy synthetic oils, like the siloxane dimeticone, are currently widely used to treat human ectoparasite infestations, acting by a physical mode of action, and have been used in a variety of presentations for killing all life stages of fleas. We have investigated the activity of low concentrations of high molecular weight dimeticone in a volatile silicone base for ability to immobilise flea life stages without asphyxiating them. We found that cat flea adults and larvae were immobilised by a surface film of dimeticone that inhibited movement of cuticular joints, apparently forming an effective sticky trap. When cocoons were treated the fleas continued to develop within the pupae but failed to emerge. An aerosol spray incorporating 0.4% concentration of dimeticone, for use as a residual household treatment, showed no significant difference in knock down capability compared with that of a widely used pyriproxifen/permethrin spray in a repeat challenge test, with effects persisting to inhibit adult flea emergence in the test arena area for more than 3 weeks after application. PMID- 24169259 TI - A phase II trial of saracatinib, an inhibitor of src kinases, in previously treated advanced non-small-cell lung cancer: the princess margaret hospital phase II consortium. AB - BACKGROUND: The src family of kinases may play a role in the malignant phenotype through effects on migration, motility, adhesion and proliferation. The activity of saracatinib, an orally available inhibitor of src kinases, was evaluated in patients with advanced, platinum-pretreated NSCLC. PATIENTS AND METHODS: Eligible patients with advanced NSCLC of any histologic subtype and who had obtained a best response to prior platinum-based chemotherapy of at least stable disease received saracatanib 175 mg orally daily in a 28 day cycle. The primary end point was the proportion of patients progression-free after 4 cycles (16 weeks) of therapy; 8 such patients of 32 evaluable were required to deem the therapy active. Immunohistochemistry for src expression was performed on archival tissue from enrolled patients. RESULTS: Thirty-seven patients received a median of 2 cycles (range, 1-14) each. Six of 31 evaluable patients were progression-free at 16 weeks. Two partial responses were observed, lasting 3.7 and 14.6 months; 1 responder had an EGFR exon 19 deletion. An additional 4 patients had stable disease for at least 4 cycles. The median progression-free and overall survival times were 1.8 and 7.6 months. No correlation between src protein expression and outcome was observed. CONCLUSIONS: There may be a subset of saracatinib responsive NSCLC that is currently molecularly undefined. Further studies of this agent in a population preselected for target mutations that potentially relevant to src pathways, such as EGFR, should be considered. PMID- 24169260 TI - Mutation of TP53 and alteration of p14(arf) expression in EGFR- and KRAS-mutated lung adenocarcinomas. AB - BACKGROUND: In lung adenocarcinoma, inactivation of the tumor suppressor p53 may abrogate a safeguard mechanism preventing the development of tumors with activating mutations in EGFR or KRAS. To assess this hypothesis, we analyzed TP53 mutations and downregulation of p14(arf), a negative regulator of p53 activated by oncogenic signals, in a retrospective series of 96 patients with primary adenocarcinoma of the lung. PATIENTS AND METHODS: Mutations in TP53 (exons 4-9), KRAS (exon 1), and EGFR (exons 18-21) were identified by direct sequencing of DNA from formalin-fixed, paraffin-embedded resected tumors. Expression of p14(arf) was semiquantitatively evaluated by immunohistochemical analysis. RESULTS: TP53, KRAS, and EGFR mutations were detected in 42 of 93 (45.2%), 15 of 95 (15.8%), and 31 of 90 (34.4%) cases, respectively. Low p14(arf) expression was observed in 19 of 91 cases (20.9%). Disruption of the p53/p14(arf) pathway (defined as TP53 mutation or decreased p14(arf) expression, or both) was observed in 18 of 31 EGFR mutated (58.1%) tumors and in 9 of 13 KRAS-mutated (69.2%) tumors. CONCLUSION: Inactivation of the p53/p14(arf) pathway is common but not systematic in EGFR- or KRAS-mutated lung adenocarcinomas. Our work highlights the need to better investigate the association between EGFR and KRAS mutations and alterations in tumor suppressor pathways. PMID- 24169261 TI - Genetic association of G896A polymorphism of TLR4 gene in leprosy through family based and case-control study designs. AB - BACKGROUND: Polymorphisms in TLR4 may change the function of the protein and alter the efficiency of immune response of host to infection. The high relevance of host gene polymorphisms with outcome of Mycobacterium leprae infection led us to study the genetic association of TLR4 G896A polymorphism in order to identify its risk among contacts of affected leprosy patients. METHODS: For case-control study design a total of 628 individuals were recruited; 17 multicase leprosy families which included 32 case-parent trios were considered for family-based study. Genotyping was done using PCR-RFLP method. RESULTS: In case-control study AA genotype was positively associated while GA genotype was negatively associated with leprosy. In family based transmission disequilibrium test (TDT) analysis allele G was found to be over transmitted to the affected individuals. CONCLUSION: Case-control study suggests that homozygous AA genotype may confer susceptibility and heterozygous GA genotype may confer resistance to leprosy, while allele A was observed to increase risk and that of allele G may confer resistance to leprosy. No strong transmission disequilibrium was detected in family-based TDT analysis, possibly due to lower number of trios. In contrast to case-control data allele G was over transmitted to the affected ones in TDT analysis. To conclude, the frequencies of genotypes in household contacts were almost the same as in leprosy patients, suggesting that contacts with AA genotype may be at higher risk of leprosy and may therefore require prophylactic inputs. PMID- 24169262 TI - The use of the brown macroalgae, Sargassum flavicans, as a potential bioindicator of industrial nutrient enrichment. AB - Nutrient bioindicators are increasingly being recognised as a diagnostic tool for nutrient enrichment of estuarine and marine ecosystems. Few studies, however, have focused on field translocation of bioindicator organisms to detect nutrient discharge from industrial waste. The brown macroalgae, Sargassum flavicans, was investigated as a potential bioindicator of nutrient-enriched industrial effluent originating from a nickel refinery in tropical north-eastern Australia. S. flavicans was translocated to a number of nutrient enriched creek and oceanic sites over two seasons and assessed for changes in stable isotope ratios of (15)N and (13)C within the plant tissue in comparison to reference sites. Nutrient uptake in macroalgae, translocated to the nutrient enriched sites adjacent to the refinery, increased 3-4-fold in delta(15)N, compared to reference sites. Using delta(15)N of translocated S. flavicans proved to be a successful method for monitoring time-integrated uptake of nitrogen, given the current lack of passive sampler technology for nutrient monitoring. PMID- 24169263 TI - Promoting quality breast cancer care: psychosocial distress screening. AB - OBJECTIVE: To evaluate the feasibility of implementing psychosocial distress screening in a breast center of a comprehensive cancer center, using a model of structure (personnel, resources), process (screening), and outcome (number of patients screened, number referred). METHODS: The first step in the project was to establish administrative support, educate and engage breast center staff, identify stakeholders and persons with expertise in the conduct of evidence based initiatives. A two-phase implementation approach was agreed upon with Phase I being screening of new patients in surgical oncology and Phase II being screening women in medical oncology. RESULTS: A total of 173 patients were screened. The new patients screened in surgical oncology reported higher average distress scores compared to patients in medical oncology (5.7 vs. 4.0). However, a greater number of patients in medical oncology reported scores >4 compared to the new patients screened in surgery (54% vs. 35%). Psychological distress was the most commonly reported distress for patients in surgery. In contrast, 60% of scores >4 in medical oncology were symptom related, managed by the nurse or physician. SIGNIFICANCE OF RESULTS: Nurse led implementation of psychosocial distress screening is feasible, addressing this important quality indicator of patient centered care. PMID- 24169264 TI - [Alarm systems for the detection of patients at risk. Clinical and healthcare repercussions]. PMID- 24169265 TI - [Hashimoto's encephalitis, report of a case]. PMID- 24169266 TI - Co-phenylcaine Forte spray: innovative ways of minimising cost. AB - OBJECTIVE: To investigate whether multiple-use Co-phenylcaine Forte(r) spray was more cost-effective than single-use vials. METHODS: A literature review was conducted to determine the risk of cross-contamination associated with multiple use topical nasal anaesthetic spray. The costs of multiple-use Co-phenylcaine Forte and single-use co-phenylcaine were compared, and potential savings were calculated. The cost of procuring these drugs from other sources was also examined. RESULTS: Switching to multiple-use Co-phenylcaine Forte spray would lead to at least 40 per cent savings if bought from our local retailer. Potential savings of more than 70 per cent could be made if the drugs were procured from sources other than our local distributor. CONCLUSION: Multiple-use Co-phenylcaine Forte spray is safe to use and more cost-effective than single-use vials. This paper illustrates how money can be saved within the National Health Service through changes in drug procurement. Similar cost savings to those calculated for our department could be made in other ENT departments nationally, depending on their annual consumption of co-phenylcaine. PMID- 24169269 TI - Classical hodgkin lymphoma as de novo B-cell malignancy after treatment of multiple myeloma in the pre-lenalidomide era. PMID- 24169268 TI - The development of a myeloablative, reduced-toxicity, conditioning regimen for cord blood transplantation. AB - Cord blood transplantation is being used with increasing frequency for patients with high-risk hematologic malignancies. Myeloablative preparative regimens provide antitumor efficacy and facilitate engraftment but are associated with higher morbidity and nonrelapse mortality rates than nonablative regimens. We evaluated 3 sequential myeloablative regimens in the cord blood transplant setting. Regimen 1 (melphalan, fludarabine, and thiotepa) produced prompt engraftment and minimal engraftment failure but was associated with a high nonrelapse mortality rate. Regimen 2 (busulfan and fludarabine) was very well tolerated but was associated with a high rate of engraftment failure and relapse. Regimen 3 (busulfan, clofarabine, fludarabine, and low-dose total body irradiation given 9 days after the chemotherapy) was associated with a low rate of engraftment failure but was logistically difficult to administer. Finally, regimen 3 that included the total body irradiation given immediately after the chemotherapy was well tolerated, with prompt engraftment and tumor control. This latter regimen appears to be effective in preliminary studies and warrants further evaluation. PMID- 24169270 TI - Incidence and trends of stroke and its subtypes in Changsha, China from 2005 to 2011. AB - During the 1990s no significant changes were found for the high incidence of ischemic stroke (IS) in Changsha, in contrast to the increase observed in Beijing and Shanghai. However, the epidemiological patterns of stroke may change with economic development. This study aimed to examine the characteristics of stroke incidence transition in Changsha from 2005 to 2011. In 2007 two communities with a registered population of about 100,000 were selected and data from stroke patients who presented between 2005 and 2007 were retrospectively collected from January to June 2008. From January to December 2007 a stroke surveillance network was established and stroke patients who presented between 2008 and 2011 were prospectively registered. From 2005 to 2011 the mean annual age-adjusted incidence of first-ever stroke was 168.5/100,000 (95% confidence interval [CI] 159.0-178.0/100,000), with 189.3/100,000 (95% CI 175.1-178.0/100,000) for men and 148.7/100,000 (95% CI 136.0-161.4/100,000) for women. The mean annual age adjusted incidence of IS, intracranial hemorrhage and subarachnoid hemorrhage was 72.6/100,000 (95% CI 66.3-78.9/100,000), 85.1/100,000 (95% CI 78.3-91.9/100,000) and 9.4/100,000 (95% CI 7.1-11.7/100,000), respectively. During the study period, the age-adjusted incidence of stroke increased at an annual rate of 3.7% (p=0.001); at 4.2% for men (p=0.001) and 3.1% for women (p=0.026). The age adjusted incidence of IS increased at an annual rate of 3.5% (p=0.003) but no significant changes were seen for hemorrhagic stroke. Characteristics of stroke incidence transition may reflect underlying changes in risk factors and there is an urgent need to identify these factors and launch appropriate public health campaigns. PMID- 24169271 TI - Clinico-radiological spectrum in enterovirus 71 infection involving the central nervous system in children. AB - Enterovirus 71 infection causes hand, foot and mouth disease in children, and can produce diverse neurologic complications. Epidemics occurring in Korea between 2009 and 2012 resulted in the death of some patients. The present study aimed to clarify the correlation between clinical features and MRI findings in patients presenting with acute neurologic manifestations related to enterovirus 71 infection. Based on their clinical features, the patients were classified into four clinical groups: (1) brainstem encephalitis (n=17), characterized by myoclonus, tremor, ataxia, and autonomic dysregulation such as pulmonary hemorrhage; (2) aseptic meningitis (n=2); (3) encephalitis (n=2), characterized by decreased consciousness, seizure, and fever without myoclonus, tremor, ataxia, and autonomic dysregulation; and (4) acute flaccid paralysis (n=1). Thirteen of the 17 patients with brainstem encephalitis showed characteristic lesions in the dorsal brainstem and bilateral cerebellar dentate nuclei on brain MRI, whereas three had no abnormality. One of the two patients with meningitis had a small lesion in the left dorsal pons. Two patients with encephalitis had no apparent MRI abnormality. One patient with acute flaccid paralysis of the right leg had contrast-enhancement of the bilateral ventral nerve roots at the lumbar spine level on MRI. Five of 13 patients with lesions in the bilateral dentate nuclei of the cerebellum exhibited no cerebellar symptoms, while two with no cerebellar lesions developed ataxia. Although most patients presenting with neurologic manifestations of enterovirus 71 infection had characteristic clinical features together with typical MRI findings, the clinical features were not necessarily consistent with MRI findings. PMID- 24169272 TI - Non-celiac wheat sensitivity as an allergic condition: personal experience and narrative review. AB - OBJECTIVES: Non-celiac wheat sensitivity (NCWS) is a newly described clinical entity characterized by symptoms, which can involve the gastrointestinal tract, the nervous system, the skin, and other organs. There is little data on the pathogenesis of NCWS and it is probable that different pathogenic mechanisms are involved in the different clinical manifestations of the disease. The only common denominator of NCWS "syndrome" is wheat consumption: the symptoms disappear on exclusion of wheat from the diet, and reappear on wheat consumption. The objective of this study was to review our prior data regarding NCWS and to review relevant medical literature regarding NCWS, with particular attention to the hypothesis that NCWS patients could suffer from non-immunoglobulin E (IgE) mediated wheat allergy. METHODS: We reviewed our data on 276 patients diagnosed with NCWS by means of double-blind placebo-controlled (DBPC) wheat challenge. The data indicating a possible wheat allergy diagnosis were examined and other data in the literature were reviewed; we review the role of serum immunoglobulin G antibodies and the basophil activation assay in food allergy, and the histology findings in the food allergy diagnosis. RESULTS: The comparison between patients suffering from NCWS and presenting with irritable bowel syndrome (IBS) and controls with IBS not due to NCWS showed that NCWS was characterized by: a personal history of food allergy in the pediatric age (0.01), coexistent atopic diseases (0.0001), positive serum anti-gliadin (0.0001) and anti betalactoglobulin (0.001) antibodies, positive cytofluorimetric assay revealing in vitro basophil activation by food antigens (0.0001), and a presence of eosinophils in the intestinal mucosa biopsies (0.0001). CONCLUSIONS: Patients with NCWS and multiple food sensitivity show several clinical, laboratory, and histological characteristics that suggest they might be suffering from non-IgE mediated food allergy. However, other pathogenic mechanisms need to be considered. PMID- 24169273 TI - Machine learning algorithms outperform conventional regression models in predicting development of hepatocellular carcinoma. AB - OBJECTIVES: Predictive models for hepatocellular carcinoma (HCC) have been limited by modest accuracy and lack of validation. Machine-learning algorithms offer a novel methodology, which may improve HCC risk prognostication among patients with cirrhosis. Our study's aim was to develop and compare predictive models for HCC development among cirrhotic patients, using conventional regression analysis and machine-learning algorithms. METHODS: We enrolled 442 patients with Child A or B cirrhosis at the University of Michigan between January 2004 and September 2006 (UM cohort) and prospectively followed them until HCC development, liver transplantation, death, or study termination. Regression analysis and machine-learning algorithms were used to construct predictive models for HCC development, which were tested on an independent validation cohort from the Hepatitis C Antiviral Long-term Treatment against Cirrhosis (HALT-C) Trial. Both models were also compared with the previously published HALT-C model. Discrimination was assessed using receiver operating characteristic curve analysis, and diagnostic accuracy was assessed with net reclassification improvement and integrated discrimination improvement statistics. RESULTS: After a median follow-up of 3.5 years, 41 patients developed HCC. The UM regression model had a c-statistic of 0.61 (95% confidence interval (CI) 0.56-0.67), whereas the machine-learning algorithm had a c-statistic of 0.64 (95% CI 0.60-0.69) in the validation cohort. The HALT-C model had a c-statistic of 0.60 (95% CI 0.50 0.70) in the validation cohort and was outperformed by the machine-learning algorithm. The machine-learning algorithm had significantly better diagnostic accuracy as assessed by net reclassification improvement (P<0.001) and integrated discrimination improvement (P=0.04). CONCLUSIONS: Machine-learning algorithms improve the accuracy of risk stratifying patients with cirrhosis and can be used to accurately identify patients at high-risk for developing HCC. PMID- 24169274 TI - Longitudinal and radial characteristics of intra-anal pressures in children using 3D high-definition anorectal manometry: new observations. AB - OBJECTIVES: The pathophysiology of fecal incontinence is not well understood. Standard or high-resolution anorectal manometry (ARM) provides simple two dimensional (2D) intra-anal pressure measurements and do not identify radial asymmetry or localize abnormal sphincter function. 3D high-definition ARM (HDARM) has 256 pressure sensors distributed circumferentially and provides a detailed topographical and 3D pressure gradient representation of the anal canal. The objective of this study was to use HDARM to characterize intra-anal pressure profiles in children during rest and squeeze. METHODS: HDARM manometric tracings of 30 children with constipation referred for ARM were reviewed. 2D pressure profiles using high-resolution manometry were used to measure the length of the high-pressure zone (HPZ). The HPZ was divided into four equal segments from the anal verge to adjust for the variable sphincter length. Longitudinal and radial measurements of the HPZ during rest and squeeze (anterior, left, posterior, right quadrants of the HPZ) were taken along each segment in 2D and 3D topographical views. A 3D reconstruction combining all patients was then constructed. RESULTS: Mean age was 149.3+/-1.8 months and mean HPZ length was 3.0+/-0.1 cm. Using 2D manometry, the mean peak HPZ pressure at rest was 72.0+/-2.5 mm Hg, and was located in the second segment of the HPZ. The mean peak HPZ pressure at squeeze was 202.9+/-13.1, and was located in the second segment. 3D measurement demonstrated both longitudinal and radial asymmetry along the anterior, left, posterior, and right quadrants of the HPZ. Left and right quadrant pressures were higher than anterior and posterior pressures at the anal verge and segment 1 during rest and squeeze. Anterior pressures were lower than posterior pressures longitudinally and radially in segments 2, 3, and 4 both during rest and squeeze. Our findings also suggest that in pediatrics it may be necessary to adjust pressure measurement to the anal canal length to get a more accurate picture. CONCLUSIONS: 3D HDARM allows for a detailed characterization of intra-anal pressures. 3D topographic pressure measurements demonstrate longitudinal and radial asymmetry of the anal canal at rest and during squeeze. This is the first time longitudinal and radial asymmetry of the anal canal has been described in children. 3D HDARM may allow for a better understanding of the mechanisms of fecal continence in children. PMID- 24169275 TI - Health data use, stewardship, and governance: ongoing gaps and challenges: a report from AMIA's 2012 Health Policy Meeting. AB - Large amounts of personal health data are being collected and made available through existing and emerging technological media and tools. While use of these data has significant potential to facilitate research, improve quality of care for individuals and populations, and reduce healthcare costs, many policy-related issues must be addressed before their full value can be realized. These include the need for widely agreed-on data stewardship principles and effective approaches to reduce or eliminate data silos and protect patient privacy. AMIA's 2012 Health Policy Meeting brought together healthcare academics, policy makers, and system stakeholders (including representatives of patient groups) to consider these topics and formulate recommendations. A review of a set of Proposed Principles of Health Data Use led to a set of findings and recommendations, including the assertions that the use of health data should be viewed as a public good and that achieving the broad benefits of this use will require understanding and support from patients. PMID- 24169276 TI - Validating a strategy for psychosocial phenotyping using a large corpus of clinical text. AB - OBJECTIVE: To develop algorithms to improve efficiency of patient phenotyping using natural language processing (NLP) on text data. Of a large number of note titles available in our database, we sought to determine those with highest yield and precision for psychosocial concepts. MATERIALS AND METHODS: From a database of over 1 billion documents from US Department of Veterans Affairs medical facilities, a random sample of 1500 documents from each of 218 enterprise note titles were chosen. Psychosocial concepts were extracted using a UIMA-AS-based NLP pipeline (v3NLP), using a lexicon of relevant concepts with negation and template format annotators. Human reviewers evaluated a subset of documents for false positives and sensitivity. High-yield documents were identified by hit rate and precision. Reasons for false positivity were characterized. RESULTS: A total of 58 707 psychosocial concepts were identified from 316 355 documents for an overall hit rate of 0.2 concepts per document (median 0.1, range 1.6-0). Of 6031 concepts reviewed from a high-yield set of note titles, the overall precision for all concept categories was 80%, with variability among note titles and concept categories. Reasons for false positivity included templating, negation, context, and alternate meaning of words. The sensitivity of the NLP system was noted to be 49% (95% CI 43% to 55%). CONCLUSIONS: Phenotyping using NLP need not involve the entire document corpus. Our methods offer a generalizable strategy for scaling NLP pipelines to large free text corpora with complex linguistic annotations in attempts to identify patients of a certain phenotype. PMID- 24169277 TI - [Expression of Foxa2 and its early alarm value of cancerous in gastric polyps]. AB - OBJECTIVE: To explore the expression of Foxa2 in different pathological types of gastric polyps and examine the correlation with cancerous risk. METHODS: According to computerize random number, a total of 2000 patients were selected to receive endoscopic biopsy during November 2011 to October 2012. Tissues were harvested from 170 with gastric polyps and suspicious cancerous lesions and their histological types detected. There were hyperplastic polyps(n = 35), adenomatous polyps(n = 31), fundic gland polyps(n = 42), advanced gastric cancer tissues (n = 32)and normal gastric mucosa tissues (n = 30). ABC immunohistochemical staining and reverse transcription(RT)-PCR were employed to detect the expression of Foxa2 in these different types of tissues. Imagepro plus was used for quantitative and statistical analyses. RESULTS: A low-level expression of Foxa2 was 3.6% +/- 1.3% in normal gastric mucosa group. And its expreesion gradually higher in proliferative inflammatory polyp group(33.1% +/- 8.0%), adenomatous polyp group (71.4% +/- 1.7%) and gastric cancer group(96.3% +/- 0.9%, all P < 0.05). Its expression was 35.6% +/- 5.6% in fundic gland polyps, similar to that of proliferative inflammatory polyp group (P > 0.05), it was markedly lower than the gastric cancer group (P < 0.05) and higher than the normal gastric mucosa group (P < 0.05). Correlation analyses of clinicopathological parameters showed that no significant correlation existed between its expression and patient gender, age, predilection, Helicobacter. pylori infection or proton pump inhibitor used (all P > 0.05). However, the size of polyps was correlated with Foxa2 (rs = 0.69, P < 0.05). CONCLUSION: The expression level of Foxa2 in different types of gastric polyps may be used as a clinical predicator of polyps risk. PMID- 24169278 TI - [Expression and prognostic value of galectin-9 in hepatocellular carcinoma patients]. AB - OBJECTIVE: To explore the prognostic value of galectin-9 in patients with hepatocellular carcinoma (HCC). METHODS: Galectin-9 was validated by immunohistochemisty in tissue microarrays from HCC patients (n = 147) and statistically assessed for the prognosis. The serum levels of galectin-9 from another independent cohort including HCC patients (n = 31) were assessed by enzyme-linked immunosorbent assay (ELISA). RESULTS: Patients with a lower expression of galectin-9 had significantly worse prognosis than those with a higher expression. The serum level of galectin-9 of HCC patients (8.36 +/- 2.12) ug/L was significantly lower than that in healthy (4.62 +/- 1.59 )ug/L and liver cirrhosis controls (5.11 +/- 1.92 )ug/L (P < 0.05). Multivariate Cox proportional hazard analysis showed that galectin-9 was an independent marker for predicting a poor prognosis of HCC patients. CONCLUSION: Involved in the poor prognosis of HCC patients, galectin-9 may be a new predictor of recurrence for HCC patients and serve as a high-priority therapeutic target. PMID- 24169279 TI - [Effects of increased body mass index upon laparoscopic radical rectal surgery and its clinical efficacy]. AB - OBJECTIVE: To assess the feasibility, the safety and short-term outcomes of laparoscopic radical rectal surgery for rectal cancer patients with increased body mass index (BMI) . METHODS: Retrospectively data reviews were conducted for 405 consecutive patients undergoing laparoscopic surgery for rectal cancer from June 2008 to June 2012. They were classified as normal-weight (NW, BMI 18.6-22.9 kg/m(2), n = 165), overweight (OW, BMI 23.0-24.9 kg/m(2), n = 125), and obese (OB, BMI >= 25.0 kg/m(2), n = 115)groups according to the categories as proposed by 2007 Chinese Obesity Surgery Treatment Guidelines. The differences of oncologic, intraoperative and postoperative status, postoperative complications, number of resected lymph nodes and short-term survival rates were compared among three groups. The data were analyzed by chi(2) or Fisher exact test. The Mann Whitney U test or analysis of variance (one-way ANOVA) was used for parametric comparisons. The survival curve was drawn by Kaplan Meier method and the survivals of 3 groups were by the Log-rank test. RESULTS: The comorbidity of patients in the NW and OW groups were less than that in the OB group(27.9% (46/165) and 30.4% (38/125) vs 47.0% (54/115), chi(2) = 12.066, P < 0.05). No significant difference existed among the groups in terms of conversion rate (9.1% (15/165), 10.4% (13/125) and 12.2% (14/115)), the rate of postoperative complications (20.6% (34/165), 21.6% (27/125) and 24.3% (28/115) ), intraoperative volume of blood loss ((105 +/- 30), (110 +/- 25) and (115 +/- 45) ml), first flatus( (2.8 +/- 1.2), (2.9 +/- 1.1) and (3.1 +/- 1.4) d), postoperative hospital stays ((13.7 +/- 5.5), (14.3 +/- 7.5) and (14.1 +/- 8.5) d, all P > 0.05), and the mean number of retrieved lymph nodes(P > 0.05). While the operation duration in the OB group were longer than that in the NW and OW groups ((250 +/- 35) vs (205 +/- 20) and (210 +/- 30) min, F = 7.216, P < 0.05) . And 368 patients (90.9%) were followed up for a median of 24 months(2-48 months). As for survival curves, no significant difference existed among three groups (P > 0.05). CONCLUSIONS: It is both safe and feasible for obese patients with increased BMI to undergo laparoscopic radical rectal cancer. And there is no effect upon immediate survival. PMID- 24169280 TI - [Occurrence of complex sleep apnea during continuous positive airway pressure therapy]. AB - OBJECTIVE: To explore the occurrence of complex sleep apnea syndrome in patients with obstructive sleep apnea during continuous positive airway pressure titration and evaluate their polysomnographic characteristics. METHODS: A total of 420 patients with obstructive sleep apnea were recruited to undergo an overnight continuous positive airway pressure titration at the Sleep Medicine Center, West China Hospital from January 2010 to December 2012. Their polysomnographic records of respiratory events, oxygen desaturation events and sleep stages were retrospectively reviewed. RESULTS: The incidence of complex sleep apnea syndrome was 7.9% (33/420) and central apnea index (9.0 +/- 5.1) /h.No significant differences existed in age, gender, body mass index and titration pressure of continuous positive airway pressure between two groups. Compared with those with non-complex sleep apnea, complex sleep apnea patients had significant increases in apnea/hypopnea index (12.8/h vs 3.6/h, P < 0.05) and oxygen desaturation index (10.3/h vs 3.8/h, P < 0.05) which mainly happened in non-rapid eye movement stage. They also showed decreases in total sleep time ((365 +/- 96) vs (402 +/- 77) min), rapid eye movement stage (16% +/- 8% vs 20% +/- 10%) , increases in non rapid eye movement stage 1 (24% +/- 17% vs 15% +/- 13%), wakefulness after sleep onset ((108 +/- 93) vs (79 +/- 61) min) and brief arousal index ((28 +/- 15) vs (20 +/- 12)/h). And the differences were statistically significant (all P < 0.05). CONCLUSIONS: Complex sleep apnea syndrome is common among Chinese patients with obstructive sleep apnea. Compared with those with non-complex sleep apnea, complex sleep apnea patients have reduced sleep time and worse sleep quality during continuous positive airway pressure therapy. PMID- 24169281 TI - [Value of cerebral spinal fluid measurement of hypocretin-1 in the diagnosis of Chinese patients with narcolepsy]. AB - OBJECTIVE: To evaluate the diagnostic value of cerebral spinal fluid (CSF) measurement of hypocretin-1 (hcrt-1) in Chinese patients with narcolepsy. METHODS: A total of 139 narcoleptic patients, including 111 narcolepsy with typical cataplexy (NC) and 28 narcolepsy without cataplexy (NWC), were diagnosed at the sleep centre of Peking University People's Hospital from April 2003 to March 2012. And 64 non-narcoleptic controls were recruited. CSF hcrt-1 levels were measured in all subjects.Receiver operating characteristic curve (ROC) was applied to determine the cutoff value of hcrt-1 for Chinese narcoleptic patients. The diagnostic utility of hcrt-1 <= 110.0 ng/L and hcrt-1 <= 30% of mean normal level defined by International Classification of Sleep Disorders-II and the new Chinese cutoff value were evaluated respectively. RESULTS: The level of hcrt-1 in narcolepsy patients was significantly lower than that of normal controls and the NC group was even lower than NWC group (20 (13, 36) vs 319 (244, 379) and 36 (15, 114) ng/L) (all P < 0.01).Using the international criteria of CSF hcrt-1 <= 110.0 ng/L or a level of 1/3 of mean normal control values, a specificity of 100% and sensitivity of 90.6% were generated.ROC curve indicated that CSF hcrt-1 level of 138.0 ng/L was the best cutoff value for the diagnosis of narcolepsy in Chinese narcoleptic patients. There were a specificity of 100%, a sensitivity of 92.8% and the area under the ROC curve of 0.98. CONCLUSIONS: CSF hcrt-1 measurement with high specificity and sensitivity is a useful diagnostic tool for Chinese narcoleptics. And the level of 138.0 ng/L may be the optimal cutoff for the diagnosis of narcolepsy in this group of patients. PMID- 24169282 TI - [Etiologic characteristics of adult patients with community-acquired pneumonia in Beijing]. AB - OBJECTIVE: To explore the etiologic characteristics of adult patients with community-acquired pneumonia (CAP) in Beijing. METHODS: A multicenter cohort of 510 adult CAP patients were enrolled from Beijing during the period of November 2010 to May 2012. Multiplex polymerase chain reaction (PCR), real-time fluorescence quantitative PCR and legionella urinary antigen were used to detect common respiratory viruses, Mycoplasma pneumoniae and legionella respectively. Bacteria were detected by sputum culture, blood culture and Streptococcus pneumoniae urinary antigen. Statistical analyses were performed for the etiologic characteristics and seasonal distribution of detected pathogens. RESULTS: Pathogens were detected in 240/500 (47.1%) study patients. The mixed infection of different pathogens was present in 42 cases (8.2%), viruses in 164 (32.2%), Mycoplasma pneumoniae in 91 (17.8%), bacteria in 26 (5.1%) and Legionella in 3 (0.6%). Among 164 patients infected with viruses, 194 viral strains were detected. Influenza virus represented the greatest proportion with 105 (54.1%) in viral infections. Between November 2010 to October 2011, Influenza A infections increased gradually in November 2010, peaked in February 2011 and declined by March 2011 in China. Mycoplasma pneumoniae was predominant in winter and spring. CONCLUSIONS: There is a high detection rate of virus and Mycoplasma pneumoniae in adult CAP patients in Beijing. And more consideration should be given to influenza virus and Mycoplasma pneumoniae infections in winter and early spring. PMID- 24169283 TI - [Correlation of cardiovascular risk factors and cognitive function]. AB - OBJECTIVE: To evaluate the relationship between cardiovascular risk factors and cognitive function in a healthy population. METHODS: A community-based cross sectional study was conducted in Shenyang. The Framingham gender-specific risk equation was employed to evaluate the cardiovascular risk factors, calculate Framingham risk score and estimate the risk of 10-year coronary heart disease (CHD). A total of 505 study subjects were divided into 3 groups according to 10 year CHD risk: low risk(<10%), moderate risk (10%-20%) and high risk groups(>20%). They were also divided into 5 groups according to age; <= 44 year old; 45-54 year old; 55-64 year old; 65-74 year old and >= 75 years old. Clock drawing test and mini-mental state examination (MMSE) were used to evaluate the cognitive function and compare it among different risk groups. And correlation coefficients between Framingham risk score and cognitive function were calculated. RESULTS: Framingham risk score, clock drawing test sore and MMSE score in the low risk group was (2.6 +/- 0.8), (4 +/- 1) and (27 +/- 3). In comparison to low risk group, Framingham risk score increased significantly (P < 0.01), MMSE score(25 +/- 4) decreased significantly (P < 0.01) in moderate risk group, Framingham risk score (9.7 +/- 1.0) increased significantly (P < 0.05) and clock drawing test scores (3 +/- 1) and MMSE scores (23 +/- 4) decreased significantly (P < 0.05) in high risk group; in comparison to moderate risk group, clock drawing test and MMSE scores decreased significantly (P < 0.05) in high risk group. There was a significantly inverse correlation between Framingham risk score and cognitive function. And the Pearson correlation coefficients were 0.196(clock drawing test, P < 0.01) and -0.333 (MMSE, P < 0.01) . CONCLUSIONS: An inverse correlation exists between cardiovascular risk factors and cognitive function in healthy population. With more risk factors and greater severity, Framingham risk score increases while cognitive function decreases. PMID- 24169284 TI - [Effects of allitridi capsules on endothelial function and clinical prognosis after percutaneous coronary intervention in coronary artery disease patients with diabetes mellitus]. AB - OBJECTIVE: To explore the effects of allitridi capsules on endothelial function and clinical prognosis after percutaneous coronary intervention (PCI) in coronary artery disease (CAD) patients with diabetes mellitus (DM). METHODS: A total of 120 CAD patients with DM undergoing PCI were randomly assigned to receive conventional (control, n = 60) and additional allitridi treatment (120 mg/day, n = 60) for 3 months.Serum nitric oxide (NO) and intercellular adhesion molecule 1 (ICAM-1) levels were determined by enzyme-linked immunosorbent assay (ELISA) immediately and at 3 months post-PCI. Endothelial function was assessed by endothelium dependent flow-mediated dilation (FMD). Duration of follow-up was 1 year after PCI. RESULTS: The clinical characteristics, serum NO and ICAM-1 levels and FMD at baseline were not different between two groups. At Month 3 post-PCI, serum NO level was markedly higher ((147 +/- 32) vs (112 +/- 24) umol/L, P = 0.009) and serum ICAM-1 level was significantly lower ((182 +/- 21) vs (232 +/- 29) umol/L, P = 0.021) in the allitridi group than in the control group.Furthermore, treatment of allitridi resulted in a significant improvement of FMD (8.2% +/- 2.4% vs 6.4% +/- 2.3%, P = 0.013). At Year 1 post-PCI, the incidence of major adverse cardiovascular event (MACE) was lower in the allitridi group than that in the control group (10.5% vs 17.2%, P = 0.022). CONCLUSIONS: Allitridi capsules significantly improve the clinical prognosis after PCI in CAD patients with DM. Its mechanism may lies in improved endothelial function and vascular inflammatory state. PMID- 24169285 TI - [Clinical analysis of tuberous sclerosis complex complicated with renal angiomyolipoma: a report of 22 cases]. AB - OBJECTIVE: To explore the diagnosis and treatment of tuberous sclerosis complex complicated with renal angiomyolipoma. METHODS: The clinical data of 22 patients with tuberous sclerosis complex complicated with renal angiomyolipoma were analyzed retrospectively. RESULTS: There were 12 males and 10 females with a mean age of 23 (1-46) years. All of them had bilateral multiple renal angiomyolipomas. The mean tumor size was 8.5 (0.7-18.0) cm in diameter. The presence or absence of clinical symptoms showed a significant correlation with tumor size.Eight patients with angiomyolipoma under 4 cm in diameter were continuously monitored at an outpatient clinic. There were 8 patients with lesions of 4-10 cm.Five of them underwent nephron-sparing surgeries and another 3 monitored at an outpatient clinic. There were 6 patients with tumor over 10 cm. Three of them underwent transcatheter arterial embolization and one case took rapamycin after embolization.One patient with concurrent renal cell carcinoma underwent partial nephrectomy. Chronic renal failure occurred in one case dying of pulmonary lymphangiomyomatosis with serious hemoptysis. During a mean follow-up of 25 months, neither severe renal hemorrhage nor symptomatic aggravation was found.In the case of rapamycin, there was 10% reduction in the size of angiomyolipoma. CONCLUSIONS: Most cases of tuberous sclerosis complex are complicated with bilateral multiple renal angiomyolipoma. The small lesions under 4 cm in diameter may be monitored at an outpatient clinic.For those larger (>4 cm) or symptomatic ones, medication, embolization or surgery is necessary. PMID- 24169286 TI - [Retroperitoneal laparoscopic decortication and adrenalectomy for the therapy of adrenal cysts]. AB - OBJECTIVE: To summarize the clinical characteristics of adrenal cysts and compare the therapeutic results of two different laparoscopic surgical techniques. METHODS: Sixteen patients of adrenal cysts were summarized retrospectively from May 2005 to June 2012. Their clinical manifestations, pathological features, therapeutic effects and prognosis were analyzed. There were 7 males and 9 females aged 39.4 (25-68) years.Eight patients were symptomatic and the others were identified incidentally. They underwent laparoscopic surgery through retroperitoneal space, including adrenalectomy (n = 11) and decortication (n = 5). RESULTS: All were confirmed as adrenal cysts by postoperative pathological examination.It accounted for around 7.5% of adrenal disease treated surgically at our department cutaneous. The diagnostic accuracy of computed tomography and magnetic resonance imaging was 11/16 and 3/3 respectively. The mean diameter of cyst was 5.3 (1-14) cm and no apparent endocrine abnormalities were found. The symptoms of 7/8 patients were relieved after a mean 48 months follow-up.No recurrence was found in this cohort. The average operative duration and estimated volume of blood loss were significantly less in laparoscopic decortication group ( (48 +/- 10) min, (16 +/- 11) ml) than laparoscopic adrenalectomy group ((74 +/- 21) min, (34 +/- 30) ml) . CONCLUSIONS: Laparoscopic surgery is an effective procedure for the treatment of adrenal cysts. And retroperitoneal laparoscopic decortication may be preferred treatment option for large benign adrenal cysts. PMID- 24169287 TI - [Diagnosis and surgical treatment of parathyroid neoplasms]. AB - OBJECTIVE: To explore the clinical features, diagnosis and surgical treatment of parathyroid neoplasms. METHODS: From January 2003 to December 2011, a total of 51 patients were recruited. Their clinical data, presentations, examinations and surgical approaches were analyzed retrospectively. RESULTS: Among them, there were parathyroid adenoma (n = 32), parathyroid cysts (n = 18) and parathyroid carcinoma (n = 1). The sensitivity and positive rate of neck ultrasonography and (99)Tc(m)-methoxyisobutylisonitrile (MIBI) were 84.3% and 93.5%, 91.7% and 100.0% respectively. The high levels of serum calcium and parathyroid hormone (PTH) in 32 cases of parathyroid adenoma and 1 case of parathyroid carcinoma returned to normal after operation. The levels of serum calcium and PTH remained normal in 18 cases of parathyroid cysts. CONCLUSIONS: The clinical manifestations of parathyroid adenoma were complex. The serum levels of calcium and PTH and neck ultrasonography are preferred screening tools for parathyroid neoplasms.(99)Tc(m) MIBI is suitable for tumor localization.Surgery is effective and safe for parathyroid neoplasm.Real time intraoperative monitoring of PTH is of great importance. PMID- 24169288 TI - [Effects of surgical operation on helper-inducer T-lymphocytes in sino-nasal neoplasms patients]. AB - OBJECTIVE: To explore the effects of surgical operation on helper-inducer T lymphocytes (Th1/Th2) in sino-nasal neoplasms. METHODS: From January 2004 to December 2011, 80 patients with malignant tumor in nasal cavities or sinuses were enrolled as experimental group and another 80 subjects with deflection of nasal septum as control group. The phorbol-12-myristate-13-acetate (PMA)-stimulated peripheral blood mononuclear cells (PBMC) were obtained from both malignant tumor and normal control tissues. And flow cytometry was used to detect the expression percentages of interleukin-4 (IL-4) in Th2 cell and interferon-gamma (IFN-gamma) in Th1 cell at pre and post-operation. RESULTS: The preoperative expression percentage of CD3(+) CD8(-) IL-4(+) cell in malignant tumor patients was higher than that in controls (6.6% +/- 1.7% vs 2.8% +/- 1.7%, P < 0.05) while the expression percentage of CD3(+) CD8(-) IFN-gamma(+) cell was lower (18.7% +/- 5.7% vs 59.3% +/- 1.5%, P < 0.05). The preoperative expression percentage of CD3(+) CD8(-) IL-4(+) cell was higher than that at postoperation (6.6% +/- 1.7 %vs 2.8% +/- 1.5%, P < 0.05). And the postoperative expression percentage of CD3(+) CD8(-) IFN-gamma(+) cell was higher than that at preoperation (54.0% +/- 4.0% vs 18.7% +/- 5.7%, P < 0.05). CONCLUSION: Surgery may restore the immune balance in patients with malignant tumors in nasal cavities or sinuses. PMID- 24169289 TI - [Safety analysis of application of medical anti-adhesion modified chitosan in cardiac surgery]. AB - OBJECTIVE: To verify the application safety of medical anti-adhesion modified chitosan (Baifeimi) in cardiac surgery. METHODS: From August to December 2010, 42 patients undergoing surgery for congenital heart disease, valvular heart disease or ischemic heart disease were selected and divided into testing (n = 22) and control (n = 20) groups. After complete intraoperative hemostasis, two sheets of anti-adhesion modified chitosan (Baifeimi) were placed on the surface of heart and vessels in the testing group and then chest was closed. And the control group underwent routine chest closing without an application of Baifeimi. The systemic and local reactions and drainage fluid were observed. The postoperative drainage fluid was subject to bacteria culture. Blood routines and laboratory tests at preoperation and Day 1 and Week 1 postoperation were performed to evaluate the changes of chemical, biological and immunological parameters. RESULTS: There was no occurrence of systemic reaction, local inflammation or exudation.Wounds were healed at Phase I. The drainage fluid of pericardium and mediastina had no significant intergroup difference. Drainage was unobstructed in the testing group. A comparison of two groups revealed that the differences of aspartate aminotransferase ( (24 +/- 17) vs (40 +/- 22) U/L), preoperative and postoperative immunoglobulin A( (1.9 +/- 0.7) vs (2.9 +/- 1.4) g/L, (2.3 +/- 0.9) vs (3.3 +/- 1.5) g/L) were statistically significant (all P < 0.05). But the average values of both group stayed within a normal range without clinical significance while other indices had no significant difference. The bacteria cultures of all patients in the control group were negative. CONCLUSIONS: Anti adhesion modified chitosan is both convenient and safe for clinical application. The duration of cardiac surgery is not extended.No systemic or local adverse event is reported. There is no interference of hepatic, renal or immune functions. PMID- 24169290 TI - [Anti-inflammation of simvastatin by polarization of murine macrophages from M1 phenotype to M2 phenotype]. AB - OBJECTIVE: To explore the effects of statin on pro-inflammatory macrophage phenotype in a murine M1 macrophage model. METHODS: Macrophages isolated from murine bone barrow were stimulated with interferon-gamma (IFN-gamma) and lipopolysaccharide (LPS) to establish a M1 macrophage model. And 1.0, 2.5, 5.0 umol/L of simvastatin were added to M1 macrophages for a 9-hour culture. Cell surface markers CD16/23 and CD206 were detected by fluorescence activated cell sorter (FACS) and interleukin-10 (IL-10) and IL-12 by ELISA. RESULTS: The CD16/32 expression was 86.39% +/- 2.24% and IL-12 secretion (1562 +/- 217) pg/ml in IFN gamma and LPS-stimulated macrophages. After a 9-hour incubation with 1.0, 2.5, 5.0 umol/L simvastatin, the CD206 expression levels were 68.10% +/- 2.48%, 75.28% +/- 1.66%, 86.32% +/- 2.19% and the secretion of IL-10 (500 +/- 5), (675 +/- 28) and (916 +/- 15) pg/ml respectively. By analysis of variance and q test of mean, the difference was statistically significant (all P < 0.01) between the groups of M1 model (9.67% +/- 5.48%, (298 +/- 11) pg/ml) . And the phenotypic features were similar to those of the groups of M2 model. CONCLUSION: Simvastatin may inhibit inflammation by enhancing the switching of M1 macrophage to M2 macrophage phenotype. PMID- 24169291 TI - [Effects of inhibition of Hedgehog signaling pathway for transforming growth factor-beta-induced epithelial-mesenchymal transition]. AB - OBJECTIVE: To elucidate the mechanism of Hedgehog pathway in the metastasis of gastric cancer and examine particularly the effect on epithelial-mesenchymal transition (EMT). METHODS: Using pharmacological and siRNA knockdown approach, the Hedgehog pathway was inhibited. The cellular morphology, protein level, invasion and metastatic abilities were measured by microscope, Western blot, Transwell invasion assay and Transwell migration assay. RESULTS: Under the inhibition of Hedgehog pathway, the invasive and migration abilities of gastric cancer decreased. The transforming growth factor (TGF) -beta could induce spindle like-shaped morphological changes with a down-regulation of epithelial characteristic (decreased E-cadherin protein level) and an up-regulation of mesenchymal characteristics (increased Vimentin protein level). There were concurrent increases of invasive and migration potentials by 3 and 4 folds respectively.However, under the continuous stimulation of TGF-beta, the inhibition of Hedgehog pathway could reverse the EMT changes, lower the expression of vimentin and reduce the invasion and metastatic abilities by 3 and 2 folds respectively. CONCLUSIONS: The inhibition of Hedgehog pathway can decrease the TGF-beta-inducing EMT.It suggests that Hedgehog pathway may play a critical role in the metastasis of gastric cancer. PMID- 24169292 TI - [Detection of carbapenem-producing Enterobacteriaceae by MALDI-TOF MS]. AB - OBJECTIVE: To evaluate a rapid matrix-assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOF MS) assay in detecting carbapenemase producing Enterobacteriaceae. METHODS: Thirty-four carbapenemase-producing Enterobacteriaceae and 50 carbapenem susceptible Enterobacteriaceae clinical isolates were tested. After a 2-hour incubation of bacteria with meropenem, the mixtures were centrifuged and the supernatants analyzed by MALDI-TOF MS. RESULTS: All spectra of carbapenem susceptible Enterobacteriaceae showed peaks of m/z 384, 406, 428 while those of carbapenemase-producing Enterobacteriaceae m/z 358, 380, 402, 424, 446, 468. And the assay of MALDI-TOF MS was highly consistent with sequencing (P = 1.000). CONCLUSION: MALDI-TOF MS can detect carbapenemase producing Enterobacteriaceae rapidly and accurately. PMID- 24169293 TI - [Analysis of 21 cases treated by total laparoscopic rectosigmoid cancer surgery with transanal natural orifice specimen extraction]. AB - OBJECTIVE: To evaluate the feasibility, safety and short-term outcomes of total laparoscopic rectosigmoid cancer surgery with transanal natural orifice specimen extraction. METHODS: From July 2012 to February 2013, 21 patients underwent total laparoscopic surgery with transanal natural orifice specimen extraction. There were 12 males and 9 females with a median age of 53 (48-77) years.Rectal cancer (n = 11) and sigmoid cancer (n = 10) were diagnosed. The clinical data such as bowel function recovery time, number of lymph nodes harvested and an incidence of anastomotic leakage was collected and retrospectively analyzed to assess the value of this technique. RESULTS: Operation was successfully accomplished without conversion into open surgery or conventional laparoscopic-assisted surgery. The median operative duration was 105 (80-165) min, the median volume of blood loss 50 (20-300) ml, the median number of lymph nodes harvested 16(8-29) and the time of first bowl movement was 48 (24-72) h. The postoperative hospitalization stay was 9 (6-12) d. There were abdominal hemorrhage (n = 1) and anastomotic leakage (n = 1). CONCLUSION: Total laparoscopic rectosigmoid cancer surgery with transanal natural orifice specimen extraction appears to be feasible, and oncologically acceptable for selected patients. PMID- 24169296 TI - Bicycle helmets: don't say something by not saying something. PMID- 24169295 TI - Potential interest of developing an integrated boost dose escalation for stereotactic irradiation of primary prostate cancer. AB - INTRODUCTION: The stereotactic irradiation is a new approach for low-risk prostate cancer. The aim of the present study was to evaluate a schema of stereotactic irradiation of the prostate with an integrated-boost into the tumor. MATERIAL AND METHODS: The prostate and the tumor were delineated by a radiologist on CT/MRI fusion. A 9-coplanar fields IMRT plan was optimized with three different dose levels: 1) 5 * 6.5 Gy to the PTV1 (plan 1), 2) 5 * 8 Gy to the PTV1 (plan 2) and 3) 5 * 6.5 Gy on the PTV1 with 5 * 8 Gy on the PTV2 (plan 3). The maximum dose (MaxD), mean dose (MD) and doses received by 2% (D2), 5% (D5), 10% (D10) and 25% (D25) of the rectum and bladder walls were used to compare the 3 IMRT plans. RESULTS: A dose escalation to entire prostate from 6.5 Gy to 8 Gy increased the rectum MD, MaxD, D2, D5, D10 and D25 by 3.75 Gy, 8.42 Gy, 7.88 Gy, 7.36 Gy, 6.67 Gy and 5.54 Gy. Similar results were observed for the bladder with 1.72 Gy, 8.28 Gy, 7.01 Gy, 5.69 Gy, 4.36 Gy and 2.42 Gy for the same dosimetric parameters. An integrated SBRT boost only to PTV2 reduced by about 50% the dose difference for rectum and bladder compared to a homogenous prostate dose escalation. Thereby, the MD, D2, D5, D10 and D25 for rectum were increased by 1.51 Gy, 4.24 Gy, 3.08 Gy, 2.84 Gy and 2.37 Gy in plan 3 compared to plan 1. CONCLUSIONS: The present planning study of an integrated SBRT boost limits the doses received by the rectum and bladder if compared to a whole prostate dose escalation for SBRT approach. PMID- 24169297 TI - Canadian Academy of Sport and Exercise Medicine position statement: mandatory use of bicycle helmets. PMID- 24169298 TI - Prevention and management of noncommunicable disease: the IOC Consensus Statement, Lausanne 2013. AB - Morbidity and mortality from preventable, noncommunicable chronic disease (NCD) threatens the health of our populations and our economies. The accumulation of vast amounts of scientific knowledge has done little to change this. New and innovative thinking is essential to foster new creative approaches that leverage and integrate evidence through the support of big data, technology, and design thinking. The purpose of this paper is to summarize the results of a consensus meeting on NCD prevention sponsored by the International Olympic Committee (IOC) in April 2013. Within the context of advocacy for multifaceted systems change, the IOC's focus is to create solutions that gain traction within health care systems. The group of participants attending the meeting achieved consensus on a strategy for the prevention and management of chronic disease that includes the following: 1. Focus on behavioral change as the core component of all clinical programs for the prevention and management of chronic disease. 2. Establish actual centers to design, implement, study, and improve preventive programs for chronic disease. 3. Use human-centered design (HCD) in the creation of prevention programs with an inclination to action, rapid prototyping and multiple iterations. 4. Extend the knowledge and skills of Sports and Exercise Medicine (SEM) professionals to build new programs for the prevention and treatment of chronic disease focused on physical activity, diet, and lifestyle. 5. Mobilize resources and leverage networks to scale and distribute programs of prevention. True innovation lies in the ability to align thinking around these core strategies to ensure successful implementation of NCD prevention and management programs within health care. The IOC and SEM community are in an ideal position to lead this disruptive change. The outcome of the consensus meeting was the creation of the IOC Non-Communicable Diseases ad hoc Working Group charged with the responsibility of moving this agenda forward. PMID- 24169299 TI - Midlife fitness predicts less burden of chronic disease in later life. AB - OBJECTIVE: To investigate the relationship between midlife fitness in healthy adults and the development of nonfatal chronic conditions (CCs) in older age. DESIGN: Cohort study. SETTING: Data on participants were drawn from the Cooper Center Longitudinal Study and linked with US Medicare claims made in the years 1999 through 2009. PARTICIPANTS: The cohort included 18 670 participants (median age, 49 years; 21% women) who had received a comprehensive clinical examination between 1970 and 2009 at the Cooper Center, were >=65 years of age and covered by Medicare between 1999 and 2009, and who reported no baseline history of CCs such as cardiovascular disease, diabetes, and cancer. The participants tended to be from upper educational and socioeconomic strata. ASSESSMENT OF RISK FACTORS: Fitness was assessed by maximal treadmill effort using the modified Balke protocol. The participants' treadmill times were classified into age- and sex specific quintiles (Q) of fitness (Q1, least fit) and converted into metabolic equivalents (MET). Clinical and anthropometric variables and physical activity were measured. MAIN OUTCOME MEASURES: The main outcome measure was the association between level of fitness in midlife (ie, at study entry) and the development of chronic conditions (specifically, congestive heart failure, ischemic heart disease, stroke, diabetes mellitus, chronic obstructive pulmonary disease, chronic kidney disease, Alzheimer's disease, and colon or lung cancer), recorded by Medicare. The conditions were each assigned a value of 1, and those present were summed for survivors at ages 70, 75, 80, and 85 years. Death was an additional outcome. Total follow-up was 120 780 person-years. MAIN RESULTS: At study entry the participants had, overall, low levels of traditional risk factors for CCs, with the less fit having somewhat less healthy risk factor profiles. The highest level of midlife fitness (Q5) was associated with developing fewer CCs compared with low midlife fitness (Q1) in men (15.6; 95% confidence interval [CI], 15.0-16.2 vs 28.2; 95% CI, 27.4-29.0 per 100 person-years) and women (11.4; 95% CI, 10.5-12.3 vs 20.1; 95% CI, 18.7-21.6 per 100 person-years). After multivariate adjustment, higher fitness remained associated with a lower risk of developing CCs (men: hazard ratio [HR], 0.95; 95% CI, 0.94-0.96 per MET; and women: HR, 0.94; 95% CI, 0.91-0.96 per MET). Level of fitness was similarly associated with the development of CCs in younger and older participants. Among the 2406 participants who died during the study period, the number of CCs among the more fit persons was significantly lower than that among the less fit; thus, in their final 5 years of life, 58.3% of fitness Q4 and Q5 versus 43.5% of Q1 had <=1 CC and 9.5% of Q4 and Q5 versus 18.3% of Q1 had >=4 CCs. CONCLUSIONS: Healthy, fit, middle-aged adults developed fewer chronic conditions in later life than unfit persons and had a lesser burden of chronic disease before death. PMID- 24169300 TI - Costing an injury prevention program in amateur adult soccer. AB - OBJECTIVE: To compare the injury-related societal costs of an injury prevention program with usual warm up programs for amateur adult male soccer players. DESIGN: Cost effectiveness analysis of a cluster-randomized controlled trial. SETTING: Regional amateur male soccer competitions in the Netherlands during the 2009 season. Cost estimates in the Netherlands are made in 2009 Euros (&OV0556;1.00~US$1.43 in late 2009). PARTICIPANTS: Soccer teams from 2 first class competitions (the second-highest Dutch amateur level) were approached. Male players aged between 18 and 40 years, who were part of the first team at the start of the season, were eligible for inclusion. Twenty-three teams including 479 players were randomized and 456 (95%) were included in the analysis. INTERVENTION: The injury prevention program was The11, which includes 10 structured exercises developed by the FIFA Medical and Research Centre. The exercises, led by trained coaches, were designed to improve the stability, strength, co-ordination, and flexibility of the trunk, hip, and leg muscles and were performed 2 or 3 times per week as warm-up sessions. Compliance with the exercises was monitored randomly by the researchers. The control teams continued their usual warm-up routines. During the season, individual participants' exposure to training sessions or matches (in minutes) was reported weekly by the coaches. All participants completed questionnaires that included playing and injury history and current occupation and hours worked. Employment (vs studying) was nonsignificantly more common in the control group than the intervention group (68% vs 56%). MAIN COST AND OUTCOME MEASURES: Costs included those of the intervention, direct healthcare costs of injury, and indirect costs such as hours of work lost, which were recorded on a recovery form. Injuries occurring during the competition season were recorded weekly by the paramedical staff of the team. An injury was defined as a physical complaint sustained by a participant that resulted from a soccer training session or soccer match, whether or not there was lost time from soccer or need for medical attention. Full recovery was defined as participation throughout a training or match session. MAIN RESULTS: The players' injury rates were almost identical in the intervention and control groups (0.93 vs 0.94, representing 60.5% and 59.7% of players). The mean cost of The11, per player, was &OV0556;14 for the intervention group and &OV0556;0 for the control group. Direct healthcare costs per player were not significantly lower in the intervention group (difference, &OV0556;-44; 95% confidence interval [CI], -17 to 111). Indirect costs were lower in the intervention group (difference, &OV0556; 172; 95% CI, -352 to -28). The total cost per player was also lower in The11 group (difference, &OV0556;-201; 95% CI, -426 to -15). Direct health care costs per injured player were not significantly lower in the intervention group (difference, &OV0556;-76; 95% CI, -285 to 18). Indirect costs were lower in The11 group (difference, &OV0556;-288; 95% CI, -589 to -49). The total per injured player was, therefore, lower in The11 group (difference, &OV0556;-350; 95% CI, 733 to -51). CONCLUSIONS: The injury prevention strategy, The11, did not lower the rate of injuries in adult male soccer players, but the costs per player and per injured player were lower in the intervention group. PMID- 24169301 TI - Updating Recommendations for Rehabilitation after ACL Reconstruction: a Review. AB - OBJECTIVE: To review recent evidence in order to update previous systematic reviews on methods of rehabilitation after anterior cruciate ligament (ACL) reconstruction. DATA SOURCES: PubMed, Embase, and the Cochrane Controlled Trials Register were searched for the period January 2006 to December 2010, using terms related to ACL, rehabilitation, and randomized controlled trial (RCT). The search was done in triplicate, and the results reconciled (85 studies identified). STUDY SELECTION: Relevant studies in English that were peer-reviewed RCTs or prospective comparative studies evaluating methods of ACL rehabilitation were included (n = 29). Evidence was evaluated by all 3 authors using the CONSORT criteria. DATA EXTRACTION: The data extracted included number of patients, ACL reconstruction method, randomization method, intervention, length of, and loss to, follow-up, outcomes assessed, bias, and findings. The review included evidence on postoperative bracing, accelerated rehabilitation, home-based rehabilitation, proprioceptive and neuromuscular training, and miscellaneous topics that were investigated by single trials. MAIN RESULTS: In 6 studies of postoperative bracing, no study found a clinically significant benefit of bracing or of restricted range of knee motion for pain control, knee laxity, or rehabilitation. Postoperative treatment without the use of a brace was not associated with less favorable outcomes. In 5 studies of accelerated strengthening, beginning eccentric quadriceps strengthening and isokinetic hamstring strengthening 2 weeks after ACL surgery improved or accelerated strength gains. Immediately postoperative weight-bearing, range of knee motion from 0 degrees to 90 degrees of flexion, and strengthening with closed-chain exercises were probably all safe. Home-based rehabilitation was evaluated in 2 studies. One study demonstrated that this intervention was at least as successful as a standard accelerated program over the long term. The other study included very low compliance expectations and other methodologic problems that precluded a useful assessment of benefit. Nine trials of neuromuscular strengthening (including perturbation, vibration, and/or balance training by various means) compared with strength, traditional rehabilitation, or placebo found some small short-term benefits to proprioceptive training and no harm from any of the treatments. Vibration training in addition to other strengthening may lead to faster proprioceptive recovery but the benefits to overall functional outcome are less clear. A study of vitamin C and E supplementation found a correlation between higher presurgery vitamin C levels and greater strength at 3 months, but this strength increase was not related to postsurgical vitamin C supplementation. Hyaluronic acid injection at 8 weeks improved ambulation and peak torque more than other doses or placebo, but poor outcomes in the control group raise questions about the quality of the standard rehabilitation program. Running interval training and continuous active motion had unclear effects. Using the uninjured leg for single-leg cycling prevented the usual loss of aerobic fitness in the postoperative period. Preoperative and postoperative video instruction decreased expectations of pain and increased self-efficacy although it made no difference to performance. CONCLUSIONS: The review of rehabilitation interventions after ACL reconstruction suggests that both accelerated and home based rehabilitation, neuromuscular training programs, hyaluronic acid injection, and single (uninjured) leg cycling may be beneficial. Preoperative and postoperative informational videos may be valuable for psychological well-being. Insufficient evidence was found to recommend bracing. PMID- 24169302 TI - How effective are injection treatments for lateral epicondylitis? AB - OBJECTIVE: To compare the effectiveness, after 3 months, of a single injection of platelet-rich plasma (PRP), glucocorticoid (GC), or saline in reducing pain in lateral epicondylitis. DESIGN: Randomized, controlled, 3-group trial (RCT). Patients and outcome assessors were blinded to intervention group. Sample size was calculated to show a clinically important difference in patient-reported pain intensity at 12 months with 17 patients per group. SETTING: Tertiary study at the Rheumatology Unit at the Diagnostic Centre of the Region Hospital Silkeborg, Denmark. PARTICIPANTS: Patients were referred to the Rheumatology Unit by general practitioners or other rheumatology or orthopedic departments. Inclusion criteria (verified by 1 physician) were lateral epicondylitis symptoms for >=3 months (pain on the lateral side of the elbow and at the lateral epicondyle on palpation and during resisted dorsiflexion of the wrist), an ultrasound (US) color Doppler flow of >= grade 2 (range, 0-4). Exclusion criteria were age <18 years, treatment with GC injection within 3 months, inflammatory diseases, and conditions causing chronic pain. The 60 included patients had a mean age of 45 years, 52% were women, 58% had >=1 previous injection, and 58% used analgesics. INTERVENTION: The patients were randomized to a single US-guided injection of PRP, GC, or saline, administered by the 1 physician who had made the diagnosis. All patients were blindfolded during blood collection and injection. They all received an injection of 10 to 15 mL of lidocaine into the peritendon before the procedure. The PRP injection was of approximately 3.5 mL of autologous platelets (collected and centrifuged for 15 minutes from 27 mL of whole blood) buffered with 8.4% sodium bicarbonate, and immediately peppered into the common tendon origin. The GC injection (1 mL triamcinolon, 40 mg/mL + 2 mL lidocaine, 10 mg/mL) was delivered through 1 site. The saline injection (3 mL saline, 0.9%) was peppered in the same manner as the PRP injection. After treatment, the patients were asked to use the arm minimally for 3 days and then gradually to return to normal use. MAIN OUTCOME MEASURES: The pain intensity scale of the Patient-Rated Tennis Elbow Evaluation (PRTEE) questionnaire was the main outcome measure (least to most pain = 0-50 points). The secondary end points included changes in functional disability using the functional section of the PRTEE, (least to most disability = 0-100 points), US changes in color Doppler signal and tendon thickness, and adverse events, which included pain after the injection. After 3 months, if the patient was unsatisfied with the result of treatment, he or she could be released from the study to seek other management. MAIN RESULTS: Ten, 11, and 13 patients (58% of the total) dropped out of the PRP, GC, and saline groups, respectively, at the 3 month follow-up, thus evaluations were only made at 1 and 3 months. At 1 month, the mean reduction in pain for the PRP group versus the saline group was 1.2 (95% confidence interval [CI], -5.0 to 7.3); for the GC group versus the saline group was -8.1 (95% CI, -14.3 to -1.9); and for the GC group versus the PRP group, -9.3 (95% CI, -15.4 to -3.2). At 3 months, the mean reduction in pain for no group was significantly greater than for others (PRP vs the saline group, -2.7; 95% CI, 8.8 to 3.5; GC vs the saline group, -3.8; 95% CI, -9.9 to 2.4; GC vs the PRP group, -1.1; 95% CI, -7.2 to 5.0). The PRTEE disability scores at 1 month also favored the GC group versus saline, but no differences were found between any groups at 3 months. The improvement in Doppler grades at 3 months favored the GC group versus the saline group and the PRP group (P<0.0001 for both comparisons). Mean reduction in tendon thickness was greater for the GC group versus the saline group (P<0.0001) and the PRP group (P=0.002). PRP injections were found to be more painful than GC and saline injections. No adverse events leading to hospitalization, and no reports of infections resulting from the injections, occurred. CONCLUSIONS: The dropout rate of 58% at 3 months showed that none of PRP, glucocorticoid, or saline injections adequately reduced the pain and disability of lateral epicondylitis. PMID- 24169303 TI - Macrophage activation and leishmanicidal activity by galactomannan and its oxovanadium (IV/V) complex in vitro. AB - Compounds that activate macrophage antimicrobial activity are potential targets for treatment of leishmaniasis. The present study investigated the in vitro immunomodulatory effects of a galactomannan (GALMAN-A) isolated from seeds of Mimosa scabrella and its oxovanadium (IV/V) complex (GALMAN-A:VO(2+)/VO(3+)) on macrophage activity. GALMAN-A increased nitric oxide levels by ~33% at a concentration of 250MUg/ml, while GALMAN-A:VO(2+)/VO(3+) decreased nitric oxide levels by ~33% at a concentration of 50MUg/ml. Furthermore, GALMAN-A increased interleukin-1 beta (IL-1beta) and interleukin-6 (IL-6) levels by 5.5 and 2.3 times, respectively, at a concentration of 25MUg/ml; at the same concentration, GALMAN-A:VO(2+)/VO(3+) promoted an increase in IL-1beta and IL-6 production by 8 and 5.5 times, respectively. However, neither GALMAN-A nor GALMAN-A:VO(2+)/VO(3+) affected tumor necrosis factor alpha (TNF-alpha) or interleukin-10 (IL-10) levels. Importantly, both GALMAN-A and GALMAN-A:VO(2+)/VO(3+) exhibited leishmanicidal activity on amastigotes of Leishmania (L.) amazonensis, reaching ~60% activity at concentrations of 100 and 25MUg/ml, respectively. These results indicate that GALMAN-A is three times more potent and its oxovanadium complex is twelve times more potent than Glucantime (300MUg/ml), which is the drug of choice in leishmaniasis treatment. The IC50 value for GALMAN-A:VO(2+)/VO(3+) was 74.4MUg/ml (0.58MUg/ml of vanadium). Thus, the significant activation of macrophages and the noted leishmanicidal effect demonstrate the need for further studies to clarify the mechanisms of action of these compounds. PMID- 24169305 TI - Torsional nystagmus in hypothalamic hamartoma. AB - Torsional nystagmus was noted in a patient with hypothalamic hamartoma. Magnetic resonance imaging revealed an exophytic hypothalamic mass extending into the pre pontine cistern and abutting ventral mesencephalon. The quickphase of the torsional nystagmus was directed towards the left side, ipsilateral to the side of compression by the hamartoma. Ipsi-lesionally directed pure torsional nystagmus in this case is attributed to the compressive lesion of ocular motor structures responsible for the neural integration of torsional and vertical eye movements, the interstitial nucleus of Cajal. [Published with video sequences]. PMID- 24169306 TI - Development of EASY-Care, for brief standardized assessment of the health and care needs of older people; with latest information about cross-national acceptability. AB - INTRODUCTION: The EASY-Care system has been developed in the past 20 years in the United States and Europe as a brief standardized method for assessing the perceptions of older people about their health and care needs and priorities for a service response. More recently, it has been adapted and tested for use in poor, middle-income, and rich countries across the world. In this article we review its development and report the latest data for cross-cultural acceptability to older people and their clinicians in 6 countries across 4 continents. METHOD: We used a multicenter, mixed-method (quantitative and qualitative) approach to assess clinician (n = 37) and patient (n = 115) perspectives of acceptability of the EASY-Care Standard (2010) instrument. Data were collected between 2008 and 2012 in Iran, Colombia, India, Lesotho, Tonga, and the United Kingdom. RESULTS: Key strengths identified included high levels of acceptability from both clinician and patient perspectives, with the tools seen as useful for identification of unmet need. Key recommendations included enhancing clarity in certain questions, ensuring it is not too long. Recommendations included minor context-specific adaptations, effective use of the screening questionnaire, and use of context-specific interviewer prompts. CONCLUSIONS: The EASY-Care Standard has high levels of acceptability from both clinicians and patients across poor, middle-income, and rich countries and has the potential to become a global gold standard for holistic person-centered assessment. PMID- 24169304 TI - Crosstalk between epigenetic readers regulates the MOZ/MORF HAT complexes. AB - The MOZ/MORF complexes represent an example of a chromatin-binding assembly whose recruitment to specific genomic regions and activity can be fine-tuned by posttranslational modifications of histones. Here we detail the structures and biological functions of epigenetic readers present in the four core subunits of the MOZ/MORF complexes, highlight the imperative role of combinatorial readout by the multiple readers, and discuss new research directions to advance our understanding of histone acetylation. PMID- 24169307 TI - Origin of the long-term variability and acceleration of FHR studied for the prevention of cerebral palsy in fetal hypoxia and general insults. AB - AIMS: The development of fetal heart rate (FHR) variability and acceleration, and their loss in the hypoxic brain damage and cerebral palsy (CP) is investigated. METHODS: FHR, movements in physiologic sinusoidal FHR and fetal movements were studied by actocardiogram. RESULTS: Periodic fetal respiratory movements evoked moderate FHR variation similar to medium variability. Small fetal movements provoked FHR variability, and large fetal movement burst developed the acceleration. The brain centers should be midbrain for variability and acceleration. FHR variability and acceleration develop by the reaction of fetal brain to fetal movements. As severe organic fetal brain damage could develop through fetal hypoxia in the loss of variability, early delivery before the loss of variability will prevent infantile CP. As the abnormal FHR would be developed by fetal brain damage in non-hypoxic fetal insults, early delivery before the loss of variability could also prevent the brain damage in viral and bacterial infections. PMID- 24169308 TI - Inactivation of high-risk human papillomaviruses by Holder pasteurization: implications for donor human milk banking. AB - AIMS: Several studies have recently reported the detection of oncogenic human papillomaviruses (HPV) in human milk of a minority of lactating mothers. These findings raised safety concerns in the context of human donor milk banking given the potential risk of HPV transmission to recipient infants. The aim of this study was to investigate whether the Holder pasteurization, a procedure currently in use in human donor milk banks for milk pasteurization, completely inactivates high-risk and low-risk HPV. METHODS: HPV pseudoviruses (PsV) were generated, spiked into cell culture medium or donor human milk and subjected to thermal inactivation. HPV PsV infectivity and morphological integrity was analyzed by cell-based assay and by electron microscopy, respectively. RESULTS: The Holder pasteurization completely inactivated the infectivity of high-risk (types 16 and 18) and low-risk (type 6) HPV both in cell culture medium and in human milk causing PsV particle disassembly. CONCLUSIONS: The results presented here indicate that the Holder pasteurization is an efficient procedure to inactivate high-risk and low-risk HPV thus preventing the potential risk of their transmission through human donor milk. PMID- 24169309 TI - Sonographic measurement of cervical length as a predictor of preterm delivery: a systematic review. AB - AIM: To evaluate if transvaginal cervical length measurement in the second trimester scan is an effective screening test for preterm delivery. METHODS: We performed a search in Medline and, for each selected article, information was extracted regarding the performance of the test in terms of sensitivity, specificity, positive, and negative likelihood ratios, in low-risk, high-risk, and multiple gestations. We also evaluated the performance of the combined test (more than one sonographic marker). RESULTS: A positive relationship was established between short cervix and preterm delivery in all articles. The majority of studies presented high specificity and positive likelihood ratio, while sensitivity and negative likelihood ratio were variable and globally poor. Better values of accuracy were found in high-risk and multiple gestations and, in all studied subgroups, for preterm delivery at lower gestational ages. CONCLUSIONS: We conclude that a short cervix is predictive of preterm delivery and can identify women that may benefit from preventive and therapeutic measures, however, a negative result is not always reassuring. PMID- 24169310 TI - Endometriosis and migraine: what is there behind the scenes? PMID- 24169311 TI - Music education and its effect on intellectual abilities in children: a systematic review. AB - Far transfer between music education and other cognitive skills, such as academic achievement, has been widely examined. However, the results of studies within similar cognitive domains are found to be inconclusive or contradictory. These differences can be traced back to the analytical methods used, differences in the forms of music education studied and differences in neural activation during the processing of these tasks. In order to gain a better picture of the relationships involved, a literature survey was performed in leading databases, such as PubMed/MedLine, psychINFO, ScienceDirect, Embase, ERIC, ASSIA and Jstor from January 2001 to January 2013. All studies included, concerned the far transfer from music education to other cognitive skills in children aged 4-13 years as compared with controls. These studies were independently selected and their quality was assessed by two authors. This systematic review shows the need to address methodological and analytical questions in greater detail. There is a general need to unify methods used in music education research. Furthermore, the hypothesis that intellectual skills, such as mathematics, reading, writing and intelligence can be divided into sub-functions, needs to be examined as one approach to the problems considered here. When this has been done, detailed analysis of cognitive transfer from music education to other disciplines should become possible. PMID- 24169312 TI - Chronic disease: a core construct in psychogeriatrics. PMID- 24169314 TI - Mechanisms of motor vehicle crashes related to burns--an analysis of the German In depth Accident Study (GIDAS) database. AB - BACKGROUND: Patients of motor vehicle crashes (MVCs) suffering burns are challenging for the rescue team and the admitting hospital. These patients often face worse outcomes than crash patients with trauma only. Our analysis of the German In-depth Accident Study (GIDAS) database researches the detailed crash mechanisms to identify potential prevention measures. METHODS: We analyzed the 2011 GIDAS database comprising 14,072 MVC patients and compared individuals with (Burns) and without (NoBurns) burns. Only complete data sets were included. Patients with burns obviously resulting of air bag deployment only were not included in the Burns group. Data acquisition by an on call team of medical and technical researchers starts at the crash scene immediately after the crash and comprises technical data as well as medical information until discharge from the hospital. Statistical analysis was done by Mann-Whitney-U-test. Level of significance was p < 0.05. RESULTS: 14,072 MVC patients with complete data sets were included in the analysis. 99 individuals suffered burns (0.7%; group "Burns"). Demographic data and injury severity showed no statistical significant difference between the two groups of Burns and NoBurns. Injury severity was measured using the Injury Severity Score (ISS). Direct frontal impact (Burns: 48.5% vs. NoBurns: 33%; p < 0.05) and high-energy impacts as represented by delta v (m/s) (Burns: 33.5 +/- 21.4 vs. NoBurns: 25.2 +/- 15.9; p < 0.05) were significantly different between groups as was mortality (Burns: 12.5% vs. NoBurns: 2.1%; p < 0.05). Type of patients' motor vehicles and type of crash opponent showed no differences. CONCLUSIONS: Our results show, that frontal and high-energy impacts are associated with a frequency of burns. This may serve automobile construction companies to improve the burn safety to prevent flames spreading from the motor compartment to the passenger compartment. Communities may impose speed limits in local crash hot spots. PMID- 24169316 TI - Chromenylchalcones with inhibitory effects on monoamine oxidase B. AB - Structure-activity relationship (SAR) calculations were used to find monoamine oxidase-B (MAO-B) inhibitors by identifying pharmacophores exhibiting high inhibitory activities. Several such chromenylchalcones were designed and synthesized accordingly. Their inhibitory effects on MAO-B were determined using an HPLC-based method and an MAO-B enzyme assay kit. (E)-3-(6-Methoxy-2H-chromen-3 yl)-1-(2-methoxyphenyl)prop-2-en-1-one exhibited a half-maximal inhibitory concentration of 320 nM. Its molecular-level binding mode with the three dimensional structure of MAO-B was elucidated using an in silico docking study. The chromenylchalcone scaffold, which is derived from natural products including isoflavonoids and chalcones, had not been previously reported as an MAO-B inhibitor. PMID- 24169315 TI - Design, synthesis, and biological activities of novel hexahydropyrazino[1,2 a]indole derivatives as potent inhibitors of apoptosis (IAP) proteins antagonists with improved membrane permeability across MDR1 expressing cells. AB - We previously reported octahydropyrrolo[1,2-a]pyrazine derivative 2 (T-3256336) as a potent antagonist for inhibitors of apoptosis (IAP) proteins. Because compound 2 was susceptible to MDR1 mediated efflux, we developed another scaffold, hexahydropyrazino[1,2-a]indole, using structure-based drug design. The fused benzene ring of this scaffold was aimed at increasing the lipophilicity and decreasing the basicity of the scaffold to improve the membrane permeability across MDR1 expressing cells. We established a chiral pool synthetic route to yield the desired tricyclic chiral isomers. Chemical modification of the core scaffold led to a representative compound 50, which showed strong inhibition of IAP binding (X chromosome-linked IAP [XIAP]: IC50 23 nM and cellular IAP [cIAP]: IC50 1.1 nM) and cell growth inhibition (MDA-MB-231 cells: GI50 2.8 nM) with high permeability and low potential of MDR1 substrate. PMID- 24169317 TI - [The treament of hyponatremia secundary to the syndrome of inappropriate antidiuretic hormone secretion]. AB - The syndrome of inappropriate antidiuretic hormone secretion (SIADH) is the most frequent cause of hyponatremia in a hospital setting. However, detailed protocols and algorithms for its management are lacking. Our objective was to develop 2 consensus algorithms for the therapy of hyponatremia due to SIADH in hospitalized patients. A multidisciplinary group made up of 2 endocrinologists, 2 nephrologists, 2 internists, and one hospital pharmacist held meetings over the period of a year. The group worked under the auspices of the European Hyponatremia Network and the corresponding Spanish medical societies. Therapeutic proposals were based on widely-accepted recommendations, expert opinion and consensus guidelines, as well as on the authors' personal experience. Two algorithms were developed. Algorithm 1 addresses acute correction of hyponatremia posing as a medical emergency, and is applicable to both severe euvolemic and hypovolemic hyponatremia. The mainstay of this algorithm is the iv use of 3% hypertonic saline solution. Specific infusion rates are proposed, as are steps to avoid or reverse overcorrection of serum sodium levels. Algorithm 2 is directed to the therapy of SIADH-induced mild or moderate, non-acute hyponatremia. It addresses when and how to use fluid restriction, solute, furosemide, and tolvaptan to achieve eunatremia in patients with SIADH. Two complementary strategies were elaborated to treat SIADH-induced hyponatremia in an attempt to increase awareness of its importance, simplify its therapy, and improve prognosis. PMID- 24169318 TI - Adrenomedullin expression in the developing human fetal lung. AB - BACKGROUND: Adrenomedullin (AM) is a vasodilator peptide produced by endothelial and smooth muscle cells in the systemic and pulmonary circulation. It promotes angiogenesis and alveolar growth and has protective effects in the cardiovascular and respiratory systems. Adrenomedullin's role in human pulmonary vascular and alveolar development is unknown. OBJECTIVE: To test the hypothesis that AM is expressed during normal human lung development and that its expression changes with advancing gestational age by investigating the messenger RNA and protein expression of AM and its receptor components, calcitonin-receptorlike receptor (CRLR), receptor activity-modifying protein (RAMP)2, and RAMP3 in human fetal lung from 10 to 24 weeks of gestation. METHODS: The gene expression of AM, CRLR, RAMP2, and RAMP3 was measured with real-time reverse-transcription polymerase chain reaction. Adrenomedullin protein expression was measured with Western blot. Immunohistochemical analyses of sections of lung tissue were performed. Statistical analysis was performed using linear regression and one-way analysis of variance followed by the Tukey range test. RESULTS: Adrenomedullin, CRLR, RAMP2, and RAMP3 transcripts were expressed in the midgestation human fetal lung. The gene expression of AM, CRLR, and RAMP2 increased with increasing gestational age, whereas the gene expression of RAMP3 decreased. Adrenomedullin protein expression increased with increasing gestational age. CONCLUSION: Adrenomedullin is expressed in the midgestation human fetal lung and its gene and protein expression increased with increasing gestational age, suggesting a role for AM in human lung development. Supporting this conclusion, the AM1 receptor components CRLR and RAMP2 gene expression also increased with increasing gestational age. Conversely, the expression of RAMP3, a structural component of the AM2 receptor, decreased with increasing gestational age, suggesting different functions for the AM receptors in human fetal lung, as it has been demonstrated in animal models. This speculation requires further investigation. PMID- 24169319 TI - Approaches to preparing young scholars for careers in interdisciplinary team science. AB - To succeed as a biomedical researcher, the ability to flourish in interdisciplinary teams of scientists is becoming ever more important. Institutions supported by the Clinical and Translational Science Awards (CTSAs) from the National Institutes of Health have a specific mandate to educate the next generation of clinical and translational researchers. While they strive to advance integrated and interdisciplinary approaches to education and career development in clinical and translational science, general approaches and evaluation strategies may differ, as there is no single, universally accepted or standardized approach. It is important, therefore, to learn about the different approaches used to determine what is effective. We implemented a Web-based survey distributed to education leaders at the 60 funded CTSA institutions; 95% responded to the survey, which included questions on the importance of preparation for interdisciplinary team science careers, methods used to provide such training, and perceived effectiveness of these training programs. The vast majority (86%) of education leaders reported that such training is important, and about half (52%) of the institutions offer such training. Methods of training most often take the form of courses and seminars, both credit bearing and noncredit. These efforts are, by and large, perceived as effective by the training program leaders, although long-term follow-up of trainees would be required to fully evaluate ultimate effectiveness. Results from the survey suggest that CTSA education directors believe that specific training in interdisciplinary team science for young investigators is very important, but few methodologies are universally practiced in CTSA institutions to provide training or to assess performance. Four specific recommendations are suggested to provide measurable strategic goals for education in team science in the context of clinical and translational research. PMID- 24169320 TI - Vancomycin-resistant enterococci among haemodialysis patients in Portugal: prevalence and molecular characterization of resistance, virulence and clonality. AB - INTRODUCTION: Vancomycin-resistant enterococci (VRE) among haemodialysis patients has increased rapidly and, to date, there is no report of this incidence in Portugal. METHODS: A total of 121 faecal samples were collected from haemodialysis patients, and then tested for VRE. Antimicrobial resistance, virulence and multilocus sequence typing (MLST) were studied. RESULTS: VRE prevalence was 3.3%. Three VRE isolates, Enterococcus faecium, Enterococcus faecalis and Enterococcus raffinosus, were multi-resistant and vanA-positive. E. faecium and E. faecalis belonged to CC17 and CC2, respectively. CONCLUSION: Haemodialysis patients in Portugal are colonized with virulent, multi-resistant enterococci from high-risk clonal complexes, representing a public health concern. PMID- 24169322 TI - [The transhepatic approach in sophisticated hepatobiliary surgery]. PMID- 24169321 TI - How spirituality is understood and taught in New Zealand medical schools. AB - OBJECTIVES: The objective of this research was to explore how spirituality is currently understood and taught in New Zealand Medical Schools. METHODS: A mixed methods study was carried out involving interviews (n = 14) and a survey (n = 73). The first stage of the study involved recorded semi-structured interviews of people involved in curriculum development from the Dunedin School of Medicine (n = 14); which then informed a cross-sectional self-reported electronic survey (n = 73). RESULTS: The results indicate that spirituality is regarded by many involved in medical education in New Zealand as an important part of healthcare that may be taught in medical schools, but also that there is little consensus among this group as to what the topic is about. SIGNIFICANCE OF RESULTS: These findings provide a basis for further discussion about including spirituality in medical curricula, and in particular indicate a need to develop a shared understanding of what 'spirituality' means and how it can be taught appropriately. As a highly secular country, these New Zealand findings are significant for medical education in other secular Western countries. Addressing spirituality with patients has been shown to positively impact a range of health outcomes, but how spirituality is taught in medical schools is still developing across the globe. PMID- 24169323 TI - [Application of anterior-inferior approach through retrohepatic tunnel for dissecting short hepatic veins in laparoscopic right hemihepatectomy]. AB - OBJECTIVE: To explore the safety and feasibility of laparoscopic right hemihepatectomy via an anterior-inferior approach through retrohepatic tunnel in the dissection of short hepatic veins (SHVs). METHODS: After partial freeing of right liver, anterior peritoneum of inferior cava vena (ICV) was opened. Retrohepatic space was dissected via an anterior-inferior approach to establish the posterior tunnel partially. Then the first branch of right side SHVs could be freed and ligated after its exposure through the right part of retrohepatic tunnel. The above procedure was repeated until the right side SHVs or the third hepatic portal became partially or completely blocked. If right side SHVs were completely freed and ligament of right liver fully isolated, right hepatic vein could be exposed and ligated and selective blockage of the second hepatic portal blood flow accomplished. This technique was applied in 7 cases of laparoscopic right hemihepatectomy through curettage transaction and aspiration with laparoscopic Peng's multifunctional operative dissector (LPMOD). RESULTS: Six patients were treated successfully. In one case of right hepatic hemangioma, small margin auxiliary hematischesis was attempted because of troublesome hemostasis of middle hepatic vein branch. All of them underwent partial dissection of right side of SHVs. Two cases had complete dissection in which right hepatic vein was freed and ligated, the second hepatic porta blood flow controlled and right hemihepatectomy anatomically achieved. Operative duration was 300-540 min [mean, 399.1 +/- 74.7]. The time of dissecting hepatic porta was 30-75 min [mean, 50.7 +/- 16.2]. The time of dissecting SHVs was 35-95 min [mean, 57.1 +/- 22.1]. The time of liver transection was 60-160 min [mean, 115.9 +/- 32.3]. Operative blood loss had a volume at 600-3000 ml [mean, 1485.7 +/- 809.2]. The postoperative hospital stay was 10-18 days [mean, 12.4 +/- 2.6]. The postoperative time for ambulation, diet and flatus was 2-4, 1-4 and 2-4 days respectively. No severe postoperative complications occurred. CONCLUSION: During laparoscopic right hemihepatectomy, dissecting SHVs is both safe and feasible through a retrohepatic tunnel via an anterior-inferior approach. PMID- 24169324 TI - [Surgical outcomes of second liver resections for recurrent hepatic metastases from colorectal cancer]. AB - OBJECTIVE: To compare the clinical efficacies and safety of primary versus second liver resection for recurrent colorectal metastases to liver. METHODS: Between January 2000 and March 2011, a total of 126 patients underwent liver resections for metastases from colorectal cancer at our institution. Among these, 16 patients underwent repeat liver resections. The comparisons were made for primary and second liver resections in blood loss volume, complications, hospital stay, operative duration and 1, 3, 5- year survival rates. RESULTS: Compared with primary liver resection group, the 1, 3, 5-year survival rates of second liver resection group were 93.8%, 56.1% and 37.4% respectively. For second hepatectomy group, blood loss volume was (323.8 +/- 230.9) ml, operative duration (216.9 +/- 79.7) min, postoperative hospital stay (23.4 +/- 13.9) days and complication rate 18.8%. Compared with primary hepatectomy, there was no difference between two groups. CONCLUSION: Second liver resection may provide long-term survival rates similar to those of primary liver resections. Repeat liver resection is warranted when potentially curative. PMID- 24169325 TI - [Relationship between the expressions of indoleamine 2, 3-dioxygenase in hepatocellular carcinoma and clinicopathological parameters]. AB - OBJECTIVE: To explore the expressions of indoleamine 2, 3-dioxygenase (IDO) in hepatocellular carcinoma and analyze its relationship with clinicopathological parameters. METHODS: Quantitative real-time polymerase chain reaction (PCR), fluorogenic quantitative PCR, immunohistochemical and immunofluorescence were used to detect the expression of indoleamine 2, 3-dioxygenase in hepatocellular carcinoma. RESULTS: The IDO mRNA expression in cancerous tissues increased markedly than that in the corresponding non-cancerous tissues (2(-DeltaDeltaCT) = 1.71, P = 0.001) . The immunohistochemical and immunofluorescence results showed that IDO protein was expressed in cytoplasm of hepatocellular carcinoma and tumor surrounding tissues. But there was no expression in normal liver tissues from benign hepatic lesions and corresponding non-cancerous tissues. An over expression of IDO protein was detected in 43 patients (48.3%) , a low expression in 25 (28.1%) and no expression in 21 (23.6%). Relationship between IDO expression and clinicopathological parameters: an over-expression of IDO in HCC was associated with recurrence, survival time, metastasis and TNM stage (P < 0.05), but not associated with patient's cirrhosis, AFP level, histological differentiation type, Barcelona clinic liver cancer stage, gender, age, HbsAg positivity, number of tumors and tumor size (P > 0.05). CONCLUSION: An over expression of IDO in HCC patients may affect patient prognosis. PMID- 24169326 TI - [Relationship between mitochondrial cytochrome oxidase mRNA expression and maternal inheritance of asthma]. AB - OBJECTIVE: To explore the relationship between the mRNA expression level of mitochondrial cytochrome oxidase and the maternal inheritance of asthma. METHODS: From January to December 2009, 220 asthma patients, 162 patient kins and 260 healthy subjects were recruited from Departments of Respiratory Critical Care Medicine and Pediatric Medicine at First Affiliated Hospital, Kunming Medical College. Lung function tests were performed and serum IgE level measured. The polymorphism of mitochondrial cytochrome oxidase gene polymorphisms was detected by direct sequencing. And the peripheral level of COX mRNA was measured by reverse transcription-polymerase chain reaction (RT-PCR). RESULTS: No significant difference existed in age, gender among 3 groups. For 3 groups, the first second forced expiratory volume (FEV1)/forced vital capacity (FVC) were 90.6 +/- 6.2, 92.3 +/- 2.3, 102.3 +/- 2.3 and FEV1 percentage of expected value (FEV1%) were (82.9 +/- 10.8)%, (94.8 +/- 5.4)% and (98.3 +/- 8.6)% respectively. The lung function was not significant difference among three groups. The mRNA expression level of mitochondrial cytochrome oxidase in peripheral blood were 0.357 +/- 0.217, 0.637 +/- 0.473 and 0.975 +/- 0.260 in the asthma, kin and control groups respectively. No significant difference existed in the expression level of COX3 mRNA among 3 groups (F = 21.45, P = 0.012). The serum level of lgE was the highest for the asthma patients. And it was significantly higher in the asthma group than that in the control group ((283.6 +/- 62.4) vs (52.3 +/- 13.7) ug/L, F = 48.31, P < 0.05). Moreover, the serum level of IgE was significantly higher in the kin group than that in the control group ((116.4 +/- 57.5) vs (52.3 +/- 13.7) ug/L, F = 20.45, P < 0.05). However, there was a negative correlation between the mRNA expression level of mitochondrial cytochrome oxidase and the serum level of IgE among 3 groups. CONCLUSIONS: The down-regulated mRNA expressin of mitochondrial cytochrome oxidase may participate in allergic inflammation by regulating the level of IgE. And the maternal inheritance of asthma is in effect. PMID- 24169327 TI - [Effects of genetic variations of cholesteryl ester transfer protein on atorvastatin treatment efficacy and clinical outcomes in patients with coronary artery disease]. AB - OBJECTIVE: To explore the polymorphism of cholesteryl ester transfer protein (CETP) gene -629C/A among the coronary heart disease (CHD) Han population of Tianjin area and evaluate the influences of genetic factors on atorvastatin therapeutic effects and clinical outcomes in pharmacogenomics and provide theoretical rationales for individualized treatment. METHODS: A total of 332 angiographically confirmed CHD patients at Tianjin Chest Hospital were recruited from October 2010 to July 2011. The CETP gene promoter polymorphism at position 629 was determined by polymerase chain reaction-restricted fragment length polymorphism (PCR-RFLP). The serum level of CETP was determined by enzyme-linked immunosorbent assay (ELISA).Lipid levels were determined at baseline and 12 months post-treatment with 20 mg/d atorvastatin in all patients. Clinical follow up were performed for more than 1 year (range, 12-23 months). And major adverse cardiac events (MACE, including death, non-fatal infarction, revascularization and stroke) were analyzed. The Kaplan-Meier Log-rank test was used to compare MACE-free survival between different genotypes. RESULTS: (1) The frequencies of variant -692A allele was 0.476, AA genotype showed reduced CETP levels and higher HDL-C levels compared with CC and CA genotypes. But it did not reach statistical significance (F = 0.893, P = 0.411 and F = 1.279, P = 0.282 respectively). Although a negative trend correlation existed between serum levels of HDL-C and CETP, it did not reach statistical significance (r = -0.151, P = 0.081) . (2) After 12-month therapy of atorvastatin, CC genotype was shown to be associated with higher LDL-C, LP(a) reduction and HDL-C elevation in response to atorvastatin compared with CA and AA genotype.LDL-C levels decreased 43.5% in CC homozygotes, 25.5% in CA heterozygotes and 11.7% in AA homozygotes (P = 0.001).HDL-C levels increased 9.2% in CC homozygotes, 6.8% in CA heterozygotes and 5.5% in AA homozygotes.However the changes of HDL-C levels in three genotypes showed no significant difference (P = 0.412). (3) There was a 7.83% incidence of MACE after a mean follow-up of (18.66 +/- 5.99) months. The outcomes were death (n = 3, 0.90%), non-fatal infarction (n = 7, 2.11%), revascularization (n = 13, 3.92%) and stroke (n = 3, 0.90%). The cumulative MACE free survival rates were 96.2% , 92.1% and 87.3% in CC, CA and AA genotypes respectively (Log-rank P = 0.444). CONCLUSION: Variant AA genotype shows a higher level of HDL-C s and a lowered level of CETP.However CC genotype offers a better benefit of statin therapy associated with lowered levels of LDL-C and LP(a). And the long-term clinical prognosis is not affected among three genotypes. PMID- 24169328 TI - [The clinical patterns and RET proto-oncogene identification of pheochromocytoma in 13 multiple endocrine neoplasia type 2A pedigrees]. AB - OBJECTIVE: To explore the clinical patterns and clinical significance for RET screening in adrenal pheochromocytoma (PHEO) associated with multiple endocrine neoplasia type 2A (MEN2A). METHODS: The clinical data of 32 PHEO patients with MEN2A from 13 unrelated MEN2A pedigrees from August 1989 to January 2013 were analyzed. The comprehensive medical data included systemic examinations and germline RET gene screening. RESULTS: Among 68 patients belonging to 13 MEN2A families, 32 (47.1%) presented with PHEO. There were 19 males and 13 females with a mean age of (41 +/- 12) years. And the mean maximum diameter of PHEO was (4.6 +/- 2.2) cm. The diagnosis of PHEO was made after medullary thyroid carcinoma (n = 12, 37.5%), simultaneously (n = 12, 37.5%), initially (n = 7, 21.9%) and death during appendectomy for PHEO-induced hypertensive crisis (n = 1, 3.1%). The diagnosis of PHEO was made before (n = 22) or after (n = 10) clinical screening. The former had 12 symptomatic cases while the latter only 1 case (12/22 vs 1/10, P = 0.024).Except for 5 asymtomatic fatal cases during non-PHEO operations, bilateral PHEO was found in 17 cases including 3 unilaterally treated cases developing another PHEO in contralateral adrenal with a lag period of 5, 10 and 17 years. There were 7 symptomatic patients in bilateral cases versus 6 in unilateral cases (7/17 vs 6/10, P = 0.440). Twenty-five patients underwent PHEO surgery: laparascopic approach in 14 cases (8 with bilateral simultaneous adrenalectomy) and open approach in 11 (2 with bilateral simultaneous adrenalectomy). And 10 patients undergoing bilateral adrenal-sparing operations or adrenalectomy required hormonal replacement therapy. During a mean observation period of 72 (1-282) months, no local recurrence, distant metastasis or Addisonian crisis were noted in 25 cases (contralateral relapse in 3 cases). Among them, 2 cases developed adrenocortical insufficiency unresponsive to an adjustment of hormonal doses.RET screening showed 4 recurrent missense substitutions in 32 MEN2A-PHEO patients: p. C634Y exon 11 (n = 27, 84.4%), p. C634R exon 11 (n = 3, 9.4%), p. C634F exon 11 (n = 1, 3.1%) and p. C618R exon 10 (n = 1, 3.1%). CONCLUSIONS: The mutations of RET proto-oncognene of PHEO in MEN2A are frequently located at codon 634. A combination of pedigree examination and RET gene screening may facilitate an early diagnosis and early treatment of asymptomatic PHEO patients in MEN2A.Laparoscopic cortical-sparing adrenalectomy for preserving adrenocortical function is a preferred surgical approach. PMID- 24169329 TI - [Serum parathyroid hormone levels predict hospitalization in outpatients of heart failure: a preliminary study]. AB - OBJECTIVE: To evaluate the predicative value of serum parathyroid hormone (PTH) levels in outpatients of heart failure (HF) for hospitalization. METHODS: A total of 102 consecutive HF outpatients were enrolled. The receiver operating characteristic (ROC) curves demonstrated the optimal cut-off points of PTH levels for hospitalization due to HF. And Logistic regression analysis model was employed to analyze the independent association between PTH and hospitalization for HF. RESULTS: The more advanced grade of New York Heart Association (NYHA), the higher serum level of PTH. The ROC curves showed PTH levels >= 56.05 ng/L were the optimal cut-off point for hospitalization for HF with a sensitivity of 90.0%, a specificity of 89.2% and the area under ROC curve of 0.92. After adjustment for predictors for hospitalization due to HF (gender, age, diabetes mellitus, hypertension, left ventricular ejection fraction, estimated glomerular filtration rate and brain natriuretic peptide), PTH levels were associated with hospitalization due to HF (OR = 1.282, 95%CI 1.026-1.362). CONCLUSION: The serum level of PTH in HF outpatients is an independent predicator for hospitalization due to HF. PMID- 24169330 TI - [Primary testicular non-Hodgkin's lymphoma: clinical analysis of 21 cases]. AB - OBJECTIVE: To explore the clinical characteristics and prognosis of patients with primary testicular non-Hodgkin's lymphoma. METHODS: The clinical profiles and prognostic factors of 21 cases newly diagnosed as primary testicular non Hodgkin's lymphoma at Peking University Cancer Hospital from January 2005 to December 2012 were retrospectively analyzed. RESULTS: Their median age was 59 (34 86) years. And they were classified as Ann Arbor stage I (n = 8), stage II (n = 2) and stage IV (n = 11). There were B symptoms (n = 4), extranodal involvement outside testis (n = 12) and elevated lactate dehydrogenase (LDH) at diagnosis (n = 6). The scores of international prognostic index (IPI) were 0-1 point (n = 10), 3 points (n = 10) and 4 points (n = 1). The regimens included orchidectomy as the initial treatment (n = 15), chemotherapy followed by radiotherapy (n = 7) and CNS prophylaxis during treatment (n = 15). All patients were pathologically diagnosed as diffuse large B-cell lymphoma. And 11 cases belonged to the non-germinal center B cell-like subgroup.First-line chemotherapy was either R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine and prednisolone) or CHOP-like-based regimen. Complete response was achieved in 85.7% of patients. The median follow up period was 18 (6-58) months. The 1, 2 and 3-year survival rates were 100%, 80% and 60% respectively. Statistical analysis showed that the first-line chemotherapy with rituximab was a prognostic factor (P = 0.038).Other factors included stage (P = 0.275), LDH level (P = 0.179) , beta2-microglobulin level (P = 0.229) and IPI (P = 0.275) . CONCLUSIONS: The prognosis of primary testicular non-Hodgkin's lymphoma is usually poor. The first-line chemotherapy with rituximab is a prognostic factor. PMID- 24169331 TI - [Application of direct lymphangiography in the diagnosis of primary chyluria]. AB - OBJECTIVE: To discuss the role of direct lymphangiography in the diagnosis of primary chyluria. METHODS: Iodized oil was infused into lymphatic vessel of unilateral foot in 25 cases. The condition of lymphatic system imaging was dynamically observed via Innova 2100-IQ digital flat-panel angiography system. RESULTS: All of them underwent direct lymphangiography. The results revealed unilateral (n = 18) or bilateral (n = 7) renal reflux of contrast media. Among 22 stenotic cases, there were partial (n = 18) or whole (n = 4) cervical section of thoracic duct, no imaging in cervicothoracic section of thoracic duct (n = 1); thin imaging in cervical section and partial thoracic section (n = 2); retroperitoneal lymphangictasia & tortuous lymphatic vessels (n = 21); reflux of contrast medium to pelvic and/or contralateral sacroiliac part (n = 13). CONCLUSION: Capable of acquiring dynamic images of chyle (lymph) circulation, direct lymphangiography provides accurate estimation for the location, scope, extent of lesions of renal chylous reflux in primary chyluria so as to guide surgery. Stenotic cervical section of thoracic duct plays an important etiologic role in primary chyluria. PMID- 24169332 TI - [Composition analyses of bilateral urinary tract calculis]. AB - OBJECTIVE: To explore the composition of bilateral urinary tract calculi so as to guide treatments. METHODS: A total of 126 patients with bilateral urinary calculi were recruited to undergo percutaneous nephrolithotomy or ureteroscopes lithotripsy. And 256 extracted stones were analyzed by infrared spectrophotometry. RESULTS: The components of these stones were mainly mixture. The compositions included calcium oxalate (n = 214, 85%), carbonate apatite (n = 113, 45%), phosphate (n = 43, 17%) and uric acid (n = 28, 11%). And 63 patients had the same stone composition in bilateral urinary stones and 26 of them were of pure calcium oxalate, 2 phosphate while another 36 mixture. Different compositions were present in 60 patients with bilateral urinary stones. CONCLUSION: The compositions of bilateral urinary stones are not always identical in a patient. The overall patient status should be considered if one side urinary stone is treated according to the composition analysis results of another side counterpart. PMID- 24169333 TI - [Electroencephalogram evaluation of hyperphenylalaninemia patients on dietetic treatments]. AB - OBJECTIVE: To explore the electroencephalographic changes of patients with hyperphenylalaninemia (HPA) after dietetic treatments. METHODS: From July 2005 to February 2010, 34 HPA patients with abnormal electroencephalograms were recruited from China-Japan Friendship Hospital. Their electroencephalographic results and clinical features were compared before and after dietetic and antiepileptic treatments. There were 16 males and 18 females with an age range of 2 months to 8 years. All electroencephalographic results were abnormal. Among them, there were epileptic discharges (n = 17), atypical sharp-slow wave complex (n = 1) and slow wave background (n = 16). All patients received a low intake of phenylalanine at 13-50 mg.kg(-1).d(-1). Twenty patients had antiepileptic drug therapy. Before and after treatment for 3 months, 6 months, 1 year and 2 years, blood phenylalanine concentration, electroencephalogram, convulsion and other clinical parameters were observed. Before and after 1 year treatment, the tests of developmental quotient (DQ) or intelligence quotient (IQ) were performed. RESULTS: The phenylalanine concentrations of the same patient group decreased significantly after 3 months, 6 months, 1 and 2 years after dietetic treatment ( (0.51 +/- 0.39) , (0.50 +/- 0.29), (0.59 +/- 0.42), (0.53 +/- 0.27) vs (1.33 +/- 0.64) mmol/L, all P = 0.000). Among 19 epileptic cases, 16 ceased after treatment. And 14 stayed convulsion-free within 3 months post-treatments, 2 cases had intermittent tonic-clonic seizures while there was 1 case of focal seizures. Fourteen cases withdrew antiepileptic medications or reduced their doses. After treatment, the electroencephalographic results became totally normal in 8 of the 19 epileptic cases. Electroencephalographic results improved in 5 cases versus pre-treatment. Spikes were controlled in 10 cases including 5 patients with hyperarrhythmia in the abnormal electroencephalographic group with epilepsy. Six cases continued abnormal electroencephalogram. In the abnormal electroencephalographic group without epilepsy (n = 15) , electroencephalograms were normal (n = 3), improved (n = 6) and continued mild abnormal waves (n = 2). However, there were 4 cases with deteriorated electroencephalogram and 3 of them showed spikes. DQ (IQ) was evaluated in 16 cases. And variable mental retardation was observed in all of them. After, year treatment, 7 cases were evaluated DQ (IQ), and their results showed improved (57 +/- 16 vs 50 +/- 16, t = -5.42, P = 0.002). CONCLUSIONS: Etiological treatment for HPA patients is important for controlling epilepsy and improving brain function. And electroencephalogram is useful for monitoring brain functions and evaluating treatment outcomes. PMID- 24169334 TI - [Therapeutic effects of muscovite on ulcerative colitis in rats]. AB - OBJECTIVE: To explore the efficacy of muscovite on iodoacetamide -induced ulcerative colitis in rats and elucidate its possible mechanism. METHODS: Ulcerative colitis was induced in female Sprague-Dawley (SD) rats by an intracolonic injection of iodoacetamide. A total of 48 rats were divided randomly(by the method of random digits table) into 6 groups: control group, model group, low-dose muscovite group (360 mg/kg), high-dose muscovite group (720 mg/kg), 5-aminosalicylie acid (5-ASA) group and muscovite plus 5-ASA group (combined treatment), and each group had 8 rats. The body weight, disease activity index (DAI), macroscopic damage and microscopic score of rats in each group were subsequently evaluated after dosing for 7 days. The protein levels of tumor necrosis factor-alpha (TNF-alpha), interleukin-8 (IL-8) and myeloperoxidase (MPO) activity were detected by enzyme-linked immunosorbent assay(ELISA) while the activity of nuclear facor(NF)-kappaB was determined by immunohistochemistry.One way ANOVA and rank-sum test were used. RESULTS: After doing, body weight macroscopic damage, microscopic score, TNF-alpha concentration, MPO and NF-kappaB activity of rats in each group were all significantly correlated with the dose of muscovite (r = 0.573, -0.647, -0.569, 0.681, -0.811, -0.842, all P < 0.05). High-dose muscovite group had no significant difference with 5-ASA group in body weightt, DAI, macroscopic damage, microscopic score, IL-8 concentration, TNF-alpha concentration, MPO and NF-kappaB activities((166 +/- 5) vs (167 +/- 5) g, 0.33 (0.00, 1.17) vs 0.17 (0.00, 0.83), 2.50 (2.00, 4.00) vs 3.00 (2.00, 3.00), 3.00 (2.00, 3.00) vs 2.50 (2.00, 3.00), (109 +/- 17) vs (111 +/- 15) pg/ml, (166 +/- 38) vs (155 +/- 45) pg/ml, (52 +/- 6) vs (49 +/- 4) U/g, 7.39 +/- 0.42 vs 7.41 +/- 0.34, all P > 0.05). The MPO and NF-kappaB activities of combined treatment group were lower than those of 5-ASA group((40 +/- 4) vs (49 +/- 4) U/g, 4.67 +/- 0.72 vs 7.41 +/- 0.34, all P < 0.05). However, other indices showed no significant difference with 5-ASA group (all P > 0.05). CONCLUSIONS: Rectal administration of muscovite ameliorates colonic inflammation of iodoacetamide-induced colitis. Its underlying mechanism is probably due to the regulation of inflammatory response. Muscovite may be a potential therapeutic agent for treatment of ulcerative colitis. PMID- 24169335 TI - [Effects of glycyrrhizin on airway mucus hypersecretion induced by interleukin-13 in rats]. AB - OBJECTIVE: To explore the effects of glycyrrhizin on airway mucus hypersecretion induced by interleukin-13 (IL-13) in rats. METHODS: A total of 50 SD rats were divided randomly into 5 groups with a random digit table: control group, IL-13 group, and different dosage (25, 50, 75 mg/kg) glycyrrhizin groups. The integral of expression intensity in positive cells of airway epithelium under mucus histochemical stain was calculated with modality-quantitative method. HBE-16 cells were divided into 6 groups: negative control (physiological saline), IL-13 control (10 ug/L IL-13+physiological saline), different concentration glycyrrhizin interference (10 ug/L IL-13+25, 50 and 75 umol/L glycyrrhizin, respectively) and positive control (10 ug/L IL-13+25 umol/L zopolrestat). The expression of mucin (MUC) 5AC mRNA, MUC5AC protein, aldose reductase (AR) activity and reactive oxygen species (ROS) content were detected by reverse transcription-polymerase chain reaction (RT-PCR), Western blot, fluorometric method and fluorescence intensity with General Oxidative Stress Indicator (CM H2DFDA) catheter respectively. RESULTS: In vivo, the integral of expression intensity in positive stain cells of airway epithelium were 0.12 +/- 0.03, 0.87 +/- 0.13, 0.56 +/- 0.08, 0.46 +/- 0.06 and 0.35 +/- 0.04 respectively while the integral of different dosage glycyrrhizin groups was significantly lower than that of IL-13 group (all P < 0.05) with dose depentency and the IL-13 group was stronger than control group (P < 0.05). In vitro, the index of AR activity and ROS at 48 h of HBE16 cells in every group were 0.156 +/- 0.021, 0.692 +/- 0.039, 0.436 +/- 0.019, 0.323 +/- 0.042 and 0.290 +/- 0.027; 5.127 +/- 0.033, 24.257 +/- 3.263, 11.966 +/- 0.283, 8.892 +/- 0.521 and 6.426 +/- 0.173 respectively. The indices of IL-13 control group were higher than those of negative control group (P < 0.05) while those of different concentration glycyrrhizin interference groups were lower than those of IL-13 control group (all P < 0.05). The expressions of MUC5AC mRNA and protein of HBE16 cells in every group were 0.82 +/ 0.05, 3.22 +/- 0.12, 2.57 +/- 0.34, 2.09 +/- 0.54 and 1.58 +/- 0.22; 0.18 +/- 0.04, 0.65 +/- 0.15, 0.48 +/- 0.11, 0.33 +/- 0.19 and 0.26 +/- 0.06 respectively. The indices of IL-13 control group were higher than those of negative control group (P < 0.05) and those of different concentration glycyrrhizin interference groups were lower than those of IL-13 control group (P < 0.05). CONCLUSION: Glycyrrhizin may inhibit the expression of MUC5AC mRNA and MUC5AC protein induced by IL-13 and control the hypersecretion of airway mucus. PMID- 24169336 TI - [Expression and significance of Toll-like receptor-4 in rats lung established by passive smoking or associated with intratracheal instillation of lipopolysaccharide]. AB - OBJECTIVE: To explore the expression and effect of Toll-like receptor 4 (TLR-4) in the lung tissue of rats established by passive smoking or intratracheal instillation of lipopolysaccharide (LPS). METHODS: Eight-week-old male Sprague Dawley rats (n = 15) were randomly divided into 3 groups, including: (1) group A: conventional breeding; (2) group B: the rats were placed into a 120-L organic glass box with twice-daily exposure to cigarette smoking plus an intratracheal instillation of water at Day 1 and 14; (3) Group C: exposure to cigarette smoking the same as group B plus intratracheal instillation of lipopolysaccharide (1 mg/kg) at Day 1 and 14. Four weeks later, general status, arterial blood gas, pulmonary function and histopathology were analyzed. The expressions of TLR-4 and nuclear factor kappa-B (NF-kappaB) were determined by immunohistochemistry. Western blot was used to measure the protein contents of TLR-4, NF-kappaB, p Ikappa-Kalpha/beta, Ikappa-Kalpha/beta, IkappaB-alpha. And real-time polymerase chain reaction (PCR) was employed to detect the mRNA levels of tumor necrosis factor alpha (TNF-alpha) and interleukin-6 (IL-6). RESULTS: Rats in Groups B and C were marantic with intermittent cough and dyspnea. Peak expiratory flow (PEF) and 50% expiratory flow-volume (EP50) were much lower in Group C ((10.6 +/- 1.4), (0.77 +/- 0.14) ml/s) than that in Groups A ((13.5 +/- 2.0), (1.01 +/- 0.08) and B (12.3 +/- 0.9), (0.91 +/- 0.10) ml/s) (all P < 0.05). Accumulated volume (AV) and carbon dioxide pressure (PCO2) were much higher in Groups B ((4358 +/- 1501) ml, (52.77 +/- 1.97) mm Hg) (1 mm Hg = 0.133 kPa) and C ((10 077 +/- 1866) ml, (51.03 +/- 4.96) mm Hg) than that in Group A ((1735 +/- 798) ml, (39.57 +/- 1.43) mm Hg) (all P < 0.05). Hematoxylin and eosin stain showed chronic bronchitis and emphysema in Groups B and C. Besides, quantitative analysis demonstrated that in unit area, mean lining interval (MLI) and destruction index (DI) in Group B ((84 +/- 13) um, 0.228 +/- 0.047) and Group C ((86 +/- 10) um, 0.294 +/- 0.060) significantly increased versus Group A ((65 +/- 6) um, 0.036 +/- 0.012) (all P < 0.05). Immunohistochemical staining indicated that the expression of TLR-4 in cytoplasm and cytomembrane and NF-kappaB in nucleus markedly increased in Groups B and C versus Group A. Relative expressions of TLR-4 and NF-kappaB assayed by Western blot increased in Group B (0.68 +/- 0.03, 0.21 +/- 0.08) and Group C (1.12 +/- 0.11, 0.59 +/- 0.06) than that in Group A (1.36 +/- 0.07, 1.04 +/- 0.08). Compared with Group A, the expression levels of TLR-4, NF-kappaB and IkappaB-alpha and the phosphorylation levels of Ikappa-Kalpha/beta in Group B and C significantly increased (all P < 0.05). The mRNA levels of TNF-alpha and IL-6 increased in Group B (3.95 +/- 0.29, 5.04 +/- 0.28) and C (5.33 +/- 0.26, 7.23 +/ 0.39) versus that in Group C (1.00 +/- 0.37, 1.00 +/- 0.25) (all P < 0.05). CONCLUSIONS: Both passive smoking and intratracheal instillation of LPS may cause lung injury analogous to chronic obstructive pulmonary disease via NF-kappaB signaling pathway. And TLR4 plays an important role in this process. PMID- 24169337 TI - [Cytosine deaminase and thymidine kinase double suicide gene system driven by carcinoembryonic antigen promoter for the treatment of colorectal carcinoma xenograft in nude mice]. AB - OBJECTIVE: To explore the therapeutic efficacy of double suicide gene system driven by carcinoembryonic antigen (CEA) promoter (Cp-CDglyTK) on colorectal carcinoma xenograft in nude mice. METHODS: The plasmid pcDNA3.1(-)Cp-CDglyTK was transfected into the CEA-positive SW480 and CEA-negative HeLa cells respectively. The expression of suicide gene was detected by RT-PCR. And the transfected cells were treated with 5-fluorocytosine (5-FC) and ganciclovir (GCV) at different concentrations and the cell-killing and bystander effects assayed by methyl thiazolyl tetrazolium (MTT). By a transplantation of cultivated cells, SW480 or HeLa cell lines were injected subcutaneously into right axillary of nude mice to establish 96 SW480 and 72 HeLa tumor animal models. Nude mice were completely randomized with statistical software according to tumor volume. For prodrug therapy, 48 SW480-bearing mice were divided equally into 4 groups of I-IV. At the same time, 48 HeLa-bearing mice were divided equally into 4 groups of V-VIII. Groups I & V received an intratumoral injection of PBS, groups II & VIGCV and 5 FC intratumorally, groups III & VII PBS intraperitoneally and groups IV & VIII GCV and 5-FC intraperitoneally. Forty-eight SW480-bearing mice were divided equally into 4 groups of IX~XII and 24 Hela-bearing ones into groups of & in therapy experiment by suicide gene plus prodrug. Six groups received an intratumoral injection of liposome Lipofectamine and plasmid CP-CDglyTK and then an intraperitoneal injection of drug. The groups of IX and received an injection of PBS, group X GCV, group XI 5-FC and groups XII & GCV and 5-FC. The observation parameters included tumor bulk, tumor weight, survival time and treatment effect in each group. RESULTS: SW480 cells transfected by plasmid pcDNA3.1(-)Cp- CDglyTK expressed CDglyTK gene. The inhibition rates of GCV and 5-FC were significantly higher than those of HeLa cells (59.87% +/- 0.21% vs 9.90% +/- 0.09%, P < 0.01). And higher inhibition rates and stronger bystander effect existed in double versus single produg (all P < 0.05). Tumor size, final tumor weight and survival time of nude mice in groups ofII, IV, VI & VIII had no significant difference with groups ofI, III, V & VII (all P < 0.05). Final tumor size and weight of group XII was significantly smaller than those of groups of IX, X and XI ((150.0 +/- 3.2) vs (522.5 +/- 1.9) and (256.8 +/- 10.4) and (260.7 +/- 2.2) mm(3), (54.1 +/- 10.4) vs (682.0 +/- 12.0) and (251.8 +/- 15.1) and (271.6 +/- 17.7) mg, all P < 0.05). Meanwhile, the tumor inhibition rate and survival time of group XII(92.1% and (25.7 +/- 0.8)d) were significant higher and longer than group X (63.1% and (21.8 +/- 0.5) d) and group XI (60.2% and (18.0 +/- 0.9) d) (all P < 0.05). However, no significant difference existed in tumor size, final tumor weight and survival time between groups and (all P > 0.05). The inhibition rate of group was merely 0.9%. CONCLUSION: CDglyTK double suicide gene system driven by CEA promoter may inhibit CEA positive colorectal cancer xenograft in prodrug treated nude mice. PMID- 24169338 TI - [Knocking down TRPC1 expression by siRNA inhibits proliferation and invasiveness of human lung adenocarcinoma cell A549 in vitro]. AB - OBJECTIVE: To evaluate the effects of down-regulated expression of transient receptor potential canonical (TRPC1) by RNA interference (RNAi) on proliferation and invasiveness of human lung adenocarcinoma cell A549 in vitro. METHODS: A549 cells were transfected with chemically synthesized small interfering RNA (siRNA) targeting TRPC1 gene. The mRNA and protein of TRPC1 were analyzed by real-time polymerase chain reaction (PCR) and Western blot respectively. To assess malignant phenotypes of transfected A549 cells, the assays of methyl thiazolyl tetrazolium (MTT), cell cycle and cell invasion were performed. RESULTS: siRNA targeting TRPC1 dramatically suppressed TRPC1 expression. In vitro study showed that siRNA targeting TRPC1 significantly inhibited cell proliferation of A549 cells with an inhibitory rate of 34.7% while negative control siRNA had no effect on cell proliferation. Flow cytometric analysis showed that siRNA targeting TRPC1 increased the number of cells in G0/G1 phase (P < 0.05) . Moreover, a knockdown of TRPC1 expression effectively inhibited cell invasiveness in A549 cells (P < 0.05) . CONCLUSION: Knocking down TRPC1 expression can inhibit proliferation and invasiveness of A549 cells in vitro. PMID- 24169339 TI - [Establishment of enzyme-linked immunosorbent assay in the detection of BP180NC16A-specific IgE and its significance in bullous pemphigoid]. AB - OBJECTIVE: To establish a method of detecting circulating immunoglobulin E (IgE) autoantibodies for BP180NC16A and evaluate its significance in bullous pemphigoid (BP). METHODS: GST-NC16A fusion proteins were expressed in Escherichia coli using the pGEX-2T expression system and purified by glutathione affinity chromatography.For optimal working conditions of enzyme-linked immunoabsorbent assay (ELISA), checkerboard titrations were performed with serial dilutions of antigen. Also optimized dilution of secondary antibody was confirmed. Sera samples from 56 patients with BP, 24 healthy controls, 18 with pemphigus and 1 with Stevens-Johnson syndrome at our hospital during February 2011 to October 2012 were examined by the modified ELISA approach. The optimal cut-off point for a positive result was selected with receiver operating characteristic analysis. RESULTS: The optimized ELISA was performed with plates coated with 500 ug/ml GST NC16A. And the optimal dilutions of sera samples and secondary antibody were 1: 10 and 1: 1000 respectively. According to the established cut-off value (0.549), 40 of 56 BP patients and none of controls had detectable levels of BP180NC16A IgE. CONCLUSION: The established ELISA provides a highly specific tool for the detection of IgE anti-BP180NC16A in BP patients. PMID- 24169340 TI - Does liver ischemic preconditioning in brain death donors induce kidney preconditioning? A retrospective analysis. AB - BACKGROUND: It is unclear whether ischemic preconditioning (IPC) of solid organs induces remote IPC (RIPC) in donors after brain death (DBD). METHODS: Outcomes in kidney recipients from 163 DBD in two randomized trials of liver IPC (5 min=62 and 10 min=101) were obtained retrospectively from the Scientific Registry of Transplant Recipients. Controls were kidney recipients from donors without IPC. Mean cold ischemia times were less than 20 hr. Primary outcomes were delayed graft function, defined as dialysis during the first posttransplantation week, and death-censored graft survival. Secondary outcomes were duration of initial hospital stay, patient survival, and estimated glomerular filtration rate 6, 12, 36, and 60 months after transplantation. RESULTS: After exclusions (40 kidneys not recovered, 21 not transplanted, 8 en bloc, 23 with extrarenal organs, and 6 with missing records), 228 recipients were included. Delayed graft function occurred in 23% of No RIPC and 28% of RIPC kidneys (P=0.54). One- and 3-year graft survival rates were 92% and 90%, respectively, in the No RIPC and 90% and 81%, respectively, in the RIPC group (P=0.12), and mean hospital stay was 9.3+/ 13.9 and 9.7+/-8.2 days, respectively (P=0.15). There were no significant between group differences in patient survival and estimated glomerular filtration rate at any time point. CONCLUSIONS: Despite design and power limitations, our results suggest that liver IPC in DBD is of no clinical benefit to kidney recipients. Inconsistent efficacy and impracticality severely limit the usefulness of IPC in DBD. Other modalities of preconditioning should be tested. PMID- 24169341 TI - Relationship between vegetable and carotene intake and risk of prostate cancer: the JACC study. AB - BACKGROUND: We examined the associations of intakes of vegetables and carotenes with risk of prostate cancer in Japanese. METHODS: A total of 15,471 Japanese men participating in the Japan Collaborative Cohort study completed a questionnaire including food intake. Of them, 143 incident prostate cancers were documented. We examined the associations stated above by using Cox proportional hazard model. RESULTS: Vegetable intake was not associated with the risk of prostate cancer, but so was dietary alpha-carotene intake. The multivariable hazard ratio (95%CI) in the secondary highest and highest quintiles of alpha-carotene intake was 0.50 (0.26-0.98) (P=0.043) and 0.46 (0.22-0.97) (P=0.041) (P for trend=0.224), respectively. Beta-carotene intake was not associated with the risk of prostate cancer. CONCLUSION: Alpha-carotene intake was associated with lower risk of prostate cancer among Japanese. PMID- 24169342 TI - The effects of multidisciplinary rehabilitation: RePCa-a randomised study among primary prostate cancer patients. AB - BACKGROUND: The objective of this study is the effectiveness of multidisciplinary rehabilitation on treatment-related adverse effects after completed radiotherapy in patients with prostate cancer (PCa). METHODS: In a single-centre oncology unit in Odense, Denmark, 161 PCa patients treated with radiotherapy and androgen deprivation therapy were randomly assigned to either a programme of two nursing counselling sessions and two instructive sessions with a physical therapist (n=79) or to usual care (n=82). Primary outcome was Expanded Prostate Cancer Index Composite (EPIC-26) urinary irritative sum-score. Before radiotherapy, pre intervention 4 weeks after radiotherapy, and after a 20-week intervention, measurements included self-reported disease-specific quality of life (QoL; EPIC 26, including urinary, bowel, sexual, and hormonal symptoms), general QoL (Short form-12, SF-12), pelvic floor muscle strength (Modified Oxford Scale), and pelvic floor electromyography. Intension-to-treat analyses were made with adjusted linear regression. RESULTS: The intervention improved, as compared with controls, urinary irritative sum-score 5.8 point (Cohen's d=0.40; P=0.011), urinary sum score (d=0.34; P=0.023), hormonal sum-score (d=0.19; P=0.018), and the SF-12 Physical Component Summary, d=0.35; P=0.002. Patients with more severe impairment gained most. Pelvic floor muscle strength measured by electromyography declined in both groups, P=0.0001. CONCLUSION: Multidisciplinary rehabilitation in irradiated PCa patients improved urinary and hormonal symptoms, and SF-12 physical QoL. PMID- 24169343 TI - Direct targeting of SUZ12/ROCK2 by miR-200b/c inhibits cholangiocarcinoma tumourigenesis and metastasis. AB - BACKGROUND: The multidrug resistance and distant metastasis of cholangiocarcinoma result in high postoperative recurrence and low long-term survival rates. It has been demonstrated that the ectopic expression of miR-200 suppresses the multidrug resistance and metastasis of cancer. However, the expression and function of miR 200 in cholangiocarcinoma has not yet been described. METHODS: In this study, we identified dysregulated microRNAs (miRNAs, miR) in cholangiocarcinoma tissue by microarray analysis, and subsequent real-time PCR and northern blot analyses validated the expression of candidate miR. We performed functional analyses and investigated the relationship between miR-200b/c expression and the properties of cholangiocarcinoma cells. A dual luciferase assay was applied to examine the effect of miRNAs on the 3'-UTR of target genes, and we demonstrated the function of the target gene by siRNA transfection identifying the downstream pathway via western blotting. RESULTS: We found significantly downregulated expression of four miR-200 family members (miR-200a/b/c/429) and then confirmed that ectopic miR-200b/200c inhibits the migration and invasion of cholangiocarcinoma cells both in vitro and in vivo. We found that miR-200b/c influenced the tumourigenesis of cholangiocarcinoma cells including their tumour-initiating capacity, sphere formation, and drug resistance. We further found that miR-200b/c regulated migration and invasion capacities by directly targeting rho-kinase 2 and regulated tumorigenic properties by directly targeting SUZ12 (a subunit of a polycomb repressor complex). CONCLUSION: Our study shows that miR-200b/c has a critical role in the regulation of the tumorigenic and metastatic capacity of cholangiocarcinoma and reveals the probable underlying mechanisms. PMID- 24169344 TI - Tumour-infiltrating lymphocytes predict for outcome in HPV-positive oropharyngeal cancer. AB - BACKGROUND: Human papillomavirus (HPV)-positive oropharyngeal cancer (OPSCC) is associated with improved survival compared with HPV-negative disease. However, a minority of HPV-positive patients have poor prognosis. Currently, there is no generally accepted strategy for identifying these patients. METHODS: We retrospectively analysed 270 consecutively treated OPSCC patients from three centres for effects of clinical, pathological, immunological, and molecular features on disease mortality. We used Cox regression to examine associations between factors and OPSCC death, and developed a prognostic model for 3-year mortality using logistic regression analysis. RESULTS: Patients with HPV-positive tumours showed improved survival (hazard ratio (HR), 0.33 (0.21-0.53)). High levels of tumour-infiltrating lymphocytes (TILs) stratified HPV-positive patients into high-risk and low-risk groups (3-year survival; HPV-positive/TIL(high)=96%, HPV-positive/TIL(low)=59%). Survival of HPV-positive/TIL(low) patients did not differ from HPV-negative patients (HR, 1.01; P=0.98). We developed a prognostic model for HPV-positive tumours using a 'training' cohort from one centre; the combination of TIL levels, heavy smoking, and T-stage were significant (AUROC=0.87). This model was validated on patients from the other centres (detection rate 67%; false-positive rate 5.6%; AUROC=0.82). INTERPRETATION: Our data suggest that an immune response, reflected by TIL levels in the primary tumour, has an important role in the improved survival seen in most HPV-positive patients, and is relevant for the clinical evaluation of HPV-positive OPSCC. PMID- 24169345 TI - Targeting focal adhesion turnover in invasive breast cancer cells by the purine derivative reversine. AB - BACKGROUND: The dynamics of focal adhesion (FA) turnover is a key determinant for the regulation of cancer cell migration. Here we investigated FA turnover in a panel of breast cancer models with distinct invasive properties and evaluated the impact of reversine on this turnover in relation to cancer cell invasion in in vitro and in vivo conditions. METHODS: Live imaging and immunofluorescence assays were used to investigate FA turnover in breast cancer cells. Biochemical studies were used to investigate the impact of reversine on FA signalling and turnover. In vivo activity was investigated using orthotopic breast cancer mouse models. RESULTS: Accelerated FA disassembly from plasma membrane protrusions was observed in invasive compared with non-invasive breast cancer cells or non-immortalised mammary epithelial cells. Reversine significantly inhibited FA disassembly leading to stable FAs, which was associated with reduced cell motility and invasion. The inhibitory effect of reversine on FA turnover accounted for a large part on its capacity to interfere with FAK function on regulating its downstream targets. In orthotopic breast cancer mouse models, reversine revealed a potent inhibitory activity on tumour progression to metastasis. CONCLUSION: These results support the utility of targeting FA turnover as a therapeutic approach for invasive breast cancer. PMID- 24169346 TI - CYP2C19 genotype-based phase I studies of a c-Met inhibitor tivantinib in combination with erlotinib, in advanced/metastatic non-small cell lung cancer. AB - BACKGROUND: A previous clinical study in non-small cell lung cancer (NSCLC) patients in Western countries suggested the potential for combination of a first in-class non-ATP-competitive c-Met inhibitor tivantinib with an epidermal growth factor receptor-tyrosine kinase inhibitor erlotinib. Polymorphisms of CYP2C19, the key metabolic enzyme for tivantinib, should be addressed to translate the previous Western study to Asian population, because higher incidence of poor metabolisers (PMs) is reported in Asian population. METHODS: Japanese patients with advanced/metastatic NSCLC received tivantinib in combination with erlotinib to evaluate safety and pharmacokinetics. Doses of tivantinib were escalated separately for extensive metabolisers (EMs) and PMs. RESULTS: Tivantinib, when combined with erlotinib, was well tolerated up to 360 mg BID for EMs and 240 mg BID for PMs, respectively. Among 25 patients (16 EMs and 9 PMs), the adverse events (AEs) related to tivantinib and/or erlotinib (>20%, any grade) were rash, diarrhoea, dry skin and nausea. Grade >=3 AEs were leukopenia, anaemia and neutropenia. No dose-limiting toxicity was observed. Pharmacokinetics profile of tivantinib was not clearly different between the combination and monotherapy. Three partial response and three long-term stable disease (>=24 weeks) were reported. CONCLUSION: Two doses of tivantinib in combination with erlotinib were recommended based on CYP2C19 genotype: 360 mg BID for EMs and 240 mg BID for PMs. PMID- 24169347 TI - Strong reduction of AGO2 expression in melanoma and cellular consequences. AB - BACKGROUND: Processing of microRNAs (miRNAs) is a highly controlled process. Deregulation of miRNA expression was observed in several types of cancer but changes in the miRNA-processing enzymes have not been analysed until today. In this study, we analysed Argonaute2 (AGO2, EIF2C2), as one main factor of the miRNA processing ensemble, in the context of cancer development, especially in melanoma. METHODS: We determined the AGO2 expression level in melanoma, as well as in other cancers, with biochemical approaches (qRT-PCR, western blot and immunofluorescence studies) and analysed the cell behaviour in migration assays. RESULTS: Specifically in melanoma, we revealed a strong reduction of AGO2 expression compared with primary melanocytes. The reduction of AGO2 expression was only found on protein level, whereas the mRNA level stayed unchanged hinting to post-transcriptional regulation. We could show that re-expression of AGO2 in melanoma leads to a strong improvement of regulatory effects due to increased functionality of small-interfering RNAs and short hairpin RNAs. CONCLUSION: We identified melanoma-specific downregulation of AGO2 and corresponding reduced RNAi efficiency. These findings will help to understand the molecular basis of malignant melanoma and can potentially lead to an improvement of therapeutic strategies. PMID- 24169348 TI - Inflammation as a validated prognostic determinant in carcinoma of unknown primary site. AB - BACKGROUND: Carcinoma of unknown primary (CUP) is a clinical presentation with a poor prognosis. Inflammation-based prognostic systems are stage-independent prognostic predictors in various malignancies. We aimed to assess the accuracy of the modified Glasgow Prognostic Score (mGPS), neutrophil/lymphocyte ratio (NLR) and platelet/lymphocyte ratio (PLR) as objective prognostic models in CUP. METHODS: We derived inflammatory scores in 60 consecutive CUP referrals to the Imperial College oncology unit between 1996 and 2011. Patient demographics, treatment and staging data and full blood profiles were collected. An independent cohort of 179 patients presenting to the Taipei Veterens Hospital between 2000 and 2009 were used as a 'validation' data set. Uni- and multivariate survival analysis was used to predict the overall survival (OS). RESULTS: Sixty patients were included: median age 61 (range: 33-86); 51% men; median OS 5.9 months (0.7 42.9); 88% with distant metastases. On univariate analysis NLR >5 (P=0.04) and mGPS (score 1-2) (P=0.03) correlated with OS. Multivariate analysis demonstrated significant hazard ratios for NLR; 2.02 (CI 1.0-4.1) (P=0.04) and mGPS; 1.52 (CI 1.0-2.3) (P=0.03). These findings were reinforced by analysis of the validation data. CONCLUSION: NLR and mGPS are independent, externally validated prognostic markers in CUP, with superior objectivity compared with performance status. PMID- 24169349 TI - Ethnic differences in breast cancer incidence in England are due to differences in known risk factors for the disease: prospective study. AB - BACKGROUND: In the United Kingdom, breast cancer incidence is lower in South Asian and Black women than in White women, but the extent to which this is due to known risk factors is unknown. In a large prospective study, we describe breast cancer incidence by ethnicity, before and after adjustment for known risk factors for the disease. METHODS: Women were recruited into the Million Women Study in 1996-2001, when information on reproductive and lifestyle factors known to influence the risk of breast cancer was obtained. Ethnicity was determined from study questionnaires and hospital admission data. Cox regression models were used to calculate adjusted relative risks (RR) for incident breast cancer in South Asians and Blacks compared with Whites. RESULTS: Analyses included 5877 South Asian, 4919 Black, and 1,038,144 White women in England. The prevalence of 8 out of the 9 risk factors for breast cancer examined, differed substantially by ethnicity (P<0.001 for each), such that South Asian and Black women were at a lower risk of the disease than White women. During 12.2 years of follow-up incident breast cancer occurred in 217 South Asians, 180 Blacks, and 45,191 Whites. As expected, breast cancer incidence was lower in South Asians (RR=0.82, 95% CI 0.72-0.94) and Blacks (RR=0.85, 0.73-0.98) than in Whites when the analyses were adjusted only for age and region of residence. However, after additional adjustment for the known risk factors for the disease, breast cancer incidence was similar to that of Whites, both in South Asians (0.95, 0.83-1.09) and in Blacks (0.91, 0.78-1.05). CONCLUSION: South Asian and Black women in England have lower incidence rates of breast cancer than White women, but this is largely, if not wholly, because of differences in known risk factors for the disease. PMID- 24169350 TI - Comparisons of vaginal and abdominal radical trachelectomy for early-stage cervical cancer: preliminary results of a multi-center research in China. AB - BACKGROUND: There are limited data comparing the prognosis and fertility outcomes of the patients with early cervical cancer treated by trans-vaginal radical trachelectomy (VRT) or abdominal radical trachelectomy (ART).The objective of this study was to compare the surgical and pathologic characteristics, the prognosis and fertility outcomes of the patients treated by VRT or ART. METHODS: Matched-case study based on a prospectively maintained database of patients underwent radical trachelectomy in 10 centres of China was designed to compare the prognosis and fertility outcomes of the patients treated by VRT or ART. RESULTS: Totally 150 cases, 77 in the VRT and 73 in the ART group, were included. VRT and ART provide similar surgical and pathological outcomes except larger specimens obtained by ART. In the ART group, no patient developed recurrent diseases, but, in the VRT group, 7 (9.8%) patients developed recurrent diseases and 2 (1.6%) patients died of the tumours (P=0.035). The rate of pregnancy in the VRT group was significantly higher than those of ART (39.5% vs 8.8%; P=0.003). The patients with tumour size >2 cm showed significant higher recurrent rate (11.6% vs 2.4%, P<0.05) and lower pregnant rate (12.5% vs 32.1%, P=0.094) compared with the patients with tumour size <2 cm. CONCLUSION: Patients treated by ART obtained better oncology results, but their fertility outcomes were unfavourable compared with VRT. Tumour size <2 cm should be emphasised as an indication for radical trachelectomy for improving the outcome of fertility and prognosis. PMID- 24169351 TI - Intratumoral regulatory T cells upregulate immunosuppressive molecules in head and neck cancer patients. AB - BACKGROUND: Although regulatory T cells (Treg) are highly enriched in human tumours compared with peripheral blood, expression of the immune-checkpoint receptors, immunosuppressive molecules and function of Treg in these two sites remains undefined. METHODS: Tumour-infiltrating lymphocytes and peripheral blood lymphocytes were isolated from a cohort of head and neck squamous cell carcinoma (HNSCC) patients. The immunosuppressive phenotypes and function of intratumoral Treg were compared with those of peripheral blood Treg. RESULTS: The frequency of immune-checkpoint receptor-positive cells was higher on intratumoral FOXP3(+)CD25(hi) Treg compared with circulating Treg (CTLA-4, P=0.002; TIM-3, P=0.002 and PD-1, P=0.002). Immunosuppressive effector molecules, LAP and ectonucleotidase CD39 were also upregulated on intratumoral FOXP3(+) Treg (P=0.002 and P=0.004, respectively). CTLA-4 and CD39 were co-expressed on the majority of intratumoral FOXP3(+)CD4(+) Treg, suggesting that these molecules have a key role in regulatory functions of these cells in situ. Notably, intratumoral Treg exhibited more potently immunosuppressive activity than circulating Treg. CONCLUSION: These results indicate that intratumoral Treg are more immunosuppressive than circulating Treg and CTLA-4 and CD39 expressed can be potential target molecules to inhibit suppressive activities of intratumoral Treg in situ. PMID- 24169352 TI - Impact of sentinel node biopsy on long-term quality of life in breast cancer patients. AB - BACKGROUND: The aim of this study was to assess long-term quality of life (QoL) over a period of 6 years in women with breast cancer (BC) who underwent sentinel lymph node biopsy (SLNB), axillary lymph node dissection (ALND), or SLNB followed by ALND. METHODS: The European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC-QLQ)-C30 and the EORTC-QLQ-BR-23 questionnaires were used to assess QoL before surgery, just after surgery, 6, 12 and 72 months later. The longitudinal effect of surgical modalities on QoL was assessed with a mixed model analysis of variance for repeated measurements. RESULTS: Five hundred and eighteen BC patients were initially included. The median follow-up was 6 years. During the follow-up, 61 patients died. None of the patients of the SLNB group developed lymphedema during follow-up and the relapse rate was similar in the different groups (P=0.62). Before surgery, global health status (P=0.52) and arm symptoms (BRAS) (P=0.99) QoL scores were similar whatever the surgical procedure. The BRAS score (P=0.0001) was better in the SLNB group 72 months after surgery. Moreover, during follow-up, patients treated with SLNB had lower arm symptoms scores than ALND patients and there was no difference for arm symptoms between patients treated with ALND and those treated with SLNB followed by complementary ALND. CONCLUSION: Long-term follow-up showed that SLNB was associated with less morbidity than ALND. PMID- 24169353 TI - First-in-human Phase I study of EZN-4176, a locked nucleic acid antisense oligonucleotide to exon 4 of the androgen receptor mRNA in patients with castration-resistant prostate cancer. AB - BACKGROUND: Prostate cancer remains dependent of androgen receptor (AR) signalling, even after emergence of castration resistance. EZN-4176 is a third generation antisense oligonucleotide that binds to the hinge region (exon 4) of AR mRNA resulting in full-length AR mRNA degradation and decreased AR protein expression. This Phase I study aimed to evaluate EZN-4176 in men with castration resistant prostate cancer (CRPC). METHODS: Patients with progressing CRPC were eligible; prior abiraterone and enzalutamide treatment were allowed. EZN-4176 was administered as a weekly (QW) 1-h intravenous infusion. The starting dose was 0.5 mg kg(-1) with a 4-week dose-limiting toxicity (DLT) period and a 3+3 modified Fibonacci dose escalation design. After determination of the DLT for weekly administration, an every 2 weeks schedule was initiated. RESULTS: A total of 22 patients were treated with EZN-4176. At 10 mg kg(-1) QW, two DLTs were observed due to grade 3-4 ALT or AST elevation. No confirmed biochemical or soft tissue responses were observed. Of eight patients with <5 circulating tumour cells at baseline, a conversion to <5 was observed in three (38%) patients. The most common EZN-4176-related toxicities (all grades) were fatigue (59%), reversible abnormalities in liver function tests ALT (41%) and AST (41%) and infusion related reactions including chills (36%) and pyrexia (14%). CONCLUSION: Activity of EZN-4176 at the doses and schedules explored was minimal. The highest dose of 10 mg kg(-1) QW was associated with significant but reversible transaminase elevation. PMID- 24169354 TI - Choline and betaine intakes are associated with reduced risk of nasopharyngeal carcinoma in adults: a case-control study. AB - BACKGROUND: Intakes of choline and betaine have been inversely related to the risk of various neoplasms, but scant data exist on nasopharyngeal carcinoma (NPC). We examined the association between consumption of choline and betaine and risk of NPC. METHODS: We conducted a case-control study with 600 incident NPC patients and 600 controls 1 : 1 matched by age, sex and household type in Guangdong, China. Dietary intake was assessed by a food frequency questionnaire through face-to-face interview. RESULTS: Intakes of total choline, betaine and choline+betaine were inversely related to NPC after adjustment for various lifestyle and dietary factors (all P-trend <0.001). Adjusted odds ratios (95% CI) for quartile 4 (vs quartile 1) were 0.42 (0.29, 0.61) for total choline, 0.50 (0.35, 0.72) for betaine and 0.44 (0.30, 0.64) for betaine+total choline. Regarding various sources of choline, lower NPC risk was associated with greater intakes of choline from phosphatidylcholine, free choline, glycerophosphocholine and phosphocholine, but not sphingomyelin. CONCLUSION: These findings are consistent with a beneficial effect of choline and betaine intakes on carcinogenesis. PMID- 24169355 TI - Phase II trial of docetaxel, cisplatin and 5FU chemotherapy in locally advanced and metastatic penis cancer (CRUK/09/001). AB - BACKGROUND: Penis cancer is rare and clinical trial evidence on which to base treatment decisions is limited. Case reports suggest that the combination of docetaxel, cisplatin and 5-flurouracil (TPF) is highly active in this disease. METHODS: Twenty-nine patients with locally advanced or metastatic squamous carcinoma of the penis were recruited into a single-arm phase II trial from nine UK centres. Up to three cycles of chemotherapy were received (docetaxel 75 mg m( 2) day 1, cisplatin 60 mg m(-2) day 1, 5-flurouracil 750 mg m(-2) per day days 1 5, repeated every 3 weeks). Primary outcome was objective response (assessed by RECIST). Fourteen or more responses in 26 evaluable patients were required to confirm a response rate of 60% or higher (Fleming-A'Hern design), warranting further evaluation. Secondary endpoints included toxicity and survival. RESULTS: 10/26 evaluable patients (38.5%, 95% CI: 20.2-59.4) achieved an objective response. Two patients with locally advanced disease achieved radiological complete remission. 65.5% of patients experienced at least one grade 3/4 adverse event. CONCLUSION: Docetaxel, cisplatin and 5FU did not reach the pre-determined threshold for further research and caused significant toxicity. Our results do not support the routine use of TPF. The observed complete responses support further investigation of combination chemotherapy in the neoadjuvant setting. PMID- 24169356 TI - MiR-125b acts as an oncogene in glioblastoma cells and inhibits cell apoptosis through p53 and p38MAPK-independent pathways. AB - BACKGROUND: We have recently identified miR-125b upregulation in glioblastoma (GMB). The aim of this study is to determine the correlation between miR-125b expression and malignant grades of glioma and the genes targeted by miR-125b. METHODS: Real-time PCR was employed to measure the expression level of miR-125b. Cell viability was evaluated by cell growth and colony formation in soft-agar assays. Cell apoptosis was determined by Hoechst 33342 staining and AnnexinV-FITC assay. The Luciferase assay was used to confirm the actual binding sites of p38MAPK mRNA. Western blot was used to detect the gene expression level. RESULTS: The expression level of miR-125b is positively correlated with the malignant grade of glioma. Ectopic expression of miR-125b promotes the proliferation of GMB cells. Knockdown of endogenous miR-125b inhibits cell proliferation and promotes cell apoptosis. Further studies reveal that p53 is regulated by miR-125b. However, downregulation of the endogenous miR-125b also results in p53 independent apoptotic pathway leading to apoptosis in p53 mutated U251 cells and p53 knockdown U87 cells. Moreover, p38MAPK is also regulated by miR-125b and downregulation of miR-125b activates the p38MAPK-induced mitochondria apoptotic pathway. CONCLUSION: High-level expression of miR-125b is associated with poor outcomes of GMB. MiR-125b may have an oncogenic role in GMB cells by promoting cell proliferation and inhibiting apoptosis. PMID- 24169357 TI - Tumour shrinkage measured with first treatment evaluation under VEGF-targeted therapy as prognostic marker in metastatic renal cell carcinoma (mRCC). AB - BACKGROUND: The aim of our analysis is to further characterise the prognostic relevance of early tumour shrinkage (TS) during VEGF-targeted therapy in mRCC, in order to explore whether this could define a group of patients with long-term survivorship. METHODS: A hundred patients were stratified into five subgroups according to their change of tumour size with first treatment evaluation: -100% to -60%; -59% to -30% and -29% to 0% TS or gain of tumour size from 1% to 19% and <=20% or occurrence of new lesions (i.e., progressive disease). RESULTS: The median PFS and OS were 10.4 months and 28.2 months, respectively. The median OS stratified according to the subgroups as described above was 77.4, 33.5, 26.9, 30.0 and 14.3 months, respectively. Multivariate analysis revealed early TS as a prognostic marker (P=0.021; HR 1.624). CONCLUSION: The extent of TS defines a small proportion of patients with an excellent prognosis. Larger studies are warranted to define the relationship of long-term survivorship and extent of TS with targeted therapies. PMID- 24169358 TI - Fulvestrant induces resistance by modulating GPER and CDK6 expression: implication of methyltransferases, deacetylases and the hSWI/SNF chromatin remodelling complex. AB - BACKGROUND: Breast cancer is the leading cause of cancer death in women living in the western hemisphere. Despite major advances in first-line endocrine therapy of advanced oestrogen receptor (ER)-positive breast cancer, the frequent recurrence of resistant cancer cells represents a serious obstacle to successful treatment. Understanding the mechanisms leading to acquired resistance, therefore, could pave the way to the development of second-line therapeutics. To this end, we generated an ER-positive breast cancer cell line (MCF-7) with resistance to the therapeutic anti-oestrogen fulvestrant (FUL) and studied the molecular changes involved in resistance. METHODS: Naive MCF-7 cells were treated with increasing FUL concentrations and the gene expression profile of the resulting FUL-resistant strain (FR.MCF-7) was compared with that of naive cells using GeneChip arrays. After validation by real-time PCR and/or western blotting, selected resistance associated genes were functionally studied by siRNA-mediated silencing or pharmacological inhibition. Furthermore, general mechanisms causing aberrant gene expression were investigated. RESULTS: Fulvestrant resistance was associated with repression of GPER and the overexpression of CDK6, whereas ERBB2, ABCG2, ER and ER-related genes (GREB1, RERG) or genes expressed in resistant breast cancer (BCAR1, BCAR3) did not contribute to resistance. Aberrant GPER and CDK6 expression was most likely caused by modification of DNA methylation and histone acetylation, respectively. Therefore, part of the resistance mechanism was loss of RB1 control. The hSWI/SNF (human SWItch/Sucrose NonFermentable) chromatin remodelling complex, which is tightly linked to nucleosome acetylation and repositioning, was also affected, because as a stress response to FUL treatment naive cells altered the expression of five subunits within a few hours (BRG1, BAF250A, BAF170, BAF155, BAF47). The aberrant constitutive expression of BAF250A, BAF170 and BAF155 and a deviant stress response of BRG1, BAF170 and BAF47 in FR.MCF-7 cells to FUL treatment accompanied acquired FUL resistance. The regular and aberrant expression profiles of BAF155 correlated directly with that of CDK6 in naive and in FR.MCF-7 cells corroborating the finding that CDK6 overexpression was due to nucleosome alterations. CONCLUSION: The study revealed that FUL resistance is associated with the dysregulation of GPER and CDK6. A mechanism leading to aberrant gene expression was most likely unscheduled chromatin remodelling by hSWI/SNF. Hence, three targets should be conceptually addressed in a second-line adjuvant therapy: the catalytic centre of SWI/SNF (BRG1) to delay the development of FUL resistance, GPER to increase sensitivity to FUL and the reconstitution of the RB1 pathway to overcome resistance. PMID- 24169359 TI - Can shear-wave elastography predict response to neoadjuvant chemotherapy in women with invasive breast cancer? AB - BACKGROUND: Response of invasive breast cancer to neoadjuvant chemotherapy (NAC) is variable, and prediction of response is imperfect. We aimed to ascertain whether tissue stiffness in breast cancers, as assessed by shear-wave elastography (SWE) before treatment, is associated with response. METHODS: We retrospectively compared pre-treatment tumour mean tissue stiffness, with post treatment Residual Cancer Burden (RCB) scores and its components in 40 women with breast cancer treated by NAC using Pearson's correlation coefficient (CC), a general linear model and multiple linear regression. Subgroup analysis was carried out for luminal, HER2-positive and basal immuno-histochemical subtypes. RESULTS: Statistically significant correlations were shown between stiffness and RCB scores and between stiffness and percentage tumour cellularity. The correlation between stiffness and percentage cellularity was strongest (CC 0.35 (P<0.0001) compared with CC 0.23 (P=0.004) for the RCB score). The results of a general linear model show that cellularity and RCB score maintain independent relationships with stiffness. By multiple linear regression, only cellularity maintained a significant relationship with stiffness. CONCLUSION: Pre-treatment tumour stiffness measured by SWE, has a statistically significant relationship with pathological response of invasive breast cancer to NAC. PMID- 24169360 TI - External multicentre validation of a nomogram predicting the risk of relapse in patients with borderline ovarian tumours. AB - BACKGROUND: The Obermair nomogram was recently developed to predict the risk of relapse in patients with borderline ovarian tumours (BOTs) based on five readily available clinical, biological, and pathological characteristics. We set out to externally validate and assess its robustness using a multi-institutional BOT database. METHODS: All consecutive patients treated for BOTs in the two participating centres between January 1980 and December 2008 and who had all the nomogram variables documented were identified for analysis. RESULTS: Three hundred and fourteen eligible patients were identified and used for external validation analysis. The median follow-up and initial relapse time were 46.43 (range: 0.1-360) and 66.64 (range: 8-77) months, respectively. The nomogram concordance index was 0.54 (95% CI, 0.52-0.56). The correspondence between the actual relapse and the nomogram predictions suggests a limited calibration of the nomogram in the validation cohort. CONCLUSION: This external validation study of the Obermair nomogram showed limitations in its generalisability to a new and independent patient population. PMID- 24169361 TI - [Follow-up of primary care patients with a NANDA I nursing diagnosis of low self esteem]. AB - OBJECTIVE: To describe the evolution and characteristics of the NANDA taxonomy I nursing diagnosis of "situational low self-esteem" (SLS) and its related factors in Primary Care patients from the towns of Fuenlabrada and Leganes in the Autonomous Community of Madrid, in the period 2003-2009. METHOD: An observational retrospective case series of patients diagnosed by their Primary Care nurse with SLS according to the NANDA I taxonomy. This case series was performed in the towns of Fuenlabrada and Leganes (Madrid). Descriptive analysis of the variables obtained from the database management software for electronic health records in Primary Care (OMI AP). Data observed in percentages. The main variable is 00120 NANDA I diagnosis: SLS. A total of 342 care plans with a SLS diagnosis having completed all the nursing process phases. The NANDA, NOC and NIC classifications were used for the diagnostic formulas, the performance criteria to measure the effectiveness and efficiency of care, and the interventions that were performed to achieve them. The assessment of the nursing process was made according to the Marjory Gordon Functional Health Patterns. RESULTS: The incidence between 2003 and 2009 increased 8-fold. The large majority (80%) were women, with 52.4% between 40 and 64 years. Eighteen percent of the cases were closed, with 88% positively resolved. The most frequent distinctive characteristic was "negative self-verbalization" (26.5%). The main related factors were "disturbed body image" (23.8%). The most established NOC was "to improve the self-esteem" (41.3%) and its evolution was positive in 61%. Just over half (53.2%) of the interventions were "to increase facing up to responsibilities" and "to boost self-esteem". More than half (55%) of the diagnoses were made due to psychological causes, with episodes of a feeling anxiety-nervousness-tension in 33%. CONCLUSIONS: Although the approach is still difficul, the resolution of psychosocial problems, particularly those of self-esteem, continue to improve. The diagnoses with follow up show positive results. We must increase our knowledge of psychosocial problems and communication skills in order to respond to the current demands of the population. PMID- 24169362 TI - [Impact of rural or urban areas on disability after a stroke]. AB - OBJECTIVES: To assess the residual disability in a sample of patients after suffering a first episode of a stroke and to compare the disability of those patients who live in rural areas with those living in urban areas. METHODOLOGY: An observational, longitudinal study of a cohort of 89 patients from a Neurology Unit, affected by cerebrovascular accident. The following factors were assessed: sociodemographic and environmental factors, co-morbidity, functional status, disability, depression and anxiety, and quality of life. The different clinical and demographic variables were compared after admission to the unit, at hospital discharge, and 3 months afterwards. Regression analyses were also carried out in order to study the association between the clinical and sociodemographic factors, and post-stroke disability. RESULTS: Compared to their previous clinical state, after suffering a stroke patients showed a higher rate of co-morbidity (P<.0001), disability (P<.0001), depression (P=.002), and a poorer quality of life (P=.013). The difference between patients coming from rural and urban areas was not statistically significant in terms of disability, quality of life, anxiety, depression, or co-morbidity. CONCLUSIONS: The level of disability, depression and co-morbidity that patients showed after suffering a stroke was similar to the results obtained in other studies. As a novel feature, there were no differences between patients living in rural areas after suffering a stroke and those living in urban areas, as regards disability, depression, or co-morbidity. PMID- 24169363 TI - Interactions between nutrition and immune function: using inflammation biomarkers to interpret micronutrient status. AB - The immune response promotes a complex series of reactions by the host in an effort to prevent ongoing tissue damage, isolate and destroy the infective organism and activate the repair processes that are necessary for restoring normal function. The homoeostatic process is known as inflammation and the early set of reactions that are induced are known as the acute phase response (APR). The APR has marked effects on the circulation, metabolism in the liver and the plasma concentration of many nutrients. The changes in nutrient concentrations follow a cyclic pattern; occurring before any clinical evidence of disease, being at their most pronounced during the disease and remaining in convalescence when all evidence of disease or trauma has disappeared. Therefore, where susceptibility to disease is high as in people who are HIV+ but still apparently healthy, obtaining an accurate measurement of nutritional status may not be possible. Accurate measurements of status are important for national statistics to plan for the proper utilisation of government resources and they are especially important to evaluate the effectiveness of nutritional interventions. Many acute phase proteins (APP) are synthesised during inflammation and they are used to monitor the progress of disease and recovery but, individually, none of their lifecycles compare well with those of the nutritional biomarkers. Nevertheless, recognising the presence of inflammation can help interpret data and, using two APP, this review paper will illustrate the methods we have developed to assist interpretation of plasma retinol, ferritin and zinc concentrations in apparently healthy, HIV+, Kenyan adults. PMID- 24169364 TI - A single session of 1 mA anodal tDCS-supported motor training does not improve motor performance in patients with multiple sclerosis. AB - PURPOSE: To assess the effects of atDCS on motor performance in patients with multiple sclerosis (MS). Previously, anodal transcranial direct current stimulation (atDCS) has been shown to improve motor performance in healthy subjects and neurodegenerative populations. However, the effect of atDCS on motor performance is not examined in MS. METHODS: In the current study, a sham controlled double-blind crossover design was used to evaluate the effect of 20 minutes of 1 mA atDCS or sham tDCS (stDCS) on a unimanual motor sequence-training task, consisting of sequential finger presses on a computer keyboard with the most impaired hand. Patients received stimulation (atDCS or stDCS) during motor training. tDCS was applied over the primary motor cortex contralateral to the most impaired hand. Motor performance was assessed immediately before, during and 30 minutes after stimulation. RESULTS: Although we need to be careful with the interpretation of the data due to lack of power, our results showed no significant effect of atDCS on motor performance. CONCLUSIONS: Our findings indicate that atDCS-supported motor training was not able to improve motor performance more than sham-supported motor training. Possibly, the effects of atDCS are mediated by specific MS-related characteristics. Furthermore, increasing atDCS intensity and offering multiple stimulation sessions might be necessary to optimize motor performance resulting from atDCS-supported motor training. PMID- 24169365 TI - Effective method of combining rTMS and motor training in stroke patients. AB - PURPOSE: Enhanced therapeutic effects of repetitive transcranial magnetic stimulation (rTMS) on the motor function of stroke patients when provided in combination with motor training have been reported. The objective of this study was to determine the most effective method for combining rTMS and motor training in stroke patients. METHODS: Fourteen stroke patients were enrolled. All patients participated in two randomly arranged intervention sessions, each of which incorporated a differently combined rTMS and motor training method. With an interleaved combination method (ICM), an rTMS train and a short period of motor training were interleaved and repeated. With a preconditioning combination method (PCM), rTMS trains were applied as preconditioning, followed by repeated blocks of motor training. The total rTMS pulses and total duration of motor training were the same in both sessions. RESULTS: Performance of a sequential finger motor task improved significantly after both the ICM and PCM interventions: movement accuracy increased and movement time decreased. The PCM-associated improvements were significantly greater than the ICM-associated improvements. Performance in the Purdue Pegboard Test and Nine-Hole Peg Test also improved significantly after both interventions but without a significant difference between the two interventions. Cortical excitability improved after both the ICM and PCM interventions but without a significant difference between the two. CONCLUSIONS: In combining rTMS and motor training, preconditioning with rTMS followed by motor training is more effective than interleaving the rTMS and motor training to facilitate the motor performance of stroke patients. PMID- 24169367 TI - Is PET-CT scan an effective tool to differentiate the ascites caused by abdominal malignancy and peritoneal tuberculosis? PMID- 24169366 TI - In situ histone landscape of nephrogenesis. AB - In the developing kidney, self-renewing progenitors respond to inductive signaling from the adjacent branching ureteric bud by undergoing mesenchyme-to epithelium transition. Nascent nephrons subsequently undergo elongation, segmentation, and differentiation into a mature renal epithelium with diverse functions. Epigenetic mechanisms have been implicated in impacting cell fate decisions during nephrogenesis; however, the chromatin landscape of nephron progenitors and daughter differentiating cells are largely unknown. Here, we examined the spatiotemporal expression patterns of histone H3 methylation and histone methyltransferases in E15.5 mouse kidneys. Kidney sections were probed with antibodies against histone modifications, enzymes, and markers of progenitors and differentiation. The results revealed that: (1) nephron progenitor cells exhibit a broad histone methylation signature that comprises both "active" and "repressive" marks (H3K4me3/K9me3/K27me3/R2me2/R17me2); (2) nascent nephrons retain high H3K4me3 but show downregulation of H3K9/K27me3 and; (3) maturing epithelial tubules acquire high levels of H3K79me2/3. Consistent with respective histone marks, the H3K4 methyltransferase, Ash2l, is expressed in progenitors and nascent nephrons, whereas the H3K9/K27 methyltransferases, G9a/Ezh2, are more enriched in progenitors than nascent nephrons. We conclude that combinatorial histone signatures correlate with cell fate decisions during nephrogenesis. PMID- 24169368 TI - Usefulness of bilateral bispectral index (BIS) monitoring in a comatose patient with myoclonic status epilepticus secondary to cefepime. AB - BACKGROUND: Status epilepticus, particularly non-convulsive status epilepticus (NCSE), is a frequent complication in patients with altered renal function receiving treatment with intravenous cefepime. To the best of our knowledge, we report the first case, illustrated by video-EEG, of a critically ill patient receiving treatment with cefepime who developed an episode of confirmed symptomatic myoclonic status epilepticus (MSE). METHODS: Case report and video EEG. RESULTS: A 60-year-old man, who had received a liver transplant due to alcoholic cirrhosis one year ago, was admitted to our intensive care unit due to septic shock. Computed tomography revealed a prostatic abscess as cause of his sepsis. On Day 27, a respiratory infection due to Pseudomona aeruginosa was diagnosed, and treatment with intravenous cefepime (2 g/8 hours) was initiated. On Day 32, his mental status deteriorated and he developed inattention, a reduced level of consciousness, and multifocal and generalised continuous myoclonic jerks. A video-EEG study was compatible with the diagnosis of symptomatic MSE. On Day 35, cefepime was stopped and general anaesthesia with midazolam was started in order to achieve a faster clinical improvement. We used the BIS-VistaTM monitor to guide general anaesthesia and detect potential episodes of NCSE. On Day 40, an EEG confirmed the existence of moderate diffuse encephalopathy. Finally, the patient died as a consequence of severe heart failure. CONCLUSIONS: Cefepime may be a cause of MSE in non-anoxic comatose patients. Clinicians should be aware of this possibility when evaluating comatose patients on cephalosporin therapy in order to establish a correct diagnostic approach and accurate prognosis. [Published with video sequences]. PMID- 24169369 TI - Post-traumatic amaurosis secondary to paraophthalmic internal carotid artery pseudoaneurysm treated with pipeline embolization device. AB - During evaluation for monocular visual loss, a 48-year-old woman was found to have a posttraumatic paraophthalmic internal carotid artery (ICA) pseudoaneurysm. She underwent reconstruction of the ophthalmic segment of the right ICA with a Pipeline embolization device but her vision did not return. PMID- 24169370 TI - The association between alcohol use and long-term care placement among older Canadians: a 14-year population-based study. AB - Studies have shown that moderate alcohol use confers protection against some of the dominant predictors of long-term care placement, including diminished cognitive functioning, physical disability, and injury. But little is known about the association between alcohol use and the likelihood of placement in long-term care facilities. A nationally representative sample of 5404 community-dwelling Canadians ages 50 years and older at baseline (1994/95) was obtained from the longitudinal National Population Health Survey. Alcohol use categories were developed based on the quantity and frequency of use in the 12 months before the interview. Cox proportional hazards models were used to estimate the association between alcohol use at baseline and subsequent placement in long-term care facilities after adjusting for covariates measured at baseline. During the 14 year follow-up period, 14% of lifetime abstainers, 10% of former drinkers, 7% of infrequent drinkers, 4% of moderate drinkers, and 3% of heavy drinkers were placed in long-term care facilities. Furthermore, the multivariate analysis revealed that abstainers, former drinkers, and infrequent drinkers were more than twice as likely to be placed in long-term care as moderate drinkers. Moderate drinking was protective against placement in long-term care facilities even after adjusting for an array of well-known confounders. The strong protective effect of moderate alcohol use on long-term care entry is likely due to a complex mix of physical, cognitive and psychosocial health factors. PMID- 24169373 TI - Dealing with Ebstein's anomaly. AB - Ebstein's anomaly is a complex congenital disorder of the tricuspid valve. Presentation in neonatal life and (early) childhood is common. Disease severity and clinical features vary widely and require a patient-tailored treatment. In this review, we describe the natural history of children and adolescents with Ebstein's anomaly, including symptoms and signs presenting at diagnosis. Current classification strategies of Ebstein's anomaly are discussed. We report on diagnostic methods for establishing the severity of disease that might enhance decision on the timing of surgical intervention. Furthermore, we describe different surgical options for severely ill neonates and multiple surgical interventions after infancy. Only with ample knowledge and understanding of the above, this complex and diverse group of patients can be correctly treated in order to improve not only duration, but also quality of life. PMID- 24169371 TI - Suicidal ideation in veterans misusing alcohol: relationships with insomnia symptoms and sleep duration. AB - OBJECTIVE: The aim of this investigation was to assess the relationships between suicidal ideation and insomnia symptoms in Veterans misusing alcohol. METHOD: Data were extracted in this retrospective chart review of Veterans referred from primary care for a behavioral health evaluation (N=161) based on evidence of heavy drinking, drug use or another behavioral problem. Suicidal ideation (SI) was assessed using the Paykel questionnaire. Insomnia symptoms were assessed with standard diary questions in an interview format and pertained to sleep latency (SL), wake after sleep onset time (WASO), sleep quality (SQ), and habitual sleep duration (HSD). The relations between suicidal ideation and insomnia symptoms were assessed using ordinal regression analyses adjusted for socio-demographic, psychiatric and addiction-related variables. RESULTS: Suicidal ideation was reported in 62 (39%) of the Veterans interviewed. In a multivariable model, only inadequate SQ was associated with suicidal ideation. Short sleepers were more likely to endorse suicidal ideation and have attempted suicide in the past year. In addition, older age, inadequate financial status, and the presence of a psychiatric disorder were also significantly associated with suicidal ideation in most of the adjusted models. CONCLUSION: Given their association with suicidal ideation, insomnia symptoms in Veterans misusing alcohol should prompt an assessment of underlying psychiatric and social factors. PMID- 24169372 TI - Drink refusal self-efficacy and implicit drinking identity: an evaluation of moderators of the relationship between self-awareness and drinking behavior. AB - This study evaluated the roles of drink refusal self-efficacy (DRSE), implicit drinking identity, and self-awareness in drinking. Self-awareness (assessed by public and private self-consciousness), DRSE, and implicit drinking identity (measured via an implicit association test; IAT) were expected to interact in predicting self-reported drinking. This research was designed to consider mixed findings related to self-awareness and drinking. Hypotheses were: 1) alcohol related outcomes would be negatively associated with self-awareness; 2) implicit drinking identity would moderate the association between self-awareness and alcohol consumption; and 3) this association would depend on whether participants were higher or lower in drink refusal self-efficacy. Participants included 218 undergraduate students. Results revealed that drinking behavior was not associated with self-awareness but was positively associated with implicit drinking identity. Of the four drinking variables (peak drinking, drinking frequency, drinks per week, and alcohol-related problems), only alcohol-related problems were positively associated with self-awareness. Furthermore, a significant two-way interaction emerged between private (but not public) self consciousness and drinking identity to predict drinking. Consistent with expectations, three-way interactions emerged between self-awareness, implicit drinking identity, and DRSE in predicting drinking. For participants low in DRSE: 1) high implicit drinking identity was associated with greater drinking frequency when private self-consciousness was low; and 2) high implicit drinking identity was associated with greater drinks per week and peak drinks when public self consciousness was low. This suggests that alcohol-related IATs may be useful tools in predicting drinking, particularly among those low in self-awareness and DRSE. PMID- 24169374 TI - Ultrasonography-guided breast-conserving surgery is superior to palpation-guided surgery for palpable breast cancer. AB - INTRODUCTION: The aim of this study was to determine the efficacy of ultrasonography (US)-guided excision of palpable breast cancer and to compare it with the standard palpation-guided breast-conserving surgery (BCS). METHODS: For this purpose, 335 women with palpable breast cancer who underwent BCS were retrospectively studied. The positive surgical margins and re-excision rates were investigated. RESULTS: Of the total cohort, 137 patients were treated with palpation-guided BCS and 198 underwent US-guided tumor excision. The tumor and patient characteristics were similar in both groups. Patient age, postmenopausal status, tumor size, histological grade, intraductal tumor component, lobular histology, and palpation-guided tumor excision were associated with increased risk of positive margins. The shave margins were re-excised at the time of original operation more often by palpation-guided localization (28.5%) than by the US-guided procedure (11.1%) (P < .0001). A surgeon was able to correctly identify the "problematic" margin in 81.1% of cases via intraoperative US and in only 17.9% via palpation (P < .0001). The re-excision rate during a second operation was significantly reduced by US-guided tumorectomy (P = .004). Of 198 patients in the US-guided group, 23 (11.6%) underwent a second operation, as did 33 of 137 patients in the palpation group (24.1%). The sensitivity and specificity of US-guided excisions were 52.7% and 97.5%, respectively, whereas the sensitivity and the specificity of palpation-guided tumor excisions were 15.5% and 65.9%, respectively. CONCLUSION: US-guided BCS is superior to palpation guided excision in predicting the closest margins, obtaining clear surgical margins, and reducing re-operations. PMID- 24169375 TI - Initial validation of the Brief Assessment of Service Satisfaction in Persons with an Intellectual Disability (BASSPID). AB - Individuals with an intellectual disability often require intensive services to promote their social participation to the fullest extent. As such, measuring satisfaction with these services appears essential to enhance the quality of life of individuals with an intellectual disability and to improve service delivery within agencies. Thus, the purpose of the study was to conduct an initial validation of the Brief Assessment of Service Satisfaction in Persons with an Intellectual Disability (BASSPID), a 15-item questionnaire designed to assess service satisfaction. To examine the structure, reliability, and validity of the BASSPID, we interviewed 98 individuals with an intellectual disability and 23 parents. Overall, the BASSPID contained one scale, which had strong content and convergent validity as well as items easily understandable for individuals with an intellectual disability. Furthermore, the questionnaire had good internal consistency and adequate test-retest reliability. However, parents generally overestimated the perceived satisfaction of their child. The study suggests that the BASSPID may be useful to assess the satisfaction of individuals with an intellectual disability, but more research is needed to examine its potential impact on improving service quality. PMID- 24169376 TI - Heterogeneity of muscle fat infiltration in children with spina bifida. AB - Children with spina bifida have well recognized functional deficits of muscle, but little is known about the associated changes in muscle anatomy and composition. This study used water-fat magnetic resonance imaging (MRI) to measure fat infiltration in the lower extremity muscles of 11 children with myelomeningocele, the most severe form of spina bifida. MRI measurements of muscle fat fraction (FF) were compared against manual muscle test (MMT) scores for muscle strength. The FF measurements were objective and reliable with mean inter-rater differences of <2% and intraclass correlation coefficients>0.98. There was a significant inverse relationship between muscle FF and MMT scores (P <= 0.001). Surprisingly, however, muscles with negligible strength (MMT 0-1) exhibited a bimodal distribution of FF with one group having FF>70% and another group having FF<20%. The MRI also revealed striking heterogeneity amongst individual muscles in the same muscle group (e.g., 4% fat in one participant's lateral gastrocnemius vs. 88% in her medial gastrocnemius), as well as significant asymmetry in FF in one participant with asymmetric strength and sensation. These results suggest that quantitative water-fat MRI may serve as a biomarker for muscle degeneration which may reveal subclinical changes useful for predicting functional potential and prognosis. PMID- 24169377 TI - [Official document of the International Society of Atherosclerosis: general recommendations for treatment of dyslipidemia. Executive summary]. PMID- 24169378 TI - Phytochemical, phylogenetic, and anti-inflammatory evaluation of 43 Urtica accessions (stinging nettle) based on UPLC-Q-TOF-MS metabolomic profiles. AB - Several species of the genus Urtica (especially Urtica dioica, Urticaceae), are used medicinally to treat a variety of ailments. To better understand the chemical diversity of the genus and to compare different accessions and different taxa of Urtica, 63 leaf samples representing a broad geographical, taxonomical and morphological diversity were evaluated under controlled conditions. A molecular phylogeny for all taxa investigated was prepared to compare phytochemical similarity with phylogenetic relatedness. Metabolites were analyzed via UPLC-PDA-MS and multivariate data analyses. In total, 43 metabolites were identified, with phenolic compounds and hydroxy fatty acids as the dominant substance groups. Principal component analysis (PCA) and hierarchical clustering analysis (HCA) provides a first structured chemotaxonomy of the genus. The molecular data present a highly resolved phylogeny with well-supported clades and subclades. U. dioica is retrieved as both para- and polyphyletic. European members of the U. dioica group and the North American subspecies share a rather similar metabolite profile and were largely retrieved as one, nearly exclusive cluster by metabolite data. This latter cluster also includes - remotely related Urtica urens, which is pharmaceutically used in the same way as U. dioica. However, most highly supported phylogenetic clades were not retrieved in the metabolite cluster analyses. Overall, metabolite profiles indicate considerable phytochemical diversity in the genus, which largely falls into a group characterized by high contents of hydroxy fatty acids (e.g., most Andean-American taxa) and another group characterized by high contents of phenolic acids (especially the U. dioica-clade). Anti-inflammatory in vitro COX1 enzyme inhibition assays suggest that bioactivity may be predicted by gross metabolic profiling in Urtica. PMID- 24169379 TI - Monoterpene indole alkaloids from the stem bark of Mitragyna diversifolia and their acetylcholine esterase inhibitory effects. AB - Five monoterpene indole alkaloids, mitradiversifoline, with a unique rearranged skeleton, specionoxeine-N(4)-oxide, 7-hydroxyisopaynantheine, 3 dehydropaynantheine, and 3-isopaynantheine-N(4)-oxide, and 10 known ones, were isolated from Mitragyna diversifolia. All the isolates were evaluated for their inhibition of acetylcholinesterase activities, and four showed moderate activities, with IC50 values of 4.1, 5.2, 10.2, and 10.3 MUM, respectively. PMID- 24169380 TI - Ictal EEG modifications in temporal lobe epilepsy. AB - Temporal lobe epilepsy is the most common type of epilepsy in adults with medically intractable, localisation-related epilepsy, amenable to surgery. Together with clinical and neuroimaging data, presurgical ictal scalp-EEG findings are often sufficient to define the epileptogenic zone. It is widely believed that ictal scalp-EEG findings in temporal lobe epilepsy are represented by 5-9-Hz lateralised rhythmic theta activity or 2-5-Hz lateralised rhythmic delta activity. On the basis of experimental models and experience with intra cerebral EEG recordings, the pattern of low-voltage fast activity is considered to be the electrophysiological hallmark of the epileptogenic zone. We reviewed the ictal scalp-EEG data relating to 111 seizures in 47 patients with temporal lobe epilepsy who underwent video-EEG recordings during presurgical work-up. We found that 35 patients (74.4%) showed flattening, low-voltage fast activity or fast activity as the initial EEG pattern. When visible, the rhythmic delta or theta activity followed the fast activity. Low-voltage fast activity, flattening or fast activity occurs in the majority of patients with temporal lobe epilepsy and represents the main ictal EEG pattern. Low-voltage fast activity (or similar) is also identifiable as the initial ictal EEG pattern in scalp-EEG recordings. PMID- 24169381 TI - Hepatocellular carcinoma in Pakistan. PMID- 24169382 TI - Assessment of professionalism in integrated curriculum: the faculty's perspective. AB - OBJECTIVE: To analyse and interpret the role of faculty members in assessing professionalism in a well-established medical school in the UK. STUDY DESIGN: A qualitative study. PLACE AND DURATION OF STUDY: School of Medicine, University of Glasgow, UK, from February to July 2011. METHODOLOGY: Used a constructivist approach, a purposive sampling technique was applied to interview those faculty members who were associated with the assessment of professionalism. A total of eight faculty members were interviewed, and the data was analysed thematically. RESULTS: The learning outcomes are assessed in both formative and summative examinations but the focus is mainly on formative assessments. Both objective and subjective assessment instruments are used, although qualitative assessment instruments evaluate the topic with greater validity. Some of the assessment instruments are used formatively as well as summatively. CONCLUSION: The assessment of professionalism is a multidimensional activity. Both formative and summative assessments together with an 'assessment for learning' strategy can be used with great effect. Here the role of formative assessment and 'assessment for learning' are more significant as they are a continuous process and their frequency and feedback will make a profound impression on students. PMID- 24169383 TI - Factors affecting patient satisfaction during endoscopic procedures. AB - OBJECTIVE: To assess the quality and patient satisfaction in Endoscopy Unit of Shifa International Hospital. STUDY DESIGN: Cross-sectional survey. PLACE AND DURATION OF STUDY: Division of Gastroenterology, Shifa International Hospital, Islamabad, Pakistan, from July 2011 to January 2012. METHODOLOGY: Quality and patient satisfaction after the endoscopic procedure was assessed using a modified GHAA-9 questionnaire. Data was analyzed using SPSS version 16. RESULTS: A total of 1028 patients were included with a mean age of 45 +/- 14.21 years. Out of all the procedures, 670 (65.17%) were gastroscopies, 181 (17.60%) were flexible sigmoidoscopies and 177 (17.21%) were colonoscopies. The maximum unsatisfactory responses were on the waiting time before the procedure (13.13 %), followed by unsatisfactory explanation of the procedure and answers to questions (7.58%). Overall, unsatisfied impression was 4.86%. The problem rate was 6.22%. CONCLUSION: The quality of procedures and level of satisfaction of patients undergoing a gastroscopy or colonoscopy was generally good. The factors that influence the satisfaction of these patients are related to communication between doctor and patient, doctor's manner and waiting time for the procedure. Feedback information in an endoscopy unit may be useful in improving standards, including the performance of endoscopists. PMID- 24169384 TI - Vitamin D deficiency in patients with tuberculosis. AB - OBJECTIVE: To determine the frequency and association of Vitamin D deficiency in patients with tuberculosis. STUDY DESIGN: Case control study. PLACE AND DURATION OF STUDY: Medical Department, Combined Military Hospital, Kharian, from July 2010 to June 2012. METHODOLOGY: One hundred and five outdoor patients of tuberculosis were selected with 255 gender matched controls. Tuberculosis was diagnosed by presence of acid fast bacilli in sputum smears, positive culture for Mycobacterium tuberculosis or demonstration of chronic caseating granulomatous inflammation in tissue specimens. Controls were drawn randomly from general population. Serum 25 hydroxyvitamin D [25 (OH) D3] levels < 25 ng/ml was considered Vitamin D deficiency. The results were analyzed on SPSS version 17. RESULTS: Mean Vitamin D levels were 23.23 +/- 6.81 ng/ml in cases, 29.27 +/- 8.89 ng/ml in controls (p < 0.0001). Vitamin D deficiency was found in 57% of cases and 33% controls (p < 0.0001). Mean Vitamin D levels were significantly lower in females with tuberculosis (20.84 ng/ml) as compared to males (25.03 ng/ml, p = 0.002). Mean BMI in patients of tuberculosis with Vitamin D deficiency were 19.51 +/- 1.77 kg/m2 and in patients with normal Vitamin D were 21.65 +/- 1.79 kg/m2 (p < 0.0001). Mean Vitamin D levels in patients with multi-drug resistant tuberculosis was lower to a mean of 15.41 +/- 4.67 ng/ml (p < 0.0001). CONCLUSION: There is significant deficiency of Vitamin D in patients with tuberculosis as compared to controls. This deficiency is more pronounced in females, individuals with low BMI, extra pulmonary and MDR tuberculosis. PMID- 24169385 TI - Agreement between serology and histology for detection of Helicobacter pylori infection. AB - OBJECTIVE: To determine the percentage agreement between serology and histology for detection of Helicobacter (H.) pylori infection. STUDY DESIGN: Cross sectional analytical study. PLACE AND DURATION OF STUDY: Department of Pathology and Microbiology, The Aga Khan University and Hospital, Karachi, from January to December 2009. METHODOLOGY: Fifty subjects were selected by non-probability purposive sampling from laboratory data who had serological testing of H. pylori IgG antibody, prior to histological evaluation of endoscopic gastric or/and duodenal biopsies. Serological Quantification of H. pylori IgG was carried out with HpG screen ELISA kit (Genesis Diagnostics, UK), using an enzyme linked immunosorbent assay for detection of IgG antibodies against H. pylori. Manufacturer's recommended cutoff value was used and results were considered positive when greater than 7 U/ml. For histological diagnosis, an expert histopathologist characterized the presence of spiral bacteria in the mucosal layer or the surface of epithelial cells on microscopic examination, as a positive test. RESULTS: An agreement of 0.72 was found by Kappa statistics between serology and histopathology results and a good diagnostic accuracy (86%) of serological testing was observed for the diagnosis of H. pylori infection. CONCLUSION: A substantial agreement was found between serology and histopathology results to detect the H. pylori infection. Laboratory-based serologic testing using ELISA technology to detect IgG antibodies is inexpensive, noninvasive and convenient method to detect the H. pylori infection in primary care setting. PMID- 24169386 TI - Comparison of real time polymerase chain reaction with microscopy and antigen detection assay for the diagnosis of malaria. AB - OBJECTIVE: To determine the sensitivity of a real time polymerase chain reaction (PCR) for malaria diagnosis and to compare its accuracy with microscopy and an antigen based rapid diagnostic test (OptiMal). STUDY DESIGN: Cross-sectional analytical study. PLACE AND DURATION OF STUDY: Military Hospital, Armed Forces Institute of Transfusion and Armed Forces Institute of Pathology, Rawalpindi, from July to December 2011. METHODOLOGY: Venous blood samples of 300 clinically suspected patients of malaria were tested for malaria parasite by microscopy and OptiMal; and malaria parasite index was calculated for the positive samples. Plasmodium genus specific real time PCR was performed on all specimens, targeting small subunit rRNA gene. Diagnostic accuracy of three tests was compared and cost analysis was done. RESULTS: Out of 300 patients, malaria parasite was detected in 110, 106 and 123 patients by microscopy, OptiMAL and PCR respectively. Real time PCR was 100% sensitive while microscopy and OptiMal had sensitivity of 89.4% and 86.2% respectively. All methods were 100% specific. The cost per test was calculated to be 0.2, 2.75 and 3.30 US$ by microscopy, OptiMal and PCR respectively, excluding the once capital cost on PCR equipment. CONCLUSION: Genus specific real time PCR for the diagnosis of malaria was successfully established as a highly sensitive and affordable technology that should be incorporated in the diagnostic algorithm in this country. PMID- 24169387 TI - Validation of modified estimated glomerular filtration rate in chronic kidney disease patients. AB - OBJECTIVE: To derive the ethnic factor and validate the modified estimated Glomerular Filtration Rate (eGFR) by Modification of Diet in Renal Disease (MDRD) equation for Chronic Kidney Disease (CKD) patients of Rawalpindi. STUDY DESIGN: Cross- sectional study. PLACE AND DURATION OF STUDY: Armed Forces Institute of Pathology (AFIP), Rawalpindi, from July 2011 to July 2012. METHODOLOGY: A total of 140 patients with CKD reporting to AFIP for GFR measurement by 99mTechnetium diethylenethiaminepenta-acetic acid (99mTc-DTPA) renal scan were consecutively inducted. Serum creatinine was measured by the Jaffe's assay on Beckman DxC 600 Analyzer prior to the renal scan. Ethnic factor for population of Rawalpindi with CKD was derived for the MDRD eGFR equation using 99mTc-DTPA renal scan by Gates method as the reference method. MDRD equation was modified by inclusion of the ethnic factor in it. Agreement between the reference GFR (rGFR) and the modified MDRD eGFR (mGFR) was assessed by applying paired samples t-test. RESULTS: Out of 140 patients of CKD, 99 (71%) were males and 41 (29%) females, with mean age of 55 +/- 13.42 years. The mean values were 32.91 +/- 14.96, 34.89 +/- 16.45, 0.971 +/- 0.20 and 33.87 +/- 15.97 for rGFR, original eGFR, ethnic factor and mGFR respectively. The mGFR with new ethnic factor of 0.971 showed improved performance as compared to original eGFR and showed a significant level of correlation with rGFR (r2 = 0.817), at a p-value of 0.000. CONCLUSION: This study validates the mGFR equation by inclusion of newly derived ethnic factor of 0.971 in the population of Rawalpindi with CKD and it was found to be not significantly different from the rGFR. PMID- 24169388 TI - Infertility and weight reduction: influence and outcome. AB - OBJECTIVE: To assess the effect of weight reduction in obese infertile women on conception rate spontaneously as well as with ovulation induction and pregnancy outcome. STUDY DESIGN: Observational experimental study. PLACE AND DURATION OF STUDY: Different private clinics at Mirpurkhas, Thana Bola Khan and Hyderabad, Sindh, Pakistan, from March 2008 to February 2011. METHODOLOGY: Infertile women who were obese with the body mass index (BMI) > 30 kg/ m2 and failed to conceive within 2 - 5 years after taking treatment of infertility for many cycles were inducted. These women underwent life style change program related to exercise and diet for 6 months and in the next 6 months they were observed for spontaneous conception. Those women who failed to conceive were prescribed ovulation induction (clomifene citrate) for the next 6 months and were observed for conception. After conception, they visited regularly during antenatal period till delivery. The data was collected and analyzed on SPSS version 17. RESULTS: The mean decrease in the body index observed was 9.6 +/- 1.23 kg/m2, spontaneous conception rate was (n = 35, 41.17%) and miscarriage rate was (n = 9, 16.66%). CONCLUSION: Weight reduction leads to high spontaneous conception rate as well as with ovulation induction therapy and improves the pregnancy outcome. PMID- 24169389 TI - Management of penile fracture and its outcome. AB - OBJECTIVE: To describe the management and outcome of patients with penile fracture. STUDY DESIGN: Case series. PLACE AND DURATION OF STUDY: Department of Urology and Renal Transplantation, Jinnah Hospital, Lahore, from March 2008 to March 2011. METHODOLOGY: Sixteen patients presenting with clinical findings / history of penile fracture were included in this study. Diagnosis was made on the basis of history and clinical findings. Surgical exploration and repair was done on the same day. In all patients, a subcoronal circumferential degloving incision was made. Rent location and dimensions management and postoperative complication were noted. Postoperatively, erection was suppressed for 4 - 5 days. All patients were discharged with advice of avoidance of sex for about 8 weeks. Patients were followed-upto 6 months. RESULTS: Majority of the patients (87.5%) were married and 13 (81.25%) were aged 18 - 45 years. The typical findings recorded in 100.0% patients were erection at time of fracture, detumescence, swelling and ecchymosis. Audible crackling sound and pain was present in 13 (81.25%) patients. Ten (62.5%) patients had rent in the proximal part of penile shaft and right lateral tear was present in 11 (68.75%) patients. Blood clots were evacuated and closure of rent was done with vicryl 2/0 (interrupted stitches). 100.0% patients had uneventful recovery with only 3 (18.75%) patients developed right chordae of erect penis after treatment. All (100.0%) patients were potent and without any problem of erection. CONCLUSION: Penile fracture is under-reported. A trauma to erect penis is essential to cause fracture. Surgical exploration and repair is the treatment of choice. PMID- 24169390 TI - Percutaneous endoscopic colostomy (PEC): an effective alternative in high risk patients with recurrent sigmoid volvulus. AB - Treatment of recurrent sigmoid volvulus is a major challenge in frail and elderly patients with multiple co-morbidities. Early management involves endoscopic decompression with high success rate, however, its recurrence make it a real challenge as most of these patients are not suitable for major colonic resection. The aim of this study was to assess the role of percutaneous endoscopic colostomy (PEC) in the treatment of recurrent sigmoid volvulus in these patients. Twelve PEC procedures were performed in 8 patients under our care. This prevented major colonic resection in 7 patients. One patient underwent sigmoid resection and died with postoperative complications. Two patients experienced minor complications. Three patients required repeat procedures for permanent PEC tube placement. Six patients managed permanently with PEC procedure. PEC is an effective treatment for recurrent sigmoid volvulus in high-risk elderly patients. PMID- 24169391 TI - Postpartum aplastic anemia presenting as pancytopenia due to malarial infection. AB - Pancytopenia is a condition with decreased numbers of all cell lines. Aplastic anemia is a common cause although malarial infection causing lysis of RBCs may also partly mimic this condition. The infection may also damage the patient's bone marrow resulting in pancytopenia as well. We present the case of a post partum female patient who reported with fever, body aches and shortness of breath one month after the delivery of her baby. All blood cell counts were decreased and peripheral blood smear showed malarial parasites. Anti-malarial treatment was initiated following which the fever subsided but, despite regular transfusions, the blood counts remained low. Bone marrow biopsy report revealed P. falciparum pigments along with hypocellularity characteristic of severe aplastic anemia. Consequently, bone marrow transplantation was advised as a therapeutic measure. This case report highlights the increased susceptibility of pregnant women to malaria in endemic areas and subsequent aplastic anemia. PMID- 24169392 TI - Primary hydatid cyst of the neck. AB - Hydatid cysts in the neck are relatively exceptional, even in areas where Echinococcus granulosis is endemic, such as Asia. Although liver and lung are frequent sites of involvement, it can involve all tissues, with neck remaining one of the most rare sites. It should come in the differential diagnosis of cystic lesion of neck, as the treatment options differ widely from common neck cysts. The role of radiological investigation is important and, in these cases, the involvement of other organs should be investigated. Serological tests may be helpful. The major treatment modality is surgical and the cyst should be excised as a whole, without being ruptured, to prevent any treatment complications, as the cyst fluid can initiate an anaphylactic reaction. Postoperative albendazole therapy is recommended particularly when there is intra-operative spillover. We report a case of an isolated hydatid cyst localized in the anterior triangle of the neck without any pulmonary or hepatic involvement. PMID- 24169393 TI - Recurrent cerebral infarctions in a young patient: combined protein C and S deficiencies. AB - The possible etiologies of cerebral infarcts in young patients often present as diagnostic dilemmas as compared to older patients. Recently, deficiencies of fibrinolytic factors have emerged as an important etiology of stroke in the young population. Thrombophilic factors have been implicated in approximately 4 - 8% of the young strokes worldwide. Combined protein C and S deficiencies is a rare cause of recurrent ischaemic stroke in young population. Only a few sporadic cases have been reported in the literature. We are reporting a case of combined protein C and S deficiency-related recurrent ischaemic stroke in an 18 years old girl. Early diagnosis and targeted therapeutic management can help such patients to prevent recurrent thrombotic episodes. PMID- 24169394 TI - Herpes simplex encephalitis presenting with normal CSF analysis. AB - A 28 years old female presented with headache, fever, altered sensorium and right side weakness for one week. She was febrile and drowsy with right sided hemiplegia and papilledema. Tuberculous or bacterial meningitis, tuberculoma and abscess were at the top of the diagnosis list followed by Herpes simplex meningo encephalitis (HSE). MRI showed abnormal signal intensity of left temporal lobe without significant post-contrast enhancement and midline shift. CSF examination was normal, gram stain and Ziehl-Neelsen stain showed no micro-organism, or acid fast bacilli. CSF for MTB PCR was negative. PCR DNA for Herpes simplex 1 on CSF was detected. Acyclovir was started and the patient was discharged after full recovery. A high index of suspicion is required for HSE diagnosis in Pakistan where other infections predominantly affect the brain and HSE may be overlooked as a potential diagnosis. PMID- 24169395 TI - Myofibroblastoma: an unusual rapidly growing benign tumour in a male breast. AB - Myofibroblastoma is an unusual benign tumour of the breast predominantly seen in men in their sixth to seventh decade. The gross appearance is that of a well circumscribed nodule, characteristically small, seldom exceeding 3 cm. We present a case of an unusually large myofibroblastoma, which mimicked a malignant breast tumour. A 40 years old male, known case of tetralogy of Fallot, was operated in infancy in abroad, presented with a rapid enlargement of right breast over 5 - 6 weeks. Examination revealed a firm 10 cm hemispherical lump occupying the whole of the right breast with normal overlying skin. Since core biopsy was inconclusive, a subcutaneous mastectomy was performed to remove the tumour, which weighed 500 gms. Histopathology and immunocytochemistry revealed a mixed classical and collagenised type of myofibroblastoma. The patient is well with no evidence of recurrence. PMID- 24169396 TI - Solid neuroendocrine carcinoma of the breast. AB - Primary neuroendocrine carcinoma of the breast is a rare disease that accounts for less than 5% of all cancers arising from the breast. The tumour cells stain positively for chromogranin and synaptophysin. This report describes the occurrence of infiltrating ductal carcinoma of breast with neuroendocrine differentiated tumour in 37 year old female. Early small cell neuroendocrine cancer of the breast that is treated with surgery and adjuvant chemotherapy shows an increased disease-free survival. She is planned for anthracycline/cyclophosphamide based chemotherapy followed by etoposide/platinum based chemotherapy. As her tumour showed ER/PR positivity, she will be given hormonal therapy subsequently, however, more extensive review is required to define a standard treatment protocol for this rare neoplasm. PMID- 24169397 TI - Diagnosis, treatment and follow-up in four children with biotinidase deficiency from Pakistan. AB - Biotinidase deficiency is an inherited disorder in which the vitamin biotin is not recycled. If untreated, affected individuals develop neurological and cutaneous symptoms. Untreated individuals with biotinidase deficiency either succumb to disease or are left with significant morbidity. We describe clinical course and follow-up of 4 children from Pakistan. All 4 presented with classical symptoms of biotinidase deficiency and responded dramatically to oral biotin within days to weeks. Biotinidase deficiency is reported in Pakistani children from different part of world, however; there is no such report from Pakistan. This highlights lack of awareness of biotinidase deficiency among physicians in Pakistan. PMID- 24169398 TI - Salmonella cholecystitis: atypical presentation of a typical condition. AB - Salmonella cholecystitis is a rare but important complication of Salmonella typhi infection. We are reporting an 11 years old female child who presented with complaints of high-grade fever, jaundice and right sided abdominal pain (Charcot's triad). Her examination showed tender hepatomegaly. Initial blood results revealed high white cell counts with left shift, deranged liver function tests. Abdominal ultrasonography revealed distended gallbladder with minimal layer of sludge seen within its lumen along with streak of pericholecystic fluid. Blood culture grew Salmonella typhi. She was successfully treated with intravenous ceftriaxone. PMID- 24169399 TI - Psychosocial experiences of women with vesicovaginal fistula: a qualitative approach. AB - Vesicovaginal fistula (VVF) is a condition associated with a number of physical and psychological consequences. In order to gain a deeper understanding of the issues faced by women diagnosed with VVF, a qualitative exploratory study was carried out to explore the experiences of women suffering from VVF. The study included 8 women hospitalized with the diagnosis of vesicovaginal fistula at Kohi Goth Women's Hospital, Karachi, Pakistan. Semi structured interviews of each participant were conducted, recorded, and transcribed. Five major themes were identified, among which all of the participants experienced physical discomforts, psychological disturbances, issues with social and interpersonal relationships and financial constraints. However, concerns with religious practices were experienced by 87.5% of the participants. Pakistani women who are suffering through VVF face many challenges. Combined efforts should be made to offer supportive services to women suffering from this condition. PMID- 24169400 TI - A newborn with lower limb gangrene due to a congenital band. PMID- 24169401 TI - Hepatitis C virus genotypes in Tirana, Albania. AB - Hepatitis C virus (HCV) infection is a worldwide concern. Knowledge of the HCV genotype is clinically important because it predicts the rate of response to therapy and guides the treatment duration. Moreover, it allows molecular epidemiology to be performed. To our knowledge, the prevalence of HCV genotypes has been assessed only once in Albania, using a line probe genotyping assay. We determined HCV genotypes by population sequencing of HCV-infected patients in Tirana, Albania. HCV genotype and sequence analyses were performed for serum samples collected from January 2011 through May 2012 from 61 HCV-seropositive patients using population sequencing of the NS3 protease gene and alternatively the NS5b gene and the 5' untranslated region (UTR). HCV RNA was retrieved from the blood samples of 50 patients. The HCV NS3 protease gene was sequenced for 28 patients and NS5b and/or 5'UTR fragments were sequenced for an additional 22 patients. The predominant genotype was 1b in 25 patients (50%), followed by genotypes 2c, 4a, 3a, and 1a in 18%, 14%, 8%, and 6% of cases, respectively. Best matches for these HCV RNAs in GenBank were obtained in different countries worldwide. One NS3 protease naturally harbored an amino acid conferring minor drug resistance to newly available HCV protease inhibitors. In conclusion, HCV-1b was predominant in the present Albanian population, as in southeastern Europe. PMID- 24169402 TI - NHS is told to improve hospital complaints system within a year. PMID- 24169403 TI - Bacterial evolution of antibiotic hypersensitivity. AB - The evolution of resistance to a single antibiotic is frequently accompanied by increased resistance to multiple other antimicrobial agents. In sharp contrast, very little is known about the frequency and mechanisms underlying collateral sensitivity. In this case, genetic adaptation under antibiotic stress yields enhanced sensitivity to other antibiotics. Using large-scale laboratory evolutionary experiments with Escherichia coli, we demonstrate that collateral sensitivity occurs frequently during the evolution of antibiotic resistance. Specifically, populations adapted to aminoglycosides have an especially low fitness in the presence of several other antibiotics. Whole-genome sequencing of laboratory-evolved strains revealed multiple mechanisms underlying aminoglycoside resistance, including a reduction in the proton-motive force (PMF) across the inner membrane. We propose that as a side effect, these mutations diminish the activity of PMF-dependent major efflux pumps (including the AcrAB transporter), leading to hypersensitivity to several other antibiotics. More generally, our work offers an insight into the mechanisms that drive the evolution of negative trade-offs under antibiotic selection. PMID- 24169404 TI - Promoters maintain their relative activity levels under different growth conditions. AB - Most genes change expression levels across conditions, but it is unclear which of these changes represents specific regulation and what determines their quantitative degree. Here, we accurately measured activities of ~900 S. cerevisiae and ~1800 E. coli promoters using fluorescent reporters. We show that in both organisms 60-90% of promoters change their expression between conditions by a constant global scaling factor that depends only on the conditions and not on the promoter's identity. Quantifying such global effects allows precise characterization of specific regulation-promoters deviating from the global scale line. These are organized into few functionally related groups that also adhere to scale lines and preserve their relative activities across conditions. Thus, only several scaling factors suffice to accurately describe genome-wide expression profiles across conditions. We present a parameter-free passive resource allocation model that quantitatively accounts for the global scaling factors. It suggests that many changes in expression across conditions result from global effects and not specific regulation, and provides means for quantitative interpretation of expression profiles. PMID- 24169406 TI - Intuition in autistic savantism: a hypothetical model based on glial-neuronal interactions. AB - The previously proposed hypothesis on the astrocyte mega-domains of autistic savantism is here further elaborated with regard to the faculty of intuition. Two mechanisms may essentially be responsible for the intuition of autistic savantism. First, the increased number of contacted synapses via the astrocyte processes enables the brain to generate a comprehensive perception of a scene in the environment. Second, to inhibit a further reflection process neuronal synapses responsible for pertinent information must be rejected by retraction of the same astrocyte processes. This second mechanism may exert the disconnections of neuronal systems and is experimentally verified. Therefore, the break-off of further social contacts may also be necessary. The testing of the hypothesis in living brains is difficult but at least partly possible in post-mortem brains. PMID- 24169405 TI - Design of orthogonal genetic switches based on a crosstalk map of sigmas, anti sigmas, and promoters. AB - Cells react to their environment through gene regulatory networks. Network integrity requires minimization of undesired crosstalk between their biomolecules. Similar constraints also limit the use of regulators when building synthetic circuits for engineering applications. Here, we mapped the promoter specificities of extracytoplasmic function (ECF) sigmas as well as the specificity of their interaction with anti-sigmas. DNA synthesis was used to build 86 ECF sigmas (two from every subgroup), their promoters, and 62 anti sigmas identified from the genomes of diverse bacteria. A subset of 20 sigmas and promoters were found to be highly orthogonal to each other. This set can be increased by combining the -35 and -10 binding domains from different subgroups to build chimeras that target sequences unrepresented in any subgroup. The orthogonal sigmas, anti-sigmas, and promoters were used to build synthetic genetic switches in Escherichia coli. This represents a genome-scale resource of the properties of ECF sigmas and a resource for synthetic biology, where this set of well-characterized regulatory parts will enable the construction of sophisticated gene expression programs. PMID- 24169407 TI - The role of aquaporin-1 in idiopathic and drug-induced intracranial hypertension. AB - Idiopathic intracranial hypertension is a common disorder affecting mainly healthy, young, overweight women. The pathogenesis of this condition is unknown, but it has been shown to follow treatment with several compounds including corticosteroids and vitamin A derivatives. This paper will offer a novel hypothesis and insight on the pathogenesis of drug induced intracranial hypertension following a review and analysis of the literature. Both corticosteroids and vitamin A derivatives have been shown to upregulate the expression of aquaporin 1, a water channel protein. Aquaporin 1 is widely distributed in the human brain and is associated with water secretion into the subarachnoid space. Aquaporin 1 was also shown to participate in the regulation of weight. Agents used for treating idiopathic intracranial hypertension reduce aquaporin 1 expression. Based on these observations, we propose that aquaporin 1 has a pathogenetic role in drug induced idiopathic intracranial hypertension. Over expression of this gene causes increased intracranial pressure, and downregulation reduces pressure and alleviates the symptomatology and complications of idiopathic intracranial hypertension. PMID- 24169408 TI - Design-with-nature for multifunctional landscapes: environmental benefits and social barriers in community development. AB - Since the early 1970s, Ian McHarg's design-with-nature concept has been inspiring landscape architects, community and regional planners, and liked-minded professionals to create designs that take advantage of ecosystem services and promote environmental and public health. This study bridges the gap in the literature that has resulted from a lack of empirical examinations on the multiple performance benefits derived through design-with-nature and the under investigated social aspect emanated from McHarg's Ecological Determinism design approach. The Woodlands, TX, USA, an ecologically designed community development under McHarg's approach, is compared with two adjacent communities that follow the conventional design approach. Using national environmental databases and multiple-year residents' survey information, this study assesses three landscape performance metrics of McHarg's approach: stormwater runoff, urban heat island effect, and social acceptance. Geographic Information Systems (GIS) was used to assess the development extent and land surface temperature distribution. Results show that McHarg's approach demonstrates benefits in reducing runoff and urban heat island effect, whereas it confronts challenges with the general acceptance of manicured landscapes and thus results in a low safety perception level when residents interact with naturally designed landscapes. The authors argue that design-with-nature warrants multifunctionality because of its intrinsic interdisciplinary approach. Moreover, education and dissemination of successful examples can achieve a greater level of awareness among the public and further promote multifunctional design for landscape sustainability. PMID- 24169409 TI - Antimicrobial effect of 7-O-butylnaringenin, a novel flavonoid, and various natural flavonoids against Helicobacter pylori strains. AB - The antimicrobial effect of a novel flavonoid (7-O-butylnaringenin) on Helicobacter pylori 26695, 51, and SS1 strains and its inhibitory effect on the urease activity of the strains were evaluated and compared with those of several natural flavonoids. First, various flavonoids were screened for antimicrobial activities using the paper disc diffusion method. Hesperetin and naringenin showed the strongest antimicrobial effects among the natural flavonoids tested, and thus hesperetin and naringenin were selected for comparison with 7-O butylnaringenin. The antimicrobial effect of 7-O-butylnaringenin was greater than that of the hesperetin and naringenin. H. pylori 51 was more sensitive to 7-O butylnaringenin (2 log reduction of colony forming units, p < 0.05) than the other two strains at 200 MUM. 7-O-Butylnaringenin also showed the highest inhibitory effect against urease activity of H. pylori. Morphological changes of H. pylori 26695 treated with these flavonoids indicated that both hesperetin and 7-O-butylnaringenin at 200 MUM damaged the cell membranes. PMID- 24169410 TI - Linking childhood and adult criminality: using a life course framework to examine childhood abuse and neglect, substance use and adult partner violence. AB - Child abuse and neglect, considered criminal acts under the Criminal Code of Canada, play an important role in substance use, violence, and other criminal behaviour in adulthood. We adopted the life course perspective to identify modifiable contextual influences and co-occurring individual, social, and familial determinants associated with adult criminality. Using in-depth interview data, a sub-sample of 13 women who had recently experienced intimate partner violence, recounted their experiences of childhood abuse, their own substance use or criminality, as well as implications of these factors on their children's life trajectories. For the purposes of this paper criminality was defined as child abuse and neglect, domestic violence, illegal substance use and underage alcohol use. Our objective was to explore, in our data: (1) patterns and trajectories of criminality from childhood to adulthood among women who were victims of violence, and (2) cumulative effects of early life exposures on experiences of criminality; with the aim of describing the life course perspective as a useful framework to understand criminality along the life trajectory. The analysis was not designed to demonstrate causal connections between early childhood and adulthood experiences of criminality. Rather we generated qualitative and quantitative hypotheses to guide future research in the field. Implications for research and interventions are discussed. PMID- 24169411 TI - Does increasing community and liquor licensees' awareness, police activity, and feedback reduce alcohol-related violent crime? A benefit-cost analysis. AB - Approximately half of all alcohol-related crime is violent crime associated with heavy episodic drinking. Multi-component interventions are highly acceptable to communities and may be effective in reducing alcohol-related crime generally, but their impact on alcohol-related violent crime has not been examined. This study evaluated the impact and benefit-cost of a multi-component intervention (increasing community and liquor licensees' awareness, police activity, and feedback) on crimes typically associated with alcohol-related violence. The intervention was tailored to weekends identified as historically problematic in 10 experimental communities in NSW, Australia, relative to 10 control ones. There was no effect on alcohol-related assaults and a small, but statistically significant and cost-beneficial, effect on alcohol-related sexual assaults: a 64% reduction in in the experimental relative to control communities, equivalent to five fewer alcohol-related sexual assaults, with a net social benefit estimated as AUD$3,938,218. The positive benefit-cost ratio was primarily a function of the value that communities placed on reducing alcohol-related harm: the intervention would need to be more than twice as effective for its economic benefits to be comparable to its costs. It is most likely that greater reductions in crimes associated with alcohol-related violence would be achieved by a combination of complementary legislative and community-based interventions. PMID- 24169412 TI - A systematic review of peer-support programs for smoking cessation in disadvantaged groups. AB - The burden of smoking is borne most by those who are socially disadvantaged and the social gradient in smoking contributes substantially to the health gap between the rich and poor. A number of factors contribute to higher tobacco use among socially disadvantaged populations including social (e.g., low social support for quitting), psychological (e.g., low self-efficacy) and physical factors (e.g., greater nicotine dependence). Current evidence for the effectiveness of peer or partner support interventions in enhancing the success of quit attempts in the general population is equivocal, largely due to study design and lack of a theoretical framework in this research. We conducted a systematic review of peer support interventions for smoking cessation in disadvantaged groups. The eight studies which met the inclusion criteria showed that interventions that improve social support for smoking cessation may be of greater importance to disadvantaged groups who experience fewer opportunities to access such support informally. Peer-support programs are emerging as highly effective and empowering ways for people to manage health issues in a socially supportive context. We discuss the potential for peer-support programs to address the high prevalence of smoking in vulnerable populations and also to build capacity in their communities. PMID- 24169413 TI - Are trainee teachers being adequately prepared to promote the health and well being of school children? A survey of current practice. AB - BACKGROUND: Teachers are a key part of the wider public health workforce in England. We conducted a survey to find out how they are trained for this role during their initial teacher education (ITE). METHODS: Between 2011 and 2012, we sent an online questionnaire to 220 ITE course managers and conducted semi structured interviews with a purposive sample of 19 course managers to explore issues in more depth. RESULTS: The response rate to the questionnaire was 34% (n = 74). Although most of the course managers felt inclusion of health and well being training in ITE was important, provision across courses was variable. Topics which are public health priorities [e.g. sex and relationships education (SRE) and drugs, alcohol and tobacco] were covered by fewer courses than other topics (e.g. child protection, emotional health and anti-bullying). Perceived barriers to training included lack of time and a belief that health and well being were low priorities in educational policy. CONCLUSIONS: Not all of tomorrow's teachers are being adequately prepared for their role in helping to address public health priorities. Educational policy does not appear to be supporting the priorities of public health policy, and this is a key barrier to health promotion training in ITE. Keywords children, educational settings, health promotion. PMID- 24169414 TI - Socio-economic deprivation and risk of emergency readmission and inpatient mortality in people with sickle cell disease in England: observational study. AB - BACKGROUND: Sickle cell disease (SCD) is a cause of frequent emergency readmissions. We examined trends in SCD emergency readmissions and inpatient mortality in England in relation to socio-economic status. METHODS: Data from Hospital Episode Statistics were extracted for all SCD patients admitted in 2005/06. The financial year 2005/06 was taken as the index year for analysis. We calculated readmission rates and inpatient mortality for patients admitted with a primary or secondary diagnosis of sickle cell anaemia with crisis and without crisis in the index year during the subsequent 5 years (2006/07-2010/11). Charlson Score was used to measure comorbidity. Using Cox proportional hazards models, we also examined the relationship between patient characteristics and both emergency readmissions and inpatient mortality. RESULTS: In 2005/06, there were 7679 SCD index admissions. Over the subsequent 5-year period, patients living in the most socio-economically deprived areas were at highest risk of readmission (54.2% readmitted over the study period compared with 28% of the least deprived group). Inpatient mortality amongst readmissions was highest in patients living in the most deprived areas [hazard ratio (HR) 2.34, 95% CI 1.41 3.90]. CONCLUSION: SCD patients from the most socio-economically deprived areas and with comorbidities are at highest risk of both SCD readmissions and in hospital mortality, suggesting that there are inequalities in healthcare access and health outcomes amongst people with SCD. PMID- 24169415 TI - Usual dietary intake among female breast cancer survivors is not significantly different from women with no cancer history: results of the National Health and Nutrition Examination Survey, 2003-2006. AB - Dietary intake is a modifiable behavior that may reduce the risk of recurrence and death among breast cancer survivors. Cancer survivors are encouraged to consume a diet rich in fruit, vegetables, and whole grains and limit red meat, processed meat, and alcohol intake. Using data from the National Health and Nutrition Examination Survey (2003-2006), this study examined whether breast cancer survivors and women with no history of cancer differed in the distribution of usual intake of foods included in the dietary recommendations for preventing cancer and recurrences. Participants completed one or two 24-hour dietary recalls. The food groups included in this analysis were whole fruit; total vegetables; dark green and orange vegetables; whole grains; red meat; processed meat; alcohol; and calories from solid fat, alcohol, and added sugar. The National Cancer Institute Method was used to estimate the distribution of usual intake and to compare breast cancer survivors (n=102) to noncancer respondents (n=2,684). Using age and cancer survivor as covariates, subgroup estimates of usual intake were constructed. No significant group differences were found, except that survivors reported a greater intake of whole grains. More than 90% of both groups did not meet recommendations for fruits, vegetables, and whole grains; 75.4% and 70.2%, respectively, consumed less than the red meat recommendation; and <10% of either group met the recommendation for percent energy from solid fat, alcohol, and added sugar. The diet of breast cancer survivors was not significantly different from women with no history of cancer. PMID- 24169416 TI - Anti-angiogenic therapy in pediatric brain tumors: an effective strategy? AB - Brain tumors are still the leading cause of cancer morbidity and mortality among children, despite different therapeutic options including neurosurgery, chemotherapy and radiation. As angiogenesis is highly crucial in brain tumor growth and progression, numerous clinical trials evaluating diverse anti angiogenic agents have been described. In the present review, we aimed to answer the question if anti-angiogenic therapy is an effective strategy in the treatment of children with brain tumors. Although some encouraging results have been published of anti-angiogenic therapy targeting vascular endothelial growth factor (VEGF)/VEGF receptor signaling or epidermal growth factor receptor (EGFR), still more insight is warranted to be highly conclusive about the efficacy of anti angiogenic therapy with currently potential upcoming anti-angiogenic agents in pediatric brain tumors. However, given the need for new therapeutic strategies, multi targeted therapy with anti-angiogenic agents anticipating on possible tumor escape mechanisms could be effective in the future treatment of pediatric brain tumors. PMID- 24169418 TI - Case study in psychobiographical ethics. AB - This article addresses ethical issues relative to the conduct and reporting of psychobiographical research. The author's recent psychobiographical study of World Chess Champion Bobby Fischer (1943-2008) is used to illustrate particular ethical challenges and responses in six areas: (1) institutional review board (IRB) evaluation and informed consent; (2) balancing objective research with respect for psychobiographical subject; (3) inviting subject or next-of-kin to read and comment on working drafts of psychobiography; (4) reporting never-before revealed sensitive information on a subject; (5) role of interdisciplinary consultation in conducting psychobiography; and (6) the value and cautions of including psychological diagnoses as part of the psychological profile. A "bill of rights and responsibilities" for the psychobiographer is introduced as a stimulus for ongoing discussion and empirical research on ethical practice in psychobiography. PMID- 24169417 TI - Consent and community engagement in diverse research contexts. AB - Consent and community engagement (CE) in health research are two aspects of a single concern-that research is carried out in a respectful manner where social value is maximized. There are important overlaps and interdependencies between consent and CE; for example, CE can provide insights into how best to tailor consent to context and can be an important component of consent processes. Engaging communities can also have intrinsic and instrumental value beyond consent; for example, as a means of showing respect and identifying appropriate ways of working respectfully. In this paper we critically examine how CE and consent processes are characterized, conducted, and evaluated in diverse health research contexts, and propose a preliminary research agenda to support future learning in these critical areas. PMID- 24169419 TI - Extending the olive branch. AB - Using data from a study of qualitative researchers' experiences with ethics review and our own lens as both researchers and REB/IRB members, we explore the ethics review process and provide recommendations for improvements. Our findings suggest that the review process would benefit from a strengthened trust relationship between REB/IRBs and qualitative researchers that would require a commitment from both sides. Regarding REBs/IRBs, increased transparency of the review process, consistent application of federal guidelines, and a more collaborative review approach may improve the trust of qualitative researchers. Regarding researchers, approaching ethics review as a form of academic peer review, similar to other types of assessments of scholarly products such as grants and publications, may promote the integration of ethics review as an intrinsic part of the research process. Recognizing that responsibility for ethical research is a shared goal of both researchers and REB/IRBs, improved collaboration and constructive interaction can assist in understanding each other's perspective and work toward the development of mutual trust and respect. PMID- 24169420 TI - Brief report. AB - Most accounts of the ethical problems facing researchers across a broad spectrum of research fields come from ethicists, ethics committees, and specialists committed to the study of ethics in human research. In contrast, this study reports on the ethical questions that researchers, themselves, report facing in their everyday practice. Fifty-five Swedish researchers contributed 109 examples of ethical dilemmas, conflicts, and problems in research. They were all researchers at the postdoctoral level in the fields of medicine, the humanities, education, and the social sciences, who devoted at least 50 percent of their working hours to research. They reported issues they face before, during, and after gathering data. Their range of issues is broader than generally discussed and points to the importance of researchers' ethical sensitivity. PMID- 24169421 TI - Participants' recall and understanding of genomic research and large-scale data sharing. AB - As genomic researchers are urged to openly share generated sequence data with other researchers, it is important to examine the utility of informed consent documents and processes, particularly as these relate to participants' engagement with and recall of the information presented to them, their objective or subjective understanding of the key elements of genomic research (e.g., data sharing), as well as how these factors influence or mediate the decisions they make. We conducted a randomized trial of three experimental informed consent documents (ICDs) with participants (n = 229) being recruited to genomic research studies; each document afforded varying control over breadth of release of genetic information. Recall and understanding, their impact on data sharing decisions, and comfort in decision making were assessed in a follow-up structured interview. Over 25% did not remember signing an ICD to participate in a genomic study, and the majority (54%) could not correctly identify with whom they had agreed to share their genomic data. However, participants felt that they understood enough to make an informed decision, and lack of recall did not impact final data sharing decisions or satisfaction with participation. These findings raise questions about the types of information participants need in order to provide valid informed consent, and whether subjective understanding and comfort with decision making are sufficient to satisfy the ethical principle of respect for persons. PMID- 24169422 TI - Emotional risks to respondents in survey research. AB - Some survey research has documented distress in respondents with pre-existing emotional vulnerabilities, suggesting the possibility of harm. In this study, respondents were interviewed about a personally distressing event; mood, stress, and emotional reactions were assessed. Two days later, respondents participated in interventions to either enhance or alleviate the effects of the initial interview. Results indicated that distressing interviews increased stress and negative mood, although no adverse events occurred. Between the interviews, moods returned to baseline. Respondents who again discussed a distressing event reported moods more negative than those who discussed a neutral or a positive event. This study provides evidence that, among nonvulnerable survey respondents, interviews on distressing topics can result in negative moods and stress, but they do not harm respondents. PMID- 24169423 TI - Perceptions of trauma research with a sample of at-risk youth. AB - Growing body of research demonstrates that participants generally report favorable perceptions of participating in trauma research. However, questions remain on the long-term impact of asking at-risk youth about trauma in settings where such questions are unexpected. Perceptions of participation were examined in the current longitudinal study comprising a sample of adolescent girls recruited from the child welfare system to participate in a healthy relationship project. Over a year, teens (n = 180) completed four research sessions during which they were interviewed about interpersonal trauma exposure and trauma related symptoms. Results indicated that adolescents reported stable, favorable benefit-to-cost ratios over time. Perceptions of research participation and symptom severity did not impact retention. PMID- 24169424 TI - Reactions to research participation in victims of childhood sexual abuse. AB - We examined whether adults with a documented or self-reported history of childhood sexual abuse (CSA) report more emotional reactions and negative responses to research participation and whether psychiatric symptoms play a moderating role in their reactions. Using a prospective cohort design, individuals with documented histories of CSA and non-abused matched controls were followed up and interviewed in adulthood (n = 460). Reactions to research participation were measured with a brief questionnaire. Concurrent symptoms of depression, anxiety, and PTSD were assessed via standardized measures. Results showed that those with a history of CSA, documented or self-reported, experienced similar reactions compared to controls. Psychiatric symptoms predicted stronger emotional reactions and more negative responses, but also greater personal benefit, regardless of CSA history. PMID- 24169426 TI - Identifcation of a novel mutation p.I240T in the FRMD7 gene in a family with congenital nystagmus. AB - Congenital Nystagmus (CN) is a genetically heterogeneous ocular disease, which causes a significant proportion of childhood visual impairment. To identify the underlying genetic defect of a CN family, twenty-two members were recruited. Genotype analysis showed that affected individuals shared a common haplotype with markers flanking FRMD7 locus. Sequencing FRMD7 revealed a T > C transition in exon 8, causing a conservative substitution of Isoleucine to Tyrosine at codon 240. By protein structural modeling, we found the mutation may disrupt the hydrophobic core and destabilize the protein structure. We reviewed the literature and found that exons 2, 8, and 9 (11.4% of the sequence of FRMD7 mRNA) represent the majority (55.3%) of the reported FRMD7 mutations. In summary, we identified a novel mutation in FRMD7, showed its molecular consequence, and revealed the mutation-rich exons of the FRMD7 gene. Collectively, this provides molecular insights for future CN clinical genetic diagnosis and treatment. PMID- 24169427 TI - Anomalous right coronary artery from the pulmonary artery (ARCAPA), and aberrant right subclavian artery in a 2-month infant with heart failure. AB - Anomalous origin of the right coronary artery from the pulmonary artery (ARCAPA) is a very rare congenital heart anomaly. Most of the cases are asymptomatic during infancy and childhood. We report ARCAPA associated with aberrant right subclavian artery in a 2-month male infant presenting with heart failure. We used computed tomography angiography for confirming the diagnosis and also for post operative follow-up. PMID- 24169429 TI - A Callixylon (Archaeopteridales, Progymnospermopsida) trunk with preserved secondary phloem from the Late Devonian of Morocco. AB - PREMISE OF THE STUDY: During the Devonian, the evolution of secondary phloem produced by a bifacial vascular cambium was a key innovation that increased the ability of plants within the lignophyte clade to redistribute photosynthates and other organic compounds throughout their body. Unraveling the secondary phloem anatomy of the first arborescent lignophytes is crucial to understand the evolution of this tissue and the physiology of early trees. METHODS: A 10 cm wide stem of Callixylon with preserved secondary phloem from the Famennian of Morocco is described using thin-sections. KEY RESULTS: The secondary phloem of this Callixylon zalesskyi-type of stem is composed of fibers, sclereids, rays, axial parenchyma, and putative sieve cells. Fibers differentiate early and are relatively abundant in the inner phloem. In the older phloem, fibers are arranged in tangential bands alternating with extensive layers of axial parenchyma. Changes between the young and old phloem involve the periclinal division and radial elongation of the axial parenchyma cells. The presence of fibers in the inner, presumably functional phloem, combined with evidence for rhythmicity in the production of different phloem cell types are documented for the first time in detail in an archaeopteridalean progymnosperm. No periderm was observed within the preserved seven millimeters of bark tissues. CONCLUSIONS: The secondary phloem anatomy supports a close affinity of archaeopteridalean progymnosperms with both aneurophytalean progymnosperms and seed plants. The production of secondary phloem might have provided an advantage to these first arborescent lignophytes over other types of Devonian early trees, especially in dry conditions. PMID- 24169430 TI - Morphological and genetic differentiation and reproductive isolation among closely related taxa in the Ipomoea series Batatas. AB - PREMISE OF THE STUDY: Identifying recently diverged taxa can be useful for studying the process of speciation. Ipomoea lacunosa and I. cordatotriloba, along with a putative homoploid hybrid, I. *leucantha, are closely related taxa, which are promising for investigating the early stages of speciation. The objectives of this investigation were to determine how distinct these purported taxa are morphologically and genetically, and to assess the magnitude of reproductive isolation among the taxa. METHODS: We measured morphological characteristics and determined genotypes at four microsatellite loci in several populations of each of the taxa in North Carolina and South Carolina to quantify genetic and morphological differentiation. We also included a previously undescribed fourth taxon, which we term 'I. austinii'. KEY RESULTS: Our study revealed that all four taxa had distinct but overlapping geographical ranges, and had significantly distinct morphologies. Patterns of microsatellite variation and the results of crosses indicate that I. *leucantha and I. austinii are morphologically and genetically distinct taxa. Each exhibits substantial reproductive isolation from the other three taxa. By contrast, microsatellite markers indicate that I. lacunosa and I. cordatotriloba exhibit little differentiation at neutral markers, despite substantial morphological differentiation, and exhibit some reproductive isolation. CONCLUSION: I. *leucantha and I. austinii should be considered separate species. Our results provide no evidence that either species originated through homoploid hybrid speciation. I. cordatotriloba and I. lacunosa should be considered incipient species, but may be experiencing considerable reciprocal gene flow. PMID- 24169431 TI - The effect of leaf shape on the thermoregulation and frost tolerance of an annual vine, Ipomoea hederacea (Convolvulaceae). AB - PREMISE OF STUDY: Leaf shape is predicted to have important ecophysiological consequences; for example, theory predicts that lobed leaves should track air temperature more closely than their entire-margined counterparts. Hence, leaf lobing may be advantageous during cold nights (~0 degrees C) when there is the risk of damage by radiation frost (a phenomenon whereby leaves fall below air temperature because of an imbalance between radiational heat loss and convective heat gain). METHODS: Here, we test whether radiation frost can lead to differential damage between leaf shapes by examining a leaf-shape polymorphism in Ipomoea hederacea, where leaves are either lobed or heart-shaped depending on a single Mendelian locus. We logged leaf temperature during midautumn, and measured chlorophyll fluorescence and survival as proxies of performance. Furthermore, we tested if the leaf-shape locus confers freezing tolerance using freezing assays on leaf tissue from different leaf shapes. KEY RESULTS: We found that lobed leaves consistently remain warmer than heart-shaped leaves during the night, but that no pattern emerged during the day, and that temperature differences between leaf shapes were typically small. Furthermore, we found that leaf types did not differ in frost tolerance, but that a 1 degrees C decrease leads to a transition from moderate to complete damage. CONCLUSIONS: Our results demonstrate that Ipomoea hederacea leaf shapes do experience different nighttime temperatures, and that only minor temperature differences can lead to disparate levels of freezing damage, suggesting that the differential thermoregulation could result in different levels of frost damage. PMID- 24169432 TI - Sublingual immunotherapy: the U.S. experience. AB - PURPOSE OF REVIEW: It is likely that approval of allergen preparations for sublingual immunotherapy (SLIT) will soon occur in the United States. This article reviews experience with SLIT in this country, concentrating on the large, multicenter trials that will provide the evidence of safety and efficacy necessary to obtain that approval. RECENT FINDINGS: Large multicenter trials have been conducted with both grass and short ragweed. In five single-season studies with sublingual grass tablets, usually starting 4 months prior to and continuing through the pollen season, the combined symptom medication score was improved 20 28% relative to placebo-treated individuals. Short ragweed tablets, initiated 4 months prior to and continued through the pollen season, reduced symptom/medication scores by 24-26%. Similar results have been reported with short ragweed aqueous extract administered sublingually. To date, there has been only one small study each with house dust mite and cat allergen extracts. All of these studies were conducted with a single allergen. One small study, comparing timothy alone to the same dose of timothy combined with nine other pollen extracts, raised still unanswered questions regarding the efficacy of SLIT with multiple allergen mixes. SUMMARY: SLIT is coming to the United States. There will be approved allergen preparations for which the appropriate dosing for efficacy and safety has been established. It would be inappropriate to use the evidence generated by these large studies to justify off-label use of allergen extracts approved for injection or the administration of multiple allergen preparations sublingually. PMID- 24169433 TI - New approaches to transcutaneous immunotherapy: targeting dendritic cells with novel allergen conjugates. AB - PURPOSE OF REVIEW: This review summarizes recent preclinical and human studies evaluating allergen-specific immunotherapy via the transcutaneous route, and provides a rationale for the application of modified allergens with reduced allergenicity. Furthermore, it covers approaches to generate hypoallergenic conjugates for specific dendritic cell targeting. RECENT FINDINGS: Efficacy and safety of specific immunotherapy by application of allergens to the skin have been demonstrated in both animal models as well as clinical trials. However, localized adverse events have been reported, and delivery of antigens via barrier disrupted skin has been linked to the induction of unwanted T helper 2-biased immune responses and allergic sensitization. Coupling of carbohydrates to allergens has been shown to induce formation of nanoparticles, which can specifically target dendritic cells and potentiate immune responses, and by masking B-cell epitopes, can render the molecules hypoallergenic. SUMMARY: Due to its abundance of immunocompetent cells, the skin represents an attractive target tissue for novel and enhanced immunotherapeutic approaches. However, in order to avoid adverse events and therapy-induced sensitizations, transcutaneous immunotherapy requires the use of formulations with reduced allergenic potential. Combining novel hypoallergenic conjugates with painless transcutaneous immunization techniques may provide an efficient and patient-friendly alternative to the standard specific immunotherapy practices. PMID- 24169434 TI - Homogeneous liquid-liquid extraction of rare earths with the betaine-betainium bis(trifluoromethylsulfonyl)imide ionic liquid system. AB - Several fundamental extraction parameters such as the kinetics and loading were studied for a new type of metal solvent extraction system with ionic liquids. The binary mixture of the ionic liquid betainium bis(trifluoromethylsulfonyl)imide and water shows thermomorphic behavior with an upper critical solution temperature (UCST), which can be used to avoid the slower mass transfer due to the generally higher viscosity of ionic liquids. A less viscous homogeneous phase and mixing on a molecular scale are obtained when the mixture is heated up above 55 degrees C. The influence of the temperature, the heating and cooling times, were studied for the extraction of neodymium(III) with betaine. A plausible and equal extraction mechanism is proposed in bis(trifluoromethylsulfonyl)imide, nitrate, and chloride media. After stripping of the metals from the ionic liquid phase, a higher recovery of the ionic liquid was obtained by salting-out of the ionic liquid fraction lost by dissolution in the aqueous phase. The change of the upper critical solution temperature by the addition of HCl or betaine was investigated. In addition, the viscosity was measured below and above the UCST as a function of the temperature. PMID- 24169435 TI - AKIP1, a cardiac hypertrophy induced protein that stimulates cardiomyocyte growth via the Akt pathway. AB - Cardiac adaptation to unremitting physiological stress typically involves hypertrophic growth of cardiomyocytes, a compensatory response that often fails and causes heart disease. Gene array analysis identified AKIP1 (A Kinase Interacting Protein 1) as a hypertrophic gene and we therefore hypothesized a potential role in the hypertrophic response. We show for the first time that both AKIP1 mRNA and protein levels increased in hypertrophic cardiomyocytes under conditions of sustained cardiac stress, including pressure overload and after myocardial infarction and in vitro in phenylephrine (PE) stimulated neonatal rat ventricular cardiomyocytes (NRVCs). AKIP1 overexpression in NRVCs markedly stimulated hypertrophic growth responses, including significantly increased cell size, augmented cytoskeletal organization and protein synthesis. Although, AKIP1 was not essential for PE induced hypertrophy in NRVCs, it did potentiate neurohormonal induced protein synthesis. AKIP1 did, however, not induce expression of pathological marker genes like ANP and beta-MHC. ERK and Akt kinase signaling pathways have been linked to hypertrophy and AKIP1 specifically induced phosphorylation of Akt. This phosphorylation of Akt was essential for activation of ribosomal rpS6 and translation elongation factor eEF2 and this readily explains the increased protein synthesis. Akt inhibition fully blocked AKIP1 induced hypertrophy, showing that this pathway is critically involved. In conclusion, our results show that AKIP1 is induced in hypertrophic hearts and can stimulate adaptive cardiomyocyte growth, which involves Akt signaling. PMID- 24169436 TI - Structural variation of bamboo lignin before and after ethanol organosolv pretreatment. AB - In order to make better use of lignocellulosic biomass for the production of renewable fuels and chemicals, it is necessary to disrupt its recalcitrant structure through pretreatment. Specifically, organosolv pretreatment is a feasible method. The main advantage of this method compared to other lignocellulosic pretreatment technologies is the extraction of high-quality lignin for the production of value-added products. In this study, bamboo was treated in a batch reactor with 70% ethanol at 180 degrees C for 2 h. Lignin fractions were isolated from the hydrolysate by centrifugation and then precipitated as ethanol organosolv lignin. Two types of milled wood lignins (MWLs) were isolated from the raw bamboo and the organosolv pretreated residue separately. After the pretreatment, a decrease of lignin (preferentially guaiacyl unit), hemicelluloses and less ordered cellulose was detected in the bamboo material. It was confirmed that the bamboo MWL is of HGS type (p-hydroxyphenyl (H), vanillin (G), syringaldehyde (S)) associated with a considerable amount of p coumarate and ferulic esters of lignin. The ethanol organosolv treatment was shown to remove significant amounts of lignin and hemicelluloses without strongly affecting lignin primary structure and its lignin functional groups. PMID- 24169437 TI - [Transanal endoscopic operations for rectal tumours]. AB - BACKGROUND: Transanal endoscopic operation (TEO) may be the technique of choice for the treatment of rectal lesions, both benign and selected malignant lesions, with similar survival rates to conventional surgery but with lower morbidity. METHODS: In this article we present a series of 70 patients operated on with this procedure (TEO) in our center. The indications were benign rectal lesions and malignant lesions at early stages (T1) 86%. The surgical procedure was performed with the the transanal endoscopic operation platform (TEO; Karl Storz, Tuttlingen, Germany) and ultrasonic scalpel (Harmonic scalpel, Ethicon Endo surgery,...). RESULTS: The indication in 43 patients was a benign lesion (adenoma), in the other 27 the diagnosis was adenocarcinoma. After the resection, 61% of the series had a malignant lesion in the pathology report: 13 patients of the 43 with a benign lesion initially had a malignant lesion in the pathology report. Postoperative morbidity was 36%, Clavien III (5,7%). 3 patients (4%) needed emergency surgery. All of the benign lesions were completely excised, but 7 malignant lesions had resection margin involvement The median follow-up time was 26,4 months (range, 1-71 months), the overall recurrence for benign tumors was 9%, 8% for malignant pT1 and 12,5% for malignant pT2. Early salvage surgery was performed on 8 patients. CONCLUSIONS: TEO allows us to excise benign rectal lesions that could not be excised with a conventional approach (endoscopic or transanal resection) with a low morbidity rate. TEO can be used for malignant rectal tumors in early stages (pT1) with pathological confirmation. PMID- 24169438 TI - Results of the first 100 single port laparoscopic cholecystectomies in a secondary care hospital. AB - INTRODUCTION: Despite the excellent results obtained with standard laparoscopic cholecystectomy, the efforts for minimizing the ports needed to reduce postoperative pain, for a quicker recovery and to improve the patient's cosmetics continue. The aim of this study is to report the results of the first 100 cases of single port laparoscopic cholecystectomy performed in a secondary care hospital. MATERIAL AND METHODS: Prospective, observational and unicentric study including 100 patients between January 2010 and April 2012. INCLUSION CRITERIA: symptomatic cholelythiasis patients over 16-years of age on whom a single port laparoscopic cholecystectomy was performed. EXCLUSION CRITERIA: history of acute cholecystitis, pancreatitis or suspected choledocholithiasis, Endoscopic retrograde cholangiopancreatography, BMI>35 and previous laparotomies. We studied epidemiological, surgical and safety variables. RESULTS: The mean patient age was 39,89 +/- 11,5 years. The mean time of the surgical procedure was 67,94 +/- 25,5 min. There were 2 cases of postoperative complications. A non-infected seroma and a biliar leak. In 2 cases the use of an accessory trocar was needed. The mean hospital stay was 1,13 +/- 0,8 days. A total of 35% patients were included in the major ambulatory surgery programme.The overall patient satisfaction survey rating showed a high level of cosmetic satisfaction in 100% of patients. CONCLUSIONS: Single port laparoscopic cholecystectomy is a good technique when performed in selected cases by expert surgeons. It is feasible to include the single port laparoscopic cholecystectomy in a major ambulatory surgery programme. We have not had serious complications. There is a high cosmetic satisfaction index with this technique. PMID- 24169439 TI - Early-onset absence epilepsy aggravated by valproic acid: a video-EEG report. AB - Early-onset absence epilepsy refers to patients with absence seizures beginning before age 4 and comprises a heterogeneous group of epilepsies. Onset of absence seizures in the first year of life is very rare. We report a boy with absence seizures with onset at age 11 months, whose seizures increased in frequency after the introduction of valproic acid (VPA) treatment and substantially improved upon cessation of treatment. The mechanism of seizure worsening did not involve VPA toxicity, encephalopathy, Glut-1 deficiency or overdosage, and the reason for absence seizure aggravation remained unclear. The patient showed complete control of absence seizures with levetiracetam treatment and the course was benign, both in terms of seizure control and neuropsychological aspects. The similar overall electroclinical picture and outcome between children with early-onset absences and those with CAE support the view that these conditions are a continuum within the wide spectrum of IGE. [Published with video sequences]. PMID- 24169440 TI - Effect of corticosteroid on arrhythmic events in patients with cardiac sarcoidosis. PMID- 24169441 TI - Factors affecting the use of anti-amoebiasis protective measures among Taiwan immigrants returning to amoebiasis-endemic regions. AB - OBJECTIVE: To investigate the predictors of use of anti-amoebiasis protective measures (AAPMs) among Taiwan immigrants returning to their country of origin, using the Health Belief Model (HBM) to guide the investigation. DESIGN: Cross sectional study. METHODS: Between March and May 2011, all permanent immigrants originating from amoebiasis-endemic countries who received services at the immigrant service centres in Taipei or Tainan and who reported that they had returned to their country of origin within the past five years were enrolled in the study. A structured questionnaire containing questions on sociodemographic characteristics and items related to the constructs of the HBM was used as the data collection instrument. RESULTS: Complete information was collected from 384 immigrants, with a response rate of 80% (384/480). The mean age of the subjects was 38.4 years (standard deviation 10.6 years). The majority (70%) of participants did not receive travel information through a pretravel consultation, and more than 17% reported that they did not use measures to prevent amoebiasis. Multiple regression analyses revealed that Chinese proficiency, pretravel consultation and lower barriers to using protective measures were significantly associated with the use of AAPMs during return trips to country of origin (R(2) = 0.45; F = 77.5; P < 0.001). CONCLUSION: The HBM significantly predicted the use of AAPMs in this study. A high proportion of immigrants did not use appropriate AAPMs when they returned to their country of origin. Educational approaches should be targeted at immigrants originating from amoebiasis-endemic regions who return to their country of origin. PMID- 24169442 TI - A light transmission technique for pore size measurement in track-etched membranes. AB - A new approach is proposed for accurate measurement of the pore sizes in a track etched PET membrane (polyethylene terephthalate) from a nanometer scale to a submicrometer scale, which only entailed UV-Vis spectrometry. PMID- 24169443 TI - Third year nursing students' viewpoints about circumstances which threaten safety in the clinical setting. AB - BACKGROUND: Evidence emphasizes that learners, educators, clinicians, programs, and organizations share the responsibility for establishing and maintaining safety throughout undergraduate nursing education. Increased knowledge about students' perceptions of threats to safety in the clinical setting may guide educators' efforts to promote the development of safe novice practitioners while preserving patient safety. OBJECTIVE: The purpose of this study was to describe third year nursing students' viewpoints of the circumstances which threaten safety in the clinical setting. METHODS: Using Q methodology, 34 third year Bachelor of Science in Nursing students sorted 43 theoretical statement cards. Each card identified a statement describing a threat to safety in the clinical setting. These statements were generated through a review of nursing literature and consultation with experts in nursing education. Centroid factor analysis and varimax rotation identified viewpoints regarding circumstances that most threaten safety. RESULTS: Three discrete viewpoints and one consensus perspective constituted students' description of threatened safety. The discrete viewpoints were labeled lack of readiness, misdirected practices, and negation of professional boundaries. There was consensus that it is most unsafe in the clinical setting when novices fail to consolidate an integrated cognitive, behavioral, and ethical identity. This unifying perspective was labeled non integration. CONCLUSION: Third year nursing students and their educators are encouraged to be mindful of the need to ensure readiness prior to entry into the clinical setting. In the clinical setting, the learning of prepared students must be guided by competent educators. Finally, both students and their educators must respect professional boundaries to promote safety for students and patients. PMID- 24169444 TI - A systematic review of the effectiveness of simulation debriefing in health professional education. AB - OBJECTIVE: The objective of this review was to identify, appraise and synthesise the best available evidence for the effectiveness of debriefing as it relates to simulation-based learning for health professionals. BACKGROUND: Simulation is defined as a technique used to replace or amplify real experiences with guided experiences that evoke or replace substantial aspects of the real world in a fully interactive manner. The use of simulation for health professional education began decades ago with the use of low-fidelity simulations and has evolved at an unprecedented pace. Debriefing is considered by many to be an integral and critical part of the simulation process. However, different debriefing approaches have developed with little objective evidence of their effectiveness. INCLUSION CRITERIA: Studies that evaluated the use of debriefing for the purpose of simulation-based learning for health professionals were included. Simulation studies not involving health professionals and those conducted in other settings such as such as military or aviation were excluded. REVIEW METHODS: A review protocol outlining the inclusion and exclusion criteria was submitted, peer reviewed by the Joanna Briggs Institute (JBI) for Evidence Based Practice, and approved prior to undertaking the review. A comprehensive search of studies published between January 2000 and September 2011 was conducted across ten electronic databases. Two independent reviewers assessed each paper prior to inclusion or exclusion using the standardised critical appraisal instruments for evidence of effectiveness developed by the Joanna Briggs Institute. RESULTS: Ten randomised controlled trials involving various debriefing methods were included in the review. Meta-analysis was not possible because of the different outcomes, control groups and interventions in the selected studies. The methods of debriefing included: post simulation debriefing, in-simulation debriefing, instructor facilitated debriefing and video-assisted instructor debriefing. In the included studies there was a statistically significant improvement pre-test to post-test in the performance of technical and nontechnical skills such as: vital signs assessment; psychomotor skills; cardiopulmonary resuscitation; task management; team working; and situational awareness, regardless of the type of debriefing conducted. Additionally, only one study reported consistent improvement in these outcomes with the use of video playback during debriefing. In two studies the effect of the debrief was evident months after the initial simulation experiences. CONCLUSION: These results support the widely held assumption that debriefing is an important component of simulation. It is recommended therefore that debriefing remains an integral component of all simulation-based learning experiences. However, the fact that there were no clinical or practical differences in outcomes when instructor facilitated debriefing was enhanced by video playback is an important finding since this approach is currently considered to be the 'gold standard' for debriefing. This finding therefore warrants further research. PMID- 24169445 TI - Individual and intervention-related factors associated with adherence to home exercise in chronic low back pain: a systematic review. AB - BACKGROUND CONTEXT: Exercise has been shown to reduce pain and increase function in patients with chronic low back pain. However up to 70% of patients do not engage in prescribed home exercise. Physiotherapists need to understand more about the complex factors influencing patients' adherence to prescribed home exercise to tailor their exercise interventions more effectively and support patients to self-manage. PURPOSE: This review identifies factors associated with adherence to health care practitioner-prescribed home exercise in adults with chronic low back pain. STUDY DESIGN: Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) guidelines were used for the reporting of this review. PATIENT SAMPLE: We explored literature in which the authors studied adherence to home exercise in adults with CLBP. OUTCOME MEASURES: Adherence to home exercise was the primary outcome. Additional outcome measures were recorded in the data extraction table. METHODS: The following databases were searched: Embase, PsychINFO, MEDLINE, PEDro, and the Cochrane Central Register of Controlled Trials. Data were independently extracted and assessed for methodologic quality by two reviewers. RESULTS: Eleven randomized controlled trials, including 1,088 participants, met the inclusion criteria. Moderate evidence was found for one individual patient subfactor and three intervention related subfactors associated with increased adherence to home exercise. These subfactors were greater health locus of control, supervision, participation in an exercise program, and participation in a general behavior change program incorporating motivational strategies. CONCLUSIONS: This is the first systematic review investigating adherence to prescribed home exercise in a chronic low back pain population. It is difficult to draw firm conclusions because the research lacks detailed descriptions of intervention content. The use of a taxonomy of behavior change techniques has been suggested to overcome this key problem. This review has highlighted the lack of standardized measures of adherence to prescribed home exercise. The development of a validated measure of adherence should be a priority because this will provide a better understanding of the multitude of factors that may influence adherence to home exercise. PMID- 24169446 TI - Activation of NOD2/RIPK2 pathway induces mitochondrial injury to oligodendrocyte precursor cells in vitro and CNS demyelination in vivo. AB - We examined the activation of innate immune pathway mediated by nucleotide binding oligomerization domain-containing protein 2 (NOD2) in oligodendrocyte precursor cells (OPCs). We show that activation of NOD2 by ligand peptidoglycan (PGN) leads to the recruitment and phosphorylation of receptor-interacting serine/threonine kinase 2 (RIPK2). Phosphorylation of RIPK2 is followed by phosphorylation of neuronal nitric oxide synthase (nNOS), increase in NOS activity and subsequent accumulation of nitric oxide (NO) mediated N tyrosinylated compounds in OPCs. The reversal of NOS activity by the nNOS inhibitor 7-nitroindazole (7-NI), but not by the iNOS inhibitor L-canavanine, supported the conclusion that the increased NOS activity was due to the selective activation of nNOS in OPCs. In addition, NO mediated injury to OPC was reflected in reduction in activity of respiratory enzymes such as complex I and IV, decrease in mitochondrial membrane potential and release of cytochrome-C from mitochondria. Furthermore, intracerebral injection of PGN into corpus callosum (CC) of rats led to the development of demyelination, which appeared as early as by day 3 post-injection, and involved the trunk of the CC by day 14. Accumulation of N-tyrosinylated proteins was seen in oligodendrocytes in regions of the CC which were in close proximity to the injection site. Taken together, these results suggest that PGN induced formation of NO, mitochondrial dysfunction and accumulation of N-tyrosinylated proteins in oligodendrocytes are likely mediators of central nervous system demyelination. PMID- 24169447 TI - Proteomic analysis of the SIRT6 interactome: novel links to genome maintenance and cellular stress signaling. AB - The chromatin regulatory factor SIRT6 plays pivotal roles in metabolism, tumor suppression, and aging biology. Despite the fundamental roles of SIRT6 in physiology and disease, only a handful of molecular and functional interactions of SIRT6 have been reported. Here, we characterize the SIRT6 interactome and identify 80+ novel SIRT6-interacting proteins. The discovery of these SIRT6 associations considerably expands knowledge of the SIRT6 interaction network, and suggests previously unknown functional interactions of SIRT6 in fundamental cellular processes. These include chromatin remodeling, mitotic chromosome segregation, protein homeostasis, and transcriptional elongation. Extended analysis of the SIRT6 interaction with G3BP1, a master stress response factor, uncovers an unexpected role and mechanism of SIRT6 in regulating stress granule assembly and cellular stress resistance. PMID- 24169448 TI - Composite ALK-negative anaplastic large cell lymphoma and small lymphocytic lymphoma involving the right inguinal lymph node. AB - Anaplastic large cell lymphoma and small lymphocytic lymphoma are two lymphoid malignancies with completely distinct morphologies and natural histories. We present a rare case of composite anaplastic large cell lymphoma and small lymphocytic lymphoma in an inguinal lymph node of an otherwise healthy 47-year old male patient. Immunohistochemical and molecular studies identified the two populations clearly. Their separation is imperative as anaplastic large cell lymphoma can be an aggressive neoplasm and easily overlooked in cases of small lymphocytic lymphoma with a small population of anaplastic large cell lymphoma cells. PMID- 24169449 TI - Is human kallikrein-11 in gastric cancer treated with surgery and adjuvant chemoradiotherapy associated with survival? AB - Human kallikreins (hKs) have been reported to be involved in human cancers, and several hKs are promising biomarkers of various cancers, such as prostate, ovarian, breast, and testicular cancer. In the present study, we aimed to evaluate the prognostic value of immunohistochemical expression of hK11 in patients with gastric cancer. The study included 55 (36 men and 19 women; 58 +/- 10 years of mean age) patients with gastric cancer treated with surgery and adjuvant chemoradiotherapy. Tissue sections were evaluated immunohistochemically with a monoclonal anti-hK11 antibody. Of the 55 patients, 35 (63.6%) were hK11 positive and 20 (36.4%) were hK11-negative. Disease-free and overall survival rates were significantly higher in patients with hK11 positive than in those with hK-11 negative expression (24 months vs. 11 months, p: 0.043; 29 months vs. 13 months, p: 0.038, respectively). In conclusion, hK11 expression in gastric cancer appears to be associated with a better prognosis. hK11 may be a prognostic biomarker of gastric cancer. On the other hand, it is needed to elucidate the mechanisms underlying the regulation of hK11 expression in gastric cancer. PMID- 24169450 TI - Structure and stress of Re(1121); chiral terraces at a racemic surface. AB - The surface structure and morphology of the clean Re(1121) surface has been investigated through combined low energy electron diffraction intensity analysis of data taken at multiple angles of incidence, scanning tunneling microscopy, and first-principles density functional calculations. The results show how this globally racemic surface terminates in two chirally distinct terraces, which show large-scale out-of-plane atomic relaxations and in-plane lateral movement of the uppermost atoms. We further identify and discuss the initial stages of step bunching upon adsorption of oxygen that leads ultimately to the large-scale faceting of the surface. Finally, we present calculations of surface stress and the response to applied surface strain, which suggest routes to the exertion of control over the expression of chirality at the surface. PMID- 24169451 TI - Genomic and epigenomic regulation of adipose tissue inflammation in obesity. AB - Chronic inflammation of adipose tissue is viewed as a hallmark of obesity and contributes to the development of type 2 diabetes and cardiovascular disease. According to current models, nutrient excess causes metabolic and structural changes in adipocytes, which initiate transcriptional programs leading to the expression of inflammatory molecules and the subsequent recruitment of immune cells. Recent advances in deciphering the underlying mechanisms revealed that key regulatory events occur at the genomic and epigenomic levels. Here we review these advances because they offer a better understanding of the mechanisms behind the complex obesogenic program in adipose tissue, and because they may help in defining new therapeutic strategies that prevent, restrict, and resolve inflammation in the context of obesity. PMID- 24169452 TI - Impact of diet in shaping gut microbiota revealed by a comparative study in infants during the six months of life. AB - The development of the gut is controlled and modulated by different interacting mechanisms, such as genetic endowment, intrinsic biological regulatory functions, environment influences and last but no least, the diet influence. In this work, we compared the fecal microbiota of breast-fed (BF), formula-fed (FF), and mixed fed (MF) infants from Hebei Province, China. By using high-throughput 16S rDNA sequencing analyses, we found some differences in gut microbiota in the three groups. Firmicutes and Proteobacteria were the dominant bacteria at the phylum level in the three groups, where FF infants showed a significant depletion in Bacteroidetes (p < 0.001) and Actinobacteria (p < 0.05). Enterobacteriaceae was the dominant bacteria at the family level in the three groups, but FF infants showed higher Enterobacteriaceae enrichment than BF and MF infants (p < 0.05); the abundance of the Bifidobacteriaceae was only 8.16% in the feces of BF infants, but higher than in MF and FF infants (p < 0.05). The number of genera detected (abundance >0.01%) in BF, MF, and FF infants was only 15, 16, and 13, respectively. This study could provide more accurate and scientific data for the future study of infant intestinal flora. PMID- 24169453 TI - Efficiency of gamma irradiation to inactivate growth and fumonisin production of Fusarium moniliforme on corn grains. AB - The efficiency of gamma irradiation (0, 1, 5, 10, 15, 20, and 30 kGy) as a sterilization method of corn samples (30 g) artificially contaminated with Fusarium moniliforme stored at normal condition (25oC with approximate relative humidity (RH) of 55%) and optimal condition (25oC with a controlled RH of 97%) was studied. The results showed that the fungal growth and the amount of fumonisin were decreased as the dose of gamma irradiation increased. Gamma irradiation at 1-5 kGy treatment significantly inhibited the growth of F. moniliforme by 1-2 log reduction on corn samples (P < 0.05). Sublethal effect of gamma irradiation was observed at 10-20 kGy doses after storage, and a complete inactivation required 30 kGy. Fungal growth and fumonisin production increased with higher humidity and longer storage time in all corn samples. This study also demonstrated that there was no strict correlation between fungal growth and fumonisin production. Storage at normal condition significantly resulted in lower growth and fumonisin production of F. moniliforme as compared with those stored at optimal condition (P < 0.05). Gamma irradiation with the dose of >= 5 kGy followed by storage at normal condition successfully prolonged the shelf life of irradiated corns, intended for human and animal consumptions, up to 7 weeks. PMID- 24169454 TI - Relationship between morphology and itaconic acid production by Aspergillus terreus. AB - The morphology of filamentous fungi closely correlates with the productivity in submerged culture. Using itaconic acid (IA) production by Aspergillus terreus as a research model, the quantitative relationship between the growth form of A. terreus and IA production was investigated. IA fermentation was scaled up from shake flasks to a 7 L stirred tank bioreactor based on the quantitative relationship. Our results demonstrated the following: (1) Three morphologies of A. terreus were formed by changing the inoculum level and shape of the flask. (2) Investigation of the effects of the three morphologies on broth rheology and IA production revealed the higher yield of IA on dry cell weight (DCW, IA/DCW) and yield of glucose on DCW (consumed glucose/DCW) were achieved during clump growth of A. terreus. (3) By varying the KH2PO4 concentration and culture temperature, the relationships between clump diameter and IA production were established, demonstrating that the yield of IA on DCW (R(2) = 0.9809) and yield of glucose on DCW (R(2) = 0.9421) were closely correlated with clump diameter. The optimum clump diameter range for higher IA production was 0.40-0.50 mm. (4) When the clump diameter was controlled at 0.45 mm by manipulating the mechanical stress in a 7 L fermentor, the yield of IA on DCW and yield of glucose on DCW were increased by 25.1% and 16.3%, respectively. The results presented in this study provide a potential approach for further enhancement of metabolite production by filamentous fungi. PMID- 24169455 TI - Development and characterization of expression vectors for Corynebacterium glutamicum. AB - In an attempt to develop a variety of expression vector systems for Corynebacterium glutamicum, six types of promoters, including Ptac, Psod, Psod with a conserved Shine-Dalgarno (SD) sequence from C. glutamicum, PilvC, PilvC with a conserved SD-1 (PilvC-M1), and PilvC with a conserved SD-2 (PilvC-M2), were cloned into a modified shuttle vector, pCXM48. According to analysis of promoter strength by quantitative reverse transcription PCR, Psod and Psod-M were superior to tac and ilvC promoters in terms of transcription activity in C. glutamicum. All of the promoters have promoter activities in Escherichia coli, and Psod-M displayed the highest level of transcriptional activity. The protein expression in constructed vectors was evaluated by measuring the fluorescence of green fluorescent protein (GFP) and SDS-PAGE. C. glutamicum harboring plasmids showed GFP fluorescence with an order of activity of PilvC > PilvC-M1 > Psod > PilvC-M2 > Psod-M, whereas all plasmids except pCSP30 with Psod displayed fluorescence activities in E. coli. Of them, the strongest level of GFP was observed in E. coli with Psod-M, and this seems to be due to the introduction of the conserved SD sequence in the translational initiation region. These results demonstrate that the expression vectors work well in both C. glutamicum and E. coli for the expression of target proteins. In addition, the vector systems harboring various promoters with different strengths, conserved SD sequences, and multiple cloning sites will provide a comfortable method for cloning and gene expression, and consequently contribute to the metabolic engineering of C. glutamicum. PMID- 24169456 TI - Well-being in pregnancy: an examination of the effect of socioeconomic, dietary and lifestyle factors including impact of a low glycaemic index dietary intervention. AB - BACKGROUND/OBJECTIVE: Well-being has been linked to the quality of diet and lifestyle in adults; however, there is a paucity of data in pregnancy. The aim of this study was to examine the relationship between well-being and socioeconomic status, diet and lifestyle during pregnancy and to consider the effect of intervention with low glycaemic index (GI) diet on well-being. SUBJECTS/METHODS: This was a cohort analysis of 619 participants of the ROLO study (Randomised cOntrol trial of LOw GI diet versus no dietary intervention to prevent recurrence of fetal macrosomia). The following data were collected: educational attainment, dietary intakes (food frequency questionnaire), physical activity (self-reported) and well-being (WHO-5-Item Wellbeing Index--expressed as a percentage). RESULTS: Well-being was positively associated with education and physical activity. Third level education was associated with a 3.07-point higher well-being percentage score, and each day that an individual achieved >30 min walking per week was associated with a 1.10-point increase in percentage well-being score, Radj(2) 2.4% (F=7.260, P=0.001). The intervention low GI group had a significantly lower percentage well-being score than the usual diet group (56.3% vs 59.9%, P=0.015). No correlation was noted between well-being and GI status calculated from food diaries (P=0.469). Well-being was not associated with micronutrient intake. CONCLUSIONS: Well-being in pregnancy was independently and positively associated with education and physical activity and negatively associated with low GI dietary intervention. These findings have significance not only for women at risk of low mood but also for healthcare professionals when counselling women about the importance of healthy lifestyle in pregnancy. PMID- 24169457 TI - Hand length as an alternative measurement of height. AB - BACKGROUND/OBJECTIVES: Despite the utmost importance of body height in evaluating nutritional status, it is not always possible to obtain its measurement and height may have to be estimated. The objective of the study was to formulate and cross-validate a regression equation to predict height using hand length measurement and also to determine if predicted height (PH) will lead to significant errors when used in body mass index (BMI) calculation. SUBJECTS/METHODS: A cross-sectional study was conducted using a consecutive sample of 465 inpatients (19-91 years), from a university hospital. Participants were randomly divided into a development sample of 311 individuals and a cross validation one. A linear regression model was used to formulate the equation. Intraclass correlation coefficients (ICCs) for single measures and differences between measured height (MH) and PH and between BMI calculated with MH (BMI(MH)) and with PH (BMI(PH)) were determined. RESULTS: The regression equation for PH is: PH (cm)=80.400+5.122 * hand length (cm)--0.195 * age (years)+6.383 * gender (gender: women 0, men 1) (R=0.87, s.e. of the estimate=4.98 cm). MH and PH were strongly correlated, ICCs: 0.67-0.74 (P<0.001). Differences were small, mean difference+/-s.d., < or = -0.6+/-4.4 cm (P > or = 0.24). BMI(MH) and BMI(PH) were strongly correlated, ICCs: 0.94-0.96 (P<0.001). Differences were small, < or = 0.3+/-1.7 kg/m2 (P > or = 0.10). CONCLUSIONS: The formulated regression equation using hand length, age and gender provides a valid estimation of height and is useful in the clinical context. PH from this regression equation can be used in BMI calculations as misclassification is small. PMID- 24169458 TI - Catch-up growth does not associate with cognitive development in Indian school age children. AB - BACKGROUND/OBJECTIVES: Stunting is significantly associated with lifetime morbidity and poorer cognitive outcomes in children. Although several studies have examined the relationship between stunting, catch-up growth and cognitive performance in young populations, this relationship has not yet been explored in school-aged children. In this study, we used data from three different nutritional intervention studies conducted over a 4-year period on school-age children in Bangalore, India to assess these relationships. SUBJECTS/METHODS: A battery of cognitive tests was conducted before each intervention to determine whether stunting status at baseline was related to cognitive performance across four separate domains, and repeated after a 6-month period to assess whether changes to stunting status is related to cognitive advancement. RESULTS: Results of independent t-tests showed that while stunted children had significantly poorer performance on short-term memory, retrieval ability and visuospatial ability tests (P=0.023, 0.026 and 0.028, respectively), there was no significant difference in the change in cognitive scores following nutritional interventions over a 6-month period between those who remained stunted and those who were no longer stunted (P>0.10). CONCLUSIONS: Evidently, stunting remains associated with cognitive ability in school-age children; however, the reversal of these effects in this age group may be quite difficult. PMID- 24169459 TI - Examining the content of weight, nutrition and physical activity advices provided by Dutch practice nurses in primary care: analysis of videotaped consultations. AB - BACKGROUND/OBJECTIVE: To examine the content of Dutch practice nurses' (PNs') advices about weight, nutrition and physical activity to overweight and obese patients. SUBJECTS/METHODS: A 100 videotaped real-life PN consultations (The Netherlands, 2010/2011) with overweight or obese patients were selected. An observational checklist was developed to assess frequency and content. Personalization of advices was scored, as also the guidelines on which PNs based their advices. Content analysis was used to identify different categories of advices. RESULTS: About one quarter of advices concerned weight, over two-thirds nutrition and one-third physical activity. Lose weight, eat less fat and be more physically active in general were the main categories for each type of advice. Despite high clarity of advices, lower scores were found for specificity and personalization. Very few nutrition advices were provided in combination with physical activity advices. CONCLUSIONS: Weight advices often related to the patient's complaint. PNs seldom set a concrete weight goal. Although benefits of physical activity were discussed, often no practical advices were provided about how to achieve this. Integrated lifestyle advice was not common: advices about nutrition and physical activity were fragmented throughout the consultation. Obesity prevention needs more emphasis in PNs' educational programs. PMID- 24169460 TI - Is a child's growth pattern early in life related to serum adipokines at the age of 10 years? AB - BACKGROUND/OBJECTIVES: Growth parameters during infancy and early childhood might predict adipokine levels later in life. This study investigates the association between peak growth velocities, body mass index (BMI) and age at adiposity rebound (AR), with leptin and adiponectin levels at age 10 years. SUBJECTS/METHODS: Peak height (PHV) and weight (PWV) velocities were calculated from height and weight measurements obtained between birth and age 2 years from 2880 children participating in the GINIplus (German Infant Nutritional Intervention plus environmental and genetic influences on allergy development) and LISAplus (Influences of Lifestyle-Related Factors on the Immune System and the Development of Allergies in Childhood plus Air Pollution and Genetics) birth cohorts. BMI and age at AR were calculated using BMI measurements between age 1.5 and 12 years. Blood samples were collected during a physical examination at age 10. Adiponectin and leptin levels were measured by radioimmunoassay. Linear regression models were fitted after adjustment for potential confounding factors and results are presented per interquartile range increase in the exposure. RESULTS: Age at AR was negatively associated with leptin in males and females (percent difference beta*: -41.71%; 95% confidence interval: (-44.34;-38.96) and beta*: -43.22%; (-45.59; -40.75), respectively). For both males and females PWV (beta*: 14.23%; (7.60; 21.26) and beta*: 18.54%; (10.76; 26.87), respectively) and BMI at AR (beta*: 63.08%; (55.04; 71.53) and beta*: 67.02%; (59.30; 75.10), respectively) were positively associated with leptin levels. PHV showed a positive effect on leptin in females only (beta*: 10.75%; (3.73; 18.25)). Growth parameters were not significantly associated with adiponectin except for age at AR among females (beta: 0.75 ng/ml; (0.42; 1.09)) and PWV among males (beta: 0.45 ng/ml; (0.11; 0.79)). CONCLUSION: Growth patterns in early life may be associated with leptin levels at age 10 years. PMID- 24169463 TI - In-vivo precision of the GE Lunar iDXA densitometer for the measurement of appendicular and trunk lean and fat mass. AB - Dual energy X-ray absorptiometry (DXA) is considered to be a reference standard for the assessment of body composition, and one particular advantage is its provision of regional body composition parameters. The objective of this study was to determine the in vivo precision of the Lunar iDXA for the measurement of appendicular and trunk lean and fat mass in a heterogeneous group of adults (n=39; age 33.5 (8.3) years; BMI 24.6 (5.4) kg m(-2)). Two consecutive total body scans were performed on each participant with re-positioning between scans. There was excellent agreement between consecutive scans for measurements of both fat and lean appendicular and trunk composition (R(2)=0.99). Precision for body composition at all regions was less than 2% coefficient of variation (CV). Precision for bilateral appendicular body composition was less than 4% CV for the arms and less than 2.5% CV for the legs. Our findings indicate that the iDXA is a valuable tool for repeat measurements of regional body composition in adults. PMID- 24169461 TI - Effect of micronutrient deficiency on QuantiFERON-TB Gold In-Tube test and tuberculin skin test in diagnosis of childhood intrathoracic tuberculosis. AB - BACKGROUND/OBJECTIVES: Data on performance of QuantiFERON-TB Gold In-Tube test (QFT) and tuberculin skin test (TST) in children with active tuberculosis from high burden countries in the context of micronutrient deficiency are scarce. The objective of this study was to evaluate the effect of micronutrient deficiency on the performance of TST and QFT in children with intrathoracic tuberculosis. SUBJECTS/METHODS: Children with probable intrathoracic tuberculosis underwent TST, QFT, gastric lavages and induced sputum examination for AFB (Acid-Fast Bacilli) smear and culture. Zinc, copper, ferritin and vitamin D were measured on stored serum samples. The study used cross-sectional data at initiation of anti tubercular therapy. RESULTS: Three hundred and sixty-two children (median age 115.5 months (interquartile range: 73, 144), 200 (55.3%) girls) were enrolled in the study. Microbiological confirmation of tuberculosis could be obtained in 128 patients. TST and QFT were positive in 337 (93%) and 297 (82%) children, respectively. Performance of both the tests was unaffected by weight-for-age and height-for-age 'z-scores' or by serum copper levels. TST was not affected by serum zinc and ferritin levels. Children with negative QFT results had lower mean serum zinc level (P=0.01) and higher ferritin levels (P=0.007) as compared to those with positive test. Higher proportion of children with positive TST were vitamin D deficient/insufficient (P=0.003). CONCLUSION: Micronutrient status, especially serum levels of zinc, may influence the performance of QFT in children with intrathoracic tuberculosis. Considering the high prevalence of zinc deficiency in developing countries, QFT should be used cautiously for diagnosing tuberculosis. PMID- 24169462 TI - The biomarker-based validity of a food frequency questionnaire to assess the intake status of folate, pyridoxine and cobalamin among Iranian primary breast cancer patients. AB - BACKGROUND/OBJECTIVES: Folate, pyridoxine and cobalamin are coenzymatically essential in one-carbon methyl metabolism, and their deficiencies could explain some alterations during breast carcinogenesis. We aimed to evaluate the validity of folate, pyridoxine and cobalamin estimates from a food frequency questionnaire (FFQ) on the basis of their corresponding fasting plasma biomarkers, in breast cancer (BC) patients. SUBJECTS/METHODS: In a prospective, consecutive case series, 149 women with primary BC aged between 30 and 69 years as a representative sample of Iranian women with BC were recruited. The 136-item FFQ was used for the validity assay. Fasting plasma folate and cobalamin were tested by automated electrochemiluminescence. The high-pressure liquid chromatography with fluorescence detection was used to determine the plasma levels of pyridoxal 5'-phosphate (PLP) and total homocysteine (tHcy). RESULTS: Area under the curve (AUC) for assessing the diagnostic accuracy of folate-related data through an FFQ was 0.74 (P<0.01) in the reference model (folate plasma level<5.9 ng/ml), with sensitivity and specificity of 68% and 63%, respectively. The positive and negative predictive values (PPV and NPV) were 96.9% and 96.8%, respectively. The AUC for cobalamin intake in the reference model (plasma cobalamin<260 pmol/l) was 0.64 (P<0.01), with 60% sensitivity and 61% specificity. Although tHcy >=10.0 MUmol/l was used as reference indicator, the folate intake (AUC=0.71, P<0.01) and cobalamin intake status (AUC=0.67, P<0.05) were also determined appropriately by FFQ. CONCLUSIONS: Dietary folate and cobalamin estimates from FFQ were significantly correlated with their fasting plasma concentrations. Our data supported the validity of new FFQ to rank individuals by dietary intake status of folate and cobalamin. PMID- 24169464 TI - Economic evaluation for protein and energy supplementation in adults: opportunities to strengthen the evidence. AB - Malnutrition is a costly problem for health care systems internationally. Malnourished individuals require longer hospital stays and more intensive nursing care than adequately nourished individuals and have been estimated to cost an additional L7.3 billion in health care expenditures in the United Kingdom alone. However, treatments for malnutrition have rarely been considered from an economic perspective. The aim of this systematic review was to identify the cost effectiveness of using protein and energy supplementation as a widely used intervention to treat adults with and at risk of malnutrition. Papers were identified that included economic evaluations of protein or energy supplementation for the treatment or prevention of malnutrition in adults. While the variety of outcome measures reported for cost-effectiveness studies made synthesis of results challenging, cost-benefit studies indicated that the savings for the health system could be substantial due to reduced lengths of hospital stay and less intensive use of health services after discharge. In summary, the available economic evidence indicates that protein and energy supplementation in treatment or prevention of malnutrition provides an opportunity to improve patient wellbeing and lower health system costs. PMID- 24169466 TI - Associations of mammographic dense and nondense areas and body mass index with risk of breast cancer. AB - Mammographic density measurements are associated with risk of breast cancer. Few studies have investigated the concurrent associations of mammographic dense and nondense areas, body mass index (weight (kg)/height (m)(2)), and ages at mammogram and diagnosis with breast cancer risk. We conducted a matched, case control study nested within the Melbourne Collaborative Cohort Study (cohort recruitment in 1990-1994 and follow-up until 2007) to estimate the associations between these factors and breast cancer risk under alternative causal models. Mammographic dense area was positively associated with risk, and the strength of this association was only slightly influenced by the choice of the causal model (relative risk per 1 standard deviation = 1.50, 95% confidence interval: 1.32, 1.70). Mammographic nondense area was inversely associated with risk under the assumption that fat in the body and fat in the breast cause breast cancer through independent mechanisms (relative risk per 1 standard deviation = 0.75, 95% confidence interval: 0.65, 0.86), whereas it was not associated with risk under the assumption that they are both proxies of adiposity. Knowledge about the biological mechanisms regulating the role played by mammographic nondense area and body fat on breast cancer risk is essential to better estimate their impacts on individual risk. PMID- 24169465 TI - U-shaped relationship between tissue docosahexaenoic acid and atrial fibrillation following cardiac surgery. AB - BACKGROUND/OBJECTIVES: Randomised controlled trials (RCTs) evaluating the effect of fish oil supplementation on postoperative atrial fibrillation (POAF) following cardiac surgery have produced mixed results. In this study, we examined relationships between levels of red blood cell (RBC) n-3 long-chain polyunsaturated fatty acids (LC-PUFAs) and the incidence of POAF. SUBJECTS/METHODS: We used combined data (n=355) from RCTs conducted in Australia and Iceland. The primary end point was defined as POAF lasting >10 min in the first 6 days following surgery. The odds ratios (ORs) for POAF were compared between quintiles of preoperative RBC n-3 LC-PUFA levels by multivariable logistic regression. RESULTS: Subjects with RBC docosahexaenoic acid (DHA) in the fourth quintile, comprising a RBC DHA range of 7.0-7.9%, had the lowest incidence of POAF. Subjects in the lowest and highest quintiles had significantly higher risk of developing POAF compared with those in the fourth quintile (OR=2.36: 95% CI; 1.07-5.24 and OR=2.45: 95% CI; 1.16-5.17, respectively). There was no association between RBC eicosapentaenoic acid levels and POAF incidence. CONCLUSIONS: The results suggest a 'U-shaped' relationship between RBC DHA levels and POAF incidence. The possibility of increased risk of POAF at high levels of DHA suggests an upper limit for n-3 LC-PUFAs in certain conditions. PMID- 24169467 TI - Effect of HT042, herbal formula, on longitudinal bone growth in spontaneous dwarf rats. AB - HT042 is a new herbal prescription consisting of Astragalus membranaceus, Phlomis umbrosa and Eleutherococcus senticosus, which are used in Korean medicine to stimulate growth in children. We investigated the effects of HT042 on the body weight, longitudinal bone growth, and bone length in spontaneous dwarf rats (SDR). Male and female SDRs were divided into three groups: the control group (DW, 10 mL/kg/day), the recombinant human GH group (rhGH; 500 ug/kg/day), and the HT042 (100 mg/kg/day) group. Each group received the respective treatments for 10 days. Body weight was measured on day 10 of treatment. On day 8, tetracycline (20 mg/kg) was injected intraperitoneally into all individuals to form a fluorescent band on the newly synthesized bone. On day 10, femur and tibia lengths were measured using PIXImus. Body weight, longitudinal bone growth, and bone length were not affected in the HT042 group. In contrast, the rhGH group showed significantly increased body weight, longitudinal bone growth, and bone length. In conclusion, HT042 does not act through a GH-like effect to promote longitudinal bone growth. PMID- 24169468 TI - Conformational analysis of geometric isomers of pitavastatin together with their lactonized analogues. AB - Super-statins are synthetic inhibitors of 3-hydroxy-3-methylglutaryl-coenzyme A reductase, which is the rate-limiting enzyme responsible for the biosynthesis of cholesterol. All of the super-statins with a C=C double bond spacer between the heterocyclic and the dihydroxycarboxylic moiety that are currently on the market exist as E-isomers. To extend the understanding of conformational and thermodynamic preferences of Z-isomeric super-statin analogues, this study focused on analyzing pitavastatin and its lactonized derivatives via NMR spectroscopy and ab initio calculations. Z-isomeric pitavastatin analogues exist in solution as a pair of interconverting rotamers, where the Gibbs free energies between the major and minor rotamers are within 0.12 and 0.25 kcal mol-1 and the rotational energy barriers are between 15.0 and 15.9 kcal mol-1. The analysis of long-range coupling constants and ab initio calculations revealed that rotation across the C5'-C7 single bond is essential for generating a pair of atropisomers. The overall comparison of the results between Z-isomeric pitavastatin and rosuvastatin analogues demonstrated that the former are to some extent more flexible to attain numerous conformations. Demonstrating how structural differences between super-statin analogues induce distinctive conformational preferences provides important insight into the super-statins' conformational variability and may well improve future drug design. PMID- 24169469 TI - Needle in the external auditory canal: an unusual complication of inferior alveolar nerve block. AB - Inferior alveolar nerve block is used to anesthetize the ipsilateral mandible. The most commonly used technique is one in which the anesthetic is injected directly into the pterygomandibular space, by an intraoral approach. The fracture of the needle, although uncommon, can lead to potentially serious complications. The needle is usually found in the pterygomandibular space, although it can migrate and damage adjacent structures, with variable consequences. The authors report an unusual case of a fractured needle, migrating to the external auditory canal, as a result of an inferior alveolar nerve block. PMID- 24169470 TI - Acknowledging historical precedence. PMID- 24169471 TI - Relationship of pectoralis major muscle size with bench press and bench throw performances. AB - This study examined the relationship of muscle size indices of the pectoralis major muscle with bench press and bench throw performances in 18 male collegiate athletes. The maximal cross-sectional area (MCSAMAx) and volume (MV) of the pectoralis major muscle were determined by magnetic resonance imaging. First, subjects were tested for their one repetition maximum bench press strength (1RMBP) using a Smith machine. At a later date, subjects performed bench throws using the Smith machine with several different loads ranging from 30.0 kg to 90% of 1RMBP. Barbell positions were measured by a linear position transducer, and bench throw power was calculated using a dynamic equation. Three trials were performed for each load. In all the trials, the maximal peak power was adopted as bench throw peak power (PPBT). The 1RMBP was significantly correlated with MCSAMAx. Similarly, the correlation coefficient between MV and PPBT was significant. In contrast to the y-intercept of the MV-PPBT regression line, that of the MCSAMAx-1RMBP regression line was not significantly different from 0. These results suggested that, although the dependence on pectoralis major muscle size is slightly different between bench press strength and bench throw power, the pectoralis major muscle size has a significant impact on bench press and throw performances. Greater muscle size leads to heavier body weight, which can be a negative factor in some sports. We therefore recommend that athletes and their coaches develop training programs for improving sports performance by balancing the advantage of increased muscle size and the potential disadvantage of increased body weight. PMID- 24169472 TI - Evaluation of isokinetic and isometric strength measures for monitoring muscle function recovery after anterior cruciate ligament reconstruction. AB - Although various strength tests and their outcome measures have been proposed for anterior cruciate ligament (ACL) reconstruction (ACLR), their measurement properties still remain relatively underexplored. The aim of this study was to investigate the longitudinal construct validity of the standard isokinetic (IKT) and isometric test (IMT), and of the IMT of alternating consecutive maximal contractions (ACMC). In addition, the concurrent validity of ACMC was assessed and compared with the validity of IMT. The strength of quadriceps and hamstrings in 20 male athletes with an anterior cruciate ligament (ACL) injury were assessed before ACLR, 4 and 6 months after ACLR, by means of IMT, ACMC, and IKT performed at 60 and 180 degrees . s(-1). Significant between-session differences in muscle strength variables were found in the involved quadriceps (F > 6.5; p <= 0.05), but not in the uninvolved leg (F < 2.5; p > 0.05). Coefficients of variations in the uninvolved leg (all below 13.5%) were lower than the involved leg (11.7 22.1%). Intraclass correlation coefficients were moderate-to-high for the uninvolved leg and low-to-high for quadriceps of the involved leg. The concurrent validity of ACMC with respect to the IKT (r = 0.57-0.92; p <= 0.05) was comparable with the validity of IMT (r = 0.52-0.87; p <= 0.05). We conclude that the explored longitudinal construct validity of most of the evaluated variables could be sufficiently sensitive to detect the effects of the applied rehabilitation procedures. In addition, the obtained sensitivity and concurrent validity and the potential advantages of ACMC over IMT, all suggest that ACMC could be a particularly promising method for routine testing of neuromuscular function after ACLR. PMID- 24169473 TI - Reliability, validity, and applicability of isolated and combined sport-specific tests of conditioning capacities in top-level junior water polo athletes. AB - Standard testing procedures are of limited applicability in water sports, such as water polo. The aim of this investigation was to construct and validate methods for determining water polo-specific conditioning capacities. We constructed 4 combined-capacity tests that were designed to mimic real-game water polo performances: sprint swimming performance, shooting performance, jumping performance, and precision performance. In all cases, combined-capacity tests included a period of standardized exhaustion followed by the performance of the targeted quality (swimming, shooting, jumping, and precision). In the first part of the study, single-capacity tests (sprint swim, in-water jump, drive shoot, and precision performance) were tested and later included in the combined-capacity tests. Study subjects consisted of 54 young male water polo players (15-18 years of age, 185.6 +/- 6.7 cm, and 83.1 +/- 9.9 kg). Most of the tests evaluated were found to be reliable with Cronbach alpha values ranging from 0.83 to 0.96 and coefficients of variation from 21 to 2% (for the single-capacity tests) and 0.75 to 0.93 test-retest correlation (intraclass correlation coefficients) with Bland Altman tight limits of agreement (for combined-capacity tests). The combined capacity tests discriminated qualitative groups of junior water polo players (national squad vs. team athletes) more effectively than single-capacity tests. This is most likely because combined-capacity tests more closely represent the complex fitness capacities required in real game situations. Strength and conditioning practitioners and coaches working with water polo athletes should consider incorporating these validated tests into their assessment protocols. PMID- 24169474 TI - The effects of traditional and enforced stopping speed and agility training on multidirectional speed and athletic function. AB - This study investigated the effects of a traditional speed and agility training program (TSA) and an enforced stopping program emphasizing deceleration (ESSA). Twenty college-aged team sport athletes (16 males, 4 females) were allocated into the training groups. Pretesting and posttesting included: 0-10, 0-20, 0-40 m sprint intervals, change-of-direction, and acceleration test (CODAT), T-test (multidirectional speed); vertical, standing broad, lateral, and drop jumps, medicine ball throw (power); Star Excursion Balance Test (posteromedial, medial, anteromedial reaches; dynamic stability); and concentric (240 degrees . s(-1)) and eccentric (30 degrees . s(-1)) knee extensor and flexor isokinetic testing (unilateral strength). Both groups completed a 6-week speed and agility program. The ESSA subjects decelerated to a stop within a specified distance in each drill. A repeated measures analysis of variance determined significant (p <= 0.05) within- and between-group changes. Effect sizes (Cohen's d) were calculated. The TSA group improved all speed tests (d = 0.29-0.96), and most power tests (d = 0.57-1.10). The ESSA group improved the 40-m sprint, CODAT, T test, and most power tests (d = 0.46-1.31) but did not significantly decrease 0 10 and 0-20 m times. The TSA group increased posteromedial and medial excursions (d = 0.97-1.89); the ESSA group increased medial excursions (d = 0.99-1.09). The ESSA group increased concentric knee extensor and flexor strength, but also increased between-leg knee flexor strength differences (d = 0.50-1.39). The loading associated with stopping can increase unilateral strength. Coaches should ensure deceleration drills allow for appropriate sprint distances before stopping, and athletes do not favor 1 leg for stopping after deceleration. PMID- 24169475 TI - The reliability and validity of a soccer-specific nonmotorised treadmill simulation (intermittent soccer performance test). AB - This study investigated the reliability and validity of a novel nonmotorised treadmill (NMT)-based soccer simulation using a novel activity category called a "variable run" to quantify fatigue during high-speed running. Twelve male University soccer players completed 3 familiarization sessions and 1 peak speed assessment before completing the intermittent soccer performance test (iSPT) twice. The 2 iSPTs were separated by 6-10 days. The total distance, sprint distance, and high-speed running distance (HSD) were 8,968 +/- 430 m, 980 +/- 75 m and 2,122 +/- 140 m, respectively. No significant difference (p > 0.05) was found between repeated trials of the iSPT for all physiological and performance variables. Reliability measures between iSPT1 and iSPT2 showed good agreement (coefficient of variation: <4.6%; intraclass correlation coefficient: >0.80). Furthermore, the variable run phase showed HSD significantly decreased (p <= 0.05) in the last 15 minutes (89 +/- 6 m) compared with the first 15 minutes (85 +/- 7 m), quantifying decrements in high-speed exercise compared with the previous literature. This study validates the iSPT as a NMT-based soccer simulation compared with the previous match-play data and is a reliable tool for assessing and monitoring physiological and performance variables in soccer players. The iSPT could be used in a number of ways including player rehabilitation, understanding the efficacy of nutritional interventions, and also the quantification of environmentally mediated decrements on soccer-specific performance. PMID- 24169476 TI - [Skin cancer education for general practitioners is recommended]. PMID- 24169477 TI - [Personal update: CME online in a new format]. PMID- 24169478 TI - [Fever and neutropenia]. PMID- 24169480 TI - [Skin cancer in primary care: frequency, need to further education and subjective diagnostic certainty. A cross sectional survey among general practitioners in Canton of Zurich]. AB - BACKGROUND: Incidence of malignant skin lesions is rising in Switzerland. We wanted to assess the frequency of patients with suspicious skin lesions in daily practice. Furthermore, we asked for diagnostic certainty and the need of further education in skin cancer. METHODS: Survey with 1212 GPs in the canton of Zurich, descriptive analysis, regression analysis. RESULTS: Response rate 41,4%. 23,2% of the GPs saw daily/weekly patients with suspicious skin lesions, another 34,8% monthly. 79,0% reported need for further education in skin cancer. This need was lower in urban GPs and in GPs with higher diagnostic certainty. CONCLUSIONS: GPs saw relatively often patients with suspicious skin lesions. Despite high diagnostic certainty, there was a clear need for further education in skin cancer. PMID- 24169481 TI - [Valvular heart disease: preoperative assessment and postoperative care]. AB - Patients with valvular heart disease or with a prosthetic heart valve replacement are seen with increasing frequency in clinical practice. The medical care and evaluation of patients with valvular heart disease before valve surgery, but also the post-operative treatment is complex and managed by general practitioners, cardiologists and cardiac surgeons. In this mini-review we will first discuss the preoperative assessment of the two most common valvulopathies, aortic stenosis and mitral regurgitation. Then we will discuss the post-operative care, which includes the management of anticoagulation, serial follow up and as well as the diagnostic assessment of complications such as thromboembolism, hemolysis, endocarditis and valve dysfunction. PMID- 24169482 TI - [What's new about total knee arthroplasty]. AB - Osteoarthritis of the knee is one of the most common problems in the orthopedic practice and its surgical technique is still challenging. This Mini-Review presents patient specific cutting blocks for the implantation of a total knee arthroplasty. PMID- 24169483 TI - [Hoarsness after a trip to the United States of America]. AB - A 52 year old Swiss presented with a sore throat and progressive hoarseness. The histology showed a granulomatous inflammation of the epiglottis. Microbiology revealed dimorphic fungi in the sputum which were identified as Histoplasma sp. The histoplasma antigen was positive in urine and serum. Antimycotic therapy with itraconazol p.o. was started and switched to Amphotericin B i. v. due to clinical deterioration. Adrenal insufficiency should be considered in any patient with disseminated histoplasmosis since both the infection as well as the antimycotic treatment may cause Morbus Addison. An alternative therapy for the disseminated histoplasmosis is voriconazol. The investigation of the travel history is an important point. PMID- 24169484 TI - [Spontaneous esophageal rupture]. PMID- 24169485 TI - [Apixaban for treatment of acute venous thromboembolism]. PMID- 24169486 TI - [Outpatient treatment of patients with acute uncomplicated diverticulitis]. PMID- 24169491 TI - Hunt appeals against ruling he exceeded his powers in action on Lewisham Hospital. PMID- 24169490 TI - Cadmium exposure and the epigenome: Exposure-associated patterns of DNA methylation in leukocytes from mother-baby pairs. AB - Cadmium (Cd) is prevalent in the environment yet understudied as a developmental toxicant. Cd partially crosses the placental barrier from mother to fetus and is linked to detrimental effects in newborns. Here we examine the relationship between levels of Cd during pregnancy and 5-methylcytosine (5mC) levels in leukocyte DNA collected from 17 mother-newborn pairs. The methylation of cytosines is an epigenetic mechanism known to impact transcriptional signaling and influence health endpoints. A methylated cytosine-guanine (CpG) island recovery assay was used to assess over 4.6 million sites spanning 16,421 CpG islands. Exposure to Cd was classified for each mother-newborn pair according to maternal blood levels and compared with levels of cotinine. Subsets of genes were identified that showed altered DNA methylation levels in their promoter regions in fetal DNA associated with levels of Cd (n = 61), cotinine (n = 366), or both (n = 30). Likewise, in maternal DNA, differentially methylated genes were identified that were associated with Cd (n = 92) or cotinine (n = 134) levels. While the gene sets were largely distinct between maternal and fetal DNA, functional similarities at the biological pathway level were identified including an enrichment of genes that encode for proteins that control transcriptional regulation and apoptosis. Furthermore, conserved DNA motifs with sequence similarity to specific transcription factor binding sites were identified within the CpG islands of the gene sets. This study provides evidence for distinct patterns of DNA methylation or "footprints" in fetal and maternal DNA associated with exposure to Cd. PMID- 24169492 TI - 5-Hydroxymethylcytosine as a useful marker to differentiate between malignant melanomas and benign melanocytic nevi. PMID- 24169493 TI - Significance of positive urine cytology on progression and cancer-specific mortality of non--muscle-invasive bladder cancer. AB - BACKGROUND: Positive results from voided urine cytology (VUC) indicate the fragility of the intercellular adhesion of bladder cancer cells, a critical biological process for invasion and metastasis, along with the presence of atypical cells. Few studies have focused on the prognostic role of VUC in non muscle-invasive bladder cancer (NMIBC). METHODS: Between 2000 and 2010, 326 patients diagnosed pathologically with Ta or T1 bladder urothelial carcinoma underwent 597 transurethral resections of bladder tumor (TURBTs). Clinicopathological data were prospectively collected at each TURBT. Reports of cells of class IIIb or greater were considered positive VUC results. Muscle invasive or metastatic recurrences were considered progression. Risk factors for progression and cancer-specific mortality (CSM) were determined using time-fixed and time-dependent Cox models. Variables at the study entry and at each TURBT were used for time-fixed and time-dependent models, respectively. RESULTS: The 5 year cumulative progression and CSM rates were, respectively, 7% and 5% (median follow-up, 46 months). The 5-year cumulative progression and CSM rates for patients with positive VUC were 20% and 15%, respectively, compared with 2% (P < .0001) and 2% (P = .0002), respectively, for patients with negative VUC results. A positive VUC result was a significant and independent risk factor for progression and CSM in the time-fixed and time-dependent models. In time dependent models, 7 predictors for progression or CSM were identified (positive VUC results, T1 disease, lack of intravesical instillation, higher prior recurrence rate, higher histological grade, male gender, and advanced age), whereas 3 predictors were identified in time-fixed models (positive VUC, T1 disease, and higher prior recurrence rate). VUC results consistently outperformed histological grade as a prognostic predictor. CONCLUSION: Positive VUC results predict the progression and CSM of NMIBC, independent of and outperforming histological grade. PMID- 24169494 TI - Role of sorafenib in overcoming resistance of chemotherapy-failure castration resistant prostate cancer. AB - BACKGROUND: Sorafenib promotes apoptosis through downstream pathways that can be deregulated in CRPC. We hypothesized that sorafenib could overcome chemotherapy resistance in CRPC. PATIENTS AND METHODS: Eligible patients were those whose disease had progressed during chemotherapy (docetaxel or mitoxantrone) or within 12 weeks of stopping either. Patients then continued or resumed their last chemotherapy regimen with the addition of sorafenib 400 mg twice daily. Patients received a maximum of 6 cycles of chemotherapy/sorafenib followed by sorafenib alone until disease progression. The primary end point was combination safety. Secondary end points were overall response, percentage of SD, and time to progression (TTP). RESULTS: Twenty-two patients (21 evaluable) were enrolled (16 patients with Gleason score >= 7). Median age was 68 years (range, 59-83 years). Median prostate-specific antigen (PSA) was 142 ng/dL (range, 13.6-9584). Visceral and bone disease were present combined in 9 patients (41%). Ten patients (47.6%) showed biochemical response (19% with > 50% PSA decline) and 16 patients (76%) achieved radiographic stability (according to Response Evaluation Criteria for Solid Tumors) after starting sorafenib for a median duration of 6 months (range, 4-12 months). Grade 3/4 nonhematologic toxicities were fatigue (n = 7, 32%), palmar-plantar erythrodysesthesia (n = 4, 18%). Dose reduction of sorafenib occurred at least once in 15 patients (68%) because of palmar-plantar erythrodysesthesia (22%) and fatigue (22%). With a median follow-up of 19 months (range, 3-46 months), median overall survival was 8 months. TTP according to PSA level was 3 months and TTP according to imaging studies and/or clinically was 6 months. Median number of treatment cycles given was 6 (range, 1-10). CONCLUSION: Sorafenib can be combined safely with chemotherapy and in some patients overcomes chemotherapy resistance. PMID- 24169495 TI - Future directions from past experience: a century of prostate radiotherapy. AB - Prostate cancer is the most commonly diagnosed noncutaneous malignancy in men, yet 100 years ago it was considered a rare disease. Over the past century, radiation therapy has evolved from a radium source placed in the urethra to today's advanced proton therapy delivered by only a few specialized centers. As techniques in radiation have evolved, the treatment of localized prostate cancer has become one of the most debated topics in oncology. Today, patients with prostate cancer must often make a difficult decision between multiple treatment modalities, each with the risk of permanent sequelae, without robust randomized data to compare every treatment option. Meanwhile, opinions of urologists and radiation oncologists about the risks and benefits involved with each modality vary widely. Further complicating the issue is rapidly advancing technology which often outpaces clinical data. This article represents a complete description of the evolution of prostate cancer radiation therapy with the goal of illuminating the historical basis for current challenges facing oncologists and their patients. PMID- 24169496 TI - Intravesical mitomycin therapy for stage T1 and tis high-grade squamous cell carcinoma of the bladder. PMID- 24169497 TI - Infection of mouse bone marrow-derived immature dendritic cells with classical swine fever virus C-strain promotes cells maturation and lymphocyte proliferation. AB - In this study, the interactions of classical swine fever virus (CSFV) C-strain and the virulent GSLZ strain with mouse bone marrow-derived immature dendritic cells (BM-imDCs) were investigated for the first time. Both the C-strain and the virulent GSLZ strain could effectively infect and replicate in mouse BM-imDCs. C strain-infected BM-imDCs showed a greatly enhanced degree of maturation, and could effectively promote the expansion and proliferation of allogeneic naive T cells. The C-strain induced a stronger Th1 response. Infection with the virulent GSLZ strain had no obvious influence on cell maturation or lymphocyte proliferation, and failed to induce any obvious immune response. The results of this study provided initial information for research of the immunologic mechanisms of CSFV using mouse DCs as the model cells. PMID- 24169498 TI - Performance assessment of a glucose control protocol in septic patients with an automated intermittent plasma glucose monitoring device. AB - BACKGROUND & AIMS: The optimal level and modality of glucose control in critically ill patients is still debated. A protocolized approach and the use of nearly-continuous technologies are recommended to manage hyperglycemia, hypoglycemia and glycemic variability. We recently proposed a pato-physiology based glucose control protocol which takes into account patient glucose/carbohydrate intake and insulin resistance. Aim of the present investigation was to assess the performance of our protocol with an automated intermittent plasma glucose monitoring device (OptiScannerTM 5000). METHODS: OptiScannerTM was used in 6 septic patients, providing glucose measurement every 15' from a side-port of an indwelling central venous catheter. Target level of glucose was 80-150 mg/dL. Insulin infusion and kcal with nutritional support were also recorded. RESULTS: 6 septic patients were studied for 319 h (1277 measurements); 58 [45-65] hours for each patient (measurements/patient: 231 [172 265]). Blood glucose was at target for 93 [90-98]% of study time. Mean plasma glucose was 126 +/- 11 mg/dL. Only 3 hypoglycemic episodes (78, 78, 69 mg/dL) were recorded. Glucose variability was limited: plasma glucose coefficient of variation was 11.7 +/- 4.0% and plasma glucose standard deviation was 14.3 +/- 5.5 mg/dL. CONCLUSIONS: The local glucose control protocol achieved satisfactory glucose control in septic patients along with a high degree of safeness. Automated intermittent plasma glucose monitoring seemed useful to assess the performance of the protocol. PMID- 24169500 TI - Cytokinesis-required Cdc14 is a signaling hub of asexual development and multi stress tolerance in Beauveria bassiana. AB - A dual-specificity, paralogue-free Cdc14 phosphatase was located in the nuclei of Beauveria bassiana (filamentous entomopathogen) and functionally characterized. Inactivation of cdc14 caused defective cytokinesis due to multinucleate cells formed in Deltacdc14 and 89% decrease of blastospore production, followed by slower growth and a loss of >= 96% conidial yield under normal conditions. These defects coincided well with drastic down-regulation of 25 genes required for mitosis and conidiation. Moreover, Deltacdc14 became hypersensitive to oxidative, osmotic, and cell wall and mitosis perturbing stresses, and lost 41-70% of conidial thermotolerance, UV-B resistance and virulence, accompanied with transcriptional down-regualtion of various signaling factors and stress responsive effectors and depressed phosphorylation signals of Hog1 and Slt2 in high-osmolarity glycerol and cell-wall integrity pathways. All changes were well restored by rescuing cdc14. Our findings indicate that Cdc14 vital for the fungal cytokinesis acts as a signaling hub in regulating not only asexual development but multi-stress responses and virulence. PMID- 24169502 TI - Effect of orbital protrusion and vertical interpalpebral distance on pterygium formation. AB - PURPOSE: To evaluate the risk factors in the development of pterygium in the Marmara region of Turkey as well as the efficacy of vertical interpalpebral distance, protrusion level and tear function in the development of pterygium. MATERIALS AND METHODS: The cases were grouped in two as the research group consisted of patients with pterygium and the control group consisted of healthy people. A total of 294 patients with pterygium (108 bilateral, 186 unilateral) and 200 controls were included in the study. All patients and control group underwent a thorough ophthalmic examination, including tear function analysis using tear film breakup time measurement, protrusion level and vertical interpalpebral distance. RESULTS: No statistically significant difference was found between the bilateral pterygium subgroup and control group in terms of vertical interpalpebral distance and protrusion value (p=0.733, p=0.625). When the pterygium eyes and the control group were compared in the unilateral pterygium subgroup, no significant difference was found in terms of vertical interpalpebral distance and protrusion value (p=0.533, p=0.209). CONCLUSIONS: While UV efficiency in pterygium was obvious, protrusion value and vertical interpalpebral distance were not found to be a risk factor in the formation of pterygium. PMID- 24169501 TI - Self-reported alcohol abstinence associated with ART initiation among HIV infected persons in rural Uganda. AB - BACKGROUND: There is limited data on the impact of anti-retroviral treatment (ART) initiation on alcohol consumption. We characterized predictors of abstaining from alcohol among HIV-infected individuals following ART initiation. METHODS: We analyzed data from a prospective cohort of HIV-infected adults in Mbarara, Uganda with quarterly measures of self-reported alcohol consumption, socio-demographics, health status, and blood draws. We used pooled logistic regression to evaluate predictors of becoming abstinent from alcohol for at least 90 days after baseline. RESULTS: Among the 502 participants, 108 (21.5%) were current drinkers who consumed alcohol within 90 days of baseline, 206 (41.0%) were former drinkers, and 188 (37.5%) were lifetime abstainers at baseline. Among current drinkers, 67 (62.0%) drank at hazardous levels. 90 of current drinkers (83.3%) abstained from alcohol at least for 90 days over 3.6 median years of follow-up [IQR 2-4.8]; of those 69 (76.7%) remained abstinent for a median duration of follow-up of 3.25 years [1.6-4.5]. Becoming abstinent was independently associated with lower baseline AUDIT score (adjusted odds ratio [AOR] 0.95 [95%CI 0.91-0.99]), baseline physical health score (AOR 0.92 [0.87 0.97]), and decreases in physical health score at follow-up visits (AOR 0.92 [0.88-0.97)). Alcohol abstinence was most likely to start immediately after ART initiation (AORs for 6 month versus 3 month visit: 0.25 [0.10-0.61]; 9 month visit or later versus 3 month visit: 0.04 [0.02-0.09]). CONCLUSIONS: We found that a large majority of drinkers starting ART reported that they became and remained abstinent from alcohol. ART initiation may be an opportune time to implement interventions for alcohol consumption and other health behaviors. PMID- 24169503 TI - An electron-deficient metallocavitand with an unusual selectivity towards substituted benzene derivatives during co-crystallizations. AB - A double-wall-hourglass-shaped metallocavitand bearing an electron-deficient cavity was self-assembled, which exhibited an unusual selectivity to substituted benzene derivatives of different electron density during co-crystallizations. PMID- 24169504 TI - Photophysics and aggregation effects of a triphenylamine-based dye sensitizer on metal-oxide nanoparticles suspended in an ion trap. AB - The photophysical behaviour of a triphenylamine-based organic dye sensitizer (Carbz-PAHTDTT) attached to alumina and titania nanoparticles (labelled Carbz-Al and Carbz-Ti, respectively) is examined in the absence and presence of the chenodeoxycholic acid (CDCA) coadsorber. The experiments are conducted in vacuo by suspending the target dye-sensitized nanoparticles within a quadrupole ion trap, where they are probed with laser radiation to obtain emission spectra and time-resolved excited state decay curves. For Carbz-Al, the dye's emission band is blue-shifted and the excited state lifetime is increased upon the coabsorption of CDCA, effects attributed to reduced dye aggregation. Compared to Carbz-Al, the Carbz-Ti excited state lifetimes are significantly shorter due to excited dye molecules injecting electrons into the titania conduction band. For Carbz-Ti, the electron injection quantum yields for the surfaces with CDCA (CDCA : dye = 25 : 1) and without CDCA are estimated to be 0.87 and 0.71, respectively. The gas phase results demonstrate that Carbz-PAHTDTT dye aggregates are detrimental to the performance of a dye-sensitized solar cell. PMID- 24169505 TI - Citrus medica "Otroj": attenuates oxidative stress and cardiac dysrhythmia in isoproterenol-induced cardiomyopathy in rats. AB - Citrus medica L. commonly known as Otroj, is an important medicinal plant reputed for its nutritious and therapeutic uses. The present work was undertaken to investigate the protective effect of the ethanolic extract of otroj (EEOT) against isoproterenol (ISO)-induced cardiotoxicity in rats. In addition, the antioxidant activity and the phenolic and flavonoidal contents were determined. Rats were administered EETO (250 and 500 mg/kg) or vehicle orally for 15 days along with ISO (85 mg/kg, s.c.) on the 14th and 15th day. ISO induced cardiac dysfunction, increased lipid peroxidation and alteration of myocyte-injury specific marker enzymes. ISO also showed an increase in levels of plasma cholesterol, triglycerides (TG), LDL-C, and VLDL-C. Moreover, the histological investigations showed myocardial necrosis and inflammation. EETO treatment brought the above parameters towards normal level. Moreover, in vitro DPPH radical scavenging and beta-carotene-linoleic acid tests of the EEOT exhibited a notable antioxidant activity in both assays used. In addition, histopathological examination reconfirmed the protective effects of EEOT. Thus, the present study reveals that C. medica alleviates myocardial damage in ISO-induced cardiac injury and demonstrates cardioprotective potential which could be attributed to its potent antioxidant and free radical scavenging activity. PMID- 24169507 TI - Advances in nutritional research on regulatory T-cells. AB - Many clinical and animal studies have shown that certain dietary components exert anti-inflammatory properties that aid in the amelioration of chronic inflammatory diseases. Among the various proposed channels through which dietary components affect immune responses, regulatory T-cells (Tregs) are emerging as key targets for the dietary prevention of chronic inflammatory diseases. In this review, immunoregulation by Tregs is briefly described, followed by a summary of recent advances and possible applications of techniques for the study of Tregs. In addition, this review provides an overview of the current knowledge on Treg regulation by certain dietary components, including vitamins, omega-3 polyunsaturated fatty acids, and polyphenols. The caveats of previous studies are also discussed in order to highlight the distinctions between dietary studies and immunological approaches. Consequently, this review may help to clarify the means by which nutritional components influence Tregs. PMID- 24169506 TI - Synthetic or food-derived vitamin C--are they equally bioavailable? AB - Vitamin C (ascorbate) is an essential water-soluble micronutrient in humans and is obtained through the diet, primarily from fruits and vegetables. In vivo, vitamin C acts as a cofactor for numerous biosynthetic enzymes required for the synthesis of amino acid-derived macromolecules, neurotransmitters, and neuropeptide hormones, and is also a cofactor for various hydroxylases involved in the regulation of gene transcription and epigenetics. Vitamin C was first chemically synthesized in the early 1930s and since then researchers have been investigating the comparative bioavailability of synthetic versus natural, food derived vitamin C. Although synthetic and food-derived vitamin C is chemically identical, fruit and vegetables are rich in numerous nutrients and phytochemicals which may influence its bioavailability. The physiological interactions of vitamin C with various bioflavonoids have been the most intensively studied to date. Here, we review animal and human studies, comprising both pharmacokinetic and steady-state designs, which have been carried out to investigate the comparative bioavailability of synthetic and food-derived vitamin C, or vitamin C in the presence of isolated bioflavonoids. Overall, a majority of animal studies have shown differences in the comparative bioavailability of synthetic versus natural vitamin C, although the results varied depending on the animal model, study design and body compartments measured. In contrast, all steady state comparative bioavailability studies in humans have shown no differences between synthetic and natural vitamin C, regardless of the subject population, study design or intervention used. Some pharmacokinetic studies in humans have shown transient and small comparative differences between synthetic and natural vitamin C, although these differences are likely to have minimal physiological impact. Study design issues and future research directions are discussed. PMID- 24169508 TI - Middle ear problems in children hospitalised because of lower respiratory tract infections: a comparison between two cohorts in Burundi and Italy. AB - OBJECTIVES: To compare the prevalence of acute otitis media (AOM) and otitis media with effusion (OME) in children hospitalized for acute lower respiratory infections (LRTIs) in Burundi and Italy. METHODS: The study, which was conducted from 1 February to 30 April 2011 at the hospital of Kiremba (Burundi, Africa) and at Paediatric Clinic 1 of the University of Milan (Italy), enrolled patients aged <5 years who were hospitalised because of LRTIs. Upon admission, the children underwent an otological examination (pneumatic otoscopy and tympanometry), and middle ear diseases were compared between the two groups. RESULTS: A total of 108 children enrolled in Burundi (44 males; median age 17 months) were compared to 108 patients enrolled in Italy (53 males; median age 19 months). About one-third of the children in Burundi (33, 30.6%) had normal middle ears. AOM was never diagnosed, whereas OME was detected in 74 children (68.5%: bilateral in 51, 68.9%, and unilateral in 23, 31.1%). The prevalence of OME decreased with increasing age: it was 86.5% in children aged <12 months, 73.7% in those aged 12 24 months, and 43.8% in those aged >24 months (p < 0.001). There was no difference in the proportion of children with OME in Burundi (68.5%) and Italy (63.9%; p = 0.47). OME was significantly more frequent in the children with pneumonia admitted in Burundi than in the children with pneumonia admitted in Italy (p = 0.004). CONCLUSIONS: In children hospitalized for lower respiratory tract infection, OME is almost as frequently seen in developing countries like Burundi, Africa, as in developed countries like Italy. Follow-up monitoring of these children might be required to assess if OME is just a transient phenomenon. PMID- 24169509 TI - Label-free detection and dynamic monitoring of drug-induced intracellular vesicle formation enabled using a 2-dimensional matched filter. AB - Analysis of vesicle formation and degradation is a central issue in autophagy research and microscopy imaging is revolutionizing the study of such dynamic events inside living cells. A limiting factor is the need for labeling techniques that are labor intensive, expensive, and not always completely reliable. To enable label-free analyses we introduced a generic computational algorithm, the label-free vesicle detector (LFVD), which relies on a matched filter designed to identify circular vesicles within cells using only phase-contrast microscopy images. First, the usefulness of the LFVD is illustrated by presenting successful detections of autophagy modulating drugs found by analyzing the human colorectal carcinoma cell line HCT116 exposed to each substance among 1266 pharmacologically active compounds. Some top hits were characterized with respect to their activity as autophagy modulators using independent in vitro labeling of acidic organelles, detection of LC3-II protein, and analysis of the autophagic flux. Selected detection results for 2 additional cell lines (DLD1 and RKO) demonstrate the generality of the method. In a second experiment, label-free monitoring of dose dependent vesicle formation kinetics is demonstrated by recorded detection of vesicles over time at different drug concentrations. In conclusion, label-free detection and dynamic monitoring of vesicle formation during autophagy is enabled using the LFVD approach introduced. PMID- 24169510 TI - Diverse roles of GSK-3: tumor promoter-tumor suppressor, target in cancer therapy. PMID- 24169511 TI - Effects of sewer conditions on the degradation of selected illicit drug residues in wastewater. AB - The stability of five illicit drug markers in wastewater was tested under different sewer conditions using laboratory-scale sewer reactors. Wastewater was spiked with deuterium labelled isotopes of cocaine, benzoyl ecgonine, methamphetamine, MDMA and 6-acetyl morphine to avoid interference from the native isotopes already present in the wastewater matrix. The sewer reactors were operated at 20 degrees C and pH 7.5, and wastewater was sampled at 0, 0.25, 0.5, 1, 2, 3, 6, 9 and 12 h to measure the transformation/degradation of these marker compounds. The results showed that while methamphetamine, MDMA and benzoyl ecgonine were stable in the sewer reactors, cocaine and 6-acetyl morphine degraded quickly. Their degradation rates are significantly higher than the values reportedly measured in wastewater alone (without biofilms). All the degradation processes followed first order kinetics. Benzoyl ecgonine and morphine were also formed from the degradation of cocaine and 6-acetyl morphine, respectively, with stable formation rates throughout the test. These findings suggest that, in sewage epidemiology, it is essential to have relevant information of the sewer system (i.e. type of sewer, hydraulic retention time) in order to accurately back-estimate the consumption of illicit drugs. More research is required to look into detailed sewer conditions (e.g. temperature, pH and ratio of biofilm area to wastewater volume among others) to identify their effects on the fate of illicit drug markers in sewer systems. PMID- 24169512 TI - Temporal shifts in cyanobacterial communities at different sites on the Nakdong River in Korea. AB - The studies of cyanobacterial blooms resulting from eutrophication or climate change and investigation of changes in the cyanobacterial community in freshwater environments are critical for the management of drinking water. Therefore, we investigated the cyanobacterial communities at 6 sites along the Nakdong River in South Korea from May 2012 to October 2012 by using high-throughput sequencing techniques and studied their relationship with various geochemical factors at sampling sites. Diverse genera (total of 175 genera) were detected within the cyanobacteria, and changes in their compositions were analyzed. The genus Prochlorococcus predominated in the May samples, especially in those obtained from the upstream part of the river, whereas the relative abundance of Microcystis and Anabaena increased with increase in water temperature. The relationship between the cyanobacterial community and environmental factors was analyzed by canonical correlation analysis, and the correlation between harmful cyanobacteria and chemical factors was analyzed by nonmetric multidimensional scaling ordination. Various environmental factors such as dissolved oxygen, pH, electric conductivity, temperature were found to affect the cyanobacterial communities in the river. The results of this study could help in the management of freshwater environments and in maintenance of drinking water quality. PMID- 24169513 TI - Cylindrospermopsis raciborskii (Cyanobacteria) exudates: chemical characterization and complexation capacity for Cu, Zn, Cd and Pb. AB - Cylindrospermopsis raciborskii is a cosmopolitan and potentially toxic planktonic Cyanobacteria that produces and exudes copious amounts of dissolved organic materials. This organism dominates the eutrophic reservoir Barra Bonita (Brazil), where it normally blooms throughout the year. This investigation focused on the characterization of such exudates analyzing their capacity to complex copper, zinc, lead and cadmium through the determination of ligand concentration (CL) and conditional stability constant (logK'ML), as well as elemental composition (C, H, N and S), the content of carbohydrates, proteins, lipids and dissolved organic carbon (DOC). The dissolved organic material was fractionated into 3 molecular weights (>30 kDa; 30-10 kDa; 10-3 kDa) and each fraction was analyzed. The results showed that in the >30 kDa and 30-10 kDa fractions carbohydrates dominate over proteins and lipids. Different CL and logK'ML were obtained for the different molecular weight fractions of the excreted organic materials, suggesting high diversity of ligands. In the >30 kDa, there were more complexing sites (CL) for Cu, but higher affinity (K') for Zn. In the 30-10 kDa fraction, the higher CL was for Cd, but the greatest affinities were for Cu and Zn. In the 10-3 kDa fraction, higher CL was obtained for Cd and Zn, while Cu and Cd had the highest strengths of association. In the environment, such diversity of ligands and strengths of association can result in a displacement of metals weakly bound to the EOM, and increase metal buffering capacity of the environment, supporting higher metal inputs before toxic effects are detected in the biota. PMID- 24169514 TI - Comparison of two poultry litter qPCR assays targeting the 16S rRNA gene of Brevibacterium sp. AB - Chicken feces commonly contain human pathogens and are also important sources of fecal pollution in environmental waters. Consequently, methods that can detect chicken fecal pollution are needed in public health and environmental monitoring studies. In this study, we compared a previously developed SYBR green qPCR assay (LA35) to a novel TaqMan qPCR assay (CL) for the environmental detection of poultry-associated fecal pollution. We tested both assays against chicken litter (n = 40), chicken fecal samples (n = 186), non-chicken fecal sources (n = 484), and environmental water samples (n = 323). Most chicken litter samples (i.e., >= 98%) were positive for both assays with relatively high signal intensities, whereas only 23% and 12% of poultry fecal samples (n = 186) were positive with the LA35 and the CL assays, respectively. Data using fecal samples from non target animal species showed that the assays are highly host-associated (>= 95%). Bayesian statistical models showed that the two assays are associated with relatively low probability of false-positive and false-negative signals in water samples. The CL marker had a lower prevalence than the LA35 assay when tested against environmental water samples (i.e., 21% vs. 31% positive signals). However, by combining the results from the two assays the detection levels increased to 41%, suggesting that using multiple assays can improve the detection of chicken-fecal pollution in environmental waters. PMID- 24169515 TI - Depth-resolved abundance and diversity of arsenite-oxidizing bacteria in the groundwater of Beimen, a blackfoot disease endemic area of southwestern Taiwan. AB - The role of arsenite oxidizers in natural attenuation of arsenic pollution necessitates studies on their abundance and diversity in arsenic-contaminated aquifers. In this study, most probable number-polymerase chain reaction (MPN-PCR) and denaturing gradient gel electrophoresis (DGGE) was applied to monitor depth wise abundance and diversity of aerobic arsenite oxidizers in arsenic-enriched groundwater of Beimen, southwestern Taiwan. The results revealed that the abundance of arsenite oxidizers ranged from 0.04 to 0.22, and the lowest ratio was observed in the most arsenic-enriched and comparatively more reduced groundwater (depth 200 m) of Beimen 1. The highest ratio was observed in the less arsenic-enriched and less reduced groundwater (depth 60 m) of Beimen 2B. DGGE profiles showed a shift in diversity of arsenite oxidizers, consisting of members of the Betaproteobacteria (61%), Alphaproteobacteria (28%) and Gammaproteobacteria (11%), depending on mainly arsenic concentration and redox level in groundwater. Groundwater with the lowest arsenic and highest dissolved oxygen at Beimen 2B harbored 78% of the arsenite oxidizers communities, while groundwater with the highest arsenic and lowest dissolved oxygen at Beimen 1 and Beimen-Jinhu harbored 17 and 22% of arsenite oxidizers communities, respectively. Pseudomonas sp. was found only in groundwater containing high arsenic at Beimen 1 and Beimen-Jinhu, while arsenite oxidizers belonging to Alpha- and Betaproteobacteria were dominated in groundwater containing low arsenic. PMID- 24169516 TI - Corrosion of carbon steel by bacteria from North Sea offshore seawater injection systems: laboratory investigation. AB - Influence of sulfidogenic bacteria, from a North Sea seawater injection system, on the corrosion of S235JR carbon steel was studied in a flow bioreactor; operating anaerobically for 100days with either inoculated or filtrated seawater. Deposits formed on steel placed in reactors contained magnesium and calcium minerals plus iron sulfide. The dominant biofilm-forming organism was an anaerobic bacterium, genus Caminicella, known to produce hydrogen sulfide and carbon dioxide. Open Circuit Potentials (OCP) of steel in the reactors was, for nearly the entire test duration, in the range -80045), suggested pitting on steel samples within the inoculated environment. However, the actual degree of corrosion could neither be directly correlated with the electrochemical data and nor with the steel corrosion in the filtrated seawater environment. Further laboratory tests are thought to clarify the noticed apparent discrepancies. PMID- 24169517 TI - An epithelial armamentarium to sense the microbiota. AB - Intestinal epithelial cells were once thought to be inert, non-responsive cells that simply acted as a physical barrier that prevents the contents of the intestinal lumen from accessing the underlying tissue. However, it is now clear that these cells express a full repertoire of Toll- and Nod-like receptors, and that their activation by components of the microbiota is vital for the development of a functional epithelium, maintenance of barrier integrity, and defense against pathogenic organisms. Additionally, mounting evidence suggests that epithelial sensing of bacteria plays a significant role in the management of the numbers and types of microbes present in the gut microbiota via the production of antimicrobial peptides and other microbe-modulatory products. This is a critical process, as it is now becoming apparent that alterations in the composition of the microbiota can predispose an individual to a wide variety of chronic diseases. In this review, we will discuss the bacterial pattern recognition receptors that are known to be expressed by the intestinal epithelium, and how each of them individually contributes to these vital protective functions. Moreover, we will review what is known about the communication between epithelial cells and various classes of underlying leukocytes, and discuss how they interact with the microbiota to form a three part relationship that maintains homeostasis in the gut. PMID- 24169518 TI - Peripheral education of the immune system by the colonic microbiota. AB - There is growing interest in understanding the effects of host-microbial interactions on host physiologic processes. Much of the work in this arena is logically focused on the interaction at mucosal surfaces as this is a primary site of interaction. However, there is ample evidence to suggest that the effects of the microbiota have a much farther reach including the systemic immune system. While there are some similarities to effects at mucosal surfaces (i.e. reduced numbers of adaptive immune cells, diminished innate responses), there are some important differences that we highlight such as the response to immunogens and bacterial antigens. We propose that understanding the details of how specific components of the microbiota influence the systemic immune system likely will have significant impact on our understanding the pathophysiology of a variety of autoimmune diseases. PMID- 24169520 TI - German Ethics Council on genetic diagnostics: trend setting? AB - On 30 April 2013, the German Ethics Council ('Council') published its opinion on 'The future of genetic diagnostics--from research to clinical application' ('the Opinion'). The Council was asked by the German government to discuss the future of genetic diagnostic methods in relation to the current applicable laws and regulations as well as the ethical stand points. The Council's 23 recommendations show that the existing regulations in Germany, and indirectly on a European level, lack in protecting consumers sufficiently. Consumer protection built the major focus of the Council's opinion. However, the opinion misses a critical overall analysis of genetic testing and, for example, the potential misuse of genetic test results by insures or the risk of disclosure toward employers. The Council missed an opportunity to discuss which barriers are necessary from a legal and ethical perspective but which still do not prohibit genetic testing and research. PMID- 24169519 TI - 20 ans apres: a second mutation in MAOA identified by targeted high-throughput sequencing in a family with altered behavior and cognition. AB - Intellectual disability (ID) is characterized by an extraordinary genetic heterogeneity, with >250 genes that have been implicated in monogenic forms of ID. Because this complexity precluded systematic testing for mutations and because clinical features are often non-specific, for some of these genes only few cases or families have been unambiguously documented. It is the case of the X linked gene encoding monoamine oxidase A (MAOA), for which only one nonsense mutation has been identified in Brunner syndrome, characterized in a single family by mild non-dysmorphic ID and impulsive, violent and aggressive behaviors. We have performed targeted high-throughput sequencing of 220 genes, including MAOA, in patients with undiagnosed ID. We identified a c.797_798delinsTT (p.C266F) missense mutation in MAOA in a boy with autism spectrum disorder, attention deficit and autoaggressive behavior. Two maternal uncles carry the mutation and have severe ID, with a history of maltreatment in early childhood. This novel missense mutation decreases MAOA enzymatic activity, leading to abnormal levels of urinary monoamines. The identification of this new point mutation confirms, for the first time since 1993, the monogenic implication of the MAOA gene in ID of various degrees, autism and behavioral disturbances. The variable expressivity of the mutation observed in male patients of this family may involve gene-environment interactions, and the identification of a perturbation in monoamine metabolism should be taken into account when prescribing psychoactive drugs in such patients. PMID- 24169521 TI - A novel indel in exon 9 of APC upregulates a 'skip exon 9' isoform and causes very severe familial adenomatous polyposis. AB - Germline mutation in the adenomatous polyposis coli (APC) gene causes the majority (80%) of familial adenomatous polyposis (FAP), an autosomal dominantly inherited form of colorectal cancer (CRC). Mutation in 5'end of exon 9 of APC usually results in an attenuated form of FAP (aFAP), characterized by later age of onset and fewer polyps. The presence of exon 9a, an in-frame isoform with exon 8 spliced to 3'end of exon 9, modulates any deleterious effect of the mutation. A third lowly expressed isoform that completely skips exon 9 is present in both healthy individuals and FAP patients. We report here an interesting case of a proband with an APC mutation in 5'end of exon 9 that presented with six synchronous advanced CRCs at age 37. The novel insertion-deletion (indel) at codon 409, c.1226-1229delTTTTinsAAA, caused upregulation of the 'skip exon 9' isoform, r934-1312del, resulting in a premature stop codon at exon 10 and a truncated protein that removed all of the beta-catenin (CTNNB1) binding motifs, thus activating the downstream T-cell transcription factor (Tcf) pathway. Exon 9a isoform was concomitantly downregulated. This finding emphasizes the necessity of examining the various isoforms of exon 9 to avoid clinical mismanagement and counseling based on just the mutation site by genomic DNA sequencing alone. PMID- 24169523 TI - Genome-wide analysis of parent-of-origin effects in non-syndromic orofacial clefts. AB - Parent-of-origin (PofO) effects, such as imprinting are a phenomenon where the effect of variants depends on parental origin. Conventional association studies assume that phenotypic effects are independent of parental origin, and are thus severely underpowered to detect such non-Mendelian effects. Risk of orofacial clefts is influenced by genetic and environmental effects, the latter including maternal-specific factors such as perinatal smoking and folate intake. To identify variants showing PofO effects in orofacial clefts we have used a modification of the family-based transmission disequilibrium test to screen for biased transmission from mothers and fathers to affected offspring, biased ratios of maternal versus paternal transmission, and biased frequencies of reciprocal classes of heterozygotes among offspring. We applied these methods to analyze published genome-wide single-nucleotide polymorphism (SNP) data from ~2500 trios mainly of European and Asian ethnicity with non-syndromic orofacial clefts, followed by analysis of 64 candidate SNPs in a replication cohort of ~1200 trios of European origin. In our combined analysis, we did not identify any SNPs achieving conventional genome-wide significance (P<5 * 10(-8)). However, we observed an overall excess of loci showing maternal versus paternal transmission bias (P=0.013), and identified two loci that showed nominally significant effects in the same direction in both the discovery and replication cohorts, raising the potential for PofO effects. These include a possible maternal-specific transmission bias associated with rs12543318 at 8q21.3, a locus identified in a recent meta-analysis of non-syndromic cleft (maternal-specific P=1.5 * 10(-7), paternal-specific P=0.17). Overall, we conclude from this analysis that there are subtle hints of PofO effects in orofacial clefting. PMID- 24169522 TI - New ZMPSTE24 (FACE1) mutations in patients affected with restrictive dermopathy or related progeroid syndromes and mutation update. AB - Restrictive dermopathy (RD) is a rare and extremely severe congenital genodermatosis, characterized by a tight rigid skin with erosions at flexure sites, multiple joint contractures, low bone density and pulmonary insufficiency generally leading to death in the perinatal period. RD is caused in most patients by compound heterozygous or homozygous ZMPSTE24 null mutations. This gene encodes a metalloprotease specifically involved in lamin A post-translational processing. Here, we report a total of 16 families for whom diagnosis and molecular defects were clearly established. Among them, we report seven new ZMPSTE24 mutations, identified in classical RD or Mandibulo-acral dysplasia (MAD) affected patients. We also report nine families with one or two affected children carrying the common, homozygous thymine insertion in exon 9 and demonstrate the lack of a founder effect. In addition, we describe several new ZMPSTE24 variants identified in unaffected controls or in patients affected with non-classical progeroid syndromes. In addition, this mutation update includes a comprehensive search of the literature on previously described ZMPSTE24 mutations and associated phenotypes. Our comprehensive analysis of the molecular pathology supported the general rule: complete loss-of-function of ZMPSTE24 leads to RD, whereas other less severe phenotypes are associated with at least one haploinsufficient allele. PMID- 24169524 TI - Allele-specific regulation of DISC1 expression by miR-135b-5p. AB - Disrupted-in-schizophrenia-1 (DISC1) gene has been established as a risk factor for various neuropsychiatric phenotypes. Both coding and regulatory variants in DISC1 have been identified and associated with these phenotypes in genetic studies. MicroRNAs (miRNAs) are important regulators of protein coding genes. Since the miRNA-mRNA target recognition mechanism is vulnerable to disruption by DNA polymorphisms, we investigated whether polymorphisms in the DISC1 3'UTR affect binding of miRNAs and lead to allele-specific regulation of DISC1. We identified four predicted polymorphic miRNA target sites in the DISC1 3'UTR, and demonstrated that miR-135b-5p regulates the level of DISC1 mRNA. Moreover, DISC1 regulation by miR-135b-5p is allele specific: miR-135b-5p only binds to the major allele (A) of rs11122396, not to the minor allele (G). Thus, the G allele may be functionally related to the DISC1-associated phenotypes by abolishing regulation by miR-135b-5p, leading to elevated DISC1 levels. PMID- 24169525 TI - HRAS mutations in bladder cancer at an early age and the possible association with the Costello Syndrome. AB - Bladder tumours of patients <20 years have a low incidence of genetic aberrations typically found in tumours in older patients. In this study, we investigated oncogene mutations in patients with bladder cancer (BC) <20 years and compared them to older age groups. Interestingly, we observed a relatively high number of HRAS mutations in tumour from young patients. These mutations were also highly uncommon in BCs of older patients, ie, p.(Gly12Ser) and p.(Gly12Ala). Germline mutations in the HRAS gene, especially p.(Gly12Ser/Ala), cause Costello Syndrome (CS), a severe congenital disorder. Indeed, one of the patients had been diagnosed with CS. We hypothesized that some of the other patients might be mosaic for the HRAS mutation and therefore could express some of the clinical features of CS, like tumour predisposition. Hence, we isolated DNA from microdissected stroma and analysed it for HRAS mutations. In the CS patient and in patient X, the mutation was also highly expressed in normal stroma. We conclude that patient X is possibly mosaic for the HRAS mutation. These results suggest that mosaicism for oncogenic HRAS mutations may increase the risk for developing BC at a young age. PMID- 24169526 TI - Dysfunctional NF-kappaB and brain myelin formation. PMID- 24169527 TI - iPSC-derived neural precursors exert a neuroprotective role in immune-mediated demyelination via the secretion of LIF. AB - The possibility of generating neural stem/precursor cells (NPCs) from induced pluripotent stem cells (iPSCs) has opened a new avenue of research that might nurture bench-to-bedside translation of cell transplantation protocols in central nervous system myelin disorders. Here we show that mouse iPSC-derived NPCs (miPSC NPCs)-when intrathecally transplanted after disease onset-ameliorate clinical and pathological features of experimental autoimmune encephalomyelitis, an animal model of multiple sclerosis. Transplanted miPSC-NPCs exert the neuroprotective effect not through cell replacement, but through the secretion of leukaemia inhibitory factor that promotes survival, differentiation and the remyelination capacity of both endogenous oligodendrocyte precursors and mature oligodendrocytes. The early preservation of tissue integrity limits blood-brain barrier damage and central nervous system infiltration of blood-borne encephalitogenic leukocytes, ultimately responsible for demyelination and axonal damage. While proposing a novel mechanism of action, our results further expand the therapeutic potential of NPCs derived from iPSCs in myelin disorders. PMID- 24169528 TI - The effect of blood flow on magnetic resonance imaging of non thermal irreversible electroporation. AB - To generate an understanding of the physiological significance of MR images of Non-Thermal Irreversible Electroporation (NTIRE) we compared the following MR imaging sequences: T1W, T2W, PD, GE, and T2 SPAIR acquired after NTIRE treatment in a rodent liver model. The parameters that were studied included the presence or absence of a Gd-based contrast agent, and in vivo and ex-vivo NTIRE treatments in the same liver. NTIRE is a new minimally invasive tissue ablation modality in which pulsed electric fields cause molecularly selective cell death while, the extracellular matrix and large blood vessels remain patent. This attribute of NTIRE is of major clinical importance as it allows treatment of undesirable tissues near critical blood vessels. The presented study results suggest that MR images acquired following NTIRE treatment are all directly related to the unique pattern of blood flow after NTIRE treatment and are not produced in the absence of blood flow. PMID- 24169530 TI - High-pressure synthesis, structural and complex magnetic properties of the ordered double perovskite Pb2NiReO6. AB - The ordered double perovskite Pb2NiReO6 has been prepared at 6 GPa and temperatures ranging from 1273 to 1373 K. Its crystal structure determined by X ray powder diffraction and selected area electron diffraction shows monoclinic symmetry with centrosymmetric space group I2/m (a = 5.6021(1) A, b = 5.6235(1) A, c = 7.9286(1) A and beta = 90.284 degrees (1)). High angle annular dark field microscopy studies reveal the existence of compositional microdomains. The compound displays a re-entrant spin-glass transition from a ferrimagnetic ordering below T(N) ~ 37 K between the Re(+5) and Ni(+3) (high spin configuration) magnetic sublattices to a spin-glass configuration. Magnetic field dependent magnetization measurements revealed wasp-waisted hysteresis loops at 5 K. These shaped features originate from the antiferromagnetic/ferromagnetic (AFM/FM) competing interactions. PMID- 24169529 TI - A label-free ultrasensitive electrochemical aptameric recognition system for protein assay based on hyperbranched rolling circle amplification. AB - A label-free ultrasensitive electrochemical aptameric sensor which combined the advantages of an aptamer and hyperbranched rolling circle amplification (HRCA) has been developed for specific recognition of a platelet-derived growth factor B chain (PDGF-BB). PMID- 24169532 TI - A propensity score matched analysis to determine if second-generation drug eluting stents outperform first-generation drug-eluting stents in a complex patient population. AB - BACKGROUND: Drug-eluting stents (DES) are routinely used in complex patients, but the impact of 1st- versus 2nd-generation DES on clinical outcomes has not been well described. This study aimed to assess the efficacy and safety of 2nd generation (everolimus-eluting) DES compared to 1st-generation (sirolimus- and paclitaxel-eluting) DES in a selected, higher-risk population with complex clinical and angiographic features. METHODS: The study included 5693 consecutive patients with the presence of >= 1 predefined complex clinical and angiographic characteristic treated with either generation DES. Using propensity score matching, the clinical outcomes of 1076 patients treated with 2nd-generation DES were compared with the outcomes of a matched population treated with 1st generation DES over 1-year follow-up. RESULTS: After matching, baseline clinical and angiographic characteristics were similar between groups. At 1-year follow up, the rate of major adverse cardiac events was 9.4% with 2nd-generation DES and 11.3% with 1st-generation DES (p=0.16). There were no significant differences in the rates of death (3.2 vs. 4.0%, p=0.30), myocardial infarction (1.6 vs. 1.3%, p=0.57), target vessel revascularization (5.9 vs. 7.3%, p=0.17) or target lesion revascularization (4.4 vs. 5.0%, p=0.50). Definite stent thrombosis was less frequent with 2nd-generation DES (0.1 vs. 0.8%, p=0.011), as was definite or probable stent thrombosis (0.7 vs. 1.6%, p=0.040). CONCLUSION: In this propensity score matched patient population with complex features undergoing percutaneous coronary intervention, the use of 2nd-generation DES was associated with lower rates of stent thrombosis, and similar 1-year major adverse cardiac events compared to 1st-generation DES. PMID- 24169533 TI - Aspirin inhibits release of platelet-derived sphingosine-1-phosphate in acute myocardial infarction. PMID- 24169534 TI - Reference values of the right ventricular outflow tract (RVOT) proximal diameter in 665 healthy children and calculation of Z-score values. PMID- 24169535 TI - Utility of N-terminal pro B-type natriuretic peptide and mean platelet volume in differentiating congestive heart failure from chronic obstructive pulmonary disease. PMID- 24169536 TI - Prognostic value of NT-proBNP in patients with systemic morphological right ventricles: a single-centre experience. AB - In systemic morphological right ventricles after atrial redirection surgery, NT proBNP is correlated with NYHA-class, ventricular function and subaortic AV-valve regurgitation (TR). The impact of NT-proBNP on adverse clinical outcomes is, however, unknown. METHODS: This prospectively designed, longitudinal, observational study evaluated NT-proBNP in 116 patients (24.9 +/- 4.2 years old, NYHA class I/II/III=97/18/1, 71 men) relative to all cardiac causes of hospitalisation, heart failure, transplantation and death. RESULTS: The mean observation time was 7.3 +/- 2.4 years. In univariate Cox proportion analysis, the predictors for all causes of hospitalisation (n=41; 35.5%) were NT-proBNP (HR: 5.99; 95%CI: 3.21-11.18), NYHA class (HR: 2.98; 95%CI: 1.62-5.5), ventricular function (HR: 1.96; 95%CI: 1.27-3.02), TR (HR: 2.39; 95%CI: 1.48 3.59), ventricular septal defect repair (HR: 1.29; 95%CI: 1.08-1.53) and a history of supraventricular tachycardia (SVT) (HR: 7.13; 95%CI: 3.74-13.59). In multivariate Cox proportion analysis, NT-proBNP (HR: 3.71; 95%CI: 1.82-7.57), SVT (HR: 4.27; 95%CI: 2.03-8.94) and ventricular septal defect repair (HR: 1.41; 95%CI: 1.15-1.72) remained independently associated with all causes of hospitalisation. For heart failure, transplantation and death, the single predictors were NT-proBNP (HR: 20.67; 95%CI: 4.69-91.78), NYHA class (HR: 6.45; 95%CI: 2.75-15.14), ventricular function (HR: 2.70; 95%CI: 1.48-4.92), TR (HR: 4.11; 95%CI: 1.99-8.47), QRS duration (HR: 2.09; 95%CI: 1.06-4.12) and SVT (HR: 8.00; 95%CI: 2.82-22.69). Multivariate Cox proportion analysis identified NT proBNP (HR: 6.82; 95%CI: 1.32-35.04) and NYHA class (HR: 6.79; 95%CI: 1.75 26.28). Using ROC curves, the ability of NT-proBNP to detect patients at risk was greater for heart failure, transplantation and death (AUC: 0.944; 95%CI: 0.900 0.988) than for all causes of hospitalisation (AUC: 0.8; 95%CI: 0.713-0.887). CONCLUSION: In systemic right ventricles, NT-proBNP is a useful risk predictor for all causes of hospitalisation and, in particular, for heart failure, transplantation and death. It therefore might be a useful tool for risk assessment in this patient population. PMID- 24169537 TI - A low-density lipoprotein-dependent effect of atorvastatin upon the systolic blood pressure reduction: meta-regression analyses of randomized trials. PMID- 24169538 TI - Energetic behavior of the pure silica ITQ-12 (ITW) zeolite under high pressure water intrusion. AB - Experimental water intrusion-extrusion isotherms were obtained at room temperature on pure silica ITW-type zeolites (ITQ-12 zeosil). The water intrusion is obtained by applying a high hydraulic pressure corresponding to the intrusion step. When the pressure is released, the water extrusion occurs at a similar pressure to that of the intrusion one. Therefore, the "ITW zeosil-water" system behaves like a spring and the phenomenon is reproducible over several cycles. Several characterization techniques have been performed before and after water intrusion-extrusion experiments in order to reveal the presence or the lack of defects after such experiments. Structural modifications at the long range order cannot be observed by XRD analysis after three water intrusion-extrusion cycles. However, solid state NMR spectroscopy provides evidence of the presence of Q3 groups revealing the breaking of some siloxane bridges after the intrusion step. The "ITW zeosil-water" system can restore 100% of the stored energy corresponding to about 8 J g(-1). PMID- 24169539 TI - Targeting PI3K, HER2 and the IL-8/JAK2 axis in metastatic breast cancer: Which combination makes the whole greater than the sum of its parts? AB - The widespread hyperactivation of the PI3K/mTOR pathway in human cancer has made it a prime target for the treatment of this disease. However, a variety of resistance mechanisms involving (re)activation of the targeted pathway or of parallel survival signaling cascades have limited the clinical success of inhibitors targeting PI3K and/or mTOR. Recent studies delineated new crosstalks between PI3K, HER2, JAK2 and IL-8 signaling, which can explain the limited efficacy of PI3K blockade when inhibitors of this pathway are used as single agents. In this review, we summarize molecular mechanisms of resistance to inhibitors of the PI3K/mTOR pathway, provide an outline of new connections between crucial oncogenic signaling pathways, and discuss the potential of new combination therapy approaches to overcome resistance. PMID- 24169540 TI - Anti-quorum sensing activity of the traditional Chinese herb, Phyllanthus amarus. AB - The discovery of quorum sensing in Proteobacteria and its function in regulating virulence determinants makes it an attractive alternative towards attenuation of bacterial pathogens. In this study, crude extracts of Phyllanthus amarus Schumach. & Thonn, a traditional Chinese herb, were screened for their anti quorum sensing properties through a series of bioassays. Only the methanolic extract of P. amarus exhibited anti-quorum sensing activity, whereby it interrupted the ability of Chromobacterium violaceum CVO26 to response towards exogenously supplied N-hexanoylhomoserine lactone and the extract reduced bioluminescence in E. coli [pSB401] and E. coli [pSB1075]. In addition to this, methanolic extract of P. amarus significantly inhibited selected quorum sensing regulated virulence determinants of Pseudomonas aeruginosa PA01. Increasing concentrations of the methanolic extracts of P. amarus reduced swarming motility, pyocyanin production and P. aeruginosa PA01 lecA::lux expression. Our data suggest that P. amarus could be useful for attenuating pathogens and hence, more local traditional herbs should be screened for its anti-quorum sensing properties as their active compounds may serve as promising anti-pathogenic drugs. PMID- 24169541 TI - Design and fabrication of low-cost 1536-chamber microfluidic microarrays for mood disorders-related serological studies. AB - Mood disorders are common mental diseases, but physiological diagnostic methods are still lacking. Since much evidence has implied a relationship between mood disorders and the protein composition of blood sera, it is conceivable to develop a serological criterion for assisting diagnosis of mood disorders, based on a correlative database with enough capacity and high quality. In this pilot study, a low-cost microfluidic microarray device for quantifying at most 384 serological biomarkers at the same time was designed for the data acquisition of the serological study. The 1,536-chamber microfluidic device was modeled on a 1,536 well microtiter plate in order to employ a common microplate reader as the detection module for measuring the chemiluminescent immunoassay tests on the chips. The microfluidic microarrays were rapidly fabricated on polymethylmethacrylate slides using carbon dioxide laser ablation, followed by effective surface treatment processing. Sixteen types of different capture antibodies were immobilized on the chips to test the corresponding hormones and cytokines. The preliminary tests indicated that the signal-to-noise ratio and the limit of detection of microfluidic microarrays have reached the level of standard ELISA tests, whereas the operation time of microfluidic microarrays was sharply reduced. PMID- 24169542 TI - A novel INS and Doppler sensors calibration method for long range underwater vehicle navigation. AB - Since the drifts of Inertial Navigation System (INS) solutions are inevitable and also grow over time, a Doppler Velocity Log (DVL) is used to aid the INS to restrain its error growth. Therefore, INS/DVL integration is a common approach for Autonomous Underwater Vehicle (AUV) navigation. The parameters including the scale factor of DVL and misalignments between INS and DVL are key factors which limit the accuracy of the INS/DVL integration. In this paper, a novel parameter calibration method is proposed. An iterative implementation of the method is designed to reduce the error caused by INS initial alignment. Furthermore, a simplified INS/DVL integration scheme is employed. The proposed method is evaluated with both river trial and sea trial data sets. Using 0.03 degrees /h(1sigma) ring laser gyroscopes, 5 * 10-5 g(1sigma) quartz accelerometers and DVL with accuracy 0.5% V +/- 0.5 cm/s, INS/DVL integrated navigation can reach an accuracy of about 10/00 of distance travelled (CEP) in a river trial and 20/00 of distance travelled (CEP) in a sea trial. PMID- 24169543 TI - A highly sensitive refractometric sensor based on cascaded SiN microring resonators. AB - We investigate a highly sensitive optical sensor based on two cascaded microring resonators exploiting the Vernier effect. The architecture consists of two microrings with a slight difference in their free spectral ranges. This allows the generation of the Vernier effect for achieving ultra-high sensitivities. The sensor chip was fabricated using a silicon nitride platform and characterized with isopropanol/ethanol mixtures. A sensitivity of 0.95 nm/% was found for isopropanol concentrations in ethanol ranging from 0% to 10%. Furthermore, a collection of measurements was carried out using aqueous sodium chloride (NaCl) in solutions of different concentrations, confirming a high sensitivity of 10.3 nm/% and a bulk refractive index sensitivity of 6,317 nm/RIU. A limit of detection of 3.16 * 10(-6) RIU was determined. These preliminary results show the potential features of cascaded silicon nitride microring resonators for real-time and free-label monitoring of biomolecules for a broad range of applications. PMID- 24169544 TI - Hypersensitivity to antibiotics in patients with cystic fibrosis. AB - BACKGROUND: Hypersensitivity reactions to parenterally administered antibiotics (HRPA) are a substantial problem in managing CF. We conducted this observational study to assess their nature and frequency as well as risk factors. METHODS: By reviewing medical records and conducting interviews, age, sex, FEV1, ?F508 genotype, pseudomonal colonisation, allergy history, antibiotic exposure and HRPA were recorded. RESULTS: Of 100 patients included in the study, 60 had >=1 HRPA. Overall, 3205 antibiotic courses with 185 HRPA were ascertained. Changes in therapy followed 65% of HRPA. Eighty-four percent of severe HRPA occurred during days 1-4. Approximately 10% of treatment courses with cefepime and piperacillin/tazobactam caused HRPA. Years of pseudomonal colonisation and cumulative annual exposure were significant risk factors. CONCLUSIONS: During days 1-4 of antibiotic treatment patients are at elevated risk for HRPA. HRPA are drug-specific and dependent on cumulative annual exposure. Elucidation of HRPA's immunological mechanisms and development of diagnostic algorithms for clinical use are required. PMID- 24169546 TI - IL-15 is required for postexercise induction of the pro-oxidative mediators PPARdelta and SIRT1 in male mice. AB - Physical exercise induces transient upregulation of the pro-oxidative mediators peroxisome proliferator-activated receptor-delta (PPARdelta), silent information regulator of transcription (sirtuin)-1 (SIRT1), PPARgamma coactivator 1alpha (PGC 1alpha), and PGC-1beta in skeletal muscle. To determine the role of the cytokine IL-15 in acute postexercise induction of these molecules, expression of these factors after a bout of exhaustive treadmill running was examined in the gastrocnemius muscle of untrained control and IL-15-knockout (KO) mice. Circulating IL-15 levels increased transiently in control mice after exercise. Control mice, but not IL-15-KO mice, upregulated muscle PPARdelta and SIRT1 protein after exercise, accompanied by a complex pattern of mRNA expression for these factors. However, in exhaustive exercise, control mice ran significantly longer than IL-15-KO mice. Therefore, in a second experiment, mice were limited to a 20-minute run, after which a similar pattern of induction of muscle PPARdelta and SIRT1 protein by control mice only was observed. In a separate experiment, IL-15-KO mice injected systemically with recombinant IL-15 upregulated muscle PPARdelta and SIRT1 mRNA within 30 minutes and also exhibited increased muscle PPARdelta protein levels by 3 hours. After exercise, both control and IL-15-KO mice downregulated IL-15 receptor-alpha (IL-15Ralpha) mRNA, whereas IL-15Ralpha-deficient mice exhibited constitutively elevated circulating IL-15 levels. These observations indicate IL-15 release after exercise is necessary for induction of PPARdelta and SIRT1 at the protein level in muscle tissue and suggest that exercise releases IL-15 normally sequestered by the IL 15Ralpha in the resting state. These findings could be used to develop an IL-15 based strategy to induce many of the metabolic benefits of physical exercise. PMID- 24169547 TI - Bone marrow leptin signaling mediates obesity-associated adipose tissue inflammation in male mice. AB - Obesity is characterized by an increased recruitment of proinflammatory macrophages to the adipose tissue (AT), leading to systemic inflammation and metabolic disease. The pathogenesis of this AT inflammation, however, remains to be elucidated. The circulating adipokine leptin is increased in obesity and is involved in immune cell function and activation. In the present study, we investigated the role of leptin in the induction of obesity-associated inflammation. We generated radiation chimeric C57BL/6J mice reconstituted with either leptin receptor-deficient (db/db) or wild-type (WT) bone marrow and challenged them with a high-fat diet (HFD) for 16 weeks. Mice reconstituted with db/db bone marrow (WT/db), had significantly lower body weight and adiposity compared with mice with WT bone marrow (WT/WT). Gonadal AT in WT/db mice displayed a 2-fold lower expression of the inflammatory genes Tnfa, Il6, and Ccl2. In addition, gonadal fat of WT/db mice contained significantly fewer crown like structures compared with WT/WT mice, and most of their AT macrophages expressed macrophage galactose-type C type lectin 1 (MGL1) and were C-C chemokine receptor type 2 (CCR2)-negative, indicative of an anti-inflammatory phenotype. Moreover, WT/db mice exhibited greater insulin sensitivity compared with WT/WT mice. These data show that disrupted leptin signaling in bone marrow-derived cells attenuates the proinflammatory conditions that mediate many of the metabolic complications that characterize obesity. Our findings establish a novel mechanism involved in the regulation of obesity-associated systemic inflammation and support the hypothesis that leptin is a proinflammatory cytokine. PMID- 24169548 TI - beta-Arrestin 1 and 2 and G protein-coupled receptor kinase 2 expression in pituitary adenomas: role in the regulation of response to somatostatin analogue treatment in patients with acromegaly. AB - Recent in vitro studies highlighted G protein-coupled receptor kinase (GRK)2 and beta-arrestins as important players in driving somatostatin receptor (SSTR) desensitization and trafficking. Our aim was to characterize GRK2 and beta arrestins expression in different pituitary adenomas and to investigate their potential role in the response to somatostatin analog (SSA) treatment in GH secreting adenomas (GHomas). We evaluated mRNA expression of multiple SSTRs, GRK2, beta-arrestin 1, and beta-arrestin 2 in 41 pituitary adenomas (31 GHomas, 6 nonfunctioning [NFPAs], and 4 prolactinomas [PRLomas]). Within the GHomas group, mRNA data were correlated with the in vivo response to an acute octreotide test and with the GH-lowering effect of SSA in cultured primary cells. beta-Arrestin 1 expression was low in all 3 adenoma histotypes. However, its expression was significantly lower in GHomas and PRLomas, compared with NFPAs (P < .01). GRK2 expression was higher in PRLomas and NFPAs compared with GHomas (P < .05). In the GHoma group, GRK2 expression was inversely correlated to beta-arrestin 1 (P < .05) and positively correlated to beta-arrestin 2 (P < .0001). SSA treatment did not affect GRK2 and beta-arrestin expression in GHomas or in cultured rat pituitary tumor GH3 cells. Noteworthy, beta-arrestin 1 was significantly lower (P < .05) in tumors responsive to octreotide treatment in vitro, whereas GRK2 and SSTR subtype 2 were significantly higher (P < .05). Likewise, beta-arrestin 1 levels were inversely correlated with the in vivo response to acute octreotide test (P = .001), whereas GRK2 and SSTR subtype 2 expression were positively correlated (P < .05). In conclusion, for the first time, we characterized GRK2, beta-arrestin 1, and beta-arrestin 2 expression in a representative number of pituitary adenomas. beta-Arrestin 1 and GRK2 seem to have a role in modulating GH secretion during SSA treatment. PMID- 24169549 TI - Skeletal actions of fasting-induced adipose factor (FIAF). AB - Several adipokines are known to influence skeletal metabolism. Fasting-induced adipose factor (FIAF) is an adipokine that gives rise to 2 further peptides in vivo, the N-terminal coiled-coil domain (FIAF(CCD)) and C-terminal fibrinogen like domain (FIAF(FLD)). The skeletal action of these peptides is still uncertain. Our results show that FIAF(CCD) is a potent inhibitor of osteoclastogenesis and function, as seen in mouse bone marrow and RAW264.7 cell cultures, and in a resorption assay using isolated primary mature osteoclasts. The inhibitory effects at 500 ng/mL were approximately 90%, 50% and 90%, respectively, in these assays. FIAF(CCD) also stimulated osteoblast mitogenesis by approximately 30% at this concentration. In comparison, FIAF(FLD) was only active in decreasing osteoblast mitogenesis, and intact FIAF had no effect in any of these assays. In murine bone marrow cultures, FIAF(CCD) reduced the expression of macrophage colony-stimulating factor (M-CSF), nuclear factor of activated T cells c1 (NFATc1) and dendritic cell-specific transmembrane protein (DC-STAMP), and to lesser extent suppressed the expression of connective tissue growth factor (CTGF). FIAF(CCD) also decreased expression of M-CSF and CTGF in stromal/osteoblastic ST2 cells. Its effect on receptor activator of nuclear factor kappaB (RANKL) and osteoprotegerin expression in bone marrow was not consistent with its inhibitory action on osteoclastogenesis, but it decreased RANKL expression in ST2 cells. In RAW264.7 cell cultures, FIAF(CCD) significantly reduced the expression of NFATc1 and DC-STAMP. In conclusion, FIAF(CCD) inhibits osteoclast differentiation and function in vitro and decreases expression of genes encoding key osteoclastogenic factors such as M-CSF, CTGF, NFATc1, and DC STAMP. FIAF(CCD)'s action on osteoclasts may be independent of the RANKL/osteoprotegerin pathway. These results suggest a novel mechanism by which adipose tissue may regulate bone resorption and skeletal health. PMID- 24169550 TI - Lactational anovulation in mice results from a selective loss of kisspeptin input to GnRH neurons. AB - In mammals, lactation is associated with a period of infertility characterized by the loss of pulsatile secretion of GnRH and cessation of ovulatory cycles. Despite the importance of lactational infertility in determining overall fecundity of a species, the mechanisms by which the suckling stimulus suppresses GnRH secretion remain unclear. Because kisspeptin neurons are critical for fertility, the aim of this study was to test the hypothesis that reduced kisspeptin expression might mediate the lactation-induced suppression of fertility, using mouse models. In the rostral periventricular area of the third ventricle (RP3V), a progressive decrease in RP3V Kiss1 mRNA levels was observed during pregnancy culminating in a 10-fold reduction during lactation compared with diestrous controls. This was associated with approximately 60% reduction in the numbers of kisspeptin-immunoreactive neurons in the RP3V detected during lactation. Similarly, in the arcuate nucleus there was also a significant decrease in Kiss1 mRNA levels during late pregnancy and midlactation, and a notable decrease in kisspeptin fiber density during lactation. The functional characteristics of the RP3V kisspeptin input to GnRH neurons were assessed using electrophysiological approaches in an acute brain slice preparation. Although endogenous RP3V kisspeptin neurons were found to activate GnRH neurons in diestrous mice, this was never observed during lactation. This did not result from an absence of kisspeptin receptors because GnRH neurons responded normally to 100 nM exogenous kisspeptin during lactation. The kisspeptin deficit in lactating mice was selective, because GnRH neurons responded normally to RP3V gamma aminobutryic acid inputs during lactation. These data demonstrate that a selective loss of RP3V kisspeptin inputs to GnRH neurons during lactation is the likely mechanism causing lactational anovulation in the mouse. PMID- 24169551 TI - Aldosterone secretagogues increase adrenal blood flow in male rats. AB - Adrenal blood flow (ABF) is closely coupled to steroid hormone release. ACTH and angiotensin (Ang) II stimulate cortisol and aldosterone secretion; however, their effects on ABF remain poorly defined. We used the laser-Doppler technique to measure rat ABF. Anesthetized male Sprague-Dawley rats were cannulated for mean arterial pressure (MAP) measurement and drug infusion. The left adrenal gland was exposed for ABF measurement. ABF and MAP changes to ACTH and Ang II were determined. Bolus injections of Ang II (0.01-1000 ng/kg) increased ABF (maximal increase = 110 +/- 18 perfusion units at 1000 ng/kg) and increased MAP at doses greater than 10 ng/kg (basal, 99.2 +/- 1.4 mm Hg; 1000 ng/kg Ang II, 149.7 +/- 3.9 mm Hg). ACTH (0.1-1000 ng/kg) increased ABF (maximum increase = 158 +/- 33 perfusion units) without increasing MAP. ABF increases induced by Ang II and ACTH were ablated by the cytochrome 450 inhibitor miconazole (2 mg/kg). Bolus injections of endothelin-1 (1-1000 ng/kg) increased ABF only at 1 ng/kg and increased MAP at 1000 ng/kg. Bolus injections of sodium nitroprusside increased ABF at 1 and 10 MUg/kg and decreased MAP at 10 MUg/kg. Thus, laser-Doppler flowmetry is a useful tool for understanding ABF regulation by peptides that stimulate steroid hormone release. Our results demonstrate that Ang II and ACTH increases in ABF are mediated by a cytochrome P450 metabolite. PMID- 24169552 TI - Loss of vascular endothelial growth factor A (VEGFA) isoforms in the testes of male mice causes subfertility, reduces sperm numbers, and alters expression of genes that regulate undifferentiated spermatogonia. AB - Vascular endothelial growth factor A (VEGFA) isoform treatment has been demonstrated to alter spermatogonial stem cell homeostasis. Therefore, we generated pDmrt1-Cre;Vegfa(-/-) (knockout, KO) mice by crossing pDmrt1-Cre mice to floxed Vegfa mice to test whether loss of all VEGFA isoforms in Sertoli and germ cells would impair spermatogenesis. When first mated, KO males took 14 days longer to get control females pregnant (P < .02) and tended to take longer for all subsequent parturition intervals (9 days; P < .07). Heterozygous males sired fewer pups per litter (P < .03) and after the first litter took 10 days longer (P < .05) to impregnate females, suggesting a more progressive loss of fertility. Reproductive organs were collected from 6-month-old male mice. There were fewer sperm per tubule in the corpus epididymides (P < .001) and fewer ZBTB16-stained undifferentiated spermatogonia (P < .003) in the testes of KO males. Testicular mRNA abundance for Bcl2 (P < .02), Bcl2:Bax (P < .02), Neurog3 (P < .007), and Ret was greater (P = .0005), tended to be greater for Sin3a and tended to be reduced for total Foxo1 (P < .07) in KO males. Immunofluorescence for CD31 and VE Cadherin showed no differences in testis vasculature; however, CD31-positive staining was evident in undifferentiated spermatogonia only in KO testes. Therefore, loss of VEGFA isoforms in Sertoli and germ cells alters genes necessary for long-term maintenance of undifferentiated spermatogonia, ultimately reducing sperm numbers and resulting in subfertility. PMID- 24169554 TI - Activity of pramlintide, rat and human amylin but not Abeta1-42 at human amylin receptors. AB - Amylin is a neuroendocrine hormone involved in glucose regulation. An amylin analog, pramlintide, is used to treat insulin-requiring diabetes. Its anorexigenic actions give it potential as an obesity treatment. There are 3 amylin receptors (AMY1, AMY2, AMY3), comprising the calcitonin receptor and receptor activity-modifying proteins 1, 2, and 3, respectively. The pharmacology of pramlintide at each subtype has not been determined whereas the unrelated peptide beta-amyloid 1-42 (Abeta1-42) has recently been proposed to be a specific agonist of the AMY3 receptor. We investigated the actions of Abeta1-42 and pramlintide, compared with human and rat amylin at the calcitonin receptor, AMY1, AMY2, and AMY3 receptors, measuring the cAMP response in human embryonic kidney 293S and Cos 7 cells. Pramlintide activated all receptors with a slight preference for AMY1. No cAMP response was detected with Abeta1-42 at any receptor, suggesting that it may not be a genuine agonist of AMY receptors. PMID- 24169553 TI - 11beta-Hydroxysteroid dehydrogenase type 1 (11beta-HSD1) inhibitors still improve metabolic phenotype in male 11beta-HSD1 knockout mice suggesting off-target mechanisms. AB - The enzyme 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1) is a target for novel type 2 diabetes and obesity therapies based on the premise that lowering of tissue glucocorticoids will have positive effects on body weight, glycemic control, and insulin sensitivity. An 11beta-HSD1 inhibitor (compound C) inhibited liver 11beta-HSD1 by >90% but led to only small improvements in metabolic parameters in high-fat diet (HFD)-fed male C57BL/6J mice. A 4-fold higher concentration produced similar enzyme inhibition but, in addition, reduced body weight (17%), food intake (28%), and glucose (22%). We hypothesized that at the higher doses compound C might be accessing the brain. However, when we developed male brain-specific 11beta-HSD1 knockout mice and fed them the HFD, they had body weight and fat pad mass and glucose and insulin responses similar to those of HFD-fed Nestin-Cre controls. We then found that administration of compound C to male global 11beta-HSD1 knockout mice elicited improvements in metabolic parameters, suggesting "off-target" mechanisms. Based on the patent literature, we synthesized another 11beta-HSD1 inhibitor (MK-0916) from a different chemical series and showed that it too had similar off-target body weight and food intake effects at high doses. In summary, a significant component of the beneficial metabolic effects of these 11beta-HSD1 inhibitors occurs via 11beta-HSD1-independent pathways, and only limited efficacy is achievable from selective 11beta-HSD1 inhibition. These data challenge the concept that inhibition of 11beta-HSD1 is likely to produce a "step-change" treatment for diabetes and/or obesity. PMID- 24169555 TI - Expression of melanin-concentrating hormone receptor 2 protects against diet induced obesity in male mice. AB - Melanin-concentrating hormone (MCH) is an orexigenic neuropeptide that is a ligand for two subtypes of MCH receptors, MCHR1 and MCHR2. MCHR1 is universally expressed in mammals ranging from rodents to humans, but the expression of MCHR2 is substantially restricted. In mammals, MCHR2 has been defined in primates as well as other species such as cats and dogs but is not seen in rodents. Although the role of MCHR1 in mediating the actions of MCH on energy balance is clearly defined using mouse models, the role of MCHR2 is harder to characterize because of its limited expression. To determine any potential role of MCHR2 in energy balance, we generated a transgenic MCHR1R2 mouse model, where human MCHR2 is coexpressed in MCHR1-expressing neurons. As shown previously, control wild-type mice expressing only native MCHR1 developed diet-induced obesity when fed a high fat diet. In contrast, MCHR1R2 mice had lower food intake, leading to their resistance to diet-induced obesity. Furthermore, we showed that MCH action is altered in MCHR1R2 mice. MCH treatment in wild-type mice inhibited the activation of the immediate-early gene c-fos, and coexpression of MCHR2 reduced the inhibitory actions of MCHR1 on this pathway. In conclusion, we developed an experimental animal model that can provide insight into the action of MCHR2 in the central nervous system and suggest that some actions of MCHR2 oppose the endogenous actions of MCHR1. PMID- 24169557 TI - Mechanisms of palmitate-induced lipotoxicity in human osteoblasts. AB - The interest in the relationship between fat and bone has increased steadily during recent years. Fat could have a lipotoxic effect on bone cells through the secretion of fatty acids. Palmitate is the most prevalent fatty acid secreted by adipocytes in vitro. Considering that palmitate has shown a high lipotoxic effect in other tissues, here we characterized the lipotoxic effect of palmitate on human osteoblasts (Obs). Initially we tested for changes in palmitoylation in this model. Subsequently we compared the capacity of Obs to differentiate and form bone nodules in the presence of palmitate. From a mechanistic approach, we assessed changes in nuclear activity of beta-catenin and runt-related transcription factor 2 (Runx2)/phosphorylated mothers against decapentaplegic (Smad) complexes using Western blotting and confocal microscopy. Quantitative real-time PCR showed negative changes in gene expression of palmitoyltransferase genes. Furthermore, palmitate negatively affected differentiation and bone nodule formation and mineralization by Obs. Although the expression of beta-catenin in palmitate-treated cells was not affected, there was a significant reduction in the transcriptional activities of both beta-catenin and Runx2. Confocal microscopy showed that whereas Runx2 and Smad-4 and -5 complex formation was increased in bone morphogenetic protein-2-treated cells, palmitate had a negative effect on protein expression and colocalization of these factors. In summary, in this study we identified potential mechanisms of palmitate-induced lipotoxicity, which include changes in palmitoylation, defective mineralization, and significant alterations in the beta-catenin and Runx2/Smad signaling pathways. Our evidence facilitates the understanding of the relationship between fat and bone and could allow the development of new potential therapies for osteoporosis in older persons. PMID- 24169556 TI - Perfluorooctanesulfonate (PFOS) perturbs male rat Sertoli cell blood-testis barrier function by affecting F-actin organization via p-FAK-Tyr(407): an in vitro study. AB - Environmental toxicants such as perfluorooctanesulfonate (PFOS) have been implicated in male reproductive dysfunction, including reduced sperm count and semen quality, in humans. However, the underlying mechanism(s) remains unknown. Herein PFOS at 10-20 MUM (~5-10 MUg/mL) was found to be more potent than bisphenol A (100 MUM) in perturbing the blood-testis barrier (BTB) function by disrupting the Sertoli cell tight junction-permeability barrier without detectable cytotoxicity. We also delineated the underlying molecular mechanism by which PFOS perturbed Sertoli cell BTB function using an in vitro model that mimics the BTB in vivo. First, PFOS perturbed F-actin organization in Sertoli cells, causing truncation of actin filaments at the BTB. Thus, the actin-based cytoskeleton was no longer capable of supporting the distribution and/or localization of actin-regulatory and adhesion proteins at the cell-cell interface necessary to maintain BTB integrity. Second, PFOS was found to perturb inter Sertoli cell gap junction (GJ) communication based on a dye-transfer assay by down-regulating the expression of connexin-43, a GJ integral membrane protein. Third, phosphorylated focal adhesion kinase (FAK)-Tyr(407) was found to protect the BTB from the destructive effects of PFOS as shown in a study via an overexpression of an FAK Y407E phosphomimetic mutant. Also, transfection of Sertoli cells with an FAK-specific microRNA, miR-135b, to knock down the expression of phosphorylated FAK-Tyr(407) was found to worsen PFOS-mediated Sertoli cell tight junction disruption. In summary, PFOS-induced BTB disruption is mediated by down-regulating phosphorylated FAK-Tyr(407) and connexin-43, which in turn perturbed F-actin organization and GJ-based intercellular communication, leading to mislocalization of actin-regulatory and adhesion proteins at the BTB. PMID- 24169558 TI - Calcium-sensing receptor mediates Ca(2+) homeostasis by modulating expression of PTH and stanniocalcin. AB - Regulation of the synthesis and/or secretion of hypocalcemic and hypercalcemic hormones by the calcium-sensing receptor (CaSR) is believed to be a major pathway for maintaining Ca(2+) homeostasis in vertebrates, based primarily on findings in mammals. However, understanding the evolution of this physiological process requires that it be described in nonmammalian species. Here, we describe the use of zebrafish as a model to investigate whether CaSR contributes to body fluid Ca(2+) homeostasis by regulating synthesis of hypercalcemic (PTH1 and PTH2) and hypocalcemic (stanniocalcin [STC]) hormones. We report that PTH1, but not PTH2, increases Ca(2+) uptake through stimulation of the expression of the gene encoding the epithelial Ca(2+) channel (ecac). Furthermore, we demonstrate that CaSR, as a Ca(2+) sensor, may affect stc-1 and pth1 expressions differently, thereby suppressing ecac expression and Ca(2+) uptake. Finally, we show that CaSR knockdown has time-dependent effects on STC-1 and PTH1 expression, and these 2 hormones have mutual effects on the expression, thus forming a possible counterbalance. These findings enhance our understanding of CaSR-PTH-STC control of Ca(2+) homeostasis in vertebrates. PMID- 24169559 TI - Reduced expression of 11beta-hydroxysteroid dehydrogenase type 2 in preeclamptic placentas is associated with decreased PPARgamma but increased PPARalpha expression. AB - Placental 11beta-hydroxysteroid dehydrogenase type 2 (11beta-HSD2) is reduced in pregnancies complicated with preeclampsia (PE). Peroxisome proliferator-activated receptors beta/delta (PPARbeta/delta) have been shown to suppress 11beta-HSD2 expression in human placental cells. Our objectives were to investigate whether the reduced 11beta-HSD2 expression is associated with the changes in PPARs in PE placentas, and whether PPARalpha and PPARgamma affect 11beta-HSD2 expression in placental cells. PPARalpha and PPARbeta/delta mRNA and protein expression was increased, whereas PPARgamma mRNA and protein expression was decreased in PE placentas. 11beta-HSD2 protein expression was inversely correlated with PPARbeta/delta in normal placentas but correlated positively with PPARgamma and inversely to PPARalpha in PE placentas. In cultured placental cells, PPARalpha agonist inhibited, whereas PPARgamma agonist stimulated, 11beta-HSD2 mRNA and protein expression and activity in a dose-dependent manner. Knockdown of retinoid X nuclear receptor alpha (RXRalpha) resulted in a loss of PPARgamma effect but not PPARalpha effect on11beta-HSD2. The PPARalpha effect remained, but the PPARgamma effect was lost in the presence of the translational inhibitor cycloheximide. PPARgamma agonist dose-dependently stimulated specificity protein 1 (Sp-1) protein expression. Inhibition or knockdown of Sp-1 resulted in a loss of the effects of PPARalpha and PPARgamma. The Sp-1 protein level was not correlated with 11beta-HSD2 and PPARs in normal placentas, whereas Sp-1 expression was correlated with 11beta-HSD2, PPARgamma, and PPARbeta/delta in PE placentas. Our data indicate that 11beta-HSD2 expression can be modulated by PPARalpha and PPARgamma in placental trophoblasts through Sp-1. Decreased 11beta HSD2 expression in PE placenta might be associated with decreased PPARgamma but increased PPARalpha expression. PMID- 24169560 TI - Endotoxemia enhances catecholamine secretion from male mouse adrenal chromaffin cells through an increase in Ca(2+) release from the endoplasmic reticulum. AB - Enhanced epinephrine secretion from adrenal chromaffin cells (ACCs) is an important homeostatic response to severe systemic inflammation during sepsis. Evidence suggests that increased activation of ACCs by preganglionic sympathetic neurons and direct alterations in ACC function contribute to this response. However, the direct effects of sepsis on ACC function have yet to be characterized. We hypothesized that sepsis enhances epinephrine secretion from ACCs by increasing intracellular Ca(2+) signaling. Plasma epinephrine concentration was increased 5-fold in the lipopolysaccharide-induced endotoxemia model of sepsis compared with saline-treated control mice. Endotoxemia significantly enhanced stimulus-evoked epinephrine secretion from isolated ACCs in vitro. Carbon fiber amperometry revealed an increase in the number of secretory events during endotoxemia, without significant changes in spike amplitude, half-width, or quantal content. ACCs isolated up to 12 hours after the induction of endotoxemia exhibited larger stimulus-evoked Ca(2+) transients compared with controls. Similarly, ACCs from cecal ligation and puncture mice also exhibited enhanced Ca(2+) signaling. Although sepsis did not significantly affect ACC excitability or voltage-gated Ca(2+) currents, a 2-fold increase in caffeine (10 mM)-stimulated Ca(2+) transients was observed during endotoxemia. Depletion of endoplasmic reticulum Ca(2+) stores using cyclopiazonic acid (10 MUM) abolished the effects of endotoxemia on catecholamine secretion from ACCs. These findings suggest that sepsis directly enhances catecholamine secretion from ACCs through an increase in Ca(2+) release from the endoplasmic reticulum. These alterations in ACC function are likely to amplify the effects of increased preganglionic sympathetic neuron activity to further enhance epinephrine levels during sepsis. PMID- 24169561 TI - The role of exchange protein directly activated by cyclic AMP 2-mediated calreticulin expression in the decidualization of human endometrial stromal cells. AB - Decidualization of human endometrial stromal cells (ESCs) accompanied by the production of prolactin (PRL) and IGF-binding protein (IGFBP) 1 and rounded-cell morphology is indispensable for the establishment and maintenance of pregnancy. Protein kinase A (PKA)-mediated cAMP signaling is known to be crucial for decidualization. We previously reported that activation of a cAMP mediator, called Exchange protein directly activated by cAMP (EPAC) promotes cAMP analog- or ovarian steroid-induced decidualization in cultured human ESCs. In addition, small interfering RNA-mediated knock-down of the EPAC subtypes, EPAC1 or EPAC2, or knock-down of Rap1, a downstream factor of EPAC signaling, blocked functional and morphological decidualization of ESCs. However, factors downstream of EPAC2 other than Rap1 have not been determined. The present study was undertaken to identify additional downstream targets of EPAC2 associated with decidualization. Using proteomic analysis, we identified calreticulin (CRT) as a potential target of EPAC2. Knock-down of CRT expression in cultured ESCs significantly inhibited PKA-selective cAMP analog- or PKA-selective cAMP analog plus EPAC-selective cAMP analog-induced PRL and IGFBP1 expression. Furthermore, CRT knock-down suppressed the ovarian steroid-stimulated PRL and IGFBP1 expression and morphological differentiation, and silencing of EPAC2 or CRT significantly increased senescence associated beta-galactosidase activity with enhanced p21 expression and decreased p53 expression. These results suggest that EPAC2 and CRT are associated with cellular senescence in ESCs. In conclusion, we demonstrate here that EPAC2 mediated CRT expression is essential for the functional and morphological differentiation of ESCs into decidual cells. Furthermore, both EPAC2 and CRT might prevent ESCs from undergoing abnormal cellular senescence during decidualization. PMID- 24169562 TI - Stress resilience: a low-anxiety genotype protects male mice from the consequences of chronic psychosocial stress. AB - Chronic psychosocial stress is a risk factor for the development of affective as well as somatic disorders. However, vulnerability to adverse stress effects varies between individuals, with previous negative life events along with genetic predisposition playing a major role. In support, we previously showed that the consequences of chronic psychosocial stress induced by chronic subordinate colony housing (CSC, 19 days) can be amplified by pre-exposing mice to repeated maternal separation during early life. To test the significance of the genetic predisposition on the effects of CSC, mice selectively bred for high (mHAB) and low (mLAB) anxiety-related behavior and nonselected CD1 mice (mNAB) were exposed to CSC in the present study. In confirmation of our previous results, CSC mice of both mHAB and mNAB lines displayed chronic stress-related symptoms including increased adrenal weight, decreased adrenal in vitro ACTH sensitivity, lower plasma corticosterone to ACTH ratio, and increased interferon-gamma secretion from isolated mesenteric lymph node cells compared with single-housed controls of the respective line. However, the CSC-induced anxiogenic effect found in mNAB was not confirmed in mHAB mice, possibly due to a ceiling effect in these highly anxious mice. Interestingly, mHAB were not more vulnerable to CSC than mNAB mice, whereas mLAB mice were resilient to CSC as indicated by all of the above mentioned parameters assessed. Taken together, our findings indicate that the genetic predisposition, in this case the innate anxiety of an individual, affects vulnerability to chronic psychosocial stress, with a low-anxiety phenotype mediating resilience to both affective and somatic consequences of CSC. PMID- 24169563 TI - Insulin-like 3-induced rat preantral follicular growth is mediated by growth differentiation factor 9. AB - The communication of somatic cells and oocytes by intrafollicular paracrine factors is essential for follicular growth in the ovary. Insulin-like 3 (INSL3) is a theca cell-secreted paracrine factor. Androgens and growth differentiation factor 9 (GDF9), an oocyte-derived growth factor, are essential for follicular development. Using a rat preantral follicle culture model, we examined in the present study the influence of INSL3 on preantral follicular growth and the molecular mechanisms involved. We have observed that the receptor for INSL3, relaxin/insulin-like family peptide receptor 2 (RXFP2), was exclusively expressed in oocytes. Recombinant INSL3 stimulated Gdf9 expression, preantral follicular growth, and testosterone synthesis in vitro. Inhibition of the cAMP/protein kinase A signaling pathway (with cAMP antagonist, 8-bromoadenosine 3',5'-cyclic monophosphorothioate, Rp-isomer) attenuated INSL3-induced Gdf9 expression and preantral follicular growth. Moreover, knocking down Gdf9 expression (with small interfering RNA) or inhibiting GDF9 signaling (with SB431542, an activin receptor like kinase receptor 5 inhibitor, or specific inhibitor of mothers against decapentaplegic homolog 3) or androgen action (with flutamide, an androgen receptor antagonist) suppressed INSL3-induced preantral follicular growth. In addition, LH and DHT regulated the expression of Insl3 mRNA in preantral follicles. These observations suggest that INSL3 is a key theca cell-derived growth factor for preantral follicle and that its action is mediated by GDF9. PMID- 24169564 TI - A selective TSH receptor antagonist inhibits stimulation of thyroid function in female mice. AB - Because the TSH receptor (TSHR) plays an important role in the pathogenesis of thyroid disease, a TSHR antagonist could be a novel treatment. We attempted to develop a small molecule, drug-like antagonist of TSHR signaling that is selective and active in vivo. We synthesized NCGC00242364 (ANTAG3) by chemical modification of a previously reported TSHR antagonist. We tested its potency, efficacy, and selectivity in a model cell system in vitro by measuring its activity to inhibit stimulation of cAMP production stimulated by TSH, LH, or FSH. We tested the in vivo activity of ANTAG3 by measuring its effects to lower serum free T4 and thyroid gene expression in female BALB/c mice continuously treated with ANTAG3 for 3 days and given low doses of TRH continuously or stimulated by a single administration of a monoclonal thyroid-stimulating antibody M22. ANTAG3 was selective for TSHR inhibition; half-maximal inhibitory doses were 2.1 MUM for TSHR and greater than 30 MUM for LH and FSH receptors. In mice treated with TRH, ANTAG3 lowered serum free T4 by 44% and lowered mRNAs for sodium-iodide cotransporter and thyroperoxidase by 75% and 83%, respectively. In mice given M22, ANTAG3 lowered serum free T4 by 38% and lowered mRNAs for sodium-iodide cotransporter and thyroperoxidase by 73% and 40%, respectively. In conclusion, we developed a selective TSHR antagonist that is effective in vivo in mice. This is the first report of a small-molecule TSHR antagonist active in vivo and may lead to a drug to treat Graves' disease. PMID- 24169565 TI - Cardiovascular depression in rats exposed to inhaled particulate matter and ozone: effects of diet-induced metabolic syndrome. AB - BACKGROUND: High ambient levels of ozone (O3) and fine particulate matter (PM2.5) are associated with cardiovascular morbidity and mortality, especially in people with preexisting cardiopulmonary diseases. Enhanced susceptibility to the toxicity of air pollutants may include individuals with metabolic syndrome (MetS). OBJECTIVE: We tested the hypothesis that cardiovascular responses to O3 and PM2.5 will be enhanced in rats with diet-induced MetS. METHODS: Male Sprague Dawley rats were fed a high-fructose diet (HFrD) to induce MetS and then exposed to O3, concentrated ambient PM2.5, or the combination of O3 plus PM2.5 for 9 days. Data related to heart rate (HR), HR variability (HRV), and blood pressure (BP) were collected. RESULTS: Consistent with MetS, HFrD rats were hypertensive and insulin resistant, and had elevated fasting levels of blood glucose and triglycerides. Decreases in HR and BP, which were found in all exposure groups, were greater and more persistent in HFrD rats compared with those fed a normal diet (ND). Coexposure to O3 plus PM2.5 induced acute drops in HR and BP in all rats, but only ND rats adapted after 2 days. HFrD rats had little exposure related changes in HRV, whereas ND rats had increased HRV during O3 exposure, modest decreases with PM2.5, and dramatic decreases during O3 plus PM2.5 coexposures. CONCLUSIONS: Cardiovascular depression in O3- and PM2.5-exposed rats was enhanced and prolonged in rats with HFrD-induced MetS. These results in rodents suggest that people with MetS may be prone to similar exaggerated BP and HR responses to inhaled air pollutants. PMID- 24169567 TI - Green chemistry and nanofabrication in a levitated Leidenfrost drop. AB - Green nanotechnology focuses on the development of new and sustainable methods of creating nanoparticles, their localized assembly and integration into useful systems and devices in a cost-effective, simple and eco-friendly manner. Here we present our experimental findings on the use of the Leidenfrost drop as an overheated and charged green chemical reactor. Employing a droplet of aqueous solution on hot substrates, this method is capable of fabricating nanoparticles, creating nanoscale coatings on complex objects and designing porous metal in suspension and foam form, all in a levitated Leidenfrost drop. As examples of the potential applications of the Leidenfrost drop, fabrication of nanoporous black gold as a plasmonic wideband superabsorber, and synthesis of superhydrophilic and thermal resistive metal-polymer hybrid foams are demonstrated. We believe that the presented nanofabrication method may be a promising strategy towards the sustainable production of functional nanomaterials. PMID- 24169569 TI - Capturing the fingerprint of Etna volcano activity in gravity and satellite radar data. AB - Long-term and high temporal resolution gravity and deformation data move us toward a better understanding of the behavior of Mt Etna during the June 1995 - December 2011 period in which the volcano exhibited magma charging phases, flank eruptions and summit crater activity. Monthly repeated gravity measurements were coupled with deformation time series using the Differential Synthetic Aperture Radar Interferometry (DInSAR) technique on two sequences of interferograms from ERS/ENVISAT and COSMO-SkyMed satellites. Combining spatiotemporal gravity and DInSAR observations provides the signature of three underlying processes at Etna: (i) magma accumulation in intermediate storage zones, (ii) magmatic intrusions at shallow depth in the South Rift area, and (iii) the seaward sliding of the volcano's eastern flank. Here we demonstrate the strength of the complementary gravity and DInSAR analysis in discerning among different processes and, thus, in detecting deep magma uprising in months to years before the onset of a new Etna eruption. PMID- 24169568 TI - Interferon lambda 4 signals via the IFNlambda receptor to regulate antiviral activity against HCV and coronaviruses. AB - The IFNL4 gene is a recently discovered type III interferon, which in a significant fraction of the human population harbours a frameshift mutation abolishing the IFNlambda4 ORF. The expression of IFNlambda4 is correlated with both poor spontaneous clearance of hepatitis C virus (HCV) and poor response to treatment with type I interferon. Here, we show that the IFNL4 gene encodes an active type III interferon, named IFNlambda4, which signals through the IFNlambdaR1 and IL-10R2 receptor chains. Recombinant IFNlambda4 is antiviral against both HCV and coronaviruses at levels comparable to IFNlambda3. However, the secretion of IFNlambda4 is impaired compared to that of IFNlambda3, and this impairment is not due to a weak signal peptide, which was previously believed. We found that IFNlambda4 gets N-linked glycosylated and that this glycosylation is required for secretion. Nevertheless, this glycosylation is not required for activity. Together, these findings result in the paradox that IFNlambda4 is strongly antiviral but a disadvantage during HCV infection. PMID- 24169570 TI - Are migrant patients really a drain on European health systems? PMID- 24169571 TI - An adhesive (19)F MRI chemical probe allows signal off-to-on-type molecular sensing in a biological environment. AB - We report a new strategy for designing a signal off-to-on-type (19)F MRI chemical probe that operates in biological environments. The present strategy is based on the control of adherence of a (19)F MRI chemical probe to certain blood proteins, accompanied by a change in transverse relaxation time of (19)F nuclei. PMID- 24169572 TI - SuhB is a regulator of multiple virulence genes and essential for pathogenesis of Pseudomonas aeruginosa. AB - During initial colonization and chronic infection, pathogenic bacteria encounter distinct host environments. Adjusting gene expression accordingly is essential for the pathogenesis. Pseudomonas aeruginosa has evolved complicated regulatory networks to regulate different sets of virulence factors to facilitate colonization and persistence. The type III secretion system (T3SS) and motility are associated with acute infections, while biofilm formation and the type VI secretion system (T6SS) are associated with chronic persistence. To identify novel regulatory genes required for pathogenesis, we screened a P. aeruginosa transposon (Tn) insertion library and found suhB to be an essential gene for the T3SS gene expression. The expression of suhB was upregulated in a mouse acute lung infection model, and loss of suhB resulted in avirulence. Suppression of T3SS gene expression in the suhB mutant is linked to a defective translation of the T3SS master regulator, ExsA. Further studies demonstrated that suhB mutation led to the upregulation of GacA and its downstream small RNAs, RsmY and RsmZ, triggering T6SS expression and biofilm formation while inhibiting the T3SS. Our results demonstrate that an in vivo-inducible gene, suhB, reciprocally regulates genes associated with acute and chronic infections and plays an essential role in the pathogenesis of P. aeruginosa. IMPORTANCE: A variety of bacterial pathogens, such as Pseudomonas aeruginosa, cause acute and chronic infections in humans. During infections, pathogens produce different sets of virulence genes for colonization, tissue damage, and dissemination and for countering host immune responses. Complex regulatory networks control the delicate tuning of gene expression in response to host environments to enable the survival and growth of invading pathogens. Here we identified suhB as a critical gene for the regulation of virulence factors in P. aeruginosa. The expression of suhB was upregulated during acute infection in an animal model, and mutation of suhB rendered P. aeruginosa avirulent. Moreover, we demonstrate that SuhB is required for the activation of virulence factors associated with acute infections while suppressing virulence factors associated with chronic infections. Our report provides new insights into the multilayered regulatory network of virulence genes in P. aeruginosa. PMID- 24169573 TI - Bactofencin A, a new type of cationic bacteriocin with unusual immunity. AB - Bacteriocin production is an important probiotic trait of intestinal bacteria. In this study, we identify a new type of bacteriocin, bactofencin A, produced by a porcine intestinal isolate Lactobacillus salivarius DPC6502, and assess its potency against pathogenic species including Staphylococcus aureus and Listeria monocytogenes. Genome sequencing of the bacteriocin producer revealed bfnA, which encodes the mature and highly basic (pI 10.59), 22-amino-acid defensin-like peptide. Matrix-assisted laser desorption ionization-time of flight (MALDI-TOF) mass spectral analysis determined that bactofencin A has a molecular mass of 2,782 Da and contains two cysteine residues that form an intramolecular disulfide bond. Although an ABC transporter and transport accessory protein were also present within the bacteriocin gene cluster, a classical bacteriocin immunity gene was not detected. Interestingly, a dltB homologue was identified downstream of bfnA. DltB is usually encoded within the dlt operon of many Gram-positive bacteria. It is responsible for d-alanylation of teichoic acids in the cell wall and has previously been associated with bacterial resistance to cationic antimicrobial peptides. Heterologous expression of this gene conferred bactofencin A-specific immunity on sensitive strains of L. salivarius and S. aureus (although not L. monocytogenes), establishing its role in bacteriocin immunity. An analysis of the distribution of bfnA revealed that it was present in four additional isolates derived from porcine origin and absent from five human isolates, suggesting that its distribution is host specific. Given its novelty, we anticipate that bactofencin A represents the prototype of a new class of bacteriocins characterized as being cationic, with a DltB homologue providing a cognate immunity function. IMPORTANCE: This study describes the identification, purification, and characterization of bactofencin A, a novel type of bacteriocin produced by L. salivarius DPC6502. Interestingly, bactofencin A is not similar to any other known bacteriocin but instead shares similarity with eukaryotic cationic antimicrobial peptides, and here, we demonstrate that it inhibits two medically significant pathogens. Genome sequence analysis of the producing strain also revealed the presence of an atypical dltB homologue in the bacteriocin gene cluster, which was lacking a classical bacteriocin immunity gene. Furthermore, cloning this gene rendered sensitive strains resistant to the bacteriocin, thereby establishing its role in providing cognate bacteriocin immunity. Four additional L. salivarius isolates, also of porcine origin, were found to contain the bacteriocin biosynthesis genes and successfully produced bactofencin A, while these genes were absent from five human-derived strains investigated. PMID- 24169574 TI - Regulation of CTnDOT conjugative transfer is a complex and highly coordinated series of events. AB - CTnDOT is a 65-kb conjugative transposon that is found in Bacteroides spp., which are one of the more abundant members within the lower human gastrointestinal tract. CTnDOT encodes resistance to the antibiotics erythromycin and tetracycline (Tc). An interesting feature of CTnDOT is that exposure to low levels of Tc induces a cascade of events that ultimately results in CTnDOT conjugative transfer. However, Tc is apparently not a switch that activates transfer but rather a signal that appears to override a series of negative regulators that inhibit premature excision and transfer of CTnDOT. In this minireview, we summarize over 20 years of research that focused on elucidating the highly coordinated regulation of excision, mobilization, and transfer of CTnDOT. IMPORTANCE: Bacteroides spp. are abundant commensals in the human colon, but they are also considered opportunistic pathogens, as they can cause life-threatening infections if they should escape the colon. Bacteroides spp. are the most common cause of anaerobic infections and are rather difficult to treat due to the prevalence of antibiotic resistance within this genus. Today over 80% of Bacteroides are resistant to tetracycline (Tc), and a study looking at both clinical and community isolates demonstrated that this resistance was specifically due to the conjugative transposon CTnDOT. PMID- 24169576 TI - A critical role for the putative NCS2 nucleobase permease YjcD in the sensitivity of Escherichia coli to cytotoxic and mutagenic purine analogs. AB - The base analogs 6-N-hydroxylaminopurine (HAP) and 2-amino-HAP (AHAP) are potent mutagens in bacteria and eukaryotic organisms. Previously, we demonstrated that a defect in the Escherichia coli ycbX gene, encoding a molybdenum cofactor dependent oxidoreductase, dramatically enhances sensitivity to the toxic and mutagenic action of these agents. In the present study, we describe the discovery and properties of a novel suppressor locus, yjcD, that strongly reduces the HAP sensitivity of the ycbX strain. Suppressor effects are also observed for other purine analogs, like AHAP, 6-mercaptopurine, 6-thioguanine, and 2-aminopurine. In contrast, the yjcD defect did not affect the sensitivity to the pyrimidine analog 5-fluorouracil. Homology searches have predicted that yjcD encodes a putative permease of the NCS2 family of nucleobase transporters. We further investigated the effects of inactivation of all other members of the NCS2 family, XanQ, XanP, PurP, UacT, UraA, RutG, YgfQ, YicO, and YbbY, and of the NCS1 family nucleobase permeases CodB and YbbW. None of these other defects significantly affected sensitivity to either HAP or AHAP. The combined data strongly suggest that YjcD is the primary importer for modified purine bases. We also present data showing that this protein may, in fact, also be a principal permease involved in transport of the normal purines guanine, hypoxanthine, and/or xanthine. IMPORTANCE: Nucleotide metabolism is a critical aspect of the overall metabolism of the cell, as it is central to the core processes of RNA and DNA synthesis. At the same time, nucleotide metabolism can be subverted by analogs of the normal DNA or RNA bases, leading to highly toxic and mutagenic effects. Thus, understanding how cells process both normal and modified bases is of fundamental importance. This work describes a novel suppressor of the toxicity of certain modified purine bases in the bacterium Escherichia coli. This suppressor encodes a putative high-affinity nucleobase transporter that mediates the import of the modified purine bases. It is also a likely candidate for the long-sought high affinity importer for the normal purines, like guanine and hypoxanthine. PMID- 24169575 TI - The ABC-type efflux pump MacAB protects Salmonella enterica serovar typhimurium from oxidative stress. AB - Multidrug efflux pumps are integral membrane proteins known to actively excrete antibiotics. The macrolide-specific pump MacAB, the only ABC-type drug efflux pump in Salmonella, has previously been linked to virulence in mice. The molecular mechanism of this link between macAB and infection is unclear. We demonstrate that macAB plays a role in the detoxification of reactive oxygen species (ROS), compounds that salmonellae are exposed to at various stages of infection. macAB is induced upon exposure to H2O2 and is critical for survival of Salmonella enterica serovar Typhimurium in the presence of peroxide. Furthermore, we determined that macAB is required for intracellular replication inside J774.A1 murine macrophages but is not required for survival in ROS-deficient J774.D9 macrophages. macAB mutants also had reduced survival in the intestine in the mouse colitis model, a model characterized by a strong neutrophilic intestinal infiltrate where bacteria may experience the cytotoxic actions of ROS. Using an Amplex red-coupled assay, macAB mutants appear to be unable to induce protection against exogenous H2O2 in vitro, in contrast to the isogenic wild type. In mixed cultures, the presence of the wild-type organism, or media preconditioned by the growth of the wild-type organism, was sufficient to rescue the macAB mutant from peroxide-mediated killing. Our data indicate that the MacAB drug efflux pump has functions beyond resistance to antibiotics and plays a role in the protection of Salmonella against oxidative stress. Intriguingly, our data also suggest the presence of a soluble anti-H2O2 compound secreted by Salmonella cells through a MacAB-dependent mechanism. IMPORTANCE: The ABC-type multidrug efflux pump MacAB is known to be required for Salmonella enterica serovar Typhimurium virulence after oral infection in mice, yet the function of this pump during infection is unknown. We show that this pump is necessary for colonization of niches in infected mice where salmonellae encounter oxidative stress during infection. MacAB is required for growth in cultured macrophages that produce reactive oxygen species (ROS) but is not needed in macrophages that do not generate ROS. In addition, we show that MacAB is required to resist peroxide-mediated killing in vitro and for the inactivation of peroxide in the media. Finally, wild-type organisms, or supernatant from wild-type organisms grown in the presence of peroxide, rescue the growth defect of macAB mutants in H2O2. MacAB appears to participate in the excretion of a compound that induces protection against ROS mediated killing, revealing a new role for this multidrug efflux pump. PMID- 24169577 TI - Microbiome assembly across multiple body sites in low-birthweight infants. AB - The purpose of this study was to evaluate the composition and richness of bacterial communities associated with low-birthweight (LBW) infants in relation to host body site, individual, and age. Bacterial 16S rRNA genes from saliva samples, skin swabs, and stool samples collected on postnatal days 8, 10, 12, 15, 18, and 21 from six LBW (five premature) infants were amplified, pyrosequenced, and analyzed within a comparative framework that included analogous data from normal-birthweight (NBW) infants and healthy adults. We found that body site was the primary determinant of bacterial community composition in the LBW infants. However, site specificity depended on postnatal age: saliva and stool compositions diverged over time but were not significantly different until the babies were 15 days old. This divergence was primarily driven by progressive temporal turnover in the distal gut, which proceeded at a rate similar to that of age-matched NBW infants. Neonatal skin was the most adult-like in microbiota composition, while saliva and stool remained the least so. Compositional variation among infants was marked and depended on body site and age. Only the smallest, most premature infant received antibiotics during the study period; this heralded a coexpansion of Pseudomonas aeruginosa and a novel Mycoplasma sp. in the oral cavity of this vaginally delivered, intubated patient. We conclude that concurrent molecular surveillance of multiple body sites in LBW neonates reveals a delayed compositional differentiation of the oral cavity and distal gut microbiota and, in the case of one infant, an abundant, uncultivated oral Mycoplasma sp., recently detected in human vaginal samples. IMPORTANCE: Complications of premature birth are the most common cause of neonatal mortality. Colonization by the indigenous microbiota, which begins at delivery, may predispose some high-risk newborns to invasive infection or necrotizing enterocolitis (NEC), and protect others, yet neonatal microbiome dynamics are poorly understood. Here, we present the first cultivation-independent time series tracking microbiota assembly across multiple body sites in a synchronous cohort of hospitalized low-birthweight (LBW) neonates. We take advantage of archived samples and publically available sequence data and compare our LBW infant findings to those from normal-birthweight (NBW) infants and healthy adults. Our results suggest potential windows of opportunity for the dispersal of microbes within and between hosts and support recent findings of substantial baseline spatiotemporal variation in microbiota composition among high-risk newborns. PMID- 24169578 TI - Altered dynamics of Candida albicans phagocytosis by macrophages and PMNs when both phagocyte subsets are present. AB - An important first line of defense against Candida albicans infections is the killing of fungal cells by professional phagocytes of the innate immune system, such as polymorphonuclear cells (PMNs) and macrophages. In this study, we employed live-cell video microscopy coupled with dynamic image analysis tools to provide insights into the complexity of C. albicans phagocytosis when macrophages and PMNs were incubated with C. albicans alone and when both phagocyte subsets were present. When C. albicans cells were incubated with only one phagocyte subtype, PMNs had a lower overall phagocytic capacity than macrophages, despite engulfing fungal cells at a higher rate once fungal cells were bound to the phagocyte surface. PMNs were more susceptible to C. albicans-mediated killing than macrophages, irrespective of the number of C. albicans cells ingested. In contrast, when both phagocyte subsets were studied in coculture, the two cell types phagocytosed and cleared C. albicans at equal rates and were equally susceptible to killing by the fungus. The increase in macrophage susceptibility to C. albicans-mediated killing was a consequence of macrophages taking up a higher proportion of hyphal cells under these conditions. In the presence of both PMNs and macrophages, C. albicans yeast cells were predominantly cleared by PMNs, which migrated at a greater speed toward fungal cells and engulfed bound cells more rapidly. These observations demonstrate that the phagocytosis of fungal pathogens depends on, and is modified by, the specific phagocyte subsets present at the site of infection. IMPORTANCE: Extensive work investigating fungal cell phagocytosis by macrophages and PMNs of the innate immune system has been carried out. These studies have been informative but have examined this phenomenon only when one phagocyte subset is present. The current study employed live-cell video microscopy to break down C. albicans phagocytosis into its component parts and examine the effect of a single phagocyte subset, versus a mixed phagocyte population, on these individual stages. Through this approach, we identified that the rate of fungal cell engulfment and rate of phagocyte killing altered significantly when both macrophages and PMNs were incubated in coculture with C. albicans compared to the rate of either phagocyte subset incubated alone with the fungus. This research highlights the significance of studying pathogen-host cell interactions with a combination of phagocytes in order to gain a greater understanding of the interactions that occur between cells of the host immune system in response to fungal invasion. PMID- 24169579 TI - Increased oxygen load in the prefrontal cortex from mouth breathing: a vector based near-infrared spectroscopy study. AB - Individuals who habitually breathe through the mouth are more likely than nasal breathers to have sleep disorders and attention deficit hyperactive disorder. We hypothesized that brain hemodynamic responses in the prefrontal cortex might be different for mouth and nasal breathing. To test this hypothesis, we measured changes in oxyhemoglobin and deoxyhemoglobin in the prefrontal cortex during mouth breathing and nasal breathing in healthy adults (n=9) using vector-based near-infrared spectroscopy. The angle k, calculated from changes in oxyhemoglobin and deoxyhemoglobin and indicating the degree of oxygen exchange, was significantly higher during mouth breathing (P<0.05), indicating an increased oxygen load. Mouth breathing also caused a significant increase in deoxyhemoglobin, but oxyhemoglobin did not increase. This difference in oxygen load in the brain arising from different breathing routes can be evaluated quantitatively using vector-based near-infrared spectroscopy. Phase responses could help to provide an earlier and more reliable diagnosis of a patient's habitual breathing route than a patient interview. PMID- 24169581 TI - Modelling clinical data shows active tissue concentration of daclatasvir is 10 fold lower than its plasma concentration. AB - OBJECTIVES: Daclatasvir is a highly potent inhibitor of hepatitis C virus. We estimated the active tissue concentration of daclatasvir in vivo. METHODS: We developed a mathematical model incorporating pharmacokinetic/pharmacodynamic and viral dynamics. By fitting the model to clinical data reported previously, we estimated the ratio between plasma drug concentration and active tissue concentration in vivo. RESULTS: The modelling results show that the active tissue concentration of daclatasvir is ~9% of the concentration measured in plasma (95% CI 1%-29%). CONCLUSIONS: Using plasma concentrations as surrogates for clinical recommendations may lead to substantial underestimation of the risk of resistance. PMID- 24169580 TI - RamA, which controls expression of the MDR efflux pump AcrAB-TolC, is regulated by the Lon protease. AB - OBJECTIVES: RamA regulates the AcrAB-TolC multidrug efflux system. Using Salmonella Typhimurium, we investigated the stability of RamA and its impact on antibiotic resistance. METHODS: To detect RamA, we introduced ramA::3XFLAG::aph into plasmid pACYC184 and transformed this into Salmonella Typhimurium SL1344ramA::cat and lon::aph mutants. An N-terminus-deleted mutant [pACYC184ramA(Delta2-21)::3XFLAG::aph] in which the first 20 amino acids of RamA were deleted was also constructed. To determine the abundance and half-life of FLAG-tagged RamA, we induced RamA with chlorpromazine (50 mg/L) and carried out western blotting using anti-FLAG antibody. Susceptibility to antibiotics and phenotypic characterization of the lon mutant was also carried out. RESULTS: We show that on removal of chlorpromazine, a known inducer of ramA, the abundance of RamA decreased to pre-induced levels. However, in cells lacking functional Lon, we found that the RamA protein was not degraded. We also demonstrated that the 21 amino acid residues of the RamA N-terminus are required for recognition by the Lon protease. Antimicrobial susceptibility and phenotypic tests showed that the lon mutant was more susceptible to fluoroquinolone antibiotics, was filamentous when observed by microscopy and grew poorly, but showed no difference in motility or the ability to form a biofilm. There was also no difference in the ability of the lon mutant to invade human intestinal cells (INT-407). CONCLUSIONS: In summary, we show that the ATP-dependent Lon protease plays an important role in regulating the expression of RamA and therefore multidrug resistance via AcrAB TolC in Salmonella Typhimurium. PMID- 24169582 TI - Successful treatment of post-neurosurgical multidrug-resistant Pseudomonas aeruginosa meningo-encephalitis with combination therapy of colistin, rifampicin and doripenem. PMID- 24169585 TI - Human papilloma virus testing in oropharyngeal squamous cell carcinoma: what the clinician should know. AB - High risk Human Papilloma virus (HR-HPV) associated oropharyngeal cancers are on the increase. Although, the scientific community is aware of the importance of Human Papilloma Virus (HPV) testing, there is no consensus on the assays that are required to reliably identify HR-HPV related tumors. A wide range of methods have been developed. The most widely used techniques include viral DNA detection, with polymerase chain reaction (PCR) or In Situ Hybridization, and p16 detected by immunohistochemistry. However, these tests provide different information and have their own specific limitations. In this review, we summarize these different techniques, in light of the recent literature. p16 Overexpression, which is an indirect marker of HPV infection, is considered by many head and neck oncologists to be the most important marker for patient stratification. We describe the frequent lack of concordance of this marker with other assays and the possible reasons for this. The latest developments in HPV testing are also reported, such as the RNAscopeTM HPV test, and how they fit into the existing framework of techniques. HPV testing must not be considered in isolation, as there are important interactions with other parameters, such as tobacco exposure. This is an important and rapidly evolving field and is likely to become pivotal to staging and choice of treatment of oropharyngeal carcinoma in the future. PMID- 24169583 TI - Differences in methylation profiles between HPV-positive and HPV-negative oropharynx squamous cell carcinoma: a systematic review. AB - Oropharyngeal squamous cell carcinoma (OPSCC) is associated with human papillomavirus (HPV). HPV-positive OPSCC is considered a distinct molecular entity with a better prognosis than HPV-negative cases of OPSCC. However, the exact pathogenic mechanisms underlying the differences in clinical and molecular behavior between HPV-positive and HPV-negative OPSCC remain poorly understood. Epigenetic events play an important role in the development of cancer. Hypermethylation of DNA in promoter regions and global hypomethylation are 2 epigenetic changes that have been frequently observed in human cancers. It is suggested that heterogeneous epigenetic changes play a role in the clinical and biological differences between HPV-positive and HPV-negative tumors. Unraveling the differences in methylation profiles of HPV-associated OPSCC may provide for promising clinical applications and may pave the road for personalized cancer treatment. This systematic review aims to assess the current state of knowledge regarding differences in promoter hypermethylation and global methylation between HPV-positive and HPV-negative OPSCC. PMID- 24169586 TI - Prevalence and risk factors for oral human papillomavirus infection in 129 women screened for cervical HPV infection. AB - BACKGROUND: Oncogenic human papillomaviruses (HPV) are known to be associated with carcinomas of the uterine cervix. Furthermore, current studies have shown that HPV-infection is also associated with a subtype of oropharyngeal cancers. In general, a sexual transmission of the viruses has been shown by numerous studies in the genital lesions. However, there are unknown factors regarding the prevalence and transmission of HPV in the oropharynx. The aim of this study was to evaluate HPV prevalence in the oropharynx in female participants with and without genital HPV infection. In addition, we analyzed risk factors for an oropharyngeal colonization with HPV in their sexual partners, too. METHODS: 129 Female participants were tested for presence of HPV-DNA by oral lavage, brush cytology of the tonsils and of the cervix. In addition, 15 male partners of these patients were included in the study. HPV-DNA was detected by PCR (polymerase chain reaction) amplification. For HPV-genotyping, PCR products were hybridized with type-specific digoxigenin-labeled oligonucleotide probes and discriminated into 14 high risk (HR) and 6 low risk (LR)-HPV types. The 129 female and 15 male participants were interviewed by a standardized questionnaire for socioeconomic details, drinking, smoking and sexual behaviours. RESULTS: 59 (45.7%) Female participants were negative for a genital HPV-infection. Of these women, 3 (5.1%) showed a positive HPV-PCR result (HR and LR) in the oropharynx. 70 (54.3%) Female participants were positive for a genital HPV infection. In this group, 4 (5.7%) had a positive HPV-detection (HR and LR) in the oral cavity and oropharynx. Female participants with cervical HPV-infection had no higher risk for HPV detection in the oropharynx (not significant). The analysis of sexual risk factors revealed no specific risk factor for an oral HPV-infection. CONCLUSION: A correlation between cervical and oral colonization by HPV could not be demonstrated in our small cohort. Our limited data suggest that sexual transmission of HPV from the cervix uteri to the oropharynx is a rare and unlikely event. PMID- 24169589 TI - Psychosocial interventions in cardiovascular disease--what are they? PMID- 24169587 TI - Effects of vitamin D3, calcipotriol and FTY720 on the expression of surface molecules and cytolytic activities of human natural killer cells and dendritic cells. AB - We describe here the effects of three drugs that are either approved or have the potential for treating multiple sclerosis (MS) patients through the in vitro activities of human natural killer (NK) cells and dendritic cells (DCs). Our results indicate that 1,25(OH)2D3, the biologically active metabolite of vitamin D3, calcipotriol and FTY720 augment IL-2-activated NK cell lysis of K562 and RAJI tumor cell lines as well as immature (i) and mature (m) DCs, with variable efficacies. These results are corroborated with the ability of the drugs to up regulate the expression of NK cytotoxicity receptors NKp30 and NKp44, as well as NKG2D on the surfaces of NK cells. Also, they down-regulate the expression of the killer inhibitory receptor CD158. The three drugs down-regulate the expression of CCR6 on the surface of iDCs, whereas vitamin D3 and calcipotriol tend to up regulate the expression of CCR7 on mDCs, suggesting that they may influence the migration of DCs into the lymph nodes. Finally, vitamin D3, calcipotriol and FTY720 enhance NK17/NK1 cell lysis of K562 cells, suggesting that a possible mechanism of action for these drugs is via activating these newly described cells. In conclusion, our results show novel mechanisms of action for vitamin D3, calcipotriol and FTY720 on cells of the innate immune system. PMID- 24169588 TI - Atractaspis aterrima toxins: the first insight into the molecular evolution of venom in side-stabbers. AB - Although snake venoms have been the subject of intense research, primarily because of their tremendous potential as a bioresource for design and development of therapeutic compounds, some specific groups of snakes, such as the genus Atractaspis, have been completely neglected. To date only limited number of toxins, such as sarafotoxins have been well characterized from this lineage. In order to investigate the molecular diversity of venom from Atractaspis aterrima the slender burrowing asp, we utilized a high-throughput transcriptomic approach completed with an original bioinformatics analysis pipeline. Surprisingly, we found that Sarafotoxins do not constitute the major ingredient of the transcriptomic cocktail; rather a large number of previously well-characterized snake venom-components were identified. Notably, we recovered a large diversity of three-finger toxins (3FTxs), which were found to have evolved under the significant influence of positive selection. From the normalized and non normalized transcriptome libraries, we were able to evaluate the relative abundance of the different toxin groups, uncover rare transcripts, and gain new insight into the transcriptomic machinery. In addition to previously characterized toxin families, we were able to detect numerous highly-transcribed compounds that possess all the key features of venom-components and may constitute new classes of toxins. PMID- 24169590 TI - Detection and management of asymptomatic myocardial injury after noncardiac surgery. PMID- 24169591 TI - Pollinator shifts and the evolution of spur length in the moth-pollinated orchid Platanthera bifolia. AB - BACKGROUND AND AIMS: Plant-pollinator interactions are thought to have shaped much of floral evolution. Yet the relative importance of pollinator shifts and coevolutionary interactions for among-population variation in floral traits in animal-pollinated species is poorly known. This study examined the adaptive significance of spur length in the moth-pollinated orchid Platanthera bifolia. METHODS: Geographical variation in the length of the floral spur of P. bifolia was documented in relation to variation in the pollinator fauna across Scandinavia, and a reciprocal translocation experiment was conducted in south east Sweden between a long-spurred woodland population and a short-spurred grassland population. KEY RESULTS: Spur length and pollinator fauna varied among regions and habitats, and spur length was positively correlated with the proboscis length of local pollinators. In the reciprocal translocation experiment, long-spurred woodland plants had higher pollination success than short-spurred grassland plants at the woodland site, while no significant difference was observed at the grassland site. CONCLUSIONS: The results are consistent with the hypothesis that optimal floral phenotype varies with the morphology of the local pollinators, and that the evolution of spur length in P. bifolia has been largely driven by pollinator shifts. PMID- 24169592 TI - Phenotypic correlates of the lianescent growth form: a review. AB - BACKGROUND: As proposed by Darwin, climbers have been assumed to allocate a smaller fraction of biomass to support organs in comparison with self-supporting plants. They have also been hypothesized to possess a set of traits associated with fast growth, resource uptake and high productivity. SCOPE: In this review, these hypotheses are evaluated by assembling and synthesizing published and unpublished data sets from across the globe concerning resource allocation, growth rates and traits of leaves, stems and roots of climbers and self supporting species. CONCLUSIONS: The majority of studies offer little support for the smaller allocation of biomass to stems or greater relative growth rates in climbers; however, these results are based on small sized (<1 kg) plants. Simulations based on allometric biomass equations demonstrate, however, that larger lianas allocate a greater fraction of above-ground biomass to leaves (and therefore less biomass to stems) compared with similar sized trees. A survey of leaf traits of lianas revealed their lower average leaf mass per area (LMA), higher N and P concentration and a slightly higher mass-based photosynthetic rate, as well as a lower concentration of phenolic-based compounds than in woody self-supporting species, consistent with the specialization of lianas towards the fast metabolism/rapid turnover end of the global trait spectra. Liana stems have an efficient hydraulic design and unique mechanical features, while roots appear to penetrate deeper soil levels than in trees and are often able to generate hydraulic pressure. Much remains to be learned, however, about these and other functional specializations of their axial organs and the associated trade-offs. Developmental switches between self-supporting, searcher and climbing shoots within the same individual are a promising field of comparative studies on trait association in lianas. Finally, some of the vast trait variability within lianas may be reduced when species with different climbing mechanisms are considered separately, and when phylogenetic conservatism is accounted for. PMID- 24169593 TI - Differential spreading of HinfI satellite DNA variants during radiation in Centaureinae. AB - BACKGROUND AND AIMS: Subtribe Centaureinae appears to be an excellent model group in which to analyse satellite DNA and assess the influence that the biology and/or the evolution of different lineages have had on the evolution of this class of repetitive DNA. Phylogenetic analyses of Centaureinae support two main phases of radiation, leading to two major groups of genera of different ages. Furthermore, different modes of evolution are observed in different lineages, reflected by morphology and DNA sequences. METHODS: The sequences of 502 repeat units of the HinfI satellite DNA family from 38 species belonging to ten genera of Centaureinae were isolated and compared. A phylogenetic reconstruction was carried out by maximum likelihood and Bayesian inference. KEY RESULTS: Up to eight different HinfI subfamilies were found, based on the presence of a set of diagnostic positions given by a specific mutation shared by all the sequences of one group. Subfamilies V-VIII were mostly found in older genera (first phase of radiation in the subtribe, late Oligocene-Miocene), although some copies of these types of repeats were also found in some species of the derived genera. Subfamilies I-IV spread mostly in species of the derived clade (second phase of radiation, Pliocene to Pleistocene), although repeats of these subfamilies exist in older species. Phylogenetic trees did not group the repeats by taxonomic affinity, but sequences were grouped by subfamily provenance. Concerted evolution was observed in HinfI subfamilies spread in older genera, whereas no genetic differentiation was found between species, and several subfamilies even coexist within the same species, in recently radiated groups or in groups with a history of recurrent hybridization of lineages. CONCLUSIONS: The results suggest that the eight HinfI subfamilies were present in the common ancestor of Centaureinae and that each spread differentially in different genera during the two main phases of radiation following the library model of satellite DNA evolution. Additionally, differential speciation pathways gave rise to differential patterns of sequence evolution in different lineages. Thus, the evolutionary history of each group of Centaureinae is reflected in HinfI satellite DNA evolution. The data reinforce the value of satellite DNA sequences as markers of evolutionary processes. PMID- 24169594 TI - Genetic evidence for predominantly hydrochoric gene flow in the invasive riparian plant Impatiens glandulifera (Himalayan balsam). AB - BACKGROUND AND AIMS: Riparian systems are prone to invasion by alien plant species. The spread of invasive riparian plants may be facilitated by hydrochory, the transport of seeds by water, but while ecological studies have highlighted the possible role of upstream source populations in the establishment and persistence of stands of invasive riparian plant species, population genetic studies have as yet not fully addressed the potential role of hydrochoric dispersal in such systems. METHODS: A population genetics approach based on a replicated bifurcate sampling design is used to test hypotheses consistent with patterns of unidirectional, linear gene flow expected under hydrochoric dispersal of the invasive riparian plant Impatiens glandulifera in two contrasting river systems. KEY RESULTS: A significant increase in levels of genetic diversity downstream was observed, consistent with the accumulation of propagules from upstream source populations, and strong evidence was found for organization of this diversity between different tributaries, reflecting the dendritic organization of the river systems studied. CONCLUSIONS: These findings indicate that hydrochory, rather than anthropogenic dispersal, is primarily responsible for the spread of I. glandulifera in these river systems, and this is relevant to potential approaches to the control of invasive riparian plant species. PMID- 24169595 TI - Floral elaiophores in Lockhartia Hook. (Orchidaceae: Oncidiinae): their distribution, diversity and anatomy. AB - BACKGROUND AND AIMS: A significant proportion of orchid species assigned to subtribe Oncidiinae produce floral oil as a food reward that attracts specialized bee pollinators. This oil is produced either by glabrous glands (epithelial elaiophores) or by tufts of secretory hairs (trichomal elaiophores). Although the structure of epithelial elaiophores in the Oncidiinae has been well documented, trichomal elaiophores are less common and have not received as much attention. Only trichomal elaiophores occur in the genus Lockhartia, and their distribution and structure are surveyed here for the first time. METHODS: Flowers of 16 species of Lockhartia were studied. The location of floral elaiophores was determined histochemically and their anatomical organization and mode of oil secretion was investigated by means of light microscopy, scanning electron microscopy and transmission electron microscopy. KEY RESULTS AND CONCLUSIONS: All species of Lockhartia investigated have trichomal elaiophores on the adaxial surface of the labellum. Histochemical tests revealed the presence of lipoidal substances within the labellar trichomes. However, the degree of oil production and the distribution of trichomes differed between the three major groups of species found within the genus. All trichomes were unicellular and, in some species, of two distinct sizes, the larger being either capitate or apically branched. The trichomal cuticle was lamellate, and often appeared distended due to the subcuticular accumulation of oil. The labellar trichomes of the three species examined using transmission electron microscopy contained dense, intensely staining cytoplasm with apically located vacuoles. Oil-laden secretory vesicles fused with the plasmalemma and discharged their contents. Oil eventually accumulated between the cell wall and cuticle of the trichome and contained electron-transparent profiles or droplets. This condition is considered unique to Lockhartia among those species of elaiophore-bearing Oncidiinae studied to date. PMID- 24169596 TI - Iron oxide-loaded hollow mesoporous silica nanocapsules for controlled drug release and hyperthermia. AB - Magnetic field-responsive iron oxide-loaded hollow mesoporous silica nanocapsules that exhibit high drug loading capacity were synthesized using polymer nanospheres as sacrificial templates. Due to their magnetic field induced heating and remotely triggered drug release capabilities, these hybrid nanomaterials provide an excellent platform for the combination of hyperthermia and chemotherapy. PMID- 24169597 TI - Efficacy of adrenal venous sampling is increased by point of care cortisol analysis. AB - Primary aldosteronism (PA) is a common cause of secondary hypertension and is caused by unilateral or bilateral adrenal disease. Treatment options depend on whether the disease is lateralized or not, which is preferably evaluated with selective adrenal venous sampling (AVS). This procedure is technically challenging, and obtaining representative samples from the adrenal veins can prove difficult. Unsuccessful AVS procedures often require reexamination. Analysis of cortisol during the procedure may enhance the success rate. We invited 21 consecutive patients to participate in a study with intra-procedural point of care cortisol analysis. When this assay showed nonrepresentative sampling, new samples were drawn after redirection of the catheter. The study patients were compared using the 21 previous procedures. The intra-procedural cortisol assay increased the success rate from 10/21 patients in the historical cohort to 17/21 patients in the study group. In four of the 17 successful procedures, repeated samples needed to be drawn. Successful sampling at first attempt improved from the first seven to the last seven study patients. Point of care cortisol analysis during AVS improves success rate and reduces the need for reexaminations, in accordance with previous studies. Successful AVS is crucial when deciding which patients with PA will benefit from surgical treatment. PMID- 24169598 TI - Luminescent liquid crystalline materials based on palladium(II) imine derivatives containing the 2-phenylpyridine core. AB - In this work we report our studies concerning the synthesis and characterisation of a series of imine derivatives that incorporate the 2-phenylpyridine (2-ppy) core. These derivatives were used in the cyclometalating reactions of platinum(II) or palladium(II) in order to prepare several complexes with liquid crystalline properties. Depending on the starting materials used as well as the solvents employed, different metal complexes were obtained, some of them showing both liquid crystalline behaviour and luminescence properties at room temperature. It was found that, even if there are two competing coordination sites, the cyclometalation process takes place always at the 2-ppy core with (for Pt) or without (for Pd) the imine bond cleavage. We successfully showed that it is possible to prepare emissive room temperature liquid crystalline materials based on double cyclopalladated heteroleptic complexes by varying the volume fraction of the long flexible alkyl tails on the ancillary benzoylthiourea (BTU) ligands. PMID- 24169599 TI - Nearly constant electrical resistance over large temperature range in Cu3NMx (M = Cu, Ag, Au) compounds. AB - Electrical resistance is a material property that usually varies enormously with temperature. Constant electrical resistivity over large temperature range has been rarely measured in a single solid. Here we report the growth of Cu3NMx (M = Cu, Ag, Au) compound films by magnetron sputtering, aiming at obtaining single solids of nearly constant electrical resistance in some temperature ranges. The increasing interstitial doping of cubic Cu3N lattice by extra metal atoms induces the semiconductor-to-metal transition in all the three systems. Nearly constant electrical resistance over 200 K, from room temperature downward, was measured in some semimetallic Cu3NMx samples, resulting from opposite temperature dependence of carrier density and carrier mobility, as revealed by Hall measurement. Cu3NAgx samples have the best performance with regard to the range of both temperature and doping level wherein a nearly constant electrical resistance can be realized. This work can inspire the search of other materials of such a quality. PMID- 24169600 TI - Towards storage of cells and gametes in dry form. AB - We review published data on cell/gamete lyophilization. Most studies have utilized the same established protocols for cryopreservation (storage in liquid nitrogen) as for cell lyophilization (dehydration of frozen samples by water sublimation). Surveying natural lyoprotectants, we suggest trehalose and late embryogenesis abundant (LEA) proteins as ideal candidates for the reversible desiccation of mammalian cells/gametes. We find that despite the numerous water subtraction techniques, scientists have relied almost exclusively on lyophilization. There is thus room for improvement in both medium formulation and water subtraction strategies for dry cell/gamete storage. We believe the development of dry processing protocols for use in biobanks of cells/gametes, at reduced cost and with minimal carbon footprint, is within our grasp. PMID- 24169601 TI - Dear DORA. PMID- 24169602 TI - The pressure dependence of the solid state structure of biphenyl from DFT calculations. AB - In this work we theoretically investigated the characteristics of the structure of biphenyl at zero temperature. The calculations were carried out with density functional theory using periodic boundary conditions. Semiempirical van der Waals (vdW) corrections were applied. We focused on the phenyl-phenyl dihedral angle and its shift with increasing pressure. We furthermore investigated the bond lengths of different bonds during the compression. The experimental transition pressure of a phase transition could be reproduced with satisfactory accuracy. PMID- 24169603 TI - Neuroprotective effects of edaravone after intraventricular hemorrhage in rats. AB - Intraventricular hemorrhage (IVH) is a severity factor and treatment target in intracerebral hemorrhage. This study aimed to investigate whether systemic edaravone, a free-radical scavenger, could attenuate the brain injury after IVH in a rat model. Our findings showed that an intraventricular injection of autologous whole blood resulted in acute brain edema, increased malondialdehyde level, and decreased superoxide dismutase enzyme activity. Immediate edaravone treatment after IVH can reduce IVH-induced brain edema and elevated lipid peroxidation. Furthermore, repeated edaravone treatment (immediately, 24 h, and 48 h after IVH) improved the IVH-induced learning and memory damage. These effects suggest that edaravone may be a potential therapeutic agent for IVH, especially those intracerebral hemorrhage patients with ventricular extension. PMID- 24169605 TI - Smooth pursuit eye movement preferentially facilitates motor-evoked potential elicited by anterior-posterior current in the brain. AB - Neural interaction between the eye and hand movement centers must be a critical part of the mechanism underlying eye-hand coordination. One of the previous findings supporting this view is smooth pursuit eye movement-induced suppression of motor-evoked potential (MEP) in the hand muscles. The purpose of this study was to determine which descending volleys contributing to MEP are preferentially modulated by smooth pursuit eye movement. MEP in the first dorsal interosseous muscle was elicited by different directions of current in the brain during the steady-state phase of smooth pursuit eye movement. Smooth pursuit eye movement facilitated MEP elicited by anterior-posterior (AP) current, but this effect was not seen in MEP elicited by lateromedial or posterior-anterior current. Latency of MEP elicited by AP current was significantly longer than latencies of MEPs elicited by other directions of current, indicating that AP current in the brain predominantly elicited later I-waves. We conclude that smooth pursuit eye movement in the steady-state phase preferentially facilitates MEP predominantly elicited by later I-waves generated by AP current in the brain. PMID- 24169604 TI - Advancing critical care medicine with stem cell therapy and hypothermia for cerebral palsy. AB - With limited clinical trials on stem cell therapy for adult stroke underway, the assessment of efficacy also needs to be considered for neonatal hypoxic-ischemic brain injury, considering its distinct symptoms. The critical nature of this condition leads to establishment of deficits that last a lifetime. Here, we will highlight the progress of current translational research, commenting on the critical nature of the disease, stem cell sources, the use of hypothermia, safety and efficacy of each treatment, modes of action, and the possibility of combination therapy. With this in mind, we reference translational guidelines established by a consortium of research partners called Stem cell Therapeutics as an Emerging Paradigm for Stroke (STEPS). The guidelines of STEPS are directed toward evaluating outcomes of cell therapy in adult stroke; however, we identify the overlapping pathology, as we believe that these guidelines will serve well in the investigation of neonatal hypoxic-ischemic therapy. Finally, we discuss emerging treatments and a case report, altogether suggesting that the potential for these treatments to be used in synergy has arrived and the time for advancing stem cell use in combination with hypothermia for cerebral palsy is now. PMID- 24169606 TI - Simon Stevens: new NHS leader who's "not just Mr Insurance USA". PMID- 24169607 TI - Lung congestion as a hidden threat in end-stage kidney disease: a call to action. PMID- 24169608 TI - Renoprotective mechanisms of ischemic postconditioning in ischemia-reperfusion injury: improved mitochondrial function and integrity. PMID- 24169609 TI - Con: Dialy- and continuous renal replacement (CRRT) trauma during renal replacement therapy: still under-recognized but on the way to better diagnostic understanding and prevention. AB - Dialy- and continuous renal replacement (CRRT) trauma are still un(der)recognized conditions that may be encountered during blood purification therapy. This particular form of trauma requires timely identification, a better understanding of pathophysiology and a definition of at-risk groups to prevent or correct any associated unwarranted effects. Among others, progress in the knowledge of antimicrobial pharmacokinetic/pharmacodynamic (PK/PD) behaviour during CRRT to obtain more efficient antimicrobial therapy with less side-effects is one key example of limiting CRRT trauma. Optimal anticipation and prevention of CRRT trauma will preserve the safe use of CRRT in haemodynamically unstable critically ill patients with acute kidney injury (AKI), especially in septic patients who are at the greatest risk. PMID- 24169610 TI - Pro: Renal replacement trauma or Paracelsus 2.0. PMID- 24169611 TI - Moderator's view: Renal replacement therapy in critically ill patients: how to 'primo non nocere'? PMID- 24169612 TI - Baseline characteristics in the Bardoxolone methyl EvAluation in patients with Chronic kidney disease and type 2 diabetes mellitus: the Occurrence of renal eveNts (BEACON) trial. AB - BACKGROUND: Type 2 diabetes mellitus (T2DM) is the most important contributing cause of end-stage renal disease (ESRD) worldwide. Bardoxolone methyl, a nuclear factor-erythroid-2-related factor 2 activator, augments estimated glomerular filtration. The Bardoxolone methyl EvAluation in patients with Chronic kidney disease and type 2 diabetes mellitus: the Occurrence of renal eveNts (BEACON) trial was designed to establish whether bardoxolone methyl slows or prevents progression to ESRD. Herein, we describe baseline characteristics of the BEACON population. METHODS: BEACON is a randomized double-blind placebo-controlled clinical trial in 2185 patients with T2DM and chronic kidney disease stage 4 (eGFR between 15 and 30 mL/min/1.73 m(2)) designed to test the hypothesis that bardoxolone methyl added to guideline-recommended treatment including inhibitors of the renin-angiotensin-aldosterone system slows or prevents progression to ESRD or cardiovascular death compared with placebo. RESULTS: Baseline characteristics (mean or percentage) of the population include age 68.5 years, female 43%, Caucasian 78%, eGFR 22.5 mL/min/1.73 m(2) and systolic/diastolic blood pressure 140/70 mmHg. The median urinary albumin:creatinine ratio was 320 mg/g and the frequency of micro- and macroalbuminuria was 30 and 51%, respectively. Anemia, abnormalities in markers of bone metabolism and elevations in cardiovascular biomarkers were frequently observed. A history of cardiovascular disease was present in 56%, neuropathy in 47% and retinopathy in 41% of patients. CONCLUSIONS: The BEACON trial enrolled a population heretofore unstudied in an international randomized controlled trial. Enrolled patients suffered with numerous co-morbid conditions and exhibited multiple laboratory abnormalities, highlighting the critical need for new therapies to optimize management of these conditions. PMID- 24169613 TI - Anticoagulant therapies for the prevention of intravascular catheters malfunction in patients undergoing haemodialysis: systematic review and meta-analysis of randomized, controlled trials. AB - BACKGROUND: Catheter malfunction (CM), including thrombosis, is associated with reduced dialysis adequacy, as well as an increased risk of catheter-related bacteraemia (CRB) and mortality. The role of alternative anticoagulant regimens for CM prevention remains uncertain. METHODS: A systematic review and meta analysis were performed examining all randomized controlled trials (RCTs) assessing interventions acting via an anticoagulant mechanism compared with conventional care for the prevention of CM in adult patients receiving haemodialysis for end-stage kidney disease. Medline, EMBASE and the Cochrane Register were searched to November 2012. The primary outcome was CM. Secondary outcomes were CRB, all-cause mortality and bleeding events (all bleeding events reported or as defined by authors). Relative risks with 95% confidence intervals (CIs) for individual trials were pooled using random effects models for treatment classes. RESULTS: The search yielded 28 trials including 3081 patients. Therapies assessed were alternative anticoagulant locking solutions (ALSs), systemic warfarin and low/no dose heparin locking solutions (normal saline locks). No significant effect on CM (18 trials, 1579 participants) was observed for alternative ALSs (9 trials, 887 participants, RR 0.85, 95% CI 0.68-1.07), or low/no dose heparin (4 trials, 231 participants, RR 0.99, CI 0.60-1.62), compared with heparin locking solutions (5000 units). Similarly, no significant effect was observed for warfarin (5 trials, 479 participants, RR 0.59, 95% CI 0.28-1.22) compared with placebo. No significant effect on CRB was observed (15 trials, 2367 participants) for alternative ALSs (11 trials, 2010 participants, RR 0.57, 95% CI 0.30-1.10), warfarin (1 trial, 174 participants, RR 2.40, 95% CI 0.88-6.52) or low/no dose heparin (3 trials, 183 participants, RR 0.76, 95% CI 0.35-1.64). All cause mortality was not affected by alternative ALSs (9 trials, 1719 participants, RR 0.83, 95% CI 0.56-1.24) or warfarin (3 trials, 403 participants, RR 0.78, 95% CI 0.37-1.65). Bleeding events were only reported in seven trials, including only two trials of warfarin, with no clear effect demonstrated. Within the alternative ALSs group, the only agent with a reduction in CM was recombinant tissue plasminogen activator (rt-PA)-locking solution (RR 0.52, 95% CI 0.32-0.86) based on the results of a single trial. Trials were mainly of high risk of bias. CONCLUSIONS: There is uncertainty on the benefits and harms of anticoagulant therapies over conventional care for prevention of CM. Further high-quality randomized trials, including safety outcomes, are needed. PMID- 24169614 TI - Iron indices and survival in maintenance hemodialysis patients with and without polycystic kidney disease. AB - BACKGROUND: Anemia is less prominent in patients with polycystic kidney disease (PKD). Such iron indices as ferritin and transferrin saturation (TSAT) values are used to guide management of anemia in individuals on maintenance hemodialysis (MHD). Optimal levels of correction of anemia and optimal levels of TSAT and ferritin are unclear in chronic kidney disease patients and have not been studied specifically in PKD. METHODS: We studied 2969 MHD patients with and 128 054 patients without PKD from 580 outpatient hemodialysis facilities between July 2001 and June 2006. Using baseline, time-dependent and time-averaged values with unadjusted and multivariable adjusted analysis models, the survival predictabilities of TSAT and ferritin were studied. RESULTS: PKD patients were 58 +/- 13 years old and included 46% women, whereas non-PKD patients were 62 +/- 15 years old and 45% women. In both PKD and non-PKD patients, a time-averaged TSAT between 30 and 40% was associated with the lowest mortality. Time-averaged ferritin between 100 and <800 ng/mL was associated with the lowest mortality in PKD patients, although this range was 500 to <800 ng/mL in non-PKD patients. CONCLUSIONS: In MHD patients with and without PKD, there was a U-shaped relationship between the average TSAT and mortality, and a TSAT of 30-40% was associated with the best survival. However, an average ferritin of 100-800 ng/mL was associated with the best survival in PKD patients, whereas that of non-PKD patients was 500-800 ng/mL. Further studies in PKD and non-PKD patients are necessary to determine whether or not therapeutic attempts to keep TSAT and ferritin levels in these ranges will improve survival. PMID- 24169618 TI - Epigenetic differences between shoots and roots in Arabidopsis reveals tissue specific regulation. AB - DNA methylation and nucleosome densities play a critical role in the regulation of gene expression. While much is known about the mechanisms of transcriptional control that are mediated by these, less is known about the degree to which they are tissue-specific. By comparing DNA methylation, nucleosome densities and transcriptional levels in different tissue types we can gain a clearer understanding of the extent to which these mechanisms influence gene expression in a tissue specific manner. We compared DNA methylation in Arabidopsis shoots and roots and found extensive differences across the genome. We computed DNA methylation differences between roots and shoots at single cytosines and found that one in every 173 cytosines was differentially methylated. In addition we compared DNA methylation with tissue specific gene expression and nucleosome density measurements to identify associations between these. We also identified a group of genes that are strongly correlated with these epigenetic marks and are significantly differentially methylated between roots and shoots. These root specific genes are part of the extensin family, and are preferentially methylated and have at least 10-fold higher expression and lower nucleosome density in roots relative to shoots. PMID- 24169619 TI - Integration in biology: Philosophical perspectives on the dynamics of interdisciplinarity. AB - This introduction to the special section on integration in biology provides an overview of the different contributions. In addition to motivating the philosophical significance of analyzing integration and interdisciplinary research, I lay out common themes and novel insights found among the special section contributions, and indicate how they exhibit current trends in the philosophical study of integration. One upshot of the contributed papers is that there are different aspects to and kinds of integration, so that rather than attempting to offer a universal construal of what integrations is, philosophers have to analyze in concrete cases in what respects particular aspects of scientific theorizing and/or practice are 'integrative' and how this instance of integration works and was achieved. PMID- 24169620 TI - Cretaceous stem chondrichthyans survived the end-Permian mass extinction. AB - Cladodontomorph sharks are Palaeozoic stem chondrichthyans thought to go extinct at the end-Permian mass extinction. This extinction preceded the diversification of euselachians, including modern sharks. Here we describe an outer-platform cladodontomorph shark tooth assemblage from the Early Cretaceous of southern France, increasing the fossil record of this group by circa 120 million years. Identification of this material rests on new histological observations and morphological evidence. Our finding shows that this lineage survived mass extinctions most likely by habitat contraction, using deep-sea refuge environments during catastrophic events. The recorded gap in the cladodontomorph lineage represents the longest gap in the fossil record for an extinct marine vertebrate group. This discovery demonstrates that the deep-sea marine diversity, poorly known during most of the fish evolutionary history, contains essential data for a complete understanding of the long-term evolution of marine fish paleobiodiversity. PMID- 24169623 TI - Self-assembled solvato-morphologically controlled photochromic crystals. AB - Here we describe, for the first time, intriguing solvato-morphological control of spiropyran-based microcrystalline structures. These microstructures exhibit reversible photoisomerization upon light irradiation (UV/Vis) in the solid-state. Finally, light-guided aggregation of these microstructures at the liquid/air interface is also demonstrated. PMID- 24169621 TI - Elucidating novel hepatitis C virus-host interactions using combined mass spectrometry and functional genomics approaches. AB - More than 170 million people worldwide are infected with the hepatitis C virus (HCV), for which future therapies are expected to rely upon a combination of oral antivirals. For a rapidly evolving virus like HCV, host-targeting antivirals are an attractive option. To decipher the role of novel HCV-host interactions, we used a proteomics approach combining immunoprecipitation of viral-host protein complexes coupled to mass spectrometry identification and functional genomics RNA interference screening of HCV partners. Here, we report the proteomics analyses of protein complexes associated with Core, NS2, NS3/4A, NS4B, NS5A, and NS5B proteins. We identified a stringent set of 98 human proteins interacting specifically with one of the viral proteins. The overlap with previous virus-host interaction studies demonstrates 24.5% shared HCV interactors overall (24/98), illustrating the reliability of the approach. The identified human proteins show enriched Gene Ontology terms associated with the endoplasmic reticulum, transport proteins with a major contribution of NS3/4A interactors, and transmembrane proteins for Core interactors. The interaction network emphasizes a high degree distribution, a high betweenness distribution, and high interconnectivity of targeted human proteins, in agreement with previous virus-host interactome studies. The set of HCV interactors also shows extensive enrichment for known targets of other viruses. The combined proteomic and gene silencing study revealed strong enrichment in modulators of HCV RNA replication, with the identification of 11 novel cofactors among our set of specific HCV partners. Finally, we report a novel immune evasion mechanism of NS3/4A protein based on its ability to affect nucleocytoplasmic transport of type I interferon-mediated signal transducer and activator of transcription 1 nuclear translocation. The study revealed highly stringent association between HCV interactors and their functional contribution to the viral replication cycle and pathogenesis. PMID- 24169622 TI - Functional proteomic discovery of Slr0110 as a central regulator of carbohydrate metabolism in Synechocystis species PCC6803. AB - The unicellular photosynthetic model-organism cyanobacterium Synechocystis sp. PCC6803 can grow photoautotrophically using CO2 or heterotrophically using glucose as the sole carbon source. Several pathways are involved in carbon metabolism in Synechocystis, and the concerted regulation of these pathways by numerous known and unknown genes is critical for the survival and growth of the organism. Here, we report that a hypothetical protein encoded by the open reading frame slr0110 is necessary for heterotrophic growth of Synechocystis. The slr0110 deletion mutant is defective in glucose uptake, heterotrophic growth, and dark viability without detectable defects in autotrophic growth, whereas the level of photosystem II and the rate of oxygen evolution are increased in the mutant. Quantitative proteomic analysis revealed that several proteins in glycolysis and the oxidative pentose phosphate pathway are down-regulated, whereas proteins in photosystem II and phycobilisome are significantly up-regulated, in the mutant. Among the down-regulated proteins are glucose transporter, glucokinase, glucose-6 phosphate isomerase, and glucose-6-phosphate dehydrogenase and its assembly protein OpcA, suggesting that glycolysis, oxidative pentose phosphate, and glycogen synthesis pathways are significantly inhibited in the mutant, which was further confirmed by enzymatic assays and quantification of glycogen content. These findings establish Slr0110 as a novel central regulator of carbon metabolism in Synechocystis, and shed light on an intricate mechanism whereby photosynthesis and carbon metabolism are well concerted to survive the crisis when one or more pathways of the system are impaired. PMID- 24169624 TI - Preoperative evaluation and preparation by anaesthesiologists only, please! PMID- 24169627 TI - Effects of biopolymer encapsulation on trans fatty acid digestibility in an in vitro human digestion system. AB - The purpose of this study was to examine the effects of biopolymer encapsulation on the digestion of trans fatty acids by using an in vitro human digestion model. We simulated the main components of the human digestive system using a dialysis tubing system that contained synthetic saliva, gastric juice, and digestive enzymes of the small intestine. Trans fatty acid-enriched fat was encapsulated with 1% chitosan, pectin, cellulose, and beta-glucan, and passed through the model system. Samples of trans fatty acid-enriched fat that were unencapsulated were more digestible than those that were encapsulated in biopolymers. Moreover, the levels of trans octadecenoic acids (18 : 1t) formed during the digestion of trans fatty acid-enriched fat were decreased upon biopolymer encapsulation. Fat samples enriched with trans fatty acids that were encapsulated with pectin or chitosan had lower free fatty acid contents and lipid oxidation values than unencapsulated control samples. These findings improve our understanding of the effects of biopolymer encapsulation on the digestion of total lipids and trans fatty acids within the gastrointestinal tract. PMID- 24169626 TI - Suicide and suicide attempt after a cancer diagnosis among young individuals. AB - BACKGROUND: Data are scarce on the potential change in suicidal behavior among adolescents and young adults after receiving a cancer diagnosis. PATIENTS AND METHODS: We conducted a population-based cohort study including 7 860 629 Swedes at the age of >=15 during 1987-2009. Among the cohort participants, 12 669 received a first diagnosis of primary cancer between the age of 15 and 30. We measured the relative risks (RRs) of suicidal behavior (defined as completed suicides or suicide attempts) after cancer diagnosis. We also carried out a case crossover study nested within the cohort to adjust for unmeasured confounders. RESULTS: Twenty-two completed suicides (versus 14 expected) and 136 suicide attempts (versus 80 expected) were identified among the cancer patients. The RR of suicidal behavior was 1.6 [95% confidence interval (CI), 1.4-1.9] after a cancer diagnosis, compared with cancer-free individuals. Risk increase was greatest immediately after diagnosis; the RR was 2.5 (95% CI 1.7-3.5) during the first year after diagnosis and was 1.5 (95% CI 1.2-1.8) thereafter. This pattern was similar for completed suicide and suicide attempts. The elevated risks were evident for majority of the main cancer types, except for cancer in thyroid, testis and melanoma. The case-crossover analysis of suicidal behavior during the first year after cancer diagnosis revealed similar results. CONCLUSIONS: Adolescents and young adults receiving a cancer diagnosis are at substantially increased risk of suicidal behavior, particularly during the first year after diagnosis. Although the absolute excess risk is modest, these findings emphasize the need to support and carefully monitor this vulnerable population. PMID- 24169628 TI - Multicenter trials using 18F-fluorodeoxyglucose (FDG) PET to predict chemotherapy response: effects of differential measurement error and bias on power calculations for unselected and enrichment designs. AB - BACKGROUND: Clinical validation of a predictive biomarker is especially difficult when the biomarker cannot be assessed retrospectively. A cost-effective, prospective multicenter replication study with rapid accrual is warranted prior to further validation studies such as a marker-based strategy for treatment selection. However, it is often unknown how measurement error and bias in a multicenter trial will differ from that in single-institution studies. PURPOSE: Power calculations using simulated data may inform the efficient design of a multicenter study to replicate single-institution findings. This case study used serial standardized uptake value (SUV) measures from (18)F-fluorodeoxyglucose (FDG) positron emission tomography (PET) to predict early response to breast cancer neoadjuvant chemotherapy. We examined the impact of accelerating accrual through increased inclusion of secondary sites with greater levels of measurement error and bias. We also examined whether enrichment designs based on breast cancer initial uptake could increase the study power for a fixed budget (200 total scans). METHODS: Reference FDG PET SUV data were selected with replacement from a single-institution trial; pathologic complete response (pCR) data were simulated using a logistic regression model predicting response by mid-therapy percent change in SUV. The impact of increased error for SUV measurements in multicenter trials was simulated by sampling from error and bias distributions: 20%-40% measurement error, 0%-40% bias, and fixed error/bias values. The proportion of patients recruited from secondary sites (with higher additional error/bias compared to primary sites) varied from 25% to 75%. RESULTS: Reference power (from source data with no added error) was 0.92 for N = 100 to detect an association between percentage change in SUV and response. With moderate (20%) simulated measurement error for 3/4, 1/2, and 1/4 of measurements and 40% for the remainder, power was 0.70, 0.61, and 0.53, respectively. Reduction of study power was similar for other manifestations of measurement error (bias as a percentage of true value, absolute error, and absolute bias). Enrichment designs, which recruit additional patients by not conducting a second scan in patients with unsuitable pre-therapy uptake (low baseline SUV), did not lead to greater power for studies constrained to the same total cost. LIMITATIONS: Simulation parameters could be incorrect, or not generalizable. Under a different logistic regression model relating mid-therapy percent change in SUV to pCR (with no relationship for patients with low baseline SUV, rather than the modest point estimate from reference data), the enrichment design did have somewhat greater power than the unselected design. CONCLUSION: Even moderate additional measurement error substantially reduced study power under both unselected and enrichment designs. PMID- 24169629 TI - Synthesis of PDE IV inhibitors. First asymmetric synthesis of two of GlaxoSmithKline's highly potent Rolipram analogues. AB - Asymmetric syntheses of two of GlaxoSmithKline's highly potent phosphodiesterase IV inhibitors CMPI 1 and CMPO 2 have been accomplished from nitroethane and simple precursors in 8 and 7 steps, respectively. The suggested synthetic strategy involves as a key stage the silylation of enantiopure six-membered cyclic nitronates. In vitro studies of PDE IVB1 inhibition revealed a significant difference in the activity of CMPI 1 and CMPO 2 enantiomers. PMID- 24169637 TI - Molecular tailoring: a possible synthetic route to hexasilabenzene. AB - The possible synthesis of hexasilabenzene was studied as the consecutive reaction of three disilyne units in order to find a suitable substituent. Although there is a reaction pathway which leads to hexasilabenzene in the case of hydrogen (A) and phenyl (B) groups, and it is thermodynamically and kinetically favourable, the reaction can easily proceed toward octasila species which makes it impossible to keep the synthesis under control and prepare hexasilabenzene. In contrast to this, using a methylated terphenyl (D) substituent, the addition of the third disilyne unit to the four-membered silicon ring (D5) is highly unfavourable because of the steric hindrance of the substituents. The terphenyl group (C), however, seems to be a perfect substituent because the reaction pathway leading to substituted hexasilabenzene consists of thermodynamically favourable steps and small activation barriers, and further reaction is hindered by the bulky substituents. We suggest synthesizing hexasilabenzene from terphenyl-halosilanes, performing reductive dehalogenation. PMID- 24169630 TI - Role of innate immunity against human papillomavirus (HPV) infections and effect of adjuvants in promoting specific immune response. AB - During the early stages of human papillomavirus (HPV) infections, the innate immune system creates a pro-inflammatory microenvironment by recruiting innate immune cells to eliminate the infected cells, initiating an effective acquired immune response. However, HPV exhibits a wide range of strategies for evading immune-surveillance, generating an anti-inflammatory microenvironment. The administration of new adjuvants, such as TLR (Toll-like receptors) agonists and alpha-galactosylceramide, has been demonstrated to reverse the anti-inflammatory microenvironment by down-regulating a number of adhesion molecules and chemo attractants and activating keratinocytes, dendritic (DC), Langerhans (LC), natural killer (NK) or natural killer T (NKT) cells; thus, promoting a strong specific cytotoxic T cell response. Therefore, these adjuvants show promise for the treatment of HPV generated lesions and may be useful to elucidate the unknown roles of immune cells in the natural history of HPV infection. This review focuses on HPV immune evasion mechanisms and on the proposed response of the innate immune system, suggesting a role for the surrounding pro-inflammatory microenvironment and the NK and NKT cells in the clearance of HPV infections. PMID- 24169638 TI - Fear conditioning, persistence of disruptive behavior and psychopathic traits: an fMRI study. AB - Children diagnosed with Disruptive Behavior Disorders (DBD), especially those with psychopathic traits, are at risk of developing persistent and severe antisocial behavior. Deficient fear conditioning may be a key mechanism underlying persistence, and has been associated with altered regional brain function in adult antisocial populations. In this study, we investigated the associations between the neural correlates of fear conditioning, persistence of childhood-onset DBD during adolescence and psychopathic traits. From a cohort of children arrested before the age of 12 years, participants who were diagnosed with Oppositional Defiant Disorder or Conduct Disorder in previous waves (mean age of onset 6.5 years, s.d. 3.2) were reassessed at mean age 17.6 years (s.d. 1.4) and categorized as persistent (n=25) or desistent (n=25) DBD. Using the Youth Psychopathic Traits Inventory and functional magnetic resonance imaging during a fear conditioning task, these subgroups were compared with 26 matched healthy controls from the same cohort. Both persistent and desistent DBD subgroups were found to show higher activation in fear processing-related brain areas during fear conditioning compared with healthy controls. In addition, regression analyses revealed that impulsive-irresponsible and grandiose manipulative psychopathic traits were associated with higher activation, whereas callous-unemotional psychopathic traits were related to lower activation in fear related areas. Finally, the association between neural activation and DBD subgroup membership was mediated by impulsive-irresponsible psychopathic traits. These results provide evidence for heterogeneity in the neurobiological mechanisms underlying psychopathic traits and antisocial behavior and, as such, underscore the need to develop personalized interventions. PMID- 24169639 TI - N-glycosylation profiling of plasma provides evidence for accelerated physiological aging in post-traumatic stress disorder. AB - The prevalence of age-related diseases is increased in individuals with post traumatic stress disorder (PTSD). However, the underlying biological mechanisms are still unclear. N-glycosylation is an age-dependent process, identified as a biomarker for physiological aging (GlycoAge Test). To investigate whether traumatic stress accelerates the aging process, we analyzed the N-glycosylation profile in n=13 individuals with PTSD, n=9 trauma-exposed individuals and in n=10 low-stress control subjects. Individuals with PTSD and trauma-exposed individuals presented an upward shift in the GlycoAge Test, equivalent to an advancement of the aging process by 15 additional years. Trauma-exposed individuals presented an intermediate N-glycosylation profile positioned between severely traumatized individuals with PTSD and low-stress control subjects. In conclusion, our data suggest that cumulative exposure to traumatic stressors accelerates the process of physiological aging. PMID- 24169641 TI - A few thoughts on measurement issues. PMID- 24169642 TI - Oxygen K-edge electron energy loss spectra of hydrous and anhydrous compounds. AB - First-principles calculations have been employed to examine the possible use of electron energy loss spectroscopy (EELS) as a tool for determining the presence of OH groups and hence hydrogen content in compounds. Our density functional theory (DFT) based calculations describe accurately the experimental EELS results for forsterite (Mg2SiO4), hambergite (Be2BO3(OH)), brucite (Mg(OH)2) and diaspore (alpha-AlOOH). DFT calculations were complemented by an experimental time resolved study of the oxygen K-edge in diaspore. The results show unambiguously that there is no connection between a pre-edge feature in the oxygen K-edge spectrum of diaspore and the presence of OH groups in the structure. Instead, the experimental study shows that the pre-edge feature in diaspore is transient. It can be explained by the presence of molecular O2, which is produced as a result of the electron irradiation. PMID- 24169643 TI - Orientational relaxation in semiflexible dendrimers. AB - The orientational relaxation dynamics of semiflexible dendrimers are theoretically calculated within the framework of optimized Rouse-Zimm formalism. Semiflexibility is modeled through appropriate restrictions in the direction and orientation of the respective bond vectors, while the hydrodynamic interactions are included via the preaveraged Oseen tensor. The time autocorrelation function M(i)(1)(t) and the second order orientational autocorrelation function P(i)(2)(t) are analyzed as a function of the branch-point functionality and the degree of semiflexibility. Our approach of calculating M(i)(1)(t) is completely different from that of the earlier studies (A. Perico and M. Guenza J. Chem. Phys., 1985, 83, 3103; J. Chem. Phys., 1986, 84, 510), where the expression of M(i)(1)(t) obtained from earlier studies does not demarcate the flexible dendrimers from the semiflexible ones. The component of global motion of the time autocorrelation function exhibits a strong dependence on both degree of semiflexibility and branch-point functionality, while the component of pulsation motion depends only on the degree of semiflexibility. But it is difficult to distinguish the difference in the extent of pulsation motion among the compressed (0 < phi < pi/2) and expanded (pi/2 < phi < pi) conformations of semiflexible dendrimers. The qualitative behavior of P(i)(2)(t) obtained from our calculations closely matches with the expression for P(exact)(2)(t) in the earlier studies. Theoretically calculated spectral density, J(omega), is found to depend on the degree of semiflexibility and the branch-point functionality for the compressed and expanded conformations of semiflexible dendrimers as a function of frequency, especially in the high frequency regime, where J(omega) decays with frequency for both compressed and expanded conformations of semiflexible dendrimers. This decay of the spectral density occurs after displaying a cross-over behavior with the variation in the degree of semiflexibility in the intermediate frequency regime. The characteristic area increases with the increase in the semiflexibility parameter, where the expanded conformations of semiflexible dendrimers record the maximum characteristic area. For the compressed conformations the relative increment of this area is considerably lower than that of the expanded conformations of semiflexible dendrimers. PMID- 24169640 TI - Gene expression profiling by mRNA sequencing reveals increased expression of immune/inflammation-related genes in the hippocampus of individuals with schizophrenia. AB - Whole-genome expression profiling in postmortem brain tissue has recently provided insight into the pathophysiology of schizophrenia. Previous microarray and RNA-Seq studies identified several biological processes including synaptic function, mitochondrial function and immune/inflammation response as altered in the cortex of subjects with schizophrenia. Now using RNA-Seq data from the hippocampus, we have identified 144 differentially expressed genes in schizophrenia cases as compared with unaffected controls. Immune/inflammation response was the main biological process over-represented in these genes. The upregulation of several of these genes, IFITM1, IFITM2, IFITM3, APOL1 (Apolipoprotein L1), ADORA2A (adenosine receptor 2A), IGFBP4 and CD163 were validated in the schizophrenia subjects using data from the SNCID database and with quantitative RT-PCR. We identified a co-expression module associated with schizophrenia that includes the majority of differentially expressed genes related to immune/inflammation response as well as with the density of parvalbumin-containing neurons in the hippocampus. The results indicate that abnormal immune/inflammation response in the hippocampus may underlie the pathophysiology of schizophrenia and may be associated with abnormalities in the parvalbumin-containing neurons that lead to the cognitive deficits of the disease. PMID- 24169644 TI - Long-term prognosis of patients with pediatric pheochromocytoma. AB - A third of patients with paraganglial tumors, pheochromocytoma, and paraganglioma, carry germline mutations in one of the susceptibility genes, RET, VHL, NF1, SDHAF2, SDHA, SDHB, SDHC, SDHD, TMEM127, and MAX. Despite increasing importance, data for long-term prognosis are scarce in pediatric presentations. The European-American-Pheochromocytoma-Paraganglioma-Registry, with a total of 2001 patients with confirmed paraganglial tumors, was the platform for this study. Molecular genetic and phenotypic classification and assessment of gene specific long-term outcome with second and/or malignant paraganglial tumors and life expectancy were performed in patients diagnosed at <18 years. Of 177 eligible registrants, 80% had mutations, 49% VHL, 15% SDHB, 10% SDHD, 4% NF1, and one patient each in RET, SDHA, and SDHC. A second primary paraganglial tumor developed in 38% with increasing frequency over time, reaching 50% at 30 years after initial diagnosis. Their prevalence was associated with hereditary disease (P=0.001), particularly in VHL and SDHD mutation carriers (VHL vs others, P=0.001 and SDHD vs others, P=0.042). A total of 16 (9%) patients with hereditary disease had malignant tumors, ten at initial diagnosis and another six during follow-up. The highest prevalence was associated with SDHB (SDHB vs others, P<0.001). Eight patients died (5%), all of whom had germline mutations. Mean life expectancy was 62 years with hereditary disease. Hereditary disease and the underlying germline mutation define the long-term prognosis of pediatric patients in terms of prevalence and time of second primaries, malignant transformation, and survival. Based on these data, gene-adjusted, specific surveillance guidelines can help effective preventive medicine. PMID- 24169645 TI - Special section on fluorescence molecular imaging honoring Prof. Roger Tsien, a pioneer in biomedical optics. PMID- 24169646 TI - Sex-linked and autosomal microsatellites provide new insights into island populations of the tammar wallaby. AB - The emerging availability of microsatellite markers from mammalian sex chromosomes provides opportunities to investigate both male- and female-mediated gene flow in wild populations, identifying patterns not apparent from the analysis of autosomal markers alone. Tammar wallabies (Macropus eugenii), once spread over the southern mainland, have been isolated on several islands off the Western Australian and South Australian coastlines for between 10,000 and 13,000 years. Here, we combine analyses of autosomal, Y-linked and X-linked microsatellite loci to investigate genetic variation in populations of this species on two islands (Kangaroo Island, South Australia and Garden Island, Western Australia). All measures of diversity were higher for the larger Kangaroo Island population, in which genetic variation was lowest at Y-linked markers and highest at autosomal markers (theta=3.291, 1.208 and 0.627 for autosomal, X linked and Y-linked data, respectively). Greater relatedness among females than males provides evidence for male-biased dispersal in this population, while sex linked markers identified genetic lineages not apparent from autosomal data alone. Overall genetic diversity in the Garden Island population was low, especially on the Y chromosome where most males shared a common haplotype, and we observed high levels of inbreeding and relatedness among individuals. Our findings highlight the utility of this approach for management actions, such as the selection of animals for translocation or captive breeding, and the ecological insights that may be gained by combining analyses of microsatellite markers on sex chromosomes with those derived from autosomes. PMID- 24169647 TI - Indirect genetic effects and kin recognition: estimating IGEs when interactions differ between kin and strangers. AB - Social interactions among individuals are widespread, both in natural and domestic populations. As a result, trait values of individuals may be affected by genes in other individuals, a phenomenon known as indirect genetic effects (IGEs). IGEs can be estimated using linear mixed models. The traditional IGE model assumes that an individual interacts equally with all its partners, whether kin or strangers. There is abundant evidence, however, that individuals behave differently towards kin as compared with strangers, which agrees with predictions from kin-selection theory. With a mix of kin and strangers, therefore, IGEs estimated from a traditional model may be incorrect, and selection based on those estimates will be suboptimal. Here we investigate whether genetic parameters for IGEs are statistically identifiable in group-structured populations when IGEs differ between kin and strangers, and develop models to estimate such parameters. First, we extend the definition of total breeding value and total heritable variance to cases where IGEs depend on relatedness. Next, we show that the full set of genetic parameters is not identifiable when IGEs differ between kin and strangers. Subsequently, we present a reduced model that yields estimates of the total heritable effects on kin, on non-kin and on all social partners of an individual, as well as the total heritable variance for response to selection. Finally we discuss the consequences of analysing data in which IGEs depend on relatedness using a traditional IGE model, and investigate group structures that may allow estimation of the full set of genetic parameters when IGEs depend on kin. PMID- 24169648 TI - Molecular evidence that the genes for dioecism and monoecism in Spinacia oleracea L. are located at different loci in a chromosomal region. AB - Spinach (Spinacia oleracea L.) is widely known to be dioecious. However, monoecious plants can also occur in this species. Sex expression in dioecious spinach plants is controlled by a single gene pair termed X and Y. Our previous study showed that a single, incompletely dominant gene, which controls the monoecious condition in spinach line 03-336, should be allelic or linked to X/Y. Here, we developed 19 AFLP markers closely linked to the monoecious gene. The AFLP markers were mapped to a 38.2-cM chromosomal region that included the monoecious gene, which is bracketed between flanking markers with a distance of 7.1 cM. The four AFLP markers developed in our studies were converted into sequence-characterized amplified region (SCAR) markers, which are linked to both the monoecious gene and Y and are common to both populations segregating for the genes. Linkage analysis using the SCAR markers suggested that the monoecious gene (M) and Y are located in different intervals, between different marker pairs. Analysis of populations segregating for both M and Y also directly demonstrates linkage of the genes at a distance of ~12 cM. The data presented in this study may be useful for breeding dioecious and highly male monoecious lines utilized as the pollen parents for hybrid seed production, as well as for studies of the evolutionary history of sexual systems in this species, and can provide a molecular basis for positional cloning of the sex-determining genes. PMID- 24169650 TI - Long-term outcome of primary endoresection of choroidal melanoma. AB - BACKGROUND: Endoresection of choroidal melanoma may offer the best hope of conserving vision in some patients but is controversial because of concerns regarding iatrogenic tumour dissemination. METHODS: Retrospective, non-randomised study of consecutive patients who underwent endoresection for choroidal melanoma at the Liverpool Ocular Oncology Centre between 1996 and 2010. RESULTS: The study included 71 patients with a mean age of 58.7 years. The tumour extended within 2 disc diameters of the optic disc in 46 (65%) eyes, involving the disc in 24 (34%) eyes. The mean largest basal tumour diameter and tumour thickness were 9.5 mm and 4.4 mm, respectively. The median follow-up was 4.1 years. The visual acuity at the latest follow-up was better than 6/30 in 31% eyes. The main causes of visual loss were foveal excision, rhegmatogenous retinal detachment (RD) and proliferative vitreo-retinopathy (PVR). Local recurrence developed in two patients (3%), who were treated by enucleation and proton beam radiotherapy, respectively. RD occurred in 16 cases (22%). Three (4%) eyes were enucleated, two because of PVR and one because of local tumour recurrence. Five patients died of metastatic disease. CONCLUSIONS: Endoresection achieved high rates of local tumour control. This operation would seem to be a useful alternative to radiotherapy as a means of conserving vision in eyes with juxtapapillary melanoma. PMID- 24169649 TI - Genome-wide profiling is a clinically relevant and affordable prognostic test in posterior uveal melanoma. AB - OBJECTIVE: This study investigated the capacity of genetic analysis of uveal melanoma samples to identify high-risk patients and discusses its clinical implications. METHODS: Patients with posterior uveal melanoma were prospectively enrolled. Tumour samples were derived from enucleated globe, fine-needle aspirates or endoresection. Chromosome 3 and 8 status was determined by array comparative genomic hybridisation (array-CGH). Patients were followed after treatment to detect metastasis. RESULTS: Four groups were classified by array CGH. Patients were divided into disomy 3 and normal chromosome 8 (D3/8nl), disomy 3 and 8q gain (D3/8g), monosomy 3 and normal chromosome 8 (M3/8nl) and monosomy 3 and 8 or 8q gain (M3/8g). Median follow-up was 28 months (range: 1-147 months). At the end of the study, 128 patients (33.7%) had developed metastasis and 96 patients had died. Univariate Cox proportional hazard analysis showed that factors associated with metastasis included basal tumour diameter p=0.0007, tumour thickness p=0.01, mixed/epithelioid cell type p=0.0009 and genomic data p<0.0001. High-risk profile was more strongly associated with metastasis than the other prognostic factors p<0.001. Multivariate Cox modelling analysis showed that the status of chromosomes 3 and 8 were the only two variables that independently contributed to prognosis: monosomy 3 alone p=0.001 and monosomy 3 and 8q gain p<0.0001. CONCLUSIONS: Array-CGH allowed identification of three prognostic groups with low, intermediate and high risk of developing metastasis. Array-CGH is a reliable and inexpensive method for uveal melanoma prognosis. This method is now currently used in France. PMID- 24169651 TI - Local tumour control and eye preservation after gamma-knife radiosurgery of choroidal melanomas. AB - BACKGROUND/AIMS: To report on local tumour control and eye preservation after gamma knife radiosurgery (GK-RS) to treat choroidal melanomas. METHODS: A total of 189 patients with choroidal melanoma were treated with GK-RS, with treatment doses between 25 and 80 Grays. The main outcome measures of our retrospective analysis were local tumour control, time to recurrence, eye retention rate and the reason for and time to secondary enucleation. Patient-associated, tumour associated and treatment-associated parameters were evaluated as potential risk factors. RESULTS: Local tumour control was achieved in 94.4% of patients. The estimated tumour control rates were 97.6% at 1 year, 94.2% at 5 years and 92.4% at 10 years after treatment. Recurrence was observed between 3.1 months and 60.7 months post-treatment (median: 13.5 months). Advanced tumour stage (Tumour, Node, Metastasis (TNM) 3-4) was the most important risk factor for recurrence (Fine Gray model; subhazard ratio, SHR: 3.3; p=0.079). The treatment dose was not related to tumour recurrence. The eye preservation rate was 81.6% at 5 years after treatment, remaining stable thereafter. Twenty-five eyes (14.1%) had to be enucleated at between 17 days and 68.0 months (median: 13.9 months) after GK-RS, and advanced tumour stage (Cox model; p=0.005), treatment dose (p=0.048), pretreatment visual acuity (p=0.016), and retinal detachment (p=0.027) were risk factors for requiring enucleation. CONCLUSIONS: GK-RS achieved a high tumour control rate, comparable to linear accelerator-based radiotherapy. Advanced TNM stage was a predictive risk factor for tumour recurrence and for secondary enucleation after GK-RS. Lower treatment doses were unrelated to tumour recurrence, although they were associated with an improved eye retention rate. PMID- 24169652 TI - Increased risk of coronary heart disease in male patients with central serous chorioretinopathy: results of a population-based cohort study. AB - AIMS: To investigate whether patients with central serous chorioretinopathy (CSCR) have increased risk of coronary heart disease (CHD). METHODS: Population based retrospective cohort and case control study. Longitudinal data from the Taiwan National Health Insurance Research Database (2000-2009) were analysed. The study cohort comprised 835 patients with a diagnosis of CSCR and 4175 age and gender matched patients without CSCR. Kaplan-Meier plots and log-rank tests were used to compare differences in the hazard rates of CHD between the CSCR and non CSCR cohorts. Stratified Cox proportional hazard models were applied to examine the association between CSCR and CHD, adjusting for potential confounding factors. RESULTS: The 5-year CHD cumulative incidence for patients with CSCR was nearly twofold that of the non-CSCR cohort (6.12% vs 3.29%, p=0.004) from the log rank test. The adjusted CHD HR of CSCR versus non-CSCR was 1.61 (95% CI 1.12 to 2.30, p=0.009) from the Cox model. Specifically, the HR for male patients was 1.72 (95% CI 1.14 to 2.59, p=0.010) and for female patients it was 1.34 (95% CI 0.64 to 2.84, p=0.438). CONCLUSIONS: Male patients with CSCR had a significantly higher CHD rate than those without CSCR, indicating that CSCR may be a potential risk factor for the development of CHD for men. PMID- 24169653 TI - Volumetric assessment of the space between the posterior hyaloid and internal limiting membrane using SD-OCT. AB - The purpose of this study was to measure, for clinical and surgical utility, the distance between the posterior hyaloid and the internal limiting membrane using a spectral domain optical-coherence tomography (SD-OCT) device. Eight eyes of eight patients with subclinical partial posterior vitreous detachment (PPVD) with vitreomacular traction syndrome were examined with SD-OCT. To quantify the vitreoretinal distance, the basic applications of SD-OCT (Spectralis HRA+OCT Heidelberg Engineering) were modified. We conducted a topographic study of the entire posterior pole by defining new maps, each generated from 19 raster scans. We obtained maps that represent the space between the residual vitreous and retina, expressed numerically and on a colour spectrum, and overlapped them on a posterior pole photograph. We also created a single map of the entire posterior pole. The mean PPVD volume in the eight eyes was 104.87+/-5.25 mm(3). This study produced detailed maps of the vitreoretinal distance, which may facilitate the study of the clinical progression of PPVD. In case of surgery the maps may help to accurately determine where surgical manipulation is needed safely apart from the retina. These maps could also assist in the assessment of pharmacological vitreolysis efficacy. PMID- 24169654 TI - Management of patients with uveal metastases at the Liverpool Ocular Oncology Centre. AB - BACKGROUND: Uveal metastasis is the most common intraocular malignancy. METHODS: This was a retrospective study of all patients with uveal metastases referred to the Liverpool Ocular Oncology Centre between January 2007 and December 2012. Biopsy was performed as a primary investigation if the clinical examination suggested metastasis with no evidence of any extraocular metastases. RESULTS: Ninety-six patients (109 eyes) were included. Breast and lung carcinomas were the most common primary malignancies, affecting 41 and 27 patients, respectively. The median time interval between detection of primary cancer and uveal metastasis was 24 months (range 1-288 months). Thirty-nine patients underwent ocular biopsy, confirming the diagnosis in all patients. The biopsy indicated the site of origin in 24 out of the 27 without a known primary tumour. In 7 of these 27 cases, previous systemic investigations had failed to identify the primary tumour. Seventy-three patients received external beam irradiation; two patients received photodynamic therapy; and two patients had Ru-106 plaque radiotherapy. The visual acuity was stable or improved in 75.5% of the cases. CONCLUSIONS: Immediate biopsy provides a quick diagnosis that may expedite treatment and improve any opportunities for conserving vision while facilitating the general oncologic management on these patients. PMID- 24169655 TI - Rotation of retinal vascular arcades and comparison with disc-fovea angle in the assessment of cycloposition. AB - BACKGROUND/AIMS: To assess the agreement between disc-fovea angle (DFA) and the retinal vascular arcades rotation to measure cycloposition. Device repeatability and reproducibility between observers were also evaluated. METHODS: Cycloplegic retinography was taken in 321 eyes of 165 normal patients and repeated in 18 eyes at least 24 h later. Two independent observers used software to determine DFA, vein-related angle (VRA) and artery-related angle (ARA) in every retinography. Mean value of related angle (MRA) (mean value of VRA and ARA) was calculated. RESULTS: Camera repeatability was good (Intra-class Correlation Coefficient, ICC 0.89). In Bland-Altman analysis, mean VRA, ARA and MRA were 4 degrees to 5 degrees different from DFA (p<0.01). There was poor correlation between DFA and other methods (ICC): DFA versus VRA 0.3, versus ARA 0.4, versus MRA 0.5. Reliability between observers was good in all methods. The multivariate analysis showed no interaction between each method and eye side, sex or observer (p>0.05). CONCLUSIONS: The rotation of retinal vascular arcades using a first-order approximation technique is no substitute to DFA when assessing torsion in fundus photographs. Of the methods tested, MRA correlated most closely, but DFA remains the gold standard for cycloposition. The rotation of vascular arcades provides a qualitative assessment, particularly in uncertain macular location. PMID- 24169656 TI - Visual and anatomical outcome after macular buckling for macular hole with associated foveoschisis in highly myopic eyes. AB - BACKGROUND: Macular hole (MH) with associated foveoschisis is very specific to highly myopic eyes with a pronounced posterior staphyloma. A high axial length increases the risk of foveoschisis, MH formation and retinal detachment secondary to a macular hole (MHRD). These highly myopic MH show poor surgical outcomes after vitrectomy and internal limiting membrane peeling compared with non-myopic MH. The posterior staphyloma seems to play an important role, and thus macular buckling could prove useful to improve both visual and anatomical results. METHODS: Sixteen highly myopic eyes with MH and associated foveoschisis that underwent macular buckling were studied. Vitrectomy combined with macular buckling was performed in all 16 eyes. Optical coherence tomography was performed to confirm MH closure in all cases. RESULTS: Combined vitrectomy and macular buckling resulted in MH closure in all patients. Best-corrected visual acuity (BCVA) improved in 13 out of 16 eyes (81.25%), remained stable in 2 eyes (12.5%) and worsened in 1 eye (6.25%). Mean preoperative BCVA was 20/125, whereas mean postoperative BCVA was 20/50. CONCLUSIONS: Combined vitrectomy and macular buckling is a safe and effective approach to achieve primary closure of MH in eyes with posterior staphyloma and associated foveoschisis. Eyes with a high axial length show a less favourable prognosis, which can be partially overcome by means of macular buckling. PMID- 24169657 TI - Defocus Incorporated Soft Contact (DISC) lens slows myopia progression in Hong Kong Chinese schoolchildren: a 2-year randomised clinical trial. AB - AIMS: To determine if 'Defocus Incorporated Soft Contact' (DISC) lens wear slows childhood myopia progression. METHODS: A 2-year double-blind randomised controlled trial was carried out in 221 children aged 8-13 years, with myopia between -1.00 and -5.00 Dioptres (D) and astigmatism <=1.00 D. Subjects were randomly assigned to the DISC (n=111) or single vision (SV; n=110) contact lens group. DISC lenses incorporated concentric rings, which provided an addition of +2.50 D, alternating with the normal distance correction. Refractive error (cycloplegic autorefraction) and axial length were measured at 6-month intervals. Differences between groups were analysed using unpaired t test. RESULTS: In total, 128 children completed the study, n=65 in the DISC group and n=63 in the SV group. Myopia progressed 25% more slowly for children in the DISC group compared with those in the control group (0.30 D/year; 95% CI -0.71 to -0.47 vs 0.4 D/year; 95% CI -0.93 to -0.65, p=0.031). Likewise, there was less axial elongation for children in the DISC versus SV groups (0.13 mm/year; 95% CI 0.20 to 0.31 vs 0.18 mm/year; 95% CI 0.30 to 0.43, p=0.009). Treatment effect correlated positively with DISC lens wearing time (r=0.342; p=0.005). Indeed, myopia in children who wore the DISC lenses for five or more hours/day progressed 46% (mean difference=-0.382 D, p=0.001; 95% CI -0.59 to -0.17) less than those in the SV group. CONCLUSIONS: The daily wearing of DISC lens significantly slowed myopia progression and axial elongation in Hong Kong schoolchildren. The findings demonstrated that simultaneous clear vision with constant myopic defocus can retard myopia progression. PMID- 24169658 TI - Correlation between visual acuity and cognitive functions. AB - A possible association between visual acuity (VA) and dementia was investigated in 2716 subjects who were aged between 53 and 102 at first visit and had varying degrees of dementia. Better VA was found to be significantly correlated with a lower dementia level (person coefficient range 0.146-0.261 over 10 years of follow-up, all correlations are significant, p<0.0001) as well as with a higher global cognitive score (person coefficient range -0.254 to -0.318 over 10 years of follow-up, all correlations are significant, p<0.0001), a grade encompassing 19 different cognitive tests. This correlation remained significant after adjustment for age, years of education, gender, use of ophthalmic drugs and years of follow-up. PMID- 24169660 TI - Homologous recombination mediated by two palindromic repeated sequences in the mitochondrial genome of Oryza. AB - Palindromic repeated sequences (PRSs) are distributed in at least ten regions of the mitochondrial (mt) genome of rice and are, apparently, mobile. In the present study, we examined the possibility of homologous recombination via some PRSs during the course of evolution of Oryza. We first performed Southern hybridization of the DNA from 11 species (18 strains) of Oryza in order to identify the distribution of PRSs in the mitochondrial genome of Oryza. The hybridization patterns revealed genome type-specific and/or species-specific variations. We speculated that homologous recombination via some PRSs might have made a contribution to such variations. After subsequent polymerase chain reaction, Southern hybridization and sequencing, we concluded that homologous recombination mediated by two PRSs occurred in the mtDNA of Oryza after divergence of the BB genome type and the other genome types of Oryza. Evidence was obtained that some PRSs were involved in both insertion and recombination events during the evolution of Oryza. Our results indicate, therefore, that PRSs have contributed considerably to the polymorphism of Oryza mtDNAs. PMID- 24169659 TI - Baiji genomes reveal low genetic variability and new insights into secondary aquatic adaptations. AB - The baiji, or Yangtze River dolphin (Lipotes vexillifer), is a flagship species for the conservation of aquatic animals and ecosystems in the Yangtze River of China; however, this species has now been recognized as functionally extinct. Here we report a high-quality draft genome and three re-sequenced genomes of L. vexillifer using Illumina short-read sequencing technology. Comparative genomic analyses reveal that cetaceans have a slow molecular clock and molecular adaptations to their aquatic lifestyle. We also find a significantly lower number of heterozygous single nucleotide polymorphisms in the baiji compared to all other mammalian genomes reported thus far. A reconstruction of the demographic history of the baiji indicates that a bottleneck occurred near the end of the last deglaciation, a time coinciding with a rapid decrease in temperature and the rise of eustatic sea level. PMID- 24169661 TI - Development of a PCR-based marker to identify rice blast resistance gene, Pi 2(t), in a segregating population. AB - The genomic clone RG64, which is tightly linked to the blast resistance gene Pi 2(t) in rice, provides means to perform marker-aided selection in a rice breeding program. The objective of this study was to investigate the possibility of generating a polymerase chain reaction (PCR)-based polymorphic marker that can distinguish the blast resistant gene, Pi-2(t), and susceptible genotypes within cultivated rice. RG64 was sequenced, and the sequence data was used to design pairs of specific primers for (PCR) amplification of genomic DNA from rice varieties differing in their blast disease responsiveness. The amplified products, known as sequenced-tagged-sites (STSs), were not polymorphic between the three varieties examined. However, cleavage of the amplified products with the restriction enzyme HaeIII generated a polymorphic fragment, known as specific amplicon polymorphism (SAP), between the resistant and the susceptible genotypes. To examine the power of the identified SAP marker in predicting the genotype of the Pi-2 (t) locus, we determined the genotypes of the F2 individuals at this locus by performing progeny testing for the disease response in the F3 generation. The results indicated an accuracy of more than 95% in identifying the resistant plants, which was similar to that using RG64 as the hybridization probe. The identification of the resistant homozygous plants increased to 100% when the markers flanking the genes were considered simultaneously. These results demonstrate the utility of SAP markers as simple and yet reliable landmarks for use in marker-assisted selection and breeding within cultivated rice. PMID- 24169662 TI - Application of approximate variances of variance components and their ratios in genetic tests. AB - The application and underlying assumptions of formulae used to estimate the variance of variance components and ratios of variance components are fully described for (1) variance components estimated using Henderson's Method 3 (HM3) and Restricted Maximum Likelihood (REML) and (2) ratios of variance components commonly used in genetic tests - biased and unbiased heritabilities. A first order Taylor series approximation is often used to estimate the variance of a ratio of two random variables (e.g., heritability), however the formula is complicated, thus making calculations prone to errors. Dickerson's approximation is considerably simpler, though relatively rarely used. In case studies using data from 148 slash pine full-sib progeny tests, Dickerson's method was found to be slightly more conservative than the Taylor series approximation when estimating the variance of heritability estimates, regardless of test size, age, or the trait (volume, which is a continuous trait, and rust resistance, which is a bernoulli trait). Both the Taylor series and Dickerson approximations compared favorably with an empirical estimate of the variance of heritability estimates, however there is some evidence of small-sample bias associated with the use of the asymptotic variance-covariances from REML variance component estimation. PMID- 24169663 TI - The Rp3 disease resistance gene of maize: mapping and characterization of introgressed alleles. AB - The Rp3 locus of maize conditions race-specific resistance to a fungal rust pathogen, Puccinia sorghi. Both morphological and DNA markers were employed to characterize alleles of Rp3 and to accurately position Rp3 on the maize genetic map. DNA marker polymorphisms distinctive to each Rp3 allele were identified, allowing the identification of specific Rp3 alleles in cases where rust races that differentiate particular alleles are not available. In a population of 427 progeny, Rp3 and Rg1 were found to be completely linked, while Lg3 was approximately 3 cM proximal on the long arm of chromosome 3. In this same population, 12 RFLP markers were mapped relative to Rp3; the closest markers were UMC102 (about 1cM distal to Rp1) and NPI114 (1-2 cM proximal). These and additional DNA probes were used to characterize the nature and extent of flanking DNA that was carried along when six different Rp3 alleles were backcrossed into a single background. Depending upon the allele investigated, a minimum of 2-10cM of polymorphic DNA flanking the Rp3 locus was retained through the introgression process. In addition, many of the probes that map near Rp3 were found to detect an additional fragment in the Rp3 region, indicating that portions of this chromosomal segment have been tendemly duplicated. The materials and results generated will permit marker-assisted entry of Rp3 into different maize backgrounds and lay the foundation for the eventual map-based cloning of Rp3. PMID- 24169664 TI - Genotype-by-environment interaction in genetic mapping of multiple quantitative trait loci. AB - The interval mapping method is widely used for the genetic mapping of quantitative trait loci (QTLs), though true resolution of quantitative variation into QTLs is hampered with this method. Separation of QTLs is troublesome, because single-QTL is models are fitted. Further, genotype-by-environment interaction, which is of great importance in many quantitative traits, can only be approached by separately analyzing the data collected in multiple environments. Here, we demonstrate for the first time a novel analytic approach (MQM mapping) that accommodates both the mapping of multiple QTLs and genotype-by environment interaction. MQM mapping is compared to interval mapping in the mapping of QTLs for flowering time in Arabidopsis thaliana under various photoperiod and vernalization conditions. PMID- 24169665 TI - Genetic analysis of heat shock proteins in maize. AB - A genetic analysis of heat shock protein (HSP) synthesis was performed in seedling leaf tissue of two maize inbred lines, their F1 hybrid and F2 progeny. Protein synthesis following a high temperature treatment was visualized by [(35)S]-methionine in vivo labelling and two-dimensional gel electrophoresis. The parental lines' HSP synthesis patterns revealed both qualitative and quantitative polymorphisms implicative of differences in HSP structural genes and regulatory factors. The F1 hybrid HSP profile indicated that synthesis of all parental HSPs conformed to dominant inheritance patterns, including complete dominance, over dominance and co-dominance. Alleles for six low-molecularweight HSPs in F2 progeny assorted according to typical 3?1 Mendelian ratios for dominant gene expression. There is evidence for unlinked gene loci of four different HSP gene pairs, but data for three other HSP gene pairs were inconclusive, perhaps reflecting linkage for one pair and complex regulatory factor interactions for the other two pairs of genes. These results clearly indicate the existence of genetic variability in HSP synthesis and emphasize the potential of partitioning their roles in thermal tolerance using genetic and molecular analyses. PMID- 24169666 TI - Characterization and analysis of simple sequence repeat (SSR) loci in seashore paspalum (Paspalum vaginatum Swartz). AB - A size-fractionated TaqI genomic library of seashore paspalum (Paspalum vaginatum Swartz) was screened for the presence of (GA) n and (CA) n simple sequence repeats (SSRs). A total of 54 clones with a positive signal were detected among 13,000 clones screened. Forty-seven clones having repeats of n[Symbol: see text] 3 were identified, of which 85% were perfect, 13% were imperfect and 2% were compound repeat sequences. Five of ten primer pairs synthesized to amplify selected loci resulted in a product in the expected size range and were subsequently used to examine SSR polymorphisms among 46 ecotypes of P. vaginatum. The number of alleles resolved on agarose or polyacrylamide gels were similar and ranged from 6 to 16 with an average of 14 per locus. Phenetic analysis of SSR polymorphisms revealed genetic relationships among the P. vaginatum ecotypes that were in general agreement with relationships determined previously by RAPD analysis of the same plant materials. Further screening of the genomic library did not identify (AT) n , trimeric or tetrameric repeats. Hybridization of an (ATT)8 oligonucleotide probe to genomic DNA isolated from I. batatas, E. coli, Citrullis lanatus and P. vaginatum suggested that the P. vaginatum genome contained significantly fewer ATT repeats than either the I. batatas or C. lanatus genome. PMID- 24169667 TI - Quantitative trait analysis of fruit quality in cucumber: QTL detection, confirmation, and comparison with mating-design variation. AB - A cross within C. sativus var. sativus (GY14 x P1432860) and molecular markers were used to determine the number, magnitudes of effect, and overall variation described for genes conditioning the quantitatively inherited traits of length, diameter, seed-cavity size, color, L/D (length/diameter), and S/D (seed-cavity size/diameter). QTL effects were detected with MAPMAKER/QTL using 100 F3 lines evaluated in a replicated field trial of two harvests over 2 years at one location. Multilocus models were constructed by fixing significant intervals and re-scanning using MAPMAKER/ QTL. Marker inclusion in multilocus models was compared to an ANOVA "backward elimination" procedure. Generally the same loci were associated with QTLs among the two methods of model construction. Heritabilities of individual QTLs were confirmed by analysis of related backcrosses (67 BC1P1 lines and 68 BC1 P2 lines). The majority of QTLs were confirmed in at least one backcross population. Pairs of backcrosses allowed overall additive variances and heritabilities to be calculated using a North Carolina Design III (NCIII design) and estimates were compared to overall variances attributable to markers. Heritability estimates using markers were comparable, but generally lower than additive variances estimated by co-variance relationships in the NCIII design. This suggests that neither the number nor the magnitude of QTL effects were overestimated. The utility of backcrosses to confirm individual QTLs and the overall variance described by QTLs is recommended to avoid false positives and over-estimation of effects. The number of QTLs, and/or the proportions of phenotypic variation described by markers and the mating design, agreed with previous reports of heritabilities employing similar germplasm. PMID- 24169668 TI - Comparison of rapeseed cultivars and resynthesized lines based on allozyme and RFLP markers. AB - It has frequently been suggested to use the resynthesis of rapeseed (Brassica napus) from B. campestris and B. oleracea to broaden its genetic base. The objective of the present study is twofold: (1) to compare the genetic variation within resynthesized rapeseed with a world-wide collection of oilseed rape cultivars, and (2) to compare genetic distances estimated from RFLP markers with distances estimated from a relatively small number of allozyme markers. We investigated 17 resynthesized lines and 24 rapeseed cultivars. Genetic distances were estimated either based on the electrophoresis of seven allozymes, with a total of 38 different bands, or based on RFLP data of 51 probe/enzyme combinations, with a total of 355 different bands. The results of allozyme and RFLP analyses agreed reasonably well. Genetic distances, estimated from two independent sets of RFLP data with 25 and 26 probe/enzyme combinations respectively, were highly correlated; hence about 50 RFLP markers are sufficient to characterize rapeseed material with a large genetic diversity. The cultivars were clustered into three groups: (1) spring rapeseed of European and Northern American origin, (2) winter rapeseed of European and Northern American origin, and (3) rapeseed of Asian origin. Several of the resynthesized rapeseed lines were similar to European winter rapeseed cultivars, whereas others had quite unique patterns. It is concluded, that resynthesized rapeseed is a valuable source for broadening the genetic variation in present breeding material of Brassica napus. However, different lines differ widely in their suitability for this purpose. PMID- 24169669 TI - DNA markers tightly linked to a gall midge resistance gene (Gm2) are potentially useful for marker-aided selection in rice breeding. AB - We have developed a polymerase chain reaction (PCR)-based assay that could effectively reduce the time period required to screen and select for Gall Midgeresistant rice lines under field conditions. The primers for the assay were designed on the basis of sequence information of two phenotype specific random amplified polymorphic DNA fragments which were found to be tightly linked to Gall Midge biotype-1 resistance gene (Gm2). The two RAPD fragments, F81700 in the susceptible parent 'ARC6650' and F10600 in the resistant parent 'Phalguna', were identified after screening 5450 loci using 520 random primers on genomic DNAs of 'ARC6650' and 'Phalguna'. These primers, when used in a multiplexed PCR, amplified specifically a 1.7-kb and 0.6-kb fragment in the susceptible and resistant parents, respectively. When this assay was performed on genomic DNAs of 44 recombinant inbred lines derived from 'ARC6650' x 'Phalguna' and 5 lines derived from other crosses where one of the parents was 'Phalguna', 'ARC6650' or their derivatives, the primers amplified a 1.7-kb fragment in all of the susceptible lines or a 0.6-kb fragment in all of the resistant ones. These markers can be of potential use in the marker-aided selection of Gall Midge biotype-1 resistant phenotypes. As screening for resistance can now be conducted independent of the availability of insects, the breeding of resistant varieties can be hastened. PMID- 24169670 TI - Mapping dominant markers using F2 matings. AB - The development of efficient methods for amplifying random DNA sequences by the polymerase chain reaction has created the basis for mapping virtually unlimited numbers of mixed-phase dominant DNA markers in one population. Although dominant markers can be efficiently mapped using many different kinds of matings, recombination frequencies and locus orders are often mis-estimated from repulsion F2 matings. The major problem with these matings, apart from excessive sampling errors of recombination frequency (theta) estimates, is the bias of the maximum likelihood estimator (MLE) of theta (theta ML). [Formula: see text] when the observed frequency of double-recessive phenotypes is 0 and the observed frequency of double-dominant phenotypes is less than 2/3 - the bias for those samples is - theta. We used simulation to estimate the mean bias of theta ML. Mean bias is a function of n and theta and decreases as n increases. Valid maps of dominant markers can be built by using sub-sets of markers linked in coupling, thereby creating male and feamle coupling maps, as long as the maps are fairly dense (about 5 cM) - the sampling errors of theta increase as theta increases for coupling linkages and are equal to those for backcross matings when theta=0. The use of F2 matings for mapping dominant markers is not necessarily proscribed because they yield twice as many useful markers as a backcross population, albeit in two maps, for the same number of DNA extractions and PCR assays; however, dominant markers can be more effeciently exploited by using doubled-haploid, recombinant-inbred, or other inbred populations. PMID- 24169671 TI - Geographical distribution of genes for resistance to formae speciales of Erysiphe graminis in common wheat. AB - The geographical distribution of Pm10, Pm11, Pm14, and Pm15 wheat genes for resistance to inappropriate formae speciales of Erysiphe graminis was investigated using gene-for-gene relationships. Pm10 and Pm15 were very common among many indigenous accessions of common wheat collected from various areas in the world. The diversity of genotypes, which consisted of allelic combination at those loci, was high near the center of origin of common wheat and decreased with increasing distance from the center. In Europe, an apparent contrast of predominant genotypes occurred between the south and the north, suggesting that these genes are useful markers for revealing the routes by which common wheat spread in Europe. On a whole, the genes for resistance to inappropriate formae speciales were observed to be widely distributed throughout the world. We suggest that the difference between these genes and the genes for resistance to races of an appropriate forma specialis may only be in their distribution and that of their corresponding avirulence genes. PMID- 24169672 TI - Infraspecific differentiation of garlic (Allium sativum L.) by isozyme and RAPD markers. AB - Garlic (Allium sativum L.) is a sterile species of considerable variability with respect to morphological and physiological features. The crop presumably originated in West to Middle Asia from its progenitor A. longicuspis Regel and was transported from there to the Mediterranean and other areas of cultivation. In order to clarify older classification schemes, often based on small or biased collections, we used isozyme and RAPD markers to analyze and structure a collection of 300 accessions, many of which were gathered in Middle Asia close to the assumed center of origin. All of the accessions were first investigated with isozymes, and 48 were selected for a RAPD analysis. The resulting molecular markers were used to construct neighbor-joining dendrograms to group the accessions and to indicate the genetic distances between them. Based on the dendrograms and in conjunction with some morphological features, we propose an infraspecific classification of garlic with four major groups. In agreement with the results of other workers, A. longicuspis lies within the range of the species A. sativum. Numerous forms with varying degrees of domestication are part of our longicuspis group, from which presumably the more derived cultivar groups originated. The origin and spreading of the crop are discussed with respect to the geographical distribution and the genetic distances of the accessions. PMID- 24169673 TI - Heterozygosity in 2n gametes of potato evaluated by RFLP markers. AB - The heterozygosity transmitted through 2n gametes in potato was evaluated by following the segregation of RFLP markers in tetraploid progeny from bilateral sexual polyploidization in a cross between two diploid (2x) interspecific hybrids which produce 2n SDR eggs or 2n FDR pollen. Out of 84 probe/enzyme combinations tested, 23 revealed polymorphism between the parents and were heterozygous in at least one of the parents. These probes characterized 13 loci distributed on five different chromosomes of the potato RFLP map. The heterozygosity transmitted through SDR and FDR gametes was estimated to be 31.8% and 71.4%, respectively. Two different indices (LH and RHI) were used to select plants showing a high level of heterozygosity in the tetraploid progeny. The recombination events and the centromere positions were estimated for chromosomes I, VI and VII, following the segregation ratios of SDR or FDR gametes produced by the parents. A different recombination rate was observed between the two interspecific hybrids. PMID- 24169674 TI - Chromosome structure of Triticum longissimum relative to wheat. AB - Homoeologous pairing at meiotic metaphase I was analyzed in T. longissimum x T. aestivum hybrids in order to reconfirm the homoeologous relationships of T. longissimum chromosomes to wheat. Hybrids between T. longissimum and 'Chinese Spring' carrying the Ph1 gene or theph1b mutation, which showed low and high pairing levels, respectively, were used. Chromosome arms associated at metaphase I were identified by C-banding. The homoeology of chromosomes 1S (l) , 2S (l) , 3S (l) , 5S (l) and 6S (l) to wheat group 1,2, 3, 5, and 6 chromosomes, respectively, was confirmed. Chromsome arms 4S (l) S and 7S (l) S showed normal homoeologous relationships to wheat. The 4S (l) L arm carries a translocated segment from 7S (l) L relative to wheat. The 7S (l) L arm seldom paired, likely because this arm lost a relatively long segment and received a very short segment in the interchange with 4S (l) L. Available data suggest that translocation 4S (l) L/7S (l) L arose in the evolution of T. longissimum, which implies that this species was not the donor of the B genome of wheat. PMID- 24169675 TI - Genetic characterisation of Act1, the activator of a non-autonomous transposable element from Petunia hybrida. AB - The line W138 of Petunia hybrida has variegated flowers because it is homozygous for the mutable an1-W138 allele. Excision of the element, causing instability, depends on the presence of the activatorAct1. The previously characterised non autonomous element dTph1 excises from the dfrC gene in response to Act1. This implies that both non-autonomous elements belong to the same transposable element family. In a range of distantly related cultivars we could detect a single functional Act1 element. Linkage analysis for 11 of these lines showed that Act1 was located on chromosome I in all cases, indicating that the element might be fixed in the genome. A group of cultivars that did not exhibit Act1 activity could be traced back to a recent common origin ('Rose of Heaven'). Cultivars within this group presumably harbour the same inactivated Act1 element. Among the lines tested were 7 lines representing the two species (P. axillaris and P. integrifolia) from which P. hybrida originated. None of these exhibited Act1 activity. We assume that Act1 is present in an inactive state in these lines and that it was activated upon interspecific crossing. In general, lines representing the two parental species and P. hybrida cultivars contain between 5 and 25 dTph1 elements. The lines R27 and W138, however, contain significantly more dTph1 elements (> 50) than all other lines. PMID- 24169676 TI - Relationship between genetic distance and heterosis for yield and morphological traits in winter canola (Brassica napus L.). AB - Genetic distance among canola cultivars was estimated through multivariate analysis. Thirty cultivars from various sources were analyzed and clustered based upon five morphological characteristics and yield components-crown diameter, number of branches plant(-1), number of pods plant(-1), number of seeds pod(-1) and yield plant(-1) -and placed in three distinct clusters. Two cultivars from each cluster were selected as parents and 15 partial-diallel inter- and intra cluster crosses were made between the six selected parents and evaluated at two locations in Michigan in 1990/1991. The association between genetic distance and mid-parent heterosis was investigated. The correlation between genetic distance and heterosis was positive and highly significant for seed yield, number of pods plant(-1), and number of seeds pod(-1). Clustering, based on yield and yield component traits, demonstrated that inter-cluster heterosis was greater than intra-cluster heterosis in the majority of cases. PMID- 24169677 TI - Estimation, variance and optimal sampling of gene diversity II. Diploid locus. AB - Nei's analysis of diversity at a diploid locus is extended to a population subdivided into a large number of subpopulations. The diversities and the heterozygotes frequency are defined with respect to the total population and unbiasedly estimated in a two-stage random cluster sampling. The fixation indices F IS, F IT andF ST are derived, then inter- and intra-population variances of the estimated parameters are studied. We show that there is a unique sample size per population which yields the best accuracy in estimatingF ST and F IS, respectively, at a given locus. These results are illustrated with an analysis of DNA diversity in a forest tree and compared to those obtained under the Hardy Weinberg assumption. PMID- 24169678 TI - Production and cytogenetics of intergeneric hybrids between Brassica napus and Orychophragmus violaceus. AB - The intergeneric hybrid between Brassica napus and Orychophragmus violaceus was obtained by means of embryo culture technique with the latter as the pollen parent. The hybrid was morphologically intermediate between its parents, but could produce a lot of seeds when selfed. Somatic separation of the genomes from the two parental species was observed during the mitotic divisions of some of the hybrid cells. Thus, the hybrid became the mixoploid in nature, consisting of haploid and diploid cells of B. napus, and a nuclear - cytoplasmic hybrid, with the cytoplasm of B. napus and the nuclei of O. violaceus, and the hybrid cells. Pollen mother cells with 19, 12 and 6 bivalents, respectively, were produced by the hybrid. From the selfed progeny of the hybrid, mainly two kinds of plants, B. napus and the hybrid, were found. The hybrid plants of the selfed progeny again produced two kinds of plants, B. napus and the hybrid. PMID- 24169679 TI - Characterization of highly variable (GA/CT) n microsatellites in the bur oak, Quercus macrocarpa. AB - The objective of this study was to ascertain the usefulness of polymerase chain reaction (PCR)-based microsatellite analysis for studying pollination and parentage in a wind-pollinated temperate tree. A small insert genomic library of the bur oak (Quercus macrocarpa) was constructed and screened for the presence of (CA/GT) n and (GA/CT) n repeats. The proportion of positive clones yielded estimates of 3*10(5) such dinucleotide repeats per genome, roughly comparable to abundances reported in other eukaryotic genomes. Thirteen positive clones were sequenced. In contrast to mammalian genomes, the (GA/CT) n motif was more abundant than the (CA/GT) n motif in these clones. The (GA/CT) n repeats also showed longer average repeat length (mean n=16.2 versus 7.3), suggesting that they are better candidates for yielding polymorphic genetic markers in oak genomes. Indeed, a survey of adult bur oaks and offspring in a small stand in northern Illinois at 3 of these (GA/CT) n microsatellite loci revealed Mendelian inheritance and extremely high levels of polymorphism, with the number of alleles at each locus ranging from 11-20 and heterozygosity ranging from 0.66 to 0.75. These results, indicating that (GA/CT) n microsatellites are both abundant and highly polymorphic in the bur oak genome, suggest that such genetic markers have tremendous potential for applications for studies of parentage, pollination and dispersal in temperate trees. PMID- 24169680 TI - Species-specific RAPD fingerprints for the closely related Picea mariana and P. rubens. AB - Species-specific molecular markers were designed to assist in the identification of closely related black spruce (Picea mariana [B.S.P.] Mill.) and red spruce (P. rubens Sarg.) in northeastern North America. Trees from six provenances of black spruce and three provenances of red spruce were sampled from outside the sympatric zone. They were first classified using a composite index of five qualitative morphological traits. The species-specific genetic markers were developed using random amplified polymorphic DNAs (RAPD) and a combination of bulk sample and individual tree analyses. Each species bulk sample was constructed from DNAs obtained from 12 trees that were from outside the sympatric zone and showed a morphological composite index specific of each species. A total of 161 primers were screened with the bulk samples. From these, 52 primers showing segregating fingerprints were further screened with the individual trees. Most of the markers observed were shared by the two species, and there was less diversity in P. rubens. A small number of markers were found to be monomorphic or nearly monomorphic and specific to either P. mariana or P. rubens. These markers remained species-specific when F1 progenies derived from independent intraspecific crosses were screened, and they were subsequently found to co segregate in hybrids derived from independent interspecific crosses here used as controls. PMID- 24169681 TI - Mitochondrial DNA diversity and male sterility in natural populations of Daucus carota ssp carota. AB - Mitochondrial variability was investigated in natural populations of wild carrot (Daucus carota ssp carota) in different regions: South of France, Greece, and various sites in the Mediterranean Basin and Asia. Total DNA was digested with two restriction endonucleases (EcoRV and HindIII) and probed with three mitochondrial DMA-specific genes (coxI, atp6, and coxII). Twenty-five different mitochondrial types were found in 80 analyzed individuals. Thirteen mitotypes were found among the 7 French populations studied. On average, 4.4 different mitotypes were observed per population, and these mitotypes were well-distributed among the populations. All of the mitochondrial types were specific to a single region. However, the proportion of shared restriction fragments between 2 mitotypes from different regions was not particularly lower than that which occurred among mitotypes from a single region. On the basis of the sexual phenotype [male-sterile (MS) or hermaphrodite] of the plants studied in situ and that of their progeny, 2 mitotypes were found to be highly associated with male sterility. Eighty percent of the plants bearing these mitotypes were MS in situ, and all of these plants produced more than 30% MS plants in their progeny. This association with male sterility was consistent in several populations, suggesting an association with a cytoplasmic male-sterility system. Moreover, these two mitotypes had very similar mitochondrial DNA restriction patterns and were well differentiated from the other mitotypes observed in wild plants and also from those observed in the two CMS types already known in the cultivated carrot. This suggests that they correspond to a third cytoplasmic sterility. PMID- 24169682 TI - Identification of the most represented repeated motifs in Arabidopsis thaliana microsatellite loci. AB - The major simple sequence repeats present in the Arabidopsis genome were identified by Southern hybridizations with 49 oligonucleotide probes matching all the possible combinations of motifs up to 4 nucleotides long. The method used allowed us to perform all the hybridizations under the same temperature conditions. A good correlation was observed with the data obtained from database analysis, indicating that the method can be useful for identifying the major classes of microsatellite loci in species for which few or no sequence data are available. AG/CT, AAG/CTT, ATG/CAT and GTG/CAC are the major motifs present in the Arabidopsis genome that can be used as convenient probes to isolate microsatellite loci by screening libraries. AAG/CTT is the more frequent of these motifs, and its relative frequency in Arabidopsis is much higher than averagely found in the plant kingdom. About 8% of the cDNA clones from an immature silique library contains AG/CT, AAG/CTT or ATG/CAT microsatellite loci. Several microsatellite loci were isolated by screening genomic and cDNA libraries. Twenty six tri-nucleotide loci were PCR amplified from four different ecotypes, and polymorphism was observed for 12 of them; 10 loci showing two alleles and 2 loci showing three alleles. PMID- 24169683 TI - Characterization of agronomic traits and markers of recombinant inbred lines from intra- and interracial populations of Phaseolus vulgaris L. AB - The value of intra- and interracial populations in common bean (Phaseolus vulgaris L.) needs to be determined in order to create useful genetic variation for maximizing gains from selection, broadening the genetic base of commercial cultivars, and making efficient use of available resources. Five large-seeded parents of race Nueva Granada (N), two small-seeded race Mesoamerica (M), and one medium-seeded race Durango (D) were hybridized to produce one intraracial (N x N) and three interracial (two N x M and one N x D) populations. Seventy-nine F2 derived F6 lines randomly taken from each population along with their parents were evaluated for agronomic traits and markers at Palmira and Popayan, Colombia, in 1990 and 1991. Variation for agronomic traits and for morphological, protein, and isozyme markers was larger in interracial populations than in the intraracial population. Mean seed yield of all lines as well as yield of the highest yielding line from two interracial populations were significantly higher than that of the intraracial population. The highest (>= 0.80+/-0.15) heritability was recorded for 100-seed weight. Values for seed yield varied from 0.19+/-0.17 to 0.50+/ 0.16. Gains from selection (at 20% selection pressure) for seed yield ranged from 3.9% to 11.4%. Seed yield was positively associated with biomass yield, pods/m(2), and days to maturity, but harvest index showed negative correlations with these traits and a positive value with 100-seed weight. Polymorphism was recorded for phaseolin, lectins, protein Group-1 and protein Group-2 fractions, and six isozyme loci. Lines with indeterminate growth habit had significantly (P < 0.01) higher seed yield than lines with determinate growth habit in a Redkloud x MAM 4 population. Also, 23 other associations of markers with agronomic traits other than seed yield were recorded. Of these associations, lines with T phaseolin, the Diap1 (2) allele, and lilac flower color tended to possess greater seed weight. PMID- 24169684 TI - Sources and genetic structure of a cluster of genes for resistance to three pathogens in lettuce. AB - The second largest cluster of resistance genes in lettuce contains at least two downy mildew resistance specificities, Dm5/8 and Dm10, as well as Tu, providing resistance against turnip mosaic virus, and plr, a recessive gene conferring resistance against Plasmopara lactucae-radicis, a root infecting downy mildew. In the present paper four additional genetic markers have been added to this cluster, three RAPD markers and one RFLP marker, CL1795. CL1795 is a member of a multigene family related to triose phosphate isomerase; other members of this family map to the other two major clusters of resistance genes in lettuce. Seven RAPD markers in the region were converted into sequence characterized amplified regions (SCARs) and used in the further analysis of the region and the mapping of Dm10. Three different segregating populations were used to map the four resistance genes relative to molecular markers. There were no significant differences in gene order or rate of recombination between the three crosses. This cluster of resistance genes spans 6.4 cM, with Dm10 1.2 cM from Dm8. Marker analysis of 20 cultivars confirmed multiple origins for Dm5/8 specificity. Two different Lactuca serriola origins for the Du5/8 specificity had previously been described and originally designated as either Dm5 or Dm8. Some ancient cultivars also had the same specificity. Previously, due to lack of recombination in genetic analyses and the same resistance specificities, it was assumed that Dm5 and Dm8 were determined by the same gene. However, molecular marker analysis clearly identified genotypes characteristic of each source. Therefore, Dm5/8 specificity is either ancient and widespread in L. serriola and some L. sativa, or else has arisen on multiple occasions as alleles at the same locus or at linked loci. PMID- 24169685 TI - US doctors join call for end to embargo against Cuba. PMID- 24169686 TI - The difference in relationship between 18F-FDG uptake and clinicopathological factors on thyroid, esophageal, and lung cancers. AB - OBJECTIVES: The aim of this study was to reveal the differences in clinicopathological factors affecting maximum standardized uptake value (SUVmax) between esophageal squamous cell carcinoma (ESCC), non-small-cell lung cancer (NSCLC), and papillary thyroid cancer (PTC). METHODS: This study consisted of 119 patients with ESCC (n=43), PTC (n=40), or NSCLC (n=36). We investigated the correlations between SUVmax and clinicopathological factors by using Spearman's correlation coefficient and the Kruskal-Wallis test. Multiple regression analysis was used to investigate which clinicopathological factors significantly affected SUVmax in each cancer type. RESULTS: The SUVmax correlated with glucose transporter-1 (GLUT-1) expression in NSCLC (r=0.536, P=0.007) and ESCC (r=0.597, P<0.001) but not in PTC. The SUVmax correlated with Ki-67 expression in NSCLC (r=0.381, P=0.022) and PTC (r=0.374, P=0.017) but not in ESCC. A high SUVmax was correlated with a higher pathological T stage (p-T stage) in NSCLC (r=0.536) and ESCC (r=0.597, both P<0.001) but not in PTC. An elevated SUVmax was significantly associated with pathological lymph node status (p-N) in NSCLC, but not in ESCC and PTC. In multiple regression analysis, p-T stage and GLUT-1 expression were statistically significant factors in ESCC, and p-T stage was a statistically significant factor in NSCLC. In PTC, Ki-67 showed a statistically significant association with SUVmax. CONCLUSION: SUVmax in NSCLC depended on the tumor invasion area; SUVmax in ESCC depended on tumor depth and GLUT-1 expression; and SUVmax in PTC might be associated with cell proliferation. The biological factors affecting SUVmax differ according to tumor type. PMID- 24169687 TI - [New data from the German Haemophilia Registry]. AB - The German Haemophilia Registry records online data from patients with haemophilia A, haemophilia B, von Willebrand's disease and other coagulation factor deficiency disorders since 2009. Patient's pseudonymised data will only be enrolled in the German Haemophilia Registry if the patient signs an informed consent. Without the informed consent, only aggregated data according to S21 German Transfusion Law are reported. These data include the number of persons with congenital haemostasis disorders classified to type of disease and severity as well as patients' age, and the consumption of clotting factor according to each group. RESULTS: The highest number of patients with haemophilia was reported in 2010: 3375 patients with haemophilia A and 614 with haemophilia B respectively; the highest number of patients with von Willebrand's disease was 1473, reported in 2011. CONCLUSION: In comparison to data from registries in Austria and Switzerland it can be assumed that most of the patients with severe haemophilia are registered in the German Haemophilia Registry whereas patients with moderate and mild forms are still missing. PMID- 24169688 TI - Diagnostic quality of CT pulmonary angiography in pulmonary thromboembolism: a comparison of three different kV values. AB - BACKGROUND: Our purpose was to evaluate the effectiveness of different kilovolt (kV) uses in computed tomography pulmonary angiography (CTPA) in the diagnosis of pulmonary thromboembolism (PTE). We also aimed to establish the optimal kV value and investigate the possibility of obtaining appropriate imaging quality with minimal radiation dose. MATERIAL AND METHODS: We compared 120, 100, and 80 kV CTPA for 90 patients in whom PTE was clinically considered. The examinations were carried out using a 128 multislice CT device (Definition AS, Siemens Medical Solutions, Forchheim, Germany). Each kV value was used on 30 patients in 3 groups. Patients in all groups were compared with respect to the mean radiation dose they received, pulmonary arterial attenuation values, image quality, and motion artefacts. RESULTS: With respect to pulmonary arterial attenuation values, imaging with 80 kV yielded significantly higher values (p<0.05). However, no difference was found between 120 kV, 100 kV, and 80 kV with respect to image quality. Similarly, no significant difference was detected between the groups with respect to pulmonary artery contrasting and motion artefacts. Statistically significant differences were present in DLP values and effective dose among all 3 groups (p<0.001). CONCLUSIONS: Using 80 kV as the low value in CTPA imaging for patients pre-diagnosed with PTE will increase the density of pulmonary arteries and decrease the amount of radiation received. PMID- 24169689 TI - NO generation by beta-AR stimulation to activate CaMKII. PMID- 24169690 TI - Wish-fulfilling medicine in practice: the opinions and arguments of lay people. AB - BACKGROUND: Wish-fulfilling medicine appears to be on the rise. It can be defined as 'doctors and other health professionals using medical means (medical technology, drugs, and so on) in a medical setting to fulfil the explicitly stated, prima facie non-medical wish of a patient'. Some instances of wish fulfilling medicine can be understood as 'human enhancements'. AIM: The aim of this study is to map the normative opinions and arguments of lay people about wish-fulfilling medicine. METHODS: We conducted a qualitative study with lay people (five focus groups). We asked their opinions about five cases and the arguments for these opinions. Furthermore, we enquired about the role of the medical profession and the treating physician, and whether the participants saw a role for the government. RESULTS: The opinions and arguments used varied according to the example discussed. For instance, increased familiarity with a procedure like breast enhancement seems to garner more acceptance for that procedure, whereas completely new examples were considered less acceptable. Various different arguments were raised in focus groups; these included: people should be allowed to make up their own minds about this (autonomy); payment of the treatment; and concerns about risks. DISCUSSION: An ethical analysis of the emerging practice of wish-fulfilling medicine should take the normative views of all parties involved into account. Thus, it is important to establish what lay people think about wish-fulfilling medicine and in particular their arguments. PMID- 24169691 TI - Ni(II) binding to the 429-460 peptide fragment from human Toll like receptor (hTLR4): a crucial role for nickel-induced contact allergy? AB - The FQH431SNLKQMSEFSVFLSLRNLIYLDISH456TH458TR fragment, containing three histidine residues, the conserved H431 and the non-conserved H456 and H458, located from 429 to 460 amino acid residues in the C-terminal portion of human Toll-like-receptor 4 (hTLR4), which is directly activated by nickel, a well known contact allergen, has been tested for Ni(II) binding. The complex formation capability of the 32-amino acid sequence with Ni(II) ions has been followed by potentiometric, UV-Vis, CD, MS and NMR measurements. Ni(II) is able to bind to all three histidines by forming macrocycle complexes at low and physiological pH. From pH 9 on, a 4N diamagnetic species (N(im), 3N(am)(-)) with the participation of an imidazole nitrogen and three deprotonated nitrogens from His28, Ser27 and Ile26 amides from the backbone of the model peptide has been determined. From the NMR results it was possible to determine that His28, which mimics the H456 residue in the protein, together with the environment around it, was mainly involved in the binding. PMID- 24169692 TI - Magnetic properties and chiral states of a trimetallic uranium complex. AB - The magnetic properties of the triangular molecular nanomagnet [UO2L]3 (L = 2-(4 tolyl)-1,3-bis(quinolyl)malondiiminate) have been investigated through electron paramagnetic resonance spectroscopy, high-field magnetization and susceptibility measurements. The experimental findings are well reproduced by a microscopic model including exchange interactions and local crystal fields. These results show that [UO2L]3 is characterized by a non-magnetic ground doublet corresponding to two oppositely twisted chiral arrangements of the uranium moments. The non axial character of single-ion crystal fields leads to quantum tunneling of the noncollinear magnetization in the presence of a magnetic field applied perpendicularly to the triangle plane. PMID- 24169693 TI - New heterocyclic systems to afford microsecond green-light isomerisable azo dyes and their use as fast molecular photochromic switches. AB - The use of benzothiazole as an electron-withdrawing group allows obtaining the fastest thermal isomerisation kinetics reported heretofore for neutral azo dyes (70 MUs at 298 K). These green light activatable molecules are valuable candidates as molecular photoswitches since they tolerate thousands of working cycles with no sign of fatigue. PMID- 24169694 TI - The concave face of decorin mediates reversible dimerization and collagen binding. AB - Decorin, the prototypical small leucine-rich proteoglycan, binds to collagen and thereby regulates collagen assembly into fibrils. The crystal structure of the decorin core protein revealed a tight dimer formed by the association of two monomers via their concave faces (Scott, P. G., McEwan, P. A., Dodd, C. M., Bergmann, E. M., Bishop, P. N., and Bella, J. (2004) Proc. Natl. Acad. Sci. U.S.A. 101, 15633-15638). Whether decorin binds collagen as a dimer has been controversial. Using analytical ultracentrifugation, we determined a dissociation constant of 1.37 +/- 0.30 MUm for the mouse decorin dimer. Dimerization could be abolished by engineering glycosylation sites into the dimer interface; other interface mutants remained dimeric. The monomeric mutants were as stable as wild type decorin in thermal unfolding experiments. Mutations on the concave face of decorin abolished collagen binding regardless of whether the mutant proteins retained the ability to dimerize or not. We conclude that the concave face of decorin mediates collagen binding and that the dimer therefore must dissociate to bind collagen. PMID- 24169695 TI - Two distinct allosteric binding sites at alpha4beta2 nicotinic acetylcholine receptors revealed by NS206 and NS9283 give unique insights to binding activity associated linkage at Cys-loop receptors. AB - Positive allosteric modulators (PAMs) of alpha4beta2 nicotinic acetylcholine receptors have the potential to improve cognitive function and alleviate pain. However, only a few selective PAMs of alpha4beta2 receptors have been described limiting both pharmacological understanding and drug-discovery efforts. Here, we describe a novel selective PAM of alpha4beta2 receptors, NS206, and compare with a previously reported PAM, NS9283. Using two-electrode voltage-clamp electrophysiology in Xenopus laevis oocytes, NS206 was observed to positively modulate acetylcholine (ACh)-evoked currents at both known alpha4beta2 stoichiometries (2alpha:3beta and 3alpha:2beta). In the presence of NS206, peak current amplitudes surpassed those of maximal efficacious ACh stimulations (Emax(ACh)) with no or limited effects at potencies and current waveforms (as inspected visually). This pharmacological action contrasted with that of NS9283, which only modulated the 3alpha:2beta receptor and acted by left shifting the ACh concentration-response relationship. Interestingly, the two modulators can act simultaneously in an additive manner at 3alpha:2beta receptors, which results in current levels exceeding Emax(ACh) and a left-shifted ACh concentration-response relationship. Through use of chimeric and point-mutated receptors, the binding site of NS206 was linked to the alpha4-subunit transmembrane domain, whereas binding of NS9283 was shown to be associated with the alphaalpha-interface in 3alpha:2beta receptors. Collectively, these data demonstrate the existence of two distinct modulatory sites in alpha4beta2 receptors with unique pharmacological attributes that can act additively. Several allosteric sites have been identified within the family of Cys-loop receptors and with the present data, a detailed picture of allosteric modulatory mechanisms of these important receptors is emerging. PMID- 24169696 TI - Structural insights into the role of the cyclic backbone in a squash trypsin inhibitor. AB - MCoTI-II is a head-to-tail cyclic peptide with potent trypsin inhibitory activity and, on the basis of its exceptional proteolytic stability, is a valuable template for the design of novel drug leads. Insights into inhibitor dynamics and interactions with biological targets are critical for drug design studies, particularly for protease targets. Here, we show that the cyclization and active site loops of MCoTI-II are flexible in solution, but when bound to trypsin, the active site loop converges to a single well defined conformation. This finding of reduced flexibility on binding is in contrast to a recent study on the homologous peptide MCoTI-I, which suggested that regions of the peptide are more flexible upon binding to trypsin. We provide a possible explanation for this discrepancy based on degradation of the complex over time. Our study also unexpectedly shows that the cyclization loop, not present in acyclic homologues, facilitates potent trypsin inhibitory activity by engaging in direct binding interactions with trypsin. PMID- 24169697 TI - Increased concentrations of fructose 2,6-bisphosphate contribute to the Warburg effect in phosphatase and tensin homolog (PTEN)-deficient cells. AB - Unlike normal differentiated cells, tumor cells metabolize glucose via glycolysis under aerobic conditions, a hallmark of cancer known as the Warburg effect. Cells lacking the commonly mutated tumor suppressor PTEN exhibit a glycolytic phenotype reminiscent of the Warburg effect. This has been traditionally attributed to the hyperactivation of PI3K/Akt signaling that results from PTEN loss. Here, we propose a novel mechanism whereby the loss of PTEN negatively affects the activity of the E3 ligase APC/C-Cdh1, resulting in the stabilization of the enzyme PFKFB3 and increased synthesis of its product fructose 2,6-bisphosphate (F2,6P2). We discovered that when compared with wild-type cells, PTEN knock-out mouse embryonic fibroblasts (PTEN KO MEF) have 2-3-fold higher concentrations of F2,6P2, the most potent allosteric activator of the glycolytic enzyme phosphofructokinase-1 (PFK-1). Reintroduction of either wild-type or phosphatase mutant PTEN in the PTEN KO cells effectively lowers F2,6P2 to the wild-type levels and reduces their lactate production. PTEN KO cells were found to have high protein levels of PFKFB3, which directly contribute to the increased concentrations of F2,6P2. PTEN enhances interaction between PFKFB3 and Cdh1, and overexpression of Cdh1 down-regulates the PFKFB3 protein level in wild-type, but not in PTEN-deficient cells. Importantly, we found that the degradation of endogenous PFKFB3 in PTEN KO cells occurs at a slower rate than in wild-type cells. Our results suggest an important role for F2,6P2 in the metabolic reprogramming of PTEN-deficient cells that has important consequences for cell proliferation. PMID- 24169699 TI - Strong cationic oxidizers: thermal decomposition, electronic structure and magnetism of their compounds. AB - Strong oxidizers could be provisionally defined as compounds for which the standard redox potential exceeds 2.0 V in the NHE scale. Compounds which contain transition or post-transition metals at their unusually high positive oxidation states constitute one important family of strong oxidizers. Majority of such systems typically exhibit either diamagnetic or 'simple' paramagnetic properties down to very low temperatures. This is connected with the fact that highest oxidation states of metals are stabilized in fluoride environment and that binary high-valence metal fluorides form either molecular(OD) or low-dimensional (usually !D) crystals. The ternary and higher fluorides are usually OD in electronic sense leading again to low ordering temperatures. The situation becomes more interesting in selected compounds of Ag(II),the strongest oxidizer among all divalent cations, where one finds 2D or even 3D magnetic ordering at elevated temperatures.Thermal stability, electronic structure and magnetic properties of strong oxidizers are discussed jointly in this contribution with emphasis on the compounds of unique divalent silver. PMID- 24169698 TI - Identification of a novel lipofuscin pigment (iisoA2E) in retina and its effects in the retinal pigment epithelial cells. AB - Lipofuscin accumulation in retinal pigment epithelial (RPE) cells of the eye implicates the etiologies of Stargardt disease and age-related macular degeneration, a leading cause of blindness in the elderly. Here, we have identified a previously unknown RPE lipofuscin component. By one- and two dimensional NMR techniques and mass spectrometry, we confirmed that this compound is a new type of pyridinium bisretinoid presenting an unusual structure, in which two polyenic side chains are attached to adjacent carbons of a pyridinium ring. This pigment is a light-induced isomer of isoA2E, rather than A2E, referred to as iisoA2E. This pigment is a fluorescent lipofuscin compound with absorbance maxima at ~430 and 352 nm detected in human, pig, mouse, and bovine eyes. Formation of iisoA2E was found in reaction mixtures of all-trans-retinal and ethanolamine. Excess intracellular accumulation of this adduct in RPE cells in vitro leads to a significant loss of cell viability and caused membrane damage. Phospholipase D mediated phosphodiester cleavage of the A2PE series generated isoA2E and iisoA2E, in addition to A2E, thus corroborating the presence of isoA2PE and iisoA2PE that may serve as biosynthetic precursors of isoA2E and iisoA2E. PMID- 24169700 TI - An overview of the understanding of ions containing solely fluorine atoms. AB - We discuss in the current paper ions containing solely fluorine atoms, F-, F2- and F3-, their corresponding cationic and/or multiply charged counterparts. While the emphasis of the paper is on gas phase species, their energetics and reactions, aqueous solutions are also discussed. In particular, biomedical and analytical aspects of F- are also considered. The new trichotomy of convenience, anthropocentrism and folksonomy is also applied to the understanding of our fluorine-containing ions. PMID- 24169701 TI - First N-allyl-aminothiadiazole copper(I) pi-complexes: synthesis and structural peculiarities of [Cu(L)CF3SO3] and [Cu2(L)2(H2O)2](SiF6) . 2.5H2O compounds (L = 2-(allyl)-amino-5-methyl-1,3,4-thiadiazole). AB - By means of alternating current electrochemical technique two crystalline copper(I) pi-complexes with fluorine containing anions [Cu(L)CF3SO3] (1) and [Cu2(L)2(H2O)2](SiF6)2 . 2.5H2O (2) (L - 2-(allyl)-amino-5-methyl-1,3,4 thiadiazole) have been obtained and characterized by X-ray single crystal diffraction and Raman spectroscopy. In both structures the organic molecule L acts as chelate-bridging tridentate ligand being connected to copper(I) by two N atoms of thiadiazole ring and C=C bond from allyl group resulting in a formation of stable cationic dimers [Cu(L)2]2+. In the structure 1 oxygen atom from triflate-anion occupies an apical position of the metal coordination polyhedron, while in 2 located far from the metal centre hexafluorosilicate anion allows an appearance of the H2O molecule in copper environment. Hydrogen bonds (D)-H...A (where D = O, N, C; A = O, F) play a significant role in formation of 2D- (1) and 3D- (2) frameworks. PMID- 24169702 TI - Reactions of xenon with iridium- and Osmiumhexafluoride. AB - Xenon and Iridiumhexafluoride react at temperatures above room temperature forming XeF+IrF6-. In presence of SbF5 FXe+IrSbF11- is formed. Xenon and Osmiumhexafluoride form in solution a blue charge transfer complex that cannot be isolated as a solid. PMID- 24169703 TI - Surface modification of polymers treated by various fluorinating media. AB - Fluorination processes of polymer surfaces are able to lead to drastic modifications of the surface properties without changing the bulk characteristics of the virgin material. In this paper, two types of polymers, i.e. ultrahigh molecular weight polyethylene (UHMWPE) and high density polyethylene (HDPE), are considered. The surface of these materials have been modified using two different fluorination routes, both carried out at room temperature: the direct fluorination with 10% F2 + 90% He gaseous mixtures and the radio-frequency plasma enhanced fluorination (PEF) using either O2/CF4 mixtures or c-C4F8. The effect of these processes on the surface of the polymer samples are compared using mostly XPS results. The different components of the C1s spectra are assigned in term of CFx bonding, giving valuable information on the surface fluorination rate. PMID- 24169704 TI - C6F5XeY molecules (Y = F and Cl): new synthetic approaches. first structural proof of the organoxenon halide molecule C6F5XeF. AB - The arylxenonium salt [C6F5Xe][BF4] reacts with different sources of nucleophiles, Y (naked fluoride, [N(CH3)4]F, the silanes, (CH3)3SiCl and (C2H5)3SiH, and the cadmiumorganyl, Cd(C6F5)2), in coordinating solvents (C2H5CN, CH3CN, CD3CN). While the products C6F5XeF, C6F5XeCl, and (C6F5)2Xe are well defined molecules, in reactions with (C2H5)3SiH only decomposition products presumably derived from and are found. Molecular parameters and intermolecular contacts in the single crystal X-ray structure of C6F5XeF are discussed. PMID- 24169705 TI - Surface passivation of natural graphite electrode for lithium ion battery by chlorine gas. AB - Surface lattice defects would act as active sites for electrochemical reduction of propylene carbonate (PC) as a solvent for lithium ion battery. Effect of surface chlorination of natural graphite powder has been investigated to improve charge/discharge characteristics of natural graphite electrode in PC-containing electrolyte solution. Chlorination of natural graphite increases not only surface chlorine but also surface oxygen, both of which would contribute to the decrease in surface lattice defects. It has been found that surface-chlorinated natural graphite samples with surface chlorine concentrations of 0.5-2.3 at% effectively suppress the electrochemical decomposition of PC, highly reducing irreversible capacities, i.e. increasing first coulombic efficiencies by 20-30% in 1 mol L-1 LiClO4-EC/DEC/PC (1:1:1 vol.). In 1 mol L-1 LiPF6-EC/EMC/PC (1:1:1 vol.), the effect of surface chlorination is observed at a higher current density. This would be attributed to decrease in surface lattice defects of natural graphite powder by the formation of covalent C-Cl and C=O bonds. PMID- 24169706 TI - Fluorination of mixed gamma-alumina/gamma-gallia xerogels with trifluoromethane: some effects on bulk and surface characteristics. AB - Interaction of single gamma-Al2O3 and gamma-Ga2O3, and mixed gamma-Al2O3/gamma Ga2O3 xerogels with CHF3 at intermediate temperatures results in partial fluorination. Fluorinated oxides remain amorphous and retain a considerable part of the initial surface area; for the fluorinated Al-based materials surface areas in all cases exceed 100 m2 g-1. Lewis acidity of mixed oxides, either before or after fluorination, is strongly influenced by the presence of surface Ga3+ ions, mainly due to their strong preference to replace highly acidic Al3+ ions in tetrahedral positions. Ion replacement leads to the formation of acidic sites with lower strengths what is confirmed by the model catalytic reaction, isomerisation of CCl2FCClF2. XPS investigations indicate that fluorination of mixed oxides is accompanied by substantial surface reconstructions and preferential formation of Al-F based phases with Ga remaining mainly in O environments. Further segregation processes, such as slow crystallisation of Al(F,OH)3.nH2O phases, are probably promoted by water adsorption. PMID- 24169707 TI - Synthesis and crystal structures of lanthanoid(III) hexafluoroarsenates with AsF3 ligands. AB - Lanthanoid(III) hexafluoroarsenates with AsF3 as a ligand were prepared with the reactions of solutions of Ln(AsF6)3 in anhydrous hydrogen fluoride and AsF3. Solid products with composition Ln(AsF3)3(AsF6)3 (Ln = La, Nd, Sm, Eu, Gd, Tb, Er, Tm) were isolated at 233 K. The attempt to prepare corresponding Yb and Lu compounds failed. Single crystals of Ln(AsF3)3(AsF6)3 (Ln = Ce, Pr) were prepared by the reaction of LnF3 (Ln = Ce, Pr) with AsF5 and aHF under solvothermal conditions above critical temperature of AsF5. During the crystallization the reduction of some AsF5 occurred and AsF3 was formed. Compounds crystallize in a hexagonal crystal system, space group P 6- 2c (a = 10.6656(7) A (Ce); 10.6383(7) A (Pr); c = 10.9113(9) A (Ce), 10.878(2) A (Pr); V = 1074.9(1) A3 (Ce), 1066.2(2) A3 (Pr); Z = 2). Ln atoms are coordinated by nine fluorine atoms in the shape of the tri-capped trigonal prism and are further connected in three-dimensional framework via trans bridging AsF6 units. Three fluorine atoms are provided by AsF3 (capped positions) and six by AsF6 units. X-ray powder analysis of Ln(AsF3)3(AsF6)3 (Ln = La, Nd, Sm, Eu, Gd, Tb, Er, Tm) show that they are isostructural with corresponding Ce and Pr compounds. PMID- 24169708 TI - The effect of fluoride ions on the corrosion behaviour of Ti metal, and Ti6-Al 7Nb and Ti-6Al-4V alloys in artificial saliva. AB - Metallic materials used for manufacture of dental implants have to exhibit high corrosion resistance in order to prevent metal release from a dental implant. Oral cavity is aggressive towards metals as it represents a multivariate environment with wide range of conditions including broad range of temperatures, pH, presence of bacteria and effect of abrasion. An increasing use of various Ti based materials for dental implants and orthodontic brackets poses the question of their corrosion resistance in the presence of fluoride ions which are present in toothpaste and mouth rinse. Corrosion behaviour of Ti metal, Ti-6Al-7Nb and Ti 6Al-4V alloys and constituent metals investigated in artificial saliva is significantly affected by the presence of fluoride ions (added as NaF), as proven by electrochemical methods. Immersion test was performed for 32 days. During that time the metal dissolution was measured by inductively coupled plasma mass spectrometry. At the end of the test the composition, thickness and morphology of the surface layers formed were investigated by X-ray photoelectron spectroscopy and scanning electron microscopy. PMID- 24169709 TI - Trifluoromethylation of perfluorinated diacylfluorides: synthesis of the diketone CF3C(O)CF2C(O)CF3 and of new perfluorinated diol (CF3)2C(OH)CF2C(OH)(CF3)2. AB - Perfluoromalonyl difluoride reacts with TMS-CF3 (1:1) in the presence of KF to give the new diketone CF2(C(O)CF3)2. A large excess (5:1) of TMS-CF3 results in the presumed potassium dialkoxide [(CF3)2COK]2CF2 which yields the 1,3 ditertiarydiol [(CF3)2C(OH)]2CF2 on reaction with H2SO4. PMID- 24169710 TI - The effect of fluorine atom on the synthesis and composition of gametocidal ethyl oxanilates. AB - Three derivatives of ethyl oxanilate were synthesized in order to test their application as gametocides on the hermaphrodite plants like common wheat (Triticum aestivum L.). A substituent at para position (F, Br, CN) of aniline defined its reactivity towards diethyl oxalate 2. Classical reaction in toluene was not selective and amidation occurred also at the second carbonyl groups of 2. Alternative synthesis under solvent-free conditions with application of low pressure for removal of EtOH provided selectively with ethyl oxanilate 3a and 3b. 4-Cyanoaniline did not react selectively and the corresponding ethyl oxanilate 3c was prepared from mono acid chloride of oxalic acid. Fluoro derivative 3a was found to be the only one that gives stable aqueous suspension for its application as chemical hybridizing agent for common wheat, while bromo- 3b and cyano- 3c analogues were not soluble enough and suspension was stable for less than 2 hours. Fluoro derivative had shown the best induction of male sterility, while in comparison with standard chemical hybridizing agent they were substantially less toxic for plant. PMID- 24169711 TI - Some chemistry of tris(pyrazolyl)methylthiolate derivatives. AB - An efficient synthetic method for the preparation of TAS tris(pyrazolyl)methylthiolate (3) is reported. Nucleophilic exchange reactions with 3 gave (pyr)C(=S)SC(pyr)3 (4) and MeSC(pyr)3 (5). 5 acts as scorpionate ligand in [MeSC(pyr)3Cr(CO)3] (6), from the decomposition of TDAE2+ [SC(pyr)3Mo(CO)3-]2 by SO2FCl TDAE2+[O=MoF4-F-Mo(=O)Cl4]2- (8) was isolated. The X-ray structures of 3-6 and 8 are discussed. PMID- 24169712 TI - Structure of 7,9,12,15,18,20,39,24,45,57-C60(CF3)10(1,2:3,4-O)2. The first regiospecific diepoxidation of a fullerene derivative. AB - An unusual regiospecific diepoxidation of an isomer of C60(CF3)10 was discovered to slowly occur in solution while exposed to air. This is the only known example of a perfluoroalkyl fullerene undergoing epoxidation under ambient conditions. This compound was characterized by a variety of analytical methods including 19F NMR spectroscopy, APCI-MS, UV-vis spectroscopy, and X-ray crystallography. Numerous oxidation methods were explored including ozonation, photolysis, thermolysis, and the chemical oxidation by m-chloroperoxobenzoic acid, none of which has yielded the diepoxide. This indicated that the process is kinetically very slow, presumably due to steric crowding around the oxygen addition sites. These findings of spontaneous diepoxidation of the otherwise stable compound have far reaching implications as more fullerenes and fullerene derivatives are being used in organic electronics, and their instability toward oxidation in ambient conditions may alter the performance of the device. PMID- 24169713 TI - New approaches for the synthesis of thiophene derivatives with anti-tumor activities. AB - The reaction of either cyclohexanone or cyclopentanone with cyanoacetylhydrazine and elemental sulfur gave the 2-aminocycloalkeno[b]thiophene derivatives 3a and 3b, respectively. The latter compounds reacted with either aromatic benzaldehydes or active methylene reagents to give the Schiff's bases 5a-d and the pyrazole derivatives 7a-d and 9a-d, respectively. On the other hand, the reaction of 3-oxo N-p-tolylbutanamide (10) with either of malononitrile or ethyl cyanoacetate gave the thiophene derivatives 13a and 13b, respectively. Compounds 13a,b were subjected to a series of heterocyclization reactions to give heterocyclic derivatives. Their cytotoxicity against the three human tumor cells lines, namely breast adenocarcinoma (MCF-7), non-small cell lung cancer (NCI-H460) and CNS cancer (SF-268) together against the normal human cell line namely the normal fibroblast cells WI 38 were measured. PMID- 24169714 TI - Cryotrap/SPME/GC/MS method for profiling of monoterpenes in cheese and their clustering according to geographic origin. AB - A variant of purge/cryotrap/thaw/static headspace Solid Phase Microextraction (SPME) was developed as a means for preconcentrating Volatile Organic Compounds (VOC) in cheese. An originally designed cryotrap partially filled with glass beads was employed that facilitated efficient flow-through of purging gas and trapping of the volatiles. In stopped-flow mode, thawing was allowed, and the same vessel was used for the exposure of the appropriate SPME fiber, effectively achieving double preconcentration. Gas chromatography/mass spectrometry (GC/MS) was subsequently employed to identify components and assess their relative chromatographic peak areas. Monoterpenes were chosen as a model group of substances, and their relative concentration profiles were evaluated as potential markers for the respective geographic origin. The procedure was tested on samples of five traditional Slovenian cheeses featuring Protected Designation of Origin (PDO): Tolminc, Mohant, Nanoski cheese, together with Bovski cheese and Karst Ewe's cheese. The dataset of the peak areas of nine prominent monoterpenes (alpha pinene, camphene, alpha-phellandrene, beta-pinene, 3-carene, 2-carene, limonene, tricyclene, and gamma-terpinene) in cheese samples showed clustering that relates the cheeses to the area of production. According to the silhouette metrics, four clusters were identified by partitioning around medoids (PAM) method. The latter packed data for Tolminc and Bovski cheese into a single cluster, closely reflecting the vicinity of their geographic origin, but classified correctly the rest of the data into separate clusters for all other cheeses. PMID- 24169715 TI - Synthesis and liquid crystalline properties of some esters of 4-ferrocenyl-4' hydroxyazobenzene. AB - The paper describes synthesis and mesogenic behavior of a new class of ferrocenomesogens obtained by esterification of 4-ferrocenyl-4'-hydroxyazobenzene with some 4-n-alkyloxybenzoic acids / 4-n-alkanoyloxy or 4-n-alkenoyloxybenzoic acids in the presence of N,N'-dicyclohexylcarbodiimide and 4 dimethylaminopyridine. Based on differential scanning calorimetry and polarized optical microscopy investigations, it was established that 12 from the 15 synthesized compounds presented liquid crystalline properties, mainly monotropic nematic. All the investigated compounds were thermally stable in the existence range of the mesophases. Molecular modeling studies have been performed in order to establish correlations between structure and liquid crystalline properties. Parameters as lengths, diameters, dipole moments and molecular asymmetry coefficients and geometries of minimum energy have been obtained. A model of a cell of minimum energy for systems containing eight molecules of type 4-((4 ferrocenyl-phenylazo)phenyl) 4-alkyloxybenzoate has been proposed. PMID- 24169716 TI - Catalytic activity of ruthenium(III) on the oxidation of an anticholinergic drug atropine sulfate monohydrate by copper(III) periodate complex in aqueous alkaline medium - decarboxylation and free radical mechanism. AB - Atropine sulfate monohydrate (ASM) is an anticholinergic drug, having a wide spectrum of activity. Hence, the kinetics of oxidation of ASM by diperiodatocuperate (DPC) in the presence of micro (10-6) amounts of Ru(III) catalyst has been investigated spectrophotometrically in aqueous alkaline medium at I = 0.50 mol dm-3. The reaction between DPC and ASM exhibits 1:2 stoichiometry (ASM:DPC) i. e., one mole of ASM require two moles of DPC to give products. The main oxidation products were confirmed by spectral studies. The reaction is first order with respect to [DPC] and [Ru(III)], while the order with respect to [ASM] and [OH-] was less than unity. The rates decreased with increase in periodate concentration. The reaction rates revealed that Ru(III) catalyzed reaction was about seven-fold faster than the uncatalyzed reaction. The catalytic constant (KC) was also determined at different temperatures. A plausible mechanism is proposed. The activation parameters with respect to slow step of the mechanism were calculated and the thermodynamic quantities were also determined. Kinetic experiments suggest that [Cu(H2IO6)(H2O)2] is the reactive Cu(III) species and [Ru(H2O)5OH]2+ is the reactive Ru(III) species. PMID- 24169717 TI - N-substituted Indole-2 and 3-carboxamide derivatives as inhibitors of human protein kinase CK2: in vitro assay and molecular modelling study. AB - Protein kinase CK2 (Casein Kinase 2) is involved in cell growth; proliferation and suppression of apoptosis. Hence, it strongly promotes cell survival and can be considered an important target for human cancers. In the present study, a series of N-substituted indole-2- and 3-carboxamide derivatives were tested for inhibitions of human recombinant protein kinase CK2 to evaluate their anticancer properties. The inhibition test revealed that the most active compound 4 (1 benzyl-N-(2,4-dichlorobenzyl)-1H-indole-2-carboxamide) showed an IC50 value of 14.6 uM towards human protein kinase CK2. A molecular docking study of the compounds with CK2 was performed and revealed the binding mode of the most active compound 4, underlying its inhibitory activity. PMID- 24169718 TI - Influence of alkali cation on the mechanical properties and durability of fly ash based geopolymers. AB - This research has provided information about the influence of alkali cations (Na+ and K+) on the mechanical properties and durability of fly ash based geopolymers. The results have shown that alkali cations have a strong influence on the mechanical properties of fly ash based geopolymers. K-geopolymers generally reach a higher value of compressive strength in comparison to Na- geopolymers. On the other hand, microstructure and phase composition of fly ash based geopolymers are not influenced by the nature of alkali cations. The ratio of main gel structure forming elements is practically not affected by the nature of alkali cations. Durability of fly ash based geopolymers in different aquatic environments is greatly dependent on the choice of alkali cations. Na- geopolymers are generally more resistant in water and aggressive environments than the K-geopolymers. The best durability of fly ash based geopolymers was observed in sea water. PMID- 24169719 TI - Self-assembled organogels formed by L-leucine dihydrazide derivative. AB - A new organogelator, benzyl (4-methyl-1-oxo-1-(2-hexadecanoylhydrazinyl)pentan-2 yl)carbamate (designated as Cbz-Leu-HdHz), was designed and synthesized, which could self-assemble in many organic solvents and form the thermally reversible physical supramolecular organogels. The gel-sol phase transition temperatures (TGS) were determined as a function of gelator concentration and the corresponding enthalpies (DeltaHg) were extracted. SEM, FT-IR and XRD were used for the investigations of the morphology and formation mechanism of organogels in the presence of the Cbz-Leu-HdHz. Based on the XRD data and molecular modeling, it was possible to propose packing modes for the formation of organogelator aggregates. PMID- 24169720 TI - Determination of the interactions between Zn2+ and water soluble polymer ligands with potential use in controlled drug delivery. AB - Biodegradable copolymers of aspartic and lactic acids were synthesized for potential use in controlled drug release. The proportion of aspartic acid moieties in the copolymers was 0.9 and 0.1, the molecules were partially branched and had absolute molar masses over 100,000 g/mol. The drug could be attached to the copolymer via metal (particularly zinc) ions, so a method to estimate the interactions between zinc ions and the water-soluble polymers by fluorescence spectroscopy was developed. The stability constants of binding of zinc and the concentrations of zinc bound to polymer were determined. The results confirm that zinc ions at pH 6 preferentially bind to side groups of aspartic acid units of the copolymers. PMID- 24169721 TI - Preparation, characterization and antibacterial activity of ZnO nanoparticles on broad spectrum of microorganisms. AB - Nano particles have received increased attention regarding their potential utility in biomedicine. In this study, we have investigated the antibacterial activity of ZnO nano particles with various particle sizes. ZnO nano particles were synthesized by conventional precipitation method using zinc sulphate and sodium hydroxide as precursors followed by the calcinations of precipitates at 350 degrees C for 6 h (sample A) and 550 degrees C for 2 h (sample B). The products were characterized by X-ray diffraction (XRD) analysis and morphology of the particles was evaluated by Scanning Electron Microscopy (SEM). Antibacterial activities against four different microorganisms were evaluated by determining the minimum inhibitory concentration (MIC), minimum bactericidal concentration (MBC) and zones of inhibitions using different concentrations of ZnO nanoparticles. The antibacterial activity was directly proportional to the concentration and inversely proportional to the particle size in all the microorganisms; moreover Gram positive bacteria were generally more affected than Gram negative bacteria. The stability of ZnO nanoparticles combined with potent antibacterial properties favours their application as antibacterials against broad spectrum of microorganisms. PMID- 24169722 TI - Decolorization and mineralization of reactive dyes, by the H2O2/UV process with electrochemically produced H2O2. AB - Decolorization of Reactive Red 238, Reactive Orange 16, Reactive Black 5 and Reactive Blue 4 was studied in the UV/H2O2 process with H2O2 being produced electrochemically. The experimental results show that decolorization increased considerably when switching on the electrochemical production of H2O2. Complete decolorization (>99%) was achieved for all dyes under the applied experimental conditions, partial mineralization (49-85%) was obtained, which depends on the type of dye. Reactive Red 238 was used to investigate operational parameters and it was found that decolorization was influenced by the applied electrical current of the electrochemical cell and flow rate. Decolorization and mineralization of Reactive Red 238 can be described by pseudo-first order kinetics. It was found that the initial concentration of Reactive Red 238 has a negative influence on the pseudo-first order reaction constant. PMID- 24169723 TI - Green synthesis of silver nanoparticles using Nelumbo nucifera seed extract and its antibacterial activity. AB - Silver nanoparticles (AgNPs) were synthesized using a Nelumbo nucifera dry seed extract, which is a simple, non-toxic, eco-friendly "green material". The synthesized nanoparticles were confirmed by the color changes and characterized by UV-visible spectroscopy. The AgNPs were stable at room temperature for 2 months. Scanning electron microscopy (SEM) revealed the formation of well dispersed and spherical shapes. Transmission electron microscopy (TEM) of the synthesized AgNPs showed the formation of spherical nanoparticles, 5.03-16.62 nm in size. Fourier transform infrared spectroscopy (FTIR) indicated the involvement of amine, aromatic and alkynes groups in the synthetic process. X-ray diffraction (XRD) confirmed the crystalline nature of AgNPs. These AgNPs were highly toxic to found to Gram negative bacteria. PMID- 24169724 TI - Arsenic release from pyrite ashes: kinetic studies. AB - Arsenic mobility in pyrite ashes was studied because of the possible effects on water systems. The batch extraction method was used to assess kinetics and extent of As release induced by contact of the material either with rainwater or groundwater. Self-established pH-Eh range of pyrite ashes/water mixtures brought both As(III) and As(V) to be present in the water phase, as neutral arsenite H3AsO3 and anionic arsenate HAsO42-, respectively. Tests in reagent water showed both rate and extent of arsenite release higher than arsenate; total As concentration ([As] = 12 ug/L) at equilibrium little exceeded its EU Maximum Concentration Level (MCL) for surface and groundwater ([As] = 10 ug/L). Tests in groundwater, instead, showed a much higher release rate and extent for arsenate than for arsenite and the chemistry of groundwater mainly influenced arsenate mobility; total As almost instantly exceeded its MCL and it was markedly higher ([As] = 31 ug/L) at equilibrium. Overall, the study has shown the environmental implications of As mobility in the pyrite ashes, also casting light on some limits of the environmental representativeness of leaching tests in reagent water. PMID- 24169725 TI - Scandium(III) triflate catalyzed 1,4-addition of cyano group to enones using tetraethylammonium cyanide as the cyanide source. AB - A novel and practical method has been developed for the synthesis of beta cyanoketones using tetraethylammonium cyanide (Et4NCN, TEACN) / Sc(III) triflate and chalcones without the liberation of toxic HCN gas. Availability, safety, easy handling of the reagents, mild conditions of the reaction and high yields, make this method an attractive protocol for the direct synthesis of cyano substituted 1,4-adducts from enones. PMID- 24169726 TI - Synergistic extraction of europium and americium into nitrobenzene by using hydrogen dicarbollylcobaltate and dodecaethylene glycol. AB - Extraction of microamounts of europium and americium by a nitrobenzene solution of hydrogen dicarbollylcobaltate (H+B-) in the presence of dodecaethylene glycol (DDEG, L) has been investigated. The equilibrium data have been explained assuming that the species HL+, H2L2+, ML3+ and MH-1L2+ (M3+ = Eu3+, Am3+; L = DDEG) are extracted into the organic phase. The values of extraction and stability constants of the complex species in nitrobenzene saturated with water have been determined. It was found that in this nitrobenzene medium, the stability constant of the EuL3+ complex is comparable with that of AmL3+. PMID- 24169727 TI - A novel analytical technique suitable for the identification of plastics. AB - The enormous development and production of plastic materials in the last century resulted in increasing numbers of such kinds of objects. Development of a simple and fast technique to classify different types of plastics could be used in many activities dealing with plastic materials such as packaging of food, sorting of used plastic materials, and also, if technique would be non-destructive, for conservation of plastic artifacts in museum collections, a relatively new field of interest since 1990. In our previous paper we introduced a non-destructive technique for fast identification of unknown plastics based on EDXRF spectrometry,1 using as a case study some plastic artifacts archived in the Museum in order to show the advantages of the nondestructive identification of plastic material. In order to validate our technique it was necessary to apply for this purpose the comparison of analyses with some of the analytical techniques, which are more suitable and so far rather widely applied in identifying some most common sorts of plastic materials. PMID- 24169728 TI - Chemical composition of natural sea salt from the Secovlje salina (Gulf of Trieste, northern Adriatic). AB - In our research the concentrations of major and minor elements were determined in natural sea salts from the Se~ovlje salina (Piran salts, Slovenia) and compared to those of selected samples of commercially available unrefined salts with different geographical origins (Croatia, Austria, Italy, Portugal, India, and Pakistan). In the case of major element contents such as sodium (Na), iron (Fe), aluminum (Al), manganese (Mn), and titanium (Ti) many similarities were observed among the analysed salt samples. On the other hand, Piran salts are characterized by lower silicon (Si) values. Among the salts from the Secovlje salina, the salt with the trade name Piran salt has a higher Mg content while Flower of salt has a lower concentration of calcium (Ca). In Slovenian samples the majority of trace element values were lower than 0.5 ug g-1, which was comparable to the results from commercially available unrefined salts. The salt composition differences observed indicate area-specific signatures related to geographic origin and diverse salt production processes. The quality of the studied salt samples is in accordance with standards established by the Codex Alimentarius Commission and the Piran salts are also suitable regarding issues of national food control. PMID- 24169729 TI - The emergence of CD20-/CD19- tumor cells after rituximab therapy for Epstein-Barr virus-associated post-transplant lymphoproliferative disorder complicated with hemophagocytic lymphohistiocytosis. AB - Post-transplant lymphoproliferative disorder (PTLD) is a well-recognized aggressive disease commonly associated with Epstein-Barr virus (EBV) infection after hematopoietic stem cell transplantation (HSCT). Although rituximab (RTX) is incorporated into the first-line therapy for EBV-PTLD patients, the outcome of the clinically overt disease is still not optimal mainly due to the regrowth of tumor cells. The proliferation of CD20-/CD19+ tumor cells is increasingly reported in RTX-treated EBV-PTLD patients, whereas the emergence of CD20-/CD19- tumor cells is barely recognized. Here, we report a fatal case of an 18-year-old patient who developed EBV-PTLD after allogeneic HSCT for anaplastic large-cell lymphoma. On day 60 after HSCT, the patient developed abdominal pain, watery diarrhea, and low-grade fever. Colon biopsy revealed the proliferation of CD20+/CD19+/EBV-encoded RNA (EBER)+ tumor cells, and an increase of EBV DNA was detected in peripheral blood (PB). He was treated with RTX for EBV-PTLD and was cleared of EBV DNA in PB. However, he manifested high-grade fever, pancytopenia, and elevated soluble interleukin-2 receptor with a prominent hemophagocytosis in bone marrow aspirates and was treated with etoposide for hemophagocytic lymphohistiocytosis (HLH) complication. He then developed EBV DNA positivity in PB and finally died of Bacteroides fragilis sepsis subsequent to bloody stool and ileus on day 163. Autopsy revealed erosion and bleeding in the whole colon with the proliferation of CD20-/CD19-/EBER+ tumor cells. Immunohistochemical analysis uncovered the CD3-/CD56-/CD79a+/CD79b+ B-cell origin of tumor cells. This case clinically demonstrates the removal of both CD20 and CD19 antigens from EBER+ B cells in an RTX-treated EBV-PTLD patient with HLH complication. PMID- 24169730 TI - Epidemiology and clinical features of respiratory adenoviral infections in children. AB - This study was aimed to describe the epidemiology, clinical features, and prognosis of respiratory adenoviral infections among children in Suzhou, China. From 1 January 2006 to 31 December 2012, medical records of 474 hospitalized patients with respiratory adenovirus infection were reviewed retrospectively. From 2006 to 2012, the virus positive rate was 1.42, 0.82, 1.45, 1.54, 0.77, 1.63, and 0.78 %, respectively; there was no outbreak in Suzhou throughout the 7 years. Adenovirus was detected in almost every month of the year with a peak from March to August. The median age was 36 months (range, 2 days-13 years); 89 % of the infections were confined to children <7 years of age, positive rates in patients between 2 ~ 7 years of age and patients >7 years of age were higher than that of patients <2 years of age (P < 0.002). Comparisons of the length of hospital stay using the log-rank test statistic demonstrated patients <2 years had a significantly longer length of hospital stay (P < 0.001). CONCLUSIONS: The study demonstrates that respiratory adenovirus infection is an important cause of hospitalization in young children. Patients less than 2 years old were associated with prolonged hospitalization. PMID- 24169731 TI - Superior mesenteric artery syndrome in a 15-year-old boy during Ramadan. AB - A previously healthy 15-year-old boy who participated in Ramadan and recently suffered from a gastro-enteritis presented at the emergency room with abdominal pain, vomiting, and marked weight loss. Abdominal X-ray and computed tomography showed upper gastrointestinal obstruction and narrowing of the distance between superior mesenteric artery and aorta abdominalis. Through these findings, superior mesenteric artery syndrome was diagnosed. Treatment consisted of placement of a nasojejunal tube for enteral feeding until weight gain was substantial. Superior mesenteric artery syndrome is rare, with a prevalence varying between 0.013 and 0.3 %. It is characterized by compression of the third part of duodenum between aorta and superior mesenteric artery, thus causing signs and symptoms of upper gastrointestinal obstruction. CONCLUSION: In general, when signs and symptoms of upper gastrointestinal obstruction are accompanied with rapid weight loss, superior mesenteric artery syndrome should be considered. PMID- 24169732 TI - Graphene-cobaltite-Pd hybrid materials for use as efficient bifunctional electrocatalysts in alkaline direct methanol fuel cells. AB - Hybrid materials comprising of Pd, MCo2O4 (where M = Mn, Co or Ni) and graphene have been prepared for use as efficient bifunctional electrocatalysts in alkaline direct methanol fuel cells. Structural and electrochemical characterizations were carried out using X-ray diffraction, transmission electron microscopy, X-ray photoelectron spectroscopy, chronoamperometry and cyclic, CO stripping, and linear sweep voltammetries. The study revealed that all the three hybrid materials are active for both methanol oxidation (MOR) and oxygen reduction (ORR) reactions in 1 M KOH. However, the Pd-MnCo2O4/GNS hybrid electrode exhibited the greatest MOR and ORR activities. This active hybrid electrode has also outstanding stability under both MOR and ORR conditions, while Pt- and other Pd based catalysts undergo degradation under similar experimental conditions. The Pd MnCo2O4/GNS hybrid catalyst exhibited superior ORR activity and stability compared to even Pt in alkaline solutions. PMID- 24169733 TI - A helically twisted imine macrocycle that allows for determining the absolute configuration of alpha-amino carboxylates. AB - Binding of alpha-amino carboxylates to a helically twisted imine macrocycle based on the indolocarbazole scaffold gives rise to characteristic circular dichroism spectra, and the patterns of the Cotton effects are consistent with the absolute configuration of alpha-amino carboxylates. PMID- 24169734 TI - Novel platinum(II) compounds with O,S bidentate ligands: synthesis, characterization, antiproliferative properties and biomolecular interactions. AB - Cisplatin and its analogues are first-line chemotherapeutic agents for the treatment of numerous human cancers. A major inconvenience in their clinical use is their strong tendency to link to sulfur compounds, especially in kidney, ultimately leading to severe nephrotoxicity. To overcome this drawback we prepared a variety of platinum complexes with sulfur ligands and analyzed their biological profiles. Here, a series of six platinum(II) compounds bearing a conserved O,S binding moiety have been synthesized and characterized as experimental anticancer agents. The six compounds differ in the nature of the O,S bidentate beta-hydroxydithiocinnamic alkyl ester ligand where both the substituents on the aromatic ring and the length of the alkyl chain may be varied. The two remaining coordination positions at the square-planar platinum(II) center are occupied by a chloride ion and a DMSO molecule. These novel platinum compounds showed an acceptable solubility profile in mixed DMSO buffer solutions and an appreciable stability at physiological pH as judged from analysis of their time-course UV-visible absorption spectra. Their anti proliferative and pro-apoptotic activities were tested against the cisplatin resistant lung cancer cell line A549. Assays revealed significant effects of the sample drugs at low concentrations (in the MUmolar range); initial structure activity-relationships are proposed. The activity of the apoptosis-promoting protein caspase 3/7 was determined; results proved that these novel platinum compounds, under the chosen experimental conditions, preferentially induce apoptosis over necrosis. Reactions with the model proteins cytochrome c, lysozyme and albumin were studied by ESI MS and ICP-OES to gain preliminary mechanistic information. The tested compounds turned out to metalate the mentioned proteins to a large extent. In view of the obtained results these novel platinum complexes qualify themselves as promising cytotoxic agents and merit, in our opinion, a deeper pharmacological evaluation as prospective anticancer agents. PMID- 24169735 TI - Does atrial pacing lead to atrial fibrillation in patients with sick sinus syndrome? Insights from the DANPACE trial. AB - AIMS: Paroxysmal atrial fibrillation (AF) is common in patients with sick-sinus syndrome (SSS) and pacemakers leading to morbidity and an increased risk of stroke or death. Previous studies indicate that atrial pacing may precipitate AF. We investigated the relation between atrial pacing and the occurrence of AF during long-term follow-up among patients with SSS, no prior AF, and dual-chamber pacemakers (DDDRs). METHODS AND RESULTS: We analysed data from 396 patients who received DDDR pacemakers in the DANPACE trial. The percentage of atrial pacing (%AP) was compared with the number of mode-switch (MS) episodes collected by the pacemaker at each follow-up as an indicator of AF. Mean follow-up was 4.2 +/- 2.4 years. The mean proportion of atrial and ventricular pacing was 59 +/- 31 and 65 +/- 33%, respectively. Approximately 72% developed AF as indicated by MS episodes at some point during follow-up. Unadjusted regression analysis indicated a relation between %AP and AF (P = 0.04), but after adjustment for possible confounders (sex, age, hypertension, diabetes, myocardial infarction, PQ interval, and left atrial diameter) there was no significant relationship (P = 0.37). CONCLUSION: Atrial fibrillation is very common among patients with SSS. No association between %AP and development of AF was found in patients with SSS. Future trials may randomize patients to different levels of AP exposure. PMID- 24169736 TI - [Development and evaluation of a dance-based exercise therapy for patients with haemophilia]. AB - So far, the use of methods derived from creative arts has not been considered in the haemophilia treatment. The AIM was to investigate the expectations for a dance-based exercise therapy for patients with haemophilia and the extent of its acceptance. PATIENTS, METHOD: The one-hour dance-based exercise therapy was offered to 30 haemophilia patients (HI30) (49 +/- 11, 30-67 years). For the evaluation of expectations, questionnaires were created and filled out by participants before and after the intervention. Additionally, 19 haemophilia patients (HF) and 20 controls without haemophilia (KF) who did not participate in the intervention were also questioned. The RESULTS show that haemophilia patients have more experience in dance than controls (HI30:62%, HF:74%, KF:45%). In contrast, the proportion of those who are currently dancing is higher in controls without haemophilia (HI30: 17%, HF: 10%, KF:26%). The termination of dance activity in patients with haemophilia who were part of the intervention was mainly due to pain (HI30: 40%, HF: 29%, KF: 0%), whereby controls without intervention terminated the dance activity mainly due to lack of time (HI30: 30%, HF: 57%, KF: 56%). Ultimately, 24 out of 30 patients with haemophilia (HI24) completed the intervention. All HI24 met their expectations. 38% felt limited by haemophilia while carrying out the exercises. The majority of the participants were able to follow the exercises well (96%) and were did not overstrain physically (92%) nor mentally (87%), also 79% did not have pain. 23 of HI24 (96%) can envision a continuation of the dance-based exercise therapy. CONCLUSION: The experience with the dance-based exercise therapy was predominantly positive. It represents an alternative sports therapy programme for patients with haemophilia. Further studies are needed in order to make statements concerning the long-term use of such training. PMID- 24169737 TI - Dependence of Monte Carlo microdosimetric computations on the simulation geometry of gold nanoparticles. AB - Recently, interactions of x-rays with gold nanoparticles (GNPs) and the resulting dose enhancement have been studied using several Monte Carlo (MC) codes (Jones et al 2010 Med. Phys. 37 3809-16, Lechtman et al 2011 Phys. Med. Biol. 56 4631-47, McMahon et al 2011 Sci. Rep. 1 1-9, Leung et al 2011 Med. Phys. 38 624-31). These MC simulations were carried out in simplified geometries and provided encouraging preliminary data in support of GNP radiotherapy. As these studies showed, radiation transport computations of clinical beams to obtain dose enhancement from nanoparticles has several challenges, mostly arising from the requirement of high spatial resolution and from the approximations used at the interface between the macroscopic clinical beam transport and the nanoscopic electron transport originating in the nanoparticle or its vicinity. We investigate the impact of MC simulation geometry on the energy deposition due to the presence of GNPs, including the effects of particle clustering and morphology. Dose enhancement due to a single and multiple GNPs using various simulation geometries is computed using GEANT4 MC radiation transport code. Various approximations in the geometry and in the phase space transition from macro- to micro-beams incident on GNPs are analyzed. Simulations using GEANT4 are compared to a deterministic code CEPXS/ONEDANT for microscopic (nm-um) geometry. Dependence on the following microscopic (u) geometry parameters is investigated: u-source-to-GNP distance (uSAD), u-beam size (uS), and GNP size (uC). Because a micro-beam represents clinical beam properties at the microscopic scale, the effect of using different types of micro-beams is also investigated. In particular, a micro-beam with the phase space of a clinical beam versus a plane-parallel beam with an equivalent photon spectrum is characterized. Furthermore, the spatial anisotropy of energy deposition around a nanoparticle is analyzed. Finally, dependence of dose enhancement on the number of GNPs in a finite cluster of nanoparticles is determined. Simulations were performed for 100 nm GNPs irradiated in water phantom by various monoenergetic (11 keV-1 MeV) and spectral (50 kVp) sources. The dose enhancement ratio (DER) is very sensitive to the specific simulation geometry (uSAD, uS, uC parameters) and u-source type. For a single GNP the spatial distribution of DER is found to be nearly isotropic with limited magnitude and relatively short range (~100-200 nm for DER significantly greater than 1). For a cluster of GNPs both the magnitude and range are found much greater (~1-2 um). The relation between DER for a cluster of GNPs and a single GNP is strongly nonlinear. Relatively strong dependence of DER on the simulation micro-geometry cautions future studies and the interpretation of existing MC results obtained in different simulations geometries. The nonlinear relation between DER for a single and multiple GNPs suggests that parameters such as the number of adjacent nanoparticles per cell and the distances between the GNPs and the cellular target may be important in assessing the biological effectiveness associated with GNP. PMID- 24169762 TI - Development of a set of oligonucleotide primers specific for genes at the Glu-1 complex loci of wheat. AB - Specific amplification of the complete coding region of all six high-molecular weight (HMW) glutenin genes present in hexaploid wheat was obtained by the polyerase chain reaction (PCR). Primers specific for the N-terminal region of the 1Dx gene and for the repetitive domain of the y-type HMW glutenin genes were also developed. Although the primers were constructed on the basis of the nucleotide sequences of HMW glutenin genes present in T. aestivum L. cv 'Cheyenne', they were very efficient in amplifying HMW glutenin genes of diploid and tetraploid wheat species. PCR analysis of HMW glutenin genes of T. urartu Tuman., T. longissimum (Schweinf. & Muschl.) Bowden and T. speltoides (Tausch) Gren. ex Richt, showed a high degree of length polymorphism, whereas a low degree of length variation was found in accessions of T. tauschii (Coss.) Schmal. Furthermore, using primers specific for the repetitive regions of HMW genes, we could demonstrate that the size variation observed was due to a different length of the central repetitive domain. The usefulness of the PCR-based approach to analyze the genetic polymorphism of HMW glutenin genes, to isolate new allelic variants, to estimate their molecular size and to verify the number of cysteine residues is discussed. PMID- 24169761 TI - Elevated circulating levels of tissue factor-positive microvesicles are associated with distant metastasis in lung cancer. AB - PURPOSE: Microvesicles (MV) in the blood stream are associated with distant metastasis in cancer. Platelet or endothelial cell-related MV actively participate in thrombogenesis, which is an important step in cancer metastasis. This study investigated the correlations between MV levels of platelet-poor plasma and distant metastasis in lung cancer. METHODS: Platelet-poor plasma from 44 treatment-naive lung cancer (23 with distant metastasis) and 19 normal subjects was used to determine the levels of glycoprotein Ibeta (CD42) + platelet MV (PMV), P-selectin (CD62P) + PMV, VE-cadherin (CD144) + endothelial MV (EMV), tissue factor (CD142) + MV, thrombin-antithrombin complex and vascular endothelial growth factor (VEGF). RESULTS: The level of CD142 + MV was significant (odds ratio 5.86, 95 % confidence interval 1.31-38.3) in predicting distant metastasis in lung cancer, and a cutoff value of 2.668 (after logarithm transformation) in the ROC curve had a specificity of 90 % and a sensitivity of 59 %. The presence of distant metastasis showed a significant correlation between CD144 + EMV and VEGF, but not between CD144 + EMV and CD42 + PMV or CD62P + PMV in lung cancer subjects. CONCLUSIONS: The finding of CD142 + MV in platelet-poor plasma may be useful for suggesting distant metastasis in lung cancer. In addition to thrombogenesis, interaction between VE-cadherin and VEGF may be needed for successful metastasis in lung cancer. PMID- 24169763 TI - Molecular marker analysis of Helianthus annuus L. 2. Construction of an RFLP linkage map for cultivated sunflower. AB - A detailed linkage map of Helianthus annuus was constructed based on segregation at 234 RFLP loci, detected by 213 probes, in an F2 population of 289 individuals (derived from a cross between the inbred lines HA89 and ZENB8). The genetic markers covered 1380 centiMorgans (cM) of the sunflower genome and were aranged in 17 linkage groups, corresponding to the haploid number of chromosomes in this species. One locus was found to be unlinked. Although the average interval size was 5.9 cM, there were a number of regions larger than 20 cM that were devoid of markers. Genotypic classes at 23 loci deviated significantly from the expected ratios (1?2?1 or 3?1), all showing a reduction in the ZENB8 homozygous class. The majority of these loci were found to map to four regions on linkage groups G, L and P. PMID- 24169764 TI - Combined genetic and physiological analysis of a locus contributing to quantitative variation. AB - The natural variation of many traits is controlled by multiple genes, individually referred to as quantitative trait loci (QTL), that interact with the environment to determine the ultimate phenotype of any individual. A QTL has yet to be described molecularly, in part because strategies to systematically identify them are underdeveloped and because the subtle nature of QTLs prevents the application of standard methods of gene identification. Therefore, it will be necessary to develop a systematic approach(es) for the identification of QTLs based upon the numerous positional data now being accumulated through molecular marker analyses. We have characterized a QTL by the following three-step approach: (1) identification of a QTL in complex populations, (2) isolation and genetic mapping of this QTL in near-isogenic lines, and (3) identification of a candidate gene using map position and physiological criteria. Using this approach we have characterized a plant height QTL in maize that maps to chromosome 9 near the centromere. Both map position and physiological criteria suggest the gibberillin biosynthesis gene dwarf3 as a candidate gene for this QTL. PMID- 24169765 TI - Abundance and characterization of simple-sequence repeats (SSRs) isolated from a size-fractionated genomic library of Brassica napus L. (rapeseed). AB - A size-fractionated library of Brassica napus L. (rapeseed), composed of 15000 clones, was screened for the presence of GA-, CA-, and GATA-simple-sequence repeats (SSRs). GA-SSRs were four- and five-fold more abundant than CA- and GATA SSRs, respectively, and present at a frequency of approximately one SSR for every 100 kb of DNA. Following the sequencing of 124 positive clones, primer pairs were designed and evaluated for seven selected SSRs. Products were amplified in an array of individuals of B. napus, B. oleracea and B. rapa, demonstrating that the seven SSRs were conserved among species. Two SSRs were polymorphic. Among 11 accessions, the dinucleotide (GA)-repeat, B.n.9A, yielded 12 fragments, while the tetranucleotide-repeat (GATA), B.n.6A2, revealed two fragments. Automated, fluorescence-based detection of polyacrylamide gels has been employed to simultaneously increase throughput, reduce unit cost, improve analytical resolution, and expedite data acquisition of SSR analysis. Though initial financial investment and technical capabilities may prevent some from directly employing our documented approach, SSR analysis warrants further investigation as a tool in genetic studies for enhancing both the conservation and utilization of genetic resources. PMID- 24169766 TI - Cytological studies of African cultivated rice, Oryza glaberrima. AB - African cultivated rice, Oryza glaberrima Steud., was cytologically characterized by using both karyotype analysis and molecular cytology. The somatic chromosomes resemble those of Asian cultivated rice, Oryza sauva L., in general morphology, although some minor differences were noted. Multicolor fluorescence in situ hybridization (McFISH) with chromosomes detected one 45s (17s-5.8s-25s) ribosomal RNA gene locus (45s rDNA) and one 5s ribosomal RNA gene locus (5s rDNA) in the chromosome complement. The 45s rDNA and 5s rDNA loci were physically mapped to the distal end of the short arm of chromosome 9 and to the proximal region of the short arm of chromosome 11 respectively, as in O. sativa. Based on the cytological observations and the physical map of the rDNA loci, the chromosomal organization of O.glaberrima and O. sativa seems to be very similar. PMID- 24169767 TI - Classification of rice germplasm. I. Analysis using ALP and PCR-based RFLP. AB - The potential of using a PCR-based approach to detect DNA polymorphism for rice germplasm classification was compared with that of Southern-based RFLP analysis. Thirty-five Iranian rice varieties were studied along with 2 typical Indica and 3 typical Japonica varieties. Thirteen mapped RFLP markers were used as hybridization probes against Southern blots containing digests of one restriction endonuclease; 12 of the 13 probes detected polymorphism in the varieties. Fifteen sets of oligonucleotides derived from sequences near the ends of the same probes and of two other mapped probes were used as primers for PCR amplification of total genomic DNA of the varieties. Amplicon length polymorphisms (ALPs) were detected with 6 of the 15 sets of primers. To identify additional polymorphism, the PCR products were digested with nine different restriction endonucleases recognizing 4- or 5-bp DNA sequences and analyzed by gel electrophoresis in agarose and polyacrylamide. RFLPs were detected for 11 sets of primers, due to point mutations and to addition/deletion events that were too small to be detected as ALPs. Because PCR products are easily generated and may be analyzed in detail through the use of restriction endonucleases that cut rice DNA frequently, PCR-based RFLP analysis is a useful tool for the classification of rice germplasm. PMID- 24169768 TI - DNA amplification fingerprinting analysis of bermudagrass (Cynodon): genetic relationships between species and interspecific crosses. AB - We have used DNA amplification fingerprinting (DAF) to study the genetic variation of bermudagrass (Cynodon) species and cultivars of interspecific crosses that exhibit leaf-blade textural characteristics ranging from coarse to fine. Arbitrary octamer primers produced complex and reproducible amplification profiles with high levels of polymorphic DNA. Phylogenetic analysis using parsimony (PAUP) and unweighted pair group cluster analysis using arithmetic means (UPGMA) grouped 13 bermudagrass cultivars into several clusters, including one containing the African-type bermudagrasses (C. transvaalensis) and another containing the common-type bermudagrasses (C. dactylon). The latter group included C. magennissii ('Sunturf') and a interspecific C. transvaalensisxC. dactylon cross ('Midiron'), 2 cultivars that exhibited leaf textural characteristics closer to the common-types. All other C. transvaalensisxC. dactylon crosses grouped between the African and common types. An extended screen of 81 octamer primers was needed to separate cultivar 'Tifway' from the irradiation-induced mutant 'Tifway II'. The use of either template endonuclease digestion prior to amplification or arbitrary mini-hairpin primers increased detection of polymorphic DNA and simplified the task of distinguishing these closely related cultivars. Alternatively, the use of capillary electrophoresis (CE) resolved fingerprints adequately and detected products with high sensitivity, thereby promising to increase throughput and the detection of polymorphic DNA. When used to fingerprint samples from commercial sources, DAF identified bermudagrass plant material on the basis of unique reference profiles generated with selected primers. DAF represents an excellent technique for bermudagrass cultivar verification, seed certification, varietal protection, and for the identification of mistakes in plantings, mislabeled plant materials, and contamination or substitutions of sod fields. PMID- 24169769 TI - Inheritance of rapeseed (Brassica napus)-specific RAPD markers and a transgene in the cross B. juncea x (B. juncea x B. napus). AB - We have examined the inheritance of 20 rapeseed (Brassica napus)-specific RAPD (randomly amplified polymorphic DNA) markers from transgenic, herbicide-tolerant rapeseed in 54 plants of the BC1 generation from the cross B. junceax(B. junceaxB. napus). Hybridization between B. juncea and B. napus, with B. juncea as the female parent, was successful both in controlled crosses and spontaneously in the field. The controlled backcrossing of selected hybrids to B. juncea, again with B. juncea as the female parent, also resulted in many seeds. The BC1 plants contained from 0 to 20 of the rapeseed RAPD markers, and the frequency of inheritance of individual RAPD markers ranged from 19% to 93%. The transgene was found in 52% of the plants analyzed. Five synteny groups of RAPD markers were identified. In the hybrids pollen fertility was 0-28%. The hybrids with the highest pollen fertility were selected as male parents for backcrossing, and pollen fertility in the BC1 plants was improved (24-90%) compared to that of the hybrids. PMID- 24169770 TI - Inheritance and mechanism of resistance to herbicides inhibiting acetolactate synthase in Sonchus oleraceus L. AB - A biotype of Sonchus oleraceus L. (Compositae) has developed resistance to herbicides inhibiting acetolactate synthase (ALS) following field selection with chlorsulfuron for 8 consecutive years. The aim of this study was to determine the inheritance and mechanism of resistance in this biotype. Determination of ALS activity and inhibition kinetics revealed that Km and Vmax did not vary greatly between the resistant and susceptible biotypes. ALS extracted from the resistant biotype was resistant to five ALS-inhibiting herbicides in an in vitro assay. ALS activity from the resistant biotype was 14 19, 2, 3 and 3 times more resistant to inhibition by chlorsulfuron, sulfometuron, imazethapyr, imazapyr and flumetsulam, respectively, than the susceptible biotype. Hybrids between the resistant and a susceptible biotype were produced, and inheritance was followed through the F1, F2 and F3 generations. F1 hybrids displayed a uniform intermediate level of resistance between resistant and susceptible parents. Three distinct phenotypes, resistant, intermediate and susceptible, were identified in the F2 generation following chlorsulfuron application. A segregation ratio of 1?2?1 was observed, indicative of the action of a single, nuclear, incompletely dominant gene. F3 families, derived from intermediate F2 individuals, segregated in a similar manner. Resistance to herbicides inhibiting ALS in this biotype of S. oleraceus is due to the effect of a single gene coding for a resistant form of the target enzyme, ALS. PMID- 24169771 TI - Standard karyotype of Triticum searsii and its relationship with other S-genome species and common wheat. AB - C-banding polymorphism was analyzed in 14 accessions of Triticum searsii from Israel, and a generalized idiogram of the species was established. One accession was homozygous for whole arm translocations T1S(s)S.4S(s)S and T1S(s)L.4S(s)L. C banding analysis was also used to identify 7 T. aestivum cv 'Chinese Spring'-T. searsii disomic chromosome addition lines, 14 ditelosomic chromosome addition lines, 21 disomic whole chromosome, and 31 ditelosomic chromosome substitution lines. The identity of these lines was further confirmed by meiotic pairing analysis. Sporophytic and gametophytic compensation tests were used to determine the homoeologous relationships of the T. searsii chromosomes. The results show that the T. searsii chromosomes do not compensate well for their wheat homoeologues. The C-banding patterns of T. searsii chromosomes are distinct from those of other S-genome species and from the B-genome chromosomes of wheat, indicating that T. searsii is not a direct B-genome donor species of T. turgidum and T. aestivum. PMID- 24169772 TI - Isolation and cytogenetic analyses of genetic sexing strains for the medfly, Ceratitis capitata. AB - Over the last 10 years, several genetic sexing strains have been isolated for the Mediterranean fruit fly, Ceratitis capitata, with the aim of improving the Sterile Insect Technique. However, a major problem with the currently used genetic sexing system, which is based on translocations, is their potential genetic instability. Therefore, careful monitoring and chromosome analyses are necessary when new genetic sexing strains are developed. Instability of a genetic sexing strain can be the consequence of recombination or the survival of aneuploid individuals occurring as a consequence of adjacent-1 segregation in the meiosis of males with Y-autosome translocations. Recently, genetic sexing strains have been isolated that show only low levels of recombination. However, many aneuploid flies are produced by these strains. Therefore, we have made an attempt to isolate new genetic sexing strains that show a low percentage of recombination and no survival of aneuploid individuals. We report their genetic behaviour and the polytene chromosome structure of these new strains. PMID- 24169773 TI - A genetic map of Prunus based on an interspecific cross between peach and almond. AB - A genetic linkage map of Prunus has been constructed using an interspecific F2 population generated from self-pollinating a single F1 plant from a cross between a dwarf peach selection (54P455) and an almond cultivar 'Padre'. Mendelian segregations were observed for 118 markers including 1 morphological (dw), 6 isozymes, 12 plum genomic, 14 almond genomic and 75 peach mesocarp specific cDNA markers. One hundred and seven markers were mapped to 9 different linkage groups covering about 800 cM map distance, and 11 markers remained unlinked. Three loci identified by three cDNA clones, PC8, PC5 and PC68.1, were tightly linked to the dw locus in linkage group 5. Segregation distortion was observed for approximately one-third of the markers, perhaps due to the interspecific nature and the reproductive (i.e. self-incompatibility) differences between peach and almond. This map will be used for adding other markers and genes controlling important traits, identifying the genomic locations and genetic characterizing of the economically important genes in the genus Prunus, as well as for markerassisted selection in breeding populations. Of particular interest are the genes controlling tree growth and form, and fruit ripening and mesocarp development in peach and almond. PMID- 24169774 TI - The use of bulk segregant analysis to identify a RAPD marker linked to leaf rust resistance in barley. AB - An F2 population from a cross between barley accession Q21861 and the Australian barley variety 'Galleon' was used to develop RAPD markers for resistance to barley leaf rust (Puccinia hordei). Resistant and susceptible DNA bulks were constructed following the classification of F2 plants by leaf rust infection type. Bulked segregant analysis was then used to identify a 2.7-kb marker, designated OU022700 and located approximately 12cM from RphQ, a leaf rust resistance gene in Q21861. The marker was generated by PCR with the oligonucleotide primer OPU-02 (Operon). Infection types of F3 progeny were used to confirm assignment of F2 genotypes. OU022700 was shown, retrospectively, to be useful in the identification of individual F2 plants that had been originally misclassified as having susceptible infection types. Both the RAPD marker and RphQ will be potentially useful in the development of new barley cultivars. PMID- 24169775 TI - Genetic analysis of opaque2 modifier gene activity in maize endosperm. AB - Modifier genes have been described that convert the soft endosperm of opaque2 mutants to a hard, vitreous phenotype. The mode of action and the components of the genetic system involved in this seed modification are poorly understood. We used genetic and biochemical analyses to investigate the number of opaque2 modifier genes, their mode of action and their relationship to the biochemical alterations in the modified endosperm. Using two inbred opaque2 lines, we showed that the activity of opaque2 modifier genes is influenced by the genetic background. Analysis of segregating progenies and recombinant inbred lines derived from crosses between opaque2 and modified opaque2 genotypes indicated two independent loci affecting seed opacity and density. Consistent association between endosperm modification and enhanced accumulation of the gamma-zein storage protein suggested that either this protein is directly involved in the process of seed modification, or else that a modifier gene could be tightly linked to the genes responsible for gamma-zein synthesis. PMID- 24169776 TI - Structural evolution of wheat chromosomes 4A, 5A, and 7B and its impact on recombination. AB - The construction of comparative genetic maps of chromosomes 4A(m) and 5A(m) of Triticum monococcum and chromosomes of homoeologous groups 4, 5 and 7 of T. aestivum has provided insight into the evolution of these chromosomes. The structures of chromosomes 4A, 5A and 7B of modern-day hexaploid bread wheat can be explained by a 4AL/5AL translocation that occurred at the diploid level and is present both in T. monococcum and T. aestivum. Three further rearrangements, a 4AL/7BS translocation, a pericentric inversion and a paracentric inversion, have taken place in the tetraploid progenitor of hexaploid wheat. These structural rearrangements and the evolution of chromosomes 4A, 5A and 7B of bread wheat are discussed. The presence of the 4AL/5AL translocation in several Triticeae genomes raises two questions - which state is the more primitive, and is the translocation of mono- or poly-phylogenetic origin?The rearrangements that have occurred in chromosome 4A resulted in segments of both arms having different positions relative to the telomere, compared to 4A(m) and to 4B and 4D. Comparisons of map length in these regions indicate that genetic length is a function of distance from the telomere, with the distal regions showing the highest recombination. PMID- 24169777 TI - A genetic map of potato (Solanum tuberosum) integrating molecular markers, including transposons, and classical markers. AB - A genetic map of potato (Solanum tuberosum L.) integrating molecular markers with morphological and isozyme markers was constructed using a backcross population of 67 diploid potato plants. A general method for map construction is described that differs from previous methods employed in potato and other outbreeding plants. First, separate maps for the female and male parents were constructed. The female map contained 132 markers, whereas the male map contained 138 markers. Second, on the basis of the markers in common the two integrated parental maps were combined into one with the computer programme JoinMap. This combined map consisted of 175 molecular markers, 10 morphological markers and 8 isozyme markers. Ninety-two of the molecular markers were derived from DNA sequences flanking either T-DNA inserts in potato or reintegrated maize transposable elements originating from these T-DNA constructs. Clusters of distorted segregation were found on chromosomes 1,2,8 and 11 for the male parent and chromosome 5 for both parents. The total length of the combined map is 1120 cM. PMID- 24169778 TI - Anthocyanin pathway in rice (Oryza sativa L): identification of a mutant showing dominant inhibition of anthocyanins in leaf and accumulation of proanthocyanidins in pericarp. AB - The present study has surveyed a collection of indica rice (Oryza sativa) lines for tissue-specific anthocyanin pigmentation pattern, which has also been used for a genetically meaningful classification. This classification helped predict probable genotypes of rice lines and, in the process, a leaf blade-specific dominant inhibitor of pigmentation (Ilb) was predicted and its presence later confirmed in two lines. We ascribe most tissue-specific accumulation of anthocyanins to the presence of a different set of Pl alleles. Cyanidin, as a major pigment, and peonidin, as a minor pigment, were detected in purple pigmented tissues. Further, the floral organ-derived tissues always contained a higher level of anthocyanins and, correspondingly, a relatively increased proportion of peonidin. One line, N22B, with a brown pericarp was identified and shown to accumulate proanthocyanidins, but with no anthocyanins, in the pericarp. We propose that the accumulation of proanthocyanidins is due to a block in the anthocyanin biosynthetic pathway in rice at the anthocyanidin synthase-mediated conversion of leucoanthocyanidin to anthocyanidin. PMID- 24169779 TI - Locus-specific primers for LMW glutenin genes on each of the group 1 chromosomes of hexaploid wheat. AB - To reveal the chromosomal location of three known low-molecular-weight (LMW) glutenin genes in wheat, we designed and used three sets of sequence-specific primers in polymerase chain reactions (PCR) on 'Chinese Spring' and its derived group 1 aneuploid nullisomic-tetrasomic stocks. Two sets proved to be chromosome specific and amplified sequences from the Glu-A3 and Glu-D3 loci, respectively. The third set was apparently composed of conserved sequences as it produced PCR products in each of the aneuploids. Two of these products were cloned, and their sequences differed from the known LMW glutenin genes at several positions. Again, primer sets specific for these sequences were designed. One set was directed to the Glu-A3 locus, the second set resulted in two PCR products differing in length, one of which was located on chromosome 1B and the other on 1D. Primer sets constructed for the latter two sequences were specific for the Glu-B3 and Glu-D3 loci, respectively. Hence, primer sets specific for each of the three homoeologous chromosomes of the group 1 (1A, 1B, 1D) are available. In addition, these locus-specific primers were assayed for their ability to distinguish among wheat cultivars. PCR products amplified with one of the Glu-A3-specific primer sets showed length polymorphisms in various wheat varieties. Varieties carrying the 1RS.1BL translocated chromosomes could be recognized by the absence of a PCR product when the Glu-B3 primer set was used. These results suggest that PCR with locus-specific primers can be useful in the molecular genetic analysis of hexaploid wheat. PMID- 24169780 TI - Identification and characterisation of sugarcane intergeneric hybrids, Saccharum officinarum x Erianthus arundinaceus, with molecular markers and DNA in situ hybridisation. AB - Molecular markers were used to characterise sugarcane intergeneric hybrids between S. officinarum and E. arundinaceus. Very simple diagnostic tools for hybrid identification among the progeny were derived from isozyme electrophoresis and a sequence-tagged PCR. Two enzyme systems (GOT and MDH B) and PCR amplification revealing spacer-size variation in the 5s-rDNA cluster were found most convenient. Specific characterisation of the two genomic components was possible using RFLP and in situ hybridisation. The strong molecular differentiation between S. officinarum and E. arundinaceus allows the identification of numerous Erianthus-specific RFLP bands in the hybrids. Genomic DNA in situ hybridisation allows for the differentiation of the chromosomes contributed by S. officinarum and E. arundinaceus in chromosome preparations of the hybrids. In situ hybridisation with the 18s-5.8s-25s rDNA probe highlights the basic chromosome numbers in the two parental species. The potential of these techniques to monitor the Erianthus genome during the introgression process is discussed. PMID- 24169781 TI - Introgression into tomato (Lycopersicon esculentum) of the L. chmielewskii sucrose accumulator gene (sucr) controlling fruit sugar composition. AB - High sucrose concentration in fruit of Lycopersicon chmielewskii is governed by the recessive sucrose accumulator gene (sucr) that is situated in the pericentromeric region of chromosome 3. The sucr gene was introgressed into the genetic background of the hexose-accumulating cultivated tomato (L. esculentum cv 'Hunt 100') by marker-assisted selection using tightly linked RFLP markers and a tomato acid invertase cDNA as probes for sucr. RFLP mapping indicated that the segment containing sucr comprised over 43.2 cM in the BC1F2 generation, representing over one-third of the total length of chromosome 3. By selecting for crossovers between sucr and the flanking visual marker r (yellow fruit flesh) and RFLP marker TG288, we were able to reduce the size of the sucr introgression fragment to 0.8-7.1 cM by the BC5 generation. Smaller recombinant fragments were not obtained despite screening a large BC6F2 population. The smallest sucr introgression reduced recombination between the flanking visual markers sy (sunny) and bls (baby lea syndrome) by 38%. To facilitate future introgression and recombination experiments, a PCR-based test for the sucr gene was developed using primers specific to the tomato invertase gene. This assay takes advantage of a small deletion that maps to the second intron of the L. chmielewskii nvertase gene. The assay detected significant allelic variation both within and between hexose- and sucrose-accumulating Lycopersicon spp. PMID- 24169782 TI - Effects of the Lycopersicon chmielewskii sucrose accumulator gene (sucr) on fruit yield and quality parameters following introgression into tomato. AB - A gene controlling fruit sucrose accumulation, sucr, was introgressed from the wild tomato species Lycopersicon chmielewskii into the genetic background of a hexose-accumulating cultivated tomato, L. esculentum. During introgression, the size of the L. chmielewskii chromosomal segment containing sucr was reduced by selection for recombination between RFLP markers for the sucr gene and flanking loci. The effects of sucr on soluble solids content, fruit size, yield and other fruit parameters were studied in the genetic background of the processing tomato cultivar 'Huntl00'. In a segregating BC5F2 generation, the smallest introgression containing sucr-associated markers was necessary and sufficient to confer high level sucrose accumulation, the effects of which were completely recessive. Fruit of sucr/sucr genotypes were smaller than those of +/sucr or +/+ genotypes at all stages of development. The timing of sugar accumulation and total sugar concentration were unaffected by sugar composition. No differences in total fruit biomass (fresh weight of red and green fruit) at harvest were observed between the genotypes, and sucrose accumulators produced greater numbers of fruit than hexose accumulators in one family. However, the proportion of ripe fruit at harvest, and hence yield of ripe fruit, as well as average ripe fruit weight and seed set were reduced in sucr/sucr genotypes. Sucrose accumulation was also associated with increased soluble solids content, consistency, serum viscosity, predicted paste yield and acidity, and decreased color rating. In the first backcross to L. chmielewskii, hexose accumulators (+/sucr) had larger fruit than sucrose accumulators (sucr/sucr), while no difference in soluble solids was detected. PMID- 24169783 TI - Long-term restricted index selection in mice designed to change fat content without changing body size. AB - The objective of this study was to determine if low secondary selection differentials, caused by selecting within full-sib families, may have accounted for the failure of an intended restricted selection index to reduce epididymal fat pad weight (EF) without changing body weight (BW) in mice. Replicate lines that had been selected within full-sib families for high (HE) or low (LE) EF, while holding BW constant, were crossed. After two generations of random mating, two replicates were sampled and selection initiated for the same restricted index criteria except that mass selection was used to increase the selection differentials. In both phases of selection the HE restricted index selection, designed to increase EF without altering BW, was in agreement with expectation. In contrast, the LE index, designed to decrease EF without changing BW, did not agree with theory since BW increased while EF decreased only slightly. Therefore, reduced selection differentials could not explain the deviation from theory. A possible explanation may reside in the restricted selection index being more sensitive to changes in genetic parameters due to shifts in gene frequency as a consequence of the selection applied. However, linkage disequilibrium and genetic drift can not be ruled out as contributing factors to the asymmetry of response. PMID- 24169784 TI - Genetic variation within and among different cultivars and landraces of Brassica campestris L. and B. oleracea L. based on isozymes. AB - Genetic variation based on isozymes was studied in 43 landraces and cultivars of Brassica campestris from China, 4 cultivars of B. campestris from Sweden and 1 from India, and 5 cultivars of B. oleracea from Sweden and 1 from China (B. alboglabra). A total of 17 isozyme loci was studied, 10 of these were polymorphic in B. campestris and 6 were polymorphic in B. oleracea. The level of heterozygosity seemed to be reduced in the Swedish cultivars compared to the Chinese landraces and cultivars of B. campestris. The level of heterozygosity in B. oleracea was even lower than that in the Swedish cultivars of B. campestris. A phylogeny of the cultivars and landraces of B. campestris showed that the B. campestris var 'yellow sarson' cultivar, originating from India, deviated significantly from the other cultivars of B. campestris. A phylogeny of the cultivars of B. oleracea confirmed the expectations that the cultivar B. alboglabra was not closely related to the cultivated forms of B. oleracea. PMID- 24169785 TI - Inheritance of isozymes in Brassica campestris L. and genetic divergence among different species of Brassiceae. AB - Electrophoretic investigations of Brassica campestris revealed 8 polymorphic loci that had not been described earlier. The inheritance of 7 of them was determined by crosses between different accessions of B. campestris. A phylogeny of B. campestris, B. nigra, B. alboglabra, Sinapis arvensis and S. alba was estimated from the analysis of 15 isozyme loci. The phylogeny showed a close relationship between B. nigra and S. arvensis and a less close relationship between B. campestris and B. oleracea. S. alba was remotely-related to all of the other species. PMID- 24169786 TI - A gene encoding a truncated large subunit of Rubisco is transcribed and salt inducible in rice. AB - Using the rice salt-tolerant mutant 20 as material, a cDNA library was constructed and two salt-inducible clones, SIR5.5 and SIR8.1, were isolated by differential screening. Homology analysis revealed that the two clones together constituted a chimeric rbcL which encoded a truncated large subunit of Rubisco with 337 amino-acids, plus 64 amino-acids of unknown origin. The expressions of both the normal and the chimeric locus appeared to be developmentally regulated and salt-inducible in shoots of the salt-tolerant mutant 20 and its original variety 77-170. In roots, their expressions were salt-inducible in the salt tolerant mutant 20 whereas no, or only premature, forms were present in the salt treated original variety 77-170. Higher concentrations of salt reduced the expressions of both normal rbcL and the chimeric locus. ABA showed no effect on their expression. PMID- 24169787 TI - WIS 2-1A: an ancient retrotransposon in the Triticeae tribe. AB - WIS 2-1A, the first retrotransposon found in wheat, has been recently studied and characterized. Southern hybridization experiments utilizing several species from the Triticeae revealed the presence of homologous sequences in all the taxa tested, showing high levels of interspecific variability and almost no intraspecific differentiation. Further experiments using in situ hybridization in several species showed that the retroposon was almost completely dispersed throughout the genomes tested. These results suggested that WIS 2-1A is an ancient element that probably was present in the unknown common ancestor of the Triticeae and that only under rare circumstances does it become active. DNA fragments homologous to the WIS 2-1A reverse transcriptase gene were isolated from most of the Triticeae species using PCR. The fragments obtained were sequenced and analyzed. Even though the sequence alignment was consistent with the phylogenetic studies made in the past, the genus Thinopyrum showed new evidence for a possible horizontal propagation of the retroelement.Mention of a trade name or proprietary product does not constitute a guarantee, warranty or recommendation of the product by the U.S. Department of Agriculture or the University of Missouri and does not imply its approval to the exclusion of other products that may be suitableAll programs and services of the U.S. Department of Agriculture are offered on a non-discriminatory basis without regard to race, colour, national origin, religion, sex, age, marital status, or handicap. PMID- 24169788 TI - Identification of quantitative trait loci (QTLs) for heading date and plant height in cultivated rice (Oryza sativa L.). AB - 'Lemont' and 'Teqing' are both semidwarf rice varieties that differ in heading date by only 6 days. However, when 'Lemont' and 'Teqing' are crossed there is transgressive segregation for both heading date (HD) and plant height (PH). By testing 2418 F4 lines with 113 well-distributed RFLP markers, we identified and mapped chromosomal regions that were largely responsible for this transgressive segregation. QHd3a, a QTL from 'Lemont' that gives 8 days earlier heading, was identified on chromosome 3 approximately 3 cM from the marker RG348. Another QTL with a large effect, QHd8a, which gives 7 days earlier heading, was identified on chromosome 8 of 'Teqing' between RG20 and RG1034. Along with a QTL, QHd9a with a phenotypic effect of 3.5 days, these genomic regions collectively explain 76.5% of the observed phenotypic variance in heading date. Four QTLs which altered plant height from 4 to 7 cm were also mapped; these collectively explain 48.8% of the observed phenotypic variation in plant height. None of the QTLs for plant height mapped to chromosome 1, the location of the semidwarf gene sd-1. All three of the HD loci mapped to approximately the same genomic locations as PH QTLs, and in all cases, there was a reduction in height of approximately 1 cm for every day of earlier heading. The correspondence between the HD and some of the PH loci suggests that genes at these chromosome locations may have pleiotropic effects on both HD and PH. The observed heterosis in the F1 plants for HD can be largely explained by the dominance for earliness of the identified HD loci and distribution of earlier heading alleles in the parents. However, overdominance observed at one of the PH QTL may, at least in part, be responsible for the observed heterosis in PH. PMID- 24169789 TI - Characterization of quantitative trait loci (QTLs) in cultivated rice contributing to field resistance to sheath blight (Rhizoctonia solani). AB - Sheath blight, caused by Rhizoctonia solani, is one of the most important diseases of rice. Despite extensive searches of the rice germ plasm, the major gene(s) which give complete resistance to the fungus have not been identified. However, there is much variation in quantitatively inherited resistance to R. solani, and this type of resistance can offer adequate protection against the pathogen under field conditions. Using 255 F4 bulked populations from a cross between the susceptible variety 'Lemont' and the resistant variety 'Teqing', 2 years of field disease evaluation and 113 well-distributed RFLP markers, we identified six quantitative trait loci (QTLs) contributing to resistance to R. solani. These QTLs are located on 6 of the 12 rice chromosomes and collectively explain approximately 60% of the genotypic variation or 47% of the phenotypic variation in the 'Lemont'x'Teqing' cross. One of these resistance QTLs (QSbr4a), which accounted for 6% of the genotypic variation in resistance to R. solani, appeared to be independent of associated morphological traits. The remaining five putative resistance loci (QSbr2a, QSbr3a, QSbr8a, QSbr9a and QSbr12a) all mapped to chromosomal regions also associated with increased plant height, three of which were also associated with QTLs causing later heading. This was consistent with the observation that heading date and plant height accounted for 47% of the genotypic variation in resistance to R. solani in this population. There were also weak associations between resistance to R. solani and leaf width, which were likely due to linkage with a QTL for this trait rather than to a physiological relationship. PMID- 24169790 TI - Optimal restricted phenotypic selection. AB - Phenotypic selection is modified by introducing upper limits on the portion (P 1) of individuals selected from a family as well as on the portion (P 2) of family number that are allowed to contribute. At a preset selection proportion, P and P 1, the maximum genetic gain is obtained by finding an optimum restriction on family number (P 2 (*) ). A numerical procedure for solving the problem of optimization is developed for infinite populations. In small populations, maximum gain and P 2 (*) can be found by simply comparing all possible P2. Numerical examples are demonstrated for infinite breeding populations, assuming a normally distributed family mean and within-family deviation. Selection and its simulation were applied to the fieldtest results of two tree species. Optimum restriction on family number is very close to P/P 1, especially when heritability is low. In the real world of tree breeding, P 2 (*) is given, or approximated, by P/P 1+1/ tm where m is the initial family number. The improvement of gain and the conservation of inbreeding effective population size are easy with high heritability and could be simultaneously obtained by using intense selection with a relatively low P 1. PMID- 24169791 TI - Differential patterns of accumulation and retention of dietary trace elements associated with coal ash during larval development and metamorphosis of an amphibian. AB - We performed an experiment in which larval gray tree frogs (Hyla chrysoscelis) were raised through metamorphosis on diets increased with a suite of elements associated with coal combustion residues (silver [Ag], arsenic [As], cadmium [Cd], chromium [Cr], copper [Cu], mercury [Hg], lead [Pb], selenium [Se], vanadium [V], and zinc [Zn]) at "low" and "high" concentrations. We quantified accumulation of metals at three life stages (mid-larval development, initiation of metamorphosis, and completion of metamorphosis) as well as effects on survival, metabolic rate, size at metamorphosis, and duration and loss of weight during metamorphosis. Most elements were accumulated in a dose-dependent pattern by some or all life stages, although this was not the case for Hg. For most elements, larval body burdens exceeded those of later life stages in some or all treatments (control, low, or high). However for Se, As, and Hg, body burdens in control and low concentrations were increased in later compared with earlier life stages. A lack of dose-dependent accumulation of Hg suggests that the presence of high concentrations of other elements (possibly Se) either inhibited accumulation or increased depuration of Hg. The duration of metamorphosis (forelimb emergence through tail resorption) was lengthened in individuals exposed to the highest concentrations of elements, but there were no other statistically significant biological effects. This study shows that patterns of accumulation and possibly depuration of metals and trace elements are complex in animals possessing complex life cycles. Further study is required to determine specific interactions affecting these patterns, in particular which elements may be responsible for affecting accumulation or retention of Hg when organisms are exposed to complex mixtures of elements. PMID- 24169792 TI - Controlled electrochemical intercalation, exfoliation and in situ nitrogen doping of graphite in nitrate-based protic ionic liquids. AB - Few-layer nitrogen-doped graphene has been prepared via fast and controlled electrochemical exfoliation of graphite in a protic ionic liquid ethylammonium nitrate. The method presents a potentially scalable approach for preparation of metal-free, N-doped graphene for use as electrocatalysts for oxygen reduction reactions. PMID- 24169793 TI - Pimarane diterpenes from the Arctic fungus Eutypella sp. D-1. AB - Two new diterpenes, libertellenone G(1) and libertellenone H(2) were isolated from the fungus Eutypella sp. D-1 isolated from the soil of high latitude of Arctic, together with two known pimarane diterpenes (3-4). The structures of 1 and 2 were elucidated from spectroscopic data (nuclear magnetic resonance, mass spectrometry and infrared). These compounds were evaluated for cytotoxic activity against seven human tumor cell lines. Compound 2 showed a range of cytotoxicity between 3.31 and 44.1 MUM. Compound 1 exhibited antibacterial activity against Escherichia coli, Bacillus subtilis and Staphylococcus aureus. PMID- 24169794 TI - Fungal peritonitis associated with Curvularia geniculata and Pithomyces species in a patient with vulvar cancer who was successfully treated with oral voriconazole. PMID- 24169795 TI - A secondary mode of action of polymyxins against Gram-negative bacteria involves the inhibition of NADH-quinone oxidoreductase activity. AB - Polymyxin B and colistin were examined for their ability to inhibit the type II NADH-quinone oxidoreductases (NDH-2) of three species of Gram-negative bacteria. Polymyxin B and colistin inhibited the NDH-2 activity in preparations from all of the isolates in a concentration-dependent manner. The mechanism of NDH-2 inhibition by polymyxin B was investigated in detail with Escherichia coli inner membrane preparations and conformed to a mixed inhibition model with respect to ubiquinone-1 and a non-competitive inhibition model with respect to NADH. These suggest that the inhibition of vital respiratory enzymes in the bacterial inner membrane represents one of the secondary modes of action for polymyxins. PMID- 24169796 TI - Postoperative bacteriuria, pyuria and urinary tract infection in patients with an orthotopic sigmoid colon neobladder replacement. AB - The purpose of this study is to investigate the prevalence of postoperative bacteriuria, pyuria and urine culture in patients with an orthotopic sigmoid colon neobladder replacement. Urine samples for bacteriuria, pyuria and urine culture, if necessary, were collected at 1, 3, 6, 9 and 12 months after surgery and the presence of blood culture and antibiotic-resistant strains, and their treatments on positive urine culture cases were investigated. Of 209 for bacteriuria and 207 for pyuria urine samples with evaluable data, 95 (45.5%) were positive for bacteriuria and 76 (36.7%) had pyuria (10 or more white blood cells per high-power field). Totally, 30 bacteria were isolated from urine culture of urinary tract infection (UTI) and Klebisiella pneumoniae, Escherichia coli, Staphylococcos aureus and Enterococcus spp. strains were representatively isolated. The incidence of pyuria significantly decreased over time (P=0.041) but that of bacteriuria did not (P=0.107). In them, there were six bacteria (20.7%) with antibiotic-resistant strains. The antibiotics used for their treatments representatively were levofloxacin in five cases, tazobactam/piperacillin in three cases and sulfamethoxazole/trimethoprim and cefepime, meropenem in two cases, respectively. In conclusion, these findings suggest that physicians taking care of sigmoid colon neobladder patients need to be aware of these high ratios of bacteriuria, pyuria and UTI, including bacteremia. PMID- 24169797 TI - Taking aim at wall teichoic acid synthesis: new biology and new leads for antibiotics. AB - Wall teichoic acids are a major and integral component of the Gram-positive cell wall. These structures are present across all species of Gram-positive bacteria and constitute roughly half of the cell wall. Despite decades of careful investigation, a definitive physiological function for wall teichoic acids remains elusive. Advances in the genetics and biochemistry of wall teichoic acid synthesis have led to a new understanding of the complexity of cell wall synthesis in Gram-positive bacteria. Indeed, these innovations have provided new molecular tools available to probe the synthesis and function of these cell wall structures. Among recent discoveries are unexpected roles for wall teichoic acid in cell division, coordination of peptidoglycan synthesis and beta-lactam resistance in methicillin-resistant Staphylococcus aureus (MRSA). Notably, wall teichoic acid biogenesis has emerged as a bona fide drug target in S. aureus, where remarkable synthetic-viable interactions among biosynthetic genes have been leveraged for the discovery and characterization of novel inhibitors of the pathway. PMID- 24169798 TI - Targeting DXP synthase in human pathogens: enzyme inhibition and antimicrobial activity of butylacetylphosphonate. AB - The unique methylerythritol phosphate pathway for isoprenoid biosynthesis is essential in most bacterial pathogens. The first enzyme in this pathway, 1-deoxy D-xylulose 5-phosphate (DXP) synthase, catalyzes a distinct thiamin diphosphate (ThDP)-dependent reaction to form DXP from D-glyceraldehyde 3-phosphate (D-GAP) and pyruvate and represents a potential anti-infective drug target. We have previously demonstrated that the unnatural bisubstrate analog, butylacetylphosphonate (BAP), exhibits selective inhibition of Escherichia coli DXP synthase over mammalian ThDP-dependent enzymes. Here, we report the selective inhibition by BAP against recombinant DXP synthase homologs from Mycobacterium tuberculosis, Yersinia pestis and Salmonella enterica. We also demonstrate antimicrobial activity of BAP against both Gram-negative and Gram-positive strains (including E. coli, S. enterica and Bacillus anthracis), and several clinically isolated pathogens. Our results suggest a mechanism of action involving inhibition of DXP synthase and show that BAP acts synergistically with established antimicrobial agents, highlighting a potential strategy to combat emerging resistance in bacterial pathogens. PMID- 24169800 TI - Identification of the allosamidin-releasing factor in allosamidin-producing Streptomyces. PMID- 24169799 TI - Mode of action and structure-activity relationship studies of geobacillin I. PMID- 24169801 TI - Enzyme analysis of the polyketide synthase leads to the discovery of a novel analog of the antibiotic alpha-lipomycin. PMID- 24169804 TI - Silver(I) supramolecular complexes generated from isophorone-based ligands: crystal structures and enhanced nonlinear optical properties through metal complexation. AB - By self-assembly of (E)-2-(3-(4-(1H-imidazol-1-yl)styryl)-5,5-dimethylcyclohex-2 enylidene)malononitrile (L(1)) and (E)-2-(3-(4-(1H-1,2,4-triazol-1-yl)styryl)-5,5 dimethylcyclohex-2-enylidene)malononitrile (L(2)) with silver(I) salts, eight new complexes, namely AgL(1)2ClO4 (1), AgL(1)2NO3 (2), [AgL(1)2NO3].C6H6 (3), [AgL(1)2OOCCF3].C6H6 (4), [AgL(1)2PF6].C6H6 (5), AgL(2)2NO3 (6), [AgL(2)OOCCF3]2 (7) and AgL(2)2PF6 (8), are presented along with an analysis of their structural features. The structures are built up through the combination of coordination bonds, Ag...pi, Ag...F (or O), hydrogen bonding, and pi...pi stacking interactions to generate new supramolecular architectures. We observed the formation of two-dimensional coordination polymers for complex 7. Solvent benzene molecules and anions are dispersed in the supramolecular structure and play a vital role in building the supramolecular structures of the complexes. The nonlinear optical (NLO) properties of the complexes were investigated using the Z scan technique and complexes 1, 2, 3, 4 and 7 show obviously nonlinear absorption compared with ligands (L(1) and L(2)). PMID- 24169802 TI - Nociceptin/orphanin FQ decreases glutamate transmission and blocks ethanol induced effects in the central amygdala of naive and ethanol-dependent rats. AB - The central nucleus of the amygdala (CeA) mediates several addiction-related processes and nociceptin/orphanin FQ (nociceptin) regulates ethanol intake and anxiety-like behaviors. Glutamatergic synapses, in the CeA and throughout the brain, are very sensitive to ethanol and contribute to alcohol reinforcement, tolerance, and dependence. Previously, we reported that in the rat CeA, acute and chronic ethanol exposures significantly decrease glutamate transmission by both pre- and postsynaptic actions. In this study, using electrophysiological techniques in an in vitro CeA slice preparation, we investigated the effects of nociceptin on glutamatergic transmission and its interaction with acute ethanol in naive and ethanol-dependent rats. We found that nociceptin (100-1000 nM) diminished basal-evoked compound glutamatergic receptor-mediated excitatory postsynaptic potentials (EPSPs) and spontaneous and miniature EPSCs (s/mEPSCs) by mainly decreasing glutamate release in the CeA of naive rats. Notably, nociceptin blocked the inhibition induced by acute ethanol (44 mM) and ethanol blocked the nociceptin-induced inhibition of evoked EPSPs in CeA neurons of naive rats. In neurons from chronic ethanol-treated (ethanol-dependent) rats, the nociceptin induced inhibition of evoked EPSP amplitude was not significantly different from that in naive rats. Application of [Nphe1]Nociceptin(1-13)NH2, a nociceptin receptor (NOP) antagonist, revealed tonic inhibitory activity of NOP on evoked CeA glutamatergic transmission only in ethanol-dependent rats. The antagonist also blocked nociceptin-induced decreases in glutamatergic responses, but did not affect ethanol-induced decreases in evoked EPSP amplitude. Taken together, these studies implicate a potential role for the nociceptin system in regulating glutamatergic transmission and a complex interaction with ethanol at CeA glutamatergic synapses. PMID- 24169803 TI - Methamphetamine causes degeneration of dopamine cell bodies and terminals of the nigrostriatal pathway evidenced by silver staining. AB - Methamphetamine is a widely abused illicit drug. Recent epidemiological studies showed that methamphetamine increases the risk for developing Parkinson's disease (PD) in agreement with animal studies showing dopaminergic neurotoxicity. We examined the effect of repeated low and medium doses vs single high dose of methamphetamine on degeneration of dopaminergic terminals and cell bodies. Mice were given methamphetamine in one of the following paradigms: three injections of 5 or 10 mg/kg at 3 h intervals or a single 30 mg/kg injection. The integrity of dopaminergic fibers and cell bodies was assessed at different time points after methamphetamine by tyrosine hydroxylase immunohistochemistry and silver staining. The 3 * 10 protocol yielded the highest loss of striatal dopaminergic terminals, followed by the 3 * 5 and 1 * 30. Some degenerating axons could be followed from the striatum to the substantia nigra pars compacta (SNpc). All protocols induced similar significant degeneration of dopaminergic neurons in the SNpc, evidenced by amino-cupric-silver-stained dopaminergic neurons. These neurons died by necrosis and apoptosis. Methamphetamine also killed striatal neurons. By using D1 Tmt/D2-GFP BAC transgenic mice, we observed that degenerating striatal neurons were equally distributed between direct and indirect medium spiny neurons. Despite the reduced number of dopaminergic neurons in the SNpc at 30 days after treatment, there was a partial time-dependent recovery of dopamine terminals beginning 3 days after treatment. Locomotor activity and motor coordination were robustly decreased 1-3 days after treatment, but recovered at later times along with dopaminergic terminals. These data provide direct evidence that methamphetamine causes long-lasting loss/degeneration of dopaminergic cell bodies in the SNpc, along with destruction of dopaminergic terminals in the striatum. PMID- 24169806 TI - In vitro and in vivo imaging application of a 1,8-naphthalimide-derived Zn(2+) fluorescent sensor with nuclear envelope penetrability. AB - A newly developed fluorescent sensor, , shows a specific turn-on response to Zn(2+) and can be excited by visible light. The in situ nuclear Zn(2+) imaging in HeLa and HepG2 cells reveals the nuclear envelope penetrability of the sensor. The specific sensor location in a zebrafish larva was also demonstrated. PMID- 24169807 TI - Linagliptin added to sulphonylurea in uncontrolled type 2 diabetes patients with moderate-to-severe renal impairment. AB - Glucose-lowering treatment options are limited for uncontrolled type 2 diabetes mellitus (T2DM) patients with advanced stages of renal impairment (RI). This retrospective analysis evaluated glycaemic efficacy and tolerability of the dipeptidyl peptidase-4 inhibitor linagliptin added to sulphonylurea. Three randomized phase 3 studies (n = 619) including T2DM subjects with moderate or severe RI [estimated glomerular filtration rate (eGFR) < 60 mL/min/1.73 m2] were analysed; only sulphonylurea-treated subjects who received additional linagliptin (n = 58) or placebo (n = 33) were evaluated. Linagliptin provided meaningful placebo-adjusted HbA1c reductions of -0.68% (95% confidence interval: -1.19, 0.17), -1.08% (-2.02, -0.14) and -0.62% (-1.25, 0.01) after 24, 18 and 12 weeks, respectively. There was a similar incidence of overall adverse events (linagliptin: 79.3%, placebo: 75.8%) and hypoglycaemia (linagliptin: 37.9%, placebo: 39.4%). Severe hypoglycaemia was more common with placebo (linagliptin: 1.7%, placebo: 6.1%). These data suggest that linagliptin is a safe and effective glucose-lowering treatment in T2DM patients with moderate-to-severe RI for whom sulphonylurea treatment is no longer sufficient. PMID- 24169805 TI - Heparanase is preferentially expressed in human psoriatic lesions and induces development of psoriasiform skin inflammation in mice. AB - Heparanase is the sole mammalian endoglycosidase that selectively degrades heparan sulfate, the key polysaccharide associated with the cell surface and extracellular matrix of a wide range of tissues. Extensively studied for its capacity to promote cancer progression, heparanase enzyme was recently implicated as an important determinant in several inflammatory disorders as well. Applying immunohistochemical staining, we detected preferential expression of heparanase by epidermal keratinocytes in human psoriatic lesions. To investigate the role of the enzyme in the pathogenesis of psoriasis, we utilized heparanase transgenic mice in a model of 12-O-tetradecanoyl phorbol 12-myristate 13-acetate-induced cutaneous inflammation. We report that over-expression of the enzyme promotes development of mouse skin lesions that strongly recapitulate the human disease in terms of histomorphological appearance and molecular/cellular characteristics. Importantly, heparanase of epidermal origin appears to facilitate abnormal activation of skin-infiltrating macrophages, thus generating psoriasis-like inflammation conditions, characterized by induction of STAT3, enhanced NF-kappaB signaling, elevated expression of TNF-alpha and increased vascularization. Taken together, our results reveal, for the first time, involvement of heparanase in the pathogenesis of psoriasis and highlight a role for the enzyme in facilitating abnormal interactions between immune and epithelial cell subsets of the affected skin. Heparanase inhibitors (currently under clinical testing in malignant diseases) could hence turn highly beneficial in psoriatic patients as well. PMID- 24169808 TI - Investigation of endothelial dysfunction and arterial stiffness in children with type 1 diabetes mellitus and the association with diastolic dysfunction. AB - OBJECTIVE: The objective of this study is to investigate endothelial dysfunction (ED) and arterial stiffness (AS) and determine the association with diastolic dysfunction in children with type 1 diabetes mellitus (DM). METHODS: A total of 42 patients without diabetic complications (mean age: 13.21 years) and 40 healthy (mean age: 13.07 years) children were included in this study. AS was assessed with ascending aorta M-mode measurements, diastolic dysfunction with pulsed wave (PW) Doppler and tissue Doppler echocardiography measurements and flow-mediated dilatation (FMD) and carotid intima-media thickness (CIMT) with high-resolution ultrasonography. RESULTS: Results of diabetic group and healthy children were compared. In diabetic group, aortic strain (8.40 +/- 2.98, 20.12 +/- 5.04; p < 0.001), aortic distensibility (7.36 +/- 2.92, 16.59 +/- 4.25; p < 0.001) and FMD% (7.70 +/- 2.83, 11.33 +/- 2.85; p < 0.001) were found decreased, and CIMT (0.52 +/- 0.09 mm, 0.47 +/- 0.08 mm; p < 0.05) was found increased. Additionally, left ventricular lateral segment and right ventricular free-wall isovolumic relaxation time (IVRT) and myocardial performance index (MPI) were found increased. Correlation analyses demonstrated a negative correlation between FMD and IVRT and MPI. CONCLUSIONS: ED and AS were found in type 1 DM patients without diabetic complications. Additionally, correlation was shown between increased AS and ED and right and left ventricular diastolic dysfunctions. PMID- 24169810 TI - Detection of Blastocystis hominis: a controversial human pathogen. AB - Blastocystis hominis has been reclassified as a protozoan parasite. Its role as a human pathogen is somewhat controversial. There has been a dramatic increase in the frequency of B. hominis infection in association with diarrhea especially in immunocompromised hosts like AIDS patients, travelers, homosexuals, day care children, animal handlers especially zoo keepers, etc. Recent reports suggest that B. hominis is an emerging pathogen; hence, we have undertaken this study to detect B. hominis from stool samples of patients attending our hospital. About 200 stool samples were tested by light microscopic examination, for observing wet mounts with saline and Lugol's iodine. Permanent staining of fecal smear by Gram's staining and modified acid fast staining was done. The stool sample which was microscopically positive for B. hominis was cultured on Lowenstein-Jensen's (LJ) medium. In one patient, the vacuolated form of B. hominis was observed in wet mount with saline preparation of stool sample. This was very clearly seen in wet mount with Lugol's iodine. In Gram's stained preparation, also the vacuolated form was observed. Detection of B. hominis was not possible by modified acid fast staining. B. hominis was also grown on LJ medium which is an egg-containing medium. Clinical microbiology laboratories should start screening of stool samples for B. hominis as it is an emerging pathogen. PMID- 24169809 TI - The serological diagnosis of human clonorchiasis by time-resolved fluoroimmunoassay based on GST2-specific IgG4 detection. AB - Due to its delayed fluorescence of a lanthanide chelate, high accuracy and low background the broad linear range, long fluorescent life-time and large Stoke's shift of europium chelates, the time-resolved fluorescence has been developed for higher sensitive immunoassay. In this article, a simple, sensitive and specific method-time-resolved fluoroimmunoassay (TRFIA) was adopted for immunoassay of clonorchiasis, and recombinant glutathione transferases 2 of Clonorchis sinensis (rCsGST2) was used as a diagnostic antigen. To evaluate this novel assay for clinical applications, 409 serum samples were investigated. The diagnostic accuracy of the antigen was evaluated by receiver-operating characteristic (ROC) analysis. The area under the ROC curve (AUC) was 0.965, 95% confidence interval (CI, 0.946, 0.985). To eliminate the random influence of ambient temperature, test parameters, photometric instruments and so on, the cut-off value was expressed as ratios between the fluorescence of sample and that of a well-defined negative control serum, and the deduced cut-off value was 9.3605. At the optimum cut-off criteria, the technique has a sensitivity of 95.80%, specificity of 93.60%. And the cross reactivity revealed that its cross reactivity with Schistosoma japonicum, round worm, hook worm, whip worm, and Toxoplasma gondii was 9.3, 8.3, 7.6, 9.8, and 5.0%, respectively. Kappa score of agreement between TRFIA and microscopic examination of stools was 0.892, P < 0.05. These combined results showed that our method is feasible and could be used for the clinical determination of clonorchiasis. PMID- 24169811 TI - Haemophilia Registry of the Medical Committee of the Swiss Haemophilia Society. Update and annual survey 2011/12. AB - The Haemophilia Registry of the Swiss Haemophilia Society is currently more than 12 years old. We present here the data as from October 31st, 2012. Registered are patients with haemophilia A and B, von Willebrand disease with VWF:R-Co < 10% and other rare factor deficiencies. For this latter group, inclusion in the Registry depends on the clinical relevance of the bleeding disorder, not on the factor level. Data come directly from the Swiss haemophilia reference and treatment centers and should be updated once a year. Currently 967 patients are registered, the majority (587) presenting with haemophilia A. Disease severity is graded according to ISTH criteria. Basic epidemiological findings are similar to those from larger registries in Europe, Canada or the USA. More that 60% of persons with haemophilia in Switzerland are treated on-demand, with the exception of young patients (<20 years) who present an 80 to 90% rate of prophylactic therapy. Nevertheless, global use of factor concentrates went continuously up over the last decade and reaches now 5.52 Units per capita, still a low value compared to other high-income European countries. A recent survey of the Registry shows that treaters' compliance with yearly data updates is insufficient; measures will be undertaken in 2013 to enhance data quality. PMID- 24169812 TI - Risk behaviors related to cigarette smoking among persons with spinal cord injury. AB - INTRODUCTION: Smoking, while detrimental to health in any population, has greater health implications for those with spinal cord injury (SCI) because of additional risks posed by SCI. The aims of this study were to document smoking status after SCI and to assess relationships between smoking status with injury severity and alcohol/pain medication use. METHODS: Participants (n = 1,076) were identified from a large rehabilitation hospital in the southeastern part of the United States. Eligibility criteria included (a) traumatic SCI resulting in residual impairment, (b) adult, and (c) 1+ years postinjury. Previous and current cigarette smoking and quitting attempts were assessed. Relationships were assessed between smoking status (current, former, and never), alcohol use, and pain medication use. RESULTS: Of participants (72% male, M age = 49.6 years, M = 16.1 years since SCI), 49.2% had never smoked, 28.2% were former smokers, and 22.6% were current smokers. Of current smokers, 39.2% attempted quitting in the past year and 77.2% had ever tried to quit. Only 29.9% of those who ever tried to quit sought professional help. Ambulatory persons, regardless of injury level, were 2.32 times more likely to be current smokers than nonambulatory persons with a high-level cervical injury. Lower socioeconomic status, binge drinking, and misuse of pain medication all predicted current smoking. CONCLUSIONS: Smoking prevalence among persons with SCI is largely consistent with the general population. Additionally, we found smoking to be associated with other risk behaviors (binge drinking and prescription medication misuse) and differs by injury severity. Future studies should assess smoking interventions, which may differ by injury severity. PMID- 24169813 TI - The predictive value of smoking expectancy and the heritability of its accuracy. AB - INTRODUCTION: Among smokers, former smokers, and never-smokers, this study aimed to (a) determine the predictive value of smoking expectancy on future smoking status, and (b) test the relative contribution of genes and environment to a person's ability to accurately predict future smoking status. For smokers, smoking expectancy reflects the intention to continue smoking; for former smokers, it reflects the intention to take up smoking again; and for never smokers, it reflects the intention to initiate smoking. METHODS: A longitudinal design was employed in which participants of the Netherlands Twin Register completed 2 consecutive surveys 2 years apart between 1993 and 2011 (3,591 adolescents aged 14-18 years), or between 1993 and 2004 (11,568 adults, aged 18+ years). Smoking expectancy was measured by asking, "Do you think you'll smoke in a year's time?", with answer categories ranging from "certainly not" to "absolutely yes" on a 5-point scale. To determine the predictive value of smoking expectancy, analyses were performed in smokers, former smokers, and never-smokers separately. Data of 2,987 adolescents and 4,911 adult twins were analyzed to estimate heritability. A dichotomous variable reflected the ability to predict future smoking status (correct/incorrect). RESULTS: Smoking expectancy significantly predicted future smoking status among former smokers and never smokers. The ability to accurately predict future smoking status was explained by additive genetic factors for 59% of adolescents and 27% of adults, with the remainder being explained by unique environmental factors. CONCLUSIONS: A single question on smoking expectancy helps predict future smoking status. Variation in how well subjects predict their future smoking behavior is influenced by genetic factors, especially during adolescence. PMID- 24169814 TI - Basal ganglia plus insula damage yields stronger disruption of smoking addiction than basal ganglia damage alone. AB - INTRODUCTION: The main objective of this study was to elucidate the importance of the basal ganglia (BG) and insula (INS) for nicotine addiction and smoking behavior. METHODS: We used a lesion study examining the effects of BG and INS damage on changes in smoking behavior and nicotine dependence over time in a prospective manner. We studied whether combined BG and INS damage yields more substantial disruption of smoking and nicotine dependence than damage to the BG alone and compared with damage to other brain regions outside the BG and INS (brain-damaged comparison [BDC] group). We obtained neuroanatomical and behavioral data for 63 neurological patients with stroke at 1 month after onset and at 3-, 6-, and 12-month follow-ups. All patients were smokers at lesion onset. RESULTS: The BG and BG + INS groups had significantly higher and more sustained rates of smoking cessation than patients with damage elsewhere. By 12 months after onset, only 14.3% of the patients in the BDC group were classified as nonsmokers. In the BG group, 37% were not smoking by the 12-month follow-up, and in the BG + INS group, smoking cessation was even more pronounced, as 75% of this group was not smoking at the 12-month epoch. CONCLUSIONS: The findings show that damage to the BG alone can cause disruption of smoking addiction, and when BG damage is combined with INS damage, the disruption increases. The latter finding is consistent with the proposal that the INS has a key role in smoking addiction. PMID- 24169815 TI - Sulfur oxidation to sulfate coupled with electron transfer to electrodes by Desulfuromonas strain TZ1. AB - Microbial oxidation of elemental sulfur with an electrode serving as the electron acceptor is of interest because this may play an important role in the recovery of electrons from sulfidic wastes and for current production in marine benthic microbial fuel cells. Enrichments initiated with a marine sediment inoculum, with elemental sulfur as the electron donor and a positively poised (+300 mV versus Ag/AgCl) anode as the electron acceptor, yielded an anode biofilm with a diversity of micro-organisms, including Thiobacillus, Sulfurimonas, Pseudomonas, Clostridium and Desulfuromonas species. Further enrichment of the anode biofilm inoculum in medium with elemental sulfur as the electron donor and Fe(III) oxide as the electron acceptor, followed by isolation in solidified sulfur/Fe(III) medium yielded a strain of Desulfuromonas, designated strain TZ1. Strain TZ1 effectively oxidized elemental sulfur to sulfate with an anode serving as the sole electron acceptor, at rates faster than Desulfobulbus propionicus, the only other organism in pure culture previously shown to oxidize S degrees with current production. The abundance of Desulfuromonas species enriched on the anodes of marine benthic fuel cells has previously been interpreted as acetate oxidation driving current production, but the results presented here suggest that sulfur-driven current production is a likely alternative. PMID- 24169816 TI - Effects of conserved residues and naturally occurring mutations on Mycobacterium tuberculosis RecG helicase activity. AB - RecG is a helicase that is conserved in nearly all bacterial species. The prototypical Escherichia coli RecG promotes regression of stalled replication forks, participates in DNA recombination and DNA repair, and prevents aberrant replication. Mycobacterium tuberculosis RecG (RecGMtb) is a DNA-dependent ATPase that unwinds a variety of DNA substrates, although its preferred substrate is a Holliday junction. Here, we performed site-directed mutagenesis of selected residues in the wedge domain and motifs Q, I, Ib and VI of RecGMtb. Three of the 10 substitution mutations engineered were detected previously as naturally occurring SNPs in the gene encoding RecGMtb. Alanine substitution mutations at residues Q292, F286, K321 and R627 abolished the RecGMtb unwinding activity, whilst RecGMtb F99A, P285S and T408A mutants exhibited ~25-50 % lower unwinding activity than WT. We also found that RecGMtb bound ATP in the absence of a DNA cofactor. PMID- 24169817 TI - Deformable image registration of CT and truncated cone-beam CT for adaptive radiation therapy. AB - Truncation of a cone-beam computed tomography (CBCT) image, mainly caused by the limited field of view (FOV) of CBCT imaging, poses challenges to the problem of deformable image registration (DIR) between computed tomography (CT) and CBCT images in adaptive radiation therapy (ART). The missing information outside the CBCT FOV usually causes incorrect deformations when a conventional DIR algorithm is utilized, which may introduce significant errors in subsequent operations such as dose calculation. In this paper, based on the observation that the missing information in the CBCT image domain does exist in the projection image domain, we propose to solve this problem by developing a hybrid deformation/reconstruction algorithm. As opposed to deforming the CT image to match the truncated CBCT image, the CT image is deformed such that its projections match all the corresponding projection images for the CBCT image. An iterative forward-backward projection algorithm is developed. Six head-and-neck cancer patient cases are used to evaluate our algorithm, five with simulated truncation and one with real truncation. It is found that our method can accurately register the CT image to the truncated CBCT image and is robust against image truncation when the portion of the truncated image is less than 40% of the total image. PMID- 24169818 TI - New developed urological protocols for the Uro Dyna-CT reduce radiation exposure of endourological patients below the levels of the low dose standard CT scans. AB - PURPOSE: Cross-sectional imaging by computed tomography (CT) is associated with higher radiation dose compared to plain X-ray. The Uro Dyna-CT provides CT-like images in the endourological operating room. Our aim was to reduce the radiation exposure of endourological patients with the Uro Dyna-CT and optimize the cross sectional image quality. MATERIALS AND METHODS: For the hard contrast protocol, two artificial stones were placed in a Rando-Alderson phantom's left kidney region. Relevant parameters of the standard abdomen protocol were changed. After each modification, two urologists subjectively evaluated the image quality. We developed two customized protocols (standard, low-dose) for hard contrast imaging. To optimize the examination protocol for soft tissue imaging a standardized cone beam phantom was used. Parameters of the preset high-resolution protocol were changed to develop a protocol with similar objective image quality but lower radiation dose. To evaluate the effective radiation dose we embedded 129 thermoluminescence dosimeters in the kidney and ureter region of the Rando Alderson phantom and performed each protocol five times (stone, soft tissue) and ten times (low-dose protocol). Mean effective dose values per 3D-examination were calculated. RESULTS: We detected a dose area product (DAP) 776.2 (standard) and 163.5 MUGym(2) (low-dose) for the stone protocols with an effective dose of 1.96 and 0.33 mSv, respectively. The soft tissue protocol produced a DAP of 5,070 MUGym(2) and an effective dose of 7.76 mSv. CONCLUSION: Our newly developed examination protocols for the Uro Dyna-CT provide CT-like image quality during urological interventions with low radiation dose. PMID- 24169819 TI - Global field synchrony during general anaesthesia. AB - BACKGROUND: Anaesthetic agents may disrupt consciousness by inhibiting long-range synchronization of brain activity. In the current study, the patterns of widespread and spatially localized synchrony during anaesthesia are investigated using a measure called global field synchrony (GFS). METHODS: The EEG obtained during routine surgery in 29 patients was analysed with GFS over the following frequency bands: delta (1.5-3.5 Hz), theta (3.5-7.5 Hz), alpha1 (8-10 Hz), alpha2 (10.5-12 Hz), beta1 (12.5-18 Hz), beta2 (18.5-21 Hz), beta3 (21.5-30 Hz), gamma1 (30.5-40 Hz), and gamma2 (60-80 Hz). In addition, localized GFS estimations over aggregate brain areas were performed. GFS was estimated over 2 s non-overlapping windows. The differences in GFS values between 'wakefulness' and 'anaesthesia' were assessed with the two-sided Wilcoxon rank-sum tests (alpha=0.05). RESULTS: Anaesthetic administration caused significant GFS changes in all frequency ranges and electrode combinations studied: (i) widespread synchrony increased in the alpha2 and beta1 ranges and decreased in all other ranges, with the exception of alpha1 and beta2, where no specific pattern was identified; and (ii) localized synchrony decreased in all areas in the delta and gamma2 ranges, while location specific changes were observed in the remaining frequency ranges. The most consistent findings were statistically significant decreases over all areas in the gamma2 range, with GFS decrease over the central-right temporal being the most consistent change. CONCLUSIONS: Significant frequency- and location dependent changes in GFS were induced by anaesthetic administration, with more robust changes identified in the gamma range. GFS can act as an aid for further and more detailed analysis regarding the particular combinations of frequency ranges and spatial locations that are most informative for the study of anaesthetic-induced unconsciousness. PMID- 24169821 TI - Comparison of the effects of albumin 5%, hydroxyethyl starch 130/0.4 6%, and Ringer's lactate on blood loss and coagulation after cardiac surgery. AB - BACKGROUND: Infusion of 5% human albumin (HA) and 6% hydroxyethyl starch 130/0.4 (HES) during cardiac surgery expand circulating volume to a greater extent than crystalloids and would be suitable for a restrictive fluid therapy regimen. However, HA and HES may affect blood coagulation and could contribute to increased transfusion requirements. METHODS: We randomly assigned 240 patients undergoing elective cardiac surgery to receive up to 50 ml kg(-1) day(-1) of either HA, HES, or Ringer's lactate (RL) as the main infusion fluid perioperatively. Study solutions were supplied in identical bottles dressed in opaque covers. The primary outcome was chest tube drainage over 24 h. Blood transfusions, thromboelastometry variables, perioperative fluid balance, renal function, mortality, intensive care unit, and hospital stay were also assessed. RESULTS: The median cumulative blood loss was not different between the groups (HA: 835, HES: 700, and RL: 670 ml). However, 35% of RL patients required blood products, compared with 62% (HA) and 64% (HES group; P=0.0003). Significantly, more study solution had to be administered in the RL group compared with the colloid groups. Total perioperative fluid balance was least positive in the HA group [6.2 (2.5) litre] compared with the HES [7.4 (3.0) litre] and RL [8.3 (2.8) litre] groups (P<0.0001). Both colloids affected clot formation and clot strength and caused slight increases in serum creatinine. CONCLUSIONS: Despite equal blood loss from chest drains, both colloids interfered with blood coagulation and produced greater haemodilution, which was associated with more transfusion of blood products compared with crystalloid use only. PMID- 24169820 TI - Lipid emulsion pretreatment has different effects on mepivacaine and bupivacaine cardiac toxicity in an isolated rat heart model. AB - BACKGROUND: The use of lipid emulsions to reduce cardiac toxicity of local anaesthetics (LAs) has shown success in experimental studies and some clinical cases, and thus has been implemented in clinical practice. However, lipid treatment is usually given after the occurrence of neurological or cardiovascular symptoms of systemic intoxication. The aim of this study was to determine if pretreatment with lipid emulsion reduces cardiac toxicity produced by bupivacaine or mepivacaine. METHODS: Isolated rat hearts were perfused with or without lipid emulsion (0.25 ml kg(-1) min(-1)) before administration of equipotent doses of bupivacaine (250 uM) or mepivacaine (1000 uM). Haemodynamic parameters and times from start of perfusion LA to a 1 min period of asystole and recovery were determined. RESULTS: Pretreatment with lipid emulsion extended the time until occurrence of asystole and decreased times to recovery in bupivacaine-induced cardiac toxicity but not in mepivacaine-induced cardiac toxicity compared with control. Lipid pretreatment impaired rate-pressure product recovery in mepivacaine-intoxicated hearts. CONCLUSIONS: This study confirms that pretreatment with a lipid emulsion reduces cardiac toxicity of LAs. The efficacy of pretreatment with lipid emulsion was LA-dependent, so pharmacokinetic properties, such as lipophilicity, might influence the effects of lipid emulsion pretreatment. PMID- 24169822 TI - A microdevice for rapid optical detection of magnetically captured rare blood pathogens. AB - Sepsis diagnosis requires development of methods to identify rare pathogen cells in small samples of human blood. Magnetic beads functionalized with pathogen binding ligands have been used to rapidly isolate microbes from blood; however, it is commonly difficult to optically detect the captured species because the excess numbers of beads required for pathogen binding physically interfere with light transmission after they have been concentrated. Here we describe a microdevice that uses microfluidics combined with optimized magnetic field concentrators and magnetic beads coated with a generic blood opsonin to efficiently capture unknown blood pathogens and spread them into a thin layer suitable for automated optical detection. Using this device, we have been able to detect fungal pathogens in less than three hours after sample collection compared to days with current technology, and with an extremely high sensitivity (<1 cell mL(-1) of human blood). PMID- 24169823 TI - Simultaneous induction of high level thermal and visible-light catalytic activities to titanium(IV) oxide by surface modification with cobalt(III) oxide clusters. AB - This study first presents a "TiO2-based eco-catalyst" working in the dark and under visible-light irradiation for the degradation of environmental organic pollutants. Molecular scale cobalt(III) oxide clusters are formed on the surface of highly active anatase TiO2 nanoparticles (Co2O3-TiO2) by the chemisorption calcination cycle method. Co2O3-TiO2 exhibits very high visible-light activities for the degradation of 2-naphthol and formic acid used as model organic pollutants. Unprecedented thermocatalytic activity is concomitantly endowed on TiO2 by the surface modification. Prolonging reaction time in the Co2O3-TiO2 photo- and thermo-catalyzed reactions leads to the decomposition of 2-naphthol and formic acid to CO2. The essential action mechanisms of the Co2O3 clusters in the photocatalysis and thermocatalysis of Co2O3-TiO2 were discussed on the basis of spectroscopic and electrochemical data. PMID- 24169825 TI - Important scaffold function of the Janus kinase 2 uncovered by a novel mouse model harboring a Jak2 activation-loop mutation. AB - Janus kinases (Jak) play essential roles in cytokine and growth factor signaling. Conventional gene targeting of Jak2, creating a null allele, leads to a block in definitive erythropoiesis as a result of failing signal transduction at the homomeric erythropoietin receptor (EpoR) and at the heteromeric interferon gamma receptor (IFNGR). To investigate the in vivo relevance of the activation loop of Jak2, a Jak2-YY1007/1008FF knockin mutation was introduced into the germline of mice. The phenotype of the Jak2(FF/FF) mouse line reveals that tyrosine residues 1007/1008 are absolutely essential for kinase function and signal transduction at the homomeric EpoR. Detailed studies using the Jak2 activation loop mutant uncover an essential scaffolding function of Jak2 within the IFNGR receptor complex and reveal that Jak1 can mediate a semi-redundant function for IFNGR signal transduction. These studies are highly important for the molecular understanding of cytokine and growth factor signaling and provide new insights for future strategies in the design of pharmacological blockers of Jak2. PMID- 24169824 TI - Leukemia cell-targeted STAT3 silencing and TLR9 triggering generate systemic antitumor immunity. AB - Signal transducer and activator of transcription 3 (STAT3) is an oncogene and immune checkpoint commonly activated in cancer cells and in tumor-associated immune cells. We previously developed an immunostimulatory strategy based on targeted Stat3 silencing in Toll-like receptor 9 (TLR9)-positive hematopoietic cells using CpG-small interfering RNA (siRNA) conjugates. Here, we assessed the therapeutic effect of systemic STAT3 blocking/TLR9 triggering in disseminated acute myeloid leukemia (AML). We used mouse Cbfb-MYH11/Mpl-induced leukemia model, which mimics human inv(16) AML. Our results demonstrate that intravenously delivered CpG-Stat3 siRNA, but not control oligonucleotides, can eradicate established AML and impair leukemia-initiating potential. These antitumor effects require host's effector T cells but not TLR9-positive antigen-presenting cells. Instead, CpG-Stat3 siRNA has direct immunogenic effect on AML cells in vivo upregulating major histocompatibility complex class-II, costimulatory and proinflammatory mediators, such as interleukin-12, while downregulating coinhibitory PD-L1 molecule. Systemic injections of CpG-Stat3 siRNA generate potent tumor antigen-specific immune responses, increase the ratio of tumor infiltrating CD8(+) T cells to regulatory T cells in various organs, and result in CD8(+) T-cell-dependent regression of leukemia. Our findings underscore the potential of using targeted STAT3 inhibition/TLR9 triggering to break tumor tolerance and induce immunity against AML and potentially other TLR9-positive blood cancers. PMID- 24169827 TI - Heterochromatin and repetitive DNA frequency variation in regenerated plants of Helianthus annuus L. AB - Plant regeneration from cotyledons of seeds of a single progeny of a pure line of Helianthus annuus was studied in respect of the nuclear DNA contents of control and regenerated plants. Control plants were divided into two groups: those developed from seeds at the periphery of the inflorescence (showing a high basic 4C DNA content) and those from seeds developed in the middle of the inflorescence (showing a low basic 4C DNA content). It was observed that plants from peripheral seeds have a higher morphogenetic potential than those from central seeds. Cytophotometric analyses indicated that plants regenerated from cotyledons of both peripheral and central seeds show the same basic 4C DNA amount, which is higher that that observed in vivo in peripheral seeds. Molecular analysis by slot blotting and hybridization with different DNA families showed that the difference in nuclear DNA content between plants from peripheral and central seeds in vivo are mainly related to differences in the frequency of highly repeated, "slow" medium repeated (MR2), and ribosomal DNA families; by contrast, the increase in DNA amount in regenerated plants is mainly due to "fast" medium repeated sequences (MR1). Moreover, the frequency of kinetically isolated "unique" sequences was higher in peripheral seeds than in central ones and still higher in regenerated plants. Optical-density measurements of interphase nuclei showed an increase of heterochromatin in regenerated plants, suggesting that, whatever DNA is amplified in these plants, it remains condensed and probably inactive. PMID- 24169828 TI - Irregular meiosis in a somatic hybrid between S. bulbocastanum and S. tuberosum detected by species-specific PCR markers and cytological analysis. AB - A system of randomly amplified polymorphic DNA (RAPD) markers was developed to facilitate the transfer of S. bulbocastanum (blb) genes into the S. tuberosum (tbr) genome by hybridization and backcrossing. DNA from tbr, blb and the hexaploid hybrid was used as a template for polymerase chain reaction (PCR) amplification. Polymorphic RAPD products, originating from 10-mer primers, specific for blb were cloned and sequenced at their ends to allow the synthesis of 18-mer primers. The 18-mer primers allowed a more reproducible assay than the corresponding RAPDs. Of eight 18-mer primer pairs, four amplified the expected products specific for blb. However, the stringency of the primer annealing conditions needed to be carefully optimized to avoid amplification of the homeologous tbr product, suggesting that the original RAPD polymorphisms were due to single base-pair changes rather than deletions or insertions. Two primers used for amplification of backcross 2 progeny segregated in a 1?1 (presence:absence) ratio; the other two were unexpectedly absent. The most likely explanation for the loss of these markers is irregular meiosis in the original hexaploid hybrid and subsequent elimination of chromosomes. Cytological analysis of the meiosis in the hybrid demonstrated widespread irregular pairing and the presence of lagging univalents. In addition, the first backcross individual used as the parent for the second backcross had 54 chromosomes instead of the predicted 60. In conclusion, our results demonstrate that PCR technology can be used for the efficient isolation of taxon-specific markers in Solanum. Furthermore, by the use of these markers we detected the loss of chromosomes that was subsequently shown by cytological analysis to be caused by irregular meiosis of the somatic hybrid. PMID- 24169829 TI - Wheat storage proteins: glutenin diversity in wild emmer, Triticum dicoccoides, in Israel and Turkey. 2. DNA diversity detected by PCR. AB - Germplasm of Triticum dicoccoides collected from different environments in Israel was evaluated by using the PCR as a molecular marker. Two pairs of primers were used in the PCR in amplifying the DNA tracts coding the high-and low-molecular weight glutenin subunits. Analyses reveal great variability within and between populations indicating the high values of this germplasm for future breeding programs to improve the protein quality in wheat. PMID- 24169826 TI - The Myc-miR-17-92 axis amplifies B-cell receptor signaling via inhibition of ITIM proteins: a novel lymphomagenic feed-forward loop. AB - The c-Myc oncoprotein regulates >15% of the human transcriptome and a limited number of microRNAs (miRNAs). Here, we establish that in a human B-lymphoid cell line, Myc-repressed, but not Myc-stimulated, genes are significantly enriched for predicted binding sites of Myc-regulated miRNAs, primarily those comprising the Myc-activated miR-17~92 cluster. Notably, gene set enrichment analysis demonstrates that miR-17~92 is a major regulator of B-cell receptor (BCR) pathway components. Many of them are immunoreceptor tyrosine inhibitory motif (ITIM) containing proteins, and ITIM proteins CD22 and FCGR2B were found to be direct targets of miR-17~92. Consistent with the propensity of ITIM proteins to recruit phosphatases, either MYC or miR-17~92 expression was necessary to sustain phosphorylation of spleen tyrosine kinase (SYK) and the B-cell linker protein (BLNK) upon ligation of the BCR. Further downstream, stimulation of the BCR response by miR-17-92 resulted in the enhanced calcium flux and elevated levels of Myc itself. Notably, inhibition of the miR-17~92 cluster in diffuse large B cell lymphoma (DLBCL) cell lines diminished the BCR response as measured by SYK and BLNK phosphorylation. Conversely, human DLBCLs of the BCR subtype express higher Myc and mir17hg transcript levels than other subtypes. Hence, the Myc-miR 17-92-BCR axis, frequently affected by genomic rearrangements, constitutes a novel lymphomagenic feed-forward loop. PMID- 24169830 TI - Wheat storage proteins: glutenin DNA diversity in wild emmer wheat, Triticum dicoccoids, in Israel and Turkey. 3. Environmental correlates and allozymic associations. AB - The diversity of high-molecular-weight (HMW) and low-molecular-weight (LMW) glutenin subunits in the tetraploid wild progenitor of wheat, Triticum dicoccoides, was studied at the DNA level by the polymerase chain reaction (PCR). The DNA diversity of HMW and LMW glutenins was shown to be correlated to environmental physical and biotic factors (climate, soil and pathogen resistance) and to allozyme variation. We conclude that glutenin DNA diversity is nonrandomly distributed and could be more optimally sampled in nature for future breeding programmes to improve bread quality. PMID- 24169831 TI - Balancing selection response and rate of inbreeding by including genetic relationships in selection decisions. AB - An iterative selection strategy, based on estimated breeding values (EBV) and average relationship among selected individuals, is proposed to optimise the balance between genetic response and inbreeding. Stochastic simulation was used to compare rates of inbreeding and genetic gain with those of other strategies. For a range of heritabilities, population sizes and mating ratios, the iterative strategy, denoted ADJEBV, outperforms other strategies, giving the greatest genetic gain at a given rate of inbreeding and the least breeding at a given genetic gain. Where selection is currently by truncation on the EBV, with a restriction on the number of full-sibs selected, it should be possible to maintain similar levels of genetic gain and inbreeding with a reduction in population size of 10-30%, by changing to the iterative strategy. If performance is measured by the reduction in cumulative inbreeding without losing more than a given amount of genetic gain relative to results obtained under truncation selection on the EBV, then with the EBV based on a family index, the performance of ADJEBV is greater at low heritability, and is generally greater than where EBV are based on individual records. When comparisons of genetic response and inbreeding are made for alternative breeding scheme designs, schemes which give higher genetic gain within acceptable inbreeding levels would usually be favoured. If comparisons are made on this basis, then the selection method used should be ADJEBV, which maximises the genetic gain for a given level of inbreeding. The results indicated that all selection strategies used to reduce inbreeding had very small effects on the variance of gain, and so differences in this respect are unlikely to affect choices among selection strategies. Selection criteria are recommended based on maximising a selection objective which specifies the desired balance between genetic gain and inbreeding. PMID- 24169832 TI - Inheritance and linkage of isozyme loci in almond. AB - The segregation of seven isozyme marker genes was investigated using eight controlled crosses in almond. The cultivar 'Nonpareil' was the maternal parent in all crosses. Pollination was achieved using eight different cultivars, and a total of 3200 individual kernels were assessed. For each isozyme the goodness-of fit test was used to test for departure from the expected frequencies assuming Mendelian inheritance. Given a higher than expected number of significant results for individual isozymes, independent segregation between pairs of isozymes was tested using the chi-square statistic on the resulting two-way contingency tables. In all crosses a highly significant association (P value< 0.001) was observed between (1) the AAT- 1 and IDH isozymes loci and (2) the LAP-1 and PGM-2 isozymes loci, which leads to the conclusion that the respective isozyme pairs are linked.In addition, a significant association (P value < 0.001) was observed between LAP-1 and GPI-2 when the pollen sources were 'Fritz', 'Mission', or 'Price', but this could not be tested for the remaining five pollen sources, 'Carmel', 'Grant', 'Keane', 'Ne plus Ultra', 'Peerless', because they are homozygous at these loci. If LAP-1 is linked with GPI-2 and PGM-2, it might be expected that we should find evidence of linkage between GPI-2 and PGM-2. The lack of a significant association between these two isozymes suggests that LAP-1 is located centrally on the chromosome. These three pairs of linked loci are the first to be reported in almond. PMID- 24169833 TI - Identification of chrysanthemum cultivars and stability of DNA fingerprint patterns. AB - Several techniques of DNA analysis were applied to identify chrysanthemum cultivars. Unrelated cultivars could be distinguished by using RAPDs (random amplified polymorphic DNAs), inter-SSR (simple sequence repeat) PCR (polymerase chain reaction), hybridization-based DNA fingerprinting, as well as RFLPs (restriction fragment length polymorphisms). Cultivars with different flower colours and belonging to one family, i.e. vegetatively derived from 1 cultivar, appeared to have the same DNA fragment patterns, whichever technique was applied. The absence of polymorphisms between different accessions of the same cultivar indicated a high stability of the observed patterns. PMID- 24169834 TI - Mapping quantitative trait loci for downy mildew resistance in pearl millet. AB - Quantitative trait loci (QTLs) for resistance to pathogen populations of Scelerospora graminicola from India, Nigeria, Niger and Senegal were mapped using a resistant x susceptible pearl millet cross. An RFLP map constructed using F2 plants was used to map QTLs for traits scored on F4 families. QTL analysis was carried out using the interval mapping programme Mapmaker/QTL. Independent inheritance of resistance to pathogen populations from India, Senegal, and populations from Niger and Nigeria was shown. These results demonstrate the existence of differing virulences in the pathogen populations from within Africa and between Africa and India. QTLs of large effect, contributing towards a large porportion of the variation in resistance, were consistently detected in repeated screens. QTLs of smaller and more variable effect were also detected. There was no QTLs that were effective against all four pathogen populations, demonstrating that pathotype-specific resistance is a major mechanism of downy mildew resistance in this cross. For all but one of the QTLs, resistance was inherited from the resistant parent and the inheritance of resistance tended to be the result of dominance or over-dominance. The implications of this research for pearl millet breeding are discussed. PMID- 24169835 TI - Mapping a new nematode resistance locus in Lycopersicon peruvianum. AB - Accessions of the wild tomato species L. peruvianum were screened with a root knot nematode population (557R) which infects tomato plants carrying the nematode resistance gene Mi. Several accessions were found to carry resistance to 557R. A L. peruvianum backcross population segregating for resistance to 557R was produced. The segregation ratio of resistant to susceptible plants suggested that a single, dominant gene was a major factor in the new resistance. This gene, which we have designated Mi-3, confers resistance against nematode strains that can infect plants carrying Mi. Mi-3, or a closely linked gene, also confers resistance to nematodes at 32 degrees C, a temperature at which Mi is not effective. Bulked-segregant analysis with resistant and susceptible DNA pools was employed to identify RAPD markers linked to this gene. Five-hundred-and-twenty oligonucleotide primers were screened and two markers linked to the new resistance gene were identified. One of the linked markers (NR14) was mapped to chromosome 12 of tomato in an L. esculentum/L. pennellii mapping population. Linkage of NR14 and Mi-3 with RFLP markers known to map on the short arm of chromosome 12 was confirmed by Southern analysis in the population segregating for Mi-3. We have positioned Mi-3 near RFLP marker TG180 which maps to the telomeric region of the short arm of chromosome 12 in tomato. PMID- 24169836 TI - Large-scale, cost-effective screening of PCR products in marker-assisted selection applications. AB - A simple, PCR-based method has been developed for the rapid genotyping of large numbers of samples. The method involves a alkaline extraction of DNA from plant tissue using a slight modification of the procedure of Wang et al. (Nucleic Acids Res 21:4153-4154, 1993). Template DNA is amplified using allelespecific associated primers (ASAPs) which, at stringent annealing temperatures, generate only a single DNA fragment and only in those individuals possessing the appropriate allele. This approach eliminates the need to separate amplified DNA fragments by electrophoresis. Instead, samples processing the appropriate allele are identified by direct staining of DNA with ethidium bromide. Total technician time required for extraction, amplification and detection of 96 samples is about 4 h, and this time requirement can be reduced by automation. Excluding labor, cost per sample is less than $0.40. The method is tested using the codominant isozyme marker, alcohol dehydrogenase (Adh-1) gene in pea (Pisum sativum), and applied to the screening of photoperiod genes in common bean (Phaseolus vulgaris L.). PMID- 24169837 TI - QTL analysis: further uses of 'marker regression'. AB - A variety of approaches are available for identifying the location and effect of QTL in segregating populations using molecular markers. However, these have problems in distinguishing two linked QTL, particularly in relation to the size of the test statistic when many independent tests are performed. An empirical method for obtaining the distribution of the test statistic for specific datasets is described, and its power for demonstrating the inadequacy of a single-QTL model is explored through computer simulation. The method is an extension of the previously described technique of 'marker regression', and it is applied here to demonstrate two situations in which it may be useful. Firstly, we examine the power of the technique to distinguish two, linked QTL from one and compare this ability with that of two contemporary methods, 'Mapmaker/QTL' and 'regression mapping'. Secondly, we show how to combine information from two, or more, populations that may be segregating for different marker loci in a given linkage group. This is illustrated for two populations having in common just two linked marker loci although the sharing of loci is not a pre-requisite. Empirical tests are used to determine whether the same or different QTL are segregating and, if they are the same QTL, whether they are the same alleles. Evidence is discussed which suggests that the upper limit to the number of QTL that can be located for any single quantitative trait in a segregating populations is 12. PMID- 24169838 TI - Identification of a RAPD marker for palmitic-acid concentration in the seed oil of spring turnip rape (Brassica rapa ssp. oleifera). AB - F2 progeny (105 individuals) from the cross Jo4002 x Sv3402 were used to identify DNA markers associated with palmitic-acid content in spring turnip rape (Brassica rapa ssp. oleifera). QTL mapping and ANOVA analysis of 140 markers exposed one linkage group with a locus controlling palmitic-acid content (LOD score 27), and one RAPD (random amplified polymorphic DNA) marker, OPB-11a, closely linked (1.4 cM) to this locus. Palmitic-acid content in the 62 F2 plants with the visible allele of marker OPB-11a was 8.45 +/-3.15%, while that in the 24 plants without it was 4.59 +/-0.97%. As oleic-acid concentration is affected by a locus on the same linkage group as the palmitic-acid locus, this locus probably controls the chain elongation from palmitic acid to oleic acid (through stearic acid). Marker OPB-11a may be used in future breeding programs of spring turnip rape to simplify and hasten the selection for palmitic-acid content. PMID- 24169839 TI - Genetic variation detected by DNA fingerprinting with a rice minisatellite probe in Oryza sativa L. AB - A rice minisatellite probe detecting DNA fingerprints was used to assess genetic variation in cultivated rice (Oryza sativa L.). Fifty-seven cultivars of rice, including 40 closely related cultivars released in the US, were studied. Rice DNA fingerprinting revealed high levels of polymorphism among distantly related cultivars. The variability of fingerprinting pattern was reduced in the closely related cultivars. A genetic similarity index (S) was computed based on shared fragments between each pair of cultivars, and genetic distance (D) was used to construct the dendrograms depicting genetic relationships among rice cultivars. Cluster analysis of genetic distance tended to group rice cultivars into different units corresponding with their varietal types and breeding pedigrees. However, by comparison with the coefficients of parentage, the criterion of relatedness based on DNA fingerprints appeared to overestimate the genetic relationships between some of the closely related US cultivars. Although this may reduce the power of fingerprints for genetic analysis, we were able to demonstrate that DNA fingerprinting with minisatellite sequences is simpler and more sensitive than most other types of marker systems in detecting genetic variation in rice. PMID- 24169840 TI - RFLP mapping of the sugary enhancer1 gene in maize. AB - RFLP marker data from an F2?3 population derived from a cross between a sugary1 (su1) and a sugary enhancer1 (su1, sel) inbred were used to construct a genetic linkage map of maize. This map includes 93 segregating marker loci distributed throughout the maize genome, providing a saturated linkage map that is suitable for linkage analysis with quantitative trait loci (QTL). This population, which has been immortalized in the form of sibbed F2?3 families, was derived from each of the 214 F2 plants and along with probe data are available to the scientific community. QTL analysis for kernel sucrose (the primary form of sugar) concentration at 20 days after pollination (DAP) uncovered the segregation of seven major QTL influencing sucrose concentration; a locus linked to umc36a described the greatest proportion of the variation (24.7%). Since maltose concentration has previously been reported to be associated with the se1 phenotype, an analysis of probe associations with maltose concentration at 40 DAP was also conducted. The highly significant association of umc36a with maltose and sucrose concentrations provided evidence that this probe is linked to se1. Phenotypic evaluation for the se1 genotype in each F2?3 family enabled us to map the gene 12.1 cM distal to umc36a. In contrast to previous work where se1 was reported to be located on chromosome four, our data strongly suggest that the sugary enhancer1 locus maps on the the distal portion of the long arm of chromosome 2 in the maize genome. PMID- 24169841 TI - Genes from Lycopersicon chmielewskii affecting tomato quality during fruit ripening. AB - Three chromosomal segments from the wild tomato, L. chmielewskii, introgressed into the L. esculentum genome have been previously mapped to the middle and terminal regions of chromosome 7 (7M, 7T respectively), and to the terminal region of chromosome 10 (10T). The present study was designed to investigate the physiological mechanisms controlled by the 7M and 7T segments on tomato soluble solids (SS) and pH, and their genetic regulation during fruit development. The effects of 7M and 7T were studied in 64 BC2F5 backcross inbred lines (BILs) developed from a cross between LA 1501 (an L. esculentum line containing the 7M and 7T fragments from L. chmielewskii), and VF145B-7879 (a processing cultivar). BILs were classified into four homozygous genotypes with respect to the introgressed segments based on RFLP analysis, and evaluated for fruit chemical characteristics at different harvest stages. Gene(s) in the 7M fragment reduce fruit water uptake during ripening increasing pH, sugars, and SS concentration. Gene(s) in the 7T fragment were found to be associated with higher mature green fruit starch concentration and red ripe fruit weight. Comparisons between tomatoes ripened on or off the vine suggest that the physiological mechanisms influenced by the L. chmielewskii alleles are dependent on the translocation of photosynthates and water during fruit ripening. PMID- 24169842 TI - Cytoplasmic DNAs and nuclear rDNA restriction fragment length polymorphisms in commercial witloof chicories. AB - Restriction fragment length polymorphisms of cytoplasmic DNAs and nuclear rDNA were analyzed in several Cichorium intybus genotypes, comprising four white inbred lines, eight red witloof experimental lines, and a number of F1 hybrids derived from two white parents. Chloroplast and mitochondrial restriction patterns led to the distinction between two different cytoplasms, called I and II. Southern hybridization using a nuclear rDNA probe revealed that all the lines possessed two types of rDNA repeat units. The shortest unit was 10 kb and was common to all lines. The largest rDNA repeat unit was 10.5 kb in lines I and 10.4 kb in lines II. In addition, a sequence heterogeneity between the 10.5 and 10.4 kb rDNA repeat units was revealed by Sac I digestion. A 10-kb rDNA unit was successively cloned, mapped, and used as a probe to check the genetic purity of F1 hybrid seeds between line I and II white parents. We found a 30% average percentage of impurities, originating both from selfing and full-sib crossing, in different open-pollinated hybrid samples. PMID- 24169843 TI - Physiological aspects of aluminium tolerance associated with the long arm of chromosome 2D of the wheat (Triticum aestivum L.) genome. AB - Aluminum (Al) uptake in roots of wheat nearisogenic lines having differing tolerances to aluminium toxicity was studied using roots and root segments immersed in a nutrient solution at a controlled pH and temperature. At low Al concentrations a mechanism preventing root tips from accumulating too much Al was observed in an Al-tolerant isoline and a 'BH1146' euploid. This mechanism was more efficient when divalent cations of calcium or magnesium were present in the nutrient medium. Al accumulation steadily increased in root tips of the Al sensitive wheat isoline during all 24 h of incubation, and the presence of divalent cations in the medium even increased Al concentration in root tissue. However, at higher Al concentrations in the medium the mechanism preventing the root tips of Al-tolerant genotypes from accumulating too much Al was not observed, and in effect Al concentration in root tips of both Al-tolerant and Al sensitive isolines increased. It is concluded that genetical factors are located on the long arm of chromosome 2D from the BH1146 euploid that control the mechanism preventing root apical meristems from accumulating too much Al at low Al concentrations in the medium. However, there must be other genetical factors also located on this chromosome segment that control Al detoxication in root tips of Al-tolerant lines at higher external Al concentrations. PMID- 24169844 TI - Transfer of Ogu cytoplasmic male sterility to Brassica juncea and improvement of the male sterile line through somatic cell fusion. AB - Male sterility conferred by ogu cytoplasm of Raphanus sativus has been transferred to Brassica juncea cv 'RLM 198' from male-sterile B. napus through repeated backcrossing and selection. The male-sterile B. juncea is, however, highly chlorotic and late. It has low female (seed) fertility and small contorted pods. To rectify these defects, protoplasts of the male sterile were fused with normal 'RLM 198' (green, self fertile). Four dark green, completely male-sterile plants were obtained and identified as putative cybrids. All the plants were backcrossed three times with 'RLM 198'. Mitochondrial and chloroplast DNA analysis of backcross progeny confirmed hybridity of the cytoplasm. The restriction pattern of the chloroplast DNA of progeny plants of three cybrids (Og 1, Og 2, Og 3) was similar to that of the green self-fertile 'RLM 198' and indicated that the correction of chlorosis resulted from chloroplast substitution. The chloroplast DNA of the lone progeny plant of the fourth cybrid (Og 10) could not be analyzed because the plant was stunted and had only a few leaves. When total cellular DNA was probed with mitochondrial probes coxI and atpA it was found that the cybrids had recombinant mitochondria. The chlorosis corrected plants were early flowering and had vastly improved seed fertility. PMID- 24169845 TI - Marker-assisted selection and marker-QTL associations in hybrid populations. AB - A detailed analysis is presented of the relationship between genetic markers and quantitative trait loci (QTLs) in the process of marker-assisted selection (MAS). We simulated MAS employing a multiple linear regression to chose from among all of the markers in the genome those to be utilized by selection and to estimate their associated effects on the trait. The simulations demonstrate that, even when such selection is quite effective, the markers utilized by selection are not necessarily the most tightly linked to the QTLs controling the trait. Moreover, the additive effects associated with the markers estimated by the regression may not accurately reflect the contributions to the trait by the most tightly linked QTLs. PMID- 24169846 TI - rRNA gene activity and control of expression mediated by methylation and imprinting during embryo development in wheat x rye hybrids. AB - Ribosomal RNA genes originating from one parent are often suppressed in interspecific hybrids. We show that treatments during germination with the cytosine analogue 5-azacytidine stably reactivate the expression of the suppressed rRNA genes of rye origin in the wheat x rye amphiploid, triticale, by preventing methylation of sites in the rye rDNA. When 5-azacytidine is applied to embryos of triticale and wheat x rye F1 hybrids nine, or more, days after fertilization, rye rRNA gene expression is stably reactivated in the resulting seedling. Earlier treatments have no effect on rye rRNA gene expression, indicating that undermethylation of DNA early in embryo development is reversible. After 9 days, the methylation status of rRNA genes in maintained throughout development. Since the change in expression follows a methylation change at particular restriction-enzyme sites, the data establish a clear correlation between gene activity and methylation in plants. PMID- 24169847 TI - Bayesian estimation and testing of gene frequencies. AB - This article explains estimation of gene frequencies from a Bayesian viewpoint using prior information. How to obtain Bayes estimators and the highest posterior density credible sets (Bayesian counterpart to classical confidence intervals) for gene frequencies is described. Tests of hypotheses are also discussed. A readily available mathematical application package is used to demonstrate the mathematical computations. PMID- 24169848 TI - The beta-binomial model for estimating heritabilities of binary traits. AB - Calculations of individual narrow-sense heritability and family mean heritability of a binary trait in stochastically simulated sib trials in completely randomized block experiments showed that in some situations estimates of "realized" heritabilities obtained from the mixed linear threshold model could be improved by application of a proposed beta-binomial model. The proposed model adopts the beta-binomial as the conjugate-prior for the distribution of probabilities of observing the binary trait in a genetic entry. Estimation of the beta parameters allows an estimation of selection response and, by linkage to a threshold model for the individual observations, the desired heritabilities can be obtained. The average bias in the betabinomial estimates of heritability and family mean heritability was less than 2%. Improvements over existing procedures were especially manifest at heritabilities above 0.3 and at low overall probabilities of observing the trait (p < 0.30). The lowest root mean square errors were consistently obtained with the algorithm proposed by Harville and Mee (1984). The beta-binomial framework, although restricted to a single random additive genetic effect, further facilitates general analysis, estimation of selection response, and calculation of reliable family mean heritability. Intraclass correlations can be estimated directly from the beta-binomial parameters. PMID- 24169849 TI - Evolution of intracerebral hemorrhage after intravenous tPA: reversal of harmful effects with mast cell stabilization. AB - Thrombolysis with tissue plasminogen activator (tPA) traditionally demands baseline imaging to rule out intracerebral hemorrhage (ICH), which causes delays in treatment. Preventing possible adverse effects of tPA on ICH would allow rapid on-site thrombolysis in patients with presumed acute ischemic stroke, reducing onset-to-treatment times. We examined how intravenous tPA alters ICH evolution during an extended follow-up, and how mast cell stabilization affects this process. Intracerebral hemorrhage was induced in rats by collagenase injection. Rats received either saline (n=10), tPA (n=13), tPA+low-dose cromoglycate (n=10), or tPA+high-dose cromoglycate (n=10). Magnetic resonance imaging was performed at 24, 48, and 72 hours after ICH induction, together with neurologic evaluations. During 72 hours of follow-up, tPA administration did not significantly increase hematoma volume (mean+/-s.d. 83.5+/-14.3 versus 66.7+/-14.7 MUL; P=0.256) or hemispheric expansion (14.5+/-5.0 versus 11.5+/-5.0%; P=0.457) compared with saline. However, tPA-treated animals had worse neurologic outcomes (P<0.05), and mortality (8/13 versus 3/10). Combining tPA with high-dose cromoglycate mitigated hemispheric expansion (7.4+/-1.7 versus 14.5+/-5.0%; P=0.01), improved neurologic outcome (P<0.001) and decreased mortality (1/10; P<0.05) compared with tPA alone. Our results suggest tPA increases neurologic deficit in ICH, an effect that was abolished by concomitant mast cell stabilization. Further studies are needed to establish the clinical relevance of these findings. PMID- 24169850 TI - Transplantation of cryopreserved human umbilical cord blood mononuclear cells does not induce sustained recovery after experimental stroke in spontaneously hypertensive rats. AB - Previous studies have highlighted the enormous potential of cell-based therapies for stroke not only to prevent ischemic brain damage, but also to amplify endogenous repair processes. Considering its widespread availability and low immunogenicity human umbilical cord blood (HUCB) is a particularly attractive stem cell source. Our goal was to investigate the neurorestorative potential of cryopreserved HUCB mononuclear cells (MNC) after permanent middle cerebral artery occlusion (MCAO) in spontaneously hypertensive rats (SHR). Human umbilical cord blood MNC or vehicle solution was administered intravenously 24 hours after MCAO. Experimental groups were as follows: (1) quantitative polymerase chain reaction (PCR) of host-derived growth factors up to 48 hours after stroke; (2) immunohistochemical analysis of astroglial scarring; (3) magnetic resonance imaging (MRI) and weekly behavioral tests for 2 months after stroke. Long-term functional outcome and lesion development on MRI were not beneficially influenced by HUCB MNC therapy. Furthermore, HUCB MNC treatment did not change local growth factor levels and glial scarring extent. In summary, we could not demonstrate neurorestorative properties of HUCB MNC after stroke in SHR. Our results advise caution regarding a prompt translation of cord blood therapy into clinical stroke trials as long as deepened knowledge about its precise modes of action is missing. PMID- 24169853 TI - Alterations of hippocampal glucose metabolism by even versus uneven medium chain triglycerides. AB - Medium chain triglycerides (MCTs) are used to treat neurologic disorders with metabolic impairments, including childhood epilepsy and early Alzheimer's disease. However, the metabolic effects of MCTs in the brain are still unclear. Here, we studied the effects of feeding even and uneven MCTs on brain glucose metabolism in the mouse. Adult mice were fed 35% (calories) of trioctanoin or triheptanoin (the triglycerides of octanoate or heptanoate, respectively) or a matching control diet for 3 weeks. Enzymatic assays and targeted metabolomics by liquid chromatography tandem mass spectrometry were used to quantify metabolites in extracts from the hippocampal formations (HFs). Both oils increased the levels of beta-hydroxybutyrate, but no other significant metabolic alterations were observed after triheptanoin feeding. The levels of glucose 6-phosphate and fructose 6-phosphate were increased in the HF of mice fed trioctanoin, whereas levels of metabolites further downstream in the glycolytic pathway and the pentose phosphate pathway were reduced. This indicates that trioctanoin reduces glucose utilization because of a decrease in phosphofructokinase activity. Trioctanoin and triheptanoin showed similar anticonvulsant effects in the 6 Hz seizure model, but it remains unknown to what extent the anticonvulsant mechanism(s) are shared. In conclusion, triheptanoin unlike trioctanoin appears to not alter glucose metabolism in the healthy brain. PMID- 24169852 TI - Cerebral pressure-flow relationship in lowlanders and natives at high altitude. AB - We investigated if dynamic cerebral pressure-flow relationships in lowlanders are altered at high altitude (HA), differ in HA natives and after return to sea level (SL). Lowlanders were tested at SL (n=16), arrival to 5,050 m, after 2-week acclimatization (with and without end-tidal PO2 normalization), and upon SL return. High-altitude natives (n=16) were tested at 5,050 m. Testing sessions involved resting spontaneous and driven (squat-stand maneuvers at very low (VLF, 0.05 Hz) and low (LF, 0.10 Hz) frequencies) measures to maximize blood pressure (BP) variability and improve assessment of the pressure-flow relationship using transfer function analysis (TFA). Blood flow velocity was assessed in the middle (MCAv) and posterior (PCAv) cerebral arteries. Spontaneous VLF and LF phases were reduced and coherence was elevated with acclimatization to HA (P<0.05), indicating impaired pressure-flow coupling. However, when BP was driven, both the frequency- and time-domain metrics were unaltered and comparable with HA natives. Acute mountain sickness was unrelated to TFA metrics. In conclusion, the driven cerebral pressure-flow relationship (in both frequency and time domains) is unaltered at 5,050 m in lowlanders and HA natives. Our findings indicate that spontaneous changes in TFA metrics do not necessarily reflect physiologically important alterations in the capacity of the brain to regulate BP. PMID- 24169854 TI - Superparamagnetic iron oxide nanoparticles stabilized by a poly(amidoamine) rhenium complex as potential theranostic probe. AB - Three-component nanocomposites, constituted by a superparamagnetic iron oxide core coated with a polymeric surfactant bearing tightly bound Re(CO)3 moieties, were prepared and fully characterized. The water soluble and biocompatible surfactant was a linear poly(amidoamine) copolymer (PAA), containing cysteamine pendants in the minority part (ISA23SH), able to coordinate Re(CO)3 fragments. For the synthesis of the nanocomposites two methods were compared, involving either (i) peptization of bare magnetite nanoparticles by interaction with the preformed ISA23SH-Re(CO)3 complex, or (ii) "one-pot" synthesis of iron oxide nanoparticles in the presence of the ISA23SH copolymer, followed by complexation of Re to the SPIO@ISA23SH nanocomposite. Full characterization by TEM, DLS, TGA, SQUID, and relaxometry showed that the second method gave better results. The magnetic cores had a roundish shape, with low dispersion (mean diameter ca. 6 nm) and a tendency to form larger aggregates (detected both by TEM and DLS), arising from multiple interactions of the polymeric coils. Aggregation did not affect the stability of the nano-suspension, found to be stable for many months without precipitate formation. The SPIO@PAA-Re nanoparticles (NPs) showed superparamagnetic behaviour and nuclear relaxivities similar or superior to commercial MRI contrast agents (CAs), which make them promising as MRI "negative" CAs. The possibility to encapsulate (186/188)Re isotopes (gamma and beta emitters) gives these novel NPs the potential to behave as bimodal nanostructures devoted to theranostic applications. PMID- 24169855 TI - Chemical conversion of beta-O-4 lignin linkage models through Cu-catalyzed aerobic amide bond formation. AB - Methods for conversion of the lignin beta-O-4 models into amide derivatives and phenols have been developed, which is achieved via chemo-selective oxidation of the secondary benzylic alcohol and subsequent Cu-catalyzed aerobic amide bond formation. PMID- 24169856 TI - Cell division: Ciliary membrane inheritance directs ciliogenesis. PMID- 24169857 TI - Nuclear organization: Microtubule shaping of the nucleus. PMID- 24169858 TI - Pulmonary functions before and after pediatric cardiac surgery. AB - This study aimed to assess pulmonary functions before and after cardiac surgery in infants with congenital heart diseases and pulmonary overflow and to clarify which echocardiographic parameter correlates best with lung mechanics. Between 2008 and 2009, 30 infants with left-to-right shunt congenital acyanotic heart diseases who had indications for reparative surgery of these lesions were assessed by echocardiography and infant pulmonary function tests before the operation and 6 months afterward. Tests using baby body plethysmography were performed to assess the following infant pulmonary functions: tidal volume, respiratory rate, respiratory system compliance (C(rs)) and respiratory system resistance, functional residual capacity (FRC), and airway resistance. The mean age of the patients was 10.47 +/- 3.38 months, and their mean weight was 6.81 +/- 1.67 kg. Ventricular septal defect and combined lesions were the predominant cardiac diseases (26.7%). Comparison of the infant pulmonary function tests showed a highly significant improvement in all the parameters between the preoperative and 6-month postoperative visits (p < 0.0001). Systolic pulmonary artery pressure had a statistically significant negative correlation with C(rs) (r = -0.493, p = 0.006) and a positive correlation with FRC (r = 0.450, p = 0.013). The findings showed that C(rs) had a statistically significant negative correlation with the pulmonary artery size (r = -0.398, p = 0.029) and the left atrium size (r = -0.395, p = 0.031), whereas the pulmonary artery size had a statistically positive correlation with effective resistance (r = 0.416, p = 0.022) and specific effective resistance (r = 0.604, p = 0.0001). Surgical correction of left-to-right shunt congenital heart diseases had a positive impact on lung compliance, airway resistance, and FRC. Noninvasive echocardiographic parameters assessing pulmonary vascular engorgement and pulmonary artery pressure were closely related to these infant pulmonary function test indexes. PMID- 24169859 TI - Risk factors and prognosis of atrioventricular block after atrial septum defect closure using the Amplatzer device. AB - Amplatzer septal occluder (ASO)-induced complications have been observed. However, little attention is paid to the atrioventricular block (AVB) induced by atrial septum defect (ASD) closure using the Amplatzer device. This study aimed to analyze the risk factors and prognosis of AVB after catheter closure and to reduce the incidence of adverse events. In this study, 706 ASD patients who received closure in our division were investigated retrospectively for the relationship between AVB and factors such as age, size of the ASD (D(d)), diameter of the occluder (D(o)), diameter of the septum (D(s)), D(o)/D(d) ratio, and D(o)/D(s) ratio. Data distribution was evaluated with the Kolmogorov-Smirnov normality test. The Wilcoxon rank sum test was used to compare non-normal distribution data. A p value lower than 0.05 was considered significant. Of the 706 patients, six had experienced the development of AVB, giving an incidence of 0.85%. The risk factors included younger age, larger size of the ASD, larger size of the device, and the D(o)/D(s) ratio (>=0.45). The milder AVB is, the better the prognosis. An AVB of III degrees and an unchanged electrocardiogram (ECG) within 3 days after the procedure are poor prognostic indicators. More attention should be paid to AVB induced by ASD closure. Younger age, size of the ASD, size of the device, and a D(o)/D(s) ratio of 0.45 or higher are the risk factors associated with AVB after closure. A timely retrieval of the device should be considered for a good prognosis. PMID- 24169860 TI - Effect of endorectal balloon positioning errors on target deformation and dosimetric quality during prostate SBRT. AB - An inflatable endorectal balloon (ERB) is often used during stereotactic body radiation therapy (SBRT) for treatment of prostate cancer in order to reduce both intrafraction motion of the target and risk of rectal toxicity. However, the ERB can exert significant force on the prostate, and this work assessed the impact of ERB position errors on deformation of the prostate and treatment dose metrics. Seventy-one cone-beam computed tomography (CBCT) image datasets of nine patients with clinical stage T1cN0M0 prostate cancer were studied. An ERB (Flexi-Cuff, EZ EM, Westbury, NY) inflated with 60 cm(3) of air was used during simulation and treatment, and daily kilovoltage (kV) CBCT imaging was performed to localize the prostate. The shape of the ERB in each CBCT was analyzed to determine errors in position, size, and shape. A deformable registration algorithm was used to track the dose received by (and deformation of) the prostate, and dosimetric values such as D95, PTV coverage, and Dice coefficient for the prostate were calculated. The average balloon position error was 0.5 cm in the inferior direction, with errors ranging from 2 cm inferiorly to 1 cm superiorly. The prostate was deformed primarily in the AP direction, and tilted primarily in the anterior posterior/superior-inferior plane. A significant correlation was seen between errors in depth of ERB insertion (DOI) and mean voxel-wise deformation, prostate tilt, Dice coefficient, and planning-to-treatment prostate inter-surface distance (p < 0.001). Dosimetrically, DOI is negatively correlated with prostate D95 and PTV coverage (p < 0.001). For the model of ERB studied, error in ERB position can cause deformations in the prostate that negatively affect treatment, and this additional aspect of setup error should be considered when ERBs are used for prostate SBRT. Before treatment, the ERB position should be verified, and the ERB should be adjusted if the error is observed to exceed tolerable values. PMID- 24169861 TI - The principles of PK-tailored prophylaxis. AB - While prophylaxis with factor VIII (FVIII) is considered the first choice therapy for patients with severe haemophilia A the optimal prophylaxis regimen is still under scientific debate. A recent study demonstrated efficacy and safety of a PK tailored prophylaxis regimen with rFVIII (ADVATE) aimed to maintain FVIII trough levels of >=1% (19). The annual bleed rate (ABR) could be significantly reduced compared to the previous on-demand treatment period (p < 0.0001) and bodily pain, a health-related quality of life dimension of the SF-36v1 questionnaire also significantly improved (p = 0.0007). Thus PK-tailored prophylaxis with ADVATE might offer a valid alternative to standard prophylaxis. Open issues to be considered for implementation of PK-tailored prophylaxis are: What FVIII trough level is needed to prevent any bleed? Do patients with target joints need higher FVIII trough levels to stay bleed-free? Are there user-friendly tools available to calculate individualized PK-driven prophylaxis doses and frequency without the need for a full 9-sample PK curve? Current knowledge on these aspects as well as some considerations about the future of PK-tailored prophylaxis is discussed. PMID- 24169863 TI - Alterations of the interstitial cells of Cajal and the microstructure of the gastrointestinal tract in KIT distal kinase mutant mice. AB - The development and maintenance of interstitial cells of Cajal (ICC) are closely associated with SCF/KIT signal activity. In this study, we evaluate the distribution of ICC in KIT distal kinase domain mutant mice (Wads) and determine whether the loss-of-function mutations in KIT easily lead to gastrointestinal (GI) disorders. ICC were examined by anti-KIT immunohistochemistry and western blotting. The GI microstructure of wild-type (WT) and Wads mice in normal intestines and incomplete intestinal obstruction was evaluated by hematoxylin and eosin staining. The results in Wads(m/m) mice were as follows. Myenteric ICC were obviously decreased in the stomach and colon and were totally absent in the small intestine. Intramuscular ICC were nearly absent in the stomach and irregularly distributed in the colon. Moreover, the smooth muscle thickness of the small intestine was increased 1.3-fold in Wads(m/m), compared to WT and Wads(m/+) mice and the diameter of the intestinal lumen was also enlarged in Wads(m/m) mice. When constructing an incomplete intestinal obstruction model, the extent of distention involved was greater in Wads mice (1.6-fold in Wads(m/+) mice and 1.8 fold in Wads(m/m) mice vs. WT mice). Meanwhile, the intestinal lumen expansion and decrease in ICC were more pronounced in Wads mice than in WT mice. Our results suggest that the KIT distal kinase domain mutation leads to an ICC loss in a subtype and location-specific pattern in Wads(m/m) mice. The injury of the KIT signaling in mutant mice results in more serious pathological manifestations after being exposed to pathogenic factors. PMID- 24169864 TI - Bone regeneration potential of allogeneic or autogeneic mesenchymal stem cells loaded onto cancellous bone granules in a rabbit radial defect model. AB - For developing a clinically effective bone regeneration strategy, we compare the bone regeneration potential of cultured allogeneic bone marrow-derived mesenchymal stem cells (BM-MSCs) and of autologous BM-MSCs loaded onto allogeneic cancellous bone granule scaffolds. A critical-sized segmental bone defect was made at the mid-shaft of both radiuses in 19 New Zealand White rabbits (NWRs). In the experimental group, allogeneic BM-MSCs loaded onto small-sized allogeneic cancellous bone granules (300~700 um in diameter) were implanted in one side of a bone defect. In the control group, autologous BM-MSCs loaded onto allogeneic cancellous granules were grafted in the other side. Bone regeneration was assessed by radiographic evaluation at 4, 8, 12 and 16 weeks post-implantation and by micro-computed tomography (micro-CT) and histological evaluation at 8 and 16 weeks. The experimental groups showed lower bone quantity indices (BQIs) than the control groups at 12 and 16 weeks (p < 0.05), although no significant difference was observed at 4 and 8 weeks (p > 0.05). Micro-CT analysis revealed that both groups had similar mean total bone volume and other parameters including trabecular thickness, number and separation at either 8 or 16 weeks. Only bone surface area revealed less area in the experimental group at 16 weeks. Histological evaluation of 8-week and 16-week specimens showed similar biologic processes of new bone formation and maturation. There was no inflammatory reaction indicating an adverse immune response in both allogeneic and autologous MSC groups. In conclusion, allogeneic BM-MSCs loaded onto allogeneic cancellous bone granules had comparable bone regeneration potential to autologous BM-MSCs in a rabbit radial defect model. PMID- 24169862 TI - Disrupted tight junctions in the small intestine of cystic fibrosis mice. AB - The tight junction (TJ) is the major determinant of paracellular permeability, which in the gut protects the body from entry of harmful substances such as microbial components. In cystic fibrosis (CF), there is increased permeability of the small intestine both in humans and in CF mice. To gain insight into the mechanisms of increased intestinal permeability in CF, I analyze the composition of the TJ in a cystic fibrosis transmembrane conductance regulator (Cftr) knockout mouse model. Significant changes in TJ gene expression in the CF intestine were found for Cldn1, Cldn7, Cldn8 and Pmp22, which were expressed at lower levels and Cldn2 that was expressed at a higher level. Protein levels of claudin-2 were increased in the CF intestine as compared to wild-type, while other TJ proteins were not significantly different. In the villus epithelium of the CF intestine, all TJ components analyzed were mislocalized to the basal cytoplasm and showed varying degrees of loss from the TJ and apico-lateral surfaces. The pore-forming claudin-2 in the CF intestine showed more intense staining but was correctly localized to the TJ, principally in the crypts that are enlarged in CF. The cytokine TNFalpha, known to affect TJ, was elevated to 160% of wild-type in the CF intestine. In summary, there is a dramatic redistribution of claudin proteins from the TJ/lateral membrane to the basal cytoplasm of the villus epithelium in the CF intestine. These changes in TJ protein localization in CF are likely to be involved in the increased permeability of the CF small intestine to macromolecules and TNFalpha may be a causative factor. PMID- 24169865 TI - Volitional control of heartbeat and its dependence on pallium. AB - It is believed that we cannot change our heart rhythm by will because the heartbeat is mainly controlled by the autonomic nervous system (ANS), which cannot be affected directly by subjective will. An experiment was designed to determine whether the heartbeat and ANS could be controlled by volition, and, if it is true, how they were controlled. It was demonstrated that the ANS could be partly controlled by volition. The volition, which tended to slow down the heartbeat, initiated synchronized activity in the medial prefrontal cortex, inhibited the sympathetic system, and then decreased the heartbeat. On the other hand, another kind of volition, which sped up the heartbeat, initiated desynchronized activity at the precentral, central, parietal, and occipital regions, inhibited the parasympathetic system and excited the sympathetic system, and then increased the heartbeat. Moreover, information flow from posterior cortex to anterior cortex was observed during the experiment. The parietal area played an important role in triggering the sensorimotor cortex and integrating the information, and the information flow from the central and precentral cortex to heart was dominant. All that demonstrated that volition can partly control the heartbeat, but the behavior was different from the motor nervous system. PMID- 24169866 TI - Synthesis and photophysical properties of novel butterfly-shaped blue emitters based on pyrene. AB - Using 1,3,5,9-tetrabromo-7-tert-butylpyrene as the bromide precursor, a series of novel butterfly-shaped 1,3,5,9-tetraaryl substituted pyrene derivatives were synthesized by the Suzuki-Miyaura cross-coupling reaction. Their thermal, photophysical, electrochemical and related properties were systematically investigated. All compounds were found to exhibit high thermal stabilities with decomposition temperatures (Td) of up to 300 degrees C. All compounds show highly blue fluorescence emissions in the spectral region of 412-469 nm in solution (Phif: 0.45-0.92) and 410-470 nm in the solid- state (Phif: 0.48-0.75). It is noteworthy that these butterfly-shaped pyrenes 4 possess low-lying HOMO levels ranging from -4.76 to -5.93 eV, which make them promising candidates in OLED applications. PMID- 24169867 TI - Acute hydrocephalus in a child with a third ventricle arachnoid cyst and coincidental enteroviral meningitis. AB - We present a 2.5-year-old child suffering from acute hydrocephalus. First, the child was diagnosed with aseptic viral meningitis. The PCR of the cerebrospinal fluid (CSF) was positive for enterovirus. Subsequently, MRI revealed that the hydrocephalus was caused by a cyst in the third ventricle. During ventriculoscopy, the cyst had all aspects of an arachnoid cyst. An endoscopic fenestration and partial removal of the cyst was performed, combined with a ventriculocisternostomy. The coincidental finding of viral meningitis and a third ventricle arachnoid cyst in a patient with acute hydrocephalus has, to our knowledge, not been described in literature before. If there is a relation between the enteroviral meningitis, the arachnoid cyst (possibly causing a pre existing subclinical hydrocephalus) and the rapidly evolving neurological deterioration, remains speculative. Proposed mechanisms, by which the viral meningitis could accelerate the disease process, are slight brain swelling or increased CSF production. This rare combination of diagnoses could also be coincidental. PMID- 24169868 TI - Traumatic carotid-cavernous fistula at the anterior ascending segment of the internal carotid artery in a pediatric patient. AB - INTRODUCTION: Traumatic carotid-cavernous fistula (CCF) in children is a rare condition. Early diagnosis and treatment is still a challenge, and it is associated with good neurological recovery. CASE SUMMARY: We present a rare case of a 10-year-old boy with mild head trauma, who developed a CCF at the anterior segment of the ascending internal carotid artery. The patient was treated with endovascular coil embolization and evolved with a favorable outcome. DISCUSSION: Most of reports in the literature address the traumatic CCF in adult patients, in which early treatment may prevent poor recovery or fatal outcomes. The diagnosis and management of this condition are discussed based on a literature review. CONCLUSION: It is important to keep a high degree of suspicion for CCF, especially in traumatic head injury associated with skull base fracture, since the early diagnosis and treatment may prevent potentially permanent neurological deficits. PMID- 24169869 TI - Aggressive plasmablastic multiple myeloma in a 42-year-old: is inflammatory bowel disease or infliximab treatment to be blamed? AB - A man in his early 40s with a history of ulcerative colitis, treated with infliximab, was diagnosed with plasmablastic multiple myeloma. He was treated with chemotherapy and stem cell transplant but developed recurrence and ultimately died from metastatic disease. Could inflammatory bowel disease or infliximab therapy have any role in development of myeloma in this young patient? The role of inflammatory bowel disease and infliximab therapy in the development of multiple myeloma is controversial but interesting and worth considering. PMID- 24169870 TI - High dose of prokinetics for refractory hiccups after chemotherapy or the return to a simple drug. AB - Hiccups in patients with cancer might be difficult to treat, impacting negatively on the quality of life. Many therapies are available, but they are usually started empirically, and often they are unsuccessful. We report a case of a man with metastatic colon cancer who after the first cycle of chemotherapy developed persistent hiccups refractory to neuroleptics and low dose of metoclopramide. After searching for the potential cause, a high dose of prokinetics was initiated in the hospital and his symptoms disappeared. This case shows how searching for potential causes helps start the right treatment immediately, and therefore it is relevant for the prompt relief from this bothersome symptom. So far, no cases reporting high doses of prokinetics to treat persistent hiccups after chemotherapy have been published. This option should be taken into account when developing hiccups and gastro-oesophageal reflux after chemotherapy, especially if low doses of prokinetics have already been tried. PMID- 24169871 TI - Morel-Lavallee lesion in a male cyclist. PMID- 24169872 TI - Renal artery aneurysm with an ovarian vein thrombosis. PMID- 24169873 TI - Dissociated sensory loss and muscle wasting in a young male with headaches: syringomyelia with type 1 Arnold-Chiari malformation. PMID- 24169875 TI - [Not Available]. PMID- 24169876 TI - Sources of indoor air pollution in New York City residences of asthmatic children. AB - Individuals spend ~90% of their time indoors in proximity to sources of particulate and gaseous air pollutants. The sulfur tracer method was used to separate indoor concentrations of particulate matter (PM) PM2.5 mass, elements and thermally resolved carbon fractions by origin in New York City residences of asthmatic children. Enrichment factors relative to sulfur concentrations were used to rank species according to the importance of their indoor sources. Mixed effects models were used to identify building characteristics and resident activities that contributed to observed concentrations. Significant indoor sources were detected for OC1, Cl, K and most remaining OC fractions. We attributed 46% of indoor PM2.5 mass to indoor sources related to OC generation indoors. These sources include cooking (NO2, Si, Cl, K, OC4 and OP), cleaning (most OC fractions), candle/incense burning (black carbon, BC) and smoking (K, OC1, OC3 and EC1). Outdoor sources accounted for 28% of indoor PM2.5 mass, mainly photochemical reaction products, metals and combustion products (EC, EC2, Br, Mn, Pb, Ni, Ti, V and S). Other indoor sources accounted for 26% and included re suspension of crustal elements (Al, Zn, Fe, Si and Ca). Indoor sources accounted for ~72% of PM2.5 mass and likely contributed to differences in the composition of indoor and outdoor PM2.5 exposures. PMID- 24169877 TI - A prospective follow-up study of the effects of chronic aircraft noise exposure on learners' reading comprehension in South Africa. AB - The purpose of this epidemiological study was to investigate the long-term effects of exposure to aircraft noise on reading comprehension on a sample of South African children. Given the impairment of reading comprehension found within the noised-exposed group before the relocation of the airport, it was the intention of this study to determine whether the effects of aircraft noise on reading comprehension remained after the relocation of the airport or whether they disappeared. A cohort of 732 learners with a mean age of 11.1 years participated at baseline measurements in 2009 and 650 (mean age=12.3) and 178 (mean age=13.1) learners were reassessed after the relocation of the airport in 2010 and 2011, respectively. The results revealed no significant effect of the groups on reading comprehension across the testing periods, but significant effects of home language were demonstrated on reading comprehension. These findings suggest that exposure to chronic aircraft noise may have a lasting impact on children's reading comprehension functioning. PMID- 24169879 TI - Size of breeding populations required for selection programs. AB - The minimum population size required for selection in order to reduce the effect of genetic drift to a particular level has been considered. The model of Nicholas was extended to include the measurement-error variance in the response variance. Situations where the sex ratios among scored and breeding individuals are unequal are also considered. When the duration of a selection experiment is relatively long, Nicholas' approximation (i.e., assuming that measurement error is negligible relative to drift) is useful in determining the minimum effective population size required. However, the measurement-error variance becomes an important source of variation in short-term (<= 5 generations) selection experiments, and should not be ignored. PMID- 24169878 TI - Weather and triggering of ventricular arrhythmias in patients with implantable cardioverter-defibrillators. AB - Outdoor ambient weather has been hypothesized to be responsible for the seasonal distribution of cardiac arrhythmias. Because people spend most of their time indoors, we hypothesized that weather-related arrhythmia risk would be better estimated using an indoor measure or an outdoor measure that correlates well with indoor conditions, such as absolute humidity. The clinical records of 203 patients in eastern Massachusetts, USA, with an implantable cardioverter defibrillator were abstracted for arrhythmias between 1995 and 2002. We used case crossover methods to examine the association between weather and ventricular arrhythmia (VA). Among 84 patients who experienced 787 VAs, lower estimated indoor temperature (odds ratio (OR)=1.16, 95% confidence interval (CI) 1.05-1.27 for a 1 degrees C decrease in the 24-h average) and lower absolute humidity (OR=1.06, 95% CI 1.03-1.08 for a 0.5 g/m(3) decrease in the 96-h average) were associated with increased risk. Lower outdoor temperature increased risk only in warmer months, likely attributable to the poor correlation between outdoor and indoor temperature during cooler months. These results suggest that lower temperature and drier air are associated with increased risk of VA onset among implantable cardioverter-defibrillator patients. PMID- 24169880 TI - Genetic localisation of transformation competence in diploid potato. AB - In the course of improving diploid potato genotypes for transformation ability, selection for specific components affecting regeneration and transformation was carried out. From a segregating population between two good regenerating clones a selection was made to yield an optimal well-transforming and fertile genotype J92 6400-A16. This plant yielded predominantly diploid transformants and was heterozygous for the gene R1, conferring resistance to Phytophthora infestans. The speed of, and competence for, regeneration and transformation on both sides of the stem explant were improved. A competence factor for tranformation was found to be linked with the R1 locus and a molecular marker on chromosome 5. The male fertility of transformants was frequently decreased to a great extent, whereas female fertility was not so markedly affected. PMID- 24169881 TI - Stable inheritance and expression of the CMS traits introduced by asymmetric protoplast fusion. AB - The donor-recipient protoplast fusion method was used to produce cybrid plants and to transfer cytoplasmic male sterility (CMS) from two cytoplasmic male sterile lines MTC-5A and MTC-9A into a fertile japonica cultivar, Sasanishiki. The CMS was expressed in the cybrid plants and was stably transmitted to their progenies. Only cytoplasmic traits of the male-sterile lines, especially the mitochondrial DNAs, were introduced into the cells of the fertile rice cultivar. More than 80% of the cybrid plants did not set any seeds upon selfing. Sterile cybrid plants set seeds only when they were fertilized with normal pollen by hand and yielded only sterile progenies. This maternally inherited sterility of the cybrid plants showed that they were characterized by CMS. The CMS of cybrid plants could be restored completely by crossing with MTC-10R which had the single dominant gene Rf-1 for restoring fertility. These results indicated that CMS was caused by the mitochondrial genome introduced through protoplast fusion. The introduced CMS was stably transmitted to their progenies during at least eight backcross generations. These results demonstrate that cybrids generated by the donor-recipient protoplast fusion technique can be used in hybrid rice breeding for the creation of new cytoplasmic male-sterile rice lines. PMID- 24169882 TI - Cytologically based physical maps of the group-2 chromosomes of wheat. AB - We have constructed cytologically based physical maps (CBPMs), depicting the chromosomal distribution of RFLP markers, of the group-2 chromosomes of common wheat (Triticum aestivum L. em Thell). Twenty-one homozygous deletion lines for 2A, 2B, and 2D were used to allocate RFLP loci to 19 deletion-interval regions. A consensus CBPM was colinearily aligned with a consensus genetic map of group-2 chromosomes. The comparison revealed greater frequency of recombination in the distal regions. Several molecularly tagged chromosome regions were identified which may be within the resolving power of pulsed-field gel electrophoresis. The CBPMs show that the available probes completely mark the group-2 chromosomes, and landmark loci for sub-arm regions were identified for targeted-mapping. PMID- 24169883 TI - Genetic mapping of soybean cyst nematode race-3 resistance loci in the soybean PI 437.654. AB - Resistance to the soybean cyst nematode (SCN) (Heterodera glycines Ichinohe) is difficult to evaluate in soybean [Glycine max (L.) Merr.] breeding. PI 437.654 has resistance to more SCN race isolates than any other known soybean. We screened 298 F6?7 recombinant-inbred lines from a cross between PI 437.654 and 'BSR101' for SCN race-3 resistance, genetically mapped 355 RFLP markers and the I locus, and tested these markers for association with resistance loci. The Rhg 4 resistance locus was within 1 cM of the I locus on linkage group A. Two additional QTLs associated with SCN resistance were located within 3cM of markers on groups G and M. These two loci were not independent because 91 of 96 lines that had a resistant-parent marker type on group G also had a resistant-parent marker type on group M. Rhg 4 and the QTL on G showed a significant interaction by together providing complete resistance to SCN race-3. Individually, the QTL on G had greater effect on resistance than did Rhg 4, but neither locus alone provided a degree of resistance much different from the susceptible parent. The nearest markers to the mapped QTLs on groups A and G had allele frequencies from the resistant parent indicating 52 resistant lines in this population, a number not significantly different from the 55 resistant lines found. Therefore, no QTLs from PI 437.654 other than those mapped here are expected to be required for resistance to SCN race-3. All 50 lines that had the PI 437.654 marker type at the nearest marker to each of the QTLs on groups A and G were resistant to SCN race 3. We believe markers near to these QTLs can be used effectively to select for SCN race-3 resistance, thereby improving the ability to breed SCN-resistant soybean varieties. PMID- 24169884 TI - Template mixing: a method of enhancing detection and interpretation of codominant RAPD markers. AB - Ten codominant RAPD markers, ranging in size from about 300 to about 1350 bp, were identified in mapping populations of chickpea (Cicer arietinum L.) and diploid strawberry (Fragaria vesca L.). A distinguishing feature of all ten markers, and perhaps of codominant RAPD markers in general, was the presence in heterozygous individuals of a non-parental, heteroduplex band migrating more slowly than either of the respective parental bands. This non-parental band could also be generated by mixing parental DNAs before PCR (template mixing). As a means of identifying primers likely to detect codominant RAPD markers, parental and mixed-template (parent-parent) PCR-product gel lanes were compared for 20 previously untested RAPD primers (10-base oligomers). Four primers that produced a total of five non-parental, heteroduplex bands in mixed-template reactions were selected, and then used to detect a total of five segregating, codominant markers and nine dominant markers in the respective F2 mapping population, a codominant marker frequency of 35.7%. When closely migrating fast and slow bands of codominant RAPDs were difficult to differentiate, parent-progeny template mixing was used to deliberately generate heteroduplex bands in fast- or slow-band F2 homozygotes, respectively, allowing confirmation of marker phenotype. PMID- 24169885 TI - Genetic diversity and phylogeny analysis of Anabaena azollae based on RFLPs detected in Azolla-Anabaena azollae DNA complexes using nif gene probes. AB - The cyanobacterium Anabaena has both symbiotic and free-living forms. The genetic diversity of Anabaena strains symbiotically associated with the aquatic fern Azolla and the evolutionary relationships among these symbionts were evaluated by means of RFLP (restriction fragment length polymorphism) experiments. Three DNA fragments corresponding to nif genes were cloned from the free-living cyanobacterium Anabaena PCC 7120 and used as probes. A mixture of Azolla, Anabaena and bacterial DNA was extracted from Azolla fronds and digested with two restriction enzymes. Single-copy RFLP signals were detected with two of the probes in all Azolla Anabaena examined. Multiple-copy RFLP signals were obtained from the third probe which corresponded to a part of the nif N gene. A total of 46 probe/enzyme combinations were scored as present or absent and used to calculate pairwise Nei's genetic distances among symbiotic Anaebaena strains. Phylogenetic trees summarizing phenetic and cladistic relationships among strains were generated according to three different evolutionary scenarios: parsimony, UPGMA and neighbour joining. All trees revealed identical phylogenetic relationships. Principal component analysis was also used to evaluate genetic similarities and revealed three groups: group one contains the cyanobacteria associated with plants from the Azolla section, group two contains those associated with plants from the pinnata species and group three contains those associated with plants from the nilotica species. The same groups had already been identified earlier in a random amplified polymorphic DNA (RAPD) analysis of Azolla-Anbaena DNA complexes, suggesting that the present Azolla taxonomy should be revised. We now suggest a taxonomy of Anabaena azollae that is parallel to such a revised Azolla taxonomy. An Azolla chloroplast DNA sequence derived from Oryza sativa was also used as an RFLP probe on Azolla DNA to confirm the presence of plant DNA in the total genomic DNA extracted from ferns with or without the symbiont. Our results also suggest that total DNA extracted from the Azolla Anabaena complexes includes both plant and symbiont DNA and can be used equally well for RFLP analysis of host plant or symbiotic cyanobacteria. PMID- 24169886 TI - Gynogenic lines of onion (Allium cepa L.): evidence of their homozygosity. AB - Haploid induction via gynogenesis offers the possibility of using doubled haploid (DH) inbred lines in onion breeding. A first DH line that originated from the open-pollinated (OP) cultivar 'Dorata di Parma' was obtained after overcoming difficulties associated with the haploidy of the regenerants. Spontaneous chromosome doubling occurs seldom in onion. The first DH line obtained was cloned and selfed to produce sufficient seeds for genetic studies. The homozygosity of the DH gynogenic line was revealed on the basis of the low standard deviations of the bulb traits polar diameter, shape index and weight with respect to those of the S1 line or the OP cultivar. In the DH line, moreover, segregation of RAPD and alpha esterase markers was not noted. Out of four primers revealing polymorphism at 16 ge-netic loci in the OP cultivar 'Dorata di Parma', none produced polymorphism in the DH gynogenic line. The Est-1 locus, homozygous in 22 plants (Est-1 (1/1) in 3 and Est-1 (2/2) in 19) and heterozygous (Est-1 (1/2)) in 11 plants of the OP cultivar, always carried the same alleles in the DH line. We also tested genetic stability during micropropagation of a second halpoid line obtained via gynogenesis from var. 'Senshyu Yellow'. Seventeen plants of this line were tested to detect changes occurring during the tissue culture process. Again no polymorphism was observed. The high genetic homogeneity observed in the two gynogenic lines of onion could be related to the absence of the callus phase during the gynogenic process. PMID- 24169887 TI - A chimeric and truncated mitochondrial atpA gene is transcribed in alloplasmic cytoplasmic male-sterile tobacco with Nicotiana bigelovii mitochondria. AB - Protoplast fusions were performed between two sexually produced alloplasmic male sterile tobacco cultivars, with cytoplasms from Nicotiana bigelovii [Nta (big)S] and N. undulata[Nta(und)S], both of which exhibit homeotic-like phenotypes affecting the petal and stamen whorls. Among the fusion products obtained, both novel male-sterile and pollen-producing cybrid plants were identified. Of the pollen-producing cybrid plants, all of which were indehiscent, some had flowers with stamens that appeared normal when compared to male-fertile tobacco plants. Other hybrid plants were incompletely restored as they exhibited petaloid structures on the anther-bearing pollen-producing stamens. In this study, gel blot analyses with mitochondrial geneprobes were conducted comparing the mitochondrial DNA of cybrids and male-sterile parents. It was found that the flower morphology typical of the Nta(big)S parental plants, as well as of the novel male-sterile cybrids, coincided with the presence of a chimeric atpA gene copy where an open reading frame of unknown origin was found to be linked in frame to the 3'-end of a truncated atpA gene. RNA gel-blot hybridizations revealed the presence of atpA transcripts in the malesterile parent Nta(big)S and novel male-sterile cybrids, but which were absent in cybrids capable of pollen production. PMID- 24169888 TI - Characterization of deletions in common wheat induced by an Aegilops cylindrica chromosome: detection of multiple chromosome rearrangements. AB - An Aegilops cylindrica chromosome induces terminal deletions of chromosomes in wheat as identified by C-banding. We are constructing high-density physical maps of wheat chromosomes and have detected additional chromosome rearrangements. Among 63 lines with chromosomal subarm deletions in group 7 chromosomes, 7 lines (11.1%) were shown to harbor additional chromosome rearrangements. Two other lines were also omitted from the physical mapping because of the nature of the breakpoint calculations. The presence or absence of chromosome-specific restriction fragment length polymorphism (RFLP) or random amplified polymorphic DNA (RAPD) markers indicated that additional interstitial deletions are present in 3 lines (4.8%) with deletions in the short chromosome arms and in 4 lines (6.3%) with deletions in the long chromosome arms. We also used chromosome pairing analysis of F1 plants of deletion lines with double ditelosomic lines of 'Chinese Spring' wheat to detect small terminal deletions. The deletion of the most distal 1% of chromosome arm 7AL was associated with a pairing reduction of 60%. PMID- 24169889 TI - Comparison of wheat physical maps with barley linkage maps for group 7 chromosomes. AB - Comparative genetic maps among the Triticeae or Gramineae provide the possibility for combining the genetics, mapping information and molecular-marker resources between different species. Dense genetic linkage maps of wheat and barley, which have a common array of molecular markers, along with deletion-based chromosome maps of Triticum aestivum L. will facilitate the construction of an integrated molecular marker-based map for the Triticeae. A set of 21 cDNA and genomic DNA clones, which had previously been used to map barley chromosome 1 (7H), were used to physically map wheat chromosomes 7A, 7B and 7D. A comparative map was constructed to estimate the degree of linkage conservation and synteny of chromosome segments between the group 7 chromosomes of the two species. The results reveal extensive homoeologies between these chromosomes, and the first evidence for an interstitial inversion on the short arm of a barley chromosome compared to the wheat homoeologue has been obtained. In a cytogenetically-based physical map of group 7 chromosomes that contain restriction-fragment-length polymorphic DNA (RFLP) and random amplified polymorphic DNA (RAPD) markers, the marker density in the most distal third of the chromosome arms was two-times higher than in the proximal region. The recombination rate in the distal third of each arm appears to be 8-15 times greater than in the proximal third of each arm where recombination of wheat chromosomes is suppressed. PMID- 24169890 TI - Improvement in the quality of seed storage protein by transformation of Brassica napus with an antisense gene for cruciferin. AB - The levels of certain essential amino acids, in particular cysteine, lysine and methionine, in the seed storage protein of a commercial spring variety of rape, Brassica napus, have been increased by the introduction of an antisense gene for cruciferin, which is the most abundant storage protein in rapeseed. The antisense construct contained part of the cruA gene in an inverted orientation, and the gene was driven by the 5' flanking region of the gene for napin such that antisense RNA was expressed in a seed-specific manner. The construct was introduced by Agrobacterium-mediated gene transfer. In self-pollinated seeds (T1 seeds) of transgenic plants there was a reduction in the levels of the alpha1beta1 and alpha2/3beta2/3 subunits of cruciferin, whereas the level of the alpha4beta4 subunit was unchanged. The total protein and lipid contents of transgenic seeds did not differ significantly from that of normal seeds. Seeds with reduced amounts of cruciferin accumulated higher amounts of napin than non transformed seeds, but the level of oleosin was unaffected. Amino-acid analysis of the seed storage protein revealed that T1 seeds with reduced amounts of cruciferin contained higher relative levels of three essential amino acids, namely, lysine, methionine and cysteine, with increases of 10%, 8% and 32% over the respective levels in non-transgenic seeds (B. napus cv Westar). PMID- 24169891 TI - Inheritance of chloroplast and mitochondrial DNA in alloplasmic forms of the genus Daucus. AB - The inheritance of mitochondrial (mt) and chloroplast (ct) DNA in the progeny from interspecific crosses between the cultivated carrot (Daucus carota sativus) and wild forms of the genus Daucus was investigated by analysis of mt and ct RFLPs in single plants of the parental and filial generations. We observed a strict maternal inheritance of the organellar DNAs in all interspecific crosses examined. Previous studies on putative F2 plants from a cross between Daucus muricatus x D. carota sativus suggested paternal inheritance of ctDNA. Our reinvestigation of this material revealed that the mtDNA of the putative F2 plants differed from the mtDNA of both putative parents. Therefore, our data suggest that the investigated material originated from other, not yet identified, parents. Consequently, the analysis of this material cannot provide evidence for a paternal inheritance of ctDNA. PMID- 24169892 TI - Domestication via hybridization of the wild tetraploid oats Avena magna and A. murphyi. AB - The wild tetraploid (2n=28) oat species Avena magna and A. murphyi have been domesticated by having been transferred from the common oat, A sativa (2n=42), the characteristics of non-shedding spikelets glabrous and yellow lemma, and reduced awn formation. Domestication has been achieved by crossing the common oat with either of the tetraploid species and then backcrossing the pentaploid hybrids with pollen of the tetraploid wild parent. Among the BC plants obtained only a few produced some seeds. Fertile tetraploids exhibiting the domesticated syndrome have been selected for in the F2 generation. Although morphologically they were almost indistinguishable from the common oat, they were tetraploids. Wild x domesticated A. magna hybrids were vigorous and fertile. They retained their spikelets at maturity, lemma color and pubescence were intermediate between the parental lines, and awns were formed only on the lower floret of the spikelet. Each of these characteristics segregated in a 3?1 fashion, indicating single gene control, as in the common oat. These four characteristics formed a linkage group in one F2 family and two linkage groups in the other two families. The usefulness of the domesticated tetraploids for oat research and production has been discussed. Taxonomically, the domesticated tetraploids were ranked as subspecies: A. magna ssp. domestica, and A. murphyi ssp. rigida. PMID- 24169893 TI - Relationships among cultivated and wild lentils revealed by RAPD analysis. AB - RAPD markers were used to distinguish between six different Lens taxa, representing cultivated lentil and its wild relatives. Twenty-four arbitrary sequence 10-mer primers were identified which revealed robust and easily interpretable amplification-product profiles. These generated a total of 88 polymorphic bands in 54 accessions and were used to partition variation within and among Lens taxa. The data showed that, of the taxa examined, ssp. orientalis is most similar to cultivated lentil. L. ervoides was the most divergent wild taxon followed by L. nigricans. The genetic similarity between the latter two species was of the same magnitude as between ssp. orientalis and cultivated lentil. In addition, species-diagnostic amplification products specific to L. odemensis, L. ervoides and L. nigricans were identified. These results correspond well with previous isozyme and RFLP studies. RAPDs, however, appear to provide a greater degree of resolution at a sub-species level. The level of variation detected within cultivated lentils suggests that RAPD markers may be an appropriate technology for the construction of genetic linkage maps between closely related Lens accessions. PMID- 24169894 TI - Are economic selection indices always superior to a desired gains index? AB - CONCLUSIONS: The comparison of different selection indices is justified only if the indices are constrated to achieve the same profit function, even when each index is not optimized with respect to that profit function.When a profit function is known and is non-linear, the desired gains index may be more efficient than the economic index. The optimum desired gains index should be determined by iterative techniques over several generations to compare the genetic progress with the economic index, because gains by the economic index are not linear and the changes observed in the initial generations of selection are not the same rates in future generations, although those changes are linear in the case of the desired gains index. PMID- 24169895 TI - Meiotic transmission of a hypomethylated repetitive DNA family in tobacco. AB - We have recently shown that hypomethylation of cytosine residues in the HRS60 family of repetitive DNA sequences can be induced with 5-azacytidine (5-azaC) in tobacco tissue cultures. We have also proven that such a DNA methylation status is maintained during the recovery of protoplasts, plant regeneration, and vegetative development. In the present paper we follow meiotic transmission of hypomethylated HRS60 DNA. Plants obtained from seeds treated with 5-azaC were either self pollinated or crossed with a non-treated control in a reciprocal way. Analysis of the methylation status of the HRS60 DNA revealed that these sequences were hypomethylated in the progenies up to the extent found in the parental 5 azaC-treated plant. Since no parent-of-origin effect was observed, we presume that both male and female gametes transmit an artificial methylation imprint to a similar extent. This result is supported by methylcytosine evaluation in the total genomic DNA samples. A temporal analysis of 5-azaC effects on germinating seeds and a phenotypic evaluation of 5-azaC-treated tobacco plants are also presented. PMID- 24169896 TI - Potential bias in inbreeding depression estimates when using pedigree relationships to assess the degree of homozygosity for loci under selection. AB - A potential bias in estimation of inbreeding depression when using pedigree relationships to assess the degree of homozygosity for loci under selection is indicated. A comparison of inbreeding coefficients based on either pedigree or genotypic frequencies indicated that, as a result of selection, the inbreeding coefficient based on pedigree might not correspond with the random drift of allelic frequencies. Apparent differences in average levels of both inbreeding coefficients were obtained depending on the genetic model (additive versus dominance, initial allelic frequencies, heritability) and the selection system assumed (no versus mass selection). In the absence of selection, allelic frequencies within a small population change over generations due to random drift, and the pedigree-based inbreeding coefficient gives a proper assessment of the accompanying probability of increased homozygosity within a 'replicate' by indicating the variance of allelic frequencies over replicates. With selection, in addition to random drift, directional change in allelic frequencies is not accounted for by the pedigree-based inbreeding coefficient. This result implies that estimation of inbreeding depression for traits under either direct or indirect selection, estimated by a regression of performance on pedigree-based coefficients, should be carefully interpreted. PMID- 24169897 TI - Isozyme polymorphism and organization of the agamic complex of the Maximae (Panicum maximum Jacq., P. infestum Anders, and P. trichocladum K. Schum.) in Tanzania. AB - The tribe Maximae (Panicum maximum Jacq., P. infestum Anders., P. trichocladum K. Schum.) includes two sympatric pools with different modes of reproduction and ploidy levels: an apomictic and tetraploid pool on the one hand, and a smaller, sexual and diploid pool on the other. From an analysis of isozyme polymorphism five main results were evident. First, overall polymorphism is considerable showing that apomixis does not lead to a reduction in diversity. Second, the isozyme polymorphism of the two pools is similar, and this may be explained by reciprocal gene flow (low, but continuous) between these two pools. Third, maximum local polymorphism is due to the simultaneous presence of P. maximum sexuals and P. infestum apomicts. A continuum exists between the two species. Fourth, a high proportion of rare alleles, arising from introgression from P. infestum, characterized the isozyme polymorphism. These rare alleles, strongly counter-selected at the diploid level, are maintained by apomixis; the frequency of triplex or quadruplex genotypes was nevertheless low. Fifth, the heterozygosity level within apomicts is not higher than that of sexuals, showing that the apomixis-polyploidy combination does not lead to a higher frequency of very heterozygous individuals. PMID- 24169898 TI - A barley RFLP map: alignment of three barley maps and comparisons to Gramineae species. AB - Several gene linkage maps have been produced for cultivated barley. We have produced a new linkage map for barley, based on a cross between Hordeum vulgare subsp. spontaneum and Hordeum vulgare subsp. vulgare (Hvs x Hvv), having a higher level of polymorphism than most of the previous barley crosses used for RFLP mapping. Of 133 markers mapped in the Hvs x Hvv F2 population, 69 were previously mapped on other barley maps, and 26 were mapped in rice, maize, or wheat. Two known gene clones were mapped as well as two morphological markers. The distributions of previously mapped markers were compared with their respective barley maps to align the different maps into one consensus map. The distributions of common markers among barley, wheat, rice and maize were also compared, indicating colinear linkage groups among these species. PMID- 24169899 TI - A molecular method for S-allele identification in apple based on allele-specific PCR. AB - cDNA sequences corresponding to two self-incompatibility alleles (S-alleles) of the apple cv 'Golden Delicious' have previously been described, and now we report the identification of three additional S-allele cDNAs of apple, one of which was isolated from a pistil cDNA library of cv 'Idared' and two of which were obtained by reverse transcription-PCR (RT-PCR) on pistil RNA of cv 'Queen's Cox'. A comparison of the deduced amino acid sequences of these five S-allele cDNAs revealed an average homology of 69%. Based on the nucleotide sequences of these S allele cDNAs, we developed a molecular technique for the diagnostic identification of the five different S-alleles in apple cultivars. The method used consists of allele-specific PCR amplification of genomic DNA followed by digestion of the amplification product with an allele-specific restriction endonuclease. Analysis of a number of apple cultivars with known S-phenotype consistently showed coincidence of phenotypic and direct molecular data of the S allele constitution of the cultivars. It is concluded that the S-allele identification approach reported here provides a rapid and useful method to determine the S-genotype of apple cultivars. PMID- 24169900 TI - Inheritance of resistance to watermelon mosaic virus in the cucumber line TMG-1: tissue-specific expression and relationship to zucchini yellow mosaic virus resistance. AB - The inbred cucumber (Cucumis sativus L.) line TMG-1 is resistant to three potyviruses:zucchini yellow mosaic virus (ZYMV), watermelon mosaic virus (WMV), and the watermelon strain of papaya ringspot virus (PRSV-W). The genetics of resistance to WMV and the relationship of WMV resistance to ZYMV resistance were examined. TMG-1 was crossed with WI-2757, a susceptible inbred line. F1, F2 and backcross progeny populations were screened for resistance to WMV and/or ZYMV. Two independently assorting factors conferred resistance to WMV. One resistance was conferred by a single recessive gene from TMG-1 (wmv-2). The second resistance was conferred by an epistatic interaction between a second recessive gene from TMG-1 (wmv-3) and either a dominant gene from WI-2757 (Wmv-4) or a third recessive gene from TMG-1 (wmv-4) located 20-30 cM from wmv-3. The two resistances exhibited tissue-specific expression. Resistance conferred by wmv-2 was expressed in the cotyledons and throughout the plant. Resistance conferred by wmv-3 + Wmv-4 (or wmv-4) was expressed only in true leaves. The gene conferring resistance to ZYMV appeared to be the same as, or tightly linked to one of the WMV resistance genes, wmv-3. PMID- 24169901 TI - Memory development: implications for adults recalling childhood experiences in the courtroom. AB - Adults frequently provide compelling, detailed accounts of early childhood experiences in the courtroom. Judges and jurors are asked to decide guilt or innocence based solely on these decades-old memories using 'common sense' notions about memory. However, these notions are not in agreement with findings from neuroscientific and behavioural studies of memory development. Without expert guidance, judges and jurors may have difficulty in properly adjudicating the weight of memory evidence in cases involving adult recollections of childhood experiences. PMID- 24169902 TI - Development of novel treatment options for patients with haemophilia. AB - Treatment of haemophilia has vastly improved over the last years, but many needs are still unmet. Baxter is continuously pursuing the aim to provide new therapeutic options to patients with haemophilia and to their treating physicians. In fact, there are several opportunities to improve existing therapies, e.g., by new indications for existing products, the introduction of new products, and by novel therapeutic approaches other than factor replacement. Among these, Baxter is working on a number of innovations, such as pharmacokinetics-tailored factor VIII prophylaxis, bypassing agent prophylaxis with FEIBA in inhibitor patients, development of a longer acting pegylated recombinant FVIII, a new recombinant factor IX, a new recombinant factor FVIIa, the first recombinant von Willebrand factor, recombinant ADAMTS13 (a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13) as well as gene therapy to cure haemophilia B. CONCLUSION: Baxter is truly committed to the benefit for the patient, and therefore engaged in providing a more and more individualized treatment, in increasing efficiency of current products, in developing new products and new approaches with added value. PMID- 24169903 TI - Congenital peribronchial myofibroblastic tumor: prenatal imaging clues to differentiate from other fetal chest lesions. AB - We present a prenatal case of congenital peribronchial myofibroblastic tumor referred as a congenital pulmonary airway malformation (CPAM) with hydrops and polyhydramnios at 30 weeks' gestational age. US and fetal MRI findings did not fit with the referral diagnosis, raising the possibility of intrinsic lung tumor. Fetal hydrops worsened and the baby was successfully delivered by ex utero intrapartum treatment (EXIT) to resection at 31 weeks' gestational age. To the best of our knowledge, this is a unique case of congenital peribronchial myofibroblastic tumor that underwent comprehensive prenatal evaluation and EXIT procedure with good outcome. PMID- 24169904 TI - Fertile transgenic barley generated by direct DNA transfer to protoplasts. AB - We report the generation of transgenic barley plants via PEG-mediated direct DNA uptake to protoplasts. Protoplasts isolated from embryogenic cell suspensions of barley (Hordeum vulgare L. cv 'Igri') were PEG-treated in a solution containing a plasmid which contained the neomycin phosphotransferase (NPT II) gene under the control of the rice actin promoter and the nos terminator. Colonies developing from the treated protoplasts were incubated in liquid medium containing the selective antibiotic G418. Surviving calli were subsequently transferred to solid media containing G418, on which embryogenic calli developed. These calli gave rise to albino and green shoots on antibiotic-free regeneration medium. NPT II ELISA revealed that approximately half of the morphogenic calli expressed the foreign gene. In total, 12 plantlets derived from NPT-positive calli survived transfer to soil. Southern hybridization analysis confirmed the stable transformation of these plants. However, the foreign gene seemed to be inactivated in plants from one transgenic line. Most of the transgenic plants set seed, and the foreign gene was transmitted and expressed in their progenies, which was ascertained by Southern hybridization and NPT II ELISA. PMID- 24169905 TI - Chromosome translocations in wild populations of tetraploid emmer wheat in Israel and Turkey. AB - Translocation frequencies (as compared to the standard chromosome arrangement typified by that in 'Chinese Spring') in 9 or more genotypes from each of 15 populations of Triticum dicoccoides in Israel were determined. Data also were obtained from 2 genotypes of the southernmost population (Jaba). A single population from Turkey was also investigated. There were 119 genotypes with translocations in the sample of 171 genotypes investigated (70%). The frequency of translocations in different populations varied from 0.27 to 1.00, and all populations had 1 or more genotypes with one or more translocations. Some populations such as Qazrin appeared to be homogeneous for translocations, but most populations were heterogeneous. A sample of 17 genotypes from 12 of the populations were crossed with the Langdon D-genome disomic substitutions to determine the identity of the chromosomes involved in the translocations. There were nine genotypes with translocations and with the exception of a 2A/2B translocation, none of them involved the same chromosomes. The B-genome chromosomes were involved in translocations more frequently than the A-genome chromosomes. Translocation frequencies (TF) of the various populations were correlated with environmental variables, primarily with water availability and humidity, and possibly also with soil type. In general, TF was higher in peripheral populations in the ecologically heterogeneous frontiers of species distribution than in the central populations located in the catchment area of the upper Jordan valley. PMID- 24169906 TI - A genetic map of rye chromosome 1R integrating RFLP and cytogenetic loci. AB - A genetic map of rye, Secale cereale L., chromosome 1R covering 247 cM was constructed utilizing 27 RFLP and four C-band markers, including terminal C bands. Genetic mapping of C-bands and the centromere, and in situ hybridization of three RFLP clones, allowed for the integration of the genetic and cytological maps. Eight contact points between the genetic and cytological maps revealed variation in the recombination distance to cytological distance ratio ranging between 0.25 and 1.95, a 7.8-fold difference. Recombination was found to be highest in the satellite region of 1RS and lowest in the most distal region of 1RL. PMID- 24169907 TI - Genic control of honey bee dance language dialect. AB - Behavioural genetic analysis of honey bee dance language shows simple Mendelian genic control over certain dance dialect differences. Worker honey bees of one parent colony (yellow) changed from round to transition dances for foraging distances of 20 m and from transition to waggle dances at 40 m. Worker bees of the other parent colony (black) made these shifts at 30 m and 90 m, respectively. F1 colonies behaved identically to their yellow parent, suggesting dominance. Progeny of backcrossing between the F1 generation and the putative recessive black parent assorted to four classes, indicating that the dialect differences studied are regulated by genes at two unlinked loci, each having two alleles. Honey bee dance communication is complex and highly integrated behaviour. Nonetheless, analysis of a small element of this behaviour, variation in response to distance, suggests that dance communication is regulated by subsets consisting of simple genic systems. PMID- 24169908 TI - RFLP and RAPD mapping of the sunflower Pl1 locus for resistance to Plasmopara halstedii race 1. AB - The Pl1 locus in sunflower, Helianthus annuus L., conferring resistance to downy mildew, Plasmopara halstedii, race 1 has been located in linkage group 1 of the consensus RFLP map of the cultivated sunflower. Bulked segregant analyses were used on 135 plants of an F2 progeny from a cross between a downy mildew susceptible line, GH, and RHA266, a line carrying Pl1. Two RFLP markers and one RAPD marker linked to the Pl1 locus have been identified. The RFLP markers are located at 5.6 cM and 7.1 cM on either side of Pl1. The RAPD marker is situated at 43.7 cM from Pl1. The significance and applications of these markers in sunflower breeding are discussed. PMID- 24169909 TI - Cytogenetic and molecular mapping of the wheat-Aegilops longissima chromatin breakpoints in powdery mildew-resistant introgression lines. AB - The amount of alien chromatin introgressed in eight wheat/Ae. longissima Pm13 recombinant lines, involving breakpoints on the short arms of wheat chromosomes 3B and 3D, was evaluated by cytogenetic and molecular approaches. For each line the residual homologous synaptic ability of the recombinant chromosome in its proximal wheat and distal alien portion was estimated through meiotic analyses. Subsequently, telocentric and RFLP mapping were used to assess the genetic distance from the wheat centromere to the wheat/Ae. longissima breakpoints. One 3B recombinant line was distinguished from the other four by the chromosome pairing and telocentric mapping analyses. RFLP analysis succeeded in differentiating the remaining four lines into two groups. Chromosome pairing and telocentric mapping of the three 3D recombinant lines suggested that all had distinct breakpoints. However, the RFLP data could not discriminate between the two more proximal translocations. Physical locations for some RFLP loci were determined by a comparison of genotypes and C-banding karyotypes. This showed a considerable expansion of the genetic map compared to its physical length. PMID- 24169910 TI - A comparison of male and female recombination frequency in wheat using RFLP maps of homoeologous group 6 and 7 chromosomes. AB - A novel approach was used to compare male and female recombination rates in wheat. Doubled haploid lines were developed from an F1 using two distinct approaches: the anther-culture technique and the Hordeum bulbosum system, from which sets of lines were developed from "male" and "female" meioses, respectively. The genotype of the lines was established at RFLP and isozyme markers polymorphic on chromosomes of homoeologous groups 6 and 7, and "male" and "female" linkage maps were calculated using this information. The markers in one segment of chromosome 6B exhibited disturbed segregation frequencies in the anther-culture population. The "male" and "female" maps differed significantly in recombination frequency between some markers on two chromosomes, and these were consistent in direction within chromosomes and inconsistent in direction between chromosomes. In two of the four chromosomes studied the "male" map was much longer than the "female" map. These results suggest that significant differences may exist in male and female recombination frequencies in bread wheat which are specific to certain chromosomal segments but are inconsistent in direction between chromosomes. Other factors, such as environmental influences, may also be important in creating differences. PMID- 24169911 TI - Rare symmetric and asymmetric Nicotiana tabacum (+) N. megalosiphon somatic hybrids recovered by selection for nuclear-encoded resistance genes and in the absence of genome inactivation. AB - Following protoplast fusion between Nicotiana tabacum (dhfr) and N. megalosiphon (nptII) somatic hybrids were selected on the basis of dual resistance to kanamycin and methotrexate. Despite strong selection for parental nuclear-encoded resistances, only nine N. tabacum (+) N. megalosiphon somatic hybrids were obtained. A preferential loss of the parental N. tabacum nuclear and organelle genome was apparent in some plants in spite of the lack of genomic inactivation by the irradiation or chemical treatment of the parental protoplasts. Only six of the nine hybrids recovered possessed both parental profiles of nuclear RFLPs and isoenzymes. The remaining three hybrids were highly asymmetric with two being identical to N. megalosiphon except for minor morphological differences and rearranged or recombined mitochondrial DNAs (mtDNA), while the other one was distinguishable only by the presence of a rearranged or recombined mtDNA, and was therefore possibly a cybrid. Overall, eight somatic hybrids possessed rearranged or recombined mtDNAs and chloroplast inheritance was non-random since eight possessed N. megalosiphon-type chloroplasts and only one had N. tabacum chloroplasts. In contrast, using the same selection approach, numerous morphologically similar symmetric somatic hybrids with nuclear RFLPs and isozymes of both the parental species were recovered from control fusions between N. tabacum and the more closely related N. sylvestris. In spite of the low frequency of recovery of symmetric N. tabacum (+) N. megalosiphon hybrids in this study, one of these hybrids displayed a significant degree of self-fertility allowing for back-crosses to transfer N. megalosiphon disease-resistance traits to N. tabacum. PMID- 24169913 TI - Quantitative trait loci affecting cotton fiber are linked to the t1 locus in upland cotton. AB - Pilose (T 1), a dominant marker in upland cotton, has been associated with coarse, short fibers. Pilose was, thereby, considered to be pleiotropic on fiber fineness and length. However, a pilose-expressing line with a fiber of average fineness was recently identified. This finding does not support pleiotropy between T 1 and fiber traits, but is indicative of linkage between pilose and loci influencing fiber characteristics. To understand the relationship between T 1 and fiber traits, a pilose line with short, coarse fiber was crossed to two t 1 lines with standard fiber characteristics. One hundred and forty-nine F2-derived F3 lines were developed from one cross, and 60 F2-derived F3 lines from the other. Seven fiber traits (elongation, maturity, micronaire reading, perimeter, 2.5% span length, strength, and wall thickness) were measured. Segregation was normal, as indicated by allelic frequencies of 0.5 for T 1 and t 1, and segregation ratios of 1?2?1 for marker genotypes. The association of homozygous T 1 lines with fibers of average fineness was again observed. Linkage between T 1 and loci affecting micronaire, perimeter, 2.5% span length, strength, and wall thickness was found in both populations. Significant additive and non-additive gene effects for each of these traits at the marker locus were found as well. The pilose marker accounted for 10-75% of the phenotypic variation associated with each trait. In conclusion, the t 1 locus is linked to numerous loci that influence fiber traits, and this linkage has previously been misinterpreted as pleiotropy. PMID- 24169912 TI - Molecular tagging of the dwarf BREIZH (Bzh) gene in Brassica napus. AB - We mapped the dwarf Bzh gene in B. napus with RAPD and RFLP markers. Research of the linked markers proceeded in two ways: a random approach through the construction of a detailed genetic map and targeting of the dwarf gene using both near-isogenic lines (NILs) and the bulked segregant analysis (BSA) method. The BSA approach was the most efficient in finding DNA markers linked to Bzh, whereas the efficiency of the NILs approach was limited by a too great similarity of the genetic background between the dwarf donor parent and the recurrent lines. Eight RAPD markers were identified as linked to Bzh, the closest being at 0.8+/-0.7 cM. The random genetic mapping approach added markers and extended the linkage group containing Bzh. This work represents the first step towards a better understanding of the dwarf mutation, the development of marker-assisted selection, and the cloning of the underlying gene responsible for dwarfing. PMID- 24169914 TI - Including genetic relationships in selection decisions: alternative methodologies. AB - Investigations are made of variations in an iterative methodology previously introduced for reducing inbreeding by including genetic relationships in selection decisions, using adjusted estimated breeding values (EBV). An alternative computing strategy for maximising the value of the population selection criterion is shown to involve less computation, which results in function values as great or greater than the original method. Alteration of weights for different types of relationships in the adjusted EBV has no detectable effect on genetic gain at a given level of inbreeding. Selection using the adjusted EBV method in one sex and truncation on EBV in the other sex results in less genetic gain at a given level of inbreeding than using adjusted EBV in both sexes, but results in more gain at a given level of inbreeding than three selection strategies that do not include genetic relationships in selection decisions. The advantage of the adjusted EBV method over these three methods is retained when selection is for a sexlimited trait. PMID- 24169915 TI - The effect of simultaneous selection on the genetic correlation. AB - The theoretical effect of simultaneous selection on the genetic correlations between two traits over 20 generations was examined using simulation. For each generation, a population of 50 male and 50 female diploid gen otypes with 15 loci, each with two alleles, was synthesized. None of the loci exhibited dominance. Five loci affected only trait 1, 5 loci only trait 2 and 5 were pleiotropic (affected both traits). Initial allelic frequencies were equal at each locus. Phenotypes were created by adding a random normal deviation for each trait to the genotype. The size of this deviation for each trait determined its heritability (h(2)). Index selection with h(2) combinations of (0.15, 0.15), (0.15,0.45) and (0.45,0.45) and relative economic weights of (1, 1) and (1, 3) for each h(2) combination was employed. In each generation, the highest ranking 25 genotypes of each sex were used to generate the next generation with single pair matings, each producing two male and two female offspring. One hundred replicates were run for both negative and positive correlations. With a positive initial value, the genetic correlation tended to decline (toward zero). The rates of change were moderately affected by index weights and h(2). With a negative initial value, the genetic correlation tended to decrease (towards -1). However, unequal heritabilities and unequal relative economic weights slowed the rate of change with the greatest imbalances tending to hold the correlation constant or move it toward zero. These simulations illustrate that changes in parameters over time can affect the selection practiced. Under some of the conditions simulated, the use of initial genetic parameter values without change could have potentially negative effects on overall genetic gain. PMID- 24169916 TI - Cytologically based physical maps of the group 3 chromosomes of wheat. AB - Cytologically based physical maps for the group 3 chromosomes of wheat were constructed by mapping 25 Triticum aestivum deletion lines with 29 T. tauschii and T. aestivum RFLP probes. The deletion lines divide chromosomes 3A, 3B, and 3D into 31 discrete intervals, of which 18 were tagged by marker loci. The comparison of the consensus physical map with a consensus RFLP linkage map of the group 3 chromosomes of wheat revealed a fairly even distribution of marker loci on the long arm, and higher recombination in the distal region. PMID- 24169917 TI - Genetics and mapping of new isozyme loci in Vicia faba L using trisomics. AB - Polymorphism in ten enzyme systems (ACO, ACP, AAT, EST, FK, ME, NAG, PRX, 6PGD, and SOD) in Vicia faba L. was analyzed, revealing 13 loci, six of which have not been reported before. Inheritance, genetics, possible location, and linkage analysis were studied in 13 different F(2) populations trisomic for four of the six chromosomes (nos. 3, 4, 5, and 6) of the species. Each of these loci exhibited typical Mendelian inheritance except for those involved in the trisomic chromosome. Five loci have been assigned to a specific chromosome: Est-2 to chromosome 3, Fk-2 to chromosome 4, Prx-1 to chromosome 5, and Sod-1 and Pgd-p to chromosome 6. Nag-1 and Pgd-c displayed a linkage of 22.8 cM indicating a clear homology with chromosome 5 of garden pea on which both markers are syntenic. PMID- 24169918 TI - Estimation of long-term genetic improvement for gerbera using the best linear unbiased prediction (BLUP) procedure. AB - Long-term genetic improvement is measured by the selection response predicted from estimates of narrow-sense heritability. Accurate estimates of selection response require partitioning the change of population mean into genetic and environmental components. A selection experiment for cut-flower yield was conducted for 16 generations in the Davis population of gerbera (Gerbera hybrida, Compositae). Breeding values were estimated for individual plants in the population using the best linear unbiased prediction (BLUP) procedure. Genetic change in each generation was calculated from the breeding values of individual plants. The results of this study indicate that long-term selection was successful and necessary for the genetic improvement in cut-flower yield. Genetic improvement in mean breeding value over 16 generations was 33 flowers. Mean breeding values increased monotonically with an S-shape pattern while environmental effects fluctuated from generation to generation. Results predict that cut-flower yield in the Davis population of gerbera will continue to respond to selection. PMID- 24169919 TI - Linkage relationships among stress-induced genes in wheat. AB - Linkage relationships among genes responding to water-deficit, salt stress, and heat shock were investigated in diploid wheat, Triticum monococcum L. The position of these gene loci relative to closely linked markers and the centromeres is reported. It is proposed to continue to use the present T. monococcum mapping population and the genetic maps based thereon as a framework for future determination of relationships among other genes related to environmental stress in the tribe Triticeae. PMID- 24169920 TI - RFLP mapping of quantitative trait loci controlling seed aliphatic-glucosinolate content in oilseed rape (Brassica napus L). AB - We report the RFLP mapping of quantitative trait loci (QTLs) which regulate the total seed aliphaticglucosinolate content in Brassica napus L. A population of 99 F1-derived doubled-haploid (DH) recombinant lines from a cross between the cultivars Stellar (low-glucosinolate) and Major (high-glucosinolate) was used for singlemarker analysis and the interval mapping of QTLs associated with total seed glucosinolates. Two major loci, GSL-1 and GSL-2, with the largest influence on total seed aliphatic-glucosinolates, were mapped onto LG 20 and LG 1, respectively. Three loci with smaller effects, GSL-3, GSL-4 and GSL-5, were tentatively mapped to LG 18, LG 4 and LG 13, respectively. The QTLs acted in an additive manner and accounted for 71 % of the variation in total seed glucosinolates, with GSL-1 and GSL-2 accounting for 33% and 17%, respectively. The recombinant population had aliphatic-glucosinolate levels of between 6 and 160 MUmoles per g(-1) dry wt of seed. Transgressive segregation for high seed glucosinolate content was apparent in 25 individuals. These phenotypes possessed Stellar alleles at GSL-3 and Major alleles at the four other GSL loci demonstrating that low-glucosinolate genotypes (i.e. Stellar) may possess alleles for high glucosinolates which are only expressed in particular genetic backgrounds. Gsl-elong and Gsl-alk, loci which regulate the ratio of individual aliphatic glucosinolates, were also mapped. Gsl-elong-1 and Gsl-elong-2, which control elongation of the alpha-amino-acid precursors, mapped to LG 18 and LG 20 and were coincident with GSL loci which regulate total seed aliphatic glucosinolates. A third tentative QTL, which regulates side-chain elongation, was tentatively mapped to LG 12. Gsl-alk, which regulates H3CS-removal and side-chain de-saturation, mapped to LG 20. PMID- 24169922 TI - Physiological aspects of genome variability in tissue culture. II. Growth phase dependent quantitative variability of repetitive BstNI fragments of primary cultures of Daucus carota L. AB - Systematic investigations on the occurrence of differential DNA replication in carrot cultures, expressed at the total genome level, were performed. The genome of Daucus carota L. could be characterized by a pattern of repetitive BstNI fragments that was independent of tissue specificity or cultivar differences. Characterization of the genomic DNA of the secondary phloem of carrot roots, in comparison to the DNA of the induced primary cultures at different growth phases, revealed dramatic differences in the copy number of the repetitive fragments. Highly proliferative tissue showed extensive reduction in the proportion of repetitive sequences in the genome in all of the 37 investigated variants. In contrast, during subsequent transition to stationary growth the repetitive fragments re-amplified. The results suggest that the quantitative genome organisation was involved in the regulation of the growth potential of cells. A hypothesis is discussed suggesting a determining influence of the observed differential DNA replication on cell-cycle rates and the cell program of proliferative tissue by structural and positioning effects on DNA loops. To study the causality of somaclonal variation, research on the relationship between physiological genome variability and the induction of heritable changes is recommended. PMID- 24169921 TI - Physiological aspects of genome variability in tissue culture. I. Growth phase dependent differential DNA methylation of the carrot genome (Daucus carota L.) during primary culture. AB - Investigations were performed on growth phase-dependent EcoRII site-specific DNA methylation of the carrot genome during primary culture to elucidate physiological aspects of genome DNA variability in tissue culture. While DNA methylation of the root cambium and the secondary phloem and petioles of carrot leaves were strikingly different, the methylation level of the secondary phloem seemed to be independent of cultivar origin, the age of the plants and the extent of secondary root growth. As was shown earlier a change in the differentiated state of the secondary phloem by tissue culture leads to changes in genome modification. Whereas de novo methylation was observed during the first 2 weeks of growth initiation, the results presented demonstrate genome de-methylation during the transition to stationary growth indicating differential epsilonnome methylation during different phases of culture. The presence of kinetin in the nutrient medium of the primary culture was found to be antagonistic to changes in genome modification in general. De novo methylation and subsequent de-methylation of the carrot genome are discussed as gross changes obviously essential to molecular genome differentiation during tissue culture. PMID- 24169923 TI - Deltahedral ferratricarbaboranes: analogues of ferrocene. AB - The neutral ferratricarbaboranes (eta(5)-RC3B8H10)Fe(eta(5)-C5H5) (R = aryl), analogues of ferrocene, have recently (2013) been synthesized by Stibr and co workers and structurally characterized by X-ray crystallography. We have now used density functional theory to study the structures of the complete series of related ferratricarbaboranes CpFeC3B(n-4)H(n-1) (n = 8 to 12). The lowest energy structures are found to have the maximum number of carbon atoms at degree 4 rather than at degree 5 vertices and avoid adjacent carbon atoms, i.e., C-C edges. This can lead to structures deviating from the most spherical closo deltahedra. For the 8-vertex CpFeC3B4H7 system, hexagonal bipyramidal structures are found to be of comparable energy to the closo bisdisphenoidal structures. For the 9-vertex CpFeC3B5H8 system the unique closo tricapped trigonal prismatic structure having carbon atoms at the three non-adjacent degree 4 vertices lies ~16 kcal mol(-1) below the next lowest energy structure. The 10-vertex CpFeC3B6H9 system has the most complicated potential energy surface of the CpFeC3B(n-4)H(n 1) structures with nine structures within 13 kcal mol(-1) of the global minimum. Six of these nine structures are based on the closo bicapped square antiprism, which has only two degree 4 vertices for carbon atoms. The remaining three low energy CpFeC3B6H9 structures are derived from the isocloso 10-vertex deltahedron with the iron atom at the unique degree 6 vertex and all three carbon atoms at degree 4 vertices. The low-energy 11-vertex CpFeC3B7H10 structures are based on the 11-vertex closo/isocloso deltahedron with the unique structure having the iron atom at the degree 6 vertex, carbon atoms at the two degree 4 vertices, and no C-C edge being the lowest energy structure. The lowest energy 12-vertex CpFeC3B8H11 structures are all based on the regular icosahedron with the three lowest energy structures having no C-C edges. The two lowest energy CpFeC3B8H11 structures correspond to those recently found experimentally in the (eta(5) RC3B8H10)Fe(eta(5)-C5H5) (R = aryl) systems. PMID- 24169924 TI - Functional DNA switches: rational design and electrochemical signaling. AB - Recent developments in nanoscience research have demonstrated that DNA switches (rationally designed DNA nanostructures) constitute a class of versatile building blocks for the fabrication and assembly of electronic devices and sensors at the nanoscale. Functional DNA sequences and structures such as aptamers, DNAzymes, G quadruplexes, and i-motifs can be readily prepared in vitro, and subsequently adapted to an electrochemical platform by coupling with redox reporters. The conformational or conduction switching of such electrode-bound DNA modules in response to an external stimulus can then be monitored by conventional voltammetric measurements. In this review, we describe how we are able to design and examine functional DNA switches, particularly those systems that utilize electrochemical signaling. We also discuss different available options for labeling functional DNA with redox reporters, and comment on the function oriented signaling pathways. PMID- 24169925 TI - An exploratory study of the efficacy and safety of yokukansan for neuropsychiatric symptoms in patients with Parkinson's disease. AB - The present study examined the efficacy and safety of yokukansan (YKS) in neuropsychiatric symptoms in patients with Parkinson's disease (PD) using the neuropsychiatric inventory (NPI). Twenty-five patients with PD (M:F 14:11; age 72 years) were enrolled and treated with YKS (7.5 g/day) for 12 weeks. The NPI was assessed at 0, 4, 8, 12 and 16 weeks. The patient's motor function and progression were evaluated using the Unified PD Rating Scale part III (UPDRS-III) and Hoehn and Yahr scale, respectively. The serum potassium concentration (sK) and all adverse events were recorded. The median NPI total score significantly decreased from 12 points at baseline to 4.0 points at 12 weeks (p = 0.00003). Within each NPI subscale, significant improvements were observed in hallucinations, anxiety and apathy. These symptoms tended to worsen after the completion of YKS treatment. Delusions, agitation, depression, euphoria, disinhibition, aberrant motor activity tended to improve but irritability showed no change. The median NPI subtotal scores, positive symptoms (delusions hallucinations-irritability) significantly decreased (p = 0.01660) and negative symptoms (anxiety-apathy) significantly decreased (p = 0.00391). Both UPDRS-III and the Hoehn and Yahr scale showed no significant change. sK decreased mildly from 4.26 +/- 0.30 to 4.08 +/- 0.33 mEq/L. Two patients showed hypokalemia lower than 3.5 mEq/L without any corresponding symptoms; two patients showed listlessness and one patient showed drug eruption. Each recovered after discontinuation of YKS. YKS improved neuropsychiatric symptoms associated with PD, including hallucinations, anxiety and apathy without severe adverse events and worsening of Parkinsonism. PMID- 24169926 TI - Tardive dystonic syndrome induced by the calcium-channel blocker amlodipine. AB - Identification of drug exposure as a cause for dystonia is important since cessation of the causative agent offers a chance for remission. We describe two patients with a cranial, cervical, pharyngo-laryngeal and axial dystonia, akathisia, breathing dysrhythmias together with depression and anxiety. Both patients were started on the calcium channel blocker (CCB) amlodipine 1 month before symptom onset. They symptoms were non-acute and due to CCBs well-known D2 antagonism; hence they were classified as a tardive dystonic syndrome. Parkinsonism and depression have been described especially for the CCB flunarizine and cinnarizine. Tardive dystonia under CCB has rarely been reported. CCB exposure should be investigated in all dystonias with cranial, cervical, pharyngo-laryngeal and axial manifestations, especially when additional akathisia, Parkinsonism and depression are present. When CCB induction is suspected, CCB cessation may offer a chance for spontaneous remission. Whether CCB exposure can deteriorate, idiopathic dystonia is unclear. Therefore, CCB should best be avoided in patients with dystonia. PMID- 24169927 TI - Spitzer's laws of neonatology--it's about time someone took a critical look at this foolishness! PMID- 24169928 TI - Case report: congenital rubella syndrome: a rare but persistent concern in the United States. AB - In countries such as the United States where rubella virus infections are rare, congenital rubella syndrome (CRS) may not be recognized in a timely manner. However, the syndrome still appears in this country, often in infants of mothers emigrating from countries with absent or suboptimal national vaccination programs. We describe a case of CRS in a term baby born to a recent US immigrant who developed a primary varicella infection in late pregnancy and demonstrated IgG titers to rubella at delivery. At presentation, the neonate had both classical findings as well as less reported vascular and neurological abnormalities seen in infants with CRS. PMID- 24169929 TI - Thinking outside of the blue box: a case presentation of neonatal methemoglobinemia. AB - We report the case of a full-term neonate who presented with cyanosis from birth secondary to methemoglobinemia precipitated by the obstetric use of bupivacaine in a spinal anaesthetic for caesarean delivery. PMID- 24169930 TI - Monitoring diaphragm electrical activity and the detection of congenital central hypoventilation syndrome in a newborn. AB - A full-term newborn infant is described with recurrent episodes of oxygen desaturation and apnea on the day of birth. The apnea did not improve with continuous positive airway pressure (CPAP) and intermittent nasal ventilation, therefore intubation and mechanical ventilation were required. A preliminary diagnosis of congenital central hypoventilation syndrome (CCHS) was made with the use of simultaneous measurements of end-tidal CO2 (EtCO2) and a diaphragm electrical activity waveform that was detected using microsensors placed on the infant's feeding tube. It was observed that during deep sleep, the diaphragm electrical activity waveform was close to 0 MUV (central apnea) and EtCO2 levels rose accordingly (central hypoventilation). Genetic testing subsequently revealed a Phox2b mutation, establishing the diagnosis of CCHS. Simultaneously measuring diaphragm electrical activity and EtCO2 is feasible and may be a valuable bedside diagnostic tool in cases of suspected CCHS before the diagnosis is confirmed with genetic testing. PMID- 24169931 TI - Influence of poor health on exit from paid employment: a systematic review. AB - The objective was to provide a systematic literature review on associations between poor health and exit from paid employment through disability pension, unemployment and early retirement, and to estimate the magnitude of these associations using meta-analyses. Medline and Embase databases were searched for longitudinal studies on the relationship between health measures and exit from paid employment. Random-effects models were used to estimate the pooled effects. In total, 29 studies were included. Self-perceived poor health was a risk factor for transition into disability pension (relative risk (RR) 3.61; 95% CI 2.44 to 5.35), unemployment (RR 1.44; 95% CI 1.26 to 1.65) and early retirement (RR 1.27; 95% CI 1.17 to 1.38). Workers with mental health problems had an increased likelihood for transition into disability pension (RR 1.80; 95% CI 1.41 to 2.31) or unemployment (RR 1.61; 95% CI 1.29 to 2.01). Chronic disease was a risk factor for transition into disability pension (RR 2.11; 95% CI 1.90 to 2.33) or unemployment (RR 1.31; 95% CI 1.14 to 1.50), but not for early retirement. This meta-analysis showed that poor health, particularly self-perceived health, is a risk factor for exit from paid employment through disability pension, unemployment and, to a lesser extent, early retirement. To increase sustained employability it should be considered to implement workplace interventions that promote good health. PMID- 24169932 TI - Unprotected left main coronary artery disease after revascularization : effect of diabetes on patient outcomes. AB - OBJECTIVE: It is unknown whether the effect of diabetes on patients with unprotected left main coronary artery (LMCA) disease differs according to the different revascularization strategies. This study was conducted to evaluate the impact of diabetes on patients with unprotected LMCA disease treated with either percutaneous coronary intervention (PCI) or coronary artery bypass grafting (CABG). PATIENTS AND METHODS: We prospectively enrolled 823 consecutive patients with unprotected LMCA disease who had drug-eluting stent (DES; n = 331) implantation or underwent CABG (n = 492) in the study. We compared the effects of diabetes on clinical outcomes according to different revascularization strategies. RESULTS: Among 823 eligible patients enrolled, 226 had diabetes. In the DES population, no significant differences were observed in occurrences of death, cardiac death, repeat revascularization, stroke, and major adverse cardiac and cerebrovascular events. However, the risks of the composite of death/myocardial infarction (MI)/stroke (21.5 % DM vs. 7.2 % non-DM; p = 0.001) and MI (15.4 % DM vs. 1.6 % non-DM; p = 0.000) were significantly higher in the diabetic patients than those without diabetes. In the CABG population, similar rates of all clinical endpoints were observed between the diabetic and nondiabetic group. CONCLUSION: Diabetes was associated with worse outcome in patients undergoing DES implantation for the treatment of unprotected LMCA disease. However, its negative prognostic impact was not found among patients undergoing CABG. PMID- 24169933 TI - [European guidelines on cardiovascular disease prevention. What has changed in 2012?]. AB - The new European Guidelines on Cardiovascular Disease Prevention (version 2012) are supported by nine medical societies. They are newly structured, shorter and more readable. Each subchapter starts with key messages and recommendations are labeled with an evidence level. The subchapter ends with "most important newest information" and "persisting gaps of evidence" for further research. Smoking and passive smoking are to be avoided, even a small amount of regular physical activity is beneficial, the Mediterranean type diet is recommended and a body mass index (BMI) between 22 and 25 is associated with the lowest mortality. A blood pressure target of <140/90 mmHg is appropriate for the vast majority of hypertensive patients. Aspirin is not recommended for primary prevention even not for diabetics without vascular disease. Cardiovascular risk is now categorized into four levels: low (<1%), medium (1% to <5%), high (5% to <10%) and very high risk (>=10%). All patients with cardiovascular disease are in the very high risk group with the corresponding treatment goals, e. g. a low density lipoprotein (LDL) cholesterol goal of <70 mg/dl (<1.8 mmol/l). Treatment adherence and behavioral changes can best be achieved by motivational interviews which demand some time. It is emphasized that the physician has the responsibility for clear recommendations in the discharge summaries after hospitalization and for offering help and feed back in the implementation phase of behavioral changes. PMID- 24169934 TI - [ESC guidelines on the management of valvular heart disease. What has changed and what is new?]. AB - In 2012 the new and collaborative "Guidelines on the management of valvular heart disease (version 2012)" were published by the European Society of Cardiology (ESC) and the European Association for Cardio-Thoracic Surgery (EACTS). These guidelines emphasize that decision-making in patients with valvular heart disease should ideally be carried out by a"heart team" with particular expertise in valvular heart disease. In aortic regurgitation pathologies of the aortic root are frequent and in patients with Marfan syndrome, surgery is indicated when the maximal ascending aortic diameter is >=50 mm, while the threshold for intervention should be lower in patients with risk factors for progression. Regarding aortic stenosis, transcatheter aortic valve implantation (TAVI) should be performed only in hospitals with on-site cardiac surgery and with a"heart team" available to assess patient risks. The TAVI procedure is indicated in patients with severe symptomatic aortic stenosis who are judged by the"heart team" to be unsuitable for surgery but have sufficient life expectancy. It should be considered for high-risk patients with severe symptomatic aortic stenosis based on the individual risk profile assessed by the"heart team". Furthermore, low flow - low gradient aortic stenosis with normal ejection fraction and the difficult topic of asymptomatic severe aortic stenosis and the indications for aortic valve replacement are discussed. With respect to mitral regurgitation, valve repair should be the preferred technique when it is expected to be durable. The topics of asymptomatic mitral regurgitation as well as percutaneous mitral valve repair using the edge to edge technique as an alternative for high risk patients are discussed. Tricuspid disease should not be forgotten and during left sided valve surgery, tricuspid valve surgery should be considered in the presence of mild to moderate secondary regurgitation if there is significant annular dilatation. Last but not least, in patients with aortic bioprostheses the use of low-dose aspirin is now favored for a 3-month postoperative period. PMID- 24169935 TI - Neurological disorders: Eaten alive! PMID- 24169936 TI - Cerebral cortex: Sizing up the columns. PMID- 24169938 TI - Synaptic transmission: Releasing the brakes. PMID- 24169937 TI - The neural basis of humour processing. AB - Humour is a vital component of human socio-affective and cognitive functioning. Recent advances in neuroscience have enabled researchers to explore this human attribute in children and adults. Humour seems to engage a core network of cortical and subcortical structures, including temporo-occipito-parietal areas involved in detecting and resolving incongruity (mismatch between expected and presented stimuli); and the mesocorticolimbic dopaminergic system and the amygdala, key structures for reward and salience processing. Examining personality effects and sex differences in the neural correlates of humour may aid in understanding typical human behaviour and the neural mechanisms underlying neuropsychiatric disorders, which can have dramatic effects on the capacity to experience social reward. PMID- 24169939 TI - Tandem regio- and diastereo-selective synthesis of halogenated C-vinyl glycosides from unactivated arylacetylenes. AB - A highly regio- and diastereo-selective synthesis of halogenated C-vinyl glycosides has been achieved from glycals and unactivated aryl acetylenes in the presence of halogenated Lewis acids via a tandem glycosylation-halogenation reaction. The Lewis acid used served the dual purpose of activating the allylic acetoxy group of glycals and serving as halogen source for Markovnikov addition across the triple bond, which makes the process atom economic. The synthesized glycosyl vinyl halides have been used as precursors for various Pd catalyzed C-C cross coupling reactions. PMID- 24169940 TI - Vibrotactile discrimination in the rat whisker system is based on neuronal coding of instantaneous kinematic cues. AB - Which physical parameter of vibrissa deflections is extracted by the rodent tactile system for discrimination? Particularly, it remains unclear whether perception has access to instantaneous kinematic parameters (i.e., the details of the trajectory) or relies on temporally integration of the movement trajectory such as frequency (e.g., spectral information) and intensity (e.g., mean speed). Here, we use a novel detection of change paradigm in head-fixed rats, which presents pulsatile vibrissa stimuli in seamless sequence for discrimination. This procedure ensures that processes of decision making can directly tap into sensory signals (no memory functions involved). We find that discrimination performance based on instantaneous kinematic cues far exceeds the ones provided by frequency and intensity. Neuronal modeling based on barrel cortex single units shows that small populations of sensitive neurons provide a transient signal that optimally fits the characteristic of the subject's perception. The present study is the first to show that perceptual read-out is superior in situations allowing the subject to base perception on detailed trajectory cues, that is, instantaneous kinematic variables. A possible impact of this finding on tactile systems of other species is suggested by evidence for instantaneous coding also in primates. PMID- 24169941 TI - Rising temperature reduces divergence in resource use strategies in coexisting parasitoid species. AB - Coexistence of species sharing the same resources is often possible if species are phylogenetically divergent in resource acquisition and allocation traits, decreasing competition between them. Developmental and life-history traits related to resource use are influenced by environmental conditions such as temperature, but thermal trait responses may differ among species. An increase in ambient temperature may, therefore, affect trait divergence within a community, and potentially species coexistence. Parasitoids are interesting models to test this hypothesis, because multiple species commonly attack the same host, and employ divergent larval and adult host use strategies. In particular, development mode (arrested or continued host growth following parasitism) has been recognized as a major organiser of parasitoid life histories. Here, we used a comparative trait-based approach to determine thermal responses of development time, body mass, egg load, metabolic rate and energy use of the coexisting Drosophila parasitoids Asobara tabida, Leptopilina heterotoma, Trichopria drosophilae and Spalangia erythromera. We compared trait values between species and development modes, and calculated trait divergence in response to temperature, using functional diversity indices. Parasitoids differed in their thermal response for dry mass, metabolic rate and lipid use throughout adult life, but only teneral lipid reserves and egg load were affected by developmental mode. Species-specific trait responses to temperature were probably determined by their adaptations in resource use (e.g. lipogenesis or ectoparasitism). Overall, trait values of parasitoid species converged at the higher temperature. Our results suggest that local effects of warming could affect host resource partitioning by reducing trait diversity in communities. PMID- 24169942 TI - Viviparity in high-altitude Phrynocephalus lizards is adaptive because embryos cannot fully develop without maternal thermoregulation. AB - Viviparous Phrynocephalus lizards (Agamidae) are mainly restricted to the Qinghai Tibet Plateau of China. In this study, we used Phrynocephalus vlangalii females kept under seven thermal regimes for the whole gestation period to test the hypothesis that viviparity in high-altitude Phrynocephalus lizards is adaptive because embryos cannot fully develop without maternal thermoregulation. All females at 24 degrees C and 93% of the females at 28 degrees C failed to give birth or produced stillborns, and proportionally fewer females gave birth at 29 or 35 degrees C than at 32 degrees C. Though the daily temperatures encountered were unsuitable for embryonic development, 95% of the females in nature and 89% of the females thermoregulating in the laboratory gave birth. There was no shift in the thermal preferences of females when they were pregnant. Although thermal conditions inside natural burrows were unsuitable for embryonic development, mass and sprint speed were both greater in neonates produced in nature. Our data show that (1) long-term exposure of P. vlangalii embryos to temperatures outside the range of 29-35 degrees C may result in the failure of development, but daily or short-term exposure may not necessarily increase embryonic mortality; (2) low gestation temperatures slow but do not arrest embryonic development, and females produce high-quality offspring in the shortest possible time by maintaining gestation temperatures close to the upper thermal limit for embryonic development; and (3) viviparity is currently adaptive at high elevations because embryos in nature cannot fully develop without relying on maternal thermoregulation. Our data validate the hypothesis tested. PMID- 24169943 TI - Non-publication of large randomized clinical trials: cross sectional analysis. AB - OBJECTIVE: To estimate the frequency with which results of large randomized clinical trials registered with ClinicalTrials.gov are not available to the public. DESIGN: Cross sectional analysis SETTING: Trials with at least 500 participants that were prospectively registered with ClinicalTrials.gov and completed prior to January 2009. DATA SOURCES: PubMed, Google Scholar, and Embase were searched to identify published manuscripts containing trial results. The final literature search occurred in November 2012. Registry entries for unpublished trials were reviewed to determine whether results for these studies were available in the ClinicalTrials.gov results database. MAIN OUTCOME MEASURES: The frequency of non-publication of trial results and, among unpublished studies, the frequency with which results are unavailable in the ClinicalTrials.gov database. RESULTS: Of 585 registered trials, 171 (29%) remained unpublished. These 171 unpublished trials had an estimated total enrollment of 299,763 study participants. The median time between study completion and the final literature search was 60 months for unpublished trials. Non-publication was more common among trials that received industry funding (150/468, 32%) than those that did not (21/117, 18%), P=0.003. Of the 171 unpublished trials, 133 (78%) had no results available in ClinicalTrials.gov. CONCLUSIONS: Among this group of large clinical trials, non-publication of results was common and the availability of results in the ClinicalTrials.gov database was limited. A substantial number of study participants were exposed to the risks of trial participation without the societal benefits that accompany the dissemination of trial results. PMID- 24169945 TI - Control of physicochemical properties and catalytic activity of tris(2,2' bipyridine)iron(II) encapsulated within the zeolite Y cavity by alkaline earth metal cations. AB - A series of materials containing the tris(2,2'-bipyridine)iron(ii) (Fe(bpy)3(2+)) complex inside zeolite Y cavities with alkaline earth metals (Mg(2+), Ca(2+), Sr(2+), Ba(2+)) as charge compensating cations have been synthesized via a "ship in the bottle" method. The influence of the alkaline earth metal cations on the physicochemical properties and catalytic activity was investigated. The successful formation of the Fe(bpy)3(2+) complex was verified by XRD, diffuse reflectance UV-vis spectroscopy, and Fe K-edge XAFS measurements. The BET surface area and the Fe content decreased in the presence of the larger alkaline earth metal, but the intensity of the MLCT adsorption band of Fe(bpy)3(2+) increased with the heavier cation. The electron density of the Fe atoms decreased, and the average interatomic bond distance Fe-N/O and the coordination number increased with the heavier alkaline earth metal cation. The encapsulation of Fe(bpy)3(2+) resulted in the creation of a photocatalytic system able to oxidize styrene to benzaldehyde and styrene oxide under visible light irradiation (lambda > 430 nm) in the presence of molecular oxygen. PMID- 24169944 TI - The effect of fall prevention exercise programmes on fall induced injuries in community dwelling older adults: systematic review and meta-analysis of randomised controlled trials. AB - OBJECTIVE: To determine whether, and to what extent, fall prevention exercise interventions for older community dwelling people are effective in preventing different types of fall related injuries. DATA SOURCES: Electronic databases (PubMed, the Cochrane Library, Embase, and CINAHL) and reference lists of included studies and relevant reviews from inception to July 2013. STUDY SELECTION: Randomised controlled trials of fall prevention exercise interventions, targeting older (>60 years) community dwelling people and providing quantitative data on injurious falls, serious falls, or fall related fractures. DATA SYNTHESIS: Based on a systematic review of the case definitions used in the selected studies, we grouped the definitions of injurious falls into more homogeneous categories to allow comparisons of results across studies and the pooling of data. For each study we extracted or calculated the rate ratio of injurious falls. Depending on the available data, a given study could contribute data relevant to one or more categories of injurious falls. A pooled rate ratio was estimated for each category of injurious falls based on random effects models. RESULTS: 17 trials involving 4305 participants were eligible for meta analysis. Four categories of falls were identified: all injurious falls, falls resulting in medical care, severe injurious falls, and falls resulting in fractures. Exercise had a significant effect in all categories, with pooled estimates of the rate ratios of 0.63 (95% confidence interval 0.51 to 0.77, 10 trials) for all injurious falls, 0.70 (0.54 to 0.92, 8 trials) for falls resulting in medical care, 0.57 (0.36 to 0.90, 7 trials) for severe injurious falls, and 0.39 (0.22 to 0.66, 6 trials) for falls resulting in fractures, but significant heterogeneity was observed between studies of all injurious falls (I(2)=50%, P=0.04). CONCLUSIONS: Exercise programmes designed to prevent falls in older adults also seem to prevent injuries caused by falls, including the most severe ones. Such programmes also reduce the rate of falls leading to medical care. PMID- 24169946 TI - Relevant bleeding diathesis due to acquired factor XIII deficiency. AB - BACKGROUND: Acquired factor XIII (FXIII) deficiency is associated with reduced clot firmness and increased bleeding in patients undergoing major surgery. In contrast, only limited information is available on the haemostatic relevance of acquired FXIII deficiency in non-surgical patients. CASE REPORT: An 81-year-old patient, who had experienced acute type-A dissection of the aorta eight years earlier, presented with a 3-year history of progressive mucocutaneous and soft tissue bleeding. Diagnostic work-up was unremarkable for global coagulation tests, but FXIII and alpha2-antiplasmin were decreased to 33% and 27%, respectively, while plasma D-dimer was elevated to > 35 mg/l. A FXIII inhibitor was excluded by mixing studies. CT scanning revealed a massively elongated and progressively dilated aorta with a false lumen reaching from the left carotid artery to the iliac bifurcation. Bleeding control was achieved by single doses of FXIII at 20-30 IU/kg body weight and tailored oral tranexamic acid. CONCLUSION: Acquired FXIII deficiency with activity levels of 30-35% may confer a severe bleeding tendency in non-surgical patients, especially in the context of increased thrombin an fibrin generation. PMID- 24169947 TI - A survey of cellulose microfibril patterns in dividing, expanding, and differentiating cells of Arabidopsis thaliana. AB - Cellulose microfibrils are critical for plant cell specialization and function. Recent advances in live cell imaging of fluorescently tagged cellulose synthases to track cellulose synthesis have greatly advanced our understanding of cellulose biosynthesis. Nevertheless, cellulose deposition patterns remain poorly described in many cell types, including those in the process of division or differentiation. In this study, we used field emission scanning electron microscopy analysis of cryo-planed tissues to determine the arrangement of cellulose microfibrils in various faces of cells undergoing cytokinesis or specialized development, including cell types in which cellulose cannot be imaged by conventional approaches. In dividing cells, we detected microfibrillar meshworks in the cell plates, consistent with the concentration at the cell plate of cellulose synthase complexes, as detected by fluorescently tagged CesA6. We also observed a loss of parallel cellulose microfibril orientation in walls of the mother cell during cytokinesis, which corresponded with the loss of fluorescently tagged cellulose synthase complexes from these surfaces. In recently formed guard cells, microfibrils were randomly organized and only formed a highly ordered circumferential pattern after pore formation. In pit fields, cellulose microfibrils were arranged in circular patterns around plasmodesmata. Microfibrils were random in most cotyledon cells except the epidermis and were parallel to the growth axis in trichomes. Deposition of cellulose microfibrils was spatially delineated in metaxylem and protoxylem cells of the inflorescence stem, supporting recent studies on microtubule exclusion mechanisms. PMID- 24169948 TI - Metabolic engineering of Corynebacterium glutamicum for 2-ketoisocaproate production. AB - 2-Ketoisocaproate (KIC) is used as a therapeutic agent, and a KIC-producing organism may serve as a platform for products deriving from this 2-keto acid. We engineered Corynebacterium glutamicum for the production of KIC from glucose by deletion of ltbR and ilvE, encoding the transcriptional repressor LtbR and transaminase B, respectively, and additional overexpression of ilvBNCD, encoding acetohydroxyacid synthase, acetohydroxyacid isomeroreductase, and dihydroxyacid dehydratase. The KIC-producing strain was improved by deletion of the methylcitrate synthase genes and by decreasing citrate synthase activity by exchange of the native promoter of the citrate synthase gene. In shake-flask fermentations under L-leucine limitation, the newly constructed strain C. glutamicum VB (pJC4ilvBNCD) produced 31 +/- 2 mM (4.0 +/- 0.3 g l(-1)) KIC and showed a product yield of about 0.26 +/- 0.02 mol per mole (0.19 +/- 0.01 g per gram) of glucose. As by-product, the strain formed about 33 mM 2-ketoisovalerate, which is a precursor of KIC. KIC production was further improved by additional expression of an isopropylmalate synthase allele (leuA (EC-G462D)), encoding an enzyme resistant towards L-leucine inhibition, and by addition of acetate as additional substrate. With glucose and acetate, the newly constructed strain produced 71 +/- 3.2 mM (9.2 +/- 0.4 g l(-1)) KIC with a yield of 0.24 +/- 0.01 mol C (KIC) per mole C (in both substrates) and with nearly no 2-ketoisovalerate by-product formation (<2 mM). Investigating the activities and regulation of the native isopropylmalate synthase and dehydratase of C. glutamicum, we observed competitive and noncompetitive inhibition, respectively, by KIC. PMID- 24169949 TI - Differential responses of ammonia/ammonium-oxidizing microorganisms in mangrove sediment to amendment of acetate and leaf litter. AB - The effects of acetate and leaf litter powder on ammonia/ammonium-oxidizing microorganisms (AOMs) in mangrove sediment were investigated in a laboratory incubation study for a period of 60 days. The results showed that different AOMs responded differently to the addition of acetate and leaf litter. A higher diversity of anaerobic ammonium-oxidizing (anammox) bacteria was observed when acetate or leaf litter was added than the control. However, acetate and leaf litter generally inhibited the growth of anammox bacteria despite that leaf litter promoted their growth in the first 5 days. The inhibitory effects on anammox bacteria were more pronounced by acetate than by leaf litter. Neither acetate nor leaf litter affected ammonia-oxidizing archaea (AOA) community structures, but promoted their growth. For ammonia-oxidizing bacteria (AOB), the addition of acetate or leaf litter resulted in changes of community structures and promoted their growth in the early phase of the incubation. In addition, the promoting effects by leaf litter on AOB growth were more obvious than acetate. These results indicated that organic substances affect AOM community structures and abundances. The study suggests that leaf litter has an important influence on the community structures and abundances of AOMs in mangrove sediment and affects the nitrogen cycle in such ecosystem. PMID- 24169950 TI - Reduction of hydrogen peroxide stress derived from fatty acid beta-oxidation improves fatty acid utilization in Escherichia coli. AB - Fatty acids are a promising raw material for substance production because of their highly reduced and anhydrous nature, which can provide higher fermentation yields than sugars. However, they are insoluble in water and are poorly utilized by microbes in industrial fermentation production. We used fatty acids as raw materials for L-lysine fermentation by emulsification and improved the limited fatty acid-utilization ability of Escherichia coli. We obtained a fatty acid utilizing mutant strain by laboratory evolution and demonstrated that it expressed lower levels of an oxidative-stress marker than wild type. The intracellular hydrogen peroxide (H2O2) concentration of a fatty acid-utilizing wild-type E. coli strain was higher than that of a glucose-utilizing wild-type E. coli strain. The novel mutation rpsA(D210Y) identified in our fatty acid utilizing mutant strain enabled us to promote cell growth, fatty-acid utilization, and L-lysine production from fatty acid. Introduction of this rpsA(D210Y) mutation into a wild-type strain resulted in lower H2O2 concentrations. The overexpression of superoxide dismutase (sodA) increased intracellular H2O2 concentrations and inhibited E. coli fatty-acid utilization, whereas overexpression of an oxidative-stress regulator (oxyS) decreased intracellular H2O2 concentrations and promoted E. coli fatty acid utilization and L-lysine production. Addition of the reactive oxygen species (ROS) scavenger thiourea promoted L-lysine production from fatty acids and decreased intracellular H2O2 concentrations. Among the ROS generated by fatty-acid beta oxidation, H2O2 critically affected E. coli growth and L-lysine production. This indicates that the regression of ROS stress promotes fatty acid utilization, which is beneficial for fatty acids used as raw materials in industrial production. PMID- 24169951 TI - Changes in intracellular metabolite pools during growth of adherent MDCK cells in two different media. AB - In bioprocess engineering, the growth of continuous cell lines is mainly studied with respect to the changes in cell concentration, the resulting demand for substrates, and the accumulation of extracellular metabolites. The underlying metabolic process rests upon intracellular metabolite pools and their interaction with enzymes in the form of substrates, products, or allosteric effectors. Here, we quantitatively analyze time courses of 29 intracellular metabolites of adherent Madin-Darby canine kidney cells during cultivation in a serum-containing medium and a serum-free medium. The cells, which originated from the same pre culture, showed similar overall growth behavior and only slight differences in their demand for the substrates glucose (GLC), glutamine (GLN), and glutamate (GLU). Analysis of intracellular metabolites, which mainly cover the glycolytic pathway, the citric acid cycle, and the nucleotide pools, revealed surprisingly similar dynamics for both cultivation conditions. Instead of a strong influence of the medium, we rather observed a growth phase-specific behavior in glycolysis and in the lower citric acid cycle. Furthermore, analysis of the lower part of glycolysis suggests the well-known regulation of pyruvate kinase by fructose 1,6 bisphosphate. The upper citric acid cycle (citrate, cis-aconitate, and isocitrate) is apparently uncoupled from the lower part (alpha-ketoglutarate, succinate, fumarate, and malate), which is in line with the characteristics of a truncated cycle. Decreased adenosine triphosphate and guanosine triphosphate pools, as well as a relatively low energy charge soon after inoculation of cells, indicate a high demand for cellular energy and the consumption of nucleotides for biosynthesis. We finally conclude that, with sufficient availability of substrates, the dynamics of GLC and GLN/GLU metabolism is influenced mainly by the cellular growth regime and regulatory function of key enzymes. PMID- 24169952 TI - Emergency medical technicians, including paramedics, in the workplace. PMID- 24169953 TI - Paul Brown BSN, MSPH, EdD, APN. Interview by Eileen Lukes. PMID- 24169954 TI - Hospital violence and the role of the occupational health nurse. AB - Between 1993 and 1999, an average of 1.7 million violent workplace incidents were recorded per year. Of the nonfatal injuries and lost days due to occupational violence, 32% occur in the health care setting. The annual incidence rate for violence against nurses is 22 incidents per 1,000 nurses. When an occupational health professional analyzes an exposure, engineering controls, administrative controls, and personal protective equipment policies are drafted to ensure the future safety of employees. This literature review identifies best practice controls used to protect health care workers from violence in the workplace. PMID- 24169955 TI - How older workers with coronary heart disease perceive the health effects of work. AB - More than 3.4 million workers have coronary heart disease (CHD) with significant work limitations and disability. Although the cohort of aging workers with CHD is growing, little is known about how older workers with CHD perceive the relationship between the work environment, including job stress, and their health. The purpose of this qualitative, descriptive study was to explore the perceptions of the health effects of work among older workers with CHD and describe how they cope with work stress. The sample was 47% female and 33% African American. Their mean age was 59.21 (+/- 5.4) years, and most (55%) worked in professional or managerial jobs. Themes emerged about perceptions of the health effects of work and coping strategies. Because older employees are a vulnerable work group, understanding the perceived health effects of work may guide future workplace program development and policy. PMID- 24169957 TI - Updated recommendations for the management of health care personnel occupationally exposed to human immunodeficiency virus. AB - The U.S. Public Health Service has released new recommendations for the management of health care personnel who experience occupational exposures to blood or other body fluids that might contain human immunodeficiency virus. PMID- 24169958 TI - Molecular architectures of multi-anthracene assemblies. AB - Anthracene, with its molecular panel-like shape and robust photophysical behaviour, is a versatile building block that is widely used to construct attractive and functional molecules and molecular assemblies through covalent and non-covalent linkages. The intrinsic photophysical, photochemical and chemical properties of the embedded anthracenes often interact to engender desirable chemical behaviours and properties in multi-anthracene assemblies. This review article focuses on molecular architectures with linear, cyclic, cage, and capsule shapes, each containing three or more anthracene subunits. PMID- 24169959 TI - A derivative of chrysin suppresses two-stage skin carcinogenesis by inhibiting mitogen- and stress-activated kinase 1. AB - Mitogen- and stress-activated kinase 1 (MSK1) is a nuclear serine/threonine protein kinase that acts downstream of both extracellular signal-regulated kinases and p38 mitogen-activated protein kinase in response to stress or mitogenic extracellular stimuli. Increasing evidence has shown that MSK1 is closely associated with malignant transformation and cancer development. MSK1 should be an effective target for cancer chemoprevention and chemotherapy. However, very few MSK1 inhibitors, especially natural compounds, have been reported. We used virtual screening of a natural products database and the active conformation of the C-terminal kinase domain of MSK1 (PDB id 3KN) as the receptor structure to identify chrysin and its derivative, compound 69407, as inhibitors of MSK1. Compared with chrysin, compound 69407 more strongly inhibited proliferation and 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced neoplastic transformation of JB6 P+ cells with lower cytotoxicity. Western blot data demonstrated that compound 69407 suppressed phosphorylation of the MSK1 downstream effector histone H3 in intact cells. Knocking down the expression of MSK1 effectively reduced the sensitivity of JB6 P+ cells to compound 69407. Moreover, topical treatment with compound 69407 before TPA application significantly reduced papilloma development in terms of number and size in a two stage mouse skin carcinogenesis model. The reduction in papilloma development was accompanied by the inhibition of histone H3 phosphorylation at Ser10 in tumors extracted from mouse skin. The results indicated that compound 69407 exerts inhibitory effects on skin tumorigenesis by directly binding with MSK1 and attenuates the MSK1/histone H3 signaling pathway, which makes it an ideal chemopreventive agent against skin cancer. PMID- 24169960 TI - Effect of a low-fat fish oil diet on proinflammatory eicosanoids and cell-cycle progression score in men undergoing radical prostatectomy. AB - We previously reported that a 4- to 6-week low-fat fish oil (LFFO) diet did not affect serum insulin-like growth factor (IGF)-1 levels (primary outcome) but resulted in lower omega-6 to omega-3 fatty acid ratios in prostate tissue and lower prostate cancer proliferation (Ki67) as compared with a Western diet. In this post hoc analysis, the effect of the LFFO intervention on serum pro inflammatory eicosanoids, leukotriene B4 (LTB4) and 15-S-hydroxyeicosatetraenoic acid [15(S)-HETE], and the cell-cycle progression (CCP) score were investigated. Serum fatty acids and eicosanoids were measured by gas chromatography and ELISA. CCP score was determined by quantitative real-time reverse transcriptase PCR (RT PCR). Associations between serum eicosanoids, Ki67, and CCP score were evaluated using partial correlation analyses. BLT1 (LTB4 receptor) expression was determined in prostate cancer cell lines and prostatectomy specimens. Serum omega 6 fatty acids and 15(S)-HETE levels were significantly reduced, and serum omega-3 levels were increased in the LFFO group relative to the Western diet group, whereas there was no change in LTB4 levels. The CCP score was significantly lower in the LFFO compared with the Western diet group. The 15(S)-HETE change correlated with tissue Ki67 (R = 0.48; P < 0.01) but not with CCP score. The LTB4 change correlated with the CCP score (r = 0.4; P = 0.02) but not with Ki67. The LTB4 receptor BLT1 was detected in prostate cancer cell lines and human prostate cancer specimens. In conclusion, an LFFO diet resulted in decreased 15(S)-HETE levels and lower CCP score relative to a Western diet. Further studies are warranted to determine whether the LFFO diet antiproliferative effects are mediated through the LTB4/BLT1 and 15(S)-HETE pathways. PMID- 24169961 TI - Exposure to excess estradiol or leptin during pregnancy increases mammary cancer risk and prevents parity-induced protective genomic changes in rats. AB - Using a preclinical model, we investigated whether excess estradiol (E2) or leptin during pregnancy affects maternal mammary tumorigenesis in rats initiated by administering carcinogen 7,12-dimethylbenz(a)anthracene (DMBA) on day 50. Two weeks later, rats were mated, and pregnant dams were treated daily with 10 MUg of 17beta-estradiol, 15 MUg of leptin, or vehicle from gestation day 8 to 19. Tumor development was assessed separately during weeks 1 to 12 and 13 to 22 after DMBA administration, because pregnancy is known to induce a transient increase in breast cancer risk, followed by a persistent reduction. Parous rats developed less (32%) mammary tumors than nulliparous rats (59%, P < 0.001), and the majority (93%) of tumors in the parous rats appeared before week 13 (vs. 41% in nulliparous rats), indicating that pregnancy induced a transient increase in breast cancer risk. Parous rats exposed to leptin (final tumor incidence 65%) or E2 (45%) during pregnancy developed mammary tumors throughout the tumor monitoring period, similar to nulliparous control rats, and the incidence was significantly higher in both the leptin- and E2-exposed dams after week 12 than in the vehicle-exposed parous dams (P < 0.001). The mammary glands of the exposed parous rats contained significantly more proliferating cells (P < 0.001). In addition, the E2- or leptin-treated parous rats did not exhibit the protective genomic signature induced by pregnancy and seen in the parous control rats. Specifically, these rats exhibited downregulation of genes involved in differentiation and immune functions and upregulation of genes involved in angiogenesis, growth, and epithelial-to-mesenchymal transition. PMID- 24169963 TI - Surgical management of ulcerative colitis in an ongoing pregnancy: report of a case and literature review. PMID- 24169962 TI - Genes with aberrant expression in murine preneoplastic intestine show epigenetic and expression changes in normal mucosa of colon cancer patients. AB - An understanding of early genetic/epigenetic changes in colorectal cancer would aid in diagnosis and prognosis. To identify these changes in human preneoplastic tissue, we first studied our mouse model in which Mthfr+/- BALB/c mice fed folate deficient diets develop intestinal tumors in contrast to Mthfr+/+ BALB/c mice fed control diets. Transcriptome profiling was performed in normal intestine from mice with low or high tumor susceptibility. We identified 12 upregulated and 51 downregulated genes in tumor-prone mice. Affected pathways included retinoid acid synthesis, lipid and glucose metabolism, apoptosis and inflammation. We compared murine candidates from this microarray analysis, and murine candidates from an earlier strain-based comparison, with a set of human genes that we had identified in previous methylome profiling of normal human colonic mucosa, from colorectal cancer patients and controls. From the extensive list of human methylome candidates, our approach uncovered five orthologous genes that had shown changes in murine expression profiles (PDK4, SPRR1A, SPRR2A, NR1H4, and PYCARD). The human orthologs were assayed by bisulfite-pyrosequencing for methylation at 14 CpGs. All CpGs exhibited significant methylation differences in normal mucosa between colorectal cancer patients and controls; expression differences for these genes were also observed. PYCARD and NR1H4 methylation differences showed promise as markers for presence of polyps in controls. We conclude that common pathways are disturbed in preneoplastic intestine in our animal model and morphologically normal mucosa of patients with colorectal cancer, and present an initial version of a DNA methylation-based signature for human preneoplastic colon. PMID- 24169964 TI - Non-allelic interaction conditioning spikelet sterility in an F2 population of indica/japonica cross in rice. AB - Significant segregation of spikelet fertility occurred in an F2 population derived from a spikelet fertility-normal F1 hybrid produced by a cross between 'Palawan', a japonica variety, and 'IR42', an indica variety. To identify factors controlling the fertility segregation, we used 104 RFLP markers covering all 12 rice chromosomes to investigate the association of spikelet fertility and marker segregation. We found that the segregation of two sets of gene pairs was significantly (P < 0.001) associated with fertility segregation. The first pair of genes was linked to RFLP marker RG778 on chromosome 12 and RFLP markers RG690/RG369 on chromosome 1. A significant reduction in fertility was observed when the plants were homozygote at RG778 with the indica allele as well as homozygote at RG690/RG369 with the japonica allele. The second pair of genes was linked to RG218 on chromosome 12 and RG650 on chromosome 7, respectively. The recombinant homozygote at these two loci showed a significant reduction on spikelet fertility. The non-allelic interaction effect was further modified by a gene linked to RG778, resulting in even lower fertility. The results of this study provides the first evidence of chromosomal localization of sporophytic sterility genes whose interaction can result in a reduction of spikelet fertility in the F2 derived from fertility-normal F1. PMID- 24169965 TI - Detection of section-specific random amplified polymorphic DNA (RAPD) markers in Lilium. AB - Random amplified polymorphic DNA (RAPD) markers were utilized for the identification of Lilium species and inter-specific hybrids. The optimum annealing temperature of the polymerase chain reaction (PCR) for the RAPD assay in Lilium was 54 degrees C, which is relatively higher than the temperature used for other genera reported by previous researchers. Among 76 primers used to amplify genomic DNA by PCR, 18 primers (24%) generated polymorphic DNA fragments in Lilium species and hybrids. Cultivars were also identified by RAPD markers. Some amplified fragments were unique to species of each section and to hybrids derived from these species; that is, they were the section-specific DNA markers. Sections, Sinomartagon, Leucolirion b, Leucolirion a and Archelirion could be identified by 6 section-specific markers amplified with five primers. Seven inter section hybrids showed the section-specific bands of both parental sections, indicating that these markers would be useful for identifying the parental sections of inter-section hybrids. PMID- 24169966 TI - Mapping of a chloroplast RFLP marker associated with the CMS cytoplasm of sugar beet (Beta vulgaris). AB - The Owen cytoplasm of male-sterile sugar beet is associated with several alterations of mitochondrial DNA and one additional HindIII site of chloroplast DNA. The region of this HindIII site has been cloned and sequenced. The site maps in a small reading frame (orf32) close to the ycf7 (orf31) gene in the petG-psbE region of chloroplast DNA. Possible functional implications of the results are discussed. The chloroplast RFLP marker described could be useful for studies on chloroplast-mitochondrial interactions, CMS of sugar beet, and the origin of the Owen cytoplasm. PMID- 24169967 TI - Study of microspore-culture responsiveness in oilseed rape (Brassica napus L.) by comparative mapping of a F2 population and two microspore-derived populations. AB - RFLP segregation analyses were performed on a F2 population and two F1 microspore derived populations from the same cross between a microspore culture-responsive parent ('Topas') and a non-responsive parent ('Westar'). A total of 145 loci were detected with 87 cDNA clones. Eighty-two markers were common across all three populations. A total of 66 markers was assembled into 18 linkage groups and 16 markers remained unlinked. Segregation distortions were significant for 29% of the markers in the F2 population and 23% and 31% in microspore-derived populations M3 and M5, respectively. An equivalent number of markers showed biased segregation towards each parental allele in the F2 population while more markers showed a significant deviation from the expected Mendelian ratio towards the responsive parent in both microspore-derived populations. Different subsets of markers showed segregation distortions in the three populations indicating that the selective pressures leading to microsporederived plants are different from those acting during selfing of the F1. Linkage groups 1 and 18 were identified as putative chromosomal regions associated with microspore-culture responsiveness. PMID- 24169968 TI - Endosperm Balance Number and the polar-nuclei activation hypotheses for endosperm development in interspecific crosses of Solanaceae and Gramineae, respectively. AB - The Endosperm Balance Number (EBN) and the polar-nuclei activation (PNA) hypotheses have been developed to interpret, explain and predict interspecific and interploidy crossabilities in the Solanums and the Gramineae, respectively. Although these two hypotheses evolved independently, they share a number of common features. Assignment of EBNs and 'activation/response values' (AVs/RVs) depend on plumpness, size, and germinability of hybrid seeds. Also, both hypotheses emphasize the importance of a balanced parental genic contribution for the normal development of endosperm. However, in the EBN hypothesis a 2 maternal?1 paternal EBN ratio is a prerequisite for successful interspecific crossability, while the PNA hypothesis is based on the stimulative strength of the male nuclei to initiate mitotic divisions in the primary endosperm nucleus and is idependent on a 2?1 ratio between the RV of the polar nuclei and the AV of the male gamete. Differences and similarities betweeen the EBN and PNA hypotheses are summarized and contrasted. It is proposed that EBN and PNA be considered as the same concept. PMID- 24169969 TI - DNA fingerprinting detects genetic variability in the pearl millet downy mildew pathogen (Sclerospora graminicola). AB - Genetic variability in six host genotype-specific pathotypes of pearl millet downy mildew pathogen S. graminicola was studied at the molecular level using mini- and micro-satellites. Our results indicated that microsatellites (GAA)6, (GACA)4, and especially (GATA)4 were quite informative and showed high levels of polymorphism among the pathotypes. The six pathotypes could be classified into five groups based on the cluster analysis of their genetic similarities, thereby confirming the existence of distinct host genotype-specific virulence in S. graminicola pathotypes. We demonstrate, for the first time, the use of DNA fingerprinting to detect genetic variation in downy mildew fungus of pearl millet. PMID- 24169970 TI - Genetic variation for foot-rot and Fusarium head-blight resistances among full sib families of a self-incompatible winter rye (Secale cereale L.) population. AB - The amount of genetic variation for resistance to foot rot caused by Pseudocercosporella herpotrichoides, Fusarium spp., and Microdochium nivale and for resistance to head blight caused by Fusarium culmorum are important parameters when estimating selection gain from recurrent selection in winter rye. One-hundred and eighty-six full-sib families of the selfincompatible population variety Halo, representing the Petkus gene pool, were tested for foot-rot resistance at five German location-year combinations (environments) and for head blight resistance in three environments with artificial inoculation in all but one environment. Foot-rot rating was based on 25 stems per plot scored individually on a 1-9 scale. Head-blight resistance was plotwise scored on a 1-9 scale and, additionally, grain-weight per spike was measured relative to the non inoculated control plots. Significant estimates of genotypic variance and medium sized heritabilities (h (2)=0.51-0.69) were observed in the combined analyses for all resistance traits. In four out of five environments, the amount of genetic variance was substantially smaller for foot-rot than for head-blight rating. Considerable environmental effects and significant genotype-environment interactions were found for both foot-rot and head-blight resistance. Coefficients of error-corrected correlation among environments were considerably closer than phenotypic correlations. No significant association was found between the resistances to both diseases (r=-0.20 to 0.17). In conclusion, intra population improvement by recurrent selection should lead to substantial higher foot-rot and head-blight resistances due to significant quantitative genetic variation within Halo. Selection should be carried out in several environments. Lack of correlation between foot-rot and head-blight resistance requires separate infection tests for improving both resistances. PMID- 24169971 TI - An integrated genetic linkage map for eucalypts using RFLP, RAPD and isozyme markers. AB - An integrated genetic linkage map for E. nitens was constructed in an outbred three-generation pedigree. Analysis of 210 RFLP, 125 RAPD and 4 isozyme loci resulted in 330 markers linked in 12 linkage groups covering 1462 cM (n=11 in eucalypts). The 12th linkage group is comprised of only 5 markers and will probably coalesce with another linkage group when further linked loci are located. Co-dominant RFLP loci segregating in both parents were used to integrate linkages identified in the male and female parents. Differences in recombination frequencies in the two parents were observed for a number of pairs of loci, and duplication of sequences was identified both within and between linkage groups. The markers were distributed randomly across the genome except for the RFLPs in linkage group 10 and for some loci showing segregation distortion, which were clustered into three regions of the map. The use of a large number of co-dominant RFLP loci in this map enables it to be used in other pedigrees of E. nitens and forms a basis for the detection and location of QTL in E. nitens and other eucalypt species. PMID- 24169972 TI - Phylogenetic relationships within Hevea brasiliensis as deduced from a polymorphic mitochondrial DNA region. AB - We have cloned a 4.5-kb mtDNA fragment showing a high RFLP polymorphism between various Hevea genotypes. Subcloning and sequencing of a 1.4-kb segment of this clone allowed us to design PCR amplification primers to isolate homologous mtDNA segments of about 0.9 kb from 23 representative genotypes of Hevea. Complete sequences from 4 genotypes showed between 6.7% and 20.2% of nucleotide diversity, suggesting the presence of a hypervariable, or hotspot, region. A sequence of 345 nucleotides within this region was determined for the 23 genotypes. The phylogenetic relationships inferred from the sequence comparison are in general agreement with the results obtained from mtDNA RFLP analysis, indicating that this polymorphic mtDNA region is a useful molecular marker for phylogenetic analysis within Hevea. PMID- 24169973 TI - Organization of nuclear ribosomal DNA and species-specific polymorphism in closely related Fraxinus excelsior and F. oxyphylla. AB - The ribosomal DNA repeat units of two closely related species of the genus Fraxinus, F. excelsior and F. oxyphylla, were characterized. The physical maps were constructed from DNA digested with BamHI, EcoRI, EcoRV and SacI, and hybridized with three heterologous probes. The presence or the absence of an EcoRV restriction site in the 18s RNA gene characterizes two ribosomal DNA unit types found in both species and which coexist in all individuals. A third unit type appeared unique to all individuals of F. oxyphylla. It carries an EcoRI site in the intergenic spacer. Each type of unit displayed length variations. The rDNA unit length of F. excelsior and F. oxyphylla was determined with EcoRV restriction. It varied between 11kb and 14.5kb in F. excelsior and between 11.8kb to 13.8kb in F. oxyphylla. Using SacI restriction, at least ten spacer length variants were observed in F. excelsior, for which a detailed analysis was conducted. Each individual carries 2-4 length variants which vary by a 0.3-kb step multiple. This length variation was assigned to the intergenic spacer. By using the entire rDNA unit of flax as probe in combination with EcoRI restriction, each species can be unambiguously discriminated. The species specific banding pattern was used to compare trees from a zone of sympatry between the two species. In some cases, a conflicting classification was obtained from morphological analysis and the use of the species-specific rDNA polymorphism. Implications for the genetic management of both species are discussed. PMID- 24169974 TI - Genetic fingerprinting of pigeonpea [Cajanus cajan (L.) Millsp.] and its wild relatives using RAPD markers. AB - Randomly amplified polymorphic DNA (RAPD) markers were used for the identification of pigeonpea [Cajanus cajan (L.) Millsp.] cultivars and their related wild species. The use of single primers of arbitrary nucleotide sequence resulted in the selective amplification of DNA fragments that were unique to individual accessions. The level of polymorphism among the wild species was extremely high, while little polymorphism was detected within Cajanus cajan accessions. All of the cultivars and wild species under study could be easily distinguished with the help of different primers, thereby indicating the immense potential of RAPD in the genetic fingerprinting of pigeonpea. On the basis of our data the genetic relationship between pigeonpea cultivars and its wild species could be established. PMID- 24169975 TI - Transposable elements as plant transformation vectors for long stretches of foreign DNA. AB - The production of transgenic plants is now routine for most crops. However, using currently available transformation methods it is still difficult and time consuming to obtain a collection of transformed individuals containing single or low-copy-number, intact transgenic inserts. Here we describe a set of broad hostrange transformation vectors based on the Ac/Ds transposition system that improve both transformation efficiency and the quality of transgenic loci. These vectors efficiently deliver long stretches of foreign DNA into the genome, leading to transgenic strains containing an intact single-copy insert of 10kb. This type of vector could be an important additional tool for the production of transgenic plants with the well-defined, foreign DNA inserts required for biosafety approval and commercialisation. PMID- 24169976 TI - Genetic characteristics of two genes for resistance to soybean mosaic virus in PI486355 soybean. AB - Soybean [Glycine max (L.) Merr.] PI486355 is resistant to all the identified strains of soybean mosaic virus (SMV) and possesses two independently inherited resistance genes. To characterize the two genes, PI486355 was crossed with the susceptible cultivars 'Lee 68' and 'Essex' and with cultivars 'Ogden' and 'Marshall', which are resistant to SMV-G1 but systemically necrotic to SMV-G7. The F2 populations and F2?3 progenies from these crosses were inoculated with SMV G7 in the greenhouse. The two resistance genes were separated in two F3?4 lines, 'LR1' and 'LR2', derived from Essex x PI486355. F1 individuals from the crosses of LR1 and LR2 with Lee 68, Ogden, and 'York' were tested with SMV-G7 in the greenhouse; the F2 populations were tested with SMV-G1 and G7. The results revealed that expression of the gene in LR1 is gene-dosage dependent, with the homozygotes conferring resistance but the heterozygotes showing systemic necrosis to SMV-G7. This gene was shown to be an allele of the Rsv1 locus and was designated as Rsv1-s. It is the only allele identified so far at the Rsv1 locus which confers resistance to SMV-G7. Rsv1-s also confers resistance to SMV-G1 through G4, but results in systemic necrosis with SMV-G5 and G6. The gene in LR2 confers resistance to strains SMV-G1 through G7 and exhibits complete dominance. It appears to be epistatic to genes at the Rsv1 locus, inhibiting the expression of the systemic necrosis conditioned by the Rsv1 alleles. SMV-G7 induced a pin point necrotic reaction on the inoculated primary leaves in LR1 but not in LR2. The unique genetic features of the two resistance genes from PI486355 will facilitate their proper use and identification in breeding and contribute to a better understanding of the interaction of SMV strains with soybean resistance genes. PMID- 24169977 TI - Inheritance of a striped-leaf mutant is associated with the cytoplasmic genome in maize. AB - A striped-leaf mutant has been identified in a Taiwanese maize line, Tainan White. The striped area is pale green at the seedling stage, and turns yellow and white at maturity, extending from the leaf blade to the sheath and the internode below the sheath. The mutant does not breed true and following self-pollination, produces three different types of progeny: green, striped and completely affected. The green type permanently loses the mutant character, while the completely affected type is lethal, without any green tissue. Only the striped type transmits the mutant phenotype to progeny, and it has a clonal distribution on the ear. Its phenotype is inherited maternally and its expression is unaffected by the paternal genotype. It cannot be inherited through the paternal parent. This pattern of inheritance, which persists after three cycles of backcrossing with the affected types as the recurrent pistillate parent, suggests that the responsible gene is located in the cytoplamic genome. PMID- 24169978 TI - Mapping of beta-glucan content and beta-glucanase activity loci in barley grain and malt. AB - Genetic study of beta-glucan content and beta-glucanase activity has been facilitated by recent developments in quantitative trait loci (QTL) analysis. QTL for barley and malt beta-glucan content and for green and finished malt beta glucanase activity were mapped using a 123-point molecular marker linkage map from the cross of Steptoe/Morex. Three QTL for barley beta-glucan, 6 QTL for malt beta-glucan, 3 QTL for beta-glucanase in green malt and 5 QTL for beta-glucanase in finished malt were detected by interval mapping procedures. The QTL with the largest effects on barley beta-glucan, malt betaglucan, green malt beta-glucanase and finished malt betaglucanase were identified on chromosomes 2,1,4 and 7, respectively. A genome map-based approach allows for dissection of relationships among barley and malt betaglucan content, green and finished malt beta-glucanase activity, and other malting quality parameters. PMID- 24169979 TI - The molecular cytogenetics of Vigna unguiculata (L.) Walp: the physical organization and characterization of 18s-5.8s-25s rRNA genes, 5s rRNA genes, telomere-like sequences, and a family of centromeric repetitive DNA sequences. AB - A knowledge of genome organization is important for understanding how genomes function and evolve, and provide information likely to be useful in plant breeding programmes involving hybridization and genetic manipulation. Molecular techniques, including in situ hybridization, molecular cloning and DNA sequencing, are proving valuable tools to investigate the structure, organization, and diversity of chromosomes in agricultural crops. Heterologous labelled 18 s-5.8 s-25 s (pTa71) and 5 s rDNAs (pTa794) were used for in situ hybridization on Vigna unguiculata (L.) Walp. chromosomes. Hybridization with 18 s-5.8 s-25 s rRNA gene probes occurred at the same chromosomal sites which were positive to the CMA fluorochrome. Silver staining of nucleolar-organizing regions indicated that all the rDNA sites detected using the 18 s-5.8 s-25 s rRNA gene probe possessed active genes. Degenerate telomeric repeats gave hybridization signals at the telomeres of most chromosomes and no intercalary sites were detected at metaphase; the sequences appear to have no preferential distribution in interphase nuclei. A repetitive DraI family from V. unguiculata was cloned (pVuKB1) and characterized. The DraI repeat is 488 nucleotides long, AT rich (74%), and hybridized on all chromosomes in the centromeric areas. The presence of this sequence family was investigated by Southern hybridization in different Vigna species and other Leguminoseae. It was only detected in V. unguiculata, and hence represents a species-specific DNA sequence. PMID- 24169980 TI - Pollen-pistil interaction in maize: effects on genetic variation of pollen traits. AB - Various factors (pollen diameter, in vitro germination and tube length, in vivo growth rate in selfed and nonselfed styles) which could possibly contribute to the competitive ability of pollen were investigated on 30 Zea mays L. inbred lines. The only factor with which pollen diameter was positively correlated was in vitro pollen-tube growth. Traits related to the early stages of growth (in vitro germination, in vitro tube length, early in vivo pollen growth rate) were all positively correlated with each other, and these early characteristics were negatively correlated with late in vivo tube growth rate, which is largely influenced by the stylar genotype. PMID- 24169981 TI - The relationship between physical and genetic distances at the Hor1 and Hor2 loci of barley estimated by two-colour fluorescent in situ hybridization. AB - The hordeins are the major class of storage proteins in barley. They are encoded by multigene families. The B- and C-hordein loci have been mapped physically to the distal end of chromosome 5 (1I) of cultivated barley by fluorescent in situ hybridization. Based on measurements of chromosomal distances between the two hordein loci, the relationship between genetic and physical distances has been estimated to be about 1 mega base pairs per centiMorgan. This is four times higher than the mean value for the barley genome as a whole and confirms the tendency to increased recombination in distal chromosome regions. The resolving power of two-colour FISH is discussed. It is concluded that the method is suitable for estimating the relationship between genetic and physical distances of regions of about 10 Mbp or larger. PMID- 24169982 TI - Genome mapping of polyploid tall fescue (Festuca arundinacea Schreb.) with RFLP markers. AB - Genetic mapping using molecular markers such as restriction fragment length polymorphisms (RFLPs) has become a powerful tool for plant geneticists and breeders. Like many economically important polyploid plant species, detailed genetic studies of hexaploid tall fescue (Festuca arundinacea Schreb.) are complicated, and no genetic map has been established. We report here the first tall fescue genetic map. This map was generated from an F2 population of HD28-56 by 'Kentucky-31' and contains 108 RFLP markers. Although the two parental plants were heterozygous, the perennial and tillering growth habit, high degree of RFLP, and disomic inheritance of tall fescue enabled us to identify the segregating homologous alleles. The map covers 1274 cM on 19 linkage groups with an average of 5 loci per linkage group (LG) and 17.9 cM between loci. Mapping the homoeologous loci detected by the same probe allowed us to identify five homoeologous groups within which the gene orders were found to be generally conserved among homoeologous chromosomes. An exception was homoeologous group 5, in which only 2 of the 3 homoeologous chromosomes were identified. Using 12 genome-specific probes, we were able to assign several linkage groups to one of the three genomes (PG1G2) in tall fescue. All the loci detected by the 11 probes specific to the G1 and/or G2 genomes, with one exception, identified loci located on 4 chromosomes of two homoeologous groups (LG2a, LG2c, LG3a, and LG3c). A P genome-specific probe was used to map a locus on LG5c. Comparative genome mapping with maize probes indicated that homoeologous group 3 and 2 chromosomes in tall fescue corresponded to maize chromosome 1. Difficulties and advantages of applying RFLP technology in polyploids with high levels of heterozygosity are discussed. PMID- 24169983 TI - Effect of oilseed rape genotype on the spontaneous hybridization rate with a weedy species:an assessment of transgene dispersal. AB - Spontaneous outcrossing of different malesterile rapeseed lines and transgenic hybrids with a population of a weedy species, Raphanus raphanistrum L., has led to the harvest of numerous seeds showing a size dimorphism. Flow cytometry analysis correlated with chromosome counts showed that all of the large seeds belonged to rapeseed, whereas the small seeds were a mixture of mostly interspecific triploid hybrids, with some trigenomic amphidiploids, diploid and haploid rapeseed plants. Significant differences were revealed between the rapeseed lines and transgenic hybrids in their ability to form interspecific hybrids with Raphanus raphanistrum under natural conditions. Resistance to the herbicide Basta was properly expressed in the triploid and amphidiploid hybrids. Low male fertility of the interspecific triploid hybrids was not correlated with seed set in the subsequent generation. PMID- 24169984 TI - A linkage map with RFLP and isozyme markers for almond. AB - Inheritance and linkage studies were conducted with seven isozyme genes and 120 RFLPs in the F1 progeny of a cross between almond cultivars 'Ferragnes' and 'Tuono'. RFLPs were detected using 57 genomic and 43 cDNA almond clones. Eight of the cDNA probes corresponded to known genes (extensin, prunin (2), alpha-tubulin, endopolygalacturonase, oleosin, actin depolymerizing factor and phosphoglyceromutase). Single-copy clones were found more frequently in the cDNA (65%) than in the genomic libraries (26%). Two maps were elaborated, one with the 93 loci heterozygous in 'Ferragnes' and another with the 69 loci heterozygous in 'Tuono'. Thirty-five loci were heterozygous in both parents and were used as bridges between both maps. Most of the segregations (91%) were of the 1?1 or 1?1?1?1 types, and data were analyzed as if they derived from two backcross populations. Eight linkage groups covering 393 cM in 'Ferragnes' and 394 in 'Tuono' were found for each map. None of the loci examined in either map was found to be unlinked. Distorted segregation ratios were mainly concentrated in two linkage groups of the 'Ferragnes' map. PMID- 24169985 TI - Mapping the genome of rapeseed (Brassica napus L.). II. Localization of genes controlling erucic acid synthesis and seed oil content. AB - A F1 microspore-derived DH population, previously used for the development of a rapeseed RFLP map, was analysed for the distribution of erucic acid and seed oil content. A clear three-class segregation for erucic acid content could be observed and the two erucic acid genes of rapeseed were mapped to two different linkage groups on the RFLP map. Although the parents of the segregating DH population showed no significant difference in seed oil content, in the DH population a transgressive segregation in oil content was observed. The segregation closely followed a normal distribution, characteristic of a quantitative trait. Using the program MAPMAKER/QTL, three QTLs for seed oil content could be mapped on three different linkage groups. The additive effects of these QTLs explain about 51% of the phenotypic variation observed for this trait in the DH population. Two of the QTLs for oil content showed a close association in location to the two erucic acid genes, indicating a direct effect of the erucic acid genes on oil content. PMID- 24169986 TI - Detection of a highly heterozygous locus in recombinant inbred lines of rice and its possible involvement in heterosis. AB - Forty-seven recombinant inbred (RI) lines derived from a cross between two indica rices, cv 'Phalguna' and the Assam land race ARC 6650, were subjected to restriction fragment length polymorphism (RFLP) analysis using cloned probes defining 150 single-copy loci uniformly dispersed on the 12 chromosomes of rice. Of the probes tested, 47 detected polymorphism between the parents. Heterozygosity was calculated for each line and for each of the polymorphic loci. Average heterozygosity per line was 9.6% but was excessive (>20%) in the 5 lines that seemed to have undergone outcrossing immediately prior to harvest. Average heterozygosity detected by each probe across the 47 RI lines was 9.7%. The majority of probes revealed the low level of heterozygosity (<8%) expected for F5 F6 lines in a species showing about 5% outbreeding. On the other hand, 7 probes exhibited heterozygosity in excess of 15%, while with a eighth probe (RG2 from chromosome 11) heterozygosity varied according to the restriction enzyme employed, ranging from 2% with SaII to 72% with EcoRV. The presence of 34 recombination sites in a segment of the genome as short as 24 kb indicates a strong selection for recombination between two neighbouring loci, one required as homozygous for the 'Phalguna' allele, and the other heterozygous. Since selection was principally for yield advantage over that of the high-yielding parent, 'Phalguna', one or both of these loci may be important for heterosis in this cross. The results also indicate that heterozygosity as measured by RFLP can depend on the particular restriction endonuclease employed. PMID- 24169987 TI - A genetic linkage map of Theobroma cacao L. AB - A linkage map of the cocoa genome comprising 193 loci has been constructed. These loci consist of 5 isozymes, 101 cDNA/RFLPs, 4 loci from genes of known function, 55 genomic DNA/RFLPs and 28 RAPDs. A population of 100 individuals derived from a cross between two heterozygous genotypes was used. Segregation analyses were performed with the JoinMap program. Ten linkage groups, which putatively correspond to the ten gametic chromosomes of cocoa, were identified. The map covers a total length of 759 cM with a 3.9 cM average distance between 2 markers. A small fraction (9%) of the markers deviated significantly from the expected Mendelian ratios. PMID- 24169988 TI - fw 2.2:a major QTL controlling fruit weight is common to both red- and green fruited tomato species. AB - We have shown that a major QTL for fruit weight (fw2.2) maps to the same position on chromosome 2 in the green-fruited wild tomato species, Lycopersicon pennellii and in the red-fruited wild tomato species, L. pimpinellifolium. An introgression line F2 derived from L. esculentum (tomato) x L. pennellii and a backcross 1 (BC1) population derived from L. esculentum x L. pimpinellifolium both place fw2.2 near TG91 and TG167 on chromosome 2 of the tomato highdensity linkage map. fw2.2 accounts for 30% and 47% of the total phenotypic variance in the L. pimpinellifolium and L. pennellii populations, respectively, indicating that this is a major QTL controlling fruit weight in both species. Partial dominance (d/a of 0.44) was observed for the L. pennellii allele of fw 2.2 as compared with the L. esculentum allele. A QTL with very similar phenotypic affects and gene action has also been identified and mapped to the same chromosomal region in other wild tomato accessions: L. cheesmanii and L. pimpinellifolium. Together, these data suggest that fw2.2 represents an orthologous QTL (i.e., derived by speciation as opposed to duplication) common to most, if not all, wild tomato species. High resolution mapping may ultimately lead to the cloning of this key locus controlling fruit development in tomato. PMID- 24169989 TI - Detection of genetic diversity in closely related bread wheat using microsatellite markers. AB - Wheat microsatellites (WMS) were used to estimate the extent of genetic diversity among 40 wheat cultivars and lines, including mainly European elite material. The 23 WMS used were located on 15 different chromosomes, and revealed a total of 142 alleles. The number of alleles ranged from 3 to 16, with an average of 6.2 alleles per WMS. The average dinucleotide repeat number ranged from 13 to 41. The correlation coefficient between the number of alleles and the average number of repeats was only slight (r s = 0.55). Based on percentage difference a dendrogram is presented, calculated by the WMS-derived data. All but two of the wheat cultivars and lines could be distinguished. Some of the resulting groups are strongly related to the pedigrees of the appropriate cultivars. Values for co ancestry (f) of 179 pairs of cultivars related by their pedigrees (f[Symbol: see text]0.1) averaged 0.29. Genetic similarity (GS) based on WMS of the same pairs averaged 0.44. The rank correlation for these pairs was slight, with r s = 0.55, but highly significant (P<0.001). The results suggest that a relatively small number of microsatellites can be used for the estimation of genetic diversity and cultivar identification in elite material of hexaploid bread wheat. PMID- 24169990 TI - Cytological, morphological and molecular analyses of controlled progenies from meiotic mutants of alfalfa producing unreduced gametes. AB - A program of sexual polyploidization was carried out in alfalfa using plants from wild diploid species that produced male or female unreduced gametes. Sixteen progenies from 2x-4x and 2x-2x crosses were examined with a combination of morphological, cytological and molecular analyses. The chromosome counts revealed diploid, tetraploid and aneuploid plants. Plants with B chromosomes were also detected. The leaf area of the plants was a useful characteristic for distinguishing tetraploid from diploid plants obtained by unilateral or bilateral sexual polyploidization. Leaf shape and leaf margin were not correlated with the ploidy levels. Plants with supernumerary chromosomes displayed obovate or elliptic leaves which differed markedly from the range of forms typical of diploid and tetraploid alfalfa plants. RAPD markers were investigated in all progeny plants to determine maternal and paternal amplification products. Three alfalfa-specific primers proved to be effective in revealing the hybrid origin of the plants. A combination of cytological, morphological and molecular analyses is essential for a detailed genetic characterization of progenies in programs of sexual polyploidization. PMID- 24169991 TI - Choice of selection environment for improving crop yields in saline areas. AB - Spatial variability in salt-affected fields is normally very high. Thus, most salinity affected lands are actually comprised of many micro-environments, ranging from low to high salinity in the same field. The evidence on testing genotypes across a broad range of salinity levels shows that the genotype-by salinity level interaction is commonly large. Thus, breeding for saline areas can be compared to what has been known as breeding for 'wide adaptation'. The target environments both for breeding for saline soils or for wide adaptation are actually a population of many possible environments, for which there exists a significant component of genotype-by-environment(G x E) interaction. Thus it is possible to study the merit of potential strategies for breeding for salinity tolerance using the tools that have been developed for the study of breeding for wide adaptation. The evidence from selection and breeding experiments for wide adaptation seems to favour testing on a representative subset of environments, including stress and non-stress locations; but the choice of these locations is complicated by the multidimensional nature of G x E. However, in the case of salt stress, the crop-yield response functions to salinity are well known. This paper presents an attempt to systematise the choice of the optimum environment(s) to select for improved yield under saline soil conditions, based on the three-piece linear equation presented by Maas and Hoffman (1977) and the theory of direct and indirect responses to selection. It is proposed that three saline levels should be enough to make a valid estimation of the suitability of a number of selection strategies. A worked example with data from a set of grain sorghum inbred lines tested on ten saline levels shows that the same selection strategies would be chosen using the information from the ten saline levels as that obtained using the two extremes and one intermediate level. PMID- 24169992 TI - Strategies for targeted transposon tagging of ABA biosynthetic mutants in tomato. AB - The ABA biosynthetic pathway has been studied in detail and the steps impaired in some ABA-deficient mutants are known. However, little is known of the molecular control mechanisms regulating ABA production in planta. A direct route for improving our understanding of these mechanisms is to transposon tag and clone the wild-type counterparts of the ABA mutant alleles. On the basis of the observation that maize transposons move preferentially to linked sites in both homologous and heterologous systems and in doing so disrupt gene function, a targeted transposon mutagenesis strategy is being developed towards cloning ABA biosynthetic genes from tomato. The possibility of using marker genes to identify T-DNA insertion sites in selected parts of the genome has been examined and compared with an inverse PCR/RFLP approach to mapping T-DNAs. PMID- 24169993 TI - Seedling-selection effects on morphological traits of mature plants in red clover. AB - Knowledge of the correlation between juvenileand mature-plant traits is critical in determining the opportunities for early stage selection. The effects of early stage selection on mature-plant performance have rarely been quantified. This study was conducted to identify seedling traints in red clover (Trifolium pratense L.) that correlate to mature-plant traits and to evaluate the effect of seedling selection on forage yields and other mature-plant traits. The results showed that relationships between most seedlingand mature-plant traits were weak (r ranged from 0.170 to 0.239). Nevertheless, selecting the top 10% seedlings for petiole length, days from emergence to full expansion of the 4th leaf (D4LE), or leaves per seedling, produced a mature-plant population with higher individual plant dry weight (IPDW1) and higher annual yield in 1993 (Y93). Selection for leaves per seedling increased IPDW1 by 23.2%. Selection for petiole length and the smallest D4LE increased Y93 by 15.7% and 13.8%, respectively. Furthermore, substantial expected genetic gains were obtained for IPDW1 and Y93 when selecting for some seedling traits. We conclude that plants and families with low potential yield can be eliminated at the seedling stage in red clover. This will allow breeders to increase the number of superior plants to be field tested or to conduct a more rigorous evaluation of the selected plants. Among the five selection schemes tested for direct selection of mature-plant traits, mass selection produced the largest genetic gain. PMID- 24169994 TI - Detection of quantitative trait loci for agronomic, yield, grain and disease characters in spring barley (Hordeum vulgare L.). AB - Quantitative trait loci (QTLs) have been revealed for characters in a segregating population from a spring barley cross between genotypes adapted to North-West Europe. Transgressive segregation was found for all the characters, which was confirmed by the regular detection of positive and negative QTLs from both parents. A QTL for all the agronomic, yield and grain characters measured except thousand grain weight was found in the region of the denso dwarfing gene locus. There were considerable differences between the location of QTLs found in the present study and those found in previous studies of North American germ plasm, revealing the diversity between the two gene pools. Thirty-one QTLs were detected in more than one environment for the 13 characters studied, although many more were detected in just one environment. Whilst biometrical analyses suggested the presence of epistasis in the genetic control of some characters, there was little evidence of interactions between the QTLs apart from those associated with yield. QTLs of large effect sometimes masked the presence of QTLs of smaller effect. PMID- 24169995 TI - Identification of the 1RS rye chromosomal segment in wheat by RAPD analysis. AB - The introgression of rye DNA into the wheat genome was studied using random decamer and specific primers with the polymerase chain reaction (PCR). DNA from paired near-isolines in Chisholm and Arkan backgrounds differing with respect to the presence of a 1 RS.1 BL translocation was amplified with 120 arbitrary sequence primers. Two of the primers (OPR 19 and OPJ07) amplified rye-specific DNA fragments. The OPR19 primer amplified a 1.35-kb fragment that appeared to be specific to the 1 RS.1 BL translocation, based on its presence only in lines carrying the 1 RS. 1 BL translocation. A fragment of the same size was also amplified in 1 RS.1 AL translocation lines. This 1 RS. 1 BL marker locus was designated Ximc 1. The other primer, OPJ07, amplified a 1.2-kb DNA sequence, that was designated Ximc 2, specific to the wheat-rye translocation in various wheat backgrounds. The sequences of the two marker loci were found to be different from each other. The Ximc 1 locus was a low-copy sequence which was also present in Balboa rye genomic DNA. Through the use of specific primers, the presence of the rye-specific marker was confirmed in hexaploid as well as in tetraploid wheat backgrounds. The use of RAPDs for the study of smaller alien introgressions into wheat is discussed. PMID- 24169996 TI - An algorithm to approximate the likelihood for pedigree data with loops by cutting. AB - This paper presents a recursive algorithm to approximate the likelihood in arbitrary pedigrees with loops. The algorithm handles any number and nesting levels of loops in pedigrees. The loops are cut as described in a previous publication and the approximate likelihood is simultaneously computed using the cut pedigree. No identification of a loop in the pedigree is necessary before the algorithm is applied. PMID- 24169997 TI - Quantitative genetic diversity and conservation strategies for an allogamous annual species, Dasypyrum villosum (L.) Candargy (Poaceae). AB - Dasypyrum villosum (L.) Candargy is a weedy annual diploid (2n = 14, VV genomes) allogamous grass species (Poaceae, Triticeae). Genetic variation for 12 traits was studied in 43 natural populations (31 from Italy and 12 from Croatia and Montenegro of former Yugoslavia) grown in a common field environment in California. Although 7 of 12 traits followed the theoretical prediction that a larger proportion of genetic variation was distributed within populations than among populations, exceptions were found for spike length, plant height, and days to flag-leaf emergence, heading, and anthesis. Covariate analysis showed that developmentally closely related characters were more likely correlated at both population and family within population levels. Geographically closer populations shared more genetic similarity than distant populations as indicated by mean coefficients of variation and cluster analysis of the Euclidean distances among populations. As few as five populations, each population with five or more half sib seeds taken randomly from 5 plants, is expected to capture more than 95% of the total genetic variation of this species in the region sampled, but sampling a much larger number of seeds per population (> 1000) for long-term storage would supply research and plant breeding needs for several decades. If seed regeneration is required, populations can be sampled from clusters having similar genetic variation, and grown in reproductive isolation or bulked seed samples from all populations of each cluster group can be grown in isolation. The former is recommended if population integrity is desired while the latter is sufficient to provide genetic resources for plant-breeding purposes. PMID- 24169998 TI - Genetic variation at the growth hormone locus in a wild pig intercross; test of association to phenotypic traits and linkage to the blood group D locus. AB - A polymorphism in the TATA-box of the porcine growth hormone (GH) gene was analysed in a wild pig/Large White intercross, in which 129 markers had been scored previously. Linkage analyses demonstrated that the GH locus belonged to a linkage group on chromosome 12 together with a previously unassigned marker, the erythrocyte antigen D (EAD) locus. The linear order of this linkage group is EAD GH-S0096-S0090-S0106-arachidonate 12-lipoxygenase (ALOX12)-inhibin beta A (INHBA). The length of the linkage group was estimated at 93 cM (sex average). The effects of the GH genotype on growth and fat deposition traits were investigated using phenotypic data from the 191 F2 animals. No significant effect of GH was detected, and we therefore conclude that this locus does not play a major role in defining the genetic differences between the wild and Large White pigs for these traits. PMID- 24169999 TI - Qualitative and quantitative characterization of RAPD variation among snap bean (Phaseolus vulgaris) genotypes. AB - Ten snap bean (Phaseolus vulgaris) genotypes were screened for polymorphism with 400 RAPD (random amplified polymorphic DNA) primers. Polymorphic RAPDs were scored and classified into three categories based on ethidium bromide staining intensity. An average of 5.19 RAPD bands were scored per primer for the 364 primers that gave scorable amplification products. An average of 2.15 polymorphic RAPDs were detected per primer. The results show that primer screening may reduce the number of RAPD reactions required for the analysis of genetic relationships among snap-bean genotypes by over 60%. Based on the analysis of the distribution of RAPD amplification, the same number of polymorphic RAPDs were amplified from different genotypes for all RAPD band intensity levels. A comparison of RAPD band amplification frequency among genotypes for the three categories of bands classified by amplification strength revealed a measurable difference in the frequencies of RAPDs classified as faint (weakly amplifying) compared to RAPD bands classified as bold (strongly amplifying) indicating a possible scoring error due to the underscoring of faint bands. Correlation analysis showed that RAPD bands amplified by the same primer are not more closely correlated then RAPD bands amplified by different primers but are more highly correlated then expected by chance. Pairwise comparisons of RAPD bands indicate that the distribution of RAPD amplification among genotypes will be a useful criterion for establishing RAPD band identity. For the average pairwise comparison of genotypes, 50% of primers tested and 15.8% of all scored RAPDs detected polymorphism. Based on RAPD data Nei's average gene diversity at a locus was 0.158 based on all scorable RAPD bands and 0.388 if only polymorphic RAPD loci were considered. RAPD-derived 1 relationships among genotypes are reported for the ten genotypes included in this study. The data presented here demonstrate that many informative, polymorphic RAPDs can be found among snap bean cultivars. These RAPDs may be useful for the unique identification of bean varieties, the organization of bean germplasm, and applications of molecular markers to bean breeding. PMID- 24170000 TI - Impact of scoring error and reproducibility RAPD data on RAPD based estimates of genetic distance. AB - RAPD band reproducibility and scoring error were evaluated for RAPDs generated by 50 RAPD primers among ten snap bean (Phaseolus vulgaris L.) genotypes. Genetic distances based on different sets of RAPD bands were compared to evaluate the impact of scoring error, reproducibility, and differences in relative amplification strength on the reproducibility of RAPD based genetic distance estimates. The measured RAPD data scoring error was 2%. Reproducibility, expressed as the percentage of RAPD bands scored that are also scored in replicate data, was 76%. The results indicate that the probability of a scored RAPD band being scored in replicate data is strongly dependent on the uniformity of amplification conditions between experiments, as well as the relative amplification strength of the RAPD band. Significant improvement in the reproducibility of scored bands and some reduction in scoring error was achieved by reducing differences in reaction conditions between replicates. Observed primer variability for the reproducibility of scored RAPDs may also facilitate the selection of primers, resulting in dramatic improvements in the reproducibility of RAPD data used in germplasm studies. Variance of genetic distances across replicates due to sampling error was found to be more than six times greater than that due to scoring error for a set of 192 RAPD bands. Genetic distance matrices computed from the RAPD bands scored in replicated data and RAPD bands that failed to be scored in replicated data were not significantly different. Differences in the ethidium bromide staining intensity of RAPD bands were not associated with significant differences in resulting genetic distance matrices. The assumption of sampling error as the only source of error was sufficient to account for the observed variation in genetic distance estimates across independent sets of RAPD bands. PMID- 24170001 TI - Identification of a RAPD marker linked to the pendula gene in Norway spruce (Picea abies (L.) Karst. f. pendula). AB - The pendula phenotype of Norway spruce [Picea abies (L.) Karst f. pendula] is characterized by narrow crowns and strong apical dominance and is controlled by a single dominant gene (P). This defined genetic control presents one of the few opportunities to map a single gene controlling a morphological trait in a forest tree. We used random amplified polymorphic DNA (RAPD) markers and bulked segregant analysis to identify one locus OPH10_720, linked to the pendula gene. The estimated recombination frequency (r) between OPH10_720 and P was 0.046 (SE r =0.032). Mapping of the pendula gene is an important first step towards the ultimate identification and cloning of this gene. PMID- 24170003 TI - Noncoding chloroplast DNA variation in Mexican pines. AB - Universal primers were used for PCR amplification of three noncoding regions of chloroplast DNA in order to study restriction site variation in 12 Mexican pine species. Two length mutations were identified that are of diagnostic value for two subgenera or sections of the genus. Phylogenetic analysis of the restriction site and length variation showed patterns of variation largely consistent with previous arrangements of these pines, except for the position of Pinus nelsonii, indicating that Pinus section Parraya Mayr, as circumscribed by Little and Critchfield (1969) and later authors, is not a monophyletic group. PMID- 24170002 TI - Transposable elements and the penetrance of quantitative characters in Drosophila melanogaster. AB - We wanted to determine whether there is a correlation between the quantitative character, the penetrance of the loss of humeral bristles in scute lines, and the distribution of transposable genetic elements in their genomes. We derived 18 isogenic lines with penetrance ranging between 2.8% and 92.0% from six mutant lines. The localization of the transposable elements (TEs) P, mdg1, Dm412, copia, gypsy and B104 was determined in all isogenic derivatives by in situ hybridization. The total number of the TE sites over all lines was 180. A comparison of the distribution of the TEs in the isogenic lines revealed the location of sites typical of lines with similar penetrance, no matter which parental line was involved. The results obtained suggest that such typical sites appear to tag the genome regions where the polygenes affecting the character in question are most likely to be found. PMID- 24170004 TI - A method for isolating and characterizing homozygous S-allele lines in Brassicae. AB - A method for isolating and characterizing homozygous S-allele lines of brassicas is described. The tester plants used are produced by crossing the parent plants with a recessive S-allele homozygote. The full method uses reciprocal crosses to identify and characterize the lines immediately. When flowering is prolonged and enables further tests to be carried out, a more efficient method that only uses single crosses initially can be used. PMID- 24170005 TI - Tagging and mapping the thermo-sensitive genic male-sterile gene in rice (Oryza sativa L.) with molecular markers. AB - The thermo-sensititve genic male-sterile (TGMS) gene in rice can alter fertility in response to temperature and is useful in the two-line system of hybrid rice production. However, little is known about the TGMS gene at the molecular level. The objective of this study was to identify molecular markers tightly linked with the TGMS gene and to map the gene onto a specific rice chromosome. Bulked segregant analysis of an F2 population from 5460s (a TGMS mutant line) x 'Hong Wan 52' was used to identify RAPD markers linked to the rice TGMS gene. Four hundred RAPD primers were screened for polymorphisms between the parents and between two bulks representing fertile and sterile plants; of these, 4 primers produced polymorphic products. Most of the polymorphic fragments contained repetitive sequences. Only one singlecopy sequence fragment was found, a 1.2-kb fragment amplified by primer OPB-19 and subsequently named TGMS1.2. TGMS1.2 was mapped on chromosome 8 with a RIL population and confirmed by remapping with a DHL population. Segregation analysis using TGMS1.2 as a probe indicated that TGMS1.2 both consegregated and was lined with the TGMS gene in this population. It is located about 6.7 cM from the TGMS gene. As TGMS1.2 is linked to the TGMS gene, the TGMS gene must be located on chromosome 8. PMID- 24170006 TI - Power of two and three-generation QTL mapping experiments in an outbred population containing full-sib or half-sib families. AB - QTL mapping experiments involve many animals to be genotyped and performance tested. Consequently, experimental designs need to be optimized to minimize the costs of data collection and genotyping. The present study has analyzed the power and efficiency of experiments with two or three-generation family structures containing full-sib families, half-sib families, or both. The focus was on data from one outbred population because the main interest is to locate genes that can be used for within-line selection. For a two generation experiment more animals had to be typed for marker loci to obtain a certain power than for a three generation experiment. Fewer trait values, however, had to be obtained for a two generation experiment than for a three-generation experiment. A two or three generation family structure with full-sib offspring was more efficient than a two or three-generation family structure with half-sib offspring. A family structure with full-sib grand-offspring, however, was less efficient than a family structure with half-sib grand-offspring. For the most efficient family structure each pair of parents had full-sib offspring that were genotyped for the marker. For the most-efficient family structure each full-sib offspring had half-sib grand-offspring for which trait values were obtained. For equal power with a heritability of 0.1 and 100 grand-offspring per full-sib offspring, 30-times less marker typings were required for this most efficient family structure than for a two-generation half-sib structure in which marker genotypes and trait values were obtained for half-sib offspring. The effect of heritability and the type of analysis (single marker or interval analysis) on the efficiency of a family structure is described. The results of this study should help to design QTL mapping experiments in an outbred population. PMID- 24170007 TI - Development and molecular cytogenetic analysis of wheat-Haynaldia villosa 6VS/6AL translocation lines specifying resistance to powdery mildew. AB - Several Triticum aestivum L.-Haynaldia villosa disomic 6VS/6AL translocation lines with powdery mildew resistance were developed from the hybridization between common wheat cultivar Yangmai 5 and alien substitution line 6V(6A). Mitotic and meiotic C-banding analysis, aneuploid analysis with double ditelosomic stocks, in situ hybridization, as well as the phenotypic assessment of powdery mildew resistance, were used to characterize these lines. The same translocated chromosome, with breakpoints near the centromere, appears to be present in all the lines, despite variation among the lines in their morphology and agronomic characteristics. The resistance gene, conferred by H. villosa and designated as Pm21, is a new and promising source of powdery mildew resistance in wheat breeding. PMID- 24170008 TI - Synthesis of high erucic acid rapeseed (Brassica napus L.) somatic hybrids with improved agronomic characters. AB - Novel Brassica napus somatic hybrids have been created through protoplast fusion of B. oleracea var. botrytis and B. rapa var. oleifera genotypes selected for high erucic acid (22:1) content in the seed oil. Fifty amphidiploids (aacc) and one putative hexaploid (aacccc) hybrid were recovered in one fusion experiment. Conversely, only one amphidiploid and numerous regenerates with higher DNA contents were produced in a similar fusion using a different B. rapa partner. Hybridity was confirmed by morphology, isozyme expression, flow cytometry, and DNA hybridization. Analysis of organellar DNA revealed a distinct bias toward the inheritance of chloroplasts from the B. rapa (aa) genome. All amphidiploids set self-pollinated seed. A erucic acid content as high as 57.4% was found in the seed oil of one regenerated plant. Fatty acid composition was stable in the R1 generation and was coupled with increased female fertility. Other novel agronomic characters in the hybrids recovered include large seed size, lodging resistance, and non-shattering seed pods. PMID- 24170009 TI - Application of Gibbs sampling for inference in a mixed major gene-polygenic inheritance model in animal populations. AB - The application of Gibbs sampling is considered for inference in a mixed inheritance model in animal populations. Implementation of the Gibbs sampler on scalar components, as used for human populations, appeared not to be efficient, and an approach with blockwise sampling of genotypes was proposed for use in animal populations. The blockwise sampling of genotypes was proposed for use in animal populations. The blockwise sampling by which genotypes of a sire and its final progeny were sampled jointly was effective in improving mixing, although further improvements could be looked for. Posterior densities of parameters were visualised from Gibbs samples; from the former highly marginalised Bayesian point and interval estimates can be obtained. PMID- 24170010 TI - Genetic distance and heterosis in Indian mustard: developmental isozymes as indicators of genetic relationships. AB - The use of isozymes as indicators of genetic diversity and as markers for the selection of agronomic traits has been proposed in different crop species. The present investigation was conducted to study the use of isozyme-derived genetic distance between parents in predicting the F1 heterosis in Indian mustard. In addition, the interaction of isozyme-based diversity with quantitative trait and pedigree-based diversity measures, and its role in predicting hybrid heterosis has also been examined. Sixteen Indian mustard lines and their 48 crosses (12 * 4, line x tester crossing) were evaluated over two environments for isozyme and quantitative morphological characters. The results from this study suggest that the heterotic response to isozymic changes is more responsive in crosses derived from morphologically and pedigree-wise related parents in comparison to crosses derived from unrelated parents. It was possible to improve heterosis predictions by partitioning the isozyme-based genetic distance into general genetic distance and specific genetic distance and correlating the latter with the specific combining ability of morphological traits. The possible reasons for these observations are discussed. PMID- 24170011 TI - The distribution of Gossypium hirsutum chromatin in G. barbadense germ plasm: molecular analysis of introgressive plant breeding. AB - Cotton is unusual among major crop plants in that two cross-fertile species are widely cultivated for a common economic product, fiber. Both historical evidence and classical genetic studies suggest that many improved forms of Gossypium barbadense ("Sea Island", "Egyptian", and "Pima" cottons) may include chromatin derived from G. hirsutum. Using 106 restriction fragment length polymorphism (RFLP) loci well distributed across the cotton genome, we revealed the amount and genomic distribution of G. hirsutum chromatin in 54 G. barbadense collections from around the world. The average G. barbadense collection was comprised of 8.9% alleles apparently derived from G. hirsutum. Pima cultivars (7.3 %) had fewer G. hirsutum alleles than Sea Island (9.0%) or Egyptian (9.6%) cultivars. G. hirsutum alleles were not randomly distributed, as 57.5% of the total introgression observed was accounted for by five specific chromosomal regions that span less than 10% of the genome. The average length of an introgressed chromosome segment was [Symbol: see text] 12.9 cM. Overlap of introgressed chromatin in different breeding programs hints that retention of these G. hirsutum chromosomal segments may impart a selective advantage to G. barbadense genotypes. Although cluster analysis generally grouped germ plasm from common classes and/or breeding programs together, no 2 genotypes were identical - thus differences in the length and repertoire of introgressed chromosome segments also permit DNA fingerprinting of G. barbadense cultivars. PMID- 24170012 TI - A genetic analysis of a tomato (Lycopersicon esculentum) genotype with a high frequency of twin spots. AB - Among pale-green tomato plants heterozygous for the xanthophyllic2 (xa-2) mutation that were transformed with a T-DNA harbouring the NPTII and GUS gene, a plant with a high frequency of green/white twin spots was found. The genetic analysis of this plant indicated that the occurrence of these twin spots was caused by a genetic defect located at the distal end of chromosome 10S, where xa 2 also is located. The genetic analysis of green plants regenerated from leaf expiants of this twin-spot plant revealed that the green sectors derive from non disjunction of the xa-2 (+) allele. In an analysis of mitotic chromosome behaviour bridges were observed in approximately 5% of the anaphases, providing arguments that a breakage-fusion-bridge cycle caused by a tissue culture-induced genomic instability is the most likely cause of this aberrant behaviour of chromosome 10. PMID- 24170013 TI - Somatic hybrids between Brassica juncea (L). Czern. and Diplotaxis harra (Forsk.) Boiss and the generation of backcross progenies. AB - An attempt to transfer genes from droughttolerant Diplotaxis harra, a wild relative of Brassica species, to an elite oil-yielding cultivar, B-85, of mustard (Brassica juncea) was made through protoplast fusion, as the two plant systems are sexually incompatible. By following the standard protocol for PEG-mediated protoplast fusion followed by high pH, high Ca(++), DMSO treatment and appropriate cell-culture technique, 16 presumptive somatic hybrid plants could be regenerated. Chromosomal analysis of four such somatic hybrids revealed that three of them were asymmetric. Analysis of morphological characters, meiotic chromosomes, and esterase isoenzyme pattern revealed that all the somatic hybrids were different from each other. Furthermore four chromosomes of each genome could undergo homoeologous pairing at meiosis indicating the possibilities for genetic recombination and chromosomal rearrangements. Irregular distribution of chromosomes at anaphase-II at meiosis has been a consistent feature of these plants. Eventually, pollen of all the somatic hybrids showed complete infertility preventing the recovery of any selfed seed. Nevertheless, ovule fertility of one somatic hybrid was not totally impaired as it had set some seeds upon backcrossing with the B. juncea parent. The esterase isoenzyme banding pattern of 24 individual progeny plants of this backcross provided evidence for their recombinant nature. It was thus confirmed that a transfer of genetic traits from Diplotaxis harra to B. juncea had indeed taken place. Furthermore, it was conceptualised that a transfer of alien genes through the protoplast-fusion technique is primarily possible in situations where meiotic pairing of the chromosomes of the two participating genomes generates recombinant gametocytes which can pass through subsequent filial generations. PMID- 24170014 TI - Cytoplasmic male-sterile synthetics: a new approach to the exploitation of heterosis in rape. AB - In addition to their application in the production of F1 hybrids in rape (Brassica napus L.), cytoplasmic male-sterility (CMS) systems may be used to produce synthetic varieties with much higher levels of heterozygosity than those expected in conventional rape synthetics. CMS synthetics are produced by compositing a CMS A-line with several male-fertile (MF) B-lines lacking nuclear alleles for fertility restoration, and increasing the resulting mixture by natural pollination. Over generations of increase, pollination of the CMS component by the MF component of the synthetic results in the progressive loss of A-line nuclear genes from the population. The initial proportions of CMS and MF plants are expected to be preserved over several generations of natural pollination if CMS and MF plants are equal in yield. Methods for estimating the heterozygosity level of CMS synthetics, taking into account the proportion of CMS plants, number of MF parents in Syn 0, and selfing rate (s) of MF plants, are presented. If completely inbred Syn 0 parents and s of 0 and 0.75 for CMS and MF plants respectively, are assumed, the heterozygosity level (1-F) of a synthetic derived from four inbred MF parents each comprising 6.25% of Syn 0 and one inbred CMS parent comprising 75% of Syn 0 is predicted to be 0.66 in Syn 5, compared to 0.30 in synthetics derived from four MF parents only. CMS synthetics offer a novel, low-cost approach to the exploitation of heterosis in rape and other species with mixed mating systems in which self-pollination predominates. PMID- 24170015 TI - Intersectionality of internalized HIV stigma and internalized substance use stigma: Implications for depressive symptoms. AB - We adopted an intersectionality framework and examined whether the relationship between internalized HIV stigma and depressive symptoms is moderated by internalized substance use stigma. A total of 85 people living with HIV with a history of substance use in the Bronx, New York, completed a survey. Results revealed evidence of moderation: Participants who internalized HIV stigma experienced greater depressive symptoms only if they also internalized substance use stigma. Researchers should examine stigma associated with multiple socially devalued characteristics to best understand how stigma impacts mental health among people living with HIV. Healthcare providers should address stigma associated with the full range of socially devalued characteristics with which people living with HIV live. PMID- 24170016 TI - Unreliable item or inconsistent person? A study of variation in health beliefs and belief-anchors to biomedical models. AB - The reliability of an item designed to measure health belief is often confounded with response consistency at the person level. The study applied contemporary measurement methods to an inventory of common sense beliefs about diabetes and used a sample of N = 563 adults with diabetes to test the hypothesis that individuals whose beliefs are congruent with a biomedical model are more consistent in their responses. Item-level analysis revealed that the domains of Causes and Medical Management were the least reliable. Person-level analysis showed that respondents who held views congruent with the biomedical model were more consistent than people who did not. PMID- 24170017 TI - Reduction-free synthesis of stable acetylide cobalamins. AB - A straightforward, reduction-free method for the synthesis of organometallic cobalamins has been developed. Stable phenylacetylide derivatives were characterized by X-ray analysis, showing a pronounced influence of the electronic nature of substituents on their structure. PMID- 24170018 TI - Tools for improving feeding strategies in a SBR with several species. AB - This paper analyzes feeding strategies in a sequential batch reactor (SBR) with the objective of reaching a given (low) substrate level as quickly as possible for a given volume of water. Inside the SBR, several species compete for a single substrate, which leads to a minimal time control problem in which the control variable is the feeding rate. Following Gajardo et al. (2008) SIAM J Control Optim 47(6):2827-2856, we allow the control variable to be a bounded measurable function of time combined with possible impulses associated with instantaneous dilutions. For this problem, the extremal trajectories of the singular arc type are characterized as the strategies used to maintain the substrate at a constant level. Since this optimization problem is difficult to solve, this characterization provides a valuable tool for investigating the optimality of various feeding strategies. Our aim is thus to illustrate the use of this tool by proposing potential optimal feeding strategies, which may then be compared with other more intuitive strategies. This aim was accomplished via several numerical experiments in which two specific strategies are compared. PMID- 24170019 TI - Alleviation of metal and BTEX inhibition on BTEX degradation using PVA immobilized degrader: kinetic model of BTEX degradation. AB - Alleviation of metal inhibition on BTEX degradation using PVA-immobilized degrader (Mycobacterium sp. CHXY119) was investigated. When BTEX of 29 mg L(-1) [B:T:E:X = 1:1:1:1 (mg)] was used, more than 99 % of BTEX was simultaneously degraded by the free cells within 170 h. In contrast, BTEX of 114-172 mg L(-1) seriously inhibited degradation. High concentrations of metals (Mn(2+): 15, Ni(2+): 10, and Zn(2+): 10 mg L(-1)) also strongly inhibited BTEX degradation by the free cells at BTEX of 29 mg L(-1). Immobilization of degraders alleviated the inhibition of BTEX and heavy metals at high concentrations. A modified non competitive inhibition model well described the BTEX degradation by the free and immobilized cells in the absence and presence of metal ions (R (2) = 0.92-0.99). The above results provide valuable information on treatment of metal-BTEX co contaminated wastewater by the immobilized degrader. PMID- 24170020 TI - Improvement of kojic acid production in Aspergillus oryzae B008 mutant strain and its uses in fermentation of concentrated corn stalk hydrolysate. AB - A strain designated M866, producing kojic acid with a high yield, was obtained by combining induced mutation using ion beam implantation and ethyl methane sulfonate treatment of a wild type strain of Aspergillus oryzae B008. The amount of kojic acid produced by the strain M866 in a shaking flask was 40.2 g/L from 100 g/L of glucose, which was 1.7 times higher than that produced by wild strain (23.58 g/L). When the mixture of glucose and xylose was used as carbon source, the resulting kojic acid production was raised with the increasing of glucose ratios in the mixture. With concentrations of glucose at 75 g/L and xylose at 25 g/L mixed in the medium, the production of kojic acid reached 90.8 %, which was slightly lower than with glucose as the sole source of carbon. In addition, the kojic acid fermentation of the concentrated hydrolysate from corn stalk was also investigated in this study, the maximum concentration of kojic acid accumulated at the end of the fermentation was 33.1 g/L and this represents the yield based on reducing sugar consumed and the overall productivity of 0.36 g/g and 0.17 g/L/h, respectively. PMID- 24170021 TI - [Neurology and carotid artery interventions. What has to be done first?]. AB - Optimum therapy for patients with carotid stenosis requires the interdisciplinary cooperation of surgeons, neurologists and angiologists. Important diagnostic methods are ultrasound sonography, contrast-enhanced computed tomography, magnetic resonance tomography and digital subtraction angiography. Treatment of carotid artery stenosis depends on whether the stenosis is symptomatic or asymptomatic. The treatment of choice (medical therapy only vs. carotid artery stenting vs. carotid endarterectomy) depends on the characteristics of the stenosis, the presence of cerebral lesions and the general physical condition of the patient. After the intervention continuous monitoring and treatment of vascular risk factors are mandatory. PMID- 24170022 TI - [Current status of carotid endarterectomy]. AB - Carotid endarterectomy (CEA) has been evaluated in many prospective randomized studies. After the introduction of carotid stenting (CAS) an alternative treatment is now available for treatment of extracranial carotid stenoses. Comparative studies have been carried out to compare these two modalities. There are two general methods for operative reconstruction available: patch angioplasty and endarterectomy. The results of the mandatory quality assurance registry between the time period 2003-2011 showed a reduction in complication rates, more operations in regional anesthesia and a higher percentage of eversion endarterectomy during the observation period. Since 2012 CAS is now also included in the national quality assurance program. PMID- 24170023 TI - [Current guidelines on carotid artery stenting. Critical evaluation]. AB - Scientific data underlying current guidelines on treatment of carotid artery stenosis is subject to interdisciplinary discussion. In particular selective weighting of the randomized European studies leads to conflicting levels of recommendation and levels of evidence, especially when directly comparing guidelines under surgical versus endovascular guidance. Surgical guidelines recommend a limitation of carotid artery stenting (CAS) to symptomatic patients with specific surgical/anatomical disadvantages and/or severe comorbidities. The European Society of Cardiology (ESC) guidelines recommend the use of CAS only in patients at increased surgical risk but at the same time requires morbidity and mortality rates comparable to those of surgical interventions. Even one step further, the American guidelines and specifically the associated comments of the German Society of Cardiology on the above mentioned ESC guidelines put CAS and carotid endarterectomy (CEA) on a par in terms of treatment alternatives, presupposing analogous CEA complication rates. Differential interpretation of the so far inadequate data is a common issue of current evidence-based medicine. The difficulty in conceptualization of new studies concerning the therapy of carotid stenosis lies in the funding these large projects and also on the high patient number required to achieve adequate statistical power. Furthermore, during the estimated long study period substantial changes of current techniques and devices can be anticipated which might render the study results in part outdated by the time of publication. However, as long as no new randomized study results comparing medical, surgical and interventional treatment of carotid stenosis are available, the question on the optimal therapy for patients with carotid artery disease remains unanswered. PMID- 24170024 TI - [Carotid artery stenting: is there a volume-outcome correlation?]. AB - Since carotid artery stenting was introduced into clinical practice as an alternative treatment option for significant carotid artery stenosis, several randomized trials have been published with different minimum requirements for the treating interventionalist and therefore different event rates. Analysis of large single center studies and registries has shown a significant decrease in event rates with an increase in experience in carotid artery stenting techniques. The randomized trials with exactly defined minimum requirements including a reasonable number of prior carotid artery interventions showed comparable results between carotid artery stenting and surgical approaches. PMID- 24170026 TI - What does MRD in leukemia really mean? PMID- 24170027 TI - Functional impact of NOTCH1 mutations in chronic lymphocytic leukemia. AB - The purpose of this study was to compare the expression and function of NOTCH1 in chronic lymphocytic leukemia (CLL) patients harboring a wild-type (WT) or mutated NOTCH1 gene. NOTCH1 mRNA and surface protein expression levels were independent of the NOTCH1 gene mutational status, consistent with the requirement for NOTCH1 signaling in this leukemia. However, compared with NOTCH1-WT CLL, mutated cases displayed biochemical and transcriptional evidence of an intense activation of the NOTCH1 pathway. In vivo, expression and activation of NOTCH1 was highest in CLL cells from the lymph nodes as confirmed by immunohistochemistry. In vitro, the NOTCH1 pathway was rapidly downregulated, suggesting that signaling relies upon micro-environmental interactions even in NOTCH1-mutated cases. Accordingly, co-culture of Jagged1(+) (the NOTCH1 ligand) nurse-like cells with autologous CLL cells sustained NOTCH1 activity over time and mediated CLL survival and resistance against pro-apoptotic stimuli, both abrogated when NOTCH1 signaling was pharmacologically switched off. Together, these results show that NOTCH1 mutations have stabilizing effects on the NOTCH1 pathway in CLL. Furthermore, micro-environmental interactions appear critical in activating the NOTCH1 pathway both in WT and mutated patients. Finally, NOTCH1 signals may create conditions that favor drug resistance, thus making NOTCH1 a potential molecular target in CLL. PMID- 24170029 TI - Fatal progressive cerebral ischemia in CML under third-line treatment with ponatinib. PMID- 24170028 TI - Alternatively spliced, truncated GCSF receptor promotes leukemogenic properties and sensitivity to JAK inhibition. AB - Granulocyte colony-stimulating factor (GCSF) drives the production of myeloid progenitor and precursor cells toward neutrophils via the GCSF receptor (GCSFR, gene name CSF3R). Children with severe congenital neutropenia chronically receive pharmacologic doses of GCSF, and ~30% will develop myelodysplasia/acute myeloid leukemia (AML) associated with GCSFR truncation mutations. In addition to mutations, multiple isoforms of CSF3R have also been reported. We found elevated expression of the alternatively spliced isoform, class IV CSF3R in adult myelodysplastic syndrome/AML patients. Aside from its association with monosomy 7 and higher rates of relapse in pediatric AML patients, little is known about the biology of the class IV isoform. We found developmental regulation of CSF3R isoforms with the class IV expression more representative of a progenitor cell stage. Striking differences were found in phosphoprotein signaling involving Janus kinase (JAK)-signal transducer and activator of transcription (STAT) and cell cycle gene expression. Enhanced proliferation by class IV GCSFR was associated with diminished STAT3 and STAT5 activation, yet showed sensitivity to JAK2 inhibitors. Alterations in the C-terminal domain of the GCSFR result in leukemic properties of enhanced growth, impaired differentiation and resistance to apoptosis, suggesting that they can behave as oncogenic drivers, sensitive to JAK2 inhibition. PMID- 24170030 TI - Hg2+ wettability and fluorescence dual-signal responsive switch based on a cysteine complex of piperidine-calix[4]arene. AB - The recognition of the mercury(II) ion (Hg(2+)) is essential because of its extreme toxicity in the environment and food. Hence we reported a novel cysteine (Cys) complex of piperidine-calix[4]arene (L) as a convenient and effective dual signal responsive switch for Hg(2+). This switch system exhibited excellent selectivity toward Hg(2+) by fluorescence (FL), (1)H NMR spectroscopy and the atomic force microscopy (AFM). More importantly, the Hg(2+)-responsive switch had an important and potential application by water contact angle (CA) on a functional micro-nano silicon surface, including intelligent microfluidic and laboratory-on-chip devices, controllable drug delivery, and self-cleaning surfaces. PMID- 24170032 TI - Host susceptibility to malaria in human and mice: compatible approaches to identify potential resistant genes. AB - There is growing evidence for human genetic factors controlling the outcome of malaria infection, while molecular basis of this genetic control is still poorly understood. Case-control and family-based studies have been carried out to identify genes underlying host susceptibility to malarial infection. Parasitemia and mild malaria have been genetically linked to human chromosomes 5q31-q33 and 6p21.3, and several immune genes located within those regions have been associated with malaria-related phenotypes. Association and linkage studies of resistance to malaria are not easy to carry out in human populations, because of the difficulty in surveying a significant number of families. Murine models have proven to be an excellent genetic tool for studying host response to malaria; their use allowed mapping 14 resistance loci, eight of them controlling parasitic levels and six controlling cerebral malaria. Once quantitative trait loci or genes have been identified, the human ortholog may then be identified. Comparative mapping studies showed that a couple of human and mouse might share similar genetically controlled mechanisms of resistance. In this way, char8, which controls parasitemia, was mapped on chromosome 11; char8 corresponds to human chromosome 5q31-q33 and contains immune genes, such as Il3, Il4, Il5, Il12b, Il13, Irf1, and Csf2. Nevertheless, part of the genetic factors controlling malaria traits might differ in both hosts because of specific host pathogen interactions. Finally, novel genetic tools including animal models were recently developed and will offer new opportunities for identifying genetic factors underlying host phenotypic response to malaria, which will help in better therapeutic strategies including vaccine and drug development. PMID- 24170031 TI - MicroRNA associated with dyslipidemia and coronary disease in humans. AB - MicroRNAs are structural components of an epigenetic mechanism of posttranscriptional regulation of messenger RNA translation. Recently, there has been significant interest in the application of microRNA as a blood-based biomarker of underlying physiological conditions. Dyslipidemia is a complex, heterogeneous condition conferring substantially increased risk for cardiovascular disease. The purpose of this review is to describe the current body of knowledge on the role of microRNA regulation of lipoprotein metabolism in humans and to discuss relevant methodological and study design considerations. We highlight the potential roles for microRNA in gene-environment interactions. PMID- 24170033 TI - Synthesis, structure and photophysical properties of [UO2X2(O=PPh3)2] (X = Cl, Br, I). AB - The synthesis of a series of uranyl compounds via oxidation of [Li(THF)4][UX5(THF)] (X = Cl, Br, I) in the presence of Ph3P=O is described. The solid state structures of [Li(O=PPh3)(MeCN)2]2[UO2Cl4], [UO2Br2(O=PPh3)2] and [Li(O=PPh3)4][I3], formed as a by-product from the oxidation of [Li(THF)4][UI5(THF)], is reported. The electronic absorption spectra and photoluminescence spectra of [UO2X2(O=PPh3)2] (X = Cl, Br, I) have been measured and no significant changes in the position of the emission (515-530 nm) or the lifetimes (ca. 1 MUs) are observed in this series. However a bathochromic shift is observed in the U-X LMCT band in the electronic absorption spectrum. PMID- 24170034 TI - [Life with haemophilia. The patient's perspective of ageing]. AB - Patients with haemophilia are growing older and may be faced with age-dependent co-morbidities. To evaluate the impact of growing age in patients with haemophilia, a questionaire was sent to members of German patients' organisations DHG and IGH with focus on medical care and psychosocial questions. This questionnaire was answered by 466 individuals (aged 50 years, 21-85 years), predominantly suffering from severe haemophilia. The majority of individuals considered the question of substitution of factor concentrates in case of bleeding as most important. Concerns were expressed regarding the financial situation and lack of medical care in higher age. The results provide an insight into issues of growing age from the patient's perspective. PMID- 24170035 TI - Primary prevention of sudden cardiac death in a low-risk child with familial hypertrophic cardiomyopathy: the role of cardiac magnetic resonance imaging. PMID- 24170036 TI - Why can't we improve the timeliness of cancer diagnosis in children, teenagers, and young adults? PMID- 24170037 TI - Asymmetry of the multifidus muscle in lumbar radicular nerve compression. AB - OBJECTIVE: The multifidus muscle is the only paraspinal lumbar muscle that is innervated by a single nerve root. This study aimes to evaluate if the asymmetry of the multifidus muscle is related to the severity of compression of the nerve root or the duration of radiculopathy. METHODS: MRI scans of 79 patients with symptomatic single level, unilateral, lumbar radiculopathy were reviewed for this retrospective case series with a nested case-control study. The cross-sectional area (CSA) of the multifidus muscle and the perpendicular distance of the multifidus to the lamina (MLD) were measured bilaterally by two radiologists and set into relation to the severity of nerve compression, duration of radiculopathy and probability of an indication for surgical decompression. RESULTS: In 67 recessal and 12 foraminal symptomatic nerve root compressions, neither the MLD ratio (severe 1.19 +/- 0.55 vs less severe nerve compression: 1.12 +/- 0.30, p = 0.664) nor the CSA ratio (severe 1 +/- 0.16 vs less severe 0.98 +/- 0.13, p = 0.577) nor the duration of symptoms significantly correlated with the degree of nerve compression. MR measurements of multifidus were not different in patients with (n = 20) and those without (n = 59) clinical muscle weakness in the extremity caused by nerve root compression. A MLD >1.5 was, however, associated with the probability of an indication for surgical decompression (OR 3, specificity 92%, PPV 73%). CONCLUSIONS: Asymmetry of the multifidus muscle correlates with neither the severity nor the duration of nerve root compression in the lumbar spine. Severe asymmetry with substantial multifidus atrophy seems associated with the probability of an indication of surgical decompression. PMID- 24170038 TI - Effect of carbonated beverages on pharyngeal swallowing in young individuals and elderly inpatients. AB - Gustatory and chemical stimulations of the oral cavity and pharyngeal mucosa by carbonated water improve pharyngeal swallowing. We compared changes in pharyngeal swallowing and sensory aspects induced by a carbonated beverage preferred by Japanese with those induced by carbonated water, a sports drink, and tap water in healthy young subjects and elderly inpatients with no swallowing problems. The duration of laryngeal elevation (DOLE) for swallowing the carbonated beverage and water in the second session was shorter compared to that for water in the first session in the elderly subjects. The DOLE and the duration of suprahyoid muscle activity for swallowing were longer in the elderly subjects than in the young subjects for all beverages. Beverages that the subjects subjectively felt were easy to swallow were the sports drink and carbonated beverage, whereas they stated that carbonated water was less easy to swallow. In the elderly subjects, swallowing ability latently decreased, even though they had no problem swallowing in their daily lives, and it was assumed that the carbonated beverage improved pharyngeal swallowing. In addition, the carbonated beverage also influenced the subsequent swallowing of water, showing a persistent effect. It was suggested that carbonated beverages are easy to swallow and effective for improving pharyngeal swallowing. PMID- 24170040 TI - In vitro optical detection of simulated blood pulse in a human tooth pulp model. AB - OBJECTIVE: Noninvasive optical methods such as photoplethysmography, established for blood pulse detection in organs, have been proposed for vitality testing of human dental pulp. However, no information is available on the mechanism of action in a closed pulp chamber and on the impairing influence of other than pulpal blood flow sources. Therefore, the aim of the present in vitro study was to develop a device for the optical detection of pulpal blood pulse and to investigate the influence of different parameters (including gingival blood flow [GBF] simulation) on the derived signals. MATERIALS AND METHODS: Air, Millipore water, human erythrocyte suspensions (HES), non-particulate hemoglobin suspension (NPHS), and lysed hemoglobin suspension (LHES) were pulsed through a flexible (silicone) or a rigid (glass) tube placed within an extracted human molar in a tooth-gingiva model. HES was additionally pulsed through a rigid tube around the tooth, simulating GBF alone or combined with the flow through the tooth by two separate peristaltic pumps. Light from high-power light-emitting diodes (625 nm (red) and 940 nm (infrared [IR]); Golden Dragon, Osram, Germany) was introduced to the coronal/buccal part of the tooth, and the signal amplitude [?U, in volts] of transmitted light was detected by a sensor at the opposite side of the tooth. Signal processing was carried out by means of a newly developed blood pulse detector. Finally, experiments were repeated with the application of rubber dam (blue, purple, pink, and black), aluminum foil, and black antistatic plastic foil. Nonparametric statistical analysis was applied (n = 5; alpha = 0.05). RESULTS: Signals were obtained for HES and LHES, but not with air, Millipore water, or NPHS. Using a flexible tube, signals for HES were higher for IR compared to red light, whereas for the rigid tube, the signals were significantly higher for red light than for IR. In general, significantly less signal amplitude was recorded for HES with the rigid glass tube than with the flexible tube, but it was still enough to be detected. ?U from gingiva compared to tooth was significantly lower for red light and higher for IR. Shielding the gingiva was effective for 940 nm light and negligible for 625 nm light. CONCLUSIONS: Pulpal blood pulse can be optically detected in a rigid environment such as a pulp chamber, but GBF may interfere with the signal and the shielding effect of the rubber dam depends on the light wavelength used. CLINICAL RELEVANCE: The optically based recording of blood pulse may be a suitable method for pulp vitality testing, if improvements in the differentiation between different sources of blood pulse are possible. PMID- 24170041 TI - pH-Triggered Au-fluorescent mesoporous silica nanoparticles for 19F MR/fluorescent multimodal cancer cellular imaging. AB - Novel pH-triggered nanoprobe were fabricated for (19)F MRI and fluorescence imaging (MRI-FI) of cancer cells. The biocompatibility, durability, high internalizing efficiency and pore architecture justify the Au-fluorescent mesoporous silica nanoparticles as ideal, highly sensitive and highly specific vectors for (19)F MRI and FI of cancer cells. PMID- 24170043 TI - Molecular-marker-facilitated investigation on the ability to stimulate N2 fixation in the rhizosphere by irrigated rice plants. AB - An F2 population, consisting of 231 individuals derived from a cross between rice cultivars with a similar growing duration, Palawan and IR42, was utilized to investigate the genetic nature of rice varietal ability to stimulate N2 fixation in the rice rhizosphere. To assess rhizospheric N2 fixation, an isotope-enriched (15)N dilution technique was employed, using (15)N-stabilized soil in pots. IR42, an indica variety, had 23% higher N derived from fixation (Ndfa) than Palawan, a javanica genotype. Normal segregation of atom% (15)N excess was obtained in the F2 population, with an average of 0.218 with 8% of plants below IR42 (0.188) and 10% of plants above Palawan (0.248). One-hundred-and-four RFLP markers mapped on 12 chromosomes were tested for linkage to the putative QTLs. Significant (P<0.01) associations between markers and segregation of atom% (15)N excess were observed for seven marker loci located on chromosomes 1, 3, 6 and 11. Four QTLs defined by the detected marker loci were identified by interval-mapping analysis. Additive gene action was found to be predominant, but for at least one locus, dominance and partial dominance effects were observed. Significant (P<0.01) epistatic effects were also identified. Individual marker loci detected between 8 and 16% of the total phenotypic variation. All four putative QTLs showed recessive gene action, and no phenotypic effects associated with heterozygosity of marker loci were observed. The results of this study suggest that rice genetic factors can be identified which affect levels of atom% (15)N excess in the soil by interacting with diazotrophs in the rice rhizosphere. PMID- 24170042 TI - CD200R signaling inhibits pro-angiogenic gene expression by macrophages and suppresses choroidal neovascularization. AB - Macrophages are rapidly conditioned by cognate and soluble signals to acquire phenotypes that deliver specific functions during inflammation, wound healing and angiogenesis. Whether inhibitory CD200R signaling regulates pro-angiogenic macrophage phenotypes with the potential to suppress ocular neovascularization is unknown. CD200R-deficient bone marrow derived macrophages (BMMPhi) were used to demonstrate that macrophages lacking this inhibitory receptor exhibit enhanced levels of Vegfa, Arg-1 and Il-1beta when stimulated with PGE2 or RPE-conditioned (PGE2-enriched) media. Endothelial tube formation in HUVECs was increased when co cultured with PGE2-conditioned CD200R(-/-) BMMPhi, and laser-induced choroidal neovascularization was enhanced in CD200R-deficient mice. In corroboration, signaling through CD200R results in the down-regulation of BMMPhi angiogenic and pro-inflammatory phenotypes. Translational potential of this pathway was investigated in the laser-induced model of choroidal neovascularization. Local delivery of a CD200R agonist mAb to target myeloid infiltrate alters macrophage phenotype and inhibits pro-angiogenic gene expression, which suppresses pathological angiogenesis and CNV development. PMID- 24170044 TI - Identification of two RAPD markers tightly linked with the Nicotiana debneyi gene for resistance to black root rot of tobacco. AB - Linkage of randomly amplified polymorphic DNA (RAPD) markers with a single dominant gene for resistance to black root rot (Chalara elegans Nag Raj and Kendrick; Syn. Thielaviopsis basicola [Berk. and Broome] Ferraris) of tobacco (Nicotiana tabacum L.), which was transferred from N. debneyi Domin, was investigated in this study. There were 2594 repeatable RAPD fragments generated by 441 primers on DNAs of 'Delgold' tobacco, a BC5F8 near isogenic line (NIL) carrying the resistance gene in a 'Delgold' background, and 'PB19', the donor parent of the resistance gene. Only 7 of these primers produced eight RAPD markers polymorphic between 'Delgold' and 'PB19', indicating there are few RAPD polymorphisms between them despite relatively dissimilar pedigrees. Five of the eight RAPD markers were not polymorphic between 'Delgold' and the NIL. All of these markers proved to be unlinked with the resistance gene in F2 linkage tests. Of the remaining three RAPD markers polymorphic between 'Delgold' and the NIL, two were shown to be strongly linked with the resistance gene; one in coupling and the other in repulsion. Application of the two RAPDs in the elimination of linkage drag associated with the N. debneyi resistance gene and marker-assisted selection for the breeding of new tobacco cultivars with the resistance gene is discussed. PMID- 24170045 TI - RFLP mapping of resistance to the blackleg disease [causal agent, Leptosphaeria maculans (Desm.) Ces. et de Not.] in canola (Brassica napus L.). AB - We report the tagging of genes involved in blackleg resistance, present in the French cultivar Cresor of B. napus, with RFLP markers. A total of 218 cDNA probes were tested on the parental cultivars Cresor (resistant) and Westar (susceptible), and 141 polymorphic markers were used in a segregating population composed of 98 doubled-haploid lines (DH). A genetic map from this cross was constructed with 175 RFLP markers and allowed us to scan for specific chromosomal associations between response to blackleg infection and RFLP markers. Canola residues infested with virulent strains of Leptosphaeria maculans were used as inoculum and a suspension of pycnidiospores from cultures of L. maculans, including the highly virulent isolate Leroy, was sprayed to increase disease pressure. QTL mapping suggested that a single chromosomal region was responsible for resistance in each of the four environments tested. This QTL accounted for a high proportion of the variation of blackleg reaction in each of the assays. A second QTL, responsible for a small proportion of the variation of blackleg reaction, was present in one of four year-site assays. A Mendelian approach, using blackleg disease ratings for classifying DH lines as resistant or susceptible, also allowed us to map resistance in the region of the highly significant LOD scores observed in each environment by interval mapping. Results strongly support the presence of a single major gene, named LmFr 1 controlling adult plant resistance to blackleg in spring oil-seed rape cultivar Cresor. Several RFLP markers were found associated with LmFr 1. PMID- 24170046 TI - Mapping genetic factors controlling pollen viability in an interspecific cross in Helianthus sect. Helianthus. AB - Segregation of 48 genetic markers, including one CMS restorer gene, one morphological character gene, six isozymes and 40 RAPD loci, was scored in a backcross progeny of an interspecific hybrid H. argophyllusxH. annuus cv RHA274. A linkage map was generated taking into account segregation distortions for 11 of the 48 loci in the frame of two different models considering locus-pair segregation in the context of either independent selection pressures or non equilibrated parental classes. The map consists of nine linkage groups and nine isolated markers covering 390 cM. Approximately half of the plants of the BC1 were male fertile as expected for the segregation of one dominant male-fertility restorer gene; however, these displayed a large range of variation for pollen viability. About 80% of this variation was explained by three genomic regions located on linkage groups 1, 2 and 3. The observation of meiotic chromosomes revealed a significant rate of mispairing (rod bivalents and tetravalents) in tight correlation with pollen viability, indicating that chromosome rearrangements (translocations) are the preponderant factors reducing pollen viability in this progeny. Cytogenetic and mapping data suggest that the three genomic regions involved in pollen-viability variation are located close to translocation points which differentiate the parental-species karyotypes. Segregation distortion was observed for loci correlated with pollen-viability variation. These were most likely the result of two possible suggested mechanisms. PMID- 24170047 TI - High crossability of wild barley (Hordeum spontaneum C. Koch) with bread wheat and the differential elimination of barley chromosomes in the hybrids. AB - Four bread wheat (Triticum aestivum L.) cultivars, 'Aobakomugi', 'Chinese Spring', 'Norin 61' and 'Shinchunaga', were pollinated with five barley lines/cultivars consisting of three cultivated barley (Hordeum vulgare L.) lines, 'Betzes', 'Kinai 5' and OHL089, and two wild barley (Hordeum spontaneum C. Koch) lines, OUH602 and OUH324. Crossability, expressed as the percentage of embryo formation, varied from 0 to 55.4% among the cross combinations. The two wild barley lines generally had a higher crossability than the previously reported best pollinator, 'Betzes', and some Japanese wheat cultivars were better as the female parent than 'Chinese Spring'. Ninety four hybrid plants were obtained from 250 embryos cultured, and their somatic chromosome numbers ranged from 21 to 36. Eighteen plants were mosaic in chromosome number. Twenty one-chromosome plants appeared most frequently (45.7%) followed by 28-chromosome plants (14.9%). C banding analysis revealed that elimination of barley chromosomes was mainly responsible for the occurrence of aneuploid plants. In hypoploids derived from 'Betzes'-crosses, chromosome 5 was preferentially eliminated as previously reported, while in hypoploids derived from OUH602-crosses, chromosome 4 was preferentially eliminated. The wild barley line OUH602 may be a useful parent for producing a new wheat-barley addition set because of its high crossability with wheat and a different pattern of chromosome elimination. PMID- 24170048 TI - Restriction fragment length polymorphism detected by cDNA and genomic DNA clones in Stylosanthes. AB - A DNA isolation method suitable for genomic library construction and RFLP analyses of the forage legume Stylosanthes was developed. Probes isolated using this method were used to investigate the feasibility of constructing RFLP-based genetic maps in this genus. Two hundred and seventy-one PstI genomic DNA and 134 cDNA clones were analysed against four Stylosanthes accessions, including two tetraploids and two diploids, with the use of two restriction enzymes, DraI and HindIII. The proportion of clones which detected single-copy sequences from the PstI genomic library was higher than that from the cDNA library, but the percentage of clones which detected low-copy sequences was doubled in the latter. There was no significant difference in the level of RFLPs detected by gDNA and cDNA probes, although the level of polymorphism was lower in the diploids. A large proportion of RFLPs seemed to have resulted from mutation/base substitution events, and this was especially the case in diploids. PMID- 24170049 TI - Genetic diversity in populations of Cronartium ribicola in plantations and natural stands of Pinus strobus. AB - Genetic diversity was studied in 22 populations of the white pine blister rust fungus Cronartium ribicola from natural stands and plantations of eastern white pine, Pinus strobus. Pseudo-allelic frequencies were estimated at each of 7 putative RAPD loci by scoring for presence or absence of amplified fragments in dikaryotic aecidiospores. Analysis of genetic distance between all pairs of populations did not reveal any trend with regard to geographic origin or type of white pine stand. In addition, when hierarchical population structure was analysed, total genetic diversity (H s =0.214) was mostly attributable to diversity within populations (H s =0.199; AMOVA phi st =0.121, P<0.01). Genetic diversity of populations relative to region of origin (east, centre, and west) or type of stand (natural stands vs plantations) was not significantly different from zero (P>0.10) Nevertheless, a significant proportion of genetic differentiation was found between populations within region or stand type (F st =0.114; phi sc =0.132, P<0.001). This result indicates that some population structure exists but that it appears to be independent of region of origin or type of stand. At least for 2 populations from white pine plantations, it appears possible that a recent introduction of a limited number of propagules was responsible for low levels of genetic diversity. We interpret these results as meaning that either long-distance dispersal is taking place between populations more than 1000 km apart or that these populations share a common recent ancestor. In addition, we suggest that C. ribicola may still be expanding its distribution by colonizing new plantations. PMID- 24170050 TI - Molecular phytogeny of conifers using RFLP analysis of PCR-amplified specific chloroplast genes. AB - We investigated the molecular phylogeny of conifers using restriction endonuclease fragment length polymorphism of six polymerase chain reaction amplified chloroplast genes - frxC, rbcL, psbA, psbD, trnK, and 16S. We detected 227 total site changes among species, representing 23, 26, 38, 48, 67, and 25 site changes in frxC, psbA, psbD, rbcL, trnK and 16S, respectively. The mean nucleotide substitution was 10.75% (SD 0.573) among species in five families. Forty maximally parsimonious trees were obtained using the Wagner parsimony method, and a 50% majority-rule consensus tree was obtained from them. Data analysis produced similar basic patterns when both the Wagner parsimony and the neighbor-joining methods were applied, and the main lineages were clearly separated. Taxaceae and Cephalotaxaceae species were used as the out-groups when applying Wagner parsimony methods. With the Wagner method, the consistency index was 0.510, the retention index was 0.879, and tree length was 435 steps. Our results indicated that Cupressaceae and Taxodiaceae are closely related families and that Sciadopitys verticillata is the basal lineage of Cupressaceae and Taxodiaceae. The neighbor-joining tree is similar to the 50% majority-rule consensus of the 40 Wagner parsimony trees except for the position of Keteleeria daversifolia, the Picea and Cedrus group, and the divergence within Cupressaceae. PMID- 24170051 TI - Mitochondrial DMA variation in plants regenerated from embryogenic callus cultures of CMS triticale. AB - The mitochondrial DNA (mtDNA) organization of primary hexaploid cytoplasmic male sterile (CMS) triticale regenerants containing Triticum timopheevi cytoplasm was analysed by hybridization experiments and compared with the mitochondrial genome organization of the corresponding regenerants with maintainer cytoplasm. Callus cultures had been derived from immature embryos, and 623 triticale plants were regenerated via somatic embryogenesis after three to four subcultures. The chondriome of 159 regenerants was investigated with regard to somaclonal variation. Six different mitochondrial gene probes and four different restriction enzymes were used for Southern blot analyses by the non-radioactive digoxigenin labeling technique. Alloplasmic regenerants showed a gain or loss of hybridization signals up to a high percentage, while euplasmic ones revealed only minor variability with respect to band stoichiometries. In 24 cases rearrangements in the mtDNA were proved. We suppose that recombination processes and selective amplification events are responsible for these findings. PMID- 24170052 TI - Variable expression of the herpes simplex virus thymidine kinase gene in Nicotiana tabacum affects negative selection. AB - The potentials and limitations of negative-selection systems based on the human herpes simplex virus thymidine kinase type-1 (HSVtk) gene, which causes sensitivity to the nucleoside analog ganciclovir, were examined in tobacco as a model system. There were great differences between individual HSVtk(+) transgenic plants in ganciclovir sensitivity. Inhibition of growth while under selection correlated with HSVtk-tianscnpt levels. Negative selection against HSVtk(+) transformants at the level of Agrobacterium-mediated transformation using a ganciclo-vir/kanamycin double-selection medium (the positive selection marker neomycin phosphotransferase-II gene was in the transformation vector) resulted in a three- to six-fold reduction in the frequency of kanamycin-resistant shoots. The efficiency of negative selection in this case was limited due to the great variation in HSVtk expression, i.e., the frequently occurring transformants with low, or no, ganciclovir sensitivity escaping negative selection. Two independently constructed HSVtk genes showed the same variability of the phenotype in Nicotiana tabacum transformants. Distinct phenotypes, ranging from no regeneration through abnormal or delayed regeneration, were observed when leaf segments were placed on shoot-inducing medium supplemented with 10(-6)-10(-3) M ganciclovir. The highest HSVtk mRNA and ganciclovir sensitivity levels were observed in plants which were transformed with the pSLJ882 chimeric construct. The pSLJ882 plant expression vector carried the coding sequence of HSVtk, whereas plasmid pCX305.1 carried an HSVtk construct retaining the untranslated 5 leader and viral 3 regions. The pCX305.1 transformants showed, at most, a delayed formation of shoots with thin stems and very narrow leaves. Ganciclovir sensitivity showed typical Mendelian segregation. A gene-dosage effect was also seen at the seedling level in the progeny of two transgenic lines. PMID- 24170053 TI - A hypervariable middle repetitive DNA sequence from citrus. AB - The use of hypervariable sequences for DNA typing of plants is focussed on microsatellites and on amplification of regions defined by random (RAPD) or defined (AFLP) primers for PCR analysis of genomes. A hypervariable length of middle repetitive DNA has been isolated from citrus that contains no obvious hypervariable structures. The fingerprinting probe was shown to have an important commercial application in the separation of zygotic from nucellar progeny. A somatic variant of the sequence within one orange tree suggests that somatic variation in hypervariable markers may be a common event. PMID- 24170054 TI - Inheritance of chloroplast and mitochondrial genomes in pedunculate oak investigated with an efficient PCR method. AB - The restriction patterns of two chloroplast fragments and one mitochondrial DNA fragment, amplified by PCR with universal primers, were studied to determine the mode of inheritance of these organelles in 143 progeny of five intraspecific crosses in pedunculate oak (Quercus robur L.). The results indicate that both genomes are maternally inherited, an observation which agrees with the commonly observed pattern of inheritance in angiosperms. They confirm that both chloroplast DNA and mitochondrial DNA can be used as a source of seed-specific markers for the study of the geographic structure of oaks. This is the first report of organelle inheritance within the Fagaceae, an important and widespread tree family. PMID- 24170055 TI - Tissue culture-induced DNA methylation polymorphisms in repetitive DNA of tomato calli and regenerated plants. AB - The propagation of plants through tissue culture can induce a variety of genetic and epigenetic changes. Variation in DNA methylation has been proposed as a mechanism that may explain at least a part of these changes. In the present study, the methylation of tomato callus DNA was compared with that of leaf DNA, from control or regenerated plants, at MspI/HpaII sites around five middle repetitive sequences. Although the methylation of the internal cytosine in the recognition sequence CCGG varied from zero to nearly full methylation, depending on the probe used, no differences were found between callus and leaf DNA. For the external cytosine, small differences were revealed between leaf and callus DNA with two probes, but no polymorphisms were detected among DNA samples of calli or DNA samples of leaves of regenerated plants. When callus DNA cut with HindIII was studied with one of the probes, H9D9, most of the signal was found in high molecular-weight DNA, as opposed to control leaf DNA where almost all the signal was in a fragment of 530 bp. Also, an extra fragment of 630 bp was found in the callus DNA that was not present in control leaf DNA. Among leaves of plants regenerated from tissue culture, the 630-bp fragment was found in 10 of 68 regenerated plants. This 630-bp fragment was present among progeny of only 4 of these 10 plants after selfing, i.e. it was partly inherited. In these cases, the fragment was not found in all progeny plants, indicating heterozygosity of the regenerated plants. The data are interpreted as indicating that a HindIII site becomes methylated in callus tissue, and that some of this methylation persists in regenerated plants and is partly transmitted to their progeny. PMID- 24170056 TI - The effect of ph mutations on homoeolgous pairing in hybrids of wheat with Triticum longissimum. AB - Homoeologous pairing at metaphase-I was analyzed in wild-type, ph2b, and ph1b hybrids of wheat and a low-pairing type of T. longissimum in order to study the effect of ph mutations on the pairing of T. longissimum chromosomes with wheat chromosomes. Chromosomes of both species, and their arms, were identified by C banding. The three types of hybrids, with low-, intermediate-, and high-pairing levels, respectively, exhibited a very similar pairing pattern which was characterized by the existence of two types, A-D and B-S(1), of preferential pairing. These results confirm that the S(1) genome of T. longissimum is closely related to the B genome of wheat. The possible use of ph1b and ph2b mutations in the transfer to wheat of genes from related species is discussed. PMID- 24170057 TI - Distribution of novel and known repeated elements of Solanum and application for the identification of somatic hybrids among Solanum species. AB - Species-specific repetitive DNA probes are a useful tool for the molecular identification of somatic hybrids. Therefore, the distribution of three repetitive DNA elements of Solanum was investigated in Solanum wild species, Solanum breeding lines, and in more distantly related species of the genera Lycopersicon, Nicotiana, and Datura. The clone pSCH15, obtained from S. circaeifolium, represents a new 168-bp repetitive element; it shows 73-79% sequence similarity to repetitive elements of S. brevidens and Lycopersicon species. The 163-bp element in pSBH6, cloned from S. bulbocastanum, turned out to be very similar (95% sequence homology) to the Lycopersicon element pLEG15/TGRI previously regarded to be present only in species of the genus Lycopersicon and in S. lycopersicoides. Lower sequence similarity of approximately 80% was observed to repetitive elements of S. brevidens which are organized differently. The repeats exhibited different degrees of specificity: by Southern hybridization the element represented by the clone pSBH6 could be detected in almost all Solanum species investigated here but only after long exposure to X-ray film. The previously described "Solanum-specific" element represented by the clone pSA287 was also found, although in a very low copy number, in Lycopersicon esculentum. Therefore, detection of the repetitive elements pSA287 and pSBH6 in those species in which the respective repeat is less represented depends on exposure time. In contrast, the element pSCH15 is prominently present only in a small number of Solanum wild species and - to some extent - in the diploid breeding lines as revealed after long exposure. Use of these repeated elements for the identification of specific genomes in protoplast-fusion hybrids between Solanum wild species and Solanum breeding lines, or between two breeding lines, was evaluated. PMID- 24170058 TI - Mapping loci controlling vernalization requirement in Brassica rapa. AB - Brassica cultivars are classified as biennial or annual based on their requirement for a period of cold treatment (vernalization) to induce flowering. Genes controlling the vernalization requirement were identified in a Brassica rapa F2 population derived from a cross between an annual and a biennial oilseed cultivar by using an RFLP linkage map and quantitative trait locus (QTL) analysis of flowering time in F3 lines. Two genomic regions were strongly associated with variation for flowering time of unvernalized plants and alleles from the biennial parent in these regions delayed flowering. These QTLs had no significant effect on flowering time after plants were vernalized for 6 weeks, suggesting that they control flowering time through the requirement for vernalization. The two B. rapa linkage groups containing these QTLs had RFLP loci in common with two B. napus linkage groups that were shown previously to contain QTLs for flowering time. An RFLP locus detected by the cold-induced gene COR6.6 cloned from Arabidopsis thaliana mapped very near to one of the B. rapa QTLs for flowering time. PMID- 24170059 TI - A Bayesian approach to the inference of diploid genotypes using haploid genotypes. AB - Morris and Spieth (1978) described a method of calculating unbiased estimates of diploid genotype frequencies given information on the genotypes of haploid cells derived from diploid individuals. They concluded that three haploids per diploid would minimize sampling variance of genotype frequencies, given a fixed total number of haploids examined. If the identity of individual diploid genotypes is needed, Morris and Spieth (1978) stated that more haploids should be collected per diploid. We extend this work by showing from a Bayesian perspective that the probability of misclassification of individuals depends not only on the number of haploids sampled, but also on the genetic structure of the population since misclassification error will increase as the frequency of heterozygotes increases. Since information on the genetic structure (allele frequencies, inbreeding coefficient) of a population is rarely known prior to the initiation of an empirical study, the usefulness of our Bayesian approach is in experimental design, by revealing the magnitude of possible misclassification errors given a particular choice of number of haploids. PMID- 24170060 TI - The transfer of a powdery mildew resistance gene from Hordeum bulbosum L to barley (H. vulgare L.) chromosome 2 (2I). AB - Hordeum bulbosum L. is a source of disease resistance genes that would be worthwhile transferring to barley (H. vulgare L.). To achieve this objective, selfed seed from a tetraploid H. vulgare x H. bulbosum hybrid was irradiated. Subsequently, a powdery mildew-resistant selection of barley phenotype (81882/83) was identified among field-grown progeny. Using molecular analyses, we have established that the H. bulbosum DNA containing the powdery mildew resistance gene had been introgressed into 81882/83 and is located on chromosome 2 (2I). Resistant plants have been backcrossed to barley to remove the adverse effects of a linked factor conditioning triploid seed formation, but there remains an association between powdery mildew resistance and non-pathogenic necrotic leaf blotching. The dominant resistance gene is allelic to a gene transferred from H. bulbosum by co-workers in Germany, but non-allelic to all other known powdery mildew resistance genes in barley. We propose Mlhb as a gene symbol for this resistance. PMID- 24170061 TI - Transfer of resistance to Xanthomonas campestris pv campestris into Brassica oleracea L. by protoplast fusion. AB - Black rot caused by the bacterium Xanthomonas campestris pv campestris is one of the most serious diseases of Brassica oleracea. Since sources of resistance to the disease within B. oleracea are insufficient and control means are limited, the development of resistant breeding lines is extremely desirable. Certain lines of B. napus contain very high resistance controlled by a dominant gene, but crossing the two species sexually is very difficult. Therefore, somatic hybrids were produced by protoplast fusion between rapid cycling B. oleracea and a B. napus line highly resistant to X. campestris pv campestris. Hybrid identity was confirmed by morphological studies, flow cytometric estimation of nuclear DNA content, and analysis of random amplified polymorphic DNA (RAPD). Inoculations with the pathogen identified four somatic hybrids with high resistance. The resistant hybrid plants were fertile and set seed when selfed or crossed reciprocally to the bridge line '15' (Quazi 1988). Direct crosses to B. oleracea were unsuccessful, but embryo rescue facilitated the production of a first backcross generation. The BC1 plants were resistant to the pathogen. Progeny from the crosses to 'line 15' were all susceptible. Embryo rescue techniques were not obligatory for the development of a second-backcross generation, and several resistant BC2 plants were obtained. PMID- 24170063 TI - Nature of 2n gamete formation and mode of inheritance in interspecific hybrids of diploid Vaccinium darrowi and tetraploid V. corymbosum. AB - RAPD markers were used to determine the level of heterozygosity transmitted via 2n gametes from V. darrowi selection Florida 4B (Fla 4B) to inter-specific hybrids with tetraploid V. corymbosum cv Bluecrop. The tetraploid hybrid US 75 was found to contain about 70% of Fla 4B's heterozygosity, a value attributed to a first-division restitution (FDR) mode of 2n gamete production. Crossovers during 2n gamete formation were evidenced by the absence of 16 dominant alleles of Fla 4B in US 75, and direct tests of segregation in a diploid population involving Fla 4B. RAPD markers that were present in both Fla 4B and US 75 were used to determine the mode of inheritance in a segregating population of US 75xV. corymbosum cv Bluetta. Thirty-one duplex loci were identified which segregated in a 5?1 ratio, indicating that US 75 undergoes tetrasomic inheritance. PMID- 24170062 TI - The cost of herbicide resistance in white-chicory: ecological implications for its commercial release. AB - Applications for the commercial release of herbicide-resistant crops, most of them transgenic, are likely to become more frequent in the coming years. The ecological concerns raised by their large scale use call for risk-assessment studies. One of the major issues in such studies is the relative fitness of the resistant line compared to the susceptible when no herbicide is applied since this will largely determine the long-term fate of the resistance gene outside of the field. Here we report on a comparison of a sulfonylurea-resistant line of white-chicory regenerated from a non-mutagenized cell culture with a supposedly isogenic susceptible biotype. The plants were grown in experimental plots at a range of densities in a replacement series. The reproductive output of the plants decreased with increasing density but no significant difference was found between the two lines for any vegetative or reproductive trait at any density. This suggests that no cost is associated with the mutation causing the resistance and that the resistance gene would not be selected against if it escaped to populations of wild chicories. PMID- 24170064 TI - Who uses multivitamins? A cross-sectional study in the Physicians' Health Study. AB - PURPOSE: The aim of this study was to examine the prevalence of self-reported multivitamin use in the Physicians' Health Study (PHS) cohort and its association with various lifestyle, clinical, and dietary factors to improve our understanding of who tends to use multivitamins. METHODS: Among 18,040 middle aged and older men, information on lifestyle and clinical factors was collected from a baseline enrollment questionnaire, and supplement use and dietary factors were assessed through a food-frequency questionnaire. Four categories of multivitamin use were considered: (1) no supplement use, (2) use of multivitamins only, (3) use of multivitamins with other individual vitamin/mineral supplements, and (4) use of other supplements only. We used logistic regression to calculate multivariate odds ratios and 95% confidence intervals of taking multivitamin supplements for various lifestyle, clinical and dietary factors. RESULTS: Overall, 36% of men reported current multivitamin use. Men who were older, current smokers, and currently using aspirin were 143, 43, and 74% more likely to use multivitamins only. Men having a history of hypercholesterolemia were 16% more likely to use multivitamins only. A 14, 24, and 26% greater likelihood of using multivitamins was also observed among men consuming more fruits and vegetables, whole grains, and tea, respectively. Similar associations were observed for the likelihood of using multivitamins with other supplements; however, men with higher physical activity, history of cancer, hypertension, higher consumption of nuts, and lower consumption of red meat and coffee were also more likely to use multivitamins with other supplements (all P < 0.05). CONCLUSION: Self-reported multivitamin use associated with lifestyle, clinical and dietary factors may be an indicator of healthy behaviors. These results provide important information for the interpretation of the recent findings from the PHS II trial and consideration of results from observational studies of multivitamin use and chronic disease. PMID- 24170066 TI - Pure laparoscopic right hepatectomy by anterior approach with hanging maneuver for large intrahepatic cholangiocarcinoma. AB - BACKGROUND: Pure laparoscopic hemihepatectomy is still a challenging procedure. However, it is a minimally invasive liver surgery that leads to rapid recovery. Intrahepatic cholangiocarcinoma has a poor prognosis, especially when it occurs with lymph node metastasis. We recently had a patient who underwent a pure laparoscopic right hepatectomy and lymph nodes dissection for a large intrahepatic cholangiocarcinoma in the right liver by an anterior approach with hanging maneuver. METHODS: Because the tumor was 77 * 50 mm in diameter, mobilization was performed after the devascularization of the right liver. After the division of the right hepatic artery and the right portal vein, short hepatic veins were sealed and divided with a bipolar vessel sealer from the anterior face of the vena cava, followed by the placement of a tape between the liver and the vena cava for hanging. By means of the hanging maneuver, parenchymal transection was performed with minimal blood loss, and the cut surface of the liver became plane. RESULTS: The operation time was 357 min, and the blood loss was 66 ml. A right hepatectomy and complete lymph node dissection adjacent to the hepatoduodenal ligament were performed successfully with a purely laparoscopic procedure. The postoperative hospital stay was 10 days. The final diagnosis of the intrahepatic cholangiocarcinoma with distant lymph node metastasis in the hepatoduodenal ligament was pT1N1M0 stage IIIb (International Union Against Cancer criteria). CONCLUSIONS: The laparoscopic procedure enabled the patient to have an early discharge and adjuvant chemotherapy of gemcitabine with S1 initiated immediately after discharge. We present a video of the described procedure. PMID- 24170065 TI - Impact of a functionalized olive oil extract on the uterus and the bone in a model of postmenopausal osteoporosis. AB - PURPOSE: The Mediterranean diet rich in fruits, vegetables and olive oil has been related to a lower osteoporosis incidence and accordingly to a reduced fracture risk. These observations might be mediated by the active constituents of extra virgin olive oil, and especially polyphenols. In the context of exploring the features of olive oil active constituents on postmenopausal osteoporosis, an extra virgin olive oil total polyphenolic fraction (TPF) was isolated and its effect on the bone loss attenuation was investigated. METHODS: Female Lewis rats were ovariectomized and fed a diet enriched with a total phenolic extract of extra virgin olive oil in a concentration of 800 mg/kg diet. RESULTS: Oleocanthal, one compound of the polyphenolic fraction, showed a higher relative estrogen receptor binding affinity to the ERalpha compared to the ERbeta. While the TPF only slightly induced the uterine wet weight (490.7 +/- 53.7 vs. 432.7 +/ 23, p = 0.058), TPF regulated estrogen response genes in the uterus (progesterone receptor, antigen identified by monoclonal antibody Ki67, complement C3). Comparing the quantified bone parameters, the oral TPF substitution did not attenuate the ovariectomy-induced bone loss. CONCLUSIONS: The administration of extra virgin olive oil polyphenols regulated uterine estrogen response marker genes in an E2-agonistic manner. The bone loss induced by estrogen ablation was not mitigated by treatment with the polyphenolic extract. PMID- 24170067 TI - Effect of electrical stimulation of the lower esophageal sphincter using endoscopically implanted temporary stimulation leads in patients with reflux disease. AB - BACKGROUND: Electrical stimulation therapy (EST) has been shown to increase lower esophageal sphincter (LES) pressure in animals; however, data on the effect of EST on LES pressure in patients with gastroesophageal reflux disease (GERD) are lacking. OBJECTIVE: The aim of our study was to investigate the effect of EST on LES pressure and esophageal function in patients with GERD. METHODS: Patients with a diagnosis of GERD responsive to proton pump inhibitors (PPIs), increased esophageal acid on 24-h pH monitoring off GERD medications, basal LES pressure >5 mmHg, hernia <2 cm and esophagitis 50) before primary LSG. The LSG was realized for patients with morbid obesity with a mean BMI of 47.1 (range 35.4-77.9). The mean interval time from the primary LSG to ReSG was 34.5 months (range 9-67 months). The indication for ReSG was insufficient weight loss for 19 patients (52.8 %), weight regain for 15 patients (41.7 %), and 2 patients underwent ReSG for invalidating gastroesophageal reflux disease. In 24 cases the Gastrografin swallow results were interpreted as primary dilatation, and in the remaining 12 cases results were interpreted as secondary dilatation. The CT scan volumetry was realized in 21 cases, and it has revealed a mean gastric volume of 387.8 cc (range 275-555 cc). All 36 cases were completed by laparoscopy with no intraoperative incidents. The mean operative time was 43 min (range 29-70 min), and the mean hospital stay was 3.9 days (range 3-16 days). One perigastric hematoma was recorded. The mean BMI decreased to 29.2 (range 20.24-37.5); the mean percentage of excess weight loss was 58.5 % (+/-25.3) (p < 0.0004) for a mean follow-up of 20 months (range 6-56 months). CONCLUSIONS: The ReSG may be a valid option for failure of primary LSG for both primary or secondary dilatation. Long-term results of ReSG are awaited to prove efficiency. Further prospective clinical trials are required to compare the outcomes of ReSG with those of Roux en Y Gastric Bypass or DS for weight loss failure after LSG. PMID- 24170070 TI - N-Heterocyclic carbene-catalyzed reactions of C-C unsaturated bonds. AB - The N-heterocyclic carbene-catalyzed reactions of C-X (X = O, S, N) unsaturated bonds are well established. However, C-C unsaturated bonds are challenging substrates for NHC-catalyzed reactions. In recent years, several reports have demonstrated that NHC-catalyzed reactions of C-C unsaturated bonds are feasible, including the umpolung of Michael acceptors, the Morita-Baylis-Hillman reaction, and the annulation reactions of vinyl sulfones, nitroalkenes, allenoates and alkynes. PMID- 24170069 TI - Transanal endoscopic microsurgery after endoscopic resection of malignant rectal polyps: a useful technique for indication to radical treatment. AB - BACKGROUND: Management of malignant rectal polyps (MRPs) after endoscopic polypectomy (EP) is still debated. It is sometimes difficult to decide whether to simply follow-up (FU) or to treat such a removed lesion. Transanal endoscopic microsurgery (TEM) could have a role both in T staging and in treating MRPs after EP. METHODS: Patients who underwent a full-thickness TEM within 3 months after an EP between January 2008 and October 2012 were retrospectively analyzed. If post TEM histology showed locally advanced rectal cancer, patients underwent a total mesorectal excision (TME) within 4-6 weeks. Patients without malignant disease or pT1sm1 cancers at post-TEM histology were followed up every 3 months for 2 years with clinical examination, flexible rectal endoscopy, and neoplastic markers monitoring. RESULTS: A total of 39 patients were included. Post-EP histology was adenocarcinoma in 27/39 cases (69.2 %) and adenoma in 12/39. Mean operative time was 64.2 min; no 30-day mortality occurred; 30-day morbidity was 2.7 % (rectal bleeding in 1/39 cases). Post-TEM histology showed a T2 cancer in 5/39 patients, four with and one without a previous cancer diagnosis, who were further treated by TME (four RARs and one APR) and are disease free with a mean FU of 24.2 months. Post-TEM histology showed adenoma in 10/39 cases and fibrosis in 24/39. These patients are disease free with a mean FU of 13 months. CONCLUSIONS: A full thickness TEM after EP of MRPs can establish the presence of residual malignant disease and its depth of invasion, precisely defining the indication to TME. In event of benign post-EP histology, TEM must be performed in presence of macroscopic residual disease, in order to obtain an RO resection and finally exclude cancer, while, in absence of macroscopic residual disease, only close FU is required. PMID- 24170071 TI - Assembly of a unique octa-nuclear copper cluster-based metal-organic framework with highly selective CO(2) adsorption over N(2) and CH(4). AB - By using 4-(pyrimidin-5-yl) benzoic acid (4-PmBC) as a ligand, a porous metal organic framework based on unique octa-nuclear copper clusters was constructed, which exhibited highly selective CO2 uptake over N2 and CH4. PMID- 24170073 TI - Morbidity and mortality of haemophilia patients in Germany. Survey results 2011/2012. AB - Since 1982, the multicenter study of the epidemiology of patients with haemophilia is carried out annually with the support of all sizes of haemophilia centers and treatment facilities. The long period of investigation has not only enabled the reporting of up-to-date mortality and morbidity status, but also of retrospective observations. The participating centers have made anonymized data available for patients with Haemophilia A, B and von Willebrand's disease (total counts for treated patients, type and severity of the disease, HIV status and causes of death). For 2011-2012 3331 patients were reported with haemophilia A or B from 32 centers. Although the mortality from HIV/AIDS in haemophilia patients continues to decline, HIV infection remains clinically relevant since an HIV/HCV coinfection can raise the risk of severe liver disease. The data from the multicenter survey were, together with the anonymized data from the Foundation for Humanitarian Aid for Persons Infected with HIV though Blood Products, comparatively descriptively compared and the temporal progression illustrated by a so-called moving average. Expectedly, haemophilia patients were shown to be under-represented by the data from the multicenter survey. Otherwise, the data are consistent. PMID- 24170074 TI - [Personalised medicine]. PMID- 24170075 TI - [Personalised medicine. Aims and challenges]. AB - Personalised medicine will address the clinical and pathophysiologic complexity of many diseases with the aim of developing therapeutic strategies more adapted for selected individuals or patient subgroups in order to improve efficacy and safety of medicinal products. This biomarker-based approach will potentially allow identification of populations at risk for chronic and life-threatening diseases and to design early intervention strategies. Personalised medicine will lead to a substantial move from costly and often inefficient health care to a hopefully more cost effective, more targeted and more preventive approach addressing participative patients with increased health literacy. Thus, it provides the basement for an ultimate paradigm shift of modern medicine, away from a "reactive" medicine to a more "proactive" and personalised health care, so called "P4 medicine". PMID- 24170072 TI - Biomolecule delivery to engineer the cellular microenvironment for regenerative medicine. AB - To realize the potential of regenerative medicine, controlling the delivery of biomolecules in the cellular microenvironment is important as these factors control cell fate. Controlled delivery for tissue engineering and regenerative medicine often requires bioengineered materials and cells capable of spatiotemporal modulation of biomolecule release and presentation. This review discusses biomolecule delivery from the outside of the cell inwards through the delivery of soluble and insoluble biomolecules as well as from the inside of the cell outwards through gene transfer. Ex vivo and in vivo therapeutic strategies are discussed, as well as combination delivery of biomolecules, scaffolds, and cells. Various applications in regenerative medicine are highlighted including bone tissue engineering and wound healing. PMID- 24170076 TI - [Ethical and theoretical medical comments on the desire and reality of individualised medicine]. AB - Starting from an epistemological position of individualized medicine this article deals with the ethical analysis of this complex topic. The need for evidence based decisions--as opposed to interest-driven decisions--is emphasised. Based on the argument of social justifiability it can be first stated as an intermediate result that genome-based research, which aims to promote individualisation of medicine, does not exclude research that uses other diagnostic markers, and the appropriate ethical standards can be applied. Second, the development of individualised preventive medicine in the field of multifactorial diseases should increasingly study the potential cost savings of genetic risk diagnosis compared to the costs for the actual treatment options. For proper, medically reasonable, ethically justifiable and socially desired implementation of all areas of individualised medicine, clear separation between research and care as well as the simultaneous implementation of ethical, legal, methodological and technical standards is desirable; however these must be continuously developed in order to respond to possible boundary changes that may arise. Finally, the challenge remains to make the efficacy, operationalisation, performance, and affordability of individualised medicine plausible in the context of social justifiability. PMID- 24170077 TI - [Importance of bioinformatics in personalised medicine]. AB - Medicine is experiencing a period of change: Extensive molecular biological data on the patient are increasingly included in diagnosis and treatment. This trend is based on the development of targeted drugs and accompanying diagnostics, which serve the purpose of providing advance evidence that the medication promises therapy success for the patient. According to this concept drugs are often given in combination. The sizes of patient groups for which a given therapy out of many possible alternatives can be expected to be successful are quite limited. The relationship between the molecular data pertaining to a patient and their disease phenotype are complex and cannot be determined manually. Thus, computer-based bioinformatics methods play a central role in interpreting the molecular data and as an instrument for providing recommendations for the practicing physician. Bioinformatics is an essential component in basic research, in the development of new concepts for diagnosis and therapy as well as in clinical practice, in which these concepts are applied to treating patients. This article discusses the role of bioinformatics in both basic research and clinical practice. We present the example of treatment of HIV patients, for which bioinformatics-assisted therapy selection has already entered clinical practice. Such a therapy concept is also predestined for other diseases (e.g., cancer). The article concludes with remarks on the prerequisites for society as a whole for ensuring success of this concept of personalised medicine as a factor of medical progress. PMID- 24170078 TI - [Personalised medicine. Paradigm shift within drug research and therapy]. AB - BACKGROUND: In the middle of the 1980s and 1990s, drug research underwent a significant change. With new knowledge gained from molecular medicine, it became possible to understand the development and course of many diseases in much more detail. As a consequence, truly new therapies were developed on the basis of natural sciences. PARADIGM SHIFT TO PERSONALISED MEDICINE: Progress in medicine is not only based on newly available therapeutic options but also implies the identification of the therapy which suits the patient best. And it is exactly here where medicine as well as drug development are currently undergoing a paradigm shift which can be characterised by the catchword "personalised medicine". TANDEMS OF THERAPEUTIC AND DIAGNOSTIC AGENTS: Personalised medicine encompasses defined tandems of therapeutic and diagnostic agents and leads to a therapy which is based on single patient groups rather than solely on disease diagnoses. In this therapy concept--in addition to the regular examination of the patient--a diagnostic test is performed to assess certain patient characteristics as a basis for the choice of therapy and/or therapy control. Primarily, it is the patient who benefits from personalised medicine by a higher probability of therapeutic success or by an increased tolerance. Thereby, personalised medicine may also increase cost efficiency in the health care sector. OUTLOOK: To introduce more personalised therapies and therefore achieve the best possible patient care as well as increased cost efficiency for the health care system in the future, all players in health care should work closely together to meet the challenges of personalised medicine. PMID- 24170079 TI - [Biomarker analysis from a pathologist's view. Founding the rationale for personalised treatment of lung cancer]. AB - The advent of genomic medicine and sequencing analysis of entire cancer genomes has rapidly improved our understanding of cancer genomics and has defined pathogenetic lesions initiating and driving cancer phenotypes in a causative manner. Moreover rapid development of small molecule inhibitors and highly selective biologicals provided effective tools to intervene with oncogenic signalling resulting from such lesions in the cancer genome. Thereby, the pathologist is now in the position to diagnose causative lesions in the cancer genome as molecular biomarkers directing the selection of patients for effective and highly selective therapies. If oncogenic driver lesions are vigorously validated preclinically and a useful diagnostic test is available, it is possible to provide a proof-of-concept at a very early stage of clinical drug development with the possibility of immediate personal benefit for participants in such phase I/II studies. This approach has significantly changed clinical testing and avoids testing proof for efficacy in large stage III clinical trials at a high failure rate. Therefore, our review summarises recent and paradigmatic progress in lung cancer biomarker diagnostics and defines academic and regulatory requirements for biomarker analysis and selective personalised therapies. PMID- 24170080 TI - [Personalised pharmacogenetics. Evidence-based guidelines and clinical application of pharmacogenetic diagnostics]. AB - The broad clinical application of pharmacogenetic diagnostics for individualised drug treatment is still limited. With the exception of oncological therapies where molecular tumor makers are frequently used to decide upon individual drug therapies, pharmacogenetic testing is not generally offered in clinical laboratory diagnostics, because the costs are not covered by general health insurance and it is not evident what consequences the results of a genotyping test may have for the individual drug treatment. Especially in the context of pharmacokinetics, bioequivalence-based concepts have been developed that allow the individual drug dosage or therapy to be adjusted to genetic polymorphisms in drug metabolism, drug transport that affect drug absorption, metabolism and elimination. Pharmacogenetic aspects are increasingly included in the product information (e.g., on its website the FDA lists more than 60 drug labels that include pharmacogenetic information). However, most pharmacogenetic information on drug labels does not give recommendations for clinical decisions to be made based on individual genotypes. This gap is currently being closed by the development of international consortia aiming to base clinical recommendations on the best available evidence by systematic review of the existing data. The Clinical Pharmacogenetics Implementation Consortium of the Pharmacogenomics Research Network (CPIC) is an international community-driven organisation that is developing peer-reviewed, freely available gene/drug guidelines that are published in full at PharmGKB (http://www.pharmgkb.org). The aim of these guidelines is to give therapeutic recommendations such as dose adjustments or suggestions for the choice of an alternative drug in the case of specific genotypes (phenotypes) that predict slow metabolism or transport of drugs or safety risks or risks of therapeutic failure. These guidelines are not mandatory but serve to facilitate the translation of pharmacogenetic knowledge from bench to bedside. PMID- 24170081 TI - [Personalised medicine in psychiatry and psychotherapy. A review of the current state-of-the-art in the biomarker-based early recognition of psychoses]. AB - The main goal of psychiatric high-risk research--the personalised early recognition and intervention of schizophrenic and affective psychoses--is one of the biggest challenges of current clinical psychiatry due to the immense socioeconomic burden of these disorders. In this regard, this review discusses the prospects and caveats of new clinical, neuropsychological, neurophysiological and imaging-based concepts aimed at optimising the current state-of-the-art of early recognition. Finally, multivariate modelling and machine learning methods are presented as a novel methodological framework facilitating the decoding of early psychosis into different intermediate phenotypes. In the future, these phenotypes could be employed for a more objective risk stratification that operates at the single-subject level. This could allow us to generate clinically applicable prognostic biomarkers for these disorders that would propel the individualised prevention of disease transition, chronification and psychopharmacological treatment resistance of psychotic disorders. PMID- 24170082 TI - [Personalised medicine for the diagnosis and treatment of allergic diseases]. AB - Immunoglobulin E (IgE) mediated allergic diseases are characterised by heterogeneous clinical phenotypes and a large variety of different sensitisation patterns. Apart from genetic predisposition several environmental factors play a role in sensitisation and elicitation of symptoms. Since the majority of clinically relevant allergens are now available as purified recombinant allergens component-resolved in vitro diagnosis allows the sensitization profile of allergic patients to be determined at the molecular level. Such data may allow physicians to draw conclusions on the severity and persistence of a given allergic disease and to predict the outcome of allergen-specific immunotherapy (SIT) However, the potential of this approach needs to be demonstrated in controlled clinical trials. Moreover, in the context of atopic dermatitis, allergic rhinitis, allergic bronchial asthma as well as the atopic march several screening-biomarkers, diagnostic and prognostic biomarkers, biomarkers of severity and predictive biomarkers are presented and discussed in this article. Traditionally a relevant proportion of allergen-specific immunotherapies is performed in a personalised manner using named patient products manufactured on the basis of an individual prescription. Such named patient products are often mixtures containing several allergen extracts from different sources. However, there is no proven evidence for the safety and efficacy of this approach. In Germany the Therapy Allergen Ordinance ("Therapieallergene-Verordnung", TAV) regulates that in the future allergen products for SIT of insect venom allergies, allergies to pollen of early flowering trees and grass pollen and house dust mite allergies cannot be marketed as named patient products, but always require a marketing authorisation. Thus personalised SIT with named patient products is restricted to the treatment of less prevalent allergies, for which the generation of state-of-the-art clinical data is more difficult. Several recombinant allergens are currently evaluated in phase III clinical trials. In contrast to allergen extracts recombinant allergens offer the possibility to treat patients with a precisely adjusted mixture of the disease-eliciting allergen molecules. However, the implementation of this personalised approach to SIT within the given regulatory framework represents a challenge to regulators. PMID- 24170083 TI - [Special considerations for the regulation of biological medicinal products in individualised medicine. More than stratified medicine]. AB - The term individualised medicine, also called personalised medicine, is commonly used as an equivalent to stratified medicine. However, this is erroneous since quite often it is forgotten that especially biological medicinal products have other aspects of individualization that go beyond mere stratification. The principles of stratified medicine have been applied for biological medicinal products for many years. A historical example is diphtheria antitoxin made from horse serum, while current examples are transfusion of red blood cells and the administration of factor VIII in haemophilia A. The stratifying aspects of these medicinal products are given by the following considerations: diphtheria antitoxin is only administered after a diagnosis of diphtheria and not in other forms of tonsillitis, red blood cells should only be transfused once blood group compatibility as been established and factor VIII replacement is only administered in haemophilia A as opposed to other acquired or hereditary disease of the coagulation system. The peculiarities of biological medicinal products, in particular the inherent variability of the drug, are especially important for autologous cellular medicinal products. In addition to the expected variability of the biological source material there is interindividual variability of patients as cell donors, which make definition of specifications and determination of criteria for pharmaceutical quality and potency tests difficult. Therapy with modified autologous cells, a common and important application of advanced therapy medicinal products, is exemplary for the special considerations that must be made when evaluating pharmaceutical quality, mode of action and toxicological properties of the biological medicine. The clinical investigation of advanced therapy medicinal products with the intent of demonstrating safety and efficacy is particularly challenging because of the complexity of therapy, which often involves invasive interventions. The development of biomarkers accelerates the process towards stratified or individualised therapies. Increased requirements for companion diagnostics are a possible consequence. Progress in analytical processes and in biotechnology make a higher degree of individualization likely, possibly to the degree that medicinal products will be individually manufactured for each patient. Current principles of medicinal product testing and market authorization may be applicable only with limitations, because the individual medicinal products are not uniform and are not repeatedly manufactured. The assessment of the process, performed on several different medicinal products manufactured by the same process could potentially serve as a basis for the assessment. For the evaluation of risk for the patient in clinical trials new concepts must be considered, which can be facilitated by interaction of regulatory authorities and developers. PMID- 24170084 TI - [Improvement of medication safety by identification of genetically predisposed subjects. Personalized clinical strategies and regulatory advices]. AB - BACKGROUND: Because adverse drug events (ADEs) have a high socio-economic impact there is an urgent need for effective prevention. In addition to process-related avoidable errors personalised approaches for the prevention of ADEs should also focus on genetic polymorphisms as potential causative agents. AIM: Using five case reports as examples therapeutic modalities are described to illustrate the clinical impact of prospective testing aimed at estimating the individual risk of susceptible subjects. MATERIAL AND METHODS: The role of the HLA system, the cytochrome P450 family, other metabolic enzymes and transport proteins are described to illustrate the broad range of genetic susceptibility. It is shown, why, when and for whom pretherapeutic tests on genetic polymorphisms are recommended to reduce the risk of ADEs. RESULTS: The determination of genetic susceptibility is already implemented in clinical practice prior to (1) carbamazepine therapy in south-east Asians and (2) treatment with abacavir independent of ethnicity. Before prescribing carbamazepine or abacavir, it is recommended that therapeutic decisions be based on these test results. CONCLUSION: The broad application of personalised medicine used as an effective tool for minimizing ADE risks is limited by the evidence-based benefit for the patient on the one hand and the costs of the test on the other hand. PMID- 24170085 TI - Background paper to the recommendation for the preferential use of live attenuated influenza vaccine in children aged 2-6 years in Germany. AB - The German Standing Committee on Vaccination (STIKO) recommends seasonal influenza vaccination for children and adolescents with chronic medical conditions that put them at risk for severe influenza illness. In addition to trivalent inactivated influenza vaccines (TIV), a trivalent live-attenuated influenza vaccine (LAIV) was licensed for children and adolescents aged 2-17 years in the European Union in 2011. Employing the methodology of the Grading of Recommendations Assessment, Development and Evaluation (GRADE) working group, we examined the evidence for efficacy and safety of LAIV relative to TIV to guide STIKO's decision on whether LAIV should be preferentially recommended for at-risk children. In our meta-analysis of data from two randomized trials directly comparing LAIV and TIV in children aged <= 6 years, the protective efficacy of LAIV against laboratory-confirmed influenza was 53 % [95 % confidence interval (CI): 45-61 %] higher than that of TIV. A similar study in individuals aged 6-17 years showed a 32 % (95 % CI: 3-52 %) higher efficacy of LAIV. The quality of the evidence for a superior protective efficacy of LAIV against all relevant clinical outcomes was rated 'moderate' for children aged 2-6 years and 'low' for the age group 7-17 years. Regarding safety outcomes, the available data suggest no significant differences between LAIV and TIV. Based on these results, STIKO recommends that LAIV should be used preferentially for influenza vaccination of at-risk children aged 2-6 years. In children and adolescents aged 7-17 years, either LAIV or TIV may be used without specific preference. Possible contraindications and the vaccinee's and his/her guardians' preferences should be taken into account. PMID- 24170086 TI - Background paper to the revised recommendation for hepatitis B vaccination of persons at particular risk and for hepatitis B postexposure prophylaxis in Germany. AB - The German Standing Committee on Vaccination (Standige Impfkommission, STIKO) recommends vaccinating risk groups against hepatitis B and gives advice for postexposure prophylaxis. STIKO has recently revised this recommendation, focusing on: (i) classification of risk groups, (ii) duration of protection after primary immunization, and (iii) anti-HBs threshold that defines successful hepatitis B vaccination. Orientating literature reviews were performed for the first objective. Examples of population subgroups at increased risk were identified and classified into three indication groups. Systematic reviews on the duration of vaccine-induced protection identified one randomized controlled trial (RCT) and nine cohort studies. When applying the grading of recommendation, assessment, development, and evaluation (GRADE) methodology, evidence from RCTs was considered of very low quality regarding the question of whether hepatitis B can be prevented for 15 years after successful primary vaccination (anti-HBs >= 10 IU/l) with a vaccine efficacy of 96 % against chronic hepatitis, 89 % against HBsAg positivity, and 73 % against isolated anti-HBc positivity. However, seven cohort studies showed that no cases of clinical hepatitis B or HBsAg positivity occurred during a maximum follow-up period of 10 years in settings comparable to the situation in Germany when anti-HBs >= 10 IU/l was used to indicate vaccination success. Less than 1 % of vaccinated study participants had isolated anti-HBc positivity. GRADE assessment of two cohort studies revealed that evidence of very low quality exists that the use of anti-HBs >= 100 IU/l to measure vaccination success leads to a lower frequency of anti-HBc positivity during follow-up than the use of anti-HBs >= 10 IU/l. The recommendation was revised according to this evidence. PMID- 24170087 TI - Discontinuous properties of current-induced magnetic domain wall depinning. AB - The current-induced motion of magnetic domain walls (DWs) confined to nanostructures is of great interest for fundamental studies as well as for technological applications in spintronic devices. Here, we present magnetic images showing the depinning properties of pulse-current-driven domain walls in well-shaped Permalloy nanowires obtained using photoemission electron microscopy combined with x-ray magnetic circular dichroism. In the vicinity of the threshold current density (Jth = 4.2 * 10(11) A.m(-2)) for the DW motion, discontinuous DW depinning and motion have been observed as a sequence of "Barkhausen jumps". A one-dimensional analytical model with a piecewise parabolic pinning potential has been introduced to reproduce the DW hopping between two nearest neighbour sites, which reveals the dynamical nature of the current-driven DW motion in the depinning regime. PMID- 24170089 TI - Co-expression of monodehydroascorbate reductase and dehydroascorbate reductase from Brassica rapa effectively confers tolerance to freezing-induced oxidative stress. AB - Plants are exposed to various environmental stresses and have therefore developed antioxidant enzymes and molecules to protect their cellular components against toxicity derived from reactive oxygen species (ROS). Ascorbate is a very important antioxidant molecule in plants, and monodehydroascorbate reductase (MDHAR; EC 1.6.5.4) and dehydroascorbate reductase (DHAR; EC 1.8.5.1) are essential to regeneration of ascorbate for maintenance of ROS scavenging ability. The MDHAR and DHAR genes from Brassica rapa were cloned, transgenic plants overexpressing either BrMDHAR and BrDHAR were established, and then, each transgenic plant was hybridized to examine the effects of co-expression of both genes conferring tolerance to freezing. Transgenic plants co-overexpressing BrMDHAR and BrDHAR showed activated expression of relative antioxidant enzymes, and enhanced levels of glutathione and phenolics under freezing condition. Then, these alteration caused by co-expression led to alleviated redox status and lipid peroxidation and consequently conferred improved tolerance against severe freezing stress compared to transgenic plants overexpressing single gene. The results of this study suggested that although each expression of BrMDHAR or BrDHAR was available to according tolerance to freezing, the simultaneous expression of two genes generated synergistic effects conferring improved tolerance more effectively even severe freezing. PMID- 24170090 TI - The effects of adenoviral transfection of the keratinocyte growth factor gene on epidermal stem cells: an in vitro study. AB - Epidermal stem cells (ESCs) are characterized as slowcycling, multi-potent, and self-renewing cells that not only maintain somatic homeostasis but also participate in tissue regeneration and repair. To examine the feasibility of adenoviral vector-mediated keratinocyte growth factor (KGF) gene transfer into in vitro-expanded ESCs, ESCs were isolated from samples of human skin, cultured in vitro, and then transfected with recombinant adenovirus (Ad) carrying the human KGF gene (AdKGF) or green fluorescent protein gene (AdGFP). The effects of KGF gene transfer on cell proliferation, cell cycle arrest, cell surface antigen phenotype, and beta-catenin expression were investigated. Compared to ESCs transfected with AdGFP, AdKGFtransfected ESCs grew well, maintained a high proliferative capacity in keratinocyte serum-free medium, and expressed high levels of beta-catenin. AdKGF infection increased the number of ESCs in the G0/G1 phase and promoted ESCs entry into the G2/M phase, but had no effect on cell surface antigen phenotype (CD49f(+)/CD71(-)). The results suggest that KGF gene transfer can stimulate ESCs to grow and undergo cell division, which can be applied to enhance cutaneous wound healing. PMID- 24170091 TI - Phosphorylation of DYNLT1 at serine 82 regulates microtubule stability and mitochondrial permeabilization in hypoxia. AB - Hypoxia-induced microtubule disruption and mitochondrial permeability transition (mPT) are crucial events leading to fatal cell damage and recent studies showed that microtubules (MTs) are involved in the modulation of mitochondrial function. Dynein light chain Tctex-type 1 (DYNLT1) is thought to be associated with MTs and mitochondria. Previously we demonstrated that DYNLT1 knockdown aggravates hypoxia induced mitochondrial permeabilization, which indicates a role of DYNLT1 in hypoxic cytoprotection. But the underlying regulatory mechanism of DYNLT1 remains illusive. Here we aimed to investigate the phosphorylation alteration of DYNLT1 at serine 82 (S82) in hypoxia (1% O2). We therefore constructed recombinant adenoviruses to generate S82E and S82A mutants, used to transfect H9c2 and HeLa cell lines. Development of hypoxia-induced mPT (MMP examining, Cyt c release and mPT pore opening assay), hypoxic energy metabolism (cellular viability and ATP quantification), and stability of MTs were examined. Our results showed that phosph-S82 (S82-P) expression was increased in early hypoxia; S82E mutation (phosphomimic) aggravated mitochondrial damage, elevated the free tubulin in cytoplasm and decreased the cellular viability; S82A mutation (dephosphomimic) seemed to diminish the hypoxia-induced injury. These data suggest that DYNLT1 phosphorylation at S82 is involved in MTs and mitochondria regulation, and their interaction and cooperation contribute to the cellular hypoxic tolerance. Thus, we provide new insights into a DYNLT1 mechanism in stabilizing MTs and mitochondria, and propose a potential therapeutic target for hypoxia cytoprotective studies. PMID- 24170092 TI - Enzymatic synthesis of apigenin glucosides by glucosyltransferase (YjiC) from Bacillus licheniformis DSM 13. AB - Apigenin, a member of the flavone subclass of flavonoids, has long been considered to have various biological activities. Its glucosides, in particular, have been reported to have higher water solubility, increased chemical stability, and enhanced biological activities. Here, the synthesis of apigenin glucosides by the in vitro glucosylation reaction was successfully performed using a UDP glucosyltransferase YjiC, from Bacillus licheniformis DSM 13. The glucosylation has been confirmed at the phenolic groups of C-4' and C-7 positions ensuing apigenin 4'-O-glucoside, apigenin 7-O-glucoside and apigenin 4',7-O-diglucoside as the products leaving the C-5 position unglucosylated. The position of glucosylation and the chemical structures of glucosides were elucidated by liquid chromatography/mass spectroscopy and nuclear magnetic resonance spectroscopy. The parameters such as pH, UDP glucose concentration and time of incubation were also analyzed during this study. PMID- 24170093 TI - HCV-specific interleukin-21+CD4+ T cells responses associated with viral control through the modulation of HCV-specific CD8+ T cells function in chronic hepatitis C patients. AB - Interleukin-21 (IL-21)+CD4+ T cells are involved in the immune response against hepatitis B virus (HBV) by secreting IL-21. However, the role of IL-21+CD4+ T cells in the immune response against chronic hepatitis C (CHC) virus infection is poorly understood. This study aimed to investigate the role of IL-21+CD4+ T cells in CHC patients and the potential mechanisms. The study subjects included nineteen CHC patients who were grouped by viral load (low, < 10(6) RNA copies/ml, n = 8; high, > 10(6) RNA copies/ml, n = 11). The peripheral frequency of HCV specific IL-21+CD4+ T cells was higher in the low viral load group and was negatively correlated with the serum HCV RNA viral load in all CHC patients. Meanwhile, IL-21+ cells accumulated in the liver in the low viral load group. In vitro, IL-21 treatment increased the expression of proliferation markers and cytolytic molecules on HCV-specific CD8+ T cells. In summary, these findings suggest that HCV-specific IL-21+CD4+ T cells might contribute to HCV control by rescuing HCV-specific CD8+ T cells in CHC patients. PMID- 24170094 TI - Real-time probing of beta-amyloid self-assembly and inhibition using fluorescence self-quenching between neighbouring dyes. AB - The fluorescence response of the Thioflavin-T (ThT) dye and derivatives has become the standard tool for detecting beta-amyloid aggregates (Abeta) in solution. However, it is accepted that ThT-based methods suffer from important drawbacks. Some of these are due to the cationic structure of ThT, which limits its application at slightly acidic conditions; whereas some limitations are related to the general use of an extrinsic-dye sensing strategy and its intrinsic requirement for the formation of a sensor-binding site during the aggregation process. Here, we introduce fluorescence-self-quenching (FSQ) between N terminally tagged peptides as a strategy to overcome some of these limitations. Using a combination of steady-state, picosecond time-resolved fluorescence and transmission electron microscopy, we characterize the fluorescence response of HiLyte fluor 555-labelled Abeta peptides and demonstrate that Abeta self-assembly organizes the covalently attached probes in close proximity to trigger the self quenching sensing process over a broad range of conditions. Importantly, we prove that N-terminal tagging of beta-amyloid peptides does not alter the self-assembly kinetics or the resulting aggregated structures. We also tested the ability of FSQ-based methods to monitor the inhibition of Abeta1-42 aggregation using the small heat-shock protein Hsp20 as a model system. Overall, FSQ-based strategies for amyloid-sensing fill the gap between current morphology-specific protocols using extrinsic dyes, and highly-specialized single-molecule techniques that are difficult to implement in high-throughput analytical determinations. When performed in Forster resonance energy transfer (FRET) format, the method becomes a ratiometric platform to gain insights into amyloid structure and for standardizing in vitro studies of amyloid aggregation. PMID- 24170095 TI - Critical role of spatial interaction between CD8+ and Foxp3+ cells in human gastric cancer: the distance matters. AB - PURPOSE: In various cancer types, an abundance of FoxP3(+) regulatory T cells (Treg) has been associated with an unfavorable outcome. Yet, the role of Treg on cancer immunity has been shown to be complex. In single cell marker technique, other tumor-infiltrating lymphocytes (TILs) such as cytotoxic CD8(+) T cells (CTL) also influenced prognosis. This study for the first time investigates the concurrent spatial distribution pattern of CD8(+) and FoxP3(+) TILs and their prognostic impact in human gastric cancer. MATERIALS AND METHODS: Tumor tissue microarrays of 50 patients with surgically treated adenocarcinoma of the cardia were studied. An immunohistochemical double staining of CD8(+) and FoxP3(+) TILs was performed. Cell counts and cell-to-cell distances in tumor epithelium and stroma were evaluated with image-processing software. Metastasis-free survival, no-evidence-of-disease survival, and overall survival were investigated (mean follow-up time 6.9 years). RESULTS: High intraepithelial infiltration of CD8(+) and FoxP3(+) TIL was associated with the improved 10-year metastasis-free survival (83 vs. 54%, p = 0.04 and 85 vs. 59%, p = 0.09, respectively). Considering cell-to-cell distance and comparing patients with functional (30-110 MUm) versus nonfunctional distances of CD8(+) and FoxP3(+) TILs, 10-year survival rates differed between 89 and 55% (p = 0.009), respectively. CONCLUSION: Prognostic influence of tumor-infiltrating immune cells in gastric cancer critically depends on their cell-to-cell distance. FoxP3(+) TILs must be located within a distance between 30 and 110 MUm of CD8(+) T cells to positively impact on prognosis. PMID- 24170097 TI - Bis(triphenyl-lambda5-phosphanylidene)ammonium fluoride: a reactive fluoride source to access the hypervalent silicates [Me(n)SiF(5-n)]- (n = 0-3). AB - A new synthesis of bis(triphenyl-lambda(5)-phosphanylidene)ammonium fluoride ((Ph3PNPPh3)F, abbreviated as (PNP)F), is described. The title compound has been fully characterized by multinuclear NMR spectroscopy, vibrational spectroscopy, elemental analysis and single crystal and powder X-ray diffraction for the first time. In the solid state (PNP)F exists as a covalent molecular compound, in which the fluoride ion is asymmetrically bonded to the two phosphorus atoms of the [PNP](+) cation. The phosphorus-fluorine bond with 181.98(13) pm is surprisingly long and the longest P-F bond in any phosphorane. (PNP)F can be assumed to be a very good source of reactive fluoride. To investigate the fluoride ion donating properties, (PNP)F was reacted with a range of different fluoromethylsilanes Me(n)SiF(4-n) (n = 0-4). Reactions of (PNP)F with the fluoromethylsilanes were performed in aceto- or propionitrile and in 1,2-dimethoxyethane under inert conditions. The resulting hypervalent fluoromethylsilicates [Me(n)SiF(5-n)](-) (n = 0-3) were fully characterized by multinuclear NMR and vibrational spectroscopy and single crystal X-ray diffraction. From the reaction of (PNP)F with Me4Si in acetonitrile, the starting materials were recovered unchanged. To aid the understanding of the experimental results the fluoride ion affinities (FIA) for these silanes have been calculated by DFT calculations on the PBE0/def2-TZVPP level of theory. The fluoride ion affinity in the series of Me(n)SiF(4-n) (n = 0 4) decreases with the number of methyl groups and is too low for Me4Si to bind a fluoride ion under these reaction conditions. PMID- 24170096 TI - C9orf72 frontotemporal lobar degeneration is characterised by frequent neuronal sense and antisense RNA foci. AB - An expanded GGGGCC repeat in a non-coding region of the C9orf72 gene is a common cause of frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis. Non-coding repeat expansions may cause disease by reducing the expression level of the gene they reside in, by producing toxic aggregates of repeat RNA termed RNA foci, or by producing toxic proteins generated by repeat associated non-ATG translation. We present the first definitive report of C9orf72 repeat sense and antisense RNA foci using a series of C9FTLD cases, and neurodegenerative disease and normal controls. A sensitive and specific fluorescence in situ hybridisation protocol was combined with protein immunostaining to show that both sense and antisense foci were frequent, specific to C9FTLD, and present in neurons of the frontal cortex, hippocampus and cerebellum. High-resolution imaging also allowed accurate analyses of foci number and subcellular localisation. RNA foci were most abundant in the frontal cortex, where 51 % of neurons contained foci. RNA foci also occurred in astrocytes, microglia and oligodendrocytes but to a lesser degree than in neurons. RNA foci were observed in both TDP-43- and p62-inclusion bearing neurons, but not at a greater frequency than expected by chance. RNA foci abundance in the frontal cortex showed a significant inverse correlation with age at onset of disease. These data establish that sense and antisense C9orf72 repeat RNA foci are a consistent and specific feature of C9FTLD, providing new insight into the pathogenesis of C9FTLD. PMID- 24170099 TI - Alemtuzumab-related thyroid dysfunction in a phase 2 trial of patients with relapsing-remitting multiple sclerosis. AB - CONTEXT: Alemtuzumab, an anti-CD52 monoclonal antibody, increased the risk of thyroid dysfunction in CAMMS223, a phase 2 trial in relapsing-remitting multiple sclerosis. OBJECTIVE: The objective of the study was a detailed description of thyroid dysfunction in CAMMS223. DESIGN: Relapsing-remitting multiple sclerosis patients (n=334) were randomized 1:1:1 to 44 MUg sc interferon-beta-1a (SC IFNB 1a, Rebif) or annual courses of 12 or 24 mg iv alemtuzumab. Thyroid function tests (TSH, free T3, free T4) and thyrotropin-binding inhibitory immunoglobulin (TBII) were assessed at screening, month 1, and quarterly thereafter; antithyroid peroxidase antibodies were assessed at screening and every 6 months. Thyroid dysfunction episodes were categorized post hoc by an endocrinologist. RESULTS: During a median follow-up of 57.3 months, 34% of alemtuzumab and 6.5% of SC IFNB 1a patients had thyroid dysfunction (P<.0001). Ten percent of alemtuzumab and 3% of SC IFNB-1a patients had more than one episode of thyroid dysfunction. With alemtuzumab, Graves' hyperthyroidism occurred in 22%, hypothyroidism in 7%, and subacute thyroiditis in 4%. Of patients with overt Graves' hyperthyroidism, 23% spontaneously became euthyroid and an additional 15% spontaneously developed hypothyroidism. Of patients with overt hypothyroidism, 74% were TBII positive. The annual incidence of a first episode of thyroid dysfunction increased each year through year 3 and then decreased each subsequent study year. CONCLUSIONS: Thyroid dysfunction was more common with alemtuzumab than with SC IFNB-1a. There were few serious episodes. Regular monitoring facilitated early detection. Unique features of this population included high prevalence of Graves' hyperthyroidism, multiple episodes of thyroid dysfunction in individual patients, spontaneous hypothyroidism after overt Graves' hyperthyroidism, and a high prevalence of TBII positive overt hypothyroidism. PMID- 24170100 TI - Hepatobiliary and Pancreatic neoplasms in patients with McCune-Albright syndrome. AB - BACKGROUND: McCune-Albright syndrome (MAS), which includes polycystic fibrous dysplasia, precocious puberty, and cafe au lait spots, is a rare disorder caused by somatic activating mutations of the GNAS gene. GNAS mutations have also been implicated in various sporadic tumors, including hepatobiliary and pancreatic neoplasms. AIM: The aim of this study was to assess the prevalence of hepatobiliary and pancreatic neoplasms in patients with McCune-Albright syndrome. PATIENTS AND METHODS: Nineteen patients diagnosed between 1995 and 2012 with MAS in a tertiary referral center for rare growth disorders were screened with dedicated gadolinium-enhanced magnetic resonance imaging for hepatobiliary and pancreatic neoplasms between June 2011 and December 2012. RESULTS: Six (32%) of the 19 screened patients were found to have hepatic, pancreatic, or biliary lesions, excluding liver hemangiomas, liver cysts, and focal nodular hyperplasia. This includes pancreatic ductal lesions observed in 4 patients, including numerous branch-duct intraductal papillary mucinous neoplasms in 3 patients. Biliary lesions were observed in 1 patient, with a large choledochal cyst also involving the left biliary branch. Finally, multiple inflammatory/telangiectatic hepatic adenomas were observed in 2 patients, including 1 with proven somatic GNAS mutation. CONCLUSION: We describe the first observation of syndromic intraductal papillary mucinous neoplasms and the new association between MAS and pancreatic neoplasms, namely intraductal papillary mucinous neoplasms of the pancreas but also rare hepatobiliary neoplasms including liver adenomas and choledochal cysts. These findings strongly suggest that somatic activating GNAS mutations, possibly through cAMP pathway disorders, are involved in the tumorigenesis of hepatobiliary and pancreatic tissues originating from the foregut endoderm and have led us to use a routine screening by dedicated magnetic resonance imaging including both pancreatobiliary and liver sequences in patients with MAS. PMID- 24170101 TI - Effects of estrogen on bone mRNA levels of sclerostin and other genes relevant to bone metabolism in postmenopausal women. AB - CONTEXT: Studies in postmenopausal women have shown that estrogen reduces circulating sclerostin levels, but effects of estrogen on skeletal sclerostin mRNA levels are unknown. OBJECTIVE: The objective of the study was to evaluate the effects of short-term estrogen treatment on bone mRNA levels of sclerostin and other genes relevant to bone metabolism. DESIGN, SETTING, AND PATIENTS: Needle bone biopsies were obtained from 20 postmenopausal women treated with transdermal estrogen for 3 weeks and 20 untreated controls. Quantitative PCR analyses were used to examine the expression of sclerostin and other genes related to bone metabolism, including 71 additional genes linked to bone density/fracture from genome-wide association studies. RESULTS: Estrogen treatment was associated with lower bone sclerostin mRNA levels (by 48%, P<.05) and with lower (by 54%, P<.01) mRNA levels of the sclerostin-related protein, sclerostin domain-containing protein 1 (SOSTDC1), which is also a Wnt/bone morphogenetic protein inhibitor. Consistent with studies in mice showing that ovariectomy increased nuclear factor-kappaB (NF-kappaB) activation, we found that estrogen treatment was associated with a significant reduction in inflammatory genes as a group (P=.028), with bone mRNA levels of NFKB2 and RELB (both encoding proteins in the NF-kappaB transcription factor complex) being significantly reduced individual genes. Eight of the 71 genome-wide association study-related genes examined were modulated by estrogen (P<.05, false discovery rate<0.10). CONCLUSION: In humans, estrogen-induced decreases in two key inhibitors of Wnt/bone morphogenetic protein signaling, sclerostin and SOSTDC1, along with reductions in NF-kappaB signaling, may be responsible for at least part of the protective effects of estrogen on bone. PMID- 24170102 TI - Residual adrenal function in autoimmune Addison's disease: improvement after tetracosactide (ACTH1-24) treatment. AB - CONTEXT: Despite lifelong steroid hormone replacement, there is excess morbidity and mortality associated with autoimmune Addison's disease. In health, adrenocortical cells undergo continuous self-renewal from a population of subcapsular progenitor cells, under the influence of ACTH, suggesting a therapeutic possibility. OBJECTIVE: We aimed to determine whether tetracosactide (synthetic ACTH1-24) could revive adrenal steroidogenic function in autoimmune Addison's disease. DESIGN, SETTING, AND PATIENTS: Thirteen patients (aged 16-65 y) with established autoimmune Addison's disease for more than 1 year were recruited at the Newcastle University Clinical Research Facility. INTERVENTION: The intervention included a 20-week study of regular sc tetracosactide (ACTH1-24) therapy. MAIN OUTCOME MEASURES: Serum and urine corticosteroids were measured during medication withdrawal at baseline and every 5 weeks during the study. RESULTS: Serum cortisol levels remained less than 100 nmol/L in 11 of 13 participants throughout the study. However, two women achieved peak serum cortisol concentrations greater than 400 nmol/L after 10 and 29 weeks of tetracosactide therapy, respectively, allowing withdrawal of corticosteroid replacement. Concurrently, urine glucocorticoid and mineralocorticoid metabolite excretion increased from subnormal to above the median of healthy controls. One of these responders remains well with improving peak serum cortisol (672 nmol/L) 28 months after stopping all treatments. The other responder showed a gradual reduction in serum cortisol and aldosterone over time, and steroid therapy was recommenced after a 28-week period without glucocorticoid replacement. CONCLUSION: This is the first study to demonstrate that established autoimmune Addison's disease is amenable to a regenerative medicine therapy approach. PMID- 24170103 TI - Deletions of the PRKAR1A locus at 17q24.2-q24.3 in Carney complex: genotype phenotype correlations and implications for genetic testing. AB - BACKGROUND: Carney complex (CNC) is a multiple neoplasia syndrome caused by PRKAR1A-inactivating mutations. One-third of the patients, however, have no detectable PRKAR1A coding sequence defects. Small deletions of the gene were previously reported in few patients, but large deletions of the chromosomal PRKAR1A locus have not been studied systematically in a large cohort of patients with CNC. SETTING: A tertiary care referral center was the setting for analysis of an international cohort of patients with CNC. METHODS: Methods included genome wide array analysis followed by fluorescent in situ hybridization, mRNA, and other studies as well as a retrospective analysis of clinical information and phenotype-genotype correlation. RESULTS: We detected 17q24.2-q24.3 deletions of varying size that included the PRKAR1A gene in 11 CNC patients (of 51 tested). Quantitative PCR showed that these patients had significantly lower PRKAR1A mRNA levels. Phenotype varied but was generally severe and included manifestations that are not commonly associated with CNC, presumably due to haploinsufficiency of other genes in addition to PRKAR1A. CONCLUSIONS: A significant number (21.6%) of patients with CNC that are negative in currently available testing may have PRKAR1A haploinsufficiency due to genomic defects that are not detected by Sanger sequencing. Array-based studies are necessary for diagnostic confirmation of these defects and should be done in patients with unusual and severe phenotypes who are PRKAR1A mutation-negative. PMID- 24170104 TI - Resveratrol and desferoxamine protect human OxLDL-treated granulosa cell subtypes from degeneration. AB - CONTEXT: Obese women suffer from anovulation and infertility, which are driven by oxidative stress caused by increased levels of lipid peroxides and circulating oxidized low-density lipoprotein (oxLDL). OxLDL binds to lectin-like oxLDL receptor 1 (LOX-1), cluster of differentiation 36 (CD36), and toll-like receptor 4 (TLR4) and causes cell death in human granulosa cells (GCs). OBJECTIVE: Our objective was to reveal whether treatment with antioxidants resveratrol (RES) and/or desferoxamine (DFO) protect GCs from oxLDL-induced damage. DESIGN AND SETTING: This basic research study was performed at the Institute of Anatomy and the Clinic of Reproductive Medicine. PATIENTS: Patients were women undergoing in vitro fertilization therapy. MAIN OUTCOME MEASURES: GC cultures were treated with oxLDL alone or with RES or DFO under serum-free conditions for up to 36 hours. Dead cells were determined by propidium iodide uptake, cleaved caspase-3 expression, and electron microscopy. Mitosis was detected by Ki-67 immunostaining. LOX-1, TLR4, CD36, and heat-shock protein 60 were examined by Western blot. Measurement of oxidative stress markers (8-iso-prostaglandin F2alpha, advanced glycation end products, and protein carbonyl content) was conducted with ELISA kits. RESULTS: Different subtypes of human GCs exposed to RES or DFO were protected as evidenced by the lack of cell death, enhanced mitosis, induction of protective autophagy, reduction of oxidative stress markers, and reduced expression of LOX-1, TLR4, CD36, and heat-shock protein 60. Importantly, RES could restore steroid biosynthesis in cytokeratin-positive GCs, which exhibited significant induction of steroidogenic acute regulatory protein. CONCLUSIONS: RES and DFO exert a protective effect on human GCs. Thus, RES and DFO may help improve the treatment of obese women or polycystic ovarian syndrome patients undergoing in vitro fertilization therapy. PMID- 24170106 TI - 24-month use of once-weekly GH, LB03002, in prepubertal children with GH deficiency. AB - BACKGROUND: Sustained-release GH formulations may provide a strategy for improving treatment compliance and persistence in GH-deficient patients. OBJECTIVE: The aim of the study was to examine efficacy and safety of LB03002, a sustained-release GH formulation for once-weekly administration. DESIGN: We conducted a phase III, 12-month, multinational, randomized, open-label, comparator-controlled trial with a 12-month uncontrolled extension. PATIENTS: Prepubertal GH treatment-naive GH-deficient children (mean age, 7.8 y) participated in the study. INTERVENTION: We administered once-weekly LB03002 (n=91) or daily GH (n=87) for 1 year, followed by once-weekly LB03002 for all patients for another year (LB03002 throughout, n=87; switched to LB03002, n=80). OUTCOME MEASURES: Height, height velocity (HV), IGF-1, GH antibodies, and adverse events were determined throughout. Primary analysis was noninferiority of LB03002 vs daily GH at 1 year by analysis of covariance. RESULTS: Mean+/-SD HV during year 1 was 11.63+/-2.60 cm/y with LB03002, and 11.97+/-3.09 cm/y with daily GH, with increases from baseline of 8.94+/-2.91 and 9.04+/-3.19 cm/y, respectively. The least square mean HV difference for LB03002 - daily GH was -0.43 cm/y (99% confidence interval, -1.45 to 0.60 cm/y). Mean HV also remained above baseline in year 2 (8.33+/-1.92 cm/y in the LB03002 throughout group, and 7.28+/-2.34 cm/y in the switched to LB03002 group). Injection site reactions occurred more frequently in LB03002-treated patients but were considered mild to moderate in >90% of cases. CONCLUSIONS: Growth response with once-weekly LB03002 in GH-deficient children is comparable to that with daily GH, achieving expected growth rates for 24 months. Once-weekly LB03002 is a strong candidate for long-term GH replacement in GH-deficient children. PMID- 24170105 TI - Insulin resistance indices are inversely associated with vitamin D binding protein concentrations. AB - CONTEXT: We hypothesized that, similar to the coordinated homeostatic regulation of most hormones, the concentration of free and bioavailable 25-hydroxyvitamin D [25(OH)D] will be tightly controlled by total 25(OH)D and vitamin D binding protein (VDBP) and that the VDBP concentrations will be associated with insulin resistance status. OBJECTIVE: Our primary objective was to investigate associations between total, free, and bioavailable 25(OH)D and VDBP. We also evaluated the relationships of VDBP with insulin resistance indices. STUDY DESIGN: The study design was cross-sectional in the setting of a university children's hospital. The relative concentration of bioavailable 25(OH)D to total 25(OH)D [bioavailable 25(OH)D/total 25(OH)D was expressed as a percentage [percentage bioavailable 25(OH)D]. RESULTS: Subjects were 47, postmenarchal, female adolescents, with a mean age of 15.8+/-1.4 years, a mean body mass index of 23.1+/-4.0 kg/m2. The total 25(OH)D was strongly associated with VDBP (rho=0.57, P<.0001). At lower total 25(OH)D concentrations, the concentration of bioavailable 25(OH)D relative to total 25(OH)D was higher (23.8% vs 14.9%, P<.0001), whereas the relative concentration of free 25(OH)D was similar (P=.44). VDBP was inversely associated with fasting insulin (rho=-0.51, P=.0003) and homeostatic model assessment of basal insulin resistance (rho=-0.45, P=.002) and positively with whole-body insulin sensitivity (rho=0.33, P=.02); these relationships persisted after adjusting for percentage fat and attenuated after adjusting for race. CONCLUSION: Our data suggest that VDBP concentrations are regulated by total 25(OH)D levels to maintain adequate concentrations of bioavailable 25(OH)D. VDBP concentrations are inversely associated with hyperinsulinemia and insulin resistance. PMID- 24170107 TI - Laminin-5gamma-2 (LAMC2) is highly expressed in anaplastic thyroid carcinoma and is associated with tumor progression, migration, and invasion by modulating signaling of EGFR. AB - CONTEXT: Anaplastic thyroid carcinoma (ATC) is an aggressive malignancy having no effective treatment. Laminin subunit-gamma-2 (LAMC2) is an epithelial basement membrane protein involved in cell migration and tumor invasion and might represent an ideal target for the development of novel therapeutic approaches for ATC. OBJECTIVE: The objective of the investigation was to study the role of LAMC2 in ATC tumorigenesis. DESIGN: LAMC2 expression was evaluated by RT-PCR, Western blotting, and immunohistochemistry in tumor specimens, adjacent noncancerous tissues, and cell lines. The short hairpin RNA (shRNA) approach was used to investigate the effect of LAMC2 knockdown on the tumorigenesis of ATC. RESULTS: LAMC2 was highly expressed in ATC samples and cell lines compared with normal thyroid tissues. Silencing LAMC2 by shRNA in ATC cells moderately inhibited cell growth in liquid culture and dramatically decreased growth in soft agar and in xenografts growing in immunodeficient mice. Silencing LAMC2 caused cell cycle arrest and significantly suppressed the migration, invasion, and wound healing of ATC cells. Rescue experiments by overexpressing LAMC2 in LAMC2 knockdown cells reversed the inhibitory effects as shown by increased cell proliferation and colony formation. Microarray data demonstrated that LAMC2 shRNA significantly altered the expression of genes associated with migration, invasion, proliferation, and survival. Immunoprecipitation studies showed that LAMC2 bound to epidermal growth factor receptor (EGFR) in the ATC cells. Silencing LAMC2 partially blocked epidermal growth factor-mediated activation of EGFR and its downstream pathway. Interestingly, cetuximab (an EGFR blocking antibody) or EGFR small interfering RNA additively enhanced the antiproliferative activity of the LAMC2 knockdown ATC cells compared with the control cells. CONCLUSIONS: To our knowledge, this is the first report investigating the effect of LAMC2 on cell growth, cell cycle, migration, invasion, and EGFR signaling in ATC cells, suggesting that LAMC2 may be a potential therapeutic target for the treatment of ATC. PMID- 24170108 TI - Dynamic PET imaging reveals heterogeneity of skeletal muscle insulin resistance. AB - PURPOSE: Skeletal muscle insulin resistance (IR) often precedes hyperglycemia and type 2 diabetes. However, variability exists within different skeletal muscle types and can be influenced by 3 primary steps of control: glucose delivery, transport, and phosphorylation. We performed dynamic positron emission tomography imaging studies to determine the extent to which heterogeneity in muscle type and control of insulin action contribute to IR. METHODS: Thirteen volunteers from normal weight to obese underwent dynamic positron emission tomography imaging of [15O]H2O, [11C]3-O-methylglucose, and [18F]fluorodeoxyglucose, measuring delivery, transport, and phosphorylation rates, respectively, in soleus and tibialis anterior muscle during a hyperinsulinemic-euglycemic clamp. Subjects were classified as insulin-sensitive (IS) or insulin-resistant (IR) based on the median systemic glucose infusion rate needed to maintain euglycemia. RESULTS: In soleus, transport kinetic rates were significantly higher (P<.05) in IS (0.126+/ 0.028 min(-1)) vs IR (0.051+/-0.008 min(-1)) subjects. These differences were not as evident in tibialis anterior. These differences were paralleled in overall insulin-stimulated tissue activity, higher in IS (0.017+/-0.001 mL.cm3.min(-1)) vs IR (0.011+/-0.002 mL.cm3.min(-1)) in soleus (P<.05), without significant differences in tibialis anterior. No significant differences were observed for either muscle in delivery or phosphorylation. Both muscle types displayed a control shift from an even distribution among the steps in IS to transport exerting greater control of systemic insulin sensitivity in IR. CONCLUSION: Lower glucose transport rates are the major feature underlying IR preceding type 2 diabetes, although substantial heterogeneity in insulin action across muscle types highlight the complexity of skeletal muscle IR. PMID- 24170110 TI - Theoretical study on the molecular mechanism of the [5 + 2] vs. [4 + 2] cyclization mediated by Lewis acid in the quinone system. AB - The thermal and Lewis acid (LA) catalyzed cyclizations of quinone 1 involved in the synthesis of Colombiasin A and Elipsaterosin B have been theoretically studied using DFT methods at the B3LYP/6-311G(d,p) computational level. B3LYP calculations suggest that the formal endo [4 + 2] cycloadduct allowing the synthesis of Colombiasin A is preferentially formed under thermal conditions, while in the presence of the BF3 LA catalyst the formal [5 + 2] cycloadduct is seen, allowing the synthesis of Elipsaterosin B. The BF3 LA catalyst not only accelerates the nucleophilic attack on the C2 carbon of the quinone framework through a more polar C-C bond formation, but also provokes a different electron density rearrangement along the nucleophilic attack favoring the subsequent C-C bond formation at the C4 carbon with the formation of the formal [5 + 2] cycloadduct. ELF bonding analysis along these cyclizations indicates that the C-C single bond formation takes place in the range of 1.91-2.1 A by C-to-C coupling of two pseudoradical centers. Along the formation of the first C2-C9 single bond, these pseudoradical centers appear at one of the most electrophilic and at one of the most nucleophilic centers of quinone 1, C2 and C9 carbons, respectively. Analysis of the Parr functions suggests that although the most favorable electrophilic/nucleophilic interaction is that involving the C2 carbon of quinone and the C12 carbon of the butadiene framework, the intramolecular nature of the cyclization prevents the corresponding reactive channel. PMID- 24170109 TI - Effects of neurokinin B administration on reproductive hormone secretion in healthy men and women. AB - BACKGROUND: Neurokinin B (NKB) is a member of the tachykinin family of peptides. Inactivating mutations in the tachykinin 3 or tachykinin 3 receptor gene are associated with pubertal failure and congenital hypogonadotrophic hypogonadism in humans. This suggests that NKB may have a critical role in human reproduction. The effects of NKB administration have not been investigated previously in humans. AIM: The aim of this study was to determine the effects of iv administration of NKB on gonadotrophin secretion in healthy male and female volunteers. METHODS: A total of 23 healthy men and 11 healthy women participated in the study. After an initial dose-finding study (study 1), men received a 4 hour infusion of vehicle (gelofusin) followed by a 4-hour infusion of NKB (2.56 or 5.12 nmol/kg/h) (study 2), and an 8-hour infusion of vehicle or NKB during different visits (study 3). Healthy women underwent a dose-finding study consisting of a 3-hour NKB administration during the follicular phase of the menstrual cycle, and the maximum dose of NKB was also tested during the preovulatory and midluteal phases of menstrual cycle (study 4). RESULTS: Mean LH, FSH, and T secretion were not significantly altered during a 90-minute infusion of NKB (0.4-5.12 nmol/kg/h), or a 4-hour infusion of NKB (5.12 nmol/kg/h). No alterations in gonadotrophin secretion or LH pulsatility were observed during an 8-hour infusion of NKB when compared with vehicle. Doses of 0.64-5.12 nmol/kg/h NKB did not significantly alter LH, FSH, or estradiol secretion in healthy women during the follicular phase of the menstrual cycle. Finally, 5.12 nmol/kg/h did not significantly alter reproductive hormone secretion during the preovulatory or midluteal phases of the menstrual cycle. CONCLUSIONS: This is the first clinical study of NKB administration. None of the doses of NKB tested were associated with significant alterations in reproductive hormone secretion in healthy male or female volunteers. These novel data add to our understanding of the physiological actions of NKB in human reproduction. PMID- 24170111 TI - Milky urine in a premature infant: questions. PMID- 24170113 TI - Patients are given new pan-European right to treatment. PMID- 24170112 TI - Tuberculosis infection in primary Sjogren's syndrome: a nationwide population based study. AB - Primary Sjogren's syndrome (pSS) is a systemic autoimmune disease and may complicate with interstitial lung disease. The risk of Mycobacterium tuberculosis (TB) infection in patients with pSS has not been determined. This nationwide population-based study aimed to explore the incidence and risk factors of TB infection in patients with pSS. We identified 4,822 pSS patients from the Taiwan National Health Insurance database and compared the incidence rates of TB infection in these patients with 48,220 randomly selected age-, sex-, and comorbidity-matched subjects without pSS. The Cox proportional hazard model was used to identify risk factors for TB in patients with pSS. The risk of TB was higher in the pSS cohort than in the control cohort with an incidence rate ratio (IRR) of 1.58 (95% confidence interval [95% CI] 1.13-2.18, p = 0.006). The risk factors for TB in the pSS cohort were age >=60 years (hazard ratio [HR] 3.22, 95% CI 1.78-5.84; p < 0.001), and corticosteroid usage, which had a dose-dependent effect in the pSS patients compared to the nonusers (daily prednisolone dose or equivalent less than 5 mg/day: HR 2.34; p = 0.020, 95% CI 1.14-4.78; 5 mg/day to less than 10 mg/day: HR 4.79, 95% CI 2.15-10.68; p < 0.001; 10 mg/day or more: HR 12.19, 95% CI 4.42-33.63; p < 0.001). Patients with pSS had a higher risk of pulmonary TB in Taiwan, which was related to age >=60 years and corticosteroid usage. PMID- 24170114 TI - Evolution of biofunctional semiconductor nanocrystals: a calorimetric investigation. AB - Semiconductor nanomaterials have found numerous applications in optoelectronic device fabrication and in platforms for drug delivery and hyperthermia cancer treatment, and in various other biomedical fields because of their high photochemical stability and size-tunable photoluminescence (PL). However, little attention has been paid to exploring the energetics of formation of these semiconductor nanoparticles. We demonstrate that formation of nanocrystals with biofunctionalization supported by widely used groups, BSA and cysteine, is an exothermic spontaneous process driven by enthalpy. The whole energetics of the reaction shows that formation of smaller particles is favored with lower synthesis temperature. Further, it is shown that the thermodynamics of nanoparticle formation is strongly influenced by the conformation of the protein matrix. We also demonstrate that protein supported formation of nanocrystals is thermodynamically more favorable compared to that involving smaller organic thiol groups. The favorable enthalpy of formation compensates unfavorable entropy, resulting in favorable Gibbs free energy. Thus, this study can open up new avenues for establishing a thermodynamic basis for the design of nanosystems with new and tunable properties. PMID- 24170115 TI - Evaluation of the effect of cagPAI genes of Helicobacter pylori on AGS epithelial cell morphology and IL-8 secretion. AB - Helicobacter pylori cagPAI genes play an important role in pathogenesis, however little is known about their functions in isolates from Turkish patients. We aimed to evaluate the intactness and the effect of the cagPAI genes (cagT, cagM, cagE, cagA) and cagA EPIYA motifs on the AGS morphological changes and IL-8 induction. Of 53 patients 38 were found infected with H. pylori. PCR amplification of the cagPAI genes showed 42.1 % intact, 39.5 % partially deleted and 18.4 % with complete deletions. Isolates from gastritis, duodenal and gastric ulcer patients with intact and partially deleted cagPAI genes induced higher IL-8 secretion than those with complete deletions. Isolates from gastritis patients had higher deletion frequencies of the cagT and cagM genes than the other two genes. Infection of AGS cells with isolates that possess intact cagPAI and EPIYA-ABC resulted in the formation of the hummingbird phenotype. The cagA positive isolates induced higher IL-8 secretion than cagA negative isolates. Isolates from DU patients with more than one EPIYA-C motif induced higher concentrations of IL 8 than those with EPIYA-ABC. In conclusion, the intactness of the cagPAI in our isolates from different patients was not conserved. An intact cagPAI was found to play an important role in the pathogenesis of DU but not GU or gastritis. The cagA gene, but not other cagPAI genes, was associated with the induction of IL-8 and the morphological changes of the AGS cells. An increase in the number of EPIYA-C motifs had noticeable effect on the formation of the hummingbird phenotype. PMID- 24170116 TI - [Radiotherapy-associated morbidity and mortality in rectal surgery]. AB - The treatment of rectal cancer has evolved significantly in recent decades. Both modern radiotherapy treatment concepts and surgical techniques have been able to improve oncological as well as functional outcomes for rectal cancer patients. Large-scale, multicenter, randomized trials have been able to demonstrate the benefits of neoadjuvant treatment over adjuvant radiotherapy. In addition, local tumor control is improved by neoadjuvant irradiation. Conversely, patients receiving a total mesorectal excision showed no survival advantage following irradiation vs. only surgically resected patients. In addition, radiation therapy is associated with a certain morbidity and mortality. This paper summarizes the available evidence regarding postoperative morbidity, mortality, and long-term chronic effects of neoadjuvant radiotherapy. PMID- 24170117 TI - [Refractory inflammatory bowel disease: surgical challenges]. AB - Surgery for inflammatory bowel disease under immunosuppressant drugs is a widely discussed topic. Because therapeutic concepts have significantly changed, almost no patient is currently without an immunosuppressant or biologic agent prior to surgery. However, the data whether biological agents and immunosuppressant are a risk factor are very inconsistent. Concerning Crohn's disease, monotherapy with immunosuppressants or biological agents seems to have no negative influence on the postoperative results. In contrast, however, for ulcerative colitis more publications recognise biologic agents and immunosuppressants as a single therapy as a risk factor for infections. To reduce the general risk, all risk factors have to be reduced. In Crohn's disease, nutritional status must be optimised, corticoids should be reduced, biological agents and immunosuppressant drugs should be stopped, protection of an eventual anastomosis by a stoma. For ulcerative colitis in high-risk patients, a three-stage restaurative proctocolectomy is favoured to a one- or two-staged proctocolectomy. PMID- 24170118 TI - Cylindrospermopsin accumulation and release by the benthic cyanobacterium Oscillatoria sp. PCC 6506 under different light conditions and growth phases. AB - We have studied the dynamics of cylindrospermopsin concentration (CYN) of a benthic cyanobacterium of the genus Oscillatoria under various light conditions over the different growth phases. The present study is the first one reporting on the effect of abiotic factors on the CYN accumulation and release by a benthic species. In particular we have measured the concentrations of both intracellular and extracellular CYN. We found that the total CYN content is highest during the exponential growth phase at intermediate light level (10 MUE m(-2) s(-1)) and during the stationary growth phase at more extreme lower and higher light levels. Our results also indicate that the amount of the extracellular form varied between 56 % and 96 % of the total CYN concentrations. We found no relationship between CYN content and growth rates. These results suggest many similarities with planktonic species but also highlight some differences. PMID- 24170120 TI - Comparison of two scleral incision techniques in 23-gauge transconjunctival vitrectomy. AB - BACKGROUND AND OBJECTIVE: To compare two 23-gauge transconjunctival vitrectomy incision techniques, parallel and perpendicular to the alignment of scleral fibers, in terms of hypotony and postoperative intraocular pressure (IOP). PATIENTS AND METHODS: Fifty-three eyes of 53 patients who underwent 23-gauge one step trocar pars plana vitrectomy were randomly assigned to undergo scleral incision parallel (group 1, 26 eyes) or perpendicular (group 2, 27 eyes) to the limbus. Patients were observed postoperatively for wound healing, leakage, endophthalmitis, IOP, and hypotony at 1 day, 1 week, and 1, 3, 6, and 9 months. RESULTS: No difference in preoperative IOP was observed (P = .229). Postoperative IOP was significantly lower in group 2 (P = .009). Hypotony rates did not differ between the groups. Intraocular gas or silicone tamponade was used intraoperatively in 26 cases. In cases in which no gas or silicone was given (n = 27), IOP measurements were significantly lower in group 2 (P = .021). There was no difference in hypotony ratios for gas/silicone injection versus no injection (P = 1.00) or in postoperative visual acuity (P = .350). Visual acuity improved significantly in both groups at follow-up examinations. CONCLUSION: Parallel and perpendicular incisions resulted in similar postoperative hypotony rates, but perpendicular incisions were associated with lower IOP. PMID- 24170119 TI - A simple assay for measuring catalase activity: a visual approach. AB - In this study, an assay that combines the ease and simplicity of the qualitative approach for measuring catalase activity was developed. The assay reagents comprised only hydrogen peroxide and Triton X-100. The enzyme-generated oxygen bubbles trapped by Triton X-100 were visualized as foam, whose height was estimated. A calibration plot using the defined unit of catalase activity yielded the best linear fit over a range of 20-300 units (U) (y = 0.3794x - 2.0909, r(2) = 0.993). The assay precision and reproducibility at 100 U were 4.6% and 4.8%, respectively. The applicability of the assay for measuring the catalase activity of various samples was assessed using laboratory strains of Escherichia coli, catalase-deficient isogenic mutants, clinically isolated Shiga toxin-producing E. coli, and human cells. The assay generated reproducible results. In conclusion, this new assay can be used to measure the catalase activity of bacterial isolates and human cells. PMID- 24170121 TI - Management of suprachoroidal 5,000-centistoke silicone oil: two contrasting approaches. AB - Two patients experienced unplanned infusion of suprachoroidal 5,000-centistoke silicone oil during vitrectomy surgery. In one patient the oil was surgically removed using an internal incision in the pars plana choroid after external aspiration failed. The oil was expressed from the suprachoroidal space through this opening into the vitreous cavity. Perfluorocarbon liquid was injected over the posterior pole to displace residual suprachoroidal oil into the vitreous cavity, and the oil was then removed via the existing sclerotomy. In the second patient, the oil was observed, and the patient had a stable visual and anatomic outcome at 1-year follow-up. PMID- 24170122 TI - Ultra-performance liquid chromatographic determination of tocopherols and retinol in human plasma. AB - A rapid, selective and sensitive ultra-performance liquid chromatography method has been developed for the detection and quantification of tocopherols and retinol in human plasma. Alpha-tocopherol, gamma-tocopherol and retinol are assayed using fluorescence detection. Excitation/emission wavelengths are 295/330 nm and 325/470 nm for the analysis of both tocopherols and retinol, respectively. Retinol acetate is employed as the internal standard. The reversed-phase method incorporates gradient elution with a mobile phase consisting of methanol and acetonitrile. Separation of vitamin compounds is achieved using a bridged ethyl hybrid C18 column. The retention times for retinol, retinol acetate, gamma tocopherol and alpha-tocopherol are 1.6, 1.8, 3.9 and 4.3 min, respectively. The limits of quantification for retinol, gamma-tocopherol and alpha-tocopherol were 0.02, 0.02 and 0.1 ug/mL, respectively. The assay method is suitable for the analysis of tocopherols and retinol in human plasma. The method may be applied following the ingestion of foods fortified with these fat-soluble vitamins. PMID- 24170123 TI - A validated chiral LC method for enantiomeric separation of nebivolol stereoisomers in bulk drugs and dosage forms on amylose-based stationary phase. AB - A novel and reproducible isocratic normal phase liquid chromatographic method was developed for the quantitative determination of 10 stereoisomers of Nebivolol in pharmaceutical bulk drugs and dosage forms. The method was developed using an amylose-based chiral stationary phase, Chiralpak AD-3 (250 * 4.6 mm, 3 MUm) column with mobile phase containing n-hexane-ethanol-isopropanol-diethanolamine in the ratio 42:45:13:0.1 (v/v/v/v). The eluted compounds were monitored at 280 nm. Ten stereoisomers of Nebivolol were well separated with resolution >2.0 for all pair of components. The developed method was validated as per International Conference on Harmonization (ICH) guidelines with respect to specificity, linearity (R(2) value >0.999), limit of detection, limit of quantification, accuracy (recovery range 95.8-103.2%), precision (relative standard deviation, RSD, <2.5%) and robustness. Nebivolol sample solutions were found to be stable when characterized over a period of 48 h. Forced degradation studies were also performed to demonstrate the stability-indicating power of the developed HPLC method. The method was found to be rugged and robust. PMID- 24170124 TI - Extraction of three bioactive diterpenoids from Andrographis paniculata: effect of the extraction techniques on extract composition and quantification of three andrographolides using high-performance liquid chromatography. AB - Andrographis paniculata (Burm.f.) wall.ex Nees (Acanthaceae) or Kalmegh is an important medicinal plant finding uses in many Ayurvedic formulations. Diterpenoid compounds andrographolides (APs) are the main bioactive phytochemicals present in leaves and herbage of A. paniculata. The efficiency of supercritical fluid extraction (SFE) using carbon dioxide was compared with the solid-liquid extraction techniques such as solvent extraction, ultrasound assisted solvent extraction and microwave-assisted solvent extraction with methanol, water and methanol-water as solvents. Also a rapid and validated reverse-phase high-performance liquid chromatography-diode array detection method was developed for the simultaneous determination of the three biologically active compounds, AP, neoandrographolide and andrograpanin, in the extracts of A. paniculata. Under the best SFE conditions tested for diterpenoids, which involved extraction at 60 degrees C and 100 bar, the extractive efficiencies were 132 and 22 ug/g for AP and neoandrographolide, respectively. The modifier percentage significantly affected the extraction efficiency. PMID- 24170126 TI - YEATS4 is a novel oncogene amplified in non-small cell lung cancer that regulates the p53 pathway. AB - Genetic analyses of lung cancer have helped found new treatments in this disease. We conducted an integrative analysis of gene expression and copy number in 261 non-small cell lung cancers (NSCLC) relative to matched normal tissues to define novel candidate oncogenes, identifying 12q13-15 and more specifically the YEATS4 gene as amplified and overexpressed in ~20% of the NSCLC cases examined. Overexpression of YEATS4 abrogated senescence in human bronchial epithelial cells. Conversely, RNAi-mediated attenuation of YEATS4 in human lung cancer cells reduced their proliferation and tumor growth, impairing colony formation and inducing cellular senescence. These effects were associated with increased levels of p21WAF1 and p53 and cleavage of PARP, implicating YEATS4 as a negative regulator of the p21-p53 pathway. We also found that YEATS4 expression affected cellular responses to cisplastin, with increased levels associated with resistance and decreased levels with sensitivity. Taken together, our findings reveal YEATS4 as a candidate oncogene amplified in NSCLC, and a novel mechanism contributing to NSCLC pathogenesis. PMID- 24170127 TI - Genome-wide binding analysis of the transcription activator ideal plant architecture1 reveals a complex network regulating rice plant architecture. AB - Ideal plant architecture1 (IPA1) is critical in regulating rice (Oryza sativa) plant architecture and substantially enhances grain yield. To elucidate its molecular basis, we first confirmed IPA1 as a functional transcription activator and then identified 1067 and 2185 genes associated with IPA1 binding sites in shoot apices and young panicles, respectively, through chromatin immunoprecipitation sequencing assays. The Squamosa promoter binding protein-box direct binding core motif GTAC was highly enriched in IPA1 binding peaks; interestingly, a previously uncharacterized indirect binding motif TGGGCC/T was found to be significantly enriched through the interaction of IPA1 with proliferating cell nuclear antigen promoter binding factor1 or promoter binding factor2. Genome-wide expression profiling by RNA sequencing revealed IPA1 roles in diverse pathways. Moreover, our results demonstrated that IPA1 could directly bind to the promoter of rice teosinte branched1, a negative regulator of tiller bud outgrowth, to suppress rice tillering, and directly and positively regulate dense and erect panicle1, an important gene regulating panicle architecture, to influence plant height and panicle length. The elucidation of target genes of IPA1 genome-wide will contribute to understanding the molecular mechanisms underlying plant architecture and to facilitating the breeding of elite varieties with ideal plant architecture. PMID- 24170128 TI - Essential role of the E3 ubiquitin ligase nopperabo1 in schizogenous intercellular space formation in the liverwort Marchantia polymorpha. AB - The vast majority of land plants develop gas-exchange tissues with intercellular spaces (ICSs) connected directly to the air. Although the developmental processes of ICS have been described in detail at the morphological and ultrastructural level in diverse land plants, little is known about the molecular mechanism responsible for ICS formation. The liverwort Marchantia polymorpha develops a multilayered tissue with a large ICS (air chamber), whose formation is initiated at selected positions of epidermal cells. We isolated a mutant of M. polymorpha showing impaired air-chamber formation, nopperabo1 (nop1), from T-DNA-tagged lines. In nop1 plants, no ICS was formed; consequently, a single-layered epidermis developed on the dorsal side of the thallus. The causal gene NOP1 encodes a Plant U-box (PUB) E3 ubiquitin ligase carrying tandem ARMADILLO (ARM) repeats in the C terminus. An in vitro ubiquitination assay indicated that the NOP1 protein possesses E3 ubiquitin ligase activity in a U-box-dependent manner. Confocal microscopy and biochemical analysis showed that NOP1 was localized to the plasma membrane. Our investigation demonstrated the essential role of the PUB ARM-type ubiquitin ligase in ICS formation in M. polymorpha, which sheds light on the molecular mechanism of schizogenous ICS formation in land plants. PMID- 24170129 TI - Copy number variation in transcriptionally active regions of sexual and apomictic Boechera demonstrates independently derived apomictic lineages. AB - In asexual (apomictic) plants, the absence of meiosis and sex is expected to lead to mutation accumulation. To compare mutation accumulation in the transcribed genomic regions of sexual and apomictic plants, we performed a double-validated analysis of copy number variation (CNV) on 10 biological replicates each of diploid sexual and diploid apomictic Boechera, using a high-density (>700 K) custom microarray. The Boechera genome demonstrated higher levels of depleted CNV, compared with enriched CNV, irrespective of reproductive mode. Genome-wide patterns of CNV revealed four divergent lineages, three of which contain both sexual and apomictic genotypes. Hence genome-wide CNV reflects at least three independent origins (i.e., expression) of apomixis from different sexual genetic backgrounds. CNV distributions for different families of transposable elements were lineage specific, and the enrichment of LINE/L1 and long term repeat/Copia elements in lineage 3 apomicts is consistent with sex and meiosis being mechanisms for purging genomic parasites. We hypothesize that significant overrepresentation of specific gene ontology classes (e.g., pollen-pistil interaction) in apomicts implies that gene enrichment could be an adaptive mechanism for genome stability in diploid apomicts by providing a polyploid-like system for buffering the effects of deleterious mutations. PMID- 24170130 TI - Establishment of a new methicillin resistant Staphylococcus aureus animal model of osteomyelitis. AB - PURPOSE: The increase in methicillin-resistant Staphylococcus aureus (MRSA) infections is currently a major health care problem. Vancomycin is still often the first-line anti-microbiological agent for treating such infections; however, a recent decline in efficacy of vancomycin in MRSA infections has raised concerns and accelerated the search for new antibiotics. The aim of this study was to establish a MRSA peri-implant osteomyelitis animal model for future testing of new anti-microbiological agents under typical MRSA infection conditions. METHODS: Eighteen randomised NZW-rabbits underwent a standardised surgical procedure with the insertion of a femoral bone implant. Animals were then divided into group 1 (MRSA inoculation, no antibiotics; M/N), group 2 (MRSA inoculation, Vancomyin; M/V), and group 3 (no MRSA inoculation, no antibiotics; N/N). The primary study outcome parameters were animal leucocyte count, animal weight, and animal body temperature at one, seven, and 42 days after surgery. Additionally, a histo morphometrical score was established and adjusted to a modified histological Smeltzer score. RESULTS: Macroscopic and histo-morphometrical findings showed a peri-implant osteomyelitis in group 1 with both increased acute and chronic infection parameters in M/N, as compared to M/V and N/N, indicating that vancomycin treatment prevented typical morphological changes of MRSA peri-implant osteomyelitis. Similarly, there was a reduction in animal weight and increase in leucocyte count and body temperature in group 1 (each p < 0.005). Vancomycin treatment again resulted in significantly reduced leucocyte count and body temperature, and increased animal body weight. CONCLUSIONS: Here we have established a peri-implant MRSA osteomyelitis model that successfully combined clinical and laboratory outcome parameters of infection with histo-morphometrical results; this model appears to be valuable for future experimental use and therapeutic monitoring of new anti-microbiological MRSA drugs. PMID- 24170131 TI - Hip hemiarthroplasty: from Venable and Bohlman to Moore and Thompson. AB - In 1939, Frederick R. Thompson of New York and Austin T. Moore of South Carolina separately developed replacements for the entire ball of the hip. These were used to treat hip fractures and also certain arthritis cases. This type of hemiarthroplasty addressed the problem of the arthritic femoral head only. The diseased acetabulum (hip socket) was not replaced. This prosthesis consisted of a metal stem that was placed into the marrow cavity of the femur, connected in one piece with a metal ball fitted into the hip socket. Bohlman and Austin T. Moore (1939) collaborated for the fabrication and implantation of a custom made 12-inch long vitallium (metal alloy invented by Venable) femoral head prosthesis for a patient with a recurrent giant cell tumour. This prosthesis functioned well and later on influenced the development of long stem femoral head prostheses. PMID- 24170132 TI - Does initial Pirani score and age influence number of Ponseti casts in children? AB - PURPOSE: The prediction of number of casts in the Ponseti method has always remained a subject of interest. We investigated the correlation of the number of casts before tenotomy with the age and initial Pirani score in Ponseti treatment of club foot. METHODS: Inclusion criteria were idiopathic clubfeet corrected by Ponseti method requiring tenotomy for equinus correction in children up to ten years of age. Defaulters (noncompliance with serial casting schedule), children with postural, non idiopathic, previously surgically treated, recurrent clubfoot and clubfoot not requiring tenotomy were not included in this study. Further, children who did not require tenotomy were also excluded. ANOVA regression analysis was used for finding correlation between initial Pirani score, age in months and number of corrective casts prior to tenotomy. RESULTS: There were a total of 297 children (442 feet) in the study. The average age of the child at presentation was 10.3 months and the average initial Pirani score was 4.8. The average number of corrective casts was seven per child (range, two to18). The regression analysis showed both Pirani and age had positive correlation with number of casts, although weak (r2 = 0.05-0.20). The initial Pirani scoring correlated ten times more than age (in months) to the number of casts. CONCLUSION: The number of casts for correction in idiopathic clubfoot, although variable, is influenced by both initial Pirani score and age. PMID- 24170133 TI - An in vivo ovine model of bone tissue alterations in simulated microgravity conditions. AB - Microgravity and its inherent reduction in body-weight associated mechanical loading encountered during spaceflight have been shown to produce deleterious effects on important human physiological processes. Rodent hindlimb unloading is the most widely-used ground-based microgravity model. Unfortunately, results from these studies are difficult to translate to the human condition due to major anatomic and physiologic differences between the two species such as bone microarchitecture and healing rates. The use of translatable ovine models to investigate orthopedic-related conditions has become increasingly popular due to similarities in size and skeletal architecture of the two species. Thus, a new translational model of simulated microgravity was developed using common external fixation techniques to shield the metatarsal bone of the ovine hindlimb during normal daily activity over an 8 week period. Bone mineral density, quantified via dual-energy X-ray absorptiometry, decreased 29.0% (p < 0.001) in the treated metatarsi. Post-sacrifice biomechanical evaluation revealed reduced bending modulus (-25.8%, p < 0.05) and failure load (-27.8%, p < 0.001) following the microgravity treatment. Microcomputed tomography and histology revealed reduced bone volume (-35.9%, p < 0.01), trabecular thickness (-30.9%, p < 0.01), trabecular number (-22.5%, p < 0.05), bone formation rate (-57.7%, p < 0.01), and osteoblast number (-52.5%, p < 0.001), as well as increased osteoclast number (269.1%, p < 0.001) in the treated metatarsi of the microgravity group. No significant alterations occurred for any outcome parameter in the Sham Surgery Group. These data indicate that the external fixation technique utilized in this model was able to effectively unload the metatarsus and induce significant radiographic, biomechanical, and histomorphometric alterations that are known to be induced by spaceflight. Further, these findings demonstrate that the physiologic mechanisms driving bone remodeling in sheep and humans during prolonged periods of unloading (specifically increased osteoclast activity) are more similar than previously utilized models, allowing more comprehensive investigations of microgravity-related bone remodeling as it relates to human spaceflight. PMID- 24170135 TI - Synthesis and characterization of an octanuclear copper(I) methanediide cluster. AB - The reaction of [K{CH((i)Pr2P=S)2(C9H6N-2)}]n (1) with one equivalent of CuCl in THF afforded a rare octanuclear copper(I) methanediide cluster (3). The structure of compound 3 as determined by X-ray crystallography was found to have eight copper atoms that form a Gyrobifastigium (J26). PMID- 24170136 TI - The effects of age, rank and neophobia on social learning in horses. AB - Social learning is said to meet the demands of complex environments in which individuals compete over resources and cooperate to share resources. Horses (Equus caballus) were thought to lack social learning skills because they feed on homogenously distributed resources with few reasons for conflict. However, the horse's social environment is complex, which raises the possibility that its capacity for social transfer of feeding behaviour has been underestimated. We conducted a social learning experiment using 30 socially kept horses of different ages. Five horses, one from each group, were chosen as demonstrators, and the remaining 25 horses were designated observers. Observers from each group were allowed to watch their group demonstrator opening a feeding apparatus. We found that young, low-ranking and more exploratory horses learned by observing older members of their own group, and the older the horse, the more slowly it appeared to learn. Social learning may be an adaptive specialisation to the social environment. Older animals may avoid the potential costs of acquiring complex and potentially disadvantageous feeding behaviours from younger group members. We argue that horses show social learning in the context of their social ecology and that research procedures must take such contexts into account. Misconceptions about the horse's sociality may have hampered earlier studies. PMID- 24170137 TI - MC1R gene variants and sporadic malignant melanoma susceptibility in the Canary Islands population. AB - Several MC1R variants are associated with increased risk of malignant melanoma (MM) in a variety of populations. We aim to examine the influence of the MC1R variants (RHC: D84E, R151C, R160W; NRHC: V60L, R163Q and the synonymous polymorphism T314T) on the MM risk in a population from the Canary Islands. Overall, 1,046 Caucasian individuals were included in the study. A thousand of them were genotyped for MC1R variants: 509 were sporadic MM patients and 491 were healthy control subjects from general population. The analysis was adjusted for age, sex, hair colour, eye colour, skin phototype and ancestry. We found that carriers of the R151C and R163Q variants were at an increased risk for melanoma OR 2.76 (1.59-4.78) and OR 5.62 (2.54-12.42), respectively. The risk of carrying RHC variants was 3.04 (1.90-4.86). Current study confirms the increased MM risk for R151C carriers. It also supports the association between R163Q variant and MM risk in the population on the Canary Islands, as opposed to reported on northern populations. These results highlight the importance of the sample population selection in this kind of studies. PMID- 24170138 TI - Mutational founder effect in recessive dystrophic epidermolysis bullosa families from Southern Tunisia. AB - Dystrophic epidermolysis bullosa (DEB) is a group of heritable bullous skin disorders caused by mutations in the COL7A1 gene. One of the most severe forms of DEB is the severe generalized [recessive dystrophic epidermolysis bullosa (RDEB SG)] subtype, which is inherited in an autosomal recessive manner. This subtype is most often due to COL7A1 mutations resulting in a premature termination codon on both alleles. We report here, the molecular investigation of 15 patients belonging to 14 nuclear families from the city of Sfax in Southern Tunisia, with clinical features of RDEB-SG complicated by squamous cell carcinoma in 3 patients. We identified two novel mutations, p.Val769LeufsX1 and p.Ala2297SerfsX91, in addition to one previously reported mutation (p.Arg2063Trp). The p.Val769LeufsX1 mutation was shared by 11 families and haplotype analysis indicated that it is a founder mutation. The p.Ala2297SerfsX91 mutation was a private mutation found in only one family. Together with the previously described recurrent mutations in Tunisia, screening for the founder p.Val769LeufsX1 mutation should provide a rapid molecular diagnosis tool for mutation screening in RDEB patients from Southern Tunisia and possibly from other Mediterranean populations sharing the same genetic background. PMID- 24170140 TI - Environmental effects on growth phenology of co-occurring Eucalyptus species. AB - Growth is one of the most important phenological cycles in a plant's life. Higher growth rates increase the competitive ability, survival and recruitment and can provide a measure of a plant's adaptive capacity to climate variability and change. This study identified the growth relationship of six Eucalyptus species to variations in temperature, soil moisture availability, photoperiod length and air humidity over 12 months. The six species represent two naturally co-occurring groups of three species each representing warm-dry and the cool-moist sclerophyll forests, respectively. Warm-dry eucalypts were found to be more tolerant of higher temperatures and lower air humidity than the cool-moist eucalypts. Within groups, species-specific responses were detected with Eucalyptus microcarpa having the widest phenological niche of the warm-dry species, exhibiting greater resistance to high temperature and lower air humidity. Temperature dependent photoperiodic responses were exhibited by all the species except Eucalyptus tricarpa and Eucalyptus sieberi, which were able to maintain growth as photoperiod shortened but temperature requirements were fulfilled. Eucalyptus obliqua exhibited a flexible growth rate and tolerance to moisture limitation which enables it to maintain its growth rate as water availability changes. The wider temperature niche exhibited by E. sieberi compared with E. obliqua and Eucalyptus radiata may improve its competitive ability over these species where winters are warm and moisture does not limit growth. With climate change expected to result in warmer and drier conditions in south-east Australia, the findings of this study suggest all cool-moist species will likely suffer negative effects on growth while the warm-dry species may still maintain current growth rates. Our findings highlight that climate driven shifts in growth phenology will likely occur as climate changes and this may facilitate changes in tree communities by altering inter-specific competition. PMID- 24170141 TI - Ensemble and ligand effects on the acetylene adsorption on ordered Pd(x)Ag(1 x)/Pd(100) surface alloys investigated by periodic DFT study. AB - The interactions of acetylene with structurally ordered PdxAg1-x/Pd(100) (x = 1, 0.75, 0.5, 0.25) surface alloys, in which Ag is presented only in the first layer as the computational model system, were investigated by gradient corrected periodic density functional calculations to unravel and understand contributions from electronic strain, electronic ligand and geometric ensemble effects. The calculated adsorption energies indicate that the hollow sites are always found to be more stable than any others and more sensitive to the Ag atoms because of the strong ensemble effect. However, the ligand effect plays a significant role in both the top and bridge adsorption sites. The electrons transferred to the acetylene molecules from the surface increase with increasing concentration of the surface atomic Ag. PMID- 24170143 TI - Outcome of acute respiratory distress syndrome patients treated with extracorporeal membrane oxygenation and brought to a referral center. AB - PURPOSE: Patients with severe acute respiratory distress syndrome (ARDS) are candidates for extracorporeal membrane oxygenation (ECMO) therapy. The evaluation of organ severity is difficult in patients considered for cannulation in a distant hospital. This study was designed to identify early factors associated with hospital mortality in ARDS patients treated with ECMO and retrieved from referring hospitals. METHODS: Data from 85 consecutive ARDS patients equipped with ECMO by our mobile team and consequently admitted to our ICU were prospectively collected and analyzed. RESULTS: The main ARDS etiologies were community-acquired bacterial pneumonia (35%), influenza pneumonia (23%) (with 12 patients having been treated during the first half of the study period), and nosocomial pneumonia (14%). The median (interquartile range) time between contact from the referring hospital and patient cannulation was 3 (1-4) h. ECMO was venovenous in 77 (91%) patients. No complications occurred during transport by our mobile unit. Forty-eight patients died at the hospital (56%). Based on a multivariate logistic regression, a score including age, SOFA score, and a diagnosis of influenza pneumonia was constructed. The probability of hospital mortality following ECMO initiation was 40% in the 0-2 score class (n = 58) and 93% in the 3-4 score class (n = 27). Patients with an influenza pneumonia diagnosis and a SOFA score before ECMO of less than 12 had a mortality rate of 22%. CONCLUSIONS: Age, SOFA score, and a diagnosis of influenza may be used to accurately evaluate the risk of death in ARDS patients considered for retrieval under ECMO from distant hospitals. PMID- 24170144 TI - Nonsustained ventricular tachycardia in a patient with acquired long QT syndrome after levomepromazine injection. PMID- 24170145 TI - Biomarker-guided de-escalation of empirical therapy is associated with lower risk for adverse outcomes. PMID- 24170146 TI - Actively transporting virus like analytes with optofluidics for rapid and ultrasensitive biodetection. AB - Effective analyte delivery is essential to achieve rapid and sensitive biodetection systems. In this article, we present an actively controlled fluidic system integrated with a suspended plasmonic nanohole sensor to achieve superior analyte delivery efficiency and ultrafast sensor response, as compared to conventional fluidic systems. 70 nm sized virus like analyte solution is used to experimentally demonstrate the system performance improvements. Sensor response time is reduced by one order of magnitude as compared to the conventional methods. A seven orders of magnitude dynamic concentration range from 10(3) to 10(9) particles mL(-1) is quantified, corresponding to a concentration window relevant to clinical diagnosis and drug screening. Our non-destructive detection system, by enabling efficient analyte delivery, fast sensing response and minimal sample volume, opens up opportunities for sensitive, rapid and real-time virus detection in infectious disease control and point-of-care applications. PMID- 24170147 TI - Incentives for improving human resource outcomes in health care: overview of reviews. AB - OBJECTIVES: To review the effectiveness of financial and nonfinancial incentives for improving the benefits (recruitment, retention, job satisfaction, absenteeism, turnover, intent to leave) of human resource strategies in health care. METHODS: Overview of 33 reviews published from 2000 to 2012 summarized the effectiveness of incentives for improving human resource outcomes in health care (such as job satisfaction, turnover rates, recruitment, and retention) that met the inclusion criteria and were assessed by at least two research members using the Assessment of Multiple Systematic Reviews quality assessment tool. Of those, 13 reviews met the quality criteria and were included in the overview. Information was extracted on a description of the review, the incentives considered, and their impact on human resource outcomes. The information on the relationship between incentives and outcomes was assessed and synthesized. RESULTS: While financial compensation is the best-recognized approach within an incentives package, there is evidence that health care practitioners respond positively to incentives linked to the quality of the working environments including opportunities for professional development, improved work life balance, interprofessional collaboration, and professional autonomy. There is less evidence that workload factors such as job demand, restructured staffing models, re-engineered work designs, ward practices, employment status, or staff skill mix have an impact on human resource outcomes. CONCLUSIONS: Overall, evidence of effective strategies for improving outcomes is mixed. While financial incentives play a key role in enhancing outcomes, they need to be considered as only one strategy within an incentives package. There is stronger evidence that improving the work place environment and instituting mechanisms for work-life balance need to be part of an overall strategy to improve outcomes for health care practitioners. PMID- 24170148 TI - Development and validation of a patient satisfaction questionnaire for outpatients attending health centres in North Indian cities. AB - OBJECTIVES: With the mandate of the Indian Government to improve health services for the population, improving patients' satisfaction with outpatient department (OPD) services is vital. Many scales developed in Western societies to assess patient satisfaction may not be appropriate to the Indian health care system. The aim of this study was to develop and conduct initial psychometric testing of a satisfaction questionnaire for patients attending OPDs in North India. METHODS: The North India Outpatient Department Satisfaction Scale (NIOPDSS) was initially constructed based on a Delphi consensus among experts. After pretesting on a small number of patients, a cross-sectional survey was conducted among 942 outpatients in Chandigarh, North India. The psychometric properties of the questionnaire in terms of content validity, construct validity, convergent and discriminant validity, and reliability were assessed. RESULTS: Eighty items were generated from the Delphi exercise. After assessing the content validity, data quality and construct validity of the questionnaire, a final instrument with 17 items representing six dimensions of patient satisfaction was developed. The internal consistency ranged from 0.72 to 0.93 and intra-class correlation coefficient ranged from 0.52 to 0.80. CONCLUSION: NIOPDSS appears to be a reliable and valid measure of patient satisfaction for patients attending OPDs in North India. Further research should be carried out with different outpatient populations to assess the wider performance of the questionnaire. PMID- 24170149 TI - Sustainability of improvements in access to outpatient specialist care in the Netherlands. AB - OBJECTIVES: To improve access to specialist outpatient clinics without adding capacity, Dutch hospitals applied the concept of 'Advanced Access'. Our aim was to determine whether initial improvements are sustained for three years and to identify the factors that influence sustainability. METHODS: Qualitative case studies in 14 outpatient specialist clinics. Access measurements at the start, finish and three years after the project were compared. Analysis of sustained and new interventions. Interviews with 52 practitioners, analysed with the constant comparative method to identify general factors that influence sustainability. RESULTS: Eleven out of 14 clinics were able to sustain or improve their reduced delays; two did not and for one it is uncertain. The clinics maintained the majority of the interventions and all introduced new interventions. Three generic factors emerged that influenced their ability to sustain the results: increased responsiveness to better match supply and demand; clinical leadership and incentives; and a shared belief that they can and should control access together. CONCLUSIONS: Reduction of delays in access can be sustained if the way of thinking and the planning system becomes demand driven and flexible and if care providers experience benefits. Unlike previous studies, senior management support and formal training was not relevant though clinical leadership and informal socialization was. Making multidisciplinary teams responsible for improvement appears to be vital. PMID- 24170150 TI - Treatment for stable HIV patients in England: can we increase efficiency and improve patient care? AB - OBJECTIVES: To estimate the costs and potential efficiency gains of changing the frequency of clinic appointments and drug dispensing arrangements for stable HIV patients compared to the costs of hospital pharmacy dispensing and home delivery. METHODS: We estimated the annual costs per patient (HIV clinic visits and either first-line treatment or a common second-line regimen, with some patients switching to a second-line regimen during the year). The cost of three-, four- and six-monthly clinic appointments and drug supply was estimated assuming hospital dispensing (incurring value-added tax) and home delivery. Three-monthly appointments and hospital drug dispensing (baseline) were compared to other strategies. RESULTS: The baseline was the most costly option (L10,587 if first line treatment and no switch to second-line regimen). Moving to six-monthly appointments and home delivery yielded savings of L1883 per patient annually. Assuming patients start on different regimens and may switch to second-line therapies, six-monthly appointments and three-monthly home delivery of drugs is the least expensive option and could result in nearly L2000 savings per patient. This translates to annual cost reduction of about L8 million for the estimated 4000 eligible patients not currently on home delivery in London, England. CONCLUSIONS: Different appointment schedules and drug supply options should be considered for stable HIV patients based on efficiency gains. However, this should be assessed for individual patients to meet their needs, especially around adherence and patient support. PMID- 24170151 TI - Monitoring the practice of vascular surgery: findings from a national registry (1996-2011). AB - BACKGROUND: The goal of this article is to present for the first time to the international community the detailed findings and outcomes of the Spanish Vascular Registry (SVR) after 16 years of experience. METHODS: We examined the nationwide registry promoted by the Spanish Society of Angiology and Vascular Surgery (1996-2011). The changes in vascular surgical activity in Spain during the period of study were examined. We evaluated the number of services, medical specialists, consultations, admissions, and operations that occurred in Spain. We also assessed the trends in therapeutic activity and the medical and social impact of vascular pathology. RESULTS: A mean of 60 centers (range = 32-83) participated in the SVR (79.3 % of the total). In the last year of the study period, 94.3 % centers (100 % of teaching centers) participated. The mean number of activities per hospital per year was 5,298 consultations, 2,625 vascular explorations, 630 hospital admissions (61 % elective and 31 % emergency), and 742 surgical procedures. A total of 29,289 carotid stenosis procedures had been registered over 16 years. Both carotid endarterectomy (CEA) and carotid artery stenting (CAS) procedures have increased in frequency over time. In 2011, CAS constituted 19.3 % of all carotid procedures. A total of 31,703 abdominal aortic aneurysm (AAA) operations were registered during the study period. Surgery for ruptured AAA remained stable over time. Since its appearance in the year 2000, endovascular treatment (EVAR) increased steadily over time. Currently, EVAR represents about half of all AAA surgery (50.2 %). The total rate of in-hospital operative deaths was 1.1 %, but in-hospital mortality for open arterial surgery was 4 %. Mortality has decreased of late. CONCLUSIONS: The SVR has enabled us to understand the development and implementation of vascular surgery throughout Spain and to note the increased healthcare activity and the better overall results obtained as a consequence. PMID- 24170152 TI - Pressurized pulse irrigation with saline reduces surgical-site infections following major hepatobiliary and pancreatic surgery: randomized controlled trial. AB - BACKGROUND: Surgical site infections (SSI) are a significant cause of postoperative morbidity. Pressurized pulse irrigation of subcutaneous tissues may lower infection rates by aiding in the debridement of necrotic tissue and reducing bacterial counts compared to simply pouring saline into the wound. METHODS: A total of 128 patients undergoing laparotomy extending beyond 2 h were randomized to treatment of wounds by pressurized pulse lavage irrigation (<15 psi) with 2 L normal saline (pulse irrigation group), or to standard irrigation with 2 L normal saline poured into the wound, immediately prior to skin closure (standard group). Only elective cases were included, and all cases were performed within a specialized hepatobiliary and pancreatic surgery unit. RESULTS: There were 62 patients managed by standard irrigation and 68 were managed by pulse irrigation. The groups were comparable in most aspects. Overall there were 16 (13 %) SSI. Significantly fewer SSI occurred in the pulse irrigation group [4 (6 %) vs. 12 (19 %); p = 0.032]. On multivariate analysis, the use of pulse irrigation was the only factor associated with a reduction in SSI with an odds ratio (OR) of 0.3 [95 % confidence interval (95 % CI) 0.1-0.8; p = 0.031]. In contrast, hospital length of stay of greater than 14 days was associated with increased infections with an OR of 7.6 (95 % CI 2.4-24.9; p = 0.001). CONCLUSIONS: Pulse irrigation of laparotomy wounds in operations exceeding 2 h duration reduced SSI after major hepatobiliary pancreatic surgery. (Australian New Zealand Clinical Trials Registry, ACTRN12612000170820). PMID- 24170153 TI - A case-matched series of immediate total-body CT scanning versus the standard radiological work-up in trauma patients. AB - BACKGROUND: In recent years computed tomography (CT) has become faster and more available in the acute trauma care setting. The aim of the present study was to compare injured patients who underwent immediate total-body CT (TBCT) scanning with patients who underwent the standard radiological work-up with respect to 30 day mortality. METHODS: Between January 2009 and April 2011, 152 consecutive patients underwent immediate TBCT scanning as part of a prospective pilot study. These patients were case-matched by age, gender, and Injury Severity Score (ISS) category with control patients from a historical cohort (July 2006-November 2007) who had undergone X-rays and focused assessment with sonography for trauma, followed by selective CT scanning. RESULTS: Despite comparable demographics, TBCT patients had a lower median Glasgow Coma Score (GCS) than controls (10 vs. 15; p < 0.001) and on-scene endotracheal intubation was performed more often (33 vs. 19 %; p = 0.004). 30-day mortality was 13 % in the TBCT patient group versus 13 % in the control group (p = 1.000). A generalized linear mixed model analysis showed that a higher in-hospital GCS [odds ratio (OR) 0.8, 95 % confidence interval (CI) 0.745-0.86; p < 0.001] and immediate TBCT scanning (OR 0.46, 95 % CI 0.236-0.895; p = 0.022) were associated with decreased 30-day mortality, while a higher ISS (OR 1.054, 95 % CI 1.028-1.08) p < 0.001) was associated with increased 30-day mortality. CONCLUSIONS: Trauma patients who underwent immediate TBCT scanning had similar absolute 30-day mortality rates compared to patients who underwent conventional imaging and selective CT scanning. However, immediate TBCT scanning was associated with a decreased 30-day mortality after correction for the impact of differences in raw ISS and in-hospital GCS. PMID- 24170154 TI - Teaching the management of surgical emergencies through a short course to surgical residents in East/Central Africa delivers excellent educational outcomes. AB - BACKGROUND: In Africa surgical trainees (residents) are often 'at the coalface' in managing surgical emergencies. A practical course on management of surgical emergencies was developed, as requested and guided by the learning needs of surgical trainees in East/Central Africa, to teach structured thinking processes in surgical emergencies; to thoroughly assess participants' knowledge, technical and non-technical skills; and to correlate assessment scores with participants' feedback on course quality. METHODS: Curriculum design was aimed at learners' needs, as guided by local trainers and previous teaching. A 5-day course was developed on emergencies in critical care and trauma, general surgery, orthopaedics, obstetrics and urology; delivered through lectures, tutorials and practical sessions, with individual mentoring. Participants' knowledge was assessed through end-of-course tests and, with their practical and non-technical skills, evaluated formatively. Opportunity for immediate detailed feedback was provided, and for follow-up 6 months later. RESULTS: All participants completed the course successfully, passed knowledge tests, and received satisfactory scores in continuous assessment. There was good correlation between formative and summative assessment scores. Candidates rated course content, delivery and usefulness very highly; 'open text' noted no such previous training. After six months 90 % of course participants indicated that the course had significantly improved their ability to manage surgical emergencies. CONCLUSIONS: An intensive course on management of surgical emergencies can be effectively delivered by a small core faculty for each specialty. Feedback from participants and local faculty indicated that this course filled a specific learning niche. Effective assessment can be based on continuous evaluation during course participation. PMID- 24170155 TI - Electrochemotherapy treatment of locally advanced and metastatic soft tissue sarcomas: results of a non-comparative phase II study. AB - AIMS: Our aim was to evaluate the activity, toxicity, and feasibility of electrochemotherapy (ECT) in patients with soft-tissue sarcomas (STS). METHODS: A two-stage phase II trial was conducted between October 2006 and March 2012. Patients (N = 34) with locally advanced or metastatic STS, unsuitable for standard oncological treatments and with maximum 3-cm deep tumors, received an intravenous bolus of bleomycin (15,000 IU/m(2)), followed by tumor electroporation according to the European Standard Operating Procedures of ECT. Outcome measures included local response according to response evaluation criteria in solid tumors (RECIST), toxicity and tumor control. Feasibility measures included the accuracy of electrode placement and the intensity of electric current flowing in tumor tissue. RESULTS: Median tumor size was 4.0 cm (range 2-12). Objective response, assessed on 71 target lesions, was 92.2 % (complete 32.3, 95 % CI 28-64). A total of 15 patients received up to four cycles due to incomplete response, but re-treatment did not significantly improve outcome (p = 0.205). After a median follow-up of 19.3 months, 2-year local control rate was 72.5 %. Median time to local failure (N = 11 patients) was 5.1 months. Tumor response (p = 0.041) and control (p = 0.047) correlated with histological grading. Relevant toxicity consisted of G3 skin ulceration and soft tissue necrosis (35 and 23 % of patients, respectively), although this was manageable on an outpatient basis. The accuracy of electrode placement was 47.1 %, and the adequacy of electroporative current 85.3 %. CONCLUSIONS: ECT may represent an active and safe treatment to achieve local control in advanced STS patients with symptomatic disease. Future research challenges include the improvement of electrode placement and voltage delivery together with the containment of soft tissue toxicity. PMID- 24170157 TI - The insular cortex: relationship to skin conductance responses to facial expression of emotion in temporal lobe epilepsy. AB - The insula plays an important role both in emotion processing and in the generation of epileptic seizures. In the current study we examined thickness of insular cortices and bilateral skin conductance responses (SCR) in healthy subjects in addition to a small number of patients with temporal lobe epilepsy. SCR measures arousal and is used to assess non-conscious responses to emotional stimuli. We used two emotion tasks, one explicitly about emotion and the other implicit. The explicit task required judgments about emotions being expressed in photographs of faces, while the implicit one required judgments about the age of the people in the photographs. Patients and healthy differed in labeling neutral faces, but not other emotions. They also differed in their SCR to emotions, though the profile depended on which hand the recordings were from. Finally, we found relationships between the thickness of the insula and SCR to each task: in the healthy group the thickness of the left insula was related to SCR to the emotion-labeling task; in the patient group it was between the thickness of the right insula and SCR in the age-labeling task. These patterns were evident only for the right hand recordings, thus underscoring the importance of bilateral recordings. PMID- 24170156 TI - Management of nocturnal enuresis. PMID- 24170158 TI - Assessment of genetically modified soybean in relation to natural variation in the soybean seed metabolome. AB - Genetically modified (GM) crops currently constitute a significant and growing part of agriculture.An important aspect of GM crop adoption is to demonstrate safety; identifying differences in end points with respect to conventional crops is a part of the safety assessment process [corrected]. Untargeted metabolomics has the ability to profile diverse classes of metabolites and thus could be an adjunct for identification of differences between the GM crop and its conventional counterpart [corrected].To account for environmental effects and introgression of GM traits into diverse genetic backgrounds, we propose that the assessment for GM crop metabolic composition should be understood within the context of the natural variation for the crop. Using a non-targeted metabolomics platform, we profiled 169 metabolites and established their dynamic ranges from the seeds of 49 conventional soybean lines representing the current commercial genetic diversity. We further demonstrated that the metabolome of a GM line had no significant deviation from natural variation within the soybean metabolome, with the exception of changes in the targeted engineered pathway. PMID- 24170159 TI - Impact of high pi-density on the coordination properties of pi-excess aromatic neutral sigma2P ligands--P(pi)-donor bonds to Ag+ and HgCl2. AB - Unprecedented coordination types of non-zerovalent d(10) transition metals (AgX, HgCl2) by pi-excess aromatic P=C ligands involving P(pi)-donor bond contributions were detected by structural and quantum chemical studies. PMID- 24170160 TI - Epithelial to mesenchymal transition (EMT) seems to be regulated differently in endometriosis and the endometrium. AB - PURPOSE: Epithelial-mesenchymal transition (EMT) endows cells with migratory and invasive properties, a prerequisite for the establishment of endometriotic lesions. However, the role EMT might play in the pathophysiology of endometriosis is still unknown. Therefore, we examined five recognized markers for EMT in endometrium and endometriosis: E-cadherin, N-cadherin, Twist, Snail and Slug. METHODS: Immunohistochemistry was used for peritoneal, ovarian and rectovaginal endometriotic lesions (n = 27) and endometrium (n = 13). Reverse transcription polymerase chain reaction was applied to tissue samples and primary cell cultures of endometriotic lesions (n = 9) and endometrium (n = 8). RESULTS: In endometriosis and endometrium E-cadherin, N-cadherin, Twist, Snail and Slug were expressed on protein and mRNA level. E-cadherin expression was strong in epithelial cells, but single E-cadherin-negative cells were frequently present in endometriosis. In endometriosis N-cadherin, Twist and Snail expression were upregulated in comparison with endometrium. The expression of E- and N-cadherin was inversely correlated, while that of N-cadherin and Twist was positively correlated. CONCLUSION: This study strongly suggests that EMT may be regulated differently in endometriosis and the endometrium. Future research should further elucidate the regulation of EMT in the endometrium and endometriosis. PMID- 24170161 TI - The role of lactobacilli and probiotics in maintaining vaginal health. AB - BACKGROUND: The vaginal microbiota of healthy women consists typically of a diversity of anaerobic and aerobic microorganisms. Lactobacilli are the most prevalent and often numerically dominant microorganisms and are relevant as a barrier to infection. The capacity of lactobacilli to adhere and compete for adhesion sites in the vaginal epithelium and the capacity to produce antimicrobial compounds (hydrogen peroxide, lactic acid, bacteriocin-like substances), are important in the impairment of colonization by pathogens. OBJECTIVE: This review summarizes the role of lactic acid bacteria in preventing illness of the host, including bacterial vaginosis, yeast vaginitis, urinary tract infection and sexually transmitted diseases. CONCLUSIONS: The administration of probiotics that colonize the vaginal tract can be important in maintaining a normal urogenital health and also to prevent or treat infections. PMID- 24170162 TI - Robotic surgery in gynecology. AB - Advantages of robotic surgery are the tridimensional and the non-restrictive flexibility because of the seven freedom degrees of the sophisticated instruments. These benefits are particularly present in case of complex oncologic surgeries like, for example, the nerve-sparing total mesometrial resection in cervical cancer and in early stage of endometrial cancer. Patients with extreme obesity and multi-morbid women can profit extremely from this innovative new technique. PMID- 24170163 TI - Preparations of SF(5)- and CF(3)-substituted arenes utilizing the 7 oxabicyclo[2.2.1]hept-2-ene synthones. AB - The synthesis of SF5- and CF3-substituted benzenes and naphthalenes from various 7-oxanorbornene derivatives utilizing SF5Cl and CF3I radical addition reactions, followed by dehydrohalogenation and aromatization, is reported. The differences in the behavior of the SF5- and CF3-containing intermediates under basic and acidic conditions are discussed. The experimentally observed high regioselectivities of the formation of 2-RF-substituted-1-naphthols agree well with the ab initio computations, revealing the first example of the SF5...HO hydrogen bonding. PMID- 24170165 TI - Neurological complications of tick borne encephalitis: the experience of 89 patients studied and literature review. AB - Tick borne encephalitis (TBE) is an acute febrile syndrome that can be complicated with neurological symptoms ranging from mild meningitis to severe encephalomyelitis. The causative agent is a virus belonging to the family of flaviviruses. We have collected a series of 89 patients and compared the clinical course with the main data of the literature of TBE. This review in addition describes the clinical manifestations associated with TBE infections, the main molecular-biological properties of these viruses, and the different factors that define the incidence and severity of disease who are frequently situated in the age group young/adult with a social harm and functional non-negligible. This review also contains diagnostic elements and neuropathological features typical of this infection and a brief summary of vaccination against TBE. PMID- 24170167 TI - The importance of curriculum-based training and assessment in interventional radiology. AB - Physician performance and outcomes are being scrutinised by health care providers to improve patient safety and cost efficiency. Patients are best served by physicians who have undergone appropriate specialist training and assessment and perform large numbers of cases to maintain their skills. The Cardiovascular and Interventional Radiological Society of Europe has put into place a curriculum for training in interventional radiology (IR) and a syllabus with an examination, the European Board of Interventional Radiology, providing evidence of attainment of an appropriate and satisfactory skill set for the safe practice of IR. This curriculum is appropriate for IR where there is a high volume of image-guided procedures in vascular and nonvascular organ systems with cross-use of minimally invasive techniques in patients with a variety of disease processes. Other specialties may require different, longer, and more focused training if their experience is "diluted" by the need to master a different skill set. PMID- 24170166 TI - Epidemiology, antibiotic therapy and outcomes of bacteremia caused by drug resistant ESKAPE pathogens in cancer patients. AB - PURPOSE: Infection due to the six ESKAPE pathogens has recently been identified as a serious emerging problem. However, there is still a lack of information on bacteremia caused by these organisms in cancer patients. We aimed to assess the epidemiology, antibiotic therapy and outcomes of bacteremia due to drug-resistant ESKAPE pathogens (rESKAPE) in patients with cancer. METHODS: All episodes of bacteremia prospectively documented in hospitalized adults with cancer from 2006 to 2011 were analyzed. RESULTS: Of 1,148 episodes of bacteremia, 392 (34 %) were caused by ESKAPE pathogens. Fifty-four episodes (4.7 %) were due to rESKAPE strains (vancomycin-resistant Enterococcus faecium 0, methicillin-resistant Staphylococcus aureus (MRSA) 13, extended-spectrum beta-lactamase (ESLB) producing Klebsiella pneumoniae 7, carbapenem-resistant Acinetobacter baumannii 4, carbapenem- and quinolone-resistant Pseudomonas aeruginosa 18 and derepression chromosomic beta-lactam and ESBL-producing Enterobacter species 12. Risk factors independently associated with rESKAPE bacteremia were comorbidities, prior antibiotic therapy, urinary catheter and urinary tract source. Inappropriate empirical antibiotic therapy was more frequent in patients with rESKAPE bacteremia than in the other cases (55.6 % vs. 21.5 %, p < 0.001). Persistence of bacteremia (25 % vs. 9.7 %), septic metastasis (8 % vs. 4 %) and early case fatality rate (23 % vs. 11 %) were more frequent in patients with rESKAPE bacteremia than in patients with other etiologies (p < 0.05). CONCLUSIONS: Bacteremia due to rESKAPE pathogens in cancer patients occurs mainly among those with comorbidities who have received prior antibiotic therapy and have a urinary tract source. These patients often receive inappropriate empirical antibiotic therapy and have a poor outcome. PMID- 24170168 TI - Foam sclerotherapy for a symptomatic hepatic cyst: a preliminary report. AB - PURPOSE: We evaluated our initial experience of performing sclerotherapy for symptomatic hepatic cysts using polidocanol foam instead of a liquid sclerosant. METHODS: Three consecutively registered patients with symptomatic hepatic cysts (one with polycystic liver disease) underwent polidocanol foam sclerotherapy. A pigtail catheter was inserted into the targeted cyst following percutaneous cyst puncture under ultrasound guidance, and the cyst fluid was aspirated. To confirm the absence of communications between the cyst and surrounding hepatic vessels, 3 % polidocanol foam sclerosant was injected at a 1:4 ratio of polidocanol to air following digital subtraction cystography with carbon dioxide. C-arm computed tomography (CT) guidance also was used to monitor foam filling of the targeted cyst. The maximum dose of sclerosant injected per treatment session did not exceed 10 ml. The catheter was kept unclamped overnight for open drainage, and additional sclerotherapy sessions were performed on subsequent days, if needed. RESULTS: Efficient sclerotherapy was achieved with an average of two sessions. The initial mean cyst volume was 1,052 ml, and gradual resolution was observed without recurrence. The mean reduction rate was 97.9 % (97.7-98.3 %), and all cyst-associated symptoms disappeared. The median follow-up period was 17 (range 6 21) months. Although one patient experienced moderate-grade fever and another moderate pain at the puncture site, no major complications were observed. CONCLUSION: Polidocanol foam sclerotherapy is a safe and effective treatment for symptomatic hepatic cysts. PMID- 24170169 TI - Inferior mesenteric artery embolization before endovascular aortic aneurysm repair using amplatzer vascular plug type 4. AB - PURPOSE: This study was designed to evaluate the efficacy and safety of Amplatzer Vascular Plug type 4 (AVP-4) for embolization of the inferior mesenteric artery (IMA) before endovascular aneurysm repair (EVAR) of the abdominal aorta to prevent endoleaks. METHODS: A single-center retrospective review of 31 patients who underwent IMA embolizations before EVAR using the AVP-4 was performed. We analyzed the insertion and detachment procedure, the technical success, and the final position of the plug. Technical success was defined as complete occlusion of the IMA. To compare the incidence of IMA-related type II endoleaks in patients with and without preoperative IMA embolization, we additionally reviewed the course of 43 patients with a preoperatively patent IMA who underwent no IMA embolization. RESULTS: Plugs with a diameter of 5, 6, and 8 mm were used in 5 (16.1 %), 21 (67.7 %), and 5 (16.1 %) patients, respectively (50-100 % oversizing). In 29 of 31 patients (93.5 %), we observed complete occlusion of the IMA within 10 min (mean 5.1 min). Precise placement of the plug in the proximal segment of the IMA without occlusion of the first IMA branches was achievable in all patients. The distance between the AVP-4 and the first branches was on average 12 (range 2-57) mm. Preoperative IMA embolization with AVP-4 significantly reduced the incidence of complex IMA-lumbar type II endoleaks after EVAR (0/31 vs. 11/43; p = 0.002). CONCLUSIONS: The AVP-4 is a safe, feasible, and technically effective embolization device for IMA embolization before EVAR. PMID- 24170171 TI - Hydration free energies of cyanide and hydroxide ions from molecular dynamics simulations with accurate force fields. AB - The evaluation of hydration free energies is a sensitive test to assess force fields used in atomistic simulations. We showed recently that the vibrational relaxation times, 1D- and 2D-infrared spectroscopies for CN(-) in water can be quantitatively described from molecular dynamics (MD) simulations with multipolar force fields and slightly enlarged van der Waals radii for the C- and N-atoms. To validate such an approach, the present work investigates the solvation free energy of cyanide in water using MD simulations with accurate multipolar electrostatics. It is found that larger van der Waals radii are indeed necessary to obtain results close to the experimental values when a multipolar force field is used. For CN(-), the van der Waals ranges refined in our previous work yield hydration free energy between -72.0 and -77.2 kcal mol(-1), which is in excellent agreement with the experimental data. In addition to the cyanide ion, we also study the hydroxide ion to show that the method used here is readily applicable to similar systems. Hydration free energies are found to sensitively depend on the intermolecular interactions, while bonded interactions are less important, as expected. We also investigate in the present work the possibility of applying the multipolar force field in scoring trajectories generated using computationally inexpensive methods, which should be useful in broader parametrization studies with reduced computational resources, as scoring is much faster than the generation of the trajectories. PMID- 24170170 TI - Effect of knowledge of APOE genotype on subjective and objective memory performance in healthy older adults. AB - OBJECTIVE: The knowledge that one carries the apolipoprotein E (APOE) epsilon4 allele risk factor for Alzheimer's disease was recently found to have little short-term psychological risk. The authors investigated the impact of knowledge of carrying the risk allele on subjective ratings of memory and objective memory test performance of older adults. METHOD: Using a nested case-control design, the authors administered objective verbal and visual memory tests and self-rating scales of memory function to 144 cognitively normal older adults (ages 52-89) with known APOE genotype who knew (epsilon4+, N=25; epsilon4-, N=49) or did not know (epsilon4+, N=25; epsilon4-, N=45) their genotype and genetic risk for Alzheimer's disease prior to neuropsychological evaluation. RESULTS: Significant genotype-by-disclosure interaction effects were observed on several memory rating scales and tests of immediate and delayed verbal recall. Older adults who knew their epsilon4+ genotype judged their memory more harshly and performed worse on an objective verbal memory test than did epsilon4+ adults who did not know. In contrast, older adults who knew their epsilon4- genotype judged their memory more positively than did epsilon4- adults who did not know, but these groups did not differ in objective memory test performance. CONCLUSIONS: Informing older adults that they have an APOE genotype associated with an increased risk of Alzheimer's disease can have adverse consequences on their perception of their memory abilities and their performance on objective memory tests. The patient's knowledge of his or her genotype and risk of Alzheimer's disease should be considered when evaluating cognition in the elderly. PMID- 24170172 TI - UV-protectant metabolites from lichens and their symbiotic partners. AB - Lichens are structurally complex symbiotic organisms that are exposed to a wide variety of external conditions (extreme temperatures, desiccation, UV radiation, etc.). These poikilohydric organisms have developed various mechanisms of photoprotection, such as light scattering, radiation screening, thermal dissipation, activation of antioxidant defense and macromolecules and membrane repair. These unique organisms produce a vast array of compounds, with more than 1000 secondary metabolites known. An important protective mechanism of lichens is the production of UV screening compounds, such as phenolic compounds (depsidones, depsides, diphenyl ethers), anthraquinones, xanthones or shikimic acid derivatives (calycin, mycosporines, scytonemin). Due to the harmful effects of the UVA wavelengths of sunlight, the search for new sunscreens remains important. We herein propose a review that focuses on the UV protectants from lichens and their symbiotic partners (lichenized fungi, green alga, cyanobacteria). In fact, lichens produce unique and/or efficient UV filters such as depsidones (lobaric acid, pannarin, etc.), depsides (atranorin, gyrophoric acid, etc.), diphenyl ethers (epiphorellic acids, buellin), bisxanthones (secalonic acids, etc.), mycosporines and MAAs, scytonemin along with classical pigments (melanin, carotenoids). We propose to classify these compounds with regard to their chemical structures and review the physicochemical properties that act as UV filters. While the most abundant lichen polyfunctionalized aromatic compounds, belonging to orsellinic derivatives, are UVB screens, these organisms produce strong UVA filters, e.g., calycin (pulvinic acid derivatives), bisxanthones (secalonic acids), scytonemin or mycosporines and MAAs with the latter ones exhibiting attractive properties as photoprotectants. PMID- 24170174 TI - Cloning, over-expression and characterization of a thermo-tolerant xylanase from Thermotoga thermarum. AB - The xyn10B gene, encoding the endo-1,4-beta-xylanase Xyn10B from Thermotoga thermarum, was cloned and expressed in Escherichia coli. The ORF of the xyn10B was 1,095 bp and encoded to mature peptide of 344 amino acids with a calculated MW of 40,531 Da. The recombinant xylanase was optimally active at 80 degrees C, pH 6.0 and retained approx. 60 % of its activity after 2 h at 75 degrees C. Apparent K m , k cat and k cat /K m values of the xylanase for beechwood xylan were 1.8 mg ml(-1), 520 s(-1) and 289 ml mg(-1) s(-1), respectively. The end products of the hydrolysis of beechwood xylan were mainly oligosaccharides but without xylose after 2 h hydrolysis. PMID- 24170175 TI - Preparation of optically-active 3-pyrrolidinol and its derivatives from 1 benzoylpyrrolidinol by hydroxylation with Aspergillus sp. and stereo-selective esterification by a commercial lipase. AB - An effective preparation scheme for optically-active 3-pyrrolidinol and its derivatives based on biological transformation is proposed. Aspergillus sp. NBRC 109513 hydroxylated 1-benzoylpyrrolidine, yielding (S)-1-benzoyl-3-pyrrolidinol with 66 % ee. Kinetic resolution of 1-benzoyl-3-pyrrolidinol by Amano PS-IM lipase formed optically-active 1-benzoyl-3-pyrrolidinol with >99 % ee. (S)-1 Benzoyl-3-pyrrolidinol was successfully converted to 3-pyrrolidinol and its derivatives with by chemical reactions (>99 % ee). PMID- 24170176 TI - Expanding the landscape of recombinant protein production in Escherichia coli. AB - Over the years, several vectors and host strains have been constructed to improve the overexpression of recombinant proteins in Escherichia coli. More recently, attention has focused on the co-expression of genes in E. coli, either by means of a single vector or by cotransformation with multiple compatible plasmids. Co expression was initially designed to generate protein complexes in vivo, and later served to extend the use of E. coli as a platform for the production of heterologous proteins. This review shows how the co-expression of genes in E. coli is challenging the production of protein complexes and proteins bearing post translational modifications or unnatural amino acids. In addition, the importance of co-expression to achieve efficient secretion of recombinant proteins in E. coli is discussed, with recent insights into the use of co-expression to overproduce membrane proteins. PMID- 24170177 TI - Nitrite (not free nitrous acid) is the main inhibitor of the anammox process at common pH conditions. AB - Nitrite is a substrate but also an inhibitor of anaerobic ammonium oxidation (anammox).There is currently no consensus on whether ionized nitrite (INi) or free nitrous acid (FNA) is the actual inhibitor of the process. The inhibition by INi and FNA on the anammox process has been analysed using a wide range of INi and FNA concentrations and by altering the pH and total nitrite conditions. The inhibitory impacts of both species were quantified through a rational inhibition equation, considering INi and FNA as substrate inhibitor and non-competitive inhibitor, respectively. Inhibitory constants were calculated with strong statistical support as 561 mg INi-N l(-1) and 0.117 mg FNA-N l(-1). Based on the model, INi is the main inhibiting species of the anammox process at pH > 7.1, which are the most common conditions occurring in field applications of anammox. PMID- 24170178 TI - Inoculation of silicon nanoparticles with silver atoms. AB - Silicon (Si) nanoparticles were coated inflight with silver (Ag) atoms using a novel method to prepare multicomponent heterostructured metal-semiconductor nanoparticles. Molecular dynamics (MD) computer simulations were employed, supported by high-resolution bright field (BF) transmission electron microscopy (HRTEM) and aberration-corrected scanning transmission electron microscopy (STEM) with a resolution <=0.1 nm in high angle annular dark field (HAADF) mode. These studies revealed that the alloying behavior and phase dynamics during the coating process are more complex than when attaching hetero-atoms to preformed nanoparticles. According to the MD simulations, Ag atoms condense, nucleate and diffuse into the liquid Si nanoparticles in a process that we term "inoculation", and a phase transition begins. Subsequent solidification involves an intermediate alloying stage that enabled us to control the microstructure and crystallinity of the solidified hybrid heterostructured nanoparticles. PMID- 24170179 TI - Why I worry about large international studies. PMID- 24170180 TI - Lurasidone monotherapy in the treatment of bipolar I depression: a randomized, double-blind, placebo-controlled study. AB - OBJECTIVE: The authors evaluated the efficacy and safety of lurasidone in the treatment of patients with major depressive episodes associated with bipolar I disorder. METHOD: Patients were randomly assigned to receive double-blind treatment with lurasidone (20-60 mg/day [N=166] or 80-120 mg/day [N=169]) or placebo (N=170) for 6 weeks. Primary and key secondary endpoints were change from baseline to week 6 on the Montgomery-Asberg Depression Rating Scale (MADRS) and depression severity score on the Clinical Global Impressions scale for use in bipolar illness (CGI-BP), respectively. RESULTS: Lurasidone treatment significantly reduced mean MADRS total scores at week 6 for both the 20-60 mg/day group (-15.4; effect size=0.51) and the 80-120 mg/day group (-15.4; effect size=0.51) compared with placebo (-10.7). Similarly, lurasidone treatment resulted in significantly greater endpoint reduction in CGI-BP depression severity scores for both the 20-60 mg/day group (-1.8; effect size=0.61) and the 80-120 mg/day group (-1.7; effect size=0.50) compared with placebo (-1.1). Both lurasidone groups also experienced significant improvements compared with placebo in anxiety symptoms and in patient-reported measures of quality of life and functional impairment. Discontinuation rates due to adverse events were similar in the 20-60 mg/day (6.6%), 80-120 mg/day (5.9%), and placebo (6.5%) groups. The most frequent adverse events associated with lurasidone were nausea, headache, akathisia, and somnolence. Minimal changes in weight, lipids, and measures of glycemic control were observed with lurasidone. CONCLUSION: Monotherapy with lurasidone in the dosage range of 20-120 mg/day significantly reduced depressive symptoms in patients with bipolar I depression. Lurasidone was well tolerated, with few changes in weight or metabolic parameters. PMID- 24170181 TI - Evidence for Borna disease virus infection in neuropsychiatric patients in three western China provinces. AB - Borna disease virus (BDV) is a non-cytolytic, neurotropic RNA virus that can infect a wide variety of vertebrate species from birds and primates to humans. Several studies have been carried out to investigate whether BDV is associated with neuropsychiatric diseases. However, this association is still inconclusive. Two panels of subjects consisting of 1,679 various neuropsychiatric patients and healthy people from three western China provinces were enrolled in this study. BDV p24 or p40 RNA in peripheral blood mononuclear cells (PBMCs) were detected in the first panel of 1,481 subjects using reverse transcription quantitative polymerase chain reaction (RT-qPCR) and cerebrospinal fluid (CSF) samples from the BDV RNA-positive individuals were subjected to BDV p24 antibodies testing by enzyme-linked immunosorbent assay (ELISA). BDV p24 or p40 RNA in PBMCs and p24 antibodies in plasma were detected in the second panel of 198 subjects by RT-qPCR and Western blot. A higher prevalence for BDV RNA was demonstrated in patients with viral encephalitis (6.70%), Guillain-Barre syndrome (6.70%), schizophrenia (9.90%) and chronic fatigue syndrome (CFS) (12.70%) compared to healthy controls in the first panel. CSF p24 antibodies were demonstrated in three viral encephalitis patients, two schizophrenia patients and two major depressive disorder (MDD) patients. The prevalences of p24 antibodies in plasma from patients with viral encephalitis (13.24%), multiple sclerosis (25.00%) and Parkinson's disease (22.73%) were significantly higher than healthy controls. This study demonstrates that BDV infection also exists in humans from three western China provinces, and suggests the involvement of the contribution of BDV in the aetiology of Chinese patients with some neuropsychiatric disorders, including viral encephalitis, schizophrenia, CFS, multiple sclerosis and Parkinson's disease. PMID- 24170182 TI - Detection of human utricular otoconia degeneration in vital specimen and implications for benign paroxysmal positional vertigo. AB - Otoconia are assumed to be involved in inner ear disorders such as benign paroxysmal positional vertigo (BPPV). Up to now, the distinct structure and morphology of intact and degenerate human utricular otoconia has been only poorly investigated on vital specimen. In this study, human otoconia were obtained from the utricle in five patients undergoing translabyrinthine vestibular schwannoma surgery. Specimens were examined by environmental scanning electron microscopy. Intact and degenerate otoconia as well as fracture particles of otoconia and bone were analyzed by energy dispersive X-ray microanalysis (EDX) and powder X-ray diffraction (XRD). Intact otoconia reveal a uniform size showing characteristic symmetry properties. Degenerative changes can be observed at several stages with gradual minor and major changes in their morphology including fragment formation. EDX analyses reveal the characteristic chemical composition also for otoconia remnants. XRD shows that intact and degenerate otoconia as well as remnants consist of the calcite modification. In conclusion, electron microscopy serves as a standard method for morphological investigations of otoconia. Human utricular otoconia show a uniform outer morphology corresponding to a calcite-based nanocomposite. Morphological changes provide further evidence for degeneration of utricular otoconia in humans, which might be a preconditioning factor causing BPPV. In case of uncertain origin, particles can be clearly assigned to otoconial origin using EDX and XRD analyses. PMID- 24170183 TI - Association of CD14 gene -159C/T polymorphism with allergic rhinitis risk: a meta analysis. AB - The -159C/T polymorphism in the CD14 gene has been implicated in susceptibility to allergic rhinitis (AR), but results were conflicting. The aim of this study is to investigate the association between the CD14-159C/T polymorphism and the risk of AR. All eligible case-control studies published up to July 2013 were identified by searching PubMed, Web of Science and CNKI. Pooled odds ratio with 95% confidence interval (95% CI) was used to access the strength of this association in fixed- or random-effects model. A total of seven case-control studies, including 887 cases and 889 controls, were selected. Overall, no significant association between the CD14-159C/T polymorphism and AR risk was found. Besides, stratified analysis with ethnicity and source of control also indicated that no significant association between CD14-159C/T and the risk of AR under all for genetic model was observed. This meta-analysis indicated that the CD14-159C/T polymorphism is not associated with AR risk. PMID- 24170184 TI - Increasing prevalence of diabetes mellitus in association with fatty liver in a Japanese population. AB - BACKGROUND: The prevalence of diabetes mellitus (DM) has been increasing. The present study was carried out to examine the relationship between this increase and fatty liver. METHODS: Japanese participants who underwent regular health examinations in 1991, 1996, 2001, 2006, and 2011 were enrolled. Fatty liver was diagnosed using ultrasonography. DM was defined as requiring the use of medication for DM, having a fasting blood glucose level >= 126 mg/dl, or hemoglobin A1c level >= 6.5 %. RESULTS: Logistic regression analysis on data from 11,235 participants (6,882 men and 4,271 women) in 2011 revealed that the association between fatty liver and DM was independent of age, body composition, and other confounders [odds ratio (OR) 1.97, 95 % confidence interval (95 % CI) 1.66-2.32 in men, and OR, 3.12; 95 % CI, 2.29-4.26 in women]. In 2006, 5,318 participants did not have DM and were able to be followed up in 2011. Fatty liver in 2006 was an independent predictor of DM in 2011 [OR 1.73 (95 % CI 1.20-2.50) in men, 4.13 (2.16-8.10) in women]. The prevalence of DM increased significantly during the 20-year period examined among both men (6.0, 8.9, 10.0, 10.8, 12.0 %, P < 0.001) and women (3.3, 4.5, 4.2, 4.1, 5.1 %, P = 0.004), accompanied with an increased prevalence of fatty liver among both men (10.8, 26.3, 33.8, 36.7, and 38.0 %, P < 0.001) and women (6.5, 16.7, 22.2, 21.3, and 20.8 %, P < 0.001). CONCLUSION: Fatty liver independently predicts both present and future DM. Fatty liver may play an important role in the recent increases in the prevalence of DM. PMID- 24170185 TI - A multiyear follow-up study examining the effectiveness of a cognitive behavioral group therapy program on the recidivism of juveniles on probation. AB - The present study evaluated the long-term effectiveness of a cognitive behavioral group therapy program titled Community Opportunity Growth. This study monitored juvenile delinquents' recidivism across a 7-year time period, with the average length to follow-up being 39 months. It was hypothesized that program graduates (N = 178) would have a significantly lower recidivism rate than a control group (program nonstarters; N = 66) and program dropouts (whose predisposing factors may have influenced their program participation; N = 150). Analyses controlled for sex, ethnicity, age, prior petitions, highest class of prior petition, and months to follow-up. Results show a general trend indicating the long-term effectiveness of the program as graduates had a lower incidence of petitions at follow-up compared with dropouts and fewer petitions compared with the other two groups. PMID- 24170186 TI - Self-reported psychopathic traits in sexually offending juveniles compared with generally offending juveniles and general population youth. AB - The aim of the current study is to gain a better insight into the relationship between sexually aggressive behaviour and psychopathy in youths; juveniles who sexually offended (JSOs) were compared with generally offending youths and a general population group. Seventy-one JSOs, 416 detained general offenders, and 331 males from the general population were assessed by means of the Youth Psychopathic traits Inventory (YPI), a self-report instrument. Sexually and generally offending juveniles had significantly lower levels of self-reported psychopathic traits than youths from the general population. Juvenile sexual offenders and generally offending juveniles did not differ in self-reported psychopathic traits. Furthermore, no differences in self-reported psychopathic traits were found between subgroups of JSOs (i.e., child molesters, solo offenders, and group offenders). The finding that self-reported psychopathic traits are less prevalent in offending juveniles than in general population youths raises questions about the usefulness of the YPI when comparing psychopathic traits between clinical samples and general-population samples. PMID- 24170187 TI - Quantitative MRI in the evaluation of articular cartilage health: reproducibility and variability with a focus on T2 mapping. AB - PURPOSE: Early diagnosis of cartilage degeneration and longitudinal tracking of cartilage health including repair following surgical intervention would benefit from the ability to detect and monitor changes of the articular cartilage non invasively and before gross morphological alterations appear. METHODS: Quantitative MR imaging has shown promising results with various imaging biomarkers such as T2 mapping, T1 rho and dGEMRIC demonstrating sensitivity in the detection of biochemical alterations within tissues of interest. However, acquiring accurate and clinically valuable quantitative data has proven challenging, and the reproducibility of the quantitative mapping technique and its values are essential. Although T2 mapping has been the focus in this discussion, all quantitative mapping techniques are subject to the same issues including variability in the imaging protocol, unloading and exercise, analysis, scanner and coil, calculation methods, and segmentation and registration concerns. RESULTS: The causes for variability between time points longitudinally in a patient, among patients, and among centres need to be understood further and the issues addressed. CONCLUSIONS: The potential clinical applications of quantitative mapping are vast, but, before the clinical community can take full advantage of this tool, it must be automated, standardized, validated, and have proven reproducibility prior to its implementation into the standard clinical care routine. PMID- 24170188 TI - The biomechanical and histological effects of platelet-rich plasma on fracture healing. AB - PURPOSE: Platelet-rich plasma (PRP) includes growth factors and proteins that accelerate and stimulate bone regeneration and tissue recovery. The aim of this study was to evaluate the effects of PRP on fracture healing in terms of biomechanics and histology. METHODS: Seventy female rats were included in this experimental study. They were divided into three groups: Group I (no PRP, n = 30), Group II (PRP added, n = 30) and Group III (control, n = 10). The left femurs of the rats in Groups I and II were osteotomized and fixed by K-wires. Although no additional intervention was performed on Group I rats, PRP was applied to the fracture sites of Group II rats. The remaining ten rats were used as the control group of the biomechanical test (Group III). In the fourth week, nine femurs from Group I and ten femurs from Group II, and in the ninth week, nine femurs from each group were removed, and bone recovery was assessed histologically according to Modified Lane-Sandhu histological scoring criteria. Three-point bending test was applied to femurs for biomechanical evaluation in the ninth week. RESULTS: Histological healing was found to be significantly higher in Group II than in Group I (p < 0.05). Furthermore, biomechanical test results showed that healing quantity and bone strength were significantly better in Group II than in Group I (p < 0.05). CONCLUSION: PRP is a widely studied material in the physiology of fracture healing. The results of this study demonstrated the ameliorative biomechanical effects of PRP on fracture healing, in addition to accelerating the histological union of fractures. In the light of these results, PRP could be a viable alternative to accelerate the healing of fractures, late unions or non-unions. LEVEL OF EVIDENCE: Prospective comparative study, Level II. PMID- 24170189 TI - Why does minimally invasive coracoclavicular ligament reconstruction using a flip button repair technique fail? An analysis of risk factors and complications. AB - PURPOSE: Aim of the present study was to evaluate the risk factors for the failure of coracoclavicular ligament reconstruction using a flip button repair technique and to analyse complications related to this procedure. METHODS: Seventy-one patients (3 female, 68 male) underwent surgical treatment using a flip button repair technique for an acute acromioclavicular joint dislocation. The following factors and its impact on clinical and radiographic outcome were assessed: age at trauma, interval between trauma and surgery, degree of displacement (according to Rockwood's classification), coracoid button position, button migration and post-operative appearance of ossifications. RESULTS: Sixty three patients were available for follow-up. The overall Constant score was 95.2 points (range 61-100 points) compared to 97 points (range 73-100 points) for the contralateral side (p = 0.05). Nine patients (14.3 %) needed surgical revision. Inappropriate positioning of the coracoid bone tunnel with subsequent button dislocation was the most frequently observed mode of failure (6 cases, 9.5 %). Button migration into the clavicle was associated with loss of reduction (p = 0.02). The patient's age at the time of trauma had a significant impact on the clinical outcome, whereas younger patients achieved better results (p = 0.02). The interval between trauma and surgery did not significantly affect the outcome (n.s.). CONCLUSION: Good to excellent clinical results can be achieved with the presented surgical technique. The age of the patient at trauma had a significant influence on the functional outcome. Furthermore, placement of the coracoid button centrally under the coracoid base is crucial to prevent failure. LEVEL OF EVIDENCE: IV. PMID- 24170192 TI - Honoring the life and work of Renee Claire Fox. PMID- 24170190 TI - Association between pre-operative magnetic resonance imaging and reparability of large and massive rotator cuff tears. AB - PURPOSE: It is recognized that a percentage of large and massive rotator cuff tears (RCTs) cannot be anatomically repaired. We hypothesized that factors identified on pre-operative MRI would be associated with rotator cuff reparability. METHODS: A single-surgeon retrospective study was performed on patients who had undergone either an anatomical or partial repair of a large or massive RCT. Pre-operative MRI images were evaluated by a fellowship-trained shoulder surgeon, blinded to the surgical outcome. Stump location, tear dimension in the coronal and sagittal plane, fatty infiltration, muscle atrophy (occupation ratio, tangent sign), and superior migration of the humeral head (acromion humeral distance, inferior glenohumeral distance, and best-fit humeral circle technique) were assessed as the predictors of repair. Logistic regression and chi square analyses were used. RESULTS: A total of sixty patients with median age 63 (range 40-83) were included. On MRI, reparability was associated with increased medial-lateral (ML) tear size (p = 0.003), but not increased AP tear size (n.s.). An association was seen between partial repair and tendon retraction to or beyond the glenoid (p = 0.0005), positive tangent sign (p = 0.04), advanced supraspinatus fatty infiltration in isolation (p = 0.046), combined advanced supraspinatus and infraspinatus fatty infiltration (p = 0.04), and superior migration of the humeral head as measured by the inferior glenohumeral distance only (p = 0.004). Multivariable analysis identified increased ML tear size as the most significant factor associated with partial repair. CONCLUSION: This study demonstrates that MRI findings of tendon retraction to or beyond the glenoid, increased inferior glenohumeral distance, and a positive tangent sign are associated with irreparability of large and massive RCTs. PMID- 24170193 TI - Clinical, tomographic aspects and relevance of torus palatinus: case report of two sisters. AB - Despite the nomenclature suggested to be a tumor, torus palatinus (TP) is an overgrowth of the bone in the palatal region and represents an anatomic variation. Its prevalence varies among the population studied and its etiology is still unclear; however, it seems to be a multifactorial disorder with genetics and environmental involvement. Surgical removal of the TP is indicated in the following circumstances: (1) deglutition and speech impairment, (2) cancer phobia, (3) traumatized mucosa over the torus, and (4) prosthetic reasons. The aim of this case report is describe cases that occurred in two sisters, emphasizing the genetic etiology of this anatomic variation. In addition, intra oral exam and computed tomography scan (axial, coronal and sagittal view) provided a detailed assessment of the TP and elimination of other possible diagnoses, furthermore allowed a better analyzes of the anatomic relation with adjacentes structures. No surgical removal was indicated for both cases. PMID- 24170195 TI - Is fosfomycin a potential treatment alternative for multidrug-resistant gram negative prostatitis? AB - BACKGROUND: Multidrug-resistant gram-negative bacterial (MDR-GNB) infections of the prostate are an increasing problem worldwide, particularly complicating transrectal ultrasound (TRUS)-guided prostate biopsy. Fluoroquinolone-based regimens, once the mainstay of many protocols, are increasingly ineffective. Fosfomycin has reasonable in vitro and urinary activity (minimum inhibitory concentration breakpoint <=64 ug/mL) against MDR-GNB, but its prostatic penetration has been uncertain, so it has not been widely recommended for the prophylaxis or treatment of MDR-GNB prostatitis. METHODS: In a prospective study of healthy men undergoing a transurethral resection of the prostate for benign prostatic hyperplasia, we assessed serum, urine, and prostatic tissue (transition zone [TZ] and peripheral zone [PZ]) fosfomycin concentrations using liquid chromatography-tandem mass spectrometry, following a single 3-g oral fosfomycin dose within 17 hours of surgery. RESULTS: Among the 26 participants, mean plasma and urinary fosfomycin levels were 11.4 +/- 7.6 ug/mL and 571 +/- 418 ug/mL, 565 +/- 149 minutes and 581 +/- 150 minutes postdose, respectively. Mean overall prostate fosfomycin levels were 6.5 +/- 4.9 ug/g (range, 0.7-22.1 ug/g), with therapeutic concentrations detectable up to 17 hours following the dose. The mean prostate to plasma ratio was 0.67 +/- 0.57. Mean concentrations within the TZ vs PZ prostate regions varied significantly (TZ, 8.3 +/- 6.6 vs PZ, 4.4 +/- 4.1 ug/g; P = .001). Only 1 patient had a mean prostatic fosfomycin concentration of <1 ug/g, whereas the majority (70%) had concentrations >=4 ug/g. CONCLUSIONS: Fosfomycin appears to achieve reasonable intraprostatic concentrations in uninflamed prostate following a single 3-g oral dose, such that it may be a potential option for prophylaxis pre-TRUS prostate biopsy and possibly for the treatment of MDR-GNB prostatitis. Formal clinical studies are now required. PMID- 24170196 TI - Concordance of resistance profiles in households of patients with multidrug resistant tuberculosis. AB - We estimated the proportion of household contacts whose drug-susceptibility test results matched those of the purported source patient with multidrug-resistant tuberculosis. Ninety-nine (88.4%) contacts had isolates resistant to isoniazid and rifampin, and 41 (36.6%) contacts had isolates with results that also matched the purported source for ethambutol, streptomycin, and pyrazinamide. PMID- 24170197 TI - Association between recent use of fluoroquinolones and rhegmatogenous retinal detachment: a population-based cohort study. AB - BACKGROUND: An association between use of oral fluoroquinolones (FQs) and retinal detachment remains controversial. This study was to determine the association of recent use of oral FQs and rhegmatogenous retinal detachment (RRD) after adjustment for confounding factors known to be associated with RRD. METHODS: This retrospective population-based cohort study with parallel groups included adults treated with an oral FQ (FQ cohort = 178 179 prescriptions) and propensity score matched adults treated with oral amoxicillin (amoxicillin cohort = 178 179 prescriptions). The data were extracted from the Taiwan National Health Insurance Research Database from 1998 to 2010. Interaction terms were used to identify populations at risk. RRD was defined according to the International Classification of Diseases, Ninth Revision, Clinical Modification. RESULTS: During the 90-day follow-up period, 96 patients (0.054%) in the FQ cohort developed RRD compared to 46 (0.026%) among the matched amoxicillin cohort. The overall adjusted hazard ratio (HR) for FQ use and RRD was 2.07 (95% confidence interval [CI], 1.45-2.96). The interval between use of oral FQs and onset of RRD was 35.5 days (interquartile range, 14-57 days). Interaction terms were not significant for age, sex, diabetes, indications for antimicrobials, or underlying ophthalmic conditions. The adjusted HRs differed for specific FQs. These were 10.68 (95% CI, 3.28-34.82) for ciprofloxacin, 2.41 (95% CI, .76-7.68) for levofloxacin, 2.00 (95% CI, 1.06-3.79) for norfloxacin, and 1.17 (95% CI, .59 2.31) for ofloxacin. CONCLUSIONS: The use of oral FQs was associated with the subsequent occurrence of RRD. The FQ risk was independent of age, sex, diabetes, indications for antimicrobials, and underlying ophthalmic conditions. Certain FQs carried higher risk of RRD. PMID- 24170198 TI - Internet-based institutional antimicrobial stewardship program resources in leading US academic medical centers. PMID- 24170199 TI - An update on the salt wars-genuine controversy, poor science, or vested interest? AB - There is unequivocal evidence that increased sodium intake is associated with increased blood pressure, and that increased blood pressure leads to increased risk of vascular diseases. Unfortunately, the published evidence directly linking sodium intake to vascular risk is inconsistent and confusing. This review, emphasising recent developments in national and international settings, considers why this is the case and how vested interests - particularly the food industry - have exploited the vacuum. We argue that legislation is the only tool that is likely to reverse the current situation wherein many millions of lives are put at risk through an unnecessary dietary additive, the reduction of which would be eminently feasible and have no conceivable disadvantage to health. PMID- 24170200 TI - miR-9 targets CXCR4 and functions as a potential tumor suppressor in nasopharyngeal carcinoma. AB - MicroRNA deregulation and pathway alterations have been implicated in nasopharyngeal carcinoma (NPC), a highly invasive and metastatic cancer widely prevalent in Southern China. In this study, we report that miR-9 is commonly downregulated in NPC specimens and NPC cell lines with important functional consequences. The reduced expression of miR-9 was inversely correlated with clinical stages and marked the progression from locoregional to metastatic tumors. The CpG island hypermethylation contributed to miR-9 silencing in NPC cell lines and tissues. Ectopic expression of miR-9 dramatically inhibited the proliferative, migratory and invasive capacities of NPC cells in vitro and in vivo. We found that miR-9 strongly reduced the expression of CXCR4 in NPC cells. Luciferase assay demonstrated that miR-9 could directly bind to the 3' untranslated region of CXCR4. Similar to the restoring miR-9 expression, CXCR4 downregulation inhibited cell growth, migration and invasion, whereas CXCR4 overexpression rescued the suppressive effect of miR-9. Mechanistic investigations revealed that CXCR4 functionally mediated the SDF-1-stimulated activation of p38 mitogen-activated protein kinase pathway in NPC cells with miR 9 downregulation or CXCR4 overexpression. In clinical specimens, CXCR4 and phospho-p38 were widely overexpressed, and the levels increased with the progression from locoregional to metastatic tumors in NPC tissues. The levels of CXCR4 were inversely correlated with miR-9 or phospho-p38 expression. Taken together, our results indicate that miR-9 functions as a tumor-suppressive microRNA in NPC, and that its suppressive effects are mediated chiefly by repressing CXCR4 expression. PMID- 24170201 TI - Loss of LKB1 and PTEN tumor suppressor genes in the ovarian surface epithelium induces papillary serous ovarian cancer. AB - Epithelial ovarian cancer presents mostly with serous, endometrioid or mucinous histology but is treated as a single disease. The development of histotype specific therapy has been challenging because of the relative lack of studies attributing disrupted pathways to a distinct histotype differentiation. mTOR activation is frequently associated with poor prognosis in serous ovarian cancer, which is the most common and most deadly histotype. However, the mechanisms dysregulating mTOR in the pathogenesis of ovarian cancer are unknown. We detected copy number loss and correlated lower expression levels of LKB1, TSC1, TSC2 and PTEN tumor suppressor genes for upstream regulators of mTOR activity in up to 80% in primary ovarian serous tumor databases, with LKB1 allelic loss-predominant. Reduced LKB1 protein was usually associated with increased mTOR activity in both serous ovarian cancer cell lines and primary tumors. Conditional deletion of Lkb1 in murine ovarian surface epithelial (OSE) cells caused papillary hyperplasia and shedding but not tumors. Simultaneous deletion of Lkb1 and Pten, however, led to development of high-grade ovarian serous histotype tumors with 100% penetrance that expressed WT1, ERalpha, PAX8, TP53 and cytokeratin 8, typical markers used in the differential diagnosis of serous ovarian cancer. Neither hysterectomy nor salpingectomy interfered with progression of ovarian tumorigenesis, suggesting that neither uterine nor Fallopian tube epithelial cells were contributing to tumorigenesis. These results implicate LKB1 loss in the OSE in the pathogenesis of serous ovarian cancer and provide a compelling rationale for investigating the therapeutic potential of targeting LKB1 signaling in patients with this deadly disease. PMID- 24170202 TI - GDSL LIPASE1 modulates plant immunity through feedback regulation of ethylene signaling. AB - Ethylene is a key signal in the regulation of plant defense responses. It is required for the expression and function of GDSL LIPASE1 (GLIP1) in Arabidopsis (Arabidopsis thaliana), which plays an important role in plant immunity. Here, we explore molecular mechanisms underlying the relationship between GLIP1 and ethylene signaling by an epistatic analysis of ethylene response mutants and GLIP1-overexpressing (35S:GLIP1) plants. We show that GLIP1 expression is regulated by ethylene signaling components and, further, that GLIP1 expression or application of petiole exudates from 35S:GLIP1 plants affects ethylene signaling both positively and negatively, leading to ETHYLENE RESPONSE FACTOR1 activation and ETHYLENE INSENSITIVE3 (EIN3) down-regulation, respectively. Additionally, 35S:GLIP1 plants or their exudates increase the expression of the salicylic acid biosynthesis gene SALICYLIC ACID INDUCTION-DEFICIENT2, known to be inhibited by EIN3 and EIN3-LIKE1. These results suggest that GLIP1 regulates plant immunity through positive and negative feedback regulation of ethylene signaling, and this is mediated by its activity to accumulate a systemic signal(s) in the phloem. We propose a model explaining how GLIP1 regulates the fine-tuning of ethylene signaling and ethylene-salicylic acid cross talk. PMID- 24170203 TI - Structure and function of nucleoside hydrolases from Physcomitrella patens and maize catalyzing the hydrolysis of purine, pyrimidine, and cytokinin ribosides. AB - We present a comprehensive characterization of the nucleoside N-ribohydrolase (NRH) family in two model plants, Physcomitrella patens (PpNRH) and maize (Zea mays; ZmNRH), using in vitro and in planta approaches. We identified two NRH subclasses in the plant kingdom; one preferentially targets the purine ribosides inosine and xanthosine, while the other is more active toward uridine and xanthosine. Both subclasses can hydrolyze plant hormones such as cytokinin ribosides. We also solved the crystal structures of two purine NRHs, PpNRH1 and ZmNRH3. Structural analyses, site-directed mutagenesis experiments, and phylogenetic studies were conducted to identify the residues responsible for the observed differences in substrate specificity between the NRH isoforms. The presence of a tyrosine at position 249 (PpNRH1 numbering) confers high hydrolase activity for purine ribosides, while an aspartate residue in this position confers high activity for uridine. Bud formation is delayed by knocking out single NRH genes in P. patens, and under conditions of nitrogen shortage, PpNRH1 deficient plants cannot salvage adenosine-bound nitrogen. All PpNRH knockout plants display elevated levels of certain purine and pyrimidine ribosides and cytokinins that reflect the substrate preferences of the knocked out enzymes. NRH enzymes thus have functions in cytokinin conversion and activation as well as in purine and pyrimidine metabolism. PMID- 24170204 TI - Aspen SUCROSE TRANSPORTER3 allocates carbon into wood fibers. AB - Wood formation in trees requires carbon import from the photosynthetic tissues. In several tree species, including Populus species, the majority of this carbon is derived from sucrose (Suc) transported in the phloem. The mechanism of radial Suc transport from phloem to developing wood is not well understood. We investigated the role of active Suc transport during secondary cell wall formation in hybrid aspen (Populus tremula * Populus tremuloides). We show that RNA interference-mediated reduction of PttSUT3 (for Suc/H(+) symporter) during secondary cell wall formation in developing wood caused thinner wood fiber walls accompanied by a reduction in cellulose and an increase in lignin. Suc content in the phloem and developing wood was not significantly changed. However, after (13)CO2 assimilation, the SUT3RNAi lines contained more (13)C than the wild type in the Suc-containing extract of developing wood. Hence, Suc was transported into developing wood, but the Suc-derived carbon was not efficiently incorporated to wood fiber walls. A yellow fluorescent protein:PttSUT3 fusion localized to plasma membrane, suggesting that reduced Suc import into developing wood fibers was the cause of the observed cell wall phenotype. The results show the importance of active Suc transport for wood formation in a symplasmically phloem-loading tree species and identify PttSUT3 as a principal transporter for carbon delivery into secondary cell wall-forming wood fibers. PMID- 24170205 TI - Physiological copper exposure in Jurkat cells induces changes in the expression of genes encoding cholesterol biosynthesis proteins. AB - Copper is an essential micronutrient that functions as an enzymatic cofactor in a wide range of cellular processes. Although adequate Cu levels are essential for normal metabolism, excess Cu can be toxic to cells. Cellular responses to copper deficiency and overload involve changes in the expression of genes directly and indirectly involved in copper metabolism. However little is known on the effect of physiological copper concentration on gene expression changes. In the current study we aimed to establish whether the expression of genes encoding enzymes related to cholesterol (hmgcs1, hmgcr, fdft) and fatty acid biosynthesis and LDL receptor can be induced by an iso-physiological copper concentration. The iso physiological copper concentration was determined as the bioavailable plasmatic copper in a healthy adult population. In doing so, two blood cell lines (Jurkat and THP-1) were exposed for 6 or 24 h to iso- or supraphysiological copper concentrations. Our results indicated that in cells exposed to an iso physiological copper concentration the early induction of genes involved in lipid metabolism was not mediated by copper itself but by the modification of the cellular redox status. Thus our results contributed to understand the involvement of copper in the regulation of cholesterol metabolism under physiological conditions. PMID- 24170206 TI - Reasons why doctors who perform well as doctors may fail the MRCGP clinical skills assessment exam. PMID- 24170207 TI - Serum pepsinogen reference intervals in apparently healthy Chinese population with latex enhanced turbidimetric immunoassay. AB - AIM: Serum pepsinogen (sPG) has been used to help in diagnosing atrophic corpus gastritis and in screening for gastric cancer non-invasively. There are as yet no reports on sPG reference intervals (RIs) with latex enhanced turbidimetric immunoassay (LIA). In this study, we established the RIs for sPG in a healthy Chinese population using LIA. METHODS: Serum PGI and PGII levels in a healthy population (aged 17-80 years) were measured simultaneously using LIA. RIs were determined following Clinical Laboratory and Standards Institute C28-A3 guidelines using a non-parametric method. RESULTS: 95% RIs in men (ng/mL) were: <=40 years old, 25.53-100.76 for PGI and <=24.42 for PGII; 41-50 years old, 26.62 124.74 for PGI and <=26.81 for PGII; and 51-80 years old, 30.40-153.25 for PGI and <=32.62 for PGII. Corresponding RIs for women (ng/mL) were: <=40 years old, 21.20-87.44 for PGI and <=25.53 for PGII; and 41-80 years, 26.40-127.46 for PGI and <=30.18 for PGII. 95% RI for PGI/PGII in both men and women at any age was >=2.51. CONCLUSIONS: We established the RIs for sPG using LIA in a healthy Chinese population, which can provide a reference for clinical and laboratory studies. PMID- 24170208 TI - Full blood count normal reference values for adults in France. AB - AIMS: To determine full blood count (FBC) normal reference values for adults. METHODS: FBC normal values for healthy adults were defined, after establishing preanalytical conditions, in a population of 33 258 subjects, 19 612 men and 13 646 women. The values were established after excluding from this population all people having conditions liable to modify, directly or indirectly, FBC parameters. RESULTS: Results for values of standard parameters are provided in detail for each parameter, by sex and by age group from 16 to 69 years of age. In addition, we present FBC values from a population of 339 subjects aged over 69 years with no comorbidities. CONCLUSIONS: These normal values are proposed for use in everyday practice. They make it possible to distinguish, without ambiguity, a normal situation from a pathological situation. Moreover, they might be used over all mainland France. PMID- 24170209 TI - Reducing inpatient heritable thrombophilia testing using a clinical decision making tool. AB - AIMS: To evaluate the impact of a clinical decision-making tool, designed to educate physicians regarding heritable thrombophilia (HT) testing, on the volume of testing in hospitalised patients in the tertiary care setting. METHODS: We performed a retrospective cohort study over a 6-year period (2007-2012) at a single tertiary care centre intervention site and two regional control sites. In January 2010, the intervention site instituted a policy change whereby physicians ordering HT testing on inpatients needed to complete a pre-preprinted order (PPO) form that outlined the limitations of HT testing in the hospitalised setting. Failure to complete the PPO within 24 h resulted in test cancellation. Our main outcome measure was the volume of HT testing performed at the three study sites. RESULTS: Introduction of the PPO resulted in a 79.4% (95% CI 71.2% to 87.6%) reduction in factor V Leiden (FVL) testing at the intervention site. This decrease was significantly greater compared with those in the two control teaching hospitals over the same time periods (33.7% and 43.6%; both p<0.001). Reductions in FVL testing postintervention were observed among all ordering specialists. Similar postintervention reductions in testing volumes were observed for antithrombin (57.4%), protein C (61.9%) and protein S (62.2%) activity assays. CONCLUSIONS: In a large tertiary care hospital, the introduction of a clinical decision-making tool significantly reduced HT testing in inpatients across clinical specialties. The impact on patient outcome should be assessed in further studies. PMID- 24170210 TI - EGFR expression in pancreatic adenocarcinoma. Relationship to tumour morphology and cell adhesion proteins. AB - AIMS: We aimed to study epidermal growth factor receptor (EGFR) expression in surgically resected pancreatic ductal adenocarcinomas (PDACs) by immunohistochemistry and their relationship to clinicopathological features, cell proliferation and cell adhesion protein expression. METHODS: A total of 99 PDACs were analysed on tissue microarrays for EGFR, E-cadherin and beta-catenin expression patterns in tumour cells. The percentage of cells expressing the three proteins (membrane, cytoplasm or nuclear pattern) and of Ki67-positive tumour cells was assessed. Tumour protein expression was studied with regard to clinicomorphological features, Ki67 index and for postsurgical survival. RESULTS: Membrane tumour EGFR correlated with histological poor differentiation (dedifferentiation), increased number of mitoses and severe tumour cell atypia (pleiomorphism) as well as with aberrant adhesion protein expression such as nuclear beta-catenin and cytoplasmic E-cadherin. Cytoplasmic tumour E-cadherin correlated with an increased Ki67-positive tumour cell component, whereas nuclear E-cadherin correlated with a shorter postsurgical overall survival, as well as with tumour necrosis and an abundant clear cell component. CONCLUSIONS: In conclusion, the results of our study suggest a complex role for EGFR in PDAC carcinogenesis, tumour expression of this protein being associated with tumour dedifferentiation, mitotic activity or pleiomorphism, as well as with aberrant tumour cell adhesion protein expression. PMID- 24170211 TI - PIASgamma expression in relation to clinicopathological, tumour factors and survival in indigenous black breast cancer women. AB - AIM: Indigenous black women with breast cancer (BC) show a high frequency of triple negative breast cancer (TNBC) comprising ER-, PR- and HER2- phenotypes and BRCA1 deficiency together with a high mortality rate, prompting speculation that risk factors could be genetic and the molecular portrait of these tumours may be different to those of Western women. Protein inhibitor of activated signal transducer (PIAS) gamma implicated in the BRCA1 deficiency and triple negative BC was investigated to establish the relationship among the small ubiquitin-like modifier marker, pathological features, biomarkers expression and clinical outcome in the black women. MATERIALS AND METHODS: This study investigated the immunoprofiles of PIASgamma in 231 Nigerian BC prepared as tissue microarrays and correlated their protein expression with clinical outcome, pathological responses and the expression of 14 other relevant biomarkers. RESULTS: PIASgamma protein expression showed a significant correlation with higher histological grade, basal like biomarkers expression (CK14, CK5/6 and EGFR), BRCA1 regulator (MTA1), p53, PI3KCA, basal-like phenotype and TNBC. Also, an inverse correlation with steroid hormones (ER and PgR), p27, MDM4, mucin 1 and BRCA1 was observed with PIASgamma expression. Univariate and multivariate survival analyses showed PIASgamma expression was a predictor of poor outcome independent of tumour histological grade and ER expression. CONCLUSIONS: PIASgamma appears to be important in breast cancer behaviour arising from Nigerian women. PIASgamma may therefore be useful for the screening of basal-like and TNBC. Also, development of novel therapies towards targeting PIASgamma functional pathways may enhance the BC management among this ethnic nationality. PMID- 24170212 TI - The value of archival tissue blocks in understanding breast cancer biology. AB - Pathological reporting of breast cancer has evolved alongside scientific advances. Such advances have led to recognition of different molecular classes of breast cancer resulting in improved disease management. The aim of this study was to establish whether these advances could be applied to archival breast cancer cases dating from the 1940s to assess historical trends. Important observations included the marked differences in pathological reporting, size of tumour and in ERalpha expression throughout the decades. PMID- 24170213 TI - Differentiation of oncocytoma from chromophobe renal cell carcinoma (RCC): can novel molecular biomarkers help solve an old problem? AB - Standard treatment of renal neoplasms remains surgical resection, and nephrectomy for localised renal cell carcinoma (RCC) still has the best chance of cure with excellent long-term results. For smaller renal masses, especially stage T1a tumours less than 4 cm, nephron-sparing surgery is often employed. However, small incidentally detected renal masses pose an important diagnostic dilemma as a proportion of them may be benign and could be managed conservatively. Renal oncocytoma is one such lesion that may pose little risk to a patient if managed with routine surveillance rather than surgery. Additionally, lower-risk RCC, such as small chromophobe RCC, may be managed in a similar way, although with more caution than the renal oncocytomas (RO). The ability to differentiate ROs from chromophobe RCCs, and from other RCCs with a greater chance of metastasis, would guide the physician and patient towards the most appropriate management, whether nephron-sparing surgical resection or conservative surveillance. Consistent accurate diagnosis of ROs is likely to remain elusive until modern molecular biomarkers are identified and applied routinely. This review focuses on the differentiation of renal oncocytomas and chromophobe RCCs. It summarises the history, epidemiology and clinical presentation of the renal neoplasms, explains the diagnostic dilemma, and describes the value, or not, of current molecular markers that are in development to assist in diagnosis of the renal neoplasms. PMID- 24170214 TI - Novel core-shell (TiO2@Silica) nanoparticles for scattering medium in a random laser: higher efficiency, lower laser threshold and lower photodegradation. AB - There has been growing interest in scattering media in recent years, due to their potential applications as solar collectors, photocatalyzers, random lasers and other novel optical devices. Here, we have introduced a novel core-shell scattering medium for a random laser composed of TiO2@Silica nanoparticles. Higher efficiency, lower laser threshold and long photobleaching lifetime in random lasers were demonstrated. This has introduced a new method or parameter (fraction of absorbed pumping), which opens a new avenue to characterize and study the scattering media. Optical chemical and colloidal stabilities were combined by coating a suitable silica shell onto TiO2 nanoparticles. PMID- 24170216 TI - Primary pulmonary synovial sarcoma: a rare primary pulmonary tumor. AB - INTRODUCTION: Pulmonary sarcomas overall are very uncommon and comprise only 0.5 % of all primary lung malignancies. The diagnosis is established only after sarcoma-like primary lung malignancies and a metastatic extrathoracic sarcoma have been excluded. Synovial sarcoma accounts for ~8 % of soft-tissue sarcomas. Synovial sarcoma arising from the pleura has rarely been reported. METHODS: We report a case of a 58-year-old woman who complained of right-sided chest pain and shortness of breath. Chest CT scan revealed a large heterogeneous mass, occupying most of the right hemithorax. Histologic diagnosis was supplemented by interphase cytogenetic (FISH) analysis. RESULTS: Computed tomography guided Tru-cut biopsy was suspicious for a sarcomatous or fibrous malignancy. However, intraoperative frozen-section diagnostics confirmed the diagnosis of a sarcoma. Immunohistochemistry showed that tumor cells expressed epithelial membrane antigen, CD99 and BCL2. Based on immunohistochemistry, the diagnosis of synovial sarcoma was suspected and was confirmed by FISH analysis. The patient was treated with right upper bilobectomy. Due to R1-resection status, postsurgical systemic chemotherapy was administered. CONCLUSIONS: Primary pulmonary synovial sarcoma is a rare primary lung tumor. Due to extensive size of the tumor with pleural and mediastinal invasion only a R1-resection status could be achieved by thoracic surgery. PMID- 24170217 TI - Serum biomarkers in patients with mesothelioma and pleural plaques and healthy subjects exposed to naturally occurring asbestos. AB - PURPOSE: This study investigated the diagnostic accuracy of the serum biomarkers osteopontin and mesothelin in discriminating mesothelioma patients from those with other, benign conditions and whether levels of the biomarkers differed in subjects who had inhaled naturally occurring asbestos compared with a non-exposed control group. METHODS: This cross-sectional study studied 24 subjects with mesothelioma, 279 subjects with pleural plaques, 123 "healthy exposed," and 120 control subjects. The Kruskal-Wallis test was performed to compare mesothelin and osteopontin levels of the groups, and receiver operating characteristics curves were generated to determine diagnostic yields of both biomarkers. Multiple linear regression analyses were used to identify associated covariates with osteopontin and mesothelin levels. RESULTS: Serum osteopontin and mesothelin levels were higher in mesothelioma than in benign asbestos-related diseases and healthy exposed subjects. Both biomarker levels were independently associated with mesothelioma, age and smoking pack years. Mesothelin levels were also associated with body mass index. The sensitivity and specificity of osteopontin in distinguishing mesothelioma from the three other groups were 75 and 86 %, respectively; those of mesothelin were 58 and 83 %, respectively. The sensitivity and specificity to discriminate mesothelioma from pleural plaques and healthy subjects were 93 and 73 %, respectively, if osteopontin and mesothelin levels were higher than their optimal cut off levels. CONCLUSIONS: The combination of serum osteopontin and mesothelin levels can help to distinguish mesothelioma from benign asbestos-related diseases and asbestos-exposed subjects. PMID- 24170218 TI - Off-target effects of plasmid-transcribed shRNAs on NFkappaB signaling pathway and cell survival of human melanoma cells. AB - Signal transducer and activator of transcription 3 (STAT3) and nuclear factor kappa-light-chain-enhancer of activated B cells (NFkappaB) are transcription factors involved in cell survival, inflammation and metastasis. Constitutively activated STAT3 is found in many cancers, including melanoma. To study the crosstalk between STAT3 and NFkappaB signaling and its role in regulation of cancer cell survival, we used RNA interference (RNAi) to down-regulate STAT3 expression in human melanoma cells. RNAi strategies including double-stranded RNA, small interfering RNA (siRNA), short hairpin RNA (shRNA) and microRNA are widely used to knock down disease-causing genes in a targeted fashion. We found that shRNAs up-regulate non-specific NFkappaB activity, while siRNA directed against STAT3 specifically increase NFkappaB activity. The basal survival of melanoma cells is unaffected by STAT3 knockdown-likely due to activation of pro survival NFkappaB signaling. Whereas, owing to off-target effects, plasmid transcribed shRNA affects melanoma survival. Our data show that shRNA-mediated gene silencing induces non-specific or off-target effects that may influence cell functions. PMID- 24170220 TI - Improvement of teamwork and safety climate following implementation of the WHO surgical safety checklist at a university hospital in Japan. AB - With the aim to optimize surgical safety, the World Health Organization (WHO) introduced the Surgical Safety Checklist (SSCL) in 2008. The SSCL has been piloted in many countries worldwide and shown to improve both safety attitudes within surgical teams and patient outcomes. In the study reported here we investigated whether implementation of the SSCL improved the teamwork and safety climate at a single university hospital in Japan. All surgical teams at the hospital implemented the SSCL in all surgical procedures with strict adherence to the SSCL implementation manual developed by WHO. Changes in safety attitudes were evaluated using the modified operating-room version of the Safety Attitudes Questionnaire (SAQ). A before and after design was used, with the questionnaire administered before and 3 months after SSCL implementation. Our analysis revealed that the mean scores on the SAQ had significantly improved 3 months after implementation of the SSCL compared to those before implementation. This finding implies that effective implementation of the SSCL could improve patient outcomes in Japan, similar to the findings of the WHO pilot study. PMID- 24170221 TI - Lurasidone as adjunctive therapy with lithium or valproate for the treatment of bipolar I depression: a randomized, double-blind, placebo-controlled study. AB - OBJECTIVE Few studies have been reported that support the efficacy of adjunctive therapy for patients with bipolar I depression who have had an insufficient response to monotherapy with mood-stabilizing agents. The authors investigated the efficacy of lurasidone, a novel antipsychotic agent, as adjunctive therapy with lithium or valproate for the treatment of bipolar I depression. METHOD Patients were randomly assigned to receive 6 weeks of double-blind adjunctive treatment with lurasidone (N=183) or placebo (N=165), added to therapeutic levels of either lithium or valproate. Primary and key secondary endpoints were change from baseline to week 6 on the Montgomery-Asberg Depression Rating Scale (MADRS) and depression severity score on the Clinical Global Impressions scale for use in bipolar illness (CGI-BP), respectively. RESULTS Lurasidone treatment significantly reduced mean MADRS total score at week 6 compared with the placebo group (-17.1 versus -13.5; effect size=0.34). Similarly, lurasidone treatment resulted in significantly greater endpoint reduction in CGI-BP depression severity scores compared with placebo (-1.96 versus -1.51; effect size=0.36) as well as significantly greater improvement in anxiety symptoms and in patient reported measures of quality of life and functional impairment. Discontinuation rates due to adverse events were 6.0% and 7.9% in the lurasidone and placebo groups, respectively. Adverse events most frequently reported for lurasidone were nausea, somnolence, tremor, akathisia, and insomnia. Minimal changes in weight, lipids, and measures of glycemic control were observed during treatment with lurasidone. CONCLUSIONS In patients with bipolar I depression, treatment with lurasidone adjunctive to lithium or valproate significantly improved depressive symptoms and was generally well tolerated. PMID- 24170222 TI - Complex rectovaginal fistula repair with non-cross-linked porcine graft augmentation. AB - AIM: Our aim was to demonstrate a unique approach to repairing a complex rectovaginal fistula using a non-cross-linked porcine dermal graft. PMID- 24170223 TI - What is the best indication for single-incision Ophira Mini Sling? Insights from a 2-year follow-up international multicentric study. AB - INTRODUCTION AND HYPOTHESIS: The Ophira Mini Sling System involves anchoring a midurethral, low-tension tape to the obturator internus muscles bilaterally at the level of the tendinous arc. Success rates in different subsets of patients are still to be defined. This work aims to identify which factors influence the 2 year outcomes of this treatment. METHODS: Analysis was based on data from a multicenter study. Endpoints for analysis included objective measurements: 1-h pad-weight (PWT), and cough stress test (CST), and questionnaires: International Consultation on Incontinence Questionnaire-Short Form (ICIQ-SF) and Urinary Distress Inventory (UDI)-6. A logistic regression analysis evaluated possible risk factors for failure. RESULTS: In all, 124 female patients with stress urinary incontinence (SUI) underwent treatment with the Ophira procedure. All patients completed 1 year of follow-up, and 95 complied with the 2-year evaluation. Longitudinal analysis showed no significant differences between results at 1 and 2 years. The 2-year overall objective results were 81 (85.3%) patients dry, six (6.3%) improved, and eight (8.4%) incontinent. A multivariate analysis revealed that previous anti-incontinence surgery was the only factor that significantly influenced surgical outcomes. Two years after treatment, women with previous failed surgeries had an odds ratio (OR) for treatment failure (based on PWT) of 4.0 [95% confidence interval (CI) 1.02-15.57). CONCLUSIONS: The Ophira procedure is an effective option for SUI treatment, with durable good results. Previous surgeries were identified as the only significant risk factor, though previously operated patients showed an acceptable success rate. PMID- 24170224 TI - Utility of dipstick urinalysis in peri- and postmenopausal women with irritative bladder symptoms. AB - INTRODUCTION AND HYPOTHESIS: Previous studies of dipstick urinalysis (UA) in asymptomatic peri- and postmenopausal women demonstrate poor sensitivity to detect a urinary tract infection (UTI). We hypothesized that sensitivity of this test would be improved in symptomatic peri- and postmenopausal women. METHODS: This was a cross-sectional study of 76 women seeking urogynecology care for irritative bladder symptoms. Subjects with a positive clean-catch (CC) dipstick UA for leukocyte esterase (LE) or nitrites (NIT) were offered enrollment. Dipstick UA was performed on CC and catheterized specimens, followed by microbiologic culture. Test characteristics were calculated for CC and catheterized UA. CC culture was compared with catheterized culture (gold standard) using Spearman's correlation coefficient. RESULTS: Data was available for analysis in 75/76 (98.7 %) enrolled subjects. Mean age was 68 +/- 11 years. Most subjects were postmenopausal (98.7 %) and Caucasian (97.3 %). Dipstick sensitivity ranged from 48 % to 87 % and 35 % to 57 % in CC and catheterized specimens, respectively. Dipstick UA from a CC specimen positive for NIT had the highest sensitivity (60.9), specificity (100), negative predictive value (85.2), and positive predictive value (100) in this population. Dipstick UA from CC and catheterized specimens had similar sensitivity for detecting UTIs. When culture results of 10(3) colony-forming units were considered positive, CC and catheterized specimens were moderately correlated (rho = 0.470). CONCLUSIONS: Dipstick UA in this study had improved sensitivity compared with previously published results in both CC and catheterized samples. Initiation of empiric antibiotic treatment in women with irritative bladder symptoms and NIT-positive CC dipstick UA prior to obtaining urine culture results is a reasonable option. PMID- 24170225 TI - Cardinal ligament surgical anatomy: cardinal points at hysterectomy. AB - INTRODUCTION AND HYPOTHESIS: The cardinal ligament (CL) still requires more precise anatomical mapping. We aim to elucidate the anatomy of the CL and the roles it plays in gynecological surgery. METHODS: Studies employed sharp dissection of 28 formalin-fixed cadaveric hemipelves and 10 unembalmed cadaveric hemipelves. RESULTS: The CL (total length averaging 10.0 cm) can be subdivided into three sections: a distal (cervical) section, on average 2.1 cm long, attached to the lateral aspect of the cervix (posteriorly, it was confluent with the attachment of the uterosacral [USL] ligament to form the cardinal-uterosacral confluence [CUSC]); an intermediate section, on average 3.4 cm long, running laterally (slightly posteriorly) from the cervix; a proximal (pelvic) section, relatively thick, triangular-shaped on cross-section, averaging 4.6 cm long, attached to the lateral pelvic sidewall, with its apex at the first branching of the internal iliac artery. Only the distal section is free of any significant neural or vascular component (ureter is in the intermediate section) and therefore safe for surgical use. The CUSC (first pedicle of a vaginal hysterectomy and later pedicle of an abdominal hysterectomy), if attached to the vaginal vault at hysterectomy has the potential for both lateral (CL) and supero posterior (USL) surgical support. This pedicle would not be subsequently accessible for other surgeries. CONCLUSIONS: Suggested cardinal points at hysterectomy are: know the CL anatomy; the distal section (as part of the CUSC) can provide vaginal vault support; the intermediate and proximal sections are surgically dangerous. PMID- 24170226 TI - Comparison of the POP-Q examination, transvaginal ultrasound, and direct anatomic measurement of cervical length. AB - INTRODUCTION AND HYPOTHESIS: Our objective was to determine the relationship between the Pelvic Organ Prolapse Quantification (POP-Q) examination for determining cervical length (CL) and CL at hysterectomy. Secondary objectives were to define cervical elongation using both measures in a urogynecologic population, determine the relationship between POP-Q estimate and CL on ultrasound (US) and examine the interobserver reliability of each mode of measurement. METHODS: This was a prospective cohort study of women scheduled for hysterectomy at the Los Angeles County + University of Southern California (LAC + USC) medical center. CLs were measured by POP-Q and at the time of hysterectomy. Transvaginal US CLs were determined when available. Exam CL (eCL) was compared with anatomic (aCL) and US (uCL) CL. Repeat measures of eCL, uCL, and aCL were all compared for interobserver reliability. RESULTS: The study enrolled 151 women. Median eCL was 3.0 cm (0.5-9.0) (n = 149); average uCL was 2.3 cm +/- 0.7 (n = 108), average aCL 2.8 cm +/- 1.1 (n = 87); eCL correlated fairly with aCL (r = 0.3, p = 0.005, n = 88) but poorly with uCL (r = -0.13, p = 0.18, n = 105); uCL correlated poorly with aCL (r = 0.19, p = 0.14, n = 64). Interobserver reliability for eCL and aCL were good to excellent (eCL alpha=0.881; aCL alpha=0.889) but for uCL adequate (alpha=0.699). The 97.5 percentile cutoff for aCL was 5.0 cm and for eCL 8.0 cm. CONCLUSIONS: The POP-Q examination estimate of CL correlates fairly with aCL at the time of hysterectomy; uCL does not appear to correlate with aCL or eCL. Cervical elongation may be defined as an anatomic length of 5.0 cm or a POP-Q estimate of 8.0 cm. PMID- 24170227 TI - Breakthrough Fusarium solani infection in a patient with acute myeloid leukemia receiving posaconazole prophylaxis. PMID- 24170228 TI - Efforts to explain low-energy nuclear reactions. PMID- 24170229 TI - Submacular choroidal varix simulating chorioretinal folds with metamorphopsia. AB - A novel case description of an isolated unilateral submacular choroidal varix simulating chorioretinal folds and inducing metamorphopsia in a 74-year-old phakic Caucasian man. Posterior segment examination revealed focal choroidal elevations corresponding to a deep, large choroidal vessel in the inferotemporal subparafoveal region. Fundus photography demonstrated a pigment epithelial detachment-like elevation inferior to the fovea, continuous with the course of a large choroidal vessel. Angiographic, indocyanine green (ICG), and spectral domain optical coherence tomography (SD-OCT) imaging revealed an isolated unilateral submacular choroidal varix with direct connection to an inferior vortex vein. The diagnosis of submacular choroidal varix should be considered when the presence of metamorphopsia and corresponding choroidal elevations that remain unchanged through gaze direction or contact lens ophthalmoscopy occur. If present, angiographic, ICG, and SD-OCT imaging are recommended for proper evaluation of submacular choroidal varix that may enhance the characteristics of this lesion. PMID- 24170230 TI - Retinal pigment epithelial detachment with disgorgement in age-related macular degeneration observed with OCT. AB - This report describes a rare appearance of retinal pigment epithelial changes in a 71-year-old woman with known long-standing, non-exudative age-related macular degeneration. She presented with visual distortion in her right eye and was found to have a retinal pigment epithelial detachment (RPED) on optical coherence tomography (OCT). Over the following 8 years, sequential OCT imaging revealed an appearance and progression of a break in the existing RPED, disgorgement of material from within the RPED, and appearance of hyper-reflective spots within the inner retinal layers, suggesting pigment epithelial cell migration. Visual acuity remained stable over this period. The RPED resolved spontaneously without treatment. The patient later developed new intraretinal hemorrhage, which was treated with intravitreal bevacizumab. PMID- 24170231 TI - Intra-aortic balloon counterpulsation in acute myocardial infarction: old and emerging indications. AB - BACKGROUND: Recent evidence questions the role of intra-aortic balloon counterpulsation (IABP) in the treatment of acute myocardial infarction (AMI) complicated by cardiogenic shock (CS). An area of increasing interest is the use of IABP for persistent ischaemia (PI). We analysed the use of IABP in patients with AMI complicated by CS or PI. METHODS: From 2008 to 2010, a total of 4076 patients were admitted to our hospital for primary percutaneous coronary intervention (PCI) for AMI. Out of those, 239 patients received an IABP either because of CS or because of PI. Characteristics and outcome of those patients are investigated. RESULTS: The mean age of the study population was 64 +/- 11 years; 75 % were male patients. Of the patients, 63 % had CS and 37 % had PI. Patients with CS had a 30-day mortality rate of 36 %; 1-year mortality was 41 %. Patients with PI had a 30-day mortality rate of 7 %; 1-year mortality was 11 %. CONCLUSIONS: Mortality in patients admitted for primary PCI because of AMI complicated by CS is high despite IABP use. Outcome in patients treated with IABP for PI is favourable and mandates further prospective studies. PMID- 24170232 TI - Basic concepts of fluid responsiveness. AB - Predicting fluid responsiveness, the response of stroke volume to fluid loading, is a relatively novel concept that aims to optimise circulation, and as such organ perfusion, while avoiding futile and potentially deleterious fluid administrations in critically ill patients. Dynamic parameters have shown to be superior in predicting the response to fluid loading compared with static cardiac filling pressures. However, in routine clinical practice the conditions necessary for dynamic parameters to predict fluid responsiveness are frequently not met. Passive leg raising as a means to alter biventricular preload in combination with subsequent measurement of the change in stroke volume can provide a fast and accurate way to guide fluid management in a broad population of critically ill patients. PMID- 24170233 TI - Concerns about the use of new oral anticoagulants for stroke prevention in elderly patients with atrial fibrillation. AB - The prevalence of atrial fibrillation (AF) and the embolic risk increase with age. Elderly AF patients are undertreated with vitamin K antagonists (VKA). The new oral anticoagulants (NOAC) dabigatran, rivaroxaban and apixaban have been shown to be non-inferior to VKA for stroke prevention in AF. We summarize the knowledge about primary and secondary stroke prevention by NOAC in AF patients >75 years of age. A literature search was carried out using the terms 'dabigatran', 'rivaroxaban', 'apixaban', 'elderly', 'octogenarians', 'atrial fibrillation' and 'anticoagulation' from 1998 to 2013. Randomized clinical trials, longitudinal studies, case series and case reports were included. Whereas studies investigating the use of VKA for stroke prevention in the 1990s were carried out by industry-independent institutions, all NOAC-investigating trials were sponsored by the manufacturers of the respective drugs. Frail elderly people were not represented in NOAC-investigating trials because of various exclusion criteria, and only one-third of patients were aged >75 years. A subgroup analysis from the dabigatran-investigating trial indicated that elderly patients might have a higher risk for extracranial bleeding complications with NOAC than with VKA. Further concerns about the use of NOAC in the elderly are the high prevalence of renal insufficiency in AF patients >75 years of age, the largely unknown risk of drug-drug and drug-food interactions, the lack of easily available laboratory monitoring tests of anticoagulant activity and the lack of an antidote. There is a need for independent studies comparing the efficacy and risk of side effects of NOAC with that of VKA in elderly AF patients. PMID- 24170234 TI - Use of vitamin K antagonist therapy in geriatrics: a French national survey from the French Society of Geriatrics and Gerontology (SFGG). AB - OBJECTIVE: We aimed to evaluate the quality and determinants of vitamin K antagonists (VKA) control among very elderly patients in geriatric settings. METHODS: A national cross-sectional survey was conducted among patients aged >=80 years who were hospitalized in rehabilitation care or institutionalized in a nursing home and who were treated by VKA. Time in therapeutic range (TTR) was computed according to Rosendaal's method. RESULTS: A total of 2,633 patients were included. Mean [+/- standard deviation (SD)] age was 87.2 +/- 4.4 years and 72.9 % were women. The main indication for VKA therapy was atrial fibrillation (AF; 71.4 %). Mean (+/-SD) TTR was 57.9 +/- 40.4 %. After backward logistic regression, poorer VKA control (TTR <50 vs. >=50 %) was associated with being hospitalized in rehabilitation care [odds ratio (OR)(rehab. vs. nursing home) = 1.41; 95 % CI 1.11-1.80], the indication for VKA treatment (OR(prosthetic heart valve vs. AF) = 4.76; 95 % CI 2.83-8.02), a recent VKA prescription (OR(<1 vs. >12 months) = 1.70; 95 % CI 1.08-2.67), the type of VKA (OR(fluindione vs. warfarin) = 1.22; 95 % CI 1.00-1.49), a history of international normalized ratio >4.5 (OR = 1.50; 95 % CI 1.21-1.84), a history of major bleeding (OR = 1.88; 95 % CI 1.00-3.53), antibiotic use (OR = 1.83; 95 % CI 1.24-2.70), and falls (OR(>=2 falls during the past year vs. <2) = 1.26; 95 % CI 1.01-1.56). CONCLUSION: Overall, VKA control remains insufficient in very old patients. Poorer VKA control was associated with taking VKA for a prosthetic heart valve, a recent VKA prescription, the use of other VKAs than warfarin, a history of overcoagulation and major bleeding, antibiotic use, and falls. PMID- 24170235 TI - Elderly patients with diabetes experience a lower rate of nocturnal hypoglycaemia with insulin degludec than with insulin glargine: a meta-analysis of phase IIIa trials. AB - BACKGROUND AND OBJECTIVE: Elderly patients with diabetes are more vulnerable to the occurrence and effects of hypoglycaemia; therefore, treatments with low risk of hypoglycaemia are preferred in this population. This study aimed to compare hypoglycaemia rates between insulin degludec (IDeg) and insulin glargine (IGlar) in elderly patients. METHODS: Hypoglycaemia data from patients >=65 years of age with type 1 (T1DM) or type 2 (T2DM) diabetes from seven randomised, treat-to target phase IIIa trials were used to compare IDeg and IGlar in a pre-planned meta-analysis. Overall, 917/4345 (21 %) randomised patients in the seven trials were elderly (634 IDeg, 283 IGlar). Overall confirmed hypoglycaemia was defined as <3.1 mmol/L or severe hypoglycaemia (symptoms requiring external assistance). Nocturnal hypoglycaemia included confirmed episodes from 0001 to 0559 hours (inclusive). Treatment comparisons of hypoglycaemia in T1DM patients were not performed due to low numbers of elderly patients with T1DM randomised (43 IDeg, 18 IGlar); statistical comparisons were also not made for severe hypoglycaemia due to the low number of events. RESULTS: In elderly patients with T2DM, the rate of overall confirmed hypoglycaemia was significantly lower with IDeg than IGlar [estimated rate ratio (ERR) 0.76 (0.61; 0.95)95 % CI]; nocturnal confirmed hypoglycaemia was also significantly lower with IDeg [ERR 0.64 (0.43; 0.95)95 % CI]. Confirmed hypoglycaemia occurred in the majority of T1DM patients, whereas severe episodes occurred infrequently and at similar rates in both treatment groups in T1DM and T2DM. CONCLUSION: Results of this pre-planned meta-analysis in elderly patients with diabetes demonstrate a significant reduction in hypoglycaemic events with IDeg relative to IGlar. PMID- 24170236 TI - Olmesartan in the treatment of hypertension in elderly patients: a review of the primary evidence. AB - Hypertension, particularly systolic hypertension, is prevalent in the elderly and increases with advancing age, in part because of age-related endothelial dysfunction and increased arterial stiffness. There is strong evidence from randomized clinical trials that supports the use of antihypertensive treatment for effective and sustained blood pressure (BP) control in older patients to reduce the risk of vascular-related morbidity and mortality, particularly cerebrovascular accidents, including stroke. Furthermore, current evidence and guidelines suggest that all major classes of antihypertensive agents are equally effective in controlling BP and preventing cardiovascular events in older patients. Diuretics are commonly used in elderly patients, but recent outcomes data have raised doubt about their long-term benefits. Renin-angiotensin system inhibitors have a better tolerability profile than diuretics. Extensive clinical evidence has demonstrated the excellent efficacy and tolerability profile of olmesartan medoxomil (OM)--an angiotensin II receptor blocker AT1 receptor antagonist--including in elderly patients. Randomized and observational studies have shown that OM provides effective BP control across the 24 h dosing interval in the elderly. It also has a good tolerability profile, a pharmacokinetic profile unaffected by age and a low propensity for drug interactions. An additional factor is that OM once-daily regimens are simple and straightforward, which can be an important factor in maintaining adherence to therapy in elderly patients. This article provides an overview of the main recent clinical evidence supporting the use of OM-based therapy in elderly patients with hypertension. PMID- 24170237 TI - Multimodality imaging approach for serial assessment of regional changes in lower extremity arteriogenesis and tissue perfusion in a porcine model of peripheral arterial disease. AB - BACKGROUND: A standard quantitative imaging approach to evaluate peripheral arterial disease does not exist. Quantitative tools for evaluating arteriogenesis in vivo are not readily available, and the feasibility of monitoring serial regional changes in lower extremity perfusion has not been examined. METHODS AND RESULTS: Serial changes in lower extremity arteriogenesis and muscle perfusion were evaluated after femoral artery occlusion in a porcine model using single photon emission tomography (SPECT)/CT imaging with postmortem validation of in vivo findings using gamma counting, postmortem imaging, and histological analysis. Hybrid 201Tl SPECT/CT imaging was performed in pigs (n=8) at baseline, immediately postocclusion, and at 1 and 4 weeks postocclusion. CT imaging was used to identify muscle regions of interest in the ischemic and nonischemic hindlimbs for quantification of regional changes in CT-defined arteriogenesis and quantification of 201Tl perfusion. Four weeks postocclusion, postmortem tissue 201Tl activity was measured by gamma counting, and immunohistochemistry was performed to assess capillary density. Relative 201Tl retention (ischemic/nonischemic) was reduced immediately postocclusion in distal and proximal muscles and remained lower in calf and gluteus muscles 4 weeks later. Analysis of CT angiography revealed collateralization at 4 weeks within proximal muscles (P<0.05). SPECT perfusion correlated with tissue gamma counting at 4 weeks (P=0.01). Increased capillary density was seen within the ischemic calf at 4 weeks (P=0.004). CONCLUSIONS: 201Tl SPECT/CT imaging permits serial, regional quantification of arteriogenesis and resting tissue perfusion after limb ischemia. This approach may be effective for detection of disease and monitoring therapy in peripheral arterial disease. PMID- 24170238 TI - Development and validation of a quantitative method to assess pedicle screw loosening in posterior spine instrumentation on plain radiographs. AB - PURPOSE: Currently, the diagnosis of pedicle screw (PS) loosening is based on a subjectively assessed halo sign, that is, a radiolucent line around the implant wider than 1 mm in plain radiographs. We aimed at development and validation of a quantitative method to diagnose PS loosening on radiographs. METHODS: Between 11/2004 and 1/2010 36 consecutive patients treated with thoraco-lumbar spine fusion with PS instrumentation without PS loosening were compared with 37 other patients who developed a clinically manifesting PS loosening. Three different angles were measured and compared regarding their capability to discriminate the loosened PS over the postoperative course. The inter-observer invariance was tested and a receiver operating characteristics curve analysis was performed. RESULTS: The angle measured between the PS axis and the cranial endplate was significantly different between the early and all later postoperative images. The Spearman correlation coefficient for the measurements of two observers at each postoperative time point ranged between 0.89 at 2 weeks to 0.94 at 2 months and 1 year postoperative. The angle change of 1.9 degrees between immediate postoperative and 6-month postoperative was 75% sensitive and 89% specific for the identification of loosened screws (AUC = 0.82). DISCUSSION: The angle between the PS axis and the cranial endplate showed good ability to change in PS loosening. A change of this angle of at least 2 degrees had a relatively high sensitivity and specificity to diagnose screw loosening. PMID- 24170239 TI - Sol-hydrothermal synthesis and optical properties of Eu3+, Tb(3+)-codoped one dimensional strontium germanate full color nano-phosphors. AB - Novel near-UV and blue excited Eu(3+), Tb(3+)-codoped one dimensional strontium germanate full-color nano-phosphors have been successfully synthesized by a simple sol-hydrothermal method. The morphologies, internal structures, chemical constitution and optical properties of the resulting samples were characterized using FE-SEM, TEM, HRTEM, EDS, XRD, FTIR, XPS, PL and PLE spectroscopy and luminescence decay curves. The results suggested that the obtained Eu(3+), Tb(3+) codoped strontium germanate nanowires are single crystal nanowires with a diameter ranging from 10 to 80 nm, average diameter of around 30 nm and the length ranging from tens to hundreds micrometers. The results of PL and PLE spectra indicated that the Eu(3+), Tb(3+)-codoped single crystal strontium germanate nanowires showed an intensive blue, blue-green, green, orange and red or green, orange and red light emission under excitation at 350-380 nm and 485 nm, respectively, which may attributed to the coexistent Eu(3+), Eu(2+) and Tb(3+) ions, and the defects located in the strontium germanate nanowires. A possible mechanism of energy transfer among the host, Eu(3+) and Tb(3+) ions was proposed. White-emission can be realized in a single-phase strontium germanate nanowire host by codoping with Tb(3+) and Eu(3+) ions. The Eu(3+), Tb(3+)-codoped one-dimensional strontium germanate full-color nano-phosphors have superior stability under electron bombardment. Because of their strong PL intensity, good CIE chromaticity and stability, the novel 1D strontium germanate full-color nano phosphors have potential applications in W-LEDs. PMID- 24170240 TI - Acute tryptophan depletion reduces nitric oxide synthase in the rat hippocampus. AB - Acute tryptophan depletion (ATD) is extensively used to investigate the role of central serotonin (5-HT). However, several studies reported that ATD had no significant effect on central 5-HT concentration and some ATD-induced changes was independent of 5-HT in the rodent brain. Therefore, the potential mechanism of ATD might not be ascribed solely to changes in the central 5-HT system. In recent studies, evidence suggests that nitric oxide synthase (NOS) is closely associated with ATD-induced changes in modulation of cerebral blood flow and metabolism, cognitive, and locomotor activity. Thus, NOS is implicated to be an underlying factor contributing to ATD-induced changes. In the present study, the effect of ATD upon central NOS levels in the rat was evaluated. Male Sprague-Dawley (SD) rats were orally administered a tryptophan-free protein-carbohydrate mixture. Then, ATD effects upon affective behavior and spatial memory were assessed by the forced swimming test (FST) and Morris water maze test, respectively. Further, NOS activity and neuronal NOS (nNOS) protein levels in the hippocampus were measured after ATD. Our experimental results showed that ATD had no influence on affective behavior in the FST or spatial memory in SD rats. Interestingly, a significant reduction of both constitutive NOS activity and nNOS protein levels after ATD was found in the hippocampus. These findings demonstrate ATD does not influence affective behavior and spatial memory despite a direct effect on hippocampal NOS. Our study might provide a valuable clue for exploring earlier reported ATD induced behavioral and neurochemical changes in rodents. PMID- 24170241 TI - Continuous adenosine A2A receptor antagonism after focal cerebral ischemia in spontaneously hypertensive rats. AB - Antagonism of the adenosine A2A receptor (A2AR) has been shown to elicit substantial neuroprotective properties when given immediately after cerebral ischemia. We asked whether the continuous application of a selective A2AR antagonist within a clinically relevant time window will be a feasible and effective approach to treat focal cerebral ischemia. To answer this question, we subjected 20 male spontaneously hypertensive rats to permanent middle cerebral artery occlusion and randomized them equally to a verum and a control group. Two hours after stroke onset, the animals received a subcutaneous implantation of an osmotic minipump filled with 5 mg kg(-1) day(-1) 8-(3-chlorostyryl) caffeine (CSC) or vehicle solution. The serum level of CSC was measured twice a day for three consecutive days. The infarct volume was determined at days 1 and 3 using magnetic resonance imaging. We found the serum level of CSC showing a bell-shaped curve with its maximum at 36 h. The infarct volume was not affected by continuous CSC treatment. These results suggest that delayed and continuous CSC application was not sufficient to treat acute ischemic stroke, potentially due to unfavorable hepatic elimination and metabolization of the pharmaceutical. PMID- 24170242 TI - Bisphenol A differently inhibits CaV3.1, Ca V3.2 and Ca V3.3 calcium channels. AB - Bisphenol A (BPA) is a widespread environmental contaminant detected in urine of 93 % of investigated US population. Recent epidemiological studies found correlation between BPA exposure and diseases including cardiovascular and neuronal disorders. BPA targets include hormone receptors and voltage-dependent ion channels. T-type calcium channels are important regulatory elements in both cardiovascular and neuronal system. Therefore, we investigated effects of BPA on T-type calcium channels. Calcium current flowing through recombinant T-type calcium channels expressed in HEK 293 cells was measured using whole-cell patch clamp. BPA inhibited the current through individual T-type calcium channel subtypes in a concentration-dependent manner with two distinguishable components in these concentration-dependencies. Nanomolar concentrations of BPA inhibited calcium current through T-type calcium channels in the order of efficiency CaV3.2 >= CaV3.1 > CaV3.3 without affecting voltage dependence and kinetics of channel gating. Micromolar concentrations of BPA accelerated kinetics of current decay, shifted voltage dependence of steady-state inactivation towards more negative values and inhibited current amplitudes. We suggest that BPA acts as a modifier of channel gating and directly plugs conductive channel pore at high concentration. Concentration range in which inhibition was observed corresponds to concentrations detected in human fluids and therefore may be relevant for evaluation of health effects of BPA. PMID- 24170243 TI - Lurasidone and bipolar disorder. PMID- 24170245 TI - Laser trapping-induced crystallization of L-phenylalanine through its high concentration domain formation. AB - We present the laser trapping-induced crystallization of L-phenylalanine through high-concentration domain formation in H2O and D2O solutions which is achieved by focusing a continuous-wave (CW) near-infrared laser beam at the solution surface. Upon laser irradiation into the H2O solution, laser trapping of the liquid-like clusters increases the local concentration, accompanying laser heating, and a single plate-like crystal is eventually prepared at the focal spot. On the other hand, in the D2O solution, a lot of the monohydrate needle-like crystals are observed, not at the focal spot where the concentration is high enough to trigger crystal nucleation, but in the 0.5-1.5 mm range from the focal spot. The dynamics and mechanism of the amazing crystallization behaviour induced by laser trapping are discussed from the viewpoints of the concentration increase due to laser heating depending on solvent, the large high-concentration domain formation by laser trapping of liquid-like clusters, and the orientational disorder of molecules/clusters at the domain edge. PMID- 24170246 TI - Importance of uterine cervical cerclage to maintain a successful pregnancy for patients who undergo vaginal radical trachelectomy. AB - BACKGROUND: We have performed 36 vaginal radical trachelectomies (RTs) for patients with early invasive uterine cervical cancer and experienced 10 deliveries. Pregnancy after RT has far higher risks of prematurity and complications such as preterm premature rupture of the membrane (pPROM) and chorioamnionitis. We report the significance of transabdominal cerclage in the follow-up of pregnancy after vaginal RT. METHODS: Our operative procedure is based on that of Dargent et al. We amputated the cervix approximately 10 mm below the isthmus. For the removal of the parametrium, we cut at the level of type II hysterectomy. A nylon suture is also placed around the residual cervix. Pregnancy courses after vaginal RT were studied in 9 patients (10 pregnancies) with respect to cervical length and several infectious signs. RESULTS: Obstetric prognosis after RT was improved with our follow-up modality. Four patients who were followed up with this modality were able to continue their pregnancies until late in the third trimester. However, it was not effective for four patients who showed cervical incompetence due to slack cerclage. They suffered from pPROM without any infectious signs and uterine contraction. Though we performed transabdominal uterine cervical cerclage for one patient in her 19th week of pregnancy, it was unsuccessful. CONCLUSIONS: Cervical cerclage placed at the time of RT played an important role in preventing dilatation of the uterine cervix and the subsequent occurrence of pPROM. Transabdominal cervical cerclage should be performed earlier in pregnancy or before pregnancy in patients who have experienced problems with cervical cerclage. PMID- 24170247 TI - Five-year potency preservation after iodine-125 prostate brachytherapy. AB - BACKGROUND: We aimed to evaluate long-term erectile function following prostate brachytherapy, based on patient characteristics and treatment factors. METHODS: Between 2003 and 2006, 665 men with localized prostate cancer were treated with (125)I permanent seed implantation. None was given adjuvant hormone therapy. Erectile function was assessed before treatment, and at 6 months, 1, 2, 3, 4 and 5 years after implantation using the Mount Sinai Erectile Function Score (MSEFS) of 0-3 (0 = no erections, 1 = erections insufficient for intercourse, 2 = suboptimal erections but sufficient for intercourse, 3 = normal erectile function). Potency was defined as score 2 or 3, and 382 men were potent before treatment. Univariate and multivariate analyses were performed on the data from these 382 patients to identify variables associated with potency preservation. RESULTS: In patients who were potent before treatment, the actuarial potency preservation rate fell to 46.2 % at 6 months after brachytherapy, and then slowly recovered reaching 52.0 % at 5 years after brachytherapy. In multivariate logistic regression analysis, patient age (p = 0.04) and pre-treatment MSEFS (p < 0.001) were predictors of 5-year potency preservation. Neoadjuvant hormone therapy affected potency preservation only at 6 months after brachytherapy. CONCLUSIONS: Patient age at implantation and pre-treatment erectile function are predictive factors for the development of erectile dysfunction following prostate brachytherapy. PMID- 24170250 TI - Racial bias unlikely to be a factor in the differential performance of candidates in the MRCGP exam. PMID- 24170249 TI - American Society of Clinical Oncology 2013 top five list in oncology. PMID- 24170248 TI - Transcription and beyond: the role of mammalian class I lysine deacetylases. AB - The Rpd3-like members of the class I lysine deacetylase family are important regulators of chromatin structure and gene expression and have pivotal functions in the control of proliferation, differentiation and development. The highly related class I deacetylases HDAC1 and HDAC2 have partially overlapping but also isoform-specific roles in diverse biological processes, whereas HDAC3 and HDAC8 have unique functions. This review describes the role of class I KDACs in the regulation of transcription as well as their non-transcriptional functions, in particular their contributions to splicing, mitosis/meiosis, replication and DNA repair. During the past years, a number of mouse loss-of-function studies provided new insights into the individual roles of class I deacetylases in cell cycle control, differentiation and tumorigenesis. Simultaneous ablation of HDAC1 and HDAC2 or single deletion of Hdac3 severely impairs cell cycle progression in all proliferating cell types indicating that these class I deacetylases are promising targets for small molecule inhibitors as anti-tumor drugs. PMID- 24170251 TI - The role of molecular structure of sugar-phosphate backbone and nucleic acid bases in the formation of single-stranded and double-stranded DNA structures. AB - Our previous DFT computations of deoxydinucleoside monophosphate complexes with Na(+)-ions (dDMPs) have demonstrated that the main characteristics of Watson Crick (WC) right-handed duplex families are predefined in the local energy minima of dDMPs. In this work, we study the mechanisms of contribution of chemically monotonous sugar-phosphate backbone and the bases into the double helix irregularity. Geometry optimization of sugar-phosphate backbone produces energy minima matching the WC DNA conformations. Studying the conformational variability of dDMPs in response to sequence permutation, we found that simple replacement of bases in the previously fully optimized dDMPs, e.g. by constructing Pyr-Pur from Pur-Pyr, and Pur-Pyr from Pyr-Pur sequences, while retaining the backbone geometry, automatically produces the mutual base position characteristic of the target sequence. Based on that, we infer that the directionality and the preferable regions of the sugar-phosphate torsions, combined with the difference of purines from pyrimidines in ring shape, determines the sequence dependence of the structure of WC DNA. No such sequence dependence exists in dDMPs corresponding to other DNA conformations (e.g., Z-family and Hoogsteen duplexes). Unlike other duplexes, WC helix is unique by its ability to match the local energy minima of the free single strand to the preferable conformations of the duplex. PMID- 24170252 TI - [Pharmaceutical treatment of bipolar depression. Evidence from clinical guidelines and treatment recommendations]. AB - Treatment of bipolar depression requires complex treatment decisions in daily routine care. The best evidence for pharmacological treatment is given for quetiapine and with limitations also in off-label use for lamotrigine, especially in combination with lithium, carbamazepine and olanzapine. Effectiveness and recommendation of antidepressants in treatment of bipolar depression remain controversial because of insufficient data. Initially, in depressive episodes a phase prophylactic treatment should be initiated or (if already existing) optimized and more severe episodes should be treated with the substances described before. In case of non-response, the combination of lithium and lamotrigine or antidepressants in combination with lithium, antiepileptics or atypical antipsychotics may be necessary. If depressive episodes occur in the course of pharmacological treatment with prophylactic agents, combination therapies of different substances, even with antidepressants, are necessary. In case of treatment-resistant depressive episodes, complex treatment strategies (e.g. combination therapies and MAO inhibitors) should be considered. PMID- 24170253 TI - Role of PGE2 in the colonic motility: PGE2 generates and enhances spontaneous contractions of longitudinal smooth muscle in the rat colon. AB - The aim of this study was to determine which PGE2 receptors (EP1-4 receptors) influence colonic motility. Mucosa-free longitudinal smooth muscle strips of the rat middle colon spontaneously induced frequent phasic contractions (giant contractions, GCs) in vitro, and the GCs were almost completely abolished by a cyclooxygenase inhibitor, piroxicam, and by an EP3 receptor antagonist, ONO-AE3 240, but enhanced by tetrodotoxin (TTX). In the presence of piroxicam, exogenous PGE2, both ONO-AE-248 (EP3 agonist), and ONO-DI-004 (EP1 agonist) induced GC-like contractions, and increased the frequency and amplitude. These effects of EP receptor agonists were insensitive to TTX and omega-conotoxins. In immunohistochemistry, the EP1 and EP3 receptors were expressed in the longitudinal smooth muscle cells. These results suggest that the endogenous PGE2 spontaneously generates and enhances the frequent phasic contractions directly activating the EP1 and EP3 receptors expressed on longitudinal smooth muscle cells in the rat middle colon. PMID- 24170254 TI - Spondyloarthritis with onset after age 45. AB - The ASAS (Assessment in SpondyloArtrhritis international Society) classification criteria for axial and peripheral spondyloarthritis permit to classify patients with age at disease onset less than 45 years. Nevertheless, these two forms of spondyloarthritis may begin after the age of 45. With the longer duration of the life expectancy, patients with this late-onset form of spondyloarthritis may be more frequently recognized in the near future. A small percentage (ranging from 3.5 to 6 %) of patients with axial SpA, as defined by the modified New York criteria, have onset of their disease after 45 years of age. Relatively more frequent is the late onset form of peripheral spondyloarthritis with the characteristics of undifferentiated spondyloarthritis. Its clinical spectrum is as broad as it is in children and very young adults. Psoriatic arthritis frequently begins over the age of 45 and occasionally after the age of 60. Some old studies had suggested than elderly-onset psoriatic arthritis is more severe than younger-onset disease, but a recent study found no such difference, and further studies are needed. PMID- 24170255 TI - The future of osteoarthritis therapeutics: emerging biological therapy. AB - Biological therapy is a thriving area of research and development, and is well established for chronic forms of rheumatoid arthritis (RA) and ankylosing spondylitis (AS). However, there is no clinically validated biological therapy for osteoarthritis (OA). Chronic forms of OA are increasingly viewed as an inflammatory disease. OA was largely regarded as a "wear and tear disease". However, the disease is now believed to involve "low grade" inflammation and the growth of blood vessels and nerves from the subchondral bone into articular cartilage. This realization has focused research effort on the development and evaluation of biological therapy that targets proinflammatory mediators, angiogenic factors and cytokines in articular cartilage, subchondral bone and synovium in chronic forms of OA. This review article provides an overview of emerging biological therapy for OA, and discusses recent molecular targets implicated in angiogenesis and neurogenesis and progress with antibody-based therapy, calcitonin, and kartogenin, the small molecule stimulator of chondrogenesis. PMID- 24170256 TI - An in vitro analysis of disintegration times of different formulations of olanzapine orodispersible tablet: a preliminary report. AB - BACKGROUND: Orodispersible tablets (ODTs) are tablet or wafer forms of medication that disintegrate in the mouth, aided only by saliva. ODTs rely on different fast dissolve/disintegration manufacturing technologies. OBJECTIVES: Disintegration time differences for several olanzapine ODT forms were investigated. Risperdal M Tab((r)) was included as a non-olanzapine ODT comparator. RESEARCH DESIGN AND METHODS: Eleven olanzapine ODT examples and orodispersible risperidone strengths were evaluated in vitro for formulation composition, manufacturing method, disintegration and dissolution characteristics, and formulation differences in comparison with freeze dried Zydis((r)) ODT. Automated dissolution test equipment captured ODT dissolution rates by measuring real-time release of active ingredient. A high-speed video camera was used to capture tablet disintegration times in warm simulated saliva. MAIN OUTCOME MEASURE: The main outcome measure was the disintegration and dissolution characteristics of the ODT formulations. RESULTS: The ODT manufacturing method was associated with time to disintegrate; the fastest were freeze dried tablets, followed by soft compressed tablets and then hard/dense tablets. Olanzapine Zydis((r)) was the only ODT that completely disintegrated in less than 4 s for all strengths (5, 10, 15, and 20 mg), followed by 5-mg Prolanz FAST((r)) (12 s) and then risperidone ODT 4 mg (40 s). Reasons for slow dissolution of the olanzapine generics may include low product potency, excipient binding, excipient solubility, active ingredient particle size and incomplete disintegration. CONCLUSIONS: Differences in the formulation and manufacturing process of olanzapine ODTs appear to have a strong influence on the disintegration time of the active compound; differences that may potentially impact their use in clinical practice. PMID- 24170257 TI - A novel mutation in STXBP1 gene in a child with epileptic encephalopathy and an atypical electroclinical pattern. AB - Mutations in STXBP1 gene, encoding the syntaxin binding protein 1, have been recently described in Ohtahara syndrome, or early infantile epileptic encephalopathy with suppression-burst pattern, and in other early-onset epileptic encephalopathies. A 3-year-old boy affected by epileptic encephalopathy started at 8 months of age is described. Focal epilepsy was characterized by drug resistance seizures with multifocal interictal and ictal electroencephalographic (EEG) features and variable EEG focus. Direct sequencing of the STXBP1 gene showed a novel de novo mutation (c.751G>A), leading to a p.Ala251Thr substitution. Based on reported data, treatment with vigabatrin was attempted and patient became immediately seizure free for 4 months. The present case further expands the clinical spectrum of "STXBP1-related encephalopathy" suggesting molecular analysis of STXBP1 in early onset epileptic encephalopathies of unknown etiology (with onset within the first year of life). In addition, the case provides valuable suggestions on seizures treatment in STXBP1 mutated subjects. PMID- 24170259 TI - Churg-Strauss syndrome in childhood: a case report. AB - Churg-Strauss syndrome is a rare form of small-vessel vasculitis. In the current report, we describe the case of a 17-year-old Czech girl predominantly characterized by peripheral neuropathy, the presence of cardiac and pulmonary involvement, hypereosinophilia, asthma, and sinusitis that led to the diagnosis of Churg-Strauss syndrome. PMID- 24170260 TI - Coupling of vessel wall morphology and function in the aorta and the carotid artery: an evaluation with MRI. AB - To evaluate the regional association between vessel wall morphology [i.e. cross sectional vessel wall area (VWA)] and function [i.e. wall stiffness expressed in the pulse wave velocity (PWV)] in both the aortic arch and the left carotid artery. Thirty-two healthy volunteers (mean age 41 +/- 16 years) underwent 3T MRI examination to assess PWV and VWA of the aorta and the left carotid artery. PWV was determined by the transit-time method with velocity-encoded MRI recordings of the systolic blood flow propagation. VWA was assessed for both the aorta and the carotid artery, by detecting lumen and outer vessel wall contours in cross sectional black blood images. Linear regression analyses were used to test associations between aortic and carotid vessel wall area and stiffness. Within the same vascular territory, correlation between PWV and VWA was stronger than across vascular territories. For the aorta, the correlation between PWVAO and VWAAO (r = 0.71, p < 0.0001) was stronger than between PWVAO and VWACA (r = 0.53, p = 0.002). For the carotid artery, the correlation between PWVCA and VWACA (r = 0.61, p < 0.0001) was stronger than between PWVCA and VWAAO (r = 0.46, p = 0.008). Morphologic and functional vessel wall properties assessed in the aortic arch and the left carotid artery are significantly stronger associated within the same vascular territory rather than across different vascular territories. PMID- 24170261 TI - The compensation for asynchronous cardiac quiescence in coronary wall MR imaging. AB - The aim of the present study was to assess the incremental benefit of compensating asynchronous cardiac quiescence in coronary wall MR imaging. With the approval of IRB, black-blood coronary wall MR imaging was performed on 30 older subjects (90 coronary wall segments). For round 1 coronary wall MR imaging, acquisition windows were traditionally set within rest period(4-chamber). Totally 51 of 90 images were ranked as "good" images and resulted in an interpretability rate of 57%. Then, an additional cine-MR was centered at coronary segments to obtain rest period(cross-sectional). The rest period(overlap) (the intersection between rest period(4-chamber) and rest period(cross-sectional)) was measured for each coronary segment. The "good" images had a longer rest period(overlap) and higher acquisition coincidence rate (the percentage of acquisition window covered by the rest period(overlap)) than "poor" images. Coronary wall rescans (round 2) were completed at 39 coronary segments that were judged as having "poor" images in round 1 scans. The acquisition window was set within the rest period(overlap). For the round 2 images, 17 of 39 (44%) coronary segments were ranked as "good" images. The overall interpretability rate (68 of 90, 76%) was significantly higher than that of the round 1 images alone. Our data demonstrated that asynchronous cardiac quiescence adversely affects the performance of coronary wall MR imaging. Individualizing acquisition windows based on multi-plane cine-MR helps to compensate for this motion discrepancy and to improve image quality. PMID- 24170258 TI - A review of environmental contributions to childhood motor skills. AB - Although much of children's motor skills have a heredity component, at least half of the variance is likely to be influenced by the environment. It is important to ascertain features of the environment that are responsible so that toxins can be avoided, children at risk can be identified, and beneficial interventions initiated. This review outlines the results of published studies and recommends the areas where further research is required. We found much confusion with little comparability concerning the ages or measures used. Few studies had sufficient power and few allowed for confounders. We found that research to date implicates associations with prenatal drinking >=4 drinks of alcohol per day; diabetes; taking antidepressant drugs; being deficient in iodine or iron; dietary fish; and postnatal depression. The child appearing to be most at risk was born of low birth weight (but not due to preterm delivery) or with neonatal problems. PMID- 24170262 TI - Near-infrared fluorescence imaging of murine atherosclerosis using an oxidized low density lipoprotein-targeted fluorochrome. AB - The aim of this study was to explore the feasibility of detecting plaques using an NIR797 fluorochrome-labeled, anti-oxLDL antibody (anti-oxLDL-NIR797) and near infrared fluorescence (NIRF) imaging in a murine model of atherosclerosis. Anti mouse oxLDL polyclonal antibodies were conjugated to NIR797 dyes to synthesis oxLDL-targeted NIRF probe. In situ and ex vivo NIRF imaging of the high cholesterol diet-induced atherosclerotic lesions of apoE-/- mice (baseline) as well as ex vivo NIRF imaging in the progression and regression group (without or with atorvastatin treatment for another 8 weeks) were performed 24 h after an intravenous injection of 1 mg/kg of anti-oxLDL-NIR797, while phosphate-buffered saline (PBS) was used for the controls. The plaque areas were investigated using Oil Red O (ORO) staining. Aortas isolated from the apoE-/- mice 24 h post injection exhibited a selective, strong, heterogeneous NIRF signal enhancement in the aortic root, arch, and bifurcation, whereas the PBS and competitive inhibition groups had limited NIRF signal changes (p < 0.05). There was a significant correlation between ORO staining and NIRF in the atherosclerotic aortas that received anti-oxLDL-NIR797. Immunofluorescence studies confirmed the colocalization of the oxLDL/macrophages and NIR797 fluorochromes. Furthermore, the atherosclerotic lesions of atorvastatin-treated mice showed reduced anti oxLDL-NIR797 uptake and oxLDL expression. These results indicate that NIRF plaque imaging is feasible with an oxLDL-targeted NIRF probe. Thus, oxLDL-based molecular imaging of atherosclerotic plaques is feasible and may provide important methods for characterizing vulnerable plaques and monitoring the response to therapeutic interventions for atherosclerosis. PMID- 24170263 TI - Calcium carbonate does not affect imatinib pharmacokinetics in healthy volunteers. AB - PURPOSE: Imatinib mesylate (Gleevec((r))/Glivec((r))) has revolutionized the treatment of chronic myeloid leukemias and gastrointestinal stromal tumors, and there is evidence for an exposure response relationship. Calcium carbonate is increasingly used as a calcium supplement and in the setting of gastric upset associated with imatinib therapy. Calcium carbonate could conceivably elevate gastric pH and complex imatinib, thereby influencing imatinib absorption and exposure. We aimed to evaluate whether use of calcium carbonate has a significant effect on imatinib pharmacokinetics. METHODS: Eleven healthy subjects were enrolled in a 2-period, open-label, single-institution, randomized crossover, fixed-schedule study. In one period, each subject received 400 mg of imatinib p.o. In the other period, 4,000 mg calcium carbonate (Tums Ultra((r))) was administered p.o. 15 min before 400 mg of imatinib. Plasma concentrations of imatinib and its active N-desmethyl metabolite CGP74588 were assayed by LC-MS; data were analyzed non-compartmentally and compared after log transformation. RESULTS: Calcium carbonate administration did not significantly affect the imatinib area under the plasma concentration versus time curve (AUC) (41.2 MUg/mL h alone vs. 40.8 MUg/mL h with calcium carbonate, P = 0.99), maximum plasma concentration (C(max)) (2.35 MUg/mL alone vs. 2.39 MUg/mL with calcium carbonate, P = 0.89). CONCLUSIONS: Our results indicate that the use of calcium carbonate does not significantly affect imatinib pharmacokinetics. PMID- 24170264 TI - Feasibility and constraints of particle targeting using the antigen-antibody interaction. AB - This work is concerned with the surface modification of fluorescent silica nanoparticles by a monoclonal antibody (M75) and the specific bioadhesion of such particles to surfaces containing the PG domain of carbonic anhydrase IX (CA IX), which is a trans-membrane protein specifically expressed on the surfaces of several tumor cell lines. The adhesion strength of antibody-bearing silica nanoparticles to antigen-bearing surfaces was investigated under laminar flow conditions in a microfluidic cell and compared to the adhesion of unmodified silica nanoparticles and nanoparticles coupled with an unspecific antibody. Adhesion to cancer cells using flow cytometry was also investigated and in all cases the adhesion strength of M75-modified nanoparticles was significantly stronger than for the unmodified or unspecific nanoparticles, up to several orders of magnitude in some cases. The specific modification of nano- and microparticles by an antibody-like protein therefore appears to be a feasible approach for the targeting of tumor cells. PMID- 24170265 TI - Unilateral versus bilateral fixation for lumbar spinal fusion: a systemic review and meta-analysis. AB - PURPOSE: The objective of this study was to systematically compare the efficacy and safety of unilateral fixation to bilateral fixation for the lumbar degenerative disease. STUDY DESIGN: Systematic review and meta-analysis. METHODS: We searched databases including PubMed Central, MEDLINE (from 1966), EMBASE (from 1980), and Cochrane Central Register of Controlled Trials databases for randomized controlled trials or non-randomized controlled trials that compare unilateral fixation with bilateral fixation for the treatment for lumbar disease. Exclusion criteria were non-controlled studies, follow-up <6 months, combined anterior and posterior surgery, lumbar tumors, and non-English writing paper. Methodologic quality was assessed, relevant data were retrieved, and the appropriate meta-analysis was performed. Two review authors independently selected studies, extracted data, and assessed the risk of bias. The main end points included the rate of fusion, visual analogue scale (VAS), Oswestry disability index (ODI), intra-operative blood loss, operating time, and the rate of complications. RESULTS: A total of seven studies were included in the meta analysis. Four relevant randomized controlled trials, one prospective study, and two retrospective studies involving 499 patients were identified. Patients in unilateral pedicle fixation group compared with bilateral pedicle screw fixation group on the fusion rate, VAS, ODI scores, and complication rate demonstrated no significant differences (P > 0.05, respectively). However, intra-operative blood loss and operating time in unilateral fixation group were significantly less than bilateral fixation group (P < 0.0001, respectively). CONCLUSIONS: Unilateral fixation seems to be an effective, feasible, and safe procedure in one or two segmental disease when compare with bilateral instrumentation. PMID- 24170266 TI - Less invasive reduction and fusion of fresh A2 and A 3 traumatic L 1-L 4 fractures with a novel vertebral body augmentation implant and short pedicle screw fixation and fusion. AB - The aim of this clinical study was to report on the efficacy in reduction and safety in PMMA leakage of a novel vertebral augmentation technique with PEEK and PMMA, together with pedicle screws in the treatment of fresh vertebral fractures in young adults. Twenty consecutive young adults aged 45 +/- 11 years with fresh burst A3/AO or severely compressed A2/AO fractures underwent via a less invasive posterior approach one-staged reduction with a novel augmentation implant and PMMA plus 3-vertebrae pedicle screw fixation and fusion. Radiologic parameters as segmental kyphosis (SKA), anterior (AVBHr) and posterior vertebral body height ratio (PVBHr), spinal canal encroachment (SCE), cement leakage and functional parameters as VAS, SF-36 were measured pre- and post-operatively. Hybrid construct restored AVBHr (P < 0.000), PVBHr (P = 0.02), SKA (P = 0.015), SCE (P = 0.002) without loss of correction at an average follow-up of 17 months. PMMA leakage occurred in 3 patients (3 vertebrae) either anteriorly to the fractured vertebral body or to the adjacent disc, but in no case to the spinal canal. Two pedicle screws were malpositioned (one medially, one laterally to the pedicle at the fracture level) without neurologic sequelae. Solid posterolateral spinal fusion occurred 8-10 months post-operatively. Pre-operative VAS and SF-36 scores improved post-operatively significantly. This study showed that this novel vertebral augmentation technique using PEEK implant and PMMA reduces and stabilizes via less invasive technique A2 and A3 vertebral fractures without loss of correction and leakage to the spinal canal. PMID- 24170268 TI - An integrated microfluidic device for the high-throughput screening of microalgal cell culture conditions that induce high growth rate and lipid content. AB - This study describes the development of a microfluidic device for the high throughput screening of culture conditions, such as the optimum sodium acetate concentration for promoting rapid growth and high lipid accumulation of Chlamydomonas reinhardtii. An analysis of the microalgal growth on the microfluidic device revealed an optimum sodium acetate concentration of 5.72 g L( 1). The lipid content, determined by the 4,4-Difluoro-1,3,5,7-tetramethyl-4-bora 3a,4a-diaza-s-indacene (BODIPY(r) 505/515) staining method, increased with the sodium acetate concentration. The results were found to be statistically reproducible with respect to cell growth and lipid production. Other nutrient conditions, including the nitrogen and phosphorus concentrations, can also be optimized on the same microfluidic platform. The microfluidic device performance results agreed well with the results obtained from the flask-scale experiments, validating that the culture conditions were scalable. Finally, we, for the first time, established a method for the absolute quantification of the microalgal lipid content in the picoliter culture volumes by comparing the on-chip and off chip data. In conclusion, we successfully demonstrated the high-throughput screening of sodium acetate concentrations that induced high growth rates and high lipid contents in C. reinhardtii cells on the microfluidic device. PMID- 24170267 TI - c-Kit-positive cardiac stem cells nested in hypoxic niches are activated by stem cell factor reversing the aging myopathy. AB - RATIONALE: Hypoxia favors stem cell quiescence, whereas normoxia is required for stem cell activation, but whether cardiac stem cell (CSC) function is regulated by the hypoxic/normoxic state of the cell is currently unknown. OBJECTIVE: A balance between hypoxic and normoxic CSCs may be present in the young heart, although this homeostatic control may be disrupted with aging. Defects in tissue oxygenation occur in the old myocardium, and this phenomenon may expand the pool of hypoxic CSCs, which are no longer involved in myocyte renewal. METHODS AND RESULTS: Here, we show that the senescent heart is characterized by an increased number of quiescent CSCs with intact telomeres that cannot re-enter the cell cycle and form a differentiated progeny. Conversely, myocyte replacement is controlled only by frequently dividing CSCs with shortened telomeres; these CSCs generate a myocyte population that is chronologically young but phenotypically old. Telomere dysfunction dictates their actual age and mechanical behavior. However, the residual subset of quiescent young CSCs can be stimulated in situ by stem cell factor reversing the aging myopathy. CONCLUSIONS: Our findings support the notion that strategies targeting CSC activation and growth interfere with the manifestations of myocardial aging in an animal model. Although caution has to be exercised in the translation of animal studies to human beings, our data strongly suggest that a pool of functionally competent CSCs persists in the senescent heart and that this stem cell compartment can promote myocyte regeneration effectively, partly correcting the aging myopathy. PMID- 24170269 TI - Quick supramolecular solvent-based microextraction for quantification of low curcuminoid content in food. AB - There is a need to monitor the consumption of curcuminoids, an EU-permitted natural colour in food, to ensure that acceptable daily intakes are not exceeded, especially by young children. This paper describes a sensitive method able to quantify low contents of curcumin (CUR), demethoxycurcumin (DMC) and bis demethoxycurcumin (BDMC) in foodstuffs. The method was based on a single-step extraction by use of a supramolecular solvent (SUPRAS) made up of reverse aggregates of decanoic acid, and direct analysis of the extract by use of liquid chromatography-photodiode array (PDA) detection. The extraction involved the stirring of 200 mg foodstuff with 600 MUL SUPRAS for 15 min. No cleanup or concentration of the extracts was required. Curcuminoid solubilisation occurred via dispersion and hydrogen bonding. The method was used for the determination of curcuminoids in different types of foodstuff (snack, gelatine, yoghurt, mayonnaise, butter, candy and fish products) that encompassed a wide range of protein, fat, carbohydrate, sugar and water contents (0.85-11.04, 0-81.11, 0.06 75, 0.06-79.48, and 10.08-85.10 g, respectively, in each 100 g of food). Method quantification limits for the foodstuffs analysed were in the ranges 2.9-7.7, 2.8 11.2 and 3.3-9.0 MUg kg(-1) for CUR, DMC and BDMC, respectively. The concentrations of curcuminoids detected in the foodstuffs and the recoveries obtained from fortified samples were in the ranges ND-284, ND-201 and ND-61.3 MUg kg(-1), and 82-106, 89-106 and 90-102 %, for CUR, DMC and BDMC, respectively. The relative standard deviations were in the range 2-7 %. This method enabled quick and simple microextraction of curcuminoids with minimal solvent consumption, while delivering accurate and precise data. PMID- 24170270 TI - Study of lysozyme resistance in Rhodococcus equi. AB - Lysozyme is an important and widespread component of the innate immune response that constitutes the first line of defense against bacterial pathogens. The bactericidal effect of this enzyme relies on its capacity to hydrolyze the bacterial cell wall and also on a nonenzymatic mechanism involving its cationic antimicrobial peptide (CAMP) properties, which leads to membrane permeabilization. In this paper, we report our findings on the lysozyme resistance ability of Rhodococcus equi, a pulmonary pathogen of young foals and, more recently, of immunocompromised patients, whose pathogenic capacity is conferred by a large virulence plasmid. Our results show that (i) R. equi can be considered to be moderately resistant to lysozyme, (ii) the activity of lysozyme largely depends on its muramidase action rather than on its CAMP activity, and (iii) the virulence plasmid confers part of its lysozyme resistance capacity to R. equi. This study is the first one to demonstrate the influence of the virulence plasmid on the stress resistance capacity of R. equi and improves our understanding of the mechanisms enabling R. equi to resist the host defenses. PMID- 24170271 TI - Selection and characterisation of FVIII-specific single chain variable fragments. AB - The development of inhibitory anti-FVIII antibodies is currently the most severe complication in the treatment of haemophilia A patients. Inhibitor eradication can be achieved by immune tolerance induction (ITI). Recent findings suggest a correlation between the FVIII-specific IgG subclass distribution and the duration or outcome of ITI. To quantify FVIII-specific IgG subclasses in patients' plasma FVIII-specific IgG standards are required. Here, the isolation of FVIII-specific single chain variable fragments (scFvs) from synthetic phage display libraries and the characterisation of their FVIII domain specificity are described. The isolated scFv 1G10, which binds to the FVIII A2 domain, was cloned into the context of the four human IgG (hIgG) subclasses and expressed in mammalian cells. Purified 1G10-hIgG1, -hIgG2, -hIgG3 and -hIgG4 are used as standards to determine the absolute amounts and relative contribution of the different FVIII-specific IgG subclasses in future studies. The results from these studies will eventually add to understanding the role of the FVIII-specific IgG subclass distribution as prognostic factor for the outcome of ITI. PMID- 24170273 TI - Evaluation of the psychometric properties of the Icelandic version of the Clinical Outcomes in Routine Evaluation-Outcome Measure, its transdiagnostic utility and cross-cultural validation. AB - BACKGROUND: The development of transdiagnostic standardized measures of psychological distress have contributed to the development of practice-based evidence networks. The translation and validation of such measures cross culturally is important if such research is to be generalized across health care systems in different countries. METHOD: Translation of the Clinical Outcomes in Routine Evaluation-Outcome Measure (CORE-OM) from English into Icelandic was undertaken according to recommended protocols. The resulting instrument was evaluated for reliability and validity in three groups: patients undergoing psychological treatment in general practice (n = 289), psychiatric outpatients (n = 98) and student controls (n = 207). The Mini-International Neuropsychiatric Interview was administered to the clinical participants. They also completed the CORE-OM and the Beck depression and anxiety inventories before and after treatment. The transdiagnostic relationship between CORE-OM scores and scores on those diagnostic measures was assessed. RESULTS: Good levels of validity, reliability and internal consistency were found for the CORE-OM and its domains and sensitivity to change over treatment shown. As anticipated, the risk domain had different characteristics than other domains. CORE-OM scores correlated strongly with both Beck Depression Inventory-Second edition and Beck Anxiety Inventory, particularly the problem domain. CONCLUSION: The Icelandic translation of the CORE-OM is psychometrically sound and can be applied in Icelandic mental health studies as it has been in English speaking settings. Nevertheless, the validity of the Icelandic version of the CORE-OM needs to be further investigated in larger and more diverse samples. KEY PRACTITIONER MESSAGE: The psychometric properties of the Icelandic version of the CORE-OM are comparable with the original English version. The results indicate transdiagnostic utility of the CORE-OM. The CORE-OM is a valuable instrument in outcome research on psychological treatment, specifically transdiagnostic treatment. PMID- 24170272 TI - A genome scan for loci shared by autism spectrum disorder and language impairment. AB - OBJECTIVE: The authors conducted a genetic linkage study of families that have both autism spectrum disorder (ASD) and language-impaired probands to find common communication impairment loci. The hypothesis was that these families have a high genetic loading for impairments in language ability, thus influencing the language and communication deficits of the family members with ASD. Comprehensive behavioral phenotyping of the families also enabled linkage analysis of quantitative measures, including normal, subclinical, and disordered variation in all family members for the three general autism symptom domains: social, communication, and compulsive behaviors. METHOD: The primary linkage analysis coded persons with either ASD or specific language impairment as "affected." The secondary linkage analysis consisted of quantitative metrics of autism-associated behaviors capturing normal to clinically severe variation, measured in all family members. RESULTS: Linkage to language phenotypes was established at two novel chromosomal loci, 15q23-26 and 16p12. The secondary analysis of normal and disordered quantitative variation in social and compulsive behaviors established linkage to two loci for social behaviors (at 14q and 15q) and one locus for repetitive behaviors (at 13q). CONCLUSION: These data indicate shared etiology of ASD and specific language impairment at two novel loci. Additionally, nonlanguage phenotypes based on social aloofness and rigid personality traits showed compelling evidence for linkage in this study group. Further genetic mapping is warranted at these loci. PMID- 24170274 TI - Increasing cervical cancer screening for a multiethnic population of women in South Texas. AB - Cervical cancer is a preventable disease. Precancers can be identified and treated through cervical screenings. The HPV vaccine prevents precancers from becoming cancers. The aim of the A Su Salud Cervical Cancer Prevention Program was to apply well-understood health promotion techniques and increase the rate of cervical cancer screening among a high-risk, multiethnic, low-income population in South Texas. Qualitative research was used to identify uptake barriers and tailor media messaging. Using existing resources, we applied evidence-based strategies in novel ways that changed personal behaviors, leading to cancer screening, risk reduction, and early detection. We created a database to track a cohort of 32,807 women and measured cervical cancer screenings over 3 years. Our analysis revealed an increase in cervical cancer screenings after use of highly targeted automated telephone reminders and media dissemination on multiple platforms. Those women at low risk for cervical cancer obtained the highest proportion of Pap tests. This innovative, theory-based program increased overall Pap tests up to 9% among women enrolled in a safety net hospital financial assistance plan. This study fills a gap in research on Pap test compliance in uninsured, mostly Hispanic women by building on cultural strengths and tailored messaging. PMID- 24170275 TI - Analysis of treatment that includes both hepatic and pulmonary resections for colorectal metastases. AB - PURPOSE: Hepatic or pulmonary resections for colorectal metastases are regarded as standard treatment worldwide; however, the clinical significance of both hepatic and pulmonary resections for colorectal metastases remains undefined. We reviewed our clinical experience to evaluate the benefit of this treatment. METHODS: Between 1986 and 2010, 186 patients underwent potentially curative hepatic and/or pulmonary resections for colorectal metastases. Of these patients, 25 underwent both treatments (Group C), 100 underwent hepatic resections alone (Group H), and 61 underwent pulmonary resections alone (Group L). Univariate and multivariate analyses of the clinical and pathological variables in Group C and comparative survival analyses between Group C and Groups H-L were performed. RESULTS: In Group C, the median survival after primary tumor resection, initial metastasectomy, and last metastasectomy were 97, 60, and 35 months, respectively, and the 5-year overall survival rates were 63, 54, and 38%, respectively. Multivariate analyses after initial metastasectomy revealed rectal tumors, multiple hepatic tumors, and simultaneous metastases as poor prognostic factors. Comparative survival analyses revealed no significant difference in overall survival between Group C and Groups H-L. CONCLUSION: Hepatic and pulmonary resections for colorectal metastases improve survival and may even offer the potential for cure in selected patients. PMID- 24170276 TI - Validity of using lobe-specific regional lymph node stations to assist navigation during lymph node dissection in early stage non-small cell lung cancer patients. AB - PURPOSE: The validity of our proposed lobe-specific regional lymph node stations (LSRLNS) was evaluated as a method for navigation during lymphadenectomy in patients with early stage non-small cell lung cancer (NSCLC). METHODS: A total of 725 NSCLC patients with c-T2N1M0 or less extensive disease who had undergone a curative operation with complete mediastinal lymph node dissection (MLND) were studied. The LSRLNS were #2, #3, #4 and #10 for the right upper lobe, #11i, #11s, #7 and #8 for the right lower lobe, #4, #5 and #6 for the left superior division, #11, #5 and #7 for the left lingular division and #11, #7 and #8 for the left lower lobe. RESULTS: If the LSRLNS were used for pathological examinations during surgery, 599 p-N0 and 39 p-N1 patients diagnosed with no metastasis would have been subjected to a selective MLND, while 20 p-N1 and 65 p-N2 patients who had a diagnosis of metastasis would have been navigated to a complete MLND. Two p-N2 patients with a diagnosis of no metastasis would have inappropriately undergone a selective MLND, resulting in the false negative rate at 0.3 %. CONCLUSION: Intra operative pathological examination using our LSRLNS may accurately reveal the status of metastasis, and appropriately lead to a selective or complete MLND in patients with c-T2N1M0 or less extensive disease. PMID- 24170277 TI - Agreeing in ignorance: mapping the routinisation of consent in ICT-services. AB - Many ICT services require that users explicitly consent to conditions of use and policies for the protection of personal information. This consent may become 'routinised'. We define the concept of routinisation and investigate to what extent routinisation occurs as well as the factors influencing routinisation in a survey study of internet use. We show that routinisation is common and that it is influenced by factors including gender, age, educational level and average daily internet use. We further explore the reasons users provide for not reading conditions and policies and show that they can be grouped in meaningful ways that may delineate different types of routinsation. PMID- 24170278 TI - Trust and safe spaces: mental health consumers' and carers' relationships with community pharmacy staff. AB - BACKGROUND: Trusting relationships between mental health consumers and health care providers are critical in the management and recovery process. Although community pharmacy staff are well placed to form relationships with mental health consumers and carers, little is known about the existence, nature or significance of consumer-staff relationships. OBJECTIVES: The aim of this study was to explore mental health consumers' and carers' perceptions of community pharmacy services, and describe the nature of their relationships with pharmacy staff. METHODS: Focus groups and semi-structured interviews were conducted with a convenience sample of 74 mental health consumers or carers who self-selected into the study. Thematic analysis was undertaken to explore participants' perspectives. RESULTS: Positive experiences of pharmacy services were perceived to encourage consumers' and carers' trust in pharmacists and promote relationship development. This was enhanced when participants felt that elements of patient-centred care were part of the pharmacy services provided. Although some participants perceived community pharmacy to have a limited role in mental health, those who had established relationships highlighted the current role of pharmacists in their care, and appeared to welcome further extensions of pharmacists' role in mental health. CONCLUSIONS: Trusting relationships between consumers and carers and community pharmacy staff were deemed to be important in mental health care and contributed to consumers' and carers' views of pharmacy as a safe health care space. Community pharmacy services that included core elements of patient-centred care appeared to facilitate relationship formation and associated benefits. Education and training is needed for community pharmacy staff to improve mental health knowledge and promote positive engagement with consumers and carers. PMID- 24170279 TI - Protective effects of ginsenoside Rg1 against colistin sulfate-induced neurotoxicity in PC12 cells. AB - The present study aimed to examine the protective effect of ginsenoside Rg1 against colistin-induced neurotoxicity in cultured rat pheochromocytoma (PC12) cells. Ginsenoside Rg1 was shown to elevate cell viability, decrease levels of malondialdehyde and intracellular reactive oxygen species, enhance activity of superoxide dismutase and glutathione, and decrease the release of cytochrome-c, formation of DNA fragmentation in colistin-treated PC12 cells. Ginsenoside Rg1 also reversed the increased caspase-9 and -3 mRNA levels caused by colistin in PC12 cells. These results suggest that ginsenoside Rg1 exerts a neuroprotective effect on colistin-induced neurotoxicity in PC12 cells, at least in part, via the inhibition of oxidative stress, prevention of apoptosis mediated via mitochondria pathway. Co-administration of ginsenoside Rg1 highlights the potential to increase the therapeutic index of colistin. PMID- 24170280 TI - Comparison of PLA microparticles and alum as adjuvants for H5N1 influenza split vaccine: adjuvanticity evaluation and preliminary action mode analysis. AB - PURPOSE: To compare the adjuvanticity of polymeric particles (new-generation adjuvant) and alum (the traditional and FDA-approved adjuvant) for H5N1 influenza split vaccine, and to investigate respective action mode. METHODS: Vaccine formulations were prepared by incubating lyophilized poly(lactic acid) (PLA) microparticles or alum within antigen solution. Antigen-specific immune responses in mice were evaluated using ELISA, ELISpot, and flow cytometry assay. Adjuvants' action modes were investigated by determining antigen persistence at injection sites, local inflammation response, antigen transport into draining lymph node, and activation of DCs in secondary lymphoid organs (SLOs). RESULTS: Alum promoted antigen-specific humoral immune response. PLA microparticles augmented both humoral immune response and cell-mediated-immunity which might enhance cross protection of influenza vaccine. With regard to action mode, alum adjuvant functions by improving antigen persistence at injection sites, inducing severe local inflammation, slightly improving antigen transport into draining lymph nodes, and improving the expression of MHC II on DCs in SLOs. PLA microparticles function by slightly improving antigen transport into draining lymph nodes, and promoting the expression of both MHC molecules and co-stimulatory molecules on DCs in SLOs. CONCLUSIONS: Considering the adjuvanticity and side effects (local inflammation) of both adjuvants, we conclude that PLA microparticles are promising alternative adjuvant for H5N1 influenza split vaccine. PMID- 24170281 TI - Multicompartimental nanoparticles for co-encapsulation and multimodal drug delivery to tumor cells and neovasculature. AB - PURPOSE: The purpose of this work was the development of a multicompartimental nanocarrier for the simultaneous encapsulation of paclitaxel (PTX) and genistein (GEN), associating antiangiogenic and cytotoxic properties in order to potentiate antitumoral activity. METHOD: Polymeric nanocapsules containing PTX were obtained by interfacial deposition of preformed polymer and coated with a phospholipid bilayer entrapping GEN. Physical-chemical and morphological characteristics were characterized, including size and size distribution, drug entrapment efficiency and drug release profile. In vivo studies were performed in EAT bearing Swiss mice. RESULTS: Entrapment efficiency for both drugs in the nanoparticles was approximately 98%. Average particle diameter was 150 nm with a monomodal distribution. In vitro assays showed distinct temporal drug release profiles for each drug. The dose of 0.2 mg/kg/day of PTX resulted in 11% tumor inhibition, however the association of 12 mg/kg/day of GEN promoted 44% tumor inhibition and a 58% decrease in VEGF levels. CONCLUSIONS: Nanoparticles containing GEN and PTX with a temporal pattern of drug release indicated that the combined effect of cytotoxic and antiangiogenic drugs present in the formulation contributed to the overall enhanced antitumor activity of the nanomedicine. PMID- 24170282 TI - Pharmacokinetics of bevacizumab after topical and intravitreal administration in human eyes. AB - BACKGROUND: Topical bevacizumab is a potential treatment modality for corneal neovascularization, and several recent studies have demonstrated its efficacy. No previous study of the pharmacokinetics of topical bevacizumab has been performed in human eyes. The purpose of this study is to investigate the pharmacokinetics of topical administration of bevacizumab in human eyes, and also to compare the pharmacokinetics of intravitreal bevacizumab injections with previously reported data. METHODS: Twenty-two (22 eyes) were included in this study, and divided into four groups: eight patients received topical bevacizumab and aqueous samples were obtained 1 hour later during cataract extraction surgery (group 1), eight patients received topical bevacizumab and vitreous samples were obtained 1 day later during pars-plana vitrectomy (PPV) (group 2), three patients received intravitreal bevacizumab and vitreous samples were obtained during PPV (group 3). Vitreous samples from three patients who received no bevacizumab served as controls (group 4). All samples underwent enzyme-linked immunosorbent assay to detect bevacizumab. RESULTS: No bevacizumab was detected in the aqueous or vitreous of any topically treated eyes. The mean vitreal half-life for intravitreally injected bevacizumab was 4.9 days in four non-vitrectomized eyes and 0.66 days in one previously vitrectomized eye. CONCLUSIONS: Topically administered bevacizumab does not penetrate the cornea into the anterior chamber and vitreous cavity, indicating that topical use for treating corneal neovascularization has minimal risk of intraocular penetration and adverse events related to intraocular vascular endothelial growth factor inhibition. The half life following intravitreal bevacizumab injection measured in this study is comparable to that of previous reports, and includes the first demonstration of a significantly reduced half-life following intravitreal injection in a previously vitrectomized eye. PMID- 24170283 TI - Lacrimal sac dacryoliths (86 samples): chemical and mineralogic analyses. AB - BACKGROUND: Because dacryoliths occur at low frequency, few studies have focused on their composition. We aimed to present findings from morphological, chemical, and mineralogic analysis of 86 dacryoliths. METHODS: We studied 86 dacryoliths obtained during 832 dacryocystorhinostomies (DCR) performed for postsaccal obstruction. We examined the samples with atomic infrared spectrometry (80 samples), amino acid analysis (17 samples), scanning electron microscopy, and an electron microprobe with an energy dispersive detector (seven samples). RESULTS: Dacryoliths were found in 86/832 DCRs (10.3 %), mostly in patients with primary acquired nasolacrimal duct obstruction. All the dacryoliths were soft, composed of organic material, including proteins and mucoproteins, with approximately 20 % amino acid content. There were no "hard" dacryoliths composed of calcium phosphate. The stones were composed of lobes and lobules built on an amorphous core material with small cavities, probably as a result of various chemical processes that produced a gaseous product. The most frequent elements found in inorganic inclusions were silicon, magnesium, sulfur, potassium, calcium, sodium, and chlorine. Also, some particles had high contents of bismuth, titanium, iron, and organic fibers. The fibers found in the core of dacryoliths suggested a potential origin from cotton swabs used in cosmetics. CONCLUSION: Dacryoliths are composed almost exclusively of organic material, including proteins and mucoproteins, with approximately 20 % amino acid content. PMID- 24170284 TI - Nurses with disabilities: their job descriptions and work expectations. AB - PURPOSE: To explore whether the job descriptions of registered nurses with disabilities actually match the work required by the job. DESIGN: This exploratory qualitative study used constant comparative analysis to simultaneously collect and analyze the data. METHOD: Newsletters and magazines for nurses as well as the snowball method were used to advertise for participants. Participants were asked to submit to an in-person or telephone audiotaped interview that utilized an unstructured interview guide. A coding structure was developed as themes emerged. Participant verification helped to ensure trustworthiness of the data. FINDINGS: Results confirmed findings from previous studies and found that nurses with disabilities who stay in nursing choose a job they can do, know and accept their limitations, have supervisors who are not nurses or who have a disability, and get accommodations so they can work. They rarely receive job descriptions, but it is assumed they can do the work because they are nurses. CONCLUSIONS: Nurse job descriptions are frequently not available or are inaccurate. There are jobs in nursing that nurses with disabilities can do competently and efficiently. Facilities and agencies should strive to retain these nurses and utilize their skills and expertise rather than focusing on what they are unable to do in the same way as a nurse without a disability. CLINICAL RELEVANCE: Nurses with disabilities are leaving nursing because they are not valued for their knowledge or abilities and are often prejudged because of the disability. The profession cannot afford to lose these nurses. PMID- 24170285 TI - [Image-guided therapy with closed MRI: an update]. AB - STANDARD RADIOLOGICAL METHODS: Standard imaging modalities for percutaneous minimally invasive therapy are ultrasound, fluoroscopy and computed tomography. METHODICAL INNOVATIONS: Magnetic resonance imaging is becoming increasingly more popular for minimally invasive procedures. The advantages are high soft-tissue contrast, the possibility of free selection of multiple imaging slices, multiple tools for intrainterventional monitoring and the absence of ionizing radiation for the patient and the interventional radiologist. ACHIEVEMENTS: Magnetic resonance imaging is a promising imaging modality for minimally invasive procedures. The most common clinical applications are thermoablative procedures for treatment of hepatic, renal and prostatic malignancies. PMID- 24170286 TI - [Percutaneous interventions in an open MR system: technical background and clinical indications]. AB - The latest and therefore more efficient open magnetic resonance (MR) scanners with a field strength of 1 T allow freehand fluoroscopic interventions with excellent image quality. Specifically designed interactive software simplifies examination planning and performance. Guidance in two imaging planes allows fast and accurate device positioning and interventional procedures during free breathing. The diagnostic and therapeutic spectrum includes a wide variety of interstitial percutaneous interventions. The most important are periradicular therapy (PRT), intra-abdominal drainage and nephrostoma placement, biopsies, especially in the breasts and liver and focal ablation therapy of malignant hepatic or renal lesions. As the approach is fast and robotic devices are not needed the method is increasingly being carried out in the clinical routine. A drawback of MR-guided interventions is the limitation in verbal communication during image acquisition. Furthermore, the portfolio of MR compatible instruments needs to be extended. PMID- 24170287 TI - [MRI for monitoring of high intensity focused ultrasound: current developments]. AB - With respect to monitoring of high intensity focused ultrasound (HIFU), synonym focused ultrasound (FUS) treatment, magnetic resonance imaging (MRI) is characterized by several advantageous properties: the precise definition and morphological characterization of the target area (before and after the intervention), the real-time visualization of the treatment effect by thermal imaging (during the intervention) and in the sense of a stereotactic system, the 3-dimensional localization of the target lesion, planning of the target volume and assessment of the achieved ablation volume (before and during the intervention). Non-enhanced T2-weighted multislice MR images are acquired for planning of the intervention. For temperature monitoring (comprising thermometry and thermodosimetry), the temperature-dependent shift of proton resonance frequency (PRFS) is most frequently employed. This method is independent of the treated tissue type or thermally induced tissue changes and facilitates a relative measurement of the temperature change based on a reference value. Future MRI applications include diffusion-weighted MRI (DWI-MRI; for the intrainterventional estimation of treatment efficacy), dynamic contrast-enhanced MRI (DCE-MRI, for the prediction of the potential and assessment of the treatment effect achieved) and motion-corrected temperature monitoring (referenceless and multibaseline thermometry). PMID- 24170288 TI - A covalent route for efficient surface modification of ordered mesoporous carbon as high performance microwave absorbers. AB - A covalent route has been successfully utilized for the surface modification of ordered mesoporous carbon (OMC) CMK-3 by in situ polymerization and grafting of methyl methacrylate (MMA) in the absence of any solvent. The modified CMK-3 carbon particles have a high loading of 19 wt% poly(methyl methacrylate) (PMMA), named PMMA-g-CMK-3, and also maintain their high surface area and mesoporous structure. The in situ polymerization technique endows a significantly enhanced electric conductivity (0.437 S m(-1)) of the resulting PMMA-g-CMK-3/PMMA composite, about two orders of magnitude higher than 1.34 * 10(-3) S m(-1) of PMMA/CMK-3 obtained by the solvent mixing method. A minimum reflection loss (RL) value of -27 dB and a broader absorption band (over 3 GHz) with RL values <-10 dB are obtained for the in situ polymerized PMMA-g-CMK-3/PMMA in a frequency range of 8.2-12.4 GHz (X-band), implying its great potential as a microwave absorbing material. The maximum absorbance efficiency for the in situ polymerized sample increases remarkably compared to that (-10 dB) of CMK-3/PMMA prepared by the solvent mixing method. Changing the thickness of the absorber can efficiently adjust the frequency corresponding to the best microwave absorbance ability. The enhanced microwave absorption by the surface modified CMK-3 is ascribed to high dielectric loss. This in situ polymerization for the surface modification of mesoporous carbons opens up a new method and idea for developing light-weight and high-performance microwave absorbing materials. PMID- 24170289 TI - Haptic two-dimensional angle categorization and discrimination. AB - This study examined the extent to which haptic perception of two-dimensional (2 D) shape is modified by the design of the perceptual task (single-interval categorization vs. two-interval discrimination), the orientation of the angles in space (oblique vs. horizontal), and the exploration strategy (one or two passes over the angle). Subjects (n = 12) explored 2-D angles using the index finger of the outstretched arm. In the categorization task, subjects scanned individual angles, categorizing each as "large" or "small" (2 angles presented in each block of trials; range 80 degrees vs. 100 degrees to 89 degrees vs. 91 degrees ; implicit standard 90 degrees ). In the discrimination task, a pair of angles was scanned (standard 90 degrees ; comparison 91-103 degrees ) and subjects identified the larger angle. The threshold for 2-D angle categorization was significantly lower than for 2-D angle discrimination, 4 degrees versus 7.2 degrees . Performance in the categorization task did not vary with either the orientation of the angles (horizontal vs. oblique, 3.9 degrees vs. 4 degrees ) or the number of passes over the angle (1 vs. 2 passes, 3.9 degrees vs. 4 degrees ). We suggest that the lower threshold with angle categorization likely reflects the reduced cognitive demands of this task. We found no evidence for a haptic oblique effect (higher threshold with oblique angles), likely reflecting the presence of an explicit external frame of reference formed by the intersection of the two bars forming the 2-D angles. Although one-interval haptic categorization is a more sensitive method for assessing 2-D haptic angle perception, perceptual invariances for exploratory strategy and angle orientation were, nevertheless, task-independent. PMID- 24170290 TI - Methylation analysis of the promoter region and intron 1 of the factor VIII gene in haemophilia A patients. AB - Methylation, CpG island, promoter, intron 1 Haemophilia A is the most common X linked inherited coagulation disorder caused by a deficiency of the factor VIII protein (FVIII). A plethora of different mutations in the factor VIII gene (F8) have been identified as causative for this bleeding disease including a few promoter mutations. However, in approximately 2-5% of all haemophilic patients, the causal mutation still remains unknown. To our knowledge, epigenetic abnormalities in regulatory regions of the F8 gene have not yet been implicated in the disease pathogenesis. We therefore developed bisulfite pyrosequencing assays to screen patients with unknown mutation status for their methylation patterns in presumed regulative regions of the F8 gene (5'UTR and intron 1). The methylation patterns of haemophilia A patients did not differ from that of controls. In three patients, chromosomal aberrations were identified which could be associated with a defective FVIII synthesis. PMID- 24170291 TI - Aromatic C-H silylation of arenes with 1-hydrosilatrane catalyzed by an iridium(I)/2,9-dimethylphenanthroline (dmphen) complex. AB - Aromatic C-H silylation of neat arenes with 1-hydrosilatrane was found to be efficiently catalyzed by iridium catalysts composed of 1/2[Ir(OMe)(cod)]2 and 2,9 dimethyl-1,10-phenanthroline at 120 degrees C to afford the corresponding silylated products in high yields. The silylated products can be used for the Hiyama cross-coupling reaction. PMID- 24170292 TI - Making climate change a priority in the NHS. PMID- 24170293 TI - Well-posedness and qualitative properties of a dynamical model for the ideal free distribution. AB - Understanding the spatial distribution of populations in heterogeneous environments is an important problem in ecology. In the case of a population of organisms that can sense the quality of their environment and move to increase their fitness, one theoretical description of the expected distribution of the population is the ideal free distribution, where individuals locate themselves to optimize fitness. A model for a dynamical process that allows a population to achieve an ideal free distribution was proposed by the Cosner (Theor Popul Biol 67:101-108, 2005). The model is based on a reaction-diffusion-advection equation with nonlinear diffusion which is similar to a porous medium equation with additional advection and population growth terms. We establish that the model is well-posed, show that solutions stabilize, determine the stationary states, discuss their stability, and describe the biological interpretation of the results. PMID- 24170294 TI - Lower gene expression for KCNS3 potassium channel subunit in parvalbumin containing neurons in the prefrontal cortex in schizophrenia. AB - OBJECTIVE: In schizophrenia, alterations in markers of cortical GABA neurotransmission are prominent in parvalbumin-containing neurons. Parvalbumin neurons selectively express KCNS3, the gene encoding the Kv9.3 potassium channel alpha-subunit. Kv9.3 subunits are present in voltage-gated potassium channels that contribute to the precise detection of coincident excitatory synaptic inputs to parvalbumin neurons. This distinctive feature of parvalbumin neurons appears important for the synchronization of cortical neural networks in gamma oscillations. Because impaired prefrontal cortical gamma-oscillations are thought to underlie the cognitive impairments in schizophrenia, the authors investigated whether KCNS3 mRNA levels are altered in the prefrontal cortex of schizophrenia subjects. METHOD: KCNS3 mRNA expression was evaluated by in situ hybridization in 22 matched pairs of schizophrenia and comparison subjects and by microarray analyses of pooled samples of individually dissected neurons that were labeled with Vicia villosa agglutinin (VVA), a parvalbumin neuron-selective marker, in a separate cohort of 14 pairs. Effects of chronic antipsychotic treatments on KCNS3 expression were tested in the prefrontal cortex of antipsychotic-exposed monkeys. RESULTS: By in situ hybridization, KCNS3 mRNA levels were 23% lower in schizophrenia subjects. At the cellular level, both KCNS3 mRNA-expressing neuron density and KCNS3 mRNA level per neuron were significantly lower. By microarray, KCNS3 mRNA levels were lower by 40% in VVA-labeled neurons from schizophrenia subjects. KCNS3 mRNA levels were not altered in antipsychotic-exposed monkeys. CONCLUSIONS: These findings reveal lower KCNS3 expression in prefrontal cortical parvalbumin neurons in schizophrenia, providing a molecular basis for compromised detection of coincident synaptic inputs to parvalbumin neurons that could contribute to altered gamma-oscillations and impaired cognition in schizophrenia. PMID- 24170295 TI - Generation of neuronal progenitor cells in response to tumors in the human brain. AB - Data from transgenic mouse models show that neuronal progenitor cells (NPCs) migrate toward experimental brain tumors and modulate the course of pathology. However, the pathways whereby NPCs are attracted to CNS neoplasms are not fully understood and it is unexplored if NPCs migrate toward brain tumors (high-grade astrocytomas) in humans. We analyzed the tumor-parenchyma interface of neurosurgical resections for the presence of (NPCs) and distinguished these physiological cells from the tumor mass. We observed that polysialic acid neural cell adhesion molecule-positive NPCs accumulate at the border of high-grade astrocytomas and display a marker profile consistent with immature migratory NPCs. Importantly, these high-grade astrocytoma-associated NPCs did not carry genetic aberrations that are indicative of the tumor. Additionally, we observed NPCs accumulating in CNS metastases. These metastatic tumors are distinguished from neural cells by defined sets of markers. Transplanting murine glioma cells embedded in a cell-impermeable hollow fiber capsule into the brains of nestin-gfp reporter mice showed that diffusible factors are sufficient to induce a neurogenic reaction. In vitro, vascular endothelial growth factor (VEGF) secreted from glioma cells increases the migratory and proliferative behavior of adult human brain-derived neural stem and progenitor cells via stimulation of VEGF receptor-2 (VEGFR-2). In vivo, inhibiting VEGFR-2 signaling with a function blocking antibody led to a reduction in NPC migration toward tumors. Overall, our data reveal a mechanism by which NPCs are attracted to CNS tumors and suggest that NPCs accumulate in human high-grade astrocytomas. PMID- 24170296 TI - Reversible and delayed isolated central sleep apnea after cervical laminectomy: report of the first case. PMID- 24170297 TI - Lateral ventricle's choroid plexus tumors surgery in children: how I do it. AB - BACKGROUND: Choroid plexus tumors (CPTs) are intraventricular lesions originating from ventricular neuroepithelium and represent up to 4% of brain neoplasms affecting pediatric population. They are more frequently benign papillomas, but malignant carcinomas can sometimes occur. METHOD: The authors present a description of surgical approach for CPTs, particularly focusing on the complications related to the cerebrospinal fluid (CSF) circulation, which may affect outcome. CONCLUSION: Microsurgical resection represents the first line treatment for CPTs. The goal is the complete removal of the tumor and the restoration of a physiological CSF circulation. PMID- 24170298 TI - Evaluation of cerebral aneurysm wall thickness in experimental aneurysms: comparison of 3T-MR imaging with direct microscopic measurements. AB - BACKGROUND: Thin aneurysm wall thickness (AWT) is thought to portend an elevated risk of intracranial aneurysm rupture. Magnetic resonance imaging (MRI) is biased by AWT overestimations. Previously, this suspected bias has been qualitatively described but never quantified. We aimed to quantify the overestimation of AWT by MRI when compared to the gold standard of AWT as measured by light microscopy of fresh aneurysm specimens (without any embedding procedure). This analysis should help to define the clinical potential of MRI estimates of AWT. METHODS: 3-Tesla (3T) MRI (contrast-enhanced T1 Flash sequences; resolution: 0.4 x 0.4 x 1.5 mm(3)) was performed in 13 experimental aneurysms. After MR acquisition, the aneurysms were retrieved, longitudinally sectioned and calibrated micrographs were obtained immediately. AWT at the dome, AWT at the neck and parent vessel wall thickness (PVT) were measured on precisely correlated MR-images and histologic micrographs by blinded independent investigators. Parameters were statistically compared (Wilcoxon test, Spearman's correlation). RESULTS: AWT was assessed and reliably measured using MRI. Interobserver variability was not significant for either method. MR overestimation was only significant below the image resolution threshold: AWT at the dome (0.24 +/- 0.06 mm vs. MR 0.30 +/- 0.08 mm; p = 0.0078; R = 0.6125), AWT at the neck (0.25 +/- 0.07 mm vs. MR 0.29 +/- 0.07 mm; p = 0.0469; R = 0.7451), PVT (0.46 +/- 0.06 mm vs. MR 0.48 +/- 0.06 mm; p = 0.5; R = 0.8568). CONCLUSION: In this experimental setting, MR overestimations were minimal (mean 0.02 mm) above the image resolution threshold. When AWT is classified in ranges defined by the MR resolution threshold, clinical usage may be beneficial. Further quantitative and comparative experimental and human studies are warranted to confirm these findings. PMID- 24170299 TI - PBMCs reflect the immune component of the WAT transcriptome--implications as biomarkers of metabolic health in the postprandial state. AB - SCOPE: Food and nutrition studies often require accessing metabolically active tissues, including adipose tissue. This can involve invasive biopsy procedures that can be a limiting factor in study design. In contrast, peripheral blood mononuclear cells (PBMCs) are a population of circulating immune cells that are easily accessible through venipuncture. As transcriptomics is of growing importance in food and metabolism research, understanding the transcriptomic relationship between these tissue types can provide insight into the utility of PBMCs in this field. METHODS AND RESULTS: We examine this relationship within eight subjects, in two postprandial states (following oral lipid tolerance test and oral glucose tolerance test). Multivariate analysis techniques were used to examine variation between tissues, samples, and subjects in order to define which genes havecommon/disparate expression profiles associated with highly defined metabolic phenotypes. We demonstrate global similarities in gene expression between PBMCs and white adipose tissue, irrespective of the metabolic challenge type. Closer examination of individual genes revealed this similarity to be strongest in pathways related to immune response/inflammation. Notably, the expression of metabolism-related nuclear receptors, including PPARs, LXR, etc. was discordant between tissues CONCLUSION: The PBMC transcriptome may therefore provide a unique insight into the inflammatory component of metabolic health, as opposed to directly reflecting the metabolic component of the adipose tissue transcriptome. PMID- 24170300 TI - [Metastatic renal cell carcinoma: primary and follow-up treatment]. AB - Systemic treatment of metastatic renal cell carcinoma has changed fundamentally in recent years. So-called targeted therapy gives patients with incurable renal cell cancer the chance of prolonged survival with acceptable quality of life and manageable side effects. Several tyrosine kinase inhibitors and mTOR inhibitors have been evaluated in various clinical settings within prospective trials. Therefore, recent medical guidelines are able to give recommendations for the management of advanced renal cell carcinoma in daily practice. The optimal therapeutic sequence of the available substances has not been defined until now; however recent data recommend the use of a tyrosine kinase inhibitor as the first line treatment. Besides standard treatment, new approaches are currently being evaluated in clinical trials. PMID- 24170302 TI - Three-dimensional image registration improves the long-term precision of in vivo micro-computed tomographic measurements in anabolic and catabolic mouse models. AB - Micro-computed tomography (micro-CT) is a widely used technique to track bone structural and mineral changes in small animals in vivo. Precise definition of volumes of interest (VOIs) in follow-up scans is required to accurately quantify these changes. To improve precision, VOIs can be transferred from baseline images onto follow-ups using image registration. We studied the performance of a registration procedure applied to in vivo data sets of anabolic and osteoporotic bone changes in mice. Micro-CT image data from two separate CD1 mouse data sets were studied. The first included a group treated with parathyroid hormone (PTH) and control and the second, an ovariectomy (OVX) group and control. Micro-CT was performed once per week for 4 weeks at the proximal tibia starting at treatment onset (PTH data set) or after surgery (OVX data set). A series consisting entirely of user-defined VOIs and a registered series where VOIs defined at baseline were transferred to follow-ups were created. Standard bone structural and mineral measurements were calculated. Image registration resulted in a 13-56 % reduction in precision error. Significant effects of registration to detect PTH induced changes in BV/TV and trabecular BMD were observed. When changes were very pronounced or small, the qualitative improvement observed for the registered data set did not reach statistical significance. This study documents an increase in long-term precision of micro-CT measurements with image registration. Sensitivity to detect changes was improved but not uniform for all parameters. Future study of this technique on images with a smaller voxel size (<19 MUm) may capture the effect in greater detail, in particular for trabecular thickness, where changes may be too small to be observed with the voxel size used here. Our results document the value of registration and indicate that the magnitude of improvement depends on the model and treatment chosen. PMID- 24170301 TI - Dynamic three-dimensional micropatterned cell co-cultures within photocurable and chemically degradable hydrogels. AB - In this paper we report on the development of dynamically controlled three dimensional (3D) micropatterned cellular co-cultures within photocurable and chemically degradable hydrogels. Specifically, we generated dynamic co-cultures of micropatterned murine embryonic stem (mES) cells with human hepatocellular carcinoma (HepG2) cells within 3D hydrogels. HepG2 cells were used due to their ability to direct the differentiation of mES cells through secreted paracrine factors. To generate dynamic co-cultures, mES cells were first encapsulated within micropatterned photocurable poly(ethylene glycol) (PEG) hydrogels. These micropatterned cell-laden PEG hydrogels were subsequently surrounded by calcium alginate (Ca-Alg) hydrogels containing HepG2 cells. After 4 days, the co-culture step was halted by exposing the system to sodium citrate solution, which removed the alginate gels and the encapsulated HepG2 cells. The encapsulated mES cells were then maintained in the resulting cultures for 16 days and cardiac differentiation was analysed. We observed that the mES cells that were exposed to HepG2 cells in the co-cultures generated cells with higher expression of cardiac genes and proteins, as well as increased spontaneous beating. Due to its ability to control the 3D microenvironment of cells in a spatially and temporally regulated manner, the method presented in this study is useful for a range of cell-culture applications related to tissue engineering and regenerative medicine. Copyright (c) 2013 John Wiley & Sons, Ltd. PMID- 24170303 TI - Deletion of serotonin 2B receptor provokes structural alterations of mouse dental tissues. AB - Rampant caries and periodontal diseases occur in patients treated with antidepressants such as serotonin reuptake inhibitors (SRIs; e.g., Prozac) which target the serotonin transporter (SERT). As the serotonin 2B receptor (5HT2BR) regulates SERT functionality and capacity to recognize SRIs, we investigated the potential role of 5HT2BR on dental tissues by exploiting 5HT2BR knockout (KO) mice. Compared to wild-type (WT) mice, several structural differences were identified in the teeth of KO mice. In the molar of KO mice, rod curvatures and twisting were altered compared to WT mice, suggesting involvement of 5HT2BR at early stages of enamel formation. The volume of the KO enamel layer was also reduced, and larger porosities were observed in the prismatic enamel, with smaller crystallite thickness. Crystallite pattern disorganization and occlusal abrasion were enhanced in female KO mice, indicating a sexual dimorphism. In the incisor, no difference was detected in the width of the enamel layer between KO and WT mice; however, enamel maturation differed in absence of 5HT2BR. Specifically, the outer aprismatic enamel border was 1.5- to 2-fold larger in KO compared to WT mice, together with a decreased etching pattern. Finally, although no noticeable difference was observed in dentin, the micro-CT three-dimensional pulp reconstruction evidenced a decrease in both length and width of dentin formation in the root canals of the KO versus WT mice. These data provide evidence that 5HT2BR-mediated signaling pathways are involved in enamel formation and dentinogenesis. PMID- 24170305 TI - Risk factors for COPD: what do NPs know? AB - PURPOSE: Chronic obstructive pulmonary disease (COPD) has been identified as the fourth leading cause of death. The primary purpose of this article is to discuss risk factors for COPD and identify at-risk populations. A secondary purpose is to report the findings of a recent survey of nurse practitioners (NPs) in Colorado regarding their knowledge about the risk factors for COPD. Data sources A list of registered NPs in the State of Colorado was obtained from the State Board of Nursing. Surveys were sent to 2916 NPs to assess their knowledge about risk factors for COPD. CONCLUSIONS: Although the response rate was less than 10%, this survey highlighted that there were gaps in knowledge especially for pediatric, women's health, and geriatric NPs. NPs are on the front lines in assisting with the prevention, early diagnosis, and management of this complex disease. IMPLICATIONS FOR PRACTICE: Formal NP educational programs (regardless of focus) should highlight that through recognition of risk factors, NPs can play a significant role in primary and secondary preventive measures that may decrease the impact of COPD. Public media campaigns to educate the public about risk factors may encourage the individual patients to address these risk factors with the primary care provider. PMID- 24170306 TI - Photochemical studies of (eta5-C5H5)Ru(PPh3)2Cl and (eta5-C5H5)Ru(PPh3)2Me: formation of Si-H and C-H bond activation products. AB - Studies examining the photochemical reactivity of CpRu(PPh3)2Cl and CpRu(PPh3)2Me towards the two electron donor ligands PEt3, C2H4, DMSO, the CH bond activatable reagents tetrahydrofuran, toluene, and pyridine, and the SiH bond activatable reagents HSiEt3 and HSi(Me)2CH=CH2) are presented. Broadband UV irradiation of CpRu(PPh3)2Cl leads to the formation of mono-substitution products such as CpRu(PPh3)(PEt3)Cl which are inert to further photochemical reaction, although thermally bis-substituted products such as CpRu(PEt3)2Cl can be formed. Room temperature irradiation of the related complex CpRu(PPh3)2Me with L = PEt3, C2H4, and DMSO also produces CpRu(PPh3)(L)Me. However, when these reactions are followed by in situ laser irradiation (325 nm source) at low temperature, three solvent activated isomers (ortho, meta and para) of CpRu(PPh3)2(C6H4Me) are detected in toluene in addition to eta(1)- and eta(3)-coordinated benzyl species. Furthermore, photolysis in THF leads to both the C-D bond activation product CpRu(PPh3)2(OC4D7) and the labile coordination complex CpRu(PPh3)(THF)Me. Now CH4 rather than CH3D is liberated which suggests the involvement of an orthometallated species. The photochemically driven reaction of CpRu(PPh3)2Me with HSiEt3 at 198 K generates CpRu(kappa(2)-2-C6H4PPh2)(SiEt3)H and thereby confirms a role for an orthometallated complex is this process. Irradiation in cyclohexane produces the known orthometallated complex, CpRu(kappa(2)-2 C6H4PPh2)(PPh3), and CH4 in accordance with this reactivity. PMID- 24170304 TI - Sensitive solid-phase detection of donor-specific antibodies as an aid highly relevant to improving allograft outcomes. AB - Transplant recipients who have had sensitizing events such as pregnancies, blood transfusions and previous transplants often develop antibodies directed against human leukocyte antigen (HLA)-molecules of the donor tissue. These pre-formed donor-specific antibodies (DSA) represent a high risk of organ failure as a consequence of antibody-mediated hyper-acute or acute allograft rejection. As a first assay to detect DSA, the complement-dependent lymphocytotoxicity assay (CDC) was established more than 40 years ago. However, this assay is characterized by several drawbacks such as a low sensitivity and a high susceptibility to various artificial factors generally not leading to valid and reliable outcomes under several circumstances that are reviewed in this article. Furthermore, only those antibodies that exert complement-fixing activity are detected. As a consequence, novel procedures that act independently of the complement system and that do not represent functional assays were generated in the format of solid phase assays (SPAs) (bead- or ELISA-based). In this article, we review the pros and cons of these sensitive SPA in comparison with the detection of DSA through the use of the traditional methods such as CDC and flow cytometric analyses. Potential drawbacks of the alternative methodological approaches comprising high background reactivity, susceptibility to environmental factors and the possible influence of subjective operators' errors concerning the interpretation of the results are summarized and critically discussed for each method. We provide a forecast on the future role of SPAs reliably excluding highly deleterious DSA, thus leading to an improved graft survival. PMID- 24170307 TI - MMP-8 genotypes influence the inflammatory response in human endotoxemia. AB - Clinical studies have reported associations between MMP-8 genotypes and clinical outcomes without exploring underlying mechanisms. This study aims to understand the influence of the rs1940475 SNP on downstream chemokine and cytokine response in human endotoxemia. Rs1940475 was genotyped in 44 healthy Caucasian males, who were challenged with an intravenous bolus of 2 ng/kg lipopolysaccharide (LPS). Plasma levels of tumor necrosis factor (TNF), interleukin (IL)-6, IL-8, and macrophage inflammatory protein (MIP)-1alpha were measured at baseline and 2, 4, 6, and 24 h after LPS infusion with high-sensitivity enzyme immunoassays. Peak TNF levels at 2 h after LPS infusion were significantly higher in subjects with AA genotype compared to subjects with AG or GG genotypes (185 pg/mL [IQR, 154 234] vs. 94 pg/mL [IQR, 65-125] vs. 107 pg/mL [IQR, 80-241], respectively; p = 0.03 between groups). Peak IL-6 levels were trend-wise higher in subjects with AA genotype compared to those with AG or GG genotypes (566 pg/mL [IQR, 294-644] vs. 278 pg/mL [IQR, 184-539] and 329 pg/mL [IQR, 240-492], respectively; p = 0.15 between groups). In contrast, peak MIP-1alpha at 2 h was highest in GG genotype carriers compared to those with AG or AA genotypes (602 pg/mL [IQR, 449-727] vs. 389 pg/mL [IQR, 375-490] and 510 pg/mL [425-813], respectively; p < 0.03 between groups). AA genotype carriers had highest peak TNF and IL-6 levels after LPS challenge, whereas peak MIP-1alpha levels were highest in GG carriers. This indicates that the rs1940475 SNP modifies the host response to inflammatory stimuli, which may in part explain previously shown associations with clinical outcomes. PMID- 24170308 TI - Association of AIRE polymorphisms with genetic susceptibility to rheumatoid arthritis in a Chinese population. AB - Recently, genetic polymorphisms within the autoimmune regulator (AIRE) have been implicated in the genetic susceptibility to rheumatoid arthritis (RA) in Japanese and Spanish. The aim of this case-control study involving 232 patients with RA and 313 ethnically matched control subjects was to investigate the association of AIRE rs2075876 and rs760426 polymorphisms with genetic predisposition to RA in a Chinese population. The genotypes of AIRE rs2075876 and rs760426 polymorphisms were determined by SNaPshot assay. A significant difference in the allele frequency of AIRE rs2075876 polymorphism between cases and controls was detected (A versus G, OR 1.33, 95 %CI 1.04-1.69, P = 0.02, P corrected (Bonferroni correction) Pc = 0.04). Significant evidence was found for the association between the minor allele A of AIRE rs2075876 polymorphism and the risk of RA under the recessive model (AA versus AG + GG, P = 7.15 * 10(-3), Pc = 1.43 * 10( 2)). The frequency of the minor allele G of AIRE rs760426 polymorphism was higher in patients compared with controls (47.8 % versus 42.1 %), and this deviation showed a trend towards significant level (P = 0.06, Pc = 0.12). The association between the minor allele G of AIRE rs760426 polymorphism with RA risk under the dominant model and the recessive model revealed that significant evidence was detected under the recessive model (GG versus GA + AA, P = 0.02, Pc = 0.04). Our results indicated that AIRE rs2075876 and rs760426 polymorphisms were involved in the genetic background of RA in the Chinese population. PMID- 24170309 TI - Integrating gerontological content across advanced practice registered nurse programs. AB - PURPOSE: Faculty members across the country are faced with integrating gerontological content and competencies across advanced practice registered nurse (APRN) programs that focus on the adult-gerontology population. The purpose of this initiative was to effectively and efficiently integrate gerontological content into the adult management courses for several APRN programs in acute and primary care at one university's college of nursing. DATA SOURCES: Current literature, resources for integrating adult-gerontology content, course evaluations, and end of program surveys were used in this project. CONCLUSION: This curricular update effectively utilized resources and engaged faculty across programs to infuse gerontological content into the adult management courses. Students from multiple programs sharing these courses benefited from gerontological lecturers, content, and learning activities. The content gaps were integrated into existing courses rather than developing a new course. Current outcome data reflect this was an effective curricular change. IMPLICATIONS FOR PRACTICE: In conjunction with meeting national requirements for integrating adult gerontology content into APRN curriculum, APRNs prepared with enhanced gerontological knowledge and skills build a workforce that is competent to improve care for older adults across the continuum of care. PMID- 24170310 TI - Delirium in the brain-injured patient. AB - PURPOSE: To differentiate between expected behavior of a newly brain-injured person and an episode of delirium. METHODS: This article reviews the different types of delirium and predisposing risk factors that place patients at risk for developing delirium. FINDINGS: This case study illustrates how delirium can mimic expected behaviors seen in patients with traumatic brain injuries and emphasizes the importance of assessing for risk factors of delirium. CONCLUSIONS: Clinicians can easily misdiagnose delirium. Nurses should assess every patient for signs and symptoms of delirium, using a standardized tool, such as the Confusion Assessment Method (CAM) or Cognitive Test for Delirium (CTD). CLINICAL RELEVANCE: Improved education on the risk factors for and symptoms of delirium is necessary for the rehabilitation nurse to ensure early diagnosis and treatment of this potentially life-threatening condition. PMID- 24170311 TI - Attitudes of Polish physicians and medical students toward breaking bad news, euthanasia and morphine administration in cancer patients. AB - Medical students and physicians should possess basic knowledge concerning medical ethics and palliative care. The aim of the study was to explore the knowledge on the end-of-life ethics and palliative care in third-year medical students and physicians during internal medicine specialty training and their attitude towards breaking bad news and euthanasia. A voluntary and anonymous questionnaire survey with the participation of 401 students and 217 physicians filled after lectures concerning ethics for medical students and after palliative medicine course for physicians during internal medicine specialty training. A total of 28 % students and 24 % physicians (p = 0.282) were ready to reveal full information to advanced cancer patients. A total of 82 % of students and 90 % of physicians (p = 0.008) would not practice euthanasia; 67 % of students and 75 % of physicians (p = 0.039) were opponents of euthanasia legalisation. A total of 70 % doctors and 23 % students indicated oral as the most preferable route of morphine administration. A total of 74 % physicians and 43 % students stated that there is no maximal dose of morphine; 64 % of doctors and 6 % of students indicated constipation as a constant adverse effect of morphine. Breaking bad news is a significant difficulty for both students and physicians. There is a small percentage of those tending to practice euthanasia and bigger accepting its legalisation with fewer physicians than students. In contrast to medical students, the majority of physicians have knowledge concerning chronic morphine use in the treatment of cancer patients. PMID- 24170313 TI - Induced and thymus-derived Foxp3+ regulatory T cells share a common niche. AB - Foxp3+ regulatory T (Treg) cells, which play a central role for the maintenance of immune homeostasis and self-tolerance, are known to be both generated in the thymus (thymus-derived, tTreg cells) and in the periphery, where they are converted from conventional CD4+ T cells (induced Treg (iTreg) cells). Recent data suggest a division of labor between these two Treg-cell subsets since their combined action was shown to be essential for protection in inflammatory disease models. Here, using the transfer colitis model, we examined whether tTreg cells and iTreg cells fill different niches within the CD4+ T-cell compartment. When naive T cells were co-transferred with either pure tTreg cells or with a mixture of tTreg cells and iTreg cells, induction of Foxp3+ Treg cells from naive T cells was not hampered by preoccupation of the Treg-cell niche. Using neuropilin-1 (Nrp1) as a surface marker to separate tTreg cells and iTreg cells, we demonstrate that tTreg cells and iTreg cells alone can completely fill the Treg cell niche and display comparable TCR repertoires. However, when transferred together Nrp1+ tTreg cells outcompeted Nrp1- iTreg cells and dominated the Treg cell compartment. Taken together, our data suggest that tTreg cells and iTreg cells share a common peripheral niche. PMID- 24170312 TI - Adiponectin and energy homeostasis. AB - White adipose tissue (WAT) is the premier energy depot. Since the discovery of the hormonal properties of adipose-secreted proteins such as leptin and adiponectin, WAT has been classified as an endocrine organ. Although many regulatory effects of the adipocyte-derived hormones on various biological systems have been identified, maintaining systemic energy homeostasis is still the essential function of most adipocyte-derived hormones. Adiponectin is one adipocyte-derived hormone and well known for its effect in improving insulin sensitivity in liver and skeletal muscle. Unlike most other adipocyte-derived hormones, adiponectin gene expression and blood concentration are inversely associated with adiposity. Interestingly, recent studies have demonstrated that, in addition to its insulin sensitizing effects, adiponectin plays an important role in maintaining energy homeostasis. In this review, we summarize the progress of research about 1) the causal relationship of adiposity, energy intake, and adiponectin gene expression; and 2) the regulatory role of adiponectin in systemic energy metabolism. PMID- 24170316 TI - Frizzled 7 maintains the undifferentiated state of human limbal stem/progenitor cells. AB - Wnt signaling pathway plays an important role in the regulation of human limbal stem/progenitor cells (LSCs). To examine the possible function of Frizzled (Fz) receptors in LSCs, the expression of 10 Fz receptors was profiled in the limbus and cornea. Only Fz7 had preferential expression in the basal limbal epithelium which contains the LSCs. The expression of Fz7 was colocalized with the putative LSC markers including p63alpha, N-cadherin and keratin (K) 14, and was minimum in cells expressing the corneal maturation marker K12. The expression of Fz7 was higher in the enriched LSCs population and decreased in cultured LSCs when there was a loss of progenitor phenotype. When the Fz7 was knocked down (Fz(KD)) using shRNA in primary LSCs, the expression of putative LSC markers ABCG2, DeltaNp63alpha, and K14 was decreased significantly. The colony forming efficiency of the Fz7(KD) LSCs was significantly decreased in the subsequent passage 1 and 2 compared to the control. Our finding suggests that Wnt signaling is one of the factors of LSC niche, and Fz7 helps to maintain the undifferentiated state of LSCs. PMID- 24170317 TI - Sox2 in the adult rat sensory nervous system. AB - Sex-determining region Y (SRY)-box 2 (Sox2) is a member of the Sox family transcription factors. In the central nervous system, Sox2 is expressed in neural stem cells from neurogenic regions, and regulates stem cell proliferation and differentiation. In the peripheral nervous system, Sox2 is found only in the immature and dedifferentiated Schwann cells, and is involved in myelination inhibition or N-cadherin redistribution. In the present immunohistochemical study, we found that Sox2 is also expressed in other cells of the adult rat peripheral nervous system. Nuclear Sox2 was observed in all satellite glial cells, non-myelinating Schwann cells, and the majority of terminal Schwann cells that form lamellar corpuscles and longitudinal lanceolate endings. Sox2 was not found in myelinating Schwann cells and terminal Schwann cells of subepidermal free nerve endings. Satellite glial cells exhibit strong Sox2 immunoreactivity, whereas non-myelinating Schwann cells show weak immunoreactivity. RT-PCR confirmed the presence of Sox2 mRNA, indicating that the cells are likely Sox2 expressors. Our findings suggest that the role of Sox2 in the peripheral nervous system may be cell-type-dependent. PMID- 24170318 TI - Revisiting schizophrenia linkage data in the NIMH Repository: reanalysis of regularized data across multiple studies. AB - OBJECTIVE: The Combined Analysis of Psychiatric Studies (CAPS) project conducted extensive review and regularization across studies of all schizophrenia linkage data available as of 2011 from the National Institute of Mental Health-funded Center for Collaborative Genomic Studies on Mental Disorders, also known as the Human Genetics Initiative (HGI). The authors reanalyzed the data using statistical methods tailored to accumulation of evidence across multiple, potentially highly heterogeneous, sets of data. METHOD: Data were subdivided based on contributing study, major population group, and presence or absence within families of schizophrenia with a substantial affective component. The posterior probability of linkage (PPL) statistical framework was used to sequentially update linkage evidence across these data subsets (omnibus results). RESULTS: While some loci previously implicated using the HGI data were also identified in the present omnibus analysis (2q36.1, 15q23), others were not. Several loci were found that had not previously been reported in the HGI samples but are supported by independent linkage or association studies (3q28, 12q23.1, 11p11.2, Xq26.1). Not surprisingly, differences were seen across population groups. Of particular interest are signals on 11p15.3, 11p11.2, and Xq26.1, for which data from families with a substantial affective component support linkage while data from the remaining families provide evidence against linkage. All three of these loci overlap with loci reported in independent studies of bipolar disorder or mixed bipolar-schizophrenia samples. CONCLUSIONS: Public data repositories provide the opportunity to leverage large multisite data sets for studying complex disorders. Analysis with a statistical method specifically designed for such data enables us to extract new information from an existing data resource. PMID- 24170319 TI - Evaluating the reliability of Persian version of ankylosing spondylitis quality of life (ASQoL) questionnaire and related clinical and demographic parameters in patients with ankylosing spondylitis. AB - Ankylosing spondylitis quality of life (ASQoL) is an instrument for assessing quality of life (QoL). The aims of this study were to assess the reliability of Persian version of ASQoL questionnaire and evaluation of QoL status and related factors in ankylosing spondylitis (AS). One hundred and sixty-three Iranian patients with AS who fulfilled modified New York criteria were enrolled. Patients were evaluated using questionnaires including demographic and clinical variables, Bath AS Disease Activity Index (BASDAI), Bath AS Functional Index (BASFI), fatigue, Bath AS Metrology Index, pain and ASQoL. Reliability and validity of Persian version of ASQoL were evaluated by test-re-test agreement, internal consistency and correlation with specific scales. Relationship of parameters with ASQoL was analyzed by multiple regression. Age, disease duration and ASQoL score (mean +/- SD) were 37.74 +/- 9.88, 14.49 +/- 8.47 and 8.02 +/- 5.28 years, respectively. Test-re-test reproducibility for ASQoL was good as assessed by intra-class correlation coefficient (ICC: 0.97, P < 0.001). Internal consistency was high (Cronbach's alpha: 0.91). Convergent validity was confirmed by correlation of ASQoL score with specific scales (BASFI, r = 0.74, BASDAI, r = 0.6, fatigue, r = 0.56, depression, r = 0.24, intermalleolar distance, r = -0.44 and educational level, r = -0.37). Persian version of ASQoL is a valid and reliable scale to assess QoL in AS. Function, fatigue, mood, hip mobility and education are the factors which should be noted to achieve the best QoL. PMID- 24170320 TI - Smoking, disease activity, permanent damage and dsDNA autoantibody production in patients with systemic lupus erythematosus. AB - The aim was to study the association of smoking with the activity and severity of systemic lupus erythematosus (SLE) and the production of antibodies to dsDNA. The study included 223 SLE patients attending the outpatient clinics at Helsinki University Central Hospital. The history of smoking was obtained by personal interview, and clinical data related to SLE by interview, clinical examination and chart review. The activity of SLE was assessed by the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) score and permanent damage by the SLICC/ACR score. Antibodies to dsDNA were determined by three ELISA assays, by the indirect immunofluorescence technique using Crithidia luciliae cells as substrates and by the Farr assay. There were no significant differences in the SLEDAI scores between current smokers (73 patients), ex-smokers (59) and never smokers (91), though current smokers tended to have lower disease activity. The SLICC/ACR scores between the groups were practically equal. Current smokers had significantly lower levels of antibodies to dsDNA than ex- and never-smokers (p = 0.025). Our study suggests that cigarette smoke may have immunosuppressive effect on autoantibody production in patients with SLE. Permanent damage was not found to be associated with smoking. PMID- 24170321 TI - Smac mimetic compound LCL161 sensitizes esophageal carcinoma cells to radiotherapy by inhibiting the expression of inhibitor of apoptosis protein. AB - Currently, unresectable esophageal squamous cell carcinoma (ESCC) is primarily treated by chemoradiotherapy. However, the outcome has not improved significantly due to radioresistance of cancer cells. This study aimed to determine the radiosensitizing effect of LCL161, a novel second mitochondrial-derived activator of caspase (Smac) mimetic, in ESCC cells. ESCC cell lines were treated with LCL161 or radiation, alone or in combination. Cell proliferation was detected by MTT assay. Radiosensitization was evaluated by clonogenic survival assay. Cell apoptosis was detected by flow cytometry. The results showed that LCL161 potently sensitized ESCC cells to radiation with a sensitization enhancement ratio of 1.4 2.0. LCL161 increased radiation-induced DNA double-stranded breaks and promoted the apoptosis of ESCC cells, which could be abrogated by a pan-caspase inhibitor z-VAD-FMK. Furthermore, LCL161 decreased the level of cIAP1 in ESCC cells in a dose-dependent manner and synthesized with irradiation to promote the activation of caspase 8 and the upregulation of TNFalpha expression in ESCC cells. In conclusion, LCL161 acts as a strong radiosensitizer in human esophageal cancer cells by inhibiting the expression of cIAP1 and promoting the activation of caspase 8, leading to enhanced apoptosis. PMID- 24170323 TI - Primary care of a child with Rett syndrome. AB - PURPOSE: To discuss the history, incidence, pathophysiology, diagnostic criteria, disease staging, clinical presentation and physical exam findings, and role of the primary care provider (PCP) as they pertain to care for a child with Rett syndrome (RS). DATA SOURCES: Review of published literature on and diagnostic criteria of RS. CONCLUSIONS: RS is a devastating X-linked neurodevelopmental disorder that affects females and a small percentage of males. RS is characterized by stereotypic wringing hand movements, social withdrawal, communication dysfunction, cognitive impairment, respiratory dysfunction, and failing locomotion. Diagnosis is generally made clinically despite available genetic testing. Advances in research have been beneficial; however, the pathophysiology of RS has proven to be elusive. RS is a complex disease that involves multiple organ systems. IMPLICATIONS FOR PRACTICE: PCPs need to be aware of how to manage RS patients if they present to the primary care office, and need to be prepared to diagnose RS early, provide appropriate interventions and referrals, understand the challenges, and understand the goal of treatment. They also should be able to provide continuity of care, provide anticipatory guidance, and engage in shared decision with families and patients. PMID- 24170322 TI - A unique missense allele of BAF155, a core BAF chromatin remodeling complex protein, causes neural tube closure defects in mice. AB - Failure of embryonic neural tube closure results in the second most common class of birth defects known as neural tube defects (NTDs). While NTDs are likely the result of complex multigenic dysfunction, it is not known whether polymorphisms in epigenetic regulators may be risk factors for NTDs. Here we characterized Baf155(msp3) , a unique ENU-induced allele in mice. Homozygous Baf155(mps3) embryos exhibit highly penetrant exencephaly, allowing us to investigate the roles of an assembled, but malfunctional BAF chromatin remodeling complex in vivo at the time of neural tube closure. Evidence of defects in proliferation and apoptosis were found within the neural tube. RNA-Seq analysis revealed that surprisingly few genes showed altered expression in Baf155 mutant neural tissue, given the broad epigenetic role of the BAF complex, but included genes involved in neural development and cell survival. Moreover, gene expression changes between individual mutants were variable even though the NTD was consistently observed. This suggests that inconsistent gene regulation contributes to failed neural tube closure. These results shed light on the role of the BAF complex in the process of neural tube closure and highlight the importance of studying missense alleles to understand epigenetic regulation during critical phases of development. PMID- 24170324 TI - The metabolism of methylsulfinylalkyl- and methylthioalkyl-glucosinolates by a selection of human gut bacteria. AB - SCOPE: Certain myrosinase-positive human gut bacteria can metabolize glucosinolates (GSLs) to produce isothiocyanates (ITC) as chemopreventive agents. We investigated glucoerucin, glucoiberin, and glucoraphanin (present in broccoli) metabolism by human gut strains. METHODS AND RESULTS: All tested bacteria metabolized glucoerucin to completion within 16 h to erucin and erucin nitrile (NIT). Lactobacillus agilis R16 metabolized only 10% of glucoiberin and glucoraphanin with no detectable products. Enterococcus casseliflavus CP1, however, metabolized 40-50% of glucoiberin and glucoraphanin producing relatively low concentrations of iberin and sulforaphane. Interestingly, Escherichia coli VL8 metabolized 80-90% of glucoiberin and glucoraphanin and also bioconverted glucoraphanin and glucoiberin to glucoerucin and glucoiberverin, respectively, producing erucin, erucin NIT, iberverin, and iberverin NIT from the two GSLs. The putative reductase enzyme in the cell-free extracts of this bacterium required both Mg(2+) and NAD(P)H as cofactors for bioconversion. The cell-free extract of E. coli VL8 containing the reductase enzyme was able to reduce both the GSL glucoraphanin and its hydrolysis product sulforaphane to glucoerucin and erucin/erucin NIT, respectively. CONCLUSION: The composition and metabolic activity of the human gut bacteria can indirectly impact on the potential chemopreventive effects of GSL-derived metabolites. PMID- 24170325 TI - The effect of lansoprazole, an OCT inhibitor, on metformin pharmacokinetics in healthy subjects. AB - PURPOSE: Gastro-esophageal reflux disease is common in patients with type 2 diabetes. A common treatment is the co-administration of proton-pump inhibitors (PPIs) and metformin. To date, however, the effects of co-administration of PPIs, which inhibit organic cation transporter (OCT) activity, on the action of metformin (a well-known substrate of OCTs) have not been clearly demonstrated. METHODS: This was a randomized, double-blind, two-way crossover, placebo controlled trial. Healthy male volunteers (n = 20) received metformin (single dose 1,000 mg on day 1 and single dose 750 mg on day 2, with a 12-h interval) co administered with placebo or with lansoprazole (30 mg). Plasma concentrations of metformin were measured up to 24 h after the second dose. The glucose-lowering effects of metformin were evaluated by the oral glucose tolerance test before and after each single dose of metformin within the 2-day period. RESULTS: Lansoprazole increased the mean metformin maximum plasma concentration and area under the plasma concentration-time curve from zero to 24 h after the second dosing by 15 and 17 %, respectively (P < 0.05). Moreover, lansoprazole prolonged the metformin elimination half-life from 3.9 to 4.5 h and decreased its renal clearance by 13 % (P < 0.05). However, lansoprazole had no effect on the maximum glucose level and the area under the serum glucose concentration-time curve of metformin. CONCLUSIONS: Collectively, we found a modest pharmacokinetic drug interaction between lansoprazole and metformin, which suggests that the concomitant use of these drugs should be appropriately monitored. Further studies are warranted to assess changes in metformin pharmacokinetics in patients with diabetes receiving long-term lansoprazole therapy. PMID- 24170326 TI - Nitric oxide controls fat deposition in dystrophic skeletal muscle by regulating fibro-adipogenic precursor differentiation. AB - Duchenne muscular dystrophy (DMD) is an hereditary disease characterized by loss of muscle fibers and their progressive substitution by fat and fibrous tissue. Mesenchymal fibro-adipogenic progenitors (FAPs) expressing the platelet-derived growth factor receptor alpha (PDGFRalpha) are an important source of fibrosis and adipogenesis in dystrophic skeletal muscle. Among the therapies suggested for dystrophy are those based on nitric oxide (NO) donating drugs, the administration of which slows disease progression. NO has been shown to act by enhancing the regenerative potential of the diseased muscle. Whether it acts also by inhibiting fibrosis and adipogenesis was not known. Here, we show in vitro that NO regulates FAP fate through inhibition of their differentiation into adipocytes. In mdx mice, an animal model of DMD, treatment with the NO donating drug molsidomine reduced the number of PDGFRalpha(+) cells as well as the deposition of both skeletal muscle fat and connective tissues. Inhibition of adipogenesis was due to NO-induced increased expression of miR-27b leading to downregulation of peroxisome proliferator-activated receptors gamma (Ppargamma1) expression in a pathway independent of cGMP generation. These findings reveal an additional effect of NO in dystrophic muscle that conceivably synergizes with its known effects on regeneration improvement and explain why NO-based therapies appear effective in the treatment of muscular dystrophy. PMID- 24170328 TI - Short Berg Balance Scale, BBS-9, as a predictor of fall risk among the aged: a prospective 12-month follow-up study. AB - BACKGROUND AND AIMS: The aim of this study was to assess the adequacy of the short, 9-item Berg Balance Scale (BBS-9) to predict fall risk among the community dwelling aged. METHODS: The subjects (n = 519) were derived from the participants in a multifactorial fall prevention intervention conducted in Pori, Finland. Receiver operating characteristic (ROC) analysis was used to determine the cut off score for BBS-9 (range 0-36) to classify aged people with a fall risk during a 12-month follow-up. Logistic regression was used to analyse the relationship of potential confounders with fall risk. The association between the cut-off score for BBS-9 and fall risk was tested using the Chi-square test. RESULTS: In determining the cut-off score of BBS-9 to classify fall risk, the highest sensitivity (0.51) and specificity (0.57) (when both presumed to be above 0.50) sum score was within the limit range 32 scores or below. The area under curve (AUC) was significantly better in the model adjusted for significant confounders (vision and the number of regularly used drugs) (AUC = 0.64) than in the unadjusted model (AUC = 0.57) (p = 0.045). Among patients who scored 32 or below in BBS-9 the incidence of multiple falls was 20.0 %, whereas among those who scored 33-36 it was 15.7 %. CONCLUSIONS: BBS-9 with the cut-off score of 32/33 together with data on vision and the number of regularly used drugs predicted moderately the risk of falling among the community-dwelling aged. PMID- 24170327 TI - A prospective, multidimensional follow-up study of a geriatric hospitalised population: predictors of discharge and well-being. AB - BACKGROUND AND AIMS: Ageing trends in populations are common amongst most European countries. One of the consequences of this trend is the increase of hospitalisation of elderly patients. To better manage the elderly population hospitalisation, it is crucial to obtain a better understanding of this population's clinical and functional conditions and their hospitalisation outcome predictors. The present prospective observational cohort study aimed at studying the variables considered predictive of the length of stay, of destination at discharge, of re-hospitalisation, and of mortality at 6 months of elderly (age >64 years, N = 329) admitted to ten geriatric units, having different missions (e.g., cognitive impairment and dementia; movement disorders; bone fractures and immobilisation syndrome; or stroke), of the St. John of God Order during a 4 month-long index period. METHODS: The patients were monitored from the first day of hospitalisation through the discharge. Researchers filled in a "Patient Schedule" based on a comprehensive set of socio-demographic and clinical variables and standardised assessment tools. We used a standardised telephone interview to re-assess patients at the 6-month follow-up. RESULTS: The BRASS score proved to be a better reliable predictor of length of stay (F = 3.9, p = 0.04) among all variables associated with higher risks of prolonged hospital stay and post-discharge problems. In addition, discharge destination was also predicted by the use of the Tinetti Scale score (OR = 0.95, 95 % CI 0.90-0.99), the Mini Mental State Examination (MMSE) score (OR = 0.1.07, 95 % CI 1.01-1.13) and by independence in daily activity as measured by the IADL scale (OR = 4.09, 95 % CI 1.46-11.44). Motor functioning resulted as a reliable predictor (OR = 2.67, 95 % CI 1.27-5.59) of re-hospitalisation in all the medical units. Lastly, female gender (OR = 0.28, 95 % CI 0.11-0.71) resulted as the only reliable variable associated with a lower mortality risk after discharge. CONCLUSION: The variables related to the clinical and functional status were reliable predictors for length of stay, for discharge destination, and for re-hospitalisation among older patients admitted to ten geriatric units in Italy. Further research is needed to establish valid and reliable predictors of mortality risk, to develop effective preventive strategies in those vulnerable populations. PMID- 24170329 TI - Locomotive and non-locomotive activities evaluated with a triaxial accelerometer in adults and elderly individuals. AB - BACKGROUND AND AIMS: Comparative data on locomotive and non-locomotive physical activity (PA) by age and gender are lacking for Japanese adults. The purpose of this study was to investigate objectively the levels of PA in each intensity in adults and older people by both genders living in Japan with triaxial accelerometry with discrimination between locomotive and non-locomotive PA. METHODS: In 571 women and 315 men aged 18-92 years from the Kanto region, PA was assessed for 6 consecutive days with a triaxial accelerometer (Active style Pro: HJA-350IT), and minutes of light and moderate-to-vigorous physical activity (MVPA) classified by metabolic equivalents were evaluated. RESULTS: Japanese elderly women over 70 years, spent less time in not only locomotive PA (light and MVPA), but also in non-locomotive MVPA. For non-locomotive light activity, however, there was no significant difference between women over 70 years and younger women. In contrast, for men, non-locomotive light activity and MVPA remained constant with age, while elderly men over 70 years spent less time in locomotive activities (light and MVPA). Women spent more time in non-locomotive activity than men, except for MVPA in elderly individuals, and time in non locomotive MVPA occupied more than half of the total MVPA in all age groups for women. CONCLUSIONS: These findings suggest that the intensity and the type of PA for Japanese were obviously affected by age, while locomotive PA for men and non locomotive light PA for Japanese women were obviously unaffected by age. The finding also indicates gender differences. Thus, evaluation of both locomotive and non-locomotive activity is important in the overall assessment of PA. PMID- 24170330 TI - Recognizing the clinical manifestations of acromegaly: case studies. AB - PURPOSE: To present case studies of a 36-year-old woman and a 73-year-old man who presented with the syndrome of acromegaly, and to provide primary care nurse practitioners (NPs) with the understanding of the clinical and laboratory features needed for early recognition and treatment of this fascinating disease. DATA SOURCES: A comprehensive review of published literature on acromegaly is presented. The findings discussed include the history, physical examination, and diagnostic studies of two patients presenting in different ways. They both saw multiple healthcare providers, and had symptoms and signs eventually leading to the diagnosis of acromegaly. CONCLUSIONS: Acromegaly is the result of excessive amounts of growth hormone (GH) and insulin-like growth factor type 1 (IGF-1), almost always caused by a benign adenoma of the pituitary gland. This leads to coarse facial features, soft tissue swelling (including the tongue), enlargement of the hands and feet, respiratory problems, hypertension, diabetes mellitus, carpal tunnel syndrome, and osteoarthritis. Early recognition and appropriate referral can reverse some of the signs and symptoms over time, and lead to decreased mortality and a markedly improved quality of life. IMPLICATIONS FOR PRACTICE: These cases exemplify the challenges faced by NPs and other healthcare providers in diagnosing patients with acromegaly. PMID- 24170331 TI - Optimization of endoglucanase and xylanase activities from Fusarium verticillioides for simultaneous saccharification and fermentation of sugarcane bagasse. AB - Enzymatic hydrolysis is an important but expensive step in the production of ethanol from biomass. Thus, the production of efficient enzymatic cocktails is of great interest for this biotechnological application. The production of endoglucanase and xylanase activites from F. verticillioides were optimized in a factorial design (2(5)) followed by a CCDR design. Endoglucanase and xylanase activities increased from 2.8 to 8.0 U/mL and from 13.4 to 114 U/mL, respectively. The optimal pH and temperature were determined for endoglucanase (5.6, 80 degrees C), cellobiase (5.6, 60 degrees C), FPase (6.0, 55 degrees C) and xylanase (7.0, 50 degrees C). The optimized crude extract was applied in saccharification and fermentation of sugarcane bagasse from which 9.7 g/L of ethanol was produced at an ethanol/biomass yield of 0.19. PMID- 24170332 TI - Role of GPs in communicating lifestyle messages that are good for health and the climate. PMID- 24170333 TI - Basal-bolus insulin therapy and glycemic control in adult patients with type 2 diabetes mellitus: a review of the literature. AB - PURPOSE: To present an integrative review related to basal-bolus insulin therapy and glycemic control in adult patients with type 2 diabetes mellitus. DATA SOURCES: A search of the Cochrane, Medline (first search and PubMed), and CINAHL electronic databases was conducted from 2004 through 2011 using the search terms "basal-bolus insulin therapy, sliding scale insulin, glycemic control, and adult." CONCLUSIONS: Comparisons were made of glycemic control, safety, adverse events, body weight, and insulin dose showing basal-bolus insulin therapy to be at least equal, if not superior to sliding scale insulin for the patient with type 2 diabetes mellitus. Overall patients using basal-bolus insulin therapy experienced better glycemic control, fewer hypoglycemic events, and had less weight gain. IMPLICATIONS FOR PRACTICE: Basal-bolus insulin therapy is recommended over sliding scale insulin for achieving glycemic control in both the inpatient and outpatient setting because of a reduced number of occurrences of hyper- or hypoglycemic events. This could translate to decreased hospitalizations, decreased length of stay, decreased healthcare costs, and improved patient outcomes. PMID- 24170334 TI - Care of the chronically ill patient with a bleeding disorder. AB - PURPOSE: This article provides an overview of hemophilia, a chronic bleeding disorder. DESIGN: The epidemiology, diagnosis, treatment, complications, and management of hemophilia are described. Collaborative care using the Hemophilia Treatment Center (HTC) Comprehensive Care Model is presented in a case study. CONCLUSIONS/CLINICAL RELEVANCE: Rehabilitation nurses may encounter patients across the lifespan with bleeding disorders and with basic hemophilia knowledge; coordination with the HTC can provide high-quality care for positive outcomes. PMID- 24170335 TI - Functional characterization of GPC-1 genes in hexaploid wheat. AB - In wheat, monocarpic senescence is a tightly regulated process during which nitrogen (N) and micronutrients stored pre-anthesis are remobilized from vegetative tissues to the developing grains. Recently, a close connection between senescence and remobilization was shown through the map-based cloning of the GPC (grain protein content) gene in wheat. GPC-B1 encodes a NAC transcription factor associated with earlier senescence and increased grain protein, iron and zinc content, and is deleted or non-functional in most commercial wheat varieties. In the current research, we identified 'loss of function' ethyl methanesulfonate mutants for the two GPC-B1 homoeologous genes; GPC-A1 and GPC-D1, in a hexaploid wheat mutant population. The single gpc-a1 and gpc-d1 mutants, the double gpc-1 mutant and control lines were grown under field conditions at four locations and were characterized for senescence, GPC, micronutrients and yield parameters. Our results show a significant delay in senescence in both the gpc-a1 and gpc-d1 single mutants and an even stronger effect in the gpc-1 double mutant in all the environments tested in this study. The accumulation of total N in the developing grains showed a similar increase in the control and gpc-1 plants until 25 days after anthesis (DAA) but at 41 and 60 DAA the control plants had higher grain N content than the gpc-1 mutants. At maturity, GPC in all mutants was significantly lower than in control plants while grain weight was unaffected. These results demonstrate that the GPC-A1 and GPC-D1 genes have a redundant function and play a major role in the regulation of monocarpic senescence and nutrient remobilization in wheat. PMID- 24170336 TI - Genome-wide identification and characterization of miRNAs in the hypocotyl and cotyledon of cauliflower (Brassica oleracea L. var. botrytis) seedlings. AB - MicroRNAs (miRNAs) are a class of small endogenous, non-coding RNAs that have key regulatory functions in plant growth, development, and other biological processes. Hypocotyl and cotyledon are the two major tissues of cauliflower (Brassica oleracea L. var. botrytis) seedlings. Tissue culture experiments have indicated that the regenerative abilities of these two tissues are significantly different. However, the characterization of miRNAs and their roles in regulating organ development in cauliflower remain unexplored. In the present study, two small RNA libraries were sequenced by Solexa sequencing technology. 99 known miRNAs belonging to 28 miRNA families were identified, in which 6 miRNA families were detected only in Brassicaceae. A total of 162 new miRNA sequences with single nucleotide substitutions corresponding to the known miRNAs, and 32 potentially novel miRNAs were also first discovered. Comparative analysis indicated that 42 of 99 known miRNAs and 17 of 32 novel miRNAs exhibited significantly differential expression between hypocotyl and cotyledon, and the differential expression of several miRNAs was further validated by stem-loop RT PCR. In addition, 235 targets for 89 known miRNAs and 198 targets for 24 novel miRNAs were predicted, and their functions were further discussed. The expression patterns of several representative targets were also confirmed by qRT-PCR analysis. The results identified that the transcriptional expression patterns of miRNAs were negatively correlated with their targets. These findings gave new insights into the characteristics of miRNAs in cauliflower, and provided important clues to elucidate the roles of miRNAs in the tissue differentiation and development of cauliflower. PMID- 24170338 TI - Fine-root system development and susceptibility to pathogen colonization. AB - Root development may exert control on plant-pathogen interactions with soil-borne pathogens by shaping the spatial and temporal availability of susceptible tissues and in turn the impact of pathogen colonization on root function. To evaluate the relationship between root development and resistance to apple replant disease (ARD) pathogens, pathogen abundance was compared across root branching orders in a bioassay with two rootstock genotypes, M.26 (highly susceptible) and CG.210 (less susceptible). Root growth, anatomical development and secondary metabolite production were evaluated as tissue resistance mechanisms. ARD pathogens primarily colonized first and second order roots, which corresponded with cortical tissue senescence and loss in second and third order roots. Defense compounds were differentially allocated across root branching orders, while defense induction or stress response was only detected in first order and pioneer roots. Our results suggest disease development is based largely on fine-root tip attrition. In accordance, the less susceptible rootstock supported lower ARD pathogen abundance and altered defense compound production in first order and pioneer roots and maintained higher rates of root growth in both the ARD soil and pasteurized control compared to the more susceptible. Thus, this rootstock's ability to maintain shoot growth in replant soil may be attributable to relative replant pathogen resistance in distal root branches as well as tolerance of infection based on rates of root growth. PMID- 24170337 TI - Differential tissue-specific expression of NtAQP1 in Arabidopsis thaliana reveals a role for this protein in stomatal and mesophyll conductance of CO2 under standard and salt-stress conditions. AB - The regulation of plant hydraulic conductance and gas conductance involves a number of different morphological, physiological and molecular mechanisms working in harmony. At the molecular level, aquaporins play a key role in the transport of water, as well as CO2, through cell membranes. Yet, their tissue-related function, which controls whole-plant gas exchange and water relations, is less understood. In this study, we examined the tissue-specific effects of the stress induced tobacco Aquaporin1 (NtAQP1), which functions as both a water and CO2 channel, on whole-plant behavior. In tobacco and tomato plants, constitutive overexpression of NtAQP1 increased net photosynthesis (A(N)), mesophyll CO2 conductance (g(m)) and stomatal conductance (g(s)) and, under stress, increased root hydraulic conductivity (L(pr)) as well. Our results revealed that NtAQP1 that is specifically expressed in the mesophyll tissue plays an important role in increasing both A(N) and g(m). Moreover, targeting NtAQP1 expression to the cells of the vascular envelope significantly improved the plants' stress response. Surprisingly, NtAQP1 expression in the guard cells did not have a significant effect under any of the tested conditions. The tissue-specific involvement of NtAQP1 in hydraulic and gas conductance via the interaction between the vasculature and the stomata is discussed. PMID- 24170339 TI - A comparative study of zirconium and titanium implants in rat: osseointegration and bone material quality. AB - Permanent metal implants are widely used in human medical treatments and orthopedics, for example as hip joint replacements. They are commonly made of titanium alloys and beyond the optimization of this established material, it is also essential to explore alternative implant materials in view of improved osseointegration. The aim of our study was to characterize the implant performance of zirconium in comparison to titanium implants. Zirconium implants have been characterized in a previous study concerning material properties and surface characteristics in vitro, such as oxide layer thickness and surface roughness. In the present study, we compare bone material quality around zirconium and titanium implants in terms of osseointegration and therefore characterized bone material properties in a rat model using a multi-method approach. We used light and electron microscopy, micro Raman spectroscopy, micro X-ray fluorescence and X-ray scattering techniques to investigate the osseointegration in terms of compositional and structural properties of the newly formed bone. Regarding the mineralization level, the mineral composition, and the alignment and order of the mineral particles, our results show that the maturity of the newly formed bone after 8 weeks of implantation is already very high. In conclusion, the bone material quality obtained for zirconium implants is at least as good as for titanium. It seems that the zirconium implants can be a good candidate for using as permanent metal prosthesis for orthopedic treatments. PMID- 24170340 TI - Evaluation of the physical and antimicrobial properties of silver doped hydroxyapatite depending on the preparation method. AB - In the present study, the effect of the preparation method on the physical and antibacterial properties of silver doped hydroxyapatite (HAp/Ag) samples was investigated. HAp/Ag with 0.1-5 % of silver was prepared using two different modified wet chemical precipitation methods. A comparison of thermal stability and thermodynamical properties indicated that the thermal stability and sintering temperature of HAp/Ag were higher than those of pure hydroxyapatite if Ca(NO3)2.4H2O, AgNO3, NH4OH and (NH4)2HPO4 were used as raw materials. Phase composition and silver release were determined by XRD and ICP-MS. The study showed that, after 50 h in simulated body fluid 0.8-1.8 % of silver of the total silver amount was released from compact HAp/Ag scaffolds, and release kinetics strongly depended on the HAp/Ag preparation method. In vitro antibacterial activity of samples from each method against the bacterial strains Staphylococcus epidermidis and Pseudomonas aeruginosa was approved. Results showed that, in the case of using Ca(OH)2, H3PO4 and AgNO3 as raw materials for HAp/Ag synthesis, higher antibacterial activity towards both bacterial strains could be obtained. PMID- 24170341 TI - Gene SGL, encoding a kinesin-like protein with transactivation activity, is involved in grain length and plant height in rice. AB - Grain shape, a complex agronomic trait, plays an important role in determining yield and quality in rice. In the present study, a mutant named short grain length (sgl) was identified among explants of tissue cultured japonica variety Kita-ake. It exhibited reduced plant height (about 72 % of WT) and short grain length (about 80 % of WT). The reduced length was due to decreased cell elongation. The Short Grain Length (SGL) gene was isolated via map-based cloning and identified to encode a kinesin-like protein. SGL was expressed in the whole plant, especially in the stem and panicles. SGL was shown to have transcriptional activity. In onion epidermal cells, SGL protein was found mainly in the nucleus. Real-time PCR analyses showed that expression levels of genes involved in gibberellin metabolic pathways were affected in the sgl mutant. These data suggested that SGL protein may be involved in regulating GA synthesis and response genes, that in turn, regulates grain length and plant height. PMID- 24170342 TI - High contents of very long-chain polyunsaturated fatty acids in different moss species. AB - Polyunsaturated fatty acids (PUFAs) are important cellular compounds with manifold biological functions. Many PUFAs are essential for the human diet and beneficial for human health. In this study, we report on the high amounts of very long-chain (vl) PUFAs (>=C20) such as arachidonic acid (AA) in seven moss species. These species were established in axenic in vitro culture, as a prerequisite for comparative metabolic studies under highly standardized laboratory conditions. In the model organism Physcomitrella patens, tissue specific differences in the fatty acid compositions between the filamentous protonema and the leafy gametophores were observed. These metabolic differences correspond with differential gene expression of fatty acid desaturase (FADS) encoding genes in both developmental stages, as determined via microarray analyses. Depending on the developmental stage and the species, AA amounts for 6 31 %, respectively, of the total fatty acids. Subcellular localization of the corresponding FADS revealed the endoplasmic reticulum as the cellular compartment for AA synthesis. Our results show that vlPUFAs are highly abundant metabolites in mosses. Standardized cultivation techniques using photobioreactors along with the availability of the P. patens genome sequence and the high rate of homologous recombination are the basis for targeted metabolic engineering in moss. The potential of producing vlPUFAs of interest from mosses will be highlighted as a promising area in plant biotechnology. PMID- 24170344 TI - Apoptotic mediators in patients with severe and non-severe dengue from Brazil. AB - Despite being the most significant arboviral disease worldwide, dengue has no antiviral treatment or reliable severity predictors. It has been shown that apoptotic cells from blood and tissues may be involved in the complex pathogenesis of dengue. However, very little is known about the interplay between proapoptotic and antiapoptotic mediators in this disease. Therefore, plasma levels of the three proapoptotic mediators Fas ligand (FasL), tumor necrosis factor-alpha (TNF-alpha), and TNF-related apoptosis-inducing ligand (TRAIL) were measured in dengue patients. Patients were classified according to the World Health Organization classification of dengue revised in 2009. Additionally, inhibitors of apoptosis protein (IAPs) were determined in plasma (Survivin) and peripheral blood mononuclear cells (PBMCs) lysates (cIAP-1, cIAP-2, XIAP). Levels of apoptotic proteins in plasma were correlated with counts of blood cells. FasL and TRAIL levels were elevated in dengue patients without warning signs when compared to patients with severe dengue and controls. Dengue patients with warning signs showed decreased levels of Survivin compared to patients with severe dengue and controls. TRAIL was inversely correlated with counts of lymphocyte subsets. In contrast, Survivin was positively correlated with leukocyte counts. There was a trend of elevated IAPs levels in PBMCs of patients with severe dengue. The results suggest a likely antiviral effect of TRAIL in dengue. It appears that TRAIL might be involved with apoptosis induction of lymphocytes, whereas IAPs might participate in protecting leukocytes from apoptosis. Further research is needed to explore the interactions between pro and antiapoptotic molecules and their implications in dengue pathogenesis. PMID- 24170345 TI - Rib cartilage characterization in patients affected by pectus excavatum. AB - Pectus excavatum (PE) is the most frequent anterior chest deformity which may be frequently associated with connective tissue disorders. We performed microscopic analyses to better understand cartilage behavior and obtain clues on its pathogenesis. In 37 PE patients, none with Marfan syndrome, we analyzed costal cartilage by light microscopy, immunohistochemistry and transmission electron microscopy. Control tissue specimens were harvested from four patients without any connective tissue disease. In both control and PE patients, chondrocytes were on the average <15 um in diameter and occupied <10% of tissue volume; in most cases the extracellular matrix was stained by alcian blue, instead of safranin; no difference between PE and control samples was significant. All samples showed an uneven collagen type II immunolabeling both within the cells and pericellular matrix, and occasionally of the territorial matrix. In all cases numerous cells underwent apoptosis accompanied by matrix condensation as shown by electron microscopy. Our results suggest that matrix composition and the cell number and size of costal cartilage are dependent on the subject and not on the disease; the microscopic organization of cartilage is correlated with the stabilization of the defective shape rather than with the onset of the deformity. PMID- 24170343 TI - Virus-induced gene silencing for comparative functional studies in Gladiolus hybridus. AB - Functional analysis of genes in gladiolus has previously been impractical due to the lack of an efficient stable genetic transformation method. However, virus induced gene silencing (VIGS) is effective in some plants which are difficult to transform through other methods. Although the Tobacco rattle virus (TRV)-based VIGS system has been developed and used for verifying gene functions in diverse plants, an appropriate TRV-VIGS approach for gladiolus has not been established yet. In this report we describe the first use of the TRV-VIGS system for gene silencing in gladiolus. Vacuum infiltration of cormels and young plants with the GhPDS-VIGS vector effectively down-regulated the PHYTOENE DESATURASE ortholog GhPDS gene and also resulted in various degrees of photobleaching in Gladiolus hybridus. The reduction in GhPDS expression was tested after TRV-based vector infection using real-time RT-PCR. In addition, the progress of TRV infection was detected by fluorescence visualization using a pTRV2: CP-GFP vector. In conclusion, the TRV-mediated VIGS described here will be an effective gene function analysis mechanism in gladiolus. PMID- 24170346 TI - Modifiable influences on female HPV vaccine uptake at the clinic encounter level: a literature review. AB - PURPOSE: A review of the literature to identify modifiable influences on female human papillomavirus (HPV) vaccine uptake relevant to clinical practice in order to support nurse practitioners (NPs) in the prevention of cervical cancer. DATA SOURCES: PubMed, CINAHL, reference lists of publications that surfaced in the electronic search. CONCLUSIONS: Six influences are modifiable and potentially amenable to being addressed at the clinic encounter level: (a) cost and insurance coverage, (b) provider recommendation, (c) vaccination opportunity, (d) HPV and HPV vaccine knowledge, (e) vaccine safety concerns, and (f) HPV risk. IMPLICATIONS FOR PRACTICE: NPs have an important role in improving HPV vaccine uptake and research suggests several areas they can address to increase vaccination during clinic visits. PMID- 24170347 TI - SHC2 gene copy number in multiple system atrophy (MSA). AB - PURPOSE: Multiple system atrophy (MSA) is a sporadic, late onset, rapidly progressing neurodegenerative disorder, which is characterized by autonomic failure, together with Parkinsonian, cerebellar, and pyramidal motor symptoms. The pathologic hallmark is the glial cytoplasmic inclusion with alpha-synuclein aggregates. MSA is thus an alpha-synucleinopathy. Recently, Sasaki et al. reported that heterozygosity for copy number loss of Src homology 2 domain containing-transforming protein 2 (SHC2) genes (heterozygous SHC2 gene deletions) occurred in DNAs from many Japanese individuals with MSA. Because background copy number variation can be distinct in different human populations, we assessed SHC2 allele copy number in DNAs from a US cohort of individuals with MSA, to determine the contribution of SHC2 gene copy number variation in an American cohort followed at a US referral center for MSA. Our cohort included 105 carefully phenotyped individuals with MSA. METHODS: We studied 105 well-characterized patients with MSA and 5 control subjects with reduced SHC2 gene copy number. We used two TaqMan Gene Copy Number Assays, to determine the copy number of two segments of the SHC2 gene that are separated by 27 kb. RESULTS: Assay results of DNAs from all of our 105 subjects with MSA showed 2 copies of both segments of their SHC2 genes. CONCLUSION: Our results indicate that SHC2 gene deletions underlie few, if any, cases of well-characterized MSA in the US population. This is in contrast to the Japanese experience reported by Sasaki et al., likely reflecting heterogeneity of the disease in different genetic backgrounds. PMID- 24170348 TI - A review of educational programs to reduce UTIs among individuals with SCI. AB - PURPOSE: To evaluate the effectiveness of educational programs in reducing urinary tract infections (UTIs) in individuals with spinal cord injuries (SCI). METHODS: A search of all relevant literature published up to and including July 2012 was conducted using multiple databases. Methodological quality was rated using the PEDro tool for randomized control trials (RCTs) and the Downs and Black tool for non-RCTs; levels of evidence were assigned using a modified Sackett scale. FINDINGS: Four articles were selected for review. As a result of an education program, a level 2 prospective control trial reported a reduction in number of UTIs (p = .02), but a level 2 RCT did not. A pre-post study found a reduction in number of UTIs while a case-control study did not; however, these studies did not compute statistics. CONCLUSIONS: There is limited positive evidence that education programs reduce the incidence of UTIs. CLINICAL RELEVANCE: Optimal urinary health of individuals with SCI may be optimized via education programs that provide information and enhance skills. PMID- 24170349 TI - Autophagy regulates homeostasis of pluripotency-associated proteins in hESCs. AB - The pluripotency of embryonic stem cells (ESCs) is maintained by intracellular networks of many pluripotency-associated (PA) proteins such as OCT4, SOX2, and NANOG. However, the mechanisms underlying the regulation of protein homeostasis for pluripotency remain elusive. Here, we first demonstrate that autophagy acts together with the ubiquitin-proteasome system (UPS) to modulate the levels of PA proteins in human ESCs (hESCs). Autophagy inhibition impaired the pluripotency despite increment of PA proteins in hESCs. Immunogold-electron microscopy confirmed localization of OCT4 molecules within autophagosomes. Also, knockdown of LC3 expression led to accumulation of PA proteins and reduction of pluripotency in hESCs. Interestingly, autophagy and the UPS showed differential kinetics in the degradation of PA proteins. Autophagy inhibition caused enhanced accumulation of both cytoplasmic and nuclear PA proteins, whereas the UPS inhibition led to preferentially degrade nuclear PA proteins. Our findings suggest that autophagy modulates homeostasis of PA proteins, providing a new insight in the regulation of pluripotency in hESCs. PMID- 24170350 TI - Genetic diversity and population structure in the US Upland cotton (Gossypium hirsutum L.). AB - KEY MESSAGE: Genetic diversity and population structure in the US Upland cotton was established and core sets of allelic richness were identified for developing association mapping populations in cotton. Elite plant breeding programs could likely benefit from the unexploited standing genetic variation of obsolete cultivars without the yield drag typically associated with wild accessions. A set of 381 accessions comprising 378 Upland (Gossypium hirsutum L.) and 3 G. barbadense L. accessions of the United States cotton belt were genotyped using 120 genome-wide SSR markers to establish the genetic diversity and population structure in tetraploid cotton. These accessions represent more than 100 years of Upland cotton breeding in the United States. Genetic diversity analysis identified a total of 546 alleles across 141 marker loci. Twenty-two percent of the alleles in Upland accessions were unique, specific to a single accession. Population structure analysis revealed extensive admixture and identified five subgroups corresponding to Southeastern, Midsouth, Southwest, and Western zones of cotton growing areas in the United States, with the three accessions of G. barbadense forming a separate cluster. Phylogenetic analysis supported the subgroups identified by STRUCTURE. Average genetic distance between G. hirsutum accessions was 0.195 indicating low levels of genetic diversity in Upland cotton germplasm pool. The results from both population structure and phylogenetic analysis were in agreement with pedigree information, although there were a few exceptions. Further, core sets of different sizes representing different levels of allelic richness in Upland cotton were identified. Establishment of genetic diversity, population structure, and identification of core sets from this study could be useful for genetic and genomic analysis and systematic utilization of the standing genetic variation in Upland cotton. PMID- 24170351 TI - Vaccinating parents experience vaccine anxiety too. AB - PURPOSE: To identify common causes of parental anxiety regarding childhood vaccinations among parents who vaccinate. Another purpose was to seek recommendations for healthcare providers to help parents overcome their anxiety when their children are immunized. DATA SOURCES: Four 1-h focus groups were conducted, each consisting of 8-10 parents. Each focus group discussion was conducted by a moderator and an assistant moderator. The moderator facilitated discussion while the assistant moderator took notes. Each session was recorded on video. The data were transcribed and analyzed for themes. CONCLUSIONS: Parents identifying themselves as being compliant with childhood vaccination requirements reported anxiety that can be divided into five major themes: parental anxiety prior to vaccination, parental anxiety during the vaccination, parental anxiety after the vaccination, parental suggestions for healthcare providers, and informational issues. IMPLICATIONS FOR PRACTICE: Making minor changes in office policies may help alleviate some parental anxiety regarding vaccinations. Providers should also create lists of credible sources about vaccination information. Because the cause of vaccine-related parental anxiety varies, targeted education is necessary to relieve common causes of vaccine anxiety, even among parents who vaccinate. PMID- 24170352 TI - Current and future assisted reproductive technologies for mammalian farm animals. AB - Reproduction in domestic animals is under control by man and the technologies developed to facilitate that control have a major impact on the efficiency of food production. Reproduction is an energy-intensive process. In beef cattle, for example, over 50 % of the total feed consumption required to produce a unit of meat protein is consumed by the dam of the meat animal (Anim Prod 27:367-379, 1978). Sows are responsible for about 20 % of the total feed needed to produce animals for slaughter (Adv Pork Prod 19:223-237, 2008). Accordingly, energy input to produce food from animal sources is reduced by increasing number of offspring per unit time a breeding female is in the herd. Using beef cattle as an example again, life-cycle efficiency for production of weaned calves is positively related to early age at puberty and short calving intervals (J Anim Sci 57:852 866, 1983). Reproductive technologies also dictate the strategies that can be used to select animals genetically for traits that improve production. Of critical importance has been artificial insemination (AI) (Anim Reprod Sci 62:143 172, 2000; Stud Hist Philos Biol Biomed Sci 38:411-441, 2007; Reprod Domest Anim 43:379-385, 2008; J Dairy Sci 92:5814-5833, 2009) and, as will be outlined in this chapter, emerging technologies offer additional opportunities for improvements in genetic selection. Given the central role of reproduction as a determinant of production efficiency and in genetic selection, improvements in reproductive technologies will be crucial to meeting the challenges created by the anticipated increases in world population (from seven billion people in 2011 to an anticipated nine billion by 2050; World population prospects: the 2010 revision, highlights and advance tables. Working Paper No. ESA/P/WP.220, New York) and by difficulties in livestock production wrought by climate change (SAT eJournal 4:1-23, 2007).The purpose of this chapter will be to highlight current and emerging reproductive technologies that have the potential to improve efficiency of livestock production. The focus will be on technologies that manipulate male and female gametes as well as the stem cells from which they are derived and the preimplantation embryo. While technology is crucial to other interventions in the reproductive process like control of seasonal breeding, hormonal regulation of ovulation, estrous cyclicity and pregnancy establishment, feeding to optimize reproduction, minimizing environmental stress, and selection of genes controlling reproduction, these will not be considered here. Rather the reader is directed to other chapters in this volume as well as some reviews on other aspects of artificial manipulation of reproduction (Reprod Fertil Dev 24:258-266, 2011; Reprod Domest Anim 43:40-47, 2008; Reprod Domest Anim 43:122 128, 2008; Soc Reprod Fertil Suppl 66:87-102, 2009; Comprehensive biotechnology, Amsterdam, pp 477-485; Dairy production medicine, Chichester, pp 153-163; Theriogenology 76:1619-1631, 2011; Theriogenology 76:1568-1582, 2011; Theriogenology 77:1-11, 2012). Given the large number of mammalian species used for production of products useful for man and the diversity in their biology and management, the review will not be comprehensive but instead will use results from species that are most illustrative of the opportunities generated by assisted reproductive technologies. PMID- 24170353 TI - Current and future reproductive technologies for avian species. AB - The global demand for poultry meat and eggs is expected to increase exponentially in the next several decades. Increasing global poultry production in the future would require significant improvements in genetics, nutrition, and managerial practices including reproduction. This chapter summarizes some of the recent developments in ameliorating reproductive dysfunction in broiler breeder chickens, cryopreservation of avian spermatozoa, sex selection, and avian transgenesis. PMID- 24170354 TI - Current and future assisted reproductive technologies for fish species. AB - The Food and Agriculture Organization of the United Nations (FAO) estimates that in 2012 aquaculture production of fish will meet or exceed that of the capture fisheries for the first time. Thus, we have just turned the corner from a predominantly hunting gathering approach to meeting our nutritional needs from fish, to a farming approach. In 2012, 327 finfish species and five hybrids were covered by FAO aquaculture statistics, although farming of carps, tilapias, salmonids, and catfishes account for most of food-fish production from aquaculture. Although for most major species at least part of production is based on what might be considered domesticated animals, only limited production in most species is based on farming of improved lines of fish or is fully independent of wild seedstock. Consistent with the infancy of most aquaculture industries, much of the development and implementation of reproductive technologies over the past 100 years has been directed at completion of the life cycle in captivity in order to increase seed production and begin the process of domestication. The selection of species to farm and the emphasis of selective breeding must also take into account other ways to modify performance of an animal. Reproductive technologies have also been developed and implemented to affect many performance traits among fishes. Examples include technologies to control gender, alter time of sexual maturation, and induce sterilization. These technologies help take advantage of sexually dimorphic growth, overcome problems with growth performance and flesh quality associated with sexual maturation, and genetic containment. Reproductive technologies developed to advance aquaculture and how these technologies have been implemented to advance various sectors of the aquaculture industry are discussed. Finally, we will present some thoughts regarding future directions for reproductive technologies and their applications in finfish aquaculture. PMID- 24170355 TI - Incorporation of genetic technologies associated with applied reproductive technologies to enhance world food production. AB - Animal breeding and reproductive physiology have been closely related throughout the history of animal production science. Artificial insemination provides the best method of increasing the influence of sires with superior genetics to improve production traits. Multiple ovulation embryo transfer (MOET) provides some ability to increase the genetic influence of the maternal line as well. The addition of genetic technologies to this paradigm allows for improved methods of selecting sires and dams carrying the best genes for production and yield of edible products and resistance to diseases and parasites. However, decreasing the number of influential parents within a population also increases the risk of propagating a recessive gene that could negatively impact the species (Reprod Domest Anim 44:792-796, 2009; BMC Genomics 11:337, 2010). Furthermore, antagonistic genotypic relationships between production traits and fertility (Anim Prod Sci 49:399-412, 2009; Anim Genet 43:442-446, 2012) suggest that care must be taken to ensure that increasing the frequency of genes with a positive influence on production does not negatively impact the fertility of the replacement females entering the herd. PMID- 24170356 TI - Impacts of reproductive technologies on beef production in the United States. AB - Estimations of world population growth indicate that by the year 2050 we will reach nine billion habitants on earth. These estimates impose a tremendous challenge in the current agricultural systems as food supply will need to increase by 100 % in the next 40 years (Food and Agriculture Organization of the United Nations 2009). Beef will be a primary protein source that will assist in meeting the requirements for a portion of the protein in diets of this expanding global populace. Beef is a high-quality protein that contains all essential amino acids for the human body and also contains additional essential nutrients such as iron, zinc, B vitamins, riboflavin, selenium, choline, and conjugated linoleic acid (CLA). Adopting reproductive technologies at greater rates than currently used is a viable method to dramatically enhance production efficiency of beef cattle enterprises.Artificial insemination (AI), estrous synchronization and fixed-time AI (TAI), semen and embryo cryopreservation, multiple ovulation and embryo transfer (MOET), in vitro fertilization, sex determination of sperm or embryos, and nuclear transfer are technologies that are used to enhance the production efficiency of beef operations. In many cases, the development of these technologies is responsible for significant changes to traditional livestock production practices. However, adoption of these technologies appears to has not grown at the same rate in the United States as other formidable beef producing nations. For example, sales of beef semen for AI increased from 3.3 to 11.9 million units between 1993 and 2011 in Brazil, whereas that in the United States has increased from 2.9 to 3.8 million units during the same period. The significant increases in adoption of reproductive technologies in developing countries is likely as a result of the development of practical estrous synchronization and TAI systems that have allowed beef producers the opportunity to eliminate detection of estrus in their AI programs with a high degree of success. In the United States, slow adoption rates of these technologies may result in a future loss of international market share of beef products as other nations take advantage not only of the additional kilogram of beef that can be produced but also the improved quality of beef that can be realized through incorporation of reproductive technologies and resultant genetic improvement. However, current difficulties the US producers have with the incorporation of applied reproductive technologies, such as TAI, MOET, and sex semen, must not be the reason to overlook and incorporate more traditional reproductive technologies such as castration, breeding season management, or weaning. In many cases, beef producers in the United States fail to incorporate these more traditional technologies, which results in a reduction in production efficiency of the US beef industry. This chapter will focus on both traditional and more developed reproductive technologies that will play a role in enhancing future production efficiencies of the US beef cattle production system. PMID- 24170357 TI - Impact of reproductive technologies on dairy food production in the dairy industry. AB - Reproductive technologies drive the efficiency of managing dairy cows because the lactation cycle of the dairy cow depends on regular calving to renew lactation yields. Achieving timely pregnancies to allow calving every 12-14 months, therefore, is critical in modern dairy production. To meet the demands to produce sufficient milk for fluid and dairy products, various technologies are applied to enhance efficiencies on the dairy farm. Artificial insemination (AI), embryo transfer, ultrasonographic and chemical detection of pregnancy, various monitors that detect or predict estrus, and handheld communication and testing devices allow managers to retrieve information to make cow-side decisions about health and reproductive status. Genomic testing of young potential sires or young heifers is now possible and can provide information about their genetic merit years before any progeny tests can be completed. In many countries, the challenge faced by dairy producers is their ability to afford these technologies in the face of rising feed and labor costs and volatile milk prices received at the farm gate. Government policies often place obstacles, trade barriers, and unfunded mandates that preclude operations from making a modest profit. Unlike nearly all other manufacturing industries, agriculture producers have little control over the price received for their products. Therefore, dairy production is vulnerable to many uncontrolled factors including climate, government policy, economic conditions, and skilled labor shortages. It is clear that the impact of emerging and current reproductive technologies is critical to the management of dairy cattle to produce sufficient milk to meet consumer demands for quality fluid and dairy products. PMID- 24170358 TI - Impact of swine reproductive technologies on pig and global food production. AB - Reproductive technologies have dramatically changed the way pigs are raised for pork production in developed and developing countries. This has involved such areas as pigs produced/sow, more consistent pig flow to market, pig growth rate and feed efficiency, carcass yield and quality, labor efficiency, and pig health. Some reproductive technologies are in widespread use for commercial pork operations [Riesenbeck, Reprod Domest Anim 46:1-3, 2011] while others are in limited use in specific segments of the industry [Knox, Reprod Domest Anim 46:4 6, 2011]. Significant changes in the efficiency of pork production have occurred as a direct result of the use of reproductive technologies that were intended to improve the transfer of genes important for food production [Gerrits et al., Theriogenology 63:283-299, 2005]. While some technologies focused on the efficiency of gene transfer, others addressed fertility and labor issues. Among livestock species, pig reproductive efficiency appears to have achieved exceptionally high rates of performance (PigCHAMP 2011) [Benchmark 2011, Ames, IA, 12-16]. From the maternal side, this includes pigs born per litter, farrowing rate, as well as litters per sow per year. On the male side, boar fertility, sperm production, and sows served per sire have improved as well [Knox et al., Theriogenology, 70:1202-1208, 2008]. These shifts in the efficiency of swine fertility have resulted in the modern pig as one of the most efficient livestock species for global food production. These reproductive changes have predominantly occurred in developed countries, but data suggests transfer and adoption of these in developing countries as well (FAO STAT 2009; FAS 2006) [World pig meat production: food and agriculture organization of the United Nations, 2009; FAS, 2006) Worldwide Pork Production, 2006]. Technological advancements in swine reproduction have had profound effects on industry structure, production, efficiency, quality, and profitability. In all cases, the adoption of these technologies has aided in the creation of a sustainable supply of safe and affordable pork for consumers around the world [den Hartog, Adv Pork Prod 15:17 24, 2004]. PMID- 24170359 TI - Impacts of reproductive technologies on beef production in South America. AB - The majority of beef cow herds in South America are constituted by Bos indicus females, which have particular reproductive features that contribute to reduced reproductive efficiency compared with that of B. taurus cohorts. Hence, several alternatives to enhance reproductive efficiency of B. indicus heifers and cows have been developed to address their inherent reproductive shortcomings. These research-based technologies are being described in detail within this chapter and have already made an impact on South American B. indicus-based production systems. These include the following: (a) hormonal protocols to induce puberty in nulliparous heifers or estrous cyclicity in postpartum cows to maximize their reproductive performance during the subsequent breeding season, (b) hormonal protocols to synchronize estrus and/or ovulation in B. indicus females to exploit their reproductive responses to artificial insemination, and (c) genetic and environmental factors that influence reproductive success in beef herds, including reproductive diseases and excitable temperament of B. indicus females, that have been investigated to support/promote the development of appropriate mitigation technologies. PMID- 24170360 TI - An Australasian perspective on the role of reproductive technologies in world food production. AB - Industries based on small ruminants are major contributors to world food supply but, in extensive grazing systems, reproductive technology is not directly relevant to most enterprises. More important is the need to respond to demand in high-profit export markets for products that are 'clean, green and ethical' (CGE). This combination of issues led to the concept of CGE management of reproduction that is based on scientific evidence but does not require complex technology. Nutrition is the major challenge because we are limited primarily to the grazing of forages and pastures, but responding to this challenge opens up opportunities-new forages can supply energy and protein whilst improving animal health and welfare, and reducing carbon emissions. A second major factor is the need for accurate coordination of nutritional inputs with reproductive events to ensure that the metabolic signals are appropriate. To control of the timing of reproduction, we need to move beyond simply managing the presence of the male and seek more precision. Our ultimate CGE package is thus based on manipulation of male socio-sexual signals as well as nutrition, in combination with greater use of ultrasound and birth-site management to prevent neonatal mortality. Finally, genetics is critical in the development of the CGE package.It would be difficult to incorporate the entire package in one hit-adaptations are needed to cover variations in genotype and the geographical and socio-economic environment, and some concepts need research and development. Therefore, we have suggested staged introduction of the elements of the package.CGE management can be simple and cost effective, and improve productivity whilst safeguarding the future of the industries in society and the marketplace. Reproductive technology might not be used by many farmers but it will be an essential tool for realizing the vision because it underpins the acceleration of genetic progress in otherwise tardy grazing industries. Finally, we suggest that the socio-economic drivers and the scientific principles of CGE management are also applicable to smallholders in developing economies. PMID- 24170361 TI - A perspective on the impact of reproductive technologies on food production in Africa. AB - Africa for the largest part is still regarded as part of the developing world and has a history of political instability, natural disasters, floods and droughts that all had an effect on the development of livestock production systems and the potential application of biotechnologies. It is expected that the human population in sub Saharan Africa will experience a growth of 1.2 % per year over the next 30 years. There is therefore pressure to increase sustainable productivity of livestock. Reproductive technologies such as Artificial Insemination in Africa were driven primarily by the need to control or prevent venereal diseases like Trichomoniases and Campylobacter fetus in cattle. Reproductive biotechnology had a limited impact in Africa due to several factors including a lack of infrastructure and animal recording systems, clear breeding objectives and continuously changing production systems and markets. Africa has a large variety of genetic resources adapted to the diverse environment and production systems and biotechnology should be applied within this context for an increase in food production. PMID- 24170362 TI - International perspectives on the impacts of reproductive technologies on food production in Asia. AB - The greatest numbers of domestic animals are raised in Asia. The Asian animal industry is characterized by the involvement of a high percentage of the population, mostly smallholders, of which 95 % rear domestic animals. In exploring the best ways to formulate sustainable society, it is essential to make the most of livestock products by applying appropriate reproductive technologies. There is no doubt that reproductive technologies such as AI and ET have made a great contribution to increase the number of excellent animals. Although more advanced cutting edge reproductive technologies have become available and some of them have indeed a potential of revolutionary changes in livestock industry, the most important problem for increasing productivity concerns the maintenance of optimum nutrition and prevention of heat stress to support reproductive performance and increased supply of animal proteins. International societies should be involved in binding together developed and newly developing countries in the construction of a novel model for future livestock rearing management that suits diverse environmental circumstances. PMID- 24170363 TI - International perspectives on impacts of reproductive technologies for world food production in Asia associated with poultry production. AB - Poultry meat and eggs are valuable sources of dietary protein in almost every country in the world. A number of breeding techniques, methods, and technology have been applied to obtain maximum production under different environmental and economic conditions. Indigenous and local breeds share 90 % of the total population of poultry in many developing countries in Asia. However, indigenous chickens are low in productivity. Many studies have found that crossbreeding of exotic with indigenous chickens resulted in birds that performed better, even superior to pure exotic chickens, with respect to body weight, egg production, survivability, fertility, hatchability, and egg quality. There are some other technologies for efficient use of male genetic resource and conservation of rare genetic make-up, namely artificial insemination and chimeric chicken, respectively. It was reported that 25 % of the world's meat supply is derived from poultry, and the proportion is increasing rapidly. The continent of Asia produces almost one third of the world's eggs. However, there are still many scopes to improve the production of poultry in many developing countries in Asia. Therefore, continuous research works would be essential to determine the suitable technologies for more poultry production to feed the increasing habitants on earth. PMID- 24170364 TI - Beef cattle in the year 2050. AB - In 2050, beef likely will be produced much as occurs currently, as (1) a by product of dairying-cull cows and calves not needed as replacements; (2) intensively managed cattle in environments rich in feed resources; or (3) extensively managed cattle grazing land unsuitable for tillage, with calves often moving to richer feed environments. Genetic progress will continue to depend on information such as weaning weights, but in addition, genetic, epigenetic, and phenotypic information will be obtained from blood, hair, semen, and/or biopsies of embryos.Most cattle will be genetically modified for efficient growth, desirable carcass traits, and management traits such as disease resistance. Some strains of cattle will have Y-chromosome-dependent terminal cross traits; sexed semen thus will automatically result in males with terminal cross characteristics and females with maternally desirable traits. In most cases, mother cows will have shorter gestations and smaller frame sizes than currently to decrease nutrient requirements for maintenance. The cow herd may disappear with some intensively managed systems; with sexed semen, each female can replace herself with a female calf and then be fattened for slaughter. The flexibility of being a ruminant will continue to be exploited by using a variety of feedstuffs, some of which are otherwise of little value. PMID- 24170365 TI - Interface chemistry engineering of protein-directed SnO2 nanocrystal-based anode for lithium-ion batteries with improved performance. AB - A novel uniform amorphous carbon-coated SnO2 nanocrystal (NCs) for use in lithium ion batteries is formed by utilizing bovine serum albumin (BSA) as both the ligand and carbon source. The SnO2 -carbon composite is then coated by a controlled thickness of polydopamine (PD) layer through in situ polymerization of dopamine. The PD-coated SnO2 -carbon composite is finally mixed with polyacrylic acid (PAA) which is used as binder to accomplish a whole anode system. A crosslink reaction is built between PAA and PD through formation of amide bonds to produce a robust network in the anode system. As a result, the designed electrode exhibits improved reversible capacity of 648 mAh/g at a current density of 100 mA/g after 100 cycles, and an enhanced rate performance of 875, 745, 639, and 523 mAh/g at current densities of 50, 100, 250, and 500 mA/g, respectively. FTIR spectra confirm the formation of crosslink reaction and the stability of the robust network during long-term cycling. The great improvement of capacity and rate performance achieved in this anode system is attributed to two stable interfaces built between the active material (SnO2 -carbon composite) and the buffer layer (PD) and between the buffer layer and the binder (PAA), which effectively diminish the volume change of SnO2 during charge/discharge process and provide a stable matrix for active materials. PMID- 24170366 TI - Long-term cumulative incidence of cervical intraepithelial neoplasia grade 3 or worse after abnormal cytology: impact of HIV infection. AB - To estimate the long term cumulative risk for cervical intraepithelial neoplasia grade 3 or worse after an abnormal cervical Pap test and to assess the effect of HIV infection on that risk. Participants in the Women's Interagency HIV Study were followed semiannually for up to 10 years. Pap tests were categorized according to the 1991 Bethesda system. Colposcopy was prescribed within 6 months of any abnormality. Risk for biopsy-confirmed CIN3 or worse after abnormal cytology and at least 12 months follow-up was assessed using Kaplan-Meier curves and compared using log-rank tests. Risk for CIN2 or worse was also assessed, since CIN2 is the threshold for treatment. After a median of 3 years of observation, 1,947 (85%) women subsequently presented for colposcopy (1,571 [81%] HIV seropositive, 376 [19%] seronegative). CIN2 or worse was found in 329 (21%) of HIV seropositive and 42 (11%) seronegative women. CIN3 or worse was found in 141 (9%) of seropositive and 22 (6%) seronegative women. In multivariable analysis, after controlling for cytology grade HIV seropositive women had an increased risk for CIN2 or worse (H.R. 1.66, 95% C.I 1.15, 2.45) but higher risk for CIN3 or worse did not reach significance (H.R. 1.33, 95% C.I. 0.79, 2.34). HIV seropositive women with abnormal Paps face a marginally increased and long term risk for cervical disease compared to HIV seronegative women, but most women with ASCUS and LSIL Pap results do not develop CIN2 or worse despite years of observation. PMID- 24170367 TI - Toxic element profiles in selected medicinal plants growing on serpentines in Bulgaria. AB - Populations of medicinal plants growing on serpentines and their respective soils were analyzed for Fe, Ni, Mn, Cr, Co, Cd, Cu, Zn, and Pb using inductively coupled plasma atomic emission spectrometry. Aqua regia extraction and 0.43 M acetic acid extraction were used for the quantification of pseudototal and bioavailable fractions, respectively, of elements in soil and nitric acid digestion for determination of total element content in plants. Screening was performed to (1) document levels of toxic metals in herbs extensively used in preparation of products and standardized extracts, (2) compare accumulation abilities of ferns and seed plants, and (3) estimate correlations between metal content in plants and their soils. The toxic element content of plants varied from site to site on a large scale. The concentrations of Fe and Ni were elevated while those of Cu, Zn, and Pb were close to average values usually found in plants. The highest concentrations for almost all elements were measured in both Teucrium species. Specific differences in metal accumulation between ferns and seed plants were not recorded. The investigated species are not hyperaccumulators but can accumulate toxic elements, in some cases exceeding permissible levels proposed by the World Health Organization and European Pharmacopoeia. The harvesting of medicinal plants from serpentines could be hazardous to humans. PMID- 24170368 TI - Deriving quantitative dynamics information for proteins and RNAs using ROTDIF with a graphical user interface. AB - To facilitate rigorous analysis of molecular motions in proteins, DNA, and RNA, we present a new version of ROTDIF, a program for determining the overall rotational diffusion tensor from single- or multiple-field nuclear magnetic resonance relaxation data. We introduce four major features that expand the program's versatility and usability. The first feature is the ability to analyze, separately or together, (13)C and/or (15)N relaxation data collected at a single or multiple fields. A significant improvement in the accuracy compared to direct analysis of R2/R1 ratios, especially critical for analysis of (13)C relaxation data, is achieved by subtracting high-frequency contributions to relaxation rates. The second new feature is an improved method for computing the rotational diffusion tensor in the presence of biased errors, such as large conformational exchange contributions, that significantly enhances the accuracy of the computation. The third new feature is the integration of the domain alignment and docking module for relaxation-based structure determination of multi-domain systems. Finally, to improve accessibility to all the program features, we introduced a graphical user interface that simplifies and speeds up the analysis of the data. Written in Java, the new ROTDIF can run on virtually any computer platform. In addition, the new ROTDIF achieves an order of magnitude speedup over the previous version by implementing a more efficient deterministic minimization algorithm. We not only demonstrate the improvement in accuracy and speed of the new algorithm for synthetic and experimental (13)C and (15)N relaxation data for several proteins and nucleic acids, but also show that careful analysis required especially for characterizing RNA dynamics allowed us to uncover subtle conformational changes in RNA as a function of temperature that were opaque to previous analysis. PMID- 24170369 TI - A PilT N-terminus domain protein SSO1118 from hyperthemophilic archaeon Sulfolobus solfataricus P2. PMID- 24170370 TI - Standardization and safety of alveolar bone-derived stem cell isolation. AB - Cell therapies utilizing mesenchymal stem cells (MSCs) could overcome limitations of traditional treatments for reconstructing craniofacial tissues. This large scale study explored a standardized methodology for the isolation and clinical scale expansion of alveolar bone marrow-derived MSCs (aBMSCs). We harvested 103 alveolar bone marrow samples from 45 patients using 1 of 3 standardized methodologies. Following aBMSC isolation, cells were characterized through cell surface marker expression and lineage-specific differentiation. Long-term cultures (> 50 population doublings [PDs]) were evaluated for transformational changes through senescence, gene expression, and karyotyping. Finally, aBMSC bone forming potential was determined in vivo. More than 0.5 cc of bone marrow was needed to predictably isolate aBMSCs, and, regardless of methodology for harvest, cell-surface marker expression of CD73, CD90, CD105, and Stro-1 was similar for aBMSCs, being 89.8%, 98.8%, 93.8%, and 3.2%, respectively; all cells were negative for CD11b, CD19, and CD45. aBMSCs exhibited multipotency, and karyotypes were normal up to 30 PDs, with significant cell senescence beginning following 35 PDs. Additionally, aBMSCs induced ectopic bone formation following subcutaneous transplantation into mice. These findings demonstrate a predictable approach for the isolation and safe clinical-scale expansion of aBMSCs, and thus, their clinical use could be considered for craniofacial regenerative therapies. PMID- 24170371 TI - Removal of interproximal dental biofilms by high-velocity water microdrops. AB - The influence of the impact of a high-velocity water microdrop on the detachment of Streptococcus mutans UA159 biofilms from the interproximal (IP) space of teeth in a training typodont was studied experimentally and computationally. Twelve-day old S. mutans biofilms in the IP space were exposed to a prototype AirFloss delivering 115 uL water at a maximum exit velocity of 60 m/sec in a 30-msec burst. Using confocal microscopy and image analysis, we obtained quantitative measurements of the percentage removal of biofilms from different locations in the IP space. The 3D geometry of the typodont and the IP spaces was obtained by micro-computed tomography (u-CT) imaging. We performed computational fluid dynamics (CFD) simulations to calculate the wall shear stress (tauw ) distribution caused by the drops on the tooth surface. A qualitative agreement and a quantitative relationship between experiments and simulations were achieved. The wall shear stress (tauw ) generated by the prototype AirFloss and its spatial distribution on the teeth surface played a key role in dictating the efficacy of biofilm removal in the IP space. PMID- 24170372 TI - Barrier formation: potential molecular mechanism of enamel fluorosis. AB - Enamel fluorosis is an irreversible structural enamel defect following exposure to supraoptimal levels of fluoride during amelogenesis. We hypothesized that fluorosis is associated with excess release of protons during formation of hypermineralized lines in the mineralizing enamel matrix. We tested this concept by analyzing fluorotic enamel defects in wild-type mice and mice deficient in anion exchanger-2a,b (Ae2a,b), a transmembrane protein in maturation ameloblasts that exchanges extracellular Cl(-) for bicarbonate. Defects were more pronounced in fluorotic Ae2a,b (-/-) mice than in fluorotic heterozygous or wild-type mice. Phenotypes included a hypermineralized surface, extensive subsurface hypomineralization, and multiple hypermineralized lines in deeper enamel. Mineral content decreased in all fluoride-exposed and Ae2a,b(-/-) mice and was strongly correlated with Cl(-). Exposure of enamel surfaces underlying maturation-stage ameloblasts to pH indicator dyes suggested the presence of diffusion barriers in fluorotic enamel. These results support the concept that fluoride stimulates hypermineralization at the mineralization front. This causes increased release of protons, which ameloblasts respond to by secreting more bicarbonates at the expense of Cl(-) levels in enamel. The fluoride-induced hypermineralized lines may form barriers that impede diffusion of proteins and mineral ions into the subsurface layers, thereby delaying biomineralization and causing retention of enamel matrix proteins. PMID- 24170373 TI - DNAJB6 myopathy: a vacuolar myopathy with childhood onset. AB - INTRODUCTION: DNAJB6 mutations cause an autosomal dominant myopathy that can manifest as limb-girdle muscular dystrophy (LGMD1D/1E) or distal-predominant myopathy. In the majority of patients this myopathy manifests in adulthood and shows vacuolar changes on muscle biopsy. METHODS: Clinical, electrophysiological, pathological, and molecular findings are reported. RESULTS: We report a 56-year old woman, who, like 3 other family members, became symptomatic in childhood with slowly progressive limb-girdle muscle weakness, normal serum creatine kinase (CK) values, and myopathic electromyographic findings. Muscle biopsy showed vacuolar changes and congophilic inclusions, and molecular analysis revealed a pathogenic mutation in the DNAJB6 gene. Differences and similarities with previously described cases are assessed. CONCLUSIONS: Childhood-onset of DNAJB6 myopathy is more frequent than previously believed; congophilic inclusions may be present in the muscle of these patients. PMID- 24170374 TI - Ensuring that international medical graduates and ethnic minority doctors have the necessary cultural awareness to provide care in the UK. PMID- 24170375 TI - Optic radiation structure and anatomy in the normally developing brain determined using diffusion MRI and tractography. AB - The optic radiation (OR) is a component of the visual system known to be myelin mature very early in life. Diffusion tensor imaging (DTI) and its unique ability to reconstruct the OR in vivo were used to study structural maturation through analysis of DTI metrics in a cohort of 90 children aged 5-18 years. As the OR is at risk of damage during epilepsy surgery, we measured its position relative to characteristic anatomical landmarks. Anatomical distances, DTI metrics and volume of the OR were investigated for age, gender and hemisphere effects. We observed changes in DTI metrics with age comparable to known trajectories in other white matter tracts. Left lateralization of DTI metrics was observed that showed a gender effect in lateralization. Sexual dimorphism of DTI metrics in the right hemisphere was also found. With respect to OR dimensions, volume was shown to be right lateralised and sexual dimorphism demonstrated for the extent of the left OR. The anatomical results presented for the OR have potentially important applications for neurosurgical planning. PMID- 24170378 TI - Gazing behavior and coordination during piano duo performance. AB - This study was designed to investigate the roles of gazing behavior during piano duo performance by highlighting coordination among performers. Experiment 1 was conducted under four conditions: invisible, only the body visible, only the head visible, and face -to -face. Experiment 2 was conducted under three conditions: invisible, only the movable head visible, and only the fixed head visible. In both experiments, performers looked toward each other just before temporal changes during coordination moments, which improved synchronization accuracy. The results also showed that gazing without movement cues to some extent facilitated synchronization, although asynchrony was greater under the restricted- movement condition than under the free- movement condition. The following results were obtained:(1) Mutual gaze is important for reducing timing lag between performers. (2) Mutual gaze modulates remarkable and arbitrary temporal expressions, such as fermata. (3) Performers may utilize movements as visual cues for strict synchronization. PMID- 24170376 TI - Word skipping during sentence reading: effects of lexicality on parafoveal processing. AB - Two experiments examined how lexical status affects the targeting of saccades during reading by using the boundary technique to vary independently the content of a letter string when seen in parafoveal preview and when directly fixated. Experiment 1 measured the skipping rate for a target word embedded in a sentence under three parafoveal preview conditions: full preview (e.g., brain-brain), pseudohomophone preview (e.g., brane-brain), and orthographic nonword control preview (e.g., brant-brain); in the first condition, the preview string was always an English word, while in the second and third conditions, it was always a nonword. Experiment 2 investigated three conditions where the preview string was always a word: full preview (e.g., beach-beach), homophone preview (e.g., beech beach), and orthographic control preview (e.g., bench-beach). None of the letter string manipulations used to create the preview conditions in the experiments disrupted sublexical orthographic or phonological patterns. In Experiment 1, higher skipping rates were observed for the full (lexical) preview condition, which consisted of a word, than for the nonword preview conditions (pseudohomophone and orthographic control). In contrast, Experiment 2 showed no difference in skipping rates across the three types of lexical preview conditions (full, homophone, and orthographic control), although preview type did influence reading times. This pattern indicates that skipping not only depends on the presence of disrupted sublexical patterns of orthography or phonology, but also is critically dependent on processes that are sensitive to the lexical status of letter strings in the parafovea. PMID- 24170377 TI - Reflexive orienting in response to short- and long-duration gaze cues in young, young-old, and old-old adults. AB - Shifting visual focus on the basis of the perceived gaze direction of another person is one form of joint attention. In the present study, we investigated whether this socially relevant form of orienting is reflexive and whether it is influenced by age. Green and Woldorff (Cognition 122:96-101, 2012) argued that rapid cueing effects (i.e., faster responses to validly than to invalidly cued targets) were limited to conditions in which a cue overlapped in time with a target. They attributed slower responses following invalid cues to the time needed to resolve the incongruent spatial information provided by the concurrently presented cue and target. In the present study, we examined the orienting responses of young (18-31 years), young-old (60-74 years), and old-old (75-91 years) adults following uninformative central gaze cues that overlapped in time with the target (Exp. 1) or that were removed prior to target presentation (Exp. 2). When the cue and target overlapped, all three groups localized validly cued targets more quickly than invalidly cued targets, and validity effects emerged earlier for the two younger groups (at 100 ms post-cue-onset) than for the old-old group (at 300 ms post-cue-onset). With a short-duration cue (Exp. 2), validity effects developed rapidly (by 100 ms) for all three groups, suggesting that validity effects resulted from reflexive orienting based on the gaze cue information rather than from cue-target conflict. Thus, although old-old adults may be slow to disengage from persistent gaze cues, attention continues to be reflexively guided by gaze cues late in life. PMID- 24170379 TI - Time-compressed spoken word primes crossmodally enhance processing of semantically congruent visual targets. AB - Findings from three experiments support the conclusion that auditory primes facilitate the processing of related targets. In Experiments 1 and 2, we employed a crossmodal Stroop color identification task with auditory color words (as primes) and visual color patches (as targets). Responses were faster for congruent priming, in comparison to neutral or incongruent priming. This effect also emerged for different levels of time compression of the auditory primes (to 30 % and 10 % of the original length; i.e., 120 and 40 ms) and turned out to be even more pronounced under high-perceptual-load conditions (Exps. 1 and 2). In Experiment 3, target-present or -absent decisions for brief target displays had to be made, thereby ruling out response-priming processes as a cause of the congruency effects. Nevertheless, target detection (d') was increased by congruent primes (30 % compression) in comparison to incongruent or neutral primes. Our results suggest semantic object-based auditory-visual interactions, which rapidly increase the denoted target object's salience. This would apply, in particular, to complex visual scenes. PMID- 24170380 TI - The influence of cognitive load on spatial search performance. AB - During search, executive function enables individuals to direct attention to potential targets, remember locations visited, and inhibit distracting information. In the present study, we investigated these executive processes in large-scale search. In our tasks, participants searched a room containing an array of illuminated locations embedded in the floor. The participants' task was to press the switches at the illuminated locations on the floor so as to locate a target that changed color when pressed. The perceptual salience of the search locations was manipulated by having some locations flashing and some static. Participants were more likely to search at flashing locations, even when they were explicitly informed that the target was equally likely to be at any location. In large-scale search, attention was captured by the perceptual salience of the flashing lights, leading to a bias to explore these targets. Despite this failure of inhibition, participants were able to restrict returns to previously visited locations, a measure of spatial memory performance. Participants were more able to inhibit exploration to flashing locations when they were not required to remember which locations had previously been visited. A concurrent digit-span memory task further disrupted inhibition during search, as did a concurrent auditory attention task. These experiments extend a load theory of attention to large-scale search, which relies on egocentric representations of space. High cognitive load on working memory leads to increased distractor interference, providing evidence for distinct roles for the executive subprocesses of memory and inhibition during large-scale search. PMID- 24170381 TI - Hand mental rotation is not systematically altered by actual body position: Laterality judgment versus same-different comparison tasks. AB - It is commonly believed that during mental rotation of body parts, participants tend to imagine their own body part moving toward the stimulus, thus using an egocentric strategy. Several studies have also shown that the mental rotation of hands is affected by the actual hand position, especially if the hand is kept in an awkward position. However, this hand posture effect, as well as the use of an egocentric strategy during mental rotation of body parts, is not systematic. Several experiments have demonstrated that manipulating the stimulus features or the paradigm could induce a shift to visual and allocentric strategies. Here, we studied the effects of hand posture and biomechanical constraints on one-hand mental rotation (laterality judgment task), two-hand mental rotation (same different judgment task), and mental rotation of one or two alphanumeric symbols (control tasks). Effects of posture and biomechanical constraints were observed solely for the laterality judgment task. Response times in the same-different hand mental rotation items were influenced by the angular disparity between the stimuli. We interpreted our result as evidence of the use of different strategies for each task. Future research should focus on disentangling the exact subprocesses in which an egocentric strategy is used, in order to propose better tests for participants with motor impairments. PMID- 24170382 TI - Reply to triage of women with minor abnormal cervical cytology: Meta-analysis of the accuracy of an assay targeting messenger ribonucleic acid of 5 high-risk human papillomavirus types. PMID- 24170383 TI - Characterization of the sugar alcohol-producing yeast Pichia anomala. AB - Sugar alcohols have been widely applied in the field of food and medicine for their unique properties. Compared to chemical production, microbial production of sugar alcohol has become attractive for its environmental and sustainable pattern. In this study, a potential yeast isolated from soil of Beijing suburbs was identified as Pichia anomala TIB-x229, and its key enzyme of D-arabitol dehydrogenase for microbial production of sugar alcohols was functionally characterized. This yeast could simultaneously produce D-arabitol, xylitol, and/or ribitol from a different ratio of sugar substrates at a high efficiency by bioconversion, and no glucose repression happened when mixed sugars of xylose and glucose were used as the substrates during the bioconversion. This yeast could also efficiently convert complicated feedstock such as xylose mother liquor to D arabitol, xylitol, and ribitol with 55 % yields. To elucidate the conversion relationship of the sugar alcohols, especially D-arabitol and xylitol, the key D arabitol dehydrogenase gene from P. anomala was cloned, expressed and purified for further in vitro characterization. The results showed that this D-arabitol dehydrogenase could catalyze arabitol to xylulose further, which is significant for xylitol production from glucose. Our study laid the foundation for improving the production of sugar alcohols by metabolic and fermentation engineering strategies. PMID- 24170384 TI - Plant-derived compounds as natural antimicrobials to control paper mill biofilms. AB - Biofilms can cause severe problems in industrial paper mills, particularly of economic and technological types (clogging of filters, sheet breaks or holes in the paper, machine breakdowns, etc.). We present here some promising results on the use of essential oil compounds to control these biofilms. Biofilms were grown on stainless-steel coupons with a microbial white water consortium sampled from an industrial paper mill. Five essential oil compounds were screened initially in the laboratory in terms of their antimicrobial activity against planktonic cells and biofilms. The three most active compounds were selected and then tested in different combinations. The combination finally selected was tested at the pilot scale to confirm its efficiency under realistic conditions. All the compounds tested were as active against biofilms as they were against planktonic cells. The most active compounds were thymol, carvacrol, and eugenol, and the most efficient combination was thymol-carvacrol. At a pilot scale, with six injections a day, 10 mM carvacrol alone prevented biocontamination for at least 10 days, and a 1 mM thymol-carvacrol combination enabled a 67 % reduction in biofilm dry matter after 11 days. The use of green antimicrobials could constitute a very promising alternative or supplement to the treatments currently applied to limit biofilm formation in the environment of paper mill machines. PMID- 24170385 TI - Smoking cessation in primary care: implementation of a proactive telephone intervention. AB - PURPOSE: To perform a smoking cessation intervention by a nurse practitioner in a primary care setting and assess its effectiveness. DATA SOURCES: The intervention developed was an operationalization of the five As from the U.S. Department of Health and Human Services' updated Clinical Practice Guideline: Treating Tobacco Use and Dependence. Data were generated from a two-group controlled intervention that compared adult smokers who either received or did not receive an intensive proactive telephone intervention focused on cessation. CONCLUSIONS: The intervention group showed movement across the stages of change, lower nicotine dependence, and increased confidence to quit. Also, 19% quit smoking and were abstinent at the end of study; none in the control group achieved abstinence. Quit rates were similar to those of other studies. The statistically necessary sample size was not attained, highlighting recruitment difficulties in smoking cessation studies. For a pilot study, the sample size was acceptable. IMPLICATIONS FOR PRACTICE: Measuring stage of change and nicotine dependence can assist clinicians in implementing cessation strategies. Although effective, a provider may find the intervention too intensive to employ with more than one patient at a time. This intervention should be evaluated with smokers ready to make a quit attempt. PMID- 24170387 TI - High-density lipoprotein: a new therapeutic target for glucose intolerance? PMID- 24170386 TI - High-density lipoprotein maintains skeletal muscle function by modulating cellular respiration in mice. AB - BACKGROUND: Abnormal glucose metabolism is a central feature of disorders with increased rates of cardiovascular disease. Low levels of high-density lipoprotein (HDL) are a key predictor for cardiovascular disease. We used genetic mouse models with increased HDL levels (apolipoprotein A-I transgenic [apoA-I tg]) and reduced HDL levels (apoA-I-deficient [apoA-I ko]) to investigate whether HDL modulates mitochondrial bioenergetics in skeletal muscle. METHODS AND RESULTS: ApoA-I ko mice exhibited fasting hyperglycemia and impaired glucose tolerance test compared with wild-type mice. Mitochondria isolated from gastrocnemius muscle of apoA-I ko mice displayed markedly blunted ATP synthesis. Endurance capacity during exercise exhaustion test was impaired in apoA-I ko mice. HDL directly enhanced glucose oxidation by increasing glycolysis and mitochondrial respiration rate in C2C12 muscle cells. ApoA-I tg mice exhibited lower fasting glucose levels, improved glucose tolerance test, increased lactate levels, reduced fat mass, associated with protection against age-induced decline of endurance capacity compared with wild-type mice. Circulating levels of fibroblast growth factor 21, a novel biomarker for mitochondrial respiratory chain deficiencies and inhibitor of white adipose lipolysis, were significantly reduced in apoA-I tg mice. Consistent with an increase in glucose utilization of skeletal muscle, genetically increased HDL and apoA-I levels in mice prevented high-fat diet-induced impairment of glucose homeostasis. CONCLUSIONS: In view of impaired mitochondrial function and decreased HDL levels in type 2 diabetes mellitus, our findings indicate that HDL-raising therapies may preserve muscle mitochondrial function and address key aspects of type 2 diabetes mellitus beyond cardiovascular disease. PMID- 24170388 TI - Biomarkers in relation to the effects of ticagrelor in comparison with clopidogrel in non-ST-elevation acute coronary syndrome patients managed with or without in-hospital revascularization: a substudy from the Prospective Randomized Platelet Inhibition and Patient Outcomes (PLATO) trial. AB - BACKGROUND: Risk stratification and the use of specific biomarkers have been proposed for tailoring treatment in patients with non-ST-elevation acute coronary syndrome (NSTE-ACS). We investigated the prognostic importance of high sensitivity troponin T (hs-TnT), N-terminal pro-brain natriuretic peptide (NT proBNP), and growth differentiation factor-15 (GDF-15) in relation to randomized treatment (ticagrelor versus clopidogrel) and management strategy (with or without revascularization) in the NSTE-ACS subgroup of the Platelet Inhibition and Patient Outcomes (PLATO) trial. METHODS AND RESULTS: Of 18 624 patients in the PLATO trial, 9946 had an entry diagnosis of NSTE-ACS and baseline blood samples available. During index hospitalization, 5357 were revascularized, and 4589 were managed without revascularization. Hs-TnT, NT-proBNP, and GDF-15 were determined and assessed according to predefined cutoff levels. Median follow-up was 9.1 months. Increasing levels of hs-TnT were associated with increasing risk of cardiovascular death, myocardial infarction, and stroke in medically managed patients (P<0.001), but not in those managed invasively. NT-proBNP and GDF-15 levels were associated with the same events independent of management strategy. Ticagrelor versus clopidogrel reduced the rate of cardiovascular death, myocardial infarction, and stroke in patients with NSTE-ACS and hs-TnT >=14.0 ng/L in both invasively and noninvasively managed patients; in patients with hs TnT <14.0 ng/L, there was no difference between ticagrelor and clopidogrel in the noninvasive group CONCLUSIONS: Hs-TnT, NT-proBNP, and GDF-15 are predictors of cardiovascular death, myocardial infarction, and stroke in patients with NSTE-ACS managed noninvasively, and NT-proBNP and GDF-15 also in those managed invasively. Elevated hs-TnT predicts substantial benefit of ticagrelor over clopidogrel both in invasively and noninvasively managed patients, but no apparent benefit was seen at normal hs-TnT. CLINICAL TRIAL REGISTRATION: URL:http://www.clinicaltrials.gov. Unique identifier: NCT00391872. PMID- 24170389 TI - Value of high-sensitivity troponin in assessing the extent of benefit provided by ticagrelor versus clopidogrel in non-ST-segment elevation acute coronary syndromes. PMID- 24170390 TI - "Quasi-freestanding" graphene-on-single walled carbon nanotube electrode for applications in organic light-emitting diode. AB - An air-stable transparent conductive film with "quasi-freestanding" graphene supported on horizontal single walled carbon nanotubes (SWCNTs) arrays is fabricated. The sheet resistance of graphene films stacked via layer-by-layer transfer (LBL) on quartz, and modified by 1-Pyrenebutyric acid N hydroxysuccinimide ester (PBASE), is reduced from 273 Omega/sq to about 76 Omega/sq. The electrical properties are stable to heat treatment (up to 200 oC) and ambient exposure. Organic light-emitting diodes (OLEDs) constructed of this carbon anode (T ~ 89.13% at 550 nm) exhibit ~88% power efficiency of OLEDs fabricated on an ITO anode (low turn on voltage ~3.1 eV, high luminance up to ~29 490 cd/m(2) , current efficiency ~14.7 cd/A). Most importantly, the entire graphene-on-SWCNT hybrid electrodes can be transferred onto plastic (PET) forming a highly-flexible OLED device, which continues to function without degradation in performance at bending angles >60 degrees . PMID- 24170391 TI - The presence of a dog attenuates cortisol and heart rate in the Trier Social Stress Test compared to human friends. AB - Limited research has addressed how social support in the form of a pet can affect both sympathetic and hypothalamic-pituitary-adrenal reactivity in response to a psychological challenge. The present study examined the effects of social support on salivary cortisol and heart rate (HR). Forty-eight participants were randomly assigned to three different conditions (human friend, novel dog, or control). All participants completed the Trier Social Stress Test and provided cortisol, HR, and State-Trait Anxiety Inventory measures. For participants paired with a dog, overall cortisol levels were attenuated throughout the experimental procedure, and HR was attenuated during the Trier Social Stress Test. For all groups, state anxiety increased after the Trier Social Stress Test, and HR during the Trier Social Stress Test was a predictor of cortisol. These results suggest that short term exposure to a novel dog in an unfamiliar setting can be beneficial. They also suggest a possible mechanism for the beneficial effect associated with affiliation with pets. PMID- 24170392 TI - Dynamic programming. AB - Independent scoring of the aligned sections to determine the quality of biological sequence alignments enables recursive definitions of the overall alignment score. This property is not only biologically meaningful but it also provides the opportunity to find the optimal alignments using dynamic programming based algorithms. Dynamic programming is an efficient problem solving technique for a class of problems that can be solved by dividing into overlapping subproblems. Pairwise sequence alignment techniques such as Needleman-Wunsch and Smith-Waterman algorithms are applications of dynamic programming on pairwise sequence alignment problems. These algorithms offer polynomial time and space solutions. In this chapter, we introduce the basic dynamic programming solutions for global, semi-global, and local alignment problems. Algorithmic improvements offering quadratic-time and linear-space programs and approximate solutions with space-reduction and seeding heuristics are discussed. We finally introduce the application of these techniques on multiple sequence alignment briefly. PMID- 24170393 TI - Heuristic alignment methods. AB - Computation of multiple sequence alignment (MSA) is usually formulated as a combinatory optimization problem of an objective function. Solving the problem for virtually all sensible objective functions is known to be NP-complete implying that some heuristics must be adopted. Several general strategies have been proven effective to obtain accurate MSAs in reasonable computational costs. This chapter is devoted to a brief summary of most successful heuristic approaches. PMID- 24170394 TI - Objective functions. AB - Multiple sequence alignment involves alignment of more than two sequences and is an NP-complete problem. Therefore, heuristic algorithms that use different criteria to find an approximation to the optimal solution are employed. At the heart of these approaches lie the scoring and objective functions that a given algorithm uses to compare competing solutions in constructing a multiple sequence alignment. These objective functions are often motivated by the biological paradigms that govern functional similarities and evolutionary relations. Most existing approaches utilize a progressive process where the final alignment is constructed sequentially by adding new sequences into an existing multiple sequence alignment matrix, which is dynamically updated. In doing this, the core scoring function to assess accuracies of pairwise alignments generally remains the same, while the objective functions used in intermediary steps differ. Nevertheless, the overall assessment of the final multiple sequence alignment is generally calculated by an extension of pairwise scorings. In this chapter, we explore different scoring and objective functions used in calculating the accuracy and optimization of a multiple sequence alignment and provide utilization of these criteria in popularly used multiple sequence alignment algorithms. PMID- 24170395 TI - Who watches the watchmen? An appraisal of benchmarks for multiple sequence alignment. AB - Multiple sequence alignment (MSA) is a fundamental and ubiquitous technique in bioinformatics used to infer related residues among biological sequences. Thus alignment accuracy is crucial to a vast range of analyses, often in ways difficult to assess in those analyses. To compare the performance of different aligners and help detect systematic errors in alignments, a number of benchmarking strategies have been pursued. Here we present an overview of the main strategies-based on simulation, consistency, protein structure, and phylogeny-and discuss their different advantages and associated risks. We outline a set of desirable characteristics for effective benchmarking, and evaluate each strategy in light of them. We conclude that there is currently no universally applicable means of benchmarking MSA, and that developers and users of alignment tools should base their choice of benchmark depending on the context of application-with a keen awareness of the assumptions underlying each benchmarking strategy. PMID- 24170396 TI - BLAST and FASTA similarity searching for multiple sequence alignment. AB - BLAST, FASTA, and other similarity searching programs seek to identify homologous proteins and DNA sequences based on excess sequence similarity. If two sequences share much more similarity than expected by chance, the simplest explanation for the excess similarity is common ancestry-homology. The most effective similarity searches compare protein sequences, rather than DNA sequences, for sequences that encode proteins, and use expectation values, rather than percent identity, to infer homology. The BLAST and FASTA packages of sequence comparison programs provide programs for comparing protein and DNA sequences to protein databases (the most sensitive searches). Protein and translated-DNA comparisons to protein databases routinely allow evolutionary look back times from 1 to 2 billion years; DNA:DNA searches are 5-10-fold less sensitive. BLAST and FASTA can be run on popular web sites, but can also be downloaded and installed on local computers. With local installation, target databases can be customized for the sequence data being characterized. With today's very large protein databases, search sensitivity can also be improved by searching smaller comprehensive databases, for example, a complete protein set from an evolutionarily neighboring model organism. By default, BLAST and FASTA use scoring strategies target for distant evolutionary relationships; for comparisons involving short domains or queries, or searches that seek relatively close homologs (e.g. mouse-human), shallower scoring matrices will be more effective. Both BLAST and FASTA provide very accurate statistical estimates, which can be used to reliably identify protein sequences that diverged more than 2 billion years ago. PMID- 24170397 TI - Clustal Omega, accurate alignment of very large numbers of sequences. AB - Clustal Omega is a completely rewritten and revised version of the widely used Clustal series of programs for multiple sequence alignment. It can deal with very large numbers (many tens of thousands) of DNA/RNA or protein sequences due to its use of the mBED algorithm for calculating guide trees. This algorithm allows very large alignment problems to be tackled very quickly, even on personal computers. The accuracy of the program has been considerably improved over earlier Clustal programs, through the use of the HHalign method for aligning profile hidden Markov models. The program currently is used from the command line or can be run on line. PMID- 24170398 TI - T-Coffee: Tree-based consistency objective function for alignment evaluation. AB - T-Coffee, for Tree-based consistency objective function for alignment evaluation, is a versatile multiple sequence alignment (MSA) method suitable for aligning virtually any type of biological sequences. T-Coffee provides more than a simple sequence aligner; rather it is a framework in which alternative alignment methods and/or extra information (i.e., structural, evolutionary, or experimental information) can be combined to reach more accurate and more meaningful MSAs. T Coffee can be used either by running input data via the Web server ( http://tcoffee.crg.cat/apps/tcoffee/index.html ) or by downloading the T-Coffee package. Here, we present how the package can be used in its command line mode to carry out the most common tasks and multiply align proteins, DNA, and RNA sequences. This chapter particularly emphasizes on the description of T-Coffee special flavors also called "modes," designed to address particular biological problems. PMID- 24170399 TI - MAFFT: iterative refinement and additional methods. AB - This chapter outlines several methods implemented in the MAFFT package. MAFFT is a popular multiple sequence alignment (MSA) program with various options for the progressive method, the iterative refinement method and other methods. We first outline basic usage of MAFFT and then describe recent practical extensions, such as dot plot and adjustment of direction in DNA alignment. We also refer to MUSCLE, another high-performance MSA program. PMID- 24170400 TI - Multiple sequence alignment using Probcons and Probalign. AB - Sequence alignment remains a fundamental task in bioinformatics. The literature contains programs that employ a host of exact and heuristic strategies available in computer science. Probcons was the first program to construct maximum expected accuracy sequence alignments with hidden Markov models and at the time of its publication achieved the highest accuracies on standard protein multiple alignment benchmarks. Probalign followed this strategy except that it used a partition function approach instead of hidden Markov models. Several programs employing both strategies have been published since then. In this chapter we describe Probcons and Probalign. PMID- 24170401 TI - Phylogeny-aware alignment with PRANK. AB - Evolutionary analyses require sequence alignments that correctly represent evolutionary homology. Evolutionary and structural homology are not the same and sequence alignments generated with methods designed for structural matching can be seriously misleading in comparative and phylogenetic analyses. The phylogeny aware alignment algorithm implemented in the program PRANK has been shown to produce good alignments for evolutionary inferences. Unlike other alignment programs, PRANK makes use of phylogenetic information to distinguish alignment gaps caused by insertions or deletions and, thereafter, handles the two types of events differently. As a by-product of the correct handling of insertions and deletions, PRANK can provide the inferred ancestral sequences as a part of the output and mark the alignment gaps differently depending on their origin in insertion or deletion events. As the algorithm infers the evolutionary history of the sequences, PRANK can be sensitive to errors in the guide phylogeny and violations on the underlying assumptions about the origin and patterns of gaps. These issues are discussed in detail and practical advice for the use of PRANK in evolutionary analysis is provided. The PRANK software and other methods discussed here can be found from the program home page at http://code.google.com/p/prank msa/. PMID- 24170402 TI - GramAlign: fast alignment driven by grammar-based phylogeny. AB - Multiple sequence alignment involves identifying related subsequences among biological sequences. When matches are found, the associated pieces are shifted so that when sequences are presented as successive rows-one sequence per row homologous residues line-up in columns. Exact alignment of more than a few sequences is known to be computationally prohibitive. Thus many heuristic algorithms have been developed to produce good alignments in an efficient amount of time by determining an order by which pairs of sequences are progressively aligned and merged. GRAMALIGN is such a progressive alignment algorithm that uses a grammar-based relative complexity distance metric to determine the alignment order. This technique allows for a computationally efficient and scalable program useful for aligning both large numbers of sequences and sets of long sequences quickly. The GRAMALIGN software is available at http://bioinfo.unl.edu/gramalign.php for both source code download and a web based alignment server. PMID- 24170403 TI - Multiple sequence alignment with DIALIGN. AB - DIALIGN is a software tool for multiple sequence alignment by combining global and local alignment features. It composes multiple alignments from local pairwise sequence similarities. This approach is particularly useful to discover conserved functional regions in sequences that share only local homologies but are otherwise unrelated. An anchoring option allows to use external information and expert knowledge in addition to primary-sequence similarity alone. The latest version of DIALIGN optionally uses matches to the PFAM database to detect weak homologies. Various versions of the program are available through Gottingen Bioinformatics Compute Server (GOBICS) at http://www.gobics.de/department/software. PMID- 24170404 TI - PicXAA: a probabilistic scheme for finding the maximum expected accuracy alignment of multiple biological sequences. AB - PicXAA is a probabilistic nonprogressive alignment algorithm that finds protein (or DNA) multiple sequence alignments with maximum expected accuracy. PicXAA greedily builds up the alignment from sequence regions with high local similarity, thereby yielding an accurate global alignment that effectively captures the local similarities across sequences. PicXAA constantly yields accurate alignment results on a wide range of reference sets that have different characteristics, with especially remarkable improvements over other leading algorithms on sequence sets with high local similarities. In this chapter, we describe the overall alignment strategy used in PicXAA and discuss several important considerations for effective deployment of the algorithm. PMID- 24170405 TI - Multiple protein sequence alignment with MSAProbs. AB - Multiple sequence alignment (MSA) generally constitutes the foundation of many bioinformatics studies involving functional, structural, and evolutionary relationship analysis between sequences. As a result of the exponential computational complexity of the exact approach to producing optimal multiple alignments, the majority of state-of-the-art MSA algorithms are designed based on the progressive alignment heuristic. In this chapter, we outline MSAProbs, a parallelized MSA algorithm for protein sequences based on progressive alignment. To achieve high alignment accuracy, this algorithm employs a hybrid combination of a pair hidden Markov model and a partition function to calculate posterior probabilities. Furthermore, we provide some practical advice on the usage of the algorithm. PMID- 24170407 TI - PRALINE: a versatile multiple sequence alignment toolkit. AB - Profile ALIgNmEnt (PRALINE) is a versatile multiple sequence alignment toolkit. In its main alignment protocol, PRALINE follows the global progressive alignment algorithm. It provides various alignment optimization strategies to address the different situations that call for protein multiple sequence alignment: global profile preprocessing, homology-extended alignment, secondary structure-guided alignment, and transmembrane aware alignment. A number of combinations of these strategies are enabled as well. PRALINE is accessible via the online server http://www.ibi.vu.nl/programs/PRALINEwww/. The server facilitates extensive visualization possibilities aiding the interpretation of alignments generated, which can be written out in pdf format for publication purposes. PRALINE also allows the sequences in the alignment to be represented in a dendrogram to show their mutual relationships according to the alignment. The chapter ends with a discussion of various issues occurring in multiple sequence alignment. PMID- 24170406 TI - Large-scale multiple sequence alignment and tree estimation using SATe. AB - SATe is a method for estimating multiple sequence alignments and trees that has been shown to produce highly accurate results for datasets with large numbers of sequences. Running SATe using its default settings is very simple, but improved accuracy can be obtained by modifying its algorithmic parameters. We provide a detailed introduction to the algorithmic approach used by SATe, and instructions for running a SATe analysis using the GUI under default settings. We also provide a discussion of how to modify these settings to obtain improved results, and how to use SATe in a phylogenetic analysis pipeline. PMID- 24170408 TI - PROMALS3D: multiple protein sequence alignment enhanced with evolutionary and three-dimensional structural information. AB - Multiple sequence alignment (MSA) is an essential tool with many applications in bioinformatics and computational biology. Accurate MSA construction for divergent proteins remains a difficult computational task. The constantly increasing protein sequences and structures in public databases could be used to improve alignment quality. PROMALS3D is a tool for protein MSA construction enhanced with additional evolutionary and structural information from database searches. PROMALS3D automatically identifies homologs from sequence and structure databases for input proteins, derives structure-based constraints from alignments of three dimensional structures, and combines them with sequence-based constraints of profile-profile alignments in a consistency-based framework to construct high quality multiple sequence alignments. PROMALS3D output is a consensus alignment enriched with sequence and structural information about input proteins and their homologs. PROMALS3D Web server and package are available at http://prodata.swmed.edu/PROMALS3D. PMID- 24170409 TI - MSACompro: improving multiple protein sequence alignment by predicted structural features. AB - Multiple Sequence Alignment (MSA) is an essential tool in protein structure modeling, gene and protein function prediction, DNA motif recognition, phylogenetic analysis, and many other bioinformatics tasks. Therefore, improving the accuracy of multiple sequence alignment is an important long-term objective in bioinformatics. We designed and developed a new method MSACompro to incorporate predicted secondary structure, relative solvent accessibility, and residue-residue contact information into the currently most accurate posterior probability-based MSA methods to improve the accuracy of multiple sequence alignments. Different from the multiple sequence alignment methods that use the tertiary structure information of some sequences, our method uses the structural information purely predicted from sequences. In this chapter, we first introduce some background and related techniques in the field of multiple sequence alignment. Then, we describe the detailed algorithm of MSACompro. Finally, we show that integrating predicted protein structural information improved the multiple sequence alignment accuracy. PMID- 24170410 TI - Ingestion of indigestible foreign materials by free grazing ruminants in Amhara Region, Ethiopia. AB - Ruminants slaughtered in Bahir-Dar, northern Ethiopia, were studied to estimate the prevalence and types of foreign bodies in the rumen and reticulum. Of the 400 cattle, 320 sheep, and 320 goats examined between November 2011 and May 2012, 41.8, 20.6 and 11.9 %, respectively, contained one or more types of foreign bodies. The prevalence of foreign bodies was significantly (P < 0.05) higher (i) in cattle than in sheep and goats, (ii) in cattle in poor body condition than those in good condition, and (iii) in the rumen than in the reticulum. The most commonly encountered materials were plastics, which resulted from the widespread use of plastic bags and improper waste disposal. Other materials found were cloth, rope, metal, and leather. The study demonstrated that ruminants in the area are ingesting various types of indigestible foreign bodies, which can hamper their health and productivity. To avert the problem, collaborative intervention schemes need to be applied involving professionals, policy makers, livestock keepers, and environmental activists. PMID- 24170411 TI - The effect of breastfeeding on childhood overweight and obesity: a systematic review of the literature. AB - BACKGROUND: Childhood obesity has reached epidemic proportions. There is increasing attention to the topic of prevention and continued debate as to whether breastfeeding (BF) is protective against childhood obesity. Previous systematic reviews on this topic were done in 2005 showing that BF was protective against childhood obesity but, because of confounding variables, the evidence was weak. OBJECTIVE: To explore the current evidence of the effect of BF on childhood obesity and provide recommendations for the nurse practitioner (NP) as a primary care provider. METHODS: A systematic review of the literature from 1/2005 to 3/2012 was done to assess the evidence on the relationship between BF and childhood obesity. RESULTS: The majority of studies identified in this article showed a relationship between BF and obesity prevention, but because of confounding maternal, child, cultural, genetic, and environmental variables, the relationship remains unclear. CONCLUSIONS: While it is possible that there are protective benefits of BF on childhood obesity, it is difficult to prove because of confounding variables. However, because of other benefits for the mother and child, BF should be encouraged. Whether obesity in childhood can be prevented by BF remains unclear. Further research controlling for confounding variables is needed to provide concrete evidence. PMID- 24170412 TI - Recurrent central nervous system white matter changes in charcot-Marie-tooth type X disease. AB - INTRODUCTION: X-linked Charcot-Marie-Tooth (CMT1X) disease is caused by mutations in the GJB1 gene. We describe a young man who presented with recurrent central nervous symptoms and transient white matter changes in the setting of a novel mutation in the GJB1 gene. METHODS: Evaluation included clinical examination, neuroimaging, electrophysiological, and molecular genetic studies. RESULTS: Clinical examination on 2 admissions 5 years apart demonstrated hemiparesis with findings of underlying peripheral neuropathy. Electrophysiologic studies revealed a sensorimotor polyneuropathy. MRI studies from both admissions revealed white matter changes, with improvement on an intervening study. Mutation analysis showed a novel mutation (c.98T>A; p.Ile33Asn) in the GJB1 gene. CONCLUSIONS: Mutations in GJB1 can result in recurrent central nervous system symptoms with transient white matter signal changes on MRI. In patients presenting with hemiparesis, the presence of signs of a peripheral neuropathy may facilitate identification of CMT1X, and is likely to affect clinical management. PMID- 24170413 TI - Unbalanced estrogen metabolism in ovarian cancer. AB - Greater exposure to estrogens is a risk factor for ovarian cancer. To investigate the role of estrogens in ovarian cancer, a spot urine sample and a saliva sample were obtained from 33 women with ovarian cancer and 34 age-matched controls. Thirty-eight estrogen metabolites, conjugates and DNA adducts were analyzed in the urine samples using ultraperformance liquid chromatography/tandem mass spectrometry, and the ratio of adducts to metabolites and conjugates was calculated for each sample. The ratio of depurinating estrogen-DNA adducts to estrogen metabolites and conjugates was significantly higher in cases compared to controls (p < 0.0001), demonstrating high specificity and sensitivity. DNA was purified from the saliva samples and analyzed for genetic polymorphisms in the genes for two estrogen-metabolizing enzymes. Women with two low-activity alleles of catechol-O-methyltransferase plus one or two high-activity alleles of cytochrome P450 1B1 had higher levels of estrogen-DNA adducts and were more likely to have ovarian cancer. These findings indicate that estrogen metabolism is unbalanced in ovarian cancer and suggest that formation of estrogen-DNA adducts plays a critical role in the initiation of ovarian cancer. PMID- 24170414 TI - Design, synthesis, and anticancer properties of novel benzophenone-conjugated coumarin analogs. AB - In the current scenario, development of anticancer drugs with specific targets is of prime importance in modern chemical biology. Observing the importance of benzophenone and coumarin nucleus, it would be worthwhile to design and synthesize novel benzophenone derivatives (8a-o) bearing the coumarin nucleus. Further, they were screened for prospective anticancer activities in vitro against the Michigan Cancer Foundation-7 (MCF-7) and Ehrlich's ascites tumor (EAT) cell lines and their biomarkers, followed by in silico studies regarding phosphoinositide 3-kinase (PI3K) and caspase by molecular docking. Benzophenones have been reported as potential drugs targeting tumor angiogenesis; thus, the formation of neovessels in an in vivo model system like CAM, which is angiogenesis dependent, was observed in the presence of compounds 8a-o. The above findings would help in understanding their putative potential as therapeutic agents for cancer patients. PMID- 24170415 TI - Triage of women with minor abnormal cervical cytology: meta-analysis of the accuracy of an assay targeting messenger ribonucleic acid of 5 high-risk human papillomavirus types. PMID- 24170417 TI - Bronchial carcinoid in college freshman with persistent focal wheeze. AB - PURPOSE: To bring attention to a rare diagnosis in the pediatric population that is in the differential diagnosis for not well-controlled asthma. DATA SOURCES: Case presentation. CONCLUSIONS: Pulmonary carcinoid tumors are rare and usually present late in adolescence. Most of these tumors are located in the proximal airways and symptoms may be similar to those of asthma including cough, wheeze, chest pain, or recurrent pneumonia. IMPLICATIONS FOR PRACTICE: Bronchial carcinoid should be in the differential diagnosis for adolescents with difficult to control asthma, who have symptoms including chronic cough and focal wheeze. Referral to a pulmonary specialist should be considered to help work up the differential diagnoses. PMID- 24170416 TI - Quantitative biodistribution and pharmacokinetics of multimodal gadolinium-based nanoparticles for lungs using ultrashort TE MRI. AB - OBJECTIVE: To study the biodistribution and lung pharmacokinetics of tracheally administered gadolinium-based contrast agents [gadoteric acid and multimodal ultra-small rigid platforms (USRPs)], to validate their pharmacokinetics against optical imaging of fluorescent USRPs, and to test their short-term toxicity. MATERIALS AND METHODS: Ultrashort echo-time (UTE) lung proton magnetic resonance imaging (MRI) was performed at 4.7-Tesla (T) after the intratracheal instillation of different concentrations of contrast agent solutions in mice. Pharmacokinetic models were implemented on the absolute concentration calculated from the MRI signal enhancement measurements. Fluorescent USRPs were used to obtain optical images with the same protocol. Bronchoalveolar lavage inflammatory cell count and serum creatinine measurement were performed on four groups of instilled mice (sham, saline, USRPs, lipopolysaccharide). RESULTS: MR and optical imaging showed similar kinetics of the USRPs, passing from the airways to the lung tissue and to the kidneys, with negligible hepatic clearance. No significant increase of lung and renal inflammation markers were observed in USRP-instilled animals. CONCLUSION: A T 1-weighted radial UTE sequence was found to be valuable in quantitatively monitoring the biodistribution and pharmacokinetics of nanoparticles in the lungs of mice. The observed favorable pharmacokinetics, which was validated by fluorescence imaging, ensures the negligible toxicity of the nanoprobes, making the USRPs and the developed protocol good candidates for applications on selected lung diseases. PMID- 24170418 TI - The specificity of learned parallelism in dual-memory retrieval. AB - Retrieval of two responses from one visually presented cue occurs sequentially at the outset of dual-retrieval practice. Exclusively for subjects who adopt a mode of grouping (i.e., synchronizing) their response execution, however, reaction times after dual-retrieval practice indicate a shift to learned retrieval parallelism (e.g., Nino & Rickard, in Journal of Experimental Psychology: Learning, Memory, and Cognition, 29, 373-388, 2003). In the present study, we investigated how this learned parallelism is achieved and why it appears to occur only for subjects who group their responses. Two main accounts were considered: a task-level versus a cue-level account. The task-level account assumes that learned retrieval parallelism occurs at the level of the task as a whole and is not limited to practiced cues. Grouping response execution may thus promote a general shift to parallel retrieval following practice. The cue-level account states that learned retrieval parallelism is specific to practiced cues. This type of parallelism may result from cue-specific response chunking that occurs uniquely as a consequence of grouped response execution. The results of two experiments favored the second account and were best interpreted in terms of a structural bottleneck model. PMID- 24170419 TI - The European Diploma in Pediatric Neuroradiology sees the light of day. PMID- 24170421 TI - Unfair to compare MRCGP exam results between people at different stages of learning. PMID- 24170422 TI - Robotic system with sweeping palpation and needle biopsy for prostate cancer diagnosis. AB - BACKGROUND: Early diagnosis of prostate cancers can be of major benefit to patients because, combined with proper treatments, it can increase the survival rate of patients. MATERIALS AND METHODS: A new device is described that can be used to increase diagnostic accuracy and decrease complications during the examination of prostate diseases. This device is designed to perform a palpation examination and needle biopsy together on prostate tissue. Ex-vivo experiments were conducted on human prostate and tissue phantoms. RESULTS: Experimental results show that the device can be used to localize hard tissues. To remove experimental artifacts, a procedure is suggested to identify the abnormal tissue regions using FEM-based-mechanical-property-characterization and the abnormal regions obtained by analysis were compared with information from pathology. These results show a high specificity (81.8%) and PPV (60.0%) for the detection of prostate cancer. CONCLUSIONS: This system can be applied to detect hard materials such as tumor and malignant tissue. PMID- 24170423 TI - Preferred tools and techniques for implantation of cardiac electronic devices in Europe: results of the European Heart Rhythm Association survey. AB - The aim of this European Heart Rhythm Association (EHRA) survey was to assess clinical practice in relation to the tools and techniques used for cardiac implantable electronic devices procedures in the European countries. Responses to the questionnaire were received from 62 members of the EHRA research network. The survey involved high-, medium-, and low-volume implanting centres, performing, respectively, more than 200, 100-199 and under 100 implants per year. The following topics were explored: the side approach for implantation, surgical techniques for pocket incision, first venous access for lead implantation, preference of lead fixation, preferred coil number for implantable cardioverter defibrillator (ICD) leads, right ventricular pacing site, generator placement site, subcutaneous ICD implantation, specific tools and techniques for cardiac resynchronization therapy (CRT), lead implantation sequence in CRT, coronary sinus cannulation technique, target site for left ventricular lead placement, strategy in left ventricular lead implant failure, mean CRT implantation time, optimization of the atrioventricular (AV) and ventriculo-ventricular intervals, CRT implants in patients with permanent atrial fibrillation, AV node ablation in patients with permanent AF. This panoramic view allows us to find out the operator preferences regarding the techniques and tools for device implantation in Europe. The results showed different practices in all the fields we investigated, nevertheless the survey also outlines a good adherence to the common standards and recommendations. PMID- 24170420 TI - The obesity-inflammation-eicosanoid axis in breast cancer. AB - Inflammation of the adipose tissues occurs in association with obesity. This inflammatory process leads to the induction of cyclooxygenase-2 (COX-2) expression and a consequent elevation in prostaglandin (PG) production, which, together with proinflammatory cytokines, induce aromatase expression and estrogen synthesis. Infiltrating macrophages support the growth of breast epithelial cells and vascular endothelial cells by producing a milieu of cytokines and growth factors. This scenario creates a microenvironment favorable to breast cancer growth and invasion. The eicosanoids promote further development and growth of breast cancers indirectly by the induction of aromatase, particularly in estrogen positive breast cancers, or by direct stimulatory effect of PGE2 and lipoxygenase (LOX) products on the more aggressive, estrogen-independent tumors. Beyond this, the local production of estrogens and proinflammatory cytokines which occurs in association with breast adipose tissue inflammation, and consequent activation of the estrogen receptor and nuclear factor-kappaB, provides a mechanism by which breast cancers develop resistance to selective estrogen receptor modulation and aromatase inhibitor therapy. The obesity-inflammation-eicosanoid axis in breast cancer does offer a therapeutic target for the prevention of relapse in breast cancer by improving the efficacy of antiaromatase therapy using COX/LOX inhibitors; however, careful consideration of menopausal status and obesity in patients is warranted. PMID- 24170424 TI - pH-responsive on-off motion of a superhydrophobic boat: towards the design of a minirobot. AB - Combining chemical reactions and stimuli-responsive surfaces as clutch system, a functional cooperating minirobot with on-off locomotion that is responsive to pH changes is fabricated. Its locomotion can be switched on by changing pH value of the solution from 1 to 13, turned off by adjusting the pH back to acidic, and restarted by transforming the solution to basic. PMID- 24170426 TI - Sleep in childhood and adolescence: age-specific sleep characteristics, common sleep disturbances and associated difficulties. AB - Sleep changes throughout the lifespan, with particularly salient alterations occurring during the first few years of life, as well as during the transition from childhood to adolescence. Such changes are partly the result of brain maturation; complex changes in the organisation of the circadian system; as well as changes in daily routine, environmental demands and responsibilities. Despite the automaticity of sleep, given that it is governed by a host of complex mechanisms, there are times when sleep becomes disturbed. Sleep disturbances in childhood are common and may stem from behavioural difficulties or abnormalities in physiological processes-and, in some cases manifest into diagnosable sleep disorders. As well as occurring exclusively, childhood sleep disturbances often co-occur with other difficulties. The purpose of this chapter is to outline the neurobiology of typical sleep/wake processes, and describe changes in sleep physiology and architecture from birth to adulthood. Furthermore, common childhood sleep disorders are described as are their associations with other traits, including all of the syndromes presented in this handbook: ASDs, ADHD, schizophrenia and emotional/behavioural difficulties. Throughout, we attempt to explain possible mechanisms underlying these disorders and their associations. PMID- 24170425 TI - Characterization of a complete genome of a circular single-stranded DNA virus from porcine stools in Korea. AB - Porcine circular single-stranded DNA viruses have been just identified from swine feces in Korea. This virus was mentioned as bovine stool-associated circular DNA virus (BoSCV)-like virus discovered from porcine stools. However, the thorough characteristics of the virus were not identified. Therefore, this research focuses on finding a full genome sequence and analyzing the genetic features of the virus. The virus, now called porcine stool-associated circular DNA virus in Korea (PoSCV Kor), consists of 2,589 bases forming circular structure. It has two major ORFs inversely encoding replicase and capsid protein, with each stem-loop structure between 5' ends and 3' ends of the two putative ORFs. This characteristics is the same as PoSCV in New Zealand, but different from chimpanzee stool-associated circular virus (ChiSCVs) and BoSCV, which have one stem-loop structure. Therefore, it would be sure that PoSCV Kor is very similar to PoSCV in respect to the genetic aspect; the same number of nucleotide bases and the amino acid identity of replicase and capsid protein (96 and 93 %, respectively). This fact could be certified through the finding that PoSCV Kor and PoSCV are in the same cluster by phylogenetic analysis based on the comparison with full-sequences of other circular ssDNA viruses. PMID- 24170427 TI - Assessment of behavioural changes in domestic cats during short-term hospitalisation. AB - We evaluated behavioural changes in domestic cats during short-term hospitalisation using a novel cat demeanour scoring system. Thirty-five healthy, client-owned cats admitted for neutering were enrolled. Cats were housed in a standardised cat ward for a short-term hospitalisation period (3-5 days) and demeanour scores were recorded once daily. The scoring system classified cats into one of five behavioural groupings: friendly and confident, friendly and shy, withdrawn and protective, withdrawn and aggressive, and overtly aggressive. Total demeanour score decreased over time (P <0.001) and the demeanour category improved (P <0.001). The intra-class correlation was 0.843 (P <0.001) and kappa was 0.606 (P <0.001), suggesting good repeatability and agreement among investigators. The demeanour scoring system was effective in detecting a change in behaviour in healthy cats undergoing short-term hospitalisation. The findings suggest that healthy cats require 2 days to acclimatise to hospitalisation. PMID- 24170428 TI - Sleeping and resting respiratory rates in healthy adult cats and cats with subclinical heart disease. AB - Sleeping and resting respiratory rates are commonly measured variables in patients with cardiac disease. However, little information is available on these variables in healthy client-owned cats or cats with subclinical heart disease (SHD). Therefore, we examined and characterized the sleeping respiratory rate (SRR) and resting respiratory rate (RRR) in 59 echocardiographically normal (EN) and 28 apparently healthy (AH) cats, and 54 SHD cats acquired by the cat owners in the home environment on eight to 10 separate occasions. The within-cat mean sleeping respiratory rate (SRRmean) in EN cats, AH cats and SHD cats with mild or moderate left atrial (LA) enlargement (as defined by quantiles of the ratio of the LA to the aorta [LA:AO]) was consistently <30 breaths/min; median SRRmean approximated 21 breaths/min. The SRRmean of SHD cats with severe LA enlargement sometimes exceeded 30 breaths/min, and was higher than SRRmean of other SHD cats (P <0.05). The within-cat mean resting respiratory rate was consistently higher than SRRmean (P <0.05). Age and geographic location, but not bodyweight, affected SRRmean in EN and AH cats. Within-cat SRR and within-cat RRR did not vary markedly from day-to-day, as evidenced by a low within-cat coefficient of variation. Data acquisition was considered easy or non-problematic by most participants. Our data provide useful guidelines for SRR and RRR, obtained in the home environment, in healthy cats and cats with SHD, and might prove useful in managing cats with clinical heart disease. Cats with SRRmean >30 breaths/min and cats with multiple SRR measurements >30 breaths/min likely warrant additional evaluation. PMID- 24170429 TI - Improving physical activity, mental health outcomes, and academic retention in college students with Freshman 5 to Thrive: COPE/Healthy Lifestyles. AB - PURPOSE: To assess the preliminary effects of a new course entitled Freshman 5 to Thrive/COPE Healthy Lifestyles on the cognitive beliefs, knowledge, mental health outcomes, healthy lifestyle choices, physical activity, and retention of college freshmen. DATA SOURCES: Measures included demographics, nutrition knowledge, healthy lifestyle beliefs, healthy lifestyle perceived difficulty, healthy lifestyle choices, Beck Youth Inventories-II (anxiety, depression, anxiety, and destructive behavior), step count via pedometer, and college retention. CONCLUSIONS: The experimental COPE (Creating Opportunities for Personal Empowerment) group had greater intentions to live a healthy lifestyle (p = .02) versus the comparison group. COPE students also significantly increased their physical activity (p = .003) from baseline to postintervention and had a higher college retention rate than students who did not take the course. In addition, there was a significant decrease in depressive and anxiety symptoms in COPE students whose baseline scores were elevated. IMPLICATIONS FOR PRACTICE: The Freshman 5 to Thrive Course is a promising intervention that can be used to enhance healthy lifestyle behaviors and improve mental health outcomes in college freshmen. PMID- 24170430 TI - A simple approach for multicolor immunofluorescence staining in different Drosophila cell types. AB - Multicolor immunostaining analysis is often a desirable tool in cell biology for most researchers. Nonetheless, this is not an easy task and often not affordable by many laboratories as it might require expensive instrumentation and sophisticated analysis software. Here, we describe a simple protocol for performing sequential immunostainings on two different Drosophila specimens. Our strategy relies on an efficient and reproducible method for removal primary antibodies and/or fluorophore-conjugated secondary antibodies that does not affect antigene integrity. We show that alternation of multiple rounds of antibody incubation and removal on the same slide, followed by registration of the same DAPI-stained image, provides a simple framework for the sequential detection of several antigens in the same cell. Given that the sample fixation procedures used for Drosophila tissues are compatible with most specimen processing protocols, we can envisage that the multicolor immunostaining strategy presented here can be also adapted to different samples including mammalian tissues and/or cells. PMID- 24170431 TI - Acquired hemoglobin C secondary to transfusion with antigen-matched red blood cells. PMID- 24170432 TI - A quality improvement project to increase influenza vaccination in healthcare personnel at a university health center. AB - PURPOSE: The purpose of this quality improvement project was to increase the healthcare personnel (HCP) influenza vaccine uptake at a university student health center. DATA SOURCES: A descriptive design was used. A preintervention survey identified facilitators and barriers to HCP's uptake of influenza vaccine. Based on the results of this survey, four interventions were implemented. The postintervention survey was administered to assess for intervention effectiveness. CONCLUSIONS: The most common facilitators for influenza vaccination uptake on the preintervention survey were as follows: (a) protect self/family, (b) free vaccine, (c) recommended by experts, and (d) convenient vaccination process. The most common barrier was concern about vaccine side effects. Postintervention, the vaccination uptake increased from 71% in 2008-2009 to 77% in 2009-2010. Free vaccine and convenient vaccination process were rated as the most effective interventions. Education and the declination form used for the project were rated less favorably. IMPLICATIONS FOR PRACTICE: Factors influencing vaccine uptake may be different across practice settings. It is important to identify facilitators and barriers that are unique to health centers to better plan and implement interventions to improve vaccination rates. Furthermore, at a time when resources are limited, it is critical to identify the most effective strategies to maximize outcomes. PMID- 24170434 TI - Challenging material patterning: fine lithography on coarse substrates. AB - Precise patterning of inorganic materials is important for many technological applications. Often lithography processes are required on challenging substrates with respect to topography, flexibility, and surface adhesion. Here we show the fabrication of artificial gunshot residues (GSR) on adhesive tape samples by means of dip-pen lithography as an example for fine lithography on coarse substrates. We deposited lead-, barium-, and antimony-containing inks on SEM adhesive tape by direct writing with a fine tip. Single as well as multiple element structures with dimensions in the range of 10-75 um were fabricated. PMID- 24170433 TI - Opposing signaling of ROCK1 and ROCK2 determines the switching of substrate specificity and the mode of migration of glioblastoma cells. AB - Despite current advances in therapy, the prognosis of patients with glioblastoma has not improved sufficiently in recent decades. This is due mainly to the highly invasive capacity of glioma cells. Little is known about the mechanisms underlying this particular characteristic. While the Rho-kinase (ROCK)-dependent signaling pathways involved in glioma migration have yet to be determined, they show promise as one of the candidates in targeted glioblastoma therapy. There are two ROCK isoforms: ROCK1, which is upregulated in glioblastoma tissue compared to normal brain tissue, and ROCK2, which is also expressed in normal brain tissue. Blockage of both of these ROCK isoforms with pharmacologic inhibitors regulates the migration process. We examined the activities of ROCK1 and ROCK2 using knockdown cell lines and the newly developed stripe assay. Selective knockdown of either ROCK1 or ROCK2 exerted antidromic effects on glioma migration: while ROCK1 deletion altered the substrate-dependent migration, deletion of ROCK2 did not. Furthermore, ROCK1 knockdown reduced cell proliferation, whereas ROCK2 knockdown enhanced it. Along the signaling pathways, key regulators of the ROCK pathway are differentially affected by ROCK1 and ROCK2. These data suggest that the balanced activation of ROCKs is responsible for the substrate-specific migration and the proliferation of glioblastoma cells. PMID- 24170435 TI - Combination treatment of human pancreatic cancer xenograft models with the epidermal growth factor receptor tyrosine kinase inhibitor erlotinib and oncolytic herpes simplex virus HF10. AB - BACKGROUND: There is the potential to use replication-competent oncolytic viruses to treat cancer. We evaluated the efficacy of HF10, a herpes simplex virus type 1 (HSV-1) mutant, in combination with erlotinib, an epidermal growth factor receptor tyrosine kinase inhibitor, in human pancreatic cancer xenograft models. METHODS: The viability of human pancreatic cancer cell lines (BxPC-3 and PANC-1) treated with HF10 and erlotinib, on their own or in combination, was determined. Effects of erlotinib on HF10 entry into tumor cells were also investigated. BxPC 3 subcutaneous tumor-bearing mice were treated with HF10 and erlotinib, on their own or in combination, with effects on tumor volume determined. Immunohistochemical examination of HSV-1 and CD31 was conducted to assess virus distribution and angiogenesis within tumors. A peritoneally disseminated BxPC-3 xenograft model was evaluated for survival. RESULTS: HF10 combined with erlotinib demonstrated the highest cytotoxicity against BxPC-3. A combination effect was not observed in PANC-1 cells, and erlotinib did not affect virus entry into tumor cells. In the peritoneally disseminated model, HF10 combined with erlotinib had no beneficial effect on survival. In the subcutaneous tumor model, combination therapy resulted in the inhibition of tumor growth to a greater extent than using each agent on its own. Immunohistochemistry revealed that virus distribution within the tumor persisted in the combination therapy group. CONCLUSIONS: Combination therapy with HF10 and erlotinib warrants further investigation to establish a new treatment strategy against human pancreatic cancers. PMID- 24170436 TI - Clinicopathological characteristics of incidental prostate cancer discovered from radical cystoprostatectomy specimen: a multicenter French study. AB - PURPOSE: The present study assessed the incidence and histopathological features of incidentally diagnosed prostate cancer (PCa) in specimens from radical cystoprostatectomy (RCP) for bladder cancer. The patient outcomes also were evaluated. METHODS: We retrospectively reviewed the histopathological features and survival data of 4,299 male patients who underwent a RCP for bladder cancer at 25 French centers between January 1996 and June 2012. No patients had preoperative clinical or biological suspicion of PCa. RESULTS: Among the 4,299 RCP specimens, PCa was diagnosed in 931 patients (21.7%). Most tumors (90.1%) were organ-confined (pT2), whereas 9.9% of them were diagnosed at a locally advanced stage (>=pT3). Gleason score was <6 in 129 cases (13.9%), 6 in 575 cases (61.7%), 7 (3 + 4) in 149 cases (16.0%), 7 (4 + 3) in 38 cases (4.1%), and >7 in 40 cases (4.3%). After a median follow-up of 25.5 months (interquartile range 14.2-47.4), 35.4% of patients had bladder cancer recurrence and 23.8% died of bladder cancer. Only 16 patients (1.9%) experienced PCa biochemical recurrence during follow-up, and no preoperative predictive factor was identified. No patients died from PCa. CONCLUSIONS: The rate of incidentally diagnosed PCa in RCP specimens was 21.7%. The majority of these PCas were organ-confined. PCa recurrence occurred in only 1.9% of cases during follow-up. PMID- 24170437 TI - The role of gender and friends' gender on peer socialization of adolescent drinking: a prospective multilevel social network analysis. AB - Although socializing effects of friends' drinking on adolescent drinking behavior have been firmly established in previous literature, study results on the importance of gender, as well as the specific role that gender may play in peer socialization, are very mixed. Given the increasing importance of gender in friendships (particularly opposite-sex friendships) during adolescence, it is necessary to better understand the nuanced roles that gender can play in peer socialization effects on alcohol use. In addition, previous studies focusing on the interplay between individual gender and friends' gender have been largely dyadic; less is known about potential gendered effects of broader social networks. The current study sought to further investigate potential effects of gender on friends' influence on adolescent drinking behavior with particular emphasis on the number of same-sex and opposite-sex friends within one's friendship network, as well as closeness to these friends. Using Waves I and II of the saturated sample of the National Longitudinal Study of Adolescent Health (Add Health), adolescent friendship networks were used to calculate the mean drinking behaviors of adolescent friends. Multi-level models estimated the effects of individual drinking behaviors, friend drinking behaviors, and school level drinking behaviors on adolescent drinking 1 year later, as well as moderating effects of gender composition of friendship groups and male and female friend closeness on the relationship between friends' drinking behaviors and adolescent drinking behavior. Results documented that gender composition of friendship groups did not influence the effect of friends' drinking on individual drinking 1 year later. However, closeness to friends did influence this relationship. As closeness to male friends decreased, the influence of their drinking behavior increased, for both boys and girls. A similar effect was found for female friends, but only for boys. Female friend closeness did not affect the relationship between peer alcohol socialization and girls' alcohol use. The findings indicate that the role of gender on alcohol socialization may be more complex than previously thought, particularly when examining the potential role that alcohol use may play as a mechanism for social bonding within opposite-sex friendships and same-sex male friendships. PMID- 24170438 TI - The protective effects of neighborhood collective efficacy on adolescent substance use and violence following exposure to violence. AB - Research has demonstrated that exposure to violence can result in many negative consequences for youth, but the degree to which neighborhood conditions may foster resiliency among victims is not well understood. This study tests the hypothesis that neighborhood collective efficacy attenuates the relationship between adolescent exposure to violence, substance use, and violence. Data were collected from 1,661 to 1,718 adolescents participating in the Project on Human Development in Chicago Neighborhoods, who were diverse in terms of sex (51% male, 49% female), race/ethnicity (48% Hispanic, 34% African American, 14% Caucasian, and 4% other race/ethnicity), and age (mean age 12 years; range 8-16). Information on neighborhood collective efficacy was obtained from adult residents, and data from the 1990 U.S. Census were used to control for neighborhood disadvantage. Based on hierarchical modeling techniques to adjust for the clustered data, Bernoulli models indicated that more exposure to violence was associated with a greater likelihood of tobacco, alcohol, and marijuana use and perpetration of violence. Poisson models suggested that victimization was also related to a greater variety of substance use and violent behaviors. A moderating effect of collective efficacy was found in models assessing the variety of substance use; the relationship between victimization and substance use was weaker for youth in neighborhoods with higher versus lower levels of collective efficacy. These findings are consistent with literature indicating that social support can ameliorate the negative impact of victimization. This investigation extends this research to show that neighborhood social support can also help to promote resiliency among adolescents. PMID- 24170440 TI - [Back to the future!]. PMID- 24170439 TI - Biodegradation of the textile dye Mordant Black 17 (Calcon) by Moraxella osloensis isolated from textile effluent-contaminated site. AB - The bacterium with dye degrading ability was isolated from effluent disposal sites of textile industries, Tirupur and was identified as Moraxella osloensis based on the biochemical and morphological characterization as well as 16S rRNA sequencing. This organism was found to decolorize 87 % of Mordant Black 17 at 100 mg l-1 under shake culture condition compared to 92 % under stationary culture condition. Maximum degradation of the dye by M. osloensis was achieved when the mineral salt medium was supplemented with 0.5 % glucose and 0.1 % ammonium nitrate at 35 degrees C. Degradation of dye was found to follow first order kinetics with the k value of 0.06282 h-1 and a R2 value of 0.955. Analyses for the identification of intermediate compounds confirmed the presence of naphthalene, naphthol, naphthoquinone, salicylic acid and catechol. Based on this finding a probable pathway for the degradation of Mordant Black 17 by M. osloensis has been proposed. PMID- 24170441 TI - [The efficiency of one-to-one support during labour - a literature analysis]. AB - Today, the way and the intensity of labour support differ internationally because of traditions, cultural background, legislation and finance issues. Moreover, the aspects of -labour support have changed in industrialized countries due to the transition from home birth to hospital birth. Technical aspects and surveillance have become more important. The increasing workload in hospitals (IQWIG 2006) as well as increasing Cesarean section rates and epidural rates are well documented (AQUA 2011). One reason for these changes might be a lack of support during childbirth. International studies emphasise the importance for continuous support in labour (Hodnett et al. 2011). This paper adds a German perspective on one-to one-care and discusses how the results from international studies can be transferred into the German midwifery context.A literature search was conducted in 12/2012.One-to-one care seems to be effective for decreasing intervention rates. Results of international studies demonstrate differences in settings, supporting persons and defining one-to-one care and impede that the right conclusions can be drawn for the German context. -Especially the effect of midwifery presence in the German context isn't conducted sufficiently.Professional care and trusting emotional support incorporated by one person seems to be the best way to deliver one-to-one care and to avoid fragmentation of care. Organisational barriers should be dismantled to realize this aim.National Research is needed to evaluate the effects of one-to-one care by midwives. PMID- 24170442 TI - [Active management of the third stage of labour (AMTSL) - the end of a 50 years dogma?]. AB - Post-partum haemorrhage (PPH) is the leading cause of maternal mortality worldwide. Since more than 50 years AMTSL has been proposed for the prevention of PPH and is still recommended in current guidelines. The 3 key components of AMTSL are the prophylactic administration of oxytocin, clamping and cutting of the umbilical cord immediately after delivery of the baby and controlled cord traction. AMTSL has proven to reduce the rate of severe PPH by 70%. Despite of the long tradition of AMTSL it is still unclear, which of the 3 components significantly contributes to the reduction in PPH. Cochrane analyses and a recent metaanalysis gave strong evidence, that prophylactic oxytocin administration reduces the risk of PPH significantly, however, the optimal dose and mode of application is still a matter of debate.Until a little while ago no randomized controlled studies exist regarding the significance of controlled cord traction and the time of cord clamping in AMTSL. A randomized WHO trial 2012 and the 2013 published TRACOR (Traction of the CORd)-trial from France could clearly demonstrate that controlled cord traction is not associated with a significant reduction in postpartum blood loss and in the risk of severe PPH. A Cochrane analysis 2008 and a recent randomized trial from Sweden came to the conclusion, that there are no significant -differences between early (< 15 s) and delayed (> 1-3 min) cord clamping in the reduction of PPH and severe PPH. Uterine massage after delivery of the placenta, placental cord drainage and umbilical vein injection of uterotonics after delivery of the baby as part of AMTSL are not evidence-based methods. It has taken 50 years since AMTSL was first described for it to become clear that prophylactic oxytocin is the most important and the only evidence-based component of AMTSL. Future guidelines and textbooks should consider these new -findings. PMID- 24170443 TI - Rising cesarean rates of twin deliveries in Germany from 1990 to 2012. AB - In the past 2 decades there has been an increasing trend for cesarean deliveries in twin pregnancies associated with increased maternal and fetal morbidity and mortality.We analyzed the mode of delivery of 18,132 twin gestations from the perinatal survey of Hessen in Germany between 1990 and 2012 and divided them into 4 categories according to the week of gestation (<28, 28-31, 32-36, >36). We further analyzed the cesarean delivery rates for the same period depending on the institutional level and divided them into 3 categories - University hospitals with perinatal center (U/PS), non-university affiliated hospitals with perinatal center (NU/PS) and smaller clinics without perinatal unit (NU/NPS).Cesarean rates changed from 63.6% (< 28), 88.9% (28-31), 59.6% (32-36) and 40% (> 36) in the year 1990 to 74.2%, 95.5%, 76.9% and 68.7% in 2012, respectively. As such, we report an overall increase of 23.5% in cesarean deliveries of twins over the last 23 years. We find an overall increase of 16.8%, 21% and 22.1% in university hospitals with perinatal units, in non-university hospitals with perinatal unit and in smaller hospitals without perinatal units, respectively. Furthermore, combined cesareans increased from 3.9% in 1990 to 7.0% in 2012.These findings indicate a dramatic increase in cesarean delivery rates for twin births from 1990 to 2012. We discuss the importance of international compatible guidelines for the conditions and technical procedures for twin deliveries. PMID- 24170444 TI - Ballantyne syndrome and congenital anaemia associated with Parvovirus B19 infection: case report and review. AB - Acute maternal Parvovirus B19 infection affects about 1% of all pregnancies worldwide. Diaplacental transmission of Parvovirus B19 during the second trimester can cause complications like foetal hydrops, premature delivery or foetal loss in about 20-30% of these pregnancies, whereas the majority of maternal infections remain clinically silent. In individual cases, foetoplacental hydrops (of various origins) can trigger a rare form of Preeclampsia in the pregnant woman. The developing maternal oedema in this situation apparently "mirrors" the hydropic state of the foetus. The symptom triad of foetal hydrops, foetoplacental oedema and maternal anasarca defines Ballantyne syndrome. We report a case of Parvovirus-induced Ballantyne syndrome including a 10-year follow-up of mother and child. While the mother recovered rapidly after (preterm) delivery, the infection complicated the first months of life of the neonate. Congenital transfusion-dependent red cell aplasia and cholestatic hepathopathy took a chronic course but resolved under IVIG treatment. Follow-up now finds both the former neonate and the mother entirely recovered. Current knowledge on Ballantyne syndrome as well as perigestational Parvovirus infections including congenital anaemia is briefly reported and pathophysiological hypotheses are discussed. PMID- 24170445 TI - Copper-induced immunotoxicity involves cell cycle arrest and cell death in the liver. AB - Inorganic copper, such as that in drinking water and copper supplements, largely bypasses the liver and enters the free copper pool of the blood directly and that promote immunosuppression. According to our previous in vivo report, we evaluate the details of the apoptotic mechanism in liver, we have investigated how copper regulates apoptotic pathways in liver. We have analyzed different protein expression by Western blotting and immunohistochemistry expression. We have also have measured mitochondrial trans-membrane potential, Annexin V assay, ROS, and CD4(+) and CD8(+) population in hepatocyte cells by flow cytometry. Copper treated mice evidenced immunotoxicity as indicated by dose-related, distinct histomorphological changes in liver. Flow cytometric analyses revealed a dose related increase in the percentages of hepatocyte cells in the Sub-G0/G1 state, further confirmed by Annexin V binding assay. In addition, the copper treatments altered the expression of apoptotic markers, further ROS generation and mitochondrial trans-membrane potential changes promote intrinsic pathway of apoptosis that was p53 independent. Apart from the role of inflammation, our findings also have identified the role of other partially responsible apoptotic molecules p73 that differentially changed due to copper treatment. Our study demonstrates how apoptotic pathways regulate copper-induced immunosuppression in liver. PMID- 24170446 TI - Evolvement of French advanced practice nurses. AB - PURPOSE: The purpose of this review is to chronicle the development of the advanced practice nurse (APN) in France and compare international APN indictors of quality care with French studies. DATA SOURCES: A review of the literature was performed by accessing the MEDLINE, Science Direct, and Cochrane Databases for studies of quality of care by APNs during 1965-2012. The author's participation on a national task force in collaboration with the French Ministry of Health provided additional information. CONCLUSIONS: After applying limits of this search, 36 studies fulfilled inclusion and exclusion criteria. In both the French and international APN nursing literature, the most frequently described quality of care measures were level of patient satisfaction and other patient outcomes (clinical and laboratory measures) according to evidence-based guidelines. In three French studies (nephrology, neuro-oncology, and urology settings), nurses performed direct patient care and were legally permitted to take on some limited responsibilities usually held by French physicians, including clinical examinations, diagnosing, and prescribing. IMPLICATIONS FOR PRACTICE: Creation of the APN role in France can respond to public health challenges including the rising incidence of chronic diseases and an impending physician shortage. Future APN research should focus on rigorous, innovative design development including collaborative care models. PMID- 24170447 TI - Recent advances in CE-mediated microanalysis for enzyme study. AB - This review gives an overview of the recent developments and applications in the use of CE-mediated microanalysis for enzyme studies. The period covers mid-2011 until mid-2013. Both off-line and in-line enzyme assays with their applications using CE are described in this article. For the in-capillary enzyme reaction, the techniques using electrophoretically mediated microanalysis (EMMA) as well as immobilized enzyme reactor (IMER) are discussed. The applications include the evaluation of enzyme activity, enzyme kinetics, enzyme inhibition, screening of enzyme inhibitors, and the study of enzyme-mediated drug metabolism. PMID- 24170448 TI - Nurse practitioners in medical rehabilitation settings: a description of practice roles and patterns. AB - PURPOSE: To describe nurse practitioner (NP) roles in medical rehabilitation settings. DATA SOURCE: Description of practice by rehabilitation NPs and physicians. CONCLUSIONS: NPs increasingly function in medical rehabilitation settings as independent or collaborative care providers. This article describes their roles at a large rehabilitation institute in acute care consultation/liaison, acute rehabilitation, and ambulatory settings. The organization has experienced greater physician efficiency and practice scope, without erosion of subjective or objective quality measures and outcomes. The authors provide specific examples of NP roles in intrathecal baclofen and cancer rehabilitation programs. IMPLICATIONS FOR PRACTICE: Advanced practice nurses can provide efficacious care to people with disabilities, resulting in cost savings, improved outcomes, and high value. Patient care by NPs is beneficial for the physicians so that they may extend their clinical realm, spend more time doing research, and participate in medical leadership. PMID- 24170449 TI - Perceptions of junior doctors and undergraduate medical students as anatomy teachers: Investigating distance along the near-peer teaching spectrum. AB - Near-peer teaching involves more experienced students acting as tutors and has been widely used in anatomy education. This approach has many advantages for the learner due to the social and cognitive congruence they share with the teacher, however, the influence of distance between the teacher and learner on these congruences has yet to be explored. The aim of this study was to compare the attitudes and perceptions of the student learner towards neuroanatomy review sessions taught by either a senior medical student or a junior doctor. The students were randomly assigned to an allocated tutor. All tutors used standardized material and had access to identical resources. The type of allocated tutor was swapped between the two teaching sessions and 99 student feedback forms were collected in total. The rating for the overall quality of the teaching session was not significantly different between the junior doctors and senior medical students (P = 0.11). However, criteria closely relating to social and cognitive congruence such as "enjoyment of the session," "delivery of the teaching," and "was it a good use of time" were all rated significantly higher for the senior medical students (P < 0.05). The results of this study suggest that small increases in distance along the near-peer teaching spectrum have an impact upon the student's perception of their learning experience. While all teachers were suitable role models it appears that junior doctors are too far removed from their own undergraduate experiences to share congruences with pre clinical medical students. PMID- 24170450 TI - Leptocarposide: a new triterpenoid glycoside from Ludwigia leptocarpa (Onagraceae). AB - A new triterpenoid bidesmoside (leptocarposide) possessing an acyl group in their glycosidic moiety (1), together with the known luteolin-8-C-glucoside (2) and 1-O beta-D-glucopyranosyl-(2S,3R,8E)-2-[(2'R)-2-hydroxypalmitoylamino]-8-octadecen 1,3-diol (3) was isolated from the n-butanol-soluble fraction of whole plant of Ludwigia leptocarpa (Nutt) Hara (Onagraceae). Structure of compound 1 has been assigned on the basis of spectroscopic data ((1)H and (13)C NMR, (1)H-(1)H COSY, HSQC, HMBC, and ROESY), mass spectrometry, and by comparison with the literature. This compound was further screened for its potential antioxidant properties by using the radical scavenging assay model 2,2-diphenyl-1-picrylhydrazyl and reveals non-potent antioxidant activities, while compound 2 shows SC50 of 0,038 mM. PMID- 24170451 TI - Clients' pretreatment role expectations, the therapeutic alliance, and clinical outcomes in outpatient therapy. AB - OBJECTIVES: The present study examined the associations between pretreatment role expectations, working alliance, and therapy outcome. A mediational model was hypothesized wherein the therapeutic alliance mediates the relationship between clients' pretreatment role expectations and psychotherapy outcome. METHOD: Sixty eight clients completed the Expectations About Counseling-Brief Form at pretreatment, the Working Alliance Inventory-Short Form Revised after Session 3, and the Outcome Questionairre-45 at both pretreatment and the final session. RESULTS: All 3 expectations factors (Personal Commitment, Facilitative Conditions, Counselor Expertise) were related to the alliance. However, only expectations for Counselor Expertise were related to outcome, although this relationship did not appear to be mediated by the alliance. CONCLUSIONS: Suggested research directions, clinical implications, and study limitations are discussed. PMID- 24170455 TI - Immunization guidelines for cochlear implant recipients. PMID- 24170452 TI - A phase 2 study of 16alpha-[18F]-fluoro-17beta-estradiol positron emission tomography (FES-PET) as a marker of hormone sensitivity in metastatic breast cancer (MBC). AB - PURPOSE: 16alpha-[(18)F]-fluoro-17beta-estradiol positron emission tomography (FES-PET) quantifies estrogen receptor (ER) expression in tumors and may provide diagnostic benefit. PROCEDURES: Women with newly diagnosed metastatic breast cancer (MBC) from an ER-positive primary tumor were imaged before starting endocrine therapy. FES uptake was evaluated qualitatively and quantitatively, and associated with response and with ER expression. RESULTS: Nineteen patients underwent FES imaging. Fifteen had a biopsy of a metastasis and 15 were evaluable for response. Five patients had quantitatively low FES uptake, six had at least one site of qualitatively FES-negative disease. All patients with an ER-negative biopsy had both low uptake and at least one site of FES-negative disease. Of response-evaluable patients, 2/2 with low FES standard uptake value tumors had progressive disease within 6 months, as did 2/3 with qualitatively FES-negative tumors. CONCLUSIONS: Low/absent FES uptake correlates with lack of ER expression. FES-positron emission tomography can help identify patients with endocrine resistant disease and safely measures ER in MBC. PMID- 24170456 TI - Endoscopic view of the sphenoid sinus seen through the posterior ethmoid sinus. PMID- 24170457 TI - Extrusion of hydroxyapatite ossicular prosthesis. PMID- 24170459 TI - Langerhans cell histiocytosis: temporal bone invasion in an adult. PMID- 24170458 TI - Office assessment of vocal fold hypomobility. PMID- 24170460 TI - Undifferentiated thyroid carcinoma. PMID- 24170461 TI - Amyloidosis: a rare case with nodular lesions on the tongue and buccal mucosa. PMID- 24170462 TI - Tracheal bronchus in an 11-month-old infant. PMID- 24170463 TI - Esophageal perforation in a patient with diverticulum following anterior discectomy and fusion. PMID- 24170464 TI - A preliminary study of the use of ultrasound in defining nasal fractures: criteria for a confident diagnosis. AB - Nasal fractures are usually diagnosed by clinical examination, with or without the support of imaging studies. While plain-film radiography lacks sensitivity and specificity for diagnosing nasal fractures, and computed tomography (CT) is not always practical or cost-effective, ultrasonography (US) may be useful in this regard. The criteria by which adult nasal fractures are reliably identified on US must be clear. We conducted a preliminary prospective, controlled, observational study to define the appearance of nasal fractures on US. We used US to image 12 patients with a clinical or radiologic (CT or x-ray) diagnosis of nasal fracture. All patients presented within 2 weeks of their injury. For comparison purposes, we also obtained US images from 12 control subjects who had no history of nasal trauma or surgery. We found that we could confidently diagnose nasal fractures on lateral-view US on the basis of a disruption of bone continuity and/or displacement of fracture segments. However, our findings were not as consistent with dorsal-view US, and we do not believe it is adequate for diagnosis. We conclude that lateral US can be used to detect nasal fractures in adults, but further studies are needed to assess its sensitivity, specificity, cost-effectiveness, and practicality. PMID- 24170465 TI - A case of chronic subdural hematoma following lumbar drainage for the management of iatrogenic cerebrospinal fluid rhinorrhea: pitfalls and lessons. AB - Chronic subdural hematoma as a complication of lumbar drain placement for the management of iatrogenic cerebrospinal fluid (CSF) leak has not been previously documented in the literature. We describe such a case in a 69-year-old man who presented with right nasal obstruction secondary to an inverted papilloma involving the paranasal sinuses. The patient underwent endoscopic sinus surgery, which included a medial maxillectomy. Surgery was complicated by a small CSF leak, which was repaired intraoperatively. Five days later, the patient experienced CSF rhinorrhea, and a lumbar drain was inserted. He developed overdrainage symptoms but was well when he was discharged. However, 22 days later he returned with right hemiparesis. Computed tomography of the brain showed a left frontoparietal subdural hematoma with a mass effect. The neurosurgical team performed an emergency drainage procedure, and the patient experienced a complete neurologic recovery. We discuss the pitfalls of lumbar drainage, the possible pathophysiology of overdrainage, and the lessons learned from this case. PMID- 24170466 TI - Transdermal scopolamine in the management of postparotidectomy salivary fistula. AB - Parotid fistula represents an uncommon complication in parotid surgery. Its early recognition contributes to successful management. The condition is distressing for both the patient and the surgeon, since conservative and operative treatment frequently fail. There is no consensus on the optimal management of parotid gland fistula. The aim of this study is to describe a new, simple procedure in the treatment of this condition using transdermal scopolamine. We report 3 cases of salivary fistulae occurring after parotidectomy. The patients were admitted to our department with swelling in the parotid region and an output of clear drainage from the drain site during oral intake. The patients were treated with a scopolamine transdermal release system applied to hairless skin overlying the parotid region. A prompt and remarkable decrease in daily salivary output was observed. Fistulae healed completely within 3 days. No collateral effects were observed. Parotid fistulae do not generally occur as a complication of parotidectomies. Their management can be difficult, and several methods of treatment have been attempted. We believe that the use of transdermal scopolamine is a valid option in the treatment of parotid fistulae without causing collateral effects. PMID- 24170467 TI - Synchronous verrucous carcinoma and inverted papilloma of the lacrimal sac: case report and clinical update. AB - Inverted papilloma is a benign epithelial tumor of the nasal cavity. It is known to coexist with malignancy in 5 to 13% of cases, with squamous cell carcinoma being the most common malignancy. Another associated malignancy, one that is extremely rare, is verrucous carcinoma. To the best of our knowledge, no case of verrucous carcinoma occurring alone or in association with another neoplasm has been described in the nasolacrimal system. We report a case of synchronous verrucous carcinoma and inverted papilloma of the lacrimal sac in a 47-year-old man. The patient presented with epiphora, nasal obstruction, swelling of the left medial canthus, and drainage of a foul-smelling fluid from the left nostril. Computed tomography and magnetic resonance imaging detected the presence of a large mass occupying the left nasal cavity and sinuses with extension into the nasopharynx. In addition, bony invasion of the anteroinferomedial wall of the left orbit was noted with extension of the tumor into the orbit itself, which resulted in lateral displacement of the left medial rectus muscle. The patient underwent endoscopic debulking of the left sinonasal lesion. Of note, the surgery had to be completed in stages because of excessive blood loss. Histopathologic examination of the intranasal component of the tumor identified it as an inverted papilloma. One month after the intranasal resection, a left dacryocystectomy was performed; histopathologic examination revealed that an invasive verrucous squamous cell carcinoma had arisen within the inverted papilloma. PMID- 24170468 TI - Glass in the frontal sinus: 28-year delayed presentation. AB - Reports of delayed presentation of foreign bodies in the frontal sinus are infrequent and likely to become rarer with the widespread availability of computed tomography in the last 2 decades. We present a case in which glass from a road traffic injury was found in the frontal sinus, causing symptoms of frontal sinusitis 28 years after the initial injury. We also present a review of the literature. PMID- 24170469 TI - Case report: Paraneoplastic neurologic syndrome associated with squamous cell carcinoma of the tonsil. AB - Paraneoplastic syndromes include a variety of disorders that affect the neurologic, endocrine, mucocutaneous, hematologic, and other systems as a result of neoplastic disease. Although their presentations vary, syndromes occur when tumor antigens exhibit cross-reactivity to similar antigens expressed by these systems. The antigens in the nervous system are called "onconeural" antigens. Although many disorders are associated with a comparatively high incidence of paraneoplastic neurologic syndromes, only a few cases have been associated with squamous cell carcinoma (SCC) of the tonsil. We report the case of a 69-year-old man who initially presented with weakness and spastic gait. He was subsequently found to have a characteristic paraneoplastic tractopathy on thoracic magnetic resonance imaging. The subsequent workup and operative intervention identified a T2N0M0 SCC of the tonsil. Following resection, the patient's overall symptoms were significantly alleviated, and his gait improved. A thorough literature search yielded no other report of a tonsillar SCC with associated paraneoplastic thoracic spine tractopathy. PMID- 24170471 TI - Arteriovenous malformation of the neck: an unusual cause of hoarseness successfully treated with endovascular techniques. AB - Hoarseness is a common presenting symptom in patients referred to the otolaryngology clinic. An arteriovenous malformation (AVM) in the neck is a previously unreported cause of hoarseness. We describe the case of a 61-year-old woman who presented with hoarseness and vocal fold paralysis, which was caused by an AVM. She was successfully treated with endovascular embolization. Devascularization of the AVM resulted in symptomatic relief of the hoarseness and resolution of the vocal fold paralysis, presumably secondary to interval reduction in edema and venous congestion. PMID- 24170470 TI - Diffuse sphenoid bone cavernous hemangioma presenting during pregnancy. AB - We present a case of diffuse sphenoid bone cavernous hemangioma in a 22-year-old primigravid woman. Her disease first manifested clinically as progressively decreasing vision in her left eye during her third trimester of pregnancy. We also discuss the known causes and some theoretical causes of cavernous hemangioma enlargement during pregnancy. PMID- 24170472 TI - Intracranial and internal jugular vein thrombosis secondary to ENT infections: a report of 3 cases. AB - We report 3 cases of rare, life-threatening intracranial and internal jugular vein (IJV) thrombosis that were caused by common ENT infections. These infections included otitis media in a 6-year-old girl, tonsillitis in a 21-year-old woman, and odontogenic sepsis in a 56-year-old woman. All 3 patients were treated with culture-directed systemic antibiotics; 2 of them also required surgical drainage (the child and the older adult). The 2 adults also received therapeutic anticoagulation, which was continued until venous recanalization was documented; the duration of combined antibiotic and anticoagulation treatment was 6 weeks. All 3 patients made uneventful recoveries. Significant morbidities associated with intracranial and IJV thrombosis were avoided as a result of prompt diagnosis and judicious treatment. PMID- 24170473 TI - Endoscopic closure of a frontocutaneous fistula. AB - A frontocutaneous fistula is a rare sequela of frontal sinus pathology. Management via an endoscopic approach is not frequently reported in the literature. We describe such an approach with the aid of still photography and imaging plus videoendoscopy, and we discuss the current literature. PMID- 24170474 TI - A case of cicatricial pemphigoid of the larynx successfully treated with plasmapheresis therapy. PMID- 24170475 TI - Dehiscence of the high jugular bulb. PMID- 24170476 TI - Endoscopic appearance of a healed skull base resection reconstructed with a pedicled nasoseptal flap. PMID- 24170477 TI - A case and a series of published cases of esthesioneuroblastoma (ENB) in which long-standing paraneoplastic SIADH had preceded ENB diagnosis. AB - Esthesioneuroblastoma (ENB) is a rare tumor of the olfactory mucosa. We treated a 50-year-old man with an ENB in the right ethmoid sinus who had been diagnosed 16 years earlier with syndrome of inappropriate antidiuretic hormone secretion (SIADH) of unknown cause. When the ENB was surgically removed, the patient's osmoregulation returned to normal-that is, his SIADH resolved completely, which suggested that the SIADH was paraneoplastic in nature. These events prompted us to review the literature to determine if there is an association between our patient's ENB and his SIADH in general and between long-standing SIADH that precedes ENB in particular. Based on our review and an extrapolation of data, we have estimated that 1,300 cases of ENB have occurred since it was first described in 1924. Of these cases, SIADH was reported in 26 cases, including ours, which represents an estimated prevalence of 2% (although we believe this is actually an underestimation of the true prevalence). Of the 26 cases, SIADH had already been present in 14 patients (54%) prior to their diagnosis of EBN for a median duration of 3.5 years. We recommend that patients with newly diagnosed EBN be evaluated for SIADH. In those who are SIADH-positive, a resolution of SIADH should be expected once the ENB has been removed. If this does not occur, one should suspect that the ENB was not completely removed. If SIADH resolves but later recurs during follow-up, then a relapse should be suspected. In long standing SIADH of unknown etiology, nasal sinus imaging should be considered. PMID- 24170478 TI - Trauma is associated with a better prognosis in intensive care patients with Acinetobacter infections. AB - PURPOSE: Acinetobacter baumannii has emerged as a common cause of infection in war-related trauma, civilian trauma and other surgical emergencies. The aim of this study was to determine prognostic factors especially trauma, in critically ill surgical patients with Acinetobacter spp. infection in a reference emergency ICU. METHODS: A retrospective review of medical records was conducted for all patients admitted to the ICU who developed Acinetobacter spp. infection from January 2007 to December 2009. Bivariate and multivariate analyses were made for 36 patients. The end-point analyzed was the in-hospital mortality. RESULTS: The initial analysis revealed a majority of young (43.6 years +/- 17.1) men (92 %), trauma victims (78 %) and an in-hospital mortality of 30 %. Patients who had not suffered trauma presented with other surgical conditions and were on average older than trauma patients (57 +/- 12 versus 40 +/- 16 years). The overall APACHE II score average was 15.3. The ventilator-associated pneumonia was the main Acinetobacter infection diagnosed. In bivariate analysis lower Glasgow coma scale (p = 0.01) was associated with increased chance of death and being victim of trauma was a protecting factor (OR: 0.16; 95 % CI: 0.03-0.89). Receiving adequate treatment made no difference to outcome (OR: 0.55; 95 % CI: 0.05-3.15). Multivariate analysis showed that only the presence of trauma was independently associated with prognosis and was a protecting factor. CONCLUSION: Trauma was a marker of good prognosis in emergency ICU patients with Acinetobacter spp. infection. PMID- 24170479 TI - Dislocation after total hip arthroplasty. AB - Dislocation remains one of the most common complications after total hip arthroplasty, regardless of the surgical approach. While multiple reasons as laxity, implant position, improper implant choice, and impingement etc. might be leading factors for dislocation, an exact identification of the exact reason is of major importance, to plan for a proper surgical or nonsurgical correction. This article describes in detail the definition, etiology, reduction, and possible treatment options for dislocation after primary and revision total hip arthroplasty that are currently used at the Endo Klinik in Hamburg. It furthermore includes a distinct overview of possible surgical treatment options, based on the main pathology leading to dislocation. PMID- 24170480 TI - The emerging role of Vitamin D in asthma management. AB - PURPOSE: Vitamin D deficiency and asthma share risk factors. Epidemiologists suggest that the U.S. prevalence of Vitamin D deficiency has increased as a result of the Westernization of culture and less time spent outdoors. Numerous studies support a patient's Vitamin D deficiency as a contributing cause to increased asthma symptoms, lower lung function levels, increased airway reactivity, and worsening asthma control. The purpose of the review article is to discuss the emerging role of Vitamin D in asthma management. DATA SOURCES: A review of original research identified through MEDLINE and CINAHL and published in English was performed. CONCLUSIONS: Research suggests promising benefits of Vitamin D supplementation in asthma patients with low (<30 ng/mL) Vitamin D levels. Evidence supports several possible mechanisms, including downregulation of allergen sensitivity and enhanced steroid responsiveness. Studies demonstrate that Vitamin D modifies airway hyperresponsiveness by minimizing airway inflammation. Ongoing studies seek to further evaluate the effects of Vitamin D supplementation on asthma and asthma morbidity. IMPLICATIONS FOR PRACTICE: While there is no consensus on the use of Vitamin D as a mainstay in asthma treatment, research supports its consideration for use in asthma patients with low Vitamin D levels. Current evidence reinforces the need to measure Vitamin D levels for all asthma patients. PMID- 24170481 TI - 1H, 13C NMR studies of new 3-aminophenol isomers linked to pyridinium salts. AB - (1)H and (13)C NMR spectroscopic data of 20 new non-symmetrical compounds were assigned by a combination of 1D and 2D NMR experiments (DEPT, HSQC, and HMBC). These compounds contain a 4-(N,N-dimethylamino)- or 4-(pyrrolidin-1-yl)pyridinium moiety and a 3-nitro-, 3-amino-, or 3-hydroxyphenyl ring, linked by p-xylene, 4,4'-dimethylbiphenyl, 1,2-bis(p-tolyl)ethane, or 1,4-bis(p-tolyl)butane. PMID- 24170482 TI - Managing asthma during pregnancy. AB - PURPOSE: Pregnant women with asthma have many concerns about their respiratory health, as well as the health of their baby. A woman's respiratory system experiences many physiological changes during pregnancy and when a diagnosis of asthma is present, the clinical effect of pregnancy on asthma is variable. Regardless of disease years, when asthma patients become pregnant, both patients and healthcare providers want to know how pregnancy affects asthma and how asthma may affect pregnancy outcomes. This article will review how to optimally manage asthma during pregnancy using an evidence-based approach that recognizes the patient's changing needs. DATA SOURCES: Literature collected from sources identified through searches of PubMed and CINAHL covering the periods from 1996 to 2012. CONCLUSION: With the implementation of evidence-based management and treatment, pregnant patients who have asthma can be positioned to better control their symptoms and avoid unwanted complications that may affect the health of their baby. IMPLICATIONS FOR PRACTICE: Pregnant patients with asthma may be cared for in a variety of healthcare settings ranging from primary care to specialty care to the emergency department. Consequently, it is imperative that healthcare providers across the array of clinical venues be proficient on how to optimize the asthma outcomes of their pregnant patients. PMID- 24170483 TI - Kabuki syndrome: a challenge for the primary care provider. AB - PURPOSE: Using a case format, the pathogenesis, clinical manifestations, diagnosis, and management of Kabuki syndrome, a rare genetic condition, is presented. Nurse practitioners (NPs) may encounter patients presenting to the primary care setting with this rare syndrome; understanding this condition may help them to better care for these patients. DATA SOURCE: A case presentation of a pediatric patient supported by the currently available literature from multiple health and medial databases. CONCLUSION: Kabuki syndrome is a rare phenomenon that occurs in 1 in every 32,000 births. A diagnosis of this syndrome may take several months to years because there are no specific tests, and the physical features may be subtle at birth, becoming more pronounced over a period of time during childhood. The degree of disease severity varies widely. IMPLICATIONS FOR PRACTICE: Understanding this syndrome increases the NP's ability to provide primary care to affected patients and their families. Management of this condition requires the NP take on the role of gatekeeper, so timely coordination of specialty or subspecialty services is provided. Special consideration should be given to monitoring caregiver fatigue and impact on siblings so family members can be directed to the appropriate support services. PMID- 24170484 TI - Impact of a quality improvement intervention on provider adherence to recommended standards of care for adults with type 2 diabetes mellitus. AB - PURPOSE: To report provider adherence to standards of care for adults with type 2 diabetes before and after a quality improvement (QI) intervention. DATA SOURCES: Pre- and post intervention data were abstracted from 50 medical records of patients with type 2 diabetes in a small primary care practice. CONCLUSION: There was a significant increase in the rates of foot and urine microalbumin screenings, documentation for dilated eye exams were not statistically significant. These findings demonstrated the effectiveness of using simple practice aids to reinforce adherence to the standards of care in diabetes. The failure to see a corresponding improvement in glycemic and blood pressure control is consistent with prior research and the need for more research in this area remain critical. IMPLICATIONS FOR PRACTICE: Ethnic minorities are more likely to have worse control of their diabetes and more likely to receive all their care in the primary care setting, QI interventions targeting primary care providers have the potential to reduce disparities in diabetes care. Future research to determine whether cultural tailoring of diabetes QI interventions will produce additional benefits above those of generic diabetes QI interventions are needed. PMID- 24170485 TI - The use of vitamin K supplementation to achieve INR stability: a systematic review and meta-analysis. AB - PURPOSE: Systematically review and quantitatively synthesize evidence on use of oral vitamin K supplementation in reducing international normalized ratio (INR) variability. DATA SOURCES: PubMed, The Cochrane Library, PsycINFO, Cumulative Index of Nursing and Allied Health Literature (CINAHL), Turning Research Into Practice (TRIP), Web of Science were searched for studies meeting predetermined inclusion/exclusion criteria. Five studies meeting criteria (three randomized trials, one quasi-experimental pre-post study, one retrospective case series) were appraised for quality and data synthesized by two reviewers. Pooled effect size of time in INR therapeutic range (TTR) was estimated using random effects meta-analysis. CONCLUSIONS: Pooled effect size representing data from four studies (678 subjects) was 0.31, 95% confidence interval 0.03-0.59 (Cochran Q = 7.1; p = .07; I(2) = 57.8) and favored vitamin K supplementation. Given wide variability among individual studies, there is not enough evidence to advise for or against the routine use of vitamin K supplementation to achieve INR stability. However, evidence does suggest that it may be of some benefit for some patients with INR instability. IMPLICATIONS FOR PRACTICE: There is insufficient evidence to support routine supplementation with vitamin K in patients on chronic anticoagulation therapy but select patients, particularly those with persistent INR instability despite known adherence to regimen and no dietary or drug-drug interactions, may benefit from the intervention. Future research is warranted. PMID- 24170486 TI - Understanding stigma in chronic health conditions: implications for nursing. AB - PURPOSE: This article explores the social processes in stigmatization and the theoretical background on the impact in chronic illness. DATA SOURCES: Review of literature from social sciences and applications to health issues. CONCLUSIONS: Understanding the social utility of stigmatization in preserving social cohesion and protecting the social order is an important function. However, this process can be harmful when applied to persons with chronic illness, such as HIV-AIDS, and psychiatric illness. These individuals often become shamed, ostracized, isolated, discredited, and socially and economically marginalized. Recent theoretical work on stigma has identified several issues and patient responses that may have implications in many other chronic conditions. Stigma is based on visible or nonvisible health conditions and can be both externally imposed or perceived in a process of self-stigma. IMPLICATIONS FOR PRACTICE: Understanding stigma can aid clinicians in providing supportive help for patients with chronic illness. Stigma has been well researched in a few chronic illnesses; however, future studies in other conditions are much needed. Recognizing the underlying social factors has potential use in health-promoting behaviors. Sensitivity to stigma allows health professionals to critically reflect on ways the healthcare environment may add to stigma for their patients. PMID- 24170487 TI - Decreasing the stigma burden of chronic pain. AB - PURPOSE: To describe stigmatizing experiences in a group of Mexican-American women with chronic pain and provide clinical implications for decreasing stigma. DATA SOURCES: This focused ethnographic study derived data from semistructured interviews, participant observations, and fieldwork. Participants provided detailed descriptions of communicating about chronic pain symptoms, treatment, and management. The sample consisted of 15 English-speaking Mexican-American women 21-65 years old (average age = 45.6 years) who had nonmalignant chronic pain symptoms for 1 year or more. CONCLUSIONS: The cultural and social norm in the United States is the expectation for objective evidence (such as an injury) to be present if a pain condition exists. In this study, this norm created suspicion and subsequent stigmatization on the part of family, co-workers, and even those with the pain syndromes, that the painful condition was imagined instead of real. IMPLICATIONS FOR PRACTICE: To decrease stigmatization of chronic pain, providers must understand their own misconceptions about chronic pain, possess the skills and resources to access and use the highest level of practice evidence available, and become an advocate for improved pain care at local, state, and national levels. PMID- 24170488 TI - Stigma perspective of siblings of children with a major childhood burn injury. AB - PURPOSE: To understand the stigma perspective of siblings of children with major burn injury. DATA SOURCES: A mixed method, qualitative-dominant study was conducted. The life story method was used for the qualitative portion. Only narratives from those family members describing the sibling's appearance change were used (N = 18 participants). CONCLUSIONS: Stigma experienced by siblings was first described by parents or noninjured siblings; they described how the sibling with changed appearance was stared at, ridiculed, or teased when they entered a new social situation. Only when specifically asked did the children with burn injury talk about their problems, saying, "This always happens when I go somewhere new." IMPLICATIONS FOR PRACTICE: Children with changed appearance focused on normalizing their lives in a positive way. Oftentimes, it was a parent or noninjured sibling who would describe manifestations of stigma and ways they tried to protect the child with burn injury. PMID- 24170489 TI - The invisible and visible stigmatization of Parkinson's disease. AB - PURPOSE: To discuss the visible and invisible stigma shared by seven men and seven women with Parkinson's disease (PD), a chronic, progressive, neurodegenerative disorder characterized by overt physical and covert psychological manifestations. DATA SOURCES: An ethnographic approach using interview data, participant observations, and fieldwork was used. Field data were generated from a 2-year exposure to two PD support groups in east Texas. The question "what does it mean to you to have Parkinson's disease"? illuminated the experience of everyday life and the existential meaning of what it means to live with this disease. CONCLUSIONS: The invisible stigma was that of a changing self, a self with PD, a form of disability, which attested to the stigma and mounting isolation. Feelings of isolation were exacerbated by both the stigmatization associated with being different, coupled with the realization that life would never be the same. Facial masking was identified as one of the visible features that were commonly reported by all participants. IMPLICATIONS FOR PRACTICE: Healthcare professionals can be more attuned to the visible and invisible manifestations of PD that are associated with stigma through the incorporation of a holistic assessment to identify perceived stigma in persons living with the disease. PMID- 24170490 TI - A comparison of the functional difficulties in staged and simultaneous open carpal tunnel decompression. AB - There is no agreement about whether patients with bilateral carpal tunnel syndrome should undergo staged or simultaneous open decompression. The purpose of this study was to quantify and compare the functional difficulties during the recovery from surgery for patients undergoing staged or simultaneous decompressions. Sixty-three patients had surgery; 33 had staged decompression (Group 1) and 30 simultaneous decompressions (Group 2). Functional difficulties were recorded using the Levine and Quick-DASH scores along with a visual analogue score for pain. There were no complications in either group. There was no significant difference in terms of pain or satisfaction. Functional difficulties were greater in the simultaneous group; however, there was no difference in completing simple tasks. Patients reported high satisfaction with either management approach. However, significantly fewer would consider undergoing simultaneous decompression again. PMID- 24170491 TI - Considerations in the surgical use of the flexor sheath and pulley system. AB - The use of the digital flexor sheath to reconstruct damaged structures in the fingers is an intriguing but under-investigated subject. The sheath is anchored firmly to the phalanges and palmar plates and has well-vascularized outer and synovial inner layers. The middle layer is strong and fibrous and not all of it is required for its main biomechanical function of maintaining the moment arm of the flexor tendons. These characteristics have led to several descriptions of different reconstructive uses. In sheath reconstruction, flaps can be used to repair damaged A2 and A4 pulleys. As an anchor, the sheath is useful for tenodeses and tendon transfers. It has been used in the correction of ulnar claw and swan neck deformities. In ligament reconstruction, the A1 pulley has been used to reconstruct the transverse intermetacarpal ligament in cleft hand and ray amputations. The sheath has also been used to cover tendon repairs and periosteal defects with the aim of decreasing adhesions. There is potential for further use of the flexor sheath in reconstructive surgery. The digital flexor sheath can be used to restore various finger functions providing its physiological roles are recognized and preserved. This review considers the different techniques described and their potential uses. PMID- 24170492 TI - Articulating new outcomes of nurse practitioner practice. AB - PURPOSE: The purpose of this article is to describe how two mid-range theories, Kolkaba's Comfort Theory and Antonovsky's Sense of Coherence can be used to illuminate the holistic nature of nurse practitioner (NP) practice. DATA SOURCES: Original research and theoretical papers related to both theories described. CONCLUSIONS: The NP role has been in existence for more than 40 years and can be found in healthcare systems in more than 60 countries around the world. Increasingly, NPs are assuming responsibility for providing primary health care to people with complex care needs. Although researchers have consistently demonstrated the NPs provide safe, effective care, and patients are satisfied with that care, theories demonstrating the holistic nature of NP practice are less evident. IMPLICATIONS FOR PRACTICE: Comfort Theory and Sense of Coherence can be used to demonstrate how the holistic nature of NP care results in patient centered outcomes. PMID- 24170493 TI - Nucleotide variability at its limit? Insights into the number and evolutionary dynamics of the sex-determining specificities of the honey bee Apis mellifera. AB - Deciphering the evolutionary processes driving nucleotide variation in multiallelic genes is limited by the number of genetic systems in which such genes occur. The complementary sex determiner (csd) gene in the honey bee Apis mellifera is an informative example for studying allelic diversity and the underlying evolutionary forces in a well-described model of balancing selection. Acting as the primary signal of sex determination, diploid individuals heterozygous for csd develop into females, whereas csd homozygotes are diploid males that have zero fitness. Examining 77 of the functional heterozygous csd allele pairs, we established a combinatorical criteria that provide insights into the minimum number of amino acid differences among those pairs. Given a data set of 244 csd sequences, we show that the total number of csd alleles found in A. mellifera ranges from 53 (locally) to 87 (worldwide), which is much higher than was previously reported (20). Using a coupon-collector model, we extrapolate the presence of in total 116-145 csd alleles worldwide. The hypervariable region (HVR) is of particular importance in determining csd allele specificity, and we provide for this region evidence of high evolutionary rate for length differences exceeding those of microsatellites. The proportion of amino acids driven by positive selection and the rate of nonsynonymous substitutions in the HVR flanking regions reach values close to 1 but differ with respect to the HVR length. Using a model of csd coalescence, we identified the high originating rate of csd specificities as a major evolutionary force, leading to an origin of a novel csd allele every 400,000 years. The csd polymorphism frequencies in natural populations indicate an excess of new mutations, whereas signs of ancestral transspecies polymorphism can still be detected. This study provides a comprehensive view of the enormous diversity and the evolutionary forces shaping a multiallelic gene. PMID- 24170494 TI - Growth rates made easy. AB - In the 1960s-1980s, determination of bacterial growth rates was an important tool in microbial genetics, biochemistry, molecular biology, and microbial physiology. The exciting technical developments of the 1990s and the 2000s eclipsed that tool; as a result, many investigators today lack experience with growth rate measurements. Recently, investigators in a number of areas have started to use measurements of bacterial growth rates for a variety of purposes. Those measurements have been greatly facilitated by the availability of microwell plate readers that permit the simultaneous measurements on up to 384 different cultures. Only the exponential (logarithmic) portions of the resulting growth curves are useful for determining growth rates, and manual determination of that portion and calculation of growth rates can be tedious for high-throughput purposes. Here, we introduce the program GrowthRates that uses plate reader output files to automatically determine the exponential portion of the curve and to automatically calculate the growth rate, the maximum culture density, and the duration of the growth lag phase. GrowthRates is freely available for Macintosh, Windows, and Linux. We discuss the effects of culture volume, the classical bacterial growth curve, and the differences between determinations in rich media and minimal (mineral salts) media. This protocol covers calibration of the plate reader, growth of culture inocula for both rich and minimal media, and experimental setup. As a guide to reliability, we report typical day-to-day variation in growth rates and variation within experiments with respect to position of wells within the plates. PMID- 24170496 TI - Development and application of a regional-scale atmospheric mercury model based on WRF/Chem: a Mediterranean area investigation. AB - The emission, transport, deposition and eventual fate of mercury (Hg) in the Mediterranean area has been studied using a modified version of the Weather Research and Forecasting model coupled with Chemistry (WRF/Chem). This model version has been developed specifically with the aim to simulate the atmospheric processes determining atmospheric Hg emissions, concentrations and deposition online at high spatial resolution. For this purpose, the gas phase chemistry of Hg and a parametrised representation of atmospheric Hg aqueous chemistry have been added to the regional acid deposition model version 2 chemical mechanism in WRF/Chem. Anthropogenic mercury emissions from the Arctic Monitoring and Assessment Programme included in the emissions preprocessor, mercury evasion from the sea surface and Hg released from biomass burning have also been included. Dry and wet deposition processes for Hg have been implemented. The model has been tested for the whole of 2009 using measurements of total gaseous mercury from the European Monitoring and Evaluation Programme monitoring network. Speciated measurement data of atmospheric elemental Hg, gaseous oxidised Hg and Hg associated with particulate matter, from a Mediterranean oceanographic campaign (June 2009), has permitted the model's ability to simulate the atmospheric redox chemistry of Hg to be assessed. The model results highlight the importance of both the boundary conditions employed and the accuracy of the mercury speciation in the emission database. The model has permitted the reevaluation of the deposition to, and the emission from, the Mediterranean Sea. In light of the well known high concentrations of methylmercury in a number of Mediterranean fish species, this information is important in establishing the mass balance of Hg for the Mediterranean Sea. The model results support the idea that the Mediterranean Sea is a net source of Hg to the atmosphere and suggest that the net flux is ~30 Mg year(-1) of elemental Hg. PMID- 24170497 TI - Contaminated land, ecological assessment, and remediation conference series (CLEAR 2012): environmental pollution and risk assessments. PMID- 24170498 TI - Speciation and distribution of copper in a mining soil using multiple synchrotron based bulk and microscopic techniques. AB - Molecular-level understanding of soil Cu speciation and distribution assists in management of Cu contamination in mining sites. In this study, one soil sample, collected from a mining site contaminated since 1950s, was characterized complementarily by multiple synchrotron-based bulk and spatially resolved techniques for the speciation and distribution of Cu as well as other related elements (Fe, Ca, Mn, K, Al, and Si). Bulk X-ray absorption near-edge structure (XANES) and extended X-ray absorption fine structure (EXAFS) spectroscopy revealed that soil Cu was predominantly associated with Fe oxides instead of soil organic matter. This agreed with the closest association of Cu to Fe by microscopic X-ray fluorescence (U-XRF) and scanning transmission X-ray microscopy (STXM) nanoanalysis, along with the non-occurrence of photoreduction of soil Cu(II) by quick Cu L3,2-edge XANES spectroscopy (Q-XANES) which often occurs when Cu organic complexes are present. Furthermore, bulk-EXAFS and STXM-coupled Fe L3,2-edge nano-XANES analysis revealed soil Cu adsorbed primarily to Fe(III) oxides by inner-sphere complexation. Additionally, Cu K-edge MU-XANES, L3,2-edge bulk-XANES, and successive Q-XANES results identified the presence of Cu2S rather than radiation-damage artifacts dominant in certain microsites of the mining soil. This study demonstrates the great benefits in use of multiple combined synchrotron-based techniques for comprehensive understanding of Cu speciation in heterogeneous soil matrix, which facilitates our prediction of Cu reactivity and environmental fate in the mining site. PMID- 24170499 TI - The role of stakeholder attitudes in managing contaminated sites: survey of Romanian stakeholder awareness. AB - The past decade has seen substantial policy effort directed at promoting the reclamation and reuse of urban brownfield or potentially contaminated land. This paper is based on the results of a survey regarding the role of stakeholder attitudes in managing contaminated sites at the Romanian level. Findings indicate that effective policies and programmes need to be framed within an understanding of the different needs of national development. While different perceptions were identified in regard to the meanings of several concepts and terms used in this field, important aspects related to the need for developing a correctly ranked and coordinated decision-making process were also identified. Additional findings indicate gaps in the legal mechanisms intended to promote brownfield rehabilitation in the course of redevelopment. At the same time, the survey respondents suggested several recommendations such as the necessity of developing a risk assessment to establish the level and extent of contamination that can endanger human health and the environmental integrity on a site and also the need for greater compatibility between land-use planning processes and environmental legislation related to contaminated site management. The paper presents general conclusions engaging all the recommendations drawn from the survey questionnaire as well as from the general current situation in Romania. PMID- 24170500 TI - Mammalian cell-line based toxicological evaluation of paper mill black liquor treated in a soil microcosm by indigenous alkalo-tolerant Bacillus sp. AB - Organic pollutants present in the soil of a microcosm containing pulp and paper mill black liquor were extracted with hexane/acetone (1:1 v/v) to study the biodegradation and detoxification potential of a Bacillus sp. gas chromatography mass spectroscopic (GC-MS) analysis performed after biodegradation showed formation of simpler compounds like p-hydroxyhydrocinnamic acid (retention time [RT] 19.3 min), homovanillic acid methyl ester (RT 21.6 min) and 3,5-dimethoxy-p coumaric alcohol (RT 24.7 min). The methyltetrazolium (MTT) assay for cytotoxicity, 7-ethoxyresorufin-O-deethylase (EROD) assay for dioxin-like behavior and alkaline comet assay for genotoxicity were carried out in the human hepatocarcinoma cell line HuH-7 before and after bacterial treatment. Bioremediation for 15 days reduced toxicity, as shown by a 139-fold increase in black liquor's LC50 value, a 343-fold reduction in benzo(a)pyrene equivalent value and a 5-fold reduction in olive tail moment. The EROD assay positively correlated with both the MTT and comet assays in post biodegradation toxicity evaluation. PMID- 24170501 TI - Bioaccumulation, subcellular, and molecular localization and damage to physiology and ultrastructure in Nymphoides peltata (Gmel.) O. Kuntze exposed to yttrium. AB - Bioaccumulation, subcellular distribution, and acute toxicity of yttrium (Y) were evaluated in Nymphoides peltata. The effects of Y concentrations of 1-5 mg L(-1) applied for 4 days were assessed by measuring changes in photosynthetic pigments, nutrient contents, enzymatic and non-enzymatic antioxidants, and ultrastructure. The accumulation of Y in subcellular fractions decreased in the order of cell wall > organelle > soluble fraction. Much more Y was located in cellulose and pectin than in other biomacromolecules. The content of some mineral elements (Mg, Ca, Fe, Mn, and Mo) increased in N. peltata, but there was an opposite effect for P and K. Meanwhile, ascorbate, and catalase activity decreased significantly for all Y concentrations. In contrast, peroxidase activity was induced, while initial rises in superoxide dismutase activity and glutathione content were followed by subsequent declines. Morphological symptoms of senescence, such as chlorosis and damage to chloroplasts and mitochondria, were observed even at the lowest Y concentration. Pigment content decreased as the Y concentration rose and the calculated EC50 and MPC of Y for N. peltata were 2 and 0.2 mg L(-1) after 4 days of exposure, respectively. The results showed that exogenous Y was highly available in water and that its high concentration in water bodies might produce harmful effects on aquatic organisms. N. peltata is proposed as a biomonitor for the assessment of metal pollution in aquatic ecosystems. PMID- 24170502 TI - Modeling bioconcentration factor (BCF) using mechanistically interpretable descriptors computed from open source tool "PaDEL-Descriptor". AB - Predictive regression-based models for bioconcentration factor (BCF) have been developed using mechanistically interpretable descriptors computed from open source tool PaDEL-Descriptor ( http://padel.nus.edu.sg/software/padeldescriptor/ ). A data set of 522 diverse chemicals has been used for this modeling study, and extended topochemical atom (ETA) indices developed by the present authors' group were chosen as the descriptors. Due to the importance of lipohilicity in modeling BCF, XLogP (computed partition coefficient) was also tried as an additional descriptor. Genetic function approximation followed by multiple linear regression algorithm was applied to select descriptors, and subsequent partial least squares analyses were performed to establish mathematical equations for BCF prediction. The model generated from only ETA indices shows importance of seven descriptors in model development, while the model generated from ETA descriptors along with XlogP shows importance of four descriptors in model development. In general, BCF depends on lipophilicity, presence of heteroatoms, presence of halogens, fused ring system, hydrogen bonding groups, etc. The developed models show excellent statistical qualities and predictive ability. The developed models were used also for prediction of an external data set available from the literature, and good quality of predictions (R (2) pred = 0.812 and 0.826) was demonstrated. Thus, BCF can be predicted using ETA and XlogP descriptors calculated from open source PaDEL-Descriptor software in the context of aquatic chemical toxicity management. PMID- 24170503 TI - What factors drive copepod community distribution in the Gulf of Gabes, Eastern Mediterranean Sea? AB - The spatial and temporal variations in copepod communities were investigated during four oceanographic cruises conducted between July 2005 and March 2007 aboard the R/V Hannibal. A close relationship was observed between the temperature, salinity, hydrographic properties and water masses characterising the Gulf of Gabes. Indeed, water thermal stratification began in May-June, and a thermocline was established at a 20-m depth, but ranged from 25 m in July to more than 30 m in September. The zooplankton community is dominated by copepods representing 69 % to 83 % of total zooplankton. Spatial and temporal variation of copepods in relation to environmental factors shows their close relationship with the hydrodynamic features of the water column. Thermal stratification in the column, established in summer, supports copepod development. In fact, copepod abundance increases gradually with rising water temperature and salinity, starting from the beginning of thermal stratification (May-June 2006) and lasting until its completion (July 2005 and September 2006). When the water column is well mixed (March 2007), copepod abundance decreased. Our finding shows that temperature and salinity seem to be the most important physical factors and thus strongly influence the taxonomic diversity and distribution of the copepod population. They are characterised by the dominance of Oithona nana, representing 75-86 % of total cyclopoid abundance. The most abundant species during the stratification period were O. nana, Acartia clausi and Stephos marsalensis in July 2005 and September 2006. However, during the mixing period, Euterpina acutifrons was more abundant, representing 21 % of the total. Unlike the copepod community, which is more abundant during the period of high stratification, phytoplankton proliferates during semi-mixed conditions. PMID- 24170505 TI - Low impact of phenanthrene dissipation on the bacterial community in grassland soil. AB - The effect of phenanthrene on the bacterial community was studied on permanent grassland soil historically presenting low contamination (i.e. less than 1 mg kg( 1)) by polycyclic aromatic hydrocarbons (PAHs). Microcosms of soil were spiked with phenanthrene at 300 mg kg(-1). After 30 days of incubation, the phenanthrene concentration decreased rapidly until its total dissipation within 90 days. During this incubation period, significant changes of the total bacterial community diversity were observed, as assessed by automated-ribosomal intergenic spacer analysis fingerprinting. In order to get a deeper view of the effect of phenanthrene on the bacterial community, the abundances of ten phyla and classes (Actinobacteria, Acidobacteria, Bacteroidetes, Alphaproteobacteria, Betaproteobacteria, Gammaproteobacteria, Firmicutes, Verrucomicrobiales, Gemmatimonadetes, and Planctomycetes) were monitored by quantitative polymerase chain reaction performed on soil DNA extracts. Interestingly, abundances of some bacterial taxa significantly changed as compared with controls. Moreover, among these bacterial groups impacted by phenanthrene spiking, some of them presented the potential of phenanthrene degradation, as assessed by PAH-ring hydroxylating dioxygenase (PAH-RHDalpha) gene detection. However, neither the abundance nor the diversity of the PAH-RHDalpha genes was significantly impacted by phenanthrene spiking, highlighting the low impact of this organic contaminant on the functional bacterial diversities in grassland soil. PMID- 24170506 TI - Influence of salinity and temperature on the activity of biosurfactants by polychaete-associated isolates. AB - Influence of different parameters on biosurfactant (BS) activity was carried out on strains that were isolated from the polychaetes Megalomma claparedei, Sabella spallanzanii and Branchiomma luctuosum and additional 30 strains that were previously identified as potential BS producers from crude oil enrichments of the same polychaete specimens. The selection of BS-producing strains from polychaete natural samples was carried out by using standard screening tests. The BS activity by each isolate was evaluated for the effect of salinity and temperature on emulsion production and surface tension reduction, during incubation in mineral medium supplemented with tetradecane or diesel oil. All isolates showed a similar time course of BS activity, and the latter was more influenced by salinity rather than temperature. Some of the BS producers belonged to genera that have not (i.e. Citricoccus, Cellulophaga, Tenacibaculum and Maribacter) or have poorly been (Psychrobacter, Vibrio, and Pseudoalteromonas) reported as able to produce BSs. This is remarkable as some of them have previously been detected in hydrocarbon-enriched samples. Results confirm that filter-feeding polychaetes are an efficient source for the isolation of BS producers. PMID- 24170507 TI - Measuring quality in pediatrics: Florida's early experiences with the CHIPRA core measure set. AB - Enacted in 2009, the Children's Health Insurance Program Reauthorization Act (CHIPRA) aims, among other things, to increase state's accountability for providing quality health care to all children in the United States. Although it is important for states to report on the measures, learning from their successes and failures is critical in producing the measures so that states will be prepared for future regulations. Florida covered roughly 2.59 million children in 2010. Administrative, medical record, registry, and survey data were used to report on 20 of the 24 CHIPRA core measures. Technical specifications from the Centers for Medicare and Medicaid Services were used. Approximately 10 months were needed to identify, collect, safeguard, and process the required data. Florida was able to build on its past experiences with performance measurement reporting and surveying. Conducting medical record reviews at the state level and producing measures that required registry data proved to be challenging. Although Florida was successful in its first year of reporting the CHIPRA core measures, certain populations were not included in some of the measures. The next phase of Florida's CHIPRA project will focus on developing and implementing a dissemination plan and creating opportunities to improve the measures. Florida has made significant progress in the early phases of reporting the CHIPRA measures. As Florida gains more experience in reporting the measures, and results from other states are released, it will be easier to put the statewide measure results into context. Once meaningful comparisons can be made, Florida will be able to better plan for the future of child health and health outcomes. PMID- 24170504 TI - Oxidative stress--implications, source and its prevention. AB - Oxidative stress has been a major predicament of present day living. It has been the product of imbalance between the processes involved in free radical generation and their neutralization by enzymatic and non-enzymatic defence mechanisms. The oxidative stress has been contributed by numerous factors including heavy metals, organic compound-rich industrial effluents, air pollutants and changing lifestyle pattern focussing mainly on alcohol consumption, dietary habits, sun exposure, nuclear emissions, etc. The most common outcome of oxidative stress is the increased damage of lipid, DNA and proteins that resulted in the development of different pathologies. Among these pathologies, cancer is the most devastating and linked to multiple mutations arising due to oxidative DNA and protein damage that ultimately affect the integrity of the genome. The chemopreventive agents particularly nutraceuticals are found to be effective in reducing cancer incidences as these components have immense antioxidative, antimutagenic and antiproliferative potentials and are an important part of our dietary components. These secondary metabolites, due to their unique chemical structure, facilitate cell-to-cell communication, repair DNA damage by the downregulation of transcription factors and inhibit the activity of protein kinases and cytochrome P450-dependent mixed function oxidases. These phytochemicals, therefore, are most appropriate in combating oxidative stress-related disorders due to their tendency to exert better protective effect without having any distinct side effect. PMID- 24170508 TI - Characteristics of overweight and obesity at age two and the association with breastfeeding in Hawai'i Women, Infants, and Children (WIC) participants. AB - Childhood obesity is associated with many adverse health effects during childhood and is linked to an increased risk for obesity in adulthood. The objective of this study was to determine the characteristics of early childhood overweight and obesity and assess the impact of breastfeeding. Data from Hawai'i's Special Supplemental Nutrition Program for Women, Infants and Children (WIC) were analyzed for children 2 years of age born between 2005 and 2009 and their mothers. Childhood overweight and obesity was examined using a log-binomial regression model to estimate prevalence ratios. In the sample population, 12.5 % of children were overweight and 8.5 % of children were obese. Significant differences in childhood overweight and obesity were seen between breastfeeding duration and other socio-demographic groups. Children who were breastfed for 6 months or more had a lower risk of childhood obesity at age two compared to those who were never breastfed (APR 0.79, 95 % CI 0.69-0.91) with adjustment for child race/ethnicity, maternal age, trimester of prenatal care entry, maternal smoking status, and child birth weight. The prevalence of early childhood overweight and obesity is associated with shorter durations of breastfeeding. Early and continued breastfeeding support and education for mothers in the WIC program that improves duration of breastfeeding may help reduce the risk of early childhood obesity. PMID- 24170509 TI - Complementary/alternative medicine use for arthritis by older women of urban rural settings. AB - PURPOSE: This study described the use of complementary/alternative medicine (CAM) for arthritis management among community-dwelling older women in urban, suburban, and rural areas. DATA SOURCES: A descriptive qualitative approach using focus group method was employed. A purposive sample of 50 women ages 66-101 who managed arthritis with CAM participated in eight semistructured focus groups: rural (n=22), suburban (n=17), and urban areas (n=11). Data were transcribed verbatim. Inductive analytic process and computer software were used for data analysis. CONCLUSIONS: A wide variety of self-help CAM were reported. Supplements were the most commonly used CAM across all locations; rural participants reported the greatest variety of CAM use. Physical symptoms, dissatisfaction with conventional medicine, perceived safety and convenience of CAM, and a desire for personal control over one's health motivated CAM use. Most participants did not fully disclose their CAM use to their primary healthcare provider (HCP). IMPLICATIONS FOR PRACTICE: Results suggest a strong need for primary HCP to purposely dialogue with their clients on CAM use when designing, organizing, and delivering arthritis care. Information on safe CAM use and greater options for effective arthritis management with CAM are needed. The value of group-based model for treating arthritis deserves further exploration. PMID- 24170510 TI - Application of a novel 3-fluid nozzle spray drying process for the microencapsulation of therapeutic agents using incompatible drug-polymer solutions. AB - The aim of this study was to evaluate a novel 3-fluid concentric nozzle (3-N) spray drying process for the microencapsulation of omeprazole sodium (OME) using Eudragit L100 (EL100). Feed solutions containing OME and/or EL100 in ethanol were assessed visually for OME stability. Addition of OME solution to EL100 solution resulted in precipitation of OME followed by degradation of OME reflected by a colour change from colourless to purple and brown. This was related to the low pH of 2.8 of the EL100 solution at which OME is unstable. Precipitation and progressive discoloration of the 2-fluid nozzle (2-N) feed solution was observed over the spray drying time course. In contrast, 3-N solutions of EL100 or OME in ethanol were stable over the spray drying period. Microparticles prepared using either nozzle showed similar characteristics and outer morphology however the internal morphology was different. DSC showed a homogenous matrix of drug and polymer for 2-N microparticles while 3-N microparticles had defined drug and polymer regions distributed as core and coat. The results of this study demonstrate that the novel 3-N spray drying process can allow the microencapsulation of a drug using an incompatible polymer and maintain the drug and polymer in separate regions of the microparticles. PMID- 24170511 TI - Nano-enabled delivery systems across the blood-brain barrier. AB - The development of drugs to treat disorders of the central nervous system (CNS) faces difficulties in achieving penetration of a drug through the blood-brain barrier (BBB) and allowing the drug to reach its intended target in the brain. There have been strategies to improve drug delivery to the brain through endogenous transport pathways such as passive diffusion, endocytosis, and active transport. Among various strategies, nano-enabled delivery systems offer a promising solution to improve the uptake and targeted delivery of drugs into the brain. Various nanocarriers including liposomes, bolaamphiphiles and nanoparticles can be used as a means to encapsulate drugs, either alone or in combination with targeting ligands. Moreover, most of materials used in nanocarrier fabrication are both biodegradable and biocompatible, thereby increasing the clinical utility of them. Here, we review the possibility to employ nano-enabled materials for delivery of drug across the BBB and the recent advances in nanotechnologies for therapy of the CNS diseases. PMID- 24170512 TI - Recrudescent meibomian gland carcinoma treated with Xeloda: case report. AB - PURPOSE: To observe the curative effect of Xeloda in meibomian gland carcinoma. METHODS: We treated a 53-year-old woman, who had recrudescent meibomian gland carcinoma, with Xeloda. RESULTS: The mass was much smaller with decreased amount of overflow pus after 4 cycles of chemotherapy with Xeloda. CONCLUSIONS: Xeloda played a significant role in treating recrudescent meibomian gland carcinoma in this patient. PMID- 24170513 TI - Mean platelet volume as a mirror of all inflammatory conditions. PMID- 24170514 TI - Baerveldt drainage tube motility in the anterior chamber. AB - PURPOSE: To investigate the stability in position of the Baerveldt glaucoma drainage tube over time and to study movement of the drainage tube in the anterior chamber (AC) under varying light conditions. METHODS: This prospective study included 70 eyes with implantation of a Baerveldt glaucoma drainage tube in the anterior chamber. Anterior segment optical coherence tomography (AS-OCT) images were made preoperatively to quantify AC depth. AS-OCT images were made twice under photopic and twice under scotopic conditions, in the angle parallel to the Baerveldt tube to quantify drainage tube position, at 3, 6, 12, and 24 months postoperatively. Tube-corneal (T-C) and tube-iris (T-I) distances were measured. Additionally, the central AC depth and the peripheral angle opening (AOD 500) were determined. Two subgroups were distinguished according to tube position: free in the AC (group 1, n = 48) and transiridal (group 2, n = 22). RESULTS: After 24 months of follow-up, the drainage tube was found to move statistically significantly closer (0.12 mm) to the corneal endothelium in group 1 (p<0.01). There was no statistically significant difference in T-C distance over time in group 2. The T-C distance did not differ under photopic versus scotopic circumstances (p = 0.32). In both groups, the T-I distance was larger under scotopic conditions, a result of pupil dilation. CONCLUSIONS: The Baerveldt glaucoma drainage tube remained in a stable position when a transiridal implantation was performed, whereas the tube moved closer to the endothelium when placed free into the AC. Transiridal implantation of the Baerveldt tube seems a safe alternative for tube implantation with respect to tube motility. PMID- 24170515 TI - Early results of selective laser trabeculoplasty in patients resistant to deep sclerectomy. AB - PURPOSE: In this study, we aimed to determine the early results of selective laser trabeculoplasty to trabeculo-Descemet membrane in patients resistant to deep sclerectomy (DS) surgery. METHODS: Twelve eyes of 12 patients that had undergone DS for primary open-angle glaucoma were enrolled. Preoperative and postoperative intraocular pressures (IOP) were measured by Goldmann applanation tonometer. Time to failure after DS was noted. Failure is described as IOP higher than 20 mm Hg. All patients underwent selective laser trabeculoplasty (SLT) after failure. Eight to 10 applications of SLT were applied over the trabeculo-Descemet membrane. Laser was applied to the surgical site only. The IOPs before SLT, at postoperative first week, first month, and third month were measured. RESULTS: Mean follow-up time was 23.5 +/- 9.5 months. Mean preoperative IOP was 34.2 +/- 6.7 mm Hg; mean postoperative IOP at first week was 12.7 +/- 3.2 mm Hg. Mean time to failure after DS procedure was 21.6 +/- 7.6 months. Mean IOP was 20.6 +/- 1.9 mm Hg just before SLT procedure. Mean IOP measurements after SLT at first week, first month, and third month were 10.5 +/- 2.2 mm Hg, 10.5 +/- 1.9 mm Hg, and 10.9 +/- 2.1 mm Hg, respectively. CONCLUSIONS: Selective laser trabeculoplasty after DS is an effective and noninvasive procedure that can be done on an outpatient basis. Our results suggest that SLT applied to the surgical site is an effective intervention in the short term but long-term results are required to assess the efficacy. PMID- 24170516 TI - Functional and anatomic changes in acute multifocal placoid pigment epitheliopathy: a case report. AB - PURPOSE: To report the functional and anatomic features of a case of acute posterior multifocal placoid pigment epitheliopathy (APMPPE). METHODS: Case report. RESULTS: A 30-year-old man presented with a decrease of visual acuity that started a few days earlier. Fundus examination showed multiple, subretinal, white-yellowish lesions at the posterior pole in both eyes, suggesting APMPPE. Symptoms and clinical signs resolved within a few weeks, leaving well-defined areas of atrophy of the retinal pigment epithelium (RPE). CONCLUSIONS: This case report emphasizes the role of the RPE in the pathogenesis of APMPPE. PMID- 24170517 TI - Temperament profile in patients with central serous chorioretinopathy: a case control study. AB - PURPOSE: To assess temperament in patients with central serous chorioretinopathy (CSCR) compared to healthy controls. METHODS: A total of 32 patients diagnosed with acute CSCR and 30 healthy controls matched by age and sex were assessed with the self-report Cloninger's Temperament and Character Inventory. Central serous chorioretinopathy was diagnosed based on fluorescein angiography and spectral optical coherence tomography. RESULTS: Significantly higher mean scores of harm avoidance in patients with CSCR were found. Differences also were noted in subscales of novelty-seeking and reward dependence. CONCLUSIONS: The patients with CSCR demonstrated less exploratory behaviors, higher risk avoidance, restraint, and low extravagance. They were more quick-tempered, disorganized, and easily frustrated, with a tendency to avoid negative and potentially harmful stimuli, less tolerance to frustration, higher level of insecurity, and higher level of anticipatory anxiety. PMID- 24170518 TI - Assessment of cortical dysfunction in infantile esotropia using fMRI. AB - PURPOSE: Functional magnetic resonance imaging (fMRI) is popular in the field of neuroimaging. The aim of this study was to explore the neural basis of infantile esotropia and locate the cortical region of fusion function defects using blood oxygen level-dependent fMRI (BOLD-fMRI). METHODS: Subjects (5 with infantile esotropia and 8 normal) were presented with a visual stimulus ?(letter E). The BOLD-fMRI was used to measure the visual cortex response as the distance between the E and the eyes changing from 20 to 100 cm using a block experimental design. Data were processed offline using statistical parametric mapping and compared between the 2 groups. RESULTS: Areas activated in the visual cortex of normal subjects were located in the bilateral frontal gyrus and left lingual visual cortex (p<0.001). The BOLD signal in the left cingulate gyrus, bilateral precuneus, and left angular gyrus was higher in the infantile esotropia group than in the controls (p<0.001). None of the visual cortical areas showed higher signal in the control individuals than in those with infantile esotropia (p<0.001). CONCLUSIONS: The bilateral frontal gyrus and left lingual visual cortex regulate normal fusion function in human eyes. In infantile esotropia, the left cingulate gyrus, bilateral precuneus, and left angular gyrus visual cortex may compensate for the fusion dysfunction. These insights may help improve the diagnosis and treatment of strabismus. PMID- 24170519 TI - Excimer laser mushroom penetrating keratoplasty: new technique. AB - PURPOSE: To evaluate retrospectively the outcomes of 15 consecutive mushroom shaped penetrating keratoplasties performed by using excimer laser for both the recipient bed and the fresh donor corneas. METHODS: Fifteen eyes of 14 patients who underwent excimer laser mushroom-shaped penetrating keratoplasty from October 13, 2010, to October 14, 2011, were included in our retrospective study. Eight were men and 6 were women, with a mean age of 31.45 +/- 6.52 (range 27-65) years. Eleven (73.3%) had postinfective central deep corneal scar; 4 (26.7%) had severe keratoconus with Descemet opacity. RESULTS: The mean follow-up was 11.9 +/- 2.7 months. The mean preoperative best-corrected visual acuity (BCVA) was 0.15 +/- 0.16; the postoperative BCVA was 0.69 +/- 0.24 after 12 months with a mean refractive astigmatism of 1.8 +/- 1.1 D. The mean preoperative endothelial cell count of the donor corneas was 2297.0 +/- 189.7 cells/mm2; after 12 months, it was 1906.5 +/- 165.8 with a decrease of 17.0%. No intraoperative complications occurred. CONCLUSIONS: Our results showed that excimer laser mushroom penetrating keratoplasty is safe. Furthermore, it does not appear to influence the visual outcomes of the penetrating keratoplasty surgery. This technique is useful for those who use an excimer laser. PMID- 24170520 TI - Introduction of a weighted scoring algorithm for the EIT-8G scale. PMID- 24170521 TI - Corneal biomechanical parameters during pregnancy. AB - PURPOSE: To evaluate the variation in biomechanical properties and central corneal thickness (CCT) for each trimester during pregnancy and to compare the values with those in nonpregnant women. METHODS: We prospectively studied the eyes of 32 pregnant and 34 age-matched non-pregnant women. The parameters included corneal hysteresis (CH), corneal resistance factor (CRF), Goldmann correlated intraocular pressure (IOP), and corneal-compensated IOP measured by the Ocular Response Analyzer (ORA). The CCT was also measured with an ultrasonic pachymeter attached to the ORA. RESULTS: The mean age was 27.0 +/- 3.8 years in the study group and 28.0 +/- 4.1 years in the control group. The mean CH measurement was 10.6 +/- 1.4 mmHg in the study group and 10.1 +/- 1.3 mmHg in the control group. The mean CRF value was 9.6 +/- 1.7 mmHg in the study group and 10.0 +/- 1.4 mmHg in the control group. The mean CCT value was 541.1 +/- 22.4 um in the study group and 536.5 +/- 27.1 um in the control group. No statistically significant differences were found regarding CH, CRF, or CCT values between the 2 groups (independent t test, p = 0.160, p = 0.355, p = 0.450, respectively). CONCLUSIONS: Hormonal changes during pregnancy may not affect corneal biomechanics. This may be due to the balanced effect of the various hormones on the cornea during pregnancy. PMID- 24170522 TI - Author reply to: Mean platelet volume in pseudoexfoliation syndrome and glaucoma. PMID- 24170523 TI - Intravitreal dexamethasone implant for macular edema following uncomplicated phacoemulsification. AB - PURPOSE: To retrospectively study the efficacy of a single 0.7-mg dexamethasone intravitreal implant in eyes with refractory macular edema secondary to uncomplicated phacoemulsification and intraocular lens implant. METHODS: In 11 eyes of 11 consecutive patients with persistent refractory macular edema, secondary uncomplicated cataract extraction, and intraocular lens implant, the injection of 0.7-mg dexamethasone implant was performed at the Clinica Oculistica, University of Bari, Italy. Best-corrected visual acuity (BCVA), central retinal thickness measured by spectral-domain optical coherence tomography, and intraocular pressure (IOP) was evaluated at baseline, 1 month, and 6 months. RESULTS: After a mean follow-up of 6.27 +/- 0.47 months, BCVA was significantly increased from 20/40 to 20/22 (p<0.0001), mean central retinal thickness decreased significantly from 462 +/- 100 to 276 +/- 8 um (p<0.0001), and IOP did not change significantly (p = 0.053). In no case were postoperative complications observed. CONCLUSIONS: A single injection of 0.7-mg dexamethasone intravitreal implant was effective in the treatment of persistent refractory macular edema secondary to uneventful phacoemulsification and in-bag lens implant. PMID- 24170524 TI - Air as tamponade for retinal detachments. AB - PURPOSE: To determine whether air can be used as a reliable tamponade agent after pars plana vitrectomy in selected primary retinal detachment (RD). METHODS: Twelve eyes with fresh RD were included. Exclusion criteria were presence of fibrosis, fixed folds, proliferative vitreoretinopathy of grade C or greater, and giant retinal tears. The number, location, and types of breaks, extension of RD, and whether the macula was attached were documented. A 25-gauge 3-port pars plana vitrectomy was carried out. Central and peripheral vitreous was removed to eliminate traction and relieve tractional forces provoked by the air bubble injected at the end. Argon endolaser or cryotherapy was applied around all breaks. Filtered air was used as an internal tamponade. Patients were followed up at 24 hours, 1 week, and 1, 3, 6, and 12 months. RESULTS: Air bubble took 10.7 days (range 7-15 days) to resolve. Visual acuity (VA) improved from 1.35 +/- 1.21 logMAR preoperatively to 0.20 +/- 0.25 after a follow-up time of 12 months. We achieved a primary postoperative success rate of 100% at 1 month and 91.6% at 12 months. CONCLUSIONS: We achieved a good success rate with air tamponade and limited laser. This approach allows for quicker VA recovery associated with a rapid disappearance of air. This may benefit patients who live at higher altitudes. PMID- 24170525 TI - Clear lens phacoemulsification in Alport syndrome: refractive results and electron microscopic analysis of the anterior lens capsule. AB - PURPOSE: To report the ocular findings of patients with Alport syndrome and the results of clear lens extraction in this patient group. METHODS: Twenty-three eyes of 15 patients with a diagnosis of Alport syndrome were included in this study. Clear corneal phacoemulsification and intraocular foldable lens implantation was performed in eyes with indeterminate refractive errors and/or poor visual acuity and anterior capsule samples were analyzed with electron microscopy. RESULTS: All patients had a history of hereditary nephritis and/or deafness as systemic involvement. Ophthalmologic examination revealed anterior lenticonus with high myopia and/or irregular astigmatism in all patients. The mean best-corrected visual acuity (BCVA) was 0.67 +/- 0.17 logMAR (range 1.0-0.4) preoperatively and 0.17 +/- 0.08 logMAR (range 0.3-0.0) postoperatively. Postoperative refractive lenticular astigmatism dramatically decreased and no ocular complications arose during the follow-up period. Transmission electron microscopic analysis of the lens capsules supported the diagnosis of Alport syndrome. CONCLUSIONS: Clear lens phacoemulsification and foldable intraocular lens implantation is a safe and effective therapeutic choice for the management of uncorrectable refractive errors and low visual acuity due to anterior lenticonus in patients with Alport syndrome. PMID- 24170526 TI - Three-dimensional molybdenum sulfide sponges for electrocatalytic water splitting. AB - Electroactive MoSx catalysts on porous 3D sponges synthezied by a simple and scalable thermolysis process are proposed. Although no conducting materials are used to host the MoSx catalysts, they still serve as efficient electrodes for hydrogen evolution. The high current density of the MoSx-coated sponges are attributed to the large electrochemical surface area and their S-rich chemical structure. PMID- 24170527 TI - Diabetes mellitus with normal renal function is associated with anaemia. AB - BACKGROUND: Anaemia is a common complication of diabetes mellitus (DM), usually related to renal failure. There is scarce information as to the levels of haemoglobin (Hb) and the rate of anaemia in diabetic patients with normal renal function. We, therefore, evaluated haemoglobin levels and the rate of anaemia in diabetic subjects with normal renal functions [estimated glomerular filtration rate (eGFR) > 60 mL/min]. METHODS: The charts of 9250 subjects who attended the Institute of Periodic Medical Examinations at the Chaim Sheba Medical Center for a routine yearly check-up were reviewed. Four hundred and forty-five subjects with type 2 DM and normal renal function were indentified and compared with those without DM who were routinely examined at the same time. Subjects' electronic records were used to build a biochemical and clinical database. RESULTS: Mean haemoglobin levels were lower in subjects with DM than in those without (14.2 vs. 14.7 g/dL, respectively; p < 0.001). Anaemia was observed in 48 (10.8%) subjects in the diabetic group and in only 12 (2.7%) in the nondiabetic group (p < 0.001). Multivariate analysis revealed that age, gender, history of gastrointestinal disease, use of beta blockers, renal function and DM were independent determinants of haemoglobin levels. After adjustment for age, gender, history of gastrointestinal tract diseases and renal function, DM remained a significant determinant of anaemia with an odds ratio of 2.15 (confidence interval: 1.07 4.31). CONCLUSIONS: Anaemia is more common in diabetic patients even when eGFR > 60 mL/min. PMID- 24170528 TI - Epidural analgesia in labour and neonatal respiratory distress: a case-control study. AB - BACKGROUND: Epidural analgesia is the commonest mode for providing pain relief in labour, with a combination of bupivacaine and fentanyl most often used in practice. OBJECTIVE: To test whether late-preterm and term neonates exposed to opioids in epidural analgesia in labour are more likely to develop respiratory distress in the immediate neonatal period. METHODS: A case-control study was conducted of singleton infants born during January 2006 to December 2010. Cases were neonates >=34 weeks gestation, who developed respiratory distress within 24 h of life requiring supplemental oxygen >=2 h and/or positive pressure ventilation in the neonatal intensive care unit. Controls were gestation and site matched neonates who did not develop any respiratory distress within the same period. The information on exposure to epidural analgesia and on potential confounding variables was obtained from the standardised delivery record, routinely filled out on all women admitted to the labour wards. RESULTS: In our study, 206 cases and 206 matched controls were enrolled. Exposure to epidural analgesia was present in 146 (70.9%) cases as compared with 131 (63.6%) of the controls. The association between exposure to epidural analgesia and respiratory distress in neonates was statistically significant upon adjustment for all potential confounders (adjusted OR: 1.75, 95% CI 1.03 to 2.99; p = 0.04). When data was separately analysed for term and late-preterm infants, the results were consistent across these subpopulations, showing no interaction effect. CONCLUSIONS: Late-preterm and term infants exposed to maternal epidural analgesia in labour are more likely to develop respiratory distress in the immediate neonatal period. PMID- 24170530 TI - Everything the nurse practitioner should know about pediatric feeding tubes. AB - PURPOSE: To provide an overview of the current feeding tubes in use in the pediatric population including feeding tube complications, and specific guidance for patients at the initiation, throughout the use of, and at the discontinuation of tube feeding. DATA SOURCES: A review of the literature was performed using multiple databases including PubMed, CINAHL, Ovid Medline, and Cochrane Library. Key words used included pediatric gastrostomy (G) tubes, nasogastric (NG) tubes, gastrojejunostomy (GJ) tubes, enteral access, and nurse practitioner (NP). CONCLUSIONS: Any child who cannot obtain nutrition orally is a candidate for enteral feeding tube access. Tube feeding is the recommended care guideline for children that are undernourished or unable to safely take-in oral nutrition. Tube feeding has been known to improve health-related quality of life. There are a number of different forms of feeding tubes that can be used in children, including NG, orogastric, G, and GJ tubes. IMPLICATIONS FOR PRACTICE: Children are being sent home regularly with enteral feeding tube access and NPs will encounter these patients in everyday practice. It is important that NPs know the risks and benefits of tube feeding as well as the types of tubes currently in use and their indications, advantages, disadvantages, and complications. PMID- 24170531 TI - The psychological impact of diabetes: a practical guide for the nurse practitioner. AB - PURPOSE: To describe the psychological impact of diabetes and to present a number of practical ways that nurse practitioners (NPs) can assess and address these concerns in the context of primary care. DATA SOURCES: Theory and research articles are reviewed from the fields of nursing and psychology describing the psychological problems unique to those with diabetes. A case study is provided for practical application of the clinical tools presented. CONCLUSIONS: The psychological consequences of diabetes can be significant, including feelings of loss, anger, depression, anxiety, and disordered eating. There are a number of useful tools and resources for NPs to use in the primary care setting to effectively manage the multifaceted impact of diabetes on patients' lives. These tools include listening, showing empathy, comprehensive assessment of psychosocial issues, equipping patients for self-management, encouraging self care, teaching stress management skills, and offering additional mental health support. Psychotherapy can help patients to address emotional and behavioral aspects of diabetes. IMPLICATIONS FOR PRACTICE: Assessing and addressing the psychological aspects of illness is an important part of caring for people with diabetes. There are many tools and resources available to NPs that can be implemented with minimal training. PMID- 24170532 TI - Does a 30-min quality improvement clinical practice meeting reviewing the recommended Papanicolaou test guidelines for adolescents improve provider adherence to guidelines in a pediatric primary care office? AB - PURPOSE: The purpose of this quality improvement project was to evaluate adherence to Papanicolaou (Pap) test guidelines 6 months prior to and 6 months following a 30-min educational clinical practice meeting in a pediatric primary care office. Guidelines for Pap tests have been revised in recent years by the American Academy of Obstetrics and Gynecology, the American Cancer Society, and the U.S. Preventive Task Force, but providers often do not adhere to the guidelines. DATA SOURCES: A total of 777 charts from a pediatric primary care office were reviewed. Eighty-four percent (652) met criteria for inclusion. CONCLUSIONS: Among sexually active adolescents, there was a statistically significant relationship between rates of Pap tests following the clinical practice meeting (chi(2) (1) = 13.5, p = .001). Prior to the meeting there were 29 Pap tests recorded, whereas after there were two Pap tests done. After the focused clinical practice meeting, providers performed far fewer Pap tests, which is in accordance with the guidelines for this population. IMPLICATIONS FOR PRACTICE: Providers may not always practice in accordance with recommended clinical practice guidelines for various reasons. Focused, in-office educational interventions via clinical practice meetings may be an effective way of discussing recommended guidelines to improve provider adherence. PMID- 24170529 TI - Recent advances in coupling capillary electrophoresis-based separation techniques to ESI and MALDI-MS. AB - Coupling CE-based separation techniques to MS creates a powerful platform for analysis of a wide range of biomolecules from complex samples because it combines the high separation efficiency of CE and the sensitivity and selectivity of MS detection. ESI and MALDI, as the most common soft ionization techniques employed for CE and MS coupling, offer distinct advantages for biomolecular characterization. This review is focused primarily on technological advances in combining CE and chip-based CE with ESI and MALDI-MS detection in the past five years. Selected applications in the analyses of metabolites, peptides, and proteins with recently developed CE-MS platforms are also highlighted. PMID- 24170533 TI - Role of mTOR inhibition in the treatment of patients with renal angiomyolipomas. AB - PURPOSE: To describe the role of mammalian target of rapamycin (mTOR) inhibition in the treatment of tuberous sclerosis complex (TSC) patients with renal angiomyolipoma in relation to available clinical data and clinical practice guidance for the nurse practitioner (NP). DATA SOURCES: A review of the scientific literature, key clinical congresses, and key clinical trials. CONCLUSIONS: TSC-associated renal angiomyolipomas have a propensity to grow over time and predispose patients to serious and life-threatening consequences. Surgery or invasive interventional therapies may not be the most optimal treatments because of the multiple, bilateral growth pattern of TSC-associated renal angiomyolipomas. Targeted therapies, such as mTOR inhibitors, which have demonstrated efficacy in maintaining and reducing renal angiomyolipoma size, are of great benefit to patients. IMPLICATIONS FOR PRACTICE: Treatment with everolimus, an oral mTOR inhibitor, offers patients a noninvasive pharmacotherapeutic treatment option. The NP, as a key member of the healthcare team overseeing TSC patients, must be knowledgeable about the safety and efficacy of mTOR inhibitors as their use in the patient population increases. PMID- 24170534 TI - Family nurse practitioner student perception of journal abstract usefulness in clinical decision making: a randomized controlled trial. AB - PURPOSE: To assess family nurse practitioner (FNP) student perception of research abstract usefulness in clinical decision making. DATA SOURCES: A randomized controlled trial conducted in a simulated environment with graduate FNP students of the Graduate School of Nursing, Uniformed Services University of the Health Sciences. Given a clinical case study and modified MEDLINE search tool accessible via an iPad device, participants were asked to develop a treatment plan and complete a data collection form. The primary measure was perceived usefulness of the research abstracts in clinical decision making regarding a simulated obese patient seeking to prevent type 2 diabetes. Secondary measures related to participant demographics and accessibility and usefulness of full-text manuscripts. CONCLUSIONS: The majority of NP students identified readily available research abstracts as useful in shaping their clinical decision making. The presence or absence of full-text manuscripts associated with the abstracts did not appear to influence the perceived abstract usefulness. The majority of students with full-text manuscript access in the timed simulated clinical encounter read at least one paper, but cited insufficient time to read full-text as a constraint. IMPLICATIONS FOR PRACTICE: Research abstracts at point of care may be valuable to FNPs if easily accessible and integrated into clinical workflow. PMID- 24170535 TI - Retrospective chart review for obesity and associated interventions among rural Mexican-American adolescents accessing healthcare services. AB - PURPOSE: To report a retrospective analysis of data routinely collected in the course of healthcare services at a rural health clinic and to assess obesity incidence and associated interventions among rural Mexican-American adolescents. DATA SOURCES: Two hundred and twelve charts reviewed; 98 (46.2%) males and 114 (53.8%) females. Data extracted included Medicaid exams conducted at the clinic within 5 years. Equal overweight or obese (n = 105, 49.5%), versus normal BMI categorizations (n = 107, 50.5%) documented overall and by gender. Female obesity higher (25.4%) than national norms (17.4%); male rates (25.5%) were within national norm. Interventions provided by nurse practitioners (94%) for 34.8%-80% of overweight/obese had limited follow-up (4%). Obesity incidence markedly increased between 13 and 18 years of age without associated interventions; 51.4% 75.6% without interventions. CONCLUSIONS: Obesity is a healthcare problem among rural Mexican-American adolescents accessing care at the rural health clinic. Obesity intervention and follow-up was suboptimal within this setting. Rural and ethnic minority adolescents experience health disparities concerning obesity prevalence and remote healthcare access. IMPLICATIONS: Obesity prevention and treatment during adolescence is a national health priority given physiologic and psychological tolls on health and potential for obesity into adulthood. Obesity assessment and translation of evidence-based interventions for rural Mexican American adolescents at rural health clinics is implicated. PMID- 24170536 TI - Creating a more positive patient experience of pelvic examination. AB - PURPOSE: To explore through descriptive comparative analysis an alternative method of pelvic examination to increase patient comfort. DATA SOURCES: Sixty-two participants were recruited from a convenience sample of patients at an ambulatory women's healthcare clinic operated by a teaching hospital in the Southwest United States. Twenty-five were examined using the conventional pelvic examination technique; 37 with a new technique that we call the Rad technique, named after a co-author of the study. Three women's health nurse practitioners were trained in both methods and alternated the exam technique used. Visualization of the cervix was measured by clinician responses to the Speculum Exam Questionnaire for Clinicians; level of pain was determined from patient responses to the Wong-Baker FACES Pain Rating Scale. Results were analyzed using a t-test for independent samples. Pain was further analyzed using chi-square test of association. CONCLUSIONS: Although the relationship between the variables of visualization and pain was not statistically significant, 16% of women in the conventional technique group reported vaginal pain compared with 5.4% in the Rad technique group. IMPLICATIONS FOR PRACTICE: Changing from the conventional pelvic examination to the Rad technique may create a more positive patient experience and thereby engage more women in recommended in gynecological health care. PMID- 24170537 TI - Level of acculturation, food intake, dietary changes, and health status of first generation Filipino Americans in Southern California. AB - PURPOSE: This exploratory descriptive study investigates the acculturation level, food intake, dietary changes and practices, health status perceptions, and diet related health indicators-body mass index (BMI), waist and hip circumferences, and waist-to-hip ratio-of first-generation Filipino Americans (FAs) in Southern California. DATA SOURCES: Healthy FA adults-20 women and 10 men-were interviewed. Acculturation level was obtained using A Short Acculturation Scale for Filipino Americans. A 24-h dietary recall elicited their food intake. Survey questions revealed dietary changes and practices, health status perceptions, and sociodemographic characteristics. Height, weight, waist and hip circumferences were measured. CONCLUSIONS: FAs consider themselves more Filipino than American, but their acculturation level reflects transitioning into biculturalism. FAs relinquish, maintain, and adapt elements of both Philippine and U.S. cultures in food intake, dietary changes, and practices. Although FAs perceive their health status as very good to excellent, many exceed the cut-off points for BMI, waist circumference, and waist-to-hip ratio. IMPLICATIONS FOR PRACTICE: This study underscores the importance of nurse practitioners and other healthcare givers conducting cultural dietary assessment as a basis for culturally appropriate dietary counseling. The inclusion of waist measurement to regularly monitor abdominal obesity-a predictor of cardiovascular disease and diabetes-is highly recommended. PMID- 24170538 TI - Medical students' and teachers' perceptions of sexual misconduct in the student teacher relationship. AB - Teachers are important role models for the development of professional behaviour of young trainee doctors. Unfortunately, sometimes they show unprofessional behaviour. To address misconduct in teaching, it is important to determine where the thresholds lie when it comes to inappropriate behaviours in student-teacher encounters. We explored to what extent students and teachers perceive certain behaviours as misconduct or as sexual harassment. We designed-with a reference group-five written vignettes describing inappropriate behaviours in the student teacher relationship. Clinical students (n = 1,195) and faculty of eight different hospitals (n = 1,497) were invited to rate to what extent they perceived each vignette as misconduct or sexual harassment. Data were analyzed using t tests and Pearson's correlations. In total 643 students (54 %) and 551 teachers (37 %) responded. All vignettes were consistently considered more as misconduct than as actual sexual harassment. At an individual level, respondents differed largely as to whether they perceived an incident as misconduct or sexual harassment. Comparison between groups showed that teachers' and students' perceptions on three vignettes differed significantly, although the direction differed. Male students were more lenient towards certain behaviours than female students. To conclude, perceptions of misconduct and sexual harassment are not univocal. We recommend making students and teachers aware that the boundaries of others may not be the same as their own. PMID- 24170539 TI - Engaging, interacting and connecting with our learners and teachers. PMID- 24170541 TI - Teaching motivational interviewing to nurse practitioner students: a pilot study. AB - PURPOSE: This quasi-experimental study examined the outcomes of a brief educational module for graduate nursing students as to using motivational interviewing (MI)-consistent counseling skills. DATA SOURCES: Pre- and posttest narrative and video-taped data, surveys, and self-report. CONCLUSIONS: Significantly fewer closed questions, more open questions, and less advice-giving without permission were noted in the narratives completed after the education. Similarly, the second videotape revealed significantly more affirmations, use of reflections, and use of more summaries when ending patient sessions. Surveys and self-report indicated strong satisfaction with the opportunity to learn MI. IMPLICATIONS FOR PRACTICE: A core competency of nurse practitioner (NP) education involves helping persons adopt positive health behaviors. While research utilizing MI has evidenced substantial success in this regard, little has been published as to how to incorporate teaching this skill set within an already content-laden NP curriculum. Including at least minimal education in MI should occur in NP programs. Eight hours of education, including video-taped practice, followed by "booster sessions" to maintain skills and increase confidence is recommended. More research is necessary to elucidate best practices of teaching this skill set to NPs and its eventual outcomes on patients' health. PMID- 24170540 TI - Associative concept learning in animals. AB - Nonhuman animals show evidence for three types of concept learning: perceptual or similarity-based in which objects/stimuli are categorized based on physical similarity; relational in which one object/stimulus is categorized relative to another (e.g., same/different); and associative in which arbitrary stimuli become interchangeable with one another by virtue of a common association with another stimulus, outcome, or response. In this article, we focus on various methods for establishing associative concepts in nonhuman animals and evaluate data documenting the development of associative classes of stimuli. We also examine the nature of the common within-class representation of samples that have been associated with the same reinforced comparison response (i.e., many-to-one matching) by describing manipulations for distinguishing possible representations. Associative concepts provide one foundation for human language such that spoken and written words and the objects they represent become members of a class of interchangeable stimuli. The mechanisms of associative concept learning and the behavioral flexibility it allows, however, are also evident in the adaptive behaviors of animals lacking language. PMID- 24170542 TI - Adhesion to fibronectin induces p27(Kip1) nuclear accumulation through down regulation of Jab1 and contributes to cell adhesion-mediated drug resistance (CAM DR) in RPMI 8,226 cells. AB - Mounting evidence has been shown that integrin-mediated cellular adhesion confers resistance to chemotherapy of multiple myeloma. The molecular mechanism underlying cell adhesion-mediated drug resistance (CAM-DR) is, however, poorly understood. In this report, we demonstrated that RPMI 8,226 cells accumulated p27(Kip1) in the nucleus when they were adhered to fibronectin (FN). The adhesion mediated p27(Kip1) nuclear recruitment was regulated via the down-regulation of Jab1, a negative regulator of cell cycle. Overexpression of Jab1 reversed the elevated p27(Kip1) in the nucleus, which needed phosphorylation of p27(Kip1) on Serine 10, whereas inhibition of Jab1 by siRNA further increased the elevated p27(Kip1). Furthermore, we found overexpression of Jab1 did not affect 8,226 cells adhesion to FN, but reversed doxorubicin or mitoxantrone-induced CAM-DR phenotype. In conclusion, our data suggest that Jab1 plays an important role in CAM-DR, which depends on pSer10-p27(Kip1)-mediated subcellular localization of p27(Kip1). The understanding of this novel molecular mechanism may prove valuable in designing new therapeutic approaches for CAM-DR in Multiple myeloma. PMID- 24170543 TI - Cidofovir: a novel antitumor agent for glioblastoma. AB - PURPOSE: Cidofovir (CDV) is an U.S. Food and Drug Administration (FDA)-approved nucleoside antiviral agent used to treat severe human cytomegalovirus (HCMV) infection. Until now, no clear therapeutic effects of CDV have been reported outside of the setting of viral infection, including a potential role for CDV as an antineoplastic agent for the treatment of brain tumors. EXPERIMENTAL DESIGN: We investigated the cytotoxicity of CDV against the glioblastoma cells, U87MG and primary SF7796, both in vitro and in vivo, using an intracranial xenograft model. Standard techniques for cell culturing, immunohistochemistry, Western blotting, and real-time PCR were employed. The survival of athymic mice (n = 8-10 per group) bearing glioblastoma tumors, treated with CDV alone or in combination with radiation, was analyzed by the Kaplan-Meier method and evaluated with a two-sided log-rank test. RESULTS: CDV possesses potent antineoplastic activity against HCMV infected glioblastoma cells. This activity is associated with the inhibition of HCMV gene expression and with activation of cellular apoptosis. Surprisingly, we also determined that CDV induces glioblastoma cell death in the absence of HCMV infection. CDV is incorporated into tumor cell DNA, which promotes double stranded DNA breaks and induces apoptosis. In the setting of ionizing radiotherapy, the standard of care for glioblastoma in humans, CDV augments radiation-induced DNA damage and, further, promotes tumor cell death. Combination therapy with CDV and radiotherapy significantly extended the survival of mice bearing intracranial glioblastoma tumors. CONCLUSION: We have identified a novel antiglioma property of the FDA-approved drug CDV, which heightens the cytotoxic effect of radiotherapy, the standard of care therapy for glioblastoma. PMID- 24170545 TI - A personalized preclinical model to evaluate the metastatic potential of patient derived colon cancer initiating cells. AB - PURPOSE: Within the aim of advancing precision oncology, we have generated a collection of patient-derived xenografts (PDX) characterized at the molecular level, and a preclinical model of colon cancer metastasis to evaluate drug response and tumor progression. EXPERIMENTAL DESIGN: We derived cells from 32 primary colorectal carcinomas and eight liver metastases and generated PDX annotated for their clinical data, gene expression, mutational, and histopathological traits. Six models were injected orthotopically into the cecum wall of NOD-SCID mice in order to evaluate metastasis. Three of them were treated with chemotherapy (oxaliplatin) and three with API2 to target AKT activity. Tumor growth and metastasis progression were analyzed by positron emission tomography (PET). RESULTS: Patient-derived cells generated tumor xenografts that recapitulated the same histopathological and genetic features as the original patients' carcinomas. We show an 87.5% tumor take rate that is one of the highest described for implanted cells derived from colorectal cancer patients. Cecal injection generated primary carcinomas and distant metastases. Oxaliplatin treatment prevented metastasis and API2 reduced tumor growth as evaluated by PET. CONCLUSIONS: Our improved protocol for cancer cell engraftment has allowed us to build a rapidly expanding collection of colorectal PDX, annotated for their clinical data, gene expression, mutational, and histopathological statuses. We have also established a mouse model for metastatic colon cancer with patient derived cells in order to monitor tumor growth, metastasis evolution, and response to treatment by PET. Our PDX models could become the best preclinical approach through which to validate new biomarkers or investigate the metastatic potential and drug-response of individual patients. PMID- 24170544 TI - Modeling RAS phenotype in colorectal cancer uncovers novel molecular traits of RAS dependency and improves prediction of response to targeted agents in patients. AB - PURPOSE: KRAS wild-type status is an imperfect predictor of sensitivity to anti EGF receptor (EGFR) monoclonal antibodies in colorectal cancer, motivating efforts to identify novel molecular aberrations driving RAS. This study aimed to build a quantitative readout of RAS pathway activity to (i) uncover molecular surrogates of RAS activity specific to colorectal cancer, (ii) improve the prediction of cetuximab response in patients, and (iii) suggest new treatment strategies. EXPERIMENTAL DESIGN: A model of RAS pathway activity was trained in a large colorectal cancer dataset and validated in three independent colorectal cancer patient datasets. Novel molecular traits were inferred from The Cancer Genome Atlas colorectal cancer data. The ability of the RAS model to predict resistance to cetuximab was tested in mouse xenografts and three independent patient cohorts. Drug sensitivity correlations between our model and large cell line compendiums were performed. RESULTS: The performance of the RAS model was remarkably robust across three validation datasets. (i) Our model confirmed the heterogeneity of the RAS phenotype in KRAS wild-type patients, and suggests novel molecular traits driving its phenotype (e.g., MED12 loss, FBXW7 mutation, MAP2K4 mutation). (ii) It improved the prediction of response and progression-free survival (HR, 2.0; P < 0.01) to cetuximab compared with KRAS mutation (xenograft and patient cohorts). (iii) Our model consistently predicted sensitivity to MAP ERK kinase (MEK) inhibitors (P < 0.01) in two cell panel screens. CONCLUSIONS: Modeling the RAS phenotype in colorectal cancer allows for the robust interrogation of RAS pathway activity across cell lines, xenografts, and patient cohorts. It demonstrates clinical utility in predicting response to anti-EGFR agents and MEK inhibitors. PMID- 24170546 TI - AXL is a key regulator of inherent and chemotherapy-induced invasion and predicts a poor clinical outcome in early-stage colon cancer. AB - PURPOSE: Despite the use of 5-fluorouracil (5-FU)-based adjuvant treatments, a large proportion of patients with high-risk stage II/III colorectal cancer will relapse. Thus, novel therapeutic strategies are needed for early-stage colorectal cancer. Residual micrometastatic disease from the primary tumor is a major cause of patient relapse. EXPERIMENTAL DESIGN: To model colorectal cancer tumor cell invasion/metastasis, we have generated invasive (KRASMT/KRASWT/+chr3/p53-null) colorectal cancer cell subpopulations. Receptor tyrosine kinase (RTK) screens were used to identify novel proteins that underpin the migratory/invasive phenotype. Migration/invasion was assessed using the XCELLigence system. Tumors from patients with early-stage colorectal cancer (N = 336) were examined for AXL expression. RESULTS: Invasive colorectal cancer cell subpopulations showed a transition from an epithelial-to-mesenchymal like phenotype with significant increases in migration, invasion, colony-forming ability, and an attenuation of EGF receptor (EGFR)/HER2 autocrine signaling. RTK arrays showed significant increases in AXL levels in all invasive sublines. Importantly, 5-FU treatment resulted in significantly increased migration and invasion, and targeting AXL using pharmacologic inhibition or RNA interference (RNAi) approaches suppressed basal and 5-FU-induced migration and invasion. Significantly, high AXL mRNA and protein expression were found to be associated with poor overall survival in early-stage colorectal cancer tissues. CONCLUSIONS: We have identified AXL as a poor prognostic marker and important mediator of cell migration/invasiveness in colorectal cancer. These findings provide support for the further investigation of AXL as a novel prognostic biomarker and therapeutic target in colorectal cancer, in particular in the adjuvant disease in which EGFR/VEGF-targeted therapies have failed. PMID- 24170548 TI - Erlotinib, gefitinib, and vandetanib inhibit human nucleoside transporters and protect cancer cells from gemcitabine cytotoxicity. AB - PURPOSE: Combinations of tyrosine kinase inhibitors (TKI) with gemcitabine have been attempted with little added benefit to patients. We hypothesized that TKIs designed to bind to ATP-binding pockets of growth factor receptors also bind to transporter proteins that recognize nucleosides. EXPERIMENTAL DESIGN: TKI inhibition of uridine transport was studied with recombinant human (h) equilibrative (E) and concentrative (C) nucleoside transporters (hENT, hCNT) produced individually in yeast. TKIs effects on uridine transport, gemcitabine accumulation, regulation of hENT1 activity, and cell viability in the presence or absence of gemcitabine were evaluated in human pancreatic and lung cancer cell lines. RESULTS: Erlotinib, gefitinib and vandetanib inhibited [(3)H]uridine transport in yeast and [(3)H]uridine and [(3)H]gemcitabine uptake in the four cell lines. Treatment of cell lines with erlotinib, gefitinib, or vandetanib for 24 hours reduced hENT1 activity which was reversed by subsequent incubation in drug-free media for 24 hours. Greater cytotoxicity was observed when gemcitabine was administered before erlotinib, gefitinib, or vandetanib than when administered together and synergy, evaluated using the CalcuSyn Software, was observed in three cell lines resulting in combination indices under 0.6 at 50% reduction of cell growth. CONCLUSIONS: Vandetanib inhibited hENT1, hENT2, hCNT1, hCNT2, and hCNT3, whereas erlotinib inhibited hENT1 and hCNT3 and gefitinib inhibited hENT1 and hCNT1. The potential for reduced accumulation of nucleoside chemotherapy drugs in tumor tissues due to inhibition of hENTs and/or hCNTs by TKIs indicates that pharmacokinetic properties of these agents must be considered when scheduling TKIs and nucleoside chemotherapy in combination. PMID- 24170547 TI - Direct inhibition of retinoblastoma phosphorylation by nimbolide causes cell cycle arrest and suppresses glioblastoma growth. AB - PURPOSE: Classical pharmacology allows the use and development of conventional phytomedicine faster and more economically than conventional drugs. This approach should be tested for their efficacy in terms of complementarity and disease control. The purpose of this study was to determine the molecular mechanisms by which nimbolide, a triterpenoid found in the well-known medicinal plant Azadirachta indica, controls glioblastoma growth. EXPERIMENTAL DESIGN: Using in vitro signaling, anchorage-independent growth, kinase assays, and xenograft models, we investigated the mechanisms of its growth inhibition in glioblastoma. RESULTS: We show that nimbolide or an ethanol soluble fraction of A. indica leaves (Azt) that contains nimbolide as the principal cytotoxic agent is highly cytotoxic against glioblastoma multiforme in vitro and in vivo. Azt caused cell cycle arrest, most prominently at the G1-S stage in glioblastoma multiforme cells expressing EGFRvIII, an oncogene present in about 20% to 25% of glioblastoma multiformes. Azt/nimbolide directly inhibited CDK4/CDK6 kinase activity leading to hypophosphorylation of the retinoblastoma protein, cell-cycle arrest at G1-S, and cell death. Independent of retinoblastoma hypophosphorylation, Azt also significantly reduced proliferative and survival advantage of glioblastoma multiforme cells in vitro and in tumor xenografts by downregulating Bcl2 and blocking growth factor-induced phosphorylation of Akt, extracellular signal regulated kinase 1/2, and STAT3. These effects were specific because Azt did not affect mTOR or other cell-cycle regulators. In vivo, Azt completely prevented initiation and inhibited progression of glioblastoma multiforme growth. CONCLUSIONS: Our preclinical findings demonstrate nimbolide as a potent anti glioma agent that blocks cell cycle and inhibits glioma growth in vitro and in vivo. PMID- 24170549 TI - Conjunctival melanomas harbor BRAF and NRAS mutations--response. PMID- 24170550 TI - Radiation exposure during sentinel lymph node biopsy for breast cancer: effect on pregnant female physicians. AB - BACKGROUND: The radionuclide (RN) method employed for sentinel lymph node biopsy is generally safe for adult medical care workers. However, the number of pregnant medical care workers who attend surgery has recently been increasing, along with the increasing number of female surgeons. In particular, female surgeons are concerned about the position of a surgeon's lower abdominal region being close to the RN injection site. We measured the exposure dose of the lower abdominal region in medical care workers and investigated the possible exposure effect on fetuses. METHODS: A dose of (99m)Tc-phytic acid (37 MBq) was subcutaneously injected into the areola of the nipple of patients. Scintigraphy and surgery were performed after 1 and 4 h, respectively. At the time of the local injection, a personal dosimeter measured the exposure dose in the surgeon, first and second assistants, anesthesiologist, and scrub nurse. RESULTS: The median exposure doses were 3, 1, 1, 0, and 0 MUSv in the surgeon, first and second assistants, anesthesiologist, and scrub nurse, respectively. Protective clothing reduced the mean exposure dose by 66 %. CONCLUSIONS: In surgeons, the exposure dose from daily life activities (1 mSv/year) corresponds to the dose received after performing 333 surgeries (using 3 MUSv as the median). However, the maximum value measured was 24 MUSv; at this value, the total exposure dose exceeds 1 mSV in the 42nd surgery. Medical care workers can further reduce their exposure dose by paying attention to the surgical procedure and to their posture and position. PMID- 24170551 TI - Effects of muscle fibre shortening on the characteristics of surface motor unit potentials. AB - Traditionally, studies dealing with muscle shortening have concentrated on assessing its impact on conduction velocity, and to this end, electrodes have been located between the end-plate and tendon regions. Possible morphologic changes in surface motor unit potentials (MUPs) as a result of muscle shortening have not, as yet, been evaluated or characterized. Using a convolutional MUP model, we investigated the effects of muscle shortening on the shape, amplitude, and duration characteristics of MUPs for different electrode positions relative to the fibre-tendon junction and for different depths of the MU in the muscle (MU to-electrode distance). It was found that the effects of muscle shortening on MUP morphology depended not only on whether the electrodes were between the end-plate and the tendon junction or beyond the tendon junction, but also on the specific distance to this junction. When the electrodes lie between the end-plate and tendon junction, it was found that (1) the muscle shortening effect is not important for superficial MUs, (2) the sensitivity of MUP amplitude to muscle shortening increases with MU-to-electrode distance, and (3) the amplitude of the MUP negative phase is not affected by muscle shortening. This study provides a basis for the interpretation of the changes in MUP characteristics in experiments where both physiological and geometrical aspects of the muscle are varied. PMID- 24170552 TI - Towards the development of a novel experimental shoulder simulator with rotating scapula and individually controlled muscle forces simulating the rotator cuff. AB - A preclinical analysis of novel implants used in shoulder surgery requires biomechanical testing conditions close to physiology. Existing shoulder experiments may only partially apply multiple cycles to simulate postoperative, repetitive loading tasks. The aim of the present study was therefore the development of an experimental shoulder simulator with rotating scapula able to perform multiple humeral movement cycles by simulating individual muscles attached to the rotator cuff. A free-hanging, metallic humerus pivoted in a polyethylene glenoid is activated by tension forces of linear electroactuators to simulate muscles of the deltoideus (DELT), supraspinatus (SSP), infraspinatus/teres minor and subscapularis. The abductors DELT and SSP apply forces with a ratio of 3:1 up to an abduction angle of 85 degrees . The rotating scapular part driven by a rotative electro actuator provides one-third to the overall arm abduction. Resulting joint forces and moments are measured by a 6 axis load cell. A linear increase in the DELT and SSP motors is shown up to a maximum of 150 and 50 N for the DELT and SSP, respectively. The force vector in the glenoid resulted in 253 N at the maximum abduction. The present investigation shows the contribution of individual muscle forces attached to the moving humerus to perform active abduction in order to reproducibly test shoulder implants. PMID- 24170553 TI - The effect of head movement on CT perfusion summary maps: simulations with CT hybrid phantom data. AB - Head movement is common during CT brain perfusion (CTP) acquisition of patients with acute ischemic stroke. The effects of this movement on the accuracy of CTP analysis has not been studied previously. The purpose of this study was to quantify the effects of head movement on CTP analysis summary maps using simulated phantom data. A dynamic digital CTP phantom dataset of 25 time frames with a simulated infarct volume was generated. Head movement was simulated by specific translations and rotations of the phantom data. Summary maps from this transformed phantom data were compared to the original data using the volumetric dice similarity coefficient (DSC). DSC for both penumbra and core strongly decreased for rotation angles larger than approximately 1 degrees , 2 degrees , and 7 degrees for, respectively, pitch, roll, and yaw. The accuracy is also sensitive for small translations in the z-direction only. Sudden movements introduced larger errors than gradual movement. These results indicate that CTP summary maps are sensitive to head movement, even for small rotations and translations. CTP scans with head movement larger than the presented values should be interpreted with extra care. PMID- 24170554 TI - Combined use of hydroxypropyl-beta-cyclodextrin and ionic liquids for the simultaneous enantioseparation of four azole antifungals by CE and a study of the synergistic effect. AB - A CE method employing a dual system of hydroxypropyl-beta-cyclodextrin (HP-beta CD) and ionic liquids (ILs) has been developed for the simultaneous enantioseparation of four azole antifungals for the first time. In this study, three different types of ILs were employed as modifiers and among them dodecyl trimethyl ammonium chloride was found to be the most effective. The effects of the concentration, cations, and anions of ILs on the enantioseparation were investigated. With the developed dual system, all the enantiomers were well separated in resolutions of 3.8, 3.5, 2.8, and 2.5 for miconazole, econazole, ketoconazole, and itraconazole, respectively. The interactions between dodecyl trimethyl ammonium chloride and HP-beta-CD were also studied using a neutral polyacrylamide coated capillary and (1) H NMR spectroscopy to further explore the synergistic effect involved. It was found that ILs improved the enantioseparation not only by changing the EOF, but also by interactions with HP-beta-CD that could change its ability of forming inclusion complex with the enantiomers. PMID- 24170555 TI - Activation of EGFR signaling from pilocytic astrocytomas to glioblastomas. AB - INTRODUCTION: EGFR analyses allow for better correlation between genotype and phenotype in astrocytomas and represent an attractive therapeutic target. Most studies emphasize analyses of EGFR in glioblastomas (GBMs) but do not analyze all grades of astrocytomas (from pilocytic to GBM). The purpose of our study was to evaluate the status of EGFR (expression, deletion, and amplification) and EGFR protein expression in all grades of astrocytomas. PATIENTS AND METHODS: We analyzed a total of 145 surgical tumor specimens that included: 22 pilocytic astrocytomas, 22 grade II astrocytomas, 17 grade III astrocytomas and 84 GBMs. The specimens were compared to 17 non-neoplastic brain tissues obtained from epilepsy surgery. EGFR expression, EGFR amplification and EGFRvIII analyses were performed by quantitative real-time PCR, and protein expression was evaluated by immunohistochemistry. RESULTS: EGFR relative overexpression and EGFR amplification were observed, respectively, in 50% and 20% of astrocytomas, while EGFRvIII was only found in GBMs (34.5%, p=0.005). Amongst EGFR-amplified GBM cases, 59% also presented EGFRvIII (p<0.001). Cytoplasmic accumulation of EGFR protein was detected in 75% of astrocytomas, and 21% of the astrocytomas showed nuclear localization (p=0.003). CONCLUSIONS: EGFR alterations were found in all grades of astrocytomas, from pilocytic to GBMs, while EGFRvIII was exclusively found in GBMs. These findings provide important information on the mechanisms involved in the progression of astrocytomas for determining whether EGFR status can be used for effective and specific therapy. PMID- 24170556 TI - Overweight, obesity and endometrial cancer risk: results from a systematic review and meta-analysis. AB - AIM: Findings from recent studies suggest that obesity may be associated with an increased risk of endometrial cancer, but several earlier studies were less conclusive. Here we strive to estimate this relationship in a meta-analysis of published data. METHODS: We searched Pubmed and Embase for studies on body mass index and the risk of endometrial cancer, published from 1989 to 2011. Data were independently extracted and analyzed using random or fixed effects meta-analysis depending on the degree of heterogeneity. RESULTS: Seven cohort studies and 11 case-control studies were included in the meta-analysis. Overall, the conditions of excess body weight ([EBW] defined as body mass index [BMI] >=25 kg/m2), obesity (BMI >=30 kg/m2) and overweight (25< BMI <30 kg/m2) were associated with an increased risk of endometrial cancer (relative risk [RR] for EBW=1.62, 95% confidence interval [CI], 1.39-1.89; for obesity RR=2.54, 95% CI, 2.11-3.06; for overweight RR=1.32, 95% CI, 1.16-1.50). Subgroup analyses showed that the positive associations were independent of study design, geographic locations, self-reported BMI, alcohol use, smoking habit, history of diabetes, hormone therapy, age at menarche, age at menopause, parity, and age at first full term pregnancy. However, there was no statistically significant association between EBW and endometrial cancer risk for measured BMI (for EBW RR=1.29, 95% CI, 0.66 2.53). CONCLUSIONS: The findings from this meta-analysis strongly support that the conditions of EBW, overweight, and obesity are all associated with an increased risk of endometrial cancer. Also, the strength of the association increases with increasing BMI. PMID- 24170557 TI - HPV-16 E2 physical status and molecular evolution in vivo in cervical carcinomas. AB - A key event in the development of cervical carcinoma is the deregulated expression of high-risk human papillomavirus (HR-HPV) oncogenes, most commonly due to HPV integration into host DNA. Here we explored whether HPV-16 E2 gene integrity is a biomarker of progressive disease with oncogenes expression. HPV-16 genome disruption was assessed by amplification of the entire E2 gene, while mRNA expression patterns of the E1, E2, E6, and E7 genes were evaluated by reverse transcription PCR (RT-PCR). As expected, E2 disruption was significantly higher among patients with cervical cancers than subjects with benign lesions (p=0.02). The status of the E2 gene correlated with tumorogenesis, and seemed also to correlate with the stage of the carcinomas, since integrated HPV-16 DNA was frequently detected in patients with advanced cancer stages (75% of stage III vs 60% stages I and II). In bivariate analysis, the lesions’ grade was most significantly associated with HPV-16 DNA disruption (p<0.05). In cervical carcinoma the deletion pattern involved more frequently the E2 gene rather than the E1 gene (62.5% vs 45.8%). The prevalence of the E6/E7 HPV-16 transcripts in cervical carcinoma specimens and in benign cervical lesions were detected with frequencies of, respectively, 91.6% and 45.4%. The mRNA levels of the HPV-16 E6/E7 genes were expressed at approximately the same levels in each physical state. We consistently observed that E6/E7 were absent or weakly detectable in the presence of E2. However, in the absence of E2 the levels of E6/E7 markedly increased (p<0.05). This study underscores the significance of investigating alternative mechanisms of E2 expression and oncogenes E6/E7 transcripts in vivo as biomarkers for disease severity in cervical carcinomas. PMID- 24170558 TI - Disturbed tumor necrosis factor system is linked with lower eGFR and chronic inflammation in hypertension. AB - BACKGROUND: The relationship between tumor necrosis factor (TNF)-related parameters and cardiorenal metabolic factors is still controversial in clinical hypertension. METHODS: Normotensive men (NT, n=60) and treated stage 2 and 3 essential hypertensive men (HT, n=89) were enrolled in this study. The relationship between TNF-related parameters and cardiorenal metabolic factors was examined in NT and HT, separately. RESULTS: HT showed higher rates of insulin resistance and enhanced chronic inflammation compared with NT. The levels of soluble TNF receptor 1 and 2 were significantly higher in HT than in NT, although TNF-alpha levels were unexpectedly lower in HT than in NT. Regression analysis indicated that the TNF-related parameters were closely linked with mild renal dysfunction both in NT and HT, and moderately related to chronic inflammation only in HT. HT taking inhibitors of the renin-angiotensin system showed improved insulin resistance, but no difference in the TNF-related parameters. CONCLUSION: These results suggest that the disturbed TNF system is closely linked with chronic inflammation rather than with insulin resistance in HT. PMID- 24170559 TI - Efficacy study of multimedia rheumatoid arthritis patient education program. AB - PURPOSE: The research goal of improving patient adherence was assessed in this randomized controlled trial of the outcomes of a 15-min multimedia educational program when compared to educational literature for rheumatoid arthritis (RA) patients. DATA SOURCES: One hundred eight RA patients from a Midwestern rheumatology outpatient clinic completed the self-reported Medication Adherence Questionnaire (MAQ), the Brief Illness Perception Questionnaire (BIPQ), and Health Assessment Questionnaire (HAQ) at baseline and 1 month after education. A paired samples t-test was use for data analyses to determine if there was a significant difference in the change between the groups at preintervention and 1 month postintervention. CONCLUSIONS: There were no significant differences in the scores between the two groups from pretest to posttest. Results from this study showed that medication adherence, illness perception, and disability were not improved by use of multimedia or the literature within 1 month. IMPLICATIONS FOR PRACTICE: Findings from this research study showed that a short multimedia educational program is as effective as printed materials to educate patients with RA about their disease and treatment. However, neither multimedia nor literature affects medication adherence, illness perception, or disability as self-reported by patients with RA. PMID- 24170560 TI - Regulation of phospholipase C-beta(1) GTPase-activating protein (GAP) function and relationship to G(q) efficacy. AB - How cells regulate Gq efficacy (initiation and termination of Gq signaling) to effect response remains a central question in pharmacology and drug discovery. Phospholipase C-beta1 (PLC-beta1) is an effector and a GTPase activating protein (GAP) specific to Galphaq. The physiological function of PLC-beta1 GAP remains unclear and controversial. GAPs are generally thought to function in deactivation of Gq signaling. However, PLC-beta1 GAP has also been shown to increase signaling efficiency through kinetic coupling with the ligand-activated GPCR. GPCRs function as guanine nucleotide exchange factors (GEF) on the G protein activation cycle. This article sets forth a new hypothesis that could unify these conflicting paradigms as it pertains to physiological signaling and native levels of protein. It is proposed that the physiological function of PLC-beta1 GAP is context-dependent and regulated by phosphatidic acid (PA). PA stimulates PLC beta1 GAP activity. In the absence of ligand, PLC-beta1 GAP does indeed deactivate Gq signaling, limiting leaky activation to set the threshold for stimulation to sharpen signal kinetics. However in the presence of activating ligand, the increase in levels of PA would stimulate PLC-beta1 GAP to kinetically couple with GPCR GEF to increase signaling efficiency. We found that PA-increased Gq efficiency is dependent on signaling via the unique PLC-beta1 PA binding domain. PMID- 24170561 TI - What you need to know about IgA deficiency: a case study. AB - PURPOSE: To provide nurse practitioners (NPs) with an overview of the physiology, pathophysiology, associated diseases clinical implications for blood transfusions for patients with immunoglobulin A deficiency (IgAD). DATA SOURCES: A review of the scientific literature was performed on IgAD using PubMed, Medline, and CINAHL. The case study of a patient with IgAD going for cardiac surgery is used to integrate this knowledge into clinical practice. CONCLUSIONS: IgAD is being identified in asymptomatic people through screening for numerous conditions. NPs receiving results on their patients may not fully comprehend the significance of IgAD. IMPLICATIONS FOR PRACTICE: Knowledge of the underlying physiology and pathophysiology of IgAD enables the NP to obtain an accurate and comprehensive patient assessment, establish differential diagnoses, and manage issues related to potential associated conditions as well as potential blood transfusion risks. PMID- 24170562 TI - Self-monitoring of blood glucose experiences of adults with type 2 diabetes. AB - PURPOSE: The purpose of this study was to analyze the experiences of self monitoring of blood glucose (SMBG) usage of adults with type 2 diabetes mellitus (T2DM) who are not using insulin. DATA SOURCES: Nineteen adults were asked to describe their experiences with self-monitoring. Data were analyzed using the grounded theory method. CONCLUSIONS: The theory of "SMBG as a Cue in T2DM Self Care" emerged from the data and is composed of four categories: (a) Engaging, (b) Checking, (c) Responding, and (d) Establishing a Pattern. Engaging marks the beginning. Frequent monitoring characterizes this stage. Checking involves evaluating and validating the blood glucose level. The most common item evaluated or validated was the effect of foods. Responding involves taking action or experiencing emotion. Actions taken centered on dietary changes. Emotions felt were dependent on the level and ranged from blame to happiness. Participants established a pattern and used SMBG regularly or sporadically. Frequency was based on obtaining "normal" patterns, the absence of symptoms, provider disinterest, and fingertip pain. IMPLICATIONS FOR PRACTICE: Participants described many benefits and struggles when incorporating SMBG into their self care. Information from this study could be used to develop effective guidelines for the use of SMBG in T2DM. PMID- 24170563 TI - In-line SPE-CE using a fritless bead string design--application for the analysis of organic sulfonates including inline SPE-CE-MS for APTS-labeled glycans. AB - Despite many advantages like high separation efficiency CE comprises the main limitation of low concentration sensitivity, when compared to HPLC. In-line SPE is an efficient way to increase concentration sensitivity. Here, a fritless in line-SPE-CE-MS method was developed in order to analyze anions of strong acids. Mixed-mode (weak anion exchange and RP) particles were used for enrichment and an acidic BGE was applied for separation. Different particle and capillary sizes were tested. A novel bead string design with a 100 MUm id column filled with particles of 90 MUm followed by a separation capillary with 50 MUm id was easy to prepare and showed the best performance with respect to separation efficiency and reproducibility. Three aromatic sulfonic acids were employed in an in-line SPE-CE UV approach for method development. Method validation was performed with respect to reproducibility, robustness, and linearity. Thereafter the method was transferred to SPE-CE-MS and applied to the analysis of glycans labeled with 8 aminopyrene-1,3,6-trisulfonic acid. Lower limits of detection in the low nM range were achieved injecting about 10 MUL of sample. This corresponds to an enrichment factor of more than 800 compared to the corresponding CE-MS method without preconcentration. PMID- 24170565 TI - Using preappraised evidence sources to guide practice decisions. AB - PURPOSE: The purpose of this article is two-fold. The first is to describe preappraised evidence sources or a top-down approach to obtaining the best available evidence. The second purpose of the article is to describe how to incorporate preappraised evidence into clinical decision making with the Best Practice Decision Guide. DATA SOURCES: The Best Practice Decision Guide begins with a query of preappraised and filtered electronic sources to obtain recommended evidence summaries, or a so-called "top-down" approach to obtaining the best available evidence. CONCLUSIONS: Information on the major issues and dilemmas encountered at each step is presented, including evaluation of clinical practice guidelines and the consideration of relevant studies to particular patients or subpopulations. IMPLICATIONS FOR PRACTICE: Recommendations for other resources to use in the appraisal process and in making final practice decision are also described in the article. PMID- 24170564 TI - Contraception and the obese woman. AB - PURPOSE: Obesity has reached epidemic rates among U.S. women of reproductive age, many of whom want to use contraception. However, some forms of contraception can have adverse effects on an obese woman's health. This article explores risks of contraception available in the United States and provides clinical recommendations for use by obese women. DATA SOURCES: Information was compiled by reviewing the scientific literature on contraception and female obesity using CINAHL, MEDLINE, PubMed search engines. CONCLUSIONS: The evidence is largely supportive of combined oral contraceptive (COC) use in carefully screened obese women without known risks factors for cardiovascular disease. The efficacy of COCs may be slightly reduced in obese women because of increased body mass. Other types of hormonal contraceptives have varying safety and efficacy reports when used by obese women. Intrauterine devices do not have reduced efficacy nor increased risks for obese women but insertion may be more difficult. Obesity has no effect on efficacy of barrier methods of contraception. IMPLICATIONS: Clinicians should conduct a careful history and physical exam with selected supporting laboratory tests when considering prescription of hormonal contraceptives for obese women. Obese women require health counseling to carefully follow directions for contraceptive use to avoid unintended pregnancy. PMID- 24170566 TI - Oral sucrose for pain control in nonneonate infants during minor painful procedures. AB - PURPOSE: To provide information regarding the effective use of oral sucrose as an analgesic for immunization and venipuncture procedures in the older infant. DATA SOURCES: Evidence-based literature including original clinical trials, reviews, and clinical practice guidelines. CONCLUSIONS: Most infants are exposed to multiple minor painful procedures during the first year of life. Oral sucrose solution in a 24% concentration at a dose of 2 mL approximately 2 min prior to the painful procedure has been shown effective in reducing pain during immunizations and venipuncture in the outpatient setting in infants aged 1-12 months old. IMPLICATIONS FOR PRACTICE: Oral sucrose solution should be used as a pain reduction intervention in infants up to 12 months of age undergoing minor painful procedures. Its proven effectiveness as an analgesic, low rate of minor adverse events, ease of administration, and excellent availability make sucrose a good choice for this purpose. Additional research is needed regarding dose response in different infant age groups, optimal concentration of sucrose solution, need for multiple sucrose dosing, adjustment for multiple painful procedures, and addition of optimal nonpharmacologic interventions as a combination approach. PMID- 24170567 TI - Mothers going to war: the role of nurse practitioners in the care of military mothers and families during deployment. AB - PURPOSE: Many military women are being called to separate from their children to go to war. Most previous research has focused upon paternal, rather than, maternal, separation. The purpose of this article is to describe the experience of military mothers and their children during wartime deployments with clinical implications for nurse practitioners (NPs) in military or community settings. DATA SOURCES: Using grounded theory methods, 37 active duty and reserve component military women participated in a one-time interview. Included were women who deployed for at least 4 months to Iraq or Afghanistan and had at least one child under the age of 12 during the separation. CONCLUSIONS: Military families present unique challenges for NPs. Mother deployments offer opportunities for intervention and anticipatory guidance across the trajectory of the separation. Military women's emotional and physical health must be supported before, during, and following deployment. IMPLICATIONS FOR PRACTICE: NPs are ideally positioned to support military families. During deployment, the NP's focus may shift to care of the children and their caregiver. Before and at reintegration, NPs are in a key position to intervene early for posttraumatic stress and support family readjustment. PMID- 24170568 TI - Improving diabetic foot care in a nurse-managed safety-net clinic. AB - PURPOSE: This article is a description of the development and implementation of a Comprehensive Diabetic Foot Care Program and assessment tool in an academically affiliated nurse-managed, multidisciplinary, safety-net clinic. The assessment tool parallels parameters identified in the Task Force Foot Care Interest Group of the American Diabetes Association's report published in 2008, "Comprehensive Foot Examination and Risk Assessment." DATA SOURCES: Review of literature, Silver City Health Center's (SCHC) 2009 Annual Report, retrospective chart review. CONCLUSIONS: Since the full implementation of SCHC's Comprehensive Diabetic Foot Care Program, there have been no hospitalizations of clinic patients for foot related complications. IMPLICATIONS FOR PRACTICE: The development of the Comprehensive Diabetic Foot Assessment tool and the implementation of the Comprehensive Diabetic Foot Care Program have resulted in positive outcomes for the patients in a nurse-managed safety-net clinic. This article demonstrates that quality healthcare services can successfully be developed and implemented in a safety-net clinic setting. PMID- 24170569 TI - What is the best measure of daytime sleepiness in adults with heart failure? AB - PURPOSE: To identify the best screening measure of daytime sleepiness in adults with heart failure (HF). DATA SOURCES: A total of 280 adults with HF completed the Epworth Sleepiness Scale, the Stanford Sleepiness Scale, and a single Likert item measuring daytime sleepiness. The sensitivity and specificity of these self report measures were assessed in relation to a measure of daytime dysfunction from poor sleep quality. CONCLUSIONS: Only 16% of the sample reported significant daytime dysfunction because of poor sleep quality. Those reporting daytime dysfunction were likely to be younger (p < .001), to be unmarried (p = .002), to have New York Heart Association (NYHA) functional class IV HF (p = .015), and to report low income (p = .006) and fewer hours of sleep (p = .015). The measure of daytime sleepiness that was most sensitive to daytime dysfunction was a single Likert item measured on a 10-point (1-10) scale. Patients with a score >=4 were 2.4 times more likely to have daytime dysfunction than those with a score <4. IMPLICATIONS FOR PRACTICE: Complaints of daytime dysfunction because of poor sleep are not common in adults with HF. Routine use of a single question about daytime sleepiness can help nurse practitioners to identify those HF patients with significant sleep issues that may require further screening. PMID- 24170570 TI - Sequence analysis of diamine oxidase gene from fava bean and its expression related to gamma-aminobutyric acid accumulation in seeds germinating under hypoxia-NaCl stress. AB - BACKGROUND: gamma-Aminobutyric acid (GABA) is synthesized via the polyamine degradation pathway in plants, with diamine oxidase (DAO) being the key enzyme. In this study the cDNA of DAO in fava bean was cloned and its expression in seeds germinating under hypoxia-NaCl stress was investigated. RESULTS: Fava bean DAO cDNA is 2199 bp long and contains 2025 bp of open reading frame that encodes 675 amino acid peptides with a calculated molecular weight of 76.31 kDa and a pI of 5.41. Hypoxia and hypoxia-NaCl stress enhanced DAO activity and resulted in GABA accumulation in germinating fava bean. However, DAO gene expression was down regulated under hypoxia compared with non-stress condition, while its expression in the cotyledon and shoot was up-regulated under hypoxia-NaCl. In addition, DAO expression could be promoted to enhance GABA accumulation after increasing the stress intensity using NaCl. DAO gene expression was significantly inhibited by aminoguanidine treatment under hypoxia but increased under hypoxia-NaCl. CONCLUSION: Under hypoxia, GABA accumulation due to NaCl was mainly concentrated in the cotyledon. The GABA content increase under hypoxia did not result from DAO gene expression, but DAO existing in seeds was activated under hypoxia. DAO gene expression was up-regulated to enhance GABA accumulation after increasing the stress intensity. PMID- 24170571 TI - Ultra-fast LC-ESI-MS/MS method for the simultaneous determination of six highly toxic Aconitum alkaloids from Aconiti kusnezoffii radix in rat plasma and its application to a pharmacokinetic study. AB - A fast, sensitive, and efficient ultra-fast LC-ESI-MS/MS method was developed for the simultaneous quantitation of six highly toxic Aconitum alkaloids, that is, aconitine, mesaconitine, hypaconitine, benzoylaconine, benzoylmesaconine, and benzoylhypaconine, in rat plasma after oral administration of crude ethanol extracts from Aconiti kusnezoffii radix by ultrasonic extraction, reflux extraction for 1 h, and reflux extraction for 3 h, respectively. The separation of six Aconitum alkaloids and aminopyrine (internal standard) was performed on an InertSustain(r) C18 column, and the quantification of the analytes was performed on a 4000Q ultra-fast LC-MS/MS system with turbo ion spray source in the positive ion and multiple-reaction monitoring mode. Absolute recoveries ranged within 65.06-85.1% for plasma samples. The intra- and interday precision and accuracy of analytes were satisfactory. The methods were validated with sensitivity reaching the lower LOQ for aconitine, mesaconitine, hypaconitine, benzoylaconine, benzoylmesaconine, and benzoylhypaconine, which were 0.025, 0.025, 0.050, 0.025, 0.025, and 0.100 ng/mL, respectively. The method was successfully applied to a pharmacokinetic study of six Aconitum alkaloids in rat plasma after oral administration of crude ethanol extracts from the raw root of Aconitum kusnezoffii Reichb. by three different extraction processes. PMID- 24170572 TI - Lower limb antagonist muscle co-activation and its relationship with gait parameters in cerebellar ataxia. AB - Increased antagonist muscle co-activation, seen in motor-impaired individuals, is an attempt by the neuromuscular system to provide mechanical stability by stiffening joints. The aim of this study was to investigate the co-activation pattern of the antagonist muscles of the ankle and knee joints during walking in patients with cerebellar ataxia, a neurological disease that strongly affects stability. Kinematic and electromyographic parameters of gait were recorded in 17 patients and 17 controls. Ankle and knee antagonist muscle co-activation indexes were measured throughout the gait cycle and during the sub-phases of gait. The indexes of ataxic patients were compared with those of controls and correlated with clinical and gait variables. Patients showed increased co-activity indexes of both ankle and knee muscles during the gait cycle as well as during the gait sub-phases. Both knee and ankle muscle co-activation indexes were positively correlated with disease severity, while ankle muscle co-activation was also positively correlated with stance and swing duration variability. Significant negative correlations were observed between the number of self-reported falls per year and knee muscle co-activation. The increased co-activation observed in these cerebellar ataxia patients may represent a compensatory strategy serving to reduce gait instability. Indeed, this mechanism allows patients to reduce the occurrence of falls. The need for this strategy, which results in excessive muscle co-contraction, increased metabolic costs and cartilage degeneration processes, could conceivably be overcome through the use of supportive braces specially designed to provide greater joint stability. PMID- 24170573 TI - Expression and characterization of recombinant human phospholipid hydroperoxide glutathione peroxidase. AB - Phospholipid hydroperoxide glutathione peroxidase (PHGPx or GPx4; EC1.11.1.12) is a selenoperoxidase that can directly reduce phospholipid and cholesterol hydroperoxides. The mature cytoplasmic GPx4 is a monomeric protein with molecular weight of 19.5 kDa. In this study, human GPx4 (hGPx4) gene was amplified from the complementary DNA library of human hepatoma cell line. Eukaryotic expression plasmid pSelExpress1-leader-GPx4 was constructed and transfected into the eukaryotic cells HEK293T. Expression of hGPx4 was detected by Western blotting, and the target protein was purified by immobilized metal affinity chromatography. The results of the activity and kinetics of the purified protein show that the obtained protein follows a "ping-pong" mechanism, which is similar to that of native cytosolic glutathione peroxidase (GPx1; EC1.11.1.9). This is the first time that hGPx4 could be expressed and purified from HEK293T cells, and this work will provide an important resource of hGPx4 for its functional study in vitro and in vivo. PMID- 24170574 TI - Stent graft visualization and planning tool for endovascular surgery using finite element analysis. AB - PURPOSE: A new approach to optimize stent graft selection for endovascular aortic repair is the use of finite element analysis. Once the finite element model is created and solved, a software module is needed to view the simulation results in the clinical work environment. A new tool for interpretation of simulation results, named Medical Postprocessor, that enables comparison of different stent graft configurations and products was designed, implemented and tested. METHODS: Aortic endovascular stent graft ring forces and sealing states in the vessel landing zone of three different configurations were provided in a surgical planning software using the Medical Imaging Interaction Tool Kit (MITK) software system. For data interpretation, software modules for 2D and 3D presentations were implemented. Ten surgeons evaluated the software features of the Medical Postprocessor. These surgeons performed usability tests and answered questionnaires based on their experience with the system. RESULTS: The Medical Postprocessor visualization system enabled vascular surgeons to determine the configuration with the highest overall fixation force in 16+/-6 s, best proximal sealing in 56+/-24s and highest proximal fixation force in 38+/- s. The majority considered the multiformat data provided helpful and found the Medical Postprocessor to be an efficient decision support system for stent graft selection. The evaluation of the user interface results in an ISONORM-conform user interface (113.5 points). CONCLUSION: The Medical Postprocessor visualization software tool for analyzing stent graft properties was evaluated by vascular surgeons. The results show that the software can assist the interpretation of simulation results to optimize stent graft configuration and sizing. PMID- 24170575 TI - Focusing on feedback: how nurse practitioners can use focus group interviews to build a patient-centered practice. AB - PURPOSE: The success or failure of clinical interventions often rests upon the degree of insight nurse practitioners (NPs) have into their patients' preferences for receiving their care. Therefore, NPs have a vested interest in understanding the perspective of their patients, which can be derived by conducting practice specific focus groups. This article offers NPs practice guidelines for conducting focus groups to improve practice and quality and making practice-related decisions. DATA SOURCES: An extensive review of the scholarly databases and scientific literature. CONCLUSIONS: Focus groups can generate valuable data for NPs in clinical practice settings. Currently, focus groups are rarely used for this purpose; however, data gathered from the population served could be invaluable for improving practice, quality, and decisions made regarding the types of services that NPs provide for their patients. IMPLICATIONS FOR PRACTICE: The benefits of an NP clinician conducting focus groups are that they provide a forum for listening to the people they serve and learning from them. The knowledge gained from patients allows the NP to tailor their interventions and care to meet the patient's needs, and may be required to make the practice thrive. PMID- 24170576 TI - Exploration of the concept of collaboration within the context of nurse practitioner-physician collaborative practice. AB - PURPOSE: Collaboration in the healthcare setting is a multifaceted process that calls for deliberate knowledge sharing and mutual accountability for patient care. The purpose of this analysis is to offer an increased understanding of the concept of collaboration within the context of nurse practitioner (NP)-physician (MD) collaborative practice. DATA SOURCES: The evolutionary method of concept analysis was utilized to explore the concept of collaboration. The process of literature retrieval and data collection was discussed. The search of several nursing and medicine databases resulted in 31 articles, including 17 qualitative and quantitative studies, which met criteria for inclusion in the concept analysis. CONCLUSIONS: Collaboration is a complex, sophisticated process that requires commitment of all parties involved. The data analysis identified the surrogate and related terms, antecedents, attributes, and consequences of collaboration within the selected context, which were recognized by major themes presented in the literature and these were discussed. An operational definition was proposed. IMPLICATIONS FOR PRACTICE: Increasing collaborative efforts among NPs and MDs may reduce hospital length of stays and healthcare costs, while enhancing professional relationships. Further research is needed to evaluate collaboration and collaborative efforts within the context of NP-MD collaborative practice. PMID- 24170578 TI - State of nutrition support teams. AB - The incidence of malnutrition in hospitalized patients is relatively high (up to 55%) despite breakthroughs in nutrition support therapies. These patients have increased morbidity and mortality, extended hospital stays, and care that is associated with higher costs. These patients are often poorly managed due to inadequate nutrition assessment and poor medical knowledge and practice in the field of nutrition. Nutrition support teams (NSTs) are interdisciplinary support teams with specialty training in nutrition that are often comprised of physicians, dietitians, nurses, and pharmacists. Their role includes nutrition assessment, determination of nutrition needs, recommendations for appropriate nutrition therapy, and management of nutrition support therapy. Studies have demonstrated significant improvements in patient nutrition status and improved clinical outcomes as well as reductions in costs when patients were appropriately managed by a multispecialty NST vs individual caregivers. Despite this, there has been steady decline in the number of formal NST in recent years (65% of hospitals in 1995 to 42% in 2008) as hospitals and other healthcare organizations look for ways to cut costs. Given the importance of nutrition status on clinical outcomes and overall healthcare costs, a number of institutions have introduced and sustained strong nutrition training and support programs and teams, demonstrating both clinical and economic benefit. The benefits of NST, training and implementation strategies, and tips for justifying these clinically and economically beneficial groups to healthcare organizations and governing bodies are discussed in this review. PMID- 24170579 TI - Malnutrition in cystic fibrosis: a review. AB - Malnutrition is one of the main burdens of disease in cystic fibrosis (CF) along with lung disease. Data from the most recent Cystic Fibrosis Foundation registry report show the prevalence of malnutrition is decreasing in the CF population primarily from interventions focusing on preventing malnutrition. Despite success of interventions and decreased prevalence of malnutrition in this population, prevention of malnutrition in CF patients remains a dilemma that must be managed throughout the life cycle. The pathogenesis of malnutrition in CF can be further categorized into 3 main areas: increased energy losses, increased energy needs, and inadequate calorie intake. The purpose of this review is to further explore the causes of malnutrition and explain current research to prevent malnutrition in the CF population. PMID- 24170580 TI - Growth failure in children: a symptom or a disease? AB - One of the most important aspects of a well-child examination is an assessment of a child's growth. Children who are failing to grow are often labeled "failure to thrive." However, close examination of the pattern of growth on standardized growth charts often allows the caregiver to characterize the growth failure as failure to grow, failure to gain weight, or failure to grow and gain weight. Such refinement of the pattern of growth failure allows for a more specific differential diagnosis and helps to focus laboratory and radiographic evaluation. PMID- 24170581 TI - Energy expenditure in acute posttraumatic amputation: comparison of four methods for assessment. AB - BACKGROUND: Adequate energy intake is a component of successful recovery after injury, yet little is known about the energy requirements in the acute period following traumatic amputation. The purpose of this study was to compare the clinical applicability of resting energy expenditure (REE) measured by a handheld calorimeter and estimated by 3 different predictive equations to that measured by the gold standard, indirect calorimetry using a metabolic cart, during the acute postamputation period of inpatient hospitalization. MATERIALS AND METHODS: Indirect calorimetry measured using both a metabolic cart and handheld calorimeter and predicted by 3 equations were used to assess energy needs of eligible subjects admitted to Brooke Army Medical Center with traumatic amputation(s). REE measured by the handheld calorimeter and estimated using 3 predictive equations (Mifflin St. Jeor, Ireton-Jones 1992, and the American College of Chest Physicians [ACCP]) were compared to the gold standard metabolic cart. Each measure was assessed for significant differences and level of clinical acceptability defined as +/- 10% REE by metabolic cart. RESULTS: Thirteen male service members with traumatic amputation(s) were included. The majority of subject's measurements using the handheld calorimeter (n = 9, 69%) and 3 predictive equations (Mifflin St. Jeor [n = 7, 54%], Ireton-Jones 1992 [n = 8, 62%], ACCP [n = 7, 54%]) fell outside of the +/- 10% range of clinical acceptability. CONCLUSION: Use of the metabolic cart for measuring energy needs remains optimal in this population. PMID- 24170582 TI - Satisfactory reliability among nursing students using the instrument PVC ASSESS to evaluate management of peripheral venous catheters. AB - PURPOSE: Nursing students should be given opportunities to participate in clinical audits during their education. However, audit tools are seldom tested for reliability among nursing students. The aim of this study was to present reliability among nursing students using the instrument PVC assess to assess management of peripheral venous catheters (PVCs) and PVC-related signs of thrombophlebitis. METHODS: PVC assess was used to assess 67 inserted PVCs in 60 patients at ten wards at a university hospital. One group of nursing students (n=4) assessed PVCs at the bedside (inter-rater reliability) and photographs of these PVCs were taken. Another group of students (n=3) assessed the PVCs in the photographs after 4 weeks (test-retest reliability). To determine reliability, proportion of agreement [P(A)] and Cohen's kappa coefficient (kappa) were calculated. RESULTS: For bedside assessment of PVCs, P(A) ranged from good to excellent (0.80-1.0) in 55% of the 26 PVC assess items that were tested. P(A) was poor (<0.70) for two items: "adherence of inner dressing to the skin" and "PVC location." In 81% of the items, kappa was between moderate and almost perfect: moderate (n=5), substantial (n=3), almost perfect (n=5). For edema at insertion site and two items on PVC dressing, kappa was fair (0.21-0.40). Regarding test retest reliability, P(A) varied between good and excellent (0.81-1) in 85%-95% of the items, and the kappa ranged between moderate and almost perfect (0.41-1) in 90%-95%. CONCLUSIONS: PVC assess demonstrated satisfactory reliability among nursing students. However, students need training in how to use the instrument before assessing PVCs. PMID- 24170583 TI - Systemic effects of a high-flow arteriovenous fistula for hemodialysis. AB - PURPOSE: Absolute treatment criteria for reducing the access volume of a high flow access (HFA, access flow>2 L/min) are absent. Previous studies suggested that a HFA may influence the systemic circulation including blood pressure (BP) and heart rate (HR). The aim of this study was to determine these parameters after access clamping in hemodialysis patients undergoing flow-reducing access surgery. METHODS: Systolic BP (SBP), diastolic BP (DBP) and HR in HFA patients undergoing flow-reducing surgery were measured intraoperatively before and after access clamping. Data were compared to values obtained in patients receiving surgery for severe hand ischemia due to an access (HAIDI, hemodialysis access induced distal ischemia). RESULTS: In 8 years, 34 patients underwent surgery for HFA (n=23) or HAIDI (n=11). Preoperative access flows in HFA were larger compared to HAIDI (3,026+/-147 vs 1,078+/-139 mL/min, respectively, p<0.001). Temporary clamping (15 sec) caused a 12+/-2 mm Hg increase in SBP (111+/-6 to 123+/-6 mm Hg, p<0.05) and a 6+/-1 mm Hg rise in DBP (57+/-4 to 63+/-5 mm Hg, p<0.05) in HFA patients. In contrast, SBP and DBP increases were not significant in HAIDI patients (+6+/-3 and +2+/-2 mm Hg, respectively, p=0.37). HR was modestly reduced in both groups following access clamping (-3+/-1 beats/min). The relationship between access flow volume and alterations in SBP best fitted a quadratic regression model, suggesting cardiovascular exhaustion with progressively higher access flows>2-2.5 L/min. CONCLUSIONS: HFA may influence systemic hemodynamics in some hemodialysis patients. The findings of this study may contribute to a tailored management of a high-flow fistula in this population. PMID- 24170584 TI - Arteriovenous fistula salvage utilizing a hybrid vascular graft. AB - INTRODUCTION: Loss of arteriovenous fistula as access for hemodialysis leads to significant morbidity and increased mortality risk. METHODS: Maintenance of this access is of paramount importance and we describe a case of a patient with a functioning radiocephalic fistula with associated arm swelling due to poor narrow caliber venous drainage above the elbow but with normal central veins. RESULTS: A hybrid vascular graft was anastomosed to the upper extent of the fistula and the nitonol stent section introduced into the patent axillary vein. CONCLUSION: The described method led to resolution of symptoms and arm swelling. The described method allowed the continued use of a mature fistula. PMID- 24170585 TI - Superior in vivo compatibility of hydrophilic polymer coated prosthetic vascular grafts. AB - PURPOSE: Protein adsorption, cell adhesion and graft patency was compared in hydrophilic versus hydrophobic polymer-coated prosthetic vascular grafts. We hypothesize that in vivo compatibility of hydrophilic polymer-coated prosthetic vascular grafts is superior to in vivo compatibility of hydrophobic grafts. METHODS: A pairwise side-to-side common carotid artery interposition graft was placed eight female landrace goats (mean weight 55 kg). Protein adsorption was assessed using Western Blot in two hydrophilic and two hydrophobic grafts harvested after three days. Graft patency was monitored for 28 days in six goats with continuous wave Doppler ultrasonography. Adherence of endothelial cells, leukocytes and platelets was determined with ELISA and compared between the two graft types after 28 days. RESULTS: After three days, more ApoA-I, albumin and VEGF and less fibrin adsorbed to hydrophilic grafts. After 28 days, compared to hydrophobic grafts, higher numbers of endothelial cells were present on hydrophilic grafts (P=0.016), and less thrombocytes and leukocytes (P=0.012 and 0.024, respectively). Two out of eight hydrophobic grafts lost patency, while none of the hydrophilic grafts failed (P=0.157). CONCLUSIONS: Hydrophilic polymer coated vascular grafts have superior in vivo compatibility when compared to hydrophobic grafts as characterized by reduced platelet and leukocyte adherence as well as higher endothelialization. PMID- 24170586 TI - Type of vascular access and location in online hemodiafiltration and its association with patient's perception of health-related quality of life. AB - PURPOSE: The aim of this work is to evaluate the patient-reported health-related quality of life (HRQOL), according to the type and location of vascular access used for dialysis procedure. METHODS: In this transversal study, 322 end-stage renal disease (ESRD) patients under online hemodiafiltration (OL-HDF, 59.63% males; 64.9+/-14.3 years) were enrolled. Arteriovenous fistula (AVF) was used by 252 patients (78.3%), whereas 70 patients (21.7%) had a central venous catheter (CVC). Besides AVF location, data on comorbidities, hematological data, iron status, dialysis adequacy, nutritional and inflammatory markers were collected. Moreover, the patients' reported HRQOL score, using the Kidney Disease Quality of Life-Short Form, was evaluated. RESULTS: ESRD patients using CVC as vascular access presented a decrease in four SF-36 domain scores, namely physical functioning, emotional well-being, role-emotional and energy/fatigue when compared with those using AVF as vascular access. Additionally, these patients also showed significant differences in ESRD target areas, namely decline in cognitive function and quality of social interaction domains. When comparing the variables according to the localization of the AVF, significant differences were found in three SF-36 domain scores, namely physical functioning, pain and general health. Moreover, we also found significant differences in ESRD target areas, namely symptoms/problem list, effects of kidney disease and quality of social interaction domains. CONCLUSIONS: Our results showed that ESRD patients under OL HDF using AVF as vascular access had higher HRQOL scores in several domains when compared with those using CVC. Additionally, we also found that dialysis patients using AVF in the left forearm presented with higher HRQOL scores. PMID- 24170587 TI - Conductive conjugated polyelectrolyte as hole-transporting layer for organic bulk heterojunction solar cells. AB - Poly(3,4-ethylenedioxythiophene):poly(styrenesulfonate) (PEDOT:PSS) has been extensively used as the hole-transporting layer (HTL) in bulk heterojunction (BHJ) solar cells, however, its anisotropic electrical conduction and intrinsic acidic nature generally limit the device performance. Here we demonstrate the application of a water/alcohol soluble CPE (CPE-K) as HTLs in BHJ solar cells, achieving a PCE up to 8.2%. The more superior and uniform vertical electrical conductivity found in CPE-K reduces the series resistance and provides efficient hole extraction. PMID- 24170588 TI - Recent therapeutic advances in gastroenterology and hepatology. PMID- 24170589 TI - An overview of corneal collagen cross-linking (CXL). AB - Corneal collagen cross-linking (CXL) was first described over a decade ago and is now considered to be one of the most important surgical innovations of modern ophthalmology. Prior to its introduction, no interventions were available to arrest, or slow down ectatic disease progression, with corneal transplantation required in the majority of cases. Unlike earlier treatments of corneal ectasias that attempted to only improve the consequences of the disease, CXL aims to address the corneal biomechanical weakening itself. The long-term safety and efficacy of CXL have been established in several studies that have documented significant improvements in all outcome measures (visual acuity, spherical equivalent, astigmatism, and keratometric findings). The emerging combination of CXL with other interventions (termed 'CXL plus') optimizes the visual and topographic outcomes. This, along with the expansion of the techniques' indications for other clinical conditions, such as microbial keratitis, highlights the continuous improvement of the initial technique and confirms its wide acceptance. Overall, CXL has already demonstrated much promise and has several clinical indications, representing a clear example of recent advances in ocular therapy. PMID- 24170590 TI - Improvement of glycemic control by re-education in insulin injection technique in patients with diabetes mellitus. AB - INTRODUCTION: The aim of this study was to evaluate the effectiveness of re education in the insulin injection technique for glycemic control. METHODS: A preliminary experimental study was performed with 87 insulin-treated diabetic outpatients (11 with type 1 diabetes, 76 with type 2 diabetes; 43 men, 44 women). All patients had been treated with insulin for more than 3 years. After answering questions about the insulin injection technique, the patients' knowledge levels were scored. Correct answers and explanation sheets were subsequently given to all patients. The physicians in charge gave a short lecture and provided 10 min of individual advice. Two, three, and four months after re-education the HbA1c and glycoalbumin levels were measured. RESULTS: The mean HbA1c levels of almost all patients significantly improved from 7.46 +/- 0.09% to 6.73 +/- 0.10% (P < 0.01), and the mean glycoalbumin levels significantly improved from 22.76 +/- 0.50% to 20.26 +/- 0.68% (P < 0.01). Twenty-five patients demonstrated a poor understanding (score of <=6 points) and showed a significant decrease in the HbA1c level from 7.62 +/- 0.20% to 6.71 +/- 0.21% (P = 0.02). Forty-three patients demonstrated a moderate understanding (score of 7 or 8 points) and showed a decrease in the HbA1c level from 7.40 +/- 0.13% to 6.68 +/- 0.07% (P = 0.07). Finally, 19 patients demonstrated a good understanding (score of >=9 points) and showed a slight decrease in the HbA1c level from 7.38 +/- 0.15% to 6.93 +/- 0.12% (P = 0.09). Patients with a poor understanding showed the largest decrease in the mean level of HbA1c. CONCLUSION: Re-education in the insulin injection technique led to an improvement in glycemic control in insulin-treated diabetic patients, especially in those with a poor understanding of the insulin injection technique. More attention should be paid to these strategies for outpatients. PMID- 24170591 TI - Nutritional treatment of pressure ulcers: what is the evidence? AB - PURPOSE: To review the literature on the nutritional treatment of pressure ulcers, with an emphasis on long-term care issues. The focus is on studies that have used high energy or high protein diets, supplementation with vitamin C, zinc, or arginine, or some combination of those four approaches. The goal of this review is to clarify the evidence (if any) supporting each nutritional treatment. DATA SOURCES: A search of the literature was conducted including PubMed, CINAHL, and MEDLINE. Search terms included "pressure ulcers," in combination with "treatment," "nutrition," "supplements," "Vitamin C," "zinc," and "arginine." CONCLUSIONS: Studies of high energy and high protein intake provide some evidence that those may be useful interventions, but the evidence is not strong. Although we have basic science providing evidence of the role of vitamin C, zinc, and arginine in wound healing processes, data on those nutrients related to pressure ulcer healing is equivocal. IMPLICATIONS FOR PRACTICE: Nurse practitioners should assess the nutritional status of patients with pressure ulcers and treat deficiencies within current guidelines. At this time, there is not strong evidence to support the use of specific nutritional supplements. PMID- 24170592 TI - Developing nurse practitioner associated metrics for outcomes assessment. AB - As nurse practitioners (NPs) assume an increasing role in providing care to hospitalized patients, measuring the impact of their care on patient outcomes and quality of care measures becomes a necessary component of performance evaluation. Developing metrics that relate to quality of care measures as well as patient outcomes based on the specific practices of an NP can help to specifically identify the impact of NP care in hospital and ambulatory care settings. New opportunities have arisen for highlighting NP outcomes that can be used to structure NP-associated metrics including the Hospital Value-Based Purchasing Program and the Joint Commission's practice evaluation standards. This manuscript discusses the use of NP-associated metrics for assessing the outcomes of NP care on patient care as well as on quality of care measures. PMID- 24170593 TI - Knee pain: an unanticipated finding related to a rare genetic disorder- abetalipoproteinemia. AB - PURPOSE: The purpose of this case study is to raise awareness about an uncommon cause of knee pain. DATA SOURCES: Review of literature was done using PubMed, CINAHL, and Medline. There was no limitation placed on the publication year. Only articles written in English were included. CONCLUSION: Knee pain is a common diagnosis that many healthcare providers see on a daily basis in their practice. Musculoskeletal injury or trauma is most commonly identified as the cause of this symptom. However, there are rare instances in which an unexpected finding in a client's history and physical exam lead us to an unexpected cause, such as abetalipoproteinemia. Abetalipoproteinemia is a rare autosomal recessive disorder in which an affected individual does not absorb lipids or the lipid-soluble vitamins A, D, E, and K. Multiple body systems are impacted by this fat malabsorption and resultant vitamin deficiencies. Without corrective supplementation, clinical manifestations which are directly related to the vitamin deficiencies will appear as presented in this case study-knee pain. IMPLICATIONS FOR PRACTICE: This case study emphasizes the need for nurse practitioners to seek out opportunities to further our knowledge which will enhance our clinical expertise as well as the quality of the health care we provide to our clients. PMID- 24170594 TI - The diagnosis less traveled: NPs' role in recognizing adult ADHD. AB - PURPOSE: To stimulate critical thought about sociocultural implications of unrecognized and undiagnosed attention deficit hyperactivity disorder (ADHD), and how these factors interface with healthcare delivery models and care that nurse practitioners (NPs) provide. DATA SOURCES: Health science databases--Psych Info, Proquest, Sage, PubMed, and authors' professional experiences. CONCLUSIONS: NPs, often the main healthcare provider for underserved populations in community practice settings, have little training in assessing adult ADHD. ADHD, often unrecognized and undiagnosed among adults, contributes to global impairments adversely affecting individuals' social, behavioral, academic, and cognitive functioning. Increased insight and awareness about adult ADHD is warranted to facilitate appropriate diagnosis. IMPLICATIONS FOR PRACTICE: ADHD is found in all sectors of our society; however, assessment and diagnosis among those whose socioeconomic status limits access to resources is a problem. Working in integrated care clinical settings facilitates recognition of patient problems and colocates resources required to manage the ADHD patient effectively. While this practice model may not be the norm, it is critical for NPs to have: (a) heightened awareness of the presentation of adult ADHD; (b) skills and/or resources to facilitate proper diagnosis of adult ADHD, and (c) models of practice that support optimal NP care delivery. PMID- 24170595 TI - Interventions for children coping with parental multiple sclerosis: a systematic review. AB - PURPOSE: A systematic review was conducted to explore ways to assist children of parents with multiple sclerosis (MS) in developing positive coping strategies. DATA SOURCES: Multiple databases including Academic Search Complex, CINAHL plus with full text, Health Source: Nursing Academic Edition, Medline with full text, and Psychology and Behavioral Sciences Collection. The review was not limited by year of publication. CONCLUSIONS: Evidence demonstrates children of parents with MS who increase their coping skills, social support, and knowledge of the disease process exhibit decreased emotional distress and increased overall life satisfaction. IMPLICATIONS FOR PRACTICE: Future research needs to explore the effects of intervention programs designed specifically to target different age levels and promote coping strategies, social support, and knowledge of MS. Healthcare providers need to address the family's needs, including children, when a parent is diagnosed with MS. PMID- 24170596 TI - Quality Improvement Project: analysis of efficiency of current order set for the diagnostic workup used to evaluate neurogenic stress myocardium in aneurysmal subarachnoid hemorrhage. AB - PURPOSE: To evaluate patterns of utilization of the aneurysmal subarachnoid hemorrhage (aSAH) protocol order set for neurogenic stress myocardium (NSM). DATA SOURCES: Retrospective chart review. CONCLUSIONS: The results of this study demonstrate that protocol order sets can be prone to omissions, variations in practice, and delays. IMPLICATIONS FOR PRACTICE: Education and implementation of an intervening compliance monitor are essential to improve utilization and correctness in use of the aSAH protocol order set for NSM. Advance practice nurses (APNs) or nursing staff could provide this service. This would improve teamwork, improve efficiency of care delivery and utilization of resources, promote leadership and improved outcomes, and promote relationship-based care. PMID- 24170597 TI - Obesity education for nurse practitioners: perspectives from nurse practitioner faculty. AB - PURPOSE: The purpose of the study was to investigate curriculum content and teaching practices about obesity in graduate nursing programs in the United States. METHODOLOGY: A survey of 1202 faculty members teaching in nurse practitioner (NP) programs was conducted using an investigator-created instrument with items based on the National Institutes of Health Obesity Education Initiative guidelines. Objective items were analyzed using descriptive and nonparametric statistics, and the open-ended questions were analyzed using content analysis. FINDINGS: NP faculty emphasized existing clinical practice guidelines, but revealed a large disparity between what is emphasized in schools of nursing and the state of the science regarding obesity etiology and management. Faculty place a priority on teaching obesity as a key factor in the development of comorbidities, and weight loss as a means of treating these comorbidities. Teaching about the pathophysiology of obesity, management of bariatric surgery patients, and pharmacologic therapy are de-emphasized. Four main themes about obesity teaching practices were identified from subjects' comments to open-ended items. CONCLUSIONS: Additional education and support are needed for faculty to teach about obesity in a way that advances the care of obese patients based on emerging scientific principles. PMID- 24170598 TI - Diagnosis of gestational diabetes mellitus: can we avoid the glucose challenge test? AB - OBJECTIVE: To identify risk factors for gestational diabetes mellitus (GDM) in patients who had either a normal or abnormal glucose tolerance test (GTT) after failing the initial glucose challenge test (GCT). If identified, consideration can be given to circumvent the glucose challenge test for those at risk. DATA SOURCES: A chart review was performed on 557 patients with abnormal GCT, 278 had an abnormal GTT (cases), and 279 had normal GTT (controls). The following risk factors were extracted: patients' age, body mass index (BMI), ethnicity, selected personal history, and family history. A primary logistic regression and secondary exploratory logistic regression were used to analyze the data. CONCLUSIONS: Of the risk factors reviewed age, BMI, and prior history of GDM were predictive of GDM in the current pregnancy. Age 30-34 had an odds ratio (OR) of 1.95, 95% confidence interval (CI) [1.25,3.05] and over 35 had an OR 3.87 CI [2.12,7.05]. BMI over 30 had an OR 1.95, CI [1.25,3.05] and prior GDM had an OR 2.82 CI [1.55,5.13]. The combination of age and BMI had a significant OR, but not a significant increase over individual risk factors. IMPLICATIONS FOR PRACTICE: Screening by risk factors to circumvent glucose challenge testing may cause unnecessary testing and cost. PMID- 24170599 TI - Integrating and mining the chromatin landscape of cell-type specificity using self-organizing maps. AB - We tested whether self-organizing maps (SOMs) could be used to effectively integrate, visualize, and mine diverse genomics data types, including complex chromatin signatures. A fine-grained SOM was trained on 72 ChIP-seq histone modifications and DNase-seq data sets from six biologically diverse cell lines studied by The ENCODE Project Consortium. We mined the resulting SOM to identify chromatin signatures related to sequence-specific transcription factor occupancy, sequence motif enrichment, and biological functions. To highlight clusters enriched for specific functions such as transcriptional promoters or enhancers, we overlaid onto the map additional data sets not used during training, such as ChIP-seq, RNA-seq, CAGE, and information on cis-acting regulatory modules from the literature. We used the SOM to parse known transcriptional enhancers according to the cell-type-specific chromatin signature, and we further corroborated this pattern on the map by EP300 (also known as p300) occupancy. New candidate cell-type-specific enhancers were identified for multiple ENCODE cell types in this way, along with new candidates for ubiquitous enhancer activity. An interactive web interface was developed to allow users to visualize and custom mine the ENCODE SOM. We conclude that large SOMs trained on chromatin data from multiple cell types provide a powerful way to identify complex relationships in genomic data at user-selected levels of granularity. PMID- 24170600 TI - A unified model for yeast transcript definition. AB - Identifying genes in the genomic context is central to a cell's ability to interpret the genome. Yet, in general, the signals used to define eukaryotic genes are poorly described. Here, we derived simple classifiers that identify where transcription will initiate and terminate using nucleic acid sequence features detectable by the yeast cell, which we integrate into a Unified Model (UM) that models transcription as a whole. The cis-elements that denote where transcription initiates function primarily through nucleosome depletion, and, using a synthetic promoter system, we show that most of these elements are sufficient to initiate transcription in vivo. Hrp1 binding sites are the major characteristic of terminators; these binding sites are often clustered in terminator regions and can terminate transcription bidirectionally. The UM predicts global transcript structure by modeling transcription of the genome using a hidden Markov model whose emissions are the outputs of the initiation and termination classifiers. We validated the novel predictions of the UM with available RNA-seq data and tested it further by directly comparing the transcript structure predicted by the model to the transcription generated by the cell for synthetic DNA segments of random design. We show that the UM identifies transcription start sites more accurately than the initiation classifier alone, indicating that the relative arrangement of promoter and terminator elements influences their function. Our model presents a concrete description of how the cell defines transcript units, explains the existence of nongenic transcripts, and provides insight into genome evolution. PMID- 24170602 TI - Physiological, phytochemical and structural changes of multi-leaf lettuce caused by salt stress. AB - BACKGROUND: Environmental stress due to salt has been described to enhance lettuce processability, shelf life and consumer acceptability. Moderate salinity causes altered leaf carotenoid, lignin, phenolic and flavonol levels without noticeable changes in the green colour and morphology of lettuce. The aim of this study was to understand the improvements in processability, due to salt stress, related to textural properties and structural characteristics. RESULTS: Physiological, phytochemical and structural changes were observed that were of significant relevance to salt stress (50, 100 and 150 mmol L(-1) NaCl). Fresh weight per plant, fresh weight per leaf, leaf area, water content, colour saturation, chlorophyll a and b and the area of the intercellular spaces decreased when the concentration of salt was increased. Solute concentration, elasticity, total and individual phenolic acids and the areas occupied by the palisade and spongy parenchyma cells increased when the concentration of salt was increased. CONCLUSION: These data illustrate that salt stress can have a positive impact on certain structural parameters, especially tissue elasticity, that can be closely linked to a higher number of cells, of lower size and high leaf strength, explaining the postharvest longevity of lettuce. However, leaf growth and visual quality could be negatively affected by salt stress. PMID- 24170601 TI - The altered landscape of the human skin microbiome in patients with primary immunodeficiencies. AB - While landmark studies have shown that microbiota activate and educate host immunity, how immune systems shape microbiomes and contribute to disease is incompletely characterized. Primary immunodeficiency (PID) patients suffer recurrent microbial infections, providing a unique opportunity to address this issue. To investigate the potential influence of host immunity on the skin microbiome, we examined skin microbiomes in patients with rare monogenic PIDs: hyper-IgE (STAT3-deficient), Wiskott-Aldrich, and dedicator of cytokinesis 8 syndromes. While specific immunologic defects differ, a shared hallmark is atopic dermatitis (AD)-like eczema. We compared bacterial and fungal skin microbiomes (41 PID, 13 AD, 49 healthy controls) at four clinically relevant sites representing the major skin microenvironments. PID skin displayed increased ecological permissiveness with altered population structures, decreased site specificity and temporal stability, and colonization with microbial species not observed in controls, including Clostridium species and Serratia marcescens. Elevated fungal diversity and increased representation of opportunistic fungi (Candida, Aspergillus) supported increased PID skin permissiveness, suggesting that skin may serve as a reservoir for the recurrent fungal infections observed in these patients. The overarching theme of increased ecological permissiveness in PID skin was counterbalanced by the maintenance of a phylum barrier in which colonization remained restricted to typical human-associated phyla. Clinical parameters, including markers of disease severity, were positively correlated with prevalence of Staphylococcus, Corynebacterium, and other less abundant taxa. This study examines differences in microbial colonization and community stability in PID skin and informs our understanding of host-microbiome interactions, suggesting a bidirectional dialogue between skin commensals and the host organism. PMID- 24170603 TI - A fluorous porous polymer monolith photo-patterned chromatographic column for the separation of a flourous/fluorescently labeled peptide within a microchip. AB - A fluorous porous polymer stationary phase is photo-patterned within a glass microfluidic chip to conduct CEC. During free radical-initiated polymerization, extraneous polymer forms and contributes to excessive microfluidic channel clogging. Nitrobenzene is explored as free radical quencher to limit clogging by minimizing extraneous polymer formation and a number of initiator to quencher ratios are explored with a 0.5:1 quencher (nitrobenzene): initiator (benzoin methyl ether) molar ratio shown to be optimal. The microchip patterned with a fluorous monolith was used to carry out the electrochromatographic analysis of a mixture containing fluorescent and fluorous labeling products. The fluorous monolithic column shows fluorous selectivity for compounds labeled with perfluoromethylene tags and a custom peptide is synthesized that possesses functional groups that can be both fluorescently and fluorously labeled. MALDI MS was used to identify the labeled fragments and microchip based electrochromatography was used to analyze the resulting labeling mixture. This is the first report to our knowledge that uses fluorous porous polymer monolith within a microchip to separate analytes using fluorous-fluorous interactions. PMID- 24170604 TI - Self-reported exercise and bone mineral density in prostate cancer patients receiving androgen deprivation therapy. AB - PURPOSE: Men with prostate cancer receiving androgen deprivation therapy (ADT) are at increased risk for decreased bone mineral density (BMD). This study evaluates the relationship between self-reported daily activity, endurance and resistance exercise, and BMD measured by dual-energy x-ray absorptiometry (DEXA) in prostate cancer patients receiving ADT. DATA SOURCES: We recruited 96 men treated with ADT for >=9 months from urology and cancer practices. The Canadian Fitness Survey assessed daily activity and exercise. Data on demographic and lifestyle characteristics and calcium and vitamin D supplementation were collected. Blood was collected for analysis of 25-OH vitamin D. A DEXA scan was performed. CONCLUSIONS: A positive association between endurance exercise and DEXA T-scores of the hip was shown. Regression analysis showed endurance exercise of medium to heavy intensity (measured as energy expenditure in MET-hours/week) was associated with T-scores of the hip (beta = 0.048; 95% CI 0.003, 0.112; p = .040) but not with spinal T-scores after controlling for age, body mass index, and alcohol use. IMPLICATIONS FOR PRACTICE: Findings are cross-sectional, but if confirmed in prospective studies suggest that increased endurance exercise is a practical measure nurse practitioners can institute to prevent low bone density in the hip of men treated with ADT. PMID- 24170605 TI - The application of anti-ESAT-6 monoclonal antibody fluorescent probe in ex vivo near-infrared fluorescence imaging in mice with pulmonary tuberculosis. AB - Here, we aimed to assess the feasibility of anti-ESAT-6 monoclonal antibody (mAb) coupling with IR783 and rhodamine fluorescent probe in the detection of ESAT-6 expression in tuberculosis tissue of mice using near-infrared fluorescence imaging. IR783 and rhodamine were conjugated to the anti-ESAT-6 mAb or IgG. Mice in the experimental group were injected with fluorescence-labeled mAb probe, and mice in the control group were injected with fluorescence-labeled non-specific IgG antibody. Twenty-four hours later, the lung tissue of mice was examined using ex vivo near-infrared fluorescence imaging. In addition, the contrast-to-noise ratio (CNR) was calculated by measuring the signal intensities of the pulmonary lesions, normal lung tissue and background noise. The frozen lung tissue section was examined under fluorescence microscopy and compared with hemoxylin and eosin (HE) staining. The ex vivo near-infrared fluorescence imaging showed that the fluorescence signal in the lung tuberculosis lesions in the experimental group was significantly enhanced, whereas there was only a weak fluorescence signal or even no fluorescence signal in the control group. CNR values were 64.40 +/- 7.02 (n = 6) and 8.75 +/- 3.87 (n = 6), respectively (t = 17.01, p < 0.001). The fluorescence accumulation distribution detected under fluorescence microscopy was consistent with HE staining of the tuberculosis region. In conclusion, anti-ESAT 6 mAb fluorescent probe could target and be applied in specific ex vivo imaging of mice tuberculosis, and may be of further use in tuberculosis in living mice. PMID- 24170606 TI - Preoperative colonic stents versus emergency surgery for acute left-sided malignant colonic obstruction: a meta-analysis. AB - PURPOSE: The purpose of this paper is to evaluate the efficacy and safety of colonic stenting as a bridge to surgery versus emergency surgery for acute left sided malignant colonic obstruction. METHODS: Randomized clinical trials (RCT) that compared the efficacy or safety of preoperative colonic stents versus emergency surgery for acute left-sided malignant colonic obstruction were searched in medical databases, including PubMed, OVID, EMBASE, and the Cochrane Library. Statistical heterogeneity between trials was evaluated by Revman 5.1 and was considered to exist at I(2) > 50%. RESULTS: Seven RCTs were identified. There was a total of 382 patients, 195 who received a colonic stent and 187 who received emergency surgery. Compared with the emergency surgery group, the colonic stent group achieved significantly more favorable rates of permanent stoma, primary anastomosis, wound infection, and overall complications. There was no significant difference between the two groups in anastomotic leakage, mortality, or intra-abdominal infection. Inspection of funnel plots for all outcome measures did not reveal evidence of publication bias. CONCLUSIONS: Self expanding metal stents serve as a safe and effective bridge to subsequent surgery in patients with obstructing left-sided colon cancer. They can significantly improve one-stage surgery rates, and decrease the rates of permanent stoma and wound infection. PMID- 24170607 TI - Is surgical intervention for cystic neoplasms of the pancreas being underutilized? PMID- 24170608 TI - Accurate HPV testing: a requirement for precision medicine for head and neck cancer. PMID- 24170609 TI - Cancer and the kidney: individualizing dosage according to renal function. PMID- 24170610 TI - GDC-0449 in patients with advanced chondrosarcomas: a French Sarcoma Group/US and French National Cancer Institute Single-Arm Phase II Collaborative Study. AB - BACKGROUND: Pre-clinical data have suggested a therapeutic role of Hedgehog (Hh) pathway inhibitors in chondrosarcoma. METHODS: This phase II trial included patients with progressive advanced chondrosarcoma. They received GDC-0449 150 mg/day (days 1-28, 28-day cycle). The primary end point was the 6-month clinical benefit rate (CBR) defined as the proportion of patients with non-progressive disease at 6 months. A 6-month CBR of 40% was considered as a reasonable objective to claim drug efficacy. RESULTS: Between February 2011 and February 2012, 45 patients were included. Twenty had received prior chemotherapy. Thirty nine were assessable for efficacy. The 6-month CBR was 25.6% (95% confidence interval 13.0-42.1). All stable patients had grade 1 or 2 conventional chondrosarcoma with documented progression within the 6 months before inclusion. All but one with available data also had overexpression of the Hh ligand. Median progression-free and overall survivals were 3.5 and 12.4 months, respectively. The most frequent adverse events were grade 1 or 2 myalgia, dysgeusia and alopecia. CONCLUSIONS: GDC-0449 did not meet the primary end point of this trial. Results suggest some activity in a subset of patients with progressive grade 1 or 2 conventional chondrosarcoma. Further studies assessing its role in combination with chemotherapy are warranted. CLINICALTRIALSGOV IDENTIFIER: NCT01267955. PMID- 24170612 TI - Biomarkers of brain injury in cerebral infections. AB - BACKGROUND: Central nervous system (CNS) infections present a major burden of disease worldwide and are associated with high rates of mortality and morbidity. Swift diagnosis and initiation of appropriate treatment are vital to minimize the risk of poor outcome; however, tools are lacking to accurately diagnose infection, assess injury severity, and predict outcome. Biomarkers of structural neurological injury could provide valuable information in addressing some of these challenges. CONTENT: In this review, we summarize experimental and clinical research on biomarkers of neurological injury in a range of CNS infectious diseases. Data suggest that in both adults and children, the biomarkers S100B and neuron-specific enlose (NSE), among others, can provide insight into the pathophysiology of CNS infection and injury severity, evolution, and response to treatment. Research into the added utility of combining a panel of biomarkers and in assessing biomarker association with clinical and radiological outcomes warrants further work. Various factors, including age, the establishment of normative values, and comparison of biomarker concentrations across different testing platforms still present challenges in biomarker application. SUMMARY: Research regarding the value of biomarkers in CNS infections is still in its infancy. However, early evidence supports their utility in diagnosis and prognosis, and potentially as effective surrogate end points in the assessment of novel interventions. PMID- 24170611 TI - The emerging genomic landscape of endometrial cancer. AB - BACKGROUND: Endometrial cancer is responsible for approximately 74 000 deaths annually among women worldwide. It is a heterogeneous disease comprising multiple histologic subtypes. In the US, the majority of deaths from endometrial carcinoma are attributed to the serous and endometrioid subtypes. An understanding of the fundamental genomic alterations that drive serous and endometrioid endometrial carcinomas lays the foundation for the identification of molecular markers that could improve the clinical management of patients presenting with these tumors. CONTENT: We review the current state of knowledge regarding somatic genomic alterations that occur in serous and endometrioid endometrial tumors. We present this knowledge in a historical context by reviewing the genomic alterations that studies of individual genes and proteins have identified over the past 2 decades or so. We then review very recent comprehensive and systematic surveys of genomic, exomic, transcriptomic, epigenomic, and proteomic alterations in serous and endometrioid endometrial carcinomas. SUMMARY: The recent mapping of the genomic landscape of serous and endometrioid endometrial carcinomas has produced the first comprehensive molecular classification of these tumors, which has distinguished 4 molecular subgroups: a POLE [polymerase (DNA directed), epsilon, catalytic subunit] ultramutated subgroup, a hypermutated/microsatellite-unstable subgroup, a copy number-low/microsatellite-stable subgroup, and a copy number high subgroup. This molecular classification may ultimately serve to refine the diagnosis and treatment of women with endometrioid and serous endometrial tumors. PMID- 24170614 TI - Elder self-neglect: the failure of coping because of cognitive and functional impairments. AB - PURPOSE: Elder self-neglect is the most frequently reported form of elder abuse, and can increase risk of death by 16-fold. It is essential that providers understand overall risk factors for elder self-neglect, and how to best address the impact of factors that limit coping, such as cognitive and functional impairments. DATA SOURCES: While research on elder self-neglect is still limited, this systematic review summarizes current data overall and the specific impact of cognitive and functional impairments. Searched Ovid-Medline, Scopus, and ISI Web of Science, with terms "self-neglect," elder*, cognitive, and function*. Two hundred and thirty-seven records were identified, which resulted in 37 articles after review for duplication, pertinence and specificity. CONCLUSION: Elder self neglect is a multifactorial syndrome. Executive dysfunction appears to be the predominant factor which inhibits appropriate decision making and problem solving. This impaired frontal lobe functioning impedes elders' ability to cope with physical disabilities, resulting in, or exacerbating, functional impairments. IMPLICATIONS FOR PRACTICE: Caring for elders who are failing to meet their own needs is clinically and ethically challenging. It requires a careful evaluation of all factors that limit coping and self-care ability, including a systematic examination of executive and functional impairments. Treatment should be interdisciplinary, and maximize safety while honoring elders' goals. PMID- 24170613 TI - Circulating fetuin-A and risk of ischemic stroke in women. AB - BACKGROUND: Fetuin-A, a protein secreted primarily by the liver, has been associated with nonalcoholic fatty liver disease and insulin resistance. In a recent study, higher circulating fetuin-A was associated with cardiovascular events, particularly ischemic stroke. However, these data have not been replicated. METHODS: A nested case control design was used to examine the relationship between fetuin-A and ischemic stroke among female participants of the Nurses' Health Study. Fetuin-A was measured in blood samples collected and stored between 1989 and 1990. A total of 459 incident cases of ischemic stroke were identified and confirmed by medical records according to the National Survey of Stroke criteria between 1990 and 2006 and matched to 459 controls by age, race/ethnicity, date of sample collection, menopausal status, postmenopausal hormone use, and smoking status. The association between fetuin-A and ischemic stroke was modeled using conditional logistic regression. RESULTS: Circulating fetuin-A was higher in women (P < 0.01) who reported increased body mass index (BMI) of >=25 kg/m(2), total cholesterol >=200 mg/dL, high-sensitivity C-reactive protein >=3 mg/L, and current hormone use at baseline. Significant partial Spearman correlations (P < 0.001), adjusted for matching factors, were found between measured concentrations of fetuin-A and triglycerides (r = 0.20), C reactive protein (r = 0.14), and BMI (r = 0.15). Fetuin-A quartiles were not significantly associated with increased risk of incident ischemic stroke when adjusted for matching factors (relative risk, 1.03; 95% CI, 0.69-1.54, extreme quartiles); additional adjustment for lifestyle factors or cardiovascular disease risk factors and biomarkers did not alter results. CONCLUSIONS: In this sample of women, fetuin-A was not significantly associated with risk of ischemic stroke. Further research is needed to explore this association. PMID- 24170615 TI - Interferon-free regimens for hepatitis C: combine and conquer. AB - Since the approval of the first direct-acting antiviral agents (DAAs), treatment for hepatitis C virus (HCV) has undergone significant transformation. A new milestone in the treatment of HCV, the approval of the first interferon-free regimens, could be achieved by the end of 2013. For patients with HCV who have absolute or relative contraindications to pegylated-interferon or have failed the currently available treatments, the arrival of new regimens will have a major impact on long-term outcomes. The combinations of DAAs in trials are numerous, and many have demonstrated sustained virologic response rates higher than 90 %. These improvements have also been observed in previous null responders and patients who failed telaprevir- or boceprevir-based regimens. Some specific subpopulations may not be perfectly served by interferon-free regimens, such as patients with genotypes 1a or 3 or cirrhosis, whereas others, such as HIV infected patients or transplant patients, will definitively benefit from regimens with a lower burden of side effects. This paper reviews the interferon-free regimens currently in phase II or III for which sustained virologic response data are available and discusses the successes and potential pitfalls of these regimens. PMID- 24170616 TI - Understanding kidney function assessment: the basics and advances. AB - PURPOSE: Multiple kidney function assessment modalities are available, but their appropriateness is constantly questioned. This review provides practitioners with in-depth understanding of kidney function assessment methods, their clinical utility, and comparisons. DATA SOURCES: PUBMED search was conducted by relevant subject headings. CONCLUSIONS: Glomerular filtration rate (GFR) is the best indicator of kidney function. Exogenous compounds like inulin help measure GFR, but endogenous substances (like creatinine) are more convenient, although exhibiting greater variability. Cystatin C is advocated as a functional marker; its clinical significance is under study. Proteinuria adds value to GFR estimation. There are commonly used equations estimating GFR like the creatinine based Cockcroft-Gault and the modification of diet in renal disease. The new creatinine-based Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation demonstrates higher accuracy of patient classification in earlier stages of disease. Recently, the Chronic Renal Insufficiency Cohort (CRIC) study has devised an equation combining serum creatinine and cystatin C in longitudinal modeling of kidney function. IMPLICATIONS FOR PRACTICE: Current GFR estimation methods have limitations, and are useful for populations they have been tested in. Practitioners should be well informed on emerging equations that provide greater accuracy in CKD diagnosis; this would help implement appropriate prevention and intervention strategies. PMID- 24170617 TI - Unexpected hemorrhage: an unusual and potentially catastrophic clinical challenge. AB - PURPOSE: Unexpected bleeding or hemorrhage related to the development of acquired factor VIII inhibitors is an emerging clinical challenge in patients. Symptoms can occur suddenly with bleeding and/or bruising that is excessive relative to the degree of injury or severity of a comorbid condition. Diagnosis is difficult, and bleeding can quickly become life threatening if not treated promptly. This review provides current information, using a patient case scenario, to improve awareness and recognition of patients presenting unexpectedly with excessive bleeding of unknown etiology. DATA SOURCES: To complete this review, a search of English-language publications was conducted using Medline and CINAHL databases (1966-2010). CONCLUSIONS: Although development of acquired factor VIII inhibitors is rare, its incidence is increasing in many different patient care settings. Improved awareness and recognition is needed to mitigate the significant patient morbidity and mortality that can occur without rapid and timely treatment by experienced hematology specialists. IMPLICATIONS FOR PRACTICE: Nurse practitioners, as front-line clinicians treating patients in various therapeutic areas, may be the first healthcare professionals who see patients with this disorder. Increased knowledge and awareness of this rare but potentially catastrophic cause of excessive bleeding can improve prompt treatment and optimize patient outcomes. PMID- 24170618 TI - Partnering with patients to promote holistic diabetes management: changing paradigms. AB - PURPOSE: To provide a review of best practice for clinical management of diabetes mellitus (DM) for nurse practitioners (NPs) and accelerate incorporation of key findings into current practice. DATA SOURCE: A search was conducted in Pub Med, Ovid, CINAHL, and Cochrane's Database of Systematic Reviews. CONCLUSIONS: There are many challenges for DM care identified in the current health system. There is a great need to change care paradigms to engage patients in partnership for enhanced management and self-management in DM. A review of the best practice evidence revealed numerous models of care, strategies, and tools available to enhance diabetes care and promote health and well-being. The primary focus of this article is to engage NP clinicians to incorporate new strategies to augment management and improve clinical outcomes. IMPLICATIONS FOR PRACTICE: Incorporation of best practice for DM management may accelerate the paradigm shift to more patient-focused care. Engaged, informed, and activated patients along with clinicians working in partnerships may enhance clinical outcomes. PMID- 24170619 TI - Nurse practitioners, wake up and smell the smoke. AB - PURPOSE: With the focus of modern health care on preventive care, and the well known benefits of smoking cessation on improving health and reducing healthcare costs, smoking cessation is a key focus of healthcare reform. To change the smoking habits of the U.S. population, two strategies are of particular importance to healthcare professionals: promoting tobacco-free environments in healthcare systems and expanding affordable and effective treatments. DATA SOURCES: Recent policy literature. CONCLUSIONS: Barriers to providing smoking cessation counseling most frequently cited by healthcare professionals are lack of training and poor reimbursement; however, recent legislation, for example, the Patient Protection and Affordable Care Act (PPACA), should make preventive services more available and affordable. Nurse practitioners (NPs) have vast experience in addressing health promotion and disease prevention, and are therefore well placed to lead this reform. However, despite consistently higher referrals of tobacco-dependent patients for smoking cessation interventions than any other group of healthcare provider, evidence suggests that NPs are not adequately trained to treat this addiction. IMPLICATIONS FOR PRACTICE: This article is a call to action for NPs to become familiar with the tobacco cessation policy changes affecting clinical practice, to become experts in tobacco treatment, and to take the lead in this healthcare reform initiative. PMID- 24170620 TI - Group cognitive behavioral therapy to improve the quality of care to opioid treated patients with chronic noncancer pain: a practice improvement project. AB - PURPOSE: To enhance outcomes of patients with chronic noncancer pain (CNCP) treated with opioids in a primary care setting by implementing an evidence-based quality improvement project. DATA SOURCES: The project consisted of the implementation of a 6-week cognitive behavioral therapy (CBT) program. Twenty-two patients with CNCP completed the program. Impact of the project was evaluated by comparing pre- and postintervention participant self-reports of mood on the Beck Depression Inventory and functional status on the Brief Pain Inventory and Short Form-36. Patient perception of treatment benefit was also measured using the Patient Global Impression of Change. Qualitative provider perceptions of the program were also collected. Paired t-test statistics were used to analyze the data. CONCLUSIONS: Mood (including negative attitude, performance difficulty, and physical complaints), and patient impression of treatment benefit improved significantly after CBT was added. Primary care providers reported that the CBT supported their overall management of these complex patients. IMPLICATIONS FOR PRACTICE: The addition of a CBT program improved selected outcomes in this self selected sample of patients with CNCP treated with opioids. PMID- 24170621 TI - Sexually transmitted infection risk perception among female college students. AB - PURPOSE: To describe perceived risk for sexually transmitted infections (STIs) and sexual risk behavior among sexually active female college students. DATA SOURCES: An online, anonymous survey was used to collect data from 458 sexually active female students between the ages of 18-24 enrolled at a private, suburban university in the mid-Atlantic region. CONCLUSION: Most women in this study did not consider themselves at risk for contracting an STI, despite low levels of condom use. Perceiving no risk and never using condoms were both more common among women with just one sex partner. Further investigation of factors contributing to individual risk perception is warranted in order to develop effective prevention programs. IMPLICATIONS FOR PRACTICE: Nurses and advanced practice nurses who work with women, particularly at-risk women, should be aware of low levels of risk perception for STIs, despite engaging in risk-taking behaviors. Education regarding strategies to reduce and prevent contracting STIs should be incorporated into encounters with women seeking health care, and in health promotion settings. PMID- 24170622 TI - Physical activity counseling intervention to promote weight loss in overweight rural women. AB - PURPOSE: To identify key behavioral factors that contribute to physical activity and weight management in overweight, rural women and determine the degree to which social support, stage of behavior change, and self-efficacy for physical activity and depressive symptoms are linked to physical activity, body weight, and body mass index (BMI). DATA SOURCES: Twenty-five overweight or obese rural women completed self-report scales and height and weight measurements; BMI was calculated. Self-report scales included the International Physical Activity Questionnaire (physical activity level), Social Support for Exercise and Social Support Questionnaire (social support), Stage of Exercise Adoption (stage of behavior change), Self-efficacy for Exercise (self-efficacy), and the Patient Health Questionnaire (depressive symptoms). CONCLUSIONS: Higher levels of physical activity were associated with greater self-efficacy and the self-esteem domain of social support. Rural women reported more depressive symptoms over the year. Women did not significantly increase physical activity and gained weight during the 1-year study. IMPLICATIONS FOR PRACTICE: Rural women have limited resources available to increase physical activity to facilitate weight loss. Routine screening and treatment for depression in rural women may need to be initiated concurrently with interventions to promote health behavior changes. PMID- 24170623 TI - The relationship of left ventricular mechanical dyssynchrony and cardiac sympathetic denervation to potential sudden cardiac death events in systolic heart failure. AB - BACKGROUND: Patients with heart failure (HF) are at increased risk for left ventricular (LV) dyssynchrony which is associated with sudden cardiac death (SCD). This study examined the association of LV mechanical dyssynchrony and cardiac sympathetic denervation with potential SCD events in symptomatic patients with HF and reduced ejection fraction (HFrEF). METHODS: Of the 917 HFrEF patients in ADMIRE-HF, 92 experienced adjudicated potential SCD events during a 17 months median follow-up. Propensity scores were used to assemble a matched cohort of 85 pairs of patients with and without potential SCD events. ADMIRE-HF subjects had rest gated SPECT Tc-99m and I-123 MIBG imaging. Perfusion images were processed using phase analysis software to derive phase standard deviation (SD), an index of mechanical dyssynchrony. RESULTS: Of the 92 patients who experienced adjudicated potential SCD events 23 had SCD, 5 fatal myocardial infarction, 7 resuscitated cardiac arrest, 46 had appropriate ICD therapy, and 11 had sustained ventricular tachycardia. Patients who experienced potential SCD events had significantly wider phase SD than matched control patients (62.3 +/- 2.4o vs 55.5 +/- 2.3o, P = .03) and were more likely to have a phase SD >= 60o (53 % vs 35 %, P = .03). Fewer patients with potential SCD events (6 % vs 15 % of the controls, P = .08) had an MIBG heart/mediastinum uptake-ratio >=1.6. CONCLUSIONS: Among symptomatic HFrEF patients, LV mechanical dyssynchrony is independently associated with potential SCD events. Phase analysis may provide incremental prognostic information on top of current indicators of SCD risk in HFrEF. PMID- 24170624 TI - Prediction of all-cause mortality from gated-SPECT global myocardial wall thickening: comparison with ejection fraction and global longitudinal 2D-strain. AB - BACKGROUND: The aim of this study was to assess the correlation between global wall thickening (GWT) obtained by gated-single photon emission computed tomography (SPECT) and echocardiographic measures [ejection fraction (EF), global longitudinal strain (GLS), and strain rate (GLSR)] and to compare their prognostic value for all-cause mortality. METHODS AND RESULTS: Seventy-four patients with referral for dipyridamole myocardial perfusion SPECT were prospectively included and underwent transthoracic echocardiography to measure left ventricular EF, GLS, and GLSR. The strongest correlation with GWT was for EF (R = 0.63, P < .001), followed by GLSR (R = -0.57, P < .001) and GLS (R = -0.53, P < .001). There were ten deaths over a period of 14.6 +/- 5.7 months. Using the multivariate Cox analysis, summed stress score (HR 1.108; P = .023), EF (HR 1.01, P = .031), GLS (HR 1.593, P = .001), and GWT (HR 0.898, P = .034) remained independent predictors of mortality. Mean survival rate evaluated by Kaplan-Meier analysis was longer in patients with GWT >= 24% (21.9 +/- 0.6 months) than those with GWT < 24% (13.6 +/- 2.7 months; P < .001). CONCLUSIONS: GWT assessed is a highly sensitive tool to detect early myocardial systolic dysfunction and may bring additional prognostic information. PMID- 24170626 TI - Cyclic vomiting syndrome: a common, underrecognized disorder. AB - PURPOSE: To increase recognition and present symptom assessment strategies for treating cyclic vomiting syndrome (CVS). DATA SOURCES: Clinical experience, a range of pediatric, gastroenterological, emergency medicine research, survey, and literature review reports on CVS. CONCLUSIONS: Improved efforts to recognize, diagnose, and treat CVS will help patients manage their symptoms and may reduce both the morbidity and costs of hospitalizations associated with this illness. IMPLICATIONS FOR PRACTICE: If promptly diagnosed and appropriately treated, CVS episodes can be aborted. Patients inappropriately treated must often be hospitalized because of complications associated with symptoms. Lifestyle changes, prophylactic and abortive migraine therapy, and supportive care are important to prevention. PMID- 24170625 TI - Condensed tannin accumulation and nitrogen fixation potential of Onobrychis viciifolia Scop. grown in a Mediterranean environment. AB - BACKGROUND: Sainfoin (Onobrychis viciifolia Scop.) is a forage legume found in temperate areas but is less widespread in Mediterranean environments. Compared with other perennial legumes, it has the advantage of containing condensed tannins (CT) that can be important for their implications on ruminant nutrition and health. Data on nitrogen (N) fixation by sainfoin in the literature originate from very different environments and only a few field data are available, so it is important to improve knowledge on the N fixation potential of this species, particularly under a Mediterranean climate. Here the accumulation pattern of polyphenolic compounds (total, non-tannic polyphenols and CT) and the N fixation potential of sainfoin were studied in order to contribute to its valorisation for sustainable farming management in Mediterranean environments. RESULTS: CT concentrations were always in the range considered beneficial for animals, not exceeding 50 g delphinidin equivalent kg-1 dry matter (DM). The regression of aerial fixed N on aerial DM showed a relationship of 22 kg fixed N t-1 aerial DM in a Mediterranean environment. CONCLUSION: A wider exploitation of sainfoin is suggested for production under rain-fed conditions, thus enlarging the limited set of available perennial legumes suitable for Mediterranean environments. PMID- 24170627 TI - Two-dimensional carrier distribution in top-gate polymer field-effect transistors: correlation between width of density of localized states and Urbach energy. AB - A general semiconductor-independent two-dimensional character of the carrier distribution in top-gate polymer field-effect transistors is revealed by analysing temperature-dependent transfer characteristics and the sub-bandgap absorption tails of the polymer semiconductors. A correlation between the extracted width of the density of states and the Urbach energy is presented, corroborating the 2D accumulation layer and demonstrating an intricate connection between optical measurements concerning disorder and charge transport in transistors. PMID- 24170628 TI - Identification and characterization of Cryptococcus neoformans protein fractions that induce protective immune responses. AB - Cryptococcus neoformans, the main causative agent of cryptococcosis, is a fungal pathogen that causes life-threatening meningoencephalitis in immunocompromised patients. To date, there is no vaccine or immunotherapy approved to treat cryptococcosis. Cell- and antibody-mediated immune responses collaborate to mediate optimal protection against C. neoformans infections. Accordingly, we identified cryptococcal protein fractions capable of stimulating cell- and antibody-mediated immune responses and determined their efficacy to elicit protection against cryptococcosis. Proteins were extracted from C. neoformans and fractionated based on molecular mass. The fractions were then evaluated by immunoblot analysis for reactivity to serum extracted from protectively immunized mice and in cytokine recall assays for their efficacy to induce pro-inflammatory and Th1-type cytokine responses associated with protection. MS analysis revealed a number of proteins with roles in stress response, signal transduction, carbohydrate metabolism, amino acid synthesis, and protein synthesis. Immunization with select protein fractions containing immunodominant antigens induced significantly prolonged survival against experimental pulmonary cryptococcosis. Our studies support using the combination of immunological and proteomic approaches to identify proteins that elicit antigen-specific antibody and Th1-type cytokine responses. The immunodominant antigens that were discovered represent attractive candidates for the development of novel subunit vaccines for treatment and/or prevention of cryptococcosis. PMID- 24170630 TI - Angiogenesis opens a way for Chinese medicine to treat stroke. AB - Based on the pathophysiology of the brain, advance in angiogenesis induced by stroke, and evidences of Chinese-medicine-mediated angiogenesis, the possibility to study the stroke-treating mechanism of Chinese medicine in angiogenesis was discussed. And regarding our previous work on angiogenesis modulated by qi tonifying and stasis-eliminating therapy following intracerebral hemorrhage, we proposed some questions, which should be taken into account in the further work. PMID- 24170631 TI - Cluster analysis for acupoint specificity of acupuncture effect based on cerebral infarction rat model. AB - OBJECTIVES: To study the acupoint specificity through the comprehensive evaluation of the acupuncture effect on rat model with the middle cerebral artery occlusion (MCAO). METHODS: Duplicated MCAO model by Zea-longa's thread ligation was assessed by Zausinger's six-point method, and rats with 1-3 scores were chosen to be grouped. According to the randomized and controlled principle, rats were divided into 6 basic control groups (including normal group, sham group, model control group, model group without intervention, Nimodipine group, lateral to-Renzhong group) and 6 acupuncture groups [including Neiguan (PC6) group, Weizhong (BL40) group, Chize (LU5) group, Sanyinjiao (SP6) group, Renzhong (DU6) group and non-acupoint group]; in each acupoint or non-acupoint 9 different parameter combinations were respectively set by orthogonal intersection method. There were in total 60 groups, and each group had 12 rats. The rats were treated by acupuncture with the lifting-thrusting manipulation every 12 h, in total 6 times. Indices of neurobehavioral scores, cerebral blood flow, infarction rate, microcirculation, and light microscope, etc. were measured. In order to comprehensively evaluate the acupuncture effect to research the specificity of acupoint, a cluster analysis was made with SPSS17.0 for the comprehensive effect scores of the samples computed according to the comprehensive evaluation models, and then sorting and classification were made for the comprehensive effect scores. RESULTS: In the acupuncture groups every acupoint had different therapeutic effect due to different acupuncture parameter combinations; among the acupuncture groups the orders of curative effect were as followings: Neiguan group was of exceptional result, Weizhong group and Sanyinjiao group were of valid results in upper level, Chize group and Renzhong group were of valid results in lower level, and non-acupoint group was of invalid result; the therapeutic result of acupoint group was superior to non-acupoint group; and the curative effect of acupuncture group was also superior to basic control group. CONCLUSION: The acupoint has the specificity of acupuncture effect, and the acupoint specificity is relative. PMID- 24170629 TI - Therapeutic effects of traditional herbal medicine on cerebral ischemia: a perspective of vascular protection. AB - Although many agents for acute ischemic stroke treatment have been developed from extensive preclinical studies, most have failed in clinical trials. As a result, researchers are seeking other methods or agents based on previous studies. Among the various prospective approaches, vascular protection might be the key for development of therapeutic agents for stroke and for improvements in the efficacy and safety of conventional therapies. Traditional medicines in Asian countries are based on clinical experiences and literature accumulated over thousands of years. To date, many studies have used traditional herbal medicines to prove or develop new agents based on stroke treatments mentioned in traditional medicinal theory or other clinical data. In the current review, we describe the vascular factors related to ischemic brain damage and the herbal medicines that impact these factors, including Salviae Miltiorrhizae Radix, Notoginseng Radix, and Curcumae Rhizoma, based on scientific reports and traditional medical theory. Further, we point out the problems associated with herbal medicines in stroke research and propose better methodologies to address these problems. PMID- 24170632 TI - Orthostatic hypotension leading to recurrent syncope episodes in a hypertensive patient: Treatment with Tianma Gouteng Decoction. PMID- 24170633 TI - How does Chinese medicine target cytokine imbalance in rheumatoid arthritis? AB - Rheumatoid arthritis (RA) manifests as an imbalance between pro- and anti inflammatory cytokines. Cytokine imbalance is suggested to play critical roles in the development of RA. Currently, various treatments for RA, including biological agents such as antibodies against inflammation mediators, or Chinese herbal medicines, intervene the disease by restoring the balance of cytokines. Chinese medicine (CM) can not only suppress the expression of pro-inflammatory cytokines, but also induce the expression of cytokines with anti-inflammatory and immunomodulatory effects. Thus, Chinese medicine can effectively reduce inflammatory cell infiltration into synovial tissue, pannus formation, and degradation of the extracellular matrix surrounding cartilage cells, thereby reducing subchondral bone damage. This paper reviews the changes of cytokine profiling during development of RA and discuss the mechanisms by which Chinese medicine restores the cytokine balance. PMID- 24170634 TI - Androgenetic alopecia (male pattern hair loss) in the United States: what treatments should primary care providers recommend? AB - PURPOSE: Androgenetic alopecia (AGA), or male pattern hair loss, affects up to 96% of Caucasian men. Characterized by gradual thinning and eventual loss of hair along frontotemporal, parietal, and vertex areas of the scalp, AGA is associated with low self-esteem, depression, and dissatisfaction with body appearance. DATA SOURCES: In this systematic review of the literature, six primary research studies conducted in the United States are evaluated for their clinical application to primary care provider practice. CONCLUSIONS: Topical minoxidil 2% 5% 1 mL twice daily or finasteride 1 mg daily are recommended as first line treatments, followed by the use of Food and Drug Administration-cleared HairMax LaserComb(r) in patients who do not respond to first line modalities. IMPLICATIONS FOR PRACTICE: Further research in novel and established treatments is recommended, along with an evidence-based clinical practice guideline for practitioners in the United States. PMID- 24170635 TI - Early recognition of Cushing's disease: a case study. AB - PURPOSE: To present a case study of a 34-year-old woman with Cushing's disease and provide nurse practitioners (NPs) with the understanding of the clinical presentation needed for early recognition and treatment of the disease. DATA SOURCES: A comprehensive review of published literature on Cushing's disease. Findings from history, physical examination, and diagnostic studies of a woman presenting to primary care NPs, physicians and other healthcare providers with multiple symptoms of Cushing's disease. CONCLUSIONS: Cushing's disease is the result of the pituitary gland producing excess amounts of adrenocorticotropic hormone (ACTH) causing the overproduction of cortisol. The disease is fairly rare and is seen mostly in women. Common chief complaints include increased facial hair, weight gain, amenorrhea, changes in the face, neck, and abdomen, with muscle wasting of the lower extremities. Untreated, diabetes mellitus and hypertension can occur and increase the patient's morbidity and mortality. Early recognition and appropriate referral can reverse the signs and symptoms over time and lead to a significantly improved quality of life. IMPLICATIONS FOR PRACTICE: This case presented the challenges faced by NPs and physicians in diagnosing patients with Cushing's disease. PMID- 24170636 TI - Transitional Care Partners: a hospital-to-home support for older adults and their caregivers. AB - PURPOSE: To describe the development, implementation, and preliminary results of the Transitional Care (TLC) Partners, a clinical demonstration program that supports the transition from hospital to home of older veterans. DATA SOURCES: Hospital records of TLC patients to track their hospital and emergency department visits before and after the TLC Partners enrollment. Caregivers of patients completed Preparedness in Caregiving and the Short Form Zarit Burden Scale during the first week of the TLC Partners enrollment and on the week when the services ended. CONCLUSIONS: The proportion of patients with one or more emergency department visits and rehospitalization is consistently lower among TLC patients compared to non-TLC patients at 30 and 60 days of hospital discharge. The mean preparedness and burden scores before and after the program essentially remained the same. IMPLICATIONS FOR PRACTICE: The description of the implementation of the TLC Partners offers an example of how nurse practitioner-led interprofessional care models can be adapted to the needs of specific healthcare systems, and how they can be monitored to evaluate their reach, effectiveness, and fidelity to the core components of proved care models. PMID- 24170637 TI - Use of a comprehensive patient safety tool in primary care practices. AB - PURPOSE: To present a tool that can be used to evaluate patient safety in both nurse-led and physician-led practices. DATA SOURCE: This article describes our experience with the Physician Practice Patient Safety Assessment (PPPSA) tool in six safety net practices-three of which were primary care nurse-managed health centers and three were physician-led federally qualified health centers. The information provided is from the tool itself and how it might be used in clinical settings, especially primary care. CONCLUSIONS: The PPPSA is a tool to measure the extent to which patient safety practices are rigorously and systematically implemented throughout a health center. The tool's methodology requires discussion and consensus, incorporating a team approach with multiple perspectives within a center. It is designed to promote changes in practices that would improve patient safety. IMPLICATIONS FOR PRACTICE: The tool has enormous relevance for primary care settings, especially those preparing themselves for patient-centered medical home status and meaningful use. But most important, it has relevance as we create healthcare environments that promote patient safety and a practice culture that is truly patient centered. PMID- 24170638 TI - Psychopharmacological treatment for military posttraumatic stress disorder: an integrative review. AB - PURPOSE: Posttraumatic stress disorder (PTSD) is a serious mental health disorder. The current first-line psychopharmacologic treatment for PTSD is selective serotonin reuptake inhibitors (SSRIs). Recently, the efficacy of SSRIs has been challenged in favor of propranolol use. This article reviews the origins of PTSD, its impact within the veteran population, psychopharmacological treatment of PTSD, and current literature on the use of propranolol for PTSD treatment. DATA SOURCES: The search strategies used included ProQuest, Medline, CINAHL, and Psychiatry Online and were searched using the key terms: PTSD, psychopharmacological treatment, SSRIs, propranolol, military, and veterans in multiple combinations. CONCLUSIONS: Studies to date indicate that (a) SSRIs are only moderately effective as a first-line treatment for PTSD and less so for military personnel, (b) propranolol has the ability to attenuate traumatic memory in primary and tertiary use, and (c) ethical and moral consideration as well as further research and testing is needed for substantiating propranolol as a first line PTSD psychopharmacological treatment. IMPLICATIONS FOR PRACTICE: Current research has shown propranolol to be an effective treatment option for PTSD. PMID- 24170639 TI - Low-density lipoprotein cholesterol control rates in the type-2 diabetic patient population within independent nurse practitioner settings. AB - PURPOSE: The purposes of this study were to describe the low-density lipoprotein cholesterol (LDL-C) control rate of patients with type-2 diabetes mellitus (DM2) treated by nurse practitioner (NP) providers, and to describe any significant differences in the population at the LDL-C goal of <100 mg/dL and patients not at goal. DATA SOURCES: Demographic data were collected from a retrospective chart review of patients with (DM2) who were treated in two primary care NP practice settings in New Hampshire where physician collaboration is not required. Data regarding smoking history, lifestyle, comorbidities, and antilipid and antidiabetes medication were collected. Physiological measurements included the body mass index (BMI), hemoglobin A1c (A1c), and the LDL-C. CONCLUSIONS: Patients with DM2 treated by NP providers were at goal with respect to the LDL-C in 71% of the cases in this study. Statin therapy was prescribed in 60.5% of the cases. Lifestyle management was recommended 92.6% of the time. IMPLICATIONS FOR PRACTICE: NPs prescribe appropriate medications, order and monitor laboratory values, in addition to providing education regarding lifestyle changes to patients with chronic diseases. Reported outcomes achieved by NP providers validate them as evidenced-based providers of quality care for patients with complex diseases such as DM2. PMID- 24170640 TI - Rural parent behaviors and expectations when caring for children with acute respiratory infections. AB - PURPOSE: To explore rural parents' behaviors and expectations regarding acute respiratory infections (ARIs) in children. DATA SOURCES: A random digit dial telephone survey administered to 655 rural adults; 176 answered questions regarding care of their children. CONCLUSIONS: Increasing fluid intake was the action most parents reported "always" taking when caring for a child with an ARI. Parents take their child to see a provider when they "just know" their child will not get better or when the child has discolored phlegm or discharge. Most reported reasons for not taking child to a provider were because the child got better on their own and they knew how to treat their child on their own. When seeing a provider for an ARI, parents considered it very important that the provider listen to the child's symptoms, examine their child for the cause of their symptoms, and provide symptom management advice. Parents expect providers to treat the ARI in one visit and allow for follow-up by phone or e-mail. IMPLICATIONS FOR PRACTICE: Nurse practitioners (NPs) in rural communities should be aware of the behaviors and expectations of parents in their practice. Awareness of these potentially unique issues will allow NPs to work with rural patients more effectively. PMID- 24170641 TI - Low-calorie diet induced weight loss may alter regulatory hormones and contribute to rebound visceral adiposity in obese persons with a family history of type-2 diabetes. AB - PURPOSE: To examine potential detrimental long-term effects of acute diet-induced weight loss on visceral adiposity, insulin resistance, cortisol, and adipokines in obese individuals at risk for type-2 diabetes. DATA SOURCES: Anthropometric measures (height, weight, waist circumference), self-report instruments, abdominal computed tomography (CT) scan, and blood samples (glucose, insulin, interleukin-6, leptin, adiponectin) were obtained from a convenience sample of 20 participants at baseline, after a 28-day low-calorie diet (800 kcal/day) intervention, and again 6 months later. CONCLUSIONS: Fifteen of 20 participants completed the 28-day diet intervention and had a mean weight loss of 15 pounds. Comparison between baseline, postdiet, and 6-month data, demonstrated that although participants had significant improvements after the diet, they regained fat mass, particularly in the visceral area. IMPLICATIONS FOR PRACTICE: Clinicians may need to revise recommendations for using low-calorie diets to achieve weight loss. Diet-induced weight cycling may contribute to dysregulation of metabolism and have long-term detrimental consequences for accumulation of visceral adipose tissue. The likelihood of success is low, with high dropout rates, and those patients who achieve weight loss are very likely to regain it. Thus, the perceived short-term benefits of calorie-restricted diets in this population likely do not outweigh the potential long-term detrimental effects. PMID- 24170643 TI - Outcomes of coronary artery interventions: comparing coronary artery bypass surgery and percutaneous coronary intervention in patients with unprotected left main stenosis. AB - PURPOSE: The purpose of this integrative review is to examine the existing literature comparing short- and long-term outcomes of both coronary artery bypass grafting (CABG) and percutaneous coronary intervention (PCI) in patients with unprotected left main coronary artery (ULMCA) stenosis. CABG has long been considered the standard of treatment for ULMCA stenosis; however, advancements in the use of PCI have made it a viable alternative treatment option. DATA SOURCES: Sixteen articles were selected from a literature search using the PubMed database, with at least 1 year of follow-up and adjustment for established risk factors. CONCLUSIONS: The majority of studies found CABG and PCI with stenting to be comparable and equally safe treatment strategies for patients with ULMCA stenosis. Some studies found that PCI had a significantly lower risk for adverse events and mortality compared to CABG. However, a large number of studies found that PCI had a higher rate of target vessel restenosis. IMPLICATIONS FOR PRACTICE: Advanced practice nurses have become a prominent and influential part of the healthcare delivery system. As such, advanced practice nurses should be educated on the current research about coronary artery interventions so that they may better screen, treat, and manage this patient population. PMID- 24170644 TI - Oral anti-pseudomonal antibiotics for cystic fibrosis. AB - BACKGROUND: Pseudomonas aeruginosa is the most common bacterial pathogen causing lung infections in people with CF and appropriate antibiotic therapy is vital. Antibiotics for pulmonary exacerbations are usually given intravenously, and for long-term treatment, via a nebuliser. Oral anti-pseudomonal antibiotics with the same efficacy and safety as intravenous or nebulised antibiotics would benefit people with CF due to ease of treatment and avoidance of hospitalisation. OBJECTIVES: To determine the benefit or harm of oral anti-pseudomonal antibiotic therapy for people with CF, colonised with Pseudomonas aeruginosa, in the:1. treatment of a pulmonary exacerbation; and 2. long-term treatment of chronic infection. SEARCH METHODS: We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group Trials Register comprising references identified from comprehensive electronic database searches and handsearches of relevant journals and abstract books of conference proceedings.We contacted pharmaceutical companies and checked reference lists of identified trials.Date of last search: 28 June 2013. SELECTION CRITERIA: Randomised or quasi-randomised controlled trials comparing any dose of oral anti-pseudomonal antibiotics, to other combinations of inhaled, oral or intravenous antibiotics, or to placebo or usual treatment for pulmonary exacerbations and long-term treatment. DATA COLLECTION AND ANALYSIS: Two authors independently selected the trials, extracted data and assessed quality. We contacted trial authors to obtain missing information. MAIN RESULTS: We included three trials examining pulmonary exacerbations (171 participants) and two trials examining long-term therapy (85 participants). We regarded the most important outcomes as quality of life and lung function. The analysis did not identify any statistically significant difference between oral anti-pseudomonal antibiotics and other treatments for these outcome measures for either pulmonary exacerbations or long-term treatment. One of the included trials reported significantly better lung function when treating a pulmonary exacerbation with ciprofloxacin when compared with intravenous treatment; however, our analysis did not confirm this finding. We found no evidence of difference between oral anti-pseudomonal antibiotics and other treatments regarding adverse events or development of antibiotic resistance, but trials were not adequately powered to detect this. None of the studies had a low risk of bias from blinding which may have an impact particularly on subjective outcomes such as quality of life. The risk of bias for other criteria could not be clearly stated across the studies. AUTHORS' CONCLUSIONS: We found no conclusive evidence that an oral anti-pseudomonal antibiotic regimen is more or less effective than an alternative treatment for either pulmonary exacerbations or long-term treatment of chronic infection with P. aeruginosa. Until results of adequately powered future trials are available, treatment needs to be selected on a pragmatic basis, based upon any available non-RCT evidence, the clinical circumstances of the individual, the known effectiveness of drugs against local strains and upon individual preference. PMID- 24170645 TI - Iodine modified carbon nitride semiconductors as visible light photocatalysts for hydrogen evolution. AB - An optimized and general synthetic strategy based on in-situ iodine modifying of polymeric graphitic carbon nitride is discussed. The as-prepared iodine functionalized g-CN shows enhanced electronic and optical properties, as well as increased photocatalytic activities in an assay of hydrogen evolution. PMID- 24170642 TI - Clinically significant drug interactions with atypical antipsychotics. AB - Atypical antipsychotics [also known as second-generation antipsychotics (SGAs)] have become a mainstay therapeutic treatment intervention for patients with schizophrenia, bipolar disorders and other psychotic conditions. These agents are commonly used with other medications--most notably, antidepressants and antiepileptic drugs. Drug interactions can take place by various pharmacokinetic, pharmacodynamic and pharmaceutical mechanisms. The pharmacokinetic profile of each SGA, especially with phase I and phase II metabolism, can allow for potentially significant drug interactions. Pharmacodynamic interactions arise when agents have comparable receptor site activity, which can lead to additive or competitive effects without alterations in measured plasma drug concentrations. Additionally, the role of drug transporters in drug interactions continues to evolve and may effect both pharmacokinetic and pharmacodynamic interactions. Pharmaceutical interactions occur when physical incompatibilities take place between agents prior to drug absorption. Approximate therapeutic plasma concentration ranges have been suggested for a number of SGAs. Drug interactions that markedly increase or decrease the concentrations of these agents beyond their ranges can lead to adverse events or diminished clinical efficacy. Most clinically significant drug interactions with SGAs occur via the cytochrome P450 (CYP) system. Many but not all drug interactions with SGAs are identified during drug discovery and pre-clinical development by employing a series of standardized in vitro and in vivo studies with known CYP inducers and inhibitors. Later therapeutic drug monitoring programmes, clinical studies and case reports offer methods to identify additional clinically significant drug interactions. Some commonly co-administered drugs with a significant potential for drug-drug interactions with selected SGAs include some SSRIs. Antiepileptic mood stabilizers such as carbamazepine and valproate, as well as other antiepileptic drugs such as phenobarbital and phenytoin, may decrease plasma SGA concentrations. Some anti-infective agents such as protease inhibitors and fluoroquinolones are of concern as well. Two additional important factors that influence drug interactions with SGAs are dose and time dependence. Smoking is very common among psychiatric patients and can induce CYP1A2 enzymes, thereby lowering expected plasma levels of certain SGAs. It is recommended that ziprasidone and lurasidone are taken with food to promote drug absorption, otherwise their bioavailability can be reduced. Clinicians must be aware of the variety of factors that can increase the likelihood of clinically significant drug interactions with SGAs, and must carefully monitor patients to maximize treatment efficacy while minimizing adverse events. PMID- 24170646 TI - Statins' effect on plasma levels of Coenzyme Q10 and improvement in myopathy with supplementation. AB - PURPOSE: Heart disease is the leading cause of death in the United States. HMG CoA reductase inhibitors, or statins, are medications at the forefront of the battle against cardiovascular disease. Despite their effectiveness, patient compliance with statins has lagged because of medication cost and adverse effects, namely myopathy. Myopathy is the most common side effect of statin use. The purpose of this review is to report plasma levels of CoQ10 in patients taking statins and then to determine the benefit of Coenzyme Q10 (CoQ10) supplementation on statin-related myopathy as evidenced by symptomatic improvement and increase in serum levels of CoQ10. DATA SOURCES: CINAHL, Medline, Health Source: Nursing/Academic Edition, and Cochrane Library. CONCLUSIONS: Evidence from this review suggests that studies showed a significant relationship between statin intake and decreased serum levels of CoQ10. A few studies showed a benefit in symptoms of myalgia or improvement of serum levels of CoQ10 with supplementation. One study showed no benefit of CoQ10 supplementation when taken with statins. There were no risks of supplementation reported in any of the studies. IMPLICATIONS FOR PRACTICE: CoQ10 supplementation might benefit those patients suffering from statin-induced myopathy as evidenced by the results of these studies. Supplementation of CoQ10 at a dose of between 30 and 200 mg daily has shown to have beneficial effects on statin myopathy with no noted side effects. Further research is necessary. PMID- 24170647 TI - AANP announces first honorary Fellow, Barbara J. Safriet. PMID- 24170648 TI - Orthostatic hypotension in older people. AB - PURPOSE: To enhance awareness of orthostatic hypotension (OH) in older populations, and guide primary care nurse practitioners (NPs) in the assessment and management of patients with OH. DATA SOURCES: Electronic data collection was conducted on studies and reviews that were published between 2005 and 2012 in English, and contained information related to the purpose of this article from following databases: PubMed, Scopus, and MEDLINE. CONCLUSIONS: OH is a syndrome that is accompanied by unfavorable symptoms such as dizziness, and headaches and can impede the individual's daily activities and quality of life. The prevalence of OH is higher in older people because of comorbidities, polypharmacy, and physiological changes that occur with aging. OH is diagnosed with serial blood pressure measurements and the primary goal of management is to relieve unfavorable symptoms and enhance patient safety. Pharmacological management is considered when nonpharmacological interventions fail. IMPLICATIONS FOR PRACTICE: OH is not a problem to be taken lightly as it is highly related to the risk of falling and cardiovascular problems, as well as increasing morbidity and mortality rates. NPs can contribute to improving the quality of life for older adults and reducing adverse consequences by understanding OH and adequately managing it. PMID- 24170649 TI - Correlates of nonalcoholic fatty liver among women receiving residential mental health care. AB - PURPOSE: To review the risk factors for diagnosis of nonalcoholic fatty liver disease (NAFLD) in women in a mental health, dual diagnosis, treatment facility. DATA SOURCES: A review of the literature and retrospective chart reviews of patients to identify factors within this population of women most closely associated with diagnosis of NAFLD. CONCLUSIONS: NAFLD is a common diagnosis and as obesity rates increase in the United States the incidence for this disease is also increasing. Identifiable risk factors are associated with the presence of this disease. Advanced practice nurses, as prescribers, need to be aware that the presence of NAFLD may interfere with drug metabolism and toxin elimination in their patients. IMPLICATIONS FOR PRACTICE: Numerous physical conditions, behavioral symptoms, and laboratory findings are identified as associated conditions of NAFLD. Patients seen in primary care practices have NAFLD, but patients in treatment centers for mental health disorders are also affected. This population is particularly at risk because of the hepatotoxic effects of many medications used in psychiatric-mental health settings. PMID- 24170650 TI - Improving diabetes outcomes by an innovative group visit model: a pilot study. AB - PURPOSE: To develop a group visit model that improves A1C, blood pressure, lipids, depression, and satisfaction among patients with diabetes that can be used in primary care practice settings. DATA SOURCES: Using a pre/post-test descriptive design, data were collected from 22 adult patients of a private family practice office. All patients had a diagnosis of diabetes and A1C of 7.5 or above. The participants consisted of over 70% of persons aged 50 or older who reported having diabetes for over 5 years. Eighty percent were female and 32% were African American. A1C, blood pressure, weight, lipids, depression, and satisfaction surveys were measured before and after the group visit series. CONCLUSIONS: The mean reduction in A1C was 1.1 points (p = .009). Weight decreased by a mean of 3.01 pounds (p = .001), diastolic blood pressure improved by a mean of 5.76 mmHg (p = .002). The Beck Depression Inventory showed significant improvement (p = .045) in depression scores. The Seattle Outpatient Satisfaction Questionnaire showed improvement (p = .028). IMPLICATIONS FOR PRACTICE: This model of care needs further testing, but preliminary data show it to be effective in improving clinical outcomes of patients with diabetes and realistic for nurse practitioner's to implement. PMID- 24170651 TI - Preparing practice scholars: teaching knowledge application in the Doctor of Nursing Practice curriculum. AB - PURPOSE: The purpose of this article is to explore the scholarship role of the Doctor of Nursing Practice (DNP) and the associated knowledge and skills required for success. DATA SOURCES: There are excellent competencies provided by national organizations that present guidelines for design and application of this practice scholar's contributions. Although evidence-based research translation is known to be essential for the DNP scholar, a consensus does not exist about the required research knowledge and skill levels that are needed. CONCLUSIONS: A model was developed to depict the scholarship roles of the DNP and the Doctor of Philosophy (PhD). This model indicates both DNP and PhD scholars are alike in their enactment of active scholarship but have different areas of expertise. They are different in their major roles that lead to the development of practice science; the DNP is the expert in knowledge application while the PhD is the expert in knowledge generation. IMPLICATIONS FOR PRACTICE: A nurse practice scholar needs to have a fundamental and strong understanding of research design and interpretation in order to appraise and implement research-based evidence into practice and conduct clinical projects. PMID- 24170652 TI - The Pediatric Obesity Initiative: development, implementation, and evaluation. AB - PURPOSE: Pediatric obesity rates have nearly tripled over the past three decades contributing to increased morbidity and mortality in the United States and around the world. Pediatric obesity is most prevalent in developed countries and affects all races, ethnicities, cultures, and age groups. To combat this epidemic locally, a team of dedicated providers developed a comprehensive evidenced-based toolkit and training program for clinical practices providing primary care services to children in a North Carolina county. DATA SOURCES: The toolkit and training program were developed using the most current treatment guidelines for pediatric obesity and included resources developed by Healthy Carolinians. One unique feature of the training was a demonstration of motivational interviewing with additional resources included in the toolkit. CONCLUSIONS: Staff and providers in three pediatric practices and the local Health Department received the training. In a 3 months follow-up survey after the training, the providers indicated that the toolkit and training program were useful but that they still did not consistently use the guidelines or tools. IMPLICATIONS FOR PRACTICE: Ensuring the use of available guidelines and resources by providers remains a challenge. Further study is needed on how to improve implementation of guidelines in primary care settings. PMID- 24170653 TI - Therapeutic options for lowering LDL-C in type 2 diabetes: a nurse practitioner's perspective. AB - PURPOSE: The majority of patients with type 2 diabetes mellitus (T2DM) have multiple risk factors for cardiovascular disease (CVD). Low-density lipoprotein cholesterol (LDL-C) is a key therapeutic target to reduce CVD risk. This article reviews therapeutic strategies that nurse practitioners (NPs) may use in the management of patients with T2DM requiring lipid management. DATA SOURCES: The evidence used in developing this review included evidence-based reviews, clinical trials, guidelines, and consensus statements. Relevant publications were identified through a search of the literature using PubMed and other search engines. CONCLUSIONS: Lowering LDL-C levels may reduce CVD risk, but achieving goals can be challenging. Lifestyle modifications (including diet, exercise, and smoking cessation) are key components of lipid management and reduction of CVD risk. Statins can be effective to reduce lipids. However, patients may not achieve lipid goals with monotherapy or may experience intolerable adverse effects. Alternative statins or statins along with other lipid-lowering agents remain good options. IMPLICATIONS FOR PRACTICE: Achieving LDL-C goals requires a comprehensive treatment plan that incorporates lifestyle and pharmacologic interventions. Patient commitment in setting goals and self-management is essential. NPs can play an important role in educating patients as well as prescribing appropriate treatments. PMID- 24170654 TI - Health literacy, self-efficacy, and self-care behaviors in patients with type 2 diabetes mellitus. AB - PURPOSE: The study purpose was to explore the relationships among health literacy, self-efficacy, and self-care behaviors of patients with type 2 diabetes. DATA SOURCES: A cross-sectional study with a descriptive correlational design was conducted. Patients (N = 150) with type 2 diabetes were recruited from diabetes clinics in the Marshall Islands. Levels of health literacy, self efficacy, and self-care behaviors were assessed by a questionnaire. CONCLUSIONS: Health literacy, receiving diabetes education, and employment status together explained 11.8% of the variance in self-efficacy (F((3,147)) = 7.58, p < .001). Patients who had higher health literacy, received more diabetes-related education, were currently employed and had better self-efficacy. Self-efficacy and marital status together explained 16.7% of the variance in self-care behaviors (F((2,148)) = 15.96, p < .001). Patients who had higher self-efficacy and who were married had better self-care behaviors. IMPLICATIONS FOR PRACTICE: Strategies are needed to incorporate the concept of self-efficacy in the design of diabetes education to promote patients' self-care behaviors, with an emphasis on dealing with hyper- or hypoglycemia, following the diet plan, and checking blood sugar levels as recommended. Diabetes education material that requires a lower literacy level may be needed for older or unemployed adult populations. PMID- 24170655 TI - CHD knowledge and risk factors among Filipino-Americans connected to primary care services. AB - PURPOSE: To examine the baseline knowledge and risk factors of coronary heart disease (CHD) among Filipino-Americans (FAs), and to identify the predictors of CHD knowledge. DATA SOURCES: A convenience sample of 120 FAs recruited from three primary care clinics in Las Vegas, Nevada between May and July, 2010. Participants were asked about their demographic data and presence of CHD risk factors using the Demographics questionnaire. CHD knowledge was examined using the Heart Disease Fact questionnaire. CONCLUSIONS: FAs connected to primary care services are knowledgeable about CHD. Predictors of CHD knowledge include: gender and education. CHD risk factors common to FAs include: hypertension, diabetes mellitus type 2, dyslipidemia, abdominal adiposity, overweight, lack of exercise, and smoking. IMPLICATIONS FOR PRACTICE: Knowledge on CHD alone may not help prevent heart disease among FAs. Behavioral and cultural factors may play a major role in the development of CHD and CHD risk factors among FAs. NPs and other health care providers serve a vital role on health promotion, disease prevention, and management of patients. The use of the Neuman's systems model can serve as a guide when caring for FAs because of its emphasis in primary and secondary prevention interventions. Nurse practitioners must provide holistic and culturally sensitive care when managing their FA patients. PMID- 24170656 TI - A personality and gender perspective on adherence and health-related quality of life in people with asthma and/or allergic rhinitis. AB - PURPOSE: Poor adherence to medication treatment for asthma and allergic rhinitis could challenge a positive health outcome. Health-related quality of life (HRQL) is an important measure of health outcome. Both personality and gender could influence adherence and perceptions of HRQL. The purpose was to clarify the role of personality and gender in relation to adherence and HRQL in people with asthma and/or rhinitis. DATA SOURCES: Participants (n = 180) with asthma and allergic rhinitis, selected from a population-based study, filled out questionnaires on the five-factor model personality traits--neuroticism, extraversion, openness to experience, agreeableness, and conscientiousness--HRQL, and adherence to medication treatment. Data were statistically analyzed using t-tests, Mann Whitney tests, bivariate correlations, and multiple regressions. CONCLUSIONS: Personality traits were associated with adherence to medication treatment in men. The influence of personality traits on HRQL also differed between men and women. These differences suggest that both a personality and gender perspective should be considered when planning care support aimed at improving adherence and HRQL in people living with asthma and/or allergic rhinitis. IMPLICATIONS FOR PRACTICE: It is suggested that both a personality and gender perspective be taken into account in care support aimed at improving adherence and HRQL in people with asthma and allergic rhinitis. PMID- 24170657 TI - An introduction of genetics in otosclerosis: a systematic review. AB - OBJECTIVE: To present an easy to read systematic review concerning the genetic etiology of otosclerosis to help health care providers in counseling otosclerosis patients more accurately. DATA SOURCES: PubMed, Embase, CINAHL, and the Cochrane Library. REVIEW METHODS: Studies on the genetic etiology of otosclerosis were selected. Association studies and family-based studies were included for further review. After quality assessment (risk of bias), data were extracted from the included studies. When available, odds ratios were presented. In case of corresponding genetic anomalies between the studies, it was the aim to combine results. RESULTS: The number of available studies with low risk of bias is limited to 2 association studies and 1 family-based study. These high-quality studies show that otosclerosis in Japanese patients is not linked to the NOG gene and that a polymorphism in the Sp1 binding site located on the COL1A1 gene is associated with otosclerosis as well as OTSC1. Association and family-based studies with moderate risk of bias show a statistically significant association with the ACE gene, AGT gene, OTSC2, RELN gene, TGFB1 gene, 11q13.1, OTSC2, OTSC5, OTSC8, and OTSC10. These results may be spurious associations due to their bias and low statistical power. CONCLUSION: The present systematic review shows that there is scattered evidence of limited quality and a lack of replication studies. It is not possible to point out 1 or more responsible genes, which play a key role within the genetic pathophysiologic mechanism of otosclerosis. PMID- 24170658 TI - Intraoperative cone-beam computed tomography and multi-slice computed tomography in temporal bone imaging for surgical treatment. AB - OBJECTIVE: Conventional computed tomography (CT) imaging is the standard imaging technique for temporal bone diseases, whereas cone-beam CT (CBCT) imaging is a very fast imaging tool with a significant less radiation dose compared with conventional CT. We hypothesize that a system for intraoperative cone-beam CT provides comparable image quality to diagnostic CT for identifying temporal bone anatomical landmarks in cadaveric specimens. STUDY DESIGN: Cross-sectional study. SETTING: University tertiary care facility. SUBJECTS AND METHODS: Twenty cadaveric temporal bones were affixed into a head phantom and scanned with both a prototype cone-beam CT C-arm and multislice helical CT. Imaging performance was evaluated by 3 otologic surgeons and 1 head and neck radiologist. Participants were presented images in a randomized order and completed landmark identification questionnaires covering 21 structures. RESULTS: CBCT and multislice CT have comparable performance in identifying temporal structures. Three otologic surgeons indicated that CBCT provided statistically equivalent performance for 19 of 21 landmarks, with CBCT superior to CT for the chorda tympani and inferior for the crura of the stapes. Subgroup analysis showed that CBCT performed superiorly for temporal bone structures compared with CT. The radiologist rated CBCT and CT as statistically equivalent for 18 of 21 landmarks, with CT superior to CBCT for the crura of stapes, chorda tympani, and sigmoid sinus. CONCLUSION: CBCT provides comparable image quality to conventional CT for temporal bone anatomical sites in cadaveric specimens. Clinical applications of low-dose CBCT imaging in surgical planning, intraoperative guidance, and postoperative assessment are promising but require further investigation. PMID- 24170659 TI - Adenotonsillectomy vs observation for management of mild obstructive sleep apnea in children. AB - OBJECTIVE: To determine the impact of adenotonsillectomy vs observation on quality of life (QOL) in children with mild obstructive sleep apnea (OSA). STUDY DESIGN: Prospective, nonrandomized trial. SETTING: Tertiary children's hospital. SUBJECTS AND METHODS: Sixty-four children (ages 3-16 years) with mild OSA (apnea hypopnea index between 1 and 5 on polysomnogram) completed the study. Caregivers chose between management options of adenotonsillectomy and observation and completed validated QOL instruments (OSA-18 and Children's Health Questionnaire) at baseline, early, and late follow-ups. The primary outcome measure was QOL. RESULTS: Thirty patients chose adenotonsillectomy, while 34 were observed. Total OSA-18 scores at baseline were significantly poorer (P = .01) in the surgery group (72.3) compared with the observation group (58.5). Four months following surgery, OSA-18 scores improved by 39.1 points over baseline (P = .0001), while there was no change for the observation group (P = .69). After 8 months, OSA-18 scores remained improved in the surgery group, and observation group scores improved by 13.4 points over baseline (P = .005). While OSA-18 scores at the late follow-up visit were poorer in the observation group, the difference was not statistically significant (P = .05). Six observation patients opted for adenotonsillectomy during the study. CONCLUSION: Quality of life significantly improves in children with mild OSA after adenotonsillectomy. In children with mild OSA who are observed, QOL improvements at early follow-up are less pronounced, but significant improvements in QOL are evident after 8 months. QOL instruments may be useful tools to help providers determine which children with mild OSA may benefit from early intervention. PMID- 24170660 TI - Dual-port thymectomy using subxiphoid approach. AB - We have previously reported single-port thymectomy (SPT) through an infrasternal approach, a procedure in which the thymus is removed through a single port. The dual-port thymectomy procedure developed by adding another port to the single port procedure has eliminated the risk of interference between forceps operated by both hands of the surgeon and has thereby significantly simplified operative procedures. This procedure provides the same operative field as that obtained by median sternotomy and has excellent maneuverability of devices. Therefore, the dual-port procedure can be used by surgeons who have not been sufficiently trained for SPT, as an alternative procedure in the event of experiencing technical difficulty during SPT, or as a new approach for thymectomy. PMID- 24170661 TI - Two-dimensional gel-based proteomic of the caries causative bacterium Streptococcus mutans UA159 and insight into the inhibitory effect of carolacton. AB - Streptococcus mutans is considered to be the most cariogenic organism. Carolacton, isolated from the myxobacterium Sorangium cellulosum, shows the ability to disturb S. mutans biofilm viability that makes it a potential anti biofilm drug. However, the molecular mechanism of carolacton remains to be elucidated. In order to use proteomics to characterize the effect of carolacton, we constructed a 2DE-based proteome reference map of the cytoplasmic and extracellular proteins for S. mutans in the present study. In total, 239 protein spots representing 192 different cytoplasmic proteins were identified by MALDI TOF MS and PMF. This represents the highest number of identified proteins so far for S. mutans UA159 in the pI range of 4-7 and would benefit further research on the physiology and pathogenicity of this strain. Based on the constructed reference map, the inhibitory effects of carolacton on S. mutans biofilm and planktonic-growing cells were investigated. The results of the comparative proteome analysis indicate that carolacton exerts its inhibitory effects by disturbing the peptidoglycan biosynthesis and degradation and thereby causes damages to the integrity of the cell envelope, leading ultimately to cell death. PMID- 24170662 TI - [Not Available]. PMID- 24170664 TI - High failure rate of ethnic minority groups in MRCGP exam comes from changes to exam and candidate selection. PMID- 24170665 TI - Therapeutic options for old world cutaneous leishmaniasis and new world cutaneous and mucocutaneous leishmaniasis. AB - Estimated worldwide incidence of tegumentary leishmaniasis (cutaneous leishmaniasis [CL] and mucocutaneous leishmaniasis [MCL]) is over 1.5 million cases per year in 82 countries, with 90 % of cases occurring in Afghanistan, Brazil, Iran, Peru, Saudi Arabia and Syria. Current treatments of CL are poorly justified and have sub-optimal effectiveness. Treatment can be based on topical or systemic regimens. These different options must be based on Leishmania species, geographic regions, and clinical presentations. In certain cases of Old World CL (OWCL), lesions can spontaneously heal without any need for therapeutic intervention. Local therapies (thermotherapy, cryotherapy, paromomycin ointment, local infiltration with antimonials) are good options with less systemic toxicity, reserving systemic treatments (azole drugs, miltefosine, antimonials, amphotericin B formulations) mainly for complex cases. The majority of New World CL (NWCL) types require systemic treatment (mainly with pentavalent antimonials), either to speed the healing or to prevent dissemination to oral-nasal mucosa as MCL (NWMCL). These types of lesions are potentially serious and always require systemic-based regimens, mainly antimonials and pentamidine; however, the associated immunotherapy is promising. This paper is an exhaustive review of the published literature on the treatment of OWCL, NWCL and NWMCL, and provides treatment recommendations stratified according to their level of evidence regarding the species of Leishmania implicated and the geographical location of the infection. PMID- 24170669 TI - Blood pressure targets for hypertension in people with diabetes mellitus. AB - BACKGROUND: When treating elevated blood pressure (BP), doctors often want to know what blood pressure target they should try to achieve. The standard blood pressure target in clinical practice for some time has been less than 140 - 160/90 - 100 mmHg for the general population of people with elevated blood pressure. Several clinical guidelines published in recent years have recommended lower targets (less than 130/80 mmHg) for people with diabetes mellitus. It is not known whether attempting to achieve targets lower than the standard target reduces mortality and morbidity in those with elevated blood pressure and diabetes. OBJECTIVES: To determine if 'lower' BP targets (any target less than 130/85 mmHg) are associated with reduction in mortality and morbidity compared with 'standard' BP targets (less than 140 - 160/90 - 100 mmHg) in people with diabetes. SEARCH METHODS: We searched the Database of Abstracts of Reviews of Effectiveness (DARE) and the Cochrane Database of Systematic Reviews for related reviews. We conducted electronic searches of the Hypertension Group Specialised Register (January 1946 - October 2013), the Cochrane Central Register of Controlled Trials (CENTRAL) (2013, Issue 9), MEDLINE (January 1946 - October 2013), EMBASE (January 1974 - October 2013) and ClinicalTrials.gov. The most recent search was performed on October 4, 2013.Other search sources were the International Clinical Trials Registry Platform (WHO ICTRP), and reference lists of all papers and relevant reviews. SELECTION CRITERIA: Randomized controlled trials comparing people with diabetes randomized to lower or to standard BP targets as previously defined, and providing data on any of the primary outcomes below. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed and established the included trials and data entry. Primary outcomes were total mortality; total serious adverse events; myocardial infarction, stroke, congestive heart failure and end-stage renal disease. Secondary outcomes were achieved mean systolic and diastolic BP, and withdrawals due to adverse effects. MAIN RESULTS: We found five randomized trials, recruiting a total of 7314 participants and with a mean follow-up of 4.5 years. Only one trial (ACCORD) compared outcomes associated with 'lower' (< 120 mmHg) or 'standard' (< 140 mmHg) systolic blood pressure targets in 4734 participants. Despite achieving a significantly lower BP (119.3/64.4 mmHg vs 133.5/70.5 mmHg, P < 0.0001), and using more antihypertensive medications, the only significant benefit in the group assigned to 'lower' systolic blood pressure (SBP) was a reduction in the incidence of stroke: risk ratio (RR) 0.58, 95% confidence interval (CI) 0.39 to 0.88, P = 0.009, absolute risk reduction 1.1%. The effect of SBP targets on mortality was compatible with both a reduction and increase in risk: RR 1.05 CI 0.84 to 1.30, low quality evidence. Trying to achieve the 'lower' SBP target was associated with a significant increase in the number of other serious adverse events: RR 2.58, 95% CI 1.70 to 3.91, P < 0.00001, absolute risk increase 2.0%.Four trials (ABCD-H, ABCD-N, ABCD-2V, and a subgroup of HOT) specifically compared clinical outcomes associated with 'lower' versus 'standard' targets for diastolic blood pressure (DBP) in people with diabetes. The total number of participants included in the DBP target analysis was 2580. Participants assigned to 'lower' DBP had a significantly lower achieved BP: 128/76 mmHg vs 135/83 mmHg, P < 0.0001. There was a trend towards reduction in total mortality in the group assigned to the 'lower' DBP target (RR 0.73, 95% CI 0.53 to 1.01), mainly due to a trend to lower non-cardiovascular mortality. There was no difference in stroke (RR 0.67, 95% CI 0.42 to 1.05), in myocardial infarction (RR 0.95, 95% CI 0.64 to 1.40) or in congestive heart failure (RR 1.06, 95% CI 0.58 to 1.92), low quality evidence. End-stage renal failure and total serious adverse events were not reported in any of the trials. A sensitivity analysis of trials comparing DBP targets < 80 mmHg (as suggested in clinical guidelines) versus < 90 mmHg showed similar results. There was a high risk of selection bias for every outcome analyzed in favor of the 'lower' target in the trials included for the analysis of DBP targets. AUTHORS' CONCLUSIONS: At the present time, evidence from randomized trials does not support blood pressure targets lower than the standard targets in people with elevated blood pressure and diabetes. More randomized controlled trials are needed, with future trials reporting total mortality, total serious adverse events as well as cardiovascular and renal events. PMID- 24170667 TI - Pharmacotherapy for disorders of consciousness: are 'awakening' drugs really a possibility? AB - Disorders of consciousness, including the coma state, vegetative state and minimally conscious state, are among the least understood and least curable conditions in modern neurology. Structural or functional injuries may produce impairments in the neuronal circuits (the ascending reticular activating system and thalamocortical loops) responsible for maintaining the wakefulness state and awareness, associated with a change in neurotransmitter concentrations. Pharmacological agents that are able to restore the levels of neurotransmitters and, consequently, neural synaptic plasticity and functional connectivity of consciousness networks, may play an important role as drugs useful in improving the consciousness state. Currently, there is growing interest in the scientific community with regard to pharmacological agents that act on the gamma amino butyric acid (GABA) system, such as zolpidem and baclofen, and monoamine systems, such as dopaminergic agents and some antidepressants. The purpose of this article is to provide a comprehensive overview of these potential 'awakening' drugs in patients with disorders of consciousness. The possible mechanisms by which these drugs may exert their effects in promoting recovery of consciousness are discussed, highlighting how many findings are often the result of sporadic events rather than prospective controlled trials or implementation of standard treatment guidelines. PMID- 24170666 TI - Therapeutic options for visceral leishmaniasis. AB - Visceral leishmaniasis (VL), also known as Kala-Azar, is a disseminated protozoal infection caused principally by Leishmania donovani and Leishmania infantum (known as Leishmania chagasi in South America). The therapeutic options for VL are diverse and depend on different factors, such as the geographical area of the infection, development of resistance to habitual treatments, HIV co-infection, malnourishment and other concomitant infections. This article provides an exhaustive review of the literature regarding studies published on the treatment of VL, and gives therapeutic recommendations stratified according to their level of evidence, the species of Leishmania implicated and the geographical location of the infection. PMID- 24170670 TI - Malabsorption anemia and iron supplement induced constipation in post-Roux-en-Y gastric bypass (RYGB) patients. AB - PURPOSE: Over 250,000 bariatric surgical procedures for the management of morbid obesity are performed in the United States annually. The Roux-en-Y gastric bypass (RYGB) is an effective bariatric procedure because of its efficacy in achieving significant weight loss, low complication rates, and outcomes in reducing cardiovascular and all cause mortality. Because food bypasses the portion of the small intestine whereby micronutrients are normally absorbed, micronutrient deficiencies following surgery may lead to iron deficiency anemia. Iron deficiency anemia is estimated to occur in 6%-50% of post-RYGB patients. Consequently, the procedure requires lifelong behavioral change to ensure therapeutic iron supplementation. DATA SOURCES: A nonsystematic literature search for clinical guidelines, review articles, and research was conducted. CONCLUSIONS: Clinical recommendations include prophylactic iron supplementation with ferrous sulfate to prevent iron deficiency anemia. Ferrous sulfate is a well established cause of constipation possibly resulting in low patient tolerability and subsequent low adherence rates. CLINICAL IMPLICATIONS: Strategies for managing the side effects of iron supplementation including constipation may require a unique approach based on the anatomical and functional changes in the post-RYGB patient and the requirement for lifelong iron supplementation. PMID- 24170671 TI - Aging differently: diet- and sex-dependent late-life mortality patterns in Drosophila melanogaster. AB - Diet effects on age-dependent mortality patterns are well documented in a large number of animal species, but studies that look at the effects of nutrient availability on late-life mortality plateaus are lacking. Here, we focus on the effect of dietary protein content (low, intermediate, and high) on mortality trajectories in late life in the fruit fly Drosophila melanogaster. According to the two theories that are mainly implicated in explaining the deceleration of mortality rate in late life (the heterogeneity/frailty theory and the Hamiltonian theory), we predict, in general, the occurrence of late-life mortality deceleration under most circumstances, independent of sex and dietary regime. However, the heterogeneity theory of late life is more flexible in allowing no mortality deceleration to occur under certain circumstances compared with the Hamiltonian theory. We applied a novel statistical approach based on Bayesian inference of age-specific mortality rates and found a deceleration of late-life mortality rates on all diets in males but only on the intermediate (standard) diet in females. The difference in mortality rate deceleration between males and females on extreme diets suggests that the existence of mortality plateaus in late life is sex and diet dependent and, therefore, not a universal characteristic of large enough cohorts. PMID- 24170672 TI - Sensorimotor and postural control factors associated with driving safety in a community-dwelling older driver population. AB - BACKGROUND: To establish whether sensorimotor function and balance are associated with on-road driving performance in older adults. METHODS: The performance of 270 community-living adults aged 70-88 years recruited via the electoral roll was measured on a battery of peripheral sensation, strength, flexibility, reaction time, and balance tests and on a standardized measure of on-road driving performance. RESULTS: Forty-seven participants (17.4%) were classified as unsafe based on their driving assessment. Unsafe driving was associated with reduced peripheral sensation, lower limb weakness, reduced neck range of motion, slow reaction time, and poor balance in univariate analyses. Multivariate logistic regression analysis identified poor vibration sensitivity, reduced quadriceps strength, and increased sway on a foam surface with eyes closed as significant and independent risk factors for unsafe driving. These variables classified participants into safe and unsafe drivers with a sensitivity of 74% and specificity of 70%. CONCLUSIONS: A number of sensorimotor and balance measures were associated with driver safety and the multivariate model comprising measures of sensation, strength, and balance was highly predictive of unsafe driving in this sample. These findings highlight important determinants of driver safety and may assist in developing efficacious driver safety strategies for older drivers. PMID- 24170674 TI - Structure-based barcoding of proteins. AB - A reduced representation in the format of a barcode has been developed to provide an overview of the topological nature of a given protein structure from 3D coordinate file. The molecular structure of a protein coordinate file from Protein Data Bank is first expressed in terms of an alpha-numero code and further converted to a barcode image. The barcode representation can be used to compare and contrast different proteins based on their structure. The utility of this method has been exemplified by comparing structural barcodes of proteins that belong to same fold family, and across different folds. In addition to this, we have attempted to provide an illustration to (i) the structural changes often seen in a given protein molecule upon interaction with ligands and (ii) Modifications in overall topology of a given protein during evolution. The program is fully downloadable from the website http://www.iitg.ac.in/probar/. PMID- 24170673 TI - Association between cerebellar gray matter volumes, gait speed, and information processing ability in older adults enrolled in the Health ABC study. AB - BACKGROUND: The cerebellum plays an important role in mobility and cognition. However, it is unclear which regions of the cerebellum are associated with gait speed and information-processing ability in older adults without overt brain damage. METHODS: Cross-sectional associations between cerebellar gray matter volumes (GMV), gait speed, and information-processing ability were explored in 231 community-dwelling adults (mean age: 83 years, 48% black, 58% female). We measured gait speed on an automated walkway and information-processing ability on the Digit Symbol Substitution test (DSST). Total and regional cerebellar GMV was measured on 3T-magnetic resonance imaging. Lobar GMV of the cerebellum, obtained by an automated parcellation process, were aggregated based on the cognitive (lobules VI, VII, VIII and crus I, II), sensorimotor (lobules II, IV, V), and vestibular (lobules IX and X) functions ascribed to the cerebellar regions. RESULTS: Larger cerebellar GMV correlated with faster gait speed and superior DSST scores (both p < .001) independent of age, gender, atrophy, and small vessel disease. After adjusting for age, gender, and atrophy, larger cognitive cerebellar GMV correlated with both faster gait speed (p = .04) and higher DSST scores (p < .001), larger sensorimotor cerebellar GMV correlated significantly with DSST alone (p = .02), and the vestibular cerebellar GMV with neither. The association between cognitive cerebellar GMV and gait speed was no longer significant after adjusting for DSST score in the linear regression models. CONCLUSIONS: The relationship between gait speed and cerebellar GMV is influenced by information-processing ability, and this relationship is stronger in subregions ascribed to cognitive than vestibular or sensorimotor functions. PMID- 24170675 TI - Gaps in the primary care of rural and underserved populations: the impact of nurse practitioners in four Mississippi Delta states. AB - PURPOSE: The shortage and distribution of primary care providers (PCPs) has left a gap in the health care of society, particularly those residents within the Lower Mississippi River Delta region, where pockets of rural and underserved populations reside. Described in this study are the workforce distribution, characteristics, and likelihood of advanced practice nurses (APNs) to practice in these communities. DATA SOURCES: Surveys were completed by 479 APNs in Arkansas, Louisiana, Mississippi, and Tennessee. Other sources included census data and the designation of Health Professional Shortage Areas as specified by Health Resources and Services Administration. CONCLUSIONS: Fifty-one percent of respondents indicated they practice in primary care; 24% practice in a designated Health Professional Shortage Areas; and 54% practice in a rural area. Family nurse practitioners (FNPs), in particular, were more likely to practice in rural and shortage areas. IMPLICATIONS: More APNs, especially nurse practitioners (NPs), are needed to address the PCP shortage. But more than just increased numbers of NPs is the need for redistribution of these providers. Efforts to expand the scope of practice and limit regulatory restrictions will enable NPs to practice more autonomously, which in turn will provide opportunities for better access and improved healthcare outcomes, especially in rural and underserved regions. Educational programs must include competencies and skill sets focused on meeting the needs of these populations. PMID- 24170676 TI - Binge eating and weight loss behaviors of overweight and obese college students. AB - PURPOSE: To investigate binge eating (BE) and weight-related behaviors in overweight and obese college students. DATA SOURCES: This was a secondary analysis of data from 487 overweight and obese college-age students from a private university in the northeastern United States. CONCLUSIONS: BE was reported by 34.9% of students. Only 6.2% of participants reported the use of compensatory behaviors (i.e., self-induced vomiting, laxative, or diuretic use) to prevent weight gain. BE was associated with smoking and exercising to lose weight. Gender differences emerged from the data as women were more likely to report being obese, the use of compensatory behaviors, and to perceive themselves as moderately or extremely overweight. IMPLICATIONS FOR PRACTICE: BE is a significant problem on college campuses and is associated with the development of obesity and eating disorders. Nurse practitioners (NPs) are in an excellent position to effect change in this population through their frequent contact with young adults in community and school-based venues. NPs are well-prepared to identify at-risk college students and provide them with individualized care, education, and support. PMID- 24170677 TI - Phenolic metabolites of anthocyanins following a dietary intervention study in post-menopausal women. AB - SCOPE: Numerous studies feeding anthocyanin-rich foods report limited bioavailability of the parent anthocyanins. The present study explores the identity and concentration of the phenolic metabolites of anthocyanins in humans. METHODS AND RESULTS: Anthocyanin metabolites were quantified in samples collected from a previously conducted 12-wk elderberry intervention study in healthy post menopausal women. Individual 1-, 2- and 3-h post-bolus urine samples and pooled plasma samples following acute (single bolus) and chronic (12-wk supplementation) anthocyanin consumption (500 mg/day) were analysed using HPLC-ESI-MS/MS. Twenty eight anthocyanin metabolites were identified in urine and 21 in plasma (including sulfates of vanillic, protocatechuic and benzoic acid). Phenolic metabolites reached peak concentrations of 1237 nM in plasma, while anthocyanin conjugates only reached concentrations of 34 nM. Similarly, in urine, phenolic metabolites were detected at concentrations of 33,185 +/- 2549 nM/mM creatinine, while anthocyanin conjugates reached concentrations of 548 +/- 219 nM/mM creatinine. There was no evidence that chronic exposure had any impact on either the profile or quantity of metabolites recovered relative to acute exposure. CONCLUSION: An extensive range of phenolic metabolites of anthocyanin was identified following elderberry consumption in humans, including 11 novel metabolites, which were identified at much higher concentrations than their parent compounds. PMID- 24170678 TI - The meaning in life for patients recently hospitalized with congestive heart failure. AB - PURPOSE: Quality of life (QOL) is based on individual values and is identified by what each person believes it to be. To provide patient centered care, practitioners must have an understanding of what each individual identifies as important in their lives. The purpose of this study was to identify what provides meaning to the lives of patients recently hospitalized with congestive heart failure (CHF). DATA SOURCE: Participants for this pilot study were a convenience sample of 32 patients hospitalized as a result of complications of CHF. Study methodology was a cross-sectional, interview style survey, utilizing the Schedule for Meaning in Life Evaluation (SMiLE). CONCLUSION: No statistical significance was found between SMiLE scores and demographic data, including number of admissions or length of time since diagnosis. These findings suggest meaning in life (MIL), and subsequently QOL, may not be related to having a diagnosis of CHF. IMPLICATIONS FOR PRACTICE: Identifying patients' relationship with their families, through the use of the SMiLE, has the ability to guide advanced planning decision making. Knowing, and preparing for, various family dynamics before the final stages of CHF may decrease episodes of care provided in opposition to patients' wishes, whether or not their wishes were previously stated or documented. PMID- 24170680 TI - Research methods for graduate students: a practical framework to guide teachers and learners. AB - PURPOSE: The purpose of this article is to present the Arrow Framework for Research Design, an organizing framework that facilitates teaching and learning of research methods, providing logical organization of interrelationships between concepts, content, and context of research methods, and practice application. The Arrow Framework was designed for teaching and learning research methods to facilitate progression of knowledge acquisition through synthesis. DATA SOURCES: The framework was developed over several years and used successfully to teach masters, DNP, and PhD nursing students across five universities. The framework is presented with incremental graphics and narrative for teaching. CONCLUSION: The Arrow Framework provides user-friendly information, in an organized and systematic approach demonstrated as successful for teaching and learning the foundational language of research, facilitating synthesis and application in scholarly endeavors. IMPLICATIONS FOR PRACTICE: The Arrow Framework will be useful for educators and students in teaching and learning research language, relationships, and application of methods. The materials are easily adaptable to slide or paper presentation, and meet learner needs for narrative and visual presentation. Teaching research design to graduate students is critical to meet the expectation that students are to understand the scientific underpinnings of nursing science and appropriate use of evidence that are essential for well educated practitioners. PMID- 24170679 TI - Levels of fatigue and distress in senior prostate cancer survivors enrolled in a 12-week randomized controlled trial of Qigong. AB - PURPOSE: Fatigue is a commonly reported symptom by prostate cancer survivors and is associated with significant distress and declines in quality of life. Qigong is a mind-body activity that consists of both physical activity and meditative aspects. This 12-week randomized controlled trial examined the feasibility and efficacy of a Qigong intervention for improving older prostate cancer survivors' levels of fatigue and distress. METHODS: Forty older (median age = 72, range = 58 93), fatigued (cut-off value of >= 1 on the CTCAEv4.0, >20 on a fatigue grading scale), and sedentary (<150 min of moderate exercise/week) prostate cancer survivors were randomized to 12 weeks of Qigong or stretching classes. Primary outcomes were feasibility (i.e., retention and class attendance rates) and fatigue [Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT Fatigue)], and secondary outcome was distress [Brief Symptom Inventory-18 (BSI 18)]. RESULTS: Study retention rates did not significantly differ between study groups (Qigong = 80 %, stretching = 65 %, p = 0.48). The Qigong group had significantly higher class attendance than the stretching group (p = 0.04). The Qigong group had significantly greater improvements in the FACIT-Fatigue (p = 0.02) and distress (i.e., BSI-18 Somatization, Anxiety, & Global Severity Index, p's < 0.05), than the Stretching group. CONCLUSIONS: This 12-week Qigong intervention was feasible and potentially efficacious in improving senior prostate cancer survivors' levels of fatigue and distress levels. Future, larger definitive randomized controlled trials are needed to confirm these benefits in older prostate cancer survivors and in racially and ethnically diverse populations. IMPLICATIONS FOR CANCER SURVIVORS: Qigong may be an effective nonpharmacological intervention for the management of senior prostate cancer survivors' fatigue and distress. PMID- 24170681 TI - Influence of lifestyle, health behavior, and health indices on the health status of underserved adults. AB - PURPOSE: To examine how lifestyle, health behavior, and health indices best predict health status in underserved adults. DATA SOURCES: Eighty-four underserved adults from a nurse-managed center completed an investigator developed instrument to measure lifestyle, health behavior, and health indices. The SF-12 Health Survey measured general (SF-1), physical (PCS), and mental (MCS) health status. CONCLUSIONS: The majority of the sample was female (64%). Sixty three percent were at or below 200% of the federal poverty level. For nonsmokers, five independent variables accounted for 47.1% of the variance in SF1 (p < .000), 33.5% in PCS-12 scores (p < .001), and 23.2% in MCS-12 scores (p = .017). For smokers, six variables accounted for 48.7% of the variance in SF1 (p = .024), 41.7% in PCS-12 scores (p = .067), and 25.4% in MCS-12 scores (p = .378). IMPLICATIONS FOR PRACTICE: Findings provide partial support for the impact of lifestyle and health behaviors on health status outcomes. Focusing concurrent interventions on improving multiple behaviors may have the greatest impact on health status outcomes. PMID- 24170682 TI - A comparison of convergently evolved insect silks that share beta-sheet molecular structure. AB - Raspy crickets produce silk webs that are used to build shelters. These webs have been found to consist of both fiber and film components. Raman spectra obtained from both components were found to be very similar for a given species. The protein structure of the fibers and films produced by both species was predominately beta-sheet with lesser amounts of beta-turns, unordered and alpha helical protein also detected. The orientation of the beta-sheet backbone in the fiber was determined to be parallel to the fiber axis. Compared to cocoon and dragline silk the orientation distribution exhibits a significant randomly orientated protein component. Amino acid analysis confirmed the presence of glycine, serine, and alanine in both species, which are known to form antiparallel beta-sheet structures. Both species, although at significantly different concentrations, where found to contain proline. This amino acid is uncommon in insect silks, and likely involved in increasing fiber elasticity. PMID- 24170683 TI - Assessment of current criteria for primary nonresponse in chronic hepatitis B patients receiving entecavir therapy. AB - A primary nonresponse to oral drugs against hepatitis B virus (HBV) is a generally accepted criterion for interrupting treatment. We investigated whether the concept of primary nonresponse suggested by current American (AASLD) and European (EASL) guidelines is appropriate for treatment with entecavir (ETV). The study included 1,254 treatment-naive patients who had pretreatment HBV DNA levels of >2,000 IU/mL and received ETV 0.5 mg/day for over 6 months. "Primary nonresponse" was defined as a <2 log drop in HBV DNA after 6 months of therapy by AASLD and as a <1 log drop after 3 months by EASL. The cumulative probability of virological response (VR; HBV DNA of <15 IU/mL) was compared in patients with and without primary nonresponse. Median time to achieve VR was significantly shorter in primary responders by AASLD than nonresponders (12 versus 24 months; P = 0.004), but the cumulative probability of achieving a VR at 54 months was similar in the two groups (95.8% versus 100%). Time to achieve a VR and cumulative probability of VR over time did not differ between primary responders and nonresponders by EASL. On-treatment virological breakthrough occurred in 18 patients with a cumulative rate of 5.6% at 72 months. ETV resistance was detected in 13 of these 18 patients (72.2%), who were all classified as primary responder according to both guidelines. CONCLUSION: Long-term ETV therapy generally leads to a VR in treatment-naive patients, although the time to achieve it is delayed in primary nonresponders. The current recommendation to change therapy in primary nonresponders needs to be modified to reflect drug differences in antiviral potency and resistance risk. PMID- 24170684 TI - The BMJ's stance on collaboration with industry. PMID- 24170685 TI - Process improvements and shared medical appointments for cardiovascular disease prevention in women. AB - PROBLEM: Cardiovascular disease (CVD) is clinically unique in women and is often underdiagnosed and undertreated. Chronic diseases account for 75% of healthcare expenditures in the United States, of which 70% are preventable through lifestyle changes and active medical management. Lifestyle modification is difficult in the context of the traditional medical visit. DESIGN: The Club Red Clinic uses a novel approach to enhance the care of women at risk for or with CVD. Through shared medical appointments (SMAs) and a multidisciplinary team approach, Club Red provides lifestyle training in addition to evidence-based practice to reduce CVD risk factors in women. In Club Red, nurse practitioners function independently and effectively in delivering lifestyle intervention for the management and prevention of CVD. SETTING: The clinic functions within an academic medical school at the University of Virginia. KEY MEASURES FOR IMPROVEMENT: Patient access, patient satisfaction, provider efficiency, and frequency of cardiovascular visits. EFFECTS OF CHANGE: Process improvements include reduced appointment wait times, improved provider efficiency (more patients seen with the SMAs), high patient satisfaction (96%), and improved adherence to recommended medical monitoring (3.8 visits/year). LESSONS LEARNED: Club Red improved patient access, patient satisfaction, medical and behavioral management, and health promotion education for women with or at risk for CVD. PMID- 24170686 TI - Novel endoscopic treatment of pharyngocele: endoscopic suture pharyngoplasty. AB - BACKGROUND: Pharyngocele or a lateral pharyngeal diverticulum (LPD) are rare lesions, which are bulgings of the pharyngeal mucosal surface through one of the weak areas of the pharynx. METHODS: The external approach has been the primary surgical treatment of pharyngoceles. The purpose of this article was for us to report an endoscopic successful treatment of pharyngocele by suture pharyngoplasty. RESULTS: Endoscopic suture pharyngoplasty does not require an external incision and hospitalization. After 3 months of abstinence from trumpet playing, the patient is back to his musical career. CONCLUSION: Because of the minimally invasive procedure, endoscopic suture pharyngoplasty can be performed in case of symptomatic pharyngoceles with a good result. PMID- 24170687 TI - A retrospective study on the effects of colistin therapy in children with multidrug-resistant Gram-negative bacterial pathogens: impact of HIV status on outcome. AB - BACKGROUND: Nosocomially acquired multidrug-resistant (MDR) Gram-negative bacteria are important contributors to paediatric intensive care unit (PICU) mortality and morbidity, with limited treatment options. AIM: To investigate the outcomes of all children treated with colistin for infection with MDR Gram negative bacteria while admitted to PICU. METHODS: Retrospective observational study of 19 months. Primary endpoints were all-cause intensive care unit mortality and safety. Secondary endpoints evaluated clinical and microbiological outcomes. Cases were stratified according to HIV status. RESULTS: Twenty-seven children received 30 colistin courses during the study period. Eight patients (29.6%) were HIV infected, six (22.2%) were HIV uninfected but exposed, and 11 (40.7%) were HIV uninfected and unexposed. Common MDR Gram-negative bacteria cultured were: Acinetobacter species (n=22, 81.5%), Pseudomonas aeruginosa (n=11, 40.7%) and Klebsiella pneumoniae (n=7, 25.9%). Mortality was 37%, with no significant difference between HIV strata. No adverse drug reactions were noted. A composite clinical improvement was noted in 16 courses (53.3%) of colistin. Only 30% of colistin courses used in HIV-infected children resulted in an improved clinical assessment as compared with 83.3% of courses in HIV uninfected/unexposed children (p=0.04). In HIV-infected children, five of 10 (50%) courses of colistin showed bacteriological clearance compared to the HIV uninfected/unexposed group where all cases showed bacterial eradication (p=0.02). CONCLUSIONS: HIV-infected children had poorer clinical and bacteriological responses to colistin treatment than HIV uninfected/unexposed. These results require confirmation with prospective studies to determine whether findings are due to poor microbial response, immunodeficiency or repeated reinfections. PMID- 24170688 TI - Use of local data to enhance uptake of published recommendations: an example from the diagnostic evaluation of precocious puberty. AB - BACKGROUND: It has been recommended that basal luteinising hormone (LH) levels be used as the initial test to identify cases of central precocious puberty (CPP) in children. However, in clinical practice, gonadotropin-releasing hormone (GnRH) stimulation tests are frequently still used. OBJECTIVE: To assess the diagnostic utility of a single LH to identify CPP in girls, as a means to safely reduce GnRH stimulation testing rates. DESIGN: Retrospective analysis of patients referred for GnRH stimulation between August 2007 and December 2010, with prospective 12 month follow-up of GnRH stimulation testing rates post implementation of management algorithm. PATIENTS: 57 girls (6.2 +/- 2.1 years) with early signs of puberty. MAIN OUTCOME MEASURE: Ability of basal LH to predict clinical pubertal progression, 6 months following the GnRH stimulation test. RESULTS: Pubertal progression occurred in 18 patients. All patients with a basal LH level >= 0.3 IU/L had subsequent pubertal progression, while 39 of 41 patients with a basal LH <= 0.2 IU/L did not progress, resulting in 100% specificity (95% CI 92% to 100%) and 90.5% sensitivity (69.6% to 98.8%). Using the locally derived algorithm, GnRH stimulation testing was redirected to patients with pubertal progression that was discordant with basal LH data. Post intervention, there was a 75% reduction in GnRH stimulation testing without comprising the rate of diagnosis of CPP. CONCLUSIONS: Our results confirm the diagnostic utility of basal LH levels in the diagnosis of CPP and demonstrate that dissemination and interpretation of local data may facilitate change in clinical practice, resulting in streamlined patient care and cost savings. PMID- 24170689 TI - Next-generation sequencing in childhood disorders. AB - Genetics has been revolutionised by recent technologies. The latest addition to these advances is next-generation sequencing, which is set to transform clinical diagnostics in every branch of medicine. In the research arena this has already been instrumental in identifying hundreds of novel genetic syndromes, making a molecular diagnosis possible for the first time in numerous refractory cases. However, the pace of change has left many clinicians bewildered by new terminology and the implications of next-generation sequencing for their clinical practice. The rapid developments have also left many diagnostic laboratories struggling to implement these new technologies with limited resources. This review explains the basic concepts of next-generation sequencing, gives examples of its role in clinically applied research and examines the challenges of its introduction into clinical practice. PMID- 24170690 TI - Metabolic syndrome: clinical perspective for best practice. AB - PURPOSE: To explore current studies on metabolic syndrome (MetS), including its complex pathophysiology and to describe the unique role of the advanced practice nurse including management and ethical decision making utilizing a case study to exemplify salient points. DATA SOURCES: From original research articles extracted from nursing and medical databases. CONCLUSIONS: MetS is a constellation of characteristics that increases the risk for the development of diabetes and cardiovascular disease. The pathophysiology of MetS is not completely understood, but is thought to involve a complex interaction between the environment, genetic susceptibility, insulin resistance, and abnormal adipose tissue function. IMPLICATIONS FOR PRACTICE: The role of the advanced practice nurse is appropriate for early intervention and counseling of patients with MetS and those who are at risk, as well as addressing the ethical challenges that accompany their care. PMID- 24170691 TI - Renal cyclooxygenase and lipoxygenase products are altered in polycystic kidneys and by dietary soy protein and fish oil treatment in the Han:SPRD-Cy rat. AB - SCOPE: Dietary fish oil (FO) and soy protein (SP) are two interventions that slow disease progression in the Han:SPRD-Cy rat model of polycystic kidney disease (PKD). Inhibition of cyclooxygenase (COX)-derived eicosanoids also reduces disease progression, but the role of lipoxygenase (LOX) products in this disease is not known. METHODS AND RESULTS: Since dietary FO and SP have been shown to alter eicosanoid formation via differing mechanisms, Han:SPRD-Cy rats were given diets containing either casein protein (CP) or SP, and soy oil (SO) or FO. Analysis of eicosanoids revealed that renal COX products were higher and LOX products were lower in diseased kidneys. SP feeding resulted in lower COX products, activity and COX1 protein and higher LOX products in the diseased kidneys in parallel with reduced renal cyst growth and fibrosis. By comparison, FO reduced both COX and LOX products produced from n-6 fatty acids and increased 3-series prostanoids in both normal and diseased cortex and medulla, but these differences did not parallel effects on disease. CONCLUSION: Renal COX-derived eicosanoids are elevated and LOX products are reduced in this model of kidney disease. The effects of dietary SP, but not FO, on renal eicosanoids parallel the effects on disease. PMID- 24170692 TI - The Appropriateness Evaluation Protocol is a poor predictor of in-hospital mortality. AB - BACKGROUND: The Appropriateness Evaluation Protocol (AEP) proposes admission criteria based only on physiological and laboratory parameters and has recently informed an Irish national bed utilisation review. Severity of illness tools can be poorly predictive of outcomes, particularly in older patients. AIMS: To assess the clinical utility of the AEP in moribund older and younger patients. METHODS: The study was conducted in four acute hospitals in South Munster, Ireland, and was of retrospective analytical cohort study design. The Hospital In-Patient Enquiry Scheme was used to ascertain patients who died within 10 days of hospital admission, over a 2-year period. Proximate death was used as a robust measure of validity of admission. Emergency department (ED) records were screened retrospectively to allocate the AEP criteria. RESULTS: There were 803 eligible in hospital deaths. Establishment of AEP criteria was available in 72.9 % (585 patients, 50.8 % female). The median length of stay until death was 4 days. Just over 30 % (179/585) of patients did not meet AEP criteria, two-fifths (72/179) of whom had been coded as severely unwell on arrival to the ED. There was no significant difference in AEP identification rates between older and younger age groups. CONCLUSIONS: Our study illustrates that the AEP is a poor predictor of mortality in all age groups, having failed to identify approximately one-third of our cohort. Based on our findings, we feel that this tool should not be used to assess the appropriateness of admission. PMID- 24170693 TI - Deletion of class A scavenger receptor deteriorates obesity-induced insulin resistance in adipose tissue. AB - Chronic low-grade inflammation, particularly in the adipose tissue, orchestrates obesity-induced insulin resistance. In this process, polarized activation of macrophages plays a crucial role. However, how macrophages contribute to insulin resistance remains obscure. Class A scavenger receptor (SR-A) is a pattern recognition receptor primarily expressed in macrophages. Through a combination of in vivo and in vitro studies, we report here that deletion of SR-A resulted in reduced insulin sensitivity in obese mice. The anti-inflammatory virtue of SR-A was accomplished by favoring M2 macrophage polarization in adipose tissue. Moreover, we demonstrate that lysophosphatidylcholine (LPC) served as an obesity related endogenous ligand for SR-A promoting M2 macrophage polarization by activation of signal transducer and activator of transcription 6 signaling. These data have unraveled a clear mechanistic link between insulin resistance and inflammation mediated by the LPC/SR-A pathway in macrophages. PMID- 24170694 TI - ITCH deficiency protects from diet-induced obesity. AB - Classically activated macrophages (M1) secrete proinflammatory cytokine and are predominant in obese adipose tissue. M2 macrophages, prevalent in lean adipose tissue, are induced by IL-13 and IL-4, mainly secreted by Th2 lymphocytes, and produce the anti-inflammatory cytokine IL-10. ITCH is a ubiquitously expressed E3 ubiquitin ligase involved in T-cell differentiation and in a wide range of inflammatory pathways. ITCH downregulation in lymphocytes causes aberrant Th2 differentiation. To investigate the role of Th2/M2 polarization in obesity related inflammation and insulin resistance, we compared wild-type and Itch(-/-) mice in a context of diet-induced obesity (high-fat diet [HFD]). When subjected to HFD, Itch(-/-) mice did not show an increase in body weight or insulin resistance; calorimetric analysis suggested an accelerated metabolism. The molecular analysis of metabolically active tissue revealed increased levels of M2 markers and genes involved in fatty acid oxidation. Histological examination of livers from Itch(-/-) mice suggested that ITCH deficiency protects mice from obesity-related nonalcoholic fatty liver disease. We also found a negative correlation between ITCH and M2 marker expression in human adipose tissues. Taken together, our data indicate that ITCH E3 ubiquitin ligase deficiency protects from the metabolic disorder caused by obesity. PMID- 24170695 TI - Epigenome-wide association study of fasting measures of glucose, insulin, and HOMA-IR in the Genetics of Lipid Lowering Drugs and Diet Network study. AB - Known genetic susceptibility loci for type 2 diabetes (T2D) explain only a small proportion of heritable T2D risk. We hypothesize that DNA methylation patterns may contribute to variation in diabetes-related risk factors, and this epigenetic variation across the genome can contribute to the missing heritability in T2D and related metabolic traits. We conducted an epigenome-wide association study for fasting glucose, insulin, and homeostasis model assessment of insulin resistance (HOMA-IR) among 837 nondiabetic participants in the Genetics of Lipid Lowering Drugs and Diet Network study, divided into discovery (N = 544) and replication (N = 293) stages. Cytosine guanine dinucleotide (CpG) methylation at ~470,000 CpG sites was assayed in CD4(+) T cells using the Illumina Infinium HumanMethylation 450 Beadchip. We fit a mixed model with the methylation status of each CpG as the dependent variable, adjusting for age, sex, study site, and T-cell purity as fixed-effects and family structure as a random-effect. A Bonferroni corrected P value of 1.1 * 10(-7) was considered significant in the discovery stage. Significant associations were tested in the replication stage using identical models. Methylation of a CpG site in ABCG1 on chromosome 21 was significantly associated with insulin (P = 1.83 * 10(-7)) and HOMA-IR (P = 1.60 * 10(-9)). Another site in the same gene was significant for HOMA-IR and of borderline significance for insulin (P = 1.29 * 10(-7) and P = 3.36 * 10(-6), respectively). Associations with the top two signals replicated for insulin and HOMA-IR (P = 5.75 * 10(-3) and P = 3.35 * 10(-2), respectively). Our findings suggest that methylation of a CpG site within ABCG1 is associated with fasting insulin and merits further evaluation as a novel disease risk marker. PMID- 24170698 TI - Health promotion, risk stratification, and treatment options to decrease hospitalization rates for community-acquired pneumonia in adults. AB - PURPOSE: Community-acquired pneumonia (CAP) is a serious illness and hospitalization for this illness is expensive. There is much the nurse practitioner (NP) can do to prevent and manage this illness. DATA SOURCES: Review of current literature, medical/nursing references, and data from the healthcare utilization project (HCUP). CONCLUSIONS: The use of health promotion, risk stratification, and current evidence-based treatment guidelines can help to decrease hospitalization rates for CAP for adults. IMPLICATIONS FOR PRACTICE: NPs are experts at health promotion and evidence-based practice. Adhering to these practices and using risk stratification, NPs can help to further decrease hospitalization rates for CAP lowering healthcare costs related to this serious illness. PMID- 24170696 TI - Exosomes released by islet-derived mesenchymal stem cells trigger autoimmune responses in NOD mice. AB - Exosomes (EXOs) are secreted, nano-sized membrane vesicles that contain potent immunostimulatory materials. We have recently demonstrated that insulinoma released EXOs can stimulate the autoimmune responses in nonobese diabetic (NOD) mice, a spontaneous disease model for type 1 diabetes. To investigate whether primary islet cells can produce EXOs, we isolated cells from the islet of Langerhans of NOD mice and cultured them in vitro. Interestingly, cultured islets release fibroblast-like, fast-replicating cells that express mesenchymal stem cell (MSC) markers, including CD105 and stem-cell antigen-1. These islet MSC-like cells release highly immunostimulatory EXOs that could activate autoreactive B and T cells endogenously primed in NOD mice. Serum EXO levels and EXO-induced interferon-gamma production were positively correlated with disease progression at the early prediabetic stage. Consistent with these observations, immunohistological analysis of pancreata showed that CD105(+) cells are restricted to the peri-islet area in normal islets but penetrate into the beta cell area as lymphocyte infiltration occurs. Immunization with EXOs promoted expansion of transferred diabetogenic T cells and accelerated the effector T cell mediated destruction of islets. Thus, EXOs could be the autoantigen carrier with potent adjuvant activities and may function as the autoimmune trigger in NOD mice. PMID- 24170699 TI - Knowledge translation: a Nurse Practitioner Clinical Ladder Advancement Program in a university-affiliated, integrated medical center. AB - PURPOSE: A Nurse Practitioner Clinical Ladder (NPCL) Advancement Program was designed to recognize and reward advanced nursing practice and promote nurse practitioner (NP) retention at New York University Hospitals Center (NYUHC). DATA SOURCES: Search of published and gray literature was conducted. Electronic databases included CINAHL, Medline, PubMed, Cochrane Library of Systematic Reviews, and the Joanna Briggs Institute. CONCLUSIONS: The NYUHC NPCL Advancement Program incorporated its current Staff Nurse Clinical Ladder, previous NP promotional program literature, and NP role competencies to support the Advanced Practice Nursing Clinical Ladder Program. The NPCL is supportive of professional development, performance evaluation, clinical practice excellence, job satisfaction, and NP retention. Program outgrowths include a progressive model of NP clinical practice, a formal NP mentoring program, NP leadership, and research opportunities. IMPLICATIONS FOR PRACTICE: Organizational commitment to a structured NPCL Advancement Program is critical for NP professional development, evolving role responsibilities, and job satisfaction. The NPCL Advancement Program provides requisite structures and processes supportive of clinical excellence. The development of the NPCL has highlighted the need for structured NP orientation and mentorship, knowledge translation, and leadership programs to meet the professional needs of NPs in diverse clinical settings. PMID- 24170700 TI - Measuring the influence of a mental health training module on the therapeutic optimism of advanced nurse practitioner students in the United Kingdom. AB - PURPOSE: To evaluate the influence of a mental health training module on the therapeutic optimism of advanced nurse practitioner (ANP) students in primary care (family practice). DATA SOURCES: Three cohorts of ANPs who undertook a Mental Health Problems in Primary Care Module as part of their MSc ANP (primary care) run by the University of Huddersfield completed the Elsom Therapeutic Optimism Scale (ETOS), in a pre- and postformat. The ETOS is a 10-item, self administered scale, which has been used to evaluate therapeutic optimism previously in mental health professionals. CONCLUSIONS AND IMPLICATIONS FOR PRACTICE: All three cohorts who completed the scale showed an improvement in their therapeutic optimism scores. With stigma having such a detrimental effect for people diagnosed with a mental health problem, ANPs who are more mental health literate facilitated by education and training in turn facilitates them to have the skills and confidence to engage and inspire hope for the person diagnosed with mental health problems. PMID- 24170697 TI - Neuroanatomical correlates of dysglycemia in young children with type 1 diabetes. AB - Studies of brain structure in type 1 diabetes (T1D) describe widespread neuroanatomical differences related to exposure to glycemic dysregulation in adults and adolescents. In this study, we investigate the neuroanatomical correlates of dysglycemia in very young children with early-onset T1D. Structural magnetic resonance images of the brain were acquired in 142 children with T1D and 68 age-matched control subjects (mean age 7.0 +/- 1.7 years) on six identical scanners. Whole-brain volumetric analyses were conducted using voxel-based morphometry to detect regional differences between groups and to investigate correlations between regional brain volumes and measures of glycemic exposure (including data from continuous glucose monitoring). Relative to control subjects, the T1D group displayed decreased gray matter volume (GMV) in bilateral occipital and cerebellar regions (P < 0.001) and increased GMV in the left inferior prefrontal, insula, and temporal pole regions (P = 0.002). Within the T1D group, hyperglycemic exposure was associated with decreased GMV in medial frontal and temporal-occipital regions and increased GMV in lateral prefrontal regions. Cognitive correlations of intelligence quotient to GMV were found in cerebellar-occipital regions and medial prefrontal cortex for control subjects, as expected, but not for the T1D group. Thus, early-onset T1D affects regions of the brain that are associated with typical cognitive development. PMID- 24170701 TI - Impact of implant size on cement filling in hip resurfacing arthroplasty. AB - Larger proportions of cement within femoral resurfacing implants might result in thermal bone necrosis. We postulate that smaller components are filled with proportionally more cement, causing an elevated failure rate. A total of 19 femoral heads were fitted with polymeric replicas of ReCap (Biomet) resurfacing components fixed with low-viscosity cement. Two specimens were used for each even size between 40 and 56 mm and one for size 58 mm. All specimens were imaged with computed tomography, and the cement thickness and bone density were analyzed. The average cement mantle thickness was 2.63 mm and was not correlated with the implant size. However, specimen with low bone density had thicker cement mantles regardless of size. The average filling index was 36.65% and was correlated to both implant size and bone density. Smaller implants and specimens with lower bone density contained proportionally more cement than larger implants. According to a linear regression model, bone density but not implant size influenced cement thickness. However, both implant size and bone density had a significant impact on the filling index. Large proportions of cement within the resurfacing head have the potential to generate thermal bone necrosis and implant failure. When considering hip resurfacing in patients with a small femoral head and/or osteoporotic bone, extra care should be taken to avoid thermal bone necrosis, and alternative cementing techniques or even cementless implants should be considered. This study should help delimiting the indications for hip resurfacing and to choose an optimal cementing technique taking implant size into account. PMID- 24170702 TI - Nineteen-year oncologic outcomes and the benefit of elective neck dissection in salivary gland adenoid cystic carcinoma. AB - BACKGROUND: The purposes of this study were to evaluate the oncologic outcomes of salivary gland adenoid cystic carcinoma (ACC) and to confirm the benefits of elective neck dissection. METHODS: We reviewed the records of 61 consecutive patients with ACC. Surgery was performed in all patients. RESULTS: The occult metastasis rate was 15.38% (4 of 26 patients) and no regional recurrence in the elective neck dissection group was identified. Among 4 clinically node positive (cN+) patients, regional metastasis was identified in 3 through therapeutic neck dissection. Regional recurrence was identified in 4 patients (4 of 31) who had never undergone elective neck treatment of clinically node negative (cN-) status, exclusively. Overall regional metastases (overall N+) were identified in 11 patients. The overall survival rate was 84.99% at 5 years, 81.13% at 10 and 15 years in (overall N-) status, contrary to 56.82% at 5 years and 28.41% at 10 years in overall N+ status (p = .025). CONCLUSION: Careful follow-up of regional status is important, and proper therapeutic and elective neck treatment can achieve regional control in ACC. Elective neck dissection is recommendable and can provide valuable staging and prognostic information. PMID- 24170703 TI - Nuclear factor (erythroid-derived 2)-like 2 activation-induced hepatic very-low density lipoprotein receptor overexpression in response to oxidative stress contributes to alcoholic liver disease in mice. AB - Chronic alcohol consumption leads to hypertriglyceridemia, which is positively associated with alcoholic liver disease (ALD). However, whether and how it contributes to the development of fatty liver and liver injury are largely unknown. In this study we demonstrate that chronic alcohol exposure differently regulates the expression of very-low-density lipoprotein receptor (VLDLR) in adipose tissue and the liver. Whereas adipose tissue VLDLR is significantly down regulated, its hepatic expression is dramatically increased after chronic alcohol feeding. While HepG2 cells stably overexpressing VLDLR manifests increased intracellular triglyceride accumulation, VLDLR-deficient mice are protective against fatty liver and liver injury after chronic alcohol exposure. Mechanistic investigations using both in vitro and in vivo systems reveal that oxidative stress-induced nuclear factor (erythroid-derived 2)-like 2 (Nrf2) activation plays a critical role in alcohol-induced VLDLR up-regulation in hepatocytes, but not in adipocytes. Oxidative stress enhances VLDLR gene expression and protein abundance in primary hepatocytes, concomitant with the Nrf2 activation. Conversely, Nrf2 gene silencing abrogates oxidative stress-induced VLDLR up regulation in the liver, but not in adipose tissue. In mice, alcohol exposure induces hepatic oxidative stress and Nrf2 activation. Supplementation of N acetylcysteine alleviates fatty liver and liver injury induced by chronic alcohol exposure, which is associated with suppressed Nrf2 activation and attenuated VLDLR increase in the liver. Furthermore, in comparison to wild-type counterparts, Nrf2-deficient mice demonstrate attenuated hepatic VLDLR expression increase in response to chronic alcohol exposure. CONCLUSION: Chronic alcohol consumption differently alters VLDLR expression in adipose tissue and the liver. Oxidative stress-induced Nrf2 activation is mechanistically involved in VLDLR overexpression in hepatocytes in response to chronic alcohol consumption. Hepatic VLDLR overexpression plays an important role in the pathogenesis of ALD. PMID- 24170704 TI - Body composition analysis by air displacement plethysmography in normal weight to extremely obese adults. AB - OBJECTIVE: To compare body composition parameters estimated by air displacement plethysmography (ADP) to dual X-ray absorptiometry (DXA) in body mass index (BMI) classifications that include extremely obese (BMI >= 40.0 kg/m(2) ), and to examine if differences between analyses were influenced by BMI. METHODS: Fat-free mass (FFM, kg), fat mass (FM, kg), and body fat (BF, %) were analyzed with both technologies. RESULTS: All outcome measures of ADP and DXA were highly correlated (r >= 0.95, P < 0.001 for FFM, FM, and BF), but Bland-Altman analyses revealed significant bias (P < 0.01 for all). ADP estimated greater FFM and lower FM and BF (P < 0.01 for all). BMI explained 27% of the variance in differences between FFM measurements (P < 0.001), and 37 and 33% of the variances in differences between FM and BF measurements, respectively (P < 0.001 for both). Within normal weight and overweight classifications, ADP estimated greater FFM and lower FM and BF (P < 0.001 for all), but the opposite occurred within the extremely obese classification; ADP estimated lower FFM and greater FM and BF (P < 0.05 for all). CONCLUSIONS: Body composition analyses by the two technologies were strongly congruent, but systematically different and influenced by BMI. Caution should be taken when utilizing ADP to estimate body composition parameters over a wide range of BMI classifications that include extremely obese. PMID- 24170705 TI - Multimedia decision support intervention: a promising approach to enhance the intention to complete an advance directive among hospitalized adults. AB - PURPOSE: We examined the acceptability and initial efficacy of a multimedia decision support (MDS) intervention to improve intention to complete an advanced directive (AD) among hospitalized adults following an episode of critical illness. DATA SOURCES: We used comparative quasi-experimental posttest only design. Forty-nine hospitalized adults, recovering from a critical illness, received either MDS or AD educational brochure. Demographic characteristics and self-report measures of AD knowledge were captured at baseline and used as covariates. Helpfulness of the intervention (acceptability) and the outcome variable, intention to complete an AD decision, were assessed after exposure to the MDS intervention or educational brochure (information-only control condition). CONCLUSIONS: The MDS was a more acceptable form of education compared to a brochure. After adjusting for covariates, participants exposed to the MDS intervention were 24.7 times more likely to intend to complete an AD compared to those who were assigned to the information-only control condition. IMPLICATIONS FOR PRACTICE: This pilot study establishes the acceptability and initial efficacy of the MDS intervention among individuals with critical illness, who are at high risk for hospital readmission life-sustaining treatment. This study illuminates a teachable moment in which patients are more receptive to interventions to complete an AD. PMID- 24170706 TI - Message control in developmental transitions; deciphering chromatin's role using zebrafish genomics. AB - Now that the sequencing of genomes has become routine, understanding how a given genome is used in different ways to obtain cell type diversity in an organism is the next frontier. How specific transcription programs are established during vertebrate embryogenesis, however, remains poorly understood. Transcription is influenced by chromatin structure, which determines the accessibility of DNA binding proteins to the genome. Although large-scale genomics approaches have uncovered specific features of chromatin structure that are diagnostic for different cell types and developmental stages, our functional understanding of chromatin in transcriptional regulation during development is very limited. In recent years, zebrafish embryogenesis has emerged as an excellent vertebrate model system to investigate the functional relationship between chromatin organization, gene regulation and development in a dynamic environment. Here, we review how studies in zebrafish have started to improve our understanding of the role of chromatin structure in genome activation and pluripotency and in the potential inheritance of transcriptional states from parent to progeny. PMID- 24170707 TI - Spondylolysis and spondylolisthesis: what the primary care provider should know. AB - PURPOSE: To provide nurse practitioners (NPs) with an overview of spondylolysis and spondylolisthesis, including the pathophysiology and etiology, incidence and prevalence, clinical presentation, diagnosis and differentials, management, and prognosis for these conditions. DATA SOURCES: Selected research, reviews, and clinical articles, and the authors' experience. CONCLUSIONS: Spondylolysis and spondylolisthesis are two common and confusing diagnoses identified by healthcare providers in the treatment of low back pain. Symptoms can vary depending on the degree of disarticulation with radiculopathy occurring in advanced grades of spondylolisthesis. Standing, lateral lumbosacral radiographs remain the gold standard for diagnosis. The majority of patients will improve with conservative treatments. Surgical options are warranted after 6 months of failed conservative treatments for patients with radiculopathy, neurogenic claudication, progressive neurological deficits, high-grade slips, or bladder and bowel symptoms. IMPLICATIONS FOR PRACTICE: NPs can distinguish these diagnoses and perform appropriate conservative management prior to referral to specialists for surgical evaluation. NPs are important providers in interdisciplinary care by assisting patients with both psychosocial and physical management of their back pain. PMID- 24170708 TI - Lifestyle modification intervention among infertile overweight and obese women with polycystic ovary syndrome. AB - PURPOSE: To implement an evidence-based lifestyle modification intervention, guided by motivational interviewing, among a sample of infertile overweight and obese women with polycystic ovary syndrome to increase chances of conception while improving overall health. DATA SOURCES: A prospective quantitative design was utilized (n = 12). Infertile overweight and obese women with polycystic ovary syndrome at an infertility practice completed questionnaires to assess diet and exercise practices at study onset and completion. Body mass index and weight measurements were obtained on participants at study onset and completion of intervention. Menstrual history was assessed by interview. CONCLUSIONS: There was a mean weight loss (p = .005) of 7(+/-5) pounds although a 5% weight reduction did not occur. Mean daily calorie (p = .005), fat (p = .006), and carbohydrate intake (p = .014) were significantly reduced. Frequency in brisk walking exercise significantly increased (p = .024). Frequency in home or gym exercise increased (p = .050). Menstrual cyclicity improved by 50% among prior amenorrheic subjects. IMPLICATIONS FOR PRACTICE: An evidence-based lifestyle modification guideline could prove to be a cost effective intervention for infertile women with polycystic ovary syndrome (PCOS) who desire pregnancy. This intervention could be integrated into the primary care and reproductive medicine visits as sole therapy or in conjunction with infertility treatment. PMID- 24170709 TI - Pediatric obesity and its effects on asthma control. AB - PURPOSE: To explore if being overweight or obese influenced asthma control in pediatric patients ages 7-18 years with persistent asthma seen in an asthma specialty office. DATA SOURCES: A retrospective chart analysis of children with an asthma diagnosis seen within an asthma specialty practice from December 1, 2009 to May 31, 2010 was utilized. Normal weight, overweight, and obese children were compared. The following four variables were examined: the number of controller asthma medications prescribed; the number of systemic corticosteroids prescribed in 1 year for asthma exacerbations; FEV1 % of predicted; and FEV1 /FVC% of predicted. CONCLUSIONS: No statistically significant difference was found between the three weight groups for the number of controller medications prescribed, number of systemic corticosteroids in 1 year, or FEV1 /FVC. A statistically significant difference was found for FEV1 %, F (2,430) = 5.51, p = .004. Overweight children had the highest mean FEV1 %, 92.47 +/- 16.74%. A statistically significant difference was found between the normal weight and overweight groups, p = .0104 and the overweight and obese groups, p = .0233. IMPLICATIONS FOR PRACTICE: In clinical practice, obese children often report more asthma symptoms. This inquiry did not show an objective decline in asthma control associated with overweight or obesity. PMID- 24170710 TI - Correlation between tissue metabolism and cellularity assessed by standardized uptake value and apparent diffusion coefficient in peritoneal metastasis. AB - PURPOSE: To evaluate the correlation between standardized uptake value (SUV) (tissue metabolism) and apparent diffusion coefficient (ADC) (water diffusivity) in peritoneal metastases. MATERIALS AND METHODS: Patients with peritoneal dissemination detected on (18)F-fluorodeoxyglucose positron emission tomography combined with computed tomography (FDG-PET/CT) were prospectively recruited for MRI examinations with informed consent and the study was approved by the local Institutional Review Board. FDG-PET/CT, diffusion-weighted imaging (DWI), MRI, and DWI/MRI images were independently reviewed by two radiologists based on visual analysis. SUVmax/SUVmean and ADCmin/ADCmean were obtained manually by drawing ROIs over the peritoneal metastases on FDG-PET/CT and DWI, respectively. Diagnostic characteristics of each technique were evaluated. Pearson's coefficient and McNemar and Kappa tests were used for statistical analysis. RESULTS: Eight patients were recruited for this prospective study and 34 peritoneal metastases were evaluated. ADCmean was significantly and negatively correlated with SUVmax (r = -0.528, P = 0.001) and SUVmean (r = -0.548, P = 0.001). ADCmin had similar correlation with SUVmax (r = -0.508, P = 0.002) and SUVmean (r = -0.513, P = 0.002). DWI/MRI had high diagnostic performance (accuracy = 98%) comparable to FDG-PET/CT, in peritoneal metastasis detection. Kappa values were excellent for all techniques. CONCLUSION: There was a significant inverse correlation between SUV and ADC. PMID- 24170711 TI - Collagen-chitosan-laminin hydrogels for the delivery of insulin-producing tissue. AB - Islet transplantation is an emerging strategy for treating patients with type 1 diabetes mellitus. Although the proof of concept for cellular replacement therapy in diabetes has been firmly established, vascularity of the transplant site and the long-term survival and function of transplanted islets remains suboptimal. In the present study, human circulating angiogenic cells (CACs) and porcine islet cells embedded in collagen-chitosan hydrogels, with and without laminin, were investigated as potential engineered biomaterials for the treatment of type 1 diabetes. Hydrogels were evaluated in vitro for their physical properties (compression, degradation, porosity and wettability) and cell compatibility. Increasing the chitosan content in the collagen-based hydrogel resulted in increased stiffness (p <= 0.04) and time to gelation (p < 0.001), but reduced porosity (from 22-28% to 16-19%). The material design formulations (10:1 vs 20:1 collagen:chitosan ratio) directly affected the cell properties. The viability of both human CACs and porcine islets embedded in the 20:1 collagen-chitosan matrix was higher at 24 h compared to the 10:1 formulation. For islet function, glucose stimulation indices for the 20:1 formulation at 24 h compared favourably with values reported in the literature, more so than the 10:1 formulations. While laminin improved the short-term viability of CACs, its presence did not confer any benefit to islet viability or function. Overall, the design features outlined in this study provided the degree of control required to establish viable tissue with potential for islet transplantation and neovascularization. Copyright (c) 2013 John Wiley & Sons, Ltd. PMID- 24170712 TI - The challenge of preconception counseling: Using reproductive life planning in primary care. AB - PURPOSE: A case study is used to explore barriers and challenges in the delivery of preconception care, and to highlight the future role of reproductive life planning in primary practice settings. DATA SOURCES: Peer-reviewed journal articles and clinical practice guidelines pertaining to preconception care. CONCLUSIONS: Because of the high rate of unintended pregnancy, preconception care should be incorporated into routine primary care for women of reproductive age. Reproductive life plans are tools that help formalize contraceptive and preconception care for women across the life span. They may prove particularly useful for women with chronic diseases and for young, low-income, and minority women. IMPLICATIONS FOR PRACTICE: With their emphasis on holistic care and patient education, nurse practitioners are well suited to incorporate elements of preconception care into the routine care they provide patients. Clinicians can modify reproductive life plans to fit the unique needs of an individual, patient population, or clinical practice. PMID- 24170713 TI - Diving below the surface of progressive disability: considering compensatory strategies as evidence of sub-clinical disability. AB - OBJECTIVES: To provide a comprehensive review regarding the role of activity and participation compensations within the disablement process, identify directions for future research, and discuss the implications of compensation pertaining to public health initiatives aimed at preventing and reversing disability. METHOD: This article evaluated how using compensatory strategies to cope with functional deficits reveals important transitions within the disablement process and signifies a unique opportunity to identify early declines in function. RESULTS: Previous research suggests that (a) adopting compensatory strategies to maintain activity/participation is strongly associated with functional decline and disease severity and significantly predicts the onset of limitations/restrictions; (b) compensation can be reliably quantified; and (c) contextual knowledge about how individuals adapt to functional decline can be used to describe transitions in the disablement process. DISCUSSION: Characterizing subtle adaptations prior to the onset of activity limitations and participation restrictions will not only aid in understanding the complex disablement process but also help inform social services and future prevention strategies. Overall, this article integrates the concept of compensation into the current model of disability and proposes a framework for identifying and interpreting compensatory behavior. PMID- 24170714 TI - Emotional Reactivity and Mortality: Longitudinal Findings From the VA Normative Aging Study. AB - OBJECTIVES: Evidence suggests a predictive association between emotion and mortality risk. However, no study has examined dynamic aspects of emotion in relation to mortality. This study used an index of emotional reactivity, defined as changes in positive or negative affect in response to daily stressors, to predict 10-year survival. METHODS: An 8-day daily diary study was conducted in 2002 on 181 men aged 58-88. Multilevel models were employed to estimate emotional reactivity coefficients, which were subsequently entered into a Cox proportional hazards model to predict mortality. RESULTS: Results indicated that positive emotional reactivity, that is, greater decreases in positive affect in response to daily stressors, increased mortality risk. Negative emotional reactivity did not predict mortality. DISCUSSION: Findings highlight the potential importance of dynamic aspects of positive affect in prediction of physical health outcomes such as mortality. PMID- 24170716 TI - Current research on widowhood: devastation and human resilience. PMID- 24170715 TI - Measurement Invariance of Cognitive Abilities Across Ethnicity, Gender, and Time Among Older Americans. AB - OBJECTIVES: The aim of this research was to test the invariance of the cognitive variables in the Health and Retirement Study/Asset Health Dynamics Among the Oldest Old studies (HRS/AHEAD) across ethnicity, gender, and time. METHOD: Analyses were conducted using a selected subsample of the HRS/AHEAD data set. The cognitive performance tests measuring episodic memory and mental status were used, and invariance of a two-factor structure was tested using confirmatory factor analyses and multilevel modeling for longitudinal data. RESULTS: Results provided some support for "strict" factorial invariance of the episodic memory and mental status measures across ethnicity and gender. Further support of weak ("metric") measurement invariance was found across time. DISCUSSION: Results of the research further our understanding of invariance of the HRS/AHEAD cognitive ability measures. Further implications are discussed. PMID- 24170717 TI - Friend and family contact and support in early widowhood. AB - OBJECTIVES: This study explored the relative contributions of friends and family to the social and emotional well-being of women and men in the first 2-6 months following the death of their spouse or partner. METHODS: Three hundred and twenty eight widowed men (39%) and women aged 50 and older completed self-administered questionnaires that included measures of contact and satisfaction with friends and family, as well as measures of affective (i.e., grief and depression) and self-evaluative (i.e., coping self-efficacy, mastery, self-esteem) responses to loss. RESULTS: Regression analyses supported the positive features of social support and interaction but particularly highlight the role of friends: ease of contact and satisfaction with friendship support were associated with more positive self-evaluative aspects of loss; greater frequency of friendship help was associated with more negative affective reactions, whereas higher satisfaction with friendship support was associated with more positive affective reactions. DISCUSSION: These analyses support the voluntary and socializing functions of friendship and social support, bolstering individuals during stressful life transitions, advancing our understanding of the underexamined and particularly distinct functions of friendship in the early phases of spousal loss. PMID- 24170718 TI - Managing Cancer And Living Meaningfully (CALM): phase 2 trial of a brief individual psychotherapy for patients with advanced cancer. AB - BACKGROUND: Advanced cancer brings substantial physical and psychosocial challenges that may contribute to emotional distress and diminish well-being. In this study, we present preliminary data concerning the effectiveness of a new brief individual psychotherapy, Managing Cancer And Living Meaningfully (CALM), designed to help individuals cope with this circumstance. AIM: To test the feasibility and preliminary effectiveness of CALM to reduce emotional distress and promote psychological well-being and growth. DESIGN: CALM is a brief, manualized, semi-structured individual psychotherapy for patients with advanced cancer. This study employed a phase 2 intervention-only design. The primary outcome was depressive symptoms and the secondary outcomes were death anxiety, attachment security, spiritual well-being and psychological growth. These were assessed at 3 months (t1) and 6 months (t2). Multilevel regression was used to model change over time. SETTING/PARTICIPANTS: A total of 50 patients with advanced or metastatic cancer were recruited from the Princess Margaret Cancer Centre, Toronto, Canada. RESULTS: A total of 39 patients (78%) were assessed at baseline, 24 (48%) at t1, and 16 (32%) at t2. Analyses revealed reductions over time in depressive symptoms: beta = -0.13, confidence interval (CI.95) = (-0.23, 0.022) and death anxiety: beta = -0.23, CI.95 (-0.40, -0.061); and an increase in spiritual well-being: beta = 0.14, CI.95 (0.026, 0.26). CONCLUSIONS: CALM may be a feasible intervention to benefit patients with advanced cancer. The results are encouraging, despite attrition and small effect sizes, and support further study. PMID- 24170719 TI - European Year of the Brain 2014 - a new impulse to strengthen the alliance for brain health. PMID- 24170720 TI - Up-regulation of Synaptotagmin IV within amyloid plaque-associated dystrophic neurons in Tg2576 mouse model of Alzheimer's disease. AB - AIM: To investigate the involvement of the vesicular membrane trafficking regulator Synaptotagmin IV (Syt IV) in Alzheimer's disease pathogenesis and to define the cell types containing increased levels of Syt IV in the beta-amyloid plaque vicinity. METHODS: Syt IV protein levels in wild type (WT) and Tg2576 mice cortex were determined by Western blot analysis and immunohistochemistry. Co localization studies using double immunofluorescence staining for Syt IV and markers for astrocytes (glial fibrillary acidic protein), microglia (major histocompatibility complex class II), neurons (neuronal specific nuclear protein), and neurites (neurofilaments) were performed in WT and Tg2576 mouse cerebral cortex. RESULTS: Western blot analysis showed higher Syt IV levels in Tg2576 mice cortex than in WT cortex. Syt IV was found only in neurons. In plaque vicinity, Syt IV was up-regulated in dystrophic neurons. The Syt IV signal was not up-regulated in the neurons of Tg2576 mice cortex without plaques (resembling the pre-symptomatic conditions). CONCLUSIONS: Syt IV up-regulation within dystrophic neurons probably reflects disrupted vesicular transport or/and impaired protein degradation occurring in Alzheimer's disease and is probably a consequence but not the cause of neuronal degeneration. Hence, Syt IV up regulation and/or its accumulation in dystrophic neurons may have adverse effects on the survival of the affected neuron. PMID- 24170721 TI - Pseudocholinesterase activity in cerebrospinal fluid as a biomarker of solid central nervous system tumors in children. AB - AIM: To determine the activity of pseudocholinesterase (PChE) in cerebrospinal fluid (CSF) and serum in children with solid central nervous system (CNS) tumor and to assess whether PChE activity could be a valid biomarker for solid CNS tumors in children. METHODS: The study and control group included 30 children each. Children in the study group had a solid CNS tumor, while those from the control group had never suffered from any tumor diseases. CSF and serum samples were collected from all participants and PChE activity was determined using the Ellman's spectrophotometric method. PChE activity in CSF was shown as a cerebrospinal fluid/serum ratio expressed in percentage, ie, PChE CSF/serum ratio. Receiver operating characteristic (ROC) curve was used to assess whether PChE activity can be used as a biomarker for identifying children with solid CNS tumors. RESULTS: Children with solid CNS tumor had significantly higher PChE activity in CSF and serum, as well as PChE CSF/serum ratio (P=0.001). PChE CSF/serum ratio in the study group was 2.38% (interquartile range [IQR] 1.14 3.97) and 1.09% (IQR 0.95-1.45) in the control group. ROC curve analysis of PChE CSF/serum ratio resulted in an area under the curve (AUC) value of 0.76 (95% confidence interval [CI] 0.63-0.88) and a cut-off of 1.09. Twenty five of 29 patients with elevated PChE CSF/serum ratio had a tumor, corresponding to a sensitivity of 83% and a specificity of 53%. CONCLUSION: PChE CSF/serum ratio may be used as a test or biomarker with good sensitivity for solid CNS tumors in children. PMID- 24170722 TI - The relationship between depressive syndrome and suicidal risk in patients with acute schizophrenia. AB - AIM: To determine the relationship between scores on five factors of the Positive and Negative Syndrome Scale (PANSS) and Calgary Depression scale for Schizophrenia (CDSS) and scores on the InterSePT Scale for Suicidal Thinking (ISST) in patients with acute schizophrenia. METHODS: Data were collected on sociodemographic and clinical characteristics of 180 drug-treated in-patients with acute schizophrenia. Their symptoms were assessed with PANSS, CDSS, and ISST and correlations between the scores were calculated. Statistically significant correlations were included in the logistic regression analysis to identify predictors of suicidal risk. RESULTS: CDSS (P<0.001) score and negative (P<0.001), disorganized (P=0.041), emotional (P<0.001), and total score on PANSS (P<0.001) showed a significant positive correlation with ISST. Stepwise logistic regression analysis revealed that CDSS scores (odds ratio [OR] 5.18; confidence interval [CI] 1.58-16.95), and disorganized (0.90; 0.81-0.99) and emotional (1.15; 1.01-1.30) factors of PANSS were predictors of suicidal risk. CONCLUSION: Our results suggested a considerable association between depressive syndrome as assessed by the PANSS emotional factor and CDSS score and suicidal risk in patients with acute schizophrenia. PMID- 24170723 TI - Availability of mental health service providers and suicide rates in Slovenia: a nationwide ecological study. AB - AIM: To investigate the influence of socioeconomic factors, mental health service availability, and prevalence of mental disorders on regional differences in the suicide rate in Slovenia. METHODS: The effects of different socioeconomic factors, mental health service availability, and mental disorders factors on suicide rates from 2000-2009 were analyzed using a general linear mixed model (GLMM). Pearson correlations were used to explore the direction and magnitude of associations. RESULTS: Among socioeconomic factors, unemployment rate ranked as the most powerful predictor of suicide and an increase of one unit in the unemployment rate increased regional suicide rate by 2.21 (beta=2.21, 95% confidence intervals [CI]=1.87-2.54, P<0.001). On the other hand, higher marriage/divorce ratio was negatively related to the suicide rate and an increase of one unit in marriage/divorce ratio reduced regional suicide rate by 1.16 (beta=-1.16, 95% CI=-2.20 to -0.13, P<0.031). The most influential mental health service availability parameter was higher psychiatrist availability (4 psychiatrists and more working at outpatient clinics per 100 000 inhabitants), which was negatively correlated with the suicide rate and reduced regional suicide rate by 2.95 (beta=-2.95, 95% CI=-4.60 to -1.31, P=0.002). Another negatively correlated factor was the antidepressant/anxiolytic ratio higher than 0.5, which reduced the regional suicide rate by 2.32 (beta=-2.32, 95% CI=-3.75 to -0.89, P=0.003). Among mental health disorders, only the prevalence of alcohol use disorders was significantly related to the regional suicide rates and an increase of one unit in the prevalence of alcohol use disorders per 1000 inhabitants increased the regional suicide rate by 0.02 (beta=0.02, 95% CI=0.01- 0.03, P=0.008). CONCLUSIONS: Besides unemployment, which was a very strong predictor of suicide rates, unequal availability of mental health services and quality of depressive disorder treatment may contribute to variations in suicide rates in different regions. PMID- 24170724 TI - Somatic comorbidity, metabolic syndrome, cardiovascular risk, and CRP in patients with recurrent depressive disorders. AB - AIM: To investigate the association between depression, metabolic syndrome (MBS), somatic, particularly cardiovascular comorbidity, and low-grade chronic inflammation assessed using C-reactive protein (CRP). METHODS: This cross sectional study included 76 patients with recurrent depressive disorder (RDD) and 72 non-depressed medical staff controls from the Department of Psychiatry, University Hospital Center Zagreb between January 2011 and June 2012. RESULTS: Seventy-five percent of patients had somatic comorbidity. The most common comorbid conditions were cardiovascular disorders (46.1%), locomotor system diseases (35.5%), carcinoma (15.8%), thyroid diseases (9.2%), and diabetes (9.2%). MTB was more common in RDD patients (31.6%) than in controls (23.6%), but the difference was not significant. Elevated CRP was found to be significantly more frequent in patients with recurrent depressive disorders (RDD) (35.5%; chi(2) test, P=0.001, Cramer V=0.29) than in controls (12.5%) and was associated with lowered high-density lipoprotein and overweight/obesity. CONCLUSION: We found some intriguing links between stress, depression, metabolic syndrome, and low grade inflammation, which may be relevant for the prevalence of somatic comorbidity in patients with RDD, but further studies are needed to confirm our results. PMID- 24170725 TI - Delinquency in incarcerated male adolescents is associated with single parenthood, exposure to more violence at home and in the community, and poorer self-image. AB - AIM: To assess the relationships between delinquency and demographic and family variables, academic performance, war stressors, home/community, school, and media violence exposure, self-image, and psychopathology. METHODS: This cross-sectional study included 100 delinquent, incarcerated male adolescents and 100 matched schoolchildren from Croatia. It lasted from January 2008 to June 2009, and used socio-demographic questionnaire, questionnaire on children's stressful and traumatic war experiences, exposure to violence scale, the Offer Self-Image Questionnaire, and Youth Self-Report Questionnaire. RESULTS: Logistic regression analysis showed that delinquency in incarcerated adolescents was more likely related to having parents who did not live together (odds ratio [OR] 2.40; confidence interval [CI] 1.18-4.90, P=0.015), being more exposed to violence at home/community (OR 3.84; CI 1.58-9.34, P=0.003), and having poorer self-image (OR 1.09; CI=1.03-1.16, P>0.002). CONCLUSION: Preventive and therapeutic interventions in incarcerated delinquents should be specifically targeted toward single parenthood, family factors, trauma oriented interventions, and focused on multiple dimensions of self-concept of adolescents. PMID- 24170726 TI - Gender and age differences in prevalence and incidence of child sexual abuse in Croatia. AB - AIM: To examine age and gender differences in the prevalence and incidence of child sexual abuse, the level of acquaintance of the child and the perpetrator, and correlations between experiencing family violence and sexual abuse on a nationally representative sample of 11, 13, and 16 years old children. METHOD: A probabilistic stratified cluster sample included 2.62% of the overall population of children aged 11 (n=1223), 13 (n=1188), and 16 (n=1233) from 40 primary and 29 secondary schools. A modified version of ISPCAN Child Abuse Screening Tool - Children's Version was used. Five items referred to child sexual abuse (CSA) for all age groups. RESULTS: In Croatia, 10.8% of children experienced some form of sexual abuse (4.8% to 16.5%, depending on the age group) during childhood and 7.7% of children experienced it during the previous year (3.7% to 11.1%, depending on the age group). Gender comparison showed no difference in the prevalence of contact sexual abuse, whereas more girls than boys experienced non contact sexual abuse. Correlations between sexual abuse and physical and psychological abuse in the family were small, but significant. CONCLUSION: Comparisons with international studies show that Croatia is a country with a low prevalence of CSA. The fact that the majority of perpetrators of sexual abuse are male and female peers indicates the urgent need to address risks of sexual victimization in the health education of children. PMID- 24170727 TI - Clinical significance of determining plasma homocysteine: case-control study on arterial and venous thrombotic patients. AB - AIM: To determine the differences in plasma homocysteine levels between three MTHFR 677 genotype subgroups in patients with thrombosis and in controls, as well as between patients with thrombosis and controls with the same MTHFR 677 genotype. METHODS: This case-control study was conducted in Clinical Center of Vojvodina, Novi Sad, from June to December 2011. We included 65 patients with either arterial or venous thrombosis (mean age, 40.97 +/- 11.38 years) and 65 controls with no history or clinical evidence of any thrombotic event (mean age, 41.23 +/- 11.12 years). Patients and controls were age- and sex-matched. RESULTS: In comparison with controls, thrombotic patients had significantly higher homocysteine levels (12.81 +/- 4.94 umol/L vs 9.82 +/- 3.68 umol/L; P<0.001) and significantly higher incidence of hyperhomocysteinemia (55% vs 22%; P<0.001; odds ratio [OR]=4.521). There were no significant differences in homocysteine levels between homozygous carriers, heterozygous carriers, and non-carriers of the MTHFR 677 mutation in either thrombotic patients (12.97 +/- 5.40 umol/L vs 12.55 +/- 5.71 umol/L vs 13.27 +/- 1.71 umol/L; P=0.100) or controls (10.07+/-2.50 umol/L vs 10.25 +/- 4.84 umol/L vs 9.20 +/- 2.44 umol/L; P=0.651). However, in comparison with controls, homozygous carriers in thrombotic patient group did not have significantly higher levels of homocysteine (12.97 +/- 5.40 umol/L vs 10.07 +/- 2.50 umol/L; P=0.072), but heterozygous carriers (12.55 +/- 5.71 umol/L vs 10.25 +/- 4.84 umol/L; P=0.020) and non-carriers (13.27 +/- 1.71 umol/L vs 9.20 +/- 2.44 umol/L; P<0.001) did. There was no significant difference in homocysteine levels between patients with arterial and venous thrombosis (12.76 +/- 3.60 umol/L vs 12.86 +/- 5.51 umol/L; P=0.990) and between patients with one thrombotic event and those with recurrent thrombotic events (12.14 +/- 3.20 umol/L vs 15.25 +/- 8.51 umol/L; P=0.254). CONCLUSION: Plasma homocysteine levels have a greater clinical significance in the prevention of thrombosis and managing its complications than MTHFR 677 genotyping. PMID- 24170728 TI - Epigenetic drug 5-azacytidine impairs proliferation of rat limb buds in an organotypic model-system in vitro. AB - AIM: To establish an organotypic in vitro model of limb bud development to verify whether epigenetic drug and teratogen 5-azacytidine (5azaC) has an effect on limb buds independent of its effects on the placenta. METHODS: Fischer strain rat fore and hindlimb buds were microsurgically isolated from 13 days old embryos and cultivated in vitro for two weeks at the air-liquid interface in Eagle's minimum essential medium (MEM) with 50% rat serum. 30 MUmol of 5azaC was added to the fresh medium. Overall growth was measured by an ocular micrometer. Routine histology, immunohistochemical detection of the proliferating cell nuclear antigen (PCNA), and stereological quantification of PCNA expression were performed. RESULTS: At four time points, significantly lower overall growth was detected for fore- and hindlimb bud explants cultivated with 5azaC in comparison to controls. After the culture period, numerical density of the PCNA signal for both types of limb buds was lower than for controls (P<0.001). Limb buds were initially covered by immature epithelium and contained mesenchyme, myotubes, single hemangioblasts, hemangioblast aggregates, blood islands, and capillaries. Regardless of the treatment, cartilage and epidermis differentiated, but cells and structures typical for vasculogenesis disappeared. CONCLUSION: Our findings, obtained outside of the maternal organism, stress the importance of compromised cell proliferation for 5azaC impact on limb buds. This investigation points to the necessity to establish alternatives to in vivo research on animals using teratogenic agents. PMID- 24170729 TI - Future of biobanks - bigger, longer, and more dimensional. PMID- 24170730 TI - The boom and bust cycle of biobanking - thinking through the life cycle of biobanks. PMID- 24170731 TI - Nursing community in Croatia and academic writing: a continuous challenge. PMID- 24170733 TI - Autoimmune hepatitis: a noninfectious killer. AB - PURPOSE: This article reviews autoimmune hepatitis (AIH) to promote early recognition, diagnosis, and referral for nurse practitioners (NPs) encountering this rare condition. DATA SOURCES: Selected research and clinical articles from Medline, PubMed, and CINAHL. CONCLUSIONS: AIH is a rare condition of unknown etiology affecting women 3.6 times more than men and may result in liver failure, subsequent liver transplantation, and death. Untreated AH is associated with up to 80% mortality. Collaboration and referral to gastroenterologists, hepatologists, and other specialists are needed to improve outcomes for this potentially devastating disease. IMPLICATIONS FOR PRACTICE: Corticosteroid treatment has long been the mainstay of treatment of AIH, although newer therapies are promising. NPs can dramatically improve outcomes by early recognition, diagnosis, referral, and monitoring for common side effects of treatment working collaboratively with specialists. PMID- 24170732 TI - Development of volume-stable adipose tissue constructs using polycaprolactone based polyurethane scaffolds and fibrin hydrogels. AB - Adipose tissue engineering aims at the restoration of soft tissue defects and the correction of contour deformities. It is therefore crucial to provide functional adipose tissue implants with appropriate volume stability. Here, we investigate two different fibrin formulations, alone or in combination with biodegradable polyurethane (PU) scaffolds as additional support structures, with regard to their suitability to generate volume-stable adipose tissue constructs. Human adipose-derived stem cells (ASCs) were incorporated in a commercially available fibrin sealant as well as a stable fibrin hydrogel previously developed by our group. The composite constructs made from the commercially available fibrin and porous poly(epsilon-caprolactone)-based polyurethane scaffolds exhibited increased volume stability as compared to fibrin gels alone; however, only constructs using the stable fibrin gels completely maintained their size and weight for 21 days. Adipogenesis of ASCs was not impaired by the additional PU scaffold. After induction with a common hormonal cocktail, for constructs with either fibrin formulation, strong adipogenic differentiation of ASCs was observed after 21 days in vitro. Furthermore, upregulation of adipogenic marker genes was demonstrated at mRNA (PPARgamma, C/EBPalpha, GLUT4 and aP2; qRT-PCR) and protein (leptin; ELISA) levels. Stable fibrin/PU constructs were further evaluated in a pilot in vivo study, resulting in areas of well-vascularized adipose tissue within the implants after only 5 weeks. Copyright (c) 2013 John Wiley & Sons, Ltd. PMID- 24170734 TI - Size matters: effects of PLGA-microsphere size in injectable CPC/PLGA on bone formation. AB - The aim of this study was to evaluate the effect of PLGA microsphere dimensions on bone formation after injection of calcium phosphate cement (CPC)/PLGA in a guinea pig tibial intramedullarly model. To this end, injectable CPC/PLGA formulations were prepared using PLGA microspheres with either a small (~25 um) or large (~100 um) diameter, which were incorporated at a 20:80 ratio (wt%) within apatite CPC. Both CPC/PLGA formulations were injected into a marrow ablated tibial intramedullary cavity and, after an implantation period of 12 weeks, histology and histomorphometry were used to address bone formation. The results demonstrated bone ingrowth throughout the entire scaffold material for both CPC/PLGA formulations upon PLGA microsphere degradation. More importantly, bone formation within the CPC matrix was > two-fold higher for CPC-PLGA with 25 um PLGA microspheres. Additionally, the pattern of bone and marrow formation showed distinct differences related to PLGA microsphere dimension. In general, this study demonstrates that PLGA microsphere dimensions of ~25 um, leading to pores of ~25 um within CPC, are sufficient for bone ingrowth and allow substantial bone formation. Further, the results demonstrate that PLGA microsphere dimensions provide a tool to control bone formation for injectable CPC/PLGA bone substitutes. Copyright (c) 2013 John Wiley & Sons, Ltd. PMID- 24170735 TI - Mapping polycomb response elements at the Drosophilla melanogaster giant locus. AB - Polycomb-group (PcG) proteins are highly conserved epigenetic transcriptional regulators. They are capable of either maintaining the transcriptional silence of target genes through many cell cycles or enabling a dynamic regulation of gene expression in stem cells. In Drosophila melanogaster, recruitment of PcG proteins to targets requires the presence of at least one polycomb response element (PRE). Although the sequence requirements for PREs are not well-defined, the presence of Pho, a PRE-binding PcG protein, is a very good PRE indicator. In this study, we identify two PRE-containing regions at the PcG target gene, giant, one at the promoter, and another approximately 6 kb upstream. PRE-containing fragments, which coincide with localized presence of Pho in chromatin immunoprecipitations, were shown to maintain restricted expression of a lacZ reporter gene in embryos and to cause pairing-sensitive silencing of the mini-white gene in eyes. Our results also reinforce previous observations that although PRE maintenance and pairing-sensitive silencing activities are closely linked, the sequence requirements for these functions are not identical. PMID- 24170736 TI - Rapid recombination mapping for high-throughput genetic screens in Drosophila. AB - Mutagenesis screens are a staple of classical genetics. Chemical-induced mutations, however, are often difficult and time-consuming to identify. Here, we report that recombination analysis with pairs of dominant visible markers provides a rapid and reliable strategy to map mutations in Drosophila melanogaster. This method requires only two generations and a total of six crosses in vials to estimate the genetic map position of the responsible lesion with high accuracy. This genetic map position can then be reliably used to identify the mutated gene through complementation testing with an average of nine deficiencies and Sanger sequencing. We have used this approach to successfully map a collection of mutations from an ethyl methanesulfonate-based mutagenesis screen on the third chromosome. We propose that this method also may be used in conjunction with whole-genome sequencing, particularly when multiple independent alleles of the mutated locus are not available. By facilitating the rapid identification of mutated genes, our mapping strategy removes a primary obstacle to the widespread use of powerful chemical mutagenesis screens to understand fundamental biological phenomena. PMID- 24170737 TI - Dynamics of adaptive alleles in divergently selected body weight lines of chickens. AB - By studying genomic changes over time in populations subjected to strong artificial directional selection, we can gain insights to the dynamics of beneficial alleles originating from the founder population or emerging as novel mutations undergoing ongoing selection. The Virginia lines are a chicken resource population generated by long-term bi-directional, single-trait selection for juvenile body weight. We studied genome-wide allele frequency changes from generation 40 to 53 using genome-wide genotypes from directional and relaxed selection lines. Overall, there were small changes in allele frequencies at individual loci over the studied time period; but, on average, the changes were greater in lines with larger phenotypic changes. This is consistent with previous findings that much of the response to selection over the first 40 years of selection was attributable to utilization of standing genetic variation at many loci in the genome, indicating a mostly polygenic architecture for body weight. Over the course of the selection experiment, the largest phenotypic response to selection was observed in the high-weight selected line, and in this line we detected a single locus where the allele frequency changed rapidly during a late stage of the experiment. This locus likely contains a novel, beneficial mutation that appeared between generations 40 and 45 and was driven to fixation in 5 to 10 generations. This result illustrates the dependence of continued long-term selection response on standing genetic variation at many loci as well as strong, novel, beneficial mutations. PMID- 24170738 TI - Comparative genome mapping between Chinook salmon (Oncorhynchus tshawytscha) and rainbow trout (O. mykiss) based on homologous microsatellite loci. AB - Comparative genome mapping can rapidly facilitate the transfer of DNA sequence information from a well-characterized species to one that is less described. Chromosome arm numbers are conserved between members of the teleost family Salmonidae, order Salmoniformes, permitting rapid alignment of large syntenic blocks of DNA between members of the group. However, extensive Robertsonian rearrangements after an ancestral whole-genome duplication event has resulted in different chromosome numbers across Salmonid taxa. In anticipation of the rapid application of genomic data across members of the Pacific salmon genus Oncorhynchus, we mapped the genome of Chinook salmon (O. tshawytscha) by using 361 microsatellite loci and compared linkage groups to those already derived for a well-characterized species rainbow trout (O. mykiss). The Chinook salmon female map length was 1526 cM, the male map 733 cM, and the consensus map between the two sexes was 2206 cM. The average female to male recombination ratio was 5.43 (range 1-42.8 across all pairwise marker comparisons). We detected 34 linkage groups that corresponded with all chromosome arms mapped with homologous loci in rainbow trout and inferred that 16 represented metacentric chromosomes and 18 represented acrocentric chromosomes. Up to 13 chromosomes were conserved between the two species, suggesting that their structure precedes the divergence between Chinook salmon and rainbow trout. However, marker order differed in one of these linkage groups. The remaining linkage group structures reflected independent Robertsonian chromosomal arrangements, possibly after divergence. The putative linkage group homologies presented here are expected to facilitate future DNA sequencing efforts in Chinook salmon. PMID- 24170739 TI - Assignment of Chinook salmon (Oncorhynchus tshawytscha) linkage groups to specific chromosomes reveals a karyotype with multiple rearrangements of the chromosome arms of rainbow trout (Oncorhynchus mykiss). AB - The Chinook salmon genetic linkage groups have been assigned to specific chromosomes using fluorescence in situ hybridization with bacterial artificial chromosome probes containing genetic markers mapped to each linkage group in Chinook salmon and rainbow trout. Comparison of the Chinook salmon chromosome map with that of rainbow trout provides strong evidence for conservation of large syntenic blocks in these species, corresponding to entire chromosome arms in the rainbow trout as expected. In almost every case, the markers were found at approximately the same location on the chromosome arm in each species, suggesting conservation of marker order on the chromosome arms of the two species in most cases. Although theoretically a few centric fissions could convert the karyotype of rainbow trout (2N = 58-64) into that of Chinook salmon (2N = 68) or vice versa, our data suggest that chromosome arms underwent multiple centric fissions and subsequent new centric fusions to form the current karyotypes. The morphology of only approximately one-third of the chromosome pairs have been conserved between the two species. PMID- 24170740 TI - Osmotic stress-induced polyamine oxidation mediates defence responses and reduces stress-enhanced grapevine susceptibility to Botrytis cinerea. AB - Abiotic factors inducing osmotic stress can influence the plant immune response and resistance to pathogen infections. In this study, the effect of polyethylene glycol (PEG)- and sucrose-induced osmotic stress on polyamine (PA) homeostasis and the basal immune response in grapevine plantlets before and after Botrytis cinerea infection was determined. Pharmacological approaches were also addressed to assess the contribution of osmotic stress-induced PA oxidation to the regulation of defence responses and the susceptibility of grapevine to B. cinerea. Following osmotic stress or pathogen infection, PA homeostasis was linked to enhanced activity of diamine oxidases (CuAO) and PA oxidases (PAO) and the production of 1,3-diaminopropane. These responses paralleled the accumulation of the main stilbenic phytoalexins, resveratrol and epsilon-viniferin and upregulation of gene transcripts including STS (a stilbene synthase), PR-2 (a beta-1,3-glucanase), PR3-4c (acidic chitinase IV), and PR-5 (a thaumatin-like protein), as well as NCED2 involved in abscisic acid biosynthesis. It was also demonstrated that leaves pre-exposed to osmotic stress and later inoculated with B. cinerea showed enhanced PA accumulation and attenuation of CuAO and PAO activities. This was consistent with the impaired production of phytoalexins and transcript levels of defence- and stress-related genes following infection, and the enhanced susceptibility to B. cinerea. Pharmacological experiments revealed that, under osmotic stress conditions, CuAO and PAO were involved in PA homeostasis and in the regulation of defence responses. Specific inhibition of CuAO and PAO in osmotically stressed leaves strongly attenuated the induction of defence responses triggered by B. cinerea infection and enhanced susceptibility to the pathogen. Taken together, this study reveals a contribution of PA catabolism to the resistance state through modulation of immune response in grapevine following osmotic stress and/or after B. cinerea infection. PMID- 24170741 TI - Lauric acid in crown daisy root exudate potently regulates root-knot nematode chemotaxis and disrupts Mi-flp-18 expression to block infection. AB - Tomato (Solanum lycopersicum) crops can be severely damaged due to parasitism by the root-knot nematode (RKN) Meloidogyne incognita, but are protected when intercropped with crown daisy (Chrysanthemum coronarium L.). Root exudate may be the determining factor for this protection. An experiment using pots linked by a tube and Petri dish experiments were undertaken to confirm that tomato-crown daisy intercropping root exudate decreased the number of nematodes and alleviated nematode damage, and to determine crown daisy root exudate-regulated nematode chemotaxis. Following a gas chromatography-mass spectrometry assay, it was found that the intercropping protection was derived from the potent bioactivity of a specific root exudate component of crown daisy, namely lauric acid. The Mi-flp-18 gene, encoding an FMRFamide-like peptide neuromodulator, regulated nematode chemotaxis and infection by RNA interference. Moreover, it was shown that lauric acid acts as both a lethal trap and a repellent for M. incognita by specifically regulating Mi-flp-18 expression in a concentration-dependent manner. Low concentrations of lauric acid (0.5-2.0mM) attract M. incognita and consequently cause death, while high concentrations (4.0mM) repel M. incognita. This study elucidates how lauric acid in crown daisy root exudate regulates nematode chemotaxis and disrupts Mi-flp-18 expression to alleviate nematode damage, and presents a general methodology for studying signalling systems affected by plant root exudates in the rhizosphere. This could lead to the development of economical and feasible strategies for controlling plant-parasitic nematodes, and provide an alternative to the use of pesticides in farming systems. PMID- 24170742 TI - Olive seed protein bodies store degrading enzymes involved in mobilization of oil bodies. AB - The major seed storage reserves in oilseeds are accumulated in protein bodies and oil bodies, and serve as an energy, carbon, and nitrogen source during germination. Here, the spatio-temporal relationships between protein bodies and several key enzymes (phospholipase A, lipase, and lipoxygenase) involved in storage lipid mobilization in cotyledon cells was analysed during in vitro seed germination. Enzyme activities were assayed in-gel and their cellular localization were determined using microscopy techniques. At seed maturity, phospholipase A and triacylglycerol lipase activities were found exclusively in protein bodies. However, after seed imbibition, these activities were shifted to the cytoplasm and the surface of the oil bodies. The activity of neutral lipases was detected by using alpha-naphthyl palmitate and it was associated mainly with protein bodies during the whole course of germination. This pattern of distribution was highly similar to the localization of neutral lipids, which progressively appeared in protein bodies. Lipoxygenase activity was found in both the protein bodies and on the surface of the oil bodies during the initial phase of seed germination. The association of lipoxygenase with oil bodies was temporally correlated with the appearance of phospholipase A and lipase activities on the surface of oil bodies. It is concluded that protein bodies not only serve as simple storage structures, but are also dynamic and multifunctional organelles directly involved in storage lipid mobilization during olive seed germination. PMID- 24170744 TI - Monitoring of ovarian activity by daily measurement of urinary excretion rates of oestrone glucuronide and pregnanediol glucuronide using the Ovarian Monitor, Part III: variability of normal menstrual cycle profiles. AB - STUDY QUESTION: What are the characteristics of, and how variable are, individual normal menstrual cycle profiles of excretion rates for the urinary metabolites oestrone glucuronide (E1G) and pregnanediol glucuronide (PdG)? SUMMARY ANSWER: There is a continuum of menstrual cycle profiles that differ from standard textbook profiles but which can be understood simply in terms of growth, atresia and ovulation of ovarian follicles. WHAT IS KNOWN ALREADY: Point-of-care assays with the Ovarian Monitor pre-coated assay tubes, using urine samples diluted to a constant volume per unit time, give laboratory accurate clinical data for individual menstrual cycles. Lay operators can perform the point-of-care assay system at home to achieve reliable and reproducible results, which can be used for natural family planning. STUDY DESIGN, SIZE, DURATION: This prospective study involved 62 women, with normal menstrual cycles, recruited from three centres: Palmerston North, New Zealand, Sydney, Australia and Santiago, Chile. The study lasted 3 years. PARTICIPANTS/MATERIALS, SETTING, METHODS: Women collected daily urine samples and determined their E1G and PdG rates with a pre-coated enzyme assay system known as the Ovarian Monitor. For two cycles, the assays were repeated in a study centre and the results were averaged to give 113 individual menstrual cycles for analysis. The cycles were displayed individually in a proprietary database program. MAIN RESULTS AND THE ROLE OF CHANCE: The individual normal hormonal profiles were more complex than the classic composite curves for 40% of the cycles. Of 113 ostensibly normal cycles, only 91 were potentially fertile and 22 had some luteal phase defect. The oestrone glucuronide and PdG excretion rates were reliable and informative in the non-invasive elucidation of ovulation and ovarian function for both simple and complex profiles. Daily monitoring revealed the variability of normal menstrual cycle profiles. The LH peaks were variable and ambiguous markers for ovulation. LIMITATIONS, REASONS FOR CAUTION: The study consisted of cycles only from women with regular cycles of 20 40 days duration. All the women were intending to avoid a pregnancy during the study thus the limits of the fertile window were not tested. WIDER IMPLICATIONS OF THE FINDINGS: The principles established in this study should apply to cycles of any length. All peaks in oestrone glucuronide excretion should be tested by concurrent measurements of PdG, which gives a positive indication of the fate of the follicle it represents. The Ovarian Monitor provides a useful addition for practitioners of natural family planning. STUDY FUNDING/COMPETING INTEREST(S): Financial support for this study was obtained from the UNDP/UNFPA/World Bank/WHO Special Programme of Research, Development and Research Training in Human Reproduction (HRP). D.G.C. is currently employed by and holds stock in Manawatu Diagnostics Ltd, a company in the development phase of a potentially competing product. The remaining authors have nothing to declare. PMID- 24170743 TI - Variation in Rubisco activase (RCAbeta) gene promoters and expression in soybean [Glycine max (L.) Merr]. AB - Understanding the genetic basis of Rubisco activase (RCA) gene regulation and altering its expression levels to optimize Rubisco activation may provide an approach to enhance plant productivity. However, the genetic mechanisms and the effect of RCA expression on phenotype are still unknown in soybean. This work analysed the expression of RCA genes and demonstrated that two RCA isoforms presented different expression patterns. Compared with GmRCAalpha, GmRCAbeta was expressed at higher mRNA and protein levels. In addition, GmRCAalpha and GmRCAbeta were positively correlated with chlorophyll fluorescence parameters and seed yield, suggesting that changes in expression of RCA has a potential applicability in breeding for enhanced soybean productivity. To identify the genetic factors that cause expression level variation of GmRCAbeta, expression quantitative trait loci (eQTL) mapping was combined with allele mining in a natural population including 219 landraces. The eQTL mapping showed that a combination of both cis- and trans-acting eQTLs might control GmRCAbeta expression. As promoters can affect both cis- and trans-acting eQTLs by altering cis-acting regulatory elements or transcription factor binding sites, this work subsequently focused on the promoter region of GmRCAbeta. Single-nucleotide polymorphisms in the GmRCAbeta promoter were identified and shown to correlate with expression level diversity. These SNPs were classified into two groups, A and B. Further transient expression showed that GUS expression driven by the group A promoter was stronger than that by the group B promoter, suggesting that promoter sequence types could influence gene expression levels. These results would improve understanding how variation within promoters affects gene expression and, ultimately, phenotypic diversity in natural populations. PMID- 24170745 TI - Left lower sleeve lobectomy by uniportal video-assisted thoracoscopic approach. AB - Endobronchial tumours requiring sleeve resection have been usually considered a contraindication for video-assisted thoracoscopic surgery (VATS). However, with new technical advances and the experience gained in VATS, sleeve lobectomy has been performed by thoracoscopy in experienced VATS centres. Right-sided sleeve anastomoses are easier to perform by VATS than left-sided ones because of the presence of the pulmonary artery and aortic arch on the left side. Most surgeons use a 3 to 4 incision VATS technique for sleeve anastomosis but the surgery can be performed by using only one incision. This is the first report of a left-sided sleeve lobectomy by uniportal approach. PMID- 24170746 TI - Recurrent oesophageal cancer complicated by tracheo-oesophageal fistula: improved palliation by means of parallel tracheal and oesophageal stenting. AB - OBJECTIVES: Recurrent oesophageal carcinoma complicated by the development of a tracheo-oesophageal fistula is a crushing condition. In this situation, endoscopic double stenting may provide a quick and safe option for palliation. METHODS: The outcomes of patients who received endoscopic parallel stent implantation for tracheo-oesophageal fistula due to recurrent oesophageal cancer at a German tertiary referral hospital between 2006 and 2013 were reviewed in a retrospective case study. RESULTS: A total of 9 patients were identified (mean age 59.9 years). Tumour entity was squamous cell carcinoma, adenocarcinoma and neuroendocrine cancer of the oesophagus in 5, 3 and 1 case, respectively. The mean interval between primary treatment and recurrence was 19.2 months. Successful double-stent placement was always feasible. Complete closure of the communication between oesophagus and respiratory system was accomplished in all cases by stent implantation. There were no stent-associated complications. The mean survival following stent insertion was 64 days (6-121 days). After successful double stenting, 5 patients were fit enough to receive palliative chemo- or radiotherapy. Seven patients were finally discharged home after adequate oral intake had been achieved. Fatal aspiration pneumonia with respiratory failure occurred in 2 cases. CONCLUSIONS: Endoscopic parallel stent implantation provides an easy and ubiquitous available technique for closure and palliation of tracheo-oesophageal fistula caused by recurrent oesophageal cancer. Immediate sealing of the fistula and relief of symptoms related to aspiration is achieved while hazardous operations are avoided. Therefore, we recommend endoscopic parallel stent insertion as the treatment of choice in case of tracheo oesophageal fistula caused by recurrent oesophageal cancer. PMID- 24170747 TI - Day and night closed-loop control in adults with type 1 diabetes: a comparison of two closed-loop algorithms driving continuous subcutaneous insulin infusion versus patient self-management. AB - OBJECTIVE: To compare two validated closed-loop (CL) algorithms versus patient self-control with CSII in terms of glycemic control. RESEARCH DESIGN AND METHODS: This study was a multicenter, randomized, three-way crossover, open-label trial in 48 patients with type 1 diabetes mellitus for at least 6 months, treated with continuous subcutaneous insulin infusion. Blood glucose was controlled for 23 h by the algorithm of the Universities of Pavia and Padova with a Safety Supervision Module developed at the Universities of Virginia and California at Santa Barbara (international artificial pancreas [iAP]), by the algorithm of University of Cambridge (CAM), or by patients themselves in open loop (OL) during three hospital admissions including meals and exercise. The main analysis was on an intention-to-treat basis. Main outcome measures included time spent in target (glucose levels between 3.9 and 8.0 mmol/L or between 3.9 and 10.0 mmol/L after meals). RESULTS: Time spent in the target range was similar in CL and OL: 62.6% for OL, 59.2% for iAP, and 58.3% for CAM. While mean glucose level was significantly lower in OL (7.19, 8.15, and 8.26 mmol/L, respectively) (overall P = 0.001), percentage of time spent in hypoglycemia (<3.9 mmol/L) was almost threefold reduced during CL (6.4%, 2.1%, and 2.0%) (overall P = 0.001) with less time <=2.8 mmol/L (overall P = 0.038). There were no significant differences in outcomes between algorithms. CONCLUSIONS: Both CAM and iAP algorithms provide safe glycemic control. PMID- 24170748 TI - Changing impact of modifiable risk factors on the incidence of major outcomes of type 1 diabetes: the Pittsburgh Epidemiology of Diabetes Complications Study. AB - OBJECTIVE: The incidence of type 1 diabetes complications appears to be decreasing, but relative contributions of risk factors are unclear. We thus estimated the effect of modifiable risk factors on the incidence of a composite end point, major outcomes of diabetes (MOD). RESEARCH DESIGN AND METHODS: The Pittsburgh Epidemiology of Diabetes Complications (EDC) Study was used to derive two cohorts based on diabetes diagnosis year (1960-1969 and 1970-1980). Baseline exam data in the current analysis for the 1960s group were collected in 1986-1988 and for the 1970s in 1996-1998. Each group was followed for 8 years for MOD incidence (diabetes-related death, myocardial infarction, revascularization procedure/blockage >=50%, stroke, end-stage renal disease, blindness, and amputation). Assessed risk factors include the following: HbA1c, hypertension, microalbuminuria, BMI, hypercholesterolemia, and smoking. Accelerated failure time models were used to estimate the acceleration factor. RESULTS: MOD incidence decreased in the 1970s cohort (15.8% [95% CI 11.6-21.4]) compared with the 1960s (22.6% [17.0-29.1]) over the 8-year follow-up (P = 0.06). Hypertension and microalbuminuria were associated with significantly accelerated MOD incidence in both cohorts (P < 0.01 for both). High HbA1c (P = 0.0005), hypercholesterolemia (P = 0.01), and current smoking (P = 0.003) significantly accelerated the incidence of MOD in the 1960s but not 1970s cohort. BMI was not associated with MOD in either cohort. CONCLUSIONS: These results suggest that hypertension and microalbuminuria remain important predictors of complications that are not being adequately addressed. PMID- 24170749 TI - Both dietary protein and fat increase postprandial glucose excursions in children with type 1 diabetes, and the effect is additive. AB - OBJECTIVE: To determine the separate and combined effects of high-protein (HP) and high-fat (HF) meals, with the same carbohydrate content, on postprandial glycemia in children using intensive insulin therapy (IIT). RESEARCH DESIGN AND METHODS: Thirty-three subjects aged 8-17 years were given 4 test breakfasts with the same carbohydrate amount but varying protein and fat quantities: low fat (LF)/low protein (LP), LF/HP, HF/LP, and HF/HP. LF and HF meals contained 4 g and 35 g fat. LP and HP meals contained 5 g and 40 g protein. An individually standardized insulin dose was given for each meal. Postprandial glycemia was assessed by 5-h continuous glucose monitoring. RESULTS: Compared with the LF/LP meal, mean glucose excursions were greater from 180 min after the LF/HP meal (2.4 mmol/L [95% CI 1.1-3.7] vs. 0.5 mmol/L [-0.8 to 1.8]; P = 0.02) and from 210 min after the HF/LP meal (1.8 mmol/L [0.3-3.2] vs. -0.5 mmol/L [-1.9 to 0.8]; P = 0.01). The HF/HP meal resulted in higher glucose excursions from 180 min to 300 min (P < 0.04) compared with all other meals. There was a reduction in the risk of hypoglycemia after the HP meals (odds ratio 0.16 [95% CI 0.06-0.41]; P < 0.001). CONCLUSIONS: Meals high in protein or fat increase glucose excursions in youth using IIT from 3 h to 5 h postmeal. Protein and fat have an additive impact on the delayed postprandial glycemic rise. Protein had a protective effect on the development of hypoglycemia. PMID- 24170750 TI - Reductions in regimen distress are associated with improved management and glycemic control over time. AB - OBJECTIVE Cross-sectional and longitudinal associations among regimen distress (RD), self-management, and glycemic control were undertaken to explore mechanisms of operation among these variables. RESEARCH DESIGN AND METHODS In a behavioral randomized control trial (RCT) to reduce RD, 392 adults with type 2 diabetes were assessed for RD, diet, exercise, medication adherence, and HbA1c at baseline and at 4 and 12 months. Associations among RD, self-management, and HbA1c were examined in cross-sectional analyses at baseline, in prospective analyses using baseline values to predict change over time, and in time-varying analyses. RESULTS At baseline, greater RD and poorer medication adherence were independently associated with higher HbA1c (P = 0.05 and P < 0.001, respectively), and greater RD was associated with poorer medication adherence (P = 0.03). No consistent pattern of significant prospective associations was found. Significant time-varying findings showed that decreases in RD were associated with improvements in medication adherence (P < 0.01), physical activity (P < 0.001), and HbA1c (P = 0.02) over time following intervention. Changes in self management were not associated with changes in HbA1c over time. CONCLUSIONS In the context of an RCT to reduce distress, RD, self-management, and HbA1c were interrelated in cross-sectional and time-varying analyses. Decreases in RD were associated with improvements in both self-management and HbA1c over 12 months. Findings point to the complex and likely multifaceted pathways of association among these key constructs, with results indicating significant linkages between RD and both self-management and glycemic control over time. PMID- 24170751 TI - Effect of glycemic treatment and microvascular complications on menopause in women with type 1 diabetes in the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) cohort. AB - OBJECTIVE We examined the impact of intensive versus conventional diabetes treatment upon menopause among women with type 1 diabetes in the Diabetes Control and Complications Trial (DCCT), a randomized controlled trial of intensive diabetes treatment, and its observational follow-up, the Epidemiology of Diabetes Interventions and Complications (EDIC) study. RESEARCH DESIGN AND METHODS In a secondary analysis of women in the DCCT/EDIC (n = 657), outcomes were the cumulative incidences of natural menopause and surgical menopause. Cox regression analyses were used to examine associations with treatment group, time-varying estimates of hemoglobin A1c (HbA1c), insulin dosage, BMI, and microvascular complications (retinopathy, nephropathy, and neuropathy). RESULTS By EDIC year 18, after an average of 28 years of follow-up, 240 (38%) women had experienced natural menopause and 115 (18%) women had experienced surgical menopause. Age at natural menopause was similar in the intensive versus conventional groups (49.9 vs. 49.0 years; P = 0.28), and age at surgical menopause was similar in the intensive versus conventional groups (40.8 vs. 42.0 years; P = 0.31). In multivariable models, treatment group, HbA1c, and microvascular complications were not associated with risk of natural or surgical menopause. Each 10 unit/day increase in insulin dosage decreased risk of natural menopause (hazard ratio [HR] 0.91, 95% CI 0.75-0.98) and each kg/m(2) increase in BMI increased risk of surgical menopause (HR 1.08, 95% CI 1.00-1.16). CONCLUSIONS In the DCCT/EDIC, intensive versus conventional treatment group and HbA1c level were not associated with menopause risk. Greater insulin dose was associated with lower menopause risk. PMID- 24170752 TI - Effect of postmenopausal status and age at menopause on type 2 diabetes and prediabetes in Japanese individuals: Toranomon Hospital Health Management Center Study 17 (TOPICS 17). AB - OBJECTIVE: Findings on the effect of menopause or age at menopause on the presence of hyperglycemia are controversial, and why women after menopause have a higher probability of having hyperglycemia than men in the same age range remains unknown. RESEARCH DESIGN AND METHODS: We reviewed data on 29,189 men, 6,308 premenopausal women, and 4,570 postmenopausal women in Japan. Odds ratios (ORs) for diabetes or prediabetes indicated by American Diabetes Association criteria were calculated for men and for pre- and postmenopausal women. RESULTS: Compared with premenopausal women, women after natural menopause had an age-adjusted OR of 1.40 (95% CI 1.03-1.89) for diabetes, and women after menopause by surgical or other causes had an age-adjusted OR of 1.59 (1.07-2.37). The age-adjusted OR in men was 4.02 (3.15-5.14). Compared with premenopausal nondiabetic women, postmenopausal nondiabetic women had a significantly elevated OR of 1.33 (1.20 1.48) for prediabetes; nondiabetic men had an OR of 1.93 (1.77-2.10) independently of age and demographic and metabolic factors. Even among women aged <50 years, postmenopausal status was significantly associated with an elevated OR (1.50 [1.18-1.91]) for dysglycemia (either diabetes or prediabetes). Postmenopausal women aged >=50 years had a particularly elevated OR for dysglycemia, regardless of age at menopause. CONCLUSIONS: The postmenopausal state was significantly associated with the presence of dysglycemia independently of normal aging, although the increased probability in postmenopausal women did not equal that in men. Among women, menopause and older age might additively influence the elevated probability of dysglycemia. PMID- 24170753 TI - Magnitude of the dawn phenomenon and its impact on the overall glucose exposure in type 2 diabetes: is this of concern? AB - OBJECTIVE: To assess the magnitude of the dawn phenomenon and its impact on the total glucose exposure in type 2 diabetes. RESEARCH DESIGN AND METHODS: A total of 248 noninsulin-treated persons with type 2 diabetes who underwent continuous glucose monitoring were divided into three groups selected by treatments: diet alone (n = 53); insulin sensitizers alone (n = 82); and insulin secretagogues alone or in combination with insulin sensitizers (n = 113). The dawn phenomenon (? glucose, mg/dL) was quantified by its absolute increment from nocturnal nadir to prebreakfast value. The participants were secondarily divided into two paired subsets after they had been separated by the presence/absence of a dawn phenomenon based on a threshold of 20 mg/dL and matched for glucose nadir. The impact of the dawn phenomenon was assessed on HbA1c and 24-h mean glucose. RESULTS: The median of ? glucose (interquartile range) was 16.0 (0-31.5 mg/dL) in the 248 subjects, and no differences were observed across groups selected by HbA1c or treatments. In the overall population, the mean impacts on HbA1c and 24 h mean glucose were 4.3 +/- 1.3 mmol/mol (0.39 +/- 0.12%) and 12.4 +/- 2.4 mg/dL, respectively. The mean impact on 24-h mean glucose was not statistically different between those on diet alone (16.7 +/- 5.9 mg/dL) compared with the two subsets treated with oral hypoglycemic agents (11.2 +/- 5.3 and 8.5 +/- 7.5 mg/dL). CONCLUSIONS: The impact of the dawn phenomenon on overall glycemic control in type 2 diabetes, as depicted by the HbA1c level, was ~0.4% and not eliminated by any of the currently available armamentarium of oral antidiabetes agents. PMID- 24170754 TI - Increased glycemic variability is independently associated with length of stay and mortality in noncritically ill hospitalized patients. AB - OBJECTIVE: To investigate the association between glycemic variability (GV) and both length of stay (LOS) and 90-day mortality in noncritically ill hospitalized patients. RESEARCH DESIGN AND METHODS: This study retrospectively analyzed 4,262 admissions to the general medicine or surgery services during a 2 year period. Patients with point-of-care glucose monitoring and a minimum of two glucose values per day on average were selected. GV was assessed by SD and coefficient of variation (CV). Data were analyzed with linear and logistic multivariate regression analysis in separate models for SD and CV. Analysis was performed with generalized estimating equations to adjust for correlation between multiple admissions in some individual cases. RESULTS: After exclusions, 935 admissions comprised the sample. Results of adjusted analysis indicate that for every 10 mg/dL increase in SD and 10-percentage point increase in CV, LOS increased by 4.4 and 9.7%, respectively. Relative risk of death in 90 days also increased by 8% for every 10-mg/dL increase in SD. These associations were independent of age, race, service of care (medicine or surgery), previous diagnosis of diabetes, HbA1c, BMI, the use of regular insulin as a sole regimen, mean glucose, and hypoglycemia occurrence during the hospitalization. CONCLUSIONS: Our results indicate that increased GV during hospitalization is independently associated with longer LOS and increased mortality in noncritically ill patients. Prospective studies with continuous glucose monitoring are necessary to investigate this association thoroughly and to generate therapeutic strategies targeted at decreasing GV. PMID- 24170755 TI - Health-related quality of life predicts major amputation and death, but not healing, in people with diabetes presenting with foot ulcers: the Eurodiale study. AB - OBJECTIVE: Low health-related quality of life (HRQoL) has been consistently reported to be associated with poor prognosis for a variety of health outcomes in various settings. We aimed to evaluate whether HRQoL in patients presenting with new diabetic foot ulcers (DFUs) has prognostic significance for ulcer healing, major amputation, and death. RESEARCH DESIGN AND METHODS: We followed 1,088 patients with new DFUs presenting for treatment at one of the 14 centers in 10 European countries participating in the Eurodiale (European Study Group on Diabetes and the Lower Extremity) study, prospectively until healing (76.9%), major amputation (4.6%), or death (6.4%) up to a maximum of 1 year. At baseline, patient and ulcer characteristics were recorded as well as EQ-5D, a standardized instrument consisting of five domains and a visual analog scale for use as a measure of HRQoL. The prognostic influence of the EQ-5D domains was evaluated in multivariable Cox regression analyses on the time-to-event data, adjusting for baseline clinical characteristics of the ulcer and comorbidities. RESULTS: While predictive effects of HRQoL, adjusted for possible confounders, were absent for healing, decreased HRQoL, especially in the physical domains, was statistically significant for major amputation (mobility, self-care, usual activities) and death (self-care, usual activities, pain/discomfort). CONCLUSIONS: Low HRQoL appears to be predictive for major amputation and death, but high HRQoL does not increase healing. Future studies into the influence of HRQoL on ulcer outcome are important in attempts to decrease treatment failure and mortality. PMID- 24170756 TI - Cohort study of insulin glargine and risk of breast, prostate, and colorectal cancer among patients with diabetes. AB - OBJECTIVE: To examine whether use of insulin glargine, compared with another long acting insulin, is associated with risk of breast, prostate, colorectal cancer, or all cancers combined. RESEARCH DESIGN AND METHODS: Computerized health records from Kaiser Permanente Northern and Southern California regions starting in 2001 and ending in 2009 were used to conduct a population-based cohort study among patients with diabetes aged >=18 years. With use of Cox regression modeling, cancer risk in users of insulin glargine (n = 27,418) was compared with cancer risk in users of NPH (n = 100,757). RESULTS: The cohort had a median follow-up of 3.3 years during which there was a median of 1.2 years of glargine use and 1.4 years of NPH use. Among users of NPH at baseline, there was no clear increase in risk of breast, prostate, colorectal, or all cancers combined associated with switching to glargine. Among those initiating insulin, ever use or >=2 years of glargine was not associated with increased risk of prostate or colorectal cancer or all cancers combined. Among initiators, the hazard ratio (HR) for breast cancer associated with ever use of glargine was 1.3 (95% CI 1.0-1.8); the HR for breast cancer associated with use of glargine for >=2 years was 1.6 or 1.7 depending on whether glargine users had also used NPH. CONCLUSIONS: Results of this study should be viewed cautiously, given the relatively short duration of glargine use to date and the large number of potential associations examined. PMID- 24170757 TI - Does a patient-managed insulin intensification strategy with insulin glargine and insulin glulisine provide similar glycemic control as a physician-managed strategy? Results of the START (Self-Titration With Apidra to Reach Target) Study: a randomized noninferiority trial. AB - OBJECTIVE Diabetes self-management is universally regarded as a foundation of diabetes care. We determined whether comparable glycemic control could be achieved by self-titration versus physician titration of a once-daily bolus insulin dose in patients with type 2 diabetes who are unable to achieve optimal glycemia control with a basal insulin. RESEARCH DESIGN AND METHODS Patients with type 2 diabetes, an HbA1c level >7% (53 mmol/mol), and either nocturnal hypoglycemia episodes or an insufficient basal insulin glargine level (with or without oral agents) to achieve a fasting plasma glucose level <=6 mmol/L (108 mg/dL) were studied. Participants all had bolus insulin glulisine added at breakfast and were allocated to either algorithm-guided patient self-titration or physician titration. The primary outcome was an HbA1c level <=7% (53 mmol/mol) without severe hypoglycemia. RESULTS After a mean (SD) follow-up of 159.4 days (36.2 days), 28.4% of participants in the self-titration arm vs. 21.2% in the physician titration arm achieved an HbA1c level of <=7% (53 mmol/mol) without severe hypoglycemia (between-group absolute difference 7.2%; 95% CI -3.2 to 17.7). The lower end of this 95% confidence interval was within the predetermined noninferiority boundary of -5% (P noninferiority = 0.011). CONCLUSIONS In stable patients with type 2 diabetes who are receiving doses of basal insulin glargine who require bolus insulin, a simple bolus insulin patient-managed titration algorithm is as effective as a physician-managed algorithm. PMID- 24170758 TI - A randomized controlled trial of cognitive behavioral therapy for adherence and depression (CBT-AD) in patients with uncontrolled type 2 diabetes. AB - OBJECTIVE: To test cognitive behavioral therapy for adherence and depression (CBT AD) in type 2 diabetes. We hypothesized that CBT-AD would improve adherence; depression; and, secondarily, hemoglobin A1c (A1C). RESEARCH DESIGN AND METHODS: Eighty-seven adults with unipolar depression and uncontrolled type 2 diabetes received enhanced treatment as usual (ETAU), including medication adherence, self monitoring of blood glucose (SMBG), and lifestyle counseling; a provider letter documented psychiatric diagnoses. Those randomized to the intervention arm also received 9-11 sessions of CBT-AD. RESULTS: Immediately after acute treatment (4 months), adjusting for baseline, CBT-AD had 20.7 percentage points greater oral medication adherence on electronic pill cap (95% CI -31.14 to -10.22, P = 0.000); 30.2 percentage points greater SMBG adherence through glucometer downloads (95% CI -42.95 to -17.37, P = 0.000); 6.44 points lower depression scores on the Montgomery-Asberg Depression Rating Scale (95% CI 2.33-10.56, P = 0.002); 0.74 points lower on the Clinical Global Impression (95% CI 0.16-1.32, P = 0.01); and 0.72 units lower A1C (95% CI 0.29-1.15, P = 0.001) relative to ETAU. Analyses of 4-, 8-, and 12-month follow-up time points indicated that CBT-AD maintained 24.3 percentage points higher medication adherence (95% CI -38.2 to -10.3, P = 0.001); 16.9 percentage points greater SMBG adherence (95% CI -33.3 to -0.5, P = 0.043); and 0.63 units lower A1C (95% CI 0.06-1.2, P = 0.03) after acute treatment ended. For depression, there was some evidence of continued improvement posttreatment, but no between-group differences. CONCLUSIONS: CBT-AD is an effective intervention for adherence, depression, and glycemic control, with enduring and clinically meaningful benefits for diabetes self-management and glycemic control in adults with type 2 diabetes and depression. PMID- 24170759 TI - Effects of randomization to intensive glucose control on adverse events, cardiovascular disease, and mortality in older versus younger adults in the ACCORD Trial. AB - OBJECTIVE: We explore the effect of randomized treatment, comparing intensive to standard glucose-lowering strategies on major cardiovascular outcomes, death, and severe adverse events in older versus younger participants in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial. RESEARCH DESIGN AND METHODS: Participants with type 2 diabetes (n = 10,251) with a mean age of 62 years, a median duration of diabetes of 10 years, and a median A1C of 8.1% (65 mmol/mol) were randomized to treatment strategies targeting either A1C <6.0% (42 mmol/mol) or 7.0-7.9% (53-63 mmol/mol) and followed for a mean of 3.7 years. Outcomes were analyzed within subgroups defined by baseline age (<65 vs. >=65 years). RESULTS: Older and younger ACCORD participants achieved similar intensive arm A1C levels and between-arm A1C differences. Within the older subgroup, similar hazards of the cardiovascular primary outcome and total mortality were observed in the two arms. While there was no intervention effect on cardiovascular mortality in the older subgroup, there was an increased risk in the intensive arm for the younger subgroup (older hazard ratio [HR] = 0.97; younger HR = 1.71; P = 0.03). Regardless of intervention arm, the older subgroup experienced higher annualized rates of severe hypoglycemia (4.45% intensive and 1.36% standard) than the younger subgroup (2.45% intensive and 0.80% standard). CONCLUSIONS: Intensive glucose lowering increased the risk of cardiovascular disease and total mortality in younger participants, whereas it had a neutral effect in older participants. The intensive to standard relative risk of severe hypoglycemia was similar in both age subgroups, with higher absolute rates in older participants within both treatment arms. PMID- 24170760 TI - Preoperative A1C and clinical outcomes in patients with diabetes undergoing major noncardiac surgical procedures. AB - OBJECTIVE: To evaluate the relationship between preoperative A1C and clinical outcomes in individuals with diabetes mellitus undergoing noncardiac surgery. RESEARCH DESIGN AND METHODS: Data were obtained from the National Surgical Quality Improvement Program database and the Research Patient Data Registry of the Brigham and Women's Hospital. Patients admitted to the hospital for >=1 day after undergoing noncardiac surgery from 2005 to 2010 were included in the study. RESULTS: Of 1,775 patients with diabetes, 622 patients (35%) had an A1C value available within 3 months before surgery. After excluding same-day surgeries, patients with diabetes were divided into four groups (A1C <=6.5% [N = 109]; >6.5 8% [N = 202]; >8-10% [N = 91]; >10% [N = 47]) and compared with age-, sex-, and BMI-matched nondiabetic control subjects (N = 888). Individuals with A1C values between 6.5 and 8% had a hospital length of stay (LOS) similar to the matched control group (P = 0.5). However, in individuals with A1C values <=6.5 or >8%, the hospital LOS was significantly longer compared with the control group (P < 0.05). Multivariate regression analysis demonstrated that a higher A1C value was associated with increased hospital LOS after adjustments for age, sex, BMI, race, type of surgery, Charlson Comorbidity Index, smoking status, and glucose level on the day of surgery (P = 0.02). There were too few events to meaningfully evaluate for death, infections, or readmission rate. CONCLUSIONS: Our study suggests that chronic hyperglycemia (A1C >8%) is associated with poor surgical outcomes (longer hospital LOS). Providing a preoperative intervention to improve glycemic control in individuals with A1C values >8% may improve surgical outcomes, but prospective studies are needed. PMID- 24170761 TI - Glycemic exposure and blood pressure influencing progression and remission of diabetic retinopathy: a longitudinal cohort study in GoDARTS. AB - OBJECTIVE: This study sought to investigate the progression and regression of diabetic retinopathy (DR) and the effects of population risk factors on the rates of transition across retinopathy stages. RESEARCH DESIGN AND METHODS: The study cohort consisted of 44,871 observed DR events between the calendar years 1990 and 2011 for 4,758 diabetic patients who were diagnosed at 35 years of age or older. The first retinal observation was recorded within a year from diagnosis, and the result was recorded as free of retinopathy. A multistate Markov model was applied for analyzing the development of DR and its relation to the patterns of changes in risk factors. RESULTS: We observed a consistent risk effect of HbA1c on the progression (no retinopathy to mild background DR [BDR] hazard ratio per SD of HbA1c [HR] 1.42 [95% CI 1.32-1.52], mild BDR to observable BDR HR 1.32 [95% CI 1.08-1.60], and observable BDR to severe nonproliferative/proliferative DR HR 2.23 [95% CI 1.16-4.29]). Similarly, systolic blood pressure (SBP) and diastolic blood pressure increased the risk for the transition from the asymptomatic phase to mild BDR (HR 1.20 [95% CI 1.11-1.30]) and the mild BDR to observable BDR (HR 1.87 [95% CI 1.46-2.40]), respectively. Regression from mild BDR to no DR was associated with lower SBP (HR 0.79 [95% CI 0.64-0.97]) and lower HbA1c (HR 0.76 [95% CI 0.64-0.89]). CONCLUSIONS: Progression and regression of DR were strongly associated with blood pressure and glycemic exposure. PMID- 24170762 TI - Intakes of dietary fiber, vegetables, and fruits and incidence of cardiovascular disease in Japanese patients with type 2 diabetes. AB - OBJECTIVE: Foods rich in fiber, such as vegetables and fruits, prevent cardiovascular disease (CVD) among healthy adults, but such data in patients with diabetes are sparse. We investigated this association in a cohort with type 2 diabetes aged 40-70 years whose HbA1c values were >= 6.5% in Japan Diabetes Society values. RESEARCH DESIGN AND METHODS: In this cohort study, 1,414 patients were analyzed after exclusion of patients with history of CVDs and nonresponders to a dietary survey. Primary outcomes were times to stroke and coronary heart disease (CHD). Hazard ratios (HRs) of dietary intake were estimated by Cox regression adjusted for systolic blood pressure, lipids, energy intake, and other confounders. RESULTS: Mean daily dietary fiber in quartiles ranged from 8.7 to 21.8 g, and mean energy intake ranged from 1,442.3 to 2,058.9 kcal. Mean daily intake of vegetables and fruits in quartiles ranged from 228.7 to 721.4 g. During the follow-up of a median of 8.1 years, 68 strokes and 96 CHDs were observed. HRs for stroke in the fourth quartile vs. the first quartile were 0.39 (95% CI 0.12 1.29, P = 0.12) for dietary fiber and 0.35 (0.13-0.96, P = 0.04) for vegetables and fruits. There were no significant associations with CHD. The HR per 1-g increase was smaller for soluble dietary fiber (0.48 [95% CI 0.30-0.79], P < 0.01) than for total (0.82 [0.73-0.93], P < 0.01) and insoluble (0.79 [0.68 0.93], P < 0.01) dietary fiber. CONCLUSIONS: Increased dietary fiber, particularly soluble fiber, and vegetables and fruits were associated with lower incident stroke but not CHD in patients with type 2 diabetes. PMID- 24170763 TI - Initiation and gradual intensification of premixed insulin lispro therapy versus Basal {+/-} mealtime insulin in patients with type 2 diabetes eating light breakfasts. AB - OBJECTIVE: We compared two strategies initiating and intensifying insulin treatment and tested for noninferiority of premixed insulin to basal +/- mealtime insulin analog in patients eating light breakfasts. RESEARCH DESIGN AND METHODS: This randomized, open-label, 48-week study compared two algorithms. Up to three injections of insulin lispro mix 25 and/or insulin lispro mix 50 (premix; premixed insulin lispro) or basal insulin glargine plus up to three injections of insulin lispro (basal+; glargine + insulin lispro) were used in type 2 diabetic patients uncontrolled with oral antihyperglycemic medication and consuming <15% daily calories at breakfast. The hypothesis was to test noninferiority of premix to basal+ for glycemic control measured by HbA1c after 48 weeks, assessed using ANCOVA with a 0.4% margin. RESULTS: Patients (n = 344; 176 [51%] females; mean [SD] age 54.3 [8.8] years; BMI 29.4 [4.6] kg/m(2); baseline HbA1c 9.02 [0.97]%) were randomized to premix (n = 171) or basal+ (n = 173). In the per-protocol analysis (n = 230), least squares means (95% CI) end point HbA1c were 7.40% (7.15 7.65) and 7.55% (7.27-7.82) in respective arms. Between-treatment difference was 0.14% (-0.42 to 0.13), with noninferiority met. Significantly more patients in premix achieved HbA1c targets of <7.0% compared with basal+ (48.2 vs. 36.2%; P = 0.024). Self-monitored blood glucose profiles, body weight changes, total insulin doses, and overall hypoglycemia (65 vs. 60%) were similar in premix and basal+ (P = 0.494), except nocturnal episodes (34.3 vs. 23.7%; P = 0.018) were more common in premix. CONCLUSIONS: Both intensive insulin strategies improved glycemic control; however, final HbA1c levels were seen above those achieved in previous treat-to-target trials, likely due to the inadequate insulin titrations and probably due to the complexity of tested insulin regimens. A higher percentage of patients achieved target HbA1c <7% with multiple premixed insulins, but this treatment resulted in more nocturnal hypoglycemia than a basal-bolus regimen. PMID- 24170764 TI - Midregional fragment of proadrenomedullin, new-onset albuminuria, and cardiovascular and all-cause mortality in patients with type 2 diabetes (ZODIAC 30). AB - OBJECTIVE: The midregional fragment of proadrenomedullin (MR-proADM) is a marker of endothelial dysfunction and has been associated with a variety of diseases. Our aim was to investigate whether MR-proADM is associated with new-onset albuminuria and cardiovascular (CV) and all-cause mortality in patients with type 2 diabetes treated in primary care. RESEARCH DESIGN AND METHODS: Patients with type 2 diabetes participating in the observational Zwolle Outpatient Diabetes Project Integrating Available Care (ZODIAC) study were included. Cox regression analyses were used to assess the relation of baseline MR-proADM with new-onset albuminuria and CV and all-cause mortality. Risk prediction capabilities of MR proADM for new-onset albuminuria and CV and all-cause mortality were assessed with Harrell's C and the integrated discrimination improvement. RESULTS: In 1,243 patients (mean age 67 [+/-12] years), the median follow-up was 5.6 years (interquartile range 3.1-10.1); 388 (31%) patients died, with 168 (12%) CV deaths. Log2 MR-proADM was associated with CV (hazard ratio 1.96 [95% CI 1.27 3.01]) and all-cause mortality (1.78 [1.34-2.36]) after adjusting for age, sex, BMI, smoking, systolic blood pressure, cholesterol-to-HDL ratio, duration of diabetes, HbA1c, ACE inhibitor/angiotensin receptor blocker, history of CV diseases, log serum creatinine, and log albumin-to-creatinine ratio. MR-proADM slightly improved mortality risk prediction. The age- and sex-adjusted, but not multivariate-adjusted, MR-proADM levels were associated with new-onset albuminuria. CONCLUSIONS: MR-proADM was associated with CV and all-cause mortality in patients with type 2 diabetes after a median follow-up of 5.6 years. There was no independent relationship with new-onset albuminuria. In the availability of an extensive set of risk factors, there was little added effect of MR-proADM in risk prediction of CV and all-cause mortality. PMID- 24170765 TI - Antihypertensive treatment and resistant hypertension in patients with type 1 diabetes by stages of diabetic nephropathy. AB - OBJECTIVE: To assess blood pressure (BP) control, antihypertensive treatment, and prevalence of resistant hypertension (RH) in patients with type 1 diabetes stratified by stage of diabetic nephropathy. RESEARCH DESIGN AND METHODS: This cross-sectional study included a nationally representative cohort of patients with type 1 diabetes (N = 3,678) from the Finnish Diabetic Nephropathy Study (FinnDiane). The data were linked to the Drug Prescription Register to obtain purchases of antihypertensive drugs 6 months prior to the baseline visit. The treatment targets were based on the American Diabetes Association guidelines. RH was defined as failure to reach BP target despite the use of three or more antihypertensive drugs of different classes (one of which was a diuretic). RESULTS: In patients with normal albumin excretion rate, 14.1% were on antihypertensive treatment and 74.6% of them had uncontrolled BP despite treatment. The corresponding figures were 60.5 and 71.2% for the microalbuminuric patients, 90.3 and 80.0% for the macroalbuminuric patients, 88.6 and 88.1% for dialysis, and 91.2 and 90.4% for kidney-transplanted patients. The prevalence of RH was 1.2% in the normoalbuminuric, 4.7% in the microalbuminuric, 28.1% in the macroalbuminuric, 36.6% in the dialysis, and 26.3% in the kidney transplant groups. Age (odds ratio 1.04 [95% CI 1.02-1.05]), estimated glomerular filtration rate (0.97 [0.96-0.97]), waist-to-hip ratio (1.44 [1.15-1.80]), triglycerides (1.19 [1.01-1.40]), microalbuminuria (2.58 [1.43-4.67]), and macroalbuminuria (5.61 [3.20-9.84]) were independently associated with RH. CONCLUSIONS: The prevalence of uncontrolled hypertension and RH increases with advanced diabetic nephropathy. These data suggest that there is an urgent need for improvement of antihypertensive treatment. PMID- 24170766 TI - Safety of nighttime 2-hour suspension of Basal insulin in pump-treated type 1 diabetes even in the absence of low glucose. AB - OBJECTIVE: An integrated sensor-augmented pump system has been introduced that interrupts basal insulin infusion for 2 h if patients fail to respond to low glucose alarms. It has been suggested that such interruptions of basal insulin due to falsely low glucose levels detected by sensor could lead to diabetic ketoacidosis. We hypothesized that random suspension of basal insulin for 2 h in the overnight period would not lead to clinically important increases in blood beta-hydroxybutyrate levels despite widely varying glucose values prior to the suspension. RESEARCH DESIGN AND METHODS: Subjects measured blood glucose and blood beta-hydroxybutyrate levels using a meter each night at 9:00 p.m., then fasted until the next morning. On control nights, the usual basal rates were continued; on experimental nights, the basal insulin infusion was reprogrammed for a 2-h zero basal rate at random times after 11:30 p.m. RESULTS: In 17 type 1 diabetic subjects (mean age 24 +/- 9 years, diabetes duration 14 +/- 11 years, A1C level 7.3 +/- 0.5% [56 mmol/mol]), blood glucose and blood beta hydroxybutyrate levels were similar at 9:00 p.m. on suspend nights (144 +/- 63 mg/dL and 0.09 +/- 0.07 mmol/L) and nonsuspend nights (151 +/- 65 mg/dL and 0.08 +/- 0.06 mmol/L) (P = 0.39 and P = 0.47, respectively). Fasting morning blood glucose levels increased after suspend nights compared with nonsuspend nights (191 +/- 68 vs. 141 +/- 75 mg/dL, P < 0.0001), and the frequency of fasting hypoglycemia decreased the morning following suspend nights (P < 0.0001). Morning blood beta-hydroxybutyrate levels were slightly higher after suspension (0.13 +/- 0.14 vs. 0.09 +/- 0.11 mmol/L, P = 0.053), but the difference was not clinically important. CONCLUSIONS: Systems that suspend basal insulin for 2 h are safe and do not lead to clinically significant ketonemia even if the blood glucose level is elevated at the time of the suspension. PMID- 24170767 TI - BAY 80-6946 is a highly selective intravenous PI3K inhibitor with potent p110alpha and p110delta activities in tumor cell lines and xenograft models. AB - Because of the complexity derived from the existence of various phosphoinositide 3-kinase (PI3K) isoforms and their differential roles in cancers, development of PI3K inhibitors with differential pharmacologic and pharmacokinetic profiles would allow best exploration in different indications, combinations, and dosing regimens. Here, we report BAY 80-6946, a highly selective and potent pan-class I PI3K inhibitor with sub-nanomolar IC50s against PI3Kalpha and PI3Kdelta. BAY 80 6946 exhibited preferential inhibition (about 10-fold) of AKT phosphorylation by PI3Kalpha compared with PI3Kbeta in cells. BAY 80-6946 showed superior antitumor activity (>40-fold) in PIK3CA mutant and/or HER2 overexpression as compared with HER2-negative and wild-type PIK3CA breast cancer cell lines. In addition, BAY 80 6946 revealed potent activity to induce apoptosis in a subset of tumor cells with aberrant activation of PI3K as a single agent. In vivo, single intravenous administration of BAY 80-6946 exhibited higher exposure and prolonged inhibition of pAKT levels in tumors versus plasma. BAY 80-6946 is efficacious in tumors with activated PI3K when dosed either continuously or intermittently. Thus, BAY 80 6946 induced 100% complete tumor regression when dosed as a single agent every second day in rats bearing HER2-amplified and PIK3CA-mutated KPL4 breast tumors. In combination with paclitaxel, weekly dosing of BAY 80-6946 is sufficient to reach sustained response in all animals bearing patient-derived non-small cell lung cancer xenografts, despite a short plasma elimination half-life (1 hour) in mice. Thus, BAY 80-6946 is a promising agent with differential pharmacologic and pharmacokinetic properties for the treatment of PI3K-dependent human tumors. PMID- 24170768 TI - Hypoxia-regulated overexpression of soluble VEGFR2 controls angiogenesis and inhibits tumor growth. AB - VEGFs are found at high levels in hypoxic tumors. As major components directing pathologic neovascularization, they regulate stromal reactions. Consequently, novel strategies targeting and inhibiting VEGF overproduction upon hypoxia offer considerable potential for modern anticancer therapies controlling rather than destroying tumor angiogenesis. Here, we report the design of a vector expressing the soluble form of VEGF receptor-2 (sVEGFR2) driven by a hypoxia-responsive element (HRE)-regulated promoter. To enable in vivo imaging by infrared visualization, mCherry and IFP1.4 coding sequences were built into the vector. Plasmid construction was validated through transfection into embryonic human kidney HEK293 and murine B16F10 melanoma cells. sVEGFR2 was expressed in hypoxic conditions only, confirming that the gene was regulated by the HRE promoter. sVEGFR2 was found to bind efficiently and specifically to murine and human VEGF A, reducing the growth of tumor and endothelial cells as well as impacting angiogenesis in vitro. The hypoxia-conditioned sVEGFR2 expression was shown to be functional in vivo: Tumor angiogenesis was inhibited and, on stable transfection of B16F10 melanoma cells, tumor growth was reduced. Enhanced expression of sVEGFR2 was accompanied by a modulation in levels of VEGF-A. The resulting balance reflected the effect on tumor growth and on control of angiogenesis. A concomitant increase of intratumor oxygen tension also suggested an influence on vessel normalization. The possibility to express an angiogenesis regulator as sVEGFR2, in a hypoxia-conditioned manner, significantly opens new strategies for tumor vessel-controlled normalization and the design of adjuvants for combined cancer therapies. PMID- 24170769 TI - Sorafenib suppresses JNK-dependent apoptosis through inhibition of ZAK. AB - Sorafenib is U.S. Food and Drug Adminstration-approved for the treatment of renal cell carcinoma and hepatocellular carcinoma and has been combined with numerous other targeted therapies and chemotherapies in the treatment of many cancers. Unfortunately, as with other RAF inhibitors, patients treated with sorafenib have a 5% to 10% rate of developing cutaneous squamous cell carcinoma (cSCC)/keratoacanthomas. Paradoxical activation of extracellular signal-regulated kinase (ERK) in BRAF wild-type cells has been implicated in RAF inhibitor-induced cSCC. Here, we report that sorafenib suppresses UV-induced apoptosis specifically by inhibiting c-jun-NH(2)-kinase (JNK) activation through the off-target inhibition of leucine zipper and sterile alpha motif-containing kinase (ZAK). Our results implicate suppression of JNK signaling, independent of the ERK pathway, as an additional mechanism of adverse effects of sorafenib. This has broad implications for combination therapies using sorafenib with other modalities that induce apoptosis. PMID- 24170770 TI - Plastin polymorphisms predict gender- and stage-specific colon cancer recurrence after adjuvant chemotherapy. AB - Tumor recurrence after curative resection remains a major problem in patients with locally advanced colorectal cancer treated with adjuvant chemotherapy. Genetic single-nucleotide polymorphisms (SNP) may serve as useful molecular markers to predict clinical outcomes in these patients and identify targets for future drug development. Recent in vitro and in vivo studies have demonstrated that the plastin genes PLS3 and LCP1 are overexpressed in colon cancer cells and play an important role in tumor cell invasion, adhesion, and migration. Hence, we hypothesized that functional genetic variations of plastin may have direct effects on the progression and prognosis of locally advanced colorectal cancer. We tested whether functional tagging polymorphisms of PLS3 and LCP1 predict time to tumor recurrence (TTR) in 732 patients (training set, 234; validation set, 498) with stage II/III colorectal cancer. The PLS3 rs11342 and LCP1 rs4941543 polymorphisms were associated with a significantly increased risk for recurrence in the training set. PLS3 rs6643869 showed a consistent association with TTR in the training and validation set, when stratified by gender and tumor location. Female patients with the PLS3 rs6643869 AA genotype had the shortest median TTR compared with those with any G allele in the training set [1.7 vs. 9.4 years; HR, 2.84; 95% confidence interval (CI), 1.32-6.1; P = 0.005] and validation set (3.3 vs. 13.7 years; HR, 2.07; 95% CI, 1.09-3.91; P = 0.021). Our findings suggest that several SNPs of the PLS3 and LCP1 genes could serve as gender- and/or stage specific molecular predictors of tumor recurrence in stage II/III patients with colorectal cancer as well as potential therapeutic targets. PMID- 24170772 TI - Fluviicola hefeinensis sp. nov., isolated from the wastewater of a chemical factory. AB - A Gram-negative, strictly aerobic, yellow-orange-pigmented, motile, short rod shaped, catalase-positive, oxidase-negative bacterium, strain MYL-8(T), was isolated from wastewater of the Jin Tai Chemical Factory in Hefei, China. Strain MYL-8(T) grew optimally at 30 degrees C, in the absence of NaCl and at pH 7. Menaquinone 6 (MK-6) was the sole respiratory quinone and the major fatty acids were iso-C15 : 0, iso-C15 : 1 G, iso-C17 : 0 3-OH and summed feature 3 (C16 : 1omega7c and/or iso-C15 : 0 2-OH). The polar lipid profile was composed predominantly of unidentified polar lipids and aminolipids. Minor amounts of phosphatidylethanolamine and unidentified phospholipids were also detectable. The DNA G+C content of strain MYL-8(T) was 43.5 mol%. The 16S rRNA gene sequence of strain MYL-8(T) showed the highest similarity to that of Fluviicola taffensis RW 262(T) (97.03 %), followed by Wandonia haliotis Haldis-1-1(T) (92.05 %), Lishizhenia caseinilytica UST040201-001(T) (91.43 %) and Lishizhenia tianjinensis JCM 15141(T) (90.61 %). DNA-DNA relatedness between strain MYL-8(T) and F. taffensis RW 262(T) was 21.35+/-0.90 %. On the basis of phenotypic, chemotaxonomic, genomic and phylogenetic data, strain MYL-8(T) is considered to represent a novel species of the genus Fluviicola, for which the name Fluviicola hefeinensis sp. nov. is proposed. The type strain is MYL-8(T) ( = KACC 16597(T) = CCTCC AB 2013168(T)). PMID- 24170771 TI - Off-target effects of c-MET inhibitors on thyroid cancer cells. AB - Aberrantly activated c-MET signaling occurs in several cancers, promoting the development of c-MET inhibitors. In this study, we found that eight of eight thyroid cancer cell lines (including six anaplastic thyroid cell lines) have prominent expression of c-MET protein. Fifty percent of the thyroid cancer cell lines (four of eight) were growth inhibited by two small molecule c-MET inhibitors (tivantinib and crizotinib) associated with apoptosis and G(2)-M cell cycle arrest. However, crizotinib did not inhibit 50% proliferation of thyroid cancer cells (SW1736 and TL3) at a concentration at which the drug completely inhibited ligand-stimulated c-MET phosphorylation. However, tivantinib was less potent than crizotinib at inhibiting c-MET phosphorylation, but was more potent than crizotinib at decreasing cell growth. Suppressing c-MET protein expression and phosphorylation using siRNA targeting c-MET did not induce cell-cycle arrest and apoptosis. Taken together, tivantinib and crizotinib have off-target(s) activity, contributing to their antitumor activity. In vivo study showed that crizotinib markedly inhibited the growth of thyroid cancer cells (SW1736) in immunodeficient mice. In summary, c-MET inhibitors (tivantinib and crizotinib) suppress the growth of aggressive thyroid cancer cells, and this potential therapeutic benefit results from their non-MET-targeting effects. PMID- 24170773 TI - Rubrobacter aplysinae sp. nov., isolated from the marine sponge Aplysina aerophoba. AB - A Gram-stain-positive, non-spore-forming bacterium (strain RV113(T)) was isolated from the marine sponge Aplysina aerophoba. 16S rRNA gene sequence analysis showed that strain RV113(T) belongs to the genus Rubrobacter, and is related most closely to Rubrobacter bracarensis VF70612_S1(T) (96.9% similarity) and more distantly related (<93%) to all other species of the genus Rubrobacter. The peptidoglycan diamino acid was lysine. Strain RV113(T) exhibited a quinone system with menaquinone MK-8 as the predominant compound. The polar lipid profile of strain RV113(T) consisted of the major compounds phosphatidylglycerol and two unidentified phosphoglycolipids. The major fatty acid was anteiso-C17 : 0omega9c. These chemotaxonomic traits are in agreement with those of other species of the genus Rubrobacter. The results of physiological and biochemical tests allowed the clear phenotypic differentiation of strain RV113(T) from all recognized Rubrobacter species. Strain RV113(T) is thus considered to represent a novel species, for which the name Rubrobacter aplysinae sp. nov. is proposed. The type strain is RV113(T) ( = DSM 27440(T) = CECT 8425(T)). PMID- 24170774 TI - Prosthecobacter algae sp. nov., isolated from activated sludge using algal metabolites. AB - A Gram-stain-negative, fusiform-shaped, facultatively anaerobic bacterial strain, designated EBTL04(T), was isolated from activated sludge using algal metabolites and taxonomically characterized through polyphasic investigation. Phylogenetic analysis based on the 16S rRNA gene sequence showed that strain EBTL04(T) belongs to the family Verrucomicrobiaceae, class Verrucomicrobiae, and is closely related to Prosthecobacter dejongeii DSM 12251(T) (98.6 % sequence similarity), Prosthecobacter fusiformis ATCC 25309(T) (97.9 %), Prosthecobacter debontii DSM 14044(T) (97.5%), Prosthecobacter vanneervenii DSM 12252(T) (94.7%) and Prosthecobacter fluviatilis KCTC 22182(T) (93.7%). The G+C content of the genomic DNA of strain EBTL04(T) was 62.7 mol%. The menaquinone MK-6 was detected as the predominant quinone. Strain EBTL04(T) contained phosphatidylethanolamine, phosphatidylglycerol and phosphatidylserine as major polar lipids. A fatty acid profile with C(16 : 1)omega5c, iso-C(14 : 0), C(16 : 0), anteiso-C(15 : 0) and C(14 : 0) as the major components supported the classification of strain EBTL04(T) in the genus Prosthecobacter. Based on several phenotypic, genotypic and chemotaxonomic features, strain EBTL04(T) was clearly differentiated from its phylogenetic neighbours. Therefore, strain EBTL04(T) should be considered to represent a novel species of the genus Prosthecobacter, for which the name Prosthecobacter algae sp. nov. is proposed. The type strain is EBTL04(T) ( = KCTC 23681(T) = JCM 18053(T)). PMID- 24170775 TI - Kordia jejudonensis sp. nov., isolated from the junction between the ocean and a freshwater spring, and emended description of the genus Kordia. AB - A Gram-staining-negative, aerobic, non-spore-forming, non-flagellated, non gliding and rod-shaped bacterial strain, SSK3-3(T), was isolated from the zone where the ocean and a freshwater spring meet at Jeju island, South Korea. Strain SSK3-3(T) grew optimally at 30 degrees C, at pH 7.0-8.0 and in the presence of 2.0% (w/v) NaCl. Phylogenetic trees based on 16S rRNA gene sequences revealed that strain SSK3-3(T) clustered with the type strains of species of the genus Kordia, with which it exhibited 96.5-97.2% 16S rRNA gene sequence similarity. Sequence similarities to the type strains of other recognized species were less than 92.2%. Strain SSK3-3(T) contained MK-6 as the predominant menaquinone and iso-C(15 : 0), iso-C(17 : 0) 3-OH, iso-C(15 : 0) 3-OH and summed feature 3 (C(16 : 1)omega7c and/or C(16 : 1)omega6c) as the major fatty acids. The major polar lipids of strain SSK3-3(T) were phosphatidylethanolamine, one unidentified lipid and one unidentified glycolipid. The DNA G+C content of strain SSK3-3(T) was 34.9 mol% and the mean DNA-DNA relatedness with Kordia periserrulae KACC 14311(T) was 12%. The differential phenotypic properties, together with the phylogenetic and genetic distinctiveness, revealed that strain SSK3-3(T) is separate from other species of the genus Kordia. On the basis of the data presented, strain SSK3-3(T) is considered to represent a novel species of the genus Kordia, for which the name Kordia jejudonensis sp. nov. is proposed. The type strain is SSK3-3(T) ( = KCTC 32426(T) = CECT 8368(T)). An emended description of the genus Kordia is also provided. PMID- 24170776 TI - Luteimonas abyssi sp. nov., isolated from deep-sea sediment. AB - Three Gram-stain-negative, strictly aerobic, rod-shaped with single polar flagellum, yellow-pigmented bacteria, designated strains XH031(T), XH038-3 and XH80-1, were isolated from deep-sea sediment of the South Pacific Gyre (41 degrees 51' S 153 degrees 6' W) during the Integrated Ocean Drilling Program (IODP) Expedition 329. Phylogenetic analysis based on 16S rRNA gene sequences indicated that the isolates belonged to the genus Luteimonas and showed the highest 16S rRNA gene sequence similarity with Luteimonas aestuarii B9(T) (96.95%), Luteimonas huabeiensis HB2(T) (96.93%) and Xanthomonas cucurbitae LMG 690(T) (96.92 %). The DNA G+C contents of the three isolates were 70.2-73.9 mol%. The major fatty acids were iso-C(15 : 0), iso-C(16 : 0), iso-C(11 : 0) and C16 : 010-methyl and/or iso-C(17 : 1)omega9c. The major respiratory quinone was ubiquinone-8 (Q-8). The major polar lipids were phosphatidylethanolamine, phosphatidylglycerol, diphosphatidylglycerol and one unknown phospholipid. On the basis of data from polyphasic analysis, the three isolates represent a novel species of the genus Luteimonas, for which the name Luteimonas abyssi sp. nov. is proposed. The type strain is XH031(T) ( = DSM 25880(T) = CGMCC 1.12611(T)). PMID- 24170777 TI - Proposal of Vibrionimonas magnilacihabitans gen. nov., sp. nov., a curved Gram stain-negative bacterium isolated from lake water. AB - A mesophilic bacterium appearing as curved rod-shaped cells was isolated from Lake Michigan water. It exhibited highest similarities with Sediminibacterium ginsengisoli DCY13(T) (94.4%); Sediminibacterium salmoneum NJ-44(T) (93.6%) and Hydrotalea flava CCUG 51397 (T) (93.1%) while similarities with other recognized species were <92.0%. The primary polar lipid was phosphatidylethanolamine, with moderate amounts of two unidentified glycolipids, three unknown polar lipids, one unknown aminophospholipid and one aminolipid. The primary respiratory quinone was MK-7 and sym-homospermidine was the primary polyamine. The major cellular fatty acids were iso-C(15 : 1)G, iso-C(15 : 0), iso-C(16 : 0) 3-OH and iso-C(17 : 0) 3 OH, with moderate amounts of iso-C(16 : 0). The presence of glycolipids differentiated the novel strains from related genera. The DNA mol% G+C content of the type strain MU-2(T) was 45.2. Results for other phenotypic and molecular analyses indicated that strain MU-2(T) is a representative of a novel genus and species for which the name Vibrionimonas magnilacihabitans is proposed. The type strain is MU-2(T) ( = NRRL B-59231 = DSM 22423). PMID- 24170778 TI - Multiple cytochrome P450 isoforms are involved in the generation of a pharmacologically active thiol metabolite, whereas paraoxonase 1 and carboxylesterase 1 catalyze the formation of a thiol metabolite isomer from ticlopidine. AB - Ticlopidine is a first-generation thienopyridine antiplatelet drug that prevents adenosine 5'-diphosphate (ADP)-induced platelet aggregation. We identified the enzymes responsible for the two-step metabolic bioactivation of ticlopidine in human liver microsomes and plasma. Formation of 2-oxo-ticlopidine, an intermediate metabolite, was NADPH dependent and cytochrome P450 (CYP) 1A2, 2B6, 2C19, and 2D6 were involved in this reaction. Conversion of 2-oxo-ticlopidine to thiol metabolites was observed in both microsomes (M1 and M2) and plasma (M1). These two metabolites were considered as isomers, and mass spectral analysis suggested that M2 was a thiol metabolite bearing an exocyclic double bond, whereas M1 was an isomer in which the double bond was migrated to an endocyclic position in the piperidine ring. The conversion of 2-oxo-ticlopidine to M1 in plasma was significantly increased by the addition of 1 mM CaCl2. In contrast, the activity in microsomes was not changed in the presence of CaCl2. M1 formation in plasma was inhibited by EDTA but not by other esterase inhibitors, whereas this activity in microsomes was substantially inhibited by carboxylesterase (CES) inhibitors such as bis-(p-nitrophenyl)phosphate (BNPP), diisopropylphosphorofluoride (DFP), and clopidogrel. The conversion of 2-oxo ticlopidine to M1 was further confirmed with recombinant paraoxonase 1 (PON1) and CES1. However, M2 was detected only in NADPH-dependent microsomal incubation, and multiple CYP isoforms were involved in M2 formation with highest contribution of CYP2B6. In vitro platelet aggregation assay demonstrated that M2 was pharmacologically active. These results collectively indicated that the formation of M2 was mediated by CYP isoforms whereas M1, an isomer of M2, was generated either by human PON1 in plasma or by CES1 in the human liver. PMID- 24170779 TI - Polarization of the innate immune response by prostaglandin E2: a puzzle of receptors and signals. AB - Eicosanoids tailor the innate immune response by supporting local inflammation and exhibiting immunomodulatory properties. Prostaglandin (PG) E2 is the most abundant eicosanoid in the inflammatory milieu due to the robust production elicited by pathogen-associated molecular patterns on cells of the innate immune system. The different functions and cell distribution of E prostanoid receptors explain the difficulty encountered thus far to delineate the actual role of PGE2 in the immune response. The biosynthesis of eicosanoids includes as the first step the Ca(2+)- and kinase-dependent activation of the cytosolic phospholipase A2, which releases arachidonic acid from membrane phospholipids, and later events depending on the transcriptional regulation of the enzymes of the cyclooxygenase routes, where PGE2 is the most relevant product. Acting in an autocrine/paracrine manner in macrophages, PGE2 induces a regulatory phenotype including the expression of interleukin (IL)-10, sphingosine kinase 1, and the tumor necrosis factor family molecule LIGHT. PGE2 also stabilizes the suppressive function of myeloid-derived suppressor cells, inhibits the release of IL-12 p70 by macrophages and dendritic cells, and may enhance the production of IL-23. PGE2 is a central component of the inflammasome-dependent induction of the eicosanoid storm that leads to massive loss of intravascular fluid, increases the mortality rate associated with coinfection by Candida ssp. and bacteria, and inhibits fungal phagocytosis. These effects have important consequences for the outcome of infections and the polarization of the immune response into the T helper cell types 2 and 17 and can be a clue to develop pharmacological tools to address infectious, autoimmune, and autoinflammatory diseases. PMID- 24170781 TI - Prescribing, recording, and reporting electron beam therapy. PMID- 24170782 TI - The international commission on radiation units and measurements. PMID- 24170780 TI - TRAF6 is a critical regulator of LMP1 functions in vivo. AB - EBV-encoded latent membrane protein 1 (LMP1) is critical for EBV-driven B-cell transformation and most EBV-associated malignancies and is also implicated in exacerbation of autoimmunity. LMP1 functionally mimics the TNFR superfamily member CD40, but LMP1-induced signals and downstream B-cell functions are amplified and sustained compared with those mediated by CD40. CD40 and LMP1 both depend upon TNFR-associated factor (TRAF) adaptor molecules to mediate signaling but use them differently. LMP1 is dependent upon TRAFs 3 and 5 to deliver B-cell activation signals, while CD40 predominantly uses TRAFs 2 and 6 for this purpose. Both LMP1 and CD40 functions in B cells require TRAF6, which physically associates with both receptors but via different binding sites. In B-cell CD40 signaling, TRAF6 is required for a particular subset of CD40-dependent immune functions in vivo. Inasmuch as CD40 and LMP1 use other TRAFs differentially, we predicted that TRAF6 is critical for a specific subset of LMP1 functions in vivo and that this subset will be overlapping but distinct from the TRAF6-requiring functions of CD40. This study tests this prediction using a B-cell-specific TRAF6 deficient mouse model. We found that B-cell TRAF6 is important for LMP1-mediated antibody and autoantibody production in mice, as well as germinal center formation, but not the secondary lymphoid organ enlargement that results from LMP1 transgenic expression. Results highlight differential TRAF6 requirements for specific B-cell functions by LMP1 versus CD40. These differences may make important contributions to the contrasts between normally regulated CD40 versus pathogenic LMP1-mediated signals. PMID- 24170783 TI - Prescribing, recording, and reporting electron beam therapy: contents. PMID- 24170785 TI - List of abbreviations. PMID- 24170784 TI - Preface. PMID- 24170787 TI - Executive summary. PMID- 24170788 TI - 1 introduction. PMID- 24170789 TI - 2 volumes. PMID- 24170790 TI - 3 physical characteristics of electron beams. PMID- 24170791 TI - 4 general recommendations for prescribing, recording, and reporting external-beam therapy. PMID- 24170792 TI - 5 recommendations for reporting doses in electron beam therapy for different clinical situations. PMID- 24170793 TI - 6 special techniques. PMID- 24170794 TI - 7 quality assurance. PMID- 24170795 TI - 8 quantities, reference points, and volumes recommended for reporting electron beam therapy: summary. PMID- 24170796 TI - Appendix: clinical examples. PMID- 24170798 TI - Comparison of psychophysical properties of two intraoral digital sensors on low contrast perceptibility. AB - OBJECTIVES: The psychophysical properties of a new complementary metal oxide semi conductor-based detector, ProSensor((r)) (Planmeca Oy, Helsinki, Finland), in terms of dose response function and perceptibility curve test were performed and compared with those of a charged couple device-based sensor, Dixi((r)) (Planmeca Oy). METHODS: Dose response functions at 66 kVp for a Dixi and a ProSensor were determined by means of multiple exposures to a homogeneous X-ray field covering the whole exposure range. The entry dose of each exposure was measured and registered. The mean grey level in each image was plotted as function of the corresponding exposures for both digital systems. Radiographs of a test object containing ten holes of increasing depth were obtained throughout the exposure range of the two digital sensors at 66 kVp. 12 observers were asked to register the number of perceptible holes in each radiograph. Based on the mean value of the observers' evaluation, the perceptibility curves were constructed, and the integral value under the perceptibility curves were compared between two intraoral sensors. RESULTS: The results based on dose response function showed that the ProSensor was more sensitive than the Dixi sensor. Paired t-test showed that the minimal perceptible low-contrast details were significantly higher for the ProSensor than for the Dixi sensor (p < 0.001). The integrals below the two perceptibility curves were 33.4 and 69.2 for the Dixi and ProSensor, respectively. CONCLUSION: Applying the new ProSensor may be beneficial to patients owing to its reduced radiation dose and increased perception for low contrast details in dentistry. PMID- 24170799 TI - Anatomically shaped cranial collimation (ACC) for lateral cephalometric radiography: a technical report. AB - Lateral cephalograms in orthodontic practice display an area cranial of the base of the skull that is not required for diagnostic evaluation. Attempts have been made to reduce the radiation dose to the patient using collimators combining the shielding of the areas above the base of the skull and below the mandible. These so-called "wedge-shaped" collimators have not become standard equipment in orthodontic offices, possibly because these collimators were not designed for today's combination panoramic-cephalometric imaging systems. It also may be that the anatomical variability of the area below the mandible makes this area unsuitable for standardized collimation. In addition, a wedge-shaped collimator shields the cervical vertebrae; therefore, assessment of skeletal maturation, which is based on the stage of development of the cervical vertebrae, cannot be performed. In this report, we describe our investigations into constructing a collimator to be attached to the cephalostat and shield the cranial area of the skull, while allowing the visualization of diagnostically relevant structures and markedly reducing the size of the irradiated area. The shape of the area shielded by this "anatomically shaped cranial collimator" (ACC) was based on mean measurements of cephalometric landmarks of 100 orthodontic patients. It appeared that this collimator reduced the area of irradiation by almost one-third without interfering with the imaging system or affecting the quality of the image. Further research is needed to validate the clinical efficacy of the collimator. PMID- 24170800 TI - Teriparatide and the treatment of bisphosphonate-related osteonecrosis of the jaw: a rat model. AB - OBJECTIVES: The objectives of this study were to establish a bisphosphonate related osteonecrosis of the jaw (BRONJ) rat model and to analyse the effects of teriparatide (TP) on this model. METHODS: Sprague-Dawley rats were divided into three groups: I-zoledronic acid (ZA, n = 10); II-ZA and teriparatide (ZA + TP, n = 10); III-control (n = 10). Osteonecrosis was induced by administering zoledronic acid to groups ZA and ZA + TP. A week after the injections, rats underwent extraction of the first left mandibular molar. Following a four week period, TP was administered to the ZA + TP group for 28 days. Upon killing, extraction sockets were examined clinically, radiologically and histopathologically. RESULTS: Clinical examination revealed necrotic bone exposure in none of the animals. MicroCT (uCT) examination showed that bone mineral density of the newly formed bone in the extraction socket was lower in the ZA group than in the ZA + TP group (p < 0.05). Histopathological examination revealed that only the ZA and ZA + TP groups developed osteonecrosis, and the osteonecrotic bone area in the ZA group was larger than that in the ZA + TP group (p < 0.05). Tartrate-resistant acid phosphatase (TRAcP) enzyme histochemistry revealed that the number of detached and large osteoclasts were higher in the ZA group than in other groups, whereas the number of apoptotic osteoclasts in both ZA and ZA + TP groups were higher than in the control group (p < 0.05). CONCLUSIONS: Our data indicate that bisphosphonate-related osteonecrosis of the jaw model used in the present study is an attractive model to investigate treatment modalities and that TP might be an effective treatment in BRONJ. PMID- 24170801 TI - A retrospective study of digital subtraction technique to detect sclerotic changes in alveolar bone on intraoral radiographs of bisphosphonate-treated patients. AB - OBJECTIVES: Several reports have suggested that sclerotic changes in cancellous bone of the jaw and thickening of the lamina dura are characteristic radiographic changes of an early silent stage of bisphosphonate (BP)-related osteonecrosis of the jaw. No quantitative evaluation has been reported to support this hypothesis. Emago((r)) software (Oral Diagnostic Systems, Amsterdam, Netherlands) can perform digital subtraction on intraoral radiographs even if they were obtained by non standardized radiography, provided the dimensional error is within a certain limit. The purpose of this study was to evaluate whether sclerotic changes of alveolar bone or thickening of lamina dura in patients using BP can be detected using the subtraction function of Emago. METHODS: The authors selected 46 pairs of intraoral radiographs of the mandibular molar area in dental patients. All radiographs were obtained at intervals of 6 months or more. Among the 46 pairs, 7 pairs were from patients who were being treated with BP (study subjects), and 39 pairs were from patients who had not been using BP (controls). All pairs of radiographs underwent digital subtraction by Emago. The number of pixels of the sclerotic areas was counted and compared between subjects and controls. RESULTS: The sclerotic changes were significantly distinguishable in two of the seven subjects (28.6%) using BP. CONCLUSIONS: Digital subtraction function of Emago was able to detect sclerotic changes in alveolar bone. Therefore, it is suggested that the subtraction function of Emago is a useful tool for quantitatively detecting sclerotic changes that are observed at an early, silent stage of BP related osteonecrosis of the jaw. PMID- 24170802 TI - Regional 3D superimposition to assess temporomandibular joint condylar morphology. AB - OBJECTIVES: To investigate the reliability of regional three-dimensional registration and superimposition methods for assessment of temporomandibular joint condylar morphology across subjects and longitudinally. METHODS: The sample consisted of cone beam CT scans of 36 patients. The across-subject comparisons included 12 controls, mean age 41.3 +/- 12.0 years, and 12 patients with temporomandibular joint osteoarthritis, mean age 41.3 +/- 14.7 years. The individual longitudinal assessments included 12 patients with temporomandibular joint osteoarthritis, mean age 37.8 +/- 16.7 years, followed up at pre-operative jaw surgery, immediately after and one-year post-operative. Surface models of all condyles were constructed from the cone beam CT scans. Two previously calibrated observers independently performed all registration methods. A landmark-based approach was used for the registration of across-subject condylar models, and temporomandibular joint osteoarthritis vs control group differences were computed with shape analysis. A voxel-based approach was used for registration of longitudinal scans calculated x, y, z degrees of freedom for translation and rotation. Two-way random intraclass correlation coefficients tested the interobserver reliability. RESULTS: Statistically significant differences between the control group and the osteoarthritis group were consistently located on the lateral and medial poles for both observers. The interobserver differences were <=0.2 mm. For individual longitudinal comparisons, the mean interobserver differences were <=0.6 mm in translation errors and 1.2 degrees in rotation errors, with excellent reliability (intraclass correlation coefficient >0.75). CONCLUSIONS: Condylar registration for across-subjects and longitudinal assessments is reliable and can be used to quantify subtle bony differences in the three-dimensional condylar morphology. PMID- 24170803 TI - Visibility of dental pulp spaces in dental ultrasound. AB - The purpose of this study was to assess the feasibility of dental ultrasound with conventional sonographic equipment. The teeth of three adult volunteers who had cone beam CT examinations performed previously with clinical indications and one extracted tooth were examined using linear and compact (hockey stick) sonographic probes. The sonographic images were compared with cone beam CT images reconstructed accordingly. Dental pulp spaces were demonstrated in all teeth not covered with prosthetic crowns. The dentin and pulp were best visualized at the level of the neck of the teeth. The dentin was hypoechoic, and the superficial layer comprising the cementum and the pulp spaces were hyperechoic. Dental ultrasound is feasible with general purpose sonographic machines. The buccal surfaces of all teeth are accessible with a compact (hockey stick) probe. Visualization and differentiation of dental pulp spaces, dentin and the superficial layer comprising cementum is possible in the portions of teeth not covered by the alveolar bone or prosthetic crowns. The dental pulp spaces are best seen at the level of the tooth neck. Pulp and endodontic fillings can be distinguished on ultrasound. PMID- 24170804 TI - Diet alters both the structure and taxonomy of the ovine gut microbial ecosystem. AB - We surveyed the ruminal metagenomes of 16 sheep under two different diets using Illumina pair-end DNA sequencing of raw microbial DNA extracted from rumen samples. The resulting sequence data were bioinformatically mapped to known prokaryotic 16S rDNA sequences to identify the taxa present in the samples and then analysed for the presence of potentially new taxa. Strikingly, the majority of the microbial individuals found did not map to known taxa from 16S sequence databases. We used a novel statistical modelling approach to compare the taxonomic distributions between animals fed a forage-based diet and those fed concentrated grains. With this model, we found significant differences between the two groups both in the dominant taxa present in the rumen and in the overall shape of the taxa abundance curves. In general, forage-fed animals have a more diverse microbial ecosystem, whereas the concentrate-fed animals have ruminal systems more heavily dominated by a few taxa. As expected, organisms from methanogenic groups are more prevalent in forage-fed animals. Finally, all of these differences appear to be grounded in an underlying common input of new microbial individuals into the rumen environment, with common organisms from one feed group being present in the other, but at much lower abundance. PMID- 24170805 TI - Patterns of genomic integration of nuclear chloroplast DNA fragments in plant species. AB - The transfer of organelle DNA fragments to the nuclear genome is frequently observed in eukaryotes. These transfers are thought to play an important role in gene and genome evolution of eukaryotes. In plants, such transfers occur from plastid to nuclear [nuclear plastid DNAs (NUPTs)] and mitochondrial to nuclear (nuclear mitochondrial DNAs) genomes. The amount and genomic organization of organelle DNA fragments have been studied in model plant species, such as Arabidopsis thaliana and rice. At present, publicly available genomic data can be used to conduct such studies in non-model plants. In this study, we analysed the amount and genomic organization of NUPTs in 17 plant species for which genome sequences are available. The amount and distribution of NUPTs varied among the species. We also estimated the distribution of NUPTs according to the time of integration (relative age) by conducting sequence similarity analysis between NUPTs and the plastid genome. The age distributions suggested that the present genomic constitutions of NUPTs could be explained by the combination of the rapidly eliminated deleterious parts and few but constantly existing less deleterious parts. PMID- 24170806 TI - SporeWeb: an interactive journey through the complete sporulation cycle of Bacillus subtilis. AB - Bacterial spores are a continuous problem for both food-based and health-related industries. Decades of scientific research dedicated towards understanding molecular and gene regulatory aspects of sporulation, spore germination and spore properties have resulted in a wealth of data and information. To facilitate obtaining a complete overview as well as new insights concerning this complex and tightly regulated process, we have developed a database-driven knowledge platform called SporeWeb (http://sporeweb.molgenrug.nl) that focuses on gene regulatory networks during sporulation in the Gram-positive bacterium Bacillus subtilis. Dynamic features allow the user to navigate through all stages of sporulation with review-like descriptions, schematic overviews on transcriptional regulation and detailed information on all regulators and the genes under their control. The Web site supports data acquisition on sporulation genes and their expression, regulon network interactions and direct links to other knowledge platforms or relevant literature. The information found on SporeWeb (including figures and tables) can and will be updated as new information becomes available in the literature. In this way, SporeWeb offers a novel, convenient and timely reference, an information source and a data acquisition tool that will aid in the general understanding of the dynamics of the complete sporulation cycle. PMID- 24170807 TI - The YEASTRACT database: an upgraded information system for the analysis of gene and genomic transcription regulation in Saccharomyces cerevisiae. AB - The YEASTRACT (http://www.yeastract.com) information system is a tool for the analysis and prediction of transcription regulatory associations in Saccharomyces cerevisiae. Last updated in June 2013, this database contains over 200,000 regulatory associations between transcription factors (TFs) and target genes, including 326 DNA binding sites for 113 TFs. All regulatory associations stored in YEASTRACT were revisited and new information was added on the experimental conditions in which those associations take place and on whether the TF is acting on its target genes as activator or repressor. Based on this information, new queries were developed allowing the selection of specific environmental conditions, experimental evidence or positive/negative regulatory effect. This release further offers tools to rank the TFs controlling a gene or genome-wide response by their relative importance, based on (i) the percentage of target genes in the data set; (ii) the enrichment of the TF regulon in the data set when compared with the genome; or (iii) the score computed using the TFRank system, which selects and prioritizes the relevant TFs by walking through the yeast regulatory network. We expect that with the new data and services made available, the system will continue to be instrumental for yeast biologists and systems biology researchers. PMID- 24170808 TI - MitoBreak: the mitochondrial DNA breakpoints database. AB - Mitochondrial DNA (mtDNA) rearrangements are key events in the development of many diseases. Investigations of mtDNA regions affected by rearrangements (i.e. breakpoints) can lead to important discoveries about rearrangement mechanisms and can offer important clues about the causes of mitochondrial diseases. Here, we present the mitochondrial DNA breakpoints database (MitoBreak; http://mitobreak.portugene.com), a free, web-accessible comprehensive list of breakpoints from three classes of somatic mtDNA rearrangements: circular deleted (deletions), circular partially duplicated (duplications) and linear mtDNAs. Currently, MitoBreak contains >1400 mtDNA rearrangements from seven species (Homo sapiens, Mus musculus, Rattus norvegicus, Macaca mulatta, Drosophila melanogaster, Caenorhabditis elegans and Podospora anserina) and their associated phenotypic information collected from nearly 400 publications. The database allows researchers to perform multiple types of data analyses through user friendly interfaces with full or partial datasets. It also permits the download of curated data and the submission of new mtDNA rearrangements. For each reported case, MitoBreak also documents the precise breakpoint positions, junction sequences, disease or associated symptoms and links to the related publications, providing a useful resource to study the causes and consequences of mtDNA structural alterations. PMID- 24170809 TI - WISECONDOR: detection of fetal aberrations from shallow sequencing maternal plasma based on a within-sample comparison scheme. AB - Genetic disorders can be detected by prenatal diagnosis using Chorionic Villus Sampling, but the 1:100 chance to result in miscarriage restricts the use to fetuses that are suspected to have an aberration. Detection of trisomy 21 cases noninvasively is now possible owing to the upswing of next-generation sequencing (NGS) because a small percentage of fetal DNA is present in maternal plasma. However, detecting other trisomies and smaller aberrations can only be realized using high-coverage NGS, making it too expensive for routine practice. We present a method, WISECONDOR (WIthin-SamplE COpy Number aberration DetectOR), which detects small aberrations using low-coverage NGS. The increased detection resolution was achieved by comparing read counts within the tested sample of each genomic region with regions on other chromosomes that behave similarly in control samples. This within-sample comparison avoids the need to re-sequence control samples. WISECONDOR correctly identified all T13, T18 and T21 cases while coverages were as low as 0.15-1.66. No false positives were identified. Moreover, WISECONDOR also identified smaller aberrations, down to 20 Mb, such as del(13)(q12.3q14.3), +i(12)(p10) and i(18)(q10). This shows that prevalent fetal copy number aberrations can be detected accurately and affordably by shallow sequencing maternal plasma. WISECONDOR is available at bioinformatics.tudelft.nl/wisecondor. PMID- 24170810 TI - A fluorescence-based assay suitable for quantitative analysis of deadenylase enzyme activity. AB - In eukaryotic cells, the shortening and removal of the poly(A) tail of cytoplasmic mRNA by deadenylase enzymes is a critical step in post transcriptional gene regulation. The ribonuclease activity of deadenylase enzymes is attributed to either a DEDD (Asp-Glu-Asp-Asp) or an endonuclease-exonuclease phosphatase domain. Both domains require the presence of two Mg2+ ions in the active site. To facilitate the biochemical analysis of deadenylase enzymes, we have developed a fluorescence-based deadenylase assay. The assay is based on end point measurement, suitable for quantitative analysis and can be adapted for 96- and 384-well microplate formats. We demonstrate the utility of the assay by screening a chemical compound library, resulting in the identification of non nucleoside inhibitors of the Caf1/CNOT7 enzyme, a catalytic subunit of the Ccr4 Not deadenylase complex. These compounds may be useful tools for the biochemical analysis of the Caf1/CNOT7 deadenylase subunit of the Ccr4-Not complex and indicate the feasibility of developing selective inhibitors of deadenylase enzymes using the fluorescence-based assay. PMID- 24170811 TI - Stress-induced changes in gene interactions in human cells. AB - Cells respond to variable environments by changing gene expression and gene interactions. To study how human cells response to stress, we analyzed the expression of >5000 genes in cultured B cells from nearly 100 normal individuals following endoplasmic reticulum stress and exposure to ionizing radiation. We identified thousands of genes that are induced or repressed. Then, we constructed coexpression networks and inferred interactions among genes. We used coexpression and machine learning analyses to study how genes interact with each other in response to stress. The results showed that for most genes, their interactions with each other are the same at baseline and in response to different stresses; however, a small set of genes acquired new interacting partners to engage in stress-specific responses. These genes with altered interacting partners are associated with diseases in which endoplasmic reticulum stress response or sensitivity to radiation has been implicated. Thus, our findings showed that to understand disease-specific pathways, it is important to identify not only genes that change expression levels but also those that alter interactions with other genes. PMID- 24170813 TI - Dyslipidaemia in children on renal replacement therapy. AB - BACKGROUND: Information on lipid abnormalities in end-stage renal disease (ESRD) mainly originates from adult patients and small paediatric studies. We describe the prevalence of dyslipidaemia, and potential determinants associated with lipid measures in a large cohort of paediatric ESRD patients. METHODS: In the ESPN/ERA EDTA registry, lipid measurements were available for 976 patients aged 2-17 years from 19 different countries from the year 2000 onwards. Dyslipidaemia was defined as triglycerides >100 mg/dL (2-9 years) or >130 mg/dL (9-17 years), high-density lipoprotein (HDL) cholesterol <40 mg/dL or non-HDL cholesterol >145 mg/dL. Missing data were supplemented using multiple imputation. RESULTS: The prevalence of dyslipidaemia was 85.1% in peritoneal dialysis (PD) patients, 76.1% in haemodialysis (HD) patients and 55.5% among renal allograft recipients. Both low and high body mass index (BMI) were associated with a less favourable lipid profile. Younger age was associated with a worse lipid profile among PD patients. HDL levels significantly improved after transplantation, whereas no significant improvements were found for triglyceride and non-HDL levels. In transplant recipients, use of cyclosporin was associated with significantly higher non-HDL and HDL levels than tacrolimus usage (P < 0.01). In transplant patients with eGFR < 29 mL/min/1.73 m(2), the mean triglyceride level was 137 mg/dL (99% confidence interval (CI): 119-159) compared with 102 mg/dL among those with eGFR > 90 mL/min/1.73 m(2) (P < 0.0001). CONCLUSIONS: Dyslipidaemia is common among paediatric ESRD patients in Europe. Young age and PD treatment are associated with worse lipid profiles. Although lipid levels generally improve after transplantation, dyslipidaemia may persist due to decreased graft function, high BMI or to the use of certain immunosuppressants. PMID- 24170812 TI - Damage-dependent regulation of MUS81-EME1 by Fanconi anemia complementation group A protein. AB - MUS81-EME1 is a DNA endonuclease involved in replication-coupled repair of DNA interstrand cross-links (ICLs). A prevalent hypothetical role of MUS81-EME1 in ICL repair is to unhook the damage by incising the leading strand at the 3' side of an ICL lesion. In this study, we report that purified MUS81-EME1 incises DNA at the 5' side of a psoralen ICL residing in fork structures. Intriguingly, ICL repair protein, Fanconi anemia complementation group A protein (FANCA), greatly enhances MUS81-EME1-mediated ICL incision. On the contrary, FANCA exhibits a two phase incision regulation when DNA is undamaged or the damage affects only one DNA strand. Studies using truncated FANCA proteins indicate that both the N- and C-moieties of the protein are required for the incision regulation. Using laser induced psoralen ICL formation in cells, we find that FANCA interacts with and recruits MUS81 to ICL lesions. This report clarifies the incision specificity of MUS81-EME1 on ICL damage and establishes that FANCA regulates the incision activity of MUS81-EME1 in a damage-dependent manner. PMID- 24170815 TI - One year following injury, pain and physical factors affect the likelihood of residual disability, but psychiatric symptoms may have a greater influence. PMID- 24170814 TI - The FIND-CKD study--a randomized controlled trial of intravenous iron versus oral iron in non-dialysis chronic kidney disease patients: background and rationale. AB - BACKGROUND: Rigorous data are sparse concerning the optimal route of administration and dosing strategy for iron therapy with or without concomitant erythropoiesis-stimulating agent (ESA) therapy for the management of iron deficiency anaemia in patients with non-dialysis dependent chronic kidney disease (ND-CKD). METHODS: FIND-CKD was a 56-week, open-label, multicentre, prospective, randomized three-arm study (NCT00994318) of 626 patients with ND-CKD and iron deficiency anaemia randomized to (i) intravenous (IV) ferric carboxymaltose (FCM) at an initial dose of 1000 mg iron with subsequent dosing as necessary to target a serum ferritin level of 400-600 ug/L (ii) IV FCM at an initial dose of 200 mg with subsequent dosing as necessary to target serum ferritin 100-200 ug/L or (iii) oral ferrous sulphate 200 mg iron/day. The primary end point was time to initiation of other anaemia management (ESA therapy, iron therapy other than study drug or blood transfusion) or a haemoglobin (Hb) trigger (two consecutive Hb values <10 g/dL without an increase of >= 0.5 g/dL). RESULTS: The background, rationale and study design of the trial are presented here. The study has been completed and results are expected in late 2013. DISCUSSION: FIND-CKD was the longest randomized trial of IV iron therapy to date. Its findings will address several unanswered questions regarding iron therapy to treat iron deficiency anaemia in patients with ND-CKD. It was also the first randomized trial to utilize both a high and low serum ferritin target range to adjust IV iron dosing, and the first not to employ Hb response as its primary end point. PMID- 24170816 TI - In Western Australia, 70% of mothers of babies with fetal alcohol syndrome did not have an alcohol-related diagnosis recorded during pregnancy. PMID- 24170817 TI - Drospirenone-containing oral contraceptives may increase the risk of venous thromboembolism. PMID- 24170818 TI - Antenatal perineal massage decreases risk of perineal trauma during birth. PMID- 24170819 TI - In women, increased dietary antioxidants are associated with reduced risk of developing heart failure. PMID- 24170820 TI - Modest salt intake reduction for 4 weeks or longer decreases blood pressure. PMID- 24170821 TI - Dosimetry of Beta rays and low-energy photons for brachytherapy with sealed sources. PMID- 24170823 TI - Dosimetry of Beta rays and low-energy photons for brachytherapy with sealed sources: contents. PMID- 24170822 TI - The international commission on radiation units and measurements. PMID- 24170824 TI - Preface. PMID- 24170827 TI - Executive summary. PMID- 24170825 TI - Symbols and acronyms. PMID- 24170828 TI - 1 introduction. PMID- 24170829 TI - 2 sources and their application in brachytherapy. PMID- 24170830 TI - 3 source specification and calibration. PMID- 24170831 TI - 4 determination of dose distributions. PMID- 24170832 TI - 5 dosimetry comparisons. PMID- 24170833 TI - 6 compilation of dosimetric reference data. PMID- 24170834 TI - 7 quality control. PMID- 24170835 TI - Appendix a: compilation of physical data. PMID- 24170836 TI - Appendix B: therapeutic applications of Beta rays and low-energy photons. PMID- 24170837 TI - Appendix C: calculation of Beta-ray dose distributions by integration of the Beta ray point-source dose function. PMID- 24170839 TI - Preface. PMID- 24170842 TI - Executive summary. PMID- 24170843 TI - Guide to the report. PMID- 24170844 TI - 1 introduction. PMID- 24170845 TI - 2 definitions. PMID- 24170846 TI - 3 theory. PMID- 24170848 TI - 5 data compilations, tables, programs and comparisons with experimental data. PMID- 24170847 TI - 4 experiment. PMID- 24170849 TI - 6 tables. PMID- 24170852 TI - The international commission on radiation units and measurements. PMID- 24170851 TI - Stopping of ions heavier than helium. PMID- 24170853 TI - Stopping of ions heavier than helium: contents. PMID- 24170854 TI - Mathematics in metal. PMID- 24170856 TI - C1q induction and global complement pathway activation do not contribute to ALS toxicity in mutant SOD1 mice. AB - Accumulating evidence from mice expressing ALS-causing mutations in superoxide dismutase (SOD1) has implicated pathological immune responses in motor neuron degeneration. This includes microglial activation, lymphocyte infiltration, and the induction of C1q, the initiating component of the classic complement system that is the protein-based arm of the innate immune response, in motor neurons of multiple ALS mouse models expressing dismutase active or inactive SOD1 mutants. Robust induction early in disease course is now identified for multiple complement components (including C1q, C4, and C3) in spinal cords of SOD1 mutant expressing mice, consistent with initial intraneuronal C1q induction, followed by global activation of the complement pathway. We now test if this activation is a mechanistic contributor to disease. Deletion of the C1q gene in mice expressing an ALS-causing mutant in SOD1 to eliminate C1q induction, and complement cascade activation that follows from it, is demonstrated to produce changes in microglial morphology accompanied by enhanced loss, not retention, of synaptic densities during disease. C1q-dependent synaptic loss is shown to be especially prominent for cholinergic C-bouton nerve terminal input onto motor neurons in affected C1q deleted SOD1 mutant mice. Nevertheless, overall onset and progression of disease are unaffected in C1q- and C3-deleted ALS mice, thus establishing that C1q induction and classic or alternative complement pathway activation do not contribute significantly to SOD1 mutant-mediated ALS pathogenesis in mice. PMID- 24170857 TI - Topology of viral evolution. AB - The tree structure is currently the accepted paradigm to represent evolutionary relationships between organisms, species or other taxa. However, horizontal, or reticulate, genomic exchanges are pervasive in nature and confound characterization of phylogenetic trees. Drawing from algebraic topology, we present a unique evolutionary framework that comprehensively captures both clonal and reticulate evolution. We show that whereas clonal evolution can be summarized as a tree, reticulate evolution exhibits nontrivial topology of dimension greater than zero. Our method effectively characterizes clonal evolution, reassortment, and recombination in RNA viruses. Beyond detecting reticulate evolution, we succinctly recapitulate the history of complex genetic exchanges involving more than two parental strains, such as the triple reassortment of H7N9 avian influenza and the formation of circulating HIV-1 recombinants. In addition, we identify recurrent, large-scale patterns of reticulate evolution, including frequent PB2-PB1-PA-NP cosegregation during avian influenza reassortment. Finally, we bound the rate of reticulate events (i.e., 20 reassortments per year in avian influenza). Our method provides an evolutionary perspective that not only captures reticulate events precluding phylogeny, but also indicates the evolutionary scales where phylogenetic inference could be accurate. PMID- 24170858 TI - The Arabidopsis ZED1 pseudokinase is required for ZAR1-mediated immunity induced by the Pseudomonas syringae type III effector HopZ1a. AB - Plant and animal pathogenic bacteria can suppress host immunity by injecting type III secreted effector (T3SE) proteins into host cells. However, T3SEs can also elicit host immunity if the host has evolved a means to recognize the presence or activity of specific T3SEs. The diverse YopJ/HopZ/AvrRxv T3SE superfamily, which is found in both animal and plant pathogens, provides examples of T3SEs playing this dual role. The T3SE HopZ1a is an acetyltransferase carried by the phytopathogen Pseudomonas syringae that elicits effector-triggered immunity (ETI) when recognized in Arabidopsis thaliana by the nucleotide-binding leucine-rich repeat (NB-LRR) protein ZAR1. However, recognition of HopZ1a does not require any known ETI-related genes. Using a forward genetics approach, we identify a unique ETI-associated gene that is essential for ZAR1-mediated immunity. The hopZ-ETI deficient1 (zed1) mutant is specifically impaired in the recognition of HopZ1a, but not the recognition of other unrelated T3SEs or in pattern recognition receptor (PRR)-triggered immunity. ZED1 directly interacts with both HopZ1a and ZAR1 and is acetylated on threonines 125 and 177 by HopZ1a. ZED1 is a nonfunctional kinase that forms part of small genomic cluster of kinases in Arabidopsis. We hypothesize that ZED1 acts as a decoy to lure HopZ1a to the ZAR1 resistance complex, resulting in ETI activation. PMID- 24170859 TI - Numb-deficient satellite cells have regeneration and proliferation defects. AB - The adaptor protein Numb has been implicated in the switch between cell proliferation and differentiation made by satellite cells during muscle repair. Using two genetic approaches to ablate Numb, we determined that, in its absence, muscle regeneration in response to injury was impaired. Single myofiber cultures demonstrated a lack of satellite cell proliferation in the absence of Numb, and the proliferation defect was confirmed in satellite cell cultures. Quantitative RT-PCR from Numb-deficient satellite cells demonstrated highly up-regulated expression of p21 and Myostatin, both inhibitors of myoblast proliferation. Transfection with Myostatin-specific siRNA rescued the proliferation defect of Numb-deficient satellite cells. Furthermore, overexpression of Numb in satellite cells inhibited Myostatin expression. These data indicate a unique function for Numb during the initial activation and proliferation of satellite cells in response to muscle injury. PMID- 24170861 TI - Compressed modes for variational problems in mathematics and physics. AB - This article describes a general formalism for obtaining spatially localized ("sparse") solutions to a class of problems in mathematical physics, which can be recast as variational optimization problems, such as the important case of Schrodinger's equation in quantum mechanics. Sparsity is achieved by adding an regularization term to the variational principle, which is shown to yield solutions with compact support ("compressed modes"). Linear combinations of these modes approximate the eigenvalue spectrum and eigenfunctions in a systematically improvable manner, and the localization properties of compressed modes make them an attractive choice for use with efficient numerical algorithms that scale linearly with the problem size. PMID- 24170862 TI - Region-specific restoration of striatal synaptic plasticity by dopamine grafts in experimental parkinsonism. AB - Intrastriatal transplantation of dopaminergic neurons can restore striatal dopamine levels and improve parkinsonian deficits, but the mechanisms underlying these effects are poorly understood. Here, we show that transplants of dopamine neurons partially restore activity-dependent synaptic plasticity in the host striatal neurons. We evaluated synaptic plasticity in regions distal or proximal to the transplant (i.e., dorsolateral and ventrolateral striatum) and compared the effects of dopamine- and serotonin-enriched grafts using a rat model of Parkinson disease. Naive rats showed comparable intrinsic membrane properties in the two subregions but distinct patterns of long-term synaptic plasticity. The ventrolateral striatum showed long-term potentiation using the same protocol that elicited long-term depression in the dorsolateral striatum. The long-term potentiation was linked to higher expression of postsynaptic AMPA and N2B NMDA subunits (GluN2B) and was dependent on the activation of GluN2A and GluN2B subunits and the D1 dopamine receptor. In both regions, the synaptic plasticity was abolished after a severe dopamine depletion and could not be restored by grafted serotonergic neurons. Solely, dopamine-enriched grafts could restore the long-term potentiation and partially restore motor deficits in the rats. The restoration could only be seen close to the graft, in the ventrolateral striatum where the graft-derived reinnervation was denser, compared with the distal dorsolateral region. These data provide proof of concept that dopamine-enriched transplants are able to functionally integrate into the host brain and restore deficits in striatal synaptic plasticity after experimental parkinsonism. The region-specific restoration might impose limitations in symptomatic improvement following neural transplantation. PMID- 24170860 TI - Targeted degradation of sense and antisense C9orf72 RNA foci as therapy for ALS and frontotemporal degeneration. AB - Expanded hexanucleotide repeats in the chromosome 9 open reading frame 72 (C9orf72) gene are the most common genetic cause of ALS and frontotemporal degeneration (FTD). Here, we identify nuclear RNA foci containing the hexanucleotide expansion (GGGGCC) in patient cells, including white blood cells, fibroblasts, glia, and multiple neuronal cell types (spinal motor, cortical, hippocampal, and cerebellar neurons). RNA foci are not present in sporadic ALS, familial ALS/FTD caused by other mutations (SOD1, TDP-43, or tau), Parkinson disease, or nonneurological controls. Antisense oligonucleotides (ASOs) are identified that reduce GGGGCC-containing nuclear foci without altering overall C9orf72 RNA levels. By contrast, siRNAs fail to reduce nuclear RNA foci despite marked reduction in overall C9orf72 RNAs. Sustained ASO-mediated lowering of C9orf72 RNAs throughout the CNS of mice is demonstrated to be well tolerated, producing no behavioral or pathological features characteristic of ALS/FTD and only limited RNA expression alterations. Genome-wide RNA profiling identifies an RNA signature in fibroblasts from patients with C9orf72 expansion. ASOs targeting sense strand repeat-containing RNAs do not correct this signature, a failure that may be explained, at least in part, by discovery of abundant RNA foci with C9orf72 repeats transcribed in the antisense (GGCCCC) direction, which are not affected by sense strand-targeting ASOs. Taken together, these findings support a therapeutic approach by ASO administration to reduce hexanucleotide repeat containing RNAs and raise the potential importance of targeting expanded RNAs transcribed in both directions. PMID- 24170864 TI - Negative production of acetoin in the photochemistry of aqueous pyruvic acid. PMID- 24170863 TI - Sulfur isotopes track the global extent and dynamics of euxinia during Cretaceous Oceanic Anoxic Event 2. AB - The Mesozoic Era is characterized by numerous oceanic anoxic events (OAEs) that are diagnostically expressed by widespread marine organic-carbon burial and coeval carbon-isotope excursions. Here we present coupled high-resolution carbon- and sulfur-isotope data from four European OAE 2 sections spanning the Cenomanian Turonian boundary that show roughly parallel positive excursions. Significantly, however, the interval of peak magnitude for carbon isotopes precedes that of sulfur isotopes with an estimated offset of a few hundred thousand years. Based on geochemical box modeling of organic-carbon and pyrite burial, the sulfur isotope excursion can be generated by transiently increasing the marine burial rate of pyrite precipitated under euxinic (i.e., anoxic and sulfidic) water column conditions. To replicate the observed isotopic offset, the model requires that enhanced levels of organic-carbon and pyrite burial continued a few hundred thousand years after peak organic-carbon burial, but that their isotope records responded differently due to dramatically different residence times for dissolved inorganic carbon and sulfate in seawater. The significant inference is that euxinia persisted post-OAE, but with its global extent dwindling over this time period. The model further suggests that only ~5% of the global seafloor area was overlain by euxinic bottom waters during OAE 2. Although this figure is ~30* greater than the small euxinic fraction present today (~0.15%), the result challenges previous suggestions that one of the best-documented OAEs was defined by globally pervasive euxinic deep waters. Our results place important controls instead on local conditions and point to the difficulty in sustaining whole-ocean euxinia. PMID- 24170865 TI - Younger Dryas impact model confuses comet facts, defies airburst physics. PMID- 24170866 TI - Preface. PMID- 24170869 TI - Executive summary. PMID- 24170870 TI - 1 introduction. PMID- 24170872 TI - 3 quantities and units for measurement and calculation in medical x-ray imaging. PMID- 24170871 TI - 2 specification of x-ray beams. PMID- 24170873 TI - 4 measurement methods. PMID- 24170874 TI - 5 methods for determining organ and tissue doses. PMID- 24170875 TI - 6 conclusions. PMID- 24170876 TI - Appendix a: backscatter factors. PMID- 24170877 TI - Appendix B: handbooks produced by the center for devices and radiological health (cdrh). PMID- 24170878 TI - Appendix C: reports produced by the german national research center for environment and health (gsf). PMID- 24170879 TI - Appendix d: reports produced by the health protection agency (hpa) (formerly national radiological protection board, nrpb). PMID- 24170880 TI - Appendix e: review of monte carlo calculations for assessment of mean glandular dose in mammography. PMID- 24170881 TI - Appendix f: pcxmc--a pc-based monte carlo program for calculating patient doses in medical x-ray examinations. PMID- 24170883 TI - Patient dosimetry for x rays used in medical imaging. PMID- 24170884 TI - The international commission on radiation units and measurements. PMID- 24170885 TI - Patient dosimetry for x rays used in medical imaging. PMID- 24170886 TI - When is 'idiopathic intracranial hypertension' no longer idiopathic? PMID- 24170887 TI - Truncated FAD synthetase for direct biocatalytic conversion of riboflavin and analogs to their corresponding flavin mononucleotides. AB - The preparation of flavin mononucleotide (FMN) and FMN analogs from their corresponding riboflavin precursors is traditionally performed in a two-step procedure. After initial enzymatic conversion of riboflavin to flavin adenine dinucleotide (FAD) by a bifunctional FAD synthetase, the adenyl moiety of FAD is hydrolyzed with snake venom phosphodiesterase to yield FMN. To simplify the protocol, we have engineered the FAD synthetase from Corynebacterium ammoniagenes by deleting its N-terminal adenylation domain. The newly created biocatalyst is stable and efficient for direct and quantitative phosphorylation of riboflavin and riboflavin analogs to their corresponding FMN cofactors at preparative-scale. PMID- 24170888 TI - Calcific malignant pheochromocytoma. PMID- 24170889 TI - My medical practice: mentors and perspectives. PMID- 24170890 TI - Takotsubo cardiomyopathy associated with opiate withdrawal. PMID- 24170891 TI - 'Face of giant panda': a rare imaging sign in Wilson's disease. PMID- 24170892 TI - A rare complication after transarterial chemoembolization for hepatocellular carcinoma. PMID- 24170893 TI - Preface. PMID- 24170896 TI - Executive summary. PMID- 24170897 TI - 1 introduction. PMID- 24170898 TI - 2 variability of environmental radioactivity and radiation. PMID- 24170899 TI - 3 general sampling concepts and principles. PMID- 24170900 TI - 4 estimating statistical quantities: mean, total, proportion, percentile, and ratio. PMID- 24170901 TI - 5 sampling to estimate spatial pattern. PMID- 24170902 TI - 6 temporal and spatio-temporal sampling problems. PMID- 24170903 TI - 7 general summary. PMID- 24170905 TI - Appendix 1. 10,000 random digits. PMID- 24170906 TI - APPENDIX 2. UPPER CRITICAL VALUES OF THE STUDENT'S t-DISTRIBUTION. PMID- 24170907 TI - Quantities and symbols used in this report. PMID- 24170908 TI - Sampling for radionuclides in the environment. PMID- 24170909 TI - The international commission on radiation units and measurements. PMID- 24170910 TI - Sampling for radionuclides in the environment: contents. PMID- 24170911 TI - Predictive values of semi-quantitative procalcitonin test and common biomarkers for the clinical outcomes of community-acquired pneumonia. AB - BACKGROUND: The semi-quantitative serum procalcitonin test (Brahms PCT-Q) is available conveniently in clinical practice. However, there are few data on the relationship between results for this semi-quantitative procalcitonin test and clinical outcomes of community-acquired pneumonia (CAP). We investigated the usefulness of this procalcitonin test for predicting the clinical outcomes of CAP in comparison with severity scoring systems and the blood urea nitrogen/serum albumin (B/A) ratio, which has been reported to be a simple but reliable prognostic indicator in our prior CAP study. METHODS: This retrospective study included data from subjects who were hospitalized for CAP from August 2010 through October 2012 and who were administered the semi-quantitative serum procalcitonin test on admission. The demographic characteristics; laboratory biomarkers; microbiological test results; Pneumonia Severity Index scores; confusion, urea nitrogen, breathing frequency, blood pressure, >= 65 years of age (CURB-65) scale scores; and age, dehydration, respiratory failure, orientation disturbance, pressure (A-DROP) scale scores on hospital admission were retrieved from their medical charts. The outcomes were mortality within 28 days of hospital admission and the need for intensive care. RESULTS: Of the 213 subjects with CAP who were enrolled in the study, 20 died within 28 days of hospital admission, and 32 required intensive care. Mortality did not differ significantly among subjects with different semi-quantitative serum procalcitonin levels; however, subjects with serum procalcitonin levels >= 10.0 ng/mL were more likely to require intensive care than those with lower levels (P < .001). The elevation of semi quantitative serum procalcitonin levels was more frequently observed in subjects with proven etiology, especially pneumococcal pneumonia. Using the receiver operating characteristic curves for mortality, the area under the curve was 0.86 for Pneumonia Severity Index class, 0.81 for B/A ratio, 0.81 for A-DROP, 0.80 for CURB-65, and 0.57 for semi-quantitative procalcitonin test. CONCLUSIONS: The semi quantitative serum procalcitonin level on hospital admission was less predictive of mortality from CAP compared with the B/A ratio. However, the subjects with serum procalcitonin levels >= 10.0 ng/mL were more likely to require intensive care than those with lower levels. PMID- 24170912 TI - Evaluation of manual and automatic manually triggered ventilation performance and ergonomics using a simulation model. AB - BACKGROUND: In the absence of endotracheal intubation, the manual bag-valve-mask (BVM) is the most frequently used ventilation technique during resuscitation. The efficiency of other devices has been poorly studied. The bench-test study described here was designed to evaluate the effectiveness of an automatic, manually triggered system, and to compare it with manual BVM ventilation. METHODS: A respiratory system bench model was assembled using a lung simulator connected to a manikin to simulate a patient with unprotected airways. Fifty health-care providers from different professional groups (emergency physicians, residents, advanced paramedics, nurses, and paramedics; n = 10 per group) evaluated manual BVM ventilation, and compared it with an automatic manually triggered device (EasyCPR). Three pathological situations were simulated (restrictive, obstructive, normal). Standard ventilation parameters were recorded; the ergonomics of the system were assessed by the health-care professionals using a standard numerical scale once the recordings were completed. RESULTS: The tidal volume fell within the standard range (400-600 mL) for 25.6% of breaths (0.6-45 breaths) using manual BVM ventilation, and for 28.6% of breaths (0.3-80 breaths) using the automatic manually triggered device (EasyCPR) (P < .0002). Peak inspiratory airway pressure was lower using the automatic manually triggered device (EasyCPR) (10.6 +/- 5 vs 15.9 +/- 10 cm H2O, P < .001). The ventilation rate fell consistently within the guidelines, in the case of the automatic manually triggered device (EasyCPR) only (10.3 +/- 2 vs 17.6 +/- 6, P < .001). Significant pulmonary overdistention was observed when using the manual BVM device during the normal and obstructive sequences. The nurses and paramedics considered the ergonomics of the automatic manually triggered device (EasyCPR) to be better than those of the manual device. CONCLUSIONS: The use of an automatic manually triggered device may improve ventilation efficiency and decrease the risk of pulmonary overdistention, while decreasing the ventilation rate. PMID- 24170913 TI - Effects of nasal positive expiratory pressure on dynamic hyperinflation and 6 minute walk test in patients with COPD. AB - INTRODUCTION: Dynamic hyperinflation is an important target in the treatment of COPD. There is increasing evidence that positive expiratory pressure (PEP) could reduce dynamic hyperinflation during exercise. PEP application through a nasal mask and a flow resistance device might have the potential to be used during daily physical activities as an auxiliary strategy of ventilatory assistance. The aim of this study was to determine the effects of nasal PEP on lung volumes during physical exercise in patients with COPD. METHODS: Twenty subjects (mean +/ SD age 69.4 +/- 6.4 years) with stable mild-to-severe COPD were randomized to undergo physical exercise with nasal PEP breathing, followed by physical exercise with habitual breathing, or vice versa. Physical exercise was induced by a standard 6-min walk test (6 MWT) protocol. PEP was applied by means of a silicone nasal mask loaded with a fixed-orifice flow resistor. Body plethysmography was performed immediately pre-exercise and post-exercise. RESULTS: Differences in mean pre- to post-exercise changes in total lung capacity (-0.63 +/- 0.80 L, P = .002), functional residual capacity (-0.48 +/- 0.86 L, P = .021), residual volume (-0.56 +/- 0.75 L, P = .004), S(pO2) (-1.7 +/- 3.4%, P = .041), and 6 MWT distance (-30.8 +/- 30.0 m, P = .001) were statistically significant between the experimental and the control interventions. CONCLUSIONS: The use of flow dependent expiratory pressure, applied with a nasal mask and a PEP device, might promote significant reduction of dynamic hyperinflation during walking exercise. Further studies are warranted addressing improvements in endurance performance under regular application of nasal PEP during physical activities. PMID- 24170914 TI - Acute upper-airway obstruction by a lingual thyroglossal duct cyst and implications for advanced airway management. PMID- 24170915 TI - Fat-free mass depletion is associated with poor exercise capacity irrespective of dynamic hyperinflation in COPD patients. AB - BACKGROUND: In patients with COPD, we investigated the effect of the fat-free mass (FFM) on maximal exercise capacity and the relationship with changes in operational lung volumes during exercise. METHODS: In a cross-sectional study 57 patients (16 females; age 65 +/- 8 y) were consecutively assessed by resting lung function, symptom-limited cardiopulmonary exercise test, and body composition by means of bioelectrical impedance analysis to measure the FFM index (FFMI; in kilograms per square meter). RESULTS: Patients were categorized as depleted (n = 14) or nondepleted (n = 43) according to FFMI. No significant difference in gender, age, and resting lung function was found between depleted and nondepleted patients. When compared with nondepleted COPD patients, the depleted COPD patients had a significantly lower O2 uptake at the peak of exercise and at anaerobic threshold as well as at peak oxygen pulse, oxygen uptake efficiency slope (OUES), and heart rate recovery (HRR) (P < .05 for all comparisons), but similar inspiratory capacity/total lung capacity at the peak of exercise. Moreover, they also reported significantly higher leg fatigue (P < .05), but not dyspnea on exertion. In all patients, significant correlations (P < .01) were found between FFMI and peak oxygen pulse, OUES, HRR, and leg fatigue. CONCLUSIONS: This study shows that FFM depletion plays a part in the reduction of exercise capacity in COPD patients, regardless of dynamic hyperinflation, and is strictly associated with poor cardiovascular response to exercise and to leg fatigue, but not with dyspnea. PMID- 24170916 TI - Tiotropium versus placebo for inadequately controlled asthma: a meta-analysis. AB - OBJECTIVE: This meta-analysis was performed to evaluate the efficacy and safety of the addition of tiotropium to standard treatment regimens for inadequately controlled asthma. METHODS: A systematic search was made of PubMed, EMBASE, MEDLINE, and CENTRAL databases, and ClinicalTrials.gov, and a hand search of leading respiratory journals. Randomized, double-blind clinical trials on the treatment of inadequately controlled asthma for >= 4 weeks with the addition of tiotropium, compared with placebo, were reviewed. Studies were pooled to odds ratio (OR) and weighted mean differences (WMDs), with 95% CI. RESULTS: Six trials met the inclusion criteria. The addition of tiotropium, compared with placebo, significantly improved all spirometric indices, including morning and evening peak expiratory flow (WMD 20.59 L/min, 95% CI 15.36-25.81 L/min, P < .001; and WMD 24.95 L/min, 95% CI 19.22-30.69 L/min, P < .001, respectively), trough and peak FEV1 (WMD 0.13 L, 95% CI 0.09-0.18 L, P < .001; and WMD 0.10 L, 95% CI 0.06 0.14 L, P < .001, respectively), the area under the curve of the first 3 h of FEV1 (WMD 0.13 L, 95% CI 0.08-0.18 L, P < .001), trough and peak FVC (WMD 0.1 L, 95% CI 0.05-0.15 L, P < .001; and WMD 0.08 L, 95% CI 0.04-0.13 L, P < .001, respectively), the area under the curve of the first 3 h of FVC (WMD 0.11 L, 95% CI 0.06-0.15 L, P < .001). The mean change in the 7-point Asthma Control Questionnaire score (WMD -0.12, 95% CI -0.21 to -0.03, P = .01) was markedly lower in tiotropium group, but not clinically important. There were no significant differences in Asthma Quality of Life Questionnaire score (WMD 0.09, 95% CI -0.01 to 0.20, P = .09), night awakenings (WMD 0.00, 95% CI -0.05 to 0.05, P = .99) or rescue medication use (WMD -0.18, 95% CI -0.36 to 0.00, P = .06). No significant increase was noticed in adverse events in the tiotropium group (OR 0.80, 95% CI 0.62-1.03, P = .08). CONCLUSIONS: The addition of tiotropium to standard treatment regimens has significantly improved lung function without increasing adverse events in patients with inadequately controlled asthma. Long term trials are required to assess the effects of the addition of tiotropium on asthma exacerbations and mortality. PMID- 24170918 TI - Preface. PMID- 24170920 TI - Executive summary. PMID- 24170917 TI - Obstructive fibrinous tracheal pseudomembrane: a rare condition in postextubation stridor. AB - Obstructive fibrinous tracheal pseudomembrane (OFTP) is an airway complication that occurs after endotracheal intubation. It originates from superficial mucosal abrasion and desquamation of necrotic tracheal epithelium at the site of cuff pressure. This condition is a rare cause of postextubation stridor. We present a case of postextubation stridor secondary to OFTP, resulting in clinical features of upper airway obstruction > 8 h after extubation. The case features complete obstruction at the tip of the endotracheal tube from OFTP. PMID- 24170921 TI - 1 introduction. PMID- 24170922 TI - 2 development of the quality system and quality manual. PMID- 24170923 TI - 3 measurement quality assurance. PMID- 24170924 TI - 4 measurement analysis methods. PMID- 24170925 TI - 5 practical applications and recommendations. PMID- 24170927 TI - Appendix a. PMID- 24170926 TI - Definitions and glossary of terms. PMID- 24170928 TI - Appendix B. PMID- 24170930 TI - Measurement quality assurance for ionizing radiation dosimetry. PMID- 24170931 TI - The international commission on radiation units and measurements. PMID- 24170932 TI - Measurement quality assurance for ionizing radiation dosimetry: contents. PMID- 24170933 TI - Insula-amygdala functional connectivity is correlated with habituation to repeated negative images. AB - Behavioral habituation during repeated exposure to aversive stimuli is an adaptive process. However, the way in which changes in self-reported emotional experience are related to the neural mechanisms supporting habituation remains unclear. We probed these mechanisms by repeatedly presenting negative images to healthy adult participants and recording behavioral and neural responses using functional magnetic resonance imaging. We were particularly interested in investigating patterns of activity in insula, given its significant role in affective integration, and in amygdala, given its association with appraisal of aversive stimuli and its frequent coactivation with insula. We found significant habituation behaviorally along with decreases in amygdala, occipital cortex and ventral prefrontal cortex (PFC) activity with repeated presentation, whereas bilateral posterior insula, dorsolateral PFC and precuneus showed increased activation. Posterior insula activation during image presentation was correlated with greater negative affect ratings for novel presentations of negative images. Further, repeated negative image presentation was associated with increased functional connectivity between left posterior insula and amygdala, and increasing insula-amygdala functional connectivity was correlated with increasing behavioral habituation. These results suggest that habituation is subserved in part by insula-amygdala connectivity and involves a change in the activity of bottom-up affective networks. PMID- 24170935 TI - Distinct signaling roles of ceramide species in yeast revealed through systematic perturbation and systems biology analyses. AB - Ceramide, the central molecule of sphingolipid metabolism, is an important bioactive molecule that participates in various cellular regulatory events and that has been implicated in disease. Deciphering ceramide signaling is challenging because multiple ceramide species exist, and many of them may have distinct functions. We applied systems biology and molecular approaches to perturb ceramide metabolism in the yeast Saccharomyces cerevisiae and inferred causal relationships between ceramide species and their potential targets by combining lipidomic, genomic, and transcriptomic analyses. We found that during heat stress, distinct metabolic mechanisms controlled the abundance of different groups of ceramide species and provided experimental support for the importance of the dihydroceramidase Ydc1 in mediating the decrease in dihydroceramides during heat stress. Additionally, distinct groups of ceramide species, with different N-acyl chains and hydroxylations, regulated different sets of functionally related genes, indicating that the structural complexity of these lipids produces functional diversity. The transcriptional modules that we identified provide a resource to begin to dissect the specific functions of ceramides. PMID- 24170934 TI - Convergence of G protein-coupled receptor and S-nitrosylation signaling determines the outcome to cardiac ischemic injury. AB - Heart failure caused by ischemic heart disease is a leading cause of death in the developed world. Treatment is currently centered on regimens involving G protein coupled receptors (GPCRs) or nitric oxide (NO). These regimens are thought to target distinct molecular pathways. We showed that these pathways were interdependent and converged on the effector GRK2 (GPCR kinase 2) to regulate myocyte survival and function. Ischemic injury coupled to GPCR activation, including GPCR desensitization and myocyte loss, required GRK2 activation, and we found that cardioprotection mediated by inhibition of GRK2 depended on endothelial nitric oxide synthase (eNOS) and was associated with S-nitrosylation of GRK2. Conversely, the cardioprotective effects of NO bioactivity were absent in a knock-in mouse with a form of GRK2 that cannot be S-nitrosylated. Because GRK2 and eNOS inhibit each other, the balance of the activities of these enzymes in the myocardium determined the outcome to ischemic injury. Our findings suggest new insights into the mechanism of action of classic drugs used to treat heart failure and new therapeutic approaches to ischemic heart disease. PMID- 24170936 TI - Collaborative practice improvement for childhood obesity in rural clinics: the Healthy Eating Active Living Telehealth Community of Practice (HEALTH COP). AB - This study assessed the impact of participation in a virtual quality improvement (QI) learning network on adherence to clinical guidelines for childhood obesity prevention in rural clinics. A total of 7 primary care clinics in rural California included in the Healthy Eating Active Living TeleHealth Community of Practice and 288 children seen in these clinics for well-child care participated in this prospective observational pre-post study. Clinics participated in a virtual QI learning network over 9 months to implement best practices and to exchange strategies for improvement. Following the intervention, documentation of weight assessment and counseling increased significantly. Children who received care from clinicians who led the implementation of the intervention at their clinic showed significant improvements in nutrition and physical activity. Virtual QI learning networks in geographically dispersed clinics can significantly increase clinicians' adherence to guidelines for childhood obesity and improve access to recommended care for rural and underserved children. PMID- 24170937 TI - Using health literacy guidelines to improve discharge education and the post hospital transition: a quality improvement project. PMID- 24170939 TI - Preface. PMID- 24170938 TI - Innovation and transformation in California's safety net health care settings: an inside perspective. AB - Health reform requires safety net settings to transform care delivery, but how they will innovate in order to achieve this transformation is unknown. Two series of key informant interviews (N = 28) were conducted in 2012 with leadership from both California's public hospital systems and community health centers. Interviews focused on how innovation was conceptualized and solicited examples of successful innovations. In contrast to disruptive innovation, interviewees often defined innovation as improving implementation, making incremental changes, and promoting integration. Many leaders gave examples of existing innovative practices to meeting their diverse patient needs, such as patient-centered approaches. Participants expressed challenges to adapting quickly, but a desire to partner together. Safety net systems have already begun implementing innovative practices supporting their key priority areas. However, more support is needed, specifically to accelerate the change needed to succeed under health reform. PMID- 24170941 TI - Executive summary. PMID- 24170942 TI - List of abbreviations and acronyms. PMID- 24170943 TI - List of symbols. PMID- 24170944 TI - 1 introduction. PMID- 24170945 TI - 2 experimental methods. PMID- 24170946 TI - 3 theoretical background. PMID- 24170947 TI - 4 calculations for atoms used for the data generation. PMID- 24170948 TI - 5 experimental data. PMID- 24170949 TI - 6 multiple-scattering angular deflections. PMID- 24170950 TI - 7 data presentation. PMID- 24170951 TI - 8 concluding remarks. PMID- 24170952 TI - Appendix a. Relativistic kinematics. PMID- 24170953 TI - Appendix B. The dirac equation. PMID- 24170954 TI - Appendix C. Quantum theory of scattering by a central potential. PMID- 24170956 TI - Elastic scattering of electrons and positrons. PMID- 24170958 TI - Elastic scattering of electrons and positrons: contents. PMID- 24170957 TI - The international commission on radiation units and measurements. PMID- 24170959 TI - A method to measure cellular adhesion utilizing a polymer micro-cantilever. AB - In the present study we engineered a micro-machined polyimide cantilever with an embedded sensing element to investigate cellular adhesion, in terms of its relative ability to stick to a cross-linker, 3,3' dithiobis[sulfosuccinimidylpropionate], coated on the cantilever surface. To achieve this objective, we investigated adhesive properties of three human prostate cancer cell lines, namely, a bone metastasis derived human prostate cancer cell line (PC3), a brain metastasis derived human prostate cancer cell line (DU145), and a subclone of PC3 (PC3-EMT14). We found that PC3-EMT14, which displays a mesenchymal phenotype, has the least adhesion compared to PC3 and DU145, which exhibit an epithelial phenotype. PMID- 24170960 TI - Study on dielectric and piezoelectric properties of 0.7 Pb(Mg1/3Nb2/3)O3-0.3 PbTiO3 single crystal with nano-patterned composite electrode. AB - Effect of nano-patterned composite electrode and backswitching poling technique on dielectric and piezoelectric properties of 0.7 Pb(Mg1/3Nb2/3)O3-0.3 PbTiO3 was studied in this paper. Composite electrode consists of Mn nano-patterns with pitch size of 200 nm, and a blanket layer of Ti/Au was fabricated using a nanolithography based lift-off process, heat treatment, and metal film sputtering. Composite electrode and backswitching poling resulted in 27% increase of d33 and 25% increase of dielectric constant, and we believe that this is attributed to regularly defined nano-domains and irreversible rhombohedral to monoclinic phase transition in crystal. The results indicate that nano-patterned composite electrode and backswitching poling has a great potential in domain engineering of relaxor single crystals for advanced devices. PMID- 24170961 TI - Clinicopathologic characteristics and prognosis of advanced gastric cancer simulating early gastric cancer. AB - BACKGROUND: Although the clinicopathologic features and prognosis of Borrmann type advanced gastric cancer has been well characterized, those of advanced gastric cancer simulating early gastric cancer (AGC simulating EGC) still remains unclear. METHODS: We reviewed 1985 gastric cancer patients who had undergone gastrectomy at our hospital to determine the clinicopathologic characteristics, susceptible sites for lymph node metastasis, and prognosis of AGC simulating EGC in comparison with Borrmann type advanced gastric cancer. RESULTS: Among 102 patients with AGC simulating EGC, 100 patients (98%) had tumors with depressed type appearance. The frequencies of serosal invasion, lymph node metastasis, lymphatic vessel invasion, blood vessel invasion, and liver metastasis were significantly lower in AGC simulating EGC than in Borrmann type tumors. The prognosis of AGC simulating EGC was significantly better than that of the Borrmann type tumors. Multivariate analysis indicated that the gross appearance was an independent prognostic factor. In patients with AGC simulating EGC which invaded to the the muscularis propria (MP), most lymph node metastasis was restricted with the perigastric lymph nodes (1st-titer lymph nodes) and lymph node metastasis to 2nd-titer lymph nodes was only observed at station 8a. CONCLUSION: AGC simulating EGC is less advanced in comparison with Borrmann type advanced gastric cancer. Based on the results of susceptible sites for lymph node metastasis in the current study, limited lymph node dissection could be indicated for AGC simulating EGC whose depth of invasion is MP. PMID- 24170962 TI - Abnormal adipose tissue distribution with unfavorable metabolic profile in five children following hematopoietic stem cell transplantation: a new etiology for acquired partial lipodystrophy. AB - We report five consecutive patients who underwent hematopoietic stem cell transplantation (HSCT) to treat leukemia or neuroblastoma early in their lives and later manifested abnormal patterns of adipose tissue distribution. Lipoatrophy was remarkable in the gluteal regions and extremities, whereas subcutaneous fat was preserved in the cheeks, neck, and abdomen. In addition, visceral fat deposition, fatty changes in the liver, and metabolic derangements such as insulin resistance and hypertriglyceridemia were evident. These features resemble Dunnigan-type familial partial lipodystrophy, which is a rare condition caused by LMNA gene mutation. These patients shared a common medical history involving HSCT, including conditioning with total body irradiation (TBI). They also received intensive chemotherapy because of multiple metastases (n = 3), relapse (n = 3), and repetitive HSCT (n = 3). We propose HSCT as a new etiology for acquired partial lipodystrophy and recommend that patients who undergo HSCT with TBI and intensive chemotherapy early in their lives must receive careful observation for the possible development of lipodystrophy and metabolic complications. PMID- 24170963 TI - Therapeutic Efficacy and Safety of GH in Japanese Children with Down Syndrome Short Stature Accompanied by GH Deficiency. AB - In this study, we investigated the effects of GH treatment in children with Down syndrome who had been diagnosed with GH deficiency (GHD). A total of 20 subjects were investigated in this study. Fourteen Down syndrome children (5 boys and 9 girls) with short stature due to GHD were treated with GH at Okayama Red Cross General Hospital, and 6 Down syndrome children (4 boys and 2 girls) with short stature due to GHD were registered in the Pfizer International Growth Database (KIGS). Height SD score (SDS) increased throughout the three-year GH treatment period. The overall mean height SDS increased from -3.5 at baseline to -2.5 after 3 yr of treatment. The mean change in height SDS during these 3 yr was 1.1. In addition, height assessment of SD score based on Down syndrome-specific growth data in the Japanese population revealed that the height SDS (Down syndrome) also increased across the 3-yr GH treatment period. The mean change in height SDS (Down syndrome) during these three years was 1.3. GH therapy was effective for Down syndrome short stature accompanied by GHD, and no new safety concerns were found in this study. PMID- 24170964 TI - A Case of Vitamin D Deficiency without Elevation of Serum Alkaline Phosphatase in a Carrier of Hypophosphatasia. AB - Elevated serum alkaline phosphatase (ALP) is a screening marker for the diagnosis of vitamin D deficiency, which may fail to be diagnosed if serum ALP is not elevated. Here, we describe a case of vitamin D deficiency without elevation of serum ALP. A 1-year-old Japanese girl was referred to our hospital for the evaluation of genu varum. Her serum intact PTH level was elevated, while her serum ALP level was normal. Furthermore, her serum 25-hydroxyvitamin D level was reduced, and her urine phosphoethanolamine (PEA) level was mildly elevated. ALPL gene analysis revealed she was a heterozygous carrier of hypophosphatasia (c.1559delT). Serum intact PTH and urine PEA evaluations were helpful for diagnosing vitamin D deficiency and hypophosphatasia carrier status, respectively. Therefore, the possibility of vitamin D deficiency without elevation of serum ALP should be considered. PMID- 24170965 TI - Brain white matter abnormality in a newborn infant with congenital adrenal hyperplasia. AB - Several studies have described brain white matter abnormalities on magnetic resonance imaging (MRI) in children and adults with congenital adrenal hyperplasia (CAH), while the brain MRI findings of newborn infants with CAH have not been clarified. We report a newborn boy with CAH who presented brain white matter abnormality on MRI. He was diagnosed as having salt-wasting CAH with a high 17-OHP level at neonatal screening and was initially treated with hydrocortisone at 8 days of age. On day 11 after birth, he had a generalized tonic seizure. No evidence of serum electrolyte abnormalities was observed. Brain MRI revealed white matter abnormalities that consisted of bilateral small diffuse hyperintensities on T1-weighted images with slightly low intensity on T2-weighted images in the watershed area. Several factors associated with brain white matter abnormalities in adults with CAH, such as increasing age, hypertension, diabetes and corticosteroid replacement, were not applicable. Although the cause of the phenomenon in this case is unclear, brain white matter abnormality could be observed in newborn infants with CAH as well as in adult patients. PMID- 24170966 TI - A Novel Deletion Mutation of SLC16A2 Encoding Monocarboxylate Transporter (MCT) 8 in a 26-year-old Japanese Patient with Allan-Herndon-Dudley Syndrome. AB - Allan-Herndon-Dudley Syndrome (AHDS), an X linked condition, is characterized by congenital hypotonia that progresses to spasticity with severe psychomotor delays, in combination with altered thyroid hormone levels, in particular, high serum T3 levels. Recently, this disease was proved to be caused by mutations in SLC16A2 coding for the monocarboxylate thyroid hormone transporter 8 (MCT8). Here we describe a 26-year -old Japanese patient with AHDS who had deletion of exon 3 of SLC16A2. PMID- 24170968 TI - On the mechanism of elasto-inertial turbulence. AB - Elasto-inertial turbulence (EIT) is a new state of turbulence found in inertial flows with polymer additives. The dynamics of turbulence generated and controlled by such additives is investigated from the perspective of the coupling between polymer dynamics and flow structures. Direct numerical simulations of channel flow with Reynolds numbers ranging from 1000 to 6000 (based on the bulk and the channel height) are used to study the formation and dynamics of elastic instabilities and their effects on the flow. The flow topology of EIT is found to differ significantly from Newtonian wall-turbulence. Structures identified by positive (rotational flow topology) and negative (extensional/compressional flow topology) second invariant Qa isosurfaces of the velocity gradient are cylindrical and aligned in the spanwise direction. Polymers are significantly stretched in sheet-like regions that extend in the streamwise direction with a small upward tilt. The Qa cylindrical structures emerge from the sheets of high polymer extension, in a mechanism of energy transfer from the fluctuations of the polymer stress work to the turbulent kinetic energy. At subcritical Reynolds numbers, EIT is observed at modest Weissenberg number (Wi, ratio polymer relaxation time to viscous time scale). For supercritical Reynolds numbers, flows approach EIT at large Wi. EIT provides new insights on the nature of the asymptotic state of polymer drag reduction (maximum drag reduction), and explains the phenomenon of early turbulence, or onset of turbulence at lower Reynolds numbers than for Newtonian flows observed in some polymeric flows. PMID- 24170969 TI - Role of Hot Water System Design on Factors Influential to Pathogen Regrowth: Temperature, Chlorine Residual, Hydrogen Evolution, and Sediment. AB - Residential water heating is linked to growth of pathogens in premise plumbing, which is the primary source of waterborne disease in the United States. Temperature and disinfectant residual are critical factors controlling increased concentration of pathogens, but understanding of how each factor varies in different water heater configurations is lacking. A direct comparative study of electric water heater systems was conducted to evaluate temporal variations in temperature and water quality parameters including dissolved oxygen levels, hydrogen evolution, total and soluble metal concentrations, and disinfectant decay. Recirculation tanks had much greater volumes of water at temperature ranges with potential for increased pathogen growth when set at 49 degrees C compared with standard tank systems without recirculation. In contrast, when set at the higher end of acceptable ranges (i.e., 60 degrees C), this relationship was reversed and recirculation systems had less volume of water at risk for pathogen growth compared with conventional systems. Recirculation tanks also tended to have much lower levels of disinfectant residual (standard systems had 40-600% higher residual), 4-6 times as much hydrogen, and 3-20 times more sediment compared with standard tanks without recirculation. On demand tankless systems had very small volumes of water at risk and relatively high levels of disinfectant residual. Recirculation systems may have distinct advantages in controlling pathogens via thermal disinfection if set at 60 degrees C, but these systems have lower levels of disinfectant residual and greater volumes at risk if set at lower temperatures. PMID- 24170970 TI - Influence of Soil Moisture on Soil Gas Vapor Concentration for Vapor Intrusion. AB - Mathematical models have been widely used in analyzing the effects of various environmental factors in the vapor intrusion process. Soil moisture content is one of the key factors determining the subsurface vapor concentration profile. This manuscript considers the effects of soil moisture profiles on the soil gas vapor concentration away from any surface capping by buildings or pavement. The "open field" soil gas vapor concentration profile is observed to be sensitive to the soil moisture distribution. The van Genuchten relations can be used for describing the soil moisture retention curve, and give results consistent with the results from a previous experimental study. Other modeling methods that account for soil moisture are evaluated. These modeling results are also compared with the measured subsurface concentration profiles in the U.S. EPA vapor intrusion database. PMID- 24170971 TI - Editorial. PMID- 24170972 TI - Modulation of rabbit muscle sarcoplasmic reticulum Ca(2+)-ATPase activity by novel quercetin derivatives. AB - Sarcoplasmic reticulum Ca(2+)-ATPase (SERCA) is the pump crucial for calcium homeostasis and its impairment results in pathologies such as myopathy, heart failure or diabetes. Modulation of SERCA activity may represent an approach to the therapy of diseases with SERCA impairment involvment. Quercetin is flavonoid known to modulate SERCA activity. We examined the effect of nine novel quercetin derivatives on the activity of the pump. We found that 5 morpholinohydroxypoxyquercetin, di(prenylferuoyl)quercetin, di(diacetylcaffeoyl) mono-(monoacetylcaffeoyl)quercetin and monoacetylferuloylquercetin stimulated the activity of SERCA. On the contrary, monochloropivaloylquercetin, tri(chloropivaloyl)quercetin, pentaacetylquercetin, tri(trimethylgalloyl)quercetin and diquercetin inhibited the activity of the pump. To identify compounds with a potential to protect SERCA against free radicals, we assessed the free radical scavenging activity of quercetin derivatives. We also related lipophilicity, an index of the ability to incorporate into the membrane of sarcoplasmic reticulum, to the modulatury effect of quercetin derivatives on SERCA activity. In addition to its ability to stimulate SERCA, di(prenylferuloyl)quercetin showed excellent radical scavenging activity. PMID- 24170973 TI - Efficacy of quercetin derivatives in prevention of ulcerative colitis in rats. AB - Reactive oxygen species has been implicated to contribute significantly to tissue injury associated with ulcerative colitis. Thus compounds with antioxidant properties could be potential therapeutic agents in this disease. Flavonoid compounds are known to possess antioxidative and antiinflammatory properties. Two derivatives of the flavonoid quercetin (Q), chloronaphthoquinone quercetin (CNC) and monochloropivaloyl quercetin (MCP), showed improved antioxidant properties and moreover, they efficiently inhibited aldose reductase activity in vitro. The aim of the work was to test the potential efficacy of quercetin and these synthetic derivatives in vivo in prevention of intestinal inflammation during ulcerative colitis in rats. Colitis was induced by intracolonic administration of acetic acid (4% solution). The control group received the same volume of saline. The vehicle dimethyl sulfoxide (DMSO) and the drugs Q, CNC or MCP were administered orally two hours and then one hour before the acetic acid or saline instillation. After 48 hours, the animals were sacrificed and the colon was weighed, measured and scored for visible damage. Acetic acid triggered an intense inflammatory response of the colon, characterised by haemorrhage, ulceration and bowel wall thickening. From the drugs tested, only CNC (2 * 50 mg/kg) effectively depressed inflammatory damage of the colon. The mechanism of this beneficial effect remains to be elucidated. PMID- 24170974 TI - Screening for antiradical efficiency of 21 semi-synthetic derivatives of quercetin in a DPPH assay. AB - The group of 21 novel semi-synthetic derivatives of quercetin was screened for the antiradical efficiency in a DPPH assay. The initial fast absorbance decrease of DPPH, corresponding to the transfer of the most labile H atoms, was followed by a much slower absorbance decline representing the residual antiradical activity of the antioxidant degradation products. Initial velocity of DPPH decolorization determined for the first 75-s interval was used as a marker of the antiradical activity. Application of the kinetic parameter allowed good discrimination between the polyphenolic compounds studied. The most efficient chloronaphthoquinone derivative (compound Ia) was characterized by antiradical activity higher than that of quercetin and comparable with that of trolox. Under the experimental conditions used, one molecule of Ia was found to quench 2.6+/ 0.1 DPPH radicals. PMID- 24170975 TI - Effect of poloxamer 407 administration on the serum lipids profile, anxiety level and protease activity in the heart and liver of mice. AB - Chronic administration of the poloxamer 407 (P-407), a block copolymer, to elevate serum lipids in mice is a well-established mouse model of hyperlipidemia and atherosclerosis. We tested the hypothesis that the activity of several types of proteases in heart and liver tissue is changed in the early stages of atherosclerosis development. Additionally, we evaluated whether increased serum lipids would induce anxiety in mice, as determined by using a 'plus-maze' test. The mice were administered P-407 by intraperitoneal injection twice a week for one month. P-407 administration to mice resulted in a marked increase in total serum cholesterol, atherogenic non-HDL-cholesterol, and especially in total triglycerides, and it also increased anxiety. Morphological changes observed in P 407-treated mice included contractile type changes in cardiomyocytes and foamy macrophages in liver. A significant increase of cysteine proteases cathepsin B and cathepsin L (at 24 h) and aspartate protease cathepsin D (at both 24 h and 5 days) was determined in heart tissue following P-407 administration. However, no changes were noted in heart matrix metalloproteinase activity. The activity of cysteine and aspartate proteases was significantly increased in liver at both 24 hours and 5 days after P-407 administration. In conclusion, administration of P 407 to mice for one month resulted in increased anxiety, and more importantly, there was an increase in the activity of heart and liver proteases secondary to sustained dyslipidemia. It is suggested that heart and liver cysteine and aspartate proteases may represent potential therapeutic targets in the early stages of atherosclerosis. PMID- 24170976 TI - Redox properties of ginger extracts: Perspectives of use of Zingiber officinale Rosc. as antidiabetic agent. AB - In traditional medicine, several medicinal plants or their extracts have been used to treat diabetes. Zingiber officinale Roscoe, known commonly as ginger, is consumed worldwide in cookeries as a spice and flavouring agent. It has been used as the spice and medicine for thousands of years. The present study was undertaken to investigate the potential protective effect of Zingiber officinale Rosc. in a model of oxidative damage to pancreatic beta cells. The free radical scavenging activities and composition of the isolated n-hexane and ethanolic extracts were confronted with their protective, antioxidant and cytotoxic effects in INS-1E beta cells. Unlike the n-hexane extract (exerting, paradoxically, stronger antiradical capacity), both low cytotoxicity and remarkable protective effects on beta cell viability, followed by lowering oxidative stress markers were found for the ethanolic extract Zingiber officinale Rosc. The present study is the first pilot study to assess the protective potential of Zingiber officinale Rosc. in a model of cytotoxic conditions imposed by diabetes in beta cells. PMID- 24170977 TI - Developmental study of mercury effects on the fruit fly (Drosophila melanogaster). AB - Environmental pollution caused by heavy metals such as mercury is one of the most important human problems. It might have severe teratogenic effects on embryonic development. Some pharmacological and physiological aspects of fruit flies (Drosophila melanogaster) are similar to humans. So the stages of egg to adult fruit fly, as a developmental model, were employed in the study. Wild adult insects were maintained in glass dishes containing standard medium at 25 degrees C in complete darkness. Five pairs of 3-day old flies were then transferred to standard culture dishes containing different concentrations of mercury ion. They were removed after 8 hours. We considered the following: The rate of larvae becoming pupae and pupae to adults; the time required for the development; the hatching rate in the second generation without mercury in the culture; the morphometric changes during development in both length and width of the eggs through two generations; larvae, pupae and adult thorax length and width. The results showed that mercury in culture (20-100 mg/l) increase the duration of larvae (p<0.01) and pupae (p<0.01) development, the rate of larvae becoming pupae (p<0.001); pupae maturation (p<0.05), the hatching rate (p<0.01), the length (p<0.05) and width of larvae (p<0.01) and pupae (p<0.001) and the length in the adult thorax (p<0.01) decreased significantly. There was no effect upon the size of eggs. There were also no larvae hatching in concentrations of 200 mg/l of mercury. Negative effects of mercury as a heavy metal are possibly due to the interference of this metal in cellular signaling pathways, such as: Notch signaling and protein synthesis during the period of development. Since it bonds chemically with the sulfur hydride groups of proteins, it causes damage to the cell membrane and decreases the amount of RNA. This is the cause of failure of many enzyme mechanisms. PMID- 24170978 TI - Implementation and evaluation of adverse drug reaction monitoring system in a tertiary care teaching hospital in Mumbai, India. AB - Adverse drug reactions (ADR) are a significant cause of morbidity and mortality, often identified only post-marketingly. Improvement in current ADR reporting, including utility of underused or innovative methods, is crucial to improve patient safety and public health. Hospital-based monitoring is one of the methods used to collect data about drug prescriptions and adverse events. The aims of this study were to identify the most frequent ADRs recognized by the attending physicians, study their nature, and to target these ADRs in order to take future preventive measures. A prospective study was conducted over a 7-month period in an internal medicine department using stimulated spontaneous reporting for identifying ADRs. Out of the 254 admissions, 32 ADRs in 37 patients (14.56%) were validated from the total of 36 suspected ADRs in 41 patients. Female predominance was noted over males in case of ADRs. Fifty percent of total ADRs occurred due to multiple drug therapy. Dermatological ADRs were found to be the most frequent (68.75%), followed by respiratory, central nervous system and gastrointestinal ADRs. The drugs most frequently involved were antibiotics, anti-tubercular agents, antigout agents, and NSAIDs. The most commonly reported reactions were itching and rashes. Out of the 32 reported ADRs, 50% of the reactions were probable, 46.87% of the reactions were possible and 3.12% of the reactions were definite. The severity assessment done by using the Hartwig and Seigel scale indicated that the majority of ADRs were 'Mild' followed by 'Moderate' and 'Severe' reactions, respectively. Out of all, 75% of ADRs were recovered. The most potent management of ADRs was found to be drug withdrawal. Our study indicated that hospital based monitoring was a good method to detect links between drug exposure and adverse drug reactions. Adequate training regarding pharmacology and optimization of drug therapy might be helpful to reduce ADR morbidity and mortality. PMID- 24170979 TI - Pluchea lanceolata protects against Benzo(a) pyrene induced renal toxicity and loss of DNA integrity. AB - Evidence from epidemiological, experimental and clinical trial data indicates that a plant based diet can reduce the risk of chronic diseases and reduces toxic effects. In the present study, we report the antioxidant and anticlastogenic activity of Pluchea lanceolata (PL), an important medicinal plant, in both in vitro and in vivo model. Benzo(a)pyrene (B(a)P) administration leads to depletion of renal glutathione and its metabolizing enzymes. Pretreatment with PL (100 and 200 mg /kg b.wt) restored renal glutathione content and its dependent enzymes significantly (p<0.001) with simultaneous increase in catalase(CAT), quinone reductase(QR) in mouse kidney. Prophylactic administration of PL prior to B (a) P administration significantly decreased the malondialdehyde(MDA), H2O2 and xanthineoxidase (XO) levels at a significance of p<0.001, at both the doses. PL extract pretreated groups showed marked inhibition in B(a)P induced micronuclei formation in mouse bone marrow cells with simultaneous restoration of DNA integrity, viz. alkaline unwinding assay and DNA damage shown by gel electrophoresis. HPTLC confirms the presence of quercetin in plant extract which could be responsible for PL protecting efficacy. In conclusion, the present findings strongly support the antioxidant efficacy of PL, possibly by modulation of antioxidant armory. PMID- 24170980 TI - Effects of MRP8, LPS, and lenalidomide on the expressions of TNF-alpha , brain enriched, and inflammation-related microRNAs in the primary astrocyte culture. AB - Astrocytes are now recognized as a heterogeneous class of cells with many important and diverse functions in healthy and diseased central nervous system (CNS). MicroRNAs (miRNAs) are small, noncoding RNAs which may have key roles in astrocytes activation in response to various stimuli. We performed quantitative real-time PCR (qPCR) to detect changes in the expressions of brain-enriched miRNAs (124, 134, 9, 132, and 138), inflammation-related miRNAs (146a, 21, 181a, 221, and 222), and tumor necrosis factor alpha (TNF- alpha ) in the rat primary astrocyte cultures after stimulation with myeloid-related protein 8 (MRP8) and lipopolysaccharides (LPS). Further, we inhibited the expression of TNF- alpha in the astrocytes by using TNF- alpha inhibitor (lenalidomide) and tested for the first time the effect of this inhibition on the expressions of the same tested miRNAs. Stimulation of the astrocytes with MRP8 or LPS leads to significant upregulation of miRNAs (124, 134, 9, 132, 146a, 21, 181a, 221, and 222), while miRNA-138 was downregulated. TNF- alpha inhibition with lenalidomide leads to opposite expressions of the tested miRNAs. These miRNAs may play an important role in activation of the astrocytes and may be a novel target for cell-specific therapeutic interventions in multiple CNS diseases. PMID- 24170981 TI - Effect of creatine monohydrate supplementation on various hematological and serum biochemical parameters of male albino mice following neonatal hypoxia-ischemia encephalopathy. AB - BACKGROUND: Present study was designed to report the effect of 2% creatine monohydrate supplementation for 8, 12 and 15 weeks on hematology and serum biochemical profile of male albino mouse following hypoxic ischemic insult on postnatal day 10. METHODS: 66 Blood samples (2% creatine monohydrate supplemented (N = 34) and unsupplemented (N = 32)) were analyzed for various hematological (blood glucose, packed cell volume, total WBC count, total RBC count) and serum biochemical parameters (cholesterol, AST, ALT, HDL, LDL, total protein, triglycerides). RESULTS: ALT had higher concentrations in mice feeding on normal diet for 8 (P > 0.01) and 12 weeks (P > 0.01) following asphyxia and in 12 weeks treatment without asphyxia (P = 0.006) when compared with the creatine supplemented mice. LDL (P = 0.011) and cholesterol (P > 0.01) had higher concentrations in mice on normal diet for 12 weeks following hypoxia ischemia. Cholesterol (P > 0.01) in 12 and glucose (P = 0.006) in 15 week treatment group had significantly lower concentrations in creatine supplemented male albino mice when compared with untreated group following hxpoic-ischemic insult. CONCLUSION: We concluded that creatine supplementation following hypoxic ischemic insult helps in maintain the normal blood chemistry. PMID- 24170982 TI - Psychopathology and continuous subcutaneous insulin infusion in type 1 diabetes. AB - AIM: Continuous subcutaneous insulin infusion (CSII) is used as an option in patients with diabetes failing to multiple daily injections (MDI). Psychological factors may play a relevant role in the failure to attain therapeutic goals in patients on MDI. This could lead to an overrepresentation of psychopathology in patients treated with CSII. METHODS: A consecutive series of 100 patients with type 1 diabetes was studied, collecting main clinical parameters and assessing psychopathology with the self-reported questionnaire Symptom Checklist 90 revised. Patients on CSII were then compared with those on MDI. RESULTS: Of the 100 enrolled patients, 44 and 56 were on CSII and MDI, respectively. Among men, those on CSII were younger than those on MDI; conversely, no difference in age was observed in women. Women on CSII showed higher scores on most Symptom Checklist 90 subscales than those on MDI, whereas no differences were observed in men. CONCLUSION: Women with type 1 diabetes treated with CSII display higher levels of psychopathology than those on MDI. This is probably the consequence of the fact that patients selected for CSII are those failing to MDI. Higher levels of psychopathology could represent a limit for the attainment and maintenance of therapeutic goals with CSII. PMID- 24170984 TI - Design of UWB monopole antenna with dual notched bands using one modified electromagnetic-bandgap structure. AB - A modified electromagnetic-bandgap (M-EBG) structure and its application to planar monopole ultra-wideband (UWB) antenna are presented. The proposed M-EBG which comprises two strip patch and an edge-located via can perform dual notched bands. By properly designing and placing strip patch near the feedline, the proposed M-EBG not only possesses a simple structure and compact size but also exhibits good band rejection. Moreover, it is easy to tune the dual notched bands by altering the dimensions of the M-EBG. A demonstration antenna with dual band notched characteristics is designed and fabricated to validate the proposed method. The results show that the proposed antenna can satisfy the requirements of VSWR < 2 over UWB 3.1-10.6 GHz, except for the rejected bands of the world interoperability for microwave access (WiMAX) and the wireless local area network (WLAN) at 3.5 GHz and 5.5 GHz, respectively. PMID- 24170983 TI - Therapeutic doses of nonsteroidal anti-inflammatory drugs inhibit osteosarcoma MG 63 osteoblast-like cells maturation, viability, and biomineralization potential. AB - Nonsteroidal anti-inflammatory drugs (NSAIDs) are frequently used to reduce pain and inflammation. However, their effect on bone metabolisms is not well known, and results in the literature are contradictory. The present study focusses on the effect of dexketoprofen, ketorolac, metamizole, and acetylsalicylic acid, at therapeutic doses, on different biochemical and phenotypic pathways in human osteoblast-like cells. Osteoblasts (MG-63 cell line) were incubated in culture medium with 1-10 MUM of dexketoprofen, ketorolac, metamizole, and acetylsalicylic acid. Flow cytometry was used to study antigenic profile and phagocytic activity. The osteoblastic differentiation was evaluated by mineralization and synthesis of collagen fibers by microscopy and alkaline phosphatase activity (ALP) by spectrophotometric assay. Short-term treatment with therapeutic doses of NSAIDs modulated differentiation, antigenic profile, and phagocyte activity of osteoblast-like cells. The treatment reduced ALP synthesis and matrix mineralization. However, nonsignificant differences were observed on collagen syntheses after treatments. The percentage of CD54 expression was increased with all treatments. CD80, CD86, and HLA-DR showed a decreased expression, which depended on NSAID and the dose applied. The treatments also decreased phagocyte activity in this cellular population. The results of this paper provide evidences that NSAIDs inhibit the osteoblast differentiation process thus reducing their ability to produce new bone mineralized extracellular matrix. PMID- 24170985 TI - Building up graphene-based conductive polymer composite thin films using reduced graphene oxide prepared by gamma-ray irradiation. AB - In this paper, reduced graphene oxide (RGO) was prepared by means of gamma -ray irradiation of graphene oxide (GO) in a water/ethanol mix solution, and we investigated the influence of reaction parameters, including ethanol concentration, absorbed dose, and dose rate during the irradiation. Due to the good dispersibility of the RGO in the mix solution, we built up flexible and conductive composite films based on the RGO and polymeric matrix through facile vacuum filtration and polymer coating. The electrical and optical properties of the obtained composite films were tested, showing good electrical conductivity with visible transmittance but strong ultraviolet absorbance. PMID- 24170987 TI - Conservative treatment in early cervical cancer. AB - PURPOSE OF REVIEW: The aim of this study was to describe fertility preservation methods to improve quality of life of early stages of cervical cancer. RECENT FINDING: Although definite treatment of early stages of cervical cancer including stages IA,IB1 and IIA non-bulky is radial hysterectomy, this method is used in perimenopousal period in which fertility preservation is not important. Whenever fertility preservation is so important, some methods like radical trachelectomy and laparoscopic lymphadenectomy are used to rule out lymphatic metastases. SUMMARY: If any visible lesion on cervix is found, pelvic MRI is helpful and during operation, trachelectomy samples are sent for frozen section and margin study. Radical trachelectomy is done vaginal or abdominal. Overall relapse rate of cervical cancer in radical trachelectomy and radical hysterectomy is the same. Complications of radical trachelectomy include chronic vaginal discharge, abnormal uterine bleeding, dysmenorrhea, inflammation and ulcer due to cercelage, amenorrhea, cervical stenosis and pregnancy complications following trachelectomy including 2(nd) trimester abortion and premature labor following cervical prematurity.The best and preferred method of labor is cesarean section. Neoadjuant chemotherapy followed by radical trachelectomy in large cervical lesions is a suitable treatment. Ultraconservative operations like large cold knife conization, simple trachelectomy with laparoscopic lymphadenectomy and sentinel lymph node mapping are suitable for very small lesions. PMID- 24170986 TI - Pharmacological control of receptor of advanced glycation end-products and its biological effects in psoriasis. AB - Receptor for advanced glycation end-products is implicated in a development of chronic inflammatory response. Aim of this paper is to provide a review on commercial and experimental medicines that can interfere with RAGE and signaling through RAGE. We searched three bibliographical databases (PubMed, Web of Science and MEDLINE) for the publications from 2005 to March 2012 and identified 5 major groups of agents that can interfere with RAGE biological effects. In the first part of this paper, we discuss AGE crosslink breakers. These chemicals destroy advanced glycation end products (AGEs) that are crosslinked to the extracellular matrix proteins and can interact with RAGE as ligands. Then, we describe two non conventional agents SAGEs and KIOM-79 that abolish certain biological effects of RAGE and have a strong anti-inflammatory potential. In the third part, we evaluate the inhibitors of the signaling cascades that underlie RAGE. Particularly, we discuss two groups of kinase inhibitors tyrphostins and the inhibitors of JAK kinases. Considering RAGE as a potential master regulator of processes that are crucial for the pathogenesis of psoriasis, we propose that these medicins may help in controlling the disease by abolishing the chronic inflammation in skin lesions. PMID- 24170988 TI - The effect of assisted reproductive technologies on gynecological cancer: report of our experiences and literature review. AB - INTRODUCTION: Infertility is as an important and common problem in couples necessitating assisted reproductive technology (ART) or drug therapy. Infertility is known as a risk factor for ovarian, breast and endometrial cancer. We aimed on evaluation of the history of primary infertility and previous ART in patients with the above-mentioned cancers. MATERIAL AND METHOD: In this retrospective study we evaluated all of the risk factors in patients with breast cancer, ovarian cancer and endometrial cancers who referred to the Gynecological Oncology Clinic in Shahid Sadoughi Hospital in Yazd, Iran from 2002 to 2012. We also investigated the history of primary infertility and ART in these patients before diagnosis of cancers. RESULTS: We gathered data from 92 patients with endometrial cancer, 84 patients with advanced epithelial ovarian cancer and 113 patients with breast cancer. There was history of infertility in 39.1% of patients with endometrial cancer who were obese (body mass index, BMI>29) and in 18.8% of patients with endometrial cancer and normal body mass index (BMI=25-29). ART had been performed in 7.3% of all patients with endometrial cancer. In patients with epithelial ovarian cancer, infertility was diagnosed in 28.4% and ART applied in 14.1%. Clomiphene with or without HCG and HMG was the most common drug used for patients with ovarian cancer. In patients with breast cancer, there was infertility in 16.5% and ART performed in 7.3%. CONCLUSION: Although infertility was present as an important and fairly common risk factor in some patients with endometrial, ovarian and breast cancer, but some other factors may be more important, including age, BMI and the etiology of infertility. Finding the association between ART and gynecological cancers needs long cohort studies with follow-up of infertile women who get the ART or drug therapy for over 15-20 years. We think BMI and age (in addition to infertility and ART) are contributing factors for development of gynecological cancers. PMID- 24170989 TI - Cervicoscopy and Microcolposcopy in the Evaluation of Squamo Columnar Junction and Cervical Canal in LSIL Patients with Inadequate or Negative Colposcopy. AB - OBJECTIVE: The present study evaluated indications' validity of cervicoscopic and microcolposcopic examination in LSIL patients with unsatisfactory or negative colposcopy. MATERIAL AND METHODS: [corrected] In the cervico-vaginal pathology unit of the "San Giovanni Calibita Fatebenefratelli" University of Rome "Tor Vergata", 119 patients with a positive cervical cytology (LSIL), were submitted to the exam for the following two indications: 1) unsatisfactory colposcopy 37 (31.1%); 2) negative colposcopy 82 (68.9%). RESULTS: Cervicoscopy allowed the SCJ visualization in 115 (9.6%) patients. In 4 patients 3.4%, the SCJ visualization was not possible due to cervical stenosis. Cervicoscopy without staining, revealed endocervical squamous columnar junction in 33 (28.7%) patients. The blue dye in panoramic view detected endocervical SCJ in 41 (35.7%), out of 115 patients (>5 mm in 34 (29.6%) patients and >10 mm in 7 (6.1%)). CONCLUSIONS: Cervicoscopic examination revealed 7.8% of CIN2-3 in LSIL patients with inadequate or negative colposcopy. In patients with negative colposcopy the percentage of undiagnosed lesions inside the cervical canal was very low. The blue dye added sensitivity to the exam. PMID- 24170990 TI - Effects of Chinese Herbal Compound "Xuemai Ning"on Rabbit Atherosclerosis Model and Expression of ABCA1. AB - OBJECTIVE: To observe the lipid and the pathological changes of carotid artery smooth muscle cells in atherosclerotic rabbits, verification of Chinese herbal compound which has improve blood lipid and anti atherosclerosis effects, focus on ABCA1 as the key receptor which participated in reverse cholesterol transport, to study the mechanism of Chinese herbal compound (Xuemai Ning). MATERIALS AND METHODS: 30 rabbits were randomly divided into blank group, model group and Chinese herbal compound (Xuemai Ning) group, The model group and the Xuemai Ning group with high fat diet and injection of vitamin D3, causing atherosclerosis model 4 weeks after the intervention of traditional Chinese medicine group, In the 4th week after Xuemai Ning group received the intervention of Chinese herbal compound. Blood lipid, the carotid artery pathological changes and expression of ABCA1 gene and protein in peritoneal macrophage surface were detected after 8 weeks. RESULTS: The carotid artery atherosclerotic plaque formation of the model group was obvious, the carotid atherosclerotic changes of the Xuemai Ning group rabbit significantly lighter than the model group. The serum lipid of model group and Xuemai Ning group were higher than that of the blank group; and the traditional Chinese medicine can up the expression of ABCA1 protein, higher than those in the model group. Expression of macrophage ABCA1 in model group was significantly up regulated at protein level higher than the blank group; and the traditional Chinese medicine can up regulate the expression of ABCA1 protein, higher than those in the model group. Expression of ABCA1 mRNA was significantly up regulated in model group, ABCA1 mRNA of Xuemai Ning group raised more significantly. CONCLUSION: Xuemai Ning can reduce triglyceride, total cholesterol and low density lipoprotein of hyperlipidemia model in rabbits serum, increase high density lipoprotein, remove foam cells in atherosclerotic cells, improve pathological of AS and up-regulate ABCA1 gene and protein so as to effectively inhibit atherosclerotic disease. PMID- 24170991 TI - Development of stability-indicating methods for cefquinome sulphate. AB - The degradation behavior of cefquinome sulphate in alkaline medium at different temperatures was investigated using both first derivative spectrophotometric and HPLC methods. The drug degradation was found to be pH and temperature dependant. The pH-rate profile indicated a first order dependence of Kobs on [OH(-)] at pHs ranging between 9 and 11. Arrhenius plot obtained at pH 10 was linear between 65 degrees and 100 degrees C. The estimated activation energy of the hydrolysis was found to be 21.1 kcal mol(-1). Stability-indicating thin-layer chromatographic method for the separation of the drug and its alkaline hydrolysis product has been developed. PMID- 24170992 TI - Cancer in pregnancy: a 10-year experience in shahid sadoughi hospital, yazd, iran. AB - INTRODUCTION: Although occurrence of cancer during pregnancy is rare, it leads to high morbidity and mortality in both mother and fetus. Recent trends in prolongation of child-bearing age have made cancer-associated pregnancies more frequent than past. As yet there are few documents concerning cancer and its related treatment outcomes during pregnancy. This study aimed at describing clinical characteristics of pregnant women with cancer in the Shahid Sadoughi hospital in Yazd, Iran. MATERIALS AND METHODS: Case series were reviewed retrospectively, which included 19 pregnant women diagnosed with cancer in Shahid Sadoughi hospital from 2002 to 2012. Data collected comprised demographics, pregnancy characteristics and outcomes, type of cancer, clinical stage, treatment and oncological. RESULTS: From 17 pregnant women with cancer, 4 women had gynecologic cancers and 13 had non-gynecologic cancers. The Following tumors were observed: breast [6], acute myeloblastic leukemia [3], uterine cervix carcinoma [3], ovary [1], chronic myelogenous leukemia [1], lymphoma [1], papillary carcinoma of thyroid [1], and pseudopapillary carcinoma of pancreas [1]. The mean age of patients was 30.6 years, and the mean gestational age at diagnosis was 21.1 weeks. Surgical treatment was performed in 3 patients, 6 patients were treated by chemotherapy, and in 3 by both. DISCUSSION: Although cancer during pregnancy is uncommon, it is considered an important problem due to unsuitable maternal and fetal outcomes and lack of standard management guidelines. Our cases represent examples of feasible or justifiable managements for them. PMID- 24170993 TI - Preoperative Topical Hypothermia used in Prolonged Severe Lower Limb Ischemia to Avoid Ischemic Damage - The First Clinical Experience. AB - Severe lower limb ischemia TASC IIB/III with sensory and motor neurologic deficiencies leads to prolonged hospital care, amputation, and death in 20-70 % of cases. We present our first clinical experience of the use of preoperative topical hypothermia to improve muscular viability in these patients. Two hours after onset of symptoms, six 4-liter plastic bags were filled with snow and packed against the ischemic leg which was protected from frost injury by a layer of towels. After surgical revascularization four hours later muscular and neural functions in the leg were completely restored. A maximum serum myoglobin of 6500 ng/L (median 12000 ng/L in similar but untreated patients) postoperatively decreased to 1400 ng/L after 27 hours. PMID- 24170994 TI - Synthesis and antioxidant activities of novel 5-chlorocurcumin, complemented by semiempirical calculations. AB - The novel curcumin derivative (1E,4Z,6E)-5-chloro-1,7-bis(4-hydroxy-3 methoxyphenyl)hepta-1,4,6-trien-3-one (5-chlorocurcumin) was prepared from natural curcumin. The newly synthesised compound was characterised by spectral studies (IR, 1H NMR, and 13C NMR). The free radical scavenging activity of 5 chlorocurcumin has been determined by measuring interaction with the stable free radical DPPH, and 5-chlorocurcumin has shown encouraging antioxidant activities. Theory calculations of the synthesised 5-chlorocurcumin were performed using molecular structures with optimised geometries. Molecular orbital calculations provided a detailed description of the orbitals, including spatial characteristics, nodal patterns, and the contributions of individual atoms. PMID- 24170995 TI - Investigation of In Vitro Drug Release from Porous Hollow Silica Nanospheres Prepared of ZnS@SiO 2 Core-Shell. AB - In this contribution, porous hollow silica nanoparticles using inorganic nanosized ZnS as a template were prepared. The hydrothermal method was used to synthesize pure ZnS nanospheres material. The ZnS@SiO2 core-shell nanocomposites were prepared using a simple sol-gel method successfully. The hollow silica nanostructures were achieved by selective removal of the ZnS core. The morphology, structure, and composition of the product were determined using powder X-ray diffraction (XRD), emission scanning electron microscopy (SEM), transmission electron microscopy (TEM), and Fourier transform infrared spectroscopy (FT-IR). The results demonstrated clearly that the pure ZnS nanoparticles are in a spherical form with the average size of 40 nm and correspond with zinc blend structure. The porous hollow silica nanoparticles obtained were exploited as drug carriers to investigate in vitro release behavior of amoxicillin in simulated body fluid (SBF). UV-visible spectrometry was carried out to determine the amount of amoxicillin entrapped in the carrier. Amoxicillin release profile from porous hollow silica nanoparticles followed a three-stage pattern and indicated a delayed release effect. PMID- 24170996 TI - The importance of trichoscopy in clinical practice. AB - Trichoscopy corresponds to scalp and hair dermoscopy and has been increasingly used as an aid in the diagnosis, follow-up, and prognosis of hair disorders. Herein, we report selected cases harbouring scalp or hair diseases, in whom trichoscopy proved to be a valuable tool in their management. A review of the recent literature on this hot topic was performed comparing the described patterns with our findings in clinically common conditions, as well as in rare hair shaft abnormalities, where trichoscopy may display pathognomonic features. In our view, trichoscopy represents a valuable link between clinical and histological diagnosis. We detailed some trichoscopic patterns, complemented with our original photographs and our insights into nondescribed patterns. PMID- 24170997 TI - Digital rectal examination standardization for inexperienced hands: teaching medical students. AB - Objectives. To standardize digital rectal examination (DRE) and set how it correlates with the comprehensive evaluation of lower urinary tract symptoms (LUTS). Methods. After scaled standardization of DRE based on fingertips graphical schema: 10 cubic centimeters-cc for each fingertip prostate surface area on DRE, four randomly selected senior medical students examined 48 male patients presenting with LUTS in an outpatient clinical setting, totaling 12 DRE each. Standardized DRE, international prostate symptom score (IPSS), serum PSA, transabdominal ultrasound (US), urodynamic evaluation, and postvoid residue were compared. Results. The mean and median PVs were US-45 and 34.7 cc (5.5 to 155) and DRE-39 and 37.5 cc (15 to 80). Comparing DRE and US by simple linear regression: US PV = 11.93 + 0.85 * (DRE PV); P = 0.0009. Among patients classified as nonobstructed, inconclusive, and obstructed, the US PVs were 29.8, 43.2, and 53.6 cc (P = 0.033), and DRE PVs were 20, 35, and 60 cc (P = 0.026), respectively. Conclusion. This is the first attempt to DRE standardization focusing on teaching-learning process, establishing a linear correlation of DRE and US PVs with only 12 examinations by inexperienced hands, satisfactorily validated in an outpatient clinical setting. PMID- 24170999 TI - Changes in serum levels of bone morphogenic protein 4 and inflammatory cytokines after bariatric surgery in severely obese korean patients with type 2 diabetes. AB - Serum bone morphogenic protein- (BMP-) 4 levels are associated with human adiposity. The aim of this study was to investigate changes in serum levels of BMP-4 and inflammatory cytokines after Roux-en-Y gastric bypass (RYGB). Fifty seven patients with type 2 diabetes underwent RYGB. Serum levels of BMP-4 and various inflammatory markers, including high-sensitivity C-reactive protein (hsCRP), free fatty acids (FFAs), and plasminogen activator inhibitor- (PAI-) 1, were measured before and 12 months after RYGB. Remission was defined as glycated hemoglobin <6.5% for at least 1 year in the absence of medications. Levels of PAI 1, hsCRP, and FFAs were significantly decreased at 1 year after RYGB. BMP-4 levels were also significantly lower at 1 year after RYGB than at baseline (P = 0.024). Of the 57 patients, 40 (70%) had diabetes remission at 1 year after surgery (remission group). Compared with patients in the nonremission group, patients in the remission group had lower PAI-1 levels and smaller visceral fat areas at baseline. There was a difference in the change in the BMP-4 level according to remission status. Our data demonstrate a significant beneficial effect of bariatric surgery on established cardiovascular risk factors and a reduction in chronic nonspecific inflammation after surgery. PMID- 24171000 TI - Microbiological effect of essential oils in combination with subgingival ultrasonic instrumentation and mouth rinsing in chronic periodontitis patients. AB - Thirty chronic periodontitis patients were randomly assigned to 3 groups: control, saline, and essential oil-containing antiseptic (EO). Subgingival plaque was collected from a total of 90 pockets across all subjects. Subsequently, subgingival ultrasonic instrumentation (SUI) was performed by using EO or saline as the irrigation agent. After continuous mouth rinsing at home with EO or saline for 7 days, subgingival plaques were sampled again. Periodontopathic bacteria were quantified using the modified Invader PLUS assay. The total bacterial count in shallow pockets (probing pocket depth (PPD) = 4-5 mm) was significantly reduced in both saline (P < 0.05) and EO groups (P < 0.01). The total bacterial count (P < 0.05) and Porphyromonas gingivalis (P < 0.01) and Tannerella forsythia (P < 0.05) count in deep pockets (PPD >=6 mm) were significantly reduced only in the EO group. In comparisons of the change ratio relative to baseline value of total bacteria counts across categories, both the saline and EO groups for PPD 4 5 mm and the EO group for PPD 6 mm showed a significantly low ratio (P < 0.05). The adjunctive use of EO may be effective in reducing subgingival bacterial counts in both shallow and deep pockets. This trial is registered with UMIN Clinical Trials Registry UMIN000007484. PMID- 24171001 TI - Clinical predictors for successful uvulopalatopharyngoplasty in the management of obstructive sleep apnea. AB - Objective. To assess the clinical parameters for successful uvulopalatopharyngoplasty in the management of obstructive sleep apnoea syndrome documented with pre- and postoperative polysomnography. Materials and Methods. A study group of 50 patients diagnosed as having OSA by full night polysomnography were assessed clinically and staged on basis of Friedman staging system. BMI and neck circumference were considered, and videoendoscopy with Muller's maneuver was done in all to document the site of obstruction. The study group divided into surgical and nonsurgical ones. Twenty-two patients out of fifty were then selected for uvulopalatopharyngoplasty. The selection of surgical group was done primarily on basis of clinical parameters like neck circumference, Friedman stage of the patient and site, and/or level of obstruction of patient. Postoperative polysomnography was done six months after surgery to document the change in AHI score. Result. The study group consists of fifty patients with mean age of 44.4 +/- 9.3 years. UPPP was done in twenty-two, and the result of the surgery as defined by 50% reduction in preoperative AHI with postoperative AHI < 20/h was seen to be 95.2%. Postoperative change in AHI done after 6-month interval was seen to be statistically significant with P value < 0.001. Conclusion. UPPP is ideal option for management of obstructive sleep apnoea syndrome in properly selected patients on the basis of Friedman stage and site of obstruction detected by videoendoscopy with Muller's maneuver. PMID- 24171002 TI - Calcium unresponsive hypocalcemic tetany: gitelman syndrome with hypocalcemia. AB - Introduction. Gitelman's syndrome (GS) is autosomal recessive renal tubular disorder characterized by hypokalemia, hypomagnesemia, hypocalciuria, metabolic alkalosis, and hyperreninemic hyperaldosteronism. It is usually associated with normal serum calcium. We report a patient presented with hypocalcemic tetany, and evaluation showed Gitelman's syndrome with hypocalcemia. Case Report. A 28-year old woman presented with cramps of the arms, legs, fatigue, and carpal spasms of one week duration. She has history of similar episodes on and off for the past two years. Her blood pressure was 98/66 mmHg. Chvostek's sign and Trousseau's sign were positive. Evaluation showed hypokalemia, hypocalcemia, hypomagnesemia, metabolic alkalosis, and hypocalciuria. Self-medication, diuretic use, laxative abuse, persistent vomiting, and diarrhoea were ruled out. Urinary prostaglandins and genetic testing could not be done because of nonavailability. To differentiate Gitelman syndrome from Bartter's syndrome (BS), thiazide loading test was done. It showed blunted fractional chloride excretion. GS was confirmed and patient was treated with spironolactone along with magnesium, calcium, and potassium supplementation. Symptomatically, she improved and did not develop episodes of tetany again. Conclusion. In tetany patient along with serum calcium measurement, serum magnesium, serum potassium, and arterial blood gases should be measured. Even though hypocalcemia in Gitelman syndrome is rare, it still can occur. PMID- 24171003 TI - A case of pulmonary hamartoma showing rapid growth. AB - A 65-year-old man was admitted for detailed examination of a growing nodular shadow in the left lung. The nodular shadow was initially detected in a routine chest X-ray check-up in March 2012 that warranted regular chest X-ray follow-up. The nodular shadow increased in size from 12 * 15 mm to 15 * 20 mm within five months. The calculated tumor doubling time (TDT) in our case was approximately 132.2 days. A malignant tumor was strongly suspected based on the rapid growth, and tumorectomy was thus performed. Cartilaginous tissue accounted for most of the pathological specimen, but a small amount of an epithelial component was observed histologically, and we diagnosed a hamartoma. Hamartoma generally shows slow annual growth, but it is important to recognize that rapid enlargement occurs in some cases. PMID- 24171005 TI - Squamous Cell Carcinoma of the Lung with Metastasis to the GI Tract Associated with EGFR Exon 19 Deletion. AB - We describe three confirmed cases of squamous cell carcinoma (SCC) of the lung with metastasis to the gastrointestinal (GI) tract, with two having epidermal growth factor receptor (EGFR) exon 19 deletions in all available specimens. One of these patients received EGFR tyrosine kinase directed therapy for a brief period with some symptom relief. Consideration of EGFR exon 19 mutation testing in SCC of the lung, particularly for those with GI tract metastasis, may identify this potentially drug-targetable entity. PMID- 24171004 TI - Severe Wound Infection with Photobacterium damselae ssp. damselae and Vibrio harveyi, following a Laceration Injury in Marine Environment: A Case Report and Review of the Literature. AB - Marine microorganisms are uncommon etiologies of skin and skin structure infections, that is, wound infections. We report a case of severe wound infection, caused by the marine Photobacterium damselae (Vibrionaceae), in a 64 year-old male patient, returning from Australia. The isolate tested positive for pPHDD1, a plasmid conferring high-level virulence. Furthermore, the wound was coinfected with Vibrio harveyi, a halophile bacterium, which has never been reported from human infections before. Identification was achieved by use of Matrix-Assisted Laser Desorption-Ionization Time of Flight Mass Spectrometry (MALDI-TOF) and confirmed by 16S rDNA sequencing. Data retrieval from bibliography was complicated since P. damselae has been renamed often with a number of synonyms present in the literature: Photobacterium damsela, Vibrio damselae, Vibrio damsela, Pasteurella damselae, and Listonella damsela. With all synonyms used as query terms, a literature search provided less than 20 cases published worldwide. A majority of those cases presenting as severe wound infection are even fatal following progression into necrotizing fasciitis. Management with daily wound dressing and antibiotic therapy (ofloxacin empirically, followed by doxycycline after availability of microbiology) led in the reported case to a favorable outcome, which seems to be, however, the exception based on a review of the available literature. PMID- 24171006 TI - Population Movement and Virus Spreading: HEV Spreading in a Pilgrimage City, Mashhad in Northeast Iran; an Example. AB - BACKGROUND: Hepatitis E Virus (HEV) infection is a significant public health concern and responsible for large outbreaks of acute hepatitis in poor sanitary and living conditions. OBJECTIVES: To investigate the impact of population movements on virus spreading, a large-scale population-based survey was performed in a pilgrimage- tourism area, the great Mashhad, capital city of Khorasan province. PATIENTS AND METHODS: A cross-sectional study was carried out among 1582 randomly selected individuals from general population of Mashhad, north east of Iran, between May to September 2009. Serum samples were tested for total anti HEV antibody using a specific enzyme linked immunoassay (ELISA) kit. RESULTS: The prevalence of HEV infection was 14.2% (225/1582) with a maximum of 25.5 % (14/55) in densely populated areas. The highest prevalence was observed in visitant areas (>= 20%) near the holly shrine with crowded hotels and inns. The differences between these areas and other districts were statistically significant (P < 0.001). The findings indicated that 13.2% (95/718) of males and 15.0% (130/864) of females were HEV positive; this difference is not significant. Seroprevalence increases with age rising , from 12.8% in subjects less than five years to 28.6% in individuals with more than 65 years old. Although, there were no meaningful differences between HEV seropositivity and socio-economic status, Illiterate individuals were significantly at higher risk for infection than educated persons (P < 0.001). CONCLUSIONS: These findings demonstrated that, high prevalence of HEV is related to populated district, which can reach to the highest rate in hotels and inns close to visitants. Traditional sanitation and water supplying systems are the second important factor for the virus transmission. Therefore, it can be concluded that such areas need efficient surveillance systems to prevent the spreading of infectious diseases. PMID- 24171007 TI - Invasive mucormycosis in a patient with liver cirrhosis: case report and review of the literature. AB - INTRODUCTION: Cutaneous Mucormycosis is a rare opportunistic infection caused by Zygomycetes class of fungi that is often fatal, requiring aggressive local control as well as systemic therapy. Few cases of mucormycosis were described in patients with liver cirrhosis, mostly rhino-orbital. To our knowledge, only two cases of upper extremity involvement was reported in cirrhosis while a few cases were reported in the post-transplant setting. We report herein the third case of upper extremity mucor infection in the setting of liver cirrhosis. CASE PRESENTATION: We described a rare case of forearm infection originating in a traumatic intravenous access portal in a 25 year-old woman with liver cirrhosis secondary to autoimmune hepatitis. DISCUSSION: She developed acute on chronic liver failure during the last trimester of pregnancy, which was terminated. Painful, erythematous lesion was noted on her right forearm in the area of intravenous access, which later became necrotic. Extensive debridement was done and histopathological examination confirmed the diagnosis of mucormycosis. The patient started on Amphotericin B. Her condition continued to deteriorate and ended up with above elbow amputation followed by right shoulder disarticulation. She died two days later due to multi-organ failure. In conclusion, forearm mucromycosis in liver cirrhosis can be fatal. PMID- 24171008 TI - Infantile hepatic hemangioendothelioma in comparison with hepatoblastoma in children: clinical and ultrasound features. AB - BACKGROUND: Infantile hepatic hemangioendothelioma (IHH) and hepatoblastoma (HBL) are respectively the most common benign and malignant liver tumors in children. OBJECTIVES: To study the clinical manifestations and the ultrasound features of the pediatric patients for distinguishing IHH from HBL. PATIENTS AND METHODS: Between 2002 and 2012, thirteen children with IHH and 38 children with HBL under the age of 10 years were included. We retrospectively reviewed the clinical and the ultrasound features of the two groups, especially including parameters as follows: age at diagnosis, gender, alpha-fetoprotein (AFP) elevation, venous involvement and Doppler ultrasound. RESULTS: Compared with HBL group, the age of IHH group was much younger (5.8 months vs. 35.1 months, P = 0.000), the AFP elevation was less likely to be detected in IHH group (23.1% vs. 89.5%, P = 0.000). Although the color flow were the same commonly observed (61.5% vs. 52.6%, P > 0.05), the spectral Doppler showed IHH was less likely to appear as arterial flow with resistance index (RI) > 0.7(12.5% vs. 75.0%, P < 0.05), characterized by arterial flow with RI < 0.7 and/or venous flow. Combined the clinical features including age (< 6 months) and normal AFP level yielded high capability in differential diagnosis, with sensitivity, specificity and Youden index of 77% (10/13), 95% (36/38), and 0.72, respectively. When combined clinical features (age and AFP) and spectral Doppler as the diagnostic criterion for distinguishing these cases with positive color flow signals, the sensitivity, specificity, accuracy and Youden Index were 88%, 95%, 89% and 0.83, respectively. CONCLUSIONS: The clinical features are effective indicators for distinguishing IHH from HBL, and the spectral Doppler may be a useful adjunct parameter for differential diagnosis. PMID- 24171009 TI - Prevalence of hepatitis d virus infection among patients with chronic hepatitis B attending birjand hepatitis clinic (East of iran) in 2012. AB - BACKGROUND: Hepatitis delta virus (HDV) is a defective RNA virus dependent on Hepatitis B virus (HBV) infection for its replication and expression. All patients with HBV infection should be tested for the presence of HDV infection. It is estimated that approximately 5% of hepatitis B surface antigen (HbsAg) carriers in the world are HDV infected patients. HBV-HDV co-infection may lead to more severe acute disease and higher risks of fulminant hepatitis, cirrhosis, and hepatocellular carcinoma than those having HBV infection alone. Also, HBV infected patients with HDV super-infection have a higher rate of progression to chronic disease and serious complications. OBJECTIVES: Our aim was to determine the prevalence of HDV infection among chronic hepatitis B (CHB) patients attending Birjand Hepatitis Clinic, East of Iran. MATERIALS AND METHODS: A cross sectional analytical study was conducted on 413 CHB patients in 2012. Serology test for anti-HDV was measured by ELISA in these patients. CHB patients had positive hepatitis B surface antigen for at least 6 months before the study entrance. RESULTS: The mean age of CHB patients was 38.5+/- 11.9 years and 55.9% of them (231 patients) were male. There were 13 cases (3.1%) with HDV infection. There was no association between positive anti-HDV serology and factors such as age, gender, carrier state, liver enzymes, and positive hepatitis B e antigen (HBeAg) serology. CONCLUSIONS: Although HDV had a low prevalence in our area, it is important for healthcare providers and policy makers to plan preventive strategies for HDV spread as well as HBV prevention programs among high risk population. PMID- 24171010 TI - Liver disease in cystic fibrosis: an update. AB - CONTEXT: Cystic fibrosis (CF) is the most widespread autosomal recessive genetic disorder that limits life expectation amongst the Caucasian population. As the median survival has increased related to early multidisciplinary intervention, other manifestations of CF have emerged especially for the broad spectrum of hepatobiliary involvement. The present study reviews the existing literature on liver disease in cystic fibrosis and describes the key issues for an adequate clinical evaluation and management of patients, with a focus on the pathogenetic, clinical and diagnostic-therapeutic aspects of liver disease in CF. EVIDENCE ACQUISITION: A literature search of electronic databases was undertaken for relevant studies published from 1990 about liver disease in cystic fibrosis. The databases searched were: EMBASE, PubMed and Cochrane Library. RESULTS: CF is due to mutations in the gene on chromosome 7 that encodes an amino acidic polypeptide named CFTR (cystic fibrosis transmembrane regulator). The hepatic manifestations include particular changes referring to the basic CFTR defect, iatrogenic lesions or consequences of the multisystem disease. Even though hepatobiliary disease is the most common non-pulmonary cause of mortality in CF (the third after pulmonary disease and transplant complications), only about the 33%of CF patients presents clinically significant hepatobiliary disease. CONCLUSIONS: Liver disease will have a growing impact on survival and quality of life of cystic fibrosis patients because a longer life expectancy and for this it is important its early recognition and a correct clinical management aimed at delaying the onset of complications. This review could represent an opportunity to encourage researchers to better investigate genotype-phenotype correlation associated with the development of cystic fibrosis liver disease, especially for non-CFTR genetic polymorphisms, and detect predisposed individuals. Therapeutic trials are needed to find strategies of fibrosis prevention and to avoid its progression prior to development its related complications. PMID- 24171011 TI - Mortality trend for tumor correlated immune system in hyperendemic area of HCV infection in southern Italy: joinpoint analysis. AB - BACKGROUND: In many regions of southern Italy, hepatitis C virus (HCV) infection represents a major health problem (with a prevalence rate between 6% and 13%). HCV is associated with different kinds of neoplasms such as non-Hodgkin lymphomas (NHL), and with auto-immune diseases (cryoglobulinemia), which develop after the virus has caused immune system alterations. OBJECTIVES: To provide updated information on trends in mortality in a major metropolitan area of southern Italy from NHL, multiple myeloma and Hodgkin disease we analyzed cancer mortality data from 1988 to 2009. MATERIALS AND METHODS: Mortality data were extracted from National death certificates by age groups, gender, residence and cause of death by the Italian national institute of statistics (ISTAT). Age-standardized mortality rates (SMR) were computed applying the direct method and using the world standard population. To quantify the recent direction of temporal trends in older populations over time, truncated age-adjusted mortality rates were calculated for people aged 65 years and older. Cancer mortality trends were described using their estimated annual percent change (EAPC) and related 95% Confidence Interval (CI). RESULTS: Statistically significant increasing EAPC was found among women for NHL (+2.0% / year), while statistically significant decrease was found among men and women for HD (-3.5% / year, -3.4% / year, respectively). No statistically significant EAPC was found for multiple myeloma. CONCLUSIONS: The association between viral hepatitis and NHL in the area of interest might provide some degree of explanation to this finding. Our data confirm that due to epidemic infection of HCV in the area of Naples, a high mortality for NHL persists, moreover the adoption of standard therapeutic protocols administered in full accordance with an evidence-based approach and current guidelines explain reduced mortality from Hodgkin lymphomas. PMID- 24171012 TI - An update on the antibiotic-based root canal irrigation solutions. AB - Antibiotics are a valuable addition to health practitioners for the management of bacterial infections. During endodontic treatment and when managing trauma to the teeth, antibiotics may be applied systemically or locally. Due to the potential risk of adverse effects of systemic applications, and the ineffectiveness of systemic prescribed antibiotics in necrotic or pulpless teeth and the periradicular tissues, the local application of antibiotics may be a more effective mode for delivering antibiotics to infected root canals. The purpose of this article is to review the history, rationale, and applications of antibiotics and antibiotic-containing irrigants in endodontics. PMID- 24171013 TI - Prevalence of referred pain with pulpal origin in the head, face and neck region. AB - INTRODUCTION: This study was designed to evaluate the prevalence of referred pain with pulpal source in the head, face and neck region among patients referred to Dental School of Shahid Beheshti University MC, Tehran, Iran in 2004. MATERIALS AND METHODS: In this cross-sectional study, 100 patients (55 males and 45 females) referred to oral medicine department of Shahid Beheshti Dental School evaluated via clinical and radiographic examination to seek their pain sources and sites. Inclusion criteria were report of pain and a dental clinician accomplished detection of pain origin. Exclusion criteria were non-odontogenic painful diseases, advanced periodontal disease, and substantial carious lesions. Visual analogue scale (VAS) was used to score pain intensity; meanwhile the patients were asked to mark the painful sites on an illustrated head and neck mannequin. RESULTS: Sixty-five percent of patients reported pain in sites which diagnostically differed from the pain source. According to statistical analysis, duration (P<0.01), spontaneity (P<0.001) and quality (P<0.01) of pain influenced its referral nature, while sex and age of patients, kind of stimulus, throbbing and intensity of pain had no considerable effect on pain referral (P>0.05). CONCLUSION: The prevalence of referred pain with pulpal origin in the head, face and neck region is moderately high which requires precise diagnosis by dental practitioners. Some hallmarks of irreversible pulpitis (e.g. spontaneous and persistent pain after elimination of stimulus) are related to pain referral. PMID- 24171014 TI - Comparison of Canal Preparation Pattern of K3 and ProTaper Rotary Files in Curved Resin Blocks. AB - INTRODUCTION: The purpose of this study was to evaluate and compare canal preparation pattern of K3 and ProTaper rotary files in curved resin blocks. MATERIALS AND METHODS: Twenty-four resin blocks were used in this experimental study and randomly divided into two groups. Their initial images were scanned. After preparation, their images were scanned again in the same position. Pre and post preparation images were superimposed by Photoshop software and the removed resin was measured in 5 different points, and then analyzed statistically by ANOVA and t-test. RESULTS: At O point (orifice), significantly (p<0.05) more outer canal wall was removed in the ProTaper group than in the K3 group. There was no significant difference at any other points of outer wall. Removed material of inner canal wall was not significantly different between the two groups. CONCLUSION: Under the condition of this study, both systems performed acceptable preparation pattern except at the beginning of the curve. PMID- 24171015 TI - Cytotoxic effect of a new endodontic cement and mineral trioxide aggregate on L929 line culture. AB - INTRODUCTION: The aim of this study was to compare the cytotoxicity of Mineral Trioxide Aggregate (MTA) and a New Endodontic Cement (NEC) on L929 mouse fibroblasts. MATERIALS AND METHODS: Different dilutions (Neat, 1/2, 1/10, 1/100) of fresh and set materials placed adjacent flasks of L929 in DMEM medium. Cellular viability was assessed using MTT assay in three time intervals (24, 48, and 72 h after mixing). Differences in mean cell viability values between materials were assessed by using the One-way ANOVA and Bonferoni post-test. Optical microscopic analysis of morphology of the untreated control and the cement-treated cell cultures were carried out in all experimental periods. RESULTS: It was indicated that there was not a significant difference in cytotoxicity among the materials of test and between them and the control group. However, there was a statistically significant difference between different time intervals within each group (P< 0.05) and between different concentration of test materials (P<0.05). In all samples, set materials showed better viability than fresh ones. CONCLUSION: According to results of this study, NEC and MTA have similar cytotoxic effect on L929 cell culture. PMID- 24171016 TI - Antimicrobial activity of three root canal irrigants on enterococcus faecalis: an in vitro study. AB - INTRODUCTION: The aim of this study was to compare the antimicrobial effects of 2.5% Sodium hypochlorite (NaOCl), 2% Chlorhexidine Gluconate (CHX) and BioPure MTAD (MTAD) on Enterococcus (E) faecalis-contaminated root canals of human extracted teeth. MATERIALS AND METHODS: Seventy human intact extracted single rooted teeth with straight root canal randomly divided into 5 groups: positive control (n=5), negative control (n=5), 2.5% NaOCl (n=20), 2% CHX (n=20), and MTAD (n=20). Each tooth was instrumented using the passive step-back technique hand and rotary instruments. E. faecalis incubated into the canals and grew for 4 weeks. Canals irrigated using three mentioned solutions for 5 minutes. Samples were taken from canal walls and transferred into Brain Heart Infusion (BHI) culture medium and placed in an incubator at 37oC for 96 hours and bacteriological evaluations were done. Chi- Square test and SPSS software were used for the statistical analysis of the results. RESULTS: Bacterial growth was seen in only one sample of MTAD group (5%), but in 4 of CHX group (20%) and 5 of NaOCl group (25%). Chi-Square test showed no statistically difference between groups. CONCLUSION: Based on the results of this study, it seems that all three solutions have acceptable antimicrobial effect on E. faecalis. PMID- 24171017 TI - Non-surgical root canal treatment of dens invaginatus 3 in a maxillary lateral incisor. AB - The aim of this case report was to describe the clinical management of an unusual dens invaginatus type 3. A case of dens invaginatus in a maxillary lateral incisor with a periapical lesion is reported. The patient presented with pain and localized swelling. Despite the complex anatomy and diagnosis of dens invaginatus, non-surgical root canal treatment was performed successfully. KEY LEARNING POINTS: - Dens invaginatus may be presented in different forms, and the etiology of this phenomenon is not fully understood. - Due to abnormal anatomical configuration, dens invaginatus presents technical difficulties in its clinical management. - Non-surgical root canal treatment can be performed successfully. PMID- 24171018 TI - A new approach to root formation. AB - In endodontics, treatment of an open apex tooth with necrotic pulp is a problem. It seems that with promotion of remnants of Hertwig's epithelial sheath or rest of malassez accompany with a good irrigation of root canal we can expect root formation. (Iranian Endodontic Journal 2008;3:42-43). PMID- 24171019 TI - Treatment outcomes of primary molars direct pulp capping after 20 months: a randomized controlled trial. AB - INTRODUCTION: The aim of this randomized controlled trial was to compare the radiographic and clinical success rates of direct pulp capping (DPC) using ProRoot mineral trioxide aggregate (MTA) or calcium enriched mixture (CEM). METHODS AND MATERIALS: A total of 42 symptom-free carious vital primary molars (21 pairs) were selected in this split mouth trial and randomly pulpotomized in two experimental groups. Pinpoint pulp exposures were covered by the same blinded operator with MTA or CEM, and then restored by amalgam. Radiographic and clinical successes were evaluated at 20 month follow-up. Data were statistically analyzed using McNemar test. RESULTS: Nineteen patients were available for 20-month follow up; only one failed tooth was extracted in the CEM group. All available teeth were symptom-free, however, the final evaluated success rate was 89% in CEM (CI 95%: 0.82-0.96) and 95% in MTA (CI 95%: 0.85-1) groups without statistical difference (P=0.360). Worst case scenario was applied for missing value analysis; assuming that the 2 lost cases in CEM group had failed and the only lost case in MTA group was due to treatment success, as a result the success of CEM and MTA were 81% (CI 95%: 0.72-0.90) and 95% (CI 95%:0.85-1), respectively, with no statistical difference (P=0.078). In the reverse scenario, the success of MTA and CEM were 86% (CI 95%: 0.78-0.94) and 90% (CI 95%: 0.82-0.98), respectively; again with no statistical difference (P=0.479). CONCLUSION: Effectiveness of MTA and CEM biomaterials for primary molars' DPC was similar; CEM can be a suitable alternative for MTA. PMID- 24171020 TI - Evaluation of the effect of tooth type and canal configuration on crown size in mandibular premolars by cone-beam computed tomography. AB - INTRODUCTION: To achieve success in treatment, one cannot ignore the knowledge of pulp anatomy. Mandibular premolars are considered to be the most difficult teeth for endodontic therapy due to high variability in their canal morphology. It is possible that a relation exists between the crown size and the number of extra canals in these teeth, so this in vitro study aims to investigate the relationship between the crown size and the uncommon morphology of mandibular premolars using Cone-Beam Computed Tomography (CBCT). MATERIALS AND METHODS: Eighty three extracted mandibular human premolars were exposed to radiation using the CBCT device. Root canal configuration was categorized according to the Vertucci's classification. The crown size was measured in three axial, coronal and sagittal sections. Finally, the relation between these two factors was evaluated with variance analysis (two-way ANOVA) and chi-square. RESULTS: The most common canal type in the mandibular first and second premolars are type I (71% and 76%, respectively), followed by type V (29% and 22%, respectively). No significant relationship was found between the crown size and extra canals in mandibular premolars (P>0.05). CONCLUSION: In this in vitro study, the average crown size in two-canalled second premolars was less than that in first premolars with a single canal; although the difference was not statistically significant. The research hypothesis was therefore rejected in both first and second mandibular premolars. PMID- 24171021 TI - Effect of smear layer on the push-out bond strength of two different compositions of white mineral trioxide aggregate. AB - INTRODUCTION: The aim of this in vitro study was to evaluate the effect of smear layer on the push-out bond strength of white mineral trioxide aggregate (WMTA) with and without disodium hydrogen phosphate (Na2HPO4). MATERIALS AND METHODS: Dentin discs with standard cavities were obtained from extracted human single rooted teeth and divided to 4 groups (n=15) according to the irrigation regimen and the canal filling material. In groups 1 and 3, canals were irrigated with normal saline; in groups 2 and 4, irrigation method included sodium hypochlorite (NaOCl) and then ethylenediaminetetra-acetic acid (EDTA). The canals were filled with WMTA in first and second groups and with WMTA+Na2HPO4; in groups 3 and 4. The samples were wrapped in wet gauze and incubated in 37 degrees C for 3 days. The push-out bond strength was then measured by means of the Universal Testing Machine and the failure modes were examined under stereomicroscope at 40* magnification. Tow-way ANOVA was used to evaluate the effect of material type and smear layer removal. Post hoc Tukey test was used for the two-by-two comparison of the groups. RESULTS: The greatest and lowest mean+/-standard deviation for push-out bond strength were observed in groups 4 (4.54+/-1.14 MPa) and 1 (1.44+/ 0.96 MPa), respectively. The effect of removing the smear layer on the push-out bond strength of WMTA+Na2HPO4 was significant (P=0.01), but not for WMTA (P=0.52). Interestingly, there was significant difference between groups 1, 3 and 2, 4 (P<0.05). The failure mode for all experimental groups was of mixed type. CONCLUSION: Under circumstances of this in vitro study, removal of smear layer increases push-out bond strength when Na2HPO4 is added to WMTA. PMID- 24171022 TI - Detection of Procedural Errors with Stainless Steel and NiTi Instruments by Undergraduate Students Using Conventional Radiograph and Cone Beam Computed Tomography. AB - INTRODUCTION: This study investigated procedural errors made during root canal preparation using stainless steel and nickel-titanium (NiTi) instruments by undergraduate students, using two diagnostic imaging methods. MATERIALS AND METHODS: Sixty human molars were divided into three groups (n=20; group 1: K Flexofile, group 2: K3, and group 3: BioRace). The root canals were filled with gutta-percha and AH Plus. Periapical radiographs and cone beam computed tomography (CBCT) images were obtained to detect procedural errors made by undergraduate students during root canal preparation. Two examiners evaluated the presence or absence of fractured instruments, perforations and canal transportations. The agreement between observers was assessed using the kappa coefficient. The Kolmogorov-Smirnov, Fisher exact, ANOVA and Tukey tests were used for statistical analysis. The level of significance was set at 5%. RESULTS: There were no significant differences in detecting procedural errors between two- and three-dimensional diagnostic imaging methods. There were no significant differences in procedural errors between stainless steel and NiTi instruments. Mean preparation time was recorded in minutes, and results were significantly different between the three groups. NiTi instruments had the lowest mean preparation time. CONCLUSION: Both periapical radiographs and CBCT identified procedural errors, however, three-dimensional images offered more diagnostic resources. The frequency of procedural errors was low for any of the endodontic instruments despite being used by inexperienced operators. PMID- 24171023 TI - Antimicrobial Efficacy of Mineral Trioxide Aggregate with and without Silver Nanoparticles. AB - INTRODUCTION: Most current root-end filling materials do not provide a perfect seal. Thus, a microscopic space is likely to exist in the interface between walls of the root-end cavity and filling material, which allows microorganisms and their products to penetrate. In addition to good sealing ability and biocompatibility, root-end filling materials should ideally have some antimicrobial activity. Therefore, this in vitro study aimed to evaluate the antimicrobial properties of Angelus white mineral trioxide aggregate (MTA) and the mixture of MTA with silver nanoparticles (1% weight; MTA/SN). MATERIALS AND METHODS: Antimicrobial properties of MTA and MTA/SN were tested by agar diffusion technique against Enterococcus faecalis, Pseudomonas aeruginosa, Staphylococcus aureus, and Candida albicans. The microbial inhibition zones around the materials were measured by a caliper with 0.1-mm accuracy. Student's t-test was used for comparison between the two groups in normal data distribution and Man-Whitney U test for non-normal distribution. RESULTS: Student's t-test revealed that for E. faecalis, C. albicans, and P. aeruginosa, microbial inhibition zone of MTA/SN was significantly greater than that of MTA (P = 0.000). Mann-Whitney U test indicated no significant difference between the effect of MTA and MTA/SN on S. aureus (P > 0.05). CONCLUSION: Based on the results of this study, adding silver nanoparticles to MTA improved its antimicrobial efficacy. PMID- 24171024 TI - Comparison of Endodontic Treatment Results Yielded from Using Normal Saline with IKI Final Rinse or NaOCl Irrigation: A 30-Month Follow-up Study. AB - INTRODUCTION: The aim of this clinical trial was to evaluate and compare the endodontic treatment results of teeth with apical periodontitis after thirty month recall with two different irrigation regimen: normal saline followed by Iodine Potassium Iodide (IKI) or sodium hypochlorite (NaOCl) irrigation alone. MATERIALS AND METHODS: Twenty seven patients (30 teeth) who had been included in the first part of our antimicrobial survey were recalled. In previous stage, root canal treatments were performed using either normal saline with IKI final rinse (n = 15) or NaOCl (n = 15) as irrigating solutions. Bacterial samples were taken before and after instrumentation. In this stage, three patients (6 teeth) were excluded from the follow-up schedule since they did not respond to the recall requests. The remaining 24 subjects (12 teeth in each NaOCl and IKI group) were examined clinically and radiologically. Post-operative and follow-up images were coded, blindly evaluated and given a periapical score according to PAI scoring system. The outcome was assessed in two ways; first, the changes in PAI score from base line to the follow-up evaluation in each group were assessed by wilcoxon signed rank test. In addition, Mann-Whitney U test was used to compare the differences between the post-operative and follow-up images of treatment groups. Second, the dichotomous variables as "healed" or "not healed" were compared. RESULTS: The Median (Min, Max) PAI scores for NaOCl group and IKI group were both 5 (3, 5) for immediate post-operative radiographs and declined to 1 (1, 2) and 2 (1, 2), respectively. A statistically significant decrease in PAI score from the base line to the follow-up evaluation was seen in both groups (P = 0.002). The decrease in NaOCl group was higher significantly in comparison to IKI group (P = 0.036). One hundred percent of the teeth were healed in both groups (PAI <= 2) and no teeth showed any abnormal clinical findings. CONCLUSION: Root canal irrigation with NaOCl resulted in a significant higher decrease in PAI scores in comparison to irrigation with normal saline followed by IKI final rinse. Although, according to results of 30-months recall, complete bone formation was observed in all samples in both groups and no teeth showed any abnormal clinical findings. These findings depict the weight of all important clinical and biological factors which together impact the results of a successful endodontic treatment. PMID- 24171025 TI - Sealing Ability of Resilon and MTA as Root-end Filling Materials: A Bacterial and Dye Leakage Study. AB - INTRODUCTION: Endodontic surgery is a valuable option for maintaining patient's natural dentition when previous orthograde endodontic treatments fail to succeed. Proper root-end preparation and placement of a retro-filling material are recommended for successful endodontic surgery. The objective of this experimental study was to compare sealing ability of Resilon/Epiphany system, as a potential root-end filling material, with ProRoot MTA using both dye and bacterial leakage models. MATERIALS AND METHODS: Ninety two single-rooted extracted human teeth were decoronated and prepared endodontically. Specimens were randomly divided into four experimental groups (n = 20) and four control groups (n = 3). After removal of apical 3 mm and root-end cavity preparation, MTA, or Resilon were used to fill root end cavities. For bacterial leakage, specimens (20 for each experimental group, 3 negative, and 3 positive controls) were subjected to E. faecalis over a 70-day period. Methylene blue was used for dye leakage (the same in number as before). Using stereomicroscope (40* mag.) complete dye leakage was assessed after 72 h. Kaplan-Meier survival analysis was performed for bacterial leakage. The data was analyzed using t-test and Chi-square analysis (alpha = 0.05). RESULTS: All of the positive controls and none of negative controls revealed leakage. Result of log rank test showed no significant difference between MTA and Resilon in time of bacterial leakage at the end of the 70 days (P > 0.05) There was also no statistical difference in complete dye leakage for both groups (P > 0.05). CONCLUSION: Leakage occurred in both MTA and Resilon as root end filling material but the difference was not statistically significant. Resilon might be noticed as a potential root-end filling material if good isolation is attainable. PMID- 24171026 TI - Evaluation of marginal adaptation of root-end filling materials using scanning electron microscopy. AB - INTRODUCTION: The importance of perfect apical seal in endodontics, more specifically in periradicular surgery, is the motivation/reason for development of root-end filling materials with favorable physical, chemical and biological characteristics. The aim of this in vitro study was to evaluate the marginal adaptation of root-end filling materials using scanning electron microscopy. MATERIALS AND METHODS: Twenty five human maxillary anterior teeth were prepared using a K-File #50 to 1 mm short of the apical foramen and filled with gutta percha and Sealapex using the lateral compaction technique. The apical 3 mm of the roots were sectioned perpendicularly to the long axis of the teeth. A 3-mm deep root-end cavity was prepared using ultrasonic tips powered by an Enac ultrasonic unit. The teeth were randomly assigned to five groups according to the materials tested including IRM, amalgam, ProRoot MTA, Super-EBA and Epiphany/Resilon. Root-end cavities were filled with the materials prepared according to the manufacturers' instructions. The root apices were carefully prepared for sputter coating and later evaluation using Scanning Electron Microscope (SEM). The images of root-end fillings were divided into four quadrants and distributed into five categories according to the level of marginal adaptation between the root-end material and the root canal walls. The Fisher exact test with Bonferroni correction was used for statistical analysis. The level of significance was set at P = 0.005. RESULTS: SEM images showed the presence of gaps in the root-end filling materials. No significant difference was observed between the tested materials (P > 0.005). CONCLUSION: ProRoot MTA, IRM, amalgam, Super-EBA and Epiphany/Resilon showed similar marginal adaptation as root-end filling materials. PMID- 24171027 TI - Microleakage of CEM Cement and ProRoot MTA as Furcal Perforation Repair Materials in Primary Teeth. AB - INTRODUCTION: Iatrogenic furcal perforation is a procedural accident in endodontic treatments of primary/permanent teeth; prognosis may be favorable if a complete seal with biomaterial is immediately established. The purpose of this in vitro study was to evaluate microleakage of calcium enriched mixture (CEM) cement and ProRoot mineral trioxide aggregate (MTA) for sealing primary molar furcal perforations. MATERIALS AND METHODS: This study was conducted on 38 extracted human primary molars. Furcation perforations were created in the pulp chamber floor. The teeth were divided randomly in two experimental groups (n=17) and two positive and negative controls (n=2). Perforations were then repaired with biomaterials. After 72 h, the teeth were submerged in 2% fuchsin dye solution for 24h. The samples were sectioned longitudinally and evaluated for dye leakage. Data analyzed statistically using ANOVA test. RESULTS: The negative and positive controls behaved as expected. Dye microleakage was observed in all experimental samples; however, there was no statistically significant difference between the microleakage of MTA (4.411+/-2.042 mm) and CEM (3.647+/-1.040 mm) groups (P>0.05). CONCLUSION: Based on the findings of this in vitro study, CEM and tooth colored ProRoot MTA have similar sealing ability for furcal perforation repair of primary molar teeth. PMID- 24171028 TI - Calcium Enriched Mixture and Mineral Trioxide Aggregate Activities against Enterococcus Faecalis in Presence of Dentin. AB - INTRODUCTION: The purpose of this in vitro study was to compare the antibacterial activity of Calcium Enriched Mixture (CEM) with ProRoot Mineral Trioxide Aggregate (MTA) against Enterococcus faecalis (E. faecalis) in the presence/absence of dentin powder. MATERIALS AND METHODS: Two series of freshly mixed (10, 50, and 100 mg), set crushed powder (10, 50, and 100 mg), and pieces of uncrushed set (50, 100 mg) of CEM and MTA were prepared (n = 32 groups). All samples were suspended in normal saline for direct exposure test against E. faecalis; in the second series, 50 mg of the dentin powder was also added to the solution. Dentin powder suspension and bacterial suspension served as negative and positive control groups, respectively (n = 2). The suspensions were incubated at room temperature for 1, 60, and 240 min; each group was tested five times and survival of the bacteria in test solutions was assessed by 10-fold serial dilutions and cultured on Brain Heart Infusion (BHI) plates. The plates were incubated at 37oC. The mean values of log10 CFU were calculated and compared in all tested groups. The total number of tests added up to 510 times. RESULTS: In presence of dentin powder, freshly mixed powder from set materials, and pieces of uncrushed set materials of both tested cements killed > 95% of the bacterial cell in 1 min. Adding dentin powder caused an increase in antibacterial activity of freshly mixed powder from crushed set CEM and MTA but no acceleration in bacterial killing was observed, when dentin was mixed with set or uncrushed cements. Dentin powder alone reduced the number of viable bacteria in the 4-hour duration. There were no significant differences between different weights of freshly mixed, crushed set powder and uncrushed set of CEM cement and MTA at different times. CONCLUSION: Under the conditions of this in vitro study, CEM cement as well as MTA have antibacterial effects against E. faecalis. The addition of equal amounts of dentin powder to the suspension of CEM or MTA resulted in swifter elimination of bacteria. PMID- 24171030 TI - Management of an intracanal separated instrument: a case report. AB - Instrument fracture within the root canal during root canal treatment is an unwanted and frustrating complication. The fractured segment may hinder cleaning and shaping procedures with potential impact on prognosis of treatment. Fracture of endodontic instrument often results from incorrect use or overuse. If breakage occurs clinically, the patient should be informed of the incident and consideration should be given whether to remove the fragment or not. When managed properly, the presence of a broken fragment per se may not adversely affect the outcome of root canal treatment. This article reports management of an intracanal separated instrument. Masserann kit along with gates glidden drills were used to remove the intracanal broken instrument. PMID- 24171029 TI - Patient-centered endodontic outcomes: a narrative review. AB - INTRODUCTION: Root canal treatment (RCT) success criteria inform us of the path to bony healing and of prognostic factors, but tell little about how the patient perceives, feels, or values RCT. Patients choose, undergo, and pay for RCT, they live with the result, and inform their community. The purpose of this narrative review was to appraise patient-centered outcomes of initial non-surgical RCT and nonsurgical retreatment, in adults. MATERIALS AND METHODS: Patient-centered RCT outcome themes were identified in the extant literature: quality of life, satisfaction, anxiety, fear, pain, tooth survival and cost. Narrative review was applied because the disparate themes and data were unsuited to systematic review or meta-analysis. RESULTS: Application of the Oral Health Impact Profile (OHIP) demonstrated that disease of pulpal origin affects quality of life with moderate severity, primarily through physical pain and psychological discomfort, and that RCT results in broad improvement of quality of life. Satisfaction with RCT is extremely high, but cost is the primary reason for dissatisfaction. Anxiety and fear affect RCT patients, profoundly influencing their behaviors, including treatment avoidance, and their pain experience. Fear of pain is "fair" to "very much" prior to RCT. Pain is widely feared, disliked, and remembered; however, disease of pulpal origin generally produces moderate, but not severe pain. RCT causes a dramatic decrease in pain prevalence and severity over the week following treatment. Survival rates of teeth after RCT are very high; complication rates are low. Cost is a barrier to RCT, but initial costs, lifetime costs, cost effectiveness, cost utility, and cost benefit all compare extremely well to the alternatives involving replacement using implants or fixed prostheses. CONCLUSION: Dentists must strive to reduce anxiety, fear, experienced and remembered pain, and to accurately inform and educate their patients with respect to technical, practical and psychosocial aspects of RCT. PMID- 24171031 TI - Comparison of characteristics of connective tissue disease-associated interstitial lung diseases, undifferentiated connective tissue disease-associated interstitial lung diseases, and idiopathic pulmonary fibrosis in Chinese Han population: a retrospective study. AB - Our study compared the prevalence and characteristics of patients with connective tissue disease-associated interstitial lung disease (CTD-ILD), undifferentiated connective tissue disease-associated interstitial lung disease (UCTD-ILD), or idiopathic pulmonary fibrosis (IPF) between January 2009 and December 2012 in West China Hospital, western China. Patients who met the criteria for ILD were included and were assigned to CTD-ILD, UCTD-ILD, or IPF group when they met the criteria for CTD, UCTD, or IPF, respectively. Clinical characteristics, laboratory tests, and high-resolution CT images were analyzed and compared among three groups. 203 patients were included, and all were Han nationality. CTD-ILD was identified in 31%, UCTD-ILD in 32%, and IPF in 37%. Gender and age differed among groups. Pulmonary symptoms were more common in IPF, while extrapulmonary symptoms were more common in CTD-ILD and UCTD-ILD group. Patients with CTD-ILD had more abnormal antibody tests than those of UCTD-ILD and IPF. Little significance was seen in HRCT images among three groups. A systematic evaluation of symptoms and serologic tests in patients with ILD can identify CTD-ILD, UCTD ILD, and IPF. PMID- 24171033 TI - Latent abnormal pathology affects long-term graft function in elder living renal allograft recipients. AB - OBJECTIVE: This study evaluated the long-term effects and clinical significance of latent abnormal pathology on elder living donor kidney graft function after renal transplantation in China. METHODS: One-hundred and thirty-eight living donor renal transplantations have been carried out at our hospital in recent years. Of these, 72 Time-Zero biopsies were performed and used in this analysis. Clinical data were retrospectively measured at 3, 6, 12, and 24 months after renal transplants. Relationships and effects from biopsy results taken from implanted donor kidney grafts were analyzed. RESULTS: Time-Zero biopsy pathology results from donor kidneys showed that 48.61% of donor kidneys had latent abnormal changes; arterial lesions of donor kidneys had significant effects on the renal function of grafts after 2 years' transplantation; correlations between donor age and arterial lesions were significant; and Time-Zero biopsy pathology results could help predict the long-term function of a renal graft. CONCLUSIONS: Existing latent pathological changes of an elder living donor kidney before transplantation could affect long-term renal function. Whether a senior donor is used should be very carefully considered. PMID- 24171032 TI - Mediators of inflammation and their effect on resident renal cells: implications in lupus nephritis. AB - Lupus nephritis affects up to 70% of patients with systemic lupus erythematosus and is a major cause of morbidity and mortality. It is characterized by a breakdown of immune tolerance, production of autoantibodies, and deposition of immune complexes within the kidney parenchyma, resulting in local inflammation and subsequent organ damage. To date, numerous mediators of inflammation have been implicated in the development and progression of lupus nephritis, and these include cytokines, chemokines, and glycosaminoglycans. Of these, type I interferons (IFNs) can increase both gene and protein expression of cytokines and chemokines associated with lupus susceptibility, and interleukin-6 (IL-6), tumor necrosis factor- alpha (TNF- alpha ) and hyaluronan have been shown to elicit both pro- and anti-inflammatory effects on infiltrating and resident renal cells depending on the status of their microenvironment. Expression of IL-6, TNF- alpha , type I IFNs, and hyaluronan are increased in the kidneys of patients and mice with active lupus nephritis and have been shown to contribute to disease pathogenesis. There is also evidence that despite clinical remission, ongoing inflammatory processes may occur within the glomerular and tubulointerstitial compartments of the kidney, which further promote kidney injury. In this review, we provide an overview of the synthesis and putative roles of IL-6, TNF- alpha , IFN- alpha , and hyaluronan in the pathogenesis of lupus nephritis focusing on their effects on human mesangial cells and proximal renal tubular epithelial cells. PMID- 24171034 TI - Primary biliary cirrhosis-specific antimitochondrial antibodies in neonatal haemochromatosis. AB - BACKGROUND AND AIM: Neonatal hemochromatosis (NH) is characterised by severe liver injury and extrahepatic siderosis sparing the reticuloendothelial system. Its aetiology is obscure, although it has been proposed as an alloimmune disease, resulting from immunological reaction to self-antigens (alloantigens) which the body recognizes as foreign. We studied an infant with NH and his mother whose sera contained antimitochondrial antibody (AMA), the hallmark of primary biliary cirrhosis (PBC). MATERIAL AND METHODS: To investigate the origin of AMA in the infant, we studied isotype distributions in serum from the mother and infant. Serum samples were obtained at diagnosis of NH, after liver transplantation (LT; age 1 month), and over the ensuing 17 months. RESULTS: At NH diagnosis, infant and maternal serum contained AMA of the IgG isotype, predominantly of the G3 and G1 subclasses. AMA strongly reacted against the pyruvate dehydrogenase complex E2 subunit (PDC-E2), the major PBC-specific AMA autoantigen. Anti-PDC-E2 responses in both infant and mother declined over time, being present 2 months after LT (mother and child) and absent 10 months later (mother) and 17 months later (child). CONCLUSION: The association of maternally transferred IgG1 and IgG3 subclass AMA with the appearance of liver damage in an infant with NH may suggest a causal link between antibody and liver damage. PMID- 24171035 TI - Clinical characteristics of Nocardia infection in patients with rheumatic diseases. AB - Although Nocardiosis has considerable recurrence and mortality rates, characteristics and risk factors of Nocardia infection have not been assessed in patients with rheumatic diseases. Here, we examined the characteristics and risk factors of Nocardia infection in rheumatic disease patients in our hospital. Ten rheumatic disease patients who developed Nocardia infection were identified by retrospectively reviewing the medical records. Possible predisposing factors for Nocardia infection were high-dose glucocorticoid treatment, concomitant use of immunosuppressants, preexisting pulmonary diseases, and diabetes mellitus. All patients had pulmonary Nocardiosis, and six of them had disseminated Nocardiosis when their pulmonary lesions were identified. PMID- 24171037 TI - Primo vascular system: past, present, and future. PMID- 24171036 TI - P53 and expression of immunological markers may identify early stage thyroid tumors. AB - BACKGROUND: Besides its major role in cell proliferation, DNA repair, and apoptosis, functional p53 protein is involved in the induction of antitumor cytotoxic-T-cell activity against carcinoma cells. We aimed to investigate p53 and immune cell markers utility as diagnostic and prognostic markers of differentiated thyroid cancer (DTC). METHODS: ACIS-III system was used to evaluate p53 and immune cell markers including tumor-associated macrophages (TAM); CD68 and tumor-infiltrating lymphocytes (TIL) subsets such as CD3, CD4, CD8, and CD20 in 206 thyroid carcinomas, 105 benign nodules, and 18 normal tissues. Also, TP53 was sequenced in 78 out of 164 patients with papillary thyroid carcinoma. RESULTS: P53 expression was observed more frequently in malignant than in benign lesions (P < 0.0001) and helped discriminate follicular patterned lesions. In addition, p53 was more frequent in smaller (P = 0.0015), unique tumors (P = 0.0286), with thyroiditis (P = 0.0486) and without metastasis at diagnosis (P = 0.0201). TAM was more frequent in P53 negative tumors (P = 0.002). Infiltration of CD8+ TIL was found in 61.7% of P53 positive and 25.6% of P53 negative DTC (P < 0.001). CONCLUSIONS: We suggest that p53 and CD8+ TIL immune profile analysis might be useful in DTC. PMID- 24171038 TI - Paeonol, a major compound of moutan cortex, attenuates Cisplatin-induced nephrotoxicity in mice. AB - Cisplatin is an effective chemotherapeutic agent that is used for the treatment of a variety of cancers; however, its nephrotoxicity limits the use of this drug. In the present study, we examined whether paeonol, a major compound of Moutan Cortex, has protective effects on cisplatin-induced acute renal failure in mice. To accomplish this, Balb/c mice (6 to 8 wk of age, weighing 20 to 25 g) were administered, Moutan Cortex (300 mg/kg) or paeonol (20 mg/kg) once a day. At day 4, mice received cisplatin (30, 20, or 10 mg/kg) intraperitoneally. The paeonol treated group showed marked attenuation of serum creatine and blood urea nitrogen levels as well as reduced levels of proinflammatory cytokines and nitric oxide when compared to the control group. In addition, the paeonol-treated group showed prolonged survival and marked attenuation of renal tissue injury. Taken together, these results demonstrated that paeonol can prevent the renal toxic effects of cisplatin. PMID- 24171039 TI - Grape seed procyanidins in pre- and mild hypertension: a registry study. AB - The efficacy of a standardized grape seed procyanidins extract (GSPE, Enovita) to decrease blood pressure when associated with nondrug intervention (diet and lifestyle modifications) was investigated in a controlled registry study involving 119 healthy, pre- and mildly hypertensive subjects. Two dosages of Enovita were evaluated (150 and 300 mg/die), using blood pressure and heart rate as the primary endpoints and complementing these observations with a laser Doppler flowmetry (LDF) investigation of the microcirculation state and an evaluation of the plasma oxidative status. After four months of treatment, a statistically significant higher, and dose-dependent, improvement in all endpoints was observed in the treatment groups compared to that of the control, with blood pressure normalizing in 93% of the higher dosage (300 mg) treatment group. Taken together, these observations suggest that GSPEs have beneficial cardiovascular effects that complement current intervention strategies in the hypertension area. The effect on blood pressure adds to the beneficial effects of GSPEs on the cardiovascular disease (CVD) phenotype associated with the oxidation of membrane lipids (endothelial dysfunction, formation of oxidized LDL, and activation of phagocytic cells). PMID- 24171040 TI - The role of complementary and alternative medicine in regenerative medicine. PMID- 24171041 TI - Corni Fructus Containing Formulation Attenuates Weight Gain in Mice with Diet Induced Obesity and Regulates Adipogenesis through AMPK. AB - Obesity is a metabolic disorder characterized by chronic inflammation and dyslipidemia and is a strong predictor for the development of hypertension, diabetes mellitus, and cardiovascular disease. This study examined the antiobesity effect of an ethanol extract of Corni Fructus containing formulation (CDAP), which is a combination of four natural components: Corni Fructus, Dioscoreae Rhizoma, Aurantii Fructus Immaturus, and Platycodonis Radix. The cellular lipid content in 3T3-L1 adipocytes was assessed by Oil Red O staining. Expressions of peroxisome proliferator-activated receptor- gamma (PPAR- gamma ), CCAAT/enhancer-binding protein- alpha (C/EBP- alpha ), and lipin-1 were determined by real-time RT-PCR. Western blot was used to determine the protein levels of PPAR- gamma , C/EBP- alpha , and AMP-activated protein kinase- alpha (AMPK- alpha ). The CDAP extract suppressed the differentiation of 3T3-L1 adipocytes by downregulating cellular induction of PPAR- gamma , C/EBP- alpha , and lipin-1. The CDAP extract also significantly upregulated phosphorylation of AMPK- alpha . An in vivo study showed that CDAP induced weight loss in mice with high-fat-diet-induced obesity. These results indicate that CDAP has a potent anti obesity effect due to the inhibition of adipocyte differentiation and adipogenesis. PMID- 24171042 TI - Sang-qi Granula Reduces Blood Pressure and Myocardial Fibrosis by Suppressing Inflammatory Responses Associated with the Peroxisome Proliferator-Activated Receptors and Nuclear Factor kappa B Protein in Spontaneously Hypertensive Rats. AB - Aim. Sang-qi Granula (SQ) is a compound prepared from Chinese herbs and is currently used for treatment of hypertension in China. Given its protective effects on cardial function in decreasing blood pressure, we investigated the mechanism of protective effects of SQ on myocardium. Methods. 16 male normal Wistar-Kyoto rats and 16 spontaneous hypertension rats (SHR) were employed without medical treatment. 16 SHR were employed with SQ treatment. Rats in each group were sacrificed at two time points (8-week treatment and 16-week treatment). Blood pressure (BP), and heart weight/body weight (HW/BW) were measured. The expression of myeloperoxidase (MCP-1), ICAM-1, TNF- alpha , and CD68-positive cells was assessed. The interstitial collagen volume fraction (CVF), perivascular collagen volume area (PVCA), and the expression of TGF- beta , Smad-3, PPAR alpha , gamma , and NF- kappa B (P65 and P50) were observed. Results. SQ significantly inhibited the elevation of the blood pressure and HW/BW of SHR. Next, SQ prevented myocardial fibrosis. Finally, a proinflammatory mediator associated with NF- kappa B (TNF- alpha , ICAM-1, MCP-1, CD68), TGF- beta , and Smad-3 related to collagen deposition, which is upregulated in SHR group, was significantly suppressed by SQ. Expression of NF- kappa B was decreased in SHQ+SQ group compared to PPAR alpha , and gamma expression was increased by SQ. Conclusion. Treatment with SQ ameliorates cardial fibrosis induced by hypertension by attenuating the upregulation of ICAM-1, TNF- alpha , MCP-1, TGF- beta , Smad-3, P65, and P50 expression and improving PPAR alpha and PPAR gamma expression level. The results suggest that SQ may be an option for preventing cardial fibrosis through PPAR signalling pathway. PMID- 24171043 TI - Redox Mechanisms of AVS022, an Oriental Polyherbal Formula, and Its Component Herbs in Protection against Induction of Matrix Metalloproteinase-1 in UVA Irradiated Keratinocyte HaCaT Cells. AB - Ayurved Siriraj HaRak (AVS022) formula has been used for topical remedy of dermatologic disorders. Oxidative stress induced by ultraviolet (UV) A irradiation could be implicated in photoaged skin through triggering matrix metalloproteinase-1 (MMP-1). We, therefore, explored the antioxidant mechanisms by which AVS022 formulation and its individual components protected against UVA dependent MMP-1 upregulation in keratinocyte HaCaT cells. TLC analysis revealed the presence of multiple phenolics including gallic acid (GA) in the AVS022 extracts. We demonstrated that pretreatment with the whole formula and individual herbal components except T. triandra protected against increased MMP-1 activity in irradiated HaCaT cells. Moreover, all herbal extracts and GA, used as the reference compound, were able to reverse cytotoxicity, oxidant production, glutathione (GSH) loss, and inactivation of catalase and glutathione peroxidase (GPx). F. racemosa was observed to yield the strongest abilities to abolish UVA mediated induction of MMP-1 and impairment of antioxidant defenses including GSH and catalase. Our observations suggest that upregulation of endogenous antioxidants could be the mechanisms by which AVS022 and its herbal components suppressed UVA-stimulated MMP-1 in HaCaT cells. In addition, pharmacological actions of AVS022 formula may be attributed to the antioxidant potential of its components, in particular F. racemosa, and several phenolics including GA. PMID- 24171044 TI - Automatic lane segmentation in TLC images using the continuous wavelet transform. AB - This paper describes a new methodology for lane detection in Thin-Layer Chromatography images. An approach based on the continuous wavelet transform is used to enhance the relevant lane information contained in the intensity profile obtained from image data projection. Lane detection proceeds in three phases: the first obtains a set of candidate lanes, which are validated or removed in the second phase; in the third phase, lane limits are calculated, and subtle lanes are recovered. The superior performance of the new solution was confirmed by a comparison with three other methodologies previously described in the literature. PMID- 24171045 TI - Principal feature analysis: a multivariate feature selection method for fMRI data. AB - Brain decoding with functional magnetic resonance imaging (fMRI) requires analysis of complex, multivariate data. Multivoxel pattern analysis (MVPA) has been widely used in recent years. MVPA treats the activation of multiple voxels from fMRI data as a pattern and decodes brain states using pattern classification methods. Feature selection is a critical procedure of MVPA because it decides which features will be included in the classification analysis of fMRI data, thereby improving the performance of the classifier. Features can be selected by limiting the analysis to specific anatomical regions or by computing univariate (voxel-wise) or multivariate statistics. However, these methods either discard some informative features or select features with redundant information. This paper introduces the principal feature analysis as a novel multivariate feature selection method for fMRI data processing. This multivariate approach aims to remove features with redundant information, thereby selecting fewer features, while retaining the most information. PMID- 24171046 TI - An unusual case of Waldenstrom's macroglobulinemia presented with nasopharyngeal involvement. AB - We report a rare case of a 68-year-old male who presented with fever, weight loss, nasal blockage, and epistaxis. Examination revealed cervical and axillary lymphadenopathy with no evidence of organomegaly. On evaluation, bone marrow aspiration showed lymphoplasmacytic infiltration. The computed tomography of the neck showed nasopharyngeal mass and the biopsy of this mass and cervical lymph node showed lymphoplasmacytic lymphoma (LPL) with high serum IgM level. Hence, a diagnosis of Waldenstrom's macroglobulinemia (WM) was made. The patient received six cycles of chemotherapy with a combination of cyclophosphamide, vincristine, and prednisolone (COP regimen). Currently, the patient is under follow-up and in complete remission (CR), one year after completion of therapy. Nasopharyngeal involvement is extremely rare in WM, and hence we report this case. PMID- 24171047 TI - Assessment of the clinical utility of the Gail model in estimating the risk of breast cancer in women from the Indian population. AB - INTRODUCTION: Breast cancer screening programmes are based on various risk models to assess the risk of breast cancer in the general population. The aim of the present study is to predict the efficacy of the Gail model (GM) in the Indian population. We did a retrospective calculation of the Gail score from the hospital records of patients with breast cancer and benign breast disease. MATERIALS AND METHODS: The Gail score was calculated in three groups. The three groups were made up of 104 patients with confirmed breast cancer (Group A), 100 patients with confirmed benign breast diseases (Group B), and 100 patient attendants (Group C). STATISTICAL ANALYSIS: The data analysis was done using SPSS 15.0, Medcal 9.0.1. RESULTS: The median Gail score in the three groups of patients was 7.5+/-3.04 in patients with breast cancer, 8.2+/-1.4 in patients with benign breast diseases, and 7.8+/-1.7 in normal people. The median Gail score was lower in patients with breast cancer when compared with normal people. CONCLUSION: The GM is not useful in identifying the risk of breast cancer in Indian women. There is a need for further studies to evaluate other genetic and environmental factors to create an appropriate model for the Indian population. PMID- 24171048 TI - Thymoma associated with hypogammaglobulinaemia and pure red cell aplasia. AB - Thymomas are neoplasias that begin in the thymus and develop in the anterior mediastinum. They are commonly associated with a variety of systemic and autoimmune disorders, such as pure red cell aplasia, hypogammaglobulinaemia, pancytopaenia, collagen diseases, and, most commonly, myasthenia gravis. The presence of inter-current infections, especially diarrhoea and pneumonia, in the presence of lymphocyte B depletion and hypogammaglobulinaemia is known as Good's syndrome and may affect up to 5% of patients with thymoma. While anaemia is present in 50%-86% of patients with Good's syndrome, only 41.9% of cases present pure red cell aplasia. Concomitance of these two conditions has only been rarely studied. We report on the case of a 55-year-old man diagnosed with advanced thymoma, who, during the progression of his disease, developed signs and symptoms suggesting Good's syndrome and pure red cell aplasia. We also performed a brief review of the literature concerning this association, its clinical characteristics, and treatment. PMID- 24171050 TI - Re-irradiation with hypo-fractionated stereotactic robotic radiotherapy for salvage in adult patients with brainstem glioma. AB - PURPOSE: Brainstem glioma (BSG) is often treated with definitive irradiation. However, subsequent progression and death occur as a rule rather than the exception, after varying periods of control. The outlook of patients with post irradiation progression is dismal, and most of these patients are treated with supportive care alone. Despite the obvious risks with an area as critical as the brainstem, it is a possibility to encounter situations wherein the patients (themselves or their associates) ask for re-irradiation, with the hope of a few extra months of life. The risk of radiation-induced brainstem toxicity may be justifiable under the strict assumption that the patients stand a chance of benefiting from re-irradiation but still may not live long enough to manifest brainstem toxicity. METHODS: Five adult BSG patients were treated with re irradiation using robotic-arm stereotactic radiation therapy (SRT) between September 2009 and July 2012, primarily at the request of the concerned patient parties. Re-irradiation doses ranged from 16 to 25 Gray (Gy) delivered by robotic arm stereotactic irradiation in 2-5 fractions. RESULTS: Four out of five patients enjoyed a prolongation of survival in the order of months (three, five, six, and 14 months), which was very significant given that all patients had severe neurological compromise and poor performance status prior to re-irradiation. One patient has survived 36 months after re-irradiation and thus has lived long enough to manifest late radiation-induced brainstem toxicity. CONCLUSION: Despite the obvious risks of brainstem toxicity associated with the use of re-irradiation for BSG, the use of fractionated stereotactic re-irradiation seems to offers prospects of additional periods of local control and augments duration of life. PMID- 24171049 TI - Vitamin supplement consumption and breast cancer risk: a review. AB - BACKGROUND: Breast cancer is the most frequently diagnosed cancer globally, and studies provide contradictory results about the possible effects of vitamin supplementation to reduce cancer risk. Our aim was to conduct a review to better investigate whether vitamin supplements given orally modify breast cancer risk. METHODS: We conducted a comprehensive, systematic bibliographic search of the medical literature to identify relevant studies. Case-control, cohort studies, and randomised controlled trials (RCTs) published up to August 2013 that reported cancer risk estimates for vitamin supplementation were included. For each study, we retrieved study characteristics, study population, exposure evaluation, and risk estimates. RESULTS: We identified 26 studies (14 cohort, 11 case-control, and one RCT) and overall, we found 104 estimates. We grouped all the estimates into six supplementation categories: vitamin A and beta-carotene, B-group vitamins and folic acid, vitamin C, vitamin D, vitamin E, and multivitamins. Only a few studies showed a statistically significant association between the consumption of supplemental vitamins and the occurrence of breast cancer, and most of the significant estimates were found in case-control studies. The results found in prospective studies seem to be in the opposite direction. CONCLUSION: The role of vitamin supplements in preventing breast cancer still remains unclear, considering our review. Although biologic mechanisms exist to support the anticancer effects of vitamins, there is no clear evidence for an effect in cancer prevention for vitamin supplements. Further investigations are warranted to elucidate the mechanisms by which vitamin supplementation can modify breast cancer development. PMID- 24171051 TI - Report on the 2013 European Multidisciplinary Cancer Congress-ECC 17, Amsterdam, 27 September-1 October 2013: nursing highlights. AB - The European Cancer Organisation (ECCO) was founded on the ideas of the former Federation of European Cancer Societies (FECS). The ECCO was officially announced at the European Cancer Conference in Barcelona in September 2007, replacing the FECS as a dynamic new entity. Through its members, the ECCO represents the interests of over 50,000 professionals in oncology. The ECCO continues to expand its outreach and education through its prestigious biennial series of Congresses. This report highlights the nursing contributions at the seventeenth ECCO Congress in Amsterdam. At the congress, there were more than 17,000 professionals involved in the struggle against cancer. A record number of abstracts (3306) were submitted, almost 40% more than the 2011 conference. Related topics during nursing sessions were often aimed at investigating the meaning of the multidisciplinary approach and what it implies for daily practice under different profiles. The debates showed that the multidisciplinary approach primarily means 'new challenges' for all the practitioners involved. The main challenge for nurses is to meet the needs of a rapidly changing society with some European peculiarities, such as the ageing population, the escalating costs of healthcare in a period of economic crises, fast changing treatments, changes in cancer services and the way nurses deliver care, and multidisciplinary empowerment as a modern concept of care. In this landscape, we also have to consider that cancer often becomes a chronic disease with an increasing number of treatment lines, an increasing number of survivors, and more conscious and exigent patients. We also have to consider the importance of diversity in cancer care. PMID- 24171053 TI - Moist heat or dry heat for delayed onset muscle soreness. AB - BACKGROUND: Heat is commonly used in physical therapy following exercise induced delayed onset muscle soreness (DOMS). Most heat modalities used in a clinical setting for DOMS are only applied for 5 to 20 minutes. This minimal heat exposure causes little, if any, change in deep tissue temperature. For this reason, long duration dry chemical heat packs are used at home to slowly and safely warm tissue and reduce potential heat damage while reducing pain associated from DOMS. Clinically, it has been shown that moist heat penetrates deep tissue faster than dry heat. Therefore, in home use chemical moist heat may be more efficacious than dry heat to provide pain relief and reduce tissue damage following exercise DOMS. However, chemical moist heat only lasts for 2 hours compared to the 8 hours duration of chemical dry heat packs. The purpose of this study was to compare the beneficial effect of dry heat versus moist heat on 100 young subjects after exercise induce DOMS. METHODS: One hundred subjects exercised for 15 minutes accomplishing squats. Before and for 3 days after, strength, muscle soreness, tissue resistance, and the force to passively move the knee were recorded. Heat and moist heat were applied in different groups either immediately after exercise or 24 hours later. RESULTS: The research results of this study showed that immediate application of heat, either dry (8 hours application) or moist (2 hours application), had a similar preservation of quadriceps muscle strength and muscle activity. Results also revealed that the greatest pain reduction was shown after immediate application of moist heat. Never the less, immediate application of dry heat had a similar effect but to a lesser extent. CONCLUSION: It should be noted that moist heat had not only similar benefits of dry heat but in some cases enhanced benefits, and with only 25% of the time of application of the dry heat. PMID- 24171052 TI - The role of vitamin d in autoimmune hepatitis. AB - Autoimmune hepatitis is an inflammation of the liver characterized by the presence of peri-portal hepatitis, hypergammaglobulinemia, and the serum autoantibodies. The disease is classified into 2 distinct types according to the nature of auto-antibodies. Disturbances of the calcium-parathyroid hormone vitamin D axis are frequently associated with chronic liver disease. Patients with AIH have a high prevalence of vitamin D deficiency. Genetic studies have provided the opportunity to determine which proteins link vitamin D to AIH pathology, namely, the major histocompatibility complex class II molecules, vitamin D receptors, toll-like receptors, cytotoxic T lymphocyte antigen-4, cytochrome P450 CYP2D6, regulatory T cells (Tregs) and the forkhead/winged helix transcription factor 3. Vitamin D also exerts its effect on AIH through non genomic factors, namely, mitogen-activated protein kinase signaling pathways, gammadeltaT cells, interferon-gamma nitric oxide synthase, and reactive oxygen stress. In conclusion, vitamin D may have a beneficial role in AIH and improves liver function in concanavalin A-induced mouse AIH. Calcitriol is best used for AIH because it is the active form of a vitamin D3 metabolite and its receptors are present in sinusoidal endothelial cells, Kupffer cells, stellate cells of normal livers, and the biliary cell line. PMID- 24171054 TI - Co-infections in children hospitalised for bronchiolitis: role of roomsharing. AB - BACKGROUND: Bronchiolitis is a major cause for hospitalisation in young children during the winter season, with respiratory syncytial virus (RSV) as the main causative virus. Apart from standard hygiene measures, cohorting of RSV-infected patients separately from RSV-negative patients is frequently applied to prevent cross-infection, although evidence to support this practice is lacking. The objective is to evaluate the risk of room sharing between RSV-positive and RSV negative patients. METHODS: We performed a prospective observational cohort study in children < 2 years hospitalised with acute bronchiolitis. During the first day of admission, patients shared one room, pending results of virological diagnosis (PCR). When diagnostic results were available, RSV-positive and RSV-negative patients were separated. Standard hygienic measures (gowns, gloves, masks, hand washing) were used in all patients. RESULTS: We included 48 patients (83% RSV positive). Co-infection was found in nine patients at admission, and two during hospitalisation (23%). The two patients with acquired co-infection had been nursed in a single room during the entire admission. None of 37 patients sharing a room with other bronchiolitis patients (20 with patients with a different virus) were co-infected during admission. Disease severity in co-infection was not worse than in mono-infection. CONCLUSION: One in five patients with bronchiolitis was co-infected, but co-infection acquired during admission was rare and was not associated with more severe disease. Room sharing between RSV positive and RSV-negative patients (on the first day of admission) did not influence the risk of co-infection, suggesting that cohorting of RSV-infected patients separate from non-RSV-infected patients may not be indicated. PMID- 24171055 TI - Efficacies of Controlling Morning Blood Pressure and Protecting the Kidneys by Treatment With Valsartan and Nifedipine CR or Valsartan and Amlodipine (MONICA Study). AB - BACKGROUND: It is controversial whether a single-pill fixed-dose combination of angiotensin II type 1 receptor blocker and calcium channel blocker (CCB) is effective for all types of hypertension. METHODS: Thirty-five patients with uncontrolled blood pressure (BP) under treatment with valsartan 80 mg/day or amlodipine 5 mg/day were enrolled. They were randomly divided into two treatment groups: a single-pill fixed-dose combination of valsartan 80 mg/day and amlodipine 5 mg/day in the morning (VA group), or valsartan 80 mg/day in the morning and nifedipine CR 20 mg/day at night (VN group), and treated for 16 weeks. If the patient did not reach the target office BP at 8 weeks, they received double doses of CCBs. RESULTS: In the VN group, morning diastolic BP was significantly lower than the respective values in the VA group at 8 weeks. The percentage of patients who required a double dose of CCB in the VN group was significantly lower than that in the VA group. At 16 weeks, the BP levels in both groups were significantly reduced. Urinary albumin/creatinine at 16 weeks was significantly less than that at 0 weeks in the VN group. CONCLUSION: Combination therapy with valsartan and nifedipine CR may help to control morning BP and protect the kidneys. PMID- 24171056 TI - Unexplained Syncope and Diagnostic Yield of Tests in Syncope According to the ICD 10 Discharge Diagnosis. AB - BACKGROUND: The etiology of syncope according to the discharge diagnosis from hospital admissions has not been examined before. Therefore the aims of this study were to examine the diagnostic yield of tests and frequency of unexplained cases during admission and after workup after an ICD-10 diagnosis of syncope. METHODS: A retrospective chart review of 600 patients discharged with the primary ICD-10 discharge diagnosis of syncope R55.9 was performed. Causes and clinical characteristics of syncope according to the physician were noted both after initial discharge and after workup. RESULTS: During a mean follow-up period of 2.5 years (SD: +/- 1.30) several diagnostic tests were used (mean number of tests per patient was 4.7 (SD: +/- -2.0)) and the mean length of admission was 2.1 days (+/- 1.5).The final diagnosis after workup was reflex syncope in 21%, cardiac 18%, orthostatic hypotension 10%, other causes 4% and unknown/unexplained syncope in 48% with wide age differences. The diagnostic yield of tests was generally low and differed widely depending on usage during admission or usage during subsequent workup. CONCLUSIONS: The underlying etiology of syncope remains difficult to establish despite the high use of diagnostic tests and the diagnostic yield of many tests implemented in the care path is generally low. PMID- 24171057 TI - Effect of carvedilol on reduction in heart rate in patients with chronic atrial fibrillation. AB - BACKGROUND: Currently, beta-blockers are used most frequently for the purpose of heart rate (HR) control in patients with atrial fibrillation (AF) in worldwide. Carvedilol is one of common beta-blockers and known to be effective for hypertension and heart failure. However, little can be found the information about the HR-lowering effect of carvedilol in patients with AF without heart failure. Therefore, we conducted this study to investigate the effect of carvedilol on HR in 3-minute electrocardiogram (ECG) and total heart beats (THBs) in 24-hour Holter ECG monitoring in patients with persistent or permanent AF. METHODS: A total of 13 hypertensive patients (73 +/- 12 years, 7 males) with AF and HR 90 bpm or more were enrolled. All patients received carvedilol from 5 mg/day. The dose of drug was titrated every 4 weeks and raised to 10 or 20 mg/day if HR was 80 bpm or more. RESULTS: Mean HR was decreased from 101.9 +/- 13.9 to 85.2 +/- 15.2 bpm (P < 0.05) after treatment with carvedilol. THBs were also significantly decreased from 128 to 115 * 1,000/day (P < 0.001). Percent reduction in HR and THBs were 13.9% and 10.7%, respectively. The scores of Atrial Fibrillation Quality of Life Questionnaire (AFQLQ) did not change. Only one patient was required to discontinue carvedilol due to congestive heart failure. CONCLUSIONS: We observed that carvedilol certainly reduced HR in patients with chronic AF. We believe that the effect of carvedilol on the reduction in HR can contribute to the management of AF patients treated with rate-control strategy. PMID- 24171058 TI - Randomized study of ondansetron versus domperidone in the treatment of children with acute gastroenteritis. AB - BACKGROUND: Acute gastroenteritis (AGE) is a common condition among children that is frequently accompanied by vomiting. Symptomatic control of vomiting is important as it improves patient's general condition and reduces the need for intravenous therapy and hospitalization. Antiemetic agents including ondansetron and domperidone are used to provide symptomatic relief but the existing studies do not provide enough evidence of better efficacy for one over another. METHODS: Seventy-six Thai children under the age of 15 with AGE were randomized to receive either ondansetron or domperidone. The primary outcome of the study was the proportion of the patients in each group who had no episode of vomiting 24 hours after the start of treatment. RESULTS: Primary outcome was met in 62% of patients in ondansetron group and 44% of patients in domperidone group (P = 0.16). Patients in domperidone group received more doses of the drug within 24 hours after the start of the treatment compared to ondansetron group (P = 0.01). No adverse effect was observed in any of the two groups. CONCLUSIONS: Ondansetron can be considered a safe comparable alternative to commonly-used domperidone in Thai children who suffer from symptoms of gastroenteritis. Larger clinical trials are needed to further explore the effectiveness of the two medications. PMID- 24171059 TI - Factors affecting myocardial infarction in cervical cancer patients: a population based study. AB - BACKGROUND: Radiotherapy (RT) or concurrent chemoradiation therapy has been suggested to increase the risk of coronary heart disease for cervical cancer patients, but the results of studies have been inconsistent. Therefore, we aimed to investigate the factors which influence the risk of developing myocardial infarction (MI) in cervical cancer patients with a large, nationwide cohort. METHODS: The study analyzed data from the 1996 to 2010 National Health Insurance Research Database provided by the National Health Research Institutes in Taiwan. The assessed number of patients with cervical cancer with radiotherapy only, surgery with bilateral oophorectomy only, and with appendectomy were 308, 323 and 229, respectively. The Kaplan-Meier method and the Cox proportional hazards model were used to assess the risk of myocardial infarction. RESULTS: The adjusted hazard ratio for cervical cancer in patients with MI was 1.97 (95% CI, 0.97 - 3.91; P = 0.05) for the group that received RT alone, and 2.13 (95% CI, 1.11 - 3.75; P = 0.01) for the surgery group when compared with controls. The more risk comorbidities they have, the higher the risk of myocardial infarction would be for the patients. CONCLUSION: The incidence of MI was significantly higher among cervical cancer patients with RT alone or surgery with bilateral oophorectomy alone than among general populations. RT might be as a factor to increase risk as bilateral oophorectomy. Whether RT itself triggers menopause or impairs the ovarian hormone production that increases the risk of MI needs to be further investigated. PMID- 24171060 TI - Motivational interviewing for adherence problems in cystic fibrosis; evaluation of training healthcare professionals. AB - BACKGROUND: Motivational interviewing (MI) offers effective strategies for enhancing behaviour change and is particularly useful for patients who exhibit poor adherence. This study evaluated MI training for cystic fibrosis (CF) teams, which comprised of one 4-hour workshop on MI principles, followed 6 months later by another on applying MI during brief consultations. METHODS: Health professionals (N = 60) from 7 teams completed questionnaires on learning outcomes 6 months after the first workshop, but before the second. Eleven participated in telephone-interview, 3 months after the second workshop. RESULTS: Quantitative analysis showed all participants used MI with a patient at least once after the first workshop and felt the approach was potentially helpful. Although self appraisal of skill and confidence in MI was 'moderate', all felt confident in their ability to develop their skills and almost all intended to use MI in the future. Qualitative analysis confirmed the positive experiences of training and of using MI in practice, particularly in relationship building. However MI was utilised depending on team support and workload pressures. CONCLUSIONS: This study showed that initial MI training with CF team-members resulted in increased knowledge and confidence about acquiring and applying MI techniques. However, this was balanced with consideration of barriers to application, further training needs and ongoing team-based support. PMID- 24171061 TI - A Case of Nephrotic Syndrome With Minimal-Change Disease and Waldenstrom's Macroglobulinemia. AB - Kidney disease is a rare complication of Waldenstrom's macroglobulinemia. We report a case of nephrotic syndrome and minimal change disease in a patient with biopsy proven Waldenstrom's macroglobulinemia. The patient presented with over 12 grams of proteinuria and was successfully treated with oral prednisone over the course of 4 weeks. Repeat serum protein electrophoresis as well as serum immunoelectrophoresis revealed no paraproteins, urine analysis was negative for protein or blood by dipstick and spot urine protein was 9 mg/dL with creatinine of 101 mg/dL at time of last office visit. This case illustrates the successful treatment with corticosteroids alone with prolonged complete remission. PMID- 24171062 TI - Empirical Use of Dopaminergic Agents for Restless Legs Syndrome Could be Associated With a Risk of Iatrogenic Parkinson's Disease. PMID- 24171063 TI - [Treatment failure in children infected with HIV in routine follow-up in a resource-limited setting in Cameroon]. PMID- 24171064 TI - [Pseudocyst of the pancreas drained spontaneously in the colon]. PMID- 24171065 TI - [Centro-facial granuloma revealing a tertiary syphilis]. PMID- 24171066 TI - [Holoprosencephaly alobar amid polymalformative syndrome: contribution of imaging in a case report]. PMID- 24171067 TI - Appendiceal GIST: report of an exceptional case and review of the literature. AB - Gastro-intestinal stromal tumors (GISTs) of the appendix are a rare entity. To date, only eight cases has been described in the literature, most of which have been of the benign type. We report a new case of an appendiceal GIST in a 75-year old man. The tumor was discovered when the patient presented with acute appendiceacal peritonitis. Preoperative diagnosis of appendiceal GIST was rarely done as tumors were usually associated with appendicitis-like symptoms. PMID- 24171068 TI - [Endometriosis of the abdominal wall: report of a rare case]. PMID- 24171069 TI - Intracardiac thrombosis in Behcet's disease: a rare complication. PMID- 24171070 TI - [Diagnosis and treatment of anthrax in palpebral localization: report of a case and review of literature]. PMID- 24171072 TI - Maternal Voluntary Exercise during Pregnancy Enhances the Spatial Learning Acquisition but not the Retention of Memory in Rat Pups via a TrkB-mediated Mechanism: The Role of Hippocampal BDNF Expression. AB - OBJECTIVE(S): The effect of maternal voluntary exercise on hippocampal BDNF level in rat offspring was studied. In addition, the possible role of hippocampal BDNF receptors in maternal exercise induced enhancement of learning in the rat pups was investigated. MATERIALS AND METHODS: Pregnant rats have been randomly assigned to sedentary control or voluntary exercise groups. Each of the exercising pregnant rats was given access to a cage that was equipped with a running wheel until the end of their pregnancy. On post natal day (PND) 36, two groups consisted of 7 male rat pups in each group from sedentary or exercised mothers were sacrificed and the hippocampus was dissected for BDNF proteins level determination. Also, bilateral injection of K252a to the hippocampus was used to block the hippocampal BDNF action on PND59 in the rat pups. RESULTS: Voluntary exercise during pregnancy significantly increased the level of BDNF protein in the hippocampus of the rat pups on PND36 compared to the control group (P=0.048). Inhibiting BDNF action abolished the exercise-induced improvement of learning acquisition in offspring in training trials (P=0.0001). No difference was observed in the platform location latency and the time spent in the target in the probe test between two groups. Conclusion : This study demonstrates that voluntary exercise during pregnancy via a TrkB-mediated mechanism enhances the spatial learning acquisition, however, not the retention of memory in the rat pups. PMID- 24171073 TI - Evaluation of immunological parameters in purified protein derivative positive tuberculin workers. AB - OBJECTIVE(S): According to the occupationally risk of infection in staff workers who have direct contact with mycobacterium species, we investigated their immunological parameters and compared with healthy purified protein derivative (PPD) negative volunteers. Materials and Methods : We investigated 20 PPD positive volunteers working at Tuberculin Unit of Razi Vaccine and Serum Research Institute and PPD negative healthy controls with no exposure or history of active tuberculosis. The percentages of circulating lymphocyte subpopulations were detected by flowcytometry. IL-4 and IFN-gamma production levels were measured by ELISA in supernatants of PPD-stimulated peripheral blood mononuclear cells (PBMCs) culture. Results : Tuberculin workers showed an increase in IFN-gamma level and significant decrease of CD4+ T cells percentage and CD4/CD8 ratio compared to PPD negative normal individuals. However the IL-4 production and percentage of other lymphocyte population has been unchanged. DISCUSSION: These observations suggest that the immunological parameters of tuberculin workers with PPD positive reaction, who are occupationally exposed to mycobacterium antigens, could be changed. Future studies will be directed towards cytokine networking and regulatory lymphocytes, which will help us validate the significant data presented in this study. PMID- 24171071 TI - Pathways to managing atopic dermatitis: consensus from the experts. PMID- 24171074 TI - Sphingomyelin Liposomes Containing Soluble Leishmania major antigens Induced Strong Th2 Immune Response in BALB/c Mice. AB - OBJECTIVE(S): Soluble Leishmania antigens (SLA) provide suitable protection against leishmaniasis in murine model when delivered by an appropriate delivery system. Liposomes have been shown to be suitable vaccine delivery systems against leishmaniasis, however, the phospholipase-A (PLA) activity of SLA is a drawback to prepare a stable liposomal SLA. One strategy to overcome this problem might be using a lipid which is resistant to PLA activity of SLA such as sphingomyelin (SM). The aim of this study was to evaluate the effect of stable SM liposomes containing SLA on the immune response induced against leishmaniasis in BALB/c mice . MATERIALS AND METHODS: BALB/c mice were immunized subcutaneously, three times with 2-week intervals, with SLA, SM-liposome-SLA, empty liposome or buffer. As criteria for protection, footpads swelling at the site of challenge and foot parasite loads were assessed. The immune responses were also evaluated by determination of IgG subtypes and the level of IFN-gamma and IL-4 in cultured splenocytes. RESULTS: The group of mice receiving SM-liposome-SLA, showed a significant large footpad swelling, higher parasite burden in foot and higher IL 4 level compared to the group immunized with buffer. In terms of IgG and IgG isotypes, there was no significant difference between the mice receiving SM liposome-SLA and the mice that received buffer. Moreover, the immune response induced by SM-liposome-SLA showed no significant difference compared with the one caused by SLA alone. CONCLUSION: It is concluded that SM-liposome-SLA is not an appropriate strategy to induce Th1 immune response and protect the mice against Leishmaniasis; however, SM-liposomes could be suitable vaccine delivery systems when a Th2 response is needed. PMID- 24171075 TI - siRNA Delivery Improvement by Co-formulation of Different Modified Polymers in Erythroleukemic Cell Line K562. AB - OBJECTIVE(S): siRNA may be a very promising tool for treatment of various diseases especially in cancer therapy due to high specificity. One of the main hurdles applications of siRNAs in vivo is optimization of the delivery strategy, especially the carrier systems. The aim of this study was to optimize siRNA delivery into suspended erythroleukemic cell line K562. MATERIALS AND METHODS: We applied polyethyleneimine (PEI) and oligoethyleneimine (OEI) derivatives alone or their co-formulation with different agents such as chloroquine (a drug known to alter lysosomal pH and thus to inhibit lysosomal degradation of macromolecules), DOPE (lipophilic agent), succinic acid (introduction of negatively charged to polymer) and transferrin (the ligand of transferring receptor which is over expressed in many types of tumors and hematopoietic cells). RESULTS: In this study it was shown that utilizing a combination of 70% OEI-HA10 (ten hexyl acrylate residues per one OEI chain) plus 30% of transferin-PEI with Luc-siRNA was highly effective for transfecting K562 cell. This co-formulation silenced luciferase activity up to 70% after short time without any significant inhibition in the luciferase activity in siCONTROL wells. CONCLUSION: In conclusion, the combination of modified PEI with transferrin and OEI by hexyl acrylate may increase siRNA delivery and reduce toxicity in hematopoietic suspended cells. PMID- 24171077 TI - Expression of recombinant streptokinase from streptococcus pyogenes and its reaction with infected human and murine sera. AB - OBJECTIVE(S): Streptokinase (SKa) is an antigenic protein which is secreted by Streptococcus pyogenes. Streptokinase induces inflammation by complement activation, which may play a role in post infectious diseases. In the present study, recombinant streptokinase from S. pyogenes was produced and showed that recombinant SKa protein was recognized by infected human sera using Western blot analysis. MATERIALS AND METHODS: In this study, the ska gene from S. pyogenes was amplified and cloned into pET32a which is a prokaryotic expression vector. pET32a ska was transformed to Escherichia coli BL21 (DE3) pLysS and gene expression was induced by IPTG. Protein production was improved by modification of composition of the bacterial culture media and altering the induction time by IPTG. The expressed protein was purified by affinity chromatography using the Ni-NTA resin. The integrity of the product was confirmed by Westernblot analysis using infected mice. Serum reactivity of five infected individuals was further analyzed against the recombinant SKa protein. RESULTS: Data indicated that recombinant SKa protein from S. pyogenes can be recognized by patient and mice sera. The concentration of the purified recombinant protein was 3.2 mg/L of initial culture. The highest amount of the expressed protein after addition of IPTG was obtained in a bacterial culture without glucose with the culture optical density of 0.8 (OD600 = 0.8). Conclusion : Present data shows, recombinant SKa protein has same epitopes with natural form of this antigen. Recombinant SKa also seemed to be a promising antigen for the serologic diagnosis of S. pyogenes infections. PMID- 24171076 TI - Effect of Restraint Stress during Gestation on Pentylenetetrazol-Induced Epileptic Behaviors in Rat Offspring. AB - OBJECTIVE(S): Epilepsy is a neurodevelopmental disorder which is strongly influenced by genetic and environmental factors. Gestational stress has been shown to be an important factor for affecting seizure susceptibility. The present study was conducted to address whether gestational stress may affect pentylentetrazol (PTZ)-induced epileptic behavior in rat offspring in a sex- and age- dependent manner. MATERIALS AND METHODS: Pregnant rats were divided into control and stressed groups (n=6 in each). In the stressed group, pregnant rats were under restraint stress and held immobile in the Plexiglas tube twice per day one hour per session for three consecutive days started on day 17 of pregnancy. To induce seizure, on postnatal days 15 (P15) and 25 (P25), PTZ (40-50 mg/kg, IP) was injected to rat offspring (n=12, one male and one female from any litter for each group/day). Then, epileptic behaviors of each rat were recorded. RESULTS: Epileptic behaviors of stressed pups showed significant changes in comparison to control ones. The time to onset of the first epileptic behavior was shortened while mean duration and frequency of tonic-clonic attacks increased in stressed pups on both P15 and P25. Female offspring were different from male offspring in terms of epileptic behavior. Moreover, focal attacks were more obvious and significantly longer in the offspring of stressed group at the age of 25 days than those of 15 day old. CONCLUSION: Prenatal restraint stress potentiated PTZ induced epileptic behavior, age and sex dependently, probably due to alteration of neural and endocrine pathways during developmental process. Male and younger rats were more sensitive to stress than female and older ones. PMID- 24171078 TI - Genetic Variations of Tumor Necrosis Factor -alpha-308 and Lymphtoxin-alpha+252 in Non-Hodgkin Lymphoma and Acute Lymphoblastic Leukemia Patients. AB - OBJECTIVE(S): Non- Hodgkin lymphoma (NHL) and acute lymphoblastic leukemia (ALL) are two main hematological malignances which have been driven from lymphoid tissue. Genetic polymorphisms in tumor necrosis factor-alpha (TNF-alpha) -308 and lymphotoxin-alpha (LT-alpha) +252 may affect their transcription and expression which leads to their high plasma level. The frequency of the TNF-alpha (-308) and LT-alpha (+ 252) polymorphisms are different for NHL and ALL cases in various populations with different ethnicity. This research is designed to investigate the prevalence and association of TNF-alpha (-308) and LT-alpha (+ 252) polymorphisms from NHL and ALL in Azarian patients and healthy individuals from Northwestern part of Iran. MATERIALS AND METHODS: Seventy subjects with ALL and 68 NHL, along with another 130 healthy subjects as control group took part in this study. Genomic DNA was extracted, then genetic polymorphisms in TNF-alpha and LT-alpha genes were analyzed with the PCR-RFLP and NCOI as restriction enzyme. A statistical analysis was performed by chi-square test using SPSS software. A P-value of <0.05 was considered statistically significant. RESULTS: A statistically significant difference of LT-alpha polymorphism was in NHL patients and control (P-value= 0.008) but there was not any association of TNF-alpha polymorphism between NHL patients and control group. A significant association for TNF-a variant was in ALL and control (P-value =0.005), however, there was no relationship about LT variant between ALL and control. CONCLUSION: The results show that there are significant differences between TNF-alpha (-308) and LT-alpha (+252) genetic polymorphisms respectively in ALL and NHL patients with control group from Northwestern part of Iran. PMID- 24171079 TI - Effects of multivitamins and known teratogens on chick cardiomyocytes micromass culture assay. AB - OBJECTIVE(S): This study aimed to find out whether the chick cardiomyocyte micromass (MM) system could be employed to predict the teratogenecity of common environmental factors. Different multivitamins and over the counter drugs were used in this study. MATERIALS AND METHODS: White Leghorn 5-day-old embryo hearts were dissected and trypsinized to produce a cardiomyocyte cell suspension in Dulbecco's Modified Eagle's Medium. The cultures were incubated at 37(0)C in 5% CO2 in air, and observations were made at 24, 48 and 144 hr, for the detection of cell beating. Cellular viability was assessed using the resazurin assay and cell protein content was assessed by the kenacid blue assay. It was observed that while not affecting total cell number folic acid, vitamin C, sodium fluoride and ginseng did not significantly reduced cell activity and beating. However cadmium chloride significantly reduced the beating, cell viability and cell protein content in micromass cultures. RESULTS: The results demonstrate the potential of the chick cardiomyocyte MM culture assay to identify teratogens/embryotoxins that alter morphology and function, which may result in either teratogenic outcome or cytotoxicity. CONCLUSION: This could form part of a screen for developmental toxicity related to cardiac function. PMID- 24171080 TI - Improvement in Memory and Brain Long-term Potentiation Deficits Due to Permanent Hypoperfusion/Ischemia by Grape Seed Extract in Rats. AB - OBJECTIVE(S): Cerebral hypoperfusion/ischemia (CHI) is a neurological disease where impaired hippocampus electrical activity and cognition caused by a serial pathophysiological events. This study aimed to evaluate the effects of chronic oral administration of grape seed extract (GSE) on passive avoidance memory and long-term potentiation (LTP) after permanent bilateral common carotid arteries occlusion (2CCAO) in male adult rats. MATERIALS AND METHODS: Thirty-two adult male Wistar rats were randomly divided into: 1) Sham+Veh, 2) Isch+Veh, 3) Sham+GSE, 4) Isch+GSE. In order to make 2CCAO as an animal model of CHI, carotid arteries were ligatured and then cut bilaterally. To evaluation of passive avoidance memory, step-down latency (STL) was measured and LTP was recorded from hippocampal dentate gyrus (DG) after high frequency stimulation (HFS) in all rats. RESULTS: We found that memory was significantly impaired in rats after CHI (P<0.001) concomitant with hippocampal LTP inhibition (P<0.05, P<0.01 for LTP1 and LTP48 respectively). GSE treatment significantly improved memory impairment and increased hippocampal LTP in rats with 2CCAO. CONCLUSION: Our results in present study suggest that GSE exhibits therapeutic potential for short-and long term memories as well as LTP in DG, which is most likely related at least in part to its antioxidative and free radical scavenging actions. PMID- 24171081 TI - Association of urinary lipocalin-2 with lupus nephritis. AB - OBJECTIVE(S): Lupus nephritis (LN) is the main cause of mortality and disability in systemic lupus erythematosus (SLE) patients. Therefore, utilizing a reliable and non-invasive method for serial measurements of renal function seems to be necessary. The aim of this study was to evaluate the role of urinary lipocalin-2 as a biomarker of renal involvement in SLE patients. MATERIALS AND METHODS: Fifty two lupus patients in this cross sectional study were divided into two groups: patients with and without nephritis. For each group, urinary lipocalin-2, values were measured and reported according to urinary lipocalin-2/creatinine. Urinary lipocalin-2/creatinine sensitivity and specificity for identifying biopsy-proven nephritis were calculated, and a receiver operating characteristic (ROC) curve was constructed. Results : The mean urinary lipocalin-2/creatinine value of patients with biopsy-proven LN was 2.99 +/- 4.1 ng/mg, and in non-LN patients was 1.16 +/- 1.27 ng/mg. Urinary lipocalin-2/creatinine levels in LN patients were significantly higher than those in non-LN patients (P- Value = 0.03). In LN patients, urinary lipocalin-2/creatinine significantly correlated with proteinuria (r = 0.68; P = 0.0001). Using a cutoff value of 0.896 ng/mg, urinary lipocalin-2/creatinine had a sensitivity of 89.7% and a specificity of 39.1% for identifying SLE patients with biopsy-proven LN. The area under the ROC curve was 0.664 +/- 0.076 with a 95% confidence interval of 0.52-0.81 (P=0.04). Analysis of variance showed that urinary lipocalin-2/creatinine is the same in different classes of LN (P-value=0.28). CONCLUSION: An important clinical conclusion is that measurement of urinary Lipocalin-2 may result in earlier diagnosis of LN. PMID- 24171082 TI - Docking studies of phthalimide pharmacophore as a sodium channel blocker. AB - OBJECTIVE(S): Recently, phthalimide derivatives were designed based on ameltolide and thalidomide as they possess a similar degree of anticonvulsant potency due to their phenytoin-like profile. The ability of phthalimide pharmacophore to interact with neuronal voltage-dependent sodium channels was studied in the batrachotoxin affinity assay. Therefore, in the present study, a series of 19 compounds of phthalimide pharmacophore possessing a variety of substituents (NO2, NH2, Me, Cl, COOH, MeO) at 2-, 3-, and 4- position of the N-phenyl ring and N-(3 amino-2-methylphenyl) succinimide, were subjected to docking studies in order to inhibit voltage-gated sodium channels. Materials and Methods : Chemical structures of all compounds were designed using HYPERCHEM program and Conformational studies were performed through semi-empirical molecular orbital calculations method followed by PM3 force field. Total energy gradient calculated as a root mean square (RMS) value, until the RMS gradient was 0.01 kcal mol(-1). Among all energy minima conformers, the global minimum of compounds was used in docking calculations. Using a model of the open pore of Na channels, docking study was performed by AUTODOCK4.2 program. Results : Docking studies have revealed that these types of ligands interacted mainly with II-S6 residues of NaV1.2 through making hydrogen bonds and have additional hydrophobic interactions with domain I, II, III and IV in the channel's inner pore. CONCLUSION: These computational studies have displayed that these compounds are capable of inhibiting Na channel, efficiently. PMID- 24171085 TI - Executive summary. PMID- 24171083 TI - Preface. PMID- 24171086 TI - 1 introduction. PMID- 24171088 TI - 3 beam delivery and properties. PMID- 24171087 TI - 2 radiation biology considerations. PMID- 24171089 TI - 4 dosimetry. PMID- 24171090 TI - 5 geometric terms, and dose and dose-volume definitions. PMID- 24171091 TI - 6 treatment planning. PMID- 24171092 TI - 7 motion management. PMID- 24171093 TI - 8 estimation and presentation of uncertainty in the delivered dose. PMID- 24171094 TI - 9 quality assurance. PMID- 24171095 TI - 10 prescribing, recording, and reporting treatment. PMID- 24171096 TI - Appendix a: implementation of the trs 398 code of practice for ionization chamber dosimetry. PMID- 24171097 TI - Appendix B: clinical examples. PMID- 24171101 TI - Bone cell communication factors and Semaphorins. AB - Bone tissue is continuously renewed throughout adult life by a process called 'remodeling', which involves a dynamic interplay among bone cells including osteoclasts, osteoblasts and osteocytes. For example, a tight coupling between bone resorption and formation is essential for the homeostasis of the skeletal system. Studies on the coupling mechanism in physiological and pathological settings have revealed that osteoclasts or osteoclastic bone resorption promote bone formation through the production of diverse coupling factors. The classical coupling factors are the molecules that promote bone formation after resorption, but there may be distinct mechanisms at work in various phases of bone remodeling. A recent study revealed that the Semaphorin 4D expressed by osteoclasts inhibits bone formation, which represents a mechanism by which coupling is dissociated. Furthermore, it has been demonstrated that osteoblastic expression of Semaphorin 3A exerts an osteoprotective effect by both suppressing bone resorption and increasing bone formation. Thus, recent advances have made it increasingly clear that bone remodeling is regulated by not only classical coupling factors, but also molecules that mediate cell-cell communication among bone cells. We propose that such factors be called bone cell communication factors, which control the delicate balance of the interaction of bone cells so as to maintain bone homeostasis. PMID- 24171102 TI - A genome-to-genome analysis of associations between human genetic variation, HIV 1 sequence diversity, and viral control. AB - HIV-1 sequence diversity is affected by selection pressures arising from host genomic factors. Using paired human and viral data from 1071 individuals, we ran >3000 genome-wide scans, testing for associations between host DNA polymorphisms, HIV-1 sequence variation and plasma viral load (VL), while considering human and viral population structure. We observed significant human SNP associations to a total of 48 HIV-1 amino acid variants (p<2.4 * 10(-12)). All associated SNPs mapped to the HLA class I region. Clinical relevance of host and pathogen variation was assessed using VL results. We identified two critical advantages to the use of viral variation for identifying host factors: (1) association signals are much stronger for HIV-1 sequence variants than VL, reflecting the 'intermediate phenotype' nature of viral variation; (2) association testing can be run without any clinical data. The proposed genome-to-genome approach highlights sites of genomic conflict and is a strategy generally applicable to studies of host-pathogen interaction. DOI:http://dx.doi.org/10.7554/eLife.01123.001. PMID- 24171106 TI - Proteins pinpoint double strand breaks. AB - Combining green fluorescent protein with a protein that only binds to double strand breaks in DNA allows these breaks-which are an important form of DNA damage-to be detected with high efficiency in living bacteria. PMID- 24171107 TI - Morphologic Changes in the Foveal Photoreceptor Layer before and after Laser Treatment in Acute and Chronic Central Serous Chorioretinopathy Documented in Spectral-Domain Optical Coherence Tomography. AB - Purpose. To analyze microstructural changes in the external limiting membrane (ELM) and photoreceptor layer before and after early and late conventional laser treatment in central serous chorioretinopathy (CSC) in 12 months follow-up study. Methods. A retrospective observational study included Group A: 19 patients (19 eyes) with symptomatic acute CSC and Group B: 16 patients (16 eyes) with symptomatic chronic CSC. Retinal microstructural changes were analyzed with SD OCT paying a particular role in examining the photoreceptor layer and ELM. Results. The length of the photoreceptors, prior to treatment, was approximately 84 MU m in Group A and 82,5 MU m in Group B. Twelve months after laser treatment, photoreceptor length was approximately 49 MU m in Group A and 43 MU m (range 20-55 MU m) in Group B. No patients in Group A had noticeable photoreceptor defects nor ELM defects, but in 15 eyes in Group B photoreceptor and ELM defects were detected (P < 0.0001). Conclusions. When analyzing the photoreceptor layer and ELM during active CSC, it is not possible to evaluate any irreversible changes which have already occurred in this layer. Damage to the photoreceptor layer and ELM in patients with chronic CSC was only found after laser treatment and the absorption of subretinal fluid. PMID- 24171105 TI - Structure and function of the Smoothened extracellular domain in vertebrate Hedgehog signaling. AB - The Hedgehog (Hh) signal is transduced across the membrane by the heptahelical protein Smoothened (Smo), a developmental regulator, oncoprotein and drug target in oncology. We present the 2.3 A crystal structure of the extracellular cysteine rich domain (CRD) of vertebrate Smo and show that it binds to oxysterols, endogenous lipids that activate Hh signaling. The oxysterol-binding groove in the Smo CRD is analogous to that used by Frizzled 8 to bind to the palmitoleyl group of Wnt ligands and to similar pockets used by other Frizzled-like CRDs to bind hydrophobic ligands. The CRD is required for signaling in response to native Hh ligands, showing that it is an important regulatory module for Smo activation. Indeed, targeting of the Smo CRD by oxysterol-inspired small molecules can block signaling by all known classes of Hh activators and by clinically relevant Smo mutants. DOI:http://dx.doi.org/10.7554/eLife.01340.001. PMID- 24171103 TI - Engineered proteins detect spontaneous DNA breakage in human and bacterial cells. AB - Spontaneous DNA breaks instigate genomic changes that fuel cancer and evolution, yet direct quantification of double-strand breaks (DSBs) has been limited. Predominant sources of spontaneous DSBs remain elusive. We report synthetic technology for quantifying DSBs using fluorescent-protein fusions of double strand DNA end-binding protein, Gam of bacteriophage Mu. In Escherichia coli GamGFP forms foci at chromosomal DSBs and pinpoints their subgenomic locations. Spontaneous DSBs occur mostly one per cell, and correspond with generations, supporting replicative models for spontaneous breakage, and providing the first true breakage rates. In mammalian cells GamGFP-labels laser-induced DSBs antagonized by end-binding protein Ku; co-localizes incompletely with DSB marker 53BP1 suggesting superior DSB-specificity; blocks resection; and demonstrates DNA breakage via APOBEC3A cytosine deaminase. We demonstrate directly that some spontaneous DSBs occur outside of S phase. The data illuminate spontaneous DNA breakage in E. coli and human cells and illustrate the versatility of fluorescent Gam for interrogation of DSBs in living cells. DOI:http://dx.doi.org/10.7554/eLife.01222.001. PMID- 24171108 TI - Simple, inexpensive technique for high-quality smartphone fundus photography in human and animal eyes. AB - Purpose. We describe in detail a relatively simple technique of fundus photography in human and rabbit eyes using a smartphone, an inexpensive app for the smartphone, and instruments that are readily available in an ophthalmic practice. Methods. Fundus images were captured with a smartphone and a 20D lens with or without a Koeppe lens. By using the coaxial light source of the phone, this system works as an indirect ophthalmoscope that creates a digital image of the fundus. The application whose software allows for independent control of focus, exposure, and light intensity during video filming was used. With this app, we recorded high-definition videos of the fundus and subsequently extracted high-quality, still images from the video clip. Results. The described technique of smartphone fundus photography was able to capture excellent high-quality fundus images in both children under anesthesia and in awake adults. Excellent images were acquired with the 20D lens alone in the clinic, and the addition of the Koeppe lens in the operating room resulted in the best quality images. Successful photodocumentation of rabbit fundus was achieved in control and experimental eyes. Conclusion. The currently described system was able to take consistently high-quality fundus photographs in patients and in animals using readily available instruments that are portable with simple power sources. It is relatively simple to master, is relatively inexpensive, and can take advantage of the expanding mobile-telephone networks for telemedicine. PMID- 24171104 TI - Global cellular response to chemotherapy-induced apoptosis. AB - How cancer cells globally struggle with a chemotherapeutic insult before succumbing to apoptosis is largely unknown. Here we use an integrated systems level examination of transcription, translation, and proteolysis to understand these events central to cancer treatment. As a model we study myeloma cells exposed to the proteasome inhibitor bortezomib, a first-line therapy. Despite robust transcriptional changes, unbiased quantitative proteomics detects production of only a few critical anti-apoptotic proteins against a background of general translation inhibition. Simultaneous ribosome profiling further reveals potential translational regulation of stress response genes. Once the apoptotic machinery is engaged, degradation by caspases is largely independent of upstream bortezomib effects. Moreover, previously uncharacterized non-caspase proteolytic events also participate in cellular deconstruction. Our systems-level data also support co-targeting the anti-apoptotic regulator HSF1 to promote cell death by bortezomib. This integrated approach offers unique, in-depth insight into apoptotic dynamics that may prove important to preclinical evaluation of any anti cancer compound. DOI:http://dx.doi.org/10.7554/eLife.01236.001. PMID- 24171109 TI - Association between Salt Intake and Albuminuria in Normotensive and Hypertensive Individuals. AB - Background. There is a little published data regarding the association between salt intake and albuminuria as an important alarm for progression of cardiovascular and renal dysfunction. We aimed to assess this relationship to emphasize the major role of restricting salt intake to minimize albuminuria and prevent these life-threatening events. Methods. The study population comprised 820 individuals. Participants were assigned to groups as follows: normal albuminuria, slight albuminuria, and clinical albuminuria. Daily salt intake was assessed on the basis of 24-hour urinary sodium excretion, since urinary sodium excretion largely equals sodium intake. Results. In normotensive participants, the mean level of urine albumin was higher in those who had higher amounts of salt intake with a significantly upward trend (the mean urinary albumin level in low-salt-diet group, in medium-salt-intake group, and in high-salt-intake group was 42.70 +/- 36.42, 46.89 +/- 38.91, and 53.38 +/- 48.23, resp., (P = 0.017)). There was a significant positive correlation between 24-hour urinary sodium secretion and the level of urine albumin (beta = 0.130, P < 0.001). The amount of salt intake was significantly associated with urine albumin concentration (beta = 3.969, SE = 1.671, P = 0.018). Conclusion. High salt intake was shown to be associated with higher level of microalbuminuria even adjusted for potential underlying risk factors. PMID- 24171110 TI - Ethical issues in mHealth research involving persons living with HIV/AIDS and substance abuse. AB - We aim to raise awareness and stimulate dialogue among investigators and research ethics committees regarding ethical issues that arise specifically in the design and conduct of mHealth research involving persons living with HIV/AIDS and substance abuse. Following a brief background discussion of mHealth research in general, we offer a case example to illustrate the characteristics of mHealth research involving people living with HIV/AIDS and substance abuse. With reference to a well-established systematic general ethical framework for biomedical research with human participants, we identify a range of ethical issues that have particular salience for the protection of participants in mHealth research on HIV/AIDS and substance abuse. PMID- 24171111 TI - A Clinical-EEG Study of Sleepiness and Psychological Symptoms in Pharmacoresistant Epilepsy Patients Treated with Lacosamide. AB - Our aim was to evaluate the EEG and clinical modifications induced by the new antiepileptic drug lacosamide (LCM) in patients with epilepsy. We evaluated 10 patients affected by focal pharmacoresistant epilepsy in which LCM (mean 250 mg/day) was added to the preexisting antiepileptic therapy, which was left unmodified. Morning waking EEG recording was performed before (t0) and at 6 months (t1) after starting LCM. At t0 and t1, patients were also administered questionnaires evaluating mood, anxiety, sleep, sleepiness, and fatigue (Beck Depression Inventory; State-Trait Anxiety Inventory Y1 and Y2; Pittsburgh Sleep Quality Index; Epworth Sleepiness Scale; Fatigue Severity Scale). We performed a quantitative analysis of EEG interictal abnormalities and background EEG power spectrum analysis. LCM as an add-on did not significantly affect anxiety, depression, sleepiness, sleep quality, and fatigue scales. Similarly, adding LCM to preexisting therapy did not modify significantly patient EEGs in terms of absolute power, relative power, mean frequency, and interictal abnormalities occurrence. In conclusion, in this small cohort of patients, we confirmed that LCM as an add-on does not affect subjective parameters which play a role, among others, in therapy tolerability, and our clinical impression was further supported by evaluation of EEG spectral analysis. PMID- 24171112 TI - Glycoconjugates and related molecules in human vascular endothelial cells. AB - Vascular endothelial cells (ECs) form the inner lining of blood vessels. They are critically involved in many physiological functions, including control of vasomotor tone, blood cell trafficking, hemostatic balance, permeability, proliferation, survival, and immunity. It is considered that impairment of EC functions leads to the development of vascular diseases. The carbohydrate antigens carried by glycoconjugates (e.g., glycoproteins, glycosphingolipids, and proteoglycans) mainly present on the cell surface serve not only as marker molecules but also as functional molecules. Recent studies have revealed that the carbohydrate composition of the EC surface is critical for these cells to perform their physiological functions. In this paper, we consider the expression and functional roles of endogenous glycoconjugates and related molecules (galectins and glycan-degrading enzymes) in human ECs. PMID- 24171113 TI - Prehospital emergency ultrasound: a review of current clinical applications, challenges, and future implications. AB - Imaging modalities in the prehospital setting are helpful in the evaluation and management of time-sensitive emergency conditions. Ultrasound is the main modality that has been applied by emergency medical services (EMS) providers in the field. This paper examines the clinical applications of ultrasound in the prehospital setting. Specific focus is on applications that provide essential information to guide triage and management of critical patients. Challenges of this modality are also described in terms of cost impact on EMS agencies, provider training, and skill maintenance in addition to challenges related to the technical aspect of ultrasound. PMID- 24171114 TI - Protocol for evaluation of robotic technology in orthopedic surgery. AB - In recent years, robots have become commonplace in surgical procedures due to their high accuracy and repeatability. The Acrobot Sculptor is an example of such a robot that can assist with unicompartmental knee replacement. In this study, we aim to evaluate the accuracy of the robot (software and hardware) in a clinical setting. We looked at (1) segmentation by comparing the segmented data from Sculptor software to other commercial software, (2) registration by checking the inter- and intraobserver repeatability of selecting set points, and finally (3) sculpting (n = 9 cases) by evaluating the achieved implant position and orientation relative to that planned. The results from segmentation and registration were found to be accurate. The highest error was observed in flexion extension orientation of femoral implant (0.4 +/- 3.7 degrees ). Mean compound rotational and translational errors for both components were 2.1 +/- 0.6 mm and 3 +/- 0.8 degrees for tibia and 2.4 +/- 1.2 mm and 4.3 +/- 1.4 degrees for the femur. The results from all processes used in Acrobot were small. Validation of robot in clinical settings is highly vital to ensure a good outcome for patients. It is therefore recommended to follow the protocol used here on other available similar products. PMID- 24171115 TI - Laser Doppler Blood-Flow Signals from Human Teeth during an Alignment and Leveling Movement Using a Superelastic Archwire. AB - Objective. The purpose of this study was to examine alterations in blood-flow signals (BFS) from human teeth during an alignment and leveling phase (superelastic wire 0.014'') in a clinical orthodontic treatment using laser doppler flowmetry (LDF). Materials and Methods. Recordings were made in 12 maxillary left central incisors. The basal value of the BFS from each tooth (without orthodontic forces) was compared with the corresponding values of BFS during four periods of observation: 20 minutes, 48 hours, 72 hours, and one month after the activation of the orthodontic appliance. Results. Statistically significant decrease of BFS was observed at 20 minutes, 48 hours, and 72 hours (P < 0.05). No differences were found comparing BFS on day 30 and the corresponding basal values. Conclusion. Under real clinical conditions, a significant decrease in BFS was verified during the initial phase of the treatment, followed by a recovery on day 30. PMID- 24171116 TI - Seroprevalence of Toxoplasma gondii in Dairy Cattle with Reproductive Problems in Sudan. AB - Toxoplasmosis, caused by Toxoplasma gondii, is one of the most common parasitic infections of humans and other warm-blooded animals in most parts of the world. The disease is common among sheep and goats and it is recognized as one of the major causes of reproductive failure in these animals. Cattle, on the other hand, can be infected, but abortion or perinatal mortality has not been recorded. This survey was carried out to study the prevalence of this disease in cattle in Khartoum and Gazira States (Sudan). 181 sera samples collected from dairy cattle with reproductive problems were assayed for antibodies to T. gondii by ELISA. The prevalence rate of T. gondii antibodies in cattle at herd level was 44.8% (13/29). Herd level infection rates were 50% and 33.3% in Khartoum and Gazira States, respectively. The overall prevalence of T. gondii at individual level in both states was 13.3% (24/181). The prevalence was 12.7% (17/134), was 14.9% (7/47) in Khartoum and Gazira State, respectively. There was significantly higher (P < 0.05) prevalence of T. gondii antibodies in the age group less than one year old (36.4%) than in other age groups and in males (30.8%) than in females (11.9%) while no significant relationship was discerned regarding breed, location, season, or signs of reproductive disease. PMID- 24171117 TI - Aryl hydrocarbon receptor ligands inhibit igf-ii and adipokine stimulated breast cancer cell proliferation. AB - Obesity increases human cancer risk and the risk for cancer recurrence. Adipocytes secrete paracrine factors termed adipokines that stimulate signaling in cancer cells that induce proliferation. The aryl hydrocarbon receptor (AHR) is a ligand-activated transcription factor that plays roles in tumorigenesis, is regulated by exogenous lipophilic chemicals, and has been explored as a therapeutic target for cancer therapy. Whether exogenous AHR ligands modulate adipokine stimulated breast cancer cell proliferation has not been investigated. We provide evidence that adipocytes secrete insulin-like growth factor 2 (IGF-2) at levels that stimulate the proliferation of human estrogen receptor (ER) positive breast cancer cells. Using highly specific AHR ligands and AHR short interfering RNA (AHR-siRNA), we show that specific ligand-activated AHR inhibits adipocyte secretome and IGF-2-stimulated breast cancer cell proliferation. We also report that a highly specific AHR agonist significantly (P < 0.05) inhibits the expression of E2F1, CCND1 (known as Cyclin D1), MYB, SRC, JAK2, and JUND in breast cancer cells. Collectively, these data suggest that drugs that target the AHR may be useful for treating cancer in human obesity. PMID- 24171118 TI - A clinical review of the association of thyroid stimulating hormone and cognitive impairment. AB - Clinical and subclinical hypothyroidism as well as overt hyperthyroidism in middle-aged and elderly adults are both associated with decreased cognitive functioning as memory, reaction time, and visuospatial organization. Subclinical hyperthyroidism (SH) or low serum concentrations of TSH concentrations have been associated with dementia in previous epidemiological studies, but the association in the elderly has not been established. There is little or no consensus regarding how thyroid function is associated with cognitive performance in the elderly. In this focused review, we have performed an examination between eleven studies from the last five years examining the association between thyroid function and cognitive performance in elderly people, a group who is overrepresented among individuals with minor abnormalities in serum TSH and thyroid hormone concentration. Six of the studies showed a consistent finding of an association between SH with cognitive impairment or dementia. In general, taking into account the largest and most powerfully designed studies, there is a strong body of evidence supporting the association between SH and cognitive impairment. The scarce number of publications on these topics indicates the need of more research especially regarding longitudinal and interventional studies thus hopefully enabling confirmation or rejection of causality between TSH abnormalities and dementia. PMID- 24171119 TI - Proximal aortic stiffness is increased in systemic lupus erythematosus activity in children and adolescents. AB - Patients with systemic lupus erythematosus (SLE) are prone to premature atherosclerosis and are at risk for the development of cardiovascular disease. Increased arterial stiffness is emerging as a marker of subclinical atherosclerosis. Purpose. To measure proximal aortic stiffness in children and adolescents with SLE. Methods. We studied 16 patients with SLE in activity (mean age 15 +/- 2.42 years; 16 females), 14 patients with SLE not in activity (mean age 15.7 +/- 1.89 years; 4 males, 10 females), and 16 age- and sex-comparable healthy children and adolescents (15.5 +/- 1.71 years; 4 males, 12 females). Disease activity was determined by the SLE disease activity index (SLEDAI). All subjects underwent echocardiography for assessment of proximal aortic pulse wave velocity (PWV) [Ao distance/Ao wave transit time in the aortic arch]. Venous blood samples were collected for ESR. Results. Patients in activity had significantly higher PWV values than controls (P < 0.05), while no significant difference was found between patients not in activity and controls. Conclusions. SLE patients with disease activity demonstrate increased PWV and arterial stiffness of the proximal aorta, while patients without disease activity do not. This suggests that inflammation secondary to SLE activity, and not subclinical atherosclerosis, is the major underlying cause for increased arterial stiffness in this age group. PMID- 24171121 TI - Age Predicts Functional Outcome in Acute Stroke Patients with rt-PA Treatment. AB - The standard treatment for acute ischemic stroke is thrombolytic therapy. There is limited data on prognostic factors of acute stroke with thrombolytic therapy particularly in Asian population. Acute ischemic stroke patients who were treated with thrombolytic therapy at Srinagarind Hospital between May 2008 and July 2010 were included. Factors associated with Barthel index more than 80 were studied by multiple logistic regression analysis. There were 75 patients included in the study. The mean NIHSS scores before treatment and at 3 months were 9.16 +/- 4.82 and 3.83 +/- 4.00, respectively, and median Barthel index at 3 months was 86. Only significant predictor for having Barthel index more than 80 points at 3 months was age (adjusted odds ratio 0.929, 95% confidence interval 0.874, 0.988). Four patients developed intracranial hemorrhage after the treatment (5%), and two died (2.6%). In conclusion, age predicts Barthel index in acute stroke patients with rt-PA treatment. PMID- 24171120 TI - Synthesis of alginate-curcumin nanocomposite and its protective role in transgenic Drosophila model of Parkinson's disease. AB - The genetic models in Drosophila provide a platform to understand the mechanism associated with degenerative diseases. The model for Parkinson's disease (PD) based on normal human alpha-synuclein ( alpha S) expression was used in the present study. The aggregation of alpha S in brain leads to the formation of Lewy bodies and selective loss of dopaminergic neurons due to oxidative stress. Polyphenols generally have the reduced oral bioavailability, increased metabolic turnover, and lower permeability through the blood brain barrier. In the present study, the effect of synthesized alginate-curcumin nanocomposite was studied on the climbing ability of the PD model flies, lipid peroxidation, and apoptosis in the brain of PD model flies. The alginate-curcumin nanocomposite at final doses of 10(-5), 10(-3), and 10(-1) g/mL was supplemented with diet, and the flies were allowed to feed for 24 days. A significant dose-dependent delay in the loss of climbing ability and reduction in the oxidative stress and apoptosis in the brain of PD model flies were observed. The results suggest that alginate-curcumin nanocomposite is potent in delaying the climbing disability of PD model flies and also reduced the oxidative stress as well as apoptosis in the brain of PD model flies. PMID- 24171122 TI - Zonisamide Induces Crystalluria without Urinary pH Changes in Children and Young Adults. AB - Purpose. Adjunctive zonisamide therapy was demonstrated to be beneficial for multiple-disabled patients with refractory childhood-onset epilepsy. Zonisamide is well tolerated, but urolithiasis and calcium sludge in the bladder were sometimes described in patients treated with antiepileptic drug polytherapy including zonisamide. In previous studies, alkaline urine and crystalluria were shown to be risk factors for urolithiasis. Therefore, the effects of zonisamide addition and withdrawal on the urinary pH and crystalluria were investigated in patients treated with antiepileptic drug polytherapy to clarify the cause of urolithiasis induced by zonisamide. Methods. The urinary pH and the degree of crystalluria were retrospectively studied in epilepsy patients one month after the addition or withdrawal of zonisamide as part of their antiepileptic drug treatment regimen over the previous three years. Results. A total of 27 zonisamide-on patients and 16 zonisamide-off patients were enrolled in the study. The urinary pH did not change after the addition or withdrawal of zonisamide. However, the degree of crystalluria significantly increased after the addition (P < 0.001) of zonisamide and decreased after its withdrawal (P < 0.01). Conclusions. Zonisamide induces crystalluria without alkalinization of the urine. Crystalluria should be carefully monitored in patients treated with zonisamide to prevent urolithiasis. PMID- 24171123 TI - Potential Toxic Levels of Cyanide in Almonds (Prunus amygdalus), Apricot Kernels (Prunus armeniaca), and Almond Syrup. AB - Under normal environmental conditions, many plants synthesize cyanogenic glycosides, which are able to release hydrogen cyanide upon hydrolysis. Each year, there are frequent livestock and occasional human victims of cyanogenic plants consumption. The present work aims to determine the hydrocyanic acid content in different samples of cyanogenic plants, selected from the Tunisian flora, and in the almond syrup. In order to evaluate their toxicity and their impact on the consumer health in the short term as well as in the long term, using the ISO 2164-1975 NT standard, relating to the determination of cyanogenic heterosides in leguminous plants. PMID- 24171124 TI - Rapunzel syndrome: a rare postpartum case. AB - The Rapunzel syndrome describes a disorder in which a significant amount of hair is swallowed, forming a trichobezoar that extends past the stomach into the small intestines. Given the indigestible nature of hair, it subsequently leads to obstruction within the gastrointestinal system. Clinically, patients may present with symptoms of gastrointestinal obstruction, including abdominal complaints such as pain, nausea, vomiting, and diarrhea. However, due to its broad and nonspecific presenting symptoms, the diagnosis of Rapunzel syndrome warrants consideration once other common etiologies have been excluded. Surgical intervention is often required to remove the abdominal mass. This unusual syndrome is often associated with psychiatric disorders, affecting young women most commonly. In this report, we will discuss a unique case of Rapunzel syndrome in a one-month postpartum woman. PMID- 24171125 TI - Paroxysmal nonkinesigenic dyskinesia with tremor. AB - Introduction. Paroxysmal nonkinesigenic dyskinesia (PNKD) consists of episodes of chorea, athetosis, or dystonia which are not triggered by movement, with complete remission between episodes. A case of genetically confirmed PNKD with simultaneous tremor has not been previously reported. Case Report. The patient is an 86-year-old right-handed female who presented with episodic stiffness, with onset at age 9. Attacks have a prodrome of difficulty in speaking, followed by abnormal sensation in extremities. Episodes consist of dystonia of trunk associated with upper and lower extremity chorea. There is complete resolution between attacks except for persistent mild head tremor and action tremor of both extremities. Attack frequency and duration as well as tremor amplitude escalated two and a half years ago, in correlation with development of breast carcinoma. Episodes improved after successful cancer treatment, but higher amplitude tremor persisted. There is an autosomal dominant family history of similar episodes but not tremor. Genetic diagnosis was confirmed via A7V mutation of the myofibrillogenesis regulator (MR-1) gene. Conclusion. Exacerbation due to another medical or psychiatric condition should be considered if there is unexpected deterioration in episode frequency or length. PNKD due to MR-1 mutation may exist even in the presence of action tremor. PMID- 24171126 TI - Management of synovial osteochondromatosis of the distal radioulnar joint with imaging features consistent with malignancy. AB - Synovial osteochondromatosis of the distal radioulnar joint is a rare entity with only 14 cases reported in the literature. Malignant transformation of synovial osteochondromatosis is the most worrisome complication of the disease. It has been described in joints such as the hip and knee but never for the distal radioulnar joint. We report a case of synovial osteochondromatosis of the distal radioulnar joint which presented with radiographic features which were worrisome for malignant transformation and required a comprehensive preoperative workup. Discussed are the preoperative management, surgical treatment, and a literature review of this rare disease. PMID- 24171127 TI - Ameloblastoma of the nasal septum origin: a case report. AB - Background. Ameloblastoma is the most common odontogenic tumor. It represents about 1% of all tumors of the jaw. Extragnathic location of the ameloblastoma is typical and extremely rare. Case Report. We report a case of ameloblastoma of the nasal septum origin, causing nasal obstruction. According to our information, this is the first reported case of ameloblastoma coming from the nasal septum as a primary tumor without maxillary sinus involvement. Conclusions. Ameloblastoma can not only locate in the maxilla and mandible, but also in other regions of the craniofacial. Ameloblastoma should be considered in the differential diagnosis of tumors causing nasal obstruction. Nonspecific clinical features of sinonasal ameloblastoma make it extremely important to perform accurate diagnostic imaging and histopathological examination. PMID- 24171128 TI - Epithelioid angiosarcoma of the septum pellucidum. AB - Primary cerebral intra-axial epithelioid angiosarcoma is an extremely rare malignancy. To the best of our knowledge we describe the first case of epithelioid angiosarcoma arisen in the septum pellucidum of a 54-years-old man. Albeit extremely rare, this neoplasia is a potential source of misdiagnosis for other aggressive malignant tumors, and it should be taken into consideration. PMID- 24171129 TI - Rare testicular tumor discovered by assault: an unusual presentation of a primary testicular neuroendocrine tumor grade 2. AB - Testicular neuroendocrine tumors (NET) or carcinoid tumors are rare neoplasms which represent 1% of all testicular tumors and can be divided into 3 subgroups: pure primary testicular NET, primary testicular NET associated with a teratoma, and NET metastases to the testis. We report an unusual presentation of a primary testicular neuroendocrine tumor in a 39-year-old male who presented after a physical altercation during a soccer game. Histology showed a diffuse infiltrating tumor with extensive involvement of the tunica albuginea and tunica vaginalis. Immunohistochemical expression of CD56, synaptophysin, and chromogranin A was strongly positive in the tumor cells. Foci of tumor cell necrosis and occasional mitotic figures as well as extensive lymph-vascular invasion were also identified. A review of the literature reveals differing opinions on the prognostic significance of primary tumor size, mitotic index, tumor necrosis, and nuclear atypia. In our patient, the increased mitotic rate (3 5 mitotic figures per 10 hpf and a Ki-67 index of 5%), foci of necrosis, and mild to moderate nuclear atypia warranted a diagnosis of neuroendocrine tumor grade 2, formerly atypical carcinoid. Long term surveillance in these patients is essential as metastasis occurs in up to 15% of cases. At the 6-month followup, the patient remains symptom free. PMID- 24171130 TI - Augmentative asenapine in a recurrent manic catatonic patient with partial response to clozapine. AB - Catatonia is a severe but treatable neuropsychiatric syndrome known since the middle of the nineteenth century. It has been considered for a long time as a subtype of schizophrenia, even though this association occurs only in 10% of cases. In contrast, it is frequently observed in bipolar patients. First-line treatment consists of benzodiazepines, while in case of resistance electroconvulsive therapy (ECT) and clozapine have shown positive results. In addition, recent studies reported the efficacy of some atypical antipsychotics. The present case shows the clinical response to augmentative asenapine in a catatonic manic patient with a partial response to clozapine. PMID- 24171131 TI - One Lung Wheezing due to Endobronchial Solitary Papilloma. AB - A 55-year-old man was referred to our hospital due to intolerant severe short of breathing and persistent cough for two hours. He had similar attacks in the past two years which were treated with bronchodilators. Computed tomography revealed endobronchial mass, which was endoscopically resected by laser. Histology revealed benign squamous papilloma. In this paper we will deal with the various nonspecific clinical presentations, etiopathology, predisposing factors, and diagnosing tests of these benign tumors, especially the important role of computed tomography. PMID- 24171132 TI - Congenital giant hydroureteric cistern in a duplex system of an infant. AB - Duplex collecting system is a congenital genitourinary anomaly commonly found incidentally. Our experience with a duplex system associated with giant hydroureter presenting as mobile abdominal swelling that was noticed from birth, constipation, and failure to thrive is described. Ultrasound and IVU did not assist in making the diagnosis, while a barium enema suggested a colonic duplication. Congenital giant hydroureter should be considered as a differential diagnosis in infants with cystic abdominal swelling. A preserved renal moiety attributed to a dilated ureteric cistern was a unique theory in this case. PMID- 24171133 TI - A case of a metanephric adenoma of the kidney surgically treated with robot assisted laparoscopic partial nephrectomy. AB - Metanephric adenomas are a rare neoplasm of the kidney with less than 200 cases reported. We report a case of a metanephric adenoma incidentally found on imaging in a 52-year-old Hispanic female and treated with robot-assisted laparoscopic partial nephrectomy. A brief review of the literature is also included. PMID- 24171134 TI - Ureteric Injury due to the Use of LigaSure. AB - Background. LigaSure is a bipolar clamping device used in open and laparoscopic surgeries for producing haemostasis in vascular pedicles up to 7 mm in diameter ("Covidien LigaSure technology: consistent, reliable, trusted vessel sealing," 2012). The use of LigaSure has made securing haemostasis and tissue dissection relatively easy especially in laparoscopic surgery; however, if not used with care it can cause damage to the surrounding structures through lateral spread of energy. Case Report. This case report discusses the induction of a thermal ureteral injury associated with the use of LigaSure. An 80-year-old gentleman was operated for bowel cancer. LigaSure was used for securing haemostasis and tissue dissection. Postoperatively, he was found to have damage to the right ureter secondary to lateral spread of energy from the jaws of LigaSure with high abdominal drain output. Conclusion. Judicious and careful use of electrosurgical devices should be done to prevent inadvertent damage to the surrounding structures. Early recognition and involvement of a urologist can prevent long term complications. PMID- 24171135 TI - Percutaneous embolization of congenital portosystemic venous fistula in an infant with down syndrome. AB - Congenital intrahepatic portosystemic venous shunts are rare vascular malformations often associated with severe complications. We describe a term male infant with Down syndrome with high output heart failure secondary to a congenital arterial to portal venous fistula that was diagnosed by Doppler ultrasound. Percutaneous embolizations of the left hepatic vein, portal vein, and communicating fistulas were performed without complications, resulting in clinical improvement. A subsequent hepatic ultrasound demonstrated resolution of the pathologic fistulous communication and shunting effects. PMID- 24171136 TI - Admission Screening of Methicillin-Resistant Staphylococcus aureus with Rapid Molecular Detection in Intensive Care Unit: A Three-Year Single-Centre Experience in Hong Kong. AB - Background. The admission screening of methicillin-resistant Staphylococcus aureus (MRSA) by rapid molecular assay is considered to be an effective method in reducing the transmission of MRSA in intensive care unit (ICU). Method. The admission screening on patients from ICU once on their admissions by BD GeneOhm MRSA assay has been introduced to Prince of Wales Hospital, Hong Kong, since 2008. The assay was performed on weekdays and reported on the day of testing. Patients pending for results were under standard precautions until the negative screening results were notified, while contact precautions were implemented for MRSA-positive patients. In this study, we compared the MRSA transmission rate in molecular screening periods (2008 to 2010) with the historical culture periods (2006 to 2007) as control. Results. A total of 4679 samples were tested; the average carriage rate of MRSA on admission was 4.45%. By comparing with the historical culture periods, the mean incidence ICU-acquired MRSA infection was reduced from 3.67 to 1.73 per 1000 patient bed days. Conclusion. The implementation of admission screening of MRSA with molecular method in intensive care unit could reduce the MRSA transmission, especially in the area with high MRSA prevalence situation in Hong Kong. PMID- 24171137 TI - Correlation of various techniques in diagnosis of tuberculous lymphadenitis on fine needle aspiration cytology. AB - Objective. To study the correlation of cytomorphological features in fine needle aspiration smears from patients suspected of having tuberculous lymphadenitis with Ziehl-Neelsen staining (ZN), auramine-rhodamine staining (ARS), and autofluorescence (AF). Methods. A total of 145 lymph nodes were aspirated, 3 air dried smears were stained with Giemsa, Ziehl-Neelsen, and auramine-rhodamine stains, and 1 smear was wet fixed for Papanicolaou staining. Needle washes were incubated in Lowenstein-Jensen medium for culture. Papanicolaou and auramine rhodamine stained smears were examined under fluorescent microscope using a blue excitation filter (450-480 nm). Results. Ninety aspirates were reported on cytomorphology as suggestive of tuberculous lymphadenitis. Smear positivity for Mycobacteria by Ziehl-Neelsen method was 26.67% (24/90), while positivity increased to 34.44% (31/90) by auramine-rhodamine and 42.22% (38/90) on autofluorescence. Culture was positive in 27.78% (25/90) aspirates. Using culture as the reference method, the statistical values of ZN, ARS, and AF were as follows: sensitivity 80.0%, 88.0%, 96.0%; specificity 93.85%, 86.15%, 78.46%; positive predictive values 83.33%, 70.97%, 63.16%; and negative predictive values 92.42%, 94.92%, 98.08%, respectively. Conclusion. There is a definite advantage of autofluorescence over Ziehl-Neelsen and auramine-rhodamine which is to detect Mycobacteria, being more sensitive as well as an inexpensive technique. Autofluorescence can be a useful addition to routine cytology for early diagnosis and effective treatment. PMID- 24171138 TI - Intoxications associated with agitation, tachycardia, hypertension, and Fever: differential diagnosis, evaluation, and management. PMID- 24171139 TI - "We cut and drink blood when we have sex. Do we have a problem?" a case report of atypical antipsychotic-treated paraphilia. PMID- 24171140 TI - Exercising an injury on purpose: relationships with borderline personality symptomatology. PMID- 24171141 TI - Risk factors for hypovitaminosis d in gerontopsychiatric patients. PMID- 24171142 TI - A case of cocaine-induced myopathy. PMID- 24171143 TI - Hirsutism in a female adolescent induced by long-acting injectable risperidone: a case report. PMID- 24171144 TI - Six-month open-label follow-up of risperidone long-acting injection use in pediatric bipolar disorder. AB - BACKGROUND: Recent studies suggest that risperidone long-acting injection (RLAI) may be considered for controlling mood episodes in bipolar disorder patients who have relapsed due to medication nonadherence or failure to respond to standard therapies. Currently, no study has reported the usefulness of RLAI in youths with bipolar disorder. The aim of this study was to evaluate short-term effects of RLAI in the naturalistic treatment of early-onset bipolar disorder and its role in symptomatic remission and adherence to treatment. METHOD: Nineteen early-onset bipolar disorder outpatients receiving RLAI were observed in a 6-month naturalistic study at the outpatient clinic of the Child and Adolescent Affective Disorders Program at the Institute of Psychiatry of the University of Sao Paulo, Sao Paulo, Brazil. All patients met DSM-IV criteria for bipolar disorder. Clinical response to RLAI was evaluated using the Children's Global Assessment Scale (CGAS) and Clinical Global Impressions scale (CGI) across 3 time periods: index time (T0), 8 weeks after (T1), and 24 weeks after (T2). These subjects were recruited from May 2008 to December 2009. RESULTS: Patients receiving RLAI presented considerable improvement in global functioning (CGAS: T0 = 20.6; T1 = 42.9; and T2 = 49.2) and clinical severity (CGI: T0 = 5.9; T1 = 3.9; and T2 = 3.4). Global CGI mean scores of clinical improvement were 2.2 at T1 and 2.4 at T2. There were no significant changes in laboratory measurements and weight throughout follow-up. CONCLUSIONS: RLAI was shown to be an alternative treatment for youths with bipolar disorder failing to respond to prior medication trials or with adherence problems. Further blind, randomized controlled studies are necessary to confirm these initial findings. TRIAL REGISTRATION: Sistema Nacional de Informacoes Sobre Etica em Pesquisa Envolvendo Seres Humanos-Commisao Nacional de Etica em Pesquisa identifier: CAAE 0709.0.015.000-06. PMID- 24171145 TI - Association between severity of depression and self-perceived cognitive difficulties among full-time employees. AB - OBJECTIVE: To assess the relationship between self-perceived deficits in cognition and severity of depression reported by individuals in full-time employment. METHOD: Individuals >= 18 years of age employed full-time with diagnosed depression excluding bipolar disorder (participants had to be told by a doctor that they had depression based on DSM-IV criteria) completed a 25-minute Web-based survey in February 2010 (study population identified by Harris Interactive, Rochester, New York). The survey used the Perceived Deficits Questionnaire (PDQ) to assess self-perceived cognitive impairment and the 9-item Patient Health Questionnaire (PHQ-9) to assess depression severity. The 20 question PDQ was used to assess self-perceived cognitive difficulties within the domains of prospective memory, retrospective memory, attention/concentration, and planning/organization (range, 0-20: higher scores indicate greater impairment). Subjects answered how often they experienced such difficulties during the previous 4 weeks (0 = never, 1 = rarely, 2 = sometimes, 3 = often, 4 = almost always). The scale ranges from 0-20 for each of the 4 subscales, with higher scores indicating greater cognitive impairment. The impact of depression on PDQ scores was assessed using a trend test based on an analysis of covariance controlling for potential confounders. RESULTS: Subjects (N = 1,051) (58% women) had a mean +/- SD age of 47 +/- 12 years; 38% held professional employment. PHQ-9 scores indicated that 423 employees (40.3%) had no depressive symptoms at the time of the survey, 319 (30.4%) had mild depression, 166 (15.8%) had moderate depression, 82 (7.8%) had moderately severe depression, and 61 (5.8%) had severe depression. Perceived cognitive functioning worsened with increasing severity of depression symptoms (P < .0001) on the basis of PDQ scores. On the basis of responses to the PDQ, in the current study, most impairment was seen in the attention/concentration and planning/organization subscales in severely depressed subjects (12.2 for both) compared with those with no depressive symptoms (4.4 and 3.5, respectively), indicating more cognitive impairment in the severely depressed subjects compared to the subjects with no depression. CONCLUSIONS: In currently employed individuals, self-perceived cognitive dysfunction worsened with increasing severity of depressive symptoms. This association was independent of antidepressant use. The greatest impairment in self-perceived cognition was observed in the planning/organization and attention/concentration subscales. PMID- 24171146 TI - Electrocardiographic abnormalities as potential contributors to premature mortality in patients with mental illness in a psychiatric day treatment program. AB - OBJECTIVE: Because patients with mental illness can die prematurely, we sought to determine if undetected cardiovascular disease might be present in a psychiatric day treatment population. METHOD: We studied 96 patients in a day treatment program seen between February 2011 and August 2012. Data were obtained through an electronic medical record database. Electrocardiographic diagnoses were assigned by 1 investigator (M.L.). Medications were categorized into classes, and problem lists revealed comorbid diagnoses. Fisher exact test (2-tailed) and analysis of variance were used to compare findings between patient groups. Electrocardiogram (ECG) findings were the primary outcome measure. RESULTS: Ninety-two ECGs were performed in 37 patients. Of these 37 patients, 70% were women, 65% were 50 years of age or younger, and 54% were people of color. ECGs were performed mainly for chest pain/dyspnea (46%) and overdose/altered mental status (27%). Of these 37 patients, 20 (54%) had abnormal ECGs, 7 (19%) had borderline findings, and 10 (27%) had normal studies. When compared with the larger group of 59 patients without ECG testing, those with abnormal ECGs were more likely to be older (mean age = 47 vs 37 years, P < .001) and have more comorbid conditions (mean no. = 10.0 vs 3.8, P < .0001). The most common abnormalities were conduction disorders (prolonged QRS >= 105 ms, or prolonged QTc >= 450 ms in men or >= 460 ms in women), coronary artery disease, and arrhythmias. CONCLUSIONS: In psychiatric outpatients who underwent ECG testing, mainly for chest pain or altered mental status, over 50% had concerning findings. Older patients with multiple comorbidities were at higher risk of having abnormal ECGs. Generalizability of these findings depends on validation in larger samples in multiple settings. PMID- 24171147 TI - Naltrexone/Bupropion combination therapy in overweight or obese patients with major depressive disorder: results of a pilot study. AB - OBJECTIVE: To evaluate the effect of 32-mg/d naltrexone sustained release and 360 mg/d bupropion sustained release (NB32) in overweight and obese patients with major depressive disorder (MDD). METHOD: Twenty-five female patients with a DSM IV diagnosis of MDD, an Inventory of Depressive Symptomatology-Self-Report score > 26, and a body mass index >= 27 and <= 43 kg/m(2) received up to 24 weeks of open-label treatment with NB32 with dietary and behavioral counseling (data collection: March 2008-July 2009). The primary endpoint was change from baseline in the Montgomery-Asberg Depression Rating Scale (MADRS) total score at 12 weeks; secondary endpoints included MADRS total score at week 24, change in weight, and Clinical Global Impressions-Improvement scale responder status (CGI-I score <= 2) at weeks 12 and 24 (modified intent-to-treat [mITT]: patients with >= 1 postbaseline MADRS total score on study drug; N = 23). RESULTS: MADRS scores showed significant reductions at weeks 12 and 24 (mITT-last observation carried forward [LOCF]: -13.1 +/- 7.1 and -15.3 +/- 8.1, respectively, P < .001 vs baseline for all). Mean +/- SD weight loss was -4.0% +/- 4.6% (mITT-LOCF) and 6.1% +/- 4.7% (observed cases) at week 12 and -5.3% +/- 6.5% (mITT-LOCF) and 9.2% +/- 6.2% (observed cases) at week 24 (P < .001 vs baseline for all). By week 24, 95% of patients (mITT-LOCF) were responders (CGI-I score <= 2) and 70% were in remission (CGI-I score = 1). The safety/tolerability profile of NB32 was consistent with its individual components; the most common adverse events were nausea, constipation, headache, and insomnia, with no serious adverse events attributed to NB32. CONCLUSION: Twenty-four weeks of open-label NB32 therapy with dietary and behavioral counseling was associated with improvement in depressive symptoms and reduced body weight in overweight/obese women with MDD. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT00624858. PMID- 24171148 TI - Educational impact of a psychiatric liaison in the medical intensive care unit: effects on attitudes and beliefs of trainees and nurses regarding delirium. AB - OBJECTIVE: Despite high rates and increased risk of mortality, delirium remains underdiagnosed and a minimal focus of formal medical education. This is the first study to examine the educational impact of a psychiatric liaison on beliefs and knowledge about delirium among both nurses and residents. METHOD: One psychiatrist spent 9 months rounding weekly in the medical intensive care unit, interacting with critical care nurses and internal medicine residents. Preintervention and postintervention surveys were distributed in July 2009 and June 2010, respectively, to staff (critical care nurses: n = 23 and n = 25, respectively; internal medicine residents: n = 31 and n = 23, respectively) and a comparison group (psychiatry residents: n = 29 and n = 23, respectively). Participants responded to 12 statements regarding delirium on a 5-point Likert scale. RESULTS: There were no statistically significant differences between the presurveys and postsurveys for any item when examining all respondents together, as well as psychiatry and internal medicine residents as individual groups. Critical care nurses showed a significant change between surveys for the statements, "Patients with new-onset anxiety or depression in the intensive care unit most commonly have delirium" (17.4% agree presurvey vs 56.0% agree postsurvey, chi(2) = 7.62, P = .006) and "Delirium is diagnosed less often than it actually occurs" (100% agree presurvey vs 80% agree postsurvey, chi(2) = 5.13, P = .023). CONCLUSIONS: Though introduction of a psychiatric liaison was very well received by clinical staff, we did not meaningfully affect the attitudes and beliefs of trainees and nurses regarding delirium. Robust and lasting changes in attitudes regarding delirium may require more intensive efforts involving longer intervention periods, greater rounding frequency, or additional didactic teaching. PMID- 24171149 TI - A rapid turn of events: sudden physical and cognitive decline. PMID- 24171150 TI - Arbitrary inference. PMID- 24171151 TI - Outcomes research resources in India: current status, need and way forward. AB - BACKGROUND: Despite their importance, the number of outcomes research studies conducted in India are lesser than other countries. Information about the distribution of existing outcomes research resources and relevant expertise can benefit researchers and research groups interested in conducting outcomes research studies and policy makers interested in funding outcomes research studies in India. We have reviewed the literature to identify and map resources described in outcomes research studies conducted in India. METHODS: We reviewed the following online biomedical databases: Pubmed, SCIRUS, CINAHL, and Google scholar and selected articles that met the following criteria: published in English, conducted on Indian population, providing information about outcomes research resources (databases/registries/electronic medical records/electronic healthcare records/hospital information systems) in India and articles describing outcomes research studies or epidemiological studies based on outcomes research resources. After shortlisting articles, we abstracted data into three datasets viz. 1. Resource dataset, 2. Bibliometric dataset and 3. Researcher dataset and carried out descriptive analysis. RESULTS: Of the 126 articles retrieved, 119 articles were selected for inclusion in the study. The tally increased to 133 articles after a secondary search. Based on the information available in the articles, we identified a total of 91 unique research resources. We observed that most of the resources were Registries (62/91) and Databases ( 23/91) and were primarily located in Maharashtra (19/91) followed by Tamil Nadu (11/91), Chandigarh (8/91) and Kerala (7/91) States. These resources primarily collected data on Cancer (44/91), Stroke (5/91) and Diabetes (4/91). Most of these resources were Institutional (38/91) and Regional resources (35/91) located in Government owned and managed Academic Institutes/Hospitals (57/91) or Privately owned and managed non - Academic Institutes/Hospitals (14/91). Data from the Population based Cancer Registry, Mumbai was used in 41 peer reviewed publications followed by Population based Cancer Registry, Chennai (17) and Rural Cancer Registry Barshi (14). Most of the articles were published in International journals (139/193) that had an impact factor of 0-1.99 (43/91) and received an average of 0-20 citations (55/91). We identified 193 researchers who are mainly located in Maharashtra (37/193) and Tamil Nadu (24/193) states and Southern (76/193) and Western zones (47/193). They were mainly affiliated to Government owned & managed Academic Institutes /Hospitals (96/193) or privately owned and managed Academic Institutes/ Hospitals (35/193). CONCLUSIONS: Given the importance of Outcomes research, relevant resources should be supported and encouraged which would help in the generation of important healthcare data that can guide health and research policy. Clarity about the distribution of outcomes research resources can facilitate future resource and funding allocation decisions for policy makers as well as help them measure research performance over time. PMID- 24171152 TI - Prevalence and risk factors of urinary incontinence among Estonian postmenopausal women. AB - AIMS: To estimate the prevalence of urinary incontinence (UI) and to assess its risk factors among postmenopausal Estonian women. METHODS: In 2004, 1363 women participating in the Estonian Postmenopausal Hormone Therapy Trial were asked at the closure visit to the trial physician about symptoms of UI. The type of incontinence was assessed with the help of a questionnaire, based on recommendations from the working group set up by the Finnish Gynaecological Association. Frequency characteristics were analysed by descriptive statistics. Risk factors were examined using logistic regression. RESULTS: Mean age of study women was 53.3 years (min = 48, max = 67; SD 4.0). The prevalence of UI was 18.12% (95% CI: 16.07 - 20.17). Stress incontinence was diagnosed in 78.83% (95% CI: 73.32 - 84.33) and urge or mixed incontinence in 21.17% (95% CI: 15.67 - 26.68) of women who reported incontinence. Prevalence of UI slightly increased with age. Women who used hormone therapy (HT) (OR 1.67; 95% CI: 1.17 - 2.39), had had hysterectomy (1.73, 95% CI: 1.06 - 2.83), and those with secondary education (OR 1.87, 95% CI: 1.23 - 2.82) or basic education (OR 3.29, 95% CI: 1.80 - 6.02) had a higher risk for UI. Parity, having a BMI over 30 kg/m(2), being a smoker or a former smoker, having diabetes and being physically or sexually active, tended to increase the risk of UI. CONCLUSIONS: About one in five postmenopausal women in Estonia reported to have UI. Risk factors linked with UI, its prevalence in other age groups and the impact of UI on quality of life deserve more research. TRIAL REGISTRATION: Number: ISRCTN35338757. PMID- 24171153 TI - Experimental measurement of tympanic membrane response for finite element model validation of a human middle ear. AB - The middle ear consists of a tympanic membrane, ligaments, tendons, and three ossicles. An important function of the tympanic membrane is to deliver exterior sound stimulus to the ossicles and inner ear. In this study, the responses of the tympanic membrane in a human ear were measured and compared with those of a finite element model of the middle ear. A laser Doppler vibrometer (LDV) was used to measure the dynamic responses of the tympanic membrane, which had the measurement point on the cone of light of the tympanic membrane. The measured subjects were five Korean male adults and a cadaver. The tympanic membranes were stimulated using pure-tone sine waves at 18 center frequencies of one-third octave band over a frequency range of 200 Hz ~10 kHz with 60 and 80 dB sound pressure levels. The measured responses were converted into the umbo displacement transfer function (UDTF) with a linearity assumption. The measured UDTFs were compared with the calculated UDTFs using a finite element model for the Korean human middle ear. The finite element model of the middle ear consists of three ossicles, a tympanic membrane, ligaments, and tendons. In the finite element model, the umbo displacements were calculated under a unit sound pressure on the tympanic membrane. The UDTF of the finite element model exhibited good agreement with that of the experimental one in low frequency range, whereas in higher frequency band, the two response functions deviated from each other, which demonstrates that the finite element model should be updated with more accurate material properties and/or a frequency dependent material model. PMID- 24171154 TI - Retrograde endoscopic lithotripsy using the innovative nanosecond electropulse method. AB - PURPOSE: The purpose of this clinical study is to assess the safety and efficiency of a novel lithotripsy method for endoscopic treatment of urinary stones throughout the urinary tract via semi-rigid and flexible endoscopes. This new method is based on the transfer of nanosecond high voltage electric pulses to the stones through flexible probes of various sizes. METHODS: The study involved 879 patients aged 19-88 with renal, ureter and bladder calculi. Gender distribution: 46.3% female and 53.7% male. The prospective single-arm study took place at three centers. The goal of the clinical study was to evaluate the safety and efficacy of a novel lithotripsy method. All treatments were performed retrograde transurethrally. A variety of probes were used for stone fragmentation at different locations. Auxiliary treatments and adverse events were recorded as per protocol. Statistical analysis was conducted using SPSS software. RESULTS: Nanosecond electropulse lithotripsy (NEPL) was found to be technically feasible for all patients with stones located in the kidney, UPJ, ureter and bladder. It requires only a few dozen pulses to disintegrate stones while causing only minor stone migration. The overall stone-free rate in the study was 96%. The average time required for executing the entire procedure was 45+/-28 min. The overwhelming majority of intraoperative complications occurred due to endoscopic manipulation when using a rigid ureterorenoscope and not due to lithotripsy impact. CONCLUSIONS: NEPL is a new, efficient and safe method for urinary stone disintegration that can be used throughout the urinary tract using rigid and flexible endoscopes. Intraoperative complications of the NEPL procedure do not exceed the percentage of adverse effects observed in other lithotripsy methods. The main advantages of relatively low-cost NEPL are fast stone fragmentation requiring only a few dozen pulses to disintegrate stones, tissue safety and availability of highly flexible probes for treating stones in the lower pole through a flexible ureterorenoscope. PMID- 24171155 TI - Co-seismic landslide topographic analysis based on multi-temporal DEM-A case study of the Wenchuan earthquake. AB - Hillslope instability has been thought to be one of the most important factors for landslide susceptibility. In this study, we apply geomorphic analysis using multi-temporal DEM data and shake intensity analysis to evaluate the topographic characteristics of the landslide areas. There are many geomorphologic analysis methods such as roughness, slope aspect, which are also as useful as slope analysis. The analyses indicate that most of the co-seismic landslides occurred in regions with roughness, hillslope and slope aspect of >1.2, >30, and between 90 and 270, respectively. However, the intersection regions from the above three methods are more accurate than that derived by applying single topographic analysis method. The ground motion data indicates that the co-seismic landslides mainly occurred on the hanging wall side of Longmen Shan Thrust Belt within the up-down and horizontal peak ground acceleration (PGA) contour of 150 PGA and 200 gal, respectively. The comparisons of pre- and post-earthquake DEM data indicate that the medium roughness and slope increased, the roughest and steepest regions decreased after the Wenchuan earthquake. However, slope aspects did not even change. Our results indicate that co-seismic landslides mainly occurred at specific regions of high roughness, southward and steep sloping areas under strong ground motion. Co-seismic landslides significantly modified the local topography, especially the hillslope and roughness. The roughest relief and steepest slope are significantly smoothed; however, the medium relief and slope become rougher and steeper, respectively. PMID- 24171156 TI - Prediction of muscular architecture of the rectus femoris and vastus lateralis from EMG during isometric contractions in soccer players. AB - OBJECTIVES: The purpose of the study was to establish regression equations that could be used to predict muscle thickness and pennation angle at different intensities from electromyography (EMG) based measures of muscle activation during isometric contractions. DESIGN: Cross-sectional study. METHODS: Simultaneous ultrasonography and EMG were used to measure pennation angle, muscle thickness and muscle activity of the rectus femoris and vastus lateralis muscles, respectively, during graded isometric knee extension contractions performed on a Cybex dynamometer. Data form fifteen male soccer players were collected in increments of approximately 25% intensity of the maximum voluntary contraction (MVC) ranging from rest to MVC. RESULTS: There was a significant correlation (P < 0.05) between ultrasound predictors and EMG measures for the muscle thickness of rectus femoris with an R(2) value of 0.68. There was no significant correlation (P > 0.05) between ultrasound pennation angle for the vastus lateralis predictors for EMG muscle activity with an R(2) value of 0.40. CONCLUSIONS: The regression equations can be used to characterise muscle thickness more accurately and to determine how it changes with contraction intensity, this provides improved estimates of muscle force when using musculoskeletal models. PMID- 24171157 TI - Illuminating the petite picture of T cell memory responses to Listeria monocytogenes. AB - The ease to culture, moderately less safety constraints in handling, and above all, hurdle free induction of an anticipated infection in mouse rendered Listeria monocytogenes the rank of a model organism for studying a variety of host immune responses. Listeria monocytogenes being an intracellular pathogen evokes potent CD8 T cell response during which CD8 T cells pass through a massive expansion phase. This is generally followed by contraction phase wherein majority of activated cells undergo apoptosis leaving behind a population of memory CD8 T cells that has potential to confer enhanced protection upon reencounter with the same pathogen. Functional attributes of various cytokines, transcription factors, receptors, adaptors, and effectors pertaining to the generation of robust memory T cell response have begun to be unravelled for better understanding of memory and opening avenues to create superior vaccine strategies. This review is an attempt to unveil related discoveries along with updating recent advances on this issue. PMID- 24171159 TI - Interdisciplinary approach to tool-handle design based on medical imaging. AB - Products are becoming increasingly complex; therefore, designers are faced with a challenging task to incorporate new functionality, higher performance, and optimal shape design. Traditional user-centered design techniques such as designing with anthropometric data do not incorporate enough subject data to design products with optimal shape for best fit to the target population. To overcome these limitations, we present an interdisciplinary approach with medical imaging. The use of this approach is being presented on the development of an optimal sized and shaped tool handle where the hand is imaged using magnetic resonance imaging machine. The obtained images of the hand are reconstructed and imported into computer-aided design software, where optimal shape of the handle is obtained with Boolean operations. Methods can be used to develop fully customized products with optimal shape to provide best fit to the target population. This increases subjective comfort rating, performance and can prevent acute and cumulative trauma disorders. Provided methods are especially suited for products where high stresses and exceptional performance is expected (high performance tools, professional sports, and military equipment, etc.). With the use of these interdisciplinary methods, the value of the product is increased, which also increases the competitiveness of the product on the market. PMID- 24171158 TI - Snake venom PLA2s inhibitors isolated from Brazilian plants: synthetic and natural molecules. AB - Ophidian envenomation is an important health problem in Brazil and other South American countries. In folk medicine, especially in developing countries, several vegetal species are employed for the treatment of snakebites in communities that lack prompt access to serum therapy. However, the identification and characterization of the effects of several new plants or their isolated compounds, which are able to inhibit the activities of snake venom, are extremely important and such studies are imperative. Snake venom contains several organic and inorganic compounds; phospholipases A2 (PLA2s) are one of the principal toxic components of venom. PLA2s display a wide variety of pharmacological activities, such as neurotoxicity, myotoxicity, cardiotoxicity, anticoagulant, hemorrhagic, and edema-inducing effects. PLA2 inhibition is of pharmacological and therapeutic interests as these enzymes are involved in several inflammatory diseases. This review describes the results of several studies of plant extracts and their isolated active principles, when used against crude snake venoms or their toxic fractions. Isolated inhibitors, such as steroids, terpenoids, and phenolic compounds, are able to inhibit PLA2s from different snake venoms. The design of specific inhibitors of PLA2s might help in the development of new pharmaceutical drugs, more specific antivenom, or even as alternative approaches for treating snakebites. PMID- 24171160 TI - Environmental Kuznets curve analysis of the economic development and nonpoint source pollution in the Ningxia Yellow River irrigation districts in China. AB - This study applies the environmental Kuznets curve to test the relationship between the regional economic growth and the different types of agricultural nonpoint source pollution loads in the Ningxia Yellow River irrigation area by using the Johnes export coefficient method. Results show that the pollution load generated by crop cultivation and livestock-breeding industries in the Ningxia Yellow River irrigation area shows an inverted U-shaped feature; however, this feature is absent in living-sewage pollution load. Crop pollution has shown a decreasing trend since 1997 because of the increased per capita income of farmers. Livestock-breeding pollution load reached its turning point when the per capita income of farmers reached 8386.74 RMB. Therefore, an increase in the per capita income of farmers corresponds to an increase in the livestock-breeding pollution load in the Ningxia Yellow River irrigation area. PMID- 24171161 TI - Constitutive optimized production of streptokinase in Saccharomyces cerevisiae utilizing glyceraldehyde 3-phosphate dehydrogenase promoter of Pichia pastoris. AB - A novel expression vector constructed from genes of Pichia pastoris was applied for heterologous gene expression in Saccharomyces cerevisiae. Recombinant streptokinase (SK) was synthesized by cloning the region encoding mature SK under the control of glyceraldehyde 3-phosphate dehydrogenase (GAP) promoter of Pichia pastoris in Saccharomyces cerevisiae. SK was intracellularly expressed constitutively, as evidenced by lyticase-nitroanilide and caseinolytic assays. The functional activity was confirmed by plasminogen activation assay and in vitro clot lysis assay. Stability and absence of toxicity to the host with the recombinant expression vector as evidenced by southern analysis and growth profile indicate the application of this expression system for large-scale production of SK. Two-stage statistical approach, Plackett-Burman (PB) design and response surface methodology (RSM) was used for SK production medium optimization. In the first stage, carbon and organic nitrogen sources were qualitatively screened by PB design and in the second stage there was quantitative optimization of four process variables, yeast extract, dextrose, pH, and temperature, by RSM. PB design resulted in dextrose and peptone as best carbon and nitrogen sources for SK production. RSM method, proved as an efficient technique for optimizing process conditions which resulted in 110% increase in SK production, 2352 IU/mL, than for unoptimized conditions. PMID- 24171162 TI - Feasibility, reproducibility, and agreement between different speckle tracking echocardiographic techniques for the assessment of longitudinal deformation. AB - BACKGROUND: Left ventricular (LV) longitudinal deformation can be assessed with new echocardiographic techniques like triplane echocardiography (3PE) and four dimensional echocardiography (4DE). We aimed to assess the feasibility, reproducibility, and agreement between these different speckle-tracking techniques for the assessment of longitudinal deformation. METHODS: 101 consecutive subjects underwent echocardiographic examination. 2D cine loops from the apical views, a triplane view, and an LV 4D full volume were acquired in all subjects. LV longitudinal strain was obtained for each imaging modality. RESULTS: 2DE analysis of LV strain was feasible in 90/101 subjects, 3PE strain in 89/101, and 4DE strain in 90/101. The mean value of 2DE and 3PE longitudinal strains was significantly higher with respect to 4DE. The relationship between 2DE and 3PE derived strains (r = 0.782) was significantly higher (z = 3.72, P < 0.001) than that between 2DE and 4DE (r = 0.429) and that between 3PE and 4DE (r = 0.510; z = 3.09, P = 0.001). The mean bias between 2DE and 4DE strains was -6.61 +/- 7.31% while -6.42 +/- 6.81% between 3PE and 4DE strains; the bias between 2DE and 3PE strain was of 0.21 +/- 4.16%. Intraobserver and interobserver variabilities were acceptable among the techniques. CONCLUSIONS: Echocardiographic techniques for the assessment of longitudinal deformation are not interchangeable, and further studies are needed to assess specific reference values. PMID- 24171163 TI - Familial aggregation of metabolic syndrome indicators in Portuguese families. AB - BACKGROUND AND AIMS: Family studies are well suited to investigate the genetic architecture underlying the metabolic syndrome (MetS). The purposes of this paper were (i) to estimate heritabilities for each of the MetS indicators, and (ii) to test the significance of familial intratrait and cross-trait correlations in MetS markers. METHODS AND RESULTS: This study included 1,363 individuals from 515 Portuguese families in which five MetS components, including waist circumference (WC), blood pressure (BP), HDL-cholesterol, triglycerides (TG), and glucose (GLU), were measured. Intratrait and cross-trait familial correlations of these five components were estimated using Generalized Estimating Equations. Each MetS component was significantly heritable (h (2) ranged from 0.12 to 0.60) and exhibited strong familial resemblance with correlations between biological relatives of similar magnitude to those observed between spouses. With respect to cross-trait correlations, familial resemblance was very weak except for the HDL TG pair. CONCLUSIONS: The present findings confirm the idea of familial aggregation in MetS traits. Spousal correlations were, in general, of the same magnitude as the biological relatives' correlations suggesting that most of the phenotypic variance in MetS traits could be explained by shared environment. PMID- 24171164 TI - Bioactive compounds and antioxidant activity of fresh and processed white cauliflower. AB - Brassica species are very rich in health-promoting phytochemicals, including phenolic compounds, vitamin C, and minerals. The objective of this study was to investigate the effect of different blanching (i.e., water and steam) and cooking (i.e., water boiling, steam boiling, microwaving, and stir-frying) methods on the nutrient components, phytochemical contents (i.e., polyphenols, carotenoids, flavonoid, and ascorbic acid), antioxidant activity measured by DPPH assay, and phenolic profiles of white cauliflower. Results showed that water boiling and water blanching processes had a great effect on the nutrient components and caused significant losses of dry matter, protein, and mineral and phytochemical contents. However, steam treatments (blanching and cooking), stir-frying, and microwaving presented the lowest reductions. Methanolic extract of fresh cauliflower had significantly the highest antioxidant activity (68.91%) followed by the extracts of steam-blanched, steam-boiled, stir-fried, and microwaved cauliflower 61.83%, 59.15%, 58.93%, and 58.24%, respectively. HPLC analysis revealed that the predominant phenolics of raw cauliflower were protocatechuic acid (192.45), quercetin (202.4), pyrogallol (18.9), vanillic acid (11.90), coumaric acid (6.94), and kaempferol (25.91) mg/100 g DW, respectively. PMID- 24171165 TI - Modulation of the effects of lung immune response on bone marrow by oral antigen exposure. AB - Allergic airway inflammation is attenuated by oral tolerization (oral exposure to allergen, followed by conventional sensitization and challenge with homologous antigen), which decreases airway allergen challenge-induced eosinophilic infiltration of the lungs and bone marrow eosinophilia. We examined its effects on bone marrow eosinophil and neutrophil production. Mice of wild type (BP-2, BALB/c, and C57BL/6) and mutant strains (lacking iNOS or CD95L) were given ovalbumin (OVA) or water (vehicle) orally and subsequently sensitized and challenged with OVA (OVA/OVA/OVA and H2O/OVA/OVA groups, resp.). Anti-OVA IgG and IgE, bone marrow eosinophil and neutrophil numbers, and eosinophil and neutrophil production ex vivo were evaluated. T lymphocytes from OVA/OVA/OVA or control H2O/OVA/OVA donors were transferred into naive syngeneic recipients, which were subsequently sensitized/challenged with OVA. Alternatively, T lymphocytes were cocultured with bone marrow eosinophil precursors from histocompatible sensitized/challenged mice. OVA/OVA/OVA mice of the BP-2 and BALB/c strains showed, relative to H2O/OVA/OVA controls, significantly decreased bone marrow eosinophil counts and ex vivo eosinopoiesis/neutropoiesis. Full effectiveness in vivo required sequential oral/subcutaneous/intranasal exposures to the same allergen. Transfer of splenic T lymphocytes from OVA/OVA/OVA donors to naive recipients prevented bone marrow eosinophilia and eosinopoiesis in response to recipient sensitization/challenge and supressed eosinopoiesis upon coculture with syngeneic bone marrow precursors from sensitized/challenged donors. PMID- 24171166 TI - Molecular and immunogenic properties of apyrase SP01B and D7-related SP04 recombinant salivary proteins of Phlebotomus perniciosus from Madrid, Spain. AB - Sand fly salivary proteins are on the spotlight to become vaccine candidates against leishmaniasis and to markers of exposure to sand fly bites due to the host immune responses they elicit. Working with the whole salivary homogenate entails serious drawbacks such as the need for maintaining sand fly colonies and the laborious task of glands dissection. In order to overcome these difficulties, producing recombinant proteins of different vectors has become a major task. In this study, a cDNA library was constructed with the salivary glands of Phlebotomus perniciosus from Madrid, Spain, the most widespread vector of Leishmania infantum in the Mediterranean basin. Analysis of the cDNA sequences showed several polymorphisms among the previously described salivary transcripts. The apyrase SP01B and the D7-related protein SP04 were successfully cloned, expressed in Escherichia coli, and purified. Besides, recombinant proteins were recognized by sera of hamsters and mice previously immunized with saliva through the exposure to uninfected sand fly bites. These results suggest that these two recombinant proteins conserved their immunogenic properties after expression in a prokaryote system. Therefore, this work contributes to expand the knowledge of P. perniciosus saliva that would be eventually used for the development of tools for vector control programs. PMID- 24171167 TI - Evaluation of fatty acid and amino acid compositions in okra (Abelmoschus esculentus) grown in different geographical locations. AB - Okra has different uses as a food and a remedy in traditional medicine. Since it produces many seeds, distribution of the plant is also quite easy. Although seed oil yield is low (4.7%), since the linoleic acid composition of the seed oil is quiet high (67.5%), it can still be used as a source of (UNSAT) unsaturated fatty acids. In this study, samples of okra grown in four different locations were analyzed to measure fatty acid and amino acid compositions. The content of the lipid extraction ranged from 4.34% to 4.52% on a dry weight basis. Quantitatively, the main okra fatty acids were palmitic acid (29.18-43.26%), linoleic acid (32.22-43.07%), linolenic acid (6.79-12.34%), stearic acid (6.36 7.73%), oleic acid (4.31-6.98%), arachidic acid (ND-3.48%), margaric acid (1.44 2.16%), pentadecylic acid (0.63-0.92%), and myristic acid (0.21-0.49%). Aspartic acid, proline, and glutamic acids were the main amino acids in okra pods, while cysteine and tyrosine were the minor amino acids. Statistical methods revealed how the fatty acid and amino acid contents in okra may be affected by the sampling location. PMID- 24171168 TI - Biomedical and clinical promises of human pluripotent stem cells for neurological disorders. AB - Neurological disorders are characterized by the chronic and progressive loss of neuronal structures and functions. There is a variability of the onsets and causes of clinical manifestations. Cell therapy has brought a new concept to overcome brain diseases, but the advancement of this therapy is limited by the demands of specialized neurons. Human pluripotent stem cells (hPSCs) have been promised as a renewable resource for generating human neurons for both laboratory and clinical purposes. By the modulations of appropriate signalling pathways, desired neuron subtypes can be obtained, and induced pluripotent stem cells (iPSCs) provide genetically matched neurons for treating patients. These hPSC derived neurons can also be used for disease modeling and drug screening. Since the most urgent problem today in transplantation is the lack of suitable donor organs and tissues, the derivation of neural progenitor cells from hPSCs has opened a new avenue for regenerative medicine. In this review, we summarize the recent reports that show how to generate neural derivatives from hPSCs, and discuss the current evidence of using these cells in animal studies. We also highlight the possibilities and concerns of translating these hPSC-derived neurons for biomedical and clinical uses in order to fight against neurological disorders. PMID- 24171169 TI - Hyaluronic acid derived from other streptococci supports Streptococcus pneumoniae in vitro biofilm formation. AB - We investigate the role of hyaluronic acid (HA) on S. pneumoniae in vitro biofilm formation and evaluate gene expressions of virulence and/or biofilm related genes. Biofilms were grown in medium supplied with HA derived from capsule of Streptococcus equi. The biomasses of biofilms were detected by crystal-violet (CV) microtiter plate assay, and the morphology was viewed under scanning electron microscope (SEM). The gene expressions were assessed by relative quantitative RT-PCR. The results showed that the HA support pneumococcal growth in planktonic form and within biofilms. The CV-microtiter plate assay detected significantly increased biofilm growth in medium containing HA. The SEM analysis revealed thick and organized biofilms in positive control and HA supplemented medium. The nanA, nanB, bgaA, strH, luxS, hysA, ugl, and PST-EIIA encoding genes were significantly upregulated in the planktonic cells grown in presence of HA, while the lytA and comA genes were downregulated. Similarly the luxS, hysA, ugl, and PST-EIIA encoding genes were significantly upregulated by more than 2-folds in HA biofilms. The results of this study indicate that the HA derived from capsule of S. equi supports pneumococcal growth in planktonic state and within biofilms and upregulated virulence and biofilm related genes. PMID- 24171170 TI - Biomaterials-based modulation of the immune system. AB - The immune system is traditionally considered from the perspective of defending against bacterial or viral infections. However, foreign materials like implants can also illicit immune responses. These immune responses are mediated by a large number of molecular signals, including cytokines, antibodies and reactive radical species, and cell types, including macrophages, neutrophils, natural killer cells, T-cells, B-cells, and dendritic cells. Most often, these molecular signals lead to the generation of fibrous encapsulation of the biomaterials, thereby shielding the body from these biomaterials. In this review we will focus on two different types of biomaterials: those that actively modulate the immune response, as seen in antigen delivery vehicles for vaccines, and those that illicit relatively small immune response, which are important for implantable materials. The first serves to actively influence the immune response by co opting certain immune pathways, while the second tries to mimic the properties of the host in an attempt to remain undetected by the immune system. As these are two very different end points, each type of biomaterial has been studied and developed separately and in recent years, many advances have been made in each respective area, which will be highlighted in this review. PMID- 24171171 TI - Advanced systems biology methods in drug discovery and translational biomedicine. AB - Systems biology is in an exponential development stage in recent years and has been widely utilized in biomedicine to better understand the molecular basis of human disease and the mechanism of drug action. Here, we discuss the fundamental concept of systems biology and its two computational methods that have been commonly used, that is, network analysis and dynamical modeling. The applications of systems biology in elucidating human disease are highlighted, consisting of human disease networks, treatment response prediction, investigation of disease mechanisms, and disease-associated gene prediction. In addition, important advances in drug discovery, to which systems biology makes significant contributions, are discussed, including drug-target networks, prediction of drug target interactions, investigation of drug adverse effects, drug repositioning, and drug combination prediction. The systems biology methods and applications covered in this review provide a framework for addressing disease mechanism and approaching drug discovery, which will facilitate the translation of research findings into clinical benefits such as novel biomarkers and promising therapies. PMID- 24171172 TI - Hypoxia and human genome stability: downregulation of BRCA2 expression in breast cancer cell lines. AB - Previously, it has been reported that hypoxia causes increased mutagenesis and alteration in DNA repair mechanisms. In 2005, an interesting study showed that hypoxia-induced decreases in BRCA1 expression and the consequent suppression of homologous recombination may lead to genetic instability. However, nothing is yet known about the involvement of BRCA2 in hypoxic conditions in breast cancer. Initially, a cell proliferation assay allowed us to hypothesize that hypoxia could negatively regulate the breast cancer cell growth in short term in vitro studies. Subsequently, we analyzed gene expression in breast cancer cell lines exposed to hypoxic condition by microarray analysis. Interestingly, genes involved in DNA damage repair pathways such as mismatch repair, nucleotide excision repair, nonhomologous end-joining and homologous recombination repair were downregulated. In particular, we focused on the BRCA2 downregulation which was confirmed at mRNA and protein level. In addition, breast cancer cells were treated with dimethyloxalylglycine (DMOG), a cell-permeable inhibitor of both proline and asparaginyl hydroxylases able to induce HIF-1 alpha stabilization in normoxia, providing results comparable to those previously described. These findings may provide new insights into the mechanisms underlying genetic instability mediated by hypoxia and BRCA involvement in sporadic breast cancers. PMID- 24171173 TI - Risk management in magnetic resonance: failure mode, effects, and criticality analysis. AB - The aim of the study was to perform a risk management procedure in "Magnetic Resonance Examination" process in order to identify the critical phases and sources of radiological errors and to identify potential improvement projects including procedures, tests, and checks to reduce the error occurrence risk. In this study we used the proactive analysis "Failure Mode Effects Criticality Analysis," a qualitative and quantitative risk management procedure; has calculated Priority Risk Index (PRI) for each activity of the process; have identified, on the PRI basis, the most critical activities and, for them, have defined improvement projects; and have recalculated the PRI after implementation of improvement projects for each activity. Time stop and audits are performed in order to control the new procedures. The results showed that the most critical tasks of "Magnetic Resonance Examination" process were the reception of the patient, the patient schedule drafting, the closing examination, and the organization of activities. Four improvement projects have been defined and executed. PRI evaluation after improvement projects implementation has shown that the risk decreased significantly following the implementation of procedures and controls defined in improvement projects, resulting in a reduction of the PRI between 43% and 100%. PMID- 24171175 TI - HPLC quantitative analysis of rhein and antidermatophytic activity of Cassia fistula pod pulp extracts of various storage conditions. AB - Cassia fistula is well known for its laxative and antifungal properties due to anthraquinone compounds in the pods. This study quantitatively analyzed rhein in the C. fistula pod pulp decoction extracts kept under various storage conditions using HPLC. The antifungal activity of the extracts and their hydrolyzed mixture was also evaluated against dermatophytes. The contents of rhein in all stored decoction extracts remained more than 95% (95.69-100.66%) of the initial amount (0.0823 +/- 0.001% w/w). There was no significant change of the extracts kept in glass vials and in aluminum foil bags. The decoction extract of C. fistula pod pulp and its hydrolyzed mixture containing anthraquinone aglycones were tested against clinical strains of dermatophytes by broth microdilution technique. The results revealed good chemical and antifungal stabilities against dermatophytes of C. fistula pod pulp decoction extracts stored under various accelerated and real time storage conditions. PMID- 24171174 TI - The use of multidimensional data to identify the molecular biomarker for pancreatic ductal adenocarcinoma. AB - Pancreatic ductal adenocarcinoma (PDAC) is a lethal disease, and the patient has an extremely poor overall survival with a less than 5% 5-year survival rate. Development of potential biomarkers provides a critical foundation for the diagnosis of PDAC. In this project, we have adopted an integrative approach to simultaneously identify biomarker and generate testable hypothesis from multidimensional omics data. We first examine genes for which expression levels are correlated with survival data. The gene list was screened with TF regulation, predicted miRNA targets information, and KEGG pathways. We identified that 273 candidate genes are correlated with patient survival data. 12 TF regulation gene sets, 11 miRNAs targets gene sets, and 15 KEGG pathways are enriched with these survival genes. Notably, CEBPA/miRNA32/PER2 signaling to the clock rhythm qualifies this pathway as a suitable target for therapeutic intervention in PDAC. PER2 expression was highly associated with survival data, thus representing a novel biomarker for earlier detection of PDAC. PMID- 24171178 TI - Cognitive diagnostic errors. PMID- 24171176 TI - Proteinase-activated receptor-2 agonist activates anti-influenza mechanisms and modulates IFNgamma-induced antiviral pathways in human neutrophils. AB - Proteinase-activated receptor-2 (PAR2) is expressed by human leukocytes and participates in the development of inflammatory diseases. Recent studies demonstrated an ability of PAR2 agonist to enhance IFNgamma-induced antiviral responses of human leukocytes. However, the precise cellular antiviral defense mechanisms triggered in leukocytes after stimulation with IFNgamma and/or PAR2 agonist remain elusive. Therefore, we aimed to identify neutrophil defense mechanisms involved in antiviral resistance. Here we demonstrated that PAR2 agonist enhanced IFNgamma-related reduction of influenza A virus (IAV) replication in human neutrophils. PAR2-mediated decrease in IAV replication was associated with reduced NS-1 transcription. Moreover, PAR2-dependent neutrophil activation resulted in enhanced myeloperoxidase degranulation and extracellular myeloperoxidase disrupted IAV. The production of ROS was elevated in response to PAR2 activation. Interestingly, IFNgamma did not influence both effects: PAR2 agonist-triggered myeloperoxidase (MPO) release and reactive oxygen species (ROS) production, which are known to limit IAV infections. In contrast, orthomyxovirus resistance gene A (MxA) protein expression was synergistically elevated through PAR2 agonist and IFNgamma in neutrophils. Altogether, these findings emphasize two PAR2-controlled antiviral mechanisms that are independent of or modulated by IFNgamma. PMID- 24171179 TI - The psychosocial and affective burden of posttraumatic neuropathy following injuries to the trigeminal nerve. AB - AIMS: To explore the impact of trigeminal nerve injuries on quality of life, including the effect of pain on psychological and affective function. METHODS: An observational, cross-sectional survey design was employed. Fifty-six patients with inferior alveolar nerve injury (IANI) and 33 patients with lingual nerve injury (LNI) completed standardized self-report measures of pain intensity, pain catastrophizing, self-efficacy to cope with pain, and mood, in addition to generic and oral health-related quality of life (HRQoL) indicators. The impact of pain severity on these aspects of psychosocial function was examined. Summary statistics were calculated for all measures and compared with norms or values of other relevant studies, when available, using t tests. The impact of pain severity on these aspects of psychosocial function was examined using analysis of variance and hierarchical multivariate regression models. RESULTS: The majority of patients reported pain associated with their nerve injury (86%). Nerve injury had a significant impact on all investigated domains, and this was closely linked with reported pain levels. Patients with severe pain showed particularly elevated levels of depression and pain catastrophizing, as well as substantially reduced HRQoL and coping efficacy levels. Pain intensity level was a significant predictor in all models except anxiety, uniquely contributing between 17% and 26% of variance to the prediction of pain catastrophizing, depression, coping efficacy, and generic and oral HRQoL. CONCLUSION: Traumatic injury to the trigeminal nerve is associated with a substantial patient burden, particularly in patients who experience severe neuropathic pain as part of their condition. These findings highlight the need to identify, develop, and evaluate more effective treatments for neuropathic pain in trigeminal nerve injury that will not only provide clinically meaningful reductions in pain but also improve patients' quality of life. PMID- 24171177 TI - Cardiac diastolic evaluation in pregnant women with abnormal glucose tolerance: an opportunity to detect the early and subclinical alterations and prevent cardiovascular diseases. AB - OBJECTIVES: of this study were to assess diastolic function in pregnant women with abnormal glucose tolerance (AGT), compared with normal glucose tolerance (NGT) women, and to evaluate the insulin resistance status and its association with Doppler-echocardiographic indexes. Echocardiograms of 108 consecutive Caucasian women with singleton pregnancies were performed. Insulin resistance status was estimated by the homeostasis model assessment of insulin resistance (HOMA-IR) and the quantitative insulin sensitivity check index (QUICKI). All the studied women showed normal diastolic patterns. Patients with AGT (50.9%), as compared with NGT women, had higher HOMA-IR (1.70 +/- 1.30 versus 1.01 +/- 0.81, P = 0.003), lower QUICKI (0.36 +/- 0.005 versus 0.40 +/- 0.06, P = 0.004), higher lateral mitral annulus late diastolic velocity (13.6 +/- 4.9 versus 11.9 +/- 4.9, P = 0.03), and higher A-wave velocity, the wave responsible for the active atrial contraction component (75.2 +/- 14.2 versus 67.7 +/- 16.2, P = 0.01). At multivariate regression analysis HOMA-IR was the only parameter associated with A wave velocity. In conclusion, women with AGT had an increased subclinical diastolic active participation, which is associated with higher levels of insulin resistance. For the increased risk of deterioration of cardiac diastolic function, earlier and more seriously than normal pregnancy, AGT women may have a careful followup to detect the early signs of cardiac alteration and to prevent cardiovascular diseases. PMID- 24171180 TI - Sleep disturbance in patients with burning mouth syndrome: a case-control study. AB - AIM: To examine sleep complaints in patients with burning mouth syndrome (BMS) and the relationships between these disturbances, negative mood, and pain. METHODS: Fifty BMS patients were compared with an equal number of healthy controls matched for age, sex, and educational level. The Pittsburgh Sleep Quality Index (PSQI), the Epworth Sleepiness Scale (ESS), the Hamilton Rating Scales for Depression (HAM-D) and Anxiety (HAM-A) were administered. Descriptive statistics, including the Mann-Whitney U test and hierarchical multiple linear regression analyses were used. RESULTS: BMS patients had higher scores in all items of the PSQI and ESS than the healthy controls (P < .001). In the BMS patients, a depressed mood and anxiety correlated positively with sleep disturbances. The Pearson correlations were 0.68 for PSQI vs HAM-D (P < .001) and 0.63 for PSQI vs HAM-A (P < .001). CONCLUSION: BMS patients reported a greater degree of sleep disorders, anxiety, and depression as compared with controls. Sleep disorders could influence quality of life of BMS patients and could be a possible treatment target. PMID- 24171181 TI - Research Diagnostic Criteria Axis II in screening and as a part of biopsychosocial subtyping of Finnish patients with temporomandibular disorder pain. AB - AIMS: To assess Research Diagnostic Criteria for Temporomandibular Disorders (RDC/TMD) Axis II variables in an initial psychosocial screening and as a part of biopsychosocial subtyping of Finnish referral patients with TMD pain for adjunct multidisciplinary assessment. METHODS: Consecutive Finnish referral patients with TMD pain (n = 135) participated in this questionnaire-based survey. Psychosocial screening was based on Graded Chronic Pain Scale (GCPS) and culturally adjusted Symptom Checklist 90-revised (SCL-90R) depression scale scores and subtyping on GCPS pain-related interference in accordance with previous treatment tailoring studies. Biopsychosocial subtyping variables included symptoms of depression and somatization, general health, pain-related worry, sleep dysfunction, and coping ability. Subtype comparisons were analyzed with Bonferroni adjusted P values and multivariable logistic regression (SAS 9.3). RESULTS: Based on psychosocial screening, 44% of the patients were psychosocially uncompromised (TMD subtype 1), 33% moderately, and 23% severely compromised (TMD subtypes 2 and 3). Compared to TMD subtype 1, TMD subtype 2 patients reported intermediate scores, and the most vulnerable TMD subtype 3 had the poorest general health, most elevated depression, somatization, worry and sleep dysfunction, and poor coping ability (P < .05). According to multivariable logistic regression, depression and worry levels were significantly higher in TMD subtype 3 compared to TMD subtype 1, whilst patients in TMD subtypes 1 and 2 reported significantly better coping ability compared to TMD subtype 3 (P < .05). CONCLUSION: The Finnish RDC/TMD Axis II was found reliable in initial TMD pain patient screening and with further biopsychosocial assessment identified three main TMD subtypes, two with compromised psychosocial profiles for adjunct multidisciplinary assessment. PMID- 24171183 TI - Application of a new palpometer for intraoral mechanical pain sensitivity assessment. AB - AIMS: To investigate the reliability and magnitude of intraoral mechanical pain sensitivity by using a palpometer with add-on devices with different physical properties. METHODS: Sixteen healthy volunteers participated. Three palpometers (0.5, 1.0, and 2.0 kg) were used. Add-on devices were put on the circular metal stamp of the palpometer. Four diameters (3, 4, 5, and 10 mm) and two shapes of the rubber-top (flat and round) of the add-on devices were tested at each force level, ie, a total of 24 combinations. Participants were stimulated at the gingival mucosa around the maxillary central incisors and first molars on both sides by using the palpometers in randomized order. Participants rated perceived stimulus intensity on a 0-50-100 numerical rating scale (NRS). Ten volunteers were examined twice on the same day and recalled for a second session for assessment of within- and between-session reliability. Intraclass correlation coefficients were calculated for reliability measures, and NRS scores were analyzed with analysis of variance. RESULTS: Reliability of NRS scores was excellent (interclass correlation coefficients 0.76 to 0.99). Analysis of NRS values corrected for pressure level revealed that there were main effects of site (P = .006), force (P < .001), size (P < .001), and shape (P < .001) but not side (P = .051). CONCLUSION: Reliability of intraoral novel palpometer measures of pressure sensitivity was excellent, and sensitivity to pressure stimulation was dependent on the applied force and physical properties of the add-on device. The study indicated that semi-quantitative assessment of intraoral mechanical sensitivity is feasible and could be applied in further studies on different intraoral pain conditions. PMID- 24171182 TI - Treatment of comorbid migraine and temporomandibular disorders: a factorial, double-blind, randomized, placebo-controlled study. AB - AIMS: To investigate the effectiveness of single and concomitant treatment of migraine and temporomandibular disorders (TMD) in women with the comorbidity. METHODS: Eligible female patients met International Classification of Headache Disorders, second edition (ICHD-2) criteria for migraine with or without aura and the Research Diagnostic Criteria for myofascial TMD (Grade ll or lll). After a run-in period (30 days), women with both migraine and TMD were enrolled into a four-arm, double-blind, placebo-controlled, factorial study testing the separate and joint effects of a migraine treatment (propranolol 90 mg) and a TMD treatment (stabilization splint [SS]) in four groups of patients. The four treatment groups were propranolol and SS (n = 22); propranolol placebo and SS (n = 23); propranolol and non-occlusal splint (NOS) (n = 23); and propranolol placebo and NOS (n = 21). The primary endpoint for migraine was change in headache days from baseline to the third month, and the secondary endpoint was change in days with at least moderate headache in the same period. The TMD endpoints included pain threshold and mandibular vertical range of motion. Data were analyzed using analysis of variance (ANOVA, Dunn's post-hoc test) or Kruskal-Wallis test. RESULTS: For the primary endpoint, in intention-to-treat (ITT) analyses (n = 94), propranolol and SS were associated with a nonsignificant reduction in the number of headache days, relative to all other groups. For per-protocol (PP) Completer analyses (n = 89), differences in the number of headache days reached significance (P < .05). The propranolol and SS group was significantly superior to the other groups on all other headache endpoints and in disability, in both ITT and PP analyses. No significant differences among groups were seen for the TMD parameters. CONCLUSION: In women with TMD and migraine, migraine significantly improved only when both conditions were treated. The best treatment choice for TMD pain in women with migraine is yet to be defined. PMID- 24171184 TI - The influence of myofascial temporomandibular disorder pain on the pressure pain threshold of women during a migraine attack. AB - AIMS: To assess the influence of myofascial temporomandibular disorder (TMD) pain on the pressure pain threshold (PPT) of masticatory muscles in women during a migraine attack. METHODS: The sample comprised 34 women, 18 to 60 years of age, with a diagnosis of episodic migraine previously confirmed by a neurologist. All subjects were evaluated using the Research Diagnostic Criteria for TMD (RDC/TMD) to determine the presence of myofascial pain. They were divided into two groups: group 1 (n = 18) included women with migraine; group 2 (n = 16) included women with migraine and myofascial TMD pain. Participants were evaluated by measuring PPT values of the masseter and anterior temporalis muscles and Achilles tendon with a pressure algometer at two moments: pain free and during a migraine attack. A three-way analysis of variance with a 5% significance level was used for statistical purposes. RESULTS: Significantly lower PPT values were found during the migraine attack, especially for women with concomitant myofascial pain, regardless of the side of the reported pain. CONCLUSION: Migraine attack is associated with a significant reduction in PPT values of masticatory muscles, which appears to be influenced by the presence of myofascial TMD pain. PMID- 24171185 TI - Pain and intramuscular release of algesic substances in the masseter muscle after experimental tooth-clenching exercises in healthy subjects. AB - AIMS: To investigate whether experimental tooth clenching leads to a release of algesic substances in the masseter muscle. METHODS: Thirty healthy subjects (16 females, 14 males) participated. During two sessions, separated by at least 1 week, intramuscular microdialysis was performed to collect masseter muscle 5 hydroxytryptamine (5-HT) and glutamate as well as the metabolic markers pyruvate and lactate. Two hours after the start of microdialysis, participants were randomized to a 20-min repetitive experimental tooth-clenching task (50% of maximal voluntary contraction) or a control session (no clenching). Pain and fatigue were measured throughout. The Friedman and Wilcoxon tests were used for statistical analyses. RESULTS: No alterations were observed in the concentrations of 5-HT, glutamate, pyruvate, and lactate over time in the clenching or control session, or between sessions at various time points. Pain (P < .01) and fatigue (P < .01) increased significantly over time in the clenching session and were significantly higher after clenching than in the control session (P < .01). CONCLUSION: Low levels of pain and fatigue developed with this experimental tooth clenching model, but they were not associated with an altered release of 5-HT, glutamate, lactate, or pyruvate. More research is required to elucidate the peripheral release of algesic substances in response to tooth clenching. PMID- 24171186 TI - Isobolographic analysis in mice of the interaction of gabapentin and nortriptyline in relieving orofacial pain. AB - AIMS: To evaluate the nature of the antinociceptive interaction of systemic administration of a combination of the anticonvulsant gabapentin with the antidepressant nortriptyline, by isobolographic analysis in the formalin orofacial pain test of mice. METHODS: The study was carried out in 168 male CF-1 mice weighing 30 g, and the protocol was to test each drug (at dosages of 1, 3, 10, 30, and 100 mg/kg of gabapentin and 0.1, 1, 3, 10, and 30 mg/kg of nortriptyline; ip) alone and in combination. The isobolographic assay has two phases: phase 1 corresponds to the 5-minute period starting immediately after the formalin injection and reflects a tonic acute pain due to peripheral nociceptor sensitization; phase 2 is recorded as the 10-minute period starting 20 minutes after the formalin injection and reflects an inflammatory pain state. Results were analyzed by Student t test for independent means. RESULTS: Gabapentin was 1.61 times more potent in phase 2 than in phase 1, and nortriptyline 1.37 times more potent in phase 2 than in phase 1. The combination of both drugs was synergic, with an index of interaction of 0.134 and 0.148 for phase 1 and phase 2, respectively. Differences in the pharmacological profiles of gabapentin and nortriptyline could underlie the synergism of the two drugs. CONCLUSION: The findings of this study are important, because they are concordant with some clinical studies and also raise the possibility of potential clinical advantages of combining gabapentin and nortriptyline in pain management, since the low doses of the components may potentially have a lower incidence of adverse reactions. PMID- 24171187 TI - Cutaneous mastocytosis as a rare differential diagnosis for unilateral chronic facial pain and erythema: a case report. AB - Cutaneous mastocytosis (CM) has been associated with urticaria, itching, and pain of the affected regions. Although the occurrence of CM in the facial skin is rare, it may be a cause of chronic facial pain, and pain characteristics may mistakenly be interpreted as trigeminal nerve pathology. However, the dermatological appearance of the different variants of cutaneous mastocytosis is distinct and should be considered as an uncommon differential diagnosis in an orofacial pain diagnostic algorithm. This article presents a case of telangiectasia macularis eruptiva perstans, a rare type of cutaneous mastocytosis, as the underlying cause of chronic facial pain, erythema, and swelling. PMID- 24171188 TI - Enhancing the sensitivity of chemiresistor gas sensors based on pristine carbon nanotubes to detect low-ppb ammonia concentrations in the environment. AB - The possibility of using novel architectures based on carbon nanotubes (CNTs) for a realistic monitoring of the air quality in an urban environment requires the capability to monitor concentrations of polluting gases in the low-ppb range. This limit has been so far virtually neglected, as most of the testing of new ammonia gas sensor devices based on CNTs is carried out above the ppm limit. In this paper, we present single-wall carbon nanotube (SWCNT) chemiresistor gas sensors operating at room temperature, displaying an enhanced sensitivity to NH3. Ammonia concentrations in air as low as 20 ppb have been measured, and a detection limit of 3 ppb is demonstrated, which is in the full range of the average NH3 concentration in an urban environment and well below the sensitivities so far reported for pristine, non-functionalized SWCNTs operating at room temperature. In addition to careful preparation of the SWCNT layers, through sonication and dielectrophoresis that improved the quality of the CNT bundle layers, the low-ppb limit is also attained by revealing and properly tracking a fast dynamics channel in the desorption process of the polluting gas molecules. PMID- 24171189 TI - Reprotoxicity of gold, silver, and gold-silver alloy nanoparticles on mammalian gametes. AB - Metal and alloy nanoparticles are increasingly developed for biomedical applications, while a firm understanding of their biocompatibility is still missing. Various properties have been reported to influence the toxic potential of nanoparticles. This study aimed to assess the impact of nanoparticle size, surface ligands and chemical composition of gold, silver or gold-silver alloy nanoparticles on mammalian gametes. An in vitro assay for porcine gametes was developed, since these are delicate primary cells, for which well-established culture systems exist and functional parameters are defined. During coincubation with oocytes for 46 h neither any of the tested gold nanoparticles nor the gold silver alloy particles with a silver molar fraction of up to 50% showed any impact on oocyte maturation. Alloy nanoparticles with 80% silver molar fraction and pure silver nanoparticles inhibited cumulus-oocyte maturation. Confocal microscopy revealed a selective uptake of gold nanoparticles by oocytes, while silver and alloy particles mainly accumulated in the cumulus cell layer surrounding the oocyte. Interestingly sperm vitality parameters (motility, membrane integrity and morphology) were not affected by any of the tested nanoparticles. Only sporadic association of nanoparticles with the sperm plasma membrane was found by transmission electron microscopy. In conclusion, mammalian oocytes were sensitive to silver containing nanoparticles. Likely, the delicate process of completing meiosis in maternal gametes features high vulnerability towards nanomaterial derived toxicity. The results imply that released Ag(+)-ions are responsible for the observed toxicity, but the compounding into an alloy seemed to alleviate the toxic effects to a certain extent. PMID- 24171190 TI - Macromolecular ion accelerator mass spectrometer. AB - We present a newly developed macromolecular ion accelerator mass spectrometer that combines a dual-ion-trap device and a macromolecular ion accelerator (MIA) to achieve the capability of analyzing samples with a mixture of large biomolecules. MIA greatly increases detection efficiency. The dual ion trap includes a quadrupole ion trap (QIT) and a linear ion trap (LIT) in tandem. The dual ion trap is mounted ahead of the MIA. The QIT is used to store multiple species, and the LIT is employed to capture the ions that are sequentially ejected out of the QIT. Subsequent to their capture, the ions inside of the LIT are extracted and transferred to the MIA. The synchronization between the QIT and MIA is bridged by the LIT. A sample containing a mixture of several large biomolecules was employed to examine the performance of this new type of mass spectrometer. The result reveals that larger biomolecules show a comparable signal to smaller biomolecules, even though the mixture contains equal quantities of each type of protein. The overall assembly produces a nearly constant detection efficiency over a broad mass range. Thus, this device provides an alternative platform to analyze complex large-protein mixtures. PMID- 24171191 TI - Self-standing mesoporous membranes toward highly selective molecular transportation. AB - Self-standing mesoporous membranes are prepared by full infiltration of ordered mesoporous silica precursors into textural macrospaces of frequently used cellulose membrane filters. We succeed in fabricating composite membranes that hardly contained large cracks/voids under the optimized conditions, realizing highly size-selective rapid transportation of biomolecules by their uniformity. Biomolecules with different sizes are precisely separated at the nanometer-level by using the mesoporous membranes. PMID- 24171192 TI - Reply: To PMID 23680604. PMID- 24171193 TI - Reply: To PMID 23680604. PMID- 24171194 TI - Reply: To PMID 23680604. PMID- 24171195 TI - Reply: To PMID 23680604. PMID- 24171196 TI - Improving the impact. Abstracts of the 23rd Conference on Epidemiology in Occupational Health, EPICOH 2013. June 18-21, 2013, Utrecht, The Netherlands. PMID- 24171197 TI - "Have you ever served in the military?" Campaign in partnership with the Joining Forces initiative. PMID- 24171198 TI - Author response. PMID- 24171199 TI - Response to Kaneko et al. PMID- 24171200 TI - Response to Suri and Schaff. PMID- 24171201 TI - Reply to Crispin et al.: Molecular model that accounts for the biological and physical properties of sialylated Fc. PMID- 24171202 TI - Reply to Cormode et al.: High-density lipoprotein mimicking synthetic nanoparticle. PMID- 24171203 TI - [Editorial comment]. PMID- 24171204 TI - Abstracts of the 13th Meeting of the International Society of Geriatric Oncology. October 23-25, 2013. Lisbon, Portugal. PMID- 24171208 TI - Systematic, in-depth analysis. PMID- 24171210 TI - Common stem -oxetine. PMID- 24171206 TI - Author reply: To PMID 23355498. PMID- 24171209 TI - Intranasal live attenuated seasonal influenza vaccine: does not challenge current practice. AB - Influenza vaccination of children is only justified when there is a risk of serious influenza complications. In 2012, a live attenuated vaccine for intranasal administration was authorised in the European Union for influenza prevention in individuals aged from 2 to less than 18 years. This type of vaccine has been available in the United States since 2003. Clinical evaluation of this live vaccine is based on three non-inferiority trials versus an injected inactivated vaccine. There are no specific trials in children at risk of serious influenza complications. Only one of these trials was double-blinded. Two trials involved children with a history of respiratory problems. Symptomatic influenza confirmed by viral culture was less frequent in these three trials after intranasal vaccination than after injection of the conventional vaccine (about 3 to 5% and 6 to 10%, respectively). There was no difference between the vaccines in terms of clinical complications of influenza, especially asthma exacerbations. Adverse effects attributed to the intranasal vaccine mainly consisted of local reactions such as rhinorrhoea and nasal congestion, as well as flu-like syndromes. Wheezing, respiratory tract infections and hospitalisation were more frequent with the intranasal vaccine than with the injected vaccine in children aged less than 1 year and in children with a history of severe respiratory illness. The intranasal vaccine is contraindicated in these children. The intranasal vaccine contains live attenuated virus strains and is therefore contraindicated in immunocompromised patients. US pharmacovigilance data suggest that severe allergic reactions to the intranasal vaccine, Guillain-Barre syndrome, and transmission of vaccine viruses to contacts are very rare. Intranasal administration seems to be more practical, especially for children. In practice, there is no firm evidence that this live attenuated influenza vaccine has any clinical advantages over injected vaccines, including in children at risk of influenza complications. In addition, this vaccine is unsuitable for the very children who are most in need of protection against influenza. It is better to stick with injected influenza vaccines. PMID- 24171211 TI - Oral fluconazole and vulvovaginal candidiasis: prevention is not always better than cure. AB - Treatment of symptomatic episodes of vulvovaginal candidiasis is effective and less risky than long-term oral fluconazole prophylaxis. PMID- 24171205 TI - The authors reply. PMID- 24171212 TI - Ferumoxytol: an intravenous iron, riskier than iron sucrose. PMID- 24171213 TI - Ciclesonide: long-term treatment of persistent asthma--no clear progress. AB - Inhaled corticosteroids such as beclometasone are the drugs of choice for long term treatment of patients with persistent asthma. There is no tangible difference in efficacy among inhaled corticosteroids, but we have the most experience with beclometasone. Ciclesonide (Alvesco, Nycomed then Takeda), another inhaled cortico-steroid, has been tested in three double-blind trials versus budesonide and six trials versus fluticasone but none versus beclometasone. These trials showed the "non-inferiority" of ciclesonide, mainly in terms of a surrogate endpoint: the change in forced expiratory volume in one second (FEV1) after 12 or 24 weeks of treatment (primary endpoint). However, the doses of ciclesonide used in these trials were higher than the standard doses while doses of the comparator corticosteroids were lower than the standard doses, thus favouring ciclesonide. Local adverse effects of inhaled corticosteroids include oral candidiasis, sore throat and hoarseness. A systematic review conducted by a Cochrane group suggests that ciclesonide does not have a better adverse effect profile than other inhaled corticosteroids used at equivalent doses. Corticosteroid inhalation can also lead to systemic absorption. The practical advantage of once-daily dosing with ciclesonide seems minor. In practice, ciclesonide is neither more effective than the inhaled corticosteroids with which it has been compared, nor does it have fewer adverse effects. It is better to continue to use beclometasone, a drug with which there is more experience. PMID- 24171215 TI - Drug-induced optic neuropathies in brief. PMID- 24171214 TI - Drug-induced peripheral neuropathies. PMID- 24171216 TI - Acitretin: no pregnancy during treatment and, as a precaution, for 3 years after discontinuation. PMID- 24171217 TI - Pramipexole: heart failure. PMID- 24171218 TI - Baclofen and severe alcohol dependence: an uncertain harm-benefit balance as of early 2013. AB - Alcohol dependence is a severe, chronic illness. Even the best-assessed drugs used to maintain abstinence are poorly effective. Some patients remain dependent after several treatment attempts. Baclofen has been tested for its capacity to reduce craving for alcohol. We reviewed the data available as of early 2013, using the standard Prescrire methodology, in order to assess the harm-benefit balance of baclofen in maintaining abstinence or moderation in alcohol-dependent patients. Two double-blind, randomised, placebo-controlled trials conducted by the same team tested baclofen 30 mg/day in 123 alcohol-dependent patients referred to alcohol treatment centres. After 1 or 3 months of followup, more patients remained abstinent in the baclofen group than in the placebo group. In another double-blind, randomised trial, baclofen 30 mg/day was not more effective than placebo in 80 alcohol-dependent patients recruited through advertisements, many of whom were seeking treatment for the first time. Three uncontrolled retrospective series reported the results obtained in 300 alcohol-dependent patients, most of whom were in treatment failure. They were treated with high, escalating doses of baclofen (on average about 150 mg per day, up to 400 mg per day) with the intention of reducing their craving for alcohol. After 3 to 24 months of follow-up, about half of the patients reported moderate or zero alcohol consumption. At moderate doses, baclofen has been used since the 1970s in the treatment of certain forms of muscle spasticity. The main adverse effects reported in this setting were drowsiness (especially early during treatment) and various neuropsychiatric disorders such as dizziness, euphoria, depression, headache, paraesthesias, speech disorders, ataxia and insomnia. The adverse effects of high-dose baclofen are mainly based on monitoring of hundreds of alcohol-dependent patients, 69 reports to French pharmacovigilance centres in 2011, and cases of overdose or accidental ingestion reported to French poison control centres. Confusion and mania were reported, and coma occurred with doses of 200 mg or more. Some data point to an increased risk of suicide. In practice, in early 2013, more data are needed on the efficacy and adverse effects of baclofen in alcohol dependence, compared with other options. Patients who have received thorough, well-balanced information, and decide to try baclofen as a last resort should be included in comparative clinical studies. PMID- 24171219 TI - Role of medications in the manaqement of alcohol dependence. PMID- 24171220 TI - PSA home tests: ban in France is welcome. AB - Prostate cancer screening based on PSA assay has an unfavourable harm-benefit balance. The decision to ban the marketing of PSA home tests in France is fully justified. PMID- 24171221 TI - Secondary cardiovascular prevention: omega-3 fatty acids ineffective. AB - A meta-analysis of comparative clinical trials including about 20,000 patients with a history of cardiovascular disease showed that omega-3 fatty acid supplementation did not reduce the risk of a subsequent cardiovascular event. PMID- 24171222 TI - Bisphenol A: a body of evidence supporting exposure reduction. AB - The "tolerable daily intake" of bisphenol A, established by the European and US regulatory agencies, is based on a small number of reproductive toxicity studies in animals, mostly funded by industry, using protocols that adhere to regulatory guidelines. Many scientists consider these regulatory toxicology tests unsuitable for the evaluation of endocrine disrupters, because they cannot be used to demonstrate the effects of low doses of bisphenol A, observed in dozens of independent studies. Results obtained in studies of high doses of bisphenol A have been extrapolated to predict the effects of low-dose exposure, according to the principle that "the dose makes the poison". The validity of this extrapolation is disputed. Some human studies suggest that bisphenol A causes coronary heart disease, increases the risk of type 2 diabetes, and has harmful effects on reproduction and development. Considerable data from rodent studies suggest that low doses of bisphenol A affect reproduction, lipid metabolism and neurological development, usually following intrauterine or postnatal exposure. In France, the use of bisphenol A in infant feeding bottles has been banned since 30 June 2010, and in food packaging intended for children aged 0 to 3 years since 1 January 2013. The ban is due to be extended to all food packaging as of 1 January 2015. Bisphenol A is not the only substance present in food packaging that could interfere with endocrine function. Too little is known yet about the toxicology of bisphenol A substitutes. Several studies have shown that exposure to bisphenol A in adults and children can be greatly reduced by choosing a varied diet based on fresh foods, and by avoiding the use of plastic tableware. To reduce exposure to bisphenol A and other chemicals with hormonal activity that are present in food packaging, it seems reasonable to encourage the consumption of fresh foods, avoiding canned food and plastic packaging for storing and reheating food and beverages. These precautionary measures are most important for food and beverages intended for pregnant women and young children. PMID- 24171223 TI - The French Sunshine Act: false transparency. PMID- 24171224 TI - [Endocrine-metabolic adjustments during Ramadan fasting in young athletes]. AB - The Islamic precept of R implies important physiological modifications due to the hydric and dietetic restrictions along a whole month plus a day, all of which have a crucial repercussion over the physical and intellectual performance of Muslims, particularly in occidental societies, in which there is no hour readjustments for daily activities. Among the imposed modifications by Ramadan in daily habits, intermittent fasting along day and night causes adaptation mechanisms to optimize the energy consumption. The objective of this study was to analyze the metabolic-endocrine changes that happen during daily working hours, along the month of fasting in young subjects who have to continue their usual activities and sport training. Ten young muslim subjects, male, healthy, set to sport training, ages in between 18 and 25 who completed Ramadan. Plasma biochemical and hormonal parameters were analyzed in plasma, a week before Ramadan, in the first and fourth of the fasting month and a week after conclusion. During Ramadan, have been observed a drop of biochemical parameters along daytime, especially those related to glycemia, being these changes stronger in the first week. The concentration of cortisol found to be significantly high during the whole month as a consequence of adaptation to the change of circadian secretion rhythms. Ramadan obliges subject's organisms to readjust their endocrine and metabolic system in order to preserve the energetic efficiency during daytime. This auto control becomes more efficient as long as the month advances due to physiological adaptations. PMID- 24171225 TI - The authors' reply. PMID- 24171226 TI - Response. PMID- 24171227 TI - [Abstracts of the 97th Congress of the Japanese Society of Legal Medicine. June 26-28, 2013, Sapporo, Japan]. PMID- 24171228 TI - [The 14th result of screening for antineoplastic agents]. PMID- 24171229 TI - [The 15th result of screening for antineoplastic agents]. PMID- 24171230 TI - Lucid dreaming verified by volitional communication during REM sleep. AB - SUMMARY: The occurrence of lucid dreaming (dreaming while being conscious that one is dreaming) has been verified for 5 selected subjects who signaled that they knew they were dreaming while continuing to dream during unequivocal REM sleep. The signals consisted of particular dream actions having observable concomitants and were performed in accordance with pre-sleep agreement. The ability of proficient lucid dreamers to signal in this manner makes possible a new approach to dream research--such subjects, while lucid, could carry out diverse dream experiments marking the exact time of particular dream events, allowing derivation of of precise psychophysiological correlations and methodical testing of hypotheses. PMID- 24171231 TI - [Structures and ways of decision making in thoracic oncology: foreword]. PMID- 24171232 TI - Early benefit assessment for pharmaceuticals in Germany: lessons for policymakers. AB - Since 2011, Germany's Pharmaceutical Market Restructuring Act has mandated that all newly introduced drugs are subject to an assessment of their benefits in relation to a comparator, typically the current standard treatment. For drugs found to have some additional benefit, the manufacturer and the statutory health insurers negotiate a price. For drugs found to have no additional benefit, their price is set in reference to the price of the comparator. This new system is intended to reduce spending on expensive new drugs that are no more effective than existing treatments, while encouraging pharmaceutical companies to invest in innovative drugs that improve health outcomes. The German experience provides lessons for the United States, where comparative effectiveness research is publicly funded but public insurance programs are limited in their ability to use its findings to make coverage or pricing decisions. PMID- 24171233 TI - [To the Editors: The impact of surgery journals. Comment on the report by Harsanyi et al., "Why is the scientometric gap widening? Deterioration of the scientific parameters of surgical specialties."]. PMID- 24171234 TI - [From the medieval manuscript copiers to the world wide web or how much does distance distort? Reply to the comment of Dr. Csaba Gaal on our article "Why is the scientometric gap widening? Deterioration of the scientific parameters of surgical specialties."]. PMID- 24171235 TI - The 18th International Leprosy Congress: Brussels 2013--a special event. AB - Everything is now in place for an excellent Congress. There have been a large number of abstracts submitted of high quality and diversity. There has been a robust process of peer review with a large panel of reviewers. The Scientific Programme is based on these submissions and already there are a large number of people from all over the world registered to attend and participate. However we recognise that it is not possible for everyone to attend and so all the plenary sessions and abstracts for the Congress will be made available in the public domain after the Congress. PMID- 24171236 TI - Quality of life and its domains in leprosy patients after neurolysis: a study using WHOQOL-BREF. AB - Surgical nerve decompression in leprosy is indicated to prevent or treat nerve damage, and to improve sensory motor function and quality of life (QoL). The purpose of this study was to describe QoL of leprosy patients after surgical nerve decompression. Participants who underwent neurolysis in the last 5 years were recruited. The assessment consisted of collecting demographic and clinical information, QoL and its domain scores. Descriptive statistical analysis of demographic and clinical data was presented. Included 33 patients (43 +/- 11.0 years) who had neurolysis with a total of 61 nerves operated. The results of WHOQOL-bref showed that overall QoL mean was 11.2 (+/- 3.63) and domains scored as follow: physical (11.0 +/- 3.56), environment (11.47 +/- 2.11), psychological (13.29 +/- 2.79) and social relations (15.03 +/- 3.66). Measures of QoL should become part of the standard battery of tools used to assess health and well-being and it may contribute to identifying patients' needs in rehabilitation. PMID- 24171237 TI - Detection of previously undetected leprosy cases in Firozabad District (U.P.), India during 2006-2009: a short communication. AB - OBJECTIVES: This study was initiated to assess the extent of undetected (new) leprosy cases in Firozabad District of U.P. METHODS: A sample survey of more than 980,000 people was undertaken in nine blocks of the district during October 2006 to March 2009, using a household questionnaire and a cross section survey. RESULTS: A total of 774 previously undetected cases were detected (7.57 NCDR/10,000 population) over the 2.5 year period of the survey. The characteristics of previously undetected cases are described by age, sex, classification, urban/rural residence and disability. CONCLUSION: There are many undetected leprosy patients in the community. Active surveys can help in detecting previously undetected cases. The current programme is based on information, education and communication (IEC) to encourage case reporting. IEC activities should be designed in such a way that people can suspect leprosy and are self-motivated to know about free treatment, its availability, and effectiveness. PMID- 24171238 TI - Late onset neuropathy in leprosy patients released from treatment: not all due to reactions? AB - OBJECTIVES: To evaluate the clinical, neurophysiological and histological features of cases of neuropathy developing after completion of anti-leprosy treatment, where biopsy showed inflammatory changes. PATIENTS AND METHODS: Seven patients were evaluated by a single neurologist. Electro-neuro-myography and peripheral nerve biopsy were performed in all patients. RESULTS: Median age was 50-6 years. Time from release from treatment and onset of symptoms ranged from 1 to 12 years (median of 6.6 years). Sensory symptoms were the most common complaint, including pain (71%) and paresthesiae (71%). Muscle weakness was found in 51% and muscle atrophy in 43% of the subjects. Peripheral nerve thickening was present in all patients. Neurophysiological studies suggested sensory-motor polyneuropathy and multiple mono-neuropathy. Nerve biopsy showed inflammatory processes with fibrosis of endoneurium, perineurium and epineurium and total or partial loss of fibres. No bacilli were detected with Wade staining. Patients treated with corticosteroids had some relief of symptoms. CONCLUSION: After release from treatment, leprosy patients may insidiously develop progressive peripheral nerve symptoms not fulfilling criteria for relapse or leprosy reactions. Sensory symptoms predominate and peripheral nerve thickening is an important finding. We speculate that these late onset symptoms are secondary to chronic immune-mediated processes in response to antigens of M. leprae. PMID- 24171239 TI - Nerve abscess in primary neuritic leprosy. AB - Nerve abscess is an infrequently reported complication of leprosy. We describe a patient with a pure neuritic type of leprosy with multiple nerve abscesses, who presented with tingling and numbness in the medial aspect of his right forearm and hand. Subsequently he developed pain, redness and swelling over the medial side of his right elbow and the flexor aspect of his right wrist. High-resolution ultrasound showed diffuse thickening of the right ulnar nerve with hypoechoic texture housing a cystic lesion with internal debris suggesting an abscess, at the cubital tunnel. Histopathological examination of the pus and tissue obtained from the abscess revealed presence of granulomas with lepra bacilli. The patient responded to surgery and multidrug therapy. In conclusion, the nerve abscess as the first manifestation of leprosy is uncommon and a high index of suspicion is required to make a correct diagnosis. PMID- 24171240 TI - Schwannoma and nerve abscess of leprosy: differential diagnosis. PMID- 24171241 TI - Pancytopenia due to lepromatous involvement of the bone marrow: successful treatment with multidrug therapy. AB - Leprosy is a chronic infectious disease with a wide spectrum of signs and symptoms depending on the ability of the host's immune system to resist the infection. The disease is frequently associated with sensory loss in skin lesions and damage in peripheral nerve trunks leading to nerve function impairment. In lepromatous leprosy, the immune system offers no protection against the multiplying bacilli and this results in heavy infiltration of the internal organs. We report a case of florid lepromatous leprosy with bone marrow suppression due to the disease, presenting with anemia, leukocytopenia and thrombocytopenia. The hematological abnormalities were fully reversed by mutidrug therapy for leprosy. We suggest that infiltration of the bone marrow by Mycobacterium leprae can cause pancytopenia, which can be cured by treatment of the leprosy alone. PMID- 24171242 TI - Ackerman's tumour of buccal mucosa in a leprosy patient. AB - Leprosy (Hansen's disease) is a chronic granulomatous disease caused by Mycobacterium leprae (Hansen's bacillus). Oral manifestations occur in 20-60% of cases, usually in lepromatous leprosy, and are well documented. They may involve both the oral hard and soft tissues. Incidence of verrucous carcinoma/Ackerman's tumour developing in anogenital region and plantar surfaces of feet in lepromatous leprosy has been sufficiently documented in the literature. However, association of oral verrucous carcinoma with lepromatous leprosy has not been established. We report for the first time a case of verrucous carcinoma of the buccal mucosa occurring in a leprotic patient, with brief review of literature on orofacial manifestations of leprosy. PMID- 24171245 TI - A conceptual protocol for translational research in the complex reality of leprosy. AB - In response to an international strategy to prioritise and focus research efforts in leprosy, this conceptual protocol outlines a research plan to address key translational research priorities. The protocol describes in broad terms a five phase psychosocial and service-related research programme to facilitate: prevention of delay in diagnosis, improvement of adherence with multi-drug therapy, the roll out of chemoprophylaxis and increased participation in community based rehabilitation. The protocol proposes a model of research utilisation and the notion of complexity to form an integrating theoretical framework for exploring and enhancing research translation. The proposed sequential research programme is characterised by traditional and participatory strategies, culminating in participatory implementation of findings. Publication of the conceptual protocol prior to operationalisation and commencement of the research aims to encourage debate, refinement of strategies, collaboration and the optimisation of resources. PMID- 24171246 TI - The trace element analysis in freshwater fish species, water and sediment in Iyidere stream (Rize-Turkey). AB - Many environmental problems like dam construction, agricultural debris, flooding and industrial establishments threaten Iyidere stream (Rize, Turkey) on the southeastern coast of the Black Sea (Turkey). The trace element concentrations in water, fish and sediments in lyidere stream (Rize, Turkey) were investigated in this study. The concentration of six different elements in ten freshwater fish species and sediment was determined using energy dispersive X-ray fluorescence method. A radioisotope excited X-ray fluorescence analysis using the method of multiple standard addition is applied for the elemental analysis of fish and sediments. Water samples for trace metals were analyzed using standard spectrophotometry methods. A qualitative analysis of spectral peaks showed that ten different freshwater fish samples (Chondrostoma colchicum, Chalcalburnus chalcoides, Salmo trutta labrax, Alburnoides bipunctatus, Leuciscus cephalus, Barbus taurus escherichia, Capoeta tinca, Neogobius kessleri, Rutilus frisii, Lampetra lanceolata) and sediment contained phosphorus (P), sulphur (S), chlorine (Cl), potassium (K), calcium (Ca) and titanium (Ti). Heavy metals as toxic elements for biota (Pb, Cd, Hg, Zn and Mn etc.) were not detected in fish, water and sediments. Thus, It can be declared that freshwater fish of Iyidere does not contains health risks for consumers in terms of metal pollution. PMID- 24171244 TI - Use of high resolution ultrasonography as an additional tool in the diagnosis of primary neuritic leprosy: a case report. PMID- 24171248 TI - Isolation of alpha-glucosidase inhibitors produced by an endophytic fungus, Colletotrichum sp. TSC13 from Taxus sumatrana. AB - Colletotrichum sp. have potential to act as antidiabetic agent, due to its alpha glucosidase inhibitory. Therefore, the objective of present study was to isolate and identify the bioactive compounds responsible for the alpha-glucosidase inhibitory activity in Colletotrichum sp. TSC13. The methanol extract of TSC13 mycelia, was partitioned with n-hexane, chloroform and ethyl acetate. The n hexane fraction exhibited the strongest alpha-glucosidase inhibitory activity. Column chromatography of this fraction resulted in 8 sub-fractions (F1-8). Fraction 3 (F3) which showed 71.4 +/- 2.4% inhibition was analysed further. Analysis using GC-MS after methylation of F3 and comparison to spectra databases and confirmation using authentic sample standards showed that F3 had two saturated fatty acid methyl esters, palmitic acid and stearic acid methyl esters and three unsaturated fatty acid methyl esters, oleic acid, linoleic acid and linoleinic acid methyl esters. Unsaturated fatty acids showed higher activity than the saturated fatty acids and the methyl esters form of unsaturated fatty acids showed slightly less active than the free acids. Further analysis using an ethyl acetate extract, it was confirmed that most of the fatty acids were present in the form of free acids. Therefore, it was concluded that the alpha-glucosidase inhibitor compounds in Colletotrichum sp. TSC13 were unsaturated fatty acids. This is the first report that a Colletotrichum sp. from T. sumatrana has alpha glucosidase inhibitory activity. PMID- 24171251 TI - Enrichment of milk with conjugated linoleic acid by supplementing diets with fish and sunflower oil. AB - There is an increase interesting in enrichment of milk with Conjugated Linoleic Acid (CLA) due to its anti-oxidative and anti-carcinogenic properties. The objective of this study was to investigate the effect of supplementing diets fed to lactating goats with sunflower, fish oil and its blend. Eight lactating Nubian goats were fed a base diet (T1), diet supplemented with 2% sunflower oil (on dry matter (DM) basis) (T2), diet supplemented with 2% fish oil (T3) and diet supplemented with 2% sunflower and fish oil (T4) for 84 day. Milk composition milk fat, protein (%) decreased in T2, T3 and T4 compared with control (T1) while there was no significant differences between treatments in milk lactose content. CLA content in milk fat was higher in response to fish oil or sunflower and fish oil blend compared with control (T1). The results indicated that supplementing diets fed to lactating goats with sunflower, fish oil increased CLA contents in the milk 2-4 times than control. PMID- 24171243 TI - Leprosy nerve abscess in Indian male, misdiagnosed as tuberculous lymphadenitis and neuroma. PMID- 24171249 TI - Prevalence of workplace violence in psychiatric wards, Tehran, Iran. AB - Workplace violence is still a problem that nurses may be exposed to in clinical wards. A psychiatric ward is among the most probable one confronting this violence. This study determined the workplace violence in psychiatric wards in Tehran, Iran. Nurses working in Razi Psychiatric Center, Tehran, Iran were enrolled using the International Workplace Violence questionnaire. Among 385 nurses of this ward, 200 subjects completed the questionnaire using a simple random sampling method with a response rate of 91.5%. The prevalence of workplace violence was 71% including mental (93.4%) and physical violence (71.6%). Verbal and sexual violence occurred in 19.1 and 5.5% of subjects, respectively. The 62.3% of the nurses did not report violence because they considered it useless (55.3%) or did not believe to be important (42.1%). The 61.2% believed to the necessity of training courses while 72.7% had completed these courses and 59.6% believed to a reporting system. The need to security guard (56.8%), taking security actions in wards (67.8%) and training of staffs (68.9%) were the most important preventive measures reported to be effective for workplace violence. It seems that training courses, establishing rules to prevent workplace violence, reporting systems, compensating losses from violence, increasing the security at workplace, increasing the number of nurses and providing especial guiding protocols against any workplace violence would promote the wards to control the workplace violence against nurses. PMID- 24171250 TI - Diagnostic value of serum P35 in comparison with tissue P35 in gastric adenocarcinoma and their relationship with microscopic prognostic factors. AB - Early diagnosis of Gastric adenocarcinoma could increase survival of the patients and also remarkably reduce treatment costs. This study aimed at evaluating the diagnostic value of serum P35 in comparison with tissue P35 in gastric adenocarcinoma and their relationship with microscopic prognostic factors. In this descriptive analytical study, 35 patients (74.3% male and 25.7% female with mean age of 63.00 +/- 12.75 years with gastric adenocarcinoma were evaluated. Blood samples were taken from all patients before gastrectomy to evaluate serum P35 with ELISA method and after surgery tissue samples were gathered to evaluate tissue P35 with immunohistochemical method. The relation between tissue and serum P35 with severity of the disease and microscopic findings was assessed. Tissue P35 was negative in 57.1%, positive in 22.9% and very positive in 20%. Mean serum P35 was 1.34 +/- 0.43 mg dL(-1). There was no relation between serum P35 and adenocarcinoma type, tumor grade, vascular and neurological invasion and number of lymph node involved. Serum P35 levels significantly increased by increase in tissue P35 positivity (p = 0.004). There was significant correlation between tissue P35 and adenocarcinoma type (p = 0.006), neurological involvement (p = 0.04) and number of involved lymph nodes (p = 0.001). Although serum P35 level was higher in cases with more lymph node involvement and vascular and neural invasion, the marker was not capable to predict the involvement degree of stomach cancer. In comparison with serum P35, tissue P35 plays more significant role in these cases. PMID- 24171252 TI - Fruits and vegetables diet improves some selected haemorheological parameters predisposing to cardiovascular disease in non insulin dependent diabetes mellitus NIDDM subjects. AB - Fruits and vegetables have been shown to contain vital components that moderate disease conditions. However, there is dearth of information of these effects in Africans diabetic subjects. Thus, we investigated the relative effect of fruits and vegetables on some selected heamorological factors associated with cardiovascular disease in diabetic subjects. Thirty diabetic subjects were selected at the cardiovascular clinic of Olabisi Onabanjo University Teaching Hospital, Sagamu, Nigeria. The subjects with mean Fasting Blood Glucose (FBG) level of 7.8 +/- 0.95 mmold L(-1) were placed on 300 g of fruits and vegetables per day, while they continued their normal medication and food intake. A significant difference (p < 0.05) was noticed between baseline and eight week values in all the parameters, Fibrinogen 262.75 +/- 2.64 to 250.57 +/- 3.98 mg dL(-1), Blood viscosity, 5.96 +/- 0.21 to 4.82 +/- 0.23 m Pas; erythrocyte sedimentation rate 49.40 +/- 2.34 to 32.8 +/- 1.26 min h(-1) and haematocrit 38.8 +/- 1.25 to 44.75 +/- 1.05%. At the eight week the fruits and vegetables were withdrawn for two weeks and the above parameters were reassessed (at the 10th week) which were compared with eight week values. Significant difference p < 0.05 was noticed in E.S.R. 32.8 +/- 1.26 to 38.8 +/- 1.23. However no significant difference (p > 0.05) was observed in haematocrit, 44.75 +/- 1.44 to 42.70 +/- 1.24, Fibrinogen, 254.5 +/- 3.98 to 250.57 +/- 3.16 mg dL(-1). The results showed that regular intake of fruits and vegetables by diabetic subjects may reduce cardiovascular risk factors. PMID- 24171247 TI - Studies of lipid profile, liver function and kidney function parameters of rat plasma after chronic administration of "Sulavajrini Vatika". AB - The successful use of Ayurvedic medicines is for many years but there is no guideline for studying the toxicity of these preparations through preclinical or clinical investigations. The present study was conducted to evaluate the effect of conventionally prepared Sulavajrini Vatika (SBB), an Ayurvedic formulation on various biochemical parameters of experimental animals after chronic administration. The animal used was albino rats (Rattus norvegicus: Sprague Dawley strain) and SBB was administered orally at a single dose of 100 mg kg(-1) b.wt. day(-1), up to 62 days. During the study, forty rats, equally of both sexes, were randomly grouped into four where one male and one female group were used as control and other groups were used as test. Among the lipid components, Triglyceride (TG) was decreased very high significantly in both sexes of animal. The decrease of Total Cholesterol (TC), Very Low Density Lipoprotein (VLDL) and high-density lipoprotein (HDL) were also highly significant. Low Density Lipoprotein (LDL) decreased in all SBB treated group. In the liver function parameters, the total protein and albumin content were increased very high significantly in both sexes of rat. But the bilirubin was decreased insignificantly in male and female rats. Serum Glutamic Pyruvic Transaminase (GPT), Glutamic Oxaloacetic Transaminase (GOT) and Alkaline Phosphatase (ALP) were decreased in all treated animals and it was very high significant. In case of kidney function parameters, creatinine was increased very high significantly but the urea was decreased very high significantly in both sexes of rat. The decrease in uric acid was not significant in none of the sexes of rat. The present study confirms that SBB can be contributory for the complications in diabetics with hyperlipidemia and nephropathy as it lowers most of the lipids components and improves liver function and kidney function parameters. PMID- 24171253 TI - Soybean growth-promotion by Pseudomonas sp. strain VS1 under salt stress. AB - In the present study, we employ Pseudomonas sp. strain VS1 showed in vitro plant growth-promotion characteristics and promoted soybean seed emergence under salt stress. Strain produced indole 3-acetic acid in the presence of salt stresses that exhibited high numbers of lateral root as compared to control. Bacterial strain exhibited growth in DF salt medium amended with 1-aminocyclopropane-1 carboxylate through ACC deaminase activity. Bacterial-treated soybean seeds were subjected to salt stress and significantly enhanced emergence at 7 days after seeding. Strain untreated soybean plants had a 33% seed germination when 200 mM NaCl was applied at 0 DAS and the root length was significantly decreased compared to the strain treated plants (LSD0.05 = 0.21). Most importantly, the application of 200 mM NaCl at 0 DAS resulted in only a 9% of lateral root in untreated plants as compared to strain treated plants. PMID- 24171254 TI - Geminivirus database (GVDB): first database of family Geminiviridae and its genera Begomovirus. AB - Geminivirus Database (GVDB) is an online interactive database of Geminiviridae family. GVDB comprises of partial and complete nucleotide sequences along with duly annotated expressed genes of isolated Begomovirus species. The in silico homology modeling, docking and recombination results obtained for different begomoviral sequences are also mentioned. This database is endowed with comprehensive information about Geminivirus members which grounds infection in various plants species in India assorting from crops, ornamentals plants and common weeds. The home page of this database offers various links associated with current research projects and also the publications related to molecular and in silico study of Begomovirus infection. The main feature of GVDB includes flexible database designs based on platform of PHP allows easy retrieval of the information. The database is made available at www.wikigeminivirus.org. PMID- 24171255 TI - Self-medication with antibiotics:a global challenge of our generation. PMID- 24171256 TI - A literature review on the adverse effects of hypothyroidism on kidney function. AB - Thyroid produce two important hormone of thyroxine or tetraidothyronine (T4) and triidothyronine (T3), which are involved in whole aspect of metabolism. T4 and T3 play vital role in all biochemical function, growth and development in human body. The basic metabolic pathways in kidney and every organ in human controlled by these hormones. T4 and T3 are involved in kidney function in health and diseases condition therefore the pathophysiology of kidney can be directly influenced and regulated by thyroid hormones. Kidney growth, haemodynamic, blood circulation, tubular, electrolyte balance and glomerular filtration rate (GFR) are among such crucial process. Hypothyroidism which accompanied with reduced thyroid hormone production adversely affect the renal functions, development and eventually leading to reduced weight, kidney vascular disorders, electrolyte, tubular transport imbalances, lower filtration rate and other adverse consequences of hypothyroidism. On other hand kidney diseases can also disrupt the thyroid function metabolism resulting in the subsequent hypothyroidism. It is an interesting subject in how thyroid and kidney in health and diseases closely interacted. For the ideal clinical follow up of either of thyroid and renal diseases the two organs should be simultaneously examined for a proper patient management. Close correlation of thyroid and kidney clinical teams are essential to check the cross reactions and adverse interactions which might be produced between these two vital organs to avoid misdiagnosis either of thyroid or kidney abnormalities. PMID- 24171257 TI - Fecundity, embryonic and ovarian development of blue swimming crab, Portunus pelagicus (Linnaeus, 1758) in coastal water of Johor, Malaysia. AB - Blue swimming crab, Portunus pelagicus is widely study and research throughout the Indo-West Pacific, but little is known of its reproductive biology in Malaysia. The present study describes the fecundity, embryonic development and ovarian development stages of the P. pelagicus from Johor coastal water, Malaysia. Carapace width range of berried crabs sampled was from 9.64 to 13.32 cm, while the body weight range was from 75 to 235 g. The mean number of egg produced by females in different sizes ranged from 105443.333 +/- 35448.075 per eggs batch. Mean egg size during embryonic development at stage 1 was 0.307 +/- 0.037, while 0.386 +/- 0.039 and 0.396 +/- 0.033 for stage 2 and stage 3, respectively. Study showed that there was significant (p < 0.05) relationship between the number of eggs and carapace width/body weight. Mean diameter oocyte during ovarian development at stage 1 was 97.732 +/- 12.391 while for stage 2 was 149.516 +/- 23.287. Stage 3 showed increasingly of size with mean diameter was 158.506 +/- 27.616 and 181.013 +/- 24.339 for stage 4. PMID- 24171258 TI - Skeletal ossification impairment in Nile Tilapia (Oreochromis niloticus) after exposure to lead acetate. AB - Heavy metal pollution represents a serious problem facing many of the aquatic organisms. Lead is one of the most toxic elements found in many industrial effluents which are metabolized inside bodies and can cause skeletal deformities by impairing developmental processes and bone formation. This study was undertaken to determine the LC50 of Pb-acetate and detect the effect of 1/10 LC50 exposure on fingerlings of Nile Tilapia (Oreochromis niloticus). Modern and accurate diagnostic methods were used; Scanning Electron Microscopy (SEM) of gills, plain X-ray and Energy-dispersive X-ray Spectroscopy (EDX) of the spinal column to explain the elemental analysis. The results indicated that the 96 h LC50 of lead acetate was 146.8 mg L(-1). SEM showed a distinct degeneration in gill filaments and pavement cells with increasing of mucus secretion after lead exposure. X-ray revealed slight dorsal spinal curvature. EDX analysis of the spinal column of treated fish showed decrease in calcium and phosphorus weight percents, on the other hand Pb appeared in treated fish but not in control ones. Finally this study can spot a light on the dangerous effects of lead toxicity in developing of fish and impairment of their skeletal ossification which may lead to skeletal deformities. PMID- 24171259 TI - Analysis of chromosome and karyotype in Bali cattle and Simmental-Bali (Simbal) crossbreed cattle. AB - Chromosome analysis is very important part for the initial analysis of genetics. Some genetics abnormalities can be detected at the chromosome level and are usually associated with the inherited diseases. Accurate and prompt information need to be obtained for the purposes of the prevention of the genetics abnormalities genetics risk. This study was aimed to find out and to analyze the different size and morphological chromosome of Bali cattle and its crosses with Simmental cattle (Simbal cattle). Ten Simbal cattle (5 male and 5 female) and 5 female Bali cattle were used in this study. Five milliliter blood was collected using venous puncture through the jugular vein of each cattle. Chromosome was derived from white blood cells (lymphocyte) of peripheral blood. The Bali cattle and Simbal cattle have diploid chromosome (2n) of 60, with 29 pair of autosomes and one pair of sex chromosome. All autosomes are acrocentric with centromere index of 25.13 to 29.52% for Simbal cattle and 21.61 to 24.84% for Bali cattle. Sex chromosomes ware sub-metacentric in Simbal cattle either male or female and metacentric in female Bali cattle. Average length of chromosomes of female Simbal, male Simbal and female Bali cattle were 0.29 +/- 0.04 micron, 0.30 +/- 0.05 micron and 0.24 +/- 0.02 micron, respectively. Chromosome size of female Bali cattle was smaller than Simbal cattle. PMID- 24171260 TI - Effect of Pueraria tuberosa DC. (Indian Kudzu) on blood pressure, fibrinolysis and oxidative stress in patients with stage 1 hypertension. AB - The Indian Kudzu (Pueraria tuberosa DC.) is an important medicinal plant widely used in Indian and Chinese traditional systems of medicine. The present study is an attempt to evaluate effect of its tubers on blood pressure, coagulation parameters and antioxidant status in patients with stage 1 (primary) hypertension. In a long-term, single blinded, placebo controlled study; 15 patients with stage 1 hypertension (group 1), were administered 3 g P. tuberosa in two divided doses while another 15 patients (group II) were administered matched placebo for a period of twelve weeks. A significant fall of 25, 11 and 16 mmHg was observed in systolic (p < 0.001), diastolic (p < 0.05) and mean (p < 0.001) blood pressure, respectively at the end of the study. Along with blood pressure reduction, there was a significant (p < 0.01) reduction in plasma fibrinogen and significant enhancement of plasma fibrinolytic activity (p < 0.001) and serum total antioxidant status (p < 0.05). It was tolerated well without any untoward side effects. PMID- 24171261 TI - Distribution of hepatitis C virus genotypes amongst the beta-thalassemia patients in North of Iran. AB - Beta-thalassemia patients have high prevalence for HCV infection. In developing countries, HCV antibody is reported to be high in this group of patients. This study carried out to determine the distribution of HCV genotypes amongst the beta thalassemia patients in North of Iran. The present study has been carried out between February and March 2010 amongst a group of 245 beta-thalassemia patients (125 male and 120 female) referred to the hospitals Mazandaran and Guilan provinces for a blood transfusion. Qualitative analysis of these samples using ELISA and PCR. The PCR positive samples were subjected to genotyping by RFLP method. Of total 245 beta-thalassemia patients who were the subjects of this study, 28 of these patients were diagnosed through PCR test to have RNA virus. For this reason, the prevalence of this illness in this study group was estimated as 11.42%. By using the RFLP technique, the above genotyping were identified and the prevalence of three genotypes, including 3a, 1a and 1b were proved. The genotype 3a was most prevalent. Out of 28 positive samples, 18 (64.3%) samples had this genotype. After that, genotype 1a with 9 positive occurrences (32.1%) and genotype 1b with only 1 positive occurrence (3.6%) were most prevalent. This study demonstrated that the main reason the beta-thalassemia patients became infected with the genotype of the virus was due to receiving infected blood that entered into Iran during the past two decades. PMID- 24171262 TI - Hippocampus and cerebellum function following imipenem treatment in male and female rats: evaluation of sex differences during developmental stage. AB - The B-Lactam antibiotics have been suggested to have some degree of neurotoxicity in experimental animals as well as in clinical situations. This study has been elucidated the alteration in hippocampal and cerebellum function following adolescent imipenem exposure in male and female rats. Hippocampus and cerebellum related behavioral dysfunction in imipenem -treated [intraperitoneally, 40 and 80 mg/kg/day for one week from 23-day-old] rats were analyzed using explorative, motor function, learning and memory tasks [grasping, rotarod, open field shuttle box and Morris water maze tests]. Exposure to imipenem especially in high dosage impaired the motor coordination in male and female rats. There weren't any differences in grasping time in male and female rats. When the rearing and grooming frequency of their recorded in open field test, both males and females were dramatically affected by exposure to imipenem. Compared to the saline, male and female rats trained one week after imipenem injection showed significant memory deficits in the shuttle box and Morris water maze tests. Results in this study suggested that animals treated with imipenem suffer from motor activity and cognitive impairment. However, hippocampal and cerebellum functions of male and female rats were profoundly affected by exposure to imipenem while no sex differences in the most variable were evident. PMID- 24171263 TI - Oxidative stress and micronutrient therapy in malaria: an in vivo study in Plasmodium berghei infected mice. AB - Free radical production from oxidative stress induced by malaria infection plays a major role in the pathogenesis of malaria. However, the use of agents with antioxidant activity may interfere with malaria progression. The study involves an in vivo evaluation of the role of some antioxidant micronutrients in the modulation of malaria infection. Rodent malaria model using Plasmodium berghei NK 65 strain (chloroquine sensitive) was used for the study. Forty five mice of either sex weighing 20.05 +/- 0.02 g were procured for the study. Forty mice were inoculated intraperitoneally with 1 x 10(7) million Plasmodium berghei infected erythrocyte and were administered with 0.2 mL of distilled water, 0.2 mL of vehicle; Tween 80 (control and vehicle group), chloroquine 25 mg kg(-1) and artesunate 4 mg kg(-1) (standard drug group), vitamin A 60 mg kg(-1), vitamin E 100 mg kg(-1), selenium 1 mg kg(-1), zinc 100 mg kg(-1) (test group F, G, H and I, respectively) 72 hours post inoculation. Antioxidant micronutrients demonstrated significant (p < 0.05) schizonticidal activity when compared with negative control during the 4 day curative test. Erythrocyte membrane disability was most markedly elevated in the tween 80 group (426.15%), followed closely by the chloroquine (373.85%) treated group and artesunate group (329.23%) and least in the zinc treated group (32.31%). There was no significant (p > 0.05) difference in MCFI values (0.115 +/- 0.002; 0.114 +/- 0.002 g dL(-1)) between vitamin A treated group and selenium treated group respectively. However, this was significant (p < 0.05) between the micronutrient treated groups and the control (negative, positive and vehicle). Conclusively, antioxidant micronutrients have antimalarial activity which may be due potentiation of erythrocyte membrane stabilization. PMID- 24171264 TI - Phylogenetic relationships between Mediterranean and middle-Asian wild species of the genus Hordeum L. as revealed by biochemical and molecular markers. AB - The phylogenetic relationships of 60 accessions of the genus Hordeum (29 Mediterranean and 20 middle-Asian wild accessions, together with nine American accessions and two of unknown origin), representing together nine species, were investigated by AFLP markers. Three hundred sixty six AFLP fragments were used for studying the molecular genetic diversity among the studied species, 339 out of them were polymorphic. Forty seven protein bands were obtained from the water soluble and the water insoluble seed storage protein by SDS-PAGE electrophoresis of 18 accessions representing nine species (two accessions/species). One band was common to all species and the other 46 bands were polymorphic. The phylogenetic tree deduced from AFLP analysis is concordant to a large extent with that deduced from seed storage protein. Highly significant cophenetic correlation coefficient was obtained between both AFLP (0.96) and seed storage protein (0.89) indicating the reliability of the results. The studied taxa were clustered according to their genome type. All Mediterranean and middle-Asian wild accessions could be integrated into the existing phylogenetic scheme. PMID- 24171265 TI - Insecticidal activity of the aqueous extracts of four under-utilized tropical plants as protectant of cowpea seeds from Callosobruchus maculatus infestation. AB - The test plants species, namely Crotaria retusa, Hyptis suaveolens, Ricinus communis and Tithonia diversifolia were extracted with water. The extracts were evaluated on Callosobruchus maculatus for mortality, oviposition and adult emergence effects. The long-term protectant ability and viability were also investigated. The results showed that the aqueous extracts from T. diversifolia were most effective on C. maculatus, followed by extract from Ricinus communis. The least potent extracts were those extracted from Crotalaria retusa and Hyptis suaveolens. Also, the extracts considerably reduced oviposition by C. maculatus. Extracts from T. diversifolia and R. communis drastically reduced infestation and subsequence damage of the treated cowpea seeds for a period of three months. Most of the treated seeds germinated after 90 days storage period. The results from this study revealed that aqueous extracts from all the four plants species were effective in controlling cowpea bruchid, C. maculatus and could serve as an alternative to synthetic insecticides for protection of stored cowpea seeds against bruchids. PMID- 24171266 TI - Anti herpes simplex-1 activity of a standard extract of Zataria multiflora Boiss. AB - In Rosmarinic Acid (RA) is a phenolic acid which has many biological activities such as antioxidant, anti inflammatory and anti viral effects. In the present study, we have studied the anti Herpes simplex type 1 (HSV-1) effect of methanolic extract of Zataria multiflora which has been standardized on the basis of RA content. Methanolic extract of Zatria multiflora was prepared by maceration method. RA content of plant extract was measured by spectrophotometry method using the calibration curve of RA. Maximum non Toxic Concentration (MNTC) of the plant was determined by neutral red method. MNTC and lower serial dilutions of extract were examined in vitro on vero cells for their effect against HSV-1 using a plaque reduction assay. Acyclovir was used as positive control. Time-dependent antiviral effect of Z. multiflora was studied by adding the extract to HSV-1 infected vero cells at different stages of infection. The percentage of RA was determined as 2.2% in Z. multiflora. This plant was effective in all used concentrations and significantly reduced plaque formation up to 100% at concentrations of 800 and 1000 microg mL(-1). Clearly Z. multiflora revealed both a time and concentration inhibition. It seems that the presence of rosmarinic acid would be a determining factor for anti HSV activity of Z. multiflora. PMID- 24171267 TI - Length-weight relationship of the freshwater clam, Galatea paradoxa (born 1778) from the Volta Estuary, Ghana. AB - The length-weight relationship of the threatened freshwater clam, Galatea paradoxa (Born 1778) from the Volta Estuary, Ghana was studied over a two-year period, from March 2008 to February 2010, to aid in the development of stock assessment models for the sustainable management of the remaining clam stock. Data reported in this study were collected at monthly intervals and covered varying depths of the Estuary ranging from 0.5 to about 10 m. Overall, a total of 5276 clams with shell lengths ranging from 3.40 to 89.24 mm and total weight from 0.10 to 154.00 g were sampled during the study period. The length-weight relationships were highly significant (p < 0.0001) for all the months and the b values ranged from 2.023 (January 2010) to 3.874 (June 2009). The calculated b values indicated that clams exhibited different growth patterns at different periods but overall, the pooled samples of 5276 individuals exhibited an isometric growth pattern (b = 3.003). The observed monthly growth patterns exhibited by G. paradoxa appeared to be largely influenced by the reproductive cycle of the organism. During the periods leading to spawning, the clams generally exhibited positive allometric growth patterns (weight increasing faster than length) which appeared to be strongly linked to the build-up of proteins and carbohydrates in their tissues. Successive negative allometric growth patterns (length increasing faster relative to weight) were, however, observed from March to June 2008 and from December 2009 to February 2010, which are possibly indicative of the loss in tissue weight that occurs as a direct result of the spawning process. It will thus be suitable to institute a close season to coincide with the spawning period of the clams to avoid the harvesting of clams during the spawning period which will enhance future recruitment of the clam stock. PMID- 24171268 TI - Hypoglycemic and antidiabetic profile of the aqueous root extracts of Leptadenia hastata in albino rats. AB - This study was designed to evaluate the antidiabetic profile and the hypoglycaemic activity of aqueous root extracts of L. hastata in normal and alloxan-induced diabetic rats model. Eighty five albino rats were used for this study out of this thirty five were used subjected to experimental diabetes by the use of alloxan at a dose of 160 mg kg(-1) body weight. Seven experimental groups of five rats per group (A-G) were used for this study. A standard antidiabetic drug (insulin) group (B) and normal saline group (G) serves as positive control. The blood glucose lowering activity of the extract, insulin and normal saline groups were monitored at 0, 1, 3, 6, 12 and 18 hpost extract administration. On the other hand the remaining fifty albino rats were used to determine the acute toxicity and the hypoglycemic activity of the extract. The blood glucose levels of the rats were monitored at 0, 7, 14, 21 and 28 days post extract administration. Oral administration of aqueous root extract at 600 and 800 mg kg( 1) b.wt have significantly (p < 0.05) decreased the blood glucose in diabetic albino rats. On the other hand the hypoglycemic activity of the aqueous root extract on normal rats at dose of 1000 mg kg(-1) b.wt have significantly (p < 0.05) decreases blood glucose level in normal albino rats. The results of the current study have demonstrated the antidiabetic and hypoglycaemic effects of L. hastata aqueous root extracts and underscore its potentials in the management of diabetes mellitus especially following prolonged use in days. PMID- 24171269 TI - Risk factors of coronary artery disease in women. AB - The present study aimed at evaluating coronary risk factors in women with definite coronary artery disease. This prospective study was conducted on 250 women with primary diagnosis of acute myocardial infarction or unstable angina. The patients were selected randomly using interview and registering the related risk factors. The primary diagnosis included 11.5% of myocardial infarction and 88.5% of unstable angina. All patients had risk factors. Diabetes was seen in 38.5%, hypertension in 78%, smoking in 27%, cholesterol > 150 mg in 98%, consumption of oral contraceptive in 57%, family history in 28% and limited physical activity in 2.6% of the patients. Body mass index of 59.6% of the patients was equal to or more than 27 kg m(-2). Also, 66.7% of the patients were post menopausal and history of premature hysterectomy was seen in 9.6% of the patients. There were 3 or more risk factors of coronary artery disease in most patients. Considering the known risk factors in women, dyslipidemia, premature menopause, hypertension, oral contraceptives, diabetes and smoking were regarded as the most common ones. PMID- 24171270 TI - Percutaneous balloon mitral valvotomy during pregnancy. AB - Rheumatic mitral valve stenosis continues to be the most frequently encountered clinically significant valvular abnormality in pregnant women. We retrospectively studied the fetal outcomes of patients with severe rheumatic Mitral Valve Stenosis (MS) admitted to hospital with heart failure and underwent Percutaneous Balloon Mitral Valvotomy (PBMV) during pregnancy. We identified all of the pregnant cases with rheumatic MS from February 1st 1994 till February 1st 2011 who underwent PBMV from medical records in the tertiary referral center of Madani Heart Hospital in Tabriz, Iran. Follow up was done by phone call and office visit. During this period 24 pregnant patients with mean ages of 29.45 +/- 5.05 (19-38) had undergone PBMV for severe MS. Fourteen patients could not be reached and were lost to follow-up. PBMV had been performed during second trimester of pregnancy in 20 cases (83.3%) and during third trimester in 4 patients (16.6%). The success rate of PBMV was 100%. Pulmonary artery pressure reduced from 58.88 +/- 21.97 to 38.50 +/- 8.87 (p < 0.05), peak and mean transmitral valve gradient reduced 25.20 +/- 9.71 to 11.03 +/- 3.61 (p < 0.0001), 14.18 +/- 7.60 to 5.00 +/- 1.39 (p = 0.004), respectively. We conducted follow up in 10 patients with good fetal outcome in all except in 2 infants who died during follow up with intractable heart failure. Twenty patients were in normal sinus rhythm at the time of procedure (83.3%) and 4 of them (16.7%) had arterial fibrillation. PBMV during pregnancy could be recommended as a relatively safe procedure for mother and fetus. PMID- 24171271 TI - Novel and emerging therapies safeguarding health of humans and their companion animals: a review. AB - Modern medicine has helped to a great extent to eradicate and cure several diseases of mankind and animals. But the existence of incurable diseases like cancer, Acquired Immunodeficiency Syndrome (AIDS), diabetes or rheumatoid arthritis, side effects of allopathic medicine, increasing trend of antibiotic resistance and chemicals and biopesticides causing dietary risk have made the situation more critical than ever before. Thus, it has become a matter of concern for the scientists and researchers to develop novel therapies. Bacteriophage therapy to treat pathogenic bacterial infections, virophage therapy for conservation of global system and avian egg yolk antibody therapy for designing prophylactic strategies against Gastrointestinal (GI) diseases are interesting approaches. Others include the use of cytokines as adjunctive immunomodulators, gene therapy focusing on diseases caused by single gene defects, RNAi technology to suppress specific gene of interest and apoptins for cancer treatment. Stem cell therapy against several diseases and ailments has also been discussed. The use of nanoparticles for better drug delivery, even though costly, has been given equal importance. Nevertheless, immunomodulation, be it through physiological, chemical or microbial products, or through essential micronutrients, probiotics, herbs or cow therapy prove to be cost-effective, causing minimum adverse reactions when compared to allopathy. Development in the field of molecular biology has created an enormous impact on vaccine development. The present review deals with all these novel and emerging therapies essential to safeguard the health of humans and companion animals. PMID- 24171272 TI - Female reproduction physiology adversely manipulated by thyroid disorders: a review of literature. AB - Proper thyroid function is vital to have a healthy reproduction system. Female sex hormones are altered due to hypothyroidism and hyperthyroidism. Female reproduction system is negatively manipulated by both hyperthyroidism and hypothyroidism and menstrual disorders are the ultimate consequences. Hypomenorrhea, polymenorrhea and oligomenorrhea are the clinical manifestation associated with hyperthyroidism and hypothyroidism, respectively. The female infertility is also adversely affected by thyrotoxicosis and myxedema, the clinical presentation of hyper and hypothyroidism. The simultaneous existence of autoimmunity which is present among some portion of pregnant women may aggravate the clinical manifestation of thyroid disorders in female reproductive physiology. Abortion, premature infants, low birth infant, are among clinical presentation of overt hypothyroidism. Auto antibody against thyroid stimulating hormone receptor and eventual hyperthyroidism considered as risk factors which require extra attention while the thyroid disorder is clinically managed during pregnancy to prevent the fetus from abnormal metabolism. The aim of this review is to elaborate the adverse role of hyperthyroidism and hypothyroidism in female reproduction physiology. PMID- 24171273 TI - Impact of introduced Nile tilapia (Oreochromis niloticus) on non-native aquatic ecosystems. AB - The global invasion of non-native aquatic ecosystems by Nile tilapia (Oreochromis niloticus) is well documented and coincides with their increased use as an aquaculture species. Aquaculture can be defined as the farming of fish or other aquatic organisms and it varies considerably in terms of production practices. Generally, freshwater finfish, such as Nile tilapia, are reared in inland ponds (closed systems). However, in several countries, floating cages are increasingly used to rear Nile tilapia in open water bodies. In such systems, escape is inevitable. The Nile tilapia is considered an omnivorous species and it ingests zooplankton, phytoplankton, or debris present in rivers. As a consequence, the release of Nile tilapia into non-native aquatic ecosystems may result in competition for food and space, thereby damaging native species. The wide environmental tolerance and high reproductive rate of Nile tilapia facilitate its use for aquaculture, but also render the species highly invasive. Here, we review the high frequency of Nile tilapia in non-native biodiversity and indicate the existence of the species under feral conditions in every country in which it has been introduced through farming systems. PMID- 24171274 TI - An improve method for somatic embryogenesis of Schisandra chinensis (Turcz.) Baillon. AB - A somatic embryogenesis protocol for plant regeneration of Schisandra chinensis (Turcz.) Baillon was established. Increased callus induction was obtained from mature zygotic embryos on Murashige and Skoog (MS) medium supplemented with 1.0 mg L(-1) N-phenyl-1,2,3-thidiazol-5-yl-urea (TDZ) or 2.0 mg L(-1) 2,4 dichlorophenoxyacetic acid (2,4-D). Addition of Zeatin (Zt) promoted the formation of embryogenic calli. To induce somatic embryogenesis, 2,4-D, TDZ and Zt were incorporated in the medium alone or in combination. Development of the maximum number of somatic embryos (81 globular, 37 heart, 52 torpedo and 37 cotyledon-stage) and germination of the highest number of embryos (50%) was observed on 1/2 MS medium supplemented with 1.0 mg L(-1) TDZ and 0.2 mg L(-1) Zt. Further development of somatic embryos into plantlets was completed in 1/2 MS medium free of plant growth regulators. PMID- 24171275 TI - Immature development of the malaria vector mosquito, Anopheles gambiae S.L. (Diptera: Culicidae), in relation to soil-substrate organic matter content of larval habitats in northcentral Nigeria. AB - This study elucidated the relationships between larval habitat soil-substrate Organic Matter Content (OMC) and immature development of the mosquito Anopheles gambiae S.L. Day-old larvae of the mosquito were reared in media substrated with typical soil samples (i.e., sandy, silt, clayey and loamy soils), from established anopheline breeding sites, to provide a gradient in soil-substrate OMC. The OMC of the soil samples were determined by ignition to a constant weight; while the developing A. gambiae mosquitoes in the culture media were monitored daily for survivorship and duration of immature life stages. The results indicated significant (p < 0.05) variation in OMC of the soil types (range = 11.21 +/- 2.91% in sandy to 29.83 +/- 2.96% in loamy soils). However, though Daily Larval Survival Rates (DLSR) were relatively high (range = 95.21 +/- 2.96 to 96.70 +/- 1.44%), as influenced by OMC, such values were not significantly different (p > 0.05) among the soil-substrate types; results contrary to those of Larval Success Rates (LSR) (i.e., range = 52.07 +/- 13.64 to 74.39 +/- 6.60%). Daily Pupation Rate (DPR) of the mosquitoes varied significantly among the soil-substrates, ranging from 13.87 +/- 2.39% in clayey to 25.00 +/- 4.30% in loamy substrates. Soil-substrate OMC significantly extended the Duration of Immature Life Stages (DILS) of the mosquitoes only in the sandy soil type (range = 12.76 +/- 1.74 to 15.81 +/- 2.40 days). On the whole, DILS was inversely related to soil-substrate OMC. Cross-correlational analysis revealed significant positive association among most of the variables tested. The findings of this study should serve as baseline information for the development of effective environmental management strategies for malaria larval-vector control. PMID- 24171276 TI - Distribution of withaferin A, an anticancer potential agent, in different parts of two varieties of Withania somnifera (L.) Dunal. grown in Sri Lanka. AB - Withania somnifera (L.) Dunal. (Family: Solanaceae) is a therapeutically important medicinal plant in traditional and Ayurveda systems of medicine in Sri Lanka. Witheferin A, is a potential anticancer compound found in W. somnifera. In the present study, attempts have been made to compare witheferin A content, in different parts of (root, stem, bark, leaf) two varieties of (LC1 and FR1) W. somnifera grown in same soil and climatic conditions. Ground sample (1g) of leaves, bark, stem and roots of two W. somnifera varieties were extracted with CHCl3 three times. Thin Layer Chromatographic analysis (TLC) of withaferin A in both plant extracts were performed on pre-coated Silica gel 60 GF254 plates in hexane: ethyl acetate: methanol (2: 14: 1) mobile phase. Densitometer scanning was performed at lambda(max) = 215 nm. HPLC of W. somnifera extracts was performed using Kromasil C18 reverse phase column. Both varieties of W. somnifera differed in withaferin A. After visualizing TLC plates with vanillin-sulphuric acid leaf and bark extracts of both varieties showed high intensity purple colour spots (R(f) 0.14) than in stem and roots. The highest amount of withaferin A (3812 ppm) was observed in leaves of variety LC1 while the lowest amount was observed in roots of variety FR1 (5 ppm). According to the results it could be concluded that content of Witheferin A was vary leaf > bark > stem > roots in both varieties. Therefore, there is a high potential of incorporation of leaves and bark of W. somnifera for the preparation of Ayurveda drug leading to anticancer activity instead of roots. PMID- 24171277 TI - Arterial injuries in extremities trauma, angiographic findings. AB - At present, trauma is a common problem and regarded as the third cause of mortality in different societies. Significant part of injuries resulting from trauma is due to vascular damages. Tissue ischemia associated with vascular injuries is regarded as medical emergencies which can result in irretrievable ischemia if it continues for 6 h. Therefore, early diagnosis and quick treatment of vascular injuries are of high importance. In this cross sectional study, all trauma patients referred with possible vascular injury to angiography department of Tabriz Imam Khomeini Hospital from Apr. 2011 to Apr., 2012 underwent angiography. The results were compared with the similar studies conducted in other countries. Out of all patients, angiography detected vascular injury in 75 cases consisting of 93.7% of men and 5.3% of women. Motor vehicle (93.3%) especially motorcycles accidents were the most common cause of the damages. Leg was the most common site of trauma (62.2%) and associated fracture was seen in 86.7% of cases. Also, double fracture of leg was the most common associated fracture. Anterior tibial artery (36%) and complete arterial occlusion (62.7%) were the most common injured vessel and vascular injury, respectively. Vascular injuries are more common in young men (20-30 years old) mainly resulted from blunt trauma associated with motor vehicle especially motorcycle accidents. Leg and anterior tibial artery were introduced as the most common site and injured artery, respectively. PMID- 24171278 TI - Phytotherapy against insomnia: extravagant claims or an alternative medicine? AB - Insomnia or sleeplessness is a disorder characterized by a personal incapability to falling or staying asleep for a desirable period of time. Apart from Valeriana officinalis and Ziziphus jujuba most of the ethnobotanicals used for sleep disorders have not been evaluated for pharmacological or clinical efficacy against insomnia. Chinese herbal medicines involving polyherbal formulations are yet to be characterized and long-term side effects are yet to be evaluated. Anti insomniac phytotherapy opens up an exciting aspect of research which might benefit a large number of patients suffering from different degrees of insomnia. PMID- 24171279 TI - [Experience of high frequency electric welding in endocrine surgery]. AB - The comparative analsis of the effectiveness of surgical interventions performed by the standard method and using electric welding technology in endocrine surgery was hold. Compared duration of surgery, amount of intraoperatve blood loss, frequency of intra- and early postoperative complications. Found that the use of weding technology ensures shorter duration of surgery, on average by 30%, amount of blood loss--by 20-50%, the frequency of intra- and early postoperative complications. PMID- 24171280 TI - [Differential surgical treatment of victims with damage to the small and large intestines in a closed abdominal injury combined, depending on the prediction of traumatic disease course and morphological changes of the intestinal wall]. AB - Use of differentiated surgical approach to the management of surgical treatment, depending on the degree of violation of systemic hemodynamics, the timing and volume of surgical procedures, depending on the prognosis of traumatic disease course of cardiac index, interventions in the small and large intestine depending on morphological changes of the intestinal wall by cardiac and stroke indexes, put method extra-enteric anastomosis in patients with damage to the small intestine and colon combined with closed abdominal injury permitted to reduce the rate of postoperative complications from 22.2 to 10.1%, mortality at 2.1 times in shock period (from 19.3 to 9.2%) and the overall mortality from 33.3 to 21.1%. PMID- 24171281 TI - [Remote results of conservative and operative treatment of patients with duodenal ulcer complicated by bleeding]. AB - Analyzed long-term outcomes of 690 patients with duodenal ulcer, complicated by bleeding in Kyiv City Centre gastrointestinal bleeding for the periods 1994-1996 (control group) and 2004-2008 (main group). In the late period of patients who were found giperhlorgidry (moderate and severe), increased by 1.4 tImes, indicating a higher voltage continuous acid production In the main group. With the introduction of modern circuits Helicobacter therapy incidence of H. pylori reduced by half. Improving modern tactical approaches to conservative treatment helped to reduce the frequency of relapses in duodenal ulcer remote period by 2.2 times, acute bleeding--in 1.9 times, increase the frequency of excellent results- in 2.8 times. PMID- 24171282 TI - [Manual-assisted laparoscopic interventions in coloproctologic diseases]. AB - Feasibility of manual-assisted laparoscopic surgery in the treatment of coloproctologic diseases was designated. The investigation included 25 patients operated on for diseases of the colon. In 11 of them made manual-assisted laparoscopic surgery. Length of cut with manual-assisted laparoscopic interventions in 3.8 times less conventional laparotomy section, the total blood loss was 2.3 times less than in open surgery. Duration of patients rehabilitation after such surgery is 1.8 times less than after laparotomy. Laparoscopic surgery of the hand asystens in coloproctology mini-invasive is, however, retain the advantages of open surgery. At the present stage of coloproctology are, on the one hand, is the first step to classic laparoscopic surgery on the other--an alternative to conversion. PMID- 24171283 TI - [Results of surgical rehabilitation of patients in the presence of external colonic fistula in conditions of district hospital]. AB - Results of treatment of 102 patients for a variety of injuries and surgical diseases of the colon, who performed the intervention, culminating in the formation of the external colonic fistula (ECF) were analyzed. After reconstructive and restorative surgery for ECF, all patients were alive. Postoperative complications occurred in 15 (20.8%) patients, including intraabdominale--in 2 (2.8%). The optimal timing of surgical rehabilitation and volume reduction or reconstructive surgery in patients over the ECF should be determined strictly individual basis, taking into account the severity and nature of the illness or injury, which required imposition of an stoma, the severity of postoperative scar and local inflammatory processes in the abdominal cavity, in laparotomic wound and fistula. Performing simultaneous operations in the surgical rehabilitation of patients with ECF practically does not increase the risk of postoperative complications. PMID- 24171284 TI - [Endoscopic drainage of biliary system in acute obstruction of common bile duct]. AB - The peculiarities of endoscopic transpapillar interventions (ETPI) application in 630 patients, age from 11 to 94 years old with acute obstruction of common bile duct (CBD) were studied. In cases, when endoscopic biliary decompression was not possible, the biliary plastic stent or nasobiliary drain were used for prevention or treatment of cholangitis. In case of insufficiency of endoscopic treatment, 92 (14.6%) patients underwent biliary surgery; 37 (5.9% of them were operated laparoscopically. PMID- 24171285 TI - [Experience of simultaneous laparoscopic cholecystectomy and gynecologic operations performance in conditions of "withous gas" laparoscopy in patients of high operation-anesthesiology risk]. AB - The results of laparoscopic cholecystectomy performance in a combination with laparoscopic gynecologic operation on the background of concomitant cardiovascular and pulmonary diseases were analyzed in 67 patients. In 26 patients (main group) the original lifting system was used, 41 (control group)- operated on classical technology. Optimal operative accesses variants a defined, carboxyperitoneum influence on the central hemodynamics in the postoperative period, time of restoration of patients, frequency of postoperative complications is studied. It is revealed that simultaneous lifting laparoscopic operations possess have conclusive advantages: frequency and severity of postoperative complications decrease, intensity of a postoperative pain syndrome, frequency of concomitant chronic diseases exacerbations, and duration of hospital treatment after operation. PMID- 24171286 TI - [Clinical and instrumental diagnosis of stratifying aneurysm of abdominal aorta]. AB - Modern concept of aneurysm and peculiarities of clinical and instrumental diagnostics of stratifying aneurysm of abdominal aorta are adduced. PMID- 24171287 TI - [Dynamics of ultrasound indicators at different methods of anesthesia in patients with occlusive disease of the lower limb arteries]. AB - The influence of the prolonged perineural femoral nerve blockade to restoration of blood flow in operated patients with occlusive disease of the lower limb arteries using an ultrasound was stadied. As for the results of the study, the use of proposed technique, reduces recovery of Vs in lower limb vessels for 3 days, Vd for 7 days and IPgk for 3 days in comparison with control group. PMID- 24171288 TI - [Influence of pathology-based surgical treatment on quality of life in patients with postthrombotyc disease of lower extremities]. AB - Quality of life (QOL) in patients with posttrombotyc disease (PTD) of lower extremity after surgical treatment due to the pathogenetic features of the disease was investigated. In 27 patients, combined with crosectomy and venexeresis the paratibial fasciotomy and closed separation perforante veins were performed. QOL was studied CIYIQ questionnaire before surgery and at 1 year after it. According to morphological studies revealed fragments leg fascia chronic destructive processes that cause disruption of normal functioning "muscle pump". The results marching samples marked venous dysfunction that manifested a significant increase in the volume of tibia during passive standing and maintaining venous stasis after walking, indicating a lack of functioning "muscle pump". The amplitude of movements in talocrural joint in 1.4 times less than the total amount of flexion and extension of the foot in patients with PTD than in the control group. According to electromyography during PTD average amplitude was reduced by 1.5 times, maximum--1.8 times than that of the control group, indicating a significant reduction in functional capacity and tone leg muscles. QOL of patients after surgery improved to 2.1 times. PMID- 24171289 TI - [Estimation of complex surgical treatment effectiveness of lower limbs infected ulcers in patients with diabetic foot syndrome]. AB - In a comparative aspect studied outcomes infected ulcers of the lower limbs in 169 patients with diabetic foot syndrome II - IV degree (from Meggit-Wagner). Analyzed the effectiveness of comprehensive conservative and surgical treatment of patients based on the regression of neurological symptoms by performance scales Total Symptom Score and Neuropathy Impairment Score Lower Limbs, as well the results of operative wound healing. PMID- 24171290 TI - [Experience of various parietal pleurectomies with decortication of lungs in pleural lesions]. AB - During 2006-2012 years different types of parietal pleurectomy (PE) with lung decortication (LD) were performed for 135 patients. Among them: 42 (31.1%)--had standart PE with LD (with performing usual thoracotomy); 34 (25.2%)--had video assisted thoracic surgery (VATS) PE with LD; 36 (26.7%)--videothoracoscopy (VTS) PE with LD; 23 (17.0%)--standart PE with LD combined with lung resection. Common effectiveness of surgical treatment was 96.3%, mortality level--1.5%, postoperative complication level--8.9%. On the early stage of pleural diseases VATS PE with LD and VTS PE with LD are more preferable. To unclear and difficult cases for performing standart PE with LD we consider that operation should begin by VTS pleural space investigation. In some cases minithoracotomy is possible with performing VATS PE with LD or standart PE with LD (performing usual thoracotomy). PMID- 24171291 TI - [Methodological paradoxes on paradigm changes of surgical tactics in traumatic instability of sternocostal frame]. AB - Scientific literature about the surgical tactics in traumatic instability sternocostal frame was conduct. Studies have shown that this type of trauma expediently are useful minimal invasive osteosynthesis. The original method of osteosynthesis ribs and sternum external fixation apparatus were proposed, its application promoted to significantly improved the results of treatment. PMID- 24171292 TI - [Specific features of abdominal perfusion remodeling at different stages of portal hypertensive syndrome]. AB - The specific features of abdominal blood flow remodulation, especially of arterial, portal and caval systems were studied, including their interactions and mutual influence at different stages of portal hypertension syndrome. According to the received conclusions treatment reccomendations are given. PMID- 24171293 TI - [Blood system reaction and hematological indices in patients with traumatic spleen injury]. AB - The study involved 183 patients, whom open splenectomy was performed on the traumatic splenic injury. According to haemograms date, were calculated 19 haematological indices and among them detected indices which the most precisely describe reaction of blood system in post-operative period. Also were revealed indices which correlate in post-operative period with values of delay between admission to a hospital and starting the operation. Monitoring of selected haematological indices will help to accurately assess of blood system reaction in patients with traumatic splenic injury in post-operative period. PMID- 24171294 TI - [Effect of frequency donations of plasma standard dose on immune reactivity of regular donors]. AB - For the date of investigation, regular donation standard dose of plasma have minimally influence on the immune reactivity of regular donors organism. Uniform enhance humoral response indicating the accumulation of reserve capacity immunity. Most likely, the planned removal from the blood plasma of stimulated local humoral response, it manifestation by protective activity of endothelial adhesion properties. PMID- 24171295 TI - [Instrumental diagnosis of recurrent lumbar spine herniated discs in different observation periods]. AB - The results of neuroimaging examination methods application in patients with true herniated disc at different time after primary discectomy were summarized. Designated structural morphological features of operated lumbar segment in early, mid and late period. The study was conducted based on a retrospective analysis of MRI and MSCT in 113 patients with recurrent herniated disc. Truth relapses at different time after the occurrence of the primary microdiscectomy with features on MRI and MSCT, combined with scar-adhesive fibrosis at various stages of its formation and varying severity stenotic changes in bone structures. MSCT is the method of choice in the early period after primary discectomy when a true recurrence combined with MRI are informative in the diagnosis of late recurrence period. PMID- 24171296 TI - [Denervation of mimic muscles during endoscopic lifting of the upper part of face]. AB - Endoscopic lifting of the upper part of face carry out in 28 patients Chemical or surgical denervation had been done for decreasing of mimic muscles activity. Medical glue with folic acid had been used for tissues fixation. Use of medical glue in conjunction with preliminary chemical denervation of mimic muscles with botulin toxin application decreases surgery duration, prevents complications and increases satisfaction of patients. PMID- 24171297 TI - [Larynx reinnervation by the main branch of ansa cervicalis use in the thyroid surgery in cases of unilateral vocal fold paralysis]. AB - The effectiveness of laryngeal reinnervation by anza cervicalis abduction in the treatment of unilateral vocal fold paralysis in thyroid surgery was study. The prospectively examined 11 patients with abduction paralysis of the larynx, which were treated by ipsilateral anastomosis of anza cervicalis main branch to the distal stump of the recurrent laryngeal nerve were performed. The survey was conducted on the pre- and postoperative stages and included videolaryngoscopy, acoustic analysis, and patient self-assessment of voice. Average follow-up was (2.98 +/- 1.04) years. The use of videolaryngoscopy showed significant improvement of the spatial positioning of the vocal folds in the postoperative period and acoustical parameters. Laryngeal reinnervation by anza cervicalis is an effective treatment for laryngeal paralysis related to operations on the thyroid gland and laryngeal function can be improve to almost normal of the spoken voice parameters and the basic functions of the larynx. PMID- 24171298 TI - Selected pathogenic characteristics of fungi from the genus Candida. AB - The prevalence of fungi from the genus Candida in humans is increasing, but the mere fact of their detection does not allow, in general, to diagnose a disease. In fact the development of fungal infection depends on several factors of the host-pathogen relationship. The occurrence of symptoms and the course of the disease are associated, inter alia, with general and immunological conditions of an infected person as well as the properties of strains. Differences between the strains responsible for asymptomatic and symptomatic invasion have been shown. Thus the determination of their pathogenicity parameters is an important element leading to proper identification, both mycological and clinical, which allows for the implementation of therapeutic intervention. There are several virulence factors that are essential for surviving in host's organism and play important role in each phase of fungal infection. This review provides an update on selected pathogenicity features: formation of hyphae and/or pseudohyphae, phenotypic switching, tropic reactions and biofilm production. PMID- 24171299 TI - Mycobiota of the air in hospital rooms and the fungal colonisation of tracheostomy tubes used by patients diagnosed with larynx cancer--preliminary research. AB - A tracheotomy tube, as well as the stoma through which it is inserted into the patient's throat, may represent a potential risk of fungal infections for patients suffering from larynx cancer. The study was aimed at evaluating the influence of the hospital room environment on the fungal colonisation of tracheotomy tubes in the case of patients diagnosed with larynx cancer and operated on in the Laryngology ward. The mycological research was carried out in the rooms of the Laryngology ward, from which 105 air samples were collected. Twenty-two Portex and metal tracheostomy tubes collected from 13 patients diagnosed with larynx cancer. Fungi were cultured on 15 tracheostomy tubes: moulds were isolated from 3 of these tubes, and fungi belonging to the genus Candida from the remaining 12. The simultaneous occurrence of the same moulds in the air and on the tracheotomy tubes was observed only in one case (Aspergillus flavus). In conclusion, the same moulds observed in the air can sometimes also be found on the tracheotomy tubes used by patients diagnosed with larynx cancer. Yeast-like fungi are isolated from tracheotomy tubes much more frequently than moulds, and this requires further mycological research. PMID- 24171300 TI - Treatment of seborrheic dermatitis: the efficiency of sertaconazole 2% cream vs. tacrolimus 0.03% cream. AB - The treatment of seborrheic dermatitis (SD) includes topical antifungal agents to eradicate Malassezia spp. corticosteroids to treat the inflammatory component of the disease, and keratolytics to remove scale and crust. The aim of this study was to compare the efficiency of sertaconazole 2% cream and tacrolimus 0.03% cream in the treatment of seborrheic dermatitis. In this clinical trial study, sixty patients suffering from SD were studied. Thirty patients received local sertaconazole 2% cream with a recommendation to use the cream twice a day for 4 weeks. In the control group, thirty patients received tacrolimus 0.03% cream twice a day for four weeks. At the time of referral, and 2 and 4 weeks after first visit, the patients were examined by a dermatologist to check the improvement of clinical symptoms. The mean ages of the sertaconazole and tacrolimus groups were 30.98 +/- 12.24 and 34.67 +/- 10.82, respectively. The highest level of satisfaction (90%) was observed 28 days after sertaconazole use. Only 83.3% satisfaction was noted in the tacrolimus group. The relationship between patient satisfaction and sertaconazole 2% cream receive in 28th day was significant (P = 0.006). Sertaconazole 2% cream may be an excellent alternative therapeutic modality for treating seborrheic dermatitis. PMID- 24171301 TI - Treatment of scabies: the topical ivermectin vs. permethrin 2.5% cream. AB - Human scabies is caused by an infestation of the skin by the human itch mite (Sarcoptes scabiei va. hominis). It is commonly treated with topical insecticides, but the treatment of choice is still controversial. The aim of this study is to compare the efficacy of topical ivermectin vs. permethrin 2.5% cream for the treatment of scabies. In total, 380 patients with scabies were enrolled, and randomized into two groups: the first group received 1% ivermectin applied topically to the affected skin at a dose of 400 microg/kg, repeated once the following week, while the second group received permethrin 2.5% cream and were told to apply this twice at one week intervals. Treatment was evaluated at intervals of 2 and 4 weeks, and if there was treatment failure at the 2-week follow-up, treatment was repeated. Two applications of topical ivermectin provided a cure rate of 63.1% at the 2-week follow-up, which increased to 84.2% at the 4-week follow-up after repeating the treatment. Treatment with two applications of permethrin 2.5% cream with a 1-week interval between them was effective in 65.8% of patients at the 2-week follow-up, which increased to 89.5% at the 4-week follow-up after this treatment was repeated. Two application of ivermectin was as effective as two applications of permethrin 2.5% cream at the 2 week follow-up. After repeating the treatment, ivermectin was as effective as permethrin 2.5% cream at the 4-week follow up. PMID- 24171302 TI - The occurrence of Demodex kutzeri Bukva, 1987 (Acari, Demodecidae) in red deer (Cervus elaphus L.) in Poland. AB - The occurrence of Demodex kutzeri Bukva, 1987 was examined and compared in red deer coming from different populations--25 red deer from northern Poland (Masurian Lake District) and 25 from southern Poland (Lower Silesia). The total prevalence of infestation in red deer by D. kutzeri was 52% with the mean intensity of 38 individuals and the intensity range of 1-135. Parameters of infestation for red deer from northern Poland were much higher (68%, 49), while for other red deer--lower (36%, 16). Demodectic mites D. kutzeri are associated with common hair follicles, therefore they can be found in different parts of the body, however most of the specimens were found in the head skin. Regardless of the location and the infestation rate (including density of mites in the skin), infestations were not accompanied by symptoms of demodecosis. PMID- 24171303 TI - Parasite communities of European perch, Perca fluviatilis L. (Actinopterygii: Perciformes: Percidae) from Lake Lebsko (Central Coast, Poland). AB - Communities of parasites of European perch from lake Lebsko were studied and compared with similar communities from the Polish coastal zone. Parasites comprised 18 autogenic and 5 allogenic species. Most individual parasites belonged to allogenic species and were in larval stages. The majority of specimens were eye parasites with Tylodelphys clavata as the eudominant species. The dominant species, Acanthocephalus lucii, belongs to the intestine parasite community. Three marine species were found: Bothriocephalus scorpii, Hysterothylacium aduncum and Echinorchynhus gadi. The results indicate that the parasite fauna consists mostly of freshwater species, common in various types of European waters, while marine species were rarely observed. PMID- 24171304 TI - Factors leading to dermatophytosis. AB - Tinea or dermatophytoses are of skin superficial and fungous infections affecting keratinized tissues such as hair, nail, and superficial layer of epidermis. This study aimed at evaluating some predisposing factors for tinea corporis, because elimination or treatment of them not only ceases spreading of the lesion but also prevents reinfection. In this descriptive cross-sectional study patients who were visited in Sina Hospital in Tabriz and had confirmed tinea corporis with direct fungal smear were selected. Other regarding were age, sex, occupation and predisposing factors. Of 76 confirmed cases, 46 (60.5%) were males and 30 (30.5%) were females. Tinea corporis was common in the third decade. The main predisposing factor was dry skin. Diabetes was found only in 4 (5.2%) patients. According to the results of the present research, xerosis was the most common factor leading to tinea corporis in these patients rather than diabetes or lymphoma that it's diagnosis, treatment and some simple educations may inhence improvement of tinea corporis and prevents other superficial infections too. PMID- 24171305 TI - Professor ordinarius Jan Drozdz DVM, PhD (1931-2013). PMID- 24171306 TI - [Databases as instruments for analysis of large-scale data sets on interactions between molecular biological objects]. AB - We have surveyed the most well-known and accessible informational resources, consolidating data on interactions of molecular biological objects. Three main criteria are discussed: quality (coverage and reliability) of the information present, ability to analyze experimental data, and ease of results visualization. Several algorithms of data analysis, base on various types of resources, and statistics for its evaluation are named. PMID- 24171307 TI - [Evidence for evolutionary changes in ontogeny: paleontological, comparative morphological, and molecular aspects]. AB - It has been noted that the integration of modern data of paleontology, comparative morphology, developmental biology, and molecular genetics forms the basis for understanding the mechanisms of evolutionary transformations of ontogeny. Paleontological and morphological evidence of the evolutionary changes in ontogeny are considered based on the data of cell and molecular biology and developmental genetics. It is shown that reorganizations of gene regulatory cascades (primarily Hox genes) play a key role in the evolution of the axial organization of animals and modifications of the limb structure of metazoans, whereas the emergence and development of new types of structures was apparently determined by the emergence of new populations of stem cells in embryogenesis (for example, neural crest cells in the evolution of vertebrates). PMID- 24171308 TI - [Relationship between the expression levels of PAPP-A metalloproteinase and growth and transcriptional factors in endometrial cancer]. AB - We have examined for the first time the relationship between the expression of PAPP-A metalloproteinase and insulin-like growth factors (IGF-I, IGF-II, VEGF) and transcription factors (NF-kappaB, HIF-1) playing an important role in pathogenesis of cancer. We also demonstrated a positive association between the level of PAPP-A metalloproteinase and the level of growth (VEGF and IGF-I) and transcription factors (NF-kappaB p50, NF-kappaB p65, HIF-1alpha). The current findings suggest an important role of PAPP-A in regulation of bioavailability of IGF-I, VEGF, activated forms of NF-kappaB, and alpha-subunits of HIF-1 in endometrial tumors. PMID- 24171310 TI - [Structure of the microbial community in soil catena of the right bank of the Oka River]. AB - The structure of the microbial community (the fungal-bacterial ratio) has been assessed by selective inhibition of the substrate-induced respiration (SIR) using streptomycin sulfate and cycloheximide antibiotics in the gray forest soil of eluvial, transite, transite-accumulative, and accumulative (meadow alluvial) facies of slope landscape on the right bank of the Oka River (near Pushchino, Moscow oblast) which represents an abandoned field, small-leaved wood, spruce forest, and meadow. The concentrations of bactericide and fungicide were selected experimentally for each landscape facies which provide the greatest SIR inhibition of the soil upon their individual application and in combination. Fungi were established to be predominant in the contribution to the total SIR which was found to be 82-97%. A dependence between the structure of the microbial community and the C/N ratio and pH of the soil was shown. PMID- 24171309 TI - [Special effects of a complex probiotic containing cellulolytic bacteria Cellulomonas on actively growing rabbits]. AB - It was shown that the association of probiotic bacteria of the genuses Bacillus and Cellulomonas form biolayers on the surface of beet marc particles. The positive effect of a fodder additive that contained the biolayer on the basis of a phytomatrix on the growth and development of young rabbits was shown. Feeding of animals with a mixed fodder that contained 0.1% preparation resulted in stimulation of digestion of all components of the food. Among other components of the mixed fodder, cellulose was digested most effectively. An increase in the biomass of symbiotic bacteria and enzymatic activity in the blindgut chymus was also observed. The positive nitrogen balance demonstrated an increase in the nitrogen content in animals and a decrease of its losses with excretion. The mechanism of response of the rabbit's organism to introduction of the complex probiotic preparation into the digestive tract is discussed. PMID- 24171311 TI - [Correlation between the output and composition of essential oil and the level of salicylic acid in mint plants at different ontogenetic stages]. AB - Dynamic changes in the content of acetylsalicylic acid and the output and qualitative composition of essential oil have been studied in mint plants (Mentha spicata L. and cultivar Medichka) during their ontogenesis with allowance for changes in weather conditions. Ontogenetic changes in the level of acetylsalicylic acid in leaf tissues are found to be similar in both cv. Medichka and M. spicata. In the case of cv. Medichka, this change is connected with the dynamics of the production and the qualitative composition of essential oil; in the case of M. spicata, this connection is less expressed. The role of acetylsalicylic acid and essential oil in plant adaptation to the environment is discussed. PMID- 24171312 TI - [Some aspects of underground organs of spotleaf orchis growth and phenolic compound accumulation at the generative stage of ontogenesis]. AB - For the first time, the time courses of the growth and accumulation of phenolic compounds (PHCs) in different parts of the organs of the underground organs of the tuberoid orchid Dactilorhyza maculata during vegetation and the winter dormancy period were studied. It was shown that the replacement of old tuberoids and adventitious roots by new ones is accompanied by active growth, photosynthate redistribution, and PHC accumulation. It was found that the tuberoid performing the function of a storage organ possessed a low PHC content, which increased at the end of vegetation and was stably high during the winter dormancy period; in spring the content decreased, most likely as a result of PHC catabolism and utilization for growth processes. It was proposed that the higher PHC content in adventitious roots and tuberoid terminal parts is determined by mycotrophy of the organs. PMID- 24171313 TI - [Are the contours of the frontal section of shell valves in Bivalvia specific?]. AB - The diagnostic importance of the character of curvature of the frontal section of shell valves in Bivalvia on the basis of determining the constant angle of the logarithmic spiral is discussed. The contours of the frontal section of shell valves in several species of mollusks of the families Margaritiferidae and Sphaeriidae have been analyzed. It is shown that in different species of the family Sphaeriidae, the values of constant angles coincide. While performing graphic constructions, it was established that the contours of the frontal section of all studied species of pearl mussels and some spheriids do not correspond to the segment of the logarithmic spiral. It was noted that the hypothesis of the species specificity of this character was not confirmed; therefore, the curvature of the frontal section of shell valves cannot be used as the main character for the systematics and species identification of bivalves. PMID- 24171314 TI - [The participation of salicylic and jasmonic acids in genetic and induced resistance of tomato to Meloidogyne incognita (Kofoid and White, 1919)]. AB - Salicylic (SA) and jasmonic (JA) acids are the best known mediators of signal systems in plants. In this investigation the participation and character of interactions between SA- and JA-signals under the induced and genetic resistance of plants to nematodes was investigated on the model system tomato (Lycopersicon esculentum) and the root-knot nematode Meloidogyne incognita. This study demonstrates that application of JA and SA to tomato foliage induces systemic effects that suppress root-knot nematode infestation, inhibition of nematode reproduction, and also increased activity of LOX and PAL, the enzymes of biosynthesis of JA and SA. JA treatment did not inhibit Mz-mediated resistance, which suggests a lack of signaling conflicts between these two forms of defense. PMID- 24171315 TI - [Correction of impairments in functions of anticoagulation and insular systems of an organism by the regulatory peptide Leu-Pro-Gly-Pro]. AB - It has been established that fivefold intranasal administration of the peptide Leu-Pro-Gly-Pro (1 mg/kg) to rats with developing refractory hyperglycemia leads to restoration and normalization of the functions of anticoagulation and insular systems. In the blood of experimental animals, there was a decrease in the sugar level and platelet aggregation and an increase in anticoagulant and all kinds of fibrinolytic (total, enzymatic, non-enzymatic, Hageman-dependent) activity. PMID- 24171316 TI - [Behavioral and acoustical characteristics of the reproductive gathering of beluga whales (Delphinapterus leucas) in the vicinity of Myagostrov, Golyi Sosnovets, and Roganka Islands (Onega Bay, the White Sea)]. AB - The structure of the summer reproductive gathering of beluga whales Delphinapterus leucas was studied in the vicinity of Myagostrov, Golyi Sosnovets, and Roganka islands (Onega Bay, the White Sea) in 2006 and 2008. The abundance, age and sex structure, behavior, and swimming and acoustic behavior were studied in detail. PMID- 24171317 TI - [Mechanism of population density compensation in island bumblebee taxocenoses (Hymenoptera, Apidae, Bombus) and the notion of reserve compensatory species]. AB - The notion of a dynamic compensatory system is discussed, characterized by the alternation of species occupying the leading position in bumblebee taxocenoses, while the total density of these pollinators in island ecosystems remains at similar levels. The functioning of the compensatory system is regulated by both abiotic factors (the weather and climate) and biotic factors (competition for trophic resources). The stability of the system is determined by the presence of reserve compensatory species capable of rapid population growth against the background of depressed abundance of other species under changing environmental conditions. PMID- 24171318 TI - [Significance of the smell of a conspecific for the spatial distribution of the common shrew Sorex araneus L]. AB - The significance of smell marks of conspecifics for the spatial distribution of common shrews was studied. The existence of two groups of individuals, which differ in their reaction to the smell of a conspecific, was shown. Individuals with different reactions were shown to have reliable differences in the sizes of the areas visited by them, the mutual location of their plots, and the percent of activity combined with the activity of the neighbor. The significance of such differences in reactions for the formation of the social system of shrews is discussed. PMID- 24171319 TI - [Heterotrophic organisms and viruses in the Oka River and Cheboksary Reservoir during the abnormally hot summer of 2010]. AB - In July 2010, abnormally high water temperature (25-29 degrees C), as well as increased biomass and phytoplankton production caused intensive development of heterotrophic bacteria and heterotrophic nanoflagellates. It was found that the abundance, biomass, and production of heterotrophic bacterioplankton, as well as the abundance and biomass of heterotrophic nanoflagellates, and the number of planktonic viruses, which were calculated on average for the reservoir under study, turned out to be higher in the years with lower water temperature (20-23 degrees C). The virus-induced mortality of bacterioplankton in the Oka River and the Cheboksary Reservoir averaged 25.4 +/- 3.4 and 22.4 +/- 2.7% of the daily bacterioplankton production. PMID- 24171320 TI - Laparoscopic cholecystectomy using standard instruments through a single umbilical incision: feasibility in Jamaica. PMID- 24171321 TI - Hydrogen/hydride ion relay--a mechanism for early electron transfer in cytochrome c oxidases. AB - Cytochrome c oxidase (COX) employs electrons obtained from cytochrome c to bring about the reduction of oxygen to water. It is known that the electrons originate from the haem edge of cytochrome c and enters bovine COX at Trp-104. It is also known that Tyr-105, Glu-198 and Asp-158 of COX subunit II play roles in the enzyme's catalysis but how these roles are linked to electron transfer remain unclear. Recently, we proposed that electrons travel from the haem edge of cytochrome c to CuA, the first metal redox centre of COX, by a hydrogen/hydride ion relay using six residues. Now using a similar computer assisted approach, we investigate the extent to which this hydride/hydrogen ion mechanism is common amongst oxidases. The crystal structures of COX from P denitrificans, R sphaeroides and T thermophilus and quinol oxidase from E coli were downloaded and their binding domains analysed. As with bovine, all four oxidases had only nine amino acid residues in that region and both the sequences and three-dimensional structures were highly conserved. We propose that these residues function as a hydrogen/hydride ion relay, participating directly in electron transfer to CuA. We further suggest that this electron transfer mechanism might be a common feature in oxidases. PMID- 24171322 TI - Comparison of techniques of detecting immunoglobulin-binding protein reactivity to immunoglobulin produced by different avian and mammalian species. AB - The rationale of this study was to use several immunological assays to investigate the reactivity of immunoglobulin binding protein (IBP) to immunoglobulins from various avian and mammalian species. The IBP studied were Staphylococcal protein A (SpA), Streptococcal protein G (SpG), Peptostreptococcal protein L (SpL) and recombinant protein LA (SpLA). The various immunological techniques used were double immunodiffusion (Ouchterlony technique) that tested positive high protein reactivities, direct and competitive enzyme-linked immunosorbent assays (ELISAs) that tested moderate and low positive protein binding capacities, respectively. In addition to sandwich ELISAs, immunoblot analyses and Ig-purification by SpA-affinity chromatography, which were sensitive tests and helpful in the screening and confirmatory tests were also used. The Ouchterlony technique showed that compared to the other proteins, SpLA had the highest range of reactivity with animal sera and purified immunoglobulins while SpL was least reactive. With the direct ELISA, SpL reacted with the raccoon sera, rabbit IgG and with IgY from bantam hens and pigeons. While with the direct ELISA, SpA reacted with sera from skunk, coyote, raccoon, mule, donkey and human. The sandwich ELISA revealed high reactivity of both SpG and SpLA with mammalian sera titres ranging from 1:32 (raccoon serum) to 1:1024 (mule and donkey sera). These results suggest that IBP can be used for the detection of immunoglobulin using various immunological assays and this is important for the diagnosis of infectious diseases in animal and bird populations studied and in the purification of immunoglobulins. PMID- 24171323 TI - Cancer in adolescents and young adults, Kingston and St Andrew, Jamaica, 1988 2007. AB - OBJECTIVE: To determine the distribution of malignancies in adolescents and young adults (AYA; 15 to 29 years) in Jamaica. METHODS: All cases of malignancies diagnosed in AYA in the period 1988-2007, were extracted from the files of the Jamaica Cancer Registry. For each case, age, gender and diagnosis were recorded and the diagnoses categorized according to the recently proposed diagnostic groups for cancers in AYA. The data were used to calculate incidence rates and relative frequencies. RESULTS: Among males, the age-specific incidence rate for the oldest age group (25-29 years) was higher than that recorded for each of the younger groups. In females, there was a progressive increase in incidence with increasing age. The age-standardized rates (ASRs) per million were 131.4 (males) and 226.1 (females). In males, the highest ASRs (per million) were those for lymphoma (34.7), carcinoma (29.3) and soft tissue sarcoma (17.2), and in females, carcinoma (121.6), lymphoma (31.4) and germ cell and trophoblastic neoplasms (14.6). Lymphoma was the commonest diagnosis in younger males, and ranked second to carcinoma in the oldest. Carcinoma and lymphoma were the commonest and second commonest diagnoses, respectively, among all three age groups in females, with carcinomas accounting for progressively greater proportions of tumours with increasing age. CONCLUSION: The incidence of malignancy in AYA in Jamaica is higher in females than in males. In both genders, increasing age is accompanied by increasing incidence and a shift from non-epithelial to epithelial malignancies. This shift occurs at an earlier age in females. PMID- 24171324 TI - Clinical evaluation with self-sequential longitudinal reference intervals: pregnancy outcome and neonatal thyroid stimulating hormone level associated with maternal thyroid diseases. AB - OBJECTIVE: We attempted to evaluate maternal thyroid function in a new self sequential longitudinal reference interval (SLRI) which we established recently. By this method, we analysed the correlation between pregnancy outcome, neonatal thyroid stimulating hormone (TSH) level and maternal thyroid diseases. METHODS: A total of 1744 pregnant women participated in the study and 1747 babies were born from those women (three bore twins). The levels of TSH, free thyroxine (FT4) and thyroid peroxidase antibodies (TPO-Ab) of mothers were quantified by electrochemistry immunoassay (ECL). The levels of neonatal blood TSH were detected by time-resolved fluorescence immunoassay (TRFIA). All data were collected and statistically analysed by SPSS 13.0 software. RESULTS: With our new SLRI method, we found that 0.11%-3.84% pregnant women would get thyroid diseases. Subclinical hypothyroidism was the most common maternal thyroid disorder. Being positive for thyroid peroxidase antibodies was a significant risk factor of subclinical hypothyroidism during pregnancy. The median, P2.5-P97.5, and interquartile range (IQR) of neonatal TSH (N-TSH) of 1747 babies were 2.72 mIU/L, 0.10-8.01 mIU/L and 2.62 mIU/L, respectively; 28.6% of pregnant women with thyroid diseases developed pregnancy complications. The prevalence was significantly higher than in the normal thyroid function group (p < 0.001). The levels of N-TSH were low correlated with maternal TSH levels (p < 0.05), but there were no significant correlations between N-TSH and maternal FT4 and maternal TPO-Ab (p > 0.05). CONCLUSIONS: Thyroid disorders, especially subclinical hypothyroidism, are common in pregnant women. These disorders are associated with pregnancy and fetal outcome. Routine maternal thyroid function screening is important and should be recommended. PMID- 24171325 TI - Perinatal autopsy rates at the University Hospital of the West Indies: 2002-2008. AB - OBJECTIVES: High perinatal autopsy rates are necessary for institutional management protocols and national policy-making. This study reviews perinatal autopsy rates and factors affecting these rates at the University Hospital of the West Indies. METHOD: All perinatal deaths (stillborn infants > or = 24 weeks gestation or 500 g; early neonatal deaths ie 0-7 days old) at the University Hospital of the West Indies, between January 2002 and December 2008, were reviewed retrospectively, using the annual perinatal audit records. The annual autopsy rates were calculated and the reasons why autopsies were not done examined. RESULTS: The average stillbirth (SB) autopsy rate was 59.6% (range 51.9 - 76.7%), while that for early neonatal deaths (ENDs) was 47.9% (range 34.4 - 63.2), with an overall average perinatal autopsy rate of 54.0% (range 42.2 - 62.2). Autopsies were requested in 79.3% and 51.7% of SBs and ENDs, respectively. Of those requested, 81.7% were done (75.2% stillbirths; 92.5% ENDs). In the ENDs, failure to request an autopsy was predominantly noted in premature infants weighing < 1000 g (75.2% of those not requested). In stillbirths, the reasons for failure to request were largely unknown with failure to gain permission accounting for only 20.3% of these cases. CONCLUSIONS: The average annual perinatal autopsy rate at the University Hospital of the West Indies between 2002 and 2008 was 54.0%. This is below the internationally recommended rate of 75%. Failure to request an autopsy was the most significant factor contributing to this. The reasons for this are not entirely clear and require further study. PMID- 24171326 TI - Childhood trauma and dissociation in patients with obsessive compulsive disorder. AB - BACKGROUND AND OBJECTIVE: The present study attempted to assess childhood trauma events and dissociative symptoms in patients with obsessive compulsive disorder (OCD). METHOD: The study included all patients who were admitted for the first time to the psychiatric outpatient unit over a 24-month period. Seventy-eight patients were diagnosed as having OCD during the two-year study period. Childhood traumatic events were assessed with a Childhood Trauma Questionnaire (CTQ). Obsessive compulsive disorder symptoms were assessed with the Yale-Brown Obsessive Compulsive Scale (Y-BOCS). A Dissociation Questionnaire (DIS-Q) was also used to measure dissociative symptoms. RESULTS: The mean of Y-BOCS points were 23.37 +/- 7.27. Dissociation questionnaire scores were between 0.40 and 3.87 and the mean was 2.23 +/- 0.76. Childhood trauma points were 1.27-4.77 and the mean was 2.38 +/- 0.56. There was no statistically significant relationship between Y-BOCS points and childhood trauma points (p > 0.05). There was a statistically significant positive relationship between Y-BOCS points and DIS-Q points. There was no statistically significant relationship between DIS-Q points and childhood trauma points (p > 0.05). CONCLUSION: Childhood trauma questionnaire points might be significant clinically, although there was not a statistically significant correlation in our study. We also conclude that dissociative symptoms among patients with OCD should alert clinicians to treatment of the disorder. PMID- 24171327 TI - A five-year retrospective review of infants with Erb-Duchenne's palsy at a teaching hospital in North Trinidad. AB - Birth injuries are devastating to parents and carers alike. They carry the possibility of residual loss of function to the infant and thus the potential for litigation. The aim of this study was to determine the incidence of Erb Duchenne's palsy and the identification of any contributing factors. A retrospective review over a five-year period, 2005-2009, was performed and an incidence of 0.94 per 1000 live births was noted. An association between both macrosomia and shoulder dystocia and the development of Erb-Duchenne palsy in the newborn was noted. The authors recommended the use of partograms and improved note documentation in the management of labour. PMID- 24171328 TI - Collaboration and research as key elements for strengthening blood donation in developing nations: the case of Grenada, West Indies. AB - OBJECTIVE: The purpose of the study was to identify ways to strengthen the collaboration between the Grenadian Blood Bank, the St George's University (SGU) chapter of the American Medical Students Association, and St George's University Health Clinic in order to improve the promotion of blood drives and increase the number of volunteer donors. METHODS: The study had two phases. Phase 1: an assessment of the strengths and needs of the collaborators and of the blood drives. Phase 2 consisted of three student assessments: a cross-sectional survey of second year medical students, a cross-sectional survey of students in the School of Arts and Sciences and a case-control study of factors affecting student donation on the day of blood drives. Embedded within both phases were service learning opportunities for students. Both phases received approval from SGU's Institutional Review Board. RESULTS: Preliminary achievements included a transient increase in blood donation of twenty per cent during five months though advertising of blood drives remains inadequate. Assessments reveal that most students lack knowledge about the drives, and time (medical students) and fear of needles and infection (Arts and Science students) are potential hindrances to blood donation. CONCLUSIONS: The Blood Bank needs to increase its profile on the university campus and develop a more effective promotion of the blood drives addressing the concerns of students. St George's University needs to continue supporting student involvement in health promotion activities and identify ways to ensure the sustainability and continuity of these activities. Collaboration and research are useful and effective means to promote blood donation. College students are potentially an excellent source of collaborators and donors if provided with the promotion skills and participation is made convenient. PMID- 24171329 TI - Intravaginal cleansing among women attending a sexually transmitted infection clinic in Kingston, Jamaica. AB - OBJECTIVES: Although common worldwide, intravaginal cleansing is associated with poor health outcomes. We sought to describe intravaginal cleansing among women attending a sexually transmitted infection (STI) clinic in Jamaica. METHODS: We examined intravaginal cleansing ("washing up inside the vagina", douching, and products or materials used) among 293 participants in a randomized trial of counselling messages at an STI clinic in Kingston. We focussed on information on intravaginal cleansing performed in the 30 days and three days preceding their baseline study visit. We describe reported cleansing behaviours and used logistic regression to identify correlates of intravaginal cleansing. RESULTS: Fifty-eight per cent of participants reported intravaginal cleansing in the previous 30 days, and 46% did so in the three days before baseline. Among those who cleansed in the previous 30 days, 88% reported doing so for hygiene unrelated to sex, and three fourths reported generally doing so more than once per day. Soap (usually with water) and water alone were the most common products used for washing; commercial douches or detergents were reported infrequently. Intravaginal cleansing in the three days before the baseline visit was positively associated with having more than one sex partner in the previous three months (adjusted odds ratio [AOR], 1.9; 95% CI, 1.1, 3.2), and negatively associated with experiencing itching in the genital area at baseline (AOR, 0.6; 95% CI, 0.4, 1.0). CONCLUSIONS: A large proportion of women attending STI clinics in Jamaica engage in frequent intravaginal cleansing, indicating a need for clinicians to discuss this topic with them accordingly. PMID- 24171330 TI - Activity of platelet activating factor acetylhydrolase following phase I periodontal therapy. AB - OBJECTIVE: Elevated levels of platelet activating factor (PAF), a potent inflammatory mediator in periodontal disease and decreased PAF levels following periodontal surgical therapy have been previously detected in gingival tissues and gingival crevicular fluid (GCF). Platelet activating factor acetylhydrolase (PAF-AH) is a calcium-independent phospholipase A2 that catalyses the hydrolysis of PAF, thereby inactivating this mediator The hypothesis, a relationship between activity of PAF-AH and healing following periodontal therapy, was tested by detecting activity of PAF-AH in GCF samples collected from sites that had undergone phase I periodontal therapy with generalized chronic periodontitis. METHODS: Twenty patients with generalized chronic periodontitis were divided into two groups (n = 10): group 1 with probing pocket depth (PPD) 4-5 mm and group 2 with PPD > or = 6-8 mm. Clinical parameters were recorded and GCF was sampled before phase I periodontal therapy and at the 2nd, 7th, 14th, 21st and 28th day follow-up evaluation visits. Activity of PAF-AH in GCF was analysed by enzyme linked immunosorbent assay (ELISA). RESULTS: Probing pocket depth at the 21st and 28th day in group 1, and PPD at the 14th, 21st and 28th day in group 2 were significantly decreased when compared to the baseline values (p < 0.001). Activity of PAF-AH (micromol/ml) was significantly decreased at the 7th, 14th, 21st and 28th day following phase I periodontal therapy in both groups 1 and 2 compared to the baseline values (p < 0.05). CONCLUSION: Platelet activating factor acetylhydrolase is detectable in GCF by ELISA and showed a continuous decrease following phase I periodontal therapy. Changes in the PAF-AH activity would be a progressive marker of periodontal healing to evaluate the success of periodontal therapies. PMID- 24171331 TI - Frequency of tooth brushing and associated factors in Mexican schoolchildren six to nine years of age. AB - OBJECTIVE: To determine the prevalence of daily tooth brushing and evaluate some variables associated. SUBJECTS AND METHODS: A cross-sectional study was carried out in 320 schoolchildren six to nine years old in Campeche, Mexico. Information on sociodemographic and socio-economic variables, oral hygiene practices and attitudes were collected through a questionnaire. The frequency of tooth brushing was categorized as "0" = fewer than seven times/week, "1" = at least once a day. In the analysis, nonparametric tests were used. RESULTS: Mean age was 6.99 +/- 1.00 years, 52.5% were boys. The prevalence of daily tooth brushing was 81.6%. In bivariate analysis, the prevalence of tooth brushing was higher (p < 0.05) among the children of mothers with higher schooling (9.80 years vs 8.47 years, p < 0.05), and in younger children (84.6% in 6-7-year olds vs 71.2% in 8-9-year olds, p < 0.05). A slight, non-significant association (p < 0.10) was noted between the current frequency of tooth brushing and an earlier age when the child first started brushing with toothpaste. There were no statistically significant differences (p > 0.05) in the frequency of tooth brushing by gender or by the mother's attitude toward the oral health of her child. CONCLUSIONS: The prevalence of daily tooth brushing was high compared to other studies. Mother's maximum level of schooling (as an indicator of socio-economic position) was associated with higher frequency of tooth brushing. Maternal characteristics are associated with the oral health behaviour of their children. PMID- 24171332 TI - Oral health status and treatment needs of Iruligas at Ramanagara District, Karnataka, India. AB - OBJECTIVES: To assess the oral health status and treatment needs of Iruliga tribal community residing at Ramanagara District, Karnataka, India. METHODS: The total population of 2605 Iruligas residing at 26 villages of Ramanagara District was included for the study. Data were collected using World Health Organization (WHO) 1997 'Oral Health Assessment Form'. Examination was done under good natural light using a mouth mirror and community periodontal index (CPI) probe. RESULTS: The total study population was 2605, comprising 1545 males and 1060 females in the age group of 1-80 years with the mean age of 30.56 +/- 19.51. The majority of Iruligas (79.8%) used chew sticks as an oral hygiene aid. Subjects with leukoplakia were found to be 3 (0.12). The most commonly seen enamel opacity/hypoplasia was diffuse opacity affecting 930 (35.7%) subjects. A mild form of dental fluorosis affected 1658 (63.65%) subjects. Subjects with bleeding were only 4.22%; subjects with calculus were 57.9%; those with shallow pockets (4 5 mm) were 22.0% and subjects with deep pockets (> or = 6 mm) were 3.67%. The prevalence of dental caries among Iruligas was found to be 7.52%. The mean number of decayed, missing, filled (DMF) permanent teeth per person was 0.55 +/- 0.1. Definite malocclusion, which required elective treatment, was noted in 14.1%. Iruligas with need for referral were found to be 29.94% (n = 780) according to the various treatment needs required for different oral diseases. CONCLUSION: This study revealed less prevalence of oral diseases among Iruligas, highlighting the role of good oral health practices prevalent among this isolated population. PMID- 24171333 TI - Tel Hashomer camptodactyly syndrome: a case report. AB - Tel Hashomer camptodactyly syndrome (THCS) is a rare autosomal recessive camptodactyly with muscular involvement. The manifestations of THCS other than camptodactyly are clubbed feet, thenar and hypothenar hypoplasia, abnormal palmar creases and dermatoglyphic ridges, spina bifida and mitral valve prolapse. The syndrome was first described by Goodman et al in 1972 and thereafter two further cases with similar phenotype were seen. Herein, we present another case report and review of the literature of other syndromes associated with camptodactyly and mitral valve prolapse. Further cases with this syndrome need to be reported for mapping of the candidate loci. This will help in planning management and genetic counselling. PMID- 24171334 TI - Transdermal methyl alcohol intoxication cause of pain relief. AB - A 60-year old female patient was found comatosed at home and taken to the hospital's Emergency Department by her relatives. It was learnt that she wrapped her knees with spirit-impregnated cotton pad for pain for one week. On physical examination, only a colour change of purple violet on her knees was noted. Metabolic acidosis with increased anion gap was detected by arterial blood analysis. The patient underwent haemodialysis. She was discharged from the hospital with no complaints, alert and rational following five days of follow-up treatment, with the diagnosis of methyl alcohol poisoning. PMID- 24171335 TI - Secondary T-cell pancreatic lymphoma mimicking acute pancreatitis. PMID- 24171336 TI - Primary bone marrow B-cell non-Hodgkin's lymphoma successfully treated with R CHOP. AB - Primary isolated bone marrow disease as a presenting feature of lymphoma is very rare. We describe the case of a Chinese with isolated bone marrow small B-cell lymphoma as a first manifestation. A 55-year old woman was admitted to our hospital with fever. Her peripheral blood smear and laboratory findings were suggestive of bicytopenia. Bone marrow specimen showed diffusely distributed small-sized lymphocytes. Combined with immunophenotypic and chromosomal analysis, a diagnosis of primary bone marrow B-cell non-Hodgkin's lymphoma was made. The patient was treated with R-CHOP (rituximab and cyclophosphamide, epirubicin, vindesine, and prednisone) regimen for six cycles. She had complete remission and is still alive without relapse. We concluded that primary bone marrow mature small B-cell lymphoma is a rare but distinctive subtype of lymphoma. The prognosis for this entity is poor but rituximab-based treatment is promising for improving its outcomes. PMID- 24171337 TI - Late onset systemic lupus erythematosus with severe hypercalcaemia. AB - We report a case of a 76-year old female presenting with symptomatic severe hypercalcaemia, and subsequently diagnosed with late onset SLE due to the presence of anaemia, leucopenia, antibodies of antinuclear (ANA), anti-dsDNA, and also kidney impairment. Serum levels of FGF23 and intact-parathyroid hormone (iPTH) were low in this patient. Serum calcium, FGF23 and iPTH levels responded to steroids, which occurred simultaneously with disease activity. On follow-up, the faster increase in FGF23 than in parathyroid hormone suggested that FGF23 might be involved in the pathogenesis of hypercalcaemia in SLE. PMID- 24171338 TI - Capgras syndrome presenting in an adolescent girl in the Caribbean. AB - The case of a 16-year old Jamaican girl who presented to the psychiatric service of a general hospital with features of Capgras syndrome is presented. Her history, treatment, progress and relevant psychodynamic and neurocognitive issues are explored. This is the first known published case of an adolescent with Capgras syndrome from the Caribbean. The case highlights that the syndrome may occur in different cultural contexts and that clinicians should be sensitive to its existence in order to avert under-diagnosis or misdiagnosis. PMID- 24171339 TI - Ophthalmic manifestations of haematological disorders. AB - Five case histories are presented. Waldenstrom's macroglobulinaemia caused bilateral central retinal vein occlusion, proptosis was the presenting feature of retro-orbital plasmacytoma in relapsed multiple myeloma, a red painful eye was due to neovascular glaucoma in primary polycythaemia, bilateral VIth nerve palsy caused convergent squint and diplopia in meningeal relapse of acute lymphoblastic leukaemia and lymphoma of the eyelid caused complete ptosis. Interdisciplinary management is described. Ophthalmological lesions in haematological disease should be promptly recognized and managed. Collaboration between ophthalmology and haematology departments may be effective for palliative management. PMID- 24171340 TI - Cushing's syndrome due to topical steroid. PMID- 24171341 TI - [Experimental study on transfection of pleiotrophin gene into adipose-derived stem cells of mice]. AB - OBJECTIVE: To study the transfection and expression of pleiotrophin (Ptn) gene in mice adipose-derived stem cells (ADSCs) so as to provide a new approach for the treatment of ischemic injury. METHODS: ADSCs from clean inbred C57BL/6W mice (weighing, 15-20 g) were isolated and cultured in vitro. The cell surface markers (CD29 and CD44) of ADSCs were identified by flow cytometry. The ADSCs were transfected with plasmid pIRES2-LEGFPN1 (containing Ptn gene coding sequence) as experimental group (group A) and with plasmid pLEGFP-N1 (containing GFP gene coding sequence) as control group (group B). After ADSCs were transfected by different plasmids respectively, the cells containing Ptn gene were selected by G418 (the best selected concentration was 200 microg/mL), and the immunophenotype of the cells was identified by flow cytometry after transfection. Meanwhile, real time fluorescence quantitative PCR and Western blot were used to analyse the expression levels of Ptn mRNA and PTN protein in selected cells. RESULTS: The mice ADSCs were isolated and cultured successfully in vitro. The positive rates of the cell surface markers CD29 and CD44 of ADSCs were 99.5% and 95.8%, respectively; the double positive rate of CD44 and CD29 was 93.6%. The positive rates of the cell surface markers CD29 and CD44 of ADSCs were 99.1% and 95.6%, respectively after transfection of Ptn gene; the double positive rate of CD44 and CD29 was 93.4%. The expression levels of Ptn gene and PTN protein in group A were significantly higher than those in group B (P < 0.05). CONCLUSION: The ADSCs can be stablely transfected by Ptn gene, the transfected ADSCs can express PTN protein highly, which is a new idea for tissue engineering of vascular reconstruction. PMID- 24171342 TI - [Concentration- or time-dependent manner of recombinant bone morphogenetic protein 2 in regulating expression of vascular endothelial growth factor]. AB - OBJECTIVE: To study biological rule of recombinant human bone morphogenetic protein 2 (rhBMP-2) in regulating the expression of vascular endothelial growth factor (VEGF) of adipose-derived stem cells (ADSCs) at different induced concentrations and time points at gene level and protein level. METHODS: ADSCs were separated from adult human adipose tissues and cultured until passage 3. After ADSCs were induced by rhBMP-2 in concentrations of 0, 50, 100, and 200 ng/mL respectively for 24 hours, and by 100 ng/mL rhBMP-2 for 3, 6, 12, 18, 24, 36, and 48 hours (ADSCs were not induced at corresponding time point as controls) respectively, the VEGF mRNA and protein expressions were detected by RT-PCR and ELISA. RESULTS: The VEGF mRNA and protein expressions induced by rhBMP-2 were concentration-dependent; the expressions were highest in a concentration of 100 ng/mL. The VEGF mRNA expression in concentrations of 50, 100, and 200 ng/mL were significantly higher than that in a concentration of 0 ng/mL (P < 0.05); and the expression in concentration of 100 ng/mL was significantly higher than that in concentrations of 50 and 200 ng/mL (P < 0.05). The VEGF protein expression in a concentration of 100 ng/mL was significantly higher than that in the other concentrations (P < 0.05). The VEGF mRNA and protein expressions induced by rhBMP 2 were time-dependent. The VEGF mRNA and protein expressions at 3 and 6 hours after induction were significantly lower than those of non-induced ADSCs (P < 0.05); the expressions were lower at 12 hours after induction, showing no significant difference when compared with those of non-induced ADSCs (P > 0.05); the expressions reached peak at 18 and 24 hours after induction, and were significantly higher than those of non-induced ADSCs (P < 0.05); the expressions decreased in induced and non-induced ADSCs at 36 and 48 hours, showing no significant difference between induced and non-induced ADSCs (P > 0.05). CONCLUSION: rhBMP-2 adjusts VEGF expression of ADSCs in a concentration- and time dependent manner. The optimum inductive concentration of rhBMP-2 is 100 ng/mL, induced to 18-24 hours is a key period when rhBMP-2 is used to promote tissue engineering bone vascularization. PMID- 24171343 TI - [Protective effect of bone marrow mesenchymal stem cells on islets from hypoxia/reoxygenation-induced injury]. AB - OBJECTIVE: To study the protective effects of bone marrow mesenchymal stem cells (BMSCs) of rhesus monkeys on porcine islets from hypoxia/reoxygenation (H/R) induced injury. METHODS: BMSCs were isolated and cultured from the marrow of 5 adult rhesus monkeys (weighing, 6-10 kg) by adherent monocytes. Islets were isolated and purified from the pancreas of 5 neonatal porcine (3-5 days old) by collagenase V digestion method, and were cultured with or without BMSCs, and exposed to hypoxia (1% O2) for 12 hours and reoxygenation for 24 or 48 hours, respectively. The experiment was divided into 4 groups: normal islet group (group A), normal islet + BMSCs group (Group B), H/R islet group (group C), and H/R islet + BMSCs group (group D). The survival rate of islets was calculated by fluorescein diacetate/propidium iodide (PI) staining. The viability of the islet cells was detected by cell counting kit 8. Apoptotic rate of islet cells was tested using Annexin V-FITC/PI labeling and flow cytometry. The stimulation index (SI) of islet function was analyzed by glucose-stimulated insulin secretion assay. RESULTS: The islet cell cluster of group C was more dispersed than that of groups A and B, and group C had more death cells; and the islet cell cluster of group D was more complete and the survival rate was higher than those of group C. The survival rate of islet was 90.2% +/- 9.1%, 88.3% +/- 5.9%, 52.3% +/- 12.1%, and 71.4% +/- 11.5% in groups A, B, C, and D respectively, it was significantly lower in groups C and D than in groups A and B (P < 0.05), but it was significantly higher in group D than in group C (P < 0.05). After coculture of BMSCs and islet at the ratio of 1:10 and 1:20 in group D, the viability of islet cells was significantly higher than that in group C (P < 0.05). The apoptotic rate was 27.1% +/- 3.2%, 24.0% +/- 1.0%, 64.3% +/- 1.8%, and 46.2% +/- 1.4% in groups A, B, C, and D respectively, it was significantly higher in groups C and D than that in groups A and B (P < 0.05), but it was significantly lower in group D than in group C (P < 0.05). There was no significant difference in SI between groups A and B at each time point (P > 0.05), but it was significantly lower in group C than in groups A and B (P < 0.05); and it was significantly higher in group D than in group C at 24 and 72 hours (P < 0.05). CONCLUSION: BMSCs of rhesus monkeys can protect islet vitality and function from H/R-induced injury. PMID- 24171344 TI - [Comparative study on combined culture of human placenta-derived mesenchymal stem cells and human umbilical vein endothelial cells from same and different individuals]. AB - OBJECTIVE: To investigate the protocols of combined culture of human placenta derived mesenchymal stem cells (HPMSCs) and human umbilical vein endothelial cells (HUVECs) from the same and different individuals on collagen material,to provide the. METHODS: Under voluntary contributions, HPMSCs were isolated and purified from human full-term placenta using collagenase IV digestion and lymphocyte separation medium, and confirmed by morphology methods and flow cytometry, and then passage 2 cells were cultured under condition of osteogenic induction. HUVECs were isolated from fresh human umbilical vein by collagenase I digestion and subcultured to purification, and cells were confirmed by immunocytochemical staining of von Willebrand factor (vWF). There were 2 groups for experiment. Passage 3 osteoblastic induced HPMSCs were co-cultured with HUVECs (1:1) from different individuals in group A and with HUVECs from the same individual in group B on collagen hydrogel. Confocal laser scanning microscope was used to observe the cellular behavior of the cell-collagen composites at 1, 3, 5, and 7 days after culturing. RESULTS: Flow cytometry showed that HPMSCs were strongly positive for CD90 and CD29, but negative for CD31, CD45, and CD34. After induction, alizarin red, alkaline phosphatase, and collagenase I staining were positive. HUVECs displayed cobble-stone morphology and stained positively for endothelial cell marker vWF. The immunofluorescent staining of CD31 showed that HUVECs in the cell-collagen composite of group B had richer layers, adhered and extended faster and better in three-dimension space than that of group A. At 7 days, the class-like microvessel lengths and the network point numbers were (6.68 +/- 0.35) mm/mm2 and (17.10 +/- 1.10)/mm2 in group A, and were (8.11 +/- 0.62) mm/mm2 and (21.30 +/- 1.41)/mm2 in group B, showing significant differences between the 2 groups (t = 0.894, P = 0.000; t = 0.732, P = 0.000). CONCLUSION: Composite implant HPMSCs and HUVECs from the same individual on collagen hydrogel is better than HPMSCs and HUVECs from different individuals in integrity and continuity of the network and angiogenesis. PMID- 24171345 TI - [Effect of carboxymethylated chitosan on proliferation and synthesis of neurotrophic factors in Schwann cells in vitro]. AB - OBJECTIVE: To investigate the effect of carboxymethylated chitosan (CMCS) on the proliferation, cell cycle, and secretion of neurotrophic factors in cultured Schwann cells (SCs). METHODS: SCs were obtained from sciatic nerves of 20 Sprague Dawley rats (3-5 days old; male or female; weighing, 25-30 g) and cultured in vitro, SCs were identified and purified by immunofluorescence against S-100. The cell counting kit 8 (CCK-8) assay was used to determine the proliferation of SCs. The SCs were divided into 4 groups: 50 microg/mL CMCS (group B), 100 microg/mL CMCS (group C), 200 microg/mL CMCS (group D), and the same amount of PBS (group A) were added. The flow cytometry was used to analyze the cell cycle of SCs; the real-time quantitative PCR and Western blot analysis were used to detect the levels of never growth factor (NGF) and ciliary neurotrophic factor (CNTF) in cultured SCs induced by CMCS. RESULTS: The purity of cultured SCs was more than 90% by immunofluorescence against S-100; the CCK-8 results indicated that CMCS in concentrations of 10-1 000 microg/mL could promote the proliferation of SCs, especially in concentrations of 200 and 500 microg/mL (P < 0.01), but no significant difference was found between 200 and 500 microg/mL (P > 0.05). CMCS at a concentration of 200 microg/mL for 24 hours induced the highest proliferation, showing significant difference when compared with that at 0 hour (P < 0.01). The percentage of cells in phase S and the proliferation index were significantly higher in groups B, C, and D than in group A (P < 0.05), in groups C and D than in group B (P < 0.05); and there was no significant difference between group C and group D (P > 0.05). Real-time quantitative PCR and Western blot results showed that the levels of NGF and CNTF in groups B, C, and D were significantly higher than those in group A (P < 0.05), especially in group D. CONCLUSION: CMCS can stimulate the proliferation, and induce the synthesis of neurotrophic factors in cultured SCs. PMID- 24171346 TI - [Effect of allogeneic chondrocytes-calcium alginate gel composite under intervention of low intensive pulsed ultrasound for repairing rabbit knee articular cartilage defect]. AB - OBJECTIVE: To investigate the effect of allogeneic chondrocytes-calcium alginate gel composite under the intervention of low intensive pulsed ultrasound (LIPUS) for repairing rabbit articular cartilage defects. METHODS: Bilateral knee articular cartilage were harvested from 8 2-week-old New Zealand white rabbits to separate the chondrocytes by mechanical-collagen type II enzyme digestion. The 3rd passage chondrocytes were diluted by 1.2% sodium alginate to 5 x 10(6) cells/mL, then mixed with CaCl2 solution to prepare chondrocytes-calcium alginate gel composite, which was treated with LIPUS for 3 days (F0: 1 MHz; PRF: 1 kHz; Amp: 60 mW/cm2; Cycle: 50; Time: 20 minutes). An articular cartilage defect of 3 mm in diameter and 3 mm in thickness was established in both knees of 18 New Zealand white rabbits (aged 28-35 weeks; weighing, 2.1-2.8 kg), and divided into 3 groups randomly, 6 rabbits in each group: LIPUS group, common group, and model group. Defect was repaired with LIPUS-intervention gel composite, non LIPUS intervention gel composite in LIPUS group and common group, respectively; defect was not treated in the model group. The general condition of rabbits was observed after operation. The repair effect was evaluated by gross and histological observations, immunohistochemical staining, and Wakitani score at 8 and 12 weeks after operation. RESULTS: Defect was filled with hyaline chondroid tissue and white chondroid tissue in LIPUS and common groups, respectively. LIPUS group was better than common group in the surface smooth degree and the degree of integration with surrounding tissue. Defect was repaired slowly, and the new tissue had poor elasticity in model group. Histological observation and Wakitani score showed that LIPUS group had better repair than common group at 8 and 12 weeks after operation; the repair effect of the 2 groups was significantly better than that of model group (P < 0.05); and significant differences in repair effect were found between at 8 and 12 weeks in LIPUS and common groups (P < 0.05). The collagen type II positive expression area and absorbance (A) value of LIPUS and common groups were significantly higher than those of model group (P < 0.05) at 8 and 12 weeks after operation, and the expression of LIPUS group was superior to that of common group at 12 weeks (P < 0.05); and significant differences were found between at 8 and 12 weeks in LIPUS group (P < 0.05), but no significant difference between 2 time points in common and model groups (P > 0.05). CONCLUSION: Allogeneic chondrocytes-calcium alginate gel composite can effectively repair articular cartilage defect. The effect of LIPUS optimized allogeneic chondrocytes-calcium alginate gel composite is better. PMID- 24171347 TI - [Local and systemic safety evaluation of regenerated rabbit bladder repaired with xenogeneous bladder acellular matrix]. AB - OBJECTIVE: To evaluate tissue regeneration, body reaction, and biological safety of xenogeneous bladder acellular matrix (BAM) that can be used to repair rabbit bladder. METHODS: Porcine BAM was prepared through physical, chemical, and enzymatic methods, and the effects of acellularization and the structure were observed with HE staining and scanning electron microscope (SEM). Eighteen New Zealand white rabbits (weighing, 2.5-3.0 kg) undergoing partial cystectomy were randomly divided into 2 groups. After partial (about 30%) cystectomy, the porcine BAM was used to replace partial rabbit bladder in the experimental group (n=12), and the incision was directly sutured as control group (n = 6). The survival condition of animals was observed after operation. At 15 days, 1, 2, 3, and 6 months after operation, the blood routine, renal function, and electrolyte were tested by collecting the blood samples. At 1, 2, 3, and 6 months after operation, maximum bladder capacity, bladder leak point pressure, and bladder compliance were measured through urodynamic studies. Then gross observation was performed for regeneration of bladder, and the specimens of the bladder were harvested for HE staining and immunohistochemical staining. The surrounding organs and local lymphoid tissues were harvested for gross observation and HE staining. RESULTS: Cell components were completely removed in the porcine BAM, showing three dimensional porous structure under SEM. All the animals survived during the experiment. At 15 days after operation, white blood cell count increased, and then returned to normal level in 2 groups, showing no significant difference between 2 groups (P > 0.05). The tests of renal function and electrolyte suggested no significant difference between 2 groups (P > 0.05). The level of serum creatinine showed a tendency of increase, but it remained within normal range at 6 months after operation. The maximum bladder capacity and compliance in experimental group were significantly higher than those in control group at 3 and 6 months after operation (P < 0.05), but no significant difference in bladder leak point pressure at each time point between 2 groups (P > 0.05). The urothelial regeneration, smooth muscle regeneration, and blood vessel regeneration were seen by histological observation in 2 groups. In the 2 groups, chronic inflammatory cells infiltration could be observed at 1 month postoperatively, and then chronic inflammatory cells decreased significantly (P < 0.05), until complete disappearance. There was no significant difference in score of chronic inflammatory cell infiltration between 2 groups at 3 and 6 months after operation (P > 0.05). The alpha-smooth muscle actin expression was significantly increased with time passing in 2 groups (P < 0.05), and it was significantly higher in control group than in experimental group at each time point (P < 0.05). In addition, gross and HE staining observations showed no abnormalities in surrounding organs and local lymphoid tissues. CONCLUSION: No immune rejection response occurs when porcine BAM is used for xenotransplantation. It is indicated that porcine BAM is relative safety for xenotransplantation. PMID- 24171348 TI - [Preparation and bio-evaluation of tissue engineered scaffold based on decellularized whole heart extracellular matrix]. AB - OBJECTIVE: To investigate a method for preparing decellularized rat heart scaffold, and to detect and evaluate the decellularized scaffold. METHODS: The decellularized rat heart scaffold was prepared by retrograde perfusion with a combination of enzymatic and Triton X-100 detergent methods to remove the populations of resident cells, and then the decellularized scaffold was observed by gross, toluidine blue staining, HE staining, scanning electron microcope (SEM), Alcian blue staining, and immunohistochemisty staining to evaluate the structure and essential component of extracellular maxtix (ECM) in the scaffold. RESULTS: Tissue engineered scaffold based on decellularized whole heart ECM was successfully prepared, which maintained not only the gross morphology of the heart, but also the intact vascular structure and ultrastructural conformation that certified by toluidine blue staining, HE staining, and SEM analyses. Alcian blue staining and immunohistochemisty staining showed that the essential components of ECM, such as collagen type I, glycosaminoglycan, fibronectin, and Laminin were remained in decellularized whole heart matrix. CONCLUSION: The decellularized whole heart ECM prepared by method mentioned can maintain the intact structure of rat heart and basic compositions of extracellular matrices, so it could be suitable for further studies of tissue engineered scaffolds for whole heart reconstruction. PMID- 24171349 TI - [Research progress of decellularization and application in tissue engineering]. AB - OBJECTIVE: To review the decellularized methods for obtaining extracellular matrix (ECM) and the applications of decellularized ECM scaffold in tissue engineering. METHODS: Recent and related literature was extensively and comprehensively reviewed. The decellularized methods were summarized and classified. The effects of different sterilization methods on decellularized scaffolds were analyzed; the evaluation criterion of extent of decellularization was put forward; and the application ofdecellularized ECM scaffold in different tissues and organs engineering field was summarized. RESULTS: The decellularized methods mainly include physical methods, chemical methods, and biological methods, and different decellularization methods have different effects on the extent of cell removal and ECM composition and structure. Therefore, the best decellularization method will be chosen according to the characteristics of the tissues and decellularization methods to achieve the ideal result. CONCLUSION: It is very important to choose the appropriate decellularized method for preparing the biological materials desired by tissue engineering. The biological scaffolds prepared by decellularized methods will play an important role in tissue engineering and regenerative medicine. PMID- 24171350 TI - [A feasibility research of minimally invasive transforaminal lumbar interbody fusion using unilateral incision and hybrid internal fixation for dural-level lumbar degenerative disease]. AB - OBJECTIVE: To investigate the feasibility and clinical outcomes of minimally invasive transforaminal lumbar interbody fusion (MIS-TLIF) using unilateral incision and internal fixation of pedicle screws and a translaminar facet screw for dural-level lumbar degenerative disease. METHODS: Between January 2010 and January 2012, 19 patients with dural-level lumbar degenerative disease was treated, including 7 males and 12 females with an average age of 50.4 years (range, 22-68 years) and a median disease duration of 37 months (range, 8 months to 15 years). The operated segments included L3-5 in 6 cases and L4-S1 in 13 cases. MIS-TLIF was performed by unilateral incision, and then pedicle screws and a translaminar facet screw were used for internal fixation. RESULTS: Operations were successfully performed in all cases. The mean operation time was 158 minutes; the mean intraoperative blood loss was 156 mL; the mean length of incision was 42 mm; the mean postoperative ambulation time was 35 hours; the mean hospitalization time was 4.1 days; and the mean length of translaminar facet screw was 51 mm. All the wounds healed by first intention. No complication occurred in the others except 1 case of dural tear. The patients were followed up 12-24 months (mean, 17.1 months). The visual analogue scale (VAS) scores for back and leg pain and Oswestry disability index (ODI) scores at postoperation were significantly improved when compared with preoperative ones (P < 0.05). The symptom disappeared gradually. The postoperative X-ray images showed that the internal fixations were in good position; all facets screws penetrated through the base of spinous process, laminar, and facets joint; of the screws, 2 (5.3%) facets screws penetrated lateral laminar, and 1 (1.8%) pedicle screw penetrated out of pedicle of vertebral arch, but no symptom of nerve injury was seen. The CT scan and three-dimensional reconstruction at postoperative 12th month showed good interbody fusion; and based on the Bridwell's interbody fusion grading system, 11 cases were rated as grade I, and 8 cases as grade II. CONCLUSIONS: MIS-TLIF by unilateral incision and internal fixation is a safe and reliable method to treat dural-level lumbar degenerative disease, and it has the advantages of short operation time, less invasion, less blood loss, and fast recovery. PMID- 24171351 TI - [Comparison of traumatic related index in serum between minimally invasive and open transforaminal lumbar interbody fusion for tissue injury]. AB - OBJECTIVE: To compare the difference of traumatic related index in serum and its significance between minimally invasive transforaminal lumbar interbody fusion (MIS-TLIF) and open TLIF. METHODS: Sixty patients were enrolled by the entry criteria between May and November 2012, and were divided into MIS-TLIF group (n = 30) and open TLIF group (n = 30). There was no significant difference in gender, age, type of lesions, disease segment, and disease duration between 2 groups (P > 0.05). The operation time, intraoperative blood loss, and postoperative hospitalization time were recorded, and the pain severity of incision was evaluated by visual analog scale (VAS). The serum levels of C-reactive protein (CRP) and creatine kinase (CK) were measured at preoperation and at 24 hours postoperatively. The levels of interleukin 6 (IL-6), IL-10, and tumor necrosis factor alpha (TNF-alpha) in serum were measured at preoperation and at 2, 4, 8, and 24 hours after operation. RESULTS: The operation time, intraoperative blood loss, and postoperative hospitalization time of MIS-TLIF group were significantly smaller than those of open TLIF group (P < 0.05), and the VAS score for incision pain in MIS-TLIF group was significantly lower than that of open TLIF group at 1, 2, and 3 days after operation (P < 0.05). The levels of CRP, CK, IL-6, and IL-10 in MIS-TLIF group were significantly lower than those in open TLIF group at 24 hours after operation (P < 0.05), but there was no significant difference between 2 groups before operation (P > 0.05). No significant difference was found in TNF alpha level between 2 groups at pre- and post-operation (P > 0.05). CONCLUSION: Compared with the open-TLIF, MIS-TLIF may significantly reduce tissue injury and systemic inflammatory reactions during the early postoperative period. PMID- 24171352 TI - [Clinical feature and preliminary surgical outcome of traumatic lumbar spondylolisthesis]. AB - OBJECTIVE: To analyze the clinical features and preliminary outcome of posterior operation for traumatic lumbar spondylolisthesis. METHODS: The clinical data of 11 patients with traumatic lumbar spondylolisthesis who underwent surgeries between January 2008 and June 2012 were retrospectively analyzed. There were 6 male and 5 female patients, aged from 13 to 60 years with a median age of 38 years. The mechanism of injury included heavy pressure injury in 4 cases, falling injury from height in 4 cases, and traffic accident injury in 3 cases. The time of injury to operation was between 3 days and 13 years (median, 20 days). According to Frankel neurological function grading, 2 patients were rated as grade E, 4 as grade D, 3 as grade C, and 2 as grade B before operation; according to Meyerding spondylolisthesis grading, 4 cases were classified as degree I, 4 as degree II, 2 as degree III, and 1 as degree IV preoperatively. The affected segments included L4 in 3 and L5 in 8 patients. The surgical fixation segments were L4, 5 in 2 patients, L5, S1 in 7, and L4-S1 in 2. Eight patients underwent circumferential fusion, while 3 patients underwent posterolateral fusion. The reduction of spondylolisthesis and bone graft fusion were assessed on X-ray films and three-dimensional CT scans during follow-up. The clinical outcomes were evaluated by visual analogue scale (VAS) and Oswestry disability index (ODI) scores. RESULTS: All patients achieved primary healing of incision after operation. And all patients were followed up 6-40 months with a median time of 12 months. There was no pulling-out or breaking of internal fixation. The fusion rate was 100% on three-dimensional CT scans, and the fusion time was 3-6 months (mean, 4.5 months). The spondylolisthesis was degree 0 in 10 cases and degree I in 1 case according to Meyerding grading, showing significant difference when compared with preoperative spondylolisthesis grading (Z = -2.979, P = 0.003). The Frankel neurological function grading were E in 6, D in 3, and C in 2 at last follow-up, which were significantly improved when compared with preoperative one (Z = -2.271, P = 0.014). At 1 week after operation and last follow-up, VAS and ODI scores were significantly improved when compared with the preoperative scores (P < 0.05); however, no significant difference was found between at 1 week and at last follow-up (P > 0.05). CONCLUSION: If lumbar X-ray films suggest multiple fractures of transverses in emergency combined with the mechanism of injury, it strongly indicates the diagnosis of traumatic lumbar spondylolisthesis, moreover earlier decompression and fusion can provide the recovering of the neurological function and satisfactory preliminary effectiveness in these patients. PMID- 24171353 TI - [Biomechanical study on effects of bone mineral density on fixation strength of expansive pedicle screw]. AB - OBJECTIVE: To evaluate the fixation strength of expansive pedicle screw (EPS) at different bone mineral density (BMD) levels, further to provide theoretical evidence for the clinical application of the EPS in patients with osteoporosis. METHODS: Fresh human cadaver spines (T12-L5 spines) were divided into 4 levels: normal BMD, osteopenia, osteoporosis, and severe osteoporosis according to the value of BMD, 12 vertebra in each level. Conventional pedicle screw (CPS) or EPS was implanted into the bilateral vertebra in CPS group and EPS group, respectively, 12 screws in each group per BMD level. Screw pullout tests were conducted. The maximum pullout strength, stiffness, and energy absorption were determined by an AG-IS material testing machine with constant rate of loading in a speed of 5 mm/min. RESULTS: With the decline of BMD from normal to severe osteoporosis level, the maximum pullout strength and the stiffness correspondingly declined (P < 0.05). In CPS group, the energy absorption gradually decreased (P < 0.05); in EPS group, significant difference was found between other different BMD levels (P < 0.05) except between normal BMD and osteopenia and between osteoporosis and severe osteoporosis (P > 0.05). At the same BMD level, the maximum pullout strength of EPS group was significantly larger than that of CPS group (P < 0.05); the stiffness of EPS group was significantly higher than that of CPS group (P < 0.05) except one at normal BMD level; and no significant difference was found in the energy absorption between 2 groups (P > 0.05) except one at osteopenia level. No significant difference was found in maximum pullout strength, stiffness, and energy absorption between EPS group at osteoporosis level and CPS group at osteopenia level (P > 0.05); however, the maximum pullout strength, stiffness, and energy absorption of EPS group at severe osteoporosis level were significantly lower than those of CPS group at osteopenia level (P < 0.05). CONCLUSION: Compared with CPS, the EPS can significantly improve the fixation strength, especially in patients with osteopenia or osteoporosis. PMID- 24171354 TI - [Influence of two kinds of bone grafting methods on bone defect gap residual rates and compressive stiffness after reduction of thoracolumbar burst fracture]. AB - OBJECTIVE: To investigate the amount of bone grafting, bone defect gap residual rates, and biomechanical stability of the injured vertebral body after reduction of thoracolumbar burst fractures, pedicle screw-rods fixation, and bone graft by bilateral pedicle or unilateral spinal canal. METHODS: Eighteen fresh lumbar spine (L1-5) specimens of calves (aged 4-6 months) were collected to establish the burst fracture model at L3 and divided into 3 groups randomly. After reduction and fixation with pedicle screws, no bone graft was given in group A (n = 6), and bone graft was performed by bilateral pedicles in group B (n = 6) and by unilateral spinal canal in group C (n = 6). The amount of bone grafting in groups B and C was recorded. The general situation of bone defect gaps was observed by the DR films and CT scanning, and the defect gap residual rates of the injured vertebrae were calculated with counting of grids. The compression stiffness was measured by ElectreForce-3510 high precision biological material testing machines. RESULTS: The amount of bone grafting was (4.58 +/- 0.66) g and (5.72 +/- 0.78) g in groups B and C respectively, showing signficant difference (t = 2.707, P = 0.022). DR films and CT scanning observation showed large bone defect gap was seen in injured vertebrae specimens of group A; however, the grafting bone grains was seen in the "eggshell" gap of the injured vertebral body, which were mainly located in the posterior part of the vertebral body, but insufficient filling of bone graft in the anterior part of the vertebral body in group B; better filling of the grafting bone grains was seen in injured vertebral body of group C, with uniform distribution. The bone defect gap residual rates were 52.0% +/- 5.5%, 39.7% +/- 2.5%, and 19.5% +/- 2.5% respectively in groups A, B, and C; group C was significantly lower than groups A and B (P < 0.05), and group B was significantly lower than group A (P < 0.05). Flexion compressive stiffness of group C was significantly higher than that of groups A and B (P < 0.05), but no significant difference was found between groups A and B (P > 0.05). Extension compressive stiffness in group C was significantly higher than that in group A (P < 0.05), but no significant difference was found between groups A and B, and between groups B and C (P > 0.05). The compression stiffness of left bending and right bending had no significant difference among 3 groups (P > 0.05). CONCLUSION: Thoracolumbar burst fracture pedicle screws fixation with bone grafting by unilateral spinal canal can implant more bone grains, has smaller bone defect gap residual rate, and better recovery of flexion compression stiffness than by bilateral pedicles. PMID- 24171355 TI - [Bipolar femoral head replacement combined with tension band wire fixation for intertrochanteric fracture in elderly osteoporotic patients]. AB - OBJECTIVE: To explore the effectiveness of bipolar femoral head replacement combined with tension band wire fixation for intertrochanteric fracture in elderly osteoporotic patients. METHODS: Bipolar femoral head replacement combined with tension band wire fixation were used for intertrochanteric fracture in 48 elderly osteoporotic patients between January 2004 and December 2010. Of 48 patients, 15 were male and 33 were female, aged 90-99 years (mean, 94.1 years). All fractures were caused by falling, and pathological fracture was excluded. It was 2-7 days (mean, 4.2 days) from fracture to surgery. According to the Tronzo Evans classification, 25 cases were rated as type IV, 20 cases as type III, and 3 cases as type II. And all of the cases were accompanied with severe osteoporosis and accompanied by more than one medical diseases, and 10 cases had spinal compression fracture. RESULTS: All patients underwent the operation successfully. Six cases died of underlying medical illness within 2 years postoperatively. A total of 39 cases were followed up 2-7 years, averaged 3.1 years. After operation, short-term mental disorders occurred in 9 cases, suspected urinary tract infection in 2 cases, sacral rear bedsore in 1 case, hip pain in 1 case, thigh pain in 1 case, and deep vein thrombosis of affected limb in 1 case. All the incisions healed by first intension, and X-ray film showed bone union in all cases; no complications of bone osteolysis, prosthesis loosening, subsidence, rupture, and heterotopic ossification occured postoperatively. No case needed revision. According to the Harris score system, the results were excellent in 5 cases, good in 28 cases, fair in 5 cases, and poor in 1 case, with an excellent and good rate of 84.6%; the score at 2 years was significantly higher than that at 6 weeks (t = -14.79, P = 0.00). The physical health score and mental health score of SF-12 at 2 years postoperatively were significantly higher than those at 6 weeks postoperatively (P < 0.05). The visual analogue scale (VAS) scores at 6 weeks and 2 years postoperatively were significantly lower than those at preoperation (P < 0.05), and the score at 2 years was significantly lower than that at 6 weeks (P < 0.05). CONCLUSION: The bipolar femoral head replacement combined with tension band wire fixation for intertrochanteric fracture in elderly osteoporotic patients has the advantages of firm fixation, early function exercise with load bearing, pain relieving, improving hip function, and avoiding complication in bed. PMID- 24171356 TI - [Effectivenes of anterolateral C-shaped approach in treatment of intertrochanteric fracture of femur in elderly patient]. AB - OBJECTIVE: To study the effectiveness of anterolateral C-shaped approach in the treatment of intertrochanteric fracture of the femur in elderly patient by comparing with traditional anterolateral approach. METHODS: Between April 2010 and November 2011, 66 patients with intertrochanteric fracture of the femur were analyzed retrospectively. Of 66 patients, 37 underwent improved anterolateral C shaped approach combined with fixation of dynamic hip screw (DHS) (improved group), and 29 underwent traditional anterolateral approach combined with fixation of DHS (conventional group). There was no significant difference in gender, age, injury cause, side, disease duration, fracture type, and complication between 2 groups (P > 0.05). The operation time, intraoperative blood loss, postoperative drainage volume, and hospitalization time were recorded; and X-ray films were taken to observe the fracture healing. The hip function was evaluated according to self-established criterion. RESULTS: The operation was successfully completed in all patients, and primary healing of incision was achieved. All patients were followed up 12-24 months (mean, 17.8 months). Bone union was achieved in both groups; the fracture healing time was 3 6 months (mean, 4.8 months). No loosening or breaking of internal fixation was observed during follow-up period. The operation time and postoperative drainage volume of improved group were significantly less than those of conventional group (P < 0.05); no significant difference was found in intraoperative blood loss and hospitalization days between 2 groups (P > 0.05). According to self-established criterion, improved group was significantly better than conventional group in recovery of hip joint motion and function at 6 and 12 months after operation (P < 0.05). CONCLUSION: Anterolateral C-shaped approach combined with DHS could minimize muscle injury and scar formation, which is beneficial to surgical exposure and early postoperative rehabilitation. PMID- 24171357 TI - [Short-term effectiveness of total hip arthroplasty for post-traumatic osteoarthritis secondary to acetabular fracture]. AB - OBJECTIVE: To discuss the short-term effectiveness of total hip arthroplasty (THA) for post-traumatic osteoarthritis secondary to acetabular fracture. METHODS: Between January 2004 and March 2012, the clinical data was analyzed retrospectively from 12 cases (13 hips) of post-traumatic osteoarthritis secondary to acetabular fracture undergoing THA. Of 12 patients, 6 were male and 6 were female, with an average age of 55.6 years (range, 40-68 years). The locations were the left hip in 5 cases, the right hip in 6 cases, and bilateral hips in 1 case. The interval between acetabular fracture and THA was 65.7 months on average (range, 12-240 months). The preoperative hip Harris score was 48.8 +/- 9.5. RESULTS: The incisions healed by first intention. No deep vein thrombosis and infection occurred postoperatively. Ten cases were followed up 1-7 years (mean, 4.8 years). The hip Harris score was 86.5 +/- 8.6 at last follow-up, showing significant difference when compared with preoperative score (t = 10.520, P = 0.006). X-ray films showed no acetabular prosthesis instability. Stem subsidence (2 mm) occurred in 1 case, peri-prosthetic osteolysis in 2 cases, and heterotopic ossification in 2 cases (Brooker type I and type II in 1 case, respectively). CONCLUSION: THA has satisfactory short-term effectiveness for post traumatic osteoarthritis secondary to acetabular fracture. The good effectiveness is based on strict case selection, pathological evaluation, and the proper acetabular reconstruction. PMID- 24171358 TI - [Experimental study on small interfering RNA silencing expression of tumor necrosis factor alpha and inhibiting osteolysis]. AB - OBJECTIVE: To investigate the possibility of gene therapy of osteolysis around artificial joint prosthesis by constructing the recombinant adenovirus which can silence tumor necrosis factor alpha (TNF-alpha). METHODS: The primer of small interfering RNA (siRNA) coding sequence of silent TNF-alpha was designed and amplified, and then RAPAD adenovirus packaging system was used to load the sequence to adenovirus, and the recombinant adenovirus Ad5-TNF-a-siRNA-CMVeGFP which lacked both E1 and E3 regions was constructed. Then 64 female BABL/C mice (weighing, 20-25 g) were randomly divided into 4 groups (n=16): blank control (group A), positive control (group B), simple adenovirus (group C), and treatment group (group D). The prosthetic-model was established in group A, and the prosthetic-loosening-model in groups B, C, and D. At 2 weeks after modeling, PBS solution was injected first, and then the same solution was injected 24 hours later in group A; titanium particle solution was injected, and then PBS solution, Ad5 E1-CMVeGFP (1 x 10(9) PFU/mL), and Ad5-TNF-alpha-siRNA-CMVeGFP (1 x 10(9) PFU/mL) were injected, respectively in groups B, C, and D 24 hours later, every 2 weeks over a 10-week period. The general condition of mice was observed after operation. The tissues were harvested for histological observation, and the expression of TNF-a was detected by Western blot at 12 weeks after operation. RESULTS: The positive clones were achieved by enzyme digestion and confirmed by DNA sequencing after loading the target genes into adenovirus vector, and then HEK293 cells were successfully transfected by recombinant adenovirus Ad5-TNF alpha-siRNA-CMVeGFP. All mice survived to the completion of the experiment. Histological observation showed that there were few inflammatory cells and osteoclasts in group A, with a good bone formation; there were a large number of inflammatory cells and osteoclasts in groups B and C, with obvious bone destruction; inflammatory cells and osteoclasts in group D was less than those in groups B and C, with no obvious bone destruction. Significant difference was found in the limiting membrane thickness and the number of osteoclasts (group A < group D < group B < group C, P < 0.05). Western blot showed that the TNF-a expression levels were 0.235 +/- 0.022, 0.561 +/- 0.031, 0.731 +/- 0.037, and 0.329 +/- 0.025 in groups A, B, C, and D respectively, showing significant difference among 4 groups (P < 0.05). CONCLUSION: The recombinant adenovirus for silencing TNF-alpha is successfully constructed, which can effectively inhibit osteolysis by silencing TNF-alpha expression in the tissues around prosthesis in mice. PMID- 24171359 TI - [Cationic liposome ceftazidime combined with nano-hydroxyapatite/beta-tricalcium phosphate for treatment of chronic osteomyelitis of rabbits]. AB - OBJECTIVE: To observe the effect of cationic liposomal ceftazidime (CLC) combined with nano-hydroxyapatite/beta-tricalcium phosphate (n-HA/beta-TCP) in the treatment of chronic osteomyelitis of rabbits. METHODS: Thirty healthy New Zealand white rabbits (4-6 months old; weighing, 2-3 kg) were selected to prepare the chronic osteomyelitis models. After 4 weeks, the gross observation, X-ray examination, and bacteriological and histopathological examinations were done; the models were made successfully in 27 rabbits. Of 27 rabbits, 24 were randomly divided into 4 groups (n = 6): only debridement was performed in group A; ceftazidime was given (90 mg/kg), twice a day for 8 weeks after debridement in group B; ceftazidime and n-HA/beta-TC were implanted after debridement in group C; and CLC and n-HA/beta-TCP were implanted after debridement in group D. Before and after treatments, X-ray examination was done, and Norden score was recorded. At 8 weeks after treatment, the specimens were harvested for gross observation and for gross bone pathological score (GBPS) using Rissing standard; half of the specimens was used for histological observation and Smeltzer scoring, the other half for bacteriological examination and calculation of the positive rate of bacteria culture. RESULTS: At 8 weeks after treatment, Norden score of group D was significantly lower than that of groups A, B, and C (P < 0.05), but no significant difference was found among groups A, B, and C (P > 0.05). At 8 weeks after treatment, sinus healed in groups C and D, but sinus was observed in groups A and B; the GBPS scores of groups C and D were significantly lower than those of groups A and B (P < 0.05). The Smeltzer scores of groups C and D were significantly lower than those of groups A and B (P < 0.05). The positive rates of bacteria culture of groups C (0) and D (0) were significantly lower than those of group A (25.0%) and group B (16.7%) (P < 0.05). CONCLUSION: CLC combined with n-HA/beta-TCP has good effect in treating chronic osteomyelitis of rabbits, and it has better effect in treating chronic osteomyelitis of rabbits than ceftazidime with n-HA/beta-TCP. PMID- 24171360 TI - [Study on accuracy of virtual surgical planning in free fibula mandibular reconstruction by using SurgiCase software]. AB - OBJECTIVE: To evaluate the directional significance of SurgiCase software in free fibula mandibular reconstruction. METHODS: Between September 2010 and March 2012, 10 patients with mandibular defect underwent free fibula mandibular reconstruction. There were 7 males and 3 females, with an age range of 19-43 years (mean, 27 years). The extent of lesions was 7 cm x 5 cm to 16 cm x 8 cm. In each case, three-dimensional spiral CT scan of the maxilla, mandible, and fibula was obtained before surgery. The CT data were imported into the SurgiCase software and the virtual surgery planning was performed. After that, the mandibular rapid prototyping was made according to customized design. The reconstruction surgery was then carried out using these preoperative data. During actual surgery, the extent of mandibular defect was from 6 cm x 3 cm to 16 cm x 5 cm; the length of fibula which was used to reconstruct mandible was 6-17 cm; and the area of flap was from 6 cm x 5 cm to 16 cm x 6 cm. RESULTS: Preoperative data could not be applied because the intraoperative size of tumor was larger than preoperative design in 1 case of mandibular ameloblastoma, and the fibula was shaped according to the actual osteotomy location; operations were performed successfully according to preoperative design in the other 9 patients. The operation time was 5-7 hours (mean, 6 hours). Primary healing of incision was obtained, without early complications. Ten patients were followed up 1 year. At last follow-up, 8 patients were satisfactory with the appearance and 2 patients complained with unsatisfied wide facial pattern. The panoramic radiograghs showed good bone healing. The range of mouth opening was 2.5-3.5 cm. CONCLUSION: SurgiCase software can provide precise data for free fibula mandibular reconstruction during surgery. It can be applied widely in clinic. PMID- 24171361 TI - [Anterolateral thigh and groin conjoined flap for emergent repair of ultra-long complex tissue defects in forearm and hand]. AB - OBJECTIVE: To evaluate the effectiveness of anterolateral thigh and groin conjoined flap in emergent repair of ultra-long complex tissue defects in forearm and hand. METHODS: Between February 2009 and October 2011, 6 patients with complex tissue defect of dorsal forearm and hand were in adminsion. There were 5 male and 1 female with an average age of 38.5 years (range, 32-47 years). Injury reasons included machine injury in 5 cases and traffic accident injury in 1 case. Injury to admission time was from 3 to 16 hours (mean, 6 hours). All case were single limb injury, including right forearm and hand injury in 4 cases and left forearm and hand injury in 2 cases. The wound area was from 36 cm x 9 cm to 48 cm x 12 cm. The type of associated injury included elbow dislocation associated with open injury in 2 cases; fractures of the radial, ulnar, and metacarpal bone in 4 cases; defects of wrist dorsal skin and extensor tendons of fingers and wrist in 5 cases; and defects of ulnar artery and ulnar nerve in 1 case. The anterolateral thigh and groin conjoined free flaps were used to repair defects in the forearm and hand in emergency. The area of flap was from 36 cm x 9 cm to 48 cm x 12 cm. Meanwhile the partial functional reconstruction was performed. The donor site was repaired by skin grafts. RESULTS: The anastomotic embolization of vascular pedicle and arteria interossea dorsalis occurred in 1 case, purulent secretion under the flap in 1 case, which were cured after symptomatic treatment; the skin flaps completely survived, and primary healing of the wounds were obtained in the other cases. The donor skin grafts survived in 2 cases, and partial necrosis of the skin graft of lower abdominal occurred in 4 cases, and healed after changing dressing. All of the 6 patients were followed up 3 to 18 months (mean, 10 months). The appearance and texture of the flaps were good. The protective sensation was recovered in 2 cases followed up for more than 14 months; no sensory recovery was observed in the other cases. At last follow-up, according to the upper extremity functional evaluation standard by Hand Surgery Branch of Chinese Medical Association, the results were excellent in 1 case, good in 4 cases, and poor in 1 case, and the excellent and good rate was 83.3%. CONCLUSION: It could get a good short-term effectiveness to use the anterolateral thigh and groin conjoined flap for emergent repair of the ultra-long and complex tissue defects in forearm and hand. PMID- 24171362 TI - [Progress of alginate-based biomedical materials]. AB - OBJECTIVE: To review the current situation of alginate-based biomedical materials, especially focus on the clinical strategies and research progress in the clinical applications and point out several key issues that should be concerned about. METHODS: Based on extensive investigation of domestic and foreign alginate-based biomedical materials research and related patent, literature, and medicine producted, the paper presented the comprehensive analysis of its research and development, application status, and then put forward several new research directions which should be focused on. RESULTS: Alginate-based biomedical materials have been widely used in clinical field with a number of patients, but mainly in the fields of wound dressings and dental impression. Heart failure treatment, embolization, tissue engineering, and stem cells culture are expected to become new directions of research and products development. CONCLUSION: Development of alginate-based new products has good clinical feasibility and necessity, but a lot of applied basic researches should be carried out in the further investigations. PMID- 24171364 TI - Finding calm amid the chaos: when it's not the patient who needs a wellness check, but the veterinarian. PMID- 24171365 TI - Feral cat management. PMID- 24171366 TI - What is your diagnosis? Chronic urethral trauma secondary to urolithiasis. PMID- 24171367 TI - Pathology in practice. Polyarteritis nodosa. PMID- 24171368 TI - Pathology in practice. Ovarian carcinoma with multifocal uterine metastasis and diffuse cystic endometrial hyperplasia. PMID- 24171369 TI - Effects of new sampling protocols on procaine penicillin G withdrawal intervals for cattle. PMID- 24171371 TI - Long-term outcome of sudden acquired retinal degeneration syndrome in dogs. AB - OBJECTIVE: To investigate long-term outcomes and owner-perceived quality of life associated with sudden acquired retinal degeneration syndrome (SARDS) in dogs. DESIGN: Survey study. ANIMALS: 100 dogs with SARDS examined at 5 academic veterinary institutions from 2005 to 2010. PROCEDURES: The diagnosis was based on documented acute vision loss, normal results of ophthalmic examinations, and evaluation of extinguished bright-flash electroretinograms. Primary owners of affected dogs completed a questionnaire addressing outcome measures including vision, systemic signs, and perceived quality of life for their dogs. RESULTS: Age at diagnosis was significantly correlated with positive outcome measures; dogs in which SARDS was diagnosed at a younger age were more likely to have alleged partial vision and higher owner-perceived quality of life. Polyphagia was the only associated systemic sign found to increase in severity over time. Medical treatment was attempted in 22% of dogs; visual improvement was not detected in any. Thirty-seven percent of respondents reported an improved relationship with their dog after diagnosis, and 95% indicated they would discourage euthanasia of dogs with SARDS. CONCLUSIONS AND CLINICAL RELEVANCE: Blindness and concurrent systemic signs associated with SARDS appeared to persist indefinitely, but only polyphagia increased in severity over time. Most owners believed their pets had good quality of life and would discourage euthanasia of dogs with SARDS. PMID- 24171370 TI - Factors influencing veterinarian referral to oncology specialists for treatment of dogs with lymphoma and osteosarcoma in Ontario, Canada. AB - OBJECTIVE: To elucidate factors influencing practitioner decisions to refer dogs with cancer to veterinary oncology specialists. DESIGN: Cross-sectional study. SAMPLE: 2,724 Ontario primary care companion animal veterinarians. PROCEDURES: Practitioners were invited to participate in a survey involving clinical scenarios of canine cancer patients, offered online and in paper format from October 2010 through January 2011. Analyses identified factors associated with the decision to refer patients to veterinary oncology specialists. RESULTS: 1,071 (39.3%) veterinarians responded, of which 603 (56.3%) recommended referral for dogs with multicentric lymphoma and appendicular osteosarcoma. Most (893/1,059 [84.3%]) practiced within < 2 hours' drive of a specialty referral center, and most (981/1,047 [93.7%]) were completely confident in the oncology service. Few (230/1,056 [21.8%] to 349/1,056 [33.0%]) were experienced with use of chemotherapeutics, whereas more (627/1,051 [59.7%]) were experienced with amputation. Referral was associated with practitioner perception of patient health status (OR, 1.54; 95% confidence interval [CI], 1.15 to 2.07), the interaction between the client's bond with the dog and the client's financial status, practitioner experience with treating cancer (OR, 2.79; 95% CI, 1.63 to 4.77), how worthwhile practitioners considered treatment to be (OR, 1.66 to 3.09; 95% CI, 1.08 to 4.72), and confidence in the referral center (OR, 2.20; 95% CI, 1. 11 to 4.34). CONCLUSIONS AND CLINICAL RELEVANCE: Several factors influenced practitioner decisions to refer dogs with lymphoma or osteosarcoma for specialty care. Understanding factors that influence these decisions may enable practitioners to appraise their referral decisions and ensure they act in the best interests of patients, clients, and the veterinary profession. PMID- 24171372 TI - Use of recombinant human thyroid-stimulating hormone for thyrotropin stimulation testing in euthyroid ferrets. AB - OBJECTIVE: To evaluate the effects of IM administration of recombinant human thyroid-stimulating hormone (rhTSH) on plasma total thyroxine (T4) concentrations in euthyroid ferrets. DESIGN: Evaluation study. ANIMALS: 25 healthy neutered ferrets (14 female and 11 male) of various ages from 2 populations (laboratory ferrets from Georgia and pet ferrets from Pennsylvania). PROCEDURES: Each ferret underwent a physical examination and standard hematologic testing to ensure it was healthy and had clinically normal thyroid function. Once determined to be euthyroid, ferrets received a single IM injection of 100 MUg of rhTSH. Blood samples were collected into plasma-separator tubes immediately before the rhTSH injection (time 0) and 4 hours after injection to measure T4 concentrations. RESULTS: Males did not differ from females in regard to prestimulation or poststimulation plasma T4 concentrations; however, prestimulation and poststimulation T4 concentrations were significantly different between the 2 groups of ferrets. A significant difference was also identified between prestimulation T4 concentration (mean +/- SD, 21.3 +/- 6.1 nmol/L) and poststimulation T4 concentration (29.9 +/- 8.2 nmol/L). All 25 ferrets had high poststimulation T4 concentrations (median difference, 7. 5 nmol/L; 10% to 90% interval, 3.26 to 17.70 nmol/L [0.25 to 1.38 MUg/dL]; range, 2.50 to 20.70 nmol/L [0.19 to 1.61 MUg/dL]); this represented a median increase in T4 concentration of 35% (10% to 90% interval, 18% to 81%; range, 8% to 126%). CONCLUSIONS AND CLINICAL RELEVANCE: Results suggested that rhTSH can be used for thyrotropin stimulation testing in ferrets when administered IM. According to the findings, a euthyroid ferret should have an increase of approximately 30% in plasma T4 concentration 4 hours after rhTSH injection. PMID- 24171373 TI - Evaluation of a modified proportional margins approach for surgical resection of mast cell tumors in dogs: 40 cases (2008-2012). AB - OBJECTIVE: To evaluate a modified proportional margins approach to resection of mast cell tumors (MCTs) in dogs. DESIGN: Retrospective case series. ANIMALS: 40 dogs with subcutaneous and cutaneous MCTs undergoing curative intent surgery. PROCEDURES: Medical records were searched to identify dogs with a cytologically or histologically confirmed diagnosis of MCT that had not previously been treated surgically and that had undergone full oncological staging. In those dogs, tumors were resected with lateral margins equivalent to the widest measured diameter of the tumor and a minimum depth of 1 well-defined fascial plane deep to the tumor. Surgical margins were evaluated histologically. Cutaneous tumors were graded by use of the Patnaik system and the 2-tier system described by Kiupel et al. The prognosis for subcutaneous tumors was assessed in accordance with published recommendations. Follow-up information on dog health status was obtained through clinical examination, the dog owners, and the referring veterinarians. RESULTS: The 40 dogs had 47 tumors. Forty-one (87%) tumors were cutaneous, and 6 (13%) were subcutaneous. On the basis of the Patnaik system, 21 (51%) cutaneous tumors were considered grade I, 18 (44%) were considered grade II, and 2 (5%) were considered grade III. On the basis of the Kiupel system, 37 (90%) cutaneous tumors were considered low grade, and 4 (10%) were considered high grade. The prognosis for the 6 subcutaneous tumors was classified as likely resulting in a shorter (2) or longer (4) survival time. Forty tumors were deemed to have been excised with clear margins and 7 with incomplete margins. Local recurrence was not recorded for any dog but was suspected for 1 (2%) tumor, although not confirmed. Interval from tumor excision to follow-up ranged from 30 to 1,140 days (median, 420 days). CONCLUSIONS AND CLINICAL RELEVANCE: The modified proportional margins system resulted in satisfactory local disease control in dogs with MCTs. PMID- 24171374 TI - Effects of urinary bladder retroflexion and surgical technique on postoperative complication rates and long-term outcome in dogs with perineal hernia: 41 cases (2002-2009). AB - OBJECTIVE: To evaluate the effects of urinary bladder retroflexion (UBR) and surgical technique on postoperative complication rates and long-term outcome in dogs with perineal hernia. DESIGN: Retrospective case series. ANIMALS: 41 client owned dogs with perineal hernia that underwent surgery between November 2002 and November 2009. PROCEDURES: Medical records were reviewed for information on dog signalment, history, physical examination findings, ultrasonographic findings, surgical techniques, intraoperative complications, duration of hospital stay, postoperative complications, and long-term outcome. RESULTS: 31 dogs had no UBR, and 10 dogs had UBR. Internal obturator muscle transposition (IOMT) was performed in 20 dogs, and a cystopexy or colopexy was performed before the IOMT (LapIOMT) in 21. Postoperative complications included tenesmus (n = 8) and urinary incontinence (1). Rates of postoperative complications were not significantly different between the no-UBR and UBR groups or between the IOMT and LapIOMT groups. Thirty-two dogs were free of clinical signs at the time of the study. The median disease-free interval did not differ significantly between dogs in the no UBR and UBR groups, but it was significantly lower in the LapIOMT group than in the IOMT group. None of the 7 dogs with UBR that were treated without cystopexy developed recurrence of UBR. CONCLUSIONS AND CLINICAL RELEVANCE: UBR was not associated with an increased rate of postoperative complications relative to no UBR and had no effect on the long-term outcome in dogs with perineal hernia. The use of IOMT alone may be recommended for clinical use because LapIOMT offered no clear advantage. PMID- 24171375 TI - Clinical features, treatment options, and outcome in dogs with thymoma: 116 cases (1999-2010). AB - OBJECTIVE: To describe clinical signs, diagnostic findings, treatment, and outcome and determine factors associated with survival time for dogs with thymoma. DESIGN: Multi-institutional retrospective case series. ANIMALS: 116 dogs with thymoma. PROCEDURES: Medical records were searched for information regarding signalment, physical examination findings, results of laboratory testing and diagnostic imaging, medical and surgical treatment, and survival data. RESULTS: Of the 116 dogs with thymoma, 44 (38%) were Labrador Retrievers and Golden Retrievers. Twenty of 116 (17%) dogs had signs of myasthenia gravis (diagnosis was confirmed for 13 dogs). At the time of thymoma diagnosis, 40 (34%) dogs had hypercalcemia, 8 (7%) dogs had a concurrent immune-mediated disease, and 31 (27%) dogs had another tumor; 16 (14%) dogs developed a second nonthymic tumor at a later date. Tumor excision was performed for 84 dogs, after which 14 (17%) had tumor recurrence; prognosis was good for dogs undergoing a second surgery. Median survival time with and without surgical treatment was 635 and 76 days, respectively. Presence of another tumor at the time of thymoma diagnosis, lack of surgical excision, and higher pathological stage were significantly associated with shorter survival time. Hypercalcemia and presence of myasthenia gravis or megaesophagus at the time of thymoma diagnosis, histopathologic subtype of thymoma, or tumor development at a later date was not associated with survival time. CONCLUSIONS AND CLINICAL RELEVANCE: Dogs with thymoma, even those with a large tumor burden or a paraneoplastic syndrome, had a good prognosis following surgery. Surgical treatment, tumor stage, and the presence of a second tumor at diagnosis influenced survival time. PMID- 24171376 TI - Diagnosis of chronic small bowel disease in cats: 100 cases (2008-2012). AB - OBJECTIVE: To determine whether a diagnosis of chronic small bowel disease could be established in a subset of cats that had clinical signs of chronic vomiting, chronic small bowel diarrhea, weight loss, or a combination of these, combined with ultrasonographically determined thickening of the small bowel. DESIGN: Retrospective case series. ANIMALS: 100 client-owned domestic cats. PROCEDURES: Medical records of cats with clinical signs of chronic vomiting, chronic small bowel diarrhea, weight loss, or a combination of these, combined with ultrasonographically determined small bowel thickening, that underwent laparotomy and multiple small bowel biopsies between 2008 and 2012 were examined. Biopsy specimens were submitted for histologic evaluation, immunohistochemical evaluation, and, when findings were ambiguous, PCR assay for antigen receptor rearrangement. RESULTS: Chronic small bowel disease was diagnosed in 99 of the 100 cats. The most common diagnoses were chronic enteritis and intestinal lymphoma. CONCLUSIONS AND CLINICAL RELEVANCE: Results suggested that cats with clinical signs of chronic small bowel disease should undergo detailed diagnostic testing because they are likely to have clinically important, diagnosable, treatable disease. Clinical signs of small bowel disease, especially weight loss and chronic or recurrent vomiting, are extremely common in cats. These signs should not be considered a normal condition and should not be ignored, regardless of common explanations given by owners, and cats with these signs should undergo appropriate diagnostic testing. PMID- 24171378 TI - Aspects of pharmaceutics. Preface. PMID- 24171377 TI - Effects of early pregnancy diagnosis by per rectal palpation of the amniotic sac on pregnancy loss in dairy cattle. AB - OBJECTIVE: To determine effects of per rectal amniotic sac palpation (ASP) for pregnancy diagnosis during early gestation on pregnancy loss in lactating cows. DESIGN: Controlled, randomized block design. ANIMALS: 368 pregnant dairy cows. PROCEDURES: Pregnancy was detected via transrectal ultrasonography (TRUS) at day 29 (day of estrus = day 0), and cows were allocated into a control group (n = 167 cows) and ASP group (180). Control cows were not subjected to pregnancy diagnosis via palpation per rectum. Per rectal ASP was performed between days 34 and 43 by only 1 experienced veterinarian. All cows were reevaluated with TRUS on days 45, 60, and 90. RESULTS: 21 cows were removed because of illness. Pregnancy loss between days 29 and 90 occurred in 44 of 347 (12.7%) cows. Pregnancy loss for the control and ASP groups from days 29 to 90 occurred in 22 of 167 (13.2%) and 22 of 180 (12.2%) cows, respectively. Late embryonic pregnancy loss (days 29 to 45) for the control and ASP groups occurred in 18 (10.8%) and 15 (8.3%) cows, respectively. Early fetal pregnancy loss (days 46 to 60) for the control and ASP groups occurred in 2 of 149 (1.3%) and 6 of 165 (3.6%) cows, respectively, and late fetal pregnancy loss (days 61 to 90) for the same groups occurred in 2 of 147 (1.4%) and 1 of 159 (0.6%) cows, respectively. CONCLUSIONS AND CLINICAL RELEVANCE: Pregnancy diagnosis via per rectal ASP during early gestation did not increase pregnancy loss in dairy cattle. PMID- 24171379 TI - Homogalacturonans from preinfused green tea: structural characterization and anticomplementary activity of their sulfated derivatives. AB - Two homogeneous water-soluble polysaccharides (TPSR4-2B and TPSR4-2C) were obtained from preinfused green tea. Their average molecular weights were estimated to be 41 kDa and 28 kDa, respectively. A combination of composition, methylation, and configuration analysis, as well as NMR spectroscopy, indicated that both TPSR4-2B and TPSR4-2C were poly-(1-4)-alpha-d-galactopyranosyluronic acid in which 30.5 +/- 0.3% and 28.3 +/- 0.5%, respectively, of uronic acid existed as methyl ester. Two sulfated derivatives (Sul-R4-2B and Sul-R4-2C) from TPSR4-2B and TPSR4-2C were prepared after sulfation with a 2:1 chlorosulfonic acid-pyridine ratio. The anticomplementary assay showed that Sul-R4-2B and Sul-R4 2C demonstrated a stronger inhibitory effect on the complement activation through the classic pathway, compared to that of heparin. Preliminary mechanism studies by using complement component depleted-sera indicated that both Sul-R4-2B and Sul R4-2C selectively interact with C1q, C1r, C1s, C2, C5, and C9 but not with C3 and C4. The relationship between DS and the anticomplementary activity of sulfated derivatives of homogalacturonans showed that low sulfated derivatives of homogalacturonans also exhibited potent anticomplementary effect, which might greatly reduce the side effects related to heparin and oversulfated chondroitin sulfate, such as anticoagulant activity and allergic-type reaction. These results suggested that sulfated derivatives of homogalacturonans might be promising drug candidates for therapeutic complement inhibition. PMID- 24171381 TI - Carbodiimide versus click chemistry for nanoparticle surface functionalization: a comparative study for the elaboration of multimodal superparamagnetic nanoparticles targeting alphavbeta3 integrins. AB - Superparamagnetic fluorescent nanoparticles targeting alphavbeta3 integrins were elaborated using two methodologies: carbodiimide coupling and click chemistries (CuACC and thiol-yne). The nanoparticles are first functionalized with hydroxymethylenebisphonates (HMBP) bearing carboxylic acid or alkyne functions. Then, a large number of these reactives functions were used for the covalent coupling of dyes, poly(ethylene glycol) (PEG), and cyclic RGD. Several methods were used to characterize the nanoparticle surface functionalization, and the magnetic properties of these contrast agents were studied using a 1.5 T clinical MRI. The affinity toward integrins was evidenced by solid-phase receptor-binding assay. In addition to their chemoselective natures, click reactions were shown to be far more efficient than the carbodiimide coupling. The grafting increase was shown to enhance targeting affinity to integrin without imparing MRI and fluorescent properties. PMID- 24171382 TI - Comments on Petrak et al.'s "psychological insulin resistance in type 2 diabetes patients regarding oral antidiabetes treatment, subcutaneous insulin injections, or inhaled insulin": considerations for language and communication. PMID- 24171384 TI - Creating diversity by site-selective peptide modification: a customizable unit affords amino acids with high optical purity. AB - The development of peptide libraries by site-selective modification of a few parent peptides would save valuable time and materials in discovery processes, but still is a difficult synthetic challenge. Herein natural hydroxyproline is introduced as a "convertible" unit for the production of a variety of optically pure amino acids, including expensive N-alkyl amino acids, and to achieve the mild, efficient, and site-selective modification of peptides. PMID- 24171385 TI - Metabolomics of ginger essential oil against alcoholic fatty liver in mice. AB - Fatty liver is significantly associated with hepatic cirrhosis and liver cancer. Excessive alcohol consumption causes alcoholic fatty liver disease (AFLD). Ginger has been reported to exhibit antioxidant potential and hepatoprotective activity. In the present study, a mouse model for AFLD was developed by employing male C57BL/6 mice that were fed an alcohol-containing liquid diet (Lieber-DeCarli diet) ad libitum. In the treatment groups, ginger essential oil (GEO) and citral were orally administered every day for 4 weeks. Serum biochemical analysis, antioxidant enzyme activity analysis, and histopathological evaluation revealed that GEO and citral exhibited hepatoprotective activity against AFLD. Metabolites in serum samples were profiled by high-performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry (HPLC-QTOF-MS). Metabolomic data indicated the amounts of metabolites such as d-glucurono-6,3-lactone, glycerol-3 phosphate, pyruvic acid, lithocholic acid, 2-pyrocatechuic acid, and prostaglandin E1 were increased after alcohol administration, but the levels were recovered in treatment groups. The analysis indicated that ginger possesses hepatoprotective properties against AFLD. Furthermore, these metabolites can serve as early noninvasive candidate biomarkers in the clinical application of AFLD for health management. PMID- 24171386 TI - Small-angle neutron scattering study of a monoclonal antibody using free-energy constraints. AB - Monoclonal antibodies (mAbs) contain hinge-like regions that enable structural flexibility of globular domains that have a direct effect on biological function. A subclass of mAbs, IgG2, have several interchain disulfide bonds in the hinge region that could potentially limit structural flexibility of the globular domains and affect the overall configuration space available to the mAb. We have characterized human IgG2 mAb in solution via small-angle neutron scattering (SANS) and interpreted the scattering data using atomistic models. Molecular Monte Carlo combined with molecular dynamics simulations of a model mAb indicate that a wide range of structural configurations are plausible, spanning radius of gyration values from ~39 to ~55 A. Structural ensembles and representative single structure solutions were derived by comparison of theoretical SANS profiles of mAb models to experimental SANS data. Additionally, molecular mechanical and solvation free-energy calculations were carried out on the ensemble of best fitting mAb structures. The results of this study indicate that low-resolution techniques like small-angle scattering combined with atomistic molecular simulations with free-energy analysis may be helpful to determine the types of intramolecular interactions that influence function and could lead to deleterious changes to mAb structure. This methodology will be useful to analyze small-angle scattering data of many macromolecular systems. PMID- 24171387 TI - beta-Eliminative releasable linkers adapted for bioconjugation of macromolecules to phenols. AB - We recently reported a chemical approach for half-life extension that utilizes sets of releasable linkers to attach drugs to macromolecules via a cleavable carbamate group (Santi et al., Proc. Nat. Acad. Sci. U.S.A. 2012, 109, 6211 6216). The linkers undergo a beta-elimination cleavage to release the free, native amine-containing drug. A limitation of the technology is the requirement for an amino group on the drug in order to form the carbamate bond, since most small molecules do not have an amine functional group. Here, we describe an approach to adapt these same beta-elimination carbamate linkers so they can be used to connect other acidic heteroatoms, in particular, phenolic hydroxyl groups. The approach utilizes a methylene adaptor to connect the drug to the carbamate nitrogen, and an electron-withdrawing group attached to carbamate nitrogen to stabilize the system against a pH-independent spontaneous cleavage. Carbamate cleavage is driven by beta-elimination to give a carboxylated aryl amino Mannich base which rapidly collapses to give the free drug, an aryl amine, and formaldehyde. PMID- 24171388 TI - New insights on photocatalytic H2 liberation from water using transition-metal oxides: lessons from cluster models of molybdenum and tungsten oxides. AB - Molecular hydrogen (H2) is an excellent alternative fuel. It can be produced from the abundantly present water on earth. Transition-metal oxides are widely used in the environmentally benign photocatalytic generation of H2 from water, thus actively driving scientific research on the mechanisms for this process. In this study, we investigate the chemical reactions of W3O5(-) and Mo3O5(-) clusters with water that shed light on a variety of key factors central to H2 generation. Our computational results explain why experimentally Mo3O5(-) forms a unique kinetic trap in its reaction while W3O5(-) undergoes a facile oxidation to form the lowest-energy isomer of W3O6(-) and liberates H2. Mechanistic insights on the reaction pathways that occur, as well as the reaction pathways that do not occur, are found to be of immense assistance to comprehend the hitherto poorly understood pivotal roles of (a) differing metal-oxygen and metal-hydrogen bond strengths, (b) the initial electrostatic complex formed, (c) the loss of entropy when these TMO clusters react with water, and (d) the geometric factors involved in the liberation of H2. PMID- 24171389 TI - Polymorphism complexity and handedness inversion in serum albumin amyloid fibrils. AB - Protein-based amyloid fibrils can show a great variety of polymorphic structures within the same protein precursor, although the origins of these structural homologues remain poorly understood. In this work we investigate the fibrillation of bovine serum albumin--a model globular protein--and we follow the polymorphic evolution by a statistical analysis of high-resolution atomic force microscopy images, complemented, at larger length scales, by concepts based on polymer physics formalism. We identify six distinct classes of coexisting amyloid fibrils, including flexible left-handed twisted ribbons, rigid right-handed helical ribbons and nanotubes. We show that the rigid fibrils originate from flexible fibrils through two diverse polymorphic transitions, first, via a single fibril transformation when the flexible left-handed twisted ribbons turn into the helical left-handed ribbons, to finally evolve into nanotube-like structures, and second, via a double-fibril transformation when two flexible left-handed twisted ribbons wind together resulting in a right-handed twisted ribbon, followed by a rigid right-handed helical ribbon polymorphic conformation. Hence, the change in handedness occurs with an increase in the level of the fibril's structural organization. PMID- 24171390 TI - Topical steroid risk analysis: differentiating between physiologic and pathologic adrenal suppression. AB - BACKGROUND: Topical corticosteroids are a mainstay of therapy for inflammatory skin disorders. Hypothalamic-pituitary-adrenal (HPA) axis suppression is a potential systemic risk of topical steroid use. Our aim was to review available data on the risk of HPA axis suppression associated with long-term topical steroid use and to distinguish between pathologic and physiologic adrenal suppression. METHODS: We performed a PubMed search for literature that evaluated the risk of HPA axis suppression associated with topical steroid use. RESULTS: Fifteen of sixteen clinical trials reviewed did not report any pathologic adrenal suppression. In the single clinical trial that reported pathologic adrenal suppression, the patients used twice the maximum recommended amount of clobetasol propionate continuously for as long as 18 months. Physiologic adrenal suppression was seen as early as 1-2 weeks after treatment with class I-IV topical corticosteroids. In about half of these patients, cortisol levels spontaneously returned to normal within a few weeks, despite continuous therapy. CONCLUSION: Even when adrenal suppression occurs, topical corticosteroids are unlikely to be associated with clinical signs or symptoms of HPA axis suppression and are extremely safe as long as they are used within the current safety guidelines. PMID- 24171391 TI - Contact interaction of double-chained surfactant layers on silica: bilayer rupture and capillary bridge formation. AB - The contact between two layers of double-chained C18 surfactants adsorbed on silica has been investigated. Using a custom-made surface forces apparatus with high stiffness, we have studied the process of (1) compression and collapse of the layers and (2) surface separation after layer collapse. A continuum mechanics model accounts for the compression and collapse of the surfactant layers. The layer compressibility and molecular energy of rupture can be inferred directly. When the surfaces are rinsed in deionized water, an intriguing structural force is observed: the resulting attractive interaction induces the diffusion of surfactant to the contact area, with the gradual buildup of a capillary bridge of the pure smectic phase of the surfactant. Models are proposed to analyze the force profile. PMID- 24171392 TI - Direct C-2 arylation of 7-azaindoles: chemoselective access to multiarylated derivatives. AB - Pd-catalyzed direct C-H arylation of N-methyl-7-azaindole at the C-2 position by diverse arylboronic acids was achieved at room temperature. The method is general and was applied in chemoselective synthesis of multiarylated 7-azaindole derivatives bearing three different aryl groups at the 2, 3, and 5 positions. PMID- 24171393 TI - Biobased chemicals in a carbon-restricted world. PMID- 24171394 TI - Carbonyl reduction pathways in drug metabolism. AB - The understanding of drug biotransformation is an important medical topic. The oxidative pathways that involve CYPs have been extensively studied in drug metabolism in contrast to the reductive pathways. This review focuses on drugs that have been reported to be reduced at the carbonyl group in vivo. Although the carbonyl reduction of these drugs is well known, our understanding of the carbonyl reducing enzymes (CRE) that perform these reactions is limited. We have summarized the published data in order to thoroughly describe the reductive metabolism of the selected drugs and to demonstrate the role of carbonyl reduction in the context of their overall metabolism. The number of drugs recognized as substrates for CREs has increased considerably in recent years. Moreover, the importance of carbonyl reduction in the overall metabolism of these drugs is often surprisingly high. Because only limited information is available about the CREs responsible for these reactions, additional research is needed to improve our understanding of the metabolism of drugs undergoing carbonyl reduction. Carbonyl reduction should be investigated during drug development because it can either positively or negatively influence drug efficacy. PMID- 24171395 TI - Choline ion interactions with DNA atoms explain unique stabilization of A-T base pairs in DNA duplexes: a microscopic view. AB - Under physiological conditions, G-C base pairs are more stable than A-T base pairs. In a previous study, we showed that in the hydrated ionic liquid of choline dihydrogen phosphate, the stabilities of these base pairs are reversed. In the present study, we elucidated the unique binding interactions of choline ions with DNA atoms from a microscopic viewpoint using molecular dynamics simulations. Three times more choline ions bind to the DNA duplex than sodium ions. Sodium ions bind closely but not stably; in contrast, the choline ions bind through multiple hydrogen bonding networks with DNA atoms stably. The affinity of choline ion for the minor groove of A-T base pairs is more than 2 times that for other groove areas. In the narrow A-T minor groove, choline ion has high affinity for the ribose atoms of thymine. Choline ions also destabilize the formation of hydrogen bonds between G-C base pairs by binding to base atoms preferentially for both of duplex and single-strand DNA, which are associated with the bonds between G-C base pairs. Our new finding will not only lead to better control of DNA stability for use in DNA nanodevices, but also provide new insight into the stability of DNA duplexes under crowding conditions found in living cells. PMID- 24171397 TI - Comparative analyses of stilbenoids in canes of major Vitis vinifera L. cultivars. AB - Grapevine canes are rich in resveratrol and its complex derivatives. These compounds have many biological activities and are needed mainly for health purposes. Canes, which are often wasted, can be used to produce these high-value compounds at low cost. We studied sixteen Vitis vinifera L. cultivars among the most widely cultivated ones worldwide. Polyphenols were extracted from their canes and identified by liquid chromatography-nuclear magnetic resonance spectroscopy. We accurately determined the content of E-epsilon-viniferin, E resveratrol, E-piceatannol, and vitisin B and, for the first time, that of hopeaphenol and miyabenol C. The canes did not contain these major stilbene compounds in similar proportions, and their abundance and order of abundance varied according to the cultivar. For instance, Pinot noir has very high levels of E-resveratrol and E-epsilon-viniferin; Gewurztraminer has very high levels of vitisin B, and Carignan and Riesling have very high levels of hopeaphenol. These findings suggest that the right cultivar should be used to obtain the highest yield of a polyphenol of interest. PMID- 24171398 TI - Concerted action of P450 plus helper protein to form the amino-hydroxy-piperidone moiety of the potent protease inhibitor crocapeptin. AB - The crocapeptins are described here as cyclic depsipeptides, isolated from cultures of the myxobacterium Chondromyces crocatus . Structure elucidation of the compounds revealed a cyanopeptolin-like skeleton, containing the characteristic amino-hydroxy-piperidone (Ahp)-heterocycle. Like the cyanopeptolins, the myxobacterial crocapeptins proved to be serine protease inhibitors. The nonribosomal origin of the peptide was confirmed by mutagenesis experiments, and the biosynthesis gene cluster was sequenced. It could be shown that the Ahp-heterocycle originates from a proline residue in the precursor molecule precrocapeptin, which is converted to crocapeptin by the tailoring enzymes CpnE and CpnF. Conversion of precrocapeptin isolated from a cpnF mutant into crocapeptin was achieved using recombinant CpnF, a cytochrome P450 enzyme responsible for hydroxylation of the proline residue in precrocapeptin. Addition of protein CpnE resulted in strongly increased conversion rates toward Ahp containing product. A mutant with 10-fold increased production of crocapeptin A was created through insertion of the Pnpt-promotor in front of the NRPS gene. PMID- 24171399 TI - Patterns of ambulatory care usage and leading treatments for rosacea. AB - BACKGROUND: Millions of rosacea sufferers are not being treated, and the reasons they do not get treatment are not well characterized. OBJECTIVE: The aim of this study is to determine the main reasons for visit, providers seen and treatments used for rosacea. METHODS: We used data from the National Ambulatory Medical Care Survey for 1993-2010, tabulating the leading reasons for visit, providers seen and treatments used in rosacea visits. RESULTS: There were 1 750 000 visits per year for rosacea. The leading reasons for visit were other diseases of the skin (25.3%), skin rash (19.6%), and discoloration or abnormal pigmentation (14.7%). Dermatologists managed 72.4% of visits. The most common treatments used were topical metronidazole (29.3%), tetracycline (11.0%), minocycline (8.5%), doxycycline (7.9%), and oral metronidazole (6.9%). LIMITATIONS: Some reasons for visit were too nonspecific to provide good insight on why the patient made a visit. CONCLUSIONS: Dermatologists manage rosacea most commonly, but primary care physicians need the proper training to diagnose it correctly. Improved strategies to reach untreated people with rosacea are needed. PMID- 24171400 TI - Pharmacodynamics of diclofenac from novel Eudragit entrapped microspheres. AB - Effective clinical utilization of non-steroidal anti-inflammatory drugs such as diclofenac sodium (DS) is significantly limited by their ulcerogenic potential and poor bioavailability after oral administration, thus necessitating the need for a better carrier to minimize these obvious limitations. The objective of this study was to evaluate Eudragit(r) RS100/RL100 microspheres formulated by the solvent-evaporation technique for improved delivery of diclofenac. Three batches of (DF1, DF2 and DF3) microspheres were prepared using different ratios of Eudragit RS-100 and RL-100 polymers based on the solvent-evaporation method. The microspheres were characterized based on morphological properties, particle size analysis and encapsulation efficiency (EE%). In vitro release of DS was investigated in both 0.1 N HCl (pH 1.2) and phosphate-buffered saline (pH 7.4), while anti-inflammatory studies were evaluated in the rat model. Maximum EE% of 86.61 +/- 0.11, 88.14 +/- 0.16 and 85.50 +/- 0.21 was obtained for DF1, DF2 and DF3, respectively. Discrete, smooth and brownish microspheres of size range 437 +/- 0.01-479 +/- 0.21 um were obtained. Release of DS from the formulation depends on the polymer ratio. All the batches exhibited good anti-inflammatory activities. Microsphere formulations based on Eudragit(r) polymers would likely offer a reliable and alternative means of delivering DS orally. PMID- 24171401 TI - Self-organized macroporous carbon structure derived from phenolic resin via spray pyrolysis for high-performance electrocatalyst. AB - The synthesis and evaluation of porous carbon derived from phenolic resin using a fast and facile spray pyrolysis method has been studied for use as a new electrocatalyst support material. By adding polystyrene latex nanoparticles as a template to the phenolic resin precursor, self-organized macroporous carbon structure was first developed. The mass ratio of phenolic resin to PSL at 0.625 gave the optimum porous morphology. Pt nanoparticles (~20 wt %) were grown on the carbon surface using a standard industrial impregnation method. Well-dispersed Pt nanoparticles of average size 3.91 nm were observed on the surface of porous carbon particles. The high catalytic performance of porous Pt/C electrocatalyst was confirmed by the high mass activity and electrochemically active surface area, which were 450.81 mA mg(-1)-Pt and 81.78 m(2) g(-1)-Pt, respectively. The porous Pt/C catalyst obtains two times higher mass activity than that of the commercial Pt/C catalyst and performs excellent durability under acid conditions. PMID- 24171402 TI - Benchmarking heterogeneous electrocatalysts for the oxygen evolution reaction. AB - Objective evaluation of the activity of electrocatalysts for water oxidation is of fundamental importance for the development of promising energy conversion technologies including integrated solar water-splitting devices, water electrolyzers, and Li-air batteries. However, current methods employed to evaluate oxygen-evolving catalysts are not standardized, making it difficult to compare the activity and stability of these materials. We report a protocol for evaluating the activity, stability, and Faradaic efficiency of electrodeposited oxygen-evolving electrocatalysts. In particular, we focus on methods for determining electrochemically active surface area and measuring electrocatalytic activity and stability under conditions relevant to an integrated solar water splitting device. Our primary figure of merit is the overpotential required to achieve a current density of 10 mA cm(-2) per geometric area, approximately the current density expected for a 10% efficient solar-to-fuels conversion device. Utilizing the aforementioned surface area measurements, one can determine electrocatalyst turnover frequencies. The reported protocol was used to examine the oxygen-evolution activity of the following systems in acidic and alkaline solutions: CoO(x), CoPi, CoFeO(x), NiO(x), NiCeO(x), NiCoO(x), NiCuO(x), NiFeO(x), and NiLaO(x). The oxygen-evolving activity of an electrodeposited IrO(x) catalyst was also investigated for comparison. Two general observations are made from comparing the catalytic performance of the OER catalysts investigated: (1) in alkaline solution, every non-noble metal system achieved 10 mA cm(-2) current densities at similar operating overpotentials between 0.35 and 0.43 V, and (2) every system but IrO(x) was unstable under oxidative conditions in acidic solutions. PMID- 24171403 TI - Treatment failure of patients using topical acne treatments: an observational retrospective cohort study. AB - BACKGROUND: While limited data from clinical trials show differences in efficacy between topical acne combination products and monotherapies, the impact in clinical practice is not explored. PURPOSE: To evaluate the effectiveness in clinical practice of prescribing topical acne combination treatments compared to monotherapy product(s) in minimizing treatment failures. METHODS: Patients diagnosed with acne (ICD-9: 706.1) by a dermatologist between January 2009 and September 2011 and initially prescribed a topical acne treatment were identified. Multivariate Cox proportional hazards models were employed to compare the hazards of treatment failure for patients initially prescribed a combination product versus one monotherapy or multiple monotherapies. Subgroup analyses were also performed. RESULTS: Three hundred and thirty-five patients were initially prescribed topical product(s) exclusively. The hazards of treatment failure for those prescribed a combination product compared to those prescribed one monotherapy product was HR = 0.91 (p = 0.65) and compared to those prescribed multiple monotherapy products was HR = 0.73 (p = 0.17). LIMITATIONS: Disease severity and treatments prescribed outside of the hospital system were not available. CONCLUSIONS: Treatment failures were consistent for patients prescribed combination product(s) or monotherapies. PMID- 24171404 TI - Molecular switch based on very weak association between BPX26C6 and two recognition units. AB - A [2]rotaxane has been constructed through metal ion-templated pseudorotaxane formation from a weakly interacting host (bis-p-xylyl[26]crown-6)/guest (diphenylurea derivative) complex and post-assembly modification to form another weakly interacting tertiary ammonium ion recognition site for the host. The combination of this pair of weakly interacting components allowed bifunctional (pH, Na(+) ions) switching of the crown ether unit, highlighting the potential applicability of weakly associated components within molecular switches. PMID- 24171405 TI - Humoral and cell-mediated immune responses elicited by poly (DL-lactide) adjuvanted filarial antigen molecules. AB - CONTEXT: In our recent studies, Brugia malayi molecules have shown interesting immune-stimulating and immune-suppressive properties. Among these, F6 a pro inflammatory (54-68 kDa) SDS-PAGE resolved fraction of the parasite when administered with Freund's complete/incomplete adjuvant in animals, elicited both Th1 and Th2 type immune responses and protects the host from filarial parasite. OBJECTIVE: The present study was aimed at developing biodegradable microspheres for filarial antigenic protein molecules and to investigate the immunoadjuvanticity of microspheres (Ms)-loaded F6 molecules. MATERIALS AND METHODS: Poly-lactide microspheres (DL-PLA-Ms) were prepared using double emulsification and solvent evaporation method; and studied their size, shape, antigen adsorption efficiency, in-process stability, and antigen release profiles. F6 and B. malayi adult worm (BmA: ~ 17 to 180 kDa) protein molecules adsorbed on the Ms were administered in a single shot into Swiss mice, subcutaneously, and investigated their immunoadjuvant effect and compared with one/two doses-schedule of plain F6/BmA. RESULTS: Immunization with F6/BmA-loaded DL-PLA-Ms resulted in upregulation of cellular proliferation, IFN- gamma, TNF alpha and NO release from host's cells stimulated with F6/BmA or LPS/Con A, IgG, IgG1 and IgG2a levels. These responses were well comparable with the responses produced by two doses of plain BmA/F6. DISCUSSION AND CONCLUSION: In conclusion, a single dose of DL-PLA-Ms-F6 induced predominantly Th1 immune responses and well comparable with two doses of plain F6. This is the first ever report on potential of DL-PLA-Ms as adjuvant for filarial immunogen. PMID- 24171406 TI - Ultrafast energy transfer and excited state coupling in an artificial photosynthetic antenna. AB - We have studied the energy transfer dynamics in an artificial light-harvesting dyad composed of a phthalocyanine (Pc) covalently linked to a carotenoid (Car). The combination of high temporal resolution transient absorption spectroscopy with global and target analysis allowed us to quantify the efficiency of the energy transfer from the S2 excited state of the Car to the Pc at 37%, close to values observed in some natural light-harvesting complexes. In addition, following selective excitation of the Pc, we have identified the spectral signatures of the S1 excited state of the Car which appear within the ~30 fs time resolution of our measurement. This strongly indicates excited state coupling between the S1 state of Car and the Qx state of Pc, with important implications for the regulation of photosynthetic activity. PMID- 24171407 TI - Metallic nanocages: synthesis of bimetallic Pt-Pd hollow nanoparticles with dendritic shells by selective chemical etching. AB - We report a facile synthesis of Pt-Pd bimetallic nanoparticles, named "metallic nanocages", with a hollow interior and porous dendritic shell. This synthesis is easily achieved by selective chemical etching of Pd cores from dendritic Pt-on-Pd nanoparticles. The obtained Pt-Pd nanocages show superior catalytic activity for methanol oxidation reaction compared to other Pt-based materials reported previously. PMID- 24171408 TI - Heterogeneous classifier fusion for ligand-based virtual screening: or, how decision making by committee can be a good thing. AB - The concept of data fusion - the combination of information from different sources describing the same object with the expectation to generate a more accurate representation - has found application in a very broad range of disciplines. In the context of ligand-based virtual screening (VS), data fusion has been applied to combine knowledge from either different active molecules or different fingerprints to improve similarity search performance. Machine-learning (ML) methods based on fusion of multiple homogeneous classifiers, in particular random forests, have also been widely applied in the ML literature. The heterogeneous version of classifier fusion - fusing the predictions from different model types - has been less explored. Here, we investigate heterogeneous classifier fusion for ligand-based VS using three different ML methods, RF, naive Bayes (NB), and logistic regression (LR), with four 2D fingerprints, atom pairs, topological torsions, RDKit fingerprint, and circular fingerprint. The methods are compared using a previously developed benchmarking platform for 2D fingerprints which is extended to ML methods in this article. The original data sets are filtered for difficulty, and a new set of challenging data sets from ChEMBL is added. Data sets were also generated for a second use case: starting from a small set of related actives instead of diverse actives. The final fused model consistently outperforms the other approaches across the broad variety of targets studied, indicating that heterogeneous classifier fusion is a very promising approach for ligand-based VS. The new data sets together with the adapted source code for ML methods are provided in the Supporting Information . PMID- 24171409 TI - Topical antibiotic monotherapy prescribing practices in acne vulgaris. AB - OBJECTIVE: The aim of this study is to evaluate the frequency of dosing topical antibiotics as monotherapy in the treatment of acne vulgaris, and physician specialty prescribing these medications. METHODS: This study is a retrospective review of all visits with a sole diagnosis of acne vulgaris (ICD-9-CM code 706.1) found on the National Ambulatory Medical Care Survey (NAMCS) in 1993-2010. We recorded the number of visits surveyed where acne vulgaris was the sole diagnosis, number of visits where topical antibiotics were the only treatment prescribed, and the specialty of physician in each encounter. RESULTS: Topical erythromycin or clindamycin were the sole medication prescribed in 0.81% of the visits recorded, with 60% of these prescriptions arising from dermatologists and 40% from non-dermatologists. The trend of prescribing topical antibiotic monotherapy is declining (p < 0.001) over the 18-year study period. CONCLUSIONS: The development of resistance of Propionibacterium acnes to topical antibiotic regimens has led to the need to re-evaluate the use of topical antibiotics in the treatment of acne vulgaris. While the rate of topical antibiotic monotherapy is declining, their use should be reserved for situations where the direct need for antibiotics arises. If a clinician feels that antibiotics are a necessary component to acne therapy, they should be used as part of a combination regimen. PMID- 24171410 TI - Fatty acid modulated human serum albumin binding of the beta-carboline alkaloids norharmane and harmane. AB - Harmane and norharmane are representative members of the large group of natural beta-carboline alkaloids featured with diverse pharmacological activities. In blood, these agents are transported by human serum albumin (HSA) which has a profound impact on the pharmacokinetic and pharmacodynamic properties of many therapeutic drugs and xenobiotics. By combination of various spectroscopic methods, the present contribution is aimed to elucidate how nonesterified fatty acids (FAs), the primary endogenous ligands of HSA, affect the binding properties of harmane and norharmane. Analysis of induced circular dichroism (CD) and fluorescence spectroscopic data indicates the inclusion of the neutral form of both molecules into the binding pocket of subdomain IIIA, which hosts two FA binding sites, too. The induced CD and UV absorption spectra of harmane and norharmane exhibit peculiar changes upon addition of FAs, suggesting the formation of ternary complexes in which the lipid ligands significantly alter the binding mode of the alkaloids via cooperative allosteric mechanism. To our knowledge, it is the first instance of the demonstration of drug-FA cobinding at site IIIA. In line with these results, molecular docking calculations showed two distinct binding positions of norharmane within subdomain IIIA. The profound increase in the affinity constants of beta-carbolines estimated in the presence of FAs predicts that the unbound, pharmacologically active serum fraction of these compounds strongly depends on the actual lipid binding profile of HSA. PMID- 24171411 TI - Long-term cycling studies on electrospun carbon nanofibers as anode material for lithium ion batteries. AB - Electrospun carbon nanofibers (CNF) have been prepared at different calcination temperatures for a prolonged time (12 h) derived from electrospun polyacrylonitrile (PAN) membranes. They are studied as anode materials in lithium ion batteries due to their high reversible capacity, improved long-term cycle performance, and good rate capacity. The fibrous morphologies of fresh electrodes and tested samples for more than 550 cycles have been compared; cyclic voltammogram (CV) has also been studied to understand the lithium intercalation/deintercalation mechanism of 1D nanomaterials. CNFs demonstrate interesting galvanostatic performance with fading capacity after the first few cycles, and the capacity increases during long-term cycling. The increasing capacity is observed accompanied by volumetric expansion on the nanofibers' edge. Results of rate capacity have also been explored for all CNF samples, and their stable electrochemical performances are further analyzed by the galvanostatic intermittent titration technique (GITT) and electrochemical impedance spectroscopy (EIS). CNF carbonized at 800 degrees C is found to have a larger lithium ion storage ability and better cyclic stability than that carbonized at 600 and 1000 degrees C. PMID- 24171412 TI - A histopathological study of Hudson River crayfish, Orconectes virilis, exposed to platinum group metals. AB - Platinum group metals (PGMs), such as platinum (Pt), palladium (Pd), and rhodium (Rh), are of increasing concern due to rising anthropogenic input to aquatic systems. In this study, PGMs' effects on bioaccumulation and histopathological changes were investigated using Orconectes virilis, a native Hudson River crayfish, as a model. Organisms were exposed to varying concentrations of water soluble PGM salts for 10 days. The following experimental treatments were established: 0.0, 1.0, 5.0, 10.0 ppm Pt(IV), 1.0 ppm Rh(III), 1.0 ppm Pd(II), and a PGM mix (1.0 ppm Pt(IV), Rh(III), Pd(II) each) dissolved in raw Hudson River water. Metal content in the tissue samples were analyzed by a Spectro Genesis ICP OES. The relationship between Pt, Pd, and Rh concentrations in different treatments and observed behavioral changes during the experiment was analyzed through One-Way ANOVA Student-Newman-Keuls multiple comparison test (P <= 0.05). Paraffin sections, 6-MUm-thick, were prepared in standard eosin-Y and hematoxylin 2 stain and examined for histological abnormalities within hepatopancreas, exoskeleton, brain, and ganglia tissue. Statistically significant differences in PGM bioaccumulation were observed in all organs, with highest concentrations found in the hepatopancreas, 81.68 mg g(-1) dw in 1.0 ppm Pd treatment, 20.03 mg g(-1) dw Rh in 1.0 ppm Rh treatment, and 81.58 mg g(-1) dw Pt in the 5.0 ppm Pt treatment. Pt bioaccumulation in the hepatopancreas and exoskeleton decreased at the highest Pt exposure treatment, suggesting severe structural damage to tissue. Hyper-segmentation of vacuoles and swelling of the vascular channels were observed in the hepatocyte structure of the hepatopancreas. Exoskeleton exhibited visible bands in the exocuticle indicating demineralization. Brain and ganglia demonstrated extensive vacuolization. Behavioral analysis showed an increase of maximum response intensity over the experimental period within each treatment. Bioaccumulation and cellular abnormalities observed in exposed aquatic organisms raise concern of PGM bio-magnification within the food chain and its effect on the environment and human health. PMID- 24171413 TI - Peripheral blood counts in workers exposed to synthetic fibres. AB - Acrylonitrile is an intermediary with possible adverse health effects in the synthesis of organic products, such as acrylic fibres. This investigation was undertaken to determine the possible changes in the peripheral blood counts in workers of a polyacrylic fibres plant. The study involved 218 workers exposed to acrylonitrile at low doses and a control group of 200 unexposed workers. The chosen subjects underwent blood tests in order to check their haematological parameters. There were no statistically significant differences between the two groups in terms of the red blood cells, haemoglobin and total number of leukocytes. An increase in the neutrophils associated with a reduction of lymphocytes, both statistically significant, was observed. The authors hypothesized that the neutrophils are influenced by the exposure to acrylonitrile at low doses. PMID- 24171414 TI - Human health risk assessment of dissolved metals in groundwater and surface waters in the Melen watershed, Turkey. AB - Determination of metal risk levels in potable water and their effects on human health are vital in assessment of water resources. Risk assessment of metals to human health in a watershed, which has not been studied before, is the main objective of the present study. Surface and groundwater sampling was carried out between September 2010 and August 2011 in the Melen Watershed, Turkey, an important drinking water resource for millions of people. Metals were analyzed in the laboratory using inductively coupled plasma. Of the 26 different metals monitored, Al, B, Ba, Cr, Cu, Fe, Mn, Mo and V were found in surface water and As, B, Ba, Cr, Cu, Mn, Mo, V and Zn in groundwater. In groundwater, unitless hazard quotient (HQ) values were 6 for As, 2.7 for Mn and 1 for Zn, while in surface water all metals were below the risk level (HQ < 1). The ingestion risk was found to be higher than the dermal uptake risk. Arsenic mean concentration was observed to be 0.044 mg/L in groundwater. The As carcinogenic risk (CR) value was higher than the internationally accepted risk level (10(-4)) and with maximum ingestion of groundwater the carcinogenic risk was found to be higher in adults than children. These results show that even unpolluted watersheds can pose a risk to human health and that potential carcinogenic impacts should receive more attention. PMID- 24171415 TI - Pyrene-stimulated reactive oxygen species generation and oxidative damage in Carassius auratus. AB - Laboratory experiments were carried out to understand the toxicology of pyrene in the goldfish Carassius auratus and investigate the potential oxidative stress induced by reactive oxygen species (ROS) in vivo in a time-dependent manner. Pyrene bioaccumulation, induction of reactive oxygen species and the consequent biochemical responses in the liver of the fish were examined. Fish were exposed to 0.05 mg/L pyrene for different periods. The pyrene concentration in fish liver was analyzed by high performance liquid chromatography (HPLC). Free radicals were detected by electron paramagnetic resonance (EPR). The activities of antioxidant enzymes, contents of nonenzymatic antioxidants and malondialdehyde (MDA) in fish liver were also determined. Results indicated that the pyrene concentrations in fish liver reached a maximum level on day 1, and then declined to a low steady state level over 7 days. The free radical significantly increased at 6 h and reached a maximum on day 2, while the superoxide dismutase (SOD) activity and MDA content were induced, and the reduced glutathione (GSH) content was inhibited by day 2. The catalase (CAT) and glutathione-S-transferase (GST) activities were significantly induced at 12 h. These results indicated that pyrene was rapidly bioaccumulated in fish resulting in redox cycling, and the production of free radical is an important mechanism of pyrene toxicity in C. auratus. The indicators of antioxidant system are sensitive and useful for the study of early biomarkers of pyrene exposure in fish. PMID- 24171416 TI - Ambient levels and temporal variations of PM2.5 and PM10 at a residential site in the mega-city, Nanjing, in the western Yangtze River Delta, China. AB - The deteriorating air quality in eastern China including the Yangtze River Delta is attracting growing public concern. In this study, we measured the ambient PM10 and fine PM2.5 in the mega-city, Nanjing at four different times. The 24-h average PM2.5 and PM10 mass concentrations were 0.033-0.234 and 0.042-0.328 mg/m(3), respectively. The daily PM10 and PM2.5 concentrations were 2.9 (2.7-3.2, at 95% confidence interval) and 4.2 (3.8-4.6) times the WHO air quality guidelines of 0.025 mg/m(3) for PM2.5 and 0.050 mg/m(3) for PM10, respectively, which indicated serious air pollution in the city. There was no obvious weekend effect. The highest PM10 pollution occurred in the wintertime, with higher PM2.5 loadings in the winter and summer. PM2.5 was correlated significantly with PM10 and the average mass fraction of PM2.5 in PM10 was about 72.5%. This fraction varied during different sampling periods, with the lowest PM2.5 fraction in the spring but minor differences among the other three seasons. PMID- 24171417 TI - Cr(III) removal from aqueous solutions: a straightforward model approaching of the adsorption in a fixed-bed column. AB - Prediction of breakthrough curves for continuous sorption characterization is generally performed by means of simple and simplified equations. These expressions hardly have any physical meaning and, also do not allow extrapolation. A novel and simple approach, based on unsteady state mass balances, is presented herein for the simulation of the adsorption of Cr(III) ions from aqueous onto a low-cost adsorbent (leonardite). The proposed model overcomes the limitations of the commonly used analytical solution-based models without the need for complex mathematical methods. A set of experimental breakthrough curves obtained from lab-scale, fixed-bed columns was used to calibrate and validate the proposed model with a minimum number of parameters to be adjusted. PMID- 24171418 TI - Copper use and accumulation in catfish culture in the Mekong Delta, Vietnam. AB - Aquaculture of Pangasius hypophthalmus (striped catfish) in Vietnam reached 1.1 million tonnes in 2011 and catfish fillets are exported worldwide. The intensive cultures of catfish mainly in earth ponds have made it necessary to apply CuSO4 and other chemicals to control external parasites and other pathogens. However, accumulation of Cu in aquaculture ponds may pose a hazard to growth of fish or to the aquatic environment. The aim of this study was to determine accumulation of Cu in sediment, water and fish in a catfish pond with a history of repeated treatment with CuSO4 in the Mekong Delta, Vietnam. Copper concentrations in pond sediment were in the interval 21.3-45.7 mg kg(-1) dw and did not exceed the Vietnamese values for soil to be used for agricultural production (70 mg kg(-1) dw.). During three samplings the total mean concentration of Cu in pond water (4 MUg L(-1)) did not exceed the LC50-value (70 MUg L(-1)) for catfish and the mean dissolved concentration of Cu (0.986 MUg L(-1)) did not seem to constitute a risk for the stability of the aquatic ecosystem. No significant variation in Cu concentrations between sampling sites in the pond and depth of sediment profile were determined. The accumulation of Cu in catfish was highest in the liver compared to the skin, gills and muscle tissue. With the current practice of removing pond sludge three to four times during a production cycle little if any Cu seems to accumulate in catfish ponds despite repeated anti-parasite treatments with CuSO4. Further studies are needed to assess the eco-toxicity and impact on agricultural production when pond sediment is discharged into aquatic recipients and used as soil fertilizer. PMID- 24171419 TI - UV light photo-Fenton degradation of polyphenols in oolong tea manufacturing wastewater. AB - The UV light photo-Fenton degradation of oolong tea polyphenols in tea manufacturing effluent that color the wastewater to a dark brown has been examined. In order to elucidate the photo-Fenton degradation mechanism of oolong tea polyphenols and find the optimal dosages of the Fenton reagents, systematic study has been conducted. For the UV light photo-Fenton degradation of oolong tea effluent being 70 mg-(polyphenol) L(-1), the optimum dosages of Fenton reagents were found to be 20 mgL(-1) of total Fe and 500 mgL(-1) of H2O2. The polyphenol degradation could be divided into two stages. The polyphenols concentration rapidly decreased to around 30% of the initial concentration within 2 min and the degradation rate significantly slowed down in the subsequent stage. After 60 min of UV light irradiation, 97% polyphenol removal was obtained. The initial quick degradation of oolong tea polyphenols suggests that hydroxyl radical generated by the photo-Fenton process might preferentially attack polyphenols having high antioxidant activity by scavenging hydroxyl radicals. Almost complete decolorization of the oolong tea effluent was achieved after 80 min. About 96% mineralization of 63 mgL(-1) TOC loading was achieved within 60 min and then further mineralization was rather slow. The complete COD removal of 239 mgL(-1) COD loading was obtained after 100 min. The present results indicate that the UV light photo-Fenton degradation process can treat tea manufacturing wastewaters very effectively. PMID- 24171420 TI - Effects of microwave, ultrasonic and enzymatic treatment on chemical and physical properties of waste-activated sludge. AB - The effects of microwave irradiation, microwave enhanced advanced oxidation process (MW/H2O2-AOP), ultrasonic and/or protease enzymatic treatments on chemical and physical properties of waste-activated sludge were studied. The different treatment mechanisms resulted in various degrees of biomass cell destruction and nutrient release, as evidenced by transformation of chemical constituents, particle size distribution, and scanning electron microscopic imaging. The microwave irradiation and the MW/H2O2-AOP resulted in higher soluble protein concentrations, but lower amino acids. High concentrations of soluble polysaccharide and deoxyribonucleic acid were also obtained in solution. The particle size distribution profile, after treatments, remained similar to that of waste-activated sludge; however, the distribution shifted toward smaller particle sizes. Ultrasonic treatment resulted in a high concentration of amino acids and overall protein disintegration/hydrolysis. Protease enzymatic treatment, after ultrasonic disintegration, further enhanced protein degradation. The particle size distribution profile for ultrasonic treatment was altered to a further nonuniform distribution. The ultrasonic plus protease treatment yielded the best results, in terms of cell wall destruction. PMID- 24171421 TI - Application of a packed bed reactor for the production of hydrogen from cheese whey permeate: effect of organic loading rate. AB - The production of H2 was studied using a packed bed reactor with polyurethane foam acting as support material. Experiments were performed using mixed microflora under non sterile conditions. The system was initially operated with synthetic wastewater as the sole substrate. Subsequently, cheese whey permeate was added to the system at varying organic loading rates (OLR). The performance of the reactor was evaluated by applying a continuous decrease in OLR. As a result, a significant decrease in H2 yields (HY) was observed with the decrease in OLR from 18.8 to 6.3 g chemical oxygen demand (COD)/L d. Microbial analysis demonstrated that the prevalence of non-hydrogen producers, Sporolactobacillus sp. and Prevotella, was the main reason for low HYs obtained. This behavior indicates that the fermentation under non-sterile conditions was favored by high concentrations of substrate by creating an adverse environment for nonhydrogen producer organisms. PMID- 24171422 TI - Nitrogen behavior in a free water surface constructed wetland used as posttreatment for anaerobically treated swine wastewater effluent. AB - The aim of this study was to evaluate the behavior of total nitrogen (TN) in its different forms in a Free Water Surface constructed wetland (FWS) used as posttreatment for anaerobically treated swine wastewater. The experiment was conducted in a glasshouse from July 2010 to November 2011. The system consists in a FWS mesocosm inoculated with Typha angustifolia L. using as pretreatment an UASB reactor (upflow anaerobic sludge blanket). The operation are based on the progressive increase of the nitrogen loading rate (NLR) (2.0-30.2 kg TN/ha.d) distributed in 12 loads, with an operational time of 20 d. The results indicate that the behavior of the TN in the FWS, mainly depends on the NLR applied, the amount of dissolved oxygen available and the seasonality. The FWS operated with an NLR between 2.0-30.2 kg TN/ha.d, presents average removal efficiency for TN of 54.8%, with a maximum removal (71.7%) between spring-summer seasons (17.3-21.7 degrees C). The availability of dissolved oxygen hinders the nitrification/denitrification processes in the FWS representing a 0.3-5.6% of TN removed.The main route of TN removal is associated with ammonia volatilization processes (2.6-40.7%), mainly to NLR over 25.8 kg TN/ha. d and with temperatures higher than 18 degrees C. In a smaller proportion, the incorporation of nitrogen via plant uptake was 10.8% whereas the TN accumulated in the sediments was a 5.0% of the TN applied during the entire operation (550 d). An appropriate control of the NLR applied, can reduce the ammonia volatilization processes and the phytotoxicity effects expressed as growth inhibition in 80.0% from 496.0 mg NH(+) 4-N/L (25.8 kg TN/ha.d). PMID- 24171423 TI - Microbial treatment of sulfur-contaminated industrial wastes. AB - The present study evaluated the microbial removal of sulfur from a solid industrial waste in liquid culture under laboratory conditions. The study involved the use of two bacteria Acidithiobacillus ferrooxidans ATCC 53987 and Acidithiobacillus thiooxidans AZCT-M125-5 isolated from a Mexican soil. Experimentation for industrial waste biotreatment was done in liquid culture using 125-mL Erlenmeyer flasks containing 30 mL Starkey modified culture medium and incubated at 30 degrees C during 7 days. The industrial waste was added at different pulp densities (8.25-100% w/v) corresponding to different sulfur contents from 0.7 to 8.63% (w/w). Sulfur-oxidizing activity of the strain AZCT M125-5 produced 281 and 262 mg/g of sulfate and a sulfur removal of 60% and 45.7% when the pulp density was set at 8.25 and 16.5% (w/v), respectively. In comparison, the strain A. ferrooxidans ATCC 53987 showed a lower sulfur-oxidizing activity with a sulfate production of 25.6 and 12.7 mg/g and a sulfur removal of 6% and 2.5% at the same pulp densities, respectively. Microbial growth was limited by pulp densities higher than 25% (w/v) of industrial waste with minimal sulfur-oxidizing activity and sulfur removal. The rate of sulfur removal for Acidithiobacillus thioxidans AZCT-M125-5 and Acidithiobacillus ferrooxidans ATCC 53987 was 0.185 and 0.0159 mg S g(-1) h(-1) with a pulp density of 16.5% (w/v), respectively. This study demonstrated that Acidithiobacillus thiooxidans AZCT M125-5 possesses a high sulfur-oxidizing activity, even at high sulfur concentration, which allows the treatment of hazardous materials. PMID- 24171424 TI - The leaching behaviour and geochemical fractionation of trace elements in hydraulically disposed weathered coal fly ash. AB - A five-step sequential extraction (SE) procedure was used to investigate the leaching behaviour and geochemical partitioning of the trace elements As, Zn, Pb, Ni, Mo, Cr and Cu in a 20-year-old fly ash (FA) dump. The weathered FA, which was hydraulically co-disposed with salt laden brine in slurry form (FA: brine ratio of 1:5), was analyzed and compared with fresh FA. The weathered FA samples were collected from three cores, drilled at a coal-fired power station in the Republic of South Africa while the fresh FA sample was collected from the hoppers in the ash collection system at the power station. The FA samples were sequentially leached using: ultrapure water; ammonium acetate buffer solution (pH 7); ammonium acetate buffer solution (pH 5); hydroxylamine hydrochloride in nitric acid (pH 2) and finally the residues were digested using a combination of HClO4: HF: HNO3 acids. Digestion of as received (unleached) FA samples was also done using a combination of HClO4: HF: HNO3 acids in order to determine the total metal content. The trace element analysis was done using ICP-OES (Varian 710-ES). The SE procedure revealed that the trace elements present in the fresh FA and the weathered FA samples obtained from the three cores could leach upon exposure to different environmental conditions. The trace elements showed continuous partitioning between five geochemical phases i.e., water soluble fraction, exchangeable fraction, carbonate fraction, Fe and Mn fraction and residual fraction. Although the highest concentration of the trace elements (ranging 65.51%-86.34%) was contained in the residual fraction, a considerable amount of each trace element (ranging 4.42%-27.43%) was released from the labile phases (water soluble, exchangeable and carbonate fractions), indicating that the trace species readily leach from the dumped FA under environmental conditions thus pose a danger to the receiving environment and to groundwater. PMID- 24171425 TI - Influence of sludge retention time and temperature on the sludge removal in a submerged membrane bioreactor: comparative study between pure oxygen and air to supply aerobic conditions. AB - Performance of a bench-scale wastewater treatment plant, which consisted of a membrane bioreactor, was monitored daily using pure oxygen and air to supply aerobic conditions with the aim of studying the increases of the aeration and sludge removal efficiencies and the effect of the temperature. The results showed the capacity of membrane bioreactor systems for removing organic matter. The alpha-factors of the aeration were determined for six different MLSS concentrations in order to understand the system working when pure oxygen and air were used to supply aerobic conditions in the system. Aeration efficiency was increased between 30.7 and 45.9% when pure oxygen was used in the operation conditions (a hydraulic retention time of 12 h and MLSS concentrations between 4,018 and 11,192 mg/L). Sludge removal efficiency increased incrementally, from 0.2 to 1.5% when pure oxygen was used at low sludge retention time and from 1.5% to 15.4% at medium sludge retention time when temperature conditions were lower than 20 degrees C. Moreover, the difference between calculated and experimental sludge retention time was lesser when pure oxygen was used to provide aerobic conditions, so the influence of the temperature decreased when the pure oxygen was used. These results showed the convenience of using pure oxygen due to the improvement in the performance of the system. PMID- 24171426 TI - Sorption of Eu(III) on granite: EPMA, LA-ICP-MS, batch and modeling studies. AB - Eu(III) sorption on granite was assessed using combined microscopic and macroscopic approaches in neutral to acidic conditions where the mobility of Eu(III) is generally considered to be high. Polished thin sections of the granite were reacted with solutions containing 10 MUM of Eu(III) and were analyzed using EPMA and LA-ICP-MS. On most of the biotite grains, Eu enrichment up to 6 wt % was observed. The Eu-enriched parts of biotite commonly lose K, which is the interlayer cation of biotite, indicating that the sorption mode of Eu(III) by the biotite is cation exchange in the interlayer. The distributions of Eu appeared along the original cracks of the biotite. Those occurrences indicate that the prior water-rock interaction along the cracks engendered modification of biotite to possess affinity to the Eu(III). Batch Eu(III) sorption experiments on granite and biotite powders were conducted as functions of pH, Eu(III) loading, and ionic strength. The macroscopic sorption behavior of biotite was consistent with that of granite. At pH > 4, there was little pH dependence but strong ionic strength dependence of Eu(III) sorption. At pH < 4, the sorption of Eu(III) abruptly decreased with decreased pH. The sorption behavior at pH > 4 was reproducible reasonably by the modeling considering single-site cation exchange reactions. The decrease of Eu(III) sorption at pH < 4 was explained by the occupation of exchangeable sites by dissolved cationic species such as Al and Fe from granite and biotite in low-pH conditions. Granites are complex mineral assemblages. However, the combined microscopic and macroscopic approaches revealed that elementary reactions by a single mineral phase can be representative of the bulk sorption reaction in complex mineral assemblages. PMID- 24171427 TI - Theoretical study of the catalytic mechanism of E1 subunit of pyruvate dehydrogenase multienzyme complex from Bacillus stearothermophilus. AB - Pyruvate dehydrogenase multienzyme complex (PDHc) is a member of a family of 2 oxo acid dehydrogenase (OADH) multienzyme complexes involved in several central points of oxidative metabolism, and the E1 subunit is the most important component in the entire PDHc catalytic system, which catalyzes the reversible transfer of an acetyl group from a pyruvate to the lipoyl group of E2 subunit lipoly domain. In this article, the catalytic mechanism of the E1 subunit has been systematically studied using density functional theory (DFT). Four possible pathways with different general acid/base catalysts in decarboxylation and reductive acylation processes were explored. Our calculation results indicate that the 4'-amino pyrimidine of ThDP and residue His128 are the most likely proton donors in the decarboxylation and reductive acylation processes, respectively. During the reaction, each C-C and C-S bond formation or cleavage process, except for the liberation of CO2, is always accompanied by a proton transfer between the substrates and proton donors. The liberation of CO2 is calculated to be the rate-limiting step for the overall reaction, with an energy barrier of 13.57 kcal/mol. The decarboxylation process is endothermic by 5.32 kcal/mol, whereas the reductive acylation process is exothermic with a value of 5.74 kcal/mol. The assignment of protonation states of the surrounding residues can greatly influence the reaction. Residues His128 and His271 play roles in positioning the first substrate pyruvate and second substrate lipoyl group, respectively. PMID- 24171428 TI - Copper-catalyzed three-component reaction: solvent-controlled regioselective synthesis of 4-amino- and 6-amino-2-iminopyridines. AB - Regioselective synthesis of multisubstituted 4-amino- and 6-amino-2 iminopyridines has been developed via the copper-catalyzed three-component reaction based on the reaction conditions selection. The reaction of sulfonyl azides, alkynes, and 2-[(amino)methylene]malononitriles catalyzed by copper(I) iodide in tetrahydrofuran at room temperature afforded substituted 4-amino-2 iminopyridines, whereas, in N,N-dimethylformamide at 50 degrees C under N2, it generated substituted 6-amino-2-iminopyridines as predominant products. PMID- 24171429 TI - Re: The effects of hyaluronic acid and carboxymethylcellulose in preventing recurrence of urethral stricture after endoscopic internal urethrotomy: a multicenter, randomized controlled, single-blinded study. PMID- 24171430 TI - Influence of structure on chemical and thermal stability of aliphatic diesters. AB - Ester group interactions with each other and with the atoms between them were investigated in order to determine dependence of chemical and thermal stabilities of aliphatic diesters on structure. Novel glycol-derived diesters with chemical formula (C17H33COO)2C(n)H(2n) were used as model systems. Chemical stability was determined using (1)H NMR and FTIR, and thermal stability and weight-loss kinetics were examined using nonisothermal TGA. Chemical stability increased with the number of methylene units (n, carbon) between the ester groups until n = 6, and no significant improvement was observed past n > 6. It is argued that other ester-dense materials, including polyesters, would behave similarly. Evidence of a strong dependence of thermal stability on chemical stability is also provided. This work shows that the chemical and thermal stabilities of ester-dense functional materials such as diesters, oligo-esters, and polyesters can be manipulated by varying the distance between the ester groups, and hence the interactions of the electron-withdrawing ester groups with its neighbors. PMID- 24171431 TI - Nonlinear scoring functions for similarity-based ligand docking and binding affinity prediction. AB - A common strategy for virtual screening considers a systematic docking of a large library of organic compounds into the target sites in protein receptors with promising leads selected based on favorable intermolecular interactions. Despite a continuous progress in the modeling of protein-ligand interactions for pharmaceutical design, important challenges still remain, thus the development of novel techniques is required. In this communication, we describe eSimDock, a new approach to ligand docking and binding affinity prediction. eSimDock employs nonlinear machine learning-based scoring functions to improve the accuracy of ligand ranking and similarity-based binding pose prediction, and to increase the tolerance to structural imperfections in the target structures. In large-scale benchmarking using the Astex/CCDC data set, we show that 53.9% (67.9%) of the predicted ligand poses have RMSD of <2 A (<3 A). Moreover, using binding sites predicted by recently developed eFindSite, eSimDock models ligand binding poses with an RMSD of 4 A for 50.0-39.7% of the complexes at the protein homology level limited to 80-40%. Simulations against non-native receptor structures, whose mean backbone rearrangements vary from 0.5 to 5.0 A Calpha-RMSD, show that the ratio of docking accuracy and the estimated upper bound is at a constant level of ~0.65. Pearson correlation coefficient between experimental and predicted by eSimDock Ki values for a large data set of the crystal structures of protein ligand complexes from BindingDB is 0.58, which decreases only to 0.46 when target structures distorted to 3.0 A Calpha-RMSD are used. Finally, two case studies demonstrate that eSimDock can be customized to specific applications as well. These encouraging results show that the performance of eSimDock is largely unaffected by the deformations of ligand binding regions, thus it represents a practical strategy for across-proteome virtual screening using protein models. eSimDock is freely available to the academic community as a Web server at http://www.brylinski.org/esimdock . PMID- 24171432 TI - Toroidal structure and DNA cleavage by the CRISPR-associated [4Fe-4S] cluster containing Cas4 nuclease SSO0001 from Sulfolobus solfataricus. AB - Cas4 proteins, a core protein family associated with the microbial system of adaptive immunity CRISPR, are predicted to function in the adaptation step of the CRISPR mechanism. Here we show that the Cas4 protein SSO0001 from the archaeon Sulfolobus solfataricus has metal-dependent endonuclease and 5'->3' exonuclease activities against single-stranded DNA, as well as ATP-independent DNA unwinding activity toward double-stranded DNA. The crystal structure of SSO0001 revealed a decameric toroid formed by five dimers with each protomer containing one [4Fe-4S] cluster and one Mn(2+) ion bound in the active site located inside the internal tunnel. The conserved RecB motif and four Cys residues are important for DNA binding and cleavage activities, whereas DNA unwinding depends on several residues located near the [4Fe-4S] cluster. Our results suggest that Cas4 proteins might contribute to the addition of novel CRISPR spacers through the formation of 3'-DNA overhangs and to the degradation of foreign DNA. PMID- 24171433 TI - Enhanced electrochemical performance of three-dimensional Ni/Si nanocable arrays as a Li-ion battery anode by nitrogen doping in the Si shell. AB - In the present study, a configuration of three-dimensional Ni core/sputtered Si shell nanocable arrays is proposed to alleviate the severe volumetric change of Si during lithiation/delithiation. In particular, the effects of N doping in the Si shell on the electrochemical performance of the nanocable array electrodes have been investigated. It has been found that reduced interfacial resistance, enhanced effective Li ion diffusion coefficient in the active material, and more stable surface passivating layer are likely to be achieved by N doping, leading to an improvement of the rate performance and cyclability when compared to the undoped nanocable array counterpart. PMID- 24171434 TI - Stabilization of distearoylphosphatidylcholine lamellar phases in propylene glycol using cholesterol. AB - Phospholipid vesicles (liposomes) formed in pharmaceutically acceptable nonaqueous polar solvents such as propylene glycol are of interest in drug delivery because of their ability to improve the bioavailability of drugs with poor aqueous solubility. We have demonstrated a stabilizing effect of cholesterol on lamellar phases formed by dispersion of distearoylphosphatidylcholine (DSPC) in water/propylene glycol (PG) solutions with glycol concentrations ranging from 0 to 100%. The stability of the dispersions was assessed by determining the effect of propylene glycol concentration on structural parameters of the lamellar phases using a complementary combination of X-ray and neutron scattering techniques at 25 degrees C and in the case of X-ray scattering at 65 degrees C. Significantly, although stable lamellar phases (and liposomes) were formed in all PG solutions at 25 degrees C, the association of the glycol with the liposomes' lamellar structures led to the formation of interdigitated phases, which were not thermostable at 65 degrees C. With the addition of equimolar quantities of cholesterol to the dispersions of DSPC, stable lamellar dispersions (and indeed liposomes) were formed in all propylene glycol solutions at 25 degrees C, with the significant lateral phase separation of the bilayer components only detectable in propylene glycol concentrations above 60% (w/w). We propose that the stability of lamellar phases of the cholesterol-containing liposomes formed in propylene glycol concentrations of up to 60% (w/w) represent potentially very valuable drug delivery vehicles for a variety of routes of administration. PMID- 24171435 TI - Primary photochemistry of the dark- and light-adapted states of the YtvA protein from Bacillus subtilis. AB - The primary (100 fs to 10 ns) and secondary (10 ns to 100 MUs) photodynamics in the type II light-oxygen-voltage (LOV) domain from the blue light YtvA photoreceptor extracted from Bacillus subtilis were explored with transient absorption spectroscopy. The photodynamics of full-length YtvA were characterized after femtosecond 400 nm excitation of both the dark-adapted D447 state and the light-adapted S390 state. The S390 state relaxes on a 43 min time scale at room temperature back into D447, which is weakly accelerated by the introduction of imidazole. This is ascribed to an obstructed cavity in YtvA that hinders access to the embedded FMN chromophore and is more open in type I LOV domains. The primary photochemistry of dark-adapted YtvA is qualitatively similar to that of the type I LOV domains, including AsLOV2 from Avena sativa, but exhibits an appreciably higher (60% greater) terminal triplet yield, estimated near the maximal PhiISC value of ~78%; the other 22% decays via non-triplet-generating fluorescence. The subsequent secondary dynamics are inhomogeneous, with three triplet populations co-evolving: the faster-decaying (I)T* population (38% occupancy) with a 200 ns decay time is nonproductive in generating the S390 adduct state, a slower (II)T* population (57% occupancy) exhibits a high yield (Phiadduct ~ 100%) in generating S390 and a third (5%) (III)T*population persists (>100 MUs) with unresolved photoactivity. The ultrafast photoswitching dynamics of the S390 state appreciably differ from those previously resolved for the type I AcLOV2 domain from Adiantum capillus-veneris [Kennis, J. T., et al. (2004) J. Am. Chem. Soc. 126, 4512], with a low-yield dissociation (Phidis ~ 2.5%) reaction, which is due to an ultrafast recombination reaction, following photodissociation, and is absent in AcLOV2, which results in the increased photoswitching activity of the latter domain. PMID- 24171438 TI - Toxicity of melamine: the public health concern. AB - Melamine contamination in food has resulted in sickness and deaths of human infants, pets, and farm animals in the past decade. The majority of the victims suffered from acute kidney injury, nephrolithiasis, and urolithiasis. Since then, animal studies have revealed the possible target organs of the melamine toxicity and the extent of the adverse effects of the contaminant. State-of-the-art analytical methods have been developed to achieve the "zero tolerance" aim for such economically motivated adulteration. These studies provide in-depth understanding of the melamine toxicity and promising analytical methods, which can help us safeguard our dairy food source. PMID- 24171436 TI - Understanding the gender disparity in bladder cancer risk: the impact of sex hormones and liver on bladder susceptibility to carcinogens. AB - It has long been known that bladder cancer (BC) incidence is approximately four fold higher in men than in women in the United States, and a similar disparity also exists in other countries. The reason for this phenomenon is not known, which impedes progress in BC prevention. However, BC incidence is also significantly higher in male animals than in their female counterparts after treatment with aromatic amines, which are principal human bladder carcinogens. These animal studies and related studies in the context of available human data provide significant insight into what may drive the excessive BC risk in men, which is the focus of this article. The carcinogenicity and biotransformation of bladder carcinogens as well as the impact of sex hormones on these processes are discussed, highlighting the novel concept that the gender disparity in BC risk may result primarily from the interplay of androgen, estrogen, and liver, with the liver functioning via its metabolic enzymes as the main decider of bladder exposure to carcinogens in the urine and the male and female hormones exerting opposing effects on carcinogenesis in the bladder and likely also on liver enzymes handling bladder carcinogens. The findings may facilitate further investigation into the mechanism of gender disparity in BC risk and may also have important implications for BC prevention. PMID- 24171440 TI - Are patients willing to participate in surveys? PMID- 24171441 TI - Noninvasive ureterocele puncture using pulsed focused ultrasound: an in vitro study. AB - PURPOSE: To evaluate the feasibility of performing noninvasive puncture of pediatric ureteroceles with cavitation-based focused ultrasound (US) (histotripsy). MATERIALS AND METHODS: A model for the ureterocele wall was developed from an excised bovine bladder wall. The model was exposed to focused US pulses in a water bath under three different US parameter sets for up to 300 seconds to create localized perforations in the wall. B-mode US imaging was used to monitor the treatment and assess potential imaging guidance and feedback. RESULTS: Punctures were formed between 46-300 seconds, depending on the focused US exposure parameters and model wall thickness. Puncture diameter was controllable through choice of exposure parameters and could be varied between 0.8-2.8 mm mean diameter. US-induced cavitation was visible on B-mode imaging, which provided targeting and treatment feedback. CONCLUSIONS: Cavitation-based focused US can create punctures in a model that mimics the tissue properties of a ureterocele wall, under guidance from US imaging. PMID- 24171437 TI - Friend or foe? The current epidemiologic evidence on selenium and human cancer risk. AB - Scientific opinion on the relationship between selenium and the risk of cancer has undergone radical change over the years, with selenium first viewed as a possible carcinogen in the 1940s then as a possible cancer preventive agent in the 1960s-2000s. More recently, randomized controlled trials have found no effect on cancer risk but suggest possible low-dose dermatologic and endocrine toxicity, and animal studies indicate both carcinogenic and cancer-preventive effects. A growing body of evidence from human and laboratory studies indicates dramatically different biological effects of the various inorganic and organic chemical forms of selenium, which may explain apparent inconsistencies across studies. These chemical form-specific effects also have important implications for exposure and health risk assessment. Overall, available epidemiologic evidence suggests no cancer preventive effect of increased selenium intake in healthy individuals and possible increased risk of other diseases and disorders. PMID- 24171442 TI - Solvation and association of 3:1 electrolytes in N,N-dimethylformamide. AB - A detailed study has been made of the solvation and ion association of the trifluoromethanesulfonate (Tf(-)) salts of aluminum(III), scandium(III), and lanthanum(III) in N,N-dimethylformamide (DMF) at 25 degrees C using dielectric relaxation spectroscopy over the frequency range of 0.1 ? nu/GHz <= 89. The spectra of all solutions exhibited either two (for ScTf3 and LaTf3) or three (for AlTf3) relaxation processes, a dominant mode centered at ~15 GHz due to the solvent and one or (for AlTf3 solutions) two solute-related processes at lower frequencies (numax ? 2 GHz). Effective solvation numbers, Zib, calculated from the solvent relaxation process indicated that all three cations were strongly solvated by DMF with Zib(0) values at infinite dilution in the order (Al(3+) ~ Sc(3+) ~ 10) < (La(3+) ~ 13), consistent with at least partial formation of a second solvation shell around each cation. One solute-related mode for each set of salt solutions was assigned to the rotational diffusion of solvent-shared ion pairs (SIPs) of 1:1 stoicheometry; the additional slower process for AlTf3 solutions in DMF was attributed to the presence of double-solvent-separated IPs. The overall association constants at infinite dilution for the 1:1 IPs, KA degrees (MTf(2+)), were significant, but as expected from Debye-Huckel considerations, the KA values decreased rapidly with increasing solute concentration. PMID- 24171443 TI - Convenient MW-assisted synthesis of unsymmetrical sulfides using sulfonyl hydrazides as aryl thiol surrogate. AB - An efficient synthesis of unsymmetrical sulfides has been achieved via the cross coupling reaction of aryl/het-aryl/benzyl halides with stable and easily workable sulfonyl hydrazides as thiol substitutes by means of [DBU][HOAc] and CuI under microwave irradiation. PMID- 24171444 TI - Kinetic and structural investigations into the allosteric and pH effect on the substrate specificity of human epithelial 15-lipoxygenase-2. AB - Lipoxygenases, important enzymes in inflammation, can regulate their substrate specificity by allosteric interactions with their own hydroperoxide products. In this work, addition of both 13-(S)-hydroxy-(9Z,11E)-octadecadienoic acid [13-(S) HODE] and 13-(S)-hydroperoxy-(6Z,9Z,11E)-octadecatrienoic acid to human epithelial 15-lipoxygenase-2 (15-LOX-2) increases the kcat/KM substrate specificity ratio of arachidonic acid (AA) and gamma-linolenic acid (GLA) by 4 fold. 13-(S)-HODE achieves this change by activating kcat/KM(AA) but inhibiting kcat/KM(GLA), which indicates that the allosteric structural changes at the active site discriminate between the length and unsaturation differences of AA and GLA to achieve opposite kinetic effects. The substrate specificity ratio is further increased, 11-fold in total, with an increase in pH, suggesting mechanistic differences between the pH and allosteric effects. Interestingly, the loss of the PLAT domain affects substrate specificity but does not eliminate the allosteric properties of 15-LOX-2, indicating that the allosteric site is located in the catalytic domain. However, the removal of the PLAT domain does change the magnitude of the allosteric effect. These data suggest that the PLAT domain moderates the communication pathway between the allosteric and catalytic sites, thus affecting substrate specificity. These results are discussed in the context of protein dimerization and other structural changes. PMID- 24171446 TI - Redox-controlled changes in cadmium solubility and solid-phase speciation in a paddy soil as affected by reducible sulfate and copper. AB - The solubility of Cd in contaminated paddy soils controls Cd uptake by rice, which is an important food safety issue. We investigated the solution and solid phase dynamics of Cd in a paddy soil spiked with ~20 mg kg(-1) Cd during 40 days of soil reduction followed by 28 days of soil reoxidation as a function of the amounts of sulfate available for microbial reduction and of Cu that competes with Cd for precipitation with biogenic sulfide. At an excess of sulfate over (Cd + Cu), dissolved Cd decreased during sulfate reduction and Cd was transformed into a poorly soluble phase identified as Cd-sulfide using Cd K-edge X-ray absorption spectroscopy (XAS). The extent of Cd-sulfide precipitation decreased with decreasing sulfate and increasing Cu contents, even if sulfate exceeded Cd. When both Cu and Cd exceeded sulfate, dissolved and mobilizable Cd remained elevated after 40 days of soil reduction. During soil reoxidation, Cd-sulfide was readily transformed back into more soluble species. Our data suggest that Cd-sulfide formation in flooded paddy soil may be limited when the amounts of Cd and other chalcophile metals significantly exceed reducible sulfate Therefore, in multimetal contaminated paddy soils with low sulfate contents, Cd may remain labile during soil flooding, which enhances the risk for Cd transfer into rice. PMID- 24171445 TI - Effect of incorporating cholesterol into DDA:TDB liposomal adjuvants on bilayer properties, biodistribution, and immune responses. AB - Cholesterol is an abundant component of mammalian cell membranes and has been extensively studied as an artificial membrane stabilizer in a wide range of phospholipid liposome systems. In this study, the aim was to investigate the role of cholesterol in cationic liposomal adjuvant system based on dimethyldioctadecylammonium (DDA) and trehalose 6,6'-dibehenate (TDB) which has been shown as a strong adjuvant system for vaccines against a wide range of diseases. Packaging of cholesterol within DDA:TDB liposomes was investigated using differential scanning calorimetery and surface pressure-area isotherms of lipid monolayers; incorporation of cholesterol into liposomal membranes promoted the formation of a liquid-condensed monolayer and removed the main phase transition temperature of the system, resulting in an increased bilayer fluidity and reduced antigen retention in vitro. In vivo biodistribution studies found that this increase in membrane fluidity did not alter deposition of liposomes and antigen at the site of injection. In terms of immune responses, early (12 days after immunization) IgG responses were reduced by inclusion of cholesterol; thereafter there were no differences in antibody (IgG, IgG1, IgG2b) responses promoted by DDA:TDB liposomes with and without cholesterol. However, significantly higher levels of IFN-gamma were induced by DDA:TDB liposomes, and liposome uptake by macrophages in vitro was also shown to be higher for DDA:TDB liposomes compared to their cholesterol-containing counterparts, suggesting that small changes in bilayer mechanics can impact both cellular interactions and immune responses. PMID- 24171447 TI - From a zwitterionic phosphasilene to base stabilized silyliumylidene-phosphide and bis(silylene) complexes. AB - The reactivity of ylide-like phosphasilene 1 [LSi(TMS)?P(TMS), L = PhC(NtBu)2] with group 10 d(10) transition metals is reported. For the first time, a reaction of a phosphasilene with a transition metal that actually involves the silicon phosphorus double bond was found. In the reaction of 1 with ethylene bis(triphenylphosphine) platinum(0), a complete silicon-phosphorus bond breakage occurs, yielding the unprecedented dinuclear platinum complex 3 [LSi{Pt(PPh3)}2P(TMS)2]. Spectroscopic, structural, and theoretical analysis of complex 3 revealed the cationic silylene (silyliumylidene) character of the silicon unit in complex 3. Similarly, formation of the analogous dinuclear palladium complex 4 [LSi{Pd(PPh3)}2P(TMS)2] from tetrakis(triphenylphosphine) palladium(0) was observed. On the other hand, in the case of bis(cyclooctadiene) nickel(0) as starting material, a distinctively different product, the bis(silylene) nickel complex 5 [{(LSi)2P(TMS)}Ni(COD)], was obtained. Complex 5 was fully characterized including X-ray diffraction analysis. Density functional theory calculations of the reaction mechanisms showed that the migration of the TMS group in the case of platinum and palladium was induced by the oxidative addition of the transition metal into the silicon-silicon bond. The respective platinum intermediate 2 [LSi{Pt(TMS)(PPh3)}P(TMS)] was also experimentally observed. This is contrasted by the reaction of nickel, in which the equilibrium of phosphasilene 1 and the phosphinosilylene 6 [LSiP(TMS)2] was utilized for a better coordination of the silicon(II) moiety in comparison with phosphorus to the transition metal center. PMID- 24171448 TI - Novel phosphamide additive to improve thermal stability of solid electrolyte interphase on graphite anode in lithium-ion batteries. AB - In this communication, a novel electrolyte additive, N,N-diallyic-diethyoxyl phosphamide (DADEPA), is described for the first time to improve the thermal stability of lithiated graphite anode in Li-ion batteries. The differential scanning calorimetry (DSC) measurement demonstrated that when the graphite was lithiated in the 5% DADEPA-containing electrolyte, the heat generation decreased sharply by half as compared with the reference, whereas the onset temperature for the main exothermic process was postponed by 20 degrees C. Electrochemical and XPS analyses indicated that the distinctive improvement in thermal safety came from a new interfacial chemistry, in which phosphorus-containing ingredients was embedded during the initial forming of the interphase. PMID- 24171449 TI - Epidemiology and molecular characterization of extended-spectrum beta-lactamase producing Enterobacter spp., Pantoea agglomerans, and Serratia marcescens isolates from a Bulgarian hospital. AB - Forty-two extended-spectrum beta-lactamase (ESBL)-producing isolates of Enterobacter aerogenes, Enterobacter cloacae, Pantoea agglomerans, and Serratia marcescens, collected consecutively during the period January-November 2011 from the University Hospital in Varna, Bulgaria, were studied to characterize their ESBLs by isoelectric focusing, group-specific PCR, and sequencing. The epidemiological relationship was evaluated by random amplified polymorphic DNA analysis (RAPD). Transferability of ESBL genes was determined by conjugation experiments. Plasmid analysis was done by replicon typing and PstI fingerprinting. The overall rate of ESBL production was 20%. The most widespread enzyme was CTX-M-3, found in 64%. It was dominant in E. aerogenes (100%) and S. marcescens (83%). SHV-12, CTX-M-3, and CTX-M-15 were found among E. cloacae isolates in 50%, 35%, and 45%, respectively. Three main CTX-M-3-producing epidemic clones of E. aerogenes and S. marcescens have been detected. Among E. cloacae isolates, six different RAPD profiles were discerned. The plasmids harboring blaCTX-M-3 belonged to IncL/M type and demonstrated similar PstI fingerprinting profiles. IncFII plasmids were detected in two CTX-M-15-producing E. cloacae isolates. Our results demonstrate wide intrahospital dissemination of clonal E. aerogenes and S. marcescens isolates, carrying IncL/M conjugative plasmids. PMID- 24171451 TI - Translating the materials genome into safer consumer products. PMID- 24171450 TI - Massive dissemination of methicillin resistant Staphylococcus aureus in bloodstream infections in a high MRSA prevalence country: establishment and diversification of EMRSA-15. AB - Portugal is the European country with the highest prevalence of methicillin resistant Staphylococcus aureus (MRSA), in which EMRSA-15 (ST22-IVh) has been the dominant clone since soon after its introduction in Portuguese hospitals in 2001. In this study, we intend to not only, assess the evolution of the invasive MRSA in Portuguese hospitals, but also to evaluate the invasive methicillin susceptible S. aureus (MSSA) population and the relationship between both populations. In the current study, two major MRSA clones were identified: EMRSA 15 that has been dominant for more than 10 years and accounts for 75% of the MRSA isolates, and ST105-II, a clone related with the New York/Japan clone (ST5-II). In contrast, among MSSA, several clonal backgrounds were identified. Despite of the massive predominance of EMRSA-15 in the last decade, an increase in spa diversity has been observed in the last few years, which suggests a recent and local diversification of this clone. Interestingly, MRSA and MSSA populations with related clonal backgrounds appear to have increased as a result of the dissemination of MRSA to the community environment. PMID- 24171452 TI - Orientational dynamics in a lyotropic room temperature ionic liquid. AB - In a previous study of room temperature ionic liquid/water mixtures, the first clearly observed biexponential decays in optical heterodyne-detected optical Kerr effect (OHD-OKE) experiments on a liquid were reported, (Sturlaugson, A. L.; Fruchey, K. S.; Fayer, M. D. J. Phys. Chem. B 2012, 116, 1777), and it was suggested that the biexponential behavior is indicative of the approach to gelation. Here, new OHD-OKE experiments on mixtures of the room temperature ionic liquid 1-methyl-3-octylimidazolium chloride (OmimCl) with water are presented. The OmimCl/water system is shown to gel over the water mole fraction range of 0.69-0.81. In the OHD-OKE decays, the biexponential behavior becomes more distinct as the gelling concentration range is approached from either high or low water concentrations. The biexponential decays are analyzed in terms of the wobbling-in-a-cone model, and the resulting diffusion constants and "relative" order parameters and cone angles are reported. Comparison of the OmimCl/water data with the previously reported room temperature ionic liquid/water OHD-OKE decays supports the previous hypothesis that the biexponential dynamics are due to the approach to the liquid-gel transition and suggests that the order of the concentration-dependent phase transition can be tuned by the choice of anion. PMID- 24171453 TI - Porous surface structure fabricated by breath figures that suppresses Pseudomonas aeruginosa biofilm formation. AB - As colonizers of medical-device surfaces, Pseudomonas aeruginosa strains present a serious source of infection and are of major concern. In this study, we fabricated films with porous surfaces by breath figures that disturb mergence by bacterial attachment, thereby impeding biofilm development. Previous studies have shown that microtopography prevents the development of P. aeruginosa biofilms. Accordingly we indented surfaces with patterns of micrometer-sized pores using breath figures at ordinary temperatures and pressures. The antimicrobial effect of surface figures was experimentally investigated by controlling the surface structure. The results suggested that pores of 5-11 MUm in diameter effectively inhibit bacterial activity. It appears that biofilm development is precluded by the decreased contact area between the films and bacteria. PMID- 24171454 TI - Prolonged capnoperitoneum does not cause postoperative ileus in pigs: safety of prolonged capnoperitoneum. AB - INTRODUCTION: Operative time is an accepted risk factor for the development of postoperative ileus (POI). Innovative surgical procedures such as robotic surgery and natural orifice transluminal endoscopic surgery (NOTES) will be associated with longer operative times. Although intraabdominal manipulation is a major factor for POI the impact of prolonged capnoperitoneum on postoperative gastrointestinal transit time (GIT-TT) has rarely been studied. MATERIAL AND METHODS: IRB approved survival pilot study to assess postoperative GIT-TT using fecal collection and chromium-oxide (Cr2O3) labeling in pigs. Twelve female pigs were randomly assigned to three groups of four animals each. Group A received eight hours anesthesia and pressure-controlled high flow capnoperitoneum (15 mmHg), group B eight hours of anesthesia only and group C no intervention. No intraoperative manipulation. The pilot study was terminated after eight days. RESULTS: None of the animals developed POI. In Group A one animal died after eight hours of general anesthesia. No differences in postoperative fecal output, Cr2O3 excretion rate or weight gain were found. CONCLUSION: This study is the first to investigate eight hours of capnoperitoneum in a survival model. GIT-TT is not affected by prolonged capnoperitoneum in pigs. No POI occurred with prolonged capnoperitoneum. Prolonged capnoperitoneum is safe regarding postoperative gastrointestinal function in innovative surgical procedures. PMID- 24171455 TI - Direct puncture embolization using N-butyl cyanoacrylate for a hepatic artery pseudoaneurysm. AB - Massive hemobilia caused by hepatic artery pseudoaneurysm is an uncommon but potentially fatal complication that can occur after biliary intervention. Previous intervention or surgery, atherosclerotic disease, inflammation and even anatomic variants may make the pseudoaneurysm inaccessible to transcatheter approach, therefore it is not always feasible. The present report describes a case of successful embolization of a hepatic artery pseudoaneurysm with N-butyl cyanoacrylate via direct puncture as an alternative approach. The case presentation is followed by the technical points and the properties of N-butyl cyanoacrylate that are particularly advantageous for use in direct puncture procedures. PMID- 24171456 TI - Impaired HCV clearance in HIV/HCV coinfected subjects treated with PegIFN and RBV due to interference of IFN signaling by IFNalphaR2a. AB - Enhanced endogenous interferon (IFN) stimulated gene (ISG) signature has been associated with nonresponsiveness to hepatitis C treatment using pegylated IFNalpha (pegIFNalpha) and ribavirin (RBV) in human immunodeficiency virus/hepatitis C virus (HIV/HCV) coinfected patients. Using a proteomic approach, we identified high levels of IFNalpha receptor 2a (IFNalphaR2a) in the serum of null responders to pegIFNalpha/RBV. IFNalphaR2a inhibited antiviral activity of all formulations of IFNalpha in JFH/Huh7.5 cells. Furthermore, serum from null responders, but not from those who achieved sustained virologic response, suppressed IFN-signaling and ISG expression in IFNalpha-stimulated PBMCs of healthy donors in an IFNalphaR2a specific fashion. An IFNalphaR2a transgenic mice model (C57BL/6) was generated that had significantly higher levels of IFNalphaR2a in the serum than the controls (P=0.001). Total ISG expression in the lymph nodes was significantly higher compared to wild-type mice (P value=0.0016). In addition, IFITM1 and SP110 had significantly increased expression in the liver, IFITM1 and ISG15 in the lymph node, and ISG15 and PLSCR1 in the spleen (P value<0.05). The underlying mechanism of resistance to hepatitis C treatment may involve transsignaling of the JAK/STAT pathway by the sIFNalphaR2a-IFNalpha/beta complex and result in the enhanced ISG signature observed in null responders. In this regard, the transgenic mice model simulated nonresponders to IFNalpha therapy and provides valuable insights into the role of sIFNalphaR2a-IFNalpha interactions in vivo. PMID- 24171458 TI - Investigation of hepatobiliary disposition of doxorubicin following intrahepatic delivery of different dosage forms. AB - Unresectable, intermediate stage hepatocellular carcinoma (HCC) is often treated palliatively in humans by doxorubicin (DOX). The drug is administered either as a drug-emulsified-in-Lipiodol (DLIP) or as drug loaded into drug eluting beads (DEB), and both formulations are administered intrahepatically. However, several aspects of their in vivo performance in the liver are still not well-understood. In this study, DLIP and DEB were investigated regarding the local and systemic pharmacokinetics (PK) of DOX and its primary metabolite doxorubicinol (DOXol). An advanced PK-multisampling site acute in vivo pig model was used for simultaneous sampling in the portal, hepatic, and femoral veins and the bile duct. The study had a randomized, parallel design with four treatment groups (TI-TIV). TI (n = 4) was used as control and received an intravenous (i.v.) infusion of DOX as a solution. TII and TIII were given a local injection in the hepatic artery with DLIP (n = 4) or DEB (n = 4), respectively. TIV (n = 2) received local injections of DLIP in the hepatic artery and bile duct simultaneously. All samples were analyzed for concentrations of DOX and DOXol with UPLC-MS/MS. Compared to DLIP, the systemic exposure for DOX with DEB was reduced (p < 0.05), in agreement with a slower in vivo release. The approximated intracellular bioavailability of DOX during 6 h appeared to be lower for DEB than DLIP. Following i.v. infusion (55 min), DOX had a liver extraction of 41 (28-53)%, and the fraction of the dose eliminated in bile of DOX and DOXol was 20 (15-22)% and 4.2 (3.2-5.2)%, respectively. The AUCbile/AUCVP for DOX and DOXol was 640 (580-660) and 5000 (3900-5400), respectively. In conclusion, DLIP might initially deliver a higher hepatocellular concentration of DOX than DEB as a consequence of its higher in vivo release rate. Thus, DLIP delivery results in higher intracellular peak concentrations that might correlate with better anticancer effects, but also higher systemic drug exposure and safety issues. PMID- 24171457 TI - Loop interactions and dynamics tune the enzymatic activity of the human histone deacetylase 8. AB - The human histone deacetylase 8 (HDAC8) is a key hydrolase in gene regulation and has been identified as a drug target for the treatment of several cancers. Previously the HDAC8 enzyme has been extensively studied using biochemical techniques, X-ray crystallography, and computational methods. Those investigations have yielded detailed information about the active site and have demonstrated that the substrate entrance surface is highly dynamic. Yet it has remained unclear how the dynamics of the entrance surface tune and influence the catalytic activity of HDAC8. Using long time scale all atom molecular dynamics simulations we have found a mechanism whereby the interactions and dynamics of two loops tune the configuration of functionally important residues of HDAC8 and could therefore influence the activity of the enzyme. We subsequently investigated this hypothesis using a well-established fluorescence activity assay and a noninvasive real-time progression assay, where deacetylation of a p53 based peptide was observed by nuclear magnetic resonance spectroscopy. Our work delivers detailed insight into the dynamic loop network of HDAC8 and provides an explanation for a number of experimental observations. PMID- 24171460 TI - Rapid identification of ligand-binding sites by using an assignment-free NMR approach. AB - In this study, we developed an assignment-free approach for rapid identification of ligand-binding sites in target proteins by using NMR. With a sophisticated cell-free stable isotope-labeling procedure that introduces (15)N- or (13)C labels to specific atoms of target proteins, this approach requires only a single series of ligand titrations with labeled targets. Using titration data, ligand binding sites in the target protein can be identified without time-consuming assignment procedures. We demonstrated the feasibility of this approach by using structurally well-characterized interactions between mitogen-activated protein (MAP) kinase p38alpha and its inhibitor 2-amino-3-benzyloxypyridine. Furthermore, we confirmed the recently proposed fatty acid binding to p38alpha and confirmed the fatty acid-binding site in the MAP kinase insert region. PMID- 24171461 TI - Anion encapsulation and geometric changes in hepta- and hexanuclear copper(I) dichalcogeno clusters: a theoretical and experimental investigation. AB - Whereas stable octanuclear clusters of the type M(I)8(E(?)E)6 (M = Cu, Ag; E(?)E = dithio or diseleno ligand) are known for being able to encapsulate a hydride or main-group anion under some circumstances, only the related hydride-containing heptanuclear [M(I)]7(H)(E(?)E)6 and empty hexanuclear [M(I)]6(E(?)E)6 species have been characterized so far. In this paper we investigate by the means of theoretical calculations and experiments the viability of empty and anion centered clusters of the type [Cu(I)]7(X)(E(?)E)6 and [Cu(I)]6(X)(E(?)E)6 (X = vacancy, H or a main-group atom). The theoretical prediction for the existence of anion-containing heptanuclear species, the shape of which is modulated by the anion nature and size, have been fully confirmed by the synthesis and characterization of [Cu7(X){S2P(O(i)Pr)2}6] (X = H, Br). This consistency between experiment and theory allows us to predict the stability and shape-modulated structure of a whole series of [Cu(I)]7(X)(E(?)E)6 (X = vacancy, H, O, S, halogen) and [Cu(I)]6(X)(E(?)E)6 (X = H, halogen) clusters. PMID- 24171462 TI - Mechanism of proton transport in ionic-liquid-doped perfluorosulfonic acid membranes. AB - Ionic-liquid-doped perfluorosulfonic acid membranes (PFSA) are promising electrolytes for intermediate/high-temperature fuel cell applications. In the present study, we examine proton-transport pathways in a triethylammonium triflate (TEATF) ionic liquid (IL)-doped Nafion membrane using quantum chemistry calculations. The IL-doped membrane matrix contains triflic acid (TFA), triflate anions (TFA(-)), triethylamine (TEA), and triethylammonium cations (TEAH(+)). Results show that proton abstraction from the sulfonic acid end groups in the membrane by TFA(-) facilitates TEAH(+) interaction with the side-chains. In the IL-doped PFSA membrane matrix, proton transfer from TFA to TEA and TFA to TFA(-) occurs. However, proton transfer from a tertiary amine cation (TEAH(+)) to a tertiary amine (TEA) does not occur without an interaction with an anion (TFA( )). An anion interaction with the amine increases its basicity, and as a consequence, it takes a proton from a cation either instantly (if the cation is freely moving) or with a small activation energy barrier of 2.62 kcal/mol (if the cation is interacting with another anion). The quantum chemistry calculations predict that anions are responsible for proton-exchange between cations and neutral molecules of a tertiary amine. Results from this study can assist the experimental choice of IL to provide enhanced proton conduction in PFSA membrane environments. PMID- 24171463 TI - Ion-induced reorientation and distribution of pentanone in the air-water boundary layer. AB - Organic material at the surface of atmospheric aerosols is ubiquitous and plays an important role in Earth's atmosphere. Small ketones, such as 3-pentanone, are found in aerosols and as surface-active species on aerosols. This study uses 3 pentanone as a model ketone to understand how such molecules adsorb at the vapor water interface on aqueous solutions containing sulfate, carbonate, or chloride ions. By combining surface spectroscopic experiments with computational methods, very detailed information about the molecular bonding, geometries, and surface orientation of 3-pentanone as a function of depth has been obtained. The results show that, for pure water, 3-pentanone resides at the topmost surface of water with the carbonyl pointing into the aqueous phase where it is weakly solvated. For Na2SO4-containing solutions, we found that sulfate ions in the boundary layer provoke changes in the geometry and interfacial position of 3-pentanone that are not seen in solutions containing sodium chloride or sodium carbonate. The results provide important insight into the behavior of ketones in the presence of salts at the surface of aerosols in the atmosphere. PMID- 24171464 TI - High-performance Bi(2)Te(3)-based topological insulator film magnetic field detector. AB - Topological insulators with the nanoscaled metallic surface state (3-5 nm) are actually of typical functional nanostructures. Significant efforts have been devoted to study new families of topological insulators and identifications of topological surface state, as well as fundamental physics issues relating to spin polarized surface electronic states in the past few years. However, transport investigations that can provide direct experimental evidence for potentially practical applications of topological insulators are limited, and realization of functional devices based on topological insulators is still under exploration. Here, using the Sn-doping Bi2Te3 polycrystalline topological insulator films, we fabricated high-performance current-controlled magnetic field detectors. When a parallel magnetic field is applied, the as-fabricated device exhibits a stable and reproducible magneto-resistance (MR) switching behavior, and the corresponding MR ratio can be modulated by the applied current. Even under such a low magnetic field (0.5 kG), the device still shows a distinguishable MR switching performance, suggesting that topological insulator devices are very sensitive to external stimulation and potentially applicable to weak magnetic field detection. PMID- 24171466 TI - Developing outcomes assessments for collaborative, cross-institutional benchmarking: progress of the Australian Medical Assessment Collaboration. AB - BACKGROUND: The Australian Medical Assessment Collaboration (AMAC) began in 2010. This article charts the development of the collaboration over its initial years. AIMS: AMAC was instigated as a way of improving the quality of medical education through the recognition of the need for tools for comparison and evaluation of learning outcomes, acknowledgement of the need for high quality assessment, and to share expertise in these areas. In a climate of increasing regulation and accountability, this collaboration was formed as a means of increasing assessment practices by, with and for medical schools. METHOD: This article provides an overview of the background issues stimulating the development of AMAC, discussion of the formation of the collaboration and reflection on the lessons learnt through these processes. RESULTS: In a relatively short space of time, AMAC has fostered substantial collaboration among schools; developed an Assessment Framework, items and an online assessment; and provided benchmarking reports to students and schools. CONCLUSION: The intention here is to provide guidance for others (within the medical education community and those in other disciplines) with similar intentions and aims, by outlining the developmental pathway of the project and the systematic lessons that the collaboration team has learnt in establishing AMAC. PMID- 24171465 TI - Discovery and synthetic refactoring of tryptophan dimer gene clusters from the environment. AB - Here we investigate bacterial tryptophan dimer (TD) biosynthesis by probing environmental DNA (eDNA) libraries for chromopyrrolic acid (CPA) synthase genes. Functional and bioinformatics analyses of TD clusters indicate that CPA synthase gene sequences diverge in concert with the functional output of their respective clusters, making this gene a powerful tool for guiding the discovery of novel TDs from the environment. Twelve unprecedented TD biosynthetic gene clusters that can be arranged into five groups (A-E) based on their ability to generate distinct TD core substructures were recovered from eDNA libraries. Four of these groups contain clusters from both cultured and culture independent studies, while the remaining group consists entirely of eDNA-derived clusters. The complete synthetic refactoring of a representative gene cluster from the latter eDNA specific group led to the characterization of the erdasporines, cytotoxins with a novel carboxy-indolocarbazole TD substructure. Analysis of CPA synthase genes in crude eDNA suggests the presence of additional TD gene clusters in soil environments. PMID- 24171467 TI - Expression, characterization, and evaluation of a RANK-binding single chain fraction variable: an osteoclast targeting drug delivery strategy. AB - A single chain Fraction variable (scFv) employs antibody-like target recognition specificity. Osteoclasts, responsible for bone resorption, express Receptor Activator of Nuclear factor Kappa B (RANK) receptors. This study aimed to express, characterize, and evaluate scFv against RANK receptors that may serve as a platform to target osteoclasts. Using phage display technology, scFv against RANK receptor was expressed and characterized by DNA sequencing, sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE), matrix-assisted laser desorption-ionization time-of-flight (MALDI TOF), enzyme-linked immunosorbent assay (ELISA), Western blot, and immunocytochemistry. The potential for cytotoxicity was evaluated using an MTT (3-[4,5-dimethylthiazol-2-yl]-2,5 diphenyl tetrazolium bromide) assay, and its cross reactivity was evaluated using ELISA. Osteoclast-like cells were generated from RAW 264.7 cells, and the osteoclast targeting ability of scFv was evaluated using immunocytochemistry. ScFv's antiresorptive efficacy was studied using a tartrate-resistant acid phosphatase (TRAP) assay and resorption assay. Anti-RANK scFv was successfully expressed and characterized. No cross reactivity with other tumor necrosis factor receptor (TNFR) members and no cytotoxic effect on a non-RANK bearing cell line were observed. It showed specificity toward a RANK receptor and an inhibitory effect on osteoclast activity. With the increase in development trends for biologics as therapeutics and growing knowledge on the importance of osteoclast targeted therapy, this study may provide a drug delivery strategy to target osteoclasts, thereby leading to a promising therapy for resorptive bone diseases. PMID- 24171470 TI - Structural and magnetic studies of a new Co(II) thiocyanato coordination polymer showing slow magnetic relaxations and a metamagnetic transition. AB - Reaction of Co(NCS)2 with 4-ethylpyridine leads to the formation of three new compounds of composition Co(NCS)2(4-ethylpyridine)4 (1), [(Co(NCS)2]2(4 ethylpyridine)6 (2), and [Co(NCS)2(4-ethylpyridine)2]n (3). In all compounds the coordination of the Co(II) ions is distorted octahedral. 1 consists of discrete monomeric complexes and in 2 two Co(II) cations are linked by pairs of MU-1,3 bridging thiocyanato ligands into dimers. In the crystal structure of 3 the Co(II) cations are connected into chains by the same bridge as in 2. Magnetic studies show that 1 and 2 are paramagnets down to a temperature of 2 K, while compound 3, which is the main object of this study, is an antiferromagnet with the Neel temperature T(N) = 3.4 K. Its magnetic structure is built from ferromagnetic chains, which are weakly antiferromagnetically coupled. With increasing magnetic field a metamagnetic transition starts at ~175 Oe, as observed for a polycrystalline sample. Magnetic relaxations, which were observed in the antiferromagnetic state, are retained at the metamagnetic transition. With decreasing field 3 remains in a state, in which except of the faster magnetic relaxation process in single chains also a slower process coexists resulting in the appearance of a magnetic hysteresis loop. PMID- 24171469 TI - Structure-activity relationship of imidazopyridinium analogues as antagonists of neuropeptide s receptor. AB - The discovery and characterization of a novel chemical series of phosphorothioyl containing imidazopyridines as potent neuropeptide S receptor antagonists is presented. The synthesis of analogues and their structure-activity relationship with respect to the Gq, Gs, and ERK pathways is detailed. The pharmacokinetics and in vivo efficacy of a potent analogue in a food intake rodent model are also included, underscoring its potential therapeutic value for the treatment of sleep, anxiety, and addiction disorders. PMID- 24171471 TI - Copper-catalyzed gem-difluoroolefination of diazo compounds with TMSCF3 via C-F bond cleavage. AB - A novel Cu-catalyzed gem-difluoroolefination of diazo compounds is described. This transformation starts from readily available TMSCF3 and diazo compounds, via trifluoromethylation followed by C-F bond cleavage, to afford the desired 1,1 difluoroalkene products. PMID- 24171472 TI - Proteome digestion specificity analysis for rational design of extended bottom-up and middle-down proteomics experiments. AB - Mass spectrometry (MS)-based bottom-up proteomics (BUP) is currently the method of choice for large-scale identification and characterization of proteins present in complex samples, such as cell lysates, body fluids, or tissues. Technically, BUP relies on MS analysis of complex mixtures of small, <3 kDa, peptides resulting from whole proteome digestion. Because of the extremely high sample complexity, further developments of detection methods and sample preparation techniques are necessary. In recent years, a number of alternative approaches such as middle-down proteomics (MDP, addressing up to 15 kDa peptides) and top down proteomics (TDP, addressing proteins exceeding 15 kDa) have been gaining particular interest. Here we report on the bioinformatics study of both common and less frequently employed digestion procedures for complex protein mixtures specifically targeting the MDP approach. The aim of this study was to maximize the yield of protein structure information from MS data by optimizing peptide size distribution and sequence specificity. We classified peptides into four categories based on molecular weight: 0.6-3 (classical BUP), 3-7 (extended BUP), 7-15 kDa (MDP), and >15 kDa (TDP). Because of instrumentation-related considerations, we first advocate for the extended BUP approach as the potential near-future improvement of BUP. Therefore, we chose to optimize the number of unique peptides in the 3-7 kDa range while maximizing the number of represented proteins. The present study considers human, yeast, and bacterial proteomes. Results of the study can be further used for designing extended BUP or MDP experimental workflows. PMID- 24171473 TI - Third-generation breathing metal-organic framework with selective, stepwise, reversible, and hysteretic adsorption properties. AB - A new 2D interdigitated and highly flexible, breathing metal-organic framework has been synthesized through a diffusion technique by using the aldrithiol linker and pyromellitate ligand. The compound shows selective, stepwise, reversible, and hysteretic adsorption properties for CO2 gas and H2O, MeOH, and CH3CN vapors. PMID- 24171474 TI - Surface functionalization of fluorine-doped tin oxide samples through electrochemical grafting. AB - Transparent conductive oxides are emerging materials in several fields, such as photovoltaics, photoelectrochemistry, and optical biosensing. Their high chemical inertia, which ensured long-term stability on one side, makes challenging the surface modification of transparent conductive oxides; long-term robust modification, high yields, and selective surface modifications are essential prerequisite for any further developments. In this work, we aim at inducing chemical functionality on fluorine-doped tin oxide surfaces (one of the most inexpensive transparent conductive oxide) by means of electrochemical grafting of aryl diazonium cations. The grafted layers are fully characterized by photoemission spectroscopy, cyclic voltammetry, and atomic force microscopy showing linear correlation between surface coverage and degree of modification. The electrochemical barrier effect of modified surfaces was studied at different pH to characterize the chemical nature of the coating. We showed immuno recognition of biotin complex built onto grafted fluorine-doped tin oxides, which opens the perspective of integrating FTO samples with biological-based devices. PMID- 24171475 TI - Profiles of rural longitudinal integrated clerkship students: a descriptive study of six consecutive student cohorts *. AB - BACKGROUND: Medical schools worldwide are challenged to address the rural primary care workforce shortage by creating community-engaged curricula to nurture student interest in rural practice. AIM: To examine the personal characteristics of six consecutive rural longitudinal integrated clerkship student cohorts to understand whom the programs attract and select and thus inform the development of such programs. METHOD: A cross-sectional cohort design was used. Six cohorts (2007-2012) completed a survey on demographics and factors that influenced their choice of rural primary care. The Temperament and Character Inventory was used to measure personality. Analysis was mainly descriptive. Where appropriate univariate analysis compared variables between groups. RESULTS: Sample size was 205 with the majority female (61%), between 25 and 29 years (64%), single (60%) and lived longest in rural communities with populations less than 20,000 (60%). Rural lifestyle, background and desire to work in underserved areas were noted to impact rural medicine interest. Professional satisfaction, personal and professional goals and family needs had the highest impact on career decisions, and financial concerns lowest. CONCLUSION: The stability of students' personal characteristics across cohorts and the workforce outcomes of this program suggest the recruitment process successfully nurtures students who will fit well into future rural practice. PMID- 24171477 TI - A Crisis in Counseling: Questioning the Role of Crisis Counselors Within Police Departments. AB - This essay highlights the author's personal journey through suicide loss and the subsequent police investigation of her spouse's death. Through a recounting of the loss itself, and details of the police interrogation and attempts at crisis counseling, the author demonstrates how current police protocol and crisis counseling initiatives may (re)victimize trauma survivors. PMID- 24171478 TI - Structure-activity relationship study of permethyl ningalin B analogues as P glycoprotein chemosensitizers. AB - A novel series of permethyl ningalin B analogues were synthesized and evaluated for their P-glycoprotein (P-gp)-modulating activities in a P-gp-overexpressing breast cancer cell line (LCC6MDR). Compounds 35 and 37, which possess one methoxy group and one benzyloxy group at aryl ring C, displayed the most potent P-gp modulating activity. A 1 MUM concentration of 35 and 37 resensitized LCC6MDR cells toward paclitaxel by 42.7-fold, with respective EC50 values of 93.5 and 110.0 nM. Their mechanism of P-gp modulation is associated with an increase in intracellular drug accumulation. Their advantages also include low cytotoxicity (IC50 for L929 fibroblast >100 MUM) and high therapeutic indexes (>909 after normalization with their EC50 values). 35 is not a substrate of P-gp. They are potentially dual-selective modulators for both P-gp and breast cancer resistance protein transporters. The present study demonstrates that these new compounds can be employed as effective and safe modulators of P-gp-mediated drug resistance in cancer cells. PMID- 24171479 TI - Staurosporine-derived inhibitors broaden the scope of analog-sensitive kinase technology. AB - Analog-sensitive (AS) kinase technology is a powerful approach for studying phospho-signaling pathways in diverse organisms and physiological processes. The key feature of this technique is that a kinase-of-interest can be mutated to sensitize it to inhibitor analogs that do not target wild-type (WT) kinases. In theory, this enables specific inhibition of any kinase in cells and in mouse models of human disease. Typically, these inhibitors are identified from a small library of molecules based on the pyrazolopyrimidine (PP) scaffold. However, we recently identified a subset of native human kinases, including the Ephrin A kinase family, that are sensitive to commonly used PP inhibitors. In an effort to develop a bioorthogonal AS-kinase inhibitor and to extend this technique to PP sensitive kinases, we sought an alternative inhibitor scaffold. Here we report the structure-based design of synthetically tractable, potent, and extremely selective AS-kinase inhibitors based on the natural product staurosporine. We demonstrate that these molecules, termed staralogs, potently target AS kinases in cells, and we employ X-ray crystallography to elucidate their mechanism of efficacy. Finally, we demonstrate that staralogs target AS mutants of PP sensitive kinases at concentrations where there is little to no inhibition of native human kinases. Thus, staralogs represent a new class of AS-kinase inhibitors and a core component of the chemical genetic tool kit for probing kinase-signaling pathways. PMID- 24171480 TI - Replication, repair, and translesion polymerase bypass of N6-oxopropenyl-2' deoxyadenosine. AB - The oxidative stress products malondialdehyde and base propenal react with DNA bases forming the adduction products 3-(2'-deoxy-beta-D-erythro pentofuranosyl)pyrimido[1,2-a]purin-10(3H)-one (M1dG) and N(6)-(oxypropenyl)-2' deoxyadenosine (OPdA). M1dG is mutagenic in vivo and miscodes in vitro, but little work has been done on OPdA. To improve our understanding of the effect of OPdA on polymerase activity and mutagenicity, we evaluated the ability of the translesion DNA polymerases hPols eta, kappa, and iota to bypass OPdA in vitro. hPols eta and kappa inserted dNTPs opposite the lesion and extended the OPdA modified primer to the terminus. hPol iota inserted dNTPs opposite OPdA but failed to fully extend the primer. Steady-state kinetic analysis indicated that these polymerases preferentially insert dTTP opposite OPdA, although less efficiently than opposite dA. Minimal incorrect base insertion was observed for all polymerases, and dCTP was the primary mis-insertion event. Examining replicative and repair polymerases revealed little effect of OPdA on the Sulfolobus solfataricus polymerase Dpo1 or the Klenow fragment of Escherichia coli DNA polymerase I. Bacteriophage T7 DNA polymerase displayed a reduced level of OPdA bypass compared to unmodified DNA, and OPdA nearly completely blocked the activity of base excision repair polymerase hPol beta. This work demonstrates that bypass of OPdA is generally error-free, modestly decreases the catalytic activity of most polymerases, and blocks hPol beta polymerase activity. Although mis-insertion opposite OPdA is relatively weak, the efficiency of bypass may introduce A -> G transitions observed in vivo. PMID- 24171483 TI - Molecular and electronic structures of complexes containing 1-(2-pyridylazo)-2 phenanthrol (PAPL): revisiting a redox-active ligand. AB - Herein we report the molecular structures and electronic properties of neutral, homoleptic, six-coordinate complexes of the general formula M(PAPL)2, where PAPL is the monoanion of 1-(2-pyridylazo)-2-phenanthrol (M = Mn, Ni, Zn). Although, the coordination chemistry of PAPL has been investigated in a few previous reports in the 1970s and 1980s, there are, to our knowledge, no reported single crystal X-ray diffraction studies of any complexes, or any other electronic property or computational studies of complexes containing the PAPL anion until now. The electronic structures of the complexes are probed with a combination of cyclic voltammetry, UV-vis spectroscopy, and spectroelectrochemical measurements. Density functional theory calculations support the redox-active nature of the PAPL ligand. In all complexes we observe two reversible ligand-centered reduction processes, suggesting it may be possible to access the open-shell radical-anionic state of the ligand. PMID- 24171484 TI - Dementia in Asia: introduction to a special section. PMID- 24171482 TI - In vitro selection of modified RNA aptamers against CD44 cancer stem cell marker. AB - Cancer stem cells (CSCs) are a subset of tumor cells that has the ability to self renew and to generate the diverse cells that comprise the tumor mass. The cell surface glycoprotein CD44 is one of the most common surface markers used to identify CSCs. Aptamers are synthetic oligonucleotides selected from pools of random sequences that can bind to a wide range of targets with high affinity and specificity. In this study, the systematic evolution of ligands by exponential enrichment (SELEX) technology was used to isolate RNA aptamers using human recombinant full-length CD44 protein and 2'-F-pyrimidine modified RNA library with a complexity of around 10(14) different molecules. Following 11 iterative rounds of SELEX, the selected aptamers were cloned and sequenced. Three different sequences were identified. The binding specificities for one of these RNA aptamers was assessed using representative breast cancer cell lines expressing CD44; namely, MDA-MB-231, MCF7, and T47D. The selected RNA aptamer (Apt1) was found to interact specifically with such cancer cells when analyzed by flow cytometry and fluorescent microscopy, with different intensities of fluorescence reflecting the level of CD44 expression on the surface of these cells. It can be concluded that the selected aptamers can be used to target CD44 positive cells, including cancer stem cells, for detection, sorting, and enrichment and for drug delivery purposes. PMID- 24171481 TI - A chemical view of oligonucleotides for exon skipping and related drug applications. PMID- 24171485 TI - Quality of informal care for persons with dementia: dimensions and correlates. AB - OBJECTIVES: The majority of persons with dementia live in the community where most of their care is provided by family members. We aimed to expand our limited knowledge about the styles of high-quality care, such as person-centered care, and poor-quality care adopted by these informal caregivers and the characteristics of those who provide better care. METHOD: We conducted a mail survey of 148 family caregivers. Caregiving styles were measured with items from existing scales that had not been analyzed together before. Factor analysis of these items was used to identify styles of caregiving, and structural equation modeling was used to identify their relationships with caregiver and care recipient characteristics. RESULTS: Three high quality-of-care factors (personalized, respectful, and compensatory) and three poor quality-of-care factors (punitive, controlling, and withdrawing) were found. The personality traits of agreeableness, openness, conscientiousness, and neuroticism were related to higher quality of care, and the trait of extraversion was related to poorer quality of care. Wishful coping - an avoidance/escape strategy - was linked to poorer quality of care. CONCLUSION: We discovered new dimensions of quality of care, some consistent with person-centered care and some antithetical to this model, and we identified for the first time caregiver personality traits and coping strategies associated with better quality of care. These results may be useful in targeting caregiver interventions to benefit both caregivers and care recipients. PMID- 24171487 TI - Functionalized graphene as an ultrathin seed layer for the atomic layer deposition of conformal high-k dielectrics on graphene. AB - Ultrathin functionalized graphene (FG) is demonstrated to work as an effective seed layer for the atomic layer deposition (ALD) of high-k dielectrics on graphene that is synthesized via chemical vapor deposition (CVD). The FG layer is prepared using a low-density oxygen plasma treatment on CVD graphene and is characterized using Raman spectroscopy and X-ray photoelectron spectroscopy (XPS). While the ALD deposition on graphene results in a patchy and rough dielectric deposition, the abundant oxygen species provided by the FG seed layer enable conformal and pinhole-free dielectric film deposition over the entire area of the graphene channel. The metal-insulator-graphene (MIG) capacitors fabricated with the FG-seeded Al2O3 exhibit superior scaling capabilities with low leakage currents when compared with the co-processed capacitors with Al seed layers. PMID- 24171488 TI - Facile synthesis of boronate-decorated polyethyleneimine-grafted hybrid magnetic nanoparticles for the highly selective enrichment of modified nucleosides and ribosylated metabolites. AB - Ribosylated metabolites, especially modified nucleosides, have been extensively evaluated as cancer-related biomarkers. Boronate adsorbents are considered to be promising materials for extracting them from complex matrices. However, the enrichment of ribosylated metabolites in low abundance is still a challenge due to the limited capacity and selectivity of the existing boronate adsorbents. In this study, a novel type of magnetic nanoparticles named Fe3O4@SiO2@PEI-FPBA was synthesized by grafting polyethyleneimine (PEI) onto the surface of Fe3O4@SiO2 before modification by boronate groups. The high density of the amino groups on the PEI chains supplied a large number of binding sites for boronate groups. Thus, the adsorption capacity (1.34 +/- 0.024 mg/g) of the nanoparticles, which is 6- to 7-fold higher than that of analogous materials, was greatly improved. The unreacted secondary amines and tertiary amines of the PEI enhanced the aqueous solubility of the nanoparticles, which could efficiently reduce nonspecific adsorption. The nanoparticles were able to capture 1,2 cis-diol nucleosides from 1000-fold interferences. Moreover, the flexible chains of PEI were favorable for effective enrichment and quick equilibration (<2 min). Finally, 60 ribose conjugates were enriched from human urine using the nanoparticles. Among them, 43 were identified to be nucleosides and other ribosylated metabolites. Nine low abundance modified nucleosides were detected for the first time. In conclusion, Fe3O4@SiO2@PEI-FPBA is an attractive candidate material for the highly selective enrichment of 1,2-cis-diol compounds. PMID- 24171489 TI - Effect of molecular composition of heparin and cellulose sulfate on multilayer formation and cell response. AB - Here, the layer-by-layer method was applied to assemble films from chitosan paired with either heparin or a semisynthetic cellulose sulfate (CS) that possessed a higher sulfation degree than heparin. Ion pairing was exploited during multilayer formation at pH 4, while hydrogen bonding is likely to occur at pH 9. Effects of polyanions and pH value during layer formation on multilayers properties were studied by surface plasmon resonance ("dry layer mass"), quartz crystal microbalance with dissipation monitoring ("wet layer mass"), water contact angle, and zeta potential measurements. Bioactivity of multilayers was studied regarding fibronectin adsorption and adhesion/proliferation of C2C12 myoblast cells. Layer growth and dry mass were higher for both polyanions at pH 4 when ion pairing occurred, while it decreased significantly with heparin at pH 9. By contrast, CS as polyanion resulted also in high layer growth and mass at pH 9, indicating a much stronger effect of hydrogen bonding between chitosan and CS. Water contact angle and zeta potential measurements indicated a more separated structure of multilayers from chitosan and heparin at pH 4, while CS led to a more fuzzy intermingled structure at both pH values. Cell behavior was highly dependent on pH during multilayer formation with heparin as polyanion and was closely related to fibronectin adsorption. By contrast, CS and chitosan did not show such dependency on pH value, where adhesion and growth of cells was high. Results of this study show that CS is an attractive candidate for multilayer formation that does not depend so strongly on pH during multilayer formation. In addition, such multilayer system also represents a good substrate for cell interactions despite the rather soft structure. As previous studies have shown specific interaction of CS with growth factors, multilayers from chitosan and CS may be of great interest for different biomedical applications. PMID- 24171491 TI - Balancing thrombotic events and bleeding in primary PCI. PMID- 24171492 TI - Cognitive and Affective Uses of a Thoracic Outlet Syndrome Facebook Support Group. AB - There are currently many disease-specific groups on Facebook in which patients may take an active part (Greene, Choudhry, Kilabuk, & Shrank, 2011). Although uses and gratifications of patient-disease groups have begun to be identified for chronic diseases, rare diseases have been omitted, even though they collectively affect roughly 30 million people in the United States and 350 million people worldwide. This study is a content analysis of one Facebook rare disease patient group, the Thoracic Outlet Syndrome (TOS) Awareness group. All wall posts were recorded and content analyzed for cognitive and affective categories and subcategories between October 9, 2011 (date of site origin), and May 1, 2012. Analysis of cognitive needs indicated TOS patients used the site more to share information about their own TOS symptoms and journey with diagnosis than to seek information. Analysis of affective needs found patients were more likely to use the site to give support and encouragement to others than to express concerns and complaints. The complaints they did express were primarily related to their frustration with the general medical community's perceived inability to diagnose and understand their disease or to question a specific doctor's diagnosis/recommendation. Results point to needs specific to TOS patients that uses and gratifications research can help clarify. PMID- 24171494 TI - Carbon nanotube buckypaper reinforced acrylonitrile-butadiene-styrene composites for electronic applications. AB - Novel acrylonitrile-butadiene-styrene (ABS) nanocomposites reinforced with pristine or functionalized single- or multiwalled carbon nanotube buckypaper (BP) sheets were manufactured via hot-compression and vacuum infiltration. Their morphology, thermal, mechanical, and electrical properties were comparatively investigated. Scanning electron microscopy and thermogravimetric analysis showed that the infiltration process leads to better BP impregnation than the hot-press technique. BPs made from functionalized or short nanotubes form compact networks that hamper the penetration of the matrix chains, whereas those composed of pristine tubes possess large pores that facilitate the polymer flow, resulting in composites with low degree of porosity and improved mechanical performance. Enhanced thermal and electrical properties are found for samples incorporating functionalized BPs since dense networks lead to more conductive pathways, and a stronger barrier effect to the diffusion of degradation products, thus better thermal stability. According to dynamic mechanical analysis these composites exhibit the highest glass transition temperatures, suggesting enhanced filler matrix interactions as corroborated by the Raman spectra. The results presented herein demonstrate that the composite performance can be tailored by controlling the BP architecture and offer useful insights into the structure-property relationships of these materials to be used in electronic applications, particularly for EMI shielding and packaging of integrated circuits. PMID- 24171493 TI - Aminothiazole-featured pirinixic acid derivatives as dual 5-lipoxygenase and microsomal prostaglandin E2 synthase-1 inhibitors with improved potency and efficiency in vivo. AB - Dual inhibition of microsomal prostaglandin E2 synthase-1 (mPGES-1) and 5 lipoxygenase (5-LO) is currently pursued as potential pharmacological strategy for treatment of inflammation and cancer. Here we present a series of 26 novel 2 aminothiazole-featured pirinixic acid derivatives as dual 5-LO/mPGES-1 inhibitors with improved potency (exemplified by compound 16 (2-[(4-chloro-6-{[4-(naphthalen 2-yl)-1,3-thiazol-2-yl]amino}pyrimidin-2-yl)sulfanyl]octanoic acid) with IC50 = 0.3 and 0.4 MUM, respectively) and bioactivity in vivo. Computational analysis presumes binding sites of 16 at the tip of the 5-LO catalytic domain and within a subpocket of the mPGES-1 active site. Compound 16 (10 MUM) hardly suppressed cyclooxygenase (COX)-1/2 activities, failed to inhibit 12/15-LOs, and is devoid of radical scavenger properties. Finally, compound 16 reduced vascular permeability and inflammatory cell infiltration in a zymosan-induced mouse peritonitis model accompanied by impaired levels of cysteinyl-leukotrienes and prostaglandin E2. Together, 2-aminothiazole-featured pirinixic acids represent potent dual 5-LO/mPGES-1 inhibitors with an attractive pharmacological profile as anti-inflammatory drugs. PMID- 24171495 TI - Different rates of singlet fission in monoclinic versus orthorhombic crystal forms of diphenylhexatriene. AB - The dynamics of singlet fission (SF) are studied in monoclinic and orthorhombic crystals of 1,6-diphenyl-1,3,5-hexatriene. Picosecond time-resolved fluorescence measurements and the presence of a strong magnetic field effect indicate that up to 90% of the initially excited singlets undergo SF in both forms. The initial SF and subsequent triplet pair dissociation rates are found to be more rapid in the monoclinic crystal by factors of 1.5 and 3.5, respectively. These results provide clear evidence that molecular organization affects the rates of triplet pair formation and separation, both important parameters for determining the ultimate utility of a SF material. PMID- 24171490 TI - Bivalirudin started during emergency transport for primary PCI. AB - BACKGROUND: Bivalirudin, as compared with heparin and glycoprotein IIb/IIIa inhibitors, has been shown to reduce rates of bleeding and death in patients undergoing primary percutaneous coronary intervention (PCI). Whether these benefits persist in contemporary practice characterized by prehospital initiation of treatment, optional use of glycoprotein IIb/IIIa inhibitors and novel P2Y12 inhibitors, and radial-artery PCI access use is unknown. METHODS: We randomly assigned 2218 patients with ST-segment elevation myocardial infarction (STEMI) who were being transported for primary PCI to receive either bivalirudin or unfractionated or low-molecular-weight heparin with optional glycoprotein IIb/IIIa inhibitors (control group). The primary outcome at 30 days was a composite of death or major bleeding not associated with coronary-artery bypass grafting (CABG), and the principal secondary outcome was a composite of death, reinfarction, or non-CABG major bleeding. RESULTS: Bivalirudin, as compared with the control intervention, reduced the risk of the primary outcome (5.1% vs. 8.5%; relative risk, 0.60; 95% confidence interval [CI], 0.43 to 0.82; P=0.001) and the principal secondary outcome (6.6% vs. 9.2%; relative risk, 0.72; 95% CI, 0.54 to 0.96; P=0.02). Bivalirudin also reduced the risk of major bleeding (2.6% vs. 6.0%; relative risk, 0.43; 95% CI, 0.28 to 0.66; P<0.001). The risk of acute stent thrombosis was higher with bivalirudin (1.1% vs. 0.2%; relative risk, 6.11; 95% CI, 1.37 to 27.24; P=0.007). There was no significant difference in rates of death (2.9% vs. 3.1%) or reinfarction (1.7% vs. 0.9%). Results were consistent across subgroups of patients. CONCLUSIONS: Bivalirudin, started during transport for primary PCI, improved 30-day clinical outcomes with a reduction in major bleeding but with an increase in acute stent thrombosis. (Funded by the Medicines Company; EUROMAX ClinicalTrials.gov number, NCT01087723.). PMID- 24171496 TI - Meso-helicates with rigid angular tetradentate ligand: design, molecular structures, and progress towards self-assembly of metal-organic nanotubes. AB - The self-assembly of two novel metallosupramolecular complexes of the general formulas [L2M2(CH3CN)4][BF4]4 (M = Co, 1a; M = Ni, 1b), where L stands for the tetradentate ligand 3,5-bis[4-(2,2'-dipyridylamino)phenylacetylenyl]toluene, is reported together with their molecular structures ascertained by single-crystal X ray diffraction studies. Complexes 1a and 1b are isostructural and show the formation of dinuclear meso-helicates with the two octahedral metal centers displaying respectively Delta and Lambda configurations. These meso-helicates display large nanocavities with metal---metal separation distance of >2 nm; furthermore, pi-pi-stacking occurs among individual units to form one-dimensional (1D) polymers which further autoassemble in another direction through pi-pi contacts among neighboring chains to generate a two-dimensional (2D) network with regular nanocavities. Our approach might be of interest to prepare metal-organic nanotubes via a bottom-up strategy depending on the assembling functional ligand and the geometry of molecular building block. PMID- 24171497 TI - Alternative splicing generates a diacylglycerol kinase alpha transcript that acts as a dominant-negative modulator of superoxide production in localized aggressive periodontitis. AB - BACKGROUND: Diacylglycerol (DAG), levels of which are tightly regulated by diacylglycerol kinases (DGKs), is a lipid mediator linked to key biologic functions. Members of the DGK family undergo alternative splicing, generating the protein diversity necessary to control different intracellular DAG pools. DGKalpha function is altered in polymorphonuclear neutrophils (PMNs) of patients with localized aggressive periodontitis (LAgP), suggesting a genetic basis. Here, the authors assess DGKalpha spliced transcripts in human LAgP neutrophils. METHODS: In an expression library of a patient with LAgP, PMNs were screened for different DGKalpha transcripts. Real-time polymerase chain reaction and in vitro expression assays were performed to assess the fate of different transcripts on protein translocation and superoxide production in human leukemia cells (HL-60) and COS-7 cells. RESULTS: A DGKalpha transcript that lacks exon 10 (DGKalphaDelta10) and generates a premature stop codon and a truncated protein was identified as being upregulated in LAgP neutrophils. In vitro assays revealed that DGKalphaDelta10 translocation occurred even in the absence of important regulatory motifs. Transfection of HL-60 neutrophil-like cells with the DGKalphaDelta10 spliced variant induced an increase in the stimulated production of superoxide anion replicating the phenotype of LAgP PMNs. CONCLUSION: DGKalphaDelta10 can act as a dominant-negative transcript that can modulate superoxide production and provides an example of genetic regulation of the inflammatory response that may be relevant to human inflammatory diseases such as LAgP. PMID- 24171498 TI - A retrospective evaluation of the survival rates of splinted and non-splinted short dental implants in posterior partially edentulous jaws. AB - BACKGROUND: The aim of the present study is to evaluate the survival rate and bone loss around short implants (<=10 mm) supporting splinted or non-splinted posterior prostheses during a follow-up period of 3 to 16 years. METHODS: A total of 453 implants from 198 patients was divided into splinted or non-splinted groups. Implant survival rate was calculated for each group, and potential risk was represented as odds ratio (OR). The final linear distance from implant platform level to the first bone-to-implant contact was compared to this same reference just after loading by digital periapical radiographs to determine the marginal bone loss (BL). RESULTS: The splinted group comprised 219 implants in 86 patients, whereas the non-splinted group included 234 implants from 112 patients. The mean follow-up period was 9.7 +/- 3.7 years. Although different success rates were found for splinted (97.7%) and non-splinted (93.2%) groups, they exhibited similar BL (1.22 +/- 0.95 mm and 1.27 +/- 1.15 mm, respectively). The success of splinted implants was associated with no other variable, whereas non-splinted implants exhibited higher risk of failure when placed in men (OR = 3.2) and when implants shorter than 10 mm were used (OR = 3.6 and 4.1 for 8.5 mm and 7 mm, respectively). Regardless of group, 71.4% of the unsuccessful implants failed before the end of the first year after loading. CONCLUSION: Non-splinted posterior short implants had a somewhat lower success rate than splinted short implants, and the failure rate in non-splinted short implants appeared to be greater in males as well as in implants <=10 mm. PMID- 24171499 TI - Proteomic analyses of human gingival and periodontal ligament fibroblasts. AB - BACKGROUND: Although human gingival fibroblasts (hGFs) and human periodontal ligament fibroblasts (hPDLFs) exhibit numerous phenotypic similarities, it has been suggested that the secretory and behavioral differences, which exist between these cell types, are a result of the membrane protein composition of these cells. METHODS: Four matched pairs of hGFs and hPDLFs were cultured. Before confluence, membrane-bound and -associated proteins from cells of the fourth passage were extracted. The processed protein samples were evaluated using capillary-liquid chromatography-nanospray tandem mass spectrometry. Global protein identification was performed on an orbitrap mass spectrometer equipped with a microspray source operated in positive ion mode. Proteome software was used to validate protein identifications derived from tandem mass spectrometry sequencing results. RESULTS: Four hundred fifty proteins were common to both hGFs and hPDLFs. Of the proteins identified, 214 were known membrane-bound or associated proteins, and 165 proteins were known nuclear-associated proteins. Twenty-seven proteins, identified from the 450 proteins, common to both hGFs and hPDLFs, were detected in statistically significant greater quantities in either hGFs or hPDLFs. More specifically, 13 proteins were detected in significantly greater quantities in hGFs, whereas 14 proteins were detected in significantly greater quantities in hPDLFs. CONCLUSIONS: Distinct differences in the cellular protein catalog may reflect the dynamic role and high energy requirements of hGFs in extracellular matrix remodeling and response to inflammatory challenge as well as the role of hPDLFs in monitoring mechanical stress and maintaining tissue homeostasis during regeneration and remineralization. PMID- 24171500 TI - Demineralization of the contacting surfaces in autologous onlay bone grafts improves bone formation and bone consolidation. AB - BACKGROUND: Autologous bone grafts are usually well consolidated after 4 to 5 months but can be incompletely interlocked with the native bone. This study investigated the effect of acid demineralization of the graft-bed interface on graft consolidation. METHODS: Onlay bone grafts were performed on the calvaria of 36 guinea pigs. Half of the animals had the graft-bed contacting surfaces demineralized with 50% citric acid (pH 1.0) for 3 minutes (test group). The other half received no demineralization (control group). The bone grafts were immobilized by a resorbable membrane glued to the recipient bed with cyanoacrylate. After 7, 30, and 90 days, specimens (n = 6) were obtained for light microscopy. Data from qualitative analysis and computerized histomorphometry were statistically processed at a significance level of 5%. RESULTS: Osteogenesis was not seen at the interface after 7 days. After 30 days, the test group showed 34.39% +/- 13.4% of the interface area filled with mineralized tissue, compared to 17.14% +/- 8.6% in the control group (P = 0.026). After 90 days, the mean percentages of mineralized tissue at the interface in the test and control specimens were 54.00% +/- 11.23% and 38.65% +/- 7.76% (P = 0.041), respectively. Within groups, a higher percentage of the area filled with mineralized tissue was seen at 90 days compared to 30 days (P = 0.004 for control and 0.041 for test). CONCLUSIONS: Demineralization of the contacting surfaces between autologous bone graft and bone bed improved new bone formation and bone consolidation. These data need to be confirmed in humans. PMID- 24171501 TI - Periodontal diseases in an Omani adult population: a preliminary study. AB - BACKGROUND: Data on the periodontal status of the adult population in the Arab world are scarce. The aim of this pilot study is to assess the prevalence, extent, and severity of periodontal diseases in an adult group from Oman. METHODS: This is a cross-sectional study of 319 teachers who were randomly sampled from the list of teachers from the Muscat region schools in Oman. Dental caries, tooth loss, and periodontal attachment loss (AL) were recorded for each of the participants. A questionnaire collected data on participants' sociodemographic characteristics, dental-care characteristics, self-rated periodontal status, and self-rated well-being. RESULTS: A total of 99% of participants had at least one site with probing depth (PD) or clinical AL of >= 3 mm. More than one third (36%) of participants had at least one site with AL >= 5 mm, and 12% had at least one site with AL >= 6 mm; for PD, the prevalence estimates were 26% and 8%, respectively, and a gradient by age group was evident across the different thresholds. Regarding the extent of disease, 17.6% of sites had PD >= 3 mm, and 21% of sites had AL >= 3 mm. CONCLUSIONS: The prevalence, extent, and severity of periodontitis were higher than estimates reported from industrialized countries, such as Australia, New Zealand, and the United States. This is of concern, especially when considering the relatively young age of the study population. Because of this high prevalence, investigation of periodontitis in a national sample of Omanis is desirable to confirm the findings of this study. PMID- 24171502 TI - Whole salivary interleukin-6 and matrix metalloproteinase-8 levels in patients with chronic periodontitis with and without prediabetes. AB - BACKGROUND: The cytokine profile in unstimulated whole saliva (UWS) of patients with prediabetes and chronic periodontitis (CP) remains uninvestigated. The aim of this study is to assess interleukin (IL)-6 and matrix metalloproteinase (MMP) 8 levels in UWS of patients with CP with and without prediabetes. METHODS: Eighty eight males (aged 39 to 51 years) were divided into three groups: group 1: 28 patients with CP and prediabetes; group 2: 30 patients with CP and without prediabetes; and group 3: 30 controls. Fasting blood glucose (FBG) and hemoglobin A1c (HbA1c) levels, periodontal parameters (plaque index, bleeding on probing, probing depth, attachment loss, and marginal bone loss), and number of missing teeth were recorded. UWS samples were collected, and UWS flow rate (UWSFR) was measured. IL-6 and MMP-8 were measured in UWS using enzyme-linked immunosorbent assay. P values <0.05 were considered statistically significant. RESULTS: Mean FBG and HbA1c levels were significantly higher in group 1 (119.3 +/- 3.1 mg/dL and 6.1% +/- 0.2%) than group 2 (80.1 +/- 3.5 mg/dL and 4.8% +/- 0.5%; P <0.001) and group 3 (75.3 +/- 2.2 mg/dL and 4.3% +/- 0.2%; P <0.05). UWSFR was significantly higher in groups 2 (0.53 +/- 0.1 mL/minute; P <0.05) and 3 (0.51 +/ 0.1 mL/minute; P <0.01) than group 1 (0.33 +/- 0.05 mL/minute). Periodontal parameters were worse in group 1 (P <0.05) and group 2 (P <0.05) than group 3. There was no difference in periodontal parameters, numbers of missing teeth, or salivary IL-6 and MMP-8 levels between patients in groups 1 and 2. CONCLUSION: Salivary IL-6 and MMP-8 levels are elevated in patients with CP with and without prediabetes. PMID- 24171503 TI - Effects of probiotic therapy on metabolic and inflammatory parameters of rats with ligature-induced periodontitis associated with restraint stress. AB - BACKGROUND: This study evaluates the effects of probiotic therapy (PT) in rats with ligature-induced periodontitis associated with restraint stress. METHODS: Sixty-four rats were divided into control, stress (STR), probiotic (PROB), periodontal disease (PD), STR-PROB, STR-PD, STR-PROB-PD, and PROB-PD groups. The probiotic was added to the drinking water for 44 days. PD was induced by a ligature. In STR groups, the animals were subjected to restraint stress for 2.5 hours per day for 30 days. RESULTS: Rats with PD exhibited increased alveolar bone loss (P <0.05), as well as increased levels of cyclooxygenase-2, serum C terminal telopeptide (CTX), p38 mitogen-activated protein kinase (p38), and receptor activator of nuclear factor-kappaB ligand and decreased levels of osteoprotegerin (OPG). Stressed rats presented high levels of C-peptide, corticosterone, and glucose (P <0.05). In general, the presence of stress reduced the expression of CTX and p38 (P <0.05). PT reduced alveolar bone loss in unstressed animals. It also decreased expression of CTX and induced increased expression of OPG in unstressed animals with PD. However, PT was not effective in preventing bone loss or altering the expression of inflammatory markers in stressed animals. PT decreased the number of inflammatory cells in the periodontal tissue (P <0.05). Groups with stress and PD showed decreased villous height and crypt depth. Stress seemed to prevent part of the probiotic beneficial effects on the small intestine. CONCLUSIONS: Based on the methodology used, PT may reduce tissue breakdown resulting from PD in unstressed rats. The protocol used for restraint stress influenced the immunomodulatory effects of PT in intestinal and periodontal tissues. PMID- 24171504 TI - Influence of periodontitis in the development of nosocomial pneumonia: a case control study. AB - BACKGROUND: Although a number of studies on the role of periodontitis in the development of nosocomial pneumonia (NP) have been published, the debate surrounding the existence and nature of this association continues. The present study investigates the influence of periodontitis in NP. METHODS: This case control study involved 315 individuals: 85 cases (with NP) and 230 controls (without NP), at a general hospital in Feira de Santana, Bahia, Brazil. Sociodemographic characteristics, health conditions, and lifestyle habits were recorded. A full-mouth periodontal examination was performed and periodontal condition assessed. The diagnosis of NP was made in accordance with established medical criteria, after physical, microbiologic, and/or radiographic examination. Logistic regression was used to calculate the strength of the association between periodontitis and NP. RESULTS: Individuals with periodontitis were three times as likely to present with NP (unadjusted odds ratio [OR unadjusted] = 3.06, 95% confidence interval [95% CI]: 1.82 to 5.15) as those without periodontal disease. After adjusting for age, time between hospitalization and data collection, last visit to dentist, smoking habit, and present occupation, the association measurement had a slight decrease (OR adjusted = 2.88, 95% CI: 1.59 to 5.19), but the results continued to be statistically significant. CONCLUSION: These findings suggest that periodontal infection may influence the development of NP, highlighting that periodontitis is a factor positively associated with this respiratory tract infection. PMID- 24171505 TI - Subpicogram per milliliter detection of interleukins using silicon photonic microring resonators and an enzymatic signal enhancement strategy. AB - The detection of biomolecules at ultralow (low to subpicogram per milliliter) concentrations and within complex, clinically relevant matrices is a formidable challenge that is complicated by limitations imposed by the Langmuir binding isotherm and mass transport, for surface-based affinity biosensors. Here we report the integration of an enzymatic signal enhancement scheme onto a multiplexable silicon photonic microring resonator detection platform. To demonstrate the analytical value of this combination, we simultaneously quantitated levels of the interleukins IL-2, IL-6, and IL-8 in undiluted cerebrospinal fluid in an assay format that is multiplexable, relatively rapid (90 min), and features a 3 order of magnitude dynamic range and a limit of detection <=1 pg/mL. The modular nature of this assay and technology should lend itself broadly amenable to different analyte classes, making it a versatile tool for biomarker analysis in clinically relevant settings. PMID- 24171506 TI - Evaluation of leptin and leptin receptor gene 3' UTR polymorphisms in essential hypertension. AB - INTRODUCTION: Leptin and leptin receptor gene polymorphisms have been associated with obesity; however, their association with blood pressure has not been fully elucidated. The aim of this study was to examine the effect of tetranucleotide repeat polymorphism in the 3' flanking region of the leptin and leptin receptor gene on blood pressure in hypertensives with obesity. METHODS: Two hundred and eighty hypertensives and 200 healthy controls were analyzed for a tetranucleotide repeat polymorphism of leptin and leptin receptor genes. Genotyping was done by amplifying DNA and determining the allele sizes using gel documentation system. Odds ratios were computed to predict the risk for hypertension caused by specific genotypes of leptin and leptin receptor genes and the effect of interaction between them on the development of hypertension was determined by MDR test. RESULTS: Significant preponderance in the incidence of male sex, obese individuals and those with positive family history was observed with significant elevation in the mean levels of SBP, DBP, BMI and reduction of HDL levels in hypertensives as compared to controls. Class I/I genotypes of leptin showed significantly high risk for developing hypertension irrespective of obesity. Genotypes of leptin receptor did not confer any risk for hypertension and cohorts studied. CONCLUSION: Homozygotes I/I were at greater risk for developing hypertension irrespective of obesity. When leptin and leptin receptor genes were considered together, synergistic interaction was observed between the two genes leading to hypertension, while the polymorphism at leptin gene and obesity was correlated. PMID- 24171507 TI - Political tug-of-war and pediatric residency funding. PMID- 24171508 TI - Are we in a medical education bubble market? PMID- 24171509 TI - Visual and participatory research methods for the development of health messages for underserved populations. AB - Mass communication health campaign messages play critical roles in public health, yet studies show mixed effectiveness in reaching and impacting underserved populations. The purpose of this study was to evaluate the benefits of using visual and participatory research techniques toward health message development targeting older Hispanic women. Demographic information and levels of physical activity were first obtained in a sample of older Mexican women (n = 23; ages 71.9 +/- 7.6 years) living in the city of Chicago. Perceptions of physical activity were then assessed using a visual research method known as photo elicitation. Health message concepts promoting physical activity were developed with a subsample of the target population using a participatory approach. Photo elicitation helped develop a unique understanding into the many factors impacting physical activity among older Mexican women. Follow-up in-depth interviews provided detailed narratives that (a) built upon visual data and (b) identified characteristic differences between physically active and inactive women. Ultimately, these findings were beneficial in constructing new, culturally tailored message concepts. Findings suggest that this method may be a valuable tool in the development of mass communication health messages, extracting rich and meaningful data from target audiences while fostering a sense of partnership between researchers and community members. Tailoring and improving the message design process around the needs of underserved populations is essential in the effort to eliminate the burden of health disparities. This study uses innovative interdisciplinary research techniques to explore new approaches to public health communication in underserved populations. PMID- 24171510 TI - Size-dependent maximization of upconversion efficiency of citrate-stabilized beta phase NaYF4:Yb(3+),Er(3+) crystals via annealing. AB - Upconversion materials show great potential in converting infrared light to visible for many optoelectronic and photovoltaic devices. One of the most promising upconverting materials is Yb(3+),Er(3+)- doped beta-NaYF4. In this study, annealing is shown to have a significant impact on the phase, morphology, and upconversion luminescence of beta-NaYF4:Yb(3+),Er(3+) crystals of varying sizes (300 nm, 700 nm, and 2.3 MUm, respectively) prepared by hydrothermal synthesis stabilized with sodium citrate. Upconversion luminescence is maximized via annealing while maintaining crystal shape and size dispersity up to a temperature dependent on initial size, with NIR-to-visible quantum yields of 2 5%. Further temperature increases result in growth and agglomeration, increasing luminescence, followed by transformation to the alpha-cubic phase resulting in decreases in overall upconversion performance and shifts to dominant red emission. This study establishes the critical link between annealing temperature and maximal upconversion luminescence in beta-NaYF4:Yb(3+),Er(3+) crystals, while maintaining particle morphology, which can be very important for technological application. PMID- 24171511 TI - A red-shifted, fast-relaxing azobenzene photoswitch for visible light control of an ionotropic glutamate receptor. AB - The use of azobenzene photoswitches has become a dependable method for rapid and exact modulation of biological processes and material science systems. The requirement of ultraviolet light for azobenzene isomerization is not ideal for biological systems due to poor tissue penetration and potentially damaging effects. While modified azobenzene cores with a red-shifted cis-to-trans isomerization have been previously described, they have not yet been incorporated into a powerful method to control protein function: the photoswitchable tethered ligand (PTL) approach. We report the synthesis and characterization of a red shifted PTL, L-MAG0460, for the light-gated ionotropic glutamate receptor LiGluR. In cultured mammalian cells, the LiGluR+L-MAG0460 system is activated rapidly by illumination with 400-520 nm light to generate a large ionic current. The current rapidly turns off in the dark as the PTL relaxes thermally back to the trans configuration. The visible light excitation and single-wavelength behavior considerably simplify use and should improve utilization in tissue. PMID- 24171513 TI - O2 reduction reaction by biologically relevant anionic ligand bound iron porphyrin complexes. AB - Iron porphyrin complex with a covalently attached thiolate ligand and another with a covalently attached phenolate ligand has been synthesized. The thiolate bound complex shows spectroscopic features characteristic of P450, including the hallmark absorption spectrum of the CO adduct. Electrocatalytic O2 reduction by this complex, which bears a terminal alkyne group, is investigated by both physiabsorbing on graphite surfaces (fast electron transfer rates) and covalent attachment to azide terminated self-assembled monolayer (physiologically relevant electron transfer rates) using the terminal alkyne group. Analysis of the steady state electrochemical kinetics reveals that this catalyst can selectively reduce O2 to H2O with a second-order k(cat.) ~10(7) M(-1 )s(-1) at pH 7. The analogous phenolate bound iron porphyrin complex reduces O2 with a second-order rate constant of 10(5) M(-1) s(-1) under the same conditions. The anionic ligand bound iron porphyrin complexes catalyze oxygen reduction reactions faster than any known synthetic heme porphyrin analogues. The kinetic parameters of O2 reduction of the synthetic thiolate bound complex, which is devoid of any second sphere effects present in protein active sites, provide fundamental insight into the role of the protein environment in tuning the reactivity of thiolate bound iron porphyrin containing metalloenzymes. PMID- 24171514 TI - Silent victims--an epidemic of childhood exposure to domestic violence. PMID- 24171515 TI - Improving patient safety through transparency. PMID- 24171516 TI - Autologous transplantation as consolidation for aggressive non-Hodgkin's lymphoma. AB - BACKGROUND: The efficacy of autologous stem-cell transplantation during the first remission in patients with diffuse, aggressive non-Hodgkin's lymphoma classified as high-intermediate risk or high risk on the International Prognostic Index remains controversial and is untested in the rituximab era. METHODS: We treated 397 patients who had disease with an age-adjusted classification of high risk or high-intermediate risk with five cycles of cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) or CHOP plus rituximab. Patients with a response were randomly assigned to receive three additional cycles of induction chemotherapy (control group) or one additional cycle of induction chemotherapy followed by autologous stem-cell transplantation (transplantation group). The primary efficacy end points were 2-year progression-free survival and overall survival. RESULTS: Of 370 induction-eligible patients, 253 were randomly assigned to the transplantation group (125) or the control group (128). Forty-six patients in the transplantation group and 68 in the control group had disease progression or died, with 2-year progression-free survival rates of 69 and 55%, respectively (hazard ratio in the control group vs. the transplantation group, 1.72; 95% confidence interval [CI], 1.18 to 2.51; P=0.005). Thirty-seven patients in the transplantation group and 47 in the control group died, with 2-year overall survival rates of 74 and 71%, respectively (hazard ratio, 1.26; 95% CI, 0.82 to 1.94; P=0.30). Exploratory analyses showed a differential treatment effect according to risk level for both progression-free survival (P=0.04 for interaction) and overall survival (P=0.01 for interaction). Among high-risk patients, the 2-year overall survival rate was 82% in the transplantation group and 64% in the control group. CONCLUSIONS: Early autologous stem-cell transplantation improved progression-free survival among patients with high intermediate-risk or high-risk disease who had a response to induction therapy. Overall survival after transplantation was not improved, probably because of the effectiveness of salvage transplantation. (Funded by the National Cancer Institute, Department of Health and Human Services, and others; SWOG-9704 ClinicalTrials.gov number, NCT00004031.). PMID- 24171519 TI - Images in clinical medicine. Trichomycosis axillaris. PMID- 24171518 TI - Circulatory shock. PMID- 24171517 TI - Cost-effectiveness of HIV treatment as prevention in serodiscordant couples. AB - BACKGROUND: The cost-effectiveness of early antiretroviral therapy (ART) in persons infected with human immunodeficiency virus (HIV) in serodiscordant couples is not known. Using a computer simulation of the progression of HIV infection and data from the HIV Prevention Trials Network 052 study, we projected the cost-effectiveness of early ART for such persons. METHODS: For HIV-infected partners in serodiscordant couples in South Africa and India, we compared the early initiation of ART with delayed ART. Five-year and lifetime outcomes included cumulative HIV transmissions, life-years, costs, and cost-effectiveness. We classified early ART as very cost-effective if its incremental cost effectiveness ratio was less than the annual per capita gross domestic product (GDP; $8,100 in South Africa and $1,500 in India), as cost-effective if the ratio was less than three times the GDP, and as cost-saving if it resulted in a decrease in total costs and an increase in life-years, as compared with delayed ART. RESULTS: In South Africa, early ART prevented opportunistic diseases and was cost-saving over a 5-year period; over a lifetime, it was very cost-effective ($590 per life-year saved). In India, early ART was cost-effective ($1,800 per life-year saved) over a 5-year period and very cost-effective ($530 per life-year saved) over a lifetime. In both countries, early ART prevented HIV transmission over short periods, but longer survival attenuated this effect; the main driver of life-years saved was a clinical benefit for treated patients. Early ART remained very cost-effective over a lifetime under most modeled assumptions in the two countries. CONCLUSIONS: In South Africa, early ART was cost-saving over a 5-year period. In both South Africa and India, early ART was projected to be very cost-effective over a lifetime. With individual, public health, and economic benefits, there is a compelling case for early ART for serodiscordant couples in resource-limited settings. (Funded by the National Institute of Allergy and Infectious Diseases and others.). PMID- 24171520 TI - Case records of the Massachusetts General Hospital. Case 34-2013. A 69-year-old man with dizziness and vomiting. PMID- 24171521 TI - Myeloablation for lymphoma--question answered? PMID- 24171522 TI - Talking with patients about other clinicians' errors. PMID- 24171523 TI - Rescue from hearing loss in Usher's syndrome. PMID- 24171524 TI - Hospital-associated Middle East respiratory syndrome coronavirus infections. PMID- 24171525 TI - Hospital-associated Middle East respiratory syndrome coronavirus infections. PMID- 24171526 TI - Treatment for high-risk smoldering myeloma. PMID- 24171527 TI - Treatment for high-risk smoldering myeloma. PMID- 24171528 TI - Treatment for high-risk smoldering myeloma. PMID- 24171529 TI - Treatment for high-risk smoldering myeloma. PMID- 24171530 TI - Treatment for high-risk smoldering myeloma. PMID- 24171531 TI - Herpes zoster. PMID- 24171532 TI - Herpes zoster. PMID- 24171533 TI - Herpes zoster. PMID- 24171534 TI - Herpes zoster. PMID- 24171535 TI - Case 23-2013: a 54-year-old woman with metformin toxicity. PMID- 24171536 TI - Case 23-2013: a 54-year-old woman with metformin toxicity. PMID- 24171537 TI - Case 23-2013: a 54-year-old woman with metformin toxicity. PMID- 24171538 TI - Case 23-2013: a 54-year-old woman with metformin toxicity. PMID- 24171539 TI - Case 23-2013: a 54-year-old woman with metformin toxicity. PMID- 24171540 TI - Retraction: CPAP for the metabolic syndrome in patients with obstructive sleep apnea. N Engl J Med 2011;365:2277-86. PMID- 24171541 TI - Images in clinical medicine. Neovascular festoons on the iris. PMID- 24171543 TI - Reappraisal of nuclear quadrupole moments of atomic halogens via relativistic coupled cluster linear response theory for the ionization process. AB - The coupled cluster based linear response theory (CCLRT) with four-component relativistic spinors is employed to compute the electric field gradients (EFG) of (35)Cl, (79)Br, and (127)I nuclei. The EFGs resulting from these calculations are combined with experimental nuclear quadrupole coupling constants (NQCC) to determine the nuclear quadrupole moments (NQM), Q of the halide nuclei. Our estimated NQMs [(35)Cl = -81.12 mb, (79)Br = 307.98 mb, and (127)I = -688.22 mb] agree well with the new atomic values [(35)Cl = -81.1(1.2), (79)Br = 302(5), and (127)I = -680(10) mb] obtained via Fock space multireference coupled cluster method with the Dirac-Coulomb-Breit Hamiltonian. Although our estimated Q((79)Br) value deviates from the accepted reference value of 313(3) mb, it agrees well with the recently recommended value, Q((79)Br) = 308.7(20) mb. Good agreement with current reference data indicates the accuracy of the proposed value for these halogen nuclei and lends credence to the results obtained via CCLRT approach. The electron affinities yielded by this method with no extra cost are also in good agreement with experimental values, which bolster our belief that the NQMs values for halogen nuclei derived here are reliable. PMID- 24171544 TI - Patterned biochemical functionalization improves aptamer-based detection of unlabeled thrombin in a sandwich assay. AB - Here we propose a platform for the detection of unlabeled human alpha-thrombin down to the picomolar range in a fluorescence-based aptamer assay. In this concept, thrombin is captured between two different thrombin binding aptamers, TBA1 (15mer) and TBA2 (29mer), each labeled with a specific fluorescent dye. One aptamer is attached to the surface, the second one is in solution and recognizes surface-captured thrombin. To improve the limit of detection and the comparability of measurements, we employed and compared two approaches to pattern the chip substrate-microcontact printing of organosilanes onto bare glass slides, and controlled printing of the capture aptamer TBA1 in arrays onto functionalized glass substrates using a nanoplotter device. The parallel presence of functionalized and control areas acts as an internal reference. We demonstrate that both techniques enable the detection of thrombin concentrations in a wide range from 0.02 to 200 nM with a detection limit at 20 pM. Finally, the developed method could be transferred to any substrate to probe different targets that have two distinct possible receptors without the need for direct target labeling. PMID- 24171545 TI - New versus old neuroleptics: efficacy versus marketing. PMID- 24171546 TI - Single molecule force spectroscopy reveals the molecular mechanical anisotropy of the FeS4 metal center in rubredoxin. AB - Mechanical anisotropy is an important feature of materials. Depending on the direction it is pulled, a material can exhibit very different mechanical properties. Mechanical anisotropy on the microscopic scale has also been observed for individual elastomeric proteins. Depending upon the direction along which it is stretched, a protein can unfold via different mechanical unfolding pathways and exhibit vastly different mechanical stability. However, it remains to be demonstrated if the concept of mechanical anisotropy can be extended to the molecular scale for small molecular objects containing only a few chemical bonds. Here, we choose the iron-sulfur center FeS4 in the simplest iron-sulfur protein rubredoxin as a model system to demonstrate the molecular level mechanical anisotropy. We used single molecule atomic force spectroscopy to investigate the mechanical rupture of the FeS4 center along different pulling directions. The FeS4 cluster is a simple molecular object with defined three-dimensional structure, where a ferric ion and four coordinating cysteinyl ligands are arranged into a distorted tetrahedral geometry. Mutating two specific residues in rubredoxin to cysteines provides anchoring points that enable us to stretch and rupture the FeS4 center along five distinct and precisely controlled directions. Our results showed that the mechanical stability as well as the rupture mechanism and kinetics of the FeS4 center are strongly dependent upon the direction along which it is stretched, suggesting that the very small and simple FeS4 center exhibits considerable mechanical anisotropy. It is likely that structural asymmetry in the FeS4 cluster and the modulation of the local environment due to partial unfolding of rubredoxin are responsible for the observed mechanical anisotropy. Our results suggest that mechanical anisotropy is a universal feature for any asymmetrical three-dimensional structure, even down to a molecular scale, and such mechanical anisotropy can be potentially utilized to control the mechanochemical reactivity of molecular objects. PMID- 24171547 TI - Reversible adhesion switching of porous fibrillar adhesive pads by humidity. AB - We report reversible adhesion switching on porous fibrillar polystyrene-block poly(2-vinyl pyridine) (PS-b-P2VP) adhesive pads by humidity changes. Adhesion at a relative humidity of 90% was more than nine times higher than at a relative humidity of 2%. On nonporous fibrillar adhesive pads of the same material, adhesion increased only by a factor of ~3.3. The switching performance remained unchanged in at least 10 successive high/low humidity cycles. Main origin of enhanced adhesion at high humidity is the humidity-induced decrease in the elastic modulus of the polar component P2VP rather than capillary force. The presence of spongelike continuous internal pore systems with walls consisting of P2VP significantly leveraged this effect. Fibrillar adhesive pads on which adhesion is switchable by humidity changes may be used for preconcentration of airborne particulates, pollutants, and germs combined with triggered surface cleaning. PMID- 24171548 TI - Noninvasive double confirmation of cocaine abuse. AB - A double confirmation procedure, based on the combined application of Ion Mobility Spectrometry (IMS) and Infrared Spectroscopy (IR), has been developed for the noninvasive unambiguous identification of cocaine consume. The use of nasal mucus as a biological specimen for cocaine abuse confirmation has been proposed as an alternative to the use of blood and urine due to its noninvasive character and the presence of the parent compound instead of its metabolites. Sampling conditions, interferences caused by cutting agents and other substances, and limits of identification (LOI) and confirmation (LOC) have been deeply evaluated. The procedure combines the high sensitivity of the IMS to identify positive samples with the high selectivity of the IR procedure to confirm positive results. Thus, the proposed two tier method has been applied to the detection and identification of cocaine in the nasal mucus of different individuals, consumers, and nonconsumers, providing results comparable with those obtained by a reference procedure. PMID- 24171549 TI - Chloro- and trifluoromethyl-substituted flanking-ring m-terphenyl isocyanides: eta6-arene binding to zero-valent molybdenum centers and comparison to alkyl substituted derivatives. AB - Presented herein are synthetic and structural studies exploring the propensity of m-terphenyl isocyanide ligands to provide flanking-ring eta(6)-arene interactions to zerovalent molybdenum centers. The alkyl-substituted m-terphenyl isocyanides CNAr(Mes2) and CNAr(Dipp2) (Ar(Mes2) = 2,6-(2,4,6-Me3C6H2)2C6H3; Ar(Dipp2) = 2,6 (2,6-(i-Pr)2C6H3)2C6H3) react with Mo(eta(6)-napthalene)2 in a 3:1 ratio to form tris-isocyanide eta(6)-arene Mo complexes, in which a flanking mesityl or 2,6 diisopropylphenyl group, respectively, of one isocyanide ligand is bound to the zerovalent molybdenum center. Thermal stability and reactivity studies show that these flanking ring eta(6)-arene interactions are particularly robust. To weaken or prevent formation of a flanking-ring eta(6)-arene interaction, and to potentially provide access to the coordinatively unsaturated [Mo(CNAr(R))3] fragment, the new halo-substituted m-terphenyl isocyanides CNAr(Clips2) and CNAr(DArF2) (Ar(Clips) = 2,6-(2,6-Cl2C6H3)2(4-t-Bu)C6H2; Ar(DArF2) = 2,6-(3,5 (CF3)2C6H3)2C6H3) have been prepared. Relative to their alkyl-substituted counterparts, synthetic and structural studies demonstrate that the flanking aryl rings of CNAr(Clips2) and CNAr(DArF2) display a lower tendency toward eta(6) binding. In the case of CNAr(DArF2), it is shown that an eta(6)-bound 3,5 bis(trifluoromethyl)phenyl group can be displaced from a zerovalent molybdenum center by three molecules of acetonitrile. This observation suggests that the CNAr(DArF2) ligand effectively masks low-valent metal centers in a fashion that provides access to low-coordinate isocyano targets such as [Mo(CNAr(R))3]. A series of Mo(CO)3(CNAr(R))3 complexes were also prepared to compare the relative pi-acidities of CNAr(Mes2), CNAr(Clips2), and CNAr(DArF2). It is found that CNAr(DArF2) shows increased pi-acidity relative to CNAr(Mes2) and CNAr(Clips2), despite the fact that its electron-withdrawing CF3 groups are fairly distal to the terminal isocyano unit. PMID- 24171551 TI - Magnetizabilities of diatomic and linear triatomic molecules in a time independent nonuniform magnetic field. AB - The theory of response of a molecule in the presence of a static nonuniform magnetic field with uniform gradient is reviewed and extended. Induced magnetic dipole, quadrupole, and anapole moments are expressed via multipole magnetic susceptibilities. Dependence of response properties on the origin of the coordinate system with respect to which they are defined is investigated. Relationships describing the change of multipole and anapole susceptibilities in a translation of the reference system are reported. For a single molecule, two quantities are invariant and, in principle, experimentally measurable, that is, the induced magnetic dipole and the interaction energy. The trace of a second rank anapole susceptibility, related to a pseudoscalar obtained by spatial averaging of the dipole-quadrupole susceptibility, of different sign for D and L enantiomeric systems, is origin independent. Therefore, in an isotropic chiral medium a homogeneous magnetic field induces an electronic anapole, having the same magnitude but opposite sign for two enantiomorphs. Calculations have been carried out for a set of diatomic and linear triatomic systems characterized by the presence of magnetic-field induced toroidal electron currents. PMID- 24171552 TI - Expanding the scope of human DNA polymerase lambda and beta inhibitors. AB - The exact biological functions of individual DNA polymerases still await clarification, and therefore appropriate reagents to probe their respective functions are required. In the present study, we report the development of a highly potent series of human DNA polymerase lambda and beta (pol lambda and beta) inhibitors based on the rhodanine scaffold. Both enzymes are involved in DNA repair and are thus considered as future drug targets. We expanded the chemical diversity of the small-molecule inhibitors arising from a high content screening and designed and synthesized 30 novel analogues. By biochemical evaluation, we discovered 23 highly active compounds against pol lambda. Importantly, 10 of these small-molecules selectively inhibited pol lambda and not the homologous pol beta. We discovered 14 small-molecules that target pol beta and found out that they are more potent than known inhibitors. We also investigated whether the discovered compounds sensitize cancer cells toward DNA damaging reagents. Thus, we cotreated human colorectal cancer cells (Caco-2) with the small-molecule inhibitors and hydrogen peroxide or the approved drug temozolomide. Interestingly, the tested compounds sensitized Caco-2 cells to both genotoxic agents in a DNA repair pathway-dependent manner. PMID- 24171553 TI - A differentially pumped dual linear quadrupole ion trap (DLQIT) mass spectrometer: a mass spectrometer capable of MS(n) experiments free from interfering reactions. AB - A novel differentially pumped dual linear quadrupole ion trap (DLQIT) mass spectrometer was designed and built to facilitate tandem MS experiments free from interfering reactions. The instrument consists of two differentially pumped Thermo Scientific linear quadrupole ion trap (LQIT) systems that have been connected via an ion transfer octupole encased in a machined manifold. Tandem MS experiments can be performed in the front trap and then the resulting product ions can be transferred via axial ejection into the back trap for further, independent tandem MS experiments in a differentially pumped area. This approach allows the examination of consecutive collision-activated dissociation (CAD) and ion-molecule reactions without unwanted side reactions that often occur when CAD and ion-molecule reactions are examined in the same space. Hence, it greatly facilitates investigations of ion structures. In addition, the overall lower pressure of the DLQIT, as compared to commercial LQIT instruments, results in a reduction of unwanted side reactions with atmospheric contaminants, such as water and oxygen, in CAD and ion-molecule experiments. PMID- 24171554 TI - Nanopore-based identification of individual nucleotides for direct RNA sequencing. AB - We describe a label-free ribobase identification method, which uses ionic current measurement to resolve ribonucleoside monophosphates or diphosphates in alpha hemolysin protein nanopores containing amino-cyclodextrin adapters. The accuracy of base identification is further investigated through the use of a guanidino modified adapter. On the basis of these findings, an exosequencing approach is envisioned in which a processive exoribonuclease (polynucleotide phosphorylase) presents sequentially cleaved ribonucleoside diphosphates to a nanopore. PMID- 24171555 TI - Phenyliodonium diacetate mediated direct synthesis of benzonitriles from styrenes through oxidative cleavage of C?C bonds. AB - A metal-free PhI(OAc)2 mediated nitrogenation of alkenes through C?C bond cleavage using inorganic ammonia salt as nitrogen source under mild conditions was developed, affording nitriles in moderate to good yields. The advantages of this reaction are mild reaction conditions, operational simplicity, and use of an ammonium salt as nitrogen source. Based upon experimental observations, a plausible reaction mechanism is proposed. PMID- 24171557 TI - Pre-exposing Canada Geese (Branta canadensis) to a low-pathogenic H1N1 avian influenza virus protects them against H5N1 HPAI virus challenge. AB - In previous studies we examined the role of Canada Geese (Branta canadensis) in the epidemiology of Eurasian highly pathogenic avian influenza (HPAI) H5N1. To expand on this and better understand how pre-exposure to heterosubtypic low pathogenic avian influenza (LPAI) viruses might influence the outcome of H5N1 HPAI infection, we pre-exposed naive juvenile Canada Geese to different North American wild-bird-origin LPAI viruses. We selected H1, H2, and H6 hemagglutinin subtype viruses based on their higher-order evolutionary relatedness to the H5 hemagglutinin. Pre-exposing Canada Geese to either H2N3 or H6N5 viruses did not protect them against a lethal H5N1 HPAI virus challenge. In addition, H5N1 was transmitted to naive control birds that were placed among both groups resulting in death by 5 days postcontact. In contrast, Canada Geese that were pre-exposed to H1N1 were protected against a lethal H5N1 challenge, shed minimal amounts of the virus into the environment, and did not transmit the infection to naive contact birds. None of the H1N1, H2N3, or H6N5 pre-exposure sera neutralized H5N1 in vitro; however, sera from H1N1-infected birds reduced virus plaque size but not number when compared with H2N3, H6N5, or negative sera, suggesting that antibodies directed against the neuraminidase may have had a role in the protective effects observed. PMID- 24171559 TI - Low-residue euthanasia of stranded mysticetes. AB - Euthanasia of stranded large whales poses logistic, safety, pharmaceutical, delivery, public relations, and disposal challenges. Reasonable arguments may be made for allowing a stranded whale to expire naturally. However, slow cardiovascular collapse from gravitational effects outside of neutral buoyancy, often combined with severely debilitating conditions, motivate humane efforts to end the animal's suffering. The size of the animal and prevailing environmental conditions often pose safety concerns for stranding personnel, which take priority over other considerations. When considering chemical euthanasia, the size of the animal also necessitates large quantities of euthanasia agents. Drug residues are a concern for relay toxicity to scavengers, particularly for pentobarbital-containing euthanasia solutions. Pentobarbital is also an environmental concern because of its stability and long persistence in aquatic environments. We describe a euthanasia technique for stranded mysticetes using readily available, relatively inexpensive, preanesthetic and anesthetic drugs (midazolam, acepromazine, xylazine) followed by saturated KCl delivered via custom-made needles and a low-cost, basic, pressurized canister. This method provides effective euthanasia while moderating personnel exposure to hazardous situations and minimizing drug residues of concern for relay toxicity. PMID- 24171560 TI - Drought reduces chytrid fungus (Batrachochytrium dendrobatidis) infection intensity and mortality but not prevalence in adult crawfish frogs (Lithobates areolatus). AB - To fully understand the impacts of the chytrid fungus Batrachochytrium dendrobatidis (Bd) on amphibians it is necessary to examine the interactions between populations and their environment. Ecologic variables can exacerbate or ameliorate Bd prevalence and infection intensity, factors that are positively related when Bd is acting on naive amphibian populations as an epidemic disease. In crawfish frogs (Lithobates areolatus), a North American species with a complex life history, we have shown that Bd acts as an endemic disease with impacts that vary seasonally; the highest infection prevalences and intensities and highest frog mortality occurred during late spring in postbreeding individuals. In this study, conducted between 28 February and 23 August 2011 in southwestern Indiana on the same population, we report an uncoupling of the previously observed relationship between Bd prevalence and intensity following an extreme drought. Specifically, there was a postdrought reduction in Bd infection intensity and mortality, but not in infection prevalence. This result suggests that the relationship between prevalence and intensity observed in Bd epidemics can be uncoupled in populations harboring endemic infections. Further, constant prevalence rates suggest either that crawfish frogs are being exposed to Bd sources independent of ambient moisture or that low-level infections below detection thresholds persist from year to year. Drought has several ecologically beneficial effects for amphibians with complex life histories, including eliminating fish and invertebrate populations that feed on larvae. To these ecologic benefits we suggest another, that drought can reduce the incidence of the severe skin disease (chytridiomycosis) due to Bd infection. PMID- 24171561 TI - Blood mineral concentrations in the endangered huemul deer (Hippocamelus bisulcus) from Chilean Patagonia. AB - Concentrations of calcium, magnesium, copper, zinc, and selenium were measured in plasma from 11 huemul (Hippocamelus bisulcus) from Chilean Patagonia. Except for zinc and copper, concentrations of these minerals were similar to those of other deer species. PMID- 24171562 TI - Trichinella surveillance in black bears (Ursus americanus) from Oregon, USA. AB - We used serology and muscle digestion to test black bears (Ursus americanus) from western Oregon, USA, for Trichinella. Results indicate black bears in Oregon are not part of a sylvatic cycle for Trichinella, and risk of human exposure to Trichinella larvae from eating black bear meat from Oregon appears low. PMID- 24171563 TI - Infection patterns in invasive and native snail hosts exposed to a parasite associated with waterfowl mortality in the upper Mississippi River, USA. AB - Bithynia tentaculata is an aquatic invasive snail first detected in the upper Mississippi River (UMR) in 2002. The snail harbors a number of parasitic trematode species, including Sphaeridiotrema pseudoglobulus, that have been implicated in waterfowl mortality in the region. We assessed the capacity of S. pseudoglobulus cercariae to infect B. tentaculata and native snails found in the UMR. Four snail species (one invasive and three native) were individually exposed to S. pseudoglobulus larvae and all were successfully infected. A subsequent experiment examining infection patterns in invasive and native hosts exposed singly or in mixed treatments revealed no difference in parasite establishment among snail species. Our results add to our understanding of S. pseudoglobulus transmission and provide insight into processes underlying waterfowl disease in the UMR. PMID- 24171564 TI - Immobilization of grizzly bears (Ursus arctos) with dexmedetomidine, tiletamine, and zolazepam. AB - Safe and effective immobilization of grizzly bears (Ursus arctos) is essential for research and management. Fast induction of anesthesia, maintenance of healthy vital rates, and predictable recoveries are priorities. From September 2010 to May 2012, we investigated these attributes in captive and wild grizzly bears anesthetized with a combination of a reversible alpha2 agonist (dexmedetomidine [dexM], the dextrorotatory enantiomer of medetomidine) and a nonreversible N methyl-d-aspartate (NMDA) agonist and tranquilizer (tiletamine and zolazepam [TZ], respectively). A smaller-than-expected dose of the combination (1.23 mg tiletamine, 1.23 mg zolazepam, and 6.04 ug dexmedetomidine per kg bear) produced reliable, fast ataxia (3.7 +/- 0.5 min, x+/-SE) and workable anesthesia (8.1 +/- 0.6 min) in captive adult grizzly bears. For wild bears darted from a helicopter, a dose of 2.06 mg tiletamine, 2.06 mg zolazepam, and 10.1 ug dexmedetomidine/kg produced ataxia in 2.5 +/- 0.3 min and anesthesia in 5.5 +/- 1.0 min. Contrary to published accounts of bear anesthesia with medetomidine, tiletamine, and zolazepam, this combination did not cause hypoxemia or hypoventilation, although mild bradycardia (<50 beats per min) occurred in most bears during the active season. With captive bears, effective dose rates during hibernation were approximately half those during the active season. The time to first signs of recovery after the initial injection of dexMTZ was influenced by heart rate (P<0.001) and drug dose (P<0.001). Intravenous (IV) injection of the reversal agent, atipamezole, significantly decreased recovery time (i.e., standing on all four feet and reacting to the surrounding environment) relative to intramuscular injection. Recovery times (25 +/- 8 min) following IV injections of the recommended dose of atipamezole (10 ug/ug of dexmedetomidine) and half that dose (5 ug/ug) did not differ. However, we recommend use of the full dose based on the appearance of a more complete recovery. Field trials confirmed that the dexMTZ + atipamezole protocol is safe, reliable, and predictable when administered to wild grizzly bears, especially during helicopter capture operations. PMID- 24171565 TI - Utility of a fecal real-time PCR protocol for detection of Mycobacterium bovis infection in African buffalo (Syncerus caffer). AB - A real-time PCR protocol for detecting Mycobacterium bovis in feces was evaluated in bovine tuberculosis-infected African buffalo (Syncerus caffer). Fecal samples spiked with 1.42 * 10(3) cells of M. bovis culture/g and Bacille Calmette-Guerin standards with 1.58 * 10(1) genome copies/well were positive by real-time PCR but all field samples were negative. PMID- 24171566 TI - Giardia in mountain gorillas (Gorilla beringei beringei), forest buffalo (Syncerus caffer), and domestic cattle in Volcanoes National Park, Rwanda. AB - Mountain gorillas (Gorilla beringei beringei) are critically endangered primates surviving in two isolated populations in protected areas within the Virunga Massif of Rwanda, Uganda, the Democratic Republic of Congo, and in Bwindi Impenetrable National Park in Uganda. Mountain gorillas face intense ecologic pressures due to their proximity to humans. Human communities outside the national parks, and numerous human activities within the national parks (including research, tourism, illegal hunting, and anti-poaching patrols), lead to a high degree of contact between mountain gorillas and wildlife, domestic animals, and humans. To assess the pathogen transmission potential between wildlife and livestock, feces of mountain gorillas, forest buffalo (Syncerus caffer nanus), and domestic cattle (Bos taurus) in Rwanda were examined for the parasites Giardia and Cryptosporidium. Giardia was found in 9% of mountain gorillas, 6% of cattle, and 2% of forest buffalo. Our study represents the first report of Giardia prevalence in forest buffalo. Cryptosporidium-like particles were also observed in all three species. Molecular characterization of Giardia isolates identified zoonotic genotype assemblage B in the gorilla samples and assemblage E in the cattle samples. Significant spatial clustering of Giardia positive samples was observed in one sector of the park. Although we did not find evidence for transmission of protozoa from forest buffalo to mountain gorillas, the genotypes of Giardia samples isolated from gorillas have been reported in humans, suggesting that the importance of humans in this ecosystem should be more closely evaluated. PMID- 24171567 TI - Prevalence of three campylobacter species, C. jejuni, C. coli, and C. lari, using multilocus sequence typing in wild birds of the Mid-Atlantic region, USA. AB - Campylobacter jejuni is responsible for the majority of bacterial foodborne gastroenteritis in the US, usually due to the consumption of undercooked poultry. Research on which avian species transmit the bacterium is limited, especially in the US. We sampled wild birds in three families-Anatidae, Scolopacidae, and Laridae-in eastern North America to determine the prevalence and specific strains of Campylobacter. The overall prevalence of Campylobacter spp. was 9.2% for all wild birds sampled (n = 781). Campylobacter jejuni was the most prevalent species (8.1%), while Campylobacter coli and Campylobacter lari prevalence estimates were low (1.4% and 0.3%, respectively). We used multilocus sequence typing PCR specific to C. jejuni to characterize clonal complexes and sequence types isolated from wild bird samples and detected 13 novel sequence types, along with a clonal complex previously only associated with human disease (ST-658). Wild birds share an increasing amount of habitat with humans as more landscapes become fragmented and developed for human needs. Wild birds are and will remain an important aspect of public health due to their ability to carry and disperse emerging zoonotic pathogens or their arthropod vectors. As basic information such as prevalence is limited or lacking from a majority of wild birds in the US, this study provides further insight into Campylobacter epidemiology, host preference, and strain characterization of C. jejuni. PMID- 24171568 TI - Oral squamous cell carcinoma in a red deer (Cervus elaphus). AB - We describe the pathomorphologic and immunophenotypic characteristics of an oral squamous cell carcinoma in a 13-yr-old, free-ranging red deer (Cervus elaphus) in Lower Saxony, Germany. PMID- 24171569 TI - PCR assay detects Mannheimia haemolytica in culture-negative pneumonic lung tissues of bighorn sheep (Ovis canadensis) from outbreaks in the western USA, 2009-2010. AB - Mannheimia haemolytica consistently causes severe bronchopneumonia and rapid death of bighorn sheep (Ovis canadensis) under experimental conditions. However, Bibersteinia trehalosi and Pasteurella multocida have been isolated from pneumonic bighorn lung tissues more frequently than M. haemolytica by culture based methods. We hypothesized that assays more sensitive than culture would detect M. haemolytica in pneumonic lung tissues more accurately. Therefore, our first objective was to develop a PCR assay specific for M. haemolytica and use it to determine if this organism was present in the pneumonic lungs of bighorns during the 2009-2010 outbreaks in Montana, Nevada, and Washington, USA. Mannheimia haemolytica was detected by the species-specific PCR assay in 77% of archived pneumonic lung tissues that were negative by culture. Leukotoxin negative M. haemolytica does not cause fatal pneumonia in bighorns. Therefore, our second objective was to determine if the leukotoxin gene was also present in the lung tissues as a means of determining the leukotoxicity of M. haemolytica that were present in the lungs. The leukotoxin-specific PCR assay detected leukotoxin gene in 91% of lung tissues that were negative for M. haemolytica by culture. Mycoplasma ovipneumoniae, an organism associated with bighorn pneumonia, was detected in 65% of pneumonic bighorn lung tissues by PCR or culture. A PCR assessment of distribution of these pathogens in the nasopharynx of healthy bighorns from populations that did not experience an all-age die-off in the past 20 yr revealed that M. ovipneumoniae was present in 31% of the animals whereas leukotoxin-positive M. haemolytica was present in only 4%. Taken together, these results indicate that culture-based methods are not reliable for detection of M. haemolytica and that leukotoxin-positive M. haemolytica was a predominant etiologic agent of the pneumonia outbreaks of 2009-2010. PMID- 24171570 TI - Evaluation of seabirds in Newfoundland and Labrador, Canada, as hosts of influenza A viruses. AB - Influenza A viruses infect a wide range of hosts, including many species of birds. Avian influenza A virus (AIV) infection appears to be most common in Anseriformes (ducks, geese, and swans) and some Charadriiformes (shorebirds and gulls), but many other birds also serve as hosts of AIV. Here, we evaluated the role of seabirds as hosts for AIV. We tested 3,160 swab samples from 13 seabird species between May 2008 and December 2011 in Newfoundland and Labrador, Canada. We also tested 156 serum samples for evidence of previous infection of AIV in Common Murres (Uria aalge) and Atlantic Puffins (Fratercula arctica). Avian influenza A virus was detected in breeding Common Murres and nonbreeding Thick billed Murres (Uria lomvia), and Common Murres also had high antibody prevalence (44%). From these findings, combined with other studies showing AIV infection in murres, we conclude that murres are important for the ecology of AIV. For other species (Razorbill, Alca torda; Leach's Storm-Petrel, Oceanodroma leucorhoa; Black-legged Kittiwake, Rissa tridactyla; Atlantic Puffin) with good coverage (>100 samples) we did not detect AIV. However, serology indicates infection does occur in Atlantic Puffins, with 22% antibody prevalence found. The possibility of virus spread through dense breeding colonies and the long distance movements of these hosts make a more thorough evaluation of the role for seabirds as hosts of AIV important. PMID- 24171571 TI - Dermocystid-chytrid coinfection in the neotropical frog Hypsiboas pulchellus (Anura: Hylidae). AB - We present gross and histologic evidence of coinfection in amphibians by fungal like parasites of the order Dermocystidia (Amphibiocystidium sp.) and the fungus Batrachochytrium dendrobatidis. The condition was observed in frogs Hypsiboas pulchellus (Hylidae) from Uruguay in 2009 to 2012. This report is the first of dermocystids in Neotropical amphibians since 1940. PMID- 24171572 TI - Morphologic and molecular identifications of digenetic trematodes in double crested cormorants (Phalacrocorax auritus) from the Mississippi Delta, USA. AB - Increasing numbers of Double-crested Cormorants (Phalacrocorax auritus) in the Mississippi River Delta, USA, have been observed over the past few decades. This piscivorous bird is a definitive host for numerous digenetic trematodes, some of which may cause pathology in a fish host. We conducted a 2-yr survey of intestinal trematodes in 35 Double-crested Cormorants collected in the Mississippi Delta. We counted gastrointestinal trematodes, identified them to species using morphometric and molecular techniques, and sequenced the 18S and cytochrome oxidase I (COI) genes. We collected 4,909 trematodes, representing five digenetic species: Drepanocephalus spathans, Hysteromorpha triloba, Pseudopsilostoma varium, Austrodiplostomum ostrowskiae, and Ascocotyle longa. The most prevalent trematode of the Double-crested Cormorants was D. spathans (91%), followed by H. triloba (78%), P. varium (74%), A. ostrowskiae (57%), and A. longa (29%). Among these, the life cycles are only known for H. triloba and A. longa. Novel DNA sequences of the COI gene were obtained for D. spathans, A. ostrowskiae, P. varium, and A. longa adults. Using these DNA sequences, the identification and confirmation of the larval stages of these parasites in the fish and snail hosts will be possible. PMID- 24171573 TI - Infection of C57BL/6 mice by Trypanosoma musculi modulates host immune responses during Brucella abortus cocolonization. AB - Brucellosis, which results in fetal abortions in domestic and wildlife animal populations, is of major concern in the US and throughout much of the world. The disease, caused by Brucella abortus, poses an economic threat to agriculture based communities. A moderately efficacious live attenuated vaccine (B. abortus strain RB51) exists. However, even with vaccine use, outbreaks occur. Evidence suggests that elk (Cervus canadensis), a wild host reservoir, are the source of recent outbreaks in domestic cattle herds in Wyoming, USA. Brucella abortus establishes a chronic, persistent infection in elk. The molecular mechanisms allowing the establishment of this persistent infective state are currently unknown. A potential mechanism could be that concurrent pathogen burdens contribute to persistence. In Wyoming, elk are chronically infected with Trypanosoma cervi, which may modulate host responses in a similar manner to that documented for other trypanosomes. To identify any synergistic relationship between the two pathogens, we simulated coinfection in the well-established murine brucellosis model using Trypanosoma musculi and B. abortus S19. Groups of C57BL/6 mice (Mus musculus) were infected with either B. abortus strain 19 (S19) or T. musculi or both. Sera were collected weekly; spleens from euthanized mice were tested to determine bacterial load near the end of normal brucellosis infection. Although changes in bacterial load were observed during the later stages of brucellosis in those mice coinfected with T. musculi, the most significant finding was the suppression of gamma interferon early during the infection along with an increase in interleukin-10 secretion compared with mice infected with either pathogen alone. These results suggest that immune modulatory events occur in the mouse during coinfection and that further experiments are warranted to determine if T. cervi impacts Brucella infection in elk. PMID- 24171574 TI - The potential role of oral pH in the persistence of Trichomonas gallinae in Cooper's Hawks (Accipiter cooperii). AB - Trichomoniasis, caused by the protozoan Trichomonas gallinae, affects a variety of species worldwide including avivorious raptors. Existing information suggests that the disease is most prevalent in young birds, and differential susceptibility to trichomoniasis among individuals in different age groups was documented in Cooper's Hawks (Accipiter cooperii) nesting in Tucson, Arizona. In that population, 85% of nestling Cooper's Hawks had T. gallinae in their oral cavity, compared to only 1% of breeding-age hawks. Trichomonads generally are sensitive to environmental pH and we explored the possibility that differences in oral pH may contribute to the differential prevalence of infection between age groups. We measured the pH of the fluid in the oral cavity in 375 Cooper's Hawks from three age groups (nestlings, fledglings, and breeding age) in Tucson, Arizona, in 2010 and 2011 and clinically tested for T. gallinae in a subsample of hawks. Oral pH of nestlings (~ 6.8) was 7.3 times less acidic than in fledgling or breeding Cooper's Hawks (~ 6.1). The incidence of T. gallinae was higher in nestlings (16%) than in either fledglings or breeding hawks (0%). Our findings indicate that oral pH becomes more acidic in Cooper's Hawks soon after they leave the nest. Trichomonas gallinae thrives when pH is between 6.5 and 7.5 (optimum 7.2), but is less viable in more acidic conditions. Higher levels of acidity in the oral cavity of fledglings and breeding Cooper's Hawks may reduce their susceptibility to trichomoniasis, and play a role in the differential prevalence of infection among age groups. PMID- 24171575 TI - Detection of drug-resistant Klebsiella pneumoniae in Chinese hares (Lepus sinensis). AB - We investigated an outbreak of acute pneumonia among adult Chinese hares (Lepus sinensis) and diarrhea among juvenile hares in Hebei Province, China, in 2012. Diagnosis was based on necropsy examination, microbial characteristics, biochemical identification, and nucleotide sequence analysis. The isolated bacteria from tissue samples of dead hares were identified as Klebsiella pneumoniae ssp. pneumoniae (K. pneumoniae). This K. pneumoniae was resistant to the antimicrobials imipenem, meropenem, penicillin, and vancomycin, but was highly sensitive to cefepime, cotrimoxazole, and enrofloxacin. Klebsiella pneumoniae is an important opportunistic pathogen, which often causes nosocomial infections in immunocompromised patients. However, the emergence of drug resistant K. pneumoniae in hares indicates the existence of increasing risk of pathogen transmission between humans and wildlife. Given the close association between wildlife, livestock, and humans, it is important to identify epidemiologic factors associated with infection in these hares to minimize the risk of K. pneumoniae transmission. PMID- 24171576 TI - Acute fatal toxoplasmosis in a Great Spotted Woodpecker (Dendrocopos major). AB - A juvenile male Great Spotted Woodpecker (Dendrocopos major), found dead at a bird feeding station in central Norway in September 2011, was examined postmortem. Its lungs were consolidated and edematous, and its spleen was enlarged. The main histopathologic diagnoses included acute protozoal necrotizing interstitial pneumonia, splenitis, and hepatitis. Toxoplasma gondii parasites were identified with immunohistochemistry in all examined organs: lung, heart, liver, kidney, and spleen. Direct multilocus genotyping of the parasites revealed that the woodpecker was killed by a T. gondii strain belonging to genotype II. This is the first report of naturally acquired fatal generalized toxoplasmosis in a Dendrocopos species. PMID- 24171577 TI - First reports of pseudorabies and winter ticks (Dermacentor albipictus) associated with an emerging feral swine (Sus scrofa) population in New Hampshire. AB - The expansion of feral swine (Sus scrofa) populations into new geographic regions is of concern not only due to increased range but also because they carry diseases and parasites that pose a threat to humans, livestock, and wildlife into new areas. Recently, emerging feral swine populations have been reported in the northeastern US and due to their adaptive nature will likely continue to spread. During 2009-2012, 49 feral swine were removed from three counties in New Hampshire. Of these, serum samples were submitted from 34 for disease surveillance testing. One of the feral swine was antibody-positive for pseudorabies virus (PRV) making it the first documented infection in feral swine in New Hampshire. Infestations of winter tick (Dermacentor albipictus) were also documented on two of the feral swine which had only been reported previously on feral swine in Texas. Feral swine may not only serve as an important host for an economically important commercial swine pathogen like PRV, but they could also increase host diversity for parasites such as the winter tick, a species that can regionally impact moose (Alces alces) survival. These findings warrant further investigation of expanding and established feral swine populations in New Hampshire as pathogen hosts and support continued effort to reduce numbers or regionally eradicate feral swine. PMID- 24171578 TI - Ear mange mites (Notoedres muris) in black and Norway rats (Rattus rattus and Rattus norvegicus) from inner-city Vancouver, Canada. AB - The ear mange mite, Notoedres muris (Astigmata: Sarcoptidae), is a parasitic burrowing mite of black and Norway rats (Rattus rattus and Rattus norvegicus), which causes a proliferative dermatitis primarily affecting the ears. We characterize the ecology of N. muris in a group of black and Norway rats trapped in an inner-city area of Vancouver, Canada. Rats (n = 725) were trapped for 1 yr (September 2011-August 2012) in 43 city blocks (0.82 km(2)) and one property (0.03 km(2)) within an international shipping port at the northern border of the study area. Mite infestation was diagnosed in 15 of 32 rats (47%, 95% confidence interval [CI] = 30.9-53.6%) trapped in a large indoor facility at the port property. No affected animals were identified outside this facility, either within the port property or in any of the blocks under study. There was a positive relationship between infestation and both weight and nose-to-rump length (proxies for age), suggesting transmission through intraspecific social contact within colonies. This is the first report of N. muris in Canada. The focal distribution of N. muris at the port may reflect an importation event. PMID- 24171579 TI - Capture of sandhill cranes using alpha-chloralose: a 10-year follow-up. AB - Seasonal adjustment of alpha-chloralose captures of sandhill cranes was associated with a modest increase in capture efficacy (+13%), decreased morbidity from exertional myopathy (-1.4%), and overall mortality (-1.7%) rates despite little change in sedation scores. Postcapture fluid administration also decreased confinement times by several hours over most sedation scores. PMID- 24171580 TI - Acute pasteurellosis in wild big brown bats (Eptesicus fuscus). AB - We report acute fatal pasteurellosis in wild big brown bats (Eptesicus fuscus) in Wisconsin, USA. Mortality of approximately 100 bats was documented over 4 wk, with no evidence for predatory injuries. Pasteurella multocida serotype 1 was isolated from multiple internal organs from four of five bats examined postmortem. PMID- 24171581 TI - Detection of Leishmania in red foxes (Vulpes vulpes) from southeastern France using real-time quantitative PCR. AB - The role of red foxes in the natural cycle of Leishmania infection is not well known. In the Var area, southeastern France, from 2006 to 2012, we conducted a longitudinal epidemiologic survey of foxes using quantitative PCR. Among 92 red foxes screened, prevalence of Leishmania infantum infection was 9%. Red foxes may be considered a bioindicator of parasite circulation in this biotope. PMID- 24171582 TI - Atomic force microscope infrared spectroscopy of griseofulvin nanocrystals. AB - The goal of this work was to evaluate the ability of photothermal-induced resonance (PTIR) to measure the local infrared absorption spectra of crystalline organic drug nanoparticles embedded within solid matrices. Herein, the first reports of the chemical characterization of sub-100 nm organic crystals are described; infrared spectra of 90 nm griseofulvin particles were obtained, confirming the chemical resolution of PTIR beyond the diffraction limit. Additionally, particle size distributions via dynamic light scattering and PTIR image analysis were found to be similar, suggesting that the PTIR measurements are not significantly affected by inhomogeneous infrared absorptivity of this system. Thus as medical applications increasingly emphasize localized drug delivery via micro/nanoengineered structures, PTIR can be used to unambiguously chemically characterize drug formulations at these length scales. PMID- 24171584 TI - Margaret sanger 1883-1966. PMID- 24171585 TI - Interracial marrage-its statutory prohibition, genetic import, and incidence. PMID- 24171583 TI - Radical product yields from the ozonolysis of short chain alkenes under atmospheric boundary layer conditions. AB - The gas-phase reaction of ozone with unsaturated volatile organic compounds (VOCs), alkenes, is an important source of the critical atmospheric oxidant OH, especially at night when other photolytic radical initiation routes cannot occur. Alkene ozonolysis is also known to directly form HO2 radicals, which may be readily converted to OH through reaction with NO, but whose formation is poorly understood. We report a study of the radical (OH, HO2, and RO2) production from a series of small alkenes (propene, 1-butene, cis-2-butene, trans-2-butene, 2 methylpropene, 2,3-dimethyl-2-butene (tetramethyl ethene, TME), and isoprene). Experiments were performed in the European Photoreactor (EUPHORE) atmospheric simulation chamber, with OH and HO2 levels directly measured by laser-induced fluorescence (LIF) and HO2 + SigmaRO2 levels measured by peroxy-radical chemical amplification (PERCA). OH yields were found to be in good agreement with the majority of previous studies performed under comparable conditions (atmospheric pressure, long time scales) using tracer and scavenger approaches. HO2 yields ranged from 4% (trans-2-butene) to 34% (2-methylpropene), lower than previous experimental determinations. Increasing humidity further reduced the HO2 yields obtained, by typically 50% for an RH increase from 0.5 to 30%, suggesting that HOx production from alkene ozonolysis may be lower than current models suggest under (humid) ambient atmospheric boundary layer conditions. The mechanistic origin of the OH and HO2 production observed is discussed in the context of previous experimental and theoretical studies. PMID- 24171586 TI - Negro-white intermarriage: forbidden sexual union. PMID- 24171587 TI - Interracial sexuality as an expression of neurotic conflict. PMID- 24171588 TI - Problems and motives in interracial relationships. PMID- 24171589 TI - Dating between American and Foreign College Students. PMID- 24171590 TI - Some Reflections on Sex Relations between Physician and Patient. PMID- 24171592 TI - Overt transference. PMID- 24171591 TI - The sexual fantasies of the psychotherapist and their use in psychotherapy. PMID- 24171594 TI - Publications received. PMID- 24171595 TI - The direct oxidative addition of O2 to a mononuclear Cr(I) complex is spin forbidden. AB - Mononuclear chromium(I) alkyne complex (i-Pr2Ph)2nacnacCr(eta(2)-C2(SiMe3)2) (1) reacts rapidly with dioxygen to yield chromium(V) dioxo species (i Pr2Ph)2nacnacCr(O)2 (2). The mechanism of this oxygen cleavage has been studied experimentally and computationally. Isotope labeling studies rule out a direct four-electron oxidative addition of O2 to one chromium atom, which involves a spin-forbidden transformation. Instead, the reaction likely proceeds via an unsymmetric binuclear chromium bis(MU-oxo) complex. The latter has been independently prepared and structurally characterized. Its reactivity with O2 is consistent with the proposed mechanism. PMID- 24171600 TI - Triflic acid-mediated rearrangements of 3-methoxy-8-oxabicyclo[3.2.1]octa-3,6 dien-2-ones: synthesis of methoxytropolones and furans. AB - Methoxytropolones are useful scaffolds for therapeutic development because of their known biological activity and established value in the synthesis of alpha hydroxytropolones. Upon treatment with triflic acid, a series of 3-methoxy-8 oxabicyclo[3.2.1]octa-3,6-dien-2-ones rearrange rapidly and cleanly to form methoxytropolones. Interestingly, bicycles that are derived from dimethyl acetylenedicarboxylate (R(2) = R(3) = CO2Me) instead form furans as the major product. PMID- 24171602 TI - Thankful for being asked. PMID- 24171601 TI - Lewis acids promoted formal intramolecular [3 + 2] parallel and cross cycloadditions of cyclopropane 1,1-diesters with allenes. AB - A novel Lewis acid promoted formal intramolecular [3 + 2] parallel/cross cycloaddition of cyclopropane 1,1-diesters with allenes has been successfully developed, in which the two C?C of allenes were involved respectively. This provides a general and efficient strategy for the construction of structurally diverse [4.3.0]nonane and [3.2.1]octane skeletons. PMID- 24171610 TI - Demand grows for an official advocate for older people. PMID- 24171611 TI - Carers are left adrift without essential support and advice on dementia. PMID- 24171613 TI - Forum focus -- our residential care homes are losing expert nurses. PMID- 24171615 TI - Left in the dark about asthma. PMID- 24171616 TI - The evidence speaks for itself. PMID- 24171620 TI - Practice question. PMID- 24171621 TI - Exploring nurses' use of language with older people. AB - The authors discuss ways in which nurses speak to older people. Research shows that the words nurses use can have a powerful effect on the wellbeing of older people. An experimental project developed at the University of Hull is described in which creative writing techniques were used to increase nursing students' and staff's sensitivity to the importance of language in care. The project enabled participants to co-create a body of work that was subsequently displayed in the faculty reception, and it showed how trusting relationships could be developed between participants. The authors are working to extend the project by finding ways to embed creative writing in the undergraduate nursing curriculum. PMID- 24171622 TI - Meeting the religious needs of residents with dementia. AB - This article considers practical strategies to help nurses working in care homes meet the religious needs of people with dementia, including attending services in homes or churches, supporting them in private prayer and at the end of life. It also considers the characteristics of person-centred care for such residents and how the Mental Capacity Act 2005 may be called on to support religious needs as dementia advances. To achieve good practice in all these aspects, staff in care homes should work in partnership with local faith communities and ensure they are aware of residents' life histories and preferences, including their faith practices. The focus of the article is on meeting the needs of Christian residents. For residents from other faith groups living in care homes not affiliated to their faith, the same general approach to meeting religious needs could be adopted as a starting point. PMID- 24171624 TI - Home truths. PMID- 24171623 TI - What motivates patients and carers to participate in dementia studies? AB - AIM: The aim of this study was to explore what motivates people to participate in dementia research. METHOD: Three focus groups, attended by carers and people with dementia who had already volunteered to take part in dementia research, were used to explore motivation. Their thoughts and feelings about brain tissue donation were also explored. An adaptation of the participation chain model was used. A fourth focus group was given a supplementary questionnaire examining use of resources. Focus group content was analysed using a content analysis approach to identify themes. FINDINGS: Individualistic motivations included increased confidence and a chance to have a say. Collectivistic motivations included 'helping through being part of something bigger'. Mobilisation (catalysing) issues included a desire for change, and 'being asked'. In response to the questionnaire participants identified that they would have taken part regardless of any tangible benefits, with all saying that they would not have been put off by any of the costs. CONCLUSION: Participants in these focus groups were keen to be involved in dementia research and discounted any potential costs to themselves. They highlighted that being asked was an important factor in engaging them in dementia research. PMID- 24171625 TI - Biochemical and functional characterization of charge-defined subfractions of high-density lipoprotein from normal adults. AB - High-density lipoprotein (HDL) is regarded as atheroprotective because it provides antioxidant and anti-inflammatory benefits and plays an important role in reverse cholesterol transport. In this paper, we outline a novel methodology for studying the heterogeneity of HDL. Using anion-exchange chromatography, we separated HDL from 6 healthy individuals into five subfractions (H1 through H5) with increasing charge and evaluated the composition and biologic activities of each subfraction. Sodium dodecyl sulfate polyacrylamide gel electrophoresis analysis showed that apolipoprotein (apo) AI and apoAII were present in all 5 subfractions; apoCI was present only in H1, and apoCIII and apoE were most abundantly present in H4 and H5. HDL-associated antioxidant enzymes such as lecithin-cholesterol acyltransferase, lipoprotein-associated phospholipase A2, and paraoxonase 1 were most abundant in H4 and H5. Lipoprotein isoforms were analyzed in each subfraction by using matrix-assisted laser desorption-time-of flight mass spectrometry. To quantify other proteins in the HDL subfractions, we used the isobaric tags for the relative and absolute quantitation approach followed by nanoflow liquid chromatography-tandem mass spectrometry analysis. Most antioxidant proteins detected were found in H4 and H5. The ability of each subfraction to induce cholesterol efflux from macrophages increased with increasing HDL electronegativity, with the exception of H5, which promoted the least efflux activity. In conclusion, anion-exchange chromatography is an attractive method for separating HDL into subfractions with distinct lipoprotein compositions and biologic activities. By comparing the properties of these subfractions, it may be possible to uncover HDL-specific proteins that play a role in disease. PMID- 24171626 TI - Methoxy-directed aryl-to-aryl 1,3-rhodium migration. AB - Through-space metal/hydrogen shift is an important strategy for transition-metal catalyzed C-H bond activation. Here we describe the synthesis and characterization of a Rh(I) 2,6-dimethoxybenzoate complex that underwent stoichiometric rearrangement via a highly unusual 1,3-rhodium migration. This aryl-to-aryl 1,3-Rh/H shift was also demonstrated in a Rh(I)-catalyzed decarboxylative conjugate addition to form a C-C bond at a meta position instead of the ipso-carboxyl position. A deuterium-labeling study under the conditions of Rh(I)-catalyzed protodecarboxylation revealed the involvement of an ortho-methoxy group in a multistep pathway of consecutive sp(3) and sp(2) C-H bond activations. PMID- 24171628 TI - Aminocarbonylation of 4-iodo-1H-imidazoles with an amino acid amide nucleophile: synthesis of constrained H-Phe-Phe-NH2 analogues. AB - A simple and an expedient process to prepare 5-aryl-1-benzyl-1H-imidazole-4 carboxamides by the aminocarbonylation of 5-aryl-4-iodo-1H-imidazoles using ex situ generation of CO from Mo(CO)6 with an amino acid amide nucleophile is reported. Furthermore, a microwave-assisted protocol for the direct C-5 arylation of 1-benzyl-1H-imidazole and a regioselective C-4 iodination method to acquire starting material for our aminocarbonylation are presented. The method can be used to prepare imidazole based peptidomimetics, herein exemplified by the synthesis of constrained H-Phe-Phe-NH2 analogues. PMID- 24171629 TI - Learning from experience. PMID- 24171630 TI - Participation in action research. PMID- 24171631 TI - An action research approach to practice, service and legislative change. AB - AIMS: To describe the action research approach taken to engage a multidisciplinary group of health professionals and managers from five rural health services with government officers in redesigning their emergency care services and informing legislative change. BACKGROUND: The diminishing size of the medical workforce across rural Victoria in Australia captured the Victorian state government's attention when this threatened the sustainability of emergency care services in rural and remote hospitals in 2006. The government funded the collaborative practice model pilot between 2006 and 2008 to develop and test an alternative model of emergency care service in which nurses practised at a more advanced and autonomous level. DATA SOURCES: Data were sourced from a combination of interviews, focus groups and patient records. REVIEW METHODS: Qualitative data were analysed using convergent interview and thematic analysis. Quantitative data were analysed using frequencies and cross tabulations. DISCUSSION: The three critical success factors owing to action research are presented. It provided a politically safe approach to service, policy and legislative change, ensured collaboration permeated the endeavour and helped to shift the focus from a technical to an emancipatory approach to action research. CONCLUSION: Action research was key to the success achieved by the participants in changing clinical practice, service delivery and the Victorian Drugs Poisons and Controlled Substances Act (1981) to authorise registered nurses to supply medicines. IMPLICATIONS FOR PRACTICE: This paper offers an approach that nurses in practice, management and government can take to drive changes at practice, service and legislative levels in advanced nursing practice. PMID- 24171632 TI - Creating communicative spaces in an action research study. AB - AIM: To argue that creating communicative spaces in an action research study gave voice to young mothers who may otherwise have remained voiceless. BACKGROUND: Underpinning the concept of the communicative space in action research is the critical social theory of Jurgen Habermas, in particular, his theory of communicative action and the ideal speech situation. The author argues that in collaborative research, the successful creation of a communicative space is vital in enabling equitable and discursive speech to take place. REVIEW METHODS: This is a methodological paper. DISCUSSION: This approach provided a discursive space to participants who ordinarily may not have interacted, and led to the sharing of different perceptions and understandings that may not otherwise have been possible. This research pointed to the possibility of the ideal speech situation, and the value of opening up a communicative space for researchers and participants. CONCLUSION: Action research for professionals is a sometimes messy and time-consuming process. However, it is a rewarding approach that uncovers layers of interpretations and understanding that have meaning for the participants involved. IMPLICATIONS FOR PRACTICE/RESEARCH: The creation of communicative spaces has the potential to enrich nursing research because of its participatory nature, making it more likely that solutions reached will have meaning to people. PMID- 24171633 TI - 'To be honest, I haven't even thought about it' - recruitment in small-scale, qualitative research in primary care. AB - AIM: To review strategies for successful recruitment in small-scale, qualitative research in primary care by exploring those used in a variety of settings and providing a reflective analysis of the strategies used in one such study. BACKGROUND: Recruitment of participants in small-scale, qualitative research in primary care is problematic. Researchers need to be more aware of the issues involved, but there is little practical guidance available to help them devise efficient strategies for maximising recruitment. DATA SOURCES: This paper draws on a study conducted in the Highlands of Scotland examining the emotional wellbeing of pregnant and non-pregnant women. This was a qualitative study using diaries and interviews over a period of nine months. Ten women were recruited over a period of more than two years. REVIEW METHODS: The author reviews the strategies for successful recruitment based on both a review of the available literature as well as the experience of one study. DISCUSSION: Recruitment of subjects to a study is one of the major elements of a research proposal and requires significant effort, yet there is little to guide researchers through this difficult process. The challenge of recruitment is seldom debated and studies rarely report problems encountered or outline approaches that proved particularly successful. The importance of successful recruitment is discussed and the arguably typical recruitment difficulties encountered by researchers conducting a study in the Highlands of Scotland are outlined. The elements that comprised successful recruitment in this and other studies are appraised. CONCLUSION: Although focused specifically on recruitment in small-scale, qualitative studies in primary care, this paper raises broader issues about the recruitment of participants in all types of research. Recruitment has implications for the trustworthiness and dependability of the data and hence the findings of research. Despite this, there remains a lack of evidence about what enhances research recruitment, leaving researchers to rely on guesswork and anecdotes. In a climate of evidence-based practice, researchers should be encouraged to include a formal evaluation of recruitment strategies in their studies and to report their findings. IMPLICATIONS FOR PRACTICE/RESEARCH: As recruitment has implications for the trustworthiness and dependability of research, researchers need to consider a wide range of recruitment strategies and include a formal evaluation of their recruitment strategies when reporting on their research. PMID- 24171634 TI - The barriers to and benefits of conducting Q-sorts in the classroom. AB - AIM: To outline the barriers to and benefits of using Q methodology in a classroom. BACKGROUND: Q methodology has been established as a systematic way to measure subjectivity that is consistent with the naturalistic paradigm. While it is often confused with quantitative methods, it provides the qualitative researcher with powerful tools to investigate the diverse subjective experiences and perceptions of participants. DATA SOURCES: Reflections in this paper stem from the experiences of the authors and are supported by literature. DISCUSSION: Barriers to conducting a Q-sort activity in the classroom are context dependent and may include limitations of the environment, time constraints as well as issues with comprehension. Despite these barriers, using a classroom for the activity can also enhance student learning, increase participation in research, clarify instructions, enrich study feedback and promote accessibility of the study population. CONCLUSION: With an understanding of potential pitfalls of using this methodology in the classroom setting, nurse researchers can develop strategies to reduce these barriers and enhance the quality of future research. IMPLICATIONS FOR PRACTICE/RESEARCH: Q-methodology is an alternate way of measuring the subjective views of individuals in a variety of settings such as clinical practice, research and educational institutions. Q-sorts may be used for research and/or classroom activities because the activity can promote discussion related to the content of a class. If using an activity like this one, educators and researchers need to be mindful of potential barriers to sorting in order to minimise them and maximise the potential of the activity. PMID- 24171635 TI - Data-analysis issues in a phenomenographic investigation of information literacy in nursing. AB - AIM: To explore two contrasting methods of phenomenographic data analysis. BACKGROUND: Phenomenography is a still-uncommon but increasingly used methodology based on qualitative interviews that allows experiences to be categorised and put into a descriptive structure for use in developing educational interventions. There are two different approaches in the literature to analysing data: the Marton and Akerlind methods. DATA SOURCES: A doctoral research project investigating the role of information literacy in evidence-based practice in nursing. REVIEW METHODS: The phenomenographic study involves open-ended interviews in which participants are asked to describe their 'life-world' where the phenomenon is experienced, covering the contexts in which it is experienced and how it is experienced. The researcher attempts to develop statements from the interview transcripts that describe representative ways of experiencing the phenomenon in the form of 'categories of description'. A category of description represents a qualitatively different way of experiencing a phenomenon. DISCUSSION: This article discusses the reasons for adopting phenomenography, phenomenography's epistemological assumptions, and the strengths and weaknesses of the two different data-analysis methods. CONCLUSION: Phenomenography's strength is its ability to develop logical structures that give a picture of the experience of a phenomenon while being able to read into the structure as much of the complexity of that experience as is consciously and practically possible. IMPLICATIONS FOR PRACTICE/RESEARCH: One method, described as the 'Akerlind' method, emerged as the appropriate method for phenomenographic studies in nursing. PMID- 24171636 TI - Congruence between the Indian Diabetes Risk Score and Australian Type 2 Diabetes Risk Assessment tool screening in Asian-Indians. AB - AIM: To evaluate the performance of the simplified Indian Diabetes Risk Score (IDRS) and the Australian Type 2 Diabetes Risk Assessment (AUSDRISK) instruments in predicting diabetes in Indian-Australians. BACKGROUND: Screening for diabetes in the general community is common and numerous scoring systems are being used to predict the risk of diabetes. DATA SOURCES: For this cross-sectional study, data were obtained from people attending the Australia India Friendship Fair. REVIEW METHODS: Data relating to risk factors for diabetes were obtained using a questionnaire and a random blood glucose level. The IDRS and AUSDRISK scores were calculated. Student's t-test, Pearson chi-square, and receiver-operating characteristic curves were used to compare the performance of the predictive scores. DISCUSSION: Data were analysed for 136 participants: 28 per cent of individuals considered to be low-risk and 35 per cent considered to be moderate risk according to AUSDRISK were classified as moderate-risk and high-risk respectively by IDRS. CONCLUSION: The two models were not congruent in predicting diabetes risk among Asian-Indians. IMPLICATIONS FOR PRACTICE/RESEARCH: The results of this study have significant implications for education relating to diabetes screening. PMID- 24171637 TI - Development of a factorial survey to explore restricting a child's movement for a clinical procedure. AB - AIM: To report on the development of a factorial survey to explore nurses' participation in restricting children's movement for clinical procedures in hospital. BACKGROUND: Exploration of implicit practices, such as restriction, is essential in ensuring that the care delivered to children addresses their developmental needs. DATA SOURCES: A questionnaire was developed that consisted of two sections: vignettes and the professional and personal characteristics of the nurse. It was sent to 166 nurses and 105 questionnaires were returned, resulting in a response rate of 63.3 per cent. REVIEW METHODS: The development of the factorial survey included identifying and determining the levels of the independent variables, identifying the dependent variable, writing the vignette frame and associated questions, and randomly generating vignettes. DISCUSSION: Reliability of the tool was established as a significant correlation was found for responses with Pearson's r=0.80. There was a small correlation between five of the 14 variables and the dependent variable 'likelihood of restricting a child for a clinical procedure'. CONCLUSION: A factorial survey was found to be a robust tool in exploring a sensitive issue, allowing for the inclusion of multiple variables for consideration in the analysis. IMPLICATIONS FOR RESEARCH/PRACTICE: The factorial survey enables rigorous exploration of the influences of personal and professional characteristics of a profession across a broad spectrum of clinical scenarios, and offers in-depth insight into the effect of differentiations in these characteristics on a variety of care delivery situations and how they influence behavioural intentions. PMID- 24171640 TI - Self-assembly of mesoscopic materials to form controlled and continuous patterns by thermo-optically manipulated laser induced microbubbles. AB - The formation of continuous patterns of nanostructured materials using directed self-assembly under external fields has generated considerable current research interest. We demonstrate for the first time such continuous patterning by inducing irreversible self-assembly leading to nucleation in mesocopic materials (inorganic, organic, and nanoparticles) using a tightly focused laser beam in an optical tweezers apparatus. A dense aqueous dispersion or solution of the material which has high absorption at the laser wavelength is taken in a sample holder so that some material is adsorbed on the top surface. A hot spot is created on the top surface when the adsorbed material absorbs the high intensity at the focus of the laser beam (a submicrometer sized spot), due to which a water vapor bubble is formed. This causes self-assembly of material around the bubble due to Gibbs-Marangoni convection and capillary flow after which the material eventually nucleates into a crystalline state. The bubble is "trapped" at the hot spot due to the temperature gradient around it and can be manipulated by thermal forces generated optically, so that the system may be described as a "thermo optical" tweezers. We translate the trapped bubble using the microscope sample holder stage of the apparatus so that the nucleation site of the material is simultaneously translated generating continuous patterns. We have demonstrated the technique using exotic inorganic materials such as soft oxometalates, an organic material such as glycine, and a fluorescent dye such as perylene as well as with carbon nanotubes. We have written patterns over lengths of nearly 1 mm at the rate of 1 Hz, with best resolution of about 4 MUm. The technique has potential for a wide range of applications ranging from solution processed printable electronics to controlled catalysis. PMID- 24171641 TI - Factors predictive of clinical pregnancy in the first intrauterine insemination cycle of 306 couples with favourable female patient characteristics. AB - The objective of this study was to evaluate the factors predictive of clinical pregnancy in the first superovulation/intrauterine insemination (SO/IUI) cycle of couples with favourable female characteristics. We analyzed retrospectively the first SO/IUI cycle of 306 infertile couples with mild male factor infertility and unexplained infertility. The women had a favourable prognosis in terms of ovarian reserve. Univariate logistic regression analyses identified body mass index (BMI) [odds ratio (OR) = 0.9, P = 0.014], sperm concentration [OR = 1.007, P = 0.007] and inseminating motile sperm count (IMC) [OR = 1.007, P = 0.032] as significant predictive factors of clinical pregnancy. Multivariate logistic regression analysis identified BMI [OR = 0.87, P = 0.008] and sperm concentration [OR = 1.008, P = 0.011] as significant factors. Pregnant and non-pregnant groups did not differ significantly in terms of the age and smoking status of the woman, duration and type of infertility, length of the stimulation, total gonadotropin dosage or antral follicle count. Of the female characteristics investigated, BMI was the most significant predictive factor of clinical pregnancy in the first SO/IUI cycle of couples with unexplained or mild male factor infertility and favourable female characteristics. In overweight women, weight loss should be advised before starting SO/IUI. Sperm concentration and IMC were significant male predictive factors for clinical pregnancy in the first SO/IUI. PMID- 24171642 TI - Game-theory-based search engine to automate the mass assignment in complex native electrospray mass spectra. AB - Electrospray ionization coupled to native mass spectrometry (MS) has evolved into an important tool in structural biology to decipher the composition of protein complexes. However, the mass analysis of heterogeneous protein assemblies is hampered because of their overlapping charge state distributions, fine structure, and peak broadening. To facilitate the mass analysis, it is of importance to automate preprocessing raw mass spectra, assigning ion series to peaks and deciphering the subunit compositions. So far, the automation of preprocessing raw mass spectra has not been accomplished; Massign was introduced to simplify data analysis and decipher the subunit compositions. In this study, we develop a search engine, AutoMass, to automatically assign ion series to peaks without any additional user input, for example, limited ranges of charge states or ion mass. AutoMass includes an ion intensity-dependent method to check for Gaussian distributions of ion series and an ion intensity-independent method to address highly overlapping and non-Gaussian distributions. The minimax theorem from game theory is adopted to define the boundaries. With AutoMass, the boundaries of ion series in the well-resolved tandem mass spectra of the hepatitis B virus (HBV) capsids and those of the mass spectrum from CRISPR-related cascade protein complex are accurately assigned. Theoretical and experimental HBV ion masses are shown in agreement up to ~0.03%. The analysis is finished within a minute on a regular workstation. Moreover, less well-resolved mass spectra, for example, complicated multimer mass spectra and norovirus capsid mass spectra at different levels of desolvation, are analyzed. In sum, this first-ever fully automatic program reveals the boundaries of overlapping ion peak series and can further aid developing high-throughput native MS and top-down proteomics. PMID- 24171643 TI - Green synthesis of silk fibroin-silver nanoparticle composites with effective antibacterial and biofilm-disrupting properties. AB - Natural polymer Bombyx mori silk fibroin is used as a biotemplate to produce silver nanoparticles in situ under light (both incandescent light and sunlight) at room temperature. Silk fibroin provides multiple functions in the whole reaction system, serving as the reducing agent of silver, and the dispersing and stabilizing agent of the resulted silver nanoparticles. As the reaction needs not any other chemicals and only uses light as power source, the synthetic route of silver nanoparticles reported here is rather environment-friendly and energy saving. The silk fibroin-silver nanoparticle composite prepared by this method can be stably stored in a usual environment (room temperature, exposure to light, and so forth) for at least one month. Such a silk fibroin-silver nanoparticle composite shows an effective antibacterial activity against the methicillin resistant Staphylococcus aureus (S. aureus) and subsequently inhibits the biofilm formation caused by the same bacterium. Moreover, a maturely formed biofilm created by methicillin-resistant S. aureus can be destroyed by the silk fibroin silver nanoparticle composite, which meets the demand of clinical application. Therefore, the silk fibroin-silver nanoparticle composite prepared by this clean and facile method is expected to be an effective and economical antimicrobial material in biomedical fields. PMID- 24171644 TI - Relative unidirectional translation in an artificial molecular assembly fueled by light. AB - Motor molecules present in nature convert energy inputs, such as a chemical fuel or incident photons of light, into directed motion and force biochemical systems away from thermal equilibrium. The ability not only to control relative movements of components in molecules but also to drive their components preferentially in one direction relative to each other using versatile stimuli is one of the keys to future technological applications. Herein, we describe a wholly synthetic small-molecule system that, under the influence of chemical reagents, electrical potential, or visible light, undergoes unidirectional relative translational motion. Altering the redox state of a cyclobis(paraquat-p-phenylene) ring simultaneously (i) inverts the relative heights of kinetic barriers presented by the two termini--one a neutral 2-isopropylphenyl group and the other a positively charged 3,5-dimethylpyridinium unit--of a constitutionally asymmetric dumbbell, which can impair the threading/dethreading of a [2]pseudorotaxane, and (ii) controls the ring's affinity for a 1,5-dioxynaphthalene binding site located in the dumbbell's central core. The formation and subsequent dissociation of the [2]pseudorotaxane by passage of the ring over the neutral and positively charged termini of the dumbbell component in one, and only one, direction relatively defined has been demonstrated by (i) spectroscopic ((1)H NMR and UV/vis) means and cyclic voltammetry as well as with (ii) DFT calculations and by (iii) comparison with control compounds in the shape of constitutionally symmetrical [2]pseudorotaxanes, one with two positively charged ends and the other with two neutral ends. The operation of the system relies solely on reversible, yet stable, noncovalent bonding interactions. Moreover, in the presence of a photosensitizer, visible-light energy is the only fuel source that is needed to drive the unidirectional molecular translation, making it feasible to repeat the operation numerous times without the buildup of byproducts. PMID- 24171647 TI - Combination of a new chiroptical probe and theoretical calculations for chirality detection of primary amines. AB - A method to determine absolute configurations of primary amines by combined use of a chiroptical probe 1 and theoretical calculations is reported. Probe 1 is linked to chiral primary amines yielding 1-amine conjugates, which exhibited exciton coupled circular dichroism in the m-quaterphenyl chromophores. The ratios between the P and M conformers of the 1-amine conjugates, which are calculated with DFT, were correlated highly with the sign and amplitude of the observed CD spectra. PMID- 24171648 TI - High-precision tracking of brownian boomerang colloidal particles confined in quasi two dimensions. AB - In this article, we present a high-precision image-processing algorithm for tracking the translational and rotational Brownian motion of boomerang-shaped colloidal particles confined in quasi-two-dimensional geometry. By measuring mean square displacements of an immobilized particle, we demonstrate that the positional and angular precision of our imaging and image-processing system can achieve 13 nm and 0.004 rad, respectively. By analyzing computer-simulated images, we demonstrate that the positional and angular accuracies of our image processing algorithm can achieve 32 nm and 0.006 rad. Because of zero correlations between the displacements in neighboring time intervals, trajectories of different videos of the same particle can be merged into a very long time trajectory, allowing for long-time averaging of different physical variables. We apply this image-processing algorithm to measure the diffusion coefficients of boomerang particles of three different apex angles and discuss the angle dependence of these diffusion coefficients. PMID- 24171649 TI - Syphilitic outer retinopathy. AB - PURPOSE: To present ocular syphilis masquerading as an outer retinopathy. METHODS: Retrospective case series, including 2 patients with features of acute zonal occult outer retinopathy (AZOOR) complex diseases. RESULTS: Laboratory results confirmed the diagnosis of syphilis in the 2 cases. Therapy with intravenous penicillin led to an improvement in symptoms, visual acuity, and ancillary testing. CONCLUSIONS: The protean ophthalmic presentations of syphilis are well known. However, AZOOR-like presentation has not been described previously. This atypical outer retinopathy should alert physicians to keep syphilis in the differential diagnosis of any inflammatory disorder. PMID- 24171650 TI - Visual loss associated with rickettsial disease. AB - Abstract Purpose: To characterize and analyze ocular involvement associated with visual loss in a cohort of patients with rickettsial disease. METHODS: Retrospective study of 16 eyes of 14 patients. RESULTS: Mean initial visual acuity (VA) was 20/63 (range, 20/800-20/25). White retinal lesions infiltrating inner retina was the most common finding occurring in 14 eyes (87.5%). It was associated with a serous retinal detachment (SRD), accurately detectable by optical coherence tomography, in 11 eyes (78.6%). Other findings included optic neuropathy in 7 eyes (43.75%), cystoid macular edema in 1 eye (6.25%), branch retinal artery occlusion in 1 eye (6.25%), and choroidal neovascularization in 1 eye (6.25%). Thirteen patients were treated with a 2-week course of oral doxycycline 200 mg/day. Mean final VA was 20/40. CONCLUSIONS: Inner retinitis, associated with mild vitritis and SRD, and optic neuropathy are the most common vision-threatening ocular manifestations of rickettsial disease. PMID- 24171651 TI - Women's views of a fertility awareness and hormonal support approach to subfertility. AB - The aim of this study was to determine the satisfaction among subfertile women of a fertility awareness-based approach, including hormonal therapy to achieve a pregnancy by natural conception. Eighty four women attending a natural fertility service completed a postal questionnaire exploring (1) the acceptability of the sympto-thermal method and (2) the acceptability of using hormone support. Acceptability rates for the fertility charting, clinical service and clinical care were 64.9-91.6%. Acceptability rates were higher in women who did conceive or had experienced past recurrent miscarriages. Taking hormonal luteal support, by any method, was more acceptable for women over 35 years compared to those under 35 years (100% vs. 69.4%, p = 0.014). Vaginal pessaries were the preferred route of administration. The use of a fertility awareness-based method appears to be acceptable amongst subfertile women intending to conceive naturally. Most women using such a method for conception would be open to the use of hormonal support during the fertility cycle or early pregnancy. PMID- 24171652 TI - Modular access to N-substituted cis-3,5-diaminopiperidines. AB - A sequence of oxidative cleavage/reductive amination/hydrogenolysis enables the preparation of N-substituted cis-3,5-diaminopiperidines from a readily available bicyclic hydrazine. This new synthetic route provides a simple and general access to RNA-friendly fragments with a good chemical diversity. PMID- 24171653 TI - Hyaluronan and phospholipid association in biolubrication. AB - It is becoming increasingly clear that the outstanding lubrication of synovial joints is achieved by a sophisticated hierarchical structure of cartilage combined with synergistic actions of surface-active components present in the synovial fluid. In this work we focus on the association of two components of the synovial fluid, hyaluronan and dipalmitoyl phosphatidyl choline (DPPC), in bulk solution and at interfaces. We demonstrate that hyaluronan associates with DPPC vesicles and adsorbs to supported DPPC bilayers. The association structures formed at the interface are sufficiently stable to allow sequential adsorption of DPPC and hyaluronan, whereby promoting the formation of thick composite layers of these two components. The lubricating ability of such composite layers was probed by the AFM colloidal probe technique and found to be very favorable with low friction coefficients and high load bearing capacity. With DPPC as the last adsorbed component, a friction coefficient of 0.01 was found up to pressures significantly above what is encountered in healthy synovial joints. Hyaluronan as the last added component increases the friction coefficient to 0.03 and decreases the load bearing capacity somewhat (but still above what is needed in the synovial joint). Our data demonstrate that self-assembly structures formed by hyaluronan and phospholipids at interfaces are efficient aqueous lubricants, and it seems plausible that such self-assembly structures contribute to the exceptional lubrication of synovial joints. PMID- 24171654 TI - Label-free surface-enhanced Raman spectroscopy for sensitive DNA detection by DNA mediated silver nanoparticle growth. AB - This work designed a label-free strategy for surface-enhanced Raman spectroscopic (SERS) detection of target DNA on a peptide nucleic acid (PNA) modified glass slide. Upon hybridization of the PNA with target DNA, the surface became negatively charged and allowed the absorption of silver ions on the DNA skeleton. After chemical reduction by hydroquinone, the formed silver nanoparticles could be further grown with a silver enhancement step to amplify the detectable SERS signal by absorbing rhodamine 6G as a SERS reporter on a silver nanoparticle surface. The growth of silver nanoparticles was characterized with X-ray photoelectron spectroscopy and a scanning electron microscopic image. The label free SERS method achieved the detection of DNA with a linear range from 1.0 * 10( 10) to 1.0 * 10(-6) M and a detection limit of 45 pM. Through introducing a hybridization chain reaction to increase the DNA length, the Raman signal was further amplified, leading to a detection limit of 3.4 pM. This approach could discriminate perfectly matched target DNA from single-base mismatch DNA. This strategy possessed good capacity to integrate other amplification techniques for sensitive, high-throughput detection of genes. PMID- 24171655 TI - Establishment of pseudoternary LiO0.5-NiO-MnO2 phase diagram by combinatorial wet process. AB - A pseudoternary LiO0.5-NiO-MnO2 reaction phase diagram was established using a combinatorial high-throughput materials exploration process to find candidate electrode materials for lithium ion secondary batteries. Each powder library was prepared using our combinatorial wet process based on the electrostatic spray deposition method and results obtained at various firing temperatures in an air atmosphere and an oxide atmosphere. In the air atmosphere, newly composed single phase regions of a layered rock salt-type structure were only found around Li2MnO3 at 800 degrees C. On the other hand, in the oxide atmosphere, most of the powder library showed the multiphase of the spinel and layered rock salt type structure. PMID- 24171656 TI - Electron transfer from hexameric copper hydrides. AB - The octahedral core of 84-electron LCuH hexamers does not dissociate appreciably in solution, although their hydride ligands undergo rapid intramolecular rearrangement. The single-electron transfer proposed as an initial step in the reaction of these hexamers with certain substrates has been observed by stopped flow techniques when [(Ph3P)CuH]6 is treated with a pyridinium cation. The same radical cation has been prepared by the oxidation of [(Ph3P)CuH]6 with Cp*2Fe(+) and its reversible formation observed by cyclic voltammetry; its UV-vis spectrum has been confirmed by spectroelectrochemistry. The 48-electron trimer [(dppbz)CuH]3 has been prepared by use of the chelating ligand 1,2 bis(diphenylphosphino)benzene (dppbz). PMID- 24171659 TI - Photolithographic olefin metathesis polymerization. AB - Patterning functional materials is a central challenge across many fields of science. The ability to lithographically fabricate micro- and nanostructures has been one of the most impactful technological breakthroughs of the last century. In part due to the complexity of the chemical processes in photoresists, there is a limited variety of materials that can currently be patterned by photolithography. We report a negative tone photoresist using a photoactivated olefin metathesis catalyst, which can be quickly prepared in a one-pot synthesis from commercially available starting materials. The resist is based on a ruthenium vinyl ether complex, widely regarded as inactive toward olefin metathesis. The combination of this photoactivated catalyst with the fidelity and functional group tolerance of ruthenium-mediated olefin metathesis enables a host of new possibilities for photopatterned materials. PMID- 24171660 TI - Nanosized films based on multicharged small molecules and oppositely charged polyelectrolytes obtained by simultaneous spray coating of interacting species. AB - Simultaneous spraying of polyelectrolytes and small multicharged molecules of opposite charges onto a vertical substrate leads to continuous buildups of organic films. Here, we investigate the rules governing the buildup of two such systems: poly(allylamine hydrochloride)/sodium citrate (PAH/citrate) and PAH/sulfated alpha-cyclodextrin (PAH/CD-S). Special attention is paid to the film growth rate as a function of the spraying rate ratio of the two constituents. This parameter was varied by increasing the spraying rate of one of the constituents while maintaining constant that of the other. For PAH/CD-S systems, whatever the constituent (PAH or CD-S) whose spraying rate was kept fixed, the film growth rate first increases and passes through a maximum before decreasing when the spraying rate of the other constituent is increased. For PAH/citrate, the film growth rate reaches a plateau value when the spraying rate of citrate is increased while that of PAH is maintained constant, whereas when the spraying rate of citrate is maintained constant and that of PAH is increased, a behavior similar to that of PAH/CD-S is observed. The composition of PAH/CD-S sprayed films determined by X-ray photoelectron spectroscopy is independent of the spraying rate ratio of the two constituents and corresponds to one allylamine for one sulfate group. For PAH/citrate, by increasing the PAH/citrate spraying rate ratio, the carboxylic/nitrogen ratio in the film increases and tends to 1. There is thus always a deficit of carboxylic groups (COO(-) + COOH) with respect to amines (NH2 + NH3(+)). Yet, the ratio (COO(-)/NH3(+)) is always close to 1, ensuring exact charge compensation. The film morphology determined by atomic force microscopy is granular for PAH/CD-S and is smooth and liquid-like for PAH/citrate. A model based on strong (respectively weak) interactions between PAH and CD-S (respectively citrate) is proposed to explain these features. PMID- 24171661 TI - Asymmetric three-component domino reaction: an original access to chiral nonracemic 1,3-thiazin-2-ones. AB - A new asymmetric three-component domino process, based on a diastereoselective hetero-Diels-Alder reaction, involving an aldehyde, an alkene, and a chiral thiocarbamate was developed. The chiral auxiliary is directly removed during this process, leading to enantioenriched 2H-1,3-thiazin-2-ones with up to 96% ee. PMID- 24171662 TI - Examination of tyrosine/adenine stacking interactions in protein complexes. AB - The pi-stacking interactions between tyrosine amino acid side chains and adenine bearing ligands are examined. Crystalline protein structures from the protein data bank (PDB) exhibiting face-to-face tyrosine/adenine arrangements were used to construct 20 unique 4-methylphenol/N9-methyladenine (p-cresol/9MeA) model systems. Full geometry optimization of the 20 crystal structures with the M06-2X density functional theory method identified 11 unique low-energy conformations. CCSD(T) complete basis set (CBS) limit interaction energies were estimated for all of the structures to determine the magnitude of the interaction between the two ring systems. CCSD(T) computations with double-zeta basis sets (e.g., 6 31G*(0.25) and aug-cc-pVDZ) indicate that the MP2 method overbinds by as much as 3.07 kcal mol(-1) for the crystal structures and 3.90 kcal mol(-1) for the optimized structures. In the 20 crystal structures, the estimated CCSD(T) CBS limit interaction energy ranges from -4.00 to -6.83 kcal mol(-1), with an average interaction energy of -5.47 kcal mol(-1), values remarkably similar to the corresponding data for phenylalanine/adenine stacking interactions. Geometry optimization significantly increases the interaction energies of the p cresol/9MeA model systems. The average estimated CCSD(T) CBS limit interaction energy of the 11 optimized structures is 3.23 kcal mol(-1) larger than that for the 20 crystal structures. PMID- 24171663 TI - Direct orbital puncture of the cavernous sinus for the treatment of a carotid cavernous dural AV fistula with a concomitant venous/lymphatic malformation. AB - A 37- year old male with a long history of a left orbital venous/lympathic malformation presented with ocular injection, increased proptosis and reduced left vision. Angiography demonstrated a carotid cavernous dural AV fistula combined with a concomitant venous/lymphatic malformation. After attempts at transvenous embolization, a direct uncomplicated transorbital puncture of the cavernous sinus via a lateral orbitotomy was performed with complete resolution of ocular symptoms. PMID- 24171664 TI - Ossifying cystic odontogenic and Schneiderian choristoma of the orbit. AB - A 12-year-old girl presented with a left infraorbital lesion, causing upward globe displacement. Imaging confirmed a mass between the globe and the orbital floor. The lesion was removed via a sub-ciliary approach and histology revealed a a mature tooth along with a periodontal ligament, oral-type mucinous glands and bone. Six years later a mass recurred at exactly the same site and on this occasion, revealed cysts containing mucin and lined by Schneiderian type epithelium. A rather complex combination of a tooth, lamellar bone, mucinous oral type glands and Schneiderian cystic epithelium is highly unusual and we have called the lesion "ossifying cystic odontogenic and Schneiderian choristoma of the orbit." PMID- 24171665 TI - Nigerian bonny light crude oil induces endocrine disruption in male rats. AB - Exposure to Nigerian bonny light crude oil (BLCO) in the southern part of Nigeria has been reported to be associated with reproductive toxicity, but there is paucity of information on its interference with steroidogenesis. This study investigated the influence of BLCO on testicular steroidogenesis and plasma levels of hormones from the pituitary and thyroid components of the brain pituitary-testicular axis. Adult male Wistar rats were orally treated with BLCO dissolved in corn oil at 0, 200 and 800 mg/kg for 7 days. Immunoblot analysis revealed that BLCO exposure suppressed steroid acute regulatory protein and androgen-binding protein expression with concomitant decrease in 3beta hydroxysteroid dehydrogenase (HSD) and 17beta-hydroxysteroid dehydrogenase activities. BLCO exposure significantly decreased plasma concentrations of follicle-stimulating hormone, luteinizing hormone, prolactin and intratesticular testosterone, but elevated thyrotropin, triiodothyronine and thyroxine above the control values. The data presented herein indicate that undue exposure to BLCO has an inhibitory effect on testicular steroidogenesis. The underlying mechanisms for BLCO-induced testicular dysfunction may involve its disruptive effect on the brain-pituitary-testicular axis. These observations highlight the potential risk to public health for a population where, unfortunately, oil spillages occur frequently. PMID- 24171666 TI - Synthesis of HCV replicase inhibitors: base-catalyzed synthesis of protected alpha-hydrazino esters and selective aerobic oxidation with catalytic Pt/Bi/C for synthesis of imidazole-4,5-dicarbaldehyde. AB - A robust convergent synthesis of the prodrugs of HCV replicase inhibitors 1-5 is described. The central 5H-imidazo[4,5-d]pyridazine core was formed from acid catalyzed cyclocondensation of an imidazole-4,5-dicarbaldehyde (20) and a alpha hydrazino ester, generated in situ from the bis-BOC-protected precursors 25 and 33. The acidic conditions not only released the otherwise unstable alpha hydrazino esters but also were the key to avoid facile decarboxylation to the parent drugs from the carboxylic ester prodrugs 1-5. The bis-BOC alpha-hydrazino esters 25 and 33 were prepared by addition of ester enolates (from 23 and 32) to di-tert-butyl azodicarboxylate via catalysis with mild inorganic bases, such as Li2CO3. A selective aerobic oxidation with catalytic 5% Pt-Bi/C in aqueous KOH was developed to provide the dicarbaldehyde 20 from the diol 27. PMID- 24171668 TI - Oxidative and stepwise grafting of dopamine inner-sphere redox couple onto electrode material: electron transfer activation of dopamine. AB - The immobilization of dopamine, a neurotransmitter, onto macroelectrode and microelectrode surfaces has been performed following two strategies. The first consists of a one-step grafting based on electrochemical oxidation of an amino group in acidic media. The second is a stepwise process starting with electrochemical grafting of diazonium, leading to the attachment of aryl layer bearing an acidic headgroup, followed by chemical coupling leading to immobilized dopamine molecules onto the electrode surface. Electrochemical, infrared (IR) spectroscopy, and X-ray photoelectron spectroscopy (XPS) analyses evidence that both methods are suitable for the immobilization of dopamine onto millimetric and micronic electrodes. The electrochemical responses of modified electrodes demonstrate that the electroactivity of the attached dopamine layer appears unaffected by the nature of the spacer, alkyl or aryl layers, suggesting that the communication, through tunneling, between the attached dopamine and the electrode is possible. More interestingly, the dopamine-modified electrode exhibits electron transfer activation toward dopamine in solution. As a result, not only does the dopamine modified electrode yield a fast electron transfer with lower DeltaE(p) (30 mV) than the majority of pretreatment procedures but also the DeltaE(p) is as small as that observed for more complex surface treatments. PMID- 24171667 TI - The role of CCL5 in the ability of adipose tissue-derived mesenchymal stem cells to support repair of ischemic regions. AB - Mesenchymal stem cells (MSC) are multipotent and possess high proliferative activity, and thus are thought to be a reliable cell source for cell therapies. Here, we isolated MSC from adult tissues--bone marrow (BM-MSC), dental tissue (DT MSC), and adipose tissue (AT-MSC)--to compare how autotransplantation of these MSC effectively supports the repair of bone fracture and ischemic tissue. An analysis by in vitro differentiation assays showed no significant difference among these MSC. The degree of calcification at the joint region of bone fracture was higher in mice transplanted with AT-MSC than in mice transplanted with BM-MSC or DT-MSC. To compare the abilities of MSC, characterize how those MSC affect the repair of ischemic tissue, vascular occlusion was performed by ligation of the femoral artery and vein. Of note, the blood flow in the ischemic region rapidly increased in mice injected with AT-MSC, as contrasted with mice injected with BM- or DT-MSC. The number of CD45- and F4/80-positive cells at the femoral region was higher in AT-MSC recipients than in recipients of BM-MSC or DT-MSC. We evaluated the mRNA expression of angiogenic and migration factors in MSC and found the expression of CCL5 mRNA was higher in AT-MSC than in BM-MSC or DT-MSC. Transplantation of AT-MSC with impaired expression of CCL5 clearly showed a significant delay in the recovery of blood flow compared with the control. These findings have fundamental implications for the modulation of AT-MSC in the repair of vasculature and bone fracture. PMID- 24171669 TI - The chemokine receptor 5 delta32 polymorphism and type 1 diabetes, Behcet's disease, and asthma: a meta-analysis. AB - OBJECTIVE: The aim of this study was to determine whether the functional chemokine receptor 5 delta32 (CCR5-Delta32) polymorphism is associated with susceptibility to type 1 diabetes (T1D), Behcet's disease (BD), and asthma. RESULTS: Fourteen studies encompassing 9,656 cases and 12,431 controls, including 6 on T1D, 5 on BD, and 3 on asthma, were available for meta-analysis. The meta analysis showed a significant negative association between T1D and the CCR5 Delta32 allele (odds ratio [OR] = 0.854, 95% confidence interval [CI] = 0.800 0.912, p = 2.2 * 10-7). Stratification by ethnicity and analysis of the Delta32Delta32 + Delta32W genotype indicated a significant negative association between the CCR5-Delta32 allele and T1D in Europeans (OR = 0.857, 95% CI = 0.802 0.915, p = 3.5 * 10-8; OR = 0.896, 95% CI = 0.808-0.932, p = 9.3 * 10-6, respectively). The meta-analysis showed a positive association between BD and the Delta32Delta32 + Delta32W genotype (OR = 1.403, 95% CI = 1.008-1.954, p = 0.045). Stratification by HLA-B51 status indicated an association between the CCR5 Delta32 allele and HLA-B51-positive BD, but not HLA-B51-negative BD (OR = 1.619, 95% CI = 1.070-2.451, p = 0.023; OR = 1.036, 95% CI = 0.674-1.593, p = 0.872, respectively). No association was found between the CCR5-Delta32 polymorphism and asthma. CONCLUSIONS: This meta-analysis demonstrates that the CCR5-Delta32 polymorphism acts as a protective factor in T1D development in Europeans, and a risk factor for BD among HLA-B51 carriers. However, no association was found between the CCR5-Delta32 polymorphism and asthma. PMID- 24171670 TI - Second harmonic light scattering from the surface of colloidal objects: theory and applications. AB - Because properties of colloids containing micro- and nano-particles are much influenced by the structure of, and interactions occurring at, the particle surface, it is important to be able to characterize the particle surface in situ and nondestructively. Nonlinear light scattering from colloidal particles has been developed into a powerful and versatile technique for characterizing particle surfaces since the first demonstration of the detection of second harmonic generation from molecules adsorbed on micrometer-sized colloidal particles by Eisenthal and co-workers (Wang, H.; Yan, E. C. Y.; Borguet, E.; Eisenthal, K. B. Second Harmonic Generation from the Surface of Centrosymmetric Particles in Bulk Solution. Chem. Phys. Lett. 1996, 259, 15-20). At present, second harmonic light scattering from the particle surface can be quantitatively described by theoretical models and used to measure the adsorption kinetics, molecular structure, and reaction rates at the surfaces of a variety of micrometer- to nanometer-sized particles, including biological cells. PMID- 24171672 TI - Melatonin attenuates phenytoin sodium-induced DNA damage. AB - Phenytoin sodium (PHT Na(+)) is a potent antiepileptic drug against epileptic seizures and is used as a prophylactic treatment in traumatic brain injury. PHT Na(+) leads to the formation of reactive oxygen species (ROS), and DNA is a crucial molecular target of ROS-initiated toxicity. Melatonin and its metabolites possess free-radical-scavenging activity. We therefore designed this study to investigate the potential protective effect of melatonin against PHT Na(+) induced DNA damage by using the comet assay in a rat model in vivo. Thirty-three 3-month-old male Wistar rats were divided into five groups of control treated with isotonic sodium chloride (a single injection of isotonic sodium chloride and 100 uL in drinking water for 10 days), ethanol treated (in drinking water for 10 days containing 100 uL of ethanol in each 300-mL drinking bottle), melatonin treated (4 mg/kg body weight [b.w.] intraperitoneally [i.p.] at the start, in drinking water for 10 days), PHT Na(+) treated (a single i.p. injection of 50 mg/kg) and PHT Na(+) (50 mg/kg b.w., single i.p.) and melatonin (4 mg/kg b.w. i.p. at the start and 4 mg/kg in drinking water for 10 days) cotreated. To determine the protective effects of melatonin, the comet assay was performed using lymphocytes isolated in different time intervals (0, 15, 30, 45 and 60 minutes) from each group of animals. On days 1, 3, 7 and 10, blood samples were taken and the comet assay technique was performed. Our present data suggest that melatonin reversed PHT Na(+)-induced DNA damage. PMID- 24171673 TI - Rhodium-catalyzed asymmetric addition of arylboronic acids to beta-nitroolefins: formal synthesis of (S)-SKF 38393. AB - An efficient enantioselective addition of an array of arylboronic acids to various beta-nitrostyrenes catalyzed by a novel and reactive rhodium-diene catalyst (S/C up to 1000) was developed, providing beta,beta-diarylnitroethanes in good to high yields (62-99%) with excellent enantioselectivities (85-97% ee). The method was extended to 2-heteroarylnitroolefins and 2-alkylnitroolefins similarly providing the desired products with high enantioselectivities and yields. The usefulness of this method was demonstrated in the formal synthesis of the enantiomer of the dopamine receptor agonist and antagonist, SKF 38393. PMID- 24171674 TI - Prebiotic systems chemistry: new perspectives for the origins of life. PMID- 24171676 TI - Denosumab and atypical femoral fractures. PMID- 24171675 TI - 2-stage revision recommended for treatment of fungal hip and knee prosthetic joint infections. AB - BACKGROUND AND PURPOSE: Fungal prosthetic joint infections are rare and difficult to treat. This systematic review was conducted to determine outcome and to give treatment recommendations. PATIENTS AND METHODS: After an extensive search of the literature, 164 patients treated for fungal hip or knee prosthetic joint infection (PJI) were reviewed. This included 8 patients from our own institutions. RESULTS: Most patients presented with pain (78%) and swelling (65%). In 68% of the patients, 1 or more risk factors for fungal PJI were found. In 51% of the patients, radiographs showed signs of loosening of the arthroplasty. Candida species were cultured from most patients (88%). In 21% of all patients, fungal culture results were first considered to be contamination. There was co-infection with bacteria in 33% of the patients. For outcome analysis, 119 patients had an adequate follow-up of at least 2 years. Staged revision was the treatment performed most often, with the highest success rate (85%). INTERPRETATION: Fungal PJI resembles chronic bacterial PJI. For diagnosis, multiple samples and prolonged culturing are essential. Fungal species should be considered to be pathogens. Co-infection with bacteria should be treated with additional antibacterial agents. We found no evidence that 1-stage revision, debridement, antibiotics, irrigation, and retention (DAIR) or antifungal therapy without surgical treatment adequately controls fungal PJI. Thus, staged revision should be the standard treatment for fungal PJI. After resection of the prosthesis, we recommend systemic antifungal treatment for at least 6 weeks-and until there are no clinical signs of infection and blood infection markers have normalized. Then reimplantation can be performed. PMID- 24171677 TI - Limb lengthening and peripheral nerve function-factors associated with deterioration of conduction. AB - BACKGROUND: and purpose Limb lengthening is performed for a diverse range of orthopedic problems. A high rate of complications has been reported in these patients, which include motor and sensory loss as a result of nerve damage. We investigated the effect of limb lengthening on peripheral nerve function. PATIENTS AND METHODS: 36 patients underwent electrophysiological testing at 3 points: (1) preoperatively, (2) after application of external fixator/corticotomy but before lengthening, and (3) after lengthening. The limb-length discrepancy was due to a congenital etiology (n = 19), a growth disturbance (n = 9), or a traumatic etiology (n = 8). RESULTS: 2 of the traumatic etiology patients had significant changes evident on electrophysiological testing preoperatively. They both deteriorated further with lengthening. 7 of the 21 patients studied showed deterioration in nerve function after lengthening, but not postoperatively, indicating that this was due to the lengthening process and not to the surgical procedure. All of these patients had a congenital etiology for their leg-length discrepancy. INTERPRETATION: As detailed electrophysiological tests were carried out before surgery, after surgery but before lengthening, and finally after completion of lengthening, it was possible to distinguish between the effects of the operation and the effects of lengthening on nerve function. The results indicate that the etiology, site (femur or tibia), and nerve (common peroneal or tibial) had a bearing on the risk of nerve injury and that these factors had a far greater effect than the total amount of lengthening. PMID- 24171678 TI - Complications after intramedullary nailing of femoral fractures in a low-income country. AB - BACKGROUND: Some surgeons believe that internal fixation of fractures carries too high a risk of infection in low-income countries (LICs) to merit its use there. However, there have been too few studies from LICs with sufficient follow-up to support this belief. We first wanted to determine whether complete follow-up could be achieved in an LIC, and secondly, we wanted to find the true microbial infection rate at our hospital and to examine the influence of HIV infection and lack of follow-up on outcomes. PATIENTS AND METHODS: 137 patients with 141 femoral fractures that were treated with intramedullary (IM) nailing were included. We compared outcomes in patients who returned for scheduled follow-up and patients who did not return but who could be contacted by phone or visited in their home village. RESULTS: 79 patients returned for follow-up as scheduled; 29 of the remaining patients were reached by phone or outreach visits, giving a total follow-up rate of 79%. 7 patients (5%) had a deep postoperative infection. All of them returned for scheduled follow-up. There were no infections in patients who did not return for follow-up, as compared to 8 of 83 nails in the group that did return as scheduled (p = 0.1). 2 deaths occurred in HIV-positive patients (2/23), while no HIV-negative patients (0/105) died less than 30 days after surgery (p = 0.03). INTERPRETATION: We found an acceptable infection rate. The risk of infection should not be used as an argument against IM nailing of femoral fractures in LICs. Many patients in Malawi did not return for follow-up because they had no complaints concerning the fracture. There was an increased postoperative mortality rate in HIV-positive patients. PMID- 24171679 TI - Acetabular dysplasia at the age of 1 year in children with neonatal instability of the hip. AB - BACKGROUND AND PURPOSE: As much as one-third of all total hip arthroplasties in patients younger than 60 years may be a consequence of developmental dysplasia of the hip (DDH). Screening and early treatment of neonatal instability of the hip (NIH) reduces the incidence of DDH. We examined the radiographic outcome at 1 year in children undergoing early treatment for NIH. SUBJECTS AND METHODS: All children born in Malmo undergo neonatal screening for NIH, and any child with suspicion of instability is referred to our clinic. We reviewed the 1-year radiographs for infants who were referred from April 2002 through December 2007. Measurements of the acetabular index at 1 year were compared between neonatally dislocated, unstable, and stable hips. RESULTS: The incidence of NIH was 7 per 1,000 live births. The referral rate was 15 per 1,000. 82% of those treated were girls. The mean acetabular index was higher in dislocated hips (25.3, 95% CI: 24.6-26.0) than in neonatally stable hips (22.7, 95% CI: 22.3-23.2). Girls had a higher mean acetabular index than boys and left hips had a higher mean acetabular index than right hips, which is in accordance with previous findings. INTERPRETATION: Even in children who are diagnosed and treated perinatally, radiographic differences in acetabular shape remain at 1 year. To determine whether this is of clinical importance, longer follow-up will be required. PMID- 24171680 TI - No superior performance of hydroxyapatite-coated acetabular cups over porous coated cups. AB - BACKGROUND AND PURPOSE: Hydroxyapatite (HA) coating is believed to improve bone implant ingrowth and long-term survival of prostheses. Recent studies, however, have challenged this view. Furthermore, HA particles may produce third-body wear and initiate aseptic loosening of implants. We report the performance of HA- and porous-coated acetabular cups in a prospective randomized trial. METHODS: This was an 8-year follow-up study of our previously published prospective randomized study to compare clinical outcomes, survival, periprosthetic bone mineral density, migration, and wear rates of HA- and porous-coated acetabular cups. Dual X-ray absorptiometry (DXA) and Ein Bild Roentgen Analyse (EBRA) measurements were used. 100 patients who underwent unilateral cementless total hip arthroplasty were randomized to either porous-coated cups or HA-coated cups. Patients were examined preoperatively and at 3, 6, and 9 months, and also 1, 3, and 8 years after surgery. 81 patients were available for 8-year follow-up, 40 with porous coated cups and 41 with HA-coated cups. RESULTS: Age, sex, bone mineral density, and clinical results (Harris hip score) were similar in the 2 groups. The survival, wear, and migration patterns of the cups were also similar in both groups. The results of periprosthetic bone mineral density scans in region of interest 2 was in favor of the porous-coated cups, but there were no differences between the 2 groups in all the remaining regions of interest. INTERPRETATION: HA coating had no statistically significant effect on clinical results, survival, wear, or migration at the 8-year follow-up. PMID- 24171681 TI - Cholesterol- and lanolin-rich diets may protect against steroid-induced osteonecrosis in rabbits. AB - BACKGROUND AND PURPOSE: It remains controversial how hypercholesterolemia influences the development of steroid-induced osteonecrosis (ON). We investigated the role of hypercholesterolemia induced by a cholesterol-rich diet on the development of ON in rabbits. METHODS: 40 adult male Japanese white rabbits were randomly divided into 2 groups. 20 rabbits were maintained on a cholesterol-rich diet for 2 weeks before receiving steroid treatment (the CHOL group). The other 20 rabbits were maintained on a standard diet (the control (CTR) group). 2 weeks after the start of the study, all 40 rabbits were injected with methylprednisolone acetate (MPSL) into the right gluteus medius muscle (20 mg/kg body weight). 2 weeks after the steroid injection, both the femora and humeri were examined histopathologically for the presence of ON. Hematological analysis of the serum lipid levels was performed every week. Based on the same protocol, we also investigated the effects of lanolin, a primary component of a cholesterol rich diet, in another group (the LA group). RESULTS: The incidence of ON in the CHOL group (3/20) was lower than that observed in the CTR group (15/20) (p < 0.001). During the whole experiment, the levels of total cholesterol and the ratio of low-density lipoprotein to high-density lipoprotein in the CHOL group were higher than those observed in the CTR group (p < 0.001). The LA group also had a lower incidence of ON (2/20), and the lipid levels in the LA group showed similar changes to those observed in the CHOL group. INTERPRETATION: Our findings suggest that preexisting hypercholesterolemia itself induced by a cholesterol rich diet does not increase the risk of developing steroid-induced ON, but rather seems to diminish it. Lanolin may be the active anti-ON component of the cholesterol diet. PMID- 24171682 TI - Sclerotherapy with polidocanol for treatment of aneurysmal bone cysts. AB - BACKGROUND AND PURPOSE: Recent data suggest that percutaneous sclerotherapy is a safe alternative to surgery for treatment of aneurysmal bone cysts (ABCs). We present our experience of this method. METHODS: We retrospectively analyzed data from 38 consecutive patients treated with repeated injections of polidocanol. Each injection consisted of 2-4 mg polidocanol per kg body weight. Radiological and clinical assessments were performed until healing. RESULTS: All cycts except 1 healed after a median of 4 (1-11) injections. A lesion failed to heal in 1 patient, who was operated. 3 patients experienced minor local inflammatory reactions. INTERPRETATION: Our results show that percutaneus sclerotherapy with polidocanol has high efficacy in the treatment of ABCs, with a low frequency of side effects. Our findings corroborate data presented in previous publications. We believe that the method will be especially valuable in ABCs of the pelvis and sacrum, where surgery is associated with considerable morbidity. PMID- 24171683 TI - Low accuracy of interpretation of rotator cuff MRI in patients with osteoarthritis. AB - BACKGROUND: Magnetic resonance imaging (MRI) is considered to be a valuable tool for the diagnosis of rotator cuff tears in patients with severe glenohumeral osteoarthritis who are indicated for total shoulder arthroplasty (TSA). We determined the sensitivity, specificity, and positive predictive value of MRI in diagnosing rotator cuff tears in such patients. METHODS: MRI reports of 100 patients who had completed a shoulder MRI prior to TSA were reviewed to determine the radiologists' interpretation of the MRI including the diagnosis, presence of a full-thickness cuff tear, and the presence of atrophy and/or fatty infiltration within the rotator cuff muscle bellies. Operative reports were used as a gold standard to determine whether a full-thickness rotator cuff tear was present. RESULTS: Preoperative MRI reports noted 33 of the 100 patients as having a full thickness rotator cuff tear, 17 of which had multiple tendon tears. 2 of the 33 patients with full tears on MRI were found to have full-thickness tears at surgery. The sensitivity, specificity, and positive predictive value for MRI detection of full-thickness tears were 100%, 68%, and 6% respectively, with a false-positive rate of 32% and an accuracy of 69%. INTERPRETATION: The study suggests that although MRI is highly sensitive, it has a low positive predictive value and moderately low specificity and accuracy in detecting full-thickness rotator cuff tears in patients with severe glenohumeral osteoarthritis. PMID- 24171684 TI - Pre- and postoperative quality of life in patients treated for scoliosis. AB - BACKGROUND AND PURPOSE: There have been few prospective reports on quality of life in patients treated surgically for scoliosis. We compared patients with idiopathic, congenital, and neuromuscular scoliosis. METHODS: Data on 9- to 20 year-old patients were collected from the SweSpine registry. EQ-5D and (for a subset) SRS-22r were assessed preoperatively and after 1 and 2 years. RESULTS: 211 patients had preoperative data: 168 with idiopathic, 11 with congenital, and 32 with neuromuscular scoliosis. Of the total, 158 patients responded to the 1 year follow-up and 149 responded to the 2-year follow-up. Preoperatively, the mean (SE) EQ-5D index was 0.76 (0.02) in the idiopathic group, 0.74 (0.07) in the congenital group, and 0.10 (0.06) in the neuromuscular group, and the SRS-22r index was 3.8 (0.1) in the idiopathic group, 4.0 (0.3) in the congenital group, and 3.3 (0.2) in the neuromuscular group. The mean EQ-5D increased by 0.06 points at 2 years in the idiopathic group, by 0.16 points in the congenital group, and by 0.15 points in the neuromuscular group. The mean SRS-22r index increased by 0.4 points at 2 years in the idiopathic group, by 0.4 points in the congenital group, and by 0.5 points in the neuromuscular group. The changes were statistically significant, with the exception of the congenital group. The number of patients who sustained at least 1 complication was 13 in the idiopathic group, 2 in the congenital group, and 9 in the neuromuscular group (p = 0.003). INTERPRETATION: The general quality of life in the idiopathic and neuromuscular group improved after surgery. PMID- 24171685 TI - Conversion to below-elbow cast after 3 weeks is safe for diaphyseal both-bone forearm fractures in children. AB - BACKGROUND: It is unclear whether it is safe to convert above-elbow cast (AEC) to below-elbow cast (BEC) in a child who has sustained a displaced diaphyseal both bone forearm fracture that is stable after reduction. In this multicenter study, we wanted to answer the question: does early conversion to BEC cause similar forearm rotation to that after treatment with AEC alone? CHILDREN AND METHODS: Children were randomly allocated to 6 weeks of AEC, or 3 weeks of AEC followed by 3 weeks of BEC. The primary outcome was limitation of pronation/supination after 6 months. The secondary outcomes were re-displacement of the fracture, limitation of flexion/extension of the wrist and elbow, complication rate, cast comfort, complaints in daily life, and cosmetics of the fractured arm. RESULTS: 62 children were treated with 6 weeks of AEC, and 65 children were treated with 3 weeks of AEC plus 3 weeks of BEC. The follow-up rate was 60/62 and 64/65, respectively with a mean time of 6.9 (4.7-13) months. The limitation of pronation/supination was similar in both groups (18 degrees for the AEC group and 11 degrees for the AEC/BEC group). The secondary outcomes were similar in both groups, with the exception of cast comfort, which was in favor of the AEC/BEC group. INTERPRETATION: Early conversion to BEC cast is safe and results in greater cast comfort. PMID- 24171686 TI - Atypical femoral fractures bilaterally in a patient receiving denosumab. PMID- 24171687 TI - Good results in postoperative and hematogenous deep infections of 89 stable total hip and knee replacements with retention of prosthesis and local antibiotics. AB - BACKGROUND: Deep postoperative and hematogenous prosthesis infections may be treated with retention of the prosthesis, if the prosthesis is stable. How long the infection may be present to preclude a good result is unclear. PATIENTS AND METHODS: We retrospectively studied 89 deep-infected stable prostheses from 69 total hip replacements and 20 total knee replacements. There were 83 early or delayed postoperative infections and 6 hematogenous. In the postoperative infections, treatment had started 12 days to 2 years after implantation. In the hematogenous infections, symptoms had been present for 6 to 9 days. The patients had been treated with debridement, prosthesis retention, systemic antibiotics, and local antibiotics: gentamicin-PMMA beads or gentamicin collagen fleeces. The minimum follow-up time was 1.5 years. We investigated how the result of the treatment had been influenced by the length of the period the infection was present, and by other variables such as host characteristics, infection stage, and type of bacteria. RESULTS: In postoperative infections, the risk of failure increased with a longer postoperative interval: from 0.2 (95% CI: 0.1-0.3) if the treatment had started >= 4 weeks postoperatively to 0.5 (CI: 0.2-0.8) if it had started at >= 8 weeks. The relative risk for success was 0.6 (CI: 0.3-0.95) if the treatment had started >= 8 weeks. In the hematogenous group, 5 of 6 infections had been treated successfully. INTERPRETATION: A longer delay before the start of the treatment caused an increased failure rate, but this must be weighed against the advantage of keeping the prosthesis. We consider a failure rate of < 50% to be acceptable, and we therefore advocate keeping the prosthesis for up to 8 weeks postoperatively, and in hematogenous infections with a short duration of symptoms. PMID- 24171688 TI - Adverse reaction to metal debris after ReCap-M2A-Magnum large-diameter-head metal on-metal total hip arthroplasty. AB - BACKGROUND AND PURPOSE: The clinical findings of adverse reaction to metal debris (ARMD) following large-diameter-head metal-on-metal total hip arthroplasty (LDH MoM THA) may include periarticular fluid collections, soft tissue masses, and gluteal muscle necrosis. The ReCap-M2a-Magnum LDH MoM THA was the most commonly used hip device at our institution from 2005 to 2012. We assessed the prevalence of and risk factors for ARMD with this device. METHODS: 74 patients (80 hips) had a ReCap-M2a-Magnum LDH MoM THA during the period August 2005 to December 2006. These patients were studied with hip MRI, serum chromium and cobalt ion measurements, the Oxford hip score questionnaire, and by clinical examination. The prevalence of ARMD was recorded and risk factors for ARMD were assessed using logistic regression models. The mean follow-up time was 6.0 (5.5-6.7) years. RESULTS: A revision operation due to ARMD was needed by 3 of 74 patients (3 of 80 hips). 8 additional patients (8 hips) had definite ARMD, but revision was not performed. 29 patients (32 hips) were considered to have a probable or possible ARMD. Altogether, 43 of 80 hips had a definite, probable, or possible ARMD and 34 patients (37 hips) were considered not to have ARMD. In 46 of 78 hips, MRI revealed a soft tissue mass or a collection of fluid (of any size). The symptoms clicking in the hip, local hip swelling, and a feeling of subluxation were associated with ARMD. INTERPRETATION: ARMD is common after ReCap-M2a-Magnum total hip arthroplasty, and we discourage the use of this device. Asymptomatic patients with a small fluid collection on MRI may not need instant revision surgery but must be followed up closely. PMID- 24171689 TI - Lower muscle regenerative potential in full-thickness supraspinatus tears compared to partial-thickness tears. AB - BACKGROUND AND PURPOSE: Rotator cuff tears are associated with secondary rotator cuff muscle pathology, which is definitive for the prognosis of rotator cuff repair. There is little information regarding the early histological and immunohistochemical nature of these muscle changes in humans. We analyzed muscle biopsies from patients with supraspinatus tendon tears. METHODS: Supraspinatus muscle biopsies were obtained from 24 patients undergoing arthroscopic repair of partial- or full-thickness supraspinatus tendon tears. Tissue was formalin-fixed and processed for histology (for assessment of fatty infiltration and other degenerative changes) or immunohistochemistry (to identify satellite cells (CD56+), proliferating cells (Ki67+), and myofibers containing predominantly type 1 or 2 myosin heavy chain (MHC)). Myofiber diameters and the relative content of MHC1 and MHC2 were determined morphometrically. RESULTS: Degenerative changes were present in both patient groups (partial and full-thickness tears). Patients with full-thickness tears had a reduced density of satellite cells, fewer proliferating cells, atrophy of MHC1+ and MHC2+ myofibers, and reduced MHC1 content. INTERPRETATION: Full-thickness tears show significantly reduced muscle proliferative capacity, myofiber atrophy, and loss of MHC1 content compared to partial-thickness supraspinatus tendon tears. PMID- 24171690 TI - Metabolism-directed structure optimization of benzimidazole-based Francisella tularensis enoyl-reductase (FabI) inhibitors. AB - 1. FabI is a potential antibiotic target against Francisella tularensis, which has been classified as a Category A biowarfare agent of high risk to public health. Our previous work demonstrated that N-benzyl benzimidazole compounds possess promising FabI inhibitory activity, but their druggability properties, including metabolic stability, are unknown. 2. The objective of this study was to characterize structure-metabolism relationships of a series of N-benzyl benzimidazole compounds to guide chemical optimization for better metabolic stability. To this end, metabolic stability data were obtained for 22 initial lead compounds using mouse hepatic microsomes. 3. Metabolic hotspots on the benzimidazole core structure as well as the benzyl ring were identified and verified by metabolite identification studies of four model compounds. Interestingly, the proposed structure-metabolism relationships did not apply to nine newly synthesized cyclopentane or oxacyclopentane derivatives of N-benzyl benzimidazole. 4. Subsequently, in silico quantitative structure-property relationship models were developed. Four molecular descriptors representing molecular polarity/polarisability, symmetry and size were identified to best explain variability in metabolic stability of different compounds. Multi-linear and non-linear regression models based on the selected molecular descriptors were developed and validated. 5. The structure-metabolism relationships for N-benzyl benzimidazole compounds should help optimization of N-benzyl benzimidazole compounds for better pharmacokinetic behavior. PMID- 24171691 TI - Aldehyde dehydrogenase activity enriches for proximal airway basal stem cells and promotes their proliferation. AB - Both basal and submucosal gland (SMG) duct stem cells of the airway epithelium are capable of sphere formation in the in vitro sphere assay, although the efficiency at which this occurs is very low. We sought to improve this efficiency of sphere formation by identifying subpopulations of airway basal stem cells (ABSC) and SMG duct cells based on their aldehyde dehydrogenase (ALDH) activity. ALDH(hi) ABSCs and SMG duct cells were highly enriched for the population of cells that could make spheres, while the co-culture of ALDH(hi) differentiated cells with the ALDH(hi) ABSCs increased their sphere-forming efficiency. Specific ALDH agonists and antagonists were used to show that airway specific ALDH isozymes are important for ABSC proliferation. Pathway analysis of gene expression profiling of ALDH(hi) and ALDH(lo) ABSCs revealed a significant upregulation of the arachidonic acid (AA) metabolism pathway in ALDH(hi) ABSCs. We confirmed the importance of this pathway in the metabolism of proliferating ALDH(hi) ABSCs using bioenergetics studies as well as agonists and antagonists of the AA pathway. These studies could lead to the development of novel strategies for altering ABSC proliferation in the airway epithelium. PMID- 24171692 TI - Effect of repeated compaction of tablets on tablet properties and work of compaction using an instrumented laboratory tablet press. AB - The repeated compaction of Avicel PH101, dicalcium phosphate dihydrate (DCP) powder, 50:50 DCP/Avicel PH101 and Starch 1500 was studied using an instrumented laboratory tablet press which measures upper punch force, punch displacement and ejection force and operates using a V-shaped compression profile. The measurement of work compaction was demonstrated, and the test materials were ranked in order of compaction behaviour Avicel PH101 > DCP/Avicel PH101 > Starch > DCP. The behaviour of the DCP/Avicel PH101 mixture was distinctly non-linear compared with the pure components. Repeated compaction and precompression had no effect on the tensile fracture strength of Avicel PH101 tablets, although small effects on friability and disintegration time were seen. Repeated compaction and precompression reduced the tensile strength and the increased disintegration time of the DCP tablets, but improved the strength and friability of Starch 1500 tablets. Based on the data reported, routine laboratory measurement of tablet work of compaction may have potential as a critical quality attribute of a powder blend for compression. The instrumented press was suitable for student use with minimal supervisor input. PMID- 24171693 TI - An insight on human skin penetration of diflunisal: lipogel versus hydrogel microemulsion. AB - Diflunisal is a NSAID used in acute and long term management of pain and inflammation associated with osteoarthritis, rheumatoid arthritis and symptoms of primary dysmenorrhea. However, its oral use is associated with side effects such as peptic ulceration, dyspepsia, gastrointestinal disturbances and bleeding. The aim of this work was to develop lecithin organogels (LO) transdermal delivery system for diflunisal and to study its human skin penetration ability in comparison with an optimized microemulsion-based hydrogel. Ternary phase diagrams were constructed using butyl lactate as an organic solvent and two commercial grades of lecithin. The formation of gel phase was lecithin concentration dependent with Phosholipion 85 G being capable of forming organogels at lower lecithin concentration than Lipoid S75. The gels prepared using butyl lactate were able to tolerate higher amounts of water than could be incorporated in the lipogels prepared with other organic solvents. All the investigated gels possessed acceptable physical properties and were able to deliver diflunisal through human skin. The lipogels delivered higher total drug amount through the skin than the hydrogel. The composition of lecithin seemed to have some effect on the skin permeability enhancement ability of the lipogel. Lecithin containing higher amount of phosphatidyl ethanolamine could provide better transdermal delivery. The elaborated lecithin organogels are potential carriers that create a good opportunity for transdermal delivery of diflunisal overcoming the side effects associating its oral route. PMID- 24171694 TI - Benign hereditary chorea related to NKX2.1: expansion of the genotypic and phenotypic spectrum. AB - AIM: Benign hereditary chorea is a dominantly inherited, childhood-onset hyperkinetic movement disorder characterized by non-progressive chorea and variable degrees of thyroid and respiratory involvement. Loss-of-function mutations in NKX2.1, a gene vital to the normal development and function of the brain, lungs, and thyroid, have been identified in a number of individuals. METHOD: Clinical data from individuals with benign hereditary chorea identified through paediatric neurology services were collected in a standardized format. The NKX2.1 gene was analysed by Sanger sequencing, multiplex ligation-dependent probe amplification, and microarray analysis. RESULTS: Six of our cohort were female and four male, median age at assessment was 8 years 6 months (range 1 y 6 mo-18 y). We identified 10 probands with NKX2.1 mutations; nine of these mutations are novel (including two whole-gene deletions) and one has been previously reported. Of the 10 individuals, eight presented with muscle hypotonia and four had evidence of hypothyroidism or respiratory involvement. Only three out of the 10 individuals had the full triad of 'brain-lung-thyroid syndrome' symptoms. Additional clinical characteristics occurring in individual participants included growth hormone deficiency, pes cavus, kyphosis, duplex kidney, and obsessive-compulsive disorder. INTERPRETATION: Our data suggest that the neurological phenotype is prominent in this condition and that many patients with benign hereditary chorea do not have the classic triad of brain-lung-thyroid syndrome. The extended phenotype may include obsessive-compulsive disorder and skeletal abnormalities. PMID- 24171695 TI - Surgery for treatment of metastatic testicular cancer. PMID- 24171697 TI - Is carpal tunnel decompression warranted for HNPP? AB - The role of carpal tunnel decompression surgery for patients that have hereditary neuropathy with liability to pressure palsy (HNPP) is currently unknown. Since recovery from carpal tunnel compression is often associated with remyelination or nodal reconstruction rather than axonal regeneration, it is uncertain whether the PMP22 deletion associated with HNPP interrupts myelin or nodal reconstitution. We describe two patients with genetically confirmed HNPP and symptomatic carpal tunnel syndrome that had clinical and electrophysiological improvement after surgical decompression. The findings indicate a capacity for conduction repair in HNPP. They also suggest a need for further investigation and discussion around whether to offer carpal tunnel decompression to symptomatic HNPP patients. PMID- 24171698 TI - Behavioral responses of goitered gazelle (Gazella subgutturosa) to parasitic activity of botflies. AB - We studied behavioral responses of goitered gazelles (Gazella subgutturosa) to hypodermic botfly (family Hypodermatidae) activity in the naturally arid conditions of Kazakhstan. We found that the reactions of goitered gazelles are very similar to the insect-repelling behaviors of other ruminants and that most behavioral responses of goitered gazelles, such as frantic running, tail movements, and grooming, are not specific to botflies. The seasonal and diurnal changes in the intensity of the behavioral responses of the goitered gazelles coincided with the parasitic activities of botfly maggots. Surprisingly, the group size of the goitered gazelles decreased during the breeding of these parasitic insects instead of increasing, as was expected according to our predictions. As an alternative, the goitered gazelles chose an opposite strategy of dispersion throughout the area to avoid infestation. This strategy is well known for other species of ungulates and was quite effective, because their infestation rate was relatively low. PMID- 24171696 TI - Local phylogenetic analysis identifies distinct trends in transmitted HIV drug resistance: implications for public health interventions. AB - BACKGROUND: HIV transmitted drug resistance (TDR) surveillance is usually conducted by sampling from a large population. However, overall TDR prevalence results may be inaccurate for many individual clinical setting. We analyzed HIV genotypes at a tertiary care setting in Ottawa, Ontario in order to evaluate local TDR patterns among sub-populations. METHOD: Genotyping reports were digitized from ART naive patients followed at the Immunodeficiency Clinic at the Ottawa Hospital, between 2008 and 2010. Quality controlled, digitized sequence data were assessed for TDR using the Stanford HIV Database. Patient characteristics were analyzed according to TDR patterns. Finally, a phylogenetic tree was constructed to elucidate the observed pattern of HIV TDR. RESULTS: Among the 155 clinic patients there was no statistically significantly difference in demographics as compared to the Ontario provincial HIV population. The clinic prevalence of TDR was 12.3%; however, in contrast to the data from Ontario, TDR patterns were inverted with a 21% prevalence among MSM and 5.5% among IDU. Furthermore, nearly 80% of the observed TDR was a D67N/K219Q pattern with 87% of these infections arising from a distinct phylogenetic cluster. CONCLUSIONS: Local patterns of TDR were distinct to what had been observed provincially. Phylogenetic analysis uncovered a cluster of related infections among MSM that appeared more likely to be recent infections. Results support a paradigm of routine local TDR surveillance to identify the sub-populations under care. Furthermore, the routine application of phylogenetic analysis in the TDR surveillance context provides insights into how best to target prevention strategies; and how to correctly measure outcomes. PMID- 24171699 TI - Effects of neck-specific exercise with or without a behavioural approach in addition to prescribed physical activity for individuals with chronic whiplash associated disorders: a prospective randomised study. AB - BACKGROUND: Up to 50% of chronic whiplash associated disorders (WAD) patients experience considerable pain and disability and remain on sick-leave. No evidence supports the use of physiotherapy treatment of chronic WAD, although exercise is recommended. Previous randomised controlled studies did not evaluate the value of adding a behavioural therapy intervention to neck-specific exercises, nor did they compare these treatments to prescription of general physical activity. Few exercise studies focus on patients with chronic WAD, and few have looked at patients' ability to return to work and the cost-effectiveness of treatments. Thus, there is a great need to develop successful evidence-based rehabilitation models. The study aim is to investigate whether neck-specific exercise with or without a behavioural approach (facilitated by a single caregiver per patient) improves functioning compared to prescription of general physical activity for individuals with chronic WAD. METHODS/DESIGN: The study is a prospective, randomised, controlled, multi-centre study with a 2-year follow-up that includes 216 patients with chronic WAD (> 6 months and < 3 years). The patients (aged 18 to 63) must be classified as WAD grade 2 or 3. Eligibility will be determined with a questionnaire, telephone interview and clinical examination. The participants will be randomised into one of three treatments: (A) neck-specific exercise followed by prescription of physical activity; (B) neck-specific exercise with a behavioural approach followed by prescription of physical activity; or (C) prescription of physical activity alone without neck-specific exercises. Treatments will be performed for 3 months. We will examine physical and psychological function, pain intensity, health care consumption, the ability to resume work and economic health benefits. An independent, blinded investigator will perform the measurements at baseline and 3, 6, 12 and 24 months after inclusion. The main study outcome will be improvement in neck-specific disability as measured with the Neck Disability Index. All treatments will be recorded in treatment diaries and medical records. DISCUSSION: The study findings will help improve the treatment of patients with chronic WAD. TRIALS REGISTRATION: ClinicalTrials.gov identifier: NCT01528579. PMID- 24171700 TI - Human amniotic fluid-derived mesenchymal cells from fetuses with a neural tube defect do not deposit collagen type i protein after TGF-beta1 stimulation in vitro. AB - In spina bifida, the neural tube fails to close during the embryonic period. Exposure of the neural tube to the amniotic fluid during pregnancy causes additional neural damage. Intrauterine tissue engineering using a biomaterial seeded with stem cells might prevent this additional damage. For this purpose, autologous cells from the amniotic fluid are an attractive source. To close the defect, it is important that these cells deposit an extracellular matrix. However, it is not known if amniotic fluid mesenchymal cells (AFMCs) from a fetus with a neural tube defect (NTD) share the same characteristics as AFMCs from a healthy fetus. We found that cells derived from fetuses with a NTD, in contrast to healthy human amniotic fluid cells, did not deposit collagen type I. Furthermore, the NTD cells showed, compared with both healthy amniotic fluid cells and fetal fibroblasts, much lower mRNA expression levels of genes that are involved in collagen biosynthesis [procollagen C-endopeptidase enhancer proteins (PCOLCE), PCOLCE2, ADAM metallopeptidase with thrombospondin type 1 motif, 2 (ADAMTS2), ADAMTS14]. This indicates that NTD-AFMCs have different characteristics compared with healthy AFMCs and might not be suitable for fetal therapy to close the defect in spina bifida patients. PMID- 24171701 TI - Physaloptera bainae n. sp. (Nematoda: Physalopteridae) parasitic in Salvator merianae (Squamata: Teiidae), with a key to Physaloptera species parasitizing reptiles from Brazil. AB - Physaloptera bainae n. sp. (Nematoda: Physalopteridae) from stomach of the large "tegu" lizard Salvator merianae (Squamata: Teiidae), collected in an ecological park that is part of the Atlantic Rainforest biome in Juiz de Fora, Minas Gerais, Brazil, is described. The new species which has females with didelphic uterus, is the only species of the genus exhibiting external teeth in the form of 4 spines that are organized in a cross-shaped pattern at the anterior apical end, with 2 minute adcloacal papillae on the anterior part of cloacal aperture in males and a large cuticular expansion at the anterior end of females. Moreover, P. bainae n. sp. can be differentiated from the other congeners by the combination of other features, e.g., number (23) and pattern of caudal papillae, spicule size (left 554-600; right 589-617) and vulval position (on the first third of body), and because the specimens are particularly large and robust. Physaloptera monodens is considered a junior synonym of P. obtusissima. In addition, a key to Physaloptera species parasitizing reptiles from Brazil is provided. PMID- 24171702 TI - Assessing the optimal location for alcohol-based hand rub dispensers in a patient room in an intensive care unit. AB - BACKGROUND: The introduction of alcohol-based hand rub dispensers has had a positive influence on compliance of healthcare workers with the recommended guidelines for hand hygiene. However, establishing the best location for alcohol based hand rub dispensers remains a problem, and no method is currently available to optimize the location of these devices. In this paper we describe a method to determine the optimal location for alcohol-based hand rub dispensers in patient rooms. METHODS: We composed a method that consists of a combination of qualitative and quantitative research methods. Firstly, different arrangements of dispensers were determined based on the results of two types of assessment: workflow observations and interviews with nurses and physicians. Each arrangement was then evaluated using two types of assessment: interviews with nurses and physicians and electronic measurements of the user frequency of the dispensers. This procedure was applied in a single-bed patient room on a thoracic surgery intensive care unit. RESULTS: The workflow observations revealed that the activities of patient care were most often at the entrance and near the computer at the right side of the test room. Healthcare workers stated that the location of the dispenser should meet several requirements. Measurements of the frequency of use showed that the dispenser located near the computer, at the back of the room, was used less frequently than the dispenser located near the sink and the dispenser located at the entrance to the room. CONCLUSION: The applied method has potential for determining the optimal location for alcohol-based hand rub dispensers in a patient room. Workflow observations and the expressed preferences of healthcare workers guide the choice for the location of alcohol-based hand rub dispensers. These choices may be optimized based on measurement of the frequency of use of the dispensers. PMID- 24171703 TI - Pedunculated lipoma causing colo-colonic intussusception: a rare case report. AB - BACKGROUND: Intussusception is a relatively common cause of intestinal obstruction in children but a rare clinical entity in adults, representing fewer than 1% of intestinal obstructions in this patient population. Colonic lipomas are uncommon nonepithelial neoplasms that are typically sessile, asymptomatic and incidentally found during endoscopy, surgery, or autopsy. CASE PRESENTATION: A 55 year old man visited our emergency department with severe abdominal pain, multiple episodes of vomiting, abdominal distension. Abdominal ultrasound sonography and computed tomography showed a sausage-shaped mass presenting as a target sign, suggestive of intussusception. Surgery revealed a hard elongated mass in the right colon wihch telescoped in the transverse colon and caused colo colonic intussusception. Rhigt hemicolectomy was performed and pathology documented a mature submucosal lipoma of the colon. We describe the difficulties in diagnosis and management of this rare cause of bowel obstruction and review the literature on adult intussusceptions. CONCLUSION: A large submucosal lipoma is a very rare cause of colon intussusception that presents as intestinal obstruction in patients without malignancy. CT and magnetic resonance imaging remain the methods of choice for studying abdominal lipomas, particularly those rising into the layers of the colonic wall. Surgical resection remains the treatment of choice and produces an excellent prognosis. PMID- 24171704 TI - A country bug in the city: urban infestation by the Chagas disease vector Triatoma infestans in Arequipa, Peru. AB - BACKGROUND: Interruption of vector-borne transmission of Trypanosoma cruzi remains an unrealized objective in many Latin American countries. The task of vector control is complicated by the emergence of vector insects in urban areas. METHODS: Utilizing data from a large-scale vector control program in Arequipa, Peru, we explored the spatial patterns of infestation by Triatoma infestans in an urban and peri-urban landscape. Multilevel logistic regression was utilized to assess the associations between household infestation and household- and locality level socio-environmental measures. RESULTS: Of 37,229 households inspected for infestation, 6,982 (18.8%; 95% CI: 18.4 - 19.2%) were infested by T. infestans. Eighty clusters of infestation were identified, ranging in area from 0.1 to 68.7 hectares and containing as few as one and as many as 1,139 infested households. Spatial dependence between infested households was significant at distances up to 2,000 meters. Household T. infestans infestation was associated with household- and locality-level factors, including housing density, elevation, land surface temperature, and locality type. CONCLUSIONS: High levels of T. infestans infestation, characterized by spatial heterogeneity, were found across extensive urban and peri-urban areas prior to vector control. Several environmental and social factors, which may directly or indirectly influence the biology and behavior of T. infestans, were associated with infestation. Spatial clustering of infestation in the urban context may both challenge and inform surveillance and control of vector reemergence after insecticide intervention. PMID- 24171705 TI - Interactions of mesenchymal stem cells with endothelial cells. AB - Recent years have witnessed the emergence of a considerable amount of data pertaining to the application of bone marrow mesenchymal stem cells (MSCs) in promoting angiogenesis in the field of regenerative medicine. Nevertheless, some authors have provided evidence that MSCs can also prevent the process of angiogenesis, which is desirable in certain pathologies such as tumor growth. Plenty of in vitro and in vivo research studies have been undertaken to illuminate the underlying mechanisms by which MSCs promote or inhibit neo angiogenesis. To date, both secretary capacity and differentiation into endothelial-like cells have been reported in MSC-based pro-angiogenic therapies. This review seeks to shed further light on interactions between MSCs and endothelial cells in different physiopathological conditions. PMID- 24171706 TI - Formulation and evaluation of mucoadhesive microspheres of tenofovir disoproxil fumarate for intravaginal use. AB - Intravaginal mucoadhesive microspheres of tenofovir disoproxil fumarate (TDF) has been formulated using chitosan as the matrix-forming mucoadhesive polymer and evaluated. Ionotropic gelation method was used to produce the microspheres. Drug polymer compatibility, percentage yield, particle size determination by optical microscopy, drug content & encapsulation efficiency, ex vivo mucoadhesion and in vitro release were evaluated. Based on the evaluation studies, F6 was selected as the best formulation and evaluated further for release kinetics and curve fitting analysis. F6 followed Korsmeyer-Peppas and Higuchi models. Accelerated stability study was conducted as per ICH guidelines. Drug content analysis, FTIR, XRD, SEM analysis showed that it remained stable for a period of six months. PMID- 24171708 TI - Jejunogastric intussusception: a rare complication of a gastrojejunostomy. PMID- 24171707 TI - Association between mutation of the NF2 gene and monosomy 22 in menopausal women with sporadic meningiomas. AB - BACKGROUND: Meningioma was the first solid tumor shown to contain a recurrent genetic alteration e.g. monosomy 22/del(22q), NF2 being the most relevant gene involved. Although monosomy 22/del(22q) is present in half of all meningiomas, and meningiomas frequently carry NF2 mutations, no study has been reported so far in which both alterations are simultaneously assessed and correlated with the features of the disease. METHODS: Here, we analyzed the frequency of both copy number changes involving chromosome 22 and NF2 mutations in 20 sporadic meningiomas using high-density SNP-arrays, interphase-FISH and PCR techniques. RESULTS: Our results show a significant frequency of NF2 mutations (6/20 patients, 30%), most of which (5/6) had not been previously reported in sporadic meningiomas. NF2 mutations involved five different exons and led to a truncated protein (p.Leu163CysfsX46, p.Phe62LeufsX61, p.Asp281MetfsX15, p.Phe285LeufsX11, p.Gln389ArgfsX37) and an in frame deletion of Phe119. Interestingly, all NF2 mutated cases were menopausal women with monosomy 22 but not del(22q). CONCLUSIONS: These results confirm and extend on previous observations about the high frequency and heterogeneity of NF2 mutations in sporadic meningiomas and indicate they could be restricted to a well-defined cytogenetic and clinical subgroup of menopausal women. Further studies in large series of patients are required to confirm our observations. PMID- 24171709 TI - Potential corridors and barriers for plague spread in Central Asia. AB - BACKGROUND: Plague (Yersinia pestis infection) is a vector-borne disease which caused millions of human deaths in the Middle Ages. The hosts of plague are mostly rodents, and the disease is spread by the fleas that feed on them. Currently, the disease still circulates amongst sylvatic rodent populations all over the world, including great gerbil (Rhombomys opimus) populations in Central Asia. Great gerbils are social desert rodents that live in family groups in burrows, which are visible on satellite images. In great gerbil populations an abundance threshold exists, above which plague can spread causing epizootics. The spatial distribution of the host species is thought to influence the plague dynamics, such as the direction of plague spread, however no detailed analysis exists on the possible functional or structural corridors and barriers that are present in this population and landscape. This study aims to fill that gap. METHODS: Three 20 by 20 km areas with known great gerbil burrow distributions were used to analyse the spatial distribution of the burrows. Object-based image analysis was used to map the landscape at several scales, and was linked to the burrow maps. A novel object-based method was developed - the mean neighbour absolute burrow density difference (MNABDD) - to identify the optimal scale and evaluate the efficacy of using landscape objects as opposed to square cells. Multiple regression using raster maps was used to identify the landscape ecological variables that explain burrow density best. Functional corridors and barriers were mapped using burrow density thresholds. Cumulative resistance of the burrow distribution to potential disease spread was evaluated using cost distance analysis. A 46-year plague surveillance dataset was used to evaluate whether plague spread was radially symmetric. RESULTS: The burrow distribution was found to be non-random and negatively correlated with Greenness, especially in the floodplain areas. Corridors and barriers showed a mostly NWSE alignment, suggesting easier spreading along this axis. This was confirmed by the analysis of the plague data. CONCLUSIONS: Plague spread had a predominantly NWSE direction, which is likely due to the NWSE alignment of corridors and barriers in the burrow distribution and the landscape. This finding may improve predictions of plague in the future and emphasizes the importance of including landscape analysis in wildlife disease studies. PMID- 24171710 TI - Leflunomide in addition to steroids improves proteinuria and renal function in adult Henoch-Schoenlein nephritis with nephrotic proteinuria. AB - AIM: Henoch-Schoenlein nephritis (HSPN) is a severe disease in adults and may cause renal insufficiency in a large portion of patients. But its rarity has led to lack of data. There are few controlled studies on therapy with immunosuppressants in HSPN adults. This study aims to evaluate the effect of leflunomide on HSPN adults with nephrotic proteinuria. METHODS: We retrospectively studied 65 adult patients who had biopsy-proven HSPN with nephrotic proteinuria. Twenty-seven patients (Group P) only received steroids, and 38 (Group P + L) were treated with leflunomide in addition to steroids. The clinical features, laboratory data and pathological findings of both groups were analyzed. RESULTS: The two groups were well-matched at baseline. After 24 months of treatment, urinary protein excretion of both groups decreased significantly from the baseline, and the estimated glomerular filtration rate (eGFR) was higher in Group P + L. Four patients in Group P and three in Group P + L developed to end-stage renal disease at the most recent follow-up. Group P + L showed better renal outcome than Group P. The treatment group and the degree of mesangial hypercellularity were significantly related to renal prognosis. CONCLUSION: Leflunomide combined with steroids is effective for treating adult HSPN with nephrotic proteinuria. PMID- 24171711 TI - Socioeconomic and psychosocial predictors of dental healthcare use among Brazilian preschool children. AB - BACKGROUND: Disparities in utilization of oral healthcare services have been attributed to socioeconomic and individual behavioral factors. Parents' socioeconomic status, demographics, schooling, and perceptions of oral health may influence their children's use of dental services. This cross-sectional study assessed the relationships between socioeconomic and psychosocial factors and the utilization of dental health services by children aged 1-5 years. METHODS: Data were collected through clinical exams and a structured questionnaire administered during the National Day of Children's Vaccination. A Poisson regression model was used to estimate prevalence ratios and 95% confidence intervals. RESULTS: Data were collected from a total of 478 children. Only 112 (23.68%) were found to have visited a dentist; 67.77% of those had seen the dentist for preventive care. Most (63.11%) used public rather than private services. The use of dental services varied according to parental socioeconomic status; children from low socioeconomic backgrounds and those whose parents rated their oral health as "poor" used dental services less frequently. The reason for visiting the dentist also varied with socioeconomic status, in that children of parents with poor socioeconomic status and who reported their child's oral health as "fair/poor" were less likely to have visited the dentist for preventive care. CONCLUSION: This study demonstrated that psychosocial and socioeconomic factors are important predictors of the utilization of dental care services. PMID- 24171712 TI - Pedigree error due to extra-pair reproduction substantially biases estimates of inbreeding depression. AB - Understanding the evolutionary dynamics of inbreeding and inbreeding depression requires unbiased estimation of inbreeding depression across diverse mating systems. However, studies estimating inbreeding depression often measure inbreeding with error, for example, based on pedigree data derived from observed parental behavior that ignore paternity error stemming from multiple mating. Such paternity error causes error in estimated coefficients of inbreeding (f) and reproductive success and could bias estimates of inbreeding depression. We used complete "apparent" pedigree data compiled from observed parental behavior and analogous "actual" pedigree data comprising genetic parentage to quantify effects of paternity error stemming from extra-pair reproduction on estimates of f, reproductive success, and inbreeding depression in free-living song sparrows (Melospiza melodia). Paternity error caused widespread error in estimates of f and male reproductive success, causing inbreeding depression in male and female annual and lifetime reproductive success and juvenile male survival to be substantially underestimated. Conversely, inbreeding depression in adult male survival tended to be overestimated when paternity error was ignored. Pedigree error stemming from extra-pair reproduction therefore caused substantial and divergent bias in estimates of inbreeding depression that could bias tests of evolutionary theories regarding inbreeding and inbreeding depression and their links to variation in mating system. PMID- 24171713 TI - Hepatocellular carcinoma in Child's A cirrhosis: a retrospective analysis of matched pairs following liver transplantation vs. liver resection according to the intention-to-treat principle. AB - This is the first matched pair analysis on the puzzling clinical problem of whether to perform liver transplantation (LT) or liver resection (LR) for Child's A hepatocellular carcinoma (HCC) patients. A total of 201 patients diagnosed with HCC and Child's A liver cirrhosis were treated with LT transarterial chemoembolization (TACE) or LR between 1998 and 2012. To achieve the most accurate study design, two groups of 57 patients were matched retrospectively according to their tumor characteristics detected by the initial computerized tomography (CT) scan. Sixteen of 57 LT candidates were not transplanted due to tumor progress during pre-treatment (TACE). Nevertheless, the retrospective analysis of the matched pairs according to the intention-to-treat principle resulted in a better five-yr overall survival (OS) rate of 54.3% for the group of LT candidates compared with 35.7% for those receiving LR (p = 0.19). In patients meeting the University of California, San Francisco (UCSF) criteria, five-yr OS reached 58.4% after LT and 45.1% after LR (p = 0.56). For Milan criteria (MC) patients, LT resulted in 57.9% and LR in 42% five-yr OS rate (p = 0.29). In conclusion, the finding of a better OS rate in LT was not statistically significant. There was also a selection bias in favor of LT, which may have influenced the OS. Therefore, particularly in regard to organ scarcity, LR remains a viable treatment option for respectable HCC in Child's A cirrhosis. PMID- 24171714 TI - Ectoparasite burdens of the common mole-rat (Cryptomys hottentotus hottentotus) from the Cape Provinces of South Africa. AB - The members of the African mole-rat family Bathyergidae are widely distributed across sub-Saharan Africa. Despite their well-studied biology and reproductive physiology, the current knowledge of their ectoparasite fauna is limited and ambiguous due to recent revisions of the bathyergid taxonomy. The common mole-rat (Cryptomys hottentotus hottentotus) is 1 of the most widely distributed species of these subterranean rodents. Ectoparasites were collected from 268 common mole rats at 2 localities (Western and Northern Cape provinces) in South Africa over the course of 18 mo with the aim to document species richness, prevalence, and abundance of these ectoparasites. The aggregation of parasite species, sex bias within a species, and seasonal variation in ectoparasite burdens were investigated. A total of 4,830 individual parasites from 4 mite species (Androlaelaps scapularis, Androlaelaps capensis, Radfordia ensifera, and 1 undetermined chigger [family Trombiculidae]), 1 flea species (Cryptopsylla ingrami), and 1 louse species (Eulinognathus hilli) were collected. With the exception of R. ensifera and the chigger, all of these ectoparasites appear to be host specific either for the host species or the Bathyergidae. Aggregation indices indicated that with the exception of E. hilli, the distribution of all parasite species was highly aggregated among hosts and sex biased. Seasonal variation in prevalence, abundance, and species richness was apparent, with greater burdens in the rainy winter season. This is likely related to seasonal variation in abiotic factors but may also be affected by the timing of host reproduction and dispersal behavior. PMID- 24171715 TI - The 2011 Famine in Somalia: lessons learnt from a failed response? AB - BACKGROUND: Famine early warning systems clearly identified the risk of famine in South Central Somalia in 2010-2011 but timely action to prevent the onset of famine was not taken. The result was large scale mortality, morbidity, and population displacement. DISCUSSION: The main factor that turned a drought related food crisis into a famine was the war that afflicted southern Somalia and the tactics adopted by the various belligerents. These included non-state actors, regional, and international governments. In disasters and complex emergencies, such as this, we posit that five conditions need to be in place to enable humanitarian agencies to provide a timely response to early warnings of famine. These are: presence; access; adequate funding; operational capacity; and legal protection for humanitarian action. In the run up to the Somalia famine each of these presented severe challenges to humanitarian action. The design of the current coordination and funding system contributed to the problems of achieving a neutral, independent, and effective humanitarian response. SUMMARY: The 2011 famine in Somalia was predicted and could have been mitigated or prevented if the humanitarian response had been timely and more effective. To improve responsiveness to early warnings, action is required to better insulate the humanitarian system from political agendas. While overcoming constraints, such as lack of access, may sometimes be beyond the scope of humanitarian actors, more could be done to enhance the perceived neutrality of parts of the humanitarian system. This should include a reappraisal of the cluster coordination system and reforms to donor funding mechanisms. PMID- 24171716 TI - Identification of a new genotype of Torque Teno Mini virus. AB - BACKGROUND: Although human torque teno viruses (TTVs) were first discovered in 1997, still many associated aspects are not clarified yet. The viruses reveal a remarkable heterogeneity and it is possible that some genotypes are more pathogenic than others. The identification of all genotypes is essential to confirm previous pathogenicity data, and an unbiased search for novel viruses is needed to identify TTVs that might be related to disease. METHOD: The virus discovery technique VIDISCA-454 was used to screen serum of 55 HIV-1 positive injecting drug users, from the Amsterdam Cohort Studies, in search for novel blood-blood transmittable viruses which are undetectable via normal diagnostics or panvirus-primer PCRs. RESULTS: A novel torque teno mini virus (TTMV) was identified in two patients and the sequence of the full genomes were determined. The virus is significantly different from the known TTMVs (< 40% amino acid identity in ORF1), yet it contains conserved characteristics that are also present in other TTMVs. The virus is chronically present in both patients, and these patients both suffered from a pneumococcal pneumonia during follow up and had extremely low B-cells counts. CONCLUSION: We describe a novel TTMV which we tentatively named TTMV-13. Further research is needed to address the epidemiology and pathogenicity of this novel virus. PMID- 24171717 TI - The Great East Japan Earthquake affected the laboratory findings of hemodialysis patients in Fukushima. AB - BACKGROUND: The aim of the present study was to investigate the impact of the Great East Japan Earthquake on laboratory findings in chronic hemodialysis (HD) patients in Fukushima. METHODS: Changes in laboratory findings and cardiothoracic ratio (CTR) between before and after the earthquake were retrospectively analyzed in 90 adult HD patients with end-stage renal disease (ESRD). Two hospitals located within 80 km from the Fukushima Daiichi Nuclear Power Plant, where American government recommended to evacuate from the area, participated in the study. HD duration was shortened by 0.5-1 hour for 1 month after the earthquake. Multivariate analyses were performed to identify the factors contributing to change of measurement values. RESULTS: Blood urea nitrogen (BUN) value was significantly transiently decreased for 1-2 weeks after the earthquake (P=0.002). In multivariate analysis, age showed a tendency to be related to the decrease of BUN level (P=0.05). Hematocrit value was significantly elevated after two months compared with that at baseline (P=0.02), although the elevation was small. The other measured values and CTR were not significantly changed compared with those before the earthquake. CONCLUSIONS: Laboratory findings and CTR did not worsen despite the shortening of HD duration. Hence, in this disaster, as far as chronic HD patients with ESRD were concerned, it was possible for the duration of HD treatment to be safely decreased. PMID- 24171718 TI - Nonadaptive processes can create the appearance of facultative cheating in microbes. AB - Adaptations to social life may take the form of facultative cheating, in which organisms cooperate with genetically similar individuals but exploit others. Consistent with this possibility, many strains of social microbes like Myxococcus bacteria and Dictyostelium amoebae have equal fitness in single-genotype social groups but outcompete other strains in mixed-genotype groups. Here we show that these observations are also consistent with an alternative, nonadaptive scenario: kin selection-mutation balance under local competition. Using simple mathematical models, we show that deleterious mutations that reduce competitiveness within social groups (growth rate, e.g.) without affecting group productivity can create fitness effects that are only expressed in the presence of other strains. In Myxococcus, mutations that delay sporulation may strongly reduce developmental competitiveness. Deleterious mutations are expected to accumulate when high levels of kin selection relatedness relax selection within groups. Interestingly, local resource competition can create nonzero "cost" and "benefit" terms in Hamilton's rule even in the absence of any cooperative trait. Our results show how deleterious mutations can play a significant role even in organisms with large populations and highlight the need to test evolutionary causes of social competition among microbes. PMID- 24171720 TI - Pyoderma gangrenosum of the penis: an important lesson. PMID- 24171719 TI - Myc is required for beta-catenin-mediated mammary stem cell amplification and tumorigenesis. AB - BACKGROUND: Basal-like breast cancer is a heterogeneous disease characterized by the expression of basal cell markers, no estrogen or progesterone receptor expression and a lack of HER2 overexpression. Recent studies have linked activation of the Wnt/beta-catenin pathway, and its downstream target, Myc, to basal-like breast cancer. Transgenic mice K5DeltaNbetacat previously generated by our team present a constitutive activation of Wnt/beta-catenin signaling in the basal myoepithelial cell layer, resulting in focal mammary hyperplasias that progress to invasive carcinomas. Mammary lesions developed by K5DeltaNbetacat mice consist essentially of basal epithelial cells that, in contrast to mammary myoepithelium, do not express smooth muscle markers. METHODS: Microarray analysis was used to compare K5DeltaNbetacat mouse tumors to human breast tumors, mammary cancer cell lines and the tumors developed in other mouse models. Cre-Lox approach was employed to delete Myc from the mammary basal cell layer of K5DeltaNbetacat mice. Stem cell amplification in K5DeltaNbetacat mouse mammary epithelium was assessed with 3D-culture and transplantation assays. RESULTS: Histological and microarray analyses of the mammary lesions of K5DeltaNbetacat females revealed their high similarity to a subset of basal-like human breast tumors with squamous differentiation. As in human basal-like carcinomas, the Myc pathway appeared to be activated in the mammary lesions of K5DeltaNbetacat mice. We found that a basal cell population with stem/progenitor characteristics was amplified in K5DeltaNbetacat mouse preneoplastic glands. Finally, the deletion of Myc from the mammary basal layer of K5DeltaNbetacat mice not only abolished the regenerative capacity of basal epithelial cells, but, in addition, completely prevented the tumorigenesis. CONCLUSIONS: These results strongly indicate that beta-catenin-induced stem cell amplification and tumorigenesis rely ultimately on the Myc pathway activation and reinforce the hypothesis that basal stem/progenitor cells may be at the origin of a subset of basal-like breast tumors. PMID- 24171723 TI - The co-use of conventional drugs and herbs among patients in Norwegian general practice: a cross-sectional study. AB - BACKGROUND: Different patient groups are known to use herbal remedies and conventional drugs concomitantly (co-use). This poses a potential risk of herb drug interaction through altering the drug's pharmacokinetics or pharmacodynamics. Little is known about co-use among patients in general practice. The primary aim of this study was to compare patients in general practice that co-use herbal remedies and conventional drugs with those who do not. The secondary aim was to register the herb-drug combinations with potential clinical relevant interactions among the co-users. METHOD: A questionnaire based cross-sectional study conducted in the autumn 2011 in a general practice office with four general practitioners (GPs) and one intern in Western Norway. Adults >18 years who came for an office visit were invited. The questionnaire asked about demographics, herbal use, conventional drug use and communication about herbal use. Multivariable logistic regression was used to compare co-users to the other patients. RESULTS: Of the 381 patients who completed the questionnaire, the prevalence of herbal use was 44%, with bilberry (41%), green tea (31%), garlic (27%), Aloe vera (26%) and echinacea (18%) as the most frequently used. Among those using conventional drugs regularly, 108 (45%) co-used herbs. Close to 40% of patients on anticoagulants co-used herbs, with garlic and bilberry as the most frequent herbs. Compared to all other patients, co-users had significantly (p < 0.05) increased odds to be female (adjOR 2.0), age above 70 years (adjOR 3.3), use herbs to treat an illness (adjOR 4.2), use two or more herbs (polyherbacy, adjOR 12.1) and having experienced adverse effects of herbal use (adjOR 37.5). Co use was also associated with use of analgesics or dermatological drugs (adjOR 5.1 and 7.9 respectively). Three out of four patients did not discuss herbal use with any health care professional. CONCLUSION: A sizable proportion of the GP patients co-used herbs with conventional drugs, also combinations with reported interaction potential or additive effects like anticoagulants and garlic. The low disclosure of herbal use to their GP, polyherbacy and the risk of interactions in vulnerable groups like elderly and chronically ill patients, warrant increased awareness among GPs. PMID- 24171724 TI - Quantitative structure-activation barrier relationship modeling for Diels-Alder ligations utilizing quantum chemical structural descriptors. AB - BACKGROUND: In the present study, we show the correlation of quantum chemical structural descriptors with the activation barriers of the Diels-Alder ligations. A set of 72 non-catalysed Diels-Alder reactions were subjected to quantitative structure-activation barrier relationship (QSABR) under the framework of theoretical quantum chemical descriptors calculated solely from the structures of diene and dienophile reactants. Experimental activation barrier data were obtained from literature. Descriptors were computed using Hartree-Fock theory using 6-31G(d) basis set as implemented in Gaussian 09 software. RESULTS: Variable selection and model development were carried out by stepwise multiple linear regression methodology. Predictive performance of the quantitative structure-activation barrier relationship (QSABR) model was assessed by training and test set concept and by calculating leave-one-out cross-validated Q2 and predictive R2 values. The QSABR model can explain and predict 86.5% and 80% of the variances, respectively, in the activation energy barrier training data. Alternatively, a neural network model based on back propagation of errors was developed to assess the nonlinearity of the sought correlations between theoretical descriptors and experimental reaction barriers. CONCLUSIONS: A reasonable predictability for the activation barrier of the test set reactions was obtained, which enabled an exploration and interpretation of the significant variables responsible for Diels-Alder interaction between dienes and dienophiles. Thus, studies in the direction of QSABR modelling that provide efficient and fast prediction of activation barriers of the Diels-Alder reactions turn out to be a meaningful alternative to transition state theory based computation. PMID- 24171725 TI - Molecular characterization and impacts of a strain of Grapevine leafroll associated virus 2 causing asymptomatic infection in a wine grape cultivar. AB - BACKGROUND: Grapevine leafroll (GLD) is considered as the most economically important virus disease affecting wine grapes (Vitis vinifera L.) in many grapevine-growing regions. GLD produces distinct symptoms in red- and white berried cultivars. In this study, we determined the complete genome sequence of an asymptomatic strain of Grapevine leafroll-associated virus 2 (GLRaV-2) and studied its impacts on fruit yield and berry quality attributes in an own-rooted, red-berried wine grape cultivar. FINDINGS: The complete genome of GLRaV-2 obtained from a red-berried wine grape cultivar Sangiovese, designated as GLRaV-2 SG, was determined to be 16,474 nucleotides in length. In pairwise comparisons, using complete genome sequences of GLRaV-2 strains available in GenBank, GLRaV-2 SG was more closely related to GLRaV-2-OR1 from Oregon, USA, and GLRaV-2-93/955 from South Africa, and distantly related to GLRaV-2-BD from Italy and GLRaV-2-RG from USA. Fruit yield estimates and berry quality analysis at the time of commercial harvest indicated that GLRaV-2-SG had little impact on fruit yield and total soluble solids, juice pH and total anthocyanins of berry skin. CONCLUSIONS: Because so little is known about the effects of asymptomatic virus infections in wine grapes, this study expanded our knowledge of the occurrence and impacts of GLRaV-2 causing asymptomatic infections. Our results indicated that an asymptomatic strain of GLRaV-2 may not cause significant effects to overall fruit yield and berry quality in own-rooted vines, but can affect its host in more subtle ways. Since disease symptoms are not apparent, relying on visual symptoms during disease surveys may result in the escape of asymptomatic strains of GLRaV 2. Thus, it is necessary to use appropriate diagnostic assays for reliable detection of viruses causing asymptomatic infections. PMID- 24171726 TI - Reliability and validity of a brief self-rated scale of health condition with acute schizophrenia. AB - AIM: The aim of this study was to develop a new Brief Scale of Self-rated Health Condition with Acute Schizophrenia (BsHAS) and to examine its reliability, validity and correlation to psychiatric symptoms. METHODS: We examined the reliability and validity of the BsHAS consisting of four items (physical health condition, mood, interpersonal fatigue and interest) for 199 inpatients with acute schizophrenia and compared the patients' subjective health conditions as assessed by the BsHAS with their objective psychiatric symptoms. RESULTS: Cronbach's alpha coefficient was 0.79, indicating that the reliability of the scale was sufficient. These four items chosen from the previous studies were approved by an expert panel, which suggested that the scale has content validity. The BsHAS total score was significantly improved at discharge. However, the effect size was only -0.24. In particular, improvement was not recognized in the interpersonal fatigue item. These findings suggest that some patients weredischarged without realizing the improvement of their health condition. The patients answered all questions without subsequently showing deteriorating symptoms, suggesting that the scale can be applied to acute-phase patients with schizophrenia. No obvious relation was recognized between the patients' subjective health condition as assessed by the BsHAS and their objective psychiatric symptoms. This result suggests that the BsHAS can provide additional information to the objective assessment of psychiatric symptoms. CONCLUSION: These results show that the BsHAS can help psychiatric professionals to know patients' subjective health conditions, and that the longitudinal use of this scale may be useful for evaluating the degree of recovery from schizophrenia. PMID- 24171727 TI - Efficacy of oregonin investigated by non-invasive evaluation in a B16 mouse melanoma model. AB - Oregonin has been reported to act as a mediator of antibiosis, a liver-protective agent, an antioxidant, an anti-inflammatory agent, and to prevent cancer outbreaks. B16 melanoma cells were separated with trypsin ethylenediaminetetraacetic acid, resuspended in 50 MUl of phosphate-buffered saline and transplanted into the backs of 6- to 8-week-old male Balb/c nude mice through subcutaneous injection. Treatment doses of oregonin were administered three times weekly, for 30 days from the 11th day after transplantation of the melanoma cells, in each group. The study consisted of a control group, a dacarbazine group, an oregonin group and a dacarbazine + oregonin group. Measurements were taken before treatment and on the 5th, 7th, 10th and 15th days after treatment for each group. Based on survival rates after transplantation, the control group showed less than 50% survival after 20 days, while the treatment groups showed at least 50% survival up to the 41st day. PMID- 24171729 TI - Rapid evolution of asymmetric reproductive incompatibilities in stalk-eyed flies. AB - The steps by which isolated populations acquire reproductive incompatibilities remain poorly understood. One potentially important process is postcopulatory sexual selection because it can generate divergence between populations in traits that influence fertilization success after copulation. Here we present a comprehensive analysis of this form of reproductive isolation by conducting reciprocal crosses between variably diverged populations of stalk-eyed flies (Teleopsis dalmanni). First, we measure seven types of reproductive incompatibility between copulation and fertilization. We then compare fertilization success to hatching success to quantify hybrid inviability. Finally, we determine if sperm competition acts to reinforce or counteract any incompatibilities. We find evidence for multiple incompatibilities in most crosses, including failure to store sperm after mating, failure of sperm to reach the site of fertilization, failure of sperm to fertilize eggs, and failure of embryos to develop. Local sperm have precedence over foreign sperm, but this effect is due mainly to differences in sperm transfer and reduced hatching success. Crosses between recently diverged populations are asymmetrical with regard to the degree and type of incompatibility. Because sexual conflict in these flies is low, postcopulatory sexual selection, rather than antagonistic coevolution, likely causes incompatibilities due to mismatches between male and female reproductive traits. PMID- 24171730 TI - Temporal trends in stroke admissions in Denmark 1997-2009. AB - BACKGROUND: The Stroke burden is increasing in many populations where health institutions may experience more patients. We wanted to examine whether incidence rates and absolute number of hospitalized stroke patients remained stable in Denmark during a 13 years period where exposure to major stroke risk factors decreased, changes in stroke treatment was implemented, and the age of the population increased. METHODS: The Danish National Patient Register was used to identify all subjects 25 years of age or above admitted with a first time stroke in Denmark from 1997-2009. Incidence rates (IRs) and age-adjusted Poisson regression analyses were used to examine trends in age-, gender- and stroke subtype (ischaemic or unspecified). RESULTS: During the 13-year observation period there were 53.5 million person-years at risk (PY) and a total of 84,626 male and 84,705 female stroke patients were admitted to Danish hospitals. The IRs of hospitalized strokes per 1000 PY was 3.21 (95% confidence interval [CI] 3.16 3.27) in 1997, 3.85 (95% CI 3.79-3.91) in 2003 and 3.22 (95% CI 3.16-3.28) in 2009, respectively.Incidence rate ratios of hospitalized stroke events adjusted for age in the period 2007-2009 compared to 1997-2000 were 0.89 (95% CI 0.87- 0.91) for men and 0.92 (95% CI 0.90-0.94) for women.The incidence of hospitalized unspecified strokes decreased from 1997 to 2009 whereas there was a steep rise in incidence for hospitalization with specified ischemic stroke during this period. CONCLUSION: This study found a constant rate of stroke hospitalization in Denmark from 1997-2009. The overall rate of hospitalized strokes adjusted for age decreased during this period. PMID- 24171732 TI - The cognitive neuroscience of memory. AB - The cognitive neuroscience of long-term memory is ingrained with the assumptions that a particular task measures a single cognitive process and that each cognitive process is mediated by a single brain region. However, these assumptions are simplistic and hindering progress toward understanding the true mechanisms of memory. This special issue of Cognitive Neuroscience presents five empirical papers and two theoretical discussion papers with peer commentaries on the spatial and/or temporal mechanisms of memory. Using fMRI, Yu et al. show ventral parietal cortex sub-regions mediate dissociable aspects of recollection, and Mickley Steinmetz et al. study time-delay effects on processes engaged during emotional versus neutral item encoding. Employing ERPs, Galli et al. investigate anticipatory activity and recall, and Evans et al. study the effect of cognitive demands on recollection activity. Using fMRI and ERPs, Herzmann et al. investigate spatial-temporal activity associated with recognition. Voss et al. review electrophysiological, fMRI, and behavioral evidence indicating implicit memory can influence explicit memory measures. Gotts et al. review electrophysiological, fMRI, and modeling evidence to evaluate proposals of repetition priming and highlight neural synchronization. These papers embrace complex cognitive and neural processes, and thus will provide a framework for future studies to investigate the mechanisms of memory. PMID- 24171731 TI - SAA1 gene variants and childhood obesity in China. AB - BACKGROUND: Obesity increases the risk for insulin resistance and metabolic syndrome in both adults and children. SAA is a member of apolipoprotein and plays an important role in maintaining glucose and lipid homeostasis. The purpose of this study was to assess SAA1 allelic variants with obesity in young school-age children. METHODS: A total of 520 consecutive children ages 5-15 years were recruited. Children were divided based on BMI z score into Obese (OB; BMI z score >=1.65; n = 253) and non-obese (NOB; n = 267). Four SNPs of the human SAA1 gene (rs12218, rs4638289, rs7131332 and rs11603089) were genotyped by use of polymerase chain reaction - restriction fragment length polymorphism (PCR-RFLP) method. RESULTS: Compared to NOB, circulating SAA levels were increased in OB, as were LDL-C, TG and TC concentration. Obese children showed increased frequency of rs12218 and rs4638289 polymorphism compared to control children. There were no differences between OB and NOB for the other 2 polymorphisms. Only the rs4638289 polymorphism showed significant contributions to higher SAA plasma levels. CONCLUSIONS: SAA1 genetic polymorphism was associated with obesity in Chinese children. PMID- 24171733 TI - The effect of emotional arousal and retention delay on subsequent-memory effects. AB - Memory for emotional experiences often persists longer than memory for neutral experiences. The present study examined how encoding processes influence memory retention across 0.5- or 24-h delays and whether these processes differ between emotionally arousing and neutral information. Participants encoded items during an fMRI scan. Immediately following the scan, and again 24-h later, participants performed a recognition memory test. The results revealed that, for emotionally arousing information, most regions showed a correspondence to subsequent-memory performance that was at least as strong after the long delay as it was after the short delay. For neutral items, by contrast, many more regions, including portions of the hippocampus and lateral prefrontal cortex, showed a stronger correspondence to subsequent-memory performance after the short delay than the long delay. These results suggest that the processes engaged at the moment of encoding have a longer-lasting relation to subsequent memory for emotionally arousing information than for neutral information. PMID- 24171734 TI - Electrophysiological insights into control over recollection. AB - Electrophysiological correlates of successful episodic retrieval were measured in an experiment where participants switched frequently between two different episodic retrieval conditions. They completed three trials of each condition before switching to the other condition. The key contrasts were between neural indices of successful retrieval that were separated according to the number of successive trials of the same condition that had been completed. An electrophysiological correlate of recollection--the left-parietal event-related potential (ERP) old/new effect--was smaller on the first and second trial than on the third successive trial that participants completed for each condition. This ERP old/new effect is assumed to index the extent to which recollection has occurred, and this outcome suggests that control over recovery of task-relevant episodic content is compromised when additional cognitive demands are imposed around the time of retrieval. PMID- 24171736 TI - Intermixing forms of memory processing within the functional organization of the medial temporal lobe memory system. AB - Abstract Voss et al. discuss evidence indicating an intermixing of implicit and explicit memory processing, and of familiarity and recollection, in tests of memory. Here I support this view, and add that the anatomy of cortical-medial temporal lobe pathways indicates a hierarchical and bidirectional functional organization of memory in which implicit memory processing contributes to familiarity, and implicit memory and familiarity processing inherently contribute to recollection. Rather than look for new ways to separate these processes, it may be as important to understand how they are integrated. PMID- 24171737 TI - You can feel it all over: Many signals potentially contribute to feelings of familiarity. AB - Abstract Voss, Lucas, and Paller provide a thought-provoking summary of their recent research showing that neural effects which are often attributed to (explicit) feelings of familiarity can instead be attributed to the (implicit) effects of conceptual priming. Here, we discuss research that shows effects of priming on (putative) behavioral and neural measures of familiarity, and consider a slightly different interpretation: That multiple neurocognitive processes can serve as signals to prior experience with a test item (i.e., can influence judgments of familiarity), and the set of signals that will be interpreted as familiarity depends on the experimental context. PMID- 24171735 TI - More than a feeling: Pervasive influences of memory without awareness of retrieval. AB - The subjective experiences of recollection and familiarity have featured prominently in the search for neurocognitive mechanisms of memory. However, these two explicit expressions of memory, which involve conscious awareness of memory retrieval, are distinct from an entire category of implicit expressions of memory that do not entail such awareness. This review summarizes recent evidence showing that neurocognitive processing related to implicit memory can powerfully influence the behavioral and neural measures typically associated with explicit memory. Although there are striking distinctions between the neurocognitive processing responsible for implicit versus explicit memory, tests designed to measure only explicit memory nonetheless often capture implicit memory processing as well. In particular, the evidence described here suggests that investigations of familiarity memory are prone to the accidental capture of implicit memory processing. These findings have considerable implications for neurocognitive accounts of memory, as they suggest that many neural and behavioral measures often accepted as signals of explicit memory instead reflect the distinct operation of implicit memory mechanisms that are only sometimes related to explicit memory expressions. Proper identification of the explicit and implicit mechanisms for memory is vital to understanding the normal operation of memory, in addition to the disrupted memory capabilities associated with many neurological disorders and mental illnesses. We suggest that future progress requires utilizing neural, behavioral, and subjective evidence to dissociate implicit and explicit memory processing so as to better understand their distinct mechanisms as well as their potential relationships. When searching for the neurocognitive mechanisms of memory, it is important to keep in mind that memory involves more than a feeling. PMID- 24171738 TI - On the contribution of unconscious processes to recognition memory. AB - Abstract Voss et al. review work showing unconscious contributions to recognition memory. An electrophysiological effect, the N300, appears to signify an unconscious recognition process. Whether such unconscious recognition requires highly specific experimental circumstances or can occur in typical types of recognition testing situations has remained a question. The fact that the N300 has also been shown to be the sole electrophysiological correlate of the recognition-without-identification effect that occurs with visual word fragments suggests that unconscious processes may contribute to a wider range of recognition testing situations than those originally investigated by Voss and colleagues. Some implications of this possibility are discussed. PMID- 24171739 TI - Reconsidering the use of "explicit" and "implicit" as terms to describe task requirements. AB - Abstract Conscious and unconscious expressions of memory-explicit and implicit memory, respectively-may be used to support performance in a given task, even when the task demands do not ostensibly require one or the other. Work from Voss, Lucas and Paller reveal that just as indirect tasks can capture the influence of explicit memory, direct tasks of memory can capture implicit memory mechanisms. Consequently, tasks cannot be truly labeled as explicit or implicit; as such labels presuppose, perhaps erroneously, the nature of memory that supports performance. PMID- 24171741 TI - "Implicit contamination" extends across multiple methodologies: Implications for fMRI. AB - Abstract The article "More than a feeling: Pervasive influences of memory without awareness of retrieval" reviews evidence from ERP studies of recognition memory that the FN400 effect typically ascribed to familiarity may index implicit memory that occurs during recognition testing. We find their argument compelling, and contend that this potential "implicit contamination" is not unique to ERP studies. We suggest an analogous problem affecting fMRI studies, focusing particularly on the perirhinal cortex. Resolving this issue is critical for understanding the relationship between memory and the medial temporal lobes. PMID- 24171740 TI - Familiarity and conceptual implicit memory: Individual differences and neural correlates. AB - Abstract Voss, Lucas, and Paller point out that explicit recognition tests can be supported by implicit processes, and that conceptual implicit memory may be reflected in ERP correlates of familiarity-based recognition. Here, we argue that an examination of individual differences indicates that familiarity is coupled with conceptual implicit memory across participants, and that fMRI and patient data indicate that the perirhinal cortex is critical for both forms of memory. We suggest that the same process that leads an item to come to mind readily in conceptual implicit tests may also lead the item to seem familiar in explicit recognition tests. PMID- 24171742 TI - It is time to fill in the gaps left by simple dissociations. AB - Abstract Our field has been dominated by the quest for dissociations. A number of the dissociations have gotten us far and the implicit/explicit one is an excellent example. It holds in the vast majority of cases and has furthered our understanding of memory considerably. There are now several very interesting exceptions to this basic rule that highlight how systems may interact and how independence is an option or a default, but not a necessity. We should not throw away the fundamental dissociation, but nor should we fail to learn from the interesting exceptions. PMID- 24171743 TI - The impact of fluency on explicit memory tasks in amnesia. AB - Abstract Distinguishing implicit and explicit memory and delineating their relationship has haunted memory researchers for decades, and Voss et al. provide an impressive overview of their work examining these issues. We briefly comment on the following: (1) There is evidence indicating that implicit memory impacts cued recall, in addition to recognition; (2) Fluency can manifest as priming in implicit memory or it can be experienced as familiarity (in association with attribution processes) in recognition tasks; and (3) The impact of fluency on accuracy of "guess" responses during recognition memory in normal subjects is reminiscent of similar effects on recognition in amnesia. PMID- 24171744 TI - Electrophysiological correlates of memory processes. AB - Abstract In this commentary we highlight what are to our minds conflicting findings that have been employed to argue for different functional accounts of the mid-frontal event-related potential (ERP) old/new effect. We also offer our views on the difficulties associated with measuring conceptual priming as well as familiarity, and reemphasise that these issues are only a sub-set of those to consider when assessing the ERP literature that is germane to the question of the proceses that the mid-frontal ERP old/new effect indexes. PMID- 24171745 TI - On the pervasive influences of implicit memory. AB - In Voss, Lucas, and Paller (2012) we reviewed evidence that behavioral, neural and subjective phenomena often considered to be hallmarks of explicit memory can be powerfully influenced by processing related to implicit memory. We argued that, as a result, behavioral and neuroimaging experiments designed to measure explicit memory are sometimes prone to capture aspects of implicit memory instead. The nine commentaries published in response to our target article largely resonated with these conclusions. Here we highlight the numerous additional insights offered by these commentaries regarding the circumstances and precise mechanisms that may characterize relationships between implicit and explicit memory, and we describe similarities and differences with our interpretations. PMID- 24171746 TI - Predictive coding, precision and synchrony. AB - Abstract Gotts, Chow and Martin provide a very nice review of repetition priming and suppression that reaches a compelling conclusion-we need to look more closely at synchronization in learning and priming. Indeed, current modeling work focuses on this issue-namely, the dynamic causal modeling of electrophysiological responses to address the role of synchrony in Bayesian explaining away. This commentary revisits the nature and relationships among the four theories in Gotts et al. and nuances some of their empirical predictions. In particular, I emphasize precision or uncertainty in predictive coding as a unifying consideration. PMID- 24171747 TI - Explaining away repetition effects via predictive coding. AB - Abstract Gotts, Chow and Martin summarize Predictive Coding models in which repetition-related decreases in neural activity reflect an "Explaining Away" of stimulus-driven neural activity. Here we elaborate the subtleties of testing such models, particularly with fMRI. PMID- 24171748 TI - Repetition accelerates neural dynamics: In defense of facilitation models. AB - Abstract Gotts, Chow and Martin give an excellent contemporary summary of the neural mechanisms that have been proposed to underlie the effects of stimulus repetition on brain and behavior. Here I comment on their Facilitation mechanism, and provide EEG evidence that repetition can accelerate neural processing. PMID- 24171749 TI - Learning-induced sharpening of neuronal tuning and adaptation: Not "mixed". AB - Abstract Gotts et al. present an attractive model of how priming can arise from neuronal adaptation effects. Their very satisfying account helps to demystify adaptation effects. In fact, adaptation effects are even less mysterious than portrayed: While Gotts et al. state that "fMRI studies in humans that have attempted to evaluate sharpening of visual object representations with experience have ... generated mixed results", referring to fMRI adaptation (fMRI-A) studies by our group and others, the results described in the cited papers are in fact entirely compatible, further establishing the usefulness of fMRI-A to probe neuronal tuning in humans. PMID- 24171750 TI - Synchrony upon repetition: One or multiple neural mechanisms? AB - Abstract A central goal of cognitive neuroscience is to understand the relationship between repetition suppression (RS) and priming. Gotts and colleagues propose a new model examining this relationship where stimulus repetition produces increased neural synchronization, thus increasing the efficiency of neural responses and potentially explaining the characterizing features of both RS and priming. While synchrony is an appealing new model, we suggest that further constraints are necessary to account for qualitatively different types of RS and priming yet to be considered by the present implementation. PMID- 24171751 TI - All in the timing: Priming, repetition suppression, and synchrony. AB - Abstract The terms "priming" and "repetition suppression" are commonly used to refer to phenomena occurring on time scales that can differ by several orders of magnitude, ranging from seconds to days or even years. The models discussed by Gotts et al. provide a thought-provoking theoretical framework for relating neuronal and behavioral plasticity. I argue that whereas both the sharpening and the Bayesian models may mediate the gradual acquisition of perceptual expertise, they are unlikely to account for more rapid behavioral changes. The synchrony model, however, could potentially operate within the timing constraints imposed by the fastest forms of repetition priming. PMID- 24171752 TI - Focusing on the frontal cortex. AB - Abstract Gotts et al. provide a timely review of the major neural models of repetition suppression (RS) and priming. They justifiably call on researchers to focus their attention on the extent to which these phenomena can be explained by changes in synchrony between cortical regions. They are relatively agnostic as to which regions may be critical to RS and priming. Here I argue we should devote more attention to the role of frontal regions, and suggest that there is a need to engage with more cognitive accounts of priming in order to develop a comprehensive neurocognitive account of priming and RS. PMID- 24171753 TI - Repetition suppression and repetition priming are processing outcomes. AB - Abstract There is considerable evidence that repetition suppression (RS) is a cortical signature of previous exposure to the environment. In many instances RS in specific brain regions is accompanied by improvements in specific behavioral measures; both observations are outcomes of repeated processing. In understanding the mechanism by which brain changes give rise to behavioral changes, it is important to consider what aspect of the environment a given brain area or set of areas processes, and how this might be expressed behaviorally. PMID- 24171754 TI - Task, time and context as potential mediators of repetition priming effects. AB - Abstract In apparent conflict with the synchronicity model, we consider three types of evidence from the auditory literature (negative priming, perceptual learning, sensory gating) that reveal stimulus repetition can be associated with decreased rather than increased early evoked responses. The difficulty with consolidating a wide range of tasks in adjudicating between theories of repetition priming might be because the potentially critical roles of task, time and context are neglected. PMID- 24171755 TI - Repetition priming and repetition suppression: Multiple mechanisms in need of testing. AB - In our Discussion Paper, we reviewed four theoretical proposals that have the potential to link the neural and behavioral phenomena of Repetition Suppression and Repetition Priming. We argued that among these proposals, the Synchrony and Bayesian Explaining Away models appear to be the most promising in addressing existing data, and we articulated a series of predictions to distinguish between them. The commentaries have helped to clarify some of these predictions, have highlighted additional evidence supporting the Facilitation and Sharpening models, and have emphasized dissociations by repetition lag and brain location. Our reply addresses these issues in turn, and we argue that progress will require the testing of Repetition Suppression, changes in neural tuning, and changes in synchronization throughout the brain and over a variety of lags and task contexts. PMID- 24171757 TI - Giant cell tumour of the rib: an unusual location for an impressive tumour. PMID- 24171758 TI - Evaluation of antihyperglycemic and antinociceptive activity of Xanthium indicum stem extract in Swiss albino mice. AB - BACKGROUND: Xanthium indicum stem is used in folk medicine of Bangladesh to control sugar in diabetic patients and to alleviate pain. The objective of the study was to evaluate antihyperglycemic and antinociceptive activity of methanolic extract of Xanthium indicum stems (XISE) in mice. METHODS: Antihyperglycemic activity was measured by oral glucose tolerance tests in glucose-loaded Swiss albino mice. Antinociceptive activity was determined by observed decreases in abdominal constrictions in acetic acid-induced gastric pain model in mice. RESULTS: The methanol extract of stems showed dose-dependent and statistically significant antihyperglycemic activity at doses of 50, 100, 200 and 400 mg per kg body weight (p values, respectively, < than 0.01, 0.01, 0.005, and 0.01). Highest reduction in blood glucose level (31.2%) was observed with the highest dose (400 mg) of the extract. A standard antihyperglycemic drug, glibenclamide, reduced blood glucose levels by 46.2%, when administered at a dose of 10 mg per kg body weight. In antinociceptive activity tests, the extract when administered at the aforementioned four doses, reduced the number of abdominal constrictions in mice, respectively, by 41.7, 50.0, 54.2, and 61.0%. In comparison, a standard antinociceptive drug, aspirin, when administered at a dose of 200 mg per kg body weight, reduced the number of abdominal constrictions by 37.5%. CONCLUSION: The experimental results obtained in the present study validate the use of X. indicum stems in folk medicines of Bangladesh to lower blood sugar in diabetic patients and to alleviate pain. PMID- 24171760 TI - Effluent syntaxin3 from dying cells affords protection against apoptosis in epidermal keratinocytes. AB - Ultra-violet B (UVB)-induced oxidative stress crucially perturbs the epidermal homeostasis, and the skin is endowed with protective mechanisms to take action against such damage. Here, we show the possible involvement of t-SNARE protein syntaxin3, a membrane fusion mediator of cytoplasmic vesicles, and which is released from dying keratinocytes, to play a role in this response. UVB irradiation, which generates reactive oxidative stress in cells, was shown to lead to the keratinocyte cell death accompanied by a release of cytoplasmic syntaxin3. We found that such extracellularly sourced syntaxin3 completely blocked the processing of a crucial effector for apoptotic cell death, caspase-3, and thus facilitated the survival of keratinocytes damaged by oxidative stress. These results demonstrate the latent prosurvival function of syntaxin3 and underline the importance of intracellular molecular elements for the maintenance of homeostasis in epidermal keratinocytes. PMID- 24171759 TI - Reduced cerebral blood flow and white matter hyperintensities predict poor sleep in heart failure. AB - BACKGROUND: Poor sleep is common in heart failure (HF), though mechanisms of sleep difficulties are not well understood. Adverse brain changes among regions important for sleep have been demonstrated in patients with HF. Cerebral hypoperfusion, a correlate of sleep quality, is also prevalent in HF and a likely contributor to white matter hyperintensities (WMH). However, no study to date has examined the effects of cerebral blood flow, WMH, and brain volume on sleep quality in HF. METHODS: Fifty-three HF patients completed the Pittsburgh Sleep Quality Index and underwent brain magnetic resonance imaging to quantify brain and WMH volume. Transcranial Doppler ultrasonography assessed cerebral blood flow velocity of the middle cerebral artery (CBF-V of the MCA). RESULTS: 75.5% of HF patients reported impaired sleep. Regression analyses adjusting for medical and demographic factors showed decreased CBF-V of the MCA and greater WMH volume were associated with poor sleep quality. No such pattern emerged on total brain or regional volume indices. CONCLUSIONS: Decreased cerebral perfusion and greater WMH may contribute to sleep difficulties in HF. Future studies are needed to confirm these findings and clarify the effects of cerebral blood flow and WMH on sleep in healthy and patient samples. PMID- 24171761 TI - Relationship between platelet volume indices with macrovascular and peripheral neuropathy complications in type 2 diabetic patients. AB - BACKGROUND: The relationship of platelet volume indices including mean platelet volume (MPV) and platelet distribution width (PDW) with carotid intima-media thickness (IMT) as well as vibration perception threshold (VPT) was investigated in type 2 diabetic patients. METHODS: A total of 500 type 2 diabetic patients (298 male, 202 female) were enrolled. Clinical and laboratory data were collected from hospital records. RESULTS: Both MPV and PDW were significantly associated with carotid IMT, after adjustment for confounding factors including age, systolic blood pressure, total cholesterol and creatinine (0.833 +/- 0.029 mm vs. 0.955 +/- 0.030 mm; 0.839 +/- 0.029 mm vs. 0.955 +/- 0.030 mm; P = 0.0015 and P = 0.022, respectively). Agreed with carotid IMT analysis results, significant association was found between PDW and VPT as tertiles (15.760 +/- 1.091V vs 20.187 +/- 1.094V, P = 0.016). In multivariable analysis, both MPV and PDW were significantly associated with VPT (P = 0.021 and P = 0.007, respectively). However, only PDW, but not MPV, was significantly associated with carotid IMT (P = 0.002). CONCLUSIONS: These findings implied the predictive value of platelets volume indices in vascular and peripheral neuropathy complications in type 2 diabetes. PMID- 24171762 TI - Correlation between optic nerve head parameters, RNFL, and CCT in patients with bilateral pseudoexfoliation using HRT-III. AB - BACKGROUND: It is well-established that eyes with pseudoexfoliation syndrome (PXS) have higher intraocular pressure (IOP). Early diagnosis of preperimetric glaucoma will assist with better management of these patients. The aim of this study is to evaluate the optic nerve head (ONH) parameters and retinal nerve fiber layer (RNFL) thickness in subjects with bilateral PXS, bilateral pseudoexfoliative glaucoma (PXG) and normal, correlating these results with central corneal thickness (CCT). DESIGN: This is a cross-sectional, case control study. All participants were from the Department of Ophthalmology, Athens University Medical School. PARTICIPANTS: A total of 55 eyes from 55 patients with PXS (27 eyes from 27 patients with PXG and 28 eyes from 28 normal subjects) were studied. METHODS: Topographic measurements of the ONH and peripapillary RNFL thickness were performed using a confocal scanning laser ophthalmoscope (the Heidelberg Retina Tomograph-III). The outcomes were correlated with the CCT of the subjects. MAIN OUTCOME MEASURES: PXS subjects and age-matched normal subjects did not differ significantly in ONH parameters. RNFL thickness was significantly lower in the PXS group compared with the normal group, but there was not a statistically significant difference with the PXG patients. Regarding the correlation with CCT, the PXG group showed negative correlation with mean (p = 0.027) and max cup depth (p = 0.031), while PXS subjects revealed a positive correlation with RNFL thickness (p = 0.032). CONCLUSIONS: Our study showed that PXS subjects may be at greater risk of RNFL thinning, presenting a statistically significant positive association of the latter parameter with the CCT. PMID- 24171763 TI - Motor development of infants exposed to maternal human immunodeficiency virus (HIV) but not infected. AB - BACKGROUND: To assess the motor development of infants exposed to maternal human immunodeficiency virus (HIV). METHODS: Thirty infants were assessed in the period from November 2009 to March 2010 at the AIDS Reference and Training Centre, in Sao Paulo, Brazil. The assessment instrument used in the research was the Alberta Infant Motor Scale (AIMS). All 30 infants used the antiretroviral drug properly for 42 consecutive days, in accordance with the protocol of the World Health Organization. RESULTS: Out of the total number of infants, 27 (90%) had proper motor performance and 3 (10%) presented motor delay, according to the AIMS. DISCUSSION: This study demonstrated that only 10% of the assessed group had developmental delay and no relation with environmental variables was detected, such as maternal level of education, social and economic issues, maternal practices, attendance at the day care center, and drug use during pregnancy. It is important to emphasize the necessity of studies with a larger number of participants. PMID- 24171764 TI - Influence of EDTA and dentine in tissue dissolution ability of sodium hypochlorite. AB - This study verified whether ethylenediaminetetraacetic acid (EDTA) influences the pulp tissue dissolution capability of different concentrations of NaOCl, in the presence of dentine. NaOCl and EDTA solutions were simultaneously mixed in flasks either containing a dentine disc or those not containing a dentine disc. Previously weighed bovine pulp tissues were immersed in the solutions for 5, 15 and 30 min. The weight loss was measured. The dissolution tests were performed in triplicate. Univariate analysis of variance, along with further Tukey's honestly significant difference pairwise comparisons, was used to verify the effect of EDTA, different concentrations of NaOCl, dentine and time of incubation on the tissue dissolution. Higher concentrations of NaOCl increased the tissue dissolution. EDTA reduced the capacity of NaOCl to dissolve pulp tissue, even in presence of dentine. Dentine negatively affects the capacity of NaOCl to dissolve pulp tissue. In conclusion, the presence of EDTA and dentine negatively affects the tissue dissolution ability of NaOCl. PMID- 24171765 TI - HPLC-DAD-ESI-MS analysis of phenolic compounds during ripening in exocarp and mesocarp of tomato fruit. AB - Identification of phenolic compounds was done by means of liquid chromatography (HPLC) coupled to mass spectrometry (MS) using the electrospray ionization interface (ESI). Quantification of phenolic compounds was carried out by using HPLC with diode array detector (DAD) in exocarp and mesocarp of tomato fruit at 6 different ripeness stages (mature-green, breakers, turning, pink, light-red, and red). Several phenolic compounds were identified including chlorogenic acid, caffeic acid, p-coumaric acid, ferulic acid, and rutin and some combined phenolic acids were tentatively identified, mainly glycosides, such as caffeoyl hexose I, caffeoyl hexose II, caffeoylquinic acid isomer, dicaffeoylquinic acid, p coumaroyl hexose I, p-coumaroyl hexose II, feruloyl hexose I, feruloyl hexose II, siringyl hexose, and caffeoyl deoxyhexose hexose. Fruit exocarp had higher quantities of total soluble phenolics (TSP) compared to mesocarp. During ripening, TSP increased in both exocarp and mesocarp, mainly in exocarp. While rutin increased, chlorogenic acid decreased in both tissues: exocarp and mesocarp. PMID- 24171766 TI - Common low-penetrance risk variants associated with breast cancer in Polish women. AB - BACKGROUND: Breast cancer is the most common type of cancer and the second leading cause of cancer-death among women in Poland. The known high-risk mutations account for 25% of familial aggregation cases and 5% of total breast cancer predisposition. Genome-wide association studies have identified a number of common low-penetrance genetic variants, but their contribution to disease risk differs between populations. METHODS: To verify selected associations with breast cancer susceptibility among Polish women, the replication study was performed, included 1424 women with breast cancer and 1788 healthy persons. Sixteen single nucleotide polymorphisms (SNPs) were analyzed using TaqMan SNP Genotyping Assays. Allele frequency differences were tested using chi2-test implemented in PLINK v1.07 and Cochran-Armitage trend test was performed using R software. RESULTS: Significant differences (Bonferroni corrected p-valuecor <= 0.0197) in the frequency of alleles distribution between all cancer and control subjects were observed for four (rs2736098, rs13281615, rs1219648, rs2981582) out of 16 SNPs. The same result was obtained for group of patients without high-risk BRCA1/2 mutations. The rs1219648 (p-valuecor <= 6.73E-03) and rs2981582 (p-valuecor <= 6.48E-03) SNPs showed significant association with both familial and sporadic cancers. Additionally, rs2736098 (p-valuecor <= 0.0234) was associated with only sporadic cancers; also in group without carriers of high-risk mutation. All these associations revealed their significance also in Cochran-Armitage trend test. Opposite to other SNPs, rs2736098 was associated with a decreased risk of breast cancer. CONCLUSION: The association of four known susceptibility SNPs, representing three individual loci, with breast cancer risk in Polish women was confirmed. One of them (rs2736098) seems to be specific for the Polish population. Due to the population differences in allele frequencies, identification of general genetic risk factors requires sets of association studies conducted on different populations. PMID- 24171767 TI - Nicotinamide phosphoribosyltransferase as a target in inflammation- related disorders. AB - NAD+ biosynthesis through nicotinamide phosphoribosyltransferase (NAMPT) holds potential as a target for the treatment of inflammatory disorders due to NAD(+)'s role in immune cell signaling and metabolism. In addition to its activity as an enzyme, NAMPT is also secreted in the extracellular space where it acts as a pro inflammatory and proangiogenic cytokine. NAMPT inhibition with FK866 has anti inflammatory activity in different models of immune disorders and it prevents ischemia-reperfusion-induced heart damage by dampening the production of neutrophil chemoattractants. NAMPT blockade with a neutralizing antibody has beneficial effects in an acute lung injury model. Last, but not least, the anticancer activity of NAMPT inhibitors may also reflect, at least in part, their ability to modify the cancer microenvironment through their anti-inflammatory properties. Overall, NAMPT inhibition holds potential for the treatment of inflammation-related disorders and the development of effective and safe NAMPT inhibitors remains an area of strong interest in pharmaceutical research. PMID- 24171768 TI - NAD+-dependent enzymes at the endoplasmic reticulum. AB - The post-translational modifications of proteins by mono- and poly-ADP ribosylation involve the cleavage of betaNAD+, with the release of its nicotinamide moiety, accompanied by the transfer of a single (mono) or several (poly) ADP-ribose molecules from betaNAD+ to a specific amino-acid residue of various cellular proteins. Thus, both mono- and poly-ADP-ribosylation are NAD+ consuming reactions. ADP-ribosylation reactions have been reported to have important roles in the nucleus, and in mitochondrial activity. Distinct subcellular NAD+ pools have been identified, not only in the nucleus and the mitochondria, but also in the endoplasmic reticulum and peroxisomes. Recent reports have shed new light on the correlation between NAD+-dependent ADP ribosylation reactions and the endoplasmic reticulum. We have demonstrated that ARTD15/PARP16 is a novel mono-ADP-ribosyltransferase with a new intracellular location, as it is associated with the endoplasmic reticulum. The endoplasmic reticulum is a membranous network of tubules, vesicles, and cisternae that are interconnected in the cytoplasm of eukaryotic cells. This intracellular compartment is responsible for many cellular functions, including facilitation of protein folding and assembly, biosynthesis of lipids, storage of intracellular Ca2+, and transport of proteins. ARTD15 might have a role in both the nucleo cytoplasmic shuttling, through importinbeta1 mono-ADP-ribosylation, and in the unfolded protein response through its ability to ADP-ribosylate two components of this pathway: PERK and IRE1. This review summarizes our present knowledge of the enzymes and targets involved in ADP-ribosylation reactions, with special regard to the novel regulatory reactions that occurs at the level of the endoplasmic reticulum, and that can affect the function of this organelle. PMID- 24171769 TI - The histone deacetylase SIRT6: at the crossroads between epigenetics, metabolism and disease. AB - SIRT6 is one of the seven members of the NAD-dependent family of sirtuins mammals. The pleotropic identity of SIRT6 is manifested into several catalytic activities such as deacetylation, deacylation and ribosylation, which allow the targeting of a variety of protein substrates, that influence the physiology of multiple cell types and tissues. SIRT6- dependent deacetylation of histone H3 at lysines 9 and 56 is required for the regulation of genes associated with glucose/ lipid metabolism as well as the maintenance of telomeric regions and the repair of DNA double strand breaks. Importantly, SIRT6 depletion alters the levels of acetylated histone H3 causing a deregulation of genes involved in glycolysis and the Myc-target network, which results in tumorigenesis. Hence, SIRT6 has been recently categorized as a tumor suppressor. The deacylation activity of SIRT6 has been attributed to the regulation of TNF-alpha secretion. However, the physiological relevance of this newly discovered catalytic activity of SIRT6 remains to be determined in vivo. SIRT6 also undergoes auto-ribosylation, which might contribute to a self-regulation of catalytic functions. SIRT6-mediated ribosylation also enhances PARP1-dependent DNA repair under oxidative stress and aging. Overall, SIRT6 is a critical enzyme required to maintain glucose/lipid homeostasis and genomic stability, thereby promoting resistance to oxidative stress and DNA damage, which are associated to age-related illness. Evocative of its ancestor, yeast Sir2, SIRT6 has the ability to increase lifespan in mice. SIRT6 deficiency is associated with various diseases including inflammation, cardiac hypertrophy, liver dysfunction, adipocyte/muscle disorders, and cancer. This review describes the most current information regarding the molecular and physiological relevance of SIRT6 in the context of epigenetics, metabolism and disease. PMID- 24171770 TI - NAADP signaling revisited. AB - Nicotinic acid adenine dinucleotide phosphate (NAADP) is the most potent Ca2+ mobilizing endogenous compound known to date. Although its Ca2+ releasing activity has been demonstrated in many cell types and in response to different extracellular stimuli, several aspects of NAADP signaling are unclear. This overview focuses on the controversial aspects and reviews NAADP's role as second messenger: endogenous concentrations and its receptor-mediated alterations, metabolism, and potential organelle and ion channel targets. Finally, the role of NAADP as Ca2+ trigger is discussed by reviewing the development of local into global Ca2+ signals evoked by NAADP. PMID- 24171771 TI - Integrative neurochemistry and neurobiology of social recognition and behavior analyzed with respect to CD38-dependent brain oxytocin secretion. AB - This review summarizes the literature and our own data regarding the role of NAD+ glycohydrolase/CD38-controlled molecular mechanisms of hypothalamic and pituitary oxytocin secretion in social behavior regulation. Current approaches to the modulation of both CD38 expression and brain cell activity that represent prospective treatments for disorders associated with altered social behavior are discussed. PMID- 24171772 TI - Multiple metamorphoses of CD38 from prognostic marker to disease modifier to therapeutic target in chronic lymphocytic leukemia. AB - Human CD38, an ecto-enzyme and a receptor, performs as an independent negative prognostic marker for patients with chronic lymphocytic leukemia (CLL), a hematological malignancy characterized by the accumulation of a population of mature B lymphocytes expressing CD5. Patients with a CD38+ CLL clone display a more aggressive form of the disease with earlier treatment requirements and ultimately shorter overall survival than patients with a CD38- clone. Several lines of evidence indicate that CD38 is not only a diagnostic marker but also a key element in the molecular network regulating disease maintenance and progression. First, CD38 is a receptor that induces proliferation and increases survival of CLL cells. Second, CD38 signals facilitate access of CLL cells to growth-favorable districts. This is achieved by enhancing i) chemotaxis towards CXCL12, ii) integrin-mediated adhesion and iii) matrix metalloprotease synthesis and secretion. Third, blocking monoclonal antibodies targeting CD38 impair CLL homing to spleen and bone marrow in xenograft models. These functions appear to be modulated by frontal interactions with CD31 as well as by lateral associations on the CLL membrane to form a large supramolecular complex similar to the invadosomes of epithelial cells. Our understanding has evolved from considering CD38 as a marker of unfavorable prognosis to recognizing its function as a disease modifier. Studies in the next few years will likely determine whether the molecule can also serve as a target for new therapies, using monoclonal antibodies, inhibitors of the enzymatic activity or both. PMID- 24171773 TI - From polypharmacology to target specificity: the case of PARP inhibitors. AB - Poly(ADP-ribose)polymerases (PARPs) catalyze a post-transcriptional modification of proteins, consisting in the attachment of mono, oligo or poly ADP-ribose units from NAD+ to specific polar residues of target proteins. The scientific interest in members of this superfamily of enzymes is continuously growing since they have been implicated in a range of diseases including stroke, cardiac ischemia, cancer, inflammation and diabetes. Despite some inhibitors of PARP-1, the founder member of the superfamily, have advanced in clinical trials for cancer therapy, and other members of PARPs have recently been proposed as interesting drug targets, challenges exist in understanding the polypharmacology of current PARP inhibitors as well as developing highly selective chemical tools to unravel specific functions of each member of the superfamily. Beginning with an overview on the molecular aspects that affect polypharmacology, in this article we discuss how these may have an impact on PARP research and drug discovery. Then, we review the most selective PARP inhibitors hitherto reported in literature, giving an update on the molecular aspects at the basis of selective PARP inhibitor design. Finally, some outlooks on current issues and future directions in this field of research are also provided. PMID- 24171774 TI - NAD metabolism and functions: a common therapeutic target for neoplastic, metabolic and neurodegenerative diseases. AB - In recent years the study of nicotinamide adenine dinucleotide (NAD) biochemistry has been the focus of attention for many researchers. Although the role of NAD in cellular metabolism and in redox reactions had been recognized for over a century, it was also during these recent studies that the precise identification of all NAD biosynthetic routes was achieved and that the variety of NAD controlled cellular processes began to emerge. Being vital not only for energy transduction, but also for intracellular signaling pathways, this pyridine nucleotide can be considered the most important link between energetic and regulatory processes. The control of such important events suggested NAD as a possible therapeutic target for the control of different pathological states, including metabolic disorders and neoplastic transformation. This review briefly summarizes the recent advances achieved in this field. PMID- 24171775 TI - NAD biosynthesis in humans--enzymes, metabolites and therapeutic aspects. AB - NAD plays a major role in all cells as substrate for signal transduction and as cofactor in metabolic redox reactions. Since NAD-dependent signaling involves degradation of the nucleotide, continuous restoration of cellular NAD pools is essential. Moreover, NAD-dependent signaling reactions, which include ADP ribosylation, protein deacetylation by sirtuins and calcium messenger synthesis, are regulated by NAD availability. Consequently, perturbations of NAD supply can have severe consequences and, in fact, have been associated with major human diseases such as age- and diet-induced disorders, neurodegenerative diseases and cancer. Given the increasing awareness of the biological roles of NAD, the routes, molecular mechanisms and regulation of NAD biosynthesis have been the subject of intense research over the last decade. Impressive progress has been made regarding the molecular identification, functional and structural characterization as well as regulation of the human NAD biosynthetic enzymes. Exciting therapeutic concepts have emerged, which aim at modulation of NAD availability by interfering with the biosynthetic network to prevent, reduce or reverse pathological conditions. Since there are several entry points into NAD synthesis, including the known vitamin B3 precursors nicotinamide and nicotinic acid, targeted nutritional supplementation is likely to have beneficial effects in various diseases. On the other hand, inhibition of NAD synthesis promotes cell death and has emerged as a therapeutic concept for cancer treatment. PMID- 24171777 TI - Hibernoma of the chest wall: to excise or not to excise? PMID- 24171778 TI - Fructose 1, 6-diphosphate regulates desmosomal proteins and collagen fibres in human skin equivalents. AB - We previously reported that fructose 1,6-diphosphate (FDP), a glycolytic metabolite, alleviates ultraviolet B-induced oxidative skin damage. Here, we further examined the effects of FDP on skin. FDP decreased the number of desmosomes, whereas it increased collagen fibres in skin equivalents (SEs). FDP significantly decreased the expression of corneodesmosomal components such as desmoglein 1 (DSG1), desmocollin 1 (DSC1) and corneodesmosin (CDSN), and desquamation-related proteases, kallikrein 5 (KLK 5) and kallikrein 7 (KLK7) in normal human epidermal keratinocytes (NHEKs). In addition, FDP treatment increased the phosphorylation of p38 MAPK, but the decreased expression of corneodesmosomal components is not recovered by the treatment of p38 MAPK inhibitors. Interestingly, FDP diminished the amplitude of Ca(2+) fluxes through down-regulation of SERCA2. Taken together, these results suggested that FDP induced a decrease in desmosomes and an increase in collagen fibres similar to the process of chemical peeling, the most common treatments for ageing skin. PMID- 24171779 TI - The influence of the Korean traditional Chungkookjang on variables of metabolic syndrome in overweight/obese subjects: study protocol. AB - BACKGROUND: Metabolic syndrome is a set of disorders that increases the risk of developing cardiovascular disease. The primary target of treatment of patients with metabolic syndrome is therapeutic lifestyle change. Numerous preclinical study have reported positive effects of chungkookjang in in vivo models of diabetes and obesity, but there is a paucity of controlled clinical trials on variables of metabolic syndrome in obese subjects. Thus, the objective of this trial is to examine the effect of chungkookjang compared to placebo on variables of metabolic syndrome in overweight/obese subjects. METHODS: This double-blind randomized controlled crossover trial will be conducted on 120 overweight/obese subjects; aged 19-29 years. Subjects will be recruited from the Chonbuk National University, Jeonju, South Korea. Enrolled subjects will be randomly assigned to two groups of equal number; one group received 35 g of chungkookjang (n = 60) and the other group received placebo (n = 60) on a regular daily basis for 12 weeks. After a 12-week washout period, the groups will be crossed over. In addition to anthropometric measures and blood pressure, glucose parameter, lipid profile, adipocytokine, and carnitine assay will be determined at baseline and 12 week. Also, safety will be assessing by measuring total bilirubin, alkaline phosphatase, alanine transaminase, aspartate aminotransferase, total protein, albumin, blood urea nitrogen, creatinine, and creatine kinase at baseline and 12 weeks. 24-hour dietary recalls were collected at the baseline and at the end of the trial. DISCUSSION: This trial will evaluate the effects of chungkookjang on variables of metabolic syndrome in overweight/obese subjects. The results of this study may contribute to the reduction of risk factor for metabolic syndrome caused by obesity. TRIAL REGISTRATION: Clinical trials NCT01811511. PMID- 24171780 TI - Pharmacokinetic analysis and tissue distribution of andrographolide in rat by a validated LC-MS/MS method. AB - CONTEXT: Andrographis paniculata (Burm.f.) Nees (Acanthaceae) is widely used in tribal medicine in India and some other countries for multiple clinical applications. It contains andrographolide (AG) (diterpenoid lactone), a major phytomarker which probably accounts for its medicinal properties. OBJECTIVE: This study investigates the site-specific distribution of AG in different tissues of rats and its pharmacokinetic parameter evaluation by using a validated liquid chromatography tandem mass spectrometry (LC-MS/MS) method. MATERIALS AND METHODS: A simple and sensitive LC-MS/MS method has been developed and validated to quantify the presence of AG in plasma and various tissues of rat following oral administration of A. paniculata extract and AG in a dose of 133.33 and 100 mg/kg/day, respectively, for four weeks. RESULTS: The present study showed that the highest concentration of AG was in kidney (156.12 ng/g) followed by liver, spleen and brain while almost same concentration was found in heart and lung. The apparent C(max), T(max), elimination half-life and total exposure (AUC(0-alpha)) were 115.81 ng/ml, 0.75, 2.45 and 278.44 ngh/ml, respectively. CONCLUSION: This was an attempt to determine the presence of AG (a known biomarker) in tissues such as kidney, heart, lungs, brain and plasma of rats using a validated LC-MS/MS method. Furthermore, the observed reduced concentration in plasma and various tissues from 1 to 8 h might be attributed to relatively rapid elimination or distribution of AG from the central compartment. PMID- 24171781 TI - Feasibility of telemedicine in detecting diabetic retinopathy and age-related macular degeneration. AB - Age-related macular degeneration and diabetic retinopathy are important causes of visual impairment and blindness in the world. Because of recent advances and newly available treatment modalities along with the devastating consequences associated with late stages of these diseases, much attention has been paid to the importance of early detection and improving patient access to specialist care. Telemedicine or, more specifically, digital retinal imaging utilizing telemedical technology has been proposed as an important alternative screening and management strategy to help meet this demand. In this paper, we perform a literature review and analysis that evaluates the validity and feasibility of telemedicine in detecting diabetic retinopathy and age-related macular degeneration. Understanding both the progress and barriers to progress that have been demonstrated in these two areas is important for future telemedicine research projects and innovations in telemedicine technology. PMID- 24171783 TI - Part 1: MRI features of focal nodular hyperplasia with an emphasis on hepatobiliary contrast agents. AB - Focal nodular hyperplasia (FNH) is the second most common benign liver tumour and typically do not require any treatment. An accurate non-invasive diagnosis is therefore vital to avoid unnecessary intervention and to reassure patients. This article discusses the demographics and pathology of FNH and reviews the appearance of FNH at MRI using liver-specific contrast agents. PMID- 24171782 TI - Evaluating the prophylaxis and long-term effectiveness of acupuncture for migraine without aura: study protocol for a randomized controlled trial. AB - BACKGROUND: The instant-treatment effect of acupuncture for patients with migraines has been corroborated in numerous studies. However, most diseases are chronic and tend to recur, so the long-term effect of acupuncture can verify the existence of sustained efficacy or the placebo effect. Evaluating the efficacy of acupuncture in the prophylaxis of migraine without aura (MWoA) in China is also important because such studies are lacking. METHODS: This trial is a multicenter, prospective, pragmatic randomized controlled clinical trial. We will randomly allocate 249 participants to three groups of 83. Patients in the individualized acupoint group will be treated with individualized acupuncture point prescriptions. The non-acupoint control group will undergo insertion of acupuncture needles at four bilateral non-points in locations not corresponding to acupuncture points. The waiting-list control group will not undergo treatment but instead will receive 20 acupuncture treatments for free after a waiting period of 24 weeks. Participants in the individualized acupoint group and non acupoint control group will receive 20 sessions over four weeks and then all participants will receive 20 weeks of follow-up. DISCUSSION: The results of our trial will help to supply evidence for the long-term acupuncture effect for MWoA in a long follow-up period, and special attention will be paid to comparison with the placebo effect. TRIAL REGISTRATION: The trial was registered at ClinicalTrials.gov (NCT01687660) on 18 September 2012. PMID- 24171784 TI - Influence of the thermal stabilization process on the volatile profile of canned tomato-based food. AB - The literature contains several papers dealing with the volatile constituents contributing to the aroma of fresh and processed tomatoes. Along with the traditional tomato-based products, tomato-based pates, characterized by complex ingredient formulations, are commonly consumed as a seasoning for pasta, and as a dressing for meats, salads, and sandwiches. To the best of our knowledge, no investigations have been published on the influence of thermal stabilization treatments on the composition of volatile compounds in tomato-based pates. To this aim, thermally stabilized and not stabilized tomato-based pates were subjected to the analysis of volatile compounds. The results obtained highlighted the influence of the thermal stabilization process on the evolution of volatile composition tomato-based pates. In particular, the terpenic compounds showed significant decreases after the thermal stabilization process treatment, due to their degradation and oxidation favored by high temperatures. The thermal stabilization caused, moreover, an increase in volatile compounds deriving from lipid oxidation and Maillard reaction, characterized by low-sensory thresholds, and from the thermal degradation of carotenoids and fresh tomato-derived compounds. PMID- 24171785 TI - Prognostic molecular markers in head and neck squamous cell carcinoma in a New Zealand population: matrix metalloproteinase-2 and sialyl Lewis x antigen. AB - OBJECTIVE: The survival rate for head and neck squamous cell carcinoma (HNSCC) is among the lowest of the major cancers and has not substantially improved in the past two decades. Tumours with similar histological features may have widely differing clinical outcomes and thus identification of prognostic and predictive biomarkers may be valuable for determining appropriate clinical management strategies. The objective of this study was to establish the prognostic significance of six molecular markers in HNSCC in a New Zealand population: matrix metalloproteinases 2 and 9 (MMP-2, MMP-9), tissue inhibitor of matrix metalloproteinase-1, sialyl Lewis antigens a and x (sLe(a) , sLe(x) ) and alpha B crystallin. METHODS: Retrospective review of 145 sequential HNSCC patients from a tertiary centre with minimum 3 years surveillance. Sections from formalin-fixed paraffin-embedded tumour blocks were immunostained for the molecular markers and scored. Cox regression modelling was used to adjust for potential confounding variables impacting on cancer survival. RESULTS: Multivariate analysis for individual biomarkers, controlling for age, sex, tumour grade, N-stage, T-stage, tumour site, smoking history and alcohol use, revealed poorer survival with tumour expression of MMP-2 (hazard ratio = 1.98, 95% confidence interval: 1.11 3.52, P = 0.021) and sLe(x) (hazard ratio = 3.22, 95% confidence interval: 1.33 7.80, P = 0.010). A stepwise analysis showed that MMP-2 and sLe(x) were independently prognostic after covariate adjustment. CONCLUSIONS: MMP-2 and sLe(x) were negative prognostic markers for survival in these HNSCC patients. This offers opportunities for clinical trials to reduce the risk of nodal and distant metastases through blocking tumour cell adhesion to endothelium. PMID- 24171786 TI - TLR2 stimulation induces cardiac inflammation but not cardiac depression in vivo. AB - BACKGROUND: Bacteria such as Staphylococcus aureus induce myocardial dysfunction in vivo. To rectify conflicting evidence about the role of TLR2 signaling and cardiac dysfunction, we hypothesized that the specific TLR2 agonist purified lipoteichoic acid (LTA) from S. aureus contributes to cardiac dysfunction in vitro and in vivo. METHODS: Wildtype (WT-) and TLR2-deficient (TLR2-D) mice were challenged with LTA and in comparison with equivalent doses of lipopolysaccharide (LPS) and CpG-oligodeoxynucleotide (CpG-ODN). TLR2-expression, NFkappaB as well as cytokine response were determined. Sarcomere shortening of isolated cardiomyocytes was analyzed in vitro and cardiac function in vivo after stimulation with LTA. RESULTS: LTA induced up-regulation of TLR2 mRNA, activation of NFkappaB and cytokine expression within 2-6 h in WT-, but not in TLR2-D hearts. Cytokines were also elevated in the serum. LPS and CpG-ODN induced a more severe cardiac inflammation. In vitro incubation of cardiomyocytes with LTA reduced sarcomere shortening via NO at stimulation frequencies <= 8 Hz only in WT cells. However, hemodynamic parameters in vivo were not affected by LTA challenge. CONCLUSIONS: LTA induced cardiac inflammation was relatively weak and sarcomere shortening was reduced only below physiological heart rates. This may explain the apparent contradiction between the in vivo and in vitro LTA effects. PMID- 24171787 TI - Feasibility and efficacy of hepatic arterial infusion chemotherapy for advanced hepatocellular carcinoma after sorafenib. AB - AIM: Sorafenib is the standard treatment for advanced hepatocellular carcinoma (HCC). However, although there is no proven therapeutic procedure following the termination of sorafenib, hepatic arterial infusion chemotherapy (HAIC) may be a treatment option in advanced HCC. The aim of this study was to evaluate feasibility and efficacy of HAIC for patients with advanced HCC as subsequent therapy. METHODS: We retrospectively evaluated 27 consecutive patients with advanced HCC who were treated with HAIC following sorafenib between June 2009 and December 2012 at our hospital. Cisplatin (20 mg/m(2) per day) was administered via the hepatic artery for 10 min, prior to the continuous administration of 5 fluorouracil (330 mg/m(2) per day) over 24 h from days 1-5 and 8-12 and the s.c. administration of pegylated interferon alpha-2b (1 MUg/kg) on days 1, 8, 15, and 22. A treatment cycle consisted of 28 days of drug administration followed by 14 days of rest. RESULTS: The toxicity profile showed that hematological toxicities were common, and grade 3/4 neutropenia and thrombocytopenia were observed (51.9% and 48.1%, respectively). Five patients (18.5%) experienced device-related complications. No unexpected adverse reactions and no treatment-related deaths were observed. Partial response was obtained in eight patients (29.6%), and stable disease was noted in nine patients (33.3%). Median progression-free survival and median survival time from initiation of HAIC were 4.0 and 7.6 months, respectively. CONCLUSIONS: Because HAIC was well tolerated and exhibited moderate antitumor activity, it is a potentially useful treatment procedure in patients with advanced HCC even after failure of sorafenib. PMID- 24171788 TI - Melanocytic nevi with special features: clinical-dermoscopic and reflectance confocal microscopic-findings. AB - Histopathology is considered the 'gold' standard for the diagnosis and classification of melanocytic nevi, but the widespread use of in vivo diagnostic technologies such as dermoscopy and reflectance confocal microscopy (RCM), has enriched profoundly the knowledge regarding the morphological variability in nevi. This is because most morphological observations made via these in vivo tools are closely correlated with features seen in histopathology. Dermoscopy has allowed for a more detailed classification of nevi. As such, dermoscopy identifies four main morphologic groups (i.e. globular, reticular, starburst and structureless blue nevi), one group of nevi located at special body sites (i.e. face, acral, nail) and one group of nevi with special features. This latter category consists of nevi of the former categories, which are typified by peculiar clinical-histopathological findings. They can be subdivided into 'melanoma simulators' including combined nevi, recurrent nevi and sclerosing nevus with pseudomelanomatous features, 'targetoid' nevi (i.e. halo, cockade, irritated targetoid haemosiderotic and eczematous nevus) and uncommon histopathological variants such as desmoplastic, white dysplastic or ballon cell nevus. While the dermoscopic and RCM patterns of the former categories have been studied in detail, little is currently known about the clinical morphology of the heterogeneous group of 'special' nevi. In this article, we describe the clinical, dermoscopic and RCM features of 'special' nevi and review the current literature on this group of melanocytic proliferations. PMID- 24171790 TI - Caruncular tumor as the first sign of T-cell lymphoma relapse. AB - The lacrimal caruncle is a modified cutaneous tissue that contains hair follicles, accessory lacrimal glands, sweat glands, lobules of fat, and sebaceous glands. Due to the nature of tissue, a variety of lesions, both benign and malignant, could arise from this area. Lymphomas of the eye and its adnexa are frequently of B-cell lineage. We would like to report a rare and unique case of a patient presenting with a caruncular tumor of CD30-positive T-cell anaplastic large cell lymphoma (T-ALCL) origin, serving as the first, initial, sole sign of recurrence of previously treated cutaneous T-ALCL. We believe this to be the first such report in the literature. We aim to emphasize the importance of considering such a condition while formulating the differential diagnosis of caruncular tumour in patients with history of T-cell lymphoma and to characterize the clinical course of such a presentation. PMID- 24171789 TI - Comparison of neuroprotective effects of extract and fractions from Agarum clathratum against experimentally induced transient cerebral ischemic damage. AB - CONTEXTS: Agarum clathratum (Laminariaceae), a typical brown algae, has been identified by National Plant Quarantine Service in Korea. The extract of A. clathratum has antioxidant activities. OBJECTIVE: We investigated the neuroprotective effects of crude-extract, ethyl acetate (EA)-, n-butanol (BU)-, dichloromethane (DCM)- and n-hexane (Hx)-fractions from A. clathratum on ischemic damage in the gerbil hippocampal CA1 region (CA1) after 5 min of transient cerebral ischemia. MATERIALS AND METHODS: Agarum clathratum was collected in Kangwon province (South Korea) and treated with 95% ethanol. The ethanol extract was suspended in distilled water and subjected to a series of partitions with EA, BU, DCM and Hx. Each of extract and fraction was orally administered with 50 mg/kg once a day for one week before ischemia--reperfusion (I-R). RESULT: In the crude-extract-, EA- and BU-fraction-treated ischemia groups, we found strong neuroprotection in the CA1--about 80-89% of CA1 pyramidal neurons survived. However, in the DCM- and Hx-fraction-treated ischemia groups, we did not find any significant neuroprotection. In addition, we observed changes in astrocytes and microglia in the ischemic CA1. In the crude-extract, EA- and BU-fraction-treated ischemia groups, the distribution pattern and activity of the glial cells were similar to that found in the sham group. DISCUSSION: Repeated supplements of crude-extract, EA- and BU-fractions of A. clathratum could protect neurons from I R injury in the hippocampal CA1 induced by transient cerebral ischemia via decrease of glial activation. PMID- 24171792 TI - Peripapillary retinal nerve fiber layer thickening associated with vitreopapillary traction. AB - PURPOSE: To report two cases of retinal nerve fiber layer (RNFL) thickening as measured by Cirrus high-definition spectral-domain optical coherence tomography (OCT) associated with vitreopapillary traction. METHODS: Consecutive peripapillary RNFL thickness assessments were performed using OCT in eyes with glaucoma and ocular hypertension. RESULTS: OCT measurements revealed RNFL thickening when compared with the prior examination. A vitreopapillary traction to the thickened side of the RNFL was noted in a cross-sectional image of the optic nerve head obtained by OCT. CONCLUSION: Given that RNFL thickening can mask glaucomatous changes of the RNFL, caution is needed in glaucoma evaluation in eyes with vitreopapillary traction to the RNFL. PMID- 24171791 TI - A clinical comparison of safety and efficacy in phacoemulsification with versus without ophthalmic viscoelastic device. AB - PURPOSE: To evaluate in a comparative manner the safety and efficacy of 1.0% sodium-Hyaluronate used during capsulorhexis and intraocular lens (IOL) implantation in phacoemulsification surgery. MATERIALS AND METHODS: 1.0% sodium Hyaluronate, which is commonly used as one of the ophthalmic viscoelastic devices, was compared to intraocular irrigating solution, which can bring up these effects. In addition, the effect of both methods on occurring corneal endothelial cell (CEC) loss was investigated. RESULTS: Each group comprised 19 eyes. The mean preoperative CEC density was 2525.68 +/- 181.85 in Group H and 2514.16 +/- 174.59 in Group V; no statistically significant difference was found between the groups (p > 0.05). Preoperative and postoperative first and twelfth week CEC densities were 2438.21 +/- 198.12 (p < 0.001) and 2390.74 +/- 202.31, respectively, in group H (p < 0.001). Preoperative and postoperative first and twelfth week CEC densities were 2415.32 +/- 197.24 (p < 0.001) and 2353.47 +/- 212.69 in group V (p < 0.001). Compared with preoperative values, decrease in CEC density on the postoperative first and twelfth weeks was not statistically significant in either group (p > 0.05). CONCLUSION: Although it was found that there was no statistically difference in terms of preventing CEC loss between 1.0% sodium-Hyaluronate and the irrigation method during phacoemulsification, it was observed clinically that 1.0% sodium-hyaluronate can make the procedure easy, safer, very helpful, especially for understanding phacoemulsification. PMID- 24171793 TI - A mild Grave's ophthalmopathy during pregnancy. AB - INTRODUCTION: Thyroid ophthalmopathy is a complication most commonly associated with Grave's disease. The disease course ranges from mild to severe, with severe cases resulting in major visual impairment. METHODS: A complete ophthalmic examination in a 35-year-old secundigravida to 14 weeks of gestation presented to the hospital for a routine ophthalmological examination with eyelid retraction in the right eye was made. We studied the course of ocular disease through the gestation with orbit ecography and a 3T MRI. RESULTS: A diagnosis of Grave's Ophthalmopathy was made. CONCLUSION: This case presents an unusual course of the GD during pregnancy and a normal post-partum relapse, according to the Th1/Th2 balance. The frequent follow-up and the use of MRI allowed a prompt identification and complete control of the disease. PMID- 24171794 TI - Clinical Course of a Presumed Metastatic Uveal Melanoma to the Contralateral Choroid. AB - We present the ultrasound and optic coherence tomography follow-up of a presumed choroidal metastasis from a contralateral melanoma. A 53-year-old male was diagnosed with uveal melanoma with extraescleral extension in his left eye. A year later, the fundus examination revealed a flat, gray-green, pigmented choroidal lesion in the right eye. The ultrasonography showed a mass, almost flat, and all these findings were compatible with a choroidal melanocytic lesion with risk factors for growth. One month later, melanocytic skin lesions appeared on the scalp, as well as small tumors. Three months later, an ultrasonography on B scan showed a growth of the tumor size. The patient developed a progressive deterioration and died. Three possibilities can explain the occurrence of a choroidal pigmented tumor in the contralateral eye: first, bilateral primary choroidal melanomas; second, both choroidal tumors are metastatic in origin from an unknown primary melanoma; and third, the contralateral tumor is a metastatic tumor from the primary choroidal melanoma. PMID- 24171795 TI - EGF receptor and COX-1/COX-2 enzyme proteins as related to corresponding mRNAs in human per-operative biopsies of colorectal cancer. AB - BACKGROUND: Cyclooxygenase (COX) and epidermal growth factor receptor (EGFR) activities promote progression of colorectal cancer. Combined treatment against these targets has not been more effective than single treatments alone. Therefore, our aim was to analyze relationships between COX and EGFR in peroperative colorectal tumor biopsies. METHOD: Tumor and colon mucosa tissue were collected at primary intended curative operations in patients according to well-recognized statistical distributions of tumor stages in colorectal cancer. COX-1, COX-2 and EGFR content in tumor and colon mucosa tissue were quantified by western blot and Q-PCR. RESULTS: COX-2 protein appeared as two bands, one at 66 kDa in almost all tumor and mucosa samples and one at 74 kDa in 73% of the tumors and in 23% of the mucosa samples. Tumor COX-2 mRNA was not different from the content in mucosa samples, while COX-2 protein was increased in tumor tissue (p < 0.0003). A correlation between 74 kDa COX-2 protein and COX-2 mRNA occurred in tumor tissue, with significantly increasing COX-2 mRNA across tumor stages. EGFR mRNA content was lower in tumor tissue (p < 0.0001), while EGFR protein was similar in tumor and mucosa samples. COX-2 and EGFR proteins showed a positive correlation in mucosa, while a negative correlation occurred in tumor tissue. Tumor tissue with high COX-2 74 kDa protein lacked EGFR protein. CONCLUSION: Our present results are compatible with the theory that COX-2 and EGFR signalling pathways are inversely related in colorectal cancer tissue. This may explain why combinatorial clinical treatments have been less rewarding. PMID- 24171796 TI - A new era of stroke prevention in atrial fibrillation: comparing a new generation of oral anticoagulants with warfarin. AB - Traditionally, warfarin has been used to prevent stroke in patients with atrial fibrillation (AF), but data from large, multinational, prospective, randomized studies suggest that novel oral anticoagulants (NOACs) may be suitable alternatives. These include the direct thrombin inhibitor dabigatran and the factor Xa inhibitors rivaroxaban, apixaban, and edoxaban. These data showed that dabigatran 150 mg twice daily was more effective at preventing stroke than warfarin, with similar rates of major bleeding, while rivaroxaban 20 mg once daily was noninferior to warfarin, with no difference in major bleeding rates. In addition, apixaban 5 mg twice daily was shown to be superior to warfarin for preventing stroke, with lower bleeding rates. Currently, edoxaban is still in clinical trials. NOACs offer more predictable anticoagulant effects than warfarin and do not require regular monitoring; however, different NOACs are associated with varied drug interactions and limitations related to use in certain patient populations. Overall, the clinical data suggest that these novel agents will offer new options for stroke prevention in patients with AF. PMID- 24171797 TI - Relevance of wide-field autofluorescence imaging in Birdshot retinochoroidopathy: descriptive analysis of 76 eyes. AB - PURPOSE: To study and classify retinal lesions in patients with birdshot disease using wide-field autofluorescence imaging and correlate them according to patients' visual status. METHODS: A multicentre study was carried out on 76 eyes of 39 patients with birdshot disease, analysing colour images and under autofluorescence using the wide-field Optomap((r)) imaging system. This was combined with a complete clinical exam and analysis of the macula with OCT. RESULTS: In over 80% of the eyes, a chorioretinal lesion has been observed under autofluorescence with a direct correlation between the extent of the lesion and visual status. The presence of macular hypo-autofluorescence was correlated with a decreased visual acuity, due to the presence of a macular oedema, active clinical inflammation or an epiretinal membrane. The hypo-autofluorescence observed correlated with the duration of the disease and the degree of inflammation in the affected eye, indicating a secondary lesion in the pigment epithelium in relation to the choroid. The pigment epithelium was affected in a diffuse manner, as in almost 50% of the eyes the wider peripheral retina was affected. CONCLUSION: Wide-field autofluorescence imaging could appear to be a useful examination when monitoring patients, to look for areas of macular hypo autofluorescence responsible for an irreversible loss of vision. PMID- 24171798 TI - Sclerosing mesenteritis: a diagnosis worth considering. PMID- 24171799 TI - Measuring the impact of a health information exchange intervention on provider based notifiable disease reporting using mixed methods: a study protocol. AB - BACKGROUND: Health information exchange (HIE) is the electronic sharing of data and information between clinical care and public health entities. Previous research has shown that using HIE to electronically report laboratory results to public health can improve surveillance practice, yet there has been little utilization of HIE for improving provider-based disease reporting. This article describes a study protocol that uses mixed methods to evaluate an intervention to electronically pre-populate provider-based notifiable disease case reporting forms with clinical, laboratory and patient data available through an operational HIE. The evaluation seeks to: (1) identify barriers and facilitators to implementation, adoption and utilization of the intervention; (2) measure impacts on workflow, provider awareness, and end-user satisfaction; and (3) describe the contextual factors that impact the effectiveness of the intervention within heterogeneous clinical settings and the HIE. METHODS/DESIGN: The intervention will be implemented over a staggered schedule in one of the largest and oldest HIE infrastructures in the U.S., the Indiana Network for Patient Care. Evaluation will be conducted utilizing a concurrent design mixed methods framework in which qualitative methods are embedded within the quantitative methods. Quantitative data will include reporting rates, timeliness and burden and report completeness and accuracy, analyzed using interrupted time-series and other pre-post comparisons. Qualitative data regarding pre-post provider perceptions of report completeness, accuracy, and timeliness, reporting burden, data quality, benefits, utility, adoption, utilization and impact on reporting workflow will be collected using semi-structured interviews and open-ended survey items. Data will be triangulated to find convergence or agreement by cross-validating results to produce a contextualized portrayal of the facilitators and barriers to implementation and use of the intervention. DISCUSSION: By applying mixed research methods and measuring context, facilitators and barriers, and individual, organizational and data quality factors that may impact adoption and utilization of the intervention, we will document whether and how the intervention streamlines provider-based manual reporting workflows, lowers barriers to reporting, increases data completeness, improves reporting timeliness and captures a greater portion of communicable disease burden in the community. PMID- 24171800 TI - Adult tobacco use practice and its correlates in eastern Ethiopia: a cross sectional study. AB - BACKGROUND: There is paucity of data on the smoking habits of rural populations in developing countries. This study aimed to explore cigarette smoking practices of a rural community in Ethiopia. METHODS: A community based cross-sectional study was conducted among 548 individuals from a random sample of households in a rural town and its surrounding rural districts. Descriptive statistics and logistic regression were performed. RESULTS: Twenty-eight percent (95% CI: 24.3% 31.6%) of the respondents were current smokers. A total of 105 (68%) smokers expressed an interest to quit while 37 (34%) had tried to quit previously but without success. There was high exposure to second-hand smoke: 285 (52%) homes allowed indoor smoking, and in 181 (33%) indoor smoking took place daily. Current smoking was strongly associated with male sex (OR = 83.0; 95% CI: 11.5 - 599.0), and being a student was found to be protective of smoking (OR = 0.04; 95% CI: 0.005 - 0.05). CONCLUSION: Cigarette smoking is prevalent among the male rural town population in Ethiopia. In addition, a high level of exposure to indoor second-hand smoke exists. There is a need for investment in rural tobacco control, including educational campaigns and cost-effective smoking cessation services. PMID- 24171801 TI - The development of a standard training toolkit for research studies that recruit pregnant women in labour. AB - Recruitment of pregnant women in labour to clinical trials poses particular challenges. Interpretation of regulation lacks consistency or clarity and variation occurs as to the training required by clinicians to safely contribute to the conduct of intrapartum studies. The Royal College of Obstetricians and Gynaecologists Intrapartum Clinical Study Group initiated the development of a pragmatic, proportionate and standardised toolkit for training clinical staff that complies with both regulatory and clinician requirements and has been peer reviewed. This approach may be useful to researchers in acute care settings that necessitate the integration of research, routine clinical practice and compliance with regulation. PMID- 24171802 TI - Pilot projects for improving product tracing along the food supply system. AB - In September 2011, the U.S. Food and Drug Administration (FDA) asked the Institute of Food Technologists (IFT) to execute product tracing pilot projects as described in Section 204 of the FDA Food Safety Modernization Act (FSMA). IFT collaborated with representatives from more than 100 organizations-including the U.S. Dept. of Agriculture, state departments of agriculture and public health, industry, and consumer groups, as well as not-for-profit organizations-to implement the pilots. The objectives of the pilot projects were 1) to identify and gather information on methods to improve product tracing of foods in the supply chain and 2) to explore and evaluate methods to rapidly and effectively identify the recipient of food to prevent or mitigate a foodborne illness outbreak and to address credible threats of serious adverse health consequences or death to humans or animals as a result of such food being adulterated or misbranded. IFT conducted evaluations to determine the impact of currently available technologies, types of data and formats, and the data acquisition process, as well as the use of technology on the ability to follow product movement through the supply chain. Results from the pilots found inconsistencies in the terminology, numbering systems, formatting, legibility, and occasionally the language that sometimes required IFT to contact the submitting firm to gain clarity, thus increasing the time required to capture data before any meaningful analysis could begin. However, the pilot participants appeared to have many of the tools and processes in place which are required to allow the capture and communication of critical track and trace information (such as, key data elements) at critical points of product transfer and transformation (such as, critical tracking events). IFT determined that costs associated with implementing a product tracing system can vary widely as determined by numerous factors: the size of the firm/facility, the method of product tracing already in use (manual or electronic), and the range of each firm's capabilities to implement or improve its product tracing system, to name a few. IFT found that there are several areas (such as uniformity and standardization, improved recordkeeping, enhanced planning and preparedness, better coordination and communication, and the use of technology) in which industry improvements and enhancements to FDA's processes would enable tracebacks and traceforwards to occur more rapidly. IFT developed 10 recommendations for FDA to consider for improving the state of system-wide food product tracing. The recommendations outlined in the report will enable FDA to conduct more rapid and effective investigations during foodborne illness outbreaks and other product tracing investigations, thus significantly enhancing protection of public health. PMID- 24171804 TI - HPLC fingerprint analysis combined with chemometrics for pattern recognition of ginger. AB - CONTEXT: Ginger, the fresh rhizome of Zingiber officinale Rosc. (Zingiberaceae), has been used worldwide; however, for a long time, there has been no standard approbated internationally for its quality control. OBJECTIVE: To establish an efficacious and combinational method and pattern recognition technique for quality control of ginger. METHODS: A simple, accurate and reliable method based on high-performance liquid chromatography with photodiode array (HPLC-PDA) detection was developed for establishing the chemical fingerprints of 10 batches of ginger from different markets in China. The method was validated in terms of precision, reproducibility and stability; and the relative standard deviations were all less than 1.57%. On the basis of this method, the fingerprints of 10 batches of ginger samples were obtained, which showed 16 common peaks. Coupled with similarity evaluation software, the similarities between each fingerprint of the sample and the simulative mean chromatogram were in the range of 0.998-1.000. Then, the chemometric techniques, including similarity analysis, hierarchical clustering analysis and principal component analysis were applied to classify the ginger samples. RESULTS AND CONCLUSION: Consistent results were obtained to show that ginger samples could be successfully classified into two groups. This study revealed that HPLC-PDA method was simple, sensitive and reliable for fingerprint analysis, and moreover, for pattern recognition and quality control of ginger. PMID- 24171803 TI - Embryonic stem cells shed new light on the developmental roles of p53. AB - The viability and subtle developmental defects of p53 knockout mice suggest that p53 does not play major role in development. However, contradictory evidence also exists. This discrepancy mainly results from the lack of molecular and cellular mechanisms and the general fact that p53 activation requires stresses. Recent studies of p53 in mouse and human ES cells and induced pluripotent stem (iPS) cells shed new light on the mechanisms of the developmental roles of p53. This review summarizes these new studies that support the developmental roles of p53, highlights the possible underlying molecular mechanisms, and discusses the potential relationship between the developmental roles and the tumor suppressive function of p53. In summary, the molecular mechanisms underlying the developmental roles of p53 are emerging, and the developmental roles and tumor suppressive function of p53 may be closely related. PMID- 24171805 TI - A case of unusual coexistence of keratoconus and optic disc pit. AB - PURPOSE: To report a case of unusual coexistence of keratoconus and optic disc pit. METHODS: A 29-year-old male patient followed up because of the left established and right subclinical keratoconus presented with blurred vision on the left eye that occurred within days. In addition to a comprehensive ophthalmic examination, computerized corneal topography (CT), corneal pachymetry, and optical coherence tomography (OCT) examination were performed. RESULTS: The corneal CT showed a mild keratoconus pattern, with a minimum corneal pachymetry of 472 in the right eye and moderate keratoconus pattern with a minimum pachymetry of 435 micron in the left eye. The OCT scans showed the presence of the optic disc pit and related maculopathy. CONCLUSIONS: This is the second report of the coexistence of keratoconus and optic disc pit in the literature. The association of these two entities is therefore less likely to be accidental. Further histopathological studies will be necessary to explain this relationship between two entities. PMID- 24171806 TI - Comparison of central corneal thickness measurements with a rotating scheimpflug camera, a specular microscope, optical low-coherence reflectometry, and ultrasound pachymetry in keratoconic eyes. AB - OBJECTIVE: To compare central corneal thickness (CCT) measurements with a rotating Scheimpflug camera (RSC), noncontact specular microscopy (SM), optical low-coherence reflectometry (OLCR), and ultrasonic pachymetry (UP) in keratoconus (KC) patients. METHOD: In this prospective study, four CCT measurements taken with an RSC, SM, OLCR, and UP were compared in 81 eyes of 44 consecutive KC patients. The KC patients were divided into four subgroups according to Amsler Krumeich's KC classification. RESULTS: The RSC and UP measurements of the CCT were not statistically significant in all the groups. Comparison of the SM vs. the OLCR measurements yielded statistically significant differences in all the KC patients and in all KC stages. In all the KC patients, RSC and OLCR showed a high correlation coefficient factor (r = 0.87, p = 0.000). CONCLUSION: CCT measurements with RSC are comparable to those achieved with UP. Compared with the other devices, according to SM measurements, the central cornea is thicker in all keratoconic eyes and in all KC grades, and it is thinner according to OLCR. RSC, UP, SM, and OLCR should not be used interchangeably in keratoconic eyes. PMID- 24171807 TI - Clinical profile and management outcome of acute dacryocystitis: two decades of experience in a tertiary eye care center. AB - AIM: To report the demographic profile, clinical presentation, and management outcome of acute dacryocystitis. METHODS: Retrospective study of 347 eyes of 320 patients, who presented to the Ophthalmic Plastic Clinic of a tertiary eye care center over a period of 22 years from January 1990 to March 2012 with acute dacryocystitis, were reviewed for demographic profile, clinical presentation, and management outcome. The numbers of patients with lacrimal disorders during the same period were retrieved to assess the incidence of acute dacryocystitis. Successful anatomical outcome was defined as patency on irrigation and a successful functional outcome was defined as resolution of infection and epiphora. RESULTS: The mean age at presentation was 37 years. The female to male ratio was 2:1. There was no difference in the laterality between the right and the left eyes. Bilateral disease was noted in 8.4% (27/320) patients. 23% (80/347) eyes presented with lacrimal abscess while 2.8% (10/347) eyes had orbital cellulitis. Intensive medical care with hospital admission was needed in 4.4% (14/320) patients. The mean time to resolution of acute symptoms was 10 days. 5.6% (18/320) patients developed a fistula, among which 83% (15/18) were following a spontaneous rupture of the lacrimal abscess. Dacryocystorhinostomy was performed in 82.5% (264/320) patients with an anatomical success of 94.5% and a functional success of 93.5%. CONCLUSIONS: Acute dacryocystitis comprises 2.4% of all patients presenting with lacrimal system disorders. Fistula formation is a sequel more commonly seen with spontaneous rupture of a lacrimal abscess. The long-term outcomes in patients presenting with acute dacryocystitis are good with a surgical success rate of 94.3%. PMID- 24171808 TI - A study of prevalence and risk factors of diabetic retinopathy in patients with non-arteritic anterior ischemic optic neuropathy (NA-AION). AB - PURPOSE: To estimate prevalence and risk factors for diabetic retinopathy (DR) in diabetic patients with Non-Arteritic Anterior Ischemic Retinopathy (NA-AION). METHODS: This was a retrospective chart review of patients with diabetes diagnosed with NA-AION. Patients with clinical anomalies affecting the optic nerve, diabetic papillopathy, and features suggestive of arteritic AION (raised erythrocyte sedimentation rate/positive temporal artery biopsy) were excluded. Clinical diagrams, notes, and fundus photographs, if available, were evaluated for optic disc edema, optic disc atrophy, presence or absence of small discs, retinal vessel abnormalities, presence of DR, and the presence of sight threatening DR (STDR). RESULTS: A total of 153 eyes of 109 subjects were included in the study. 82 subjects (75.2%) were men. Mean age of the subjects was 55 +/- 9 years. 58 subjects (53.7%) had hypertension and 21 (19.3%) were insulin dependent. 80 subjects (52.3%) had a duration of diabetes of five years or greater. DR with NA-AION was seen in 46 eyes (30.1%, 95% CI: 22.7 to 37.4) and STDR with NA-AION was seen in 20 eyes (13.1%, 95% CI: 7.7 to 18.5). Logistic regression analysis revealed the duration of diabetes to be significantly associated with both the presence of DR (OR: 1.07, 95% CI: 1.01 to 1.14, p = 0.02) and STDR (OR 1.08, 95% CI: 1.02-1.15, p = 0.01). CONCLUSIONS: Prevalence of DR and STDR in eyes with NA-AION was 30.1% and 13.1%, respectively. Duration of diabetes was an important risk factor for both presence and severity of DR in subjects with NA-AION. PMID- 24171809 TI - Branch retinal vein occlusion: treatment modalities: an update of the literature. AB - BACKGROUND: Retinal vein occlusion is the second most common retinal vascular disorder after diabetic retinopathy and is considered to be an important cause of visual loss. In this review, our purpose is to update the literature about the treatment alternatives for branch retinal vein occlusion. METHODS: Eligible papers were identified by a comprehensive literature search of PubMed, using the terms "branch retinal vein occlusion," "therapy," "intervention," "treatment," "vitrectomy," "sheathotomy," "laser," "anti-VEGF," "pegaptanib," "bevacizumab," "ranibizumab," "triamcinolone," "dexamethasone," "corticosteroids," "non steroids," "diclofenac," "hemodilution," "fibrinolysis," "tPA," and "BRVO." Additional papers were also selected from reference lists of papers identified by the electronic database search. RESULTS: Treatment modalities were analyzed. CONCLUSIONS: There are several treatment modalities for branch retinal vein occlusion and specifically for its complications, such as macular edema, vitreous hemorrhage, retinal neovascularization, and retinal detachment, including anti aggregative therapy and fibrinolysis, isovolemic hemodilution, vitrectomy with or without sheathotomy, peripheral scatter and macular grid retinal laser therapy, non-steroid agents, intravitreal steroids, and intravitreal anti-vascular endothelial growth factors (anti-VEGFs). PMID- 24171810 TI - Macula and retinal nerve fiber layer in migraine patients: analysis by spectral domain optic coherence tomography. AB - AIM: Investigating the retinal nerve fiber layer (RNFL), macular and ganglion cell complex thickness in eyes of migraine patients using optical coherence tomography. METHODS: The study was designed as an observational cross-sectional study. 50 patients with migraine (30 patients with aura and 20 patients without aura) and 50 healthy volunteers were included. Optical coherence tomography was performed with Optovue technology. The fast RNFL thickness (3.4) scan, MM5, and GCC acquisition protocols were used. RESULTS: There was no statistically significant difference in retinal thickness in any of the quadrants between the control group and the migraine patients (p > 0.05). The average RNFL thickness (110.50 vs 102.84 microns, p = 0.03) was significantly thinner in migrainers as compared to the control. The ANOVA did not reveal any significant difference between migrainers with aura, migrainers without aura, and the control group. The VAS (visual analogue scale) score of migraine patients was not statistically significantly correlated with any of the parameters, while the length of migraine history was negatively correlated with the average RNFL thickness (r = -0.32, p = 0.03). CONCLUSION: The average RNFL thickness in the migraine patients was found to be thinner than that in the control group. In addition, we found a negative weak correlation between length of migraine history and the average RNFL thickness, supporting the possible association between these pathologies. PMID- 24171811 TI - Evaluation of potential topical and systemic neuroprotective agents for ocular hypertension-induced retinal ischemia-reperfusion injury. AB - OBJECTIVE: To evaluate for drugs with superior neuroprotective efficacy and investigate their underlying mechanisms related to antioxidation. PROCEDURES: Brinzolamide (1%), timolol (0.5%), minocycline (22 mg/kg), lidocaine (1.5 mg/kg), and methylprednisolone (30 mg/kg) were administered to Sprague-Dawley (SD) rats. The retina was evaluated by electroretinography and histological analysis. The antioxidative capacity of drugs was evaluated to clarify the underlying mechanism. The oxidant/antioxidant profiles of plasma, red blood cells, and retina were analyzed by lipid peroxidation (malondialdehyde) and by measuring the activities of antioxidants. Proteomic analysis was used to investigate the possible protective mechanisms of the drug against ischemia-reperfusion injury. RESULTS: The results suggested that timolol, methylprednisolone, and minocycline protected retinal function. Methylprednisolone and minocycline possessed good antioxidative activity. Brinzolamide and lidocaine preserved the structural integrity of the retina, but not retinal function. CONCLUSION: Methylprednisolone, minocycline, and timolol have potential acute or delayed benefit in retinal ischemia-reperfusion injury. Their neuroprotective actions depend at least partially on the ability to alleviate oxidative stress. PMID- 24171812 TI - Design and validation of a pericentromeric BAC clone set aimed at improving diagnosis and phenotype prediction of supernumerary marker chromosomes. AB - BACKGROUND: Small supernumerary marker chromosomes (sSMCs) are additional, structurally abnormal chromosomes, generally smaller than chromosome 20 of the same metaphase spread. Due to their small size, they are difficult to characterize by conventional cytogenetics alone. In regard to their clinical effects, sSMCs are a heterogeneous group: in particular, sSMCs containing pericentromeric euchromatin are likely to be associated with abnormal outcomes, although exceptions have been reported. To improve characterization of the genetic content of sSMCs, several approaches might be applied based on different molecular and molecular-cytogenetic assays, e.g., fluorescent in situ hybridization (FISH), array-based comparative genomic hybridization (array CGH), and multiplex ligation-dependent probe amplification (MLPA).To provide a complementary tool for the characterization of sSMCs, we constructed and validated a new, FISH-based, pericentromeric Bacterial Artificial Chromosome (BAC) clone set that with a high resolution spans the most proximal euchromatic sequences of all human chromosome arms, excluding the acrocentric short arms. RESULTS: By FISH analysis, we assayed 561 pericentromeric BAC probes and excluded 75 that showed a wrong chromosomal localization. The remaining 486 probes were used to establish 43 BAC-based pericentromeric panels. Each panel consists of a core, which with a high resolution covers the most proximal euchromatic ~0.7 Mb (on average) of each chromosome arm and generally bridges the heterochromatin/euchromatin junction, as well as clones located proximally and distally to the core. The pericentromeric clone set was subsequently validated by the characterization of 19 sSMCs. Using the core probes, we could rapidly distinguish between heterochromatic (1/19) and euchromatic (11/19) sSMCs, and estimate the euchromatic DNA content, which ranged from approximately 0.13 to more than 10 Mb. The characterization was not completed for seven sSMCs due to a lack of information about the covered region in the reference sequence (1/19) or sample insufficiency (6/19). CONCLUSIONS: Our results demonstrate that this pericentromeric clone set is useful as an alternative tool for sSMC characterization, primarily in cases of very small SMCs that contain either heterochromatin exclusively or a tiny amount of euchromatic sequence, and also in cases of low-level or cryptic mosaicism. The resulting data will foster knowledge of human proximal euchromatic regions involved in chromosomal imbalances, thereby improving genotype-phenotype correlations. PMID- 24171813 TI - Linking sensory neurons to visually guided behavior: relating MST activity to steering in a virtual environment. AB - Many complex behaviors rely on guidance from sensations. To perform these behaviors, the motor system must decode information relevant to the task from the sensory system. However, identifying the neurons responsible for encoding the appropriate sensory information remains a difficult problem for neurophysiologists. A key step toward identifying candidate systems is finding neurons or groups of neurons capable of representing the stimuli adequately to support behavior. A traditional approach involves quantitatively measuring the performance of single neurons and comparing this to the performance of the animal. One of the strongest pieces of evidence in support of a neuronal population being involved in a behavioral task comes from the signals being sufficient to support behavior. Numerous experiments using perceptual decision tasks show that visual cortical neurons in many areas have this property. However, most visually guided behaviors are not categorical but continuous and dynamic. In this article, we review the concept of sufficiency and the tools used to measure neural and behavioral performance. We show how concepts from information theory can be used to measure the ongoing performance of both neurons and animal behavior. Finally, we apply these tools to dorsal medial superior temporal (MSTd) neurons and demonstrate that these neurons can represent stimuli important to navigation to a distant goal. We find that MSTd neurons represent ongoing steering error in a virtual-reality steering task. Although most individual neurons were insufficient to support the behavior, some very nearly matched the animal's estimation performance. These results are consistent with many results from perceptual experiments and in line with the predictions of Mountcastle's "lower envelope principle." PMID- 24171814 TI - A framework for assessing health system resilience in an economic crisis: Ireland as a test case. AB - BACKGROUND: The financial crisis that hit the global economy in 2007 was unprecedented in the post war era. In general the crisis has created a difficult environment for health systems globally. The purpose of this paper is to develop a framework for assessing the resilience of health systems in terms of how they have adjusted to economic crisis. Resilience can be understood as the capacity of a system to absorb change but continue to retain essentially the same identity and function. The Irish health system is used as a case study to assess the usefulness of this framework. METHODS: The authors identify three forms of resilience: financial, adaptive and transformatory. Indicators of performance are presented to allow for testing of the framework and measurement of system performance. Both quantitative and qualitative methods were used to yield data for the Irish case study. Quantitative data were collected from government documents and sources to understand the depth of the recession and the different dimensions of the response. Semi-structured interviews were conducted with key decision makers to understand the reasons for decisions made. RESULTS: In the Irish case there is mixed evidence on resilience. Health funding was initially protected but was then followed by deep cuts as the crisis deepened. There is strong evidence for adaptive resilience, with the health system showing efficiency gains from the recession. Nevertheless, easy efficiencies have been made and continued austerity will mean cuts in entitlements and services. The prospects for building and maintaining transformatory resilience are unsure. While the direction of reform is clear, and has been preserved to date, it is not certain whether it will remain manageable given continued austerity, some loss of sovereignty and capacity limitations. CONCLUSIONS: The three aspects of resilience proved a useful categorisation of performance measurement though there is overlap between them. Transformatory resilience may be more difficult to assess precisely. It would be useful to test out the framework against other country experiences and refine the measures and indicators. Further research on both the comparative resilience of different health systems and building resilience in preparation for crises is encouraged. PMID- 24171815 TI - Anti-CCP antibody in a patient with generalized discoid lupus erythematosus, vasculitis and acute interstitial lung disease but not rheumatoid arthritis. PMID- 24171816 TI - Mutagenicity of edible palm oil on the Ghanaian market before and after repeated heating. AB - Red palm oil produced in Ghana largely by village folks has never been tested for its mutagenic potential. The study aimed at determining the mutagenicity of high energy heated red palm oil (RRPO) and refined, bleached imported palm oil (PO) on the Ghanaian market. Samples of RRPO and PO were 1* and 5* heated for 10 min at 180 degrees C with a cooling period of 5 h in-between. Unheated, together with heated samples, were tested for mutagenicity using Salmonella typhimurium TA 98 and TA 100 tester stains. Unheated PO was negative for the Ames mutagenicity test with TA 98 strain. However, 1* and 5* heated PO were mutagenic (P = 0.05, each). Testing PO, using TA 100 strain was negative. RRPO was mutagenic with TA 98 strain for heated oils (P = 0.05, each). Assays with TA 100 strain showed highly significant mutations (P = 0.001, each) that increased with increasing heating frequency. PO 1* and 5* heated samples caused significant frameshift mutation in the S. typhimurium TA 98 strain. RRPO caused highly significant point and frameshift mutations in heated samples. Furthermore, unheated RRPO mutagenic potential has serious health implications. PMID- 24171817 TI - Breast adenomyoepithelioma: a case report with malignant proliferation of epithelial and myoepithelial elements. AB - BACKGROUND: Breast adenomyoepithelioma is an unusual tumor characterized by a biphasic proliferation of epithelial and myoepithelial cells. Most breast adenomyoepitheliomas are considered to be benign or to have a low-grade malignant potential, characterized by propensity for local recurrence. Malignant changes arising in this lesion are extremely rare and may involve one or both cellular components. CASE REPORT: We discuss a case of a 60 year-old woman who began to experience pain in her right breast in January 2009. Breast ultrasound and mammography were performed showing a rounded, hypoechoic solid lesion with ill defined margins in the right inner-inferior quadrant, suspicious of malignancy. Quadrantectomy of the inner-inferior quadrant of the right breast with sampling of ipsilateral axillary lymph nodes was performed. The histological analysis confirmed the diagnosis of adenomyoepithelioma with focal malignant change of the epithelial component, associated with high-grade malignant myoepithelial change. The patient was treated with adjuvant radiotherapy and her right breast received a dose of Gy 50 with a boost of Gy 10 to the tumor bed. At present, the patient shows no sign of tumor recurrence. CONCLUSION: Breast malignant adenomyoepithelioma is a rare tumor which should be considered in the differential diagnosis of other solid breast lesions. Only few cases have been reported in the literature. Diagnosis, optimal therapy and predicting the outcome are problematic issues due to the rarity of this disease which appears to have hematogenous rather than lymphatic spread and usually occurs in primary tumors >= 1.6 cm in size. PMID- 24171819 TI - Accelerated sample preparation and formation of astragaloside IV in Astragali Radix. AB - Abstract Context: Astragali Radix (Huangqi; Astragalus mongholicus BUNGE, Fabaceae) is used in herbal medicinal products as well as in many food supplements. In traditional Chinese medicine, the roots are used for its Qi tonifying, immunostimulant, cardioprotective, hepatoprotective and hypoglycemic effects. Objective: Astragaloside IV (AGS-IV), a cycloartane-type triterpene glycoside is used as a marker compound for the quality control of Astragali Radix in various pharmacopoeias. Materials and methods: In this study, we analyzed the content of AGS-IV and other astragalosides in various commercial samples of Huangqi by reversed-phase HPLC using evaporative light scattering detection. Results: The analyses revealed that AGS-IV is formed during sample preparation from acylated astragalosides like astragaloside I and astragaloside II, when using the assay method of the European Pharmacopoeia. Discussion and conclusion: For consistent assay results, the extraction methods of the pharmacopoeias should be re-evaluated and optimized. Alternatively, the hydrolysis by ammonia could be omitted and the genuine compounds like astragaloside I, II and malonyl-AGS-I could be considered for the quality control of Astragali Radix. PMID- 24171818 TI - Autophagic/lysosomal dysfunction in Alzheimer's disease. AB - Autophagy serves as the sole catabolic mechanism for degrading organelles and protein aggregates. Increasing evidence implicates autophagic dysfunction in Alzheimer's disease (AD) and other neurodegenerative diseases associated with protein misprocessing and accumulation. Under physiologic conditions, the autophagic/lysosomal system efficiently recycles organelles and substrate proteins. However, reduced autophagy function leads to the accumulation of proteins and autophagic and lysosomal vesicles. These vesicles contain toxic lysosomal hydrolases as well as the proper cellular machinery to generate amyloid beta, the major component of AD plaques. Here, we provide an overview of current research focused on the relevance of autophagic/lysosomal dysfunction in AD pathogenesis as well as potential therapeutic targets aimed at restoring autophagic/lysosomal pathway function. PMID- 24171820 TI - Respiratory syncytial virus: how, why and what to do. AB - Bronchiolitis is the leading cause of hospitalization of infants and young children worldwide. Respiratory syncytial virus (RSV) is the most common cause of bronchiolitis in infants. Studies conducted using molecular diagnostic assays confirmed that RSV accounts for over 50% of bronchiolitis in young children requiring hospitalization. Those studies demonstrate that it is common to identify RSV in association with a second viral agent but it is yet unclear whether the simultaneous detection of two or even three viruses is associated with increased disease severity. Despite extensive efforts, a vaccine for prevention of RSV infection is not yet available. Palivizumab a humanized monoclonal antibody directed against the F protein of RSV is the only agent licensed to prevent severe RSV disease in high-risk children. Among the new antivirals being developed for treatment of RSV infections, an RNA-interference based agent has demonstrated promising results for treatment of lung transplant recipients with acute RSV infection. PMID- 24171821 TI - Breast cancer: current developments in molecular approaches to diagnosis and treatment. AB - Due to the high heterogeneity of breast cancers, numerous recent patents describe improved methods of detection and classification which promise better patient prognosis and treatment. In particular, there has been a shift towards more effective genetic screening to identify specific mutations associated with breast tumours, which may lead to "personalised medicine" with improved outcomes. Two challenging areas of breast cancer research involve the development of treatments for the highly aggressive triple negative breast cancer subtype as well as the chemotherapy-resistant cancer stem cell subpopulation. In addition, despite numerous recent advances in breast cancer treatment in woman, male breast cancer remains poorly understood and there are limited therapies available which are developed specifically for men. This review serves to report on important developments in the treatment of breast malignancies patented in the past two years as well as to highlight the current gaps in the field of breast cancer therapeutics and areas which require further study. PMID- 24171822 TI - Status of anti-lung cancer drug patents applications in China from 2003 to 2012. AB - BACKGROUND: During the past 10 years, dramatic progress has been made in the development of effective lung cancer drugs in China. However, little is known about their patents. OBJECTIVE: To summarize and analyze lung cancer patents or potential drug candidates issued in China over the last 10 years, and thus help researchers and developers to understand the current situation and potential candidates of lung cancer drug patents in China. METHODS: Data were obtained from China Intellectual Property Right Net (CNIPR), a website maintained by the Intellectual Property Publishing House (IPPH) subordinate to the State Intellectual Property Office (SIPO), and analyzed by bibliometric methods. RESULTS: A total of 707 lung cancer drug patents have been granted in China over the past 10 years. These patents include synthetic compounds, traditional Chinese medicines (TCM), combinations of synthetic compounds and TCM, biological products and medical apparatus. Current TCM approaches focus primarily on alteration of natural product rather than whole herb treatments, and there is an effort to modify TCM components and natural products to achieve optimal cancer targeting effects. The patents on synthetic lung cancer drug compounds in China mainly focus on well-known targets, such as EGFR, which comprises 93% of patents for validated targets. CONCLUSION: There has been a surge in lung cancer patents filed in China in recent years due to advancements in the Chinese pharmaceutical industries, improved practices that protect intellectual property rights, and a growing demand for lung cancer drugs. Therefore, there are great opportunities for obtaining lung cancer drug patents, particularly patents on active ingredients from TCM in China. PMID- 24171823 TI - Pegylated interferon in HBeAg-positive and -negative chronic hepatitis B patients: post-treatment 1-year results of three Turkish centres. AB - In this study, we aimed to evaluate the 1-year post-treatment follow-up results of 112 patients who received pegylated interferon (PEG-IFN) for 52 weeks. HBeAg negativity/seroconversion and/or negative HBV-DNA at the end of the treatment were considered as response. Patients who had response at the end of treatment but had HBV-DNA breakthrough during 1-year follow-up were considered as relapse. The study group comprised 112 cases (34 HBeAg-positive, 78 HBeAg-negative). In HBeAg-positive and -negative cases, end-of-treatment response rates were 2.9% and 60.2%, whereas 1-year sustained virological response rates were 0 and 33.3%, respectively. When we compared relapse cases versus cases with response at the end of 1-year follow-up, being female and having low viral load were the two parameters associated with higher response rates (Chi-square, P = 0.028; Mann Whitney U test, P = 0.023). Overall non-response rates to PEG-IFN were high (57.1%). Results in HBeAg-positive cases were disappointing. PMID- 24171824 TI - Regeneration of toxigenic Pasteurella multocida induced severe turbinate atrophy in pigs detected by computed tomography. AB - BACKGROUND: Atrophic rhinitis is a widely prevalent infectious disease of swine caused by Bordetella bronchiseptica and Pasteurella multocida. The course of the disease is considered to be different depending on the principal aetiological agents distinguishing B. bronchiseptica induced non-progressive and toxigenic P. multocida produced progressive forms. In order to compare the pathological events of the two forms of the disease, the development of nasal lesions has longitudinally been studied in pigs infected by either B. bronchiseptica alone or B. bronchiseptica and toxigenic P. multocida together using computed tomography to visualise the nasal structures. RESULTS: B. bronchiseptica infection alone caused moderately severe nasal turbinate atrophy and these lesions completely regenerated by the time of slaughter. Unexpectedly, complete regeneration of the bony structures of the nasal cavity was also observed in pigs infected by B. bronchiseptica and toxigenic P. multocida together in spite of seeing severe turbinate atrophy in most of the infected animals around the age of six weeks. CONCLUSIONS: B. bronchiseptica mono-infection has been confirmed to cause only mild to moderate and transient lesions, at least in high health status pigs. Even severe turbinate atrophy induced by B. bronchiseptica and toxigenic P. multocida combined infection is able to be reorganised to their normal anatomical structure. Computed tomography has further been verified to be a useful tool to examine the pathological events of atrophic rhinitis in a longitudinal manner. PMID- 24171825 TI - Molecular subtypes in ductal carcinoma in situ of the breast and their relation to prognosis: a population-based cohort study. AB - BACKGROUND: Different molecular subtypes of breast cancer have been identified based on gene expression profiling. Treatment suggestions based on an approximation of these subtypes by immunohistochemical criteria have been published by the St Gallen international expert consensus panel. Ductal carcinoma in situ (DCIS) can be classified into the same molecular subtypes. Our aim was to study the relation between these newly defined subtypes and prognosis in DCIS. METHODS: TMA including 458 women from a population-based cohort with DCIS diagnosed 1986-2004 was used. Stainings for ER, PR, HER2 and Ki67 were used to classify the surrogate molecular subtypes according to the St Gallen criteria from 2011. The associations with prognosis were examined using Kaplan-Meier analyses and Cox proportional hazards regression models. RESULTS: Surrogate molecular subtyping could be done in 381 cases. Mean follow up was 164 months. Of the classified DCIS 186 were Luminal A (48.8%), 33 Luminal B/HER2- (8.7%), 74 Luminal B/HER2+ (17.4%), 61 HER2+/ER- (16.0%) and 27 Triple Negative (7.1%). One hundred and two women had a local recurrence of which 58 were invasive. Twenty two women had generalised disease, 8 without a prior local recurrence. We could not find a prognostic significance of the molecular subtypes other than a higher risk of developing breast cancer after more than 10 years of follow-up among women with a Triple Negative DCIS (OR 3.2; 95% CI 1.1-9.8). CONCLUSIONS: The results from this large population-based cohort, with long-term follow up failed to demonstrate a prognostic value for the surrogate molecular subtyping of DCIS using the St Gallen criteria up to ten years after diagnosis. More than ten years after diagnosis Triple Negative DCIS had an elevated risk of recurrence. PMID- 24171826 TI - Re-examining the cognitive phenotype in autism: a study with young Chinese children. AB - Deficits consistently found in autism include an impaired "theory of mind", weak central coherence, and deficits in executive function. The current study examined whether this traditional cluster of symptoms existed in a group of Chinese speaking children with autism. Sixteen high-functioning, non-retarded children with autism were matched to 16 typically developing (TD) children on gender, non verbal IQ and age. Non-verbal IQ's of all participants were measured using the Raven Progressive Matrices. Each participant was tested individually on measures of "theory of mind", central coherence and executive function. Results indicated that most, but not all, participants with autism performed significantly poorer on two standard measures of first-order "theory of mind," although there was no significant difference on two other measures of that domain. As expected, they performed significantly worse on executive function tasks. However, the hypothesis of weak central coherence in autism was not substantiated. There was no evidence that these three cognitive impairments co-existed in individuals with autism. More likely, each of these deficits appears singly or in pair instead of forming a cluster. PMID- 24171827 TI - Efficacy of beta blockers in the management of problem behaviours in people with intellectual disabilities: a systematic review. AB - Both medication and non-medication based strategies are used in the management of problem behaviours in individuals with intellectual disabilities. Beta adrenoceptor blocking medications are one group of drugs used for this purpose. However, despite its regular use, the evidence for the efficacy of these drugs for in this context is lacking. A systematic review was conducted to establish the research evidence for the efficacy of beta blockers in problem behaviours in adults and children with intellectual disabilities. Although the research identified supported the efficacy of beta blockers for this indication the overall quality of studies identified was poor and no randomised controlled trials were identified. There is a need for more robust research into the use of beta blockers for people with intellectual disabilities who show problem behaviours. PMID- 24171828 TI - Effect of maturation on suprasegmental speech processing in full- and preterm infants: a mismatch negativity study. AB - Infants born prematurely are at higher risk for later linguistic deficits present in delayed or atypical processing of phonetic and prosodic information. In order to be able to specify the nature of this atypical development, it is important to investigate the role of early experience in language perception. According to the concept of Gonzalez-Gomez and Nazzi (2012) there is a special intrauterine sensitivity to the prosodic features of languages that should have a special role in language acquisition. Therefore, we may also assume that pre- and full-term infants having months difference in intrauterine experience show different maturation patterns of processing prosodic and phonetic information present at word level. The aim of our study was to investigate the effect of these differences on word stress pattern vs. phoneme information processing. Two age groups of infants (6 and 10 month-olds) were included in our study. 21 of 46 of the total of infants investigated were prematurely born with low birth weight. We used the mismatch negativity (MMN) event related brain potential (ERP) component, a widely used electrophysiological correlate of acoustic change detection, for testing the assumed developmental changes of phoneme and word stress discrimination. In a passive oddball paradigm we used a word as standard, a pseudo-word as phoneme deviant, and an illegally uttered word as stress deviant. Our results showed no differences in MMN responses in the phoneme deviant condition between the groups, meaning a relatively intact maturation of phoneme processing of preterm infants as compared to their contemporaries. However, the mismatch responses measured in the stress condition revealed significant between group differences. These results strengthen the view that the total length of intrauterine experience influences the time of emergence of prosodic processing. PMID- 24171829 TI - Acute disseminated encephalomyelitis without optic neuritis followed by optic neuritis in a child due to the sudden cessation of steroid therapy. AB - Acute disseminated encephalitis (ADEM) is an autoimmune demyelinating disorder of the central nervous system that usually occurs in children after viral infection or vaccination. It is not uncommon for ADEM to be accompanied by optic neuritis. However, ADEM followed by optic neuritis is a rare. We report the case of a 6 year-old girl who initially presented with ADEM (without optic neuritis) due to a live measles, mumps, and rubella vaccine and was treated with intravenous high dose corticosteroids. After steroid therapy, she recovered neurologically and was not prescribed any medication, including an oral steroid taper, for use after discharge. Three weeks later, she developed unilateral optic neuritis and was again treated with steroid therapy. This is a rare case of ADEM without optic neuritis in a child, followed by optic neuritis due to the sudden cessation of steroid therapy. Further studies and follow-ups are needed to determine whether ADEM followed by optic neuritis can be considered a specific clinical form of this disorder. PMID- 24171830 TI - Scleral-fixated posterior chamber intraocular lens implantation in pediatric and adult patients. AB - PURPOSE: To evaluate the results of scleral-fixated posterior chamber intraocular lenses (SFIOL) in pediatric and adult patients. METHODS: We carried out a retrospective analysis of 129 eyes of 120 patients (adult group, n = 96; pediatric group, n = 24) who underwent SFIOL implantation. Outcome measures were indications, corrected distance visual acuity (CDVA), change in visual acuity, and complications. RESULTS: The median follow-up time was six months (minimum: 6; maximum: 55 months). The median preoperative CDVAs were similar between the groups (p = 0,253). The median postoperative CDVA was 0.2 (min: hand motion; max: 0.8) in pediatric patients and 0.5 (min: hand motion; max: 1.0) in adult patients in decimal notation, (p = 0.017). The CDVA improved at least one Snellen line or remained unchanged in all pediatric eyes, and in 87 (90.6%) adult eyes. The change in visual acuity was similar between the groups (p = 0.296). CONCLUSION: In both pediatric and adult patients, SFIOL implantation ends with favorable outcomes over the short term. PMID- 24171831 TI - Serous retinal detachment and cystoid macular edema in a patient with Wyburn Mason syndrome. AB - Wyburn-Mason syndrome is a rare phacomatosis characterized by unilateral arteriovenous malformations (AVMs) involving the brain, retina, and (rarely) the skin. The diagnosis is concluded with dilated fundus examination and markedly dilated tortuous vascular loops with arteriovenous communications on fluorescent angiography. We present a 14-year-old male patient with Wyburn-Mason syndrome who developed serous macular neuroretinal detachment, cystoid macular edema (CME), and consequent visual deterioration in the left eye. To the best of our knowledge, this is the first report of a patient with Wyburn-Mason syndrome who developed serous retinal detachment and CME. PMID- 24171832 TI - Local and systemic complications after intravitreal administration of anti vascular endothelial growth factor agents in the treatment of different ocular diseases: a five-year retrospective study. AB - PURPOSE: To observe the frequency of complications in patients undergoing intravitreal anti-VEGF injections for different ocular diseases in a five-year period. MATERIALS AND METHODS: Charts of patients receiving intravitreal anti VEGF were retrospectively reviewed. Out of 1173 eyes, 762 were treated with bevacizumab, 382 with ranibizumab, and 29 with pegaptanib. Data recorded included demographic information, clinical findings, total injections received, and info about the onset of adverse effects. RESULTS: 12.86% of the eyes treated with bevacizumab presented side-effects, while ratings in the ranibizumab and pegaptanib groups were 15.97% and 20.69%, respectively. Odds ratios calculated comparing incidences after each anti-VEGF are 0.78 (bevacizumab versus ranibizumab, p = 0.152), 0.57 (bevacizumab versus pegaptanib, p = 0.227), and 0.73 (ranibizumab versus pegaptanib, p = 0.508). A total of 185 complications were detected (62.16% after bevacizumab). Ocular side-effects registered were 40 cases of sustained intraocular pression (IOP) elevation, one infectious uveitis, one retinal detachment, and one sub-retinal hemorrhage. Other cases were related to transient IOP elevation immediately after injection. Systemic complications registered were one case of nausea, one episode of chest pain with acute vision loss, and one case of acute blood hypertension. CONCLUSIONS: The majority of significant complications occurred in patients receiving multiple bevacizumab administrations. However, results may be affected by the difference in the utilization amount for each drug. AMD patients were the most represented, probably due to greater indication to treatment. PMID- 24171833 TI - Expression of vascular endothelial growth factor (VEGF) in macrophages, fibroblasts, and endothelial cells in pterygium treated with 5-Fluorouracil. AB - PURPOSE: To evaluate the VEGF expression in macrophages, fibroblasts, and endothelial cells from pterygium before and after 5-fluorouracil (5-FU) exposure. METHODS: 68 excised pterygia (42 primary and 26 recurrent) were studied by immunohistochemistry, to analyze its expression in cells from pterygium and normal conjunctiva. VEGF expression was evaluated before and after a 5-FU subconjunctival injection 15 days prior to surgery. RESULTS: Expression in macrophages was moderate in normal conjunctiva and low to moderate in pterygium tissues. In fibroblasts, it was negative or low in both tissues. Pterygium had a higher proportion of high VEGF expression in endothelial cells compared to normal tissue (p < 0.05). 5-FU did not have any influence on expression. CONCLUSION: VEGF expression in pterygium macrophages, fibroblasts, and endothelial cells was low and similar to that normal in conjunctival tissue. High VEGF expression was found in pterygium endothelial cells compared to normal conjunctiva. 5-FU does not impact VEGF expression. PMID- 24171834 TI - Macular hole after phakic intraocular lens implantation: two cases with divergent manifestations. AB - Abstract We describe two cases of a macular hole (MH) which had divergent manifestations and clinical courses following implantation of an Implantable Collamer Lens (ICL) in two high myopic patients. The onset of symptoms and shape of the holes, which were observed by optical coherence tomography and fundoscopy, and prognosis of the visual acuity after the surgery of each patient, were quite different. In the first patient, the symptom was an acute onset. Fundoscopy showed a cuneiform-shaped hole with internal limiting membrane defect around the hole. The prognosis after the surgery was very poor, and the best corrected visual acuity was 0.08 after complete anatomical closure. In another patient, the MH showed insidious progression with disease-free interval from ICL implantation to MH onset. After the surgery, the best corrected visual acuity was recovered to 1.0. PMID- 24171835 TI - Complex small supernumerary marker chromosomes - an update. AB - BACKGROUND: Complex small supernumerary marker chromosomes (sSMC) constitute one of the smallest subgroups of sSMC in general. Complex sSMC consist of chromosomal material derived from more than one chromosome; the best known representative of this group is the derivative chromosome 22 {der(22)t(11;22)} or Emanuel syndrome. In 2008 we speculated that complex sSMC could be part of an underestimated entity. RESULTS: Here, the overall yet reported 412 complex sSMC are summarized. They constitute 8.4% of all yet in detail characterized sSMC cases. The majority of the complex sSMC is contributed by patients suffering from Emanuel syndrome (82%). Besides there are a der(22)t(8;22)(q24.1;q11.1) and a der(13)t(13;18)(q11;p11.21) or der(21)t(18;21)(p11.21;q11.1) = der(13 or 21)t(13 or 21;18) syndrome. The latter two represent another 2.6% and 2.2% of the complex sSMC-cases, respectively. The large majority of complex sSMC has a centric minute shape and derives from an acrocentric chromosome. Nonetheless, complex sSMC can involve material from each chromosomal origin. Most complex sSMC are inherited form a balanced translocation in one parent and are non-mosaic. Interestingly, there are hot spots for the chromosomal breakpoints involved. CONCLUSIONS: Complex sSMC need to be considered in diagnostics, especially in non-mosaic, centric minute shaped sSMC. As yet three complex-sSMC-associated syndromes are identified. As recurrent breakpoints in the complex sSMC were characterized, it is to be expected that more syndromes are identified in this subgroup of sSMC. Overall, complex sSMC emphasize once more the importance of detailed cytogenetic analyses, especially in patients with idiopathic mental retardation. PMID- 24171836 TI - Prevalence and public health relevance of micronutrient deficiencies and undernutrition in pre-school children and women of reproductive age in Cote d'Ivoire, West Africa. AB - OBJECTIVE: To provide nationally representative data on the prevalence of anaemia, vitamin A and Fe deficiencies among pre-school age children (pre-SAC) and non-pregnant women of reproductive age (WRA), and on vitamin B12 and folate deficiencies in WRA, and the influence of inflammation on their interpretation. DESIGN: A cross-sectional survey to measure anthropometry, malaria parasitaemia and micronutrient status. Specifically, blood samples were analysed for Hb, plasma ferritin, soluble transferrin receptors, C-reactive protein, alpha1-acid glycoprotein, retinol-binding protein, vitamin B12 and folate. SETTING: Cote d'Ivoire in 2007. SUBJECTS: Nine hundred and twenty-eight WRA and 879 pre-SAC. RESULTS: In WRA, prevalence of Plasmodium parasitaemia (5 %) was low, but inflammation (34 %) was higher. Anaemia was a severe public health problem and prevalence differed by residency and eco-region. Inflammation-adjusted Fe deficiency was highest in urban areas (20 %). Nationally, folate deficiency was 86 %, higher in urban areas and varied by eco-region. Prevalence of vitamin B12 deficiency was low but higher in the rural areas and the north. Inflammation adjusted vitamin A deficiency was very low (1 %). In pre-SAC, prevalence of inflammation (67 %) and Plasmodium parasites (25 %) was high; the latter was associated with poverty, rural residency and higher ferritin concentrations. Anaemia was classified as a severe public health problem (72 %), and was higher in rural areas (76 %) and the north (87 %). A quarter of pre-SAC suffered from vitamin A deficiency (inflammation-adjusted) and prevalence of undernutrition was high. CONCLUSIONS: Prevalence of inflammation, Plasmodium parasitaemia and micronutrient deficiencies were high in Cote d'Ivoire, particularly in pre-SAC. Nutritional interventions should be accompanied by strategies to reduce exposure to infections. PMID- 24171837 TI - Serum antibodies against betaH-crystallins in the American Cocker Spaniel. AB - OBJECTIVE: To detect antibodies for lens betaH-crystallins in the serum from the American Cocker Spaniel (ACS) presenting with and without cataracts and with and without uveitis. ANIMAL STUDIED: Seventy-three American Cocker Spaniels and six normal Beagles. PROCEDURES: Sera were collected from 73 ACSs, including those with normal lenses and those with cataracts, or uveitis. Fractionated, normal Beagle lens betaH-crystallins were separated by one- or two-dimensional electrophoresis. The separated lens betaH-crystallins were used on immunoblots as sentinel substrates against which the ACS sera were tested for the presence of antibodies against betaH-crystallins. RESULTS: Sera from approximately two-thirds of study animals contained antibodies to some betaH-crystallin polypeptides, but reactivity varied among patients. Contrary to some hypotheses, serum antibodies to groups of betaH-crystallins did not relate to the stages of cataract. However, detailed analysis by two-dimensional immunoblotting and mass spectrometry showed that three spots originating from betaA1-crystallin were detected only in sera from cataract patients. CONCLUSION: Serum antibodies to betaA1-crystallin may be associated with the development of cataract. PMID- 24171838 TI - The disutility of tooth loss: a comparison of patient and professional values. AB - OBJECTIVES: The objectives of this study are to study how tooth loss affects the utility of the dentition from both patient and professional perspectives and to compare patient and professional utility values. METHODS: One hundred six patients and 118 dentists were asked to read 19 different written scenarios accompanied by visual images and models, describing mouths with missing teeth, and to indicate on a visual analog scale the value of that oral health state. RESULTS: Both groups of participants attached the greatest utility to missing incisor teeth and disutility of tooth loss decreased as the tooth in question became nearer the back of the mouth. When dentist and patient utility values for the loss of different tooth types were compared, using independent t-tests, differences were statistically significant for only one tooth loss scenario - the loss of upper canines. CONCLUSIONS: The patient and professional groups valued tooth loss scenarios in a similar way. This finding is contrary to the majority of previous studies comparing patient and professional utilities. PMID- 24171839 TI - Important challenges for coordination and inter-municipal cooperation in health care services: a Delphi study. AB - BACKGROUND: Demographical changes have stimulated a coordination reform in the Norwegian health care sector, creating new working practices and extending coordination within and between primary and hospital care, increasing the need for inter-municipal cooperation (IMC). This study aimed to identify challenges to coordination and IMC in the Norwegian health care sector as a basis for further theorizing and managerial advice in this growing area of research and practice. METHODS: A Delphi study of consensus development was used. Experts in coordination and IMC in health care services were selected by the healthcare manager or the councillor in their respective municipalities. In the first round, an expert panel received open-ended questions addressing possible challenges, and their answers were categorized and consolidated as the basis for further validation in the second round. The expert panel members were then asked to point out important statements in the third round, before the most important statements ranked by a majority of the members were rated again in the fourth round, including the option to explain the ratings. The same procedure was used in round five, with the exception that the expert panel members could view the consolidated results of their previous rankings as the basis for a new and final rating. The statements reaching consensus in round five were abstracted and themed. RESULTS: Nineteen experts consented to participate. Nine experts (47%) completed all of the five rounds. Eight statements concerning coordination reached consensus, resulting in four themes covering these challenges: different culture, uneven balance of power, lack of the possibility to communicate electronically, and demanding tasks in relation to resources. Three statements regarding challenges to IMC reached consensus, resulting in following themes: coopetition, complex leadership, and resistance to change. CONCLUSIONS: This study identified several important challenges for coordination and it supports previous research. IMC in health care services deals with challenges other than coordination, and these must be addressed specifically. Our study contributes to extended knowledge of theoretical and practical implications in the field of coordination and IMC in health care sector. PMID- 24171840 TI - Heart remodeling induced by adjuvant trastuzumab-containing chemotherapy for breast cancer overexpressing human epidermal growth factor receptor type 2: a prospective study. AB - We aimed to investigate the cardiac changes in patients with human epidermal growth factor receptor 2 (HER2)-positive breast cancer treated with trastuzumab in an adjuvant setting. Two hundred and fifty-three women with HER2-positive breast cancer were included. The assessment of cardiovascular system and echocardiography were performed and compared at baseline, at the termination of trastuzumab therapy and 6 months latter. Left heart remodeling was defined arbitrary as the change in at least one of the analyzed echocardiographic parameters of >=standard deviation (SD) (in model I) or >=2*SD (in model II) after 6-month follow-up. After 6-month follow-up 39 (31.7%), 27 (22%), 14 (11.4%), 10 (8.1%), 5 (4.1%) and 1 (0.8%), women had at least one parameter with a change exceeding mean difference >=SD, respectively; and 30 (24.4%), 9 (7.5%), 3 (2.4%), 2 (1.6%) 1 (0.8%) exceeding mean difference >=2SD. In stepwise multivariate regression analysis sedentary life style (OR16.7, p=0.003), positive cardiovascular family history (OR 6,9; p=0.013) and left ventricular ejection fraction change after 3 months (OR 1.2; p=0.007) were independent predictors of left heart remodeling in model I, whereas hypertension (OR 5.6; p=0.06) and positive cardiovascular family history (OR 3.9; p=0.032) were independent predictors of heart remodeling in model II. In conclusion, trastuzumab induces LV and left atrial cavity dilatation together with LV systolic function impairment. PMID- 24171841 TI - Perceived importance of prospective memory failures in adults with traumatic brain injury. AB - Prospective memory (PM) is the ability to carry out an intended action in the future. Failures in PM are often observed as more frequent in individuals with traumatic brain injury (TBI) than controls. However, it remains unknown how individuals with TBI and their significant others perceive the importance of these PM problems. In the current study, four groups (38 TBI, 34 TBI-other, 34 controls, 31 control-other) were recruited to report on the perceived importance of PM failures using Part B of the Comprehensive Assessments of Prospective Memory (CAPM). Individuals with TBI perceived PM failures as being more important than did their significant others. Controls' ratings did not differ from their significant others. There were no statistically significant differences in rated importance for PM problems involving the basic activities of daily living (BADL) component and those involving the instrumental activities of daily living (IADL) component. Implications of the results are discussed in terms of the motivation of people with TBI. PMID- 24171843 TI - Descemet stripping endothelial keratoplasty for a failed penetrating keratoplasty graft in a pseudophakic patient with a toric intraocular lens: a case report. AB - BACKGROUND: To report a patient with penetrating keratoplasty (PKP) graft endothelial failure implanted with toric intraocular lens (IOL) who was treated with Descemet stripping endothelial keratoplasty (DSAEK). CASE PRESENTATION: A 40 year old male patient implanted with toric intraocular lens for the treatment of post PKP astigmatism, presented for the treatment of graft endothelial failure'. The patient had uncorrected distance visual acuity (UDVA) 20/200 not correcting with manifest refraction. The patient reported excellent visual acuity after cataract surgery and toric IOL implantation. DSAEK was performed in order to minimally affect keratometry and retain correspondence of the anterior cornea astigmatism with the toric IOL astigmatic power. Three months postoperatively the cornea was clear with no edema. UDVA was 20/40 and corrected distance visual acuity was 20/25 with +1.50-1.00 * 20. CONCLUSIONS: This report describes a unique case of DSAEK for treatment of a failed PKP in a patient previously implanted with a toric IOL. DSAEK was an effective alternative of PKP in this patient for the preservation of the toric IOL's effect. PMID- 24171842 TI - Weight management for overweight and obese men delivered through professional football clubs: a pilot randomized trial. AB - BACKGROUND: The prevalence of male obesity is increasing, but men are less likely than women to attend existing weight management programmes. We have taken a novel approach to reducing perceived barriers to weight loss for men by using professional football (soccer) clubs to encourage participation in a weight management group programme, gender-sensitised in content and style of delivery. Football Fans in Training (FFIT) provides 12 weeks of weight loss, physical activity and healthy eating advice at top professional football clubs in Scotland. This pilot randomized trial explored the feasibility of using these clubs as a setting for a randomized controlled trial of 12 month weight loss following men's participation in FFIT. METHODS: A two-arm pilot trial at two Scottish Premier League football clubs (one large, one smaller), with 103 men (aged 35-65, body mass index (BMI) >=27 kg/m2) individually randomized to the intervention (n=51, received the pilot programme (p-FFIT) immediately) and waitlist comparison (n=52, received p-FFIT after four months) groups. Feasibility of recruitment, randomization, data collection and retention were assessed. Objective physical measurements (weight, waist circumference, blood pressure, body composition) and questionnaires (self-reported physical activity, diet, alcohol consumption, psychological outcomes) were obtained from both groups by fieldworkers trained to standard protocols at baseline and 12 weeks, and from the intervention group at 6 and 12 months. Qualitative methods elicited men's experiences of participation in the pilot trial. RESULTS: Following a short recruitment period, the recruitment target was achieved at the large, but not smaller, club. Participants' mean age was 47.1 +/- 8.4 years; mean BMI 34.5 +/- 5.0 kg/m2. Retention through the trial was good (>80% at 12 weeks and 6 months; >75% at 12 months), and 76% attended at least 80% of available programme delivery sessions. At 12 weeks, the intervention group lost significantly more weight than the comparison group (4.6% c.f. -0.6%, p<.001) and many maintained this to 12 months (intervention group baseline-12 month weight loss: 3.5%, p<.001). There were also improvements in self-reported physical activity and diet, many sustained long term. CONCLUSIONS: The results demonstrated the feasibility of trial procedures and the potential of FFIT to engage men in sustained weight loss and positive lifestyle change. They supported the conduct of a fully-powered randomized controlled trial. PMID- 24171844 TI - Mycobacterium bovis: characteristics of wildlife reservoir hosts. AB - Mycobacterium bovis is the cause of tuberculosis in animals and sometimes humans. Many developed nations have long-standing programmes to eradicate tuberculosis in livestock, principally cattle. As disease prevalence in cattle decreases these efforts are sometimes impeded by passage of M. bovis from wildlife to cattle. In epidemiological terms, disease can persist in some wildlife species, creating disease reservoirs, if the basic reproduction rate (R0) and critical community size (CCS) thresholds are achieved. Recognized wildlife reservoir hosts of M. bovis include the brushtail possum (Trichosurus vulpecula) in New Zealand, European badger (Meles meles) in Great Britain and Ireland, African buffalo (Syncerus caffer) in South Africa, wild boar (Sus scrofa) in the Iberian Peninsula and white-tailed deer (Odocoileus virginianus) in Michigan, USA. The epidemiological concepts of R0 and CCS are related to more tangible disease/pathogen characteristics such as prevalence, pathogen-induced pathology, host behaviour and ecology. An understanding of both epidemiological and disease/pathogen characteristics is necessary to identify wildlife reservoirs of M. bovis. In some cases, there is a single wildlife reservoir host involved in transmission of M. bovis to cattle. Complexity increases, however, in multihost systems where multiple potential reservoir hosts exist. Bovine tuberculosis eradication efforts require elimination of M. bovis transmission between wildlife reservoirs and cattle. For successful eradication identification of true wildlife reservoirs is critical, as disease control efforts are most effective when directed towards true reservoirs. PMID- 24171845 TI - Review of the diagnosis of tuberculosis in non-bovid wildlife species using immunological methods--an update of published work since 2009. AB - The infection of both captive and free-ranging wildlife species with pathogenic mycobacteria (including Mycobacterium tuberculosis) poses a zoonotic risk and continues to cause challenges for the livestock industry, zoos and governments around the world. Central to the management and control of tuberculosis is timely and accurate diagnosis. In many cases, bacterial culture is insufficiently sensitive and confirmation of TB post-mortem is neither feasible nor desirable. In this context, there is still considerable research interest in, and need for, immunological methods for diagnosis. Reviews on this topic were published in 2005 and 2009, but since then veterinarians and other researchers have continued to evaluate immunodiagnostic approaches to TB. These include serological tests such as lateral-flow devices, and enzyme-linked immunosorbent assay (ELISA) and those based on evaluation of cell-mediated immunity, such as the tuberculin skin test and interferon-gamma release assay (IGRA). Since 2009, the range of publications on this topic has been extended to a number of new species, including South American camelids, black rhinoceros, lions and non-human primates. Therefore, it seemed appropriate to review the literature in the 3 years since 2009 and provide an overview of progress. PMID- 24171846 TI - Preliminary assessment of bovine tuberculosis at the livestock/wildlife interface in two protected areas of northern Botswana. AB - Protected areas of northern Botswana such as the Okavango Delta (OD) or Chobe National Park (CNP) are well-known hot spots for the conservation of African wildlife. However, their infection status regarding bovine tuberculosis (BTB) at the domestic/wildlife interface has never been investigated. To provide preliminary baseline data on the circulation of Mycobacterium bovis in those sites, we performed a cross-sectional survey on 130 buffalo in both protected areas (60 individuals from CNP and 70 from OD) and 818 cattle in their surrounding communal lands (369 in CNP and 449 in the OD). Whole-blood samples were tested using a commercial interferon-gamma assay (IFN-gamma) with modifications. The apparent BTB prevalence in buffalo was nil in CNP and 0.7% 95% CI [0.2-1.9] in the OD, while the apparent BTB prevalence in cattle was 0.7% 95% CI [0.2-2.1] in the OD and 2.4% 95% CI [1.2-4.7] in CNP. True prevalence values calculated on the basis of the locally applicable IFN-gamma test performance suggested that BTB prevalence was nil in both buffalo populations and in cattle from the OD interface, but reached 2.3% 95% CI [0.2-4.5] in cattle populations around CNP. The results of a questionnaire survey conducted among a sample of farmers living in the communities adjacent to each conservation area (97 and 38 persons in the OD and CNP, respectively) suggested a higher risk of the circulation of M. bovis at the wildlife/livestock interface of the CNP than at that of the OD. However, further comprehensive studies are needed to confirm the circulation of M. bovis and to monitor the inter-species and transboundary transmission of BTB in northern Botswana. PMID- 24171847 TI - Sex-related heterogeneity in the life-history correlates of Mycobacterium bovis infection in European badgers (Meles meles). AB - Heterogeneity in the progression of disease amongst individual wild animals may impact on both pathogen and host dynamics at the population level, through differential effects on transmission, mortality and reproductive output. The role of the European badger (Meles meles) as a reservoir host for Mycobacterium bovis infection in the UK and Ireland has been the focus of intense research for many years. Here, we investigate life-history correlates of infection in a high density undisturbed badger population naturally infected with M. bovis. We found no evidence of a significant impact of M. bovis infection on female reproductive activity or success, with evidence of reproduction continuing successfully for several years in the face of M. bovis excretion. We also found evidence to support the hypothesis that female badgers are more resilient to established M. bovis infection than male badgers, with longer survival times following the detection of bacterial excretion. We discuss the importance of infectious breeding females in the persistence of M. bovis in badger populations, and how our findings in male badgers are consistent with testosterone-induced immunosuppression. In addition, we found significant weight loss in badgers with evidence of disseminated infection, based on the culture of M. bovis from body systems other than the respiratory tract. For females, there was a gradual loss of weight as infection progressed, whereas males only experienced substantial weight loss when infection had progressed to the point of dissemination. We discuss how these differences may be explained in terms of resource allocation and physiological trade-offs. PMID- 24171848 TI - Mycobacterium tuberculosis at the human/wildlife interface in a high TB burden country. AB - This study reports on an investigation of Mycobacterium tuberculosis cases in mostly captive wild animals using molecular typing tools [Variable Number of Tandem Repeat (VNTR) typing and Restriction Fragment Length Polymorphism typing]. The investigation included cases from (i) the National Zoological Gardens of South Africa (NZG) recorded between 2002 and 2011; (ii) Johannesburg Zoo, where tuberculosis was first diagnosed in 2007 and has since been detected in three antelope species; (iii) a rehabilitation centre for vervet monkeys (Chlorocebus pygerythrus) in which M. tuberculosis was diagnosed in 2008; and (iv) incidental cases in other facilities including a sable antelope (Hippotragus niger), two unrelated cases in chacma baboons (Papio ursinus) (one of which was from a free ranging troop) and a colony of capuchin monkeys (Cebus capucinus). Identical genetic profiles of the latter three isolates indicate the persistence of a single M. tuberculosis strain in this population since at least 2006. Results of the outbreak investigation in the captive vervet monkey colony indicate that it was caused by two unrelated strains, while all 13 M. tuberculosis isolates from 11 animal species in the NZG showed different VNTR patterns. A substantial increase in tuberculosis cases of 60% was recorded in the NZG, compared with the previous reporting period 1991-2001, and may indicate a countrywide trend of increasing spillover of human tuberculosis to wild animals. South Africa ranks among the countries with the highest-tuberculosis burden worldwide, complicated by an increasing rate of multidrug-resistant strains. Exposure and infection of captive wildlife in this high prevalence setting is therefore a growing concern for wildlife conservation but also for human health through potential spillback. PMID- 24171849 TI - The elephant interferon gamma assay: a contribution to diagnosis of tuberculosis in elephants. AB - Mycobacterium tuberculosis (M. tb) has been shown to be the main causative agent of tuberculosis in elephants worldwide. M. tb may be transmitted from infected humans to other species including elephants and vice versa, in case of prolonged intensive contact. An accurate diagnostic approach covering all phases of the infection in elephants is required. As M. tb is an intracellular pathogen and cell-mediated immune (CMI) responses are elicited early after infection, the skin test is the CMI assay of choice in humans and cattle. However, this test is not applicable in elephants. The interferon gamma (IFN-gamma) assay is considered a good alternative for the skin test in general, validated for use in cattle and humans. This study was aimed at development of an IFN-gamma assay applicable for diagnosis of tuberculosis in elephants. Recombinant elephant IFN-gamma (rEpIFN gamma) produced in eukaryotic cells was used to immunize mice and generate the monoclonal antibodies. Hybridomas were screened for IFN-gamma-specific monoclonal antibody production and subcloned, and antibodies were isotyped and affinity purified. Western blot confirmed recognition of the rEpIFN-gamma. The optimal combination of capture and detection antibodies selected was able to detect rEpIFN-gamma in concentrations as low as 1 pg/ml. The assay was shown to be able to detect the native elephant IFN-gamma, elicited in positive-control cultures (pokeweed mitogen (PWM), phorbol myristate acetate plus ionomycin (PMA/I)) of both Asian and African elephant whole-blood cultures (WBC). Preliminary data were generated using WBC from non-infected elephants, a M. tb infection-suspected elephant and a culture-confirmed M. tb-infected elephant. The latter showed measurable production of IFN-gamma after stimulation with ESAT6/CFP10 PPDB and PPDA in concentration ranges as elicited in WBC by Mycobacterium tuberculosis complex (MTBC)-specific antigens in other species. Hence, the IFN-gamma assay presented potential as a diagnostic tool for the detection of elephant tuberculosis. Validation of the assay will require its application in large populations of non-infected and infected elephants. PMID- 24171850 TI - Towards establishing a rhinoceros-specific interferon-gamma (IFN-gamma) assay for diagnosis of tuberculosis. AB - Mycobacterium bovis is the causal agent of bovine tuberculosis (BTB), with a diverse host range, extending from livestock to domestic and captive wild animals as well as free-ranging wildlife species. In South Africa, BTB is endemic in the Kruger National Park (KNP) and the Hluluwe iMfolozi National Park (HiP), where the high prevalence of M. bovis infections in buffalo herds has led to infection of a number of wildlife species. This has raised concerns about the spillover into the rhinoceros population, a species known to be susceptible to both M. bovis and Mycobacterium tuberculosis, jeopardizing breeding and relocation projects that serve to conserve and protect this species. In view of the advantages of the interferon-gamma (IFN-gamma) assay in the diagnosis of BTB in a variety of species worldwide, such an assay has been developed for rhinoceroses by Morar and co-workers in 2007. In this study, this assay was optimized using recombinant eukaryotic rhinoceros IFN-gamma and the lower detection limit was calculated to be 0.5 ng/ml. Subsequently, assessing the detection of native rhinoceros IFN-gamma protein in whole-blood samples revealed stimulation with each of the mitogens: pokeweed (PWM), phytohaemagglutinin (PHA) & phorbol 12 myristate 13-acetate and calcium ionophore (PMA/CaI), though most prominently with the latter two. In addition, samples collected from 52 clinically healthy rhinoceroses, of presumed negative BTB status, from two different areas in South Africa were used to determine the cut-off value for a negative test result. This was calculated to be 0.10 (OD490 nm ) and as determined in this study is a preliminary recommendation based on IFN-gamma responses observed in samples from BTB-free rhinoceroses only. PMID- 24171851 TI - Performance of diagnostic tests for bovine tuberculosis in North American furbearers and implications for surveillance. AB - Risks of bovine tuberculosis (bTB) transmission from free-ranging wildlife to livestock remain a concern in the United States, in both known endemic areas and where spillover from recently-infected livestock herds occurs. Federal agriculture officials in the United States (US) have recommended surveillance of non-cervid furbearers to determine whether free-ranging wildlife in the vicinity of cattle herd breakdowns are bTB infected, yet the efficacy of common diagnostic tests in these species is largely unknown. We calculated the sensitivity, specificity, predictive values and positive likelihood ratios for bTB infection in carcasses of sixteen species of furbearers tested via: (i) the presence of gross lesions compatible with bTB; (ii) histopathology consistent with bTB; and (iii) the presence of acid-fast bacilli (AFB) on histopathology. The gold standard comparison test was mycobacterial culture of cranial +/- visceral lymph nodes pooled for each animal. Forty-two animals distributed across six species cultured bTB positive from among 1522 furbearers tested over thirteen years. The sensitivity of all three tests was poor (10%, 22% and 24% for gross lesions, AFB and histopathology, respectively), while specificities (all >= 99%) and negative predictive values (all >= 97%) were high. Positive predictive values varied widely (31-75%). Likelihood ratios for culture positivity given a positive test result showed AFB on histopathology to be the most reliable test, and gross lesions the least, though confidence intervals were wide and overlapping. While non-cervid furbearers may prove useful in North American bTB surveillance, wildlife managers should be aware of factors that may abate their utility and complicate interpretation of surveillance. PMID- 24171852 TI - Prevalence and distribution of non-tuberculous mycobacteria (NTM) in cattle, African buffaloes (Syncerus caffer) and their environments in South Africa. AB - It has been hypothesized that a variety of non-tuberculous mycobacteria (NTM) species to which livestock and wildlife species are naturally exposed induce broadly cross-reactive anti-mycobacterial immune responses which interfere with current standard diagnostic assays. Non-tuberculous mycobacteria have also been implicated in Mycobacterium bovis-specific immune responsiveness, hence potentially the development of tuberculosis. Cattle and African buffaloes are both maintenance hosts of bovine tuberculosis (BTB) in South Africa, yet the effective diagnosis and control in these species may be hampered by adverse effects of NTM. As part of an investigation of the role of NTM in the immune responsiveness of cattle and African buffaloes to NTM, we conducted a countrywide survey to establish the prevalent NTM species and their distribution in the natural environments of these animals. A total of 1123 samples (water, soil, nasal and pharyngeal swabs) were collected for mycobacterium isolation. In addition, NTM isolated from tissue samples between 1991 and 2011 were included in the analysis. Mycobacteria were isolated from 56% of the samples from the countrywide survey. A total of 420 NTM isolates from soil, water, animal tissues and animal-derived swab samples were genotyped with the following results: 302 belonged to 40 known NTM species, 79 were found to be closely related to 23 known NTM species, and 38 isolates were found to be potentially novel species that are not currently listed in the RIDOM and NCBI BLAST databases. The four NTM species or closely related groups most frequently isolated in this survey included Mycobacterium terrae (11.2% of isolates), a group of mycobacteria closely related to Mycobacterium moriokaense (referred to as M. moriokaense-like) (8.1% of isolates), Mycobacterium nonchromogenicum (7.4% of isolates) and Mycobacterium vaccae/M. vanbaalenii (5.2% of isolates). The phylogenetic analysis of the M. moriokaense-like isolates, based on the 16S rRNA sequences, revealed at least eight clusters, possibly associated with eight different NTM species. Our findings provide account of NTM species diversity and associated prevalences in cattle and African buffaloes and their environments in South Africa. The identification of the most prevalent NTM species in this study will allow for a targeted investigation of their effects on host immune responses. PMID- 24171853 TI - A strategic approach to eradication of bovine TB from wildlife in New Zealand. AB - A review and amendment of New Zealand's National Pest Management Strategy for bovine tuberculosis (TB) has led to adoption of new strategy objectives for localized eradication of disease from the principal wildlife maintenance host and infecting vector for farmed cattle and deer, the brushtail possum Trichosurus vulpecula. Historic programmes have been based on management of disease within herds and control of wildlife directed towards reducing infected herd prevalence. From July 2011, the TB strategy has been redirected towards eradication of TB from possums and other wildlife over a total area of at least 2.5 million hectares over a 15-year period. The amended strategy is intended to provide large scale proof of concept, using two extensive bush areas, that TB can be eradicated from wildlife in New Zealand in the longer term, leading to eventual savings in control programmes needed to protect cattle and deer herds from infection. Achievement of strategy objectives will be supported by major research together with technical and managerial improvements in wildlife TB control and surveillance, and these are reviewed. PMID- 24171854 TI - Temporal trend of tuberculosis in wild ungulates from Mediterranean Spain. AB - Tuberculosis (TB), a chronic disease caused by infection with the Mycobacterium tuberculosis complex, is endemic in wild boar (Sus scrofa) and red deer (Cervus elaphus) in south-central Spain. Understanding the temporal dynamics of this chronic infection requires long time series data collection over large areas. The aim of this paper was to identify the determinants of TB prevalence and severity in both species in Ciudad Real province, Spain, from 2000 to 2012. Study variables included management, population dynamics, and a range of geographical and climatological factors. The prevalence of TB in wild boar increased from 50% to 63% since the study commenced. This may be due to an increased hunting bag (a proxy for population abundance), which was correlated with TB infection rates. Low rainfall (a stochastic factor) was associated with higher individual risk of TB presence and progression, resulting in an increased proportion of severe cases of wild boar TB in dry years. This was probably a result of increased food restriction leading to a higher susceptibility to TB. In contrast, red deer TB showed an apparent stable trend, which may be a consequence of the species' higher and stable population size. Hunting management, characterized by fencing, was associated with a higher risk of TB in both wild boar and red deer, suggesting that intensive hunting management may have contributed to exacerbated TB figures. This difference was more marked in red deer than in wild boar, probably because fencing imposes less restriction on movement, population mixing and TB spread to wild boar than to deer. Our findings on TB dynamics are fundamental for assessing the impact of future disease-control actions (e.g. field vaccination). Moreover, such control plans must operate in the long term and cover large areas. PMID- 24171855 TI - Epidemiology caught in the causal web of bovine tuberculosis. AB - Bovine tuberculosis in domestic cattle in the presence of significant infection levels in wild animal species represents a major challenge for disease control. The use of wild animal population density reduction as part of risk management policies is highly controversial from the perspectives of scientific effectiveness and societal acceptability. The experience in Great Britain in dealing with this problem over the last 20 years demonstrates the need to engage in an integrated approach towards risk governance to more effectively deal with such a complex and contentious multifactorial animal disease problem. As part of this process, the traditional emphasis on bioscientific, in particular epidemiological, research needs to be complemented by relevant social science approaches. In addition, the risk assessment as well as the risk management should have effective participatory elements. PMID- 24171856 TI - Evaluation of the discriminatory power of variable number of tandem repeat typing of Mycobacterium bovis isolates from southern Africa. AB - The usefulness of variable number tandem repeat (VNTR) typing based on limited numbers of loci has previously proven inferior compared to IS6110-RFLP typing when applied to the study of the molecular epidemiology of bovine tuberculosis (BTB) in both livestock and wildlife in southern Africa. In this study, the discriminatory power of 29 published VNTR loci in the characterization of 131 Mycobacterium bovis strains isolated predominantly from wildlife and a smaller number from livestock in southern Africa was assessed. Allelic diversities calculated when loci were evaluated on a selected panel of 23 M. bovis isolates with identified varying degrees of genetic relatedness from different geographic origins as well as M. bovis BCG ranged from 0.00 to 0.63. Of the 29 loci tested, 13 were polymorphic (QUB 11a, QUB 11b, QUB 18, ETR-B and -C, Mtub 21, MIRU 16 and 26, ETR-E, QUB 26, MIRU 23, ETR-A, and Mtub 12). In addition, a comparative evaluation of the 13 loci on a panel of 65 isolates previously characterized by IS6110 restriction fragment length polymorphism (RFLP) typing and further evaluation on 41 isolates with no typing history from Kruger National Park (KNP) highlighted that M. bovis from epidemiologically unrelated cases of BTB in different geographic regions can be adequately distinguished. However, there is a need for improvement of the method to fully discriminate between the parental KNP strain and its clones to allow the detection of evolutionary events causing transmission between and within wildlife species. PMID- 24171857 TI - Influence of porcine circovirus type 2 infections on bovine tuberculosis in wild boar populations. AB - The wild boar is an important reservoir of bovine tuberculosis (bTB) in south western Spain. Some risk factors such as wild boar density or age have been associated with the presence of high prevalences of bTB in wild boar. However, the influence of other risk factors such as co-infections with other pathogens has not yet been studied. This work aims to assess the influence of porcine circovirus type 2 (PCV-2) infection on bTB prevalence and bTB lesional patterns observed in wild boar. The presence of bTB-like lesions was evaluated in 551 hunted wild boar from 11 different game estates in south-western Spain, with a known history of bTB. Tuberculosis prevalences in each estate were calculated based on the percentage of animals found with bTB-like lesions. The percentage of animals with generalized bTB lesional patterns (bTB lesions in more than one organ) was also assessed. The prevalence of PCV-2 was studied in each estate using a specific PCR assay. The relationship between PCV-2 and bTB prevalences and between PCV-2 infections and the presence of generalized lesional patterns in wild boar were analysed. A statistical relationship between the prevalences of bTB and PCV-2 was found, with bTB prevalences being higher in estates where prevalences of PCV-2 were high. On the other hand, animals infected with PCV-2 were more likely to develop a generalized lesional pattern. Porcine circovirus type 2 prevalences seem to be associated with prevalences of bTB in wild boar. PCV-2 infection may aggravate the development and severity of bTB, favouring the presence of generalized lesional patterns and raising the risk of contagion in these estates. The implementation of sanitary measures that focus on the control of PCV-2 infection may be necessary as a preliminary measure in bTB control programmes for wild boar. PMID- 24171858 TI - Control strategies for wildlife tuberculosis in Ireland. AB - The principal domestic maintenance host for Mycobacterium bovis is infected cattle. In countries where comprehensive surveillance schemes have been applied, tuberculosis rarely affects an animal to the extent that it presents with clinical disease. In the latter stages of an eradication campaign, the aim is to maintain the disease-free status of clear herds and eliminate foci of infection in herds as well as restricting movement of infected animals from these herds, other than to slaughter. However, the eradication of tuberculosis from cattle herds may be compromised if infected wildlife species, such as Eurasian badgers (Meles meles), share the same environment and contribute to transmission of infection. The options for dealing with tuberculosis in the wildlife reservoir hosts are limited to segregation of domestic animals from the wildlife, culling of the wildlife host or vaccination. Options are further limited by conservation and social reasons, particularly where culling is concerned. In Ireland and the UK, vaccination of badgers against M. bovis, if successfully employed, could directly facilitate the completion of bovine tuberculosis eradication. Programmes of research into vaccination of badgers are being undertaken in both countries, and there is clear evidence that vaccination induces protection. Vaccine trials in captive badgers have established that the M. bovis bacille Calmette-Guerin (BCG) vaccine can induce a protective response that limits the distribution and severity of tuberculosis disease following experimental challenge. In Ireland, a large-scale field trial of oral BCG vaccination is being conducted to measure the protection generated in wild badgers subjected to natural transmission of infection and to estimate vaccine efficacy. The results will provide a framework for the development and implementation of a national strategy to address the disease in badger populations and if successful will remove this major impediment to tuberculosis eradication from cattle. PMID- 24171859 TI - Overview of vaccination trials for control of tuberculosis in cattle, wildlife and humans. AB - Vaccination is a key strategy for control of tuberculosis (TB), and considerable progress has been made in the past 5 years to develop improved vaccines for humans and animals, differentiate vaccinated animals from those infected with Mycobacterium bovis and deliver vaccines to wildlife. Studies have moved from testing vaccines in small animal models to clinical trials in humans and from experimental challenge studies in cattle and wildlife to evaluation of vaccines in the field. Candidate vaccines undergoing testing in humans include live mycobacterial vaccines to replace bacille Calmette Guerin (BCG), subunit vaccines (virus vector or protein) to boost BCG and therapeutic vaccines used as an adjunct to chemotherapy. In cattle, a number of diagnostic tests have been developed and successfully tested for differentiating infected from vaccinated animals, which will facilitate the use of BCG vaccine in cattle. Encouraging results have been obtained from recent field trials in cattle using BCG vaccine to protect against natural exposure to M. bovis. To date, no subunit TB vaccines have induced improved protection compared with that for BCG, but prime-boost combinations of BCG with DNA, protein or virus-vectored vaccines have induced better protection than BCG vaccine alone. Development of an oral bait BCG formulation has demonstrated the practicality of delivering TB vaccines to wildlife. Oral BCG preparations have induced protection against experimental challenge of M. bovis in possums, badgers, wild boar and white-tailed deer and against natural exposure to M. bovis in possums. Recent progress in TB vaccine development has provided much impetus for their future use. PMID- 24171860 TI - Mycobacteria and disease in southern Africa. AB - The genus Mycobacterium consists of over 120 known species, some of which (e.g. M. bovis and M. tuberculosis) contribute extensively to the burden of infectious disease in humans and animals, whilst others are commonly found in the environment but may rarely if ever be disease-causing. This paper reviews the mycobacteria found in southern Africa, focussing on those in the M. tuberculosis complex as well as the non-tuberculous mycobacteria (NTM), identifying those found in the area and including those causing disease in humans and animals, and outlines some recent reports describing the distribution and prevalence of the disease in Africa. Difficulties in diagnosis, host preference and reaction, immunology and transmission are discussed. PMID- 24171861 TI - Wildlife tuberculosis. Preface. PMID- 24171862 TI - Secret of the major birch pollen allergen Bet v 1: identification of the physiological ligand. AB - The major birch pollen allergen Bet v 1 is the main elicitor of airborne type I allergies and belongs to the PR-10 family (pathogenesis-related proteins 10). Bet v 1 is the most extensively studied allergen, and is well characterized at a biochemical and immunological level; however, its physiological function remains elusive. In the present study, we identify Q3OS (quercetin-3-O-sophoroside) as the natural ligand of Bet v 1. We isolated Q3OS bound to Bet v 1 from mature birch pollen and confirmed its binding by reconstitution of the Bet v 1-Q3OS complex. Fluorescence and UV-visible spectroscopy experiments, as well as HSQC (heteronuclear single-quantum coherence) titration, and the comparison with model compounds, such as quercetin, indicated the specificity of Q3OS binding. Elucidation of the binding site by NMR combined with a computational model resulted in a more detailed understanding and shed light on the physiological function of Bet v 1. We postulate that the binding of Q3OS to Bet v 1 plays an important, but as yet unclear, role during the inflammation response and Bet v 1 recognition by IgE. PMID- 24171863 TI - Genetic markers associated with progression in early mycosis fungoides. AB - BACKGROUND: Mycosis fungoides (MF) is a rare, but potentially devastating malignancy. It classically presents with cutaneous patches and plaques and can progress to tumours on the skin with lymph node, blood and visceral involvement. While most patients with MF have a relatively benign disease course, a subset of patients will develop progressive disease that is often fatal. OBJECTIVE: The aim of this study was to identify genetic markers in early MF limited to the skin (stages IA-IIA) that distinguish those patients who will have progressive disease from those who will not, so that early appropriate treatment may be instituted. METHODS: The study includes 18 patients who were diagnosed with early stage MF at the time of biopsy and had follow-up to determine which patients developed progressive disease. RNA was extracted from skin biopsy specimens and analysed for expression of CD3, FOXP3, IFNgamma, Interleukin (IL)-4, IL-13, KIR3DL2, MICB, PLS3 and STAT4 by quantitative real-time polymerase chain reaction. RESULTS/CONCLUSIONS: Reduced expression of FOXP3 and STAT4 and increased expression of IL-4 relative to CD3 expression levels were significantly associated with MF progression. Further studies will be needed to fully assess the usefulness of these genetic markers to predict disease progression and guide treatment options in patients diagnosed with early MF. PMID- 24171865 TI - Morel-Lavallee lesions of the knee: a closed degloving injury: a report of two cases. PMID- 24171864 TI - Integrating multiple oestrogen receptor alpha ChIP studies: overlap with disease susceptibility regions, DNase I hypersensitivity peaks and gene expression. AB - BACKGROUND: A wealth of nuclear receptor binding data has been generated by the application of chromatin immunoprecipitation (ChIP) techniques. However, there have been relatively few attempts to apply these datasets to human complex disease or traits. METHODS: We integrated multiple oestrogen receptor alpha (ESR1) ChIP datasets in the Genomic Hyperbrowser. We analysed these datasets for overlap with DNase I hypersensitivity peaks, differentially expressed genes with estradiol treatment and regions near single nucleotide polymorphisms associated with sex-related diseases and traits. We used FIMO to scan ESR1 binding sites for classical ESR1 binding motifs drawn from the JASPAR database. RESULTS: We found that binding sites present in multiple datasets were enriched for classical ESR1 binding motifs, DNase I hypersensitivity peaks and differentially expressed genes after estradiol treatment compared with those present in only few datasets. There was significant enrichment of ESR1 binding present in multiple datasets near genomic regions associated with breast cancer (7.45-fold, p = 0.001), height (2.45-fold, p = 0.002), multiple sclerosis (5.97-fold, p < 0.0002) and prostate cancer (4.47-fold, p = 0.0008), and suggestive evidence of ESR1 enrichment for regions associated with coronary artery disease, ovarian cancer, Parkinson's disease, polycystic ovarian syndrome and testicular cancer. Integration of multiple cell line ESR1 ChIP datasets also increases overlap with ESR1 ChIP-seq peaks from primary cancer samples, further supporting this approach as helpful in identifying true positive ESR1 binding sites in cell line systems. CONCLUSIONS: Our study suggests that integration of multiple ChIP datasets can highlight binding sites likely to be of particular biological importance and can provide important insights into understanding human health and disease. However, it also highlights the high number of likely false positive binding sites in ChIP datasets drawn from cell lines and illustrates the importance of considering multiple independent experiments together. PMID- 24171866 TI - Botulinum toxin as a postoperative diplopia test - it can also reduce the angle of deviation prior to surgery. AB - PURPOSE: To investigate how frequently botulinum toxin, when used as a postoperative diplopia test, reduces the angle of deviation prior to subsequent strabismus surgery. METHODS: A retrospective study of 39 adult patients with constant concomitant horizontal strabismus who had undergone botulinum toxin injections to assess the risk of postoperative diplopia and then subsequently underwent strabismus surgery. RESULTS: Fourteen out of 39 patients (36%) sustained a reduction of 15 prism diopters or more for near and/or distance when comparing the pre-injection angle of deviation with the preoperative angle of deviation. CONCLUSION: Approximately one-third of patients receiving botulinum toxin as a postoperative diplopia test maintained a significant reduction in the angle of their deviation prior to undergoing surgery. PMID- 24171867 TI - The transfer and implementation of an Aboriginal Australian wellbeing program: a grounded theory study. AB - BACKGROUND: The concepts and standard practices of implementation, largely originating in developed countries, cannot necessarily be simply transferred into diverse cultural contexts. There has been relative inattention in the implementation science literature paid to the implementation of interventions targeting minority Indigenous populations within developed countries. This suggests that the implementation literature may be bypassing population groups within developed countries who suffer some of the greatest disadvantage. Within the context of Aboriginal Australian health improvement, this study considers the impact of political and cultural issues by examining the transfer and implementation of the Family Wellbeing program across 56 places over a 20-year period. METHODS: A theoretical model of program transfer was developed using constructivist-grounded theory methods. Data were generated by conducting in depth interviews with 18 Aboriginal and non-Aboriginal research respondents who had been active in transferring the program. Data were categorised into higher order abstract concepts and the core impetus for and process of program transfer were identified. RESULTS: Organizations transferred the program by using it as a vehicle for supporting inside-out empowerment. The impetus to support inside-out empowerment referred to support for Aboriginal people's participation, responsibility for and control of their own affairs, and the associated ripple effects to family members, organizations, communities, and ultimately reconciliation with Australian society at large. Program transfer occurred through a multi-levelled process of embracing relatedness which included relatedness with self, others, and structural conditions; all three were necessary at both individual and organizational levels. CONCLUSIONS: Similar to international implementation models, the model of supporting inside-out empowerment by embracing relatedness involved individuals, organizations, and interpersonal and inter-organizational networks. However, the model suggests that for minority Indigenous populations within developed countries, implementation approaches may require greater attention to the empowering nature of the intervention and its implementation, and multiple levels of relatedness by individuals and organizations with self, others, and the structural conditions. Key elements of the theoretical model provide a useful blueprint to inform the transfer of other empowerment programs to minority Indigenous and other disadvantaged populations on a case-by-case basis. PMID- 24171868 TI - A look at the grouping effect on population-level risk assessment of radon induced lung cancer. AB - On the basis of considerable knowledge gained by studying health effects in uranium and other underground miners who worked in radon-rich environments, radon exposure has been identified as a cause of lung cancer. Recent pooled analyses of residential studies have shown that radon poses a similar risk of causing lung cancer in the general public when exposure occurs at generally lower levels found in homes. With the increasing accessibility of statistical data via the internet, people are performing their own analyses and asking why, in some cases, the lung cancer occurrence at the community level does not correlate to the radon levels. This study uses statistical data available to the general public from official websites and performs simple analyses. The results clearly show the difficulty in linking observed lung cancer incidence rates at the provincial/territorial level, with possible cause, such as smoking or radon exposure. Even the effect of smoking, a well-documented cause of lung cancer, can be overlooked or misinterpreted if the data being investigated is too general (i.e., summary data at population level) or is influenced by other factors. These difficulties with simple comparisons are one of the main reasons that epidemiological studies of lung cancer incidence and radon exposure requires the use of cohorts or case controls at the individual level as opposed to the more easily performed ecological studies at the population level. PMID- 24171869 TI - The Swedish municipal food distribution service to the elderly living at home as experienced by the recipient's relatives. AB - The municipal Food distribution service (FD) to the elderly living at home is a part of the public social and care service in Sweden, The objective of this service is to ensure proper food intake for persons who are unable to do their own shopping, and prepare their own meals. The foremost reasons for the need of the FD service are in situations where there are illness related physical or psychological limitations.This means that the Swedish welfare system takes on the responsibility for its citizens when they have a legal social related need of care. Further, according to the Swedish social legislation, children or other relatives have no legal obligations to take care of their parents or elderly disabled relatives. This also means that the children or relatives of elderly people requiring social support have no legal right to be involved in the evaluation procedure of need assessment or the outcome of any social and care services granted by the Swedish social welfare system. The aim of the present study was to gain insight into how the relatives of elderly people living at home in Sweden experience the municipal service of ready-made meals distributed daily. The data was collected using in-depth interviews with relatives of elderly persons who use the municipal food distribution (FD) service (n=8). The transcribed interview material was analysed using the grounded theory method. The findings of this study revealed that the relatives of the municipal FD service recipients advocate for a food preparation service in the home of the recipient rather than the distribution of ready-made meals from a central kitchen. The results also revealed that the participating relatives felt frustrated by the legal limitations that make it impossible for them to influence the municipal FD service. The findings in this study also indicate that relatives should be considered as a resource in this matter and could actively participate, and have a positive influence on the quality of the municipal FD service for the elderly. The results of the study could have implications for nursing, public administration and gerontology. PMID- 24171870 TI - The assessment of dyspnea during the vigorous intensity exercise by three Dyspnea Rating Scales in inactive medical personnel. AB - It is well recognized that exercise is good for health especially as it's known to prevent metabolic syndromes such as diabetes, hypertension and heart disease. To reap the benefits from exercise the most appropriate level of intensity must be determined, the level of intensity ranging from low, low to moderate to hard (vigorous). This study is aimed to 1. To investigate and evaluate 3 subjective rating scales. The Borg scale, the Combined Numerical Rating Scale (NRS) + FACES Dyspnea Rating Scale (FACES) and the Likert scale, during hard (vigorous) exercise. 2. To compare the effectiveness of the Borg scale and Combined Numerical Rating Scale (NRS) + FACES Dyspnea Rating Scale during the hard (vigorous) intensity exercise. This study uses a descriptive methodology. The sample group was 73 medical personnel that were leading an inactive life style, volunteers from Phramongkutklao Hospital. Participants were randomly divided into 3 groups. Group 1, those to report using the Borg Scale, group 2 using NRS + FACES, and group 3 to subjectively assess the intensity of the exercise using the Likert scale during a treadmill Exercise Stress Test (EST) using the Bruce protocol. The upper limit of the intensity in the study was equal to 85% of the maximal heart rate of all participants. The subjective reporting of the experienced level of dyspnea was undertaken immediately after the completion of exercise. The average age of participants was 23.37 years old. The 26 participants reporting using the Borg scale had mean Borg scale score of 13.46+1.77, a mode score of 15. The 24 participants reporting intensity levels through NRS +FACES had a mean NRS + FACES score of 6.83+1.09 and mode on the NRS + FACES scale equal to 7. The Likert scale group evaluated 23 participants with a mean Likert scale score of 2.74. That is those choosing Levels 2 and 3 were 6 (26.9%) and 17 participants (73.95%), respectively. Comparing the two groups with the Borg scale at equal to or greater than 15 and NRS + FACES greater than or equal to 7 using a Chi-square test showed that there were no statistical significant differences at p = 0.084. Using Spearman's rank correlation coefficient it was found that the subjective rating of intensity in the 3 different groups was not statistically significantly related to heart rate at 85% of maximal heart rate (P>0.05). NRS + FACES, the evaluation of the intensity of exercise at the hard (vigorous) level, was not statistically significantly different from the Borg scale. PMID- 24171871 TI - The long-term impact of education on diabetes for older people: a systematic review. AB - BACKGROUND: Although enthusiasm is growing for diabetic education programs for older people, data regarding their effectiveness and their long-term impact on self-management were neglected. PURPOSE: To systematically review diabetes mellitus education that has long-term effects on the self-management of older diabetic people. DATA SOURCES: The authors searched multiple sources dated through September 2012, including the Cochrane Library, MEDLINE, PsycINFO, Nursing and Allied Health databases, and the bibliographies of 50 previous reviews. METHODS AND DATA EXTRACTION: Electronic databases were searched for controlled studies in English, published from 1987 to 2012, assessing the effects of long-term education for older people. Reviewers extracted study data using a structured abstraction form. Aggregated information about the effects of long term education programs on older people with diabetes was used for making adjustments in the review. RESULTS: The pooled estimate of the long-term effects of education was a 0.5 percentage point reduction (95% confidence interval), modest but significant improvement. The evidence also supports that long-term education is beneficial for improving diabetic patient self-care management in terms of glycemic control. PMID- 24171872 TI - A comparative study of self-regulation in substance dependent and non-dependent individuals. AB - BACKGROUND: Several factors influence the beginning and maintenance of substance use. The purpose of this study was to examine as well as to compare 'self regulation' in both substance dependent and non-substance dependent individuals. METHOD: In a cross-sectional study 228 (118 substance dependent and 110 with no history of using substance) participants aged 16-55 were recruited. All of the participants were asked to complete the Self-Regulation Inventory (SRI-25) and a demographic characteristics data checklist. Data was analyzed using descriptive statistics (frequency, mean and standard deviation) and the t-test. RESULTS: The results showed significant differences between substance dependent and non- substance dependent groups in all the scales of the self-regulation inventory including positive actions, controllability, expression of feelings and needs, assertiveness, and well-being seeking (p<0.01). CONCLUSION: Self-regulation and self-control skills in drug dependent individuals are lower than those without substance dependence individuals. It is concluded that substance use may related to a deficiency in self-control and regulation of feelings. Therefore, for prevention and treatment of substance dependence disorder, it is necessary to work out and exploit strategies that include the improvement of self-regulation. PMID- 24171873 TI - Stigma toward schizophrenia among parents of high school students. AB - Stigma toward schizophrenia is an important area of research as it is frequently a barrier to early intervention. This study attempted to identify factors underlying stigma in Japan. Because even adolescents can develop schizophrenia, 357 Japanese parents of high school students were enrolled. All parents lived outside the areas affected by the Tohoku earthquake that occurred on March 11, 2011 (ie, parts of Iwate, Miyagi, and Fukushima prefectures). Factor analysis using the Link Devaluation-Discrimination Measure identified two factors: comparison with an able-bodied person and non-comparison with an able-bodied person. Regression analysis revealed that family structure had independent effects on factor 2 (p <0.05), and ANOVA showed that education had independent effects on factor 2 (p<0.05). These results suggest that education programs that seek to counteract stigma should target curricula in high schools and vocational schools. PMID- 24171874 TI - Subdural empyema in children. AB - Subdural Empyema in infants and children might be life threatening if not managed properly. A search of the Pub Med database was carried out using a combination of the following terms: Subdural empyema, children, and management. Neurosurgical textbooks were reviewed as well. The prevalence, etiology, clinical features, investigations and management of SDE are reviewed in this article. Conservative management with antibiotics and follow up imaging is recommended if there are no focal deficits, change in mental status or if the patient is responding well to antibiotics. Alternatively, craniotomy is warranted in addition to antibiotics therapy. The surgeon might opt for burr holes in case the patient is frail or in septic shock. PMID- 24171875 TI - Effect of mycobacterial drug resistance patterns on patients' survival: a cohort study in Thailand. AB - BACKGROUND: Drug resistance substantially increases tuberculosis (TB) mortality. This study aimed to describe the prevalence of mycobacterial drug resistance pattern and association of common resistance patterns with TB mortality in Thailand. METHOD: A retrospective cohort study was conducted using TB surveillance data. A total of 9,518 culture-confirmed, pulmonary TB patients registered from 1 October 2004 to 31 December 2008 from the Thailand TB Active Surveillance Network were included in this study. Patients were followed up until TB treatment completion or death. Mycobacterial drug resistance patterns were categorized as pan-susceptible, rifampicin resistance, isoniazid monoresistance, and ethambutol/streptomycin resistance. Drug susceptibility testing (DST) was determined by Mycobacterial Growth Indicator Tube (MGIT) liquid culture systems. Survival analysis was applied. RESULT: Isoniazid monoresistance was the most common pattern, while rifampicin resistance had the largest impact on mortality. Cox regression analysis showed a significantly higher risk of death among patients with rifampicin resistance (adjusted hazard ratio (aHR) 1.9, 95% confident interval (CI), 1.5-2.5) and isoniazid monoresistance (aHR 1.4, 95% CI 1.1-1.7) than those with pan-susceptible group after adjustment for age, nationality, human immunodeficiency virus (HIV) and antiretroviral therapy (ART) status, diabetes mellitus, cavitary disease on chest x-ray, treatment observation, and province. HIV co-infection was associated with higher mortality in patients both on ART (aHR 1.9, 95% CI 1.5-2.5) and not on ART (aHR 8.1, 95% CI 6.8-9.8). CONCLUSION: Rifampicin resistance and isoniazid monoresistance were associated with increased TB mortality. HIV-coinfection was associated with a higher risk of death including among those taking antiretroviral therapy. PMID- 24171876 TI - Price, promotion, and availability of nutrition information: a descriptive study of a popular fast food chain in New York City. AB - Legislation in NYC requires chain restaurants to post calorie information on menu boards in an effort to help consumers make more informed decisions about food and beverage items they are purchasing. While this is a step in the right direction in light of the current obesity epidemic, there are other issues that warrant attention in a fast food setting, namely the pricing of healthy food options, promotional strategies, and access to comprehensive nutrition information. This study focused on a popular fast-food chain in NYC. The study's aims were threefold: (1) to determine the cost differential between the healthiest meal item on the chain's general menu and meal items available specifically on a reduced cost menu for one dollar (US$1.00); (2) to identify and describe the promotions advertised in the windows of these restaurants, as well as the nutrition content of promoted items; and (3) to ascertain availability of comprehensive nutrition information to consumers within the restaurants. We found the healthiest meal item to be significantly higher in price than less nutritious meal items available for $1.00 (t=146.9, p<.001), with the mean cost differential equal to $4.33 (95% CI: $4.27, $4.39). Window promotions generally advertised less healthful menu items, which may aid in priming customers to purchase these versus more healthful options. Comprehensive nutrition information beyond calorie counts was not readily accessible prior to purchasing. In addition to improving access to comprehensive nutrition information, advertising more of and lowering the prices of nutritious options may encourage consumers to purchase healthier foods in a fast food setting. Additional research in this area is needed in other geographic locations and restaurant chains. PMID- 24171877 TI - Predictors of stress of parents of a child with cancer: a Jordanian perspective. AB - BACKGROUND: Most paediatric oncology studies agree that being parents of a child with cancer is an emotionally stressful event. Although an increasing number of studies have investigated psychological stress of parents of a child with cancer, few of these studies have included both parents or investigated the predictors of high stress levels for the mothers and the fathers. Moreover, studies published over the last few decades were limited to Western countries and have shown inconsistent findings about parental perceived stress whose children have cancer. This study explored differences in predictors of perceived stress between Jordanian mothers and fathers of children with cancer. METHODS: This study involved a survey of 300 couples parenting a child with cancer. Participants answered the Arabic version of the Perceived Stress Scale 10-items, demographic and characteristics check list questionnaires. The main aims were to measure perceived stress levels for mothers and fathers, explore the predictors associated with high perceived stress levels and make a comparison between them. FINDINGS: Mothers reported significantly higher stress levels than fathers (p<0.001), with a large effect size (0.30). Some of the factors associated with mothers and fathers high stress levels affected both parents whereas employment status affected only fathers' stress levels. CONCLUSIONS: These findings indicate the need to work with the mothers and the fathers with a child with cancer in Jordan to recognise their psychological needs at the time of diagnosis and followed by on-going psychological support for both parents. PMID- 24171878 TI - Position of social determinants of health in urban man-made lakes plans. AB - BACKGROUND AND OBJECTIVE: A social determinants approach proposes that enhancing living conditions in areas such as income, housing, transportation, employment, education, social support, and health services is central to improving the health of urban populations. Urban development projects can be costly but have health impacts. The benefit derived from the creation of man-made lakes in developing countries is usually associated with great risks; however, the evidence for physical and non-physical health benefits of urban man-made lake is unclear. The aim of this paper is to formulate a conceptual framework of associations between urban man-made lakes and social determinants of health. METHOD: This study was a qualitative study carried out using one focus group discussion and 16 individual interviews. Data were analyzed based on deductive-inductive content analysis approach. RESULTS: Participants' points of view were analyzed within 261 codes. Data analysis matrix was the conceptual framework of social determinants of health commission and its sub-groups, thus, two structural and mediating determinants categories as well as their sub-sets were created accordingly. In addition, some extra sub-sets including environment, air quality, weather changes, noise pollution, pathogenesis, quality of life, shortage of available resources, region popularity, ethnicity, tourism, social and physical development of children, unintentional injuries, aesthetic, and spirituality were extracted beyond the matrix factors, which were placed in each of above categories based on their thematic content. CONCLUSION: This paper has illustrated that the quality and type of man-made lake provided within communities can have a significant and sustained impact on community's health and wellbeing. Therefore, in order to strengthen positive effects and reduce negative effects of any developmental projects within community, their impacts on public health should be taken into consideration. PMID- 24171879 TI - Bridging the gap between the technological singularity and mainstream medicine: highlighting a course on technology and the future of medicine. AB - The "technological singularity" is defined as that putative point in time forecasted to occur in the mid twenty-first century when machines will become smarter than humans, leading humans and machines to merge. It is hypothesized that this event will have a profound influence on medicine and population health. This work describes a new course on Technology and the Future of Medicine developed by a diverse, multi-disciplinary group of faculty members at a Canadian university. The course began as a continuous professional learning course and was later established as a recognized graduate course. We describe the philosophy of the course, the barriers encountered in course development, and some of the idiosyncratic solutions that were developed to overcome these, including the use of YouTube audience retention analytics. We hope that this report might provide a useful template for other institutions attempting to set up similar programs. PMID- 24171880 TI - The effect of gabapentin on intensity and duration of hot flashes in postmenopausal women: a randomized controlled trial. AB - BACKGROUND: Menopause is the stage of time in which the menstruation stops following the loss of ovarian activity. The purpose of this study was to find out the effectiveness of gabapentin on hot flashes in postmenopausal women. MATERIALS & METHODS: A randomized controlled trial from Feb 2010 to 2011 was conducted. Sixty postmenopausal women who were referred to obstetrics and gynecology ward of two educational hospitals were recruited and divided into two groups (intervention and control). Intervention group received 300 mg gabapentin three times a day for three months, while control group received placebo. The Intensity and duration of hot flashes in women scored and recorded using visual analog scale. Independent, Paired t-test and chi-square test were used for analyzing data. RESULTS: Intensity of hot flashes in the beginning of research in the intervention group was significantly different with the first, second and third follow-up visit (P<0.05). Also at the end of intervention a significant difference between intervention and control groups were observed regarding the intensity, frequency and duration of hot flashes (P<0.05 and P=0.01 respectively). CONCLUSION: According to the findings of this study; it appears that the use of gabapentin could decrease the intensity, duration and frequency of hot flashes in postmenopausal women. For postmenopausal women who hormone therapy is contraindicated, gabapentine could be an acceptable alternative. PMID- 24171881 TI - Content validity of CASA-Q cough domains and UCSD-SOBQ for use in patients with Idiopathic Pulmonary Fibrosis. AB - PURPOSE: The study objective was to assess the content validity of the Cough and Sputum Assessment Questionnaire (CASA-Q) cough domains and the UCSD Shortness of Breath Questionnaire (SOBQ) for use in patients with Idiopathic Pulmonary Fibrosis (IPF). METHODS: Cross-sectional, qualitative study with cognitive interviews in patients with IPF. Study outcomes included relevance, comprehension of item meaning, understanding of the instructions, recall period, response options, and concept saturation. RESULTS: Interviews were conducted with 18 IPF patients. The mean age was 68.9 years (SD 11.9), 77.8% were male, and 88.9% were Caucasian. The intended meaning of the CASA-Q cough domain items was clearly understood by most of the participants (89-100%). All participants understood the CASA-Q instructions; the correct recall period was reported by 89% of the patients, and the response options were understood by 76%. The intended meaning of the UCSD-SOBQ items was relevant and clearly understood by all participants. Participants understood the instructions (83%) and all patients understood the response options (100%). The reported recall period varied based on the type of activity performed. No concepts were missing, suggesting that saturation was demonstrated for both measures. CONCLUSIONS: This study provides evidence for content validity for the CASA-Q cough domains and the UCSD-SOBQ for patients with IPF. Items of both questionnaires were understood and perceived as relevant to measure the key symptoms of IPF. The results of this study support the use of these instruments in IPF clinical trials as well as further studies of their psychometric properties. PMID- 24171882 TI - Prevalence of metabolic syndrome in type 2 diabetes mellitus using NCEP-ATPIII, IDF and WHO definition and its agreement in Gwalior Chambal region of Central India. AB - The aim of study was to determine the prevalence of metabolic syndrome (MetS) in people with type 2 diabetes mellitus (T2DM). National Cholesterol Education Program (NCEP) ATPIII Criteria, International Diabetes Federation and the World Health Organization (WHO) definitions were used in quantifying the metabolic syndrome and also the concordance between these three criteria's used for identifying metabolic syndrome. METHODS: This cross-sectional study involved 700 type 2 diabetic subjects from the urban areas of Gwalior Chambal region (Central India). Subjects in the age group of 28- 87 yrs were included in the study. Type I diabetics, pregnant ladies and those with chronic viral and bacterial infections and serious metabolic disorders were excluded from the study. Fasting blood glucose, Blood lipids (T-cholesterol, triglyceride, HDL-cholesterol) were assessed and anthropometry blood pressure were measured from all the subjects. RESULTS: The Prevalence of metabolic syndrome was found to be 45.8%, 57.7% and 28% following NCEP-ATPIII Criteria, IDF and WHO definitions, respectively. Using all the three definitions the prevalence was higher in women in all age groups. ATP III and IDF criteria showed good agreement (k 0.68) compared to ATP III with WHO (k 0.54) and IDF with WHO (k 0.34) criteria. Highest prevalence was observed following IDF definition. CONCLUSIONS: A good agreement was observed between ATPIII and IDF criteria. Maximum prevalence of Metabolic syndrome was recorded when IDF criteria was followed. NCEP-ATPIII criteria for the diagnosis of MetS and this criterion reflected equal importance to the every variable and showed a good agreement between the different criteria used. PMID- 24171884 TI - Evaluation of occupational factors on continuation of breastfeeding and formula initiation in employed mothers. AB - BACKGROUND AND OBJECTIVE: During recent decades, women have been increasingly involved in social activities. Despite the fact that mothers prefer to breastfeed, their return to work is associated with a reduction in breastfeeding frequency and duration. The present study evaluates the impact of occupational factors on continuation of breastfeeding and formula initiation in employed mothers with infants aged 6-12 months in Bandar-Abbas, Iran in 2010. METHOD AND MATERIALS: This is a descriptive-analytic study on employed mothers with infants aged 6-12 months referring to healthcare centers of Bandar-Abbas in 2010. Data were collected through a questionnaire dealing with work-related factors in mothers' workplace. FINDINGS: Out of 212 mothers who responded, 52.38% used formula to feed their children, and 27.36% had discontinued breastfeeding. The rate of formula use was significantly higher in mothers who had less than 6 months of maternity leave, those who did not have a suitable nursery or place to milk themselves and preserve the milk in their workplace, those working more than 6 hours per day, and those who could not take a breastfeeding break. CONCLUSION: It is essential to identify and support breastfeeding employed women. The employers should provide facilities such as nurseries, a suitable physical space for milking, as well as the equipment necessary for milk preservation. Also, such mothers should be granted breastfeeding breaks to feed their child or milk their breasts. PMID- 24171883 TI - Coronary Heart Disease and Emotional Intelligence. AB - BACKGROUND: Coronary Heart Disease (CHD) is associated with emotions, especially negative ones, namely anxiety and depression. Emotional Intelligence (EI) is a psychological model that consists of a variety of emotional skills. AIMS: The aim of the present study was to examine the relation between different dimensions of Emotional Intelligence and coronary heart disease. METHODS: A total of 300 participants were studied during a 3-year period in an attempt to partially replicate and further expand a previous study conducted in Greece among CHD patients, which indicated a strong association between certain dimensions of Emotional Intelligence and the incidence of CHD. All participants completed a self-report questionnaire, assessing several aspects of Emotional Intelligence. FINDINGS: The results showed that there is a link between the regulation of emotions and the occurrence of CHD. CONCLUSIONS: The evidence reported in the present study makes stronger the claim that EI plays a significant role in the occurrence of CHD. PMID- 24171885 TI - Critical thinking dispositions of nursing students in Asian and non-Asian countries: a literature review. AB - Critical thinking disposition represents an inclination of a person to use possessed skills in relation to critical thinking. The trend of critical thinking has been described as inner motivation to solve problems and make decisions by thinking. In nursing as a practical profession, the concept of critical thinking dispositions is important component in helping to manage complex health situations and to deal with patient issues effectively. Willingness to think critically is a prerequisite for safe and subtly performance. The results of studies show critical thinking dispositions of nursing students in Asian countries are different from non-Asian countries. Aim of this literature review was to compare critical thinking dispositions of nursing students in Asian and non-Asian countries. Literature review was done in English and Persian databases. The results showed of the 795 articles published in English and Persian language that studied critical thinking, 73 ones studied critical thinking skills and dispositions in nursing education, and relationship between teaching methods and critical thinking skills and dispositions in nursing education of different countries. Fifteen of seventy three articles assessed critical thinking dispositions in nursing students. Limited studies showed that the Asian nursing students had mostly undermining score of the critical thinking dispositions, while non-Asian countries tend to positive scores. The reasons for these differences could be due to issues such as environmental, educational methods and cultural differences. However, future studies should measure critical thinking disposition by discipline-based tools. PMID- 24171886 TI - Discharge against medical advice: a case study in a public teaching hospital in Tehran, Iran in 2012. AB - Discharging against medical advice is to leave the hospital despite the advice of the doctor, which can result in complications and readmissions. This study aimed to examine the prevalence of patients' discharge against medical advice (DAMA) and their reasons in a public teaching hospital in Tehran, Iran in 2012. This was an applied and cross-sectional study in which all patients (2601 patients) who had been discharged against medical advice from the studied hospital in 2012 were studied. Required data were collected using a data collection form. Collected data were analyzed using SPSS 18.0 and descriptive and analytical tests including Frequencies and Fisher's Exact Test. The most and least common reasons for DAMA were, respectively, feeling complete recovery by patients (45.4%) and financial problems (1.3%). The results showed that there were significant differences between DAMA prevalence and patients' sex and age (P<0.001). The prevalence of DAMA in the studied hospital was high and according to the existence of social work units in every hospital, it is recommended that patients' consultation with the hospital social workers should be considered as an obligatory stage of the discharge against medical advice process in order to inform patients about its complications and adverse consequences. PMID- 24171887 TI - Role of socio-psychological factors in perceived quality of care rendered by traditional medical practitioners in Ibadan, Nigeria. AB - BACKGROUND: It was the aim of the current research to investigate perceived service quality rendered by traditional medical practitioners and the role of socio-psychological factors in the perception. METHODS: The first part, a quantitative cross-sectional survey utilized a 93-item questionnaire to examine the influence of quality of life, general health perception, socio-economic status and personality factors on perceived service quality. The second part, a qualitative study utilized 5 FGDs and 2 KIIs to explore consumers' evaluation of perceived service quality. Five research questions were raised. The 336 purposively-selected participants were attendees of traditional-health clinics/centers in Ibadan with a mean age of x(-)=30.60+/-9.97. FINDINGS: The FGD respondents opined that the scope of orthodox-medicine does not cover certain illnesses. 77.8% of the participants attested to the affordability and promptness of services in traditional hospitals; acknowledging that its perceived efficacy (i.e. 56.8%) motivate patronage of traditional-health service. The 2x2x3 ANOVA revealed significant main effect of quality of life (F[1,270]=41.05, p<.001) and socio-economic status (F[2,270]=36.34; p<.001); as well as interaction effect of quality of life, general health and socio-economic status (F[1,270]=9.624, p<.002); while the regression analysis showed independent influence of extraversion (B= 0.31; p<.001), agreeableness (B=0.303; p<.001) and openness to experience (B=0.166; p<.01). CONCLUSION: This sample acknowledged that traditional health care met quality standards. The role of socio-psychological factors in the quality appraisal was established. The need for better regulation and validation of traditional health care in assuring evidence based care was suggested. PMID- 24171888 TI - Results of double blind placebo controlled trial to assess the effect of vitamin B6 on managing of nausea and vomiting in pediatrics with acute gastroenteritis. AB - BACKGROUND: Gastroenteritis and respiratory tract infections are the most common childhood diseases. Despite the common use of vitamin B6 to control vomiting in children with gastroenteritis, no study has been performed in this field. This study aimed to assess the value of vitamin B6 in the prevention of vomiting in patients with mild to moderate gastroenteritis. METHODOLOGY: This study was a double blind controlled clinical trial on 96 children with mild to moderate gastroenteritis with age range of 6 months to 12 years admitted in Mofid Children's Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran. Patients were randomly assigned to two groups of 48 subjects matched for age, sex and symptoms of dehydration. Vitamin B6 was given in case group and control group was given placebo. The severity of dehydration and vomiting in patients before and after treatment were evaluated by a physician. All data were recorded in the questionnaire and results in the two treatment groups were compared by using SPSS software (Version 15, Chicago, IL, USA). RESULTS: The mean +/- SD age of patients whom underwent Vitamin B6 treatment was 2.9+/-2.4 versus 2.5+/-2 in placebo group. Significant difference between mean age, gender, and severity of dehydration in children of two groups wasn't observed. After treatment in both treatment groups, 40 patients (83.3%) had mild dehydration, and 8 patients (16.7%) had moderate dehydration. Vomiting was noted in 28 patients (58.3%) after treatment with vitamin B6 and in 37 patients (77.1%) after treatment with placebo. The mean frequency of vomiting after treatment with vitamin B6 was 1.7+/-1.3 times and in the control group (treated with distilled water) was 1.5+/-0.77 time, but no significant difference between the severity of dehydration, controlling vomiting and the mean frequency of vomiting was observed in both groups (P>0.05). CONCLUSION: It seems that the use of oral vitamin B6 treatment has no benefit and impact compared with the placebo. Thus, use of vitamin B6 in the prevention of vomiting due to acute mild to moderate gastroenteritis is not only scientifically, but in the present study it was proved to be ineffective. This work was done on a comparative basis and further researches are recommended. PMID- 24171889 TI - Obvious and hidden anxiety and the related factors in operating room nurses employed in general hospital, Qazvin, Iran: a cross-sectional study. AB - BACKGROUND: Health promotion and security of manpower in a society is one of the pillars to progress a society. Anxiety, is the most common psychological disorder in societies and occupations like nursing' anesthesia technicians and operation room technicians. The aim of this study was to investigate prevalence of anxiety, and its severity in Iranian nurses working in operation room. Also, we determined the most important associated factors with anxiety. METHODS: In this cross sectional study' 152 nurses working in operating room participated. The tool to gather the data was a questionnaire, that included three parts; demographic information' obvious anxiety questions and hidden anxiety questions of Spielburger. Obtained data was analysed with SPSS 16 software. RESULTS: The majority of participants were females (94.7%) with experience at work less than 10 years (84.9%). The average scores of participants in obvious and hidden anxiety were 41.9+/-39.4 (range 20 to 75) and 39.4+/-8.2 (range 20 to 70), respectively. Anxiety level was significantly higher in females than males (P=0.04). The most prevalent cause of anxiety, was contact with infected biological factors (23% of nurses). The less important cause was concern about retirement (42.8% of nurses). CONCLUSION: Our results suggest that, anxiety disorders is prevalent in Iranian nurses working in public city hospitals, which warrants immediate programs for intervention to improve working situations in work place. PMID- 24171890 TI - Relationship between bone mineral density and maturity index in cervical smears, serum estradiol levels and body mass index. AB - OBJECTIVES: Osteoporosis is a systemic skeletal disease with a consequent increased risk of fracture, decreased quality of life and economic burdens for both the patients and health care system. While Dual energy X-Ray absorptiometry remains the gold standard for assessment of bone mineral density, it cannot be requested for all patients for obvious reasons. By determining other variables that may correlate with osteoporosis, we can identify individuals who may be at risk for osteoporosis earlier. Then, they can be treated at the earlier stages of the disease. In the present study, relationships between bone mineral density, maturity index in cervical smear, serum estradiol level and body mass index were examined. MATERIALS & METHODS: The present study performed on 128 women, who had been referred for bone mineral densitometry. Blood samples were obtained for determination of serum estradiol level. Cervical smear was taken for assessment of cell's maturity. Cervical smears were examined by a pathologist and were sorted as atrophic or mature. Body mass index was calculated too. Relationships among Body mass index, serum estradiol level, and maturity index and bone mineral densitometry were analyzed using proper statistical tests. RESULTS: Maturity index had significant relationship with T Score in the spine and femoral neck (P<0.001). Significant relationships were found between serum estradiol level and femoral neck T Score (P<0.004) and spine T Score (P<0.008). Also a significant relationship was found between body mass index and bone mineral density. CONCLUSION: Pap smear is a routine examination which is performed mainly for screening purposes in gynecology. It is non-invasive, simple and low-priced. Results of current study suggest that women with atrophic cervical smear should be examined more rigorously for osteoporosis. If any patient has atrophic maturity index in her cervical smear, she will be at much higher risk of osteoporosis. PMID- 24171891 TI - Children's glycemic control: mother's knowledge and socioeconomic status. AB - The present study was designed to examine the role of socioeconomic status (SES) of the mother's knowledge about different aspects of diabetes and the glycemic control of type 1 children with diabetes. Samples were taken from successive admissions to the outpatient diabetes clinics in Prince Sultan Medical Military City (PSMMC), Riyadh, Saudi Arabia. A well designed questionnaire covering different aspects including demographic data, educational background, and socioeconomic status of the care providers was used to collect information from mothers of type 1 diabetes mellitus (T1DM) children. The questionnaire was designed on the basis of the Michigan diabetes knowledge scale and also on the basis of food habits of Saudi Arabia and it was validated. The questionnaire was completed after interviewing the mothers during visits to the PSMMC hospital. Every mother was asked with those particular questions. Glycemic control was assessed by glycosylated haemoglobin (HbA1c). The socio-demographic data of mothers was recorded by self-report. It was found that, there was significant variation in the knowledge of diabetes among mothers with different ages (P 0.05). No significant results were observed between family income and diabetes knowledge (p>0.05).However, a positive relationship was observed with higher income and higher knowledge. There was a significant association between mothers knowledge of diabetes and HbA1C level (r = -0.1739, p.<0.05) indicating that, higher knowledge ultimately leads to greater control of HbA1c level. A significant association was also observed between education and HbA1c level (r= 02538, p<0.05) with children of mothers with higher level of education showing a better control of glycated haemoglobin levels. However, no significant association was found between monthly family income and HbA1C level. In conclusion, the current study illustrated that, mothers with more knowledge of diabetes and with better education were maintaining a better glycemic control of their children, irrespective of the socio-economic status. It was found that, to improve glycemic control and to decrease acute and chronic complications of diabetes in children, mother's knowledge and education is needed. PMID- 24171892 TI - Health hybrid concept analysis in old people. AB - BACKGROUND: It seems necessary to study the health status of this age group to promote their health and prevent disease as well as care planning. In order to achieve this goal, a clear definition of the concept of elderly health is essential. METHOD: Hybrid concept analysis, our research design, utilizes both theoretical analysis of literature and empirical observation to define a concept. We chose the hybrid concept analysis method because its inclusion of old people perspectives enriches the limited health research literature. The method consists of three phases: theory, fieldwork, and analysis. RESULTS: In comparison, we can conclude that health in the elderly people is something more than the absence of illness and 4 physical, mental, social and spiritual domains which are referred to in the definition of a theoretical stage are supported by the findings. The relative health was also proposed against the complete welfare and comfort for the elderly and it showed that their expectations are less than their ages. In addition, the elderly have expressed the family as a preference and the researcher believes that this theme is context based because it has emerged following the interview. Since the family has a special place according to the Iranian culture and religion and the family health is a priority in their health. In addition, the daily activities have been raised as a major theme that can be considered as the physical health but the elderly have expressed it apart from the physical health. CONCLUSION: Health among the old is a concept that is affected by genetic, environmental, healthcare services and lifestyle-related factors and involves proportional physical, mental, social, familial, spiritual, and economical welfare along with the ability to handle daily life activities which is measurable through medical and functional approaches. PMID- 24171893 TI - Knowledge, attitudes and behaviour of Greek adults towards salt consumption: a Hellenic Food Authority project. AB - OBJECTIVE: To investigate the knowledge, attitudes and behaviour of Greek adults towards salt as well as their differences with respect to gender, age and level of education. DESIGN: Cross-sectional, observational survey. SETTING: Voluntary participation to a telephone interview, using a seventeen-item questionnaire. SUBJECTS: Greek adults aged over 25 years (n 3609), nationally representative according to age, gender and geographical distribution of the Greek population, were interviewed. RESULTS: More women of all age groups compared with men reported adding salt during cooking (P < 0.001), while less reported adding salt on the plate (P < 0.001). Also, more women believed that salt added during cooking was the main source of salt in the diet (P < 0.001). Participants aged 25 34, 35-44 and 45-54 years old had better knowledge of the harmful effects of salt on health compared with the 55+ years age group (P = 0.002, P = 0.001, P < 0.001, respectively); respondents in the aforementioned age groups also knew that children should consume less salt than adults compared with 55+ years age group (P = 0.004, P < 0.001, P < 0.001, respectively). Respondents with secondary and higher educational status were more likely to avoid consumption of processed foods (P < 0.001) and to check the nutrition information on food packaging as compared with respondents having basic education status (P < 0.001). CONCLUSIONS: Awareness needs to be raised regarding salt recommendations for adults and children, sources of sodium in the diet and adding less salt during cooking, as well as reading food labels. Future campaigns for salt reduction should consider gender, age and level of education differences regarding knowledge, attitudes and behaviour towards salt. PMID- 24171894 TI - Changes in health care utilisation following a reform involving choice and privatisation in Swedish primary care: a five-year follow-up of GP-visits. AB - BACKGROUND: The organisation of Swedish primary health care has changed following introduction of free choice of provider for the population in combination with freedom of establishment for private primary care providers. Our aim was to investigate changes in individual health care utilisation following choice and privatisation in Swedish primary care from an equity perspective, in subgroups defined by age, gender and family income. METHODS: The study is based on register data years 2007-2011 from the Skane Regional Council (population 1.2 million) regarding individual health care utilisation in the form of visits to general practitioner (GP). Health utilisation data was matched with data about individual's age, gender and family income provided by Statistics Sweden. Multilevel, logistic regression models were constructed to analyse changes in health utilisation in different subgroups and the probability of a GP-visit before and after reform. RESULTS: Health care utilisation in terms of both number of individuals that had visited a GP and number of GP-visits per capita increased in all defined subgroups, but to a varying degree. Multilevel logistic regression showed that individuals of both genders aged above 64 and belonging to a family with an income above median had more advantage of the reform, OR 1.25-1.29. CONCLUSIONS: Reforms involving choice and privatisation in Swedish primary health care improved access to GP-visits generally, but more so for individuals belonging to a family with income above the median. PMID- 24171895 TI - Acupuncture with non-steroidal anti-inflammatory drugs (NSAIDs) versus acupuncture or NSAIDs alone for the treatment of chronic neck pain: an assessor blinded randomised controlled pilot study. AB - OBJECTIVE: To investigate the feasibility and sample size required for a full scale randomised controlled trial of the effectiveness of acupuncture with non steroidal anti-inflammatory drugs (NSAIDs) for chronic neck pain compared with acupuncture or NSAID treatment alone. METHODS: A total of 45 patients with chronic neck pain participated in the study. For 3 weeks the acupuncture with NSAIDs treatment group took NSAIDs (zaltoprofen, 80 mg) daily while receiving acupuncture treatment three times a week. The acupuncture treatment group received treatment three times a week and the NSAID treatment group took NSAIDs daily. The primary outcomes were to determine the feasibility and to calculate the sample size. As secondary outcomes, pain intensity and pain-related symptoms for chronic neck pain were measured. RESULTS: With regard to enrolment and dropout rates, 88.2% of patients consented to be recruited to the trial and 15.6% of participants were lost to follow-up. The sample size for a full-scale trial was estimated to be 120 patients. Although preliminary, there was a significant change in the visual analogue scale (VAS) for neck pain intensity between the baseline measurement and each point of assessment in all groups. However, there was no difference in VAS scores between the three groups. CONCLUSIONS: This pilot study has provided the feasibility and sample size for a full-scale trial of acupuncture with NSAIDs for chronic neck pain compared with acupuncture or NSAID treatment alone. Further research is needed to validate the effects of acupuncture with NSAIDs. PMID- 24171896 TI - Ophthalmic diagnostic tests, orbital anatomy, and adnexal histology of the broad snouted caiman (Caiman latirostris). AB - PURPOSE: The aim of this study was to establish normal ophthalmic parameters for selected diagnostic tests, and to describe the orbital anatomy and adnexal histology of the broad-snouted caiman. METHOD: A total of 35 Caiman latirostris that were free of obvious ocular diseases were used to measure the parameters in this investigation. Ages ranged from 5 to 15 years. Ophthalmic diagnostic tests were conducted, including evaluation of tear production with Schirmer Tear test-1 (STT1), culture of the conjunctival bacterial flora, applanation tonometry, conjunctival cytology, nictiating membrane incursion frequency test (NMIFT), endodontic absorbent paper point tear test (EAPPTT), palpebral fissure length measurement (PFL) and B-mode ultrasonography. Adnexal histology and skull samples were studied. RESULTS: Mean (+/-SD) STT1 was 3.4 +/- 3.6 mm/min (95% confidence interval of 2.01-4.78 mm/min), intraocular pressure (IOP) was 12.9 +/- 6.2 mmHg, NMIFT was 6.0 +/- 3.5, EAPPTT was 17.1 +/- 2.5 mm/min, PFL was 28.9 +/- 3.0 mm, anterior chamber depth was 3.1 +/- 0.3 mm, lens axial length was 8.4 +/- 0.6 mm, vitreous chamber depth was 7.9 +/- 0.7 mm and axial globe length was 19.9 +/- 1.3 mm. For all animals evaluated, Bacillus sp., Diphteroids and Staphylococcus sp. were predominant. PMID- 24171897 TI - Association between the perceived environment and physical activity among adults in Latin America: a systematic review. AB - BACKGROUND: Activity friendly environments have been identified as promising strategies to increase physical activity levels in the population. Associations between perceived environmental attributes and physical activity in Latin America may vary from those observed in high income countries. The objective of this systematic review is to identify which perceived environmental attributes are associated with physical activity in Latin America. METHODS: Systematic literature search of articles published in English, Portuguese, and Spanish in four databases was conducted (PubMed, Virtual Health Library, EBSCO, and Web of Science). Associations with environmental attributes were analyzed separately for physical activity domains. Fifteen articles were included in the analysis. RESULTS: All studies had cross-sectional designs. The majority of associations were statistically non-significant, and only four associations were found in the unexpected direction. Leisure-time and transport-related physical activity were the domains most frequently included in the studies and had higher number of associations in the expected direction. Leisure-time physical activity showed a convincing association in the expected direction with safety during the day. Transport-related physical activity had a convincing association with presence of street lighting. CONCLUSIONS: This study shows that perceived environmental attributes and their relationship with physical activity appears to be domain, and context specific. In addition, findings from this study show inconsistencies with the information gathered from high-income countries. PMID- 24171898 TI - An organ culture system to model early degenerative changes of the intervertebral disc II: profiling global gene expression changes. AB - INTRODUCTION: Despite many advances in our understanding of the molecular basis of disc degeneration, there remains a paucity of preclinical models which can be used to study the biochemical and molecular events that drive disc degeneration, and the effects of potential therapeutic interventions. The goal of this study is to characterize global gene expression changes in a disc organ culture system that mimics early nontraumatic disc degeneration. METHODS: To mimic a degenerative insult, rat intervertebral discs were cultured in the presence of TNF-alpha, IL-1beta and serum-limiting conditions. Gene expression analysis was performed using a microarray to identify differential gene expression between experimental and control groups. Differential pattern of gene expression was confirmed using quantitative reverse transcriptase polymerase chain reaction (qRT PCR) or Western blot. RESULTS: Treatment resulted in significant changes in expression of more than 1,000 genes affecting many aspects of cell function including cellular movement, the cell cycle, cellular development, and cell death and proliferation. Many of the most highly upregulated and downregulated genes have known functions in disc degeneration and extracellular matrix hemostasis. Construction of gene networks based on known cellular pathways and expression data from our analysis demonstrated that the network associated with cell death, cell cycle regulation and DNA replication and repair was most heavily affected in this model of disc degeneration. CONCLUSIONS: This rat organ culture model uses cytokine exposure to induce wide gene expression changes with the most affected genes having known reported functions in disc degeneration. We propose that this model is a valuable tool to study the etiology of disc degeneration and evaluate potential therapeutic treatments. PMID- 24171899 TI - Life histories of hosts and pathogens predict patterns in tropical fungal plant diseases. AB - Plant pathogens affect the fitness of their hosts and maintain biodiversity. However, we lack theories to predict the type and intensity of infections in wild plants. Here we demonstrate using fungal pathogens of tropical plants that an examination of the life histories of hosts and pathogens can reveal general patterns in their interactions. Fungal infections were more commonly reported for light-demanding than for shade-tolerant species and for evergreen rather than for deciduous hosts. Both patterns are consistent with classical defence theory, which predicts lower resistance in fast-growing species and suggests that the deciduous habit can reduce enemy populations. In our literature survey, necrotrophs were found mainly to infect shade-tolerant woody species whereas biotrophs dominated in light-demanding herbaceous hosts. Far-red signalling and its inhibitory effects on jasmonic acid signalling are likely to explain this phenomenon. Multiple changes between the necrotrophic and the symptomless endophytic lifestyle at the ecological and evolutionary scale indicate that endophytes should be considered when trying to understand large-scale patterns in the fungal infections of plants. Combining knowledge about the molecular mechanisms of pathogen resistance with classical defence theory enables the formulation of testable predictions concerning general patterns in the infections of wild plants by fungal pathogens. PMID- 24171901 TI - Understanding the human parental brain: a critical role of the orbitofrontal cortex. AB - The bond between a parent and an infant often appears to form effortlessly and intuitively, and this relationship is fundamental to infant survival and development. Parenting is considered to depend on specific brain networks that are largely conserved across species and in place even before parenthood. Efforts to understand the neural basis of parenting in humans have focused on the overlapping networks implicated in reward and social cognition, within which the orbitofrontal cortex (OFC) is considered to be a crucial hub. This review examines emerging evidence that the OFC may be engaged in several phases of parent-infant interactions, from early, privileged orienting to infant cues, to ongoing monitoring of interactions and subsequent learning. Specifically, we review evidence suggesting that the OFC rapidly responds to a range of infant communicative cues, such as faces and voices, supporting their efficient processing. Crucially, this early orienting response may be fundamental in supporting adults to respond rapidly and appropriately to infant needs. We suggest a number of avenues for future research, including investigating neural activity in disrupted parenting, exploring multimodal cues, and consideration of neuroendocrine involvement in responsivity to infant cues. An increased understanding of the brain basis of caregiving will provide insight into our greatest challenge: parenting our young. PMID- 24171902 TI - Adapting effects of emotional expression in anxiety: evidence for an enhanced Late Positive Potential. AB - An adaptation paradigm was used to investigate the influence of a previously experienced visual context on the interpretation of ambiguous emotional expressions. Affective classification of fear-neutral ambiguous expressions was performed following repeated exposure to either fearful or neutral faces. There was a shift in the behavioral classification of morphs toward "fear" following adaptation to neutral compared to adaptation to fear with a nonsignificant trend toward the high-anxiety group compared to the low being more influenced by the context. The event-related potential (ERP) data revealed a more pronounced late positive potential (LPP), beginning at ~400 ms poststimulus onset, in the high but not the low-anxiety group following adaptation to neutral compared to fear. In addition, as the size of the behavioral adaptation increased, there was a linear increase in the magnitude of the late-LPP. However, context-sensitivity effects are not restricted to trait anxiety, with similar effects observed with state anxiety and depression. These data support the proposal that negative moods are associated with increased sensitivity to visual contextual influences from top-down elaborative modulations, as reflected in an enhanced LPP deflection. PMID- 24171904 TI - Health system support for childbirth care in Southern Tanzania: results from a health facility census. AB - BACKGROUND: Progress towards reaching Millennium Development Goals four (child health) and five (maternal health) is lagging behind, particularly in sub-Saharan Africa, despite increasing efforts to scale up high impact interventions. Increasing the proportion of birth attended by a skilled attendant is a main indicator of progress, but not much is known about the quality of childbirth care delivered by these skilled attendants. With a view to reducing maternal mortality through health systems improvement we describe the care routinely offered in childbirth at dispensaries, health centres and hospitals in five districts in rural Southern Tanzania. We use data from a health facility census assessing 159 facilities in five districts in early 2009. A structural and operational assessment was undertaken based on staff reports using a modular questionnaire assessing staffing, work load, equipment and supplies as well as interventions routinely implemented during childbirth. RESULTS: Health centres and dispensaries attended a median of eight and four deliveries every month respectively. Dispensaries had a median of 2.5 (IQR 2-3) health workers including auxiliary staff instead of the recommended four clinical officer and certified nurses. Only 28% of first-line facilities (dispensaries and health centres) reported offering active management in the third stage of labour (AMTSL). Essential childbirth care comprising eight interventions including AMTSL, infection prevention, partograph use including foetal monitoring and newborn care including early breastfeeding, thermal care at birth and prevention of ophthalmia neonatorum was offered by 5% of dispensaries, 38% of health centres and 50% of hospitals consistently. No first-line facility had provided all signal functions for emergency obstetric complications in the previous six months. CONCLUSIONS: Essential interventions for childbirth care are not routinely implemented in first-line facilities or hospitals. Dispensaries have both low staffing and low caseload which constrains the ability to provide high-quality childbirth care. Improvements in quality of care are essential so that women delivering in facility receive "skilled attendance" and adequate care for common obstetric complications such as post partum haemorrhage. PMID- 24171905 TI - Role of illness representations and coping in patients with atopic dermatitis: a cross-sectional study. AB - BACKGROUND: Atopic dermatitis (AD) is a skin disease accompanied by psychological burden. It has been shown for other chronic diseases that illness representations and coping strategies are associated with disease-related burden and other outcome variables like time until patients return to work or health care use. OBJECTIVE: The goal of this cross-sectional study was to investigate whether illness representations and coping strategies are correlated with the severity of AD and self-rated physical impairment of the patients. METHODS: A total of 109 AD patients were examined at the beginning of their stay at a rehabilitation centre. They filled in validated questionnaires to measure illness perceptions (IPQ), coping strategies (EBS) and self-rated physical well-being (FEW). In addition, the severity of AD (SCORAD) was determined by a doctor. RESULTS: Linear regression analysis revealed that a considerable amount of the variance in self rated physical well-being (51%) could be predicted by particular illness perceptions and coping. Subsequent multiple mediation analyses indicated that certain coping strategies (active problem solving and depressive reactions) mediated the effect of illness representations on self-rated physical well-being. In contrast, only 7.4% of the SCORAD could be predicted by the IPQ scale illness identity. CONCLUSION: This study showed that illness representations and coping are highly associated with self-rated physical impairment in AD patients. Therefore, this patient group might profit from cognitive behavioural interventions designed to alter patients' illness perceptions. The hypothesis that a modification in illness perceptions leads to a faster recovery and a more rapid return to work should be tested in future randomized controlled trials. PMID- 24171906 TI - Validation of the Brazilian version of the Pediatric Outcomes Data Collection Instrument: a cross-sectional evaluation in children and adolescents with juvenile idiopathic arthritis. AB - BACKGROUND: There is a lack of health-related quality of life (HRQOL) questionnaires to evaluate pediatric musculoskeletal diseases in Brazil. The Pediatric Outcome Data Collection Instrument (PODCI) is widely used elsewhere for pediatric patients with musculoskeletal disorders, but it has not been fully validated in Brazil. Validation of the PODCI in the Brazilian Portuguese language is important to improve the assessment of pediatric patients with musculoskeletal diseases and to compare Brazilian study results with results from the international literature. This study aimed to analyze the test-re-test reliability and the convergent validity indicators for the quality of life scores obtained by application of the PODCI to children and adolescents with juvenile idiopathic arthritis (JIA). METHODS: The PODCI underwent translation, transcultural adaptation, and field testing. Fifty-seven children and adolescents with JIA were administered the PODCI questionnaire. The Child Health Questionnaire - Parent Form 28 (CHQ PF-28) was used as the gold standard. Pain scales were employed, clinical examinations were performed, and laboratory inflammatory activity tests were conducted. RESULTS: The three versions of the PODCI exhibited good internal consistency (Cronbach's alpha coefficient > 0.70), good reproducibility (p < 0.05), and good correlation compared with the gold standard (CHQ), as shown by a Spearman coefficient (Rho) > 0.40 (p < 0.05). CONCLUSIONS: The PODCI was validated in patients with JIA in Brazil. This questionnaire was found to be valid, precise, and reliable. It can be successfully applied in research conducted by healthcare professionals who work with children and adolescents with musculoskeletal system disorders. PMID- 24171907 TI - A dual conformation of the post-decarboxylation intermediate is associated with distinct enzyme states in mycobacterial KGD (alpha-ketoglutarate decarboxylase). AB - alpha-Ketoacid dehydrogenases are large multi-enzyme machineries that orchestrate the oxidative decarboxylation of alpha-ketoacids with the concomitant production of acyl-CoA and NADH. The first reaction, catalysed by alpha-ketoacid decarboxylases (E1 enzymes), needs a thiamine diphosphate cofactor and represents the overall rate-limiting step. Although the catalytic cycles of E1 from the pyruvate dehydrogenase (E1p) and branched-chain alpha-ketoacid dehydrogenase (E1b) complexes have been elucidated, little structural information is available on E1o, the first component of the alpha-ketoglutarate dehydrogenase complex, despite the central role of this complex at the branching point between the TCA (tricarboxylic acid) cycle and glutamate metabolism. In the present study, we provide structural evidence that MsKGD, the E1o (alpha-ketoglutarate decarboxylase) from Mycobacterium smegmatis, shows two conformations of the post decarboxylation intermediate, each one associated with a distinct enzyme state. We also provide an overall picture of the catalytic cycle, reconstructed by either crystallographic snapshots or modelling. The results of the present study show that the conformational change leading the enzyme from the initial (early) to the late state, although not required for decarboxylation, plays an essential role in catalysis and possibly in the regulation of mycobacterial E1o. PMID- 24171909 TI - Intrahepatic segment V biliary enteric bypass. PMID- 24171908 TI - A novel approach for establishing benchmark CBCT/CT deformable image registrations in prostate cancer radiotherapy. AB - Deformable image registration (DIR) is an integral component for adaptive radiation therapy. However, accurate registration between daily cone-beam computed tomography (CBCT) and treatment planning CT is challenging, due to significant daily variations in rectal and bladder fillings as well as the increased noise levels in CBCT images. Another significant challenge is the lack of 'ground-truth' registrations in the clinical setting, which is necessary for quantitative evaluation of various registration algorithms. The aim of this study is to establish benchmark registrations of clinical patient data. Three pairs of CT/CBCT datasets were chosen for this institutional review board approved retrospective study. On each image, in order to reduce the contouring uncertainty, ten independent sets of organs were manually delineated by five physicians. The mean contour set for each image was derived from the ten contours. A set of distinctive points (round natural calcifications and three implanted prostate fiducial markers) were also manually identified. The mean contours and point features were then incorporated as constraints into a B-spline based DIR algorithm. Further, a rigidity penalty was imposed on the femurs and pelvic bones to preserve their rigidity. A piecewise-rigid registration approach was adapted to account for the differences in femur pose and the sliding motion between bones. For each registration, the magnitude of the spatial Jacobian (|JAC|) was calculated to quantify the tissue compression and expansion. Deformation grids and finite-element-model-based unbalanced energy maps were also reviewed visually to evaluate the physical soundness of the resultant deformations. Organ DICE indices (indicating the degree of overlap between registered organs) and residual misalignments of the fiducial landmarks were quantified. Manual organ delineation on CBCT images varied significantly among physicians with overall mean DICE index of only 0.7 among redundant contours. Seminal vesicle contours were found to have the lowest correlation amongst physicians (DICE = 0.5). After DIR, the organ surfaces between CBCT and planning CT were in good alignment with mean DICE indices of 0.9 for prostate, rectum, and bladder, and 0.8 for seminal vesicles. The Jacobian magnitudes |JAC| in the prostate, rectum, and seminal vesicles were in the range of 0.4-1.5, indicating mild compression/expansion. The bladder volume differences were larger between CBCT and CT images with mean |JAC| values of 2.2, 0.7, and 1.0 for three respective patients. Bone deformation was negligible (|JAC| = ~ 1.0). The difference between corresponding landmark points between CBCT and CT was less than 1.0 mm after DIR. We have presented a novel method of establishing benchmark DIR accuracy between CT and CBCT images in the pelvic region. The method incorporates manually delineated organ surfaces and landmark points as well as pixel similarity in the optimization, while ensuring bone rigidity and avoiding excessive deformation in soft tissue organs. Redundant contouring is necessary to reduce the overall registration uncertainty. PMID- 24171910 TI - Screening for adolescent idiopathic scoliosis: an information statement by the scoliosis research society international task force. AB - BACKGROUND: Routine screening of scoliosis is a controversial subject and screening efforts vary greatly around the world. METHODS: Consensus was sought among an international group of experts (seven spine surgeons and one clinical epidemiologist) using a modified Delphi approach. The consensus achieved was based on careful analysis of a recent critical review of the literature on scoliosis screening, performed using a conceptual framework of analysis focusing on five main dimensions: technical, clinical, program, cost and treatment effectiveness. FINDINGS: A consensus was obtained in all five dimensions of analysis, resulting in 10 statements and recommendations. In summary, there is scientific evidence to support the value of scoliosis screening with respect to technical efficacy, clinical, program and treatment effectiveness, but there insufficient evidence to make a statement with respect to cost effectiveness. Scoliosis screening should be aimed at identifying suspected cases of scoliosis that will be referred for diagnostic evaluation and confirmed, or ruled out, with a clinically significant scoliosis. The scoliometer is currently the best tool available for scoliosis screening and there is moderate evidence to recommend referral with values between 5 degrees and 7 degrees. There is moderate evidence that scoliosis screening allows for detection and referral of patients at an earlier stage of the clinical course, and there is low evidence suggesting that scoliosis patients detected by screening are less likely to need surgery than those who did not have screening. There is strong evidence to support treatment by bracing. INTERPRETATION: This information statement by an expert panel supports scoliosis screening in 4 of the 5 domains studied, using a framework of analysis which includes all of the World Health Organisation criteria for a valid screening procedure. PMID- 24171911 TI - Whole genome and tandem duplicate retention facilitated glucosinolate pathway diversification in the mustard family. AB - Plants share a common history of successive whole-genome duplication (WGD) events retaining genomic patterns of duplicate gene copies (ohnologs) organized in conserved syntenic blocks. Duplication was often proposed to affect the origin of novel traits during evolution. However, genetic evidence linking WGD to pathway diversification is scarce. We show that WGD and tandem duplication (TD) accelerated genetic versatility of plant secondary metabolism, exemplified with the glucosinolate (GS) pathway in the mustard family. GS biosynthesis is a well studied trait, employing at least 52 biosynthetic and regulatory genes in the model plant Arabidopsis. In a phylogenomics approach, we identified 67 GS loci in Aethionema arabicum of the tribe Aethionemae, sister group to all mustard family members. All but one of the Arabidopsis GS gene families evolved orthologs in Aethionema and all but one of the orthologous sequence pairs exhibit synteny. The 45% fraction of duplicates among all protein-coding genes in Arabidopsis was increased to 95% and 97% for Arabidopsis and Aethionema GS pathway inventory, respectively. Compared with the 22% average for all protein-coding genes in Arabidopsis, 52% and 56% of Aethionema and Arabidopsis GS loci align to ohnolog copies dating back to the last common WGD event. Although 15% of all Arabidopsis genes are organized in tandem arrays, 45% and 48% of GS loci in Arabidopsis and Aethionema descend from TD, respectively. We describe a sequential combination of TD and WGD events driving gene family extension, thereby expanding the evolutionary playground for functional diversification and thus potential novelty and success. PMID- 24171912 TI - Positive selection in nucleoporins challenges constraints on early expressed genes in Drosophila development. AB - Developmental conservation among related species is a common generalization known as von Baer's third law and implies that early stages of development are the most refractory to change. The "hourglass model" is an alternative view that proposes that middle stages are the most constrained during development. To investigate this issue, we undertook a genomic approach and provide insights into how natural selection operates on genes expressed during the first 24 h of Drosophila ontogeny in the six species of the melanogaster group for which whole genome sequences are available. Having studied the rate of evolution of more than 2,000 developmental genes, our results showed differential selective pressures at different moments of embryogenesis. In many Drosophila species, early zygotic genes evolved slower than maternal genes indicating that mid-embryogenesis is the stage most refractory to evolutionary change. Interestingly, positively selected genes were found in all embryonic stages even during the period with the highest developmental constraint, emphasizing that positive selection and negative selection are not mutually exclusive as it is often mistakenly considered. Among the fastest evolving genes, we identified a network of nucleoporins (Nups) as part of the maternal transcriptome. Specifically, the acceleration of Nups was driven by positive selection only in the more recently diverged species. Because many Nups are involved in hybrid incompatibilities between species of the Drosophila melanogaster subgroup, our results link rapid evolution of early developmental genes with reproductive isolation. In summary, our study revealed that even within functional groups of genes evolving under strong negative selection many positively selected genes could be recognized. Understanding these exceptions to the broad evolutionary conservation of early expressed developmental genes can shed light into relevant processes driving the evolution of species divergence. PMID- 24171913 TI - Is the school food environment conducive to healthy eating in poorly resourced South African schools? AB - OBJECTIVE: To assess the school food environment in terms of breakfast consumption, school meals, learners' lunch box, school vending and classroom activities related to nutrition. DESIGN: Cross-sectional survey. SETTING: Ninety purposively selected poorly resourced schools in South Africa. SUBJECTS: Questionnaires were completed by school principals (n 85), school feeding coordinators (n 77), food handlers (n 84), educators (n 687), randomly selected grade 5 to 7 learners (n 2547) and a convenience sample of parents (n 731). The school menu (n 75), meal served on the survey day, and foods at tuck shops and food vendors (n 74) were recorded. RESULTS: Twenty-two per cent of learners had not eaten breakfast; 24 % brought a lunch box, mostly with bread. Vegetables (61 %) were more often on the school menu than fruit (28 %) and were served in 41 % of schools on the survey day compared with 4 % serving fruit. Fifty-seven per cent of learners brought money to school. Parents advised learners to buy fruit (37 %) and healthy foods (23 %). Tuck shops and vendors sold mostly unhealthy foods. Lack of money/poverty (74 %) and high food prices (68 %) were major challenges for healthy eating. Most (83 %) educators showed interest in nutrition, but only 15 % had received training in nutrition. Eighty-one per cent of educators taught nutrition as part of school subjects. CONCLUSIONS: The school food environment has large scope for improvement towards promoting healthy eating. This includes increasing access to vegetables and fruit, encouraging learners to carry a healthy lunch box, and regulating foods sold through tuck shops and food vendors. PMID- 24171914 TI - A conventional strabismus surgical approach for lost medial rectus muscles. AB - We present 3 cases of successful conventional strabismus surgery to retrieve lost medial rectus (MR) muscles. In all cases the lost MR muscle was retrieved and re attached to the intended scleral point. Two patients had residual exotropia, while the third case was orthophoric after surgery. The retrieval of lost MR muscle using conventional strabismus surgery technique can be successfully achieved if the lost MR muscle is recognized early and the re-operation is performed by an experienced surgeon. PMID- 24171915 TI - Productivity impact of headache on a heavy-manufacturing workforce in Turkey. AB - BACKGROUND: Headache disorders cause substantial productivity losses through absenteeism and impaired effectiveness at work (presenteeism). We measured productivity losses from both causes at a heavy-manufacturing company with a largely male workforce in north-western Turkey. METHODS: We used the HALT Index as the survey instrument. We first assessed productivity losses by surveying the entire workforce. Because we anticipated much non-participation, we also applied HALT at the annual health-checks provided to all employees by the company's on site health clinic. RESULTS: Mean age of the workforce (N = 7,200) was 31 yr. About two thirds (90% male) were manual workers rotating weekly through early, late and night shifts. One third (50% male) were clerical/managerial, working a standard 5-day week. In the first assessment, 3,939 questionnaires (54.7%) were returned with usable data. In the previous 3 months, absenteeism of >=1 day was reported by 360 respondents (9.1%), of whom 4 (0.10%) recorded >=45 days (average per worker: 0.92 days/yr). Presenteeism equivalent to >=1 day's absence was reported by 1,187 respondents (29.4%) (average per worker: 6.0 days/yr). We estimated that 23,519 days/yr were lost in total among respondents (2.3% of workforce capacity). In the first 6 months of annual health-checks, 2,691 employees (37.4%) attended (94.4% male). Absenteeism was reported by 40 (1.5%), with 74 days lost, presenteeism by 348 (12.9%), with 1,240 days lost. We estimated that, altogether, 41,771 man-days/yr were lost in the entire workforce (2.4% of capacity; 94% due to presenteeism), closely matching the earlier estimate. A small minority (5.7%) of those with headache, who were only 2.5% of the workforce, accounted for >45% of presenteeism-related lost productivity. CONCLUSION: The high productivity losses in a largely male workforce were surprising. Possible factors were the nature of the work - manual labour for two thirds, often heavy - and the recurring schedule disturbances of shift-work. There was a highly-disabled minority. PMID- 24171916 TI - Hypertension among adults in the United States: National Health and Nutrition Examination Survey, 2011-2012. AB - The overall prevalence of hypertension has not changed appreciably since 2009 2010. The age-adjusted prevalence of hypertension among U.S. adults was 29.1% in 2011-2012. Among adults with hypertension in 2011-2012, 82.8% were aware of their hypertension, 75.7% were currently taking medication to lower their blood pressure, and 51.9% had their blood pressure controlled to less than 140/90 mm Hg. Men and women had similar prevalence and awareness of hypertension, but more women than men were treating their hypertension and had it under control. Young adults aged 18-39 continued to have lower awareness, treatment, and control of their hypertension compared with older adults. Hypertension prevalence was still highest among non-Hispanic black adults. However, awareness, treatment, and control of hypertension were similar among non-Hispanic black, non-Hispanic white, and Hispanic adults. Non-Hispanic Asian adults had a lower prevalence of awareness than the other race and Hispanic origin groups, and lower treatment than non-Hispanic white and non-Hispanic black adults. However, hypertension control was similar among non-Hispanic Asian adults and the other race and Hispanic origin groups. Hypertension is a common and manageable chronic condition. Based on recent national data from 2011-2012, treatment of hypertension exceeded the Healthy People 2020 target goal of 69.5%. However, the control of hypertension has neither met the goal of the Healthy People 2020 (61.2% by 2020) nor the Million Hearts Initiative (65% by 2017). These results provide evidence for continued efforts to improve the management of hypertension in order to attain these goals. PMID- 24171917 TI - Maternal care and subsocial behaviour in spiders. AB - While most spiders are solitary and opportunistically cannibalistic, a variety of social organisations has evolved in a minority of spider species. One form of social organisation is subsociality, in which siblings remain together with their parent for some period of time but disperse prior to independent reproduction. We review the literature on subsocial and maternal behaviour in spiders to highlight areas in which subsocial spiders have informed our understanding of social evolution and to identify promising areas of future research. We show that subsocial behaviour has evolved independently at least 18 times in spiders, across a wide phylogenetic distribution. Subsocial behaviour is diverse in terms of the form of care provided by the mother, the duration of care and sibling association, the degree of interaction and cooperation among siblings, and the use of vibratory and chemical communication. Subsocial spiders are useful model organisms to study various topics in ecology, such as kin recognition and the evolution of cheating and its impact on societies. Further, why social behaviour evolved in some lineages and not others is currently a topic of debate in behavioural ecology, and we argue that spiders offer an opportunity to untangle the ecological causes of parental care, which forms the basis of many other animal societies. PMID- 24171918 TI - Disease identification based on ambulatory drugs dispensation and in-hospital ICD 10 diagnoses: a comparison. AB - BACKGROUND: Pharmacy-based case mix measures are an alternative source of information to the relatively scarce outpatient diagnoses data. But most published tools use national drug nomenclatures and offer no head-to-head comparisons between drugs-related and diagnoses-based categories. The objective of the study was to test the accuracy of drugs-based morbidity groups derived from the World Health Organization Anatomical Therapeutic Chemical Classification of drugs by checking them against diagnoses-based groups. METHODS: We compared drugs-based categories with their diagnoses-based analogues using anonymous data on 108,915 individuals insured with one of four companies. They were followed throughout 2005 and 2006 and hospitalized at least once during this period. The agreement between the two approaches was measured by weighted kappa coefficients. The reproducibility of the drugs-based morbidity measure over the 2 years was assessed for all enrollees. RESULTS: Eighty percent used a drug associated with at least one of the 60 morbidity categories derived from drugs dispensation. After accounting for inpatient under-coding, fifteen conditions agreed sufficiently with their diagnoses-based counterparts to be considered alternative strategies to diagnoses. In addition, they exhibited good reproducibility and allowed prevalence estimates in accordance with national estimates. For 22 conditions, drugs-based information identified accurately a subset of the population defined by diagnoses. CONCLUSIONS: Most categories provide insurers with health status information that could be exploited for healthcare expenditure prediction or ambulatory cost control, especially when ambulatory diagnoses are not available. However, due to insufficient concordance with their diagnoses based analogues, their use for morbidity indicators is limited. PMID- 24171919 TI - Nonoxidized, biologically active parathyroid hormone determines mortality in hemodialysis patients. AB - BACKGROUND: It was shown that nonoxidized PTH (n-oxPTH) is bioactive, whereas the oxidation of PTH results in a loss of biological activity. METHODS: In this study we analyzed the association of n-oxPTH on mortality in hemodialysis patients using a recently developed assay system. RESULTS: Hemodialysis patients (224 men, 116 women) had a median age of 66 years. One hundred seventy patients (50%) died during the follow-up period of 5 years. Median n-oxPTH levels were higher in survivors (7.2 ng/L) compared with deceased patients (5.0 ng/L; P = .002). Survival analysis showed an increased survival in the highest n-oxPTH tertile compared with the lowest n-oxPTH tertile (chi2, 14.3; P = .0008). Median survival was 1702 days in the highest n-oxPTH tertile, whereas it was only 453 days in the lowest n-oxPTH tertile. Multivariable-adjusted Cox regression showed that higher age increased odds for death, whereas higher n-oxPTH reduced the odds for death. Another model analyzing a subgroup of patients with intact PTH (iPTH) concentrations at baseline above the upper normal range of the iPTH assay (70 ng/L) revealed that mortality in this subgroup was associated with oxidized PTH but not with n-oxPTH levels. CONCLUSIONS: The predictive power of n-oxPTH and iPTH on the mortality of hemodialysis patients differs substantially. Measurements of n-oxPTH may reflect the hormone status more precisely. The iPTH associated mortality is most likely describing oxidative stress-related mortality. PMID- 24171920 TI - Thyroid function tests and mortality in aged hospitalized patients: a 7-year prospective observational study. AB - CONTEXT: Several alterations in thyroid function test (TFT) results have been associated with mortality in elderly patients. OBJECTIVE: Our aim was to investigate the relationship between TFT results and all-cause and cardiovascular (CV) mortality in aged hospitalized patients. DESIGN: A 7-year prospective observational study was conducted. TFTs were performed at hospital admission, and mortality was registered in the follow-up period. PATIENTS: Participants were 404 patients aged >65 years admitted to the Department of Geriatrics, Hospital General, Segovia, Spain, for any reason during 2005. MAIN OUTCOME MEASURES: The study evaluated the association between TFT results and mortality from all causes and CV diseases. METHODS: TSH, free T4, and free T3 (FT3) were measured on the first day of admission. In-hospital and total survival times, number of deaths, and all-cause and CV mortality were registered until the census date on January 1, 2012. RESULTS: During the study, 323 patients (80%) died. Kaplan-Meier analysis showed that median survival time for all-cause mortality was significantly lower in patients in the first tertile of serum FT3, in the first tertile of TSH, and in the first tertile of serum free T4 concentrations. Multivariate adjusted Cox regression analysis showed that the history of cancer (hazard ratio, 1.60; 95% confidence interval, 1.12-2.28; P = .009), age (1.03; 1.01-1.06; P = .003), and FT3 levels (0.72; 0.63-0.84; P < .001) were significant factors related to all-cause mortality. The cause of death was known in 202 patients. Of this group, 61 patients (30.2%) died of CV disease. Patients in the first tertile of TSH and FT3 exhibited a significant higher mortality due to CV disease. In the adjusted Cox regression analysis, FT3 was a significant predictor of CV mortality (0.76; 0.63-0.91; P = .004). CONCLUSIONS: Alterations in TFT results during hospitalization are associated with long-term mortality in elderly patients. In particular, low FT3 levels are significantly related to all-cause and CV mortality. PMID- 24171921 TI - Cost-effectiveness and cost utility analysis of three pneumococcal conjugate vaccines in children of Peru. AB - BACKGROUND: The clinical and economic burden associated with invasive and non invasive pneumococcal and non-typeable Haemophilus influenzae (NTHi) diseases is substantial in the Latin America and Caribbean region, where pneumococcal vaccines have only been introduced to a few countries. This study analyzed the cost-effectiveness and cost utility of three different pneumococcal conjugate vaccines (PCVs) for Peru. METHODS: A Markov model that simulated the disease processes in a birth cohort over a lifetime, within 1,128 month cycles was used to evaluate the cost-effectiveness of 10-valent pneumococcal NTHi protein D conjugate vaccine (PHiD-CV) and 7- and 13-valent PCVs (PCV-7 and PCV-13). Expected quality-adjusted life years (QALYs), cost-savings and incremental cost effectiveness ratios (ICERs) were calculated. RESULTS: Without vaccination, pneumonia was associated with the greatest health economic burden (90% of QALYs lost and 63% of lifetime direct medical costs); while acute otitis media (AOM) was responsible for 1% of QALYs lost and 25% of direct medical costs. All vaccines were predicted to be cost-effective for Peru, with PHiD-CV being most cost-effective. PHiD-CV was predicted to generate 50 more QALYs gained and required a reduced investment (-US$ 3.4 million) versus PCV-13 (discounted data), and was therefore dominant and cost saving. The probabilistic sensitivity analysis showed that PHiD-CV generated more QALYs gained at a reduced cost than PCV-13 in 84% of the simulations and less QALYs gains at a reduced cost in 16%. Additional scenarios using different assumptions on vaccine efficacies based on previous evidence were explored, but no significant change in the overall cost effective results were observed. CONCLUSIONS: The results of this modeling study predict that PCVs are likely to be a cost-effective strategy to help relieve the epidemiological and economic burden associated with pediatric pneumococcal and NTHi diseases for Peru. PHiD-CV is likely to be a dominant (better health gains at a reduced net cost) intervention compared to PCV-13 or PCV-7. The most significant drivers for these results are the better health and economic profile of PHiD-CV against AOM and its reduced cost per dose available through the PAHO Revolving Fund in the LAC region. PMID- 24171922 TI - Experimental drought reduces the transfer of recently fixed plant carbon to soil microbes and alters the bacterial community composition in a mountain meadow. AB - Drought affects plants and soil microorganisms, but it is still not clear how it alters the carbon (C) transfer at the plant-microbial interface. Here, we tested direct and indirect effects of drought on soil microbes and microbial turnover of recent plant-derived C in a mountain meadow. Microbial community composition was assessed using phospholipid fatty acids (PLFAs); the allocation of recent plant derived C to microbial groups was analysed by pulse-labelling of canopy sections with (13) CO2 and the subsequent tracing of the label into microbial PLFAs. Microbial biomass was significantly higher in plots exposed to a severe experimental drought. In addition, drought induced a shift of the microbial community composition, mainly driven by an increase of Gram-positive bacteria. Drought reduced belowground C allocation, but not the transfer of recently plant assimilated C to fungi, and in particular reduced tracer uptake by bacteria. This was accompanied by an increase of (13) C in the extractable organic C pool during drought, which was even more pronounced after plots were mown. We conclude that drought weakened the link between plant and bacterial, but not fungal, C turnover, and facilitated the growth of potentially slow-growing, drought-adapted soil microbes, such as Gram-positive bacteria. PMID- 24171923 TI - Robot-assisted radical prostatectomy: a case series of the first 100 patients- constitutional introduction and implementation on the basis of comprehensive department of minimal invasive surgery center. AB - BACKGROUND: Although a very small number of Japanese hospitals had been performing robotic surgery before 2011, the number now using it is increasing rapidly due to the application of health insurance to robotic surgery for prostate cancer (PCa) since April, 2012. We report our initial experience of treating 100 patients by robot-assisted radical prostatectomy (RARP) with a focus on constitutional introduction and implementation based on minimal invasive surgery center (MISC) and patient outcomes. METHODS: The MISC involved all of the hospital sections related to robotic surgery including four surgery departments, anesthesiology, operating room nurses, medical engineers. The data were prospectively collected from the first 100 consecutive patients who underwent RARP under supervision of MISC for localized PCa from October 2010 to December 2012. RESULTS: During the period of our initial 100 cases of RARP, the gynecology, respiratory and digestive surgery departments performed initial cases of 20, 33 and 23 robotic surgeries under control of MISC. Peri-operative complications in RARP appeared to be minimal with no cases of intra-operative open conversion. The positive surgical margin rate was 19% for the entire series. At the median follow-up time of 11.9 months, 91% of patients had undetectable PSA levels, and 76% of patients were not using pads. Sequential urinary functional data indicated a significant beneficial effect on lower urinary tract symptoms beyond cancer control over a period of several months. Although the pre-operative potent patient number was small, the transitions of constant potency recovery at precise time points were shown according to different nerve sparing procedures. CONCLUSIONS: This is the first report of an initial 100 RARP cases that were implemented using the constitutional framework of an academic institution. The MISC is providing immeasurable benefits from the aspects of patient safety and education for the robotic surgical team. RARP is a safe and efficient method for achieving PCa control together with functional preservation, even during the initial trial for this procedure. PMID- 24171924 TI - Characterization of WZ4003 and HTH-01-015 as selective inhibitors of the LKB1 tumour-suppressor-activated NUAK kinases. AB - The related NUAK1 and NUAK2 are members of the AMPK (AMP-activated protein kinase) family of protein kinases that are activated by the LKB1 (liver kinase B1) tumour suppressor kinase. Recent work suggests they play important roles in regulating key biological processes including Myc-driven tumorigenesis, senescence, cell adhesion and neuronal polarity. In the present paper we describe the first highly specific protein kinase inhibitors of NUAK kinases namely WZ4003 and HTH-01-015. WZ4003 inhibits both NUAK isoforms (IC50 for NUAK1 is 20 nM and for NUAK2 is 100 nM), whereas HTH-01-015 inhibits only NUAK1 (IC50 is 100 nM). These compounds display extreme selectivity and do not significantly inhibit the activity of 139 other kinases that were tested including ten AMPK family members. In all cell lines tested, WZ4003 and HTH-01-015 inhibit the phosphorylation of the only well-characterized substrate, MYPT1 (myosin phosphate-targeting subunit 1) that is phosphorylated by NUAK1 at Ser(445). We also identify a mutation (A195T) that does not affect basal NUAK1 activity, but renders it ~50-fold resistant to both WZ4003 and HTH-01-015. Consistent with NUAK1 mediating the phosphorylation of MYPT1 we find that in cells overexpressing drug-resistant NUAK1[A195T], but not wild-type NUAK1, phosphorylation of MYPT1 at Ser(445) is no longer suppressed by WZ4003 or HTH-01-015. We also demonstrate that administration of WZ4003 and HTH-01-015 to MEFs (mouse embryonic fibroblasts) significantly inhibits migration in a wound-healing assay to a similar extent as NUAK1-knockout. WZ4003 and HTH-01-015 also inhibit proliferation of MEFs to the same extent as NUAK1 knockout and U2OS cells to the same extent as NUAK1 shRNA knockdown. We find that WZ4003 and HTH-01-015 impaired the invasive potential of U2OS cells in a 3D cell invasion assay to the same extent as NUAK1 knockdown. The results of the present study indicate that WZ4003 and HTH-01-015 will serve as useful chemical probes to delineate the biological roles of the NUAK kinases. PMID- 24171925 TI - Signalling endosomes in axonal transport: travel updates on the molecular highway. AB - Neurons are highly polarised cells. They make contact with their targets through long axons, along which a steady flux of proteins, lipids, nucleic acids and organelles is constantly maintained. This process is crucial to the development and maintenance of the nervous system, as proven by the many neurodegenerative disorders associated with defective axonal transport. Specific pools of endocytic organelles, which travel along the axon towards the cell body, have assumed a growing importance by virtue of their transported signals. These organelles, named signalling endosomes, vehicle growth factors, such as neurotrophins, and their signalling receptors all the way from the axon terminals to the neuronal cell body. Due to the central importance of neurotrophins in neuronal development and survival, significant efforts have gone over the years into the study of long range neutrophin trafficking and signalling. Recent evidence has pointed to a role of signalling endosomes in the axonal retrograde transport of many morphogenetic and survival factors, increasing their importance even further. In light of these findings, signalling endosomes have shown potential for integration of different growth factors signals and the ability to decode them by differential sorting in the neuronal cell body. In this review we aim to discuss the state of the field regarding the nature and dynamics of signalling endosomes, their signalling capabilities, their energy requirements for axonal transport and last but not least, their importance in health and disease. PMID- 24171926 TI - Down-regulation of miR-138 promotes colorectal cancer metastasis via directly targeting TWIST2. AB - BACKGROUND: Colorectal cancer (CRC) is the most common digestive system malignancy. The molecular events involved in the development and progression of CRC remain unclear. Recently, more and more evidences have showed that deregulated miRNAs participate in colorectal carcinogenesis. METHODS: The expression levels of miR-138 were first examined in CRC cell lines and tumor tissues by real-time PCR. The in vitro and in vivo functional effects of miR-138 were examined further. Luciferase reporter assays were conducted to confirm the targeting associations. Kaplan-Meier analysis and log-rank tests were performed to estimate the overall survival and disease free survival rate. RESULTS: miR-138 was found to be down-regulated in human colorectal cancer tissues and cell lines. Ectopic expression of miR-138 resulted in a dramatic inhibition of CRC migration and invasion in vitro and in vivo. Twist basic helix-loop-helix transcription factor 2 gene (TWIST2) was identified as one of the functional target. Restoration of miR-138 resulted in a dramatic reduction of the expression of TWIST2 at both mRNA and protein levels by directly targeting its 3'-untranslated region (3'UTR). Up-regulation of TWIST2 was detected in CRC tumors compared with adjacent normal tissues (P < 0.001) and is inversely correlated with miR-138 expression. We also identified that down-regulation of miR-138 was associated with lymph node metastasis, distant metastasis, and always predicted poor prognosis. CONCLUSION: These data highlight a pivotal role for miR-138 in the regulation of CRC metastasis by targeting TWIST2, and suggest a potential application of miR-138 in prognosis prediction and CRC treatment. PMID- 24171930 TI - Kinesthesis can make an invisible hand visible. AB - Self-generated body movements have reliable visual consequences. This predictive association between vision and action likely underlies modulatory effects of action on visual processing. However, it is unknown whether actions can have generative effects on visual perception. We asked whether, in total darkness, self-generated body movements are sufficient to evoke normally concomitant visual perceptions. Using a deceptive experimental design, we discovered that waving one's own hand in front of one's covered eyes can cause visual sensations of motion. Conjecturing that these visual sensations arise from multisensory connectivity, we showed that grapheme-color synesthetes experience substantially stronger kinesthesis-induced visual sensations than nonsynesthetes do. Finally, we found that the perceived vividness of kinesthesis-induced visual sensations predicted participants' ability to smoothly track self-generated hand movements with their eyes in darkness, which indicates that these sensations function like typical retinally driven visual sensations. Evidently, even in the complete absence of external visual input, the brain predicts visual consequences of actions. PMID- 24171931 TI - Developmental reversals in risky decision making: intelligence agents show larger decision biases than college students. AB - Intelligence agents make risky decisions routinely, with serious consequences for national security. Although common sense and most theories imply that experienced intelligence professionals should be less prone to irrational inconsistencies than college students, we show the opposite. Moreover, the growth of experience based intuition predicts this developmental reversal. We presented intelligence agents, college students, and postcollege adults with 30 risky-choice problems in gain and loss frames and then compared the three groups' decisions. The agents not only exhibited larger framing biases than the students, but also were more confident in their decisions. The postcollege adults (who were selected to be similar to the students) occupied an interesting middle ground, being generally as biased as the students (sometimes more biased) but less biased than the agents. An experimental manipulation testing an explanation for these effects, derived from fuzzy-trace theory, made the students look as biased as the agents. These results show that, although framing biases are irrational (because equivalent outcomes are treated differently), they are the ironical output of cognitively advanced mechanisms of meaning making. PMID- 24171932 TI - Hunger games: fluctuations in blood glucose levels influence support for social welfare. AB - Social-welfare policies are a modern instantiation of a phenomenon that has pervaded human evolutionary history: resource sharing. Ancestrally, food was a key shared resource in situations of temporary hunger. If evolved human psychology continues to shape how individuals think about current, evolutionarily novel conditions, this invites the prediction that attitudes regarding welfare politics are influenced by short-term fluctuations in hunger. Using blood glucose levels as a physiological indicator of hunger, we tested this prediction in a study in which participants were randomly assigned to conditions in which they consumed soft drinks containing either carbohydrates or an artificial sweetener. Analyses showed that participants with experimentally induced low blood glucose levels expressed stronger support for social welfare. Using an incentivized measure of actual sharing behavior (the dictator game), we further demonstrated that this increased support for social welfare does not translate into genuinely increased sharing motivations. Rather, we suggest that it is "cheap talk" aimed at increasing the sharing efforts of other individuals. PMID- 24171933 TI - Mother's education is the most important factor in socio-economic inequality of child stunting in Iran. AB - OBJECTIVE: Malnutrition is one of the most important health problems, especially in developing countries. The present study aimed to describe the socio-economic inequality in stunting and its determinants in Iran for the first time. DESIGN: Cross-sectional, population-based survey, carried out in 2009. Using randomized cluster sampling, weight and height of children were measured and anthropometric indices were calculated based on child growth standards given by the WHO. Socio economic status of families was determined using principal component analysis on household assets and social specifications of families. The concentration index was used to calculate socio-economic inequality in stunting and its determinants were measured by decomposition of this index. Factors affecting the gap between socio-economic groups were recognized by using the Oaxaca-Blinder decomposition method. SETTING: Shahroud District in north-eastern Iran. SUBJECTS: Children (n 1395) aged <6 years. RESULTS: The concentration index for socio-economic inequality in stunting was -0.1913. Mother's education contributed 70 % in decomposition of this index. Mean height-for-age Z-score was -0.544 and -0.335 for low and high socio-economic groups, respectively. Mother's education was the factor contributing most to the gap between these two groups. CONCLUSIONS: There was a significant socio-economic inequality in the studied children. If mother's education is distributed equally in all the different groups of Iranian society, one can expect to eliminate 70 % of the socio-economic inequalities. Even in high socio-economic groups, the mean height-for-age Z-score was lower than the international standards. These issues emphasize the necessity of applying new interventions especially for the improvement of maternal education. PMID- 24171934 TI - A novel composite material specifically developed for ultrasound bone phantoms: cortical, trabecular and skull. AB - In the various stages of developing diagnostic and therapeutic equipment, the use of phantoms can play a very important role in improving the process, help in implementation, testing and calibrations. Phantoms are especially useful in developing new applications and training new doctors in medical schools. However, devices that use different physical factors, such as MRI, Ultrasound, CT Scan, etc will require the phantom to be made of different physical properties. In this paper we introduce the properties of recently designed new materials for developing phantoms for ultrasonic human body investigation, which in today's market make up more than 30% in the world of phantoms. We developed a novel composite material which allows fabrication of various kinds of ultrasound bone phantoms to mimic most of the acoustical properties of human bones. In contrast to the ex vivo tissues, the proposed material can maintain the physical and acoustical properties unchanged for long periods of time; moreover, these properties can be custom designed and created to suit specific needs. As a result, we introduce three examples of ultrasound phantoms that we manufactured in our laboratory: cortical, trabecular and skull bone phantoms. The paper also presents the results of a comparison study between the acoustical and physical properties of actual human bones (reported in the referenced literatures) and the phantoms manufactured by us. PMID- 24171935 TI - Parapharyngeal pleomorphic adenoma as a cause of severe obstructive sleep apnoea. PMID- 24171936 TI - Comparison of two commonly used reference materials for exercise bicycle tests with a Swedish clinical database of patients with normal outcome. AB - BACKGROUND: Reference values for working capacity, blood pressure, heart rate, perceived exertion, etc. during bicycle exercise tests have been sought after for many years. This is because earlier commonly used reference values for physical work capacity have been either too low or too high when compared to the clinical experience of several Swedish departments of clinical physiology. The aim of the study was to compare two commonly used reference materials with normal outcomes from a clinical database. METHODS: Data from a clinical database of standardized exercise tests in Kalmar, Sweden, between 2004 and 2012, and having been judged as normal, were divided into 5-year categories of 5-10 to 75-80 years of age covering people from 7 to 80 years of age. RESULTS: Maximal working capacity (Wmax ), maximal heart rate, maximal systolic blood pressure and maximal perceived exertion are presented for each of the 15 age categories. Regression equations are also presented for each sex with age and height as independent predictors. Quantitative comparisons of Wmax are calculated for the three materials and possible explanations discussed. CONCLUSIONS: Values of Wmax lie between the two reference materials most commonly used in Sweden. In addition, the present material covers subjects aged 7-19 years. PMID- 24171937 TI - Treating lateral epicondylitis with corticosteroid injections or non electrotherapeutical physiotherapy: a systematic review. AB - OBJECTIVES: To evaluate the current evidence for the efficacy of corticosteroid injection and non-electrotherapeutic physiotherapy compared with control for treating lateral epicondylitis. DESIGN: Systematic review. PARTICIPANTS: We searched five databases in September 2012 for randomised controlled studies with a minimum quality rating. Of the 640 studies retrieved, 11 were included, representing 1161 patients of both sexes and all ages. INTERVENTIONS: Corticosteroid injection and non-electrotherapeutic physiotherapy. OUTCOME MEASURES: Relative risk (RR) or standardised mean difference (SMD) for overall improvement, pain and grip strength at 4-12, 26 and 52 weeks of follow-up. RESULTS: Corticosteroid injection gave a short-term reduction in pain versus no intervention or non-steroidal anti-inflammatory drugs (SMD -1.43, 95% CI -1.64 to -1.23). At intermediate follow-up, we found an increase in pain (SMD 0.32, 95% CI 0.13 to 0.51), reduction in grip strength (SMD -0.48, 95% CI -0.73 to -0.24) and negative effect on the overall improvement effect (RR 0.66 (0.53 to 0.81)). For corticosteroid injection versus lidocaine injection, the evidence was conflicting. At long-term follow-up, there was no difference on overall improvement and grip strength, with conflicting evidence for pain. Manipulation and exercise versus no intervention showed beneficial effect at short-term follow up (overall improvement RR 2.75, 95% CI 1.30 to 5.82), but no significant difference at intermediate or long-term follow-up. We found moderate evidence for short-term and long-term effects of eccentric exercise and stretching versus no intervention. For exercise versus no intervention and eccentric or concentric exercise and stretching versus stretching alone, we found moderate evidence of no short-term effect. CONCLUSIONS: Corticosteroid injections have a short-term beneficial effect on lateral epicondylitis, but a negative effect in the intermediate term. Evidence on the long-term effect is conflicting. Manipulation and exercise and exercise and stretching have a short-term effect, with the latter also having a long-term effect. PMID- 24171938 TI - Experiences of leaders in the implementation of Lean in a teaching hospital- barriers and facilitators in clinical practices: a qualitative study. AB - OBJECTIVES: To date, experiences of leaders in the implementation of Lean after a Lean Training Programme have not been systematically investigated within teaching hospitals. Existing studies have identified barriers and facilitators only from an improvement programme perspective and have not considered the experiences of leaders themselves. This study aims to bridge this gap. DESIGN: Semistructured, indepth interviews. SETTING: One of largest teaching hospitals in the Netherlands. PARTICIPANTS: 31 medical, surgical and nursing professionals with an average of 19.2 years of supervisory experience. All professionals were appointed to a Lean Training Programme and were directly involved in the implementation of Lean. RESULTS: The evidence obtained in this study shows that, from the perspectives of participants, leadership management support, a continuous learning environment and cross-departmental cooperation play a significant role in successful Lean implementation. The results suggest that a Lean Training Programme contributed to positive outcomes in personal and professional skills that were evident during the first 4 months after programme completion. CONCLUSIONS: Implementing Lean in a teaching hospital setting is a challenge because of the ambiguous and complex environment of a highly professionalised organisation. The study found that leadership management support and a continuous learning environment are important facilitators of Lean implementation. To increase the successful outcomes of leadership actions, training should be supplemented with actions to remove perceived barriers. This requires the involvement of all professionals, the crossing of departmental boundaries and a focus on meaning-making processes rather than simply 'implementing' facts. Therefore, this research suggests that programme participants, such as staff members and leaders, can mutually explore the meanings of Lean thinking and working for their own contexts. By entering this shared learning process (eg, learning on the job) the ownership of Lean implementation could also increase. PMID- 24171939 TI - Timing of access to secondary healthcare services for diabetes management and lower extremity amputation in people with diabetes: a protocol of a case-control study. AB - BACKGROUND: Lower extremity amputation (LEA) is a complication of diabetes and a marker of the quality of diabetes care. Clinical and sociodemographic determinants of LEA in people with diabetes are well known. However, the role of service-related factors has been less well explored. Early referral to secondary healthcare is assumed to prevent the occurrence of LEA. The objective of this study is to investigate a possible association between the timing of patient access to secondary healthcare services for diabetes management, as a key marker of service-related factors, and LEA in patients with diabetes. METHODS/DESIGN: This is a case-control study. The source population is people with diabetes. Cases will be people with diabetes who have undergone a first major LEA, identified from the hospital discharge data at each of three regional centres for diabetes care. Controls will be patients with diabetes without LEA admitted to the same centre either electively or as an emergency. Frequency-matching will be applied for gender, type of diabetes, year and centre of LEA. Three controls per case will be selected from the same population as the cases. With a power of 90% to detect OR of 0.4 for an association between 'good quality care' and LEA in people with diabetes, 107 cases and 321 controls are required. Services involved in diabetes management are endocrinology, ophthalmology, renal, cardiology, vascular surgery and podiatry; timing of first contact with any of these services is the main exploratory variable. Using unconditional logistic regression, an association between this exposure and the outcome of major LEA in people with diabetes will be explored, while adjusting for confounders. ETHICS AND DISSEMINATION: Ethical approval was granted by the Clinical Research Ethics Committee of the Cork Teaching Hospitals, Ireland. Results will be presented at conferences and published in peer-reviewed journals. PMID- 24171940 TI - Respiratory infections in preterm infants and subsequent asthma: a cohort study. AB - OBJECTIVES: To investigate whether gestational age modifies the association of airway infections that result in hospital admission during the first year after birth, with subsequent asthma risk after age 5 years. SETTING: Hospital inpatients and a general population comparison group in Sweden followed for subsequent diagnoses in primary and secondary care. PARTICIPANTS: National registers identified 42 334 children admitted to hospital for respiratory infection in their first year after birth during 1981-1995, individually matched with 211 594 children not admitted to hospital for infection during their first year. PRIMARY OUTCOME: Asthma diagnoses and prescribed asthma treatments after the age of 5 years identified through registers. RESULTS: Cox regression was used to identify a HR (and 95% CI) of 1.51 (1.47 to 1.51) for the association of respiratory infection before 1 year of age with asthma after age 5 years, after adjustment for sex, gestational age, chronic lung disease, maternal asthma and maternal smoking. When stratified by gestational age (and with additional adjustment for birth weight), there is statistically significant effect modification by gestational age, with the highest magnitude asthma risk among those born with a gestational age of less than 28 weeks, producing an adjusted HR of 2.22 (1.59 to 3.09). This higher magnitude asthma risk persisted until after age 10 years, but differences in risk by gestational age were less pronounced for asthma after age 16 years. CONCLUSIONS: Extremely preterm infants are most likely to have chronic respiratory sequelae following respiratory infections in early life. PMID- 24171941 TI - Positive imagery cognitive bias modification (CBM) and internet-based cognitive behavioural therapy (iCBT) versus control CBM and iCBT for depression: study protocol for a parallel-group randomised controlled trial. AB - INTRODUCTION: The current randomised controlled trial will evaluate the efficacy of an internet-delivered positive imagery cognitive bias modification (CBM) intervention for depression when compared with an active control condition and help establish the additive benefit of positive imagery CBM when delivered in combination with internet cognitive behavioural therapy for depression. METHODS AND ANALYSIS: Patients meeting diagnostic criteria for a current major depressive episode will be recruited through the research arm of a not-for-profit clinical and research unit in Australia. The minimum sample size for each group (alpha set at 0.05, power at 0.80) was identified as 29, but at least 10% more will be recruited to hedge against expected attrition. We will measure the impact of CBM on primary measures of depressive symptoms (Beck Depression Inventory-second edition (BDI-II), Patient Health Questionnaire (PHQ9)) and interpretive bias (ambiguous scenarios test-depression), and on a secondary measure of psychological distress (Kessler-10 (K10)) following the 1-week CBM intervention. Secondary outcome measures of psychological distress (K10), as well as disability (WHO disability assessment schedule-II), repetitive negative thinking (repetitive thinking questionnaire), and anxiety (state trait anxiety inventory-trait version) will be evaluated following completion of the 11-week combined intervention, in addition to the BDI-II and PHQ9. Intent-to-treat marginal and mixed effect models using restricted maximum likelihood estimation will be used to evaluate the primary hypotheses. Clinically significant change will be defined as high-end state functioning (a BDI-II score <14) combined with a total score reduction greater than the reliable change index score. Maintenance of gains will be assessed at 3-month follow-up. ETHICS AND DISSEMINATION: The current trial protocol has been approved by the Human Research Ethics Committee of St Vincent's Hospital and the University of New South Wales, Sydney. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry: ACTRN12613000139774 and Clinicaltrials.gov: NCT01787513. This trial protocol is written in compliance with the Standard Protocol Items: recommendations for Interventional Trials (SPIRIT) guidelines. PMID- 24171942 TI - The effect of genomic information on optimal contribution selection in livestock breeding programs. AB - BACKGROUND: Long-term benefits in animal breeding programs require that increases in genetic merit be balanced with the need to maintain diversity (lost due to inbreeding). This can be achieved by using optimal contribution selection. The availability of high-density DNA marker information enables the incorporation of genomic data into optimal contribution selection but this raises the question about how this information affects the balance between genetic merit and diversity. METHODS: The effect of using genomic information in optimal contribution selection was examined based on simulated and real data on dairy bulls. We compared the genetic merit of selected animals at various levels of co ancestry restrictions when using estimated breeding values based on parent average, genomic or progeny test information. Furthermore, we estimated the proportion of variation in estimated breeding values that is due to within-family differences. RESULTS: Optimal selection on genomic estimated breeding values increased genetic gain. Genetic merit was further increased using genomic rather than pedigree-based measures of co-ancestry under an inbreeding restriction policy. Using genomic instead of pedigree relationships to restrict inbreeding had a significant effect only when the population consisted of many large full sib families; with a half-sib family structure, no difference was observed. In real data from dairy bulls, optimal contribution selection based on genomic estimated breeding values allowed for additional improvements in genetic merit at low to moderate inbreeding levels. Genomic estimated breeding values were more accurate and showed more within-family variation than parent average breeding values; for genomic estimated breeding values, 30 to 40% of the variation was due to within-family differences. Finally, there was no difference between constraining inbreeding via pedigree or genomic relationships in the real data. CONCLUSIONS: The use of genomic estimated breeding values increased genetic gain in optimal contribution selection. Genomic estimated breeding values were more accurate and showed more within-family variation, which led to higher genetic gains for the same restriction on inbreeding. Using genomic relationships to restrict inbreeding provided no additional gain, except in the case of very large full-sib families. PMID- 24171943 TI - Expression of the senescence marker p16INK4a in skin biopsies of acute lymphoblastic leukemia survivors: a pilot study. AB - BACKGROUND: Most childhood cancer survivors will develop ionizing radiation treatment-related health conditions that, in many instances, resemble age associated pathologies. Treatment-induced premature senescence could be an underlying mechanism. FINDINGS: Here we wanted to know whether the expression of p16INK4a, a senescence/aging biomarker, is increased in skin biopsies of acute lymphoblastic leukemia survivors (ALL), previously exposed to chemotherapy and radiation therapy. Several years post-treatments, we found p16INK4a mRNA levels are 5.8 times higher in scalp skin biopsies (targeted by cranial irradiation therapy) compared to buttocks skin biopsies (n = 10, p = 0.01). CONCLUSIONS: These results demonstrate for the first time that premature senescence is induced in pediatric cancer survivors and that p16INK4a expression could be used as a potential biomarker in this population. PMID- 24171945 TI - The association between retirement and age on physical activity in older adults. AB - BACKGROUND: retirement is a major life change that is likely to affect lifestyles and yet little is still known about its influence on physical activity (PA). This study objectively quantified sedentary behaviour and ambulatory activity outcomes in retired and non-retired older, community-dwelling adults. METHODS: PA was quantified in 98 community-dwelling older adults (69.1 +/- 7.6 years) who wore an activPAL PA monitor (accelerometer) for seven consecutive days. Outcomes representing the volume, pattern and variability of sedentary behaviour and ambulatory activity were derived from the cross-sectional accelerometer data. The association between retirement, ageing and their interaction on sedentary and ambulatory outcomes were examined. RESULTS: being retired was associated with a reduced percentage of sedentary behaviour; reduced long bouts of sitting (>55 min) and increased the percentage of ambulatory activity. The volume of sedentary behaviour increased with age, whereas ambulatory activity reduced with age. Measures of pattern and variability did not change with retirement or age. With respect to recommended amounts of PA, there was no difference between retired and employed adults and only 21% achieved the recommended 150 min/week (accumulated in >=10 min bouts of walking). CONCLUSION: while retirement was associated with a greater volume of PA, most older adults do not meet current recommended PA guidelines. Interventions are needed to increase PA in older adults in the years leading to and after the transition to retirement. PMID- 24171944 TI - Strategies for the multiplex mapping of genes to traits. AB - Rewiring and optimization of metabolic networks to enable the production of commercially valuable chemicals is a central goal of metabolic engineering. This prospect is challenged by the complexity of metabolic networks, lack of complete knowledge of gene function(s), and the vast combinatorial genotype space that is available for exploration and optimization. Various approaches have thus been developed to aid in the efficient identification of genes that contribute to a variety of different phenotypes, allowing more rapid design and engineering of traits desired for industrial applications. This review will highlight recent technologies that have enhanced capabilities to map genotype-phenotype relationships on a genome wide scale and emphasize how such approaches enable more efficient design and engineering of complex phenotypes. PMID- 24171946 TI - The risk of adverse outcomes in hospitalized older patients in relation to a frailty index based on a comprehensive geriatric assessment. AB - BACKGROUND: prognostication for frail older adults is complex, especially when they become seriously ill. OBJECTIVES: to test the measurement properties, especially the predictive validity, of a frailty index based on a comprehensive geriatric assessment (FI-CGA) in an acute care setting in relation to the risk of death, length of stay and discharge destination. DESIGN AND SETTING: prospective cohort study. Inpatient medical units in a teaching, acute care hospital. SUBJECTS: individuals on inpatient medical units in a hospital, n = 752, aged 75+ years, were evaluated on their first hospital day; to test reliability, a subsample (n = 231) was seen again on Day 3. MEASUREMENTS: all frailty data collected routinely as part of a CGA were used to create the FI-CGA. Mortality data were reviewed from hospital records, claims data, Social Security Death Index and interviews with Discharge Managers. RESULTS: thirty-day mortality was 93 (12.4%; 95% confidence interval (CI) = 10-15%) of whom 52 died in hospital. The risk of dying increased with each 0.01 increment in the FI-CGA: hazard ratio (HR) = 1.05, (95% CI = 1.04-1.07). People who were discharged home had the lowest admitting mean FI-CGA = 0.38 (+/-standard deviation 0.11) compared with those who died, FI-CGA = 0.51 (+/-0.12) or were discharged to nursing home, FI-CGA = 0.49 (+/-0.11). Likewise, increasing FI-CGA values on admission were significantly associated with a longer length of hospital stay. CONCLUSIONS: frailty, measured by the FI-CGA, was independently associated with a higher risk of death and other adverse outcomes in older people admitted to an acute care hospital. PMID- 24171947 TI - Coverage and parental perceptions of influenza vaccination among parents of children aged 6 to 23 months in Hong Kong. AB - BACKGROUND: The impact of influenza on young children can be severe and even fatal. Influenza vaccination (IV) has been shown to be effective in reducing complications of influenza among children. This study investigated the prevalence and factors of IV among children aged 6-23 months in Hong Kong. METHODS: A sample of 401 Chinese parents of children aged 6-23 months were interviewed at local Maternal and Child Health Centers. Socio-demographic information, variables related to Health Belief Model, including perceptions about the child's chance of contracting influenza, perceived harm of influenza on children, perceived benefits and side-effects of IV, having received recommendations from health professionals to uptake IV, and IV behaviors of the children were measured. Multivariate analysis was used to examine factors associated with IV behaviors of children. RESULTS: Only 9% of the children had ever been vaccinated. Among those parents who had heard of IV (92.0%), substantial proportions perceived that IV could reduce the risk of influenza-induced complications (70.5%), hospitalization (70.5%) and death (65.9%). Relatively few of the participants believed that IV had no side effects (17.1%) and even less had been recommended by health care professionals to uptake IV (10.6%). Results from multivariate analysis showed that physician recommendations were associated with a higher likelihood for IV among younger children, whilst parental perceptions of the side effects of IV was associated with a lower likelihood for IV. CONCLUSION: The prevalence of IV among children aged 6-23 months in Hong Kong was very low. Promotion of IV with the component of physician recommendations and parents' knowledge about IV safety for this group is warranted. PMID- 24171948 TI - The psychological impact of strabismus: does the angle really matter? AB - INTRODUCTION: The psychological impact of strabismus is well recognized. Patients with strabismus have lower levels of psychological well being compared to normal controls. Few studies have evaluated the relationship between levels of psychological distress and the angle of deviation, age, sex, presence of diplopia, visual acuity and direction of deviation. METHODS: 50 patients with strabismus who attended the adult strabismus clinic were included in this questionnaire based prospective study. The Psychological Impact questionnaire was used to assess the psychological impact of noticeable strabismus. We measured the angle of deviation, age, sex, presence of diplopia, visual acuity and direction of deviation and correlated these with psychological impact scores. Student's t test and Pearson's correlation coefficient (r) were used in statistical analysis. RESULTS: The average age was 48 years (range 15-84) and there were 26 females and 24 males. There was no correlation between psychological impact score and the maximum degree of horizontal deviation r = 0.02 (95% CI -0.26 to 0.29), p = 0.9, the maximum angle of vertical deviation r = 0.26 (95% CI -0.01 to 0.51), p = 0.06, age r = -0.09 (95% CI -0.36 to 0.19), p = 0.5, sex (p = 0.96), presence of diplopia (p = 0.6), visual acuity of the worse eye r = -0.01 (95% CI -0.29 to 0.27), p = 0.9 and direction of deviation (p = 0.8 for eso-deviations compared to exo-deviations, p = 0.4 for horizontal compared to vertical deviations). There was a slight negative correlation between psychological impact score and visual acuity of the better eye r = -0.28 (95% CI -0.52 to -0.01), p = 0.04. CONCLUSION: The psychological impact of strabismus does not appear to be related to the patient's angle of deviation, age, sex, presence of diplopia, visual acuity or direction of deviation. Larger studies are required using strabismus specific tools for evaluating psychological impact to further investigate these findings. PMID- 24171949 TI - The amphibian skin-associated microbiome across species, space and life history stages. AB - Skin-associated bacteria of amphibians are increasingly recognized for their role in defence against pathogens, yet we have little understanding of their basic ecology. Here, we use high-throughput 16S rRNA gene sequencing to examine the host and environmental influences on the skin microbiota of the cohabiting amphibian species Anaxyrus boreas, Pseudacris regilla, Taricha torosa and Lithobates catesbeianus from the Central Valley in California. We also studied populations of Rana cascadae over a large geographic range in the Klamath Mountain range of Northern California, and across developmental stages within a single site. Dominant bacterial phylotypes on amphibian skin included taxa from Bacteroidetes, Gammaproteobacteria, Alphaproteobacteria, Firmicutes, Sphingobacteria and Actinobacteria. Amphibian species identity was the strongest predictor of microbial community composition. Secondarily, within a given amphibian species, wetland site explained significant variation. Amphibian associated microbiota differed systematically from microbial assemblages in their environments. Rana cascadae tadpoles have skin bacterial communities distinct from postmetamorphic conspecifics, indicating a strong developmental shift in the skin microbes following metamorphosis. Establishing patterns observed in the skin microbiota of wild amphibians and environmental factors that underlie them is necessary to understand skin symbiont community assembly, and ultimately, the role skin microbiota play in the extended host phenotype including disease resistance. PMID- 24171951 TI - Natural products as lead structures: chemical transformations to create lead-like libraries. AB - In this review, we analyze and illustrate the variation of the two main lead-like descriptors [molecular weight (MW) and the partition coefficient (logP)] in the generation of libraries in which a natural product (NP) is used as the guiding structure. Despite the different approaches used to create NP-like libraries, controlling these descriptors during the synthetic process is important to generate lead-like libraries. From this analysis, we present a schematic approach to the generation of lead-like libraries that can be applied to any starting NP. PMID- 24171950 TI - Moving forward in clinical trials for ALS: motor neurons lead the way please. AB - Amyotrophic lateral sclerosis (ALS) is one of the most complex motor neuron diseases. Even though scientific discoveries are accelerating with an unprecedented pace, to date more than 30 clinical trials have ended with failure and staggering frustration. There are too many compounds that increase life span in mice, but too little evidence that they will improve human condition. Increasing the chances of success for future clinical trials requires advancement of preclinical tests. Recent developments, which enable the visualization of diseased motor neurons, have the potential to bring novel insight. As we change our focus from mice to motor neurons, it is possible to foster a new vision that translates into effective and long-term treatment strategies in ALS and related motor neuron disorders (MND). PMID- 24171952 TI - Neuroendocrine tumors: insights into innovative therapeutic options and rational development of targeted therapies. AB - Neuroendocrine tumors (NETs) are heterogeneous neoplasms with respect to molecular characteristics and clinical outcome. Although slow-growing, NETs are often late diagnosed, already showing invasion of adjacent tissues and metastases. Precise knowledge of NET biological and molecular features has opened the door to the identification of novel pharmacological targets. Therapeutic options include somatostatin analogs, alone or in combination with interferon alpha, multi-targeted tyrosine kinase inhibitors (e.g. sunitinib) or mammalian target of rapamycin (mTOR) inhibitors (e.g. everolimus). Antiangiogenic approaches and anti insulin-like growth factor receptor (IGFR) compounds have been also proposed as combination therapies with the aforementioned compounds. This review will focus on recent studies that have improved therapeutic strategies in NETs, discussing management challenges such as drug resistance development as well as focusing on the need for predictive biomarkers to design distinct drug combinations and optimize pharmacological control. PMID- 24171953 TI - [Efficacy and safety of the HAA regimen as induction chemotherapy in 236 de novo acute myeloid leukemia]. AB - OBJECTIVE: To evaluate the efficacy and safety of the HAA regimen (homoharringtonine, cytarabine and aclarubicin) as induction chemotherapy in de novo acute myeloid leukemia (AML). METHODS: The efficacy and safety of 236 de novo AML patients who received the HAA regimen as induction chemotherapy were retrospectively analyzed. The complete remission (CR) rate was assayed. Kaplan Meier method was used to estimate overall survival (OS) and relapse free survival (RFS), and the differences were compared by Log-rank test. RESULTS: The overall CR rate was 78.0%, and 65.7% of the patients attained CR in the first induction cycle. The early death rate was 4.7%. The median followup time was 41(1-161) months. The estimated 5-year OS and 5-year RFS rates were 44.9% and 45.5%, respectively. The CR rates of patients with favorable, intermediate and unfavorable cytogenetics were 92.9%,78.6%and 41.7%, respectively. The 5-year OS of favorable and intermediate group were 61.1% and 45.1%, respectively. The 5- year RFS of favorable and intermediate group were 49.0% and 45.4%, respectively. The median survival time of unfavorable group was only 5 months. The side effects associated with the HAA regimen were tolerable, in which the most common toxicities were myelosuppression and infection. CONCLUSION: The HAA regimen is associated with a higher rate of CR and longer survival time and its toxicity could be tolerated. PMID- 24171954 TI - [Acute myeloid leukemia with t(11;12)(p15;q13) translocation: two cases report and literature review]. AB - OBJECTIVE: To investigate the clinical and laboratory features of acute myeloid leukemia (AML) with t(11;12)(p15;q13) translocation. METHODS: Two cases of AML with t(11;12)(p15;q13) translocation were reported and the related literatures were reviewed. RESULTS: The diagnosis of AML-M3 was supported by morphological, cytochemical staining and electron microscope tests. A rare t(11;12)(p15;q13) translocation, but not classical t(15;17)(q22;q12) translocation and PML- RARalpha fusion gene, was detected in both cases. Both of the patients were refractory to differentiation induction therapy such as retinoic acid and arsenic trioxide. CONCLUSION: AML is a group of heterogeneous disease derived from hematopoietic stem cell. Cytogenetic characteristic is important for diagnosis, prognosis stratification and therapy selection. Because of the heterogeneity of clinical and molecular features, it is unsuitable to classify AML with t(11;12)(p15;q13) as AML with recurrent cytogenetic aberration. This group of disease may benefit from allogeneic hematopoietic stem cell transplantation. PMID- 24171955 TI - [Long-term follow-up of childhood low-risk ALL patients treated with SCMC-ALL 2005 protocol]. AB - OBJECTIVE: To evaluate the long-term efficacy of SCMC-ALL-2005 protocol in treatment of low-risk childhood acute lymphoblastic leukemia (ALL). METHODS: From May 1, 2005 to April 30, 2009, 387 patients enrolled into SCMC-ALL-2005 protocol. Based on the characteristics of cell morphology, immunology, cytogenetics and molecular biology and treatment response, 158 patients were fit into the low-risk treatment group. All the cases were registered in pediatric oncology network database (POND). The clinical characteristics and outcome were analyzed. RESULTS: Until December 31, 2012, the 5-year event free survival (EFS) and overall survival (OS) is (77.76+/-3.37)% and (89.55+/-2.83)%, respectively. Median follow up time is 5.33 y (3.75-7.70 y). Five patients (3.16%) died of complication, all of them were severe infections. Twenty-seven patients (17.09%) relapsed, including 13 bone marrow relapse (8.23%), 5 testis relapse (5.32% of boys, 2 of unilateral and 3 bilateral), 6 central nerve system relapse (CNS, 3.80%), 1 relapse in both bone marrow and CNS, 1 relapse in both bone marrow and testis, and 1 right ovary and fallopian tube relapse. Relapse is related to positive minimal residual disease. Two cases (1.27%) occurred second tumors, 4 patients (2.53%) gave up treatment in complete remission without special reasons. CONCLUSION: The EFS and life quality of SCMC-ALL-2005 protocol in the treatment of childhood low-risk ALL is satisfactory. The treatment-related mortality rate is lower, and the long-term EFS is higher than that of XH-99 protocol. PMID- 24171956 TI - [Clinical and laboratory features of T-cell prolymphocytic leukemia in China]. AB - OBJECTIVE: To investigate the clinical and laboratory characteristics and survival of Chinese patients with T- cell prolymphocytic leukemia (T-PLL). METHODS: Eleven patients with T-PLL admitted in our hospital from Jan 2006 to Oct 2012 were retrospectively analyzed. RESULTS: Of the 11 patients, nine were males and two females, with the median age of 56.0(19-69) years old. All the patients, except for three, presented with leukocytosis. The incidence of hyperleukocytosis (1/11) was less frequent than that in the British series (75%) (P=0.000). Lymphocyte counts in peripheral blood were increased in 9 of the 11 patients with the median absolute lymphocyte count (ALC) of 17.22(0.58-148.83)*109/L. Superficial lymphadenopathy and splenomegaly were the most common physical signs. It was common that serum lactate dehydrogenase (LDH) and beta 2 microglobulin(beta2-MG)were higher than normal level. All cases were positive for CD2/CD3/CD5/TCRalphabeta, negative for CD1a /HLA-DR and TdT, and most of them were strong positive for CD7 expression. By chromosome analyses, most cases. (9/10) have normal chromosome. This rate is significantly higher than that of the British and American series (3% and 25%, respectively) (P=0.000, P=0.001). The 14q11 abnormality and trisomy 8q, which are common among Western cases, were not observed in any of our cases. With a median follow-up of 23.0 months, three patients died. Two year progress free survival (PFS) and overall survival (OS) were 53.3% and 50%, respectively. There were 3 patients with PFS over a number of years, whether it should be considered as the T-chronic lymphocytic leukemia (T CLL) is worthy of further studies. CONCLUSION: The common clinical manifestations of T-PLL patients were increased lymphocyte counts and lymphadenopathy as well as splenomegaly. And most cases have high level of blood LDH and beta2- MG and normal chromosome karyotype. PMID- 24171957 TI - [Detection of heterogeneity and evolution of subclones in t(8;21) AML by QM FISH]. AB - OBJECTIVE: To explore the heterogeneous subclones in acute myeloid leukemia (AML) with t(8;21) by quantitative multicolor- fluorescence in situ hybridization (QM FISH), and to figure out whether there is putative ancestral relationship among different subclones. METHODS: Bacterial artificial chromosomes (BAC) clones that contain the targeted genes including AML1, ETO, WT1, p27 and c-kit were searched in the data base UCSC Genome Bioinformatics. Multicolor FISH probes were prepared by linking fluorescein labeled dUTP or dCTP to targeted genes by nick translation. Bone marrow mononuclear cells from t (8;21) AML patients are dropped on to the wet surface of glass slides after hypotonic treatment and fixation. After hybridization, the fluorescence signals were captured by Zeiss fluorescence microscope. The copy number of AML1, ETO, WT1, p27, c- kit and the AML1-ETO fusion gene in AML1-ETO positive cells was counted. The cells with same signals were defined as a subclone. Various subclones were recorded and their proportions were calculated, and their evolutionary relationship was deduced. The subclones in matched primary and relapsed samples were compared, the evolution of dominant clones were figured out and the genomic abnormality that is associated with relapse and drug resistance were speculated. RESULTS: In this study, 36 primary AML with t(8;21) cases and 1 relapsed case paired with the primary case were detected. In these 36 primary cases, 4 cases (11.1%) acquired additional AML1-ETO fusion signal, 3(8.3%) had additional AML1 signal, 4(11.1%) had additional ETO signal, 20(55.6%) had additional WT1 signal, 15(41.7%) had additional p27 signal and 14(38.9%) had additional c-kit signal. In addition, 10(27.8%) displayed AML1 signal deletion, and such an aberration represents statistic significance in male patients. It seems that male patients usually accompany AML1 signal deletion. Of 36 cases, 28(77.8 %) harbored at least 2 subclones (ranged from 2 to 10). According to the genetic signature of subclones, we can assemble a putative ancestral tree, and the genetic architecture is linear or branching. In particular, the clonal architecture of the relapsed sample exhibited significant clonal evolution compared to its paired sample at diagnosis, including proportion changes in dominant clone, subclone disappearance and appearance of new dominant clones. CONCLUSION: Genomic abnormality is very diverse in t(8;21) AML. Subclones have linear or complex branching evolutionary histories, and clonal architecture is dynamic. PMID- 24171958 TI - [Clinical significance of mast cells and IL-9 in B-NHL]. AB - OBJECTIVE: To investigate the role of mast cells and interleukin-9 (IL-9) in B cell non-Hodgkin lymphoma (B-NHL) development and its clinical significance. METHODS: The expression level of CD117 in tumor tissues of 32 B-NHL patients was determined by Western blot. The infiltration of CD117+ mast cells (MCs) in human B-NHL tumor tissues was observed by immunohistochemistry staining. To evaluate the correlations between the data from CD117+ MCs and biological markers of human B-NHL, a Spearman correlation coefficient (rs) was calculated. IL-9 levels in sera of B-NHL patients were measured by ELISA. Effects of IL-9 on expressions of functional genes of mouse bone marrow-derived mast cells (BMMCs) were detected by real-time quantitative RT-PCR. RESULTS: The expression of CD117 was upregulated significantly in human B-cell NHL involved tissues when compared with that of controls (0.0551+/-0.0064 vs 0.0192+/-0.0072, P<0.01). Infiltration of more CD117+ MCs was found in tissues from B-cell NHL subjects compared with that of controls. IL-9 level in serum samples from patients with B-cell NHL was higher than that from healthy controls. Addition of rIL-9 to the culture gave rise to increase in the purity of mouse BMMCs in the first three weeks. In vitro culture experiments showed that the addition of IL-9 could induce the differentiation of mouse BMMC and the expressions of MC-related genes, including CD117, Fcer1alpha, Mcpt1 and Mcpt5. CONCLUSION: Our study showed that IL-9 promoted immune response mediated by MCs, and probably played important roles in B-NHL growth. Pharmacological or targeted inhibition of mast cells or IL-9 activity may provide new strategy for B-cell NHL therapy. PMID- 24171959 TI - [Clinical study of COAD-B regimen in treatment of patients with relapsed/refractory non-Hodgkin lymphoma]. AB - OBJECTIVE: To investigate the efficacy, adverse events and long-term survival of cyclophosphamide, vindesine, cytarabine, dexamethasone and bleomycin (COAD-B) regimen for relapsed and refractory non-Hodgkin lymphoma (NHL). METHODS: Eighty six patients diagnosed with relapsed or refractory NHL were included in our study from January 2007 to January 2013. The chemotherapy regimen was COAD-B, the therapeutic efficacy was evaluated every 2 courses. Once the stable disease (SD) or progress of the disease (PD) achieved, the patients would switch to other second-line regimens. RESULTS: The overall response rate (ORR) was 67.4%, median remission duration was 13 months (3-51 months); 1-,2- and 4-year overall survival (OS) rates were 75.4%, 56.8% and 40.0%, respectively; 1-, 2- and 4-year progression-free survival (PFS) rates were 50.3%, 39.4% and 27.5%, respectively. The main adverse reaction of patients was myelosuppression. The response to chemotherapy and long- term survival of the relapsed patients were significantly better than that of the refractory ones, and the difference had statistical significance. CONCLUSION: COAD-B could be the salvage regimen for relapsed and refractory NHL. PMID- 24171960 TI - [The prognostic impact of 1p21 deletion on newly diagnosed multiple myeloma patients receiving thalidomide-based first-line treatment]. AB - OBJECTIVE: To explore the deletion rate, clinical correlation and prognostic significance of 1p21 deletion, a novel genetic prognostic index, in patients with multiple myeloma (MM). METHODS: The interphase fluorescence in situ hybridization (I-FISH) was performed on purified CD138+ plasma cells from 78 newly diagnosed patients from Sep 2007 to Sep 2012 receiving thalidomide-based chemotherapy by using BAC probe covered 1p21.2 region that contains the human cell division cycle 14A (HCDC14A) gene. Deletion rate, the cell percentage of deletion, clinical relevance and prognostic significance were analyzed in myeloma patients. RESULTS: Among 78 patients, there were 51 males and 27 females, the median age was 59(42 81). The deletion rate of 1p21.2 was 23.1%. Some patients had amplification (amp) of 1p with amp rate of 5.1% in 1p21.2, the amp rate was significantly lower than the deletion rate (P=0.001). 1p21.2 deletion was positively correlated with renal lesion (Cr>=177 MUmol/L), high percentage of plasma cells in bone marrow, high LDH (>=220 U/L) and high beta2-MG (P=0.014, 0.000, 0.010 and 0.022, respectively). With a median follow-up time of 15.0(1.0-53.5) months, the estimated median progressionfree survival (PFS) and overall survival (OS) time for patients with 1p21 deletion was (12.0+/-2.7) and (14.0+/-3.4) months, however those were (30.0+/-8.0) and (38.5+/-1.8) months in patients without 1p21 deletion, respectively (P=0.000). On multivariate analysis, which included complex karyotype, LDH>=220 U/L, renal lesion and del(17p13), 1p21 deletion remained as an independent risk factor for PFS (HR: 3.312, 95% CI: 1.095-10.017, P=0.034) and OS (HR: 4.961, 95% CI: 1.487-16.552, P=0.009). CONCLUSION: 1p21 deletion is an important genetic prognosis indicator in multiple myeloma patients. PMID- 24171961 TI - [Efficacy and safety study of subcutaneous injection of bortezomib in the treatment of de novo patients with multiple myeloma]. AB - OBJECTIVE: To explore the efficacy and safety of subcutaneous injection of bortezomib in the treatment of de novo multiple myeloma (MM) patients. METHODS: A total of 36 MM patients treated with bortezomib, adriamycin and dexamethasone (PAD) from January 2012 to April 2013 were analyzed. Among them, 18 received improved PAD (improved PAD group) with the subcutaneous injection of bortezomib, another 18 received conventional PAD (PAD group). The efficacy and safety of two groups were analyzed. RESULTS: Except 4 cases can not be assessed, 32 patients were evaluated. Of 32 cases, 19(59.4%) achieved complete remission (CR) or very good partial remission (VGPR) after induction therapy, which were 61.1% and 57.1% for PAD group and improved PAD group, respectively (P=1.000). No significant difference between the time to achieve maximum effectiveness in two groups was detected. In the PAD group, one patient (5.6%) died of serious lung infection and eight (44.4%) experienced grade 3 or higher adverse events, while only one (5.6%) discontinued treatment in improved PAD group due to similar toxicity. Compared to PAD group, grade 3 or worse adverse events was significantly reduced in improved PAD group, the most common symptoms were leucopenia (33.3% vs 61.1%, P=0.086), thrombocytopenia (50.0% vs 61.1%), anaemia (27.8% vs 16.7%), infection (16.7% vs 50.0%, P=0.075), diarrhea (5.6% vs 33.3%, P=0.088), peripheral neuropathy(0 vs 27.8%, P=0.045). CONCLUSION: The improved PAD regimen by changing bortezomib from intravenous administration to subcutaneous injection significantly reduced adverse events, improved the safety of clinical application of bortezomib without affecting curative effect, and had great progress. PMID- 24171962 TI - [Relationship between polymorphisms of tumor necrosis factor alpha gene and primary myelodysplastic syndromes]. AB - OBJECTIVE: To investigate the association of single nucleus polymorphisms(SNP)of tumor necrosis factor alpha (TNF-alpha) gene (-308 G>A and -238 G>A genotypes) with susceptibility to primary myelodysplastic syndromes (MDS). METHODS: Two SNPs (TNF-alpha-308 G>A,TNF-alpha-238 G>A) of TNF-alpha gene were detected by Taqman probes in 341 MDS patients and 365 unrelated-healthy controls. RESULTS: Compared to healthy controls, the frequency of TNF-alpha-308 AA+AG genotype and A allele increased (18% vs 10%, P=0.015, 9% vs 5%, P=0.021, respectively) in refractory cytopenia with multilineage dysplasia (RCMD) patients. There was no correlation of TNF-alpha-308 G>A genotype and allele frequency between MDS and controls. No difference in the genotype and allele frequency of TNF-alpha-238 G>A were found between controls and MDS or the subtypes of MDS (P>0.05). We did not find any linkage between plasma level of TNF-alpha and TNF-alpha-308 G>A or TNF-alpha-238 G>A genotype. Statistic differences were observed between platelet count[58(1 611)*109/L vs 90(7-352)*109/L]and bone marrow blasts in MDS patients carrying TNF alpha-308 G>A GG and AA+AG genotype (P=0.024, 0.019, respectively). CONCLUSION: TNF-alpha-308 G>A polymorphism was correlated with susceptibility to MDS-RCMD. PMID- 24171963 TI - [Study on abnormal iron metabolism and iron overload in patients with aplastic anemia]. AB - OBJECTIVE: To investigate the abnormalities of iron metabolism, the prevalence and risk factors of iron overload and clinical characteristics of patients with aplastic anemia (AA). METHODS: A cross-sectional study was conducted on 520 newly diagnosed AA patients. RESULTS: Iron overload was observed in 66(13%) of 520 AA patients,in which a higher prevalence of iron overload was seen not only in patients with infections(19/86, 22%)than those without infections (47/434, 11%, P<0.01), but also in patients with hepatitis associated AA(HAAA) (6/22, 19%) than the idiopathic cases (60/488, 12%, P>0.05). Excluded the patients with infections and/or HAAA, 43 of 405(11%)cases had iron overload, including 14 of 248(6%) cases without history of blood transfusion and 29 of 157 patients (18%, P<0.01) with transfusion. In univariate analysis, higher levels of serum ferritin (SF), serum iron (SI) and transferrin saturation (TS) were mainly observed in adult male patients with severe AA (SAA) and significantly upward with increasing blood transfusion (P<0.01). No differences of soluble transferrin receptor (sTfR) were observed between adults and children, males and females, hepatitis and idiopathic AA. However, patients with infections had significantly lower level of sTfR (0.50 mg/L) than cases without infections (0.79 mg/L, P<0.01). The level of sTfR in SAA patients (0.70 mg/L) was only half of that in non-SAA (NSAA) (1.36 mg/L, P<0.01). Patients with increasing blood transfusion had significantly downward levels of sTfR (P<0.01). In multivariate analysis, more than 8 U blood transfusion (OR=10.52, P<0.01), adults (OR=3.48, P<0.01), males (OR=3.32, P<0.01) and infections (OR=2.09, P<0.01) were independent risk factors. CONCLUSION: AA patients had higher iron burden and were high-risk populations occurring iron overload. The iron overload occurred in 18% of patients with blood transfusion and in 6% of patients without transfusion. PMID- 24171964 TI - [A clinical comparative study on treatment of severe newly diagnosed immune thrombocytopenia by recombinant human thrombopoietin combined with glucocorticoid]. AB - OBJECTIVE: To evaluate the efficacy and safety of recombinant human thrombopoietin (rhTPO) combined with glucocorticoid in treatment of severe newly diagnosed primary immune thrombocytopenia (ITP). METHODS: From June 2009 to December 2012, 24 male patients and 38 female patients with the diagnosis of severe primary ITP in our hospital were randomized into trial group (31 cases) or control group (31 cases), the median age was 50 years (range: 21-84 years). Trial group was treated with rhTPO combined with glucocorticoid, and control group was treated with glucocorticoid only. RESULTS: At the day 3, 7 and 14 from the beginning of treatment, the average platelet count (APC) in trial group[(35.5+/ 24.9)*109/L, (135.2+/-94.9)*109/L and (192.0+/-109.1)*109/L]were significantly higher than that in control group[(24.5+/-15.6)*109/L, (78.2+/-121.9)*109/L and (95.8+/-60.5)*109/L, P=0.022, 0.009 and 0.001, respectively]. There was no significant difference in APC between the two groups at day 28 and 90 after treatment[(147.8+/-59.1)*109/L vs (105.1+/-56.9)*109/L, P=0.243; (137.4+/ 52.3)*109/L vs (104.3+/-59.8)*109/L, P=0.568, respectively]. At the day 7, 14 and 28, the complete response rates in trial group were 61.3%, 87.1% and 80.6%, which were also significantly higher than that in control group (16.1%, 29.0% and 48.3%, P=0.000, 0.000 and 0.004, respectively). The median time to response in trial group was 3 days while in the control group was 5 days; the median duration of complete response in trial group was 76 days while in the control group was 54 days. In trial group, there were 4 cases treated with platelet transfusion, while in control group there were 11 cases, respectively. CONCLUSION: For patients with severe primary ITP, rhTPO combined with glucocorticoid could rapidly increase the platelet count, significantly improve the complete response rate and prolonged the effect with a low incidence of tolerable adverse events compared to single use of glucocorticoid. rhTPO combined with glucocorticoid could be a new therapeutic choice to those patients. PMID- 24171965 TI - [Differentiation potential of CD41+ cells derived from the mouse aorta-gonad mesonephros region, yolk sac and embryonic circulating blood]. AB - OBJECTIVE: To compare the differentiation ability difference of hematopoietic, mesenchymal and endothelial potential between CD41+ cells derived from the mouse aorta-gonadmesonephros (AGM) region, yolk sac (YS) and embryonic circulating blood (CB). METHODS: CD41+ cells were sorted from AGM, YS and CB. The CD45 and c kit expression were studied in CD41+ cells by flow cytometry. IL-3 and bone morphogenetic protein 4 (BMP-4) treatment together with semi solid culture were used to assess hematopoietic potential difference of CD41+ cells. Immunofluorescence staining of alpha-SMA was used to assess mesenchymal potential difference. The endothelial cell induction system was used to assess endothelial potential difference. RESULTS: The proportions of CD45+ cells in CD41+ population were 51.9% (AGM), 45.8% (YS) and 22.2% (CB), respectively, while those of c-kit+ cells were 40.0% (AGM), 39.6% (YS) and 36.2% (CB), respectively. After stimulated by IL-3 factor, the number of total colonies increased in all three groups derived CD41+ cells compared to that of unstimulated group[(14.1+/-1.9) vs (1.2+/ 0.2), (32.4+/-1.1) vs (18.4+/-2.2) and (41.8+/-0.9) vs (10.4+/-1.8)], (P<0.01). After stimulated by BMP-4 factor, compared to unstimulated group, CFU-Mix colony number in CD41+ cells from AGM region and YS were significantly decreased[(0.5+/ 0.6) vs (3.2+/-0.8), (1.3+/-0.7) vs (7.4+/-1.7)](P<0.01), but there was no difference in CB group[(2.5+/-0.5) vs (3.9+/-1.5)](P>0.01). The mesenchymal marker alpha-SMA was highly expressed in CD41+ cells from AGM region and YS, but lowly expressed in CD41+ cells from CB. CONCLUSION: There are some differences between CD41+ cells in AGM region, YS and CB on hematopoietic cell surface marker expression, hematopoietic colony formation with IL-3 and BMP-4 stimulation. PMID- 24171966 TI - [Intracranial sarcoma as the first symptom of myeloid sarcoma: a case report and literature review]. PMID- 24171967 TI - [Pulmonary lasmacytoma as the first manifestation of IgM multiple myeloma: a case report and literature review]. PMID- 24171968 TI - [Granulomatous pneumonitis after allogenetic bone marrow transplantation: a case report]. PMID- 24171969 TI - [A comparative study of fludarabine-based versus CHOP-like regimens in untreated primary indolent lymphoma]. PMID- 24171970 TI - [Diagnosis value of gamma-IFN on the specific pathogen infection associated hemophagocytic lymphohistocytosis]. PMID- 24171971 TI - [Expression and significance of MUM1/IRF4 in hematological malignancies]. PMID- 24171972 TI - [Thoughts on differential diagnosis between aplastic anemia and hypoplastic myelodysplastic syndrome]. PMID- 24171973 TI - [Microtransplantation for treatment of Burkitt lymphoma]. PMID- 24171974 TI - Rheumatoid arthritis following PEG-interferon-alfa-2a plus ribavirin treatment for chronic hepatitis C: a case report and review of the literature. AB - BACKGROUND: The combination of Pegylated Interferon-alpha (PEG-IFN-alpha) and ribavirin is the current standard of care for the treatment of HCV infection. Unfortunately, IFN-alpha may lead to the induction or exacerbation of autoimmune diseases, such as psoriasis, thyroiditis, systemic lupus erythematosus and, rarely, rheumatoid arthritis (RA). CASE PRESENTATION: We report the case of a man affected with chronic hepatitis C (CHC) due to HCV genotype 3a infection, who developed RA after a complete course of PEG-IFN-alpha and ribavirin. Nine weeks after cessation of antiviral treatment, the patient developed symmetrical polyarthritis, with pain and edema in the wrists, knees, shoulders and metacarpophalangeal joints; magnetic resonance imaging detected initial bone erosions with juxta-articular osteopenia in wrist, knee and hand joints. Anti cyclic citrullinated peptide (anti-CCP) antibodies were positive. CONCLUSIONS: Autoimmune diseases, including RA, may occur when treating chronic hepatitis C with PEG-IFN-alpha and ribavirin; therefore, a close surveillance for the occurrence of autoimmune phenomena should be suggested in the setting of HCV management. PMID- 24171975 TI - In vitro evaluation of the minimum bactericidal concentrations of different root end filling materials. AB - AIM: The aim of this study was to evaluate the minimum bactericidal concentrations (MBC) of root-end filling materials ProRoot MTA, MTA Angelus and IRM. MATERIALS AND METHODS: Macrodilution broth method was used. Microorganisms used were: Staphylococcus aureus (ATCC 29213), Enterococcus faecalis (ATCC 29212) and Streptococcus mutans. Serial two-fold dilutions of root-end filling samples were prepared in macrodilution tubes with concentrations ranging from 1/2 to 1/512. The samples dilutions were incubated for 24 hours. After incubation, 0.1 ml of diluted culture was inoculated onto the surface of supplemented sheep blood agar (Merck, Germany) and all plates were incubated at 37 degrees C in aerobic condition for 24 hours. The MBC was defined as the lowest concentration of root end filling samples where no growth was recorded. RESULTS: MBC of both mineral trioxide aggregate (MTA) products against S. aureus were recorded as 15.62 mg/ml and for IRM 31.25 mg/ml MBC for both MTA groups against E. faecalis were recorded as 31.25 mg/ml and for IRM 62.5 mg/ml. MBC of all root-end filling samples against S. mutans were recorded as 62.5 mg/ml. CONCLUSION: All tested root-end filling materials showed acceptable MBC against S. aureus and E. faecalis. CLINICAL SIGNIFICANCE: All tested materials can be used safely for filling of a root-end cavity. PMID- 24171976 TI - Effect of trichloroacetic acid hydrogel on self-etch adhesive bond strength to dental tissues. AB - INTRODUCTION: Trichloroacetic acid (TCA) is a soft tissue cauterizing agent applied to gingival margins prior to cervical tooth-colored restorations. The present in vitro study evaluated the effects of two different concentrations of TCA hydrogel as a hemostatic/preconditioning agent on the shear bond strength (SBS) of a self-etch adhesive to tooth structures. MATERIALS AND METHODS: Thirty six flat enamel and 36 flat dentin surfaces were prepared using human molars; each group was subdivided into three subgroups (n = 12). The groups were made ready as follows: In groups 1 (E1 and D1), the enamel (E) and dentin (D) surfaces were designated as control groups and remained intact. In groups 2 (E2 and D2), 35% TCA gel was applied to enamel and dentin surfaces for 30 seconds. In groups 3 (E3 and D3), 50% TCA gel was applied to enamel and dentin surfaces for 30 seconds. Clearfil SE Bond and Z100 composite resin were applied to the surfaces according to manufacturers' instructions. After 24 hours of incubation and thermocycling, the composite cylinders underwent an SBS test in a DARTEC test machine. Data were analyzed using the ANOVA and Scheffe's test (alpha=0.05). RESULTS: The mean SBS+/-SD in the study groups were 34.73+/-5.66, 35.32+/-7.3, 23.75+/-9.67, 20.94+/-9.84, 19.32+/-6.20, 23.50+/-6.63 MPa in the E1, E2, E3, D1, D2 and D3 groups, respectively. ANOVA revealed significant differences between the SBS values of enamel groups (p=0.001). There were no significant differences between the dentin groups (p=0.425). CONCLUSION: Application of 35 and 50% concentrations of TCA to dentin had no detrimental effect on the bond produced by two-step self-etch adhesive under study; however, application of only 35% TCA to enamel did not result in a detrimental effect on the same adhesive. PMID- 24171977 TI - Comparison of antibacterial activity of glass-ionomer cement and amalgam in class two restorations by Streptococcus mutans count analysis at fixed intervals: an in vivo study. AB - AIM: The purpose of the present study was to determine the influence of glass ionomer cement and amalgam restoration on the level of Streptococcus mutans in the interproximal plaque at periodic intervals and also to compare these values. MATERIALS AND METHODS: Seventeen adult patients having two proximal carious lesions on any quadrant of the jaw (either opposing or contralateral) were selected for this study. Carious lesions were diagnosed clinically and from bitewing radiographs. Of the two carious lesions, one was restored with glass ionomer cermet cement and another with amalgam. Plaque samples were collected from interproximal areas before and at 1 month and 3 months post-treatment in a test tube containing 5 ml of modified Stuart's liquid transport fluid. Identification of organisms in the colony was done after Gram staining. RESULTS: Comparison of values before restoration and after restoration at 1 month interval showed a statistically significant decrease (p<0.001). Similarly, comparison of values before and after restorations at 3 months also showed statistically significant decrease (p<0.02). But comparison of restorations of 1 and 3 months intervals showed no statistical significant difference (p>0.05). CONCLUSION: Glass ionomer restorations have definite advantage over the amalgam, as the tunnel preparation is more conservative and fluoride release from the glass ionomer inhibits the growth of S. mutans in the plaque. CLINICAL SIGNIFICANCE: Glass ionomer cement should be preferred over amalgam in conservatively prepared restorations as it reduces the microbial activities due to fluoride release. PMID- 24171978 TI - Potential effect of neutrophil functional disorders on pathogenesis of aggressive periodontitis. AB - INTRODUCTION: Leukocytes play a key role in maintaining the balance between an effective host defence response to microorganisms and periodontal tissue destruction. Neutrophil dysfunction has been associated with increased susceptibility to periodontal diseases. We undertook this study to determine to what extent neutrophil dysfunction constitutes to the pathogenesis of aggressive periodontitis (AgP) in tropical country like ours. MATERIALS AND METHODS: Age- and sex-matched groups consisting of 20 subjects each of generalized aggressive periodontitis (GAP)-cases and nonperiodontitis (NP)-controls. diabetes mellitus, HIV infection, prolonged antibiotic use and smoking were excluded. Each neutrophil function was assessed using the chemotactic assay using case in, phagocytosis assay, candidacidal assay (for intracellular killing) and NBT assay (for respiratory burst failure). STATISTICAL ANALYSIS USED: Student's t-test, Fisher's exact test and Chi-square test. RESULTS: In the study 17 out of 20 subjects (85%) had at least one abnormal neutrophil assay either hypofunctional or hyperfunctional of which 16 (80%) had hypofunctional assays and 8 (40%) had hyperfunctional assays. Defective phagocytosis was the commonest (50%) followed by chemotactic defect (45%), defective respiratory burst (40%) and defective intracellular killing (30%). Mean of chemotaxis assay was significantly less in AgP when compared to controls (103 vs 129 um, p=0.002), similarly for phagocytic defect (3.45 vs 4.65, p<=0.001) and with candidacidal assay (26.80 vs 37.35, p<0.001). CONCLUSION: The prevalence of neutrophil dysfunction, predominantly hypofunctional, was significantly very high in GAP patients with few even having hyperactive respiratory burst function. Multiple level neutrophil defects could account for the aggressive nature of AgP even in apparently healthy subjects. PMID- 24171979 TI - A double blind study on the efficacy of local application of hemocoagulase solution in wound healing. AB - AIM: The present double blind study has been designed to evaluate the efficacy of local application of hemocoagulase solution as compared to a placebo in wound healing following dental extraction. MATERIALS AND METHODS: A total of 20 patients who required dental extraction for orthodontic intervention were included. The hemocoagulase solution and a placebo were locally applied to the extraction sockets and the efficacy of the solution in terms of bleeding control, anti-inflammatory responses, its antiseptic properties and efficacy in wound healing were evaluated. RESULTS: The mean time required to achieve hemostasis was found to be 1.37 minutes in side A (test) and 2.33 minutes in side B (control) indicating that side A achieved faster hemostasis when compared to side B. At the 6th hour postoperatively, bleeding was not evident on either sides, and the amount of pain in side A was found to be less compared to side B. The number of RBCs, polymorphs, chronic inflammatory cells were not different in both the groups, whereas at 3rd postoperative day epithelial cells were greater in side A (test) compared to side B (control). Biopsy reports on the 12th postoperative day indicated that the number of fibroblasts, epithelial cells, collagen count was found to be greater in side A (test) compared to side B (control). CONCLUSION: The topical hemocoagulase solution may be advocated in the field of oral and maxillofacial surgery, as a hemostatic agent and promoter of wound healing. However, further studies, with large number of cases and different clinical situations should be considered to authenticate the efficacy of this hemocoagulase solution in the practice of oral and maxillofacial surgery. CLINICAL SIGNIFICANCE: Wound healing plays an important role in the success of any surgical procedure, such as extractions, and the hemocoagulase system may act as a hemostatic agent and a promoter of wound healing. PMID- 24171980 TI - Effect of submucosal injection of dexamethasone on postoperative discomfort after third molar surgery: a prospective study. AB - AIM: To evaluate the relative ability of 4 mg dose of intraoperative dexamethasone, administered submucosally, to reduce the postoperative discomfort after third molar surgery. MATERIALS AND METHODS: A total of 100 patients requiring surgical removal of a single mandibular third molar were included. The experimental group (50) received dexamethasone 4 mg as submucosal injection and control group (50) received no drugs. The maximum interincisal distance and facial contours were measured at baseline and at postsurgery days 2 and 7. The measurement of pain was done using visual analog scale (VAS). RESULTS: None of the patients developed wound infection or any serious postoperative complications. Postoperative edema tended to be less severe on the second postoperative day in the experimental group and the result was statistically significant. There were no significant differences in the reduction of pain and trismus between the two groups studied. CONCLUSION: Submucosal administration of dexamethasone sodium phosphate (4 mg) results in reduction of postoperative edema, comparable with or greater than other routes of administration. Presumably, a higher effective drug concentration at the site of injury without loss due to distribution to other compartments may be achieved, and the submucosal route is convenient for both the surgeon and the patient. CLINICAL SIGNIFICANCE: Submucosal route of administration of dexamethasone (4 mg) is effective in reducing postoperative discomfort after third molar surgeries. PMID- 24171981 TI - Maxillary sinus functions and complications with lateral window and osteotome sinus floor elevation procedures followed by dental implants placement: a retrospective study in 60 patients. AB - AIM: The aim of the study was to evaluate retrospectively maxillary sinus functions and complications by using generally accepted diagnostic criteria with lateral window and osteotome sinus floor elevation (OSFE) procedures followed by dental implants placement. MATERIALS AND METHODS: A group of 60 patients in whom a SFE with the two procedures (lateral window and OSFE) followed by dental implants placement had been performed were evaluated retrospectively for sinus functions and complications from the time of procedure up to 24 months using a questionnaire, conventional clinical and radiographic examination. RESULTS: Number of patients suffered dizziness accompanied by nausea immediately after OSFE was more than the lateral window procedure and the symptoms disappeared within 2 to 4 weeks. Maxillary sinus membrane perforations occurred and small for 4 out of 79 procedures, two cases for OSFE and two for lateral window procedure had been repaired. No more complications had been detected for all the patients up to 24 months. CONCLUSION: Based on the results of this study, SFE with lateral window and osteotome procedures followed by dental implants placement did not interfere with maxillary sinus function and no obvious complications had been detected up to 24 months. CLINICAL SIGNIFICANCE: The clinician performs SFE with either lateral window or osteotome procedures needs to understand the difficulties and morbidity arising in the event of complications and must be able to correctly judge the individual risk and the presence of modifying factors that may cause these complications. PMID- 24171982 TI - Flare-up rate in molars with periapical radiolucency in one-visit vs two-visit endodontic treatment. AB - PURPOSE: The objective of this study was to compare postobturation flare-ups following single and two-visit endodontic treatment of molar teeth with periapical radiolucency. MATERIALS AND METHODS: A total of 100 patients with asymptomatic molar teeth with periapical radiolucency were selected. They were randomly allocated into two groups. Fifty patients received complete endodontic treatment in one-visit. Fifty patients received treatment by debridement and instrumentation at the first visit followed by obturation at the second visit. RESULTS: 10% of patients had flare-ups in the single visit group and 8% of patients had flare-ups in the two-visit group. Number of visits did not affect the success of endodontic treatment (p>0.05). Age, gender and tooth type had no effects on the occurrence of flare-ups regardless the number of visits (p>0.05). CONCLUSION: One-visit endodontic treatment was as successful as two-visit endodontic treatment as evaluated by rate of flareups in asymptomatic molar teeth with periapical radiolucency. PMID- 24171983 TI - Comparison of rate of canine retraction into recent extraction site with and without gingival fiberotomy: a clinical study. AB - AIM: Retraction of maxillary canines after first premolar extractions is a very common orthodontic task in cases of crowding or for the correction of large overjet. Many studies have been done to increase the rate of retraction. The aim is to compare the rate of canine retraction into recent extraction site with and without circumferential supracrestal fiberotomy. MATERIALS AND METHODS: The rate of movement of the canines into the recent extraction site of the first premolar with or without circumferential supracrestal fiberotomy was measured in 14 patients aged 13 to 22 years. The study was done on 9 maxillary and 5 mandibular arches. The appliance used in the present study was the preadjusted edgewise (0.022 inch Roth prescription) and retraction performed by frictionless mechanics using Composite T Loop. The distalization of canines was measured at regular intervals (T1, T2, T3 and T4). Recordings of the positions of the canines at the beginning and at different intervals were made from dental casts. RESULTS: The mean difference between the two sides for the total time span T1-T4, for maxillary arch was 0.36 mm and for mandibular arch was 0.60 mm respectively. CONCLUSION: There can be various factors that affect the rate of tooth movement. Factors like bone density, bone metabolism, and turnover in the periodontal ligament, amount of force applied may be responsible for the variation. CLINICAL SIGNIFICANCE: No clinically significant increased rate of retraction of cuspids in the recent extraction site with fiberotomy was found in comparison to the retraction in recent extraction site without fiberotomy. PMID- 24171984 TI - A clinical study to correlate maxillary anterior natural teeth with that of the commercially available acrylic and porcelain shade guides. AB - The success of the dental treatment as perceived by our patients is often preferentially evaluated on the appearance of the restoration. Usually visual determination is unreliable and inconsistent, complicated by the inability of the shade guide to cover the entire dental color range and also there is lack of logical order of arrangement of the tabs. Hence a clinical study is planned to perform visual shade selection in standardized conditions to correlate the shades of maxillary anterior natural teeth in adult subjects of Davengere district origin to one acrylic and three porcelain shade guides commercially available in India. PMID- 24171985 TI - Clinical and radiographic evaluation of regenerative potential of GTR membrane (Biomesh(r)) along with alloplastic bone graft (Biograft(r)) in the treatment of periodontal intrabony defects. AB - BACKGROUND AND OBJECTIVES: The primary goal of periodontal therapy is to restore the tooth supporting tissues lost due to periodontal disease. The aim of the present study was to compare the efficacy of combination of GTR membrane and alloplastc bone graft with open flap debridement (OFD) in treatment of periodontal intrabony defects. METHODS: Twenty paired intrabony defects were surgically treated using split mouth design. The defects were randomly assigned to treatment with OFD, GTR membrane+bone graft (test) or OFD alone (control). The clinical efficacy of two treatment modalities was evaluated at 6 months postoperatively by clinical, radiographical parameters. The measurements included probing pocket depth (PD), clinical attachment level (CAL), gingival recession (GR), bone fill (BF), bone density (BD). RESULTS: The mean reduction in PD at 0 to 6 months was 3.20+/-0.82 mm and CAL gain of 3.10+/-1.51 mm occurred in the GTR membrane+bone graft (test) group; corresponding values for OFD (control) were 2.10+/-0.63 mm and 1.90+/-0.57 mm. Similar pattern of improvement was observed when radiographically postoperative evaluation was made. All improvement in different parameters was statistically significant (p<0.01). CONCLUSION: Treatment with a combination of collagen membrane and bone graft led to a significantly more favorable clinical outcome in intrabony defects as compared to open flap debridement alone. PMID- 24171986 TI - To evaluate and compare the efficacy, cleaning ability of hand and two rotary systems in root canal retreatment. AB - AIM: To evaluate and compare the efficacy, cleaning ability of hand and two rotary systems in root canal retreatment. METHODOLOGY: Sixty extracted premolars were retreated with following systems: Group -ProTaper Universal retreatment files, Group 2-ProFile system, Group 3-H-file. Specimens were split longitudinally and amount of remaining gutta-percha on the canal walls was assessed using direct visual scoring with the aid of stereomicroscope. Results were statistically analyzed using ANOVA test. RESULTS: Completely clean root canal walls were not achieved with any of the techniques investigated. However, all three systems proved to be effective for gutta-percha removal. Significant difference was found between ProTaper universal retreatment file and H-file, and also between ProFile and H-file. CONCLUSION: Under the conditions of the present study, ProTaper Universal retreatment files left significantly less guttapercha and sealer than ProFile and H-file. CLINICAL SIGNIFICANCE: Rotary systems in combination with gutta-percha solvents can perform superiorly as compared to the time tested traditional hand instrumentation in root canal retreatment. PMID- 24171987 TI - Surgical elevation of bilateral maxillary sinus floor with a combination of autogenous bone and lyophilized bovine bone. AB - AIM: Realize the surgery of sinus lifting floor to allow the installation of osseointegrated implants for oral rehabilitation, with the combination of different biomaterials, autogenous bone and lyophilized bovine bone. BACKGROUND: Oral rehabilitation using the installation of osseointegrated implants is an alternative surgical approach that results in the satisfactory form, function and esthetics of the dental units. CASE REPORT: After clinical, dental and laboratory assessment, a 47-year-old female patient underwent full maxillary oral rehabilitation involving the installation of osseointegrated implants to allow her to meet the physiological demands of occlusion and mastication. It was found that the patient had fully pneumatized maxillary sinuses with insufficient height to anchor implants, with a loss of the vertical dimension of the occlusal and masticatory functions due to general dental loss, compounded by the use of ill fitting dentures; hence, the choice was made to take autogenous bone from the patient's chin area and supplement it with lyophilized bovine bone as collateral for larger areas to be grafted. It was also decided to avulse the remaining tooth units due to their impairment by periodontal disease. CONCLUSION: Bone grafts do not constitute suitable alternatives in the cosmetic and functional rehabilitation of the maxilla in patients requiring bilateral sinus elevation. The chin region provides bone tissue that, when complemented by lyophilized bovine bone grafts, ensures greater volume and less invasive surgery. In the case described here, a height gain of approximately 550% was obtained, making it possible to anchor seven implants. CLINICAL SIGNIFICANCE: In this study, the surgical procedures used for grafting a combination of autogenous and lyophilized bovine bone, aimed to elevate the maxillary sinus floor to allow the installation of osseointegrated implants for oral rehabilitation. PMID- 24171988 TI - Shaping potential of manual NiTi K-File and rotary ProTaper and analyzing the final outcome of shaped canals using CT. AB - AIM: To assess and compare the shaping potential of manual NiTi K-files and Rotary ProTaper instruments in narrow canals using CT. OBJECTIVE: To assess the shaping potential of manual NiTi K-files and Rotary ProTaper and analyzing the final outcome of shaped canals using CT and determining different variables, like * Working time * Change in volume * Change in cross-sectional area. MATERIALS AND METHODS: From a pool of fifty freshly extracted permanent maxillary molars (1st and 2nd), 30 were selected with curvatures (20 to 40 degrees ) (Schneider 1971). Tissue fragments and calcified debries were removed from the teeth by scaling. The teeth were then stored in normal saline until used. All the mesiobuccal canals were scanned by CT to obtain preinstrumented images. Teeth were scaled and stored in normal saline. This study was divided in two groups with 15 samples each. GROUP I (PROTAPER ROTARY): Canals were instrumented with Protaper Rotary instruments using crown down technique according to manufacturer's instructions. GROUP II (NITI K-FILE): Were instrumented by NiTi K-files using step back technique with a quarter turn/pull motion. EVALUATIONS OF WORKING TIME: Comparative evaluations of working time was done for both the experimental groups. CT ANALYSIS AND MEASUREMENTS: The samples were analyzed and evaluated for: * Postinstrumentation change in volume. * Postinstrumentation change in cross-sections area. RESULT: From the observations and statistical analysis carried out in this study, it was found that: There was a statistically significant difference between all the parameters judged for the present study that is: 1. Instrumentation with ProTaper Rotary system took significantly less time than instrumentation with manual NiTi K-file. 2. Change in the canal volume following instrumentation with ProTaper Rotary was significantly greater than that produced by manual NITi K-file. 3. a. Change in cross-section area at 2 and 3 mm from the apex was significantly greater with manual NiTi K-file as compared to ProTaper Rotary. b. Change in cross sections at 4.5, 6 and 7.5 mm from the apex with ProTaper Rotary was significantly greater than that produced by manual NITi K-file. CONCLUSION: This clearly establishes that there is a drastic difference in the shaping ability of manual and Rotary NiTi instruments used with step back and crown down technique respectively with the rotary instrumentation being faster and producing greater changes in the canal anatomy. PMID- 24171989 TI - Antimicrobial efficacy of octenidine hydrochloride, MTAD and chlorhexidine gluconate mixed with calcium hydroxide. AB - OBJECTIVE: The aim of this in vitro study was to investigate whether mixing with calcium hydroxide [Ca(OH)2] affects the antimicrobial action of Octenidine hydrochloride (Octenisept), MTAD and chlorhexidine against Enterococcus faecalis and Candida albicans. MATERIALS AND METHODS: Freshly grown cultures of Enterococcus faecalis, Candida albicans and a mixture of both strains were incubated in agar plates containing brain-heart infusion broth (BHIB). Zones of inhibition were measured at 24 and 48 hours. Statistical analysis was performed using Mann-Whitney U test and Kruskal-Wallis one-way analysis of variance (ANOVA, both p=0.05). RESULTS: Mixing with Ca(OH)2 significantly increased the antibacterial effect of Octenisept (p<0.05), but did not alter its antifungal activity. Only chlorhexidine showed more antibacterial and antifungal efficiency compared to its Ca(OH)2-mixed version (both p<0.05). Mixing with Ca(OH)2 decreased the antibacterial efficacy of MTAD, but increased its antifungal effect (both p<0.05). CONCLUSION: These results demonstrate the differential effects of Ca(OH)2 addition on the antimicrobial action of the tested endodontic medicaments in vitro. Ca(OH)2 was as effective as its combination with all of the tested medicaments. PMID- 24171990 TI - Microleakage of a self-adhesive class V composite on primary and permanent dentitions. AB - AIM: This study aimed to evaluate the microleakage of Class V restorations filled with a 7th-generation self-adhesive composite. MATERIALS AND METHODS: In 40 permanent premolars and 80 primary canines, 160 Class V cavities were prepared, which were filled with four restorative materials (n of each material=20 permanent and 20 primary restorations): control: nonbonded composite (Heliomolar), GI: glass ionomer (Fuji IX GP), BC: bonded Heliomolar, SC: self adhesive composite (Embrace WetBond). Dye penetration was scored 0 to 4 at 160 coronal and 160 gingival margins under 40* magnification by two examiners. The data were analyzed with Mann-Whitney U test (alpha=0.01). RESULTS: The mean microleakages of the materials (in the order of 'control, GI, BC, SC') at each margin-dentition (n=20 margins) were: coronal-permanent (3.25+/-0.72, 2.75+/ 0.72, 0.35+/-0.59, 2.7+/-0.73), coronal-primary (3.3+/-0.66, 2.85+/-0.88, 0.55+/ 0.76, 2.65+/-1.14), gingival-permanent (3.35+/-0.67, 0.85+/-0.67, 2.95+/-0.83, 1.55+/-1.23), and gingival-primary (3.25+/-0.72, 0.85+/-0.59, 2.85+/-0.89, 2.85+/ 0.93). Compared with the control microleakage at each margin-dentition (each group's n=20 margins), BC microleakage was significantly lesser at coronal margins only (p=0.000), GI microleakage was lower at gingival margins only (p=0.000), and SC microleakage was smaller at gingival margins of permanent teeth only (p=0.000). After combining coronal/gingival margins, only SC microleakage in primary dentition (n=40 margins) was not significantly lesser than the control in primary teeth (p=0.018); and microleakage of all other material-dentitions were lesser than corresponding control-dentitions (p=0.000). Permanent and primary teeth had similar results for all material-margins (p>0.5) except for SC at gingival margins (p=0.001). CONCLUSION: SC should be used only at gingival margins of permanent teeth. CLINICAL SIGNIFICANCE: Application of self-adhesive composite should be limited to gingival margins of permanent teeth. PMID- 24171991 TI - Histometric study of resorption on replanted teeth with enamel matrix-derived protein. AB - BACKGROUND: Enamel matrix-derived proteins (Emdogain) stimulate the proliferation of periodontal ligament cells, contributing to their regeneration. AIM: This study was to perform histometric assessment of root surface resorption in replanted teeth with the use of Emdogain(r). MATERIALS AND METHODS: Male Wistar rats (Rattus norvegicus), weighing 180 to 200 gm, were anesthetized, subjected to extraction of the upper right incisor tooth, which was then replanted into the alveoli with the following treatment: (a) control group--tooth with root canal filled with calcium hydroxide paste and (b) treated group--tooth with root canal filled with enamel matrix-derived protein. The animals were sacrificed 25 days after tooth replantation. The maxilla was processed to obtain thin sections (6 u) and stained with hematoxylin and eosin. The resorption volume percentage of each dental element was calculated from the cementoenamel junction to the apex. RESULTS: Quantification of resorption revealed that Emdogaintreated teeth showed a lower percentage of resorption (31.58%) compared to controls (80.48%) (statistically significant values--t-test p-value=0.0431). CONCLUSION: It was concluded that Emdogain used as root canal filling has properties capable of showing a lower percentage of resorption in replanted teeth. PMID- 24171992 TI - The effect of eugenol-free temporary cement's remnants on retention of full metal crowns: comparative study. AB - INTRODUCTION: The aim of this study was to evaluate the effects of eugenol-free temporary cement's remnants on the retentive strength of full metal crowns luted via zinc phosphate and resin cement (Maxcem) to the tooth structure. MATERIALS AND METHODS: Forty complete standardized Ni-Cr crowns in four groups were cemented by two types of permanent cements: zinc phosphate cement and resin cement (Maxcem). In the two groups before permanent cementation of crowns, temporary acrylic crowns were cemented by eugenol-free temporary cement. Crowns' retention was evaluated by Universal testing machine. All data were analyzed by means of one-way ANOVA test in SPSS software version 11.5 (alpha=0.05). RESULTS: There was no significant difference in groups with prior using eugenol-free temporary cement and groups with just using two permanents cement (p value>=0.05). DISCUSSION: The application of temporary cement before permanent cementation of full metal crowns does not have any adverse effect on retention of full metal crowns, when temporary cements are removed properly. PMID- 24171993 TI - Comparison of orange oil and chloroform as gutta- percha solvents in endodontic retreatment. AB - OBJECTIVE: To compare the efficacy of gutta-percha removal achieved with simple mechanical technique using two different solvents. MATERIALS AND METHODS: It was an in vitro experimental study conducted at the Aga Khan University Hospital, Karachi, Pakistan on 27 extracted human molars divided into two groups by alternate sampling technique. The teeth were prepared by manual filing and obturated with gutta-percha and calcium hydroxide sealer. Two drops of the assigned solvent were placed on the orifice of the obturated canal and Gates Glidden drills #1, 2 and 3 were used for removal of coronal gutta-percha. Manual filing was done for removal of remaining gutta-percha and the solvent was used in drops until needed. Postoperative periapical radiographs were taken to visualize the remaining gutta-percha left in the canals. Descriptive statistics (mean and SD) of the variables such as tooth type, obturation length and canal curvatures were determined. Chi-square and independent sample t-tests were applied and level of significance was set at 0.05. RESULTS: There was 5.19 (3.8) mm of remaining gutta-percha in the orange oil group and 5.37 (4.2) mm in the chloroform group (p=0.90). CONCLUSION: There is no statistically significant difference between the orange oil and chloroform when used as solvent for removing gutta-percha. PMID- 24171994 TI - Surface roughness of polyvinyl siloxane impression materials following chemical disinfection, autoclave and microwave sterilization. AB - BACKGROUND: Autoclave sterilization and microwave sterilization has been suggested as the effective methods for the disinfection of elastomeric impressions, but subjecting elastomeric impressions to extreme temperature may have adverse effects on critical properties of the elastomers. AIM: To evaluate the effect of chemical disinfection as well as autoclave and microwave sterilization on the surface roughness of elastomeric impression materials. MATERIALS AND METHODS: The surface roughness of five commercially available polyvinyl siloxane impression materials (Coltene President, Affinis Perfect impression, Aquasil, 3M ESPE Express and GC Exafast) were evaluated after subjecting them to chemical disinfection, autoclaving and microwave sterilization using a Talysurf Intra 50 instrument. Twenty specimens from each material were fabricated and divided into four equal groups, three experimental and one control (n=25). The differences in the mean surface roughness between the treatment groups were recorded and statistically analyzed. RESULTS: No statistically significant increase in the surface roughness was observed when the specimens were subjected to chemical disinfection and autoclave sterilization, increase in roughness and discoloration was observed in all the materials when specimens were subjected to microwave sterilization. CONCLUSION: Chemical disinfection did not have a significant effect but, since it is less effective, autoclave sterilization can be considered effective and autoclaving did not show any specimen discoloration as in microwave sterilization. Microwave sterilization may be considered when impressions are used to make diagnostic casts. A significant increase in surface roughness may produce rougher casts, resulting in rougher tissue surfaces for denture and cast restorations. CLINICAL SIGNIFICANCE: Autoclave sterilization of vinyl polysiloxane elastomeric impressions for 5 minutes at 134 degrees C at 20 psi may be considered an effective method over chemical disinfection and microwave sterilization, because chemical disinfection does not eliminate all disease-causing microorganisms and microwave sterilization leads to a rougher impression surface. PMID- 24171995 TI - Comparison of galvanic corrosion potential of metal injection molded brackets to that of conventional metal brackets with nickel-titanium and copper nickel titanium archwire combinations. AB - AIM: The aim of the study is to investigate the galvanic corrosion potential of metal injection molding (MIM) brackets to that of conventional brackets under similar in vitro conditions with nickel-titanium and copper nickel-titanium archwires. MATERIALS AND METHODS: Twenty-five maxillary premolar MIM stainless steel brackets and 25 conventional stainless steel brackets and archwires, 0.16 inch, each 10 mm length, 25 nickeltitanium wires, 25 copper nickel-titanium wires were used. They were divided into four groups which had five samples each. Combination of MIM bracket with copper nickel-titanium wire, MIM bracket with nickel-titanium wire and conventional stainless steel brackets with copper nickel titanium wire and conventional stainless steel brackets with nickel-titanium wires which later were suspended in 350 ml of 1 M lactic acid solution media. Galvanic corrosion potential of four groups were analyzed under similar in vitro conditions. Precorrosion and postcorrosion elemental composition of MIM and conventional stainless steel bracket by scanning electron microscope (SEM) with energy dispersive spectroscope (EDS) was done. RESULTS: MIM bracket showed decreased corrosion susceptibility than conventional bracket with copper nickeltitanium wire. Both MIM and conventional bracket showed similar corrosion resistance potential in association with nickel-titanium archwires. It seems that both brackets are more compatible with copper nickel-titanium archwires regarding the decrease in the consequences of galvanic reaction. The EDS analysis showed that the MIM brackets with copper nickel-titanium wires released less metal ions than conventional bracket with copper nickeltitanium wires. CONCLUSION: MIM brackets showed decreased corrosion susceptibility, copper nickel-titanium archwires are compatible with both the brackets than nickel-titanium archwires. CLINICAL SIGNIFICANCE: Clinically MIM and conventional brackets behaved more or less similarly in terms of corrosion resistance. In order to decrease the corrosion potential of MIM brackets, more precise manufacturing technique should be improved to get a more smoother surface finish. PMID- 24171996 TI - Influence of post fit and post length on fracture resistance: an in vitro study. AB - BACKGROUND AND OBJECTIVES: As root filled teeth often have insufficient coronal tooth structure, placement of a post is occasionally necessary to provide adequate retention for the core and final restoration. The aim of the present study was to investigate (i) the impact of post fit (form-congruence) and (ii) the influence of post length on the fracture resistance of severely damaged root filled extracted teeth. MATERIALS AND METHODS: Forty single-rooted human teeth were root filled and divided into four groups (n = 10 per group). Post spaces were prepared with a depth of 6 mm (groups 1, 3) and 3 mm (groups 2, 4). Form congruence with a maximal fit of the post within the root canal space was obtained in groups 1 and 2, whereas there was no form-congruence in groups 3 and 4. In all groups, glass fiber reinforced composite (FRC) posts were adhesively cemented and direct composite crown buildups were fabricated without a ferrule. Specimens were subjected to thermocycling and cyclic loading followed by application of static load until failure. Loads-to-failure [in N] were compared among the groups. RESULTS: Post fit did not have a significant influence on fracture resistance, irrespective of the post length. Both groups with post insertion depths of 6 mm resulted in significantly higher mean failure loads (group 1: 274.27 N; group 3: 277.16 N) than the groups with post space preparation of 3 mm (group 2: 250.40 N; group 4: 255.48 N). INTERPRETATION AND CONCLUSION: Within the limitations of this study, the fracture resistance of teeth restored with FRC posts and direct resin composite crowns without ferrules was not influenced by post fit within the root canal. These results imply that excessive post space preparation aimed at producing an optimal circumferential post fit is not required to improve fracture resistance of roots. PMID- 24171997 TI - Contemporary issues in clinical dental teaching. AB - AIM: This research project sought to explore the issue of what constitutes effective clinical teaching in the minds of both students and teachers. BACKGROUND: As stakeholders of the dental clinical setting, teachers and students have valuable practical insights to share with the academic and professional community as to what constitutes effective dental teaching. CASE DESCRIPTION: An explorative qualitative study of dental teachers' and students' perceptions of clinical teaching was carried out at the Faculty of Dentistry of Sydney University. Thirty-one clinical teachers and 12 students participated in this case study through an online questionnaire survey and a focus group, respectively. Responses were categorized in three major clusters, namely, instructional, curricular or organizational. CONCLUSION: The findings reveal that both groups hold similar opinions on what constitutes effective clinical instruction including a shared passion for learning and teaching, being clear and organized, demonstrating clinical competencies as well as engaging in professional self-reflection. Most of the issues fell into the instructional cluster where establishing a positive relationship with students including providing constructive feedback at the clinical session came up as key factors contributing to the student experience. CLINICAL SIGNIFICANCE: There is a demand from both students and teachers to standardize clinical procedures and protocols as well as having a greater synchronization in time and content between lectures and clinical work. PMID- 24171998 TI - Awareness of basic life support among staff and students in a dental school. AB - AIM: To assess and compare the knowledge of basic life support (BLS) among third, fourth and fifth (III, IV and V) year Bachelor of Dental Surgery (BDS) clinical students, dental interns, postgraduate students and Bachelor of Dental Surgery (BDS) and Master of Dental Surgery (MDS) faculty of Panineeya Institute of Dental Sciences and Hospital, Hyderabad, India. MATERIALS AND METHODS: A BLS questionnaire consisting of 22 questions was used to assess the levels of III, IV and V years BDS clinical students, dental interns, postgraduate students and BDS and MDS faculty of Panineeya Institute of Dental Sciences and Hospital, Hyderabad, India. Statistical Package for Social Sciences software (SPSS version 12.0) was used to analyze the statistical data. The p<0.05 was considered statistically significant. RESULTS: A total of 338 respondents took part in the study. When gender comparison was done with correct knowledge responses, statistically significant differences were noted for Q6, Q9, Q12, Q13, Q15 and Q17. For age groups and educational qualifications, significant difference was observed for all questions. It was noted that III, IV and V year undergraduate clinical students and half of interns had adequate knowledge when compared to postgraduate students (6.9%), BDS tutors (0.00%) and MDS staff (10.7%). CONCLUSION: The study concludes that there is a significant lack of knowledge among postgraduates students BDS and MDS faculty, regarding BLS when compared to III, IV and V year's clinical BDS students and dental interns. This study emphasizes the need for all health care professionals to regularly update the knowledge and skills regarding BLS. PMID- 24171999 TI - The prevalence of dental anomalies in orthodontic patients at the State University of New York at Buffalo. AB - OBJECTIVE: To determine the prevalence of permanent tooth anomalies in patients attending the graduate orthodontic clinic at the State University of New York at Buffalo. MATERIALS AND METHODS: Charts of 496 subjects (310 females and 186 males) met the inclusion criteria for this study. The mean ages were 16 years and 3 months for the combined gender sample that received orthodontic treatment in the graduate orthodontic clinic between 2007 and 2010. Full pretreatment records (intraoral photographs, digital study models, lateral cephalograms and panoramic radiographs) were used for the assessment. Charts were examined for these anomalies: agenesis, supernumerary, impaction and delayed tooth eruption. Subjects were categorized by gender and ethnicity. The percentages of the anomalies were assessed according to type of malocclusion, gender, race, location, tooth class and region in the dental arches. RESULTS: Sixty-four subjects (12.9%) had at least one occurrence of delayed eruption and impaction (DEI), followed by 47 subjects (9.5%) who had at least one occurrence of agenesis, and seven (1.4%) had a supernumerary condition. Approximately 80% of the subjects had no dental anomalies. The presence of more than one anomaly was observed in 61 subjects. Twelve subjects (2.4%) had both agenesis and DEI. Agenesis tended to be more common in class II malocclusions (p=0.012). CONCLUSION: The prevalence of permanent tooth anomalies was (20.4%). The percentage occurrence of DEI was the highest (12.9%) followed by dental agenesis (9.5%) and supernumerary teeth (1.4%) in the orthodontic patients at the State University of New York at Buffalo. PMID- 24172000 TI - A survey of complete denture patients experiencing difficulties with their prostheses. AB - OBJECTIVE: The objective of this study was to investigate the problems faced by patients having complete dentures and the cleanliness of dentures by the patients. MATERIALS AND METHODS: This cross-sectional study is done with a sample of 178 patients having complete prosthesis since 1 year. A self-administered structured questionnaire pretested through a pilot survey was used in the study. The data were analyzed using the SPSS version 16.0. The Student's t-test, ANOVA and post hoc test were used as test of significance. RESULTS: Mastication discomfort and looseness of denture were the most common complaints followed by lack of retention (35.4%), bad breath (29.8%), tongue restriction (26.4%) and food accumulation (24.7%). There was a significant relationship of complaints with age groups (p=0.00). CLINICAL SIGNIFICANCE: This study concluded that most of the patients were present with complaints due to dentures. So, dental professionals should pay serious attention to their patients for subjective acceptable result of the dentures and also advice them to properly maintain hygiene of dentures. PMID- 24172001 TI - Attitude of general dental practitioners toward root canal treatment procedures in India. AB - OBJECTIVE: The percentage of general dental practitioners is very common in India, so the purpose of this study was to assess attitude of general dental practitioners toward root canal treatment (RCT) procedures. MATERIALS AND METHODS: In a cross-sectional study, 178 dentists (96 males and 82 females) were surveyed using a selfadministered, structured questionnaire pretested through a pilot survey. The questionnaire collected information regarding RCT procedures among participants. Data were analyzed using SPSS version 15. Frequency and percentage distributions were calculated. RESULTS: In the present study most of the participants, i.e. 86.4% reported that they perform (RCT) procedures in posterior teeth. Isolation is mainly done with cotton rolls only (74.6%) and very few are using rubber dam in their practice (3.2%). Radiographs were not taken after every step in most of the cases. Rotary instruments were used in less number of cases and K-files were the most popular instruments (66.2%). Also single sitting RCT was not commonly seen. CLINICAL SIGNIFICANCE: This study indicates that most of the general dental practitioners' do not comply with quality standards guidelines such as use of rubber dam as isolation. So dentist should update their knowledge and practices with current techniques and materials through CDE programs. PMID- 24172002 TI - Comparative analysis of rationale used by dentists and patient for final esthetic outcome of dental treatment. AB - AIM: To compare and evaluate the perceptions of esthetics among dentists and patients regarding the final esthetic outcome of a dental treatment. BACKGROUND: Esthetics is a matter of perception and is associated with the way different people look at an object. What constitutes esthetic for a particular person may not be acceptable for another. Hence it is subjective in nature. This becomes more obvious during the post-treatment evaluation of esthetics by dentist and the concerned patient. Opinion seldom matches. Hence, the study is a necessary part of the process of understanding the mind of dentist and patient regarding what constitutes esthetics. TECHNIQUE: A survey has been conducted by means of a questionnaire consisting of 10 questions, on two groups of people. First group consists of 100 dentists picked at random in Kanyakumari district of Tamil Nadu, India. Second group consisted of 100 patients who required complete denture prosthesis. The second group was divided into two subgroups A and B. Subgroup A consisting of 50 men and subgroup B consisting of 50 women. In each subgroup 25 patients were selected in age group of 40 to 50 and 25 patients were selected in the age group of 50 to 60. The questionnaire was given to both the groups and asked to fill up, which was then statistically analyzed to look for patterns of thought process among them. RESULTS: Results were subjected to statistical analysis by Student's t-test. CONCLUSION: Perceptions of esthetics differs from dentist who is educated regarding esthetic principles of treatment and a patient who is not subjected to such education. Since, the questions were formulated such that patients could better understand the underlying problem, the final outcome of survey is a proof that dentists need to take into account what the patient regards as esthetics in order to provide a satisfactory treatment. CLINICAL AND ACADEMIC SIGNIFICANCE: The current study helps the dentist to better educate the patient regarding esthetics so that patient appreciates the final scientifically based esthetic outcome of treatment. It also helps the dental students to understand the underlying patient's thought process regarding esthetics. PMID- 24172003 TI - Assessment of palatal masticatory mucosa: a cross-sectional study. AB - AIM: To treat mucogingival problems palatal masticatory mucosa is used as a donor material. This study aimed to determine the thickness of donor palatal mucosa and associations of age and gender in Indian subjects aged 14 to 60 years by direct clinical technique. MATERIALS AND METHODS: Forty systemically and periodontally healthy Indian subjects (20 males; 20 females; age range of 14 to 60 years) enrolled in this study. Under local anesthesia bone sounding technique was performed at 15 defined and predetermined points. The Wilcoxon test was used to determine the difference in mucosal thickness between the age groups and between genders. Significance of the difference between individuals of different body mass index (BMI) was assessed by independent t-test. RESULTS: With mean thickness of 2.0 to 3.7 mm, the younger age group demonstrated significantly thinner donor mucosa (mean 2.8+/-0.3 mm) than the older age group (mean 3.1+/-0.3 mm). Within the same age group though statistically not significant; males had thicker mucosa than females. From the canine to second premolar areas and in the sites furthest from the gingival margin mucosa thickness increased. When correlated with subject's BMI, in all probed sites males demonstrated significantly a thicker mucosa than females. Within each group subjects with high BMI demonstrated thicker donor mucosa. CONCLUSION: Current study showed that in both adult and young individuals, premolar and canine areas can be the right site for harvesting donor tissue. Even in young subjects subepithelial connective tissue (CT) graft can be harvested in adequate volume. Donor tissue thickness can be influenced by factors like genetics and race, which need to be further evaluated. CLINICAL SIGNIFICANCE: Premolar and canine areas serve as appropriate choice to harvest palatal masticatory mucosa. Even in young patients the volume of donor tissue available is sufficient enough to consider the subepithelial CT graft procedure. Donor tissue thickness can be influenced by factors like genetics and race, which need to be further evaluated. PMID- 24172004 TI - Johanson-Blizzard syndrome: dental findings and management. AB - AIM: Oral rehabilitation of a child with Johanson-Blizzard syndrome (JBS). BACKGROUND: JBS is an extremely rare inherited disorder characterized by unusually small nose that appears 'beak shaped' due to the absence (aplasia) or underdevelopment (hypoplasia) of the nostrils (nasal alae), abnormally small, malformed primary (deciduous) teeth and misshapen or absent secondary (permanent) teeth, hearing disorder, hypothyroidism, dwarfism, malabsorption and mental retardation. It is sometimes described as a form of ectodermal dysplasia. CASE REPORT: Oral findings in JBS are very obscure in the literature. The present report describes oral findings in an 8 years old boy with JBS and his oral rehabilitation. CONCLUSION: JBS has an emotional consequence for the affected individuals at early ages. Oral rehabilitation in this case had a very positive impact on the child's mind. CLINICAL SIGNIFICANCE: Early identification and treatment of this disease is of great importance to rehabilitate the patient on functional, esthetic and psychological front. PMID- 24172005 TI - Ameloblastic fibrodentinoma: report of a rare case. AB - AIM: This is to report a rare case of ameloblastic fibrodentinoma (AFD), including detailed history, histopathologic as well as radiographic findings. Her condition, a mixed odontogenic tumor, has rarely been reported in publications. We also included the gist of theories put forward regarding the histogenesis of this lesion. BACKGROUND: AFD is a rare and controversial entity; it boasts a variety of classifications and terminology based on its unique biological nature as well as histopathological features. CASE DESCRIPTION: The patient was a 13 year-old girl with a chief complaint of central unerupted tooth on the left mandible. Cone beam computed tomographic images revealed a mixed pericoronal and multilocular lesion surrounding the crown of the aforementioned tooth, displacing it apically to a large extent. CONCLUSION: It is important to differentiate AFD from other benign mixed odontogenic tumors with similar radiographic appearance because of different therapeutic approaches in some of these tumors. CLINICAL SIGNIFICANCE: From the clinical point of view, it is of paramount significance for dental practitioners to assess any delayed tooth eruption (more than 6 months and in comparison with its counterpart on the opposite side) radiographically to ascertain or rule out any such similar lesions. PMID- 24172006 TI - Arrest of root formation in relation to permanent mandibular incisors: a rare case report. AB - AIM: To report a rare case of arrested root formation of permanent incisors in a young boy with mixed dentition and its management. BACKGROUND: Traumatic injury to a primary tooth may damage the underlying permanent tooth germ and affect its development. The extent of the malformation depends upon the developmental stage of the permanent tooth and the intensity of trauma. Discoloration and hypoplasia of the crown, dilaceration, root angulation and disturbances in eruption are commonly seen developmental disturbances following trauma. However, partial or complete arrest of root formation is a rare developmental sequela of trauma to primary teeth. Attempt should be made to retain these natural teeth during the mixed dentition period. CASE DESCRIPTION: A case is presented of a young boy with rare occurrence of arrested root formation of permanent mandibular incisors, following trauma to the primary predecessors. Clinically these teeth exhibited mobility and radiographic examination showed absence of root formation in relation to the incisors. The treatment plan was to retain the natural permanent teeth for a maximum period and to stabilize them until a more permanent replacement could be carried out. As the patient had mixed dentition, immediate stabilization was done using fiber reinforced splint until further definitive treatment is carried out. Early diagnosis of developmental disturbances in permanent teeth resulting from trauma at a young age is necessary. Regular follow up appointments, through clinical and radiographic examination and timely intervention may minimize or even avoid harm to the developing tooth. PMID- 24172007 TI - Endodontic retreatment of dens invaginatus presenting with gutta-percha overfilling at the attached gingiva and chronic apical periodontitis: unusual clinical report. AB - AIM: This work describes the retreatment of an unusual case of dens invaginatus with gutta-percha overfilling at the gingival mucosa and chronic apical periodontitis in a 34-year-old woman. Initial periapical radiograph showed the presence of type II dens invaginatus with poor quality obturation, root perforation and chronic apical periodontitis of tooth 22. BACKGROUND: Dens invaginatus is a tooth malformation caused by infolding of the dental papilla during tooth development. This anomaly has been associated with increased prevalence of pulpal and periapical diseases. CASE DESCRIPTION: Conventional endodontic retreatment was performed using rotary files and calcium hydroxide paste as intracanal dressing. After 7 days, root canal was filled with guttapercha points and Sealapex(r) sealer. Obturation was radiographically followed and, after 3 years, absence of fistula and periapical radiolucency was observed, thus conventional endodontic therapy proved to be successful. CONCLUSION: Conventional endodontic retreatment of type II dens invaginatus has been successful for a 3-year period, showing a better treatment alternative. CLINICAL SIGNIFICANCE: Conservative endodontic retreatment of dens invaginatus should be considered to promote periapical healing with complete reconstitution of bone and periodontal ligament regeneration without signs of recurrence over a period of 3 years. Moreover, it preserves the entire tooth. PMID- 24172008 TI - Preoperative gingival conditioning as a guide for implant installation and to achieve proper dentogingival contours. AB - A successful esthetic outcome for implant-supported dentures depends on the careful manipulation of peri-implant tissue as well as the precise placement of the implant. In addition, careful surgical and prosthetic planning is essential for esthetically important areas, especially in partially edentulous cases. This study describes a clinical case that presented absent maxillary central incisors in which prior prosthetic planning was used to perform provisional restorations, that was used to condition the gingival tissues and guide implant installation. These procedures made it possible to achieve a dentogingival contour, interdental papillae, and an emergence profile in the edentulous area. The techniques outlined here proved to be sufficient and support the peri-implant tissues to create a more esthetic final prosthesis. PMID- 24172009 TI - Analysis of the peri-implant soft tissues in contact with zirconia abutments: an evidence-based literature review. AB - AIM: The aim of this study is to evaluate through a literature review, the soft tissue response in contact with zirconia abutments, including case reports comparing prosthetics rehabilitations with zirconia and titanium abutments upto 3 years of follow-up as well as the factors that should be considered on implant's abutment selection. BACKGROUND: Metallic abutments can provide grayish color when in contact with thin soft tissues which may lead the implant prosthetic treatment to failure. In this context, the abutments of zirconia stand out because there is an excellent linking between esthetics and the health of peri-implant soft tissues. MATERIALS AND METHODS: A consult of the published researches was made on the PubMed database from 2000 to September 2012. The including criteria were: literature reviews, clinical studies and case reports in English that focused on the response of the soft tissue in contact with zirconia implant abutments. The studies that were not in English and did not match the tackled issue were excluded. RESULTS: A total of 32 articles were found. According to the search strategy, just 16 articles were selected for this review. Three studies affirmed that zirconia abutments have an excellent soft tissue response; one study showed increased gingival recession with zirconia abutments and nine studies do not stand out any difference on biological behavior between titanium and zirconia abutments. Three studies affirmed that zirconia abutments provide natural gingival appearance, anatomic contour and greater esthetics. CONCLUSION: The use of zirconia abutments is recommended for anterior regions because of their greater optical properties and esthetic results and more studies should be performed and analyzed longitudinally regarding their biological response. CLINICAL SIGNIFICANCE: The zirconia abutments have been established to be essential in order to achieve great esthetic results in cases of thin peri implant soft tissues and in regions where the three-dimensional placement of implants is more superficial. PMID- 24172010 TI - mHealth: the emerging sub-segment of eHealth. PMID- 24172011 TI - Relative validity of a semi-quantitative FFQ in 3-year-old Polish children. AB - OBJECTIVES: The aim of the study was to assess the relative validity of a semi quantitative FFQ (SFFQ) which measures the usual dietary intake of 3-year-old children. DESIGN: The children's daily dietary intake was measured using the SFFQ. The average intake of three 24 h dietary recalls (24hDR) was calculated as a reference method. Wilcoxon's rank test and Spearman's rank-correlation coefficient were used to compare nutrient intakes assessed by both methods. The level of agreement between the SFFQ and the repeated 24hDR was determined by the Bland-Altman method. To assess the agreement in quartile distribution, the weighted kappa coefficient (kappa w) was used. SETTING: Krakow, Poland. SUBJECTS: One hundred and forty-three 3-year-old children and their mothers, participants of a prospective cohort study. RESULTS: Overall, the SFFQ overestimated energy and nutrient intakes compared with the repeated 24hDR. The median correlation coefficient for energy and nutrient intakes was 0.456, with higher results for Ca, P and riboflavin. Although the kappa w value showed only slight to fair agreement between the two methods, about 75 % of the children were classified into the same or adjacent quartile and the level of agreement assessed by the Bland-Altman method for most of the nutrients investigated was good. CONCLUSIONS: The study indicated that the SFFQ might be a useful tool to assess dietary intakes of nutrients by small children, especially for ranking them according their nutrient intake. PMID- 24172012 TI - Novel immunohistochemical data indicate that the female foetal urethra is more than an epithelial tube. AB - The female urethra has often been neglected in previous studies on the development of the human urogenital system. Our aim has been to reach a consensus on the organogenesis of the female urethra and the vagina with respect to interactions between the epithelia with different evolutionary origins. Therefore we tried to clarify open questions on the spatiotemporal distribution of molecular markers raised against mesenchymal and epithelial structures within the developing human female urethra. Furthermore, we draw comparisons regarding gender-specific aspects in urethral development. To this effect, we used molecular markers such as different cytokeratins (CKs), p63, Ki67, uroplakin III, E-cadherin, vimentin, smooth muscle actin (SMA), cleaved caspase 3 and paired box gene 2 (PAX 2) to phenotype developmental changes. Terminal Deoxynucleotidyl Transferase dUTP Nick End Labeling (TUNEL) assay was additionally performed to reveal apoptosis. We examined different gestational stages starting from week (W) 8 until W 15. Immunohistochemistry showed a distinct staining pattern for p63 and CK17, both markers for stem cells, ensuing from the urogenital sinus (UGS) proceeding into the Muellerian duct (MD). This was observed throughout development and might be a stimulus for the formation of the vaginal anlagen that derive from the MD. In the attachment area of the MD we detected a conglomeration of cells with different embryonic origins. The epithelium of the UGS became transitional at W 9 after fertilization, and the differentiation advanced in a cranial to caudal direction. The paraurethral glands showed a slightly different staining profile than the urethral epithelium, which may be able to explain why carcinomas of these structures display various histological appearances. In addition, we could show that during the development of the female urogenital system the primary incidence is the formation of the urethra. This is followed by the establishment of the vagina, which clearly depends on the proper differentiation of the UGS/urethra. PMID- 24172013 TI - Mood and coping in clinically isolated syndrome and multiple sclerosis. AB - OBJECTIVE: Few studies have examined behavioural changes in the early phase of multiple sclerosis (MS). The aim of the study is to investigate mood alterations and to explore coping strategies regarding patients with clinically isolated syndrome (CIS) and relapsing-remitting MS (RRMS). MATERIALS AND METHODS: The communication of diagnosis was made by one neurologist using a standardized approach. Depression, anxiety and coping questionnaires were filled in within 1 month from the diagnosis and at 3, 6, 12, 18 and 24 months subsequently. RESULTS: Thirty-nine patients were examined (11 CIS, 28 RRMS), also 39 healthy controls. At entry, patients showed a lower degree of hostile behaviour and a higher level of depression than the controls. At follow-up, a reduction in depression, anxiety and a better coping adjustment was observed. A higher reliance on 'Accepting responsibilities' coping score was seen in patients with higher levels of depression and anxiety. No significant differences were revealed by group comparisons between CIS and RRMS. CONCLUSIONS: This study highlights transient mood alterations and an improving of adaptive coping over a period of time in patients with CIS and RRMS. Similar emotional reactions and coping in clinical subgroups suggest that these factors are independent from the type of information provided during the communication of the diagnosis. PMID- 24172014 TI - Update of the human and mouse SERPIN gene superfamily. AB - The serpin family comprises a structurally similar, yet functionally diverse, set of proteins. Named originally for their function as serine proteinase inhibitors, many of its members are not inhibitors but rather chaperones, involved in storage, transport, and other roles. Serpins are found in genomes of all kingdoms, with 36 human protein-coding genes and five pseudogenes. The mouse has 60 Serpin functional genes, many of which are orthologous to human SERPIN genes and some of which have expanded into multiple paralogous genes. Serpins are found in tissues throughout the body; whereas most are extracellular, there is a class of intracellular serpins. Serpins appear to have roles in inflammation, immune function, tumorigenesis, blood clotting, dementia, and cancer metastasis. Further characterization of these proteins will likely reveal potential biomarkers and therapeutic targets for disease. PMID- 24172015 TI - Smooth muscle-specific myosin phosphatase target subunit 1 (MYPT1): an important piece of the puzzle. PMID- 24172016 TI - The effect of a modeling resin and thermocycling on the surface hardness, roughness, and color of different resin composites. AB - STATEMENT OF PROBLEM: The application of modeling resin could affect the surface quality and color of resin composites. PURPOSE: To evaluate the effects of modeling resin on the microhardness, roughness, and color of composite restorations, with and without thermocycling. METHODS: Sixty disc-shaped specimens for each resin composite were prepared in three groups: Group 1: A resin composite disc was cured against a polyester matrix and finished/polished; Group 2: A composite instrument was wetted with Bisco Modeling Resin (Bisco, Schaumburg, IL, USA) to smooth the composite surface, which was cured against a polyester matrix and finished/polished; Group 3: A composite instrument was wetted with modeling resin to smooth the composite surface, which was cured against a polyester matrix. Microhardness, roughness, and color were measured 24 hours after curing and after 10,000 thermocycles. RESULTS: Modeling resin significantly influenced the microhardness of GrandioSO (Voco, Cuxhaven, Germany) and Gradia Direct Posterior (GC America, Alsip, IL, USA), and the surface roughness of GrandioSO, Filtek Silorane (3M ESPE, St Paul, MN, USA), and Aelite All Purpose Body (Bisco) (p < 0.05). The microhardness of the Group 1 resin composites was affected by thermocycling (p < 0.05); however, thermocycling had no significant effect on surface roughness (p > 0.05). Tested composites showed clinically perceptible color changes after thermocycling. In Group 1, Filtek Ultimate (3M ESPE) showed the lowest color change (p < 0.05), and in Group 2, Filtek Silorane showed the highest significant color changes (p < 0.05). CONCLUSIONS: Modeling resin did not affect the microhardness, surface roughness, and color of Aelite LS Posterior (Bisco), Filtek Ultimate (3M ESPE), and Clearfil Majesty Esthetic (Kuraray Medical Inc, Tokyo, Japan) specimens. Also, thermocycling process only affected microhardness of tested resin composites. CLINICAL SIGNIFICANCE: The effect of modeling resin on surface microhardness, roughness, and color stability of composite materials depends on the type of resin composite. In clinical practice, the adverse effects of modeling resin might be alleviated by a proper finishing and polishing procedure. PMID- 24172018 TI - Adjuvant and immunostimulatory effects of LPS and beta-glucan on immune response in Japanese flounder, Paralichthys olivaceus. AB - In order to investigate the adjuvant and immunostimulatory effects of LPS and beta-glucan, a highly effective vaccine candidate for Edwardsiella tarda known as glyceraldehyde-3-phosphate dehydrogenase (GAPDH) was recombinantly expressed in Escherichia coli, which was intramuscularly injected into Japanese flounder alone or containing LPS or beta-glucan. ELISA analysis of sera showed that the fish immunized with rGAPDH containing LPS or beta-glucan had significant higher antibody titers than rGAPDH immunization group at day 14 and 30 (P<0.05). Flow cytometric analysis showed that the surface immunoglobulin positive (sIg+) lymphocytes percentages in head kidney of the immunized fish exhibited significant higher than the fish of control group at day 14 and 30, and immunization with rGAPDH containing LPS or beta-glucan could induce significant higher sIg+ percentages than immunization with rGAPDH alone. Simultaneously, the expressions of genes coding for immunoregulatory molecules involved in innate and acquired responses, including IFN-gamma, IL-1beta, IL-6, TNF-alpha, TCRalpha, IgM, C-type lysozyme and MHC-IIalpha were analyzed by quantitative PCR. The transcription levels of all selected genes except TNF-alpha displayed up regulation after immunization, and immunization with rGAPDH containing LPS or beta-glucan could induce significant higher levels than that induced only by rGAPDH. Moreover, to investigate the protection against infection, challenge with E. tarda was performed at day 30 after immunization. Fish immunized with rGAPDH containing beta-glucan exhibited the highest relative percentage survival (RPS) of 63% compared to the other groups. These results indicated that LPS and beta glucan employed as co-immunostimulatory molecules could significantly trigger the innate and acquired immune responses in Japanese flounder. PMID- 24172017 TI - Conservation genomic analysis of domestic and wild pig populations from the Iberian Peninsula. AB - BACKGROUND: Inbreeding is among the major concerns in management of local livestock populations. The effective population size of these populations tends to be small, which enhances the risk of fitness reduction and extinction. High density SNP data make it possible to undertake novel approaches in conservation genetics of endangered breeds and wild populations.A total of 97 representative samples of domestic and wild pig populations from the Iberian Peninsula, subjected to different levels of threat with extinction, were genotyped with a 60 K SNP panel. Data analyses based on: (i) allele frequency differences; (ii) linkage disequilibrium and (iii) runs of homozygosity were integrated to study population relationships, inbreeding and demographic history. RESULTS: The domestic pigs analyzed belonged to local Spanish and Portuguese breeds: Iberian ? including the variants Retinto Iberian, Negro Iberian and Manchado de Jabugo ?, Bisaro and Chato Murciano. The population structure and persistence of phase analysis suggested high genetic relations between Iberian variants, with recent crossbreeding of Manchado de Jabugo with other pig populations. Chato Murciano showed a high frequency of long runs of homozygosity indicating recent inbreeding and reflecting the recent bottleneck reported by historical records. The Chato Murciano and the Manchado de Jabugo breeds presented the lowest effective population sizes in accordance with their status of highly inbred breeds. The Iberian wild boar presented a high frequency of short runs of homozygosity indicating past small population size but no signs of recent inbreeding. The Iberian breed showed higher genetic similarities with Iberian wild boar than the other domestic breeds. CONCLUSIONS: High-density SNP data provided a consistent overview of population structure, demographic history and inbreeding of minority breeds and wild pig populations from the Iberian Peninsula. Despite the very different background of the populations used, we found a good agreement between the different analyses. Our results are also in agreement with historical reports and provide insight in the events that shaped the current genetic variation of pig populations from the Iberian Peninsula. The results exposed will aid to design and implement strategies for the future management of endangered minority pig breeds and wild populations. PMID- 24172019 TI - The effectors of innate immunity: DAMPs, DAMEs, or DIMEs? PMID- 24172020 TI - Psychometric evaluation of the German version of the Patient Activation Measure (PAM13). AB - BACKGROUND: The Patient Activation Measure (PAM) consists of 13 items and assesses patient (or consumer) self-reported knowledge, skills, and confidence for self-management of one's health or chronic condition. The aim of this study was to translate the original American version of the PAM13 into German and to test the psychometric properties of the German version in an elderly, multimorbid population with various chronic conditions. METHODS: Translation was performed by a standardized forward-backward translation process. The PAM13 was sent to 9.075 participants enrolled in a randomized controlled study. 4.306 participants responded to the questionnaire. Descriptive and reliability analyses were carried out. To examine scale properties, Andrich's Rasch Rating Scale Model was fitted. RESULTS: The internal consistency is good (alpha = 0.88) and the item-rest correlations were found as strong to moderate. The unidimensionality of the construct was confirmed, with a variance explanation of 40.9% and good model-fits for the Rasch model. However, the lowest response options were very rarely used across all items (below 5%) and ranking order of items according to their difficulty was substantially different from that of the American version. Differential item functioning (DIF) was found in subgroups (sex, age, health status), but differences were small. CONCLUSION: The German version of the PAM13 showed acceptable reliability and the model-fit statistics confirmed the Rasch model. The different ranking order of the items and the unfair distribution of the response options suggest further research on validation and revision of the construct. PMID- 24172021 TI - Broken heart stories: understanding Aboriginal women's cardiac problems. AB - Many Aboriginal communities call heart problems, and in particular cardiovascular disease, "White man's sickness." At the same time, Aboriginal women present with some of the highest rates of this disease. Against this backdrop, we explored how women with cardiac problems understand their heart health and used narrative discursive methods to analyze interviews conducted with women from two First Nations in North America. The women told stories that were riddled with contradictions, unfolding a complicated personal and cultural reality of living with cardiovascular disease. In many stories, heart disease was described as resulting from a "community imbalance" in the wake of colonialism whereby the women had to take over the traditional roles of men. Their ideas of heart disease risk and healing flowed from this understanding. They derived a sense of strength, however, from their ability to undertake both gender roles. Based on our findings, we provide some recommendations for cardiac care. PMID- 24172022 TI - Palliative bypass for small bowel carcinoid with mesenteric mass and vascular encasement. PMID- 24172023 TI - Does carbon storage limit tree growth? PMID- 24172024 TI - A cluster randomised controlled trial to determine the clinical effectiveness and cost-effectiveness of classroom-based cognitive-behavioural therapy (CBT) in reducing symptoms of depression in high-risk adolescents. AB - BACKGROUND: Depression in adolescents is a significant problem that impairs everyday functioning and increases the risk of severe mental health disorders in adulthood. Although this is a major problem, relatively few adolescents with, or at risk of developing, depression are identified and referred for treatment. This suggests the need to investigate alternative approaches whereby preventative interventions are made widely available in schools. OBJECTIVE: To investigate the clinical effectiveness and cost-effectiveness of classroom-based cognitive behavioural therapy (CBT) in reducing symptoms of depression in high-risk adolescents. DESIGN: Cluster randomised controlled trial. Year groups ( n = 28) randomly allocated on a 1 : 1 : 1 basis to one of three trial arms once all schools were recruited and balanced for number of classes, number of students, Personal, Social and Health Education (PSHE) lesson frequency, and scheduling of PSHE. SETTING: Year groups 8 to 11 (ages 12-16 years) in mixed-sex secondary schools in the UK. Data were collected between 2009 and 2011. PARTICIPANTS: Young people who attended PSHE at participating schools were eligible ( n = 5503). Of the 5030 who agreed to participate, 1064 (21.2%) were classified as 'high risk': 392 in the classroom-based CBT arm, 374 in the attention control PSHE arm and 298 in the usual PSHE arm. Primary outcome data on the high-risk group at 12 months were available for classroom-based CBT ( n = 296), attention control PSHE ( n = 308) and usual PSHE ( n = 242). INTERVENTIONS: The Resourceful Adolescent Programme (RAP) is a focused CBT-based intervention adapted for the UK (RAP-UK) and delivered by two facilitators external to the school. Control groups were usual PSHE (usual school curriculum delivered by teachers) and attention control (usual school PSHE with additional support from two facilitators). Interventions were delivered universally to whole classes. PRIMARY OUTCOMES: Clinical effectiveness: symptoms of depression [Short Mood and Feelings Questionnaire (SMFQ)] in adolescents at high risk of depression 12 months from baseline. Cost effectiveness: incremental cost-effectiveness ratios (ICERs) based on SMFQ score and quality-adjusted life-years (from European Quality of Life-5 Dimensions scores) between baseline and 12 months. Process evaluation: reach, attrition and qualitative feedback from service recipients and providers. RESULTS: SMFQ scores had decreased for high-risk adolescents in all trial arms at 12 months, but there was no difference between arms [classroom-based CBT vs. usual PSHE adjusted difference in means 0.97, 95% confidence interval (CI) -0.34 to 2.28; classroom based CBT vs. attention control PSHE -0.63, 95% CI -1.99 to 0.73]. Costs of interventions per child were estimated at L41.96 for classroom-based CBT and L34.45 for attention control PSHE. Fieller's method was used to obtain a parametric estimate of the 95% CI for the ICERs and construct the cost effectiveness acceptability curve, confirming that classroom-based CBT was not cost-effective relative to the controls. Reach of classroom-based CBT was good and attrition was low (median 80% attending >= 60% of sessions), but feedback indicated some difficulties with acceptability and sustainability. CONCLUSIONS: Classroom-based CBT, attention control PSHE and usual PSHE produced similar outcomes. Classroom-based CBT may result in increased self-awareness and reporting of depressive symptoms. Classroom-based CBT was not shown to be cost effective. While schools are a convenient way of reaching a wide range of young people, implementing classroom-based CBT within schools is challenging, particularly with regard to fitting programmes into a busy timetable, the lack of value placed on PSHE, and difficulties engaging with teachers and young people. Wider use of classroom-based depression prevention programmes should not be undertaken without further research. If universal preventative approaches are to be pursued, their clinical effectiveness and cost-effectiveness with younger children (aged 10-11 years), before the incidence of depression increases, should be investigated. Alternatively, the clinical effectiveness of indicated school based programmes targeting those already displaying symptoms of depression should be investigated. TRIAL REGISTRATION: Current Controlled Trials ISRCTN19083628. FUNDING: This project was funded by the NIHR Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 17, No. 47. See the HTA programme website for further project information. PMID- 24172025 TI - A molecular gut content study of Themisto abyssorum (Amphipoda) from Arctic hydrothermal vent and cold seep systems. AB - The use of DNA as a marker for prey inside the gut of predators has been instrumental in further understanding of known and unknown interactions. Molecular approaches are in particular useful in unavailable environments like the deep sea. Trophic interactions in the deep sea are difficult to observe in situ, correct deep-sea experimental laboratory conditions are difficult to obtain, animals rarely survive the sampling, or the study organisms feed during the sampling due to long hauls. Preliminary studies of vent and seep systems in the Nordic Seas have identified the temperate-cold-water pelagic amphipod Themisto abyssorum as a potentially important predator in these chemosynthetic habitats. However, the prey of this deep-sea predator is poorly known, and we applied denaturing high performance liquid chromatography (DHPLC) to investigate the predator-prey interactions of T. abyssorum in deep-water vent and seep systems. Two deep-water hydrothermally active localities (The Jan Mayen and Loki's Castle vent fields) and one cold seep locality (The Hakon Mosby mud volcano) in the Nordic Seas were sampled, genomic DNA of the stomachs of T. abyssorum was extracted, and 18S rDNA gene was amplified and used to map the stomach content. We found a wide range of organisms including micro-eukaryotes, metazoans and detritus. Themisto abyssorum specimens from Loki's Castle had the highest diversity of prey. The wide range of prey items found suggests that T. abyssorum might be involved in more than one trophic level and should be regarded as an omnivore and not a strict carnivore as have previously been suggested. PMID- 24172026 TI - Effect of robotic surgery on hysterectomy trends: implications for resident education. AB - STUDY OBJECTIVE: To compare the surgical approach used for hysterectomy at 2 teaching hospitals before and after introduction of the robotic surgical system. DESIGN: Retrospective cohort study (Canadian Task Force classification II-3). SETTING: Two gynecologic training sites at the University of Hawaii. PATIENTS: Women who underwent hysterectomy between January 1, 2005, and December 31, 2011. MEASUREMENTS AND MAIN RESULTS: ICD-9 procedural codes were used to identify hysterectomies performed between January 1, 2005, and December 31, 2011. Hysterectomies were categorized according to surgical approach: abdominal, vaginal, laparoscopic-assisted vaginal/total laparoscopic, and robotic. Each hysterectomy was also categorized according to primary preoperative diagnosis as general gynecology, gynecologic oncology, and urogynecology. The rates and numbers of hysterectomies performed during 2005-2006 (2 years before acquisition of the robot), 2007-2008 (first 2 years with the robot), and 2009-2011 (3-5 years after acquiring the robot) were compared using chi(2) tests and analysis of variance. The numbers of hysterectomies reported in resident case logs were also collected and compared. A total of 5894 hysterectomies were performed between 2005 and 2011. The total number of hysterectomies performed at Hospital A, which acquired the robotic surgical system, increased over time (p = .04) but remained stable at Hospital B, which did not acquire the robotic surgical system. At Hospital A, the number of robotic hysterectomies increased as the number of abdominal hysterectomies decreased (p < .001), a trend consistent across all diagnostic categories. The number of vaginal and laparoscopic hysterectomies remained stable. Resident case logs also reflected a decrease in the number of abdominal hysterectomies (p = .002) and an increase in the number of combined laparoscopic/robotic hysterectomies (p < .001) performed. The total number of hysterectomies performed by residents was unchanged. CONCLUSION: Introduction of the robotic surgical system was associated with significant changes in the numbers and types of hysterectomies performed in both general and subspecialty gynecology. Although abdominal hysterectomies decreased as robotic hysterectomies increased, other hysterectomies did not. These trends mirror reported resident surgical experience and have implications for resident education. PMID- 24172027 TI - Social capital and health in the least developed countries: a critical review of the literature and implications for a future research agenda. AB - Research on the linkage between social capital and health has grown in recent years; however, there is a dearth of evidence from resource-poor countries. This review examines the association between social capital and physical health (including health behaviours) in the least developed countries (LDCs). Citations were searched using three databases from 1990 to 2011 using the keyword 'social capital' combined with the name of each of the 48 LDCs. Of the 14 studies reviewed, 12 took place in Africa and 2 in South Asia. All used cross-sectional study designs, including five qualitative and nine quantitative studies. The literature reviewed suggests that social capital is an important factor for improving health in resource-poor settings; however, more research is needed in order to determine the best measures for social capital and elucidate the mechanisms through which social capital affects health in the developing world. Future research on social capital and health in the developing world should focus on applying appropriate theoretical conceptualisations of social capital to the developing country context, adapting and validating instruments for measuring social capital, and examining multilevel models of social capital and health in developing countries. PMID- 24172028 TI - Teachers' knowledge, attitudes and experience in sexual abuse prevention education in El Salvador. AB - Research on how to prevent child sexual abuse (CSA) in developing nations is practically non-existent. We sought to determine Salvadoran teachers' knowledge, attitudes, experience and barriers to CSA detection and reporting to assess the need for a CSA prevention programme and to assess barriers in conducting such a programme. One hundred teachers completed a questionnaire while they visited the Tin Marin Children's Museum in San Salvador. Nineteen of these teachers also participated in a focus group. We found that 89% of teachers reported at least two signs and symptoms of child abuse. One hundred per cent of teachers agreed that it is their responsibility to teach students about sexual abuse. Unusual for a study of this kind, parental migration was mentioned as making children vulnerable to CSA, and fear of gang violence and retribution was identified as interfering with teachers' ability to protect children. We conclude that Salvadoran teachers were knowledgeable about CSA detection and reporting and would support a programme in which they are trained to speak to their students about this topic. Barriers to reporting child abuse, such as teachers' safety and fear, need to be addressed in future CSA prevention programmes. PMID- 24172031 TI - Long lasting dysautonomia due to botulinum toxin B poisoning: clinical-laboratory follow up and difficulties in initial diagnosis. AB - BACKGROUND: Botulism is an acute form of poisoning caused by one of four types (A, B, E, F) toxins produced by Clostridium botulinum, ananaerobic, spore forming bacillus. Usually diagnosis of botulism is considered in patients with predominant motor symptoms: muscle weakness with intact sensation and preserved mental function. CASE PRESENTATION: We report a case of 56-year-old Caucasian female with a history of arterial hypertension, who presented with acute respiratory failure and bilateral ptosis misdiagnosed as brainstem ischemia. She had severe external and internal ophtalmoplegia, and autonomic dysfunction with neither motor nor sensory symptoms from upper and lower limbs. Diagnosis of botulinum toxin poisoning was made and confirmed by serum antibody testing in the mouse inoculation test. CONCLUSIONS: Ophtalmoplegia, autonomic dysfunction and respiratory failure can be caused by botulism. Early treatment and intensive care is essential for survival and recovery. The electrophysiological tests are crucial to correct and rapid diagnosis. Botulism (especially type B) should be considered in any case of acute or predominant isolated autonomic dysfunction. PMID- 24172032 TI - Thermodynamic evaluation of the binding of bisphosphonates to human farnesyl pyrophosphate synthase. AB - Bisphosphonates (BPs) are the drug of choice for treating bone diseases such as osteoporosis, Paget's disease, and metastatic bone disease. BPs with nitrogen containing side chains (N-BPs) are known to act as inhibitors for farnesyl pyrophosphate synthase (FPPS), a key enzyme in the mevalonate pathway. In this study, we evaluated the effect of different side chains on the binding affinity of BPs to human FPPS using calorimetric techniques. Differential scanning calorimetry (DSC) was used to determine the thermal unfolding of FPPS in the presence of BPs. The addition of a series of clinically available BPs increased the structural stability of human FPPS by preferential binding, as indicated by an increase in the FPPS unfolding temperature. The magnitude of the increase was correlated with in vivo antiresorptive efficacy, suggesting that the stabilization of FPPS underlies the inhibitory effect of the BPs. Isothermal titration calorimetry (ITC) experiments were performed to evaluate the binding thermodynamics of BPs against human FPPS. Analysis of the binding energetics revealed that over 30 years of optimization practiced by different pharmaceutical companies has enhanced the enthalpic contribution as well as binding affinity of BPs. The larger enthalpic contribution observed for newer, more potent BPs derives from both improved hydrogen bonding interactions and shape complementarity based on comparisons of our results with available structure information. PMID- 24172030 TI - Increased pfmdr1 gene copy number and the decline in pfcrt and pfmdr1 resistance alleles in Ghanaian Plasmodium falciparum isolates after the change of anti malarial drug treatment policy. AB - BACKGROUND: With the introduction of artemisinin-based combination therapy (ACT) in 2005, monitoring of anti-malarial drug efficacy, which includes the use of molecular tools to detect known genetic markers of parasite resistance, is important for first-hand information on the changes in parasite susceptibility to drugs in Ghana. This study investigated the Plasmodium falciparum multidrug resistance gene (pfmdr1) copy number, mutations and the chloroquine resistance transporter gene (pfcrt) mutations in Ghanaian isolates collected in seven years to detect the trends in prevalence of mutations. METHODS: Archived filter paper blood blots collected from children aged below five years with uncomplicated malaria in 2003-2010 at sentinel sites were used. Using quantitative real-time polymerase chain reaction (qRT-PCR), 756 samples were assessed for pfmdr1 gene copy number. PCR and restriction fragment length polymorphism (RFLP) were used to detect alleles of pfmdr1 86 in 1,102 samples, pfmdr1 184, 1034, 1042 and 1246 in 832 samples and pfcrt 76 in 1,063 samples. Merozoite surface protein 2 (msp2) genotyping was done to select monoclonal infections for copy number analysis. RESULTS: The percentage of isolates with increased pfmdr1 copy number were 4, 27, 9, and 18% for 2003-04, 2005-06, 2007-08 and 2010, respectively. Significant increasing trends for prevalence of pfmdr1 N86 (*(2) = 96.31, p <0.001) and pfcrt K76 (*(2) = 64.50, p <0.001) and decreasing trends in pfmdr1 Y86 (x(2) = 38.52, p <0.001) and pfcrt T76 (x(2) = 43.49, p <0.001) were observed from 2003-2010. The pfmdr1 F184 and Y184 prevalence showed an increasing and decreasing trends respectively but were not significant (*(2) = 7.39,p=0.060; *(2) = 7.49, p = 0.057 respectively). The pfmdr1 N86-F184-D1246 haplotype, which is alleged to be selected by artemether-lumefantrine showed a significant increasing trend (*(2) = 20.75, p < 0.001). CONCLUSION: Increased pfmdr1 gene copy number was observed in the isolates analysed and this finding has implications for the use of ACT in the country although no resistance has been reported. The decreasing trend in the prevalence of chloroquine resistance markers after change of treatment policy presents the possibility for future introduction of chloroquine as prophylaxis for malaria risk groups such as children and pregnant women in Ghana. PMID- 24172033 TI - Tricuspid valve obstruction and right heart failure due to a giant right atrial myxoma arising from the superior vena cava. AB - Myxomas are the most common primary cardiac tumors. The cardiac myxomas are mostly diagnosed within the atria, and only a few such tumors are reported to have arisen from atrioventricular valves or pulmonary vessels. The authors here present a case of 59-year-old Chinese woman who was hospitalized for exacerbating symptoms of tricuspid stenosis and right heart failure. Echocardiography revealed a giant right atrial myxoma arising from an extremely rare site, the anterior wall of the superior vena cava. With the aid of transesophageal echocardiography, the surgical resection was performed successfully with the patient achieving complete recovery. PMID- 24172034 TI - Protective effect of omega-3 fatty acid against mercury chloride intoxication in mice. AB - The aim of this study was to investigate the protective effect of omega-3 fatty acid in HgCI2 toxicity in mice. Levels of malondialdehyde (MDA), reduced glutathione (GSH), nitric oxide (NO) and total sialic acid (TSA), and histopathological changes in selected organs were evaluated. Twenty-eight mice were equally divided into 4 groups, namely Groups I-IV. Group I animals received intraperitoneal (ip) injection of physiological saline solution; Group II animals received ip injection of 0.4mg/kg/day HgCI2; Group III animals received ip injection of 0.4mg/kg/day HgCI2 in addition to subcutaneous (sc) injection of 0.5g/kg/day omega-3 fatty acid; and Group IV animals received sc injection of 0.5g/kg/day omega-3 fatty acid. All treatments lasted 7 days. The levels of MDA, NO and TSA were significantly higher in Group II and lower in Groups III and IV as compared to the Group I. GSH level was the highest in Group IV. In histopathology, severe degeneration in liver and kidney was observed in Group II animals. These degrading changes were seen to be reduced greatly in Group III animals. The results suggested that omega-3 fatty acid might attenuate HgCI2 induced toxicity by improving antioxidant status and acute phase response in mice. PMID- 24172035 TI - Severe mental illness and induction of labour: outcomes for women at a specialist antenatal clinic in Western Australia. AB - BACKGROUND: Limited evidence is available around induction of labour (IOL) and obstetric outcomes for pregnant women with severe mental illness (SMI). AIMS: Our study examined obstetric and neonatal outcomes for women attending a specialist childbirth and mental illness (CAMI) antenatal clinic in Perth, Western Australia (WA), who experienced or did not experience IOL. METHODS: A retrospective study was conducted between December 2007 and May 2012 (n = 222), using patient records and computerised perinatal data collected by the Obstetrics and Gynaecology Clinical Care Unit. Descriptive statistics and univariate comparisons using Mann Whitney tests and X(2) tests were conducted using SPSS. RESULTS: The overall rate of IOL in this study group was 40%, which was significantly higher than the WA Mother Baby Statistics by 11.6% (95% CI 4.9-18.3%, P < 0.002). Of those induced, 30% (27 of 185) were induced for psychiatric reasons. Women with schizophrenia were more likely to have IOL for an obstetric/fetal reason than a psychiatric reason (45% vs. 15%, P = 0.051). Women who experienced an IOL were less likely to have a spontaneous vaginal delivery (SVD) and more likely to have an assisted vaginal birth or emergency caesarean section (P = 0.040). Irrespective of labour onset, special care nursery admission (SCN) rates were similar and high for both groups (36% vs. 32%, P = 0.599). CONCLUSION: Obstetric management for women with SMI is complex, and psychiatric factors as well as medical factors must be considered to ensure the best outcomes for mother and infant. PMID- 24172036 TI - Immediate placement and loading of implants: minding the basics of bone biology. PMID- 24172037 TI - Vessel-wall imaging and quantification of flow-mediated dilation using water selective 3D SSFP-echo. AB - BACKGROUND: To introduce a new, efficient method for vessel-wall imaging of carotid and peripheral arteries by means of a flow-sensitive 3D water-selective SSFP-echo pulse sequence. METHODS: Periodic applications of RF pulses will generate two transverse steady states, immediately after and before an RF pulse; the latter being referred to as the SSFP-echo. The SSFP-echo signal for water protons in blood is spoiled as a result of moving spins losing phase coherence in the presence of a gradient pulse along the flow direction. Bloch equation simulations were performed over a wide range of velocities to evaluate the flow sensitivity of the SSFP-echo signal. Vessel walls of carotid and femoral and popliteal arteries were imaged at 3 T. In two patients with peripheral artery disease the femoral arteries were imaged bilaterally to demonstrate method's potential to visualize atherosclerotic plaques. The method was also evaluated as a means to measure femoral artery flow-mediated dilation (FMD) in response to cuff-induced ischemia in four subjects. RESULTS: The SSFP-echo pulse sequence, which does not have a dedicated blood signal suppression preparation, achieved low blood signal permitting discrimination of the carotid and peripheral arterial walls with in-plane spatial resolution ranging from 0.5 to 0.69 mm and slice thickness of 2 to 3 mm, i.e. comparable to conventional 2D vessel-wall imaging techniques. The results of the simulations were in good agreement with analytical solution and observations for both vascular territories examined. Scan time ranged from 2.5 to 5 s per slice yielding a contrast-to-noise ratio between the vessel wall and lumen from 3.5 to 17. Mean femoral FMD in the four subjects was 9%, in good qualitative agreement with literature values. CONCLUSIONS: Water selective 3D SSFP-echo pulse sequence is a potential alternative to 2D vessel wall imaging. The proposed method is fast, robust, applicable to a wide range of flow velocities, and straightforward to implement. PMID- 24172038 TI - BMI and sociodemographic correlates of body image perception and attitudes in school-aged children. AB - OBJECTIVE: The aim of the present study was to identify correlates of body image perception and dissatisfaction among school-aged children from Colombia, a country undergoing the nutrition transition. DESIGN: Cross-sectional study. Using child-adapted Stunkard scales, children were asked to indicate the silhouette that most closely represented their current and desired body shapes. Body image dissatisfaction (BID) score was estimated as current minus desired silhouette. Height and weight were measured in all children. Sociodemographic data were collected through questionnaires completed by the children's mothers. SETTING: Public primary schools in Bogota, Colombia. SUBJECTS: Children aged 5-12 years (n 629) and their mothers. RESULTS: Mean BID score was 0.1 (SD 1.7). The strongest predictor of BID was actual BMI-for-age Z-score (BAZ). Compared with children with BAZ >= -1 and < 1, those with BAZ >= 2 had a 1.9 units higher BID score (P for trend < 0.0001). BID tended to be higher in girls than boys at any level of BAZ. Other correlates of BID included child's height-for-age Z-score, maternal BMI and dissatisfaction with the child's body, and home ownership. CONCLUSIONS: Among school-aged children from a country experiencing the nutrition transition, body image perception was associated with the child's weight and height, and with maternal BMI, dissatisfaction with the child's body and socio-economic level. PMID- 24172039 TI - MazF6 toxin of Mycobacterium tuberculosis demonstrates antitoxin specificity and is coupled to regulation of cell growth by a Soj-like protein. AB - BACKGROUND: Molecular programs employed by Mycobacterium tuberculosis (Mtb) for the establishment of non-replicating persistence (NRP) are poorly understood. In order to investigate mechanisms regulating entry into NRP, we asked how cell cycle regulation is linked to downstream adaptations that ultimately result in NRP. Based on previous reports and our recent studies, we reason that, in order to establish NRP, cells are halted in the cell cycle at the point of septum formation by coupled regulatory mechanisms. RESULTS: Using bioinformatic consensus modeling, we identified an alternative cell cycle regulatory element, Soj(Mtb) encoded by rv1708. Soj(Mtb) coordinates a regulatory mechanism involving cell cycle control at the point of septum formation and elicits the induction of the MazF6 toxin. MazF6 functions as an mRNA interferase leading to bacteriostasis that can be prevented by interaction with its cognate antitoxin, MazE6. Further, MazEF6 acts independently of other Maz family toxin:antitoxin pairs. Notably, soj(Mtb) and mazEF6 transcripts where identified at 20, 40 and 100 days post infection in increasing abundance indicating a role in adaption during chronic infection. CONCLUSIONS: Here we present the first evidence of a coupled regulatory system in which cell cycle regulation via Soj(Mtb) is linked to downstream adaptations that are facilitated through the activity of the MazEF6 TA pair. PMID- 24172040 TI - A giant phyllodes tumour with sepsis. PMID- 24172041 TI - Body mass index and health-related quality of life among young Swiss men. AB - BACKGROUND: Studies about the association between body mass index (BMI) and health-related quality of life (HRQOL) are often limited, because they 1) did not include a broad range of health-risk behaviors as covariates; 2) relied on clinical samples, which might lead to biased results; and 3) did not incorporate underweight individuals. Hence, this study aims to examine associations between BMI (from being underweight through obesity) and HRQOL in a population-based sample, while considering multiple health-risk behaviors (low physical activity, risky alcohol consumption, daily cigarette smoking, frequent cannabis use) as well as socio-demographic characteristics. METHODS: A total of 5 387 young Swiss men (mean age = 19.99; standard deviation = 1.24) of a cross-sectional population based study were included. BMI was calculated (kg/m2) based on self-reported height and weight and divided into 'underweight' (<18.5), 'normal weight' (18.5 24.9), 'overweight' (25.0-29.9) and 'obese' (>=30.0). Mental and physical HRQOL was assessed via the SF-12v2. Self-reported information on physical activity, substance use (alcohol, cigarettes, and cannabis) and socio-demographic characteristics also was collected. Logistic regression analyses were conducted to study the associations between BMI categories and below average mental or physical HRQOL. Substance use variables and socio-demographic variables were used as covariates. RESULTS: Altogether, 76.3% were normal weight, whereas 3.3% were underweight, 16.5% overweight and 3.9% obese. Being overweight or obese was associated with reduced physical HRQOL (adjusted OR [95% CI] = 1.58 [1.18-2.13] and 2.45 [1.57-3.83], respectively), whereas being underweight predicted reduced mental HRQOL (adjusted OR [95% CI] = 1.49 [1.08-2.05]). Surprisingly, obesity decreased the likelihood of experiencing below average mental HRQOL (adjusted OR [95% CI] = 0.66 [0.46-0.94]). Besides BMI, expressed as a categorical variable, all health-risk behaviors and socio-demographic variables were associated with reduced physical and/or mental HRQOL. CONCLUSIONS: Deviations from normal weight are, even after controlling for important health-risk behaviors and socio demographic characteristics, associated with compromised physical or mental HRQOL among young men. Hence, preventive programs should aim to preserve or re establish normal weight. The self-appraised positive mental well-being of obese men noted here, which possibly reflects a response shift, might complicate such efforts. PMID- 24172042 TI - AXL/epidermal growth factor receptor (EGFR) complexes in breast cancer--culprits for resistance to EGFR inhibitors? AB - Epidermal growth factor receptor (EGFR) is highly expressed in triple-negative breast cancer (TNBC), and elevated levels correlate with poor prognosis. In analogy with the paradigm of oncogene addiction, blocking EGFR in TNBC was expected to have clinical efficacy - but this has not been the case. Reasons for these results have remained elusive. Recently, Meyer and colleagues showed interplay between EGFR and the epithelial-to-mesenchymal transition-associated AXL receptor in TNBC cells, which might provide some clues. PMID- 24172043 TI - Lack of sustained response of advanced dermatomyositis to autologous haematopoietic cell transplantation. PMID- 24172045 TI - Performance of a HRP-2/pLDH based rapid diagnostic test at the Bangladesh-India Myanmar border areas for diagnosis of clinical malaria. AB - BACKGROUND: The rapid diagnostic test (RDT) has been adopted in contemporary malaria control and management programmes around the world as it represents a fast and apt alternative for malaria diagnosis in a resource-limited setting. This study assessed the performance of a HRP-2/pLDH based RDT (Parascreen(r) Pan/Pf) in a laboratory setting utilizing clinical samples obtained from the field. METHODS: Whole blood samples were obtained from febrile patients referred for malaria diagnosis by clinicians from two different Upazila Health Complexes (UHCs) located near the Bangladesh-India and Bangladesh-Myanmar border where malaria is endemic. RDT was performed on archived samples and sensitivity and specificity evaluated with expert microscopy (EM) and quantitative PCR (qPCR). RESULTS: A total of 327 clinical samples were made available for the study, of which 153 were Plasmodium falciparum-positive and 54 were Plasmodium vivax positive. In comparison with EM, for P. falciparum malaria, the RDT had sensitivity: 96.0% (95% CI, 91.2-98.3) and specificity: 98.2% (95% CI, 94.6-99.5) and for P. vivax, sensitivity: 90.7% (95% CI, 78.9-96.5) and specificity: 98.9% (95% CI, 96.5-99.7). Comparison with qPCR showed, for P. falciparum malaria, sensitivity: 95.4% (95% CI, 90.5-98.0) and specificity: 98.8% (95% CI, 95.4-99.7) and for P. vivax malaria, sensitivity: 89.0% (95% CI,77.0-95.4) and specificity: 98.8% (95% CI, 96.5-99.7). Sensitivity varied according to different parasitaemia for falciparum and vivax malaria diagnosis. CONCLUSION: Parascreen(r) Pan/Pf Rapid test for malaria showed acceptable sensitivity and specificity in border belt endemic areas of Bangladesh when compared with EM and qPCR. PMID- 24172046 TI - Social factors affecting seasonal variation in bovine trypanosomiasis on the Jos Plateau, Nigeria. AB - BACKGROUND: African Animal Trypanosomiasis (AAT) is a widespread disease of livestock in Nigeria and presents a major constraint to rural economic development. The Jos Plateau was considered free from tsetse flies and the trypanosomes they transmit due to its high altitude and this trypanosomiasis free status attracted large numbers of cattle-keeping pastoralists to the area. The Jos Plateau now plays a major role in the national cattle industry in Nigeria, accommodating approximately 7% of the national herd, supporting 300,000 pastoralists and over one million cattle. During the past two decades tsetse flies have invaded the Jos Plateau and animal trypanosomiasis has become a significant problem for livestock keepers. Here we investigate the epidemiology of trypanosomiasis as a re-emerging disease on the Plateau, examining the social factors that influence prevalence and seasonal variation of bovine trypanosomiasis. METHODS: In 2008 a longitudinal two-stage cluster survey was undertaken on the Jos Plateau. Cattle were sampled in the dry, early wet and late wet seasons. Parasite identification was undertaken using species-specific polymerase chain reactions to determine the prevalence and distribution of bovine trypanosomiasis. Participatory rural appraisal was also conducted to determine knowledge, attitudes and practices concerning animal husbandry and disease control. RESULTS: Significant seasonal variation between the dry season and late wet season was recorded across the Jos Plateau, consistent with expected variation in tsetse populations. However, marked seasonal variations were also observed at village level to create 3 distinct groups: Group 1 in which 50% of villages followed the general pattern of low prevalence in the dry season and high prevalence in the wet season; Group 2 in which 16.7% of villages showed no seasonal variation and Group 3 in which 33.3% of villages showed greater disease prevalence in the dry season than in the wet season. CONCLUSIONS: There was high seasonal variation at the village level determined by management as well as climatic factors. The growing influence of management factors on the epidemiology of trypanosomiasis highlights the impact of recent changes in land use and natural resource competition on animal husbandry decisions in the extensive pastoral production system. PMID- 24172047 TI - Discography: the data, the myth, and reality. PMID- 24172048 TI - Retractor-assisted endoscopic nerve decompression in entrapment neuropathy. PMID- 24172049 TI - Predictors of outcome in patients with cervical spondylotic myelopathy undergoing surgical treatment: the evidence and the international common practice. PMID- 24172051 TI - Lipid-laden bronchoalveolar macrophages in asthma and chronic cough. AB - BACKGROUND: The presence of lipids in alveolar macrophages (AMs) may impair their phagocytic response, and determine airway inflammation and obstruction. OBJECTIVE: To determine the factors such as severity of asthma, chronic cough, airway inflammation and obesity that may influence the presence of lipids in lung macrophages. METHODS: Bronchoalveolar lavage fluid (BALF) was obtained from 38 asthmatics (21 severe and 17 mild/moderate), 16 subjects with chronic cough and 11 healthy control subjects. The presence of lipids in macrophages was detected using an Oil-red-O stain and an index of lipid-laden macrophages (LLMI) was obtained. RESULTS: LLMI scores were higher in healthy subjects (median 48 [IQR 10 61]) and the severe asthma group (37 [11.5-61]) compared to mild/moderate asthmatics (7 [0.5-37]; p < 0.05 each). Subjects reporting a history of gastro oesophageal reflux disease (GORD) had higher LLMI values (41.5 [11.3-138] versus 13 [0-39.3], p = 0.02). There was no significant correlation between LLMI and chronic cough, BAL cell differential counts, FEV1, FEV1/FVC or body mass index (BMI). CONCLUSIONS: The reduced LLMI in mild/moderate asthma may be related to lower incidence of GORD. However, this was not related to the degree of airflow obstruction, obesity or airway inflammation. PMID- 24172050 TI - Understanding the X chromosome inactivation cycle in mice: a comprehensive view provided by nuclear transfer. AB - During mouse development, imprinted X chromosome inactivation (XCI) is observed in preimplantation embryos and is inherited to the placental lineage, whereas random XCI is initiated in the embryonic proper. Xist RNA, which triggers XCI, is expressed ectopically in cloned embryos produced by somatic cell nuclear transfer (SCNT). To understand these mechanisms, we undertook a large-scale nuclear transfer study using different donor cells throughout the life cycle. The Xist expression patterns in the reconstructed embryos suggested that the nature of imprinted XCI is the maternal Xist-repressing imprint established at the last stage of oogenesis. Contrary to the prevailing model, this maternal imprint is erased in both the embryonic and extraembryonic lineages. The lack of the Xist repressing imprint in the postimplantation somatic cells clearly explains how the SCNT embryos undergo ectopic Xist expression. Our data provide a comprehensive view of the XCI cycle in mice, which is essential information for future investigations of XCI mechanisms. PMID- 24172053 TI - Surgical Training and Education in Promoting Professionalism: a comparative assessment of virtue-based leadership development in otolaryngology-head and neck surgery residents. AB - INTRODUCTION: Surgical Training and Education in Promoting Professionalism (STEPP) was developed in 2011 to train tomorrow's leaders during residency. It is based on virtue ethics and takes an approach similar to West Point military academy. The purpose of this research was: (i) to compare the virtue profiles of our residents with that of the military cohort using a standardized virtue assessment tool; and (ii) to assess the value of virtue education on residents. METHODS: As part of STEPP, otolaryngology residents participated in a virtue based validated assessment tool called Virtue in Action (VIA) Inventory. This was completed at the initiation of STEPP in July 2011 as well as 1 year later in June 2012. Comparison of the VIA to a military cohort was performed. Leadership 'Basic Training' is a series of forums focused on virtues of initiative, integrity, responsibility, self-discipline, and accountability. A pre- and post-test was administered assessing resident perceptions of the value of this 'Basic Training'. RESULTS: Virtues are shared between otolaryngology residents (n=9) and military personnel (n=2,433) as there were no significant differences in strength scores between two military comparison groups and otolaryngology-head and neck surgery (OHNS) residents. There was a significant improvement (p<0.001) in the understanding of components of the leadership vision and a significant improvement in the understanding of key leadership concepts based on 'Basic Training'. All residents responded in the post-test that the STEPP program was valuable, up from 56%. CONCLUSIONS: A virtue-based approach is valued by residents as a part of leadership training during residency. PMID- 24172054 TI - Moderate-dose glucocorticoids as salvage therapy for severe pneumonia in renal transplant recipients: a single-center feasibility study. AB - This study aimed to assess the effectiveness and safety of moderate-dose glucocorticoids (GCs) with mechanical ventilation as salvage therapy for renal transplant recipients with severe pneumonia, which was non-responsive to conventional treatment. A retrospective study was conducted involving renal transplant recipients diagnosed with severe pneumonia and did not respond to conventional treatment. All immunosuppressants were then completely withdrawn, and the patients were initially administered with methylprednisolone at doses of 2.0-2.5 mg/kg/day once every 12 h. This dosage was continued until oxygenation improved, and the treatment was gradually tapered (by 20 mg every 2-3 days) to the previous maintenance dosage. Ten patients were recruited from year 2008 to 2012. Two patients who underwent emergency endotracheal intubation were intubated on days 3 and 8, respectively, another one died from recurrent pneumothorax. The mean PaO2/FiO2 of the nine survivors was significantly increased by the increasing treatment duration; whereas the lung injury scores (LIS) and the sequential organ failure assessment (SOFA) score were both significantly decreased. The use of moderate-dose GCs may play a role as salvage therapy for renal transplant recipients with severe pneumonia. However, further study with larger trials to is needed. PMID- 24172055 TI - Automated preoperative assessment of endothelial dysfunction and risk stratification for perioperative myocardial injury in patients undergoing non cardiac surgery. AB - BACKGROUND: Myocardial injury after non-cardiac surgery (MINS) is a common complication with associated serious morbidity and mortality. Endothelial dysfunction might play an important role in MINS, and its rapid assessment could provide a novel method of risk stratification before surgery. METHODS: We studied 238 subjects scheduled to undergo intermediate or high-risk surgery in a two centre prospective study to determine whether preoperative endothelial dysfunction identified by a reactive hyperaemia-peripheral arterial tonometry (RH PAT) index could provide effective risk stratification for MINS, defined as serum troponin >=0.04 MUg litre(-1), within 3 postoperative days. RESULTS: The primary outcome occurred in 35 subjects (14.7%). Endothelial dysfunction was defined as an RH-PAT index of <=1.22. Adjusted for age, Lee index and a composite measure of the extent of surgery, endothelial dysfunction was associated with MINS [odds ratio 10.1, 95% confidence interval (CI) 3.3-30.9, P=0.001] and increased time to discharge from hospital after surgery (hazard ratio 0.39, 95% CI 0.23-0.65, P=0.001). Endothelial dysfunction identified MINS with a sensitivity of 31%, a specificity of 96%, and a positive diagnostic likelihood ratio of 8.0. Risk classification for MINS was improved by the addition of RH-PAT-defined endothelial dysfunction to the Lee index (c-statistic increased from 0.69 to 0.77; integrated discrimination improvement 0.11, P=0.003). However, prognostic utility varied widely between sites. CONCLUSIONS: For patients undergoing non cardiac surgery, non-invasive assessment of endothelial function might enhance preoperative risk stratification for perioperative myocardial injury. However, unexplained large inter-site variation in prognostic utility could limit widespread application and needs to be further understood. PMID- 24172056 TI - Flow dynamics using high-frequency jet ventilation in a model of bronchopleural fistula. AB - BACKGROUND: Positive pressure ventilation in patients with a bronchopleural fistula (BPF) is associated with variable, unpredictable gas leaks that can impair gas exchange. The optimum settings for high-frequency jet ventilation in this scenario are unclear. We investigated flow dynamics with BPFs of 2 and 10 mm, at various positions and with different jet ventilator settings in a bench top model. METHODS: A 2 or 10 mm length fistula was created at proximal, middle, or distal sites in standard artificial ventilator 'test' lungs and cadaveric porcine lungs. The effects of alterations in frequency, applied pressure, and on entrained, expired, and leak volumes were determined using gauge and differential pressure sensors. RESULTS: Entrained, delivered, and leak volumes were affected markedly by ventilator settings, particularly frequency: leaks were much greater at frequencies <100 min(-1). The leak/expired volume ratio varied between 0% and 92%. Leak and entrained volumes increased progressively with more proximally situated fistulae, whereas the measured expired volume decreased. Leak volumes with a 2 mm fistula were approximately half that of a 10 mm fistula across all ventilator frequencies. All volumes increased with increased driving pressure. The optimum injection time varied depending on BPF position and the accepted compromise between leak and expired volumes. Entrained volume contributed up to 50% of the total tidal volume. CONCLUSIONS: These data suggest that gas leak will be minimized and ventilator volumes maintained during jet ventilation using frequencies >200 min(-1) and lower driving pressures, but confirmatory clinical studies are required. Values displayed by the jet ventilator are unreliable. PMID- 24172057 TI - Earplugs and eye masks vs routine care prevent sleep impairment in post anaesthesia care unit: a randomized study. AB - BACKGROUND: Post-anaesthesia care units (PACUs) with 24/7 activity and consequently artificial light and noise may disturb the sleep of patients who require prolonged medical supervision. After one postoperative night, we compared sleep quality in patients with and without noise (earplug) and light (eye mask) protection. METHODS: After ethical board approval, 46 patients without any neurological or respiratory failure undergoing major non-cardiac surgery were prospectively included. They were randomized to sleep with or without protective devices during the first postoperative night in the PACU. Sleep quality was simultaneously measured by sleep-quality scales (Spiegel score and Medical Outcomes Study Sleep), nurses' assessment, and through a wrist actigraph (Actiwatch). Secondary outcomes such as pain control and nocturnal activity were recorded. Comparisons between groups were made by Student's t-test or non parametric test for repeated measures as appropriate (SPSS 10.0). A P-value <0.05 was considered significant. RESULTS: Data from 41 patients were analysed. Protective devices during the first postoperative night prevented a decrease in sleep quality compared with standard care, as evaluated by the Spiegel scale: 20 (4) vs 15 (5), P=0.006. These devices significantly decreased the need for a nap [50% 95% confidence interval (CI) (20-80) vs 95% 95% CI (85-100), P<0.001], but had no effect on sleep length evaluated by Actiwatch. The total consumption of morphine was significantly reduced in the first 24 h [respectively, 15(12) mg and 27(17) mg, P=0.02]. CONCLUSIONS: Earplugs and eye masks applied in the PACU during the first postoperative night significantly preserve sleep quality. Such non-invasive and cheap devices may be generalized in the PACU or in intensive care units. PMID- 24172058 TI - Effect of laser phototherapy on enzymatic activity of salivary glands of hamsters treated with 5-Fluorouracil. AB - The chemotherapeutic agent 5-Fluorouracil (5-FU) can induce salivary gland hypofunction (SGH); however, previous studies did not reach final conclusions on the influence of this drug on glandular tissue. Thus, the aim of this study was to investigate the effect of 5-FU on submandibular (SMs) and sublingual glands (SLs), as well as, the effect of laser phototherapy (LPT) on SGH induced by 5-FU. Eighty-five hamsters were divided into three groups: control (C), chemotherapy (CT) and laser (L), and the SGH was induced by two injections of 5-FU in groups CT and L. The irradiation was performed using a diode (lambda780 nm/20 mW/5 J cm( 2)/0.2 J and 10 s per point/spot size of 0.04 cm(2)) and applied daily. On the euthanasia day, SMs and SLs were removed and biochemical analyses were carried out. The lactate dehydrogenase activity was increased in group CT when compared with group C for SLs and SMs (P < 0.05). In addition, the peroxidase and catalase activities were increased and superoxide dismutase was decreased by 5-FU (P < 0.05). However, LPT appears to be a protective mechanism against oxidative stress, tending to alter the activity of these antioxidant enzymes, suggesting LPT as a promising therapy to modulate the 5-FU harmful effect. PMID- 24172059 TI - The mechanisms of action of plasma exchange. AB - The initial description of therapeutic plasma exchange (TPE) in an animal model was published almost 100 years ago. Since that time, this treatment has been applied to a wide variety of diseases but limited research has been published examining the mechanisms of action of TPE. The therapeutic effects of TPE could include the removal of pathological substances from the blood, such as monoclonal paraproteins and autoantibodies, as well as the replacement of deficient plasma components when plasma is used as a replacement fluid. Beyond these potential mechanisms, other possible mechanisms include possible alterations in lymphocyte proliferation and function that could sensitize these cells to immunosuppressant and chemotherapeutic agents and alterations in the immune system including changes in B and T cell numbers and activation, increased T suppressor function, and alteration in T-helper cell type 1/2 (Th1/Th2) ratio. Much remains unknown about the mechanisms of action of TPE, indicating a need for basic research into this therapy. PMID- 24172060 TI - Cytochalasin H, an active anti-angiogenic constituent of the ethanol extract of Gleditsia sinensis thorns. AB - Angiogenesis, the process of new vessel formation from the pre-existing blood vasculature, is critical for continuous tumor growth and is considered to be a validated antitumor target. The results of our previous study demonstrate the anti-angiogenic potential of an extract of Gleditsia sinensis thorns, which has been traditionally used in Korean medicine to remedy diverse diseases, including tumors. In the present study, we attempted to identify the active anti-angiogenic constituents of the ethanol extract of G. sinensis thorns (EEGS). By virtue of in vitro activity-guided fractionation using human umbilical vein endothelial cells (HUVEC) primary endothelial cells, chromatographic separation, and NMR spectral analyses, we isolated and identified the potent active constituent, cytochalasin H, a biologically active secondary metabolite of fungi. This unexpected active constituent may have originated from the endophytic fungi, Chaetomium globosum, which naturally populate G. sinensis, the identity of which was determined by analysis of fungal community. Cytochalasin H isolated from the EEGS showed in vitro anti-angiogenic activities such as suppressed cell growth and mobility in HUVEC, and inhibited the pro-angiogenic protein-induced formation of new blood vessels in vivo. The anti-angiogenic effect of cytochalasin H was in part due to reduced expression of pro-angiogenic factor, such as endothelin-1. This is the first report regarding the isolation and identification of cytochalasin H, as an active anti-angiogenic constituent of G. sinensis thorns. PMID- 24172061 TI - Different effects of epigenetic modifiers on the cytotoxicity induced by 5 fluorouracil, irinotecan or oxaliplatin in colon cancer cells. AB - We investigated the effects of epigenetic modifiers such as DNA methyltransferase (DNMT) or histone deacetylase (HDAC) inhibitors on the cytotoxicity induced by 3 anticancer drugs (5-fluorouracil (5-FU), irinotecan (CPT-11) or its active form SN38, and oxaliplatin (L-OHP)) in human colorectal cancer (CRC) cells. Cytotoxicity in 4 CRC cell lines (HT29, SW480, SW48 and HCT116) was examined by colorimetric assay after drug treatment for 72 h. The effects of drug combinations were analyzed by an isobologram method. SW480 cells showed the lowest sensitivity to cytotoxicity induced by the anticancer drugs among the 4 CRC cell lines. In SW480 cells, DNMT inhibitors, such as decitabine (DAC), azacytidine and zebularine (Zeb), showed synergic effects on the cytotoxicity induced by anticancer drugs except for SN-38 plus Zeb, while HDAC inhibitors, trichostatin A, suberoylanilide hydroxamic acid and valproic acid, showed antagonistic effects. DAC showed the most potent synergic effects among the epigenetic modifiers studied. Thus, we examined whether the synergic effect of DAC is observed in other different CRC cell lines, HT29, SW48 and HCT116 cells. In all 4 CRC cell lines, the cytotoxicity of L-OHP was enhanced in a synergic manner by co-treatment with DAC. However, synergic effects of DAC with 5-FU or CPT-11 (SN-38) were not observed in 4 CRC cell lines. PMID- 24172062 TI - Identification and detection of genetically modified papaya resistant to papaya ringspot virus strains in Thailand. AB - Many lines of genetically modified (GM) papaya (Carica papaya Linnaeus) have been developed worldwide to resist infection from various strains of papaya ringspot virus (PRSV). We found an unidentified and unauthorized GM papaya in imported processed papaya food. Transgenic vector construct that provides resistance to the PRSV strains isolated in Thailand was detected. An original and specific real time polymerase chain reaction method was generated to qualitatively detect the PRSV-Thailand-resistant GM papaya. PMID- 24172063 TI - Risk factors for childhood overweight: a 30-month longitudinal study of 3- to 6 year-old children. AB - OBJECTIVE: The increasing prevalence of childhood overweight is an important health issue. There is a need for longitudinal research among children in order to identify risk factors for childhood overweight. The objective of the present research was to identify potential sociodemographic and behavioural risk factors for development of childhood overweight among 3- to 6-year-old children. DESIGN: Longitudinal study. SETTING: Sixteen pre-primary and primary schools. SUBJECTS: BMI Z-scores at baseline and two follow-up measurements were calculated for 568 children. Sociodemographic, parental adiposity, familial composition, child's diet, physical activity and sedentary behavioural data were collected through questionnaires. RESULTS: Several risk factors for the development of childhood overweight were found. Being an only child, lower maternal educational level, maternal and paternal overweight, more than 1 h screen time on weekdays and high soft drinks consumption were shown to be positively associated with the development of childhood overweight. CONCLUSIONS: Although behavioural factors are important, our findings support the thesis that interventions on the prevention of childhood overweight should focus on high-risk groups, i.e. children from low socio-economic background or with high parental BMI. Interventions should address the whole family and take into account their lifestyle and structure. PMID- 24172065 TI - Plasma surface modification of rigid contact lenses decreases bacterial adhesion. AB - OBJECTIVE: Contact lens safety is an important topic in clinical studies. Corneal infections usually occur because of the use of bacteria-carrying contact lenses. The current study investigated the impact of plasma surface modification on bacterial adherence to rigid contact lenses made of fluorosilicone acrylate materials. METHODS: Boston XO and XO2 contact lenses were modified using plasma technology (XO-P and XO2-P groups). Untreated lenses were used as controls. Plasma-treated and control lenses were incubated in solutions containing Staphylococcus aureus or Pseudomonas aeruginosa. MTT colorimetry, colony-forming unit counting method, and scanning electron microscopy were used to measure bacterial adhesion. RESULTS: MTT colorimetry measurements showed that the optical density (OD) values of XO-P and XO2-P were significantly lower than those of XO and XO2, respectively, after incubation with S. aureus (P < 0.01). The OD value of XO-P was also much lower than that of XO after incubation with P. aeruginosa (P < 0.01). Colony-forming unit counting revealed that a significantly lower number of bacterial colonies attached to the XO-P versus XO lenses and to the XO2 P versus XO2 lenses incubated with S. aureus (P < 0.01). Fewer bacterial colonies attached to the XO-P versus XO lenses incubated with P. aeruginosa (P < 0.01). Further, scanning electron microscopy suggested different bacterial adhesion morphology on plasma-treated versus control lenses. CONCLUSION: Plasma surface modification can significantly decrease bacterial adhesion to fluorosilicone acrylate contact lenses. This study provides important evidence of a unique benefit of plasma technology in contact lens surface modification. PMID- 24172064 TI - Influenza vaccination acceptance among diverse pregnant women and its impact on infant immunization. AB - OBJECTIVE: We examined pregnant women's likelihood of vaccinating their infants against seasonal influenza via a randomized message framing study. Using Prospect Theory, we tested gain- and loss-frame message effects and demographic and psychosocial correlates of influenza immunization intention. We also explored interactions among pregnant women who viewed "Contagion" to understand cultural influences on message perception. METHODS: Pregnant women ages 18-50 participated in a randomized message framing study from September 2011 through May 2012 that included exposure to intervention or control messages, coupled with questionnaire completion. Venue-based sampling was used to recruit racial and ethnic minority female participants at locations throughout Atlanta, Georgia. Bivariate and multivariate analyses were conducted to evaluate key outcomes. RESULTS: The study population (n = 261) included many lower income (<= $20,000/yearly household earnings) pregnant participants (69.2%, n = 171) inclusive of Black/African Americans (88.5%, n = 230), Hispanic/Latinas (7.3%, n = 19), and Other/Multicultural women (4.2%, n = 11). Both gain [OR = 2.13, 90% CI: (1.120, 4.048)] and loss-frame messages [OR = 2.02, 90% CI: (1.083, 3.787)] were significantly associated with infant influenza vaccination intention compared with the control condition. Intention to immunize against influenza during pregnancy had a strong effect on intent to immunize infants [OR = 10.83, 90%CI: (4.923, 23.825)]. Those who had seen the feature film "Contagion" (n = 54, 20.69%) viewed gain- and loss-framed messages as appealing (x (2) = 6.03, p = 0.05), novel (x (2) = 6.24, p = 0.03), and easy to remember (x (2) = 16.33, P = 0.0003). CONCLUSIONS: In this population, both gain- and loss-framed messages were positively associated with increased maternal intent to immunize infants against influenza. Message resonance was enhanced among those who saw the film "Contagion." Additionally, history of immunization was strongly associated with infant immunization intention. : PMID- 24172066 TI - Subjective satisfaction in long-term orthokeratology patients. AB - PURPOSE: To evaluate the subjective satisfaction in visual stability, night vision complains, and light distortion phenomena, and also the number of hours and days per week of lens wear, in patients with myopia undergoing orthokeratology (OK) treatment for at least 1 year. METHODS: A visual analog scale (VAS) questionnaire containing 18 items was administered to 44 patients, 29 women and 15 men (mean age, 24.39 +/- 9.11 years), with a baseline spherical equivalent refractive error of -2.40 +/- 0.94 diopters and astigmatism up to -0.5 diopters. Average treatment period by the time of data collection was 19 +/- 7 months. Patients rated their satisfaction with the correction, with complaints of visual distortion being graded on a scale of 0 to 10, where 0 indicated no discomfort at all. RESULTS: More than 50% of patients skipped lens wear at least 1 night per week. The most common wearing pattern was 6-8 hours a day for 72.7% with 54.5% of patients wearing lenses every 2-3 nights only. Subjective vision scores after lens removal was 9.1 +/- 1.1 after having worn the lenses and 8.1 +/ 1.4 after skipping lens wear for 1 night. Subjective vision scores before lens insertion at the end of the day was 6.9 +/- 2.0 and 5.8 +/- 2.4, respectively. The number of hours until noticeable blur reduced with increased level of baseline myopia (r = 0.396; P < 0.001). CONCLUSION: Orthokeratology patients show an irregular wearing pattern after 1 year of treatment that has significant effects on the subjective visual performance over the next day of skipping lens wear. Light distortion under low-light conditions seems to be a transient complication of the treatment and most of the patients report an improvement after the first weeks of treatment. PMID- 24172067 TI - Ultraviolet A and riboflavin therapy as an adjunct in corneal ulcer refractory to medical treatment. AB - OBJECTIVE: To present a case of corneal ulcer unresponsive to medical treatment, successfully treated with the use of ultraviolet (UV) A and riboflavin collagen crosslinking (CXL) administered twice. METHODS: A 68-year-old diabetic male patient was diagnosed with unilateral severe corneal ulcer. Gram and Giemsa stains and corneal culture results were performed twice, but no specific pathogen could be detected. The clinical presentation suggested fungal infection. The ulcer was unresponsive to extensive medical treatment administered for 10 days. There was an initial response to topical and intrastromal voriconazole administration; however, this was followed by reactivation. Therefore, UVA riboflavin treatment was performed when the patient was still on medical therapy. RESULTS: The stromal infiltrate appeared inactive 1 week after UVA-riboflavin CXL treatment. However, reactivation was noticed on the second week, and a second UVA riboflavin treatment was planned and performed 3 weeks after the first one. The epithelial defect disappeared, and the stromal infiltrate stayed inactive starting from the first week of the second UVA-riboflavin treatment until the last follow-up examination at month 6. CONCLUSION: The UVA-riboflavin CXL may be considered in the management of corneal ulcers unresponsive to medical management. PMID- 24172068 TI - Top Notch cancer stem cells by paracrine NF-kappaB signaling in breast cancer. AB - Cancer stem cells are likely to play critical roles in metastasis, therapy resistance, and recurrence of hematological and solid malignancies. It is well known that the stem cell niche plays a key role for asymmetric division and homeostasis of normal stem cells, whereas cancer stem cells seem to use these niches. Among many pathways involved in self-renewal of cancer stem cells, nuclear factor-kappa B (NF-kappaB) signaling has been documented to promote their expansion in a cell-autonomous fashion. A recent study, however, suggests that paracrine NF-kappaB activation promotes the expansion of cancer stem cells through the activation of Notch in basal-type breast cancer cells. PMID- 24172069 TI - Routine mapping of Fusarium wilt resistance in BC(1) populations of Arabidopsis thaliana. AB - BACKGROUND: Susceptibility to Fusarium wilt disease varies among wild accessions of Arabidopsis thaliana. Six RESISTANCE TO FUSARIUM OXYSPORUM (RFO) quantitative trait loci (QTLs) controlling the resistance of accession Columbia-0 (Col-0) and susceptibility of Taynuilt-0 to Fusarium oxysporum forma specialis matthioli (FOM) are detected in a recombinant population derived from a single backcross of the F1 hybrid (BC1). In particular, the RFO1 QTL appears to interact with three other loci, RFO2, RFO4 and RFO6, and is attributed to the gene At1g79670. RESULTS: When resistance to FOM was mapped in a new BC(1) population, in which the loss-of-function mutant of At1g79670 replaced wild type as the Col-0 parent, RFO1's major effect and RFO1's interaction with RFO2, RFO4 and RFO6 were absent, showing that At1g79670 alone accounts for the RFO1 QTL. Resistance of two QTLs, RFO3 and RFO5, was independent of RFO1 and was reproduced in the new BC(1) population. In analysis of a third BC1 population, resistance to a second pathogen, F. oxysporum forma specialis conglutinans race 1 (FOC1), was mapped and the major effect locus RFO7 was identified. CONCLUSIONS: Natural quantitative resistance to F. oxysporum is largely specific to the infecting forma specialis because different RFO loci were responsible for resistance to FOM and FOC1. The mapping of quantitative disease resistance traits in BC(1) populations, generated from crosses between sequenced Arabidopsis accessions, can be a routine procedure when genome-wide genotyping is efficient, economical and accessible. PMID- 24172070 TI - Changes of Marginal Bone Level in Patients with "Progressive Bone Loss" at Branemark System(r) Implants: A Radiographic Follow-Up Study over an Average of 9 Years. AB - BACKGROUND: Patients have in many studies been identified with progressive bone loss and peri-implantitis problems, but few studies are available where these groups of patients have been followed up. PURPOSE: The purpose of this paper is to study further progression of bone loss in a cohort of 182 patients that have been reported to suffer from "progressive" bone loss and peri-implantitis. MATERIALS AND METHODS: Altogether, 182 patients that have earlier been identified to suffer from "progressive" bone loss formed the present study group. Data from patients' files have been retrieved, and intraoral radiographs have been analyzed for further bone level changes. Bone loss has been measured from time of inclusion into the present group to last available radiographs. Within each patient, one or several implants were diagnosed to suffer from "progressive" bone loss (affected), whereas others are not (unaffected). RESULTS: Altogether, 145 patients (80%) were radiographically followed up on an average of 9.1 years (SD 3.77) after inclusion. Twenty-four implants (3.1%) were lost in 16 patients (11%). Marginal bone loss was on an average 0.3 mm (SD 0.75) at stable implants with only small differences between "affected" and "unaffected" implants. In total, 67 implants (8.6%) presented an annual bone loss of >0.2 mm. Oral hygienist treatment and/or peri-implantitis surgery did not neither reduce implant failure rate nor marginal bone loss in 88 treated patients as compared with untreated patients. CONCLUSIONS: Less than one-third of the patients identified with "progressive bone loss" showed one or more implants as failures or with high annual bone loss (>0.2 mm) during follow-up (11.6% of implants). Treated patients (oral hygienist and/or surgery) did not perform better than untreated patients with regard to bone loss or implant failure. PMID- 24172071 TI - Giant lateral left ventricular wall aneurysm sparing the submitral apparatus. AB - Left ventricular aneurysms are a frequent and serious complication following acute transmural myocardial infarction and are most commonly located at the ventricular apex. The majority of these patients presents with severe mitral insufficiency, congestive heart failure, systemic embolism and sudden cardiac death. Giant aneurysms occurring in a submitral position between anterior and posterior papillary muscles on the lateral ventricular wall constitute a minor entity and those leaving the mitral apparatus intact are extremely rare.Herein, we report the case of a 57 y/o Caucasian male patient with a past medical history of coronary artery disease and myocardial infarction with a giant left ventricular aneurysm measuring 15x10x8 cm in diameter. Despite the size of the aneurysm and its close topographical relation to the posterior mitral annulus the mitral apparatus was intact with a competent valve and normal left atrial size. He underwent successful surgical ventricular restoration. PMID- 24172072 TI - Superficial thrombophlebitis of the abdominal veins as a complication of ruptured aortocaval fistula surgery. PMID- 24172073 TI - Adult human nasal mesenchymal-like stem cells restore cochlear spiral ganglion neurons after experimental lesion. AB - A loss of sensory hair cells or spiral ganglion neurons from the inner ear causes deafness, affecting millions of people. Currently, there is no effective therapy to repair the inner ear sensory structures in humans. Cochlear implantation can restore input, but only if auditory neurons remain intact. Efforts to develop stem cell-based treatments for deafness have demonstrated progress, most notably utilizing embryonic-derived cells. In an effort to bypass limitations of embryonic or induced pluripotent stem cells that may impede the translation to clinical applications, we sought to utilize an alternative cell source. Here, we show that adult human mesenchymal-like stem cells (MSCs) obtained from nasal tissue can repair spiral ganglion loss in experimentally lesioned cochlear cultures from neonatal rats. Stem cells engraft into gentamicin-lesioned organotypic cultures and orchestrate the restoration of the spiral ganglion neuronal population, involving both direct neuronal differentiation and secondary effects on endogenous cells. As a physiologic assay, nasal MSC-derived cells engrafted into lesioned spiral ganglia demonstrate responses to infrared laser stimulus that are consistent with those typical of excitable cells. The addition of a pharmacologic activator of the canonical Wnt/beta-catenin pathway concurrent with stem cell treatment promoted robust neuronal differentiation. The availability of an effective adult autologous cell source for inner ear tissue repair should contribute to efforts to translate cell-based strategies to the clinic. PMID- 24172074 TI - Eating out is associated with self-reported food poisoning: a Western Australia population perspective, 1998 to 2009. AB - OBJECTIVE: To explore factors associated with self-reported food poisoning among Western Australian adults between 1998 and 2009. DESIGN: Data were pooled from four Nutrition Monitoring Surveys Series which included information on suspected food poisoning among Western Australian adults. Descriptive statistics and multinomial regression analyses were used to describe factors associated with self-reported food poisoning, food safety knowledge and behaviours. SETTING: Population of Western Australia estimated to be 2.5 million in 2009. SUBJECTS: A representative sample of 4494 adults aged between 18 and 64 years. RESULTS: There was no significant change in self-reported food poisoning over time, with about 18 % saying they had suspected food poisoning in the last 6 months. Overall, 2.1% said they had confirmed their food-borne illness with a nurse of doctor. People less than 34 years old, those with a university degree and people who ate meals out on the day prior to the survey (one meal: OR = 1.30, 95% CI 1.04, 1.62; two meals: OR = 2.21, 95% CI 1.30, 3.76) were the most likely to report food poisoning. Younger people were also more likely to have their food poisoning confirmed by a health professional. Use of refrigerator thermometers and cool bags for storing food increased significantly between 2004 and 2009. CONCLUSIONS: Findings support the inclusion of food safety advice in dietary recommendations. Food safety and handling education and training is recommended for food businesses, particularly the takeaway food sector, and for consumers. Because food poisoning is reported more often by younger people, food safety education should begin during childhood. PMID- 24172075 TI - Off-pump coronary artery bypass grafting does not increase the 1-year mortality compared to on-pump: a meta-analysis of randomized controlled trials. PMID- 24172076 TI - Usefulness of phase analysis to differentiate ischemic and non-ischemic etiologies of left ventricular systolic dysfunction in patients with heart failure. AB - BACKGROUND: The detection of significant coronary artery disease (CAD) in patients with heart failure (HF) from left ventricular (LV) systolic dysfunction is crucial. We evaluated the usefulness of LV mechanical dyssynchrony as assessed by phase analysis compared with conventional gated single-photon emission computed tomography to identify ischemic etiology in patients with HF. METHODS AND RESULTS: Forty-one consecutive patients who were initially admitted to hospital due to HF resulting from systolic dysfunction were evaluated. All patients underwent cardiac catheterization. LV mechanical dyssynchrony was evaluated using SyncToolTM to obtain the phase SD and histogram bandwidth. The changes in phase SD and histogram bandwidth with stress were calculated. The summed stress score, summed difference score, and changes in phase SD and histogram bandwidth with stress were greater in 26 patients with CAD than in 15 patients without CAD (P=0.001 and P=0.01). On multivariate analysis a phase SD of >14 degrees (odds ratio [OR], 16.7) and a summed stress score of >17 (OR, 8.0) best differentiated LV dysfunction of ischemic and non-ischemic etiologies, with a sensitivity of 89% and a specificity of 87% (chi(2)=20), compared with summed stress score only (sensitivity, 46%; specificity, 87%; chi(2)=4.5). CONCLUSIONS: The addition of phase analysis to conventional perfusion analysis enables better differentiation of the etiology of HF in patients with systolic dysfunction. PMID- 24172077 TI - Histological characteristics of myocardial bridge with an ultrasonic echolucent band. Comparison between intravascular ultrasound and histology. PMID- 24172078 TI - Clinical and echocardiographic correlates of mortality in medically treated patients with severe isolated aortic stenosis and normal left ventricular ejection fraction. AB - BACKGROUND: Many symptomatic patients with severe aortic stenosis (AS) and preserved left ventricular ejection fraction (LVEF) are denied surgery and have a grim prognosis with medical management. METHODS AND RESULTS: Between 2003 and 2012, among 550 patients with severe isolated AS and preserved LVEF on transthoracic echocardiography, 241 did not undergo aortic valve replacement (mean age, 83.2+/-7.6 years; 54% female; aortic valve area index, 0.40+/ 0.13cm(2)/m(2); mean LVEF, 64.8+/-7.6%) and 67% presented with cardiac symptoms. At a mean follow-up of 25.5+/-25.1 months, 134 patients (56%) had died. Survival at 1, 5 and 9.5 years was 71%, 28% at 12%, respectively. Median survival was 36.3 months (95% confidence interval [CI]: 27.2-42.4 months). In unadjusted analyses, age, heart failure, hypertension, renal insufficiency, left atrial size, pulmonary artery systolic pressure (PASP), relative wall thickness and LV mass/LV end diastolic volume ratio were associated with mortality. On multivariate analysis adjusted for all significant univariate predictors, age >=78 years, history of hypertension, left atrial diameter >=40mm and PASP >=42mmHg gave a joint area under the curve of 0.80 (95% CI: 0.73-0.86) for mortality. CONCLUSIONS: In medically treated patients with severe isolated AS and preserved LVEF, older age, history of hypertension, and echo-Doppler variables reflecting LV diastolic dysfunction are independent predictors of death. PMID- 24172079 TI - Photodynamic and Nail Penetration Enhancing Effects of Novel Multifunctional Photosensitizers Designed for The Treatment of Onychomycosis. AB - Novel multifunctional photosensitizers (MFPSs), 5,10,15-tris(4-N methylpyridinium)-20-(4-phenylthio)-[21H,23H]-porphine trichloride (PORTH) and 5,10,15-tris(4-N-methylpyridinium)-20-(4-(butyramido-methylcysteinyl) hydroxyphenyl)-[21H,23H]-porphine trichloride (PORTHE), derived from 5,10,15 Tris(4-methylpyridinium)-20-phenyl-[21H,23H]-porphine trichloride (Sylsens B) and designed for treatment of onychomycosis were characterized and their functionality evaluated. MFPSs should function as nail penetration enhancer and as photosensitizer for photodynamic treatment (PDT) of onychomycosis. Spectrophotometry was used to characterize MFPSs with and without 532 nm continuous-wave 5 mW cm(-2) laser light (+/- argon/mannitol/NaN3 ). Nail penetration enhancement was screened (pH 5, pH 8) using water uptake in nails and fluorescence microscopy. PDT efficacy was tested (pH 5, +/- argon/mannitol/NaN3 ) in vitro with Trichophyton mentagrophytus microconida (532 nm, 5 mW cm(-2) ). A light-dependent absorbance decrease and fluorescence increase were found, PORTH being less photostable. Argon and mannitol increased PORTH and PORTHE photostability; NaN3 had no effect. PDT (0.6 J cm(-2) , 2 MUm) showed 4.6 log kill for PORTH, 4.4 for Sylsens B and 3.2 for PORTHE (4.1 for 10 MUm). Argon increased PORTHE, but decreased PORTH PDT efficacy; NaN3 increased PDT effect of both MFPSs whereas mannitol increased PDT effect of PORTHE only. Similar penetration enhancement effects were observed for PORTH (pH 5 and 8) and PORTHE (pH 8). PORTHE is more photostable, effective under low oxygen conditions and thus realistic candidate for onychomycosis PDT. PMID- 24172080 TI - Amorphous calcium phosphate nanoparticles could function as a novel cancer therapeutic agent by employing a suitable targeted drug delivery platform. AB - Employment of nanovehicular system for delivering apoptogenic agent to cancer cells for inducing apoptosis has widely been investigated. Loading efficacy and controlled release of the agents are of the inseparable obstacles that hamper the efforts in reaching an efficacious targeted cancer therapy method. When the carrier itself is apoptogenic, then there is no need to load the carrier with apoptogenic agent and just delivering of the particle to the specific location matters. Hence, we hypothesize that amorphous calcium phosphate nanoparticle (ACPN) is a potent candidate for apoptosis induction, although encapsulation in liposome shell, and surface decoration with targeting ligand (TL), and cell penetrating peptide (CPP) plays a pivotal role in the employment of this agent. It is well understood that elevation in cytosolic Ca2+ ([Ca2+]c) would result in the induction of apoptosis. ACPN has the potential to cause imbalance in this medium by elevating [Ca2+]c. Owning to the fact that the nanoparticles should be delivered into cytosol, it is necessary to trap them in a liposomal shell for evading endocytosis. It was demonstrated that employment of the trans-activator of transcription (TAT) as CPP eminently enhances the efficacy of endosomal escape; therefore, the platform is designed in a way that TAT is positioned on the surface of the liposome. Due to the fact that the apoptosis should be induced in sole cancer cells, Folate as TL is also attached on the surface of the liposome. This hypothesis heralds the new generation of chemotherapeutic agents and platforms which could have less side effect than the most common ones, in addition to other advantages they have. PMID- 24172081 TI - Haematopoietic cell transplantation for acute leukaemia and advanced myelodysplastic syndrome in Fanconi anaemia. AB - Acute leukaemia or advanced myelodysplastic syndrome (MDS >= 5% blasts) in Fanconi anaemia (FA) patients is associated with a poor prognosis. We report 21 FA patients with acute leukaemia or advanced MDS who underwent haematopoietic cell transplantation (HCT) at the University of Minnesota between 1988 and 2011. Six patients had biallelic BRCA2 mutations. Eight patients received pre transplant cytoreduction, with 3 achieving complete remission. HCT donor source included human leucocyte antigen-matched sibling (n = 2) or alternative donors (n = 19). Neutrophil engraftment was 95% for the entire cohort, and the incidence of acute graft-versus-host disease was 19%. 5-year overall survival (OS) was 33%, with a relapse rate of 24%, with similar OS in patients with biallelic BRCA2 mutations. Our study supports the use of HCT in the treatment of FA patients with acute leukaemia or advanced MDS, however, the role of chemotherapy prior to HCT remains unclear for this population. FA patients with biallelic BRCA2 are unique and may benefit from higher dose chemotherapy relative to other complementation groups. PMID- 24172082 TI - Using hierarchical Bayesian binary probit models to analyze crash injury severity on high speed facilities with real-time traffic data. AB - Severe crashes are causing serious social and economic loss, and because of this, reducing crash injury severity has become one of the key objectives of the high speed facilities' (freeway and expressway) management. Traditional crash injury severity analysis utilized data mainly from crash reports concerning the crash occurrence information, drivers' characteristics and roadway geometric related variables. In this study, real-time traffic and weather data were introduced to analyze the crash injury severity. The space mean speeds captured by the Automatic Vehicle Identification (AVI) system on the two roadways were used as explanatory variables in this study; and data from a mountainous freeway (I-70 in Colorado) and an urban expressway (State Road 408 in Orlando) have been used to identify the analysis result's consistence. Binary probit (BP) models were estimated to classify the non-severe (property damage only) crashes and severe (injury and fatality) crashes. Firstly, Bayesian BP models' results were compared to the results from Maximum Likelihood Estimation BP models and it was concluded that Bayesian inference was superior with more significant variables. Then different levels of hierarchical Bayesian BP models were developed with random effects accounting for the unobserved heterogeneity at segment level and crash individual level, respectively. Modeling results from both studied locations demonstrate that large variations of speed prior to the crash occurrence would increase the likelihood of severe crash occurrence. Moreover, with considering unobserved heterogeneity in the Bayesian BP models, the model goodness-of-fit has improved substantially. Finally, possible future applications of the model results and the hierarchical Bayesian probit models were discussed. PMID- 24172083 TI - Landscape heritage objects' effect on driving: a combined driving simulator and questionnaire study. AB - According to the literature, landscape (panoramas, heritage objects e.g. landmarks) affects people in various ways. Data are primarily developed by asking people (interviews, photo sessions, focus groups) about their preferences, but to a lesser degree by measuring how the body reacts to such objects. Personal experience while driving a car through a landscape is even more rare. In this paper we study how different types of objects in the landscape affect drivers during their drive. A high-fidelity moving-base driving simulator was used to measure choice of speed and lateral position in combination with stress (heart rate measure) and eye tracking. The data were supplemented with questionnaires. Eighteen test drivers (8 men and 10 women) with a mean age of 37 were recruited. The test drivers were exposed to different new and old types of landscape objects such as 19th century church, wind turbine, 17th century milestone and bus stop, placed at different distances from the road driven. The findings are in some respect contradictory, but it was concluded that that 33% of the test drivers felt stressed during the drive. All test drivers said that they had felt calm at times during the drive but the reason for this was only to a minor degree connected with old and modern objects. The open landscape was experienced as conducive to acceleration. Most objects were, to a small degree, experienced (subjective data) as having a speed-reducing effect, much in line with the simulator data (objective data). Objects close to the road affected the drivers' choice of' lateral position. No significant differences could be observed concerning the test drivers' gaze between old or modern objects, but a significant difference was observed between the test drivers' gaze between road stretches with faraway objects and stretches without objects. No meaningful, significant differences were found for the drivers' stress levels as measured by heart rate. PMID- 24172084 TI - Gap acceptance of violators at signalised pedestrian crossings. AB - Gap acceptance of violating pedestrians was studied at seven stretches of signalised pedestrian crossings in Singapore. The provision of the traffic light signals provide a 'safer' crossing option to these pedestrians, as compared to uncontrolled crossings and mid-block arterial roads. However, there are still people choosing to cross at the riskier period (Red Man phase). The paper discusses about the size of traffic gaps rejected and accepted by pedestrians and the behaviour of riskier pedestrians (those adapting partial gap). The likelihood of pedestrians accepting gaps between vehicular traffic as a combination of different influencing independent variables such as traffic, environmental and personal factors was studied and modelled using logistic regression. PMID- 24172085 TI - Feasibility of force platform based roadside drowsiness screening - a pilot study. AB - Previous research on driver drowsiness detection has focused on developing in-car systems that continuously monitor the driver while driving and warn him/her when drowsiness compromises safety. In occupational settings a simple test of postural control has showed sensitivity to work shift induced fatigue in drivers. Whether the test is feasible for surveillance purposes in roadside settings is unknown. The present research sought to evaluate the feasibility of using a force platform test of postural control as a breathalyzer-like drowsiness-test at the roadside. Seventy-one commercial drivers stopped by at our measurement sites and volunteered to participate in the study. We tested postural control with a computerized force platform, on which the drivers stood eyes open while it sampled body center-of-pressure excursions at 33Hz for 30s and scored postural control as the area of the 95% confidence ellipse enclosing the excursions. The drivers also completed the Karolinska Sleepiness Scale (KSS) and we recorded each driver's wake up time, time on task, and time of testing. Five of the seventy-one drivers exhibited significantly poorer postural control than their peers (P=0.03). The wake up times and times on task for these five drivers indicated that they were on a night shift schedule or had a long time on task. Furthermore, their postural control and KSS scores correlated (r=-0.88, P=0.04), whereas the scores did not correlate for their peers (r=0.10, P=0.48). These results indicate that the force platform test identified drivers, whose impairment in postural control was drowsiness-related. Specifically, the test identified the few drivers in this roadside sample whose wake- and work histories resembled a night shift schedule. In this kind of roadside setting, with a demographically heterogeneous group and interindividual differences in people's responses to drowsiness, it suggests that the method, further developed, may provide a drowsiness test for roadside surveillance. PMID- 24172086 TI - Cyclists' red-light running behaviours: an examination of risk-taking, opportunistic, and law-obeying behaviours. AB - Literature has suggested that bicyclists' red-light violations (RLVs) tend not to cause accidents although RLV is a frequent and typical bicyclist's behaviour. High association between bicyclist RLVs and accidents were, however, revealed in Taiwan. The current research explores bicyclists' RLVs by classifying crossing behaviours into three distinct manners: risk-taking, opportunistic, and law obeying. Other variables, as well as bicyclists' crossing behaviours, were captured through the use of video cameras that were installed at selected intersections in Taoyuan County, Taiwan. Considering the unobserved heterogeneity, this research develops a mixed logit model of bicyclists' three distinct crossing behaviours. Several variables (pupils in uniform, speed limit with 60km/h) appear to have heterogeneous effects, lending support to the use of mixed logit models in bicyclist RLV research. Several factors were found to significantly increase the likelihood of bicyclists' risky behaviours, most notably: intersections with short red-light duration, T/Y intersections, when riders were pupils in uniform, when riders were riding electric bicycles, when riders were unhelmeted. Implications of the research findings, and the concluding remarks, are finally provided. PMID- 24172087 TI - A systematic review on the influence of pre-existing disability on sustaining injury. AB - OBJECTIVE: To systematically review studies measuring the influence of pre existing disability on the risk of sustaining an injury. DESIGN: Systematic review. DATA SOURCES: Electronic databases searched included Medline (Pubmed), ProQuest, Ovid and EMBASE. INCLUSION CRITERIA: Studies (1990-2010) in international peer-reviewed journals were identified with main inclusion criteria being that the study assessed involvement of injury sustained by persons with and without pre-existing disability. METHODS: Studies were collated by design and methods, and evaluation of results. RESULTS: Twenty-two studies met the inclusion criteria of our review. All studies found that persons with disabilities were at a significantly higher risk of sustaining injuries than those without. Persons with disability had a 30-450% increased odds (odds ratio 1.3-5.5) of sustaining injury compared to persons without disability. Among persons with pre-existing disability, the high risk groups of sustaining an injury are children and elderly. CONCLUSIONS: People with disabilities experience a higher risk to sustain an injury in comparison to the healthy population. There is a high need for large epidemiological studies of injury among persons with disability, to better address these unique risk profiles in order to prevent additional disability or secondary conditions. PMID- 24172088 TI - Exploring the effects of roadway characteristics on the frequency and severity of head-on crashes: case studies from Malaysian federal roads. AB - Head-on crashes are among the most severe collision types and of great concern to road safety authorities. Therefore, it justifies more efforts to reduce both the frequency and severity of this collision type. To this end, it is necessary to first identify factors associating with the crash occurrence. This can be done by developing crash prediction models that relate crash outcomes to a set of contributing factors. This study intends to identify the factors affecting both the frequency and severity of head-on crashes that occurred on 448 segments of five federal roads in Malaysia. Data on road characteristics and crash history were collected on the study segments during a 4-year period between 2007 and 2010. The frequency of head-on crashes were fitted by developing and comparing seven count-data models including Poisson, standard negative binomial (NB), random-effect negative binomial, hurdle Poisson, hurdle negative binomial, zero inflated Poisson, and zero-inflated negative binomial models. To model crash severity, a random-effect generalized ordered probit model (REGOPM) was used given a head-on crash had occurred. With respect to the crash frequency, the random-effect negative binomial (RENB) model was found to outperform the other models according to goodness of fit measures. Based on the results of the model, the variables horizontal curvature, terrain type, heavy-vehicle traffic, and access points were found to be positively related to the frequency of head-on crashes, while posted speed limit and shoulder width decreased the crash frequency. With regard to the crash severity, the results of REGOPM showed that horizontal curvature, paved shoulder width, terrain type, and side friction were associated with more severe crashes, whereas land use, access points, and presence of median reduced the probability of severe crashes. Based on the results of this study, some potential countermeasures were proposed to minimize the risk of head-on crashes. PMID- 24172090 TI - Diagnostic performance of fluorine 18 fluorodeoxyglucose positron emission tomography imaging for detection of primary lesion and staging of endometrial cancer patients: systematic review and meta-analysis of the literature. AB - OBJECTIVES: Fluorine 18 fluorodeoxyglucose positron emission tomography ((18)F FDG PET) imaging has been used for staging of endometrial cancer. In the current study, we systematically searched the available literature on the accuracy of (18)F-FDG PET imaging for staging of endometrial cancer. METHODS: PubMed, SCOPUS, ISI Web of Knowledge, Science Direct, and Springer were searched using "endometr* AND PET" as the search terms. All studies evaluating the accuracy of (18)F-FDG PET in the staging of endometrial carcinoma were included. Statistical pooling of diagnostic accuracy indices was done using random-effects model. Cochrane Q test and I(2) index were used for heterogeneity evaluation. RESULTS: Sixteen studies (807 patients in total) were included in the meta-analysis. Sensitivity and specificity for detection of the primary lesions were 81.8% (77.9%-85.3%) and 89.8% (79.2%-96.2%); for lymph node staging were 72.3% (63.8%-79.8%) and 92.9% (90.6%-94.8%); and for distant metastasis detection were 95.7% (85.5%-99.5%) and 95.4% (92.7%-97.3%). CONCLUSIONS: Because of low sensitivity, diagnostic utility of (18)F-FDG PET imaging is limited in primary tumor detection and lymph node staging of endometrial cancer patients. However, high specificities ensure high positive predictive values in these 2 indications. Diagnostic performance of (18)F-FDG PET imaging is much better in detection of distant metastases. Larger studies with better design are needed to draw any more definite conclusion. PMID- 24172091 TI - The effects of metformin on ovarian cancer: a systematic review. AB - OBJECTIVE: The potential therapeutic effects of metformin on several cancers were reported. However, the evidence of the effects of metformin on ovarian cancer is still limited and inconclusive. This systematic review and meta-analysis study aim to summarize the existing evidence of the therapeutic effects of metformin on ovarian cancer. METHODS: We performed systematic searches using electronic databases including PubMed and EMBASE until December 2012. Key words included "metformin" AND ("ovarian cancer" OR "ovary tumor"). All human studies assessing the effects of metformin on ovarian cancer were eligible for inclusion. All articles were reviewed independently by 2 authors with a standardized approach for the purpose of study, study design, patient characteristics, exposure, and outcomes. The data were pooled using a random-effects model. RESULTS: Of 190 studies retrieved, only 3 observational studies and 1 report of 2 randomized controlled trials were included. Among those studies, 2 reported the effects of metformin on survival outcomes of ovarian cancer, whereas the other 2 reported the effects of metformin on ovarian cancer prevention. The findings of studies reporting the effects on survival outcomes indicated that metformin may prolong overall, disease-specific, and progression-free survival in ovarian cancer patients. The results of studies reporting the effects of metformin on ovarian cancer prevention were meta-analyzed. It indicated that metformin tended to decrease occurrence of ovarian cancer among diabetic patients with the pooled odds ratio of 0.57 (95% confidence interval, 0.16-1.99). CONCLUSIONS: Our findings showed the potential therapeutic effects of metformin on survival outcomes of ovarian cancer and ovarian cancer prevention. However, most of the evidence was observational studies. There is a call for further well-conducted controlled clinical trials to confirm the effects of metformin on ovarian cancer survival and ovarian cancer prevention. PMID- 24172092 TI - Establishment of primary xenograft model from newly characterized patient extrauterine carcinosarcoma. AB - BACKGROUND AND OBJECTIVE: The aim of this study was to characterize primary cells from extrauterine carcinosarcoma (CS) and to establish a primary CS xenograft mouse model. METHODS: Primary cells were isolated from a patient with CS and cultured in vitro. Primary CS cells were verified for their ability to consecutively generate tumorigenesis in NOD/SCID mice. The properties of xenograft tumor and explants cells were investigated by immunohistochemistry, cytogenetic, and FACS analysis. Anticancer drug susceptibility of primary CS was analyzed using CCK-8. RESULTS: Primary CS cells greater than 27 passages in vitro showed an ability of a series of xenograft tumorigenesis in vivo having the same marker expression and cytogenetic character as that of original tumor. In addition, explants of xenograft tumors retained their original characteristics in the in vitro culture system. Finally, the analysis of the susceptibility to anticancer drug revealed that primary CS cells were susceptible to both doxorubicin and nilotinib, which are tyrosine kinase inhibitors. CONCLUSIONS: The primary CS cells and the primary CS xenograft tumorigenesis introduce a new therapeutic model for targeting cancer and also explore a deeper understanding of generation of the tumor itself. PMID- 24172093 TI - Polymorphisms in base excision repair genes are associated with endometrial cancer risk among postmenopausal Japanese women. AB - OBJECTIVES: Polymorphisms in base excision repair (BER) genes are associated with risk for several types of cancers but have not been studied with respect to endometrial cancer among Japanese women. Therefore, we conducted a case-control study to explore the association between polymorphisms in BER genes and the risk for endometrial cancer. METHODS/MATERIALS: This study included a total of 91 postmenopausal subjects with endometrial cancer and 261 controls without cancer who visited the Aichi Cancer Center between 2001 and 2005. We focused on single nucleotide polymorphisms within coding regions of 5 BER genes (OGG1, MUTYH, XRCC1, APEX1, and PARP1). To assess lifestyle in the etiology of endometrial cancer, we used a self-administered questionnaire. Associations were evaluated using multivariate unconditional logistic regression models. We also assessed whether there were intergenic associations or an interaction with obesity. RESULTS: We observed a significant association between endometrial cancer risk and XRCC1 rs1799782 (C > T, Arg194Trp) and XRCC1 rs25487 (G > A, Arg399Gln). We uncovered a significant association between obesity (body mass index, >= 25) and rs25487. The XRCC1 polymorphisms were in complete linkage disequilibrium, and the XRCC1 haplotype TG associated significantly with endometrial cancer risk. The interaction between the CA haplotype and body mass index was marginally significant, whereas interaction between haplotype in XRCC1 and rs1136410 (PARP1) was not significant. CONCLUSIONS: We found a significant association between endometrial cancer risk and XRCC1 polymorphisms and haplotype TG in postmenopausal Japanese women. PMID- 24172095 TI - Ovarian cancer: sites of recurrence. AB - INTRODUCTION: Improved knowledge of recurrence sites after contemporary surgical management of ovarian cancer is needed. MATERIAL AND METHODS: We retrospectively reviewed consecutive patients managed for epithelial ovarian or tubal cancer with surgery and platinum-based chemotherapy between January 1, 2005, and December 31, 2009, in a tertiary teaching hospital. The site of first recurrence was recorded. Univariate analysis was performed to identify factors associated with site specific recurrence. Overall survival and progression-free survival were computed using the Kaplan-Meier method, and log-rank tests were performed to assess the impact on survival of the variables of interest. RESULTS: Recurrences were noted in 3 (20%) of 15 International Federation of Gynecologists and Obstetricians stage I to IIa patients and 36 (62.1%) of 58 International Federation of Gynecologists and Obstetricians IIb to IV patients, and the median progression free survival was 21.6 (2.5-71) and 19.3 (1.8-67.6) months, respectively. In the advanced-disease group, 75% of recurrences involved the peritoneum and 40% were confined to the peritoneum; peritoneal recurrences developed at both treated and untreated sites. Peritoneal recurrence was associated with greater initial peritoneal involvement (Sugarbaker score, 12.1 +/- 8.2 vs 7.1 +/- 7.4; P = 0.01) and residual postoperative tumor. Nodal recurrences were noted in 38% of all recurrences, usually in combination with peritoneal recurrence and in the abdominal territories. Isolated distant metastasis was a rare mode of recurrence (8%). CONCLUSIONS: The peritoneum is the main recurrence site in both early and advanced ovarian cancer. Initial disease spread and extent of surgery are associated with the recurrence risk. This article supports the view that more attention should be directed toward extensive treatment of the peritoneum. PMID- 24172094 TI - A phase 2 study of oxaliplatin combined with continuous infusion topotecan for patients with previously treated ovarian cancer. AB - BACKGROUND: Phase 2 trials suggest that prolonged intravenous (IV) infusion of the topoisomerase 1 inhibitor topotecan may be less toxic than when given by standard IV bolus 5-day administration. Oxaliplatin exhibits efficacy in platinum pretreated disease and shows preclinical synergy with topoisomerase 1 inhibitors. We sought to determine the efficacy and safety of oxaliplatin plus infusion topotecan in recurrent platinum-pretreated ovarian cancer. METHODS: Patients with recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancers previously treated with 1 to 2 prior regimens including platinum and taxane received oxaliplatin (85 mg/m(2) day 1 and day 15) and topotecan (0.4 mg/m(2) per day) by continuous IV infusion over 14 days every 4 weeks. The primary objective of the trial was to estimate the objective response rate in platinum-resistant disease (stratum 1) and in platinum-sensitive disease (stratum 2). Toxicities were assessed in all patients. RESULTS: Thirty-eight patients received 144 cycles of therapy (median, 4; range, 1-6). The most common grade 3 and grade 4 toxicities included thrombocytopenia (grade 3, 37%; and grade 4, 19%), neutropenia (grade 3, 37%; grade 4, 11%), and anemia (grade 3, 15%). Response occurred in 4 of 19 patients in stratum I (21%; 95% confidence intervals, 6%-46%) and 9 of 19 patients in stratum 2 (47%; 95% CI, 24%-71%). Three in each stratum had lengthy complete responses. CONCLUSIONS: Biweekly oxaliplatin plus a 14-day continuous IV infusion of topotecan, given monthly, is an active regimen in platinum-pretreated ovarian cancer and merits additional evaluation. PMID- 24172096 TI - Differentiation of ovarian cancers from borderline ovarian tumors on the basis of evaluation of tumor vascularity in multi-row detector computed tomography- comparison with histopathology. AB - OBJECTIVE: The aim of this study was to evaluate the feasibility of multi detector row computed tomography (MDCT) in the differentiation between borderline ovarian tumors and ovarian cancer on the basis of tumor morphology and specific features of tumor vascularity in correlation with the results at pathology. METHODS: A triphasic MDCT protocol was used for the analysis of tumor vascularity. The following features were taken into account: (1) The number of vessels in papillary projections, solid-tissue component, and septa (2 vs >2), (2) serpentine and chaotic configuration of vessels, (3) presence of microaneurysms, and (4) presence of arteriovenous microfistulas. Masses with at least 3 of 4 features were considered ovarian cancer (group A) and masses with 2 features or less as borderline tumor (group B). Radiological findings were compared with results of postoperative pathology. RESULTS: Pathologic vessels were found in all 56 patients. Thirty-two patients were included in group A and 24 in group B. The results of pathology were as follows: in group A: 31 malignant tumors, including 31 ovarian carcinomas and 1 benign cystadenoma; in group B: 22 borderline ovarian tumors, 1 benign cystadenoma, and 1 ovarian cancer. CONCLUSIONS: Morphological evaluation of tumor vascularity in MDCT seems to be an efficient method of differentiating between borderline ovarian tumors and ovarian carcinomas. Because of a small number of cases in the current study, a further research seems justified to confirm our results. The presented MDCT-angiographic criteria showed high sensitivity (97%) and specificity (96%) in differentiation of borderline ovarian tumors and ovarian cancers as compared with pathology. The presented CT-angiographic criteria of malignancy showed an excellent interobserver agreement. PMID- 24172097 TI - Clinical outcome of isolated serous tubal intraepithelial carcinomas (STIC). AB - OBJECTIVE: Risk-reducing salpingo-oophorectomy (RRSO) is recommended for women with BRCA mutation due to increased risk of pelvic serous carcinoma. Serous tubal intraepithelial carcinoma (STIC) is a pathologic finding of unknown clinical significance. This study evaluates the clinical outcome of patients with isolated STIC. MATERIALS/METHODS: We retrospectively reviewed the medical records of consecutive patients with a germline BRCA1/2 mutation or a high-risk personal or family history of ovarian cancer who underwent RRSO between January 2006 and June 2011. All patients had peritoneal washings collected. All surgical specimens were assessed using the sectioning and extensively examining the fimbria protocol, with immunohistochemistry when indicated. p53 signature lesions and secretory cell outgrowths were excluded. RESULTS: Of 593 patients who underwent RRSO, isolated STIC was diagnosed in 12 patients (2%). Five patients (42%) were BRCA1 positive, 5 patients (42%) were BRCA2 positive, and 2 patients (17%) had high risk family history. Preoperatively, all patients with STIC had normal CA-125 levels and/or pelvic imaging results. Seven patients underwent hysterectomy and omentectomy, 6 patients (46%) had pelvic node dissections, and 5 patients (39%) had para-aortic node dissections. With the exception of positive peritoneal washings in 1 patient, no invasive or metastatic disease was identified. No patient received adjuvant chemotherapy. At median follow-up of 28 months (range, 16-44 months), no recurrences have been identified. CONCLUSIONS: Among the cases of isolated STIC after RRSO reported in the literature, the yield of surgical staging is low, and short-term clinical outcomes are favorable. Peritoneal washings are the most common site of disease spread. Individualized management is warranted until additional data become available. PMID- 24172099 TI - Treatment outcomes in completely resected stage I to stage IV uterine carcinosarcoma with rhabdomyosarcoma differentiation. AB - OBJECTIVE: To evaluate overall survival (OS) and progression-free survival (PFS) after adjuvant therapy in stage I to stage IV uterine carcinosarcoma with rhabdomyosarcoma differentiation. METHODS: Memorial Sloan-Kettering Cancer Center medical records from 1990 to 2012 were reviewed. Patients who received chemotherapy with or without radiation therapy (RT), or RT alone, for completely resected stage I to stage IV uterine carcinosarcoma with rhabdomyosarcoma differentiation were included. RESULTS: Of 53 patients, International Federation of Gynecology and Obstetrics stage distribution was as follows: I, 13 (24.5%); II, 8 (15.1%); III, 13 (24.5%); and IV, 19 (35.9%). Forty-one (77.4%) of 53 patients received adjuvant chemotherapy, and 34% of the patients who received chemotherapy also received pelvic RT or intravaginal brachytherapy (IVRT). Twelve (22.6%) of the 53 patients received only pelvic RT with/without IVRT. Paclitaxel carboplatin was the most commonly used adjuvant chemotherapy treatment. The median PFS for the entire cohort was 13.4 months (95% confidence interval [CI], 10.5-17.0). The median OS for the entire cohort was 23.0 months (95% CI, 16.9 34.3). The median PFS periods by stage were 15.9 months for stages I/II versus 11.2 months for stages III/IV (P = 0.012). Median OS was not reached in the early stage cohort. The median OS for the late-stage cohort was 20.9 months (P = 0.004). The median PFS periods by treatment were 10.4 months for pelvic RT with/without IVRT group versus 13.1 months for chemotherapy with/without pelvic RT with/without IVRT group (P = 0.498). The median OS periods by treatment were 23.6 months for chemotherapy with/without pelvic RT with/without IVRT group versus 16.9 months for pelvic RT with/without IVRT group (P = 0.501). CONCLUSION: The results suggest that chemotherapy alone or in combination with RT is associated with longer PFS and OS compared to RT alone. Only the stage of disease significantly affected PFS and OS. PMID- 24172100 TI - Current surgical principle for uterine cervical cancer of stages Ia2, Ib1, and IIa1 in Japan: a survey of the Japanese Gynecologic Oncology Group. AB - OBJECTIVE: The objective of this study was to determine the current operative principle of uterine cervical cancer of stages Ia2, Ib1, and IIa1 (International Federation of Gynecology and Obstetrics) in Japan by surveying member institutions of the Japanese Gynecologic Oncology Group (JGOG). METHODS: We conducted a survey to assess the current operative principle, including indications and treatment, at all 199 active member institutions of the JGOG. RESULTS: A total of 166 institutions (83.4%) responded to the survey. For Ia2 squamous cell carcinoma without the need to preserve fertility, modified radical hysterectomy was performed, and lymph node dissection was done in about 85%. At 60% of JGOG institutions, it was considered that less invasive procedures might be suitable. At the majority of JGOG institutions, radical surgery and lymph node dissection were considered necessary for stages Ib1 and IIa1 squamous cell carcinoma, with 70% considering that less invasive procedures might not be suitable. CONCLUSIONS: This survey provides information regarding the current status of surgical principle for uterine cervical cancer (stages Ia2, Ib1, and IIa1) in Japan. PMID- 24172098 TI - The impact of perioperative packed red blood cell transfusion on survival in epithelial ovarian cancer. AB - OBJECTIVE: Perioperative packed red blood cell transfusion (PRBCT) has been implicated as a negative prognostic marker in surgical oncology. There is a paucity of evidence on the impact of PRBCT on outcomes in epithelial ovarian cancer (EOC). We assessed whether PRBCT is an independent risk factor of recurrence and death from EOC. METHODS: Perioperative patient characteristics and process-of-care variables (defined by the National Surgical Quality Improvement Program) were retrospectively abstracted from 587 women who underwent primary EOC staging between January 2, 2003, and December 29, 2008. Associations with receipt of PRBCT were evaluated using univariate logistic regression models. The associations between receipt of PRBCT and disease-free survival and overall survival were evaluated using multivariable Cox proportional hazards models and using propensity score matching and stratification, respectively. RESULTS: The rate of PRBCT was 77.0%. The mean +/- SD units transfused was 4.1 +/- 3.1 U. In the univariate analysis, receipt of PRBCT was significantly associated with older age, advanced stage (>= IIIA), undergoing splenectomy, higher surgical complexity, serous histologic diagnosis, greater estimated blood loss, longer operating time, the presence of residual disease, and lower preoperative albumin and hemoglobin. Perioperative packed red blood cell transfusion was not associated with an increased risk for recurrence or death, in an analysis adjusting for other risk factors in a multivariable model or in an analysis using propensity score matching or stratification to control for differences between the patients with and without PRBCT. CONCLUSIONS: Perioperative packed red blood cell transfusion does not seem to be directly associated with recurrence and death in EOC. However, lower preoperative hemoglobin was associated with a higher risk for recurrence. The need for PRBCT seems to be a stronger prognostic indicator than the receipt of PRBCT. PMID- 24172101 TI - Follow-up study of patients with cervical intraepithelial neoplasia grade 1 overexpressing p16Ink4a. AB - OBJECTIVE: The p16 (p16(Ink4a)) tumor-suppressor protein is a biomarker for activated expression of human papillomavirus oncogenes. However, data are insufficient to determine whether p16 overexpression predicts the risk for progression of low-grade cervical intraepithelial neoplasia (CIN). This study was aimed at evaluating the risk for progression to CIN2 or worse during a 3-year follow-up of an unselected series of 739 patients with CIN1 biopsy specimens tested for p16 expression. METHODS: Positivity of p16 was defined as a diffuse overexpression in the basal/parabasal cell layers. Selection biases were ruled out using a control group of 523 patients with CIN1 biopsies not tested for p16 expression. Analysis was based on the ratio of progression rates. RESULTS: In the first year of follow-up, the 216 patients (29%) with p16-positive CIN1 had a higher progression rate (12.3%) than did the 523 patients with p16-negative CIN1 (2.2%) (rate ratio, 5.5; 95% confidence interval [CI], 2.59-11.71). In the second and third years, differences were smaller (rate ratio, 1.32 and 1.14, respectively) and not significant. The patients with p16-positive CIN1 also had a lower risk for regression to normal in the first year of follow-up (rate ratio, 0.55; 95% confidence interval, 0.42-0.71) and nonsignificant changes in the second and third years (rate ratio, 0.81 and 0.84, respectively). CONCLUSIONS: The patients with p16-positive CIN1 had an increased risk for progression that was concentrated in the first year of follow-up. Immunostaining of p16 could have a role in short-term surveillance of patients with CIN1. Further research should focus on midterm/long-term outcomes of p16-positive CIN1. PMID- 24172102 TI - Platinum-free interval in second-line chemotherapy for recurrent cervical cancer. AB - OBJECTIVE: The purpose of this study was to determine whether the platinum-free interval (PFI) was a predictive indicator in second-line treatment of cervical cancer in patients who had undergone prior platinum-based chemotherapy. The role of the PFI in selecting the second-line regimen in other gynecologic malignancies is also discussed. METHODS: In this retrospective study, we examined the clinical records of patients with recurrent or metastatic cervical cancer who had received platinum-containing combination regimens as second-line chemotherapy. All patients had received prior platinum-containing chemotherapy or concurrent chemoradiotherapy. RESULTS: The overall response rate to second-line chemotherapy was 25.8%; 7 patients achieved a complete response and 17 a partial response. The median progression-free survival (PFS) was 5.1 months and median overall survival (OS) was 13.5 months. The response rate was 12.5%, 14.2%, 20.0%, 22.2%, and 55.0%; median PFS was 4.0, 5.1, 4.4, 5.8, and 7.4 months; and median OS was 10.2, 14.4, 11.9, 16.3, and 19.7 months when PFI was within 3, 3 to 5, 6 to 11, 12 to 23, and more than 24 months, respectively. Age (>50 years), size (>3 cm), prior radiotherapy, and PFI (>24 months) were identified as prognostic factors in the multivariate analysis for PFS and OS. CONCLUSIONS: The results indicate that a PFI of more than 24 months is the discriminating point between platinum-sensitive and platinum-resistance cervical cancer. This indicates that PFI offers a useful tool in selecting agents for second-line chemotherapy in a wide range of gynecologic malignancies. PMID- 24172103 TI - Laparoscopic lymphadenectomy in advanced cervical cancer: prognostic and therapeutic value. AB - OBJECTIVE: Clinical benefit of surgical staging in locally advanced cervical cancer has not yet been proved. The goal of this study was to analyze the prognostic and therapeutic value of laparoscopic para-aortic lymphadenectomy with selective excision of suspicious pelvic nodes in patients with locally advanced cervical cancer. METHODS: This is a retrospective study including 109 women treated in a single institution from 2000 to 2009. The International Federation of Gynecology and Obstetrics stage was IB2 in 12 women, IIB in 58 women, and IIIB in 39 women. None had suspicious para-aortic nodes by presurgical imaging evaluation. All patients underwent extraperitoneal para-aortic laparoscopic lymphadenectomy with selective excision of enlarged pelvic nodes and received pelvic radiotherapy with concomitant chemotherapy. Extended lumboaortic radiation therapy was added to patients with metastatic para-aortic nodes. The mean +/- SD follow-up time was 43.1 +/- 33.7 months. RESULTS: Metastatic lymph nodes were identified in 23 (21.1%) of 109 patients in the para-aortic area and in 24 (53.3%) of 45 patients who underwent selective excision of pelvic nodes. Patients with nodal metastases had increased risk of mortality than those with negative nodes independently of the location (pelvic and/or para-aortic) of the metastases (hazard ratio, 4.07; 95% confidence interval, 1.36-12.16 for patients with pelvic metastases [P = 0.012]; and 3.73; 95% confidence interval, 1.38-10.09 for patients with para-aortic metastases [P = 0.010]). In the subset of women with para-aortic metastases treated by extended lumboaortic radiation therapy, neither the number of lymph nodes removed nor the number of positive nodes were associated with survival (P = 0.556 and P = 0.195, respectively). CONCLUSION: Para-aortic and pelvic lymphadenectomy provides valuable information about mortality risk in patients with locally advanced cervical cancer. PMID- 24172104 TI - Incidence and predictors of venous thromboembolism after debulking surgery for epithelial ovarian cancer. AB - OBJECTIVE: The aim of this study was to determine the incidence and the risk factors of venous thromboembolism (VTE) within 30 days after primary surgery for epithelial ovarian cancer (EOC). METHODS: In a historical cohort study, we estimated the postoperative 30-day cumulative incidence of VTE among consecutive Mayo Clinic patients undergoing primary cytoreduction for EOC between January 2, 2003, and December 29, 2008. We tested perioperative patient characteristics and process-of-care variables (defined by the National Surgical Quality Improvement Program, >130 variables) as potential predictors of postoperative VTE using the Cox proportional hazards modeling. RESULTS: Among 569 cases of primary EOC cytoreduction and/or staging and no recent VTE, 35 developed symptomatic VTE within 30 days after surgery (cumulative incidence = 6.5%; 95% confidence interval, 4.4%-8.6%). Within the cohort, 95 (16.7%) received graduated compression stockings (GCSs), 367 (64.5%) had sequential compression devices + GCSs, and 69 (12.1%) had sequential compression devices + GCSs + postoperative heparin, with VTE rates of 1.1%, 7.4%, and 5.8%, respectively (P = 0.07, chi(2) test). The remaining 38 (6.7%) received various other chemical and mechanical prophylaxis regimens. In the multivariate analysis, current or past tobacco smoking, longer hospital stay, and a remote history of VTE significantly increased the risk for postoperative VTE. CONCLUSIONS: Venous thromboembolism is a substantial postoperative complication among women with EOC, and the high cumulative rate of VTE within 30 days after primary surgery suggests that a more aggressive strategy is needed for VTE prevention. In addition, because longer hospital stay is independently associated with a higher risk for VTE, methods to decrease length of stay and minimize factors that contribute to prolonged hospitalization are warranted. PMID- 24172105 TI - Single-port laparoscopic extraperitoneal para-aortic lymphadenectomy. AB - OBJECTIVE: The aim of this study was to evaluate the feasibility and the safety of single-port extraperitoneal laparoscopic para-aortic lymphadenectomy for patients with gynecologic cancer. METHODS: From July 2012 to January 2013, a total of 7 patients with gynecologic cancer underwent a laparoscopic pelvic and para-aortic lymphadenectomy with a single-port device. An extraperitoneal approach was performed for para-aortic lymphadenectomy using only one 2.5-cm incision on the left side. In 6 patients, additionally, hysterectomy and pelvic lymphadenectomy with conventional laparoscopy were performed to complete the treatment. RESULTS: Aortic dissection was complete in all cases without complications. The median age of the patients was 63 years (range, 48-78 years), and the median patient body mass index was 31 kg/m(2) (range, 19-38 kg/m(2)). The median number of para-aortic nodes was 17 (range, 10-25); the median operative time was 204 minutes (range, 120-300 minutes). The median hospital stay was 4 days (range, 3-6 days). No patient encountered postoperative complications. CONCLUSIONS: This study demonstrates the feasibility of single-port laparoscopic extraperitoneal para-aortic lymphadenectomy. PMID- 24172106 TI - Self-reported sexual, bowel and bladder function in cervical cancer patients following different treatment modalities: longitudinal prospective cohort study. AB - OBJECTIVE: Conventional radical hysterectomy with pelvic lymphadenectomy (RHL) for early-stage cervical cancer is associated with significant bladder, anorectal, and sexual dysfunction. Nerve-sparing modification of RHL (NS-RHL) has been developed with the aim to reduce surgical treatment-related morbidity. Postoperative radiation therapy (RT) is offered to patients with unfavorable prognostic features to improve local control. The aim of the study was to assess self-reported morbidity of various types of treatment in cervical cancer patients. METHODS: Self-reported symptoms were prospectively assessed before and 1 and 2 years after treatment by the Dutch Gynaecologic Leiden Questionnaire. RESULTS: Included were 229 women (123 NS-RHL and 106 conventional RHL). Ninety four (41%) received RT. Up to 2 years (response rate, 81%), women reported significantly more bowel, bladder, and sexual symptoms compared with the pretreatment situation. No significant difference was found between the conventional RHL and NS-RHL with the exception of the unexpected finding that a smaller percentage in the NS-RHL group (34% vs 68%) complained about numbness of the labia and/ or thigh. Radiation therapy had a negative impact on diarrhea, urine incontinence, lymphedema, and sexual symptoms (especially a narrow/short vagina). CONCLUSIONS: In the current longitudinal cohort study, treatment for early-stage cervical cancer was associated with worse subjective bladder, anorectal, and sexual functioning, irrespective of the surgical procedure used. Postoperative RT resulted in a significant deterioration of these functions. The results have to be interpreted with caution in view of the study design and method used. PMID- 24172108 TI - Higher rates of adolescent substance use in child welfare versus community populations in the United States. AB - OBJECTIVE: Youth substance use exacts costly consequences for a variety of important health outcomes. We examined and compared prevalence rates and a common set of psychosocial factors of lifetime and current substance use among child welfare-involved youths and community youths from two nationally representative data sets. METHOD: Using the National Survey of Child and Adolescent Well-Being and the National Longitudinal Study of Adolescent Health, we compared prevalence rates and conducted logistic regression models for eight binary outcome measures of substance use: lifetime and current use of alcohol, inhalant, marijuana, and other illicit drugs to examine predictors of substance involvement in the two samples. RESULTS: Substance use prevalence was higher among child welfare involved youths than community youths for lifetime marijuana use, lifetime and current inhalant use, and lifetime and current other illicit drug use. Among both child welfare-involved and community youths, delinquency was the factor most strongly associated with all lifetime substance use outcomes. Notably, family structure and parental closeness were important protective factors against current substance use among child welfare-involved youths. For community youths, poorer emotional health was the strongest indicator of current substance use. CONCLUSIONS: Substance use among all adolescents is a critical public health concern. Given the heightened vulnerability of child welfare-involved youths, it is particularly important to focus prevention and early intervention efforts on this population. Further research should explore additional factors associated with substance use among these youths so that child welfare and behavioral health systems may jointly target prevention and intervention efforts. PMID- 24172107 TI - Epidemiology of malaria in an area of seasonal transmission in Niger and implications for the design of a seasonal malaria chemoprevention strategy. AB - BACKGROUND: Few data are available about malaria epidemiological situation in Niger. However, implementation of new strategies such as vaccination or seasonal treatment of a target population requires the knowledge of baseline epidemiological features of malaria. A population-based study was conducted to provide better characterization of malaria seasonal variations and population groups the most at risk in this particular area. METHODS: From July 2007 to December 2009, presumptive cases of malaria among a study population living in a typical Sahelian village of Niger were recorded, and confirmed by microscopic examination. In parallel, asymptomatic carriers were actively detected at the end of each dry season in 2007, 2008 and 2009. RESULTS: Among the 965 presumptive malaria cases recorded, 29% were confirmed by microscopic examination. The incidence of malaria was found to decrease significantly with age (p < 0.01). The mean annual incidence was 0.254. The results show that the risk of malaria was higher in children under ten years (p < 0.0001). The number of malaria episodes generally followed the temporal pattern of changes in precipitation levels, with a peak of transmission in August and September. One-thousand and ninety subjects were submitted to an active detection of asymptomatic carriage of whom 16% tested positive; asymptomatic carriage decreased with increasing age. A higher prevalence of gametocyte carriage among asymptomatic population was recorded in children aged two to ten years, though it did not reach significance. CONCLUSIONS: In Southern Niger, malaria transmission mostly occurs from July to October. Children aged two to ten years are the most at risk of malaria, and may also represent the main reservoir for gametocytes. Strategies such as intermittent preventive treatment in children (IPTc) could be of interest in this area, where malaria transmission is highly seasonal. Based on these preliminary data, a pilot study could be implemented in Zindarou using IPTc targeting children aged two to ten years, during the three months of malaria transmission, together with an accurate monitoring of drug resistance. PMID- 24172109 TI - Risk for inhalant initiation among middle school students: understanding individual, family, and peer risk and protective factors. AB - OBJECTIVE: Because initiation of inhalants at an early age is associated with a range of health and behavioral problems, including an increased likelihood of inhalant dependence (based on criteria from the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition), we conducted discrete time survival analyses to determine the role of time-invariant and time-variant (over five waves) risk and protective factors as well as grade in inhalant initiation among middle school students. METHOD: The current study uses data from 3,215 students who were initially surveyed as sixth graders in 2008-2009 and were resurveyed in seventh and eighth grades. Students were part of a larger substance use prevention trial conducted in greater Los Angeles. The sample is racially/ethnically diverse (54% Hispanic/Latino, 16% Asian, 14% White, 3% African American) and 51% male. RESULTS: Seventeen percent of youths initiated inhalants during middle school. Higher drug refusal self-efficacy, familism (i.e., values related to family), and parental respect were associated with decreased odds of inhalant initiation. Having a significant adult or older sibling who used substances was associated with increased risk of initiation, but adult influence declined linearly and by the end of seventh grade was no longer a risk factor. Self-rated popularity was associated with inhalant initiation in seventh grade only, and perceived substance use by peers was associated with inhalant initiation in sixth grade only. CONCLUSIONS: The influence of adults, siblings, and peers on inhalant use may be strongest in sixth and seventh grade. Interventions to prevent inhalant initiation should target sixth and seventh graders, address influence by family and peers, and provide skills training to improve drug refusal self-efficacy. PMID- 24172111 TI - Do alcohol compliance checks decrease underage sales at neighboring establishments? AB - OBJECTIVE: Underage alcohol compliance checks conducted by law enforcement agencies can reduce the likelihood of illegal alcohol sales at checked alcohol establishments, and theory suggests that an alcohol establishment that is checked may warn nearby establishments that compliance checks are being conducted in the area. In this study, we examined whether the effects of compliance checks diffuse to neighboring establishments. METHOD: We used data from the Complying with the Minimum Drinking Age trial, which included more than 2,000 compliance checks conducted at more than 900 alcohol establishments. The primary outcome was the sale of alcohol to a pseudo-underage buyer without the need for age identification. A multilevel logistic regression was used to model the effect of a compliance check at each establishment as well as the effect of compliance checks at neighboring establishments within 500 m (stratified into four equal radius concentric rings), after buyer, license, establishment, and community level variables were controlled for. RESULTS: We observed a decrease in the likelihood of establishments selling alcohol to underage youth after they had been checked by law enforcement, but these effects quickly decayed over time. Establishments that had a close neighbor (within 125 m) checked in the past 90 days were also less likely to sell alcohol to young-appearing buyers. The spatial effect of compliance checks on other establishments decayed rapidly with increasing distance. CONCLUSIONS: Results confirm the hypothesis that the effects of police compliance checks do spill over to neighboring establishments. These findings have implications for the development of an optimal schedule of police compliance checks. PMID- 24172110 TI - Mental health, sleep quality, drinking motives, and alcohol-related consequences: a path-analytic model. AB - OBJECTIVE: Poor mental health, sleep problems, drinking motivations, and high risk drinking are prevalent among college students. However, research designed to explicate the interrelationships among these health risk behaviors is lacking. This study was designed to assess the direct and indirect influences of poor mental health (a latent factor consisting of depression, anxiety, and stress) to alcohol use and alcohol-related consequences through the mediators of global sleep quality and drinking motives in a comprehensive model. METHOD: Participants were 1,044 heavy-drinking college students (66.3% female) who completed online surveys. RESULTS: A hybrid structural equation model tested hypotheses involving relations leading from poor mental health to drinking motives and poorer global sleep quality to drinking outcomes. Results showed that poor mental health significantly predicted all four subscales of drinking motivations (social, coping, conformity, and enhancement) as well as poor sleep. Most of the drinking motives and poor sleep were found to explain alcohol use and negative alcohol consequences. Poor sleep predicted alcohol consequences, even after controlling for all other variables in the model. The hypothesized mediational pathways were examined with tests of indirect effects. CONCLUSIONS: This is the first study to assess concomitantly the relationships among three vital health-related domains (mental health, sleep behavior, and alcohol risk) in college students. Findings offer important implications for college personnel and interventionists interested in reducing alcohol risk by focusing on alleviating mental health problems and poor sleep quality. PMID- 24172112 TI - Who suggests drinking less? Demographic and national differences in informal social controls on drinking. AB - OBJECTIVE: The purpose of this study was to examine variation in reports of pressuring others to drink less, as a form of informal social control of drinking, across countries and different types of relationship to the respondent. METHOD: A cross-sectional survey was administered to 19,945 respondents ages 18 69 years in 14 countries included in the data set of the Gender, Alcohol and Culture: An International Study (GENACIS). Outcome variables were respondents' reports of pressuring others to drink less (yes/no) across a variety of relationships (their partners, other family members, workmates, or friends). Multilevel, multivariable logistic regression analysis was carried out on each outcome variable. The fixed-effects components included the Level 1 (individual) covariates of respondent age, gender, drinking status, and education level as well as the Level 2 (country level) covariates of percentage female drinkers and purchasing power parity. The random-effects components included country and current drinking status. RESULTS: Respondents most frequently reported pressuring male friends to drink less (18%), followed by male family members (other than partners, 15%), partners (15%), work colleagues (12%), female friends (9%), female family members (other than partners, 6%), and children (5%). There was marked variation across countries, with pressuring frequently reported in Uganda, Costa Rica, and Nicaragua across most relationship types. Multivariable logistic regression revealed consistent effects of gender, with women more likely than men to report pressuring others to drink less across most relationship types. The patterns in relation to education status and age were less consistent and varied across relationship type. CONCLUSIONS: Informal social control of drinking varies dramatically according to whom is most likely to pressure whom to drink less as well as the country in which people live. PMID- 24172113 TI - Impulsivity, variation in the cannabinoid receptor (CNR1) and fatty acid amide hydrolase (FAAH) genes, and marijuana-related problems. AB - OBJECTIVE: Impulsivity is associated with increased marijuana use and subsequent marijuana-related problems among marijuana users. In addition, single nucleotide polymorphisms (SNPs) in the cannabinoid receptor 1 (CNR1) and fatty acid amide hydrolase (FAAH) genes have been associated with cannabis-related phenotypes. This exploratory study tested whether the association between different aspects of impulsivity and the number of marijuana-related problems among users is explicated by variation in these putative cannabinoid-related genes. METHOD: A total of 151 young adult regular marijuana users (used on M= 41.4% of the prior 60 days, SD = 24.3%) provided DNA and completed measures of trait (Barratt Impulsiveness Scale) and behavioral impulsivity (Stop Signal Task and Delay Discounting Questionnaire), as well as a self-report of marijuana-related problems. Three CNR1 and five FAAH SNPs were genotyped, tested for haplotype blocks, and subsequently examined for association with phenotypes described above. RESULTS: CNR1 variation significantly moderated the association between trait-level, but not behavioral, impulsivity and marijuana-related problems, such that the combination of higher trait impulsivity and CNR1 variation was associated with a greater number of marijuana-related problems. In contrast, there were no significant FAAH by impulsivity interactions; however, there was a main effect of FAAH on marijuana-related problems. CONCLUSIONS: These findings support an association with CNR1 and FAAH genes and marijuana-related problems among regular marijuana users. CNR1 variation emerged as a moderator of the relationship between trait impulsivity and marijuana problems, thus suggesting that marijuana users with CNR1 risk variants and a higher trait impulsivity are at greater risk for developing marijuana-related problems and supporting a role for CNR1 in a broader impulsivity phenotype. PMID- 24172114 TI - Prevalence of and associations with papsak wine consumption among farm workers in the Western Cape Province, South Africa. AB - OBJECTIVE: Until it was banned in 2007, inexpensive, atypically packaged wine, colloquially termed "papsak," was popular in poorer South African communities, which suffer a high burden of disease from alcohol. This study describes the prevalence of alcohol and papsak consumption, problem drinking (defined by a potentially problematic CAGE score of >=2), and their associations among farm workers in the Western Cape Province. METHOD: A cross-sectional analytical study was conducted in two farming areas using cluster sampling of farm worker households. Interview data from 347 male and 114 female respondents were analyzed. RESULTS: Among respondents, 69% (95% CI [63.1, 74.3]) were current drinkers. Among drinkers, 50.6% (95% CI [41.9, 59.3]) preferred papsak and 73% (95% CI [65.5, 79.3]) had potentially problematic CAGE scores (CAGE >= 2). Papsak drinkers were more likely to have CAGE scores of 2 or more than drinkers of other alcoholic beverages (adjusted odds ratio = 2.8, 95% CI [1.4, 5.5]). Increasing levels of socioeconomic deprivation predicted both current drinking and preferred papsak consumption. Additional risk factors for preferring papsak were age 35 years or older, being married, being Coloured, and residing in the district in which papsak was produced. CONCLUSIONS: Current drinking and symptoms of problem drinking were substantially higher in these farm workers compared with general provincial population levels. CAGE scores of 2 or more among female farm workers exceeded provincial estimates by 3.5 times. Problem drinking was strongly associated with papsak consumption, most likely because of affordability; however, the significant association between residence near papsak production and preferred papsak consumption highlights the consequence of easy access. Restrictions on papsak were warranted and may contribute to the prevention of alcohol-related harm in marginalized communities. PMID- 24172115 TI - Representativeness of patients enrolled in influential clinical trials: a comparison of substance dependence with other medical disorders. AB - OBJECTIVE: The purpose of this study was to determine whether randomized trials of treatments for substance dependence differ from those for other medical disorders on quality of enrollment information reporting and sample representativeness. METHOD: Twenty highly cited clinical trials (publication date 2002-2010) of treatments for each of 14 prevalent disorders were identified by structured literature search. The disorders were alcohol dependence, drug dependence, nicotine dependence, Alzheimer's disease, breast cancer, colorectal cancer, chronic obstructive pulmonary disease, depression, diabetes, HIV/AIDS, hypertension, ischemic heart disease, lung cancer, and schizophrenia. The 280 clinical trials were coded for number of individuals screened for eligibility, number of screened individuals meeting eligibility criteria, and number of eligible individuals refusing to participate. RESULTS: Substance-dependence treatment trials were significantly more likely to track and report enrollment information (75% vs. 45% of clinical trials for other disorders, p < .001). Substance-dependence trials did not differ from trials focused on other disorders on mean rate of non-enrollment. Across disorders, the primary driver of non enrollment appeared to be clinical trial exclusion criteria rather than eligible patients refusing to enroll. CONCLUSIONS: Relative to other disorders, trials in the substance-dependence field do a better (although imperfect) job of tracking and reporting enrollment information. Low enrollment rates and unrepresentative samples are not challenges unique to treatment outcome studies in the substance dependence field. Across a range of disorders, clinical trials that use eligibility criteria judiciously are more likely to produce findings that generalize to front-line clinical practice than are trials that restrict enrollment to a small and unrepresentative subset of patients. PMID- 24172116 TI - Predictors of dropout in an outpatient treatment for problem drinkers including cognitive-behavioral therapy and the opioid antagonist naltrexone. AB - OBJECTIVE: This study investigated predictors of dropout in an outpatient treatment program for problem drinking that included individual cognitive behavioral therapy combined with naltrexone. Specifically, we investigated whether sociodemographic factors, severity of alcohol dependence, history of problem drinking, or intensity of alcohol craving assessed at the beginning of the treatment predicted dropout from an outpatient program among a sample of 372 patients (65% male). We also investigated whether the effectiveness of the treatment (the change in alcohol consumption and symptoms of alcohol craving) or adherence to naltrexone was related to dropout. METHOD: Predictors of dropout were investigated using an analysis of covariance with the number of attended treatment sessions as an independent variable. RESULTS: Our results demonstrated that the treatment entry factors predictive of dropout were younger age, lower severity of alcohol dependence, better ability to resist and control alcohol use, and lower obsession with alcohol. In addition, those who dropped out were more likely to begin the program by abstaining from alcohol and had lower adherence to naltrexone use than those who completed the program. The length of stay for treatment was not related to change in alcohol consumption. CONCLUSIONS: Patients with less severe alcohol-related problems may lack motivation for treatment, specifically cognitive-behavioral therapy and naltrexone. These patients may benefit more from less intensive treatments. PMID- 24172117 TI - Telephone-based self-change modules help stabilize early natural recovery in problem drinkers. AB - OBJECTIVE: Self-guided attempts to resolve drinking problems are common, but little is known about the processes by which supportive interventions of lower intensity might promote resolution. This study investigated how brief supportive educational modules delivered as part of an interactive voice response self monitoring (IVR SM) system helped stabilize initial resolution among otherwise untreated problem drinkers. METHOD: Recently resolved problem drinkers allocated to the intervention group of a randomized controlled trial were offered IVR access for 24 weeks to report daily drinking and hear weekly educational modules designed to support resolution. Using data from the 70 active IVR callers, hierarchical linear models evaluated whether module retrieval reduced subsequent alcohol consumption, including high-risk drinking, and whether module retrieval attenuated the effects on drinking of established proximal risk factors for relapse (e.g., urges, drug use, and weekends). The analyses controlled for initial resolution status (abstinence or low-risk drinking). RESULTS: Urges, drug use, and weekends were associated with increased drinking reports on the next IVR call (all ps < .01), whereas retrieving a module was associated with decreases in next-call drinking reports, including high-risk drinking episodes (p < .05). Module retrieval, however, did not reduce or buffer the effects of urges on drinking. Findings were similar across initially abstinent and low-risk drinkers. CONCLUSIONS: IVR-delivered supportive educational modules may help stabilize initial problem-drinking resolutions, but mechanisms of change deserve more study. The study adds to evidence of the co-occurring negative effects of multiple behavioral and environmental risk factors on the temporal patterning of post-recovery alcohol use. PMID- 24172118 TI - Cigarette smoking initiation during college predicts future alcohol involvement: a matched-samples study. AB - OBJECTIVE: Little is known about the relationship between cigarette smoking initiation and subsequent alcohol involvement. To address this question, the present study compared alcohol use between students who initiated smoking during college and a matched sample of never-smoking students. We hypothesized greater increases in alcohol involvement among smoking initiators, mediated by exposure to cigarette use situations. METHOD: Included in the present study were 104 Chinese American and Korean American undergraduates who at baseline (freshman year) reported never having smoked a cigarette. Subjects were drawn from 433 participants in a naturalistic longitudinal study of tobacco use who were assessed annually each year in college. Cigarette smoking status was assessed annually as part of a structured interview. Initiators and never-smokers were matched on gender, ethnicity, baseline alcohol use, parental smoking status, and behavioral undercontrol. RESULTS: As predicted, participants who initiated smoking during college reported significantly greater increases in the number of past-30-day total drinks consumed (p < .001) and reported greater prevalence of heavy drinking episodes (p < .05). The effect of smoking initiation on the change in the number of past-30-day drinks at the final assessment was partially mediated by exposure to smoking (p < .05). Exploratory analyses indicated that greater recent smoking significantly predicted increased alcohol consumption over and above the effect of exposure. CONCLUSIONS: Students who initiate smoking during college appear at risk for increased alcohol involvement. Part of this risk is explained by environmental contextual factors, specifically exposure to situations involving other smokers that also may result in greater exposure to alcohol use. PMID- 24172119 TI - Improving base rate estimation of alcohol misuse in the military: a preliminary report. AB - OBJECTIVE: Stigma associated with behavioral health problems in the military pose challenges to accurate base rate estimations. Recent work has highlighted the importance of anonymous assessment methods, yet no study to date has assessed the ability of anonymous self-report measures to mitigate the impact of stigma on honest reporting. This study used the unmatched count technique (UCT), a form of randomized response techniques, to gain information about the accuracy of base rate estimates of alcohol misuse derived via anonymous assessment of Operation Enduring Freedom/Operation Iraqi Freedom active duty service members. METHOD: A cross-sectional, convenience sample of 184 active-duty service members, recruited via online websites for military populations, provided data on two facets of alcohol misuse (drinking more than intended and feeling the need to reduce use) via traditional self-report and the UCT. RESULTS: The UCT revealed significantly higher rates relative to traditional anonymous assessment for both drinking more than intended (51.9% vs. 23.4%) and feeling the need to reduce use (39.3% vs. 18.2%). CONCLUSIONS: These data suggest that anonymity does not completely mitigate the impact of stigma on endorsing behavioral health concerns in the military. Our results, although preliminary, suggest that published rates of alcohol misuse in the military may underestimate the true rates of these concerns. The UCT has significant potential to improve base rate estimation of sensitive behaviors in the military. PMID- 24172120 TI - Assessing the stimulant and sedative effects of alcohol with explicit and implicit measures in a balanced placebo design. AB - OBJECTIVE: Alcohol consumption is characterized by bi-phasic stimulant and sedative effects. In previous studies, various tools were used to assess these effects, including expectancy questionnaires, implicit association tests, and self-report scales. The present study was aimed at clarifying the relationships between these measures. METHOD: Three different measures were used to directly or indirectly assess the stimulant and sedative effects of alcohol in 61 undergraduate students. The participants completed the Alcohol Expectancy Questionnaire (AEQ) and performed two unipolar Implicit Association Tasks to assess implicit associations between alcohol and the concepts of "stimulation" and "sedation." The levels of alcohol consumption also were recorded by means of the Alcohol Use Disorders Identification Test. An alcohol (0.4 g/kg) or placebo challenge was then administered using a balanced placebo design. After alcohol/placebo administration, the participants completed the Biphasic Alcohol Effects Scale (BAES). RESULTS: Alcohol consumption significantly correlated with AEQ alcohol explicit expectancies of arousal and relaxation, whereas no significant correlations were obtained with the implicit associations. There were positive correlations between AEQ and BAES subscales, especially for the arousal subscale of the AEQ. Self-reported sedation recorded with the BAES was significantly affected by what the participants believed that they had drunk but not by the actual consumption of alcohol. CONCLUSIONS: These findings indicate that alcohol explicit expectancies of arousal measured with the AEQ best predict current alcohol consumption. Regarding explicit measures of alcohol-induced stimulation and sedation, BAES sub-scales seem to be more affected by alcohol drinking expectations than by actual alcohol consumption. PMID- 24172121 TI - Need for informed consent in substance use studies--harm of bias? AB - OBJECTIVE: The aim of this study was to examine the differences between those who gave informed consent to a study on substance use and those who did not, and to analyze whether differences changed with varying nonconsent rates. METHOD: Cross sectional questionnaire data on demographics, alcohol, smoking, and cannabis use were obtained for 6,099 French- and 5,720 German-speaking 20-year-old Swiss men. Enrollment took place over 11 months for the Cohort Study on Substance Use Risk Factors (C-SURF). Consenters and nonconsenters were asked to complete a short questionnaire. Data for nearly the entire population were available because 94% responded. Weekly differences in consent rates were analyzed. Regressions examined the associations of substance use with consent giving and consent rates and the interaction between the two. RESULTS: Nonconsenters had higher substance use patterns, although they were more often alcohol abstainers; differences were small and not always significant and did not decrease as consent rates increased. CONCLUSIONS: Substance use currently is a minor sensitive topic among young men, resulting in small differences between nonconsenters and consenters. As consent rates increase, additional individuals are similar to those observed at lower consent rates. Estimates of analytical studies looking at associations of substance use with other variables will not differ at reasonable consent rates of 50%-80%. Descriptive prevalence studies may be biased, but only at very low rates of consent. PMID- 24172122 TI - Thursday drinking and academic load among college women. AB - OBJECTIVE: Research indicates that alcohol consumption by college students fluctuates across the semester, with consumption changing because of social events and calendar holidays. In addition, some research indicates that Thursday alcohol consumption is a function of Friday course schedule. Students with courses after 10 a.m. or not at all on Friday are more likely to consume alcohol on Thursday nights. Furthermore, college women are increasingly consuming alcohol at higher levels and comprise a larger portion of college students in comparison with their male counterparts. The current study was aimed at examining patterns of Thursday night alcohol consumption and academic load among female college students. METHOD: College students (N = 383, 100% female) participated in a 10 week paper- and web-based survey on alcohol consumption. After completion of the study, academic records of the participants were retrieved for objective measures of academic load. RESULTS: Patterns of Thursday alcohol consumption relate to timing and difficulty of the first course on Friday. However, patterns of Thursday alcohol consumption were not related to other aspects of academic load (e.g., number of academic credits, fall semester grade-point average, cumulative grade-point average, other Friday courses). CONCLUSIONS: It seems that female students who are more likely to consume alcohol on Thursday night have made academic scheduling decisions to allow for this experience. These decisions seem to not adversely affect their grade-point average. Findings suggest that changes to the academic calendar to curb alcohol consumption warrant further investigation. PMID- 24172123 TI - "Craving": exploring the components of the Desires for Alcohol Questionnaire (DAQ) and the relation to the severity of alcohol problems. AB - OBJECTIVE: The aims of this study were (a) to explore the components of craving, as measured by the Desires for Alcohol Questionnaire (DAQ), and (b) to examine how craving may relate to the severity of alcohol problems. METHOD: A total of 106 patients seeking treatment for an alcohol use disorder (AUD) completed the DAQ and Alcohol Use Disorders Identification Test (AUDIT). The overall sample was predominantly male (63%) with a mean age of 44 years. Sixty-one percent of the participants were abstinent from alcohol at the time of the study. Principal components analysis was conducted on the DAQ for the overall, abstinent, and currently drinking samples. Correlations were computed between the DAQ and AUDIT scores, and differences in craving between the abstinent and currently drinking samples were investigated. RESULTS: Components of craving, as measured by the DAQ, included the desire to drink, the ability to control drinking, positive reinforcement and negative reinforcement. Drinkers displayed stronger cravings (Mdn = 47.00, interquartile range [IQR] = 32.0-65.0) than those currently abstinent (Mdn = 33.00, IQR = 26.0-43.0; U = 850.0; z = 3.127, p < .01; r = .30). The intensity of craving increased with the severity of the AUD in current drinkers (r = .739, p < .001). CONCLUSIONS: Because of the small sample size, the results of the study should be regarded as preliminary. The components of craving, as measured by the DAQ, support those previously identified in the literature. The study supports the notion that craving is positively associated with the severity of an AUD. PMID- 24172124 TI - A wearable sensor system for monitoring cigarette smoking. AB - OBJECTIVE: Available methods of smoking assessment (e.g., self-report, portable puff-topography instruments) do not permit the collection of accurate measures of smoking behavior while minimizing reactivity to the assessment procedure. This article suggests a new method for monitoring cigarette smoking based on a wearable sensor system (Personal Automatic Cigarette Tracker [PACT]) that is completely transparent to the end user and does not require any conscious effort to achieve reliable monitoring of smoking in free-living individuals. METHOD: The proposed sensor system consists of a respiratory inductance plethysmograph for monitoring of breathing and a hand gesture sensor for detecting a cigarette at the mouth. The wearable sensor system was tested in a laboratory study of 20 individuals who performed 12 different activities including cigarette smoking. Signal processing was applied to evaluate the uniqueness of breathing patterns and their correlation with hand gestures. RESULTS: The results indicate that smoking manifests unique breathing patterns that are highly correlated with hand to-mouth cigarette gestures and suggest that these signals can potentially be used to identify and characterize individual smoke inhalations. CONCLUSIONS: With the future development of signal processing and pattern-recognition methods, PACT can be used to automatically assess the frequency of smoking and inhalation patterns (such as depth of inhalation and smoke holding) throughout the day and provide an objective method of assessing the effectiveness of behavioral and pharmacological smoking interventions. PMID- 24172126 TI - The NBOMe series: a novel, dangerous group of hallucinogenic drugs. PMID- 24172125 TI - Al-Anon family groups: newcomers and members. AB - OBJECTIVE: Empirical knowledge is lacking about Al-Anon Family Groups (Al-Anon), the most widely used form of help by people concerned about another's drinking, partly because conducting research on 12-step groups is challenging. Our purpose was to describe a new method of obtaining survey data from 12-step group attendees and to examine influences on initial Al-Anon attendance and attendees' recent life contexts and functioning. METHOD: Al-Anon's World Service Office sent a mailing to a random sample of groups, which subsequently yielded surveys from newcomers (n = 359) and stable members (n = 264). RESULTS: Reasons for groups' nonparticipation included having infrequent newcomers and the study being seen as either contrary to the 12 Traditions or too uncomfortable for newcomers. Main concerns prompting initial Al-Anon attendance were problems with overall quality of life and with the Al-Anon trigger (a significant drinking individual), and being stressed and angry. Goals for Al-Anon attendance were related to the following concerns: better quality of life, fewer trigger-related problems, and less stress. Members reported better functioning in some of these domains (quality of life, relationship with the trigger) but did not differ from newcomers on physical and psychological health. Newcomers were more likely to have recently drunk alcohol and to have obtained treatment for their own substance misuse problems. CONCLUSIONS: This method of collecting data from 12 step group attendees yielded valid data and also was seen by many in Al-Anon as consistent with the Traditions. Both newcomers and members had aimed to improve their overall quality of life and well-being through Al-Anon, and, indeed, members were more satisfied with their quality of life than were newcomers. PMID- 24172127 TI - Autologous Ilium Grafts: Long-Term Results on Immediate or Staged Functional Rehabilitation of Mandibular Segmental Defects Using Dental Implants after Tumor Resection. AB - BACKGROUND: It is a challenge for clinicians to restore oral function in patients with segmental defects of the mandible because of tumor extirpation. Dental implant therapy following vascularized autologous ilium grafts is an effective method to restore oral function in patients with mandibular segmental defects. PURPOSE: The aim of this retrospective study was to investigate the long-term clinical outcomes of ilium grafts combined with immediate or staged mandibular dental implant therapy to restore craniofacial defects resulting from tumor resection. MATERIALS AND METHODS: Over a 5-year period (2000-2004), 32 patients who underwent mandibular segmental resection for tumors were treated with vascularized ilium grafts to augment bone volume. Seventeen patients received phase I therapy (immediate placement of implants), and 15 patients underwent phase II therapy (delayed placement of implants). A total of 110 dental implants were placed in these patients for mandibular restoration of the defective areas. Information regarding implant success and survival rates, marginal bone loss, soft tissue inflammation, complications of prosthesis, and patient satisfaction for the 8 to 12 years following oral reconstruction was obtained from patient records. RESULTS: Although there was mild evidence of bone graft resorption, the vascularized autogenous ilium bone grafts were successful in all patients. The cumulative patient survival and success rate of the implants were 96.4% and 91.8%, respectively. The mean peri-implant bone resorption ranged from 1.0 to 1.2 mm over the 8- to 12-year follow-up period. The annual mean number of complications/repairs was from 0.11 to 0.07 per patient during the 8- to 12-year follow-up. Over 80% of the patients were fully satisfied with their restoration of oral function. CONCLUSIONS: This study demonstrates that reconstruction of mandibular segmental defects because of resection of mandibular tumors using dental implants therapy combined with vascularized autogenous ilium grafts is an effective method to restore oral function. PMID- 24172128 TI - Help us find the cures. AB - Despite significant advances in research, breast cancer is still the most common form of cancer, with 50,000 cases diagnosed and 12,000 dying of the disease each year in the UK. In October 2013, Breast Cancer Campaign published a Gap Analysis of breast cancer research that provides us with what we need to know about and what we now need to do to overcome - prevent, cure and outlive - breast cancer. In addition to highlighting the gaps in our understanding of breast cancer, the paper identifies five strategic solutions, which require a collaborative approach amongst researchers in academia and industry, funders, donors, policy-makers and parliamentarians, healthcare professionals and patients to achieve significant progress. Breast Cancer Campaign is calling for funding organizations to reverse the decline in resources targeted towards breast cancer research, an improved and collaborative infrastructure to support breast cancer research, multidisciplinary collaboration and improved clinical trial design. We hope that breast cancer can be overcome by 2050, but this can only be achieved through collaboration with others. The actions that will make a difference have been identified and we must act now. PMID- 24172129 TI - Sources and structures of mitotic crossovers that arise when BLM helicase is absent in Drosophila. AB - The Bloom syndrome helicase, BLM, has numerous functions that prevent mitotic crossovers. We used unique features of Drosophila melanogaster to investigate origins and properties of mitotic crossovers that occur when BLM is absent. Induction of lesions that block replication forks increased crossover frequencies, consistent with functions for BLM in responding to fork blockage. In contrast, treatment with hydroxyurea, which stalls forks, did not elevate crossovers, even though mutants lacking BLM are sensitive to killing by this agent. To learn about sources of spontaneous recombination, we mapped mitotic crossovers in mutants lacking BLM. In the male germline, irradiation-induced crossovers were distributed randomly across the euchromatin, but spontaneous crossovers were nonrandom. We suggest that regions of the genome with a high frequency of mitotic crossovers may be analogous to common fragile sites in the human genome. Interestingly, in the male germline there is a paucity of crossovers in the interval that spans the pericentric heterochromatin, but in the female germline this interval is more prone to crossing over. Finally, our system allowed us to recover pairs of reciprocal crossover chromosomes. Sequencing of these revealed the existence of gene conversion tracts and did not provide any evidence for mutations associated with crossovers. These findings provide important new insights into sources and structures of mitotic crossovers and functions of BLM helicase. PMID- 24172130 TI - The evolution and consequences of sex-specific reproductive variance. AB - Natural selection favors alleles that increase the number of offspring produced by their carriers. But in a world that is inherently uncertain within generations, selection also favors alleles that reduce the variance in the number of offspring produced. If previous studies have established this principle, they have largely ignored fundamental aspects of sexual reproduction and therefore how selection on sex-specific reproductive variance operates. To study the evolution and consequences of sex-specific reproductive variance, we present a population genetic model of phenotypic evolution in a dioecious population that incorporates previously neglected components of reproductive variance. First, we derive the probability of fixation for mutations that affect male and/or female reproductive phenotypes under sex-specific selection. We find that even in the simplest scenarios, the direction of selection is altered when reproductive variance is taken into account. In particular, previously unaccounted for covariances between the reproductive outputs of different individuals are expected to play a significant role in determining the direction of selection. Then, the probability of fixation is used to develop a stochastic model of joint male and female phenotypic evolution. We find that sex-specific reproductive variance can be responsible for changes in the course of long-term evolution. Finally, the model is applied to an example of parental-care evolution. Overall, our model allows for the evolutionary analysis of social traits in finite and dioecious populations, where interactions can occur within and between sexes under a realistic scenario of reproduction. PMID- 24172131 TI - Inducible protein traps with dominant phenotypes for functional analysis of the Drosophila genome. AB - The Drosophila melanogaster genome has been extensively characterized, but there remains a pressing need to associate gene products with phenotypes, subcellular localizations, and interaction partners. A multifunctional, Minos transposon based protein trapping system called Hostile takeover (Hto) was developed to facilitate in vivo analyses of endogenous genes, including live imaging, purification of protein complexes, and mutagenesis. The Hto transposon features a UAS enhancer with a basal promoter, followed by an artificial exon 1 and a standard 5' splice site. Upon GAL4 induction, exon 1 can splice to the next exon downstream in the flanking genomic DNA, belonging to a random target gene. Exon 1 encodes a dual tag (FLAG epitope and mCherry red fluorescent protein), which becomes fused to the target protein. Hto was mobilized throughout the genome and then activated by eye-specific GAL4; an F1 screen for abnormal eye phenotypes was used to identify inserts that express disruptive fusion proteins. Approximately 1.7% of new inserts cause eye phenotypes. Of the first 23 verified target genes, 21 can be described as regulators of cell biology and development. Most are transcription factor genes, including AP-2, CG17181, cut, klu, mamo, Sox102F, and sv. Other target genes [l(1)G0232, nuf, pum, and Syt4] make cytoplasmic proteins, and these lines produce diverse fluorescence localization patterns. Hto permits the expression of stable carboxy-terminal subfragments of proteins, which are rarely tested in conventional genetic screens. Some of these may disrupt specific cell pathways, as exemplified by truncated forms of Mastermind and Nuf. PMID- 24172132 TI - The basis for evolution of DNA-binding specificity of the Aft1 transcription factor in yeasts. AB - The Saccharomyces cerevisiae Aft1 and Kluyveromyces lactis KlAft are orthologous yeast transcription activators that regulate the expression of the same group of iron-uptake genes but bind to the different DNA sites: TGCACCC for Aft1 and PuCACCC for KlAft. To establish whether the DNA-binding mechanisms of Aft1 and KlAft have diverged during the evolution of the Aft-type transcription factor, we examined the function of a nonconserved region in their DNA-binding domains. A large part of this region is composed of a sequence predicted to be disordered in structure and potentially phosphorylated. We show with deletion mutant analyses that this sequence is essential for the binding of Aft1 to its DNA site and for the iron uptake and growth of S. cerevisiae under iron-limited conditions. We constructed hybrid proteins by exchanging the nonconserved regions of Aft1 and KlAft. We show that the Aft1 region is necessary and sufficient for KlAft to bind efficiently to the Aft1 DNA site in S. cerevisiae and to complement the iron dependent phenotype of the aft1Deltaaft2Delta mutant. This demonstrates that the changes in the nonconserved region of the Aft-type DNA-binding domain have led to changes in the DNA-binding specificity and have major consequences for the regulation of iron homeostasis. The combination of bioinformatic and experimental analyses indicates that the sequence TGCACCC is the most probable ancestral Aft type element. Our findings suggest that the changes in the nonconserved region of the DNA-binding domain are responsible for the evolution of the TGCACCC sequence toward PuCACCC in the K. lactis species. PMID- 24172133 TI - Inference of the properties of the recombination process from whole bacterial genomes. AB - Patterns of linkage disequilibrium, homoplasy, and incompatibility are difficult to interpret because they depend on several factors, including the recombination process and the population structure. Here we introduce a novel model-based framework to infer recombination properties from such summary statistics in bacterial genomes. The underlying model is sequentially Markovian so that data can be simulated very efficiently, and we use approximate Bayesian computation techniques to infer parameters. As this does not require us to calculate the likelihood function, the model can be easily extended to investigate less probed aspects of recombination. In particular, we extend our model to account for the bias in the recombination process whereby closely related bacteria recombine more often with one another. We show that this model provides a good fit to a data set of Bacillus cereus genomes and estimate several recombination properties, including the rate of bias in recombination. All the methods described in this article are implemented in a software package that is freely available for download at http://code.google.com/p/clonalorigin/. PMID- 24172134 TI - A novel role for Cet1p mRNA 5'-triphosphatase in promoter proximal accumulation of RNA polymerase II in Saccharomyces cerevisiase. AB - Yeast mRNA 5'-triphosphatase, Cet1p, recognizes phosphorylated-RNA polymerase II as a component of capping machinery via Ceg1p for cotranscriptional formation of mRNA cap structure that recruits cap-binding complex (CBC) and protects mRNA from exonucleases. Here, we show that the accumulation of RNA polymerase II at the promoter proximal site of ADH1 is significantly enhanced in the absence of Cet1p. Similar results are also found at other genes. Cet1p is recruited to the 5' end of the coding sequence, and its absence impairs mRNA capping, and hence CBC recruitment. However, such an impaired recruitment of CBC does not enhance promoter proximal accumulation of RNA polymerase II. Thus, Cet1p specifically lowers the accumulation of RNA polymerase II at the promoter proximal site independently of mRNA cap structure or CBC. Further, we show that Cet1p's N terminal domain, which is not involved in mRNA capping, decreases promoter proximal accumulation of RNA polymerase II. An accumulation of RNA polymerase II at the promoter proximal site in the absence of Cet1p's N-terminal domain is correlated with reduced transcription. Collectively, our results demonstrate a novel role of Cet1p in regulation of promoter proximal accumulation of RNA polymerase II independently of mRNA capping activity, and hence transcription in vivo. PMID- 24172135 TI - Crossover heterogeneity in the absence of hotspots in Caenorhabditis elegans. AB - Crossovers play mechanical roles in meiotic chromosome segregation, generate genetic diversity by producing new allelic combinations, and facilitate evolution by decoupling linked alleles. In almost every species studied to date, crossover distributions are dramatically nonuniform, differing among sexes and across genomes, with spatial variation in crossover rates on scales from whole chromosomes to subkilobase hotspots. To understand the regulatory forces dictating these heterogeneous distributions a crucial first step is the fine scale characterization of crossover distributions. Here we define the wild-type distribution of crossovers along a region of the C. elegans chromosome II at unprecedented resolution, using recombinant chromosomes of 243 hermaphrodites and 226 males. We find that well-characterized large-scale domains, with little fine scale rate heterogeneity, dominate this region's crossover landscape. Using the Gini coefficient as a summary statistic, we find that this region of the C. elegans genome has the least heterogeneous fine-scale crossover distribution yet observed among model organisms, and we show by simulation that the data are incompatible with a mammalian-type hotspot-rich landscape. The large-scale structural domains-the low-recombination center and the high-recombination arm have a discrete boundary that we localize to a small region. This boundary coincides with the arm-center boundary defined both by nuclear-envelope attachment of DNA in somatic cells and GC content, consistent with proposals that these features of chromosome organization may be mechanical causes and evolutionary consequences of crossover recombination. PMID- 24172136 TI - Candidemia in the critically ill: initial therapy and outcome in mechanically ventilated patients. AB - BACKGROUND: Mortality among critically ill patients with candidemia is very high. We sought to determine whether the choice of initial antifungal therapy is associated with survival among these patients, using need for mechanical ventilatory support as a marker of critical illness. METHODS: Cohort analysis of outcomes among mechanically ventilated patients with candidemia from the 24 North American academic medical centers contributing to the Prospective Antifungal Therapy (PATH) Alliance registry. Patients were included if they received either fluconazole or an echinocandin as initial monotherapy. RESULTS: Of 5272 patients in the PATH registry at the time of data abstraction, 1014 were ventilated and concomitantly had candidemia, with 689 eligible for analysis. 28-day survival was higher among the 374 patients treated initially with fluconazole than among the 315 treated with an echinocandin (66% versus 51%, P < .001). Initial fluconazole therapy remained associated with improved survival after adjusting for non treatment factors in the overall population (hazard ratio .75, 95% CI .59-.96), and also among patients with albicans infection (hazard ratio .62, 95% CI .44 .88). While not statistically significant, fluconazole appeared to be associated with higher mortality among patients infected with glabrata (HR 1.13, 95% CI .70 1.84). CONCLUSIONS: Among ventilated patients with candidemia, those receiving fluconazole as initial monotherapy were significantly more likely to survive than those treated with an echinocandin. This difference persisted after adjustment for non-treatment factors. PMID- 24172138 TI - Gastric granular cell tumour clinically mimicking carcinoid tumour treated by endoscopic submucosal dissection. PMID- 24172137 TI - The roles of catabolic factors in the development of osteoarthritis. AB - Osteoarthritis (OA) is the most prevalent disease of articular joints characterized by joint space narrowing on X-ray, joint pain, and a loss of joint function through progressive cartilage degradation and intermittent synovial inflammation. Current in vitro models of OA are often monolayer cultured primary cells exposed to high concentrations of cytokines or chemokines, usually IL-1beta or TNF-alpha. IL-1beta could play a role in the early progression or even initiation of OA as evidenced by many of the in vitro studies. However, the inconsistent or outright lack of detectable IL-1beta combined with high concentrations of the natural inhibitor IL-1Ra in the OA synovial fluid makes the idea of OA being IL-1beta-driven questionable. Further, other stimulants, including IL-6 and matrix fragments, have been shown in vitro to cause many of the effects seen in OA at relevant concentrations found in the OA synovial fluid. More work with these stimulants and IL-1beta-independent models needs to be done. Concurrently, research should be conducted with patients with OA as early as possible in the progression of their disease to be able to potentially identify, target, and treat the initiation of the disease. PMID- 24172139 TI - Functional roles of Nurr1, Pitx3, and Lmx1a in neurogenesis and phenotype specification of dopamine neurons during in vitro differentiation of embryonic stem cells. AB - To elucidate detailed functional mechanisms of key fate-determining transcription factors (eg, Nurr1, Pitx3, and Lmx1a) and their functional interplay for midbrain dopamine (mDA) neurons, we developed highly efficient gain-of-function system by transducing the neural progenitors (NPs) derived from embryonic stem cells (ESCs) with retroviral vectors, allowing the analysis of downstream molecular and cellular effects. Overexpression of each factors, Nurr1, Pitx3, and Lmx1a robustly promoted the dopaminergic differentiation of ESC-NP cells exposed to sonic hedgehog (SHH) and fibroblast growth factor 8 (FGF8). In addition, each of these factors directly interacts with potential binding sites within the tyrosine hydroxylase (TH) gene and activated its promoter activity. Interestingly, however, overexpression of Nurr1, but not of Pitx3 or Lmx1a, generated a significant number of nonneuronal TH-positive cells. In line with this, Pitx3 and Lmx1a, but not Nurr1, induced expression of the Ngn2 gene, which is critical for neurogenesis. We also observed that Pitx3 directly bound to its potential binding sites within the Ngn2 gene and the pan-neuronal marker beta-tubulin III gene, suggesting that Pitx3 contributes to mDA neurogenesis by directly regulating these genes. Taken together, our data demonstrate that key mDA regulators (Nurr1, Pitx3, and Lmx1a) play overlapping as well as distinct roles during neurogenesis and neurotransmitter phenotype determination of mDA neurons. PMID- 24172141 TI - Coarse-grain modelling of protein-protein interactions. AB - Here, we review recent advances towards the modelling of protein-protein interactions (PPI) at the coarse-grained (CG) level, a technique that is now widely used to understand protein affinity, aggregation and self-assembly behaviour. PPI models of soluble proteins and membrane proteins are separately described, but we note the parallel development that is present in both research fields with three important themes: firstly, combining CG modelling with knowledge-based approaches to predict and refine protein-protein complexes; secondly, using physics-based CG models for de novo prediction of protein-protein complexes; and thirdly modelling of large scale protein aggregates. PMID- 24172140 TI - Localizing intramyocardially embedded left anterior descending artery during coronary bypass surgery: literature review. AB - Proper detection of the deeply embedded left anterior descending artery remains a challenge. Many authors proposed different methods for artery identification, such as ultrasound Doppler, cineangiography, retrograde dissection overlying tissues, and exposure over the probe. Choice of the technique often depends on the surgeon's acquaintance and experience. The article compares and summarizes different procedures for the detection of intramyocardially located left anterior descending artery. PMID- 24172142 TI - Identifying patients with chronic conditions using pharmacy data in Switzerland: an updated mapping approach to the classification of medications. AB - BACKGROUND: Quantifying population health is important for public health policy. Since national disease registers recording clinical diagnoses are often not available, pharmacy data were frequently used to identify chronic conditions (CCs) in populations. However, most approaches mapping prescribed drugs to CCs are outdated and unambiguous. The aim of this study was to provide an improved and updated mapping approach to the classification of medications. Furthermore, we aimed to give an overview of the proportions of patients with CCs in Switzerland using this new mapping approach. METHODS: The database included medical and pharmacy claims data (2011) from patients aged 18 years or older. Based on prescription drug data and using the Anatomical Therapeutic Chemical (ATC) classification system, patients with CCs were identified by a medical expert review. Proportions of patients with CCs were calculated by sex and age groups. We constructed multiple logistic regression models to assess the association between patient characteristics and having a CC, as well as between risk factors (diabetes, hyperlipidemia) for cardiovascular diseases (CVD) and CVD as one of the most prevalent CCs. RESULTS: A total of 22 CCs were identified. In 2011, 62% of the 932'612 subjects enrolled have been prescribed a drug for the treatment of at least one CC. Rheumatologic conditions, CVD and pain were the most frequent CCs. 29% of the persons had CVD, 10% both CVD and hyperlipidemia, 4% CVD and diabetes, and 2% suffered from all of the three conditions. The regression model showed that diabetes and hyperlipidemia were strongly associated with CVD. CONCLUSIONS: Using pharmacy claims data, we developed an updated and improved approach for a feasible and efficient measure of patients' chronic disease status. Pharmacy drug data may be a valuable source for measuring population's burden of disease, when clinical data are missing. This approach may contribute to health policy debates about health services sources and risk adjustment modelling. PMID- 24172144 TI - Use of glycosylated haemoglobin as diagnostic tool in Greenland: prevalence of diagnosed diabetes mellitus. AB - BACKGROUND: The prevalence of undiagnosed diabetes mellitus (DM) in Greenland has been reported very high with only 30% of cases diagnosed. In 2010, glycosylated hemoglobin (A1C) was introduced as a diagnostic tool in Greenland. However, the current use of A1c is unknown as well as the current prevalence of diagnosed DM.The aim of this study was firstly to estimate the use of A1C as diagnostic tool within the first 27 months after introducing the method and secondly to estimate the age and gender specific prevalence of diagnosed DM in Greenland in 2012. METHODS: This study was perfomed as a cross-sectional register study using data from electronic medical records (EMR). To analyse the use of A1C as diagnostic tool:A sample amongst all Greenlanders at or above age 35 old was used to determine the number of individuals screened with A1C within a 27 month period, excluding those already known to have DM.To estimate the prevalence of diagnosted DM: Patients with DM were identified electronically using a statistic module run on data in the EMR. Age and gender specific prevalence was estimated using the Greenlandic population as of 1 January 2012 as the background population. RESULTS: The test sample resulted in a study group of 1008 individuals from which 2.3% (23) were excluded because they were already known to have DM. Among the remaining 985, 13.6% were tested with A1C at least once during the 27 months of observation. DM was diagnosed in 7.5% (10) of the tested persons and in 1.0% of the whole group.Regarding prevalence, a total of 920 patients with diagnosed DM were identified. The total prevalence among adults aged 20-79 years old was 2.20% (95% CI: 2.05-2.34) with no significant difference between genders. CONCLUSION: Testing for DM using A1C as diagnostic tool is used in Greenland. The prevalence of diagnosed DM in Greenland remains low although increasing. Undiagnosed DM may still be an important issue in Greenland. PMID- 24172143 TI - Glucocorticoids suppress hypoxia-induced COX-2 and hypoxia inducible factor 1alpha expression through the induction of glucocorticoid-induced leucine zipper. AB - BACKGROUND AND PURPOSE: The COX-2/PGE2 pathway in hypoxic cancer cells has important implications for stimulation of inflammation and tumourigenesis. However, the mechanism by which glucocorticoid receptors (GRs) inhibit COX-2 during hypoxia has not been elucidated. Hence, we explored the mechanisms underlying glucocorticoid-mediated inhibition of hypoxia-induced COX-2 in human distal lung epithelial A549 cells. EXPERIMENTAL APPROACH: The expressions of COX 2 and glucocorticoid-induced leucine zipper (GILZ) in A549 cells were determined by Western blot and/or quantitative real time-PCR respectively. The anti-invasive effect of GILZ on A549 cells was evaluated using the matrigel invasion assay. KEY RESULTS: The hypoxia-induced increase in COX-2 protein and mRNA levels and promoter activity were suppressed by dexamethasone, and this effect of dexamethasone was antagonized by the GR antagonist RU486. Overexpression of GILZ in A549 cells also inhibited hypoxia-induced COX-2 expression levels and knockdown of GILZ reduced the glucocorticoid-mediated inhibition of hypoxia induced COX-2 expression, indicating that the inhibitory effects of dexamethasone on hypoxia-induced COX-2 are mediated by GILZ. GILZ suppressed the expression of hypoxia inducible factor (HIF)-1alpha at the protein level and affected its signalling pathway. Hypoxia-induced cell invasion was also dramatically reduced by GILZ expression. CONCLUSION AND IMPLICATIONS: Dexamethasone-induced upregulation of GILZ not only inhibits the hypoxic-evoked induction of COX-2 expression and cell invasion but further blocks the HIF-1 pathway by destabilizing HIF-1alpha expression. Taken together, these findings suggest that the suppression of hypoxia-induced COX-2 by glucocorticoids is mediated by GILZ. Hence, GILZ is a potential key therapeutic target for suppression of inflammation under hypoxia. PMID- 24172145 TI - The influence of patients' preference/attitude towards psychotherapy and antidepressant medication on the treatment of major depressive disorder. AB - BACKGROUND AND OBJECTIVES: Preferences and attitudes patients hold towards treatment are important, as these can influence treatment outcome. In depression research, the influence of patients' preference/attitudes on outcome and dropout has mainly been studied for antidepressant medication, and less for psychological treatments. We investigated the effects of patients' preference and attitudes towards psychological treatment and antidepressant medication on treatment outcome and dropout, and tested specificity of effects. METHODS: Data are based on a randomized trial testing the effectiveness of behavioural activation (BA) vs antidepressant medication (ADM) for major depression (MDD) in Iran. Patients with MDD (N = 100) were randomized to BA (N = 50) or ADM (N = 50). Patients' preference/attitudes towards psychotherapy and ADM were assessed at baseline and associated with dropout and treatment outcome using logistic regression and multilevel analysis. RESULTS: High scores on psychotherapy preference/attitude and low scores on ADM preference/attitude predicted dropout from ADM, while no association between dropout and preference/attitude was found in BA. Psychotherapy preference/attitude moderated the differential effect of BA and ADM on one outcome measure, but the association disappeared after one year. LIMITATIONS: Because in Iran most patients have only access to ADM, offering a psychological treatment for depression could attract especially those patients that prefer this newly available treatment. CONCLUSIONS: Patients' preferences and attitudes towards depression treatments influence dropout from ADM, and moderate the short-term difference in effectiveness between BA and ADM. The fact that dropout from BA was not affected by preference/attitude speaks for its acceptability among patients. PMID- 24172146 TI - Efficacy of body exposure as treatment component for patients with eating disorders. AB - BACKGROUND AND OBJECTIVES: Body exposure and cognitive restructuring are well known interventions in cognitive-behavioral therapies for patients with eating disorders. Though promising, little is known about the impact of body exposure on body dissatisfaction, overvaluation of weight and shape and other aspects of eating disorder psychopathology. Thus, the aim of the two studies presented here is to evaluate the efficacy of mirror exposure and video exposure on body dissatisfaction, weight and shape concerns and other aspects of eating disorder psychopathology. METHOD STUDY 1: Fourteen women diagnosed with Eating Disorders Not Otherwise Specified (EDNOS; DSM-IV-TR) were treated in repeated mirror exposure sessions. Assessments were carried out before (baseline) and after body exposure. RESULTS STUDY 1: Measures of body dissatisfaction, shape concerns and eating disorder psychopathology were significantly improved at the post treatment assessment. METHOD STUDY 2: Thirteen women with Bulimia Nervosa (BN; DSM-IV-TR) received repeated mirror and video exposure sessions. Measures were assessed before (baseline) and after body exposure. RESULTS STUDY 2: Body image dissatisfaction was significantly improved at post treatment assessment. LIMITATIONS: These preliminary results are based on subjective data from two small clinical samples. Comparisons between the studies are limited by design variations. CONCLUSIONS: The studies provide evidence that body exposure is a promising technique for treatment of body dissatisfaction in EDNOS and BN. Moreover, in EDNOS shape concern and aspects of eating disorder psychopathology were improved after body exposure. Reasons for the lack of change in shape and weight concern as well as in eating disorder psychopathology in BN are discussed. PMID- 24172147 TI - Surface plasma resonant effect of gold nanoparticles on the photoelectrodes of dye-sensitized solar cells. AB - In this study, we prepared different shapes of gold nanoparticles by seed mediated growth method and applied them on the photoelectrodes of dye-sensitized solar cells (DSSCs) to study the surface plasma resonant (SPR) effect of gold nanoparticles on the photoelectrodes of dye-sensitized solar cells. The analyses of field emission scanning electron microscopy show that the average diameter of the spherical gold nanoparticles is 45 nm, the average length and width of the short gold nanorods were 55 and 22 nm, respectively, and the average length and width of the long gold nanorods were 55 and 14 nm, respectively. The aspect ratio of the short and long gold nanorods was about 2.5 and 4, respectively. The results of ultraviolet-visible absorption spectra show that the absorption wavelength is about 540 nm for spherical gold nanoparticles, and the absorption of the gold nanorods reveals two peaks. One is about 510 to 520 nm, and the other is about 670 and 710 nm for the short and long gold nanorods, respectively. The best conversion efficiency of the dye-sensitized solar cells with spherical gold nanoparticles and short and long gold nanorods added in is 6.77%, 7.08%, and 7.29%, respectively, and is higher than that of the cells without gold nanoparticles, which is 6.21%. This result indicates that the effect of gold nanoparticles on the photoelectrodes can increase the conductivity and reduce the recombination of charges in the photoelectrodes, resulting in the increase of conversion efficiency for DSSCs. In addition, the long gold nanorods have stronger SPR effect than the spherical gold nanoparticles and short gold nanorods at long wavelength. This may be the reason for the higher conversion efficiency of DSSCs with long gold nanorods than those of the cells with spherical gold nanoparticles and short gold nanorods. PMID- 24172148 TI - The data - sources and validation. AB - The basis for all observational studies is the availability of appropriate data of high quality. Data may be collected specifically for the research purpose in question (so-called "primary data"), but data collected for other purposes (so called "secondary data") are also sometimes used and useful in research. High accuracy and precision are required (irrespective of the source of the data) to arrive at correct and unbiased results efficiently. Both careful planning prior to the start of the data acquisition and thorough procedures for data entry are obvious prerequisites to achieve high-quality data. However, data should also be subjected to a thorough validation after the collection. Primary data are mainly validated through proper screening, by using various descriptive statistical methods. Validation of secondary data is associated with specific conditions - the first of which is to be aware of the limitations in its usefulness imposed by procedures during collection. Approaches for validation of secondary data will be briefly discussed in the paper, and include patient chart review, combining with data from other sources, two-stage sampling, and aggregated methods. PMID- 24172149 TI - Seroprevalence of human Malawi polyomavirus. AB - The seroprevalence of the recently discovered human Malawi polyomavirus (MWPyV) was determined by virus-like particle-based enzyme-linked immunosorbent assay (ELISA) in age-stratified Italian subjects. The findings indicated that MWPyV infection occurs early in life, and seroprevalence was shown to reach 42% in adulthood. PMID- 24172150 TI - Comparison of the Bruker Biotyper and Vitek MS matrix-assisted laser desorption ionization-time of flight mass spectrometry systems for identification of mycobacteria using simplified protein extraction protocols. AB - Matrix-assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOF MS) has recently been described as a fast and inexpensive method for the identification of mycobacteria. Although mycobacteria require extraction prior to MALDI-TOF MS analysis, previously published protocols have been relatively complex, involving significant hands-on time and materials not often found in the clinical laboratory. In this study, we tested two simplified protein extraction protocols developed at the University of Washington (UW) and by bioMerieux (BMX) for use with two different mass spectrometry platforms (the Bruker MALDI Biotyper and the bioMerieux Vitek MS, respectively). Both extraction protocols included vortexing with silica beads in the presence of ethanol. The commercial Bruker database was also augmented with an in-house database composed of 123 clinical Mycobacterium strains. A total of 198 clinical strains, representing 18 Mycobacterium species, were correctly identified to the species level 94.9% of the time when extracted using the UW protocol and compared to the augmented database. The BMX protocol and Vitek MS system resulted in correct species-level identifications for 94.4% of these strains. In contrast, only 79.3% of the strains were identified to the species level by the nonaugmented Bruker database, although the use of a lower identification score threshold (>=1.7) increased the identification rate to 93.9%, with two misidentifications that were unlikely to be clinically relevant. The two simplified protein extraction protocols described in this study are easy to use for identifying commonly encountered Mycobacterium species. PMID- 24172151 TI - Genotypic and epidemiologic trends of norovirus outbreaks in the United States, 2009 to 2013. AB - Noroviruses are the leading cause of epidemic acute gastroenteritis in the United States. From September 2009 through August 2013, 3,960 norovirus outbreaks were reported to CaliciNet. Of the 2,895 outbreaks with a known transmission route, person-to-person and food-borne transmissions were reported for 2,425 (83.7%) and 465 (16.1%) of the outbreaks, respectively. A total of 2,475 outbreaks (62.5%) occurred in long-term care facilities (LTCF), 389 (9.8%) in restaurants, and 227 (5.7%) in schools. A total of 435 outbreaks (11%) were typed as genogroup I (GI) and 3,525 (89%) as GII noroviruses. GII.4 viruses caused 2,853 (72%) of all outbreaks, of which 94% typed as either GII.4 New Orleans or GII.4 Sydney. In addition, three non-GII.4 viruses, i.e., GII.12, GII.1, and GI.6, caused 528 (13%) of all outbreaks. Several non-GII.4 genotypes (GI.3, GI.6, GI.7, GII.3, GII.6, and GII.12) were significantly more associated with food-borne transmission (odds ratio, 1.9 to 7.1; P < 0.05). Patients in LTCF and people >=65 years of age were at higher risk for GII.4 infections than those in other settings and with other genotypes (P < 0.05). Phylogeographic analysis identified three major dispersions from two geographic locations that were responsible for the GI.6 outbreaks from 2011 to 2013. In conclusion, our data demonstrate the cyclic emergence of new (non-GII.4) norovirus strains, and several genotypes are more often associated with food-borne outbreaks. These surveillance data can be used to improve viral food-borne surveillance and to help guide studies to develop and evaluate targeted prevention methods such as norovirus vaccines, antivirals, and environmental decontamination methods. PMID- 24172152 TI - First report of brain abscess caused by a satelliting phenotypic variant of Helcococcus kunzii. AB - Helcococcus kunzii was isolated from a brain abscess in a diabetic patient with cholesteatoma and demonstrated satellitism around Staphylococcus aureus in culture. This is the first reported case of severe central nervous system infection due to H. kunzii and the first description of a satelliting phenotypic variant of this organism. PMID- 24172153 TI - Hepatitis C virus late relapse after sustained virologic response from interferon and ribavirin treatment as confirmed by RNA sequencing. AB - Hepatitis C virus (HCV) viremia is unusual (<5%) after successful treatment, defined as sustained virologic response (SVR) or undetectable HCV PCR 12 to 24 weeks after therapy. We present a case of late virologic relapse (de novo infection was excluded by RNA sequencing) after SVR followed by spontaneous viral clearance. PMID- 24172154 TI - Proposal of a consensus set of hypervariable mycobacterial interspersed repetitive-unit-variable-number tandem-repeat loci for subtyping of Mycobacterium tuberculosis Beijing isolates. AB - Mycobacterium tuberculosis Beijing strains represent targets of special importance for molecular surveillance of tuberculosis (TB), especially because they are associated with spread of multidrug resistance in some world regions. Standard 24-locus mycobacterial interspersed repetitive-unit-variable-number tandem-repeat (MIRU-VNTR) typing lacks resolution power for accurately discriminating closely related clones that often compose Beijing strain populations. Therefore, we evaluated a set of 7 additional, hypervariable MIRU VNTR loci for better resolution and tracing of such strains, using a collection of 535 Beijing isolates from six world regions where these strains are known to be prevalent. The typeability and interlaboratory reproducibility of these hypervariable loci were lower than those of the 24 standard loci. Three loci (2163a, 3155, and 3336) were excluded because of their redundant variability and/or more frequent noninterpretable results compared to the 4 other markers. The use of the remaining 4-locus set (1982, 3232, 3820, and 4120) increased the number of types by 52% (from 223 to 340) and reduced the clustering rate from 58.3 to 36.6%, when combined with the use of the standard 24-locus set. Known major clonal complexes/24-locus-based clusters were all subdivided, although the degree of subdivision varied depending on the complex. Only five single-locus variations were detected among the hypervariable loci of an additional panel of 92 isolates, representing 15 years of clonal spread of a single Beijing strain in a geographically restricted setting. On this calibrated basis, we propose this 4 locus set as a consensus for subtyping Beijing clonal complexes and clusters, after standard typing. PMID- 24172155 TI - Discordance across several methods for drug susceptibility testing of drug resistant Mycobacterium tuberculosis isolates in a single laboratory. AB - Given the increases in drug-resistant tuberculosis, laboratory capacities for drug susceptibility testing are being scaled up worldwide. A laboratory must decide among several endorsed methodologies. We evaluated 87 Mycobacterium tuberculosis isolates for concordance of susceptibility results across six methods: the L-J proportion method, MGIT 960 SIRE AST, Gene/Xpert MTB/RIF, GenoType MTBDRplus line probe assay, MycoTB MIC plate, and a laboratory-developed mycobacteriophage quantitative PCR (qPCR)-based method. Most (80%) isolates were multidrug resistant. Of the culture-based methods, the mycobacteriophage qPCR method was fastest, the L-J proportion method was the slowest, and the MGIT method required the most repeat testing (P < 0.05). For isoniazid (INH), 82% of isolates were susceptible by all methods or resistant by all methods, whereas for rifampin (RIF), ethambutol (EMB), and streptomycin (STR), such complete concordance was observed in 77%, 50%, and 51% of isolates, respectively (P < 0.05 for INH or RIF versus EMB or STR). The discrepancies of EMB and STR stemmed largely from diminished concordance of the MGIT EMB results (kappa coefficient range, 0.26 to 0.30) and the L-J STR result (kappa range, 0.35 to 0.45) versus other methods. Phage qPCR and the MycoTB MIC plate were the only methods that yielded second-line susceptibilities and revealed significant quantitative correlations for all drugs except cycloserine, as well as moderate to excellent kappa coefficients for all drugs except for para-aminosalicylic acid. In summary, the performance of M. tuberculosis susceptibility testing differs by platform and by drug. Laboratories should carefully consider these factors before choosing one methodology, particularly in settings where EMB and STR results are clinically important. PMID- 24172156 TI - Toxin-producing Clostridium difficile strains as long-term gut colonizers in healthy infants. AB - Clostridium difficile is a colonizer of the human gut, and toxin-producing strains may cause diarrhea if the infectious burden is heavy. Infants are more frequently colonized than adults, but they rarely develop C. difficile disease. It is not known whether strains of C. difficile differ in the capacity to colonize and persist in the human gut microbiota. Here, we strain typed isolates of C. difficile that had colonized 42 healthy infants followed from birth to >=12 months of age by using PCR ribotyping of the 16S-23S rRNA intergenic spacer region. The isolates were also characterized regarding carriage of the toxin genes tcdA, tcdB, and cdtA/B and the capacity to produce toxin B in vitro. Most strains (71%) were toxin producers, and 51% belonged to the 001 or 014 ribotypes, which often cause disease in adults. These ribotypes were significantly more likely than others to persist for >=6 months in the infant micobiota, and they were isolated from 13/15 children carrying such long-term-colonizing strains. Ribotype 001 strains were often acquired in the first week of life and attained higher population counts than other C. difficile ribotypes in newborn infants' feces. Several toxin-negative ribotypes were identified, two of which (GI and GIII) were long-term colonizers, each found in one infant. Our results suggest that the toxin-producing C. difficile ribotypes 001 and 014 have special fitness in the infantile gut microbiota. Toxin-producing strains colonizing young children for long time periods may represent a reservoir for strains causing disease in adults. PMID- 24172157 TI - Rapid whole-genome sequencing for detection and characterization of microorganisms directly from clinical samples. AB - Whole-genome sequencing (WGS) is becoming available as a routine tool for clinical microbiology. If applied directly on clinical samples, this could further reduce diagnostic times and thereby improve control and treatment. A major bottleneck is the availability of fast and reliable bioinformatic tools. This study was conducted to evaluate the applicability of WGS directly on clinical samples and to develop easy-to-use bioinformatic tools for the analysis of sequencing data. Thirty-five random urine samples from patients with suspected urinary tract infections were examined using conventional microbiology, WGS of isolated bacteria, and direct sequencing on pellets from the urine samples. A rapid method for analyzing the sequence data was developed. Bacteria were cultivated from 19 samples but in pure cultures from only 17 samples. WGS improved the identification of the cultivated bacteria, and almost complete agreement was observed between phenotypic and predicted antimicrobial susceptibilities. Complete agreement was observed between species identification, multilocus sequence typing, and phylogenetic relationships for Escherichia coli and Enterococcus faecalis isolates when the results of WGS of cultured isolates and urine samples were directly compared. Sequencing directly from the urine enabled bacterial identification in polymicrobial samples. Additional putative pathogenic strains were observed in some culture-negative samples. WGS directly on clinical samples can provide clinically relevant information and drastically reduce diagnostic times. This may prove very useful, but the need for data analysis is still a hurdle to clinical implementation. To overcome this problem, a publicly available bioinformatic tool was developed in this study. PMID- 24172158 TI - A modified root reinforcement technique for acute aortic dissection with a weakened aortic root: a modified Florida sleeve technique and two cases report. AB - Despite marvelous advances in repair for acute type A aortic dissection over past decades, it remains challenging to repair the aortic root when aortic dissection extended to the sinuses causes the fragile root because of its thinner layers, which are susceptible to suture trauma. Here, we describe a modified Florida sleeve technique to strengthen the weakened aortic root. After mobilization of the aortic root and the coronary arteries, a designed Dacron tube graft was wrapped outside the sinuses as neo-adventitia to reinforce the dissected weakened wall. During surgery for aortic dissection, our technique is easy and effective to reinforce a weakened root and avoid bleeding. Furthermore, this might be an alternative technique to restore and maintain the geometry of the aortic root. PMID- 24172159 TI - Factors associated with antidepressant, anxiolytic, and other psychotropic medication use to treat psychiatric symptoms in the city of Sao Paulo, Brazil. AB - The objective of this study was to examine the prevalence and characteristics of adult psychotropic medication use in Sao Paulo, Brazil. Information on lifetime and 12-month psychotropic medication use, and psychiatric status was obtained from a representative sample of 2000 adults aged 18-65 years in Sao Paulo, Brazil. Lifetime and 12-month use of psychotropic medications was 16.8 and 7.1%, respectively. Of the 22.8% of patients with current psychiatric problems, 29.5% reported lifetime use and 15.8% (5.6% of the sample) reported 12-month use (anxiolytics: 2.7%, antidepressants: 1.8%, alternative medicines: 0.9%, antipsychotics: 0.4%, mood stabilizers: 0.4%, hypnotics: 0.3%; multiple class use occurred). The most frequent prescribers were psychiatrists and general practitioners. Determinants of use included identification as a psychiatric case (four-fold increased odds), being female (three-fold increase), age (4-5% per additional year), and lower odds if married. Education, employment status, and birth in Sao Paulo were not associated with use. Income did not affect anxiolytic use, but antidepressant and alternative medicine use was associated with higher income. These results show that psychotropic drug use was comparatively low. Only 15.8% of patients with psychiatric problems reported recent psychotropic use. Comparable with other studies, use was greater among women and increased with age. PMID- 24172160 TI - The efficacy of extended-release levomilnacipran in moderate to severe major depressive disorder: secondary and post-hoc analyses from a randomized, double blind, placebo-controlled study. AB - Levomilnacipran (1S, 2R-milnacipran) is a potent and selective serotonin and norepinephrine reuptake inhibitor that is Food and Drug Administration approved for once-daily treatment of major depressive disorder in adults. Secondary and post-hoc analyses were carried out on data from a positive 10-week, randomized, double-blind, placebo-controlled, parallel-group, multicenter, proof-of-concept trial (EudraCT Number: 2006-002404-34) on 75 or 100 mg/day levomilnacipran extended release (ER). Included outpatients (18-70 years) met the criteria for a major depressive episode. There was a statistically significant difference in favor of levomilnacipran ER versus placebo in change from baseline to week 10 on every Montgomery Asberg Depression Rating Scale (MADRS) single item (mixed effects model for repeated measures; P<0.05) and most Hamilton Depression Rating Scale (HAMD17) single items. Significantly more levomilnacipran ER versus placebo patients (P < 0.05) achieved 'complete' (MADRS <= 5; 24 vs. 10%) and 'sustained' (MADRS <= 10 in Weeks 4-10; 16 vs. 10%) remission, Sheehan Disability Scale (SDS) response (total score <= 12 and each item score <= 4; 52 vs. 35%) and remission (total score <= 6 and each item score <= 2; 26 vs. 17%), and combined symptomatic (MADRS) and functional (SDS) remission (19 vs. 8%). Treatment effects of similar magnitude were observed in the severe depression subgroup (MADRS >= 30). These results demonstrate the benefit of levomilnacipran ER over placebo for patients with symptomatic and functional impairment associated with major depressive disorder. PMID- 24172161 TI - Debunking the placebo effect in depression: the effect of patient and investigator expectation on escitalopram efficacy. AB - In approximately half of the major depressive disorder (MDD) antidepressant trials published in the last decade, 30% or more of the patients assigned to the placebo arm showed clinically significant improvements. Attempts to reduce the placebo effect in a variety of ways have proven mostly unsuccessful. The aim of this study was to determine whether trial design has an effect on the efficacy outcome in a mock placebo versus escitalopram treatment of adult outpatients with MDD. An 8-week study was designed to evaluate the placebo effect on the response to fixed doses of escitalopram (10 and 20 mg/day) in patients with MDD. The variables affecting placebo response evaluated were as follows: patient expectation, rater expectation, three different outcome measures and the number of visits during the study. Investigators were blinded to the inclusion and exclusion criteria. Forty patients were randomized to receive what they and their treating physicians conceived of as double-blind treatment. The mean age of the patients in the group was 45.1 years, 19 women (47.5%) and 21 men. The mean change from baseline to week 8 in the Montgomery-Asberg Depression Rating Scale total score was -13.7 for participants with 'monthly' visits and -12.9 for the 'fortnightly' group (P=0.75). In each group, 14/16 responders and their physicians thought that they were receiving active treatment. Of 22 nonresponsive patients, 17 thought that they had been receiving placebo. The pharmacological effect of escitalopram observed in the present study is almost identical to that observed in open-label studies, even when patients and clinicians are misled by the study design, placebo presence or raters' blindability. PMID- 24172162 TI - Differential impacts of care-giving across three caregiver groups in Canada: end of-life care, long-term care and short-term care. AB - Using data from Statistic Canada's General Social Survey Cycle 21 (GSS 2007), this study explores whether differences exist in the impacts of care-giving among three groups of caregivers providing informal care either in the caregiver's or recipient's home, or in other locations within the community: (i) those providing end-of-life (EOL) care (n = 471); (ii) those providing long-term care (more than 2 years) for someone with a chronic condition or long-term illness (n = 2722); and (iii) those providing short-term care (less than 2 years) for someone with a chronic condition or long-term illness (n = 2381). This study lays out the variation in sociodemographic characteristics across the three caregiver groups while also building on our understanding of the differential impacts of care giving through an analysis of determinants. All three groups of caregivers shared a number of sociodemographic characteristics, including being female, married, employed and living in a Census Metropolitan Area (CMA). With respect to health, EOL caregivers were found to have significantly higher levels of 'fair or poor' self-assessed health than the other two groups. Overall, the findings suggest that EOL caregivers are negatively impacted by the often additional role of care giving, more so than both short-term and long-term caregivers. EOL caregivers experienced a higher proportion of negative impacts on their social and activity patterns. Furthermore, EOL caregivers incurred greater financial costs than the other two types of informal caregivers. The impacts of EOL care-giving also negatively influence employment for caregivers when compared with the other caregiver groups. Consequently, EOL caregivers, overall, experienced greater negative impacts, including negative health outcomes, than did long-term or short term caregivers. This provides the evidence for the assertion that EOL care giving is the most intense type of care-giving, potentially causing the greatest caregiver burden; this is shown through the greater negative impacts experienced by the EOL caregivers when compared with the short-term and long-term caregivers. PMID- 24172164 TI - A Prospective Experimental Study to Investigate the Peritoneal Adhesion Formation of Argon Plasma Coagulation (APC) Versus a Novel Aerosol Plasma in a Rat Model. AB - BACKGROUND: This is a prospective, randomized, controlled, single-blinded study to investigate peritoneal adhesion formation of standard argon plasma coagulation (APC) versus aerosol plasma coagulation in a rat model. METHODS: Bilateral lesions were created on the abdominal wall of 16 female Wistar rats with standard and aerosol plasma coagulation APC energy in a standard fashion. After 10 days, the rats were killed humanely to evaluate the peritoneal trauma sites. Adhesion incidence, quantity, and quality were scored 10 days postoperatively and studied histopathologically. RESULTS: Average energy intake was 97.7 +/- 3.1 J for APC and 93.8 +/- 4.2 J for aerosol plasma coagulation. Incidence of adhesion formation was 74.2% for standard APC and 16.1% for aerosol plasma coagulation (P < .0001). Standard APC mainly results in dense adhesions. Histological evaluation revealed no significant difference with regard to the average depth of lesions created by APC and aerosol plasma coagulation (P = 0.21) at day 10; both groups showed an identical morphology of necrosis and granulation tissue formation. CONCLUSIONS: This study compares adhesion formation of standard APC versus aerosol plasma coagulation in a rat model. Standard APC produced significantly more adhesions. Aerosol plasma coagulation creates fewer adhesions, which are of lower grade, which seems to be achieved mainly by improved peritoneal conditioning in this animal model. PMID- 24172163 TI - The impact of rapid malaria diagnostic tests upon anti-malarial sales in community pharmacies in Gwagwalada, Nigeria. AB - BACKGROUND: Rapid diagnostics tests for malaria (RDT) have become established as a practical solution to the challenges of parasitological confirmation of malaria before treatment in the public sector. However, little is known of their impact in private health sector facilities, such as pharmacies and drug shops. This study aimed to assess the incidence of malaria among unwell patients seeking anti malarial treatment in two community pharmacies in Nigeria and measure the impact RDTs have on anti-malarial sales. METHODS: This was a comparison study of two pharmacies located in the suburbs of Gwagwalada, in the Federal Capital Territory of Nigeria, between May and July 2012. In the intervention arm, patients seeking to purchase anti-malarials had an RDT performed before treatment while the control pharmacy continued normal routine practice. RESULTS: A total of 1,226 participants were enrolled into the study. The incidence of malaria in the intervention arm (n = 619) was 13.6% and adolescent participants had a statistically significant higher incidence (26.0%) compared to adults (11.9%) (P = 0.001). A history of fever in the last 48 hours was associated with a statistically significant higher incidence of malaria (28.3%) (P < 0.001). Having a RDT test reduced the chance of purchasing an anti-malarial by 42% (95% CI: 38% 46%) compared to not having a test. 51.6% (276) of the study participants with a RDT negative result still purchased anti-malarials, especially if anti-malarials had been recommended by a health professional (58.9%) compared to self-referral (44.2%) (P = 0.001). Patients with RDT negative results were also more likely to purchase an anti-malarial if there was a reported malaria positive laboratory test prior to presentation (66.2%; P = 0.007), a history of fever in the last 48 hours (60.5%; P = 0.027), and primary school education or less (69.4%; P = 0.009). After adjusting for age group and gender differences, having at least a secondary school education reduced the chance of buying an anti-malarial (OR 0.504 (95% CI: 0.256-0.993)) compared to having primary education or lower. CONCLUSION: The study highlights the enormous potential for improving appropriate prescription of anti-malarials in pharmacies and preventing unnecessary use of artemisinin combination therapy (ACT). PMID- 24172165 TI - Feasibility study of utilizing ultraportable projectors for endoscopic video display (with videos). AB - BACKGROUND: Modern endoscopy requires video display. Recent miniaturized, ultraportable projectors are affordable, durable, and offer quality image display. OBJECTIVE: Explore feasibility of using ultraportable projectors in endoscopy. METHODS: Prospective bench-top comparison; clinical feasibility study. Masked comparison study of images displayed via 2 Samsung ultraportable light emitting diode projectors (pocket-sized SP-HO3; pico projector SP-P410M) and 1 Microvision Showwx-II Laser pico projector. BENCH-TOP FEASIBILITY STUDY: Prerecorded endoscopic video was streamed via computer. CLINICAL COMPARISON STUDY: Live high-definition endoscopy video was simultaneously displayed through each processor onto a standard liquid crystal display monitor and projected onto a portable, pull-down projection screen. Endoscopists, endoscopy nurses, and technicians rated video images; ratings were analyzed by linear mixed-effects regression models with random intercepts. RESULTS: All projectors were easy to set up, adjust, focus, and operate, with no real-time lapse for any. Bench-top study outcomes: Samsung pico preferred to Laser pico, overall rating 1.5 units higher (95% confidence interval [CI] = 0.7-2.4), P < .001; Samsung pocket preferred to Laser pico, 3.3 units higher (95% CI = 2.4-4.1), P < .001; Samsung pocket preferred to Samsung pico, 1.7 units higher (95% CI = 0.9-2.5), P < .001. The clinical comparison study confirmed the Samsung pocket projector as best, with a higher overall rating of 2.3 units (95% CI = 1.6-3.0), P < .001, than Samsung pico. CONCLUSIONS: Low brightness currently limits pico projector use in clinical endoscopy. The pocket projector, with higher brightness levels (170 lumens), is clinically useful. Continued improvements to ultraportable projectors will supply a needed niche in endoscopy through portability, reduced cost, and equal or better image quality. PMID- 24172166 TI - Portal vein arterialization as a bridge procedure against acute liver failure after extended hepatectomy for hilar cholangiocarcinoma. AB - BACKGROUND: Acute liver failure (ALF) is a severe and highly fatal complication arising after extended hepatobiliary surgery. The aim of this study was to investigate the primary management experience of portal vein arterialization (PVA) as a bridge procedure to reduce the risk of ALF for hilar cholangiocarcinoma (HCCA) after extended hepatectomy. METHOD: Between January 2010 and January 2012, 4 patients with HCCA with possible involvement of the right and/or left hepatic artery underwent resectional surgery with reconstruction of the right or left artery blood flow by arterializations of portal vein. RESULTS: The arteries used for this surgical procedure included gastroduodenal artery (n = 2), common hepatic artery (n = 1), and right gastroepiploic artery (n = 1). PVA was verified as a key point during the course of the disorder between surgery and postoperative recovery. During follow-up, 1 patient suffered secondary portal hypertension and was subsequently cured by interventional artery coil embolization. CONCLUSION: PVA can be indicated where there is arterial involvement in HCCA patients who have undergone extended hepatectomy or trisectionectomy. PMID- 24172167 TI - Development and clinical implementation of a hemostatic balloon device for rectal cancer surgery. AB - BACKGROUND: Surgery for locally advanced and recurrent rectal carcinoma can be associated with major blood loss. OBJECTIVE: We developed a promising technique using a hemostatic balloon to stop uncontrollable bleeding. DESIGN: Models were developed using pelvic magnetic resonance imaging scans, and these models were tested in a cadaveric study. Eventually a model was tested in a clinical setting. The Hemostatic Balloon Device was placed in patients in whom during surgery uncontrollable bleeding from the venous presacral plexus occurred. SETTINGS: A tertiary referral hospital for locally advanced and recurrent rectal cancer. PATIENTS: Patients receiving multimodality treatment for primary or recurrent locally advanced rectal carcinomas. MAIN OUTCOME MEASURES: First the developed prototypes were tested in a cadaveric study where the developing pressure on the pelvic wall was measured. Second, the Hemostatic Balloon Device was placed in patients in whom during surgery uncontrollable bleeding from the venous presacral plexus occurred. RESULTS: The balloon was used in 9 patients. Median volume of blood loss was 7500 mL. In 8 patients treatment with the hemostatic balloon was successful. In 1 patient the balloon was dislocated cranially and the pelvis was packed with surgical gauzes. LIMITATIONS: These first results are promising but further research is needed to evaluate how effective the balloon is in controlling massive bleeding during rectal cancer surgery. Future perspectives include a possibly thinner silicon rubber that can be stretched more easily with a lower inflated volume. DISCUSSION: The hemostatic balloon is a new and promising technique for accomplishing hemostasis with controllable pressure on the pelvic cavity wall and can be removed without the need for a second laparotomy. PMID- 24172168 TI - Endoscopic tattooing to mark distal margin for low anterior rectal and select sigmoid resections. AB - Obtaining a reliable distal margin during anterior colorectal resection can be difficult. In this study, endoscopic transmural tattoos were placed to mark the distal transection point in patients with distal colorectal neoplasms who undergo bowel resection. In the operating room, before surgery, sigmoidoscopy is performed with a 2-channel scope using CO2 insufflation. Through channel 1, a biopsy forceps, marked 5 cm from its end, is inserted to the tumor's distal edge; in channel 2, a sclerotherapy catheter is placed. The scope is then withdrawn and forceps inserted at the same rate until the mark is seen, next, via the needle catheter, 4 tattoos are placed at that level circumferentially. After rectal mobilization, visible external tattoos guide stapler placement. If no tattoo is seen, sigmoidoscopy is done and the tattoos used to guide stapler placement. In all 27 patients, the tattoos guided stapler placement; tattoos were seen via the abdomen in 26 and the stapler placed as per tattoos in 25. In 2 patients, repeat endoscopy was done and tattoos used to guide or confirm stapler placement. The margin was <=1 cm from target in 74% while in 22% the margin was 2 to 3.5 cm off target (mean deviation from target margin = 0.33 cm). In conclusion, this method facilitates stapler placement and provides more reliable margins. PMID- 24172170 TI - Upper endoscopy and random biopsies: endoscopic findings with disconcordant pathology. PMID- 24172169 TI - An optimized five-gene multi-platform predictor of hormone receptor negative and triple negative breast cancer metastatic risk. AB - INTRODUCTION: Outcome predictors in use today are prognostic only for hormone receptor-positive (HRpos) breast cancer. Although microarray-derived multigene predictors of hormone receptor-negative (HRneg) and/or triple negative (Tneg) breast cancer recurrence risk are emerging, to date none have been transferred to clinically suitable assay platforms (for example, RT-PCR) or validated against formalin-fixed paraffin-embedded (FFPE) HRneg/Tneg samples. METHODS: Multiplexed RT-PCR was used to assay two microarray-derived HRneg/Tneg prognostic signatures IR-7 and Buck-4) in a pooled FFPE collection of 139 chemotherapy-naive HRneg breast cancers. The prognostic value of the RTPCR measured gene signatures were evaluated as continuous and dichotomous variables, and in conditional risk models incorporating clinical parameters. An optimized five-gene index was derived by evaluating gene combinations from both signatures. RESULTS: RT-PCR measured IR-7 and Buck-4 signatures proved prognostic as continuous variables; and conditional risk modeling chose nodal status, the IR-7 signature, and tumor grade as significant predictors of distant recurrence (DR). From the Buck-4 and IR-7 signatures, an optimized five-gene (TNFRSF17, CLIC5, HLA-F, CXCL13, XCL2) predictor was generated, referred to as the Integrated Cytokine Score (ICS) based on its functional pathway linkage through interferon-gamma and IL-10. Across all FFPE cases, the ICS was prognostic as either a continuous or dichotomous variable, and conditional risk modeling selected nodal status and ICS as DR predictors. Further dichotomization of node-negative/ICS-low FFPE cases identified a subset of low-grade HRneg tumors with <10% 5-year DR risk. The prognostic value of ICS was reaffirmed in two previously studied microarray assayed cohorts containing 274 node-negative and chemotherapy naive HRneg breast cancers, including 95 Tneg cases where it proved prognostically independent of Tneg molecular subtyping. In additional HRneg/Tneg microarray assayed cohorts, the five-gene ICS also proved prognostic irrespective of primary tumor nodal status and adjuvant chemotherapy intervention. CONCLUSION: We advanced the measurement of two previously reported microarray-derived HRneg/Tneg breast cancer prognostic signatures for use in FFPE samples, and derived an optimized five-gene Integrated Cytokine Score (ICS) with multi-platform capability of predicting metastatic outcome from primary HRneg/Tneg tumors independent of nodal status, adjuvant chemotherapy use, and Tneg molecular subtype. PMID- 24172171 TI - Comparison of 44-hour and fixed 24-hour ambulatory blood pressure monitoring in dialysis patients. AB - The two most commonly used strategies to evaluate dialysis patients' blood pressure (BP) level are 44-hour and 24-hour ambulatory blood pressure monitoring (ABPM). The objective of this study was to find an appropriate 24-hour period that correlated well with the 44-hour BP level and determine the differences between these strategies. In a group of 51 dialysis patients, the authors performed 44-hour ABPM and extracted data for a fixed 24-hour ABPM. The fixed 24 hour ABPM started at 6 am on the nondialysis day. A strong correlation was found between all parameters of 44-hour and the fixed 24-hour ABPM, with paired sample t test showing only small magnitude changes in a few parameters. Both 24-hour ABPM and 44-hour ABPM were superior to clinic BP in predicting left ventricular mass index (LVMI) by multiple regression analysis. It was found that 44-hour ambulatory arterial stiffness index (AASI), but not 24-hour AASI, had a positive association with LVMI (r=0.328, P=.021). However, after adjustment for 44-hour systolic blood pressure, this association disappeared. Fixed 24-hour ABPM is a good surrogate of 44-hour ABPM to some extent, while 44-hour ABPM can provide more accurate and detailed information. PMID- 24172172 TI - Burnout in intensive care units - a consideration of the possible prevalence and frequency of new risk factors: a descriptive correlational multicentre study. AB - BACKGROUND: The provision of Intensive Care (IC) can lead to a health care provider's physical, psychological and emotional exhaustion, which may develop into burnout. We notice the absence of specific studies regarding this syndrome in Portuguese Intensive Care Units (ICUs). Our main objective is to study the incidence and risk factors of burnout in Portuguese ICUs. METHODS: A self fulfilment questionnaire containing 3 items: (i) socio-demographic data of the study population; (ii) experiences in the workplace; (iii) Maslach Burnout Inventory (MBI) - was applied to evaluate the influence of distinct factors on the prevalence of burnout among physicians and nurses working in ICUs. RESULTS: Three hundred professionals (82 physicians and 218 nurses) from ten ICUs were included in the study, out of a total of 445 who were eligible. There was a high rate of burnout among professionals working in Portuguese ICUs, with 31% having a high level of burnout. However, when burnout levels among nurses and physicians were compared, no significant difference was found. Using multivariate analysis, we identified gender as being a risk factor, where female status increases the risk of burnout. In addition, higher levels of burnout were associated with conflicts and ethical decision making regarding withdrawing treatments. Having a temporary work contract was also identified as a risk factor. Conversely, working for another service of the same health care institution acts as a protective factor. CONCLUSIONS: A high rate of burnout was identified among professionals working in Portuguese ICUs. This study highlights some new risk factors for burnout (ethical decision making, temporary work contracts), and also protective ones (maintaining activity in other settings outside the ICU) that were not previously reported. Preventive and interventive programmes to avoid and reduce burnout syndrome are of paramount importance in the future organization of ICUs and should take the above results into account. PMID- 24172173 TI - Quantifying respiratory complications post-adenotonsillectomy in patients with normal or inconclusive overnight oximetry. AB - BACKGROUND: Children with sleep-disordered breathing (SDB) are at risk of developing post-operative respiratory complications following adenotonsillectomy (T&A). Our goal was to describe and quantify these complications following T&A in children with clinical SDB but with a pre-operative overnight home oximetry score of "normal/inconclusive" (McGill Oximetry Score (MOS) of 1), and to determine whether these children could safely undergo surgery in peripheral hospitals or outpatient surgical centers. METHODS: We performed a retrospective chart review of patients 3 years and older who had T&A between 2003 and 2010 at 2 of our institution's hospitals. To be included in the study, in addition to not having severe comorbidities, children had to have undergone an overnight home oximetry within 12 months of surgery that was normal or inconclusive (MOS of 1). This was defined as fewer than 3 episodes of oxygen desaturation below 90% and stable baseline saturation over 95%. Medical charts were reviewed for major and minor postoperative respiratory complications. The main outcome measure was post-T&A respiratory complications. RESULTS: Out of 2708 T&A patients, 231 met the inclusion criteria. No patient had a major postoperative respiratory complication requiring re-intubation or admission to the intensive care unit. Five patients (2.16%) had minor respiratory complications but only one required admission to the ward. CONCLUSIONS: An overnight home oximetry that is "normal/inconclusive" (MOS of 1) can be used as a screening tool to identify patients with sleep disordered breathing who can be safely sent to peripheral hospitals or outpatient surgical centers for T&A. PMID- 24172174 TI - The Baltic Sea Diet Score: a tool for assessing healthy eating in Nordic countries. AB - OBJECTIVE: The health-related effects of the Nordic diet remain mostly unidentified. We created a Baltic Sea Diet Score (BSDS) for epidemiological research to indicate adherence to a healthy Nordic diet. We examined associations between the score and nutrient intakes that are considered important in promoting public health. We also examined the performance of the BSDS under two different cut-off strategies. DESIGN: The cross-sectional study included two phases of the National FINRISK 2007 Study. Diet was assessed using a validated FFQ. Food and nutrient intakes were calculated using in-house software. Nine components were selected for the score. Each component was scored according to both sex-specific consumption quartiles (BSDS-Q) and medians (BSDS-M), and summed to give the final score values. SETTING: A large representative sample of the Finnish population. SUBJECTS: Men (n 2217) and women (n 2493) aged 25 to 74 years. RESULTS: In the age- and energy-adjusted model, adherence to the diet was associated with a higher intake of carbohydrates (E%), and lower intakes of SFA (E%) and alcohol (E%, where E% is percentage of total energy intake; P < 0.01). Furthermore, the intakes of fibre, Fe, vitamins A, C and D, and folate were higher among participants who adhered to the diet (P < 0.05). After further adjustments, the results remained significant (P < 0.05) and did not differ remarkably between BSDS-Q and BSDS-M. CONCLUSIONS: The BSDS can be used as a measure of a healthy Nordic diet to assess diet-health relationships in public health surveys in Nordic countries. PMID- 24172176 TI - Mo doping-enhanced dye absorption of Bi2Se3 nanoflowers. AB - A simple solvothermal approach is explored to prepare Bi2-xMoxSe3 nanostructures by employing N,N-dimethylformamide (DMF) as the solvent. Mo plays an important role in the assembly of the Bi2-xMoxSe3 nanostructures from nanoplates to nanoflowers. Structural and morphological studies indicate that the resulting products are large specific surface area single-crystalline Bi2-xMoxSe3 nanoflowers self-assembled from thin nanoplates during the reaction process. The absorption properties of the as-prepared samples are investigated with Rhodamine B (RhB) as dye, and it is found that the Bi1.85Mo0.15Se3 nanoflowers show an optimal adsorption capacity, implying that Mo doping not only changes the morphologies of the nanostructures but also enhances their absorption behaviors. PMID- 24172175 TI - Human fetal and adult bone marrow-derived mesenchymal stem cells use different signaling pathways for the initiation of chondrogenesis. AB - Cartilage injuries and osteoarthritis are leading causes of disability in developed countries. The regeneration of damaged articular cartilage using cell transplantation or tissue engineering holds much promise but requires the identification of an appropriate cell source with a high proliferative propensity and consistent chondrogenic capacity. Human fetal mesenchymal stem cells (MSCs) have been isolated from a range of perinatal tissues, including first-trimester bone marrow, and have demonstrated enhanced expansion and differentiation potential. However, their ability to form mature chondrocytes for use in cartilage tissue engineering has not been clearly established. Here, we compare the chondrogenic potential of human MSCs isolated from fetal and adult bone marrow and show distinct differences in their responsiveness to specific growth factors. Transforming growth factor beta 3 (TGFbeta3) induced chondrogenesis in adult but not fetal MSCs. In contrast, bone morphogenetic protein 2 (BMP2) induced chondrogenesis in fetal but not adult MSCs. When fetal MSCs co-stimulated with BMP2 and TGFbeta3 were used for cartilage tissue engineering, they generated tissue with type II collagen and proteoglycan content comparable to adult MSCs treated with TGFbeta3 alone. Investigation of the TGFbeta/BMP signaling pathway showed that TGFbeta3 induced phosphorylation of SMAD3 in adult but not fetal MSCs. These findings demonstrate that the initiation of chondrogenesis is modulated by distinct signaling mechanisms in fetal and adult MSCs. This study establishes the feasibility of using fetal MSCs in cartilage repair applications and proposes their potential as an in vitro system for modeling chondrogenic differentiation and skeletal development studies. PMID- 24172177 TI - Novel pharmacological therapies for management of chronic constipation. AB - Chronic constipation is a common health problem that significantly affects the quality of life of patients and impacts in terms of costs; current treatments based on fiber and laxatives cause dissatisfaction to doctors and patients in more than half of the cases. New drugs are now available or in very advanced stages of research, with different and innovative mechanisms of action as prucalopride, lubiprostone, and linaclotide. Prucalopride an enterokinetic, is a selective high-affinity 5-hydroxytryptamine (5-HT)4 receptor agonist of serotonin that increases the peristaltic reflex and the colonic contractions; lubiprostone, a type 2 chlorine channel activator, or linaclotide, a guanylate cyclase-C agonist of enterocytes, both prosecretory agents, stimulate the secretion of fluid within the intestinal lumen. In general, these promising drugs have proven efficacy and safety as a specific therapeutic option in patients with chronic constipation. Yet the solution might not be sufficient for everybody and still without the ideal drug that might be useful in all cases, the pharmacological revolution for colonic motility disorders has arrived. PMID- 24172178 TI - Validation of a clinical prediction scale for hospital-onset Clostridium difficile infection. AB - OBJECTIVE: The aim of this study was to validate a clinical prediction scale for hospital-onset Clostridium difficile infection (CDI). METHODS: The study included a consecutive cohort of patients admitted to the adult medical service over a period of 17 months (June 2011 to October 2012). The clinical prediction scale comprised of new-onset loose stools (5 points), length of hospital stay >7days (4 points), aged 65 years or older (3 points), resides in long-term care facility (2 points), broad spectrum antibiotics use (1 point), and hypoalbuminemia (1 point). The hospital-onset CDI cases were defined as any new-onset diarrhea after 48 hours of hospital admission that tested positive on polymerase chain reaction assay for C. difficile toxin gene in the absence of history of CDI in the prior 8 weeks. The predictive performance of the scale was assessed using area under the receiver operating curve. RESULTS: A total of 10,357 patients were admitted to the medical service, of which, 7026 stayed in hospital beyond 48 hours. Mean (SD) age was 68.5 (18.2) years and 41.9% patients were male. A total of 1030 patients were tested for C. difficile toxin gene using polymerase chain reaction assay, of which, 159 patients were positive and 62 of them were unique hospital-onset CDI cases. The scale had area under the receiver operating curve of 0.94 [95% confidence interval (CI), 0.92-0.95]. At the cutoff score of 9, scale was 98.3% (95% CI, 90.2-99.9) sensitive and 85.2% (95% CI, 84.3-86.0) specific. CONCLUSIONS: Our study results support excellent predictive performance of a clinical prediction scale for hospital-onset CDI. This simple scale can be used in risk stratification leading to prompt tailoring of modifiable risk factors, empirical treatment, and use of probiotics. PMID- 24172180 TI - Objective detection of esophagopharyngeal reflux in patients with hoarseness and endoscopic signs of laryngeal inflammation. AB - GOALS: We aimed to quantify pharyngeal exposure to gastric contents in patients diagnosed with reflux-related hoarseness and healthy controls using new diagnostic techniques. BACKGROUND: Hoarseness with typical signs on laryngoscopy is commonly thought to be caused by esophagopharyngeal reflux. New methods are proposed to assess pharyngeal exposure to gastric contents. They are suggested to measure: (1) liquid or mixed gas-liquid acid and nonacid reflux with impedance pH, (2) aerosolized acid reflux (Dx-pH measuring system), and (3) pepsin in the saliva. STUDY: Twenty-one patients with hoarseness and positive laryngoscopy and 10 controls underwent simultaneous impedance pH, Dx-pH monitoring, and saliva pepsin sampling (5 samples in 24 h). RESULTS: Of the 21 patients, 10 had impedance pH-detected reflux plus at least 1 other test positive. These patients were more likely to have symptomatic relief after proton pump inhibitor therapy. Three of the 21 patients had all 3 tests positive and 4 had all tests negative. None of the controls had impedance pH-detected reflux. Two controls had a positive Dx-pH "RYAN score" and 1 control had >1 saliva sample positive for pepsin. Only 11% of Dx-pH drops to pH<4, 15% pH drops to pH<5, and 10% of pH drops to pH<5.5 coincided with impedance pH-detected reflux in the esophageal body. Positive pepsin saliva samples were preceded by more reflux events [3 (range, 0 to 10)] in the previous 60 minutes than negative samples [0 (range, 0 to 7)] (P<0.0001). CONCLUSION: A subgroup of patients with hoarseness (10/21) had objective detection of the esophagopharyngeal reflux. We propose that these patients are more likely to benefit from further intense antireflux therapy. Detection of pepsin in the saliva may be a useful screening tool in these patients. PMID- 24172179 TI - Issues in hypertriglyceridemic pancreatitis: an update. AB - Hypertriglyceridemia (HTG) is a well-established but underestimated cause of acute pancreatitis and recurrent acute pancreatitis. The clinical presentation of HTG-induced pancreatitis (HTG pancreatitis) is similar to other causes. Pancreatitis secondary to HTG is typically seen in the presence of one or more secondary factors (uncontrolled diabetes, alcoholism, medications, pregnancy) in a patient with an underlying common genetic abnormality of lipoprotein metabolism (familial combined hyperlipidemia or familial HTG). Less commonly, a patient with rare genetic abnormality (familial chylomicronemic syndrome) with or without an additional secondary factor is encountered. The risk of acute pancreatitis in patients with serum triglycerides >1000 and >2000 mg/dL is ~ 5% and 10% to 20%, respectively. It is not clear whether HTG pancreatitis is more severe than when it is due to other causes. Clinical management of HTG pancreatitis is similar to that of other causes. Insulin infusion in diabetic patients with HTG can rapidly reduce triglyceride (TG) levels. Use of apheresis is still experimental and better designed studies are needed to clarify its role in the management of HTG pancreatitis. Diet, lifestyle changes, and control of secondary factors are key to the treatment, and medications are useful adjuncts to the long-term management of TG levels. Control of TG levels to 500 mg/dL or less can effectively prevent recurrences of pancreatitis. PMID- 24172181 TI - Steroid-resistant Cronkhite-Canada syndrome successfully treated by cyclosporine and azathioprine. PMID- 24172182 TI - Hepatitis C direct-acting antiviral agents: changing the paradigm of hepatitis C treatment in HIV-infected patients. AB - Hepatitis C virus (HCV)-related liver disease is a major source of mortality in HIV-infected patients. Approximately one third of all patients with HIV are co infected with HCV. Patients co-infected with HIV/HCV have shown lower rates of sustained virologic response with pegylated-interferon and weight-based ribavirin as well as more rapid progression of fibrosis than those with HCV mono-infection. Several direct-acting antiviral agents (DAAs), developed originally for HCV mono infection, are being reevaluated for HIV/HCV co-infection. In addition, entirely new DAAs are being developed, including, interferon-free regimens with fewer side effects, allowing novel treatment opportunities for difficult-to-treat patients. In order for HCV DAAs to be successfully used in the HIV/HCV co-infected population several hurdles must be overcome, including adverse event management and drug-drug interactions. The aim of this review is to discuss the results of trials for new HCV therapies being developed for HIV/HCV co-infected patients and the impact of interferon-free regimens on treatment in the future. PMID- 24172183 TI - Radiofrequency ablation versus hepatic resection for small hepatocellular carcinoma: a meta-analysis of randomized controlled trials. AB - BACKGROUND AND GOALS: Whether radiofrequency ablation or hepatic resection is superior for improving the survival in patients with small hepatocellular carcinoma (HCC) remains controversial. A meta-analysis of randomized controlled trials was performed to examine this issue. METHODS: PubMed, EMBASE, and Cochrane Library databases were used to identify all randomized controlled trials comparing the survival between small HCC patients receiving radiofrequency ablation and hepatic resection. The hazard ratio (HR) was pooled to compare the overall survival and recurrence-free survival rates. The odds ratio was pooled to compare the incidence of treatment-related complications. The mean difference was pooled to compare the hospitalization duration. Heterogeneity among studies was assessed. RESULTS: Three randomized controlled trials were included in this meta analysis. All patients met the Milan criteria. Hepatic resection was superior to radiofrequency ablation for the improvement of overall survival [HR=1.41; 95% confidence interval (CI), 1.06-1.89; P=0.02] and recurrence-free survival (HR=1.41; 95% CI, 1.14-1.74; P=0.001). Heterogeneity among studies was not significant (overall survival: P=0.14; recurrence-free survival: P=0.28). Patients treated with hepatic resection had a significantly higher incidence of treatment-related complications (odds ratio=0.12; 95% CI, 0.03-0.47; P=0.002) and a significantly longer hospitalization duration (mean difference: -8.77; 95% CI, 10.36 to -7.18; P<0.00001) than those treated with radiofrequency ablation. Heterogeneity among studies was significant (treatment-related complications: P=0.006; hospitalization duration: P=0.003). No hospital death occurred in the 2 groups. CONCLUSIONS: Evidence from the meta-analysis of randomized controlled trials suggested that hepatic resection might improve the overall survival and recurrence-free survival in small HCC patients, whereas increase the complications and hospitalization duration. However, this conclusion should be explained with caution, due to the absence of further subgroup analysis with respect to the outcome in patients with different tumor size (<3 and 3 to 5 cm). PMID- 24172184 TI - A risk scoring system to predict in-hospital mortality in patients with cirrhosis presenting with upper gastrointestinal bleeding. AB - GOALS: We aimed to develop a simple and practical risk scoring system to predict in-hospital mortality in cirrhotics presenting with upper gastrointestinal (GI) bleeding. STUDY: Extensive clinical data were captured in patients with documented cirrhosis who underwent endoscopic evaluation for upper GI bleeding between January 1, 2003 and June 30, 2011 at Parkland Memorial Hospital. Predictors of mortality were identified by multivariate regression analysis. RESULTS: A total of 884 patients with cirrhosis admitted for upper GI bleeding were identified; 809 patients survived and 75 died (8.4%). The etiology of bleeding was similar in both groups, with bleeding attributed to esophageal varices in 59% of survivors and 60% of non-survivors (ulcer disease and other etiologies of bleeding accounted for the other causes of bleeding). Mortality was 8.6% and 8.3% in patients with variceal bleeding and nonvariceal bleeding, respectively. While survivors and those who died were similarly matched with regard to gender, age, ethnicity and etiology of cirrhosis, patients who died had lower systolic blood pressures, higher pulse rates and lower mean arterial pressures at admission than patients who survived. Non-survivors were more likely to be Childs C (61% vs. 19%, P<0.001). Multivariate regression analysis identified the following 4 predictors of in-hospital mortality: use of vasoactive pressors, number of packed red blood cells transfused, model for end-stage liver disease (MELD) score, and serum albumin. A receiver operating characteristic curve including these 4 variables yielded an area under the receiver operating characteristic (AUROC) curve of 0.94 (95% confidence interval, 0.91-0.98). Classification and Regression Tree analysis yielded similar results, identifying vasoactive pressors and then MELD>21 as the most important decision nodes for predicting death. By comparison, using the Rockall scoring system in the same patients, the AUROC curve was 0.70 (95% confidence interval, 0.64-0.76 and the comparison of the University of Texas Southwestern model to the Rockall model revealed P<0.0001). A validation set comprised of 150 unique admissions between July 1, 2011 and July 31, 2012, had an AUROC of 0.92, and the outcomes of 97% of the subjects in this set were accurately predicted by the risk score model. CONCLUSIONS: Use of vasoactive agents, packed red blood cell transfusion, albumin, and MELD score were highly predictive of in-hospital mortality in cirrhotics presenting with upper GI bleeding. These variables were used to formulate a clinical risk scoring system for in-hospital mortality, which is available at: http://medweb.musc.edu/LogisticModelPredictor. PMID- 24172186 TI - The effects of social isolation on steroid hormone levels are modulated by previous social status and context in a cichlid fish. AB - Social isolation is a major stressor which impacts the physiology, behaviour and health of individuals in gregarious species. However, depending on conditional and contextual factors, such as social status and group composition, social isolation may be perceived differently by different individuals or even by the same individuals at different times. Here we tested the effects of social status (territorial vs. non-territorial) and previous group composition (i.e. type of social group: mixed sex group with two territorial males, TT vs. mixed sex group with one territorial and one non-territorial male, TnT) on the hormonal response (androgens and cortisol) to social isolation in a cichlid fish (Oreochromis mossambicus). The different steroid hormones measured responded differentially to social isolation, and their response was modulated by social factors. Social isolation elicited a decrease of 11-keto formation only in territorial males, whereas non-territorial males present a non-significant trend for increasing KT levels. Testosterone did not respond to social isolation. Cortisol only increased in isolated individuals from TnT groups irrespective of social status (i.e. both in territorials and non-territorials). These results suggest that it is the perception of social isolation and not the objective structure of the situation that triggers the hormonal response to isolation. PMID- 24172185 TI - The influence of cannabinoids on generic traits of neurodegeneration. AB - In an increasingly ageing population, the incidence of neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease and Huntington's disease are rising. While the aetiologies of these disorders are different, a number of common mechanisms that underlie their neurodegenerative components have been elucidated; namely neuroinflammation, excitotoxicity, mitochondrial dysfunction and reduced trophic support. Current therapies focus on treatment of the symptoms and attempt to delay the progression of these diseases but there is currently no cure. Modulation of the endogenous cannabinoid system is emerging as a potentially viable option in the treatment of neurodegeneration. Endocannabinoid signalling has been found to be altered in many neurodegenerative disorders. To this end, pharmacological manipulation of the endogenous cannabinoid system, as well as application of phytocannabinoids and synthetic cannabinoids have been investigated. Signalling from the CB1 and CB2 receptors are known to be involved in the regulation of Ca(2+) homeostasis, mitochondrial function, trophic support and inflammatory status, respectively, while other receptors gated by cannabinoids such as PPARgamma, are gaining interest in their anti-inflammatory properties. Through multiple lines of evidence, this evolutionarily conserved neurosignalling system has shown neuroprotective capabilities and is therefore a potential target for neurodegenerative disorders. This review details the mechanisms of neurodegeneration and highlights the beneficial effects of cannabinoid treatment. LINKED ARTICLES: This article is part of a themed section on Cannabinoids 2013. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2014.171.issue-6. PMID- 24172187 TI - Tobacco use patterns in tuberculosis patients with high rates of human immunodeficiency virus co-infection in South Africa. AB - BACKGROUND: Tuberculosis (TB) patients who smoke tobacco are at an increased risk for adverse TB treatment outcomes. This study describes tobacco use patterns among newly diagnosed TB patients, their readiness to quit, and their beliefs about tobacco-related health effects in a high HIV-burden setting in South Africa. Socio-economic and demographic factors associated with smoking were also determined. METHODS: This was a cross-sectional analysis of baseline data collected for a smoking cessation study at six large tuberculosis clinics in a South African township (N = 1926). We collected information on current and past tobacco use, socio-economic and demographic status, beliefs regarding the harmful effects of smoking and quit behaviour, and motivation, using structured interviewer-administered questionnaires. TB- and HIV-related information was obtained from patient records. Data analysis entailed descriptive statistics, followed by multivariate logistic regression with backward elimination, adjusted for clustering by facility. RESULTS: Just over one fifth of respondents (21.8%, 420/1924) reported currently smoking tobacco (males 37.6%, females 4.6%). By contrast, only 1.8% (35/1918) of all respondents reported being past smokers. Of the current smokers, about half (51.8%, 211/407) had previously attempted to quit, mainly for health reasons. The majority of respondents (89.3%, 1675/1875) believed tobacco smoking was harmful for their health and smokers were highly motivated to quit (median score 9, interquartile range 7-10). Smoking was less common among female respondents (Odds Ratio [OR] 0.10, 95% Confidence Interval [CI] 0.06-0.19) and respondents who had completed high school (OR 0.57, 95% CI 0.39-0.84), but was more common among respondents who do occasional work (OR 2.82, 95% CI 1.58-5.02), respondents who to bed hungry regularly (OR 4.19, 95% CI 2.42-7.25), those who have an alcohol problem (OR 5.79, 95% CI 3.24-10.34) and those who use illicit substances (OR 10.81, 95% CI 4.62-25.3). CONCLUSIONS: Despite documented evidence of its harmful effects, smoking is prevalent among male TB patients in this high HIV-prevalence population. Few patients have managed to quit smoking on their own. However, patients are highly motivated to stop smoking. We recommend implementing and evaluating a smoking cessation programme in tandem with TB services. PMID- 24172188 TI - Open versus minimally invasive sacroiliac joint fusion: a multi-center comparison of perioperative measures and clinical outcomes. AB - BACKGROUND: Sacroiliac (SI) joint pain is an under diagnosed source of low back pain due in part to lack of visible pathology on radiographs and symptoms mimicking other back-related disorders. Open SI joint fusion has been performed since the 1920s. This technique has fallen out of favor with the introduction of minimally invasive options. To date there has been no direct comparison between open and MIS SI joint fusion. METHODS: We conducted a multi-center, retrospective comparative cohort study of patients who underwent SI joint fusion using either an open surgical (OS) technique using a combination of screws and cages or a minimally invasive surgical (MIS) technique with a series of titanium plasma spray (TPS) coated triangular implants. Operative measures including surgical operating time, length of hospitalization and estimated blood loss (EBL) were collected along with demographics and medical history, surgical complications, and 12- and 24-month pain scores. Improvements in pain were compared after matching for age and gender and controlling for a history of lumbar spine fusion using repeated measures analysis of variance. RESULTS: Data were available for 263 patients treated by 7 surgeons; 149 patients treated with OS and 114 treated with MIS SI joint fusion. Compared to OS patients, MIS patients were on average 10 years older (mean age 57 vs. 46) and 69% of all patients were female. MIS operative measures of EBL, operating time and length of hospitalization were significantly lower than open surgery (p < 0.001). Pain relief, measured as change from baseline to 12 months in VAS pain rating, was 3.5 points lower in the MIS vs. OS group (-6.2 vs. -2.7 points, p < 0.001). When matched for age, gender and a history of prior lumbar spinal fusion, postoperative pain scores were on average 3.0 points (95% CI 2.1 - 4.0) lower in MIS vs. OS (rANOVA p < 0.001). CONCLUSIONS: In this multi-center comparative study, patients who underwent either OS or MIS SI joint fusion showed postoperative improvements in pain score. Compared to OS patients, patients who underwent MIS SI joint fusion had significantly greater pain relief and more favorable perioperative surgical measures. PMID- 24172189 TI - 3D vector analysis of mandibular condyle stability in mandibular setback surgery with bicortical bioabsorbable screw fixation. AB - INTRODUCTION: Bioabsorbable screws became widely used for stable fixation in orthognathic surgery as biomechanical technology advanced. Recently, 3D image analyses begin to be used to evaluate surgical changes. The purpose of this study was to evaluate, using 3D vector analysis, the stability of bicortical bioabsorbable screw fixation in mandibular setback using a sagittal split ramus osteotomy. Spatial change of the mandibular condyle was determined by 3D coordinates containing directional information. MATERIALS AND METHODS: Bicortical screw fixation was performed using either a bioabsorbable screw (25 patients) or a titanium screw (5 patients) in orthognathic surgery. Pre- and post-operative CT images (6 months after surgery) were superimposed digitally. A 3D coordinate (X, Y, Z) and vectors were employed to quantify spatial changes of the condyle and analysed statistically. RESULTS: Measuring on 3D image showed stable error about 0.16 mm. There were no significant differences in the total spatial changes of the condyle between titanium and bioabsorbable screws with the exception of the lateral-medial direction of the condylar centre (P = 0.042). The directional vector components were stable, regardless of mandibular setback. CONCLUSION: In 3D vector analysis, bioabsorbable screw fixation in SSRO with distal segment osteotomy shows clinically acceptable postoperative condylar position stability. PMID- 24172190 TI - Do atrial differences in endothelial damage, leukocyte and platelet activation, or tissue factor activity contribute to chamber-specific thrombogenic status in patients with atrial fibrillation? AB - BACKGROUND: Thrombi form mainly in the left rather than the right atria of patients with atrial fibrillation (AF), the reason of this predilection being unknown. OBJECTIVE: The purpose of this study was to investigate whether atrial specific differences in endothelial damage, leukocyte activation, platelet stimulation, and tissue factor activity occur in patients with AF. METHODS: Twenty-two patients (16 men, 6 women; age 56 +/- 8 years; 16 paroxysmal AF, 6 persistent AF) with AF undergoing pulmonary vein isolation were investigated. Blood samples from the left and the right atrium were obtained at the start of the procedure. Microparticles (MPs) released by apoptotic/stimulated cells were measured by capture assays. Their procoagulant abilities were quantified by functional prothrombinase and tissue factor assays and their cellular origin were determined (endothelium, platelet, leukocyte). Platelet reactivity was evaluated by whole blood flow cytometry for expression of platelet P-selectin (CD62P), active glycoprotein IIb/IIIa receptor (PAC-1). Platelet aggregation was evaluated using ADP, TRAP and collagen-induced whole blood aggregometry. RESULTS: There were no atrial-specific differences in the levels of total procoagulant MPs, leukocyte-derived-MPs or platelet-derived MPs. Conversely, endothelial-derived MPs and tissue factor activity and collagen-induced platelet aggregation were slightly elevated in the right atrium (P < 0.05). CONCLUSIONS: Our data show no evidence for increased thrombogenic status in the left atrium that would account for its greater propensity for thrombus formation in patients with AF. PMID- 24172191 TI - Frontiers of model animals for neuroscience: two prosperous aging model animals for promoting neuroscience research. AB - A model animal showing spontaneous onset is a useful tool for investigating the mechanism of disease. Here, I would like to introduce two aging model animals expected to be useful for neuroscience research: the senescence-accelerated mouse (SAM) and the klotho mouse. The SAM was developed as a mouse showing a senescence related phenotype such as a short lifespan or rapid advancement of senescence. In particular, SAMP8 and SAMP10 show age-related impairment of learning and memory. SAMP8 has spontaneous spongy degeneration in the brain stem and spinal cord with aging, and immunohistochemical studies reveal excess protein expression of amyloid precursor protein and amyloid beta in the brain, indicating that SAMP8 is a model for Alzheimer's disease. SAMP10 also shows age-related impairment of learning and memory, but it does not seem to correspond to Alzheimer's disease because senile plaques primarily composed of amyloid beta or neurofibrillary tangles primarily composed of phosphorylated tau were not observed. However, severe atrophy in the frontal cortex, entorhinal cortex, amygdala, and nucleus accumbens can be seen in this strain in an age-dependent manner, indicating that SAMP10 is a model for normal aging. The klotho mouse shows a phenotype, regulated by only one gene named alpha-klotho, similar to human progeria. The alpha-klotho gene is mainly expressed in the kidney and brain, and oxidative stress is involved in the deterioration of cognitive function of the klotho mouse. These animal models are potentially useful for neuroscience research now and in the near future. PMID- 24172192 TI - Mycobacterium tuberculosis infection in rhesus monkeys (Macaca mulatta) and evaluation of ESAT-6 and CFP10 as immunodiagnostic antigens. AB - Tuberculosis (TB) in nonhuman primates is a serious menace to the welfare of the animals and human who come into contact with them, while the rapid, accurate, and robust diagnosis is challenging. In this study, we first sought to establish an appropriate primate TB model resembling natural TB in nonhuman primates. Four rhesus monkeys (Macaca mulatta) of Chinese origin were infected intratracheally with two low doses of M. tuberculosis H37Rv. Regardless of the infectious doses, all monkeys were demonstrated to be successfully infected by clinical assessments, tuberculin skin test conversions, peripheral immune responses, gross observations, histopathology analysis, and M. tuberculosis burdens. Furthermore, we extended the usefulness of this model for assessing the following immunodiagnostic antigens: CFP10, ESAT-6, CFP10-ESAT-6, and an antigen cocktail of CFP10 and ESAT-6. The data showed that CFP10 was an M. tuberculosis-specific, "early" antigen used for serodiagnosis of TB in nonhuman primates. In conclusion, we established a useful primate TB model depending on low doses of M .tuberculosis and affording new opportunities for studies of M. tuberculosis disease and diagnostics. PMID- 24172193 TI - Novel ROSA26 Cre-reporter knock-in C57BL/6N mice exhibiting green emission before and red emission after Cre-mediated recombination. AB - The Cre/loxP system is a strategy for controlling temporal and/or spatial gene expression through genome alteration in mice. As successful Cre/loxP genome alteration depends on Cre-driver mice, Cre-reporter mice are essential for validation of Cre gene expression in vivo. In most Cre-reporter mouse strains, although the presence of reporter product indicates the expression of Cre recombinase, it has remained unclear whether a lack of reporter signal indicates either no Cre recombinase expression or insufficient reporter gene promoter activity. We produced a novel ROSA26 knock-in Cre-reporter C57BL/6N strain exhibiting green emission before and red after Cre-mediated recombination, designated as strain R26GRR. Ubiquitous green fluorescence and no red fluorescence were observed in R26GRR mice. To investigate the activation of tdsRed, EGFP-excised R26GRR, R26RR, mice were produced through the crossing of C57BL/6N mice with R26GRR/Ayu1-Cre F1 mice. R26RR mice showed extraordinarily strong red fluorescence in almost all tissues examined, suggesting ubiquitous activation of the second reporter in all tissues after Cre/loxP recombination. Moreover, endothelial cell lineage and pancreatic islet-specific expression of red fluorescence were detected in R26GRR/Tie2-Cre F1 mice and R26GRR /Ins1-Cre F1 mice, respectively. These results indicated that R26GRR mice are a useful novel Cre-reporter mouse strain. In addition, R26GRR mice with a pure C57BL/6N background represent a valuable source of green-to-red photoconvertible cells following Cre/loxP recombination for application in transplantation studies. The R26GRR mouse strain will be available from RIKEN BioResource Center (http://www.brc.riken.jp/lab/animal/en/). PMID- 24172194 TI - Effects of aged garlic extract on left ventricular diastolic function and fibrosis in a rat hypertension model. AB - Daily consumption of garlic is known to lower the risk of hypertension and ischemic heart disease. In this study, we examined whether aged garlic extract (AGE) prevents hypertension and the progression of compensated left ventricular (LV) hypertrophy in Dahl salt-sensitive (DS) rats. DS rats were randomly divided into three groups: those fed an 8% NaCl diet until 18 weeks of age (8% NaCl group), those additionally treated with AGE (8% NaCl + AGE group), and control rats maintained on a diet containing 0.3% NaCl until 18 weeks of age (0.3% NaCl group). AGE was administered orally by gastric gavage once a day until 18 weeks of age. LV mass was significantly higher in the 8% NaCl + AGE group than in the 0.3% NaCl group at 18 weeks of age, but significantly lower in the 8% NaCl + AGE group than in the 8% NaCl group. No significant differences were observed in systolic blood pressure (SBP) between the 8% NaCl and 8% NaCl + AGE groups at 12 and 18 weeks of age. LV end-diastolic pressure and pressure half-time at 12 and 18 weeks of age were significantly lower in the 8% NaCl + AGE group compared with the 8% NaCl group. AGE significantly reduced LV interstitial fibrosis at 12 and 18 weeks of age. Chronic AGE intake attenuated LV diastolic dysfunction and fibrosis without significantly decreasing SBP in hypertensive DS rats. PMID- 24172195 TI - Analysis of cationic amino acid transport activity in canine lens epithelial cells. AB - Cationic amino acid transport activity in a canine lens epithelial cells (LEC) line was investigated. The transporter activity of arginine was 0.424 +/- 0.047 nmol/mg protein min, while the presence of N-ethylmaleimide, an inhibitor of the canine cationic amino acid transporter (CAT), reduced transport activity by 30%. A full-length cDNA sequence of canine CAT1 was 2558 bp long and was predicted to encode the 629 amino acid polypeptides. The deduced amino acid sequence of canine CAT1 showed similarities of 92.1% and 88.6% to those of the human and mouse, respectively. Western blot analysis detected a band at 70 kDa in a membrane protein sample of LEC. RT-PCR analysis confirmed that CAT1 was ubiquitously detected in all tissues examined. PMID- 24172196 TI - Natural killer T cells in adipose tissue are activated in lean mice. AB - Adipose tissues are closely connected with the immune system. It has been suggested that metabolic syndromes such as type 2 diabetes, arteriosclerosis and liver steatosis can be attributed to adipose tissue inflammation characterized by macrophage infiltration. To understand a physiological and pathological role of natural killer T (NKT) cells on inflammation in adipose tissue, we characterized a subset of NKT cells in abdominal and subcutaneous adipose tissues in C57BL/6J mice fed normal or high-fat diets. NKT cells comprised a larger portion of lymphocytes in adipose tissues compared with the spleen and peripheral blood, with epididymal adipose tissue having the highest number of NKT cells. Furthermore, some NKT cells in adipose tissues expressed higher levels of CD69 and intracellular interferon-gamma, whereas the Vbeta repertoires of NKT cells in adipose tissues were similar to other cells. In obese mice fed a high-fat diet, adipose tissue inflammation had little effect on the Vbeta repertoire of NKT cells in epididymal adipose tissues. We speculate that the NKT cells in adipose tissues may form an equivalent subset in other tissues and that these subsets are likely to participate in adipose tissue inflammation. Additionally, the high expression level of CD69 and intracellular IFN-gamma raises the possibility that NKT cells in adipose tissue may be stimulated by some physiological mechanism. PMID- 24172197 TI - Effects of transport stress on serum alkaline phosphatase activity in beagle dogs. AB - Here, to determine the effects of transport stress on blood parameters in dogs, we investigated the changes in hematologic and serum chemical parameters in healthy beagle dogs transported from Beijing, China, to Osaka, Japan, to obtain the background data. Only the activity of serum alkaline phosphatase increased clearly upon arrival, a change attributed to transport stress, but the activity gradually reduced afterward. No marked changes in levels of other blood parameters were noted. Our findings here suggest that alkaline phosphatase is a useful tool for studying transport stress. PMID- 24172198 TI - Compound heterozygosity of the functionally null Cdh23(v-ngt) and hypomorphic Cdh23(ahl) alleles leads to early-onset progressive hearing loss in mice. AB - The waltzer (v) mouse mutant harbors a mutation in Cadherin 23 (Cdh23) and is a model for Usher syndrome type 1D, which is characterized by congenital deafness, vestibular dysfunction, and prepubertal onset of progressive retinitis pigmentosa. In mice, functionally null Cdh23 mutations affect stereociliary morphogenesis and the polarity of both cochlear and vestibular hair cells. In contrast, the murine Cdh23(ahl) allele, which harbors a hypomorphic mutation, causes an increase in susceptibility to age-related hearing loss in many inbred strains. We produced congenic mice by crossing mice carrying the v niigata (Cdh23(v-ngt)) null allele with mice carrying the hypomorphic Cdh23(ahl) allele on the C57BL/6J background, and we then analyzed the animals' balance and hearing phenotypes. Although the Cdh23(v-ngt/ahl) compound heterozygous mice exhibited normal vestibular function, their hearing ability was abnormal: the mice exhibited higher thresholds of auditory brainstem response (ABR) and rapid age dependent elevation of ABR thresholds compared with Cdh23(ahl/ahl) homozygous mice. We found that the stereocilia developed normally but were progressively disrupted in Cdh23(v-ngt/ahl) mice. In hair cells, CDH23 localizes to the tip links of stereocilia, which are thought to gate the mechanoelectrical transduction channels in hair cells. We hypothesize that the reduction of Cdh23 gene dosage in Cdh23(v-ngt/ahl) mice leads to the degeneration of stereocilia, which consequently reduces tip link tension. These findings indicate that CDH23 plays an important role in the maintenance of tip links during the aging process. PMID- 24172199 TI - Porcine adiponectin receptor 1 transgene resists high-fat/sucrose diet-induced weight gain, hepatosteatosis and insulin resistance in mice. AB - Adiponectin and its receptors have been demonstrated to play important roles in regulating glucose and lipid metabolism in mice. Obesity, type II diabetes and cardiovascular disease are highly correlated with down-regulated adiponectin signaling. In this study, we generated mice overexpressing the porcine Adipor1 transgene (pAdipor1) to study its beneficial effects in metabolic syndromes as expressed in diet-induced obesity, hepatosteatosis and insulin resistance. Wild type (WT) and pAdipor1 transgenic mice were fed ad libitum with a standard chow diet (Chow) or a high-fat/sucrose diet (HFSD) for 24 weeks, beginning at 6 to 7 weeks of age. There were 12 mice per genetic/diet/sex group. When challenged with HFSD to induce obesity, the pAdipor1 transgenic mice resisted development of weight gain, hepatosteatosis and insulin resistance. These mice had lowered plasma adiponectin, triglyceride and glycerol concentrations compared to WT mice. Moreover, we found that (indicated by mRNA levels) fatty acid oxidation was enhanced in skeletal muscle and adipose tissue, and liver lipogenesis was inhibited. The pAdipor1 transgene also restored HFSD-reduced phosphoenolpyruvate carboxykinase 1 (Pck1) and glucose transporter 4 mRNA in the adipose tissues, implying that the increased Pck1 may promote glyceroneogenesis to reduce glucose intolerance and thus activate the flux of glyceride-glycerol to resist diet induced weight gain in the adipose tissues. Taken together, we demonstrated that pAdipor1 can prevent diet-induced weight gain and insulin resistance. Our findings may provide potential therapeutic strategies for treating metabolic syndromes and obesity, such as treatment with an ADIPOR1 agonist or activation of Adipor1 downstream targets. PMID- 24172200 TI - Identification and characterization of the merozoite surface protein 1 (msp1) gene in a host-generalist avian malaria parasite, Plasmodium relictum (lineages SGS1 and GRW4) with the use of blood transcriptome. AB - BACKGROUND: The merozoite surface protein 1 (msp1) is one of the most studied vaccine candidate genes in mammalian Plasmodium spp. to have been used for investigations of epidemiology, population structures, and immunity to infections. However methodological difficulties have impeded the use of nuclear markers such as msp1 in Plasmodium parasites causing avian malaria. Data from an infection transcriptome of the host generalist avian malaria parasite Plasmodium relictum was used to identify and characterize the msp1 gene from two different isolates (mtDNA lineages SGS1 and GRW4). The aim was to investigate whether the msp1 gene in avian malaria species shares the properties of the msp1 gene in Plasmodium falciparum in terms of block variability, conserved anchor points and repeat motifs, and further to investigate the degree to which the gene might be informative in avian malaria parasites for population and epidemiological studies. METHODS: Reads from 454 sequencing of birds infected with avian malaria was used to develop Sanger sequencing protocols for the msp1 gene of P. relictum. Genetic variability between variable and conserved blocks of the gene was compared within and between avian malaria parasite species, including P. falciparum. Genetic variability of the msp1 gene in P. relictum was compared with six other nuclear genes and the mtDNA gene cytochrome b. RESULTS: The msp1 gene of P. relictum shares the same general pattern of variable and conserved blocks as found in P. falciparum, although the variable blocks exhibited less variability than P. falciparum. The variation across the gene blocks in P. falciparum spanned from being as conserved as within species variation in P. relictum to being as variable as between the two avian malaria species (P. relictum and Plasmodium gallinaceum) in the variable blocks. In P. relictum the highly conserved p19 region of the peptide was identified, which included two epidermal growth factor-like domains and a fully conserved GPI anchor point. CONCLUSION: This study provides protocols for evaluation of the msp1 gene in the avian malaria generalist parasite P. relictum. The msp1 gene in avian Plasmodium shares the genetic properties seen in P. falciparum, indicating evolutionary conserved functions for the gene. The data on the variable blocks of the gene show that the msp1 gene in P. relictum might serve as a good candidate gene for future population and epidemiological studies of the parasite. PMID- 24172202 TI - Expression and clinicopathological significance of miR-146a in hepatocellular carcinoma tissues. AB - BACKGROUND: Aberrant expression of microRNA-146a (miR-146a) has been found in several classes of cancers. However, its expression and clinicopathological contribution in hepatocellular carcinoma (HCC) has not been fully elucidated. OBJECTIVE: To explore the clinicopathological significance of the miR-146a level in HCC formalin-fixed paraffin-embedded (FFPE) tissue. METHODS: Eighty-five HCC samples and their para-cancerous normal liver tissues were collected. Total mRNA including miRNA was extracted, and miR-146a expression was determined using real time RT-PCR. Furthermore, the correlation between the miR-146a expression and clinicopathological parameters was investigated. RESULTS: MicroRNA-146a expression in HCC tissues was lower compared with that in adjacent non-cancerous hepatic tissues. MicroRNA-146a expression was also related to clinical TNM stage, metastasis, portal vein tumor embolus, and number of tumor nodes. CONCLUSIONS: Down-regulation of miR-146a is related to HCC carcinogenesis and deterioration of HCC. MicroRNA-146a may act as a suppressor miRNA of HCC, and it is therefore a potential prognostic biomarker for HCC patients. PMID- 24172203 TI - Escalated handling of young C57BL/6 mice results in altered Morris water maze performance. AB - BACKGROUND: The handling of experimental animals prior to experimental interventions is often poorly described, even though it may affect the final functional outcome. This study explores how the use of repeated handling of C57BL/6 mice prior to Morris water maze (MWM) tests can affect the performance. METHODS AND MATERIALS: The handled animals were subjected to the escalating handling protocol, with the investigator spending 5 min per day per cage for 8 days prior to the MWM test. On the last days of handling, the mice were introduced to water and the concept of a hidden platform. The MWM test consisted of four daily trials for 90 s per day for 4 days with a hidden platform. A probe test was performed 4 days after the last learning trial. Control animals were not handled prior to MWM. RESULTS: Handling reduced the latency to find the platform on the first 2 days of the MWM tests and reduced thigmotaxis. The mice increased their swim speed and elicited more explorative behavior in the learning trials and to some lesser extent in the probe trials. CONCLUSIONS: The improvement in MWM navigation was most likely due to reduced stress and anxiety regarding the investigator and the test. Handled mice displayed less variability than non handled mice, suggesting that by using a controlled handling protocol prior to the experiments fewer C57BL/6 mice would be needed to achieve statistically significant differences in studies of learning and spatial memory using MWM. PMID- 24172201 TI - Functional transcriptomics in the post-ENCODE era. AB - The last decade has seen tremendous effort committed to the annotation of the human genome sequence, most notably perhaps in the form of the ENCODE project. One of the major findings of ENCODE, and other genome analysis projects, is that the human transcriptome is far larger and more complex than previously thought. This complexity manifests, for example, as alternative splicing within protein coding genes, as well as in the discovery of thousands of long noncoding RNAs. It is also possible that significant numbers of human transcripts have not yet been described by annotation projects, while existing transcript models are frequently incomplete. The question as to what proportion of this complexity is truly functional remains open, however, and this ambiguity presents a serious challenge to genome scientists. In this article, we will discuss the current state of human transcriptome annotation, drawing on our experience gained in generating the GENCODE gene annotation set. We highlight the gaps in our knowledge of transcript functionality that remain, and consider the potential computational and experimental strategies that can be used to help close them. We propose that an understanding of the true overlap between transcriptional complexity and functionality will not be gained in the short term. However, significant steps toward obtaining this knowledge can now be taken by using an integrated strategy, combining all of the experimental resources at our disposal. PMID- 24172204 TI - H syndrome: the first 79 patients. AB - BACKGROUND: H syndrome is an autosomal recessive genodermatosis with multisystem involvement caused by mutations in SLC29A3. OBJECTIVE: We sought to investigate the clinical and molecular findings in 79 patients with this disorder. METHODS: A total of 79 patients were included, of which 13 are newly reported cases. Because of the phenotypic similarity and molecular overlap with H syndrome, we included 18 patients with allelic disorders. For 31 patients described by others, data were gathered from the medical literature. RESULTS: The most common clinical features (>45% of patients) were hyperpigmentation, phalangeal flexion contractures, hearing loss, and short stature. Insulin-dependent diabetes mellitus and lymphadenopathy mimicking Rosai-Dorfman disease were each found in approximately 20%. Additional systemic features were described in less than 15% of cases. Marked interfamilial and intrafamilial clinical variability exists. Twenty mutations have been identified in SLC29A3, with no genotype-phenotype correlation. LIMITATIONS: In the 31 patients described by others, data were collected from the medical literature. CONCLUSIONS: H syndrome is a multisystemic disease with clinical variability. Consequently, all SLC29A3-related diseases should be considered a single entity. Recognition of the pleomorphic nature of H syndrome is important for diagnosis of additional patients. PMID- 24172205 TI - Bone ultrasound velocity in pediatric intensive care unit: a pilot study. AB - BACKGROUND: Bone loss has been documented in adults in intensive care wards. Children admitted to pediatric intensive care units (PICU) are also exposed to many potential risk factors for bone loss such as immobilization, catabolic state, and nutritional depletion. Quantitative ultrasound technique that measures speed of sound (SOS) correlates with bone mineral density (BMD) and strength. Herein is a clinical prospective longitudinal, observational pilot study to evaluate early bone changes that occur during the first few days of PICU admission. METHODS: Children are hospitalized in a pediatric intensive under general anesthesia and muscle paralysis. Bone SOS at the mid-shaft tibia was measured on the first day of hospitalization and on days 2 to 3 thereafter. RESULTS: Nineteen children were studied. Bone SOS decreased during the first 3 days of hospitalization from 3,297 +/- 315 to 3,260 +/- 311 m/min (p < 0.05). The decrease was approximately 1% of the original SOS over the first 2 to 3 days of admission. CONCLUSION: There is a significant decrease in bone strength after 3 days in pediatric patients admitted to an intensive care department. Longitudinal studies of a larger group of children are necessary to determine the clinical meaning of the results and to possibly evaluate preventive approaches. PMID- 24172206 TI - Hafnium-silicon precipitate structure determination in a new heat-resistant ferritic alloy by precession electron diffraction techniques. AB - The structure determination of an HfSi4 precipitate has been carried out by a combination of two precession electron diffraction techniques: high precession angle, 2.2 degrees , single pattern collection at eight different zone axes and low precession angle, 0.5 degrees , serial collection of patterns obtained by increasing tilts of 1 degrees . A three-dimensional reconstruction of the associated reciprocal space shows an orthorhombic unit cell with parameters a = 11.4 A, b = 11.8 A, c = 14.6 A, and an extinction condition of (hkl) h + k odd. The merged intensities from the high angle precession patterns have been symmetry tested for possible space groups (SG) fulfilling this condition and a best symmetrization residual found at 18% for SG 65 Cmmm. Use of the SIR2011 direct methods program allowed solving the structure with a structure residual of 18%. The precipitate objects of this study were reproducibly found in a newly implemented alloy, designed according to molecular orbital theory. PMID- 24172207 TI - Priming BCL-2 to kill: the combination therapy of tamoxifen and ABT-199 in ER+ breast cancer. AB - The B-cell lymphoma/leukemia 2 protein (BCL-2) may help many types of cancers to evade cell death. However, identifying exactly where this is the case is a challenge. ABT-199 is a small molecule that selectively inhibits BCL-2, which is currently in clinical trials in lymphoid malignancies. While inhibiting BCL-2 by itself can cause cell death in hematopoietic tumors, single-agent activity is harder to observe in solid tumors. Combining ABT-199 with tamoxifen, the standard endocrine therapy for estrogen receptor-positive breast cancers, 85% of which have BCL-2 expression, represents a new strategy to prime cancer cells for apoptosis and elicit better cancer cell death responses. PMID- 24172208 TI - Verrucous carcinoma of the upper arm. PMID- 24172209 TI - A phase III, double-blind, placebo-controlled, flexible-dose study of levomilnacipran extended-release in patients with major depressive disorder. AB - Levomilnacipran (1S, 2R-milnacipran) is a potent and selective serotonin and norepinephrine reuptake inhibitor; an extended-release (ER) formulation allows for once-daily dosing. This phase III study (NCT01034462) evaluated the efficacy, the safety, and the tolerability of 40 to 120 mg/d of levomilnacipran ER versus placebo in the treatment of patients (18-80 y) with major depressive disorder. This multicenter, randomized, double-blind, placebo-controlled, parallel-group, flexible-dose study comprised a 1-week single-blind, placebo run-in period; an 8 week double-blind treatment; and a 2-week double-blind down-taper period. The primary efficacy parameter was total score change from baseline to week 8 on the Montgomery-Asberg Depression Rating Scale (MADRS); the secondary efficacy was the Sheehan Disability Scale. Analysis was performed using the mixed-effects model for repeated measures on a modified intent-to-treat population. A total of 434 patients received at least 1 dose of double-blind treatment (safety population); 429 patients also had 1 or more postbaseline MADRS assessments (modified intent to-treat population). The least squares mean differences and 95% confidence interval were statistically significant in favor of levomilnacipran ER versus placebo for the MADRS total score (-3.095 [-5.256, -0.935]; P = 0.0051) and the SDS total score (-2.632 [-4.193, -1.070]; P = 0.0010) change from baseline to week 8. Adverse events were reported in 61.8% of the placebo patients and in 81.6% of the levomilnacipran ER patients. Frequently reported adverse events (>= 5% in levomilnacipran ER and twice the rate of placebo) were nausea, dizziness, constipation, tachycardia, urinary hesitation, hyperhidrosis, insomnia, vomiting, hypertension, and ejaculation disorder. In conclusion, there was a statistically significant difference in the score change from baseline to week 8 between levomilnacipran ER and placebo on several depression rating scales, reflecting symptomatic and functional improvement; treatment was generally well tolerated. PMID- 24172210 TI - Molecular docking studies of marine diterpenes as inhibitors of wild-type and mutants HIV-1 reverse transcriptase. AB - AIDS is a pandemic responsible for more than 35 million deaths. The emergence of resistant mutations due to drug use is the biggest cause of treatment failure. Marine organisms are sources of different molecules, some of which offer promising HIV-1 reverse transcriptase (RT) inhibitory activity, such as the diterpenes dolabelladienotriol (THD, IC50 = 16.5 uM), (6R)-6-hydroxydichotoma 3,14-diene-1,17-dial (HDD, IC50 = 10 uM) and (6R)-6-acetoxydichotoma-3,14-diene 1,17-dial (ADD, IC50 = 35 uM), isolated from a brown algae of the genus Dictyota, showing low toxicity. In this work, we evaluated the structure-activity relationship (SAR) of THD, HDD and ADD as anti HIV-1 RT, using a molecular modeling approach. The analyses of stereoelectronic parameters revealed a direct relationship between activity and HOMO (Highest Occupied Molecular Orbital)-LUMO (Lowest Unoccupied Molecular Orbital) gap (E(LUMO)-E(HOMO)), where antiviral profile increases with larger HOMO-LUMO gap values. We also performed molecular docking studies of THD into HIV-1 RT wild-type and 12 different mutants, which showed a seahorse conformation, hydrophobic interactions and hydrogen bonds with important residues of the binding pocket. Based on in vitro experiments and docking studies, we demonstrated that mutations have little influence in positioning and interactions of THD. Following a rational drug design, we suggest a modification of THD to improve its biological activity. PMID- 24172211 TI - Formation of a volunteer harmful algal bloom network in British Columbia, Canada, following an outbreak of diarrhetic shellfish poisoning. AB - Evidence for shellfish toxin illness in British Columbia (BC) on the west coast of Canada can be traced back to 1793. For over two hundred years, domestically acquired bivalve shellfish toxin illnesses in BC were solely ascribed to paralytic shellfish poisonings caused by algal blooms of Alexandrium. This changed in 2011, when BC experienced its first outbreak of diarrhetic shellfish poisoning (DSP). As a result of this outbreak, Canada's first DSP symposium was held in November, 2012, in North Vancouver, BC. Three of the objectives of the symposium were to provide a forum to educate key stakeholders on this emerging issue, to identify research and surveillance priorities and to create a DSP network. The purpose of this paper is to review what is known about shellfish poisoning in BC and to describe a novel volunteer network that arose following the symposium. The newly formed network was designed for industry shellfish growers to identify harmful algae bloom events, so that they may take actions to mitigate the effects of harmful blooms on shellfish morbidity. The network will also inform public health and regulatory stakeholders of potentially emerging issues in shellfish growing areas. PMID- 24172212 TI - A stable-isotope mass spectrometry-based metabolic footprinting approach to analyze exudates from phytoplankton. AB - Phytoplankton exudates play an important role in pelagic ecology and biogeochemical cycles of elements. Exuded compounds fuel the microbial food web and often encompass bioactive secondary metabolites like sex pheromones, allelochemicals, antibiotics, or feeding attractants that mediate biological interactions. Despite this importance, little is known about the bioactive compounds present in phytoplankton exudates. We report a stable-isotope metabolic footprinting method to characterise exudates from aquatic autotrophs. Exudates from (13)C-enriched alga were concentrated by solid phase extraction and analysed by high-resolution Fourier transform ion cyclotron resonance mass spectrometry. We used the harmful algal bloom forming dinoflagellate Alexandrium tamarense to prove the method. An algorithm was developed to automatically pinpoint just those metabolites with highly (13)C-enriched isotope signatures, allowing us to discover algal exudates from the complex seawater background. The stable-isotope pattern (SIP) of the detected metabolites then allowed for more accurate assignment to an empirical formula, a critical first step in their identification. This automated workflow provides an effective way to explore the chemical nature of the solutes exuded from phytoplankton cells and will facilitate the discovery of novel dissolved bioactive compounds. PMID- 24172213 TI - Anti HSV-1 activity of halistanol sulfate and halistanol sulfate C isolated from Brazilian marine sponge Petromica citrina (Demospongiae). AB - The n-butanol fraction (BF) obtained from the crude extract of the marine sponge Petromica citrina, the halistanol-enriched fraction (TSH fraction), and the isolated compounds halistanol sulfate (1) and halistanol sulfate C (2), were evaluated for their inhibitory effects on the replication of the Herpes Simplex Virus type 1 (HSV-1, KOS strain) by the viral plaque number reduction assay. The TSH fraction was the most effective against HSV-1 replication (SI = 15.33), whereas compounds 1 (SI = 2.46) and 2 (SI = 1.95) were less active. The most active fraction and these compounds were also assayed to determine the viral multiplication step(s) upon which they act as well as their potential synergistic effects. The anti-HSV-1 activity detected was mediated by the inhibition of virus attachment and by the penetration into Vero cells, the virucidal effect on virus particles, and by the impairment in levels of ICP27 and gD proteins of HSV-1. In summary, these results suggest that the anti-HSV-1 activity of TSH fraction detected is possibly related to the synergic effects of compounds 1 and 2. PMID- 24172215 TI - Fluorescence energy transfer in quantum dot/azo dye complexes in polymer track membranes. AB - Fluorescence resonance energy transfer in complexes of semiconductor CdSe/ZnS quantum dots with molecules of heterocyclic azo dyes, 1-(2-pyridylazo)-2-naphthol and 4-(2-pyridylazo) resorcinol, formed at high quantum dot concentration in the polymer pore track membranes were studied by steady-state and transient PL spectroscopy. The effect of interaction between the complexes and free quantum dots on the efficiency of the fluorescence energy transfer and quantum dot luminescence quenching was found and discussed. PMID- 24172214 TI - Anti-diabetic effect of balanced deep-sea water and its mode of action in high fat diet induced diabetic mice. AB - In this study, we investigated the effects of balanced deep-sea water (BDSW) on hyperglycemia and glucose intolerance in high-fat diet (HFD)-induced diabetic C57BL/6J mice. BDSW was prepared by mixing deep-sea water (DSW) mineral extracts and desalinated water to give a final hardness of 500-2000. Mice given an HFD with BDSW showed lowered fasting plasma glucose levels compared to HFD-fed mice. Oral and intraperitoneal glucose tolerance tests showed that BDSW improves impaired glucose tolerance in HFD-fed mice. Histopathological evaluation of the pancreas showed that BDSW recovers the size of the pancreatic islets of Langerhans, and increases the secretion of insulin and glucagon in HFD-fed mice. Quantitative reverse transcription polymerase chain reaction results revealed that the expression of hepatic genes involved in glucogenesis, glycogenolysis and glucose oxidation were suppressed, while those in glucose uptake, beta-oxidation, and glucose oxidation in muscle were increased in mice fed HFD with BDSW. BDSW increased AMP-dependent kinase (AMPK) phosphorylation in 3T3-L1 pre- and mature adipocytes and improved impaired AMPK phosphorylation in the muscles and livers of HFD-induced diabetic mice. BDSW stimulated phosphoinositol-3-kinase and AMPK pathway-mediated glucose uptake in 3T3-L1 adipocytes. Taken together, these results suggest that BDSW has potential as an anti-diabetic agent, given its ability to suppress hyperglycemia and improve glucose intolerance by increasing glucose uptake. PMID- 24172216 TI - Association between winter season and risk of death from cardiovascular diseases: a study in more than half a million inpatients in Beijing, China. AB - BACKGROUND: Seasonal associations of cardiovascular mortality have been noted in most populations of European origin years ago, but are not well evaluated in Asian populations recently. METHODS: Utilizing the electronic Hospitalization Summary Reports (HSRs) from 32 top-ranked hospitals in Beijing, China, we evaluated the association between winter season and the risk of cardiovascular death among hospitalized individuals. General additive models and logistic regression models were adjusted for confounding factors. RESULTS: Older patients who were admitted to the hospital in the winter months (January, February, November and December) had a death risk that was increased by approximately 30% to 50% (P < 0.01) over those who were admitted in May. However, younger patients did not seem to experience the same seasonal variations in death risk. The excess winter deaths among older patients were associated with ischemic heart disease (RR = 1.22; 95% CI 1.13 to 1.31), pulmonary heart disease (RR = 1.42; 95% CI 1.10 to 1.83), cardiac arrhythmias (RR = 1.67; 95% CI 1.36 to 2.05), heart failure (RR = 1.30; 95% CI 1.09 to 1.54), ischemic stroke (RR = 1.30; 95% CI 1.17 to 1.43), and other cerebrovascular diseases (RR = 1.78; 95% CI 1.40 to 2.25). The risks of mortality were higher in winter months than in the month of May, regardless of the presence or absence of respiratory disease. CONCLUSIONS: Winter season was associated with a substantially increased risk of cardiovascular death among older Chinese cardiovascular inpatients. PMID- 24172218 TI - Stability of the Tomonaga-Luttinger liquid state in gamma-irradiated carbon nanotube bundles. AB - We report experimental results for the changes in conductivity of single-wall carbon nanotube bundles when irradiated by (60)Co gamma-rays in various environments. In the current study the samples investigated were irradiated in hermetic cells, either evacuated (0.1 Pa) or filled with hydrogen or deuterium at atmospheric pressure. In situ measurements of the resistance change as a function of irradiation dose at room temperature are presented. It was found that, for all irradiation conditions, the normalized resistance versus irradiation dose demonstrates a logarithmic behaviour. A phenomenological model for the observed dependence is derived. The current-voltage characteristics of the irradiated samples were measured in the temperature range from 4.5 to 300 K using short (10 ns) electric pulses, and the results demonstrate a scaling behaviour. This scaling occurs in the universal coordinates that correspond to the Tomonaga Luttinger liquid concept. Our results confirm the existence of the Tomonaga Luttinger liquid phase up to room temperature in carbon nanotubes after gamma irradiation to a dose of 5 * 10(7) rad in vacuum, 1.7 * 10(7) rad in hydrogen and 1.24 * 10(8) rad in deuterium. PMID- 24172217 TI - High prevalence of type 2 diabetes among the urban middle class in Bangladesh. AB - BACKGROUND: The prevalence of type-2 diabetes and metabolic syndrome are increasing in the developing world; we assessed their prevalence among the urban middle class in Bangladesh. METHODS: In this cross-sectional survey (n = 402), we randomly selected consenting adults (>= 30 years) from a middle-income neighborhood in Dhaka. We assessed demography, lifestyle, and health status, measured physical indices and blood pressure and obtained blood samples. We evaluated two primary outcomes: (1) type-2 diabetes (fasting blood glucose >= 7.0 mmol/L or hemoglobin A1C >= 6.5% (48 mmol/mol) or diabetes medication use) and (2) insulin resistance (type-2 diabetes or metabolic syndrome using International Diabetes Federation criteria). RESULTS: Mean age and Quetelet's (body mass) index were 49.4 +/- 12.6 years and 27.0 +/- 5.1 kg/m2; 83% were married, 41% had >=12 years of education, 47% were employed, 47% had a family history of diabetes. Thirty-five percent had type-2 diabetes and 45% had metabolic syndrome. In multivariate models older age and family history of diabetes were significantly associated with type-2 diabetes. Older age, female sex, overweight or obese, high wealth index and positive family history of diabetes were significantly associated with insulin resistance. Participants with type-2 diabetes or insulin resistance had significantly poorer physical health only if they had associated cardiovascular disease. CONCLUSIONS: The prevalence of type-2 diabetes and metabolic syndrome among the middle class in Dhaka is alarmingly high. Screening services should be implemented while researchers focus on strategies to lessen the incidence and morbidity associated with these conditions. PMID- 24172219 TI - Validity, reliability and prevalence of four 'clinical content' subtypes of depression. AB - Although depression is often diagnosed via reference to a list of nine criteria which may be used to form a unitary diagnosis, there is significant variation in the content of those nine criteria to justify consideration of four 'clinical content' subtypes of depression based upon differences in symptomatology. Each of those four subtypes has previously been described for their different causes, underlying neurobiological pathways, and treatment requirements. This paper reports on the validity, reliability and prevalence of those four subtypes of depression across three samples of participants. Validity is demonstrated and satisfactory reliability values are reported for each subtype, plus significant correlations between items used to measure each subtype, arguing for the individual homogeneity of each of these four subtypes. Prevalence data indicated that there were significant subtype differences at the sample and individual level, challenging the usage of a single global depression score. These results argue for further consideration of these subtypes when researching depression and in planning individualised treatment regimes. PMID- 24172220 TI - Prior hormonal treatment, but not sexual experience, reduces the negative effects of restraint on female sexual behavior. AB - These experiments were designed to determine if prior sexual experience reduced the negative effect of mild stress on female sexual behavior. In the first experiment, ovariectomized rats were hormonally primed with estradiol benzoate and progesterone for 3 consecutive weeks during which they received six mating experiences in a male's home cage or received no sexual experience. The next week, females were primed with 10 MUg estradiol benzoate two days before a 5 min restraint. Both groups were resistant to the negative effects of the stressor. In the second experiment, females received 0, 1, 2, or 3 weeks of 10 MUg estradiol benzoate and were restrained on the fourth week after priming with 10 MUg estradiol benzoate. Rats without prior hormonal priming showed a decline in lordosis behavior after restraint but prior priming with estradiol benzoate reduced this effect. In the third experiment, rats received 3 weeks of hormonal priming with estradiol benzoate and progesterone with or without sexual experience. An additional group received no sexual experience or hormonal priming. Females were then given a 3-week hormone vacation before testing in the restraint paradigm. All groups showed a decline in lordosis behavior after restraint. The fourth experiment was identical to the third except that sexual experience in the male's cage and in a pacing apparatus were compared. There was no effect of either type of sexual experience on the response to restraint. Possible mechanisms responsible for effects of prior hormonal priming are presented and the absence of an effect of sexual experience is discussed in comparison to findings in male rats. PMID- 24172221 TI - The neurology of rhizomelic chondrodysplasia punctata. AB - BACKGROUND: To describe the neurologic profiles of Rhizomelic chondrodysplasia punctata (RCDP); a peroxisomal disorder clinically characterized by skeletal abnormalities, congenital cataracts, severe growth and developmental impairments and immobility of joints. Defective plasmalogen biosynthesis is the main biochemical feature. METHODS: Observational study including review of clinical and biochemical abnormalities, genotype, presence of seizures and neurophysiological studies of a cohort of 16 patients with RCDP. RESULTS: Patients with the severe phenotype nearly failed to achieve any motor or cognitive skills, whereas patients with the milder phenotype had profound intellectual disability but were able to walk and had verbal communication skills. Eighty-eight percent of patients developed epileptic seizures. The age of onset paralleled the severity of the clinical and biochemical phenotype. Myoclonic jerks, followed by atypical absences were most frequently observed. All patients with clinical seizures had interictal encephalographic evidence of epilepsy. Visual evoked (VEP) and brain auditory potential (BAEP) studies showed initial normal latency times in 93% of patients. Deterioration of VEP occurred in a minority in both the severe and the milder phenotype. BAEP and somatosensory evoked potentials (SSEP) were more likely to become abnormal in the severe phenotype. Plasmalogens were deficient in all patients. In the milder phenotype levels of plasmalogens were significantly higher in erythrocytes than in the severe phenotype. Phytanic acid levels ranged from normal to severely increased, but had no relation with the neurological phenotype. CONCLUSION: Neurodevelopmental deficits and age-related occurrence of seizures are characteristic of RCDP and are related to the rest-activity in plasmalogen biosynthesis. Evoked potential studies are more likely to become abnormal in the severe phenotype, but are of no predictive value in single cases of RCDP. PMID- 24172222 TI - Activity of the HMGB1-derived immunostimulatory peptide Hp91 resides in the helical C-terminal portion and is enhanced by dimerization. AB - We have previously shown that an 18 amino acid long peptide, named Hp91, whose sequence corresponds to a region within the endogenous protein HMGB1, activates dendritic cells (DCs) and acts as adjuvant in vivo by potentiating Th1-type antigen-specific immune responses. We analyzed the structure-function relationship of the Hp91 peptide to investigate the amino acids and structure responsible for immune responses. We found that the cysteine at position 16 of Hp91 enabled formation of reversible peptide dimmers, monomer and dimmer were compared for DC binding and activation. Stable monomers and dimers were generated using a maleimide conjugation reaction. The dimer showed enhanced ability to bind to and activate DCs. Furthermore, the C-terminal 9 amino acids of Hp91, named UC1018 were sufficient for DC binding and Circular dichroism showed that UC1018 assumes an alpha-helical structure. The ninemer peptide UC1018 induced more potent antigen-specific CTL responses in vivo as compared to Hp91 and it protected mice from tumor development when used in a prophylactic vaccine setting. We have identified a short alpha helical peptide that acts as potent adjuvant inducing protective immune responses in vivo. PMID- 24172223 TI - A systematic analysis of the complement pathways in patients with neuromyelitis optica indicates alteration but no activation during remission. AB - Neuromyelitis optica (NMO) is an autoimmune demyelinating inflammatory disorder, mediated by pathogenic autoantibodies against aquaporin 4 (AQP4), the main water channel of the central nervous system (CNS). NMO is characterized by local IgG deposition and complement activation within the CNS, but the three complement pathways have not been systematically investigated. We evaluated the overall activation of the classical, alternative, and MBL-lectin pathways in the peripheral blood of 25 patients with AQP4-seropositive NMO spectrum during remission and 113 healthy controls by three ways: (1) we measured the concentrations of native complement proteins of the three pathways [C1-inhibitor (C1-inh), C1q, C4, C3, C5, factor I, factor B, properdin]; (2) the concentrations of complement products suggesting in vivo activation (C1rC1sC1-inh, C3a, C3bBbP, and SC5b-9); and (3) the total activity of the three complement pathways. Additionally we measured levels of C1rC1sC1-inh, C3a, C3bBbP in cerebrospinal fluid (CSF) of 6 patients with relapsing NMO and of 18 patients with relapsing multiple sclerosis (MS). The serological studies indicated that total complement activity of the classical [median (interquartile range) 72 (61-82) vs. 65 (56-73) CH50/mL; p=0.0122] and of the lectin pathways [73 (59-111) vs. 49 (3-92)%; p=0.0078)] were elevated compared with the controls, whereas that of the alternative pathway was not significantly different. The levels of C3 [1.1 (0.9 1.3) vs. 1.4 (1.2-1.5)g/L; p<0.0001], factor B [89 (77-115) vs. 103 (93-113)%; p=0.0397] and factor I [85 (69-95) vs. 101 (93-107)%; p=0.0007], as well as of properdin [92 (74-104) vs. 108 (97-122)%; p=0.0028] were significantly lower in the patients than in the controls. The only increase in the patients was ascertained in the relative concentration of C1rC1sC1-inh vs. the C1-inhibitor (42.3 [31.9-65.0] vs. 30.8 [13.5-43.5] AU/mg; p=0.0007). The absolute and relative levels of the other complement activation products were not elevated in the patients. On the contrary, the serum concentrations of C3a, C3bBbP, and SC5b 9 of the patients were lower than those of the controls. The absolute concentration of the complement activation products (C1rC1sC1-inh, C3bBbP, C3a) and the ratio of C3bBbP/C1rC1sC1-inh did not differ in NMO and MS CSF samples. The ratio of C3bBbP/C1rC1sC1-inh was similar in NMO plasma and CSF samples. We found a higher ratio of C3bBbP/C1rC1sC1-inh in the plasma of control subjects compared to those in any pathological samples. Our results do not indicate substantial systemic complement activation if NMO activity is adequately controlled; nevertheless, the complement system is abnormally affected even during remission. The relative ancillarity of the alternative compared to the classical pathway may also suggest that suppression of the alternative pathway by treatment may be important to achieve remission. PMID- 24172224 TI - Anti-CD14 antibody reduces LPS responsiveness via TLR4 internalization in human monocytes. AB - CD14 is an LPS sensing receptor that is primarily expressed in monocytes. CD14 binds and transfers bacterial LPS to the surface TLR4:MD-2 complex to enable its recognition. After recognizing LPS, this complex produces the first intracellular signals via TIRAP and MyD88, after which surface TLR4/LPS complex is rapidly internalized and produces additional signals via TRAM and TRIF. It was recently suggested that CD14 is a key regulator of LPS-induced TLR4 endocytosis and second signaling. In the present study, we showed that surface TLR4 expressions of human primary monocytes and cell line THP-1 were significantly reduced after treatment with anti-CD14 Ab. Among three anti-CD14 Abs with different epitope specificities used in this study, My4, which has an epitope specificity for LPS binding domain of the CD14 molecule, was found to be the most potent at reduction of surface expression of TLR4 as well as CD14. To test the reason for this reduction, we performed an in vitro internalization assay using anti-TLR4 Ab conjugated with toxin. The results of this analysis indicated surface CD14 ligation-mediated TLR4 internalization, and the mechanism of the internalization was found to be partially clathrin-dependent. We next examined NF-kappaB/AP-1 activation and TNF alpha production of THP-1XBlue-CD14 cells in response to LPS challenge with or without My4 pre-treatment. The results revealed that NF-kappaB/AP-1 activation and TNF-alpha production of cells treated with My4 were significantly impaired when compared to the control. Our results suggest that membrane CD14 ligation mediated TLR4 internalization is a novel mechanism for effective down-regulation of surface expression of TLR4 and subsequent reduction of LPS response of human monocytes. PMID- 24172225 TI - Involvement of Fcalpha/MUR (CD351) in autoantibody production. AB - Antibody exerts various immune responses via binding to Fc receptors expressed on immune cells. Although several reports have demonstrated that IgM prevents autoantibody production, the role of IgM Fc receptors is largely unknown. To analyze the involvement of Fcalpha/MUR (CD351), an Fc receptor for IgM and IgA expressed on B cells and follicular dendritic cells (FDCs), in IgM-mediated suppression of autoantibody production, we generated mice deficient in Fcalpha/MUR on the background of MRL/MpJ-Fas(lpr/lpr) (Fcamr(-/-)Fas(lpr/lpr)) mice. Fcamr(-/-)Fas(lpr/lpr) mice showed significantly lower titers of IgG autoantibodies against double strand (ds) DNA, histone and cardiolipin in the sera than did Fcamr(+/+)Fas(lpr/lpr) mice. Moreover, Fcamr(-/-)Fas(lpr/lpr) mice showed higher survival rate at the ages of 28, 32 and 40 weeks old, compared with Fcamr(+/+)Fas(lpr/lpr) mice. These results suggest that Fcalpha/MUR enhances, rather than suppresses, autoantibody production. PMID- 24172226 TI - Cloning, expression in E. coli and immunological characterization of Par j 3.0201, a Parietaria pollen profilin variant. AB - Parietaria judaica pollen is one of the main sources of allergens in the Mediterranean area. Its allergenic composition has been studied in detail showing the presence of two major allergens (Par j 1 and Par j 2) and two minor allergens belonging to the profilin and calcium binding protein families of allergens (Par j 3 and Par j 4, respectively). Clinical reports support the hypothesis of a limited cross-reactivity between profilin from Parietaria and unrelated sources. We screened a P. judaica cDNA library to identify novel forms of profilins with allergenic activity. This strategy allowed us to isolate a 767 bp cDNA containing the information for a 131 amino acids protein with homology to profilins from unrelated sources greater than that observed with the already published Parietaria profilins. This profilin was expressed in Escherichia coli as a recombinant protein and its immunological prevalence was studied in a population of Parietaria allergic patients from Southern Europe. Immunoblotting analysis showed that the Parietaria profilin was recognized by IgE from 6.5% of the allergic population. Finally, a selected population of profilin allergic patients was enrolled to demonstrate the cross-reactivity of this novel variant with other profilins from grass and date palm. In conclusion, molecular cloning and immunological studies have allowed the isolation, expression and immunological characterization of a novel cross-reactive profilin allergen from P. judaica pollen named Par j 3.0201. PMID- 24172227 TI - Short-term exposure to oleandrin enhances responses to IL-8 by increasing cell surface IL-8 receptors. AB - BACKGROUND AND PURPOSE: One of the first steps in host defence is the migration of leukocytes. IL-8 and its receptors are a chemokine system essential to such migration. Up-regulation of these receptors would be a viable strategy to treat dysfunctional host defence. Here, we studied the effects of the plant glycoside oleandrin on responses to IL-8 in a human monocytic cell line. EXPERIMENTAL APPROACH: U937 cells were incubated with oleandrin (1-200 ng mL(-1) ) for either 1 h (pulse) or for 24 h (non-pulse). Apoptosis; activation of NF-kappaB, AP-1 and NFAT; calcineurin activity and IL-8 receptors (CXCR1 and CXCR2) were measured using Western blotting, RT-PCR and reporter gene assays. KEY RESULTS: Pulse exposure to oleandrin did not induce apoptosis or cytoxicity as observed after non-pulse exposure. Pulse exposure enhanced activation of NF-kappaB induced by IL 8 but not that induced by TNF-alpha, IL-1, EGF or LPS. Exposure to other apoptosis-inducing compounds (azadirachtin, resveratrol, thiadiazolidine, or benzofuran) did not enhance activation of NF-kappaB. Pulse exposure to oleandrin increased expression of IL-8 receptors and chemotaxis, release of enzymes and activation of NF-kappaB, NFAT and AP-1 along with increased IL-8-mediated calcineurin activation, and wound healing. Pulse exposure increased numbers of cell surface IL-8 receptors. CONCLUSIONS AND IMPLICATIONS: Short-term (1 h; pulse) exposure to a toxic glycoside oleandrin, enhanced biological responses to IL-8 in monocytic cells, without cytoxicity. Pulse exposure to oleandrin could provide a viable therapy for those conditions where leukocyte migration is defective. PMID- 24172228 TI - The percentage flow-mediated dilation index: a large-sample investigation of its appropriateness, potential for bias and causal nexus in vascular medicine. AB - The percentage flow-mediated dilation index (FMD%) scales the increase in arterial diameter (Ddiff) as a constant proportion of baseline artery diameter (Dbase). We have demonstrated, albeit with small samples, that the scaling properties of FMD% can lead to biased inferences on endothelial dysfunction. Therefore, we aimed to investigate the underlying rationale and potential bias of FMD% using a selection of new examples from the large (n = 3499) and diverse Multi-Ethnic Study of Atherosclerosis (MESA). In this dataset, we found that smaller values of Ddiff are associated with larger values of Dbase, which contradicts the scaling properties of FMD%. Consequently, FMD% 'over-scales' and naturally generates an even stronger negative correlation between itself and Dbase. Using a data simulation, we show that this FMD%-Dbase correlation can be a statistical artefact due to inappropriate scaling. The new examples we present from MESA indicate that FMD% biases the differences in flow-mediated response between men and women, Framingham risk score categories, and diseased and healthy people. We demonstrate how FMD%, as an exposure for predicting cardiovascular disease, is confounded by its dependency on Dbase, which itself could be clinically important. This critical review, incorporating an allometric analysis of a large dataset, suggests that the FMD% index has a less-than-clear rationale, can itself generate the Dbase-dependency problem, provides biased estimates of differences in the flow-mediated response, complicates the interpretation of the flow-mediated protocol and clouds the causal pathway to vascular disease. These interpretative problems can be resolved by applying accepted allometric principles to the flow-mediated response. PMID- 24172229 TI - Management of subclavian artery in-stent restenosis. AB - Stenotic and occlusive diseases of the subclavian and brachiocephalic arteries can cause a significant morbidity as it can lead to symptomatic ischemia affecting the upper extremities, brain and, in some cases, the heart. An endovascular approach with primary stenting or provisional stenting has become the primary modality of revascularization of subclavian artery stenosis. In-stent restenosis can be treated with percutaneous transluminal angioplasty or repeat stenting and although stents offer superior long-term patency over balloon angioplasty alone for de novo lesions, there are no data regarding primary versus provisional stenting in subclavian in-stent restenosis. Here we describe a case of subclavian in-stent restenosis treated with just balloon angioplasty and demonstrate that provisional stenting with angioplasty alone when the percutaneous transluminal angioplasty results are excellent is a reasonable alternative to primary stent placement for subclavian in-stent restenosis. PMID- 24172230 TI - DNA duplex stability as discriminative characteristic for Escherichia coli sigma(54)- and sigma(28)- dependent promoter sequences. AB - The advent of modern high-throughput sequencing has made it possible to generate vast quantities of genomic sequence data. However, the processing of this volume of information, including prediction of gene-coding and regulatory sequences remains an important bottleneck in bioinformatics research. In this work, we integrated DNA duplex stability into the repertoire of a Neural Network (NN) capable of predicting promoter regions with augmented accuracy, specificity and sensitivity. We took our method beyond a simplistic analysis based on a single sigma subunit of RNA polymerase, incorporating the six main sigma-subunits of Escherichia coli. This methodology employed successfully re-discovered known promoter sequences recognized by E. coli RNA polymerase subunits sigma(24), sigma(28), sigma(32), sigma(38), sigma(54) and sigma(70), with highlighted accuracies for sigma(28)- and sigma(54)- dependent promoter sequences (values obtained were 80% and 78.8%, respectively). Furthermore, the discrimination of promoters according to the sigma factor made it possible to extract functional commonalities for the genes expressed by each type of promoter. The DNA duplex stability rises as a distinctive feature which improves the recognition and classification of sigma(28)- and sigma(54)- dependent promoter sequences. The findings presented in this report underscore the usefulness of including DNA biophysical parameters into NN learning algorithms to increase accuracy, specificity and sensitivity in promoter beyond what is accomplished based on sequence alone. PMID- 24172231 TI - Atrioesophageal fistula during cryoballoon ablation for atrial fibrillation. AB - To date, there is 1 case report publication of AE fistula during the employment of the first-generation cryoballoon (Gen-1). Recently the Arctic Front Advance system (second-generation cryoballoon) was introduced into the US and EU markets. For the purpose of peer education, we report a case of AE fistula that occurred during the utilization of the second-generation cryoballoon (Gen-2). Additionally, we review current best practices that may reduce the risk of AE fistula during any AF ablation procedure. PMID- 24172232 TI - Prevalence of clinically captured and confirmed malaria among HIV seropositve clinic attendants in five hospitals in Ghana. AB - BACKGROUND: Malaria is associated with an increase in HIV viral load and a fall in CD4-cell count. Conversely, HIV infection disrupts the acquired immune responses to malaria and the efficacy of antimalarial drugs. This study was carried out in five Ghanaian hospitals to estimate the prevalence of clinically confirmed malaria among HIV patients by evaluating their hospital records. METHODS: This retrospective descriptive cross sectional study reviewed and collected data on malaria, using Case Record Forms from HIV patients' folders in five hospitals in Ghana. RESULTS: There were 933 patients records made up of 272 (29.2%) males and 661 (70.8%) females. Majority of the patients were aged between 21-40 (63.6%) years and the rest were between the ages 1-20 (2.8%) years, 41-60 (31.6%) years and 61-80 (2.1%) years of age.A total of 38.1% (355/933) of the patients were clinically suspected of having clinical malaria. Of these 339 (95.5%) were referred to the laboratory for confirmation of the diagnosis of malaria. Only 4.4% (15/339) of patients tested were confirmed as cases of malaria among the patients that were clinically suspected of having malaria and subsequently confirmed. Fever, was not significantly associated with a confirmed diagnosis of malaria [OR = 3.11, 95% CI: (0.63, 15.37), P = 0.142]. CONCLUSIONS: There was a 4.4% prevalence of confirmed malaria and 38.1% of presumptively diagnosed malaria from the case records of HIV patients from the selected hospitals in Ghana. PMID- 24172233 TI - Neutrophil to lymphocyte ratio in acute ST-segment elevation myocardial infarction. AB - BACKGROUND: Spontaneous early patency of infarct-related artery (IRA) on arrival for primary percutaneous coronary intervention is associated with better short- and long-term prognosis in patients with ST-segment elevation myocardial infarction (STEMI). We aimed to investigate whether the hemographic parameters on admission are associated with spontaneous IRA patency. METHODS: This was a retrospective study of 1,625 patients with acute STEMI who underwent primary percutaneous coronary intervention<12 hours after the onset of symptoms. RESULTS: Angiography showed patent IRA (prethrombolysis in myocardial infarction [TIMI] grade 3 flow) in 160 (9.8%) patients. Neutrophil count on admission (7.8+/ 2.4*103/MUL versus 9.7+/-3.8*103/MUL; P<0.001) was significantly lower and lymphocyte count (2.4+/-1.0*103/MUL versus 1.9+/-1.1*103/MUL; P<0.001) on admission was significantly higher in the patent IRA group. Neutrophil to lymphocyte ratio (NLR) was significantly lower in the patent IRA group (4.1+/-3.2 versus 6.9+/-5.5; P<0.001). Admission leukocyte counts (13+/-4.0*103/MUL versus 12+/-3.4*103/MUL; P<0.001) and NLR (7.2+/-5.8 versus 5.5+/-4.4; P<0.001) of the patients with TIMI thrombus score>=4 were significantly higher than patients with TIMI thrombus score<4. In the multivariate analysis, NLR>=4.5 (3.17 [95% confidence interval: 2.04-4.92]; P<0.001) was found to be independently predicting an occluded IRA on initial angiography with a sensitivity of 62.7% and a specificity of 70%. CONCLUSIONS: NLR on admission is significantly related to angiographic thrombus burden and spontaneous early IRA patency in patients with acute STEMI. PMID- 24172234 TI - Churg-Strauss angiitis. AB - Churg-Strauss angiitis is a rare vasculitic disorder affecting small- and medium sized blood vessels. It is clinically characterized by the presence of a wide spectrum of multisystem organ involvement, with allergic rhinitis, asthma and peripheral blood eosinophilia as the most typical manifestations. The authors describe 2 cases of Churg-Strauss angiitis from an urban community of Southern Louisiana, exhibiting an atypical presentation with myocardial ischemia and cerebrovascular complications. Epidemiology, pathophysiology and clinical overview are presented. The therapeutic management is also discussed. PMID- 24172235 TI - Bergman's triad: fat embolism syndrome. PMID- 24172236 TI - Extra-anatomic neo-aorta for adult abdominal aortic coarctation. PMID- 24172237 TI - Early diagnosis of sepsis-related hepatic dysfunction and its prognostic impact on survival: a prospective study with the LiMAx test. AB - INTRODUCTION: Liver dysfunction can derive from severe sepsis and might be associated with poor prognosis. However, diagnosis of septic liver dysfunction is challenging due to a lack of appropriate tests. Measurement of maximal liver function capacity (LiMAx test) has been successfully evaluated as a new diagnostic test in liver resection and transplantation. The aim of this study was to evaluate the LiMAx test during sepsis in comparison to biochemical tests and the indocyanin green test (ICG-PDR). METHODS: We prospectively investigated 28 patients (8 female and 20 male, age range 35 to 80 years) suffering from sepsis on a surgical ICU. All patients received routine resuscitation from septic shock (surgery, fluids, catecholamines, antibiotic drugs). The first LiMAx test and ICG PDR were carried out within the first 24 hours after onset of septic symptoms, followed by day 2, 5 and 10. Other biochemical parameters and scores determining the severity of illness were measured daily. Clinical outcome parameters were examined after 90 days or at the end of treatment. The population was divided into 2 groups (group A: non-survivors or ICU length of stay (ICU-LOS) >30 days versus group B: survivors and ICU-LOS <30 days) for analysis. RESULTS: Epidemiological baseline characteristics of both groups were similar. Group A patients had significant lower LiMAx and ICG-PDR values than patients in group B. Determination of ICG-PDR by finger probe failed in 14.3% of tests due to insufficient peripheral pulses. Respiratory, renal and hepatic dysfunction (LiMAx and ICG-PDR) were associated with prolonged ICU-LOS. Only LiMAx <100 MUg/kg/h and respiratory dysfunction were associated with increased mortality. For LiMAx <100 MUg/kg/h receiver operating characteristic-analysis revealed a 100% sensitivity and 77% specificity for death. CONCLUSIONS: Sepsis-related hepatic dysfunction can be diagnosed early and effectively by the LiMAx test. The extent of LiMAx impairment is predictive for patient morbidity and mortality. The sensitivity and specificity of the LiMAx test was superior to that of ICG-PDR regarding the prediction of mortality. PMID- 24172238 TI - Ultrasound Doppler renal resistive index: a useful tool for the management of the hypertensive patient. AB - The Doppler-derived renal resistive index has been used for years in a variety of clinical settings such as the assessment of chronic renal allograft rejection, detection and management of renal artery stenosis, evaluation of progression risk in chronic kidney disease, differential diagnosis in acute and chronic obstructive renal disease, and more recently as a predictor of renal and global outcome in the critically ill patient. More recently, evidence has been accumulating showing that an increased renal resistive index not only reflects changes in intrarenal perfusion but is also related to systemic hemodynamics and the presence of subclinical atherosclerosis, and may thus provide useful prognostic information in patients with primary hypertension. On the basis of these results, the evaluation of renal resistive index has been proposed in the assessment and management of patients with primary hypertension to complement other signs of renal abnormalities. PMID- 24172239 TI - Low rate of resistant hypertension in Chinese patients with hypertension: an analysis of the HOT-CHINA study. AB - OBJECTIVE: The rate of resistant hypertension in China is unknown. This is an analysis of resistant hypertension based on Hypertension Optimal Treatment Study in China. METHODS: The study was conducted in 148 cities in mainland China from April 2001 to February 2002, which included 54,590 hypertensive patients (>=18 years of age), and used a five-step treatment programme. Patients not achieving blood pressure (BP) target (<140/90 mmHg) within 2 weeks received preplanned additional drugs. Resistant hypertension was defined in the participants with uncontrolled hypertension after 2 weeks of treatment on Step 5. RESULTS: The rate of resistant hypertension was 1.9%. Patients with resistant hypertension were characterized by following features: higher male percentage (65.6 vs. 60.2%); younger age (59.51+/-13.02 vs. 61.76+/-12.27 years); higher BMI (24.8+/-3.5 vs. 24.0+/-3.4 kg/m); longer disease course; higher fasting blood glucose (6.60+/ 2.69 vs. 5.99+/-2.12 mmol/l); higher total cholesterol (5.67+/-1.63 vs. 5.32+/ 1.24 mmol/l); higher triglycerides (2.15+/-1.32 vs. 1.96+/-1.09 mmol/l); and higher percentage of grade 3 hypertension (71.1 vs. 27.2%) (all P<0.001). Patients with resistant hypertension also had a higher rate of metabolic syndrome (45.9 vs. 35.4%), diabetes mellitus (25.5 vs. 14.7%) and history of myocardial infarction (4.7 vs. 3.3%) or stroke (17.0 vs. 11.6%) (P<0.001). Multivariate analyses revealed an association of resistant hypertension with younger age, higher BP, BMI, longer disease course, higher fasting blood glucose and total cholesterol (P<0.05). CONCLUSION: Resistant hypertension in Chinese patients is associated with overweight/obesity, higher BP and metabolic syndrome. The rate of resistant hypertension in China, however, is much lower than previously reported. Another intriguing characteristic is the association of resistant hypertension with younger age. PMID- 24172240 TI - Effect of pressure on thermal stability of g-quadruplex DNA and double-stranded DNA structures. AB - Pressure is a thermodynamic parameter that can induce structural changes in biomolecules due to a volumetric decrease. Although most proteins are denatured by pressure over 100 MPa because they have the large cavities inside their structures, the double-stranded structure of DNA is stabilized or destabilized only marginally depending on the sequence and salt conditions. The thermal stability of the G-quadruplex DNA structure, an important non-canonical structure that likely impacts gene expression in cells, remarkably decreases with increasing pressure. Volumetric analysis revealed that human telomeric DNA changed by more than 50 cm3 mol-1 during the transition from a random coil to a quadruplex form. This value is approximately ten times larger than that for duplex DNA under similar conditions. The volumetric analysis also suggested that the formation of G-quadruplex DNA involves significant hydration changes. The presence of a cosolute such as poly(ethylene glycol) largely repressed the pressure effect on the stability of G-quadruplex due to alteration in stabilities of the interactions with hydrating water. This review discusses the importance of local perturbations of pressure on DNA structures involved in regulation of gene expression and highlights the potential for application of high-pressure chemistry in nucleic acid-based nanotechnology. PMID- 24172241 TI - Dillenia Suffruticosa extract inhibits proliferation of human breast cancer cell lines (MCF-7 and MDA-MB-231) via induction of G2/M arrest and apoptosis. AB - The present research was designed to evaluate the anticancer properties of Dillenia suffruticosa extract. Our focus was on the mode of cell death and cell cycle arrest induced in breast cancer cells by the active fractions (designated as D/F4, D/F5 and EA/P2) derived from chromatographic fractionation of D. suffruticosa extracts. The results showed that the active fractions are more cytotoxic towards MCF-7 (estrogen positive breast cancer cells) and MDA-MB-231 (estrogen negative breast cancer cells) as compared to other selected cancer cell lines that included HeLa, A459 and CaOV3. The induction of cell death through apoptosis by the active fractions on the breast cancer cells was confirmed by Annexin V-FITC and PI staining. Cell cycle analysis revealed that D/F4 and EA/P2 induced G2/M phase cell cycle arrest in MCF-7 cells. On the other hand, MDA-MB 231 cells treated with D/F4 and D/F5 accumulated in the sub-G1 phase without cell cycle arrest, suggesting the induction of cell death through apoptosis. The data suggest that the active fractions of D. suffruticosa extract eliminated breast cancer cells through induction of apoptosis and cell cycle arrest. The reason why MCF-7 was more sensitive towards the treatment than MDA-MB-231 remains unclear. This warrants further work, especially on the role of hormones in response towards cytotoxic agents. In addition, more studies on the mechanisms underlying the induction of apoptosis and cell cycle arrest by the plant extract also need to be carried out. PMID- 24172242 TI - Preparation and optimization of triptolide-loaded solid lipid nanoparticles for oral delivery with reduced gastric irritation. AB - Triptolide (TP) often causes adverse reactions in the gastrointestinal tract when it is administered orally. This study aimed to prepare and optimize triptolide loaded solid lipid nanoparticles (TP-SLN) with reduced gastric irritation. The microemulsion technique was used to formulate TP-SLN employing a five-level central composite design (CCD) that was developed for exploring the optimum levels of three independent variables on particle size, encapsulation efficiency (EE) and drug loading (DL). Quadratic polynomial models were generated to predict and evaluate the three independent variables with respect to the three responses. The optimized TP-SLN was predicted to comprise fraction of lipid of 49.73%, surfactant to co-surfactant ratio of 3.25, and lipid to drug ratio of 55.27, which showed particle size of 179.8 +/- 5.7 nm, EE of 56.5 +/- 0.18% and DL of 1.02 +/- 0.003% that were in good agreement with predicted values. In addition, the optimized nanoparticles manifested a sustained-release pattern in vitro and were stable during 3 h of incubation in simulated gastric fluids without significant size change and the majority (91%) of the drug was protected. Furthermore, the nanoparticles did not show obvious gastric irritation caused by oral administration of TP in rats. PMID- 24172243 TI - Anti-tumor effects of atractylenolide I isolated from Atractylodes macrocephala in human lung carcinoma cell lines. AB - Atractylenolide I (ATL-1) is the major sesquiterpenoid of Atractylodes macrocephala. This study was designed to investigate whether ATL-1 induced apoptosis in A549 and HCC827 cells in vitro and in vivo. In our results, ATL-1 significantly decreased the percentage of in vitro viability, in a dose-dependent manner. In addition, DAPI staining and flow cytometry tests demonstrated the induction of apoptosis by ATL-I. Western blot analysis indicated that the protein levels of caspase-3, caspase-9 and Bax were increased in A549 and HCC827 cells after ATL-I exposure; to the contrary, the expressions of Bcl-2, Bcl-XL were decreased after treatment with ATL-1. In the in vivo study, ATL-I effectively suppressed tumor growth (A549) in transplanted tumor nude mice with up-regulation of caspase-3, caspase-9, and Bax and down-regulation of Bcl-2 and Bcl-XL. In conclusion, our results demonstrated that ATL-I has significant antitumor activity in lung carcinoma cells, and the possible mechanism of action may be related to apoptosis induced by ATL-I via a mitochondria-mediated apoptosis pathway. PMID- 24172244 TI - Synthesis, characterization, X-ray structure and biological activities of C-5 bromo-2-hydroxyphenylcalix[4]-2-methyl resorcinarene. AB - C-5-bromo-2-hydroxyphenylcalix[4]-2-methylresorcinarene (I) was synthesized by cyclocondensation of 5-bromo-2-hydroxybenzaldehyde and 2-methylresorcinol in the presence of concentrated HCl. Compound I was characterized by infrared and nuclear magnetic resonance spectroscopic data. X-ray analysis showed that this compound crystallized in a triclinic system with space group of Pi, a = 15.9592(16)A, b = 16.9417(17)A, c = 17.0974(17)A, alpha = 68.656(3) degrees , beta = 85.689(3) degrees , gamma = 81.631(3) degrees , Z = 2 and V = 4258.6(7)A3. The molecule adopts a chair (C2h) conformation. The thermal properties and antioxidant activity were also investigated. It was strongly antiviral against HSV-1 and weakly antibacterial against Gram-positive bacteria. Cytotoxicity testing on Vero cells showed that it is non-toxic, with a CC50 of more than 0.4 mg/mL. PMID- 24172245 TI - A genome-wide association study of third molar agenesis in Japanese and Korean populations. AB - Tooth agenesis is the most common developmental anomaly of human dentition, occurring most often in the third molar (wisdom tooth). It is affected by genetic variation, so this study aimed to identify susceptibility genes associated with third molar agenesis. Examination of panoramic radiographs and medical history about third molar extraction were used to diagnose third molar agenesis. We then conducted a genome-wide association study of 149 cases with at least one-third molar agenesis and 338 controls from Japan and Korea using the Illumina HumanOmniExpress BeadChip. After rigorous quality-control filtering, approximately 550 000 single-nucleotide polymorphisms (SNPs) were analyzed in association tests with the status. We identified three SNPs showing evidence of association at P<1 * 10(-5) and 69 SNPs showing evidence of association at P<1 * 10(-4). SNP rs1469622, which maps to an intron of THSD7B (thrombospondin, type I, domain containing 7B) on chromosome 2, showed the strongest association (combined odds ratio=1.88, 95% confidence interval=1.43-2.47, P=7.5 * 10(-6)). The identified SNPs may be considered candidates for future replication studies in independent samples. PMID- 24172246 TI - Novel mutation in AAA domain of BCS1L causing Bjornstad syndrome. AB - Bjornstad syndrome is an extremely rare condition characterized by pilitorti and nerve deafness. Only few large families have been reported worldwide. Here we describe a large Pakistani family with five affected individuals. The hair fibers of all the patients were twisted around their axis and devoid of any pigment. In addition the patients had a moderate-to-severe degree of hearing impairment. Genotyping with high-density single-nucleotide polymorphism arrays showed homozygosity in two intervals on chromosome 2. Linkage with one of these regions (genomic position 218745685-221025443, hg19) was confirmed. This region encompasses the BCS1L gene. Mutations in this gene have previously been associated with Bjornstad's syndrome. We sequenced the BCS1L gene for identification of the causative mutation in the family. A novel homozygous missense mutation c.901T>A was identified, which segregated with the disease in the family. This mutation results in the amino acid change p.Tyr301Asn and was predicted to be pathogenic by bioinformatics tools. PMID- 24172247 TI - Correlation of PLS3 expression with disease severity in children with spinal muscular atrophy. AB - Spinal muscular atrophy (SMA) is a common autosomal recessive neuromuscular disease in children caused by homozygous deletion of the survival motor neuron 1 gene (SMN1). Plastin 3 (PLS3) has been identified as a protective modifier of SMA. We analyzed the levels of PLS3 expression in peripheral blood from 65 children with SMA and 59 healthy controls by using real-time PCR. In healthy controls, younger children (?3 years) showed >1.75-fold higher levels of PLS3 expression than did older child cohorts (~3-6 years, ~6-12 years and >12 years). In the older female subjects with SMA (>3 years), PLS3 expression was 56.7% lower in type II subjects than in type III patients (P=0.011). When these female subjects carried three copies of SMN2, PLS3 expression was 62.6% lower in the type II subjects than in type III subjects (P=0.008). Moreover, there was a trend toward higher PLS3 expression in older female patients who could walk unaided (>3 years and SMN2 copy number=3) than those who could not. However, these differences were not observed in male subjects examined by SMA clinical type and SMN2 copy number (P>0.05). We concluded that the PLS3 gene may have an age- and gender-specific role in the clinical severity of SMA in children afflicted with this condition. PMID- 24172248 TI - How confidence intervals become confusion intervals. AB - BACKGROUND: Controversies are common in medicine. Some arise when the conclusions of research publications directly contradict each other, creating uncertainty for frontline clinicians. DISCUSSION: In this paper, we review how researchers can look at very similar data yet have completely different conclusions based purely on an over-reliance of statistical significance and an unclear understanding of confidence intervals. The dogmatic adherence to statistical significant thresholds can lead authors to write dichotomized absolute conclusions while ignoring the broader interpretations of very consistent findings. We describe three examples of controversy around the potential benefit of a medication, a comparison between new medications, and a medication with a potential harm. The examples include the highest levels of evidence, both meta-analyses and randomized controlled trials. We will show how in each case the confidence intervals and point estimates were very similar. The only identifiable differences to account for the contrasting conclusions arise from the serendipitous finding of confidence intervals that either marginally cross or just fail to cross the line of statistical significance. SUMMARY: These opposing conclusions are false disagreements that create unnecessary clinical uncertainty. We provide helpful recommendations in approaching conflicting conclusions when they are associated with remarkably similar results. PMID- 24172250 TI - Ninos Sanos, Familia Sana: Mexican immigrant study protocol for a multifaceted CBPR intervention to combat childhood obesity in two rural California towns. AB - BACKGROUND: Overweight and obese children are likely to develop serious health problems. Among children in the U.S., Latino children are affected disproportionally by the obesity epidemic. Ninos Sanos, Familia Sana (Healthy Children, Healthy Family) is a five-year, multi-faceted intervention study to decrease the rate of BMI growth in Mexican origin children in California's Central Valley. This paper describes the methodology applied to develop and launch the study. METHODS/DESIGN: Investigators use a community-based participatory research approach to develop a quasi-experimental intervention consisting of four main components including nutrition, physical activity, economic and art-community engagement. Each component's definition, method of delivery, data collection and evaluation are described. Strategies to maintain engagement of the comparison community are reported as well. DISCUSSION: We present a study methodology for an obesity prevention intervention in communities with unique environmental conditions due to rural and isolated location, limited infrastructure capacity and limited resources. This combined with numerous cultural considerations and an unstable population with limited exposure to researcher expectations necessitates reassessment and adaptation of recruitment strategies, intervention delivery and data collection methods. Trial registration # NCT01900613. TRIAL REGISTRATION: NCT01900613. PMID- 24172251 TI - Boundary condition and pre-strain effects on the free standing indentation response of graphene monolayer. AB - Using molecular mechanics simulations, we investigated the true pre-stress/pre strain state of graphene in free standing indentation and the effect of the pre strain (epsilon0) on the free standing indentation response of graphene is also considered. We found that there is essentially no effective pre-tension in graphene during free standing indentation and the reported pre-tensile stress determined from the indentation tests does not show the true pre-stress state of graphene, which is a 'fake stress' caused by the assumption (the indenter tip displacement is equal to the displacement of graphene) typically used in the classic indentation analysis. A negative epsilon0 will increase the van der Waals (VDW) interaction between the indenter tip and graphene to cause a larger overestimation of both values of the elastic modulus (E) and the nonlinear elastic constant (c) of graphene from the classic indentation analysis. However, applying a positive epsilon0 in graphene, the VDW effect will be significantly decreased, and a more accurate value of E can be obtained, but the value of c will decrease to zero, which may become an effective way to more accurately obtain the elastic stiffness of graphene from indentation tests. PMID- 24172252 TI - An unexpected intracardiac echocardiography finding on the cavotricuspid isthmus. PMID- 24172249 TI - Histone H3 lysine 4 methyltransferases and demethylases in self-renewal and differentiation of stem cells. AB - Epigenetic mechanisms are fundamental to understanding the regulatory networks of gene expression that govern stem cell maintenance and differentiation. Methylated histone H3 lysine 4 (H3K4) has emerged as a key epigenetic signal for gene transcription; it is dynamically modulated by several specific H3K4 methyltransferases and demethylases. Recent studies have described new epigenetic mechanisms by which H3K4 methylation modifiers control self-renewal and lineage commitments of stem cells. Such advances in stem cell biology would have a high impact on the research fields of cancer stem cell and regenerative medicine. In this review, we discuss the recent progress in understanding the roles of H3K4 methylation modifiers in regulating embryonic and adult stem cells' fates. PMID- 24172253 TI - Development of a minimal chemically defined medium for Ketogulonicigenium vulgare WSH001 based on its genome-scale metabolic model. AB - Commercial production of 2-keto-l-gulonic acid (2-KLG), the immediate precursor of l-ascorbic acid, is by Ketogulonicigenium vulgare in co-culture with Bacillus megaterium. We used flux balance analysis (FBA) to study a genome-scale metabolic model (GSMM) of K. vulgare, iWZ663, and found that K. vulgare is deficient in nutrient biosynthetic pathways. Individually omitting l-glycine, l-cysteine, l methionine, l-tryptophan, adenine, thymine, thiamine and pantothenate from complete chemically defined medium (CDM), caused biomass formation of K. vulgare to decrease to 1%, 21%, 16%, 1%, 26%, 57%, 73% and 24%, respectively. Based on these results and FBA, a minimal chemically defined medium (MCDM) was developed that supported monoculture of K. vulgare (0.28OD600) and 2-KLG production (3.59g/L), which were similar to those in complete CDM or corn steep liquor powder (CSLP) medium. This study demonstrated the potential of using GSMM and FBA to characterize nutrient requirements, optimize CDM, and study interactions in co culture. PMID- 24172254 TI - Bioconversion of l-glutamic acid to alpha-ketoglutaric acid by an immobilized whole-cell biocatalyst expressing l-amino acid deaminase from Proteus mirabilis. AB - The goal of this work was to develop an immobilized whole-cell biocatalytic process for the environment-friendly synthesis of alpha-ketoglutaric acid (alpha KG) from l-glutamic acid. We compared the suitability of Escherichia coli and Bacillus subtilis strains overexpressing Proteus mirabilisl-amino acid deaminase (l-AAD) as potential biocatalysts. Although both recombinant strains were biocatalytically active, the performance of B. subtilis was superior to that of E. coli. With l-glutamic acid as the substrate, alpha-KG production levels by membranes isolated from B. subtilis and E. coli were 55.3+/-1.73 and 21.7+/ 0.39MUg/mg protein/min, respectively. The maximal conversion ratio of l-glutamic acid to alpha-KG was 31% (w/w) under the following optimal conditions: 15g/L l glutamic acid, 20g/L whole-cell biocatalyst, 5mM MgCl2, 40 degrees C, pH 8.0, and 24-h incubation. Immobilization of whole cells with alginate increased the recyclability by an average of 23.33% per cycle. This work established an efficient one-step biotransformation process for the production of alpha-KG using immobilized whole B. subtilis overexpressing P. mirabilisl-AAD. Compared with traditional multistep chemical synthesis, the biocatalytic process described here has the advantage of reducing environmental pollution and thus has great potential for the large-scale production of alpha-KG. PMID- 24172255 TI - Physiological indicators of stress and meat and carcass characteristics in tail bitten slaughter pigs. AB - BACKGROUND: Tail biting is a common welfare problem in pig production and in addition to being a sign of underlying welfare problems, tail biting reduces welfare in itself. The aim of this study was to evaluate the effects of tail biting on different pre and post mortem indicators of stress in slaughter pigs and on carcass and meat characteristics. A total of 12 tail bitten (TB) and 13 control (C) pigs from a farm with a long-term tail biting problem were selected for salivary cortisol analyses before and after transport to the slaughterhouse. After stunning, samples were taken for the analysis of serum cortisol, blood lactate, intestinal heat shock protein 70 (HSP70), and meat quality characteristics. In addition, body temperature immediately after and muscle temperature 35 min after stunning were measured, as well as lean meat percentage and carcass weight. RESULTS: TB pigs showed a lower cortisol response to the transport-induced stress than C pigs and also had a lower serum cortisol concentration after stunning. HSP70 content in the small intestine was higher in the TB pigs than in C pigs. TB pigs had a considerably lower carcass weight therefore produced a lower total amount of lean meat per carcass than C pigs. CONCLUSIONS: This study suggests that prolonged or repeated stress in the form of tail biting causes a blunted stress response, possibly a sign of hypocortisolism. In addition, it underlines the importance of reducing tail biting, both from an animal welfare and an economic point-of-view. PMID- 24172256 TI - Treatment A) lifestyle modification: executive summary of the Japan Atherosclerosis Society(JAS) guidelines for the diagnosis and prevention of atherosclerotic cardiovascular diseases in Japan--2012 version. PMID- 24172257 TI - Homozygous loss-of-function mutation of the LEPREL1 gene causes severe non syndromic high myopia with early-onset cataract. AB - High myopia is a severe visual impairment which can increase the risk of retinal degeneration, subretinal hemorrhage, choroidal neovascularization, cataract and retinal detachment. We recruited an autosomal-recessive high myopia family, with affected subjects who also present early-onset cataract, retinal degeneration and other complications. Using targeted capturing and whole exome sequencing, we identified a homozygous non-sense mutation in the LEPREL1 gene which causes premature termination of the translation at the fifth amino acid (c.13C>T; p.Q5X), co-segregating with the phenotypes. LEPREL1 encodes a proline hydroxylase called prolyl 3-hydroxylase 2 (P3H2), a 2-oxoglutarate-dependent dioxygenase that hydroxylates collagens. The results show that LEPREL1 plays an important role in eye development and homozygous loss-of-function mutation of this gene can cause severely high myopia and early-onset cataract. Our study also strongly suggests that the disruption of collagen modification is one of the pathogenic mechanisms of high myopia and cataract. PMID- 24172258 TI - Improving the efficiency of ITO/nc-TiO2/CdS/P3HT:PCBM/PEDOT:PSS/Ag inverted solar cells by sensitizing TiO2 nanocrystalline film with chemical bath-deposited CdS quantum dots. AB - An improvement in the power conversion efficiency (PCE) of the inverted organic solar cell (ITO/nc-TiO2/P3HT:PCBM/PEDOT:PSS/Ag) is realized by depositing CdS quantum dots (QDs) on a nanocrystalline TiO2 (nc-TiO2) film as a light absorption material and an electron-selective material. The CdS QDs were deposited via a chemical bath deposition (CBD) method. Our results show that the best PCE of 3.37% for the ITO/nc-TiO2/CdS/P3HT:PCBM/PEDOT:PSS/Ag cell is about 1.13 times that (2.98%) of the cell without CdS QDs (i.e., ITO/nc TiO2/P3HT:PCBM/PEDOT:PSS/Ag). The improved PCE can be mainly attributed to the increased light absorption and the reduced recombination of charge carriers from the TiO2 to the P3HT:PCBM film due to the introduced CdS QDs. PMID- 24172259 TI - Cardiac decompression on extracorporeal life support: a review and discussion of the literature. AB - Extracorporeal life support is a worldwide expanding technology for patients in critical cardiogenic shock. The device is usually attached to the femoral vessels using percutaneous techniques. Despite sufficient extracorporeal circulatory support, an unclear number of patients develop high end-diastolic pressures leading to left ventricular distension and pulmonary edema, and ventricular thrombus formation may evolve. This article discusses the strategies to prevent ventricular distension by conservative, interventional, and surgical means, also illustrated by case presentations. PMID- 24172260 TI - Levosimendan may improve weaning outcomes in venoarterial ECMO patients. AB - Venoarterial extracorporeal membrane oxygenation (VA-ECMO) provides temporary mechanical circulatory support in patients with refractory cardiogenic shock, allowing time for cardiac recovery. Levosimendan is a calcium sensitizer with inotropic and vasodilatory effects used in the treatment of severe heart failure. It does not increase myocardial oxygen consumption. Its maximum hemodynamic response is seen 24-48 h after stopping infusion, but its effects can persist for 7-9 d owing to active metabolites. We sought to investigate whether the use of levosimendan improves weaning outcomes in patients on VA-ECMO. Six consecutive patients with cardiogenic shock were placed on femorofemoral VA-ECMO support and received levosimendan 24 h before the planned weaning (group A). As control group (group B), we retrospectively reviewed the VA-ECMO implanted at our institution before the introduction of the levosimendan protocol. These patients received only traditional inotropes. The weaning rate was 83.33% in group A and 27.3% in group B. The survival rate was 66.66% and 36.4%, respectively. In group A, three of six patients (50%) required inotropic/vasopressor support after ECMO cessation, while in group B 11 of 11 patients (100%) required support. In our case series, pretreatment with levosimendan seems to facilitate weaning from VA ECMO, reducing the need for high-dose inotropes. PMID- 24172261 TI - Long-term animal model of venovenous extracorporeal membrane oxygenation with atrial septal defect as a bridge to lung transplantation. AB - This study evaluated the effectiveness of an atrial septal defect (ASD) with venovenous extracorporeal membrane oxygenation (vv-ECMO) as a bridge to transplantation. Sheep (56 +/- 3 kg; n = 7) underwent a right-sided thoracotomy to create the ASD (diameter = 1 cm) and place instrumentation and a pulmonary artery (PA) occluder. After recovery, animals were placed on ECMO, and the PA was constricted to generate a twofold rise in right ventricular (RV) systolic pressure. Sheep were then maintained for 60 hours on ECMO, and data were collected hourly. Five sheep survived 60 hours. One sheep died because of a circuit clot extending into the RV, and another died presumably because of an arrhythmia. Mean right ventricular pressure (mRVP) was 19 +/- 3 mm Hg at baseline, averaged 27 +/- 7 mm Hg over the experiment, but was not statistically significant (p = 0.27) due to one sheep without an increase. Cardiac output was 6.8 +/- 1.2 L/min at baseline, averaged 6.0 +/- 1.0 L/min during the experiment, and was statistically unchanged (p = 0.34). Average arterial oxygen saturation and PCO2 over the experiment were 96.8 +/- 1.4% and 31.8 +/- 3.4 mm Hg, respectively. In conclusion, an ASD combined with vv-ECMO maintains normal systemic hemodynamics and arterial blood gases during a long-term increase in RV afterload. PMID- 24172262 TI - Prevention of percutaneous driveline infection after left ventricular assist device implantation: prophylactic antibiotics are not necessary. AB - Infection is a major source of morbidity and mortality after ventricular assist device (VAD) implantation. The percutaneous driveline is the most common site of infection in these patients and often serves as a portal to deeper pump infections. There are no data defining the role of prophylactic antibiotics in preventing these infections. We compared all patients who underwent primary HeartMate II VAD implantation at two different institutions employing two different driveline infection prevention strategies between February 2007 and September 2011. While all patients received perioperative antibiotics, driveline maintenance strategies included sterile dressing changes with Hibiclens application without continued prophylactic antibiotics (Abx) (Mayo Clinic, n = 141, No Abx) and sterile dressing changes with continued prophylactic antibiotics (University of Michigan Hospital, n = 144, Abx). Although gender was similar between cohorts (Abx: 79% male vs. No Abx: 84% male, p = 0.25), median age at implant (Abx: 59 vs. No Abx: 64, p = 0.001) and destination therapy as indication for VAD (Abx: 22% vs. No Abx: 60%, p < 0.001) were significantly different. Follow-up was available in all late survivors (Abx: 140 patients, No Abx: 127 patients). Median duration of support was similar between groups (Abx: 12.3 months vs. No Abx: 11 months, p = 0.44). Total patient-years of device support were 172 years for 140 patients in the Abx cohort and 146 years for 127 patients in the No Abx cohort. Driveline drainage/infection was observed in 25 of 140 patients (18%) in the Abx group and 16 of 127 (13%) in the No Abx group (p = 0.15). Device exchange for major driveline infection was performed in seven patients in the Abx group and 0 patients in the No Abx group. Total driveline infection events per patient-years of support were 0.15 for the Abx group and 0.11 in the No Abx group (p = 0.43). There was no significant difference in the raw incidence of major driveline infections or driveline infections per patient years of support in patients who were maintained on prophylactic antibiotics compared with those who were not. These data suggest that other factors may be more important than prophylactic antibiotics in preventing driveline infections. PMID- 24172263 TI - Postimplant left ventricular assist device fit analysis using three-dimensional reconstruction. AB - Left ventricular assist devices (LVADs) are blood pumps that augment the function of the failing heart to improve perfusion, resulting in improved survival. For LVADs to effectively unload the left ventricle, the inflow cannula (IC) should be unobstructed and ideally aligned with the heart's mitral valve (MV). We examined IC orientation deviation from a hypothesized conventional angle (45 degrees right-posterior) and the approximate angle for direct IC-MV alignment in many patients. Three-dimensional anatomic models were created from computed tomography scans for 24 LVAD-implanted patients, and angles were measured between the IC and the apical z-axis in both the coronal and the sagittal planes. Common surgical IC angulation was found to be 22 +/- 15 degrees rightward and 21 +/- 12 degrees posterior from the apical z-axis; 38% (n = 9) of patients fell in this range. Direct IC-MV angulation was found to be 34 +/- 8 degrees rightward and 15 +/- 7 degrees posterior; only 8% (n = 2) of patients fell in this range. Rightward deviation toward ventricular septal wall and anterior deviation toward LV anterior freewall are associated with mortalities more so than leftward and posterior deviation. In conclusion, anatomic reconstruction may be a useful preoperative tool to obtain general population and patient-specific alignment for optimal LVAD implantation. PMID- 24172264 TI - Standard intra-aortic counterpulsation balloon may cause temporary occlusion of mesenterial and renal arteries. AB - The study was to test the hypothesis that mesenteric and renal arteries may be occluded by intra-aortic balloon pumps (IABPs), despite correct positioning. Computed tomography scans of 107 patients (34.6% women and 65.4% men) were evaluated for diameter and distance measurements of the descending aorta. Renal perfusion was examined with duplex sonography. Mean distances between left subclavian artery and celiac trunk, between the left subclavian and superior mesenteric artery, and between the left subclavian and renal artery were 214.5 +/ 22.3, 229.5 +/- 22.3, and 242.9 +/- 22.1 mm, respectively. Statistical assessment of aortic distances in patient population showed no correlation between the length of the descending aorta and body mass index (BMI) and height (men: R(2) < 0.13; women: R(2) < 0.3). An impaired arterial perfusion of the renal parenchyma existed in three of the 12 patients; three of the 12 demonstrated diastolic oscillatory flow over the renal arteries; two of the 12 patients presented both during IABP support. Autopsy observation was used to observe the position of the IABP catheter. The correlation between patient height/BMI and the distances between subclavian artery and renal/visceral branches is weak. Therefore, even if positioned correctly, intra-aortic balloon catheters may be too long and could potentially cause occlusion of aortic branches. PMID- 24172265 TI - Systemic and myocardial inflammatory response in coronary artery bypass graft surgery with miniaturized extracorporeal circulation: differences with a standard circuit and off-pump technique in a randomized clinical trial. AB - Inflammatory response and hemodilution are the main drawbacks of extracorporeal circulation. We hypothesize that the use of miniaturized extracorporeal circulation (MECC) might lower the systemic and myocardial inflammatory patterns compared with a standard system (SECC) and off-pump coronary artery bypass grafting (OPCABG). Sixty-one patients undergoing isolated coronary artery bypass graft were prospectively randomized to MECC (n = 19), SECC (n = 20), or OPCABG (n = 22). Blood samples were collected from radial artery and coronary sinus to analyze blood lactate, hemodilution, and markers for inflammation and endothelial activation such as tumor necrosis factor (TNF)-alpha, interleukin-6, monocyte chemotactic protein-1, and E-selectin. No differences were observed in early clinical outcome. Interleukin -6 levels increased in every group during and after cardiac surgery, whereas TNF-alpha values grew in the SECC group (p = 0.05). E selectin systemic values decreased during and after operation (p = 0.001) in every group. Monocyte chemotactic protein-1 systemic and cardiac levels raised only in SECC group (p = 0.014). In conclusion, MECC is comparable to SECC and OPCABG in the clinical outcome of low-risk patients, and it might be extensively used with no additional intraoperative risk. The analysis of the inflammatory patterns of endothelial activation shows MECC as effective as OPCABG, suggesting further studies to clarify MECC recommendation in high-risk patients. PMID- 24172266 TI - Effects of sodium on measuring relative blood volume during hemodialysis differ by techniques. AB - Recording the relative blood volume is a standard feature of modern dialysis devices, enabling feedback guidance of ultrafiltration and dialysate conductivity. Technically, the process is based on optical or ultrasonic methods. On the grounds of clinical evidence suggesting a malfunction of the optical hemoglobin (Hb)-dependent absorbance method in the presence of sodium changes, we compared the system with the ultrasonic method. Six patients underwent hemodialysis with a step sodium profile (140, 150, 130, and 140 mmol/L, hourly switch), with two dialysis devices featuring the optical and the ultrasonic blood volume detector, respectively. The ultrasonic system recorded a decreasing blood volume throughout the treatment. With the optical method, changes in dialysate sodium led to inverse deviations of the blood volume curve. In another treatment without profile administering, a bolus of hypertonic sodium led to the detection of a rapid 8.7% reduction in blood volume with the optical method, which was not observed with the ultrasonic device. Blood volume monitors using the optical absorbance device are influenced by osmotic changes. An increase in osmolality produces a paradox drop in the measured blood volume and vice versa rendering the monitor inappropriate for use in sodium profiling. PMID- 24172267 TI - Study of discrepancies between recorded and actual blood flow in hemodialysis patients. AB - Adequate blood flow (Qb) is necessary for effective hemodialysis (HD). Aim of the study was to examine relationship between the actually delivered Qb (dQb) and reported Qb (rQb) with dialysis machine. One hundred HD patients with arteriovenous fistula were enrolled. Delivered Qb was measured at the beginning and end of each HD session. dQb/rQb < 1 indicated a discrepancy between actual dQb and rQb reported using a dialysis machine. In addition, dQb/rQb was examined in HD patients using needles of different gauges during treatment. The average levels of dQb/rQb at start and end of HD session were 1.01 +/- 0.04 and 0.98 +/- 0.05, respectively. In the 16 gauge and 17 gauge needle groups, the percentage of patients with dQb/rQb < 1 increased in accordance with the increase in rQb or as the HD session progressed. In the 15 gauge needle group, the percentage of patients with dQb/rQb < 1 was <50% at any level of rQb. Selection of needle gauge is important factors for determining actual dQb in HD patients. PMID- 24172268 TI - Actually delivered dose of continuous renal replacement therapy is underestimated in hemofiltration. AB - Dose determination in continuous renal replacement therapy (CRRT) is controversial. Most clinical trials use effluent flow rate as a surrogate of the dose. However, such definition may overestimate actually delivered dose due to declining filter function. The current study aimed to determine the difference between prescribed and delivered clearance and its association with transmembrane pressure. Hemofiltration was done in a mixed pre- and postdilution mode. Creatinine concentrations in serum and effluent fluid were measured simultaneously at 4, 10, 16, 28, 40, 52, and 64 hours for an individual hemofilter. Prescribed clearance (K) was estimated as the effluent flow rate corrected for predilution, and delivered clearance (Kx) was estimated using the ratio of serum and effluent creatinine. A total of 60 patients involving 248 filters were included in our analysis. The mean filter life span was 37.7 hours (standard deviation: 17.6). K overestimated Kx by 9.3% (95% confidence interval: 4.4% to 32.3%). The differences between K and Kx increased progressively over time. Transmembrane pressure was significantly correlated to the reduction with a Spearman's rho of 0.44 (p < 0.001). K significantly overestimates Kx during CRRT, and the difference increases progressively over time. Filters are recommended to be changed at 48-72 hours on a routine basis. PMID- 24172269 TI - A regional blood flow model for glucose and insulin kinetics during hemodialysis. AB - The distribution and elimination of a bolus of glucose injected during hemodialysis (HD) was examined using a distributed double-pool regional blood flow model. Intracorporeal glucose disposal was assumed as insulin-independent (lambda) in the central high-flow compartment comprising blood, brain, and internal organs, including pancreatic insulin secretion (a, C1) and hepatic insulin clearance (alpha). Insulin-dependent (gamma) glucose utilization was allocated to the low-flow system comprising muscle, skin, and bone. This model was compared with a compact single-pool model using the same model parameters except for the distribution volume (V). Six parameters (C1, a, alpha, lambda, gamma, and V) were identified from data obtained in seven nondiabetic patients (59-115 kg). The fraction Fd of glucose removed by HD significantly (p < 0.05) correlated with baseline glucose concentration Cg,0 (5.561 +/- 0.646 mmol/L; r = 0.535), extracorporeal clearance Kg (0.137 +/- 0.024 L/min; r = 0.537), a (0.278 +/- 0.095 L/mmol, r = -0.586), and lambda (0.099 +/- 0.078 L/min, r = -0.587). V was much larger in the double-compartment (17.8 +/- 5.1 L) than in the single compartment model (10.0 +/- 3.0 L). The modeled glucose compartment volumes could be of interest for fluid management in HD patients. The use of extracorporeal glucose disposal to detect impaired glucose utilization (a, lambda) remains to be validated in diabetic HD patients. PMID- 24172270 TI - Prolonged duration ECMO for ARDS: futility, native lung recovery, or transplantation? AB - Extracorporeal membrane oxygenation (ECMO) is recommended as a treatment modality for severe acute respiratory distress syndrome (PaO2/FiO2 <= 100 mm Hg with positive end-expiratory pressure >= 5 cm H2O) as defined by the Berlin definition. The reported usual duration of ECMO in these patients is 7-10 days. However, increasing reports of prolonged duration ECMO (>14 days) for respiratory failure document survival rates of 50-70% with native lung recovery, and ECMO bridge to lung transplantation has been performed at many centers. At present, there are no established national criteria for when to consider futility or lung transplantation in adult patients requiring ECMO for acute respiratory failure. We report a case of prolonged duration venovenous-ECMO (1,347 hours, 56.13 days), with native lung recovery and discuss treatment strategies to optimize native lung recovery in ECMO patients. The lung may have unexpected regenerative capacity with native lung recovery after prolonged mechanical support, similar to acute kidney injury and native renal recovery. We recommend redefining irreversible lung injury and futility in ECMO. PMID- 24172271 TI - Chitosan-cross-linked nanofibrous PHBV nerve guide for rat sciatic nerve regeneration across a defect bridge. AB - The aim of this study was to produce a chitosan-cross-linked nanofibrous biodegradable poly (3-hydroxybutyrate-co-3-hydroxyvalerate) nerve conduit. The artificial nerve scaffold designed by electrospinning method and cross-linked with chitosan by chemical method. Afterwards, the scaffolds were evaluated by microscopic, physical, and mechanical analyses and cell culture assays with Schwann cells. The conduits were implanted into a 10 mm gap in the sciatic nerves of the rats. Four months after surgery, the regenerated nerves were evaluated by macroscopic assessments and histology. This polymeric conduit had sufficiently good mechanical properties to serve as a nerve guide. Cellular experiments showed a better cell adhesion, growth, and proliferation inside the cross-linked nanofibrous scaffolds compared with un-cross-linked ones, also Schwann cells well attached on chitosan-cross-linked nanofibrous surface. The in vivo results demonstrated that in the nanofibrous graft, the sciatic nerve trunk had been reconstructed with restoration of nerve continuity and formatted nerve fibers with myelination. This neural conduit appears to have the right organization for testing in vivo nerve tissue engineering studies. PMID- 24172272 TI - Left ventricular assist device inflow cannula thrombus: characterization with two dimensional transthoracic echocardiography. AB - Thrombotic complications are inherent to current generation nonpulsatile left ventricular assist devices. The clinical expression of device thrombosis ranges from catastrophic failure to protracted and indolent. We report the case of a 79 year-old patient who received a left ventricular assist device as destination therapy and presented only with vague clinical symptoms. He was found to have a large thrombus in close proximity with the inflow cannula at the left ventricular apex, raising the question of mechanical obstruction. We describe the step-by step contrast-enhanced two-dimensional transthoracic echocardiographic examination which allowed to obtain diagnostic acoustic tomograms of the inflow cannula and obviated the need for any additional imaging modalities. Transthoracic echocardiography (TTE) is the most common imaging modality used in the clinical follow-up of left ventricular assist device recipients. A frequent clinical indication for TTE is to exclude left ventricular apical thrombus near the inflow cannula. Imaging of the inflow cannula at the left ventricular apex in the traditional apical 4 chamber, apical 2 chamber, and parasternal long axis views is challenging by TTE mainly because of poor acoustic windows, image artifacts, large body habitus, and operator experience. PMID- 24172273 TI - Left thoracotomy HeartWare implantation with outflow graft anastomosis to the descending aorta: a simplified bridge for patients with multiple previous sternotomies. AB - Advances in mechanical circulatory support have been critical in bridging patients awaiting heart transplantation. In addition, improvement in device durability has enabled left ventricular assist device therapy to be applied as destination therapy in those not felt to be transplant candidate. Because of the increasing complexity of patients, there continues to be a need for alternative strategies for device implantation to bridge high-risk patients awaiting heart transplantation, wherein the risks of numerous previous sternotomies may be prohibitive. We present a unique technique for placement of the HeartWare ventricular assist device via left anterior thoracotomy to the descending aorta in a patient awaiting heart transplantation with a history of multiple previous sternotomies. PMID- 24172274 TI - A crisis of the heart: an acute reversible cardiomyopathy bridged to recovery in a patient with Addison's disease. AB - Primary adrenal insufficiency or Addison's disease is a rare disorder often difficult to diagnose on presentation by the nature of its associated nonspecific symptoms, such as nausea or weakness. Cardiovascular complications of the condition are usually limited to hypovolemic hypotension; however, we highlight here a rare, dramatic case of a fulminant adrenal crisis in a young man primarily marked by acute biventricular systolic failure and cardiogenic shock. The patient was successfully treated with corticosteroid replacement and bridged with temporary mechanical circulatory support to eventual complete the recovery of native myocardial function. PMID- 24172275 TI - Respiratory dialysis for avoidance of intubation in acute exacerbation of COPD. AB - Noninvasive ventilatory support has become the standard of care for patients with chronic obstructive pulmonary disease (COPD) experiencing exacerbations leading to acute hypercapnic respiratory failure. Despite advances in the use of noninvasive ventilation and the associated improvement in survival, as many as 26% of these patients fail noninvasive support and have a higher subsequent risk of mortality than patients treated initially with invasive mechanical ventilation. We report the use of a novel device to avoid invasive mechanical ventilation in two patients who were experiencing acute hypercapnic respiratory failure because of an exacerbation of COPD and were deteriorating, despite support with noninvasive ventilation. This device provided partial extracorporeal carbon dioxide removal at dialysis-like settings through a single 15.5 Fr venovenous cannula inserted percutaneously through the right femoral vein. The primary results were rapid reduction in arterial carbon dioxide and correction of pH. Neither patient required intubation, despite imminent failure of noninvasive ventilation before initiation of extracorporeal support. Both patients were weaned from noninvasive and extracorporeal support within 3 days. We concluded that low-flow extracorporeal carbon dioxide removal, or respiratory dialysis, is a viable option for avoiding intubation and invasive mechanical ventilation in patients with COPD experiencing an exacerbation who are failing noninvasive ventilatory support. PMID- 24172276 TI - Better lactate clearance associated with good neurologic outcome in survivors who treated with therapeutic hypothermia after out-of-hospital cardiac arrest. AB - INTRODUCTION: Several methods have been proposed to evaluate neurological outcome in out-of-hospital cardiac arrest (OHCA) patients. Blood lactate has been recognized as a reliable prognostic marker for trauma, sepsis, or cardiac arrest. The objective of this study was to examine the association between initial lactate level or lactate clearance and neurologic outcome in OHCA survivors who were treated with therapeutic hypothermia. METHODS: This retrospective cohort study included patients who underwent protocol-based 24-hour therapeutic hypothermia after OHCA between January 2010 and March 2012. Serum lactate levels were measured at the start of therapy (0 hours), and after 6 hours, 12 hours, 24 hours, 48 hours and 72 hours. The 6 hour and 12 hour lactate clearance were calculated afterwards. Patients' neurologic outcome was assessed at one month after cardiac arrest; good neurological outcome was defined as Cerebral Performance Category one or two. The primary outcome was an association between initial lactate level and good neurologic outcome. The secondary outcome was an association between lactate clearance and good neurologic outcome in patients with initial lactate level >2.5 mmol/l. RESULTS: Out of the 76 patients enrolled, 34 (44.7%) had a good neurologic outcome. The initial lactate level showed no significant difference between good and poor neurologic outcome groups (6.07 +/-4 .09 mmol/L vs 7.13 +/- 3.99 mmol/L, P = 0.42), However, lactate levels at 6 hours, 12 hours, 24 hours, and 48 hours in the good neurologic outcome group were lower than in the poor neurologic outcome group (3.81 +/- 2.81 vs 6.00 +/- 3.22 P <0.01, 2.95 +/- 2.07 vs 5.00 +/- 3.49 P <0.01, 2.17 +/- 1.24 vs 3.86 +/- 3.92 P <0.01, 1.57 +/- 1.02 vs 2.21 +/- 1.35 P = 0.03, respectively). The secondary analysis showed that the 6-hour and 12-hour lactate clearance was higher for good neurologic outcome patients (35.3 +/- 34.6% vs 6.89 +/- 47.4% P = 0.01, 54.5 +/- 23.7% vs 25.6 +/- 43.7% P <0.01, respectively). After adjusting for potential confounding variables, the 12-hour lactate clearance still showed a statistically significant difference (P = 0.02). CONCLUSION: The lactate clearance rate, and not the initial lactate level, was associated with neurological outcome in OHCA patients after therapeutic hypothermia. PMID- 24172277 TI - Anaemia in inflammatory bowel disease: a population-based 10-year follow-up. AB - BACKGROUND: The point prevalence estimates of anaemia in patients with inflammatory bowel disease (IBD) range between 6% and 74%. The variation is probably due to differences in the definition of anaemia and the study populations. AIM: To retrospectively determine the prevalence of anaemia at diagnosis and at the 1-, 5- and 10-year follow-ups in patients with IBD from a prospectively followed, population-based inception cohort (the IBSEN Study). To compare the prevalence of anaemia after a 10-year disease course with the prevalence of anaemia in the background population, and to assess clinical factors associated with anaemia at diagnosis and during follow-up. METHODS: Newly diagnosed IBD patients were included in a population-based, prospective cohort. Follow-up was performed at 1, 5 and 10 years. All visits included clinical examinations and blood samples. Anaemia was defined according to the WHO. RESULTS: A total of 756 patients (UC, n = 519 and CD, n = 237) were included; 48.8% of CD and 20.2% of UC patients were anaemic at diagnosis (P < 0.001). The proportion of patients with anaemia decreased during the disease course in all patients, except in women with CD. After 10 years of disease, the relative risk for anaemia was increased in all groups, except for women with UC. The variables associated with anaemia were generally unchanged during the disease course, and elevated CRP was the strongest predictor of risk. CONCLUSIONS: Anaemia was more common in CD than in UC. The prevalence of anaemia decreased during the disease course. Women with CD were at high risk for anaemia. Elevated CRP was independently associated with anaemia. PMID- 24172278 TI - Spontaneous cholecystocutaneous fistula by gallstone erosion into abdominal wall. PMID- 24172279 TI - MRI findings and early diagnosis of general paresis of the insane. AB - The objective of this study was to improve the knowledge of the clinical and MRI presentation of general paresis of the insane (GPI) and achieve its early diagnosis. Fifteen patients with GPI were gathered. Their clinical data and brain MRI information were analyzed. The age range was 33-62 years (mean: 48.8 years). The disease lasted 34 days-28 months (mean: 10.87 months). Treponema pallidum hemagglutination assays (TPHAs) on the cerebrospinal fluid (CSF) and sera were positive. All patients were human immunodeficiency virus (HIV) negative and primarily showed progressive cognitive impairment, mostly accompanied with emotional disturbance and psychosis. The accompanying symptoms included epilepsy (n = 7), ataxia (n = 5), cerebral vascular disease (n = 3), and limbs tremor (n = 2). Typical Argyll Robertson's pupil was observed in two cases. A CSF examination showed elevated white blood cell (WBC) and protein level. Purely cerebral atrophy was found in three cases. Abnormal high signals were found in nine cases in different brain area, mainly in bilateral temporal, insular, and frontal lobes and hippocampus in T2-weighted and fluid-attenuated inversion recovery (FLAIR), which was accompanied by cerebral and/or hippocampus atrophy. Purely atrophy of bilateral or unilateral hippocampus was found in two cases. Cerebral infarction lesions were found in three cases. Contrary to the previous reports, the hippocampal atrophy and bilateral abnormal signals of hippocampus and temporal lobe in brain MRI were more common in cases with GPI. Abnormal signals were probably related to proliferation of glial cells rather than cytotoxic edema. The pathogenesis of the abnormal signals needs to be further explored. General paresis of the insane has a wide variety of central nervous system manifestations, either clinically or neuroradiologically. Identification of these presentations could be important for early diagnosis. PMID- 24172280 TI - Potential application of electronic olfaction systems in feedstuffs analysis and animal nutrition. AB - Electronic Olfaction Systems (EOSs) based on a variety of gas-sensing technologies have been developed to simulate in a simplified manner animal olfactory sensing systems. EOSs have been successfully applied to many applications and fields, including food technology and agriculture. Less information is available for EOS applications in the feed technology and animal nutrition sectors. Volatile Organic Compounds (VOCs), which are derived from both forages and concentrate ingredients of farm animal rations, are considered and described in this review as olfactory markers for feedstock quality and safety evaluation. EOS applications to detect VOCs from feedstuffs (as analytical matrices) are described, and some future scenarios are hypothesised. Furthermore, some EOS applications in animal feeding behaviour and organoleptic feed assessment are also described. PMID- 24172281 TI - Hyperspectral proximal sensing of Salix Alba trees in the Sacco river valley (Latium, Italy). AB - Recent developments in hardware and software have increased the possibilities and reduced the costs of hyperspectral proximal sensing. Through the analysis of high resolution spectroscopic measurements at the laboratory or field scales, this monitoring technique is suitable for quantitative estimates of biochemical and biophysical variables related to the physiological state of vegetation. Two systems for hyperspectral imaging have been designed and developed at DICEA Sapienza University of Rome, one based on the use of spectrometers, the other on tunable interference filters. Both systems provide a high spectral and spatial resolution with low weight, power consumption and cost. This paper describes the set-up of the tunable filter platform and its application to the investigation of the environmental status of the region crossed by the Sacco river (Latium, Italy). This was achieved by analyzing the spectral response given by tree samples, with roots partly or wholly submerged in the river, located upstream and downstream of an industrial area affected by contamination. Data acquired is represented as reflectance indices as well as reflectance values. Broadband and narrowband indices based on pigment content and carotenoids vs. chlorophyll content suggest tree samples located upstream of the contaminated area are 'healthier' than those downstream. PMID- 24172282 TI - Combining electrochemical impedance spectroscopy and surface plasmon resonance into one simultaneous read-out system for the detection of surface interactions. AB - In this article we describe the integration of impedance spectroscopy (EIS) and surface plasmon resonance (SPR) into one surface analytic device. A polydimethylsiloxane (PDMS) flow cell is created, matching the dimensions of a commercially available sensor chip used for SPR measurements. This flow cell allowed simultaneous measurements between an EIS and a SPR setup. After a successful integration, a proof of principle study was conducted to investigate any signs of interference between the two systems during a measurement. The flow cell was rinsed with 10 mM Tris-HCl and 1* PBS buffer in an alternating manner, while impedance and shifts of the resonance angle were monitored. After achieving a successful proof of principle, a usability test was conducted. It was assessed whether simultaneous detection occurred when: (i) Protein A is adsorbed to the gold surface of the chip; (ii) The non-occupied zone is blocked with BSA molecules and (iii) IgG1 is bound to the Protein A. The results indicate a successful merge between SPR and EIS. PMID- 24172283 TI - Discriminating crop, weeds and soil surface with a terrestrial LIDAR sensor. AB - In this study, the evaluation of the accuracy and performance of a light detection and ranging (LIDAR) sensor for vegetation using distance and reflection measurements aiming to detect and discriminate maize plants and weeds from soil surface was done. The study continues a previous work carried out in a maize field in Spain with a LIDAR sensor using exclusively one index, the height profile. The current system uses a combination of the two mentioned indexes. The experiment was carried out in a maize field at growth stage 12-14, at 16 different locations selected to represent the widest possible density of three weeds: Echinochloa crus-galli (L.) P.Beauv., Lamium purpureum L., Galium aparine L.and Veronica persica Poir.. A terrestrial LIDAR sensor was mounted on a tripod pointing to the inter-row area, with its horizontal axis and the field of view pointing vertically downwards to the ground, scanning a vertical plane with the potential presence of vegetation. Immediately after the LIDAR data acquisition (distances and reflection measurements), actual heights of plants were estimated using an appropriate methodology. For that purpose, digital images were taken of each sampled area. Data showed a high correlation between LIDAR measured height and actual plant heights (R2 = 0.75). Binary logistic regression between weed presence/absence and the sensor readings (LIDAR height and reflection values) was used to validate the accuracy of the sensor. This permitted the discrimination of vegetation from the ground with an accuracy of up to 95%. In addition, a Canonical Discrimination Analysis (CDA) was able to discriminate mostly between soil and vegetation and, to a far lesser extent, between crop and weeds. The studied methodology arises as a good system for weed detection, which in combination with other principles, such as vision-based technologies, could improve the efficiency and accuracy of herbicide spraying. PMID- 24172284 TI - Localized surface plasmon resonance with five-branched gold nanostars in a plastic optical fiber for bio-chemical sensor implementation. AB - In this paper a refractive index sensor based on localized surface plasmon resonance (LSPR) in a Plastic Optical Fiber (POF), is presented and experimentally tested. LSPR is achieved exploiting five-branched gold nanostars (GNS) obtained using Triton X-100 in a seed-growth synthesis. They have the uncommon feature of three localized surface plasmon resonances. The strongest LSPRs fall in two ranges, one in the 600-900 nm range (LSPR 2) and the other one in the 1,100-1,600 nm range (LSPR 3), both sensible to refractive index changes. Anyway, due to the extremely strong attenuation (>10(2) dB/m) of the employed POF in the 1,100-1,600 nm range, only LSPR 2 will be exploited for refractive index change measurements, useful for bio-chemical sensing applications, as a proof of principle of the possibility of realizing a compact, low cost and easy-to-use GNS based device. PMID- 24172285 TI - On the use of a low-cost thermal sensor to improve Kinect people detection in a mobile robot. AB - Detecting people is a key capability for robots that operate in populated environments. In this paper, we have adopted a hierarchical approach that combines classifiers created using supervised learning in order to identify whether a person is in the view-scope of the robot or not. Our approach makes use of vision, depth and thermal sensors mounted on top of a mobile platform. The set of sensors is set up combining the rich data source offered by a Kinect sensor, which provides vision and depth at low cost, and a thermopile array sensor. Experimental results carried out with a mobile platform in a manufacturing shop floor and in a science museum have shown that the false positive rate achieved using any single cue is drastically reduced. The performance of our algorithm improves other well-known approaches, such as C4 and histogram of oriented gradients (HOG). PMID- 24172286 TI - A microfluidic bioreactor with in situ SERS imaging for the study of controlled flow patterns of biofilm precursor materials. AB - A microfluidic bioreactor with an easy to fabricate nano-plasmonic surface is demonstrated for studies of biofilms and their precursor materials via Surface Enhanced Raman Spectroscopy (SERS). The system uses a novel design to induce sheath flow confinement of a sodium citrate biofilm precursor stream against the SERS imaging surface to measure spatial variations in the concentration profile. The unoptimised SERS enhancement was approximately 2.5 * 10(4), thereby improving data acquisition time, reducing laser power requirements and enabling a citrate detection limit of 0.1 mM, which was well below the concentrations used in biofilm nutrient solutions. The flow confinement was observed by both optical microscopy and SERS imaging with good complementarity. We demonstrate the new bioreactor by growing flow-templated biofilms on the microchannel wall. This work opens the way for in situ spectral imaging of biofilms and their biochemical environment under dynamic flow conditions. PMID- 24172287 TI - Fabrication and characterization of CMOS-MEMS magnetic microsensors. AB - This study investigates the design and fabrication of magnetic microsensors using the commercial 0.35 MUm complementary metal oxide semiconductor (CMOS) process. The magnetic sensor is composed of springs and interdigitated electrodes, and it is actuated by the Lorentz force. The finite element method (FEM) software CoventorWare is adopted to simulate the displacement and capacitance of the magnetic sensor. A post-CMOS process is utilized to release the suspended structure. The post-process uses an anisotropic dry etching to etch the silicon dioxide layer and an isotropic dry etching to remove the silicon substrate. When a magnetic field is applied to the magnetic sensor, it generates a change in capacitance. A sensing circuit is employed to convert the capacitance variation of the sensor into the output voltage. The experimental results show that the output voltage of the magnetic microsensor varies from 0.05 to 1.94 V in the magnetic field range of 5-200 mT. PMID- 24172288 TI - A biometric authentication model using hand gesture images. AB - A novel hand biometric authentication method based on measurements of the user's stationary hand gesture of hand sign language is proposed. The measurement of hand gestures could be sequentially acquired by a low-cost video camera. There could possibly be another level of contextual information, associated with these hand signs to be used in biometric authentication. As an analogue, instead of typing a password 'iloveu' in text which is relatively vulnerable over a communication network, a signer can encode a biometric password using a sequence of hand signs, 'i' , 'l' , 'o' , 'v' , 'e' , and 'u'. Subsequently the features from the hand gesture images are extracted which are integrally fuzzy in nature, to be recognized by a classification model for telling if this signer is who he claimed himself to be, by examining over his hand shape and the postures in doing those signs. It is believed that everybody has certain slight but unique behavioral characteristics in sign language, so are the different hand shape compositions. Simple and efficient image processing algorithms are used in hand sign recognition, including intensity profiling, color histogram and dimensionality analysis, coupled with several popular machine learning algorithms. Computer simulation is conducted for investigating the efficacy of this novel biometric authentication model which shows up to 93.75% recognition accuracy. PMID- 24172289 TI - Liver protective effect of ursodeoxycholic acid includes regulation of ADAM17 activity. AB - BACKGROUND: Ursodeoxycholic acid (UDCA) is used to treat primary biliary cirrhosis, intrahepatic cholestasis, and other cholestatic conditions. Although much has been learned about the molecular basis of the disease pathophysiology, our understanding of the effects of UDCA remains unclear. Possibly underlying its cytoprotective, anti-apoptotic, anti-oxidative effects, UDCA was reported to regulate the expression of TNFalpha and other inflammatory cytokines. However, it is not known if this effect involves also modulation of ADAM family of metalloproteinases, which are responsible for release of ectodomains of inflammatory cytokines from the cell surface. We hypothesized that UDCA modulates ADAM17 activity, resulting in amelioration of cholestasis in a murine model of bile duct ligation (BDL). METHODS: The effect of UDCA on ADAM17 activity was studied using the human liver hepatocellular carcinoma cell line HepG2. Untransfected cells or cells ectopically expressing human ADAM17 were cultured with or without UDCA and further activated using phorbol-12-myristate-13-acetate (PMA). The expression and release of ADAM17 substrates, TNFalpha, TGFalpha, and c Met receptor (or its soluble form, sMet) were evaluated using ELISA and quantitative real-time (qRT) PCR. Immunoblotting analyses were conducted to evaluate expression and activation of ADAM17 as well as the level of ERK1/2 phosphorylation after UDCA treatment. The regulation of tissue inhibitor of metalloproteinases-1 (TIMP-1) by UDCA was studied using zymography and qRT-PCR. A mouse model of acute cholestasis was induced by common BDL technique, during which mice received daily orogastric gavage with either UDCA or vehicle only. Liver injury was quantified using alkaline phosphatase (ALP), relative liver weight, and confirmed by histological analysis. ADAM17 substrates in sera were assessed using a bead multiplex assay. RESULTS: UDCA decreases amount of shed TNFalpha, TGFalpha, and sMet in cell culture media and the phosphorylation of ERK1/2. These effects are mediated by the reduction of ADAM17 activity in PMA stimulated cells although the expression ADAM17 is not affected. UDCA reduced the level of the mature form of ADAM17. Moreover, UDCA regulates the expression of TIMP-1 and gelatinases activity in PMA stimulated cells. A BDL-induced acute cholangitis model was characterized by increased relative liver weight, serum levels of ALP, sMet, and loss of intracellular glycogen. UDCA administration significantly decreased ALP and sMet levels, and reduced relative liver weight. Furthermore, hepatocytes of UDCA-treated animals retained their metabolic activity as evidenced by the amount of glycogen storage. CONCLUSIONS: The beneficial effect of UDCA appears to be mediated in part by the inhibition of ADAM17 activation and, thus, the release of TNFalpha, a strong pro-inflammatory factor. The release of other ADAM17 substrates, TGFalpha and sMet, are also regulated this way, pointing to a general impact on the release of ADAM17 substrates, which are pivotal for liver regeneration and function. In parallel, UDCA upregulates TIMP-1 that in turn inhibits matrix metalloproteinases, which destroy the hepatic ECM in diseased liver. This control of extracellular matrix turnover represents an additional beneficial path of UDCA treatment. PMID- 24172290 TI - Salt reduction in the United Kingdom: a successful experiment in public health. AB - The United Kingdom has successfully implemented a salt reduction programme. We carried out a comprehensive analysis of the programme with an aim of providing a step-by-step guide of developing and implementing a national salt reduction strategy, which other countries could follow. The key components include (1) setting up an action group with strong leadership and scientific credibility; (2) determining salt intake by measuring 24-h urinary sodium, identifying the sources of salt by dietary record; (3) setting a target for population salt intake and developing a salt reduction strategy; (4) setting progressively lower salt targets for different categories of food, with a clear time frame for the industry to achieve; (5) working with the industry to reformulate food with less salt; (6) engaging and recruiting of ministerial support and potential threat of regulation by the Department of Health (DH); (7) clear nutritional labelling; (8) consumer awareness campaign; and (9) monitoring progress by (a) frequent surveys and media publicity of salt content in food, including naming and shaming, (b) repeated 24-h urinary sodium at 3-5 year intervals. Since the salt reduction programme started in 2003/2004, significant progress has been made as demonstrated by the reductions in salt content in many processed food and a 15% reduction in 24-h urinary sodium over 7 years (from 9.5 to 8.1 g per day, P<0.05). The UK salt reduction programme reduced the population's salt intake by gradual reformulation on a voluntary basis. Several countries are following the United Kingdom's lead. The challenge now is to engage other countries with appropriate local modifications. A reduction in salt intake worldwide will result in major public health improvements and cost savings. PMID- 24172291 TI - The role of L-arginine in the prevention and treatment of pre-eclampsia: a systematic review of randomised trials. AB - Pre-eclampsia is a significant health issue in pregnancy, complicating between 2 8% of pregnancies. L-arginine is an important mediator of vasodilation with a potential preventative role in pregnancy related hypertensive diseases. We aimed to systematically review randomised trials in the literature assessing the role of L-arginine in prevention and treatment of pre-eclampsia. We searched the Cochrane Controlled Trials Register, PUBMED, and the Australian and International Clinical Trials Registry, to identify randomised trials involving pregnant women where L-arginine was administered for pre-eclampsia to improve maternal and infant health outcomes. We identified eight randomised trials, seven of which were included. The methodological quality was fair, with a combined sample size of 884 women. For women at risk of pre-eclampsia, L-arginine was associated with a reduction in pre-eclampsia (RR: 0.34, 95% CI: 0.21-0.55), when compared with placebo and a reduction in risk of preterm birth (RR: 0.48 and 95% CI: 0.28 to 0.81). For women with established hypertensive disease, L-arginine was associated with a reduction in pre-eclampsia (RR: 0.21; 95% CI: 0.05-0.98). L-arginine may have a role in the prevention and/or treatment of pre-eclampsia. Further well designed and adequately powered trials are warranted, both in women at risk of pre-eclampsia and in women with established disease. PMID- 24172292 TI - Exercise training improves endothelial function in resistance arteries of young prehypertensives. AB - Prehypertension is associated with reduced conduit artery endothelial function and perturbation of oxidant/antioxidant status. It is unknown whether endothelial dysfunction persists to resistance arteries and whether exercise training affects oxidant/antioxidant balance in young prehypertensives. We examined resistance artery function using venous occlusion plethysmography measurement of forearm (FBF) and calf blood flow (CBF) at rest and during reactive hyperaemia (RH), as well as lipid peroxidation (8-iso-PGF2alpha) and antioxidant capacity (Trolox equivalent antioxidant capacity; TEAC) before and after exercise intervention or time control. Forty-three unmedicated prehypertensive and 15 matched normotensive time controls met screening requirements and participated in the study (age: 21.1+/-0.8 years). Prehypertensive subjects were randomly assigned to resistance exercise training (PHRT; n=15), endurance exercise training (PHET; n=13) or time control groups (PHTC; n=15). Treatment groups exercised 3 days per week for 8 weeks. Peak and total FBF were lower in prehypertensives than normotensives (12.7+/-1.2 ml min(-1) per100 ml tissue and 89.1+/-7.7 ml min(-1) per 100 ml tissue vs 16.3+/-1.0 ml min(-1) per 100 ml tissue and 123.3+/-6.4 ml min(-1) per 100 ml tissue, respectively; P<0.05). Peak and total CBF were lower in prehypertensives than normotensives (15.3+/-1.2 ml min(-1) per 100 ml tissue and 74+/-8.3 ml min(-1) per 100 ml tissue vs 20.9+/-1.4 ml min(-1) per 100 ml tissue and 107+/-9.2 ml min(-1) per 100 ml tissue, respectively; P<0.05). PHRT and PHET improved humoral measures of TEAC (+24 and +30%) and 8-iso-PGF2alpha (-43 and 40%, respectively; P < or = 0.05). This study provides evidence that young prehypertensives exhibit reduced resistance artery endothelial function and that short-term (8 weeks) resistance or endurance training are effective in improving resistance artery endothelial function and oxidant/antioxidant balance in young prehypertensives. PMID- 24172294 TI - Probing Majorana modes in the tunneling spectra of a resonant level. AB - Unambiguous identification of Majorana physics presents an outstanding problem whose solution could render topological quantum computing feasible. We develop a numerical approach to treat finite-size superconducting chains supporting Majorana modes, which is based on iterative application of a two-site Bogoliubov transformation. We demonstrate the applicability of the method by studying a resonant level attached to the superconductor subject to external perturbations. In the topological phase, we show that the spectrum of a single resonant level allows us to distinguish peaks coming from Majorana physics from the Kondo resonance. PMID- 24172293 TI - The relationship of brachial-ankle pulse wave velocity to future cardiovascular disease events in the general Japanese population: the Takashima Study. AB - Brachial-ankle pulse wave velocity (baPWV) is a non-invasive measure of arterial stiffness obtained using an automated system. Although baPWVs have been widely used as a non-invasive marker for evaluation of arterial stiffness, evidence for the prognostic value of baPWV in the general population is scarce. In this study, we assessed the association between baPWV and future cardiovascular disease (CVD) incidence in a Japanese population. From 2002 to 2009, baPWV was measured in a total of 4164 men and women without a history of CVD, and they were followed up until the end of 2009 with a median follow-up period of 6.5 years. Hazard ratios (HRs) for CVD incidence according to baPWV levels were calculated using a Cox proportional hazards model adjusted for potential confounding factors, including seated or supine blood pressure (BP). During the follow-up period, we observed 40 incident cases of CVD. In multivariable-adjusted model, baPWV as a continuous variable was not significantly associated with future CVD risk after adjustment for supine BP. However, compared with lower baPWV category (<18 m s(-1)), higher baPWV (< or = 18.0 m s(-1)) was significantly associated with an increased CVD risk (HR: 2.70, 95% confidence interval: 1.18-6.19). Higher baPWV (< or = 18.0 m s(-1)) would be an independent predictor of future CVD event in the general Japanese population. PMID- 24172295 TI - Interactions of black tea polyphenols with human gut microbiota: implications for gut and cardiovascular health. AB - Epidemiologic studies have convincingly associated consumption of black tea with reduced cardiovascular risk. Research on the bioactive molecules has traditionally been focused on polyphenols, such as catechins. Black tea polyphenols (BTPs), however, mainly consist of high-molecular-weight species that predominantly persist in the colon. There, they can undergo a wide range of bioconversions by the resident colonic microbiota but can in turn also modulate gut microbial diversity. The impact of BTPs on colon microbial composition can now be assessed by microbiomics technologies. Novel metabolomics platforms coupled to de novo identification are currently available to cover the large diversity of BTP bioconversions by the gut microbiota. Nutrikinetic modeling has been proven to be critical for defining nutritional phenotypes related to gut microbial bioconversion capacity. The bioactivity of circulating metabolites has been studied only to a certain extent. Bioassays dedicated to specific aspects of gut and cardiovascular health have been used, although often at physiologically irrelevant concentrations and with limited coverage of relevant metabolite classes and their conjugated forms. Evidence for cardiovascular benefits of BTPs points toward antiinflammatory and blood pressure-lowering properties and improvement in platelet and endothelial function for specific microbial bioconversion products. Clearly, more work is needed to fill in existing knowledge gaps and to assess the in vitro and in vivo bioactivity of known and newly identified BTP metabolites. It is also of interest to assess how phenotypic variation in gut microbial BTP bioconversion capacity relates to gut and cardiovascular health predisposition. PMID- 24172296 TI - Tea and bone health: steps forward in translational nutrition. AB - Osteoporosis is a major health problem in the aging population worldwide. Cross sectional and retrospective evidence indicates that tea consumption may be a promising approach in mitigating bone loss and in reducing risk of osteoporotic fractures among older adults. Tea polyphenols enhance osteoblastogenesis and suppress osteoclastogenesis in vitro. Animal studies reveal that intake of tea polyphenols have pronounced positive effects on bone as shown by higher bone mass and trabecular bone volume, number, and thickness and lower trabecular separation via increasing bone formation and inhibition of bone resorption, resulting in greater bone strength. These osteoprotective effects appear to be mediated through antioxidant or antiinflammatory pathways along with their downstream signaling mechanisms. A short-term clinical trial of green tea polyphenols has translated the findings from ovariectomized animals to postmenopausal osteopenic women through evaluation of bioavailability, safety, bone turnover markers, muscle strength, and quality of life. For future studies, preclinical animal studies to optimize the dose of tea polyphenols for maximum osteoprotective efficacy and a follow-up short-term dose-response trial in postmenopausal osteopenic women are necessary to inform the design of randomized controlled studies in at-risk populations. Advanced imaging technology should also contribute to determining the effective dose of tea polyphenols in achieving better bone mass, microarchitecture integrity, and bone strength, which are critical steps for translating the putative benefit of tea consumption in osteoporosis management into clinical practice and dietary guidelines. PMID- 24172297 TI - Effects of anti-obesity drugs, diet, and exercise on weight-loss maintenance after a very-low-calorie diet or low-calorie diet: a systematic review and meta analysis of randomized controlled trials. AB - BACKGROUND: Weight-loss maintenance remains a major challenge in obesity treatment. OBJECTIVE: The objective was to evaluate the effects of anti-obesity drugs, diet, or exercise on weight-loss maintenance after an initial very-low calorie diet (VLCD)/low-calorie diet (LCD) period (<1000 kcal/d). DESIGN: We conducted a systematic review by using MEDLINE, the Cochrane Controlled Trial Register, and EMBASE from January 1981 to February 2013. We included randomized controlled trials that evaluated weight-loss maintenance strategies after a VLCD/LCD period. Two authors performed independent data extraction by using a predefined data template. All pooled analyses were based on random-effects models. RESULTS: Twenty studies with a total of 27 intervention arms and 3017 participants were included with the following treatment categories: anti-obesity drugs (3 arms; n = 658), meal replacements (4 arms; n = 322), high-protein diets (6 arms; n = 865), dietary supplements (6 arms; n = 261), other diets (3 arms; n = 564), and exercise (5 arms; n = 347). During the VLCD/LCD period, the pooled mean weight change was -12.3 kg (median duration: 8 wk; range 3-16 wk). Compared with controls, anti-obesity drugs improved weight-loss maintenance by 3.5 kg [95% CI: 1.5, 5.5 kg; median duration: 18 mo (12-36 mo)], meal replacements by 3.9 kg [95% CI: 2.8, 5.0 kg; median duration: 12 mo (10-26 mo)], and high-protein diets by 1.5 kg [95% CI: 0.8, 2.1 kg; median duration: 5 mo (3-12 mo)]. Exercise [0.8 kg; 95% CI: -1.2, 2.8 kg; median duration: 10 mo (6-12 mo)] and dietary supplements [0.0 kg; 95% CI: -1.4, 1.4 kg; median duration: 3 mo (3-14 mo)] did not significantly improve weight-loss maintenance compared with control. CONCLUSION: Anti-obesity drugs, meal replacements, and high-protein diets were associated with improved weight-loss maintenance after a VLCD/LCD period, whereas no significant improvements were seen for dietary supplements and exercise. PMID- 24172298 TI - Tea and flavonoids: where we are, where to go next. AB - There is a need to evaluate the evidence about the health effects of tea flavonoids and to provide valid, specific, and actionable tea consumption information to consumers. Emerging evidence suggests that the flavonoids in tea may be associated with beneficial health outcomes, whereas the benefits and risks of tea extracts and supplements are less well known. The next steps in developing tea science should include a focus on the most promising leads, such as reducing the risk of cardiovascular disease and stroke, rather than pursuing smaller, more diffuse studies of many different health outcomes. Future tea research should also include the use of common reference standards, better characterization of intervention products, and application of batteries of biomarkers of intakes and outcomes across studies, which will allow a common body of evidence to be developed. Mechanistic studies should determine which tea bioactive constituents have effects, whether they act alone or in combination, and how they influence health. Clinical studies should use well-characterized test products, better descriptions of baseline diets, and validated biomarkers of intake and disease risk reduction. There should be more attention to careful safety monitoring and adverse event reporting. Epidemiologic investigations should be of sufficient size and duration to detect small effects, involve populations most likely to benefit, use more complete tea exposure assessment, and include both intermediary markers of risk as well as morbidity and mortality outcomes. The construction of a strong foundation of scientific evidence on tea and health outcomes is essential for developing more specific and actionable messages on tea for consumers. PMID- 24172299 TI - Cellular targets for the beneficial actions of tea polyphenols. AB - Green and black teas contain different biologically active polyphenolic compounds that might offer protection against a variety of human diseases. Although promising experimental and clinical data have shown protective effects, limited information is available on how these beneficial effects of tea polyphenols are mediated at the cellular level. Evidence is accumulating that catechins in green tea as well as theaflavins and thearubigins from black tea are the substances responsible for the physiologic effects of tea in vitro. The green tea catechin epigallocatechin-3-gallate (EGCG) is generally considered to be the biologically most active compound in vitro. The changes in the activities of various protein kinases, growth factors, and transcription factors represent a common mechanism involved in cellular effects of tea polyphenols. In addition to modification of intracellular signaling by activation of cellular receptors, it was shown that, at least for EGCG, tea polyphenols can enter the cells and directly interact with their molecular targets within cells. There, they frequently result in opposite effects in primary compared with tumor cells. Although tea polyphenols were long regarded as antioxidants, research in recent years has uncovered their prooxidant properties. The use of high nonphysiologic concentrations in many cell culture studies raises questions about the biological relevance of the observed effects for the in vivo situation. Efforts to attribute functional effects in vivo to specific molecular targets at the cellular level are still ongoing. PMID- 24172300 TI - Does tea prevent cancer? Evidence from laboratory and human intervention studies. AB - Tea (Camellia sinensis) is a widely consumed beverage and has been extensively studied for its cancer-preventive activity. Both the polyphenolic constituents as well as the caffeine in tea have been implicated as potential cancer-preventive compounds; the relative importance seems to depend on the cancer type. Green tea and the green tea catechin have been shown to inhibit tumorigenesis at a number of organ sites and to be effective when administered either during the initiation or postinitiation phases of carcinogenesis. Black tea, although not as well studied as green tea, has also shown cancer-preventive effects in laboratory models. A number of potential mechanisms have been proposed to account for the cancer-preventive effects of tea, including modulation of phase II metabolism, alterations in redox environment, inhibition of growth factor signaling, and others. In addition to the laboratory studies, there is a growing body of human intervention studies suggesting that tea can slow cancer progression and modify biomarkers relevant to carcinogenesis. Although available data are promising, many questions remain with regard to the dose-response relations of tea constituents in various models, the primary mechanisms of action, and the potential for combination chemoprevention strategies that involve tea as well as other dietary or pharmaceutical agents. The present review examines the available data from laboratory animal and human intervention studies on tea and cancer prevention. These data were evaluated, and areas for further research are identified. PMID- 24172301 TI - Catechin- and caffeine-rich teas for control of body weight in humans. AB - Maintaining the level of daily energy expenditure during weight loss and weight maintenance is as important as maintaining satiety while decreasing energy intake. In this context, different catechin- and caffeine-rich teas (CCRTs), such as green, oolong, and white teas, as well as caffeine have been proposed as tools for maintaining or enhancing energy expenditure and for increasing fat oxidation. Tea polyphenols have been proposed to counteract the decrease in metabolic rate that is usually present during weight loss. Their effects may be of particular importance during weight maintenance after weight loss. Although the thermogenic effect of CCRT has the potential to produce significant effects on these metabolic targets as well as on fat absorption and energy intake, possibly via its impact on the gut microbiota and gene expression, a clinically meaningful outcome also depends on compliance by the subjects. Limitations to this approach require further examination, including moderating factors such as genetic predisposition, habitual caffeine intake, and catechin composition and dose. Nevertheless, CCRTs may be useful agents that could help in preventing a positive energy balance and obesity. PMID- 24172302 TI - Introduction to the proceedings of the Fifth International Scientific Symposium on Tea and Human Health. PMID- 24172303 TI - Acute effects of tea consumption on attention and mood. AB - Tea has historically been associated with mood and performance benefits, such as relaxation and concentration. This review summarizes the research on the acute effects of tea, and its ingredients theanine and caffeine, on attention and mood. Consistent with abundant research on the benefits of caffeine, the performance benefits of tea were identified in a number of studies, with particularly consistent evidence for improved attention. Tea consumption also consistently improved self-reported alertness and arousal, whereas effects on pleasure or relaxation were less consistent. In addition to the research on caffeine in real life performance, 2 recent studies have provided a broader perspective on tea's effects on psychological function in that they showed beneficial effects in related areas such as work performance and creativity. These studies showed the validity of laboratory findings by supporting the idea that tea consumption has acute benefits on both mood and performance in real-life situations. PMID- 24172304 TI - Insulin resistance and inflammation predict kinetic body weight changes in response to dietary weight loss and maintenance in overweight and obese subjects by using a Bayesian network approach. AB - BACKGROUND: The ability to identify obese subjects who will lose weight in response to energy restriction is an important strategy in obesity treatment. OBJECTIVE: We aimed to identify obese subjects who would lose weight and maintain weight loss through 6 wk of energy restriction and 6 wk of weight maintenance. DESIGN: Fifty obese or overweight subjects underwent a 6-wk energy-restricted, high-protein diet followed by another 6 wk of weight maintenance. Network modeling by using combined biological, gut microbiota, and environmental factors was performed to identify predictors of weight trajectories. RESULTS: On the basis of body weight trajectories, 3 subject clusters were identified. Clusters A and B lost more weight during energy restriction. During the stabilization phase, cluster A continued to lose weight, whereas cluster B remained stable. Cluster C lost less and rapidly regained weight during the stabilization period. At baseline, cluster C had the highest plasma insulin, interleukin (IL)-6, adipose tissue inflammation (HAM56+ cells), and Lactobacillus/Leuconostoc/Pediococcus numbers in fecal samples. Weight regain after energy restriction correlated positively with insulin resistance (homeostasis model assessment of insulin resistance: r = 0.5, P = 0.0002) and inflammatory markers (IL-6; r = 0.43, P = 0.002) at baseline. The Bayesian network identified plasma insulin, IL-6, leukocyte number, and adipose tissue (HAM56) at baseline as predictors that were sufficient to characterize the 3 clusters. The prediction accuracy reached 75.5%. CONCLUSION: The resistance to weight loss and proneness to weight regain could be predicted by the combination of high plasma insulin and inflammatory markers before dietary intervention. PMID- 24172305 TI - Cancer prevention by green tea: evidence from epidemiologic studies. AB - In contrast to the consistent results of an inhibitory effect of green tea extracts and tea polyphenols on the development and growth of carcinogen-induced tumors in experimental animal models, results from human studies are mixed. Both observational and intervention studies have provided evidence in support of a protective role of green tea intake in the development of oral-digestive tract cancer or an inhibitory role of oral supplementation of green tea extract on a precancerous lesion of oral cavity. Evidence in support of green tea intake against the development of liver cancer risk is limited and inconsistent. An inverse association between green tea intake and lung cancer risk has been observed among never smokers but not among smokers. Although observational studies do not support a beneficial role of tea intake against the development of prostate cancer, several phase 2 clinical trials have shown an inhibitory effect of green tea extract against the progression of prostate premalignant lesions to malignant tumors. Prospective epidemiologic studies so far have not provided evidence for a protective effect of green tea consumption on breast cancer development. Current data neither confirm nor refute a definitive cancer preventive role of green tea intake. Large randomized intervention trials on the efficacy of green tea polyphenols or extracts are required before a recommendation for green tea consumption for cancer prevention should be made. PMID- 24172307 TI - Human studies on the absorption, distribution, metabolism, and excretion of tea polyphenols. AB - Recent research on the bioavailability of flavan-3-ols after ingestion of green tea by humans is reviewed. Glucuronide, sulfate, and methyl metabolites of (epi)catechin and (epi)gallocatechin glucuronide reach peak nanomolar per liter plasma concentrations 1.6-2.3 h after intake, indicating absorption in the small intestine. The concentrations then decline, and only trace amounts remain 8 h after ingestion. Urinary excretion of metabolites over a 24-h period after green tea consumption corresponded to 28.5% of the ingested (epi)catechin and 11.4% of (epi)gallocatechin, suggesting higher absorption than that of most other flavonoids. The fate of (-)-epicatechin-3-O-gallate, the main flavan-3-ol in green tea, is unclear because it appears unmetabolized in low concentrations in plasma but is not excreted in urine. Possible enterohepatic recirculation of flavan-3-ols is discussed along with the impact of dose and other food components on flavan-3-ol bioavailability. Approximately two-thirds of the ingested flavan-3 ols pass from the small to the large intestine where the action of the microbiota results in their conversion to C-6-C-5 phenylvalerolactones and phenylvaleric acids, which undergo side-chain shortening to produce C-6-C-1 phenolic and aromatic acids that enter the bloodstream and are excreted in urine in amounts equivalent to 36% of flavan-3-ol intake. Some of these colon-derived catabolites may have a role in vivo in the potential protective effects of tea consumption. Although black tea, which contains theaflavins and thearubigins, is widely consumed in the Western world, there is surprisingly little research on the absorption and metabolism of these compounds after ingestion and their potential impact on health. PMID- 24172306 TI - The Mediterranean-style dietary pattern and mortality among men and women with cardiovascular disease. AB - BACKGROUND: The role of the Mediterranean diet among individuals with previous cardiovascular disease (CVD) is uncertain. OBJECTIVE: The aim of this study was to assess the association between the Alternate Mediterranean Diet (aMED) score and all-cause, cardiovascular, and cancer mortality in men and women with CVD from the Health Professionals Follow-Up Study and the Nurses' Health Study. DESIGN: This study included 6137 men and 11,278 women with myocardial infarction, stroke, angina pectoris, coronary bypass, and coronary angioplasty. Diet was first assessed in 1986 for men and in 1980 for women with a food-frequency questionnaire (FFQ) and then repeatedly every 2-4 y. Cumulative consumption was calculated with all available FFQs from the diagnosis of CVD to the end of the follow-up in 2008. RESULTS: During a median follow-up of 7.7 y (IQR: 4.2-11.8) for men and 5.8 y (IQR: 3.8-8.0) for women, we documented 1982 deaths (1142 from CVD and 344 from cancer) among men and 1468 deaths (666 from CVD and 197 from cancer) among women. In multivariable Cox regression models, the pooled RR of all cause mortality from a comparison of the top with the bottom quintiles of the aMED score was 0.81 (95% CI: 0.72, 0.91; P-trend < 0.001). The corresponding pooled RR for CVD mortality was 0.85 (95% CI: 0.67, 1.09; P-trend = 0.30), for cancer mortality was 0.85 (95% CI: 0.65, 1.11; P-trend = 0.10), and for other causes was 0.79 (95% CI: 0.65, 0.97; P-trend = 0.01). A 2-point increase in adherence to the aMED score was associated with a 7% (95% CI: 3%, 11%) reduction in the risk of total mortality. CONCLUSION: Adherence to a Mediterranean-style dietary pattern was associated with lower all-cause mortality in individuals with CVD. PMID- 24172308 TI - Tea, flavonoids, and cardiovascular health: endothelial protection. AB - Several studies have suggested that tea consumption might protect against the development and progression of cardiovascular disease, one of the leading causes of morbidity and mortality worldwide. The endothelium plays a pivotal role in arterial homeostasis. Reduced nitric oxide (NO) bioavailability with endothelial dysfunction is considered the earliest step in the pathogenesis of atherosclerosis. Endothelial dysfunction has been considered an important and independent predictor of future development of cardiovascular risk and events. The association between brachial NO-dependent flow-mediated dilation (FMD) and cardiovascular disease risk has been investigated in several prospective studies, suggesting that FMD is inversely associated with future cardiovascular events. Dietary flavonoids and tea consumption have been described to improve endothelial function and FMD. A proposed mechanism by which dietary flavonoids could affect FMD is that they improve the bioactivity of the endothelium-derived vasodilator NO by enhancing NO synthesis or by decreasing superoxide-mediated NO breakdown. This could be of clinical relevance and may suggest a mechanistic explanation for the reduced risk of cardiovascular events and stroke observed among tea drinkers in the different studies. The purpose of this article is to provide an overview of the relation between tea consumption and cardiovascular disease, with a focus on clinical implications resulting from the beneficial effects of tea consumption on endothelial function. PMID- 24172309 TI - Dietary medium-chain triglyceride supplementation has no effect on apolipoprotein B-48 and apolipoprotein B-100 kinetics in insulin-resistant men. AB - BACKGROUND: Medium-chain triglyceride (MCT) supplements are used by clinicians to treat patients with severe hypertriglyceridemia who are at risk of pancreatitis. However, the potential mechanisms underlying the effects of MCT on triglyceride rich lipoprotein (TRL) metabolism have not yet been thoroughly examined in humans. OBJECTIVE: This double-blind randomized crossover study compared the impact of 4 wk of supplementation with 20 g MCT oil/d or 20 g corn oil/d on the kinetics of apolipoprotein (apo) B-48-containing TRLs and apo B-100-containing very-low-density lipoprotein (VLDL), as well as on the expression of key intestinal genes involved in lipid metabolism in 28 obese, insulin-resistant men. DESIGN: The in vivo kinetics of TRL apo B-48 and VLDL apo B-100 were assessed by using a primed-constant infusion of l-[5,5,5-d3]leucine for 12 h in the fed state. Real-time polymerase chain reaction quantification was performed on duodenal biopsy samples taken at the end of each phase of supplementation. RESULTS: Compared with corn oil, MCT supplements had no significant effect on plasma lipoprotein profile or TRL apo B-48 and VLDL apo B-100 kinetics. Positive correlations were observed between the intestinal expression of several key genes involved in lipoprotein metabolism in a subgroup of participants (n = 16) after MCT supplementation. However, there was no difference between MCT and the corn oil control supplement in the intestinal messenger RNA expression levels of these key genes. CONCLUSION: These data indicate that short-term supplementation with MCT has a neutral effect on TRL apo B-48 and VLDL apo B-100 kinetics and on the intestinal expression of genes involved in lipid and fatty acid metabolism in men with insulin resistance. This trial was registered at www.clinicaltrials.gov as NCT01806142. PMID- 24172310 TI - Tea consumption and cardiovascular disease risk. AB - BACKGROUND: The present analysis was conducted in response to inconsistent epidemiologic studies on the relation between consumption of tea and cardiovascular diseases. OBJECTIVE: We undertook a literature review of the consistency and strength of the associations between tea and cardiovascular diseases on the basis of published observational studies and meta-analyses addressing tea or tea flavonoids and cardiovascular disease risk. DESIGN: We performed a search in 3 databases for meta-analyses and compared them with studies they subsumed. We performed an additional search for subsequent studies to determine whether the conclusions were consistent. RESULTS: Many epidemiologic studies have been conducted and summarized in 5 meta-analyses on either tea consumption or flavonoid consumption and cardiovascular disease or the subset of stroke. Heterogeneity of effect was seen when the outcome included all cardiovascular diseases. In the case of stroke, a consistent, dose-response association with tea consumption on both incidence and mortality was noted with RRs of 0.80 (95% CI: 0.65, 0.98) for flavonoids and 0.79 (95% CI: 0.73, 0.85) for tea when high and low intakes were compared or the addition of 3 cups/d was estimated. CONCLUSION: Thus, the strength of this evidence supports the hypothesis that tea consumption might lower the risk of stroke. PMID- 24172311 TI - Quality measures for the care of patients with lateral epicondylalgia. AB - BACKGROUND: Lateral epicondylalgia (LE) defines a condition of varying degrees of pain near the lateral epicondyle. Studies on the management of LE indicated unexplained variations in the use of pharmacologic, non-pharmacological and surgical treatments. The main aim of this paper was to develop and evaluate clinical quality measures (QMs) or quality indicators, which may be used to assess the quality of the processes of examination, education and treatment of patients with LE. METHODS: Different QMs were developed by a multidisciplinary group of experts in Quality Management of Health Services during a period of one year. The process was based following a 3-step model: i) review and proportion of existing evidence-based recommendations; ii) review and development of quality measures; iii) pilot testing of feasibility and reliability of the indicators leading to a final consensus by the whole panel. RESULTS: Overall, a set of 12 potential indicators related to medical and physical therapy assessment and treatment were developed to measure the performance of LE care. Different systematic reviews and randomized control trials supported each of the indicators judged to be valid during the expert panel process. Application of the new indicator set was found to be feasible; only the measurement of two quality measures had light barriers. Reliability was mostly excellent (Kappa > 0.8). CONCLUSIONS: A set of good practice indicators has been built and pilot tested as feasible and reliable. The chosen 3-step standardized evidence-based process ensures maximum clarity, acceptance and sustainability of the developed indicators. PMID- 24172313 TI - Spontaneous cerebrospinal fluid otorrhea and rhinorrhea in idiopathic intracranial hypertension patients. PMID- 24172312 TI - Enhancing myogenic differentiation of pluripotent stem cells with small molecule inducers. AB - Pluripotent stem cells are able to differentiate into many types of cell lineages in response to differentiation cues. However, a pure population of lineage specific cells is desirable for any potential clinical application. Therefore, induction of the pluripotent stem cells with lineage-specific regulatory signals, or small molecule inducers, is a prerequisite for effectively directing lineage specification for cell-based therapeutics. In this article, we provide in-depth analysis of recent research findings on small molecule inducers of the skeletal muscle lineage. We also provide perspectives on how different signaling pathways and chromatin dynamics converge to direct the differentiation of skeletal myocytes. PMID- 24172315 TI - Clinical features of patients with Guillain-Barre syndrome at seven hospitals on the East Coast of Australia. AB - To document the clinical features of Guillain-Barre syndrome (GBS) in Australia, we performed a retrospective analysis of all patients admitted to several hospitals along the East Coast of Australia from 2000 to 2012. Using hospital records, we reviewed all patients with a diagnosis of GBS admitted to seven hospitals. From these, we report information of subjects who fulfilled standard diagnostic criteria. We excluded patients where inadequate information was available or who were under the age of 18. We report the features of 335 patients, in 228 of whom neurophysiological data were available. There were 168 cases of acute inflammatory demyelinating polyneuropathy (AIDP), 17 of acute motor axonal neuropathy (AMAN), 4 of acute motor and sensory axonal neuropathy (AMSAN), and 35 of Miller-Fisher syndrome (MFS). The median age at onset was 52.5 years (18-89 years) with a male : female ratio of 1.61 : 1. Upper respiratory tract infections were the most frequently identified trigger (151 subjects, 44.5%). Most patients were severely affected, with 42.7% of subjects bedbound, and an additional 24% requiring ventilatory support. GBS affects adults of all ages and usually follows a severe clinical course. In contrast to other autoimmune diseases, males are more frequently affected. A wide variety of triggering factors leads to a relatively stereotypical clinical syndrome. The most common variant of GBS in Australia is AIDP. This study shows that the clinical features of GBS in Australia are similar to that previously reported and confirms the male predominance, increased incidence with age, and frequent evidence of peripheral nerve demyelination as features of GBS. PMID- 24172314 TI - Approach to the older patient with cancer. AB - The incidence of cancer increases with advanced age. And as the world population ages, clinicians will be faced with a growing number of older patients with cancer. The challenge that clinicians face involves carefully choosing the type of therapeutic care plan that is most appropriate given a person's level of physical reserve, medical comorbidities, and psychosocial resources. Inclusion of assessment tools in clinical practice such as a comprehensive geriatric assessment can assist clinicians in identifying patients who will benefit from aggressive cancer care or palliative measures. The role of palliative care, especially in the frail older patient, is critical in improving quality of life. Improvement in best care practices in older patients with cancer requires their inclusion in clinical trials. PMID- 24172316 TI - Bringing together the academic drug discovery community. AB - The newly formed Academic Drug Discovery Consortium (ADDC) aims to support the growing numbers of university centres engaged in drug discovery that have emerged in response to recent changes in the drug discovery ecosystem. PMID- 24172317 TI - Make or break for first splice-modulating agents. PMID- 24172318 TI - IL-17 antibodies gain momentum. PMID- 24172322 TI - Trial watch: Success in amyloidosis trials supports potential of systemic RNAi. PMID- 24172323 TI - Deal watch: Biogen and Amicus to pursue genetically validated Parkinson's disease target. PMID- 24172324 TI - A promise to a court doesn't avoid infringement. PMID- 24172325 TI - Patents related to glycine transporters. PMID- 24172326 TI - Dan Tagle. Interview by Asher Mullard. PMID- 24172327 TI - Advances in prostate cancer treatment. PMID- 24172328 TI - Anticancer drugs: IDH2 drives cancer in vivo. PMID- 24172329 TI - Neurodegenerative disorders: A PIR-fect storm. PMID- 24172335 TI - TALEN-induced gene knock out in Drosophila. AB - We report here a case study of TALEN-induced gene knock out of the trachealess gene of Drosophila. Two pairs of TALEN constructs caused targeted mutation in the germ line of 39% and 17% of injected animals, respectively. In the extreme case 100% of the progeny of TALEN-injected fly was mutated, suggesting that highly efficient biallelic germ line mutagenesis was achieved. The mutagenic efficiency of the TALEN pairs paralleled their activity of single strand annealing (SSA) assay in cultured cells. All mutations were deletion of 1 to 20 base pairs. Merit and demerit of TALEN-based gene knockout approach compared to other genome editing technologies is discussed. PMID- 24172333 TI - MicroRNAs and other non-coding RNAs as targets for anticancer drug development. AB - The first cancer-targeted microRNA (miRNA) drug - MRX34, a liposome-based miR-34 mimic - entered Phase I clinical trials in patients with advanced hepatocellular carcinoma in April 2013, and miRNA therapeutics are attracting special attention from both academia and biotechnology companies. Although miRNAs are the most studied non-coding RNAs (ncRNAs) to date, the importance of long non-coding RNAs (lncRNAs) is increasingly being recognized. Here, we summarize the roles of miRNAs and lncRNAs in cancer, with a focus on the recently identified novel mechanisms of action, and discuss the current strategies in designing ncRNA targeting therapeutics, as well as the associated challenges. PMID- 24172337 TI - Thrombin activity in normal vitreous liquid. AB - An intact blood-retina barrier (BRB) ensures the homeostatic regulation of the retinal environment by preventing proteins and enzymes to pass from the blood stream into the retinal tissue as well as the vitreous cavity ('nonleaky eyes'). Nevertheless, thrombin is needed within the eye to avoid bleeding events. It might, furthermore, play an essential role in preventing BRB breakdown ('leaky eyes'). Until today, the intraocular thrombin activity as well as the source of the latter has not been investigated. The present work was conducted to evaluate whether intravitreal thrombin activity is present in eyes without BRB breakdown. Therefore, 16 vitreal taps were harvested at the beginning of a standard 23-gauge three-port pars plana vitrectomy. These 200 MUl undiluted vitreous samples were instantly stabilized by 1 + 1 mixture with 5% human albumin, followed by 1 + 1 mixture of such an aliquot with 2.5 mol/l arginine, pH 8.6, and frozen at -20 degrees C. After thawing at 23 degrees C, thrombin activity was analyzed chromogenically in the presence of arginine protection against unspecific cleavage of the chromogenic substrate. Intravitreal thrombin was detected in all 16 analyzed samples and thrombin activity exhibited to be 1.5 +/- 1.0 mIU/ml (mean value +/- SD; range: 0.2-3.25 mIU/ml). Thus, our investigation is the first successful quantification of the physiologic intraocular activity of thrombin. Further studies will evaluate intravitreal thrombin activities in eyes with BRB breakdown and compare those results with the physiologic activities demonstrated herein. Standardized intraocular thrombin activity might be a new diagnostic parameter in ophthalmology. PMID- 24172334 TI - Glycine transporters as novel therapeutic targets in schizophrenia, alcohol dependence and pain. AB - Glycine transporters are endogenous regulators of the dual functions of glycine, which acts as a classical inhibitory neurotransmitter at glycinergic synapses and as a modulator of neuronal excitation mediated by NMDA (N-methyl-D-aspartate) receptors at glutamatergic synapses. The two major subtypes of glycine transporters, GlyT1 and GlyT2, have been linked to the pathogenesis and/or treatment of central and peripheral nervous system disorders, including schizophrenia and related affective and cognitive disturbances, alcohol dependence, pain, epilepsy, breathing disorders and startle disease (also known as hyperekplexia). This Review examines the rationale for the therapeutic potential of GlyT1 and GlyT2 inhibition, and surveys the latest advances in the biology of glycine reuptake and transport as well as the drug discovery and clinical development of compounds that block glycine transporters. PMID- 24172336 TI - A combinatorial approach of Proteomics and Systems Biology in unravelling the mechanisms of acute kidney injury (AKI): involvement of NMDA receptor GRIN1 in murine AKI. AB - BACKGROUND: Acute kidney injury (AKI) is a frequent condition in hospitalised patients undergoing major surgery or the critically ill and is associated with increased mortality. Based on the volume of the published literature addressing this condition, reporting both supporting as well as conflicting molecular evidence, it is apparent that a comprehensive analysis strategy is required to understand and fully delineate molecular events and pathways which can be used to describe disease induction and progression as well as lead to a more targeted approach in intervention therapies. RESULTS: We used a Systems Biology approach coupled with a de-novo high-resolution proteomic analysis of kidney cortex samples from a mouse model of folic acid-induced AKI (12 animals in total) and show comprehensive mapping of signalling cascades, gene activation events and metabolite interference by mapping high-resolution proteomic datasets onto a de novo hypothesis-free dataspace. The findings support the involvement of the glutamatergic signalling system in AKI, induced by over-activation of the N methyl-D-aspartate (NMDA)-receptor leading to apoptosis and necrosis by Ca2+ influx, calpain and caspase activation, and co-occurring reactive oxygen species (ROS) production to DNA fragmentation and NAD-rundown. The specific over activation of the NMDA receptor may be triggered by the p53-induced protein kinase Dapk1, which is a known non-reversible cell death inducer in a neurological context. The pathway mapping is consistent with the involvement of the Renin-Angiotensin Aldosterone System (RAAS), corticoid and TNFalpha signalling, leading to ROS production and gene activation through NFkappaB, PPARgamma, SMAD and HIF1alpha trans-activation, as well as p53 signalling cascade activation. Key elements of the RAAS-glutamatergic axis were assembled as a novel hypothetical pathway and validated by immunohistochemistry. CONCLUSIONS: This study shows to our knowledge for the first time in a molecular signal transduction pathway map how AKI is induced, progresses through specific signalling cascades that may lead to end-effects such as apoptosis and necrosis by uncoupling of the NMDA receptor. Our results can potentially pave the way for a targeted pharmacological intervention in disease progression or induction. PMID- 24172338 TI - Abstracts of the 41st Annual Meeting of the Japan Society for Clinical Immunology. PMID- 24172536 TI - Eukaryotic ribosome biogenesis at a glance. AB - Ribosomes play a pivotal role in the molecular life of every cell. Moreover, synthesis of ribosomes is one of the most energetically demanding of all cellular processes. In eukaryotic cells, ribosome biogenesis requires the coordinated activity of all three RNA polymerases and the orchestrated work of many (>200) transiently associated ribosome assembly factors. The biogenesis of ribosomes is a tightly regulated activity and it is inextricably linked to other fundamental cellular processes, including growth and cell division. Furthermore, recent studies have demonstrated that defects in ribosome biogenesis are associated with several hereditary diseases. In this Cell Science at a Glance article and the accompanying poster, we summarise the current knowledge on eukaryotic ribosome biogenesis, with an emphasis on the yeast model system. PMID- 24172535 TI - Meeting report - TGF-beta superfamily: signaling in development and disease. AB - The latest advances on the transforming growth factor beta (TGF-beta) and bone morphogenetic protein (BMP) signaling pathways were reported at the July 2013 FASEB Summer Research Conference 'The TGF-beta Superfamily: Development and Disease'. The meeting was held in Steamboat Springs, Colorado, USA at 6700 feet above sea level in the Rocky Mountains. This was the seventh biannual meeting in the series. In attendance were investigators from a broad range of disciplines with a common interest in the mechanics of TGF-beta and BMP signaling pathways, their normal developmental and homeostatic functions, and the diseases associated with pathway misregulation. PMID- 24172538 TI - Short-term effects of noisy pressure support ventilation in patients with acute hypoxemic respiratory failure. AB - INTRODUCTION: This study aims at comparing the very short-term effects of conventional and noisy (variable) pressure support ventilation (PSV) in mechanically ventilated patients with acute hypoxemic respiratory failure. METHODS: Thirteen mechanically ventilated patients with acute hypoxemic respiratory failure were enrolled in this monocentric, randomized crossover study. Patients were mechanically ventilated with conventional and noisy PSV, for one hour each, in random sequence. Pressure support was titrated to reach tidal volumes approximately 8 mL/kg in both modes. The level of positive end-expiratory pressure and fraction of inspired oxygen were kept unchanged in both modes. The coefficient of variation of pressure support during noisy PSV was set at 30%. Gas exchange, hemodynamics, lung functional parameters, distribution of ventilation by electrical impedance tomography, breathing patterns and patient-ventilator synchrony were analyzed. RESULTS: Noisy PSV was not associated with any adverse event, and was well tolerated by all patients. Gas exchange, hemodynamics, respiratory mechanics and spatial distribution of ventilation did not differ significantly between conventional and noisy PSV. Noisy PSV increased the variability of tidal volume (24.4 +/- 7.8% vs. 13.7 +/- 9.1%, P <0.05) and was associated with a reduced number of asynchrony events compared to conventional PSV (5 (0 to 15)/30 min vs. 10 (1 to 37)/30 min, P <0.05). CONCLUSIONS: In the very short term, noisy PSV proved safe and feasible in patients with acute hypoxemic respiratory failure. Compared to conventional PSV, noisy PSV increased the variability of tidal volumes, and was associated with improved patient ventilator synchrony, at comparable levels of gas exchange. TRIAL REGISTRATION: ClinicialTrials.gov, NCT00786292. PMID- 24172539 TI - Modeling the Adenoma and Serrated pathway to Colorectal CAncer (ASCCA). AB - Several colorectal cancer (CRC) screening models have been developed describing the progression of adenomas to CRC. Currently, there is increasing evidence that serrated lesions can also develop into CRC. It is not clear whether screening tests have the same test characteristics for serrated lesions as for adenomas, but lower sensitivities have been suggested. Models that ignore this type of colorectal lesions may provide overly optimistic predictions of the screen induced reduction in CRC incidence. To address this issue, we have developed the Adenoma and Serrated pathway to Colorectal CAncer (ASCCA) model that includes the adenoma-carcinoma pathway and the serrated pathway to CRC as well as characteristics of colorectal lesions. The model structure and the calibration procedure are described in detail. Calibration resulted in 19 parameter sets for the adenoma-carcinoma pathway and 13 for the serrated pathway that match the age- and sex-specific adenoma and serrated lesion prevalence in the COlonoscopy versus COlonography Screening (COCOS) trial, Dutch CRC incidence and mortality rates, and a number of other intermediate outcomes concerning characteristics of colorectal lesions. As an example, we simulated outcomes for a biennial fecal immunochemical test screening program and a hypothetical one-time colonoscopy screening program. Inclusion of the serrated pathway influenced the predicted effectiveness of screening when serrated lesions are associated with lower screening test sensitivity or when they are not removed. To our knowledge, this is the first model that explicitly includes the serrated pathway and characteristics of colorectal lesions. It is suitable for the evaluation of the (cost)effectiveness of potential screening strategies for CRC. PMID- 24172537 TI - Genetic and molecular alterations in pancreatic cancer: implications for personalized medicine. AB - Recent advances in human genomics and biotechnologies have profound impacts on medical research and clinical practice. Individual genomic information, including DNA sequences and gene expression profiles, can be used for prediction, prevention, diagnosis, and treatment for many complex diseases. Personalized medicine attempts to tailor medical care to individual patients by incorporating their genomic information. In a case of pancreatic cancer, the fourth leading cause of cancer death in the United States, alteration in many genes as well as molecular profiles in blood, pancreas tissue, and pancreas juice has recently been discovered to be closely associated with tumorigenesis or prognosis of the cancer. This review aims to summarize recent advances of important genes, proteins, and microRNAs that play a critical role in the pathogenesis of pancreatic cancer, and to provide implications for personalized medicine in pancreatic cancer. PMID- 24172540 TI - An analog of the host-defense peptide hymenochirin-1B with potent broad-spectrum activity against multidrug-resistant bacteria and immunomodulatory properties. AB - Hymenochirin-1B (IKLSPETKDN(10)LKKVLKGAIK(20)GAIAVAKMV.NH2) is a cationic, amphipathic, alpha-helical, host-defense peptide, first isolated from skin secretions of the Congo clawed frog Hymenochirus boettgeri (Pipidae). Structure activity relationships were investigated by synthesizing analogs in which the Pro(5), Glu(6) and Asp(9) on the hydrophilic face of the alpha-helix are substituted by one or more l-lysine or d-lysine residues. Although replacement with l-lysine generates analogs with increased antimicrobial potency against a range of Gram-positive and Gram-negative bacteria (up to 8-fold), the peptides are more hemolytic. Increasing the cationicity of hymenochirin-1B while reducing the helicity by substitutions with d-lysine generates analogs that are between 2 and 8 fold more potent than the native peptide and are equally or less hemolytic. [E6k,D9k]hymenochirin-1B represents a candidate for drug development as it shows high potency against clinical isolates of methicillin-resistant Staphylococcus aureus (MRSA) and a range of Gram-negative bacteria, including multidrug resistant strains of Acinetobacter baumannii and Stenotrophomonas maltophilia (MIC in the range 0.8-3.1 MUM) and NDM-1 carbapenemase-producing clinical isolates of Klebsiella pneumoniae, Escherichia coli, Enterobacter cloacae and Citrobacter freundii (MIC in the range 3.1-6.25 MUM), and low hemolytic activity (LC50=302 MUM). [E6k,D9k]hymenochirin-1B, at a concentration of 2.5 MUM, significantly (P<0.05) stimulates the production of the anti-inflammatory cytokines IL-4 and IL-10 by human peripheral blood mononuclear cells but is without significant effect on production of the pro-inflammatory cytokines TNF alpha and IL-17. PMID- 24172541 TI - Higher Orexin A levels in lumbar compared to ventricular CSF: a study in idiopathic normal pressure hydrocephalus. AB - Orexin A (ORX-A) is implicated in the regulation of various physiological processes, including sleep/wake cycles and reward/motivation. The hypothalamic ORX-A neurons project throughout the brain and spinal cord. In the present study we established and compared ORX-A levels in lumbar and ventricular cerebrospinal fluid (CSF) samples, drawn from idiopathic normal pressure hydrocephalus (INPH) patients, during respectively, lumbar puncture and shunt placement. Ventricular and lumbar CSF levels of total protein and of the dopamine, serotonin and norepinephrine metabolites HVA, 5-HIAA and MHPG respectively, were also estimated. ORX-A was quantified using a commercially available radioimmunoassay kit. Neurotransmitter metabolites were quantified by high performance liquid chromatography. Expectedly, HVA and 5-HIAA levels were significantly higher and total protein levels lower in ventricular compared to lumbar CSF while there were no differences in MHPG levels. However, in contrast to HVA and 5-HIAA and similar to total protein, lumbar ORX-A levels were significantly higher than ventricular levels. The higher lumbar compared to ventricular ORX-A levels may reflect elevated contributions from the spinal cord. The finding of a ventriculo-lumbar difference for ORX-A should be considered in studies utilizing its CSF levels in assessing Orexin system status. PMID- 24172542 TI - Temporal bone pneumatisation: a computed tomography study of pneumatized articular tubercle. AB - AIM: To determine the prevalence and characteristics of pneumatized articular tubercle (PAT) at computed tomography (CT), and to determine whether the presence of PAT is a predictor of larger pneumatized spaces of temporal bone. MATERIALS AND METHODS: A retrospective study was performed using axial, sagittal and coronal CT images of 225 patients who attended a private medical imaging centre. Age and gender were recorded for all patients and, for cases of PAT, laterality and types were also recorded. Temporal bone pneumatization was recorded based on three reference structures on axial images. The Chi-square and Mann-Whitney U tests were used. RESULTS: Of the 225 patients, 43 (9.55%) had PAT, of whom 24 were female and 19 were male. This difference was not statistically significant (p > 0.05). The age range of the patients with PAT was 8-67 years. Of the 43 patients, 24 had unilateral and 19 had bilateral PAT. Fifteen cases of PAT were unilocular and 28 were multilocular. Cases of PAT showed larger pneumatized spaces of other parts of the temporal bone (p = 0.0001). CONCLUSION: It is possible that PAT is a more frequent condition than is commonly perceived. The degree of pneumatization of temporal bone can be estimated by the evaluation of the air cells around the articular tubercle. CT is highly recommended in patients with PAT undergoing surgical treatment to determine the exact size and relationship of PAT to other parts of temporal bone. PMID- 24172543 TI - Meta-analysis to compare the accuracy of GeneXpert, MODS and the WHO 2007 algorithm for diagnosis of smear-negative pulmonary tuberculosis. AB - BACKGROUND: Smear-negative pulmonary tuberculosis (SN-PTB), which is common in HIV-infected patients, is difficult to diagnose using smear microscopy alone. In 2007, the WHO developed an algorithm to improve the diagnosis and management of smear-negative tuberculosis in HIV prevalent and resource constrained settings. Implementation of the algorithm required individuals with presumptive TB to be initially evaluated using two sputum microscopy examinations followed by clinical diagnosis that may include chest X-ray and antibiotic treatment in smear-negative individuals. Since that time, the WHO has endorsed several new tests for diagnosis of tuberculosis. However, it is unclear how the new tests perform when compared to the WHO 2007 algorithm in diagnosis of SN-PTB. Using meta-analysis study design, we summarized and compared the accuracy of Xpert(r) MTB/Rif assay (GeneXpert) and Microscopic Observation Drug Susceptibility assay (MODS), with the WHO 2007 algorithm in the diagnosis of SN-PTB. METHODS: A systematic review and meta-analysis of publications on GeneXpert, or MODS, or the WHO 2007 algorithm for diagnosis of SN-PTB, using culture as reference test was performed. Meta-Disc software was used to obtain pooled sensitivity and specificity of the diagnostic methods. Heterogeneity in the accuracy estimates was tested by reviewing the generated forest plots, sROC curves and the Spearman correlation coefficient of the logit of true positive rate versus the logit of false positive rate. RESULTS: Twenty-four publications on all three diagnostic methods were meta analyzed. The pooled sensitivity and specificity for detection of smear-negative pulmonary tuberculosis were 67% and 98% for GeneXpert, 73% and 91% for MODS, and 61% and 69% for WHO 2007 algorithm, respectively. The sensitivity of GeneXpert reduced from 67% to 54% when sub-group analysis of studies with patient HIV prevalence >= 30% was performed. CONCLUSION: The GeneXpert, MODS, and the WHO algorithm have moderate to high accuracy for the diagnosis of SN-PTB. However, the accuracy of the tests is extremely variable. The setting and context under which the tests are conducted in addition to several other factors could explain this variability. There is therefore need to investigate these factors further. The information from these studies would inform the adoption and placement of these new tests. PMID- 24172545 TI - Editing the Nepalese Journal of Ophthalmology: a voyage of five years. PMID- 24172546 TI - Ophthalmic oncology in Nepal - an area requiring special attention. PMID- 24172544 TI - Epigenetic regulation in adult stem cells and cancers. AB - Adult stem cells maintain tissue homeostasis by their ability to both self-renew and differentiate to distinct cell types. Multiple signaling pathways have been shown to play essential roles as extrinsic cues in maintaining adult stem cell identity and activity. Recent studies also show dynamic regulation by epigenetic mechanisms as intrinsic factors in multiple adult stem cell lineages. Emerging evidence demonstrates intimate crosstalk between these two mechanisms. Misregulation of adult stem cell activity could lead to tumorigenesis, and it has been proposed that cancer stem cells may be responsible for tumor growth and metastasis. However, it is unclear whether cancer stem cells share commonalities with normal adult stem cells. In this review, we will focus on recent discoveries of epigenetic regulation in multiple adult stem cell lineages. We will also discuss how epigenetic mechanisms regulate cancer stem cell activity and probe the common and different features between cancer stem cells and normal adult stem cells. PMID- 24172547 TI - Correlation of progression of diabetic retinopathy with the alterations in retrobulbar circulation. AB - INTRODUCTION: Color Doppler Imaging (CDI) is used widely to study retrobulbar circulation. OBJECTIVES: To determine the association between progression of diabetic retinopathy (DR) and alterations in retrobulbar arterial circulation using CDI studies. MATERIALS AND METHODS: Prospective observational case series. It is single institutional study of 50 eyes of nonproliferative diabetic retinopathy in 50 patients with type II diabetes mellitus. DR was graded according to ETDRS system. Retrobulbar circulation was studied in patients for Peak systolic velocity (PSV), End diastolic velocity (EDV) and Resistive index (RI) in Central retinal artery (CRA), Ophthalmic artery (OA) and Posterior ciliary artery (PCA) using CDI initially and reevaluated after 6 months or later for any change in retinopathy grade and arterial circulation parameters. The patients were grouped as Group I not showing progression of DR and Group II showing progression. The two groups were compared for any significant change in CDI parameters. RESULTS: The baseline resistive indices were higher than normal population. There was significant increase in RI in PCA and CRA in all patients after 6 months. 14 patients (28%) showed progression of DR and 36 (72%) did not show progression of DR. There was no significant association with progression of retinopathy and CDI findings. (p=>0.05). CONCLUSION: The retrobulbar arterial circulation seems to be affected in all diabetics with DR. The changes appear to be progressive. The CDI findings in arterial circulation however lack predictive power for progression of diabetic retinopathy in non proliferative DR. PMID- 24172548 TI - Prospective comparison of chilled versus room temperature saline irrigation in alcohol-assisted photorefractive keratectomy. AB - INTRODUCTION: Chilled saline is commonly used to irrigate the ocular surface after photorefractive keratectomy (PRK) and is often considered by the patients to be uncomfortable. Room temperature (non-chilled) saline may be a safe and less painful alternative. OBJECTIVES: To compare pain and visual outcomes after irrigating the ocular surface with chilled saline versus room temperature saline in alcohol assisted PRK. MATERIALS AND METHODS: In this prospective, single masked, randomized, contralateral eye study, myopic eyes were treated with PRK. Immediately after laser ablation one eye was irrigated with chilled saline and the other with non-chilled saline. Primary outcomes measured were pain, haze, uncorrected (UCVA) and best-corrected (BCVA) visual acuities, and manifest refraction. RESULTS: Each group comprised of 40 eyes. There was no significant difference in pain between the groups at any point during five days after surgery. At 6 months the mean UCVA was -0.08 logMAR +/- .077 [SD] (20/17) and 0.07 +/- .074 logMAR (20/17) in the chilled and non-chilled groups respectively (p =.35). Both groups achieved 95% UCVA of 20/20 or better. The manifest refraction spherical equivalent (MRSE) was -0.05 +/- 0.21 D and -0.025 +/- 0.27 D respectively (p = .79). There were no lines lost of BCVA and no haze observed. Similar outcomes were observed with regard to pain and vision in both groups. CONCLUSION: The use of room temperature saline irrigation during PRK appears to be safe and effective. PMID- 24172549 TI - Computer vision syndrome: a study of knowledge and practices in university students. AB - INTRODUCTION: Computer vision syndrome (CVS) is a condition in which a person experiences one or more of eye symptoms as a result of prolonged working on a computer. OBJECTIVES: To determine the prevalence of CVS symptoms, knowledge and practices of computer use in students studying in different universities in Malaysia, and to evaluate the association of various factors in computer use with the occurrence of symptoms. MATERIAL AND METHODS: In a cross sectional, questionnaire survey study, data was collected in college students regarding the demography, use of spectacles, duration of daily continuous use of computer, symptoms of CVS, preventive measures taken to reduce the symptoms, use of radiation filter on the computer screen, and lighting in the room. RESULTS: A total of 795 students, aged between 18 and 25 years, from five universities in Malaysia were surveyed. The prevalence of symptoms of CVS (one or more) was found to be 89.9%; the most disturbing symptom was headache (19.7%) followed by eye strain (16.4%). Students who used computer for more than 2 hours per day experienced significantly more symptoms of CVS (p=0.0001). Looking at far objects in-between the work was significantly (p=0.0008) associated with less frequency of CVS symptoms. The use of radiation filter on the screen (p=0.6777) did not help in reducing the CVS symptoms. CONCLUSION: Ninety percent of university students in Malaysia experienced symptoms related to CVS, which was seen more often in those who used computer for more than 2 hours continuously per day. PMID- 24172550 TI - Retinoblastoma: geographic distribution and presentation at a tertiary eye care centre in Kathmandu, Nepal. AB - INTRODUCTION: Several aspects of retinoblastoma in Nepal remain enigmatic. OBJECTIVE: To assess the demographic and geographic distribution, clinical presentation, and treatment methods of retinoblastoma at a tertiary level ophthalmic institution in Kathmandu, Nepal. MATERIALS AND METHODS: A retrospective analysis of all the patients diagnosed with retinoblastoma at Tilganga Institute of Ophthalmology from July 2004 to June 2008 was performed. The main outcome measures included region of residence, treatment options and histopathological findings. The histopathological analysis was performed on enucleated and exenterated specimens. STATISTICS: The statistical analysis was performed with SPSS Version 11.5. Descriptive statistics are represented as mean +/- standard deviation. All tests were two-sided and the P-values of less than 0.05 were considered statistically significant. RESULTS: Thirty patients presented with retinoblastoma during the study period. The mean age at presentation was 2.5 +/- 1.6 years (range five months to seven years). Ten of the 12 patients who presented with bilateral retinoblastoma (83 %) were from the Terai region of Nepal. The ratio of unilateral to bilateral cases in the Terai region was 1:2. This differed significantly with the ratio in the hilly region (Fisher's Exact Test, p = 0.0012). The mean duration of symptoms before presentation was 2.5 3.2 months (range three days to 12 months). Twenty-four patients (80 %) presented with leukocoria. Eleven patients (36.6 %) presented with leukocoria as their only symptom. Ninety-seven percent of the patients underwent either enucleation (90 %) or exenteration (6.7 %) of at least one eye. CONCLUSION: Bilateral retinoblastoma is more prevalent in the Terai region of Nepal. The majority of the patients present with leucokoria and are treated with enucleation. PMID- 24172551 TI - Successful treatment of lower eyelid epiblepharon by injection of botulinum toxin A in patients under two years of age. AB - INTRODUCTION: Epiblepharon is characterized by a cutaneous horizontal fold adjacent to the lid margin. Some cases showed spontaneous resolution, others required surgical treatment. We propose a medical treatment with botulinum toxin type A (BTX-A). OBJECTIVE: To provide clinical evidence of the usefulness of botulinum toxin type A (BTX-A) in patients with lower eyelid epiblepharon. SUBJECTS AND METHODS: This was a prospective, non-randomized, nonmasked study. Patients with lower eyelid epiblepharon with corneal eyelash contact were included in the study. The scale proposed by Khwarg and Lee (1997) was used to assess the epiblepharon clinical evaluation. A single dose of 12.5 IU of BTX-A (Dysport (r)) was directly injected into the medial pre-tarsal orbicularis muscle region in the lower eyelid. Patients were evaluated before the injection and at 1, 4, 12 and 24 weeks after the injection. We performed descriptive statistics and Wilcoxon Signed Rank Test, comparing prior injection measurements to post injection measurements at the 24th week. A p less than 0.05 was considered statistically significant. Each eye was separately analyzed. RESULTS: Fourteen eyes of seven Hispanic patients were treated, five female and two male. The mean age was 8.4 months (4 - 14 months). The height of the skin-fold, the area of the cornea touched by the cilia and the symptoms score improved after the first week of BTX-A injection and remained so until the end of study (p less than 0.05). No major complications were noted. CONCLUSION: The effect of a single 12.5 IU injection of BTX-A (Dysport (r)) into the medial orbicularis muscle portion in the lower eyelid epiblepharon patients successfully improves the clinical signs and symptoms. PMID- 24172552 TI - Surgical outcomes of minimally invasive vitrectomy surgery in Eales' disease. AB - INTRODUCTION: The results of surgical outcomes of 20 gauge pars plana vitrectomy in Eales' disease are available in the scientific literature. However, all these studies have been done using the 20 gauge vitrectomy systems and most studies have been conducted in a retrospective manner. OBJECTIVE: To evaluate the outcomes and safety of 23 gauge vitrectomy in complications of Eales' disease. MATERIALS AND METHODS: STUDY DESIGN: Consecutive interventional case series. PARTICIPANTS: Seventy-six eyes of 72 nonconsecutive patients undergoing 23-gauge vitrectomy for complications of Eales' disease were enrolled. The participants were followed up for a minimum of one year. INTERVENTION: The participants underwent a complete demographic, medical and ophthalmic evaluation. A 23-gauge vitrectomy was performed. Endotamponade was used when necessary. Perioperative and postoperative events were recorded. Primary outcome measures were visual acuity and complications arising due to surgery. RESULTS: Indication for surgery was non-clearing vitreous hemorrhage in 89.4% (68/76) and secondary retinal detachment in 10.6% (8). Visual acuity improved from Log Mar 1.80 +/- 0.19 units preoperatively to Log Mar 0.47+/-0.59. Best-corrected visual acuity equivalent to Snellen 6/9 was achieved in 77. 6% of eyes. . Surgical failure was seen in 6.5% cases. Four cases were lost due to progression to neovascular glaucoma and 1 case was lost to severe residual retinal detachment. Iatrogenic portside retinal breaks occurred in 3.9% (3), post-vitrectomy retinal detachment 2.6% ( 2), hypotony 1.3% (1) and cataract in 38.1% (28) cases. CONCLUSION: 23-gauge sutureless vitrectomy in patients with Eales' disease is a safe and effective technique with acceptable level of risk and complications. PMID- 24172553 TI - Optical coherence tomography in diabetic macular edema: patterns and related risk factors. AB - INTRODUCTION: Diabetic Macular Edema (DME) is an important cause of vision loss in diabetic retinopathy. Optical Coherence Tomography (OCT) is a non-invasive modality that produces high-resolution images of retinal layers. OBJECTIVE: To evaluate the prevalence of DME patterns and their association with risk factors and visual acuity. MATERIALS AND METHODS: In this cross-sectional study, type 2 diabetics with macular edema referred to our center during a ten-month period underwent OCT. Patients with macular edema due to causes other than diabetes and with OCT images of improper quality were excluded from the study. Four distinct patterns were found in the OCT images. A questionnaire including age, sex, duration of diabetes, serum TG and cholesterol, HbA1c, BMI and visual acuity, as well as the findings of OCT images were filled for the subjects. RESULTS: Eighty six eyes from 46 patients were evaluated. The most and the least common patterns were sponge-like retinal swelling (SLRS) and posterior hyaloidal traction (PHT) found in 64.0% and 5.8% of the subjects, respectively. A sub-retinal fluid pattern was more common in males (p=0.011) and in patients with serum TG > 200mg/dl (p=0.037). There were significant associations between central foveal (r=0.45, p less than 0.001), nasal (r=0.35, p=0.001) and temporal (r=0.32, p=0.003) thicknesses with visual acuity. Moreover, the highest thickness (462.4+/ 119.2MUm) and also the worst visual acuity (1.0+/-0.5logMAR) pertained to the cystoid macular edema (CME) pattern. CONCLUSION: Our study showed that the most common OCT pattern of DME is the sponge-like retinal swelling, while posterior hyaloidal traction has the lowest prevalence. A higher foveal thickness and a lower visual acuity are seen in the CME pattern. PMID- 24172554 TI - A study on plasma homocysteine level in age-related macular degeneration. AB - INTRODUCTION: Age-related macular degeneration (AMD) related to adverse vascular changes is the most frequent cause of irreversible visual impairment in the elderly. Elevated plasma concentrations of serum homocysteine have been shown to increase the risk of vascular disease. OBJECTIVE: To assess the relationship between plasma homocysteine level and age related macular degeneration. MATERIALS AND METHODS: A case control study was conducted in a tertiary eye care hospital with 32 diagnosed AMD patients. The patients were compared for plasma homocysteine levels with a control group of 32 patients without AMD. A 1.5 ml of fasting venous blood sample was obtained from each participant. Plasma homocysteine level was measured by high performance liquid chromatography. The main outcome measure was hyperhomocysteinemia, defined as a plasma homocysteine level above 15 MUmol/l. RESULTS: Hyperhomocysteinemia was found in 10 blood samples (83.3 %) of patients in the wet AMD group, in 16 (80 %) blood samples in the dry AMD group, and in 12 blood samples (37%) of controls. The mean +/- SD homocysteine level in the AMD group was 16.86 +/- 3.52 MUmol/L, while in the non AMD control group it was 14.53 +/- 4.08 MUmol/L. This difference was statistically significant (p-value = 0.0186). In the individual analysis, it was also found out that the homocysteine level differed significantly between cases and controls in only the wet variety of AMD. CONCLUSION: Hyperhomocysteinemia was significantly associated with the wet AMD variety but not with the dry AMD. Thus, homocysteine by oxidative stress and vascular dysfunction can be an important risk factor in the pathogenesis of AMD. PMID- 24172555 TI - A comparative study of intraocular pressure measurement by three tonometers in normal subjects. AB - INTRODUCTION: Contact Goldmann applanation tonometry (GAT) is gold standard for measuring intraocular pressure; however its routine use is limited by its non portability and the need for a Slit Lamp Microscope. The Portable Perkins tonometer is also considered gold standard because it is based on the same principles as the GAT. The iCare is a newly introduced, portable, non-contact tonometer (NCT) that measures intraocular pressure (IOP) using a thin metallic probe. OBJECTIVE: To evaluate reliability and accuracy of IOP measurements using iCare and Keeler Pulsair tonometers against Perkins tonometer. SUBJECTS AND METHODS: A comparative, randomized, prospective clinical study conducted on 166 eyes of 83 (n=83) subjects in the age group 14 to 71 years. The pressures were first recorded by iCare and Pulsair and then by Perkins. The SPSS 11.00 version was used for analysis. RESULTS: Mean pressures and standard deviation (+/-SD) for iCare, Pulsair and Perkins were 14.62(+/- 2.47), 14.53(+/-3.36) and 13.06(+/ 2.69) and the Standard Error of the Mean (SEM) was 0.27, 0.36 and 0.30 respectively. There was a good correlation between iCare and Perkins with statistically significant difference (r=0.610, p less than 0.05). Regression analysis was performed. Using the Bland-Altman analysis 95% Limits of Agreement (LoA) for iCare and Pulsair were determined as -6.1 to 2.9 and -4.5 to 7.5 respectively. CONCLUSION: Although both tonometers overestimated the Perkins values, Pulsair showed a better agreement with Perkins tonometer than iCare tonometer. PMID- 24172556 TI - Indications for keratoplasty in Nepal: 2005 - 2010. AB - INTRODUCTION: Corneal disease, especially infective keratitis, is one of the major causes of visual impairment and blindness in developing countries. OBJECTIVE: To find out the current indications for keratoplasty, how these indications have changed over time as well as how they are different from those in other parts of the world. MATERIALS AND METHODS: A retrospective study of a case series of 645 keratoplasty surgeries (589 patients) was conducted at the Tilganga Institute of Ophthalmology from January 2005 to December 2010. OUTCOME MEASURES: The cases were evaluated in terms of demographic parameters, preoperative diagnosis and the type of surgery performed. RESULTS: The most common indication for surgery was active infectious keratitis (264 eyes, 40.9 %), followed by corneal opacity (173 eyes, 26.8 %), regraft (73 eyes, 11.2 %), bullous keratopathy (58 eyes, 9.0 %), keratoconus (45 eyes, 7.0 %) and corneal dystrophy (11 eyes, 1.7 %). The mean recipient age was 41.7 +/- 19.9 years with over a half of the patients between 15 to 49 years of age. More men (64.1 %) underwent keratoplasty than women (35.8 %). 59.8 % of the eyes with infectious keratitis had a perforated corneal ulcer. 49.7 % of corneal opacities were due to previous infectious keratitis. 72 % of regrafts were for endothelial failure of various causes. In older patients (> 50 years), bullous keratopathy was an important indication, after infectious keratitis. Keratoconus and corneal scar were major causes of keratoplasty in children of 14 years or less. Four percent of the patients had keratoplasty in both the eyes. 17.1 % of the patients who had one eye operated on had a blind fellow eye with a vision of less than 3/60. CONCLUSION: Currently, keratitis, either active or healed, is the major indication for keratoplasty, suggesting that improved primary eye health care is necessary to decrease the prevalence of corneal blindness. PMID- 24172557 TI - Keratometric astigmatism evaluation after trabeculectomy. AB - INTRODUCTION: Post-operative astigmatism is one of the most important causes for diminution of vision after trabeculectomy. OBJECTIVE: To evaluate the induced corneal astigmatism following trabeculectomy with the use of 8-0 silk suture. MATERIALS AND METHODS: A prospective interventional study was done including 100 consecutive eyes of 84 patients who underwent trabeculectomy with the use of 8-0 silk suture. The postoperative induced astigmatism on the 1st post-operative day, 3rd week and after 6 months was determined. STATISTICS: Vector analysis was performed on the data using a computerized method for calculating the surgically induced astigmatism (SIA) for each eye at every time point postoperatively. In order to analyze group changes, we also performed vector decomposition which gave us a mathematical expression of the changes in astigmatism "with the rule" (WTR) or "against the rule" (ATR). RESULTS: The mean age of all the patients was 53.31 11.39 years. The mean 1st post-operative surgically induced astigmatism (SIA) was 2.73 D ( 99 degree ) which reduced to 0.41 D ( 58 degree) at the 3rd week and 0.43 ( 21 degree) at 6 months. The mean WTR astigmatism was 4.46 D and ART astigmatism was 1.42 D on the 1st post-operative day which was significantly high ( p less than 0.0001). At the 3rd week and 6 months WTR astigmatism ( 1.40 D and 1.08D ) and ATR astigmatism (1.27 D and 1.10 D) showed no significant changes (p=0.69,0.97 respectively. CONCLUSION: Trabeculectomy with the use of 8/0 silk sutures showed significantly high 1st post-operative day SIA which nevertheless perished fast to a minimum amount at just 3 weeks. PMID- 24172558 TI - Comparison between limbal (von Noorden) and para limbal (Santiago) conjunctival incisions for adjustable recessions of horizontal recti. AB - INTRODUCTION: Both limbal and para limbal conjunctival incisions are routinely used in strabismus surgery with comparable results however their outcome has not been compared while using adjustable sutures. OBJECTIVE: To compare limbal (von Noorden) and para limbal (Santiago) conjunctival incisions for adjustable recessions of horizontal recti. SUBJECTS AND METHODS: Uniocular adjustable recessions (with conventional non adjustable resection) in 24 appropriate patients were performed according to standard slip knot technique. The patients were assigned to the two groups after obtaining an informed consent using systematmic randomization. Twelve patients in first group received the von Noorden incision with bare sclera closure and 12 in the second group received the Santiago's modification of Swan incision with deferred closure. The surgeries were performed by a single surgeon and the adjustments performed after 24 hours. The incisions were studied on the established subjective (pain) and objective (hyperaemia, chemosis, discharge and gap in incision) variables at follow ups of 1st day post adjustment, 2 weeks and 12 weeks. STATISTICS: 'Repeated Measures Anova' test was used for statistical analysis. A p value Less than 0.05 was considered statistically significant. RESULTS: The limbal incision was superior to the paralimbal incision on both objective and subjective criteria by 'Repeated Measures Anova' test. CONCLUSION: We recommend using limbal incision and avoiding para limbal incisions while performing adjustable recessions. PMID- 24172559 TI - Prevalence and determinants of xerophthalmia in rural children of Uttarpradesh, India. AB - INTRODUCTION: Vitamin A deficiency (VAD) is recognized as a major cause of blindness among children in India. OBJECTIVE: To find out the prevalence of VAD in rural children of Uttar Pradesh, India. MATERIALS AND METHODS: This cross sectional study was undertaken amongst children (0-15 years) in a rural area of Bareilly (Uttar Pradesh) where the study population was selected by simple random sampling out of villages under a Primary Health Centre. Out of 844 children, 802 participated in the study. The WHO classification of xerophthalmia was used. RESULTS: Overall, the prevalence of xerophthalmia was 5.4 %. The prevalence of Bitot's spots was 0.9 % in children under six years of age and 3.3 % in children above six years. The prevalence of xerophthalmia was significantly more in older children. Overall, the prevalence of anemia was found to be 11.8 % in the study population. A significantly high prevalence of xerophthalmia (OR= 5.7; 95 % CI = 2.8 - 11.5) was observed in children suffering from anemia. CONCLUSION: The presence of a milder manifestation of xerophthalmia and a 0.9 % prevalence of Bitot's spot in children under six years of age in the present study shows a declining trend of VAD although it is still a public health problem. The higher prevalence in children above six years of age shows that apart from strengthening of Vitamin A prophylaxis programs, health education is needed for dietary diversification to include vegetables and fruits in the diet for long-term sustainability in improving the vitamin A status of children of all age groups. PMID- 24172560 TI - Corneal edema after phacoemulsification surgery in patients with type II diabetes mellitus. AB - INTRODUCTION: Corneal edema delays early visual recovery after phacoemulsification surgery in diabetes mellitus. OBJECTIVE: To compare corneal edema of eyes in patients with type II diabetes mellitus and in non-diabetics after phacoemusification surgery. MATERIALS AND METHODS: A hospital-based, retrospective study involving 96 eyes that underwent phacoemulsification surgery for immature cataract at the Department of Ophthalmology, Kathmandu Medical College Teaching Hospital, Kathmandu, Nepal was carried out. Evaluation was performed of 33 eyes in patients with diabetes mellitus (diabetic group) and of 63 eyes in patients without diabetes mellitus (non-diabetic group). All diabetic patients had controlled blood glucose for at least one week prior to the surgery. The operated eye was examined before surgery and on one day, one week, and one month after surgery. Intraocular pressure was measured on each visit. MAIN OUTCOME MEASURES: The findings of post-operative corneal edema and visual acuity between the diabetic and non-diabetic groups were studied and compared. RESULTS: There was no difference clinically in any pre-operative corneal examination between the diabetic and non-diabetic groups. The corneal edema after surgery was significantly higher in the diabetic group than in the non-diabetic group (p less than 0.001). The number of patients with corneal edema one day and one week after surgery was significantly higher in the diabetic group than in the non-diabetic group (after 1 day, OR = 62.5; 95 % CI = 15.31 - 255.11, p less than 0.000) and after 1 week, OR = 6.77; 95 % CI = 1.28 - 35.76, p less than 0.006). CONCLUSION: Corneal edema following phacoemusification surgery in diabetic eyes is likely to be more frequent than in non-diabetic eyes. PMID- 24172561 TI - Outcome of the patients with post-operative cluster endophthalmitis referred to a tertiary level eye care center in Nepal. AB - INTRODUCTION: The causative organism and treatment outcomes of post operative endophthalmitis may vary depending on several factors. OBJECTIVE: To find out the causative organisms and visual outcome after an outbreak of post-operative endophthalmitis. MATERIALS AND METHODS: An interventional prospective series of cases of clinically suspected endophthalmitis was studied. Eleven patients who presented within 48 hours after manual cataract surgery on the same day, by a one surgeon in a single center were enrolled in the study. They underwent both anterior chamber and vitreous aspiration and all of them received intravitreal Vancomycin, Amikacin and Dexamethasone. Samples were subjected to microbiological evaluation. All patients were followed up till 8 weeks for clinical and visual outcome. RESULTS: Of the 11 eyes of suspected endopthalmitis, only one vitreous aspiration showed Gram negative bacilli on Gram stain and 3 vitreous aspirates showed Gram positive cocci. Of the 11 eyes, 3(42.85%) had culture positive on vitreous aspirate. In 2 cases E Coli was isolated and in 1 Staphylococcus aureus was isolated. After 48 hours of intravitreal injection, 10 out of 11 eyes improved and in one, intravitreal injection of vancomycin, amikacin and dexamethasone was repeated. The best corrected visual acuity of 6/9 was achieved in 2 patients, 5 had 6/18, 2 had 6/60 and 2 had 5/60 at the end of eight weeks. CONCLUSION: Staphylococcus aureus and E coli can cause endophthalmitis immediately on the first day post-operatively. Clinically suspected endophthalmitis treated with antibiotics and steroid intravitreal injection can result in better visual outcome. PMID- 24172562 TI - Calcium carbide related ocular burn injuries during mango ripening season of West Bengal, eastern India. AB - INTRODUCTION: Calcium carbide used in fruit ripening industry as a cheap alternative to natural plant hormone ethylene produces highly inflammable acetylene gas. Inadvertent ignition of this gas can cause severe ocular burn injury with unilateral or bilateral blindness. OBJECTIVE: To determine the characteristics and visual outcome of ocular burn injuries from calcium carbide during mango ripening season of West Bengal, eastern India. MATERIALS AND METHODS: A prospective study of all cases of calcium carbide related ocular burn injury attending a tertiary care hospital during mango ripening season was carried out. The demographic features, characteristics of the injury, management and outcomes were recorded. RESULTS: Fifty five eyes of 33 patients were studied. Males were more commonly affected (20 patients, 60.6%) than females. The injury was bilateral in 22 patients (66.66%). Seventeen patients (51.51%) were below 20 years of age. Ten eyes had open globe injuries and 45 eyes had closed globe injuries. One eye of a patient had to be enucleated (3%). Children below 14 years of age were mainly injured while playing with indigenous fireworks of shooting carbide. Middle aged women were affected particularly during ignition of evening lamps. Carbide lamp was another source of injury. CONCLUSION: Males are more commonly affected by calcium carbide related ocular injuries. Children and young adults are the common victims. Such injuries can involve both the eyes and cause a permanent visual disability. PMID- 24172563 TI - Myopia in school children from high mountain region of Nepal. AB - OBJECTIVE: Myopia is emerging as a public health problem in school going children. Prevalence of myopia differs in different geographical areas, race, ethnic groups and socioeconomic background. Purpose of this study was to find out myopia prevalence in schoolchildren from very high mountain region of Nepal. MATERIALS AND METHODS: It was a cross sectional descriptive study. Vision screening was conducted in Snowland School among the children who come from high mountain region. Vision screening was done by volunteers using standard Snellen's chart. Those who failed screening test underwent a detailed ophthalmological examination by a pediatric ophthalmologist. RESULTS: A total of 140 children had their vision assessed. Mean age was 13.9yrs (+/-2.8yrs SD). On screening, 28.5% children (n=40) had vision less than 6/9 in at least one eye. Seven children were already wearing myopic glasses, among which only 2 had vision 6/9 or better. Out of 40 children, 10% (n=4) had vision 6/9 or better and 90% (n=36) had refractive error. Out of these 36 children, myopia was present in all (100%).Hence prevalence of Myopia in total school population was 27% (n=38).All the children had simple Myopia from 0.5D-3.5D. After refractive correction, all the children had best corrected visual acuity of 6/9 or better. 86 % (n=120) children never had their eyes checked before. Conclusion The study showed high prevalence of myopia and was only ocular morbidity present in children. The result of this study can be a baseline in conducting large population based study in children from high mountains of Nepal. PMID- 24172564 TI - Retinal functional imager (RFI): non-invasive functional imaging of the retina. AB - Retinal functional imager (RFI) is a unique non-invasive functional imaging system with novel capabilities for visualizing the retina. The objective of this review was to show the utility of non-invasive functional imaging in various disorders. Electronic literature search was carried out using the websites www.pubmed.gov and www.google.com. The search words were retinal functional imager and non-invasive retinal imaging used in combination. The articles published or translated into English were studied. The RFI directly measures hemodynamic parameters such as retinal blood-flow velocity, oximetric state, metabolic responses to photic activation and generates capillary perfusion maps (CPM) that provides retinal vasculature detail similar to flourescein angiography. All of these parameters stand in a direct relationship to the function and therefore the health of the retina, and are known to be degraded in the course of retinal diseases. Detecting changes in retinal function aid early diagnosis and treatment as functional changes often precede structural changes in many retinal disorders. PMID- 24172565 TI - Ocular imaging findings of bilateral optic disc pit in a child. AB - BACKGROUND: To report a rare condition of bilateral optic disc pit in a child. CASE DESCRIPTION: A ten-year-old female was admitted with a complaint of headache. Visual acuity was 20/20 in both eyes (OU). Anterior segment examination was normal in OU. Fundus examination revealed optic disc pit (ODP) located temporally with a diameter of 1/5 disc diameter in OU. Intraocular pressure was within normal limits in both eyes. Macular optical coherence tomography (OCT) showed a loss of retinal tissue at the site corresponding to the ODP in both eyes. Retinal nerve fiber OCT revealed decreased RNFL thickness at the temporal side of the optic nerve, corresponding to the ODP in both eyes. The patient and patient's parents were informed about the disease and called for follow-up examinations every 6 months. In addition, the family was informed about optic pit maculopathy (OPM) and, they were told to return immediately if the patient ever complained of decreased vision in either of her eyes. After a follow-up period of 12 months, visual acuity remained stable, and no complications secondary to ODP were detected. CONCLUSION: Optic disc pit is diagnosed incidentally unless it is complicated with OPM. The retinal nerve fiber layer thickness is decreased at the side of the optic nerve corresponding to the ODP. PMID- 24172566 TI - A rare case of a solitary intraocular neurofibroma. AB - BACKGROUND: Solitary neurofibroma in the absence of neurofibromatosis is of rare occurrence and very few cases have been reported till date. OBJECTIVE: To report a case of a solitary intra-ocular neurofibroma. CASE: A 65-year-old man presented to us with a large swelling appearing to arise from right pthisical eye for the past one and a half years. After knowing the extent and origin of mass lesion, right eyeball was enucleated and subjected to histopathological examination which revealed intraocular neurofibroma in the absence of neurofibromatosis which is of very rare occurrence. CONCLUSION: The isolated neurofibroma of intraocular origin can present as an isolated orbital mass without systemic features. PMID- 24172567 TI - Conjunctival Kaposi's sarcoma as the initial manifestation of acquired inmunodeficiency syndrome. AB - Abstract Introduction: Kaposi's sarcoma is a common neoplasm in patients with acquired immunodeficiency syndrome (AIDS). Its presentation as an initial manifestation of AIDS is very rare . OBJECTIVE: To report a rare case with Kaposi's's sarcoma as an initial manifestation of AIDS. CASE: We report the case of a 37-year-old man who was a parenteral drug addict, HIV seropositive and was not under any treatment with a conjunctival lesion which was diagnosed as Kaposi's sarcoma after surgical resection. Conjunctival Kaposi's sarcoma is present frequently in HIV patients and lesions may be mistaken with other conjunctival lesions. PMID- 24172568 TI - Impacted iron nail in the orbit and maxillary sinus through a corneo-scleral perforation: a case report. AB - INTRODUCTION: Open globe injury is one of the commonest ophthalmic emergencies, and when accompanied by intraocular foreign bodies, the condition carries a poorer prognosis. OBJECTIVE: To report a rare case of perforating injury of the globe with an iron nail which got lodged in the maxillary sinus. CASE: A ten-year old boy presented with the history of sudden painful loss of vision in his right eye. He reported that he was hit forcefully by the tail of a cow a day before the presentation. There was no perception of light in that eye. The ocular examination revealed a full thickness corneo-scleral perforation with prolapsed uveal tissue. The X-ray of the right orbit showed an impacted foreign body in the inferior orbit and computed tomography scan of the orbit confirmed the presence of a vertically impacted metal piece in the right orbit and right maxillary sinus. The repair of the perforation and removal of the impacted nail was done in two stages. The globe anatomy was maintained but the vision could not be restored due to the grave nature of the trauma. CONCLUSION: Perforating globe injury is an important cause of monocular blindness. PMID- 24172569 TI - Traumatic avulsion and bilateral eye loss: report of two cases. AB - BACKGROUND: The optic nerve and the globes are resistant to mild to moderate trauma and bilateral avulsion of the eyes is rare with only a few cases reported in the literature. CASE: We report two cases of traumatic bilateral eye avulsion. The first case was secondary to a bear bite and was managed successfully, although the eyes were not salvageable whereas the second case which was due to physical assault expired due to associated severe head injury. CONCLUSION: Traumatic bilateral globe avulsion/loss is a rare complication of trauma. In developing countries like Nepal, poverty, forest encroachment activities, extensive deforestation, frequent domestic disturbances and lack of education are some of the circumstances that increase the probability of such visual injuries. PMID- 24172570 TI - Recurrence of uveal malignant melanoma: a case report. AB - BACKGROUND: Malignant melanoma of uveal tract is a rare ocular malignancy. It is one of the significant causes of ocular morbidity and mortality which is less commonly seen in children. CASE: We report an unusual case of orbital recurrence of malignant melanoma in a 14-year old boy who had previously undergone enucleation of the left painful blind eye 8 months ago. He was diagnosed to have uveal malignant melanoma elsewhere which was confirmed by histopathology. Orbital recurrence was managed with modified exenteration with adjuvant chemotherapy and radiotherapy. CONCLUSION: In all treated cases of uveal melanoma, close follow up examination and monitoring is necessary for early diagnosis of the recurrence and to plan for further management. PMID- 24172571 TI - Ocular myocysticercosis: an unusual case of ptosis. AB - BACKGROUND: Cysticercosis is common in endemic countries like India. It can have various clinical manifestations depending on the tissue involved. It refers to a parasitic infestation by Cysticercus cellulosae, the larval form of the pork tapeworm or Taenia solium. OBJECTIVE: To report an unusual case of ocular cysticercosis involving the levator palpebrae superioris and superior rectus muscle of the right eye. CASE DESCRIPTION: A young, male adult was diagnosed by Magnetic Resonance Imaging (MRI) scan of the skull and orbit to have right-sided ocular cysticercosis. The patient was treated with oral prednisolone and albendazole, to which he showed a significant improvement. CONCLUSION: Ocular myocysticercosis can be diagnosed by MRI and be treated medically with steroid and albendazole. PMID- 24172572 TI - Central retinal arterial occlusion (CRAO) after phacoemulsification-a rare complication. AB - BACKGROUND: While peribulbar anesthesia is generally safe, a remote risk of retinal vascular accident exists and its routine use should be done with caution. OBJECTIVE: To report a case of central retinal artery occlusion (CRAO) that occurred within 24 hours of routine uneventful phacoemulsification cataract surgery using peribulbar anesthesia. We share our experience of a 45-year old man who underwent uneventful clear corneal temporal incision phacoemulsification cataract surgery using peribulbar lignocain injection with adrenaline. CASE: A Patient who underwent routine phacoemulsification surgery of left eye for posterior sub-capsular cataract under peribulbar anesthesia developed central retinal artery occlusion in the immediate post-operative period. The surgery was uneventful. CONCLUSION: Central retinal artery occlusion is a rare but dreadful complication seen after uneventful phacoemulsification and the cause is mainly due to anesthesia related. PMID- 24172573 TI - Conjunctival impression cytology. PMID- 24172574 TI - Blepharoptosis and cysticercosis. PMID- 24172575 TI - Schwannoma of the sigmoid colon: a rare cause of sigmoidorectal intussusception. PMID- 24172577 TI - Brush sign on 3-T T2*-weighted MRI as a potential predictor of hemorrhagic transformation after tissue plasminogen activator therapy. AB - BACKGROUND AND PURPOSE: The brush sign (BS) is the enlargement of medullary veins on 3-T T2*-weighted MRI seen in patients with ischemic stroke because of major cerebral artery occlusion. However, the clinical relevance of BS in patients with acute stroke remains unclear. We assessed the correlation between detecting BS with the development of hemorrhagic transformation after intravenous thrombolysis. METHODS: We enrolled consecutive patients with M1 or M2 occlusion treated with intravenous tissue plasminogen activator. We classified the patients into 2 groups: the group positive for BS (P-BS) and the group negative for BS (N BS). We investigated the differences in MRI findings and the clinical outcome between the 2 groups. RESULTS: The subjects consisted of 36 patients (19 men; mean age, 74.7 years). Twenty-one patients (58%) had M1 occlusion, and 15 (42%) had M2 occlusion. Twenty-five patients (69%) were classified into the P-BS group and 11 (31%) into the N-BS group. Recanalization was observed in 15 (60%) and 10 (90%) patients in the P-BS and N-BS groups, respectively (P=0.116). Hemorrhagic transformation on MRI was observed more frequently in the P-BS group than in the N-BS group (64% versus 18%; P=0.027). A good outcome (mRS, 0-1) at discharge was found in 24% of patients in the P-BS group and in 45% of patients in the N-BS group (P=0.152). A multivariate logistic regression analysis revealed that the presence of BS (odds ratio, 9.08; 95% confidence interval, 1.4-59.8; P=0.022) was independently associated with hemorrhagic transformation. CONCLUSIONS: BS may predict the development of hemorrhagic transformation in patients with acute stroke treated with intravenous tissue plasminogen activator. PMID- 24172578 TI - Vasa vasorum enhancement on computerized tomographic angiography correlates with symptomatic patients with 50% to 70% carotid artery stenosis. AB - BACKGROUND AND PURPOSE: Significant stenosis of the internal carotid artery (ICA) is an established stroke risk factor. Recent evidence suggests that features within the atherosclerotic plaque also have prognostic value. The purpose of this study was to correlate the enhancement of the vasa vasorum (VV) overlying the carotid artery plaque with acute neurological symptoms in patients with 50% to 70% ICA stenosis. METHODS: We conducted a 4-year retrospective computerized tomographic angiographic review to identify patients with 50% to 70% stenosis of the ICA. Three types of plaques were identified: enhancing VV, calcified, and nonenhancing-noncalcified. Medical records were reviewed for cardiovascular risk factors and neurological status, and imaging was reviewed for signs of a recent stroke. RESULTS: We identified a total of 428 patients with 50% to 70% ICA stenosis: 103 (24.1%) had enhancing VV, 202 (47.2%) calcified, and 123 (28.7%) nonenhancing-noncalcified arteries; 97 were symptomatic and 331 asymptomatic. Thirty-three (34%) symptomatic subjects demonstrated enhancing VV, 42 (20%) had calcified arterial plaques, and 22 (17%) had nonenhancing-noncalcified arterial plaques. Fisher exact tests revealed that the proportion of symptomatic individuals with enhancing VV plaque was double that of the other groups combined (P=0.015; odds ratio, 1.92; 95% confidence interval, 1.17-3.16). Regression analyses confirmed this association as independent from other known cardiovascular risk factors. CONCLUSIONS: In patients with 50% to 70% ICA stenosis, VV enhancement recognized on computed tomographic angiography is strongly associated with acute neurological symptoms compared with calcified and nonenhancing-noncalcified arterial plaques. This finding may aid in the identification of patients at increased risk for ischemic stroke within populations with the same degree of stenosis. PMID- 24172576 TI - Prostaglandin F2alpha FP receptor antagonist improves outcomes after experimental traumatic brain injury. AB - BACKGROUND: Injuries to the brain promote upregulation of prostaglandins, notably the proinflammatory PGF2alpha, and overactivation of their cognate G-protein coupled FP receptor, which could exacerbate neuronal damage. Our study is focused on investigation of the FP receptor as a target for novel neuroprotective drugs in a preclinical animal traumatic brain injury (TBI) model. METHODS: Accordingly, the effects of acute intraperitoneal post-treatment with selective FP antagonist AL-8810 were studied in wildtype (WT) and FP receptor knockout (FP-/-) mice after controlled cortical impact (CCI). Neurological impairments were evaluated using neurological deficit scores (NDS) and the grip strength test. Cortical lesions and overall brain pathology were assessed using immunohistochemistry. RESULTS: Morphological analyses of cerebral vasculature and anastomoses revealed no differences between WT and FP-/- mice. CCI produced cortical lesions characterized by cavitation, neuronal loss, and hematoma with a volume of 20.0 +/ 1.0 mm(3) and significant hippocampal swelling (146.5 +/- 7.4% of contralateral) compared with sham (P < 0.05). Post-treatment with AL-8810 (1 to 10 mg/kg) had no significant effect on cortical lesions, which suggests the irreversible effect of primary CCI injury, but significantly reduced hippocampal swelling to a size not significantly different from the sham group. Post-treatment with AL-8810 at a dose of 10 mg/kg significantly improved NDS at 24 and 48 hours after CCI (P < 0.001 and P < 0.01, respectively). In the AL-8810 group, CCI-induced decrease in grip strength was three-fold (2.93 +/- 1.71) less and significantly different than in the saline-treated group. The FP-/- mice had significantly less hippocampal swelling, but not NDS, compared with WT mice. In addition, immunohistochemistry showed that pharmacologic blockade and genetic deletion of FP receptor led to attenuation of CCI-induced gliosis and microglial activation in selected brain regions. CONCLUSION: This study provides, for the first time, demonstration of the unique role of the FP receptor as a potential target for disease-modifying CNS drugs for treatment of acute traumatic injury. PMID- 24172579 TI - Does sex influence the response to intravenous thrombolysis in ischemic stroke?: answers from safe implementation of treatments in Stroke-International Stroke Thrombolysis Register. AB - BACKGROUND AND PURPOSE: Women are more likely to have a worse outcome after an acute stroke than men. Some studies have suggested that women also benefit less from intravenous thrombolysis after an acute ischemic stroke, but others found no sex differences in safety and efficacy. We aimed to evaluate differences in 3 month outcome between sexes in intravenous tissue-type plasminogen activator treated patients registered in the Safe Implementation of Treatments in Stroke International Stroke Thrombolysis Register. METHODS: A total of 45 079 patients treated with intravenous alteplase were recorded from 2002 to 2011. Main outcome measures were symptomatic intracerebral hemorrhage, functional independence (modified Rankin Scale score, 0-2), and mortality at 3 months. RESULTS: Among 25 777 (57.2%) men and 19 302 (42.8%) women, we found no difference in the rate of symptomatic intracerebral hemorrhage (P=0.13), a significantly higher likelihood of functional independence at 3 months in men (P<0.0001) and a higher mortality in women when compared with men (P<0.00001). After adjustment for confounding variables, we did not observe any difference between sexes in functional outcome (odds ratio, 1.03; 95% confidence interval, 0.97-1.09; P=0.39), whereas male sex was related to a higher risk of mortality (odds ratio, 1.19; 95% confidence interval, 1.10-1.29; P=0.00003) and symptomatic intracerebral hemorrhage (odds ratio, 1.25, 95% confidence interval, 1.04-1.51; P=0.02). CONCLUSIONS: Data from Safe Implementation of Treatments in Stroke-International Stroke Thrombolysis Register suggest that intravenous thrombolysis may modify the observed survival and recovery advantage for men expected in the natural course of an ischemic stroke, with a possible larger beneficial treatment effect in women when compared with men. PMID- 24172580 TI - Deferoxamine attenuates white matter injury in a piglet intracerebral hemorrhage model. AB - BACKGROUND AND PURPOSE: Deferoxamine reduces neuronal death in a piglet model of intracerebral hemorrhage (ICH). This study examined the effect of deferoxamine on perihematomal white matter edema in piglets. METHODS: ICH was induced by an injection of autologous blood into the right frontal lobe of piglets. In the first part of study, the time course of edema formation was determined. In the second part, the effects of deferoxamine on ICH-induced white matter edema, tumor necrosis factor alpha, and receptor-interacting protein kinase 1 were examined. RESULTS: ICH resulted in marked brain edema and increased tumor necrosis factor alpha and receptor-interacting protein kinase 1 levels in white matter. Systemic treatment with deferoxamine markedly reduced white matter tumor necrosis factor alpha and receptor-interacting protein kinase 1 levels and attenuated white matter edema after ICH. CONCLUSIONS: Deferoxamine reduces white matter edema, tumor necrosis factor alpha, and receptor-interacting protein kinase 1 levels after ICH in piglets, suggesting deferoxamine is a potential effective therapeutic agent for patients with ICH. PMID- 24172581 TI - Preventable readmissions within 30 days of ischemic stroke among Medicare beneficiaries. AB - BACKGROUND AND PURPOSE: The Centers for Medicare and Medicaid Services proposes to use 30-day hospital readmissions after ischemic stroke as part of the Hospital Inpatient Quality Reporting Program for payment determination beginning in 2016. The proportion of poststroke readmissions that is potentially preventable is unknown. METHODS: Thirty-day readmissions for all Medicare fee-for-service beneficiaries aged>=65 years discharged alive with a primary diagnosis of ischemic stroke (International Classification of Diseases, Ninth Revision, Clinical Modification 433, 434, 436) between December 2005 and November 2006 were analyzed. Preventable readmissions were identified based on 14 Prevention Quality Indicators developed for use with administrative data by the US Agency for Healthcare Research and Quality. National, hospital-level, and regional preventable readmission rates were estimated. Random-effects logistic regression was also used to determine patient-level factors associated with preventable readmissions. RESULTS: Among 307 887 ischemic stroke discharges, 44 379 (14.4%) were readmitted within 30 days; 5322 (1.7% of all discharges) were the result of a preventable cause (eg, pneumonia), and 39 057 (12.7%) were for other reasons (eg, cancer). In multivariate analysis, older age and cardiovascular-related comorbid conditions were strong predictors of preventable readmissions. Preventable readmission rates were highest in the Southeast, Mid-Atlantic, and US territories and lowest in the Mountain and Pacific regions. CONCLUSIONS: On the basis of Agency for Healthcare Research and Quality Prevention Quality Indicators, we found that a small proportion of readmissions after ischemic stroke were classified as preventable. Although other causes of readmissions not reflected in the Agency for Healthcare Research and Quality measures could also be avoidable, hospital-level programs intended to reduce all-cause readmissions and costs should target high-risk patients. PMID- 24172583 TI - Is action tremor in Parkinson's disease related to resting tremor? AB - OBJECTIVE: Action tremor (AT) and resting tremor (RT) have been widely cited in many studies with Parkinson's disease (PD) patients, but studies looking at the association between the two tremor types are few and show inconsistent results. This study will look at the prevalence and association of AT and RT in a large sample of idiopathic PD patients, and will put the results into context with the literature. METHODS: A retrospective chart review analysis of 332 patients with idiopathic PD was performed. Prevalence rates of particular tremor types were noted. The presence of AT was analyzed relative to the presence and severity of RT. RESULTS: Nearly all individuals with AT also had RT. The concurrence of the two tremor types was found to be highly significant by statistical analysis (P < 0.0001). The severity of RT, measured by its laterality, may also be of importance, albeit to a much smaller extent if at all. Neither presence of tremor nor type of tremor present was influenced by patient gender, age, or Hoehn and Yahr stage of PD. CONCLUSIONS: The results indicate that AT has extensive presence in PD. This and its seemingly close relationship to RT suggest that AT may be considered a variant of RT, particularly in PD patients. The degree of association between RT and AT needs to be further analyzed in PD, as well as in essential tremor (ET) and ET-PD. PMID- 24172582 TI - Bryostatin improves survival and reduces ischemic brain injury in aged rats after acute ischemic stroke. AB - BACKGROUND AND PURPOSE: Bryostatin, a potent protein kinase C (PKC) activator, has demonstrated therapeutic efficacy in preclinical models of associative memory, Alzheimer disease, global ischemia, and traumatic brain injury. In this study, we tested the hypothesis that administration of bryostatin provides a therapeutic benefit in reducing brain injury and improving stroke outcome using a clinically relevant model of cerebral ischemia with tissue plasminogen activator reperfusion in aged rats. METHODS: Acute cerebral ischemia was produced by reversible occlusion of the right middle cerebral artery (MCAO) in 18- to 20 month-old female Sprague-Dawley rats using an autologous blood clot with tissue plasminogen activator-mediated reperfusion. Bryostatin was administered at 6 hours post-MCAO, then at 3, 6, 9, 12, 15, and 18 days after MCAO. Functional assessment was conducted at 2, 7, 14, and 21 days after MCAO. Lesion volume and hemispheric swelling/atrophy were performed at 2, 7, and 21 days post-MCAO. Histological assessment of PKC isozymes was performed at 24 hours post-MCAO. RESULTS: Bryostatin-treated rats showed improved survival post-MCAO, especially during the first 4 days. Repeated administration of bryostatin post-MCAO resulted in reduced infarct volume, hemispheric swelling/atrophy, and improved neurological function at 21 days post-MCAO. Changes in alphaPKC expression and epsilonPKC expression in neurons were noted in bryostatin-treated rats at 24 hours post-MCAO. CONCLUSIONS: Repeated bryostatin administration post-MCAO protected the brain from severe neurological injury post-MCAO. Bryostatin treatment improved survival rate, reduced lesion volume, salvaged tissue in infarcted hemisphere by reducing necrosis and peri-infarct astrogliosis, and improved functional outcome after MCAO. PMID- 24172584 TI - Digital breast tomosynthesis image reconstruction using 2D and 3D total variation minimization. AB - BACKGROUND: Digital breast tomosynthesis (DBT) is an emerging imaging modality which produces three-dimensional radiographic images of breast. DBT reconstructs tomographic images from a limited view angle, thus data acquired from DBT is not sufficient enough to reconstruct an exact image. It was proven that a sparse image from a highly undersampled data can be reconstructed via compressed sensing (CS) techniques. This can be done by minimizing the l1 norm of the gradient of the image which can also be defined as total variation (TV) minimization. In tomosynthesis imaging problem, this idea was utilized by minimizing total variation of image reconstructed by algebraic reconstruction technique (ART). Previous studies have largely addressed 2-dimensional (2D) TV minimization and only few of them have mentioned 3-dimensional (3D) TV minimization. However, quantitative analysis of 2D and 3D TV minimization with ART in DBT imaging has not been studied. METHODS: In this paper two different DBT image reconstruction algorithms with total variation minimization have been developed and a comprehensive quantitative analysis of these two methods and ART has been carried out: The first method is ART + TV2D where TV is applied to each slice independently. The other method is ART + TV3D in which TV is applied by formulating the minimization problem 3D considering all slices. RESULTS: A 3D phantom which roughly simulates a breast tomosynthesis image was designed to evaluate the performance of the methods both quantitatively and qualitatively in the sense of visual assessment, structural similarity (SSIM), root means square error (RMSE) of a specific layer of interest (LOI) and total error values. Both methods show superior results in reducing out-of-focus slice blur compared to ART. CONCLUSIONS: Computer simulations show that ART + TV3D method substantially enhances the reconstructed image with fewer artifacts and smaller error rates than the other two algorithms under the same configuration and parameters and it provides faster convergence rate. PMID- 24172585 TI - Inaccurate weight perception is associated with extreme weight-management practices in U.S. high school students. AB - OBJECTIVE: The objective of the present study was to examine whether adolescents' weight perception accuracy (WPA) was associated with extreme weight-management practices (EWPs) in differing body mass index (BMI) categories. METHODS: WPA, overassessment, and underassessment were determined by comparing self-reported BMI and weight perception among U.S. high school students in the 2009 National Youth Risk Behavior Survey. BMI was classified as follows: underweight (<5th percentile), healthy weight (5th to <85th), overweight (>=85th to <95th), and obese (>=95th). WPA was considered inaccurate if BMI and weight perception were discordant. Overassessors thought they were heavier than they were (among underweight/healthy groups); underassessors thought they were lighter than they were (among healthy/overweight/obese groups). EWPs included >=1 of fasting, use of diet pills, or purging/laxative use. Logit models were fitted for different BMI sex strata. RESULTS: In the final sample of 14,722 US high school students with complete data, 20.2%, 85.7%, 5.8%, and 80.9% of those who were underweight, healthy weight, overweight, and obese, inaccurately assessed their weight, respectively. In turn, 11.4% and 17.6% of accurate and inaccurate assessors engaged in EWPs, respectively. After adjustment, underweight girls who overassessed their weight had 12.6 times higher odds of EWPs (95% confidence interval 3.4-46.6). Moreover, there were elevated odds of EWPs among healthy weight students who overassessed their weight. CONCLUSIONS: Overassessing healthy weight students and underweight girls had higher odds of >=1 EWPs, likely related to an unhealthy desire to lose weight. The present study demonstrates a need to further educate clinicians on WPA and its relation to EWPs even among those of healthy weight who may be seen as not at risk. PMID- 24172586 TI - Fatal Hepatic Hemorrhage from Peliosis Hepatis with X-linked Myotubular Myopathy. PMID- 24172587 TI - High fat feeding promotes obesity and renal inflammation and protects against post cardiopulmonary bypass acute kidney injury in swine. AB - INTRODUCTION: Obesity confers a survival advantage in the critically ill and in patients undergoing cardiac surgery. We explored whether an obesogenic high fat diet could confer protection against post cardiopulmonary bypass (CPB) acute kidney injury (AKI) in a swine model. METHODS: In this study, 28 anaesthetised adult female Landrace White swine (55 to 70 kg) were allocated into a 4 group design to either 2.5 hours of CPB or Sham operation with or without pre procedural high fat (HF) feeding containing 15% lard, 1.5% cholesterol and 1% cholic acid for 12-weeks (Groups: Sham, CPB, CPB + HF and Sham + HF). Our primary endpoint was creatinine clearance measured at 1.5 and 24 hours post intervention. This is a validated index of the glomerular filtration rate (GFR) in swine and an endpoint used in our clinical studies. Secondary endpoints included measures of systemic and renal inflammation, endothelial homeostasis, tubular injury and dysfunction, and inflammatory cell signalling. Differences between groups were calculated using analysis of variance with adjustment for baseline differences for repeated measures. RESULTS: CPB in pigs fed a normal chow diet resulted in AKI. This was characterised by reductions in GFR sustained for up to 24 hours post injury relative to Sham operated pigs fed a normal diet; mean difference 50.2 ml/min (95% CI 5.9 to 94.4). Post CPB AKI was also characterised by renal inflammation, parallel activation of both pro-inflammatory (NF-kB, iNOS) and pro survival pathways (pAkt, p70s6k, HIF-1alpha) and apoptosis. Pigs fed a 12-week high fat diet developed obesity and hyperlipidaemia. This was associated with increased redox sensitive pro-inflammatory and anti-apoptotic signalling, and tubular epithelial cell proliferation. High fat feeding also protected swine against post CPB AKI; mean difference in creatinine clearance CPB - CPB + HF 65.3 ml/min (95% CI -106.9 to -23.7), by preserving endothelial homeostasis and function, and preventing the reductions in GFR, loss of ATP and tubular apoptosis that characterise the extension phase of AKI in swine at 24 hours post injury. Reno-protection was not attributed to pAkt signaling. CONCLUSIONS: A high fat diet promoted obesity and renal inflammation and prevented post CPB AKI in swine. This study provides insights into the obesity paradox and the failure of anti inflammatory interventions to improve clinical outcomes in patients at risk of post cardiac surgery AKI. PMID- 24172588 TI - Decompression only versus fusion surgery for lumbar stenosis in elderly patients over 75 years old: which is reasonable? AB - As the population ages, more elderly patients suffer from spinal stenosis requiring lumbar fusion. However, there are few and conflicting results regarding the clinical outcome of lumbar fusion. The purpose of this study is to evaluate the safety and efficiency of posterior lumbar interbody fusion (PLIF) in over 75 year-old patients and analyze the relative effectiveness of lumbar spinal fusion surgery compared with decompression surgery for spinal stenosis. This retrospective review evaluated 25 patients aged 75 to 93 who were diagnosed with spinal stenosis and underwent PLIF for 24 months. The control group included 25 patients who were matched for age, gender, level, race, and severity of stenosis, and who underwent decompressive laminectomy and flavectomy without fusion (DLF). The fusion rate in the PLIF group was 32.0%, 84.0%, and 96.0% at 6, 12, and 24 months, respectively. During the follow-up period, 4 (16%) and 2 (8%) patients underwent revision surgery in the DLF and PLIF groups, respectively. The back pain in the DLF group decreased from 5.6 to 2.1 at 6 months and then substantially increased to 3.4 at 24 months. The decrease in back pain score after treatment was greater in the PLIF group compared to the DLF group (P < 0.01) with a statistically significant difference in the trend in the two groups over time (P < 0.01). Even in elderly patients, lumbar surgery appears to be a safe and justifiable treatment for spinal stenosis. Lumbar fusion surgery rather than decompressive surgery was recommended for those patients who mainly complained of back pain. PMID- 24172589 TI - Symptomatic osteochondroma of lumbosacral spine: report of 5 cases. AB - We describe 5 cases of osteochondroma (OC) originating from lumbosacral spine which caused radiculopathy. Four cases originated from the lumbar spine; all from L4 inferior articular process and presented L5 radiculopathy, the other one case originated from the sacrum; the case from S1 superior articular process presented L5 radiculopathy. In all cases, definitive diagnosis was made with histopathological findings; typical cartilaginous capping was confirmed. The functional recovery was completed in all 5 cases. As for imaging study, post myelography computed tomography revealed the most diagnostic tool for understanding the relationship between nerve tissue and the tumor. In all 5 patients, the tumors contained a high signal intensity on T2-weighted images in the central medullary area. OCs are sometimes difficult to diagnose because they mimic other conditions like bony spur formation due to osteoarthritis, so we should never fail to confirm the histopathological diagnosis of such lesions when suspected. PMID- 24172590 TI - Presentation with recurrent intractable headache: a patient with moyamoya syndrome--case report. AB - This clinical case report represents an interesting manifestation of a neurovascular condition that can be easily overlooked by the practicing healthcare provider. In the United States, a Hispanic patient of non-Asian descent presented with atypical symptoms of intractable headache and nausea with no evidence of neurologic deficits. Further diagnostic work-up was performed as the patient was not responding to traditional analgesic medication administration. Ultimately, cerebral angiogram revealed vascular occlusion with collateral circulation consistent with moyamoya syndrome. Discussion of the challenges and available clinical guidance for healthcare professionals dealing with patients presenting with intractable headache are presented in this report. PMID- 24172591 TI - Usefulness of FMISO-PET for glioma analysis. AB - Glioma is one of the most common brain tumors in adults. Its diagnosis and management have been determined by histological classifications. It is difficult to establish new paradigms because the pathology has matured and a great deal of knowledge has accumulated. On the other hand, we understand that there are limitations to this gold-standard because of the heterogeneity of glioma. Thus, it is necessary to find new criteria independent of conventional morphological diagnosis. Molecular imaging such as positron emission tomography (PET) is one of the most promising approaches to this challenge. PET provides live information of metabolism through the behavior of single molecules. The advantage of PET is that its noninvasive analysis does not require tissue sample, therefore examination can be performed repeatedly. This is very useful for capturing changes in the biological nature of tumor without biopsy. In the present clinical practice for glioma, (18)F-fluorodeoxyglucose (FDG) PET is the most common tracer for predicting prognosis and differentiating other malignant brain tumors. Amino acid tracers such as (11)C-methionine (MET) are the most useful for detecting distribution of glioma, including low-grade. Tracers to image hypoxia are under investigation for potential clinical use, and recently, (18)F-fluoromisonidazole (FMISO) has been suggested as an effective tracer to distinguish glioblastoma multiforme from others. PMID- 24172592 TI - Posterolateral sulcus approach for spinal intramedullary tumor of lateral location: technical note. AB - Posterolateral sulcus (PLS) approach of the spinal cord, being equivalent to the dorsal root entry zone myelotomy, may offer the satisfactory exposure of the spinal intramedullary tumor if applied appropriately. Eight consecutive patients with spinal intramedullary tumors of lateral location underwent the surgery of PLS approach in our institute. There were 6 male and 2 female patients, ranging in age from 34 to 72 years (mean, 57 years). PLS approach was indicated for the intramedullary tumor situated laterally in the spinal cord and that do not contact the posterior or lateral surfaces on magnetic resonance (MR) images before surgery. Total removal of the tumor was achieved in 6 cases except of 2 cases of anaplastic astrocytoma. All 6 patients with total removal of the tumor demonstrated the modest or mild deterioration of motor function on the approach side early after surgery, which resolved within 1 month after surgery. Average grade of the modified McCormick functional schema was 3.5 before surgery and improved to 3.0 at 3 months after surgery. These 6 patients demonstrated satisfactory pain relief early after surgery. Average grade of the sensory pain scale was 2.7 before surgery and improved to 1.7 at 3 months after surgery. PLS approach can be one of the surgical choices to the spinal intramedullary tumors, if applied appropriately. Better indication for PLS approach may be the tumors of the uneven location within the spinal cord associated with moderate or severe local pain. PMID- 24172593 TI - Overexpression of copper transporter CTR1 in the brain barrier of North Ronaldsay sheep: implications for the study of neurodegenerative disease. AB - Age-related regulatory failure of the brain barrier towards the influx of redox metals such as copper and iron may be associated with the pathological changes that characterize dementias such as Alzheimer's diseases (ADs) and amyotrophic lateral sclerosis (ALS). The integrity of the brain barrier to regulate copper in the brain is maintained by the complex interplay of membrane-located transporters, of which copper transporter 1 (CTR1) exerts a defining role. North Ronaldsay (NR) sheep are a primitive breed that have adapted to a copper deficient environment by an enhanced uptake of the metal, resulting in copper overload in the liver and brain. This study reports that CTR1 is overexpressed in both the blood-brain barrier (BBB) and the blood-cerebrospinal fluid barrier (BCB) of adult NR sheep when compared with a domesticated breed. The excess copper is stored ultimately in astrocytes as non-injurious copper-metallothionein (MT). NR sheep have apparently retained an immature regulatory setting for CTR1 in the BBB, promoting facilitated copper uptake into the brain. This putative failure of maturation of CTR1 allows insight into the regulatory control of brain copper homeostasis, whereby the BBB and BCB act in concert to sequester excess copper and protect neurons from injury. The elevated copper content of the ageing human brain may derive from a dysregulation of CTR1 at the brain barrier, with a return to the default (immature) setting and implications for neurodegenerative disease. PMID- 24172594 TI - Impairment of systemic microvascular endothelial and smooth muscle function in individuals with early-onset coronary artery disease: studies with laser speckle contrast imaging. AB - OBJECTIVES: The assessment of systemic microvascular reactivity is currently considered to be critical in the stratification of cardiovascular risk. In the present study, we compared skin microvascular function in individuals with early onset (premature) coronary artery disease (EOCAD, n=30) with that of age-matched and sex-matched healthy individuals (n=30). MATERIALS AND METHODS: Using laser speckle contrast imaging, cutaneous blood flow was assessed in the forearm at rest and during reactivity tests, including postocclusive reactive hyperemia and the iontophoresis of acetylcholine or sodium nitroprusside with increasing currents of 30, 60, 90, 120, 150, and 180 MUA for 10-s intervals spaced 1 min apart. Carotid intima-media thickness was evaluated using an ultrasound system and a 7.5 MHz ultrasound transducer. RESULTS: The endothelium-dependent skin microvascular vasodilator responses that were induced by both acetylcholine and postocclusive reactive hyperemia were significantly reduced in patients with EOCAD compared with healthy individuals. The vasodilator responses that were induced by sodium nitroprusside were also significantly reduced in individuals with EOCAD. These systemic microvascular alterations were concurrent with increased carotid intima-media thickness in these patients. CONCLUSION: Laser speckle contrast imaging identifies endothelial-dependent and endothelial independent microvascular dysfunction in individuals presenting with EOCAD, and thus could be valuable as an early peripheral marker of atherothrombotic disease. PMID- 24172595 TI - Structural study of alpha-Bi2O3 under pressure. AB - An experimental and theoretical study of the structural properties of monoclinic bismuth oxide (alpha-Bi2O3) under high pressures is here reported. Both synthetic and mineral bismite powder samples have been compressed up to 45 GPa and their equations of state have been determined with angle-dispersive x-ray diffraction measurements. Experimental results have been also compared with theoretical calculations which suggest the possibility of several phase transitions below 10 GPa. However, experiments reveal only a pressure-induced amorphization between 15 and 25 GPa, depending on sample quality and deviatoric stresses. The amorphous phase has been followed up to 45 GPa and its nature discussed. PMID- 24172596 TI - Inverting ion images without Abel inversion: maximum entropy reconstruction of velocity maps. AB - A new method for the reconstruction of velocity maps from ion images is presented, which is based on the maximum entropy concept. In contrast to other methods used for Abel inversion the new method never applies an inversion or smoothing to the data. Instead, it iteratively finds the map which is the most likely cause for the observed data, using the correct likelihood criterion for data sampled from a Poissonian distribution. The entropy criterion minimizes the information content in this map, which hence contains no information for which there is no evidence in the data. Two implementations are proposed, and their performance is demonstrated with simulated and experimental data: Maximum Entropy Velocity Image Reconstruction (MEVIR) obtains a two-dimensional slice through the velocity distribution and can be compared directly to Abel inversion. Maximum Entropy Velocity Legendre Reconstruction (MEVELER) finds one-dimensional distribution functions Q(l)(v) in an expansion of the velocity distribution in Legendre polynomials P((cos theta) for the angular dependence. Both MEVIR and MEVELER can be used for the analysis of ion images with intensities as low as 0.01 counts per pixel, with MEVELER performing significantly better than MEVIR for images with low intensity. Both methods perform better than pBASEX, in particular for images with less than one average count per pixel. PMID- 24172597 TI - Contact sensitizing potential of pyrogallol and 5-amino-o-cresol in female BALB/c mice. AB - Hair dye components such as pyrogallol and cresol have been shown previously to promote allergic reactions such as rashes, dermal inflammation, irritation and dermatitis. The objective of this study was to determine the contact sensitization potential of pyrogallol (PYR) and 5-amino-o-cresol (AOC) when applied dermally to female BALB/c mice. Measurement of the contact hypersensitivity response was initially accomplished using the local lymph node assay. For PYR, significant increases in the proliferation of lymph node cells were observed at concentrations of 0.5% (w/v) and higher. For AOC, borderline increases, albeit significant, in auricular lymph node cell proliferation were observed at 5% and 10%. Results from the irritancy assay suggested that PYR, but not AOC, was an irritant. To further delineate whether PYR was primarily an irritant or a contact sensitizer, the mouse ear swelling test (MEST) was conducted. A significant increase in mouse ear thickness was observed at 72h following challenge with 0.5% PYR in mice that had been sensitized with 5% PYR. In contrast, no effects were observed in the MEST in mice sensitized and challenged with the highest achievable concentration of AOC (10%). Additional studies examining lymph node subpopulations and CD86 (B7.2) expression by B cells further support the indication that PYR was a sensitizer in BALB/c mice. The results demonstrate that PYR is both a sensitizer and an irritant in female BALB/c mice. However, the contact sensitization potential of AOC is minimal in this strain of mouse. PMID- 24172598 TI - Diuron metabolites and urothelial cytotoxicity: in vivo, in vitro and molecular approaches. AB - Diuron is carcinogenic to the rat urinary bladder at high dietary levels. The proposed mode of action (MOA) for diuron is urothelial cytotoxicity and necrosis followed by regenerative urothelial hyperplasia. Diuron-induced urothelial cytotoxicity is not due to urinary solids. Diuron is extensively metabolized, and in rats, N-(3,4-dichlorophenyl)urea (DCPU) and 4,5-dichloro-2-hydroxyphenyl urea (2-OH-DCPU) were the predominant urinary metabolites; lesser metabolites included N-(3,4-dichlorophenyl)-3-methylurea (DCPMU) and trace levels of 3,4 dichloroaniline (DCA). In humans, DCPMU and DCPU have been found in the urine after a case of product abuse. To aid in elucidating the MOA of diuron and to evaluate the metabolites that are responsible for the diuron toxicity in the bladder epithelium, we investigated the urinary concentrations of metabolites in male Wistar rats treated with 2500ppm of diuron, the urothelial cytotoxicity in vitro of the metabolites and their gene expression profiles. DCPU was found in rat urine at concentrations substantially greater than the in vitro IC50 and induced more gene expression alterations than the other metabolites tested. 2-OH DCPU was present in urine at a concentration approximately half of the in vitro IC50, whereas DCPMU and DCA were present in urine at concentrations well below the IC50. For the diuron-induced MOA for the rat bladder, we suggest that DCPU is the primary metabolite responsible for the urothelial cytotoxicity with some contribution also by 2-OH-DCPU. This study supports a MOA for diuron-induced bladder effects in rats consisting of metabolism to DCPU (and 2-OH-DCPU to a lesser extent), concentration and excretion in urine, urothelial cytotoxicity, and regenerative proliferation. PMID- 24172599 TI - Response to Rogers et al. PMID- 24172600 TI - Thrombus morphology may be an indicator for aneurysm expansion. PMID- 24172601 TI - Late occurrence of brachial artery aneurysm after the closure of a long-standing vascular access for hemodialysis: a pathogenetic hypothesis. PMID- 24172602 TI - Tension pneumomediastinum after blunt chest trauma. PMID- 24172603 TI - Uranium and thorium sequential separation from norm samples by using a SIA system. AB - This study presents a sequential radiochemical separation method for uranium and thorium isotopes using a novel Sequential Injection Analysis (SIA) system with an extraction chromatographic resin (UTEVA). After the separation, uranium and thorium isotopes have been quantified by using alpha-particle spectrometry. The developed method has been tested by analyzing an intercomparison sample (phosphogypsum sample) from International Atomic Energy Agency (IAEA) with better recoveries for uranium and thorium than the obtained by using a classical method (93% for uranium using the new methodology and 82% with the classical method, and in the case of thorium the recoveries were 70% for the semi-automated method and 60% for the classical strategy). Afterwards, the method was successfully applied to different Naturally Occurring Radioactive Material (NORM) samples, in particular sludge samples taken from a drinking water treatment plant (DWTP) and also sediment samples taken from an area of influence of the dicalcium phosphate (DCP) factory located close to the Ebro river reservoir in Flix (Catalonia). The obtained results have also been compared with the obtained by the classical method and from that comparison it has been demonstrated that the presented strategy is a good alternative to existing methods offering some advantages as minimization of sample handling, reduction of solvents volume and also an important reduction of the time per analysis. PMID- 24172604 TI - Hadley cell influence on (7)Be activity concentrations at Australian mainland IMS radionuclide particulate stations. AB - Beryllium-7 ((7)Be) daily data from the four International Monitoring System (IMS) radionuclide particulate stations on mainland Australia are analysed over the period 2001 to 2011. The analysis indicates that levels of (7)Be in surface air at the stations follow annual cycles, with yearly peak activity concentrations occurring later at stations further south. The yearly peak migrates north-south at a rate of approximately 4.4 degrees latitude per month. The change in phase of the (7)Be annual cycle between the stations corresponds with the seasonal migration of the Southern Hemisphere Hadley cell across mainland Australia. The implication is that the changing position of the downward limb of the Southern Hemisphere Hadley cell regulates the phase of the annual cycle in (7)Be activity concentrations in surface air in the Australian region. PMID- 24172605 TI - Development, description and validation of a Tritium Environmental Release Model (TERM). AB - Tritium is a radioisotope of hydrogen that exists naturally in the environment and may also be released through anthropogenic activities. It bonds readily with hydrogen and oxygen atoms to form tritiated water, which then cycles through the hydrosphere. This paper seeks to model the migration of tritiated species throughout the environment - including atmospheric, river and coastal systems - more comprehensively and more consistently across release scenarios than is currently in the literature. A review of the features and underlying conceptual models of some existing tritium release models was conducted, and an underlying aggregated conceptual process model defined, which is presented. The new model, dubbed 'Tritium Environmental Release Model' (TERM), was then tested against multiple validation sets from literature, including experimental data and reference tests for tritium models. TERM has been shown to be capable of providing reasonable results which are broadly comparable with atmospheric HTO release models from the literature, spanning both continuous and discrete release conditions. TERM also performed well when compared with atmospheric data. TERM is believed to be a useful tool for examining discrete and continuous atmospheric releases or combinations thereof. TERM also includes further capabilities (e.g. river and coastal release scenarios) that may be applicable to certain scenarios that atmospheric models alone may not handle well. PMID- 24172606 TI - Potential of a new MRI for visualizing cerebellar involvement in progressive supranuclear palsy. AB - OBJECTIVES: We assessed the usefulness of differential diagnosis of parkinsonism by evaluating lesions of the decussation of the superior cerebellar peduncle (SCP) in patients with progressive supranuclear palsy (PSP) using a new MRI procedure known as readout segmentation of long variable echo-trains (RESOLVE). METHODS: We evaluated 100 cases, consisting of 20 with PSP, 24 with Parkinson's disease (PD), 13 with multiple system atrophy with predominant parkinsonism (MSA P), 18 with multiple system atrophy with predominant cerebellar ataxia (MSA-C), and 24 controls. All patients were scored on the Unified Parkinson's Disease Rating Scale Part III and the Scale for the Assessment and Rating Scale of Ataxia, and MRI using RESOLVE was conducted. RESULTS: Images acquired by this MRI procedure clearly showed high intensity areas corresponding to the decussation of the SCP in all controls, PD, and MSA patients. In contrast, ten of the 20 PSP patients exhibited abnormal iso intensities of the decussation of the SCP, while the other 10 showed high intensity signals. Among the PSP patients, there were no differences in clinical features between those with and those without visualization of the decussation of the SCP. Iso intensity signals had a sensitivity of 50% and a specificity of 100% for differentiating PSP from PD, MSA, and controls. CONCLUSION: This MRI procedure (RESOLVE) shows a potential for detecting the involvement of the decussation of the SCP in PSP, and can be used for discriminating PSP from PD and MSA-P. PMID- 24172607 TI - Serum activin A and B levels predict outcome in patients with acute respiratory failure: a prospective cohort study. AB - INTRODUCTION: 30 day mortality in patients with Acute Respiratory Failure (ARF) is approximately 30%, defined as patients requiring ventilator support for more than 6 hours. Novel biomarkers are needed to predict patient outcomes and to guide potential future therapies. The activins A and B, members of the Transforming Growth Factor beta family of proteins, and their binding protein, follistatin, have recently been shown to be important regulators of inflammation and fibrosis but no substantial data are available concerning their roles in ARF. METHODS: Specific assays for activin A, B and follistatin were used and the results analyzed according to diagnostic groups as well as according to standard measures in intensive care. Multivariable logistic regression was used to create a model to predict death at 90 days and 12 months from the onset of the ARF. RESULTS: Serum activin A and B were significantly elevated in most patients and in most of the diagnostic groups. Patients who had activin A and/or B concentrations above the reference maximum were significantly more likely to die in the 12 months following admission [either activin A or B above reference maximum: Positive Likelihood Ratio [LR+] 1.65 [95% CI 1.28-2.12, P = 0.00013]; both activin A and B above reference maximum: LR + 2.78 [95% CI 1.96-3.95, P < 0.00001]. The predictive model at 12 months had an overall accuracy of 80.2% [95% CI 76.6-83.3%]. CONCLUSIONS: The measurement of activin A and B levels in these patients with ARF would have assisted in predicting those at greatest risk of death. Given the existing data from animal studies linking high activin A levels to significant inflammatory challenges, the results from this study suggest that approaches to modulate activin A and B bioactivity should be explored as potential therapeutic agents. PMID- 24172608 TI - Benchtop fabrication of three-dimensional reconfigurable microfluidic devices from paper-polymer composite. AB - We presented a benchtop technique that can fabricate reconfigurable, three dimensional (3D) microfluidic devices made from a soft paper-polymer composite. This fabrication approach can produce microchannels at a minimal width of 100 MUm and can be used to prototype 3D microfluidic devices by simple bending and stretching. The entire fabrication process can be finished in 2 hours on a laboratory bench without the need for special equipment involved in lithography. Various functional microfluidic devices (e.g., droplet generator and reconfigurable electronic circuit) were prepared using this paper-polymer hybrid microfluidic system. The developed method can be applied in a wide range of standard applications and emerging technologies such as liquid-phase electronics. PMID- 24172609 TI - Illusory position shift induced by motion within a moving envelope during smooth pursuit eye movements. AB - The static envelope of a Gabor patch with a moving carrier appears to shift in the direction of the carrier motion; this phenomenon is known as the motion induced position shift (De Valois & De Valois, 1991; Ramachandran & Anstis, 1990). This conventional stimulus configuration contains at least three covarying factors: the retinal carrier velocity, the environmental carrier velocity, and the carrier velocity relative to the envelope velocity, which happens to be zero. We manipulated these velocities independently to identify which is critical, and we measured the perceived position of the moving Gabor patch relative to a reference stimulus moving in the same direction at the same speed. In the first experiment, the position of the moving envelope observed with fixation appeared to shift in the direction of the carrier velocity relative to the envelope velocity. Furthermore, the illusion was more pronounced when the carrier moved in a direction opposite to that of the envelope. In the second and third experiments, we measured the illusion during smooth-pursuit eye movement in which the envelope was either static or moving, thereby dissociating retinal and environmental velocities. Under all conditions, the illusion occurred according to the envelope-relative velocity of the carrier. Additionally, the illusion was more pronounced when the carrier and envelope moved in opposite directions. We conclude that the carrier's envelope-relative velocity is the primary determinant of the motion-induced position shift. PMID- 24172610 TI - A slingshot rather than a cannon. PMID- 24172611 TI - [Difficulties to sleep--too much hypnotics]. PMID- 24172612 TI - [Wrong focus]. PMID- 24172613 TI - [Misconceptions about the market]. PMID- 24172614 TI - [Medicine is politics]. PMID- 24172615 TI - [No significant effect of PSA screening]. PMID- 24172616 TI - [Feedback]. PMID- 24172620 TI - The PRWHE form in Norwegian--assessment of hand and wrist afflictions. PMID- 24172621 TI - [Should grades be reintroduced in medical education?]. PMID- 24172622 TI - Health care related to workplace bullying. PMID- 24172623 TI - [Working after the age of 67 and retirement]. PMID- 24172626 TI - Chloramphenicol eye drops in the treatment of conditions indicative of maxillary sinusitis. AB - BACKGROUND: Our own clinical experience of general practice over the last 15 years has indicated that chloramphenicol eye drops may have a favourable effect on many patients troubled by symptoms indicative of acute maxillary sinusitis. We wanted to conduct a pilot study to test whether this observation could be verified. MATERIAL AND METHOD: Treatment with chloramphenicol eye drops or systemic peroral antibiotics was tested on patients with symptoms indicative of acute maxillary sinusitis. The patients were randomised to two groups, one of which received systemic peroral antibiotics, the other received chloramphenicol eye drops. RESULTS: A total of 33 patients were included in the trial--27 women and six men--15 of whom were randomised to the tablet group and 18 of whom were randomised to the chloramphenicol group. The patients who were treated with tablets experienced clear improvement after an average of 5.0 days, while patients who were treated with chloramphenicol eye drops, experienced improvement after 3.7 days (p = 0.047). Of the patients in the chloramphenicol group, 14 described improvement within three days, while this applied to only five patients in the tablet group. INTERPRETATION: Treatment with chloramphenicol eye drops appears to represent a treatment option for some patients with symptoms indicative of acute maxillary sinusitis. In the pilot study, the period of treatment before symptoms improved was shorter in patients who were given eye drops than in patients who were given systemic peroral antibiotics. These promising results give grounds to undertake studies on a larger scale. PMID- 24172627 TI - [Dispensing of benzodiazepines and Z drugs by Norwegian pharmacies 2004-2011]. AB - BACKGROUND: In Norway, total sales of benzodiazepines and Z drugs (zopiclone and zolpidem) have increased since the mid-1990s. On the basis of data from the Norwegian Prescription Database, we have studied the choice of medications and patterns of use in various gender and age groups. MATERIAL AND METHOD: Numbers for redemptions of benzodiazepines and Z drugs in Norwegian pharmacies for the years 2004-2011 were collected from the Prescription Registry. Population figures were collected from Statistics Norway. Consumption was calculated by the number of DDDs (defined daily doses). RESULTS: Among those who were supplied with benzodiazepines or Z drugs, recipients of more than 2 DDDs per day (heavy users) accounted for a small group. We registered an extensive use of Z drugs among older women, many of whom were prescribed an amount corresponding to a regular daily use of 1-2 DDDs. The total prescription of alprazolam and nitrazepam/flunitrazepam was minor, but high dosages were not uncommon among those who were prescribed these drugs. Only a small proportion of the patients who were prescribed clonazepam received a reimbursable prescription. The prescribing of a number of benzodiazepines and Z drugs at the same time remains not uncommon. INTERPRETATION: Prescribing of Z drugs to the elderly, and to women in particular, may indicate that many people in this group are regular users of sedative hypnotics, which is contrary to the guidelines. A considerable proportion of the prescriptions for clonazepam are outside of the approved indications. Among the users of the drugs studied, only a small fraction were heavy users, but since the use is widespread, this represents a considerable number of individuals. PMID- 24172628 TI - Malignant melanoma--diagnosis, treatment and follow-up in Norway. AB - BACKGROUND: The incidence of malignant melanoma in Norway is among the highest in the world and rising, with approximately 1 500 persons receiving the diagnosis annually. Correct surgical primary treatment cures 80-90%, while 10-20% experience relapses. The treatment of a metastatic malignant melanoma has changed considerably in the last 1-2 years as a result of clinical experience with new drugs. The current publication provides an updated overview of the treatment of malignant melanoma in Norway. METHOD: The article is based on a search in PubMed and on the authors' own research and clinical experience. RESULTS: After several decades with almost no change in the treatment of malignant melanoma, we have seen a positive development over the past couple of years. New treatment methods for malignant melanoma with distant spreading metastases have yielded favourable results in selected patients and are currently established in cancer departments in Norway. INTERPRETATION: Rapid and correct primary treatment is curing most patients with malignant melanoma. New drugs offer hope for selected patient groups with metastatic disease. Several new types of targeted treatment are being tested in clinical studies in Norway and elsewhere in the world. PMID- 24172629 TI - [A young woman with acute abdominal pain]. PMID- 24172630 TI - [Acute abdominal pain--the usual suspects?]. PMID- 24172631 TI - Treatment of acute radiation injuries. PMID- 24172632 TI - [The marginal with Huntington's disease]. PMID- 24172633 TI - [Use caution--cliche or useful information?]. PMID- 24172636 TI - Stability of unfrozen whole blood DNA for remote genotypic analysis of HIV-1 coreceptor tropism. AB - BACKGROUND: Maraviroc is an HIV-1 coreceptor antagonist that has shown good efficacy and tolerability in treatment-naive and treatment-experienced patients harboring CCR5-tropic virus. The use of Maraviroc in treatment simplification in patients with suppressed plasma HIV-1 RNA requires analysis of HIV-1 DNA. Coreceptor tropism testing is often performed remotely at reference laboratories. In this study paired whole blood stored at + 4 degrees C and at-20 degrees C were compared as a source for genotypic coreceptor tropism testing. METHODS: Two hundred paired whole blood samples from different patients were analysed. Each sample was stored in two different conditions: one aliquot was stored at-20 degrees C until spin column DNA extraction (WB20) and one aliquot was stored at +4 degrees C for two weeks and then placed at room temperature (22-24 degrees C) for two days before DNA extraction (WB4). Subsequently, a fragment encompassing the HIV-1 gp120 V3 domain was amplified by a singlicate nested PCR followed by triplicate nested PCR in the negative samples. A randomly selected panel of 20 paired WB4 and WB20 duplicate amplification products were sequenced and coreceptor tropism was inferred by geno2pheno [coreceptor]. RESULTS: WB20 yielded a higher amount of DNA than WB4 (median [IQR] values 332.5 ng/MUl [117.5-401] and 107 ng/MUl [56.6-318], respectively; P < 0.001). However, the DNA purity was higher for WB4 than for WB20 (median distance from the optimal OD260/280 ratio, 0.14 [0.07-0.79] and 0.96 [0.36-1.10], respectively; P < 0.0001). The number of samples successfully amplified was 152 (76.0%) for WB20 and 155 (77.5%) for WB4 with the first PCR and 179 (89.5%) for WB20 and 181 (90.5%) for WB4 (P = ns) following subsequent triplicate analysis. The inferred coreceptor tropism was concordant in 18 out of 20 paired WB4 and WB20 samples. Two samples yielded discordant results, consistent with the discordance rate within duplicates from the same sample source (2/20 with WB4 and 1/20 with WB20) due to the inherent gp120 V3 variability. CONCLUSIONS: Storing whole blood at +4 degrees C for up to two weeks and shipping at room temperature is a convenient method for obtaining HIV-1 gp120 V3 sequence information via testing at a remote laboratory in patients with suppressed viremia. PMID- 24172638 TI - The prevalence of turner syndrome in girls presenting with coarctation of the aorta. AB - OBJECTIVE: To determine the prevalence of Turner syndrome in girls presenting with coarctation of the aorta (CoA). STUDY DESIGN: A total of 132 girls with known structural CoA was identified. Those girls who had no previous karyotype analysis performed were asked to participate in a research study in which a banded karyotype with 50-cell count was performed. RESULTS: Of 132 girls with CoA, 55 (41.7%) had karyotype analysis within 6 months of cardiac diagnosis. Three girls underwent karyotyping later because of clinical concerns. Of the 74 girls with CoA who had not had a karyotype, 38 (51.4%) consented to the study. Results were available for 37 girls. All were 46,XX. Five patients with Turner syndrome were identified in the 95 girls with CoA who had karyotype analysis (4 from early karyotype and 1 diagnosed later), which translated into a minimum prevalence of 5.3% of Turner syndrome in this group of girls with CoA. In addition, one infant with a 20-cell 46,XX karyotype had features of Turner syndrome. CONCLUSION: Our study demonstrated for the first time in a large cohort that 5.3% of girls presenting with CoA are found to have Turner syndrome when karyotyping is performed. Given the spectrum of preventable and treatable health problems after the diagnosis of Turner syndrome, we believe that all girls with CoA should have a karyotype analysis, ideally with at least 50-cell count, at the time of diagnosis of CoA. PMID- 24172637 TI - In vivo analysis of highly conserved Nef activities in HIV-1 replication and pathogenesis. AB - BACKGROUND: The HIV-1 accessory protein, Nef, is decisive for progression to AIDS. In vitro characterization of the protein has described many Nef activities of unknown in vivo significance including CD4 downregulation and a number of activities that depend on Nef interacting with host SH3 domain proteins. Here, we use the BLT humanized mouse model of HIV-1 infection to assess their impact on viral replication and pathogenesis and the selection pressure to restore these activities using enforced in vivo evolution. RESULTS: We followed the evolution of HIV-1LAI (LAI) with a frame-shifted nef (LAINeffs) during infection of BLT mice. LAINeffs was rapidly replaced in blood by virus with short deletions in nef that restored the open reading frame (LAINeffs?-1 and LAINeffs?-13). Subsequently, LAINeffs?-1 was often replaced by wild type LAI. Unexpectedly, LAINeffs?-1 and LAINeffs?-13 Nefs were specifically defective for CD4 downregulation activity. Viruses with these mutant nefs were used to infect BLT mice. LAINeffs?-1 and LAINeffs?-13 exhibited three-fold reduced viral replication (compared to LAI) and a 50% reduction of systemic CD4+ T cells (>90% for LAI) demonstrating the importance of CD4 downregulation. These results also demonstrate that functions other than CD4 downregulation enhanced viral replication and pathogenesis of LAINeffs?-1 and LAINeffs?-13 compared to LAINeffs. To gain insight into the nature of these activities, we constructed the double mutant P72A/P75A. Multiple Nef activities can be negated by mutating the SH3 domain binding site (P72Q73V74P75L76R77) to P72A/P75A and this mutation does not affect CD4 downregulation. Virus with nef mutated to P72A/P75A closely resembled the wild-type virus in vivo as viral replication and pathogenesis was not significantly altered. Unlike LAINeffs described above, the P72A/P75A mutation had a very weak tendency to revert to wild type sequence. CONCLUSIONS: The in vivo phenotype of Nef is significantly dependent on CD4 downregulation but minimally on the numerous Nef activities that require an intact SH3 domain binding motif. These results suggest that CD4 downregulation plus one or more unknown Nef activities contribute to enhanced viral replication and pathogenesis and are suitable targets for anti-HIV therapy. Enforced evolution studies in BLT mice will greatly facilitate identification of these critical activities. PMID- 24172640 TI - A nine-year population-based cohort study on the risk of multiple sclerosis in patients with optic neuritis. AB - Patients with optic neuritis (ON) are at an increased risk of developing multiple sclerosis (MS), an illness that may result in physical dysfunction and short life expectancy. Information on the conversion rate to MS of patients with ON is essential in determining the impact of ON on the incidence of MS. Previous Taiwanese studies on the risk of MS in patients with ON were all hospital based, thereby limiting the generalizability of the findings. We aimed to estimate the risk of MS in patients with ON using a nationally representative sample. A cohort of 2,741 patients who sought outpatient care for ON in 2000 was identified from Taiwan's National Health Insurance claims. The control group consisted of 27,330 age- and sex-matched subjects randomly selected from all beneficiaries in 2000. The person-year approach with Poisson assumption was used to estimate the incidence rate of MS from 2000 to 2008. The relative risk of outpatient visit or hospitalization for MS was estimated using the Cox proportional hazard model. The incidence rates of MS in the ON and control groups were 25.6 and 0.4, respectively, per 10,000 person-years; these values represent a relative risk estimate of 30.84 (95% confidence interval: 14.48 to 65.73) after the potential confounders were considered. Female or younger patients with ON were associated with a significantly elevated risk of developing MS. This study found that Taiwanese patients with ON are at a substantially high relative risk of developing MS. In addition to patients with ON, female and younger people should also receive intensive neurological care to further reduce their risk of developing MS. PMID- 24172639 TI - Joint estimation of causal effects from observational and intervention gene expression data. AB - BACKGROUND: In recent years, there has been great interest in using transcriptomic data to infer gene regulatory networks. For the time being, methodological development in this area has primarily made use of graphical Gaussian models for observational wild-type data, resulting in undirected graphs that are not able to accurately highlight causal relationships among genes. In the present work, we seek to improve the estimation of causal effects among genes by jointly modeling observational transcriptomic data with arbitrarily complex intervention data obtained by performing partial, single, or multiple gene knock outs or knock-downs. RESULTS: Using the framework of causal Gaussian Bayesian networks, we propose a Markov chain Monte Carlo algorithm with a Mallows proposal model and analytical likelihood maximization to sample from the posterior distribution of causal node orderings, and in turn, to estimate causal effects. The main advantage of the proposed algorithm over previously proposed methods is its flexibility to accommodate any kind of intervention design, including partial or multiple knock-out experiments. Using simulated data as well as data from the Dialogue for Reverse Engineering Assessments and Methods (DREAM) 2007 challenge, the proposed method was compared to two alternative approaches: one requiring a complete, single knock-out design, and one able to model only observational data. CONCLUSIONS: The proposed algorithm was found to perform as well as, and in most cases better, than the alternative methods in terms of accuracy for the estimation of causal effects. In addition, multiple knock-outs proved to contribute valuable additional information compared to single knock-outs. Finally, the simulation study confirmed that it is not possible to estimate the causal ordering of genes from observational data alone. In all cases, we found that the inclusion of intervention experiments enabled more accurate estimation of causal regulatory relationships than the use of wild-type data alone. PMID- 24172641 TI - Cryoultrasound therapy in the treatment of chronic plantar fasciitis with heel spurs. A randomized controlled clinical study. AB - BACKGROUND: Plantar fasciitis is one of the most common causes of pain in the inferior heel and is very frequent in some running sports. It affects up to 10% of general population and accounts for 11% to 15% of all foot pain symptomatology. Several treatments have been suggested, but there is no evidence supporting a specific conservative management strategy. AIM: Evaluation of the efficacy of combined cryoultrasound therapy on chronic plantar fasciitis with heel spurs resistant to pharmacological and instrumental therapies. DESIGN: Single-blind randomized clinical trial. POPULATION: 102 consecutive patients affected by chronic plantar fasciitis with painful symptomatology for at least 6 months, intensity of pain higher than 5 on the VAS score, presence of heel spurs, use of plantar orthoses and ineffectiveness of previous therapies. METHODS: The patients were randomized into two groups: Group A treated with cryoultrasound therapy and Group B with cryotherapy. Our protocol was based on 10 daily treatments, lasting 20 minutes. Each participant was evaluated using VAS score before (T0) the treatment and 3 months (T1), 12 months (T2) and 18 months (T3) after. Effectiveness index was calculated from T1 to T3. RESULTS: Both treatments have been found effective. The difference in pain intensity on the VAS scale between the two groups at T2 was 4.35 points in favor of Group A (IC 95% 3.75; 4.95; P<0.001), reaching the primary end point. The difference in pain intensity on the VAS scale between the two groups at T1, T2 and T3 was 3.00, 4.35 and 4.81 respectively, showing a statistically significant difference between VAS average scores at all follow-ups in favor of Group A. Scores of at least 66% at the effectiveness index were only achieved in Group A (P values <0.001). CONCLUSION: Cryoultrasound therapy could be an efficient treatment option for chronic plantar fasciitis. CLINICAL REHABILITATION IMPACT: Cryoultrasound therapy promises an effective and long-lasting clinical improvement in patients with chronic plantar fasciitis, granted its high therapeutic efficiency, patients' satisfaction, its limited cost and its short and repeatable protocol of use. PMID- 24172643 TI - Rehabilitation after hip and knee arthroplasty: where are we now? Work in progress to build up evidence-based protocols. PMID- 24172642 TI - Physical exercise after knee arthroplasty: a systematic review of controlled trials. AB - Total knee arthroplasty (TKA) is the gold standard treatment for end-stage knee osteoarthritis. Most patients report successful long-term outcomes and reduced pain after TKA, but recovery is variable and the majority of patients continue to demonstrate lower extremity muscle weakness and functional deficits compared to age-matched control subjects. Given the potential positive influence of postoperative rehabilitation and the lack of established standards for prescribing exercise paradigms after TKA, the purpose of this study was to systematically review randomized, controlled studies to determine the effectiveness of postoperative outpatient care on short- and long-term functional recovery. Nineteen studies were identified as highly relevant for the review and four categories of postoperative intervention were discussed: 1) strengthening exercises; 2) aquatic therapy; 3) balance training; and 4) clinical environment. Optimal outpatient physical therapy protocols should include: strengthening and intensive functional exercises given through land-based or aquatic programs, the intensity of which is increased based on patient progress. Due to the highly individualized characteristics of these types of exercises, outpatient physical therapy performed in a clinic under the supervision of a trained physical therapist may provide the best long-term outcomes after the surgery. Supervised or remotely supervised therapy may be effective at reducing some of the impairments following TKA, but several studies without direct oversight produced poor results. Most studies did not accurately describe the "usual care" or control groups and information about the dose, frequency, intensity and duration of the rehabilitation protocols were lacking from several studies. PMID- 24172644 TI - Which type of exercise therapy is effective after hip arthroplasty? A systematic review of randomized controlled trials. AB - BACKGROUND: Early multidisciplinary rehabilitation can improve the recovery after total hip arthroplasty (THA). However, optimal exercise therapy has not been defined. We aimed to answer the question: "Which type and/or timing of exercise therapy is effective following THA?" DESIGN: Systematic review. METHODS: We searched four databases: MEDLINE, PEDro, Cochrane Library, and Cinahl since January 2008 till December 2012. Literature before 2008 was not searched for, because it was previously analyzed by two systematic reviews. Eligible criteria for studies were: Randomized Controlled Trials (RCTs); English language; interventions on type and/or timing of physical exercise initiating after THA; outcome measures including at least one among impairment, activity, participation, quality of life, or length of stay in hospital. RESULTS: Eleven papers on nine RCTs were identified. Trial quality was mixed. PEDro scores ranged from four to eight. Exercise therapy varied greatly in type and timing. Each of the nine RCTs addressed a specific issue and overall the results were sparse. In the early postoperative phase favorable outcomes were due to ergometer cycling and maximal strength training. Inconclusive results were reported for aquatic exercises, bed exercises without external resistance or without its progressive increase according to the overload principle, and timing. In the late postoperative phase (> 8 weeks postoperatively) advantages were due to weight bearing exercises. CONCLUSION: Insufficient evidence exists to build up a detailed evidence-based exercise protocol after THA. Sparse results from few RCTs support specific exercise types which should be added to the usual mobility training in THA patients. PMID- 24172645 TI - Spontaneous resolution of a solitary osteochondroma of the distal femur: a case report and review of the literature. AB - Osteochondromata are common, benign tumours mainly affecting long-bone metaphyses. They comprise 35% of all primary benign bone tumours and 8% of all bone tumours overall, although their true incidence is unknown as many remain undiagnosed. They can cause multiple symptoms including pain and referral for excision is not uncommon. What is less recognized is their potential for spontaneous regression, a phenomenon that renders excision surgery, with its potential risks, unnecessary. We present an illustrated case of a spontaneously resolved, solitary osteochondroma in a young male, highlighting that solitary osteochondromata can actually resolve and in the asymptomatic child, a period of watchful waiting can be an appropriate option, avoiding a potentially unnecessary surgical excision with recognized complications. PMID- 24172646 TI - Evaluation of upper-extremity function following surgical treatment of displaced proximal humerus fractures in children. AB - This study aims to assess the functional outcome of children treated with elastic stable intramedullary nailing (ESIN) for displaced proximal humerus fractures using the short version of the disabilities of the arm, shoulder, and hand outcome questionnaire (Quick DASH). Fifty-eight consecutive children with displaced proximal humerus fractures were treated with ESIN. Fifty-two children (89.7%) were available for follow-up and responded to the questionnaire after hardware removal. Average age at time of injury was 11.1 +/- 2.8 years (range, 4 15.9). Among the 52 patients available for evaluation, 37 had a Quick DASH score of 0 (71.1%), seven a score of 2.3 (13.5%), four a score of 4.5 (7.7%), and four a score of 6.5 (7.7%). Shoulder and elbow ranges of motion were comparable with the noninjured side. No skin irritation or local infections were observed. There was no radiographic evidence of delayed union, refracture, hardware migration, or secondary displacement. Mean follow-up was 18.3 +/- 8.3 months (range, 6-39.5). Our study reports good functional outcomes in children with closed isolated fractures, both physeal and metaphyseal, of the proximal humerus treated with ESIN. The use of a standardized rating scale is recommended to homogeneously compare functional outcome and may facilitate the comparison of clinical outcome in different patient populations. PMID- 24172647 TI - New perspectives for direct PDMS microfabrication using a CD-DVD laser. AB - A simple and inexpensive alternative to high-power lasers for the direct fabrication of microchannels and rapid prototyping of poly-dimethylsiloxane (PDMS) is presented. By focusing the infrared laser beam of a commercial, low power CD-DVD unit on absorbing carbon micro-cluster additives, highly localized PDMS combustion can be used to etch the polymer, which is otherwise transparent at such wavelengths. Thanks to a precise and automated control of laser conditions, laser-induced incandescence is originated at the material surface and produces high-resolution micropatterns that present properties normally induced with lasers of much greater energies in PDMS: formation of in situ nanodomains, local fluorescence and waveguide patterns. An extensive study of the phenomenon and its performance for PDMS microfabrication are presented. PMID- 24172648 TI - Comparison of serum anti-Mullerian hormone levels following hysterectomy and myomectomy for benign gynaecological conditions. AB - OBJECTIVE: To compare serum anti-Mullerian hormone (AMH) levels following hysterectomy and myomectomy. STUDY DESIGN: Prospective longitudinal observational study. Serum AMH, follicle stimulating hormone (FSH) and luteinizing hormone (LH) levels were measured pre-operatively (T1) and 2 days (T2) and 3 months (T3) following hysterectomy and myomectomy in 70 women aged 36-45 years. Hysterectomy (laparoscopy-assisted vaginal hysterectomy=10; total abdominal hysterectomy=25) with conservation of both ovaries for benign diseases of the uterus was performed in 35 women, and myomectomy (laparoscopy myomectomy=15; open myomectomy=20) was performed in another 35 women. The follow-up period was 3 months following surgery. The results were analysed using the t-test or one-way analysis of variance by repeated-measures ANOVA. RESULTS: Serum AMH in the hysterectomy group was 1.08+/-0.77 ng/ml at T1, 0.78+/-0.58 ng/ml at T2 and 0.81+/-0.58 ng/ml at T3; the level was significantly lower at T2 and T3 compared with T1. In the myomectomy group, the corresponding values were 1.54+/-0.95 ng/ml, 1.18+/-0.77 ng/ml and 1.50+/-0.58 ng/ml; serum AMH was significantly lower at T2 compared with T1, but the difference between T3 and T1 was not significant. There were no significant differences in serum FSH and LH in either group between these three time points. CONCLUSION: Serum AMH was significantly lower 2 days and 3 months following hysterectomy compared with the pre-operative level. Following myomectomy, serum AMH was significantly lower than the pre-operative level 2 days following the procedure, but was similar to the pre-operative level 3 months after surgery. Therefore, hysterectomy may have a more lasting adverse effect on ovarian reserve than myomectomy. A long-term study of AMH levels is needed. PMID- 24172650 TI - Study of crystal-field excitations and infrared active phonons in the multiferroic hexagonal DyMnO3. AB - In hexagonal DyMnO3, Dy(3+) crystal-field excitations are studied as a function of temperature and applied magnetic field. They are complemented with the measurements of infrared active phonon frequency shifts under applied magnetic field at T = 4.2 K. Between TN = 68 K and T = 10 K, the absence of Dy(3+) Kramers doublet splittings at either the C3 or the C3v site symmetries indicates that the Mn(3+) magnetic order effective exchange field has no component parallel to the c axis at either site. Below T = 10 K, the ground state Kramers doublet splits under the Dy(3+) internal effective field as well as the applied magnetic field. Also, relatively strong infrared active phonon energy shifts are observed in magneto-infrared reflectance measurements at T = 4.2 K, allowing the calculation of the induced electric polarization changes as a function of the applied magnetic field. Such changes are associated with a large magnetoelectric effect in DyMnO3, arising from a charge transfer between Dy(3+) and apical oxygen ions. PMID- 24172649 TI - Revisiting the roles of progesterone and allopregnanolone in the nervous system: resurgence of the progesterone receptors. AB - Progesterone is commonly considered as a female reproductive hormone and is well known for its role in pregnancy. It is less well appreciated that progesterone and its metabolite allopregnanolone are also male hormones, as they are produced in both sexes by the adrenal glands. In addition, they are synthesized within the nervous system. Progesterone and allopregnanolone are associated with adaptation to stress, and increased production of progesterone within the brain may be part of the response of neural cells to injury. Progesterone receptors (PR) are widely distributed throughout the brain, but their study has been mainly limited to the hypothalamus and reproductive functions, and the extra-hypothalamic receptors have been neglected. This lack of information about brain functions of PR is unexpected, as the protective and trophic effects of progesterone are much investigated, and as the therapeutic potential of progesterone as a neuroprotective and promyelinating agent is currently being assessed in clinical trials. The little attention devoted to the brain functions of PR may relate to the widely accepted assumption that non-reproductive actions of progesterone may be mainly mediated by allopregnanolone, which does not bind to PR, but acts as a potent positive modulator of gamma-aminobutyric acid type A (GABA(A) receptors. The aim of this review is to critically discuss effects of progesterone on the nervous system via PR, and of allopregnanolone via its modulation of GABA(A) receptors, with main focus on the brain. PMID- 24172651 TI - Longitudinal Modeling of the Relationship Between Mean Plasma Glucose and HbA1c Following Antidiabetic Treatments. AB - Late-phase clinical trials within diabetes generally have a duration of 12-24 weeks, where 12 weeks may be too short to reach steady-state glycated hemoglobin (HbA1c). The main determinant for HbA1c is blood glucose, which reaches steady state much sooner. In spite of this, few publications have used individual data to assess the time course of both glucose and HbA1c, for predicting HbA1c. In this paper, we present an approach for predicting HbA1c at end-of-trial (24-28 weeks) using glucose and HbA1c measurements up to 12 weeks. The approach was evaluated using data from 4 trials covering 12 treatment arms (oral antidiabetic drug, glucagon-like peptide-1, and insulin treatment) with measurements at 24-28 weeks to evaluate predictions vs. observations. HbA1c percentage was predicted for each arm at end-of-trial with a mean prediction error of 0.14% [0.01;0.24]. Furthermore, end points in terms of HbA1c reductions relative to comparator were accurately predicted. The proposed model provides a good basis to optimize late stage clinical development within diabetes.CPT: Pharmacometrics & Systems Pharmacology (2013) 2, e82; doi:10.1038/psp.2013.58; advance online publication 30 October 2013. PMID- 24172652 TI - The effects of soft contact lens use on cornea and patient's recovery after autograft pterygium surgery. AB - PURPOSE: To investigate usage of soft contact lens (SCL) on post-operative pain relief and daily, activity due to pterygium surgery. METHODS: Autograft pterygium surgery was performed to 63 eyes of 63 patients. After surgery in 30, eyes of 30 patients in group-1, SCL was placed on the cornea. In 33 patients of group-2, antibiotic, pomade was applied and tightly covered with bandage. Follow-up visits were performed on 24th and, 48th h after the surgery. Re-epithelization time and pain scores were compared. RESULTS: Patients' 24th h pain score was 2.96 +/- 0.76 in group-1, and 4.15 +/- 0.75 in group-2. The mean, pain score for 48 h was 1.66 +/- 0.66 in group-1, and 2.96 +/- 0.68 in group-2. Patients' pain scores for, both 24th h and 48th h were lower in group-1 (p<0.01). The mean re-epithelization times in, group 1 and 2 were 48 and 56.7h, respectively. Corneal re epithelization is improved in patients, with SCL compared to group 2. CONCLUSION: SCL seems effective on reducing post-operative pain and eye stinging, and may accelerate, corneal re-epithelization and maintaining daily activities. PMID- 24172653 TI - Comparative biological evaluation of two [99mTc(CO)3]-dextran pyrazolyl mannose conjugates developed for use in sentinel lymph node detection. AB - AIM: This work aims to develop receptor based alternatives to the conventional colloidal tracers in sentinel lymph node (SLN) detection. In this study, we report the detailed biological evaluation of two dextran pyrazolyl mannose derivatives towards this purpose. METHODS: The dextran pyrazolyl mannose derivatives (DAPM4 and DAPM8) were labeled with the [99mTc(CO)3(H2O)3]+ core. In vitro saturation binding studies for the ligands were performed in mannose receptor-bearing RAW 264.7 macrophage precursor cells. Localization and pharmacokinetics studies of the tracers were conducted in normal Wistar rats with different ligand concentrations using in vivo activity distribution and scintigraphic imaging techniques. RESULTS: The ligands were labeled with the [99mTc(CO)3)]+ core in high yield and radiochemical purity (>90%). DAPM4 and DAPM8 showed specific uptake in RAW 264.7 cells. In vivo localization studies showed concentration-dependent uptake and selective retention of the [99mTc] labeled complexes of DAPM4 and DAPM8 in the sentinel node with highly favorable values of popliteal extraction [PE] (%PEDAPM4=92.94%,%PEDAPM8=91.80% at 180 min p.i.) and rapid clearance from the site of injection when administered at 50 ug/mL ligand concentration. CONCLUSION: [99mTc(CO)3]-complexes of DAPM4 and DAPM8 show good in vivo potential to undergo further testing as agents for SLN detection in the clinic and their biological efficacy varies depending upon the concentration of ligands used for the procedure. PMID- 24172654 TI - T1rho magnetic resonance imaging for detection of early cartilage changes in knees of asymptomatic collegiate female impact and nonimpact athletes. AB - OBJECTIVE: To determine if T1rho magnetic resonance imaging (T1rho MRI) could assess early articular cartilage changes in knees of asymptomatic female collegiate athletes. It was hypothesized that impact cohort would demonstrate greater changes than nonimpact cohort. DESIGN: An institutional review board approved prospective cohort study. Blinded MRI analyses. SETTING: Participants from collegiate athletic program. Imaging at university hospital, February 2008 to July 2009. PARTICIPANTS: Inclusion criteria were female collegiate athletes in athletic season and asymptomatic. Exclusion criteria were previous/current knee injuries/surgeries. Twenty-one female NCAA Division I athletes, 11 impact (basketball players) and 10 nonimpact (swimmers) participants were consented and imaged with 3.0-T MRI (Siemens) and T1rho sequence (University of Pennsylvania). One patient was removed (injury diagnosis). Final roster was 10 impact and 10 nonimpact participants. No difference in cohort body mass index, height, or weight. MAIN OUTCOME MEASURES: Average T1rho relaxation times (ART) for patellar and femoral cartilage to analyze defined regions and depth and modified International Cartilage Repair Society classification. RESULTS: Statistical analyses showed that ART of radial zone of central third weight-bearing region of cartilage in basketball players was significantly greater (P = 0.041) than swimmers and ART of the superficial zone in basketball players was significantly less (P = 0.003) than that of swimmers. For both groups, the ART of superficial zones were significantly greater than that of radial zones (P < 0.001). Four impact athletes showed macroscopic changes (none in nonimpact cohort). CONCLUSIONS: T1rho MRI detected early changes in articular cartilage of asymptomatic collegiate female impact athletes, with significant differences between cohorts in radial zone of central third weight-bearing region and superficial zones ART. Both cohorts showed increased ART in superficial zone. Four impact athletes showed macroscopic changes. CLINICAL RELEVANCE: This study demonstrates a quantitative MRI sequence able to detect signal differences in articular cartilage in asymptomatic athletes. PMID- 24172655 TI - Judo-related traumatic posterior sternoclavicular joint dislocation in a child. AB - Judo is a combat sport with high risk of injury. We present a rare case of traumatic left posterior sternoclavicular (SC) joint dislocation, inflicted to a 12-year-old boy during a judo contest. An extensive literature review did not reveal any case of posterior SC joint dislocation in judo. The patient was treated with closed reduction under general anesthesia. At 2-year follow-up, his left upper extremity had full range of motion, and he did not complain of any residual symptoms. He decided to discontinue judo training; however, he participates in other physically demanding sports. Although not often encountered, posterior SC joint dislocation is a challenging and critical medical problem that can be fatal if not promptly diagnosed and treated on time and should be considered in the differential diagnosis of trauma-related anterior chest pain. PMID- 24172656 TI - Comparison of a physiotherapy program versus dexamethasone injections for plantar fasciopathy in prolonged standing workers: a randomized clinical trial. AB - OBJECTIVE: To investigate the effectiveness of a physiotherapy-based exercise program versus dexamethasone injection for chronic plantar fasciopathy in workers standing for prolonged periods of time. DESIGN: A parallel group nonblinded randomized controlled trial with 12-week follow-up. SETTING: An outpatient sports medicine clinic in Vancouver, British Columbia, Canada. PARTICIPANTS: Fifty-six workers required to stand for greater than 5 h/d with chronic plantar fasciopathy took part. Diagnosis from a physiotherapist must include signs of structural changes to the plantar fascia seen on ultrasound. INTERVENTIONS: The PHYSIO group included 7 physiotherapy-led exercises performed daily over a 12-week period. The INJECTION group received 1 palpation-guided dexamethasone injection followed by a daily routine of calf stretching. MAIN OUTCOME MEASURES: The Foot and Ankle Disability Index (FADI) scores 12-weeks postintervention and ultrasound-based measures of ligament appearance. RESULTS: At follow-up, both groups reported significant improvements in FADI and visual analog scales for pain at work and with activities of daily living at 6 and 12 weeks compared with baseline scores (P < 0.001). There were no significant between-group differences. There were no significant changes to plantar fascia thickness reported at the 6- and 12-week follow-up point. Both the number of cases with focal anechoic areas and the size of these anechoic areas improved significantly in the PHYSIO (P = 0.003) and INJECTION (P < 0.001) groups at 12-week follow-up. CONCLUSIONS: Workers standing for prolonged periods experienced the same short-term therapeutic effectiveness with a physiotherapy-led exercise program compared with an injection of corticosteroid with stretching. PMID- 24172657 TI - Investigating the need for complex vs. simple scenarios to improve predictions of aquatic ecosystem exposure with the SoilPlus model. AB - A spatially-explicit version of the recent multimedia fate model SoilPlus was developed and applied to predict the runoff of three pesticides in a small agricultural watershed in north-eastern Italy. In order to evaluate model response to increasing spatial resolution, a tiered simulation approach was adopted, also using a dynamic model for surface water (DynA model), to predict the fate of pesticides in runoff water and sediment, and concentrations in river water. Simulation outputs were compared to water concentrations measured in the basin. Results showed that a high spatial resolution and scenario complexity improved model predictions of metolachlor and terbuthylazine in runoff to an acceptable performance (R(2) = 0.64-0.70). The importance was also shown of a field-based database of properties (i.e. soil texture and organic carbon, rainfall and water flow, pesticides half-life in soil) in reducing the distance between predicted and measured surface water concentrations and its relevance for risk assessment. PMID- 24172658 TI - Long-term behaviour of 137Cs in spruce bark in coniferous forests in the Czech Republic. AB - Activity concentrations of (137)Cs were detected in more than 400 outer spruce bark samples collected at sites variably affected by Chernobyl fallout across the Czech Republic in 1995 and 2010. The temporal changes in the (137)Cs activities were found. The mean effective half-life (TEF) for (137)Cs in spruce bark was 9.6 years, and the mean environmental half-life (TE) was 14 years. The effective half lives were significantly higher in areas with higher long-term annual precipitation sums. Coefficient a in linear regression y = ax + b of half-lives on precipitation sums was 0.015 y mm(-1) for TEF and 0.036 y mm(-1) for TE. The aggregated transfer factor of (137)Cs from soil to bark was determined and the pre-Chernobyl bark contamination related to year 2010 was estimated. PMID- 24172659 TI - Influential parameters on particle concentration and size distribution in the mainstream of e-cigarettes. AB - Electronic cigarette-generated mainstream aerosols were characterized in terms of particle number concentrations and size distributions through a Condensation Particle Counter and a Fast Mobility Particle Sizer spectrometer, respectively. A thermodilution system was also used to properly sample and dilute the mainstream aerosol. Different types of electronic cigarettes, liquid flavors, liquid nicotine contents, as well as different puffing times were tested. Conventional tobacco cigarettes were also investigated. The total particle number concentration peak (for 2-s puff), averaged across the different electronic cigarette types and liquids, was measured equal to 4.39 +/- 0.42 * 10(9) part. cm(-3), then comparable to the conventional cigarette one (3.14 +/- 0.61 * 10(9) part. cm(-3)). Puffing times and nicotine contents were found to influence the particle concentration, whereas no significant differences were recognized in terms of flavors and types of cigarettes used. Particle number distribution modes of the electronic cigarette-generated aerosol were in the 120-165 nm range, then similar to the conventional cigarette one. PMID- 24172660 TI - Characterization of regulatory features of housekeeping and tissue-specific regulators within tissue regulatory networks. AB - BACKGROUND: Transcription factors (TFs) and miRNAs are essential for the regulation of gene expression; however, the global view of human gene regulatory networks remains poorly understood. For example, how is the expression of so many genes regulated by limited cohorts of regulators and how are genes differentially expressed in different tissues despite the genetic code being the same in all tissues? RESULTS: We analyzed the network properties of housekeeping and tissue specific genes in gene regulatory networks from seven human tissues. Our results show that different classes of genes behave quite differently in these networks. Tissue-specific miRNAs show a higher average target number compared with non tissue specific miRNAs, which indicates that tissue-specific miRNAs tend to regulate different sets of targets. Tissue-specific TFs exhibit higher in-degree, out-degree, cluster coefficient and betweenness values, indicating that they occupy central positions in the regulatory network and that they transfer genetic information from upstream genes to downstream genes more quickly than other TFs. Housekeeping TFs tend to have higher cluster coefficients compared with other genes that are neither housekeeping nor tissue specific, indicating that housekeeping TFs tend to regulate their targets synergistically. Several topological properties of disease-associated miRNAs and genes were found to be significantly different from those of non-disease-associated miRNAs and genes. CONCLUSIONS: Tissue-specific miRNAs, TFs and disease genes have particular topological properties within the transcriptional regulatory networks of the seven human tissues examined. The tendency of tissue-specific miRNAs to regulate different sets of genes shows that a particular tissue-specific miRNA and its target gene set may form a regulatory module to execute particular functions in the process of tissue differentiation. The regulatory patterns of tissue-specific TFs reflect their vital role in regulatory networks and their importance to biological functions in their respective tissues. The topological differences between disease and non-disease genes may aid the discovery of new disease genes or drug targets. Determining the network properties of these regulatory factors will help define the basic principles of human gene regulation and the molecular mechanisms of disease. PMID- 24172661 TI - Warfarin associated intracerebral hemorrhage in Hong Kong Chinese. AB - OBJECTIVES: Warfarin-associated intracerebral hemorrhage (WICH) is a serious neurological condition associated with significant mortality and morbidity. We aimed to study the clinical features and factors that predict clinical outcome of Chinese patients with WICH. METHODS: Medical records of patients with spontaneous intracerebral hemorrhage (ICH) admitted to our hospital between July 2001 and June 2010 were reviewed and those with WICH were studied in detail retrospectively. RESULTS: Fifty-one patients with WICH were studied. The mean age was 74.3 +/- 10.5 years and 52.9% of the patients were female. The mean international normalized ratio (INR) on presentation was 2.9 +/- 1.0. The median ICH volume was 23.3 (10.4-59.3) ml. The mortality rate at 3-6 months for WICH was 62.0%. Multivariate logistic analysis revealed that an initial ICH volume of > 20 ml (OR 34.4, P = 0.037) and presence of intraventricular hemorrhage (OR 22.9, P = 0.046) were independently associated with poor outcome. Supratherapeutic INR (INR > 3.0) on admission (P = 0.724) and complete correction of INR within 24 hours after admission (P = 0.486) were not independent predictors of poor outcome. The median ICH volumes did not differ between INR groups (18.2 (9.4 61.1) ml for INR <= 3 vs 27.3 (13.7-58.5) ml for INR > 3, P = 0.718). Neurological deterioration (ND) was documented in 19 (63.3%) of the 30 patients included in a smaller sub-cohort, and was associated with poor neurological outcome (OR 20.7, P = 0.027). Warfarin was resumed in 7 of the 20 survivors. There were two episodes of recurrent WICH and one episode of ischemic stroke during a mean follow-up duration of 5.4 years. In survivors who were not resumed on warfarin, there were two episodes of recurrent ICH and 12 episodes of ischemic vascular events (nine ischemic strokes) during a mean follow-up duration of 2.6 years. CONCLUSION: Warfarin-associated intracerebral hemorrhage is a very serious complication of warfarin therapy with high mortality and morbidity. Initial ICH volume, presence of intraventricular hemorrhage, and ND are independent predictors of clinical outcome. PMID- 24172662 TI - Toward an mHealth Intervention for Smoking Cessation. AB - The prevalence of tobacco dependence in the United States (US) remains alarming. Invariably, smoke-related health problems are the leading preventable causes of death in the US. Research has shown that a culturally tailored cessation counseling program can help reduce smoking and other tobacco usage. In this paper, we present a mobile health (mHealth) solution that leverages the Short Message Service (SMS) or text messaging feature of mobile devices to motivate behavior change among tobacco users. Our approach implements the Theory of Planned Behavior (TPB) and a phase-based framework. We make contributions to improving previous mHealth intervention approaches by delivering personalized and evidence-based motivational SMS messages to participants. Our proposed solution implements machine learning algorithms that take the participant's demographic profile and previous smoking behavior into account. We discuss our preliminary evaluation of the system against a couple of pseudo-scenarios and our observation of the system's performance. PMID- 24172664 TI - The pediatric fracture of the scaphoid in patients aged 13 years and under: an epidemiological study. AB - BACKGROUND: Fractures of the scaphoid are uncommon in the pediatric population. Despite their rarity, a significant number of children are referred to the fracture clinic for a suspected scaphoid fracture. The aim of this study was to report on the current incidence, pattern of injury, and the long-term outcomes following this injury in the pediatric population. METHODS: Analysis of all pediatric scaphoid fractures presenting to a tertiary pediatric hospital (aged 13 y and under) over a 5-year period was performed. The case notes, radiographs, and other imaging studies for these patients were reviewed. Long-term functional outcome was assessed using Disabilities of the Arm, Shoulder and Hand (DASH) questionnaire. RESULTS: Fifty-six patients of the 838 (6.7%) referred for a suspected scaphoid fracture were identified as having a confirmed diagnosis of a scaphoid fracture, giving an average annual incidence of 11 per 100,000. This group consisted of 39 boys (70%) and 17 girls (30%). The average age of incidence in boys was 12.2 years and in girls was 10.3 years (P<0.001). No scaphoid fractures were observed in boys below the age of 11 years and in girls below the age of 9 years. The most common type of fracture was a distal pole fracture (45 patients). One patient sustained a proximal pole fracture and went on to develop a nonunion. The duration of treatment in cast was shorter in distal pole fractures than in other types (P<0.001). At a mean follow-up of 70 months (range, 46 to 104 mo), 60% reported no limitation or impact when reporting a range of daily functional activities (mean DASH score=3.0). CONCLUSIONS: There is a suggestion that the overall incidence of scaphoid fractures in the pediatric population is increasing, but children aged 13 years and under continue to maintain a distinct fracture pattern when compared with adolescents and adults. The majority involves the distal third of the scaphoid and carries a good prognosis with conservative management. LEVEL OF EVIDENCE: Prognostic study, Level 4. PMID- 24172663 TI - EXCAVATOR: detecting copy number variants from whole-exome sequencing data. AB - We developed a novel software tool, EXCAVATOR, for the detection of copy number variants (CNVs) from whole-exome sequencing data. EXCAVATOR combines a three-step normalization procedure with a novel heterogeneous hidden Markov model algorithm and a calling method that classifies genomic regions into five copy number states. We validate EXCAVATOR on three datasets and compare the results with three other methods. These analyses show that EXCAVATOR outperforms the other methods and is therefore a valuable tool for the investigation of CNVs in largescale projects, as well as in clinical research and diagnostics. EXCAVATOR is freely available at http://sourceforge.net/projects/excavatortool/. PMID- 24172665 TI - Characteristics of spinal injuries secondary to nonaccidental trauma. AB - BACKGROUND: Nonaccidental trauma (NAT) is considered an uncommon cause of spine trauma in the pediatric population. Little has been published on such injuries and no large series is available in the literature. The purpose of this study is to describe the incidence and characteristics of spine trauma secondary to NAT. METHODS: An IRB-approved retrospective review of all patients presenting to a single level 1 pediatric trauma center with a spinal injury between 2003 and 2011 was performed. Patients were identified using our institution's trauma registry. Medical records were reviewed to identify all spine injuries that occurred as a result of NAT. These cases were reviewed for details regarding injury mechanism, type and location of injury, associated injuries, and the treatment. Our institution's NAT database was also queried to identify the total number of patients formally determined to have sustained any injury as a result of NAT during the same period. RESULTS: NAT was the cause of 11/342 (3.2%) spine injuries diagnosed during the study period. A total of 726 cases of NAT were identified, with spine injury present in 1.5%. All patients with spine trauma secondary to NAT were under the age of 2 years with an average age of 7 months. Among patients below 2 years with spinal trauma, NAT was tied as the most common mechanism, resulting in 38% of injuries. Eight of the 11 patients' spine injuries were cervical and 7 of these injuries were in the atlanto-occipital and atlantoaxial regions. Multilevel spine trauma was present in 64% of patients. Associated head and thoracic trauma was present in 73% and 36% of patients, respectively. Neurological injury was found in 54% of patients. The majority of injuries were treated nonoperatively and 1 patient required surgical management. CONCLUSIONS: NAT represents a very common yet often overlooked cause of spinal trauma in children under the age of 2 years. Because of its frequency in this age group, clinicians should consider including an assessment of the spine in all young NAT patients. Patients with spinal trauma sustained as a result of NAT must undergo a thorough evaluation for associated injuries remote to the spine, neurological deficit, and multilevel spine injury. SUMMARY: NAT is a common mechanism of spinal injury in patients below 2 years of age. PMID- 24172666 TI - Ewing sarcoma of the acetabulum in children: a "growth plate-based" surgical strategy. AB - BACKGROUND: Surgical strategy for Ewing sarcoma (ES) of the pelvis relies on Enneking classification. In adults, in case the acetabulum is involved, excision of the entire acetabulum is needed and often leads to loss of function. In children, the surgeon may adopt a strategy, such as in metaphyseal tumors of long bones where an unaffected growth plate allows a transepiphyseal resection, therefore sparing the joint. METHODS: We present a "triradiate cartilage strategy" for the excision of ES of the pubic component of the acetabulum, which allows a wide resection while preserving most of the socket. The approach is ilioinguinal. Osteotomies of the iliopubic and ischio pubicrami are performed, followed by hip arthrotomy and anterior dislocation. Transacetabular resection is achieved using osteotomes, under image intensifier guidance, with no further reconstruction. Cases are presented for 2 boys aged 6.5 and 9.5 years, treated with chemotherapy and transacetabular resection. RESULTS: Resections were all rated R0. Patient #1 remained asymptomatic, including during sport activities, and had normal hip range of motion at 12-year follow-up. Radiograph demonstrated mild protrusio acetabuli. Patient #2 had no complain at 3-year follow-up with normal hip range of motion, although he presented with an equinus gait. Radiographs demonstrated a well-covered femoral head without medial shift. CONCLUSIONS: A "growth plate-based" surgical strategy can be adapted to malignant pelvic tumors in skeletally immature children. This technique leaves intact the ilio ischiatic component of the triradiate cartilage, which, according to Ponseti, contributes the most to the growth of the acetabulum. Joint sparing improves the functional result and decreases the risk of complication. LEVEL OF EVIDENCE: IV. PMID- 24172667 TI - Displaced intra-articular fractures of the great toe in children: intervene with caution! AB - BACKGROUND: Intra-articular fractures of the proximal phalanx of the great toe in children are extremely rare and sparsely reported in the literature. We have noted a series of these fractures at our institution. The purpose of this report is to present a retrospective case series of children with intra-articular fractures managed operatively in order to highlight the inherent difficulties in managing these fractures. METHODS: Operative notes and billing records were searched from 2001 to 2011 to identify all children aged 18 years or younger who underwent surgical intervention for an intra-articular fracture of the proximal phalanx of the great toe. Charts and imaging studies were retrospectively reviewed to identify the mechanism of injury, fracture classification, operative details, clinical results, and complications. RESULTS: Seven boys and 3 girls with a mean age of 12.6 years (range, 8.7 to 15.7 y) were identified. The mechanism of injury was a direct blow from a stubbed toe (8 cases) or a dropped object onto the foot (2 cases). There were 7 intra-articular fractures of the proximal phalanx base, 4 of which occurred in the setting of an open physis. Mean fracture displacement was 4.4 mm. Open reduction was necessary in 9 cases, with K wire fixation used in 9 cases. Median follow-up was 50.5 months (range, 11 to 123 mo). Seven fractures healed at a mean of 7.9 weeks. Nine patients returned to full activity without limitation at latest follow-up. Six patients had significant complications: 2 underwent revision open reduction internal fixation (one for postoperative redisplacement and the other for painful nonunion), 1 suffered a refracture, 1 developed posttraumatic arthritis requiring interphalangeal joint fusion, 1 developed an asymptomatic fibrous nonunion with avascular necrosis of the fragment, and 1 had K-wire migration necessitating early surgical removal. CONCLUSIONS: Intra-articular fractures of the great toe primarily occur in adolescents after direct impact injuries. The most common location was the proximal phalangeal base. There is a high complication rate after surgical intervention, although most patients were asymptomatic at latest follow-up. LEVEL OF EVIDENCE: IV (retrospective case series). PMID- 24172668 TI - Medial malleolar screw versus tension-band plate hemiepiphysiodesis for ankle valgus in the skeletally immature. AB - BACKGROUND: Ankle valgus is frequently encountered in skeletally immature patients in association with a variety of musculoskeletal disorders. Guided growth with temporary medial malleolar transphyseal screw (MMS) hemiepiphysiodesis is an established surgical treatment capable of correcting the angular deformity, but is often complicated by symptomatic screw head prominence and difficult hardware removal. Tension-band plate (TBP) hemiepiphysiodesis has recently been advocated as an alternative; however, the relative efficacy of these 2 techniques has not been directly investigated. Thus, the purpose of this study was to compare MMS and TBP in treatment of pediatric ankle valgus deformity. METHODS: Medical records and radiographs of all patients undergoing distal tibial medial hemiepiphysiodesis for ankle valgus between January 1, 2005 and November 1, 2010 at a pediatric orthopaedic specialty hospital were retrospectively reviewed. Radiographs obtained preoperatively and at 6-month intervals postoperatively were reviewed and the tibiotalar angle was measured. Patient age, sex, underlying diagnosis, concurrent surgical procedures, surgical and postoperative complications, and the presence or absence of symptomatic hardware complaints were documented. RESULTS: Sixty ankles in 42 patients met the inclusion criteria, with adequate radiographs and minimum postoperative follow-up of 12 months (mean: 34 mo). Thirty-five ankles were treated with MMS, and 25 with TBP. Good mean correction of the tibiotalar angle was achieved in both groups (MMS: pre-77.1 degrees to post-87.8 degrees over 25.2 mo; TBP: pre-81.3 to post 87.6 over 20.0 mo). The mean rate of correction was faster in ankles treated with MMS than TBP, but differences did not reach statistical significance (0.55 vs. 0.36 degrees/mo, respectively; P=0.057). Complications included 6 hardware related surgical complications in MMS ankles (17.1%) and 1 in TBP ankles (4.0%). The incidence of symptomatic hardware complaints was low in both groups (MMS, 5.7%; TBP, 0%). CONCLUSIONS: Both MMS and TBP techniques can result in successful correction of ankle valgus in the growing child. Although the rate of deformity correction may be faster with MMS, TBP seems to be associated with fewer hardware related complications. This information may aid the clinician in selecting the surgical option most appropriate for each individual patient. LEVEL OF EVIDENCE: Level II-retrospective study. PMID- 24172669 TI - The efficacy and complications of 2-hole 3.5 mm reconstruction plates and 4 mm noncanulated cancellous screws for temporary hemiepiphysiodesis around the knee. AB - BACKGROUND: Persistent angular deformities around the knee can lead to growth plate damage in childhood and osteoarthritis in adulthood. The treatment options include osteotomy and hemiepiphysiodesis. Tension-band plate hemiepiphysiodesis with 8-plate is an effective way to correct these deformities. However, its high cost makes it less available in many countries. In the present series, we have used 3.5 mm reconstruction plates for tension-band temporary hemiepiphysiodesis. METHODS: Twenty-one patients with bilateral angular deformities of the knee (42 extremities) underwent temporary hemiepiphysiodesis with 3.5 mm reconstruction plates. The diagnosis, BMI, weight, amount of correction of the deformity age, and device failure were analyzed. The mean follow-up period after plate removal was 17 months (ranging from 8 to 24 mo). RESULTS: The mean age of the patients was 10 years and 3 months (+/- 2 y and 10 mo). Complete correction of the deformities was achieved in 86% of patients. Of the 58 plate and screw constructs, 10% had screw breakage. Patients with genu valgum had 2 screw failures (6.25%), but in the genu varum group there were 4 screw failures (40%). Of the 3 patients who did not have complete correction of the deformities, 2 had mucopolysaccharidosis and 1 was nearing skeletal maturity (16 y old). The age of the patient, body weight, BMI, and degrees of angulation did not have any statistically significant correlation with the screw failure. Screw failures in female patients were more common than in male patients. All implant failures occurred in idiopathic patients. CONCLUSIONS: The efficacy of 3.5 mm reconstruction plates for temporary hemiepiphysiodesis around the knee is similar to that of 8-plates. However, the reconstruction plates have a lower cost and are easily available. Noncanulated 3.5 or 4.5 mm cortical screws seem to be superior to 4 mm noncanulated cancellous screws. LEVEL OF EVIDENCE: Level 3. PMID- 24172670 TI - A retrospective review of femoral nerve block for postoperative analgesia after knee surgery in the pediatric population. AB - BACKGROUND: To investigate the outcomes of pediatric patients receiving a femoral nerve block (FNB) in addition to general anesthesia for arthroscopic knee surgery compared with those receiving general anesthesia alone. METHODS: This retrospective review included all patients undergoing arthroscopic knee surgery from January 2009 to January 2011 under general anesthesia both with and without a FNB. After the induction of general anesthesia, those patients selected for regional anesthesia received a FNB using real-time ultrasound or nerve stimulator guidance. For the FNB, 0.2 to 0.4 mL/kg of local anesthetic solution was injected around the femoral nerve at the level of the inguinal crease. Intra-articular injection of bupivacaine (0.25%, 10 mL) was administered by the surgeon for all patients not receiving a FNB. Additional analgesic medications, PACU length of stay, duration of hospitalization, hospital course, and any acute or nonacute complications were recorded and evaluated. RESULTS: There were no adverse effects related to the FNB. Using a 0 to 10 visual analogue scale (0=no pain), there was a statistically significant difference in both the high (4.0 +/- 4.0 vs. 5.3 +/- 3.1, P=0.0004) and low (1.5 +/- 1.8 vs. 2.1 +/- 2.0, P=0.002) pain scores in patients who received a FNB versus those who did not with the scores being lower in those who had received a FNB. There was a decreased need for the use of opioids postoperatively (61% vs. 71%, P=0.04) and a decreased duration of postoperative stay in patients who were admitted to the hospital (11.7 +/- 8.1 vs. 15.8 +/- 10 h, P=0.044) in individuals who had a FNB. There was a significantly lower admission rate in patients undergoing anterior cruciate ligament repair in the FNB group (72% vs. 95%, P=0.001). There was no difference in the incidence of postoperative nausea and vomiting between the groups. CONCLUSION: After arthroscopic knee surgery in pediatric patients, a FNB shortens hospital stay, reduces opioid requirements, and decreases postoperative pain scores. For anterior cruciate ligament repairs, FNB lowers postoperative admission rates. CLINICAL EVIDENCE: Level III. PMID- 24172671 TI - Posterior sternoclavicular joint injuries in skeletally immature patients. AB - BACKGROUND: Posterior injuries to the sternoclavicular (SC) joint are uncommon. In the skeletally immature (SI) population, these injuries have been described as either dislocations of the SC joint or fractures of the medial clavicular physis. The current literature and standardized test questions state that a posterior SC injury, in a SI patient, is more likely a physeal fracture than a SC joint dislocation. However, this injury characterization is based on case reports or small case series. The purpose of this study is to characterize posterior SC injuries in SI patients in terms of the prevalence of dislocation versus medial clavicle physeal fracture. METHODS: A retrospective review was performed of 48 SI patients treated for posterior SC joint injuries over a 20-year period with a mean age of 15.4 years (range, 13 to 18 y). Forty patients underwent open reduction and internal fixation as their definitive treatment and 8 patients were treated exclusively with closed reduction. Patients treated operatively were utilized in determining the prevalence of SC joint dislocation versus physeal fracture. RESULTS: All patients treated operatively underwent primary repair without reconstruction. Twenty (50%), of the 40 patients treated operatively had a true SC joint dislocation and 20 patients (50%) had a medial clavicle physeal fracture. Twenty-two (46%) of the 48 total patients had an attempted closed reduction of which only 8 (36%) were successful. Among the 14 unsuccessful closed reductions, 12 (86%) were true dislocations (P<0.001). All successful closed reductions occurred in patients within 24 hours from injury. Eleven of the 48 (23%) patients' injuries were missed on initial presentation. CONCLUSIONS: Posterior SC joint dislocation and medial clavicular physeal fracture both occur with roughly equivalent prevalence in patients with an open medial physis. An attempted closed reduction may be more successful if performed within 24 hours after injury. Patients who fail attempts at closed reduction are more likely to have a posterior SC joint dislocation than a physeal fracture. Posterior SC joint injury may be missed in nearly 25% of patients on initial presentation. LEVEL OF EVIDENCE: Level IV-retrospective case series. PMID- 24172672 TI - Functional outcome analysis of triplane and tillaux fractures after closed reduction and percutaneous fixation. AB - BACKGROUND: There are limited data regarding the outcomes of triplane and tillaux fractures. The purpose of our study was to provide a long-term follow-up analysis of the functional outcomes as they relate to articular displacement using validated outcome tools. METHODS: A retrospective chart and radiographic review was performed to identify the age, the sex, the treatment method, complications, the fracture type, and articular displacement. Most patients underwent closed reduction with percutaneous fixation. We used 2 validated outcome measures, namely the Foot and Ankle Outcomes Score and the Marx Activity Scale, to assess functional results at a minimum of 2 years from the time of injury. RESULTS: We identified 78 patients between 2000 and 2009 who underwent computed tomographic scan evaluation of either a triplane (n=58) or a tillaux fracture (n=20). Triplane fractures occurred at a significantly younger age than tillaux fractures for both men and women (P=0.01). Women were found to suffer transitional fractures at a younger age than men (P<0.001). Patients with residual articular displacement of up to 2.4 mm after definitive treatment did not have worse functional outcomes compared with those who had an anatomic reduction on any of the Foot and Ankle Outcomes Score subscales and the Marx Activity Scale. Similarly, there was no correlation between the magnitude of residual gap or step off with functional outcome when the gap and step-off are <2.5 mm. Patients with longer-term follow-up (>4 y) did not have deterioration of function compared with those with a follow-up of 2 to 4 years. CONCLUSIONS: Tillaux and triplane fractures have good medium-term outcomes after reduction and fixation. Using primarily closed reduction and percutaneous fixation techniques, patients with a residual displacement of <2.5 mm after treatment have a uniformly good result. Functional results do not deteriorate at longer-term follow-up (4 to 10 y) as long as adequate reduction has been achieved. Percutaneous fixation yielded uniformly good results on all scales. LEVEL OF EVIDENCE: Therapeutic level III. PMID- 24172673 TI - Open surgical treatment of femoroacetabular impingement in adolescent athletes: preliminary report on improvement of physical activity level. AB - BACKGROUND: The surgical dislocation of the hip (SDH) approach has gained popularity in the treatment of femoroacetabular impingement (FAI) secondary to pediatric hip disorders. However, it has been suggested that SDH may preclude a return to previous levels of function in athletes. The purpose of this study was (1) to determine the level of activity and pain in young athletes before and after open hip surgery through an SDH approach for the treatment of FAI; (2) to investigate how clinical improvement correlates with physical activity; (3) to determine whether articular cartilage injury and the complexity of surgical procedures are associated with improvement in activity level and pain. METHODS: SDH was utilized in 29 young athletes treated for symptomatic FAI (20 males 9 females, age range 12.7 to 20.7 years (mean age, 17 y)). Evaluation included sport(s) played, University of California Los Angeles (UCLA) physical activity level, and clinical outcome in terms of Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC)-Pain scores. Intraoperative articular cartilage status and anteroposterior pelvic and lateral hip radiographs were assessed. RESULTS: All patients had regularly participated in one or more of 13 distinct sports. The median UCLA score increased with marginal significance (P=0.057) after surgery. Change in the level of pain from preoperatively to postoperatively, as measured by the WOMAC-Pain subscale, was found to be statistically significant (P=0.0024). A statistically significant correlation between changes in UCLA and WOMAC was estimated (rho=-0.61, P<=0.001). No statistically significant correlation was found between change in UCLA and the addition of a second procedure other than femoral head-neck osteochondroplasty. Finally, no statistically significant correlation was found between severity of cartilage injury and change in UCLA or WOMAC scores. The femoral alpha-angle improved an average of 22.7 degrees (P<0.001) after surgery. CONCLUSIONS: Pain relief and maintenance or improvement in activity level may be achieved with open FAI surgery through an SDH approach in young athletes. Although this approach is more invasive than hip arthroscopy, it should be considered in the management of adolescents with FAI and complex hip deformities associated with pediatric disorders such as slipped capital femoral epiphysis and Perthes disease. LEVEL OF EVIDENCE: Level IV-case series; retrospective. PMID- 24172674 TI - Improving diagnostic efficiency: analysis of pelvic MRI versus emergency hip aspiration for suspected hip sepsis. AB - BACKGROUND: Accurately diagnosing and treating childhood hip sepsis is challenging. Adjacent bone and soft-tissue infections are common and can lead to delayed and inappropriate treatment. This study evaluated the effect of early advanced imaging (bone scan, magnetic resonance imaging) in the management of suspected hip sepsis. METHODS: A retrospective review of pediatric patients admitted between 2003 and 2009 with suspected hip sepsis was performed. Patients were classified into 2 categories: group I-immediate hip aspiration or group II advanced imaging performed before intervention. RESULTS: In total, 130 patients (53 in group I and 77 in group II) were included. No significant differences were found between the groups with regard to laboratory values, temperature, number of anesthetics, and length of hospital stay. However, patients in group I were younger than in group II (5.4 vs. 7.3 y, P=0.02) and more patients in group I were unable to bear weight on the affected limb compared with group II (83% vs. 61%, P=0.009). In group I, 36 patients (68%) had a septic hip compared with 35 patients (45%) in group II. In group I, 16 patients (30%) required reoperation versus 13 (17%) patients in group II. Results from the multivariate analysis demonstrated that reoperation was required 2.8 times (95% confidence interval, 1.12-6.78) more often in group I as compared with group II (P=0.03). CONCLUSIONS: Advanced imaging performed before hip aspiration improves diagnostic efficacy and may decrease the need for reoperation. LEVEL OF EVIDENCE: III. PMID- 24172675 TI - Ischial apophyseal avulsions: proximal hamstring repair with bony fragment excision. AB - BACKGROUND: Avulsion injury of the hamstring muscles from their origin on the ischium is an uncommon injury. In persons aged 14 to 25 years, such an avulsion may include detachment of an epiphyseal fragment at the growth plate of the ischial apophysis. The literature suggests that surgery is not necessary unless there is a large displacement of the fragment. The objective of this report is to present evidence that treatment planning should be based on symptoms, regardless of displacement. METHODS: Between July 1998 and July 2002, 3 consecutive patients with avulsion of the immature ischial apophysis were evaluated by the senior author. In each case the bony fragment was excised and the hamstrings were reattached to the ischium with suture anchors. All patients were assessed postoperatively by biodex strength testing. RESULTS: The average age of the patients was 15 years and the average time to repair was 7 months from the time of injury. The average retraction was 3.7 cm. The average follow-up period was 78 months. The average strength was 86% and the average power was 100% compared with the contralateral side at the final follow-up. In all 3 cases pain was relieved, and with adequate rehabilitation normal strength was regained and the subjects returned to sport. There was one complication involving an activity-related peroneal nerve palsy. This was treated by neurolysis with good functional return. CONCLUSIONS: The 3 cases presented here suggest that treatment should be planned on the basis of pain and disability rather than pathology, and that surgical treatment can effectively address a chronic condition. Each case requires an individualized treatment plan and should include a consideration of the patient's functional goals. PMID- 24172676 TI - Is it worthwhile to routinely ultrasound screen children with idiopathic clubfoot for hip dysplasia? AB - PURPOSE: Patients with idiopathic clubfoot are considered at increased risk for having developmental dysplasia of the hips (DDH). However, the studies showing this association have been relatively small. Many clinicians who treat idiopathic clubfoot routinely screen the hips of these patients with ultrasound or radiograph due to the concerns of increased risk of DDH. We evaluated a large clubfoot population to determine the risk of DDH and compare this to a population of children without clubfoot. We also evaluated if the clubfoot patients found to have DDH would have been discovered by standard DDH screening. METHODS: We identified infants in 3 states (MA, NY, NC), who were reported to each state's birth defects registry as having a clubfoot. A second cohort of infants without clubfoot was also identified as a control group. Mothers of these children were contacted to be included in the study, and a computer-assisted telephone interview was administered by one of the study nurses, including questions about treatment of DDH. The child's median age at interview was 7 months. Mothers of clubfoot cases were also contacted for follow-up at mean age of 3.3 years. RESULTS: Families of 677 patients with clubfoot and 2037 controls were interviewed. A total of 5/677 (0.74%) patients with clubfoot and 5/2037 (0.25%) controls reported having their infant treated with a brace or harness for hip problems (P=0.134). Of the patients with clubfoot, 2 of them did not need treatment for their DDH and 2 would have been discovered by standard hip screening. Follow-up study at 3.3 years of age found no serious late hip dysplasia. CONCLUSIONS: Treatment of DDH was uncommon in all children; the higher proportion in infants with clubfoot was not statistically different than controls. Of the patients with clubfoot and DDH, standard hip screening would have been appropriate and others did not need treatment. These data suggest that routine hip ultrasound or radiographic screening of idiopathic clubfoot patients is not necessary unless indicated by the standard infant hip screening. LEVEL OF EVIDENCE: Level 3 study. PMID- 24172677 TI - Arthroscopic versus conservative treatment of first anterior dislocation of the shoulder in adolescents. AB - BACKGROUND: Conservative treatment of posttraumatic antero-inferior shoulder instability leads to a high failure rate in a young and active population. However, treatment in an adolescent age group is not well documented. METHODS: We conducted a prospective study with adolescent patients (age 15 to 18 y) who suffered a first traumatic anterior dislocation of the shoulder. Two groups of patients were formed. The first group was treated with early arthroscopic stabilization and the second was treated conservatively. There were 43 shoulders in the operative group and 29 shoulders in the conservative group. The rehabilitation protocol was the same for both groups. All patients were followed up prospectively after 12, 24, and 36 months using Rowe Score. RESULTS: A total of 38 shoulders in the surgical group and 27 shoulders in the conservative group could be completely evaluated. From the conservative group, 19 patients (70.3%) suffered a recurrence of the instability. From the arthroscopic group, 5 patients (13.1%) suffered a recurrence of the instability. CONCLUSIONS: In an adolescent population (15 to 18 y), conservative treatment after first traumatic shoulder dislocation including immobilization in internal rotation leads to a significantly higher and unacceptable high failure rate compared with early arthroscopic stabilization. LEVEL OF EVIDENCE: Level II-prospective comparative study. PMID- 24172678 TI - Intraobserver and interobserver reliability and the role of fracture morphology in classifying femoral shaft fractures in young children. AB - BACKGROUND: Spiral fractures of long bones have long been cited as indications of non-accidental trauma (NAT) in children; however, fracture types are only loosely defined in the literature, and intraobserver and interobserver variability in defining femoral fracture patterns is rarely mentioned. We sought to determine reliability in classifying femoral fractures in young children using a standard series of radiographs shown to physicians with varied backgrounds and training and to determine if a quantitative approach based on objective measurements made on plain radiographs could improve definition of these fractures. METHODS: On 50 radiographs, the fracture ratio--fracture length divided by bone diameter--was determined and radiographs were reviewed by 14 observers, including pediatric orthopaedic surgeons, emergency room physicians, and musculoskeletal radiologists, who classified the fractures as transverse, oblique, or spiral. A second review of the images in a different order was carried out at least 10 days after the first. RESULTS: Overall, intraobserver agreement was strong, whereas interobserver reliability was moderate. Experience level did not correlate with either result. Complete agreement among all observers occurred for only 5 fractures: 3 transverse and 2 spiral. An average fracture ratio near 1.0 appeared to be predictive of a transverse fracture and a ratio of >3.0, a spiral fracture; ratios between these 2 values resulted in essentially random classification. CONCLUSIONS: The ability to reproducibly classify femoral fractures in young children is highly variable among physicians of different specialties. These results support the belief that fracture morphology has little predictive value in NAT because of the wide variability in what observers classify as a spiral fracture of the femur. Caution should be used in the use of descriptive terms such as spiral, oblique, or transverse when classifying femoral fractures, as well as when evaluating children for possible NAT, because of the variability in classification. LEVEL OF EVIDENCE: Level III-diagnostic study. PMID- 24172679 TI - Epidemiology, diagnosis, and treatment of pericapsular pyomyositis of the hip in children. AB - BACKGROUND: The yield of synovial fluid cultures in patients meeting clinical criteria for septic hip arthritis remains low. In the presence of positive blood cultures, these patients are diagnosed and treated as "presumed septic arthritis." We hypothesized that some of these patients may instead have an extra articular infection, such as pericapsular pyomyositis. METHODS: An IRB-approved prospective study of children with suspected septic hip arthritis at a tertiary care children's hospital over a 2-year time period was conducted. Children were evaluated with a previously published clinical algorithm with the addition of magnetic resonance imaging (MRI). RESULTS: Of the 53 patients presenting with an acutely irritable hip, 32% were found to have pericapsular pyomyositis, whereas 15% were diagnosed with septic arthritis. Although C-reactive protein (CRP, >=33.1 mg/L) performed well at predicting infection, there were no significant differences in CRP, erythrocyte sedimentation rate, white blood cell count, temperature, or weight-bearing status in children with septic arthritis compared with pericapsular pyomyositis. In addition to MRI, there was a difference in the size of hip effusion on ultrasound, which was significantly smaller in cases of pericapsular pyomyositis. CRP (>=74.3 mg/L) was found to be predictive of need for surgical intervention in children with pericapsular pyomyositis. CONCLUSIONS: Correct anatomic diagnosis of the site of infection is essential for the efficient care of the child. Herein, we found that pericapsular pyomyositis is twice as common as septic arthritis in children presenting with an acutely irritable hip. Clinical algorithms are incapable of differentiating these pathologies suggesting that both be considered under the current diagnosis previously referred to as "presumed septic arthritis." Incorrect diagnosis of a septic arthritis in the presence of a pericapsular pyomyositis could potentially lead to unnecessary debridement of the joint in the presence of extra-articular infection, thus contaminating the joint. Conversely, debriding the joint instead of the epicenter of the infection can prolong the infectious process. For these reasons, we conclude that MRI has the potential to improve the clinical care of children by providing a more precise diagnosis. LEVEL OF EVIDENCE: Level II "Diagnostic" [Development of diagnostic criteria on the basis of consecutive patients (with universally applied reference "gold" standard)]. PMID- 24172680 TI - Characterization of radiation exposure in early-onset scoliosis patients treated with the vertical expandable prosthetic titanium rib. AB - BACKGROUND: The evaluation and treatment of patients with early-onset scoliosis requires multiple imaging studies and involves potential exposure to high cumulative lifetime doses of ionizing radiation. The Vertical Expandable Prosthetic Titanium Rib (VEPTR) used in the treatment of early-onset scoliosis requires numerous lengthening procedures and frequent radiographic follow-up. The purpose of this study was to quantify the ionizing radiation exposure in pediatric patients undergoing VEPTR treatment and to identify factors that place patients with early-onset scoliosis at greater risk of radiation exposure. METHODS: Data were collected by retrospective review of the records of all patients with early-onset scoliosis who were treated with a VEPTR over a 4-year period (2007 to 2010). Diagnostic radiographs, computed tomography, intraoperative fluoroscopy, and nuclear medicine studies were identified and analyzed for ionizing radiation exposure. Total radiation exposure was determined and compared for risk factors such as etiology (eg, neuromuscular or congenital) and surgeon experience. In addition, radiographic studies directly related and unrelated to scoliosis treatment were compared. RESULTS: Twenty-four patients had 121 surgical procedures (mean 5.0/patients) and 962 imaging studies (mean 40/patients). The mean estimated cumulative radiation dose per patient during follow-up was 86.7 mSv (range, 42.6 to 174.9 mSv) with a mean dose per year of 34 mSv (range, 22.9 to 47.1 mSv). Patients with congenital scoliosis received greater mean amounts of radiation (35.2 mSv) than patients with neuromuscular scoliosis (31.9 mSv). Patients treated within the first 2 years of the study period had higher radiation exposure (42.4 mSv) compared with patients treated in the last 2 years (24.9 mSv) (P<0.001). CONCLUSIONS: Ionizing radiation is an inevitable side effect of the VEPTR treatment for early-onset scoliosis. There are differences in the amount and sources of radiation exposure between patients with early-onset scoliosis secondary to congenital and neuromuscular causes. Surgeon experience is correlated with decreased levels of radiation exposure. Awareness of the potential for high levels of radiation exposure, as well as patient and surgeon-related factors involved, may lead to more effective radiation-reduction strategies. LEVEL OF EVIDENCE: Level IV--retrospective case study. PMID- 24172681 TI - Current state of pediatric orthopaedic disaster response. PMID- 24172682 TI - Obstructive lung disease is common in children with syndromic and congenital scoliosis: a preliminary study. AB - BACKGROUND: It is well known that restrictive lung disease (RLD) is associated with scoliosis. This study identifies that obstructive lung disease (OLD) is associated with syndromic scoliosis and congenital scoliosis. METHODS: We searched a local database for patients with scoliosis who underwent a pulmonary function testing (PFT) from 2004 to 2009. All patients with congenital scoliosis or syndromic thoracolumbar scoliosis with a Cobb angle of >=40 degrees and acceptable and repeatable PFT testing were included in the study. OLD was defined as an forced expiratory volume in the first second/forced vital capacity ratio below 95% confidence interval. Bronchoscopy videos and computed tomography scans or magnetic resonance images were reviewed to identify anatomic causes of lower airway disease. RESULTS: A total of 18 patients met the criteria for inclusion. The median age at diagnosis was 11.3 years. The median primary Cobb angle was 60 degrees. The prevalence of OLD was 33% and RLD was 57%. The 6 children with OLD underwent preoperative bronchoscopy and chest computed tomography or magnetic resonance imaging to identify anatomic causes of lower airway obstruction. The 4 children with OLD and right-sided major thoracic curves had compression of the right mainstem bronchus between the spine (posterior) and the right pulmonary artery (anterior). The 2 children with OLD and left-sided major thoracic curves had compression of the left mainstem bronchus between the spine (posterior) and the descending aorta (anterior) or the left atrium (anterior). CONCLUSIONS: In our study, the prevalence of OLD in children with congenital scoliosis or syndromic scoliosis was 33%, which was elevated when compared with the population prevalence of 2% to 5%. Mainstem airway compression from spine rotation was discovered to be the potential mechanism of disease. LEVEL OF EVIDENCE: Level IV, prognostic study investigating the effect of a patient characteristic on the outcome of disease. PMID- 24172683 TI - C3 glomerulopathy: consensus report. AB - C3 glomerulopathy is a recently introduced pathological entity whose original definition was glomerular pathology characterized by C3 accumulation with absent or scanty immunoglobulin deposition. In August 2012, an invited group of experts (comprising the authors of this document) in renal pathology, nephrology, complement biology, and complement therapeutics met to discuss C3 glomerulopathy in the first C3 Glomerulopathy Meeting. The objectives were to reach a consensus on: the definition of C3 glomerulopathy, appropriate complement investigations that should be performed in these patients, and how complement therapeutics should be explored in the condition. This meeting report represents the current consensus view of the group. PMID- 24172685 TI - Five reasons for the lack of nursing students' motivation to learn public health. AB - Prevention is better than cure. Public health plays an important role in promoting prevent medicine. To obtain the abilities to provide appropriate nursing services, learning public health is necessary for students who want to become registered nurses. When teachers teach public health to nursing students, it is important to motivate them to learn it. Therefore, we investigated the reasons for the lack of motivation to learn public health by conducting a questionnaire survey. The subjects were female nursing students in 29 vocational schools in Kanagawa and Chiba prefectures of Japan that allow graduation after a 3-year study period. We asked the students whether or not they had completed the subject of public health and analyzed those students who answered affirmatively. We analyzed 1,553 respondents whose average age was 22.6 +/- 5.2 years (range, 18 to 45). Using factor analysis, we discovered the 5 reasons that lead to the lack of nursing students' motivation to learn public health: "Difficulties acquiring knowledge of public health," "Inappropriate attitudes of public health teachers," "Thinking lightly about the national examination in the field of public health," "Lack of understanding the importance of learning public health," and "Future plans that do not specialize in public health." Using multiple linear regression analysis, these 5 reasons were significant predictors for the lack of students' motivation. Older students also had significantly less motivation to learn public health than did younger students. When teachers instruct their students, they should teach public health better with the present knowledge. PMID- 24172684 TI - Early B-cell factor 1 is an essential transcription factor for postnatal glomerular maturation. AB - The coordination of multiple cytokines and transcription factors with their downstream signaling pathways has been shown to be integral to nephron maturation. Here we present a completely novel role for the helix-loop-helix transcription factor Early B-cell factor 1 (Ebf1), originally identified for B cell maturation, for the proper maturation of glomerular cells from mesenchymal progenitors. The expression of Ebf1 was both spatially and temporally regulated within the developing cortex and glomeruli. Using Ebf1-null mice, we then identified biochemical, metabolic, and histological abnormalities in renal development that arose in the absence of this transcription factor. In the Ebf1 knockout mice, the developed kidneys show thinned cortices and reduced glomerular maturation. The glomeruli showed abnormal vascularization and severely effaced podocytes. The mice exhibited early albuminuria and elevated blood urea nitrogen levels. Moreover, the glomerular filtration rate was reduced >66% and the expression of podocyte-derived vascular endothelial growth factor A was decreased compared with wild-type control mice. Thus, Ebf1 has a significant and novel role in glomerular development, podocyte maturation, and the maintenance of kidney integrity and function. PMID- 24172686 TI - Discovery of coumarin derivatives as fluorescence acceptors for intrinsic fluorescence resonance energy transfer of proteins. AB - Coumarin analogues were synthezised and evaluated as acceptors for the intrinsic fluorescence resonance energy transfer (iFRET) of tryptophan residues in target proteins. The fluorescence properties such as quantum yields, iFRET efficiencies, and Forster distances of the prepared coumarin analogs were determined in a model system, by their conjugation to biotin, utilizing streptavidin (SAV) as the iFRET donor. The coumarin derivatives reported here represent the most efficient iFRET acceptors for tryptophan, known to date. PMID- 24172687 TI - Oxidation of gas-phase hydrated protonated/deprotonated cysteine: how many water ligands are sufficient to approach solution-phase photooxidation chemistry? AB - We present a study on the reactions of singlet oxygen O2[a(1)Deltag] with hydrated protonated and deprotonated cysteine (Cys) in the gas phase, including measurements of the effects of collision energy (E(col)) and hydration number on reaction cross sections over a center-of-mass E(col) range from 0.05 to 1.0 eV. The aim is to probe how successive addition of water molecules changes the oxidation chemistry of Cys in the gas phase. Hydrated clusters, generated by electrospray ionization, have structures of HSCH2CH(NH3(+))CO2H(H2O)(1,2) and HSCH2CH(NH2)CO2(-)(H2O)(1,2) for protonated and deprotonated forms, respectively. In contrast to (1)O2 reactions with dehydrated protonated/deprotonated Cys of which hydroperoxide products all decomposed, reactions with hydrated protonated/deprotonated Cys yielded stable hydroperoxide products, analogous to photooxidation reaction of Cys in solution. We investigated the number of water ligands necessary to produce a stable hydroperoxide, and found that a single water molecule suffices--that is, to relax nascent, energized hydroperoxide in the hydrated cluster by elimination of water. Hydrated protonated Cys shows higher reaction efficiency than the hydrated deprotonated one, particularly with the addition of the second water ligand. Reactions of hydrated protonated/deprotonated Cys are suppressed by E(col), becoming negligible at E(col) >= 0.5 eV. Density functional theory calculations were used to locate reaction coordinates for these systems. Quasi-classical, direct dynamics trajectory simulations were performed for HSCH2CH(NH3(+))CO2H(H2O) + (1)O2 at the B3LYP/4-31G(d) level of theory. Analysis of trajectories highlights the importance of complex mediation in the early stages of the reaction, and illustrates that water can catalyze proton transfer within the hydrated complex. PMID- 24172688 TI - Vibration response imaging versus perfusion scan in lung cancer surgery evaluation. AB - OBJECTIVE: Ventilation/perfusion scan is a standard procedure in high-risk surgical patients to predict pulmonary function after surgery. Vibration response imaging is a technique that could be used in these patients. The objective of our study was to compare this imaging technique with the usual scanning technique for predicting postoperative forced expiratory volume. METHODS: We assessed 48 patients with lung cancer who were candidates for lung resection. Forced spirometry, vibration response imaging, and ventilation/perfusion scan were performed in patients before surgery, and spirometry was performed after intervention. RESULTS: We included 48 patients (43 men; mean age, 64 years) undergoing lung cancer surgery (32 lobectomies/16 pneumonectomies). On comparison of both techniques, for pneumonectomy, we found a concordance of 0.84 (95% confidence interval, 0.76-0.92) and Bland-Altman limits of agreement of -0.33 to +0.45, with an average difference of 0.064. By comparing postoperative spirometry with vibration response imaging, we found a concordance of 0.66 (95% confidence interval, 0.38-0.93) and Bland-Altman limits of agreement of -0.60 to +0.33, with an average difference of -0.13. CONCLUSIONS: The 2 techniques presented good concordance values. Vibration response imaging shows non-negligible confidence intervals. Vibration response imaging may be useful in preoperative algorithms in patients before lung cancer surgery. PMID- 24172689 TI - Sometimes an ounce of extracorporeal membrane oxygenation prevention is worth a pound of extracorporeal membrane oxygenation cure. PMID- 24172690 TI - Transient right ventricular dysfunction caused by retractor during lower hemisternotomy mitral valve repair in a patient with pectus excavatum. PMID- 24172691 TI - Early clinical and angiographic outcomes after robotic-assisted coronary artery bypass surgery. AB - OBJECTIVE: Robotic-assisted coronary artery bypass grafting has emerged as an alternative to traditional coronary artery bypass grafting or percutaneous intervention for patients with coronary artery disease. However, the safety and efficacy of this minimally invasive procedure have not been established in large series. METHODS: From October 2009 to September 2012, 307 consecutive robotic assisted coronary artery bypass grafting procedures were performed at a single US institution by 2 surgeons. Isolated, off-pump, left internal thoracic artery to left anterior descending coronary artery grafting was planned via a 3- to 4-cm non-rib-spreading minithoracotomy after robotic left internal thoracic artery harvest in all patients. Hybrid coronary revascularization was planned in 159 patients (51.8%). Of the 199 angiograms (64.8%) performed before discharge, 63 were performed as completion angiograms in a hybrid suite immediately after left internal thoracic artery-left anterior descending artery grafting. RESULTS: Thirty-day mortality occurred in 4 patients (1.3%), conversion to sternotomy occurred in 16 patients (5.2%), postoperative myocardial infarction occurred in 5 patients (1.6%), and reexploration for bleeding occurred in 7 patients (2.3%). There was 1 (0.3%) postoperative stroke. For the 199 patients with follow-up angiography before discharge, the left internal thoracic artery was confirmed to be patent (<50% stenosis) in 189 patients (95.0%). Among the 10 patients with significant (>=50% stenosis) defects, 5 had graft occlusion or distal left anterior descending occlusion, 2 had poor flow distal to the anastomosis, and 3 had anastomotic lesions (>=50% stenosis). Among the 63 patients with intraoperative completion angiography, 5 patients underwent surgical graft revision, 3 patients underwent minithoracotomy, and 2 patients underwent conversion to sternotomy. CONCLUSIONS: Robotic-assisted coronary artery bypass grafting is an effective alternative to traditional coronary artery bypass grafting for patients with single or multivessel coronary artery disease, with comparable short-term clinical and angiographic results. PMID- 24172693 TI - Molecular dynamics evidence for alkali-metal rattling in the beta-pyrochlores, AOs2O6 (A = K, Rb, Cs). AB - We have used ab initio molecular dynamics simulations validated against inelastic neutron scattering data to study alkali-metal dynamics in the beta-pyrochlore osmates AOs2O6 (A=K, Rb, Cs) at 300 K to gain insight into the microscopic nature of rattling dynamics in these materials. Our results provide new evidence at the microscopic level for rattling dynamics: (1) the elemental magnitude spectra calculated from the MD show a striking dominance by the alkali metals at low energies indicating weak coupling to the cage, (2) the atomic root-mean-square displacements for the alkali metals are significantly larger than for the other atoms, e.g., 25% and 150% larger than O and Os, respectively, in KOs2O6, and (3) motions of the alkali metals are weakly correlated to the dynamics in their immediate environment, e.g. K in KOs2O6 is 6 times less sensitive to its local environment than Os, indicating weak bonding of the K. There is broadening of the elemental spectra of the alkali metals from Cs to K corresponding to a similar broadening of the local potential around these atoms as determined from potential of mean-force calculations. This feature of the spectra is partly explained by the well-known increase in the relative cage volume with decreasing atomic size of the alkali metal. We find that for the smallest rattler in this series (K) the larger relative cage volume allows this atom freedom to explore a large space inside the cage leading to vibration at a broader range of frequencies, hence a broader spectrum. Thus, since K is considered the best rattler in this series, these findings suggest that a significant feature of a good rattler is the ability to vibrate at several different but closely spaced frequencies. PMID- 24172692 TI - An international multicenter study comparing arrhythmia prevalence between the intracardiac lateral tunnel and the extracardiac conduit type of Fontan operations. AB - OBJECTIVE: The study objective was to determine whether the extracardiac conduit Fontan confers an arrhythmia advantage over the intracardiac lateral tunnel Fontan. METHODS: This multicenter study of 1271 patients compared bradyarrhythmia (defined as need for pacing) and tachyarrhythmia (defined as needing antiarrhythmic therapy) between 602 patients undergoing the intracardiac Fontan and 669 patients undergoing the extracardiac Fontan. The median age at the time of the Fontan procedure was 2.1 years (interquartile range, 1.6-3.2 years) for the intracardiac group and 3.0 years (interquartile range, 2.4-3.9) for the extracardiac group (P < .0001). The median follow-up was 9.2 years (interquartile range, 5-12.8) for the intracardiac group and 4.7 years (interquartile range, 2.8 7.7) for the extracardiac group (P < .0001). RESULTS: Early postoperative (<30 days) bradyarrhythmia occurred in 24 patients (4%) in the intracardiac group and 73 patients (11%) in the extracardiac group (P < .0001). Early postoperative (<30 days) tachyarrhythmia occurred in 32 patients (5%) in the intracardiac group and 53 patients (8%) in the extracardiac group (P = not significant). Late (>30 days) bradyarrhythmia occurred in 105 patients (18%) in the intracardiac group and 63 patients (9%) in the extracardiac group (P < .0001). Late (>30 days) tachyarrhythmia occurred in 58 patients (10%) in the intracardiac group and 23 patients (3%) in the extracardiac group (P < .0001). By multivariate analysis factoring time since surgery, more patients in the extracardiac group had early bradycardia (odds ratio, 2.9; 95% confidence interval, 1.8-4.6), with no difference in early tachycardia, late bradycardia, or late tachycardia. CONCLUSIONS: Overall arrhythmia burden is similar between the 2 groups, but the extracardiac Fontan group had a higher incidence of early bradyarrhythmias. There was no difference in the incidence of late tachyarrhythmias over time between the 2 operations. Therefore, the type of Fontan performed should be based on factors other than an anticipated reduction in arrhythmia burden from the extracardiac conduit. PMID- 24172694 TI - High-functioning autism spectrum disorder associated with CHARGE syndrome: a case report. PMID- 24172695 TI - Type 1 diabetes, diabetic nephropathy, and pregnancy: a systematic review and meta-study. AB - BACKGROUND: In the last decade, significant improvements have been achieved in maternal-fetal and diabetic care which make pregnancy possible in an increasing number of type 1 diabetic women with end-organ damage. Optimal counseling is important to make the advancements available to the relevant patients and to ensure the safety of mother and child. A systematic review will help to provide a survey of the available methods and to promote optimal counseling. OBJECTIVES: To review the literature on diabetic nephropathy and pregnancy in type 1 diabetes. METHODS: Medline, Embase, and the Cochrane Library were scanned in November 2012 (MESH, Emtree, and free terms on pregnancy and diabetic nephropathy). Studies were selected that report on pregnancy outcomes in type 1 diabetic patients with diabetic nephropathy in 1980-2012 (i.e. since the detection of microalbuminuria). Case reports with less than 5 cases and reports on kidney grafts were excluded. Paper selection and data extraction were performed in duplicate and matched for consistency. As the relevant reports were highly heterogeneous, we decided to perform a narrative review, with discussions oriented towards the period of publication. RESULTS: Of the 1058 references considered, 34 fulfilled the selection criteria, and one was added from reference lists. The number of cases considered in the reports, which generally involved single-center studies, ranged from 5 to 311. The following issues were significant: (i) the evidence is scattered over many reports of differing format and involving small series (only 2 included over 100 patients), (ii) definitions are non-homogeneous, (iii) risks for pregnancy-related adverse events are increased (preterm delivery, caesarean section, perinatal death, and stillbirth) and do not substantially change over time, except for stillbirth (from over 10% to about 5%), (iv) the increase in risks with nephropathy progression needs confirmation in large homogeneous series, (v) the newly reported increase in malformations in diabetic nephropathy underlines the need for further studies. CONCLUSIONS: The heterogeneous evidence from studies on diabetic nephropathy in pregnancy emphasizes the need for further perspective studies on this issue. PMID- 24172696 TI - Low total testosterone levels are associated with the metabolic syndrome in elderly men: the role of body weight, lipids, insulin resistance, and inflammation; the Ikaria study. AB - BACKGROUND: The prevalence of the metabolic syndrome (MetS) increases with age. Among other changes, testosterone levels decline with age. The relationship between testosterone levels and MetS components in older subjects has not been clearly defined until today. OBJECTIVES: The aim of this work was to evaluate the relationship between total serum testosterone levels and MetS and its components. METHODS: The working sample consisted of 467 elderly individuals (mean age 75 +/- 6 years old, n = 220 men) from Ikaria Island, Greece. MetS was defined according to the NCEP ATPIII criteria. RESULTS: MetS prevalence was 52% in men and 64% in women. Those with MetS had lower testosterone levels; a 10 ng/dl increase in testosterone was associated with a 3% reduction in odds of having MetS in men (95% CI: 0.95-0.99), but not in women. This remained the result after various adjustments had been made, including daily hours of sleep. Testosterone was inversely associated with abnormal waist circumference, high-sensitivity C reactive protein (hs-CRP), insulin, and HDL cholesterol levels in men only. When lipid categories, hs-CRP, BMI, and insulin resistance levels were taken into account, testosterone lost its significance in predicting MetS (p < 0.20), suggesting that these markers possess a mediating effect. CONCLUSIONS: In elderly men, low serum testosterone was associated with MetS. Lipids, BMI, inflammation, and insulin resistance levels seem to explain this relationship, suggesting a potential mediating effect. This finding may support a research hypothesis relating serum testosterone to cardiovascular disease, which requires further research. PMID- 24172697 TI - Dessert formulation using sucralose and dextrin affects favorably postprandial response to glucose, insulin, and C-peptide in type 2 diabetic patients. AB - BACKGROUND: Dessert compositions may conform to diabetic diet when it contains low sugar or artificial sweetener to replace sugar. However, it is still questionable whether glycemic control in type 2 diabetes patients is improved by the use of diet-conforming dessert compositions. OBJECTIVE: To compare, in type 2 diabetes patients, the glycemic, insulin, and C-peptide responses to seven modified dessert compositions for diabetics (D-dessert) with the response to seven similar desserts of non-modified composition, used as control desserts (C dessert). METHODS: Seventy type 2 diabetes patients were allocated to seven groups of ten. On three occasions, each patient received either the meal which consisted of bread and cheese, or the meal and D-dessert, or the meal and the respective C-dessert. Differences in postprandial glucose, insulin, and C-peptide were evaluated using analysis of repeated measures at 0, 30, 60, 90, and 120 min after consumption. RESULTS: D-cake and D-pastry cream resulted in lower glucose levels (8.81 +/- 0.32 mmol/l and 8.67 +/- 0.36 mmol/l, respectively) and D strawberry jelly in lower insulin levels (16.46 +/- 2.66 MUU/ml) than the respective C-desserts (9.99 +/- 0.32 mmol/l for C-cake, 9.28 +/- 0.36 mmol/l for C-pastry cream, and 27.42 +/- 2.66 MUU/ml for C-strawberry jelly) (p < 0.05). Compared with the meal, D-cake did not increase glucose or insulin levels (p < 0.05), while C-cake did (p < 0.05). D-pastry cream increased glucose to a lesser extent than C-pastry cream (p < 0.05). Similar effects were reported for D-milk dessert, D-millefeuille, and D-chocolate on glucose, insulin, and C-peptide at specific timepoints. D-creme caramel showed no effect. CONCLUSIONS: Some desserts formulated with sugar substitutes and soluble fiber may have a favorable effect on postprandial levels of glucose, insulin, and C-peptide in type 2 diabetic patients. PMID- 24172698 TI - Postpartum outcomes in women with gestational diabetes and their offspring: POGO study design and first-year results. AB - BACKGROUND: Gestational diabetes mellitus (GDM) is a risk factor for mothers to develop type 2 diabetes (T2D) postpartum, and for their children to develop obesity. The aim of the ongoing POGO study is to identify long-lasting changes in the maternal and fetal metabolism and microbiome, after GDM, which contribute to subsequent development of T2D and obesity. METHODS: Women screened for GDM are asked to attend a postpartum study visit together with their offspring. At the visit, demographic, nutritional, and anthropometric data are recorded. Additionally, data about physical activity, metabolism, and genetic susceptibility are collected using accelerometers, breath gas analyses, 75g oral glucose tolerance tests (OGTT), and bio-samples such as blood and stool. RESULTS: To date, 121 women (median follow-up time postpartum: 5.5 years) have been enrolled together with 133 index children. GDM has been diagnosed using OGTT in 105 women (and 117 children). It showed that 47 mothers had abnormal glucose tolerance, including 19 cases of impaired glucose tolerance, 19 of impaired fasting glucose, eight with T2D, and one with type 1 diabetes (T1D). The prevalence of obesity in the offspring of GDM mothers was 5.1%. Of 61 children tested by OGTT, three were diagnosed with impaired glucose tolerance, another three with impaired fasting glucose, and none with T1D or T2D. CONCLUSIONS: The POGO study will contribute to the understanding of the pathogenesis of T2D and obesity after GDM, and will thus help to develop appropriate prevention and intervention strategies. This article presents the first results of the ongoing study, which are looking promising. PMID- 24172699 TI - Alpha-lipoic acid improves subclinical left ventricular dysfunction in asymptomatic patients with type 1 diabetes. AB - BACKGROUND: Oxidative stress plays an important role in the development of diabetic cardiomyopathy. Alpha-lipoic acid (ALA) is a powerful antioxidant that may have a protective role in diabetic cardiac dysfunction. AIM: We investigated the possible beneficial effect of alpha-lipoic acid on diabetic left ventricular (LV) dysfunction in children and adolescents with asymptomatic type 1 diabetes (T1D). SUBJECTS AND METHODS: Thirty T1D patients (aged 10-14) were randomized to receive insulin treatment (n = 15) or insulin plus alpha-lipoic acid 300 mg twice daily (n = 15) for four months. Age and sex matched healthy controls (n = 15) were also included. Patients were evaluated with conventional 2-dimensional echocardiographic examination (2D), pulsed tissue Doppler (PTD), and 2 dimensional longitudinal strain echocardiography (2DS) before and after therapy. Glutathione, malondialdhyde (MDA), nitric oxide (NO), tumor necrosis factor-alpha (TNF-alpha), Fas ligand (Fas-L), matrix metalloproteinase 2 (MMP-2), and troponin I were determined and correlated to echocardiographic parameters. RESULTS: Diabetic patients had significantly lower levels of glutathione and significantly higher MDA, NO, TNF-alpha, Fas-L, MMP-2, and troponin-I levels than control subjects. The expression of transforming growth factor beta (TGF-beta) mRNA in peripheral blood mononuclear cells was also increased in diabetic patients. Significant correlations of mitral e'/a' ratio and left ventricular global peak systolic strain with glutathione, MDA, NO, TNF-alpha, and Fas-L were observed in diabetic patients. Alpha-lipoic acid significantly increased glutathione level and significantly decreased MDA, NO, TNF-alpha, Fas-L, MMP-2, troponin-I levels, and TGF-beta gene expression. Moreover, alpha-lipoic acid significantly increased mitral e'/a' ratio and left ventricular global peak systolic strain in diabetic patients. CONCLUSION: These findings suggest that alpha-lipoic acid may have a role in preventing the development of diabetic cardiomyopathy in type 1 diabetes. PMID- 24172701 TI - Ruptured intracranial aneurysms in young adults: seeing the forest for the trees. PMID- 24172700 TI - Severe diabetic nephropathy in type 1 diabetes and pregnancy--a case series. AB - BACKGROUND: Diabetes and nephropathy are important challenges during pregnancy, increasingly encountered because of the advances in maternal-fetal care. AIM: To evaluate the maternal and fetal outcomes recorded in "severe" diabetic nephropathy in type 1 diabetic patients referred to nephrological healtcare. METHODS: The study was performed in an outpatient unit dedicated to kidney diseases in pregnancy (with joint nephrological and obstetric follow-up and strict cooperation with the diabetes unit). 383 pregnancies were referred to the outpatient unit in 2000-2012, 14 of which were complicated by type 1 diabetes. The report includes 12 deliveries, including 2 pregnancies in 1 patient; one twin pregnancy; 2 spontaneous abortions were not included. All cases had long-standing type 1 diabetes (median of 21 (15-31) years), relatively high median age (35 (29 40) years) and end-organ damage (all patients presented laser-treated retinopathy and half of them clinical neuropathy). Median glomerular filtration rate (GFR) at referral was 67 ml/min (48-122.6), proteinuria was 1.6 g/day (0.1-6.3 g/day). RESULTS: Proteinuria steeply increased in 11/12 patients, reaching the nephrotic range in nine (6 above 5 g/day). One patient increased by 2 chronic kidney disease (CKD) stages. Support therapy included blood pressure and diabetes control, bed rest, and moderate protein restriction. All children were preterm (7 early preterm); early spontaneous labor occurred in 4/12 patients. All singletons were appropriate for gestational age and developed normally after birth. The male twin child died 6 days after birth (after surgery for great vessel transposition). CONCLUSIONS: Diabetic patients with severe diabetic nephropathy are still present a considerable challenge. Therefore, further investigations are required, particularly on proteinuria management and the occurrence of spontaneous labor. PMID- 24172702 TI - Dual role of astrocytes in perinatal asphyxia injury and neuroprotection. AB - Perinatal asphyxia represents an important cause of severe neurological deficits including delayed mental and motor development, epilepsy, major cognitive deficits and blindness. However, at the moment, most of the therapeutic strategies were not well targeted toward the processes that induced the brain injury during perinatal asphyxia. Traditionally, experimental research focused on neurons, whereas astrocytes have been more related with the damage mechanisms of perinatal asphyxia. In this work, we propose to review possible protective as well as deleterious roles of astrocytes in the asphyctic brain with the aim to stimulate further research in this area of perinatal asphyxia still not well studied. PMID- 24172703 TI - Recurrent epistaxis in children. AB - INTRODUCTION: Up to 9% of children may have recurrent nosebleeds, usually originating from the anterior septum, but the majority grow out of the problem. METHODS AND OUTCOMES: We conducted a systematic review and aimed to answer the following clinical question: What are the effects of treatments for recurrent idiopathic epistaxis in children? We searched: Medline, Embase, The Cochrane Library, and other important databases up to June 2013 (Clinical Evidence reviews are updated periodically; please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA). RESULTS: We found 5 systematic reviews or RCTs that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions. CONCLUSIONS: In this systematic review we present information relating to the effectiveness and safety of the following interventions: antiseptic cream (containing chlorhexidine hydrochloride, neomycin sulfate, or both), petroleum jelly, and silver nitrate cautery. PMID- 24172705 TI - [Advances in radiation oncology for metastatic bone disease]. AB - INTRODUCTION: Irradiation of bone metastases primarily aims at alleviating pain, preventing fracture in the short term. The higher doses and more conformal dose distribution achievable while saving healthy tissue with new irradiation techniques have induced a paradigm shift in the management of bone metastases in a growing number of clinical situations. MATERIALS AND METHODS: A search of the English and French literature was conducted using the keywords: bone metastases, radiotherapy, interventional radiology, vertebroplasty, radiofrequency, chemoembolization. RESULTS-DISCUSSION: Stereotactic irradiation yields pain relief rates greater than 90% in Phase I/II and retrospective studies. IMRT (static, rotational, helical) and stereotactic irradiation yield local control rates of 75-90% at 2 years. Some situations previously evaluated as palliative are currently treated more aggressively with optimized radiation sometimes combined modality interventional radiology. CONCLUSION: A recommendation can only be made for stereotactic irradiation in vertebral oligometastases or reirradiation. In the absence of a sufficient level of evidence, the increasing use of conformal irradiation techniques can only reflect the daily practice and the patient benefit while integrating economic logic care. The impact of these aggressive approaches on survival remains to be formally demonstrated by interventional prospective studies or observatories including quality of life items and minimal 2-year follow-up. PMID- 24172704 TI - Sequence analysis of T-cell repertoires in health and disease. AB - T-cell antigen receptor (TCR) variability enables the cellular immune system to discriminate between self and non-self. High-throughput TCR sequencing (TCR-seq) involves the use of next generation sequencing platforms to generate large numbers of short DNA sequences covering key regions of the TCR coding sequence, which enables quantification of T-cell diversity at unprecedented resolution. TCR seq studies have provided new insights into the healthy human T-cell repertoire, such as revised estimates of repertoire size and the understanding that TCR specificities are shared among individuals more frequently than previously anticipated. In the context of disease, TCR-seq has been instrumental in characterizing the recovery of the immune repertoire after hematopoietic stem cell transplantation, and the method has been used to develop biomarkers and diagnostics for various infectious and neoplastic diseases. However, T-cell repertoire sequencing is still in its infancy. It is expected that maturation of the field will involve the introduction of improved, standardized tools for data handling, deposition and statistical analysis, as well as the emergence of new and equivalently large-scale technologies for T-cell functional analysis and antigen discovery. In this review, we introduce this nascent field and TCR-seq methodology, we discuss recent insights into healthy and diseased TCR repertoires, and we examine the applications and challenges for TCR-seq in the clinic. PMID- 24172706 TI - The origin of local strain in highly epitaxial oxide thin films. AB - The ability to control the microstructures and physical properties of hetero epitaxial functional oxide thin films and artificial structures is a long-sought goal in functional materials research. Normally, only the lattice misfit between the film and the substrate is considered to govern the physical properties of the epitaxial films. In fact, the mismatch of film unit cell arrangement and the Surface-Step-Terrace (SST) dimension of the substrate, named as "SST residual matching", is another key factor that significantly influence the properties of the epitaxial film. The nature of strong local strain induced from both lattice mismatch and the SST residual matching on ferroelectric (Ba,Sr)TiO3 and ferromagnetic (La,Ca)MnO3 thin films are systematically investigated and it is demonstrated that this combined effect has a dramatic impact on the physical properties of highly epitaxial oxide thin films. A giant anomalous magnetoresistance effect (~10(10)) was achieved from the as-designed vicinal surfaces. PMID- 24172707 TI - The rise and fall of the phragmoplast microtubule array. AB - The cytokinetic apparatus, the phragmoplast, contains a bipolar microtubule (MT) framework that has the MT plus ends concentrated at or near the division site. This anti-parallel MT array provides tracks for the transport of Golgi-derived vesicles toward the plus ends so that materials enclosed are subsequently deposited at the division site. Here we will discuss a proposed model of the centrifugal expansion of the phragmoplast that takes place concomitantly with the assembly of the cell plate, the ultimate product of vesicle fusion. The expansion is a result of continuous MT assembly at the phragmoplast periphery while the MTs toward the center of the phragmoplast are disassembled. These events are the result of MT-dependent MT polymerization, bundling of anti-parallel MTs coming from opposite sides of the division plane that occurs selectively at the phragmoplast periphery, positioning of the plus ends of cross-linked MTs at or near the division site by establishing a minimal MT-overlapping zone, and debundling of anti-parallel MTs that is triggered by phosphorylation of MT associated proteins. The debundled MTs are disassembled at last by factors including the MT severing enzyme katanin. PMID- 24172708 TI - Controlled formation of GeSi nanostructures on periodic Si (001) sub-micro pillars. AB - Self-assembled GeSi nanostructures on periodic Si (001) sub-micro pillars (SMPs) are systematically studied. Different GeSi nanostructures, including circularly arranged quantum dots, quantum rings and quantum dot molecules can be readily obtained at the edge of the pillars by controlling the growth temperatures and the diameter of the pillar. These phenomena are explained by taking into account the surface chemical potential around the top terrace of SMPs, which is considerably affected by the formation of {113} facets. Our results demonstrate a feasible route to obtain novel periodic Si pillars embedded with the desired GeSi nanostructures, which have promising applications in optoelectronic devices. PMID- 24172709 TI - Online Real-Time Presentation of Virtual Experiences for External Viewers. AB - Externally observing the experience of a participant in a virtual environment is generally accomplished by viewing an egocentric perspective. Monitoring this view can often be difficult for others to watch due to unwanted camera motions that appear unnatural and unmotivated. We present a novel method for reducing the unnaturalness of these camera motions by minimizing camera movement while maintaining the context of the participant's observations. For each time-step, we compare the parts of the scene viewed by the virtual participant to the parts of the scene viewed by the camera. Based on the similarity of these two viewpoints we next determine how the camera should be adjusted. We present two means of adjustment, one which continuously adjusts the camera and a second which attempts to stop camera movement when possible. Empirical evaluation shows that our method can produce paths that have substantially shorter travel distances, are easier to watch and maintain the original observations of the participant's virtual experience. PMID- 24172710 TI - Survival of patients with small cell lung cancer undergoing lung resection in England, 1998-2009. AB - INTRODUCTION: Chemotherapy or chemoradiotherapy is the recommended treatment for small cell lung cancer (SCLC), except in stage I disease where clinical guidelines state there may be a role for surgery based on favourable outcomes in case series. Evidence supporting adjuvant chemotherapy in resected SCLC is limited but this is widely offered. METHODS: Data on 359 873 patients who were diagnosed with a first primary lung cancer in England between 1998 and 2009 were grouped according to histology (SCLC or non-SCLC (NSCLC)) and whether they underwent a surgical resection. We explored their survival using Kaplan-Meier analysis and Cox regression, adjusting for age, sex, comorbidity and socioeconomic status. RESULTS: The survival of 465 patients with resected SCLC was lower than patients with resected NSCLC (5-year survival 31% and 45%, respectively), but much higher than patients of either group who were not resected (3%). The difference between resected SCLC and NSCLC diminished with time after surgery. Survival was superior for the subgroup of 198 'elective' SCLC cases where the diagnosis was most likely known before resection than for the subgroup of 267 'incidental' cases where the SCLC diagnosis was likely to have been made after resection. CONCLUSIONS: These data serve as a natural experiment testing the survival after surgical management of SCLC according to NSCLC principles. Patients with SCLC treated surgically for early stage disease may have survival outcomes that approach those of NSCLC, supporting the emerging clinical practice of offering surgical resection to selected patients with SCLC. PMID- 24172711 TI - Authors' response to letter to the editor concerning our SKUP3 trial. PMID- 24172712 TI - EBUS-centred versus EUS-centred mediastinal staging in lung cancer: a randomised controlled trial. AB - BACKGROUND: The impact of procedure sequence and primary procedure has not been studied in the combined application of endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) and endoscopic ultrasound-guided fine needle aspiration (EUS-FNA) in lung cancer staging. METHODS: In a randomised controlled trial, 160 patients with histologically confirmed or strongly suspected potentially operable non-small cell lung cancer were enrolled (Group A, n=80, EBUS-centred; Group B, n=80, EUS-centred). EBUS-TBNA and EUS-FNA with an ultrasound bronchoscope were used as the first procedures in Groups A and B, respectively, and secondary procedures (EUS-FNA in Group A, EBUS-TBNA in Group B) were added. RESULTS: Diagnostic values were evaluated in 148 patients (74 in each group). In Groups A and B the diagnostic accuracy (93.2% (95% CI 87.5% to 99.0%) vs 97.3% (95% CI 93.6% to 101.0%), p=0.245) and sensitivity (85.3% (95% CI 68.9% to 95.0%) vs 92.0% (95% CI 74.0% to 99.0%), p=0.431) in detecting mediastinal metastasis were not statistically different. In Group A, adding EUS-FNA to EBUS TBNA did not significantly increase the accuracy (from 91.9% to 93.2%, p=0.754) or sensitivity (from 82.4% to 85.3%, p=0.742). In group B, adding EBUS-TBNA to EUS-FNA increased the accuracy (from 86.5% to 97.3%, p=0.016) and sensitivity (from 60.0% to 92.0%, p=0.008). There were no intergroup differences in procedure time, cardiorespiratory parameters during procedures, complications or patient satisfaction. CONCLUSIONS: Using a combination of EBUS-TBNA and EUS-FNA in mediastinal staging, we found that diagnostic values and patient satisfaction were not different between the EBUS-centred and EUS-centred groups. However, the necessity for EBUS-TBNA following EUS suggests that EBUS-TBNA is a better primary procedure in endoscopic mediastinal staging of potentially operable lung cancer. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov number NCT01385111. PMID- 24172714 TI - Automatic microfiber filtration (AMF) of surface water: impact on water quality and biofouling evolution. AB - In the current study we examined the impact of thread filtration using an automatic microfiber filter on Lake Kinneret water quality and as a new application to control biofouling over time. We found that automatic microfiber filtration (AMF) reduced total iron and aluminum in water by over 80%. Particle analysis (>2 MUm) revealed a total particle removal efficiency of ~ 90%, with AMF removal efficiency increasing with increasing particle size and decreasing particle circularity. Regarding microbiological parameters, AMF did not affect bacterial counts or composition in the water. However, it did control biofilm evolution and affected its microbial community composition. AMF controlled biofilm over time by maintaining premature biofilms of less than 10 MUm mean thickness compared to biofilms of unfiltered water (up to 60 MUm mean thickness). In addition, biofilms developing in AMF filtered water contained relatively low levels of extracellular polymeric substances. While biofilms of unfiltered water were dominated by Proteobacteria (<= 50%) followed by Bacteroidetes (20-30%) during all 4 weeks of the experiment, biofilms of AMF filtered water were dominated by Proteobacteria (<= 90%) and especially Alphaproteobacteria after 2 weeks, and Chloroflexi (~ 60%) after 4 weeks. The decrease in Bacteroidetes might originate from removal of transparent exopolymer particles, which are occasionally colonized by Bacteroidetes. The increase in Alphaproteobacteria and Chloroflexi was explained by these robust groups' ability to adjust to different environments. PMID- 24172715 TI - Serum lipid levels are associated with the prevalence but not with the disease progression of multiple system atrophy in a Chinese population. AB - OBJECTIVES: Alpha-synuclein is involved in the pathogenesis of multiple system atrophy (MSA) and can be regulated by lipids. This study aims to validate the correlation between lipid levels and the prevalence of MSA as well as its progression. METHODS: A total of 234 patients with probable MSA and 240 age- and gender-matched healthy controls were included in this study. Lipid contents, including total cholesterol, low-density lipoprotein cholesterol (LDL-C), high density lipoprotein cholesterol (HDL-C), and triglyceride (TG), were evaluated. The unified MSA rating scale (UMSARS) was used to assess the severity of MSA. RESULTS: Lipid levels in MSA patients were significantly lower than those in healthy controls. Patients with MSA-C were significantly younger, had higher body mass indices (BMIs), higher UMSARS scores, and lower HDL-C contents compared with MSA-P patients. Subjects with the lowest quartiles and the second quartiles of total cholesterol, LDL-C, and HDL-C had high prevalence of MSA compared with subjects with the highest quartiles. No correlation was found between the mean rate of annualized changes and serum levels of lipids as well as other independent factors, such as age, BMI, gender, subtypes (C-type or P-type), and disease duration at the initial visit, in 107 followed-up MSA patients. DISCUSSION: Low levels of total cholesterol, LDL-C, HDL-C, and TG increased the prevalence of MSA in a Chinese population. Patients with MSA-C showed significantly lower levels of HDL-C than MSA-P patients. However, lipids did not deteriorate or improve the progression of MSA. PMID- 24172716 TI - Role of CYP3A in isoniazid metabolism in vivo. AB - Isoniazid (INH), a first-line drug for tuberculosis control, frequently causes liver injury. Multiple previous reports suggest that CYP3A is involved in INH metabolism, bioactivation and hepatotoxicity, although direct evidence is unavailable. In the current study, wild-type and Cyp3a-null mice were used to determine the potential role of Cyp3a in INH metabolism in vivo. Compared to wild type mice, there were no significant differences in the pharmacokinetic profiles of INH or acetyl-isoniazid in Cyp3a-null mice after an oral administration of 50 mg/kg INH. With the same treatment, distribution of INH and its major metabolites was similar in the liver of wild-type and Cyp3a-null mice. A reactive metabolite of INH was trapped by N-alpha-acetyl-L-lysine in mouse liver microsomes, but Cyp3a does not contribute to this bioactivation pathway. In addition, no liver injury was observed in wild-type or Cyp3a-null mice treated with 60 or 120 mg/kg INH. In summary, Cyp3a has no effect on systemic pharmacokinetics of INH in mice. Further studies are needed to determine whether and how exactly CYP3A is involved in INH bioactivation and hepatotoxicity. PMID- 24172717 TI - Sex differences in the constitutive gene expression of sulfotransferases and UDP glucuronosyltransferases in the pig liver: androgen-mediated regulation. AB - Using two breeds (Meishan and Landrace) of pigs and their crossbred offspring (ML, Meishan * Landrace; LM, Landrace * Meishan), of which males have genetically different serum androgen levels, we examined whether or not serum androgen plays a crucial role in the constitutive gene expression of hepatic sulfotransferases (SULTs) and UDP-glucuronosyltransferases (UGTs). Real-time RT-PCR analyses showed that in Meishan, ML, and LM pigs, SULT1A1 and SULT2A1 mRNA levels were lower in males having high levels of serum androgen (>38 ng/ml) than in females, whereas those of UGT1A1, UGT1A6, and UGT2B31 were just the opposite. In Landrace pigs having low levels of serum androgen (<22 ng/ml), no such sex differences in expression levels were observed. Moreover, castration of male Meishan pigs altered the gene expression patterns of SULTs and UGTs to female levels. Testosterone-treatment to the castrated males and intact females of either pig breed resulted in decreased SULT1A1 and SULT2A1 and increased UGT1A1, UGT1A6, and UGT2B31 mRNA levels. These findings demonstrate that androgen is one of the physiological factors that determine sexual dimorphism on the constitutive gene expression of SULTs and UGTs in the pig liver. PMID- 24172718 TI - Cocktail-substrate approach-based high-throughput assay for evaluation of direct and time-dependent inhibition of multiple cytochrome P450 isoforms. AB - Avoiding drug-drug interactions (DDIs) mediated through inhibition of cytochrome P450 (CYP) activity is highly desirable. Direct inhibition (DI) of CYP through new chemical entities (NCEs) or time-dependent inhibition (TDI) through reactive metabolites should be elucidated at an early stage of drug discovery research. In particular, TDI of CYP occurring through reactive metabolites may be irreversible and even sustained, causing far more serious DDIs for TDIs than for DIs. Furthermore, it is important to ascertain whether an NCE inhibits multiple CYP isoforms. Hence, using a cocktail-substrate approach that we previously established (in which the activity of 8 CYP isoforms is simultaneously evaluated in a single run), we evaluated the IC50 values of direct inhibitors and TDI parameters (kobs, shifted IC50, KI and kinact) of time-dependent inhibitors that affect multiple CYP isoforms. The IC50 values for 8 CYP isoforms obtained using the cocktail-substrate approach were nearly identical to values previously reported. The TDI parameters for CYP1A2, 2C9, 2C19, 2D6, and CYP3A4/5 obtained using the cocktail-substrate approach were also nearly identical to those obtained using a single-substrate approach. Thus, the cocktail-substrate approach is useful for evaluating DI and TDI in the early stages of drug discovery and development processes. PMID- 24172719 TI - Preexercise energy drink consumption does not improve endurance cycling performance but increases lactate, monocyte, and interleukin-6 response. AB - The purpose of this study was to investigate the influence of an energy drink (ED) on cycling performance and immune-related variables. Eleven trained male cyclists (33.4 +/- 8.9 years; 81 +/- 7.6 kg; maximal VO2, 52 +/- 3.4 ml.kg( 1).min(-1)) consumed 500 ml of (a) ED (2.0 g taurine, 1.2 g glucuronolactone, 160 mg caffeine, 56 g carbohydrate [CHO], and B vitamins), (b) cola matched for caffeine and CHO (CC), or (c) flavored placebo (PL: sparking water and flavoring) 50 minutes before racing in a randomized, crossover design. Performance was measured as time to complete (TTC) a 25-mile simulated road race. Blood was collected at baseline, 30 minutes after drink consumption, during exercise at miles 5 (M5), 15 (M15), and immediately (POEX) and 30 minutes (30minPO) after exercise. TTC was not different (p > 0.05) among trials (ED, 68.6 +/- 2.7; CC, 68.9 +/- 3.8; PL, 69.6 +/- 3.8 minutes). Consumption of CC and ED elicited a mild hypoglycemia elicited a mild hypoglycemia during cycling. POEX interleukin-6 (IL 6) was greatest after ED, whereas CC IL-6 was greater than PL (10.2 +/- 1.6, 6.7 +/- 0.6, and 4.8 +/- 0.7 pg.ml(-1), respectively; p < 0.001). Cycling increased leukocyte number in all conditions with ED leukocyte number greater than that of PL at M15 (9.8 +/- 0.6, 8.5 +/- 0.3 * 10(6) cells.mL(-1)). Energy drink induced an earlier recruitment of monocytes to the blood stream than CC. Mean fat oxidation was greater in PL compared with CC (0.43 +/- 0.06 and 0.28 +/- 0.04 g.min(-1); p = 0.033) but did not differ between ED (0.32 +/- 0.06) and PL. Lactate was higher in ED compared with CC and PL at M5 and M15 (p = 0.003), but there was no significant influence of either ED or CC on performance. Carbohydrate and caffeine consumption before endurance cycling significantly increased the IL-6 release and leukocytosis, and the additional ingredients in ED seem to have further augmented these responses. PMID- 24172720 TI - Shoulder muscle activation levels during four closed kinetic chain exercises with and without Redcord slings. AB - During resistance training protocols, people are often encouraged to target the scapular stabilizing musculature (middle and lower trapezius and serratus anterior) while minimizing shoulder prime mover activation (upper trapezius and large glenohumeral muscles) in their training regime, especially in overhead athletes with scapular dyskinesis. To increase the activation levels in the stabilizing muscles without drastically increasing the activation in the prime movers, unstable surfaces are frequently used during closed kinetic chain (CKC) exercises. However, the specific influence of Redcord slings (RS) as an unstable surface tool on the shoulder muscle activation levels has rarely been investigated, despite these results may be used for adequate exercise selection. Therefore, a controlled laboratory study was performed on 47 healthy subjects (age, 22 +/- 4.31 years; height, 176 +/- 0.083 cm; weight, 69 +/- 8.57 kg) during 4 CKC exercises without and with RS: half push-up (HPU), knee push-up (KPU), knee prone bridging plus (KPBP), and pull-up. When using RS, serratus anterior muscle activation decreased during the KPU and KPBP exercise. In addition, a drastic increase in pectoralis major muscle activation was found during the HPU and KPBP exercise. Consequently, the use of RS does not necessarily imply that higher levels of scapular stabilizer muscle activation will be attained. These findings suggest that RS might be an appropriate training tool when used within a general strengthening program but should not be preferred over a stable base of support when training for specific scapular stabilization purposes. PMID- 24172721 TI - The effects of incline and level-grade high-intensity interval treadmill training on running economy and muscle power in well-trained distance runners. AB - Despite a paucity of evidence, uphill running has been touted as a sport-specific resistance-to-movement training tactic capable of enhancing metabolic, muscular, and neuromuscular processes in distance runners in ways similar to previously established resistance-to-movement training methods, such as heavy and/or explosive strength training and plyometric training. Therefore, the purpose of this investigation included documenting the effects of incline and level-grade interval treadmill training on indices of running economy (RE) (i.e., oxygen consumption [VO2] and blood lactate [BLa] responses of submaximal running) and muscle power. Thirty-two well-trained distance runners (age, 27.4 +/- 3.8 years; body mass, 64.8 +/- 8.9 kg; height, 173.6 +/- 6.4 cm; and VO2max, 60.9 +/- 8.5 ml.min(-1).kg(-1)) received assignment to an uphill (GHill = 12), level-grade (GFlat = 12), or control (GCon = 8) group. GHill and GFlat completed 12 interval and 12 continuous run sessions over 6 weeks, whereas GCon maintained their normal training. Dependent variables measured before and after training were VO2 and BLa at 2 separate velocities associated with lactate threshold (VLT) (VO2-60% and VO2 80%; and BLa-60% and BLa-80%, respectively); percentage of VO2max at lactate threshold (%VO2max at VLT); muscle power as assessed through a horizontal 5-jump test (5Jmax); and isokinetic knee extension and flexion at 3 angular velocities (90, 180, and 300 degrees .s(-1)). Statistical significance was set to p <= 0.05. All groups significantly improved 5Jmax, VO2-60%, VO2-80%, BLa-60%, and BLa-80%. Additionally, GHill and GFlat significantly improved %VO2max at VLT. Other indices of RE and muscle power did not improve. We conclude incline treadmill training effective for improving the components of RE, but insufficient as a resistance-to-movement exercise for enhancing muscle power output. PMID- 24172722 TI - The influence of soccer playing actions on the recovery kinetics after a soccer match. AB - This study examined the relationship between the frequency of playing actions performed during a soccer match and the recovery kinetics after the match. Time motion analyses were performed on 10 professional soccer players during 4 competitive matches (14 observations) to determine the number of playing actions completed by players. Subjective ratings, creatine kinase, and physical tests (countermovement jump [CMJ], isometric maximum voluntary contraction of the hamstrings, 6-second sprint on a nonmotorized treadmill) were performed before the match and 24 hours, 48 hours, and 72 hours after the match. During the 72 hour recovery period, CMJ, isometric strength of the hamstring muscles, and peak sprint speed significantly (p <= 0.05) decreased, whereas muscle soreness increased (p <= 0.05). Significant correlations were observed between the increase in muscle soreness and number of short sprints (<5 m) performed at 48 hours (r = 0.74; confidence interval [CI], 0.35-0.91; p < 0.01) and 72 hours (r = 0.57; CI, 0.05-0.84; p <= 0.05) after match play. A significant relationship (r = -0.55; CI, -0.84 to -0.03; p <= 0.05) was also observed between CMJ performance decrement at 24 hours and the number of hard changes in direction performed. Soccer match play resulted in significant neuromuscular fatigue for up to 72 hours after match and was dependent on the number of sprints and hard changes in direction performed during the match. Time motion analysis data currently used during a soccer match should quantify hard changes in direction, acceleration and deceleration phases to enable better estimations of postmatch fatigue. PMID- 24172723 TI - Maximal and ventilatory thresholds cardiorespiratory responses to three water aerobic exercises compared with treadmill on land. AB - The purpose of this study was to compare the cardiorespiratory responses of young women to exercise at the first ventilatory threshold (VT1), the second ventilatory threshold (VT2), and at maximum effort (MAX) between maximal incremental tests performed using water aerobic exercises and a treadmill on land (TL). Twenty women (24.0 +/- 2.5 years; 163.3 +/- 6.7 cm; 60.0 +/- 6.7 kg) underwent 4 maximal tests in randomized order, with a 48-hour interval between tests. Three tests involved performing water aerobic exercises (stationary running, frontal kick, and cross-country skiing) and 1 TL. Oxygen uptake (VO2), ventilation (VE), and heart rate were measured throughout the tests, and their values at the VT1, VT2, and MAX intensities were determined by 3 independent, experienced physiologists. Repeated measures analysis of variance with Bonferroni post hoc tests were used for comparisons between tests (alpha = 0.05). Heart rate was significantly higher in the TL condition compared with the water aerobic exercises at the VT1 (p = 0.001), VT2 (p < 0.001), and MAX (p < 0.001) intensities. VO2 and VE had similar values across the 4 protocols at the VT1 intensity, but significantly higher values were observed with TL (VO2: p < 0.001; VE: p < 0.001) at the VT2 intensity. At the MAX intensity, VO2 was significantly higher with TL compared with the 3 water aerobic exercises (p < 0.001), whereas no significant differences in VE between the 4 protocols were found. These results suggest that the prescription of water aerobics classes should be based on specific maximal tests for water aerobic exercises. Training intensities could be overestimated if they were based on maximal tests on dry land. PMID- 24172724 TI - Olympic weightlifting and plyometric training with children provides similar or greater performance improvements than traditional resistance training. AB - A number of organizations recommend that advanced resistance training (RT) techniques can be implemented with children. The objective of this study was to evaluate the effectiveness of Olympic-style weightlifting (OWL), plyometrics, and traditional RT programs with children. Sixty-three children (10-12 years) were randomly allocated to a 12-week control OWL, plyometric, or traditional RT program. Pre- and post-training tests included body mass index (BMI), sum of skinfolds, countermovement jump (CMJ), horizontal jump, balance, 5- and 20-m sprint times, isokinetic force and power at 60 and 300 degrees . s(-1). Magnitude-based inferences were used to analyze the likelihood of an effect having a standardized (Cohen's) effect size exceeding 0.20. All interventions were generally superior to the control group. Olympic weightlifting was >80% likely to provide substantially better improvements than plyometric training for CMJ, horizontal jump, and 5- and 20-m sprint times, whereas >75% likely to substantially exceed traditional RT for balance and isokinetic power at 300 degrees . s(-1). Plyometric training was >78% likely to elicit substantially better training adaptations than traditional RT for balance, isokinetic force at 60 and 300 degrees . s(-1), isokinetic power at 300 degrees . s(-1), and 5- and 20-m sprints. Traditional RT only exceeded plyometric training for BMI and isokinetic power at 60 degrees . s(-1). Hence, OWL and plyometrics can provide similar or greater performance adaptations for children. It is recommended that any of the 3 training modalities can be implemented under professional supervision with proper training progressions to enhance training adaptations in children. PMID- 24172725 TI - Effect of compression stockings on physiological responses and running performance in division III collegiate cross-country runners during a maximal treadmill test. AB - There is a growing trend for runners to use compression stockings (CS) to improve performance. The purpose of this study was to determine the effect of CS on physiological variables associated with running performance. Participants were 10 NCAA division III cross-country runners. The study used a randomized, crossover design with 2 conditions (with CS and without CS). Both conditions consisted of a maximal treadmill test that involved 3-minute stages of increasing speed and incline, separated by a minute and one-half walking recovery stage. Seven days later, the participants repeated the maximal test but switched CS condition. Heart rate, blood lactate (BLa), blood lactate threshold, maximal oxygen consumption (VO2max), respiratory exchange ratio, rating of perceived exertion, and time to fatigue were measured. Before and during the maximal treadmill tests, the variables showed no significant difference (p <= 0.05) between the CS conditions. Blood lactate was lower while wearing CS when measured during recovery at the 1-minute (CS = 13.3 +/- 2.9 mmol . L(-1), non-CS = 14.8 +/- 2.8 mmol . L(-1), p = 0.03) and the 5-minute (CS = 11.0 +/- 2.7 mmol . L(-1), non-CS = 12.8 +/- 2.8 mmol . L(-1), p = 0.02) periods. Time to fatigue was longer without CS (CS = 23.570 +/- 2.39 minutes, non-CS = 23.93 +/- 2.49 minutes, p = 0.04). These findings suggest that CS may not improve running performance, but could lend credence to certain manufacturers' claims of improved recovery through lower BLa values after exercise. PMID- 24172728 TI - A crystal-clear mechanism of chronic kidney disease. AB - Knauf et al. demonstrate that prolonged activation of the intrarenal inflammasome is responsible for the loss of kidney function in oxalate crystal nephropathy. These findings suggest new therapeutic opportunities for patients suffering from severe hereditary kidney diseases such as primary hyperoxaluria, and reveal a previously unappreciated general mechanism of kidney disease progression that may also contribute to conditions other than crystal nephropathy. PMID- 24172729 TI - The role of the kidney in protein metabolism: the capacity of tubular lysosomal proteolysis in nephrotic syndrome. AB - The kidneys play an important role in protein metabolism. Renal tubules reabsorb 3 g of albumin under normal conditions, and exhibit a 6-fold increase in the reabsorption of albumin in patients with focal segmental glomerulosclerosis. The capacity of tubular lysosomal proteolysis can be increased up to 8-fold; however, proteinuria over the capacity of tubular handling may cause tubulointerstitial damage in patients with nephrotic syndrome. PMID- 24172730 TI - Biocompatible peritoneal dialysis solutions: many questions but few answers. AB - The clinical value of biocompatible peritoneal dialysis solutions is uncertain because of inconsistent findings in randomized controlled trials. A systematic review by Cho et al. examining 20 such trials suggests a beneficial effect on residual renal function. However, the finding is not robust and may relate to decreased ultrafiltration causing hypervolemia. Future prescribing of these biocompatible solutions will probably continue to be driven by opinion, marketing, and cost considerations rather than by evidence-based medicine. PMID- 24172731 TI - The terminator mouse: salvation for primary cell culture. AB - The Terminator had to come back from the future already several times in an effort to bring salvation to mankind. In the present issue of Kidney International, Guo et al. brought us a novel transgenic mouse model: the terminator mouse. This highly elegant mouse may facilitate significantly the derivation of primary cultures of a specific cell type from a tissue containing multiple cell populations. PMID- 24172732 TI - Interstitial fluid homeostasis and pressure: news from the black box. AB - Extracellular volume expansion may lead to elevated blood pressure. This long term adaptation of the vascular bed to extracellular volume overload is considered a multifactorial and not perfectly understood 'autoregulatory' event, which is difficult to measure. In this issue, Ebah and colleagues demonstrate a direct relationship between fluid overload and pressure in CKD patients. Surprise, instead of intravascular volume, interstitial fluids and pressures were measured. Finally! PMID- 24172733 TI - Serum phosphorus in people with chronic kidney disease: you are what you eat. AB - This issue of Kidney International includes two important articles about serum phosphorus and its treatment. The article by Cannata-Andia and colleagues describes a rigorous observational study of the association between serum phosphorus level, phosphate binder use, and clinical outcomes including all-cause and cardiovascular mortality. The article by Mehrotra and colleagues addresses the association between serum phosphorus, socioeconomic status, and mortality among participants in the US-based KEEP program. PMID- 24172734 TI - Awaiting the OSCAR subanalysis of subjects according to the presence of proteinuria. PMID- 24172735 TI - The authors reply. PMID- 24172736 TI - The authors reply. PMID- 24172737 TI - Why are complements activated in anti-neutrophil cytoplasmic antibody-associated vasculitis? PMID- 24172738 TI - Could interleukin-17 be a therapeutic target of steroid-dependent minimal change disease? PMID- 24172739 TI - Is there equivalency of intact albuminuria and albumin peptideuria in nephrotic states? PMID- 24172740 TI - The authors reply. PMID- 24172741 TI - The author replies. PMID- 24172742 TI - The authors reply. PMID- 24172743 TI - Changes in dialysis treatment modalities during institution of flat-rate reimbursement and quality assurance programs. PMID- 24172744 TI - Multidisciplinary care and immortal time bias. PMID- 24172745 TI - The authors reply. PMID- 24172746 TI - Nephrology follow-up and all-cause mortality of severe acute kidney injury survivors. PMID- 24172747 TI - The authors reply. PMID- 24172748 TI - Unusual presentation of a common disease in an ESRD patient. PMID- 24172749 TI - A kidney transplant patient with ileocecal inflammation. Sodium polystyrene sulfonate-associated intestinal ulcer and foreign-body reaction. PMID- 24172750 TI - Effect of oxindolimine copper(II) and zinc(II) complexes on human topoisomerase I activity. AB - The ability of oxindolimine copper(II) and zinc(II) complexes, known to have antitumor activity, to inhibit human topoisomerase IB has been tested through enzymatic kinetic assays and molecular docking simulations. These copper and zinc compounds are able to inhibit remarkably the cleavage reaction and only partially the religation step, the copper compound being more efficient than the zinc one. A complete inhibition activity of the cleavage is only obtained when the enzyme is pre-incubated with the compound, the inhibition being irreversible and reversible for the copper and zinc compounds, respectively. The relative stability of such complexes was estimated by competitive equilibria with human serum albumin (HSA), monitored by CD spectroscopy. The copper species shows a log KCuL = 17.2, while the analogous zinc complex exhibits a log KZnL = 7.2. Molecular docking simulation studies show that the almost square planar geometry of the copper compound allows a direct coordination of the metal with two amino acids (Glu492, Asp563) of the enzyme at variance of the zinc compound which has a more tetrahedral geometry. Altogether, the data indicate that the different coordination geometry achieved by the two transition metal ions has an important role in modulating their efficiency as topoisomerase I inhibitors. PMID- 24172751 TI - Dexamethasone differentially regulates Bcl-2 family proteins in human proliferative chondrocytes: role of pro-apoptotic Bid. AB - Glucocorticoids (GCs) are widely used to treat inflammatory diseases and cancers. A multitude of undesired side effects have been reported in GC-treated patients including decreased linear bone growth. We have previously reported that GCs activate the caspase cascade and trigger Bax-mediated mitochondrial apoptosis in growth plate chondrocytes causing growth retardation in young mice. To further explore the role of mitochondrial apoptosis in GC-induced bone growth retardation, a number of pro- and anti-apoptotic proteins were studied in ex vivo cultures of human growth plate cartilage and human HCS-2/8 proliferative chondrocytes exposed to dexamethasone. Dexamethasone was found to increase the pro-apoptotic proteins Bcl-xS, Bad, and Bak as well as the proteolysis of Bid. Anti-Bid small interfering RNA partially rescued the chondrocytes from dexamethasone-induced apoptosis. Taken together, our data suggest that GC treatment differentially regulates Bcl-2 family member proteins to facilitate mitochondrial apoptosis in proliferative chondrocytes thereby contributing to GC induced bone growth impairment. Prevention of this imbalance between pro- and anti-apoptotic Bcl-2 family proteins may provide a new strategy to protect from adverse effects of GCs on bone growth. PMID- 24172752 TI - Effect of doping on electronic structure and photocatalytic behavior of amorphous TiO2. AB - Visible light photocatalysts based on doped crystalline forms of titanium dioxide (TiO2) have attracted significant scientific attention in recent decades. Amorphous TiO2, despite many merits over crystalline phases, has not been studied as thoroughly. In this paper, an in-depth analysis of the electronic properties of doped amorphous TiO2 is performed using density functional theory with Hubbard's energy correction (DFT + U). Monodoping with p-type (N) and n-type (Nb) dopants shows appreciable bandgap reduction, but leads to recombination centers due to the presence of uncompensated charges. To resolve this issue, charge compensation via codoping is attempted. The charge compensated codoping not only reduces the bandgap by 0.4 eV but also eliminates the bandgap states present in monodoped systems responsible for charge carrier recombination. Furthermore, the localized tail states present in the aTiO2 system are eliminated to a large extent which leads to a decrease in the charge recombination and an increase in the charge migration. Thus, appropriate doping of amorphous TiO2 may lead to an alternative route for the development of visible light photocatalysts. PMID- 24172753 TI - Relapse among cigarette smokers: the CARDIA longitudinal study - 1985-2011. AB - RATIONALE: There is little information about long-term relapse patterns for cigarette smokers. OBJECTIVE: To describe long-term prevalence of relapse and related smoking patterns by sex, race, age, and education level among a community based cohort of young adults followed for 25 years. METHODS: We examined 25 years of data from Coronary Artery Risk Development in Young Adults (CARDIA), an ongoing study of a community-based cohort of 5115 men and women aged 18 to 30 years at baseline with periodic re-examinations. At each examination smoking, quitting, and relapse were queried. We examined prevalence of smoking relapse among 3603 participants who attended at least 6 of the 8 examinations. RESULTS: About 53% of 3603 participants never reported smoking on a regular basis. Among the remaining 1682 ever smokers, 52.8% of those who reported current smoking at baseline were still smoking by the end of the study, compared to 10.7% of those who initiated smoking by year 5. Among those classified as former smokers at baseline, 39% relapsed at least once; of these, 69.5% had quit again by the end of the study. Maximum education level attained, age at study baseline, and race were associated with failure to quit smoking by the end of the study and relapse among those who did quit. Maximum education level attained and age at study baseline were also associated with ability to successfully quit after a relapse. CONCLUSIONS: Smoking relapse after quitting is common, especially in those with lower education level. Education was the strongest predictor of all three outcomes. Improvements in access to treatment and treatment options, especially for underserved populations, are needed to prevent relapse when smokers quit. PMID- 24172754 TI - Can symptom relief be provided in the home to palliative care cancer patients by the primary caregivers? An Indian study. AB - BACKGROUND: A large proportion of cancer deaths occur in the developing world, with limited resources for palliative care. Many patients dying at home experience difficult symptoms. OBJECTIVE: The objective of this study was to assess the feasibility of a structured training program on symptom management along with an acute symptom management kit for primary caregivers of cancer patients receiving home care. METHODS: Descriptive design was used. Thirty primary caregivers of cancer patients attending the palliative care clinic in Vellore, South India, were provided training on the administration of drugs for acute symptoms. A plastic box with partitions for drugs specific to symptom was provided. On follow-up visits, the usage of the kit, drugs used, and routes of administration were noted. A structured questionnaire with a 4-point scale was used to assess primary caregiver views and satisfaction. RESULTS: Of primary caregivers, 96.7% used a kit. The common medications used were morphine, metoclopramide, dexamethasone, and benzodiazepines. Seventy-three percent of primary caregivers administered subcutaneous injections at home. Hospital visits for acute symptoms reduced by 80%; 90% were satisfied with the training received; 73% stated it was not a burden to treat the patient at home. CONCLUSION: The training program and acute symptom management kit were favorably received and appropriately used by caregivers of diverse backgrounds. Rural backgrounds and illiteracy were not barriers to acceptance. IMPLICATION FOR PRACTICE: Healthcare professionals should train caregivers during hospital visits, empowering them to manage acute symptoms and provide simple nursing care. This is doubly important in countries where resources are limited and palliative care facilities scarce. PMID- 24172755 TI - Predictors of change in quality of life of family caregivers of patients near the end of life with advanced cancer. AB - BACKGROUND: Caregiving for a person with cancer at end of life can be stressful physically and emotionally. Understanding the predictors of change in family caregivers' quality of life (QoL) is important in facilitating the development of interventions to help these family caregivers. OBJECTIVE: The aim of this study was to examine the change in QoL of family caregivers of home hospice patients in Singapore near the end of life with advanced cancer from baseline to after 2 months. METHODS: This was a longitudinal survey. Ninety-three caregivers were surveyed. Instruments included the Caregiver Quality of Life Index-Cancer, Social Support Questionnaire, and Spiritual Perspective Scale. RESULTS: Caregivers' spiritual-related interactions scores increased from baseline to 2 months using paired t test (t = 2.33, P = .02). Multivariate regression analysis showed that caregivers with higher social support satisfaction (beta = .60, P = .000) and who had a religion predicted (beta = .55, P = .001) higher QoL. Caregivers of patients diagnosed with breast cancer and cancer in the female reproductive organs (beta = -.33, P = .03) predicted lower QoL. CONCLUSION: This study elucidated the importance of caregivers' social support satisfaction during their caregiving journey. There is a need to enhance spiritual care for caregivers. IMPLICATIONS FOR PRACTICE: Support for caregivers could be increased by organizing mutual support groups and having volunteers to befriend caregivers. Spiritual care could be enhanced by regular assessment of spiritual needs, offering open discussions and sharing on spirituality and religion, and facilitating contacts with religious groups if caregivers required. PMID- 24172756 TI - Fibrous dysplasia of the nasal bone: case reports and literature review. AB - INTRODUCTION: Craniofacial fibrous dysplasia commonly affects the larger mandible and the maxillary bones. Although involvement of the frontal, temporal and sphenoid bones has been described, fibrous dysplasia of the nasal bone has not been previously described; the two cases reported here have been made rarer by their isolated involvement. Clinical management is dependent on disease activity and patient symptoms. OBJECTIVE: To present two cases of isolated fibrous dysplasia of the nasal bone: a 46-year-old woman with gradual widening of the nasal bridge and a 47-year-old man with an incidental finding of a nasal bone mass. METHOD: Two case reports. RESULTS: The 46-year-old woman underwent excision of the lesion while the 47-year-old man opted for watchful waiting. CONCLUSION: We have presented the first case reports of fibrous dysplasia of the nasal bone. The care of these patients should be customised to their needs and wishes. PMID- 24172757 TI - Communicating good care: a qualitative study of what people with urological cancer value in interactions with health care providers. AB - PURPOSE: Communication with health care providers is important to help meet cancer patients' information and support needs. It can significantly affect the extent to which patients feel cared for, respected and involved, and it can influence a range of cancer care processes and outcomes. This paper presents findings from a study which explored urological cancer patients' experiences of care, focussing on insights into what they appeared to value in their interactions with health care providers and why. METHOD: In-depth interviews were undertaken with 20 men and 6 women with different types of urological cancer at a range of times since diagnosis. Interviews were audio-recorded, transcribed and thematically analysed using an established interpretive approach. RESULTS: Patients valued being treated as someone who mattered and was worthy of care; being recognised and responded to as an individual; and experiencing support for autonomy/agency. Reasons for their valuations related to the implications of communicative interactions for the ways patients thought health professionals related to them 'as persons'. Our findings highlight the value of relational aspects of communication for: indicating to patients what clinicians think of their worth; facilitating individualised care; and enabling patients to contribute to their own care. CONCLUSIONS: Efforts to improve health care provider-patient communication should attend not only to the transfer of information about the condition and its management but to the range of features of interactions that can signal to people how health care providers relate to them as persons. PMID- 24172758 TI - Solution processed molecular floating gate for flexible flash memories. AB - Solution processed fullerene (C60) molecular floating gate layer has been employed in low voltage nonvolatile memory device on flexible substrates. We systematically studied the charge trapping mechanism of the fullerene floating gate for both p-type pentacene and n-type copper hexadecafluorophthalocyanine (F16CuPc) semiconductor in a transistor based flash memory architecture. The devices based on pentacene as semiconductor exhibited both hole and electron trapping ability, whereas devices with F16CuPc trapped electrons alone due to abundant electron density. All the devices exhibited large memory window, long charge retention time, good endurance property and excellent flexibility. The obtained results have great potential for application in large area flexible electronic devices. PMID- 24172759 TI - Surgical anatomy of the orbital region, local anesthesia and general considerations. AB - Orbital region may be divided into four sectors: medial canthus, lateral canthus, lower lid and upper lid. A vertical section of a lid shows 5 layers: skin, subcutaneous tissue with orbicularis muscle, fibrous layer (tarsus-aponeurosis), plain fibers muscle layer (Muller's), conjunctiva. The first two layers form the "anterior lamella" and the other ones the "posterior lamella", divided by the grey line. In this review Authors describe with all details the orbital region and the eyelid layers, considering the most important concepts for surgery. Finally they resume basics of local anesthesia in ophthalmoplastic surgery. PMID- 24172760 TI - Eyelid benign and malignant tumors: issues in classification, excision and reconstruction. AB - In the orbital region the variety of tumors is so vast that even an expert oculoplastic surgeon may be deceived. The various tumors may be classified as benign, precancerous and malignant. Approximately 5-10% of all skin cancers occur in the eyelids. Incidence studies indicate that basal cell carcinoma is the most frequent malignant eyelid tumor, followed by squamous cell carcinoma, sebaceous gland carcinoma and malignant melanoma. Malignant neoplasms represent the leading cause of plastic reconstruction in orbital region, followed by cicatricial retraction, post-traumatic loss of tissue, congenital colobomas. Aim of this review is to classify benign and malignant lesions; to consider the surgical removal approach to the lesion (Mohs micrographic surgery, frozen sections, biopsy, immediate removal and reconstruction with permanent sections) and finally to consider reconstruction techniques with grafts and flaps. PMID- 24172761 TI - Ectropion, entropion, trichiasis. AB - Aim of this review was to describe ectropion, entropion and trichiasis and their therapy. These eyelid pathologies are characterised by common symptoms (redness, excessive tearing and irritation of the eye) and by altered balance of the anterior and posterior lamellae of the eyelids. They involve more frequently the inferior eyelid and the therapy is mainly surgical. Parasurgical therapy may play a role as a temporary measure. PMID- 24172762 TI - Blepharoptosis. AB - Blepharoptosis of the upper eyelid is a common condition among patients presenting for oculoplastic surgery. Although there are many types of ptosis, the two most frequent clinical cases are simple congenital ptosis in young patients and senile ptosis in adults. Patient examination is important to distinguish these from other more infrequent types of ptosis, such as those neurogenic, myogenic and posttraumatic. These latter cases may require specific therapeutic strategies. Ptosis can usually be corrected surgically. The article discusses guidelines for the choice of intervention. Various different surgical techniques are also presented, together with results and complications. PMID- 24172763 TI - Blepharoplastic: essential review. AB - In the periorbital the major aging changes are a drooping of the brow (brow ptosis), excessive accumulation of skin in the upper lid (dermatochalasis), and a prolapse of orbital fat, in the upper and lower lids caused by weakening of the septum and orbital connective tissues. The specific anatomical abnormalities of each individual patients should be identified and the relationship between each other should be identified in order to determine a correct surgical plan. In this review we will analyze different surgical techniques. PMID- 24172764 TI - The role of fibrinogen in trauma-induced coagulopathy. AB - Fibrinogen plays an essential role in clot formation and stability. Importantly it seems to be the most vulnerable coagulation factor, reaching critical levels earlier than the others during the course of severe injury. A variety of causes of fibrinogen depletion in major trauma have been identified, such as blood loss, dilution, consumption, hyperfibrinolysis, hypothermia and acidosis. Low concentrations of fibrinogen are associated with an increased risk of diffuse microvascular bleeding. Therefore, repeated measurements of plasma fibrinogen concentration are strongly recommended in trauma patients with major bleeding. Recent guidelines recommend maintaining plasma fibrinogen concentration at 1.5-2 g/l in coagulopathic patients. It has been shown that early fibrinogen substitution is associated with improved outcome. PMID- 24172765 TI - Prediction of a large number of electron pockets near the band edges in type-VIII clathrate Si46 and its physical properties from first principles. AB - The material design of type-VIII clathrate Si46 is presented based on first principles. The structural, electronic, elastic, vibrational, and thermodynamic properties of this hypothetical material are presented. Our results predict that type-VIII clathrate Si46 is an indirect semiconductor with a bandgap of 1.24 eV. The band structure revealed an interestingly large number of electron pockets near both conduction and valance band edges. Such a large density of states near the band edges, which is higher than that of the best thermoelectric materials discovered so far, can result in a large thermoelectric power factor (>0.004 W m( 1) K(-2)) making it a promising candidate for thermoelectric applications. The elastic properties as well as the vibrational modes and the phonon state densities of this material were also calculated. Our calculations predict that the heat capacity at constant volume (isochoric) of this clathrate increases smoothly with temperature and approaches the Dulong-Petit value near room temperature. The electronic band structure shows a large number of valleys closely packed around the valance band edge, which is rare among the known semiconducting materials. These valleys can contribute to transport at high temperature resulting in a possibly high performance (ZT > 1.5) p-type thermoelectric material. PMID- 24172766 TI - Identification of two new antigen epitopes on the putative capsid protein encoded by torque teno sus virus type 1 ORF1. AB - Torque teno sus virus type 1 (TTSuV1) ORF1 is considered to encode the viral capsid (Cap) protein, which is crucial for the induction of TTSuV1-specific antibodies and protective immunity in the host. Eight monoclonal antibodies (mAbs) directed against the Cap protein were generated and biologically characterized. The immunoreactivity of the Cap protein expressed in transfected 293T cells for these mAbs was determined with an immunoperoxidase monolayer assay. The antigen epitopes of the Cap protein were mapped using these mAbs and truncated Cap proteins expressed in Escherichia coli. Fine epitope mapping was then performed with a panel of synthesized polypeptides. All the mAbs reacted with the Cap protein C fragment expressed in E. coli. One antigenic epitope of the Cap protein, which reacted with seven mAbs, had the polypeptide sequence (536)HPKYAGQGGGYTT(548), whereas another epitope recognized by the 1E9 mAb had the polypeptide sequence (549)EIGHQGITAASLR(561). It is interesting that the two new epitopes are adjacent, but mutually independent. This study should facilitate further investigation of the antigenic differences and enable the differential diagnosis of the virus. PMID- 24172767 TI - Variable duration of decaffeinated green tea extract ingestion on exercise metabolism. AB - PURPOSE: The aim of this study was to investigate if the duration of decaffeinated green tea extract (dGTE) ingestion plays a role in augmenting fat oxidation rates during moderate-intensity exercise. METHODS: In a crossover, placebo-controlled design, 19 healthy males (mean +/- SD; age = 21 +/- 2 yr, weight = 75.0 +/- 7.0 kg, body mass index = 23.2 +/- 2.2 kg.m, maximal oxygen consumption [VO2max] = 55.4 +/- 4.6 mL.kg.min) ingested dGTE and placebo (PLA) for 28 d, separated by a 28-d washout period. On the first day (dGTE 1 or PLA 1) and after 7 d (dGTE 7 or PLA 7) and 28 d (dGTE 28 or PLA 28), participants completed a 30-min cycle exercise bout (50% Wmax), 2 h after ingestion. Indirect calorimetry was used to calculate rates of whole-body fat and carbohydrate oxidation during exercise. Blood samples were collected at rest and during exercise for analysis of plasma fatty acids, glycerol, and epigallocatechin gallate. RESULTS: The ingestion of dGTE did not significantly change whole-body fat oxidation rates during exercise on day 1, 7, or 28 compared with PLA. There were also no changes in plasma concentrations of fatty acids and glycerol at rest and during exercise as a result of dGTE ingestion at any time point compared with PLA. Plasma epigallocatechin gallate concentrations, immediately before the exercise bout, in the three dGTE trials were elevated compared with PLA but not different between 1, 7, and 28 d. CONCLUSION: In contrast to previous reports, we found that the duration of dGTE ingestion had no effect on whole-body fat oxidation rates or fat metabolism-related blood metabolites during exercise in physically active healthy males. PMID- 24172768 TI - The necessity of having asthma predictive scores in children. PMID- 24172769 TI - Sesquiterpenyl indoles. AB - The natural product sesquiterpenyl indoles are structural hybrids from farnesyl pyrophosphate and tryptophan or its precursors, often with unusual and complex structural features, many of them with interesting biological activities. In this review the compounds of this class known until now are classified, a biosynthetic approach of each group is proposed and a review of the synthesis or synthetic approaches is communicated. PMID- 24172770 TI - Septic shock during platelet transfusion in a patient with acute myeloid leukaemia. AB - Although rare, transfusion-associated bacterial contamination (TABC) is nowadays the main risk associated with platelet concentrate (PC) transfusion. Consequences vary from spontaneously resolving symptoms to severe sepsis and death. In this report we have summarised a case of bacterial contamination and sepsis during PC transfusion in a patient with acute myeloid leukaemia. Fifteen minutes after the PC transfusion began, she developed chills and rapidly worsened to septic shock. The episode was managed appropriately. The patient's blood cultures and PC unit cultures grew Escherichia coli. The microbiological susceptibilities of isolates from the patient and platelet bag were identical. No other source of E coli was found. Donor and blood products issued from the same donation investigations were negative. The causality between sepsis and PC transfusion might be difficult to confirm. As no method is available in daily practice to eliminate TABC risk, physicians should always consider TABC by immediately stopping the transfusion and conducting appropriate investigations. PMID- 24172771 TI - Direct puncture sclerotherapy of a thoracic duct cyst presenting as an enlarging left supraclavicular mass. AB - A 58-year-old woman presented with a palpable mass at the base of the left neck which she had first noticed 12 years previously, shortly after abdominal surgery. The mass had progressively enlarged, resulting in dysphagia, dyspnea and occasional pain. Imaging showed a septated but otherwise simple cystic mass extending into the mediastinum and containing lymphocytic fluid on aspiration. A diagnosis of the rare entity of a thoracic duct cyst with supraclavicular extension was made. The patient opted for percutaneous sclerotherapy of the lesion, which was performed using glacial acetic acid. This resulted in complete resolution of the mass with one treatment. After exclusion of other causes of cystic left supraclavicular masses including cystic neoplasms and pseudoaneurysms of the carotid or subclavian arteries, direct puncture sclerotherapy can be safe and effective. PMID- 24172772 TI - Metastatic transitional cell carcinoma of the tibia radiologically mimicking osteosarcoma. AB - We report a case of a 73-year-old lady with transitional cell carcinoma and no evidence of metastatic disease presenting with gradual weight loss, pretibial swelling and painful weightbearing. Investigations revealed a lesion of the right tibial diaphysis. The radiological and clinical appearance was that of primary osteosarcoma. Biopsy results revealed metastatic transitional cell carcinoma of the tibia. Intramedullary nailing was performed which relieved pain on weightbearing. The patient declined radiotherapy and was started on a palliative care regimen. This case illustrates the importance of histological diagnosis in the treatment of diaphyseal lesions. PMID- 24172773 TI - Rhinocerebral mucormycosis in a patient with type 1 diabetes presenting as toothache: a case report from Himalayan region of India. AB - Mucormycosis is an angioinvasive infection caused by ubiquitous filamentous fungi of the order Mucorales. It is a rapidly progressive fatal infection mostly reported in susceptible individuals, such as those with poorly controlled diabetes or those with defects in phagocytic function. Rhinocerebral mucormycosis is the most common type of mucormycosis in diabetic patients. This case report describes a 17-year-old girl with type 1 diabetes mellitus presenting with rhinocerebral mucormycosis. The patient presented with a history of toothache and facial pain with oedema of left half of face, periorbital oedema and depressed conciousness. She had hyperglycaemia with diabetic ketoacidosis and rapidly developed hemiparesis progressing to quadriparesis and died within 3 days of admission. The current report emphasises the importance of having a high index of suspicion when dealing with patients with diabetes presenting with facial pain or cellulitis and prompt initiation of medical therapy along with surgical debridement for control of rhinocerebral mucormycosis. PMID- 24172774 TI - Gorlin syndrome. PMID- 24172775 TI - Thelazia callipaeda discovered by chance during cataract surgery. PMID- 24172776 TI - Aluminium phosphide-induced leukopenia. AB - Acute intoxication from the pesticide aluminium phosphide is a relatively rare, life-threatening condition in which cardiovascular decompensation is the most feared problem. We report the case of a patient exposed to aluminium phosphide liberated phosphine gas. It resulted in the development of a gastroenteritis-like syndrome accompanied by severe reduction in white blood cell numbers as an early and prominent manifestation. By affecting important physiological processes such as mitochondrial function and reactive oxygen species homeostasis, phosphine could cause severe toxicity. After presenting the characteristics of certain leucocyte subpopulations we provide the current molecular understanding of the observed leukopenia which in part seems paradoxical. PMID- 24172777 TI - Evisceration for the management of ocular trauma. AB - Despite the eye being surrounded by orbital bones and protective mechanisms such as the blink reflex, it is vulnerable to trauma. The two key issues to consider when presented with a case of ocular trauma are the visual potential of the eye and the risk of sympathetic ophthalmia. The Ocular Trauma Score can be used to assess the visual potential of the injured eye. Surgical management may be either repair or removal of the eye (evisceration or enucleation). Herein we describe a case of ocular trauma and the decision-making process in the management of the injury. PMID- 24172778 TI - Recurrent atraumatic metatarsal, rib and sacral insufficiency fractures in a woman with the antiphospholipid syndrome. AB - Antiphospholipid syndrome (APS) is characterised by recurrent arterial and/or venous thromboses and recurrent late miscarriages in the presence of antiphospholipid antibodies, and can be a hugely debilitating disorder. While the commonest thrombotic manifestations of this condition such as deep vein thrombosis and stroke are well documented, there has been increasing recognition of numerous less common complications in most organ systems. We present a female patient with APS and a lupus-like illness who had atraumatic sacral fractures as well as multiple spontaneous fractures affecting her ribs and the metatarsals in both her feet. PMID- 24172779 TI - Acquired male urethral diverticulum: a complication following artificial urethral sphincter implantation. AB - The authors report a case of a 72-year-old patient who underwent radical prostatectomy in 2003 due to prostate cancer. During follow-up, he presented with permanent and severe urinary stress incontinence for which he underwent an artificial urinary sphincter implantation in 2009. After infection of the device, followed by the development of a urinary fistula, the artificial urinary sphincter was removed. He presented no new signs or symptoms for 2 years, during which he remained completely incontinent. In April 2012, he developed a painless scrotal swelling close to the median raphe. On manual compression, it showed urinary leakage and disappeared completely, only to reappear several hours later. Auxiliary examinations revealed a bulbar urethral diverticulum which was subsequently excised. A urethroplasty was performed during the same procedure. The patient presented with no further complications. Although still suffering from complete urinary incontinence, he refused any kind of surgery for the time being. PMID- 24172780 TI - Massive splenomegaly and lymphopenia: a unique case of obstructive shock. AB - We present a patient with intravascular large B-cell lymphoma (IVLBCL)-induced obstructive shock. This case represents a unique presentation of the disease, while highlighting the difficulty of establishing the diagnosis. Although there was a high clinical suspicion for a lymphomatous process, the obstructive shock component of the patient's presentation was perplexing. It was not until the autopsy reports demonstrated lymphocytes within the pulmonary vasculature that the clinical picture of altered mental status, weight loss and obstructive shock were unified to the diagnosis of intravascular large B-cell lymphoma. PMID- 24172781 TI - Visible intestinal peristalsis. PMID- 24172782 TI - MRI in rabies encephalitis. PMID- 24172784 TI - Going green: phytohormone mimetics for drought rescue. PMID- 24172785 TI - Magnetic resonance imaging features of breast leukemia. AB - Breast leukemia is extremely rare. Only 7 other reports describe its magnetic resonance (MR) imaging findings. This report describes a case of breast leukemia presenting as isolated intramammary leukemic relapse in the breasts after complete remission of acute myeloid leukemia. Dynamic contrast-enhanced MR imaging showed diffuse heterogeneous non-mass-like enhancement in one breast and a diffuse irregular heterogeneously enhancing mass in the other. Previous reports of MR imaging findings in breast leukemia have included only mass-like lesions; hence, the finding reported here is uncommon. PMID- 24172786 TI - Bifid tail of the pancreas with localized acute pancreatitis. AB - Bifid tail of the pancreas is an extremely rare developmental anomaly, and its clinical importance is not well known. We report the case of a 28-year-old man with acute pancreatitis limited to one side of a bifid tail with no otherwise detectable parenchymal edema on magnetic resonance (MR) imaging. Neither was there evidence of other anatomical ductal abnormalities that could have contributed to the patient's pancreatitis. To the best of our knowledge, this is the first report to suggest that bifid tail of the pancreas might cause acute pancreatitis. PMID- 24172787 TI - What is the most effective tool for detecting prostate cancer using a standard MR scanner? AB - PURPOSE: We aimed to determine which of the following magnetic resonance (MR) imaging sequences is most effective for detecting prostate cancer: T2-weighted (T2W), dynamic contrast-enhanced (DCE) T1-weighted (T1W), or diffusion-weighted (DWI) imaging or apparent diffusion coefficient (ADC) mapping. MATERIALS AND METHODS: We included 37 male patients with prostate cancer who underwent MR imaging before radical prostatectomy in this retrospective study. Sixty-four foci (>5 mm in size; 35 in the peripheral zone [PZ], 29 in the transitional zone [TZ]) were histopathologically determined to be prostate cancer. We determined the capacity of T2W, DCE-T1W, DWI, ADC mapping alone, and the combination of ADC mapping with DWI, and conventional MR sequences to detect prostate cancer, including their sensitivity and positive predictive value (PPV), with reference to the results obtained in histopathological examinations of whole-mount sections. RESULTS: In the PZ, sensitivities were 31.4% (T2W), 37.1% (DCE-T1W), 51.4% (DWI), and 71.4% (ADC mapping); PPVs were 78.6% (T2W), 92.9% (DCE-T1W), 94.7% (DWI), and 96.0% (ADC mapping). Sensitivity was significantly higher of ADC mapping than other sequences. In the TZ, sensitivities were 55.1% (T2W), 44.8% (DCE-T1W), 82.8% (DWI), and 89.7% (ADC mapping); PPVs were 64.0% (T2W), 46.4% (DCE-T1W), 70.6% (DWI), and 72.2% (ADC mapping). Sensitivity was significantly higher of ADC mapping and DWI than conventional MR imaging, but there was no significant correlation between DWI/ADC mapping and T2W/DCE-T1W with respect to PPVs. Combining sequences did not improve sensitivity; only the PPV in the TZ improved when ADC mapping was combined with DCE-T1W. CONCLUSION: ADC mapping is the most effective standard MR imaging tool for detecting prostate cancer. The addition of DCE-T1W may improve the PPV of ADC mapping for diagnosing cancer in the TZ. PMID- 24172788 TI - Natural course of hypovascular nodules detected on gadoxetic acid-enhanced MR imaging: presence of fat is a risk factor for hypervascularization. AB - PURPOSE: Hypovascular nodules that exhibit hypointensity in hepatocyte-phase images of gadoxetic acid-enhanced magnetic resonance (MR) imaging are frequently encountered in clinical practice. We investigated risk factors for the development of these nodules into hypervascular hepatocellular carcinoma (HCC). METHODS: We retrospectively reviewed our institutional database and identified 302 patients who underwent gadoxetic acid-enhanced MR imaging for suspected or confirmed HCC from February 1, 2008 to January 30, 2011. We excluded patients who were examined for metastasis of other malignancies or for other hepatic tumors, such as focal nodular hyperplasia. We identified hypovascular nodules that were hypointense in hepatocyte-phase images, recorded their characteristics, and calculated the cumulative hypervascularization rate for nodules that were followed up. RESULTS: Of the 302 patients, 82 had hypovascular nodules (178 nodules; mean size, 9.3 mm). Sixty nodules were followed up for over 6 months, and eight progressed to hypervascular HCC. Hypervascularization occurred more frequently in nodules with fat than those without (P<0.01). The cumulative hypervascularization rate was 5.1% over a year. CONCLUSION: The presence of intralesional fat was found to be a risk factor for hypervascularization of hypovascular nodules that exhibited hypointensity in the hepatocyte-phase images of gadoxetic acid-enhanced MR imaging. PMID- 24172789 TI - Clear cell adenocarcinoma arising from clear cell adenofibroma of the ovary: value of DWI and DCE-MRI. AB - Clear cell adenofibroma (CCAF) is a rare surface epithelial-stromal tumor of the ovary and recently considered another precursor of clear cell adenocarcinoma (CCA) other than endometrioma. We report magnetic resonance (MR) findings of a borderline CCAF that contained a small CCA focus. The tumor manifested a characteristic "black sponge" appearance. The CCA focus showed high signal intensity on diffusion-weighted imaging (DWI) and early enhancement on dynamic contrast-enhanced (DCE) MR imaging (DCE-MRI), and the CCAF components showed low signal intensity on DWI and gradually increasing contrast enhancement on DCE-MRI. PMID- 24172790 TI - Establishing normal diameter range of the cochlear and facial nerves with 3D-CISS at 3T. AB - PURPOSE: We explored normal diameter values of the cochlear (CN) and facial (FN) nerves on 3-dimensional constructive interference in steady state (3D-CISS) using a 3-tesla magnetic resonance (MR) imaging scanner. METHODS: A total of 142 patients underwent MR imaging of the inner ear at 3T. We retrospectively analyzed data from 172 ears. All ears had normal hearing and no history of ipsilateral facial palsy. Parasagittal images of 0.5-mm thickness perpendicular to the internal auditory canal were reconstructed from 0.4-mm thick axial 3D-CISS images for all ears. Two independent radiologists measured the long diameter (LD), short diameter (SD), and cross-sectional area (CSA) of each CN and FN. For each measurement, we calculated the mean value from the 2 observers and evaluated interobserver agreement. We also evaluated the correlation between nerve diameter and sex and age. RESULTS: Both observers could perform measurements in 157 CN from 172 ears (91%) and 165 FN from 172 ears (96%). For the CN, the mean LD was 1.35+/-0.16 mm, the mean SD was 0.99+/-0.18 mm, and the mean CSA was 1.07+/-0.30 mm2; for the FN, the mean values were 1.18+/-0.17 mm (LD), 0.87+/-0.16 mm (SD), and 0.83+/-0.27 mm2 (CSA). Interobserver reliability was good for each measurement (r=0.569 to 0.691, P<0.01). The diameters of the 2 nerves tended to be larger in men, but only the CSA of the FN was significantly larger in men (P<0.05). Age did not affect nerve diameter. CONCLUSION: We present normal values of CN and FN diameters on 3D-CISS at 3T. Our results warrant further study to clarify the pathophysiological state of the CN or FN using 3D-CISS. PMID- 24172791 TI - Usefulness of dual echo volumetric isotropic turbo spin echo acquisition (VISTA) in MR imaging of the temporomandibular joint. AB - PURPOSE: We investigated the ability to detect the articular disk and joint effusion of the temporomandibular joint (TMJ) of a method of dual echo volumetric isotropic turbo spin echo acquisition (DE-VISTA) additional fusion images (AFI). METHODS: DE-VISTA was performed in the 26 TMJ of 13 volunteers and 26 TMJ of 13 patients. Two-dimensional (2D) dual echo turbo spin echo was performed in the 26 TMJ of 13 volunteers. On a workstation, we added proton density-weighted images (PDWI) and T2 weighted images (T2WI) of the DE-VISTA per voxel to reconstruct DE VISTA-AFI. Two radiologists reviewed these images visually and quantitatively. RESULTS: Visual evaluation of the articular disk was equivalent between DE-VISTA AFI and 2D-PDWI. The sliding thin-slab multiplanar reformation (MPR) method of DE VISTA-AFI could detect all articular disks. The ratio of contrast (CR) of adipose tissue by the articular disk to that of the articular disk itself was significantly higher in DE-VISTA-AFI than DE-VISTA-PDWI (P<0.05) in patients and volunteers with closed or open mouth. In volunteers, the CR between adipose tissue and the disk on DE-VISTA-AFI was marginally significant to that on 2D-PDWI at opened mouth (P=0.071) and not significantly different (P=0.18) from that at closed mouth. Joint effusion could be identified in DE-VISTA-AFI in all 8 joints that had joint effusion in DE-VISTA-T2WI but in only 3 of those joints in 2D T2WI. The CR of joint effusion to adipose tissue on DE-VISTA-AFI did not differ significantly from that on DE-VISTA-PDWI. However, using DE-VISTA-T2WI in addition to DE-VISTA-PDWI, we could visually identify joint effusion on DE-VISTA AFI that could not be identified on DE-VISTA-PDWI alone. CONCLUSION: DE-VISTA-AFI can depict the articular disk and a small amount of joint effusion by the required plane of MPR using the sliding thin-slab MPR method. PMID- 24172792 TI - MR spectroscopy of the prostate at 3T: measurements of relaxation times and quantification of prostate metabolites using water as an internal reference. AB - PURPOSE: We performed single-voxel magnetic resonance spectroscopy (MRS) of the human prostate at 3 tesla using a surface coil to measure prostate water, choline (Cho), creatine (Cr), and citrate (Cit) relaxation times T1, T2, and to estimate concentrations of Cho, Cr, and Cit in healthy volunteers. METHODS: In nine of 17 healthy volunteers, we performed experiments to estimate relaxation time, and we used the spectra of the other eight to compute metabolite concentrations. Spectra were processed by LCModel and AMARES (advanced method for accurate, robust, and efficient spectral fitting) algorithms. T1 and T2 values were obtained by monoexponential fitting of the spectral intensities. Metabolite concentrations were estimated using prostate tissue water as an internal concentration reference. RESULTS: Relaxation times are reported for prostate water (T1, 2163+/ 166 ms; T2, 110+/-18 ms), Cho (T1, 987+/-71 ms; T2, 239+/-24 ms), Cr (T1, 1128+/ 149 ms; T2, 188+/-20 ms), and Cit (T1, 476+/-70 ms; T2, 228+/-42 ms). Mean concentrations in healthy prostate were Cho, 2.6+/-0.3 mM, Cr, 5.8+/-1.3 mM, and Cit, 26.9+/-5.5 mM. CONCLUSION: We observed metabolite relaxation times and concentrations consistent with published values of healthy volunteers at 1.5 and 3T. T1 values increased and T2 slightly decreased with magnetic field strength. Our preliminary patient results indicate that water-referenced quantitative MRS of the human prostate is a promising tool for monitoring therapeutic effects and detecting tumor relapse, i.e., in situations when Cit intensity is small or undetectable. PMID- 24172793 TI - Semi-quantification of endolymphatic size on MR imaging after intravenous injection of single-dose gadodiamide: comparison between two types of processing strategies. AB - PURPOSE: Many inner ear disorders, including Meniere's disease, are believed to be based on endolymphatic hydrops. We evaluated a newly proposed method for semi quantification of endolymphatic size in patients with suspected endolymphatic hydrops that uses 2 kinds of processed magnetic resonance (MR) images. METHODS: Twenty-four consecutive patients underwent heavily T2-weighted (hT2W) MR cisternography (MRC), hT2W 3-dimensional (3D) fluid-attenuated inversion recovery (FLAIR) with inversion time of 2250 ms (positive perilymph image, PPI), and hT2W 3D-IR with inversion time of 2050 ms (positive endolymph image, PEI) 4 hours after intravenous administration of single-dose gadolinium-based contrast material (IV-SD-GBCM). Two images were generated using 2 new methods to process PPI, PEI, and MRC. Three radiologists contoured the cochlea and vestibule on MRC, copied regions of interest (ROIs) onto the 2 kinds of generated images, and semi quantitatively measured the size of the endolymph for the cochlea and vestibule by setting a threshold pixel value. RESULTS: Each observer noted a strong linear correlation between endolymphatic size of both the cochlea and vestibule of the 2 kinds of generated images. The Pearson correlation coefficients (r) were 0.783, 0.734, and 0.800 in the cochlea and 0.924, 0.930, and 0.933 in the vestibule (P<0.001, for all). In both the cochlea and vestibule, repeated-measures analysis of variance showed no statistically significant difference between observers. CONCLUSION: Use of the 2 kinds of generated images generated from MR images obtained 4 hours after IV-SD-GBCM might enable semi-quantification of endolymphatic size with little observer dependency. PMID- 24172794 TI - Safety of gadopentetate dimeglumine after 120 million administrations over 25 years of clinical use. AB - PURPOSE: We evaluated the safety of gadopentetate dimeglumine (Gd-DTPA), the first contrast agent for magnetic resonance imaging, using pharmacovigilance data for spontaneously reported adverse events (AEs) after 120 million cumulative administrations worldwide. METHODS: We analyzed spontaneously reported AEs for Gd DTPA for pre-specified time periods between 1988 and 2011. RESULTS: Since the market introduction of Gd-DTPA in 1988, its global utilization reached 120 million cumulative administrations in 2011, more than 80% of which was by the USA, countries in the European Union (EU), and Japan. The global AE reporting rate was 21.2 in 100,000 administrations in 1988 and 14.4 in 100,000 administrations by 2011. Regional differences included higher reporting rates in the USA and Japan, and reporting rates lower than global rates in the EU. The reported rate of global serious AEs changed from 1.4 in 100,000 administrations in 1988 to 4.0 in 100,000 administrations in 2011. The highest number of reports of nephrogenic systemic fibrosis (NSF) was received from 2006 to 2008. Since 2009, no report of a current onset of NSF has been received. The reduced report rate of NSF may be due to increased awareness about the use of gadolinium-based contrast agents (GBCAs). CONCLUSION: After more than 120 million cumulative administrations, Gd-DTPA is a widely used GBCA that shows a consistently low and stable incidence of AEs. PMID- 24172795 TI - High rate capability caused by surface cubic spinels in Li-rich layer-structured cathodes for Li-ion batteries. AB - Modified Li-rich layered cathode Li(Li0.2Mn0.54Ni0.13Co0.13)O2 has been synthesized by a simple strategy of using surface treatment with various amounts (0-30 wt.%) of Super P (carbon black). Based on detailed characterizations from X ray diffraction (XRD), high resolution transmission electron microscope (HRTEM), X-ray photoelectron spectroscopy (XPS) and electrochemical impedance spectroscopy (EIS), it is suggested that the phase transformation from Li2MnO3-type of structure to spinel-like phase take place at the surface regions of particles during post annealing process at 350 degrees C, leading to increase in both first coulombic efficiency and rate capability, from 78% and 100 mAh . g(-1) (charge capacity at 2500 mA . g(-1)) of the pristine material to 93.4% and 200 mAh . g(-1). The evidences of spinel formation and the reasons for electrochemical enhancement are systematically investigated. PMID- 24172796 TI - Toward immunosuppressive effects on liver transplantation in rat model: tacrolimus loaded poly(ethylene glycol)-poly(D,L-lactide) nanoparticle with longer survival time. AB - In this study, tacrolimus (FK506) was encapsulated into a biodegradable poly(ethylene glycol)-poly(D,L-lactide) (MPEG-PLA) block copolymer using a double emulsion-solvent evaporation technique. Drug loading (DL) and encapsulation efficiency (EE) can be changed by varying the mass ratio of FK506/MPEG-PLA. Furthermore, transmission electron microscope (TEM) and Malvern Zetasizer were used to investigate the properties of FK506/MPEG-PLA nanoparticles (DL=9.5%), which were monodisperse (PDI=0.100 +/- 0.023) with a mean particle size of 90.5 +/- 1.5 nm. Compared with FK506 capsule, in vitro release profile showed that FK506/MPEG-PLA nanoparticles exhibited sustained release. Meanwhile, the higher concentration and longer retention time in plasma were also confirmed in vivo. We further preliminarily evaluated immunosuppressive effect on liver transplantation in rat model. The survival time of the rat administrated FK506/MPEG-PLA nanoparticles was obviously prolonged than that of the control group administrated FK506 capsule. PMID- 24172797 TI - Abstracts presented at the European Society for Pediatric Urology (ESPU) meetings (2003-2010): characteristics and outcome. AB - OBJECTIVE: To determine the characteristics and outcome of abstracts presented to the meetings of the European Society for Pediatric Urology (ESPU). MATERIAL AND METHODS: Abstract books from 2003 to 2010 were reviewed and subsequent publication of presented abstracts determined by MEDLINE/PubMed search. RESULTS: Of 1194 abstracts, 50-78% per year originated from 15 to 20 European countries and 50-22% from 8 to 13 non-European countries; 233 (19%) were basic science and 961 (81%) clinical. Clinical abstracts included 135 (14%) multicenter/prospective/randomized trials. These figures did not change significantly over time. A total of 564 (47%) abstracts were subsequently published, 65% within 1 year of the meeting, mostly in the Journal of Urology (33%) and the Journal of Pediatric Urology (21%). Multicenter/prospective/randomized trials studies (OR 2.03; 95% CI 1.37-2.96) and abstracts originating from outside Europe (OR 1.61; 95% CI 1.26-2.05) were significantly more likely to be subsequently published in full. CONCLUSION: The ESPU meetings are a true occasion for international exchange of scientific endeavors. Almost half of the abstracts are subsequently published. The Journal of Urology and the Journal of Pediatric Urology are consistently the two major target journals for publication. Non-European countries, irrespective of whether English-speaking or not, seem significantly more likely to publish their abstracts. PMID- 24172798 TI - Response to Commentary to 'Priapism in children: a comprehensive review and clinical guideline'. PMID- 24172799 TI - The effects of chronic usage of enzyme inhibitors and angiotensin receptor blockers on contrast-induced nephropathy in low-risk patients. PMID- 24172800 TI - About contrast-induced nephropathy. PMID- 24172801 TI - Flow-mediated dilatation measurement as a simple practical method in Behcet's diseases without cardiovascular involvement. PMID- 24172802 TI - Differential diagnosis of cardiomyopathies: Utility of cardiac magnetic resonance imaging. PMID- 24172803 TI - The protection of therapeutic lifestyle change in individuals with prehypertension; a valuable study. PMID- 24172804 TI - Comment on ''Traditional coronary risk factors in healthy Turkish military personnel between 20 and 50 years old: focus on high-density lipoprotein cholesterol''. PMID- 24172805 TI - [Surgical treatment of hypertension]. PMID- 24172806 TI - [As cardiologists how much do we take into account the guideline recommendations while prescribing oral anticoagulants to patients with atrial fibrillation our clinical practice? A striking result!]. PMID- 24172807 TI - Familial sick sinus syndrome. PMID- 24172808 TI - Awareness about preventable cardiovascular risk factors of students attending Faculties of Nursing and Literature. PMID- 24172809 TI - Long-term prostaglandin E1 use in newborns with duct-dependent congenital heart diseases: one year experience of a tertiary neonatal intensive care unit in Turkey. PMID- 24172810 TI - Adult overweight and cardiovascular system: risk or disease? PMID- 24172811 TI - An imaging of paradox flow in coronary artery collateralization. PMID- 24172812 TI - Pancardiac hydatid cyst. PMID- 24172813 TI - ''Lovely Heart'' on echocardiography: An unusual left ventricular pseudoaneurysm diagnosed incidentally. PMID- 24172814 TI - Multimodality imaging of type 4 persistent truncus arteriosus in an adult patient. PMID- 24172815 TI - Successful extraction of broken pacemaker leads by using a snare-loop device and radiofrequency ablation catheter. PMID- 24172816 TI - Transarterial closure of long tubular PDA by duct occluder in an infant with interrupted inferior vena cava and azygos continuation. PMID- 24172817 TI - Patient with nonechogenic chest and pleuritic chest pain. PMID- 24172818 TI - Out of the ordinary image in common iliac vein. PMID- 24172819 TI - Effect of phenytoin treatment on cell proliferation in the hippocampus and the heart and related neuroendocrine changes under non-stress and stress conditions. AB - OBJECTIVE: Phenytoin is an antiepileptic drug that has been shown to reduce some neurotoxic effects of glutamate in states when glutamate neurotransmission is increased, such as neurodegeneration and stress. In the present study, we tested the hypothesis that treatment with phenytoin prevents stress-induced alterations in the production of new cells in the hippocampus and in the heart. METHODS: Adult male Wistar rats were exposed to repeated hypokinesis (restraint, 2 hours daily) and were treated with phenytoin (20 mg/kg/day, s.c.) or vehicle for 8 days. On the 7th day, all animals were treated with 5-bromo-2'-deoxyuridine (BrdU), a marker of cell proliferation. RESULTS: The treatment with phenytoin under both control and stress conditions resulted in an inhibitory effect on cell proliferation, which was more evident in the heart than in the hippocampus. Repeated treatment with phenytoin led to adrenal gland hypertrophy as well as to a marginal increase in plasma renin activity. Basal and stress-induced concentrations of adrenal steroids were unchanged by phenytoin administration. DISCUSSION: Treatment with the glutamate release inhibiting drug phenytoin did not prevent negative consequences of repeated stress exposure on cell proliferation in Wistar rats. Treatment with phenytoin even deepened stress induced reduction of cell proliferation in the heart. It cannot be excluded that the phenytoin-induced increase in plasma renin activity observed in the present study may occur during therapeutic use of phenytoin and contribute to its adverse effects. PMID- 24172820 TI - Docosahexaenoic acid, protectin synthesis: relevance against atherothrombogenesis. AB - DHA is an abundant nutrient from marine lipids: its specific biological effects have been investigated in human volunteers, taking into consideration the dose effects. We report herein that, at dosages below 1 g/d, DHA proved to be effective in lowering blood platelet function and exhibited an 'antioxidant' effect. However, this was no longer the case following 1.6 g/d, showing then a U shape response. The antioxidant effect has been observed in platelets as well as LDL, of which the redox status is assumed to be crucial in their relationship with atherosclerosis. Second, the oxygenated products of DHA, especially protectins produced by lipoxygenases, have been considered for their potential to affect blood platelets and leucocytes. It is concluded that DHA is an interesting nutrient to reduce atherothrombogenesis, possibly through complementary mechanisms involving lipoxygenase products of DHA. PMID- 24172821 TI - Preventing postoperative nausea and vomiting. PMID- 24172823 TI - Serum neutrophil gelatinase-associated lipocalin (NGAL) in patients with Shiga toxin mediated haemolytic uraemic syndrome (STEC-HUS). AB - Neutrophil gelatinase-associated lipocalin (NGAL) is an increasingly used biomarker for acute kidney injury (AKI). Its utility in adult patients with AKI caused by Shiga toxin producing Escherichia coli infection (STEC)-associated haemolytic-uraemic syndrome (HUS), remains unknown. We aimed to evaluate the prognostic value of serum NGAL admission levels for the need of renal replacement therapy (RRT) in STEC-HUS patients. Baseline serum NGAL was determined by ELISA in 39 patients with STEC O104:H4 infection cared for at Hannover Medical School during the outbreak in Germany through May-July 2011. Patients with HUS had significant higher NGAL levels than healthy controls (379 [248 - 540] vs 39.0 [37.5-45] ng/ml, p < 0.0001). During clinical course, 24 patients required RRT at a median of five days after admission. NGAL admission levels were higher in patients requiring RRT (476 (344-639) ng/ml) compared to patients not requiring RRT (257 (196-426) ng/ml; p < 0.001). Unadjusted and adjusted logistic regression analyses identified NGAL as an independent predictor for need of RRT. In a combined model, a joint NGAL/AKIN classification approach improved the predictive accuracy for need of RRT over either marker alone. The combined categorical cut off point defined by NGAL >= 330 ng/ml and presence of AKI (AKIN >= I) on admission correctly identified 20 of 24 patients requiring RRT (odds ratio 20, sensitivity 83%, specificity 80%, negative predictive value 75%, positive predictive value 87%). NGAL may serve as an adjunctive tool to improve risk prediction in patients with STEC-HUS. PMID- 24172824 TI - Feasibility of targeted next-generation sequencing of the TP53 and ATM genes in chronic lymphocytic leukemia. PMID- 24172825 TI - Synergistic anti-leukemic activity of imatinib in combination with a small molecule Grb2 SH2 domain binding antagonist. PMID- 24172826 TI - Origin of n- and p-type conductivity in undoped alpha-PbO: role of defects. AB - First-principles calculations have been applied to study the crystallographic defects in alpha-PbO in order to understand an origin of n- and p-type conductivity in otherwise undoped alpha-PbO. It was found that deposition in an oxygen-deficient environment defined in our simulations by the Pb-rich/O-poor limit stimulates a formation of O vacancies and Pb interstitials both characterized by quite low formation energies ~1.0 eV. The O vacancy, being occupied by two electrons, shifts the balance of electrons and holes between these two defects to an excess of electrons (four electrons against two holes) that causes n-type doping. For the Pb-poor/O-rich limit, an excess of oxygen triggers the formation of the O interstitials characterized by such a low formation energy that a spontaneous appearance of this defect is predicted. It is shown that the concentration of O interstitials is able to reach an extreme magnitude equal to the number of possible defect sites (~10(22) cm(-3)). The localized state formed by the O interstitial is occupied by two holes and because there are no other defects in reasonable concentration to balance the hole redundancy, p-type doping is induced. PMID- 24172827 TI - The GEOS study: designing a geospatially optimised trauma system for Scotland. PMID- 24172828 TI - Odontostomatological aspects in patients with Williams syndrome: a series of 4 cases. AB - The authors examined four patients with Williams syndrome presenting characteristic odontostomatological alterations. Agenesis, dental deposits, chewing difficulties due to bone malformations and poor cooperation of patients with malformations also in other districts and mental and physical retardation require the dentist to adopt different approaches, from restorative to orthodontic treatment, from periodontal to professional oral hygiene treatment. PMID- 24172829 TI - Partnership between tobacco control programs and offices of mental health needed to reduce smoking rates in the United States. PMID- 24172831 TI - The diversity and abundance of polychaetes (Annelida) are altered in sediments impacted by alumina refinery discharge in the Northern Territory, Australia. AB - We collected polychaete diversity and abundance data at a range of impacted and reference sites near an alumina refinery in Melville Bay, northern Australia. The aims were to measure the impact of sediment modified by the alumina refinery discharge on polychaete communities and secondly to gather baseline data from which to measure future changes. Polychaete communities in both soft-bottom habitats and subtidal areas adjacent to mangrove forests were studied. We also developed and deployed an artificial substratum device to sample polychaetes associated with hard-substrate habitats. For each habitat, polychaete community composition was different between impacted and reference sites and at multiple time points. The impact of future changes either from bioremediation or management practices can be measured against these baseline data. Indicator species analysis was used to identify polychaete species that were significantly different at the locations tested, and we discuss their potential as indicator species. PMID- 24172832 TI - Differences in DNA methylation by extent of breast cancer family history in unaffected women. AB - Breast cancer clusters within families but genetic factors identified to date explain only a portion of this clustering. Lower global DNA methylation in white blood cells (WBC) has been associated with increased breast cancer risk. We examined whether WBC DNA methylation varies by extent of breast cancer family history in unaffected women from high-risk breast cancer families. We evaluated DNA methylation levels in LINE-1, Alu and Sat2 in 333 cancer-free female family members of the New York site of the Breast Cancer Family Registry, the minority of which were known BRCA1 or BRCA2 mutation carriers. We used generalized estimated equation models to test for differences in DNA methylation levels by extent of their breast cancer family history after adjusting for age. All unaffected women had at least one sister affected with breast cancer. LINE-1 and Sat2 DNA methylation levels were lower in individuals with 3 or more (3+) first degree relatives with breast cancer relative to women with only one first-degree relative. For LINE-1, Alu, and Sat2, having 3+ affected first-degree relatives was associated with a decrease of 23.4% (95%CI = -46.8%, 0.1%), 17.9% (95%CI = 39.5%, 3.7%) and 11.4% (95% CI = -20.3%, -2.5%), respectively, relative to individuals with only one affected first-degree relative, but the results were only statistically significant for Sat2. Individuals having an affected mother had 17.9% lower LINE-1 DNA methylation levels (95% CI = -28.8%, -7.1%) when compared with those not having an affected mother. No associations were observed for Alu or Sat2 by maternal breast cancer status. If replicated, these results indicate that lower global WBC DNA methylation levels in families with extensive cancer histories may be one explanation for the clustering of cancers in these families. Family clustering of disease may reflect epigenetic as well as genetic and shared environmental factors. PMID- 24172833 TI - The effects of antegrade cerebral perfusion on immediate postoperative outcome in neonatal and infant aortic arch repair concomitant with intracardiac surgery. PMID- 24172834 TI - Assessment of cardio-ankle vascular index in patients with cardiac syndrome-X: an observational study. AB - OBJECTIVE: Arterial stiffness is associated with major adverse cardiovascular events. Cardio-ankle vascular index (CAVI), a novel marker of arterial stiffness, which is weakly influenced by systolic blood pressure, is a sensitive marker the atherosclerosis and arteriolosclerosis. The aim of this study is to investigate arterial stiffness by CAVI in patients with cardiac syndrome X (CSX). METHODS: The present study was observational and cross sectional, and involved 49 patients (26 male) with CSX (angina-like chest pain, positive electrocardiographic ischemic changes at treadmill exercise test, angiographically normal coronary arteries) and 54 healthy subjects (21 male). CAVI was measured by VaSera-1000 CAVI instrument. Statistical analysis was performed using the Chi-square, Student t-test, correlation analysis and logistic regression analysis. RESULTS: The CAVI and pulse pressure were significantly increased in patients with CSX compared to control group (7.50 +/- 1.50, 6.49 +/- 0.77, p<0.001; 53.00 +/- 10.06, 47.39 +/- 8.17, p=0.002, consecutively). In contrast, there were no significant differences in the age, weight, height, body mass index, waist circumference, hip circumference, systolic blood pressure, diastolic blood pressure, mean blood pressure, glucose, low density lipoprotein level, high density lipoprotein level, triglyceride, estimated creatinine clearance, hemoglobin, left atrium diameter, left ventricular mass, LVM index and ejection fraction. CAVI was the only independent predictor of CSX in logistic regression analysis (OR=1.780, 95% CI: 1.157-2.737, p=0.009). CONCLUSION: CAVI is increased in syndrome X patients and is an independent predictor of this syndrome. PMID- 24172835 TI - Relationship of QT dispersion with sex hormones and insulin in young women with polycystic ovary syndrome: an observational study. AB - OBJECTIVE: Polycystic ovary syndrome (PCOS) is a common endocrinopathy in reproductive women. Cardiovascular disease risk factors are more frequent in this population. We aimed in this study to investigate presence of QT dispersion and effects of sex hormones and insulin on QT duration in young PCOS patients. METHODS: This present study was cross-sectional observational study. A total of 47 women, 25 patients with PCOS and 22 healthy, were included. Serum testosterone, estradiol and insulin levels were studied and electrocardiography was performed at 2nd or 3th days of menstrual cycle. The study population was divided into groups according to serum testosterone and estradiol levels. Sub groups and pairwise groups were compared by Mann-Whitney U or student t-test. The associations of QTc durations with hormone levels were calculated using Spearman rank correlation analysis. The results were evaluated at the p<0.05 significance level. RESULTS: No differences found between groups regarding to demographic parameters. Estradiol and testosterone levels were higher in patients with PCOS (41.12 +/- 13.59 vs. 35.57 +/- 19.29 pg/mL, p=0.09 and 105 +/- 58.5 vs. 17.6 +/- 10.9 ng/dL, p=0.01, respectively). QT dispersion was significantly longer in PCOS patients (47.1 vs. 32.7 ms, p=0.01). A positive correlation was found between the serum insulin level and QTc min, QTc max, and QTc mean (r=0.402, p=0.011; r=0.341, p=0.033; r=0.337, p=0.036; respectively). QT dispersion with serum testosterone and estradiol levels were positively correlated (r=0.525, p=0.001 and r=0.326, p=0.046; respectively). CONCLUSION: Our results suggest that QT dispersion is prolonged and testosterone, estradiol and insulin are associated with QT duration in young PCOS patients. PMID- 24172836 TI - Predictors of functional capacity in younger and elderly chronic heart failure patients: an observational study. AB - OBJECTIVE: The prevalence of chronic heart failure (CHF) in the elderly population is growing. Identification of risk factors in patients with CHF is important. Recent studies suggest that red cell distribution width (RDW) has prognostic significance in these patients. We aimed to evaluate the relationship of RDW with clinical and laboratory parameters in patients with young and elderly CHF patients. METHODS: We evaluated patients with CHF with an ejection fraction (EF) of <50% in this observational cross-sectional study. Exclusion criteria were decompensated CHF, malignancy and end-stage renal disease. Clinical information, functional capacity (FC), hemoglobin, RDW, EF, and pro-B type natriuretic peptide (proBNP) were recorded. The younger and elderly groups were compared and correlation of RDW with clinical and laboratory parameters were analyzed in each group. Ordinal regression analysis was performed to determine independent correlates of increased FC. RESULTS: Seventy young and 47 elderly cases were enrolled. The groups were similar regarding EF, proBNP and FC. RDW showed stronger correlation with FC in the young group (r=0.627, p<0.001) compared to the elderly group (r=0.332, p=0.023). In the younger group, there was a negative correlation between RDW and EF (r=-0.278, p=0.021) and a positive correlation between RDW and proBNP (r=0.487, p<0.001). RDW (OR=16.36, 95% CI 0.33-0.96, p<0.001), EF [OR=7.75, 95% CI (-0.16)-(-0.03), p=0.005] and usage of RAS inhibitors (OR=6.7, 95% CI 0.57-3.36, p=0.007) were independent predictors of increased FC. CONCLUSION: We found a stronger correlation between RDW and EF, proBNP and FC in the younger patients compared the elderly group. RDW is a simple, inexpensive and easily accessible parameter that may be considered risk predictor especially in younger patients with CHF. PMID- 24172837 TI - The evaluation of relationship between adiponectin levels and epicardial adipose tissue thickness with low cardiac risk in Gilbert's syndrome: an observational study. AB - OBJECTIVE: Atherosclerotic heart diseases are less frequently seen in patients with Gilbert's syndrome (GS). We aimed to investigate whether serum adiponectin (APN) and epicardial adipose tissue (EAT) thickness have an effect beside the antioxidant effect of bilirubin in lowering the incidence of the atherosclerotic process. METHODS: Sixty-eight patients diagnosed with GS (39 females and 29 males) who had applied at the internal medicine clinic of the hospital were included in this cross-sectional, observational study. The control group included 63 healthy people (39 females and 24 males). EAT thickness was measured by echocardiography. The serum APN levels were also checked. Statistical analysis was performed by using independent sample t-test, Pearson correlation and linear regression analyses. RESULTS: The mean age of the GS group was 28 +/- 9 years, and the average EAT thickness was found to be 2.5 +/- 0.1 mm. The mean age of the control group was 26 +/- 6 years, and the average EAT thickness was found to be 4.2 +/- 0.5 mm. When comparing the two groups, the EAT thickness of the GS group was found to be significantly lower (p<0.001) than that of the control group. In the GS group the APN was 14.9 +/- 4.2 mg/L, and in the control group the APN was 12.6 +/- 4.5 mg/L (p<0.022). We found that total bilirubin (beta=-1,607, p<0,001) and indirect bilirubin (beta=1,086, p<0,001) have an independent association with decreased EAT thickness. CONCLUSION: EAT thickness is associated with coronary atherosclerosis. Low EAT thickness may be related with low release of proinflammatory cytokine. High levels of APN may be related high anti inflammatory effect. Therefore, low EAT thickness and high levels of APN may demonstrate protective effect on atherosclerotic heart diseases in GS patients. PMID- 24172838 TI - Position-sensitive spectral splitting with a plasmonic nanowire on silicon chip. AB - On-chip nanophotonics serves as the foundation for the new generation of information technology, but it is challenged by the diffraction limit of light. With the capabilities of confining light into (deep) subwavelength volumes, plasmonics makes it possible to dramatically miniaturize optical devices so as to integrate them into silicon chips. Here we demonstrate that by cascading nano corrugation gratings with different periodicities on silver nanowires atop silicon, different colors can be spatially separated and chronologically released at different grating junctions. The released light frequency depends on the grating arrangement and corrugation periodicities. Hence the nanowire acts as a spectral splitter for sorting/demultiplexing photons at different nano-scale positions with a ten-femtosecond-level interval. Such nanowires can be constructed further into compact 2D networks or circuits. We believe that this study provides a new and promising approach for realizing spatiotemporal sensitive spectral splitting and optical signal processing on nanoscales, and for general integration of nanophotonics with microelectronics. PMID- 24172839 TI - Acute toxic effects of 3,3'-iminodipropionitrile on hypothalamic-pituitary gonadal axis in male rats. AB - Exposure to 3,3'-iminodipropionitrile (IDPN) causes persistent neurotoxicity, while its reproductive toxicity in female rats is transient, indicating that gonadotropin-releasing hormone (GnRH) neurons and gonadotrophs receive little or no damage from IDPN and that the transient gonadal toxicity may be also observed in males. To clarify these points, the acute toxic effects of IDPN on hypothalamic-pituitary-gonadal axis of male rats were examined histologically, biochemically and serologically. A single intraperitoneal injection of IDPN (1000 mg/kg body weight) induced signs of neurotoxicity within a day; nevertheless, GnRH neurons were not affected throughout the experimental period. Four days after IDPN treatment, the plasma level of testosterone but not gonadotropins decreased and active caspase 3-immunopositive spermatids increased; both parameters returned to normal levels afterwards. Data from our studies revealed that while IDPN had little or no toxic effect on GnRH neurons or gonadotrophs it was transiently toxic to gonads in both sexes. PMID- 24172840 TI - Cytomegalovirus infection in preterm triplets transmitted via breast milk. AB - Cytomegalovirus (CMV) may transmit perinatally or from breast milk. The risk for development of symptomatic CMV disease in very-low-birth-weight premature infants after transmission from maternal breast milk is not clear. There are scarce data in the literature about congenital CMV infection in multiple pregnancies, being mostly with twin gestations. Here we present a unique case of triplets with CMV infection transmitted via breast milk. PMID- 24172841 TI - Experimental models of chronic subdural hematoma. AB - OBJECTIVES: Chronic subdural hematoma (CSDH) is a common neurosurgical problem. Most studies of pathogenesis and treatment involve humans. Advances in understanding of human diseases may be made using animal models. We reviewed all animal models of CSDH and report here their results, conclusions and limitations in order to set a baseline upon which further advanced experimental work related to this disease can be made. METHODS: PubMed, Medline, Embase and ISI Web of Knowledge were searched with no time limits using the keyword 'chronic subdural hematoma' and MeSH term 'hematoma, subdural, chronic'. The authors reviewed all papers written related to this disease and selected all publications involving animals. There were no other restrictions. The findings and conclusions of the papers are summarized here. No formal analysis was done because of the variation in species used, methods for induction of CSDH, times of assessment and reporting of results. RESULTS: Attempts to create CSDH have been made in mice, rats, cats, dogs and monkeys. Methods include injection or surgical implantation of clotted blood or various other blood products and mixtures into the potential subdural space or the subcutaneous space. No intracranial model produced a progressively expanding CSDH. Transient hematoma expansion with liquification could be produced by subcutaneous injections in some models. Spontaneous subdural blood collections were found after creation of hydrocephalus in mice by systemic injection of the neurotoxin, 6-aminonicotinamide. The histology of the hematoma membranes in several models resembles the appearance in humans. None of the models has been replicated since its first description. DISCUSSION: We did not find a report of a reproducible, well-described animal model of human CSDH. PMID- 24172842 TI - A naturalistic, randomized, controlled trial combining cognitive remediation with cognitive-behavioural therapy after first-episode non-affective psychosis. AB - BACKGROUND: Cognitive remediation (CR) preceding cognitive-behavioural therapy for psychosis (CBTp) was trialled within routine clinical services, with the hypothesis that following first-episode non-affective psychosis CR would enhance CBTp efficacy by improving neuropsychological performance. METHOD: A total of 61 patients with DSM-IV non-affective psychoses waiting for routine CBTp were randomized to computerized CR over 12 weeks, supported by a trained support worker, or time-matched social contact (SC). Primary outcome was the blind-rated Psychotic Symptoms Rating Scale (PSYRATS). Secondary outcomes included measures of CBTp progress, cognition, symptoms, insight and self-esteem: all at baseline, after CR (12 weeks) and after CBTp (42 weeks). PSYRATS and global neuropsychological efficacy were tested using mixed-effects models with a group * time interaction term. Measures of CBTp progress and some neuropsychological measures were modelled by regression. RESULTS: There was no significant difference between the CR and SC groups in PSYRATS (group * time coefficient 0.3, 95% confidence interval -0.4 to 1.1, p = 0.39). However, after CR CBTp was shorter [median 7 sessions, interquartile range (IQR) 2-12 after CR; median 13, IQR 4-18 after SC; model p = 0.011] and linked to better insight (p = 0.02). Global cognition did not improve significantly more after CR (p = 0.20) but executive function did (Wisconsin Card Sort, p = 0.012). CONCLUSIONS: CBTp courses preceded by CR were far shorter but achieved the same outcome as CBTp preceded by an active control, consistent with neuropsychological improvement enhancing CBTp. CR was delivered by staff with minimal training, offering the potential to reduce the costs of CBTp considerably. PMID- 24172843 TI - Assessment of apixaban plasma levels by laboratory tests: suitability of three anti-Xa assays. A multicentre French GEHT study. AB - While laboratory monitoring is not required in patients treated with apixaban, a direct factor-Xa inhibitor, assessment of its concentration is useful in some critical situations. However, few data are available on its effect on coagulation tests and on the suitability of anti-Xa assays for its quantification. It was the objective of this study to identify laboratory tests suitable for apixaban concentration assessment. Coagulation tests - PT and aPTT- and anti-Xa assays were performed in apixaban-spiked plasma samples. To evaluate the sensitivity of PT and aPTT to apixaban, we conducted a first monocenter part, with a wide range of concentrations (50-1,000 ng/ml), a large panel of reagents (20 reagents), and two coagulometers (STAR(r), Stago and ACL TOP(r), IL), and a second multicenter part involving 13 laboratories using either a common PT reagent (RecombiPlastin2G(r)) or the local PT and aPTT reagents. In the multicentre part, five blinded apixaban-spiked plasma samples (0/100/200/400/800 ng/ml - checked by HPLC-MS/MS) were used; apixaban concentrations were measured with three anti-Xa assays, apixaban calibrators and controls (Stago). PT and aPTT tests using a large panel of reagents displayed a low sensitivity to a wide range of apixaban concentrations. The concentrations to double PT ranged from 400 to >1,000 ng/ml with the 10 reagents. With the three anti-Xa assays, inter-laboratory precision and accuracy were below 11% and 12%, respectively. In conclusion, whereas PT and aPTT tests were not sensitive enough to detect apixaban, the three anti-Xa assays tested using lyophilised apixaban calibrators and controls allowed to reliably quantify a wide range of apixaban concentrations. PMID- 24172845 TI - Pulmonary M. tuberculosis infection delays Th1 immunity via immunoadaptor DAP12 regulated IRAK-M and IL-10 expression in antigen-presenting cells. AB - Interaction of mycobacteria with the host leads to retarded expression of T helper cell type 1 (Th1) immunity in the lung. However, the immune mechanisms remain poorly understood. Using in vivo and in vitro models of Mycobacterium tuberculosis (M. tb) infection, we find the immunoadaptor DAP12 (DNAX-activating protein of 12 kDa) in antigen-presenting cells (APCs) to be critically involved in this process. Upon infection of APCs, DAP12 is required for IRAK-M (interleukin-1 receptor-associated kinase M) expression, which in turn induces interleukin-10 (IL-10) and an immune-suppressed phenotype of APCs, thus leading to suppressed Th1 cell activation. Lack of DAP12 reduces APC IL-10 production and increases their Th1 cell-activating capability, resulting in expedited Th1 responses and enhanced protection. On the other hand, adoptively transferred DAP12-competent APCs suppress Th1 cell activation within DAP12-deficient hosts, and blockade of IL-10 aborts the ability of DAP12-competent APCs to suppress Th1 activation. Our study identifies the DAP12/IRAK-M/IL-10 to be a novel molecular pathway in APCs exploited by mycobacterial pathogens, allowing infection a foothold in the lung. PMID- 24172846 TI - Oxidative stress-mediated iNKT-cell activation is involved in COPD pathogenesis. AB - Chronic obstructive pulmonary disease (COPD) is a major clinical challenge mostly due to cigarette smoke (CS) exposure. Invariant natural killer T (iNKT) cells are potent immunoregulatory cells that have a crucial role in inflammation. In the current study, we investigate the role of iNKT cells in COPD pathogenesis. The frequency of activated NKT cells was found to be increased in peripheral blood of COPD patients relative to controls. In mice chronically exposed to CS, activated iNKT cells accumulated in the lungs and strongly contributed to the pathogenesis. The detrimental role of iNKT cells was confirmed in an acute model of oxidative stress, an effect that depended on interleukin (IL)-17. CS extracts directly activated mouse and human dendritic cells (DC) and airway epithelial cells (AECs) to trigger interferongamma and/or IL-17 production by iNKT cells, an effect ablated by the anti-oxidant N-acetylcystein. In mice, this treatment abrogates iNKT-cell accumulation in the lung and abolished the development of COPD. Together, activation of iNKT cells by oxidative stress in DC and AECs participates in the development of experimental COPD, a finding that might be exploited at a therapeutic level. PMID- 24172847 TI - IL-1alpha released from damaged epithelial cells is sufficient and essential to trigger inflammatory responses in human lung fibroblasts. AB - Activation of the innate immune system plays a key role in exacerbations of chronic lung disease, yet the potential role of lung fibroblasts in innate immunity and the identity of epithelial danger signals (alarmins) that may contribute to this process are unclear. The objective of the study was to identify lung epithelial-derived alarmins released during endoplasmic reticulum stress (ER stress) and oxidative stress and evaluate their potential to induce innate immune responses in lung fibroblasts. We found that treatment of primary human lung fibroblasts (PHLFs) with conditioned media from damaged lung epithelial cells significantly upregulated interleukin IL-6, IL-8, monocyte chemotactic protein-1, and granulocyte macrophage colony-stimulating factor expression (P<0.05). This effect was reduced with anti-IL-1alpha or IL-1Ra but not anti-IL-1beta antibody. Costimulation with a Toll-like receptor 3 ligand, polyinosinic-polycytidylic acid (poly I:C), significantly accentuated the IL 1alpha-induced inflammatory phenotype in PHLFs, and this effect was blocked with inhibitor of nuclear factor kappa-B kinase subunit beta and TGFbeta-activated kinase-1 inhibitors. Finally, Il1r1-/- and Il1a-/- mice exhibit reduced bronchoalveolar lavage (BAL) neutrophilia and collagen deposition in response to bleomycin treatment. We conclude that IL-1alpha plays a pivotal role in triggering proinflammatory responses in fibroblasts and this process is accentuated in the presence of double-stranded RNA. This mechanism may be important in the repeated cycles of injury and exacerbation in chronic lung disease. PMID- 24172848 TI - Early-life exposure to combustion-derived particulate matter causes pulmonary immunosuppression. AB - Elevated levels of combustion-derived particulate matter (CDPM) are a risk factor for the development of lung diseases such as asthma. Studies have shown that CDPM exacerbates asthma, inducing acute lung dysfunction and inflammation; however, the impact of CDPM exposure on early immunological responses to allergens remains unclear. To determine the effects of early-life CDPM exposure on allergic asthma development in infants, we exposed infant mice to CDPM and then induced a mouse model of asthma using house dust mite (HDM) allergen. Mice exposed to CDPM+HDM failed to develop a typical asthma phenotype including airway hyper responsiveness, T-helper type 2 (Th2) inflammation, Muc5ac expression, eosinophilia, and HDM-specific immunoglobulin (Ig) compared with HDM-exposed mice. Although HDM-specific IgE was attenuated, total IgE was twofold higher in CDPM+HDM mice compared with HDM mice. We further demonstrate that CDPM exposure during early life induced an immunosuppressive environment in the lung, concurrent with increases in tolerogenic dendritic cells and regulatory T cells, resulting in the suppression of Th2 responses. Despite having early immunosuppression, these mice develop severe allergic inflammation when challenged with allergen as adults. These findings demonstrate a mechanism whereby CDPM exposure modulates adaptive immunity, inducing specific antigen tolerance while amplifying total IgE, and leading to a predisposition to develop asthma upon rechallenge later in life. PMID- 24172849 TI - Mesenchymal stem cell therapy induces glucocorticoid synthesis in colonic mucosa and suppresses radiation-activated T cells: new insights into MSC immunomodulation. AB - Non-neoplastic tissues around an abdomino-pelvic tumor can be damaged by the radiotherapy protocol, leading to chronic gastrointestinal complications that affect the quality of life with substantial mortality. Stem cell-based approaches using immunosuppressive bone marrow mesenchymal stem cells (MSCs) are promising cell therapy tools. In a rat model of radiation proctitis, we evidenced that a single MSC injection reduces colonic mucosa damages induced by ionizing radiation with improvement of the re-epithelization process for up to 21 days. Immune cell infiltrate and inflammatory molecule expressions in the colonic mucosa were investigated. We report that MSC therapy specifically reduces T-cell infiltration and proliferation, and increases apoptosis of radiation-activated T cells. We assessed the underlying molecular mechanisms and found that interleukin-10 and regulatory T lymphocytes are not involved in the immunosuppressive process in this model. However, an increased level of corticosterone secretion and HSD11b1 (11beta-hydroxysteroid dehydrogenase type 1)-steroidogenic enzyme expression was detected in colonic mucosa 21 days after MSC treatment. Moreover, blocking the glucocorticoid (GC) receptor using the RU486 molecule statistically enhances the allogenic lymphocyte proliferation inhibited by MSCs in vitro and abrogates the mucosal protection induced by MSC treatment in vivo. Using the irradiation model, we found evidence for a new MSC immunosuppressive mechanism involving GCs. PMID- 24172850 TI - Parapneumonic pleural effusions caused by Streptococcus pneumoniae serotype 3 in children immunized with 13-valent conjugated pneumococcal vaccine. AB - During 2012, Streptococcus pneumoniae serotype 3 was identified by polymerase chain reaction in 15 out of 20 (75%) pleural fluid specimens from children with pneumococcal pneumonia complicated by parapneumonic pleural effusion in Greece. One-third of these children had been immunized with the 13-valent conjugated pneumococcal vaccine after the age of 12 months, according to the national immunization schedule. PMID- 24172851 TI - Inhalation solutions--which ones may be mixed? Physico-chemical compatibility of drug solutions in nebulizers--update 2013. AB - Many patients suffering from chronic respiratory diseases rely on inhalation therapy with nebulizers. About 25% of patients who need to inhale several different drugs per day save time by mixing them for simultaneous inhalation. This review presents a comprehensive overview of the available data concerning physico-chemical compatibility of commonly mixed nebulizer solutions and suspensions. Information is based on our in vitro studies and a thorough literature search. Results indicate that many nebulizer solutions/suspensions are mixable without provoking incompatibilities. However, certain excipients contained in some of the tested drug products could be identified as a reason for incompatibilities, e.g. impaired activity of dornase alfa. Studies assessing the aerosol characteristics of compatible mixtures nebulized with commonly used nebulizers are limited and should be encouraged. The clinical efficacy of simultaneous inhalation of duplicate, tripartite or quadripartite mixtures must be evaluated in clinical studies before final recommendations for the inhalation regimens can be made. PMID- 24172852 TI - Interpretive flexibility in mobile health: lessons from a government-sponsored home care program. AB - BACKGROUND: Mobile technologies have emerged as important tools that health care personnel can use to gain easy access to client data anywhere. This is particularly useful for nurses and care workers in home health care as they provide services to clients in many different settings. Although a growing body of evidence supports the use of mobile technologies, the diverse implications of mobile health have yet to be fully documented. OBJECTIVE: Our objective was to examine a large-scale government-sponsored mobile health implementation program in the Danish home care sector and to understand how the technology was used differently across home care agencies. METHODS: We chose to perform a longitudinal case study with embedded units of analysis. We included multiple data sources, such as written materials, a survey to managers across all 98 Danish municipalities, and semistructured interviews with managers, care workers, and nurses in three selected home care agencies. We used process models of change to help analyze the overall implementation process from a longitudinal perspective and to identify antecedent conditions, key events, and practical outcomes. RESULTS: Strong collaboration between major stakeholders in the Danish home care sector (government bodies, vendors, consultants, interest organizations, and managers) helped initiate and energize the change process, and government funding supported quick and widespread technology adoption. However, although supported by the same government-sponsored program, mobile technology proved to have considerable interpretive flexibility with variation in perceived nature of technology, technology strategy, and technology use between agencies. What was first seen as a very promising innovation across the Danish home care sector subsequently became the topic of debate as technology use arrangements ran counter to existing norms and values in individual agencies. CONCLUSIONS: Government-sponsored programs can have both positive and negative results, and managers need to be aware of this and the interpretive flexibility of mobile technology. Mobile technology implementation is a complex process that is best studied by combining organization-level analysis with features of the wider sociopolitical and interorganizational environment. PMID- 24172853 TI - Atomic distribution, local structure and cation size effect in o-R1-xCaxMnO3 (R = Dy, Y, and Ho). AB - We propose new interatomic potentials for the small rare-earth-based orthorhombic RMnO3 (R = Dy, Y, Ho), which accurately model the structural properties of these extreme cases of lanthanide manganate series. They are further employed to investigate the intrinsic defects in o-RMnO3 and the cation distribution and local structure in o-R1-xCaxMnO3 (R = Dy, Y, Ho). Schottky disorders are found to be the dominant structural defects, and the possibility of a small degree of anti site disorder of R and Mn ions over A and B sites is found. The introduced Ca dopants tend to form chemically and structurally like CaMnO3 clusters in the lightly doped system, which can be regarded as representations of microscopic phase separation. The local structural disorder is reduced with increasing doping density. For o-R0.5Ca0.5MnO3 (R = Dy, Y, Ho), the charge ordering state is intrinsically favored, and the layer stripe model is shown to be energetically more favorable and structurally more reasonable. Moreover, the tendency to form charge ordered stripes increases with the decrease of R size. The local structure in the layer stripe pattern deviates largely from the average structure: RMnO3 like and CaMnO3-like layers are formed. The size of R ion has a significant influence on the doping effect on Jahn-Teller (JT) distortion and a manganate with a larger R will experience a larger reduction on the anisotropy of Mn-O bonds in Mn(3+)O6 octahedra. However, the change of octahedral tilting upon doping does not vary much with R radii. PMID- 24172854 TI - Role of Montgomery T-tube stent for laryngotracheal stenosis. AB - OBJECTIVE: To identify the indications, complications and outcome of patients of LTS managed with Montgomery T-tube stenting and review the current literature about the role of stenting in LTS. METHODS: Retrospective chart reviews of 39 patients of laryngotracheal stenosis managed by T-tube stenting for temporary or definitive treatment during the period 2004-2011 were considered. The data on indications for stenting, type of stent, problems/complications of stenting, duration of stenting, additional intervention and outcome of management were collected, tabulated and analyzed. RESULTS: Of the 51 cases of laryngotracheal stenosis 39 patients were treated by Montgomery T-tube stenting. There was no mortality associated with the procedure or stenting. 82% of the patients were successfully decannulated. The problems and complications encountered were crusting within the tube in 44% and granulation at the subglottis in 33%. Two patients had complication due to T-tube itself: One patient developed tracheomalacia and the other had stenosis at both ends of the T-tube. CONCLUSION: Stenting still has a role in management of inoperable or in some deadlock situations where resection anastomosis is not feasible. It is easier to introduce the stent and to maintain it. Complications are minor and can be managed easily. It is safe for long term use. We emphasize that the treating surgeon needs to use prudence while treating stenosis using stents. PMID- 24172855 TI - A photo-degradable gene delivery system for enhanced nuclear gene transcription. AB - There currently exists a significant gap in our understanding of how the detailed chemical characteristics of polycation gene carriers influence their delivery performances in overcoming an important cellular-level transport barrier, i.e., intranuclear gene transcription. In this study, a UV-degradable gene carrier material (ENE4-1) was synthesized by crosslinking low molecular weight branched polyethylenimine (bPEI-2k) molecules using UV-cleavable o-nitrobenzyl urethane (NBU) as the linker molecule. NBU degrades upon exposure to mild UV irradiation. Therefore, this UV-degradable carrier allows us to control the chemical characteristics of the polymer/DNA complex (polyplex) particles at desired locations within the intracellular environment. By using this photolytic DNA carrier, we found that the exact timing of the UV degradation significantly influences the gene transfection efficiencies of ENE4-1/DNA(pGL2) polyplexes in HeLa cells. Interestingly, even if the polyplexes were UV-degraded at different intracellular locations/times, their nuclear entry efficiency was not influenced by the location/timing of UV degradation. The UV treatment did not influence the size or binding strength of the polyplexes. However, we confirmed that the degradation of the carrier molecules impacts the chemical characteristics of the polyplexes (it produces carbamic acid and nitrosobenzyl aldehyde groups on ENE4 1). We believe that these anionic acid groups enhance the interaction of the polyplexes with nuclear transcription proteins and thus the final gene expression levels; this effect was found to occur, even though UV irradiation itself has a general effect of reducing transfection efficiencies. Excess (uncomplexed) ENE4-1 polymers appear to not play any role in the UV-enhanced gene transcription phenomenon. PMID- 24172856 TI - The effect of multivalent Sonic hedgehog on differentiation of human embryonic stem cells into dopaminergic and GABAergic neurons. AB - Stem cell differentiation is regulated by complex repertoires of signaling ligands which often use multivalent interactions, where multiple ligands tethered to one entity interact with multiple cellular receptors to yield oligomeric complexes. One such ligand is Sonic hedgehog (Shh), whose posttranslational lipid modifications and assembly into multimers enhance its biological potency, potentially through receptor clustering. Investigations of Shh typically utilize recombinant, monomeric protein, and thus the impact of multivalency on ligand potency is unexplored. Among its many activities, Shh is required for ventralization of the midbrain and forebrain and is therefore critical for the development of midbrain dopaminergic (mDA) and forebrain gamma-aminobutyric acid (GABA) inhibitory neurons. We have designed multivalent biomaterials presenting Shh in defined spatial arrangements and investigated the role of Shh valency in ventral specification of human embryonic stem cells (hESCs) into these therapeutically relevant cell types. Multivalent Shh conjugates with optimal valencies, compared to the monomeric Shh, increased the percentages of neurons belonging to mDA or forebrain GABAergic fates from 33% to 60% or 52% to 86%, respectively. Thus, multivalent Shh bioconjugates can enhance neuronal lineage commitment of pluripotent stem cells and thereby facilitate efficient derivation of neurons that could be used to treat Parkinson's and epilepsy patients. PMID- 24172857 TI - Comprehensive genomic analyses of a metastatic colon cancer to the lung by whole exome sequencing and gene expression analysis. AB - We performed whole exome sequencing and gene expression analysis on a metastatic colon cancer to the lung, along with the adjacent normal tissue of the lung. Whole exome sequencing uncovered 71 high-confidence non-synonymous mutations. We selected 16 mutation candidates, and 13 out of 16 mutations were validated by targeted deep sequencing using the Ion Torrent PGM customized AmpliSeq panel. By integrating mutation, copy number and gene expression microarray data, we identified a JAZF1 mutation with a gain-of-copy, suggesting its oncogenic potential for the lung metastasis from colon cancer. Our pathway analyses showed that the identified mutations closely reflected characteristics of the metastatic site (lung) while mRNA gene expression patterns kept genetic information of its primary tumor (colon). The most significant gene expression network was the 'Colorectal Cancer Metastasis Signaling', containing 6 (ADCY2, ADCY9, APC, GNB5, K-ras and LRP6) out of the 71 mutated genes. Some of these mutated genes (ADCY9, ADCY2, GNB5, K-ras, HDAC6 and ARHGEF17) also belong to the 'Phospholipase C Signaling' network, which suggests that this pathway and its mutated genes may contribute to a lung metastasis from colon cancer. PMID- 24172858 TI - A dealloying process of core-shell Au@AuAg nanorods for porous nanorods with enhanced catalytic activity. AB - One-dimensional porous metallic nanomaterials have attracted much attention due to their unique shape and hollow structure. Herein, the gold nanorods in a porous shell of an AuAg alloy are synthesized via a dealloying process of the core-shell Au@AuAg nanorods at room temperature. The formation of tiny pores in the shell results in the huge red-shift, sharp decrease and drastic broadening of longitudinal surface plasmon resonance absorption. The continuous removal of silver from the porous nanorods leads to the breakage of tiny pores and leaves a rough surface on the nanorods behind. The rough surface gradually becomes smooth in the subsequent dealloying process. The surface structures of these intermediates are correlated with their absorption spectra and catalytic activities for the catalytic reduction of p-nitrophenol. The porous nanorods show a higher catalytic efficiency than the gold nanorods, the core-shell nanorods and the rough nanorods. The results indicate that the dealloying of anisotropic bimetal nanomaterials not only provides an effective pathway to carve the structures on the nanoscale but also offers numerous opportunities to observe novel optical properties and enhanced catalysis performances. PMID- 24172859 TI - The PPARbeta agonist L-165041 promotes VEGF mRNA stabilization in HPV18-harboring HeLa cells through a receptor-independent mechanism. AB - Peroxisome Proliferator-Activated Receptor-beta (PPARbeta) is a ligand-inducible transcription factor activated by both natural (fatty acids and derivatives) and high affinity synthetic agonists. It is thought to play a role in angiogenesis development and Vascular Endothelial Growth Factor (VEGF) regulation but its contribution remains unclear. Until now, the PPARbeta agonism effect on VEGF expression in cervical cancer cells was unknown. This led to our interest in assessing the effect of PPARbeta activation on the regulation of different VEGF isoforms mRNA expression and the impact of E6 viral oncoprotein and its target p53 on this regulation in cervical cancer cells. Here, we showed that the PPARbeta agonist L-165041 induces VEGF(121), VEGF(165) and VEGF(189) expression in HPV (Human Papillomavirus) positive HeLa cells but not in HPV negative cells. The underlying mechanisms did involve neither E6 oncoprotein nor p53. We highlighted a novel mode of PPARbeta ligand action including a post transcriptional regulation of VEGF mRNA expression through the p38 MAPK signaling pathway and the activation of the mRNA-stabilizing factor HuR. But most importantly, we clearly demonstrated that L-165041 acts independently of PPARbeta since its effect was not reversed by a chemical inhibition with a specific antagonist and the siRNA-mediated knockdown of the nuclear receptor. As VEGF is crucial for cancer development, the impact of PPARbeta ligands on VEGF production is of high importance. Thus, the molecular mechanism of their action has to be elucidated and as a result, PPARbeta agonists currently in clinical trials should be carefully monitored. PMID- 24172860 TI - Anfibatide, a novel GPIb complex antagonist, inhibits platelet adhesion and thrombus formation in vitro and in vivo in murine models of thrombosis. AB - Platelet adhesion and aggregation at the sites of vascular injury are key events for thrombosis and haemostasis. It has been well demonstrated that interaction between glycoprotein (GP) Ibalpha and von Willebrand factor (VWF) initiates platelet adhesion and contributes to platelet aggregation, particularly at high shear. GPIb has long been suggested as a desirable antithrombotic target, but anti-GPIb therapy has never been successfully developed. Here, we evaluated the antithrombotic potential of Anfibatide, a novel snake venom-derived GPIb antagonist.We found Anfibatide inhibited washed murine platelet aggregation induced by ristocetin and recombinant murine VWF. It also blocked botrocetin induced binding of murine plasma VWF to recombinant human GPIbalpha. Interestingly, Anfibatide did not inhibit botrocetin-induced aggregation of platelet-rich plasma, indicating that its binding site may differ from other snake venom-derived GPIb antagonists. Anfibatide strongly inhibited platelet adhesion, aggregation, and thrombus formation in perfusion chambers at high shear conditions and efficiently dissolved preformed thrombi. Anfibatide also inhibited thrombus growth at low shear conditions, though less than at high shear. Using intravital microscopy, we found that Anfibatide markedly inhibited thrombosis in laser-injured cremaster vessels and prevented vessel occlusion in FeCl3-injured mesenteric vessels. Importantly, Anfibatide further inhibited residual thrombosis in VWF-deficient mice, suggesting that Anfibatide has additional antithrombotic effect beyond its inhibitory role in GPIb-VWF interaction. Anfibatide did not significantly cause platelet activation, prolong tail bleeding time, or cause bleeding diathesis in mice. Thus, consistent with the data from an ongoing clinical trial, the data from this study suggests that Anfibatide is a potent and safe antithrombotic agent. PMID- 24172861 TI - Coxsackievirus A6-induced hand-foot-mouth disease. AB - IMPORTANCE: Hand-foot-mouth disease (HFMD) is an acute, self-limited, highly contagious viral illness that commonly affects children younger than 5 years. It is most typically caused by enterovirus 71 or coxsackievirus A16 and results in asymptomatic infection or mild disease. Immunocompetent adults are rarely affected. Recently, there have been increasing reports of a more severe form of HFMD associated with fevers, joint pains, and widespread painful eruptions. Some of these patients required hospitalization for supportive care. These severe cases were most commonly caused by coxsackievirus A6. OBSERVATIONS: We describe a 37-year-old white man with widespread, crusted, pruritic papules on the scalp, ears, and face and a purpuric and targetoid painful vesicular eruption on his hands and feet, with associated fevers, neurologic symptoms, and arthritis, who required hospitalization for supportive care. His infection with coxsackievirus A6 was confirmed based on polymerase chain reaction from his oral mucosa and cutaneous vesicle fluid. CONCLUSIONS AND RELEVANCE: Dermatologists should be familiar with the severe variant of HFMD caused by coxsackievirus A6, include it in their differential diagnosis of acute febrile blistering diseases, and be aware that certain patients may require hospitalization. PMID- 24172862 TI - Maternal depressive symptoms related to Epstein-Barr virus reactivation in late pregnancy. AB - We examined the relationship between maternal depressive symptoms in late pregnancy and Epstein-Barr virus reactivation before delivery. In this prospective observational study, prevalence of Epstein-Barr virus reactivation within one week before delivery was compared between 163 pregnant women with depressive symptoms at 33 to 34 weeks of gestation and a computer-generated control group of 163 pregnant healthy women without depressive symptoms. Depressive symptoms at 33 to 34 weeks of gestation were significantly related to the prevalence of Epstein-Barr virus reactivation before delivery after adjustment for potential confounders (adjusted OR = 2.74, 95%CI: 1.23-6.08). Compared to that in the control group, the prevalence of Epstein-Barr virus reactivation was higher in women with depressive symptoms accompanied by higher negative coping (24.2% compared with 7.9%; adjusted OR = 3.67, 95%CI: 1.47-9.16). Maternal depressive symptoms in late pregnancy are associated with Epstein-Barr virus reactivation, and this association could be moderated by maternal coping style. PMID- 24172863 TI - Analysis of interventional treatments of Budd-Chiari Syndrome and the related complications: a study of 1006 cases. AB - AIM: The aim of this paper was to investigate the cause of intraoperative and postoperative complications in Budd-Chiari syndrome (BCS) and its prevention. METHODS: BCS Patients (1035) who were treated between 1990 and 2009 were included in the present study. Among these patients, there were 651 cases with inferior vena cava occlusion, 273 cases with hepatic vein obstruction and 111 cases with both the symptoms. Treatment for 28 patients failed due to various causes and 1 case diagnosed of obstruction in the right hepatic vein was not treated due to the compensation from the middle and left hepatic vein. The remaining 1006 cases were resolved by the percutaneous transluminal angioplasty (PTA), of which 746 cases had only PTA and 260 cases had both PTA and stent. RESULTS: There were complications in 66 (6.56%) cases after intervention and 2 patients (0.199%) died. Accidental surgical penetration of the pericardium or cardiac tamponade (0.99%) led to the death of 10 patients, among which 4 cases had cardiac tamponade and one died due to the tamponade. In 2 (0.199%) patients there was stent migration into the right atrium from inferior vena cava. Pleural bleeding was seen in 1 case (0.099%) and abdominal bleeding in 2 cases (0.199%). Two cases (0.199%) had pulmonary obstruction. A single (0.099%) case had chocolate cyst rupture in thrombolytic process. Twenty-seven patients had acute re-stenosis after the surgery, among which 22 (2.95%, 22/746) had the stenosis after only PTA and 5 (1.92%, 5/260) had the stenosis after receiving both PTA and stent. 3 (0.298%) cases had pseudoaneurysm at the puncturing site. Puncture site bleeding and local hematoma was seen in 10 cases (0.99%), whereas 4 cases (0.398%) had leg phlebothrombosis on the same side of the puncture site. CONCLUSION: Interventional treatment is a safe and effective way to treat BCS. Various effective measures should be taken to avoid and lower the incidence of complications. PMID- 24172864 TI - Characterization of a Brg1 hypomorphic allele demonstrates that genetic and biochemical activity are tightly correlated. AB - Mammalian SWI/SNF-related complexes are recruited to the promoters of numerous target genes, and the BRG1 catalytic subunit confers ATPase activity necessary to slide or evict nucleosomes and to regulate transcription. Based on gene-targeting experiments in mice, BRG1 is essential for early embryonic development. However, Brg1 null mutants have provided limited insight into gene-dosage considerations and structure-function relationships. To extend our knowledge of BRG1 function, we describe the genetic and biochemical characteristics of an ENU-induced hypomorphic mutation that encodes a protein with a single amino-acid substitution (E1083G) within the bilobal ATPase/chromatin-remodeling domain. Brg1(ENU1/ENU1) mice have ~50% genetic activity and survive embryogenesis but exhibit a postnatal developmental phenotype associated with runting and incompletely penetrant lethality. The E1083G mutant protein is stable, and experiments with recombinant FLAG-tagged BRG1 proteins demonstrated that it retains full ATPase activity. Yet the biochemical activity of the mutant protein is diminished to ~50% of normal in chromatin-remodeling assays. Consistent with these findings, the E1083G substitution is predicted to disrupt a structurally conserved alpha-helix within the lobe that participates in DNA translocation but does not contain the ATPase catalytic site. We propose that this alpha-helix participates in the DNA translocation cycle by mechanistically linking DNA interaction surfaces at the DNA entry/anchor point to those within the Helicase C domain of lobe 2 of the bilobal ATPase motor. Taken together, these results demonstrate that BRG1 genetic and biochemical activities are tightly correlated. They also indicate that BRG1 ATPase activity is necessary but not sufficient for chromatin remodeling. PMID- 24172865 TI - Adipocyte regeneration after free fat transplantation: promotion by stromal vascular fraction cells. AB - Our objective was to explore the mechanism of cell-assisted adipose transplantation by using freshly isolated human stromal vascular fraction (SVF) cells and to observe the dynamic changes of the graft after transplantation. The SVF was isolated from human liposuction aspirates, and 0.5 ml adipose tissue was mixed with 1 * 10(6) SVF cells or culture medium then injected to nude mice subcutaneously. At 1, 4, 7, 14, 30, 60, and 90 days after transplantation, samples were harvested for 1) general observation and retention rate; 2) whole mount stain; 3) H&E stain; 4) immunohistochemical staining for S100, CD68, and CD34; 5) ELISA for VEGF and bFGF; 6) peroxisome proliferator-activated receptor gamma (PPARgamma) fluorescence in situ hybridization. The retention rate in the experiment group was markedly higher than that in the control group. Whole-mount stain shows most of the cells in the center of the graft could not survive the ischemia until day 14. Histology showed new vessels on the surface of the graft at 3 days. However, in the control group, fewer newly formed vessels were detected until day 7. In the late stage of transplantation, gradual fibrosis was found in the graft, and the tissue was divided into a grid-like structure. A large number of round neonatal adipocytes with big nuclei in the center were found surrounding the new vessels, which were S100 and CD34 positive and CD68 negative. In the late stage of transplantation, most of the neonatal adipocytes were human PPARgamma positive. Moreover, the SVF group showed a higher level of VEGF and bFGF. SVF assisting adipose transplantation could increase the retention rate of the graft through promoting adipose tissue regeneration via secretion of growth factors, promotion of angiogenesis, and increasing the density of mesenchymal stem cells. PMID- 24172866 TI - Therapeutic potential of genetically modified mesenchymal stem cells after neonatal hypoxic-ischemic brain damage. AB - Mesenchymal stem cells (MSCs) have been shown to improve outcomes after neonatal hypoxic-ischemic (HI) brain injury possibly by secretion of growth factors stimulating repair processes. We investigated whether MSCs, modified to secrete specific growth factors, can further enhance recovery. Using an in vitro assay, we show that MSC-secreting brain derived neurotrophic factor (BDNF), epidermal growth factor-like 7 (EGFL7), persephin (PSP), or sonic hedgehog (SHH) regulate proliferation and differentiation of neural stem cells. Moreover, mice that received an intranasal application of 100,000 MSC-BDNF showed significantly improved outcomes as demonstrated by improved motor function and decreased lesion volume compared with mice treated with empty vector (EV) MSCs. Treatment with MSC EGFL7 improved motor function but had no effect on lesion size. Treatment with MSC-PSP or MSC-SHH neither improved outcome nor reduced lesion size in comparison with MSC-EV-treated mice. Moreover, mice treated with MSC-SHH showed even decreased functional outcomes when compared with those treated with MSC-EV. Treatment with MSC-BDNF induced cell proliferation in the ischemic hemisphere lasting at least 18 days after MSC administration, whereas treatment with MSC-EV did not. These data suggest that gene-modified cell therapy might be a useful approach to consider for treatment of neonatal HI brain damage. However, care must be taken when selecting the agent to overexpress. PMID- 24172868 TI - 3D hierarchically porous Cu-BiOCl nanocomposite films: one-step electrochemical synthesis, structural characterization and nanomechanical and photoluminescent properties. AB - Three-dimensional (3D) hierarchically porous composite Cu-BiOCl films have been prepared by a facile one-step galvanostatic electrodeposition process from acidic electrolytic solutions containing Cu(ii) and Bi(iii) chloride salts and Triton X 100. The films show spherical, micron-sized pores that spread over the whole film thickness. In turn, the pore walls are made of randomly packed BiOCl nanoplates that are assembled leaving micro-nanopore voids beneath. It is believed that Cu grows within the interstitial spaces between the hydrogen bubbles produced from the reduction of H(+) ions. Then, the BiOCl sheets accommodate in the porous network defined by the Cu building blocks. The presence of Cu tends to enhance the mechanical stability of the composite material. The resulting porous Cu-BiOCl films exhibit homogeneous and stable-in-time photoluminescent response arising from the BiOCl component that spreads over the entire 3D porous structure, as demonstrated by confocal scanning laser microscopy. A broad-band emission covering the entire visible range, in the wavelength interval 450-750 nm, is obtained. The present work paves the way for the facile and controlled preparation of a new generation of photoluminescent membranes. PMID- 24172867 TI - Ultrasound-activated agents comprised of 5FU-bearing nanoparticles bonded to microbubbles inhibit solid tumor growth and improve survival. AB - Nanoparticle (NP) drug delivery vehicles may eventually offer improved tumor treatments; however, NP delivery from the bloodstream to tumors can be hindered by poor convective and/or diffusive transport. We tested whether poly(lactic-co glycolic acid) NP delivery can be improved by covalently linking them to ultrasound (US)-activated microbubbles in a "composite-agent" formulation and whether drug 5-fluorouracil (5FU)-loaded NPs delivered in this fashion inhibit the growth of tumors that are typically not responsive to intravenously administered 5FU. After intravenous composite-agent injection, C6 gliomas implanted on Rag-1(-/-) mice were exposed to pulsed 1 MHz US, resulting in the delivery of 16% of the initial NP dose per gram tissue. This represented a five- to 57-fold increase in NP delivery when compared to multiple control groups. 5FU bearing NP delivery from the composite-agent formulation resulted in a 67% reduction in tumor volume at 7 days after treatment, and animal survival increased significantly when compared to intravenous soluble 5FU administration. We conclude that NP delivery from US-activated composite agents may improve tumor treatment by offering a combination of better targeting, enhanced payload delivery, and controlled local drug release. PMID- 24172869 TI - Analysis of syncytial nuclear aggregates in preeclampsia shows increased sectioning artefacts and decreased inter-villous bridges compared to healthy placentas. AB - Syncytial nuclear aggregates (SNAs) are increased in pregnancy complications and include 'true' syncytial knots and inter-villous bridges. Apparent nuclear overlay caused by sectioning artefacts are frequently counted from single sections. Haematoxylin and eosin stained serial sections were assessed for frequency of SNA subtypes in placentas from normal, preeclamptic and fetal growth restricted (FGR) pregnancies. There were more sectioning artefacts and syncytial knots and fewer bridges in samples from preeclampsia compared to controls. There were no significant differences between FGR and control samples. This suggests the villous tree in preeclampsia has less inherent structural support and trophoblast cell dynamics are different. PMID- 24172870 TI - A unique epigenetic signature is associated with active DNA replication loci in human embryonic stem cells. AB - The cellular epigenetic landscape changes as pluripotent stem cells differentiate to somatic cells or when differentiated cells transform to a cancerous state. These epigenetic changes are commonly correlated with differences in gene expression. Whether active DNA replication is also associated with distinct chromatin environments in these developmentally and phenotypically diverse cell types has not been known. Here, we used BrdU-seq to map active DNA replication loci in human embryonic stem cells (hESCs), normal primary fibroblasts and a cancer cell line, and correlated these maps to the epigenome. In all cell lines, the majority of BrdU peaks were enriched in euchromatin and at DNA repetitive elements, especially at microsatellite repeats, and coincided with previously determined replication origins. The most prominent BrdU peaks were shared between all cells but a sizable fraction of the peaks were specific to each cell type and associated with cell type-specific genes. Surprisingly, the BrdU peaks that were common to all cell lines were associated with H3K18ac, H3K56ac, and H4K20me1 histone marks only in hESCs but not in normal fibroblasts or cancer cells. Depletion of the histone acetyltransferases for H3K18 and H3K56 dramatically decreased the number and intensity of BrdU peaks in hESCs. Our data reveal a unique epigenetic signature that distinguishes active replication loci in hESCs from normal somatic or malignant cells. PMID- 24172872 TI - Corticosteroid for severe acute exacerbation of chronic hepatitis B. PMID- 24172871 TI - Interactive effects of in utero nutrition and genetic inheritance on cognition: new evidence using sibling comparisons. AB - A large literature links early environments and later outcomes, such as cognition; however, little is known about the mechanisms. One potential mechanism is sensitivity to early environments that is moderated or amplified by the genotype. With this mechanism in mind, a complementary literature outside economics examines the interaction between genes and environments, but often problems of endogeneity and bias in estimation are uncorrected. A key issue in the literature is exploring environmental variation that is not exogenous, which is potentially problematic if there are gene-environment correlation or gene-gene interactions. Using sibling pairs with genetic data in the Wisconsin Longitudinal Study we extend a previous, and widely cited, gene-environment study that explores an interaction between the FADS2 gene, which is associated with the processing of essential fatty acids related to cognitive development, and early life nutrition in explaining later-life IQ. Our base OLS findings suggest that individuals with specific FADS2 variants gain roughly 0.15 standard deviations in IQ for each standard deviation increase in birth weight, our measure of the early nutrition environment; while, individuals with other variants of FADS2 do not have a statistically significant association with early nutrition, implying the genotype is influencing the effects of environmental exposure. When including family-level fixed effects, however, the magnitude of the gene-environment interaction is reduced by half and statistical significance dissipates, implying the interaction between FADS2 and early nutrition in explaining later life IQ may in part be due to unobserved, family-level factors. The example has wider implications for the practice of investigating gene-environment interactions when the environmental exposure is not exogenous and robustness to unobserved variation in the genome is not controlled for in the analysis. PMID- 24172875 TI - Using risk group profiles as a lightweight qualitative approach for intervention development: an example of prevention of tick bites and lyme disease. AB - BACKGROUND: Many public health campaigns use a one-size-fits-all strategy to achieve their desired effect. Public health campaigns for tick bites and Lyme disease (LD) in many countries convey all relevant preventive measures to all members of the public. Although preventing tick bites (eg, by wearing protective clothing or using repellants) and checking for tick bites after visiting a risk area are effective and cost-efficient methods to prevent an individual from contracting a tick-borne disease, public compliance to these methods is low. OBJECTIVE: We aimed to identify the group of individuals within the general Dutch population that are at high risk of being bitten by a tick or developing LD and to describe their characteristics, knowledge, and perceptions. The incidence of patients visiting their general practitioner for tick bites and erythema migrans (the first sign of LD) has increased tremendously in the last decades in the Netherlands and other European countries; therefore, our efforts can be used to counter this troubling trend. METHODS: We conducted in-depth semi-structured interviews to identify individuals belonging to the average risk group. Participants were recruited in two ways. Patients who visited two municipal health services travel health clinics (one in a high-endemic area and one in a low-endemic area) were asked to participate. This resulted in 18 interviews. Further, parents were recruited using the convenience sampling method, which resulted in 7 interviews. We discontinued interviewing when the point of data saturation was reached. We analyzed the results immediately after each interview to identify the point of data saturation. Data saturation is when the new interviews provided no new information compared to the previous interviews. The interviews were transcribed and analyzed using inductive thematic analysis. RESULTS: We identified four groups at risk of being bitten by ticks and developing LD among the general Dutch population. The groups were as follows: (1) outdoor people that check for tick bites, (2) outdoor people that do not check for tick bites, (3) parents that check their children for tick bites, and (4) parents that do not check their children for tick bites. Previous experience with ticks or LD was the main denominator between the groups. Checking for tick bites is a more easily adopted measure than preventing tick bites. Therefore, for all groups, public health efforts in the future should primarily emphasize on the importance of checking for tick bites. CONCLUSIONS: The lightweight qualitative approach presented in this paper is highly relevant in tailoring public health efforts toward specific groups. The profiles of members in each risk group and the motivations underlying the behaviors of the members in each risk group can be used to determine the features and content of a targeted communication strategy about ticks and LD. PMID- 24172876 TI - Activity clocks: spreading dynamics on temporal networks of human contact. AB - Dynamical processes on time-varying complex networks are key to understanding and modeling a broad variety of processes in socio-technical systems. Here we focus on empirical temporal networks of human proximity and we aim at understanding the factors that, in simulation, shape the arrival time distribution of simple spreading processes. Abandoning the notion of wall-clock time in favour of node specific clocks based on activity exposes robust statistical patterns in the arrival times across different social contexts. Using randomization strategies and generative models constrained by data, we show that these patterns can be understood in terms of heterogeneous inter-event time distributions coupled with heterogeneous numbers of events per edge. We also show, both empirically and by using a synthetic dataset, that significant deviations from the above behavior can be caused by the presence of edge classes with strong activity correlations. PMID- 24172877 TI - The Women's Health Initiative trial and related studies: 10 years later: a clinician's view. AB - The Women's Health Initiative (WHI) assessed the long-term effects of hormone therapy (HT) in postmenopausal women. The WHI started HT treatment on women aged 50-79 years in order to ascertain these effects. The study was ended early, due to findings of increased risk of coronary heart disease, breast cancer, stroke, and thromboembolic complications in women receiving estrogen plus progestin, compared to placebo. An increased risk of thromboembolic complications was also demonstrated in the estrogen only component of the WHI. The WHI results were initially reported for all subjects, and showed little difference when data were not analyzed by age. New WHI sub-analyses stratifying results by age, and an extended follow-up of the WHI offer a more complete picture of the effects of HT, revealing that starting HT in postmenopausal women less than ten years from last menstrual period appears to have less risk. In addition, hysterectomized women treated with estrogen only in the WHI have showed less risk of adverse outcomes than women in the estrogen plus progestin group. In this paper, we review data supporting the use of HT administered to postmenopausal women, showing it to have more benefit than risk for symptom control, prevention of bone mineral loss and fracture, and improvement of the metabolic profile in women who began HT when they were less than 60 years of age and had their last menstrual period less than ten years previous. In hysterectomized women treated with estrogen only, a reduction in breast cancer risk was noted in all age groups. The WHI raised many important questions. Ten years later, some have been answered, including confirmation that HT for most newly menopausal women is safe and effective. The treatment of the aging woman, including hormone treatment after menopause, should remain one of our highest research priorities. This article is part of a Special Issue entitled 'Menopause'. PMID- 24172878 TI - Comorbidity in adults with epilepsy--United States, 2010. AB - Epilepsy, a spectrum disorder characterized by recurring seizures, affects approximately 2.3 million U.S. adults. Epilepsy poses challenges because of uncontrolled seizures, treatment complexity, social disadvantages (e.g., unemployment), and stigma. Persons with epilepsy are at increased risk for early mortality and for comorbidities that can complicate epilepsy management, increase health-care costs, and shorten the lifespan. Numerous studies have described higher rates of psychiatric comorbidity (e.g., depression and anxiety) in persons with epilepsy. However, fewer studies have examined nonpsychiatric comorbidity in a nationally representative U.S. sample of adults with epilepsy. To assess the prevalence of nonpsychiatric comorbidities, CDC analyzed data from the 2010 National Health Interview Survey (NHIS). Adults with epilepsy had a higher prevalence of cardiovascular, respiratory, some inflammatory, and other disorders (e.g., headache, migraine, and various other types of pain) than adults without epilepsy. Public health agencies can work with health-care providers, the Epilepsy Foundation, and other partners to ensure that adults with epilepsy have access to health promotion resources and chronic disease self-management programs. PMID- 24172879 TI - Influenza vaccination among pregnant women--Massachusetts, 2009-2010. AB - The emergence of the novel influenza A (H1N1) pdm09 (pH1N1) strain in 2009 required a coordinated public health response, especially among high-risk populations. Because pregnant women were at increased risk for influenza-related complications and hospitalization compared with the general population, the American College of Obstetricians and Gynecologists and the Advisory Committee on Immunization Practices recommended pregnant women receive both the pH1N1 vaccine and the annual seasonal vaccine during the 2009-10 influenza season as a safe and effective way of protecting both mother and infant. To describe acceptance, predictors, and barriers to influenza vaccination among pregnant women in Massachusetts during the 2009-10 influenza season, the Massachusetts Department of Public Health (MDPH) analyzed data from supplemental influenza questions on the Massachusetts Pregnancy Risk Assessment Monitoring System (PRAMS) survey. The results indicated that 67.5% of residents who had live births in Massachusetts during September 2009-May 2010 received the seasonal vaccine, and 57.6% received the pH1N1 vaccine. Women who were non-Hispanic blacks, aged <25 years, Medicaid beneficiaries, or lived in a household with an income at or below the federal poverty level were significantly less likely to receive the seasonal vaccine. For the pH1N1 vaccine, only being non-Hispanic black was associated with being less likely to have been vaccinated. Vaccination rates were significantly higher among women whose provider offered or recommended the seasonal (75.8%) and pH1N1 (68.1%) vaccines compared with those who did not receive a recommendation (32.4% and 8.6%, respectively). Coverage in Massachusetts was among the highest of 29 PRAMS sites and might have reflected strategic efforts by MDPH to support vaccine education and equity across the state. PMID- 24172880 TI - Global routine vaccination coverage--2012. AB - In 1974, the World Health Organization (WHO) established the Expanded Programme on Immunization to ensure that all children have access to routinely recommended vaccines. Despite improvement in global coverage with the third dose of diphtheria-tetanus-pertussis (DTP) vaccine (DTP3), from 5% in 1974 to 83% in 2011, almost one fifth of the world's children still had not received their third dose of the DTP series during their first year of life. In May 2012, the World Health Assembly endorsed the Global Vaccine Action Plan (GVAP) to guide the Decade of Vaccines' vision to extend benefits of immunization to all persons. GVAP's key indicators include achieving and sustaining 90% national DTP3 coverage and >=80% DTP3 coverage in every district by 2015. During 2012, as in the 2 preceding years, an estimated 83% of infants worldwide received 3 doses of DTP vaccine; however, coverage varied among the WHO regions. Among 194 WHO member states, 131 (68%) achieved >=90% DTP3 national coverage, and 59 (30%) achieved >=80% DTP3 coverage in every district. However, 22.6 million children did not receive 3 DTP doses, a key indicator of immunization program performance. Strengthening national immunization systems, especially in countries with the greatest number of undervaccinated children, should be a global priority to reduce morbidity and mortality from vaccine-preventable diseases. PMID- 24172881 TI - outbreaks of cyclosporiasis--United States, June-August 2013. AB - During June-August 2013, CDC, state and local public health officials, and the Food and Drug Administration (FDA) investigated an unusually large number of reports of cyclosporiasis (compared with annual reports to the National Notifiable Disease Surveillance System [e.g., 123 cases in 2012]), an intestinal infection caused by the parasite Cyclospora cayetanensis. By September 20, CDC had been notified of 643 cases from 25 states, primarily Texas (278 cases), Iowa (153), and Nebraska (86). Investigations in Iowa and Nebraska showed that restaurant-associated cases in these two states were linked to a salad mix that contained iceberg lettuce, romaine lettuce, red cabbage, and carrots. Most patients in Iowa and Nebraska became ill during June 15-29; cases reported during July and August were primarily from Texas. PMID- 24172882 TI - Salmonella typhimurium infections associated with a community college microbiology laboratory--Maine, 2013. AB - On May 2, 2013, a case of salmonellosis was reported to the Maine Center for Disease Control and Prevention. The patient reported symptoms of diarrhea, fever, abdominal pain, and nausea, after attending a community college microbiology laboratory class. A second case was reported on May 8. Epidemiologic interviews conducted with both patients indicated common exposure at a community college, including one patient specifically naming the other patient. PMID- 24172883 TI - Prognostic indices for cerebral venous thrombosis on CT perfusion: a prospective study. AB - PURPOSE: We determined the prognostic significance of CT perfusion characteristics of patients with cerebral venous sinus thrombosis (CVST) and assessed the change in perfusion parameters following anticoagulation therapy. MATERIALS AND METHODS: 20 patients with CVST diagnosed on non-contrast computed tomography (NCCT), magnetic resonance imaging (MRI), and magnetic resonance venography (MRV) were included in this study. The initial CT perfusion study was performed at the time of admission. The following perfusion parameters: relative cerebral blood flow (rCBF), relative cerebral blood volume (rCBV), and relative mean transit time (rMTT) were calculated in the core and periphery of the affected area of the brain. Follow-up CT perfusion studies were performed at 1 month following anticoagulation therapy and the perfusion parameters thus obtained were compared with pre-treatment results. Receiver operating characteristic (ROC) curve analysis was performed to determine the prognostic significance of perfusion parameters. RESULTS: All patients in this study showed areas of hypoperfusion on CT perfusion. To determine the favorable clinical outcome on basis of perfusion parameters, ROC curve analysis was performed which showed that the optimal threshold for rCBF>60.5%, rCBV>75.5%, and rMTT<148.5% correlated with better clinical outcomes. Post treatment perfusion parameters showed significant correlation in core of the lesion (p<0.05) than in the periphery. CONCLUSION: CT perfusion studies in CVST are a good prognostic tool and yield valuable information regarding clinical outcome. PMID- 24172884 TI - Androgen receptor decreases CMYC and KRAS expression by upregulating let-7a expression in ER-, PR-, AR+ breast cancer. AB - It is generally known that the decision to use anti-estrogen therapy is based on the expression of estrogen and progesterone receptors in breast cancers. Recent studies have shown that androgen receptor (AR) is frequently expressed in ER-, PR breast cancer and plays an important role in the prognosis of breast cancer patients. Furthermore, AR can increase the global expression of microRNAs, post transcriptional gene regulators that play a crucial role in the initiation and progression of breast cancer. In this study, we investigated the functions and relations of AR, related miRNAs and target proteins in ER-, PR-, AR+ breast cancer. The results showed that androgen-induced AR activating signal directly upregulates let-7a expression, downregulates CMYC and KRAS protein expression, and inhibits cell proliferation in ER-, PR-, AR+ breast cancer cells. Overexpression of let-7a inhibits cell proliferation and downregulates CMYC and KRAS protein expression, whereas inhibition of let-7a expression by specific antisense oligonucleo-tides increases cell growth and upregulates CMYC and KRAS protein expression. We performed in situ hybridization for let-7a and immunohistochemical staining for CMYC and KRAS using sequential sections obtained from surgically-resected breast cancer tissues and observed an inverse correlation between the staining pattern of let-7a and its target proteins. Androgen-induced AR activating signal upregulates let-7a that targets CMYC and KRAS and contributes to ER-, PR-, AR+ breast cancer pathogenesis. Elucidation of this pathway will help develop new therapies. PMID- 24172885 TI - The structural conditions for oxygen supply to muscle cells: the Krogh cylinder model. PMID- 24172886 TI - Possible age-related hearing loss (presbycusis) and corresponding change in echolocation parameters in a stranded Indo-Pacific humpback dolphin. AB - The hearing and echolocation clicks of a stranded Indo-Pacific humpback dolphin (Sousa chinensis) in Zhuhai, China, were studied. This animal had been repeatedly observed in the wild before it was stranded and its age was estimated to be ~40 years. The animal's hearing was measured using a non-invasive auditory evoked potential (AEP) method. Echolocation clicks produced by the dolphin were recorded when the animal was freely swimming in a 7.5 m (width)*22 m (length)*4.8 m (structural depth) pool with a water depth of ~2.5 m. The hearing and echolocation clicks of the studied dolphin were compared with those of a conspecific younger individual, ~13 years of age. The results suggested that the cut-off frequency of the high-frequency hearing of the studied dolphin was ~30-40 kHz lower than that of the younger individual. The peak and centre frequencies of the clicks produced by the older dolphin were ~16 kHz lower than those of the clicks produced by the younger animal. Considering that the older dolphin was ~40 years old, its lower high-frequency hearing range with lower click peak and centre frequencies could probably be explained by age-related hearing loss (presbycusis). PMID- 24172887 TI - Blood flow dynamics in the snake spectacle. AB - The eyes of snakes are shielded beneath a layer of transparent integument referred to as the 'reptilian spectacle'. Well adapted to vision by virtue of its optical transparency, it nevertheless retains one characteristic of the integument that would otherwise prove detrimental to vision: its vascularity. Given the potential consequence of spectacle blood vessels on visual clarity, one might expect adaptations to have evolved that mitigate their negative impact. Earlier research demonstrated an adaptation to their spatial layout in only one species to reduce the vessels' density in the region serving the foveal and binocular visual fields. Here, we present a study of spectacle blood flow dynamics and provide evidence of a mechanism to mitigate the spectacle blood vessels' deleterious effect on vision by regulation of blood flow through them. It was found that when snakes are at rest and undisturbed, spectacle vessels undergo cycles of dilation and constriction, such that the majority of the time the vessels are fully constricted, effectively removing them from the visual field. When snakes are presented with a visual threat, spectacle vessels constrict and remain constricted for longer periods than occur during the resting cycles, thus guaranteeing the best possible visual capabilities in times of need. Finally, during the snakes' renewal phase when they are generating a new stratum corneum, the resting cycle is abolished, spectacle vessels remain dilated and blood flow remains strong and continuous. The significance of these findings in terms of the visual capabilities and physiology of snakes is discussed. PMID- 24172888 TI - Experimental verification of dynamic soaring in albatrosses. AB - Dynamic soaring is a small-scale flight manoeuvre which is the basis for the extreme flight performance of albatrosses and other large seabirds to travel huge distances in sustained non-flapping flight. As experimental data with sufficient resolution of these small-scale movements are not available, knowledge is lacking about dynamic soaring and the physical mechanism of the energy gain of the bird from the wind. With new in-house developments of GPS logging units for recording raw phase observations and of a dedicated mathematical method for postprocessing these measurements, it was possible to determine the small-scale flight manoeuvre with the required high precision. Experimental results from tracking 16 wandering albatrosses (Diomedea exulans) in the southern Indian Ocean show the characteristic pattern of dynamic soaring. This pattern consists of four flight phases comprising a windward climb, an upper curve, a leeward descent and a lower curve, which are continually repeated. It is shown that the primary energy gain from the shear wind is attained in the upper curve where the bird changes the flight direction from windward to leeward. As a result, the upper curve is the characteristic flight phase of dynamic soaring for achieving the energy gain necessary for sustained non-flapping flight. PMID- 24172889 TI - Hemoglobin function and allosteric regulation in semi-fossorial rodents (family Sciuridae) with different altitudinal ranges. AB - Semi-fossorial ground squirrels face challenges to respiratory gas transport associated with the chronic hypoxia and hypercapnia of underground burrows, and such challenges are compounded in species that are native to high altitude. During hibernation, such species must also contend with vicissitudes of blood gas concentrations and plasma pH caused by episodic breathing. Here, we report an analysis of hemoglobin (Hb) function in six species of marmotine ground squirrels with different altitudinal distributions. Regardless of their native altitude, all species have high Hb-O2 affinities, mainly due to suppressed sensitivities to allosteric effectors [2,3-diphosphoglycerate (DPG) and chloride ions]. This suppressed anion sensitivity is surprising given that all canonical anion-binding sites are conserved. Two sciurid species, the golden-mantled and thirteen-lined ground squirrel, have Hb-O2 affinities that are characterized by high pH sensitivity and low thermal sensitivity relative to the Hbs of humans and other mammals. The pronounced Bohr effect is surprising in light of highly unusual amino acid substitutions at the C-termini that are known to abolish the Bohr effect in human HbA. Taken together, the high O2 affinity of sciurid Hbs suggests an enhanced capacity for pulmonary O2 loading under hypoxic and hypercapnic conditions, while the large Bohr effect should help to ensure efficient O2 unloading in tissue capillaries. In spite of the relatively low thermal sensitivities of the sciurid Hbs, our results indicate that the effect of hypothermia on Hb oxygenation is the main factor contributing to the increased blood-O2 affinity in hibernating ground squirrels. PMID- 24172891 TI - Third generation P2Y12 antagonists inhibit platelet aggregation more effectively than clopidogrel in a myocardial infarction registry. AB - The current standard of antiplatelet therapy of patients after myocardial infarction includes the P2Y12 receptor antagonists clopidogrel, prasugrel or ticagrelor. This study aimed to compare the antiplatelet effect of clopidogrel, prasugrel and ticagrelor in patients after myocardial infarction. In a single centre registry the antiplatelet effect of clopidogrel, prasugrel and ticagrelor was investigated by aggregometry in patients after myocardial infarction. To assess the overall capacity of platelet aggregation whole blood was induced with thrombin receptor activating peptide (TRAP; 32 uM). To specifically quantify the effect of P2Y12 antagonists, whole blood was stimulated with 6.4 uM adenosine diphophosphate (ADP). Relative ADP induced aggregation (r-ADP-agg) was defined as the ADP-TRAP ratio to reflect an individual degree of P2Y12-dependent platelet inhibition.Platelet function of 238 patients was analysed [clopidogrel (n=58), prasugrel (n=65), ticagrelor (n=115)]. The r-ADP-agg was 35 +/- 14% for patients receiving clopidogrel, 28 +/- 10% for patients receiving prasugrel and 26 +/- 11% for patients receiving ticagrelor. The r-ADP-agg was significantly lower in patients treated with prasugrel (p=0.0024) or ticagrelor (p<0.0001) compared to clopidogrel. There was no significant difference between patients receiving prasugrel or ticagrelor (p=0.2559). In conclusion, prasugrel and ticagrelor provide a stronger platelet inhibition compared to clopidogrel in patients after myocardial infarction. No significant difference in platelet inhibition was detected between prasugrel and ticagrelor. (registry for patients after Myocardial Infarction Treated with AntiPlatelet agents; DRKS00003146). PMID- 24172892 TI - Topical timolol for recalcitrant wounds. PMID- 24172893 TI - Extrasolar planets: An infernal Earth. PMID- 24172894 TI - HIV: Antibodies advance the search for a cure. PMID- 24172895 TI - A small-molecule AdipoR agonist for type 2 diabetes and short life in obesity. AB - Adiponectin secreted from adipocytes binds to adiponectin receptors AdipoR1 and AdipoR2, and exerts antidiabetic effects via activation of AMPK and PPAR-alpha pathways, respectively. Levels of adiponectin in plasma are reduced in obesity, which causes insulin resistance and type 2 diabetes. Thus, orally active small molecules that bind to and activate AdipoR1 and AdipoR2 could ameliorate obesity related diseases such as type 2 diabetes. Here we report the identification of orally active synthetic small-molecule AdipoR agonists. One of these compounds, AdipoR agonist (AdipoRon), bound to both AdipoR1 and AdipoR2 in vitro. AdipoRon showed very similar effects to adiponectin in muscle and liver, such as activation of AMPK and PPAR-alpha pathways, and ameliorated insulin resistance and glucose intolerance in mice fed a high-fat diet, which was completely obliterated in AdipoR1 and AdipoR2 double-knockout mice. Moreover, AdipoRon ameliorated diabetes of genetically obese rodent model db/db mice, and prolonged the shortened lifespan of db/db mice on a high-fat diet. Thus, orally active AdipoR agonists such as AdipoRon are a promising therapeutic approach for the treatment of obesity-related diseases such as type 2 diabetes. PMID- 24172896 TI - Antibody-mediated immunotherapy of macaques chronically infected with SHIV suppresses viraemia. AB - Neutralizing antibodies can confer immunity to primate lentiviruses by blocking infection in macaque models of AIDS. However, earlier studies of anti-human immunodeficiency virus type 1 (HIV-1) neutralizing antibodies administered to infected individuals or humanized mice reported poor control of virus replication and the rapid emergence of resistant variants. A new generation of anti-HIV-1 monoclonal antibodies, possessing extraordinary potency and breadth of neutralizing activity, has recently been isolated from infected individuals. These neutralizing antibodies target different regions of the HIV-1 envelope glycoprotein including the CD4-binding site, glycans located in the V1/V2, V3 and V4 regions, and the membrane proximal external region of gp41 (refs 9-14). Here we have examined two of the new antibodies, directed to the CD4-binding site and the V3 region (3BNC117 and 10-1074, respectively), for their ability to block infection and suppress viraemia in macaques infected with the R5 tropic simian human immunodeficiency virus (SHIV)-AD8, which emulates many of the pathogenic and immunogenic properties of HIV-1 during infections of rhesus macaques. Either antibody alone can potently block virus acquisition. When administered individually to recently infected macaques, the 10-1074 antibody caused a rapid decline in virus load to undetectable levels for 4-7 days, followed by virus rebound during which neutralization-resistant variants became detectable. When administered together, a single treatment rapidly suppressed plasma viraemia for 3-5 weeks in some long-term chronically SHIV-infected animals with low CD4(+) T cell levels. A second cycle of anti-HIV-1 monoclonal antibody therapy, administered to two previously treated animals, successfully controlled virus rebound. These results indicate that immunotherapy or a combination of immunotherapy plus conventional antiretroviral drugs might be useful as a treatment for chronically HIV-1-infected individuals experiencing immune dysfunction. PMID- 24172898 TI - A rocky composition for an Earth-sized exoplanet. AB - Planets with sizes between that of Earth (with radius R Earth symbol) and Neptune (about 4R Earth symbol) are now known to be common around Sun-like stars. Most such planets have been discovered through the transit technique, by which the planet's size can be determined from the fraction of starlight blocked by the planet as it passes in front of its star. Measuring the planet's mass--and hence its density, which is a clue to its composition--is more difficult. Planets of size 2-4R Earth symbol have proved to have a wide range of densities, implying a diversity of compositions, but these measurements did not extend to planets as small as Earth. Here we report Doppler spectroscopic measurements of the mass of the Earth-sized planet Kepler-78b, which orbits its host star every 8.5 hours (ref. 6). Given a radius of 1.20 +/- 0.09 R Earth symbol and a mass of 1.69 +/- 0.41 R Earth symbol, the planet's mean density of 5.3 +/- 1.8 g cm(-3) is similar to Earth's, suggesting a composition of rock and iron. PMID- 24172897 TI - Staphylococcus delta-toxin induces allergic skin disease by activating mast cells. AB - Atopic dermatitis is a chronic inflammatory skin disease that affects 15-30% of children and approximately 5% of adults in industrialized countries. Although the pathogenesis of atopic dermatitis is not fully understood, the disease is mediated by an abnormal immunoglobulin-E immune response in the setting of skin barrier dysfunction. Mast cells contribute to immunoglobulin-E-mediated allergic disorders including atopic dermatitis. Upon activation, mast cells release their membrane-bound cytosolic granules leading to the release of several molecules that are important in the pathogenesis of atopic dermatitis and host defence. More than 90% of patients with atopic dermatitis are colonized with Staphylococcus aureus in the lesional skin whereas most healthy individuals do not harbour the pathogen. Several staphylococcal exotoxins can act as superantigens and/or antigens in models of atopic dermatitis. However, the role of these staphylococcal exotoxins in disease pathogenesis remains unclear. Here we report that culture supernatants of S. aureus contain potent mast-cell degranulation activity. Biochemical analysis identified delta-toxin as the mast cell degranulation-inducing factor produced by S. aureus. Mast cell degranulation induced by delta-toxin depended on phosphoinositide 3-kinase and calcium (Ca(2+)) influx; however, unlike that mediated by immunoglobulin-E crosslinking, it did not require the spleen tyrosine kinase. In addition, immunoglobulin-E enhanced delta-toxin-induced mast cell degranulation in the absence of antigen. Furthermore, S. aureus isolates recovered from patients with atopic dermatitis produced large amounts of delta-toxin. Skin colonization with S. aureus, but not a mutant deficient in delta-toxin, promoted immunoglobulin-E and interleukin-4 production, as well as inflammatory skin disease. Furthermore, enhancement of immunoglobulin-E production and dermatitis by delta-toxin was abrogated in Kit(W sh/W-sh) mast-cell-deficient mice and restored by mast cell reconstitution. These studies identify delta-toxin as a potent inducer of mast cell degranulation and suggest a mechanistic link between S. aureus colonization and allergic skin disease. PMID- 24172899 TI - Psychology: Good and bad news on the adolescent brain. PMID- 24172900 TI - Evolutionary ecology: Novelty makes the heart grow fonder. PMID- 24172901 TI - Isolation and characterization of a bat SARS-like coronavirus that uses the ACE2 receptor. AB - The 2002-3 pandemic caused by severe acute respiratory syndrome coronavirus (SARS CoV) was one of the most significant public health events in recent history. An ongoing outbreak of Middle East respiratory syndrome coronavirus suggests that this group of viruses remains a key threat and that their distribution is wider than previously recognized. Although bats have been suggested to be the natural reservoirs of both viruses, attempts to isolate the progenitor virus of SARS-CoV from bats have been unsuccessful. Diverse SARS-like coronaviruses (SL-CoVs) have now been reported from bats in China, Europe and Africa, but none is considered a direct progenitor of SARS-CoV because of their phylogenetic disparity from this virus and the inability of their spike proteins to use the SARS-CoV cellular receptor molecule, the human angiotensin converting enzyme II (ACE2). Here we report whole-genome sequences of two novel bat coronaviruses from Chinese horseshoe bats (family: Rhinolophidae) in Yunnan, China: RsSHC014 and Rs3367. These viruses are far more closely related to SARS-CoV than any previously identified bat coronaviruses, particularly in the receptor binding domain of the spike protein. Most importantly, we report the first recorded isolation of a live SL-CoV (bat SL-CoV-WIV1) from bat faecal samples in Vero E6 cells, which has typical coronavirus morphology, 99.9% sequence identity to Rs3367 and uses ACE2 from humans, civets and Chinese horseshoe bats for cell entry. Preliminary in vitro testing indicates that WIV1 also has a broad species tropism. Our results provide the strongest evidence to date that Chinese horseshoe bats are natural reservoirs of SARS-CoV, and that intermediate hosts may not be necessary for direct human infection by some bat SL-CoVs. They also highlight the importance of pathogen-discovery programs targeting high-risk wildlife groups in emerging disease hotspots as a strategy for pandemic preparedness. PMID- 24172902 TI - An Earth-sized planet with an Earth-like density. AB - Recent analyses of data from the NASA Kepler spacecraft have established that planets with radii within 25 per cent of the Earth's (R Earth symbol) are commonplace throughout the Galaxy, orbiting at least 16.5 per cent of Sun-like stars. Because these studies were sensitive to the sizes of the planets but not their masses, the question remains whether these Earth-sized planets are indeed similar to the Earth in bulk composition. The smallest planets for which masses have been accurately determined are Kepler-10b (1.42 R Earth symbol) and Kepler 36b (1.49 R Earth symbol), which are both significantly larger than the Earth. Recently, the planet Kepler-78b was discovered and found to have a radius of only 1.16 R Earth symbol. Here we report that the mass of this planet is 1.86 Earth masses. The resulting mean density of the planet is 5.57 g cm(-3), which is similar to that of the Earth and implies a composition of iron and rock. PMID- 24172903 TI - Derivation of novel human ground state naive pluripotent stem cells. AB - Mouse embryonic stem (ES) cells are isolated from the inner cell mass of blastocysts, and can be preserved in vitro in a naive inner-cell-mass-like configuration by providing exogenous stimulation with leukaemia inhibitory factor (LIF) and small molecule inhibition of ERK1/ERK2 and GSK3beta signalling (termed 2i/LIF conditions). Hallmarks of naive pluripotency include driving Oct4 (also known as Pou5f1) transcription by its distal enhancer, retaining a pre inactivation X chromosome state, and global reduction in DNA methylation and in H3K27me3 repressive chromatin mark deposition on developmental regulatory gene promoters. Upon withdrawal of 2i/LIF, naive mouse ES cells can drift towards a primed pluripotent state resembling that of the post-implantation epiblast. Although human ES cells share several molecular features with naive mouse ES cells, they also share a variety of epigenetic properties with primed murine epiblast stem cells (EpiSCs). These include predominant use of the proximal enhancer element to maintain OCT4 expression, pronounced tendency for X chromosome inactivation in most female human ES cells, increase in DNA methylation and prominent deposition of H3K27me3 and bivalent domain acquisition on lineage regulatory genes. The feasibility of establishing human ground state naive pluripotency in vitro with equivalent molecular and functional features to those characterized in mouse ES cells remains to be defined. Here we establish defined conditions that facilitate the derivation of genetically unmodified human naive pluripotent stem cells from already established primed human ES cells, from somatic cells through induced pluripotent stem (iPS) cell reprogramming or directly from blastocysts. The novel naive pluripotent cells validated herein retain molecular characteristics and functional properties that are highly similar to mouse naive ES cells, and distinct from conventional primed human pluripotent cells. This includes competence in the generation of cross-species chimaeric mouse embryos that underwent organogenesis following microinjection of human naive iPS cells into mouse morulas. Collectively, our findings establish new avenues for regenerative medicine, patient-specific iPS cell disease modelling and the study of early human development in vitro and in vivo. PMID- 24172904 TI - Mating advantage for rare males in wild guppy populations. AB - To understand the processes that maintain genetic diversity is a long-standing challenge in evolutionary biology, with implications for predicting disease resistance, response to environmental change, and population persistence. Simple population genetic models are not sufficient to explain the high levels of genetic diversity sometimes observed in ecologically important traits. In guppies (Poecilia reticulata), male colour pattern is both diverse and heritable, and is arguably one of the most extreme examples of morphological polymorphism known. Negative frequency-dependent selection (NFDS), a form of selection in which genotypes are favoured when they are rare, can potentially maintain such extensive polymorphism, but few experimental studies have confirmed its operation in nature. Here we use highly replicated experimental manipulations of natural populations to show that males with rare colour patterns have higher reproductive fitness, demonstrating NFDS mediated by sexual selection. Rare males acquired more mates and sired more offspring compared to common males and, as previously reported, had higher rates of survival. Orange colour, implicated in other studies of sexual selection in guppies, did predict male reproductive success, but only in one of three populations. These data support the hypothesis that NFDS maintains diversity in the colour patterns of male guppies through two selective agents, mates and predators. Similar field-based manipulations of genotype frequencies could provide a powerful approach to reveal the underlying ecological and behavioural mechanisms that maintain genetic and phenotypic diversity. PMID- 24172906 TI - Contribution of Gag and protease to variation in susceptibility to protease inhibitors between different strains of subtype B human immunodeficiency virus type 1. AB - Recent reports have shown that human immunodeficiency virus type 1 (HIV-1) Gag can directly affect susceptibility to protease inhibitors (PIs) in the absence of known resistance mutations in protease. Inclusion of co-evolved Gag alongside protease in phenotypic drug susceptibility assays can alter PI susceptibility in comparison with protease with a WT Gag. Using a single-replication-cycle assay encompassing full-length Gag together with protease we demonstrated significant variation in PI susceptibility between a number of PI-naive subtype B viruses. Six publicly available subtype B molecular clones, namely HXB2, NL4-3, SF2, YU2, JRFL and 89.6, displayed up to nine-fold reduced PI susceptibility in comparison with the assay reference strain. For two molecular clones, YU2 and JRFL, Gag contributed solely to the observed reduction in susceptibility, with the N terminal region of Gag contributing significantly. Gag and protease from treatment-naive, patient-derived viruses also demonstrated significant variation in susceptibility, with up to a 17-fold reduction to atazanavir in comparison with the assay reference strain. In contrast to the molecular clones, protease was the main determinant of the reduced susceptibility. Common polymorphisms in protease, including I13V, L63P and A71T, were shown to contribute to this reduction in PI susceptibility, in the absence of major resistance mutations. This study demonstrated significant variation in PI susceptibility of treatment naive patient viruses, and provided further evidence of the independent role of Gag, the protease substrate and in particular the N-terminus of Gag in PI susceptibility. It also highlighted the importance of considering co-evolved Gag and protease when assessing PI susceptibility. PMID- 24172905 TI - Therapeutic efficacy of potent neutralizing HIV-1-specific monoclonal antibodies in SHIV-infected rhesus monkeys. AB - Human immunodeficiency virus type 1 (HIV-1)-specific monoclonal antibodies with extraordinary potency and breadth have recently been described. In humanized mice, combinations of monoclonal antibodies have been shown to suppress viraemia, but the therapeutic potential of these monoclonal antibodies has not yet been evaluated in primates with an intact immune system. Here we show that administration of a cocktail of HIV-1-specific monoclonal antibodies, as well as the single glycan-dependent monoclonal antibody PGT121, resulted in a rapid and precipitous decline of plasma viraemia to undetectable levels in rhesus monkeys chronically infected with the pathogenic simian-human immunodeficiency virus SHIV SF162P3. A single monoclonal antibody infusion afforded up to a 3.1 log decline of plasma viral RNA in 7 days and also reduced proviral DNA in peripheral blood, gastrointestinal mucosa and lymph nodes without the development of viral resistance. Moreover, after monoclonal antibody administration, host Gag-specific T-lymphocyte responses showed improved functionality. Virus rebounded in most animals after a median of 56 days when serum monoclonal antibody titres had declined to undetectable levels, although, notably, a subset of animals maintained long-term virological control in the absence of further monoclonal antibody infusions. These data demonstrate a profound therapeutic effect of potent neutralizing HIV-1-specific monoclonal antibodies in SHIV-infected rhesus monkeys as well as an impact on host immune responses. Our findings strongly encourage the investigation of monoclonal antibody therapy for HIV-1 in humans. PMID- 24172907 TI - Ovine herpesvirus-2-encoded microRNAs target virus genes involved in virus latency. AB - Herpesviruses encode microRNAs (miRNAs) that target both virus and host genes; however, their role in herpesvirus biology is understood poorly. We identified previously eight miRNAs encoded by ovine herpesvirus-2 (OvHV-2), the causative agent of malignant catarrhal fever (MCF), and have now investigated the role of these miRNAs in regulating expression of OvHV-2 genes that play important roles in virus biology. ORF20 (cell cycle inhibition), ORF50 (reactivation) and ORF73 (latency maintenance) each contain predicted targets for several OvHV-2 miRNAs. Co-transfection of miRNA mimics with luciferase reporter constructs containing the predicted targets showed the 5' UTRs of ORF20 and ORF73 contain functional targets for ovhv-miR-2 and ovhv2-miR-8, respectively, and the 3' UTR of ORF50 contains a functional target for ovhv2-miR-5. Transfection of BJ1035 cells (an OvHV-2-infected bovine T-cell line) with the relevant miRNA mimic resulted in a significant decrease in ORF50 and a smaller but non-significant decrease in ORF20. However, we were unable to demonstrate a decrease in ORF73. MCF is a disease of dysregulated lymphocyte proliferation; miRNA inhibition of ORF20 expression may play a role in this aberrant lymphocyte proliferation. The proteins encoded by ORF50 and ORF73 play opposing roles in latency. It has been hypothesized that miRNA-induced inhibition of virus genes acts to ensure that fluctuations in virus mRNA levels do not result in reactivation under conditions that are unfavourable for viral replication and our data supported this hypothesis. PMID- 24172908 TI - Mouse dental pulp stem cells support human umbilical cord blood-derived hematopoietic stem/progenitor cells in vitro. AB - It is well documented that specialized mesenchymal stem/stromal cells (MSCs) constitute the hematopoietic stem cell (HSC) niche in the bone marrow (BM), and these MSCs support/maintain the HSCs in an undifferentiated state. A number of studies have demonstrated that BM-derived MSCs (BM-MSCs) can support HSCs in vitro. However, it remains unclear whether nonhematopoietic tissue-derived MSC like cells, such as dental pulp stem cells (DPSCs), have the ability to support HSCs. In this study, we prospectively isolated DPSCs from mouse mandibular incisors by fluorescence-activated cell sorting (FACS) using BM-MSC markers, such as PDGFRalpha and Sca-1. The PDGFRalpha and Sca-1 double-positive DPSCs and BM MSCs showed similar morphologies and expression patterns of MSC markers. The ability of the DPSCs to support hematopoietic stem/progenitor cells (HSPCs) was then analyzed by an in vitro coculture system. Moreover, their HSC-supporting activity was evaluated by in vivo xenotransplantation assays using NOD/Shi scid/IL-2Rgammac(null) (NOG) mice. Interestingly, the DPSCs supported human cord blood (CB)-derived CD34-positive (CD34(+)), as well as CD34-negative (CD34(-)), HSCs. The supporting activities of DPSCs for human CB-derived CD34(+) and CD34(-) HSCs were comparable to those of BM-MSCs. The results of the present study demonstrated, for the first time, that prospectively isolated murine PDGFRalpha and Sca-1 double-positive DPSCs could support primitive human CD34(+) and CD34(-) HSCs in vitro. PMID- 24172909 TI - Switching modes in easy and hard axis magnetic reversal in a self-assembled antidot array. AB - We study the reversal mechanisms in a self-assembled, hexagonally ordered Fe antidot array with a period of 200 nm and an antidot diameter of 100 nm which was prepared by polystyrene nanosphere lithography. Direction-dependent information in such a self-assembled sample is obtained by measuring the anisotropic magnetoresistance (AMR) through constrictions processed by focused ion beam milling in nearest neighbor and next nearest neighbor directions. We show that such an originally integral method can be used to investigate the strong in-plane anisotropy introduced by the antidot lattice. The easy and hard axis reversal mechanisms and corresponding AMR signals are modeled by micromagnetic simulations. Additional in-field magnetic force microscopy studies allow the correlation of microscopic switching to features in the integral AMR. We find that the easy axis of magnetization is connected to a distinct periodic magnetic domain pattern, which can be observed during the whole magnetization reversal. While this process is driven by nucleation and propagation of reversed domains, the hard axis reversal is characterized by a (stepwise) rotation of the magnetization via the antidot lattice' easy axes. PMID- 24172910 TI - Lapatinib alters the malignant phenotype of osteosarcoma cells via downregulation of the activity of the HER2-PI3K/AKT-FASN axis in vitro. AB - Lapatinib, an inhibitor of human epidermal growth factor receptor 2 (HER2) phosphorylation, has been reported to inhibit several types of tumors such as HER2-overexpressing breast cancer. However, the effect of lapatinib on the malignant phenotype of human osteosarcoma (OS) cells and the potential molecular mechanisms remain unclear. To elucidate the effect of lapatinib on OS, two OS cell lines, U2-OS and MG-63, were utilized in the present study. Various concentrations of lapatinib were used to treat OS cells for different time durations. Cell proliferation was evaluated by MTT and colony formation assays. Flow cytometry (FCM) was used to evaluate cell apoptosis. Wound healing and Transwell invasion assays were performed to examine the migratory and invasive abilities of the cells. To investigate the possible molecular mechanisms involved, the expression of p-HER2, phosphatidylinositol 3-kinase (PI3K), p-AKT, AKT and fatty acid synthase (FASN) protein was detected by western blotting. MTT assays showed that lapatinib inhibited the proliferation of U2-OS and MG-63 cells in a dose- and time-dependent manner, and the rate of colony formation of the lapatinib-treated cells was significantly lower when compared to those cells not treated with lapatinib in both cell lines. FCM assay revealed a significantly higher apoptotic rate in the lapatinib-treated OS cells. Wound healing and Transwell invasion assays revealed that the migratory and invasive abilities of OS cells were significantly inhibited by lapatinib (P<0.05). Western blotting showed that lapatinib suppressed the activity of HER2-PI3K/AKT-FASN in U2-OS and MG-63 cells in vitro. These results suggest that lapatinib may alter the malignant phenotype of OS cells via downregulation of the activity of the HER2 PI3K/AKT-FASN signaling pathway in vitro. Thus, lapatinib may be an effective chemotherapeutic agent for the treatment of osteosarcoma. PMID- 24172911 TI - Induction of altered mRNA expression profiles caused by fibrous and granular dust. AB - Natural and synthetic fibres and particles are being introduced into the workplace and environment daily. Comparative analyses of the induced signalling pathways are essential in order to understand the potential hazards of these particles. To identify the molecular characteristics of particles and fibres, we selected crocidolite and chrysotile asbestos as representatives for fibered dust and titanium dioxide (TiO2) (100-200 nm), zirconium dioxide (ZrO2) (50-100 nm) and hematite (Fe2O3) (20 nm) as representatives for bio-persistent granular dust. SV-40 virus-transformed human bronchial epithelial cells (BEAS-2B) were exposed to well-defined fibres and particles. RT2 ProfilerTM PCR Array Human Stress & Toxicity PathwayFinder was used to compare the relative mRNA expression of 84 genes. A detailed characterization of the dust samples used in this study was accomplished to ensure comparability to other studies. Investigation of mRNA expression of 84 signalling molecules attributed to pathways such as DNA damage and repair; oxidative/metabolic stress; growth arrest and senescence; inflammation, proliferation and carcinogenesis; and heat shock and apoptosis revealed that crocidolite and chrysotile asbestos induced mRNA expression of pathway molecules involved in proliferation and carcinogenesis, as well as inflammation. Titanium dioxide, zirconium dioxide and hematite mainly induced pathway molecules responsible for oxidative/metabolic stress and inflammation. Our findings suggest that the hazards of fibered dust mainly include the induction of direct toxicity by altering signalling pathways such as carcinogenesis and proliferation, while granular dust shows indirect toxicity by altering signalling pathways involved in inflammatory processes. PCR arrays, therefore, may be a helpful tool to estimate the hazard risk of new materials. PMID- 24172912 TI - Hematocrit is associated with fibrosis in patients with nonalcoholic steatohepatitis. AB - OBJECTIVES: Hematocrit levels are commonly elevated in patients with nonalcoholic fatty liver disease (NAFLD) and related to hypoxia and hyperlipidemia. AIM: This study was conducted to investigate the association between elevated hematocrit and liver histology in patients with NAFLD. PATIENTS AND METHODS: We examined 215 consecutive adults with biopsy-proven NAFLD (108 with steatosis alone, 107 with nonalcoholic steatohepatitis) and 110 controls. The stage of fibrosis was measured using a four-point scale. All underwent anthropometric and metabolic profiling. Hematocrit and related hematologic variables such as blood viscosity and red blood cell count were also measured. RESULTS: NAFLD morbidity was found to be positively correlated with hematocrit levels. After adjusting for age, smoking, diabetes, BMI, homeostasis model assessment of insulin resistance, triglycerides, and obstructive sleep apnea, patients with hematocrit levels in the highest quartile were seen to have had an odds ratio of 3.05 (95% confidence interval 2.12-4.36, P=0.015) for NAFLD in males. Hematocrit levels increased significantly (P<0.001) in steatosis (42.4+/-4.6%) compared with control groups (38.2+/-4.2%), and in nonalcoholic steatohepatitis (45.1+/-5.2%) compared with steatosis patients. On multivariate analysis, hematocrit levels were found to be strongly and independently associated with fibrosis (beta=0.205, P=0.030). Moreover, hematocrit levels increased with the severity of hepatic fibrosis (P<0.05). CONCLUSION: Our results indicate that hematocrit levels are significantly increased and independently associated with fibrosis in NAFLD patients. Therefore, hematocrit levels may have potential interest as a clinical marker of NAFLD severity. PMID- 24172913 TI - PX-12 inhibits the growth of A549 lung cancer cells via G2/M phase arrest and ROS dependent apoptosis. AB - PX-12 (1-methylpropyl 2-imidazolyl disulfide) is an inhibitor of thioredoxin (Trx 1), which has antitumor effects. However, little is known about the toxicological effect of PX-12 on cancer cells. We investigated the anti-growth effects of PX-12 on A549 lung cancer cells in relation to reactive oxygen species (ROS) and glutathione (GSH) levels. Based on MTT assays, PX-12 inhibited the growth of A549 cells with an IC50 of approximately 20 uM at 72 h. DNA flow cytometric analysis indicated that PX-12 significantly induced the G2/M phase arrest of the cell cycle in A549 cells. This agent also induced apoptotic cell death, as demonstrated by Annexin V-FITC staining cells and the loss of mitochondrial membrane potential MMP (?psim). In addition, the administration of Bax siRNA attenuated PX-12-induced A549 cell death. All the tested caspase inhibitors, especially Z-VAD significantly prevented apoptosis induced by PX-12. With respect to ROS and GSH levels, PX-12 increased ROS levels including O2(*)- in A549 cells and induced GSH depletion. N-acetyl cysteine (NAC) markedly reduced ROS levels in PX-12-treated A549 cells. NAC also prevented apoptotic cell death and GSH depletion induced by PX-12. This is the first report to show that PX-12 inhibits the growth of A549 cells via G2/M phase arrest, and Bax-mediated and ROS dependent apoptosis. PMID- 24172914 TI - Retina measurements for diagnosis of Parkinson disease. AB - PURPOSE: To test the diagnostic ability of spectral domain optical coherence tomography for the detection of Parkinson disease using retinal nerve fiber layer and retinal thickness parameters. Retinal pigment epithelium produces levodopa. METHODS: Patients with Parkinson disease (n = 111) and healthy subjects (n = 200) were enrolled. The Spectralis optical coherence tomography was used to obtain retinal nerve fiber layer thickness and retinal measurements. Two linear discriminant functions (LDFs) were developed, one using retinal nerve fiber layer parameters and another using retinal thickness. A validating set was used to test the performance of both LDFs. Receiver operating characteristic curves were plotted and compared with the standard parameters provided by optical coherence tomography for both LDFs. Sensitivity and specificity were used to evaluate diagnostic performance. RESULTS: The Retinal LDF combines only retinal thickness parameters and provided the best performance: 31.173 + 0.026 * temporal outer - 0.267 * superior outer + 0.159 * nasal outer - 0.197 * inferior outer - 0.060 * superior inner + 0.049 * foveal thickness. The largest areas under the receiver operating characteristic curve were 0.902 for Retinal LDF. The Retinal LDF yielded the highest sensitivity values. CONCLUSION: Measurements of retinal thickness differentiate between subjects who are healthy and those with advanced Parkinson disease. PMID- 24172915 TI - Methods of developing a core collection of annual Medicago species. AB - A core collection is a subset of a large germplasm collection that contains accessions chosen to represent the genetic variability of the germplasm collection. The purpose of the core collection is to improve management and use of a germplasm collection. Core collections are usually assembled by grouping accessions and selecting from within these groups. The objective of this study was to compare 11 methods of assembling a core collection of the U.S. National collection of annual Medicago species. These methods differed in their use of passport and evaluation data as well as their selection strategy. Another objective was to compare core collections with sample sizes of 5%, 10% and 17% of the germplasm collection. Core collections assembled with evaluation data and cluster analysis better represented the germplasm collection than core collections assembled based solely on passport data and random selection of accessions, The Relative Diversity and the logarithm methods generated better core collections than the proportional method. The 5% and 10% sample size core collection were judged insufficient to represent the germplasm collection. PMID- 24172916 TI - Inheritance of seed alpha-amylase inhibitor in the common bean and genetic relationship to arcelin. AB - The inheritance of seed alpha-amylase inhibitor in the common bean and the genetic relationships among the variants and six arcelin variants in the common bean were investigated by crossing between accessions containing different alphaAI and arcelin variants. All seed proteins in parental, F1 and F2 seeds from the crosses were examined by Western-blot analysis. All F1 seeds gave combined alphaAI banding patterns from parents on the blotting membranes. The segregation of F2 seeds for alphaAI variants indicated that the polypeptides of alphaAI variants were inherited as single co-dominant units. Moreover, alphaAI and arcelin behaved as a single block in crosses, indicating a close linkage relationship between the genes controlling these proteins. PMID- 24172917 TI - Random amplified polymorphic DNA variation in the eggplant, Solanum melongena L. (Solanaceae). AB - RAPD analysis was carried out on 52 accessions of Solanum melongena (eggplant) and related weedy forms known as "insanum". Twenty-two primers amplified 130 fragments. Solanum melongena exhibited 117 of the fragments, all of which were also present in insanum. Insanum displayed an additional 13 fragments not found in S. melongena. Overall, the insanum accessions were more diverse than those of S. melongena. The calculated similarity between them was 0.947. The RAPD results were closely concordant with the results of an electrophoretic isozyme survey performed on the same accessions. The concordance of the results shows that even though S. melongena and insanum are highly diverse morphologically, it is no longer appropriate to distinguish them taxonomically. PMID- 24172918 TI - Estimating allelic diversity generated by excision of different transposon types. AB - Methods are presented for calculating the number and type of different DNA sequences generated by base excision and insertion events at a given site in a known DNA sequence. We calculate, for example, that excision of the Mu1 transposon from the bz1::Mu1 allele of maize should generate more than 500,000 unique alleles given the extent of base deletion (up to 34 bases removed) and base insertion (0-5 bases) observed thus far in sequenced excision alleles. Analysis of this universe of potential alleles can, for example, be used to predict the frequency of creation of stop codons or repair-generated duplications. In general, knowledge of the distribution of alleles can be used to evaluate models of both excision and repair by determining whether particular events occur more frequently than expected. Such quantitative analysis complements the qualitative description provided by the DNA sequence of individual events. Similar methods can be used to evaluate the outcome of other cases of DNA breakage and repair such as programmed V(D)J recombination in immunoglobin genes. PMID- 24172919 TI - Linkage between loci of quantitative traits and marker loci: multi-trait analysis with a single marker. AB - An efficient approach to increase the resolution power of linkage analysis between a quantitative trait locus (QTL) and a marker is described in this paper. It is based on a counting of the correlations between the QTs of interest. Such correlations may be caused by the segregation of other genes, environmental effects and physiological limitations. Let a QT locus A/a affect two correlated traits, x and y. Then, within the framework of mixture models, the accuracy of the parameter estimates may be seriously increased, if bivariate densities f aa(x, y), f Aa(x, y) and f AA(x, y) rather than the marginals are considered as the basis for mixture decomposition. The efficiency of the proposed method was demonstrated employing Monte-Carlo simulations. Several types of progeny were considered, including backcross, F2 and recombinant inbred lines. It was shown that provided the correlation between the traits involved was high enough, a good resolution to the problem is possible even if the QTL groups are strongly overlapping for their marginal densities. PMID- 24172920 TI - RFLP-based assay of Sorghum bicolor (L.) Moench genetic diversity. AB - Sixty-two single-copy sorghum DNA clones were used to compare restriction fragment patterns of 53 sorghum accessions from Africa, Asia and the United States. Included were accessions from five morphological races of the cultivated subspecies bicolor, and four races of the wild subspecies verticilliflorum. From two to twelve alleles were detected with each probe. There was greater nuclear diversity in the wild subspecies (255 alleles in ten accessions) than in the domestic accessions (236 alleles in 37 accessions). Overall, 204 of the 340 alleles (60%) that were detected occurred in both subspecies. Phylogenetic analysis using parsimony separated the subspecies into separate clusters, with one group of intermediate accessions. Though exceptions were common, especially for the race bicolor, accessions classified as the same morphological race tended to group together on the basis of RFLP similarities. Selection for traits such as forage quality may have led to accessions genetically more similar to other races being classified as bicolors, which have a loose, small-grained panicle similar to wild races. Population statistics, calculated using four nuclear and four cytoplasmic probes that detect two alleles each, revealed a low but significant amount of heterozygosity, and showed little differentiation in alleles in the wild and cultivated subspecies. Outcrossing with foreign pollen appears to have been more important than migration via seed dispersal as a mechanism for gene flow between the wild and domestic accessions included in this study. PMID- 24172921 TI - High-resolution flow karyotyping and chromosome sorting in Vicia faba lines with standard and reconstructed karyotypes. AB - Flow cytometric analysis has been performed on chromosomes isolated from formaldehyde-fixed root tips in a Vicia faba (2n = 12) line with a standard (wild type) karyotype and in six V. faba translocation lines with reconstructed karyotypes. The resolution of individual chromosome types on histograms of chromosome fluorescence intensity (flow karyotypes) depended on the type of fluorochrome used for chromosome staining. The highest degree of resolution was achieved with 4',6-diamidino-2-phenylindole (DAPI). The lower resolution obtained after staining with mithramycin A (MIT) and propidium iodide (PI) was probably due to the sensitivity of these stains to changes in chromatin structure induced by formaldehyde fixation. After the staining with DAPI, only 1 chromosome type could be discriminated in the line with a standard karyotype. In the translocation lines, the number of chromosome types resolved on flow karyotypes ranged from 2 in the G and the ACB lines to all (6) chromosome types in the EFK and EF lines. Refined flow karyotyping permitted the sorting of a total of 15 different chromosome types from five of the translocation lines. It is expected that flow sorting of chromosomes from reconstructed karyotypes will become a powerful tool in the study of nuclear genome organisation in V. faba. PMID- 24172922 TI - Isozyme variation among teak (Tectona grandis L.f.) provenances. AB - Fourteen enzyme systems were analysed in leaf parenchyma of nine native and introduced populations of teak. These enzyme systems were encoded by 20 putative loci of which 18 were polymorphic. Populations showed a general lack of heterozygosity (average FIS = 0.11). On average over the 18 polymorphic loci, the genetic differentiation among provenances varied according to the estimator: 0.09 for GST, 0.12 for FST and 0.19 for delta. The cluster analysis showed two main gene pools, the first consisted of the Indian provenances and the second of African, Indonesian and Thai provenances. Genetic distances among populations of the same group were similar, and lower than the genetic distances between populations from different groups. The factorial analysis on genotypes of seedlings also showed the same geographic differentiation into two major groups. The possible natural distribution of teak in Java is discussed. PMID- 24172923 TI - Allozyme evidence for polyzygotic polyembryony in Siberian stone pine (Pinus sibirica Du Tour). AB - Approximately 4000 mature seeds from 350 trees in nine populations (12-75 trees per population) of Siberian stone pine were investigated for multiple embryos (polyembryony). Haploid megagametophytes and embryos were genotyped for eight allozyme loci. Eight-yone seeds (2.11%) had more than 1 embryo. Of these, 71 seeds had 2 embryos (1.85%), 6 seeds had 3 embryos (0.16%), 3 seeds had 4 embryos (0.08%) and 1 seed had 6 embryos (0.026%). Allozyme comparison of megagametophytes and embryos could distinquish two types of polyembryony in 56 of the 81 seeds. In 28 seeds (50%) the polyembryony was polyzygotic (independent fertilizations of more than one egg cell in the ovule); 25 seeds (45%) had most likely monozygotic polyembryony (genetically identical embryos resulting from the cleavage of a single proembryo) and 3 seeds had both genetically different and genetically identical embryos. To the best of our knowledge, this is the first genetic evidence for the form of polyembryony in conifer seeds. PMID- 24172924 TI - The production of gynogenetic Atlantic salmon, Salmo salar L. AB - The production of Atlantic salmon gynogenomes by the combined use of a novel method for sperm irradiation and differently timed high hydrostatic pressure shocks is described. Sperm solutions were exposed to UV irradiation in a temperature-controlled flow-through device. Eggs fertilised with such sperm were exposed to shocks of 9500 psi at 30 min or approximately 7 h after fertilisation in order to produce meiotic and mitotic gynogenomes respectively. Yields of meiotic gynogenomes were generally high (up to 95%); those of mitotic gynogenomes were lower (range 2-20%). Analyses of the offspring by ploidy status and fingerprinting confirmed their gynogenetic origin. Small numbers of mitotic gynogenetic fish were grown on for 2 years in fresh and salt water. S1/S2 ratios were lower in gynogenetic fish and mean age at maturity was greater. Of the presumptive gynogenetic fish subjected to destructive sampling (n = 87) all were female. PMID- 24172925 TI - Cytological and molecular relationships between Larix decidua, L. leptolepis and Larix x eurolepis: identification of species-specific Chromosoms and synchronization of mitotic cells. AB - The effects of different concentrations of hydroxyurea (HU) and aphidicolin (APH) on the mitotic index (MI) were compared in cells of embryogenic cultures of Larix decidua, L. leptolepis, and L. decidua x L. leptolepis (Larix x eurolepis). The highest enhancement of the MI was obtained with HU at 1.25 mM and 0.6% colchicine. In general the MI decreased with an increase of HU or APH concentration (over 1.25 mM for HU and 5 MUM for APH). Detailed karyotype analyses were made on the somatic complement of L. decidua, L. leptolepis, and their hybrid. These karyotypes were asymmetrical and advanced, with the smaller chromosomes being more submedian than the larger ones. The topography of chromosome 7 of L. decidua and chromosome 9 of L. leptolepis was found to be the most significant cytotaxonomic characteristic in differentiating these two species. Cytological data indicate that Japanese larch (L. leptolepis) is phylogenetically closer to European larch (L. decidua) than the Siberian larch group (L. sibirica and L. sukaczewii). Chromosomes with unusually long kinetochores were found in both species and the hybrid. Hyperploid cells (2n = 25) were observed in the hybrid (Larix x eurolepis) material analyzed. A genomic L. decidua probe hybridized strongly to dots of DNA from L. leptolepis indicating that there is high sequence homology between these two species. PMID- 24172926 TI - A linkage map for sugi (Cryptomeria japonica) based on RFLP, RAPD, and isozyme loci. AB - A linkage map for sugi was constructed on the basis of restriction fragment length polymorphism (RFLP), random amplified polymorphic DNA (RAPD), and isozyme loci using a three-generation pedigree prepared for genetic analysis of heartwood color. A total of 128 RFLP (123 cDNA and 5 genomic probes), 33 RAPD, 2 isozyme, and 1 morphological (dwarf) loci segregated in 73 progeny. Of the 164 segregating loci, 145 loci were distributed in 20 linkage groups. Of these loci, 91 with confirmed map positions were assigned to 13 linkage groups, covering a total of 887.3 cM. A clustering of markers with distorted segregation was observed in 6 linkage groups. In the four clusters, distortions with a reduction in the number of homozygotes from one parent only were found. PMID- 24172927 TI - Determining the linkage of disease-resistance genes to molecular markers: the LOD SCORE method revisited with regard to necessary sample sizes. AB - Some approaches to molecular marker-assisted linkage detection for a dominant disease-resistance trait based on a segregating F2 population are discussed. Analysis of two-point linkage is carried out by the traditional measure of maximum lod score. It depends on (1) the maximum-likelihood estimate of the recombination fraction between the marker and the disease-resistance gene locus, (2) the observed absolute frequencies, and (3) the unknown number of tested individuals. If one replaces the absolute frequencies by expressions depending on the unknown sample size and the maximum-likelihood estimate of recombination value, the conventional rule for significant linkage (maximum lod score exceeds a given linkage threshold) can be resolved for the sample size. For each sub population used for linkage analysis [susceptible (= recessive) individuals, resistant (= dominant) individuals, complete F2] this approach gives a lower bound for the necessary number of individuals required for the detection of significant two-point linkage by the lod-score method. PMID- 24172928 TI - Isozyme diversity in sour, sweet, and ground cherry. AB - Thirty-six sour (Prunus cerasus L.), sweet (P. avium L.), and ground cherry (P. fruticosa Pall.) selections were evaluated for seven enzyme systems and principal coordinate analysis was used to examine isozyme divergence among these cherry species. The enzyme systems studied were phosphoglucose isomerase (PGI), isocitrate dehydrogenase (IDH), phosphoglucomutase (PGM), 6-phosphogluconate dehydrogenase (6-PGD), leucine aminopeptidase (LAP), shikimate dehydrogenase (SKDH), and malate dehydrogenase (MDH). The first principal coordinate, which accounted for 41% of the total variation, separated the diploid sweet cherry selections from the sour, ground, and sour x ground cherry tetraploids. An additional 86 selections were evaluated for up to six of the enzyme systems to determine the polymorphisms at the enzyme loci and the level of heterozygosity between the diploid sweet cherry and the tetraploid species and interspecific hybrids. 6-PGD was the most polymorphic enzyme exhibiting 16 patterns. The tetraploid cherry species were more heterozygous than the diploid sweet cherry with an average heterozygosity of 78% compared to 19% for the diploids. PMID- 24172929 TI - RAPD mapping of three QTLs determining trichome formation in Microseris hybrid H27 (Asteraceae:Lactuceae). AB - Segregation for 289 random amplified polymorphic DNA markers (RAPDs) has been determined in 106 F2 plants of an interspecific hybrid (H27) between Microseris douglasii (strain B14) and M. bigelovii (C94). Multicelluar trichomes ("type D", specific for Microseris) occur on the leaf teeth of early vegetative rosettes of the B14 parent and on the leaf blades of later rosettes in both parents. Trichomes on the leaf blades appear earlier and eventually more densely in B14. Segregation for trichome appearance is quantitative and strongly transgressive in the F2 hybrid. Cosegregation between RAPDs and trichome phenotypes combined with linkage data have revealed a main gene ("quantitative trait locus A", QTL-A) with a pleiotropic effect on all trichome characters and two unlinked additive modifiers (QTL-B, QTL-C). Alleles of both modifiers reduce the main gene effect in each parent. Their recombination explains the occurrence of plants with transgressive phenotypes in the hybrid offspring. Additional QTLs affecting trichomes are at and below the level of statistical significance. PMID- 24172930 TI - Construction of near-isogenic lines to investigate the efficiency of different resistance genes to anthracnose. AB - A suitable experimental model was designed with the aim of investigating the specific effect of different resistance genes in the Phaseolus vulgaris - Colletotrichum lindemuthianum interaction. The four resistance genes examined were chosen because they confer a different phenotype (resistance or susceptibility) to the lines carrying them when challenged by a range of C. lindemuthianum races. These different resistance genes were introgressed independently into the same susceptible recipient line. The isogenicity of the five near-isogenic lines (NILs) thus obtained (four resistant lines, one susceptible line = recipient line) was assessed by a RAPD analysis. The hypersensitive reaction occurred at the same time after infection, whatever the resistance gene present, when the NILs were challenged by the avirulent race 9 of the pathogen. In contrast, the pathogen development was arrested more or less rapidly in the different NILs. At the first stages of the infection process, the transcripts encoding phenylalanine ammonia-lyase were accumulated to a different extent in the different resistant NILs but always to a higher level than in the susceptible recipient line. These results suggest that the different resistance genes operate through more than one way in the production of defense factors. PMID- 24172931 TI - Meiosis and fertility of F1 hybrids between hexaploid bread wheat and decaploid tall wheatgrass (Thinopyrum ponticum). AB - As the first step in the transfer of barely yellow dwarf virus resistance and salt tolerance from decaploid tall wheatgrass (Thinopyrum ponticum) into hexaploid bread wheat (Triticum aestivum L.), octoploid intergeneric hybrids (2n = 8x = 56) were synthesized by crossing the tall wheatgrass cultivar 'Alkar' with wheat cvs. 'Fukuhokomugi' ('Fuko') and 'Chinese Spring'. ('Fuko' x 'Alkar') F1 hybrids were studied in detail. The F1 hybrids were perennial and generally resembled the male wheatgrass parent with regard to morphological features and gliadin profile. Most hybrids were euploid with 56 chromosomes and showed high chromosome pairing. On an average, in 6 hybrids 83.6% of the complement showed chiasmatic association, some between wheat and wheatgrass chromosomes. Such a high homoeologous pairing would be obtained if Ph1, the major homoeologous pairing suppressor in wheat, was somehow inactivated. Some of the 'Fuko' x 'Alkar' hybrids had high pollen fertility (18.5-42.0% with a mean of 31.5%) and high seed fertility (3-29 seeds wtih a mean of 12.3 seeds per spike), offering excellent opportunities for their direct backcrossing onto the wheat parent. PMID- 24172932 TI - Morphological and cytological characteristics of some wheat x barley hybrids. AB - As initial step in the transfer of dwarf bunt resistance from barley into wheat, the two cereal crops were hybridized. Using the wheat cultivars 'Fukuhokomugi' and 'Chinese Spring' (AABBDD genomes) as female parents and barley cultivar 'Luther' (II genome) as male, we synthesized 9 euploid hybrids (2n = 4x = 28; ABDI genomes). The hybrids were vigorous, but highly sterile. Meiotic analyses of seven hybrids showed considerable variation in chromosome pairing. Of the hybrids involving 'Fukuhokomugi' 3 had high pairing with a mean of 5.08-6.72 chiasmata per cell, while others had 2.16-3.52 chiasmata per cell. As many as 12 bivalents in some pollen mother cells would suggest at least some pairing between wheat and barley chromosomes. This level of homoeologous pairing, coupled with some, albeit low, female fertility of the F1 hybrids, could offer an opportunity for intergeneric gene transfers from barley into wheat and vice versa. PMID- 24172933 TI - Identification of a set of RFLP probes for subspecies differentiation in Oryza sativa L. AB - Sixty-eight indica-japonica tester-differentiating RFLP probes were tested in seven indica and seven japonica varieties of rice (Oryza sativa L.) with four enzyme digestions (EcoRI, EcoRV, HindIII and DraI). Twenty-one DNA clones were isolated as indica-japonica subspecies-differentiating probes. A set of 13 probes was established as core probes for subspecies differentiation and a pooled blotting analysis was carried out to facilitate the application of RFLP in rice genetics and breeding practice. A dendrogram of 12 wide-compatibility varieties was constructed based on RFLPs detected by 13 core probes with single enzyme digestions. It was speculated that most RFLPs of indica-japonica differentiating probes were generated by insertions/deletions, which may be of great significance for the origin and differentiation of subspecies in Oryza sativa L. PMID- 24172934 TI - Isolation and characterization of RAPD-based markers linked to the beet cyst nematode resistance locus (Hs1 (pat-1)) on chromosome 1 of B. patellaris. AB - A beet cyst nematode (BCN)-resistant telosomic addition of B. patellaris chromosome 1 in B. vulgaris was used to isolate 6 RAPD markers linked to the BCN resistance locus Hs1 (pat-1). Southern analysis showed that the analyzed RAPD products contain either low-, middle or high-repetitive DNA. The relative positions of the random amplified polymorphic DNA (RAPD) markers and of the restriction fragment length polymorphism (RFLP) loci corresponding to the low repetitive RAPD products were determined by deletion mapping using a panel of seven nematode-resistant B. patellaris chromosome-1 fragment additions. One RAPD marker, OPB11800, was found to be present in two copies on the long arm telosome of B. patellaris chromosome 1. These copies are closely linked to the BCN resistance gene and flank the gene on both sides. On the basis of the nucleotide sequence of OPB11800, sequence-tagged site (STS) primers were developed that amplify specific fragments derived from the two OPB11800 loci. These STS markers can be used in the map-based cloning of the BCN gene, as they define start and finishing points of a chromosomal walk towards the Hs1 (pat-1) locus. Two copies of the middle-repetitive OPX21100 marker were mapped in the same interval of the deletion mapping panel as the resistance gene locus and thereby belong to the nearest markers as yet found for the BCN gene in B. patellaris. PMID- 24172935 TI - Factors affecting Citrus tree isozyme-gene expression. AB - Ten enzymatic systems of Citrus species and cultivars have been evaluated for identification purposes and for genetic variability studies. The following factors that could affect their expression were studied: season of sampling, location, rootstock, position of the branch, infection, and age of the tree. Differences involving the presence-absence of the Cu/Zn SOD within the same tree were found. This difference is mainly related to the position of the leaf relative to the sunlight. No change was observed at any of the ten enzymatic systems assayed regarding the location, the rootstock, the growing condition, the season, or the infection with most virus and virus-like pathogens. Viroids induced noticeable changes on 6PG and PRXa zymograms in C. medica. A new peroxidase (not present in healthy plants) was detected that could be related to appearance of symptoms. This may induce errors when trees without sanitary control are characterized by this enzymatic system. On the other hand, it provides a new possibility for studying the plant response to the presence of viroids. An effect of age, from 3 months up to 12 years, was observed on citrange Troyer and mandarin Cleopatra PRX, MDH and 6PG patterns. An important change occurs around the first year, most likely related to the end of the seedling stage. This is followed by a long transition phase, the end of which (around 9 years later) coincides with a change in the PRX pattern. These age-related changes seem to involve post-translational modifications of pre-existing isozymes. PMID- 24172936 TI - Use of seedling progeny tests for genetical studies as part of a potato (Solanum tuberosum subsp. tuberosum) breeding programme. AB - A diallel set of crosses, including selfs and some reciprocal crosses, was made between 15 parents chosen for their male fertility from those included in a tetraploid potato (Solanum tuberosum subsp. tuberosum) breeding programme at the Scottish Crop Research Institute. Seedling progeny tests were used to evaluate the progenies for non-race-specific resistance to late blight (Phytophthora infestans) in both foliage and tubers, quantitative resistance to the white potato cystnematode (PCN) (Globodera pallida) and the commercial worth of their tubers as judged by breeders' visual preference. No reciprocal differences were found. Comparisons of the selfs and crosses revealed inbreeding depression for breeders' preference, which varied among the parents from negligible to severe, whilst there were also statistically significant differences for foliage and tuber blight, but not for PCN. When the selfs were omitted from the combining ability analyses, large differences in general combining ability (GCA) were found for all four traits, and smaller differences in specific combining ability for tuber blight and breeders' preference. The only statistically significant correlation between GCAs for different traits was a favourable one of r = 0.56 between foliage and tuber resistance to late blight. It was concluded that prospects were good for simultaneously improving all four traits by multitrait genotypic recurrent selection. PMID- 24172937 TI - Effects of cardiorespiratory fitness enhancement on deficits in visuospatial working memory in children with developmental coordination disorder: a cognitive electrophysiological study. AB - The present study aimed to explore the effectiveness of chronic aerobic exercise intervention on the behavioral and neuroelectric performances of children with developmental coordination disorder (DCD) when carrying out a visuospatial working memory (VSWM) task. Twenty typically developing children and 40 children with DCD, equally divided into DCD-training and DCD nontraining groups, performed the cognitive task with concomitant event-related potential recording before and after 16 weeks of endurance training. Results indicated that the children with DCD displayed VSWM deficits with regard to behavioral performance (i.e., slower reaction time and low accuracy rate) and the neuroelectric indices (i.e., smaller P3 and pSW amplitudes) during the retrieval-process phase as reported in previous studies. However, after the exercise intervention, DCD-training group showed significantly higher accuracy rates and enhanced P3 amplitudes during the encoding and retrieval-process phases, compared with their pre-training performances. These findings suggest that increased cardiorespiratory fitness could effectively improve the performance of the VSWM task in children with DCD, by enabling the allocation of greater working memory resources related to encoding and retrieval. PMID- 24172938 TI - Anti-prothrombin (aPT) and anti-phosphatidylserine/prothrombin (aPS/PT) antibodies and the risk of thrombosis in the antiphospholipid syndrome. A systematic review. AB - Antibodies to prothrombin are detected by directly coating prothrombin on irradiated ELISA plates (aPT) or by using the phosphatidylserine/prothrombin complex as antigen (aPS/PT). Although these antibodies have both been associated with antiphospholipid syndrome (APS) and a correlation between the two assays have been reported, it seems that aPT and aPS/PT belong to different populations of autoantibodies. It was our objective to systematically review the available evidence on aPT and aPS/PT antibodies and the risk of thrombosis in APS. Medline reports published between 1988 and 2013 investigating aPT and aPS/PT as a risk factor for thrombosis were included. Whenever possible, antibody isotype(s) and site of thrombosis were analysed. This systematic review is based on available data from more than 7,000 patients and controls from 38 studies analysing aPT and 10 aPS/PT. Antibodies to prothrombin (both aPT and aPS/PT) increased the risk of thrombosis (odds ratio [OR] 2.3; 95% confidence interval [CI] 1.72-3.5). aPS/PT seemed to represent a stronger risk factor for thrombosis, both arterial and/or venous than aPT (OR 5.11; 95%CI 4.2-6.3 and OR 1.82; 95%CI 1.44-2.75, respectively). In conclusion, routine measurement of aPS/PT (but not aPT) might be useful in establishing the thrombotic risk of patients with previous thrombosis and/or systemic lupus erythematosus. Their inclusion as laboratory criteria for the APS should be indisputably further explored. PMID- 24172939 TI - Malaria surveillance--United States, 2011. AB - PROBLEM/CONDITION: Malaria in humans is caused by intraerythrocytic protozoa of the genus Plasmodium. These parasites are transmitted by the bite of an infective female Anopheles mosquito. The majority of malaria infections in the United States occur among persons who have traveled to regions with ongoing malaria transmission. However, malaria is also occasionally acquired by persons who have not traveled out of the country, through exposure to infected blood products, congenital transmission, laboratory exposure, or local mosquitoborne transmission. Malaria surveillance in the United States is conducted to identify episodes of local transmission and to guide prevention recommendations for travelers. PERIOD COVERED: This report summarizes cases in persons with onset of illness in 2011 and summarizes trends during previous years. DESCRIPTION OF SYSTEM: Malaria cases diagnosed by blood film, polymerase chain reaction, or rapid diagnostic tests are mandated to be reported to local and state health departments by health-care providers or laboratory staff. Case investigations are conducted by local and state health departments, and reports are transmitted to CDC through the National Malaria Surveillance System, National Notifiable Diseases Surveillance System, or direct CDC consults. Data from these reporting systems serve as the basis for this report. RESULTS: CDC received 1,925 reported cases of malaria with an onset of symptoms in 2011 among persons in the United States, including 1,920 cases classified as imported, one laboratory-acquired case, one transfusion-related case, two congenital cases, and one cryptic case. The total number of cases represents an increase of 14% from the 1,691 cases reported for 2010 and the largest number of reported cases since 1971. Plasmodium falciparum, P. vivax, P. malariae, and P. ovale were identified in 49%, 22%, 3%, and 3% of cases, respectively. Twenty-one (1%) patients were infected by two species. The infecting species was unreported or undetermined in 23% of cases, an increase of 5 percentage points from 2010. Of the 871 patients who reported purpose of travel, 607 (70%) were visiting friends or relatives (VFR). Among the 929 cases in U.S. civilians for whom information on chemoprophylaxis use and travel region was known, 57 (6%) patients reported that they had followed and adhered to a chemoprophylactic drug regimen recommended by CDC for the regions to which they had traveled. Thirty-seven cases were reported in pregnant women, among whom only one adhered to chemoprophylaxis. Among all reported cases, significantly more cases (n=275 [14%]) were classified as severe infections in 2011 compared with 2010 (n=183 [11%]; p=0.0018; chi square). Five persons with malaria died in 2011. After 2 years of improvement in completion of data elements on the malaria case form, higher percentages of incomplete data in 2011 for residential status (from 11% in 2010 to 19% in 2011) and species (from 18% in 2010 to 22% in 2011) were noted. INTERPRETATION: The number of cases reported in 2011 marked the largest number of cases since 1971 (N = 3,180). Despite progress in reducing the global burden of malaria, the disease remains endemic in many regions, and the use of appropriate prevention measures by travelers is still inadequate. PUBLIC HEALTH ACTIONS: Completion of data elements on the malaria case report form decreased in 2011 compared with 2010. This incomplete reporting compromises efforts to examine trends in malaria cases and prevent infections. VFR travelers continue to be a difficult population to reach with effective malaria prevention strategies. Evidence-based prevention strategies that effectively target VFR travelers need to be developed and implemented to have a substantial impact on the numbers of imported malaria cases in the United States. Although more persons with cases reported taking chemoprophylaxis to prevent malaria, the majority reported not taking it, and adherence was poor among those who did take chemoprophylaxis. Proper use of malaria chemoprophylaxis will prevent the majority of malaria illness and reduce the risk for severe disease (http://www.cdc.gov/malaria/travelers/drugs.html). Malaria infections can be fatal if not diagnosed and treated promptly with antimalarial medications appropriate for the patient's age and medical history, the likely country of malaria acquisition, and previous use of antimalarial chemoprophylaxis. Clinicians should consult the CDC Guidelines for Treatment of Malaria and contact the CDC's Malaria Hotline for case management advice, when needed. Malaria treatment recommendations can be obtained online (http://www.cdc.gov/malaria/diagnosis_treatment) or by calling the Malaria Hotline (770-488-7788 or toll-free at 855-856-4713). PMID- 24172940 TI - Mn12 single molecule magnets deposited on MU-SQUID sensors: the role of interphases and structural modifications. AB - Direct measurements of the linear ac susceptibility and magnetic relaxation of a few Mn12 monolayers deposited on a MU-SQUID sensor are reported. In order to integrate the molecules into the device, DPN has been the technique of choice. It enabled the structuration of the molecules on the most sensitive areas of the sensor without the need for any previous functionalization of the molecule or the substrate, while controlling the number of molecular units deposited on each array. The measurements reveal that their characteristic SMM behaviour is lost, a fact that is attributed to molecular distortions originated by the strong surface tensions arising at the molecular interphases. PMID- 24172942 TI - Science's rightful place is in service of society. PMID- 24172941 TI - TRPA1 detects environmental chemicals and induces avoidance behavior and arousal from sleep. AB - Detecting threats and escaping before serious confrontations are important for animals to avoid danger and death. Transient receptor potential ankyrin 1 (TRPA1), a member of the TRP superfamily, is expressed in a subset of sensory neurons and mediates nociception evoked by pungent chemicals. Using behavioral testing, we found that TRPA1 knockout mice failed to avoid entering a chamber filled with vapor of formalin, allyl isothiocyanate, and acrolein. The avoidance behavior was blocked by nasal but not subcutaneous administration of a blocker to TRPA1. We also found that TRPA1 knockout mice did not wake when exposed to formalin during sleep. Additionally, the spinal trigeminal nucleus, the first relay neurons of the trigeminal system, showed massive expression of c-Fos after a brief (3 min) exposure to formalin vapor. TRPA1 seems to be a sentinel for environmental chemicals and induces avoidance behaviors and waking by way of the trigeminal system. PMID- 24172954 TI - Polio risk looms over Europe. PMID- 24172955 TI - Root of maths genius sought. PMID- 24172956 TI - Black holes shrink but endure. PMID- 24172957 TI - Lightning network tested out in Guinea. PMID- 24172958 TI - Astronomers revisit dwarf stars' promise. PMID- 24172960 TI - Farmers dig into soil quality. PMID- 24172961 TI - Astronomy: Southern star. PMID- 24172962 TI - Ecology: Lady of the lakes. PMID- 24172967 TI - Anthropocene: keep the guard up. PMID- 24172968 TI - Visual acuity: Bird vision offers sharp insight. PMID- 24172969 TI - Anthropocene: action makes sense. PMID- 24172970 TI - IPCC: Climate panel is ripe for examination. PMID- 24172971 TI - City trees: Urban greening needs better data. PMID- 24172972 TI - David Hunter Hubel (1926-2013). PMID- 24172973 TI - Ecology: Drivers of decoupling in drylands. PMID- 24172975 TI - Water management: The data gap. PMID- 24172976 TI - A uniform metal distribution in the intergalactic medium of the Perseus cluster of galaxies. AB - Most of the metals (elements heavier than helium) produced by stars in the member galaxies of clusters currently reside within the hot, X-ray-emitting intra cluster gas. Observations of X-ray line emission from this intergalactic medium have suggested a relatively small cluster-to-cluster scatter outside the cluster centres and enrichment with iron out to large radii, leading to the idea that the metal enrichment occurred early in the history of the Universe. Models with early enrichment predict a uniform metal distribution at large radii in clusters, whereas those with late-time enrichment are expected to introduce significant spatial variations of the metallicity. To discriminate clearly between these competing models, it is essential to test for potential inhomogeneities by measuring the abundances out to large radii along multiple directions in clusters, which has not hitherto been done. Here we report a remarkably uniform iron abundance, as a function of radius and azimuth, that is statistically consistent with a constant value of ZFe = 0.306 +/- 0.012 in solar units out to the edge of the nearby Perseus cluster. This homogeneous distribution requires that most of the metal enrichment of the intergalactic medium occurred before the cluster formed, probably more than ten billion years ago, during the period of maximal star formation and black hole activity. PMID- 24172977 TI - Coupling a single electron to a Bose-Einstein condensate. AB - The coupling of electrons to matter lies at the heart of our understanding of material properties such as electrical conductivity. Electron-phonon coupling can lead to the formation of a Cooper pair out of two repelling electrons, which forms the basis for Bardeen-Cooper-Schrieffer superconductivity. Here we study the interaction of a single localized electron with a Bose-Einstein condensate and show that the electron can excite phonons and eventually trigger a collective oscillation of the whole condensate. We find that the coupling is surprisingly strong compared to that of ionic impurities, owing to the more favourable mass ratio. The electron is held in place by a single charged ionic core, forming a Rydberg bound state. This Rydberg electron is described by a wavefunction extending to a size of up to eight micrometres, comparable to the dimensions of the condensate. In such a state, corresponding to a principal quantum number of n = 202, the Rydberg electron is interacting with several tens of thousands of condensed atoms contained within its orbit. We observe surprisingly long lifetimes and finite size effects caused by the electron exploring the outer regions of the condensate. We anticipate future experiments on electron orbital imaging, the investigation of phonon-mediated coupling of single electrons, and applications in quantum optics. PMID- 24172978 TI - Gradual demise of a thin southern Laurentide ice sheet recorded by Mississippi drainage. AB - At the Last Glacial Maximum (LGM), about 21,000 years before present, land-based ice sheets held enough water to reduce global mean sea level by 130 metres. Yet after decades of study, major uncertainties remain as to the distribution of that ice. Here we test four reconstructions of North American deglacial ice-sheet history by quantitatively connecting them to high-resolution oxygen isotope (delta(18)O) records from the Gulf of Mexico using a water mixing model. For each reconstruction, we route meltwater and seasonal runoff through the time-evolving Mississippi drainage basin, which co-evolves with ice geometry and changing topography as ice loads deform the solid Earth and produce spatially variable sea level in a process known as glacial isostatic adjustment. The delta(18)O records show that the Mississippi-drained southern Laurentide ice sheet contributed only 5.4 +/- 2.1 metres to global sea level rise, of which 0.66 +/- 0.07 metres were released during the meltwater pulse 1A event 14,650-14,310 years before present, far less water than previously thought. In contrast, the three reconstructions based on glacial isostatic adjustment overpredict the delta(18)O-based post-LGM meltwater volume by a factor of 1.6 to 3.6. The fourth reconstruction, which is based on ice physics, has a low enough Mississippi-routed meltwater discharge to be consistent with delta(18)O constraints, but also contains the largest LGM North American ice volume. This suggests that modelling based on ice physics may be the best way of matching isotopic records while also sequestering enough water in the North American ice sheets to match the observed LGM sea level fall. PMID- 24172979 TI - Decoupling of soil nutrient cycles as a function of aridity in global drylands. AB - The biogeochemical cycles of carbon (C), nitrogen (N) and phosphorus (P) are interlinked by primary production, respiration and decomposition in terrestrial ecosystems. It has been suggested that the C, N and P cycles could become uncoupled under rapid climate change because of the different degrees of control exerted on the supply of these elements by biological and geochemical processes. Climatic controls on biogeochemical cycles are particularly relevant in arid, semi-arid and dry sub-humid ecosystems (drylands) because their biological activity is mainly driven by water availability. The increase in aridity predicted for the twenty-first century in many drylands worldwide may therefore threaten the balance between these cycles, differentially affecting the availability of essential nutrients. Here we evaluate how aridity affects the balance between C, N and P in soils collected from 224 dryland sites from all continents except Antarctica. We find a negative effect of aridity on the concentration of soil organic C and total N, but a positive effect on the concentration of inorganic P. Aridity is negatively related to plant cover, which may favour the dominance of physical processes such as rock weathering, a major source of P to ecosystems, over biological processes that provide more C and N, such as litter decomposition. Our findings suggest that any predicted increase in aridity with climate change will probably reduce the concentrations of N and C in global drylands, but increase that of P. These changes would uncouple the C, N and P cycles in drylands and could negatively affect the provision of key services provided by these ecosystems. PMID- 24172981 TI - Knockdown of LGR5 suppresses the proliferation of glioma cells in vitro and in vivo. AB - Leucine-rich repeat containing G protein-coupled receptor 5 (LGR5), one of the target genes of the Wnt signaling pathway, has recently been identified as a marker for brain cancer stem-like cells. However, the role of LGR5 in glioma is poorly understood. The aim of the present study was to investigate the relationship between LGR5 expression and pathological grade in glioma, and the impact of LGR5 on the proliferation of glioma cells in vitro and in vivo. Firstly, LGR5 expression was immunohistochemically evaluated in 54 resected gliomas of different pathologic grades, and its association with Ki-67 was evaluated. Subsequently, using western blotting and qRT-PCR, the expression of LGR5 was assessed in three glioma cell lines U87, U118 and U251. Moreover, the effects of LGR5 knockdown by siRNA on glioma cell proliferation, cell cycle, clone formation and tumorsphere formation in vitro and gliomagenesis in vivo were assessed. The results revealed that i) LGR5 was positively expressed in all glioma specimens and its expression increased with pathologic grade and Ki-67 expression; ii) LGR5 was highly expressed in three glioma cell lines and its expression was reduced significantly by siRNA; and iii) RNAi-mediated downregulation of endogenous LGR5 in U87 cells resulted in the suppression of cell proliferation, arrest of the cell cycle, and reduction in clone and tumorsphere formation in vitro. In addition, LGR5 depletion significantly inhibited tumor orthotopic xenograft growth in nude mice. These findings indicate that LGR5 plays a major role in gliomagenesis by promoting neoplastic cell proliferation, suggesting LGR5 as a molecular marker for pathology and a novel therapeutic target for malignant glioma. PMID- 24172982 TI - Intercellular communication and some structural aspects of membrane junctions in a simple cell system. AB - AChironomus salivary gland consists of a chain of 30 giant cells (G-cells) and 4 to 6 flat cells (F-cells) spanning a lumen. The surface membranes of these cells are linked by two kinds of organized structures: theseptate junction, taking up nearly the entire surface of cell contact, and thegap junction, occupying a small fraction of this surface. (These junctional structures are examined in the electron microscope after La infiltration.) All cells are joined to their immediate neighbors by septate junctions, the G- to G-cells, the F- to F-cells, and the F- to G-cells; the G-cells, at least, are also joined by gap junctions. All cells are also in communication with each other: small inorganic ions, fluorescein (mol. wt. 330) and Procion Yellow (mol. wt. ~550) pass from one cell interior to the next. PMID- 24172983 TI - Junctional membrane permeability : Depression by substitution of Li for extracellular Na, and by long-term lack of Ca and Mg; restoration by cell repolarization. AB - Substitution of extracellular Na(+) by Li(+) causes depression of junctional membrane permeability inChironomus salivary gland cells; within 3 hr, permeability falls to so low a level that neither fluorescein nor the smaller inorganic ions any longer traverse the junctional membrane in detectable amounts (uncoupling). The effect is Li-specific: if choline(+) is the Na(+) substitute, coupling is unchanged. The Li-produced uncoupling is not reversed by restitution of Na(+). Long-term exposure (>1 hr) of the cells to Ca, Mg-free medium leads also to uncoupling. This uncoupling is fully reversible by early restitution of Ca(++) or Mg(++). Coupling is maintained in the presence of either Ca(++) or Mg(++), so long as the total divalent concentration is about 12MM. The uncoupling in Ca, Mg-free medium ensues regardless of whether the main monovalent cation is Na, Li or choline.The uncouplings are accompanied by cell depolarization. Repolarization of the cells by inward current causes restoration of coupling; the junctional conductance rises again to its normal level. The effect was shown for Li-produced uncoupling, for uncoupling by prolonged absence of external Ca(++) and Mg(++), and for uncoupling produced by dinitrophenol. In all cases, the recoupling has the same features: (1) it develops rapidly upon application of the polarizing current; (2) it is cumulative; (3) it is transient, but outlasts the current; and (4) it appears not to depend on the particular ions carrying the current from the electrodes to the cell. The recoupling is due to repolarization of nonjunctional cell membrane; recoupling can be produced at zero net currernt through the junctional membrane. Recoupling takes place also as a result of chemically produced repolarization; restoration of theK gradients in uncoupled cells causes partial recoupling during the repolarization phase.An explanation of the results on coupling is proposed in terms of known mechanisms of regulation of Ca(++) flux in cells. The uncouplings are explained by actions raising the Ca(++) level in the cytoplasmic environment of the junctional membranes; the recoupling is explained by actions lowering this Ca(++) level. PMID- 24172984 TI - Junctional membrane permeability : Effects of divalent cations. AB - Junctional membranes ofChironomus salivary gland cells were exposed to test media of varying divalent cation concentration through a hole (estimated diameter ~10 MU) in a cell's nonjunctional surface membrane. Junctional conductance is markedly depressed by Ca(++), Mg(++), Sr(++), Ba(++) and Mn(++). The order of potency is Ca(++)>Mg(++)>Sr(++)>Ba(++); the minimal effective concentration for Ca is 4 to 8*10(-5) M. Tests with Ca(++) show that, at least, this ion also depresses junctional permeability to fluorescein (mol. wt. 330). The permeability depression is confined to the junctional membranes to which (exogenous) Ca(++) has direct access via the hole. The permeability change produced by Ca(++) is apparently fast enough to limit transjunctional flux of this ion. The depression is reversed by repolarization of the nonjunctional membrane with inward current when the junctional membrane is exposed to divalent cation-free medium, but not when it is exposed to medium containing 10(-3) M Ca.Perforation of the nonjunctional membrane in divalent cation-free medium leads to transient depression of junctional permeability when the membrane hole is large enough to cause nearly complete cell depolarization. This depression can be prevented by clamping the membrane potential with inward current. Smaller holes (estimated diameter ~2 MU) seal in the presence of divalent cations; the ion diffusion barrier is restored within 14 to 30 min of divalent cation application. PMID- 24172985 TI - Ion metabolism in aHalobacterium : II. Ion concentrations in cells at different levels of metabolism. AB - The changes in concentration of K(+), Na(+) and Cl(-) are given in growing cultures of aHalobacterium species subjected to cold, lack of O2 or starvation. In growing cells, the ion concentration ratios across the cell membrane were 1,000?1 (inside:outside) for K(+) and 1?2 for Na(+). In bacteria with a low rate of endogenous metabolism induced by 24-hr starvation, the ratios were 500?1 for K(+) and 1?4 for Na(+). O2 and a substrate were required for K(+) uptake in growing bacteria, but not for the maintenance of K(+) and Na(+) gradients in starving bacteria. The exchange of K(+), Na(+) and Li(+) across the cell membrane of starving bacteria was found to have a time constant for 50% completion of the process of 20 to 30 sec. The exchange of cell Cl(-) with NO 3 (-) was a twostage process with time constants of approximately 2 min and 2-1/2 hr. The results are explained in terms of the binding of most of the cell K(+) which brings about the distribution of Na(+) and Cl(-) according to the Gibbs-Donnan equilibrium; the role of metabolism is to induce changes in the mean ion-activity coefficients. PMID- 24172986 TI - Changes in extrinsic fluorescence intensity of the electroplax membrane during electrical excitation. AB - The fluorescent dye 1-anilinonapthalene-8-sulfonic acid (ANS) has been used as a probe of changes in membrane conformation accompanying excitation of the electroplax ofElectrophorus electricus. ANS binds reversibly to the excitable membrane at rest. During generation of an action potential, an increase in ANS fluorescence intensity is observed which resembles but does not strictly follow the membrane potential. Experiments using the current-clamp technique have demonstrated a linear relationship between the change in membrane potential and the change in ANS fluorescence intensity. The change in fluorescence intensity is not a consequence of binding to membrane sites of increased affinity nor of an electrophoretic concentration of ANS molecules at the membrane surface.It is not known whether the change in fluorescence intensity is due to a change in quantum yield of bound ANS or to an increase in the amount of bound ANS. In either case, the change in fluorescence intensity may be interpreted as a change in membrane conformation. PMID- 24172987 TI - A small GTPase-like protein fragment of Mycoplasma promotes tumor cell migration and proliferation in vitro via interaction with Rac1 and Stat3. AB - The Mycoplasma genus comprises a group of microbes that cause persistent infection in humans and its role in promoting tumor development has long been a concern. Although mixtures of components isolated from Mycoplasma have been shown to activate host Rho family small GTPases and Stat3, no individual factor with this activity has been reported. In the current study, a conserved small GTPase like protein fragment (SGLP) from Mycoplasma pulmonis chromosome partition protein, Smc, was identified as a virulence factor. SGLP was observed to interact with Rac1 and Stat3. The wild-type (wt) SGLP, which contains a WxxxE motif, induced activation of Rac1 and phosphorylation of Stat3 at the tyrosine-705 residue, while the SGLP mutant containing a mutation from WxxxE to AxxxA did not exert the same effects. Moreover, SGLP-induced Stat3 phosphorylation was observed to be dependent upon Rac1 activity. Furthermore, wt SGLP was observed to promote cell migration and increase bromodeoxyuridine incorporation in HeLa cells and the SGLP mutant did not elicit these effects in HeLa cells. In conclusion, the current observations suggest that SGLP is an important virulence factor of Mycoplasma, which contributes to tumor cell migration and proliferation in vitro via interaction with Rac1 and Stat3. PMID- 24172988 TI - Molecular imaging based on x-ray fluorescent high-Z tracers. AB - We propose a novel x-ray fluorescence imaging setup for the in vivo detection of high-Z tracer distributions. The main novel aspect is the use of an analyzer based, energy-resolved detection method together with a radial, scatter reducing collimator. The aim of this work is to show the feasibility of this method by measuring the Bragg reflected K-fluorescence signal of an iodine solution sample in a proof of principle experiment and to estimate the potential of the complete imaging setup using a Monte Carlo simulation, including a quantification of the minimal detectable tracer concentration for in vivo imaging. The proof of principle experiment shows that even for a small detector area of approximately 7 mm(2), the collimated and Bragg reflected K-fluorescence signal of a sample containing an iodine solution with a concentration of 50 ug ml(-1) can be detected. The Monte Carlo simulation also shows that the proposed x-ray fluorescence imaging setup has the potential to image distributions of high-Z tracers in vivo at a radiation dose of a few mGy and at tracer concentrations down to 1 ug ml(-1) for iodine in small animals. PMID- 24172999 TI - Challenges in optimizing isotretinoin use for acne vulgaris. PMID- 24173000 TI - Riociguat approved for pulmonary hypertension. PMID- 24173001 TI - Congressional fellows help set health care policy. PMID- 24173002 TI - Antiretroviral stewardship program reduces drug errors. PMID- 24173004 TI - Incompatibility of ciprofloxacin and meropenem injections. PMID- 24173005 TI - Stability of cyclosporine diluted with 0.9% sodium chloride injection or 5% dextrose injection and stored in ethylene-vinyl acetate containers. PMID- 24173006 TI - Clinical video telehealth in a cardiology pharmacotherapy clinic. PMID- 24173007 TI - Risk of posttransplant lymphoproliferative disorder associated with use of belatacept. AB - PURPOSE: Published evidence on a rare but serious malignancy associated with use of the first biological agent approved for long-term maintenance immunosuppression in renal transplant recipients is reviewed. SUMMARY: Belatacept (Nulojix, Bristol-Myers Squibb) is approved by the Food and Drug Administration for use in combination therapy to prevent renal graft rejection in patients who are Epstein-Barr virus seropositive. Belatacept appears to offer some advantages over calcineurin inhibitor-based regimens (e.g., no need for therapeutic drug monitoring), but its use poses a risk of posttransplant lymphoproliferative disorder (PTLD), a rapidly progressing and often lethal malignancy. The efficacy and safety of more-intensive and less-intensive belatacept regimens were established in two Phase III clinical trials, which found that rates of patient and graft survival were comparable to those in cyclosporine users; belatacept was shown to be superior in preserving renal function. The occurrence of PTLD, particularly PTLD involving the central nervous system, in 0-4% of belatacept treated patients in clinical trials prompted postmarketing initiatives: (1) implementation of a risk evaluation and mitigation strategy (REMS) program to help ensure the safe and proper use of belatacept, (2) longitudinal studies to better define the risks and outcomes of belatacept therapy, and (3) a manufacturer-created patient registry to track belatacept use and encourage voluntary reporting of associated adverse events. CONCLUSION: Appropriate patient selection and adherence to REMS requirements, including patient counseling and facilitation of registry enrollment, are essential in mitigating the increased risk of PTLD associated with belatacept therapy. PMID- 24173008 TI - A review of tuberculosis: Focus on bedaquiline. AB - PURPOSE: The history and prevalence of tuberculosis and the role of bedaquiline in multidrug-resistant (MDR) tuberculosis are reviewed. SUMMARY: Tuberculosis continues to cause significant morbidity and mortality worldwide. Increasing rates of drug-resistant tuberculosis are a significant concern and pose serious implications for current and future treatment of the disease. In December 2012, the Food and Drug Administration approved bedaquiline as part of the treatment regimen for pulmonary MDR tuberculosis. Bedaquiline's unique mechanism of action presents an alternative approach to current antimycobacterial killing. By directly inhibiting adenosine triphosphate (ATP) synthase, bedaquiline is effective against both replicating and dormant mycobacteria. Pulmonary cavitary lesions can contain heterogeneous populations. This potential mix of semireplicating and hypometabolic mycobacteria is more difficult to eliminate with conventional antitubercular drugs, thus increasing the risk of resistance. No in vitro cross-resistance between bedaquiline and currently available antitubercular agents has been observed thus far. Because bedaquiline targets a completely different enzyme, cross-resistance with other conventional agents remains unlikely. Enhanced sterilizing capacity via synergistic depletion of ATP further exhibits the promising potential of bedaquiline with pyrazinamide. A course of bedaquiline requires 24 weeks of therapy in combination with other antitubercular drugs. CONCLUSION: The approval of bedaquiline represents a major milestone in MDR tuberculosis therapy. Bedaquiline should be considered in patients who have not responded to a regimen containing four second-line drugs and pyrazinamide and patients with documented evidence of MDR tuberculosis resistant to fluoroquinolones. The exact role of bedaquiline cannot be determined until further efficacy and safety data are obtained through ongoing Phase III trials. PMID- 24173009 TI - Biosimilars: Implications for health-system pharmacists. AB - PURPOSE: An update on scientific and regulatory challenges in the rapidly evolving field of biosimilar product development is presented. SUMMARY: The U.S. market for biosimilar products (i.e., highly similar "follow-on" versions of approved biological drugs) is expected to expand with establishment of an expedited-approval pathway for biosimilars similar to that implemented in European Union countries eight years ago. In 2012, the Food and Drug Administration (FDA) published draft guidance clarifying the requirements of the biosimilars approval pathway; although no biosimilar has yet been approved via that pathway, FDA is engaged in ongoing meetings with a number of potential applicants. Due to molecular differences between innovator products and biosimilar versions, biosimilars are highly sensitive to manufacturing changes that can potentially have important safety and efficacy implications. Establishing the interchangeability of biosimilar and innovator drugs may be difficult at first, and it is possible that some biosimilars might not carry all the same indications for which the reference drug is approved. Pharmaceutical cost savings attained through the use of biosimilars are expected to average 20 30%. With several top-selling biologicals likely to lose patent exclusivity by 2020, health systems should prepare for the availability of new biosimilars by addressing formulary management and therapeutic interchange issues, pharmacovigilance and patient safety concerns, and related financial and operational issues. CONCLUSION: Over the coming years, biosimilars will present opportunities for health care organizations to manage the growth of pharmaceutical expenditures. Pharmacists can play a key role in preparing health systems for projected rapid expansion in the use of biosimilars and associated medication-use policy challenges. PMID- 24173010 TI - Implementation of a nontraditional postgraduate year 1 pharmacy residency program. AB - PURPOSE: The development and implementation of a nontraditional pharmacy residency program at a Veterans Affairs medical center (VAMC) are described. SUMMARY: The nontraditional pharmacy residency program at Lebanon VAMC was designed in accordance with the ASHP accreditation standard. The residency program was structured to meet staff needs without compromising patient care or significantly affecting the pharmacy services provided. The purpose statement, intended outcomes, and learning goals and objectives of the nontraditional pharmacy residency program were formulated to be equivalent to those of a traditional one-year pharmacy residency program, enabling practicing pharmacists to obtain similar overall learning experiences. The nontraditional residency program at Lebanon VAMC spans two years. The non-traditional program structure is based on a four- to six-week residency learning experience that alternates with a comparable time in the work schedule. Each required or elective learning experience ranges from four to six weeks. Longitudinal learning experiences may extend up to two years. One pharmacist was matched and began the residency in July 2012 as the inaugural nontraditional postgraduate year 1 (PGY1) pharmacy resident at Lebanon VAMC, the second institution to implement the nontraditional program within the Veterans Health Administration. The resident is expected to complete the program in June 2014 and remain committed to the Lebanon VAMC pharmacy service for a minimum of two years thereafter. CONCLUSION: A nontraditional PGY1 pharmacy residency program was successfully developed and implemented for pharmacists who aspire to complete residency training and improve their clinical, leadership, and preceptorship skills. PMID- 24173011 TI - Implementation of an i.v.-compounding robot in a hospital-based cancer center pharmacy. AB - PURPOSE: The implementation of a robotic device for compounding patient-specific chemotherapy doses is described, including a review of data on the robot's performance over a 13-month period. SUMMARY: The automated system prepares individualized i.v. chemotherapy doses in a variety of infusion bags and syringes; more than 50 drugs are validated for use in the machine. The robot is programmed to recognize the physical parameters of syringes and vials and uses photographic identification, barcode identification, and gravimetric measurements to ensure that the correct ingredients are compounded and the final dose is accurate. The implementation timeline, including site preparation, logistics planning, installation, calibration, staff training, development of a pharmacy information system (PIS) interface, and validation by the state board of pharmacy, was about 10 months. In its first 13 months of operation, the robot was used to prepare 7384 medication doses; 85 doses (1.2%) found to be outside the desired accuracy range (+/-4%) were manually modified by pharmacy staff. Ongoing system monitoring has identified mechanical and materials-related problems including vial-recognition failures (in many instances, these issues were resolved by the system operator and robotic compounding proceeded successfully), interface issues affecting robot-PIS communication, and human errors such as the loading of an incorrect vial or bag into the machine. Through staff training, information technology improvements, and workflow adjustments, the robot's throughput has been steadily improved. CONCLUSION: An i.v.-compounding robot was successfully implemented in a cancer center pharmacy. The robot performs compounding tasks safely and accurately and has been integrated into the pharmacy's workflow. PMID- 24173012 TI - Thickness distribution of the glenohumeral joint cartilage: a quantitative study using computed tomography. AB - PURPOSE: Among late signs like sclerosis, cysts and osteophytes, alteration of cartilage is a common problem in osteoarthritis. To detect abnormal states in the glenohumeral joint, the physiologic distribution of the cartilage thickness must be known, which will allow physicians to better advise patients. High-resolution computed tomography (CT) data in soft tissue kernel provide highly accurate quantitative results and are a useful method to determine the geometrical situation of the glenohumeral joint. The objective of this study was to characterize the distribution of the thickness of the glenohumeral joint cartilage using CT. METHODS: To investigate the distribution of thickness of the joint cartilage, CT images in soft tissue kernel of nine specimens were analyzed using image visualization software. Statistical analysis of the obtained data was performed using the ANOVA test. RESULTS: Results showed different patterns in the glenoid cavity than in humeral head. Cartilage thickness in all glenoids showed maxima in the inferior and anterior portion, whereas central areas are covered with the thinnest cartilage layer. Maximum cartilage thickness in the humeral head was found in the central and superior parts. CONCLUSION: We could show that the distribution of cartilage thickness in the glenohumeral joint is not homogenous and that there exist several reproducible patterns. Evaluation of cartilage thickness in the glenohumeral joint is of high interest in basic and clinical research. PMID- 24173013 TI - Pseudo-intraventricular hemorrhage from a deep calcarine fissure. AB - Evidence of areas of increased attenuation density within lateral ventricles at computed tomography (CT) of the brain is a finding of acute or subacute intraventricular hemorrhage. The purpose of this case report is to describe a 14 year-old female who presented with an episode of complicated migraine. Brain CT showed an area of high attenuation density (35 Hounsfield Units) in the trigone and occipital horn of the right lateral ventricle, mimicking a blood-fluid level from subacute intraventricular hemorrhage. Magnetic resonance imaging (MRI) of the brain showed that this resulted from gray matter lining a deep calcarine fissure. A deep calcarine fissure may mimic intraventricular hemorrhage at CT. Correct CT and MRI interpretation allows to avoid invasive diagnostic tests including lumbar puncture or intra-arterial catheter angiography. PMID- 24173014 TI - Robot-assisted vertebral body augmentation: a radiation reduction tool. AB - STUDY DESIGN: Retrospective. OBJECTIVE: To assess radiation exposure time during robot-guided vertebral body augmentation compared with other published findings. SUMMARY OF BACKGROUND DATA: Rising incidence of vertebral compression fractures in the aging population result in widespread use of vertebral body cement augmentation with significant radiation exposure to the surgeon, operating room staff, and patient. Radiation exposure leads to higher cancer rates among orthopedic and spine surgeons and patients. METHODS: Thirty-three patients with 60 vertebral compression fractures underwent robot-guided vertebral body augmentation performed by 2 surgeons simultaneously injecting cement at 2 levels under pulsed fluoroscopy. The age of patients was in the range from 29 to 92 (mean, 67 yr). One to 6 vertebrae were augmented per case (average 2). Twenty five patients had osteoporotic fractures and 8 had pathological fractures. Robotic guidance data included execution rate, accuracy of guidance, total surgical time, and time required for robotic guidance. Radiation-related data included the average preoperative computed tomographic effective dose, radiation time for calibration, registration, placement of Kirschner wires, and total procedure radiation time. Radiation time per level and surgeon's exposure were calculated. RESULTS: Kyphoplasty was performed in 15 patients (1 sacroplasty), vertebroplasty in 13, and intravertebral expanding implants in 5. The average preoperative computed tomographic effective dose was 50 mSv (18-81). Average operative time was 118 minutes (49-350). Mean robotic guidance took 36 minutes. Average operative radiation time was 46.1 seconds per level (33-160). Average exposure time of the surgeons and the operating room staff per augmented level was 37.6 seconds. The execution rate was 99%, with an accuracy of 99%. Two complications (hemothorax and superficial wound infection) occurred. CONCLUSION: The radiation exposure of the surgeon and the operating room staff in a series of robot-assisted vertebral body augmentation was 74% lower than published results on fluoroscopy guidance and approximately 50% lower than the literature on navigated augmentation. LEVEL OF EVIDENCE: 4. PMID- 24173015 TI - Computed tomographic morphometric analysis of the pediatric occipital condyle for occipital condyle screw placement. AB - STUDY DESIGN: This study is a computed tomographic (CT)-based morphometric analysis of the pediatric occipital condyles as related to occipital condyle screw placement. OBJECTIVE: To quantify reference data concerning the dimensions of the immature occipital condyles to guide the placement of occipital condyle screw. SUMMARY OF BACKGROUND DATA: To the best of our knowledge, no published study has provided insight into the anatomy of occipital condyle of the pediatric population with different age groups. METHODS: Sixty-nine pediatric patients were divided into 4 age groups, and their occipital condyles were studied on CT scans. Condylar length, width, height, sagittal angle, and sagittal angle lengths were measured on Philips Brilliance 16 CT. RESULTS: The mean pediatric coronal height, sagittal length, and axial width noted statistically significant age-related differences were 9.0 mm, 21.3 mm, and 9.8 mm, respectively. The mean sagittal angle for all patients was 27.2 +/- 5.1 degrees (range, 15.1-41.0 degrees ). In 82.6% (114/138) of the occipital condyles, the anatomy could accept the occipital condyle screw (width >=8 mm and height >=6.5 mm). CONCLUSION: Our investigation provides insight into the anatomy of occipital condyle of the pediatric population with different age groups. As the pediatric occipital condyles have sufficient occipital bone for appropriate fixation or fusion, the occipital condyle screws fixation is a feasible technique for children. Even so, given the evolution of this technique being still in its infancy and the complexity inherent to the craniovertebral junction, a careful radiological analysis of occipital condyle must be required in preoperative planning and feasibility determination. LEVEL OF EVIDENCE: N/A. PMID- 24173016 TI - Predictors of postoperative pain trajectories in adolescent idiopathic scoliosis. AB - STUDY DESIGN: Prospective observational study. OBJECTIVE: To determine the typical trajectory of pain during the first 6 months after spinal fusion surgery for adolescent idiopathic scoliosis (AIS) and the extent to which certain demographic, medical, and psychological variables modify this trajectory. SUMMARY OF BACKGROUND DATA: Pain after spinal fusion surgery for AIS may not improve predictably with elapsed healing time, and limited data exist on predictors of the course of pain during the initial months after surgery. METHODS: Fifty patients ages 11 to 17 (mean = 14.5, standard deviation = 1.9) with AIS and undergoing posterior spinal fusion surgery comprised the study sample. Pain outcomes were assessed at 4 time points after surgery (2-week, 6-week, 3-month, and 6-month postsurgery). Preoperative predictor variables comprising demographics, baseline Cobb angle, body mass index, baseline pain, and psychological variables (anxiety, negative mood, and confidence in ability to control pain) were assessed 2 weeks before surgery. Perioperative predictor variables comprising pain, pain coping efficacy, negative mood, surgery length, length and lowest level of fusion, and analgesic use were assessed by self-report or record review. Multilevel growth models were used to evaluate hypotheses pertaining to predictors of pain trajectories. RESULTS: Pain level on average declined predictably with days since surgery (b = -0.14 to -0.19, P < 0.01). For 22% of adolescents, pain was at or above baseline levels through 6 months after surgery. Greater baseline pain and anxiety predicted slower improvement in pain, whereas greater confidence in ability to control pain predicted more rapid declines in pain. None of the demographic or medical variables reliably modified postsurgical pain trajectories. CONCLUSION: Although pain typically declines predictably with healing time from spinal fusion surgery for AIS, higher preoperative levels of pain and anxiety may be risk factors for chronic postsurgical pain whereas greater pain coping efficacy may help optimize postsurgical pain outcomes. LEVEL OF EVIDENCE: 3. PMID- 24173017 TI - Preoperative pain pattern predicts surgical outcome more than type of surgery in patients with central spinal stenosis without concomitant spondylolisthesis: a register study of 9051 patients. AB - STUDY DESIGN: A register cohort study. OBJECTIVE: To evaluate outcome of surgery for lumbar spinal stenosis without concomitant degenerative spondylolisthesis according to predominance of pain and to analyze the role of spinal fusion in conjunction with decompression in patients with predominant back pain (BP) or leg pain (LP). SUMMARY OF BACKGROUND DATA: Predominance of BP is associated with inferior outcome of surgery for central spinal stenosis. It is unknown if using spinal fusion improves outcomes. METHODS: In a register study of 9051 patients, we studied outcome of surgery in terms of BP and LP visual analogue scale, function (the Oswestry Disability Index and self-estimated walking distance), health-related quality of life (Short-Form 36 and EuroQol), and patient satisfaction. Outcome was analyzed for 4 groups at 1- and 2-year follow-ups; preoperative BP was equal to or worse than LP and decompression, preoperative BP was equal to or worse than LP and decompression and fusion, preoperative BP was less than LP and decompression, preoperative BP was less than decompression and fusion. RESULTS: Patients with concomitant fusion were younger and had higher BP and Oswestry Disability Index scores and lower preoperative EuroQol. Predominant BP was associated with inferior outcome in terms of pain, health-related quality of life, and function. Patients most often satisfied (69%) were patients with BP less than LP treated with decompression and fusion and the least satisfied group was patients with BP equal to or worse than LP treated with decompression (54%). Fusion was not only associated with higher EuroQol at 1-year follow-up for patients with predominant BP, but also associated with increased LP at 2-year follow-up in patients with predominant LP. Patients with predominant BP experienced small gains in the physical component summary with fusion. CONCLUSION: Predominance of BP is associated with inferior outcome. Using spinal fusion improves unadjusted outcome but the benefit is small and not clinically significant and generally disappears in the adjusted analysis. LEVEL OF EVIDENCE: 4. PMID- 24173018 TI - Psychometric properties of the PROMIS physical function item bank in patients with spinal disorders. AB - STUDY DESIGN: Patient-reported outcomes provide vital information when assessing effectiveness of clinical care. Yet, most patient-reported outcome instruments are limited by lack of validation and reliability to measure PF adequately. As part of the Patient-Reported Outcomes Measurement Information System (PROMIS), a PF item bank consisting of 124 items has been developed. OBJECTIVE: There is validation evidence for the PROMIS PF item bank in the general orthopedic patient population in general, but has yet to be validated in the patient with spinal disorders. This study aims to evaluate the psychometric properties of the PROMIS PF item bank specifically for patients presenting with spine-related complaints. SUMMARY OF BACKGROUND DATA: Data were collected from adult patients visiting a university spine clinic for back and neck problems. All patients older than 18 years were eligible to participate. A total of 438 patients (49% male) were enrolled in this prospective study. Patients were 18- to 89-year old and presented with back problems (n = 286) and neck problems (n = 152). All patients were administered a 131 item questionnaire. METHODS: Conventional descriptive statistics such as means, standard deviations, and proportions were conducted to examine patient characteristics. A Rasch model was used to examine the psychometric properties of the instrument including dimensionality, floor/ceiling effects, reliabilities, and item bias. RESULTS: Results showed that a single PF dimension was supported by the data (i.e., unexplained variance was 2.9%). The instrument had 1.7% ceiling effect and 0.2% floor effect. Item reliability was 1.00 and person reliability was 0.99. We found evidence of item response bias associated with sex, age, and education in some items. CONCLUSION: The PROMIS PF item bank adequately addressed outcomes of patients with spinal disorders as reliabilities were excellent, minimal ceiling/floor effect existed, and item bias was limited. Future effort should be focused on eliminating, rescaling, or modifying those items that had item bias. LEVEL OF EVIDENCE: 2. PMID- 24173019 TI - Incidence, outcomes, and mortality of reintubation after anterior cervical fusion. AB - STUDY DESIGN: Retrospective database analysis. OBJECTIVE: To compare perioperative patient characteristics, hospital resource utilization, and early postoperative outcomes in patients requiring reintubation after anterior cervical fusion (ACF). SUMMARY OF BACKGROUND DATA: Airway compromise is a potential complication after anterior cervical surgery. Postsurgical soft-tissue edema or hematoma formation may be so severe that an unplanned reintubation may be required. The rate of reintubation after ACF and the effect on hospital outcomes remains unknown. METHODS: The Nationwide Inpatient Sample database was queried from 2002-2011. Patients undergoing elective ACF procedures for degenerative diagnoses were selected. Those who required an unplanned reintubation after ACF were identified. Patient demographics, comorbidities, length of stay, costs, number of levels fused, and mortality were analyzed. SPSS version 20 was used for statistical analysis and a P < 0.001 denoted statistical significance. RESULTS: A total of 262,425 patients underwent an elective ACF between 2002 and 2011 of which 1464 patients (5.6 per 1000 cases) required reintubation during their admission. The rate of reintubation was statistically greater for 3+-level fusions than the 1- to 2-level fusion cases. On average, patients requiring reintubation were older and had a greater number of comorbidities. These patients also incurred a significantly greater hospital stay and total hospital costs than unaffected patients. In addition, significant predictors for reintubation included 3+-level fusions, congestive heart failure, anemia, postoperative aspiration pneumonia, hematoma, thromboembolic events, and dysphagia. CONCLUSION: The reintubation rate after an elective ACF is 0.5%, and it increases to 1.6% after 3+-level fusions. Older patients with greater comorbidities are at an increased risk for reintubation. Given the greater LOS, costs and mortality associated with reintubation, it is imperative to identify patients at increased risk to help improve patient outcomes and decrease hospital resource utilization. LEVEL OF EVIDENCE: 4. PMID- 24173020 TI - Impact of diabetes on the outcomes of cervical laminoplasty: a prospective cohort study of more than 500 patients with cervical spondylotic myelopathy. AB - STUDY DESIGN: A prospective cohort study. OBJECTIVE: This study aimed to compare the outcome of cervical laminoplasty between diabetic patients and nondiabetic patients with cervical spondylotic myelopathy. SUMMARY OF BACKGROUND DATA: A few retrospective studies have investigated the outcomes of cervical myelopathy in diabetic patients; therefore, our large-scale cohort study was designed to assess these outcomes in cervical spondylotic myelopathy. METHODS: In total, 505 consecutive patients with cervical spondylotic myelopathy (311 males, 194 females; mean age, 66.6 yr; range, 41-91 yr) who underwent double-door laminoplasty were prospectively enrolled. They were followed up for more than 12 months after surgery (mean follow-up period, 25.6 +/- 12.6 mo). The patients were divided on the basis of diabetic criteria for glucose intolerance into 2 groups: the diabetic group (n = 105) and nondiabetic group (n = 400). We evaluated differences in pre- and postoperative Japanese Orthopaedic Association (JOA) scores, recovery rate, achieved JOA scores (postoperative JOA score - preoperative JOA score), and complications between both groups. RESULTS: The mean JOA scores in the diabetic and nondiabetic groups were 10.1 and 10.8 points before surgery and 13.1 and 13.9 points after surgery, respectively. The diabetic group showed significantly low pre- and postoperative JOA scores and low recovery rate of JOA scores compared with the nondiabetic group (47.3% vs. 53.6%, P < 0.05). However, mean achieved JOA scores in the diabetic and nondiabetic groups were 3.0 and 3.1 points respectively, with no significant difference between both groups (P = 0.343). The groups showed no significant difference in the postoperative complication rate. CONCLUSION: Pre- and postoperative JOA scores and recovery rates were lower in the diabetic group than the nondiabetic group. However, the achieved JOA scores were not significantly different between both groups. Diabetic and nondiabetic patients experienced similar benefits from laminoplasty. LEVEL OF EVIDENCE: 3. PMID- 24173021 TI - The paternally imprinted DLK1-GTL2 locus is differentially methylated in embryonal and alveolar rhabdomyosarcomas. AB - Parental imprinting of differentially methylated regions (DMRs) contributes to appropriate expression of several developmentally important genes from paternally or maternally derived chromosomes. Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma in children and is associated with altered expression of certain parentally imprinted genes. As previously reported, RMS cells display loss of imprinting (LOI) of the DMR at the IGF2-H19 locus, resulting in insulin-like growth factor 2 (IGF2) transcription from both paternally and maternally inherited chromosomes, and overall IGF2 overexpression. As the DLK1-GTL2 locus is structurally similar to the IGF2-H19 locus, the status of parental imprinting of the DLK1-GTL2 locus was studied in RMS. We observed that while both embryonal and alveolar rhabdomyosarcomas (ERMS and ARMS, respectively) show LOI of the DMR at the IGF2-H19 locus, imprinting of the DMR at the DLK1-GTL2 locus varies in association with the histological subtype of RMS. We found that, while ERMS tumors consistently show LOI of the DMR at the DLK1-GTL2 locus, ARMS tumors have erasure of imprinting (EOI) at this locus. These changes in imprinting status of the DLK1-GTL2 locus result in a higher GTL2/DLK1 mRNA ratio in ARMS as compared to ERMS. This difference in imprinting elucidates a novel genetic difference between these two RMS subtypes and may provide a potential diagnostic tool to distinguish between these subtypes. PMID- 24173022 TI - Assessment of an oral Mycobacterium bovis BCG vaccine and an inactivated M. bovis preparation for wild boar in terms of adverse reactions, vaccine strain survival, and uptake by nontarget species. AB - Wildlife vaccination is increasingly being considered as an option for tuberculosis control. We combined data from laboratory trials and an ongoing field trial to assess the risk of an oral Mycobacterium bovis BCG vaccine and a prototype heat-inactivated Mycobacterium bovis preparation for Eurasian wild boar (Sus scrofa). We studied adverse reactions, BCG survival, BCG excretion, and bait uptake by nontarget species. No adverse reactions were observed after administration of BCG (n = 27) or inactivated M. bovis (n = 21). BCG was not found at necropsy (175 to 300 days postvaccination [n = 27]). No BCG excretion was detected in fecal samples (n = 162) or in urine or nasal, oral, or fecal swab samples at 258 days postvaccination (n = 29). In the field, we found no evidence of loss of BCG viability in baits collected after 36 h (temperature range, 11 degrees C to 41 degrees C). Camera trapping showed that wild boar (39%) and birds (56%) were the most frequent visitors to bait stations (selective feeders). Wild boar activity patterns were nocturnal, while diurnal activities were recorded for all bird species. We found large proportions of chewed capsules (29%) (likely ingestion of the vaccine) and lost baits (39%) (presumably consumed), and the proportion of chewed capsules showed a positive correlation with the presence of wild boar. Both results suggest proper bait consumption (68%). These results indicate that BCG vaccination in wild boar is safe and that, while bait consumption by other species is possible, this can be minimized by using selective cages and strict timing of bait deployment. PMID- 24173023 TI - Dengue virus subverts the interferon induction pathway via NS2B/3 protease IkappaB kinase epsilon interaction. AB - Dengue is the world's most common mosquito-borne viral infection and a leading cause of morbidity throughout the tropics and subtropics. Viruses are known to evade the establishment of an antiviral state by regulating the activation of interferon regulatory factor 3 (IRF3), a critical transcription factor in the alpha/beta interferon induction pathway. Here, we show that dengue virus (DENV) circumvents the induction of the retinoic acid-inducible gene I-like receptor (RLR) pathway during infection by blocking serine 386 phosphorylation and nuclear translocation of IRF3. This effect is associated with the expression of nonstructural 2B/3 protein (NS2B/3) protease in human cells. Using interaction assays, we found that NS2B/3 interacts with the cellular IkappaB kinase epsilon (IKKepsilon). Docking computational analysis revealed that in this interaction, NS2B/3 masks the kinase domain of IKKepsilon and potentially affects its functionality. This observation is supported by the DENV-associated inhibition of the kinase activity of IKKepsilon. Our data identify IKKepsilon as a novel target of DENV NS2B/3 protease. PMID- 24173024 TI - Acquisition of oral microbes and associated systemic responses of newborn nonhuman primates. AB - The acquisition and development of the complex oral microbiome remain ill defined. While selected species of oral bacteria have been examined in relation to their initial colonization in neonates, a more detailed understanding of the dynamics of the microbiome has been developed only in adults. The current investigation used a nonhuman primate model to document the kinetics of colonization of the oral cavities of newborns and infants by a range of oral commensals and pathogens. Differences in colonization were evaluated in newborns from mothers who were maintained on an oral hygiene regimen pre- and postparturition with those displaying naturally acquired gingivitis/periodontitis. The results demonstrate distinct profiles of acquisition of selected oral bacteria, with the transmission of targeted pathogens, Porphyromonas gingivalis and Aggregatibacter actinomycetemcomitans, being passed on primarily from mothers with gingivitis/periodontitis. This colonization resulted in defined patterns of systemic antibody responses in the infants. The significant relative risk measures for infection with the pathogens, as well as the relationship of oral infection and blood serum antibody levels, were consistent with those of the newborns from mothers with gingivitis/periodontitis. These findings indicate that the early acquisition of potentially pathogenic oral bacterial species might impact the development of mucosal responses in the gingiva and may provide an enhanced risk for the development of periodontitis later in life. PMID- 24173025 TI - Blood collection tubes influence serum ficolin-1 and ficolin-2 levels. AB - The ficolins are members of a recently discovered family of host innate opsonins that can activate the lectin pathway of complement. The ficolins bind many ligands, although they are typically described as binding acetylated sugars. Ficolin-1 (M-ficolin) and ficolin-2 (L-ficolin) are known to bind Streptococcus pneumoniae serotypes 19C and 11A, respectively. While studying the binding of ficolins to pneumococci, we found variations in ficolin-2 binding among serum samples collected in different types of blood collection tubes. Plastic tubes, which contain a silica clot activator, yielded sera with reduced ficolin-2 binding and apparent ficolin-2 levels. We found that the silica clot activator eluted from plastic red-top tubes inhibited ficolin-2 ligand binding, while other related proteins, like mannose-binding lectin (MBL) and ficolin-1, were not affected. These tube types did not affect the concentrations of other related opsonins (C1q, MBL, or ficolin-3 [H-ficolin]). Interestingly, we also found that ficolin-1 levels were increased 2- to 3-fold in plastic serum separator tubes compared to the increases in other tube types. These findings have implications for future ficolin-1 and ficolin-2 studies, as proper sample collection and handling are essential. PMID- 24173026 TI - Use of antigen-specific interleukin-2 to differentiate between cattle vaccinated with Mycobacterium bovis BCG and cattle infected with M. bovis. AB - We describe here the application of a novel bovine interleukin-2 (IL-2) enzyme linked immunosorbent assay (ELISA) for the measurement of antigen-specific IL-2 in cattle naturally infected with Mycobacterium bovis and in cattle vaccinated with Mycobacterium bovis BCG and then experimentally challenged with pathogenic M. bovis. Supernatants from whole-blood cultures stimulated with mycobacterial antigen (bovine purified protein derivative [PPDB] or the peptide cocktail ESAT6 CFP10) were assessed using a sandwich ELISA consisting of a new recombinant monoclonal fragment capture antibody and a commercially available polyclonal anti bovine-IL-2. The production of IL-2 was compared to the production of gamma interferon (IFN-gamma) in the same antigen-stimulated whole-blood supernatants. The data show that cattle infected with M. bovis produced quantifiable levels of antigen-specific IL-2, while IL-2 levels in cattle vaccinated with M. bovis BCG did not. Furthermore, cattle vaccinated with M. bovis BCG and then challenged with pathogenic M. bovis displayed a more rapid induction of IL-2 but ultimately had lower levels of infection-induced IL-2 than did unvaccinated challenge control cattle. These data suggest that IL-2 responses are not detectable post BCG vaccination and that these responses may require infection with virulent M. bovis to develop. This may be useful to differentiate infected cattle from uninfected or BCG-vaccinated cattle, although the overall sensitivity is relatively low, particularly in single intradermal comparative cervical tuberculin (SICCT)-negative infected animals. Furthermore, the strength of the IL 2 response may correlate with pathology, which poses interesting questions on the immunobiology of bovine tuberculosis in contrast to human tuberculosis, which is discussed. PMID- 24173027 TI - Antibody response to Achromobacter xylosoxidans during HIV infection is associated with lower CD4 levels and increased lymphocyte activation. AB - Inflammation during HIV infection is associated with worse disease outcomes and progression. Many mechanisms have been indicted, including HIV itself, coinfections, and gut microbial translocation. Concerning microbial translocation, we hypothesized that adaptive immune responses to a specific bacterial species known to be present in gut-associated lymphoid tissue are higher among HIV-infected individuals than among HIV-uninfected controls and are associated with T cell activation and lower CD4 T cell counts. By characterizing the IgG response to Achromobacter xylosoxidans, we found that HIV-infected participants who were immunoresponsive (n = 48) had significantly lower CD4 percentages (P = 0.01), greater CD4 activation (percentages of RA(-) CD38(+)) (P = 0.03), and higher soluble CD14 (P = 0.01). HIV-positive individuals had higher anti-A. xylosoxidans IgG titers than HIV-uninfected individuals (P = 0.04). The results suggest an abnormal adaptive immune activation to gut microflora during HIV infection. PMID- 24173028 TI - Safety and immunogenicity of single-dose live oral cholera vaccine strain CVD 103 HgR, prepared from new master and working cell banks. AB - Currently, no cholera vaccine is available for persons traveling from the United States to areas of high cholera transmission and who for reasons of occupation or host factors are at increased risk for development of the disease. A single-dose oral cholera vaccine with a rapid onset of protection would be particularly useful for such travelers and might also be an adjunct control measure for cholera outbreaks. The attenuated Vibrio cholerae O1 vaccine strain CVD 103-HgR harbors a 94% deletion of the cholera toxin A subunit gene (ctxA) and has a mercury resistance gene inserted in the gene encoding hemolysin A. We undertook a phase I randomized placebo-controlled two-site trial to assess the safety and immunogenicity of a preliminary formulation of CVD 103-HgR prepared from new master and working cell banks. Healthy young adults were randomized (5:1 vaccinees to placebo recipients) to receive a single oral dose of ~4.4 * 10(8) CFU of vaccine or a placebo. Blood serum vibriocidal and cholera toxin-specific IgG antibodies were measured before and 10, 14, and 28 days following vaccination or placebo. Excretion of the vaccine strain in the stool was assessed during the first week postvaccination. A total of 66 subjects were enrolled, comprising 55 vaccinees and 11 placebo recipients. The vaccine was well tolerated. The overall vibriocidal and anti-cholera toxin seroconversion rates were 89% and 57%, respectively. CVD 103-HgR is undergoing renewed manufacture for licensure in the United States under the auspices of PaxVax. Our data mimic those from previous commercial formulations that elicited vibriocidal antibody seroconversion (a correlate of protection) in ~90% of vaccinees. (This study has been registered at ClinicalTrials.gov under registration no. NCT01585181.). PMID- 24173029 TI - Safety, immunogenicity, and antibody persistence following an investigational Streptococcus pneumoniae and Haemophilus influenzae triple-protein vaccine in a phase 1 randomized controlled study in healthy adults. AB - We investigated a protein-based nontypeable Haemophilus influenzae (NTHi) and pneumococcal (HiP) vaccine containing pneumococcal histidine triad D (PhtD), detoxified pneumolysin (dPly), and NTHi protein D (PD) in adults. In a phase I study, 40 healthy 18- to 40-year-old subjects were randomized (2:2:1) to receive two HiP doses administered 60 days apart, with or without AS03 adjuvant (HiP-AS and HiP groups, respectively), or Engerix B (GlaxoSmithKline, Belgium) as a control. Safety, antibodies, and antigen-specific CD4(+) T-cell immune responses were assessed before and until 480 days after vaccination. No serious adverse events were reported, and no subject withdrew due to an adverse event. Local and systemic symptoms were reported more frequently in the HiP-AS group than in the other two groups. The frequency and intensity of local and systemic symptoms appeared to increase after the second dose of HiP-AS or HiP but not Engerix B. Antibody geometric mean concentrations (GMCs) for PhtD, dPly, and PD increased after each dose of HiP-AS or HiP, with higher GMCs being observed in the HiP-AS group (statistically significant for anti-PD after dose 1 and anti-Ply after dose 2). GMCs remained higher at day 420 than prior to vaccination in both the HiP-AS and HiP groups. Antigen-specific CD4(+) T cells increased after each dose but were unmeasurable by day 480. Two doses of an investigational PhtD-dPly-PD protein vaccine induced humoral immunity and antigen-specific CD4(+) T-cell responses after each dose, with generally higher responses when the vaccine was administered with AS03. HiP combined with AS03 appeared to be more reactogenic than the antigens alone. (This study has been registered at ClinicalTrials.gov under registration no. NCT00814489.). PMID- 24173030 TI - Size-tunable TiO2 nanorod microspheres synthesised via a one-pot solvothermal method and used as the scattering layer for dye-sensitized solar cells. AB - TiO2 microspheres assembled by single crystalline rutile TiO2 nanorods were synthesized by one-pot solvothermal treatment at 180 degrees C based on an aqueous-organic mixture solution containing n-hexane, distilled water, titanium n butoxide and hydrochloric acid. The spheres had a radiative structure from the center, and their diameters were controlled in the range from 1 to 5 MUm by adjusting the volume of the reactant water. Nitrogen adsorption-desorption isotherms showed that all the as-prepared microspheres had relatively high specific surface areas of about 50 m(2) g(-1). The 1 MUm sized TiO2 nanorod microspheres were fabricated as a scattering overlayer in DSSCs, leading to a remarkable improvement in the power conversion efficiency: 8.22% of the bi-layer DSSCs versus 7.00% for the reference cell made of a single-layer film prepared from nanocrystalline TiO2. Such improvement was mainly attributed to the enhanced light harvesting and dye loading brought by the effective scattering centers. PMID- 24173032 TI - Hugh Esmor Huxley (1924-2013). PMID- 24173031 TI - Familial dysautonomia model reveals Ikbkap deletion causes apoptosis of Pax3+ progenitors and peripheral neurons. AB - Familial dysautonomia (FD) is a devastating developmental and progressive peripheral neuropathy caused by a mutation in the gene inhibitor of kappa B kinase complex-associated protein (IKBKAP). To identify the cellular and molecular mechanisms that cause FD, we generated mice in which Ikbkap expression is ablated in the peripheral nervous system and identify the steps in peripheral nervous system development that are Ikbkap-dependent. We show that Ikbkap is not required for trunk neural crest migration or pathfinding, nor for the formation of dorsal root or sympathetic ganglia, or the adrenal medulla. Instead, Ikbkap is essential for the second wave of neurogenesis during which the majority of tropomyosin-related kinase A (TrkA(+)) nociceptors and thermoreceptors arise. In its absence, approximately half the normal complement of TrkA(+) neurons are lost, which we show is partly due to p53-mediated premature differentiation and death of mitotically-active progenitors that express the paired-box gene Pax3 and give rise to the majority of TrkA(+) neurons. By the end of sensory development, the number of TrkC neurons is significantly increased, which may result from an increase in Runx3(+) cells. Furthermore, our data demonstrate that TrkA(+) (but not TrkC(+)) sensory and sympathetic neurons undergo exacerbated Caspase 3 mediated programmed cell death in the absence of Ikbkap and that this death is not due to a reduction in nerve growth factor synthesis. In summary, these data suggest that FD does not result from a failure in trunk neural crest migration, but rather from a critical function for Ikbkap in TrkA progenitors and TrkA(+) neurons. PMID- 24173033 TI - Structures of intermediate transport states of ZneA, a Zn(II)/proton antiporter. AB - Efflux pumps belonging to the ubiquitous resistance-nodulation-cell division (RND) superfamily transport substrates out of cells by coupling proton conduction across the membrane to a conformationally driven pumping cycle. The heavy metal resistant bacteria Cupriavidus metallidurans CH34 relies notably on as many as 12 heavy metal efflux pumps of the RND superfamily. Here we show that C. metallidurans CH34 ZneA is a proton driven efflux pump specific for Zn(II), and that transport of substrates through the transmembrane domain may be electrogenic. We report two X-ray crystal structures of ZneA in intermediate transport conformations, at 3.0 and 3.7 A resolution. The trimeric ZneA structures capture protomer conformations that differ in the spatial arrangement and Zn(II) occupancies at a proximal and a distal substrate binding site. Structural comparison shows that transport of substrates through a tunnel that links the two binding sites, toward an exit portal, is mediated by the conformation of a short 14-aa loop. Taken together, the ZneA structures presented here provide mechanistic insights into the conformational changes required for substrate efflux by RND superfamily transporters. PMID- 24173034 TI - Submillisecond second harmonic holographic imaging of biological specimens in three dimensions. AB - Optical microscopy has played a critical role for discovery in biomedical sciences since Hooke's introduction of the compound microscope. Recent years have witnessed explosive growth in optical microscopy tools and techniques. Information in microscopy is garnered through contrast mechanisms, usually absorption, scattering, or phase shifts introduced by spatial structure in the sample. The emergence of nonlinear optical contrast mechanisms reveals new information from biological specimens. However, the intensity dependence of nonlinear interactions leads to weak signals, preventing the observation of high speed dynamics in the 3D context of biological samples. Here, we show that for second harmonic generation imaging, we can increase the 3D volume imaging speed from sub-Hertz speeds to rates in excess of 1,500 volumes imaged per second. This transformational capability is possible by exploiting coherent scattering of second harmonic light from an entire specimen volume, enabling new observational capabilities in biological systems. PMID- 24173035 TI - Eukaryotic resistance to fluoride toxicity mediated by a widespread family of fluoride export proteins. AB - Fluorine is an abundant element and is toxic to organisms from bacteria to humans, but the mechanisms by which eukaryotes resist fluoride toxicity are unknown. The Escherichia coli gene crcB was recently shown to be regulated by a fluoride-responsive riboswitch, implicating it in fluoride response. There are >8,000 crcB homologs across all domains of life, indicating that it has an important role in biology. Here we demonstrate that eukaryotic homologs [renamed FEX (fluoride exporter)] function in fluoride export. FEX KOs in three eukaryotic model organisms, Neurospora crassa, Saccharomyces cerevisiae, and Candida albicans, are highly sensitized to fluoride (>200-fold) but not to other halides. Some of these KO strains are unable to grow in fluoride concentrations found in tap water. Using the radioactive isotope of fluoride, (18)F, we developed an assay to measure the intracellular fluoride concentration and show that the FEX deletion strains accumulate fluoride in excess of the external concentration, providing direct evidence of FEX function in fluoride efflux. In addition, they are more sensitive to lower pH in the presence of fluoride. These results demonstrate that eukaryotic FEX genes encode a previously unrecognized class of fluoride exporter necessary for survival in standard environmental conditions. PMID- 24173036 TI - Highly expressed loci are vulnerable to misleading ChIP localization of multiple unrelated proteins. AB - Chromatin immunoprecipitation (ChIP) is the gold-standard technique for localizing nuclear proteins in the genome. We used ChIP, in combination with deep sequencing (Seq), to study the genome-wide distribution of the Silent information regulator (Sir) complex in Saccharomyces cerevisiae. We analyzed ChIP-Seq peaks of the Sir2, Sir3, and Sir4 silencing proteins and discovered 238 unexpected euchromatic loci that exhibited enrichment of all three. Surprisingly, published ChIP-Seq datasets for the Ste12 transcription factor and the centromeric Cse4 protein indicated that these proteins were also enriched in the same euchromatic regions with the high Sir protein levels. The 238 loci, termed "hyper-ChIPable", were in highly expressed regions with strong polymerase II and polymerase III enrichment signals, and the correlation between transcription level and ChIP enrichment was not limited to these 238 loci but extended genome-wide. The apparent enrichment of various proteins at hyper-ChIPable loci was not a consequence of artifacts associated with deep sequencing methods, as confirmed by ChIP-quantitative PCR. The localization of unrelated proteins, including the entire silencing complex, to the most highly transcribed genes was highly suggestive of a technical issue with the immunoprecipitations. ChIP-Seq on chromatin immunoprecipitated with a nuclear-localized GFP reproduced the above enrichment in an expression-dependent manner: induction of the GAL genes resulted in an increased ChIP signal of the GFP protein at these loci, with presumably no biological relevance. Whereas ChIP is a broadly valuable technique, some published conclusions based upon ChIP procedures may merit reevaluation in light of these findings. PMID- 24173037 TI - No bull: upholding community standards in public sharing of biological datasets. PMID- 24173038 TI - Superconductivity in Ca10(Ir4As8)(Fe2As2)5 with Square-Planar Coordination of Iridium. AB - We report the unprecedented square-planar coordination of iridium in the iron iridium arsenide Ca(10)(Ir(4)As(8))(Fe(2)As(2))5. This material experiences superconductivity at 16 K. X-ray photoemission spectroscopy and first-principles band calculation suggest Ir(II) oxidation state, which yields electrically conductive Ir(4)As(8) layers. Such metallic spacer layers are thought to enhance the interlayer coupling of Fe(2)As(2), in which superconductivity emerges, thus offering a way to control the superconducting transition temperature. PMID- 24173039 TI - Red blood cell distribution width and the risk of cardiovascular morbidity and all-cause mortality. A population-based study. AB - Red blood cell distribution width (RDW) has been shown to predict cardiovascular mortality in various populations, but studies were less conclusive regarding cardiovascular morbidity. We aimed at evaluating the prognostic effect of RDW on cardiovascular morbidity and all-cause mortality in the largest community cohort to date.We utilised the computerised database of a large community based healthcare maintenance organization (HMO) in Israel to identify a cohort of 225,006 eligible patients aged 40 or above who performed a blood count during 2006. We evaluated the relationship between 1% increments of RDW values and major cardiovascular events and all-cause mortality over a period of five years. A total of 21,939 incident cases of a major cardiovascular event and 4,287 deaths were documented during a total of six years of follow up, respectively. In comparison with patients with RDW level <13%, the hazard ratio for total mortality gradually increased to 4.57 (95% confidence interval [CI]: 3.35-6.24, p<0.001) among male patients and to 3.26 (95% CI: 2.49-4.28, p<0.001) among female patients with a RDW of 17% or above. Similar results were evident in anaemic and non-anaemic populations. RDW above 17% was also associated with a modest increased risk of major cardiovascular events in females 1.26 (95% CI: 1.03-1.52, p=0.021), while in men it was not significant, 1.08 (95% CI: 0.82 1.41, p=NS). In conclusion, increasing RDW levels significantly increased risk of cardiovascular morbidity and all-cause mortality. Our observation is evident in both anaemic and non-anaemic patients. PMID- 24173040 TI - Full randomness from arbitrarily deterministic events. AB - Do completely unpredictable events exist? Classical physics excludes fundamental randomness. Although quantum theory makes probabilistic predictions, this does not imply that nature is random, as randomness should be certified without relying on the complete structure of the theory being used. Bell tests approach the question from this perspective. However, they require prior perfect randomness, falling into a circular reasoning. A Bell test that generates perfect random bits from bits possessing high-but less than perfect-randomness has recently been obtained. Yet, the main question remained open: does any initial randomness suffice to certify perfect randomness? Here we show that this is indeed the case. We provide a Bell test that uses arbitrarily imperfect random bits to produce bits that are, under the non-signalling principle assumption, perfectly random. This provides the first protocol attaining full randomness amplification. Our results have strong implications onto the debate of whether there exist events that are fully random. PMID- 24173041 TI - Novel immunomodulatory approaches for the management of multiple sclerosis. AB - We provide a focused review of novel immunomodulatory approaches for the treatment of multiple sclerosis, the most common acquired inflammatory demyelinating disease of humans. The requirement for such a review was stimulated by the emerging application of novel oral medications and the need for the practicing physician to place these within the treatment paradigm. We provide a conceptual diagram of our current view of the pathogenesis of demyelination and remyelination in this disorder. In addition, we include a working template on how to use a tier 1 and tier 2 approach to medications as the disease worsens in the individual. We emphasize the approach of treatment based on "individualized medicine," tailored to the specific needs of each patient. In the future, we envision new drugs to enhance remyelination and protect neurons and axons from death in order to promote central nervous system regeneration and repair. PMID- 24173042 TI - Anti-tuberculosis drugs decrease viability and stimulate the expression of chondrocyte marker genes in human nucleus pulposus cells. AB - Isoniazid (INH), rifampicin (RIF), ethambutol (ETH) and pyrazinamide (PYR) are first-line drugs used in anti-tuberculosis (TB) therapy. However, no studies have been conducted concerning the effect of anti-TB drugs on the cells of the intervertebral discs (IVDs), the predominant location of the osteoarticular form of TB (OATB). Cells from the nucleus pulposus (NP), which are located in the center of the IVDs, were obtained from 12 adolescent patients who underwent surgery due to idiopathic scoliosis. The NP cells were incubated for 24 h with transforming growth factor beta1 (TGF-beta1) and each anti-TB drug (INH, RIF, ETH and PYR), separately. Incubation with 2.5 ng/ml TGF-beta1 resulted in an 80% decrease in ACAN mRNA levels; while 5 ug/ml INH led to a 2.3-fold increase in COL2A1 and a 2.9-fold increase in ACAN mRNA levels. Treatment with 10 ug/ml RIF initiated a 2.2-fold increase in COL1A1 mRNA levels and 5 ug/ml PYR resulted in an 8-fold increase in SOX9 mRNA levels. Following 192 h of treatment with INH and RIF, NP cell viability was diminished; however, no drugs modified the concentrations of glycosaminoglycans (GAGs). This study aimed to determine the effect of anti-TB drugs on the expression of chondrocyte marker genes in human IVD cells. Anti-TB drugs increased the expression of chondrocyte marker genes and diminished the viability of IVD cells. This study demonstrated that in addition to the common side effects of anti-TB drugs, these drugs also have an effect on IVD cells. PMID- 24173043 TI - A chromosome 5-specific repetitive DNA sequence in rice (Oryza sativa L). AB - Repetitive DNA sequences in the rice genome comprise more than half of the nuclear DNA. The isolation and characterization of these repetitive DNA sequences should lead to a better understanding of rice chromosome structure and genome organization. We report here the characterization and chromosome localization of a chromosome 5-specific repetitive DNA sequence. This repetitive DNA sequence was estimated to have at least 900 copies. DNA sequence analysis of three genomic clones which contain the repeat unit indicated that the DNA sequences have two sub-repeat units of 37 bp and 19 bp, connected by 30-to 90-bp short sequences with high similarity. RFLP mapping and physical mapping by fluorescence in situ hybridization (FISH) indicated that almost all copies of the repetitive DNA sequence are located in the centromeric heterochromatic region of the long arm of chromosome 5. The strategy for cloning such repetitive DNA sequences and their uses in rice genome research are discussed. PMID- 24173044 TI - Mitochondrial gene variation and phylogenetic relationships in the genus Beta. AB - Restriction fragment length polymorphisms (RFLPs) for three mitochondrial genes, coxI, coxII and atpA, were used to determine mitochondrial (mt) DNA diversity in 21 accessions of the genus Beta representing wild and cultivated species. On the basis of distribution of the RFLP patterns these Beta genotypes were assigned into six distinct chondriome groups. A high degree of heterogeneity was found to exist between the mitochondrial genomes of the sugarbeet cultivar and the wild species of Procumbentes section. The polymorphic fragments from wild Beta species were cloned and subjected to fine mapping. We found that most of the RFLPs are due to sequence rearrangements rather than point mutations. Our data also suggest that the close linkage between coxII and coxI is taxonomically localized to an evolutionary lineage that led to Vulgares and Corollinae species but not to Procumbentes species. This linkage is most likely to have arisen via the mutation(s) that inserted the DNA segment containing coxI downstream of coxII in the common ancestor of Vulgares and Corollinae species. The results are discussed with regard to the taxonomic and phylogenetic relationships of the Beta species. PMID- 24173045 TI - RFLP markers linked to scald (Rhynchosporium secalis) resistance gene Rh2 in barley. AB - Rhynchosporium secalis is the causal organism of barley scald disease. A number of resistance genes against the fungus are well known; one of them, the single dominant Rh2 resistance gene, has been mapped on the linkage map of barley using RFLP (restriction fragment length polymorphism) markers. The Rh2 gene was located on the distal part of chromosome arm 1S co-segregating with the RFLP marker CDO545 in 85 doubled-haploid progeny plants. The spring barley test population used was a cross between the 6-rowed American spring barley cv Atlas, C.I. 4118, carrying the Rh2 resistance gene, and a Bavarian 2-rowed malting barley cv Steffi, susceptible for R. secalis. The assessment of resistance versus susceptibility was based on artificial infections with a one-spore inoculum in greenhouse tests and with pathotype mixtures in field tests. By testing a pathotype mixture of German origin good resistance was found for the Rh2 gene in the field. PMID- 24173046 TI - Quantitative trait locus analysis of a recombinant inbred line population derived from a Lycopersicon esculentum x Lycopersicon cheesmanii cross. AB - Quantitative trait loci influencing fruit traits were identified by restriction fragment length polymorphism (RFLP) analysis in a population of recombinant inbred lines (RIL) derived from a cross of the cultivated tomato, Lycopersicon esculentum with a related wild species Lycopersicon cheesmanii. One hundred thirty-two polymorphic RFLP loci spaced throughout the tomato genome were scored for 97 F8 RIL families. Fruit weight and soluble solids were measured in replicated trials during 1991 and 1992. Seed weight was measured in 1992. Significant (P<0.01 level) quantitative trait locus (QTL) associations of marker loci were identified for each trait. A total of 73 significant marker locus-trait associations were detected for the three traits measured. Fifty-three of these associations were for fruit weight and soluble solids, many of which involved marker loci signficantly associated with both traits. QTL with large effects on all three traits were detected on chromosome 6. Greater homozygosity at many loci in the RIL population as compared to F2 populations and greater genomic coverage resulted in increased precision in the estimation of QTL effects, and large proportions of the total phenotypic variance were explained by marker class variation at significant marker loci for many traits. The RIL population was effective in detecting and discriminating among QTL for these traits previously identified in other investigations despite skewed segregation ratios at many marker loci. Large additive effects were measured at significant marker loci. Lower fruit weight, higher soluble solids, and lower seed weight were generally associated with RFLP alleles from theL. cheesmanii parent. PMID- 24173047 TI - Genetic mapping of QTLs controlling vegetative propagation in Eucalyptus grandis and E. urophylla using a pseudo-testcross strategy and RAPD markers. AB - We have extended the combined use of the "pseudo-testcross" mapping strategy and RAPD markers to map quantitative trait loci (QTLs) controlling traits related to vegetative propagation in Eucalyptus. QTL analyses were performed using two different interval mapping approaches, MAPMAKER-QTL (maximum likelihood) and QTL STAT (non-linear least squares). A total of ten QTLs were detected for micropropagation response (measured as fresh weight of shoots, FWS), six for stump sprouting ability (measured as # stump sprout cuttings, #Cutt) and four for rooting ability (measured as % rooting of cuttings, %Root). With the exception of three QTLs, both interval-mapping methods yielded similar results in terms of QTL detection. Discrepancies in the most likely QTL location were observed between the two methods. In 75% of the cases the most likely position was in the same, or in an adjacent, interval. Standardized gene substitution effects for the QTLs detected were typically between 0.46 and 2.1 phenotypic standard deviations (sigmap), while differences between the family mean and the favorable QTL genotype were between 0.25 and 1.07 (sigmap). Multipoint estimates of the total genetic variation explained by the QTLs (89.0% for FWS, 67.1 % for#Cutt, 62.7% for %Root) indicate that a large proportion of the variation in these traits is controlled by a relatively small number of major-effect QTLs. In this cross, E. grandis is responsible for most of the inherited variation in the ability to form shoots, while E. urophylla contributes most of the ability in rooting. QTL mapping in the pseudo-testcross configuration relies on withinfamily linkage disequilibrium to establish marker/trait associations. With this approach QTL analysis is possible in any available full-sib family generated from undomesticated and highly heterozygous organisms such as forest trees. QTL mapping on two-generation pedigrees opens the possibility of using already existing families in retrospective QTL analyses to gather the quantitative data necessary for marker-assisted tree breeding. PMID- 24173048 TI - Genetic diagnosis of cytoplasmic male sterile cybrid plants of rice. AB - Twelve Japanese rice cultivars were converted to CMS by asymmetric protoplast fusion with MTC-5A, the cytoplasm of which was derived from an indica rice, Chinsurah Boro II. With the exception of the cybrids that had a nucleus from Hoshiyutaka, most of these cybrid plants were sterile. The unique sequence downstream from the mitochondrial atp6 of MTC-5A was specifically amplified in the sterile cybrid plants by PCR. All progenies of the cybrid plants carrying this unique sequence were sterile. On the other hand, in some of the sterile cybrid plants in which the unique sequence was not amplified by PCR, fertility was recovered in their progenies. Somaclonal mutation may have caused sterility in these cybrids. Only the cybrid plants that had the unique sequence detected by PCR were CMS. Thus, the CMS plants can be selected rapidly and easily by PCR, at an early stage of plant regeneration. Soon after transplanting the regenerated plants to a green house, fertile cybrids and sterile cybrids produced by somaclonal mutation can be removed. These findings also show that the unique region downstream from atp6 is tightly linked with the CMS phenotype. PMID- 24173049 TI - Biochemical and molecular diagnostics of Thinopyrum bessarabicum chromosomes in Triticum aestivum germ plasm. AB - Thinopyrum bessarabicum (2n=2x=14, JJ) is a self-fertile salt-tolerant grass species, and its hybridization with Triticum aestivum to achieve the transfer of this attributes has been promoted. For the detection of alien introgression, development of diagnostic markers of Th. bessarabicum chromosomes in the wheat background has emerged as an important aspect in our intergeneric hybridization program. Six proteins/isozymes-high-molecular-weight glutenins, superoxide dismutase, grain esterase, beta-amylase, glutamate oxaloacetate transaminase and alpha-amylase -were identified as positive markers for detecting the presence of Th. bessarabicum chromosomes in the advanced backcross derivatives of T. aestivum/Th. bessarabicum//n(*) T. aestivum. Fluorescent in situ hybridization further enabled the detection of complete and translocated arms of Th. bessarabicum chromosomes in the T. aestivum background. These diagnostic markers served for tentatively characterizing a distinct set of Th. bessarabicum disomic additions to wheat (2n=44) and have facilitated establishing the homoeology of these added chromosomes. PMID- 24173050 TI - Suppression of recombination in wide hybrids of Petunia hybrida as revealed by genetic mapping of marker transgenes. AB - In the course of a heterologous transposon tagging experiment in Petunia hybrida (n=7), 135 independent T-DNA loci were tested for linkage to the target genes Hf1 and Fl, which are located on the two largest chromosomes. Approximately one-third (47) of these T-DNA loci were linked to one of these two markers. Of these 47 linkedloci, 19 mapped within 1 cM of its marker, indicating a highly non-random genetic distribution of introduced loci. However, rather than non-random integration within both of the marked chromosomes, this probably reflects a suppression of recombination around these marker loci in the particular wide hybrids used for mapping. This hypothesis was tested by measuring recombination between linked T-DNAs in an inbred background. Inbred recombination levels were found to be at least 3-fold higher around the Hf1 locus and 12-fold higher around Fl compared to the wide hybrids. These findings may reflect the origin of P. hybrida by hybridization of wild species, and while relevant to genetic mapping in petunia in particular they may also have more general significance for any mapping strategies involving the use of wide hybrids in other species. PMID- 24173051 TI - Locating genes associated with root morphology and drought avoidance in rice via linkage to molecular markers. AB - This research was undertaken to identify and map quantitative trait loci (QTLs) associated with five parameters of rice root morphology and to determine if these QTLs are located in the same chromosomal regions as QTLs associated with drought avoidance/tolerance. Root thickness, root:shoot ratio, root dry weight per tiller, deep root dry weight per tiller, and maximum root length were measured in three replicated experiments (runs) of 203 recombinant inbred lines grown in a greenhouse. The lines were from a cross between indica cultivar Co39 andjaponica cultivar Moroberekan. The 203 RI lines were also grown in three replicated field experiments where they were drought-stressed at the seedling, early vegetative, and late-vegetative growth stage and assigned a visual rating based on leaf rolling as to their degree of drought avoidance/tolerance. The QTL analysis of greenhouse and field data was done using single-marker analysis (ANOVA) and interval analysis (Mapmaker QTL). Most QTLs that were identified were associated with root thickness, root/shoot ratio, and root dry weight per tiller, and only a few with deep root weight. None were reliably associated with maximum root depth due to genotype-by-experiment interaction. Root thickness and root dry weight per tiller were the characters found to be the least influenced by environmental differences between greenhouse runs. Correlations of root parameters measured in greenhouse experiments with field drought avoidance/tolerance were significant but not highly predictive. Twelve of the fourteen chromosomal regions containing putative QTLs associated with field drought avoidance/tolerance also contained QTLs associated with root morphology. Thus, selecting for Moroberekan alleles at marker loci associated with the putative root QTLs identified in this study may be an effective strategy for altering the root phenotype of rice towards that commonly associated with drought-resistant cultivars. PMID- 24173052 TI - Identification of molecular markers linked to the Agropyron elongatum-derived leaf rust resistance gene Lr24 in wheat. AB - The objective of this study was to identify molecular markers linked to the wheat leaf rust resistance gene Lr24 derived from Agropyron elongatum (3DL/3Ag translocation). Two near isogenic lines (NILs), 'Arina' and Lr24/7 (*) "Arina", were screened for polymorphism at the DNA level with 115 RFLP probes. Twenty-one of these probes map to the homoeologous group 3. In addition, 360 RAPD primers were tested on the NILs. Six RFLP probes showed polymorphism between the NILs, and 11 RAPD primers detected one additional band in the resistant NIL. The genetic linkage of the polymorphic markers with Lr24 was tested on a segregating F2 population (150 plants) derived from a cross between the leaf rust resistant Lr24/7 (*) "Arina" and the susceptible spelt (Triticum spelta) variety 'Oberkulmer'. All 6 RFLP markers were completely linked to Lr24: one was inherited as a codominant marker (PSR1205), one was in coupling phase (PSR1203) and 4 were in repulsion phase (PSR388, PSR904, PSR931, PSR1067) with Lr24. The localization of these probes on chromosome 3D was confirmed by nulli-tetrasomic analysis. Distorted genotypic segregation was found for the Codominant RFLP marker PSR1205. This distortion can be explained by the occurrence of hemizygous plants. One of the 11 RAPD markers (OPJ-09) also showed complete linkage to theLr24 resistance gene. The polymorphic RAPD fragment was cloned and sequenced. Specific primers were synthesized, and they produced an amplification product only in the resistant plants. This specific marker allows a reliable and rapid screening of a large number of genotypes in practical breeding. Analysis of 6 additional lines containing Lr24 revealed that 3 lines have a smaller chromosomal segment of A. elongatum than lines derived from 'Agent', a commonly used gene donor for the Lr24 resistance gene. PMID- 24173053 TI - A single nuclear locus phylogeny of soybean based on DNA sequence. AB - Soybean [Glycine max (L.) Merr.] evolution was examined by sequencing portions of the restriction fragment length polymorphism (RFLP) locus A-199a of 21 taxa from the Glycininae and 1 from the Phaseoleae. Four hundred nucleotides were determined in each, aligned, and then compared for these taxa. Within the annual soybean subgenus (Soja), the four accessions differed at as many as 2.2% of the nucleotides. Among 13 perennial soybean species (subgenus Glycine), nucleotide variation ranged from 1.7% to 8.4%. The nucleotide difference between the two soybean subgenera was 3.0-7.0%. Nucleotide variation between the genus Glycine and the related genera of Neonotonia, Amphicarpa, Teramnus, and Phaseolus ranged from 8.2% to 16.4%. In addition to nucleotide substitutions, insertions/deletions (indels) differences were also observed and were consistent with nucleotide-based analysis. Cladistic analysis of the A-199a sequences was performed using Wagner parsimony to construct a soybean phylogeny. Sixteen equally parsimonious trees were produced from these data. The trees were 246 steps in length with a consistency index of 0.78. Indels distribution upon the consensus topology revealed a pattern congruent with the nucleotide-based phylogeny. The current taxonomic status of the soybean subgenera and the related genera of Neonotonia, Amphicarpa, and Teramnus were well-supported and appear monophyletic in this analysis. Homoplasy within the subgenus Glycine led to a lack of resolved topology for many of these 13 taxa. However, the Glycine clade topology was consistent with phylogenies proposed using crossing experiments and cpDNA RFLPs. These genera were arranged from ancestral to derived as: Teramnus, Amphicarpa, Neonotonia, and Glycine when Phaseolus vulgaris was used as an outgroup. PMID- 24173054 TI - DNA fingerprinting to detect genetic variation in rice using hypervariable DNA sequences. AB - The suitability of miniand microsatellite related DNA sequences capable of detecting multiple loci was investigated for their ability to generate DNA fingerprints in rice. These included R18.1, a cattle-derived probe, the M13 repeat probe, pV47, a human minisatellite probe; and repeats in the Per gene, telomere, chi sequence and 3' hypervariable region of apolipoprotein B. With the R18.1, pV47 and M13 repeat probes, the level of polymorphism was high enough to identify all of the cultivars and wild rice species used in this study. R18.1, which showed the highest level of polymorphism, was estimated to identify up to 2.5*10(20) genotypes of rice. In a F2 population of a 'Basmati-370' and 'Taichung 65' cross, loci detected by R18.1 segregated in a Mendelian fashion. DNA fingerprints were somatically stable and the hybridization patterns were identical among different plants of the same cultivar. Application of the above molecular genetic markers for identification of rice genotypes is reported here for the first time. PMID- 24173055 TI - A cytogenetic ladder-map of the wheat homoeologous group-4 chromosomes. AB - We report the results of chromosome maps of wheat homoeologous chromosomes 4A, 4B, and 4D using 40 RFLP markers and 39 homozygous deletion lines. Deletion breakpoints divide the chromosomes into 45 subarm intervals with 32 intervals distinguished by molecular markers. The chromosome maps confirm the homoeology of arms 4AS to 4BL and 4DL, and 4AL to 4BS and 4DS. The chromosome map of 4A reveals novel information concerning the 4AL-5AL-7BS cyclical translocation. The presence of homoeologous group-4 long-arm markers, Xksu G10 and Xpsr 1051, intervening between the translocated 5AL and 7BS chromosome segments in 4AL suggests that the translocation events are more complex than was earlier believed. Chromosome maps confirm a pericentric inversion in Chinese Spring chromosome 4B. The consensus chromosome map is compared to the genetic map of wheat to construct a cytogenetic ladder-map (CLM). The CLM reveals an unequal distribution of recombination along the length of the chromosome arms. Recombination is highest in the distal half, and low in the proximal half, of the chromosome arms. PMID- 24173056 TI - Allozyme, chloroplast DNA and RAPD markers for determining genetic relationships between Abies alba and the relic population of Abies nebrodensis. AB - Allozyme, chloroplast (cpDNA) and random amplified polymorphic DNA (RAPD) markers have been used to estimate genetic and taxonomic relationships among different populations of Abies alba and the relic population of A. nebrodensis. Twelve isozyme gene loci, as well as restriction fragment length polymorphism (RFLP) at cpDNA spacer regions between t-RNA genes were analysed. Moreover, a set of 60 random sequence 10-mer primers were tested. Over all isozyme loci, evident differences in allele frequencies among A. nebrodensis and A. alba populations were found, particularly at 2 loci, phosphoglucose isomerase (Pgi-a) and shikimate dehydrogenase (Skd-a). More than 10% of the total genetic diversity was due to differences among populations. High values of genetic distances among populations were also found. Out of the 60 primers tested, 12 resulted in a polymorphic banding pattern both within and among populations. A total of 84 RAPD fragments were produced by the 12 selected primers. A phenogram of relationships among populations was constructed based on RAPD band sharing: the differentiation of the A. nebrodensis population was evident. The analysis of molecular variance (AMOVA) was used to apportion the variation among individuals within populations and among populations. There was considerable variation within each population: even so, genetic divergence was found among populations. This pattern of genetic variation was very different from that reported for inbred species. Identical cpDNA amplification and restriction patterns were observed among all the individuals sampled from the populations. Taken together, the results of allozyme and RAPDs show a clear differentiation among A. nebrodensis and A. alba populations and provide support for their classification into two different taxonomic groups. PMID- 24173057 TI - Heterologous transformation of Agrocybe aegerita with a bacterial neomycin resistance gene fused to a fungal promoter-like DNA sequence. AB - DNA sequences of the basidiomycete Agrocybe aegerita were cloned in E. coli based on their ability to drive the expression of the bacterial promoterless tetracycline (Tc)-resistance gene. A 0.48% frequency of the cloned sequences promoted antibiotic-resistance. The sequence conferring the highest Tc resistance (40 MUg/ml) was selected to drive the expression in E. coli of two other promoterless genes encoding chloramphenicol and neomycin resistance. One of the derivative vectors, pN13-A2, carrying a chimeric neomycin-resistance gene, was used to transform an A. aegerita neomycin-sensitive strain by protoplast electroporation. Transformation frequencies ranged from 1 to 2.8 transformants per MUg of DNA per 10(3) viable cells, in a relatively high background of spontaneous-resistant colonies (2% of the surviving protoplasts). Molecular analyses showed that transformation had occurred by the integration of pN13-A2 sequences, either ectopically or at the resident locus carrying the A. aegerita promoter-like sequence, with probable molecular rearrangements. The nucleotide sequence of the promoter-like fragment revealed the presence of a CT motif that is known to be involved in a promoter function in some highly expressed genes of filamentous fungi. PMID- 24173058 TI - Genomic analysis in maritime pine (Pinus pinaster). Comparison of two RAPD maps using selfed and open-pollinated seeds of the same individual. AB - Two genomic maps were constructed for one individual tree of maritime pine, Pinus pinaster Ait., using a common set of 263 RAPD markers (random amplified polymorphic DNA). The RAPD markers were chosen from a larger number of polymorphic RAPD fragments on the basis of repeatability and inheritance in a three-generation pedigree. The maps were constructed from two independent mapping samples of 62 megagametophytes (In) from a self cross and from an open-pollinated cross. The markers were grouped (LOD>=4; theta<=0.25) and assigned to 13 major and 5 minor linkage groups. Two framework maps were constructed using the ordering criterion of interval support>=3. Comparison of the two framework maps suggested that the locus order was incorrect for 2% of the framework markers. A bootstrap analysis showed that this error rate was representative for our data set. The results showed that framework maps constructed using RAPD markers were repeatable and that differences in locus order for maps of different genotypes or species could result from chance. The total map distance was 1380 cM, and the map provided coverage of approximately 90% of the genome. PMID- 24173059 TI - Phylogenetic relationships of cultivated Prunus species from an analysis of chloroplast DNA variation. AB - Chloroplast DNA (cpDNA) restriction-site mutations in seven cultivated Prunus species were compared to establish the phylogenetic relationships among them. Mutations were detected in 3.2-kb and 2.1-kb amplified regions of variable cpDNA, cut with 21 and 10 restriction endonucleases, respectively, to reveal polymorphisms. Parsimony and cluster analyses were performed. The species pairs P. persica-P. dulcis, P. domestica-P. salicina, and P.cerasus-P. fruticosa were completely monophyletic. All of the species were grouped with conventional subgenus classifications. The subgenus Cerasus was the most diverged. Cerasus ancestors separated from the remainder of Prunus relatively early in the development of the genus. P. persica-P. dulcis, P. domestica-P. salicina and P. armeniaca formed a second monophyletic group. Prunophora species were less diverged than Amygdalus species. The results also suggest that the rate of mutation in Cerasus spp. chloroplast genomes is significantly greater than for the other subgenera sampled. PMID- 24173060 TI - RFLP analysis of an Aegilops ventricosa chromosome that carries a gene conferring resistance to leaf rust (Puccinia recondita) when transferred to hexaploid wheat. AB - RFLP analysis has been used to characterise XM(v), a chromosome of Aegilops ventricosa present in a disomic addition line of wheat. This chromosome is known to carry a major gene conferring resistance to leaf rust (Lr). The analysis demonstrated that XM(v) is translocated with respect to the standard wheat genome, and consists of a segment of the short arm of homoeologous group 2 attached to a group 6 chromosome lacking a distal part of the short arm. Lr was located to the region of XM(v) with homoeology to 2S by analysis of a leaf rust susceptible deletion line that was found to lack the entire 2S segment. Confirmation and refinement of the location of Lr was obtained by analysis of a spontaneous resistant translocation in which a small part of XM(v) had been transferred to wheat chromosome 2A. PMID- 24173061 TI - The identification of duplicate accessions within a rice germplasm collection using RAPD analysis. AB - A set of accessions of Oryza sativa from the International Rice Research Institute (Philippines) that included known and suspected duplicates as well as closely related germplasm has been subjected to RAPD analysis. The number of primers, the number of polymorphic bands and the total number of bands were determined that will allow the accurate discrimination of these categories of accessions, including the identification of true and suspected duplicates. Two procedures have been described that could be employed on a more general basis for identifying duplicates in genetic resources collections, and further discussion on the values of such activities is presented. PMID- 24173062 TI - Pollen fertility restoration by nuclear gene Fr in CMS common bean: an Fr linkage map and the mode of Fr action. AB - The Fr gene in common bean, Phaseolus vulgaris L., is a unique gene for the study of plant nuclear-mitochondrial interactions because it appears to directly influence plant mitochondrial genome structure, resulting in the restoration of pollen fertility in cytoplasmic male sterile plants. This gene action is distinct from other pollen fertility restoration systems characterized to date. As a first step towards the map-based cloning of this unusual nuclear gene, we identified RAPD markers linked to Fr using bulked segregant analysis of near-isogenic lines. Using DNA gel blot hybridization, we localized the identified RAPD markers to a linkage group on the common bean RFLP map and constructed a linkage map of the Fr region using both RAPD markers and RFLP markers. Analysis of the mode of Fr action with the aid of identified Fr-linked DNA markers indicated that Fr functions in a semidominant fashion, showing dosage effect in controlling the dynamics of a heteroplasmic mitochondrial population. We also present our observations on the developmental distinctions, crucial in the accurate mapping of the Fr gene, between spontaneous cytoplasmic reversion and Fr-driven fertility restoration, two phenomena that are phenotypically indistinguishable. PMID- 24173063 TI - Assessment of the type and degree of restriction fragment length polymorphism (RFLP) in diploid species of the genus Triticum. AB - The A genome of the Triticeae is carried by three diploid species and subspecies of the genus Triticum: T. monococcum ssp. monococcum, T. monococcum ssp. boeoticum, and T. urartu, the A-genome donor of bread wheat. These species carry many genes of agronomic interest, including disease resistances, and may also be used for the genetic mapping of the A genome. The aim of this study was to evaluate the variability present in a sample of 25 accessions representative of this group using RFLP markers. Twenty probes, consisting of genomic DNA or cDNA from wheat, were used in combination with four restriction enzymes. A high level of polymorphism was found, especially at the interspecific level. Selecting the most informative enzymes appeared to be of great importance in order to obtain a stable structure for the diversity observed with only 20 probes. The results are largely consistent with taxonomy and data relating to geographical origins. The probes were also tested on 14 wheat cutivars. A good correlation coefficient was found for their informative values on wheat cultivars and diploid lines. Whether the group of species studied here would be useful for genetic mapping remains to be determined. Nevertheless, RFLP markers will be useful to follow genes that can possibly be introgressed from these species into cultivated wheat. PMID- 24173064 TI - Identification of RAPD markers linked to a black leaf spot resistance gene in Chinese elm. AB - Black leaf spot (Stegophora ulmea) is a common foliage disease on Chinese (Ulmus parvifolia) and Siberian elms (U. pumila), two species which have been widely used as sources of Dutch-elm disease-resistance genes for interspecific elm hybrids. A dominant gene controlling resistance to black leaf spot was identified in a population derived from self-pollination of a single U. parvifolia tree. Using RAPD markers, in combination with bulked segregant analysis, we have identified three markers linked to this resistance gene. A survey of Chinese-elm hybrids revealed that the same gene is likely to confer a high level of resistance to black leaf spot in interspecific elm hybrids, although other genetic factors may also be involved in the determination of a disease phenotype. PMID- 24173065 TI - A correlation method for detecting and estimating linkage between a marker locus and a quantitative trait locus using inbred lines. AB - The advent of molecular genetic markers has stimulated interest in detecting linkage between a marker locus and a quantitative trait locus (QTL) because the marker locus, even without direct effect on the quantitative trait, could be useful in increasing the response to selection. A correlation method for detecting and estimating linkage between a marker locus and a QTL is described using selfing and sib-mating populations. Computer simulations were performed to estimate the power of the method, the sample size (N) needed to detect linkage, and the recombination value (r). The power of this method was a function of the expected recombination value E(r), the standardized difference (d) between the QTL genotypic means, and N. The power was highest at complete linkage, decreased with an increase in E(r), and then increased at E(r)=0.5. A larger d and N led to a higher power. The sample size needed to detect linkage was dependent upon E(r) and d. The sample size had a minimum value at E(r)=0, increased with an increase in E(r) and a decrease in d. In general, the r was overestimated. With an increase in d, the r was closer to its expectation. Detection of linkage by the proposed method under incomplete linkage was more efficient than estimation of recombination values. The correlation method and the method of comparison of marker-genotype means have a similar power when there is linkage, but the former has a slightly higher power than the latter when there is no linkage. PMID- 24173066 TI - Development of a consensus linkage RFLP map of cultivated sunflower (Helianthus annuus L.). AB - This paper provides the first description of a consensus map of the cultivated sunflower genome (Helianthus annuus L., n=17 chromosomes), based on RFLP. A total of 180 probe-enzyme combinations were mapped on at least one of five segregating progenies (three F2 and two BC1 populations), revealing 237 loci that did not show any distortion of segregation. The consensus linkage map obtained with these loci covers 1150 cM and consists of 16 linkage groups of more than 20 cM, 7 groups of less than 20 cM and 18 unlinked loci. The mean distance between loci is 7 cM, but in some regions intervals of 20 cM remain. Genotypic and gametic segregation distortions affect about 7% of loci. It was found that 25% of the probes mapped using several different restriction enzymes or that on different progenies they revealed 2 or more loci. PMID- 24173067 TI - Organization of the mitochondrial Cob 2 pseudogene in different lines of rice. AB - In the fertile rice line IR 36 there are two copies of the apocytochrome b (cob) gene: a functional copy, cob 1, and a pseudogene, cob 2 (Kaleikau et al. 1992). In a survey of diverse rice lines, we found that cob 2 was absent in the wild abortive(WA)-type cytoplasmic male-sterile cytoplasm, but was present in the fertile lines. While cob 1 was conserved among all the lines, fertile and sterile, the cob 2 region was different in the fertile lines tested. The 5' regions of most cob 2 loci were similar to cob 1 (about 4 kb of the flanking region and most of the coding region), but the 3' region varied among different fertile lines. The point of divergence, the break-point, from the cob 1 sequence was conserved in all the cob 2 regions tested. In all the cob 2 regions, this break-point seems to be linked to the variable region of cob 2 through a conserved 192-bp segment, which is not a part of cob 1. It is proposed that the cob 2 regions could have been produced by recombination or insertion events involving cob 1 and the 192-bp segment which is present at different locations in the mitochondrial genomes of the various rice lines. PMID- 24173068 TI - Chromosome localization and characterization of a family of long interspersed repetitive DNA elements from the genus Zea. AB - This paper describes the characterization and chromosomal distribution of new long repetitive sequences present in all species of the genus Zea. These sequences constitute a family of moderately repetitive elements ranging approximately from 1350 to 1700 copies per haploid genome in modern maize (Zea mays ssp. mays) and teosinte (Zea diploperennis), respectively. The elements are long, probably larger than 9 kb, and they show a highly conserved internal organization among Zea subspecies and species. The elements are present in all maize chromosomes in an interspersed pattern of distribution, are absent from centromeric and pericentric heterochromatin, and with some clustering in the distal regions of chromosome arms. PMID- 24173069 TI - Characterization of a highly repeated DNA component of perennial oats (Helictotrichon, Poaceae) with sequence similarity to a A-genome-specific satellite DNA of rice (Oryza). AB - The taxonomic relationships among perennial oats (Helictotrichon Besser ex Schultes & Schultes, Aveninae, Aveneae, Poaceae) have been studied using highly repeated satellite DNA as a molecular marker. Highly repetitive sequences were isolated from restriction endonuclease digests of nuclear DNA of Helictotrichon convolutum, and satellite repeats (approximately 365 bp in length) were cloned, sequenced and compared among each other. They exhibited an intraspecific sequence variability of 6-9%. This satellite DNA, CON1, is differentially distributed within the genus Helictotrichon. In species of the subgenus Helictotrichon a high copy number is detectable, whereas in representatives of the subgenera Pratavenastrum and Pubavenastrum the number of copies per genome is rather low. Surprisingly, the satellite DNA repeat CON1 shows 74% sequence similarity to an A genome specific repetitive DNA of Oryza (rice). PMID- 24173070 TI - The effects of selection for sodium transport and of selection for agronomic characteristics upon salt resistance in rice (Oryza sativa L.). AB - A multiple cross was constructed with the aim of combining component traits for the complex salinity resistance character. The aim was to combine donors for physiological traits with the agronomically desirable semidwarf/intermediate plant type and with the overall salinity resistance of the traditional tall land races. We report a study of selection strategies in the resulting breeding population. The effects of early selection for agronomic traits and early selection for low sodium transport were compared with a control population in which minimal selection was practised. Conventional selection for agronomic characters at early generations selected against low sodium-transporting (and thus potentially salt-tolerant) genotypes. In contrast, mild early selection for low sodium transport enriched the population in potentially salt-resistant genotypes but did not select against agronomic (semi-dwarf/intermediate) genotypes. It is concluded that selection for agronomic traits should be made after selection for salt resistance and, ideally, should be delayed until the population has reached near-homozygosity. PMID- 24173071 TI - Variation in protein and RNA synthesis activity in isolated mitochondria of the developing rice (Oryza sativa L.) panicle. AB - We have studied variation in mitochondrial protein and RNA synthesis during the development of a specialized rice (Oryza sativa L.) reproductive organ in a bacteria-free environment. Mitochondria were prepared from the maturing panicle during microsporogenesis when meiosis occurred and from etiolated seedlings at two growth stages. We found (1) that there was no discernible qualitative difference among the polypeptides synthesized by these three mitochondrial samples; (2) that the quantity of proteins synthesized by panicle mitochondria was approximately 3 times that of the seedling mitochondria, while the two seedling samples exhibited only a minor quantitative difference; (3) that panicle and seedling mitochondria samples synthesized qualitatively the same RNA but at distinctly different rates and that more RNA products were synthesized by panicle than by seedling mitochondria. These results, taken together, suggest that either the regulation of mitochondrial transcription and translation or the copy number of mitochondrial DNA per mitochondrion change discretely in the developing panicle and consequently that the level of mitochondrial gene expression increases considerably during the development of the reproductive structure in rice. PMID- 24173072 TI - RAPD linkage mapping in a longleaf pine x slash pine F1 family. AB - Random amplified polymorphic DNAs (RAPDs) were used to construct linkage maps of the parent of a longleaf pine (Pinus palustris Mill.) slash pine (Pinus elliottii Englm.) F1 family. A total of 247 segregating loci [233 (1?1), 14 (3?1)] and 87 polymorphic (between parents), but non-segregating, loci were identified. The 233 loci segregating 1?1 (testcross configuration) were used to construct parent specific linkage maps, 132 for the longleaf-pine parent and 101 for the slash pine parent. The resulting linkage maps consisted of 122 marker loci in 18 groups (three or more loci) and three pairs (1367.5 cM) for longleaf pine, and 91 marker loci in 13 groups and six pairs for slash pine (952.9 cM). Genome size estimates based on two-point linkage data ranged from 2348 to 2392 cM for longleaf pine, and from 2292 to 2372 cM for slash pine. Linkage of 3?1 loci to testcross loci in each of the parental maps was used to infer further linkages within maps, as well as potentially homologous counterparts between maps. Three of the longleaf-pine linkage groups appear to be potentially homologous counterparts to four different slash-pine linkage groups. The number of heterozygous loci (previously testcross in parents) per F1 individual, ranged from 96 to 130. With the 87 polymorphic, but non-segregating, loci that should also be heterozygous in the F1 progeny, a maximum of 183-217 heterozygous loci could be available for mapping early height growth (EHG) loci and for applying genomic selection in backcross populations. PMID- 24173073 TI - An examination of the ability of RAPD markers to determine the relationships within and between Rubus species. AB - RAPD markers were generated from 13 different Rubus species in order to assess the degree of similarity between species from the important subgenera. All ten primers revealed scorable polymorphisms within both the closely related and the genetically diverse individuals. Three hundred and seventy-two markers were generated and scored from the material analysed. Estimates of similarity, dendrograms and principle co-ordinate analysis were calculated, with the results generally being in agreemen with previous classifications of the species studied, confirming the validity and usefulness of the RAPD method. However, amongst the species studied, R. macraei of the Idaeobats proved more diverse and grouped in with both the Idaeobats and Eubats at only 26% similarity. PMID- 24173074 TI - Gene flow from cultivated to wild raspberries in Scotland: developing a basis for risk assessment for testing and deployment of transgenic cultivars. AB - In order to help establish a basis for assessing the risk associated with the testing and large-scale deploymen of transgenic raspberries, wild and feral raspberry populations in Scotland were surveyed for evidence of the escape of genes introduced into raspberry cultivars by traditional breeding. The genes concerned were introduced into cultivars using traditional breeding techniques and were deployed at known times 20 to 30 years prior to the present survey. Escape of the semidominant L 1 gene, affecting fruit size and plant morphology, could not be detected after 30 years in test plots at the Scottish Crop Research Institute near Dundee. The recessive gene s, conferring spinelessness, was detected at very low frequencies (estimated at 0.004) in wild populations within the commercial production locales where cultivars carrying this gene had been introduced on a large scale beginning 21-years prior to this survey. This gene was not, however, found in any areas remote from the commercial production locales. The results of the survey indicate that escape does occur following large-scale deployment but that gene flow events are probably infrequent and spread is localized for genes having probable neutral selective value. PMID- 24173075 TI - Chloroplast DNA variation and parentage analysis in 55 apples. AB - The chloroplastic atpB-rbcL spacer and the first 53 codons of the rbcL coding sequence was sequenced for 40 apple cultivars and 15 wild species. This chloroplast DNA region is 904 base pairs long, and only five mutations sites were found among the tested samples. Although the cpDNA variation was low, some parentages are proposed based on the maternal inheritance of plastid DNA: the male and female parents are specified, or else suggested, for Worcester, Discovery, Starking, Starkrimson, Kidd's Orange Red, Priscilla, and Gloster, as well as for the putative wild origin for Malus x domestica. PMID- 24173076 TI - PCR-generated molecular markers for the invertase gene and sucrose accumulation in tomato. AB - The green-fruited tomato species, Lycopersicon hirsutum, unlike the domesticated red-fruited species, L. esculentum, accumulates sucrose during the final stages of fruit development, concomitant with the loss of soluble acid invertase activity. In order to study the genetic linkage of sucrose accumulation to the invertase gene, part of the invertase gene from L. hirsutum was cloned, sequenced and the sequence compared with the invertase sequence of the red-fruited L. esculentum. Several base changes were found in the coding region of the two invertase genes. Based on these base -pair differences, we developed a species specific PCR assay capable of determining, in a single PCR reaction, the origin of the invertase gene in segregating seedlings of an interspecific cross. Our results indicate that the invertase gene is genetically linked to sucrose accumulation in the green-fruited L. hirsutum. PMID- 24173077 TI - Inheritance of B subunits of glutenin and omega-and gamma-gliadins in tetraploid wheats. AB - A double-1RS wheat-rye translocation line lacking all B subunits of glutenin was produced in durum wheat cv 'Langdon' for use in backcrosses and testcrosses in the study of the inheritance of low-molecular-weight (LMW) glutenin subunits in tetraploid wheats. The B subunits of glutenin and gamma-and omega-gliadin bands present in parents derived from Triticum durum and T. dicoccoides, encoded by Glu 3 and Gli-1 loci, respectively, were found to be inherited mainly as units (blocks), as reported previously. Two rare recombination events between the Glu A3 and Gli-A1 loci were detected in testcross progeny from 'Edmore' x T. dicoccoides landrace 19-27. Several rare recombinants were also detected within the 1BS-controlled B subunits of glutenin blocks, suggesting that there are two separate tightly linked loci (3.07+/-1.35 cM) within the Glu-B3 'locus'. Evidence was also obtained for the presence of an additional locus coding for a B subunit of glutenin in 'Edmore' that is loosely linked (20.9+/-3.18%) with the main Glu B3 'locus'. PMID- 24173078 TI - Chromosomal location of genes for stem rust resistance derived from 'Waldron' wheat. AB - The chromosomal locations of genes for resistance to stem rust (Puccinia graminis Pers.: Pers. f. sp. tritici Eriks. & E. Henn.) in the wheat (Triticum aestivum L.) cultivar 'Waldron' (WDR) were determined by monosomic analyses. Wheat lines WDR-B1, -C2, -E4, and -F1,which have single genes for resistance to stem rust derived previously from WDR sel. 'Little Club', were crossed onto a complete set of 21 'Chinese Spring' monosomics. The F2 and backcross-F1 (BC1F1) seedlings from each of the 84 crosses were tested for reaction to culture 111-SS2 (CRL-LCBB) of stem rust, and a few selected segregants were analyzed cytologically for chromosome number. The F2 from 2 crosses of WDR-C2, -E4 and -F1 and the BC1F1 from 2 crosses of WDR-F1 were tested also with culture Or11c (CRL-QBCN). Significant deviations from disomic ratios towards monosomic ratios in the F2 and BC1F1 were used to determine which chromosomes carried the genes for resistance. Cytological analyses of certain BC1F1 and susceptible F2 plants were used to help identify the location of the genes for rust resistance. WDR-B1 has a gene, herein designated Sr41, for resistance on chromosome 4D. WDR-C2 has a gene on chromosome 7 A that may be the same as one previously designated SrWld2. WDR-E4 has a gene on chromosome 2A, possibly SrWld1, which is effective against most or all North American stem rust cultures. WDR-F1 has a gene on chromosome 6B that is the same as or similar to Sr11. PMID- 24173079 TI - Wheat lines monogenic for resistance to stem rust from the wheat cultivar 'Waldron'. AB - The Triticum aestivum L. cultivar 'Waldron' has long lasting resistance to most North American stem rust (Puccinia graminis Pers.:Pers. f. sp. tritici Eriks. and E. Henn.) isolates. The objective of this research was to develop wheat lines monogenic for resistance to stem rust from 'Waldron' using allelism tests and tests for reaction to a series of ten stem rust cultures having a range of virulences. Twelve lines homozygous for single resistance genes were selected as parents of a diallel cross to test for allelism among genes for resistance. We identified 6 lines or groups of lines (WDR-A1, the WDR-B1 and WDR-B2 group, the WDR-C1 and WDR-C2 group, WDR-D1, the WDR-E1, WDR-E2, WDR-E3, and WDR-E4 group, and WDR-F1) that carried different single genes for resistance from 'Waldron'. A seventh line (WDR-G1) probably has two genes for resistance, one in common with WDR-C1 and WDR-C2. The gene in the WDR-E group is probably the same as SrWld1, and the one in WDR-F1 the same as Sri11. 'Waldron' probably has two or more genes for resistance to stem rust that previous genetic studies did not detect. PMID- 24173080 TI - Sensitivity of random amplified polymorphic DNA analysis to detect genetic change in sugarcane during tissue culture. AB - Random amplified polymorphic DNA (RAPD) analysis using 10-mer oligonucleotide primers efficiently differentiated sugarcane cultivars and proved suitable for detecting gross genetic change such as that which can occur in sugarcane subjected to prolonged tissue culture, for example in protoplast-derived callus. However, RAPD analysis was not sufficiently sensitive to detect smaller genetic changes that occur during sugarcane genetic transformation. The length of DNA scored for polymorphism per primer averaged 13.2 kb, or 0.0001% of the typical sugarcane genome size of 1.2 * 107 kb (2C). RAPD analysis of sugarcane plants regenerated from embryogenic callus revealed very few polymorphisms, indicating that gross genetic change is infrequent during this tissue culture procedure, although epigenetic effects result in transient morphological changes in regenerated plants. More sensitive variations on the RAPD technique may increase the practicality of DNA-based screening of regenerated plant lines to reveal somaclonal variants. PMID- 24173081 TI - RFLP mapping of the vernalization (Vrn1) and frost resistance (Fr1) genes on chromosome 5A of wheat. AB - A population of single chromosome recombinant lines was developed from the cross between a frost-sensitive, vernalization-insensitive substitution line, 'Chinese Spring' (Triticum spelta 5A) and a frost-tolerant, vernalization-sensitive line, 'Chinese Spring' ('Cheyenne' 5A), and used to map the genes Vrn1 and Fr1 controlling vernalization requirement and frost tolerance, respectively, relative to RFLP markers located on this chromosome. The Vrn1 and Fr1 loci were located closely linked on the distal portion of the long arm of 5AL, but contrary to previous observations, recombination between them was found. Three RFLP markers, Xpsr426, Xcdo504 and Xwg644 were tightly linked to both. The location of Vrn1 suggests that it is homoeologous to other spring habit genes in related species, particularly the Sh2 locus on chromosome 7 (5H) of barley and the Sp1 locus on chromosome 5R of rye. PMID- 24173082 TI - Isolation of mitochondrial DNA sequences that distinguish male-sterility-inducing cytoplasms in Sorghum bicolor (L.) Moench. AB - We have demonstrated that sorghum DNA sequences of mitochondrial origin can be used to distinguish different male-sterility-inducing cytoplasms. Six DNA clones containing single-copy mitochondrial sequences were hybridized on Southern blots to restriction enzyme-digested DNA of 28 sorghum lines representing sources of different cytoplasmic male-sterility (CMS) groups. Four cytoplasmic types were defined on the basis of the pattern of DNA fragments detected. Similar analyses of 50 additional diverse sorghum accessions suggested that three of the four cytoplasmic types may be diagnostic for CMS. Also, three other cytoplasmic types were discovered. These and other mitochondrial DNA clones may be useful molecular tools for "fingerprinting" sterility-inducing cytoplasms in breeding programs, determining cytoplasmic diversity among germ plasm accessions, and identifying new sources of cytoplasm that induce male sterility. PMID- 24173083 TI - A transposable element in diverse corn lines, Ubiquitous (Uq): allelism test. AB - Since the discovery of the Uq transposable element system in the early 1980s, studies of Uq distribution have shown that Uq is pervasive in genetic stocks and corn populations including BSSS, the Illinois oil and protein lines, 'Lancaster', 'Jarvis' and several others. The assumption made was that Uq might have provided the variation that has contributed to maize breeding progress. Of the several inbreds tested in previous studies, only IaI159, one of the contributors to BSSS, contained an active Uq. The main question posed in our experiments was that of chromosomal location(s), or allelic relationships, of active Uq elements in diverse corn populations. Results showed that these Uq elements are allelic, linked or independent, though most found from corn populations show quite distant or independent linkage relationships with each other. The lack of a linear linkage map among these Uq elements may be interpreted to have resulted from transposition events and this might have led to the differentiated instability of an individual Uq element that was found to be variable. Other questions also discussed relate to the origin of Uq elements in corn populations and their role(s) in plant breeding. PMID- 24173084 TI - Detection of the apomictic mode of reproduction in maize-Tripsacum hybrids using maize RFLP markers. AB - Polyploid plants in the genus Tripsacum, a wild relative of maize, reproduce through gametophytic apomixis of the diplosporous type, an asexual mode of reproduction through seed. Moving gene(s) responsible for the apomictic trait into crop plants would open new areas in plant breeding and agriculture. Efforts to transfer apomixis from Tripsacum into maize at CIMMYT resulted in numerou intergeneric F1 hybrids obtained from various Tripsacum species. A bulk-segregant analysis was carried out to identify molecular markers linked to diplospory in T. dactyloides. This was possible because of numerous genome similarities among related species in the Andropogoneae. On the basis of maize RFLP probes, three restriction fragments co-segregating with diplospory were identified in one maize Tripsacum dactyloides F1 population that segregated 1?1 for the mode of reproduction. The markers were also found to be linked in the maize RFLP map, on the distal end of the long arm of chromosome 6. These results support a simple inheritance of diplospory in Tripsacum. Manipulation of the mode of reproduction in maize-Tripsacum backcross generations, and implications for the transfer of apomixis into maize, are discussed. PMID- 24173085 TI - Short interspersed CAN SINE elements as prognostic markers in canine mammary neoplasia. AB - The genome of mammals is characterized by a large number of non-LTR retrotransposons, and among them, the CAN SINEs are characteristics of the canine species. Small amounts of DNA freely circulate in normal blood serum and high amounts are found in human patients with cancer, characterizing it as a candidate tumor-biomarker. The aim of this study was to estimate, through its absolute expression, the number of copies of CAN SINE sequences present in free circulating DNA of female dogs with mammary cancer, in order to correlate with the clinical and pathological characteristics and the follow-up period. The copy number of CAN SINE sequences was estimated by qPCR in 28 female dogs with mammary neoplasia. The univariate analysis showed an increased number of copies in female dogs with mammary tumor in female dogs >10 years old (p=0.02) and tumor time >18 months (p<0.05). The Kaplan-Meier test demonstrated a negative correlation between an increased number of copies and survival time (p=0.03). High amounts of CAN SINE fragments can be good markers for the detection of tumor DNA in blood and may characterize it as a marker of poor prognosis, being related to female dogs with shorter survival times. This estimate can be used as a prognostic marker in non-invasive breast cancer research and is useful in predicting tumor progression and patient monitoring. PMID- 24173086 TI - High-dose isotretinoin treatment and the rate of retrial, relapse, and adverse effects in patients with acne vulgaris. AB - IMPORTANCE: Isotretinoin is the most effective treatment for acne. The ideal dosing regimen is unknown. OBJECTIVE: To determine the rates of relapse of acne vulgaris and retrial of isotretinoin after high cumulative-dose treatment and the changes to the adverse effect profile. DESIGN, SETTING, AND PARTICIPANTS: A prospective, observational, intervention study was conducted from August 1, 2008, to August 31, 2010, in a single academic tertiary care center with multiple providers. A total of 180 patients with acne resistant to other treatments were enrolled. Of these, 116 participated in the 12-month follow-up survey, for a response rate of 64.4%. EXPOSURE: Patients received isotretinoin, with dosing based on the providers' judgment. Patients were divided into 2 groups on the basis of cumulative dosing (<220 mg/kg and >= 220 mg/kg). MAIN OUTCOMES AND MEASURES: Relapse (treatment with a prescription topical or oral acne medication after a course of isotretinoin) or retrial (retreatment with isotretinoin) at 12 month follow-up and adverse effects experienced during and after 12 months of treatment. RESULTS The mean age of the participants was 19.3 years, 51.9% were female, and 74.1% were white. At 12 months' follow-up, 97.4% of the patients reported that their acne was improved. Overall, acne in 32.7% of patients in the study relapsed at 12 months, and 1.72% of the patients required a retrial. In the lower-dose treatment group (<220 mg/kg), the relapse rate was 47.4% (95% CI, 32.3%-63.0%) compared with 26.9% (95% CI, 18.3%-37.8%) in the high-dose group (P = .03). Almost 100% of the patients in both treatment groups developed cheilitis and xerosis during treatment. Retinoid dermatitis was significantly more common in the high-dose treatment group (53.8% vs 31.6%; P = .02). None of the other adverse effects was significantly different between the 2 groups. CONCLUSIONS AND RELEVANCE: The dosing regimen used in the present study is considerably higher than that used in previous studies of isotretinoin. At 1 year after completion of isotretinoin treatment, we found that patients receiving 220 mg/kg or more had a significantly decreased risk of relapse. Rash was the only adverse effect that was significantly more common in the high-dose group during treatment. This study suggests that significantly higher doses of isotretinoin are effective for treating acne and decreasing relapse rates without increasing adverse effects. PMID- 24173087 TI - A highly specific q-RT-PCR assay to address the relevance of the JAK2WT and JAK2V617F expression levels and control genes in Ph-negative myeloproliferative neoplasms. AB - In Ph- myeloproliferative neoplasms, the quantification of the JAK2V617F transcripts may provide some advantages over the DNA allele burden determination. We developed a q-RT-PCR to assess the JAK2WT and JAK2V617F mRNA expression in 105 cases (23 donors, 13 secondary polycythemia, 22 polycythemia vera (PV), 38 essential thrombocythemia (ET), and 9 primary myelofibrosis (PMF)). Compared with the standard allele-specific oligonucleotide (ASO)-PCR technique, our assay showed a 100 % concordance rate detecting the JAK2V617F mutation in 22/22 PV (100 %), 29/38 (76.3 %) ET, and 5/9 (55.5 %) PMF cases, respectively. The sensitivity of the assay was 0.01 %. Comparing DNA and RNA samples, we found that the JAK2V617F mutational ratios were significantly higher at the RNA level both in PV (p = 0.005) and ET (p = 0.001) samples. In PV patients, JAK2WT expression levels positively correlated with the platelets (PLTs) (p = 0.003) whereas a trend to negative correlation was observed with the Hb levels (p = 0.051). JAK2V617F positive cases showed the lowest JAK2WT and ABL1 mRNA expression levels. In all the samples, the expression pattern of beta-glucoronidase (GUSB) was more homogeneous than that of ABL1 or beta2 microglobulin (B2M). Using GUSB as normalizator gene, a significant increase of the JAK2V617F mRNA levels was seen in two ET patients at time of progression to PV. In conclusion, the proposed q-RT PCR is a sensitive and accurate method to quantify the JAK2 mutational status that can also show clinical correlations suggesting the impact of the residual amount of the JAK2WT allele on the Ph- MPN disease phenotype. Our observations also preclude the use of ABL1 as a housekeeping gene for these neoplasms. PMID- 24173088 TI - Pulmonary lymphocyte-rich classical Hodgkin lymphoma with early response to ABVD therapy. PMID- 24173089 TI - Hepatitis B virus reactivation associated with ruxolitinib. PMID- 24173096 TI - Depolarization of electroplax membrane in calcium-free ringer's solution. AB - Electrical stimulation, either cathodal or anodal, of the monocellular electroplax preparation in Ca-free Ringer's solution results in a sustained depolarization which is determined by the amount of current passed through the cell. The membrane potential recovers only when Ca is added again. These changes take place at the innervated side of the electroplax only. This depolarization of the membrane is pH-dependent; it depolarizes more at pH 6.0 than at pH 9.0. The membrane does not depolarize and the action potential is not blocked within an hour in Ca-free solution unless the cell is stimulated. The sustained depolarization is not prevented or reversed by curare, tetracaine, physostigmine, tetrodotoxin, and tetraethylammonium.After stimulation, the outward K current remains unchanged regardless of whether Ca is present. In contrast, the inward current is dependent on Ca in the outside solution on the innervated membrane; in the absence of Ca following stimulation, the inward K current is decreased.The depolarization by carbamylcholine is reduced in Ca-free and increased in Mgfree Ringer's solution. In contrast to the depolarization induced by electrical stimulation, these carbamylcholine depolarizations may be reversed by washing with Ca-free or Ca- and Mg-free Ringer's solution. PMID- 24173097 TI - The transport of potassium through lipid bilayer membranes by the neutral carriers valinomycin and monactin : Experimental studies to a previously proposed model. AB - Stationary conductance experiments on neutral and negatively charged bilayer membranes in the presence of valinomycin or monactin agree with a recently proposed carrier transport model, which is common to both carrier types. This model assumes an interface reaction between a cation from the aqueous solution and a carrier molecule from the membrane phase to establish charge transport across the interface. The transport across the membrane interior is described by some kind of "Eyring model". The discussion of the current-voltage characteristic, the dependence of membrane conductance on the carrier and K(+) concentrations, and the comparison with appropriate experiments allow correlation of the different rate constants of the transport model. The results show that the rate constants partly depend on the surface charge of the membranes. This dependency can be described by introducing the Gouy-Chapman theory for charged surfaces into the transport model.It was found that the carrier molecules could be added either to the aqueous phase or to the membrane-forming solution. The quantitative treatment of this phenomenon gives an evaluation of the partition coefficient of the carrier molecules between the membrane bulk phase and water. PMID- 24173098 TI - Interactions of the fluorescent anion 1-anilino-8-naphthalene sulfonate with membrane charges in human red cell ghosts. AB - The interaction of the fluorescent anion 1-anilino-8-naphthalene sulfonate (ANS) with erythrocyte membranes was studied as a function of the charges in the membrane. The membrane charges were altered by including in the incubation medium the organic ions tetraphenylboron (TPB(-)), tetraphenylarsonium (TPA(+)) and tetraphenylphosphonium (TPP(+)) which differ in charge but have similar structure and high affinity for the membrane. TPB(-) decreases whereas TPA(+) and TPP(+) increase ANS fluorescence arising from the membrane. The fluorescence changes are accompanied by variations in the affinity and capacity of the membrane for ANS. The fluorescence arising under conditions where all the ANS present is within the membrane (by extrapolation to infinite membrane concentration) does not vary with these ions. Salicylate and SCN(-) which inhbit anion permeability also decrease ANS fluorescence with no apparent change in quantum yield. These results indicate that ANS exists as an anion in the membrane, associated with the regions involved in ion permeability, and that the concentration of ANS in the membrane is a function of the concentration of all the ions present in the medium and their relative affinities for the membrane. Thus, variations in ANS fluorescence reflect redistributions of the ANS ions following changes in electrostatic interactions with the membrane fixed charges. PMID- 24173099 TI - Lipid pattern and Na(+)-K (+)-dependent adenosine triphosphatase activity in the salt gland of duck before and after adaptation to hypertonic saline. AB - Ducks (Anas platyrhynchos) were fed hypertonic saline for eight days, resulting in an activation and hypertrophy of the salt gland. The Na(+)-K(+)-dependent adenosine triphosphatase, an enzyme generally assumed to be part of the active Na transport system, increased its specific activity by about 200% during this activation. Sulfatides, the major glycolipids of the salt gland, increased their concentration to the same extent. Cholesterol, cerebrosides, and six phospholipid classes showed an increase of 20-80%. PMID- 24173100 TI - Studies of electric capacitance of membranes : II. Conformational change in a model membrane composed of a filter paper and a lipid analogue. AB - The electric capacitance and conductance of a model membrane composed of a hydrophobic filter paper and a synthetic lipid analogue, i.e., dioleylphosphate, immersed in an electrolyte solution were observed with various frequencies ranging from 20 to 3*10(6) Hz. With successive increase of salt concentration in the external solution, the capacitance and conductance of the membrane increased discontinuously at a certain critical value of the external salt concentration. This variation of the capacitance and conductance of the membrane with the salt concentration was found to be reversible, and the critical value of salt concentration was independent of the adsorbed quantity of the lipid, and of the pore size of the filter paper as far as the adsorbed quantity of the dioleylphosphate was large.A theoretical analysis based on the membrane model for the filter paper-phospholipid system proposed in Part I of this series revealed that the dioleylphosphate impregnated in the filter paper changed its conformation from oil droplets or globular micelles to a number of bilayer membranes when the salt concentration reached the critical value for a given pair of electrolyte species and the membrane. The conformational change of the lipid analogue in the filter paper is discussed in connection with the ability of formation and stability of a black bilayer membrane of the dioleylphosphate. PMID- 24173101 TI - Permeability of bimolecular membranes made from lipid extracts of human red cell ghosts to sugars. AB - Spherical lipid bimolecular membranes of a large surface area separating two aqueous solutions were formed from the total lipid extracts of human red cell ghosts and from their individual lipid components. The isotopic permeabilities of these membranes to biologically important sugars and to a related polyol were measured. The observedD-glucose permeabilities of the bimolecular membranes of the total lipid, phosphatidyl choline, phosphatidyl ethanolamine, sphingomyelin, and cholesterol were 2.35, 2.51, 2.23, 1.35, and 0.62*10(-10) cm/sec, respectively. These permeabilities are about four to five orders of magnitude lower than that of the intact red cell membrane. The permeabilities of the bimolecular membrane made from an identical extract of the total lipid to different sugars varied: the values forD-glucose,D-mannose,D-ribose,D-fructose, 2 deoxy-D-glucose, 3-0-methyl-D-glucose, andD-mannitol were 2.3, 2.6, 8.9, 0.38, 16.1, 11.2, and 0.44*10(-10) cm/sec, respectively. The pattern of the difference is neither parallel with nor as extensive as that observed with the intact red cell membrane. The observed permeabilities of the lipid membranes, however, agree qualitatively with what is predicted by an analysis of non-specific movements of nonelectrolytes across the cell membranes. The failure of the membrane lipids to reproduce the carrier function in a structure most closely approximating that of living membranes strongly suggests that some membrane components other than lipids are required for this function. PMID- 24173103 TI - Geochronology and heavy metal flux to Guanabara Bay, Rio de Janeiro state: a preliminary study. AB - Guanabara Bay, located in Rio de Janeiro state. It is surrounded by the second most important metropolitan area of the country. Over recent decades, land disturbance and urbanization in the surrounding area has significantly increased sediment input to the bay and had a negative effect on its overall environmental. This is especially related to high volumes of untreated sewage and industrial effluents. This study evaluates the history of this human impact through detailed examination of a sediment core taken from the northern portion of Guanabara Bay. A geochronology is established using 210Pb dating and related to organic carbon and heavy metal fluxes to the sediments. This gave a calculated net average sedimentation rate for the core of 0.67 cm.year-1. The organic carbon and heavy metals flux started to increase at the beginning of the last century and the highest values was observed in the top of the cores. PMID- 24173102 TI - Direct control of Na(+)-K(+)-2Cl(-)-cotransport protein (NKCC1) expression with aldosterone. AB - Sodium/potassium/chloride cotransporter (NKCC1) proteins play important roles in Na(+) and K(+) concentrations in key physiological systems, including cardiac, vascular, renal, nervous, and sensory systems. NKCC1 levels and functionality are altered in certain disease states, and tend to decline with age. A sensitive, effective way of regulating NKCC1 protein expression has significant biotherapeutic possibilities. The purpose of the present investigation was to determine if the naturally occurring hormone aldosterone (ALD) could regulate NKCC1 protein expression. Application of ALD to a human cell line (HT-29) revealed that ALD can regulate NKCC1 protein expression, quite sensitively and rapidly, independent of mRNA expression changes. Utilization of a specific inhibitor of mineralocorticoid receptors, eplerenone, implicated these receptors as part of the ALD mechanism of action. Further experiments with cycloheximide (protein synthesis inhibitor) and MG132 (proteasome inhibitor) revealed that ALD can upregulate NKCC1 by increasing protein stability, i.e., reducing ubiquitination of NKCC1. Having a procedure for controlling NKCC1 protein expression opens the doors for therapeutic interventions for diseases involving the mis-regulation or depletion of NKCC1 proteins, for example during aging. PMID- 24173104 TI - Evaluation of the photodynamic activity of xanthene dyes on Artemia salina described by chemometric approaches. AB - The development of drugs for photodynamic therapy (PDT) is an important area of research due to their growing use in medical applications. Therefore, it is important to develop new bioassay methods for PDT photosensitizers that are inexpensive, easy to handle and highly sensitive to environmental conditions. Xanthene dyes (fluorescein, rose bengal B, erythrosine B and eosin Y) with LED light sources were investigated using Artemia salina as a bioindicator of photodynamic activity. In this study, three factors were investigated: (i) photosensitizers concentration, (ii) the LED irradiation time and (iii) the waiting time between the addition of the photosensitizers and the beginning of the irradiation. To analyze the photo-killing of A. salina, it was employed a 23 full factorial design. The death of A. salina was related to dye structure and the interaction between the irradiation time and the photosensitizers concentration. About 60% of crustaceans death was obtained using rose bengal B, which presentes the highest quantum yield of singlet oxygen due to the number of iodide substituents in the xanthenes ring. The proposed bioassay using A. salina, xanthene dyes and LED irradiation was found suitable for quantitative PDT drug evaluation. PMID- 24173105 TI - Horse spleen segmentation technique as large animal model of preclinical trials. AB - The parenchymal distribution of the splenic artery was studied in order to obtain anatomical basis for partial splenectomy. Thirty two spleens were studied, 26 spleens of healthy horses weighing 320 to 450 kg, aged 3 to 12 years and 6 spleens of fetus removed from slaughterhouse. The spleens were submitted to arteriography and scintigraphy in order to have their vascular pattern examined and compared to the external aspect of the organ aiming establish anatomo surgical segments. All radiographs were photographed with a digital camera and the digital images were submitted to a measuring system for comparative analysis of areas of dorsal and ventral anatomo-surgical segments. Anatomical investigations into the angioarchitecture of the equine spleen showed a paucivascular area, which coincides with a thinner external area, allowing the organ to be divided in two anatomo-surgical segments of approximately 50% of the organ each. PMID- 24173107 TI - Hierarchical chirality transfer in the growth of Towel Gourd tendrils. AB - Chirality plays a significant role in the physical properties and biological functions of many biological materials, e.g., climbing tendrils and twisted leaves, which exhibit chiral growth. However, the mechanisms underlying the chiral growth of biological materials remain unclear. In this paper, we investigate how the Towel Gourd tendrils achieve their chiral growth. Our experiments reveal that the tendrils have a hierarchy of chirality, which transfers from the lower levels to the higher. The change in the helical angle of cellulose fibrils at the subcellular level induces an intrinsic torsion of tendrils, leading to the formation of the helical morphology of tendril filaments. A chirality transfer model is presented to elucidate the chiral growth of tendrils. This present study may help understand various chiral phenomena observed in biological materials. It also suggests that chirality transfer can be utilized in the development of hierarchically chiral materials having unique properties. PMID- 24173108 TI - Acute emergence and reversion of influenza A virus quasispecies within CD8+ T cell antigenic peptides. AB - Influenza A virus-specific CD8(+) cytotoxic T lymphocytes (CTLs) provide a degree of cross-strain protection that is potentially subverted by mutation. Here we describe the sequential emergence of such variants within CTL epitopes for a persistently infected, immunocompromised infant. Further analysis in immunodeficient and wild-type mice supports the view that CTL escape variants arise frequently in influenza, accumulate with time and revert in the absence of immune pressure under MHCI-mismatched conditions. Viral fitness, the abundance of endogenous CD8(+) T cell responses and T cell receptor repertoire diversity influence the nature of these de novo mutants. Structural characterization of dominant escape variants shows how the peptide-MHCI interaction is modified to affect variant-MHCI stability. The mechanism of influenza virus escape thus looks comparable to that recognized for chronic RNA viruses like HIV and HCV, suggesting that immunocompromised patients with prolonged viral infection could have an important part in the emergence of influenza quasispecies. PMID- 24173109 TI - Serum response factor induces epithelial to mesenchymal transition with resistance to sorafenib in hepatocellular carcinoma. AB - The epithelial to mesenchymal transition (EMT) is a crucial process in tumor progression. EMT of tumor cells not only causes increased metastasis, but also contributes to drug resistance. Serum response factor (SRF) is a transcription factor that plays a central role in carcinogenesis and tumor progression in several types of cancers. We investigated the effect of EMT-related SRF, focusing on its promotion of chemoresistance against sorafenib in hepatocellular carcinoma (HCC). We examined SRF and Snail expression in 146 cases of HCCs by immunohistochemistry. We also examined the chemoresistance effect of SRF in HCC cells by transfecting HLE cells with SRF cDNA and SH-J1 cells with SRF antisense cDNA. Expression of SRF and Snail were detected in 37.6% (55 of 146 cases) and in 12.3% (18 of 146 cases) of the HCCs, respectively. None of the tumor-free liver tissues showed SRF or Snail expression. SRF expression was closely correlated with the expression of Snail (p<0.001) and expression of both SRF and Snail showed significant correlation with the high histological grade (p=0.015 and 0.003, respectively). Overexpression of SRF in HLE cells led to increased expression of mesenchymal markers, as well as increased cell growth and colony formation. Overexpression of SRF also led to a significant reduction in the cytotoxic effect of sorafenib in HLE cells. Conversely, inhibition of SRF expression in the SH-J1 cells significantly enhanced the apoptotic effects of sorafenib, along with the reduced expression of mesenchymal markers and restored the expression of E-cadherin. These results suggest that SRF is critical for HCC to acquire a mesenchymal phenotype, which leads to resistance against a sorafenib mediated apoptotic effect. PMID- 24173110 TI - Association between single nucleotide polymorphisms in the p53 pathway and response to radiotherapy in patients with nasopharyngeal carcinoma. AB - Single nucleotide polymorphisms (SNPs) in the p53, MDM2 and p21 genes of the p53 pathway have been extensively studied. The main aim of the current retrospective study was to evaluate the possible predictive value of SNPs in the p53 pathway in locoregionally advanced nasopharyngeal carcinoma (NPC) in response to radiotherapy. In total, 75 consecutive patients with locoregionally advanced NPC were enrolled. Three SNPs in the p53 pathway were identified using the Sanger sequencing method from retrospectively collected paraffin-embedded biopsy specimens. The effects of genetic polymorphisms on patient progression-free survival (PFS) were analyzed using the Cox proportional hazards model, Kaplan Meier method and log-rank test. All of the selected subjects completed questionnaires on smoking habits prior to treatment. Multivariate analysis showed that the p53 codon 72 Pro/Pro genotype [hazard ratio (HR), 0.300; 95% confidence interval (CI), 0.092-0.983; P=0.047] and heavy smoking (>=30 pack-years) (HR, 2.899; 95% CI, 1.349-6.229; P=0.006) are independent significant prognostic factors for PFS in patients with locoregionally advanced NPC. Moreover, mean times to disease progression for heavy smokers (>=20 pack-years) carrying p53 codon 72 Arg/Arg, p21 codon 31 Arg/Arg and MDM2 309 SNP G/G genotypes were only 14.78 +/- 3.00, 11.00 +/- 0.58 and 11.17 +/- 1.85 months, respectively. These time scales were less than half of those recorded for patients containing other genotypes and moderate smokers (<20 pack-years). In conclusion, the p53 codon 72 polymorphism is an independent prognostic marker for locoregionally advanced NPC. Moreover, analysis of SNPs in the p53 pathway may facilitate the identification of patients at high risk of poor disease outcome in subgroups of heavy smokers. PMID- 24173111 TI - Chloroplast DNAs of Spinacia, Petunia and Spirodela have a similar gene organization. AB - We have located the positions of the genes coding for the alpha, beta and epsilon subunits of the ATPase complex on Spirodela oligorhiza chloroplast DNA by means of heterologous hybridization with Spinacia cpDNA fragments.The overall cpDNA sequence organization of Petunia hybrida and Spirodela was compared. We hybridized well-characterized, cloned Spirodela cpDNA fragments with size fractionated Petunia cpDNA digested by Sall. It appears that the monocotyledonous Spirodela and the dicotyledonous Petunia cpDNA share a common sequence organization around their entire circumference. These observations, together with data reported in the literature, indicate a strikingly similar genetic organization of the chloroplast genome in widely divergent plants. PMID- 24173112 TI - Molecular cloning and characterization of the chloroplast ribosomal RNA genes from Spirodela oligorhiza. AB - The organization of the chloroplast ribosomal RNA genes in Spirodela oligorhiza has been determined. We have therefore characterized two cloned BamHI fragments containing the genes for the large and small rRNA genes, and two PstI fragments, each containing one of the two large, invertedly repeated regions of chloroplast DNA. Characterization was performed by restriction endonuclease mapping, DNA/RNA hybridization and electronmicroscopic R-loop analysis.The results show that the rRNA genes are present in the order 16S, 23S, 4.5S and 5S. The 16S (1.5 kb) and 23S (2.9 kb) rRNA genes are separated by a spacer of 2.25 kb. There appears to be a close resemblance between the organization of the chloroplast rRNA genes in Spirodela oligorhiza and other higher plants so far examined. PMID- 24173113 TI - Physical and gene mapping of chloroplast DNA from normal and cytoplasmic male sterile (radish cytoplasm) lines of Brassica napus. AB - Using the restriction endonucleases SaII, SmaI, BgII and KpnI, physical maps of chloroplast DNA isolated from normal and cytoplasmic male sterile (radish cytoplasm) lines of B. napus were constructed and compared. In this study, a rapid and simple procedure was developed for the isolation of chloroplast DNA restriction fragments from low gelling temperature agarose gels.The overall structural organization of N and cms B. napus appears to be rather similar to that of cpDNAs of other higher plants. It is composed of two identical sequences (each about 15 Md) arranged as an inverted repeat separated by two single copy regions of different sizes (about 54 and 15 Md). In both genomes the ribosomal RNAs are encoded by duplicate genes situated at one end of the inverted repeat. The two chloroplast genomes are distinguished by a point mutation in the rRNA locus. Genes for the large subunit of ribulose-1.5-biphosphate carboxylase and a 32 kilodalton photosystem II polypeptide are separated by a minimum of 30 Md of DNA within the large single copy region. PMID- 24173114 TI - The structure of the gene for subunit I of cytochrome c oxidase in Neurospora crassa mitochondria. AB - We have sequenced the gene for cytochrome c oxidase subunit 1 (CO I) in Neurospora crassa mitochondrial DNA. The gene is coded by the same strand as the rRNA and tRNA genes. The coding sequence predicts a protein of 557 amino acids, starting with methionine, and ending with asparagine. Comparison to the N terminal amino acid sequence of the mature protein (Werner et al. 1980) reveals that the methionine is located at position -2. No other upstream AUG codons have been found in frame. The C-terminal part of the gene is about 70 basepairs longer than the corresponding parts of the Saccharomyces and mammalian genes. The homology between the Neurospora coding sequence and those of yeast and mammals is very high. As compared to Saccharomyces, the introns il through i5 are absent. PMID- 24173115 TI - Mitochondrial DNA size diversity in the Dekkera/Brettanomyces yeasts. AB - Restriction endonuclease digestion of mitocondrial DNAs from the nine Dekkera/Brettanomyces yeasts have revealed that three separate pairs of species, namely D. bruxellensis/B. lambicus; B. abstinens/B. custersii and B. anomalus/B. clausenii have identical genomes. This observation suggests that such analysis of mtDNA could be an important procedure for yeast taxonomy. Sizes of mtDNAs showed a graded range from the 28 kbp molecule in B. custersianus to the 100 kbp molecule in B. custersii. Furthermore, although the mtDNAs from D. intermedia (72 kbp) and D. bruxellensis (82 kbp) differ in size by 10 kbp the restriction enzyme fragmentation patterns are generally similar. The differences are reminiscent of mtDNA polymorphisms found in strains of Saccharomyces cervisiae which result from insertions or deletions, chiefly within genic sequences. By analogy, the two Dekkera species may, on further analysis, be revealed as variants of a single species. PMID- 24173116 TI - Sporulation and respiratory metabolism in the "petite negative" yeast Hansenula saturnuss. AB - Upon transition from growth medium to acetate sporulation medium buffered at pH 6.1 with 0.2 M PIPES, Hansenula saturnus showed a respiratory activity which was 88% antimycin A sensitive (1st) and 12% high azide sensitive (3rd), as in acetate complete growth medium. After ? 10 h, 3rd respiration declined and oxygen consumption was inhibited by the simultaneous addition of antimycin A and hydroxamate, a situation which lasted until the appearance of the first asci. Later on, 1st and 3rd respiration reappeared and asci formation was completed under these respiratory conditions. The growth in the presence of antimycin A or erythromycin affected only quantitatively the ascospore production and this is because in sporulation medium there was a de novo synthesis of the mitochondrial components of the respiratory chain. Cells which were avoid of 1st respiration but possessed 2nd or 3rd respiration could sporulate, indicating that these alternative respirations also have a role in the process. This was confirmed by the inhibition of sporulation as occurred in the presence of inhibitors of 1st, 2nd and 3rd respiration in sporulation medium. PMID- 24173117 TI - Non-Utilization of sucrose by the petite mutant of a distiller's yeast. AB - A number of yeast strains are known to be unable to metabolize several sugars (galactose, maltose, alpha-methylglucoside) when converted to their petite mutants. The basis of this phenomenon is considered to be the loss of the ability to transport the sugars across the cell membrane. However, sucrose is believed to be hydrolyzed before the products are transported into the cell, and the enzyme responsible (invertase) is thought to be either present in the periplasmic space or to be bound to the outer surface of the cytoplasmic membrane. Hence the loss of the ability to metabolize sucrose may infer the impairment of the mechanism for transport of invertase to its normal location outside the cytoplasm. We have found a distiller's yeast strain which has lost the ability to metabolize sucrose when it is converted to the petite mutant, and we report here some of its properties. We have shown that the cell produces invertase, which is present in the cell-free extract, but not in the pellet of cell walls and unbroken cells, though we have not determined whether the enzyme is present in the cytoplasm in the glycosylated or the unglycosylated form. The ability of the strain to ferment sucrose is also impaired in respiratory-competent cells, when the determination is made under anaerobic conditions. PMID- 24173118 TI - Trans-nuclear action of the nit-2 regulatory gene product and study of two additional nitrogen control genes in Neurospora crassa. AB - The nit-2 gene of Neurospora crassa is a major regulatory gene for control of nitrogen metabolism. Synthesis of the enzyme L-amino acid oxidase requires a functional nit-2 gene product and is also controlled by amino acid induction and nitrogen catabolite repression. Electrophoretic variants of L-amino acid oxidase have been employed to demonstrate that in heterokaryons, a nit-2 (+) gene product can turn on the expression of this enzyme in its own nucleus and also in nuclei that possess a nit-2 mutant. This trans-nuclear effect is only partial since the variant coded for in the nucleus containing the nit-2 mutant allele is always present in lower amounts than the alternative form.Two additional putative nitrogen control genes, MS5 and en(am)1, have been found to have clear effects upon the expression of L-amino acid oxidase. The en(am)1 mutant appears to result in an unusual case of reversal of the control present in wild-type: the enzyme is expressed in a constitutive fashion and inducers, required for enzyme synthesis in wild-type, actually reduce the level of L-amino acid oxidase in en(am)1. The MS5 mutant shows a substantial release from the usual nitrogen catabolite repression exerted by glutamine in wild-type. PMID- 24173119 TI - Analysis of the effect of radiation repair mutations on the DEL1 mutator region of Saccharomyces cerevisiae. AB - In DEL1 strains of the yeast, Saccharomyces cerevisiae, the iso-1-cytochrome c (CYC1) region is flanked on either side by Tyl elements in direct orientation which promote cyc1 deletions of the bracketed DNA in the haploid cell. In this study, we asked which genes might control this event by testing the possibility that the DEL1 mutation mechanism requires an enzyme (or enzymes) that is also utilized in the repair of damaged DNA. To this end, we independently coupled eight repair mutations, rad3-2, rad4-4, rad6-1, rad6-3, rad9-1, rev3-1, rad50-1, and rad51-1, toDEL1 and asked whether DEL1 was still functional. We found that none of these rad mutations significantly affects the mutation frequency of 10( 6)-10(-5) established in DEL1 strains for the CYC1 locus. Furthermore, we determined that ste7, a temperature-sensitive sterile allele known to alter gene regulation in Ty-mediated mutations, is not required for DEL1 function. Finally, DEL1 is not temperature-sensitive at 23 degrees or 37 degrees C. PMID- 24173120 TI - Two biochemically and genetically different forms of L dsRNA of Saccharomyces cerevisiae exist: One form, L2, is correlated. AB - Nucleic acid extracted from killer strains of Saccharomyces cerevisiae and run on agarose gels under sub-optimal conditions for M dsRNA yielded two species of L dsRNA (L1 and L2) which migrated at slightly different rates. L2 dsRNA was shown to be dependent upon MAK3, MAK10 and PES1 but not MAK1 nuclear genes for its maintenance. L1 was shown to be independent of all of these genes.[HOK] a non Mendelian genetic element which enables a replication-defective M genome, [KIL sd1], to be maintained in a SKl (+) host (Wickner and Toh-e 1982) was found to be present in an M-o derivative of the strain K7 which possesses L2 but not L1. Curing of L2 at elevated temperatures resulted in a co-curing of [HOK] and it is therefore concluded that either L2 is equivalent to or else it encodes [HOK]. PMID- 24173121 TI - Production and genetic analysis of yeast cybrids. AB - Data presented here demonstrate that fusion of protoplasts of two different haploid strains of Saccharomyces cerevisiae having the same mating type leads to the formation of "fusants" and "cytoplasmic hybrids". The nuclear and cytoplasmic genome of a "fusant" combine those of the parent haploid strains. The "cytoplasmic hybrid" possesses the haploid genome of one parent and the combined cytoplasmic genomes of both. In mouse cells lines such products have been termed "cybrids" and this term has therefore been adopted here (Bunn and Wallace 1974). PMID- 24173122 TI - Transformation of Ustilago maydis by a plasmid containing yeast 2-micron DNA. AB - U. maydis has been transformed to aminoglycoside antibiotic resistance by plasmid pMP81 DNA, which contains the yeast LEU-2 gene and 2-micron DNA inserted into pCRI, encoding a gene for an aminoglycoside phosphotransferase. The resistant phenotype of transformants is mitotically unstable in the absence of antibiotics. Closed, circular pMP81 DNA was detected in transformant DNA preparations by hybridization to pCR1 DNA and by transformation of Escherichia coli to kanamycin resistance. Plasmid pMP81 DNA recovered from the transformant was not rearranged at the gross sequence level as a result of transmission in U. maydis. Preliminary evidence suggests that the yeast 2-micron DNA promotes autonomous plasmid replication in U. maydis, albeit inefficiently, resulting in low transformation frequencies and plasmid copy numbers. PMID- 24173123 TI - Chromosomal DNA sequences from Ustilago maydis promote autonomous replication of plasmids in Saccharomyces cerevisiae. AB - U. maydis chromosomal DNA sequences which promote the autonomous replication of plasmid YIp5 in S. cerevisiae YNN27 have been isolated and three of them characterised in some detail. Their properties are idential to yeast ars sequences in that plasmids containing them are maintained extrachromosomally as circular double-stranded DNA molecules, are mitotically unstable in yeast transformants and transform yeast at high frequencies. There is no sequence homology between the three U. maydis sequences and they are not reiterated in the U. maydis genome. PMID- 24173124 TI - Deferoxamine enhances cell migration and invasion through promotion of HIF-1alpha expression and epithelial-mesenchymal transition in colorectal cancer. AB - Deferoxamine (DFX), a metal chelator, has been previously reported to induce hypoxia and hypoxia-inducible factor-1alpha (HIF-1alpha) expression. HIF-1alpha is a common inducer of epithelial-mesenchymal transition (EMT) in many solid tumors. However, the effect of DFX on cancer metastasis and the related mechanisms are not well established. In the present study, we aimed to ascertain whether DFX enhances EMT and cancer metastasis in colorectal cancer. After confirmation of DFX-inducing HIF-1alpha expression, we examined the effect of DFX on cell adhesion, migration and invasion abilities and found a positive effect on the above functions. Consequently, cell morphology, cell growth and expression of EMT markers were assessed in cells with or without DFX treatment. We found that cells exposed to DFX were more isolated. They were spindle-shaped and looked similar to fibroblast-like cells, accompanied by increased anchorage-independent growth. DFX-treated cells expressed E-cadherin and plakoglobin at a higher level, and vimentin and N-cadherin at a lower level, when compared with these levels in control cells. Furthermore, the expression of E-cadherin in the cell membrane was markedly decreased in DFX-treated cells. These results suggest that DFX promotes cancer migration and invasion via a process consistent with EMT in colorectal cancer. PMID- 24173125 TI - Melanosome uptake is associated with the proliferation and differentiation of keratinocytes. AB - Melanosomes are synthesized in melanocytes and transferred to neighboring keratinocytes. However, the associations of melanosome uptake with the proliferation and differentiation of keratinocytes are not fully understood. We examined the associations of melanosome uptake with keratinocyte differentiation and proliferation. SV40T-transformed human epidermal keratinocytes (SV-HEKs) were treated with isolated melanosomes. The effects of melanosome uptake on the proliferation and differentiation of the keratinocytes were analyzed by Western blotting and flow cytometry. The relationship between melanosome uptake and keratinocyte differentiation status was verified by determining the melanin content in the cells. Melanosomes reduced the proliferation of SV-HEKs in a dose dependent manner, but did not induce differentiation. Melanosome uptake was higher in differentiating keratinocytes compared to non-differentiating keratinocytes, and inhibited significantly by PAR-2 inhibitor. Melanosomes inhibit keratinocyte proliferation. Moreover, melanosome uptake is influenced by keratinocyte differentiation status, being highest in mid-stage differentiating keratinocytes in a PAR-2 dependent manner. PMID- 24173126 TI - Human beta papillomavirus DNA study in primary cutaneous squamous cell carcinomas and their corresponding metastases. AB - The association between beta human papillomavirus (HPV) types and cutaneous squamous cell carcinomas (cSCCs) is controversial. Several studies have found such an association, especially at early stages of carcinogenesis, but the presence of beta HPV types in aggressive cSCCs has only been reported in three patients previously. We aimed to search for beta HPV DNA in primary cSCCs and their corresponding lymph node metastases in a series of patients. The presence of DNA from 25 beta HPV types was determined using a multiplex PCR protocol in 35 primary cSCCs from 35 patients and their corresponding lymph node metastases. DNA from beta HPV types was detected in 9 % of primary cSCCs and in 13 % of metastases. No primary cutaneous SCC or lymphatic metastases were found to share the same HPV DNA. These data suggest that beta HPV types do not play an etiopathogenic role in advanced stages of squamous cell carcinogenesis. PMID- 24173127 TI - A rapid method for the isolation of L-cell surface membranes using an aqueous two phase polymer system. AB - A dextran-polythylene glycol aqueous two-phase system has been used to separate cell surface membranes from other cellular organelles. The surface membranes have been identified on the basis of morphology, content of Na(+), K(+)-ATPase, and presence of surface antigen as detected by a(51)Cr release method. Contamination of the surface membrane preparations by smooth endoplasmic reticulum, mitochondria, and nuclei has been found to be minimal. An average of 6.5% of the total protein was found in the membrane fraction. Less than two hours is required to isolate the membrane fraction after preparation of a Dounce homogenate. Fractionation by aqueous two-phase polymer systems appears to be a rapid and effective method for the isolation of surface membranes. PMID- 24173128 TI - Transport mechanism of hydrophobic ions through lipid bilayer membranes. AB - Evidence is presented that the transport of lipid-soluble ions through bilayer membranes occurs in three distinct steps: (1) adsorption to the membranesolution interface; (2) passage over an activation barrier to the opposite interface; and (3) desorption into the aqueous solution. Support for this mechanism comes from a consideration of the potential energy of the ion, which has a minimum in the interface. The formal analysis of the model shows that the rate constants of the individual transport steps can be determined from the relaxation of the electric current after a sudden change in the voltage. Such relaxation experiments have been carried out with dipicrylamine and tetraphenylborate as permeable ions. In both cases the rate-determining step is the jump from the adsorption site into the aqueous phase. Furthermore, it has been found that with increasing ion concentration the membrane conductance goes through a maximum. In accordance with the model recently developed by L. J. Bruner, this behavior is explained by a saturation of the interface, which leads to a blocking of the conductance at high concentrations. PMID- 24173129 TI - On the mass dependence of diffusion within biological membranes and polymers. AB - A simple probability argument suggests that the diffusion coefficient for biological membranes (and polymers) should vary exponentially with the reciprocal of the molecular weight of the diffusant. A test of this relationship shows that it fits the experimental data at least as well as the empirical relation previously proposed. Since the present treatment has some theoretical justification, it would seem to be preferred. PMID- 24173130 TI - Spontaneous and induced changes in the membrane potential and resistance ofAcetabularia mediterranea. AB - The normal resting potential across theAcetabularia mediterranea cell membrane is -170 mV and the resistance is about 0.1 kOmega.cm(2). The time courses of potential and resistance changes have been studied in connection with several slow dynamic properties of the membrane. These effects include spontaneous and stimulated depolarizing spikes, spontaneous repolarization after prolonged maintenance of a quasistable depolarized condition, and a hyperpolarizing response when current is applied to the cell in this depolarized state. These processes show considerable similarities to each other, which suggests that they might all be explained by changes in permeability to Cl(-). In normal conditions, membrane punch-through occurs with a relatively small hyperpolarizing bias. PMID- 24173131 TI - Effects of valinomycin, ouabain, and potassium on glycolysis and intracellular pH of Ehrlich ascites tumor cells. AB - Both valinomycin and ouabain block reaccumulation of K(+) by Ehrlich ascites tumor cells depleted of K(+) and cause loss of K(+) from high-K(+) cells. Glucose largely reverses the effect of valinomycin and to a lesser extent that of ouabain.In cells depleted of K(+), glucose utilization and lactate production are impaired. Neither extracellular pH (pHe) nor intracellular pH (pHi) falls to the extent seen in non-depleted glycolyzing cells. Addition of K(+) to depleted cells reverses these effects. Valinomycin increases glycolysis in K(+)-depleted cells but to a greater extent in nondepleted or K(+)-repleted cells. The increase in lactate production caused by valinomycin is accompanied by a correspondingly greater fall in pHe and pHi. Valinomycin, unlike other uncoupling agents, does not abolish the pH gradient across the plasma membrane. Increased utilization of glucose resulting from addition of K(+) to K(+)-depleted cells or addition of valinomycin either to depleted or non-depleted cells can be entirely accounted for by increased lactate production. Ouabain blocks the stimulatory effect of added K(+) on K(+)-depleted cells and has an inhibitory effect on glycolysis in non-depleted cells. It does not obliterate the difference in glycolytic activity between K(+)-depleted and nondepleted cells. Ouabain does not completely block the effect of valinomycin in augmenting glycolysis in depleted or non-depleted cells. Increased accumulation of glycolytic intermediates, particularly dihydroxyacetone phosphate, is found in glycolyzing K(+)-depleted cells. The most marked accumulation was found in ouabain-treated K(+)-deficient cells. PMID- 24173132 TI - The thickness, composition and structure of some lipid bilayers and natural membranes. AB - It has been shown that the capacitance, thickness and composition of black lipid films may depend strongly on the hydrocarbon solvent used in their formation. By the use of n-hexadecane, films have been formed which contain effectively no solvent and which are comparable to the leaflets of the mesomorphic phase of the pure lipid. These films have capacitances of ca. 0.6 MUF/cm(2) and hydrocarbon thicknesses of ca. 31 A. Thinner black films of higher capacitances are also described.The capacitances of biological membranes are, in contrast, nearer to 1 MUF/cm(2), and it is suggested that the hydrocarbon region in these membranes may often be thinner than in the lipid leaflets. This suggestion is consistent with some X-ray and lipid composition data. It is pointed out that if the membranes contain abnormally thin lipid leaflets, the area per polar head group of the phospholipid must be increased, and that hydrocarbon is thereby exposed to the aqueous phases. Non-polar protein residues could then interact with these hydrocarbon areas, thus tending to stabilize the expanded leaflet. PMID- 24173133 TI - Venous thromboembolism prevention in pediatric trauma--time for national guidelines. PMID- 24173134 TI - Experimental cardiac arrest treatment with adrenaline, vasopressin, or placebo. AB - BACKGROUND: The effect of vasoconstrictors in prolonged cardiopulmonary resuscitation (CPR) has not been fully clarified. OBJECTIVES: To evaluate adrenaline and vasopressin pressure effect, and observe the return of spontaneous circulation (ROSC). METHODS: A prospective, randomized, blinded, and placebo controlled study. After seven minutes of untreated ventricular fibrillation, pigs received two minutes cycles of CPR. Defibrillation was attempted (4 J/kg) once at 9 minutes, and after every cycle if a shockable rhythm was present, after what CPR was immediately resumed. At 9 minutes and every five minutes intervals, 0.02 mg/kg (n = 12 pigs) adrenaline, or 0.4 U/kg (n = 12) vasopressin, or 0.2 mL/kg (n = 8) 0.9% saline solution was administered. CPR continued for 30 minutes or until the ROSC. RESULTS: Coronary perfusion pressure increased to about 20 mmHg in the three groups. Following vasoconstrictors doses, pressure level reached 35 mmHg versus 15 mmHg with placebo (p < 0.001). Vasopressin effect remained at 15-20 mmHg after three doses versus zero with adrenaline or placebo. ROSC rate differed (p = 0.031) among adrenaline (10/12), vasopressin (6/12), and placebo (2/8). Time to-ROSC did not differ (16 minutes), nor the number of doses previously received (one or two). There was no difference between vasoconstrictors, but against placebo, only adrenaline significantly increased the ROSC rate (p = 0.019). CONCLUSION: The vasoconstrictors initial pressure effect was equivalent and vasopressin maintained a late effect at prolonged resuscitation. Nevertheless, when compared with placebo, only adrenaline significantly increased the ROSC rate. PMID- 24173135 TI - P wave indices to predict atrial fibrillation recurrences post pulmonary vein isolation. AB - BACKGROUND: P-wave indices are appealing markers for predicting atrial fibrillation (AF) recurrences post ablation. OBJECTIVE: This study evaluates the value of P wave indices to predict recurrences post pulmonary vein isolation (PVI) in patients with paroxysmal AF. METHODS: We selected 198 patients (57 +/- 8 years, 150 males) with symptomatic drug-refractory paroxysmal AF undergoing PVI in our hospital. A 12-lead electrocardiogram was used to measure P wave duration in lead II, P wave terminal force (PWTF) in lead V1, P wave axis and dispersion. RESULTS: During a follow-up of 9 +/- 3 months, recurrences occurred in 60 (30.3%) patients. The patients that had AF recurrence had longer mean P wave duration (122.9 +/- 10.3 vs 104.3 +/- 14.2 ms, p < 0.001), larger P wave dispersion (40.7 +/- 1.7 ms vs 36.6 +/- 3.2 ms, p < 0.001). P wave duration > 125 ms has 60% sensitivity, 90% specificity, positive predictive value (PPV) of 72% and negative predictive value (NPV) of 83.7%, whereas P wave dispersion > 40 ms has 78% sensitivity, 67% specificity, PPV of 51% and NPV of 87.6% 48/66 (72.7%) patients with PWTF < -0.04 mm/second vs 12/132(9%) with PWTF > -0.04 mm/second showed recurrence of AF (p < 0.001). P wave axis was not different between two groups. On multivariate analysis, P wave indices were not independent from left atrial size and age. CONCLUSIONS: P wave duration > 125 ms, P wave dispersion > 40 ms and PWTF in V1 < -0.04 mm/sec are good clinical predictors of AF recurrences post PVI in patients with paroxysmal atrial fibrillation; however they were not independent from left atrial size and age. PMID- 24173136 TI - Subcutaneous tissue thickness is an independent predictor of image noise in cardiac CT. AB - BACKGROUND: Few data on the definition of simple robust parameters to predict image noise in cardiac computed tomography (CT) exist. OBJECTIVES: To evaluate the value of a simple measure of subcutaneous tissue as a predictor of image noise in cardiac CT. METHODS: 86 patients underwent prospective ECG-gated coronary computed tomographic angiography (CTA) and coronary calcium scoring (CAC) with 120 kV and 150 mA. The image quality was objectively measured by the image noise in the aorta in the cardiac CTA, and low noise was defined as noise < 30 HU. The chest anteroposterior diameter and lateral width, the image noise in the aorta and the skin-sternum (SS) thickness were measured as predictors of cardiac CTA noise. The association of the predictors and image noise was performed by using Pearson correlation. RESULTS: The mean radiation dose was 3.5 +/- 1.5 mSv. The mean image noise in CT was 36.3 +/- 8.5 HU, and the mean image noise in non-contrast scan was 17.7 +/- 4.4 HU. All predictors were independently associated with cardiac CTA noise. The best predictors were SS thickness, with a correlation of 0.70 (p < 0.001), and noise in the non-contrast images, with a correlation of 0.73 (p < 0.001). When evaluating the ability to predict low image noise, the areas under the ROC curve for the non-contrast noise and for the SS thickness were 0.837 and 0.864, respectively. CONCLUSION: Both SS thickness and CAC noise are simple accurate predictors of cardiac CTA image noise. Those parameters can be incorporated in standard CT protocols to adequately adjust radiation exposure. PMID- 24173137 TI - Ratcheted diffusion transport through crowded nanochannels. AB - The problem of transport through nanochannels is one of the major questions in cell biology, with a wide range of applications. In this paper we discuss the process of spontaneous translocation of molecules (Brownian particles) by ratcheted diffusion: a problem relevant for protein translocation along bacterial flagella or injectosome complex, or DNA translocation by bacteriophages. We use molecular dynamics simulations and statistical theory to identify two regimes of transport: at low rate of particle injection into the channel the process is controlled by the individual diffusion towards the open end (the first passage problem), while at a higher rate of injection the crowded regime sets in. In this regime the particle density in the channel reaches a constant saturation level and the resistance force increases substantially, due to the osmotic pressure build-up. To achieve a steady-state transport, the apparatus that injects new particles into a crowded channel has to operate with an increasing power consumption, proportional to the length of the channel and the required rate of transport. The analysis of resistance force, and accordingly--the power required to inject the particles into a crowded channel to overcome its clogging, is also relevant for many microfluidics applications. PMID- 24173138 TI - Association between gamma-glutamyl transferase and metabolic syndrome: a cross sectional study of an adult population in Beijing. AB - The relationship between liver enzymes and clustered components of metabolic syndrome (MetS) is explored and the predictive power of gamma-glutamyl transferase (GGT) for the diagnosis of MetS in an adult population in Beijing is investigated. A total of 10,553 adults aged 20-65 years who underwent health examinations at Beijing Tongren Hospital in 2012 were enrolled in the study. Multivariate logistic regression analysis is conducted to determine the associations between the levels of various liver enzymes and clustered components of MetS. A receiver operating characteristic analysis is used to determine the optimal cut-off value of GGT for the diagnosis of MetS. A high level of GGT is found to be positively associated with clustered components of MetS in both men and women after adjusting for age, body mass index (BMI), history of alcoholic fatty liver, and the presence of taking anti-hypertensive, anti-dyslipidemic, and anti-diabetic drugs. Among all components of MetS, GGT is more predictive of triglyceride, and BMI. The area-under-the-curve values of GGT for discriminating MetS from normal metabolic status in men and women are 0.73 and 0.80, respectively. The optimal cut-off value of GGT for men is 31.50 U/L, demonstrating a sensitivity of 74.00% and specificity of 62.00%. For women, it is 19.50 U/L (sensitivity 76.00% and specificity 70.00%). GGT is therefore recommended as a useful diagnostic marker for MetS, because the test is inexpensive, highly sensitive, and frequently encountered in clinical practice. PMID- 24173139 TI - How technology in care at home affects patient self-care and self-management: a scoping review. AB - The use of technology in care at home has potential benefits such as improved quality of care. This includes greater focus on the patients' role in managing their health and increased patient involvement in the care process. The objective of this scoping review is to analyse the existing evidence for effects of technology in home-based care on patients' self-care and self-management. Using suitable search terms we searched the databases of Pubmed, Embase, Cochrane Library, Cinahl, Picarta and NIVEL dating from 2002 to 2012. Thirty-three studies (six review studies and twenty-seven individual studies) were selected. Effects were extracted from each study and were classified. In almost all the studies, the concepts self-care and self-management are not clearly defined or operationalized. Therefore, based on a meta-analysis, we made a new classification of outcome measures, with hierarchical levels: (1) competence (2) illness-management (3) independence (social participation, autonomy). In general, patient outcomes appear to be positive or promising, but most studies were pilot studies. We did not find strong evidence that technology in care at home has (a positive) effect on patient self-care and self-management according to the above classification. Future research is needed to clarify how technology can be used to maximize its benefits. PMID- 24173140 TI - Extreme heat and health: perspectives from health service providers in rural and remote communities in South Australia. AB - Among the challenges for rural communities and health services in Australia, climate change and increasing extreme heat are emerging as additional stressors. Effective public health responses to extreme heat require an understanding of the impact on health and well-being, and the risk or protective factors within communities. This study draws on lived experiences to explore these issues in eleven rural and remote communities across South Australia, framing these within a socio-ecological model. Semi-structured interviews with health service providers (n = 13), and a thematic analysis of these data, has identified particular challenges for rural communities and their health services during extreme heat. The findings draw attention to the social impacts of extreme heat in rural communities, the protective factors (independence, social support, education, community safety), and challenges for adaptation (vulnerabilities, infrastructure, community demographics, housing and local industries). With temperatures increasing across South Australia, there is a need for local planning and low-cost strategies to address heat-exacerbating factors in rural communities, to minimise the impact of extreme heat in the future. PMID- 24173141 TI - Spatio-temporal epidemiology of human West Nile virus disease in South Dakota. AB - Despite a cold temperate climate and low human population density, the Northern Great Plains has become a persistent hot spot for human West Nile virus (WNV) disease in North America. Understanding the spatial and temporal patterns of WNV can provide insights into the epidemiological and ecological factors that influence disease emergence and persistence. We analyzed the 1,962 cases of human WNV disease that occurred in South Dakota from 2002-2012 to identify the geographic distribution, seasonal cycles, and interannual variability of disease risk. The geographic and seasonal patterns of WNV have changed since the invasion and initial epidemic in 2002-2003, with cases shifting toward the eastern portion of South Dakota and occurring earlier in the transmission season in more recent years. WNV cases were temporally autocorrelated at lags of up to six weeks and early season cumulative case numbers were correlated with seasonal totals, indicating the possibility of using these data for short-term early detection of outbreaks. Epidemiological data are likely to be most effective for early warning of WNV virus outbreaks if they are integrated with entomological surveillance and environmental monitoring to leverage the strengths and minimize the weaknesses of each information source. PMID- 24173142 TI - Walking for well-being: are group walks in certain types of natural environments better for well-being than group walks in urban environments? AB - The benefits of walking in natural environments for well-being are increasingly understood. However, less well known are the impacts different types of natural environments have on psychological and emotional well-being. This cross-sectional study investigated whether group walks in specific types of natural environments were associated with greater psychological and emotional well-being compared to group walks in urban environments. Individuals who frequently attended a walking group once a week or more (n = 708) were surveyed on mental well-being (Warwick Edinburgh Mental Well-being Scale), depression (Major Depressive Inventory), perceived stress (Perceived Stress Scale) and emotional well-being (Positive and Negative Affect Schedule). Compared to group walks in urban environments, group walks in farmland were significantly associated with less perceived stress and negative affect, and greater mental well-being. Group walks in green corridors were significantly associated with less perceived stress and negative affect. There were no significant differences between the effect of any environment types on depression or positive affect. Outdoor walking group programs could be endorsed through "green prescriptions" to improve psychological and emotional well-being, as well as physical activity. PMID- 24173143 TI - Gallic acid induces apoptosis and inhibits cell migration by upregulating miR 518b in SW1353 human chondrosarcoma cells. AB - Gallic acid (GA), a natural agent, is widely distri-buted in plants with a range of biological effects and has been of potential interest as anticancer agent. However, its effects on chondrosarcoma cell apoptosis are still undefined. In the present study, the possible mechanisms of GA-induced apoptosis were explored in SW1353 cells, a human chondrosarcoma cell line. Our results showed that GA inhibited cell viability dose- and time-dependently. Morphological examination of GA-treated cells exhibited the typical features of cell death, such as rounding up of the cells and cell shrinkage. Wound-healing assay indicated that GA inhibited the migratory abilities of SW1353 cells. Hoechst 33258 staining assay and Annexin V/PI staining assay exhibited apoptosis induction by GA. To determine the molecular mechanism of GA-induced apoptosis, the expression levels Bcl-2, Bax, caspase-3 and caspase-9 were determined in SW1353 cells treated with GA. We found that GA downregulated the expression of the anti-apoptotic protein Bcl-2, and upregulated the expression of the pro-apoptotic protein Bax, and the activation of caspase-3 and caspase-9. To identify the possible mechanisms, the changes of microRNA expression were tested using the miRCURYTM LNA expression array. It was observed that the miR-518b gene was upregulated in treated cells. Taken together, these data show that GA induces apoptosis and inhibits cell migration by upregulating miR-518b in SW1353 cells. PMID- 24173144 TI - KIR3DL1 genetic diversity and phenotypic variation in the Chinese Han population. AB - Allelic polymorphism and expression variation of killer cell immunoglobulin-like receptor (KIR) 3DL1 on natural killer (NK) cells differ among populations. To determine whether the phenotypic variants are due to KIR polymorphism, transcription or copy number, the allelic polymorphism, mRNA levels and antigen expression of KIR3DL1 were assessed in 162 individuals. We characterized 13 KIR3DL1 alleles, five of which were novel. In addition, 21 genotypes were identified. The correlation between the binding patterns of NK cells to anti KIR3DL1 and KIR3DL1 alleles was also examined. NK cells with different 3DL1 alleles showed distinct binding levels to anti-KIR3DL1. The binding frequencies of NK cells to anti-KIR3DL1 were not accordant with their binding levels, but both associated with the allele copy numbers. The mRNA expression amounts of individuals with two copy alleles were higher than those of individuals with one copy allele. Our data indicate that both the allele copy number and polymorphism of KIR3DL1 influence the antigen expression on the NK-cell surface, but only the copy number was associated with mRNA expression. PMID- 24173145 TI - A comprehensive analysis of the binding of anti-KIR antibodies to activating KIRs. AB - Analysis of killer cell immunoglobulin-like receptor (KIR) expression has been notoriously difficult because of the cross-reactivity of available antibodies, in particular between activating and inhibitory isoforms. We undertook a comprehensive study of available anti-KIR antibodies binding to activating KIRs (a-KIRs). Using cell lines stably transfected with a-KIRs (KIR2DS1-S5 and KIR3DS1), we confirmed documented binding specificities. In addition, we show that clones HPMA4 and 143211-previously assumed to be specific for KIR2DS1/L1 and KIR2DL1, respectively-bind KIR2DS5 and KIR2DS3 (HPMA4), and KIR2DS5 (143211). Other antibodies with previously undocumented binding were JJC11.6 (recognizing KIR2DS3) and 5.133 (recognizing all a-KIRs except KIR2DS1 and KIR2DS3). The novel KIR2DS5 reactivities were confirmed by blocking with soluble KIR-Fc fusion proteins, and by reverse transcriptase-PCR analysis of sorted primary natural killer cells. In conclusion, we show formerly undocumented binding properties of anti-KIR antibodies. These cross-reactivities should be taken into account when analyzing KIR expression. PMID- 24173146 TI - Association of low-density lipoprotein receptor genotypes with hepatitis C viral load. AB - Several data suggest that low-density lipoprotein receptor (LDLR) is a co receptor for hepatitis C virus (HCV). Soluble LDLR can inhibit HCV infectivity; greater plasma low-density lipoprotein levels are associated with treatment success; LDLR genotypes have a synergistic impact on the likelihood of achieving SVR with Peg-IFN plus RBV, as well as on viral kinetics after starting treatment. The objective of this study was to assess the impact of genetic polymorphisms in genes related to cholesterol synthesis and transport pathways on pre-treatment plasma HCV viral load (VL). A total of 442 patients infected with HCV and treatment naive were prospectively recruited. One hundred forty-four SNPs located in 40 genes from the cholesterol synthesis/transport and IL28B were genotyped and analyzed for genetic association with pre-treatment plasma HCV VL. SNPs rs1433099 and rs2569540 of LDLR showed association with plasma HCV VL (P=4 * 10(-4) and P=2 * 10(-3)) in patients infected with genotypes 1 and 4. A haplotype including the last three exons of LDLR showed association with the cutoff level of 600 000 IU ml(-1) VL for genotypes 1 and 4 (OR=0.27; P=8 * 10(-6)), as well as a quantitative VL (mean+/-s.d.: 6.19+/-0.9 vs CC+CG 5.58+/-1.1 logIU ml(-1), P=8 * 10(-5)). LDLR genotypes are a major genetic factor influencing HCV VL in patients infected with genotypes 1 and 4. PMID- 24173148 TI - Isolation and characterization of yeast DNA repair genes : I. Cloning of the RAD52 gene. AB - The RAD52 gene of Saccharomyces cerevisiae has previously been shown to be involved in both recombination and DNA repair. Here we report on the cloning of this gene. A plasmid containing a 5.9 kb yeast DNA fragment inserted into the BamH1 site of the YEp13 vector has been isolated and shown to complement the X ray sensitive phenotype of the rad52-1 mutation. The rad52-1 cells containing the plasmid form larger colonies than similar cells having lost the plasmid. This plasmid has been shown not to complement either the U.V. sensitivity or the recombination defect of the E. coli recA mutation. From the insert various fragments have been subcloned into the YRp7 and YIp5 vectors. Integration events of two of the subclones have been genetically mapped to the chromosomal location of RAD52, indicating that the structural gene has been cloned. A 1.97 kb BamH1 fragment subcloned into YRp7 in one orientation complements the rad52-1 mutation, while the same fragment in the opposite orientation fails to complement. Various other subclones indicate that a BglII site, within the BamH1 fragment, is in the RAD52 gene. This BglII site has been deleted by Sl-nuclease digestion and the resulting deletion inactivates the RAD52 gene. BAL31 deletions from one end of a 1.9 kb Sal1-BamH1 fragment have been isolated; up to 0.9 kb can be deleted without loss of RAD52 activity, indicating that the RAD52 gene is approximately 1 kb or less in length. PMID- 24173147 TI - Differential CTLA-4 expression in human CD4+ versus CD8+ T cells is associated with increased NFAT1 and inhibition of CD4+ proliferation. AB - Cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) is a costimulatory molecule that negatively regulates T-cell activation. Originally identified in murine CD8(+) T cells, it has been found to be rapidly induced on human T cells. Furthermore, CTLA-4 is expressed on regulatory T cells. Clinically, targeting CTLA-4 has clinical utility in the treatment of melanoma. Whether the expression of CTLA-4 is differentially regulated in CD8(+) vs CD4(+) human T cells is unclear. Here, we analyzed CTLA-4 in normal human CD4(+) and CD8(+) T-cell subsets and show for the first time that CTLA-4 is expressed significantly higher in the CD4(+) T cells than in CD8(+) T cells. CTLA-4 is higher at the protein and the transcriptional levels in CD4(+) T cells. This increase is due to the activation of the CTLA-4 promoter, which undergoes acetylation at the proximal promoter. Furthermore, we show that blocking CTLA-4 on CD4(+) T cells permits greater proliferation in CD4(+) vs CD8(+) cells. These findings demonstrate a differential regulation of CTLA-4 on CD4(+) and CD8(+) T-cell subsets, which is likely important to the clinical efficacy for anti-CTLA-4 therapies. The findings hint to strategies to modulate CTLA-4 expression by targeting epigenetic transcription to alter the immune response. PMID- 24173149 TI - Isolation and characterization of yeast DNA repair genes : II. Isolation of plasmids that complement the mutations rad50-1, rad51-1, rad54-3, and rad55-3. AB - Plasmids that complement the yeast mutations rad50-1, rad51-1, rad54-3 and rad55 3 were obtained by transforming strains that carried a leu2 marker and the particular rad mutation, with YEp13 plasmids containing near random yeast DNA inserts. Integration of these plasmids or of fragments of these plasmids was accomplished. Genetic studies using the integrants established the presence of the genes RAD51, RAD54 and RAD55 in the respective plasmids. However, a BamHI subclone of the rad50-1 complementing plasmid failed to integrate at the RAD50 locus, indicating that no homology exists between this fragment and the RAD50 gene.A BamHI fragment from the RAD54 plasmid was shown to be internal to the RAD54 gene: its integration within a wild type copy of RAD54 causes the cell to become Rad(-); its excision is X-ray inducible and restores the Rad(+) phenotype. Since cells bearing a disrupted copy of RAD54 are able to survive, we conclude that this gene is not essential. PMID- 24173150 TI - The genetic fine structure of nonsense suppressors in Schizosaccharomyces pombe : II. sup8 and sup10. AB - Meiotic fine-structure maps of two efficient UGA suppressors of Schizosaccharomyces pombe which are known (sup8-e) or inferred (sup10-e) to code for two leucine tRNAs carrying the mutant anticodon U(*)CA (Kohli et al. 1979, 1980a, b; Wetzel et al. 1979; Mao et al. 1981) are presented. In both cases, the recombination frequencies given by the primary site of the anticodon mutation fitwell into the map defined by the sites of a number of inactivating secondary mutations. This contrasts the corresponding situation found in the serine tRNA genes sup3 and sup9 where the anticodon site exhibits a specific marker effect which strongly increases recombination frequencies in crosses with all revertant sites, due to a decrease in the efficiency of excision repair of base-pair mismatches whenever the anticodon site is included in hybrid-DNA (Hofer et al. 1979; Munz and Leupold 1979; Thuriaux et al. 1980). A pronounced specific marker effect which leads to a several fold increase of the recombination frequencies over those expected is observed, however, at one of the secondary inactivating sites mapping in the leucine tRNA gene sup8. PMID- 24173151 TI - STA10: A gene involved in the control of starch utilization by Saccharomyces. AB - Genetic analysis of crosses carried out between starch utilizing strains of Saccharomyces diastaticus and laboratory strains of S. cerevisiae has revealed the existence of a gene which inhibits the expression of the amylolytic capability in the resulting hybrids, as well as in the meiotic offspring of the crosses. This gene is unlinked to any of the three STA genes which are known to be responsible for starch utilization by S. diastaticus. PMID- 24173152 TI - Transcription of the rRNA gene cluster in Aspergillus nidulanss. AB - Transcription of rDNA in Aspergillus nidulans was examined by hybridizing labeled cloned rDNA fragments to blots of RNA gels. One processing pathway was found. PMID- 24173153 TI - DNA insertions which affect the expression of the yeast iso-2-cytochrome c gene. AB - The plasmid YCpCYC7(2) was constructed containing the Saccharomyces cerevisiae CYC7 gene, encoding the iso-2-cytochrome c protein, replicative sequences and selective markers from both E. coli and yeast, and the centromere of yeast chromosome III. The expression of the plasmid-CYC7 gene in yeast was similar to the low level expression characteristic of the chromosomal CYC7 gene. A number of insertions into the sequences 5' to the gene were constructed in vitro. The insertion at 142 by 5' to the coding sequence of a 400 by fragment which lies 5' to the CYC1 gene and is known to be essential for the high rates of CYC1 transcription increased transcription of the CYC7 gene to levels characteristic of CYC1 transcription. On the other hand, the insertion of random DNA fragments at the same position gave mostly decreased CYC7 transcription. In addition to these in vitro constructions, a mutant plasmid was selected which had increased CYC7 transcription. This mutation was caused by the insertion of the bacterial IS1 element 313 by 5' to the CYC7 coding sequence. The significance of these results is discussed in terms of two alternative models for CYC7 gene expression. PMID- 24173154 TI - Visualization of chromosomes in mitotically arrested cells of the fission yeast Schizosaccharomyces pombe. AB - Three sets of mitotic chromosomes were observed in wild type or cdc mutants (nda3 KM311 and nda2-KM52) of the fission yeast S. pombe by the DAPI staining method. The block of microtubular functions by thiabendazole or by the mutations caused their individual appearance in mitotically arrested cells. The chromosomes have a characteristic size; the length ratio of short, medium and long ones was roughly 1:2:3, consistent with the previous genetical data (Kohli et al. 1977). Double staining with ethidium bromide and DAPI showed that the nucleolus was always associated with the shortest chromosome. Pair-like structures resembling sister chromatids were also seen. PMID- 24173155 TI - Localization and nucleotide sequence of the gene for the ATP synthase proteolipid subunit on the spinach plastid chromosome. AB - A 1.6 kbp DNA segment of spinach plastid DNA has been shown to carry the gene for the proteolipid subunit of the ATP synthase. Each plastid chromosome contains one copy of this gene which is located in the large single-copy region of the chromosome near that of the ATP synthase alpha subunit. These two genes are transcribed in the same direction and probably in distinct RNA species. The proteolipid gene was located by hybrid-selection mapping, by transcription/translation of recombinant DNAs and by nucleotide sequencing. The in vitro product was identified by electrophoretic criteria including its characteristic shift in electrophoretic mobility upon incubation with dicyclohexylcarbodiimide, and immunology. The nucleotide sequence of the proteolipid gene is uninterrupted. The deduced amino acid sequence coincides with the published amino acid sequence for this protein and shows little homology with the published sequence of the proteolipid subunit of E. coli. PMID- 24173156 TI - Comparison of the cyanelle DNA from two different strains of Cyanophora paradoxa. AB - The cyanelle DNA from two different strains of Cyanophora paradoxa (strain LB555UTEX and strain 1555) was investigated.The cyanelle DNA from both strains showed a buoyant density in neutral CsCI gradients of 1.692 g/cm(3). The total molecular weight, as judged by restriction endonuclease analysis, of the two cyanelle DNAs differed. In strain LB555UTEX the size of the cyanelle DNA was equivalent to 127 +/- 1 kb whereas in strain 1555 a size of 138 +/- 1 kb was consistently found. The sizes of individual DNA fragments and the number of recognition sites for a particular restriction endonuclease appeared largely unrelated.A high amount of cross hybridization, as judged by reciprocal heterologous DNA hybridizations, however indicated a high degree of sequence homology between the two cyanelle DNAs. Under comparable conditions, cyanelle DNA hybridized nearly exclusively with the dG+dC-rich rRNA transcription units from plastid DNAs. Up to now conserved restriction endonuclease recognition sites between the two cyanelle DNAs were only observed within the cyanelle rRNA genes which are present twice on both cyanelle DNAs. PMID- 24173157 TI - Extrachromosomal genetics of Claviceps purpurea : I. Mitochondrial DNA and mitochondrial plasmids. AB - In order to establish a system for gene cloning in the ergot fungus Claviceps purpurea mitochondrial DNA was purified from two wild strains and four descendants of production strains. A characterization of the mt DNA with respect to buoyant density, molecular weight (45 kb corresponding to acontour lenght of 14 MUm) showed no differences. However, considerable differences were detected in the restriction pattern, with the exception of two commercial strains of possibly common origin. From this it follows that restriction patterns of mt DNA may be used as finger prints to identify related strains.In one of the wild strains plasmids associated with the mitochondria were found. A characterization of two species p11 and p12 having molecular weights of 6.6 and 5.3 kb revealed that these genetic units are linear having respective contour lengths of 2.1 and 1.7 MUm. According to Southern blot analyses both plasmids show homology to each other, but not to the mitochondrial "chromosome". Accordingly, p11 and p12, despite localization in the mitochondria, are evidently not an integral part of the mt "chromosome". The possibility to use the mt DNA and mitochondrial plasmids to establish a vector system for molecular cloning in imperfect strains of Claviceps purpurea has been pointed out. PMID- 24173158 TI - Mitochondrial DNA from Podospora anserina : IV. The large ribosomal RNA gene contains two long intervening sequences. AB - We have examined the structure of the rRNA genes from the mitochondrial genome of Podospora anserina. Using R-loop analysis, nuclease protection experiments, and Southern blot hybridization analysis we have observed two intervening sequences (IVS) in the large rRNA gene, and none in the small rRNA gene. the IVS sequences are 1.65 kbp and 2.73 kbp long, and the larger of the two is in the position of the conserved IVS found in the mitochondrial genomes of other fungi. We have detected precursor transcripts for the large rRNA, and these data support the observation of two IVS in this gene. We also note that the large and small rRNA genes are separated by approximately 6 kbp of DNA. PMID- 24173159 TI - Use of mitochondrial mutants in the isolation of hybrids involving industrial yeast strains : IV. Characterization of an intergeneric hybrid, Saccharomyces diastaticus x Hansenula capsulata, obtained by protoplast fusion. AB - A hybrid of Saccharomyces diastaticus x Hansenula capsulate was obtained by conversion of the S. diastaticus parent to a petite, protoplasting and fusion of the strains and isolation of the hybrids on selective media, containing glycerol or galactose. All of the single-cell clones obtained resembled S. diastaticus in morphology, and fermented glucose, galactose, maltose, sucrose and starch. The hybrid sporulated, producing spores resembling those of S. diastaticus, but in asci which differed somewhat morphologically. The stability of the hybrid depended on the composition of the maintenance media, as hybrid clones maintained on glycerol medium lost their ability to sporulate after a few transfers and the cellular morphology altered to a form more closely resembling H. capsulate, and those maintained on glucose-containing medium lost the ability to utilize glycerol. Cultures maintained on yeast extract-starch medium retained the ability to sporulate and utilize glycerol. However, dissection of asci from the hybrid yielded clones, some of which had lost the ability to metabolize glycerol but which still sporulated. These clones had an unaltered cytochxome spectrum, and in other ways appeared to be respiratory competent. Washed cells of hybrids grown on galactose or starch as sole carbon source metabolized starch, as shown by respirometric measurements, but cells maintained on glycerol as sole carbon source had lost this ability. There was some evidence that the addition of vitamins stimulated oxygen uptake on starch by the hybrids. The formation of sporulating hybrids in the cross may permit the genetic analysis of other Saccharomyces x Hansenula crosses. PMID- 24173160 TI - Nuclear association in yeast of a hybrid vector containing mitochondrial DNA. AB - The hybrid vector pCP2, consisting of the bacterial plasmid pBR325, the nuclear gene Leu-2 of Saccharomyces cerevisiae and a fragment of mitochondrial DNA from Cephalosporium acremonium, was found to associate with the nucleus in a transformed strain of Saccharomyces cerevisiae. This was inducted by (1) efficient expression of the Leu-2 gene as evidenced by a short generation time on selective medium; (2) independence of Leu-2 gene expression from mitochondrial protein synthesis, since pCP2 was shown to replicate and to be expressed in petite mutants; (3) association of pCP2 with isolated DNA from nuclei as proved by transformation experiments with E. coli. PMID- 24173161 TI - The magnitude of nonelectrolyte selectivity in the gallbladder epithelium. AB - The permeability of the rabbit gallbladder epithelium to nonelectrolytes was determinted by radioactive tracer techniques and by a rapid osmotic procedure. As expected from empirical and theoretical considerations, there was a good agreement between the selectivity sequences obtained by the two methods for the sixteen compounds used in this study. Although the permeability coefficients are directly related to their bulk-phase partition coefficients, the gallbladder behaves as if the membranes controlling selectivatity are more hydrophilic than isobutanol. The relation between permeability coefficients and molecular weight also show that these membranes are less viscous than other single cell membranes. Small polar solutes exhibit lower apparent activiation energies for permeation than larger solutes, and this is taken as support for the view that small polar molecules permeate across this tissue via a polar pathway. Inutin and sucrose permeability coefficients are in the ratio of their free-solution diffusion coefficients, and the apparent surcose activation energy is indistinguishable from that reported for diffusion in aqueous solution. These latter observations may be explained by the presence of a few large "pores" in the epithelium. PMID- 24173162 TI - Influence of external cations on caffeine-induced tension: Calcium extrusion in crayfish muscle. AB - The transience of caffeine-induced tensions in crayfish muscle fibers indicates a caffeine-insensitive, Ca-transport system in these fibers. Analysis of the changes in relaxation time of caffeine tensions following ionic substitutions in the crayfish saline leads to the conclusions that this Ca-transport system is located in the sarcolemma and that the extrusion process involves binding of external cations, in particular Na. PMID- 24173163 TI - Evidence which suggests the existence of lipid regions discrete from those of the protein in mitochondrial and red blood cell membranes. AB - The action of phospholipase C(EC 3.1.4.3) on erythrocyte ghosts and submitochondrial particles results in a marked change in the molecular structure of the phospholipid regions of the membrane but in no change in the environments (i.e., structure) of the sulfydryl and tyrosyl residues of the membrane proteins as determined by electron spin resonance "spin label" studies. These results hold true whether the membrane is one containing a relatively high proportion of cholesterol (erythrocyte) or one containing very little cholesterol (mitochondrial). The relevance of these findings to current membrane models is discussed. PMID- 24173164 TI - Contributions of various ions to the resting and action potentials of crayfish medial giant axons. AB - The membrane of crayfish medial giant axons is permeable at rest to ions in the rank K>Na>Ca>Cl. With K present, variation of the other ions has little or no effect, but with K absent the axon hyperpolarizes when Na is reduced or eliminated by replacement with Tris (slope ca. 30 mV/decade Na0). The hyperpolarization is independent of the presence of Cl or its absence (substitution with methanesulfonate or isethionate). The resistance increases progressively as Na is removed. These changes persist after the spike is blocked with tetrodotoxin. An increase in Ca causes depolarization (slope ca. 20 mV/decade) provided K, Na and Cl are all absent, but in the presence of Cl there is little or no change in membrane potential on increasing Ca to 150MM. The depolarization induced by Ca is associated with an increased resistance. Spike electrogenesis involves Ca activation as well as Na activation, but the after depolarization at the end of the spike is due to a conductance increase for Ca. Two alternative equivalent circuits for the resting and active membrane are discussed. PMID- 24173165 TI - Determination of the driving force of the Na(+) pump in toad bladder by means of vasopressin. AB - Vasopressin stimulates Na(+) transport across toad bladder largely or entirely by decreasing the resistance to Na(+) entry into the transporting epithelial cells. Therefore, the hormone should induce proportional changes in short circuit current (I S ) and tissue conductance; the ratio of these changes should equal the driving force (E Na) of the Na(+) pump.Administration of vasopressin provided a rapid, reversible and reproducible technique for the measurement ofE Na. Values calculated forE Na ranged from 74 to 186 mV, in agreement with previously published estimates. The results were not dependent on the vasopressin concentration over a wide range of concentrations.Ouabain, an agent thought to inhibit specifically the Na(+) pump, decreased bothI S andE Na. On the other hand, amiloride, a diuretic thought to block specifically Na(+) entry, markedly reducedI S , without reducingE Na.It is concluded that vasopressin constitutes a probe for the rapid reproducible determination ofE Na under a wide variety of physiological conditions. PMID- 24173166 TI - Immunotoxicology: challenges in the 21st century and in vitro opportunities. AB - Over the last two decades, little has changed in the practice of immunotoxicity testing for regulatory purposes, especially for immunosuppression, and autoimmunity is still a challenge. Current guidelines still rely on animal tests, which include some immune endpoints in repeated dose tests and trigger dedicated tests only when certain alerts indicate a problem. At the same time, however, a wealth of in vitro approaches has been developed, but few have been adopted for routine testing. The extent to which immunotoxicity of chemicals represents a health problem for the human population at low levels of exposure is unclear: it appears that responses of healthy individuals to immunological challenges differ widely and most immunomodulators have few adverse effects except when they coincide with an infectious or malignant challenge or when early in life exposure is expected, in which cases the odds of progressing into infection, autoimmune diseases, or cancer can be changed. The enormous overcapacity of immune defense, the presence of compensatory mechanisms, and their fast restoration each contribute to limiting health threats for the individual, though on a population base also minor immunomodulation may result in increased morbidity. In vitro alternative approaches may allow screening for problematic substances and prioritize them for in vivo testing. New approaches are emerging from mapping pathways of immunotoxicity. Increasingly, the contribution of inflammatory and infectious components to the adverse outcome pathways of chemicals is recognized for various hazards, urging inclusion of tests for proinflammatory and immunomodulatory properties of chemicals into integrated testing strategies. PMID- 24173167 TI - Generation of genetically-modified human differentiated cells for toxicological tests and the study of neurodegenerative diseases. AB - Human differentiated cell types, such as neurons or hepatocytes, are of limited availability, and their use for experiments requiring ectopic gene expression is challenging. Using the human conditionally-immortalized neuronal precursor line LUHMES, we explored whether genetic modification in the proliferating state could be used for experiments in the differentiated post-mitotic neurons. First, alpha synuclein (ASYN), a gene associated with the pathology of Parkinson's disease, was overexpressed. Increased amounts of the protein were tolerated without change of phenotype, and this approach now allows further studies on protein variants. Knockdown of ASYN attenuated the toxicity of the parkinsonian toxicant 1-methyl-4 phenylpyridinium (MPP+). Different lentiviral constructs then were tested: cells labeled ubiquitously with green (GFP) or red fluorescent protein (RFP) allowed the quantification of neurite growth and of its disturbance by toxicants; expression of proteins of interest could be targeted to different organelles; production of two different proteins from a single read-through construct was achieved successfully by an expression strategy using a linker peptide between the two proteins, which is cleaved by deubiquitinases; LUHMES, labeled with GFP in the cytosol and RFP in the mitochondria, were used to quantify mitochondrial mobility along the neurites. MPP+ reduced such organelle movement before any other detectable cellular change, and this toxicity was prevented by simultaneous treatment with the antioxidant ascorbic acid. Thus, a strategy has been outlined here to study new functional endpoints, and subtle changes of structure and proteostasis relevant in toxicology and biomedicine in post-mitotic human cells. PMID- 24173168 TI - In vitro and in vivo testing methods of epigenomic endpoints for evaluating endocrine disruptors. AB - Epigenetic modulations underlie critical developmental processes and contribute to determining adult phenotype. Alterations to the phenotype, due to exposure to environmental insults during sensitive periods of development, are mediated through alterations in epigenetic programming in affected tissues. Originally prepared for the Organisation of Economic Cooperation and Development (OECD), this detailed review evaluates the potential role of chemical-induced epigenetic modifications to endocrine signaling pathways during sensitive windows of exposure as a mechanism of endocrine disruption, along with the examination of potential methods for assessing such disruption. Potential targets of disruption along putative adverse outcome pathways associated with the signaling pathways are identified, along with assays that show promise in evaluating the target in a screening and testing program such that in vitro methods are used where possible, and animal experiments only where in vitro methods are not available. Monitoring such epigenetic marks in response to toxicant exposure may in future provide a valuable tool for predicting adverse outcomes, but a more robust basis for Test Guideline recommendations is still needed. Although there is evidence to suggest that epigenomic dysregulation might mediate effects of exposures to endocrine disruptors, it is uncertain as to whether these changes are truly predictive of adverse outcome(s). Adverse effects observed in the OECD transgenerational assays could be used to inform future tests specifically designed to investigate the epigenetic mechanism of action. Follow-up studies should include both an epigenetic as well as a genomic component to differentiate between the contributions of potentially compensatory mechanisms. PMID- 24173169 TI - From pathways to people: applying the adverse outcome pathway (AOP) for skin sensitization to risk assessment. AB - Consumer safety risk assessment of skin sensitization requires information on both consumer exposure to the ingredient through product use and the hazardous properties of the ingredient. Significant progress has been made in determining the hazard potential of ingredients without animal testing. However, hazard identification is insufficient for risk assessment, and an understanding of the dose-response is needed. Obtaining such knowledge without animal testing is challenging and requires applying available mechanistic knowledge to both assay development and the integration of these data. The recent OECD report "The Adverse Outcome Pathway for Skin Sensitization Initiated by Covalent Binding to Proteins" presents the available mechanistic knowledge of the sensitization response within an adverse outcome pathway (AOP). We propose to use this AOP as the mechanistic basis for physiologically- and mechanistically-based toxicokinetic-toxicodynamic models of the sensitization response. The approach would be informed by non-animal data, provide predictions of the dose-response required for risk assessment, and would be evaluated against human clinical data. PMID- 24173170 TI - A roadmap for hazard monitoring and risk assessment of marine biotoxins on the basis of chemical and biological test systems. AB - Aquatic food accounts for over 40% of global animal food products, and the potential contamination with toxins of algal origin--marine biotoxins--poses a health threat for consumers. The gold standards to assess toxins in aquatic food have traditionally been in vivo methods, i.e., the mouse as well as the rat bioassay. Besides ethical concerns, there is also a need for more reliable test methods because of low inter-species comparability, high intra-species variability, the high number of false positive and negative results as well as questionable extrapolation of quantitative risk to humans. For this reason, a transatlantic group of experts in the field of marine biotoxins was convened from academia and regulatory safety authorities to discuss future approaches to marine biotoxin testing. In this report they provide a background on the toxin classes, on their chemical characterization, the epidemiology, on risk assessment and management, as well as on their assumed mode of action. Most importantly, physiological functional assays such as in vitro bioassays and also analytical techniques, e.g., liquid chromatography coupled mass spectrometry (LC-MS), as substitutes for the rodent bioassay are reviewed. This forms the basis for recommendations on methodologies for hazard monitoring and risk assessment, establishment of causality of intoxications in human cases, a roadmap for research and development of human-relevant functional assays, as well as new approaches for a consumer directed safety concept. PMID- 24173171 TI - Endometrial cancer: results of clinical and histopathological staging compared to magnetic resonance imaging using an endorectal surface coil. AB - PURPOSE: The aim of this study was to evaluate the staging accuracy of magnetic resonance imaging (MRI) with an endorectal surface coil on patients with endometrial cancer compared to results obtained using the International Federation of Gynecology and Obstetrics (FIGO) classification and histopathology. METHODS: In this prospective study, patients with biopsy-proven endometrial cancer were staged clinically using the FIGO classification before undergoing 1.5 T MRI with an endorectal surface coil (eMRI). The staging results from the FIGO classification and from eMRI were compared with the histopathological results after surgery. Furthermore, each patient was given a questionnaire designed by the authors to evaluate the patients' opinions on eMRI. The responses were examined using the methods of descriptive analysis. RESULTS: A total of 33 consecutive patients were recruited and clinically staged before undergoing eMRI. Subsequently, 21 patients underwent primary surgery and 12 patients primary radiochemotherapy. The FIGO stages were identical to the histopathological results in 17 (81 %) cases, and those of eMRI were identical in 15 (71 %). In 13 (62 %) cases, FIGO and eMRI staged identically. In 12 (57 %) of the 21 cases, all three staging modalities diagnosed the same tumor stage. eMRI overstaged the tumor in four patients and understaged it in two. All T1a tumors were staged correctly by eMRI. Eighteen patients answered the questionnaire, of whom 11 (61 %) patients stated that their experience with eMRI was overall positive. CONCLUSIONS: It seems feasible in principle to employ eMRI for diagnosing patients with endometrial cancer stage T1a. Yet, the results of eMRI for our study population were not better than the results obtained using the FIGO classification or than those from using MRI without an endorectal surface coil. eMRI thus does not meet the expectations based on its use in other pelvic tumor entities. PMID- 24173172 TI - Cesarean section on maternal request: the viewpoint of expectant women. AB - PURPOSE: To determine the women's perception and factors influencing willingness to have cesarean section on maternal request (CSMR) in the absence of medical or obstetric indication. METHODS: A cross-sectional questionnaire-based survey of 752 antenatal clinic attendees at Ekiti State University Teaching Hospital (EKSUTH), Ado-Ekiti. Pre-tested questionnaires were used to elicit information on socio-demographic and obstetric variables, awareness and perspective of CSMR and the willingness to request CS without physician's recommendation. Frequency tables were generated and univariate and multivariate logistic regression were used to determine factors that influenced CSMR using SPSS software version 16.0. RESULTS: Forty-eight (6.4 %) of the respondents reported willingness to request CS. The most common motivations for the request were fear of losing the baby during labor, delay in conception and fear of labor pains. Analysis by simple logistic regression and multiple regression showed age, parity and educational status were not significantly related to the decision for CSMR. CONCLUSION: CSMR is an evolving entity in obstetrics practice in the developing countries. Delay in conception, fear of labor pain and loss of baby during labor appear to be strong motivations. PMID- 24173174 TI - Paracoccidioidomycosis: epidemiological, clinical, diagnostic and treatment up dating. AB - Paracoccidioidomycosis is an acute - to chronic systemic mycosis caused by fungi of the genus Paracoccidioides. Due to its frequent tegument clinical expression, paracoccidioidomycosis is an important disease for dermatologists, who must be up to-date about it. This article focuses on recent epidemiological data and discusses the new insights coming from molecular studies, as well as those related to clinical, diagnostic and therapeutic aspects. In the latter section, we give particular attention to the guideline on paracoccidioidomycosis organized by specialists in this subject. PMID- 24173175 TI - Dermoscopic features of thin melanomas: a comparative study of melanoma in situ and invasive melanomas smaller than or equal to 1mm. AB - BACKGROUND: Dermoscopy allows the early detection of melanomas. The preoperative determination of Breslow index by dermoscopy could be useful in planning the surgical approach and in selecting patients for sentinel lymph node biopsy. OBJECTIVES: This study aims at describing the dermoscopic features of thin melanomas and comparing melanomas in situ with invasive melanomas less than or equal to 1 mm thick. METHODS: This was an observational retrospective study in which the dermoscopy photographs of 41 thin melanomas were evaluated. Three observers evaluated together 14 dermoscopic criteria. RESULTS: Among thin melanomas, the most frequent criteria were presence of asymmetry in two axes in 95% of cases (39 cases), 3 or more colors in 80.4% of cases (33 cases), atypical dots or globules in 58.5% of cases (24 cases) and atypical network or streaks in 53.6% of cases (22 cases). The group of invasive melanomas presented with a higher frequency and statistical significance (p <0.05) 3 or more colors (OR: 16.1), milky red areas (OR: 4.8) and blue-white veil (OR: 20.4), and a greater tendency to have streaks or atypical network (OR: 3.66). CONCLUSIONS: Thin melanomas tend to have asymmetry in the two axes, 3 or more colors, atypical dots or globules and atypical network or streaks. Melanomas in situ tend to have up to 2 colors, no blue-white veil and no milky red area. Invasive melanomas tend to have 3 or more colors, a milky red area, blue-white veil, and atypical network or streaks. Further studies are needed to confirm these findings. PMID- 24173176 TI - Cytokine detection for the diagnosis of chromium allergy. AB - BACKGROUND: Patch testing remains the gold standard method for the identification of the etiologic agent of allergic contact dermatitis. However, it is a subjective, time-consuming exam whose technique demands special care and which presents some contraindications, which hamper its use. In a recent study, we showed that the proliferation assay can suitably replace patch testing for the diagnosis of chromium allergy, which had been previously demonstrated only for nickel allergy. In this study, we try to refine the method by reducing the incubation period of cultures for lymphocyte proliferation assays in response to chromium. OBJECTIVE: Develop an alternative or complementary diagnostic test for chromium allergic contact dermatitis. METHODS: We compared the production of 9 cytokines (IFN-gamma, IL-2, IL-4, IL-5, IL-10, IL-12, IL-13, IL-17 and RANTES) between 18 chromium-allergic patients and 19 controls. RESULTS: Chromium increased the production of IFN-y, IL-5, IL-2 and IL-13 in allergic patients, but only IL-2 and especially IL-13 helped discriminate allergic patients from controls. The sensitivity, specificity and accuracy found with IL-13 were about 80%. CONCLUSIONS: IL-13 and IL-2 detection may be used to diagnose chromium allergy in 2-day cultures. However, in general, the 6-day cultures seem to be superior for this purpose. PMID- 24173177 TI - Differences in age and topographic distribution of the different histological subtypes of basal cell carcinoma, Taubate (SP), Brazil. AB - BACKGROUND: Basal cell carcinoma is the most common form of cancer in humans. OBJECTIVES: To identify the epidemiology of basal cell carcinoma in Taubate-SP and verify a possible association between topography and the different histological subtypes of this tumor. METHODS: This was a cross-sectional study conducted at The University Hospital of Taubate between 01/01/08 and 12/31/09. The study included patients with a confirmed diagnosis of basal cell carcinoma, of both genders, without age restrictions. The variables studied were incidence of basal cell carcinoma, topography, histological subtype, skin color, age and gender. We employed the chi-square test to identify the association between histological subtype and topography, and the student's t test to compare the mean age of onset for the different histological subtypes. RESULTS: The study included 239 individuals. The mean age of the sample was 68.0 years. Male subjects (57.7%) and whites (87.1%) predominated in the study. The predominant histological subtype was nodular (34.7%), followed by the superficial subtype. The most frequent sites of involvement were the head and neck (areas exposed to light), with predominance of the nasal region. The superficial subtype was an exception, as it showed a strong association with unexposed areas like the trunk. The mean age of onset of superficial basal cell carcinoma also differed from that of the other histological subtypes, 63.0 and 69.0 years, respectively. CONCLUSION: The results of this study suggest an association of the superficial histological subtype with younger patients and unexposed areas of the body, linking this type of tumor with a pattern of intermittent sun exposure, more similar to the standard photocarcinogenesis of melanoma. PMID- 24173178 TI - Comparative study of actinic keratosis treatment with 3% diclofenac sodium and 5% 5-fluorouracil. AB - BACKGROUND: Actinic keratosis is a frequent lesion which occurs in sunlight exposed areas. Diclofenac sodium and 5-Fluorouracil are effective, non-invasive and easy-to-apply topical treatment options. OBJECTIVES: To assess and compare the effectiveness of 3% diclofenac sodium associated with 2.5% hyaluronic acid and of 5% 5-Fluorouracil for the treatment of actinic keratosis, as well as the patient's degree of satisfaction and tolerability. METHODS: 28 patients with a clinical diagnosis of actinic keratosis were randomized to receive diclofenac sodium or 5-Fluorouracil and were clinically assessed before and after treatment as well as 8 weeks after the end of treatment. Modified versions of the Investigator and Patient Global Improvement Scores were used. RESULTS: The average number of lesions in the diclofenac sodium group before and after treatment was 13.6 and 6.6 (p<0,001), respectively, while it was 17.4 and 3.15 (p<0.001) in the 5-Fluorouracil group. There was a significant reduction in the number of lesions in the 5-Fluorouracil group in relation to the diclofenac sodium group (p<0.001). To the non-blinded physician, there was a higher satisfactory therapeutic response in the 5-Fluorouracil group (p<0.001); to the blinded physician, there was a higher satisfactory response in this same group, although not statistically significant (p=0.09). There was a high degree of satisfaction in both groups (73% in the diclofenac sodium group and 77% in the 5 Fluorouracil group; p=0.827). Regarding adverse effects, the diclofenac sodium group presented a higher degree of satisfaction (93.3% vs 38.4%; p=0.008). Erythema, edema, crusts and itching were significantly higher in the 5 Fluorouracil group. CONCLUSION: We concluded that 5-Fluorouracil was more effective; however, it showed lower tolerability than diclofenac sodium. PMID- 24173179 TI - Comparative study of the prevalence of sepsis in patients admitted to dermatology and internal medicine wards. AB - BACKGROUND: Sepsis is a common cause of morbidity and mortality among hospitalized patients. The prevalence of this condition has increased significantly in different parts of the world. Patients admitted to dermatology wards often have severe loss of skin barrier and use systemic corticosteroids, which favor the development of sepsis. OBJECTIVES: To evaluate the prevalence of sepsis among patients admitted to a dermatology ward compared to that among patients admitted to an internal medicine ward. METHODS: It is a cross-sectional, observational, comparative study that was conducted at Hospital Santa Casa de Belo Horizonte. Data were collected from all patients admitted to four hospital beds at the dermatology and internal medicine wards between July 2008 and July 2009. Medical records were analyzed for the occurrence of sepsis, dermatologic diagnoses, comorbidities, types of pathogens and most commonly used antibiotics. RESULTS: We analyzed 185 medical records. The prevalence of sepsis was 7.6% among patients admitted to the dermatology ward and 2.2% (p = 0.10) among those admitted to the internal medicine ward. Patients with comorbidities, diabetes mellitus and cancer did not show a higher incidence of sepsis. The main agent found was Staphylococcus aureus, and the most commonly used antibiotics were ciprofloxacin and oxacillin. There was a significant association between sepsis and the use of systemic corticosteroids (p <0.001). CONCLUSION: It becomes clear that epidemiological studies on sepsis should be performed more extensively and accurately in Brazil so that efforts to prevent and treat this serious disease can be made more effectively. PMID- 24173180 TI - American cutaneous leishmaniasis: epidemiological profile of patients treated in Londrina from 1998 to 2009. AB - BACKGROUND: American cutaneous leishmaniasis is a dermatozoonosis of compulsory notification with relevant morbidity. The disease is considered endemic in northern Parana. OBJECTIVES: To evaluate the clinical, laboratory and epidemiological aspects of patients with American cutaneous leishmaniasis treated at Clinics Hospital, State University of Londrina, Brazil (Parana). METHODS: This was an observational, cross-sectional, retrospective and descriptive study. The medical records of patients with American cutaneous leishmaniasis treated at the University Hospital of Londrina - Parana, from 1998 to 2009 were evaluated. RESULTS: A total of 470 patients, with prevalence of 8.72 cases / 100,000 inhabitants, participated in the study. Most patients were male, aged 21-40 years, with a single ulcerated lesion as the most common clinical presentation, located mainly in an exposed area of the body. With regard to immunological tests, the Montenegro intradermal reaction was positive in 84.4% of cases. Treatment with pentavalent antimony was well tolerated, and patient follow-up for a year occurred in 59% of cases. CONCLUSION: American cutaneous leishmaniasis is still an endemic disease in the region, with a high potential for morbidity, but with a cure rate of around 95% after treatment. The use of immunological techniques facilitates the diagnosis of clinically suspicious cases. PMID- 24173181 TI - Prognosis of patients with systemic lupus erythematosus and discoid lesions. AB - BACKGROUND: It has been observed that patients with systemic lupus erythematosus and discoid lesions have a milder systemic disease. OBJECTIVE: To compare the clinical, demographic and autoantibody profile of systemic lupus erythematosus patients with and without discoid lesions. METHODS: We carried out a retrospective study involving 288 systemic lupus erythematosus patients who met at least four classification criteria of the American College of Rheumatology for systemic lupus erythematosus, comparing the clinical, serological and demographic factors between patients with and without discoid manifestations. RESULTS: Of the 288 patients, 13.8% had discoid lesions. Univariate analysis found no differences in the prevalence of malar rash, photosensitivity, arthritis, serositis, leukopenia, lymphopenia and hemolytic anemia or anemia of the central nervous system (p = ns). Renal lesions were more common in those without discoid lesions (p =0.016), and hemolysis (p<0.0001) was more common in those with discoid lesions. Regarding the profile of autoantibodies, only the anti-RNP antibody was more common in those with discoid events (p =0.04). In a logistic regression study, only the renal lesions and anti-RNP maintained their associations with discoid manifestations. CONCLUSION: Patients with lesions of systemic lupus erythematosus and discoid lesions have lower prevalence of renal involvement and a greater presence of anti RNP. PMID- 24173182 TI - Psoriasis: correlation between severity index (PASI) and quality of life index (DLQI) in patients assessed before and after systemic treatment. AB - BACKGROUND: Psoriasis is a chronic inflammatory disease of the skin that affects patients of all ages and both genders. The impact of the disease on quality of life is greater among patients with moderate to severe psoriasis. OBJECTIVE: to establish a correlation between the psoriasis area and severity index (PASI) and the Dermatology Life Quality Index (DLQI) based on a quality of life questionnaire adapted to the Brazilian context for patients with plaque psoriasis before and after systemic treatment. METHODS: This was a cross-sectional, descriptive study of psoriasis patients who did not undergo treatment or who manifested clinical activity of the disease. Patients were evaluated according to the PASI and the quality of life questionnaire adapted to the Brazilian context before and 60 days after systemic treatment. RESULTS: Thirty-five patients participated in the study. Twenty-six were men, with a mean age of 46 years. There was no correlation between the PASI and the quality of life questionnaire adapted to the Brazilian context, but there was a correlation between the PASI and some items of the quality of life questionnaire adapted to the Brazilian context, such as jobs involving public contact. CONCLUSION: The non-correlation between the PASI and the quality of life questionnaire adapted to the Brazilian context in this work may be associated with a history of chronic disease, which implies greater acceptance of the illness, or may be related to the low income and social status of the patients studied. The correlation observed among patients with careers involving public contact suggests that some professions are more impacted by the disease. It may be necessary to adapt the quality of life questionnaire to patients with a low income and cultural and social limitations. The small sample size (n=35 patients) and the short follow-up period of 60 days were some of the limitations of this work. PMID- 24173183 TI - Update on therapy for superficial mycoses: review article part I. AB - Superficial fungal infections of the hair, skin and nails are a major cause of morbidity in the world. Choosing the right treatment is not always simple because of the possibility of drug interactions and side effects. The first part of the article discusses the main treatments for superficial mycoses - keratophytoses, dermatophytosis, candidiasis, with a practical approach to the most commonly-used topical and systemic drugs , referring also to their dosage and duration of use. Promising new, antifungal therapeutic alternatives are also highlighted, as well as available options on the Brazilian and world markets. PMID- 24173184 TI - Cutaneous field cancerization: clinical, histopathological and therapeutic aspects. AB - The concept of "field cancerization" was first introduced by Slaughter in 1953 when studying the presence of histologically abnormal tissue surrounding oral squamous cell carcinoma. It was proposed to explain the development of multiple primary tumors and locally recurrent cancer. Organ systems in which field cancerization has been described since then are: head and neck (oral cavity, oropharynx, and larynx), lung, vulva, esophagus, cervix, breast, skin, colon, and bladder. Recent molecular studies support the carcinogenesis model in which the development of a field with genetically altered cells plays a central role. An important clinical implication is that fields often remain after the surgery for the primary tumor and may lead to new cancers, designated presently as "a second primary tumor" or "local recurrence," depending on the exact site and time interval. In conclusion, the development of an expanding pre-neoplastic field appears to be a critical step in epithelial carcinogenesis with important clinical consequences. Diagnosis and treatment of epithelial cancers should not only be focused on the tumor but also on the field from which it developed. The most important etiopathogenetic, clinical, histopathological and therapeutic aspects of field cancerization are reviewed in this article. PMID- 24173185 TI - Understanding the type 1 reactional state for early diagnosis and treatment: a way to avoid disability in leprosy. AB - A type 1 reaction or reversal reaction is expressed clinically by inflammatory exacerbation of the skin lesions and nerve trunks, consequently leading to sensory and motor alterations. It occurs in non-polar forms of leprosy, although it can occur in a small percentage of sub-polar LL treated patients. Disabilities, deformities and morbidity, still present in leprosy, are mainly caused by these acute episodes. The recognition of reactional states is imperative for an early approach and efficient management, to avoid the emergence of disabilities that stigmatize the disease. This review aims to describe the clinical aspects, immunopathogenesis, epidemiology, histopathological features and therapeutics of type 1 reactions. PMID- 24173186 TI - Atrophic dermatofibroma. AB - Dermatofibroma is a benign fibrohistiocytic tumor, common and easily diagnosed when classical clinicopathologic features are present. The atrophic variant of dermatofibroma is of uncertain origin. This lesion is characterized clinically by a flat or atrophic and depressible surface. Histopathological features show reduction of the thickness of the dermis and elastic fibers. We report a typical case of this uncommon and probably underdiagnosed variant. PMID- 24173187 TI - Erosive pustular dermatosis of the scalp successfully treated with oral prednisone and topical tacrolimus. AB - Erosive pustular dermatosis of the scalp is a rare inflammatory disorder of the scalp, affecting elderly patients after local trauma and leading to scarring or cicatricial alopecia. CASE REPORT: An elderly female patient complained of painful pustules on the parietal region bilaterally with progressive enlargement and ulceration. A biopsy suggested erosive pustular dermatosis of the scalp and the patient was treated with prednisone 40 mg/day and 0.1% topical tacrolimus. After 10 weeks complete closure of the eroded areas was observed and a stable scarring alopecia developed. PMID- 24173188 TI - Chronic graft-versus-host disease: clinical presentation of multiple lesions of lichenoid and atrophic pattern. AB - Graft-versus-host disease is observed mainly in recipients of hematopoietic cell transplantation and is expressed by cutaneous or systemic signals and symptoms. Graft-versus-host disease is clinically classified as acute or chronic. Chronic Graft-versus-host disease occurs in up to 70% of hematopoietic cell transplanted patients and its clinical manifestations have important impact on morbidity and quality of life. The authors report an expressive cutaneous, oral and adnexal involvement in a patient with chronic Graft-versus-host disease with multiple lesions of lichenoid and atrophic pattern. PMID- 24173189 TI - Pigmented eccrine poroma: report of an atypical case with the use of dermoscopy. AB - Poromas are uncommon benign neoplasms originating from the terminal ductal portion of the sweat glands, mainly characterized by skin-colored or pink papules or nodules, usually on the extremities. Due to their rarity, the pigmented form clinical hypothesis is hardly ever suggested and psychopathology is fundamental. We report a case of pigmented eccrine poroma in the right palmer area, a location considered atypical. We stress the importance of dermoscopy as a method for diagnosis of poromas, especially in the differential diagnosis with other pigmented nodular-popular lesions. PMID- 24173190 TI - Case report of cutaneous histiocytic sarcoma: diagnostic and therapeutic dilemmas. AB - Histiocytic sarcoma is a rare hematologic malignant neoplasia originating from histiocytic or dendritic cell clones. The lesions may be in nodal or extranodal sites, most commonly in the gastrointestinal tract. A small number of cases presents as unique cutaneous lesions. The definitive diagnosis is made by positivity for the immunohistochemical markers CD163, CD68, CD4 and lysozyme. The treatment is controversial, often with combined systemic chemotherapy. This is a case of cutaneous histiocytic sarcoma in an 82-year-old patient presenting two nodular lesions in the breast and right arm which were treated with simple excision and multidisciplinary follow-up, avoiding aggressive management and exhaustive investigations. Although most studies report aggressive evolution, the patient had good and stable clinical status during the twelve-month follow-up period. PMID- 24173191 TI - Non-cultured melanocyte/keratinocyte transplantation for the treatment of stable vitiligo on the face: report of two cases. AB - There are many alternatives to treat vitiligo, including surgical procedures, which are recommended for patients resistant to other therapies. The melanocyte/keratinocyte transplantation consists in the separation of epidermal cells obtained from a donor site and spreading these cells on the depigmented and dermabraded recipient area. Two patients were submitted to transplantation, showing more than 70% repigmentation in the treated areas after four months, both with excellent degree of satisfaction. The method requires some laboratory skills, but represents a simple and safe procedure. PMID- 24173192 TI - Folliculitis decalvans: the use of dermatoscopy as an auxiliary tool in clinical diagnosis. AB - Folliculitis decalvans is an inflammatory presentation of cicatrizing alopecia characterized by inflammatory perifollicular papules and pustules. It generally occurs in adult males, predominantly involving the vertex and occipital areas of the scalp. The use of dermatoscopy in hair and scalp diseases improves diagnostic accuracy. Some trichoscopic findings, such as follicular tufts, perifollicular erythema, crusts and pustules, can be observed in folliculitis decalvans. More research on the pathogenesis and treatment options of this disfiguring disease is required for improving patient management. PMID- 24173193 TI - Dermoscopy examination of petechial lesions in a patient with Dermatitis Herpetiformis. AB - An uncommon skin manifestation of Dermatitis Herpetiformis is palmar and plantar purpura. Dermoscopic examination is useful for any skin condition since it allows recognition of structures that are not discernible to the naked eye. A 22 year old Caucasian man was admitted with excoriated lesions and pruritus. Petechial lesions could be seen on volar aspect of the digits on the hands and feet. Dermoscopy examination revealed erythematous and violaceous dots and erythematous and brown dots. PMID- 24173194 TI - Ectopic cutaneous Schistosomiasis. AB - The authors report a case of ectopic cutaneous schistosomiasis in a 35 year-old female who presented clustered reddish macules and papules on the left buttock. The diagnosis was not suspected during clinical evaluation and required visualization of Schistosoma mansoni eggs on sections of tissue. PMID- 24173195 TI - Case for diagnosis. AB - Ketron-Goodman disease was formerly considered a disseminated type of pagetoid reticulosis. However, according to the new classification consensus, it should be regarded as aggressive epidermotropic CD8 T-cutaneous lymphoma, cutaneous gamma/delta T-lymphoma, or tumor-stage mycosis fungoides, depending on the clinical-histological picture. This case highlights a rare and challenging presentation of Ketron-Goodman disease with an indolent presentation and evolution and good response to a low-grade treatment regimen, not fitting well into the new classification criteria. PMID- 24173196 TI - Case for diagnosis. AB - Human scabies is an intensely pruritic skin infestation caused by Sarcoptes scabiei var. hominis. Crusted scabies (previously known as Norwegian scabies) is a rare form, very contagious and transmitted by direct contact with the skin. Despite being readily treatable, a delayed diagnosis often leads to widespread infestation of contacts, and therefore difficult to restrain. This case concerns a patient where dermoscopy (with scabetic burrows and a visible hand-glider structure), together with direct microscopic examination, allowed a prompt diagnosis, thereby reinforcing the increasing importance of this technique in daily practice. PMID- 24173197 TI - Case for diagnosis. AB - An 83 year-old man was observed for an 8 year-long pruritic, erythematous plaque of the left axilla. He had been continuously medicated with topical antifungals and steroids with occasional symptomatic relief, but with disease progression. After a clinical and histological diagnosis of Extramammary Paget's Disease, a total excision with wide margins was performed. He remains disease-free 12 months after surgery. We report this rare presentation of Extramammary Paget's Disease on a male patient. PMID- 24173198 TI - Do you know this syndrome? AB - Cowden's disease or multiple hamartoma syndrome is an autosomal dominant inherited disease and the main dermatological features are facial trichilemmomas (hamartomas of the follicular infundibula), oral fibroma and benign acral keratoses. The importance of this disease lays in the increased susceptibility to malignization of some lesions, especially breast, thyroid and genitourinary tract. Despite its varied phenotypic expression, this disease is generally unknown. Consequently, many cases are undiagnosed or diagnosis comes at a late stage, which reinforces the importance of an early investigation of the disease so the patient may have periodic check-ups to discover and treat malignancies. PMID- 24173199 TI - Do you know this syndrome? AB - The hyperimmunoglobulin E syndrome, or Job's syndrome is a rare primary immunodeficiency characterized by recurrent skin abscesses, recurrent respiratory tract infections, and high levels of IgE, eosinophilia, bone and dental changes. We report the case of a fourteen-year-old male patient presenting this disease, with both typical and also some relatively sporadic manifestations. We performed a literature review on the syndrome and its associated clinical findings. PMID- 24173200 TI - Atopic Dermatitis, food allergy and dietary interventions. A tale of controversy. AB - Atopic Dermatitis has long been a controversial entity in regard its relationship to food allergy. Indeed, inter-discipline disparity in the way dermatologists and allergologists perceive the food allergy/atopic dermatitis interplay, hampers the design of concise therapeutic strategies and conveys conflicting messages to the patients. Within this conceptual frame, food exclusion regimes are rendered a contentious option. On the basis of this acknowledgment, we opted to put the emphasis on the discrepant perceptions surrounding such therapeutic regimes and to share our view pertaining to their appropriate implementation. PMID- 24173201 TI - Pyschodermatology: a trip through history. AB - The interaction between the mind and diseases of the skin has been the study focus for many researchers worldwide. The field of Psychodermatology, or Psychocutaneous Medicine, is the result of the merging of two major medical specialties, psychiatry and dermatology. Although the history of Psychodermatology is rather old and interesting, the field has only recently gained popularity. Since ancient times, philosophers, surgeons, dermatologists and psychiatrists have reported the presence of psychocutaneous diseases in various scenarios. In this article, the authors describe curious and remarkable facts in the history of Psychodermatology. PMID- 24173202 TI - Conservative treatment of penile carcinoma - a retrospective study of 10 years. AB - Conservative treatment of penile squamous cell carcinoma has been advocated as a method of choice for tumours at early stages. Thirty patients with a mean age of 63.2 years were treated with CO2 laser ablation, radical local excision with preputial flap, direct closure or healing by secondary intention, circumcision alone or associated with CO2 laser and topical imiquimod. Sixteen patients had local recurrence. Partial penectomy was necessary in 3 patients. Conservative treatments of penile squamous cell carcinoma in early stages (<= T1a) do not seem to compromise the survival rate, so it may be advisable for this subset of patients. PMID- 24173203 TI - The use of the Er:YAG 2940nm laser associated with amorolfine lacquer in the treatment of onychomycosis. AB - Onychomycosis is a common disease, accounting for up to 50% of all ungual pathologies. We have been developing a clinical trial (ClinicalTrials.gov: NCT01528813) using a 2940nm Er:YAG laser to fractionally ablate human nails in vivo, aiming to increase topical amorolfine lacquer delivery to the nail unit, increasing the efficacy of topical treatment of distal and lateral subungual onychomycosis. Partial results have shown an increase in areas of nail plate free of disease. We believe that ablative lasers can increase the efficacy of topical onychomycosis treatment. PMID- 24173204 TI - Fingertip and nasal tip thermal burn in crack cocaine user. AB - Crack cocaine addiction is a public health problem in Brazil. It is an endemic disease that affects rural and urban areas. The Ministry of Health has launched emergency programs for the treatment of dependents and to combat drug trafficking. Recognition of dermatological signs of this disease is important because through them the diagnosis can be suspected and early treatment of patients with crack cocaine addiction be provided. PMID- 24173205 TI - Comments regarding the article: Case for diagnosis: Abrikossoff Tumor: unusual location. PMID- 24173206 TI - Functional nanoparticles for biomedical applications. PMID- 24173207 TI - Chemotherapy after portal vein embolization to protect against tumor growth during liver hypertrophy before hepatectomy. AB - IMPORTANCE: Portal vein embolization improves the safety of liver resection by increasing the size of residual liver, but the embolization may increase tumor growth during the waiting period before definitive hepatectomy. OBJECTIVE: To determine whether the administration of chemotherapy mitigates tumor growth after portal vein embolization (PVE) performed before major hepatectomy for metastatic colorectal cancer. DESIGN, SETTING, AND PARTICIPANTS: Review of prospectively collected data at Memorial-Sloan Kettering Cancer Center was conducted. The database included patients subjected to PVE before major hepatectomy for metastatic colorectal cancer. MAIN OUTCOMES AND MEASURES: Lesions in both the embolized and nonembolized lobes of the liver before and 1 month after PVE were measured and Response Evaluation Criteria in Solid Tumors were applied to assess disease status. Assessment of survival was based on receipt of post-PVE chemotherapy and then stratified by subsequent resectability. RESULTS: Two hundred eight tumors were measured in 64 patients; 53 tumors were in patients undergoing post-PVE chemotherapy. Approximately one-third of the lesions progressed after PVE when no chemotherapy was administered. This did not differ significantly according to whether tumors were ipsilateral or contralateral to the PVE. When chemotherapy was administered, there was a significantly lower rate of progression (18.9%, P = .03). In long-term follow-up, treatment with post-PVE chemotherapy was also independently associated with improved survival (P < .006). CONCLUSIONS AND RELEVANCE: Chemotherapy does not retard growth of the liver after PVE and may prevent cancer progression. Thus, the combination of PVE and chemotherapy may enhance both oncologic and operative safety. PMID- 24173208 TI - Autophagy induction by low-dose cisplatin: the role of p53 in autophagy. AB - The majority of chemotherapy treatments for lung cancer use cisplatin; however, its use is limited as it has several side-effects. Autophagy (or type II cell death) is an important mechanism by which programmed cell death occurs. The purpose of this study was to determine whether low-dose cisplatin treatment induces autophagy in lung cancer cells. We also examined whether autophagy inhibition results in p53-mediated apoptosis. NCI-H460 (wild-type p53) and NCI H1299 (null-type p53) cells were treated with 5 or 20 uM cisplatin for 12, 24 or 48 h. An MTT assay was performed to measure the cell viability following cisplatin treatment. To detect cisplatin-induced autophagy, cell morphology (autophagic vacuole) and LC3 localization were examined. The outcome of autophagy inhibition was determined using 3-methyladenine (3-MA) to detect Annexin V (+), propidium iodide (PI) (-) and acridine orange (+) cells by FACS analysis. To determine whether cisplatin induced autophagy, we examined the role of p53 as a cell survival regulator in autophagy. Low-doses of cisplatin (5 uM) induced cell death and this was augmented by 3-MA in both cell lines. Autophagic vacuoles and cytoplasmic LC3 formation was more evident in H460 cells than in H1299 cells. The induction of autophagy by low-dose cisplatin was increased by 2-fold in H460 compared to H1299 cells. However, the tests for apoptosis showed no difference between the 2 cell lines. Following 3-MA pretreatment, cisplatin-induced autophagy was found to be markedly reduced (a 3-fold reduction) in wild-type p53 compared to null-type p53 cells. However, cisplatin-induced apoptosis increased in wild-type p53 compared to null-type p53 cells. Autophagy induction and apoptotic shift after autophagy inhibition may be mediated by p53 activation in lung cancer cells treated with low-dose cisplatin. PMID- 24173209 TI - Production of alginate by Azotobacter vinelandii grown at two bioreactor scales under oxygen-limited conditions. AB - The oxygen transfer rate (OTR) was evaluated as a scale-up criterion for alginate production in 3- and 14-L stirred fermentors. Batch cultures were performed at different agitation rates (200, 300, and 600 rpm) and airflow rates (0.25, 0.5, and 1 vvm), resulting in different maximum OTR levels (OTRmax). Although the two reactors had a similar OTRmax (19 mmol L(-1) h(-1)) and produced the same alginate concentration (3.8 g L(-1)), during the cell growth period the maximum molecular weight of the alginate was 1,250 kDa in the 3-L stirred fermentor and 590 kDa in 14-L stirred fermentor. The results showed for the first time the evolution of the molecular weight of alginate and OTR profiles for two different scales of stirred fermentors. There was a different maximum specific oxygen uptake rate between the two fermenters, reaching 8.3 mmol g(-1) h(-1) in 3-L bioreactor and 10.6 mmol g(-1) h(-1) in 14-L bioreactor, which could explain the different molecular weights observed. These findings open the possibility of using [Formula: see text] instead of OTRmax as a scaling criterion to produce polymers with similar molecular weights during fermentation. PMID- 24173210 TI - Solvent-mediated folding of dicarboxylate dianions: aliphatic chain length dependence and origin of the IR intensity quenching. AB - We combine infrared photodissociation spectroscopy with quantum chemical calculations to characterize the hydration behavior of microsolvated dicarboxylate dianions, (CH2)m(COO(-))2.(H2O)n, as a function of the aliphatic chain length m. We find evidence for solvent-mediated folding transitions, signaled by the intensity quenching of the symmetric carboxylate stretching modes, for all three species studied (m = 2, 4, 8). The number of water molecules required to induce folding increases monotonically with the chain length and is n = 9-12, n = 13, and n = 18-19 for succinate (m = 2), adipate (m = 4), and sebacate (m = 8), respectively. In the special case of succinate, the structural transition is complicated by the possibility of bridging water molecules that bind to both carboxylates with merely minimal chain deformation. On the basis of vibrational calculations on a set of model systems, we identify the factors responsible for intensity quenching. In particular, we find that the effect of hydrogen bonds on the carboxylate stretching mode intensities is strongly orientation dependent. PMID- 24173211 TI - Novel dielectric anomalies due to spin-chains above and below Neel temperature in Ca3Co2O6. AB - We bring out novel dielectric behavior of a spin-chain compound, Ca3Co2O6, undergoing Neel order at (TN = ) 24 K. It is found that the virgin curve in the plot of isothermal dielectric constant (epsilon') versus magnetic-field lies outside the 'butterfly-shaped' envelope curve well below TN (e.g., 2.6 K), with a signature of a partial arrest of the high-field magnetoelectric (ME) phase in zero-field after travelling through magnetic-field-induced magnetic transitions. This behavior is in contrast to that observed in the isothermal magnetization data. Thus, this work brings out a novel case for 'phase-coexistence phenomenon' due to ME coupling. Another strange finding is that there is a weak, but a broad, peak in epsilon' around 85-115 K well above TN, attributable to incipient spin chain magnetic ordering. This finding should inspire further work to study ME coupling on artificial assemblies of magnetic chains, also keeping in mind miniaturization required for possible applications. PMID- 24173212 TI - B lymphocytes from patients with a hypomorphic mutation in STAT3 resist Epstein Barr virus-driven cell proliferation. AB - Epstein-Barr virus (EBV) oncogenes exert potent B cell proliferative effects. EBV infection gives rise to B cell lines that readily proliferate in culture. This ability of EBV represents a powerful tool to study cell proliferation. In efforts to delineate the contribution of signal transducer and activator of transcription 3 (STAT3) toward EBV-driven cell proliferation, we have discovered that B cells from patients with autosomal dominant hyper-IgE syndrome (AD-HIES) resist such EBV oncogene-driven outgrowth of cells. Patients with AD-HIES have a dominant negative mutation in their STAT3 gene which renders most of the protein nonfunctional. Exposure of healthy subject-derived B cells to EBV resulted in early activation of STAT3, rapidly followed by increased expression of its mRNA and protein. STAT3 upregulation preceded the expression of EBNA2, temporally one of the first viral oncogenes to be expressed. We found that STAT3 was necessary for subsequent survival and for proliferation of EBV-infected cells past the S phase of the cell cycle. Consequently, B cells from AD-HIES patients were prone to dying and accumulated in the S phase, thereby accounting for impaired cell outgrowth. Of importance, we have now identified a cohort of patients with a primary immunodeficiency disorder whose B cells oppose EBV-driven proliferative signals. These findings simultaneously reveal how EBV manipulates host STAT3 even before expression of viral oncogenes to facilitate cell survival and proliferation, processes fundamental to EBV lymphomagenesis. PMID- 24173213 TI - The cellular peptidyl-prolyl cis/trans isomerase Pin1 regulates reactivation of Kaposi's sarcoma-associated herpesvirus from latency. AB - Kaposi's sarcoma-associated herpesvirus (KSHV) causes Kaposi's sarcoma and primary effusion lymphoma. KSHV-infected cells are predominantly latent, with a subset undergoing lytic reactivation. Rta is the essential lytic switch protein that reactivates virus by forming transactivation-competent complexes with the Notch effector protein RBP-Jk and promoter DNA. Strikingly, Rta homolog analysis reveals that prolines constitute 17% of conserved residues. Rta is also highly phosphorylated in vivo. We previously demonstrated that proline content determines Rta homotetramerization and function. We hypothesize that proline directed modifications regulate Rta function by controlling binding to peptidyl prolyl cis/trans isomerases (PPIases). Cellular PPIase Pin1 binds specifically to phosphoserine- or phosphothreonine-proline (pS/T-P) motifs in target proteins. Pin1 dysregulation is implicated in myriad human cancers and can be subverted by viruses. Our data show that KSHV Rta protein contains potential pS/T-P motifs and binds directly to Pin1. Rta transactivation is enhanced by Pin1 at two delayed early viral promoters in uninfected cells. Pin1's effect, however, suggests a rheostat-like influence on Rta function. We show that in infected cells, endogenous Pin1 is active during reactivation and enhances Rta-dependent early protein expression induced by multiple signals, as well as DNA replication. Surprisingly, ablation of Pin1 activity by the chemical juglone or dominant negative Pin1 enhanced late gene expression and production of infectious virus, while ectopic Pin1 showed inhibitory effects. Our data thus suggest that Pin1 is a unique, dose-dependent molecular timer that enhances Rta protein function, but inhibits late gene synthesis and virion production, during KSHV lytic reactivation. PMID- 24173214 TI - The innate immune factor apolipoprotein L1 restricts HIV-1 infection. AB - Apolipoprotein L1 (APOL1) is a major component of the human innate immune response against African trypanosomes. Although the mechanism of the trypanolytic activity of circulating APOL1 has been recently clarified, the intracellular function(s) of APOL1 in human cells remains poorly defined. Like that of many genes linked to host immunity, APOL1 expression is induced by proinflammatory cytokines gamma interferon (IFN-gamma) and tumor necrosis factor alpha (TNF alpha). Additionally, IFN-gamma-polarized macrophages that potently restrict HIV 1 replication express APOL1, which suggests that APOL1 may contribute to HIV-1 suppression. Here, we report that APOL1 inhibits HIV-1 replication by multiple mechanisms. We found that APOL1 protein targeted HIV-1 Gag for degradation by the endolysosomal pathway. Interestingly, we found that APOL1 stimulated both endocytosis and lysosomal biogenesis by promoting nuclear localization of transcription factor EB (TFEB) and expression of TFEB target genes. Moreover, we demonstrated that APOL1 depletes cellular viral accessory protein Vif, which counteracts the host restriction factor APOBEC3G, via a pathway involving degradation of Vif in lysosomes and by secretion of Vif in microvesicles. As a result of Vif depletion by APOL1, APOBEC3G was not degraded and reduced infectivity of progeny virions. In support of this model, we also showed that endogenous expression of APOL1 in differentiated U937 monocytic cells stimulated with IFN-gamma resulted in a reduced production of virus particles. This finding supports the hypothesis that induction of APOL1 contributes to HIV-1 suppression in differentiated monocytes. Deciphering the precise mechanism of APOL1-mediated HIV-1 restriction may facilitate the design of unique therapeutics to target HIV 1 replication. PMID- 24173215 TI - Hemagglutinin receptor specificity and structural analyses of respiratory droplet transmissible H5N1 viruses. AB - Two ferret-adapted H5N1 viruses capable of respiratory droplet transmission have been reported with mutations in the hemagglutinin receptor-binding site and stalk domains. Glycan microarray analysis reveals that both viruses exhibit a strong shift toward binding to "human-type" alpha2-6 sialosides but with notable differences in fine specificity. Crystal structure analysis further shows that the stalk mutation causes no obvious perturbation of the receptor-binding pocket, consistent with its impact on hemagglutinin stability without affecting receptor specificity. PMID- 24173216 TI - Variation of two primate lineage-specific residues in human SAMHD1 confers resistance to N terminus-targeted SIV Vpx proteins. AB - Sterile alpha motif and HD domain-containing protein 1 (SAMHD1) restricts human immunodeficiency virus type 1 (HIV-1) infection in myeloid cells but is inactivated by certain classes of simian immunodeficiency virus (SIV) Vpx proteins. Vpx proteins recruit the DCAF1-CRL4 E3 ubiquitin ligase to trigger species-specific SAMHD1 degradation. Determinants of SIV Vpx-mediated primate SAMHD1 degradation have been mapped to its C terminus. In this study, we have identified the N terminus of human SAMHD1 as a major species-specific determinant of Vpx-mediated suppression. The SIVmnd2 and SIVrcm Vpx proteins recognize the N terminus of rhesus, but not human, SAMHD1. We have also demonstrated that variation of two primate lineage-specific residues between human and rhesus SAMHD1 proteins determine resistance to SIVmnd2 and SIVrcm Vpx proteins. These residues (Cys15 and Ser52) are sequentially mutated to Phe in different lineages of Old World monkeys. Consequently, SIVmnd2 and SIVrcm Vpx proteins that could recognize Phe15- and Phe52-containing SAMHD1 could not inactivate human SAMHD1, which contains Cys15 and Ser52. In contrast, SIVmac Vpx, which targets the C terminus of SAMHD1 molecules, could inactivate various primate SAMHD1 molecules with divergent C-terminal sequences. Both C terminus-targeted SIVmac Vpx and N terminus-targeted SIVrcm Vpx require DCAF1 for the induction of SAMHD1 degradation. The ability of SIV Vpx to restrict SAMHD1 among different primate species is a manifestation of the SAMHD1 evolutionary pattern among those species. PMID- 24173217 TI - Delayed sequelae of neonatal respiratory syncytial virus infection are dependent on cells of the innate immune system. AB - Infection with respiratory syncytial virus (RSV) in neonatal mice leads to exacerbated disease if mice are reinfected with the same virus as adults. Both T cells and the host major histocompatibility complex genotype contribute to this phenomenon, but the part played by innate immunity has not been defined. Since macrophages and natural killer (NK) cells play key roles in regulating inflammation during RSV infection of adult mice, we studied the role of these cells in exacerbated inflammation following neonatal RSV sensitization/adult reinfection. Compared to mice undergoing primary infection as adults, neonatally sensitized mice showed enhanced airway fluid levels of interleukin-6 (IL-6), alpha interferon (IFN-alpha), CXCL1 (keratinocyte chemoattractant/KC), and tumor necrosis factor alpha (TNF-alpha) at 12 to 24 h after reinfection and IL-4, IL-5, IFN-gamma, and CCL11 (eotaxin) at day 4 after reinfection. Weight loss during reinfection was accompanied by an initial influx of NK cells and granulocytes into the airways and lungs, followed by T cells. NK cell depletion during reinfection attenuated weight loss but did not alter T cell responses. Depletion of alveolar macrophages with inhaled clodronate liposomes reduced both NK and T cell numbers and attenuated weight loss. These findings indicate a hitherto unappreciated role for the innate immune response in governing the pathogenic recall responses to RSV infection. PMID- 24173218 TI - Autophagy benefits the replication of Newcastle disease virus in chicken cells and tissues. AB - Newcastle disease virus (NDV) is an important avian pathogen. We previously reported that NDV triggers autophagy in U251 glioma cells, resulting in enhanced virus replication. In this study, we investigated whether NDV triggers autophagy in chicken cells and tissues to enhance virus replication. We demonstrated that NDV infection induced steady-state autophagy in chicken-derived DF-1 cells and in primary chicken embryo fibroblast (CEF) cells, evident through increased double- or single-membrane vesicles, the accumulation of green fluorescent protein (GFP) LC3 dots, and the conversion of LC3-I to LC3-II. In addition, we measured autophagic flux by monitoring p62/SQSTM1 degradation, LC3-II turnover, and GFP LC3 lysosomal delivery and proteolysis, to confirm that NDV infection induced the complete autophagic process. Inhibition of autophagy by pharmacological inhibitors and RNA interference reduced virus replication, indicating an important role for autophagy in NDV infection. Furthermore, we conducted in vivo experiments and observed the conversion of LC3-I to LC3-II in heart, liver, spleen, lung, and kidney of NDV-infected chickens. Regulation of the induction of autophagy with wortmannin, chloroquine, or starvation treatment affects NDV production and pathogenesis in tissues of both lung and intestine; however, treatment with rapamycin, an autophagy inducer of mammalian cells, showed no detectable changes in chicken cells and tissues. Moreover, administration of the autophagy inhibitor wortmannin increased the survival rate of NDV-infected chickens. Our studies provide strong evidence that NDV infection induces autophagy which benefits NDV replication in chicken cells and tissues. PMID- 24173219 TI - Replication of oral BK virus in human salivary gland cells. AB - BK polyomavirus (BKPyV) is the most common viral pathogen among allograft patients. Increasing evidence links BKPyV to the human oral compartment and to HIV-associated salivary gland disease (HIVSGD). To date, few studies have analyzed orally derived BKPyV. This study aimed to characterize BKPyV isolated from throat wash (TW) samples from HIVSGD patients. The replication potential of HIVSGD-derived clinical isolates HIVSGD-1 and HIVSGD-2, both containing the noncoding control region (NCCR) architecture OPQPQQS, were assessed and compared to urine-derived virus. The BKPyV isolates displayed significant variation in replication potential. Whole-genome alignment of the two isolates revealed three nucleotide differences that were analyzed for a potential effect on the viral life cycle. Analysis revealed a negligible difference in NCCR promoter activity despite sequence variation and emphasized the importance of functional T antigen (Tag) for efficient replication. HIVSGD-1 encoded full-length Tag, underwent productive infection in both human salivary gland cells and kidney cells, and expressed viral DNA and Tag protein. Additionally, HIVSGD-1 generated DNase resistant particles and by far surpassed the replication potential of the kidney derived isolate in HSG cells. HIVSGD-2 encoded a truncated form of Tag and replicated much less efficiently. Quantitation of infectious virus, via the fluorescent forming unit assay, suggested that HIVSGD BKPyV had preferential tropism for salivary gland cells over kidney cells. Similarly, the results suggested that kidney-derived virus had preferential tropism for kidney cells over salivary gland cells. Evidence of HIVSGD-derived BKPyV oral tropism and adept viral replication in human salivary gland cells corroborated the potential link between HIVSGD pathogenesis and BKPyV. PMID- 24173220 TI - A novel cytotoxic sequence contributes to influenza A viral protein PB1-F2 pathogenicity and predisposition to secondary bacterial infection. AB - Enhancement of cell death is a distinguishing feature of H1N1 influenza virus A/Puerto Rico/8/34 protein PB1-F2. Comparing the sequences (amino acids [aa] 61 to 87 using PB1-F2 amino acid numbering) of the PB1-F2-derived C-terminal peptides from influenza A viruses inducing high or low levels of cell death, we identified a unique I68, L69, and V70 motif in A/Puerto Rico/8/34 PB1-F2 responsible for promotion of the peptide's cytotoxicity and permeabilization of the mitochondrial membrane. When administered to mice, a 27-mer PB1-F2-derived C terminal peptide with this amino acid motif caused significantly greater weight loss and pulmonary inflammation than the peptide without it (due to I68T, L69Q, and V70G mutations). Similar to the wild-type peptide, A/Puerto Rico/8/34 elicited significantly higher levels of macrophages, neutrophils, and cytokines in the bronchoalveolar lavage fluid of mice than its mutant counterpart 7 days after infection. Additionally, infection of mice with A/Puerto Rico/8/34 significantly enhanced the levels of morphologically transformed epithelial and immune mononuclear cells recruited in the airways compared with the mutant virus. In the mouse bacterial superinfection model, both peptide and virus with the I68, L69, and V70 sequence accelerated development of pneumococcal pneumonia, as reflected by increased levels of viral and bacterial lung titers and by greater mortality. Here we provide evidence suggesting that the newly identified cytotoxic sequence I68, L69, and V70 of A/Puerto Rico/8/34 PB1-F2 contributes to the pathogenesis of both primary viral and secondary bacterial infections. PMID- 24173221 TI - Hepatocyte nuclear factor 4alpha and downstream secreted phospholipase A2 GXIIB regulate production of infectious hepatitis C virus. AB - Hepatitis C virus (HCV) is a major cause of chronic hepatitis, liver cirrhosis, and hepatocellular carcinoma in humans. The life cycle of HCV is closely associated with the metabolism of lipids, especially very-low-density lipoprotein (VLDL) in hepatocytes. Hepatocyte nuclear factor 4alpha (HNF4alpha), the most abundant transcription factor in the liver, regulates the VLDL secretory pathway. However, the effects of HNF4alpha on the HCV life cycle are unclear. In this study, we investigated the regulatory effects of HNF4alpha on HCV assembly and secretion. HCV in HNF4alpha-deficient hepatocytes showed reduced assembly and secretion but unchanged entry and RNA replication. Bezafibrate, a chemical inhibitor of HNF4alpha, suppressed HCV assembly and secretion. HNF4alpha downregulation resulted in rearrangement of cytosolic lipid droplets (LDs), as evidenced by the aggregation of large LDs and distorted cytosolic distribution. Phospholipase A2 GXIIB (PLA2GXIIB), an HNF4alpha-regulated factor involved in VLDL secretion, was found to be crucial in HCV secretion. PLA2GXIIB expression was upregulated in hepatocytes harboring HCV subgenomic replicons or in HCV infected hepatocytes. This upregulation was transcriptionally controlled in an HNF4alpha-dependent manner after HCV infection. Furthermore, PLA2GXIIB combined with microsomal triglyceride transfer protein was found to be responsible for the regulation of HNF4alpha-induced HCV infectivity. These results suggest that HNF4alpha and its downstream PLA2GXIIB are important factors affecting the late stage of the HCV life cycle and may serve as potential drug targets for the treatment of HCV infection. PMID- 24173223 TI - Ultradeep pyrosequencing and molecular modeling identify key structural features of hepatitis B virus RNase H, a putative target for antiviral intervention. AB - Last-generation nucleoside/nucleotide analogues are potent against hepatitis B virus (HBV) and have a high barrier to resistance. However, delayed responses have been observed in patients previously exposed to other drugs of the same class, long-term resistance is possible, and cure of infection cannot be achieved with these therapies, emphasizing the need for alternative therapeutic approaches. The HBV RNase H represents an interesting target because its enzyme activity is essential to the HBV life cycle. The goal of our study was to characterize the structure of the HBV RNase H by computing a 3-dimensional molecular model derived from E. coli RNase H and analyzing 2,326 sequences of all HBV genotypes available in public databases and 958,000 sequences generated by means of ultradeep pyrosequencing of sequences from a homogenous population of 73 treatment-naive patients infected with HBV genotype D. Our data revealed that (i) the putative 4th catalytic residue displays unexpected variability that could be explained by the overlap of the HBx gene and has no apparent impact on HBV replicative capacity and that (ii) the C-helix-containing basic protrusion, which is required to guide the RNA/DNA heteroduplex into the catalytic site, is highly conserved and bears unique structural properties that can be used to target HBV specific RNase H inhibitors without cross-species activity. The model shows substantial differences from other known RNases H and paves the way for functional and structural studies as a prerequisite to the development of new inhibitors of the HBV cell cycle specifically targeting RNase H activity. PMID- 24173222 TI - Hepatitis C virus RNA replication and virus particle assembly require specific dimerization of the NS4A protein transmembrane domain. AB - Hepatitis C virus (HCV) NS4A is a single-pass transmembrane (TM) protein essential for viral replication and particle assembly. The sequence of the NS4A TM domain is highly conserved, suggesting that it may be important for protein protein interactions. To test this hypothesis, we measured the potential dimerization of the NS4A TM domain in a well-characterized two-hybrid TM protein interaction system. The NS4A TM domain exhibited a strong homotypic interaction that was comparable in affinity to glycophorin A, a well-studied human blood group antigen that forms TM homodimers. Several mutations predicted to cluster on a common surface of the NS4A TM helix caused significant reductions in dimerization, suggesting that these residues form an interface for NS4A dimerization. Mutations in the NS4A TM domain were further examined in the JFH-1 genotype 2a replicon system; importantly, all mutations that destabilized NS4A dimers also caused defects in RNA replication and/or virus assembly. Computational modeling of NS4A TM interactions suggests a right-handed dimeric interaction of helices with an interface that is consistent with the mutational effects. Furthermore, defects in NS4A oligomerization and virus particle assembly of two mutants were rescued by NS4A A15S, a TM mutation recently identified through forward genetics as a cell culture-adaptive mutation. Together, these data provide the first example of a functionally important TM dimer interface within an HCV nonstructural protein and reveal a fundamental role of the NS4A TM domain in coordinating HCV RNA replication and virus particle assembly. PMID- 24173224 TI - Sodium hydrogen exchangers contribute to arenavirus cell entry. AB - Several arenaviruses, chiefly Lassa virus (LASV), cause hemorrhagic fever (HF) disease in humans and pose a great public health concern in the regions in which they are endemic. Moreover, evidence indicates that the worldwide-distributed prototypic arenavirus lymphocytic choriomeningitis virus (LCMV) is a neglected human pathogen of clinical significance. The limited existing armamentarium to combat human-pathogenic arenaviruses underscores the importance of developing novel antiarenaviral drugs, a task that would be facilitated by the identification and characterization of virus-host cell factor interactions that contribute to the arenavirus life cycle. A genome-wide small interfering RNA (siRNA) screen identified sodium hydrogen exchanger 3 (NHE3) as required for efficient multiplication of LCMV in HeLa cells, but the mechanisms by which NHE activity contributed to the life cycle of LCMV remain unknown. Here we show that treatment with the NHE inhibitor 5-(N-ethyl-N-isopropyl) amiloride (EIPA) resulted in a robust inhibition of LCMV multiplication in both rodent (BHK-21) and human (A549) cells. EIPA-mediated inhibition was due not to interference with virus RNA replication, gene expression, or budding but rather to a blockade of virus cell entry. EIPA also inhibited cell entry mediated by the glycoproteins of the HF arenaviruses LASV and Junin virus (JUNV). Pharmacological and genetic studies revealed that cell entry of LCMV in A549 cells depended on actin remodeling and Pak1, suggesting a macropinocytosis-like cell entry pathway. Finally, zoniporide, an NHE inhibitor being explored as a therapeutic agent to treat myocardial infarction, inhibited LCMV propagation in culture cells. Our findings indicate that targeting NHEs could be a novel strategy to combat human pathogenic arenaviruses. PMID- 24173225 TI - Characterization of blockade antibody responses in GII.2.1976 Snow Mountain virus infected subjects. AB - Snow Mountain virus (GII.2.1976) is the prototype strain of GII.2 noroviruses (NoVs), which cause an estimated 8% of norovirus outbreaks, yet little is known about the immunobiology of these viruses. To define the human immune response induced by SMV infection and the antigenic relationship between different GII.2 strains that have circulated between 1976 and 2010, we developed a panel of four GII.2 variant virus-like particles (VLPs) and compared their antigenicities by enzyme immunoassay (EIA) and surrogate antibody neutralization (blockade) assays. Volunteers infected with GII.2.1976 developed a mean 167-fold increase in blockade response against the homotypic VLP by day 8 postchallenge. Blockade extended cross-genotype activity in some individuals but not cross-genogroup activity. Polyclonal sera from GII.2.1976-infected volunteers blocked GII.2.1976 significantly better than they blocked GII.2.2002, GII.2.2008, and GII.2.2010, suggesting that blockade epitopes within the GII.2 strains have evolved in the past decade. To potentially map these epitope changes, we developed mouse monoclonal antibodies (MAbs) against GII.2.1976 VLPs and compared their reactivities to a panel of norovirus VLPs. One MAb had broad cross-genogroup EIA reactivity to a nonblockade, linear, conserved epitope. Six MAbs recognized conformational epitopes exclusive to the GII.2 strains. Two MAbs recognized GII.2 blockade epitopes, and both blocked the entire panel of GII.2 variants. These data indicate that the GII.2 strains, unlike the predominant GII.4 strains, have undergone only a limited amount of evolution in blockade epitopes between 1976 and 2010 and indicate that the GII.2-protective component of a multivalent norovirus vaccine may not require frequent reformulation. PMID- 24173226 TI - The bacteriostatic protein lipocalin 2 is induced in the central nervous system of mice with west Nile virus encephalitis. AB - Lipocalin 2 (Lcn2) is a bacteriostatic factor produced during the innate immune response to bacterial infection. Whether Lcn2 has a function in viral infection is unknown. We investigated the regulation and function of Lcn2 in the central nervous system (CNS) of mice during West Nile virus (WNV) encephalitis. Lcn2 mRNA and protein were induced in the brain by day 5, and this induction increased further by day 7 postinfection but was delayed compared with the induction of the toll-like receptor 3 (TLR3) gene, retinoic acid-inducible gene 1 (RIG-I), and melanoma differentiation-associated protein 5 (MDA5) gene. The Lcn2 mRNA and protein were both found at high levels in the choroid plexus, vascular endothelium, macrophage/microglia, and astrocytes. However, some neuronal subsets contained Lcn2 protein but no detectable mRNA. In Lcn2 knockout (KO) mice, with the exception of CXC motif chemokine 5 (CXCL5), which was significantly more downregulated than in wild-type (WT) mice, expression levels of a number of other host response genes were similar in the two genotypes. The brain from Lcn2 and WT mice with WNV encephalitis contained similar numbers of infiltrating macrophages, granulocytes, and T cells. Lcn2 KO and WT mice had no significant difference in tissue viral loads or survival after infection with different doses of WNV. We conclude that Lcn2 gene expression is induced to high levels in a time-dependent fashion in a variety of cells and regions of the CNS of mice with WNV encephalitis. The function of Lcn2 in the host response to WNV infection remains largely unknown, but our data indicate that it is dispensable as an antiviral or immunoregulatory factor in WNV encephalitis. PMID- 24173227 TI - Analysis of serine codon conservation reveals diverse phenotypic constraints on hepatitis C virus glycoprotein evolution. AB - Serine is encoded by two divergent codon types, UCN and AGY, which are not interchangeable by a single nucleotide substitution. Switching between codon types therefore occurs via intermediates (threonine or cysteine) or via simultaneous tandem substitutions. Hepatitis C virus (HCV) chronically infects 2 to 3% of the global population. The highly variable glycoproteins E1 and E2 decorate the surface of the viral envelope, facilitate cellular entry, and are targets for host immunity. Comparative sequence analysis of globally sampled E1E2 genes, coupled with phylogenetic analysis, reveals the signatures of multiple archaic codon-switching events at seven highly conserved serine residues. Limited detection of intermediate phenotypes indicates that associated fitness costs restrict their fixation in divergent HCV lineages. Mutational pathways underlying codon switching were probed via reverse genetics, assessing glycoprotein functionality using multiple in vitro systems. These data demonstrate selection against intermediate phenotypes can act at the structural/functional level, with some intermediates displaying impaired virion assembly and/or decreased capacity for target cell entry. These effects act in residue/isolate-specific manner. Selection against intermediates is also provided by humoral targeting, with some intermediates exhibiting increased epitope exposure and enhanced neutralization sensitivity, despite maintaining a capacity for target cell entry. Thus, purifying selection against intermediates limits their frequencies in globally sampled strains, with divergent functional constraints at the protein level restricting the fixation of deleterious mutations. Overall our study provides an experimental framework for identification of barriers limiting viral substitutional evolution and indicates that serine codon-switching represents a genomic "fossil record" of historical purifying selection against E1E2 intermediate phenotypes. PMID- 24173228 TI - Type I interferon limits the capacity of bluetongue virus to infect hematopoietic precursors and dendritic cells in vitro and in vivo. AB - Hematopoietic stem cells (HSCs) give rise to progenitors with potential to produce multiple cell types, including dendritic cells (DCs). DCs are the principal antigen-presenting cells and represent the crucial link between innate and adaptive immune responses. Bluetongue virus (BTV), an economically important Orbivirus of the Reoviridae family, causes a hemorrhagic disease mainly in sheep and occasionally in other species of ruminants. BTV is transmitted between its mammalian hosts by certain species of biting midges (Culicoides spp.) and is a potent alpha interferon (IFN-alpha) inducer. In the present report, we show that BTV infects cells of hematopoietic origin but not HSCs in immunocompetent sheep. However, BTV infects HSCs in the absence of type I IFN (IFN-I) signaling in vitro and in vivo. Infection of HSCs in vitro results in cellular death by apoptosis. Furthermore, BTV infects bone marrow-derived DCs (BM-DCs), interfering with their development to mature DCs in the absence of type I IFN signaling. Costimulatory molecules CD80 and CD86 and costimulatory molecules CD40 and major histocompatibility complex class II (MHC-II) are affected by BTV infection, suggesting that BTV interferes with DC antigen-presenting capacity. In vivo, different DC populations are also affected during the course of infection, probably as a result of a direct effect of BTV replication in DCs and the production of infectious virus. These new findings suggest that BTV infection of HSCs and DCs can impair the immune response, leading to persistence or animal death, and that this relies on IFN-I. PMID- 24173229 TI - Sendai virus C proteins regulate viral genome and antigenome synthesis to dictate the negative genome polarity. AB - The order Mononegavirales comprises a large number of nonsegmented negative strand RNA viruses (NNSVs). How the genome polarity is determined is a central issue in RNA virus biology. Using a prototypic species, vesicular stomatitis virus (VSV), it has been established that the negative polarity of the viral genome is defined solely by different strengths of the cis-acting replication promoters located at the 3' ends of the genome and antigenome, resulting in the predominance of the genome over the antigenome. This VSV paradigm has long been applied for the Mononegavirales in general without concrete proof. We now found that another prototypic species, Sendai virus (SeV), undergoes a marked shift from the early antigenome-dominant to the late genome-dominant phase during the course of infection. This shift appeared to be governed primarily by the expression of the accessory C protein, because no such shift occurred in a recombinant SeV with the C gene deleted, and antigenomes were dominant throughout infection, generating antigenome-dominant and noninfectious progeny virions. Therefore, we proposed for the first time a trans-regulatory mechanism, the SeV paradigm, to dictate the genome polarity of an NNSV. A series of promoter-swapped SeV recombinants suggested the importance of the primary as well as secondary structures of the promoters in this trans-regulation. PMID- 24173230 TI - Immunosuppression facilitates the reactivation of latent papillomavirus infections. AB - At mucosal sites, papillomavirus genomes can persist in the epithelial basal layer following immune-mediated regression. Subsequent T-cell depletion stimulates a 3- to 5-log increase in the viral copy number, to levels associated with productive infection. Reappearance of microlesions was rare within the short time frame of our experiments but was observed in one instance. Our studies provide direct evidence that immunosuppression can trigger the reactivation of latent papillomavirus genomes, as previously proposed in humans. PMID- 24173231 TI - Herpes simplex virus 1 protein kinase Us3 phosphorylates viral dUTPase and regulates its catalytic activity in infected cells. AB - Us3 is a serine-threonine protein kinase encoded by herpes simplex virus 1 (HSV 1). In this study, a large-scale phosphoproteomic analysis of titanium dioxide affinity chromatography-enriched phosphopeptides from HSV-1-infected cells using high-accuracy mass spectrometry (MS) and subsequent analyses showed that Us3 phosphorylated HSV-1-encoded dUTPase (vdUTPase) at serine 187 (Ser-187) in HSV-1 infected cells. Thus, the following observations were made. (i) In in vitro kinase assays, Ser-187 in the vdUTPase domain was specifically phosphorylated by Us3. (ii) Phosphorylation of vdUTPase Ser-187 in HSV-1-infected cells was detected by phosphate-affinity polyacrylamide gel electrophoresis analyses and was dependent on the kinase activity of Us3. (iii) Replacement of Ser-187 with alanine (S187A) in vdUTPase and an amino acid substitution in Us3 that inactivated its kinase activity significantly downregulated the enzymatic activity of vdUTPase in HSV-1-infected cells, whereas a phosphomimetic substitution at vdUTPase Ser-187 restored the wild-type enzymatic activity of vdUTPase. (iv) The vdUTPase S187A mutation as well as the kinase-dead mutation in Us3 significantly reduced HSV-1 replication in human neuroblastoma SK-N-SH cells at a multiplicity of infection (MOI) of 5 but not at an MOI of 0.01, whereas the phosphomimetic substitution at vdUTPase Ser-187 restored the wild-type viral replication at an MOI of 5. In contrast, these mutations had no effect on HSV-1 replication in Vero and HEp-2 cells. Collectively, our results suggested that Us3 phosphorylation of vdUTPase Ser-187 promoted HSV-1 replication in a manner dependent on cell types and MOIs by regulating optimal enzymatic activity of vdUTPase. PMID- 24173232 TI - Apolipoprotein E codetermines tissue tropism of hepatitis C virus and is crucial for viral cell-to-cell transmission by contributing to a postenvelopment step of assembly. AB - Hepatitis C virus (HCV) predominantly infects human hepatocytes, although extrahepatic virus reservoirs are being discussed. Infection of cells is initiated via cell-free and direct cell-to-cell transmission routes. Cell type specific determinants of HCV entry and RNA replication have been reported. Moreover, several host factors required for synthesis and secretion of lipoproteins from liver cells, in part expressed in tissue-specific fashion, have been implicated in HCV assembly. However, the minimal cell type-specific requirements for HCV assembly have remained elusive. Here we report that production of HCV trans-complemented particles (HCVTCP) from nonliver cells depends on ectopic expression of apolipoprotein E (ApoE). For efficient virus production by full-length HCV genomes, microRNA 122 (miR-122)-mediated enhancement of RNA replication is additionally required. Typical properties of cell culture-grown HCV (HCVcc) particles from ApoE-expressing nonliver cells are comparable to those of virions derived from human hepatoma cells, although specific infectivity of virions is modestly reduced. Thus, apolipoprotein B (ApoB), microsomal triglyceride transfer protein (MTTP), and apolipoprotein C1 (ApoC1), previously implicated in HCV assembly, are dispensable for production of infectious HCV. In the absence of ApoE, release of core protein from infected cells is reduced, and production of extracellular as well as intracellular infectivity is ablated. Since envelopment of capsids was not impaired, we conclude that ApoE acts after capsid envelopment but prior to secretion of infectious HCV. Remarkably, the lack of ApoE also abrogated direct HCV cell-to cell transmission. These findings highlight ApoE as a host factor codetermining HCV tissue tropism due to its involvement in a late assembly step and viral cell to-cell transmission. PMID- 24173233 TI - Exposure to mimivirus collagen promotes arthritis. AB - Collagens, the most abundant proteins in animals, also occur in some recently described nucleocytoplasmic large DNA viruses such as Mimiviridae, which replicate in amoebae. To clarify the impact of viral collagens on the immune response of animals exposed to Mimiviridae, we have investigated the localization of collagens in Acanthamoeba polyphaga mimivirus particles and the response of mice to immunization with mimivirus particles. Using protein biotinylation, we have first shown that viral collagen encoded by open reading frame L71 is present at the surface of mimivirus particles. Exposure to mimivirus collagens elicited the production of anti-collagen antibodies in DBA/1 mice immunized intradermally with mimivirus protein extracts. This antibody response also targeted mouse collagen type II and was accompanied by T-cell reactivity to collagen and joint inflammation, as observed in collagen-induced arthritis following immunization of mice with bovine collagen type II. The broad distribution of nucleocytoplasmic large DNA viruses in the environment suggests that humans are constantly exposed to such large virus particles. A survey of blood sera from healthy human subjects and from rheumatoid arthritis patients indeed demonstrated that 30% of healthy subject and 36% of rheumatoid arthritis sera recognized the major mimivirus capsid protein L425. Moreover, whereas 6% of healthy-subject sera recognized the mimivirus collagen protein L71, 22% of rheumatoid arthritis sera were positive for mimivirus L71. Accordingly, our study shows that environmental exposure to mimivirus represents a risk factor in triggering autoimmunity to collagens. PMID- 24173234 TI - Rodent herpesvirus Peru encodes a secreted chemokine decoy receptor. AB - Viruses have long been studied not only for their pathology and associated disease but also as model systems for understanding cellular and immunological processes. Rodent herpesvirus Peru (RHVP) is a recently characterized rhadinovirus related to murine gammaherpesvirus 68 (MHV68) and Kaposi's sarcoma associated herpesvirus (KSHV) that establishes acute and latent infection in laboratory mice. RHVP encodes numerous unique proteins that we hypothesize might facilitate host immune evasion during infection. We report here that open reading frame (ORF) R17 encodes a high-affinity chemokine binding protein that broadly recognizes human and murine CC and C chemokines. The interaction of R17 with chemokines is generally characterized by rapid association kinetics, and in the case of CCL3, CCL4, CCL5, CCL24, and XCL1, extremely stable complexes are formed. Functionally, R17 potently inhibited CCL2-driven chemotaxis of the human monocytic cell line THP-1, CCL3-driven chemotaxis of peripheral blood mononuclear cells, and CCL2-mediated calcium flux. Our studies also reveal that R17 binds to glycosaminoglycans (GAGs) in a process dependent upon two BBXB motifs and that chemokine and GAG binding can occur simultaneously at distinct sites. Collectively, these studies suggest that R17 may play a role in RHVP immune evasion through the targeted sabotage of chemokine-mediated immune surveillance. PMID- 24173236 TI - Solid-state NMR in the analysis of drugs and naturally occurring materials. AB - This article presents some of the solid-state NMR (SSNMR) techniques used in the pharmaceutical and biomedical research. Solid-state magic angle spinning (MAS) NMR provides structural information on powder amorphous solids for which single crystal diffraction structures cannot be obtained. NMR is non-destructive; the powder sample may be used for further studies. Quantitative results can be obtained, although solid-state NMR spectra are not normally quantitative. As compared with other techniques, MAS NMR is insensitive and requires a significant amount of the powder sample (2-100mg) to fill the 1.3-7 mm ZrO2 rotor. This is its main drawback, since natural compounds isolated from plants, microorganisms or cell cultures are difficult to obtain in quantities higher than a few milligrams. Multinuclear MAS NMR routinely uses (1)H and (13)C nuclei, less frequently (15)N, (19)F, (31)P, (77)Se, (29)Si, (43)Ca or (23)Na. The article focuses on the pharmaceutical applications of SSNMR, the studies were aimed to control over manufacturing processes (e.g. crystallization and milling) investigation of chemical and physical stability of solid forms both as pure drug and in a formulated product. SSNMR is used in combination with some other analytical methods (DSC, XRD, FT-IR) and theoretical calculations of NMR parameters. Biologically active compounds, such as amino acids and small peptides, steroids and flavonoids were studied by SSNMR methods (part 4) providing valuable structural information. The SSNMR experiments performed on biopolymers and large natural products like proteins, cellulose and lipid layers are commented upon briefly in part 5. PMID- 24173235 TI - Reselection of a genomic upstream open reading frame in mouse hepatitis coronavirus 5'-untranslated-region mutants. AB - An AUG-initiated upstream open reading frame (uORF) encoding a potential polypeptide of 3 to 13 amino acids (aa) is found within the 5' untranslated region (UTR) of >75% of coronavirus genomes based on 38 reference strains. Potential CUG-initiated uORFs are also found in many strains. The AUG-initiated uORF is presumably translated following genomic 5'-end cap-dependent ribosomal scanning, but its function is unknown. Here, in a reverse-genetics study with mouse hepatitis coronavirus, the following were observed. (i) When the uORF AUG initiating codon was replaced with a UAG stop codon along with a U112A mutation to maintain a uORF-harboring stem-loop 4 structure, an unimpaired virus with wild type (WT) growth kinetics was recovered. However, reversion was found at all mutated sites within five virus passages. (ii) When the uORF was fused with genomic (main) ORF1 by converting three in-frame stop codons to nonstop codons, a uORF-ORF1 fusion protein was made, and virus replicated at WT levels. However, a frameshifting G insertion at virus passage 7 established a slightly 5'-extended original uORF. (iii) When uAUG-eliminating deletions of 20, 30, or 51 nucleotides (nt) were made within stem-loop 4, viable but debilitated virus was recovered. However, a C80U mutation in the first mutant and an A77G mutation in the second appeared by passage 10, which generated alternate uORFs that correlated with restored WT growth kinetics. In vitro, the uORF-disrupting nondeletion mutants showed enhanced translation of the downstream ORF1 compared with the WT. These results together suggest that the uORF represses ORF1 translation yet plays a beneficial but nonessential role in coronavirus replication in cell culture. PMID- 24173237 TI - MiR-205 is progressively down-regulated in lymph node metastasis but fails as a prognostic biomarker in high-risk prostate cancer. AB - The treatment of high-risk prostate cancer (HRPCa) is a tremendous challenge for uro-oncologists. The identification of predictive moleculobiological markers allowing risk assessment of lymph node metastasis and systemic progression is essential in establishing effective treatment. In the current study, we investigate the prognostic potential of miR-205 in HRPCa study and validation cohorts, setting defined clinical endpoints for both. We demonstrate miR-205 to be significantly down-regulated in over 70% of the HRPCa samples analysed and that reconstitution of miR-205 causes inhibition of proliferation and invasiveness in prostate cancer (PCa) cell lines. Additionally, miR-205 is increasingly down-regulated in lymph node metastases compared to the primary tumour indicating that miR-205 plays a role in migration of PCa cells from the original location into extraprostatic tissue. Nevertheless, down-regulation of miR-205 in primary PCa was not correlated to the synchronous presence of metastasis and failed to predict the outcome for HRPCa patients. Moreover, we found a tendency for miR-205 up-regulation to correlate with an adverse outcome of PCa patients suggesting a pivotal role of miR-205 in tumourigenesis. Overall, we showed that miR-205 is involved in the development and metastasis of PCa, but failed to work as a useful clinical biomarker in HRPCa. These findings might have implications for the use of miR-205 as a prognostic or therapeutic target in HRPCa. PMID- 24173238 TI - Glycosyltransferase GLT8D2 positively regulates ApoB100 protein expression in hepatocytes. AB - Non-alcoholic fatty liver disease (NAFLD) is characterized by triglyceride (TG) accumulation in hepatocytes. Very low density lipoprotein (VLDL) is a major secretory product of the liver that transports endogenously synthesized TG. Disrupted VLDL secretion may contribute to the accumulation of TG in hepatocytes. ApoB100 (apolipoprotein B100) is a glycoprotein and an essential protein component of VLDL. Its glycosylation may affect VLDL assembly and secretion. However, which glycosyltransferase catalyzes apoB100 glycosylation is unknown. In this study, we cloned the GLT8D2 (glycosyltransferase 8 domain containing 2) gene from HepG2 cells and generated a series of plasmids for in vitro studies of its molecular functions. We discovered that GLT8D2 was localized in the ER, interacted with apoB100, and positively regulated the levels of apoB100 protein in HepG2 cells. Based on these results, we propose that GLT8D2 is a glycosyltransferase of apoB100 that regulates apoB100 levels in hepatocytes. PMID- 24173239 TI - Cosmetic appreciation of lateralization of peripheral facial palsy: 'preference for left or right, true or mirror image?'. AB - There have been several studies in the past depicting asymmetry in 'normal' human faces. Evidence supports the fact that the right hemisphere is superior in the recognition of emotions expressed by the human face and indicates a right hemispheric specialization for processing emotional information. The primary aim of this study is to determine whether there is a difference in cosmetic appreciation of a left peripheral facial palsy compared to a right peripheral facial palsy? Pictures of patients with a facial palsy with House-Brackmann II-VI were reversed as a mirror image and offered as a pair of pictures, together with the true image. Forty-two patients and 24 medical professionals familiar with facial palsy were asked to choose the most attractive photograph. The primary 'end' point was the most attractive side in the pictures chosen by medical professionals and patients. The secondary 'end' points consisted of the preferences for the mirror or true image, and influences of the House-Brackmann score and age. Medical professionals preferred the photographs from patients with a right and left peripheral facial palsy (PFP) in, respectively, a mean of 44 % (41-48 %) and 56 % (52-59 %) of the pictures (p = 0.02). When comparing mirror and true image, patients with a left-sided facial palsy chose their mirror and true image as most attractive in 90 and 10 %, respectively (p < 0.05). Patients with a right-sided facial palsy chose their mirror and true image in 30 and 70 %, respectively (p > 0.05). Subanalysis of patients with a PFP House-Brackmann score V and VI showed that medical professionals did not have a significant preference for a left nor right-sided facial palsy. Patients with a left-sided facial palsy chose their mirror image in all cases and patients with a right-sided palsy chose their mirror and true image in resp. 33 and 67 %. The House-Brackmann score (p = 0.52) and age (p = 0.73) of the patients did not influence preferences. This study, demonstrating that medical professionals find a right-sided facial palsy cosmetically less attractive than a left-sided, has clinical relevance. Patients, especially with a left-sided facial palsy, tend to choose for their mirror image, although this choice seems to be influenced by hemispheric specialization and familiarity. PMID- 24173240 TI - Inflammatory factor-specific sumoylation regulates NF-kappaB signalling in glomerular cells from diabetic rats. AB - OBJECTIVE: The activation of nuclear factor (NF)-kappaB by cytokines under hyperglycaemic conditions is a potential mechanism for complications in diabetes. We investigated whether small ubiquitin-like modifier 4 (SUMO4) regulates renal NF-kappaB signalling in diabetic rats. METHODS: Histological changes in kidney were analysed in diabetic GK rats. The expressions of tumour necrosis factor (TNF)-alpha, NF-kappaB (p65), IkappaBalpha and SUMO4 in renal tissues were examined by immunohistochemistry and Western blotting. Primary cultured glomerular endothelial cells from rats were stimulated by TNF-alpha or interleukin (IL)-2. RESULTS: The renal expression of TNF-alpha, NF-kappaB (p65), IkappaBalpha and SUMO4 was significantly higher in diabetic GK rats than in control rats. In control rats, no nuclear translocation was observed for IkappaBalpha or NF-kappaB (p65). However, in diabetic GK rats, translocation of NF-kappaB (p65) and IkappaBalpha into the nucleus was observed, and the expression of SUMO4 and IkappaBalpha was up-regulated in the glomerular endothelial cells. SUMO4 was localised in both the cytoplasm and nucleus, while IkappaBalpha was predominantly located in the nucleus after stimulation with TNF alpha. In contrast, SUMO4 was localised in the nucleus, and increased cytoplasm SUMO4 localisation was found after stimulation with IL-2. CONCLUSIONS: SUMO4 plays a role in regulating NF-kappaB signalling in glomerular cells. Cytokines have a unique effect in regulating the sumoylation of NF-kappaB. PMID- 24173242 TI - Resistance of transgenic silkworm to BmNPV could be improved by silencing ie-1 and lef-1 genes. AB - RNA interference (RNAi)-mediated viral inhibition has been used in several organisms for improving viral resistance. In the present study, we reported the use of transgenic RNAi in preventing Bombyx mori nucleopolyhedrovirus (BmNPV) multiplication in the transgenic silkworm B. mori. We targeted the BmNPV immediate-early-1 (ie-1) and late expression factor-1 (lef-1) genes in the transiently transfected BmN cells, in the stable transformed BmN cell line and in the transgenic silkworms. We generated four piggyBac-based vectors containing short double-stranded ie-1 RNA (sdsie-1), short double-stranded lef-1 RNA (sdslef 1), long double-stranded ie-1 RNA (ldsie-1) and both sdsie-1 and sdslef-1 (sds ie1-lef1) expression cassettes. Strong viral repression was observed in the transiently transfected cells and in the stable transformed BmN cells transfected with sds-ie-1, sdslef-1, ldsie-1 or sds-ie-lef. The decrease of ie-1 mRNA level in the sds-ie1-lef1 transiently transfected cells was most obvious among the cells transfected with different vectors. The inhibitory effect of viral multiplication was decreased in a viral dose-dependent manner; the infection ratio of transfected cells for sds-ie-1, sdslef-1, ldsie-1 and sds-ie-lef decreased by 18.83%, 13.73%, 6.93% and 30.63%, respectively, compared with control cells 5 days after infection. We generated transgenic silkworms using transgenic vector piggyantiIE-lef1-neo with sds-ie1-lef1 expression cassette; the fourth instar larvae of transgenic silkworms of generation G5 exhibited stronger resistance to BmNPV, the mortalities for the transgenic silkworms and control silkworms were 60% and 100%, respectively, at 11 days after inoculation with BmNPV (10(6) occlusion bodies per ml). These results suggest that double-stranded RNA expression of essential genes of BmNPV is a feasible method for breeding silkworms with a high antiviral capacity. PMID- 24173241 TI - Role of Angptl4 in vascular permeability and inflammation. AB - BACKGROUND: Angptl4 is a secreted protein involved in the regulation of vascular permeability, angiogenesis, and inflammatory responses in different kinds of tissues. Increases of vascular permeability and abnormality changes in angiogenesis contribute to the pathogenesis of tumor metastasis, ischemic reperfusion injury. Inflammatory response associated with Angptl4 also leads to minimal change glomerulonephritis, wound healing. However, the role of Angptl4 in vascular permeability, angiogenesis, and inflammation is controversy. Hence, an underlying mechanism of Angptl4 in different kind of tissues needs to be further clarified. METHODS: Keywords such as angptl4, vascular permeability, angiogenesis, inflammation, and endothelial cells were used in search tool of PUBMED, and then the literatures associated with Angptl4 were founded and read. RESULTS: Data have established Angptl4 as the key modulator of both vascular permeability and angiogenesis; furthermore, it may also be related to the progression of metastatic tumors, cardiovascular events, and inflammatory diseases. This view focuses on the recent advances in our understanding of the role of Angptl4 in vascular permeability, angiogenesis, inflammatory signaling and the link between Angptl4 and multiple diseases such as cancer, cardiovascular diseases, diabetic retinopathy, and kidney diseases. CONCLUSIONS: Taken together, Angptl4 modulates vascular permeability, angiogenesis, inflammatory signaling, and associated diseases. The use of Angptl4-modulating agents such as certain drugs, food constituents (such as fatty acids), nuclear factor (such as PPARalpha), and bacteria may treat associated diseases such as tumor metastasis, ischemic-reperfusion injury, inflammation, and chronic low-grade inflammation. However, the diverse physiological functions of Angptl4 in different tissues can lead to potentially deleterious side effects when used as a therapeutic target. In this regard, a better understanding of the underlying mechanisms for Angptl4 in different tissues is necessary. PMID- 24173243 TI - Expression of major histocompatibility complex class I-related chain A/B (MICA/B) in pancreatic carcinoma. AB - Major histocompatibility complex class I-related chain A and B (MICA/B) are two stress-inducible ligands that bind to the immunoreceptor NKG2D and play an important role in mediating cytotoxicity of NK and T cells. Release of MIC molecules from the cell surface is thought to constitute an immune escape mechanism of tumor cells and thus could be associated with more aggressive course of tumor growth. In this study, we investigated the expression of MICA/B in ductal pancreatic carcinoma and serum in relation to tumor stage, differentiation and survival. MICA/B expression in tumor tissues and sera from patients with pancreatic cancer were analyzed by immunohistochemical staining (IHC), western blotting and ELISA, respectively. MICA/B expression was present in 17 of 22 (77%) of the tumors but not in normal pancreatic ductal epithelial cells. Poorly differentiated tumors showed more pronounced MICA/B expression compared to differentiated tumors, but did not correlate significantly to other tumor characteristics. MICA/B-negative tumors displayed significantly lower incidence of lymph node metastases (p<0.01), and less mortality within 3 years following resection (p<0.02). In conclusion, tissue levels of MICA/B expression were elevated in pancreatic cancer cells without elevated levels in serum, despite well-recognized acute phase reactants in serum. Poorly differentiated tumors showed high MICA/B expression, which was related to extended tumor lymph node metastases and less frequent long-term survival. PMID- 24173244 TI - Venous thromboembolism after trauma: when do children become adults? AB - IMPORTANCE: No national standardized guidelines exist to date for venous thromboembolism (VTE) prophylaxis after pediatric trauma. While the risk of VTE after trauma is generally lower for children than for adults, the precise age at which the risk of VTE increases is not clear. OBJECTIVE: To identify the age at which the risk of VTE after trauma increases from the low rate seen in children toward the higher rate seen in adults. DESIGN, SETTING, AND PARTICIPANTS: Multivariable logistic regression models were used to estimate the association between age and the odds of VTE when adjusting for other VTE risk factors. Participants included 402 329 patients 21 years or younger who were admitted following traumatic injury between January 1, 2008, and December 31, 2010, at US trauma centers participating in the National Trauma Data Bank. MAIN OUTCOMES AND MEASURES: Diagnosis of VTE as a complication during hospital admission. RESULTS: Venous thromboembolism was diagnosed in 1655 patients (0.4%). Those having VTE were more severely injured compared with those not having VTE and more frequently required critical care, blood transfusion, central line placement, mechanical ventilation, and surgery. The risk of VTE was low among younger patients, occurring in 0.1% of patients 12 years or younger, but increased to 0.3% in patients aged 13 to 15 years and to 0.8% in patients 16 years or older. These findings remained when adjusting for other factors, with patients aged 13 to 15 years (adjusted odds ratio, 1.96, 95% CI 1.53-2.52; P < .001) and patients aged 16 to 21 years (adjusted odds ratio, 3.77; 95% CI, 3.00-4.75; P < .001) having a significantly higher odds of being diagnosed as having VTE compared with patients aged 0 to 12 years. These findings were consistent across the level of injury severity and the type of trauma center. CONCLUSIONS AND RELEVANCE: The risk of VTE varies considerably across patient age and increases most dramatically at age 16 years, after a smaller increase at age 13 years. These findings can be used to guide future research into the development of standardized guidelines for VTE prophylaxis after pediatric trauma. PMID- 24173245 TI - Effect of PDGF-BB, IGF-I growth factors and their combination carried by liposomes in tooth socket healing. AB - This work evaluated the bone-forming potential of the platelet-derived growth factor isoform BB (PDGF-BB), insulin-like growth factor I (IGF-I), and mixed PDGF BB/IGF-I delivered in liposomes compared with phosphate buffered saline (PBS), in the healing process of rat tooth sockets. One hundred and twelve Wistar rats were randomized into 7 groups of 16 animals each and were evaluated at 3, 7, 14 and 21 days after extraction of the maxillary second molars. The left sockets were treated with PBS (P), empty liposome (L), IGF-I in PBS (IP), IGF-I in liposome (IL), PDGF-BB in PBS (PDP), PDGF-BB in liposome (PDL) and both growth factors (GFs) together within liposomes (PDIL). The right sockets were filled with blood clot (BC). Histological and histomorphometric analyses were used to evaluate the formation of new bone and blood vessels. Immunohistochemistry was performed to evaluate the expression of osteocalcin and vascular endothelial growth factor (VEGF) during bone repair. Data were tested statistically using a Tukey's test according to a Dunn's analysis and Mann-Whitney U test followed by Kruskal-Wallis one-way analysis. Results were considered significant when p<0.05. A significantly higher percentage of bone trabeculae and a higher number of blood vessels were observed in the IL, PDL and PDIL groups (p<0.05). However, these GF liposome groups had statistically similar results. Immunohistochemical assays first detected osteocalcin and VEGF expression at 3 days followed by a peak at 7 days. Lower immunoreactivity levels were observed in the BC, L, P, IP and PDP groups compared with the IL, PDL and PDIL groups (p<0.05). The results suggest that GFs carried by liposomes, either in isolated or mixed forms, enhanced the healing process in rat tooth sockets. The differential expression of the osteogenic markers VEGF and osteocalcin in the early phases of bone healing support these findings. PMID- 24173246 TI - Effect of low-level laser therapy (lambda660 nm) on angiogenesis in wound healing: a immunohistochemical study in a rodent model. AB - The aim of the present investigation was to evaluate the angiogenesis on dorsal cutaneous wounds in a rodent model treated with lambda660 nm laser light. New vessel formation is a multistep process involving vessel sprouting, endothelial cell migration, proliferation and tube formation. Although several in vivo studies have shown that laser phototherapy influences tissue repair, a fully understanding of angiogenesis mechanisms are not yet known. Twenty-four young adult male Wistar rats weighing between 200 and 250 g were used. Under general anesthesia, one excisional wound was created on the dorsum of each animal and they were randomly distributed into two groups: one control and one treated with laser (lambda660 nm, 16 mW, 10 J/cm2). Each group was subdivided into three subgroups according to the animal death timing (2, 4 and 6 days). Laser irradiation started immediately after surgery and was repeated every other day during the experiment and marked with Sirius Red, specific for collagen, and immunomarked with anti-TGF-beta and anti-von Willebrand factor. Marked sections underwent histological analysis by light microscopy and the mean area of the wound of each animal was calculated and analyzed by ANOVA and Tukey's test (alpha=0.05). Although at some death periods, collagen expression and number of blood vessels on irradiated animals were higher than in the control ones, no significant differences were found at any time in relation to TGF-beta expression (p>0.05). It was concluded that laser treatment (lambda660 nm) contributed to increase angiogenesis. PMID- 24173247 TI - Morphological changes of condyles and Helkimo clinical dysfunction index in patients treated with Herbst--orthodontic appliance. AB - This study evaluated the morphological changes in the temporomandibular joint (TMJ) condyles and calculated the Helkimo clinical dysfunction index (CDI) in adolescents with Class II Division 1 malocclusion and mandibular retrognathism treated with the Herbst appliance (phase I) and fixed orthodontic appliances (phase II). Thirty-two consecutive adolescents underwent phase I, and 23 completed phase II. The TMJs were evaluated qualitatively using magnetic resonance imaging (MRI) at the beginning of treatment (T1), during phase I (T2), at the end of phase I (T3) and at the end of phase II (T4). The CDI was calculated at T1, T3 and T4. From T1 to T3 (p=0.326), there were no changes in condyle morphology in 86.0% of the TMJs. From T3 to T4 (p<0.05) and T1 to T4 (p<0.05), changes occurred in 39.1% and 43.4% of the condyles. No significant changes in CDI occurred from T1 to T3, T3 to T4 and T1 to T4 (p=1.000; 86.6%, 76.2% and 76.2% concordance). After phase I, there were practically no changes in condyle morphology. At the end of phase II, a mild flattening was observed in some condyles. It may be concluded that no significant changes occurred in CDI after both treatment phases. PMID- 24173248 TI - Effect of finish line on marginal fit of sintered gold copings. AB - The aim of this study was to evaluate the vertical marginal gap of sintered gold copings and metal-ceramic crowns with different finish line preparations: a beveled round shoulder (BRS) and a beveled long chamfer (BLC), testing the null hypotheses that there are no differences in marginal gap regardless of finish line and phase of restoration (coping or crown). Stainless steel master models were fabricated to simulate tooth preparation for metal-ceramic crowns with different finish lines (BRS and BLC). Ten dies were obtained from each model. Preparations were coated with 2 layers of spacer to 1 mm from the margin. Sintercast gold copings were prepared, sintered and adjusted to the dies. The copings (n=10) were placed onto the master model and the marginal gap was measured in 24 equidistant points using optical microscopy (X230). An opaque and two body ceramic layers were subsequently applied to the copings and the same measuring procedure was performed for the crowns. The data were analyzed statistically using paired and unpaired Student's t-test (alpha=0.05). Mean marginal gap values (um) for the copings and crowns were, respectively: 113.6 and 117.1 for the BRS; and 58.2 and 74.3 for the BLC preparation. Significantly greater marginal gaps (p=0.0307) were found for restorations with BRS than with BLC finish line, which also showed statistically significant differences in the gap size between coping and crown (p=0.001). In conclusion, marginal gap is influenced by ceramic application on copings fabricated on BLC preparation, and greater marginal gaps were found for restorations with BRS finish line, rejecting the experimental null hypotheses. PMID- 24173249 TI - Influence of volume and activation mode on polymerization shrinkage forces of resin cements. AB - The concern with the polymerization shrinkage of restorative resin composites also applies to resin cements. The aim of this study was to evaluate the influence of volume and polymerization mode on forces generated during polymerization shrinkage (FGPS) of resin cements. Two light-cured resin cements- Variolink II (VL; Ivoclar Vivadent) and Nexus 3 (NX; Kerr)--and two self-cured resin cements - Multilink (ML; Ivoclar Vivadent) and Cement Post (CP; Angelus) - were inserted between two rectangular steel bases (6x2 mm) with distance set at 0.1, 0.3 and 0.5 mm, establishing a variation of volume. These steel bases were attached to a universal test machine with 50 kg load cell and forces (N) were registered for 10 min. Values of maximum forces generated by each material were subjected to two-way ANOVA and Tukey's test for individual comparisons (alpha=0.05). VL, NX and CP developed increasing FGPS as the volume of material increased, while ML presented the opposite behavior. It may be concluded that higher volume increases FGPS even with a concomitant decrease of C-factor, unless the resin cements present lower force generation rates as a function of time in combination with a low C-factor, resulting in stress relief and consequently lower values of FGPS. PMID- 24173250 TI - Bond durability of Er:YAG laser-prepared primary tooth enamel. AB - This study evaluated in vitro the influence of thermocycling and water storage (WS) on the shear bond strength (SBS) of composite resin in cavities prepared in primary tooth enamel with conventional bur or Er:YAG laser. The test surfaces were obtained from 48 primary molars and randomly assigned to 2 groups (n=24), according to cavity preparation: A: bur-preparation and B: Er:YAG laser irradiation. The specimens were restored with an etch-and-rinse adhesive system and composite resin. Each group was divided into 4 subgroups (n=6) according to WS duration and number of thermal cycles (TCs): I: 24 h WS/no thermocycling; II: 7 days WS/500 TCs; III: 1 month WS/2,000 TCs; IV: 6 months WS/12,000 TCs. The specimens were tested to failure in shear strength at a crosshead speed of 0.5 mm/min. Data were analyzed statistically by two-way ANOVA and Tukey's test. SBS means (S.D.) in MPa were: AI: 17.45 (2.03), AII:16.38 (1.49), AIII: 6.88 (0.66), AIV: 7.77 (1.53), BI: 12.32 (0.99), BII: 15.37 (2.24), BIII: 15.05 (2.01) and BIV 5.51 (1.01). WS duration and number of TCs influenced significantly the SBS values only for BIV (p<0.05). AI presented the highest SBS value, which was statistically similar to those of AII, BII and BIII. In conclusion, the adhesion of an etch-and-rinse adhesive to Er:YAG laser-irradiated primary tooth enamel was affected by the methods used to simulate degradation of the adhesive interface only when 6 months WS/12,000 TCs were employed. PMID- 24173251 TI - Effect of replacing a component of a self-etch adhesive by chlorhexidine on bonding to dentin. AB - The purpose of this study was to evaluate the effect of replacing a component of the self-etch adhesive Adper Scotchbond SE (liquid A + liquid B) by 2% chlorhexidine (CHX) on bond strength to dentin after 1 day, 3 months or 6 months of water storage. Eight human teeth were sectioned to expose a flat dentin surface and were then randomly assigned to 2 groups. In the control group, the dentin surfaces were treated with the adhesive according to the manufacturer's instructions. In the experimental group, liquid A was replaced by 2% CHX. Next, a 6-mm-high resin composite block was incrementally built on the bonded surfaces. The restored teeth were then sectioned to produce stick-shaped specimens (cross sectional area - 0.8 mm2). The microtensile bond strength (uTBS) was recorded, and the failure modes were assessed. Data were analyzed by two-way repeated measures ANOVA (alpha=0.05). Four additional teeth were processed in order to conduct a micromorphological analysis of the resin-dentin interface. The uTBS values did not significantly decrease after water storage in either the control or the experimental group, whose values did not differ significantly irrespective of storage time. The morphological aspect of the bonding interface appears not to have been affected by CHX. A higher incidence of cohesive failures within the adhesive and mixed failures (cohesive within adhesive and resin composite) was observed for both groups. It may be concluded that dentin pre-treatment with 2% CHX did not influence significantly the bonding performance of the evaluated adhesive. PMID- 24173252 TI - Can the cure time of endodontic sealers affect bond strength to root dentin? AB - The cure time of endodontic sealers may influence the bond strength of fiber posts to root dentin. Forty teeth were selected and endodontically filled using calcium hydroxide cement and then divided into 2 groups according to the time elapsed between endodontic filling and post luting (n = 20): Immediately - glass fiber post luting immediately after endodontic filling; and Delayed - post luting performed 7 days after endodontic filling. The roots were also subdivided according to resin cement used for post luting (RelyX ARC and RelyX Unicem). The specimens were stored at 37 degrees C for 24 h and sectioned in six 1-mm-thick slices from cervical, middle and apical thirds. The slice specimens were submitted to a push-out test at a crosshead speed of 0.5 mm/min, and the bond strength values obtained (MPa) were submitted to two-way ANOVA in a split-plot arrangement and Tukey's test (alpha=0.05). For both RelyX ARC and Unicem, the bond strength was significantly higher when the posts were cemented 7 days after the endodontic treatment. RelyX Unicem showed significantly higher bond strength values than RelyX ARC for both cementation periods. It was concluded that post luting should be made after the complete setting of the root canal sealer. Self adhesive resin cement should be preferred for fiber post luting. PMID- 24173253 TI - One-year water sorption and solubility of "all-in-one" adhesives. AB - The aim of this study was to evaluate the water sorption and solubility of different adhesives. Adper Easy Bond, Adper Single Bond Plus, Bond Force, Clearfil SE Bond (bonding resin only), and Xeno IV were the materials evaluated. Ten disks of each adhesive were made in Teflon molds and evaporation of any volatile components was allowed. The disks were weighed daily in an analytical balance until a constant mass was obtained (m1). Disks were then immersed in water for 12 months when their wet weight was recorded (m2). The disks were again weighed daily until a constant mass was obtained and the final weight recorded (m3). Water sorption and solubility (percentages) were calculated using the recorded mass values. Kruskal-Wallis tests were used to compare the average water sorption and solubility among the different adhesives. Mann-Whitney tests with a Bonferroni correction were used to determine the pairwise differences between adhesives in water sorption and solubility. The level of significance was set at 0.05. Water sorption and solubility were significantly different among the groups (p<0.05). Pairwise comparisons showed no significant differences (p>0.05) between Adper Single Bond Plus and Bond Force, or between Clearfil SE Bond and Xeno IV in either water sorption or solubility. Xeno IV did not differ from Adper Easy Bond in water sorption (p>0.05). Water sorption and solubility of all-in-one adhesives increased with time, and the rates of increase were composition-dependent. The results suggest that monomers other than HEMA contribute to water sorption and solubility of adhesive systems from different categories. PMID- 24173254 TI - Effect of surface pretreatments on the microtensile bond strength of lithium disilicate ceramic repaired with composite resin. AB - The aim of this study was to evaluate the influence of ceramic surface treatments and silane drying temperature on the microtensile bond strength (uTBS) of a resin composite to a lithium disilicate ceramic. Twenty blocks (7x7x5 mm) of lithium disilicate-based hot-pressed ceramic were fabricated and randomly divided into 4 groups: G1: acid etching with 9.5% hydrofluoric acid for 20 s and drying silane with room-temperature air; G2: acid etching with 9.5% hydrofluoric acid for 20 s and drying silane with 45 +/- 5 degrees C warm air; G3: airborne-particle abrasion with 50 um aluminum oxide particles and drying silane with 45 +/- 5 degrees C warm air; G4: airborne-particle abrasion with 50 um aluminum oxide particles and drying silane with air at room-temperature. After treatments, an adhesive system (Single Bond 2) was applied, light-cured and direct restorations were built up with a resin composite (Filtek Z250). Each specimen was stored in distilled water at 37 degrees C for 24 h and cut into ceramic-composite beams with 1 mm2 of cross-sectional area for uTBS testing. Statistical analysis was performed with one-way ANOVA and Student-Newman-Keuls test (alpha=0.05). uTBS means (S.D.) in MPa were: G1: 32.14 (7.98), G2: 35.00 (7.77) and G3: 18.36 (6.17). All specimens of G4 failed during the cutting. G1 and G2 presented significantly higher uTBS than G3 (p<0.05). There was no statistically significant difference between G1 and G2 (p>0.05). As far as the bond strength is concerned, surface pretreatment of lithium-disilicate ceramic with hydrofluoric acid and silane application can be used as an alternative to repair ceramic restorations with composite resin, while surface pretreatment with sandblasting should be avoided. PMID- 24173255 TI - Efficacy of denture cleansers in reducing microbial counts from removable partial dentures: a short-term clinical evaluation. AB - This clinical study investigated if daily immersion in denture cleansers reduces microbial counts on removable partial denture's (RPD) biofilm. Twenty-five RPD wearer volunteers were selected and instructed to complement the hygiene of their dentures by immersing them in an enzymatic peroxide-based denture cleanser (Polident(r) 3 minute) once a day for 3 min for a period of 15 days. The biofilm was collected from RPD surfaces with a swab immediately before (baseline) and after the experimental period. The samples were placed in sterile saline solution, sonicated at 7 W and then plated on specific culture media to quantify total microorganisms, total streptococci and Candida spp. counts. Data from both collections were compared by paired t-test (alpha=0.05). It was observed a significant reduction on total microorganisms' counts in RPD biofilm after denture cleanser use (p=0.007). This reduction was also observed for total streptococci (p=0.0428), but no difference was observed on Candida spp. counts. It was concluded that daily use of denture cleanser improved denture hygiene by reducing total microorganisms and total streptococci from RPD surface but had no effect on Candida spp. population. PMID- 24173256 TI - Effectiveness of denture cleanser associated with microwave disinfection and brushing of complete dentures: in vivo study. AB - Complete dentures acts as a reservoir for microbial colonization, which may lead to systemic infections. Microwave irradiation has been used as an efficient method of denture disinfection. Even though current methods eliminate denture base microorganisms, a recurrence rate of denture stomatitis (DS) is still observed among denture-wearing patients. It was hypothesized that microwave disinfection kills microorganisms but do not remove dead bacteria from the denture surface. To test this hypothesis, the biofilm found in the dentures of 10 patients with DS was evaluated. In addition, the effects of microwave irradiation plus brushing (MW+B) on the denture biofilm and the combination of denture cleanser with microwave irradiation and brushing (MW+DC+B) for the removal of denture-accumulating microorganisms were investigated. Microbiological data were analyzed statistically by nonparametric analysis (Friedman/Wilcoxon, alpha=0.05). MW+B and MW+DC+B were effective in reducing the rate of microorganisms (99.2% and 99.5% respectively), but without significant difference between them (p=0.553). However, it was observed that the complete removal of microorganisms from denture surface was only possible when all regimens were combined (MW+DC+B). Microwave irradiation in combination with soaking in denture cleanser and brushing effectively disinfected the dentures and removed denture biofilm. PMID- 24173257 TI - Similar sealability between bioceramic putty ready-to-use repair cement and white MTA. AB - This study was designed to assess the ability to prevent glucose penetration of a bioceramic putty ready-to-use repair cement comparing to white mineral trioxide aggregate (WMTA). After root canal instrumentation, the apical 3 mm of maxillary incisors were resected and root-end cavities with depth of 3 mm were prepared with ultrasound and filled with the tested materials (15 roots per group). All roots were mounted in a double chamber system to assess glucose penetration using 15 psi pressure application. After 1 h, glucose concentrations in the lower chamber were measured following an enzymatic reaction. Four roots were used as controls. The Mann-Whitney test verified differences in glucose leakage between groups and the Tukey's test was used for multiple comparisons. Significance level was set at 5%. There was no significant difference in glucose leakage between iRoot BP Plus and White MTA groups. iRoot BP Plus had a similar ability to that of white MTA in preventing glucose leakage as a root-end filling material. PMID- 24173258 TI - Comparison of two techniques for selection of master gutta-percha cone using micro-computed tomography. AB - This study used micro-computed tomography (micro-CT) to evaluate the fit of the master gutta-percha cone at time of cone fit, gutta-percha volume in the filling material, and the filling material volume in relation to the canal at the apical limit of the working length. Root canals of 20 maxillary central incisors were prepared with rotary instruments and distributed into two groups (n=10). The gutta-percha cone tip was either plasticized (apical thermal impression technique - ATI) or not (conventional technique - CT), and its apical fit was checked. The apical 1 mm of working length was examined with a micro-CT, canals were filled with gutta-percha and sealer, and new micro-CT scans were obtained. In CT, gutta percha filled 35.83 +/- 15.05% of the canal at cone selection and 38.72 +/- 11.64% after filling. In ATI, these values were 23.14 +/- 7.74% and 26.98 +/- 20.40%, respectively. Gutta-percha volume in the filling material, and filling material volume in relation to the canal were, respectively, 61.28 +/- 11.64% and 87.76 +/- 9.98% for CT, and 73.00 +/- 20.41% and 89.96 +/- 9.08% for ATI. No significant difference was found between cone selection and after canal filling, for either CT (p=0.593) or ATI (p=0.4975). The techniques did not differ significantly with respect to gutta-percha volume in the filling material (p=0.132) and filling material volume in relation to the canal (p=0.612). An ideal fit of the master gutta-percha cone at working length was not achieved regardless of the cone selection technique, and the material-filled area was similar for both techniques. PMID- 24173259 TI - Onset and duration period of pulpal anesthesia of articaine and lidocaine in inferior alveolar nerve block. AB - The purpose of this prospective, randomized, double blind study was to compare the onset and duration periods of pulpal anesthesia using 2% lidocaine with 1:100,000 epinephrine, 4% articaine with 1:100,000 epinephrine and 4% articaine with 1:200,000 epinephrine in inferior alveolar nerve block (IANB). Thirty subjects received 1.8 mL of each of the three local anesthetic solutions in IANB. Onset and duration periods of pulpal anesthesia were determined using electric pulp stimulation. The mean time of onset of pulpal anesthesia was 8.7, 7.4 and 7.7 min and the mean duration of pulpal anesthesia was 61.8, 106.6 and 88.0 min for 2% lidocaine with 1:100,000 epinephrine, 4% articaine with 1:100,000 epinephrine and 4% articaine with 1:200,000 epinephrine, respectively. For onset, there was only a significant difference between 2% lidocaine with 1:100,000 epinephrine and 4% articaine with 1:100,000 epinephrine (p=0.037). For duration, there was significant difference for all the local anesthetic solutions (p<=0.05). In conclusion, 4% articaine with 1:100,000 epinephrine exhibited faster onset and also had longest duration of pulpal anesthesia in IANB. PMID- 24173260 TI - Radioprotective effect of sodium selenite on developing teeth. AB - Radioprotective agents like selenium are used to reduce the damage caused by radiation in healthy tissues. The aim of this study was to evaluate the effect of sodium selenite on the development of the molars of offspring of rats irradiated during odontogenesis. Twenty pregnant rats were randomly divided into 4 groups: control, irradiated, selenium and selenium/irradiated. The selenium and selenium/irradiated groups received 0.3 mg/kg of sodium selenite at 18 days of pregnancy. The rats of the irradiated and selenium/irradiated groups received a single dose of 4 Gy of X rays on the abdominal region at the 19th day of pregnancy. The offspring was sacrificed at 3 and 4 days after birth for evaluation of the birefringence of the enamel organic matrix, and at 30 days for evaluation of the intercuspal dimensions of the molars. The selenium/irradiated group was similar to the irradiated group with respect to the thickness and irregularity of the enamel organic matrix region in the evaluated birefringence, as the intercuspal dimensions of the molars. In conclusion, sodium selenite had no radioprotective action on the development of the molars of offspring of rats irradiated during odontogenesis and had a toxic effect in the initial time. PMID- 24173261 TI - Levels of immunoglobulin A1 in peri-implant fluid and saliva from patients with mucositis: a preliminary study. AB - There are no studies evaluating the possible use of immunoglobulin A1 (IgA1) as an early marker for peri-implant inflammation. The aim of this study was to evaluate the IgA1 levels in peri-implant sulcular fluid (PISF) and saliva of partially edentulous patients as an indicator of mucositis. Twenty-seven patients were examined to determine the peri-implant status based on probing depth and bleeding on probing. Saliva and PISF around dental implants were collected and the IgA1 levels were evaluated by Elisa assay. IgA1 in saliva and PISF of these patients were compared and their correlations with clinical parameters were evaluated. Differences in IgA1 levels in saliva (821.1 +/- 290.6; 779.8 +/- 401.5) and PISF (26.6 +/- 20.7; 25.1 +/- 20.5) of healthy and mucositis groups, respectively were not observed (p>0.05). Correlation between clinical parameters and IgA1 in saliva or PISF was not observed in healthy or mucositis groups (p=0.607; p=0.826, respectively). These results suggest that IgA1 cannot be used as an immunological marker of mucositis. PMID- 24173262 TI - Perception of smile esthetics varies between patients and dental professionals when recession defects are present. AB - The aim of this study was to compare the smile esthetic perception of patients, dental students and dentists faced to different situations concerning gingival margin position. A total of 123 individuals (41 patients, 41 dental students and 41 dentists) completed a structured questionnaire and evaluated 6 pictures of the same smile modified in Adobe Photoshop(r) image-editing software representing: no gingival recession, 2 mm recession in one maxillary lateral incisor, 2 mm recession in both maxillary lateral incisors, 2 mm recession in one maxillary canine, 2 mm recession in both maxillary canines and generalized 2 mm recession. The visual analogue scale (VAS) was used to rate the esthetic perception. Mean VAS values were calculated and compared among gingival situations as well as group of respondents by one-way ANOVA, with an alpha level of 0.05. VAS analysis revealed that mean values ranged from 4.2 (+/-1.8) to 6.8 (+/-1.7). Images with no gingival recession received the highest score by all groups, with statistically significant differences among dentists and dental students. However, patients scored images with no recession with significantly lower ranks as compared with dentists and dental students. No significant differences were observed among patients for any of the situations. When dentists and dental students were compared, the worst situation was observed for generalized gingival recession, with scores 4.2 (+/-1.8) and 4.9 (+/-1.8), respectively. Patients and dental professionals had different perceptions about esthetics related to gingival margin position. PMID- 24173263 TI - Linear and angular deviations of implants placed in experimental casts with stereolithographic drill guides fixed by o'ring ortho implant devices. AB - The aim of this study was to evaluate whether the introduction of a device, resulting from the combination of an o'ring attachment with an orthodontic implant (o'ring ortho implant, O'ROI), to affix the surgical template of CAD/CAM guided implant surgery contribute to minimizing the deviations in the position and inclination of implants at the time of their placement. Ten models simulating bone tissue were fabricated and randomly divided into 2 groups: 5 with the scanning and surgical template of the usual technique, representing the Control Group (C), and 5 with scanning and surgical templates fixed by o'ring ortho implants (O'ROI), representing the Test Group (T). Forty implants measuring 4*11 mm were placed in the groups, using the respective templates. The results were evaluated by the fusion of CT images of the planned and placed implants. The locations and axes were compared. There were no statistically significant differences for the angular (Tukey's test F = 1.06 and p = 0. 3124) and linear (ANOVA F = 2.54 and p = 0.11) deviations. However, the angular values of Group T showed a lower standard deviation in comparison with those of Group C. The use of o'ring ortho implants (O'ROI) is able to minimize the angular and linear deviation of implants at the time of their placement. PMID- 24173264 TI - Oral and maxillofacial trauma in Brazilian children and adolescents. AB - Children and adolescents are frequently victims of oral and maxillofacial trauma. The purpose of this study was to determine the characteristics of oral and maxillofacial trauma that resulted in police records, in children and adolescents aged between 0 and 16 years during a period of 5 years. Among the 28,200 reports analyzed, 463 were included in the study. The men:women ratio observed was 1.6:1 and the most prevalent age range was between 15-16 years (44.40%). Most trauma cases resulted from physical assault (64.50%) and culminated in soft-tissue lesion (80.36%). Excoriations (28.64%) leaded as the most frequent type of lesion, and the maxillary region (22.63%) was the most common location of injury. The most common type of dental lesion was dental trauma (54.76%), and bone fractures prevailed in the nasal region (36.7%). The findings of this survey may contribute to plan and execute preventive measures as well as to guide curative measures aimed at this population group. PMID- 24173266 TI - Fluoride release/uptake from different orthodontic adhesives: a 30-month longitudinal study. AB - The aim of this study was to test the null hypothesis that there is no difference in fluoride release between resin-modified glass ionomer cements (RMGICs) and composites in the long term. The materials were divided into 5 groups: a nonfluoride-releasing composite - Group TXT (Transbond XT), a fluoride-releasing composite - Group QC (Quick-Cure), and three RMGICs - Groups FOLC, FOB and MC (Fuji Ortho LC, Fuji Ortho Band, and Multi-Cure). Fluoride release was measured at time intervals of 1 h, 1, 7, 14, 21 and 29 days, followed by further evaluations performed at 6, 12, 18, 24 and 30 months using selective ion electrodes connected to an ionic analyzer. Fluoride releasing and re-releasing experiments were analyzed using the Kruskal-Wallis test and Mann-Whitney test with the Bonferroni correction. The amount of fluoride released by FOB was larger in comparison with the other adhesives (p=0.01). In the long-term, FOLC and MC had a similar performance (p>0.05). The composites presented a low fluoride release, but fluoride ion uptake and re-release capacity of QC was statistically significant (p<0.05) during the experiment. In conclusion, the null hypothesis was rejected, the RMGIC Fuji Ortho Band and the composite Quick-Cure presented greater fluoride release and re-release capacity when recharged. PMID- 24173265 TI - Effect of early membrane removal on the treatment of mandibular class II furcation defects--a controlled clinical trial with re-entry after 12 months. AB - In a previous study in dogs, the early removal of expanded polytetrafluoroethylene (ePTFE) membrane (2 weeks after placement) showed histomorphometric results (of new bone, cementum and periodontal ligament) similar to that obtained with membrane removal at 4 weeks after placement. This study evaluated the influence of early removal of an ePTFE membrane on the treatment of Class II furcation defects. Twelve patients who provided 12 pairs of mandibular furcation defects were recruited for the study. Baseline clinical measurements were recorded: plaque index (PI), gingival index (GI), bleeding on probing (BOP), probing depth (PD), gingival margin position (GMP) and relative clinical attachment level (RCAL). Full flaps were elevated and hard tissue measurements were performed during the surgery: relative vertical (RVBL) and horizontal (RHBL) bone level. The ePTFE membranes were adapted and sutured to their correspondent tooth and removed at 2 weeks in the test group (TGr) and at 4 weeks in the control group (CGr). After 1 year all sites were re-entered, and soft and hard tissue measurements were recorded. There were no statistically significant differences between TGr and CGr for any baseline measurement. After 12 months, there were no statistically significant differences between TGr and CGr in the PD (p=0.74), GMP (p=0.76) and RCAL (p=0.44) values. However, the RHBL resolution was significant for both groups (CGr p=0.01 and TGr p=0.02), without difference between groups (p=0.39). Early removal of membranes did not affect the outcome on the treatment of Class II furcation defects. PMID- 24173267 TI - Dynamics of microbial colonization of the oral cavity in newborns. AB - The host defense mechanisms are not well developed in neonates. The aim of this study was to evaluate the dynamics of microbial colonization of the oral cavity in newborns. Eighty-one samples of the oral microbiota were obtained from 51 healthy newborns 10 min to 53 h after birth by gently rubbing sterile swabs onto the surface of the tongue, cheek mucosa, alveolar process and palate. After microbiological processing, counting of the colony forming units of streptococci, staphylococci and Gram-negative aerobic bacilli was performed. Between 10 min and 8 h, Staphylococcus epidermidis was detected in 30.7% of the samples; between 8 and 16 h, S. epidermidis was detected in 69.5% of the samples and streptococci in 56.5% of the samples; between 16 and 24 h, S. epidermidis, streptococci and S. aureus were detected in 77.78%, 85.18% and 37.03% of the samples, respectively. Between 24 and 53 h, S. epidermidis was detected in 88.89%, streptococci in 94.4% and S. aureus in 33.3% of the samples. Mutans streptococci were not detected in any of the samples. The adoption of strict hygienic measures by the mother and the nursing staff should be emphasized to avoid or at least delay the occurrence of infections caused by microorganisms in newborns. In addition, hospital procedures must be aseptic and invasive interventions must be minimized. PMID- 24173268 TI - Fine needle aspiration cytology and intralesional steroid injection in a central giant cell granuloma affecting the gingiva: a new clinical approach. AB - Central giant cell granuloma (CGCG) is a benign jaw lesion predominantly found in the mandible of young female patients with a variable clinical behavior. Although surgical management is regarded as the main treatment modality for this lesion, the use of intralesional injections of steroids has been recently advocated for its treatment. In addition to this conservative management, the use of fine needle aspiration cytology (FNAC) for diagnosing CGCGs has been proven a safe and efficient approach, especially useful in cases with lesions located in esthetic regions. Herein, it is described a case of CGCG extending to the overlying gingiva of a 15-year-old male patient diagnosed by FNAC and subsequently treated with intralesional injections of a solution of triamcinolone acetonide and ethanolamine oleate that led to an important clinical remission, allowing a more conservative surgical procedure for preservation of gingival esthetics. Therefore, both procedures can be considered as management options for CGCG of the jaws. PMID- 24173269 TI - Root reconstructed with mineral trioxide aggregate and guided tissue regeneration in apical surgery: a 5-year follow-up. AB - Apical surgery should be considered as the last treatment option and employed when conventional endodontic treatment does not provide the expected result. In teeth undergoing apical surgery, the type of retrograde filling material is one of the factors interfering with the repair of periapical tissues. The material in intimate contact with the periapical tissues plays a fundamental role in the repair process. Several materials have been studied and indicated for use in apical surgery procedures, but the mineral trioxide aggregate (MTA) is still the most frequently used one. Guided tissue regeneration (GTR) techniques have been proposed as an adjunct to apical surgery to enhance bone healing. Here is reported a clinical case in which apical surgery was performed in conjunction with MTA-based root reconstruction of the maxillary right second incisor. After the apical surgery, a root-end cavity was prepared at the vestibular face of the involved tooth and filled with MTA. A bovine bone graft and a cortical collagen membrane were placed on the bone defect. After 5 years, clinical and radiographic assessments showed that the treatment was successful. It may be concluded that MTA presents favorable characteristics in adverse conditions and can be used in conjunction with GTR in cases involving root reconstruction. PMID- 24173270 TI - Evidence for the alkaline nature of parental carbonatite melts at Oka complex in Canada. AB - The Earth's sole active carbonatite volcano, Oldoinyo Lengai (Tanzania), is presently erupting unique natrocarbonatite lavas that are characterized by Na- and K-bearing magmatic carbonates of nyerereite [Na2Ca(CO3)2] and gregoryite [(Na2,K2,Ca)CO3]. Contrarily, the vast majority of older, plutonic carbonatite occurrences worldwide are dominated by Ca-(calcite) or Mg-(dolomite)-rich magmatic carbonates. Consequently, this leads to the conundrum as to the composition of primary, mantle-derived carbonatite liquids. Here we report a detailed chemical investigation of melt inclusions associated with intrusive (plutonic) calcite-rich carbonatites from the ~120 Ma carbonatite complex of Oka (Canada). Melt inclusions are hosted by magnetite (Fe3O4), which crystallizes through a significant period of carbonatite melt solidification. Our results indicate mineral assemblages within the melt inclusions that are consistent with those documented in natrocarbonatite lavas. We propose therefore that derivation of alkali-enriched parental carbonatite melts has been more prevalent than that preserved in the geological record. PMID- 24173271 TI - Left ventricular diastolic function is associated with symptom status in severe aortic valve stenosis. AB - BACKGROUND: In aortic valve stenosis (AS), the occurrence of heart failure symptoms does not always correlate with severity of valve stenosis and left ventricular (LV) function. Therefore, we tested the hypothesis that symptomatic patients with AS have impaired diastolic, longitudinal systolic function, and left atrial dilatation compared with asymptomatic patients. METHODS AND RESULTS: In a retrospective descriptive study, we compared clinical characteristics and echocardiographic parameters in 99 symptomatic and 139 asymptomatic patients with severe AS and LV ejection fraction >=50%. Independent predictors of symptomatic state were identified using logistic regression analysis. Symptomatic patients were younger (72+/-10 versus 76+/-12 years of age; P=0.002), presented less often with atrial fibrillation (13% versus 24%; P=0.05) and chronic obstructive pulmonary disease (2% versus 19%; P<0.001), and had a lower prevalence of hypertension (73% versus 40%; P<0.001). Despite similar AS severity, symptomatic patients had higher LV mass index (120+/-39 versus 95+/-25 g/m2; P<0.0001), increased relative wall thickness (0.61+/-0.15 versus 0.50+/-0.11; P<0.0001), shorter mitral deceleration time (199+/-58 versus 268+/-62 ms; P<0.0001), and increased left atrial volume index (49+/-18 versus 42+/-15 mL/m2; P=0.02). When adjusting for age, history of hypertension, atrial fibrillation, and chronic obstructive pulmonary disease in a multivariable logistic regression analysis, LV mass index, relative wall thickness, left atrial volume index, and deceleration time were still associated with the presence of symptoms. CONCLUSIONS: The present study demonstrates that symptomatic status in severe AS is associated with impaired diastolic function, LV hypertrophy, concentric remodeling, and left atrial dilatation when corrected for indices of AS severity. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00294775. PMID- 24173272 TI - Changes in right ventricular function measured by cardiac magnetic resonance imaging in patients receiving pulmonary arterial hypertension-targeted therapy: the EURO-MR study. AB - BACKGROUND: Most measures that predict survival in pulmonary hypertension (PH) relate directly to, or correlate with, right ventricular (RV) function. Direct assessment of RV function using noninvasive techniques such as cardiac MRI may therefore be an appropriate way of determining response to therapy and monitoring disease progression in PH. METHODS AND RESULTS: In this pan-European study, 91 patients with PH (mean pulmonary arterial pressure 46+/-15 mm Hg) underwent clinical and cardiac MRI assessments at baseline and after 12 months of disease targeted therapy (predominantly endothelin receptor antagonists [47.3%] or phosphodiesterase type-5 inhibitors [25.3%]). At month 12, functional class had improved in 21 patients, was unchanged in 63 patients, and had deteriorated in 7 patients. Significant improvements were achieved in RV and left ventricular ejection fraction (P<0.001 and P=0.0007, respectively), RV stroke volume index (P<0.0001), and left ventricular end-diastolic volume index (P=0.0015). Increases in 6-minute walk distance were significant (P<0.0001) and correlated with change in RV ejection fraction and left ventricular end-diastolic volume, although correlation coefficients were low (r=0.28, P=0.01 and r=0.26, P=0.02, respectively). CONCLUSIONS: On-treatment changes in cardiac MRI-derived variables from left and right sides of the heart reflected changes in functional class and survival in patients with PH. Direct measurement of RV function using cardiac MRI can fully assess potential benefits of treatment in PH. PMID- 24173274 TI - UV-induced mitotic co-segregation of genetic markers in Candida albicans: Evidence for linkage. AB - Parasexual genetic studies of the medically important yeast Candida albicans were performed using the method of UV-induced mitotic segregation. UV-ir-radiation of the Hoffmann-La Roche type culture of C. albicans yielded a limited spectrum of mutants at a relatively high frequency. This observation suggested natural heterozygosity. Canavanine-sensitive (CanS) segregants were induced at a frequency of 7.6 * 10(-3). Double mutants that were both CanS and methionine (Met(-)) auxotrophs were induced at a frequency of 7.4 * 10(-3). The single Met( ) segregant class was missing indicating linkage. UV-induced CanS or Met(-)CanS segregants occurred occasionally in twin-sectored colonies. Analyses of the sectors as well as the observed and missing classes of segregants indicated that gens met and can are linked in the cis configuration. The proposed gene order is: centromere -met - can. Thus, it is concluded that the Hoffmann-La Roche strain of C. albicans is naturally heterozygous at two linked loci. These findings are consistent with diploidy. PMID- 24173273 TI - Validation of noninvasive indices of global systolic function in patients with normal and abnormal loading conditions: a simultaneous echocardiography pressure volume catheterization study. AB - BACKGROUND: Noninvasive indices based on Doppler echocardiography are increasingly used in clinical cardiovascular research to evaluate left ventricular global systolic chamber function. Our objectives were to clinically validate ultrasound-based methods of global systolic chamber function to account for differences between patients in conditions of abnormal load, and to assess their sensitivity to load confounders. METHODS AND RESULTS: Twenty-seven patients (8 dilated cardiomyopathy, 10 normal ejection fraction, and 9 end-stage liver disease) underwent simultaneous echocardiography and left heart catheterization with pressure-conductance instrumentation. The reference index, maximal elastance (Emax), was calculated from pressure-volume loop data obtained during acute inferior vena cava occlusion. A wide range of values were observed for left ventricular systolic chamber function (Emax: 2.8+/-1.0 mm Hg/mL), preload, and afterload. Among the noninvasive indices tested, the peak ejection intraventricular pressure difference showed the best correlation with Emax (R=0.75). A significant but weaker correlation with Emax was observed for ejection fraction (R=0.41), midwall fractional shortening (R=0.51), global circumferential strain (R=-0.53), and strain rate (R=-0.46). Longitudinal strain and strain rate failed to correlate with Emax, as did noninvasive single-beat estimations of this index. Principal component and multiple regression analyses demonstrated that peak ejection intraventricular pressure difference was less sensitive to load, whereas ejection fraction and longitudinal strain and strain rate were heavily influenced by afterload. CONCLUSIONS: Current ultrasound methods have limited accuracy to characterize global left ventricular systolic chamber function in a given patient. The Doppler-derived peak ejection intraventricular pressure difference should be preferred for this purpose because it best correlates with the reference index and is more robust in conditions of abnormal load. PMID- 24173275 TI - Cloning of the delta-aminolevulinic acid synthase structural gene in yeast. AB - HEM1, the structural gene for delta-aminolevulinic acid synthase, has been isolated on recombinant plasmids. A yeast genomic pool constructed in the E. coli - yeast shuttle vector YEp13 was used to clone the HEM1 gene by complementation. A leu2 hem1 yeast mutants was transformed with the yeast genomic pool and hybrid YEp13 plasmids carrying the HEM1 gene were cloned by their ability to complement both the leu2 and hem1 mutations in the recipient strain. The yeast transformants, bearing the HEM1-containing plasmids pYe(HEM1), showed a 24-28 fold increase in delta-aminolevulinic acid synthase activity and in the intracellular content of delta-aminolevulinic acid (5-8 fold) as compared to wild type strains, suggesting that the p(HEM1) gene is being expressed as a catalytically active enzyme which can be transported into the mitochondria. However, the transformant strains did not present higher-than-normal content of heme or cytochromes either in glucose or in glycerol media, indicating that the production of delta-aminolevulinic acid is not the rate-limiting step in heme biosynthesis in yeast. PMID- 24173276 TI - Isolation and characterisation of a double-stranded RNA virus-like particle from the yeast Yarrowia lipolytica. AB - A virus-like particle (VLP) of 50 nm diameter has been isolated from the hydrocarbon-utilising yeast Yarrowia (Saccharomycopsis) lipolytica. The VLP contains a linear, double-stranded RNA molecule of MW 3.8 * 10(6) and has a major capsid protein of MW 75,700. PMID- 24173277 TI - Cloning of photoreactivation repair gene and excision repair gene of the yeast Saccharomyces cerevisiae. AB - The photoreactivation repair gene (PHR1) of the yeast Saccharomyces cerevisiae was cloned in a hybrid plasmid (pJDB207), which is able to replicate as a multicopy episome in S. cerevisiae and Escherichia coli cells. The size of the DNA fragment found to have the photoreactivation activity was 3.0 kb, determined by recloning of the isolated fragment. In wild type cells transformed by the plasmid containing the PHR1 gene, the number of DNA photolyase molecules was 15 times greater than in wild type cells with pJDB207 only. Using the same receptor strain the excision repair gen RAD1 was also isolated. The size of the insert of the DNA which complements excision repair deficiency in recipient yeast cells was 5.7 kb. The recipient cells after transformation with the plasmid containing RAD1 showed the same UV-sensitivty as wild type cells with pJDB207 only. PMID- 24173278 TI - Isolation and characterization of a maltose transport mutant in the yeast Saccharomyces cerevisiae. AB - Yeast strains carrying a functional MAL locus are inducible for the co-ordinate synthesis of both maltase and maltose permease when grown in the presence of maltose. Whether the maltose permease is encoded by a gene at the MAL loci has remained unclear due to the lack of mutants in this function. To isolate mutants defective in maltose transport, a positive selection strategy was employed in which a number of Mal(-) mutants were obtained. Among these one Mal- mutant was isolated which had normal levels of wild-type maltase in cell free extracts. This isolate, designated MGT1, has a defect in maltose transport (malT1), detected by its markedly lower uptake of [(14)C]maltose, and by its growth on media containing 10% but not 2% maltose. Since the Km of maltose uptake is altered 10 fold in this mutant and the Vmax remains unchanged, it is suggested that the mutation alters the structure of the maltose permease involved in transport of the disaccharide into the cell rather than its regulation.A genetic analysis of the malT1 mutation shows that it is in a gene allelic to one at the MAL1 locus. Transformation of this mutant to the Mal(+) phenotype using a chimeric yeast/E. coli shuttle plasmid containing a subcloned fragment of the MAL6 locus suggests that the presence of a functional analogue of the gene encoding the maltose transport function is an integral part of the MAL6 locus as well. PMID- 24173279 TI - Both the chloroplast and nuclear genomes of Chlamydomonas reinhardi share homology with Escherichia coli genes for transcriptional and translational components. AB - Considerable DNA sequence homology can be detected between the Escherichia coli genes coding for translational and transcriptional components and both the chloroplast and nuclear genomes of Chlamydomonas reinhardi. Labeled chloroplast DNA was demonstrated to hybridize to DNA fragments of the transducing phages lambdafus3 and lambdaspc2 that encode ribosomal proteins of the alpha and S10 operons. Further, chloroplast DNA probes hybridize to fragments of lambdartf (d) 18 that encode the beta and beta' subunits of RNA polymerase. The regions homologous to the ribosomal protein and RNA polymerase genes were located on the chloroplast DNA physical map by probing restriction fragments of chloroplast DNA with phage or plasmid fragments carrying these E. coli genes. Probing nuclear DNA with bacterial gene probes revealed DNA fragments homologous to elongation factor and ribosomal protein genes. Most surprisingly, sequences homologous to the beta subunit of RNA polymerase were found not only in chloroplast DNA but in nuclear DNA as well. PMID- 24173280 TI - Cytological detection of the basis of uniparental inheritance of plastid DNA in Chlamydomonas moewusii. AB - By using the fluorochrome 4'-6-diamidino-2-phenylindole (DAPI) to stain DNA one can follow the pattern of events affecting plastid DNA which occur in the formation and maturation of individual zygotes of the green flagellate Chlamydomonas moewusii. This species, like C. reinhardi, expresses uniparental inheritance of plastid DNA characters among zygote progeny, and is particularly favorable for cytological observation because the locale of the contribution of each gamete can still be recognized in mature zygotes. Gametes contribute equal numbers of DNA nucleoids, and amounts of plastid DNA (as measured by DAPI-DNA micro spectrofluorometry), to the zygote at fusion. Starting at nine hours, coincident with the further fusion of cell contents, plastid DNA disappears from the plastid contributed by one gamete. Further slow coalescence of nucleoids leads to a final nucleoid number per zygote approximately 1/3 of the sum of the 2 gametes.The DNA loss from one gamete plastid may require plastid contact to be initiated. Both light and nutrient availability affect the final number and distribution of plastid DNA nucleoids in the mature zygote. These observations are related to known genetic and biochemical data on uniparental inheritance of plastid characters. PMID- 24173281 TI - DNA sequence analysis of the mitochondrial plasmid of Podospora anserinaa. AB - The nucleotide sequence in three regions of the mitochondrial plasmid (p1DNA) of Podospora anserina has been determined for almost 1,000 by of the altogether 2.4 kb. The first region beginning around excision point E1 comprises 652 by and is characterized by an AT content of about 58%. A long open reading frame (URF) (555 bp) can be attributed to this region coding for an unidentified polypeptide. No reading frame could be attributed to the second region (247 bp), since in all 6 possible phases numerous termination codons were detected. Its AT content was found to be 71%. The third region (87 bp) which ends with excision point E2 is too small for further analysis.From these data it follows that the p1DNA consists of two regions with different functions at least. However, only the larger one beginning near excision point E1 appears to code for a protein. PMID- 24173282 TI - Recombinational analysis of oxi2 mutants and preliminary analysis of their translation products in S. cerevisiae. AB - Genetic and biochemical studies were performed with mutants allocated to the mitochondrial oxi2 gene.Recombinational analysis of 19 oxi2 mutants was performed using alpha and a mutant strains derived from the same genetic background. The frequencies of wild-type recombinants in oxi2 (-) * oxi2 (-) crosses varied from 0.002 to 17%. The map of oxi2 mutations constructed on the basis of these frequencies shows many internal inconsistencies. In the course of rho (-) deletion mapping five classes of oxi2 mutations were distinguished. The results of deletion analysis are in agreement with those of recombinational mapping.The analysis of mitochondrial translation products by SDS-polyacrylamide electrophoresis of 20 oxi2 mutants shows that 17 of them are connected with conspicuous changes of 22 kd polypeptide band corresponding to subunit III of cytochrome oxidase. At least four of them carried instead of subunit III clearly visible significantly shorter polypeptides (12.8 to 20.1 kd). These were, most likely, shorter fragments of subunit III resulting from chain termination mutations. Colinearity was observed between the lenght of new polypeptides and the positions of the respective mutations on the recombinational map. These data confirm hat oxi2 encodes subunit III of cytochrome oxidase and suggest that translation of the oxi2 gene is in the direction from V303 to V273. PMID- 24173283 TI - Mitotic segregation of 2 MUm-pbr322 chimaeric plasmids in yeast. AB - Mitotic segregation of three 2 MUm-pBR322 chimaeric plasmids (YEp6, YEp21, and YEp24) was studied in yeast. Each displayed a characteristic rate of loss: YEp6 was lost at approximately twice the rate of YEp21 and YEp24. The loss rates were not significantly increased when two chimaeric plasmids were coresident, nor was the endogenous 2 MUm plasmid itself displaced. Therefore these plasmids appear to be compatible in yeast. PMID- 24173284 TI - Requirement for phosphorylation of P53 at Ser312 in suppression of chemical carcinogenesis. AB - The p53 tumour suppressor is activated in response to a wide variety of genotoxic stresses, frequently via post-translational modification. Using a knock in mouse model with a Ser312 to Ala mutation, we show here that phosphorylation of p53 on Ser312 helps to prevent tumour induction by the alkylating agent MNU, which predominantly caused T cell lymphomas. This is consistent with our previous observation that p53(312A/A) mice are more susceptible to X-ray induced tumourigenesis. Phosphorylation on Ser312 aids p53's interaction with E2F1, and enhances p53-mediated apoptosis. Loss of E2F1 alone does not affect tumour susceptibility to MNU, but its absence partially rescues tumour formation in p53(312A/A) mice, thus reflecting the oncogenic properties of E2F1. Our data confirms the participation of Ser312 phosphorylation in tumour suppression by p53. PMID- 24173285 TI - The evolution of X chromosome inactivation in mammals: the demise of Ohno's hypothesis? AB - Ohno's hypothesis states that dosage compensation in mammals evolved in two steps: a twofold hyperactivation of the X chromosome in both sexes to compensate for gene losses on the Y chromosome, and silencing of one X (X-chromosome inactivation, XCI) in females to restore optimal dosage. Recent tests of this hypothesis have returned contradictory results. In this review, we explain this ongoing controversy and argue that a novel view on dosage compensation evolution in mammals is starting to emerge. Ohno's hypothesis may be true for a few, dosage sensitive genes only. If so few genes are compensated, then why has XCI evolved as a chromosome-wide mechanism? This and several other questions raised by the new data in mammals are discussed, and future research directions are proposed. PMID- 24173286 TI - Androgen receptor is negatively correlated with the methylation-mediated transcriptional repression of miR-375 in human prostate cancer cells. AB - Androgen receptor (AR) plays a critical role during the development and progression of prostate cancer in which microRNA miR-375 is overexpressed and correlated with tumor progression. Although DNA methylation is a key mechanism for the repression of gene expression, the relationship between AR and the expression or the hypermethylation of miR-375 is unknown. In this study, we found that AR-positive prostate cancer (PCa) cells showed high expression levels and hypomethylation of the miR-375. In contrast, AR-negative PCa cells displayed low levels and hypermethylation of the miR-375. Addition of 5-Aza-2'-deoxycytidine, a specific inhibitor of DNA methylation, into the culture medium reversed the low expression levels of miR-375 in the AR negative PCa cells. In addition, the total activity levels of DNA methyltransferases (DNMTs) were high in AR-negative PCa cells, in which hypermethylation of miR-375 promoter and low expression levels of miR-375 were observed. Taken together, these findings indicate that the negative correlation between AR and total DNMT activity is one of mechanisms to influence the methylation status of miR-375 promoter, which in turn regulates the expression of miR-375. PMID- 24173287 TI - In Vitro excitation of purified membrane fragments by cholinergic agonists : I. Pharmalogical properties of the excitable membrane fragments. AB - Excitation of membrane fragments by cholinergic agonists is measuredin vitro by a filtration technique. Membrane fragments which contain high levels of the enzyme acetylcholinesterase and presumably originate from the innervated excitable faces of electroplax are first purified from homogenates of electric organ ofElectrophorus electricus by centrifugation in a sucrose gradient. Then the fragments, which make closed vesicles or microsacs, are equilibrated overnight with a medium containing(22)Na(+). After equilibration of the inside of the microsacs with the outside medium, the suspension is diluted into a nonradioactive medium. The(22)Na(+) content of the microsacs as a function of time is then followed by rapid filtration on Millipore filters. In the presence of cholinergic agonists, the time course of(22)Na(+) release changes: the rate of(22)Na(+) release increases. This increase is blocked byd-tubocurarine and is absent with microsacs derived from the non-innervated inexcitable membrane of the electroplax. The response to cholinergic agonists is thus followed on a completely cell-free system, in a well-defined environment. The dose-response curves to cholinergic agents obtainedin vitro agree, quantitatively, with the dose-response curves recordedin vivo by electrophysiological methods. In particular, the dose-response curve to agonists is sigmoid, the antagonism betweend-tubocurarine and carbamylcholine competitive, and the antagonism between tetracaine and carbamylcholine noncompetitive. The effects of two different affinity labeling reagents on the response to agonists and on the catalytic activity of acetylcholinesterase are followed in parallel on the same microsac preparation. The effects of dithiothreitol and of gramicidin A on the microsacs are studied and are found to be similar to those observedin vivo with the isolated electroplax. PMID- 24173288 TI - In Vitro excitation of purified membrane fragments by cholinergic agonists : II. The permeability change caused by cholinergic agonists. AB - The effect of carbamylcholine (Carb) on the release of(22)Na(+) by excitable microsacs is reversible: Carb does not promote an irreversible lysis of the microsacs. The microsacs form closed vesicles which are more permeable to water than to solutes present in physiological media; their apparent volume is controlled by the osmotic pressure of the medium in which they are equilibrated; they behave like micro-osmometers. In the presence of Carb, the apparent volume of the microsacs does not change: Carb has no significant effect on water permeability.The time course of(22)Na(+) release does not follow a simple exponential law and is fitted by a minimum of three exponentials. The complex kinetics are not due to electrical effects but presumably are caused by an heterogeneity both in size and in nature of the microsacs population.Microsacs at rest are permeable to(45)Ca(+),(42)K(+) and(22)Na(+), and to(36)Cl(-) but slightly or not at all to(32)S-SO -2 (4) . In the presence of Carb, the permeability to(22)Na(+),(42)K(+) and(45)Ca(++) increases, whereas the permeability to(14)C-tetraethylammonium and(14)C-choline does not change. Carb has no effect on the permeability to negatively charged or uncharged permeants.The kinetics of(22)Na(+) efflux is independent of the total concentration of Na(+) either inside or outside the microsacs. The outward transport of Na(+) thus varies only with the concentration of ion facing theinside of the membrane. Efflux of(42)K(+) follows the same laws as the efflux of(22)Na(+) except that it is blocked by(+)Na ions present in the outside medium. PMID- 24173289 TI - In vitro excitation of purified membrane fragments by cholinergic agonists : III. Comparison of the dose-response curves to decamethonium with the corresponding binding curves of decamethonium to the cholinergic receptor. AB - The reversible binding of(14)C-decamethonium (Deca) to excitable microsacs prepared from the electric tissue ofElectrophorus electricus is followed by an ultracentrifugal assay. alpha-Bungarotoxin, a snake venom toxin, blocks irreversibly the binding of(14)C-Deca. The displacement is partial. The fraction of(14)C-Deca displaced by alpha-bungarotoxin corresponds to molecules of Deca bound to the cholinergic receptor site, whereas the fraction of(14)C-Deca bound in the presence of alpha-bungarotoxin corresponds to molecules bound to the catalytic site of acetylcholinesterase (AcChE). The total number of cholinergic receptor sites is found to be close but not identical to the total number of catalytic sites of AcChE.On the same preparation of microsacs, the binding of(14)C-Deca and the permeability response corresponding to a given concentration of Deca are measured as a function of increased concentration of Deca. The dose response curve and the binding curve superimpose almost exactly; in other words, the "apparent" affinity of Deca coincides with its "real" affinity. Displacement of(14)C-Deca byd-tubocurarine gives an "apparent" affinity ford-tubocurarine which coincides as well with its "real" affinity.The transport properties of the ionophore controlled by one Deca binding site are estimated. PMID- 24173290 TI - In vitro excitation of purified membrane fragments by cholinergic agonists : IV. Ultrastructure, at high resolution, of the AcChE-Rich and ATPase-rich microsacs. AB - Membrane fragments rich in acetylcholinesterase (AcChE) or in Na(+)-K(+)-ATPase are observed under the electron microscope on thin sections after fixation, after negative staining of unfixed material, and after freeze-etching. Both classes of membrane fragments make closed approximately spherical vesicles, or microsacs. The preparation appears to be free from mitochondria, nuclear envelopes or other cytoplasmic contamination. A subunit structure is seen with both kinds of microsacs by freeze-etching and negative staining, but the size, shape and arrangement of the subunits are different in the two classes of membrane fragments. On thin sections, globular repeating units are seen only with the AcChE-rich microsacs; the membrane of the ATPase-rich microsacs shows a classic triple-layered structure. PMID- 24173291 TI - The insulin-like growth factor 2 (IGF2) mRNA-binding protein p62/IGF2BP2-2 as a promoter of NAFLD and HCC? PMID- 24173293 TI - Quality of life after restorative proctocolectomy in Muslim patients. PMID- 24173292 TI - Myofibroblastic cells function as progenitors to regenerate murine livers after partial hepatectomy. AB - OBJECTIVE: Smoothened (SMO), a coreceptor of the Hedgehog (Hh) pathway, promotes fibrogenic repair of chronic liver injury. We investigated the roles of SMO+ myofibroblast (MF) in liver regeneration by conditional deletion of SMO in alpha smooth muscle actin (alphaSMA)+ cells after partial hepatectomy (PH). DESIGN: alphaSMA-Cre-ER(T2)*SMO/flox mice were treated with vehicle (VEH) or tamoxifen (TMX), and sacrificed 24-96 h post-PH. Regenerating livers were analysed for proliferation, progenitors and fibrosis by qRT-PCR and quantitative immunohistochemistry (IHC). Results were normalised to liver segments resected at PH. For lineage-tracing studies, alphaSMA-Cre-ER(T2)*ROSA-Stop-flox-yellow fluorescent protein (YFP) mice were treated with VEH or TMX; livers were stained for YFP, and hepatocytes isolated 48 and 72 h post-PH were analysed for YFP by flow cytometric analysis (FACS). RESULTS: Post-PH, VEH-alphaSMA-SMO mice increased expression of Hh-genes, transiently accumulated MF, fibrosis and liver progenitors, and ultimately exhibited proliferation of hepatocytes and cholangiocytes. In contrast, TMX-alphaSMA-SMO mice showed loss of whole liver SMO expression, repression of Hh-genes, enhanced accumulation of quiescent HSC but reduced accumulation of MF, fibrosis and progenitors, as well as inhibition of hepatocyte and cholangiocyte proliferation, and reduced recovery of liver weight. In TMX-alphaSMA-YFP mice, many progenitors, cholangiocytes and up to 25% of hepatocytes were YFP+ by 48-72 h after PH, indicating that liver epithelial cells were derived from alphaSMA-YFP+ cells. CONCLUSIONS: Hh signalling promotes transition of quiescent hepatic stellate cells to fibrogenic MF, some of which become progenitors that regenerate the liver epithelial compartment after PH. Hence, scarring is a component of successful liver regeneration. PMID- 24173294 TI - Gene expression profiling-derived immunohistochemistry signature with high prognostic value in colorectal carcinoma. AB - OBJECTIVE: Gene expression profiling provides an opportunity to develop robust prognostic markers of colorectal carcinoma (CRC). However, the markers have not been applied for clinical decision making. We aimed to develop an immunohistochemistry signature using microarray data for predicting CRC prognosis. DESIGN: We evaluated 25 CRC gene signatures in independent microarray datasets with prognosis information and constructed a subnetwork using signatures with high concordance and repeatable prognostic values. Tumours were examined immunohistochemically for the expression of network-centric and the top overlapping molecules. Prognostic values were assessed in 682 patients from Shanghai, China (training cohort) and validated in 343 patients from Guangzhou, China (validation cohort). Median follow-up duration was 58 months. All p values are two-sided. RESULTS: Five signatures were selected to construct a subnetwork. The expression of GRB2, PTPN11, ITGB1 and POSTN in cancer cells, each significantly associated with disease-free survival, were selected to construct an immunohistochemistry signature. Patients were dichotomised into high-risk and low-risk subgroups with an optimal risk score (1.55). Compared with low-risk patients, high-risk patients had shorter disease-specific survival (DSS) in the training (HR=6.62; 95% CI 3.70 to 11.85) and validation cohorts (HR=3.53; 95% CI 2.13 to 5.84) in multivariate Cox analyses. The signature better predicted DSS than did tumour-node-metastasis staging in both cohorts. In those who received postoperative chemotherapy, high-risk score predicted shorter DSS in the training (HR=6.35; 95% CI 3.55 to 11.36) and validation cohorts (HR=5.56; 95% CI 2.25 to 13.71). CONCLUSIONS: Our immunohistochemistry signature may be clinically practical for personalised prediction of CRC prognosis. PMID- 24173296 TI - Diabetes in bearded women (Achard-Thiers-Syndrome) : A clinical and metabolic study of 20 cases. AB - Twenty patients, selected on the basis of simultaneous existence of overt diabetes and marked hirsutism, were submitted to clinical and biological investigations. Obesity, hypertension and angiopathy were present in most of these patients. Metabolic investigations afforded valuable proof of hypercorticism associated with depressed activity of insulin. Nevertheless, increased steroiduria was also observed in groups of non-hirsute diabetic women carefully paired for age. Thus the Achard-Thiers syndrome cannot be separated with certainty from common overt diabetes. PMID- 24173295 TI - Cluster analysis of cognitive deficits may mark heterogeneity in schizophrenia in terms of outcome and response to treatment. AB - Cognitive impairments are central to schizophrenia, but their clinical utility for tagging heterogeneity in lifetime outcome and response to treatment is not conclusive. By exploiting four cognitive domains consistently showing large deficits in studies, we tested whether cluster analysis would define separate subsets of patients and then whether the disease heterogeneity marked by these clusters would be related to lifetime outcome and response to treatment. A total of 112 schizophrenia patients completed a neuropsychological evaluation. The PANSS, GAF-S and GAF-F were rated at the onset and endpoint of the illness trajectory. A blind judgment of the lifetime response to treatment was made. The first cluster presented near-normal cognitive performance. Two other clusters of severely impaired patients were identified: one generally impaired in the four cognitive domains and another selectively impaired in visual episodic memory and processing speed, each relating to a different lifetime evolution of disease and treatment response. Although the two impaired clusters were clinically indistinguishable in symptom severity and functioning at disease onset, patients with selective cognitive impairments demonstrated better improvement at outcome, whereas the generally impaired patients were more likely to be treatment refractory. The findings have implications for the management of patients and for clinical trials since particular combinations of cognitive deficits in patients would influence their treatment response. PMID- 24173297 TI - Obesity and diabetes mellitus with striking congenital hyperplasia of the islets of langerhans in spiny mice (Acomys Cahirinus) : I. Histological findings and preliminary metabolic observations. AB - Spiny mice (Acomys) are a group of small rodents indigenous to the Eastern Mediterranean and Africa. The Acomys Cahirinus strain reported on here is indigenous to Israel. The strain is characterized by striking and congenital hyperplasia of the islets of Langerhans, primarily of the beta cells. The endocrine tissue contributes up to 15 per cent of the pancreatic mass in adults, up to 25 per cent in the newborn. Pancreatic insulin content may be as high as 100 units per gram wet weight. When fedad libitum in the laboratory approximately one-half of the animals become obese, while approximately 15 per cent develop a diabetes mellitus-like state with moderate hyperglycemia, glucosuria, and, less frequently, ketonuria accompanied by weight loss and, ultimately, death. The development of the diabetic state is associated with degranulation and, later, striking glycogenic degeneration of the beta cells of the islets of Langerhans. There is also severe glycogenic nephrosis and myocardosis and preliminary observations suggest the presence of thickening of the capillary basement membrane of the renal glomeruli and in the endocrine pancreas. The interrelationships of hyperplasia of the islets of Langerhans, obesity, and diabetes mellitus are as yet to be established, as are the genetic characteristics of each of these entities. An important area of potential usefulness derives from the degree of the hyperplasia of the endocrine tissue, since this should greatly facilitate ultrastructural studies, microdissection and transplantation, as well as organ or tissue culture work. Also, the association of anomalies observed in these spiny mice may, through their systematic study, provide clues for the study of the association of diabetes and obesity with relative hyperinsulinism in man. PMID- 24173298 TI - Kidney lesions in rats with severe long-term alloxan diabetes : I. Influence of age, alloxan damage, and insulin administration. AB - Alloxan diabetes was induced in rats by intraperitoneal injection or by injection into the vena cava. In 3 groups the renal vessels were clamped during, and for some minutes after, the injection. The histological appearance of the kidneys after 5, 10 and 15 months of diabetes was compared with findings in groups of untreated rats of the same age as well as in non-diabetic rats treated with insulin throughout comparable periods. The glomeruli of the alloxan diabetic rats showed changes similar but not quite identical to the human diabetic glomerulopathy. These changes were present only after diabetes of 10 months. The main difference is that the rats showed no actual nodules and that the PAS positive hyalinosis of the arterioles, characteristic of human longterm diabetes, was absent. The glomerular changes are not age-conditioned, and the results do not suggest that the administration of insulin or direct alloxan damage played any role in inducing these lesions. Tubular damage (atrophy, dilatation) and interstitial fibrosis were most marked in rats which had not been protected against the high initial alloxan concentration in the blood by clamping the renal vessels. PMID- 24173299 TI - [Not Available]. AB - Serum levels of non-esterified fatty acids, free glycerol and esterified fatty acids were estimated in obese patients and in persons of normal weight after intravenous administration of tolbutamide and glucose. In obesity non-esterified fatty acids and glycerol levels were roughly twice as high as in the non-obese, whereas no difference in levels of esterified fatty acids was found between the two groups. Following administration of tolbutamide or glucose, there was a decrease of concentration of non-esterified fatty acids and glycerol to a minimum during the two hours of observation. In obesity, non-esterified fatty acids and glycerol decreased relatively more than in persons of normal weight. This behaviour is interpreted as due to increased insulin secretion in obesity. The difference in changes in concentration of non-esterified fatty acids and glyoerol in response to a variety of test situations may well be the result of both the glucose-dependent lipogenetic and the glucose-independent antilipolytic effect of insulin. The antilipolytic effect of insulin is discussed with reference to the metabolic aspects of obesity. PMID- 24173300 TI - [Not Available]. AB - Oral (o.GTT) and intravenous glucose tolerance tests (i.v. GTT) were carried out on 492 patients of both sexes, aged from 5 to 78 years. Three hundred and fifty nine non-diabetics in all were suspected clinically of reduced carbohydrate tolerance leaving 133 patients for comparison (controls). In 102 obesity was noted, 221 had a family history of diabetes and 36 had experienced complications with previous pregnancies. Patients were divided into two groups: i.e. below and above 40 years of age and subdivided again according to normal weight or obesity. At the oral test 100 g glucose was given and the blood sugar determined every 30 min for 180 min. The intravenous test was performed according toCONARD's method(5). Age did not affect the glucose tolerance test in the healthy patient (controls), and following oral or intravenous tests no appreciable difference was noted between the younger and older groups, apart from the 60 min oral estimation; the average age of the older group, however, being relatively low at 54 years. Both groups together showed a general upper biological limit (mean value + 2s D ). The oral tests in patients below 40 years of age with accompanying slight obesity, in patients with a family history of diabetes and in patients of normal weight with complications in previous pregnancies, showed no appreciable difference from those of the corresponding age groups of normal weight; yet the intravenous test was significantly different in all groups concerned. In the case of patients of the same age but with gross obesity (more than + 30% according to Broca), in patients with a family history of diabetes with accompanying obesity and in obese patients with complications in previous pregnancies, significantly abnormal curves were found with the oral as well as i.v. test. In the same groups, above the age of 40 years, in comparison with controls of normal weight and corresponding age, the curves of the oral as well as intravenous tests were significantly different and became more so when gross obesity was present or other symptoms were combined with obesity. In patients clinically suspected of impaired glucose tolerance the carbohydrate tolerance became poorer with increasing age and obesity. According to our observations it would appear simpler to elicit a reduced glucose tolerance with the i.v. method than with the oral test. PMID- 24173301 TI - "Bound" insulin: in vivo and in vitro biologic activity. AB - Partially purified preparations of human serum "bound" insulin were injected intraperitoneally or intravenously into intact fed, fasted or fasted-refed rats, or incubatedin vitro with their isolated epididymal adipose tissue. The biologic activity of "bound" insulin on muscle and adipose tissue,in vivo andin vitro, was compared with the activity of crystalline insulin standards. "Bound" and crystalline insulin injected intraperitoneally into rats stimulated the incorporation of glucose-u-(14)C into the glycogen of muscle and into the glycogen and fat of adipose tissue. The activities of both "bound" and crystalline insulin were affected by the nutritional state of the animals. Intravenous administration of partially purified "bound" insulin or crystalline insulin stimulated the incorporation of glucose-u-(14)C into the muscle glycogen of intact fed, fasted or fasted-refed rats and into the fat of the adipose tissue of fed or fasted-refed rats. "Bound" insulin, but not crystalline insulin stimulated fat synthesis in the adipose tissue of fasted rats. "Bound" or crystalline insulin, at the concentration used, failed to stimulate glycogen synthesis in adipose tissue. "Bound" insulin stimulated the oxidation of glucose into CO2 in isolated rat adipose tissue and the incorporation of glucose-u-(14)C into the glycogen and fat of the adipose tissue. The effect of "bound" or crystalline insulin on isolated adipose tissue was also affected by the nutritional state of the animal. PMID- 24173302 TI - [Not Available]. AB - The present study presents a simplified method for the measurement of insulin like activity through its effect on stimulation of glucose-1-(14)C oxidation by adipose tissue. Forty determinations can be carried out by two persons in a single day and only two rats are required. The index of precision is in the neighbourhood of 0.13. When the method was applied to the measurement of total insulin-like activity in dialyzed human serum obtained from fasting subjects, the results obtained varied between 78-1020 MUU/ml (465 +/- 68 MUU/ml). Approximately 40 per cent of the total insulin-like activity was suppressible in the presence of insulin antibodies partially purified from guinea pig serum. This was true both for dialyzed serum from fasting subjects and for acid ethanol extracts of serum. There was no increase in the insulin-like activity of serum upon dilution, provided that the radioactivity of the(14)CO2 formed was directly plotted against the decreasing serum concentrations. A fictitious increase in the insulin-like activity was obtained, however, when the radioactivity was transformed into insulin equivalents by comparison with a standard curve in buffer. It would seem that this is the result of the observation that insulin standard curves in the presence of serum are flatter than is the case in Krebs-Ringer buffer. PMID- 24173303 TI - A quantitative evaluation of the relative efficiency of gelatine and albumin in preventing insulin adsorption to glass. AB - Albumin has been found to be more effective than gelatine in preventing insulin loss from insulin containing solutions. It is probable that this has led to falsely elevated levels of insulin-like activity (ILA) reported with bio-assays. Preparations of crystalline human albumin have been found to be free from ILA and from insulin measured by the radio-immuno-assay. Other human albumin prepared by acid-ethanol extraction (that has been shown previously to contain insulin antagonistic properties on the isolated rat hemidiaphragm) has contained significant ILA on the isolated rat fat pad and also contained insulin demonstrable by radio-immuno-assay. PMID- 24173304 TI - The double-antibody immunoassay of insulin : A standardized second antibody reaction that eliminates spurious results with human serum. AB - 1. Tracer(131)I-guinea-pig gamma globulin provides a useful check of the efficiency of the insulin-antibody precipitation. It is employed (a) for the accurate preliminary standardization of the precipitating antibody; and (b) during assays to assess completeness of precipitation (in monitor tubes). 2. Similar assays of human serum frequently yield spuriously high results; two responsible factors are (a) suboptimal second antibody precipitation arising from accentuation by serum of the "prozone phenomenon", and (b) cross-reaction of rabbit anti-guinea-pig serum with human proteins. The former can be overcome by using ideal concentrations of reactants, prolonging incubation, and incorporating a standard amount of heparin, during the second reaction. The latter is minimized by using a rabbit anti-serum made to pure guinea-pig gamma globulin. 3. The double antibody method, thus modified, has proved consistently reliable. In the assay of human serum samples diluted 1/10 (i.e. 0.1 ml volumes of serum) optimal precipitation always occurs. Undiluted serum samples (i.e. 1.0 ml volumes) can also be assayed satisfactorily, when the occasional sub-optimal precipitation can be identified and a correction derived from the monitor tubes to yield a valid reading. PMID- 24173305 TI - [Not Available]. AB - The object of this study was that of getting additional insight into the mechanism of proteinuria through analysis of the permeability of the glomerular filter for higher molecular weight proteins in patients with proteinuria resulting from diabetic nephropathy. Fifty hospitalized patients with insulin requiring diabetes mellitus were selected according to the presence of proteinuria and divided into two groups: group I, with or without only minor symptoms of diabetic angiopathy; group II, with moderate to severe diabetic nephropathy and retinopathy grades 1 to 3. In all patients the urinary excretion of haptoglobins (Hp) and of isoagglutins (IA) was measured, as well as the Hp level in the serum and the overall profile of serum and urine proteins. The results indicate that the urinary excretion of Hp and IA could be correlated to some extent with the severity of diabetic nephropathy, whereas the serum level of Hp failed to exhibit any clear-cut anomalies in the presence of diabetic angiopathy. In patients with severe nephropathy, the albumin/globulin ratio in the urine was increased approximately twofold over that in serum, despite a grossly unaltered profile of serum proteins. These results suggest that the "functional pore size" of the renal filter is increased in diabetic nephropathy, but that the mechanism of proteinuria also involves degradation of serum proteins during passage through the kidney. PMID- 24173306 TI - [Not Available]. AB - The pancreatic capillaries of 25 diabetics with Kimmelstiel-Wilson glomerulosclerosis and 54 without, were examined for PAS-positive homogeneous thickening of the wall. 70 nondiabetic patients were used as controls. The average age of each of the 3 groups was close to 70 years. Homogeneous capillary lesions were found in approximately 1/3 of the cases with glomerulosclerosis, in 1/7 of those without glomerulosclerosis, and not at all in nondiabetics. The homogeneous lesion is mainly situated in the extrainsular capillaries. Histochemically it differs from the similar PAS-positive nodular lesion in Kimmelstiel-Wilson glomerulosclerosis by a negative result in the periodic acid auramin-Schiff-reaction and its resistance towards pectinase. In the homogeneous lesion of capillaries there is no deposition of fibrin as in hyalinosis of arteries and arterioles. The hyalinosis of the pancreatic islets, repeatedly found in diabetics, has staining properties completely different from the homogeneous capillary lesion. The pathogenesis of this homogeneous capillary lesion remains unclarified. PMID- 24173307 TI - Pathological changes in the central and peripheral nervous system of young long term diabetics : I. Diabetic encephalopathy. AB - A study of the clinical observations and the neuropathological findings in the brain of 16 juvenile diabetics dying of diabetic angiopathy after many years of diabetes is presented. A characteristic histological pattern was observed in all the cases consisting of diffuse degenerative abnormalities of the brain tissue, often with severe pseudocalcinosis or with atrophy of the dentate nucleus, demyelinisation of the cranial nerves, fibrosis of the leptomeninges and angiopathy. The degenerative changes were so pronounced that a dual pathogenesis seems likely; viz. an ischemia caused by the angiopathy and a primary diabetic abnormality of the brain tissue. The clinical symptoms of cerebral disease varied from insignificant to pronounced. A correlation was found between the symptoms and the number of areas of softening in the brain. The histological pattern differs from that seen in other clinical conditions and justifies the term diabetic encephalopathy. PMID- 24173308 TI - The inactivation of the biological properties of insulin by 131 I labelling or irradation. AB - The various biological properties of crystalline insulin labelled with(131)I and crystalline insulin submitted to irradiation were studied. The properties investigated were the hypoglycemie, convulsive and antigenic activities, and the effect on the glucose uptake of the diaphragm and the epididymal fat pad of the rat. It was observed that the(131)I-insulin rapidly lost its hypoglycemie activity and its insulin effectin vitro, whereas the antigenic and the convulsive activities were retained longer. The irradiated insulin behaved in the same manner. The influence of the radioactive labelling was also studied on the reaction between insulin and anti-insulin antibodies. PMID- 24173309 TI - Clinical application of "Dextrostix" in estimating blood glucose levels. AB - 1. In its present form Dextrostix does not provide a reliable measure of blood glucose. 2. When modified and simplified it proved of great value in the management of diabetes in certain clinical situations. PMID- 24173311 TI - Effective utilization and appropriate selection of genetically engineered mouse models for translational integration of mouse and human trials. AB - The landscape of cancer research and therapy has radically changed over the past decades in at least two major respects: Our ability to model cancer in the mouse has risen to an unprecedented level of accuracy at the same time that novel cancer drugs have been developed in record numbers. This has led to an explosion in genetically engineered mouse model (GEMM) research, as GEMMs can potentially be used to test and optimize drugs in a variety of ways: preclinically (before testing in human patients), coclinically (in parallel with human testing), and postclinically (to optimize standard of care therapy). Thus the potential applications of faithful GEMMs of cancer have expanded from analysis of causal relationships between genetic aberrancies and tumorigenesis in preclinical efforts to a more comprehensive and systematic utilization of GEMMs for drug testing and clinical trial optimization. As GEMM research has grown, however, few standard protocols have been put in place regarding GEMM trials done in parallel with human trials (the "coclinical" approach), or in situations in which the available cohort of human patients is too small for valid statistical analysis. The success of such efforts will require an increased attention to the rigor with which mouse and human clinical efforts are designed, executed, and integrated. PMID- 24173312 TI - Infrastructure needs for translational integration of mouse and human trials. AB - Advances in the treatment of human cancer are frequently limited by the inability to test novel drugs and drug combinations in patients in a rapid and streamlined manner. Increasing data from the application of clinically relevant mouse models has highlighted the ability of preclinical trials in mice to address this problem, and has paved the way for what is now termed the "Co-Clinical Trial Project," in which mouse trials are performed concurrently with human trials. This in turn enables efficient patient stratification and therapy optimization based on molecular determinants for effective treatment of cancer. To fully realize the potential of preclinical, coclinical, and postclinical trials in mice, there is a need to establish key principles for carrying out therapeutic mouse trials, to standardize practices for performing such trials, and to establish mouse hospitals where trials can be integrated with corresponding clinical trial efforts in humans. Here we describe critical infrastructural components that are required for effective implementation of such efforts and suggest a model for how mouse hospitals for clinical trials should be established. PMID- 24173313 TI - Structured reporting in anatomic pathology for coclinical trials: the caELMIR model. AB - Electronic media, with their tremendous potential for storing, retrieving, and integrating data, are an essential part of modern collaborative multidisciplinary science. Structured reporting is a fundamental aspect of keeping accurate, searchable electronic records. This discussion on structured reporting in anatomic pathology for pre- and coclinical trials in animal models provides background information for scientists who are not familiar with structured reporting. Practical examples are provided using a working database system for preclinical research-caELMIR (Cancer Electronic Laboratory Management Information and Retrieval)-developed by the U.S. National Cancer Institute's (NCI's) Mouse Models of Human Cancers Consortium (MMHCC). PMID- 24173314 TI - Mouse to human blood-based cancer biomarker discovery strategies. AB - There is an urgent need for noninvasive molecular tests to assist in the detection of cancers. There is additionally a need for prognostic and predictive markers and for monitoring for disease recurrence. The improved understanding of molecular features of common cancers and the availability of genetically engineered mouse models (GEMMs) of cancer have resulted in increased interest in the application of mouse models to the discovery of cancer biomarkers relevant to humans. Unlike humans, mouse models allow sampling of tumor and host tissues and biological fluids at defined time points in the course of tumor development and progression. Interrogation of the genome, transcriptome, proteome, and metabolome of tumors and biological fluids from mouse models engineered to recapitulate human tumors makes it possible to apply a systems approach to define biomarker signatures from the earliest stages of tumor development to advanced stages and metastasis and signatures reflective of driver genes and pathways. PMID- 24173315 TI - Evaluation of cancer immunity in mice. AB - There have been significant advances in the development and application of novel therapeutic approaches and improved diagnostics for cancer in the past decade. Manipulation and/or assessment of cancer-specific immunity have been central to these advances. Murine models are a standard for the preclinical development of cancer immunotherapeutics. However, critical advances in our understanding of the role of the immune microenvironment and the assessment of cancer-specific immunity have not been fully applied to rodent models. Methods to preserve the function of immune cells after cryopreservation and standard approaches to quantitative immune assays have not been developed. Furthermore, a detailed evaluation of the immune tumor environment, which can impact a clinical response to different agents, is rarely undertaken as models are being contemplated. Rapid translation of immunoncology agents to the clinic will require standardization of immunologic assay methods and a more detailed immunologic characterization of common mouse models. Outlined here are the critical elements in assessing immunity in cancer mouse models and suggestions concerning the standardization of approaches when using these models for the study of immunoncology. PMID- 24173316 TI - Cross-species analysis of mouse and human cancer genomes. AB - Fundamental advances in our understanding of the human cancer genome have been made over the last five years, driven largely by the development of next generation sequencing (NGS) technologies. Here we will discuss the tools and technologies that have been used to profile human tumors, how they may be applied to the analysis of the mouse cancer genome, and the results thus far. In addition to mutations that disrupt cancer genes, NGS is also being applied to the analysis of the transcriptome of cancers, and, through the use of techniques such as ChIP Seq, the protein-DNA landscape is also being revealed. Gaining a comprehensive picture of the mouse cancer genome, at the DNA level and through the analysis of the transcriptome and regulatory landscape, will allow us to "biofilter" for driver genes in more complex human cancers and represents a critical test to determine which mouse cancer models are faithful genetic surrogates of the human disease. PMID- 24173318 TI - Halofuginone induces the apoptosis of breast cancer cells and inhibits migration via downregulation of matrix metalloproteinase-9. AB - Halofuginone (HF) is extracted from Dichroa febrifuga, a plant used in traditional medicine. We report that the HF extract inhibits the growth of breast cancer cells and induces the generation of reactive oxygen species (ROS) and apoptosis, an important feature of potential anticancer agents. In addition, HF significantly reduces the migration and invasion of MCF-7 and MDA-MB-231 human breast cancer cells after 12-O-tetraecanoylphorbol-13-acetate (TPA) stimulation. As matrix metalloproteinase-9 plays a critical role in tumor metastasis, we analyzed its expression with the HF extract treatment. Western blot analysis and gelatin zymography showed that HF suppresses MMP-9 expression and activity concentration-dependently. HF also decreases the nuclear protein levels of nuclear factor kappa B (NF-kappaB) and c-fos (AP-1), critical transcription factors regulating MMP-9 expression through binding the MMP-9 promoter region. Luciferase assays showed that HF decreases TPA-induced MMP-9 promoter binding activities of NF-kappaB and AP-1. Taken together, these are the first results indicating that halofuginone may represent a promising new agent for breast cancer chemotherapy. PMID- 24173320 TI - Preface. PMID- 24173322 TI - Executive summary. PMID- 24173319 TI - Theoretical insights into the adsorption of neutral, radical and anionic thiophenols on gold(111). AB - The interaction of thiol and thiolate containing molecules with gold (S-Au) has gained increasing interest because of its applications in molecular electronic devices and catalysis. In this context, the enhanced conductivity of thiophenol compared to alkanethiol represents an opportunity to develop more sensitive and selective gold-based devices by incorporating molecules with the aryl-thiol moiety into their structures. As has been proposed earlier, the thiol moiety is deprotonated after binding to gold, hence, we present here a comparative study of the S-Au bond strength between several neutral and deprotonated aromatic-sulfur systems in their anionic and radical forms with a detailed description of the nature of this interaction. The study was performed by means of computational chemistry methods, using a cluster of 42 Au atoms as a model of the Au(111) surface that allowed us to provide new chemical insights to control the S-Au interface interaction strength. Our results revealed that the thiophenols-gold interaction is mainly dispersive where the interaction energies range between 31 and 43 kcal mol(-1). The radical and anionic thiophenolates-gold interaction increases due to a strong charge transfer character, depicting interaction energies in the range of 50 to 55 kcal mol(-1) and 62 to 92 kcal mol(-1), respectively. These results suggest that for the anionic thiophenolate the binding strength can be tailored according to the electron-donor capabilities of the ligand which in turn can be finely tuned by several substituents. Our results are of possible impact for the design of new devices. PMID- 24173317 TI - Comprehensive quantitative comparison of the membrane proteome, phosphoproteome, and sialiome of human embryonic and neural stem cells. AB - Human embryonic stem cells (hESCs) can differentiate into neural stem cells (NSCs), which can further be differentiated into neurons and glia cells. Therefore, these cells have huge potential as source for treatment of neurological diseases. Membrane-associated proteins are very important in cellular signaling and recognition, and their function and activity are frequently regulated by post-translational modifications such as phosphorylation and glycosylation. To obtain information about membrane-associated proteins and their modified amino acids potentially involved in changes of hESCs and NSCs as well as to investigate potential new markers for these two cell stages, we performed large-scale quantitative membrane-proteomic of hESCs and NSCs. This approach employed membrane purification followed by peptide dimethyl labeling and peptide enrichment to study the membrane subproteome as well as changes in phosphorylation and sialylation between hESCs and NSCs. Combining proteomics and modification specific proteomics we identified a total of 5105 proteins whereof 57% contained transmembrane domains or signal peptides. The enrichment strategy yielded a total of 10,087 phosphorylated peptides in which 78% of phosphopeptides were identified with >=99% confidence in site assignment and 1810 unique formerly sialylated N-linked glycopeptides. Several proteins were identified as significantly regulated in hESCs and NSC, including proteins involved in the early embryonic and neural development. In the latter group of proteins, we could identify potential NSC markers as Crumbs 2 and several novel proteins. A motif analysis of the altered phosphosites showed a sequence consensus motif (R-X XpS/T) significantly up-regulated in NSC. This motif is among other kinases recognized by the calmodulin-dependent protein kinase-2, emphasizing a possible importance of this kinase for this cell stage. Collectively, this data represent the most diverse set of post-translational modifications reported for hESCs and NSCs. This study revealed potential markers to distinguish NSCs from hESCs and will contribute to improve our understanding on the differentiation process. PMID- 24173323 TI - 1. Introduction. PMID- 24173324 TI - 2. Optimized Treatment Planning for IMRT. PMID- 24173325 TI - 3. Special Considerations Regarding Absorbed-Dose and Dose-Volume Prescribing and Reporting in IMRT. PMID- 24173326 TI - 4. Definition of volumes. PMID- 24173327 TI - 5. Planning aims, prescription, and technical data. PMID- 24173328 TI - Appendix A: Physical Aspects of IMRT. PMID- 24173329 TI - Appendix B: clinical examples. PMID- 24173333 TI - Cloning vectors of mitochondrial origin for eukaryotes: A new concept in genetic engineering. PMID- 24173334 TI - Replication and recombination of 2-um DNA in Schizosaccharomyces pombe. AB - Any one of the inverted sequences present on the 2-um DNA from Saccharomyces cerevisiae can promote replication of chimeric plasmids in Schizosaccharomyces pombe. When however a complete 2-um molecule is present on the transforming plasmids, these are very unstable and systematically rearranged in S. pombe. Two types of transformation are observed in this case. One results from chromosomal integration of the incoming DNA. The second is dependent on a site specific recombination event between two molecules of the incoming DNA and results in a stably replicating dimeric structure. The choice between both pathways seems to depend on the expression of 2-um function(s) in S. pombe. PMID- 24173335 TI - Mapping the Chloroplast DNA of Vicia faba. AB - A complete clone bank representing the chloroplast DNA from Vicia faba has been constructed. A total of 15 fragments (10 Pst1, 1 Pst1-EcoR1 and 4 Sal1 fragments) were inserted into the vector pBR322 and transformed into the E. coli strain HB101. The cloned fragments were used as the main tools in constructing the physical map of Vicia faba for the restriction endonucleases Pst1, Kpn1 and Xho1. The identity of the cloned fragments was demonstrated by restriction analysis and blot hybridization. The information generated was used to construct the map. The 16S and 23S rRNA genes and the gene for the large subunit of ribulose-1,5 bisphosphate carboxylase have been positioned on the map using heterologous probes. The orientation of the gene for the large subunit of RuBP carboxylase has also been determined. PMID- 24173336 TI - In vivo transcriptional products of the chloroplast DNA of Euglena gracilis. AB - Cloned chloroplast restriction endonuclease DNA fragments were used as hybridization probes to identify the in vivo transcriptional products of the chloroplast genome from the alga Euglena gracilis. Total cellular RNA was size fractionated by electrophoresis in denaturing gels and transferred to nitrocellulose paper. Individual plasmids containing specific chloroplast DNA fragments were radioactively labeled in vitro and hybridized to the immobilized RNA. The stable RNAs in the chloroplast were identified on the basis of their size and their origin on the chloroplast genome. Several transcripts were shown to be developmentally expressed. Some transcripts showed a possible precursor product relationship. The rDNA was shown to be transcribed as a large transcript and then processed to the, mature rRNAs. PMID- 24173337 TI - The mitochondrial genome of the fission yeast schizosaccharomyces pombe : I. isolation and physical mapping of mitochondrial DNA. AB - 1) We have identified by electron microscopy and isolated a circular DNA species of approximately 6 um contour length from DNase treated mitochondrial fractions of the petite negative yeast Schizosaccharomyces pombe (S. pombe). 2) Another molecular species of about 3 um length is also present in mitochondrial fractions. These molecules, however, disappear after DNase treatment or extensive washing, indicating their extramitochondrial location. There is evidence (Fournier et al. 1981) that these molecules represent a multicopy plasmid coding for the genes of cytoplasmic ribosomal RNAs. 3) A restriction enzyme cleavage map of the 6 um species was constructed using twelve enzymes. Physical mapping revealed a genome length of approximately 18.9 kilobase pairs, thus confirming the electron microscopic data. 4) Northern hybridization of mitochondrial RNA with restriction fragments of mitochondrial DNA revealed two major signals which are attributed to the small and large ribosomal RNA. Apparently both rRNA genes map close together. 5) Spontaneous mit(-) deletion mutants were characterized phenotypically and the location of their deletions was determined. 6) In strains carrying a cytoplasmic mutator (Seitz-Mayr and Wolf 1982) or derived from mutator strains four restriction sites have been mapped, which are not present in the mitochondrial DNA of the parental strain. These extra sites are very likely consequences of the action of the mutator. 7) In conclusion we have presented evidence that the 6 um circular DNA species is the mitochondrial genome of fission yeast. Special features of this genome are discussed in comparison with other mitochondrial genomes. PMID- 24173338 TI - A mutant of Saccharomyces cerevisiae defective in arginyl-tRNA-protein transferase. AB - A mutant of Saccharomyces cerevisiae deficient in arginyl-tRNA-protein transferase has been isolated. The responsible mutation designated ate1, was localized near the centromere of chromosome VII. It probably involves the structural gene for the transferase since residual enzyme activity in the mutant is temperature-sensitive. PMID- 24173339 TI - Uracil-DNA glycosylase defective mutants of Ustilago maydis. AB - Uracil-DNA glycosylase activity can be measured in cell-free extracts of Ustilago maydis and in its general properties the enzyme resembles the same glycosylase from other organisms. A rapid assay was used to screen nearly 1,000 clones from cells treated with N-methyl-N'-nitro-N-nitrosoguanidine, and five isolates had <1 30% of wild-type enzyme activity. All these ung (-) strains were unstable since they frequently recovered normal enzyme activity (ung (+)), and two were lost for this reason. The ung (-) strains were also variable in morphology, and two which were slow growing, produced faster growing ung (+) sectors. However, in preliminary experiments, ung (-) strains were shown to be only weak mutators. Two ung (-) mutants were crossed to wild-type and ung (-1) progeny were recovered, which were also variable in morphology and reverted to ung (+). It was found that a standard metabolic enzyme, glucose-6-phosphate dehydrogenase, was significantly more heat-labile in ung (-) strains than wild-type. The results indicate that the presence of uracil in DNA may have more severe physiological effects in eukaryotes than in prokaryotes. Over 1,000 isolates form Chinese hamster ovary (CHO) cells treated with ethyl methane sulphonate, were also tested for uracil DNA glycosylase activity, but no stable ung (-) strain was recovered. PMID- 24173340 TI - Multiple drug resistance in the fission yeast Schizosaccharomyces pombe: Correlation between drug and amino acid uptake and membrane ATPase activities. AB - Cyh3 and cyh4, multiple drug resistant strains of Schizosaccharomyces pombe, show a much reduced uptake of trichodermin, chloramphenicol, cycloheximide, L-lysine, glycine, L-threonine, L-glutamine, L-arginine and L-glutamic acid when compared to wild type. The plasma membrane and mitochondrial ATPase activities of these mutants are also greatly reduced. Since the uptake of such compounds is likely to be driven by a proton electrochemical gradient set up by the membrane ATPase it is suggested that the primary effect of these mutations is at the level of the membrane ATPase. Another drug resistant strain, cyh1, which is resistant only to high levels of cycloheximide, shows increased uptake of trichodermin, L-lysine, glycine, L-threonine, L-glutamine when compared to wild type. The plasma membrane and mitochondrial ATPases of cyh1 are considerably greater than those of wild type. It has been shown previously that cyh1 possesses an altered 60S ribosonal subunit protein when compared to wild type and this makes it resistant to cycloheximide. There is no obvious explanation as to how this change could lead to the alterations in drug and amino acid uptake and in ATPase activities observed. PMID- 24173341 TI - Mating factor dependence of G1 cell cycle mutants of Saccharomyces cerevisiae. AB - Mutants in four G1 cdc strains of Saccharomyces cerevisiae were isolated which failed to show division arrest in the presence of alpha-factor. The cell cycle properties, terminal arrest morphology and mating competence of these mutants at the restrictive temperature were examined. The G1 specific arrest of the cdc 36 and cdc39 mutants is dependent upon the availability of an intact mating factor response system in Mat a cells. Cdc28 and cdc37 mutants exert their cell cycle blocks independently of the mating factor pathway. It is likely that the nature of the primary growth defect in cdc36 and cdc39 mutants is such that the alpha factor pathway is activated in the absence of the pheromone at the restrictive temperature and that G1 arrest is a secondary consequence of a non-cycle specific event in such mutants. PMID- 24173342 TI - Meiotic dysgenesis associated with behavioral mutants of Phycomyces. AB - Phycomyces mutants, recently isolated for enhanced bending responses (hypertropic phenotype), have unusual genetic properties. In sexual crosses between hypertropic mutants and other strains, the progeny showed the following features: a) many incomplete tetrads, b) distortion of segregation ratios, c) progeny with nonparental phenotypes when hypertropic strains carrying mutations in the same gene or even the same allele were crossed, and d) morphologically abnormal progeny with phenotypes unrelated to those of the parents. In particular, the mesophorogenic colonies, which produced short sporangiophores, were genetically unstable; their mycelia produced sectors with normal morphology and segregated several alleles for different markers. Most of the phenomena (mutation, segregation distortion, and sterility) described in this paper resemble the "hybrid dysgenesis" syndrome in Drosophila. The results suggest that all seven hypertropic mutations affect the process of meiosis and thereby lead to unstable aneuploid progeny. PMID- 24173343 TI - Some genetical and biochemical attempts to elucidate the energetics of sugar uptake and explain the Kluyver effect in the yeast Kluyveromyces lactis. AB - A mutant of Kluyveromyces lactis is described which did not grow with substrates giving the Kluyver effect. In addition it could not grow with non-fermentable carbon sources, although it was not respiratory deficient. Abolition of respiration by cyanide also caused inability to grow with substrates showing the Kluyver effect in the wild-type strain. When the yeasts were using substrates showing the Kluyver effect, shifting to anaerobic conditions gave an immediate decrease in the intracellular concentration of D-glucose 6-phosphate. The results obtained were consistent with the need of a common respiratory and/or anabolic pathway for the utilization of these substrates. PMID- 24173344 TI - Evaluation of the neuromuscular compartments in the peroneus longus muscle through electrical stimulation and accelerometry. AB - BACKGROUND: Muscles are innervated exclusively by a nerve branch and possess definite actions. However, mammalian skeletal muscles, such as the trapezius, the medial gastrocnemius, and the peroneus longus, are compartmentalized. In the peroneus longus muscle, multiple motor points, which innervate individual neuromuscular compartments (NMC), the superior (S-NMC), anteroinferior (AI-NMC), and posteroinferior (PI-NMC), have been described. The contribution of each neuromuscular compartment to the final action of the muscle is fundamental for the rehabilitation of patients afflicted by neurological and muscle dysfunctions. Interventions are often based on electrical principles that take advantage of the physiological characteristics of muscles and nerves to generate therapeutic effects. OBJECTIVE: To compare the effects of stimulating the different neuromuscular compartments (NMCs) of the peroneus longus muscle on the motor threshold (MT) and acceleration of the foot. METHOD: This is a cross-sectional study comprising 37 subjects. The three NMCs of the peroneus longus muscle were stimulated, and the acceleration of the foot and the motor threshold of each NMC were evaluated. A repeated measures analysis of variance with Bonferroni corrections of two intra-subjects factors was performed. RESULTS: The stimulation of the different NMCs did not result in any differences in MT (F=2.635, P=0.079). There were significant differences between the axes of acceleration caused by the stimulation of the different NMCs (F=56,233; P=0.000). The stimulation of the posteroinferior compartment resulted in the greatest acceleration in the X-axis (mean 0.614; standard deviation 0.253). CONCLUSIONS: The posteroinferior compartment primarily contributes to the eversion movement of the foot. NMCs have specific functional roles that contribute to the actions of the muscles to which they belong. PMID- 24173345 TI - Effects of dorsal and lateral decubitus on peak expiratory flow in healthy subjects. AB - BACKGROUND: One of the measures of the pulmonary function is the peak expiratory flow (PEF) that can be defined as the major flow obtained in an expiratory pressure after a complete inspiration to the level of the total lung capacity. This measure depends on the effort and strength of expiratory muscles, the airway diameter and the lung volume. OBJECTIVE: To compare the results of the peak expiratory flow in healthy male and female obtained in a seated position and dorsal decubitus (DD), right lateral decubitus (RLD) and left lateral decubitus (LLD). METHOD: Thirty young subjects with mean age 22.7 years, healthy and non smokers were included at the study, 15 of male sex. They did spirometry and IPAQ questionnaire to check the normal pulmonary function and physical activity level. The measures of PEF were performed in four positions, being performed 3 measures in which position, in a random order. Statistical analysis was performed according to Student's t test, with significance level set at 5%. RESULTS: There was a difference between the values obtained in sitting position (481+/-117.1 L/min) with DD(453.2+/-116.3 L/min) and RLD (454+/-112.9 L/min) (p<0.05), however, did not find a significant difference between the sitting position and LLD (469+/-83 L/min). CONCLUSIONS: Body position affects the values of PEF, with decreasing values in DD and RLD. The LLD can be an alternative to optimize the expiratory flow in situations of constraint to the sitting position. PMID- 24173346 TI - The effect of outpatient physical therapy intervention on pelvic floor muscles in women with urinary incontinence. AB - OBJECTIVE: To assess the effect of a weekly, short-term physical therapy intervention on the pelvic floor muscles and urinary incontinence (UI) among patients of the public health system. METHOD: Quasi-experimental before-and-after study. Clinical history and function evaluation were performed using perineal bidigital maneuvers and perineometry. The intervention consisted of transvaginal electrical stimulation and pelvic floor kinesiotherapy. Data were analyzed using the paired t test or Wilcoxon signed-rank test, Pearson product-moment correlation coefficient or Spearman's rank correlation coefficient. A value of P<0.05 was considered significant. RESULTS: Eight-two women 55.1+/-10.9 years-old were evaluated. Mixed urinary incontinence (MUI), stress urinary incontinence (SUI) and urge urinary incontinence (UUI) were observed in 52.4%, 36.6% and 11%, respectively. The length of UI was 6.0 years (3.0-10). Approximately 13.64 physical therapy sessions were held on average. There was no difference in perineometry measurements following the intervention (40.6+/-24.1 versus 41.7+/ 25.4, P=0.098). Muscle function significantly increased (P<0.01) in the bidigital maneuver. The patients reported being continent or satisfied with the treatment in 88.9% of cases. CONCLUSIONS: The results demonstrated an increase in muscle function and the attainment of urinary continence or treatment satisfaction in most cases. PMID- 24173347 TI - Gross Motor Function Classification System Expanded & Revised (GMFCS E & R): reliability between therapists and parents in Brazil. AB - BACKGROUND: Several studies have demonstrated the importance of using the Gross Motor Function Classification System (GMFCS) to classify gross motor function in children with cerebral palsy, but the reliability of the expanded and revised version has not been examined in Brazil (GMFCS E & R). OBJECTIVE: To determine the intra- and inter-rater reliability of the Portuguese-Brazil version of the GMFCS E & R applied by therapists and compare to classification provided by parents of children with cerebral palsy. METHOD: Data were obtained from 90 children with cerebral palsy, aged 4 to 18 years old, attending the neurology or rehabilitation service of a Brazilian hospital. Therapists classified the children's motor function using the GMFCS E & R and parents used the Brazilian Portuguese version of the GMFCS Family Report Questionnaire. Intra- and inter rater reliability was obtained through percentage agreement and Cohen's unweighted Kappa statistics (k). The Chi-square test was used to identify significant differences in the classification of parents and therapists. RESULTS: Almost perfect agreement was reached between the therapists [K=0.90 (95% confidence interval 0.83-0.97)] and intra-raters (therapists) with K=1.00 [95% confidence interval (1.00-1.00)], p<0.001. Agreement between therapists and parents was substantial (k=0.716, confidence interval 0.596-0.836), though parents classify gross motor impairment more severely than therapists (p=0.04). CONCLUSIONS: The Portuguese version of the GMFCS E & R is reliable for use by parents and therapists. Parents tend to classify their children's limitations more severely, because they know their performance in different environments. PMID- 24173348 TI - Stabilometric response during single-leg stance after lower limb muscle fatigue. AB - OBJECTIVE: This study sought to analyze the effect of muscle fatigue induced by active isotonic resistance training at a moderate intensity by measuring the knee extension motion during the stabilometric response in a single-leg stance among healthy university students who perform resistance training on a regular basis. METHOD: Eleven healthy university students were subjected to a one-repetition maximum (1RM) test. In addition, stabilometric assessment was performed before and after the intervention and consisted of a muscle fatiguing protocol, in which knee extension was selected as the fatiguing task. The Shapiro-Wilk test was used to investigate the normality of the data, and the Wilcoxon test was used to compare the stabilometric parameters before and after induction of muscle fatigue, at a significance level of p<=0.05. Descriptive statistics were used in the analysis of the volunteers' age, height, body mass, and body mass index (BMI). RESULTS: The sample population was 23.1+/-2.7 years of age, averaged 1.79.2+/-0.07 m in height and 75.6+/-8.0 Kg in weight, and had a BMI of 23.27+/ 3.71 Kg.m-2. The volunteers performed exercises 3.36+/-1.12 days/week and achieved a load of 124.54+/-22.07 Kg on 1RM and 74.72+/-13.24 Kg on 60% 1RM. The center of pressure (CoP) oscillation on the mediolateral plane before and after fatigue induction was 2.89+/-0.89 mm and 4.09+/-0.59 mm, respectively, while the corresponding values on the anteroposterior plane were 2.5+/-2.2 mm and 4.09+/ 2.26 mm, respectively. The CoP oscillation amplitude on the anteroposterior and mediolateral planes exhibited a significant difference before and after fatigue induction (p=0.04 and p=0.05, respectively). CONCLUSIONS: The present study showed that muscle fatigue affects postural control, particularly with the mediolateral and anteroposterior CoP excursion. PMID- 24173349 TI - Comparison of quality-of-life instruments for assessing the participation after stroke based on the International Classification of Functioning, Disability and Health (ICF). AB - BACKGROUND: According to the International Classification of Functioning, Disability and Health (ICF), the participation component is considered to be the most complex component characterized in existing instruments that assess quality of life related to health (HRQoL). Questionnaires such as the Nottingham Health Profile (NHP) and the Stroke-Specific Quality of Life (SS-QOL) are currently used to evaluate the participation of individuals in life activities after stroke. However, because participation and HRQoL are different constructs, it is unclear whether these instruments are best suited to this evaluation. OBJECTIVE: To investigate whether the NHP and SS-QOL are suitable instruments for assessing the participation component of ICF. METHOD: A cross-sectional study was conducted in which a sample of 35 individuals completed the SS-QOL and NHP. The study correlated the total score on the questionnaires with the scores on items that evaluate the participation component of the ICF. Both analyses used the Spearman correlation coefficient (r). RESULTS: There was a statistically significant, positive and strong correlation between total score on the SS-QOL and NHP and the score on specific components related to participation (r=0.8, p=0.001 and r=0.9, p=0.001, respectively). CONCLUSIONS: Both the NHP and the SS-QOL show strong correlations between the total score and the score on items that assess the participation categories of the ICF. However, the SS-QOL questionnaire appeared to be the most complete for this assessment because it evaluates more distinct domains and contains the largest number of items related to participation. PMID- 24173350 TI - Strength of the respiratory and lower limb muscles and functional capacity in chronic stroke survivors with different physical activity levels. AB - BACKGROUND: The assessment of strength and its relationships with functional capacity could contribute to more specific and effective disability management of stroke survivors. OBJECTIVE: To compare and investigate associations between measures of strength and functional capacity of 98 chronic stroke survivors, stratified into three groups, according to their physical activity levels. METHOD: The physical activity levels were classified as impaired, moderately active, and active, based on their Human Activity Profile (HAP) scores. Strength was assessed by the maximal inspiratory (MIP) and expiratory (MEP) pressures and by the residual deficits (RDs) of work of the lower limb and trunk muscles, whereas functional capacity was evaluated by the distance covered during the six minute walking test (6MWT). RESULTS: One-way analyses of variance revealed significant differences between the groups, except between the active and moderately active groups regarding the RDS of the hip and knee flexors/extensors and ankle dorsiflexors (2.91 C57BL6/J) mice. Diabetes was associated with an increase in the M1-to-M2 ratio by 6 wk after the induction of diabetes. Macrophage depletion in diabetic CD11b-DTR mice significantly attenuated albuminuria, kidney macrophage recruitment, and glomerular histological changes and preserved kidney nephrin and podocin expression compared with diabetic CD11b DTR mice treated with mutant DT. These data were confirmed in chimeric mice indicating a direct role of bone marrow-derived macrophages in DN. In vitro, podocytes grown in high-glucose media significantly increased macrophage migration compared with podocytes grown in normal glucose media. In addition, classically activated M1 macrophages, but not M2 macrophages, induced podocyte permeability. These findings provide evidence showing that macrophages directly contribute to kidney injury in DN, perhaps by altering podocyte integrity through the proinflammatory M1 subset of macrophages. Attenuating the deleterious effects of macrophages on podocytes could provide a new therapeutic approach to the treatment of DN. PMID- 24173357 TI - Semicarbazide-sensitive amine oxidase and kidney disease. AB - With better understanding of the molecular mechanisms underpinning chronic kidney disease, the roles of inflammation and fibrosis are becoming increasingly inseparable. The progression of renal disease is characterized by pathomorphological changes that consist of early inflammatory responses followed by tubulointerstitial fibrosis, tubular atrophy, and glomerular and vascular sclerosis. Currently available therapies that reduce hypertension, proteinuria, hyperglycemia, and interruption of the renin-angiotensin-aldosterone system are at best only partially effective. Hence, there remains a need to explore agents targeting nonrenin-angiotensin-aldosterone system pathways. In this review, we discuss mechanistic aspects in the physiological and pathological role of semicarbazide-sensitive amine oxidase, a protein enzyme involved in cellular trafficking and inflammation, with respect to the kidney. We explore the evidence for the use of semicarbazide-sensitive amine oxidase inhibitors as potential agents in renal fibrosis to delay the onset and progression of chronic kidney disease. PMID- 24173358 TI - Hyperuricemia predicts future metabolic syndrome: a 4-year follow-up study of a large screened cohort in Okinawa, Japan. AB - The aim of this study was to determine whether hyperuricemia could predict future metabolic syndrome (MetS) in a large screened cohort of Japanese male and female subjects. We evaluated 5936 subjects (3144 male subjects, 2792 female subjects; mean age 48.7 years) who underwent health checkup programs in 2006 and 2010, who were MetS free in 2006. At baseline, hyperuricemia was detected in 927 male subjects (29.5%) and 276 female subjects (9.9%). Subjects with baseline hyperuricemia had significantly higher MetS prevalence in 2010 than those without (male subjects: 34.8 vs. 20.6%, P<0.0001; female subjects: 15.6 vs. 4.8%, P<0.0001). Compared with subjects in the first quintile of uric acid levels at baseline, the age-adjusted odds ratios (ORs) for MetS cumulative incidence among subjects in the third, fourth and fifth quintiles were, 1.8 (95% confidence interval (CI): 1.4-2.4: P<0.0001), 2.1 (95% CI: 1.6-2.8: P<0.0001) and 3.2 (95% CI: 2.4-4.1: P<0.0001), respectively, for male subjects and 2.4 (95% CI: 1.3-4.7: P=0.0075), 3.0 (95% CI: 1.6-5.7: P=0.0010) and 4.8 (95% CI: 2.6-8.8: P<0.0001), respectively for female subjects. Multivariable logistic analysis revealed that hyperuricemia was significantly associated with MetS cumulative incidence in male subjects (OR 1.5: 95% CI: 1.3-1.8, P<0.0001) and female (OR 2.0, 95% CI: 1.3-3.0, P<0.0001). In conclusion, hyperuricemia is a significant and independent predictor of MetS in Japanese male and female subjects. For both genders, MetS risk increases with increased serum uric acid levels. PMID- 24173359 TI - Understanding of sodium content labeled on food packages by Japanese people. AB - Salt reduction is one of the most important lifestyle modifications for the prevention of hypertension. The health promotion law regulates the labeling of the nutrient content of food in Japan and, the level of sodium, not salt (sodium chloride), has to be printed on the labels of manufactured foods. In order to control their salt intake, consumers need to apply a conversion factor to the sodium levels listed on the labels to obtain the salt equivalent. However, it is not known whether people have the knowledge appropriate for making the conversion. We carried out a questionnaire survey at the 7th National Shokuiku (food education) Conference in 2012, asking subjects to determine the salt equivalent of 1000 mg of sodium on food labels. We also asked about the target values of salt reduction in grams in the Dietary Reference Intakes for Japanese 2010 (DRI2010) and the Guidelines for Management of Hypertension 2009 by the Japanese Society of Hypertension (JSH2009). We analyzed the data from 683 respondents (169 men and 514 women); only 13.3% of respondents gave a correct answer for the salt equivalent of 1000 mg of sodium (2.50-2.60 g), whereas 61.8 and 40.4% of respondents chose the correct target values for salt reduction according to DRI2010 and JSH2009, respectively. In conclusion, few people could convert sodium content to salt, which suggested difficulty in using food labels to control their salt intake. Salt content in grams, not sodium content, should be labeled on food packages for effective salt reduction and prevention of hypertension. PMID- 24173360 TI - Macro- and microvascular alterations in patients with metabolic syndrome: sugar makes the difference. AB - Metabolic syndrome (MS) is associated with adverse cardiovascular events, although its prognostic significance over and beyond the clustering risk factors is controversial. Moreover, there are no data on the possible differentiation of target organ damage among patients with MS according to the grade of its distinct components. We studied 500 hypertensive patients with MS and we assessed vascular damage according to glucose metabolic status (1, normal glucose metabolism (NG); 2, impaired fasting glucose (IFG); 3, impaired glucose tolerance (IGT); and 4, diabetes mellitus II (DM II)). Macrovascular damage was assessed with arterial stiffness by measuring carotid-femoral pulse wave velocity (PWV). Microvascular damage was assessed with albumin excretion by estimating the albumin-creatinine ratio (ACR). There was a significant progressive increase in PWV from group 1 to group 4 (from 7.97 to 8.83 to 8.94 to 10.27 m s(-1), respectively) that remained statistically significant even after adjustment for several confounders (P<0.001). Similar trends were also observed for ACR (from 27.44 to 29.94 to 36.26 to 73.07 mg g(-1), P<0.001). In multiple regression analysis, both PWV and ACR were independently related to glucose metabolic status (P=0.001 and P<0.001, respectively). Vascular alterations among patients with MS differ according to the grade of glucose dysregulation. Considering the adverse prognostic role of arterial stiffness and microalbuminuria, it might be argued that the cardiovascular risk is not homogeneously distributed among patients with MS but is largely determined by glucose metabolic status. PMID- 24173361 TI - Temporal variations of NDVI and correlations between NDVI and hydro climatological variables at Lake Baiyangdian, China. AB - In this paper, correlations between vegetation dynamics (represented by the normalized difference vegetation index (NDVI)) and hydro-climatological factors were systematically studied in Lake Baiyangdian during the period from April 1998 to July 2008. Six hydro-climatological variables including lake volume, water level, air temperature, precipitation, evaporation, and sunshine duration were used, as well as extracted NDVI series data representing vegetation dynamics. Mann-Kendall tests were used to detect trends in NDVI and hydro-climatological variation, and a Bayesian information criterion method was used to detect their abrupt changes. A redundancy analysis (RDA) was used to determine the major hydro climatological factors contributing to NDVI variation at monthly, seasonal, and yearly scales. The results were as follows: (1) the trend analysis revealed that only sunshine duration significantly increased over the study period, with an inter-annual increase of 3.6 h/year (p < 0.01), whereas inter-annual NDVI trends were negligible; (2) the abrupt change detection showed that a major hydro climatological change occurred in 2004, when abrupt changes occurred in lake volume, water level, and sunlight duration; and (3) the RDA showed that evaporation and temperature were highly correlated with monthly changes in NDVI. At larger time scales, however, water level and lake volume gradually became more important than evaporation and precipitation in terms of their influence on NDVI. These results suggest that water availability is the most important factor in vegetation restoration. In this paper, we recommend a practical strategy for lake ecosystem restoration that takes into account changes in NDVI. PMID- 24173362 TI - In vivo differentiation of human periodontal ligament cells leads to formation of dental hard tissue. AB - OBJECTIVE: Following trauma, periodontal disease, or orthodontic tooth movement, residual periodontal ligament (PDL) cells at the defect site are considered mandatory for successful regeneration of the injured structures. Recent developments in tissue engineering focus, as one pillar, on the transplantation of PDL cells to support periodontal regeneration processes. Here, we examined the ability of osteogenically predifferentiated PDL cells to undergo further osteoblastic or cementoblastic differentiation and to mineralize their extracellular matrix when transplanted in an in vivo microenvironment. MATERIALS AND METHODS: Using collagen sponges as carriers, osteogenically predifferentiated human PDL cells were transplanted subcutaneously into six immunocompromised CD 1(r) nude mice. Following explantation after 28 days, osteogenic and cementogenic marker protein expression was visualized immunohistochemically. RESULTS: After 28 days, transplanted PDL cells revealed both cellular, cytoplasmatic and extracellular immunoreactivity for the chosen markers alkaline phosphatase, osteopontin, PTH-receptor 1, and osteocalcin. Specific osteogenic and cementoblastic differentiation was demonstrated by RUNX2 and CEMP1 immunoreactivity. Early stages of mineralization were demonstrated by calcium and phosphate staining. CONCLUSION: Our results reinforce the previously published reports of PDL cell mineralization in vivo and further demonstrate the successful induction of specific osteogenic and cementogenic differentiation of transplanted human PDL cells in vivo. These findings reveal promising possibilities for supporting periodontal remodeling and regeneration processes with PDL cells being potential target cells with which to influence the process of orthodontically induced root resorption. PMID- 24173363 TI - Classification of temporomandibular joint erosion, arthritis, and inflammation in patients with juvenile idiopathic arthritis. AB - INTRODUCTION: Juvenile idiopathic arthritis is the most common disease in pediatric rheumatology. It is characterized by chronically progressive joint destruction. The temporomandibular joints (TMJs) are involved in up to 87% of patients and may take an asymptomatic course in 69% of cases. Other than contrast enhanced magnetic resonance imaging (MRI), there are no reliable screening symptoms or non-invasive procedures available to diagnose the inflammation in its acute form. The goal of this study was to establish an imaging-based classification system for TMJ erosion via MRI and cone-beam computed tomography (CBCT) in an effort to improve indication-specific treatment approaches and to facilitate the comparison of findings. MATERIALS AND METHODS: A total of 46 patients were included. Contrast-enhanced MRI and CBCT images obtained during treatment by pediatric rheumatologists and orthodontists were available from 23 patients with juvenile idiopathic arthritis. We devised a classification system combining the findings of both imaging techniques based on this patient sample in comparison with CBCT findings from an age- and gender-matched group of 23 non arthritis patients, taking into consideration the available literature and administration of contrast medium. RESULTS: Our cohort of 46 patients comprised 60% female and 40% male patients with a mean age of 14 years, providing a total of 92 TMJs for evaluation. We were able to apply the findings efficiently and conveniently to this classification system with no relevant interobserver differences. Mild structural abnormalities were noted in 21% of TMJs in the control group, whereas 83% of TMJs in the arthritis group exhibited severe anomalies, including cases of extreme destruction. Age and gender did not affect the degree of destruction significantly. CONCLUSION: This is the first classification system to link CBCT and MRI with the use of contrast medium. Contrast-enhanced MRI is an internationally recognized technique that permits acute inflammation to be unequivocally diagnosed. Although structural erosion of the TMJs in our arthritis group was generally severe and significant, we were surprised to observe some cases that were clinically asymptomatic. PMID- 24173364 TI - Numerical simulation and biomechanical analysis of an orthodontically treated periodontally damaged dentition. AB - BACKGROUND AND OBJECTIVE: Once periodontitis has been completely resolved, one common follow-up method is to carry out orthodontic treatment to take advantage of the residual bone, i.e., via tooth intrusion. In this study, the biomechanical behavior of teeth in a reduced periodontium was studied by numerically simulating upper-incisor intrusion accomplished with various orthodontic mechanics. MATERIALS AND METHODS: Using the finite element method, a patient-customized 3D model of a periodontally reduced dentition was generated in order to simulate tooth movement. The morphology of this upper-jaw model was derived from cone-beam computed tomography (CBCT) datasets of four patients. Material parameters were adopted from previous investigations, including teeth (E=20 GPa), periodontal ligament (PDL) (bilinear elastic; E1=0.05 MPa; E2=0.20 MPa; epsilon12=7%), and bone (homogeneous, isotropic; E=2 GPa). Two intrusion scenarios were used, the first drawing from Burstone's segmented-arch technique to intrude four splinted incisors at a time, and the second one using cantilevers to intrude single incisors. The aforementioned PDL material parameters were varied in several ways to simulate different biological and biomechanical states of PDL. All simulations were recalculated with an idealized, periodontally intact model to assess the effect of bone loss by way of comparison. RESULTS: Single-tooth intrusion via cantilever mechanics was accompanied by less rotation than the segmented-arch approach. Both intrusion systems involved significantly greater degrees of tooth displacement and PDL load in the periodontally reduced model. CONCLUSION: Periodontally reduced dentitions are associated with an increased load on periodontal tissue. This can be counteracted by reducing orthodontic force levels and by selecting mechanics that do not harm the tissue. In so doing, the use of numerical methods may greatly facilitate individualized computer-aided treatment planning strategies. PMID- 24173365 TI - Impact of pre-existing chronic conditions on age differences in sickness absence after a musculoskeletal work injury: a path analysis approach. AB - OBJECTIVES: This study aims to examine the extent to which a greater prevalence of pre-existing chronic conditions among older workers explains why older age is associated with longer duration of sickness absence (SA) following a musculoskeletal work-related injury in British Columbia. METHODS: A secondary analysis of workers' compensation claims in British Columbia over three time periods (1997-1998; 2001-2002, and 2005-2006), the study comprised 102 997 and 53 882 claims among men and women, respectively. Path models examined the relationships between age and days of absence and the relative contribution of eight different pre-existing chronic conditions (osteoarthritis, rheumatoid arthritis, hypertension, coronary heart disease, diabetes, thyroid conditions, hearing problems, and depression) to this relationship. Models were adjusted for individual, injury, occupational, and industrial covariates. RESULTS: The relationship between age and length of SA was stronger for men than women. A statistically significant indirect effect was present between older age, diabetes, and longer days of SA among both men and women. Indirect effects between age and days of SA were also present through osteoarthritis, among men but not women, and coronary heart disease, among women but not men. Depression was associated with longer duration of SA but was most prevalent among middle aged claimants. Approximately 70-78% of the effect of age on days of SA remained unexplained after accounting for pre-existing conditions. CONCLUSIONS: Pre existing chronic conditions, specifically diabetes, osteoarthritis and coronary heart disease, represent important factors that explain why older age is associated with more days of SA following a musculoskeletal injury. Given the increasing prevalence of chronic conditions among labor market participants (and subsequently injured workers) moderate reductions in age differences in SA could be gained by better understanding the mechanisms linking these conditions to longer durations of SA. PMID- 24173367 TI - Flow through randomly curved manifolds. AB - We present a computational study of the transport properties of campylotic (intrinsically curved) media. It is found that the relation between the flow through a campylotic media, consisting of randomly located curvature perturbations, and the average Ricci scalar of the system, exhibits two distinct functional expressions, depending on whether the typical spatial extent of the curvature perturbation lies above or below the critical value maximizing the overall scalar of curvature. Furthermore, the flow through such systems as a function of the number of curvature perturbations is found to present a sublinear behavior for large concentrations, due to the interference between curvature perturbations leading to an overall less curved space. We have also characterized the flux through such media as a function of the local Reynolds number and the scale of interaction between impurities. For the purpose of this study, we have also developed and validated a new lattice Boltzmann model. PMID- 24173368 TI - Rural and urban Medicare beneficiaries use remarkably similar amounts of health care services. AB - Medicare payment policies for rural health care providers are influenced by the assumption that the limited supply of physicians in rural areas causes rural Medicare beneficiaries to receive fewer health care services than their urban counterparts do. This assumption has contributed to the growth in special payments to rural providers. As a result, Medicare pays rural providers $3 billion more each year in special payments than they would receive under traditional payment rates. To test the validity of the assumption that rural beneficiaries systematically receive less care, we analyzed claims data for all Medicare fee-for-service beneficiaries in 2008, stratified by rural/urban status and region. After adjusting for health status, we found no significant differences between rural and urban beneficiaries in either the amount of health care received or satisfaction with access to care. Although there were systematic differences in the amount of care used across regions of the country, there was very little difference within a region between rural and urban areas. To the extent that Medicare payment policies are designed to ensure access, they should be assessed on the basis of achieving similar service use rather than similar local physician supply. They should also be targeted to isolated rural providers needed to preserve access to care. PMID- 24173366 TI - A reappraisal of the role of circulating (progenitor) cells in the pathobiology of diabetic complications. AB - Traditionally, the development of diabetic complications has been attributed to the biochemical pathways driving hyperglycaemic cell damage, while reparatory mechanisms have been long overlooked. A more comprehensive view of the balance between damage and repair suggests that an impaired regenerative capacity of bone marrow (BM)-derived cells strongly contributes to defective re-endothelisation and neoangiogenesis in diabetes. Although recent technological advances have redefined the biology and function of endothelial progenitor cells (EPCs), interest in BM-derived vasculotropic cells in the setting of diabetes and its complications remains high. Several circulating cell types of haematopoietic and non-haematopoietic origin are affected by diabetes and are potentially involved in the pathobiology of chronic complications. In addition to classical EPCs, these include circulating (pro-)angiogenic cells, polarised monocytes/macrophages (M1 and M2), myeloid calcifying cells and smooth muscle progenitor cells, having disparate roles in vascular biology. In parallel with the study of elusive progenitor cell phenotypes, it has been recognised that diabetes induces a profound remodelling of the BM stem cell niche. The alteration of circulating (progenitor) cells in the BM is now believed to be the link among distant end organ complications. The field is rapidly evolving and interest is shifting from specific cell populations to the complex network of interactions that orchestrate trafficking of circulating vasculotropic cells. PMID- 24173369 TI - Combination of quercetin and hyperoside has anticancer effects on renal cancer cells through inhibition of oncogenic microRNA-27a. AB - Quercetin and hyperoside (QH) in combination (1:1 ratio) have previously been shown to inhibit the growth of human leukemia cells. Here, we investigated the anticancer activity of the same mixture in 786-O renal cancer cells. QH decreased the generation of reactive oxygen species (ROS) by up to 2.25-fold and increased the antioxidant capacity by up to 3-fold in 786-O cells (3.8-60 MUg/ml), whereas IC50 values for viability were 18.2, 18.7 and 11.8 MUg/ml, respectively. QH also induced caspase-3 cleavage (2-fold) and increased PARP cleavage. Specificity protein (Sp) transcription factors are overexpressed in cancer cells and regulate genes required for cell proliferation, survival and angiogenesis. QH treatment decreased the expression of Sp1, Sp3 and Sp4 mRNA and this was accompanied by decreased protein expression. Moreover, expression of the Sp-dependent anti apoptotic survival gene survivin was also significantly reduced, both at the mRNA and protein levels. QH decreased microRNA-27a (miR-27a) and induced the zinc finger protein ZBTB10, an Sp-repressor, suggesting that interactions between QH and the miR-27a-ZBTB10 axis play a role in Sp downregulation. This was confirmed by transfection of cells with a specific mimic for miR-27a, which partially reversed the effects of QH. These findings are consistent with previous studies on botanical anticancer agents in colon cancer cells. PMID- 24173371 TI - Extracellular matrix composition and interstitial pH modulate NHE1-mediated melanoma cell motility. AB - The activity of the Na+/H+ exchanger NHE1 is required for human melanoma cell adhesion and migration. The goal of the present study was to suppress mouse melanoma (B16V) cell invasion in vivo by inhibiting NHE1. Intravital observations in mobilized left liver lobes of laparotomized male Sprague-Dawley rats disclosed that five minutes after intra-arterial administration of the B16V cell suspension, cells adhered to the endothelia of liver sinusoidal capillaries and started to migrate into the surrounding liver tissue. In the presence of the NHE1 specific inhibitor cariporide, migration/invasion was reduced by about 50% while adhesion was not lowered. Time-lapse video microscopy and adhesion/invasion assays revealed that in vitro, blockade of NHE1 by cariporide i) significantly decreased the migratory speed of the cells and ii) completely inhibited the invasive behavior of both an artificial, basement membrane-like and a dermis-like matrix. Cells were more motile on the basement membrane and more invasive on the dermis-like matrix. Small-animal PET (positron-emission tomography) analyses of B16V metastasis in female C57BL/6 mice showed that, although NHE1 inhibition hardly affected the percentage of animals developing metastases or relapses, metastases seem to get directed to the lungs in cariporide-treated animals while animals feeding on the standard diet show metastases spread all over the body. We conclude that i) B16V cells prefer to invade a dermis-like rather than a basement membrane-like matrix; ii) the extracellular matrix (ECM) composition strongly impacts on NHE1-dependent in vitro cell motility and invasion; and iii) the lungs are metastasis-prone and impair the efficiency of cariporide due to their ECM composition and the pulmonary interstitial (extravascular) pH. PMID- 24173372 TI - Cryptotanshinone induces G1 cell cycle arrest and autophagic cell death by activating the AMP-activated protein kinase signal pathway in HepG2 hepatoma. AB - AMP-activated protein kinase (AMPK) performs a pivotal function in energy homeostasis via the monitoring of intracellular energy status. Once activated under the various metabolic stress conditions, AMPK regulates a multitude of metabolic pathways to balance cellular energy. In addition, AMPK also induces cell cycle arrest or apoptosis through several tumor suppressors including LKB1, TSC2, and p53. LKB1 is a direct upstream kinase of AMPK, while TSC2 and p53 are direct substrates of AMPK. Therefore, it is expected that activators of AMPK signal pathway might be useful for treatment or prevention of cancer. In the present study, we report that cryptotanshinone, a natural compound isolated from Salvia miltiorrhiza, robustly activated AMPK signaling pathway, including LKB1, p53, TSC2, thereby leading to suppression of mTORC1 in a number of LKB1 expressing cancer cells including HepG2 human hepatoma, but not in LKB1-deficient cancer cells. Cryptotanshinone induced HepG2 cell cycle arrest at the G1 phase in an AMPK-dependent manner, and a portion of cells underwent apoptosis as a result of long-term treatment. It also induced autophagic HepG2 cell death in an AMPK dependent manner. Cryptotanshinone significantly attenuated tumor growth in an HCT116 cancer xenograft in vivo model, with a substantial activation of AMPK signal pathways. Collectively, we demonstrate for the first time that cryptotanshinone harbors the therapeutic potential for the treatment of cancer through AMPK activation. PMID- 24173373 TI - Curcumin regulates the metabolism of low density lipoproteins by improving the C to-U RNA editing efficiency of apolipoprotein B in primary rat hepatocytes. AB - There are two isoforms of apolipoprotein B (apoB) in mammals: apoB-100 and apoB 48. The latter is generated by C-to-U editing of apoB mRNA, catalyzed by the apolipoprotein B mRNA editing enzyme, namely, catalytic polypeptide 1 (APOBEC-1). Lipid particles containing apoB-48 are cleared from the plasma more rapidly than those containing apoB-100 and thus do not contribute to plaque formation in the arterial wall. In the present study, we analyzed whether curcumin is capable of regulating lipid metabolism by improving the level of apoB mRNA editing. The cytotoxicity of curcumin in hepatocytes was determined using the 3-(4,5 dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay and the levels of APOBEC-1 mRNA and protein were analyzed by real-time quantitative polymerase chain reaction (qRT-PCR) and western blotting. The efficiency of apoB mRNA editing was determined by reverse transcription PCR (RT-PCR) products and cloning sequencing analysis. We demonstrated that curcumin concentrations up to 70 uM had no significant cytotoxic effects on primary rat hepatocytes at 24 h. At 15 uM, curcumin significantly increased the expression of APOBEC-1 mRNA and protein, and increased the editing level of apoB mRNA from 3.13 to 7.53%. At 25 uM, curcumin reduced the expression of APOBEC-1; however, it did not affect the apoB mRNA editing level. Our data suggested that curcumin at a concentration of 15 uM raised the level of apoB-48 and reduced the level of apoB-100 by increasing the expression of APOBEC-1 in primary rat hepatocytes; therefore, curcumin may be a novel preventative therapy for atherosclerosis. PMID- 24173374 TI - The value of coronary angiography in the work-up of atrial myxomas. AB - Atrial myxomas are the most common primary cardiac tumors. They are highly vascular with evidence of neovascularization and a characteristic"tumor blush" in approximately half of the cases. Although the visualization of feeding vessels has several clinical and therapeutic implications, there is still no consensus on the indication of preoperative coronary angiography to assess tumor vascularity except in patients with angina or those older than 40 years to rule out coronary artery disease. Herein, I present a case of an incidentally discovered right atrial mass receiving vascular supply from the right coronary artery. The mass was successfully excised and the diagnosis of cardiac myxoma was confirmed via histopathology. A review of the value of coronary angiography in detecting myxoma neovascularization is provided, which suggests that it can offer additional valuable information that can alter the surgical approach and therefore may be considered prior to myxoma resection. PMID- 24173375 TI - Successful treatment of cocaine-induced cardiotoxicity with carvedilol therapy. PMID- 24173376 TI - Right ventricular outflow tract function in chronic obstructive pulmonary disease. AB - BACKGROUND: It is clinically important to evaluate the severity of right ventricular (RV) overload in patients with chronic obstructive pulmonary disease (COPD), which is often associated with changes in the structure and the function of the right ventricle. Noninvasive and reliable assessment of RV function would be an essential determinant of RV load and a clinically useful factor for assessing cardiovascular risk in COPD patients. OBJECTIVE: The aim of this study was to investigate the clinical application value of right ventricular outflow tract (RVOT) systolic function measured by transthoracic echocardiography in patients with COPD. PATIENTS AND METHODS: We prospectively investigated COPD male patients and compared them with healthy controls. In addition to RV conventional echocardiographic parameters, RVOT size and fractional shortening (RVOT-FS) parameters were also assessed. RESULTS: Fifty-five COPD patients (all men; mean age, 62 +/- 9 years) participated in the study, and were compared with a control group consisting of 21male, healthy, nonsmoking subjects with a mean age of 58 +/ 11 years. The RVOT-FS was impaired in COPD patients than healthy controls (27.8 +/- 15.5 vs. 57.5 +/- 8.6, p < 0.001), and was correlated positively with tricuspid annular plane systolic excursion (TAPSE; r = 0.583, p < 0.001) and pulmonary acceleration time (r = 0.666, p < 0.001) and inversely with pulmonary artery systolic pressure (r = 0.605, p < 0.001) and functional capacity(r = - 0.589, p < 0.001). There was a statistically significant difference in RVOT-FS among the COPD subgroups with regard to New York Heart Association functional classification (p < 0.001). CONCLUSION: The RVOT-FS is a noninvasive easily applicable measure of RV systolic function and is well correlated with functional capacity in COPD patients. Its combination with long-axis measurements via TAPSE and transtricuspid Doppler analysis may provide a comprehensive evaluation of the RV performance in COPD patients. PMID- 24173377 TI - Calcified thrombosed left ventricular aneurysm. PMID- 24173378 TI - Against storytelling of scientific results. PMID- 24173379 TI - Reply to: "against storytelling of scientific results". PMID- 24173380 TI - ScientiFig: a tool to build publication-ready scientific figures. PMID- 24173382 TI - Neuroscience waves to the crowd. PMID- 24173381 TI - The need for transparency and good practices in the qPCR literature. AB - Two surveys of over 1,700 publications whose authors use quantitative real-time PCR (qPCR) reveal a lack of transparent and comprehensive reporting of essential technical information. Reporting standards are significantly improved in publications that cite the Minimum Information for Publication of Quantitative Real-Time PCR Experiments (MIQE) guidelines, although such publications are still vastly outnumbered by those that do not. PMID- 24173383 TI - Making connections: using networks to stratify human tumors. PMID- 24173384 TI - Wire-in-tube structure fabricated by single capillary electrospinning via nanoscale Kirkendall effect: the case of nickel-zinc ferrite. AB - Wire-in-tube structures have previously been prepared using an electrospinning method by means of tuning hydrolysis/alcoholysis of a precursor solution. Nickel zinc ferrite (Ni0.5Zn0.5Fe2O4) nanowire-in-nanotubes have been prepared as a demonstration. The detailed nanoscale characterization, formation process and magnetic properties of Ni0.5Zn0.5Fe2O4 nanowire-in-nanotubes has been studied comprehensively. The average diameters of the outer tubes and inner wires of Ni0.5Zn0.5Fe2O4 nanowire-in-nanotubes are around 120 nm and 42 nm, respectively. Each fully calcined individual nanowire-in-nanotube, either the outer-tube or the inner-wire, is composed of Ni0.5Zn0.5Fe2O4 monocrystallites stacked along the longitudinal direction with random orientation. The process of calcining electrospun polymer composite nanofibres can be viewed as a morphologically template nucleation and precursor diffusion process. This allows the nitrates precursor to diffuse toward the surface of the nanofibres while the oxides (decomposed from hydroxides and nitrates) products diffuse to the core region of the nanofibres; the amorphous nanofibres transforming thereby into crystalline nanowire-in-nanotubes. In addition, the magnetic properties of the Ni0.5Zn0.5Fe2O4 nanowire-in-nanotubes were also examined. It is believed that this nanowire-in-nanotube (sometimes called core-shell) structure, with its uniform size and well-controlled orientation of the long nanowire-in-nanotubes, is particularly attractive for use in the field of nano-fluidic devices and nano energy harvesting devices. PMID- 24173385 TI - Effect of taste sensation on cough reflex sensitivity. AB - Cough is among the most common symptoms with which people present for medical attention, but evidence-based treatments remain limited. One issue compromising interpretation of clinical trials of cough preparations is that control formulations often are nearly as effective as those that contain active ingredients. This observation has caused some researchers to propose that one or more nominally inactive ingredients may have some physiological effects. For example, most liquid cough preparations are highly sweetened, and it has been suggested that sweet taste might modulate cough sensitivity. The fact that honey has been used for thousands of years as a cough remedy is consistent with this idea. However, empirical evidence for modulation of cough sensitivity by taste was lacking. Evidence is still sparse, but relevant experiments have now been published: rinsing the mouth with a sweet sucrose solution increased cough thresholds in a single-inhalation capsaicin challenge. Furthermore, rinsing the mouth with a bitter solution did not affect thresholds, an important demonstration of specificity. The underlying mechanisms of cough suppression by sweet taste are still unclear. However, extant data suggest that modulation of cough sensitivity by taste is a promising area for further investigation. Such work may lead to greater understanding of apparent placebo effects in clinical trials and provide empirical support for therapies based on stimulation of taste nerves. PMID- 24173386 TI - Inhibitor effects on photosynthesis, respiration and active ion transport inHydrodictyon africanum. AB - The effects of various inhibitors on photosynthesis, respiration, and active influx of K and Cl in light and dark inHydrodictyon africanum is reported. The inhibitors used were arsenate (uncouples electron-transport phosphorylations), dicyclohexylcarbodiimide (energy-transfer inhibitor in electron-transport phosphorylation), quinacrine (uncouples photophosphorylation and inhibits oxidative phosphorylation), and ethionine (traps adenylates as S-adenosyl ethionine). The action of these inhibitors, and of those previously used onHydrodictyon africanum, suggests that K influx requires ATP, while Cl influx requires some earlier manifestation of the ATP synthesizing process. Possible reasons for the greater sensitivity of K influx than of CO2 fixation to treatments which interfere with photophosphorylation are discussed. PMID- 24173387 TI - Measurement of the composition of epithelial cells from the toad urinary bladder. AB - Two methods are described by which epithelial cells from toad urinary bladders can be obtained for analysis of their intracellular water and electrolyte contents. In the first, a method similar to that described in 1968 by J. T. Gatzy and W. O. Berndt, sheets of epithelial cells are scraped from bladders after incubation in sodium Ringer's and collagenase (400 mg/liter). The scraped cells were incubated under various conditions and their composition subsequently determined. Oxygen consumption was also measured. In the second method, epithelial cells were scraped from hemibladders removed from chambers. These cells were then analyzed without further incubation. The morphology of epithelial cells obtained by each method is illustrated. Both methods yield similar results and evidence is provided that the derived intracellular values obtained truly reflect the composition of the epithelial cells. PMID- 24173388 TI - Effects of vasopressin on the water and ionic composition of toad bladder epithelial cells. AB - Isolated sheets of epithelial cells as well as epithelial cells scraped from paired hemibladders mounted in chambers both showed significant increases in water, sodium and chloride contents after exposure to vasopressin (100 mU/ml), without any change in potassium content. In the isolated cells these changes were prevented by amiloride (10(-5) M), suggesting that the gain of sodium after vasopressin occurs across the mucosal membrane. This hypothesis was confirmed in experiments in which it was found that, in hemibladders mounted in chambers and bathed on their mucosal surface by sodium Ringer's with(24)Na, the gains of chemical sodium and(24)Na after vasopressin were equivalent. PMID- 24173389 TI - Enzyme activities of human erythrocyte ghosts: effects of various treatments. AB - Ghosts of human erythrocytes prepared by hypotonic hemolysis were assayed for aldolase, triosephosphate isomerase, glyceraldehyde phosphate dehydrogenase, phosphoglycerate kinase, pyruvate kinase, lactate dehydrogenase, and glutathione peroxidase and reductase. Cryptic activity of the enzymes was demonstrated by an increase in activity on dilution with water, which caused fragmentation of the ghosts. Aldolase and glyceraldehyde phosphate dehydrogenase were classed as firmly bound; phosphoglycerate kinase was intermediate; the others were loosely bound. Triton X-100 increased the activities of aldolase, glyceraldehyde phosphate dehydrogenase, and phosphoglycerate kinase. The pH of the medium had little effect upon the firmly bound enzymes but it markedly affected the retention of hemoglobin and the activities of the loosely bound enzymes. The presence of Mg or Ca ions enhanced the retention of hemoglobin and the activity of lactate dehydrogenase and pyruvate kinase, with little effect on aldolase and glyceraldehyde phosphate dehydrogenase. Ghosts diluted in water disintegrated into fragments and tubules or vesicles; Mg or Ca at 1MM afforded protection against this. When ghosts were treated with Triton X-100 and adenosine triphosphate, they contracted to about one-seventh of their volume. The shrunken ghosts had lost a considerable proportion of their cholesterol and protein to the medium. PMID- 24173390 TI - The permeability of the human red blood cell to sulfate ions. AB - Sulfate permeability was measured at Donnan equilibrium as a function of three variables, the sulfate, chloride, and hydrogen ion concentration in the medium. The data were used for a quantitative evaluation of a number of typical predictions of a fixed charge model of the ion permeable regions of the red blood cell membrane. It could be shown that more than 1,000-fold variations of sulfate flux,[Formula: see text], could be represented as a function of a single variable SO 4m (2-) , the sulfate concentration in the membrane. SO 4m (2-) was calculated from the measured values of all three variables by means of a previously published equation (Passow,Progress in Biophysics and Molecular Biology, vol. 19, pt. II, pp. 425-467, 1969). In this equation, two constants can be arbitrarily chosen:A, the sum of the charged and uncharged forms of dissociable fixed charges, andK, the dissociation constant of the fixed charges. For the present calculations, the previously obtained valuesA=2.5 andK=1.10(-9) were used. The resulting relationship between[Formula: see text] and SO 4m (2-) was found to obey the equation[Formula: see text] wherec I=1.62.10(-9),c II=2.3.10(-2),a=4.94 gave the best fit for data obtained at 27 degrees C. The exponential increase of[Formula: see text] with SO 4m (2-) suggests that there exists a cooperative facilitation of sulfate flux with increasing SO 4m (2-) . Measurements of the apparant activation energy of sulfate flux yielded a value of 32.7 Kcal/mole. This value was independent of the pH at which the measurements were made. PMID- 24173392 TI - Three Wnt genes expressed in a wide variety of tissues during development of the zebrafish, Danio rerio: developmental and evolutionary perspectives. AB - Proteins encoded by the Wnt family of genes act as signals and have been shown to play important roles in a wide variety of developmental processes. Here we describe the cloning of three Wnt family members from the zebrafish, Danio rerio, which encode proteins with homology to murine Wnt-2, -4 and -5A/B. The expression patterns of the latter two zebrafish genes, designated ZfWnt4 and ZfWnt5 show considerable similarity with their homologues in other vertebrates; ZfWnt2, however, is expressed in the developing viscera in a pattern distinct from its closest murine homologue. In the light of the similarities and differences in the patterns of expression of these genes relative to their homologues in other vertebrates, we speculate on their possible functions. PMID- 24173391 TI - Downregulation of miR-183 inhibits apoptosis and enhances the invasive potential of endometrial stromal cells in endometriosis. AB - Endometriosis is a common gynecological disease, yet its pathogenesis remains poorly understood. Recent studies have demonstrated that the aberrant expression of certain microRNAs (miRNAs) may correlate with the development and progression of endometriosis. In this study, we profiled several differentially expressed miRNAs in the normal, eutopic and ectopic endometrium by miRNA microarray screening analysis, among which, miR-183 was found to be downregulated in the ectopic and eutopic tissues, and the result was further confirmed by real-time PCR (qPCR). Functional analysis indicated that miR-183 plays a promotional role in endometrial stromal cell (ESC) apoptosis and has a negative regulatory impact on the invasive ability of cells, although it has no effect on ESC proliferation. Ovarian steroids (17beta-estradiol and progesterone) and inflammatory factors (tumor necrosis factor-alpha and interleukin-6) decreased the expression of miR 183 in the ESCs. This regulatory function may further manifest the growth and invasive potential of ESCs by altering the expression of miR-183. These findings suggest that the downregulation of miR-183 expression is involved in the development and progression of endometriosis. PMID- 24173393 TI - Inducible ternary control of transgene expression and cell ablation in Drosophila. AB - In Drosophila, P-GAL4 enhancer trap lines can target expression of a cloned gene, under control of a UASGAL element, to any cells of interest. However, additional expression of GAL4 in other cells can produce unwanted lethality or side-effects, particularly when it drives expression of a toxic gene product. To target the toxic gene product ricin A chain specifically to adult neurons, we have superimposed a second layer of regulation on the GAL4 control. We have constructed flies in which an effector gene is separated from UASGAL by a polyadenylation site flanked by two FRT sites in the same orientation. A recombination event between the two FRT sites, catalysed by yeast FLP recombinase, brings the effector gene under control of UASGAL. Consequently, expression of the effector gene is turned on in that cell and its descendants, if they also express GAL4. Recombinase is supplied by heat shock induction of a FLP transgene, allowing both timing and frequency of recombination events to be regulated. Using a lacZ effector (reporter) to test the system, we have generated labelled clones in the embryonic mesoderm and shown that most recombination events occur soon after FLP recombinase is supplied. By substituting the ricin A chain gene for lacZ, we have performed mosaic cell ablations in one GAL4 line that marks the adult giant descending neurons, and in a second which marks mushroom body neurons. In a number of cases we observed loss of one or both the adult giant descending neurons, or of subsets of mushroom body neurons. In association with the mushroom body ablations, we also observed misrouting of surviving axons. PMID- 24173394 TI - Cell-cell communication in nematode embryos: differences between Cephalobus spec. and Caenorhabditis elegans. AB - During early nematode embryogenesis a series of asymmetric cleavages in the germ line generates several somatic founder cells and a primordial germ cell. We have found previously that the two soil nematodes Cephalobus spec. and Caenorhabditis elegans express considerable differences in the order of events and spatial arrangement of cells during early embryogenesis. With the help of microinjected fluorescent marker dyes, we show here that these dissimilarities partner major differences in the pattern of intercellular communication. Whilst in C. elegans all early blastomeres become dye-coupled simultaneously, in Cephalobus communication is established progressively in the sequence in which cells are born. In addition, in Cephalobus but not C. elegans, sequential lucifer yellow accumulation indicates stepwise changes in the state of early blastomeres: if injected into the uncleaved zygote, for example, the dye becomes equally distributed to all cells at first but rapidly accumulates in a single blastomere in the 4-cell stage. We speculate that such a redistribution mechanism may be involved in the differential segregation of cytoplasmic components to individual blastomeres. The most dramatic difference between the two species was found with respect to the transfer of high molecular weight molecules. In contrast to C. elegans, in Cephalobus not only small lucifer dyes but also high molecular weight dextrans can diffuse along specific pathways between early somatic cells indicating the presence of large communication channels. However, a transfer of dextran into or out of germ line cells never takes place. The origin of these channels as midbodies of previous mitoses and their potential role for normal development is discussed. Tissue-specific dye-coupling compartments in the slow developing Cephalobus are established in the same order but at a considerably earlier developmental stage than in C. elegans suggesting that this process may depend more on parameters like available time for transcription rather than the number of cell cycles passed through. PMID- 24173395 TI - Two orthodenticle-related genes in the short-germ beetle Tribolium castaneum. AB - To investigate the molecular basis of head evolution, we searched for genes related to the Drosophila orthodenticle (otd) homeobox gene in the short-germ beetle Tribolium castaneum. Unexpectedly, we found that there are two otd-related genes in Tribolium, with predicted homeodomains highly similar to that of the single Drosophila gene. One of the two genes (Tc otd-1) is more related in both amino acid sequence and expression pattern to fruitfly otd. Tc otd-1 is expressed in a broad anterior stripe in the blastoderm embryo, suggesting a role in early head segmentation similar to that of the Drosophila gene. The second gene (Tc otd 2) is more similar in sequence to the otd-related genes isolated from different vertebrate species (the Otx gene family). Tc otd-2 is not transcribed in the blastoderm, but is expressed later in more limited subsets of cells in the anterior brain. Both Tribolium genes and the Drosophila gene are, unlike the vertebrate genes, also expressed at the developing ventral midline of the embryo. Our results are consistent with the idea that an otd/Otx gene specified anterior head structures in the last ancestor common to arthropods and vertebrates. Within the arthropod lineage, we propose that this gene acquired a function in cells at the developing midline prior to the duplication that generated the two Tribolium genes. PMID- 24173396 TI - Transplanted wing and leg imaginal discs in Drosophila melanogaster demonstrate interactions between epidermis and myoblasts in muscle formation. AB - Adult muscle development in Drosophila is intimately associated with the development of the nervous system and epidermis. During metamorphosis, myoblasts from the wing imaginal disc reach target sites on the developing pupal epidermis and begin the formation of multinucleate myofibres of the dorsal thorax. The paths taken by pupal myoblasts could be specified by the nervous system and/or the epidermis. Using genetically marked donor pupal wing and leg discs transplanted onto pupal hosts, we have generated animals that have ectopic wings or legs and have examined the formation of adult muscle types. We show that thoracic myoblasts migrate over both host and donor epidermis when the transplant site on the host is thoracic. However, when the transplant site is on the abdomen, thoracic myoblasts do not migrate over abdominal epidermis. Our results show that the epidermis plays an important role in determining the migration pattern of myoblasts. Since muscles are multinucleate cells that form by the fusion of myoblasts, one way in which their molecular characteristics could be achieved is by some myoblasts acting as "founders". These myoblasts could influence the pattern of gene expression of those nuclei that fuse with them. We have examined, again using disc transplant experiments, if myoblasts on discs have the capacity to express fibre-specific genes as distinct from this property being conferred by other extra-discs myoblasts. Our results demonstrate that disc associated myoblasts can indeed fuse with each other to express fibre-specific genes. We synthesize the results presented here with those from earlier experiments to suggest a mechanism for muscle patterning in the adult thorax. PMID- 24173397 TI - cis-Regulatory elements conserved in the proximal promoter region of an ascidian embryonic muscle myosin heavy-chain gene. AB - The B-line muscle cells of the ascidian embryo are specified autonomously depending on determinants prelocalized in the myoplasm of unfertilized eggs. Expression of muscle-specific actin and myosin heavy-chain genes commences in the B-line presumptive muscle cells as early as the 32-cell stage. To explore the intrinsic genetic program for this differentiation, we analysed cis-regulatory elements of the Halocynthia roretzi muscle myosin heavy-chain gene (HrMHC1). Comparison of the entire amino acid sequence of HrMHC1 with those of other invertebrates and vertebrates indicated that HrMHC1 resembles myosin heavy-chain of vertebrate skeletal and cardiac muscles. A fusion gene was constructed consisting of 132 bp upstream the 5'-end of HrMHC1 gene fused to a bacterial lacZ reporter. When the fusion gene was microinjected into fertilized eggs, the reporter gene was eventually expressed only in muscle cells of tailbud embryos. It has been reported that 103 bp of sequence 5' of the transcription start site of the ascidian embryonic muscle actin gene (HrMA4) contains information sufficient for muscle-specific expression (Hikosaka et al. 1994). Comparison of the 132 bp of sequence 5' of the HrMHC1 gene with the 103 bp of sequence 5' of the HrMA4 gene revealed several common motifs shared by the two genes (E-box, GATA box and Boxes A, B, T1 and T2). Point mutations inserted into these motifs suggested that the Box T1/T2 (TTTTTTCTTTCA) is critical for the promoter activity of the HrMHC1 gene. PMID- 24173398 TI - Differential expression of annexin V during spermatogenesis in the newt Cynops pyrrhogaster. AB - In order to isolate genes whose expression is up-regulated after the initiation of meiosis, we screened a cDNA expression library of newt testes with antiserum against homogenates of testes derived from the spermatogonial and spermatocyte stages. We report the isolation of spermatocyte-specific cDNA clones encoding a newt homologue of the calcium-dependent phospholipid-binding protein, annexin V. Northern blot analysis showed that newt annexin V mRNA was 1.7 kb in length and was expressed strongly in testes, but weakly in other organs. In situ hybridization revealed that the expression of newt annexin mRNA was barely observed in spermatogonia, but increased significantly in leptotene-zygotene primary spermatocytes and reached a maximum level in pachytene spermatocytes and round spermatids. The newt annexin V cDNA predicted a 323-amino acid protein and had a 68% homology to human annexin V. The predicted amino acid sequence contained a conserved 4-fold internal repeat of approximately 70 residues like other annexin proteins. Immunoblot analysis using the monoclonal antibody against newt annexin V showed that the protein was expressed scarcely in spermatogonia but was abundantly expressed in stages from primary spermatocytes to spermatids; this pattern was consistent to that of the mRNA. Immunohistochemical analysis revealed that newt annexin V was localized in the cytoplasm of the spermatogenic cells, but not in somatic cells such as Sertoli cells or pericystic cells. These results indicate that the expression of newt annexin V is up-regulated in the spermatogenic cells after the initiation of meiosis and suggest that newt annexin V plays an important role in spermatogenesis. PMID- 24173399 TI - Molecular characterization of myoplasmin-C1: a cytoskeletal component localized in the myoplasm of the ascidian egg. AB - Myoplasmin-C1 is a polypeptide detected by a monoclonal antibody, which is localized in the myoplasm of ascidian eggs. Since microinjection of the antibody blocks larval muscle development, myoplasmin-C1 may play a role in muscle cell differentiation (Nishikata et al. 1987). Isolation and characterization of myoplasmin-C1 cDNA clones revealed that the predicted amino acid sequence of myoplasmin-C1 had no similarity to any known protein. However, the deduced protein contains heptad repeats similar to those in myosin heavy chain, tropomyosin and the Drosophila Bicaudal D gene product, suggesting that it is a filamentous component of the myoplasmic cytoskeleton. The predicted amino acid sequence also showed several possible phosphorylation sites. Consistent with the prediction that myoplasmin-C1 is a cytoskeletal component, the protein remained in the myoplasmic cytoskeletal domain after detergent extraction. These results suggest that myoplasmin-C1 is a cytoskeletal component of the myoplasm and that it plays a role in anchoring and segregating muscle determinants. PMID- 24173400 TI - Spatial and temporal expression pattern of Bombyx fork head/SGF-1 gene in embryogenesis. AB - The embryonic expression of Bombyx fkh/SGF-1 gene has been analysed using in situ hybridization and immunohistochemistry. Both transcripts and protein were first detected in the most anterior and posterior regions at the time of germ anlage formation, and were successively expressed in the foregut and hindgut at later stages. A weaker expression was also detected in the elongated midgut. By the time embryo retraction was finished transcripts and protein were also detectable in the invaginated whole silk glands, and after the blastokinesis stage the products were restricted to the middle and posterior silk glands achieving a state required for the SGF-1 distribution for later stages. Expression could also be detected in the central and peripheral nervous systems. From these observations, we propose that Bombyx Fkh/SGF-1 may play a role in organogenesis processes such as those of the gut, silk glands, and nervous systems, act as a region specific homeotic gene, and in spite of clear embryonic developmental differences between Drosophila and Bombyx, two terminals may be determined by region specific genes such as Bombyx fkh/SGF-1 as opposed to segmental development. PMID- 24173401 TI - Chromophore-assisted laser inactivation of even skipped in Drosophila precisely phenocopies genetic loss of function. AB - The even skipped (eve) gene in Drosophila encodes a homeo-domain protein that acts as a trancriptional regulator during early embryogenesis. We show that an injection of a monoclonal antibody against the eve homeodomain in conjunction with chromophore-assisted laser inactivation (CALI) precisely phenocopies the eve mutant phenotype. Depending on the time of the laser treatment, both the early pair-rule function, as well as the later segmental function of eve can be blocked. This suggests that it might be possible to employ CALI to analyse the function of transcriptional regulators in species that are not amenable to genetic analysis. PMID- 24173402 TI - [History, nation and race in the context of the Centennial Exhibition of 1922]. AB - The subjects addressed in this article are the public and academic debates about the history of Brazil that took place in the context of the Centennial Exhibition held in 1922 in the city of Rio de Janeiro. The aim is to highlight how certain concepts of nation and race were debated in academic discussions about history, anthropology and archaeology, how they were related to the nation's history, and how they ultimately became a part of the nation's self-image. Furthermore, the article investigates how and by whom these ideals were contested. PMID- 24173403 TI - [The global constitution of the Brazilian nation: issues concerning immigration in the 1930s and 40s]. AB - This article shows that the concept of nation and nationalist interpretations were at the heart of discourses about immigration in Brazil in the 1930s and 40s. These national references cannot, however, be comprehended unless they are seen from a global perspective. The historical actors were engaged in scientific debates that were circulating around the globe, and they were also aware of the international nature of the subject. I intend to demonstrate these hypotheses with the help of two examples: the sociology of migration in Brazil, and the discourses of German-speaking immigrants to Brazil. PMID- 24173405 TI - Inhibition of adipogenesis in 3T3-L1 cells and suppression of abdominal fat accumulation in high-fat diet-feeding C57BL/6J mice after downregulation of hyaluronic acid. AB - OBJECTIVE: Adipogenesis can be spatially and temporally regulated by extracellular matrix (ECM). We hypothesized that the regulation of hyaluronic acid (HA), a component of the ECM, can affect adipogenesis in fat cells. The effects of HA on adipogenesis were investigated in vitro in 3T3-L1 cells and in vivo in high-fat diet-feeding C57BL/6J mice. METHODS: We investigated the effects of HA by degradation of pre-existing or synthesized HA and artificial inhibition of HA synthesis in adipogenesis. RESULTS: In vitro adipogenesis in 3T3-L1 cells was inhibited by treating them with exogenous hyaluronidase (HYAL) and with 4 methylumbelliferone, which inhibited the synthesis of HA in a concentration dependent manner. In vivo, abdominal fat accumulation in high-fat diet-feeding C57BL/6J mice was suppressed by exogenous HYAL 10(4) IU injections, which was associated with reduction of lipid accumulation in liver and increase of insulin sensitivity. CONCLUSION: Changes in the ECM such as accumulation of high molecular weight of HA by HAS and degradation of HA by endogenous HYAL were essential for adipogenesis both in vitro and in vivo. PMID- 24173406 TI - The impact of prophylactic intravenous lidocaine on opioid-induced cough: a meta analysis of randomized controlled trials. AB - BACKGROUND: Opioids are commonly used for general anesthesia, but reflex cough can occur after an intravenous injection. We have performed a meta-analysis of randomized controlled trials (RCTs) that evaluated the effectiveness and safety of prophylactic lidocaine administered intravenously (IV) on opioid-induced cough (OIC) during induction in patients undergoing general anesthesia. METHODS: We searched three bibliographic databases (PubMed, Embase, and the Cochrane Central Register of Controlled Trials) to identify studies meeting a priori inclusion criteria and also conducted a secondary reference review. The information used to calculate the relationship between lidocaine prophylaxis and the risk and severity of OIC was extracted by two principal investigators, respectively. RESULTS: Six RCTs with a total of 1,740 participants were included in this meta analysis. Overall, prophylactic lidocaine administered IV reduced both the risk of OIC [pooled risk ratio (RR) 0.471; 95 % confidence interval (CI) 0.355-0.625; P = 0.074; heterogeneity test, I (2) = 50.3 %] and its severity (weighed mean difference -0.316; 95 % CI -0.480 to -0.151; P = 0.038; heterogeneity test, I (2) = 60.5 %). Sub-group analysis indicated a significant reduction in the incidence of both fentanyl-induced cough (FIC) and remifentanil-induced cough (RIC), but it appeared that lidocaine only alleviated the severity of FIC. Further sub-group analysis indicated that the lowest effect dose of lidocaine for preventing the prevalence of OIC was 0.5 mg/kg. No severe adverse effects were reported. CONCLUSIONS: Our meta-analysis establishes the effectiveness of prophylactic lidocaine administered IV for the prevention of OIC during induction. The lowest effective dose of lidocaine on the risk of OIC appeared to be 0.5 mg/kg. PMID- 24173407 TI - The factor structure of the CES-D in a sample of Rwandan genocide survivors. AB - BACKGROUND: Past research suggests that culture shapes the way psychopathology is experienced and expressed. Standard psychiatric assessment instruments may therefore not capture the same underlying constructs in different contexts. The present study investigated the factor structure of a standard depression scale in a sample of Rwandan genocide survivors. METHODS: One hundred ninety six Rwandan adults provided socio-demographic information and completed the Center for Epidemiological Studies-Depression scale (CES-D), one of the most widely used self-report instruments assessing depressive symptoms, as part of a larger study on well-being and mental health in Rwanda. RESULTS: A two-factor solution provided the best fit for these CES-D data. The first factor corresponded to general depressive symptoms (including depressed affect, somatic symptoms, and interpersonal concerns) and explained 37.20% of the variance. The second factor included items assessing positive affect and explained 8.68% of the variance. CONCLUSIONS: The two-factor solution found in the present study deviates from the commonly reported four-factor structure, but is consistent with studies showing that depressed affect and somatic symptoms may not be experienced as distinct in certain non-Western and minority cultural groups. PMID- 24173408 TI - The 1% of the population accountable for 63% of all violent crime convictions. AB - PURPOSE: Population-based studies on violent crime and background factors may provide an understanding of the relationships between susceptibility factors and crime. We aimed to determine the distribution of violent crime convictions in the Swedish population 1973-2004 and to identify criminal, academic, parental, and psychiatric risk factors for persistence in violent crime. METHOD: The nationwide multi-generation register was used with many other linked nationwide registers to select participants. All individuals born in 1958-1980 (2,393,765 individuals) were included. Persistent violent offenders (those with a lifetime history of three or more violent crime convictions) were compared with individuals having one or two such convictions, and to matched non-offenders. Independent variables were gender, age of first conviction for a violent crime, nonviolent crime convictions, and diagnoses for major mental disorders, personality disorders, and substance use disorders. RESULTS: A total of 93,642 individuals (3.9%) had at least one violent conviction. The distribution of convictions was highly skewed; 24,342 persistent violent offenders (1.0% of the total population) accounted for 63.2% of all convictions. Persistence in violence was associated with male sex (OR 2.5), personality disorder (OR 2.3), violent crime conviction before age 19 (OR 2.0), drug-related offenses (OR 1.9), nonviolent criminality (OR 1.9), substance use disorder (OR 1.9), and major mental disorder (OR 1.3). CONCLUSIONS: The majority of violent crimes are perpetrated by a small number of persistent violent offenders, typically males, characterized by early onset of violent criminality, substance abuse, personality disorders, and nonviolent criminality. PMID- 24173404 TI - The obesity paradox in heart failure patients with preserved versus reduced ejection fraction: a meta-analysis of individual patient data. AB - BACKGROUND: In heart failure (HF), obesity, defined as body mass index (BMI) >=30 kg m(-2), is paradoxically associated with higher survival rates compared with normal-weight patients (the 'obesity paradox'). We sought to determine if the obesity paradox differed by HF subtype (reduced ejection fraction (HF-REF) versus preserved ejection fraction (HF-PEF)). PATIENTS AND METHODS: A sub-analysis of the MAGGIC meta-analysis of patient-level data from 14 HF studies was performed. Subjects were divided into five BMI groups: <22.5, 22.5-24.9 (referent), 25-29.9, 30-34.9 and >=35 kg m(-2). Cox proportional hazards models adjusted for age, sex, aetiology (ischaemic or non-ischaemic), hypertension, diabetes and baseline blood pressure, stratified by study, were used to examine the independent association between BMI and 3-year total mortality. Analyses were conducted for the overall group and within HF-REF and HF-PEF groups. RESULTS: BMI data were available for 23 967 subjects (mean age, 66.8 years; 32% women; 46% NYHA Class II; 50% Class III) and 5609 (23%) died by 3 years. Obese patients were younger, more likely to receive cardiovascular (CV) drug treatment, and had higher comorbidity burdens. Compared with BMI levels between 22.5 and 24.9 kg m(-2), the adjusted relative hazards for 3-year mortality in subjects with HF-REF were: hazard ratios (HR)=1.31 (95% confidence interval=1.15-1.50) for BMI <22.5, 0.85 (0.76-0.96) for BMI 25.0-29.9, 0.64 (0.55-0.74) for BMI 30.0-34.9 and 0.95 (0.78-1.15) for BMI >=35. Corresponding adjusted HRs for those with HF-PEF were: 1.12 (95% confidence interval=0.80-1.57) for BMI <22.5, 0.74 (0.56-0.97) for BMI 25.0-29.9, 0.64 (0.46 0.88) for BMI 30.0-34.9 and 0.71 (0.49-1.05) for BMI >=35. CONCLUSIONS: In patients with chronic HF, the obesity paradox was present in both those with reduced and preserved ventricular systolic function. Mortality in both HF subtypes was U-shaped, with a nadir at 30.0-34.9 kg m(-2). PMID- 24173409 TI - Growth in patients with mucopolysaccharidosis type III (Sanfilippo disease). AB - BACKGROUND: Mucopolysaccharidosis III (MPS III), known as Sanfilippo disease, is a lysosomal storage disorder mainly characterized by progressive neurodegeneration with cognitive decline and relatively attenuated somatic signs and symptoms. Although short stature is invariably present in patients with the other mucopolysaccharidoses, it has not been sufficiently addressed in MPS III. The aim of this study was to investigate growth data of a large Dutch MPS III cohort in order to construct growth charts for MPS III patients. METHODS: Height, weight, head circumference (HC), and body mass index (BMI) data from 118 MPS III patients were used to construct reference curves, using the lambda, mu, sigma (LMS) method. Genotype-group comparisons for height standard deviation scores (SDS) were performed by Kruskal-Wallis analysis for different age groups. RESULTS: Birth weight and length were within normal ranges for gestational age and showed a significantly stunted growth from age 6 years onward. Mean final heights were 169.7 cm (-2.0 SDS) and 165.4 cm (-0.84 SDS) for adult male and female, patients, respectively. Phenotypic severity, as assessed by genotyping, correlated with growth pattern and final height. In addition, mean BMI and HC SDS were significantly higher when compared with Dutch standards for both boys and girls. CONCLUSIONS: Growth in MPS III is stunted mainly in patients with the severe phenotype. We provide disease-specific growth references that can be used for clinical management of MPS III patients and may be of value for future treatment studies. PMID- 24173410 TI - Prevalence of Fabry disease in male patients with unexplained left ventricular hypertrophy in primary cardiology practice: prospective Fabry cardiomyopathy screening study (FACSS). AB - BACKGROUND: A number of studies have already investigated the prevalence of Fabry disease (FD) in adult patients with unexplained left ventricular hypertrophy (LVH) with rates varying from 0 % up to 12 % reflecting referral and gender bias as well as differences in diagnostic methodology. We aimed to perform a prospective screening study evaluating the prevalence of FD in male patients older than 30 years with strictly defined unexplained LVH followed by general cardiologists. METHODS: A predefined number of 100 men with unexplained LVH, defined as maximal wall thickness >= 13 mm, were identified during an echocardiographic examination in primary cardiology practice and screened by assessing alpha-galactosidase A activity in dried blood spots (DBS) or in plasma. RESULTS: Four men (52 +/- 4 years, maximal LV wall thickness 18 +/- 3 mm) were diagnosed with FD confirmed by enzyme analysis in leukocytes as well as by genetic analysis. Mild extracardiac manifestations of FD were present in two of them. CONCLUSIONS: The prevalence of FD in our cohort of male patients followed in primary cardiology practice with strictly defined otherwise unexplained LVH was 4 %. We recommend systematic screening for FD in all men older than 30 years with LVH of unknown etiology even in the absence of obvious extracardiac manifestations of FD. PMID- 24173411 TI - Long-term clinical outcome, therapy and mild mitochondrial dysfunction in hyperprolinemia. AB - Although hyperprolinemia type-II has a discriminative metabolic phenotype and is frequently associated with neurological system involvement, the casual relation between the metabolic abnormalities and the clinical features, except for those of the secondary B6 deficiency, has been frequently debated. In order to evaluate disease frequency and the neuro-metabolic outcome we searched our laboratory database between 1992 and 2010, including 20,991 urinary organic acid profiles. From these individuals 16,720 parallel blood samples were available, and were investigated by serum amino acid analysis. We also evaluated the clinical, neurological, psychological features, laboratory data and vitamin levels and therapeutic effect in metabolically confirmed hyperprolinemia. Due to the mitochondrial localization of both ALDH4A1 and PRODH mitochondrial enzyme complex activity was evaluated and oxygen consumption was measured to assess ATP production in patient-fibroblasts. The Mitochondrial Disease Score was used to evaluate clinical mitochondrial dysfunction. The child behavior checklist was used to screen for psychopathology. We found four patients with increased urinary P5C diagnosed with hyperprolinemia type II, and only one patient had hyperprolinemia type I. All children with hyperprolinemia type II had low normal B6 concentration, and three of the patients had biochemical markers suggesting mitochondrial dysfunction. Mitochondrial dysfunction was confirmed in a muscle biopsy in one case. Intellectual disability was found in two adolescent patients. All patients showed seizures and significant behavioral problems, including anxiety and hallucinations. The clinical course was non-progressive and independent from the B6 concentration and B6 therapy. Hyperprolinemia is a rare inborn error. Individuals with hyperprolinemia should be monitored closely due to their frequent behavioral problems. PMID- 24173412 TI - Physical map of the mitochondrial DNA from the phycomycete Allomyces macrogynus including the position of the ribosomal RNA genes and of an intervening sequence in the large rRNA gene. AB - The mitochondrial (mt) DNA of the aquatic phycomycete Allomyces macrogynus is a circular molecule with a size of 56.1 kbp. The cleavage sites for the restriction enzymes SalI and PvuI were mapped by comparing the partial denaturation patterns of isolated restriction fragments with the pattern of the intact circle.The genes coding for the small and large ribosomal RNA (rRNA) were located on the restriction map by heteroduplex and R-loop analysis. The gene coding for the large rRNA contains an intervening sequence, app. 0.7 kbp in size, near the 3' end of the gene. The two rRNA genes are encoded on the same strand of the mtDNA and separated by a region of 17-18 kbp.This rRNA gene organization is similar to that found with members of the Ascomycetes. PMID- 24173413 TI - Perturbation of chloroplast gene transmission in diploid and triploid zygotes of Chlamydomonas reinhardi by 5-fluorodeoxyuridine. AB - Haploid cells or diploid cells homozygous (mt(+)/mt(+) or mt(-)/mt(-)) or heterozygous (mt(+)/mt(-) phenotypically mt(-)) for the mating-type locus and homoplasmic for a chloroplast marker conferring resistance to an antibiotic were crossed with haploid cells of opposite mating-type and carrying another chloroplast marker. Before mating, one or both of the parental strains were grown for 8 days on agar containing 1 mM 5-fluorodeoxyuridine (FUdR), which selectively reduces the amount of chloroplast DNA in Chlamydomonas. In all cases, the chloroplast allele of the treated parent was less frequently transmitted to the meiotic progeny of the zygote than in the corresponding control cross. The effect of FUdR was more pronounced on haploid cells than on diploid cells which initially contained a two-fold higher amount of chloroplast DNA.The results are discussed in relation to current models for uniparental inheritance of non Mendelian genes. PMID- 24173414 TI - Biased and non-biased transmission of chloroplast genes in somatic fusion products of Chlamydomonas reinhardtii. AB - The mode of chloroplast gene inheritance in the somatic fusion products of Chlamydomonas reinhardtii was studied. Polyethylene glycol-induced fusion was made between vegetative or gametic cells of the same or of opposite mating type after the cell walls had been removed using the lytic enzyme prepared from mating medium. The results demonstrated that the chloroplast gene transmission patterns in the fusion products at various combinations can be divided into two types; a biased and non-biased transmission. The biased transmission in favor of the mt (+) (maternal) chloroplast genomes was observed only when mt (+) gamete had been fused artificially with m (-) gamete. The polarized transmission was not changed significantly by fusing two mating type gametes after deflagellation. Furthermore, the pattern was quite similar to that seen in the vegetative zygotes obtained by sexual cross. Nonbiased transmission was seen in the fusion products obtained by all other combinations. In these cases, the chloroplast genes from both parents were transmitted to the progeny in roughly equal frequency. The results indicate that the preferential elimination of paternal (mt (-)) chloroplast alleles that leads to the maternal inheritance depends upon the fusion of two gametes heterozygous at the mating type locus. PMID- 24173415 TI - Gene amplification in yeast: CUP1 copy number regulates copper resistance. AB - The CUP1 locus in yeast confers resistance to copper toxicity. We determined the molecular basis for copper resistance in three yeast strains, with differing degrees of resistance. Increased resistance to copper is associated with overproduction of a low molecular weight copper-binding protein, copper-chelatin. Increased chelatin synthesis results from amplification of the CUP1(r) gene and increased synthesis of the copper inducible mRNA. The copper resistance level of a given strain correlates directly with the gene copy number.Strains containing one copy and ten tandemly iterated copies of the CUP1 gene were studied. From the latter, a haploid strain with enhanced resistance was isolated following several selection cycles at elevated copper concentrations. This strain was disomic for chromosome VIII, the chromosome containing the CUP1 locus. The disomic chromosomes exhibit differential CUP1 gene amplification: 11 and 14 tandemly organized repeat units are found in the respective chromosome VIII homologues. We propose that the molecular mechanisms of gene amplification involve unequal sister chromatid exchange and intrachromosomal gene conversion, as well as disomy. PMID- 24173416 TI - Drug-dependent mutants in yeast Saccharomyces cerevisiae. AB - Mutations in sup1 and sup2 genes may cause cycloheximide-dependent growth in yeast Saccharomyces cerevisiae. Two classes of such mutants are described in the paper: 1) high temperature sensitive mutants, which do not express their sensitivity to nonpermissive temperature in the presence of cycloheximide (conditionally dependent) and 2) mutants unable to grow in the absence of the drug (true dependent). Some of the mutants of both classes express dependence toward another antibiotic - trichodermine. The binding of H(3)-labelled cycloheximide studied by equilibrium dialysis has demonstrated that both 80S ribosomes and 60S subunits isolated from conditionally dependent mutant showed a higher affinity for the drug compared to that of a parent strain. The number of binding sites per ribosome or per 60S subunit in the cycloheximide dependent mutant remains unchanged.Circular dichroism spectra of a mutant ribosomes in the presence as well as in the absence of antibiotic revealed that sup1 and sup2 mutations alter conformation of the yeast cytoplasmic ribosomes. The binding of cycloheximide to mutant ribosomes induces a conformational shift, which presumably compensates for their functional defect. PMID- 24173417 TI - The effect of canavanine on the maintenance in yeast of chimeric plasmids containing portions of the 2-um DNA plasmid. AB - We have found that the application of the amino acid analog canavanine to a culture of yeast cells transformed with chimeric plasmids based on the yeast 2-um DNA plasmid increases the percentage of cells which have lost the transforming plasmid. This effect is found whether the plasmid carries the CAN1 sensitive allele and the yeast strain carries a can1 mutation confering resistance, or the plasmid contains no CAN1 allele and the yeast strain carries the wild-type CAN1 sensitive allele. Canavanine exerts this effect on yeast strains transformed with chimeric plasmids containing either a portion or the entire 2-um DNA plasmid, yet canavanine does not appear to effect the maintenance of the native 2-um DNA plasmid complement within the cell. The effect of canavanine on strains transformed with chimeric plasmids is the same whether or not the yeast strain also contains native 2-um plasmid DNA. Neither the amino acid analog ethionine, the protein synthesis inhibitor cycloheximide, nor the DNA replication inhibitor hydroxyurea exhibit this effect. Some of the experimental results suggest that canavanine may be a curing agent rather than an agent which selects for spontaneous plasmid loss. PMID- 24173418 TI - Leucine biosynthesis in yeast : Identification of two genes (LEU4, LEU5) that affect alpha-Isopropylmalate synthase activity and evidence that LEU1 and LEU2 gene expression is controlled by alpha-Isopropylmalate and the product of a regulatory gene. AB - Tetrad analysis indicates that alpha-isopropylmalate synthase activity of yeast is determined by two separate genes, designated LEU4 and LEU5. LEU4 is identified as a structural gene. LEU5 either encodes another alpha-isopropylmalate synthase activity by itself or provides some function needed for the expression of a second structural gene. The properties of mutants affecting the biosynthesis of leucine and its regulation suggest that the expression of LEU1 and LEU2 (structural genes encoding isopropylmalate isomerase and beta-isopropylmalate dehydrogenase, respectively) is controlled by a complex of a-isopropylmalate and a regulatory element (the LEU3 gene product). Similarities and differences between yeast and Neurospora crassa with respect to leucine biosynthesis are discussed. PMID- 24173419 TI - Segregation of heterogeneous rDNA segments during demagnification of a Neurospora crassa strain possessing a double nucleolar organizer. AB - We have produced a duplication strain of Neurospora crassa, DpAR33-PR-6, which contains two cytologically visible nucleoli (a DNO or double nucleolar organizer strain). When freshly generated, this strain has approximately twice the number of rRNA cistrons found in the parental (single nucleolar organizer) strains. After several serial propagations, there is a marked reduction in rRNA cistron number, approximating that of the SNO parental strains. This reduction in rRNA cistrons ("demagnification") was not achieved by breakdown of the VL->IVL translocation used to generate the duplication, as rDNA from the two parents can be distinguished by the size of the non-transcribed spacer region in the rDNA repeat unit of each strain. rDNA characteristic of both parents is present even after demagnification, in approximately equal amounts, suggesting the rRNA cistrons are lost randomly and non-preferentially from each homologous chromatid. In addition, the steady-state growth rate appears to be affected by rRNA cistron number, decreasing in freshly generated DNO strains relative to the parental strains, and returning to parental levels after demagnification. PMID- 24173420 TI - Polymorphisms in DNA of Coprinus cinereus. AB - Two types of DNA sequence polymorphisms were found among different geographic isolates of the basidiomycete fungus Coprinus einereus. These strains showed gains and losses of restriction enzyme recognition sites as well as extensive insertion/ deletion variation within DNA sequences present in a single copy per haploid genome. The same types of DNA sequence variants were also found within the tandemly repeated ribosomal RNA genes in these strains. There appears to be very little interspersed repetitive DNA in Coprinus, since all the randomly selected cloned DNA sequences studied in this survey were present only once in each haploid genome. PMID- 24173421 TI - Trehalose: Its role in germination of Saccharomyces cerevisiae. AB - Mutants with specific lesions were used to differentiate between the functions of glycogen and trehalose in S. cerevisiae. Diploids which harbor the glc1/glc1 mutation depend upon the phosphorylated, less active form of glycogen synthase and show a more active, phosphorylated form, of the enzyme trehalase. These conditions are due to a lesion in the regulating subunit of the cAMP-dependent protein kinase. Such cells are unable to sporulate. Diploids which contain the sst1/sst1 mutation have normal glycogen metabolism but their trehalose-6 phosphate synthase is not active. Such strains sporulate but germination is poor and only one-spore tetrads are formed. These results confirm that glycogen is needed to trigger sporulation while trehalose plays a role in the germination process. Different systems, I and II, of trehalose accumulation were proposed. System I would require the UDPG-linked trehalose synthase, whereas system II would constitute an alternative pathway, specifically induced or activated by the expression of a MAL gene. The presence of system II in its constitutive form in the constructed diploids would favour trehalose synthesis during growth on glucose, however, it did not overcome the glycogen deficiency during sporulation nor the lack of trehalose for germination. It seems that only system I, namely trehalose 6-P-synthase, plays a role in the germination process. PMID- 24173422 TI - Variation of mutation and recombination frequencies over a range of thymidylate concentrations in a diploid thymidylate auxotroph. AB - A diploid yeast thymidylate auxotroph was grown under conditions of thymidylate stress ranging from depletion to excess levels of the nucleotide. High concentrations of thymidylate were mutagenic and recombinagenic whereas starvation for thymine nucleotides was recombinagenic and only slightly mutagenic. These results are discussed in relation to possible mutagenic and recombinagenic mechanisms of nucleotide pool imbalances. PMID- 24173423 TI - Paternal inheritance of the mitochondrial dna in interspecific crosses of the aquatic fungus allomyces. AB - We have demonstrated by gel analysis of restricted DNA paternal inheritance of mitochondrial DNA in interspecific crosses between A. macrogynus and A. arbuscula. PMID- 24173424 TI - Mitochondrial genetics of Coprinus: Recombination of mitochondrial genomes. AB - The formation of the sexual mycelium or dikaryon in the basidiomycete Coprinus cinereus involves exchange and migration of nuclei without accompanying exchange of mitochondria. The dikaryotic growth which appears around the periphery of mated monokaryons has exclusively the mitochondrial genome of the recipient cells. Recombination of mitochondrial genomes is not, however, precluded during dikaryosis. Using monokaryons with different mitochondrial gene mutations, [acu 10] causing cytochrome aa 3 deficiency and[cap-1.1] conferring resistance to chloramphenicol, it was shown that recombinant mitochondria arise in the zone of contact of mated monokaryons. PMID- 24173425 TI - Cloning of photoreactivation repair gene and excision repair gene of the yeast Saccharomyces cerevisiae. PMID- 24173426 TI - Characteristics of community-onset NDM-1-producing Klebsiella pneumoniae isolates. AB - Multilocus sequence typing and in vitro antimicrobial susceptibility testing were performed for three community-onset New Delhi metallo-beta-lactamase-1 (NDM-1) producing Klebsiella pneumoniae isolates from Korea. The genetic structure surrounding the blaNDM-1 gene was determined in blaNDM-1-harbouring plasmids. Three NDM-1-producing K. pneumoniae isolates were found to belong to the same clone (sequence type 340). Each of these isolates showed the same genetic structure surrounding the blaNDM-1 gene. The genes blaNDM-1, bleMBL, trpF and dsbC were flanked by two intact insertion sequences, ISAba125 and IS26, which may promote horizontal gene transfer. The blaNDM-1-harbouring plasmids conferred antimicrobial resistance to carbapenems, cephalosporins, aminoglycosides and aztreonam in transconjugants. It can be speculated that either the entire blaNDM 1-harbouring plasmids or just the part of the plasmid containing the blaNDM-1 gene may have transferred between K. pneumoniae and Escherichia coli. Following the transfer, the isolate disseminated throughout Korea. This study suggests the need for monitoring the dissemination of NDM-1-producing isolates across countries or continents due to their potential transferability via ISAba125- and IS26-associated transposons. PMID- 24173427 TI - KPC-2 carbapenemase and DHA-1 AmpC determinants carried on the same plasmid in Enterobacter aerogenes. AB - This study was conducted to analyse the presence of a plasmid-mediated carbapenem resistance mechanism in a clinical Enterobacter aerogenes isolate from a patient from Jiangsu province, People's Republic of China. PCR and sequencing confirmed that the isolate harboured Klebsiella pneumoniae carbapenemase (KPC)-2, DHA-1 and TEM-1 beta-lactamase genes. Both the KPC-2 and DHA-1 genes were transferred to Escherichia coli C600 by transconjugation, and Southern blotting confirmed that these two genes were located on the same plasmid, which was of approximately 56 kb in size. The Enterobacter aerogenes isolate was resistant to carbapenems and other tested antimicrobial agents. The Escherichia coli transconjugant showed reduced susceptibility but not resistance to carbapenems and other beta-lactams, indicating the presence of another, possibly permeability-related, resistance mechanism in the clinical isolate. PMID- 24173428 TI - SC35 promotes splicing of the C5-V6-C6 isoform of CD44 pre-mRNA. AB - CD44 is a cell membrane glycoprotein that mediates the response of cells to their cellular microenvironment and regulates growth, survival, differentiation and motility. CD44 pre-mRNA contains 20 exons, 10 of which are alternatively spliced. Among the CD44 spliced variants, one of the V6 exon-containing isoforms, the V4-7 variant which contains variable exons 4, 5, 6 and 7, confers metastatic potential to non-metastatic cells. However, the splicing regulation of the V6 exon is not completely understood. SC35 is an arginine-serine rich protein that regulates alternative splicing of various pre-mRNAs. In the present study, we established a stable cell line which indicates inclusion or skipping of the V6 exon with the RFP or GFP signal. Using this stable cell line, we found that the V6 exon and flanking introns of CD44 pre-mRNA contained SC35 response elements that regulate V6 splicing. RT-PCR analyses of the endogenous CD44 splicing showed that SC35 promotes the production of the C5-V6-C6 isoform. shRNA knockdown of SC35 showed that reduced expression of SC35 decreased expression of the V6 exon-containing isoforms. Our results reveal a novel mechanism of CD44V6 splicing. PMID- 24173429 TI - A strategy for trade monitoring and substitution of the organs of threatened animals. AB - The use of threatened animals as a source of traditional medicines is accelerating the extinction of such species and imposes great challenges to animal conservation. In this study, we propose a feasible strategy for the conservation of threatened medicinal animals that combines trade monitoring and the search for substitutes. First, DNA barcoding provides a powerful technique for monitoring the trade of animal species, which helps in restricting the excessive use and illegal trade of such species. Second, pharmacological tests have been adopted to evaluate the biological equivalence of threatened and domestic animals; based on such testing, potential substitutes are recommended. Based on a review of threatened animal species and their substitutes, we find that the search for substitutes deserves special attention; however, this work is far from complete. These results may be of great value for the conservation of threatened animals and maintaining the heritage of traditional medicine. PMID- 24173430 TI - Safe motherhood voucher programme coverage of health facility deliveries among poor women in South-western Uganda. AB - There has been increased interest in and experimentation with demand-side mechanisms such as the use of vouchers that place purchasing power in the hands of targeted consumers to improve the uptake of healthcare services in low-income settings. A key measure of the success of such interventions is the extent to which the programmes have succeeded in reaching the target populations. This article estimates the coverage of facility deliveries by a maternal health voucher programme in South-western Uganda and examines whether such coverage is correlated with district-level characteristics such as poverty density and the number of contracted facilities. Analysis entails estimating the voucher coverage of health facility deliveries among the general population and poor population (PP) using programme data for 2010, which was the most complete calendar year of implementation of the Uganda safe motherhood (SM) voucher programme. The results show that: (1) the programme paid for 38% of estimated deliveries among the PP in the targeted districts, (2) there was a significant negative correlation between the poverty density in a district and proportions of births to poor women that were covered by the programme and (3) improving coverage of health facility deliveries for poor women is dependent upon increasing the sales and redemption rates. The findings suggest that to the extent that the programme stimulated demand for SM services by new users, it has the potential of increasing facility based births among poor women in the region. In addition, the significant negative correlation between the poverty density and the proportions of facility based births to poor women that are covered by the voucher programme suggests that there is need to increase both voucher sales and the rate of redemption to improve coverage in districts with high levels of poverty. PMID- 24173432 TI - Pathogenesis of endometriosis: the role of initial infection and subsequent sterile inflammation (Review). AB - Endometriosis is a common type of chronic inflammatory disease with an immunological background. In this review, we aimed to explore the contemporary literature on the infection and sterile inflammation that support the pathogenesis of endometriosis. This article reviews the English-language literature on inflammatory, environmental, immunological and oxidative factors associated with endometriosis in an effort to identify factors that cause a predisposition to endometriosis. Intrauterine microbes may be critical for the initiation of endometriosis; the initial activation of pathogen recognition receptors by microbial stimuli results in the activation of proinflammatory pathways and innate immunity. In addition to their response to various exogenous pathogen-associated molecular patterns, Toll-like receptors (TLRs) also recognize a wide range of endogenous danger-associated molecular patterns (DAMPs). The increased expression levels of DAMPs may be involved in the subsequent process of nuclear transcription factor-kappaB-dependent sterile inflammation. Oxidative stress, secondary to the influx of iron during retrograde menstruation, is involved in the progression of endometriosis. DAMP-mediated danger signals and oxidative stress are bidirectional during sterile inflammation (danger signal spiral). This review supports the hypothesis that there are at least two distinct phases of endometriosis development: The initial wave of TLR activation in modulating innate immune responses would be followed by the second big wave of sterile inflammation. PMID- 24173433 TI - Defining and mapping the person with osteoarthritis for population studies and public health. AB - OBJECTIVE: To determine population-based estimates for the prevalence of the person with OA, predicted to be the single greatest cause of disability in the general population by 2030, in order to inform the planning and commissioning of health, social care and prevention services. METHODS: A postal survey to all adults >=50 years of age registered with eight general practices in the UK. Self reported data on chronic joint pain in four body regions (hand, hip, knee, foot) and the disabling nature of the pain was collected to determine gender and age group specific prevalence estimates of clinical OA in the joint region and in the person. Multiple imputation and weighted logistic regression was used to allow for missing data. RESULTS: A total of 26 705 mailed surveys resulted in 18 474 responses (adjusted response = 71.8%). Approximately half of the mailed population had OA in at least one of the four regions (53.23%, 95% CI 52.3, 54.1) and less than half of these had disabling OA (21.87%, 95% CI 21.2, 22.5). The more joint regions involved, the more likely that the OA was disabling. OA prevalence was higher in females and increased with age. Applied to the population of England, this yielded an estimated 3.5 million persons with disabling OA, including 1.45 million people between 50 and 65 years of age and 370 000 >=85 years of age. CONCLUSIONS: A simple approach to defining the person with OA can contribute to population comparisons, public health projections and health care needs assessments. PMID- 24173434 TI - Persistence of Staphylococcus aureus colonization among individuals with immune mediated inflammatory diseases treated with TNF-alpha inhibitor therapy. AB - OBJECTIVE: We investigated the relationship between Staphylococcus aureus colonization and the use of immunosuppressive therapies in patients with immune mediated inflammatory diseases (IMIDs). METHODS: We prospectively enrolled IMID patients from the rheumatology and dermatology departments of Oregon Health & Science University. At enrolment, we surveyed patients for S. aureus infection risk factors and those using immune-modulating therapies, and evaluated their colonization status with bilateral nares and inguinal fold cultures. Patients were asked to follow up 6-12 months later for reassessment of colonization status by repeat culture. S. aureus isolates were tested for the presence of methicillin resistance by PCR. RESULTS: We enrolled a total of 548 IMID patients. At enrolment, 219 (40.0%) patients were colonized with S. aureus, of which 27 (12.3%) were methicillin-resistant S. aureus (MRSA). Baseline colonization rates were similar between TNF-alpha inhibitor users and non-users (40.5% and 39.4%, P = 0.79), but were significantly higher for psoriasis patients compared with those with RA (43.5% and 31.8%, P = 0.02). A total of 384 patients were available for follow-up. Patients who were colonized at enrolment were more likely to be colonized at follow-up if they were treated with TNF-alpha inhibitors during the study as compared to patients without TNF-alpha inhibitor exposure [odds ratio (OR) = 2.2 (95% CI 1.1, 4.2), P = 0.02]. CONCLUSION: Patients with psoriasis are more likely to be colonized with S. aureus than patients with RA. Patients who are colonized with S. aureus are more likely to remain colonized if exposed to TNF-alpha inhibitors. PMID- 24173435 TI - A giant congenital melanocytic nevus associated with neurocutaneous melanosis. PMID- 24173437 TI - Theoretical foundations for a quantitative approach to paleogenetics : Part II: Proteins. AB - It is shown that simply counting the number of amino acid differences between two homologous present day proteins may underestimate the number of mutagenic events that have occurred by more than a factor of three. In a previous paper (Part I) it was shown how to correct quantitatively for multiple mutagenic events at the same base site and for back mutation at that site. In this paper formulas are derived to correct for multiple mutagenic events within the same codon triplet and for the degeneracy of the genetic code. These formulas are related to the often used concept of minimum mutation distance, and it is demonstrated that the latter underestimates the number of 3-base changes (per codon) by more than an order of magnitude. The formulas developed in this paper are shown to be capable of detectinga priori, and with statistical significance, the nonrandomness that is known from experiment to exist in theA fibrinopeptides of ox, reindeer, sheep, and goat; the formulas also show, with statistical significance, that the assumption of a single ancestral DNA does not suffice to explain the known number of amino acid differences which occur between pairs of these fibrinopeptides.More explicitly, the following problems are solved: 1. Consider a protein ofT amino acids which is coded by a polynucleotide ofL = 3 T individual nucleotide bases. Let exactlyX mutagenic events occur randomly along the length of this polynucleotide. After theX mutagenic events have occurred, a numberA, less than or equal toT, amino acid sites will differ from the corresponding sites in the ancestral protein. An explicit formula forN(A), the average number of amino acid substitutions that have occurred, is derived. 2. Because of chance identities, the number of amino acid differencesN(d) between two homologous present day proteins will be less thanN 1 (A) plusN 2 (A), where the subscripts refer to each homologue; a formula forN(d) is derived. 3. The limits of validity of the commonly used approximationN(A)=1/2N(d) are derived. 4. Formulas are given which permit the estimation of the proportion of amino acid substitutions which have occurred by one base, two base, and three base changes. PMID- 24173438 TI - Evolutionary rate of cistrons and DNA divergence. AB - The ratio of DNA divergence to cistron divergence was estimated for various comparisons ofDrosophila and mammalian species. It was shown that a negative correlation exists between this ratio and the length of one generation. It was proposed that the majority of the amino acid substitutions in evolution are the result of random fixation of nearly neutral mutations for which selection intensity fluctuates considerably but the average selection coefficient is very slightly negative. On the other hand, the evolutionary rate of DNA divergence is negatively correlated with the generation time if the majority of mutations are completely neutral and if mutation rate at the nucleotide level is mildly dependent on the generation time. PMID- 24173439 TI - Separate physiological roles for two isozymes of pyridine nucleotide-linked glycerol-3-phosphate dehydrogenase in chicken. AB - Two isozymes of diphosphopyridine nucleotide-linked glycerol-3-P dehydrogenase (E.C. 1.1.1.8) were studied with respect to their tissue distribution in chicken, their ontogeny in chicken liver, and their avian taxonomic distribution. These isozymes in chicken are designated "liver type" and "muscle type" based on the tissue of highest concentration.Electrophoretic analysis shows that the liver type is found in small amounts or is undetectable in all tissues studied exept liver. The muscle type is found in skeletal muscles and kidney. Presumptive hybrid enzymes occur at low levels in chicken liver and kidney.The tissue distribution of glycerol-3-P dehydrogenase in several birds capable of sustained flight is different than in chicken. A single electrophoretic form is predominant in both liver and breast muscle with the activity in liver about ten times greater than in breast muscle. Chicken liver and breast muscle extracts have similar levels of glycerol-3-P dehydrogenase activity.Glycerol-3-P dehydrogenase, solely of the liver type, appears simultaneously with liver formation in the chicken embryo and reaches peak concentrations in the liver between the 10th and 14th day of embryonic development. This embryonic pattern is quite different from the muscle type in breast muscle where the enzyme does not appear until after hatching.These observations, when correlated with the metabolism of lipids and carbohydrates in liver and breast muscle of chicken and birds capable of sustained flight, lend support to a hypothesis that the two isozymes have distinct physiological roles. The liver type is associated with the metabolism of the glycerol moiety of triglycerides and phospholipids whereas the muscle type operates in concert with muscle type lactate dehydrogenase to oxidize DPNH during anaerobic muscle glycolysis. The role of glycerol-3-P dehydrogenase in muscle appears to be essential for prolonging anaerobic glycolysis. It is proposed that the isozymes of glycerol-3-P dehydrogenase originated by gene duplication and then diverged via selective evolution to fulfill the metabolic roles proposed. PMID- 24173440 TI - Phylogenetic measurement in procaryotes by primary structural characterization. AB - Oligonucleotide cataloguing has been used to characterize a number of 5S RNA species from various Procaryotes. Such catalogs can be used to establish certain and detailed phylogenetic relationships among organisms. Confining attention at present to four Families of Procaryotes, theEnterobacteriaceae, theBacillaceae, theAchromobacteraceae, and thePseudomonadaceae, we have shown that the conventionally accepted classification of these organisms which places the first three in the orderEubacteriales, and the last in the orderPseudomonadales, is not phylogenetically valid. PMID- 24173441 TI - Considerations regarding the regulation of gene transcription and messenger translation. AB - The RNA sequences in the region of the coat protein gene of MS2/R17 phage, of the maturation protein gene ofQbeta and of a 6s-RNA transcribed from a presumptive gene oflambda were examined. All but five of the 61 amino acid codons are present in these messages and although there is some evidence of a bias in the frequency of utilization of the codons, there is little evidence to suggest that any codons may be forbidden. It is shown that selection has not reduced useless protein synthesis by minimizing the number of out of register AUG's or maximizing the number of out of register terminating codons in messenger RNA. Secondary structures of the RNA's were formulated using a modification of the diagonal method of Tinocoet al. (1971). Of the 12 AUG triplets considered in the sequences only one is a primary attachment site for ribosomes and it is the only one of the 12 that appears in end loops with none of the bases paired. A thirteenth AUG triplet appears at the beginning of the 6s-RNAlambda gene. Its occurrence in an end loop free of base pairing suggests that this is a ribosome binding site. It is speculated (1), that transcriptase may recognize its binding site on the DNA by a procedure that is in part the analogue of the protein synthetase recognizing its binding-initiation site, namely that as the DNA strands are separated, a secondary structure forms in the sense strand with a CAT in the end loop; (2), that reverse transcriptase might be useful as a means of keeping multiple copies of a gene identical if it were to correct the sense strand DNA in a DNA-RNA hybrid; and (3), that processing of RNA in the intercistronic region normally occurs in the same manner as translation, namely, moving the RNA through, three nucleotides at a time. PMID- 24173442 TI - The partial sequence of the first 30 residues from the amino-terminus of hemoglobin B in the hagfish,Eptatretus stoutii: Homology with lamprey hemoglobin. AB - The partial sequence of the first 30 residues from the amino-terminus of hemoglobin B in the hagfish,Eptatretus stoutii, has been determined. Considerable homology was found between this sequence and the corresponding sequence of lamprey hemoglobin. Both hagfish and lamprey hemoglobins have an additional segment of 9 residues at the amino-terminus as compared with mammalian hemoglobins. PMID- 24173443 TI - Clusters of alpha-LiFeO2 nanoparticles incorporated into multi-walled carbon nanotubes: a lithium-ion battery cathode with enhanced lithium storage properties. AB - We report the preparation of a novel nanocomposite architecture of alpha-LiFeO2 MWCNT based on clusters of alpha-LiFeO2 nanoparticles incorporated into multiwalled carbon nanotubes (MWCNTs). The composite represents a promising cathode material for lithium-ion batteries. The preparation of the nanocomposite is achieved by combining a molten salt precipitation process and a radio frequency oxygen plasma for the first time. We demonstrate that clusters of alpha LiFeO2 nanoparticles incorporated into MWCNTs are capable of delivering a stable and high reversible capacity of 147 mA h g(-1) at 1 C after 100 cycles with the first cycle Coulombic efficiency of ~95%. The rate capability of the composite is significantly improved and its reversible capacity is measured to be 101 mA h g( 1) at a high current rate of 10 C. Both rate capability and cycling stability are not simply a result of introduction of functionalized MWCNTs but most likely originate from the unique composite structure of clusters of alpha-LiFeO2 nanoparticles integrated into a network of MWCNTs. The excellent electrochemical performance of this new nanocomposite opens up new opportunities in the development of high-performance electrode materials for energy storage application using the radio frequency oxygen plasma technique. PMID- 24173444 TI - Transfer parameters for ICRP reference animals and plants collected from a forest ecosystem. AB - The International Commission on Radiological Protection (ICRP) have suggested the identification of a series of terrestrial, marine and freshwater sites from which samples of each Reference animal and plant (RAP) could be systematically collected and analysed. We describe the first such study in which six of the eight terrestrial RAPs, and associated soil samples, were collected from a site located in a managed coniferous forestry plantation in north-west England. Adult life stages of species representing six of the terrestrial RAPs (Wild grass, Pine tree, Deer, Rat, Earthworm and Bee) were sampled and analysed to determine concentrations of 60 elements and gamma-emitting radionuclides. The resultant data have been used to derive concentration ratios (CR(wo-soil)) relating element/radionuclide concentrations in the RAPs to those in soil. This paper presents the first-reported transfer parameters for a number of the RAP-element combinations. Where possible, the derived CR(wo-soil) values are compared with the ICRPs-recommended values and any appreciable differences discussed. PMID- 24173445 TI - Suppression of acetate mutants in Coprinus : I. Identification of two isoaccepting tRNA suppressors of a missense mutation. AB - The acu-1 gene of Coprinus is the structural gene for acetyl-CoA synthetase. Cell free extracts of acu-1.4 mutants lack detectable enzyme activity. Two recessive informational suppressor genes were identified, supa4.1(+) and supa4.2(+) mapping <1.0 and 12.0 units from acu-1 respectively. Comparison of growth of suppressed mutants on selective (acetate) and non-selective (glucose) media indicated that supa4.1(+) was more efficient than supa4.2(+) but both restored an identically temperature sensitive enzyme function. Measurement of enzyme activity in cell free extracts showed that supa4.1(+) restored 29% wild type enzyme activity whereas supa4.2(+) restored 42%. Km for acetate of suppressed enzymes was indistinguishable from wild type but both had an identical but much reduced half life at 45 degrees C compared with wild type. These observations are consistent with supa4.1(+) and supa4.2(+) being tRNA suppressors derived by mutation in two genes encoding isoaccepting tRNAs. PMID- 24173446 TI - Suppression of acetate mutants in Coprinus : II. Correlation of recessiveness and dosage effects with suppressed enzyme level. AB - Recessiveness and dosage effects of two suppressor genes in Coprinus were correlated with suppressed enzyme activity in cell free extracts. Wild type, the suppressible acu-1.4 mutation and suppressor gene mutations supa4.1(+) and supa4.2(+) were used to construct appropriate diploid strains which allowed comparison of the following situations: (i) wild type, (ii) unsuppressed mutant (iii) homoallelism for a single suppressor, (iv) heterozygosity for a single suppressor (sup (+)/sup (-)) and (v)heterozygosity for two nonallelic suppressors. Extracts of the unsuppressed mutant had no enzyme activity whereas extracts of both the homoallelic suppressor strains had the suppressed level of some 20% wild type acetyl-CoA synthetase activity. Diploids heterozygous for sup (+)/sup (-) were acu(-) in phenotype. These had only 3-6% wild type enzyme activity, a level too low to support growth on acetate and hence the apparent recessiveness of each sup (+) mutation. The doubly heterozygous diploid had exactly the same level of enzyme activity as homoallelic diploids, 20% wild type, hence the acu (+) suppressed phenotype. PMID- 24173447 TI - Polyamines enhance the efficiency of tRNA-mediated readthrough of amber and UGA termination codons in a yeast cell-free system. AB - The effects of polyamines (spermidine and putrescine) on yeast suppressor tRNA mediated readthrough of amber and UGA termination codons, in a homologous cell free system, was examined. The efficiency of readthrough in a [psi+] lysate, mediated by exogenous suppressor tRNA, was significantly increased by polyamines as was the efficiency of endogenous UGA readthrough. The addition of polyamines, in the absence of exogenous suppressor tRNA, did not induce amber or ochre readthrough, nor could polyamines restore efficient termination readthrough in [psi(-)] lysates. It is concluded that polyamines interact with tRNA to increase the strength and specificity of the codon: anticodon interaction. PMID- 24173448 TI - Analysis of yeast DNA by alkaline filter elution. AB - The method of analysis of DNA in mammalian cells by alkaline elution from filters (Kohn et al. 1974) was adapted for studies on yeast DNA. By this technique spheroplasts obtained from yeast cells are lysed on filters and single-stranded DNA fragments selectively eluted by alkaline solutions. The procedure was applied to monitor the occurrence of replication intermediates and production of DNA single-strand breakage by MMS, and its repair in growth medium. PMID- 24173449 TI - The study of a rDNA replicator in Saccharomyces. AB - We have previously demonstrated that the loss of Rcp-CEN3, a centromeric plasmid containing yeast rDNA autonomously replicating sequences (ARS) is as high as around 50% per generation for most yeast strains. In this study we have attempted to elucidate mechanisms underlying the high mitotic instability of Rcp-CEN3. For this purpose a tandem duplication of a rDNA ARS was constructed in Rcp-CEN3. The new plasmid having two ARSs possesses a markedly higher mitotic stability as compared to a monoARS Rcp-CEN3. The mitotic stability of this centromere containing plasmid which has two replicators corresponds to the calculated value for the mitotic stability of two monoARS plasmids Rcp-CEN3 in given cells. Genetic analysis has demonstrated that both plasmids having one or two ARSs are maintained in the single copy state. These results demonstrate that the mitotic instability of centromeric plasmid Rcp-CEN3 carrying a rDNA ARS is associated with the absence of stringent control of replication from the rDNA ARS. A possible mechanism of replication of the chromosomal rDNA repeats in yeast is discussed in the light of this data. PMID- 24173450 TI - Interactions Between the MAT locus and the rad52-1 mutation in yeast. AB - The directed and controlled switching of mating type which occurs in homothallic forms of the yeast Saccharomyces cerevisiaee is dependent upon the presence of the wild type RAD52 gene. The RAD52 gene is also required for spontaneous mitotic and meiotic recombination. It has been observed that the two haploid mating types of yeast respond differently to the presence of the rad52-1 mutation and the gene conferring the ability to switch mating type (the HO allele). Cells of genotype MATa rad52-1 HO remain as stable haploids instead of switching; cells with genotype MATalpha rad52-1 HO are inviable. However, some laboratory strains of yeast harbor a MATa allele which, like MATalpha, is inviable. Both allelic forms of a switch normally in wild type (RAD52) strains. This suggests that the difference between the two MATa alleles may help define the interaction which occurs between the mating type locus and the RAD52 gene product. The difference between the two MATa alleles is not due to major sequence rearrangements, but probably reflects a change of relatively few base pairs. Normally wild type haploid cells which contain the HO gene switch mating type, and then opposite mating types fuse to form MATa/MATalpha diploids. In such diploids the HO gene is not expressed, and switching does not occur. Strains which have only a (or only alpha) information of both MAT and the silent copies switch repeatedly. Digestion of DNA from such strains with appropriate restriction enzymes generates two fragments of DNA resulting from a spontaneous double stranded break in the MAT locus (Strathern et al. 1982). Viable MATa HO rad52-1 strains do not have these fragments. PMID- 24173451 TI - Protein secretion in yeast: Two chromosomal mutants that oversecrete killer toxin in Saccharomyces cerevisiae. AB - Two chromosomal mutations in yeast that result in oversecretion of the K1 killer toxin protein were examined. A recessive mutation in gene ski5 appears to lead to toxin oversecretion through a defect in a cell surface, PMSF-inhibited protease. A wild type killer strain degraded toxin following synthesis, and degradation could be partially prevented by addition of PMSF to the growth medium. The ski5 mutation caused an approximate ten fold oversecretion of toxin, similar to that seen in a PMSF-treated wild type culture, and no increased oversecretion in the presence of PMSF. The ski5 mutation caused oversecretion of other low molecular weight secreted proteins and appeared to oversecrete the alpha-factor pheromone, as judged by activity tests. The ski5 mutation was complemented by mutations in ski genes 1-4, and the mutant was not supersensitive to mating pheromones or K2 killer toxin.We also examined killer strains with a mutation in the nuclear gene krel which results in a defective (1->6)-beta-D-glucan cell wall receptor for killer toxin. Such strains oversecrete toxin into the growth medium, but also, unexpectedly, oversecrete most other secreted proteins. The defect in (1->6)-beta D-glucan in these mutants appears to perturb the partitioning of secreted proteins between the cell wall and the medium. PMID- 24173452 TI - Transcription of a mitochondrial plasmid during senescence in Podospora anserina. AB - In the ascomycete fungus Podospora anserina, cellular senescence is characterized by the excision, circularization, and amplification of specific segments of the non-senescent mitochondrial genome. During senescence, various plasmids can be found in the mitochondria, and different senescent events produce different plasmid populations. In this paper we have examined the transcriptional activity of one mitochondrial plasmid (alpha-sen DNA) and have contrasted this with the non-senescent mitochondrial genome of rapidly (A(+)) and slowly (s(+)) senescing races. In non-senescent and senescent mitochondria we observe two RNAs which are homologous to alpha-sen DNA and to the parental locus on the native genome. These are 2.4 and 2.5 kb long and have different 5' ends while overlapping throughout most of their lengths. They may represent different transcripts for alpha-sen DNA and the parental genome and indicate that excision of the plasmid begins 450 bp from the 5' end of the genomic coding sequence. Transcription of the alpha-sen DNA plasmid appears to be active in both senescent and in non-senescent mycelia. PMID- 24173453 TI - Spontaneous and induced mitotic recombination in Ustilago violacea detected at the cellular level. AB - Spontaneous and induced mitotic recombination in the heterobasidiomycete Ustilago violacea was detected at the cellular level using a sporidial morphology mutation. Mitotic recombination was induced by ultraviolet light (UV), nitrogen mustard (NM) and metabolically nonactivated cyclophosphamide (CP). The effects of low (14 degrees C) and high (30 degrees C) temperature and culture age on induced mitotic recombination are reported. Low temperature after inductive treatment uniformly reduced mitotic recombination. High temperature increased UV induced recombination, had no effect on NM-induced recombination and reduced CP induced recombination to the spontaneous level. Temperature alone had no effect on mitotic recombination. Ultraviolet light-induced recombination was correlated with the rate of cell division and cell survival as cells passed from log to stationary phase growth. Detection of mitotic recombination at the cellular level is discussed as a method to assay postreplication repair of genetic damage and as a screen for agents which induce genetic damage in eukaryotic cells. PMID- 24173454 TI - Chloroplast and nuclear DNA fragments from Chlamydomonas promoting high frequency transformation of yeast. AB - A hybrid plasmid (pLG4) containing pBR325 and the yeast arg4 gene was constructed then used to isolate DNA fragments of Chlamydomonas able to promote high frequency transformation of yeast. Three plasmids containing EcoRI restriction fragments of chloroplast DNA and two plasmids containing Aval fragments of nuclear DNA were shown to support autonomous replication of plasmids in yeast. The three EcoRI fragments correspond to restriction fragments R4, R5 and R11 of native chloroplast DNA. These fragments are clustered in the physical map of chloroplast DNA constructed by Rochaix (1978). All isolated plasmids were shown to transform yeast at high frequency but the yeast transformants were quite unstable mitotically. Potential cloning sites are still available in the new plasmids which could be used as vectors in yeast and possibly in Chlamydomonas itself. PMID- 24173455 TI - Characterization of inverted repeat sequences and ribosomal RNA genes of chloroplast DNA from Chlorella ellipsoidea. AB - Chloroplast DNA isolated from a green alga Chlorella was shown by agarose gel electrophoresis and electron microscopy to contain a pair of large inverted repeat sequences of ca. 23 kbp. Electron microscopy revealed that the repeats were separated from each other by a small single strand loop of 29.5 kbp and a large single strand region of 98.5 kbp.Digestion with the restriction endonucleases Kpnl, Sstl, and Xhol, and hybridization with (32)P-labelled tobacco rDNAs revealed that the genes for 16S and 23S rRNAs are present in the repeated sequences. From the hybridization pattern, a restriction map around the sequences were constructed, and the rRNA genes were found to be on the 10.8 kbp SstI fragment. This location was supported by electron microscopy (R-loop formation).Unlike Chlamydomonas reinhardii, Chlorella lacks a large intron in its 23S rRNA gene, and the 16S-23S spacer region is considerably long; the organization of rRNA operon is similar to that of higher plants. PMID- 24173456 TI - Persistent heteroplasmic cells for mitochondrial genes in Saccharomyces cerevisiae. AB - Genes in mitochondria and chloroplasts segregate rapidly during vegetative reproduction. Models to explain this vegetative segregation invoke either random segregation of organelle DNA molecules, or nonrandom segregation with random recombination events. All such models are basically stochastic. To look at vegetative segregation we took heteroplasmic (HET) cells containing mitochondrial mutations at the cap1, eryl and olil loci from several crosses. HETs were repeatedly selected and subcloned. Even after three to five successive subclonings (approximately 60-100 generations) some cells remained heteroplasmic. This confirms and extends previous observations of persistent HETs by Rank and Bech-Hansen (1972) and Forster and Kleese (1975), and by Bolen et al. (1980) for chloroplast genes in Chlamydomonas. PMID- 24173457 TI - Monthly to interannual variability of microbial eukaryote assemblages at four depths in the eastern North Pacific. AB - The monthly, seasonal and interannual variability of microbial eukaryote assemblages were examined at 5 m, the deep chlorophyll maximum, 150 m and 500 m at the San Pedro Ocean Time-series station (eastern North Pacific). The depths spanned transitions in temperature, light, nutrients and oxygen, and included a persistently hypoxic environment at 500 m. Terminal restriction fragment length polymorphism was used for the analysis of 237 samples that were collected between September 2000 and December 2010. Spatiotemporal variability patterns of microeukaryote assemblages indicated the presence of distinct shallow and deep communities at the SPOT station, presumably reflecting taxa that were specifically adapted for the conditions in those environments. Community similarity values between assemblages collected 1 month apart at each depth ranged between ~20% and ~84% (averages were ~50-59%). The assemblage at 5 m was temporally more dynamic than deeper assemblages and also displayed substantial interannual variability during the first ~3 years of the study. Evidence of seasonality was detected for the microbial eukaryote assemblage at 5 m between January 2008 and December 2010 and at 150 m between September 2000 and December 2003. Seasonality was not detected for assemblages at the deep chlorophyll a maximum, which varied in depth seasonally, or at 500 m. Microbial eukaryote assemblages exhibited cyclical patterns in at least 1 year at each depth, implying an annual resetting of communities. Substantial interannual variability was detected for assemblages at all depths and represented the largest source of temporal variability in this temperate coastal ecosystem. PMID- 24173458 TI - Ectomycorrhizal fungi contribute to soil organic matter cycling in sub-boreal forests. AB - Soils of northern temperate and boreal forests represent a large terrestrial carbon (C) sink. The fate of this C under elevated atmospheric CO2 and climate change is still uncertain. A fundamental knowledge gap is the extent to which ectomycorrhizal fungi (EMF) and saprotrophic fungi contribute to C cycling in the systems by soil organic matter (SOM) decomposition. In this study, we used a novel approach to generate and compare enzymatically active EMF hyphae-dominated and saprotrophic hyphae-enriched communities under field conditions. Fermentation humus (FH)-filled mesh bags, surrounded by a sand barrier, effectively trapped EMF hyphae with a community structure comparable to that found in the surrounding FH layer, at both trophic and taxonomic levels. In contrast, over half the sequences from mesh bags with no sand barrier were identified as belonging to saprotrophic fungi. The EMF hyphae-dominated systems exhibited levels of hydrolytic and oxidative enzyme activities that were comparable to or higher than saprotroph-enriched systems. The enzymes assayed included those associated with both labile and recalcitrant SOM degradation. Our study shows that EMF hyphae are likely important contributors to current SOM turnover in sub-boreal systems. Our results also suggest that any increased EMF biomass that might result from higher below-ground C allocation by trees would not suppress C fluxes from sub-boreal soils. PMID- 24173459 TI - Microevolution of Renibacterium salmoninarum: evidence for intercontinental dissemination associated with fish movements. AB - Renibacterium salmoninarum is the causative agent of bacterial kidney disease, a major pathogen of salmonid fish species worldwide. Very low levels of intra species genetic diversity have hampered efforts to understand the transmission dynamics and recent evolutionary history of this Gram-positive bacterium. We exploited recent advances in the next-generation sequencing technology to generate genome-wide single-nucleotide polymorphism (SNP) data from 68 diverse R. salmoninarum isolates representing broad geographical and temporal ranges and different host species. Phylogenetic analysis robustly delineated two lineages (lineage 1 and lineage 2); futhermore, dating analysis estimated that the time to the most recent ancestor of all the isolates is 1239 years ago (95% credible interval (CI) 444-2720 years ago). Our data reveal the intercontinental spread of lineage 1 over the last century, concurrent with anthropogenic movement of live fish, feed and ova for aquaculture purposes and stocking of recreational fisheries, whilst lineage 2 appears to have been endemic in wild Eastern Atlantic salmonid stocks before commercial activity. The high resolution of the SNP-based analyses allowed us to separate closely related isolates linked to neighboring fish farms, indicating that they formed part of single outbreaks. We were able to demonstrate that the main lineage 1 subgroup of R. salmoninarum isolated from Norway and the UK likely represent an introduction to these areas ~40 years ago. This study demonstrates the promise of this technology for analysis of micro and medium scale evolutionary relationships in veterinary and environmental microorganisms, as well as human pathogens. PMID- 24173460 TI - Syntrophy in microbial fuel cells. PMID- 24173462 TI - Distinct functions of the Drosophila genes Serrate and Delta revealed by ectopic expression during wing development. AB - The Drosophila gene Serrate encodes a transmembrane protein with 14 epidermal growth factor-(EGF)-like repeats in its extracellular portion. It has been suggested to act as a signal in the developing wing from the dorsal side to induce the organising centre at the dorsal/ventral compartment boundary, which is required for growth and patterning of the wing. Ectopic expression of Serrate during wing development induces ectopic outgrowth of ventral wing tissue and the formation of an additional wing margin. Here we present data to suggest that both events are mediated by genes that are required for normal wing development, including Notch as receptor. In order for Serrate to elicit these responses the concomitant expression of wingless seems to be required. The lack of wings in flies devoid of Serrate function can be partially restored by Gal4-mediated expression of Serrate, whilst expression of wingless is not sufficient. Ectopic expression of Delta, which encodes a structurally very similar transmembrane protein with EGF-like repeats, provokes wing outgrowth and induction of a new margin under all conditions tested here, both on the dorsal and ventral side. Our data further suggest that Serrate can act as an activating ligand for the Notch receptor only under certain circumstances; it inhibits Notch function under other conditions. PMID- 24173463 TI - Polar effects of lithium in the heart of the zebrafish Danio rerio. AB - The molecular signalling mechanisms that are believed to govern the patterning of the heart early in embryonic development are not well understood. We have investigated the events which occur during patterning of the vertebrate heart by exposing gastrula stage zebrafish embryos to lithium, which is known to affect the phosphoinositol signalling pathway. Treatment of embryos at 50% epiboly (5.25 h after fertilization at 28.5 degrees C) with 0.3 M LiCl for 5-15 min, results in embryos with defects which range from mild to severe, depending on the length of time the embryos are exposed to lithium. In the heart, defects appear progressively in the inflow tract, the sinus venosus and atrium. By using an antibody that recognizes an atrium-specific isoform of myosin, our results show that lithium treatment at gastrulation specifically affects the atrium and sinus venosus, and has little obvious effect on the ventricle. Defects induced by lithium differ from those induced by retinoic acid (RA) treatment of similarly staged embryos, and suggest that lithium and RA may affect the patterning signals important for establishment of the vertebrate heart by acting on different populations of cells or by influencing different patterning pathways. PMID- 24173464 TI - The role of Ca(2+) in progesterone-induced germinal vesicle breakdown of Xenopus laevis oocytes: the synergic effects of microtubule depolymerization and Ca(2+). AB - By monitoring (45)Ca(2+) influx and efflux from oocytes a transient increase followed by a transient decrease in the Ca(2+)-content of progesterone-treated oocytes was observed. Chelation of intracellular Ca(2+) with EGTA or BAPTA-type buffers inhibited progesterone-induced GVBD. Buffers with a mid-range Kd (~1.5 MUM) were most effective in inhibiting GVBD whereas buffers with a Kd above or below this value were less effective. These observations indicate that intracellular Ca(2+), probably in the form of a localized release, is required for progesterone-induced oocyte maturation. However, Ca(2+) alone was insufficient to induce GVBD. When the effects of nocodazole and taxol upon this Ca(2+)-requirement were tested, we observed that taxol-induced microtubule polymerization not only delayed progesterone-induced GVBD but also completely inhibited it in combination with BAPTA-AM. Conversely, nocodazole-induced microtubule depolymerization in combination with ionophore A23187 not only accelerated progesterone-induced GVBD, but also induced GVBD in the absence of progesterone. The combined treatment of oocytes with nocodazole and InsP3, or with cold treatment and ionophore A23187 also induced GVBD in the absence of progesterone. Thus, Ca(2+) and microtubule depolymerization synergistically promote GVBD. In both nocodazole- and cold-treated oocytes, the GV was displaced to the periphery of the oocyte and underwent GVBD when treated with A23187. However, when the GV was displaced to the cortex by a centrifugal force under conditions that would not cause microtubule depolymerization and the oocyte was treated with A23187, oocytes did not undergo GVBD. PMID- 24173461 TI - 'Candidatus Competibacter'-lineage genomes retrieved from metagenomes reveal functional metabolic diversity. AB - The glycogen-accumulating organism (GAO) 'Candidatus Competibacter' (Competibacter) uses aerobically stored glycogen to enable anaerobic carbon uptake, which is subsequently stored as polyhydroxyalkanoates (PHAs). This biphasic metabolism is key for the Competibacter to survive under the cyclic anaerobic-'feast': aerobic-'famine' regime of enhanced biological phosphorus removal (EBPR) wastewater treatment systems. As they do not contribute to phosphorus (P) removal, but compete for resources with the polyphosphate accumulating organisms (PAO), thought responsible for P removal, their proliferation theoretically reduces the EBPR capacity. In this study, two complete genomes from Competibacter were obtained from laboratory-scale enrichment reactors through metagenomics. Phylogenetic analysis identified the two genomes, 'Candidatus Competibacter denitrificans' and 'Candidatus Contendobacter odensis', as being affiliated with Competibacter-lineage subgroups 1 and 5, respectively. Both have genes for glycogen and PHA cycling and for the metabolism of volatile fatty acids. Marked differences were found in their potential for the Embden-Meyerhof-Parnas and Entner-Doudoroff glycolytic pathways, as well as for denitrification, nitrogen fixation, fermentation, trehalose synthesis and utilisation of glucose and lactate. Genetic comparison of P metabolism pathways with sequenced PAOs revealed the absence of the Pit phosphate transporter in the Competibacter-lineage genomes--identifying a key metabolic difference with the PAO physiology. These genomes are the first from any GAO organism and provide new insights into the complex interaction and niche competition between PAOs and GAOs in EBPR systems. PMID- 24173465 TI - Variation of cleavage pattern permitting normal development in a sand dollar, Peronella japonica: comparison with other sand dollars. AB - Peronella japonica, a sand dollar, forms an abbreviated pluteus larva and metamorphoses within 3 days without feeding. In the present study, the cleavage pattern of Peronella embryos was found to be quite irregular in the vegetal blastomeres at the fourth cleavage. Less than half of the embryos examined formed four typical micromeres. The majority formed zero, one, two or three typical micromeres of regular size, and the blastomere(s) remaining in the vegetal-most region was atypical in size and/or its direction of division. Most embryos were able to form pluteus larvae and a considerable proportion of these metamorphosed into juvenile sea urchins, regardless of whether or not they had formed four typical micromeres of regular size, although embryos which formed no typical micromeres developed into pluteus larvae less frequently. The micromere progeny in Peronella embryos form skeletogenic mesenchyme cells. The average numbers of skeletogenic mesenchyme cells in the three sand dollar species, Clypeaster japonicus, Astriclypeus manni and P. japonica were 62, 122 and 219, respectively. In these species, the skeletogenic mesenchyme cell-specific glycoprotein (msp130) was first detected immediately after ingression of the primary mesenchyme cells, spicules appeared at the early gastrula stage and triradiate spicules were found in late gastrulae. Appearance of these characteristics was markedly accelerated in the embryos of A. manni and P. japonica in comparison with those of C. japonicus. Each step in the formation of larval spicules was equally accelerated in A. manni and P. japonica, although the appearance of the adult skeleton was further accelerated in P. japonica in comparison with A. manni, possibly because of omission of the four- to eight-armed pluteus stages. PMID- 24173466 TI - The early stages of ommatidial development in the flour beetle Tribolium castaneum (Coleoptera; Tenebrionidae). AB - Using electron microscopy, the first stages of ommatidial development in the flour beetle Tribolium castaneum were analysed in relation to the cellular architecture of the adult compound eye and were compared to the corresponding patterning process in the fruit fly Drosophila melanogaster. The ommatidia of the slightly horse-shoe shaped beetle compound eye contain six peripheral and two central retinula cells. The rhabdomere of the posteriorly located central photoreceptor cell is restricted to the distal half of the rhabdom whilst that of the anterior one is restricted to its proximal half. The development of the compound eye takes place in an external eye imaginal disc. Most stages of ommatidial development, as known from Drosophila, i.e. arc-like cell groups, five cell clusters, immature eight-cell clusters and symmetrical eight-cell clusters, are very precisely conserved between the two species. Two major differences exist: 1. In Tribolium, the cone cell precursor cells synchronously join to the immature eight-cell cluster. As a consequence, the symmetrical eight-cell cluster immediately transforms into a four-cone-cell cluster. 2. The maturing ommatidia do not undergo rotation in Tribolium. Overall, no morphological indiation for an equator in the adult Tribolium compound eye could be found. Considering the strong evolutionary conservation of early ommatidial development, homology of photoreceptor cells of distantly related insects is proposed to be inferred from their ontogenetic origin. PMID- 24173467 TI - Restricting oxygen supply to the prospective dorsal side does not reverse axis polarity in embryos of Xenopus laevis. AB - During the first cell cycle, the prospective dorsal side of the embryo of Xenopus laevis becomes enriched in mitochondria relative to the ventral side. This differential distribution of mitochondria persists throughout early development, but it is not known if it is of functional significance, since there do not appear to be dorsal-ventral differences in metabolic rate. However, the unilateral anaerobiosis experiments of Landstrom and Lovtrup do suggest a role for energy metabolism in determining axis polarity. These experiments apparently show that restricting oxygen supply to the prospective dorsal side causes a reversal of dorsal-ventral axis polarity. We have reinvestigated this point using cell-marking techniques. We find that although gastrulation is initiated at the open end of the tube, the polarity of neural plate development is unaffected. Thus, definitive dorsal-ventral polarity is not affected by the experimental treatment, and it is unlikely that gradients of energy metabolism have a role in specifying axis polarity in X. laevis. PMID- 24173468 TI - Transcription of a zebrafish gene of the hairy-Enhancer of split family delineates the midbrain anlage in the neural plate. AB - her5 encodes a basic helix-loop-helix (bHLH) protein with all features characteristic of the Drosophila hairy-E(spl) family. her5 is expressed in a band of cells within the neural anlage from about 90% epiboly on to at least 36 h postfertilization (hpf). After completion of brain morphogenesis, her5-expressing cells are located in the caudal region of the midbrain, at the boundary with the rhombencephalon. Labelling of cells within the her5 expression domain in the neural plate by injection of fluorescein-dextran allows their labelled progeny to be localized in the 36-hpf-old embryo using an anti-fluorescein antibody. This shows that the her5 expression domain corresponds to the midbrain primordium, including both the tectum and the tegmentum, in the neural plate. A possible function for her5 in regionalization of the brain and/or control of the midbrain hindbrain boundary is discussed. PMID- 24173470 TI - Combined endovascular and surgical treatment of fusiform aneurysms of the basilar artery: technical note. AB - BACKGROUND: To present the combined treatment of fusiform basilar artery aneurysms consisting of a surgical posterior fossa decompressive craniectomy and ventriculoperitoneal (VP) shunt operation at the same sitting, before the endovascular procedure with telescopic stenting of the aneurysmatic vessel segment in four cases. METHODS: Combined treatment involving surgical procedure consisting of ventriculoperitoneal shunt placement for hydrocephalus and an occipital bone craniectomy and C1 vertebrae posterior laminectomy to decompress the posterior fossa in the same session. After surgery, the patients were loaded with acetylsalicylic acid and clopidogrel, and then the endovascular treatment was performed. RESULTS: All of the procedures were performed successfully without technical difficulty. The patients tolerated the procedures well and all cases showed remodelling with the overlapping stent technique. The patients were discharged home with baseline neurological situation and computed tomography (CT) angiography was performed at the 3rd month. CONCLUSION: This technique is a safer endovascular approach to treating symptomatic fusiform basilar artery aneurysms by protecting patients from both the haemorrhagic complications of anticoagulant therapy and thrombotic complications due to the interruption of anticoagulant therapy, while treating the hydrocephalus and compression by surgical means. PMID- 24173471 TI - Complex interaction between the immune system and adipose tissue (Review). AB - We review the studies on the links between obesity, the immune system and lifestyle (limited or excessive calorie intake) that provoke changes in the current therapeutic course. There is no doubt that the positive energy balance of the body affects the immune cells, and consequently, the changes intracellular pathways, leading to the disruption of their function. Research suggests that metformin, a drug long used to treat diabetes, and an alternative remedy in the treatment of obesity, increases the activity of 5-adenosinemonophosphate (AMP) activated kinase (AMPK). Thus, this review comes to the conclusion that alongside traditional methods, such as reducing calorie intake and increasing the energy expenditure of the body, the therapeutic outcome may be improved by implementing drugs affecting the activity of AMPK. In future, other new therapeutic options may be available. The targeting receptors or immunocompetent cells residing in adipose tissue may help to reduce the effects of obesity. PMID- 24173472 TI - Displacing lateral meniscus masquerading as patella dislocation. AB - PURPOSE: To alert the treating clinician to an uncommon knee meniscal condition that often masquerades as a more common patella condition. METHODS: Retrospective chart review of a series of cases was undertaken. A series of 12 knees in 11 patients were referred to an orthopaedic surgeon with a diagnosis of recurrent lateral patella dislocation. Three knees had undergone patella realignment surgery with continuance of symptoms. Eight patients had prior magnetic resonance images read as no meniscal pathology and no acute patella/patella retinacular injury. All patients presented for a consult with a similar history. RESULTS: Under anaesthesia, all knees had a stable patella as judged by physical examination. At the time of surgery, six patients had a frank tear in the lateral meniscus, all of which were readily displaceable. Six knees showed a displaceable lateral meniscus with attenuation but not a visible frank tear. Ten menisci were treated with repair, and two knees underwent partial lateral meniscectomies. Patient follow-up of minimally 18 months revealed no further episodes of "knee cap dislocation" or symptoms of catching and locking. CONCLUSIONS: The clinician treating a patient with a history of a knee locking in flexion should have a high index of suspicion for a lateral meniscus tear or an unstable hypermobile lateral meniscus, despite patient report of perceived patella movement. History of symptoms occurring in knee flexion and attention to patella physical examination should be key factors in this diagnostic conundrum. LEVEL OF EVIDENCE: Retrospective chart review, Level IV. PMID- 24173473 TI - "Half" a doctor is worse than none. PMID- 24173474 TI - More surgeons, less trauma. PMID- 24173476 TI - Acute intestinal obstruction due to gallstone ileus. AB - OBJECTIVE: To perform a systematic review of the history, available image exams and clinical approach to the diagnosis and treatment of gallstone ileus. METHOD: Retrospective study in a university hospital including all cases of SBO treated over a period of 23 years. According to the surgical treatment the patients were divided into two groups: (1) enterolithotomy with cholecystectomy performed later (two-stage surgery); and (2) enterolithotomy, cholecystectomy and fistula closure (one-stage surgery). RESULTS: Twelve patients were included in the study, including 11 females (91,6%), with a mean age of 72.2 years. All patients presented associated diseases, mainly arterial hypertension (75%). All except one patient had multiple SBO symptoms. Gallstone ileus diagnosis was achieved in six patients (50%) before laparotomy. There were 8 patients in group 1 and 4 in group 2, and the morbidity was, respectively, 33.3% and 8.3%. Overall mortality was 16.6% (one patient in each group). CONCLUSIONS: Gallstone ileus should be suspected in the elderly with SBO symptoms. Early diagnosis can reduce post operative complications. Treatment is urgent laparotomy, and surgical treatment must be individualized for each case. The majority of patients in this study were treated with enterolithotomy, with cholecystectomy being performed later in two symptomatic patients. PMID- 24173475 TI - Comparative analysis of trauma characteristics between elderly and superelderly. AB - OBJECTIVE: To compare the characteristics of trauma in the elderly under and over 80-years-old. METHODS: We conducted a retrospective analysis of protocols of blunt trauma victims aged over 70 years. Individuals aged between 70 and 79 years were included in group I, those aged 80 years or greater in group II. Statistical analysis was performed using the Student t, chi-square and Fisher tests, considering p <0.05 as significant. RESULTS: The study included 281 patients (group I-149, group II-132). The age ranged between 70 and 99 years (79.1 + 6.7 years), with 52.3% male. Group II had lower average abdomen AIS (0.10 + 0.59 vs. 0.00 + 0.00, p = 0.029), lower incidence of male victims (59.1% vs. 44 , 3%, p = 0.013), higher incidence of falling from standing height (44.3% vs. 65.2%, p = 0.028) and lower frequency of upper limb fractures (9.4% vs. 2.3 %, p = 0.010) than Group I. There was no significant difference in comparison of other variables between the groups. CONCLUSION: Trauma in the elderly is a serious public health problem, with a tendency to progressive worsening with population aging. Data from this study help us with a clearer picture of trauma in the over 80 elders, a subgroup that deserves special attention. PMID- 24173477 TI - Comparative study of trauma in the elderly and non-elderly patients in a University Hospital in Curitiba. AB - OBJECTIVE: To compare and identify differences in the profile of elderly and non elderly patients with trauma. METHODS: We conducted a comparative, cross sectional, retrospective, quantitative study with 3112 patients between November, 25th 2010 and February, 25th 2011; patients were classified into GI: elderly (60 years or older) and GA: non-elderly (13-59 years). We collected information on the mechanism of trauma, injuries and factors associated with the event, which were compared between groups by using chi-square, Student t and proportions tests. RESULTS: Falls were more frequent in GI, mostly from the standing height, while violence and traffic accidents (especially with motorcycles) were the most important in GA. Both groups possessed mild trauma (bruises, sprains) as the most frequent, followed by traumatic brain injury (TBI) and fractures. Femur fractures were more common in the elderly, and hand and wrist fractures in the nonelderly. The elderly were hospitalized fewer days and there was no difference as for complications, need for intensive care unit (ICU), or mortality between groups. CONCLUSION: Falls from the standing height are more frequent in the elderly, and motorcycle accidents and interpersonal violence in the non-elderly. Both groups had superficial injuries, head trauma and fractures as major injuries. The elderly were hospitalized for less time. There was no difference in the need for ICU, complications and mortality. PMID- 24173478 TI - Epidemiological profile of work-related accidents with biological exposure among medical students in a surgical emergency room. AB - OBJECTIVE: To evaluate the accidents with biological material among medical students interning in a trauma emergency room and identify key related situations, attributed causes and prevention. METHODS: we conducted a study with a quantitative approach. Data were collected through a questionnaire applied via internet, with closed, multiple-choice questions regarding accidents with biological material. The sample comprised 100 students. RESULTS: thirty-two had accidents with biological material. Higher-risk activities were local anesthesia (39.47%), suture (18.42%) and needle recapping (15.79%). The main routes of exposure to biological material were the eyes or mucosa, with 34%, and syringe needle puncture, with 45%. After contamination, only 52% reported the accident to the responsible department. CONCLUSION: The main causes of accidents and routes of exposure found may be attributed to several factors, such as lack of training and failure to use personal protective equipment. Educational and preventive actions are extremely important to reduce the incidence of accidents with biological materials and improve the conduct of post-exposure. It is important to understand the main causes attributed and situations related, so as general and effective measures can be applied. PMID- 24173479 TI - Evaluation of gasometric parameters in trauma patients during mobile prehospital care. AB - OBJECTIVE: To evaluate gasometric differences of severe trauma patients requiring intubation in prehospital care. METHODS: Patients requiring airway management were submitted to collection of arterial blood samples at the beginning of pre hospital care and at arrival at the Emergency Room. We analyzed: Glasgow Coma Scale, respiratory rate, arterial pH, arterial partial pressure of CO2 (PaCO2), arterial partial pressure of O2 (PaO2), base excess (BE), hemoglobin O2 saturation (SpO2) and the relation of PaO2 and inspired O2 (PaO2/FiO2). RESULTS: There was statistical significance of the mean differences between the data collected at the site of the accident and at the entrance of the ER as for respiratory rate (p = 0.0181), Glasgow Coma Scale (p = 0.0084), PaO2 (p <0.0001) and SpO2 (p = 0.0018). CONCLUSION: tracheal intubation changes the parameters PaO2 and SpO2. There was no difference in metabolic parameters (pH, bicarbonate and base excess). In the analysis of blood gas parameters between survivors and non-survivors there was statistical difference between PaO2, hemoglobin oxygen saturation and base excess. PMID- 24173480 TI - Traumatic brain injury by a firearm projectile: a 16 years experience of the neurosurgery service of Santa Casa de Sao Paulo. AB - OBJECTIVE: To evaluate the epidemiology and prognostic factors associated with traumatic brain injury by a firearm projectile (FAP). METHODS: We reviewed the medical records of 181 patients in the Department of Neurosurgery of Santa Casa de Sao Paulo (Sao Paulo Holy House) diagnosed with traumatic brain injury (TBI) resulting from FAP from January 1991 to December 2005. Were evaluated: age, sex, Glasgow Coma Scale (GCS) on admission, brain region affected by the FAP, type of injury (penetrating or tangential), type of treatment and outcome, based on GCS. The relationship between therapeutic strategy and outcome was analyzed using the Chi-square test with Yates correction. The Fisher test was used to verify the same correlation individually for each group stratified by GCS on admission. RESULTS: Of the 181 patients, 85% were male (n = 154) and 15% female (n = 27). Mean age was 31.04 years (+/- 10.98). The mostly affected brain region was the frontal lobe (27.6%), followed by temporal (24.86%) and occipital (16.57%) ones. Of the TBIs evaluated, 16% were tangential and 84%, penetrating. CONCLUSION: Patients undergoing surgical treatment had better outcome than those submitted to conservative treatment, and patients who were more severe at admission (GCS 3-8) have better results with the neurosurgical procedure. PMID- 24173481 TI - Identifying severe abdominal injuries during the initial assessment in blunt trauma patients. AB - OBJECTIVE: To evaluate the predictive factors of severe abdominal injuries (SAI) identified in the initial assessment of blunt trauma victims. METHODS: A retrospective analysis of data from blunt trauma victims older than 13 years undergoing abdominal computed tomography and/or laparotomy was carried out. Serious injuries were considered with an Abbreviated Injury Scale (AIS) greater than or equal to three. Variables were compared between both A (SAI) and B (no SAI). We conducted an initial univariate statistical analysis to identify the variables associated with the presence of SAI. From these we selected those that had p<0.20 and could be evaluated on admission of the patient for multivariate analysis (logistic regression). RESULTS: The sample consisted of 331 cases and 140 (42.3%) patients had abdominal injuries. Of these, 101 (30.5%) had abdominal injury with AIS e" 3 (Group A). In univariate analysis, conditions significantly associated with the SAI (p<0.05): systolic blood pressure (SBP) in the pre hospital setting (p = 0.019), SBP at admission (p<0.001), heart rate at admission (p = 0.047), altered physical examination of the abdomen (p <0.001) and the presence of pelvic fractures (p = 0.006). The following variables were significantly and independently correlated with the presence of severe abdominal injuries: SBP at admission (p = 0.034), altered abdominal physical examination (p<0.001), lower limb fracture (p<0.044), motorcycle accident as mechanism of injury (p = 0.017) and positive FAST (p <0.001). CONCLUSION: the variables present at baseline were significantly associated with the presence of SAI: SBP, physical examination, altered abdominal examination, presence of open fractures of the lower limb, motorcycle accident and positive FAST. PMID- 24173482 TI - Negative pressure wound therapy in complex trauma of perineum. AB - OBJECTIVE: To review the experience (2011 and 2012) of Wound Center of Plastic Surgery Service, Clinics Hospital, Faculty of Medicine, University of Sao Paulo, with treatment of complex traumatic wounds in the perineal region with the association of negative pressure wound therapy followed by a surgical skin coverage procedure. METHODS: This was retrospective analysis of ten patients with complex wound in the perineum resulting from trauma assisted by the Department of Plastic Surgery in HC-USP. Negative pressure was used as an alternative for improving local conditions, seeking definitive treatment with skin grafts or flaps. RESULTS: Negative pressure was used to prepare the wound bed. In patients, the mean time of use of negative pressure system was 25.9 days, with dressing changes every 4.6 days. After negative pressure therapy, 11 local flaps were performed in nine patients, with fasciocutaneous anterolateral thigh flap used in four of these. Mean hospital stay was 58.2 days and accompaniment in Plastic Surgery was 40.5 days. CONCLUSION: The use of negative pressure therapy led to improvement of local wound conditions faster than traditional dressings, without significant complications, proving to be the current best alternative as an adjunct for the treatment of this type of injury, always followed by surgical reconstruction with grafts and flaps. PMID- 24173483 TI - Hepatic trauma: a 21-year experience. AB - OBJECTIVE: To evaluate the epidemiological aspects, behavior, morbidity and treatment outcomes for liver trauma. METHODS: We conducted a retrospective study of patients over 13 years of age admitted to a university hospital from 1990 to 2010, submitted to surgery or nonoperative management (NOM). RESULTS: 748 patients were admitted with liver trauma. The most common mechanism of injury was penetrating trauma (461 cases, 61.6%), blunt trauma occurring in 287 patients (38.4%). According to the degree of liver injury (AAST-OIS) in blunt trauma we predominantly observed Grades I and II and in penetrating trauma, Grade III. NOM was performed in 25.7% of patients with blunt injury. As for surgical procedures, suturing was performed more frequently (41.2%). The liver-related morbidity was 16.7%. The survival rate for patients with liver trauma was 73.5% for blunt and 84.2% for penetrating trauma. Mortality in complex trauma was 45.9%. CONCLUSION: trauma remains more common in younger populations and in males. There was a reduction of penetrating liver trauma. NOM proved safe and effective, and often has been used to treat patients with penetrating liver trauma. Morbidity was high and mortality was higher in victims of blunt trauma and complex liver injuries. PMID- 24173484 TI - Nonoperative management of splenic injury grade IV is safe using rigid protocol. AB - OBJECTIVE: To demonstrate the protocol and experience of our service in the nonoperative management (NOM) of grade IV blunt splenic injuries. METHODS: This is a retrospective study based on trauma registry of a university hospital between 1990-2010. Charts of all patients with splenic injury were reviewed and patients with grade IV lesions treated nonoperatively were included in the study. RESULTS: ninety-four patients with grade IV blunt splenic injury were admitted during this period. Twenty-six (27.6%) met the inclusion criteria for NOM. The average systolic blood pressure on admission was 113.07 +/- 22.22 mmHg, RTS 7.66 +/- 0.49 and ISS 18.34 +/- 3.90. Ten patients (38.5%) required blood transfusion, with a mean of 1.92 +/- 1.77 packed red cells per patient. Associated abdominal injuries were present in two patients (7.7%). NOM failed in two patients (7.7%), operated on due to worsening of abdominal pain and hypovolemic shock. No patient developed complications related to the spleen and there were no deaths in this series. Average length of hospital stay was 7.12 +/- 1.98 days. CONCLUSION: Nonoperative treatment of grade IV splenic injuries in blunt abdominal trauma is safe when a rigid protocol is followed. PMID- 24173485 TI - Non operative management of renal gunshot wounds. AB - OBJECTIVE: To analyze the experience of nonoperative management (NOM) of renal injuries caused by a firearm projectiles (FAP) in the right thoraco-abdominal region in patients with hemodynamic stability and no signs of peritoneal irritation, highlighting the assessment of the safety of this approach. METHODS: This was a prospective study with patients sustaining injuries by FAP in the right thoraco-abdominal region and kidney lesions, treated at the Joao XXIII Hospital (FHEMIG) in Belo Horizonte, from January 2005 to December 2012. Inclusion criteria were: hemodynamic stability, renal morphofunctional study by CT and no signs of peritoneal irritation. RESULTS: A total of 128 patients met the inclusion criteria of the protocol and underwent NOM for right thoraco abdominal injury by FAP. Of these, 37 (28.9%) had renal injuries. Trauma indexes: RTS 7.8, ISS16, and TRISS 99%. Lesions grade II and grade III were the most frequent. The most commonly associated intra-abdominal injury was of the liver, present in 81.1% of cases. Two patients (5.4%) had failed nonoperative treatment. CONCLUSION: The nonoperative treatment of such renal lesions, when properly indicated, has a high success rate, low complication rate and increases the chance of renal preservation. It is safe for well-selected patients in trauma centers with adequate infrastructure, experienced professionals and use of a specific protocol. PMID- 24173486 TI - Guidelines for discharge: do standardized cards help in patient understanding? AB - OBJECTIVE: To determine whether the addition of discharge standard illustrated cards improves understanding of patients in the emergency room. METHODS: We conducted a prospective, randomized, interventional study with 228 patients discharged from the emergency department. All patients were interviewed and tested for the level of understanding of discharge instructions. Some of them received the intervention, with the standard cards, and another did not, constituting the control group. RESULTS: The average of followed discharge guidelines of the group that received the cards was higher than the control group, with statistical significance (p=0.009). When segregated by age, the group between 16 and 35 years of both sexes had the best average of followed guidelines, statistically, than the average of the control group (p=0.01). The difference between the mean orientations between the control group and the card for patients undergoing procedures was statistically significant (p=0.02); as for the stratification according to the number of procedures, the significance increases when that is equal to 1 (p=0.001) and decreased the more procedures were carried out. CONCLUSION: The introduction of discharge standard orientation cards was associated with improvement in the understanding of patients. Without replacing the verbal directions, which establishes dialogue and doctor-patient bonding, cards appear as auxiliary elements, facilitating understanding and care guidelines. PMID- 24173487 TI - Early nutritional therapy in trauma: after A, B, C, D, E, the importance of the F (FEED). AB - A significant number of deaths in trauma occurs days to weeks after the initial injury, being caused by infection and organ failure related to hypercatabolism and consequent acute protein malnutrition. Nutritional therapy should be planned and included with other routines of resuscitation for patients with multiple trauma and severe burns. The rapid acquisition of a route for nutritional support is important to start early nutritional therapy within 48 hours of care. The enteral route is the preferred option in traumatized postoperative patients but the parenteral route should be prescribed when enteral feeding is contraindicated or inadequate. After the initial measures dictated by ATLS, synthesized in the A (airway), B (breathing), C (circulation), D (disability) and E (exposure), we include the letter F (feed) to emphasize the importance of early nutritional care in trauma. PMID- 24173488 TI - Update in the classification and treatment of complex renal injuries. AB - The "Evidence-Based Telemedicine - Trauma and Acute Care Surgery" (EBT-TACS) Journal Club performed a critical review of the literature and selected three up to-date articles on the management of renal trauma defined as American Association for the Surgery of Trauma (AAST) injury grade III-V. The first paper was the proposal for the AAST grade 4renal injury substratification into grades 4a (Low Risk) and 4b (High Risk). The second paper was a revision of the current AAST renal injury grading system, expanding to include segmental vascular injuries and to establish a more rigorous definition of severe grade IV and V renal injuries.The last article analyses the diagnostic angiography and angioembolization in the acute management of renal trauma using a national data set in the USA. The EBT-TACS Journal Club elaborated conclusions and recommendations for the management of high-grade renal trauma. PMID- 24173489 TI - Penile fracture with urethral trauma. AB - We reported a case of a twenty-nine-year-old male who presented a penile fracture associated with urethral injury caused by a sexual intercourse. An ideal anamnesis and a special physical examination were determinant to correct diagnostics. Ultrasonography and uretrocistography must be performed for confirmation. The treatment is based on the presence of associated urethral injury. The surgical repair of cavernous body and urethra can produce good results, with a favorable prognosis and minimal rate of complications. PMID- 24173490 TI - Variation in protein structure and function: Primate hemoglobins. AB - Variation in structure among primate hemoglobins is associated with variation in function. This supports the hypothesis that most substitutions observed among homologous proteins in different species have been fixed by natural selection because they contribute to the fitness of the genotype. It does not support the concept that most substitutions result from the fixation of neutral alleles by genetic drift. PMID- 24173491 TI - Population size and rate of evolution. AB - It is suggested that in evolution there is much substitution of nearly neutral mutations, for which the selection intensity varies from time to time or from region to region. Since the variance among the selection coefficients of new mutants decreases when the environment becomes uniform, the probability of a mutant being advantageous to the species as a whole increases in more uniform environment (Fig. 1).Therefore the rate of gene substitution increases in smaller populations, as smaller populations are likely to be distributed over less varied environments.The adequacy of the model was discussed in relation with the following facts or plausible postulates. 1. A large number of amino acid substitutions during a period corresponding to the formation of new species. 2. Rapid evolution at the phenotypic level of populations having a small size. 3. Many extinctions and expansions of the species in the past. PMID- 24173492 TI - Dipeptide frequencies in proteins and the CpG deficiency in vertebrate DNA. AB - Analysis of vertebrate protein sequences totalling 4040 residues shows that amino acids with a high proportion of codons ending in C occur with significantly reduced frequency before amino acids whose codons start with G. This effect is not shown by "control" bacterial protein sequences. The consequent implication of shortage of XXC. GXX codon pairs in vertebrate messenger RNA is discussed in relation to the extreme rarity of the base doublet CpG in vertebrate DNA. PMID- 24173493 TI - Non-enzymic beta-decarboxylation of aspartic acid. AB - Non-enzymicbeta-decarboxylation of aspartic acid at 85 degrees is catalyzed by Al(3+) and pyridoxal. The reaction is optimum at pH 4.0. Both Al(3+) and pyridoxal are specifically required because replacing these by other cations or by other vitamin B6 derivatives greatly lowers the formation of alanine. Conversion of 8 umoles of aspartic acid to alanine is optimum in presence of 1umole of Al(3+) and 5 umoles of pyridoxal. Increasing the concentration of pyridoxal to more than 5 umoles lowers the alanine formation by the latter being converted to pyruvate by transamination with the excess pyridoxal.Studies on the mechanism of decarboxylation suggest that aspartic acid is first converted to oxalacetic acid by transamination with pyridoxal which in turn is converted to pyridoxamine. This is followed by decarboxylation of oxalacetic acid to form pyruvic acid which transaminates with pyridoxamine to form alanine. The results are interpreted to suggest that the non-enzymic aspartatebeta-decarboxylation process is closely related to and inseparable from the non-enzymic transamination process in a manner analogous to that reported for the highly purified asparatebeta-decarboxylase. The possible significance of these results to prebiotic molecular evolution is briefly discussed. PMID- 24173495 TI - A note on the hypothesis: Protein polymorphism as a phase of molecular evolution. AB - Assuming that various kinds of balancing selection contribute only a small fraction of naturally occuring genetic variation, it is shown that if a fair fraction of evolutionary change in protein is due to neutral mutants, most of naturally occurring polymorphism must be due to random drift of neutral genes. PMID- 24173496 TI - Chair interconversion and reactivity of mannuronic acid esters. AB - Mannopyranosyluronic acids display a very unusual conformation behavior in that they often prefer to adopt a (1)C4 chair conformation. They are endowed with a strikingly high reactivity when used in a glycosylation reaction as a glycosyl donor. To investigate the unusual conformational behavior a series of mannuronic acid ester derivatives, comprising anomeric triflate species and O-methyl glycosides, was examined by dynamic NMR experiments, through lineshape analysis of (1)H and (19)F NMR spectra at various temperatures from -80 degrees C to 0 degrees C. Exchange rates between (4)C1 and (1)C4 chair conformations were found to depend on the electronic properties and the size of the C2 substituent (F, N3 or OBn) and the aglycon, with higher exchange rates for the glycosyl triflates and smaller C2 substituents. Low temperature (19)F exchange spectroscopy experiments showed that the covalently bound anomeric triflates did not exchange with free triflate species present in the reaction mixture. To relate the conformational behavior of the intermediate triflates to their reactivity in a glycosylation reaction, their relative reactivity was determined via competition reactions monitored by (1)H NMR spectroscopy at low temperature. The 2-O-benzyl ether compound was found to be most reactive whereas the 2-fluoro compound - the most flexible of the studied compounds - was least reactive. Whereas the ring flip of the mannuronic acids is important for the enhanced reactivity of the donors, the rate of the ring-flip has little influence on the relative reactivity. PMID- 24173497 TI - Potential of [18F]-fluoromisonidazole positron-emission tomography for radiotherapy planning in head and neck squamous cell carcinomas. AB - BACKGROUND AND PURPOSE: Positron-emission tomography (PET) with [(18)F] fluoromisonidazole (FMISO) permits consideration of radiotherapy dose escalation to hypoxic volumes in head and neck cancers (HNC). However, the definition of FMISO volumes remains problematic. The aims of this study are to confirm that delayed acquisition at 4 h is most appropriate for FMISO-PET imaging and to assess different methods of volume segmentation. PATIENTS AND METHODS: A total of 15 HNC patients underwent several FMISO-PET/computed tomography (CT) acquisitions 2, 3 and 4 h after FMISO injection. Three automatic methods of PET image segmentation were tested: fixed threshold, adaptive threshold based on the ratio between tumour-derived and background activities (R(T/B)) and the fuzzy locally adaptive Bayesian (FLAB) method. The hypoxic fraction (HF), which is defined as the ratio between the FMISO and CT volumes, was also calculated. RESULTS: The R(T/B) for images acquired at 2, 3 and 4 h differed significantly, with mean values of 2.5 (1.7-2.9), 3 (2-4.5) and 3.4 (2.3-6.1), respectively. The mean tumour volume, as defined manually using CT images, was 39.1 ml (1.2-116 ml). After 4 h, the mean FMISO volumes were 18.9 (0.1-81), 9.5 (0.9-33.1) and 12.5 ml (0.9-38.4 ml) with fixed threshold, adaptive threshold and the FLAB method, respectively; median HF values were 0.47 (0.1-1.93), 0.25 (0.11-0.75) and 0.35 (0.14-1.05), respectively. FMISO volumes were significantly different. CONCLUSION: The best contrast is obtained at the 4-hour acquisition time. Large discrepancies were found between the three tested methods of volume segmentation. PMID- 24173498 TI - Evaluation of the expression of stem cell markers in human breast cancer reveals a correlation with clinical progression and metastatic disease in ductal carcinoma. AB - The tumor stem cell theory could explain how patients with metastatic disease show clinical relapse several months after starting treatment due to the survival of a small group of cells with unique characteristics. We examined the distribution and expression of a panel of stem cell markers in human breast cancer primary tumors. Human breast tissues were processed for immunohistochemistry, and RNA was extracted for analysis by quantitative-PCR. Immunohistochemical assay revealed that CD44 was strongly expressed in background endothelia and epithelia. CD133 expression was lost in tumor-associated endothelial cells. Conversely, CD49b was strongly stained in the tumors, associated vessels and ducts but was weakly stained in the background epithelia. q-PCR analysis revealed that CD44 and PSCA were reduced in patients with poor outcome (metastatic disease and death from breast cancer), with a marked reduction in ductal carcinoma, particularly with metastasis to bone although these did not reach significant difference. CD133 was significantly reduced in patients with metastatic disease and was also significantly reduced in patients with ductal carcinoma/bone metastasis. Conversely, CD49F was increased in patients with a poor outcome and those with ductal cancer and bone metastases. This is the first study to determine the distribution and expression pattern of these stem cell markers in human breast cancer. There was a significant association between loss of expression and metastatic disease in patients with breast cancer. Such differential expression may play a part in breast cancer disease progression, and suggests that the current stem cell theory may not hold true for all cancer types. PMID- 24173499 TI - The role of the neurokinin-1 receptor in stress-induced reinstatement of alcohol and cocaine seeking. AB - Neurokinin-1 receptors (NK1Rs) have been shown to mediate alcohol and opiate, but not cocaine reward in rodents. We recently reported that NK1R antagonism also blocks stress-induced reinstatement of alcohol seeking in rats, but it is presently unknown whether these antirelapse properties extend to other drug classes. Although some work has suggested that intracranial substance P (SP) infusion reinstates cocaine seeking following extinction, no studies have indicated a direct role for the NK1R in reinstatement of cocaine seeking. Here, we explored the effect of the NK1R antagonist L822429 on yohimbine-induced reinstatement of alcohol or cocaine seeking in Long-Evans rats. Consistent with our previous findings with footshock-induced reinstatement of alcohol seeking in Wistar rats, we found that L822429 attenuates yohimbine-induced reinstatement of alcohol seeking, but does not affect baseline alcohol self-administration. We observed a similar suppression of yohimbine-induced reinstatement of cocaine seeking by L822429, and found that Long-Evans rats exhibit greater sensitivity to NK1R antagonism than Wistar rats. Accordingly, Long-Evans rats exhibit differences in the expression of NK1Rs in some subcortical brain regions. Combined, our findings suggest that while NK1R antagonism differentially influences alcohol- and cocaine-related behavior, this receptor mediates stress induced seeking of both drugs. PMID- 24173500 TI - Epithelial-mesenchymal transition is necessary for acquired resistance to cisplatin and increases the metastatic potential of nasopharyngeal carcinoma cells. AB - Radiotherapy and adjuvant cisplatin (DDP) chemotherapy are standard approaches used in the treatment of nasopharyngeal carcinoma (NPC). However, resistance to chemotherapy has recently become more common, resulting in the failure of this combination therapy for NPC. The aim of the present study was to assess the cellular morphology, motility and molecular changes in DDP-resistant NPC cells in relation to epithelial-mesenchymal transition (EMT). CNE2 cells were continuously exposed to increasing doses of DDP to establish a stable cell line resistant to DDP (CNE2/DDP cells). The human NPC cell lines, HNE1, CNE2, HNE1/DDP and CNE2/DDP, were used to examine the association between chemoresistance and the acquisition of an EMT-like phenotype of cancer cells. The DDP-resistant cells were less sensitive than the HNE1 cells to treatment with DDP, and were shown by a cell viability assay, western blot analysis and qRT-PCR to have acquired chemoresistance. The HNE1/DDP cells examined by wound healing and Transwell Boyden chamber assays exhibited an increased migration and invasion potential. The DDP-resistant cells exhibited morphological and molecular changes consistent with EMT, as observed by western blot analysis and qRT-PCR. These changes included becoming more spindle-like in shape, a loss of polarity and formation of pseudopodia, the downregulation of E-cadherin and beta-catenin and the upregulation of vimentin, fibronectin and matrix metalloproteinase (MMP)-9. Moreover, the levels of the EMT-related transcription factors, Snail, Slug, Twist and zinc finger E-box binding homeobox 1 (ZEB1), were higher in the DDP-resistant NPC cells. These data suggest that the development of DDP resistance of NPC cells is accompanied by inducible EMT-like changes with an increased metastatic potential in vitro. Further elucidation of the association between resistance to DDP and EMT may facilitate the future development of novel therapeutic approaches for the treatment of chemoresistant tumors. PMID- 24173502 TI - Effect of concentrated growth factors on beagle periodontal ligament stem cells in vitro. AB - Identifying a reliable and effective cytokine or growth factor group has been the focus of stem cell osteogenic induction studies. Concentrated growth factors (CGFs) as the novel generation of platelet concentrate products, appear to exhibit a superior clinical and biotechnological application potential, however, there are few studies that have demonstrated this effect. This study investigated the proliferation and differentiation of periodontal ligament stem cells (PDLSCs) co-cultured with CGFs. The rate of proliferation was analyzed by cell counting and an MTT assay. Mineralization nodule counts, alkaline phosphatase activity detection, qPCR, western blot analysis and immunohistochemistry were used to analyze mineralization effects. The results showed that CGF significantly promoted the proliferation of PDLSCs, and exhibited a dose-dependent effect on the activation and differentiation of the stem cells. The application of CGF on PDLSC proliferation and osteoinduction may offer numerous clinical and biotechnological application strategies. PMID- 24173501 TI - Acceptance of a community-based navigator program for cancer control among urban African Americans. AB - Patient navigation is now a standard component of cancer care in many oncology facilities, but a fundamental question for navigator programs, especially in medically underserved populations, is whether or not individuals will use this service. In this study, we evaluated acceptance of a community-based navigator program for cancer control and identified factors having significant independent associations with navigation acceptance in an urban sample of African Americans. Participants were African American men and women ages 50-75 who were residents in an urban metropolitan city who were referred for navigation. Of 240 participants, 76% completed navigation. Age and perceived risk of developing cancer had a significant independent association with navigation acceptance. Participants who believed that they were at high risk for developing cancer had a lower likelihood of completing navigation compared with those who believed that they had a low risk for developing this disease. The likelihood of completing navigation increased with increases in age. None of the socioeconomic factors or health care variables had a significant association with navigation acceptance. There are few barriers to using community-based navigation for cancer control among urban African Americans. Continued efforts are needed to develop and implement community-based programs for cancer control that are easy to use and address the needs of medically underserved populations. PMID- 24173503 TI - Turning indium oxide into a superior electrocatalyst: deterministic heteroatoms. AB - The efficient electrocatalysts for many heterogeneous catalytic processes in energy conversion and storage systems must possess necessary surface active sites. Here we identify, from X-ray photoelectron spectroscopy and density functional theory calculations, that controlling charge density redistribution via the atomic-scale incorporation of heteroatoms is paramount to import surface active sites. We engineer the deterministic nitrogen atoms inserting the bulk material to preferentially expose active sites to turn the inactive material into a sufficient electrocatalyst. The excellent electrocatalytic activity of N-In2O3 nanocrystals leads to higher performance of dye-sensitized solar cells (DSCs) than the DSCs fabricated with Pt. The successful strategy provides the rational design of transforming abundant materials into high-efficient electrocatalysts. More importantly, the exciting discovery of turning the commonly used transparent conductive oxide (TCO) in DSCs into counter electrode material means that except for decreasing the cost, the device structure and processing techniques of DSCs can be simplified in future. PMID- 24173504 TI - Mitochondrial and nuclear mitoribosomal suppressors that enable misreading of ochre codons in yeast mitochondria : I. Isolation, localization and allelism of suppressors. AB - A systematic search for suppressors of mutations which cause a deficiency in the splicing of mitochondrial RNA has been undertaken. These splicing mutations were localized in the mRNA-maturase coding sequence of the second intron of the cob boxgene, i.e. in the box3locus. A total of 953 revertants (mostly spontaneous in origin) were isolated and their genetic nature (nuclear vs. mitochondrial) and phenotype characterized.Most revertants were mitochondrially determined and displayed a wild-type phenotype. A mitochondrial suppressor unlinked with the box3 (-)target mutation was uncovered among the revertants displaying a pseudo wild phenotype: out of 26 revertants analyzed, derived from 7 different box3(-) mutants only one such suppressor mutation mim3-1 was found. It was localized by rho(-) deletion mapping in the region between the oxi2 and oxi3 gene, within (or in the vicinity) the gene specifying the 15S ribosomal RNA.Nuclear suppressors were isolated from seven different box3 (-)mutants. All were recessive and had a pseudo-wild phenotype. Three such suppressors nam3-1, nam3-2 and nam3-3 were investigated more extensively. Tetrad analysis has shown that they are alleles of the same nuclear locus NAM3 and mitotic analysis has shown that they do not segregate mitotically. PMID- 24173505 TI - Mitochondrial and nuclear mitoribosomal suppressors that enable misreading of ochre codons in yeast mitochondria : II. Specificity and extent of suppressor action. AB - We describe studies on the action spectra of the mitochondrial suppressor mim3-1 and the three alleles of nuclear suppressor nam3. Their specificity of action was tested on 516 mit (-) mutations located in different mitochondrial genes. The degree of suppression was quantified by the extent of cytochrome oxidase and cytochrome b synthesis. We show that the four suppressors are allele-specific gene-nonspecific informational suppressors. They would act by changing the structure of the small mitoribosomal subunit which would decrease fidelity of translation enabling misreading of some but not all ochre codons. The implications of the results on the role of intron encoded maturases are discussed. PMID- 24173506 TI - The effect of paromomycin and [psi] on the suppression of mitochondrial mutations in Saccharomyces cerevisiae. AB - Paromomycin has been found to suppress certain nonsense mutations located in several mitochondrial genes in yeast. In the mosaic genes, paromomycin preferentially suppresses those mutations located in the introns. There is a strong correlation between this phenotypic suppression by paromomycin and the genetic suppression due to various informational mitoribosomal suppressors. No effect of the cytoplasmic element [psi] on mitoribosomal protein synthesis was observed. This work provides strong evidence for the translation of mRNA maturase proteins from open reading frames of the mitochondrial introns. PMID- 24173507 TI - Mitotic intragenic recombination in the yeast Saccharomyces: marker-effects on conversion and reciprocity of recombination. AB - We have made a large scale analysis of prototrophic products of spontaneous and induced mitotic recombination within LYS2 gene of the yeast Saccharomyces. The mutant alleles staying in heterozygote with the wild type allele were uncovered and analysed.Among thirteen lys2 mutations used in the study three had reduced frequencies of mitotic gene conversion. These rarely converting mutations gave a remarkably high proportion of reciprocal events (up to 38%) in pairwise combinations, never seen for any other pair of alleles studied. Two of these mutations are the deletions of large parts of LYS2 gene.The results suggest that mispairing in the region of deletion blocks the hybrid DNA migration and leads to the reduced conversion ability of deletions. Comparison of uncovered alleles ratio in all allele combinations tested lead us to another hypothesis about bidirectional migration of hybrid DNA. PMID- 24173508 TI - Purification and genetic control of alpha-pheromone-inactivating glycoproteins in the yeast Saccharomyces cerevisiae. AB - Two kinds of a-mating-type-specific proteins inactivating alpha pheromone (alpha factor) were purified from heat shock extract of MATa cells. Their molecular weights were estimated to be 400,000 and 200,000 by gel filtration. Both proteins were detected in MATa SST1 cells but not in MATalpha SST1, MATa sst1-1 and MATa/MATalpha SST1/SST1 cells. In addition, the proteins were detected in matalpha2-1 SST1 cells but not in matalpha1-2 SST1 cells. From these results, it is concluded that these proteins are synthesized under the control of the SST1 gene and responsible for the Barrier action of MATa cells. The relationship of these proteins to the secreted Barrier protein having a higher molecular weight is discussed. PMID- 24173509 TI - The primary structure of a gene encoding yeast ribosomal protein L34. AB - Sequence analysis revealed that a gene coding for yeast ribosomal protein L34 comprises an amino acid coding region of 339 nucleotides which is interrupted by an intron after the 19th codon. Like for other yeast ribosomal protein genes analyzed thus far a strong codon bias was observed. The flanking and intervening sequences of this gene encoding L34 show several elements that are conserved in a number of split ribosomal protein genes in yeast. Northern blot analysis using an intron-specific probe demonstrated that the sequenced gene copy coding for L34 is transcribed in vivo. PMID- 24173510 TI - Electrophoretical and immunological comparison of the ribosomal proteins of the fungus Podospora anserina and the yeast Saccharomyces cerevisiae. AB - The ribosomal proteins of two ascomycetes Podospora anserina and Saccharomyces cerevisiae, were compared by two dimensional electrophoresis in two different gel systems and we found only five pairs of proteins which have kept homologous physico-chemical properties under these conditions. An immunological analysis was performed by radioimmunodetection of proteins blotted on nitrocellulose sheet after separation by electrophoresis, with four sera directed against the r proteins of each subunit of these fungi. So, we pointed out many common antigenic sites present on proteins which do not co-migrate except for yeast L3 and L1 of P. anserina which have the same properties. PMID- 24173511 TI - Induction of thermotolerance and mitotic recombination by heat-shock in Ustilago maydiss. AB - Wild-type cells of Ustilago maydis which have been briefly heated at 42 degrees C subsequently acquire resistance to the lethal effects of a higher temperature (48 degrees C). This induced thermotolerance develops over a 2 h period after treatment at 42 degrees C and is dependent on protein synthesis. It is distinct from the cellular response to DNA-damaging agents, since mutants deficient in this and other repair processes show the same induced thermotolerance as wild type cells. However, UV-light treatment does induce some resistance to subsequent heat treatment. A single 48 degrees C heat treatment increases recombination in heteroallelic diploids, but the same treatment of thermotolerant cells does not stimulate recombination. This suggests that heat treatment can damage DNA, but thermotolerant cells are protected from such damage. PMID- 24173512 TI - Neurospora mutants sensitive both to mutagens and to histidine. AB - Previous work in this and other laboratories showed that histidine strongly inhibits growth of mutants at ten out of 20 known mutagen-sensitivity loci in Neurospora, and that nine of the histidine-sensitive mutants disturb meiosis when homozygous. These and other results suggested that histidine affects recombination or DNA repair. Current work with the histidine-sensitive mutant uvs 6 shows that it is also inhibited by several other metabolites but none of them is as effective as histidine. On minimal medium without histidine or other inhibitors, uvs-6 first grows normally, then slows drastically and begins stop start growth. Conidia from stop-start uvs-6 mycelia produce rejuvenated cultures. The stop-start growth, UV-sensitivity, histidine-sensitivity, and recessive meiotic characters of uvs-6 segregated together in crosses, and reverted together. In tests on other mutagen-sensitive mutants, sensitivity to histidine was strongly correlated with stop-start growth and with sensitivity to other metabolites. Histidine induces premature stop-start growth in at least two mutants. Several possible explanations for the histidine-sensitivity have been excluded. PMID- 24173513 TI - Mitochondrial DNA of Chlamydomonas reinhardtii: the DNA sequence of a region showing homology with mammalian URF2. AB - A 1.27 kb DNA fragment of the 15 kb DNA of Chlamydomonas reinhardtii has been cloned and sequenced. A 906 bp long open reading frame was found showing homology with the URF2 genes of mammals and insects. This homology is functional evidence for Chlamydomonas reinhardtii 15 kb DNA representing indeed mitochondrial DNA. This is the first report of an URF2 gene in mitochondria of a photosynthetic organism. The absence of a TGA codon within the gene suggests that it is used as stop codon like in higher plants and not as tryptophan like in animal and fungal mitochondria. PMID- 24173514 TI - Chloroplast gene suppression of defective ribulosebisphosphate carboxylase/oxygenase in Chlamydomonas reinhardii: evidence for stable heteroplasmic genes. AB - The rcl-u-1-18-5B chloroplast mutation results in the absence of ribulose-1,5 bisphosphate carboxylase/oxygenase (Rubisco) holoenzyme in the green alga Chlamydomonas reinhardii. The 18-5B mutant strain lacks photosynthesis and displays alight-sensitive, acetate-requiring phenotype. In the present investigations, revertants of 18-5B were recovered that regained photosynthetic competence. These revertants have decreased levels of Rubisco holoenzyme relative to wild type and display heteroplasmicity, segregating wild-type (revertant) and acetate-requiring phenotypes during vegetative growth or through meiosis. One of these revertants, R10-I, was studied further. The heteroplasmicity associated with photoautotrophically-grown R10-I was found to be stable through subcloning and heritable through several crosses. During growth in acetate medium in the dark, where photosynthesis provides no selective advantage, the wild-type phenotype was lost. Acetate-requiring segregants became homoplasmic but wild-type segregants did not. Organellar intergenic-suppression is discussed in light of the observed stable heteroplasmicity. PMID- 24173515 TI - Transcription of ribosomal DNA in chloroplasts of Spirodela oligorhizaa. AB - The genes for the two large ribosomal RNAs (16S and 23S) and for the 4.5S rRNA in Spirodela oligorhiza chloroplast DNA are transcribed as one large, 7,000 nucleotides long precursor rRNA.Using S1-nuclease mapping, we have determined that the transcript ends 135 nucleotides 3' distal of the 4.5S rRNA gene. 5S rRNA therefore, is most likely transcribed separately.Northern blotting of chloroplast RNA with distinct probes derived from the rDNA region reveals RNAs, which can be described as intermediates in the processing of the large precursor. With these findings a pathway for the maturation of this precursor is proposed. PMID- 24173516 TI - Characterization of soybean chloroplast ribosomal RNA genes. AB - Soybean chloroplast (cp) ribosomal RNA genes were located by hybridizing labeled homologous probes to filter bound cpDNA fragments. The soybean chloroplast chromosome, like those of most other plants, contains duplicate sets of ribosomal genes arranged in an inverted orientation. The inverted repeated regions are separated by two single copy regions of 21 and 116 kilobasepairs (kb). Cloned rDNA was mapped with numerous restriction endonucleases. This detailed study shows that the ribosomal genes are arranged in the sequence 5' -16S - Spacer - 23S - 3', and that both 16S and 23S rRNAs are transcribed from the same strand of DNA. Quantitative comparison of rDNA sequence divergence between soybean and tobacco indicates that the highest degree of divergence is in the spacer region, possibly due to an insertion/deletion. PMID- 24173517 TI - An improved isolation procedure for yeast two-micrometer minichromosomes. AB - Two micrometer minichromosomes from Saccharomyces cerevisiae were isolated without detergent using metrizamide gradients. 2 MUm minichromosomes showed a lower density in metrizamide gradients relative to genomic chromatin. Our results suggest a lower ratio of proteins to DNA in 2-MUm minichromosomes as compared with genomic chromatin. The procedure described herein yields minichromosomes free of cellular chromatin and ribosomal protein contamination. This method may be useful for the isolation and characterization of other yeast minichromosomes. PMID- 24173518 TI - Limb development in a primitive crustacean, Triops longicaudatus: subdivision of the early limb bud gives rise to multibranched limbs. AB - Recent advances in developmental genetics of Drosophila have uncovered some of the key molecules involved in the positioning and outgrowth of the leg primordia. Although expression patterns of these molecules have been analyzed in several arthropod species, broad comparisons of mechanisms of limb development among arthropods remain somewhat speculative since no detailed studies of limb development exist for crustaceans, the postulated sister group of insects. As a basis for such comparisons, we analysed limb development in a primitive branchiopod crustacean, Triops longicaudatus. Adults have a series of similar limbs with eight branches or lobes that project from the main shaft. Phalloidin staining of developing limbs buds shows the distal epithelial ridge of the early limb bud exhibits eight folds that extend in a dorsal ventral (D/V) arc across the body. These initial folds subsequently form the eight lobes of the adult limb. This study demonstrates that, in a primitive crustacean, branched limbs do not arise via sequential splitting. Current models of limb development based on Drosophila do not provide a mechanism for establishing eight branches along the D/V axis of a segment. Although the events that position limbs on a body segment appear to be conserved between insects and crustaceans, mechanisms of limb branching may not. PMID- 24173519 TI - In vivo diversification and migrations of chick embryo heart muscle cells: a morphometric analysis with ALV- and SNV-based non-replicative vectors. AB - By means of a reporter gene we previously demonstrated that non-replicative Avian Leukemia Virus- and Spleen Necrosis Virus-based retroviral vectors were preferentially expressed in the heart of avian embryos from different species. Using a computer-assisted approach, we now compare clones tagged by the two types of vectors, for volume, anatomical and subanatomical localisation, number of Hoechst-stained cell nuclei and mean cell division time during the period of heart morphogenesis, i.e. from stages 17-19 to 34 of Hamburger and Hamilton (1951). This analysis demonstrates that clones labelled by the two types of viruses display similar features and bring about new insights on the relationships between mitotic and migratory properties of the myocardial cells and histogenesis of the heart. Since only exteriormost cells were tagged with our inoculation procedure, our analysis shows that: (1) at stages 17-19, the myocardium is composed of cells with diverse potentials; some cells still retain the capacity to divide extensively and participate to different heart muscle layers, whilst most are restricted in their multiplication potential and contribute to single muscle layers; (2) about half of the clones are located deep in the heart wall, revealing extensive cell migrations from the heart surface to the ventricular trabeculae, the first migrating cells tagged being detected 20 h after viral inoculation. The presence of these cells is consistent with the finding of a large number of compact trabecular clones 5 days later suggesting that these cells divide mainly after completing migration. Our approach provides new insights as well as quantitative data on the different processes involved in heart morphogenesis, namely multiplication, migration and localisation of heart muscle cells. PMID- 24173520 TI - Genetic mosaic analysis of decapentaplegic and wingless gene function in the Drosophila leg. AB - Genetically mosaic flies were constructed which lack a functional decapentaplegic (dpp) or wingless (wg) gene in portions of their leg epidermis, and the leg cuticle was examined for defects. Although dpp has previously been shown to be transcribed both ventrally and dorsally, virtually the only dpp-null clones that affect leg anatomy are those which reside dorsally. Conversely, wg-null clones only cause leg defects when they reside ventrally - a result that was expected, given that wg is only expressed ventrally. Both findings are consistent with models of leg development in which the future tip of the leg is specified by an interaction between dpp and wg at the center of the leg disc. Null clones can cause mirror-image cuticular duplications confined to individual leg segments. Double-ventral, mirror-image patterns are observed with dpp-null clones, and double-dorsal patterns with wg-null clones. Clones that are doubly mutant (null for both dpp and wg) manifest reduced frequencies for both types of duplications. Duplications can include cells from surrounding non-mutant territory. Such nonautonomy implies that both dpp and wg are involved in positional signaling, not merely in the maintenance of cellular identities. However, neither gene product appears to function as a morphogen for the entire leg disc, since the effects of each gene's null clones are restricted to a discrete part of the circumference. Interestingly, the circumferential domains where dpp and wg are needed are complementary to one another. PMID- 24173521 TI - A novel antigen is shared by retinal pigment epithelium and pigmented neural crest. AB - Pigment cells in vertebrate embryos are formed in both the central and peripheral nervous system. The neural crest, a largely pluripotent population of precursor cells derived from the embryonic neural tube, gives rise to pigment cells which migrate widely in head and trunk.The retinal pigment epithelium is derived from the optic cup, which arises from ectoderm of the neural tube. We have generated an antibody, ips6, which stains an antigen common to pigment cells of retinal pigment epithelium and neural crest. Ips6 stains retinal pigment epithelium and choroid as well as a subset of crest cells that migrate in pathways typical of melanoblasts. Immunoreactivity is seen first in the eye and later in a subset of migrating crest cells. Crest cells in the amphibian embryo migrate along specific, stereotyped routes; ips6 immunoreactive cells are found in some but not all of these pathways. In older wild-type embryos, cells expressing ips6 appear coincident with pigment-containing cells in the flank, head, eye and embryonic gut. In older animals, staining in the eye extends to the intraretinal segment of optic nerve and interstices between photoreceptors and cells at the retinal periphery. We suggest that the ips6 antibody defines an antigen common to pigment cells of central and peripheral origin. PMID- 24173522 TI - The paternal sex ratio chromosome induces chromosome loss independently of Wolbachia in the wasp Nasonia vitripennis. AB - The paternal sex ratio chromosome (PSR) is a paternally-inherited supernumerary chromosome found in some males of Nasonia vitripennis. PSR induces the loss of N. vitripennis's paternal autosomes in early fertilized embryos. Previous examinations have not directly addressed the complication of PSR's co-occurrence with Wolbachia. Wolbachia is the name assigned to a group of cytoplasmic bacteria which induce numerous reproductive alterations in their hosts. In Nasonia, Wolbachia cause cytoplasmic incompatibility (CI) which also results in paternal chromosome loss. Here we address the question of whether PSR's function (i.e. PSR's transmission and/or ability to induce chromosome loss) depends upon or interacts with Wolbachia. A strain of PSR males is artificially cleared of Wolbachia. Test crosses and cytological observations of this strain demonstrate that PSR's transmission and ability to induce chromosome loss is not dependent upon Wolbachia. Comparisons suggest an absence of interactions between PSR and Wolbachia when they co-occur. Fluorescent and confocal microscopy are used to examine and compare early embryos. Observations demonstrate that microtubule interactions with chromatin do not appear to cause the initial loss of the paternal chromosomes. Cytological observations presented here also differ from previous reports of PSR- and Wolbachia-induced chromosome loss. PMID- 24173523 TI - Expression of pharyngeal gill-specific genes in the ascidian Halocynthia roretzi. AB - The most primitive chordates may have arisen with a shift to internal feeding through the use of the pharyngeal gill slits and endostyle for extracting suspended food from the water. Therefore, the pharyngeal gill and endostyle, in addition to notochord and nerve cord, are structures key to an understanding of the molecular developmental mechanisms underlying the origin and evolution of chordates. In this and a following study, isolation of cDNA clones for genes that are specifically expressed in the pharyngeal gill or endostyle in the ascidian Halocynthia roretzi was attempted. Differential screening of a pharyngeal gill cDNA library and an endostyle cDNA library with total pharyngeal-gill cDNA probes yielded cDNA clones for two pharyngeal gill-specific genes, HrPhG1 and HrPhG2. Northern blot analysis showed a 3.0-kb transcript of HrPhG1 and a 2.0-kb transcript of HrPhG2. Predicted amino acid sequences of the gene products suggested that both genes encode secretory proteins with no significant match to known proteins. In adults, both HrPhG1 and HrPhG2 genes were only expressed in the pharyngeal gill and not in other tissues including the endostyle, body-wall muscle, gonad, gut and digestive gland. HrPhG1 and HrPhG2 transcripts were undetectable in embryos and larvae, and were first detected in juveniles 3 days after initiation of metamorphosis. In situ hybridization revealed that the expression of HrPhG1 and HrPhG2 was restricted to differentiating pharyngeal-wall epithelium, with intense signals in the area surrounding the stigma or gill slit. These genes may serve as probes for further analyses of molecular mechanisms underlying the occurrence of pharyngeal gill and formation of gill slits during chordate evolution. PMID- 24173524 TI - Expression of endostyle-specific genes in the ascidian Halocynthia roretzi. AB - The endostyle is a special organ in the pharynx of Urochordata, Cephalochordata and Cyclostomata. This organ may have arisen in their common ancestor with a shift to internal feeding for extracting suspended food from the water. In addition, the endostyle has functional homology to the vertebrate thyroid gland. The endostyle is therefore another key structure in the understanding of the origin and evolution of chordates. Following a previous report of the pharyngeal gill-specific genes, we report here the isolation and characterization of cDNA clones for endostyle-specific genes HrEnds1 and HrEnds2 of the ascidian Halocynthia roretzi. These cDNA clones were obtained by differential screening of an endostyle cDNA library and a pharyngeal gill cDNA library with total endostyle cDNA probes. Both transcripts were abundant in the library; each represented about 10% of the cDNA clones of the library. The HrEnds1 transcript was small in size, about 600 bp in length. Although the predicted amino acid sequence of the gene product showed no similarity to known proteins, mean hydropathy profiles suggested that HrENDS1 is a type Ib protein or secreted protein. The HrEnds2 transcript was about 2.5 kb in length. Although the HrEnds2 gene product showed no sequence similarity to known proteins, mean hydropathy profiles suggested that HrENDS2 is a secreted protein. The transcripts of both genes were not detected in embryos, larvae and early juveniles but were evident in 1-month-old young adult after several compositional zones were organized in the endostyle. In situ hybridization revealed that distribution of transcripts of both genes was restricted to zone 6, the protein-secreting glandular element of the endostyle. These genes may be useful for further analysis of molecular mechanisms involved in endostyle development. PMID- 24173525 TI - Matching chelators to radiometals for radiopharmaceuticals. AB - Radiometals comprise many useful radioactive isotopes of various metallic elements. When properly harnessed, these have valuable emission properties that can be used for diagnostic imaging techniques, such as single photon emission computed tomography (SPECT, e.g.(67)Ga, (99m)Tc, (111)In, (177)Lu) and positron emission tomography (PET, e.g.(68)Ga, (64)Cu, (44)Sc, (86)Y, (89)Zr), as well as therapeutic applications (e.g.(47)Sc, (114m)In, (177)Lu, (90)Y, (212/213)Bi, (212)Pb, (225)Ac, (186/188)Re). A fundamental critical component of a radiometal based radiopharmaceutical is the chelator, the ligand system that binds the radiometal ion in a tight stable coordination complex so that it can be properly directed to a desirable molecular target in vivo. This article is a guide for selecting the optimal match between chelator and radiometal for use in these systems. The article briefly introduces a selection of relevant and high impact radiometals, and their potential utility to the fields of radiochemistry, nuclear medicine, and molecular imaging. A description of radiometal-based radiopharmaceuticals is provided, and several key design considerations are discussed. The experimental methods by which chelators are assessed for their suitability with a variety of radiometal ions is explained, and a large selection of the most common and most promising chelators are evaluated and discussed for their potential use with a variety of radiometals. Comprehensive tables have been assembled to provide a convenient and accessible overview of the field of radiometal chelating agents. PMID- 24173526 TI - Indirect food web interactions mediated by predator-rodent dynamics: relative roles of lemmings and voles. AB - Production cycles in birds are proposed as prime cases of indirect interactions in food webs. They are thought to be driven by predators switching from rodents to bird nests in the crash phase of rodent population cycles. Although rodent cycles are geographically widespread and found in different rodent taxa, bird production cycles appear to be most profound in the high Arctic where lemmings dominate. We hypothesized that this may be due to arctic lemmings inducing stronger predator responses than boreal voles. We tested this hypothesis by estimating predation rates in dummy bird nests during a rodent cycle in low Arctic tundra. Here, the rodent community consists of a spatially variable mix of one lemming (Lemmus lemmus) and two vole species (Myodes rufocanus and Microtus oeconomus) with similar abundances. In consistence with our hypothesis, lemming peak abundances predicted well crash-phase nest predation rates, whereas the vole abundances had no predictive ability. Corvids were found to be the most important nest predators. Lemmings appear to be accessible to the whole predator community which makes them particularly powerful drivers of food web dynamics. PMID- 24173527 TI - Expression of nipP.w of Pectobacterium wasabiae is dependent on functional flgKL flagellar genes. AB - While flagellum-driven motility is hypothesized to play a role in the virulence of Pectobacterium species, there is no direct evidence that genes involved in flagellum assembly regulate the synthesis of virulence factors. The purpose of this study was to identify genes that affect the production or secretion of necrosis-inducing protein (Nip) in the strain SCC3193. Transposon mutagenesis of an RpoS strain overexpressing NipP.w was performed, and a mutant associated with decreased necrosis of tobacco leaves was detected. The mutant contained a transposon in the regulatory region upstream of the flagellar genes flgK and flgL. Additional mutants were generated related to the flagellar genes fliC and fliA. The mutation in flgKL, but not those in fliC and fliA, inhibited nipP.w transcription. Moreover, the regulatory effect of the flgKL mutation on nipP.w transcription was partially dependent on the Rcs phosphorelay. Secretion of NipP.w was also dependent on a type II secretion mechanism. Overall, the results of this study indicate that the flgKL mutation is responsible for reduced motility and lower levels of nipP.w expression. PMID- 24173528 TI - Synthesis and fluorescence characteristics of ATP-based FRET probes. AB - Adenosine triphosphate (ATP) analogues labelled with two dyes suitable for undergoing Forster Resonance Energy Transfer (FRET) have the potential to be valuable tools to continuously study the enzymatic activity of ATP consuming enzymes. Here, we present a synthesis strategy that allows obtaining these ATP analogues in a straight-forward manner. Earlier studies indicate that modifying ATP at the O2'- and the gamma-position is a very promising starting point for the design of these probes. We synthesized probes modified with five different combinations of dyes attached to these positions and investigated their fluorescence characteristics in the non-cleaved state as well as after enzymatic hydrolysis. All presented probes largely change their fluorescence characteristics upon cleavage. They include ratiometric FRET probes as well as dark quenched analogues. For typical in vitro applications a combination of the sulfonated polymethine dyes Sulfo-Cy3 and Sulfo-Cy5 seems to be most promising due to their excellent solubility in aqueous buffer and a large change of fluorescence characteristics upon cleavage. For this combination of dyes we also synthesized analogues modified at the gamma- and the C2- or the O3'-position, respectively, as these attachment sites are also well accepted by certain ATP consuming enzymes. These analogues show comparably large changes in fluorescence characteristics. Overall, we present new ATP-based FRET probes that have the potential to enable monitoring the enzymatic activity of ATP consuming enzymes. PMID- 24173529 TI - Awareness of biologically confirmed HCV among a community residing sample of drug users in Baltimore City. AB - The present study sought to examine: (1) the prevalence and correlates of biologically confirmed Hepatitis C (HCV) and (2) the prevalence and correlates of prior HCV diagnosis and an unmet need for HCV treatment, among a community residing sample of drug users. The current study used a subset of HCV tested participants from the larger NEURO-HIV Epidemiologic Study from Baltimore, Maryland (M(age) = 34.81, SD = 9.25; 46% female). All participants were tested for HCV at baseline. Self-report was used to assess awareness of an HCV diagnosis and participation in treatment. Of the 782 participants tested for HCV, 19% reported having received an HCV diagnosis in the past while 48% tested positive for HCV. Only 6% reported having received treatment for any form of hepatitis. Of those who tested HCV positive, 63% reported never being diagnosed, and only 13% received any treatment for HCV. We found that only 35% of those who reported a prior HCV diagnosis received any treatment. The findings regarding lack of HCV awareness and diagnosis were considerable as expected. These deficits suggest that there are numerous gaps in patients' knowledge and beliefs regarding HCV that may interfere at multiple steps along the path from diagnosis to treatment. This study clearly demonstrates that a critical need exists to improve public knowledge of HCV risk factors, the need for testing, and the availability of effective treatment. PMID- 24173531 TI - Li(x)FeF6 (x = 2, 3, 4) battery materials: structural, electronic and lithium diffusion properties. AB - Lithium iron fluoride materials have attracted recent interest as cathode materials for lithium ion batteries. The electrochemical properties of the high energy density Li(x)FeF6 (x = 2, 3, 4) materials have been evaluated using a combination of potential-based and DFT computational methods. Voltages of 6.1 V and 3.0 V are found for lithium intercalation from Li2FeF6 to alpha-Li3FeF6 and alpha-Li3FeF6 to Li4FeF6 respectively. The calculated density of states indicate that Li2FeF6 possesses metallic states that become strongly insulating after lithium intercalation to form alpha-Li3FeF6. The large energy gain associated with this metal-insulator transition is likely to contribute to the associated large voltage of 6.1 V. Molecular dynamics simulations of lithium diffusion in alpha-Li3FeF6 at typical battery operating temperatures indicate high lithium-ion mobility with low activation barriers. These results suggest the potential for good rate performance of lithium iron fluoride cathode materials. PMID- 24173530 TI - HIV testing of tuberculosis patients by public and private providers in New York City. AB - Thirty percent of tuberculosis (TB) patients in New York City in 2007 were not tested for HIV, which may be attributable to differential testing behaviors between private and public TB providers. Adult TB cases in New York City from 2001 to 2007 (n = 5,172) were evaluated for an association between TB provider type (private or public) and HIV testing. Outcomes examined were offers of HIV tests and patient refusal of HIV testing, using multivariate logistic and binomial regression, respectively. HIV test offers were less frequent among patients who visited only private providers than patients who visited only public providers [males: adjusted odds ratio (aOR) 0.33, 95% confidence interval (CI) 0.15-0.74; females: aOR 0.26, 95% CI 0.12-0.57]. Changing from private to public providers was associated with an increase in HIV tests offered among male patients (aOR 1.96, 95% CI 1.04-3.70). Among patients who did not use substances, those who visited only private providers were more likely to refuse HIV testing than those who visited only public providers [males: adjusted prevalence ratio (aPR) 1.26, 95% CI 0.99-1.60; females: aPR 1.78, 95% CI 1.43-2.22]. Patients of private providers were less likely to have an HIV test performed during their TB treatment. Education of TB providers should emphasize HIV testing of all TB patients, especially among patients who are traditionally considered low-risk. PMID- 24173532 TI - Downregulation of Hsp70 inhibits apoptosis induced by sialic acid-binding lectin (leczyme). AB - Heat shock proteins (Hsps) are molecular chaperones that maintain homeostasis of organisms. In regards to the Hsps, many studies have investigated the structure, expression, localization and functions of Hsp70 and Hsc70 including expression in the glycosphingolipid-enriched microdomain (GEM) on the cell surface and involvement in cell death. Sialic acid-binding lectin (SBL) isolated from oocytes of Rana catesbeiana is a multifunctional protein which has lectin activity, ribonuclease activity and antitumor activity. SBL has potential as a new type of anticancer drug, since it causes cancer-selective induction of apoptosis by multiple signaling pathways in which RNA is its target; and the participation of the mitochondrial pathway and the endoplasmic reticulum (ER) stress-mediated pathway has been suggested. It has also been suggested that receptor(s) for SBL (SBLR) may exist in the GEM on the cell surface. In the present study, we studied the possible involvement of Hsp70 and Hsc70 in SBL-induced apoptosis. We showed that Hsp70 and Hsc70 were expressed on the P388 cell surface similar to SBLR, and their distribution in cells dramatically changed immediately prior to the execution of apoptosis following stimulation of SBL. Functional study of Hsp70 revealed that decreased expression of Hsp70 diminished the apoptosis induced by SBL. It is suggested that Hsp70 participates in the antitumor effect of SBL. PMID- 24173533 TI - Alcohol consumption and risk of melanoma and non-melanoma skin cancer in the Women's Health Initiative. AB - PURPOSE: The relationship between alcohol consumption and preference of alcohol type with hazard of melanoma (MM) and risk of non-melanoma skin cancer (NMSC) was examined in the Women's Health Initiative (WHI) Observational Study (OS). METHODS: A prospective cohort of 59,575 White postmenopausal women in the WHI OS (mean age 63.6) was analyzed. Cox proportional hazards models and logistic regression techniques were used to assess the hazard and risk of physician adjudicated MM and self-reported NMSC, respectively, after adjusting for potential confounders including measures of sun exposure and skin type. RESULTS: Over 10.2 mean years of follow-up, 532 MM cases and 9,593 NMSC cases occurred. A significant relationship between amount of alcohol consumed and both MM and NMSC was observed, with those who consume 7+ drinks per week having a higher hazard of MM (HR 1.64 (1.09, 2.49), p global = 0.0013) and higher risk of NMSC (OR 1.23 (1.11, 1.36), p global < 0.0001) compared to non-drinkers. Lifetime alcohol consumption was also positively associated with hazard of MM (p = 0.0011) and risk of NMSC (p < 0.0001). Further, compared to non-drinkers, a preference for either white wine or liquor was associated with an increased hazard of MM (HR 1.52 (1.02, 2.27) for white wine; HR 1.65 (1.07, 2.55) for liquor) and risk of NMSC (OR 1.16 (1.05, 1.28) for white wine; OR 1.26 (1.13, 1.41) for liquor). CONCLUSIONS: Higher current alcohol consumption, higher lifetime alcohol consumption, and a preference for white wine or liquor were associated with increased hazard of MM and risk of NMSC. PMID- 24173534 TI - Physical activity, sex steroid, and growth factor concentrations in pre- and post menopausal women: a cross-sectional study within the EPIC cohort. AB - PURPOSE: Increased physical activity (PA) is associated with a reduced risk of several cancers. PA may reduce cancer risk by changing endogenous hormones levels, but relatively little research has focused on this topic. The purpose of this study was to elucidate the relation between PA and endogenous hormone concentrations. METHODS: A cross-sectional analysis of 798 pre- and 1,360 post menopausal women included as controls in case-control studies on endogenous hormones (steroids, progesterone, sex-hormone-binding globulin (SHBG), and growth factors) levels, and cancer risk nested within European Prospective Investigation into Cancer and Nutrition cohort was performed. Multivariate regression analyses were performed to compare geometric mean levels of hormones and SHBG by categories of PA. RESULTS: In pre-menopausal women, active women had 19 % significantly lower concentrations of androstenedione, 14 % lower testosterone, and 20 % lower free testosterone than inactive women, while no differences were observed for estrogens, progesterone, SHBG, and growth factors. In post menopausal women, active women had 18 % significantly lower estradiol and 20 % lower free estradiol concentrations than inactive women, while no differences were observed for the other hormones and SHBG. More vigorous forms of physical activity were associated with higher insulin-like growth factor-I concentrations. Adjustment for body mass index did not alter the associations. Overall, the percentage of variance in hormone concentrations explained by PA levels was <2 %. CONCLUSIONS: Our results support the hypothesis of an influence, although small in magnitude, of PA on sex hormone levels in blood, independent of body size. PMID- 24173535 TI - Pooled cohort study on height and risk of cancer and cancer death. AB - PURPOSE: To assess the association between height and risk of cancer and cancer death. METHODS: The metabolic syndrome and cancer project is a prospective pooled cohort study of 585,928 participants from seven cohorts in Austria, Norway, and Sweden. Hazard ratios (HRs) and 95 % confidence intervals (CIs) for cancer incidence and death were estimated in height categories and per 5-cm increment for each cancer site using Cox proportional hazards model. RESULTS: During a mean follow-up of 12.7 years (SD = 7.2), 38,862 participants were diagnosed with cancer and 13,547 participants died of cancer. Increased height (per 5-cm increment) was associated with an increased overall cancer risk in women, HR 1.07 (95 % CI 1.06-1.09), and in men, HR 1.04 (95 % CI 1.03-1.06). The highest HR was seen for malignant melanoma in women, HR 1.17 (95 % CI 1.11-1.24), and in men HR 1.12 (95 % CI 1.08-1.19). Height was also associated with increased risk of cancer death in women, HR 1.03 (95 % CI 1.01-1.16), and in men, HR 1.03 (95 % CI 1.01-1.05). The highest HR was observed for breast cancer death in postmenopausal women (>60 years), HR 1.10 (95 % CI 1.00-1.21), and death from renal cell carcinoma in men, HR 1.18 (95 % CI 1.07-1.30). All these associations were independent of body mass index. CONCLUSION: Height was associated with risk of cancer and cancer death indicating that factors related to height such as hormonal and genetic factors stimulate both cancer development and progression. PMID- 24173536 TI - Atypical femoral fractures: retrospective radiological study of 319 femoral fractures and presentation of clinical cases. AB - SUMMARY: There is still no clarity on the etiology and epidemiology of atypical femoral fractures. The purpose is to show, after a radiological review, that the incidence of atypical fractures is higher than that reported in the literature when compared to "typical" fractures that occurred in the same anatomical site. INTRODUCTION: At present, it is difficult to define the true incidence of atypical fractures associated with bisphosphonate. Our purpose is to show that the incidence of atypical fractures is higher than that reported in the literature when compared to "typical" fractures that occurred in the same anatomical site. METHODS: The authors analyzed 319 femoral fracture Rxs of patients over 60 who have had access to the PS of Clinical Orthopaedics and Traumatology II of the University of Pisa from January 2011 to February 2013. The atypical fractures have been investigated from clinical point of view, biohumoral exams, densitometry and contralateral femur X-rays, and in one case using SPECT Tc. RESULTS: The total number of femoral fractures was 319. The medial femur fractures were 60 (46 females and 14 males), and the lateral ones were 316 (237 females and 79 males). Subtrochanteric and diaphyseal fractures were 40 (29 females and 11 males). Among these cases, two atypical fracture cases were related to female patients, one was 79 years old and the other was 77. CONCLUSIONS: The most recent literature reports that the incidence of atypical fractures is 0.6 %. However, taking into consideration only the fracture locations suitable for the identification of atypical fractures, the percentage rises to 5 %. To date, there is still no clarity on the exact etiology of fractures even if it seems to be related to a bone mineral component alteration. PMID- 24173538 TI - Bladder cancer: No cohesion for cohesin's role. PMID- 24173537 TI - Brazilian Microbiome Project: revealing the unexplored microbial diversity- challenges and prospects. AB - The Brazilian Microbiome Project (BMP) aims to assemble a Brazilian Metagenomic Consortium/Database. At present, many metagenomic projects underway in Brazil are widely known. Our goal in this initiative is to co-ordinate and standardize these together with new projects to come. It is estimated that Brazil hosts approximately 20 % of the entire world's macroorganism biological diversity. It is 1 of the 17 countries that share nearly 70 % of the world's catalogued animal and plant species, and is recognized as one of the most megadiverse countries. At the end of 2012, Brazil has joined GBIF (Global Biodiversity Information Facility), as associated member, to improve the access to the Brazilian biodiversity data in a free and open way. This was an important step toward increasing international collaboration and clearly shows the commitment of the Brazilian government in directing national policies toward sustainable development. Despite its importance, the Brazilian microbial diversity is still considered to be largely unknown, and it is clear that to maintain ecosystem dynamics and to sustainably manage land use, it is crucial to understand the biological and functional diversity of the system. This is the first attempt to collect and collate information about Brazilian microbial genetic and functional diversity in a systematic and holistic manner. The success of the BMP depends on a massive collaborative effort of both the Brazilian and international scientific communities, and therefore, we invite all colleagues to participate in this project. PMID- 24173540 TI - Growth sensitivity in the epiphyseal growth plate, liver and muscle of SD rats is significantly enhanced by treatment with a fermented soybean product (cheonggukjang) through stimulation of growth hormone secretion. AB - Cheonggukjang (CKJ), a fermented soybean product, has been reported to have beneficial effects on various chronic diseases, including cardiovascular disease, cancer and immune diseases. To investigate whether CKJ induces growth sensitivity in mammals, alterations of key parameters related to their growth were analyzed. Sprague-Dawley (SD) rats were treated with a high concentration of CKJ (H-CKJ) or a low concentration of CKJ (L-CKJ) for 10 days, and compared with vehicle-treated rats. The CKJ contained a high concentration of total flavonoids, phenolic compounds, daidzein and genistein, compared with the non-fermented soybean product. Body weight was higher in the H-CKJ-treated group compared with that in the vehicle- and L-CKJ-treated groups, whereas the weights of three organs (the brain, liver and kidney) were higher in the L-CKJ-treated group compared with the remaining two groups. However, no significant differences in femur length and weight were detected between the CKJ- and vehicle-treated groups. The thickness of the epiphyseal growth plate in proximal femoral epiphysis was broadest in the H-CKJ-treated group compared with the vehicle- and L-CKJ-treated groups. Furthermore, the level of growth hormone (GH) was highest in the serum of the L CKJ-treated group, although that of the H-CKJ-treated group was lower compared with that in the L-CKJ group. Moreover, the expression levels of the GH receptor increased in the liver tissue, but not in the muscle tissue, of the L-CKJ- and H CKJ-treated groups. In the downstream signaling pathway of the GH receptor, the phosphorylation levels of Akt and Erk were differentially regulated between the liver and muscle. These results suggest that CKJ extract may enhance the sensitivity of the femur, liver and muscle epiphyseal growth plate in SD rats, through the upregulation of GH secretion. PMID- 24173541 TI - Preclinical activity profile and therapeutic efficacy of the HSP90 inhibitor ganetespib in triple-negative breast cancer. AB - PURPOSE: Treatment options for patients with triple-negative breast cancer (TNBC) are largely limited to systemic chemotherapies, which have shown disappointing efficacy in the metastatic setting. Here, we undertook a comprehensive evaluation of the activity of ganetespib, a potent inhibitor of HSP90, in this malignancy. EXPERIMENTAL DESIGN: The antitumor and antimetastatic activity of ganetespib was investigated using TNBC cell lines and xenograft models. Combinatorial drug analyses were performed with chemotherapeutic agents and concomitant effects on DNA damage and cell-cycle disruption were assessed in vitro; antitumor efficacy was assessed in vivo. Metabolic and objective tumor responses were evaluated in patients with metastatic TNBC undergoing ganetespib treatment. RESULTS: Ganetespib simultaneously deactivated multiple oncogenic pathways to potently reduce cell viability in TNBC cell lines, and suppressed lung metastases in experimental models. Ganetespib potentiated the cytotoxic activity of doxorubicin via enhanced DNA damage and mitotic arrest, conferring superior efficacy to the doxorubicin-cyclophosphamide regimen in TNBC xenografts. Ganetespib also promoted mitotic catastrophe and apoptosis in combination with taxanes in vitro, and these effects translated to significantly improved combinatorial activity in vivo. Marked tumor shrinkage of metastatic lung and lymphatic lesions were seen in patients on ganetespib monotherapy. CONCLUSION: The preclinical activity profile and clinical evidence of tumor regression suggest that ganetespib offers considerable promise as a new therapeutic candidate to target TNBC. PMID- 24173542 TI - Neoadjuvant imatinib in advanced primary or locally recurrent dermatofibrosarcoma protuberans: a multicenter phase II DeCOG trial with long-term follow-up. AB - PURPOSE: Dermatofibrosarcoma protuberans (DFSP) is a rare cutaneous tumor. COL1A1 PDGFB gene fusion is frequent in DFSP, rendering tumor cell proliferation and survival dependent on PDGFRbeta (platelet-derived growth factor receptor beta) signaling. This trial investigated imatinib as neoadjuvant treatment of DFSP, including long-term follow-up. EXPERIMENTAL DESIGN: The primary endpoint of this multicenter phase II trial was response; secondary endpoints were safety, tumor relapse, and response biomarkers. Patients with advanced primary or locally recurrent DFSP and measurable disease by RECIST (response evaluation criteria in solid tumors) were eligible and received imatinib 600 mg/d until definitive surgery with histopathologic proof of tumor-free margins. RESULTS: Sixteen patients received imatinib, and 14 patients were evaluable for all endpoints. Median treatment duration was 3.1 months; median tumor shrinkage was 31.5%. Best overall response was 7.1% complete response (CR), 50.0% partial response (PR), 35.7% stable disease, and 7.1% progressive disease (PD). Toxicity was moderate with 25.0% grade 3 and 4 events. During a median follow-up of 6.4 years, one patient developed secondary resistance to imatinib but responded to second-line sunitinib. This patient also presented local recurrence, distant metastasis, and death from DFSP. Exploratory analysis showed that response to imatinib was associated with decreased tumor cellularity and formation of strong hyalinic fibrosis. Weak PDGFRB phosphorylation and pigmented-type DFSP were associated with nonresponse. Additional to PDGFRB, the kinases EGFR and insulin receptor were found activated in a high percentage of DFSPs. CONCLUSION: The neoadjuvant use of imatinib 600 mg/d in DFSP is efficacious and well tolerated. Long-term follow-up results do not definitely support smaller surgical margins after successful imatinib pretreatment, and presume that secondary resistance to imatinib might promote accelerated disease progression. PMID- 24173543 TI - Safety, pharmacokinetics, pharmacodynamics, and antitumor activity of dalantercept, an activin receptor-like kinase-1 ligand trap, in patients with advanced cancer. AB - PURPOSE: The angiogenesis inhibitor dalantercept (formerly ACE-041) is a soluble form of activin receptor-like kinase-1 (ALK1) that prevents activation of endogenous ALK1 by bone morphogenetic protein-9 (BMP9) and BMP10 and exhibits antitumor activity in preclinical models. This first-in-human study of dalantercept evaluated its safety, tolerability, pharmacokinetics, pharmacodynamics, and antitumor activity in adults with advanced solid tumors. EXPERIMENTAL DESIGN: Patients in dose-escalating cohorts received dalantercept subcutaneously at one of seven dose levels (0.1-4.8 mg/kg) every 3 weeks until disease progression. Patients in an expansion cohort received dalantercept at 0.8 or 1.6 mg/kg every 3 weeks until disease progression. RESULTS: In 37 patients receiving dalantercept, the most common treatment-related adverse events were peripheral edema, fatigue, and anemia. Edema and fluid retention were dose limiting toxicities and responded to diuretic therapy. No clinically significant, treatment-related hypertension, proteinuria, gross hemorrhage, or gastrointestinal perforations were observed. One patient with refractory squamous cell cancer of the head and neck had a partial response, and 13 patients had stable disease according to RECISTv1.1, eight of whom had prolonged periods (>=12 weeks) of stable disease. Correlative pharmacodynamic markers included tumor metabolic activity and tumor blood flow, which decreased from baseline in 63% and 82% of evaluable patients, respectively, and telangiectasia in eight patients. CONCLUSION: Dalantercept was well-tolerated at doses up to 1.6 mg/kg, with a safety profile distinct from inhibitors of the VEGF pathway. Dalantercept displayed promising antitumor activity in patients with advanced refractory cancer, and multiple phase II studies are underway. PMID- 24173544 TI - [Pain therapy in emergency medicine. Focus on emergency admissions]. AB - With a prevalence of 50-80 % pain is one of the main symptoms of emergency admission patients worldwide; however, study results demonstrate that only 30-50 % of patients receive adequate analgesia. Therefore, in the USA quality indicators have been established by the Centers for Medicare & Medicaid Services (CMS) since 2010 within the framework of quality assurance of emergency admissions, e.g. the time window until the start of pain therapy. Despite the prescribed pain evaluation as part of many existing triage systems, e.g. the Manchester triage system (MTS), emergency severity index (ESI), Australasian triage scale (ATS), Canadian triage and acuity scale (CATS), in most emergency rooms there is no standardized, documented pain assessment and pain intensity is documented by using the appropriate pain scales in only 30 % of cases. Lack of knowledge and training and lack of awareness by the nursing and medical staff regarding pain perception and management represent the main causal factors. Studies on the situation of pain therapy in German emergency departments are not currently available. Due to the increasing number of central emergency departments and interdisciplinary teams of physicians and nurses, it seems sensible to introduce interdisciplinary standards of treatment to achieve the greatest possible safety in the use of analgesics in the emergency room. It is important to incorporate the experiences of the various clinical departments in the standards. This article aims to provide an overview of the situation in pain management in emergency departments and to serve as a basis for recommendations for pain therapy in German emergency departments. This article particularly discusses the possibilities of pain evaluation, treatment options with various medications and under specific conditions, e.g. for children, pregnant women or the elderly or alternative ways of pain management. PMID- 24173545 TI - [Obstetric anesthesia : More than just standard solutions are necessary]. PMID- 24173547 TI - Invited commentary: Body mass index and mortality. AB - In the midst of an epidemic of obesity, epidemiologists are seeking to establish the relationship of body mass index (BMI; weight (kg)/height (m)(2)) with mortality. In an accompanying article, Adams et al. (Am J Epidemiol. 2014;179(2):135-144) used a subsample of the National Institutes of Health-AARP Diet and Health Study cohort, recruited in 1995-1996 (109,947 people), to examine associations of BMI in early (18 years) and middle (35 and 50 years) adulthood with mortality, as well as the effect of weight gain between these ages on subsequent mortality during 12.5 years' follow-up. They report a positive association between BMI and mortality at each age (using BMI 18.5-22.4 as the referent). Furthermore, there were strong positive associations of weight gain between ages 18 and 35 years and ages 35 and 50 years with mortality. Attainment of a BMI of 25 or higher at a younger age increased risk of death. The findings contrast sharply with those of a recent systematic review and meta-analysis of 97 studies, which found that only the grade 2 and 3 obesity categories (i.e., BMI >= 35) were responsible for elevated risk of mortality, with slight protection from overweight (25.0-29.9). Due consideration of the limitations of BMI as a measure of detrimental adiposity and of mortality measures alone to inform clinical practice is indicated. PMID- 24173546 TI - Effect of ultrasound-guided intercostal nerve block on postoperative pain after percutaneous nephrolithotomy : prospective randomized controlled study. AB - BACKGROUND: The aim of the study was to investigate the effect of preoperative ultrasound-guided (US) intercostal nerve block (ICNB) in the 11th and 12th intercostal spaces on postoperative pain control and tramadol consumption in patients undergoing percutaneous nephrolithotomy (PCNL). METHODS: After obtaining ethical committee approval and written informed patient consent, 40 patients were randomly allocated to the ICNB group or the control group. For the ICNB group US guided ICNB was performed with 0.5 % bupivacaine and 1/200,000 epinephrine at the 11th and 12th intercostal spaces after premedication. A sham block was performed for the control group and postoperative pain and tramadol consumption were recorded by anesthesiologists blinded to the treatment. RESULTS: Postoperative visual analog scale scores at all follow-up times were found to be significantly lower in the ICNB group than in the control group (p < 0.05). The mean 24 h intravenous tramadol consumption was 97.5 +/- 39.5 mg for the ICNB group which was significantly lower than the 199.7 +/- 77.6 mg recorded for the control group (p < 0.05). CONCLUSION: In PCNL with nephrostomy tube placement US-guided ICNB performed at the 11th and 12th intercostal spaces provided effective analgesia. PMID- 24173548 TI - Maximum likelihood, profile likelihood, and penalized likelihood: a primer. AB - The method of maximum likelihood is widely used in epidemiology, yet many epidemiologists receive little or no education in the conceptual underpinnings of the approach. Here we provide a primer on maximum likelihood and some important extensions which have proven useful in epidemiologic research, and which reveal connections between maximum likelihood and Bayesian methods. For a given data set and probability model, maximum likelihood finds values of the model parameters that give the observed data the highest probability. As with all inferential statistical methods, maximum likelihood is based on an assumed model and cannot account for bias sources that are not controlled by the model or the study design. Maximum likelihood is nonetheless popular, because it is computationally straightforward and intuitive and because maximum likelihood estimators have desirable large-sample properties in the (largely fictitious) case in which the model has been correctly specified. Here, we work through an example to illustrate the mechanics of maximum likelihood estimation and indicate how improvements can be made easily with commercial software. We then describe recent extensions and generalizations which are better suited to observational health research and which should arguably replace standard maximum likelihood as the default method. PMID- 24173551 TI - The effect of activin A on signal transduction pathways in PC12 cells subjected to oxygen and glucose deprivation. AB - The processes and mechanisms underlying brain injuries due to ischemia and anoxia have yet to be determined. Additionally, few clinical treatements are currently available. Activins have a protective role in the restoration, differentiation, and survival of injured cells, including Activin A (ActA), which acts as a neuroprotectant. However, its exact mechanism of action remains to be determined. ActA has been shown to protect neurons following ischemic brain injury. In this study, PC12 cells were differentiated into neuron-like cells after stimulation with nerve growth factor to prepare an oxygen/glucose deprivation (OGD) model in neurons. The differentiated PC12 cells, subjected to the OGD model, were exposed to ActA. Results showed that the PC12 survival rate decreased after OGD, leading to an increase in caspase-3 expression in these cells. Pretreatment with ActA was able to partially prevent OGD-induced apoptosis, likely through the downregulation of caspase-3. Futhermore, ActA pretreatment increased the expression of key proteins in the ActA/Smads signal transduction pathway, which may promote neuroprotection after OGD. Therefore, exogenous ActA may function as a neuroprotectant and provide a novel therapeutic treatment for ischemic brain injury. PMID- 24173552 TI - An alpha-mating-type-specific mutation causing specific defect in sexual agglutinability in the yeast Saccharomyces cerevisiae. AB - We have identified a recessive alpha-mating-type-specific gene agalphal causing agglutinability defect without significant effects on other sexual activities. a cells carrying agalphal showed sexual agglutination with alpha cells but alpha cells carrying agalphal showed sexual agglutination with neither alpha cells nor a cells. alpha cells carrying agalphal produced alpha pheromone and responded to a pheromone just like wild alpha cells. alpha cells carrying agalphal showed a little decreased but significant mating ability when tested on solid media or membrane filter. The agalphal mutant is different from any alpha-specific ste mutants found so far in many sexual activities. The agalphal gene is recessive, and unlinked to the mating type locus. Biological significance of the alpha mating type agglutinability is discussed based on the results obtained with the mutant. PMID- 24173550 TI - Body mass and weight change in adults in relation to mortality risk. AB - Using data from the National Institutes of Health-AARP Diet and Health Study, we evaluated the influence of adulthood weight history on mortality risk. The National Institutes of Health-AARP Diet and Health Study is an observational cohort study of US men and women who were aged 50-71 years at entry in 1995-1996. This analysis focused on 109,947 subjects who had never smoked and were younger than age 70 years. We estimated hazard ratios of total and cause-specific mortality for recalled body mass index (BMI; weight (kg)/height (m)(2)) at ages 18, 35, and 50 years; weight change across 3 adult age intervals; and the effect of first attaining an elevated BMI at 4 successive ages. During 12.5 years' follow-up through 2009, 12,017 deaths occurred. BMI at all ages was positively related to mortality. Weight gain was positively related to mortality, with stronger associations for gain between ages 18 and 35 years and ages 35 and 50 years than between ages 50 and 69 years. Mortality risks were higher in persons who attained or exceeded a BMI of 25.0 at a younger age than in persons who reached that threshold later in adulthood, and risks were lowest in persons who maintained a BMI below 25.0. Heavier initial BMI and weight gain in early to middle adulthood strongly predicted mortality risk in persons aged 50-69 years. PMID- 24173553 TI - A mutation affecting sexual agglutinability in MATalpha locus of Saccharomyces cerevisiae. AB - A temperature-sensitive non-agglutinative mutant of Saccharomyces cerevisiae was isolated and characterized. The mutation, sag2, affected sexual agglutination, conjugation and production of alpha-mating pheromone at a restrictive temperature, but not the response to alpha-mating pheromone. Genetic analyses showed that the mutation was recessive and in the MATalpha locus. The sag2 mutation complemented with matalpha2 but not with matalpha1 These results suggest that sag2 is in the MATalpha1 gene and that at a restrictive temperature the mutation, sag2, inactivated the MATalpha1 product, a positive regulator of alpha mating functions. The sag2 mutation is like matalpha1-5 in its retention of response to alpha-mating pheromone. However, at 25 degrees C, sag2 cells were competent to mate, whereas matalpha1-5 cells were not. Hence, sag2 is regarded as a new allele in the MATalpha1 gene, which we designate matalpha1-11. PMID- 24173554 TI - Genetic mapping of leucine-inserting UAA suppressors in Saccharomyces cerevisiae. AB - Of S. cerevisiae UAA specific suppressors three leucine-insertors have been remaining unmapped. Mapping of them was attempted by using a set of eight strains that contained a total of 60 markers distributing over the entire genome; the markers were about 30 cM apart and they covered about 70% of the genome. Two supressors, SUP28 and SUP33, were localized on the right arm of chromosome XIV and on the left arm of chromosome XI, respectively. The other suppressor, SUP32, was not mapped, but its location was confined to a few regions in the genome. The present result and the previously available informations clearly show that the UAA suppressor loci are dispersedly distributing ovet the entire S. cerevisiae genome. PMID- 24173555 TI - Localization of three chloroplast ribosomal protein genes at the left junction of the large single copy region and the inverted repeat of Spirodela oligorhiza chloroplast DNA. AB - In order to determine the localization of ribosomal protein genes on the chloroplast genome of Spirodela, we have followed two different approaches: First, antisera were prepared against purified 30S, 50S and 70S chloroplast ribosomal proteins from Spinacia. These antisera react with about two third of the chloroplast ribosomal proteins as shown by protein blot and immunoprecipitation experiments. Recombinant plasmids carrying the Spirodela BamHI-G or PstI-I cpDNA fragment both direct the synthesis of a 15 kD chloroplast ribosomal protein in a DNA dependent E. coli cell free system. This was confirmed by molecular weight determination, immunoprecipitation and competition immunoprecipitation experiments. Second, heterologous hybridization with the rps19 gene probe from Nicotiana revealed the localization of this gene on the chloroplast DNA of Spirodela within the BamHI-G fragment at the left junction of the large single copy region and the inverted repeat. Furthermore we show that the recombinant plasmid carrying Nicotiana rps19 also directs the synthesis of another chloroplast ribosomal protein in an E. coli cell free system. The identity of this protein is discussed. PMID- 24173556 TI - The chloroplast genome of Euglena gracilis: the mosaic structure of a DNA segment linking the extra 16S rRNA gene with the rrn operon A. AB - We have completed the analysis of a DNA segment of the chloroplast genome of Euglena gracilis Klebs, Z-strain, which links the 3' end of the extra 16S rRNA gene with the 5' end of the 16S rRNA gene of the rrn operon A. This region is a mosaic of several structural elements and contains an intact rrn interoperon spacer of 1,080 bp, an extra 5S rRNA gene, an open reading frame for 406 codons (ORF 406) which is flanked by short inverted repeats and a short direct repeat originating from the rrn interoperon spacer. It seems that a once complete rrn operon underwent in the past an insertion/deletion event leaving intact the 16S and 5S rRNA but totally excising the 16S-23S intergenic spacer and the 23S rRNA gene. Instead a protein coding gene of yet unknown function was inserted along with other structural elements. PMID- 24173557 TI - True reversion of a mutation in the chloroplast gene encoding the large subunit of ribulosebisphosphate carboxylase/oxygenase in Chlamydomonas. AB - The ribulosebisphosphate carboxylase/oxygenase-defective Chlamydomonas mutant, 10 6C, was the first mutant to be physically defined in chloroplast DNA. In this report, a photosynthesis-competent revertant of the 10-6C mutant has been found to result from true reversion within the chloroplast large-subunit gene. This result supports the original assignment of the 10-6C mutation within the large subunit gene. PMID- 24173558 TI - Recombination within the inverted repeat sequences of the Chlamydomonas reinhardii chloroplast genome produces two orientation isomers. AB - Two orientations of the Chlamydomonas reinhardii chloroplast (ct) genome are shown to be produced by recombination within the inverted repeat (IR) sequences that separate the two single copy (SC) regions. SC region 1 is bounded on its two ends by EeoRI restriction endonuclease fragments of 3.2 and 4.7 kilobase pairs (kb) (Rochaix 1978). The 3.2 kb EeoRI fragment overlaps a 51.3 kb BglII fragment spanning one of the 19.7 kb IR sequences, and the 4.7 kb EcoRI fragment overlaps a 42.1 kb BglII fragment spanning the other 19.7 kb IR sequence. We have shown by hybridization analysis that the 3.2 kb fragment also overlaps a BgIII fragment with a predicted size of 52.3 kb, and that the 4.7 kb fragment also overlaps a BglII fragment of a predicted size of 41.1 kb. The second set of BglII fragments are isomers produced by recombination localized to the IR region. The two isomers are present in approximately equimolar ratio. Knowledge of the isomeric composition of the C. reinhardii ctDNA is essential for establishing a correlation between genetic and physical maps of the ct genome. PMID- 24173559 TI - Change in cytoplasmic ribosome properties during gametogenesis in the alga Chlamydomonas reinhardtii. AB - Cytoplasmic (80S) ribosomes isolated from gametes and vegetative cells of the unicellular alga Chlamydomonas reinhardtii have been compared. Ribosomes of these two cell types differ in their susceptibility towards aminoglycoside antibiotics while their response to other antibiotics are similar. Electrophoregrams of ribosomal proteins show clear-cut differences between the two kinds of ribosomes. PMID- 24173560 TI - A comparison between mitochondrial DNA of an isogenic male-sterile (5) and male fertile (F) couple (HA89) of sunflower. AB - Mitochondrial DNA from etiolated seedling of male-fertile (F) and male-sterile (S) sunflower (Helianthus annuus L.) has been investigated for the first time in an isogenic couple HA89. 1. The mt-DNAs isolated from the S and F cytoplasms give a sharp and symmetrical band at 1.706 g/ml in an analytical CsCI gradient ultracentrifugation. 2. In polyacrylamide gel it is found that mitochondria from F cytoplasm contain a Low-Molecular-Weight (LMW) mt-DNA molecule of 1.45 Kilobase pairs (kb) in addition to the major mt-DNA. On the contrary, mitochondria from S cytoplasm contain no LMW molecule. Treatments with DNAse, RNAse and Nuclease S1 show that this LMW mt-DNA molecule consists of a supercoiled circular DNA. The length and form of the LMW molecule are confirmed by electron microscopy observations. 3. The mt-DNAs from S and F cytoplasms have also been investigated using restriction endonuclease digestions (Sa11, Xho1, Bg11). The electrophoresis of the resulting fragments reveals several differences between the S and F cytoplasm. It is not known whether the differences observed between F and S mt DNA are correlated with the cytoplasmic male sterility phenotype. PMID- 24173562 TI - Modified oligodeoxynucleotide primers for reverse-transcription of target RNAs that can discriminate among length variants at the 3'-terminus. AB - To discriminate among miRNA length variants, we synthesized conformationally restricted or unrestricted oligonucleotides containing a cyclohexyl phosphate residue. These oligonucleotides formed duplexes with length-matched complementary miRNAs more tightly than with length variants. The use of one of these modified oligodeoxynucleotides as a reverse transcription primer enabled a novel RT-PCR that can discriminate among miRNA length variants. PMID- 24173561 TI - Optical control of neuronal excitation and inhibition using a single opsin protein, ChR2. AB - The effect of electrical stimulation on neuronal membrane potential is frequency dependent. Low frequency electrical stimulation can evoke action potentials, whereas high frequency stimulation can inhibit action potential transmission. Optical stimulation of channelrhodopsin-2 (ChR2) expressed in neuronal membranes can also excite action potentials. However, it is unknown whether optical stimulation of ChR2-expressing neurons produces a transition from excitation to inhibition with increasing light pulse frequencies. Here we report optical inhibition of motor neuron and muscle activity in vivo in the cooled sciatic nerves of Thy1-ChR2-EYFP mice. We also demonstrate all-optical single-wavelength control of neuronal excitation and inhibition without co-expression of inhibitory and excitatory opsins. This all-optical system is free from stimulation-induced electrical artifacts and thus provides a new approach to investigate mechanisms of high frequency inhibition in neuronal circuits in vivo and in vitro. PMID- 24173563 TI - The Tribolium decapentaplegic gene is similar in sequence, structure, and expression to the Drosophila dpp gene. AB - We are characterizing members of the Transforming Growth Factor-beta (TGF-beta) superfamily in the red flour beetle, Tribolium castaneum, in order to examine the evolutionary conservation of the structure and function of TGF-beta-like genes during insect development. A decapentaplegic-like gene of the TGF-beta superfamily was isolated in Tribolium (Tc dpp) that is similar in sequence, organization, and expression to the Drosophila melanogaster dpp gene (Dm dpp). Conserved features include a high degree of sequence similarity in both the pro domain and mature domains of the encoded polypeptide. In addition, the position of an intron within the protein-coding region is conserved in Tc dpp, Dm dpp, and two bone morphogenetic protein genes of the TGF-beta superfamily in humans, BMP2 and BMP4. Consensus binding sites for the dorsal transcription factor are found within this intron in Tc dpp similar to the intronic location of several dorsal binding sites in Dm dpp. During embryogenesis, Tc dpp is expressed in an anterior cap of serosa cells at the blastoderm stage, in the dorsal ectoderm at the lateral edges of the developing and extended germ band, and in the distal tips of developing embryonic appendages. Several aspects of embryonic expression, similar in both flies and beetles, suggest conserved roles for dpp in cellular communication during the development of these distantly related insects. PMID- 24173564 TI - Response to insulin and the expression pattern of a gene encoding an insulin receptor homologue suggest a role for an insulin-like molecule in regulating growth and patterning in Hydra. AB - A gene encoding a receptor protein-tyrosine kinase closely related to the vertebrate insulin receptor has been identified in the Cnidarian Hydra vulgaris. The gene is expressed in both epithelial layers of the adult polyp. A particularly high level of expression is seen in the ectoderm of the proximal portions of the tentacles and in a ring of ectodermal cells at the border between the foot basal disk and body column. The expression pattern of the gene in asexual buds is dynamic; expression is high throughout the newly emerging bud but the area of high expression becomes restricted to the apex as the bud lengthens. When the bud begins hypostome and tentacle formation, a high level of expression appears at the bases of the emerging tentacles. Finally, a ring of high expression appears just above the foot of the bud, completing the pattern seen in the adult polyp. The presence of this receptor and its pattern of expression suggested that an endogenous molecule related to insulin plays a role in regulating cell division in the body column and in differentiation of the tentacle and foot cells in Hydra, with the switch between the two being determined by the level of the receptor. Treatment of Hydra polyps with mammalian insulin caused an increase in the number of ectodermal and endodermal cells undergoing DNA synthesis. PMID- 24173565 TI - Mutations affecting pigmentation and shape of the adult zebrafish. AB - Mutations causing a visible phenotype in the adult serve as valuable visible genetic markers in multicellular genetic model organisms such as Drosophila melanogaster, Caenorhabditis elegans and Arabidopsis thaliana. In a large scale screen for mutations affecting early development of the zebrafish, we identified a number of mutations that are homozygous viable or semiviable. Here we describe viable mutations which produce visible phenotypes in the adult fish. These predominantly affect the fins and pigmentation, but also the eyes and body length of the adult. A number of dominant mutations caused visible phenotypes in the adult fish. Mutations in three genes, long fin, another long fin and wanda affected fin formation in the adult. Four mutations were found to cause a dominant reduction of the overall body length in the adult. The adult pigment pattern was found to be changed by dominant mutations in wanda, asterix, obelix, leopard, salz and pfeffer. Among the recessive mutations producing visible phenotypes in the homozygous adult, a group of mutations that failed to produce melanin was assayed for tyrosinase activity. Mutations in sandy produced embryos that failed to express tyrosinase activity. These are potentially useful for using tyrosinase as a marker for the generation of transgenic lines of zebrafish. PMID- 24173566 TI - Glial cells phagocytose neuronal debris during the metamorphosis of the central nervous system in Drosophila melanogaster. AB - Using electron microscopy we demonstrate that degenerating neurons and cellular debris resulting from neuronal reorganization are phagocytosed by glial cells in the brain and nerve cord of the fruitfly Drosophila melanogaster during the first few hours following pupariation. At this stage several classes of glial cells appear to be engaged in intense phagocytosis. In the cell body rind, neuronal cell bodies are engulfed and phagocytosed by the same glial cells that enwrap healthy neurons in this region. In the neuropil, cellular debris in tracts and synaptic centres resulting from metamorphic re-differentiation of larval neurons is phagocytosed by neuropil-associated glial cells. Phagocytic glial cells are hypertrophied, produce large amounts of lysosome-like bodies and contain a large number of mitochondria, condensed chromatin bodies, membranes and other remains from neuronal degeneration in phagosomes. PMID- 24173567 TI - Pattern duplications in larvae of the polyembryonic wasp Copidosoma floridanum. AB - Copidosoma floridanum is a polyembryonic wasp that undergoes total cleavage of the egg followed by proliferation of blastomeres to produce up to 2,000 embryos from a single egg. This unusual mode of development raises several questions about how axial polarity is established in individual embryonic primordia. By examining embryonic development of larvae with duplicated structures (conjoined larvae), we determined that conjoined larvae form by mislocalization of two embryonic primordia to a common chamber of the extraembryonic membrane that surrounds individual embryos. Analysis of an anterior marker, Distalless, in mislocalized early embryos indicated that anterior structures form independently of one another. This suggests each embryonic primordium has some intrinsic polarity. However, during germband extension embryos usually fuse in register with each other, resulting in conjoined larvae with heads facing each other. Analysis of the posterior segmental marker, Engrailed, in conjoined embryos suggested that fusion in register initiates during germband extension. Thus, even though embryonic primordia initially have a random axial orientation, conjoined larvae usually possess a common orientation due to reorientation during germband extension. These observations suggest that differential cellular affinities during segmentation play an important role in embryo fusion. PMID- 24173568 TI - Cloning of a B-type cyclin homolog from Bombyx mori and the profiles of its mRNA level in non-diapause and diapause eggs. AB - To understand the molecular mechanism of G2-arrest of cell division in embryonic diapause of the silkworm, Bombyx mori, we have cloned a cDNA encoding a Bombyx homolog of B-type cyclin. Levels of Bm cyclin-B mRNA were examined during diapause stage and early embryogenesis. The results showed that this G2-arrest did not always correspond to lowered transcriptional levels of cyclin-B, and that the mRNA accumulated in oocytes began to be degraded during the first hour after oviposition, i.e. the first meiosis, suggesting that the penetration of sperm triggered the degradation of maternal cyclin-B mRNA. PMID- 24173569 TI - Multicolour whole-mount in situ hybridization to Drosophila embryos. AB - We report an extended whole-mount in situ hybridization procedure for Drosophila embryos. By using probes labelled with digoxigenin, fluorescein and biotin, respectively, this protocol allows the detection in three colours of RNAs derived from three different genes. Hybridized probes are detected by consecutive staining with appropriate alkaline phosphatase conjugates using different chromogenic substrate combinations, and serial removal of the antibody conjugates by low pH washes. PMID- 24173570 TI - Assessment of stroke risk in southern Arizona, the pairing of acculturation and stroke risk factor development. AB - Stroke is a leading cause of mortality in the United States. Hispanics have the same incidence of stroke, but are more likely to have subsequent strokes than non Hispanic whites. This difference in outcome may be attributable to differences in stroke risk factor awareness. Patients at a community health center in Tucson, AZ completed an anonymous survey regarding existing and perceived health issues. Patient responses were compared in terms of ethnicity and acculturation, as indicated by language preference. Patient responses (n = 301, Spanish: 150, English: 151) indicated that proportionately fewer non-acculturated Hispanics than acculturated Hispanic and non-Hispanic patients indicated that they were at risk for stroke. Acculturated Hispanics and non-Hispanics displayed similar morbidity trends, including increased obesity, hypertension, diabetes, heart problems, depression, and previous stroke. These findings suggest that Hispanics become less healthy and more at risk for stroke and stroke risk factors as they become acculturated. PMID- 24173572 TI - 2013: another good year for EJNMMI. PMID- 24173571 TI - Synthesis and evaluation of 18F-labeled benzylguanidine analogs for targeting the human norepinephrine transporter. AB - PURPOSE: Both (131)I- and (123)I-labeled meta-iodobenzylguanidine (MIBG) have been widely used in the clinic for targeted imaging of the norepinephrine transporter (NET). The human NET (hNET) gene has been imaged successfully with (124)I-MIBG positron emission tomography (PET) at time points of >24 h post injection (p.i.). (18)F-labeled MIBG analogs may be ideal to image hNET expression at time points of <8 h p.i. We developed improved methods for the synthesis of known MIBG analogs, [(18)F]MFBG and [(18)F]PFBG and evaluated them in hNET reporter gene-transduced C6 rat glioma cells and xenografts. METHODS: [(18)F]MFBG and [(18)F]PFBG were synthesized manually using a three-step synthetic scheme. Wild-type and hNET reporter gene-transduced C6 rat glioma cells and xenografts were used to comparatively evaluate the (18)F-labeled analogs with [(123)I]/[(124)I]MIBG. RESULTS: The fluorination efficacy on benzonitrile was predominantly determined by the position of the trimethylammonium group. The para isomer afforded higher yields (75 +/- 7%) than meta-isomer (21 +/- 5%). The reaction of [(18)F]fluorobenzylamine with 1H-pyrazole-1-carboximidamide was more efficient than with 2-methyl-2-thiopseudourea. The overall radiochemical yields (decay-corrected) were 11 +/- 2% (n = 12) for [(18)F]MFBG and 41 +/- 12% (n = 5) for [(18)F]PFBG, respectively. The specific uptakes of [(18)F]MFBG and [(18)F]PFBG were similar in C6-hNET cells, but 4-fold less than that of [(123)I]/[(124)I]MIBG. However, in vivo [(18)F]MFBG accumulation in C6-hNET tumors was 1.6-fold higher than that of [(18)F]PFBG at 1 h p.i., whereas their uptakes were similar at 4 h. Despite [(18)F]MFBG having a 2.8-fold lower affinity to hNET and approximately 4-fold lower cell uptake in vitro compared to [(123)I]/[(124)I]MIBG, PET imaging demonstrated that [(18)F]MFBG was able to visualize C6-hNET xenografts better than [(124)I]MIBG. Biodistribution studies showed [(18)F]MFBG and (123)I-MIBG had a similar tumor accumulation, which was lower than that of no-carrier-added [(124)I]MIBG, but [(18)F]MFBG showed a significantly more rapid body clearance and lower uptake in most non-targeting organs. CONCLUSION: [(18)F]MFBG and [(18)F]PFBG were synthesized in reasonable radiochemical yields under milder conditions. [(18)F]MFBG is a better PET ligand to image hNET expression in vivo at 1-4 h p.i. than both [(18)F]PFBG and [(123)I]/[(124)I]MIBG. PMID- 24173573 TI - Synthesis and characterization of some water soluble Zn(II) complexes with (E)-N (pyridin-2-ylmethylene)arylamines that regulate tumour cell death by interacting with DNA. AB - The synthesis and spectroscopic properties of nine water soluble zinc(II) complexes of (E)-N-(pyridin-2-ylmethylene)arylamines (L(n)) with the general formula [Zn(X)2(L(n))] (X = Cl(-), Br(-), I(-); (1-8)) and [Zn(MU-N3)(N3)(L(3))]2 (9) are reported. The complexes were characterized by elemental analysis and their spectroscopic properties were studied using UV-Visible, fluorescence, IR and (1)H NMR spectroscopies. The solid state structures of zinc(II) complexes 2-4 and 6-9 were established by single crystal X-ray crystallography. The majority of the structures are mononuclear with tetra-coordinate zinc centres (2-4, 6 and 7) except where L carries an additional donor atom capable of coordinating zinc (8), in which case the zinc atom has a distorted square pyramidal geometry. The centrosymmetric molecule of [Zn(MU-N3)(N3)(L(3))]2 (9) is binuclear with the zinc atoms in a trigonal bipyramidal coordination environment. In general, the dichlorozinc derivatives 1, 3-5 and 8 exhibited moderately elevated in vitro cytotoxic potency towards the human epithelial cervical carcinoma (HeLa) cell line, with 4 as the best performer (IC50 value of 18 MUM). Apoptosis-inducing activity, assessed by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, showed that the zinc complexes interacted with DNA and thereby interfered the DNA binding of several transcription factors to its promoter sites, thus inhibiting gene transcription required for the biological activity of cells. PMID- 24173574 TI - Induction of G2/M phase cell cycle arrest and apoptosis by ginsenoside Rf in human osteosarcoma MG-63 cells through the mitochondrial pathway. AB - Ginsenosides, extracted from the traditional Chinese herb ginseng, are a series of novel natural anticancer products known for their favorable safety and efficacy profiles. The present study aimed to investigate the cytotoxicity of ginsenoside Rf to human osteosarcoma cells and to explore the anticancer molecular mechanisms of ginsenoside Rf. Five human osteosarcoma cell lines (MG 63, OS732, U-2OS, HOS and SAOS-2) were employed to investigate the cytotoxicity of ginsenoside Rf by MTT and colony forming assays. After treatment with ginsenoside Rf, MG-63 cells which were the most sensitive to ginsenoside Rf, were subjected to flow cytometry to detect cell cycle distribution and apoptosis, and nuclear morphological changes were visualized by Hoechst 33258 staining. Caspase 3, -8 and -9 activities were also evaluated. The expression of cell cycle markers including cyclin B1 and Cdk1 was detected by RT-PCR and western blotting. The expression of apoptotic genes Bcl-2 and Bax and the release of cytochrome c were also examined by western blotting. Change in the mitochondrial membrane potential was observed by JC-1 staining in situ. Our results demonstrated that the cytotoxicity of ginsenoside Rf to these human osteosarcoma cell lines was dose dependent, and the MG-63 cells were the most sensitive to exposure to ginsenoside Rf. Additionally, ginsenoside Rf induced G2/M phase cell cycle arrest and apoptosis in MG-63 cells. Furthermore, we observed upregulation of Bax and downregulation of Bcl-2, Cdk1 and cyclin B1, the activation of caspase-3 and -9 and the release of cytochrome c in MG-63 cells following treatment with ginsenoside Rf. Our findings demonstrated that ginsenoside Rf induces G2/M phase cell cycle arrest and apoptosis in human osteosarcoma MG-63 cells through the mitochondrial pathway, suggesting that ginsenoside Rf, as an effective natural product, may have a therapeutic effect on human osteosarcoma. PMID- 24173576 TI - [Surgery and teaching]. PMID- 24173577 TI - [Skills lab from the surgical point of view. Experiences from the Magdeburg Medical School--The University of Magdeburg]. AB - INTRODUCTION: For the acquisition of practical skills, the separate learning atmosphere of a skills lab(oratory) is very suitable. Numerous educational objectives of surgical teaching can be pursued using phantoms, manikins or mutual training among students prior to real practical use during clinical traineeships or internships. AIM AND METHOD: This article provides a compact, systematic overview of the skills lab concept, based on published aspects in selected and relatively recent topic-related references from PubMed(r) including our own approaches, as well as comments and experiences with regard to its further development. In particular, the Magdeburg concept to use the local skills lab MAMBA for surgical teaching within the practical training is demonstrated, which has developed step by step from a basically pure bedside teaching and which includes student tutors in practical teaching in surgery. RESULTS: By founding the Magdeburg educational and training center options for a practical education, in particular, in surgery were created. The great majority of students accepted the conceptual idea and it has so far been well received. As a first step several well selected topics of practical training during human medical studies were increasingly taught by students who received a didactic course of instruction which also included aspects of the educational objectives. For the future tutorials led by students are planned going beyond the teaching contents of the practical courses and can, thus, lead to a networking with educational objectives of other disciplines. There are not only curricular but also facultative courses in MAMBA which have been steadily optimized since the beginning. This Magdeburg's concept is planned to be further developed for which there is enough room for development with regard to organizational aspects (personnel and room). PMID- 24173580 TI - The role of chromosomal retention of noncoding RNA in meiosis. AB - Meiosis is a process of fundamental importance for sexually reproducing eukaryotes. During meiosis, homologous chromosomes pair with each other and undergo homologous recombination, ultimately producing haploid sets of recombined chromosomes that will be inherited by the offspring. Compared with the extensive progress that has been made in understanding the molecular mechanisms underlying recombination, how homologous sequences pair with each other is still poorly understood. The diversity of the underlying mechanisms of pairing present in different organisms further increases the complexity of this problem. Involvement of meiosis-specific noncoding RNA in the pairing of homologous chromosomes has been found in the fission yeast Schizosaccharomyces pombe. Although different organisms may have developed other or additional systems that are involved in chromosome pairing, the findings in S. pombe will provide new insights into understanding the roles of noncoding RNA in meiosis. PMID- 24173579 TI - RNAi function, diversity, and loss in the fungal kingdom. AB - RNAi is conserved and has been studied in a broad cross-section of the fungal kingdom, including Neurospora crassa, Schizosaccharomyces pombe, Cryptococcus neoformans, and Mucor circinelloides. And yet well known species, including the model yeast Saccharomyces cerevisiae and the plant pathogen Ustilago maydis, have lost RNAi, providing insights and opportunities to illuminate benefits conferred both by the presence of RNAi and its loss. Some of the earliest studies of RNAi were conducted in Neurospora, contemporaneously with the elucidation of RNAi in Caenorhabditis elegans. RNAi is a key epigenetic mechanism for maintaining genomic stability and integrity, as well as to defend against viruses, and given its ubiquity was likely present in the last eukaryotic common ancestor. In this review, we describe the diversity of RNAi mechanisms found in the fungi, highlighting recent work in Neurospora, S. pombe, and Cryptococcus. Finally, we consider frequent, independent losses of RNAi in diverse fungal lineages and both review and speculate on evolutionary forces that may drive the losses or result therefrom. PMID- 24173581 TI - The role of vitamin D deficiency in cardiovascular disease: where do we stand in 2013? AB - The high worldwide prevalence of vitamin D deficiency is largely the result of low sunlight exposure with subsequently limited cutaneous vitamin D production. Classic manifestations of vitamin D deficiency are linked to disturbances in bone and mineral metabolism, but the identification of the vitamin D receptor in almost every human cell suggests a broader role of vitamin D for overall and cardiovascular health. The various cardiovascular protective actions of vitamin D such as anti-diabetic and anti-hypertensive effects including renin suppression as well as protection against atherosclerosis and heart diseases are well defined in previous experimental studies. In line with this, large epidemiological studies have highlighted vitamin D deficiency as a marker of cardiovascular risk. However, randomized controlled trials (RCTs) on vitamin D have largely failed to show its beneficial effects on cardiovascular diseases and its conventional risk factors. While most prior vitamin D RCTs were not designed to assess cardiovascular outcomes, some large RCTs have been initiated to evaluate the efficacy of vitamin D supplementation on cardiovascular events in the general population. When considering the history of previous disappointing vitamin RCTs in general populations, more emphasis should be placed on RCTs among severely vitamin D-deficient populations who would most likely benefit from vitamin D treatment. At present, vitamin D deficiency can only be considered a cardiovascular risk marker, as vitamin D supplementation with doses recommended for osteoporosis treatment is neither proven to be beneficial nor harmful in cardiovascular diseases. PMID- 24173582 TI - Isolation and osteogenic differentiation of skeletal muscle-derived stem cells for bone tissue engineering. AB - The purpose of this study was to investigate the isolation and culture of muscle derived stem cells (MDSCs) and their capability to differentiate into osteoblasts in vitro. Skeletal muscle tissue was obtained from double hind limbs of New Zealand white rabbits under sterile conditions and isolated by collagenase digestion. Following passages in basic medium, the primary cells were desmin (+), myosin (+) and CD105 (+). Differentiation of MDSCs was induced by osteogenic medium. Using a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide assay, the differentiated cell population was found to proliferate faster than the undifferentiated. Alkaline phosphatase staining and alizarin red staining revealed that the differentiated cells were mineralized in vitro. Quantitative polymerase chain reaction assays also showed increased mRNA expression of osteogenic genes in differentiated cells. In conclusion, stem cells were successfully isolated and cultured from rabbit skeletal muscle tissue and were able to differentiate into osteoblasts following induction. These observations may indicate an ideal stem cell source for tissue engineering. PMID- 24173583 TI - Wideband THz time domain spectroscopy based on optical rectification and electro optic sampling. AB - We present an analytical model describing the full electromagnetic propagation in a THz time-domain spectroscopy (THz-TDS) system, from the THz pulses via Optical Rectification to the detection via Electro Optic-Sampling. While several investigations deal singularly with the many elements that constitute a THz-TDS, in our work we pay particular attention to the modelling of the time-frequency behaviour of all the stages which compose the experimental set-up. Therefore, our model considers the following main aspects: (i) pump beam focusing into the generation crystal; (ii) phase-matching inside both the generation and detection crystals; (iii) chromatic dispersion and absorption inside the crystals; (iv) Fabry-Perot effect; (v) diffraction outside, i.e. along the propagation, (vi) focalization and overlapping between THz and probe beams, (vii) electro-optic sampling. In order to validate our model, we report on the comparison between the simulations and the experimental data obtained from the same set-up, showing their good agreement. PMID- 24173585 TI - Anti-Aspergillus Prophylaxis in Lung Transplantation: A Systematic Review and Meta-analysis. AB - Aspergillus is the most common cause of invasive fungal infection in lung transplant recipients. Most transplant centers employ routine antifungal prophylaxis to prevent the development of invasive aspergillosis (IA). We identified 22 studies from the literature to perform a systematic review and meta analysis, in order to assess the development of IA and Aspergillus colonization with and without antifungal prophylaxis. Similarly, differences in the toxicities of different formulations of amphotericin-B and azoles were analyzed. Nineteen of 235 (8.1 %) and 28 of 196 (14.3 %) developed IA in the universal prophylaxis and no-prophylaxis arms, respectively (RR: 0.36, CI: 0.05-2.62). We did not find a significant reduction in IA or Aspergillus colonization with universal anti aspergillus prophylaxis. There was no difference in the adverse events of inhaled amphotericin-B deoxycholate and lipid formulations of inhaled amphotericin-B. However, voriconazole was more hepatotoxic than itraconazole. These results should be interpreted with caution due to heterogeneity of the studies. A multicenter randomized controlled trial is warranted to assess the efficacy of anti-aspergillus prophylaxis in lung transplant recipients. PMID- 24173584 TI - Central nervous system immune reconstitution inflammatory syndrome. AB - Central nervous system immune reconstitution inflammatory syndrome (CNS-IRIS) develops in 9 %-47 % of persons with HIV infection and a CNS opportunistic infection who start antiretroviral therapy and is associated with a mortality rate of 13 %-75 %. These rates vary according to the causative pathogen. Common CNS-IRIS events occur in relation to Cryptococcus, tuberculosis (TB), and JC virus, but several other mycobacteria, fungi, and viruses have been associated with IRIS. IRIS symptoms often mimic the original infection, and diagnosis necessitates consideration of treatment failure, microbial resistance, and an additional neurological infection. These diagnostic challenges often delay IRIS diagnosis and treatment. Corticosteroids have been used to treat CNS-IRIS, with variable responses; the best supportive evidence exists for the treatment of TB IRIS. Pathogenic mechanisms vary: Cryptococcal IRIS is characterized by a paucity of cerebrospinal inflammation prior to antiretroviral therapy, whereas higher levels of inflammatory markers at baseline predispose to TB meningitis IRIS. This review focuses on advances in the understanding of CNS-IRIS over the past 2 years. PMID- 24173586 TI - Clinical safety and pharmacology trial. AB - Guidelines for establishing clinical safety of microbicides in early clinical studies have evolved significantly since the first trials. In addition, because of the difficulty of establishing efficacy of a microbicide prior to Phase III testing, there has been an increasing emphasis on establishing pharmacokinetic (PK)/pharmacodynamic (PD) relationships using genital samples collected in vivo in Phase I studies. A healthy pipeline is critical to success; however, it is unlikely that the majority of microbicide candidates will progress to clinical testing. Those that do enter clinical testing may have different mechanisms of action than early candidates. Given this, drug-specific modifications for early clinical assessment will need to be considered. These emerging issues associated with early clinical trials of microbicides will be reviewed, along with recommendations for future clinical safety and PK/PD evaluation. PMID- 24173587 TI - Distribution of cytoplasmic determinants in unfertilized eggs of the ascidian Halocynthia roretzi. AB - Cytoplasmic determinants that specify the fate of endoderm, muscle and epidermis cells are known to be localized in specific areas of fertilized eggs of ascidians. The presence of such cytoplasmic determinants in unfertilized eggs was demonstrated in previous studies, but no information has yet been proved about their distribution. To investigate the distribution of cytoplasmic determinants in unfertilized eggs, we devised a method for distinguishing the polarity of unfertilized eggs using vital staining and we performed cytoplasmic-transfer experiments by fusing blastomeres and cytoplasmic fragments from various identified regions of unfertilized eggs. Cytoplasmic fragments, that contained cortical and subcortical material, from five different positions along the animal vegetal axis were prepared, and they were fused with a4.2 (presumptive-epidermis) or A4.1 (non-epidermis) blastomeres. The ectopic development of endoderm, muscle and epidermis cells that was promoted by the transplanted cytoplasm was assessed by examining the expression of alkaline phosphatase (ALP), myosin and epidermis specific antigen, respectively. Differentiation of endoderm and muscle was observed at higher frequencies as cytoplasmic fragments closer to the vegetal pole were transplanted. Conversely, formation of epidermis was observed at higher frequencies as cytoplasmic fragments closer to the animal pole were transplanted. The results suggest that, in cortical and subcortical regions of unfertilized ascidian eggs, endoderm and muscle determinants are widely distributed along a gradient, with maximum activity at the vegetal pole, whilst epidermis determinants are also distributed along a gradient but with maximum activity at the animal pole. PMID- 24173588 TI - Expression of ecdysteroid-regulated transcripts in the silk gland of the wax moth, Galleria mellonella. AB - Expression of six different transcripts encoding members of the nuclear receptor superfamily was studied in whole silk glands of the wax moth, Galleria mellonella, during development and in response to 20-hydroxyecdysone (20E) and juvenile hormone (JH II) in vitro. Nucleic acid probes specific to Galleria homologs of the Drosophila E75 early gene and the delayed early gene DHR3 were used to follow mRNAs encoding isoforms A and B of the E75 protein and GHR3 protein, respectively. Among these mRNAs, E75A mRNA appeared first during the larval molt and was most rapidly induced by 20E, while E75B and GHR3 mRNAs appeared with a 2 h delay. Unlike E75B mRNA, GHR3 mRNA required protein synthesis for its full induction. The 20E-induced levels of E75A mRNA were increased one and a half-fold within 1 h in the presence of 10-100 ng/ml JH II in cultured silk glands. Antisense cRNA probes for the Manduca sexta ecdysone receptor isoforms EcR-A and EcR-B1 detected transcripts that were directly induced by 20E in cultured silk glands. The levels of the putative EcR-A mRNA were high relative to those of EcR-B1 mRNA in silk glands at molting and metamorphosis. An antisense cRNA probe for the Manduca Ultraspiracle homolog detected a 4 kb mRNA that was most abundant around the time of larval ecdysis but was not induced by 20E in vitro. PMID- 24173589 TI - The spalt-related gene of Drosophila melanogaster is a member of an ancient gene family, defined by the adjacent, region-specific homeotic gene spalt. AB - We report the full coding sequence of a new Drosophila gene, spalt-related, which is homologous and adjacent to the region-specific homeotic gene, spalt. Both genes have three widely spaced sets of C2H2 zinc finger motifs, but spalt-related encodes a fourth pair of C-terminal fingers resembling the Xenopus homologue, Xsal-1. The degrees of sequence divergence among all three members of this family are comparable, suggesting that the Drosophila genes originated from an ancient gene duplication. The spalt-related gene is expressed with quantitative variations from mid-embryogenesis (8-12 h) to the adult stage, but not in ovaries or early embryos. Expression is localized to limited parts of the body, including specific cell populations in the nervous system. In the wing disc, spalt and spalt-related are expressed in indistinguishable domains; in the nervous system and some other organs the expression patterns extensively overlap but are not identical, indicating that the genes have partially diverged in terms of developmental regulation. A characteristic central set of zinc fingers specifically binds to an A/T-rich consensus sequence, defining some DNA binding properties of this ancient family of nuclear factors. PMID- 24173590 TI - The role of ecdysone in the induction and maintenance of hsp27 transcripts during larval and prepupal development of Drosophila. AB - The Drosophila melanogaster small heat-shock gene hsp27 carries the canonic ecdysone response element (EcRE) at -537. This EcRE has been used extensively both in cultured cells and in vitro for studies of the ecdysone response. We have characterised the developmental expression of hsp27 in wild-type larval and prepupal salivary glands in parallel with that of the E74B and E74A primary ecdysone response transcripts, which are induced in the mid and late third larval instar by a minor and major increase in ecdysone titre respectively. The induction of hsp27 occurs between these two events in larvae and in parallel with that of E74A in prepupae. Transcript levels are severely reduced in ecd1 and dor (22) (deep orange) mutant larvae but are only moderately reduced in larvae mutant for the Broad-Complex allele br (t435) . By culturing salivary glands of different ages with low (1.8*10(-8) M) or high (1.8*10(-6) M) concentrations of hormone, we show that the response of an EcRE varies during development and that the timing of the response cannot be predicted solely from its apparent strength in cell line analyses. PMID- 24173591 TI - Regulated expression of the retinoblastoma gene product by fibroblast growth factor but not by activin during mesoderm induction in Xenopus. AB - The retinoblastoma (RB) gene is a tumor suppressor gene that plays an important role in cell cycle arrest and in the terminal differentiation of skeletal myoblasts. Differentiation into muscle occurs in Xenopus embryo explants during mesoderm induction by fibroblast growth factor (FGF) or activin A. We examined expression of the RB gene product (pRB) during mesoderm induction in vivo and in vitro. We show that hypo- and hyper-phosphorylated forms of pRB are present during early development and that expression of both forms increases significantly during the blastula stage, concomitant with mesoderm induction. Further investigation revealed that pRB is enriched in the presumptive mesoderm of the blastula stage embryo. In animal cap explants induced by Xenopus bFGF (XbFGF), pRB expression levels increased approximately tenfold while no increase was observed in explants induced by activin. However, when explants were induced by XbFGF in the presence of sodium orthovanadate, a compound previously shown to synergize with FGF to produce more dorsal "activin-like" inductions than FGF alone, only a slight increase in pRB expression was observed. Furthermore, upregulation of pRB during mesoderm induction in vitro displayed an inverse correlation with expression of XFKH1, a marker for notochord. These results suggest that pRB may be important for patterning along the dorsoventral axis. PMID- 24173592 TI - The hydrozoan life cycle: a small secreted protein is involved in specification of the polyp stage. AB - In the life cycle of many Hydrozoa (Cnidaria), the pelagic medusa is produced by a budding process from the sessile polyp stage. In order to investigate the molecular mechanisms controlling medusa budding, we screened a cDNA library made from Podocoryne carnea (Cnidaria, Hydrozoa, Anthomedusa) for life-stage-specific genes. As a result of this screening, a gene called Pol-1 was isolated. The deduced amino acid sequence of Pol-1 suggests that the translation product is a small, very acidic secreted protein, with repeated domains. This novel gene is specifically expressed in epithelial muscle cells of polyps and early medusa buds of Podocoryne. In more advanced medusa bud stages and liberated medusae, Pol-1 expression is not observed. However, reexpression can be induced experimentally in medusa buds where Pol-1 transcription normally is switched off. When isolated and traumatized they will dedifferentiate and transform back into polyps. Reexpression of the Pol-1 message is observed 2 days after traumatization, when the medusa-typical structures have dedifferentiated but polyp-structures have not yet formed. These results indicate that the Pol-1 gene is involved in the specification of the polyp stage. The pattern of expression of Pol-1 further suggests that, during the medusa budding process, a tightly controlled switch from polyp- to medusa-specific gene expression occurs which is reversible in the case of regeneration. PMID- 24173593 TI - Homeotic duplication of the pelvic body segment in regenerating tadpole tails induced by retinoic acid. AB - Homeosis, the ectopic formation of a body part, is one of the key phenomena that prompted the identification of the essential selector genes controlling body organization. Shared elements of such homeotic genes exist in all studied animal classes, but homeotic transformations of the same order of magnitude as in insects, such as the duplication of the thorax in Drosophila mutants, have not been described in vertebrates. Here we investigate the capacity of retinoic acid to modify tail regeneration in amphibians. We show that retinoic acid causes the formation of an additional body segment in regenerating tails of Rana temporaria tadpoles. A second pelvic section, including vertebral elements, pelvic girdle elements and limb buds, forms at the mid-tail level. This is the first report of a homeotic duplication of a whole body segment in vertebrate axial regeneration. PMID- 24173594 TI - 2D gene expression parameters of wing imaginal disc of Drosophila for developmental analysis. AB - By using high resolution two-dimensional (2D) gel electrophoresis coupled with computer-analysis we have established a quantitative Drosophila wing imaginal disc protein database of third instar larvae as a reference to be used for comparative purposes in genetic studies. A general catalogue integrated by 1,184 (35)S-methionine-labelled polypeptides from wing imaginal disc has been obtained. The level of expression for all the proteins has been quantitatively determined. The quantitative reproducibility of the analysis system has been estimated and all the controls studied as database reference to interpret the results of experiments with mutant discs. One example, corresponding to iro (1) mutation, has been used to show how some of the changes observed with mutant discs clearly extend out of the limits defined by the controls. This enables us to generate comparative parameters for the study of proliferation, morphogenesis and differentiation of Drosophila and opens the possibility of rapidly defining the nature and quantity of changes in patterns of gene expression in developmental genetic studies. PMID- 24173595 TI - Mesoscale structures from magnetocapillary self-assembly. AB - When identical soft ferromagnetic particles are suspended at some water-air interface, capillary attraction is balanced by magnetic repulsion induced by a vertical magnetic field. By adjusting the magnetic field strength, the equilibrium interdistance between particles can be tuned. The aim of this paper is to study the ordering of particles for large assemblies. We have found an upper size limit above which the assembly collapses due to capillary effects. Before reaching this critical number of particles, defects are always present and limit the perfect ordering expected for that system. This is due to the curvature of the interface induced by the weight of the self-assembly. PMID- 24173596 TI - Protective effects of nimodipine on cerebrovascular function in chronic alcoholic encephalopathy. AB - In the present study, we used chronic gavage administration of alcohol with gradual increases in alcohol concentration and volume to generate a rat model of chronic alcohol intoxication. We measured the changes in biological, behavioral, pathological and vascular injury-related molecular biological markers, and explored the effects of nimodipine intervention on alcohol intoxication. We found that chronic alcohol consumption induced a variety of behavioral abnormalities, accompanied by severe pathological changes in cerebral arterioles, prefrontal cortex and cerebellar tissue, as well as an upregulation of vascular endothelial growth factor (VEGF), leptin receptor (ob-R) and endothelin-1 (ET-1). Treatment with mimodipine for 15 days significantly improved behavioral abnormalities, alleviated the pathological changes in blood vessels and brain tissues, increased VEGF expression, decreased ob-R expression, reduced plasma ET-1 leakage and protected vascular and neuronal functions. PMID- 24173597 TI - Characterisation of solitary pulmonary lesions combining visual perfusion and quantitative diffusion MR imaging. AB - OBJECTIVE: To evaluate the diagnostic accuracy of dynamic contrast-enhanced (DCE) magnetic resonance (MR) and diffusion-weighted imaging (DWI) sequences for defining benignity or malignancy of solitary pulmonary lesions (SPL). METHODS: First, 54 consecutive patients with SPL, clinically staged (CT and PET or integrated PET-CT) as N0M0, were included in this prospective study. An additional 3-Tesla MR examination including DCE and DWI was performed 1 day before the surgical procedure. Histopathology of the surgical specimen served as the standard of reference. Subsequently, this functional method of SPL characterisation was validated with a second cohort of 54 patients. RESULTS: In the feasibility group, 11 benign and 43 malignant SPL were included. Using the combination of conventional MR sequences with visual interpretation of DCE-MR curves resulted in a sensitivity, specificity and accuracy of 100%, 55% and 91%, respectively. These results can be improved by DWI (with a cut-off value of 1.52 * 10(-3) mm(2)/s for ADChigh) leading to a sensitivity, specificity and accuracy of 98%, 82% and 94%, respectively. In the validation group these results were confirmed. CONCLUSION: Visual DCE-MR-based curve interpretation can be used for initial differentiation of benign from malignant SPL, while additional quantitative DWI-based interpretation can further improve the specificity. KEY POINTS: * Magnetic resonance imaging is increasingly being used to help differentiate lung lesions. * Solitary pulmonary lesions (SPL) are accurately characterised by combining DCE-MRI and DWI. * Visual DCE-MRI assessment facilitates the diagnostic throughput in patients with SPL. * DWI provides additional information in inconclusive DCE-MRI (type B pattern). PMID- 24173598 TI - Comparative kinetics of damage to the plasma and mitochondrial membranes by intra cellularly synthesized and externally-provided photosensitizers using multi-color FACS. AB - Photodynamic therapy (PDT) of cancer involves inflicting lethal damage to the cells of malignant tumors, primarily by singlet oxygen that is generated following light-absorption in a photosensitizer molecule. Dysfunction of cells is manifested in many ways, including peroxidation of cellular components, membrane rupture, depolarization of electric potentials, termination of mitochondrial activity, onset of apoptosis and necrosis and eventually cell lysis. These events do not necessarily occur in linear fashion and different types of damage to cell components occur, most probably, in parallel. In this report we measured the relative rates of damage to two cellular membranes: the plasma membrane and the mitochondrial membrane. We employed photosensitizers of diverse hydrophobicities and used different incubation procedures, which lead to their different intra cellular localizations. We monitored the damage that was inflicted on these membranes, by employing optical probes of membrane integrity, in a multi-color FACS experiment. The potentiometric indicator JC-1 monitored the electric cross membrane potential of the mitochondria and the fluorometric indicator Draq7 monitored the rupture of the plasma membrane. We show that the electric depolarization of the mitochondrial membrane and the damage to the enveloping plasma membrane proceed with different kinetics that reflect the molecular character and intracellular location of the sensitizer: PpIX that is synthesized in the cells from ALA causes rapid mitochondrial damage and very slow damage to the plasma membrane, while externally added PpIX has an opposite effect. The hydrophilic sensitizer HypS4 can be taken up by the cells by different incubation conditions, and these affect its intracellular location, and as a consequence either the plasma membrane or the mitochondria is damaged first. A similar correlation was found for additional extracellularly-provided photosensitizers HP and PpIX. PMID- 24173599 TI - When depression doesn't lead with depression. PMID- 24173600 TI - Correctional services and prison chaplaincy in Australia: an exploratory study. AB - This paper summarizes an exploratory study undertaken to consider the work of Australian chaplaincy personnel ministering to prisoners within correctional facilities. This qualitative research was not concerned with specific correctional institutions per se, but predominantly about the perspectives of chaplains concerning their professional contribution and issues they experienced while trying to provide pastoral care to prisoners. Data from a single-focus group indicated that prison chaplains were striving to fulfill religious and spiritual duties according to national and international standards for the treatment of prisoners. Given various frustrations identified by participants, that either impeded or thwarted their professional role as chaplains, a number of improvements were subsequently identified in order to develop the efficiency and effectiveness of chaplaincy and thus maximize the benefits of pastoral care to prisoners. Implications of this exploratory study relate not only to prison chaplaincy but also to ecclesiastical organizations, correctional facilities, governments and the need of support for further research to be conducted. PMID- 24173601 TI - A faith-based community partnership to address HIV/AIDS in the southern United States: implementation, challenges, and lessons learned. AB - Though race and region are not by themselves risk factors for HIV infection, regional and racial disparities exist in the burden of HIV/AIDS in the US. Specifically, African Americans in the southern US appear to bear the brunt of this burden due to a complex set of upstream factors like structural and cultural influences that do not facilitate HIV/AIDS awareness, HIV testing, or sexual risk reduction techniques while perpetuating HIV/AIDS-related stigma. Strategies proposed to mitigate the burden among this population have included establishing partnerships and collaborations with non-traditional entities like African American churches and other faith-based organizations. Though efforts to partner with the African American church are not necessarily novel, most of these efforts do not present a model that focuses on building the capacity of the African American church to address these upstream factors and sustain these interventions. This article will describe Project Fostering AIDS Initiatives That Heal (F.A.I.T.H), a faith-based model for successfully developing, implementing, and sustaining locally developed HIV/AIDS prevention interventions in African American churches in South Carolina. This was achieved by engaging the faith community and the provision of technical assistance, grant funding and training for project personnel. Elements of success, challenges, and lessons learned during this process will also be discussed. PMID- 24173602 TI - Should my provider pray with me? Perspectives of urban adolescents with asthma on addressing religious and spiritual issues in hypothetical clinical settings. AB - This qualitative study examined the preferences of urban adolescents with asthma for including religious/spiritual (R/S) inquiry in a variety of hypothetical clinical encounters. Twenty-one urban adolescents (M(age) = 15.6 years, 52 % female, 81 % African American) with asthma participated in a semi-structured interview. Interviews were transcribed and underwent a thematic analysis. R/S preferences were contextual rather than personal, driven by: (1) acuity of the hypothetical clinical context; (2) nature of the patient-provider relationship; and (3) level of R/S intervention/inquiry. Most adolescents welcomed prayer if near death, but did not see the relevance of R/S in a routine office visit. PMID- 24173603 TI - Quantitative in situ TEM tensile fatigue testing on nanocrystalline metallic ultrathin films. AB - A unique technique to perform quantitative in situ transmission electron microscopy (TEM) fatigue testing on ultrathin films and nanomaterials is demonstrated. The technique relies on a microelectromechanical system (MEMS) device to actuate a nanospecimen and measure its mechanical response. Compared to previously demonstrated MEMS-based in situ TEM techniques, the technique takes advantage of two identical capacitive sensors on each side of the specimen to measure electronically elongation (with nm resolution) and applied force (with MUN resolution). Monotonic and fatigue tests were performed on nanocrystalline gold ultrathin film specimens that were manipulated and fixed onto the MEMS device without the use of a focused ion-beam microscope (and therefore, importantly, without any associated surface damage). The major advantage of the technique is its capability to use TEM imaging solely for high magnification microstructural observations while the MEMS device provides continuous tracking of the material's response, thereby expanding the capabilities of MEMS-based techniques towards more complex in situ TEM nanomechanical tests, such as fatigue tests. PMID- 24173604 TI - Investigating the rheological properties of native plant latex. AB - Plant latex, the source of natural rubber, has been of interest to mankind for millennia, with much of the research on its rheological (flow) properties focused towards industrial application. However, little is known regarding the rheology of the native material as produced by the plant, a key factor in determining latex's biological functions. In this study, we outline a method for rheological comparison between native latices that requires a minimum of preparatory steps. Our approach provides quantitative insights into the coagulation mechanisms of Euphorbia and Ficus latex allowing interpretation within a comparative evolutionary framework. Our findings reveal that in laboratory conditions both latices behave like non-Newtonian materials with the coagulation of Euphorbia latex being mediated by a slow evaporative process (more than 60 min), whereas Ficus appears to use additional biochemical components to increase the rate of coagulation (more than 30 min). Based on these results, we propose two different primary defensive roles for latex in these plants: the delivery of anti-herbivory compounds (Euphorbia) and rapid wound healing (Ficus). PMID- 24173605 TI - Thermal decomposition of carboxylate ionic liquids: trends and mechanisms. AB - The thermal stability of a series of dialkylimidazolium carboxylate ionic liquids has been investigated using a broad range of experimental and computational techniques. Ionic liquids incorporating fluoroalkyl carboxylate anions were found to have profoundly differing thermal stabilities and decomposition mechanisms compared with their non-fluorinated analogues. 1-Ethyl-3-methylimidazolium acetate was observed to largely decompose via an S(N)2 nucleophilic substitution reaction when under inert gas conditions, predominantly at the imidazolium methyl substituent. The Arrhenius equations for thermal decomposition of 1-ethyl-3 methylimidazolium acetate, and the C(2)-methylated analogue 1-ethyl-2,3 dimethylimidazolium acetate, were determined from isothermal Thermogravimetric Analysis experiments. The low thermal stability of 1-ethyl-3-methylimidazolium acetate has important implications for biomass experiments employing this ionic liquid. For these two ionic liquids, ion pair and transition state structures were optimised using Density Functional Theory. The activation barriers for the S(N)2 nucleophilic substitution mechanisms are in good agreement with the experimentally determined values. PMID- 24173606 TI - Prophylactic oxytocin for the third stage of labour to prevent postpartum haemorrhage. AB - BACKGROUND: Active management of the third stage of labour has been shown to reduce the risk of postpartum haemorrhage (PPH) greater than 1000 mL. One aspect of the active management protocol is the administration of prophylactic uterotonics, however, the type of uterotonic, dose, and route of administration vary across the globe and may have an impact on maternal outcomes. OBJECTIVES: To determine the effectiveness of prophylactic oxytocin at any dose to prevent PPH and other adverse maternal outcomes related to the third stage of labour. SEARCH METHODS: We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (31 May 2013). SELECTION CRITERIA: Randomised or quasi-randomised controlled trials including pregnant women anticipating a vaginal delivery where prophylactic oxytocin was given during management of the third stage of labour. The primary outcomes were blood loss > 500 mL and the use of therapeutic uterotonics. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed trials for inclusion, assessed trial quality and extracted data. Data were checked for accuracy. MAIN RESULTS: This updated review included 20 trials (involving 10,806 women). Prophylactic oxytocin versus placebo Prophylactic oxytocin compared with placebo reduced the risk of PPH greater than 500 mL, (risk ratio (RR) 0.53; 95% confidence interval (CI) 0.38 to 0.74; six trials, 4203 women; T2 = 0.11, I2 = 78%) and the need for therapeutic uterotonics (RR 0.56; 95% CI 0.36 to 0.87, four trials, 3174 women; T2 = 0.10, I2 = 58%). The benefit of prophylactic oxytocin to prevent PPH greater than 500 mL was seen in all subgroups. Decreased use of therapeutic uterotonics was only seen in the following subgroups: randomised trials with low risk of bias (RR 0.58; 95% CI 0.36 to 0.92; three trials, 3122 women; T2 = 0.11, I2 = 69%); trials that performed active management of the third stage (RR 0.39; 95% CI 0.26 to 0.58; one trial, 1901 women; heterogeneity not applicable); trials that delivered oxytocin as an IV bolus (RR 0.57; 95% CI 0.39 to 0.82; one trial, 1000 women; heterogeneity not applicable); and in trials that gave oxytocin at a dose of 10 IU (RR 0.48; 95% CI 0.33 to 0.68; two trials, 2901 women; T2 = 0.02, I2 = 27%). Prophylactic oxytocin versus ergot alkaloids. Prophylactic oxytocin was superior to ergot alkaloids in preventing PPH greater than 500 mL (RR 0.76; 95% CI 0.61 to 0.94; five trials, 2226 women; T2 = 0.00, I2 = 0%). The benefit of oxytocin over ergot alkaloids to prevent PPH greater than 500 mL only persisted in the subgroups of quasi-randomised trials (RR 0.71, 95% CI 0.53 to 0.96; three trials, 1402 women; T2 = 0.00, I2 = 0%) and in trials that performed active management of the third stage of labour (RR 0.58; 95% CI 0.38 to 0.89; two trials, 943 women; T2 = 0.00, I2 = 0%). Use of prophylactic oxytocin was associated with fewer side effects compared with use of ergot alkaloids; including decreased nausea between delivery of the baby and discharge from the labour ward (RR 0.18; 95% CI 0.06 to 0.53; three trials, 1091 women; T2 = 0.41, I2 = 41%) and vomiting between delivery of the baby and discharge from the labour ward (RR 0.07; 95% CI 0.02 to 0.25; three trials, 1091 women; T2 = 0.45, I2 = 30%). Prophylactic oxytocin + ergometrine versus ergot alkaloids: There was no benefit seen in the combination of oxytocin and ergometrine versus ergometrine alone in preventing PPH greater than 500 mL (RR 0.90; 95% CI 0.34 to 2.41; five trials, 2891 women; T2 = 0.89, I2 = 80%). The use of oxytocin and ergometrine was associated with increased mean blood loss (MD 61.0 mL; 95% CI 6.00 to 116.00 mL; fixed-effect analysis; one trial, 34 women; heterogeneity not applicable).In all three comparisons, there was no difference in mean length of the third stage or need for manual removal of the placenta between treatment arms. AUTHORS' CONCLUSIONS: Prophylactic oxytocin at any dose decreases both PPH greater than 500 mL and the need for therapeutic uterotonics compared to placebo alone. Taking into account the subgroup analyses from both primary outcomes, to achieve maximal benefit providers may opt to implement a practice of giving prophylactic oxytocin as part of the active management of the third stage of labour at a dose of 10 IU given as an IV bolus. If IV delivery is not possible, IM delivery may be used as this route of delivery did show a benefit to prevent PPH greater than 500 mL and there was a trend to decrease the need for therapeutic uterotonics, albeit not statistically significant.Prophylactic oxytocin was superior to ergot alkaloids in preventing PPH greater than 500 mL; however, in subgroup analysis this benefit did not persist when only randomised trials with low risk of methodologic bias were analysed. Based on this, there is limited high-quality evidence supporting a benefit of prophylactic oxytocin over ergot alkaloids. However, the use of prophylactic oxytocin was associated with fewer side effects, specifically nausea and vomiting, making oxytocin the more desirable option for routine use to prevent PPH.There is no evidence of benefit when adding oxytocin to ergometrine compared to ergot alkaloids alone, and there may even be increased harm as one study showed evidence that using the combination was associated with increased mean blood loss compared to ergot alkaloids alone.Importantly, there is no evidence to suggest that prophylactic oxytocin increases the risk of retained placenta when compared to placebo or ergot alkaloids.More placebo-controlled, randomised, and double-blinded trials are needed to improve the quality of data used to evaluate the effective dose, timing, and route of administration of prophylactic oxytocin to prevent PPH. In addition, more trials are needed especially, but not only, in low- and middle-income countries to evaluate these interventions in the birth centres that shoulder the majority of the burden of PPH in order to improve maternal morbidity and mortality worldwide. PMID- 24173607 TI - [Lupoid rosacea as a special form of rosacea: review of pathogenesis and therapeutic options]. AB - Lupoid or granulomatous rosacea is classified as a special form of rosacea which along with the typical rosacea symptoms features monomorphic yellow-brown and red papules and nodules on the cheeks and periorificial areas. Histology shows noncaseating epithelioid cell granulomas with surrounding mononuclear cell infiltrates. It is difficult to treat. Currently, the only officially approved systemic treatment is tetracycline. However, there is a broad experience with off label use of isotretinoin (10-20 mg daily). We describe a patient with an excellent response to 20 mg isotretinoin daily. PMID- 24173608 TI - 18F-FDG uptake on PET is a predictive marker of thymidylate synthase expression in patients with thoracic neoplasms. AB - The aim of this study was to investigate the relationship between the expression levels of thymidylate synthase (TS) and 2-[18F]-fluoro-2-deoxy-D-glucose (18F FDG) uptake on positron emission tomography (PET) in various thoracic neoplasms. In total, 392 patients [non-small cell lung cancer (NSCLC) (n=140), malignant pleural mesothelioma (MPM) (n=21), pulmonary metastatic tumors (PMT) (n=148), thymic epithelial tumors (n=49) and pulmonary neuroendocrine (NE) tumor (n=34)] who underwent 18F-FDG PET before treatment were included in this study. Tumor sections were stained using immunohistochemistry for determination of TS, orotate phosphoribosyltransferase (OPRT), dihydropyrimidine dehydrogenase (DPD), vascular endothelial growth factor (VEGF), microvessel density (MVD), CD34 and p53. The expression of TS in thoracic neoplasms had a positivity of 58% (230/392), and the positive rates of TS expression in NSCLC, PMT, thymic epithelial tumor, NE tumor and MPM samples were 56, 57, 57, 85 and 47%, respectively. The positivity of TS expression was significantly higher in NE tumors compared to that in other thoracic tumors. A statistically significant correlation between TS expression and 18F-FDG uptake was observed in thoracic neoplasms, in particular primary lung adenocarcinomas, high-grade NE tumors, thymomas and MPMs. Moreover, TS expression was closely associated with angiogenesis, DPD, OPRT and p53. Our results indicated that SUV(max) by 18F-FDG uptake may be an alternative biomarker for predicting TS expression in patients with primary lung adenocarcinoma, high-grade NE tumor, thymoma and MPM. PMID- 24173609 TI - The most characteristic lesions and radiologic signs of Crohn disease of the small bowel: air enteroclysis, MDCT, endoscopy, and pathology. AB - This pictorial essay describes the most characteristic lesions and radiologic signs of Crohn disease of the small bowel: nodular lymphoid hyperplasia, abnormal mucosal folds, villous pattern, aphthous ulcerations, linear ulcerations, cobblestone pattern, string sign, target sign, comb sign, creeping fat, sinus tracts, fistulas, and abscesses. Each description includes the definition, a correlation with the pathologic findings, an explanation of the possible physiopathologic mechanism, sample radiologic images with air enteroclysis or MDCT, the correspondence with the endoscopic findings when possible, and a list of differential diagnoses. PMID- 24173610 TI - Optimised formation of blue Maillard reaction products of xylose and glycine model systems and associated antioxidant activity. AB - BACKGROUND: A blue colour can be formed in the xylose (Xyl) and glycine (Gly) Maillard reaction (MR) model system. However, there are fewer studies on the reaction conditions for the blue Maillard reaction products (MRPs). The objective of this study is to investigate characteristic colour formation and antioxidant activities in four different MR model systems and to determine the optimum reaction conditions for the blue colour formation in a Xyl-Gly MR model system, using the random centroid optimisation program. RESULTS: The blue colour with an absorbance peak at 630 nm appeared before browning in the Xyl-Gly MR model system, while no blue colour formation but only browning was observed in the xylose-alanine, xylose-aspartic acid and glucose-glycine MR model systems. The Xyl-Gly MR model system also showed higher antioxidant activity than the other three model systems. The optimum conditions for blue colour formation were as follows: xylose and glycine ratio 1:0.16 (M:M), 0.20 mol L-1 NaHCO3, 406.1 mL L-1 ethanol, initial pH 8.63, 33.7 degrees C for 22.06 h, which gave a much brighter blue colour and a higher peak at 630 nm. CONCLUSION: A characteristic blue colour could be formed in the Xyl-Gly MR model system and the optimum conditions for the blue colour formation were proposed and confirmed. PMID- 24173611 TI - Chronic daily headache in the elderly. AB - Disabling headache disorders are ubiquitous in all age groups, including the elderly, yet they are under-recognized, underdiagnosed and undertreated worldwide. Surveys and clinic-based research reports on headache disorders in elderly populations are extremely limited in number. Chronic daily headache (CDH) is an important and growing subtype of primary headache disorders, associated with increased burden and disruption to quality of life. CDH can be divided into two forms, based on headache duration. Common forms of primary headache disorders of long duration (>4 hours) were comprehensively defined in the third edition of the International Classification of Headache Disorders (ICHD-3 beta). These include chronic migraine, chronic tension-type headache, new daily persistent headache, and hemicrania continua. Rarer short-duration (<4 hours) forms of CDH are chronic cluster headache, chronic paroxysmal hemicrania, SUNCT, and hypnic headache. Accurate diagnosis, management, and relief of the burden of CDH in the elderly population present numerous unique challenges as the "aging world" continues to grow. In order to implement appropriate coping strategies for the elderly, it is essential to establish the correct diagnosis at each step and to exercise caution in differentiating from secondary causes, while always taking into consideration the unique needs and limitations of the aged body. PMID- 24173612 TI - Altitude headache. AB - High altitude headache (HAH) has been defined by the International Headache Society as a headache that appears within 24 hours after ascent to 2,500 m or higher [1**]. The headache can appear in isolation or as part of acute mountain sickness (AMS), which has more dramatic symptoms than the headache alone. If symptoms are ignored, more serious conditions such as high altitude cerebral edema (HACE), high altitude pulmonary edema (HAPE), or even death may ensue. While there is no definitive understanding of the underlying pathophysiologic mechanism, it is speculated that HAH occurs from the combination of hypoxemia induced intracranial vasodilation and subsequent cerebral edema. There are a number of preventive measures that can be adopted prior to ascending, including acclimatization and various medications. A variety of pharmacological interventions are also available to clinicians to treat this extremely widespread condition. PMID- 24173613 TI - Theoretical investigation on the mechanism and kinetics of the ring-opening polymerization of epsilon-caprolactone initiated by tin(II) alkoxides. AB - A theoretical investigation of the ring-opening polymerization (ROP) mechanism of epsilon-caprolactone (CL) with tin(II) alkoxide, Sn(OR)2 initiators (R = n-C4H9, i-C4H9, t-C4H9, n-C6H13, n-C8H17) was studied. The density functional theory at B3LYP level was used to perform the modeled reactions. A coordination-insertion mechanism was found to occur via two transition states. Starting with a coordination of CL onto tin center led to a nucleophilic addition of the carbonyl group of CL, followed by the exchange of alkoxide ligand. The CL ring opening was completed through classical acyl-oxygen bond cleavage. The reaction barrier heights of epsilon-caprolactone with different initiators were calculated using potential energy profiles. The reaction of epsilon-caprolactone with Sn(OR)2 having R = n-C4H9 has the least value of barrier height compared to other reactions. The rate constants for each reaction were calculated using the transition state theory with TheRATE program. The rate constants are in good agreement with available experimental data. PMID- 24173614 TI - DMS triggers apoptosis associated with the inhibition of SPHK1/NF-kappaB activation and increase in intracellular Ca2+ concentration in human cancer cells. AB - N,N-Dimethyl-D-erythro-sphingosine (DMS) is known to induce cell apoptosis by specifically inhibiting sphingosine kinase 1 (SPHK1) and modulating the activity of cellular ceramide levels. The present study investigated the effects and the mechanism(s) of action of DMS in human lung cancer cells. We found that DMS dose dependently suppressed cell proliferation and induced cell apoptosis in the human lung cancer cell line, A549. Mechanistically, treatment with DMS suppressed the activation of SPHK1 and nuclear factor-kappaB (NF-kappaB) p65, but increased intracellular [Ca2+]i in A549 cells. This study demonstrates that DMS triggers the apoptosis of human lung cancer cells through the modulation of SPHK1, NF kappaB and calcium signaling. These molecules may represent targets for anticancer drug design. PMID- 24173615 TI - Generalized anxiety disorder and social anxiety disorder in youth: are they distinguishable? AB - The current study was designed to examine diagnostic validity of social anxiety disorder (SOC) and generalized anxiety disorder (GAD) in youth, and implications of comorbidity of the disorders for nosology. Children (n = 130) with SOC, GAD, or both disorders (COMORBID) and their parents were administered diagnostic interviews and self-report measures. Confirmatory factor analyses (CFAs) and ANOVAs were performed for the three groups (SOC, GAD, COMORBID). Second-order CFAs for both parent and child informants suggested that SOC and GAD are two specific facets of a general anxiety factor. ANOVA analyses revealed the two pure groups differed only on parent-reported SOC symptoms and GAD worry symptoms, as hypothesized. COMORBID children had higher scores than SOC group on parent reported GAD symptoms, worry, and behavioral inhibition, and COMORBID children had higher scores than GAD group on parent-reported SOC symptoms and social anxiety. Results may have implications for assessment of GAD and SOC. PMID- 24173616 TI - Anatomical and electrophysiological changes in striatal TH interneurons after loss of the nigrostriatal dopaminergic pathway. AB - Using transgenic mice that express enhanced green fluorescent protein (EGFP) under the control of the tyrosine hydroxylase (TH) promoter, we have previously shown that there are approximately 3,000 striatal EGFP-TH interneurons per hemisphere in mice. Here, we report that striatal TH-EGFP interneurons exhibit a small, transient but significant increase in number after unilateral destruction of the nigrostriatal dopaminergic pathway. The increase in cell number is accompanied by electrophysiological and morphological changes. The intrinsic electrophysiological properties of EGFP-TH interneurons ipsilateral to 6-OHDA lesion were similar to those originally reported in intact mice except for a significant reduction in the duration of a characteristic depolarization induced plateau potential. There was a significant change in the distribution of the four previously described electrophysiologically distinct subtypes of striatal TH interneurons. There was a concomitant increase in the frequency of both spontaneous excitatory and inhibitory post-synaptic currents, while their amplitudes did not change. Nigrostriatal lesions did not affect somatic size or dendritic length or branching, but resulted in an increase in the density of proximal dendritic spines and spine-like appendages in EGFP-TH interneurons. The changes indicate that electrophysiology properties and morphology of striatal EGFP-TH interneurons depend on endogenous levels of dopamine arising from the nigrostriatal pathway. Furthermore, these changes may serve to help compensate for the changes in activity of spiny projection neurons that occur following loss of the nigrostriatal innervation in experimental or in early idiopathic Parkinson's disease by increasing feedforward GABAergic inhibition exerted by these interneurons. PMID- 24173617 TI - Retrograde transneuronal degeneration in the retina and lateral geniculate nucleus of the V1-lesioned marmoset monkey. AB - Retrograde transneuronal degeneration (RTD) of retinal ganglion cells and dorsal lateral geniculate (LGN) neurons are well described following a lesion of the primary visual cortex (V1) in both Old World monkeys and humans. Based on previous studies of New World monkeys and prosimians, it was suggested that these species displayed no RTD following a lesion of V1. In this study of the New World marmoset monkey, 1 year after a unilateral V1 lesion either in adults or at 14 days after birth, we observed ~20 % ganglion cell (GC) loss in adult but ~70 % in infants. This finding is similar to the RTD previously described for Old World Macaca monkeys. Furthermore, in infants we find a similar amount of RTD at 3 weeks and 1 year following lesion, demonstrating that RTD is very rapid in neonates. This highlights the importance of trying to prevent the rapid onset of RTD following a lesion of V1 in early life as a strategy for improved functional recovery. Despite differences in GC loss, there was little difference between LGN degeneration in infant versus adult lesions. A wedge on the horizontal meridian corresponding to the LGN foveal representation revealed extensive neuronal loss. Retinal afferent input was labeled by cholera toxin B subunit. Input to the degenerated parvocellular layers was difficult to detect, while input to magnocellular and koniocellular layers was reduced but still apparent. Our demonstration that the New World marmoset monkey shares many of the features of neuroplasticity with Old World Macaca monkeys and humans emphasizes the opportunity and benefit of marmosets as models of visual cortical injury. PMID- 24173619 TI - Fyn kinase regulates type II PtdIns 4-kinases in RBL 2H3 cells. AB - Type II phosphatidylinositol 4-kinases are implicated in FcepsilonRI-mediated signaling cascades leading to release of inflammatory molecules. Cross-linking of FcepsilonRI on RBL 2H3 cells results in protein tyrosine phosphorylation and activation of type II PtdIns 4-kinase activity. Protein tyrosine kinase(s) that phosphorylate type II PtdIns 4-kinase(s) in RBL 2H3 cells remains elusive and is being addressed in this manuscript. Anti-Fyn kinase antibodies co immunoprecipitated type II PtdIns 4-kinase activity from FcepsilonRI cross-linked RBL 2H3 cells. In reciprocal assays, His-tagged types II PtdIns 4-kinases were shown to pull down Fyn kinase. Further, anti-Fyn immunoprecipitates were shown to phosphorylate type II PtdIns 4-kinase alpha and beta in in vitro assays. Pull down studies with GST-Fyn-SH2 and GST-Fyn-SH3 domains showed that type II PtdIns 4-kinases associate with Fyn-SH2 domain. Knockdown of Fyn kinase in RBL 2H3 cells abrogated activation of type II PtdIns 4-kinase activity in response to FcepsilonRI cross-linking and type II PtdIns 4-kinase activity in anti phosphotyrosine immunoprecipitates. Knockdown of Fyn kinase was also strongly correlated with a reduction in beta-hexosaminidase release in response to FcepsilonRI cross-linking. These results suggest that type II PtdIns 4-kinases act downstream of Fyn kinase in FcepsilonRI signaling cascades and are regulated by Fyn kinase. PMID- 24173618 TI - Addressing risks to advance mental health research. AB - IMPORTANCE: Risk communication and management are essential to the ethical conduct of research, yet addressing risks may be time consuming for investigators and institutional review boards may reject study designs that seem too risky. This can discourage needed research, particularly in higher-risk protocols or those enrolling potentially vulnerable individuals, such as those with some level of suicidality. Improved mechanisms for addressing research risks may facilitate much needed psychiatric research. OBJECTIVE: To provide mental health researchers with practical approaches to (1) identify and define various intrinsic research risks, (2) communicate these risks to others (eg, potential participants, regulatory bodies, and society), (3) manage these risks during the course of a study, and (4) justify the risks. EVIDENCE REVIEW: As part of a National Institute of Mental Health-funded scientific meeting series, a public conference and a closed-session expert panel meeting were held on managing and disclosing risks in mental health clinical trials. The expert panel reviewed the literature with a focus on empirical studies and developed recommendations for best practices and further research on managing and disclosing risks in mental health clinical trials. No institutional review board-review was required because there were no human subjects. FINDINGS: Challenges, current data, practical strategies, and topics for future research are addressed for each of 4 key areas pertaining to management and disclosure of risks in clinical trials: identifying and defining risks, communicating risks, managing risks during studies, and justifying research risks. CONCLUSIONS AND RELEVANCE: Empirical data on risk communication, managing risks, and the benefits of research can support the ethical conduct of mental health research and may help investigators better conceptualize and confront risks and to gain institutional review board-approval. PMID- 24173621 TI - Plasmonic interferometric sensor arrays for high-performance label-free biomolecular detection. AB - A plasmonic interferometric biosensor that consists of arrays of circular aperture-groove nanostructures patterned on a gold film for phase-sensitive biomolecular detection is demonstrated. The phase and amplitude of interfering surface plasmon polaritons (SPPs) in the proposed device can be effectively engineered by structural tuning, providing flexible and efficient control over the plasmon line shape observed through SPP interference. Spectral fringes with high contrast, narrow linewidth, and large amplitude have been experimentally measured and permit the sensitive detection of protein surface coverage as low as 0.4 pg mm(-2). This sensor resolution compares favorably with commercial prism based surface plasmon resonance systems (0.1 pg mm(-2)) but is achieved here using a significantly simpler collinear transmission geometry, a miniaturized sensor footprint, and a low-cost compact spectrometer. Furthermore, we also demonstrate superior sensor performance using the intensity interrogation method, which can be combined with CCD imaging to upscale our platform to high-throughput array sensing. A novel low-background interferometric sensing scheme yields a high sensing figure of merit (FOM*) of 146 in the visible region, surpassing that of previous plasmonic biosensors and facilitating ultrasensitive high-throughput detection. PMID- 24173620 TI - Troxerutin suppresses lipid abnormalities in the heart of high-fat-high-fructose diet-fed mice. AB - The reversal effect of troxerutin (TX) on obesity, insulin resistance, lipid accumulation, oxidative damage, and hypertension induced in the high-fat-high fructose diet (HFFD)-fed mice model of metabolic syndrome was investigated. Adult male Mus musculus mice of body weight 25-30 g were fed either control diet or HFFD. Each group was divided into two and treated or untreated with TX (150 mg/kg bw, p.o.) from the 16th day. Assays were done in plasma and heart after 30 and 60 days of the experimental period. Significant increase in the levels of glucose and insulin, blood pressure (BP), and oxidative stress were observed after 30 days of HFFD feeding as compared to control. Animals fed HFFD for 60 days developed more severe changes in the above parameters compared to those fed for 30 days. Hearts of HFFD-fed mice registered downregulation of peroxisome proliferator-activated receptor-alpha and peroxisome proliferator-activated receptor gamma coactivator-1alpha, carnitine palmitoyl transferse-1b and AMP activated protein kinase; and upregulation of cluster of differentiation 36, fatty acid-binding protein-1, and sterol regulatory element-binding protein-1c after 60 days. TX administration restricted obesity (as seen by Lee's index); improved whole body insulin sensitivity; reduced BP, lipid accumulation, and oxidative damage; upregulated fatty acid (FA) oxidation; and downregulated FA transport and lipogenesis. Histology of heart revealed that TX diminishes inflammatory cell infiltration and fatty degeneration in HFFD-fed mice. The antioxidant property of TX and its ability to influence lipid regulatory genes could be the underlying mechanisms for its beneficial effects. PMID- 24173622 TI - The challenges of clinical trials in fragile X syndrome. AB - RATIONALE: Advances in understanding the underlying mechanisms of conditions such as fragile X syndrome (FXS) and autism spectrum disorders have revealed heterogeneous populations. Recent trials of novel FXS therapies have highlighted several challenges including subpopulations with possibly differential therapeutic responses, the lack of specific outcome measures capturing the full range of improvements of patients with FXS, and a lack of biomarkers that can track whether a specific mechanism is responsive to a new drug and whether the response correlates with clinical improvement. OBJECTIVES: We review the phenotypic heterogeneity of FXS and the implications for clinical research in FXS and other neurodevelopmental disorders. RESULTS: Residual levels of fragile X mental retardation protein (FMRP) expression explain in part the heterogeneity in the FXS phenotype; studies indicate a correlation with both cognitive and behavioral deficits. However, this does not fully explain the extent of phenotypic variance observed or the variability of drug response. Post hoc analyses of studies involving the selective mGluR5 antagonist mavoglurant and the GABAB agonist arbaclofen have uncovered significant therapeutic responses following patient stratification according to FMR1 promoter methylation patterns or baseline severity of social withdrawal, respectively. Future studies designed to quantify disease modification will need to develop new strategies to track changes effectively over time and in multiple symptom domains. CONCLUSION: Appropriate selection of patients and outcome measures is central to optimizing future clinical investigations of these complex disorders. PMID- 24173623 TI - A randomized, placebo-controlled, double-blind trial of sertraline for postpartum depression. AB - RATIONALE: Postpartum depression (PMD) occurs in roughly 10 % of postpartum women and negatively impacts the mother and her offspring, but there are few placebo controlled studies of antidepressant treatment in this population. OBJECTIVE: The objective was this study is to compare the selective serotonin reuptake inhibitor (SSRI) sertraline to placebo for treating PMD. METHODS: This was a single-center, 6-week, randomized double-blind placebo-controlled trial of sertraline with a 1 week placebo lead-in. The participants (n = 38) were women with depression onset within 3 months of delivery; a subset (n = 27) met strict DSM-IV criteria for PMD (onset within 4 weeks of delivery). The participants were prescribed sertraline 50 mg or placebo daily to a maximum of 200 mg/day. Primary outcome variables were the Hamilton Depression Rating Scale (HAM-D) and Clinical Global Impressions (CGI) scores, which were used to determine the rates of response and remission. RESULTS: Sertraline produced a significantly greater response rate (59 %) than placebo (26 %) and a more than twofold increased remission rate (53 % vs. 21 %). Mixed models did not reveal significant group by time effects, although in the subset of women who met the DSM-IV criteria, there was a statistically significant group by time effect for the HAM-D, Hamilton Anxiety Rating Scale (HAM-A), and CGI. CONCLUSIONS: Women with PMD are more likely to have a remission of their depression with sertraline treatment, a finding that is more pronounced in women who have onset of depression within 4 weeks of childbirth. These data support the continued use of 4 weeks for the DSM-5 postpartum onset specifier for major depressive disorder. PMID- 24173624 TI - Dose-dependent effects of wheel running on cocaine-seeking and prefrontal cortex Bdnf exon IV expression in rats. AB - RATIONALE: Physical activity, and specifically exercise, has shown promise as an intervention for drug addiction; however, the exercise conditions that produce the most efficacious response, as well as its underlying mechanism, are unknown. OBJECTIVE: In this study, we examined the dose-dependent effects of wheel running, an animal model of exercise, during abstinence on subsequent cocaine seeking and associated changes in prefrontal cortex (PFC) brain-derived neurotrophic factor (Bdnf) exon IV expression, a marker of epigenetic regulation implicated in cocaine relapse and known to be regulated by exercise. METHODS: Cocaine-seeking was assessed under a within-session extinction/cue-induced reinstatement procedure following extended access cocaine or saline self administration (24-h/day, 4 discrete trials/h, 10 days, 1.5 mg/kg/infusion) and a 14-day abstinence period. During abstinence, rats had either locked or unlocked running wheel access for 1, 2, or 6 h/day. Bdnf exon IV expression was assessed using quantitative real-time polymerase chain reaction. RESULTS: Cocaine-seeking was highest under the locked wheel condition, and wheel running dose dependently attenuated this effect. Cocaine increased Bdnf exon IV expression, and wheel running dose dependently attenuated this increase, with complete blockade in rats given 6-h/day access. Notably, the efficacy of exercise was inversely associated with Bdnf exon IV expression, and both its efficacy and its effects on Bdnf exon IV expression were mimicked by treatment during abstinence with sodium butyrate, a histone deacetylase inhibitor that, like exercise, modulates gene transcription, including Bdnf exon IV expression. CONCLUSION: Taken together, these results indicate that the efficacy of exercise is dose dependent and likely mediated through epigenetic regulation of PFC Bdnf. PMID- 24173626 TI - More efficient induction of antitumor T cell immunity by exosomes from CD40L gene modified lung tumor cells. AB - The incidence of lung cancer increases annually. However, the effects of the present methods for the treatment of lung cancer are extremely poor. It has been reported that exosomes from heat-stressed 3LL Lewis lung tumor cells effectively elicit systemic antitumor immunity. CD40 signaling is critical in the activation of dendritic cells (DCs), which are important in the induction of antitumor immunity. In the present study, exosomes from CD40 ligand gene-modified 3LL tumor cells (CD40L-EXO) were identified to be more immunogenic compared with control EXO and lac Z-EXO. CD40L-EXO induced a more mature phenotype of the DCs and promoted them to secrete high levels of interleukin-12. CD40L-EXO-treated DCs induced a greater proliferation of allogeneic T cells in the mixed lymphocyte reaction. Moreover, CD40L-EXO induced robust tumor antigen-specific CD4+ T cell proliferation ex vivo. CD40L-EXO were also extremely effective in the protective and therapeutic antitumor tests in vivo. These results indicate that CD40L-EXO may be used as an efficient vaccine for lung cancer immunotherapy. PMID- 24173625 TI - The role of ligand coordination on the cytotoxicity of cationic quantum dots in HeLa cells. AB - The effect of ligand structure on the cytotoxicity of cationic CdSe/ZnS quantum dots (QDs) was systematically investigated using mono- and bidentate ligands. Monothiol-functionalized QDs are more cytotoxic than dithiol-functionalized QDs. PMID- 24173628 TI - Improving mental health systems in Africa. PMID- 24173627 TI - Ablative efficiency of 532-nm laser vaporization compared to transurethral resection of the prostate: results from a prospective three-dimensional ultrasound volumetry study. AB - PURPOSE: To assess and compare postoperative prostate volume changes following 532-nm laser vaporization (LV) and transurethral resection of the prostate (TURP). To investigate whether differences in volume reduction are associated with differences in clinical outcome. METHODS: In this prospective, non randomized study, 184 consecutive patients undergoing 120 W LV (n = 98) or TURP (n = 86) were included. Transrectal three-dimensional ultrasound and planimetric volumetry of the prostate were performed preoperatively, after catheter removal, 6 weeks, 6 and 12 months. Additionally, clinical outcome parameters were recorded. Mann-Whitney U test and analysis of covariance were utilized for statistical analysis. RESULTS: Postoperatively, a significant prostate volume reduction was detectable in both groups. However, the relative volume reduction was lower following LV (18.4 vs. 34.7 %, p < 0.001). After 6 weeks, prostate volumes continued to decrease in both groups, yet differences between the groups were less pronounced. Nonetheless, the relative volume reduction remained significantly lower following LV (12 months 43.3 vs. 50.3 %, p < 0.001). All clinical outcome parameters improved significantly in both groups. However, the maximum flow rate (Q max) and prostate-specific antigen (PSA) reduction were significantly lower following LV. Subgroup analyses revealed significant differences only if the initial prostate volume was >40 ml. Re-operations were necessary in three patients following LV. CONCLUSIONS: The modest but significantly lower volume reduction following LV was associated with a lower PSA reduction, a lower Q max and more re-operations. Given the lack of long-term results after LV, our results are helpful for preoperative patient counseling. Patients with large prostates and no clear indication for the laser might not benefit from the procedure. PMID- 24173629 TI - Homemade heroin substitute causing hallucinations. PMID- 24173630 TI - Sodium valproate for the treatment of mania in a patient with Charcot-Marie-Tooth disease. PMID- 24173631 TI - The accuracy of interpreting key psychiatric terms by ad hoc interpreters at a South African psychiatric hospital. AB - OBJECTIVE: This study examined the competence and accuracy of ad hoc interpreters in interpreting key psychiatric terms at a South African psychiatric hospital METHODS: Nine individuals were asked to translate key psychiatric terms from English to Xhosa. These translations were then back-translated by independent translators, who do not have knowledge of psychiatric terminology. These back translations were then compared with the original English. RESULTS: It was clear that not all the participants were fully competent in English. None had formal training in interpreting or psychiatric terminology. Not all of the participants were familiar with the psychiatric concepts that clinicians use and they often made mistakes while interpreting. CONCLUSION: The competency levels of interpreters are unsatisfactory to ensure the optimal delivery of mental health care. It is clear that there is a need for trained interpreters in South Africa, as the continuous use of untrained interpreters compromises the effectiveness of mental health care and could lead to adverse health outcomes. PMID- 24173632 TI - Mild cognitive impairment and dementia in a heterogeneous elderly population: prevalence and risk profile. AB - OBJECTIVE: To describe the demographic, clinical and risk profile of Mild Cognitive Impairment and dementia in a sample of elderly South Africans within a residential setting. METHOD: One hundred and forty participants residing in a group of residential homes for the elderly were assessed by psychiatrists and assigned diagnoses of dementia or Mild Cognitive Impairment (MCI). Participants diagnosed with dementia were also offered haematological investigations and a CT scan of the brain. RESULTS: The sample consisted of 140 participants comprising 46.4% White, 29.3% Coloured, 20% Asian and 4.3% Black participants. There were 97 (69.3%) females and 106 (75.7%) participants had less than 12 years of education. Eleven (7.9%) dementia and 38 (27.1%) MCI cases were diagnosed. Increasing age was associated with cognitive impairment (MCI and dementia) (p=.020) but there was no association between gender and cognitive impairment (p=.165). MCI was significantly associated with a lower education level (p=.036) and no association was found between depression (current-p=.646; past-p=.719) and dementia or MCI. The presence of vascular risk factors (n=140) ranged from 66.4% (hypertension) to 14.3% (stroke). Subjective memory complaints were significantly associated with cognitive impairment (p=.001). Except for the use of the telephone (p=.225) and the television (p=.08), impairment in all domains of instrumental activities of daily living that were assessed were significantly associated with a dementia diagnosis. CONCLUSION: The study showed that cognitive impairment was associated with increasing age and low education levels. The presence of vascular risk factors places this population at risk for future cognitive decline. PMID- 24173633 TI - Post traumatic stress disorder and resilience in veterans who served in the South African border war. AB - OBJECTIVE: The psychological impact of the South African border war on veterans has received little or no attention. This study determined the prevalence of post traumatic stress disorder (PTSD), and extent of resilience among a cohort of veterans. METHOD: Of 1527 former students who matriculated from a Johannesburg high school from 1975 to 1988, only 109 were reachable for convenience and snowballing recruitment into this study. An anonymous, internet-based questionnaire was used to obtain information on demography, combat exposure, drug and alcohol use, traumatic events in later life, and recourse to medication and counselling. The Impact of Event Scale - Revised (IES-R) assessed for PTSD and the Connor Davidson Resilience Scale (CDRISC) measured resilience. Data were processed with STATA; version 11 statistical software package. Analysis included Chi square test and regression analysis. RESULTS: The response rate was 49.5% (n=54). The prevalence of PTSD was 33% and significantly associated with combat exposure (p=.012). Despite high prevalence of PTSD in those exposed to combat, 94% showed normal to above-normal level of resilience. CD-RISC scores showed no association with the IES-R. Only current cannabis use was significantly linked with PTSD (p=.044). CONCLUSION: Although the prevalence of PTSD found in this sample was higher than in comparable international studies, this cohort of former SA national servicemen, showed high levels of resilience. The current use of cannabis within the context of prior exposure to military national service or combat should prompt clinicians to screen for the presence of PTSD-associated symptoms. PMID- 24173634 TI - Screening a heterogeneous elderly South African population for cognitive impairment: the utility and performance of the Mini- Mental State Examination, Six Item Screener, Subjective Memory Rating Scale and Deterioration Cognitive Observee. AB - OBJECTIVE: The aim of this study was to report on the prevalence of cognitive impairment, and to assess the performance and utility of subjective, objective and informant screening tools in a heterogeneous community sample. METHOD: A sample of 302 elderly participants (>60 years) living in residential homes in a large city in South Africa were screened for the presence of cognitive impairment using objective (Mini-Mental State Examination [MMSE] and Six Item Screener [SIS]), subjective (Subjective Memory Complaint [SMC]and Subjective Memory Rating Scale [SMRS]) and informant (Deterioration Cognitive Observee [DECO]) screening tools. All tools were compared to the MMSE and the influence of demographic variables on the performance on these tools was considered. RESULTS: Significantly lower MMSE scores were found in participants aged 80-89 years (p=.023) and those who had 8-11 years of education (p=.002). For every one additional year of education, participants were 0.71 times less likely to screen positive on the MMSE. Differential item functioning on various components of the MMSE was demonstrated due to the effects of education, race and gender. There was significant differential performance between the recommended and alternate attention/concentration items (p<.001) with the alternate item favouring better performance. Based on the MMSE cutoff score of < 23, the prevalence of cognitive impairment was 16.9%; the prevalence yielded by the remaining tools ranged from 10.5% using the DECO to 46% as determined by the presence of a SMC. Using the MMSE as the reference standard for the presence of cognitive impairment, the SIS, SMC, SMRS and DECO had sensitivities of 82.3%, 54.6%, 17.0% and 37.5%, and specificities of 71.3%, 57.6%, 87.4% and 96.7% respectively. Age and race influenced performance on the MMSE, SIS and SMRS. CONCLUSION: Different types of cognitive screening tools yielded varying sensitivities and specificities for identifying cognitive impairment when compared to the MMSE. The influence of race, age and education on test performance highlights the need for suitable, culture-fair screening tools. Locally, the alternate item for attention/concentration should be preferred. PMID- 24173635 TI - The prevalence of metabolic syndrome and its associated factors in long-term patients in a specialist psychiatric hospital in South Africa. AB - OBJECTIVE: The aims of this study were to determine the prevalence of metabolic disorders in long-term psychiatric patients, and the relationship between known risk factors and these metabolic disorders. METHODS: All psychiatric in-patients >=18 years, who had been admitted >=six months were invited to participate. Eighty-four patients participated. They were interviewed, examined, measured and blood tests conducted to determine several demographic and clinical variables including age, gender, weight, blood pressure and fasting blood glucose. RESULTS: The prevalence of the metabolic disorders were: metabolic syndrome 32%, hypertension 32%, diabetes mellitus 8%, cholesterol dyslipidaemia 32%, triglyceride dyslipidaemia 29%, low density lipoprotein (LDL) dyslipidaemia 50%, overweight 37%, and obesity 24%. Black African and female patients were more likely to have metabolic syndrome. Female patients were more likely to have cholesterol dyslipidaemia and obesity. Hypertension was associated with age. Ninety-six percent of patients with dyslipidaemia were newly diagnosed during the study. Three out of the seven previously diagnosed diabetic patients had raised fasting blood glucose levels. CONCLUSION: The prevalence of metabolic syndrome falls towards the lower limits of the expected prevalence rate. Race and gender showed a moderate statistical association with metabolic syndrome. There is a lack of screening for dyslipidaemia in this setting. Diabetic patients should be referred to specialist diabetic clinics for better monitoring and control. PMID- 24173636 TI - Understanding cohort differences in appraisals of reconstruction priorities of mental health systems in postconflict Liberia. AB - OBJECTIVE: This study analyzes the relationship between informants' age and their assessment of mental health needs in postconflict society and examines if mental health needs assessment priorities differ depending upon whether or not the informant was exposed to the Liberian civil war. METHODS: cross-sectional survey was conducted in March 2009 to obtain data on mental health needs of Liberian children, adolescents and young adults. A total of 171 individuals were interviewed. The data were analyzed using a two- way ANOVA. RESULTS: Elder respondents expressed a preference for young adults to receive services in a church/mosque (F = 4.020, p < .05); for adolescents in volunteer programs (F = 3.987, p < .05) and for children in sports programs (F = 4.396, p < .05). Experiencing conflict did exert some influence on treatment setting preferences. Those who resided outside Liberia during the conflict cited a preference for traditional healers and medical clinics. However, this preference was for the children and young adult age categories. Those who experienced the civil war reported significantly higher preferences for adolescent services to be located in medical clinics, with traditional healers, and in churches/mosques. CONCLUSION: This study provides additional support for the premise that the utilization of psychiatric services needs to be viewed from the perspective of Liberians and that there are differences in preferences across groups. Our results suggest that service providers and policy makers take into account the age of the patient when deciding where to locate treatment settings for the population. PMID- 24173637 TI - How social media affects our practice. PMID- 24173638 TI - The Cochrane Collaboration: 20 years strong. PMID- 24173640 TI - Analysis of bacterial diversity in sponges collected off Chujado, an Island in Korea, using barcoded 454 pyrosequencing: analysis of a distinctive sponge group containing Chloroflexi. AB - The bacterial diversity of 14 sponges belonging to 5 different orders that were collected around Chuja Island, Korea was investigated using barcoded 454 pyrosequencing. The sponges contained many unidentified bacterial groups (e.g. more than half of the taxa at the family level) that were known only in environmental sequences and obtained from culture-independent methods. Five of the sponges were clustered into one notable group (CF group), which was distinguished from the other sponges in accordance with bacterial composition (the other sponges may be separated into more groups but clustering is not clear). The CF group contained high amounts of Chloroflexi (25.0-47.7%) and moderate amounts of Gemmatimonadetes (2.3-7.0%), AncK6 (0.6-2.2%), PAUC34f (0.8 6.0%), Acidobacteria (3.7-9.6%), and SBR1093 (1.8-5.6%) exclusively or almost exclusively to this group. Sponges in the CF group also showed higher diversity (e.g. Shannon index) than the other sponges and contained group-specific taxonomic lineages (e.g. class or family level) from group-specific phyla and even from the Proteobacteria and Actinobacteria, which were detected in all sponges at the phylum level. The CF group may be one of the most distinctive groups in sponges in terms of bacterial diversity. PMID- 24173639 TI - Bioactive activities of natural products against herpesvirus infection. AB - More than 90% of adults have been infected with at least one human herpesvirus, which establish long-term latent infection for the life of the host. While anti viral drugs exist that limit herpesvirus replication, many of these are ineffective against latent infection. Moreover, drug-resistant strains of herpesvirus emerge following chemotherapeutic treatment. For example, resistance to acyclovir and related nucleoside analogues can occur when mutations arise in either HSV thymidine kinase or DNA polymerases. Thus, there exists an unmet medical need to develop new anti-herpesvirus agents with different mechanisms of action. In this Review, we discuss the promise of anti-herpetic substances derived from natural products including extracts and pure compounds from potential herbal medicines. One example is Glycyrrhizic acid isolated from licorice that shows promising antiviral activity towards human gammaherpesviruses. Secondly, we discuss anti-herpetic mechanisms utilized by several natural products in molecular level. While nucleoside analogues inhibit replicating herpesviruses in lytic replication, some natural products can disrupt the herpesvirus latent infection in the host cell. In addition, natural products can stimulate immune responses against herpesviral infection. These findings suggest that natural products could be one of the best choices for development of new treatments for latent herpesvirus infection, and may provide synergistic anti viral activity when supplemented with nucleoside analogues. Therefore, it is important to identify which natural products are more efficacious anti-herpetic agents, and to understand the molecular mechanism in detail for further advance in the anti-viral therapies. PMID- 24173641 TI - Comparative proteomics analysis of sarcosine insoluble outer membrane proteins from clarithromycin resistant and sensitive strains of Helicobacter pylori. AB - Helicobacter pylori causes disease manifestations in humans including chronic gastric and peptic ulcers, gastric cancer, and lymphoid tissue lymphoma. Increasing rates of H. pylori clarithromycin resistance has led to higher rates of disease development. Because antibiotic resistance involves modifications of outer membrane proteins (OMP) in other Gram-negative bacteria, this study focuses on identification of H. pylori OMP's using comparative proteomic analyses of clarithromycin-susceptible and -resistant H. pylori strains. Comparative proteomics analyses of isolated sarcosine-insoluble OMP fractions from clarithromycin-susceptible and -resistant H. pylori strains were performed by 1) one dimensional sodium dodecyl sulphate-polyacrylamide gel electrophoresis protein separation and 2) in-gel digestion of the isolated proteins and mass spectrometry analysis by Matrix Assisted Laser Desorption Ionization-tandem mass spectrometry. Iron-regulated membrane protein, UreaseB, EF-Tu, and putative OMP were down-regulated; HopT (BabB) transmembrane protein, HofC, and OMP31 were up regulated in clarithromycin-resistant H. pylori. Western blotting and real time PCR, respectively, validated UreaseB subunit and EF-Tu changes at the protein level, and mRNA expression of HofC and HopT. This limited proteomic study provides evidence that alteration of the outer membrane proteins' profile may be a novel mechanism involved in clarithromycin resistance in H. pylori. PMID- 24173642 TI - Crystal structure of XoLAP, a leucine aminopeptidase, from Xanthomonas oryzae pv. oryzae. AB - Aminopeptidases are metalloproteinases that degrade N-terminal residues from protein and play important roles in cell growth and development by controlling cell homeostasis and protein maturation. We determined the crystal structure of XoLAP, a leucyl aminopeptidase, at 2.6 A resolution from Xanthomonas oryzae pv. oryzae, causing the destructive rice disease of bacterial blight. It is the first crystal structure of aminopeptidase from phytopathogens as a drug target. XoLAP existed as a hexamer and the monomer structure consisted of an N-terminal cap domain and a C-terminal peptidase domain with two divalent zinc ions. XoLAP structure was compared with BlLAP and EcLAP (EcPepA) structures. Based on the structural comparison, the molecular model of XoLAP in complex with the natural aminopeptidase inhibitor of microginin FR1 was proposed. The model structure will be useful to develop a novel antibacterial drug against Xoo. PMID- 24173643 TI - Safety evaluation of Lactobacillus paracasei subsp. paracasei LC-01, a probiotic bacterium. AB - The safety of Lactobacillus paracasei subsp. paracasei LC-01 was evaluated for its use as a potential probiotic. In our in vitro study, the antibiotic resistance and the ability to produce biogenic amine were determined. The results showed that the strain was sensitive to all tested antibiotics and did not produce biogenic amine except for tyramine. The oral toxicity of this strain was evaluated in Balb/C mice. One hundred mice were divided into 10 groups. Four groups were administered 0, 10(8), 10(9), or 10(10) CFU/mouse per day dissolved in saline solution respectively, for 28 days. Three groups were injected intraperitoneally with 10(9) CFU/mouse dissolved in saline solution, and were killed 2, 5, and 10 days after injection. The last 3 groups were injected with the vehicle as controls respectively. The results showed that oral administration of the strain had no adverse effects on mouse body weight and that there was no treatment-associated bacterial translocation. Intraperitoneal administration caused a significant translocation to liver, spleen and kidney. However, this translocation did not cause illness or death throughout the experiment. The results suggest that L. paracasei subsp. paracasei LC-01 is likely to be safe for human consumption. PMID- 24173644 TI - Experimental phasing using zinc and sulfur anomalous signals measured at the zinc absorption peak. AB - Iron is an essential transition metal required for bacterial growth and survival. Excess free iron can lead to the generation of reactive oxygen species that can cause severe damage to cellular functions. Cells have developed iron-sensing regulators to maintain iron homeostasis at the transcription level. The ferric uptake regulator (Fur) is an iron-responsive regulator that controls the expression of genes involved in iron homeostasis, bacterial virulence, stress resistance, and redox metabolism. Here, we report the expression, purification, crystallization, and phasing of the apo-form of Bacillus subtilis Fur (BsFur) in the absence of regulatory metal ions. Crystals were obtained by microbatch crystallization method at 295 K and diffraction data at a resolution of 2.6 A was collected at the zinc peak wavelength (lambda=1.2823 A). Experimental phasing identified the positions of one zinc atom and four sulfur atoms of cysteine residues coordinating the zinc atom, indicating that the data contained a meaningful anomalous scattering originating from the ordered zinc-coordinating sulfur atoms, in spite of the small anomalous signals of sulfur atoms at the examined wavelength. PMID- 24173645 TI - Characterization of Streptococcus pneumoniae N-acetylglucosamine-6-phosphate deacetylase as a novel diagnostic marker. AB - The identification of novel diagnostic markers of pathogenic bacteria is essential for improving the accuracy of diagnoses and for developing targeted vaccines. Streptococcus pneumoniae is a significant human pathogenic bacterium that causes pneumonia. N-acetylglucosamine-6-phosphate deacetylase (NagA) was identified in a protein mixture secreted by S. pneumoniae and its strong immunogenicity was confirmed in an immuno-proteomic assay against the anti-serum of the secreted protein mixture. In this study, recombinant S. pneumoniae NagA protein was expressed and purified to analyze its protein characteristics, immunospecificity, and immunogenicity, thereby facilitating its evaluation as a novel diagnostic marker for S. pneumoniae. Mass spectrometry analysis showed that S. pneumoniae NagA contains four internal disulfide bonds and that it does not undergo post-translational modification. S. pneumoniae NagA antibodies successfully detected NagA from different S. pneumoniae strains, whereas NagA from other pathogenic bacteria species was not detected. In addition, mice infected with S. pneumoniae generated NagA antibodies in an effective manner. These results suggest that NagA has potential as a novel diagnostic marker for S. pneumoniae because of its high immunogenicity and immunospecificity. PMID- 24173646 TI - The anti-influenza virus effect of Phellinus igniarius extract. AB - Herbal medicine has been used in the orient for thousands of years to treat large and small ailments, including microbial infections. Although there are treatments for influenza virus infection, there is no treatment for drug-resistant viruses. It is time that we explored and exploited the multi-component nature of herbal extracts as multi-drug combination therapies. Here, we present data on the anti influenza virus effect of a medicinal mushroom, Phellinus igniarius. The P. igniarius water extract was effective against influenza A and B viruses, including 2009 pandemic H1N1, human H3N2, avian H9N2, and oseltamivir-resistant H1N1 viruses. Virological assays revealed that the extract may interfere with one or more early events in the influenza virus replication cycle, including viral attachment to the target cell. Therefore, our results provide new insights into the use of P. igniarius as an anti-influenza medicine. PMID- 24173647 TI - Adjuvant efficacy of mOMV against avian influenza virus infection in mice. AB - Highly pathogenic avian influenza H5N1 viruses are found chiefly in birds and have caused severe disease and death in infected humans. Development of influenza vaccines capable of inducing heterosubtypic immunity against a broad range of influenza viruses is the best option for the preparedness, since vaccination remains the principal method in controlling influenza viral infections. Here, a mOMV-adjuvanted recombinant H5N2 (rH5N2) whole virus antigen vaccine with A/Environment/Korea/W149/06(H5N1)-derived H5 HA and A/Chicken/Korea/ma116/04(H9N2)-derived N2 NA in the backbone of A/Puerto Rico/8/34(H1N1) was prepared and generated by reverse genetics. Groups of mice were vaccinated by a prime-boost regime with the rH5N2 vaccine (1.75 MUg of HA with/without 10 MUg mOMV or aluminum hydroxide adjuvant for comparison). At two weeks post-immunizations, vaccinated mice were challenged with lethal doses of 10(3.5) EID50/ml of H5N1 or H9N2 avian influenza viruses, and were monitored for 15 days. Both mOMV- and alum-adjuvant vaccine groups had high survival rates after H5N1 infection and low levels of body weight changes compared to control groups. Interestingly, the mOMV-adjuvanted group induced better cross-reactive antibody responses serologically and promoted cross-protectivity against H5N1 and H9N2 virus challenges. Our results suggest that mOMV could be used as a vaccine adjuvant in the development of effective vaccines used to control influenza A virus transmission. PMID- 24173648 TI - Anaerobic cellulolytic rumen fungal populations in goats fed with and without Leucaena leucocephala hybrid, as determined by real-time PCR. AB - The effect of Leucaena leucocephala hybrid-Bahru (LLB), which contains a high concentration of condensed tannins, on cellulolytic rumen fungal population in goats was investigated using real-time PCR. The fungal population in goats fed LLB was inhibited during the first 10 days of feeding, but after 15 days of feeding, there was a tremendous increase of fungal population (157.0 MUg/ml), which was about fourfold more than that in control goats (39.7 MUg/ml). However, after this period, the fungal population decreased continuously, and at 30 days of feeding, the fungal population (50.6 MUg/ml) was not significantly different from that in control goats (55.4 MUg/ml). PMID- 24173649 TI - Two novel Talaromyces species isolated from medicinal crops in Korea. AB - Two novel biverticillate Talaromyces species, T. angelicus and T. cnidii, were collected from the medicinal crops Angelica gigas and Cnidium officinale, respectively, in Korea. Phylogenetic analyses with the nuclear ribosomal internal transcribed spacer (ITS) region and the beta-tubulin gene as well as morphological analyses revealed that the two species differ from any known Talaromyces species. Talaromyces angelicus is related to T. flavovirens in the phylogeny of the ITS region, but the new species is grouped together with Penicillium liani and T. pinophilus in terms of its beta-tubulin phylogeny, and its growth rate on Czapek yeast autolysate differs from that of T. flavovirens. Talaromyces cnidii is phylogenetically similar to T. siamensis, but exhibits differences in the morphologies of the colony margin, metulae, and conidia. PMID- 24173651 TI - New insights in the activation of human cholesterol esterase to design potent anti-cholesterol drugs. AB - Primary hypercholesterolemia is the root cause for major health issues like coronary heart disease and atherosclerosis. Regulating plasma cholesterol level, which is the product of biosynthesis as well as dietary intake, has become one of the major therapeutic strategies to effectively control these diseases. Human cholesterol esterase (hCEase) is an interesting target involved in the regulation of plasma cholesterol level and thus inhibition of this enzyme is highly effective in the treatment of hypercholesterolemia. This study was designed to understand the activation mechanism that enables the enzyme to accommodate long chain fatty acids and to identify the structural elements for the successful catalysis. Primarily the activation efficiencies of three different bile salts were studied and compared using molecular dynamics simulations. Based on the conformations of major surface loops, hydrogen bond interactions, and distance analyses, taurocholate was concluded as the preferred activator of the enzyme. Furthermore, the importance of two bile salt binding sites (proximal and remote) and the crucial role of 7alpha-OH group of the bile salts in the activation of hCEase was examined and evidenced. The results of our study explain the structural insights of the activation mechanism and show the key features of the bile salts responsible for the enzyme activation which are very useful in hypolipidemic drug designing strategies. PMID- 24173652 TI - Histological assessment of therapeutic response in breast cancer. AB - Histological assessment of the therapeutic response to neoadjuvant therapy gives us information regarding the efficacy of a given treatment in individual patients. Such information is useful for guiding selection of appropriate therapeutic strategies after surgery. In many studies of neoadjuvant chemotherapy (NAC) for breast cancer, both the histological therapeutic effect in the primary lesion and the lymph node metastatic status are significantly related to prognosis. The histological assessment of therapeutic response helps determine prognosis in breast cancer treated with NAC; however, methodological problems remain. There are many different histological criteria currently used to assess therapeutic response. Even when the same criteria are used, use of different methods for examination of surgical material can cause different results for the same patient case. When histological therapeutic effect is determined in daily clinical practice, pathologists have to describe the criteria used and their examination methods. Histological criteria for evaluation of therapeutic response and methods for examination of surgical materials after neoadjuvant therapy must be standardized in the near future. PMID- 24173653 TI - Earlier and better high-resolution single breast imaging during bilateral breast dynamic scans at 3-T MRI: comparison with post dynamic high-resolution imaging. AB - BACKGROUND: Breast MRI protocols have been improved by using a combination of dynamic scans for bilateral breasts and high-resolution imaging for a single breast which can be obtained during dynamic scans by recent technological advances. The purpose of this study was to compare high-resolution imaging during dynamic scans (HR-intra) with high-resolution imaging obtained post dynamic scans (HR-post). METHODS: Fifty-five women with pathologically proven breast cancer who underwent breast dynamic scans at 3-T MRI from February to September 2009 were enrolled in this study. Tumoral contrasts to the background breast tissue were compared by three radiologists independently in a blinded fashion. Results of visual assessment were categorized into three groups as follows: HR-intra being better (IB), equal (E), and HR-post being better (PB). The contrast to noise ratio (CNR) of the tumor and the signal to noise ratio of the normal breast gland (SNR) were compared between HR-intra and HR-post. RESULTS: Two patients were excluded because of poor MR imaging quality. Three radiologists separately categorized 64.2, 79.2, and 77.4 % of lesions as IB. The CNR of the tumor of HR intra (mean +/- SD = 6.9 +/- 4.0) was significantly higher than that of HR-post (6.0 +/- 3.7, p < 0.0001). The SNR of the normal breast gland of HR-intra (9.5 +/ 1.7) was significantly lower than that of HR-post (10.0 +/- 1.9, p < 0.0001). CONCLUSION: HR-intra during dynamic MRI provided earlier and better tumor to normal breast gland contrast than HR-post. PMID- 24173654 TI - Reversal effect of bufalin on multidrug resistance in human hepatocellular carcinoma BEL-7402/5-FU cells. AB - Multidrug resistance (MDR) is a major obstacle to chemotherapy in patients with hepatocellular carcinoma (HCC). To overcome MDR and improve chemotherapeutic efficacy, novel reversal agents with higher efficacy and lower toxicity are urgently needed for HCC. The present study was designed to examine the potential reversal activity of bufalin, a toxic ligand isolated from the traditional Chinese medicine 'Chansu' and to elucidate the possible related mechanisms. A multidrug-resistant HCC cell line, BEL-7402/5-FU, was used as the cell model. The working concentration of bufalin as an effective reversal agent, and the cell viability in the reversal experiments were determined by MTT assay. The effects of bufalin at a non-cytotoxic dose on cell cycle distribution, apoptosis and drug efflux pump activity were measured by flow cytometry. Qualitative observation of apoptosis was also carried out by confocal microscopy. Furthermore, the effects of bufalin on the expression of potential genes involved in MDR of BEL-7402/5-FU cells, including thymidylate synthase (TS), P-glycoprotein (P-gp), multidrug resistance protein 1 (MRP1), B-cell lymphoma-extra large (Bcl-xL) and Bcl-2 associated X protein (Bax), were determined using real-time PCR and western blot analysis. The results showed that bufalin at a concentration of 1 nM enhanced the chemosensitivity of BEL-7402/5-FU cells to 5-FU with a reversal fold of 3.8 which was similar to that of 1 uM verapamil. Bufalin significantly arrested the cell cycle at the G0/G1 phase, induced apoptosis through an increase in the Bax/Bcl-xL ratio, inhibited drug efflux pump activity via downregulation of MRP1, and reduced the expression of TS in BEL-7402/5-FU cells. The present study revealed that bufalin effectively reversed MDR in BEL-7402/5-FU cells through multiple pathways. The combination of bufalin with cytotoxic drugs may serve as a promising strategy for the chemotherapy of HCC. PMID- 24173655 TI - Imprinted electrodes for enhanced light trapping in solution processed solar cells. AB - A simple approach is demonstrated to combine a light trapping scheme and a conductive substrate for solution processed solar cells. By means of soft lithography, a new light-trapping architecture can be integrated as the bottom electrode for emerging thin-film solar-cell technologies without added costs, fully compatible with low-temperature processes, and yielding an enhancement in the photocurrent without altering the rest of the electrical performance of the device. PMID- 24173656 TI - New developments in behavioral treatments for substance use disorders. AB - After decades of defining which behavioral treatments are effective for treating addictions, the focus has shifted to exploring how these treatments work, how best to disseminate and implement them in the community, and what underlying factors can be manipulated in order to increase the rates of treatment success. These pursuits have led to advances in our understanding of the mechanisms of treatment effects, the incorporation of technology into the delivery of current treatments and development of novel applications to support relapse prevention, as well as the inclusion of neurocognitive approaches to target the automatic and higher-order processes underlying addictive behaviors. Although such advances have the promise of leading to better treatments for more individuals, there is still much work required for these promises to be realized. The following review will highlight some of these recent developments and provide a glimpse into the future of behavioral treatments. PMID- 24173657 TI - Increased prefrontal cortex activity during negative emotion regulation as a predictor of depression symptom severity trajectory over 6 months. AB - IMPORTANCE: Emotion regulation is critically disrupted in depression, and the use of paradigms that tap into these processes may uncover essential changes in neurobiology during treatment. In addition, because neuroimaging outcome studies of depression commonly use only baseline and end-point data-which are more prone to week-to-week noise in symptomatology-we sought to use all data points over the course of a 6-month trial. OBJECTIVE: To examine changes in neurobiology resulting from successful treatment. DESIGN, SETTING, AND PARTICIPANTS: Double blind trial examining changes in the neural circuits involved in emotion regulation resulting from 1 of 2 antidepressant treatments during a 6-month trial. Twenty-one patients with major depressive disorder and without other Axis I or Axis II diagnoses were scanned before treatment and 2 and 6 months into treatment at the university's functional magnetic resonance imaging facility. INTERVENTIONS: Venlafaxine hydrochloride extended release (with doses of up to 300 mg) or fluoxetine hydrochloride (with doses of up to 80 mg). MAIN OUTCOMES AND MEASURES: Neural activity, as measured using functional magnetic resonance imaging during performance of an emotion regulation paradigm, as well as regular assessments of symptom severity using the Hamilton Depression Rating Scale. For use of all data points, slope trajectories were calculated for rate of change in depression severity and for rate of change in neural engagement. RESULTS: The depressed individuals who showed the steepest decrease in depression severity over the 6-month period were the same individuals who showed the most rapid increases in activity in Brodmann area 10 and the right dorsolateral prefrontal cortex activity when regulating negative affect over the same time frame. This relationship was more robust when using only the baseline and end-point data. CONCLUSIONS AND RELEVANCE: Changes in prefrontal cortex engagement when regulating negative affect correlate with changes in depression severity over 6 months. These results are buttressed by calculating these statistics, which are more reliable and robust to week-to-week variation than are difference scores. PMID- 24173658 TI - An audit of first afebrile seizure management in an Irish tertiary pediatric setting. AB - The objective of this study was to compare the first afebrile seizure management with internationally recognized standards in an Irish tertiary pediatric setting. Twenty-one management standards were derived from a combination of British (NICE 2004) and North American (AAN 2003) guidelines. Cases of first afebrile seizure presenting to a pediatric emergency department between July 2007 and June 2010 were assessed against the standards. On completion, the standards developed were presented to the relevant stakeholders, a nurse-developed parental advice sheet was introduced, and a re-audit was performed from July 2010 to June 2011. Forty children were identified in the initial audit period (A1) and 41 over the re audit (A2). No case achieved full compliance with the devised standards in the audit period. A median compliance score of 15 (range 5-20) was achieved in A1 and 17 (range 11-21) in A2 [mean rank 31.93 versus 49.85; p(1,1) < 0.0001]. Optimal compliance (total score of >=17) with devised standards was achieved in 6/40 patients in A1 and in 21/41 patients in A2 [chi (2) = 11.95; p(1,1) = 0.001]. CONCLUSION: We demonstrated an initial lack of compliance with international guidelines on management of a common medical presentation, first afebrile seizure, and demonstrated that improvements can be achieved by identification of appropriate standards and critical appraisal of the compliance with these standards through both formal and informal education. PMID- 24173659 TI - Quantum dot-NBD-liposome luminescent probes for monitoring phospholipase A2 activity. AB - In this paper we describe the fabrication and characterization of new liposome encapsulated quantum dot-fluorescence resonance energy transfer (FRET)-based probes for monitoring the enzymatic activity of phospholipase A2. To fabricate the probes, luminescent CdSe/ZnS quantum dots capped with trioctylphosphine oxide (TOPO) ligands were incorporated into the lipid bilayer of unilamellar liposomes with an average diameter of approximately 100 nm. Incorporating TOPO capped quantum dots in liposomes enabled their use in aqueous solution while maintaining their hydrophobicity and excellent photophysical properties. The phospholipid bilayer was labeled with the fluorophore NBD C6-HPC (2-(6-(7-nitrobenz-2-oxa-1,3 diazol-4-yl)amino)hexanoyl-1-hexa decanoyl-sn-glycero-3-phosphocholine). The luminescent quantum dots acted as FRET donors and the NBD dye molecules acted as FRET acceptors. The probe response was based on FRET interactions between the quantum dots and the NBD dye molecules. The NBD dye molecules were cleaved and released to the solution in the presence of the enzyme phospholipase A2. This led to an increase of the luminescence of the quantum dots and to a corresponding decrease in the fluorescence of the NBD molecules, because of a decrease in FRET efficiency between the quantum dots and the NBD dye molecules. Because the quantum dots were not attached covalently to the phospholipids, they did not hinder the enzyme activity as a result of steric effects. The probes were able to detect amounts of phospholipase A2 as low as 0.0075 U mL(-1) and to monitor enzyme activity in real time. The probes were also used to screen phospholipase A2 inhibitors. For example, we found that the inhibition efficiency of MJ33 (1 hexadecyl-3-(trifluoroethyl)-sn-glycero-2-phosphomethanol) was higher than that of OBAA (3-(4-octadecyl)benzoylacrylic acid). PMID- 24173660 TI - A qualitative/quantitative approach for the detection of 37 tryptamine-derived designer drugs, 5 beta-carbolines, ibogaine, and yohimbine in human urine and plasma using standard urine screening and multi-analyte approaches. AB - The first synthetic tryptamines have entered the designer drug market in the late 1990s and were distributed as psychedelic recreational drugs. In the meantime, several analogs have been brought onto the market indicating a growing interest in this drug class. So far, only scarce analytical data were available on the detectability of tryptamines in human biosamples. Therefore, the aim of the presented study was the development and full validation of a method for their detection in human urine and plasma and their quantification in human plasma. The liquid chromatography-linear ion trap mass spectrometry method presented covered 37 tryptamines as well as five beta-carbolines, ibogaine, and yohimbine. Compounds were analyzed after protein precipitation of urine or fast liquid liquid extraction of plasma using an LXQ linear ion trap coupled to an Accela ultra ultra high-performance liquid chromatography system. Data mining was performed via information-dependent acquisition or targeted product ion scan mode with positive electrospray ionization. The assay was selective for all tested substances with limits of detection in urine between 10 and 100 ng/mL and in plasma between 1 and 100 ng/mL. A validated quantification in plasma according to international recommendation could be demonstrated for 33 out of 44 analytes. PMID- 24173661 TI - Relationship between the matrix effect and the physicochemical properties of analytes in gas chromatography. AB - The phenomenon "matrix-induced chromatographic response enhancement" (matrix effect) causes quantitative errors in gas chromatography (GC) analyses. This effect varies according to the analyte nature, matrix type and concentration, and GC-system parameters. By focusing on the physicochemical properties of analytes, a predictive model was developed for the matrix effect using quantitative structure-property relationships. Experimental values of the matrix effect were determined for 58 compounds in a serum extract obtained from solid-phase extraction as the matrix. Eight molecular descriptors were selected, and the matrix-effect model was developed by multiple linear regression. The developed model predicted values for the matrix effect without any further experimental measurements. It also indicated that the molecular polarity (particularly H-bond donors) and volume of the analyte increase the matrix effect, while hydrophobicity and increasing number of nonpolar carbon atoms in the analyte decrease the matrix effect. The model was applied to the analysis of barbiturates. The predicted values indicated that N-methylation decreases the matrix effect, and the relative predicted values were effective for the selection of an internal standard. The obtained insight into the matrix effect and the prediction data will be helpful for developing quantitative analysis strategies. PMID- 24173662 TI - Treatment of liver cancer in mice by the intratumoral injection of an octreotide based temperature-sensitive gel. AB - Octreotide (OCT) can inhibit tumor growth with few side-effects. In this study, we hypothesized that an OCT- and poloxamer 407 (P407)-based temperature-sensitive gel may compensate for the short half-life of OCT, which may thus lead to the development of a novel therapy for patients with end-stage liver cancer by intratumoral injection. The proliferation and apoptosis of mouse Hca-F hepatocellular carcinoma cells were determined by MTT assay and Annexin V-PI staining. A mouse model of hepatocellular carcinoma was established by the subcutaneous transplantion of Hca-F cells and OCT-P407 or OCT solution were injected into the tumors, followed by the detection of OCT levels by high performance liquid chromatography (HPLC) over a specific time period. OCT-P407, ethanol, OCT, P407 or normal saline (NS) were injected into the tumors and the tumor size, weight and inhibition rate were measured 8 days later. Additionally, the expression of somatostatin receptor-2 (SSTR-2), vascular endothelial growth factor (VEGF) and caspase-3 was detected by immunohistochemistry and RT-PCR. Compared with the OCT group, the tumor inhibition rate and the apoptotic rate in the OCT-P407 group were higher and the effects were longer. The tumor size and weight in the OCT-P407 group were lower and the tumor inhibition rate higher compared with the OCT, P407 and NS groups, with the exception of the ethanol group. The protein and mRNA expression of SSTR-2 and caspase-3 in the OCT-P407 group was higher, and that of VEFG was lower compared with the other groups, with the exception of the ethanol group. In the present study, we demonstrate that the intratumoral injection of OCT-P407 maintains OCT local effective concentration and prolongs its action time, with a greater therapeutic effect than that of OCT on its own. Although ethanol is more effective in certain aspects, its tumor inhibitory effects are similar to OCT-P407 and as such, OCT-P407 may be a suitable alternative. PMID- 24173664 TI - Green synthesis of silver nanoclusters supported on carbon nanodots: enhanced photoluminescence and high catalytic activity for oxygen reduction reaction. AB - Metal nanoclusters exhibit unusual optical and catalytic properties due to their unique electronic structures. Here, surfactant-free silver nanoclusters supported on carbon nanodots were synthesized through a facile and green approach with only glucose and AgNO3 as precursors and without any other protecting ligands and reducing agents. The hybrid nanoclusters exhibited enhanced blue fluorescence compared to the carbon nanodots. More importantly, the "surface-clean" silver nanoclusters have remarkable electrocatalytic performance towards oxygen reduction reaction (ORR) with the most efficient four-electron transfer process. Moreover, compared with commercial Pt/C catalyst, the Pt-free hybrid clusters showed comparable catalytic performance for ORR but much higher tolerance to methanol crossover. Such silver nanoclusters will provide broad applications in fluorescence-related areas and in fuel cells as an efficient Pt-free catalyst with low cost and high catalytic performance. PMID- 24173663 TI - Ultrasensitive and fast bottom-up analysis of femtogram amounts of complex proteome digests. AB - Femtogram proteomics: An ultrasensitive capillary zone electrophoresis-mass spectrometry system that is based on an improved nanospray interface has been developed. This system is used for the analysis of picogram to femtogram amounts of E. coli digests; for example, over 100 proteins were identified from 16 pg digests by tandem mass spectrometry. AMTs=accurate mass and time tags. PMID- 24173665 TI - Pien Tze Huang suppresses the stem-like side population in colorectal cancer cells. AB - Accumulating evidence suggests that a small population of cells termed cancer stem cells (CSCs) are crucial in tumor development and drug resistance, leading to cancer relapse and metastasis and eventually the failure of clinical cancer treatment. Therefore, targeting CSCs is a promising approach for anticancer therapies. Due to the drug resistance and adverse effects of currently used chemotherapies, traditional Chinese medicines (TCM) have recently received attention due to the relatively few side-effects. Thus, they have been used as important alternative remedies for various diseases, including cancer. Pien Tze Huang (PZH), a well-known TCM formula that was first prescribed more than 450 years ago in the Ming Dynasty, has been used in China and Southeast Asia for centuries as a folk remedy for various types of cancer. Previously, it was reported that PZH inhibits colon cancer growth via the promotion of cancer cell apoptosis and inhibition of cell proliferation and tumor angiogenesis, which is probably mediated by its regulatory effect on multiple intracellular signaling pathways. To elucidate the mechanism of the tumoricidal activity of PZH, the aim of the present study was to investigate the effect of PZH on CSCs that were isolated as the side population (SP) from the HT-29 colorectal cancer cell line. The results demonstrated that PZH significantly and dose-dependently reduced the percentage of the colorectal cancer stem-like SP cells, decreased the viability and sphere-forming capacity of HT-29 SP cells, indicating that PZH is potent in suppressing the growth of colorectal cancer stem cells. Moreover, PZH treatment in HT-29 SP cells markedly inhibited the mRNA levels of ABCB1 and ABCG2, which are members of the ABC transporter superfamily, thereby contributing to the SP phenotype and multi-drug resistance. Findings of the present study suggest that inhibiting the growth of CSCs is a potential mechanism by which PZH can be used in cancer treatment. PMID- 24173666 TI - Sudden infant death syndrome (SIDS) and polymorphisms in Monoamine oxidase A gene (MAOA): a revisit. AB - Literature describes multiple possible links between genetic variations in the neuroadrenergic system and the occurrence of sudden infant death syndrome. The X chromosomal Monoamine oxidase A (MAOA) is one of the genes with regulatory activity in the noradrenergic and serotonergic neuronal systems and a polymorphism of the promoter which affects the activity of this gene has been proclaimed to contribute significantly to the prevalence of sudden infant death syndrome (SIDS) in three studies from 2009, 2012 and 2013. However, these studies described different significant correlations regarding gender or age of children. Since several studies, suggesting associations between genetic variations and SIDS, were disproved by follow-up analysis, this study was conducted to take a closer look at the MAOA gene and its polymorphisms. The functional MAOA promoter length polymorphism was investigated in 261 SIDS cases and 93 control subjects. Moreover, the allele distribution of 12 coding and non-coding single nucleotide polymorphisms (SNPs) of the MAOA gene was examined in 285 SIDS cases and 93 controls by a minisequencing technique. In contrast to prior studies with fewer individuals, no significant correlations between the occurrence of SIDS and the frequency of allele variants of the promoter polymorphism could be demonstrated, even including the results from the abovementioned previous studies. Regarding the SNPs, three statistically significant associations were observed which had not been described before. This study clearly disproves interactions between MAOA promoter polymorphisms and SIDS, even if variations in single nucleotide polymorphisms of MAOA should be subjected to further analysis to clarify their impact on SIDS. PMID- 24173667 TI - Comments on Tongue protrusion as an indicator of vital burning. PMID- 24173668 TI - Progestogen for preventing miscarriage. AB - BACKGROUND: Progesterone, a female sex hormone, is known to induce secretory changes in the lining of the uterus essential for successful implantation of a fertilized egg. It has been suggested that a causative factor in many cases of miscarriage may be inadequate secretion of progesterone. Therefore, progestogens have been used, beginning in the first trimester of pregnancy, in an attempt to prevent spontaneous miscarriage. OBJECTIVES: To determine the efficacy and safety of progestogens as a preventative therapy against miscarriage. SEARCH METHODS: We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (1 August 2013), reference lists from relevant articles, attempting to contact authors where necessary, and contacted experts in the field for unpublished works. SELECTION CRITERIA: Randomized or quasi-randomized controlled trials comparing progestogens with placebo or no treatment given in an effort to prevent miscarriage. DATA COLLECTION AND ANALYSIS: Two review authors assessed trial quality and extracted data. MAIN RESULTS: Fourteen trials (2158 women) are included. The meta-analysis of all women, regardless of gravidity and number of previous miscarriages, showed no statistically significant difference in the risk of miscarriage between progestogen and placebo or no treatment groups (Peto odds ratio (Peto OR) 0.99; 95% confidence interval (CI) 0.78 to 1.24) and no statistically significant difference in the incidence of adverse effect in either mother or baby.A subgroup analysis of placebo controlled trials did not find a difference in the rate of miscarriage with the use of progestogen (10 trials, 1028 women; Peto OR 1.15; 95% CI 0.88 to 1.50).In a subgroup analysis of four trials involving women who had recurrent miscarriages (three or more consecutive miscarriages; four trials, 225 women), progestogen treatment showed a statistically significant decrease in miscarriage rate compared to placebo or no treatment (Peto OR 0.39; 95% CI 0.21 to 0.72). However, these four trials were of poorer methodological quality. No statistically significant differences were found between the route of administration of progestogen (oral, intramuscular, vaginal) versus placebo or no treatment. No significant differences in the rates of preterm birth, neonatal death, or fetal genital anomalies/virilization were found between progestogen therapy versus placebo/control. AUTHORS' CONCLUSIONS: There is no evidence to support the routine use of progestogen to prevent miscarriage in early to mid-pregnancy. However, there seems to be evidence of benefit in women with a history of recurrent miscarriage. Treatment for these women may be warranted given the reduced rates of miscarriage in the treatment group and the finding of no statistically significant difference between treatment and control groups in rates of adverse effects suffered by either mother or baby in the available evidence. Larger trials are currently underway to inform treatment for this group of women. PMID- 24173669 TI - [Granular cell tumors of the orbit: diagnostics and therapeutic aspects exemplified by a case report]. AB - BACKGROUND: Granular cell tumors (Abrikossoff's tumor) are very rare, mostly benign tumors of neurogenic origin which preferentially occur in the upper aerodigestive tract. Granular cell tumors rarely originate in the orbit and are therefore a diagnostic and therapeutic challenge. METHOD AND PATIENTS: A 42-year old male patient presented to the Orthoptic Department of the University Eye Clinic in Salzburg with motility disturbances and diplopia in the right eye. The clinical examination revealed right-sided exophthalmos and shrinking of the choroid and retina due to a retrobulbar mass. The radiological examination showed an infiltrative tumor 1.7 * 1.3 cm in size in the lower temporal quarter of the orbit. Due to the localization a sonographically controlled fine needle puncture was carried out for preoperative diagnostics by a specialist in clinical cytology. The cytological examination confirmed the presence of a granular cell tumor. The tumor was excised via a conjunctival access route. RESULTS: Motility testing in the postoperative course control showed an improvement in the findings and the exophthalmos was clearly regressive. Vision improved from 0.5 preoperatively to 1.0 postoperatively. During the postoperative observational period of 12 months no recurrences occurred. Clinical control examinations are planned every 3 months and imaging controls every 6 months. CONCLUSION: Granular cell tumors of the orbit should be included in the differential diagnostics of orbital tumors despite the low incidence. A sonographically controlled fine needle puncture is an adequate procedure with respect to the diagnostics and further therapy for poorly differentiated tumors of the orbit with a suspicion of infiltrative growth and for which in toto resection is questionably possible. A complete surgical excision should be the aim of treatment of granular cell tumors. Continuous clinical and imaging control is necessary to enable early recognition of recurrences. PMID- 24173671 TI - Advances in transition metal-catalyzed asymmetric hydrogenation of heteroaromatic compounds. AB - Transition metal-catalyzed asymmetric hydrogenation of heteroaromatic compounds is undoubtedly a straightforward and environmentally friendly method for the synthesis of a wide range of optically active heterocyclic compounds, which are widespread and ubiquitous in naturally occurring and artificial bioactive molecules. Over the past decade, a number of transition metal (Ir, Rh, Ru, and Pd) catalysts bearing chiral phosphorus ligands, amine-tosylamine ligands, and N heterocyclic carbene ligands have been developed for such challenging transformation. This review will describe the significant contributions concerning the transition metal-catalyzed asymmetric hydrogenation of N-, O-, and S-containing heteroaromatic compounds, with emphasis on the evolution of different chiral ligands, related catalyst immobilization, and mechanism investigations. PMID- 24173670 TI - Dose conversion ratio in hemodialysis patients switched from darbepoetin alfa to PEG-epoetin beta: AFFIRM study. AB - INTRODUCTION: There is limited information published on switching erythropoiesis stimulating agent (ESA) treatment for anemia associated with chronic kidney disease (CKD) from darbepoetin alfa (DA) to methoxy polyethylene glycol-epoetin beta (PEG-Epo) outside the protocol of interventional clinical studies. AFFIRM (Aranesp Efficiency Relative to Mircera) was a retrospective, multi-site, observational study designed to estimate the population mean maintenance dose conversion ratio [DCR; dose ratio achieving comparable hemoglobin level (Hb) between two evaluation periods] in European hemodialysis patients whose treatment was switched from DA to PEG-Epo. METHODS: Eligible patients had received hemodialysis for >= 12 months and DA for >= 7 months. Data were collected from 7 months before until 7 months after switching treatment. DCR was calculated for patients with Hb and ESA data available in both evaluation periods (EP; Months 1 and 2 were defined as the pre-switch EP, and Months 6 and 7 as the post-switch EP). Red blood cell transfusions pre- and post-switch were quantified. RESULTS: Of 302 patients enrolled, 206 had data available for DCR analysis. The geometric mean DCR was 1.17 (95% CI 1.05, 1.29). Regression analysis indicated a non-linear relationship between pre- and post-switch ESA doses; DCR decreased with increasing pre-switch DA dose. The geometric mean weekly ESA doses were 24.1 MUg DA in the pre-switch EP and 28.6 MUg PEG-Epo in the post-switch EP. Mean Hb was 11.5 g/dL in the pre-switch EP and 11.4 g/dL in the post-switch EP. There were 16 transfusions and 34 units transfused in the pre-switch period, versus 48 transfusions and 95 units transfused post-switch. Excluding patients receiving a transfusion within 90 days of or during either EP, the DCR was 1.21 (95% CI 1.09, 1.35). CONCLUSION: In these hemodialysis patients switched from DA to PEG-Epo the DCR was 1.17 and 1.21 after accounting for the effect of transfusions. The number of transfusions and units transfused increased approximately threefold from the pre-switch to the post-switch period. PMID- 24173672 TI - Enantiopure supramolecular cages: synthesis and chiral recognition properties. AB - Enantiopure compounds are ubiquitous in the chemical sciences and present a particular interest in the field of molecular recognition and host-guest systems. Indeed, chiral molecular receptors are at the basis of numerous biological recognition processes and have important implications in biochemistry or pharmacology. Chemists have been investigating this field for several decades, which has led to the development of the synthesis of chiral hosts, their enantiomeric differentiation, and the studies of their recognition properties towards important and bio-relevant chiral guest substrates. The design of molecular cages is a rather difficult task that is even more demanding when enantiopure molecules are required. In this review we chose to present the main families of synthetic organic supramolecular cages that have been developed, whose structures contain stereogenic centers or present an inherent chirality, giving rise to chiral supramolecular cages. Particular attention is given to obtaining enantiopure compounds. Their recognition properties are also underlined. A last important aspect of the review is to present how chiroptical spectroscopies can be used to characterize the recognition phenomena displayed by supramolecular cages. PMID- 24173673 TI - Metal-organic cooperative catalysis in C-C bond activation. AB - This review describes recent advances that have been made in studies of transition metal-promoted metal-organic cooperative C-C single bond activation reactions of unstrained organic substances, which use 2-aminopicoline as a temporal chelating ligand. In addition, metal-organic cooperative C-C double bond and C-C triple bond cleavage processes are discussed in association with transition metal-catalyzed C-H bond activation. Recent progress made in these areas has opened up the new paradigms in synthetic organic chemistry for the construction of organic frameworks by structural reorganization of organic backbones. Among the many strategies devised, chelation-assisted C-C bond cleavage reactions, which operate through cooperation between metal complexes and organic substances, have attracted perhaps the greatest attention. Utilizing this approach, efficient C-C single bond activation reactions have been developed for a variety of substrates, including linear alkyl ketones, secondary alcohols, primary amines, and cycloalkanones. In addition, reactions that lead to cleavage of C-C double and triple bonds can be facilitated by using the metal-organic cooperation strategy. C-C double bonds in alpha,beta-enones can be cleaved by addition of cyclohexylamine, which facilitates Michael addition and retro-Mannich type fragmentation cascades proceeding via beta-aminoketimine intermediates. Aldehydes, which serve as one of the fragmentation products of these processes, can be trapped by chelation-assisted hydroacylation reactions to produce ketones. Finally, C-C triple bond cleavage of alkynes can be achieved through hydroacylation reactions with aldehydes and subsequent C-C double bond cleavage of the resulting alpha,beta-enones. PMID- 24173674 TI - Diastereo- and enantioselective synthesis of organometallic bis(helicene)s by a combination of C-H activation and dynamic isomerization. AB - Homochiral and heterochiral cis-bis-cycloplatinated-[6]helicene derivatives 1b(1,2), as representative examples of platina[6]helicenes that share a common platinum center, have been prepared. A diastereo- and enantioselective synthesis, which combines CH activation and dynamic isomerization from heterochiral structure 1b(2) into homochiral structure 1b(1), is also described. Overall, this isomerization process results in the transfer of chiral information from one helicene moiety to the other one. The chiroptical properties of homochiral (P)- and (M)-1b(1) were greatly modified upon oxidation into their corresponding (P)- and (M)-diiodo-Pt(IV) complexes (5). The changes were also analyzed by performing theoretical calculations. C-H activation in the synthesis of organometallic helicenes is further demonstrated by the preparation of cis-bis-cycloplatinated [8]helicene 1c. PMID- 24173675 TI - Smith-Petersen and early development of hip arthroplasty. AB - Dr. Marius N. Smith-Petersen, in Boston, MA, USA, introduced the mould arthroplasty (1923). He used a reactive synovial-like membrane that he found had developed around a piece of glass he had removed from a workman's back, which had been imbedded there for a year. The original design was a ball-shaped, hollow hemisphere of glass that could fit over the femoral head of the hip joint. The objective was to stimulate cartilage regeneration on both sides of the moulded glass joint. Smith-Peterson intended to remove the glass after the cartilage had been restored. Glass provided a new, smooth surface for movement, and although proving biocompatible, it could not withstand the stresses of walking and quickly failed. Smith-Petersen succeeded in his endeavour by using Vitallium alloy. PMID- 24173676 TI - Low-dose dexamethasone with levobupivacaine improves analgesia after supraclavicular brachial plexus blockade. AB - PURPOSE: We conducted ultrasound-guided single-shot supraclavicular blockade and investigated the analgesic effect of dexamethasone added to levobupivacaine. The aim of this study was to determine whether the addition of low-dose dexamethasone to levobupivacaine would prolong the duration of analgesia sufficiently to avoid additional intravenous analgesic use for the first 24 hours postoperatively. METHODS: This randomised controlled study assessed 70 patients undergoing upper extremity surgery. Patients were eligible if there 18 years or over with American Society of Anaesthesiologists (ASA) physical status I, II or III. Patients were randomly assigned to receive 25 ml 0.5% levobupivacaine plus four milligrams dexamethasone (group 1) or 25 ml 0.5% levobupivacaine plus one millilitre saline (group 2). Pain scores, analgesic consumption and time estimation at which they perceived that sensory and motor blockade started and resolved were recorded. RESULTS: Duration of sensory (1,260 min. in group 1 vs 600 min. in group 2) and motor (1,200 min. in group 1 vs 700 min. in group 2) blockade were significantly longer in group 1 (P < 0.05). Postoperative pain levels in group 1 were significantly lower (P < 0.05) at all investigation times. Analgesia consumption was significantly lower (P < 0.05) in group 1; at six and 12 hours, no patient required additional analgesia, and at 24 hours, only two patients compared with 17 in the levobupivacaine group required additional analgesia. CONCLUSION: Using single-shot low-dose dexamethasone in a mixture with levobupivacaine results in prolonged analgesia duration and less analgesic use compared with levobupivacaine alone. PMID- 24173677 TI - The relationship between the survival of total knee arthroplasty and postoperative coronal, sagittal and rotational alignment of knee prosthesis. AB - PURPOSE: Our study sought to address four issues: (1) the relationship between postoperative overall anatomical knee alignment and the survival of total knee prostheses; (2) the relationship between postoperative coronal alignment of the femoral and tibial component and implant survival; (3) the relationship between postoperative sagittal alignment of the femoral and tibial components and implant survival; and (4) the relationship between postoperative rotational alignment of the femoral and tibial component and implant survival. METHODS: We reviewed 1,696 consecutive patients (3,048 knees). Radiographic and computed tomographic examinations were performed to determine the alignment of the femoral and tibial components. The mean duration of follow-up was 15.8 years (range, 11-18 years). RESULTS: Thirty (1.0%) of the 3,048 total knee arthroplasties failed for a reason other than infection and periprosthetic fracture. Risk factors for failure of the components were: overall anatomical knee alignment less than 3 degrees valgus, coronal alignment of the femoral component less than 2.0 degrees valgus, flexion of the femoral component greater than 3 degrees , coronal alignment of the tibial component less than 90 degrees , sagittal alignment of the tibial component less than 0 degrees or greater than 7 degrees slope, and external rotational alignment of the femoral and tibial components less than 2 degrees CONCLUSION: In order to improve the survival rate of the knee prosthesis, we believe that a surgeon should aim to place the total knee components in the position of: overall anatomical knee alignment at an angle of 3-7.5 degrees valgus; femoral component alignment, 2-8.0 degrees valgus; femoral sagittal alignment, 0-3 degrees ; tibial coronal alignment, 90 degrees ; tibial sagittal alignment, 0-7 degrees ; femoral rotational alignment, 2-5 degrees external rotation; and tibial rotational alignment, 2-5 degrees external rotation. PMID- 24173678 TI - The Renaissance and the universal surgeon: Giovanni Andrea Della Croce, a master of traumatology. AB - All the medical knowledge of all time in one book, the universal and perfect manual for the Renaissance surgeon, and the man who wrote it. This paper depicts the life and works of Giovanni Andrea della Croce, a 16th Century physician and surgeon, who, endowed with true spirit of Renaissance humanism, wanted to teach and share all his medical knowledge through his opus magnum, titled "Universal Surgery Complete with All the Relevant Parts for the Optimum Surgeon". An extraordinary book which truly represents a defining moment and a founding stone for traumatology, written by a lesser known historical personality, but nonetheless the Renaissance Master of Traumatology. PMID- 24173679 TI - Regulation of major vault protein expression by upstream stimulating factor 1 in SW620 human colon cancer cells. AB - Major vault protein (MVP) is the main constituent of the vault ribonucleoprotein particle and is identical to lung resistance-related protein (LRP). Although MVP is also expressed in several types of normal tissues, little is known about its physiological role. In the present study, we identified the crucial MVP promoter elements that regulate MVP expression. An examination of tissue expression profiles revealed that MVP was expressed in the heart, placenta, lung, liver, kidney and pancreas. Elements of the MVP promoter contain binding sites for transcription factors, STAT, p53, Sp1, E-box, GATA, MyoD and Y-box. By deletion analysis, a conserved proximal E-box binding site was demonstrated to be important for human MVP promoter transactivation. Introduction of siRNA against upstream stimulating factor (USF) 1, which is known to bind the E-box binding site, decreased the expression of MVP in SW620 and ACHN cells. Using a chromatin immunoprecipitation (ChIP) assay, USF1 bound the MVP promoter in SW620 cells. These findings suggest that USF1 binding to an E-box element may be critical for basal MVP promoter activation. The results of the present study are useful in understanding the molecular mechanisms regulating MVP gene expression, and may aid in elucidating the physiological functions of MVP. PMID- 24173680 TI - What's cost got to do with it? Association between hospital costs and frequency of admissions among "high users" of hospital care. AB - BACKGROUND: Efforts to curb healthcare spending have included interventions that target frequently hospitalized individuals. It is unclear the extent to which the most frequently hospitalized individuals also represent the costliest individuals. OBJECTIVE: To examine the relationship between 2 types of "high users" commonly targeted in cost-containment interventions-those incurring the highest hospital costs ("high cost") and those incurring the highest number of hospitalizations ("high admit"). DESIGN, SETTING, AND PATIENTS: Cross-sectional study of 2566 individuals with a primary care physician and at least 1 hospitalization within an academic health system from 2010 to 2011. MEASUREMENTS: Overlap between the population constituting the top decile of hospital costs and the population constituting the top decile of hospitalizations; characteristics of the 3 resulting high user subgroups. RESULTS: Only 48% of individuals who were high cost (>$65,000) were also high admit (>= 3 hospitalizations). Compared to hospitalizations incurred by high cost-high admit individuals (n = 605), hospitalizations incurred by high cost-low admit individuals (n = 206) were more likely to be for surgical procedures (58 vs 22%, P < 0.001), had a higher cost ($68,000 vs $28,000, P < 0.001), longer length of stay (10 vs 5 days, P < 0.001), and were less likely to be a 30-day readmission (17 vs 47%, P < 0.001). CONCLUSIONS: Stratifying high admit individuals by costs and high cost individuals by hospitalizations yields 3 distinct high user subgroups with important differences in clinical characteristics and utilization patterns. Consideration of these distinct subgroups may lead to better-tailored interventions and achieve greater cost savings. PMID- 24173681 TI - Long-term evaluation of cognition after glioma surgery in eloquent areas. AB - Preservation of cognition is an important outcome measure in eloquent area glioma surgery. Glioma patients may have pre-operative deficits in one or more cognitive domains which could deteriorate post-operatively. It is assumed that these impairments recover within 3 months; some studies however, still detected cognitive decline. Longer follow-up is necessary to elucidate the conclusive effects of surgery. 45 patients with gliomas (low- and high-grade, but without contrast enhancement at diagnosis) in eloquent areas were assessed pre operatively, 3 months and 1 year post-operatively with a neuropsychological test protocol. Patients' performance was compared to normal population and between test-moments. Univariate analyses were performed between cognitive change and tumor-characteristics (localization, grade, volume, extent of resection [EOR]) and treatment-related factors (radio-/chemotherapy). Pre- and post-operatively, impairments were found in all cognitive domains; language, memory, attention and executive functions (p < 0.05). Post-operatively, permanent improvement was observed on a memory test (verbal recall: t = -1.931, p = 0.034), whereas deterioration was found on a language test (category fluency: t = 2.517, p = 0.030). Between 3 months and 1 year, patients improved on 2 language tests (naming: t = -2.781, p = 0.026 and letter fluency: t = -1.975, p = 0.047). There was no influence of tumor- or treatment-related factors on cognitive change. The findings underline the importance of cognitive testing at longer term post operatively, as cognitive recovery took longer than 3 months, especially within the language domain. However, this longitudinal follow-up study showed that glioma surgery is possible without major long-term damage of cognitive functions. Tumor characteristics and EOR are no additional risk factors for cognitive outcome. PMID- 24173682 TI - Patterns of failure after radiosurgery to two different target volumes of enhancing lesions with and without FLAIR abnormalities in recurrent glioblastoma multiforme. AB - Glioblastoma multiforme (GBM) invades beyond enhancing boundaries, and tumor cells are believed to exist in edematous peritumoral regions. We hypothesize that the concomitant treatment of both enhancing and FLAIR abnormalities on MRI by fractionated radiosurgery (FRS) would reduce local and regional recurrence. The purpose of this study was to demonstrate patterns of failure after FRS with simultaneous differential doses to two different target volumes of contrast enhancing lesions with/without FLAIR abnormality in recurrent GBM. Fifty-three patients with recurrent GBM were treated with FRS between 2008 and 2012. FRS was offered for the patients who had progressive tumors after the initial surgical resection followed by chemoradiation, and second-line chemotherapy. Radiosurgery Regimen A was 32 Gy (8 Gy * 4 treatments) to the contrast enhancing lesion only. Regimen B was 32 Gy (8 Gy * 4) to the contrast enhancing lesion and 24 Gy (6 Gy * 4) to the FLAIR abnormality delivered concomitantly. The study endpoint was radiographic failure on MRI at 2 months after FRS. Median survival after FRS was 7.5 months, and median progression-free survival after FRS was 4 months. Overall 82.4 % (42/51 lesions) recurred during follow-up. The local and regional failure rate was significantly lower in Regimen B (52 %) than in Regimen A (86.7 %) (p = 0.003). No sign of tumor progression in 10 % of Regimen A versus 28.6 % of Regimen B was shown during followup (p = 0.04). Instead, distant failure rate was higher in Regimen B. In conclusions, FRS was found to be a safe and effective salvage therapy for recurrent GBM. FRS to both contrast enhancing and FLAIR abnormalities appeared to improve local tumor control, and reduce regional tumor progression. PMID- 24173683 TI - Treatment outcomes in glioblastoma patients aged 76 years or older: a multicenter retrospective cohort study. AB - Age is one of the most important prognostic factors in glioblastoma patients, but no standard treatment has been established for elderly patients with this condition. We therefore conducted a retrospective cohort study to evaluate treatment regimens and outcomes in elderly glioblastoma patients. The study population consisted of 79 glioblastoma patients aged >= 76 years (median age 78.0 years; 34 men and 45 women). The median preoperative Karnofsky performance status (KPS) score was 60. Surgical procedures were classified as biopsy (31 patients, 39.2 %), <95 % resection of the tumor (21 patients, 26.9 %), and >= 95 % resection of the tumor (26 patients, 33.3 %). Sixty-seven patients (81.0 %) received radiotherapy and 45 patients (57.0 %) received chemotherapy. The median overall progression-free survival time was 6.8 months, and the median overall survival time was 9.8 months. Patients aged >= 78 years were significantly less likely to receive radiotherapy (p = 0.004). Patients with a postoperative KPS score of >= 60 were significantly more likely to receive maintenance chemotherapy (p = 0.008). Multivariate analyses identified two independent prognostic factors: postoperative KPS score >= 60 (hazard ratio [HR] = 0.531, 95 % confidence interval [CI] 0.315-0.894, p = 0.017) and temozolomide therapy (HR = 0.442, 95 % CI 0.25-0.784, p < 0.001).The findings of this study suggest that postoperative KPS score is an important prognostic factor for glioblastoma patients aged >= 76 years, and that these patients may benefit from temozolomide therapy. PMID- 24173684 TI - Efficacy and selectivity of nilotinib on NF1-associated tumors in vitro. AB - Neurofibromatosis type 1 is a tumor suppressor gene disorder which predisposes patients to cutaneous neurofibromas, plexiform neurofibromas (PNFs) and malignant peripheral nerve sheath tumors (MPNSTs) among other neoplasias and manifestation. In this study, we examined the efficiency of nilotinib on PNF-derived Schwann cells and on cells of established MPNST lines in vitro. Nilotinib treatment for 10 days led to decreased proliferation, viability and vitality of the cells with 50 % inhibitory concentration (IC50) for proliferation varying from 3.1 to 9.0 MUM. We further addressed selectivity of the drug for tumor cells by simultaneously examining its efficacy on tumor cells (Schwann cells) and non tumor cells (fibroblasts) from the same tumor. For four out of the six PNFs studied, IC50 was lower in Schwann cells than in fibroblasts for all parameters measured (proliferation, vitality and viability), indicating good drug selectivity. In addition, nilotinib induced apoptosis and suppressed collagenase activity. Our results suggest that nilotinib may provide a treatment option for some PNFs and MPNSTs and our in vitro model of comparative treatment on tumor and non-tumor cells may provide a prototype of preclinical drug screening system toward personalized treatment. PMID- 24173685 TI - First records of talon cusps on baboon maxillary incisors argue for standardizing terminology and prompt a hypothesis of their formation. AB - Dental characters can provide vital clues for understanding intra- and intertaxonomic morphological variation and its underlying genetic and environmental components. However, the unambiguous identification of particular traits and their comparative study is often confounded by lack of consistent terminology in the relevant literature. This difficulty is exacerbated when the etiologies are not completely understood, as is the case with talon cusps. To date, research on talon cusps has focused on modern humans. In many instances, descriptions of talon cusps appear in clinical case studies focusing on their treatment and removal. What is lacking in those discussions, though, is a comparative framework, in which the occurrence of talon cusps in nonhuman primates, and possibly other mammals, is established and understood. Here, we report on a taloned upper central incisor of a wild baboon (Papio hamadryas ursinus) from South Africa. The anomalous incisor of this individual includes an exaggerated accessory cusp diagnosed as a Type II talon. Microcomputed tomographic and radiographic analyses show that the taloned cusp possesses enamel, dentin, and pulp. In addition, we identified an unclassifiable talon cusp on a central maxillary incisor of a baboon skull housed in the Smithsonian Institution's Natural History Museum collection. Our observations of talon cusps on baboon incisors demonstrate that, with regard to this phenomenon, systematic study of nonhuman primates is much needed, along with a consistent use of terminology in the anatomical and anthropological literature. Finally, we present a hypothesis of the formation of talon cusps on mammalian incisors. PMID- 24173686 TI - A comparison of methods for constructing confidence intervals after phase II/III clinical trials. AB - Recently, in order to accelerate drug development, trials that use adaptive seamless designs such as phase II/III clinical trials have been proposed. Phase II/III clinical trials combine traditional phases II and III into a single trial that is conducted in two stages. Using stage 1 data, an interim analysis is performed to answer phase II objectives and after collection of stage 2 data, a final confirmatory analysis is performed to answer phase III objectives. In this paper we consider phase II/III clinical trials in which, at stage 1, several experimental treatments are compared to a control and the apparently most effective experimental treatment is selected to continue to stage 2. Although these trials are attractive because the confirmatory analysis includes phase II data from stage 1, the inference methods used for trials that compare a single experimental treatment to a control and do not have an interim analysis are no longer appropriate. Several methods for analysing phase II/III clinical trials have been developed. These methods are recent and so there is little literature on extensive comparisons of their characteristics. In this paper we review and compare the various methods available for constructing confidence intervals after phase II/III clinical trials. PMID- 24173687 TI - Tetrandrine induces apoptosis and triggers a caspase cascade in U2-OS and MG-63 cells through the intrinsic and extrinsic pathways. AB - Although neoadjuvant chemotherapy has improved the survival rate of osteosarcoma patients, drug resistance remains a predominant obstacle to improving efficacy and necessitates the development of novel chemotherapeutical agents. The aim of this study was to investigate whether tetrandrine (TET) induces apoptosis in the U-2OS and MG-63 osteosarcoma cell lines and to further determine the underlying mechanism. This study investigated the effects of TET on osteosarcoma in vitro. To examine the antitumor effects of TET on osteosarcoma, the two osteosarcoma cell lines were treated with TET and subjected to apoptosis assays. The results revealed that TET induced the apoptosis of osteosarcoma cells in a time- and dose dependent manner. Furthermore, the apoptosis of osteosarcoma cells was accompanied by increased cytochrome c (Cyto-C), apoptotic protease-activating factor (Apaf)-1, Bid and Bax activation and reduced Bcl-2 and Bcl-xl activation, demonstrating that the apoptosis may have occurred through the mitochondrial pathway. In conclusion, the results suggest that TET is a promising agent for osteosarcoma therapy. PMID- 24173688 TI - Multiple-line cross QTL mapping for biomass yield and plant height in triticale (* Triticosecale Wittmack). AB - KEY MESSAGE: QTL mapping in multiple families identifies trait-specific and pleiotropic QTL for biomass yield and plant height in triticale. Triticale shows a broad genetic variation for biomass yield which is of interest for a range of purposes, including bioenergy. Plant height is a major contributor to biomass yield and in this study, we investigated the genetic architecture underlying biomass yield and plant height by multiple-line cross QTL mapping. We employed 647 doubled haploid lines from four mapping populations that have been evaluated in four environments and genotyped with 1710 DArT markers. Twelve QTL were identified for plant height and nine for biomass yield which cross-validated explained 59.6 and 38.2 % of the genotypic variance, respectively. A major QTL for both traits was identified on chromosome 5R which likely corresponds to the dominant dwarfing gene Ddw1. In addition, we detected epistatic QTL for plant height and biomass yield which, however, contributed only little to the genetic architecture of the traits. In conclusion, our results demonstrate the potential of genomic approaches for a knowledge-based improvement of biomass yield in triticale. PMID- 24173689 TI - Towards controllable growth of self-assembled SiGe single and double quantum dot nanostructures. AB - Fabrication of semiconductor single and double quantum dot (QD) nanostructures is of utmost importance due to their promising applications in the study of advanced cavity quantum electrodynamics, quantum optics and solid-state spin qubits. We present results about the controllable growth of self-assembled single and double SiGe QD arrays with an ultra-low areal density of 1 * 10(7) cm(-2) on nanohole patterned Si substrates via molecular beam epitaxy. The two dots in a double QD (DQD) aligned along the elongation direction of the nanoholes and show unsymmetrical features in both size and composition due to the asymmetric nanohole profiles after Si buffer layer growth. The interdot spacing between the two dots in a DQD could well be adjusted by changing the elongation ratio of nanoholes. Moreover, whether a single or a double QD formed in a given nanohole was found to be determined by the growth temperature of the Si buffer layer, the reason of which is given by the calculation of the surface chemical potential around the nanoholes after the buffer layer growth. PMID- 24173690 TI - Direct catalytic asymmetric synthesis of N-heterocycles from commodity acid chlorides by employing alpha,beta-unsaturated acylammonium salts. AB - Taming the beast, asymmetrically: Modulation of the reactivity of acid chlorides, using cinchona alkaloid catalysts, results in chiral alpha,beta-unsaturated acylammoniums, which react with nucleophiles enantioselectively to give pyrrolidinones, piperid-2-ones, and dihydropyridinones. This nucleophile catalyzed Michael/proton transfer/lactamization or lactonization organocascade leads to chiral intermediates previously employed for the synthesis of bioactive pharmaceuticals. PMID- 24173691 TI - Maintenance therapy with calcium channel blockers for preventing preterm birth after threatened preterm labour. AB - BACKGROUND: Calcium channel blocker maintenance therapy is one of the types of tocolytic therapy that may be used after an episode of threatened preterm labour (and usually an initial dose of tocolytic therapy) in an attempt to prevent the onset of further preterm contractions. OBJECTIVES: To assess the effects of calcium channel blockers as maintenance therapy on preventing preterm birth after threatened preterm labour. SEARCH METHODS: We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (31 May 2013) and reference lists of retrieved studies. SELECTION CRITERIA: Randomised controlled trials of calcium channel blockers used as maintenance therapy to prevent preterm birth after threatened preterm labour, compared with placebo or no treatment. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed study eligibility, extracted data and assessed the risk of bias of included studies. MAIN RESULTS: We included six trials that enrolled 794 women and their babies and all assessed nifedipine as calcium channel blocker maintenance therapy. The six trials were judged to be at a moderate risk of bias overall. No differences in the incidence of preterm birth (risk ratio (RR) 0.97; 95% confidence interval (CI) 0.87 to 1.09; five trials, 681 women), birth within 48 hours of treatment (RR 0.46; 95% CI 0.07 to 3.00; two trials, 128 women) or neonatal mortality (average RR 0.75; 95% CI 0.05 to 11.76; two trials, 133 infants) were seen when nifedipine maintenance therapy was compared with placebo or no treatment. No stillbirths were reported in the one trial that provided data for this outcome. No trials reported on longer-term follow-up of infants.Women receiving nifedipine maintenance therapy were significantly more likely to have their pregnancy prolonged (mean difference (MD) 5.35 days; 95% CI 0.49 to 10.21; four trials, 275 women); however, no differences between groups were shown for birth at less than 34 weeks' gestation, birth at less than 28 weeks' gestation, birth within seven days of treatment, or gestational age at birth. No significant differences were shown between the nifedipine and control groups for any of the secondary neonatal morbidities reported. Similarly, no significant differences were seen for the outcomes relating to the use of health services, except for in one trial, where infants whose mothers received nifedipine were significantly more likely to have a longer length of hospital stay as compared with infants born to mothers who received a placebo (MD 14.00 days; 95% CI 4.21 to 23.79; 60 infants). AUTHORS' CONCLUSIONS: Based on the current available evidence, maintenance treatment with a calcium channel blocker after threatened preterm labour does not prevent preterm birth or improve maternal or infant outcomes. PMID- 24173692 TI - Scleroderma-related lung disease: are adipokines involved pathogenically? AB - Scleroderma is a systemic autoimmune disease of unknown etiology whose characteristic features include endothelial cell dysfunction, fibroblast proliferation, and immune dysregulation. Although almost any organ can be pathologically involved in scleroderma, lung complications including interstitial lung disease (ILD) and pulmonary arterial hypertension (PAH) are the leading cause of death in patients with this condition. Currently, the molecular mechanisms leading to development of scleroderma-related lung disease are poorly understood; however, the systemic nature of this condition has led many to implicate circulating factors in the pathogenesis of some of its organ impairment. In this article we focus on a new class of circulating factors derived from adipose-tissue called adipokines, which are known to be altered in scleroderma. Recently, the adipokines adiponectin and leptin have been found to regulate biological activity in endothelial, fibroblast, and immune cell types in lung and in many other tissues. The pleiotropic nature of these circulating factors and their functional activity on many cell types implicated in the pathogenesis of ILD and PAH suggest these hormones may be mechanistically involved in the onset and/or progression of scleroderma-related lung diseases. PMID- 24173693 TI - Yoga in rheumatic diseases. AB - Yoga is a popular activity which may be well suited to some individuals with specific rheumatic disorders. Regular yoga practice can increase muscle strength and endurance, proprioception, and balance, with emphasis on movement through a full range of motion to increase flexibility and mobility. Additional beneficial elements of yoga include breathing, relaxation, body awareness, and meditation, which can reduce stress and anxiety and promote a sense of calmness, general well being, and improved quality of life. Yoga also encourages a meditative focus, increased body awareness and mindfulness; some evidence suggests yoga may help reduce inflammatory mediators including C-reactive protein and interleukin-6. Yoga is best learned under the supervision of qualified teachers who are well informed about the potential musculoskeletal needs of each individual. Here, we briefly review the literature on yoga for healthy, musculoskeletal, and rheumatic disease populations and offer recommendations for discussing ways to begin yoga with patients. PMID- 24173694 TI - Olanzapine is effective for refractory chemotherapy-induced nausea and vomiting irrespective of chemotherapy emetogenicity. AB - PURPOSE: The role of olanzapine added to a dopamine antagonist and benzodiazepine for the treatment of refractory chemotherapy-induced nausea and vomiting (CINV) is incompletely characterized in all levels of chemotherapy emetogenicity. This retrospective study evaluated the efficacy of the addition of olanzapine in adults experiencing refractory CINV stratified by chemotherapy emetogenicity. METHODS: Thirty-three adults who experienced CINV refractory to guideline recommended prophylaxis and breakthrough antiemetics (dopamine antagonists and benzodiazepines) and received at least one dose of olanzapine 5-10 mg per os were evaluated. Failure was defined as >5 emesis events in 24 h or more than 10 cumulative doses of rescue antiemetics following first olanzapine dose per treatment cycle. Post hoc analyses investigated variables impacting olanzapine efficacy. RESULTS: The addition of olanzapine demonstrated an overall success rate of 70 %. This success rate did not differ between chemotherapy regimens of high versus low-to-moderate emetogenicity (p = 0.79), prophylaxis with serotonin antagonist plus corticosteroid and aprepitant versus serotonin antagonist alone (p = 0.77), or age over 50 versus <=50 years (p > 0.99). A trend toward greater benefit was seen in women (p = 0.08). CONCLUSIONS: The addition of olanzapine to a dopamine antagonist and benzodiazepine demonstrated high efficacy rates for refractory CINV irrespective of chemotherapy emetogenicity. The high success rates among all groups suggests that incomplete resolution of CINV with prophylactic serotonin antagonists and breakthrough dopamine antagonists plus benzodiazepine may benefit from the addition of olanzapine regardless of gender, degree of chemotherapy emetogenicity, number of prophylactic antiemetics, or age. The trend toward greater control of emesis in women merits further investigation. PMID- 24173695 TI - Prognostic value of tumor volume for patients with nasopharyngeal carcinoma treated with concurrent chemotherapy and intensity-modulated radiotherapy. AB - PURPOSE: We aimed to analyze prognostic factors in patients with nasopharyngeal carcinoma (NPC) treated with concurrent chemotherapy and intensity-modulated radiotherapy (IMRT); in addition, we aimed to elucidate the value of primary gross tumor volume (GTVp) in predicting prognosis of patients. METHODS: Between February 2001 and December 2008, 321 patients with NPC treated with concurrent chemotherapy and IMRT were analyzed retrospectively. GTVp was calculated from treatment planning computed tomography scans. A receiver operating characteristics (ROC) curve was used to determine the best cutoff point of GTVp. RESULTS: The 5-year local failure-free survival (LFFS), distant metastasis-free survival (DMFS), disease-free survival (DFS), and overall survival (OS) for NPC patients were 93.8, 80.1, 73.0, and 83.7 %, respectively. Univariate and multivariate analyses indicated that GTVp had exhibited a statistically significant correlation with LFFS, DMFS, DFS, and OS (P < 0.05, all), whereas T classification was not an independent prognostic factor. According to ROC curve analysis, 49 and 19 mL were determined as the cutoff points of GTVp for local control and distant metastasis, respectively. Based on this, 321 patients were divided into three volume subgroups. LFFS, DMFS, DFS, and OS demonstrated significant differences among patients in different volume subgroups (P < 0.001, all) and were superior to T classification for predicting prognosis of NPC patients. CONCLUSIONS: Primary gross tumor volume is an independent prognostic factor in local control, distant metastasis, disease-free survival, and overall survival in NPC. An adjusted TNM staging system that includes GTVp as a quantitative indicator to evaluate prognosis is warranted. PMID- 24173697 TI - Characterization of microRNA expression profiles in patients with intervertebral disc degeneration. AB - Intervertebral disc degeneration (IDD) is associated with lower back pain and is a global burden with severe healthcare and socioeconomic consequences. However, the underlying mechanisms of IDD remain largely unelucidated. Accumulating evidence has indicasted that newly defined gene regulators, microRNAs (miRNAs), play a vital role in neurodegenerative, pathophysiological and certain reproductive disorders. To characterize the differential miRNA expression profiles between IDD and spinal cord injury, specimens from 3 patients with IDD and 3 with spinal cord injury were selected for microarray analysis. Total RNA from these 6 specimens was extracted and subjected to global miRNA expression analysis using the Exiqon miRCURYTM LNA Array (v.16.0). The microarray data were then validated by quantitative reverse transcription polymerase chain reaction (qRT-PCR). In addition, bioinformatics analysis was performed to investigate the dysregulated miRNA target genes and signaling pathways involved. Among the miRNAs analyzed, 25 miRNAs were found to be upregulated and 26 were found to be downregulated in the IDD group compared with the spinal cord injury group. The qRT-PCR results validated the microarray data. Bioinformatics analysis indicated that the signaling pathways most likely to be controlled by these miRNAs were the phosphoinositide 3-kinase (PI3K)-Akt, mitogen-activated protein kinase (MAPK), epidermal growth factor receptor (EGFR; ErbB) and Wnt pathways. Our results demonstrated that the miRNA expression in patients with IDD differed significantly from that in patients who sustained injury to the intervertebral disc. Our data indicate that the dysregulated miRNAs control the signaling pathways important for the maintenance of IDD. Further studies on miRNA target gene identification and biological functions may address the specific regulatory mechanisms of miRNAs in IDD, and may provide valuable insight into the diagnosis and treatment of IDD. PMID- 24173696 TI - Changes in the peripheral blood and bone marrow from untreated advanced breast cancer patients that are associated with the establishment of bone metastases. AB - Bone metastasis is an incurable complication of breast cancer affecting 70-80 % of advanced patients. It is a multistep process that includes tumour cell mobilisation, intravasation, survival in the circulation, extravasation, migration and proliferation in the bone marrow/bone. Although novel findings demonstrate the bone marrow microenvironment significance in bone metastatic progression, a majority of studies have focused on end-stage disease and little is known about how the pre-metastatic niche arises in the bone marrow/bone tissues. We demonstrated a significant increase in patients' peripheral blood plasma ability to induce transendothelial migration of MCF-7 cells compared with healthy volunteers. Moreover, high RANKL, MIF and OPG levels in patients' peripheral blood could play a role in the intravasation, angiogenesis, survival and epithelial-mesenchymal transition of circulating tumour cells. Also, we observed a significant increase in patients' bone marrow plasma capacity to induce transendothelial migration of MDA-MB231 and MCF-7 cells compared with healthy volunteers. Furthermore, patients' bone marrow mesenchymal stem cells could control the recruitment of tumour cells, modifying the MCF-7 and MDA-MB231 cell migration. In addition, we found a significantly higher MDA-MB231 cell proliferation when we used patients' bone marrow plasma compared with healthy volunteers. Interestingly, PDGF-AB, ICAM-1 and VCAM-1 levels in patients' bone marrow were significantly higher than the values of healthy volunteers, suggesting that they could be involved in the cancer cell extravasation, bone resorption and cancer cell proliferation. We believe that these results can reveal new information about what alterations happen in the bone marrow of advanced breast cancer patients before bone colonisation, changes that create optimal soil for the metastatic cascade progression. PMID- 24173698 TI - Ascorbate metabolism in rice genotypes differing in zinc efficiency. AB - Effects of zinc (Zn) deficiency on shoot metabolites were investigated in contrasting rice (Oryza sativa L.) genotypes with special focus on ascorbic acid (AsA) biosynthesis, recycling, and catabolism. The genotypes IR74 (sensitive) and RIL46 (tolerant) were subjected to -Zn and control treatments for 3 weeks, and samples were taken at three different stages representing the pre-stress phase, emergence of visible stress, and severe visible stress. The emergence of visible symptoms was paralleled by an increase in lipid peroxidation and a decrease in AsA concentration in the sensitive, but not in the tolerant genotype. The tolerant RIL46 showed enhanced transcript levels of several genes involved in the mannose/L-galactose pathway to AsA biosynthesis, and significant up-regulation of a gene involved in the putative alternative myo-inositol pathway under low Zn stress. The level of most AsA precursors was negatively affected by Zn deficiency, but RIL46 had a constitutively higher level of non-phosphorylated precursors. Products of AsA catabolism such as oxalate and threonate did not accumulate in either genotype, suggesting that AsA degradation did not contribute to the stress-induced decline of the AsA pool in IR74. Further factors possibly contributing to tolerance in RIL46 included an almost fivefold higher proline level under -Zn stress and significantly higher trehalose content. The implications of these compounds in AsA metabolism and Zn efficiency thus deserve further attention. PMID- 24173699 TI - Wavelength-controlled photocleavage for the orthogonal and sequential release of multiple proteins. AB - On the right wavelength: Photolabile molecular units that undergo photocleavage under light of different wavelengths can be used for the independent release of different dyes/proteins from a single, preloaded storage hydrogel. The controlled release of each protein allowed them to be delivered sequentially and at experimenter-determined times. PMID- 24173703 TI - Executive summary. PMID- 24173701 TI - Preface. PMID- 24173704 TI - The international commission on radiation units and measurements. PMID- 24173700 TI - Recent advances in metabolic imaging. AB - Abnormalities in myocardial substrate metabolism play a central role in the manifestations of most forms of cardiac disease such as ischemic heart disease, heart failure, hypertensive heart disease, and the cardiomyopathy due to either obesity or diabetes mellitus. Their importance is exemplified by both the development of numerous imaging tools designed to detect the specific metabolic perturbations or signatures related to these different diseases, and the vigorous efforts in drug discovery/development targeting various aspects of myocardial metabolism. Since the prior review in 2005, we have gained new insights into how perturbations in myocardial metabolism contribute to various forms of cardiac disease. For example, the application of advanced molecular biologic techniques and the development of elegant genetic models have highlighted the pleiotropic actions of cellular metabolism on energy transfer, signal transduction, cardiac growth, gene expression, and viability. In parallel, there have been significant advances in instrumentation, radiopharmaceutical design, and small animal imaging, which now permit a near completion of the translational pathway linking in-vitro measurements of metabolism with the human condition. In this review, most of the key advances in metabolic imaging will be described, their contribution to cardiovascular research highlighted, and potential new clinical applications proposed. PMID- 24173705 TI - 1. Introduction. PMID- 24173706 TI - 2. Definitions of quantities and terms. PMID- 24173708 TI - 4. Cosmic-radiation fields at aircraft flight altitudes. PMID- 24173707 TI - 3. Radiation protection considerations. PMID- 24173709 TI - 5. Dosimetry of radiation fields in aircraft. PMID- 24173710 TI - 6. Reference data. PMID- 24173712 TI - Increased soluble vascular adhesion molecule-1 concentration is associated with impaired coronary flow reserve in cardiac syndrome X. AB - It is well known that both atherosclerosis initiated by endothelial dysfunction due to inflammatory cascade and coronary flow reserve (CFR) are useful in the functional or risk assessment of coronary microcirculation. The aim of this study is to elucidate the association between early atherosclerotic inflammatory markers and CFR using transthoracic echocardiography (TTE) in subjects with cardiac syndrome X. A total of 135 individuals (mean age 56 +/- 9 years, 79 males and 56 females) with angina or angina-like chest pain and a normal coronary angiogram were enrolled. The early inflammatory biomarkers related to atherosclerosis, namely soluble vascular adhesion molecule-1 (sVCAM-1), interleukin-6 (IL-6), monocyte chemoattractant protein-1 (MCP-1), and lipoprotein associated phospholipase A2 (Lp-PLA2), were compared with analyzed CFR, using TTE and adenosine or dipyridamole, measured within 2 weeks after coronary angiography. There was an inverse correlation between sVCAM-1 and CFR (r = 0.225, P = 0.014). In the two groups divided by a CFR of 2.0, sVCAM-1 was significantly higher in the group with CFR <2.0 than in the group with CFR >=2.0 (n = 21: 757 +/- 323 ng/ml, vs n = 114: 628 +/- 146 ng/ml, P = 0.007). In multivariate analysis, sVCAM-1 was an independent factor related to a CFR <2.0 (odds ratio 1.003, 95 % confidence interval 1.001-1.006, P = 0.023). Our results showed that sVCAM-1 levels were inversely associated with CFR using TTE in cardiac syndrome X. Further studies are warranted to validate whether increased sVCAM-1 concentration, as an inflammatory modulator, is reflected in the presence of subclinical coronary atherosclerosis. PMID- 24173713 TI - Direct observation of microtubule pushing by cortical dynein in living cells. AB - Microtubules are under the influence of forces mediated by cytoplasmic dynein motors associated with the cell cortex. If such microtubules are free to move, they are rapidly transported inside cells. Here we directly observe fluorescent protein-labeled cortical dynein speckles and motile microtubules. We find that several dynein complex subunits, including the heavy chain, the intermediate chain, and the associated dynactin subunit Dctn1 (also known as p150glued) form spatially resolved, dynamic speckles at the cell cortex, which are preferentially associated with microtubules. Measurements of bleaching and dissociation kinetics at the cell cortex reveal that these speckles often contain multiple labeled dynein heavy-chain molecules and turn over rapidly within seconds. The dynamic behavior of microtubules, such as directional movement, bending, or rotation, is influenced by association with dynein speckles, suggesting a direct physical and functional interaction. Our results support a model in which rapid turnover of cell cortex-associated dynein complexes facilitates their search to efficiently capture and push microtubules directionally with leading plus ends. PMID- 24173714 TI - Substrate stiffness regulates solubility of cellular vimentin. AB - The intermediate filament protein vimentin is involved in the regulation of cell behavior, morphology, and mechanical properties. Previous studies using cells cultured on glass or plastic substrates showed that vimentin is largely insoluble. Although substrate stiffness was shown to alter many aspects of cell behavior, changes in vimentin organization were not reported. Our results show for the first time that mesenchymal stem cells (hMSCs), endothelial cells, and fibroblasts cultured on different-stiffness substrates exhibit biphasic changes in vimentin detergent solubility, which increases from nearly 0 to 67% in hMSCs coincident with increases in cell spreading and membrane ruffling. When imaged, the detergent-soluble vimentin appears to consist of small fragments the length of one or several unit-length filaments. Vimentin detergent solubility decreases when these cells are subjected to serum starvation, allowed to form cell-cell contacts, after microtubule disruption, or inhibition of Rac1, Rho-activated kinase, or p21-activated kinase. Inhibiting myosin or actin assembly increases vimentin solubility on rigid substrates. These data suggest that in the mechanical environment in vivo, vimentin is more dynamic than previously reported and its assembly state is sensitive to stimuli that alter cellular tension and morphology. PMID- 24173715 TI - Autophagosomes contribute to intracellular lipid distribution in enterocytes. AB - Enterocytes, the intestinal absorptive cells, have to deal with massive alimentary lipids upon food consumption. They orchestrate complex lipid trafficking events that lead to the secretion of triglyceride-rich lipoproteins and/or the intracellular transient storage of lipids as lipid droplets (LDs). LDs originate from the endoplasmic reticulum (ER) membrane and are mainly composed of a triglyceride (TG) and cholesterol-ester core surrounded by a phospholipid and cholesterol monolayer and specific coat proteins. The pivotal role of LDs in cellular lipid homeostasis is clearly established, but processes regulating LD dynamics in enterocytes are poorly understood. Here we show that delivery of alimentary lipid micelles to polarized human enterocytes induces an immediate autophagic response, accompanied by phosphatidylinositol-3-phosphate appearance at the ER membrane. We observe a specific and rapid capture of newly synthesized LD at the ER membrane by nascent autophagosomal structures. By combining pharmacological and genetic approaches, we demonstrate that autophagy is a key player in TG targeting to lysosomes. Our results highlight the yet-unraveled role of autophagy in the regulation of TG distribution, trafficking, and turnover in human enterocytes. PMID- 24173716 TI - Persistent telomere cohesion triggers a prolonged anaphase. AB - Telomeres use distinct mechanisms (not used by arms or centromeres) to mediate cohesion between sister chromatids. However, the motivation for a specialized mechanism at telomeres is not well understood. Here we show, using fluorescence in situ hybridization and live-cell imaging, that persistent sister chromatid cohesion at telomeres triggers a prolonged anaphase in normal human cells and cancer cells. Excess cohesion at telomeres can be induced by inhibition of tankyrase 1, a poly(ADP-ribose) polymerase that is required for resolution of telomere cohesion, or by overexpression of proteins required to establish telomere cohesion, the shelterin subunit TIN2 and the cohesin subunit SA1. Regardless of the method of induction, excess cohesion at telomeres in mitosis prevents a robust and efficient anaphase. SA1- or TIN2-induced excess cohesion and anaphase delay can be rescued by overexpression of tankyrase 1. Moreover, we show that primary fibroblasts, which accumulate excess telomere cohesion at mitosis naturally during replicative aging, undergo a similar delay in anaphase progression that can also be rescued by overexpression of tankyrase 1. Our study demonstrates that there are opposing forces that regulate telomere cohesion. The observation that cells respond to unresolved telomere cohesion by delaying (but not completely disrupting) anaphase progression suggests a mechanism for tolerating excess cohesion and maintaining telomere integrity. This attempt to deal with telomere damage may be ultimately futile for aging fibroblasts but useful for cancer cells. PMID- 24173717 TI - A cellular genome-wide association study reveals human variation in microtubule stability and a role in inflammatory cell death. AB - Pyroptosis is proinflammatory cell death that occurs in response to certain microbes. Activation of the protease caspase-1 by molecular platforms called inflammasomes is required for pyroptosis. We performed a cellular genome-wide association study (GWAS) using Salmonella typhimurium infection of human lymphoblastoid cell lines as a means of dissecting the genetic architecture of susceptibility to pyroptosis and identifying unknown regulatory mechanisms. Cellular GWAS revealed that a common human genetic difference that regulates pyroptosis also alters microtubule stability. An intergenic single-nucleotide polymorphism on chromosome 18 is associated with decreased pyroptosis and increased expression of TUBB6 (tubulin, beta 6 class V). TUBB6 is unique among tubulin isoforms in that its overexpression can completely disrupt the microtubule network. Cells from individuals with higher levels of TUBB6 expression have lower microtubule stability and less pyroptosis. Reducing TUBB6 expression or stabilizing microtubules pharmacologically with paclitaxel (Taxol) increases pyroptosis without affecting the other major readout of caspase-1 activation, interleukin-1beta secretion. The results reveal a new role for microtubules and possibly specific tubulin isoforms in the execution of pyroptosis. Furthermore, the finding that there is common diversity in TUBB6 expression and microtubule stability could have broad consequences for other microtubule-dependent phenotypes, diseases, and pharmacological responses. PMID- 24173720 TI - Reply: Time-lapse parameters could not predict pregnancy: a hasty conclusion? PMID- 24173719 TI - Review of a rheumatology triage system: simple, accurate, and effective. AB - Rheumatology triage systems exist to expedite care for those with inflammatory arthritis (IA). This study presents the first 22-month experience of a simple and unique Canadian university-based triage system. Triage accuracy is analyzed as is the effect on access to care for patients with IA. The triage rheumatologist screens all incoming referral letters to attempt to identify possible diagnoses and, consequently, assigns urgency of assessment. The wait time for patients with IA after introduction of the triage system was compared to a random sample of IA patients from the year preceding the triage system. All newly referred IA patients who were incorrectly triaged as a non-inflammatory process were identified, with a subsequent chart review examining for features that may have influenced the triage status. Three thousand four hundred seventy-six new referrals were seen, with 344 patients receiving a final diagnosis of IA. The median wait time for all patients was 57.0 days, 37.5 days for IA patients, and 25.0 days for IA patients assigned a soon urgency status. Compared to the preceding year, this latter group with inflammatory arthritis was seen 25.0 days sooner (p < 0.0001). Thirty-one patients with inflammatory arthritis were incorrectly screened as a non-inflammatory process, 10 of whom had features in the referral letter or investigations suggestive of IA. This triage system correctly identifies patients with IA with an accuracy of 91.0 % and effectively reduces their wait time when assigned an appropriate urgency status. Utilization of this triage system may be universally applicable, accurate, and a cost effective way to optimize rheumatology patients' access to care. PMID- 24173718 TI - NEAT1 long noncoding RNA regulates transcription via protein sequestration within subnuclear bodies. AB - Paraspeckles are subnuclear structures formed around nuclear paraspeckle assembly transcript 1 (NEAT1)/MENepsilon/beta long noncoding RNA (lncRNA). Here we show that paraspeckles become dramatically enlarged after proteasome inhibition. This enlargement is mainly caused by NEAT1 transcriptional up-regulation rather than accumulation of undegraded paraspeckle proteins. Of interest, however, using immuno-electron microscopy, we find that key paraspeckle proteins become effectively depleted from the nucleoplasm by 50% when paraspeckle assembly is enhanced, suggesting a sequestration mechanism. We also perform microarrays from NEAT1-knockdown cells and find that NEAT1 represses transcription of several genes, including the RNA-specific adenosine deaminase B2 (ADARB2) gene. In contrast, the NEAT1-binding paraspeckle protein splicing factor proline/glutamine rich (SFPQ) is required for ADARB2 transcription. This leads us to hypothesize that ADARB2 expression is controlled by NEAT1-dependent sequestration of SFPQ. Accordingly, we find that ADARB2 expression is strongly reduced upon enhanced SFPQ sequestration by proteasome inhibition, with concomitant reduction in SFPQ binding to the ADARB2 promoter. Finally, NEAT1(-/-) fibroblasts are more sensitive to proteasome inhibition, which triggers cell death, suggesting that paraspeckles/NEAT1 attenuates the cell death pathway. These data further confirm that paraspeckles are stress-responsive nuclear bodies and provide a model in which induced NEAT1 controls target gene transcription by protein sequestration into paraspeckles. PMID- 24173721 TI - Advanced glycation end products and their relevance in female reproduction. AB - STUDY QUESTION: Do advanced glycation end products (AGEs) and their receptors play a role in female reproduction? SUMMARY ANSWER: AGEs might contribute to the etiology of polycystic ovary syndrome (PCOS) and infertility. WHAT IS KNOWN ALREADY: The endogenous AGEs are produced in the body by chemical reactions. Exogenous sources of AGEs are diet and smoking. AGEs have been proposed to be among the main intermediaries involved in several diseases, such as metabolic syndrome, type 2 diabetes mellitus, cardiovascular disease, ovarian aging, inflammation, neurodegenerative disorders and PCOS. STUDY DESIGN, SIZE, DURATION: A systematic review was performed for all available basic science and clinical peer-reviewed articles published in PubMed from 1987 to date. Abstracts of annual meetings of the Endocrine Society and American Society for Reproductive Medicine were also reviewed. PARTICIPANTS/MATERIALS, SETTING, METHODS: A total of 275 publications and scientific abstracts were identified from the initial search. Sixty-two papers and four published scientific abstracts were selected for full review. The main outcomes were the regulatory effects of AGEs on: (i) granulosa cells, adipocyte physiology, obesity and insulin resistance in women with PCOS and in polycystic ovary animal models and (ii) infertility and measures of ovarian reserve. MAIN RESULTS AND THE ROLE OF CHANCE: There is an intricate relationship between the AGE-RAGE (receptor for AGEs) system and some aspects of PCOS, such as granulosa cell dysfunction, adipocyte pathophysiology, obesity and insulin resistance. Additionally, irregular ovarian AGE signaling might in part explain the abnormal ovarian histology observed in women with PCOS. The ovarian dysfunction due to AGEs in women without PCOS suggests a role for the AGE-RAGE system in the ovarian follicular environment, and might relate to assisted reproduction technology outcome and measures of ovarian reserve. LIMITATIONS, REASONS FOR CAUTION: The body of literature currently available limits these findings. The results obtained from granulosa cell lines and animal models may not fully extrapolate to humans. WIDER IMPLICATIONS OF THE FINDINGS: This review underscores a critical need to unveil the exact mechanistic actions of AGEs in reproductive physiology and more specifically the hypothalamic-pituitary-ovarian axis. AGE inhibitors might present an emerging therapeutic approach with significant applications in the context of PCOS and infertility. STUDY FUNDING/COMPETING INTEREST(S): American Society for Reproductive Medicine New Investigator Award and University of Vermont College of Medicine Internal Funds. No competing interests. PMID- 24173723 TI - Foreword. PMID- 24173722 TI - Time-lapse parameters could not predict pregnancy: a hasty conclusion? PMID- 24173724 TI - Editorial. PMID- 24173725 TI - The development of aesthetic plastic surgery: A history. AB - Aesthetic plastic surgery had its origins, probably with Dieffenbach, in the mid 1800's. In its earliest stages great use was made of external incisions in the facial region, which were obvious to the casual observer. Yet the true beginning of aesthetic plastic surgery as we know it today, was not until 1887, when John Orlando Roe introduced an intranasal corrective operation on the nose. From that time onward, aesthetic plastic surgery developed in a fascinating manner over the subsequent decades to become the fine scientific art we take for granted today. PMID- 24173726 TI - Some technical considerations in primary rhinoplasty. AB - Technique in rhinoplasty is discussed in terms of safety, facility, and versatility. Nasal appearance results from the anatomic variation of the component parts. Technique should reflect modifications necessary to correct unpleasant features while respecting anatomic limitations. Techniques are described for dorsal reduction and tip modification by methods that consider surgical exposure and the relation between structural anatomy and external appearance. PMID- 24173727 TI - Aesthetic judgment in the surgery of appearance. AB - The aesthetic judgment of human appearance differs from that of the visual arts in that the former is determined not only by the degree of balance and harmony of proportions of its component parts, but also by such factors as body posture and movement and facial expression. Since these are influenced by ethnic background, environment, education, health, and mood of the individual, human appearance from the surgeon's point of view cannot be judged solely on its relationship to the proportions of a classic beauty ideal. From the patient's point of view, judgment of his own appearance introduces a subjective element and involves the way he sees himself in relation to his social environment. His aesthetic judgment is thus rooted in social psychology and modified by certain aspects of his individual psychologic makeup. As far as the patient's daily contacts are concerned, their judgment of his appearance is based on criteria similar to those of the surgeon, but perhaps more strongly influenced by the psychology of interpersonal relationships. PMID- 24173728 TI - Reduction mammoplasty: Borrowing the good points of many techniques. AB - The purposes of the reduction mammoplasty are: (a) relief of the pain and discomfort of heavy, pendulous breasts; (b) a normal and pleasing appearance with the brassiere in place and the patient clothed; (c) a reasonable, pleasing contour to the breasts, from front and side, without the support of clothing or brassiere; (d) normally sensitive nipples that become erect on stimulation; (e) minimal apparent permanent scarring; (f) ideally, intact ducts to the nipple; (g) a breast of size allowing for examination for breast masses; (h) eradication of breast masses; (i) a happy patient.Certain circumstances-such as the presence of considerable amounts of diseased breast tissue, scars from resections of lesions of the breasts or from trauma, and massive hypertrophy of the breasts which may dictate a technique requiring free tranplantation of nipples and areolae understandably may forestall achievement of some of these objectives. However, several of the recent techniques allow the surgeon to achieve these goals in a large percentage of cases. A combination of the better aspects of these techniques, with minor variations, may allow the surgeon to deal even better and more consistently with the problem. The author's technique evolved from the salient points of other techniques he considered desirable enough to borrow. PMID- 24173729 TI - Surgery for oriental eyelids: Some refinements in technique. AB - Surgery of Oriental eyelids falls into two broad groups. One method uses the conjunctival approach, and the other, the external skin approach. Technical refinements in the skin approach method which the author has developed over the last 10 years are described. PMID- 24173730 TI - Aesthetic surgery in the perioral region. AB - The authors describe six procedures used for the correction of various symptoms of the aging process in the perioral region, featuring augmentation cheiloplasty and smoothening of the nasolabial crease. PMID- 24173731 TI - Aesthetic plastic surgery: Some caveats. AB - Aesthetic plastic surgery requires particular expertise in determining the patient's potential postoperative satisfaction. As the demand for this surgical specialty increases, so too do the possible psychological hazards associated with patient selection. Because the complaints of patients with minimal defects and their evaluation of the cosmetic results tend to be highly subjective-in contrast to the more objective and realistic complaints of those with marked disfigurement careful interviewing of candidates is essential. In special need of skillful screening are those patients who, although they may present some correctable imperfection, are not only vague as to what they think they want done and what they expect but also are unaware of the underlying causes of their self discontent. Such individuals, once accepted for surgery, can present management problems that may lead to outcomes detrimental to themselves, to the surgeon, or to both. PMID- 24173732 TI - Personal contribution for the surgical treatment of negroid noses. AB - The author describes the characteristics of a Brazilian negroid nose and describes a surgical technique in which the nasal dorsum is corrected by one of the commonly employed methods.For treatment of the tip, nasal solum, columella, and nostrils, he has created a flap made up of those structures in which the rotation from the outside to the inside and from beneath to above heightens the tip, with lengthening of the columella and narrowing of the nostrils. PMID- 24173733 TI - Some observations on breast augmentation procedures over the past two decades. AB - The author describes his experience with various methods of breast augmentation over the past 20 years, with particular reference to the fate of dermofat grafts. PMID- 24173734 TI - ISAPS and the plastic surgeon: Report of survey. PMID- 24173735 TI - Further progress in the axillary approach in augmentation mammaplasty: Prevention of incapsulation. AB - Over the last 21/2 years since we have been practicing moving the implant in a relatively large cavity, incapsulation has been reduced to a minimum. Only implants without patches and profile have been used. Since 1973 the axillary approach has been successfully applied in 727 cases of augmentation mammaplasty. PMID- 24173736 TI - Gigantomastia : Treatment by the B technique. AB - CONCLUSION: In the author's and some other surgeons' hands, the B technique has served as an excellent method of performing mastopexies and breast reductions running the whole gamut from mere skin removal to gigantomastias. Its advantages are operative speed, absence of grafting, a scar that does not violate the medial half of the thorax, and a breast projection that lasts. In addition, nipple sensitivity is usually preserved. PMID- 24173737 TI - Evaluating patient satisfaction with the face lift, eyelid operation, or both. AB - A sampling of the many relationships that were investigated is presented. The study was intended to be descriptive or observational rather than inferential. The data represent a sample of a surgeon's patients who had had the face lift and/or eyelid operation. Hence, perhaps, the major limitation of the study is that all conclusions pertain to only such patients. Although experience and intuition may lead one to suspect that similar results would likely be obtained from a random sampling of similar patients of other plastic surgeons, such inferences cannot be made until further large-scale research is undertaken. In the interim, enough information has been gleaned from the present investigation to permit more effective treatment of future patients-both pre- and postoperatively. PMID- 24173738 TI - Aesthetic surgery of Oriental eyelids. AB - The technique for creation of a double eyelid with simultaneous reduction of the mongolian fold is presented as representative of aesthetic surgery of Oriental eyelids. The author's principle in correcting the mongolian fold is to first reduce the lining layer as a framework of the fold and then trim excess skin. PMID- 24173739 TI - A procedure for mammary reduction and mastopexy: Summary of 100 personally performed operations. AB - CONCLUSIONS: The advantages of this modified Ragnell procedure are that a conical breast is formed, the submammary scar is short and inconspicuous, and the operation is safe. PMID- 24173740 TI - Chin augmentation: Subperiosteal and supraperiosteal implants. AB - Implants placed in subperiosteal pockets may erode more deeply into the mandible than those placed above the periosteum. Those positioned supraperiosteally are more likely to shift and certainly are more mobile when pressure is put on the chin. Implants extending laterally far enough to produce a graceful flow of chin into cheek may be difficult to insert through a small incision. A technique is presented in which a two-piece carved silicone rubber implant is placed beneath periosteum laterally and above periosteum centrally. Results to date indicate that firm fixation with lateral tapering adequate to prevent an unpleasantly concentrated chin occurs. Insertion is accomplished easily through a small incision. PMID- 24173741 TI - The "Unpleasant" smile. AB - A simple procedure is described to correct what the authors call the unpleasant smile. The procedure consists of "hiding" the excessively visible upper arch mucosa exposed during smiling, and it usually solves the aesthetic problem in patients who reject a more complicated maxillofacial approach. Basically, the technique involves creating a synechia between the upper lip and the periosteum of the maxillary arch. This synechia eliminates overexcursion of the lip during smiling. PMID- 24173742 TI - A template (pattern) method of abdominal lipectomy. PMID- 24173743 TI - The history of blepharoplasty to correct blepharochalasis. PMID- 24173744 TI - Ophthalmic plastic surgery: The pioneers and their heritage in reconstructive surgery of the eyelids. PMID- 24173745 TI - Ethics in aesthetic surgery. PMID- 24173746 TI - Anatomical and technical refinements for abdominoplasty. AB - Several important details pertinent to the classic transversal low-incision abdominoplasty, commonly underestimated, are pointed out. Metameric sensitivity distribution is focused in the normal individual and then transformed by abdominoplasty. Emphasis is also given to the vascularization, lymphatic drainage, and treatment of the muscle-aponeurotic plane and femoral cutaneous nerve under effects of abdominoplasty. Attention is called to how effectively they can help to obtain symmetric postoperative results and how important it is to have a normal-looking, aesthetically pleasing navel. First introduced as a corrective procedure for abdomens grossly deformed by lipodystrophies or greatly compromised by hernias or problems related to multiple surgeries, abdominoplasty is no longer merely a reconstructive procedure. In the last 10 years, requests for abdominoplasty for aesthetic improvement of lax skin, "striae," and scars of even "good quality" situated in the infraumbilical area have increased in indirect proportion to the size of today's bathing suits.The great number of cosmetic abdominal surgeries calls for a better solution to problems such as the placement and quality of scars, the positioning of the umbilicus, and the resulting waistline. An increasing number of demands are made regarding minute details of asymmetry, sensibility, edema, and pain. Like the young surgeon in training, we had to search our anatomy books to find explanations and ways to avoid problems justifiable in earlier days but unacceptable today. PMID- 24173747 TI - The McKissock breast reduction. AB - Data on 26 patients with breast hypertrophy operated by the McKissock method are summarized.The advantages of the method include the following: (a) simplicity in planning; (b) facility in teaching and execution; (c) safety; (d) applicability to a large variety of patients and: (e) uniformly satisfactory results. Two case reports are presented and the literature is reviewed. PMID- 24173748 TI - Buried hair in scalp closure : Is it a problem? AB - This paper addresses itself to the question of what happens to buried hair in a wound. A case is reported of hair which was buried 5 months prior to a scar revision. The pathologic description is accompanied by discussion of hair strands and their dissolution. PMID- 24173749 TI - Changes in facial expression as a result of plastic surgery in mongoloid children. PMID- 24173750 TI - The forehead lift : Some hints to secure better results. AB - The operation for the forehead lift is reviewed considering the experience acquired in recent years in order to facilitate its safe execution. Particular attention is given to the removal of factors limiting the free upward movement of the frontal flap, such as preparation of the meso temporalis. The treatment of the muscular layer is updated and a number of safety measures are proposed to prevent any undue damage to the blood and nervous supply of the region. PMID- 24173751 TI - The viola player's deformity. AB - One never associates the fine arts with an occupational hazard. Among musicians, the callus of the violin or viola player is a most characteristic and unique professional mark. PMID- 24173752 TI - Cosmetic blepharoplasty using an electrocauterization technique. AB - A technique for creating thesuperior palpebral fold in Orientals and Caucasians without suture fixation to the tarsal plate is described. Essentially, the fold is created by a series of pinpoint electrocauterizations of the superficial tissues lying immediately external to the tarsus and the orbicularis oculi muscle. PMID- 24173753 TI - Surgical correction of the unusually short nose. AB - We present a personal method for the surgical correction of the traumatic or iatrogenic short nose. The lengthening is achieved by an advancement of the muco perichondrial wall, a manoeuver whose result is stabilized by means of cartilage grafts. PMID- 24173754 TI - Aesthetic surgery of the aging hand. AB - Preliminary considerations are made about the aesthetic surgery of the hands, stressing the fact that little interest has been devoted to this field. The senile changes of the hand are analyzed, mentioning the presence of sagging and wrinkling, the appearance of senile lentigos and senile keratoses, as well as dilatation of the dorsal veins.The etiology and histology of the senile changes are reviewed, including the effects of actinic rays and gravitational forces. A rational approach is undertaken by means of excision of the sagging skin, phleboexeresis, and chemical exfoliation. Our experience in the last 5 years is analyzed. PMID- 24173755 TI - Vicryl sutures. AB - Polyglactin 910 (Vicryl) approaches the desired qualities of an absorbable suture material. Laboratory investigations, clinical studies and the authors' own experience with this welcomed addition to the surgeon's armamentarium are reviewed. PMID- 24173756 TI - Leporine (cleft lip) nose. AB - The authors refer to the surgical technique used for correction of the leporine nose, occurring with unilateral cleft lip, and the variations according to the length of the columella. PMID- 24173757 TI - Volumetric breast measurement during surgery. AB - Unequal breasts following reduction mammaplasty sometimes provide an unfavourable result, despite careful measurements of removed tissue during surgery-Accurate comparison of breast volume during surgery could prevent this problem.-The authors have devised a simple, sterilizable, "mammasizer" which is capable of providing the surgeon with this essential information the moment he most requires it-prior to completion of surgery. PMID- 24173758 TI - Double antihelix: Its significance in the correction of prominent ears. AB - In performing otoplasty for correction of prominent ears, the aesthetic plastic surgeon may be faced with the existence of two antihelical folds especially if the conchal wall is too high. Thinning of the cartilage opposite and in between these two folds transforms them into a gently curved single fold that leads to a good aesthetic result. PMID- 24173760 TI - Problems and pitfalls in blepharoplasty. AB - Complications during or after blepharoplasty operations are described. These range from errors in assessing the patient's psychological state and the state of their health, through the more common physical sequelae of bleeding with haematoma formation, ectropion, hypertrophy of scars, etc., to complications affecting the function of the eye itself. The possibility of blindness arising as a result of blepharoplasty surgery is discussed, as are the theories of its causation, and the steps which may be taken to avert permanent loss of vision. PMID- 24173759 TI - History of rhinoplasty. PMID- 24173761 TI - Cervical lift: Surgical correction of fat contour problems combined with full width platysma muscle flaps. AB - Correction of neck deformities due to fat, platysma muscle bands, or a combination of these deformities along with sagging of all neck tissue can be satisfactorily corrected by surgery. A knowledge of the anatomy of the face and neck is necessary in order to make an accurate diagnosis of the anatomical causes and to execute appropriate and safe surgical correction. A combination of thorough fat removal and full-width platysma muscle flaps converted into deep layer sling support can eliminate the objectionable neck features, prevent recurring vertical muscle bands, produce pleasing neck contours along with a definition of the mandibular border, and avoid the problems which frequently occur when techniques which rely on skin tension or skin traction alone are used. PMID- 24173762 TI - External incisions on the nose. AB - Scars on the nose are very inconspicuous. For this reason it is possible to correct various types of nasal deformities employing external incisions. The most commonly employed of these are analyzed. Special references are made to correction of cleft lip and Latin American (Mestizo) noses. A small triangle resected in the anterior part of the nostril can change a flared nostril to a narrower one. When very fine sutures are used, the scars are almost invisible after a few months. PMID- 24173763 TI - Reaction to silicone implants in the guinea pig. AB - Many papers have been published on the lack of reaction around silicone implants both in the experimental animal and the human. A study with human silicone implants with silicone gel interior shows loss of the silicone fluid from intact silicone sac. A solid silicone disc subjected to 5 pounds weight for one week loses silicone to the underlying paper. In the guinea pig, some capsules surrounding solid silicone implants, silicone sacs with saline, and silicone sac with silicone gel show vacuole or amorphous materials (silicone) with a thickening of the capsule and associated inflammatory reaction. These vacuoles or amorphous material resembles the silicone found in capsules around intact human silicone jell prosthesis. The presence of silicone with associated thickening of the capsule and inflammatory reaction may be one cause of firmness in the human after breast augmentation by silicone implants. PMID- 24173764 TI - Dermabrasion of the skin: Prevention and/or treatment of hyperpigmentation. AB - Dermabrasion of the face for multiple conditions requiring reconstructive surgery is still a valuable tool for the plastic and reconstructive surgeon. This article deals specifically with one of the most important complications, namely, hyperpigmentation.The specific effect of estrogens on hyperpigmentation and the manner of dealing with it by the use of hydroquinone ointment are discussed. Illustrative case histories and photographs are shown. The reversal of the hyperpigmentation caused by estrogens and treated by hydroquinone ointment are explained, and the conclusion is reached that this management leads to permanent satisfactory results. PMID- 24173765 TI - Cosmetic advantages of augmenting the hypoplastic breast via the transaxillary route. AB - Augmentation mammoplasty by the transaxillary approach is an acceptable and safe technique with few complications. Proper preoperative planning and attention to surgical detail result in symmetrical and natural appearing breasts. The major advantage is related to the present female attire and desires to have a concealed scar. In about 3 months the incision is hardly noticeable and the woman is very pleased. PMID- 24173766 TI - Injuries of the great auricular nerve in rhytidectomy. AB - The great auricular nerve is most frequently injured in the course of rhytidectomy. Frequency of such injuries is many times higher than that of all other nerves combined. Estimate of such frequency cannot be obtained because many surgeons pay little attention to this complication. Patients often accept the discomfort of anesthesia of the external ear as a normal sequel of the operation, although an occasional neurotic patient may complain of the sensation of having his ear cut off. If the proximal end of the cut nerve becomes attached to the skin flap, neuroma will cause a trigger point on the lateral part of the neck. This may lead to a bizarre complaint of migraine-like pain on the side of the face. Two patients with neuroma of the great auricular nerve were seen, 1 and 2 years, respectively, after rhytidectomy. Diagnosis was confirmed by an operation. Repair of this nerve, either at the time of the operation or several years later, has a very favorable prognosis.The anatomy of this nerve and the precautions necessary to avoid injury during rhytidectomy will be discussed. PMID- 24173767 TI - Strain-promoted azide-alkyne cycloaddition with ruthenium(II)-azido complexes. AB - The reactivity of an exemplary ruthenium(II)-azido complex towards non-activated, electron-deficient, and towards strain-activated alkynes at room temperature and low millimolar azide and alkyne concentrations has been investigated. Non activated terminal and internal alkynes failed to react under such conditions, even under copper(I) catalysis conditions. In contrast, as expected, rapid cycloaddition was observed with electron-deficient dimethyl acetylenedicarboxylate (DMAD) as the dipolarophile. Since DMAD and related propargylic esters are excellent Michael acceptors and thus unsuitable for biological applications, we investigated the reactivity of the azido complex towards cycloaddition with derivatives of cyclooctyne (OCT), bicyclo[6.1.0]non-4 yne (BCN), and azadibenzocyclooctyne (ADIBO). While no reaction could be observed in the case of the less strained cyclooctyne OCT, the highly strained cyclooctynes BCN and ADIBO readily reacted with the azido complex, providing the corresponding stable triazolato complexes, which were amenable to purification by conventional silica gel column chromatography. An X-ray crystal structure of an ADIBO cycloadduct was obtained and verified that the formed 1,2,3-triazolato ligand coordinates the metal center through the central N2 atom. Importantly, the determined second-order rate constant for the ADIBO cycloaddition with the azido complex (k2=6.9 * 10(-2) M(-1) s(-1)) is comparable to the rate determined for the ADIBO cycloaddition with organic benzyl azide (k2=4.0 * 10(-1) M(-1) s(-1)). Our results demonstrate that it is possible to transfer the concept of strain promoted azide-alkyne cycloaddition (SPAAC) from purely organic azides to metal coordinated azido ligands. The favorable reaction kinetics for the ADIBO-azido ligand cycloaddition and the well-proven bioorthogonality of strain-activated alkynes should pave the way for applications in living biological systems. PMID- 24173768 TI - REV-ERB-ALPHA circadian gene variant associates with obesity in two independent populations: Mediterranean and North American. AB - SCOPE: Despite the solid connection between REV-ERB and obesity, the information about whether genetic variations at this locus may be associated with obesity traits is scarce. Therefore our objective was to study the association between REV-ERB-ALPHA1 rs2314339 and obesity in two independent populations. METHODS AND RESULTS: Participants were 2214 subjects from Spanish Mediterranean (n = 1404) and North American (n = 810) populations. Anthropometric, biochemical, dietary, and genotype analyses were performed. We found novel associations between the REV ERB-ALPHA1 rs2314339 genotype and obesity in two independent populations: in Spanish Mediterranean and North American groups, the frequency of the minor allele-carriers (AA+ AG) was significantly lower in the "abdominally obese" group than in those of the "nonabdominally obese" group (p < 0.05). Minor allele carriers had lower probability of abdominal obesity than noncarriers, and the effect was of similar magnitude for both populations (OR ~ 1.50). There were consistent associations between REV-ERB-ALPHA1 genotype and obesity-related traits (p < 0.05). Energy intake was not significantly associated with REV-ERB ALPHA1 rs2314339. However, physical activity significantly differed by genotype. A significant interaction between the REV-ERB-ALPHA1 variant and monounsaturated fatty-acids (MUFA) intake for obesity was also detected in the Mediterranean population. CONCLUSION: This new discovery highlights the importance of REV-ERB ALPHA1 in obesity and provides evidence for the connection between our biological clock and obesity-related traits. PMID- 24173769 TI - Berberine enhances chemosensitivity to irinotecan in colon cancer via inhibition of NF-kappaB. AB - Previous studies have shown that irinotecan (CPT-11) impairs chemotherapy-induced apoptosis by activating nuclear factor-kappaB (NF-kappaB) and a number of strategies have been employed to augment chemosensitivity through the suppression of NF-kappaB activation. Berberine, a botanical alkaloid, was reported to enhance chemosensitivity to 5-fluorouracil and doxorubicin by suppressing NF-kappaB activation. In the present study, the effect of berberine on CPT-11-induced apoptosis was investigated through the inhibition of NF-kappaB. Inhibition of NF kappaB activation by p65 small interfering RNA was shown to potentiate apoptosis induced by CPT-11. Berberine suppressed CPT-11-induced NF-kappaB activation in a dose-dependent manner and enhanced chemosensitivity to CPT-11 by downregulating NF-kappaB activation of antiapoptotic genes, c-IAP1, c-IAP2, survivin and Bcl-xL. The current observations indicate that berberine inhibits NF-kappaB activation and may be used to enhance CPT-11-induced apoptosis in colon cancer. PMID- 24173771 TI - Lactose avoidance for young children with acute diarrhoea. AB - BACKGROUND: Young children with acute diarrhoea, typically due to infectious gastroenteritis, may temporarily stop producing lactase, the intestinal enzyme that digests lactose. This means they may not digest lactose, the main sugar in milk, and this may worsen or prolong the diarrhoeal illness. However, there is uncertainty whether avoiding lactose-containing milk or milk products helps young children recover from acute diarrhoea more quickly. OBJECTIVES: To assess if avoiding or reducing intake of lactose-containing milk or milk products shortens the duration and severity of illness in young children with acute diarrhoea. We also sought other indicators of morbidity and overall mortality. SEARCH METHODS: We searched the Cochrane Infectious Diseases Group Specialized Register (14 May 2013), Cochrane Central Register of Controlled Trials (CENTRAL) published in The Cochrane Library (Issue 4, 2013), MEDLINE (1996 to 14 May 2013), EMBASE (1974 to 14 May 2013), and LILACS (1982 to 14 May 2013), and the reference lists of potentially relevant trials, key conference proceedings, and wrote to individuals and organizations in the field. SELECTION CRITERIA: Randomized or quasi randomized controlled trials that assessed the effects of avoiding or reducing exposure to lactose in young children under five years with acute diarrhoea. DATA COLLECTION AND ANALYSIS: We extracted data using the standard methods of the Cochrane Infectious Diseases Group, and two review authors independently evaluated trial quality and data extraction. Continuous outcomes were compared using mean difference (MD), and dichotomous outcomes using the risk ratio (RR). We presented all results with 95% confidence intervals (CI) and assessed the quality of evidence using the GRADE approach. MAIN RESULTS: We included 33 trials enrolling 2973 children with acute diarrhoea. Twenty-nine trials were exclusively conducted on inpatients, all from high- or middle-income countries. Fifteen trials included children aged below 12 months, and 22 excluded children who were being breast-fed.Compared to lactose-containing milk, milk products, or foodstuffs, lactose-free products may reduce the duration of diarrhoea by an average of about 18 hours (MD -17.77, 95% CI -25.32 to -10.21, 16 trials, 1467 participants, low quality evidence). Lactose-free products probably also reduce treatment failure (defined variously as continued or worsening diarrhoea or vomiting, the need for additional rehydration therapy, or continuing weight loss) by around a half (RR 0.52, 95% CI 0.39 to 0.68, 18 trials, 1470 participants, moderate quality evidence).Diluted lactose-containing milk has not been shown to reduce the duration of diarrhoea compared to undiluted milk or milk products (five trials, 417 participants, low quality evidence), but may reduce the risk of treatment failure (RR 0.65, 95% CI 0.45 to 0.94, nine trials, 687 participants, low quality evidence). AUTHORS' CONCLUSIONS: In young children with acute diarrhoea who are not predominantly breast-fed, change to a lactose-free diet may result in earlier resolution of acute diarrhoea and reduce treatment failure. Diluting lactose-containing formulas may also have some benefits but further trials are required to have confidence in this finding. There are no trials from low-income countries, where mortality for diarrhoea is high, and malnutrition is more common. PMID- 24173770 TI - In vivo analysis of insulin-like growth factor type 1 receptor humanized monoclonal antibody MK-0646 and small molecule kinase inhibitor OSI-906 in colorectal cancer. AB - The development and characterization of effective anticancer drugs against colorectal cancer (CRC) is of urgent need since it is the second most common cause of cancer death. The study was designed to evaluate the effects of two IGF 1R antagonists, MK-0646, a recombinant fully humanized monoclonal antibody and OSI-906, a small molecule tyrosine kinase inhibitor on CRC cells. Xenograft study was performed on IGF-1R-dependent CRC cell lines for analyzing the antitumor activity of MK-0646 and OSI-906. Tumor proliferation and apoptosis were assessed using Ki67 and TUNEL assays, respectively. We also performed in vitro characterization of MK-0646 and OSI-906 treatment on CRC cells to identify mechanisms associated with drug-induced cell death. Exposure of the GEO and CBS tumor xenografts to MK-0646 or OSI-906 led to a decrease in tumor growth. TUNEL analysis showed an increase of approximately 45-55% in apoptotic cells in both MK 0646 and OSI-906 treated tumor samples. We report the novel finding that treatment with IGF-1R antagonists led to downregulation of X-linked inhibitor of apoptosis (XIAP) protein involved in cell survival and inhibition of cell death. In conclusion, IGF-1R antagonists (MK-0646 and OSI-906) demonstrated single agent inhibition of subcutaneous CRC xenograft growth. This was coupled to pro apoptotic effects resulting in downregulation of XIAP and inhibition of cell survival. We report a novel mechanism by which MK-0646 and OSI-906 elicits cell death in vivo and in vitro. Moreover, these results indicate that MK-0646 and OSI 906 may be potential anticancer candidates for the treatment of patients with IGF 1R-dependent CRC. PMID- 24173772 TI - Fathead minnow response to broad-range exposure of beta-sitosterol concentrations during life-cycle testing. AB - The beta-sitosterol concentration in pulp and paper mill effluents is typically greater than that of other phytosterols and has been shown to cause a variety of effects in fish. The authors exposed fathead minnow (Pimephales promelas) to low (22 +/- 0.93 ug/L), medium-low (70 +/- 2.1 ug/L), medium-high (237 +/- 5.5 ug/L), and high (745 +/- 16.2 ug/L) concentrations of beta-sitosterol as well as negative (water), positive (ethynyl estradiol, 16 +/- 0.58 ng/L), and carrier (0.6 mL/L acetone) controls. Fish were monitored over a full life cycle for population-level endpoints including growth and survival, reproductive endpoints (e.g. fecundity, sex steroids and vitellogenin, gonado-/hepatosomatic indices, and gonad histology). No significant differences were seen in fish growth, mortality, or reproduction with beta-sitosterol exposure, although a trend for lower egg production in beta-sitosterol exposures relative to the water control may be related to the acetone carrier. All ethynyl estradiol-exposed fish were smaller, showed female characteristics, and did not spawn. Sex steroid and vitellogenin were highly variable with no detectable treatment-related differences. Gonadal tissue showed no beta-sitosterol-related differences in reproductive development and spawning capability, although most ethynyl estradiol exposed males had ovarian tissue and were not spawning-capable. The results indicate that beta-sitosterol exposure had little apparent impact on fathead minnow survival, growth, and reproduction even at concentrations >10 times that of typical effluents, although small sample size and variability precluded fully evaluating treatment responses on sex steroids and vitellogenin. PMID- 24173773 TI - Biochemical markers of recombinant human insulin-like growth factor-I (rhIGF I)/rhIGF binding protein-3 (rhIGFBP-3) misuse in athletes. AB - Insulin-like growth factor-I (IGF-I) is reportedly misused by elite athletes, either alone or with growth hormone (GH). The GH-2000 and GH-2004 research groups previously developed a method for detecting GH misuse based on the GH-sensitive markers IGF-I and procollagen type III amino-terminal propeptide (P-III-NP). Both markers increase in response to rhIGF-I/rhIGF binding protein-3 (rhIGFBP-3) administration in recreational athletes. The aim of this pilot study was to assess the effect of rhIGF-I/rhIGFBP-3 administration on other serum markers of the GH-IGF axis and on other bone and collagen markers. Twenty-six female and 30 male recreational athletes were randomized to 28 days' treatment with placebo or rhIGF-I/rhIGFBP-3 complex, followed by 56 days' washout. GH-IGF axis markers (IGFBP-2, IGFBP-3, acid-labile subunit (ALS) and IGF-II) and bone and collagen markers (procollagen type I carboxy-terminal propeptide (PICP), type I collagen cross-linked carboxy-terminal telopeptide (ICTP) and osteocalcin) were measured using commercial immunoassays. In women in the high dose treatment group, mean IGF-II decreased by 53% (P=0.0028) on Day 21. Mean IGFBP-2 increased by 119% (P=0.0039) and mean ALS decreased by 40% (P=0.0022) on Day 21. There were no significant changes in IGFBP-3, osteocalcin, ICTP or PICP. In men in the high dose group, mean IGF-II decreased by 51% on Day 21 (P<0.0001). Mean IGFBP-2 increased by 125% on Day 21 (P=0.0003). There were no significant changes in IGFBP-3, ALS, osteocalcin, ICTP or PICP. Serum IGFBP-2 and IGF-II may be useful markers of rhIGF-I/rhIGFBP-3 administration in both women and men while ALS may also be a useful marker in women; these markers are now undergoing further evaluation. PMID- 24173774 TI - The fate of Kruppel-like factor 9-positive hepatic carcinoma cells may be determined by the programmed cell death protein 5. AB - Liver cancer in men is the fifth most frequently diagnosed cancer worldwide. Human Kruppel-like factor (KLF9) gene, localized on human chromosome 9q13, has been implicated in mediating a diverse range of biological processes including stem cell maintenance and differentiation of T- and B-lymphocytes. In this study, we confirmed that the levels of KLF9 mRNA and protein were lower in hepatocellular carcinoma (HCC) tissue compared to normal tissue. In addition, we confirmed that upregulation of KLF9 inhibited cell proliferation and mobility and induce apoptosis in HepG2 cells depending on programmed cell death protein 5 (PDCD5) expression. However, no interaction was found between KLF9 and PDCD5 using fluorescence resonance energy transfer (FRET) and co-immunoprecipitation (co-IP). We confirmed that PDCD5 overexpression stimulated the promoter activities of KLF9 by luciferase reporter assays. PMID- 24173776 TI - Critical crystal growth of graphene on dielectric substrates at low temperature for electronic devices. PMID- 24173775 TI - Neuroprotective effect of Decalepis hamiltonii in paraquat-induced neurotoxicity in Drosophila melanogaster: biochemical and behavioral evidences. AB - In this paper, we have demonstrated for the first time, the antioxidant and neuroprotective effects of Decalepis hamiltonii (Dh) root extract against paraquat (PQ)-induced oxidative stress and neurotoxicity in Drosophila melanogaster. Exposure of adult D. melanogaster (Oregon K) to PQ induced oxidative stress as evidenced by glutathione depletion, lipid peroxidation and enhanced activities of antioxidant enzymes such as catalase, superoxide dismutase as well as elevated levels of acetylcholine esterase. Pretreatment of flies by feeding with Dh extract (0.1, 0.5 %) for 14 days boosted the activities of antioxidant enzymes and prevented the PQ-induced oxidative stress. Dietary feeding of Dh extract prior to PQ exposure showed a lower incidence of mortality and enhanced motor activities of flies in a negative geotaxis assay; both suggesting the neuroprotective potential of Dh. Based on the results, we contemplate that the roots of Dh might prevent and ameliorate the human diseases caused by oxidative stress. The neuroprotective action of Dh can be attributed to the antioxidant constituents while the precise mechanism of its action needs further investigations. PMID- 24173777 TI - Molecular marker analysis of genes controlling morphological variation in Brassica rapa (syn. campestris). AB - Construction of a detailed RFLP linkage map of B. rapa (syn. campestris) made it possible, for the first time, to study individual genes controlling quantitative traits in this species. Ninety-five F2 individuals from a cross of Chinese cabbage cv 'Michihili' by Spring broccoli were analyzed for segregation at 220 RFLP loci and for variation in leaf, stem, and flowering characteristics. The number, location, and magnitude of genes underlying 28 traits were determined by using an interval mapping method. Zero to five putative quantitative trait loci (QTL) were detected for each of the traits examined. There were unequal gene effects on the expression of many traits, and the inheritance patterns of traits ranged from those controlled by a single major gene plus minor genes to those controlled by polygenes with small and similar effects. The effect of marker locus density on detection of QTL was analyzed, and the results showed that the number of QTL detected did not change when the number of marker loci used for QTL mapping was decreased from 220 to 126; however, a further reduction from 126 to 56 caused more than 15% loss of the total QTL detected. The detection of putative minor QTL by removing the masking effects of major QTL was explored. PMID- 24173778 TI - Nuclear DNA content of Vitis species, cultivars, and other genera of the Vitaceae. AB - The nuclear DNA content was analyzed in Vitis species, hybrid cultivars, and genera of the Vitaceae using flow cytometry. Significant variation was found among Vitis species, hybrids, and other genera of the Vitaceae (Ampelopsis and Parthenocissus). DNA content was estimated to range from 0.98 to 1.05 pg/2C within V. labrusca (ns) and 0.86 to 1.00 pg/2C within V. vinifera (ns). Genotypes from Vitis and Parthenocissus were similar in nuclear DNA content (approximately 1.00 pg/2C) whereas they differed significantly from Ampelopsis (1.39 pg/2C). No correlation between DNA content and the center of origin of genotypes of the Vitaceae was noted. Based on the present study, the Vitis genome size is 475 Mbp, 96% of which is non-coding. Knowledge of DNA content is useful in order to understand the complexity of the Vitis genome and to establish a relationship between the genetic and physical map for map-based cloning. PMID- 24173779 TI - Integration of the classical and RFLP linkage maps of the short arm of tomato chromosome 1. AB - The classical map of the short arm of chromosome 1 of tomato (Lycopersicon esculentum) has been shown to contain inaccuracies while the RFLP map of this region is known to be generally accurate. Molecular analysis of populations derived from crosses between L. esculentum lines carrying chromosome 1 classical markers and L. pennellii has enabled us to produce an integrated classical and RFLP marker map of this region. New data concerning the linkage relationships between classical markers have also been combined with previous data to produce a new classical map of the short arm of chromosome 1. The orders of the classical markers on these two new maps are in almost complete agreement and are very different to that shown on the previous classical map. PMID- 24173780 TI - Genetic diversity in European and Mediterranean faba bean germ plasm revealed by RAPD markers. AB - Broadening of the genetic base and systematic exploitation of heterosis in faba bean requires reliable information on the genetic diversity in the germ plasm. Three groups of faba bean inbred lines were examined by means of RAPDs (random amplified polymorphic DNAs) assays: 13 European small-seeded lines, 6 European large-seeded lines, and 9 Mediterranean lines. Out of 59 primers, 35 were informative and yielded 365 bands, 289 of which were polymorphic with a mean of 8.3 bands per primer. Monomorphic bands were omitted from the analyses and genetic distances (GD) were estimated via the coefficient of Jaccard. The mean GD among the European small-seeded lines was significantly greater than those among the lines of the other two groups. Repeatability of GD estimates was high. Cluster (UPGMA) and principal coordinate analyses identified European small seeded lines and Mediterranean lines as distinct groups with European large seeded lines located in between. The results are in harmony with published archaeobotanical findings. We conclude that RAPDs are useful for classification of germ plasm and identification of divergent heterotic groups in faba bean. PMID- 24173781 TI - Thinopyrum distichum addition lines: production, morphological and cytological characterisation of 11 disomic addition lines and stable addition-substitution line. AB - Plants of the partial amphiploid Inia 66/Thinopyrum distichum (2n = 70)//Inia 66 (2n = 56) were used as male parents in crosses with the monosomic series in the common wheat cultivar Inia 66. The genome and homoeologous group of the monosomic used in the cross affected the distribution of chromosome number of the progeny plants in the F2 and F4. Meiosis in the pollen mother cells of the B1F7 partial amphiploids was not stable, and not different from that of the B1F1 in which univalents and multivalents were observed. Disomic addition lines were selected on the basis of morphology and meiotic stability in the F2, F4 and F5. Eleven of the fourteen possible wheat-Th. distichum disomic addition lines were identified using chromosome C-band pattern, as well as size and arm ratio, as genetic markers. Addition of T. distichum chromosome J (dll) produced a phenotype indicating homoeology with wheat group-2 chromosomes. Clear indications of homoeology based on morphological characteristics were not obtained in any of the other addition lines, probably due to the mixed homoeology of the Th. distichum chromosomes relative to wheat. The addition lines were all susceptible to leaf rust, unlike the germplasm-line Indis which carries a leaf rust resistance gene on a translocation segment derived from Th. distichum. Instability of meiotic pairing was observed in all addition lines. The stability, or not, of progeny chromosome counts did not reflect the level of chromosome pairing instability in the parental plants. SDS-PAGE for gliadin-type seed proteins revealed two addition lines which expressed seed storage proteins uncommon to Inia 66 but typical of Th. distichum. PMID- 24173783 TI - Theory for modelling means and covariances in a two-breed population with dominance inheritance. AB - This paper presents theory and methods to compute genotypic means and covariances in a two breed population under dominance inheritance, assuming multiple unlinked loci. It is shown that the genotypic mean is a linear function of five location parameters and that the genotypic covariance between relatives is a linear function of 25 dispersion parameters. Recursive procedures are given to compute the necessary identity coefficients. In the absence of inbreeding, the number of parameters for the mean is reduced from five to three and the number for the covariance is reduced from 25 to 12. In a two-breed population, for traits exhibiting dominance, the theory presented here can be used to obtain genetic evaluations by best linear unbiased prediction and to estimate genetic parameters by maximum likelihood. PMID- 24173782 TI - The use of microsatellite DNA markers for soybean genotype identification. AB - Conventional morphological and pigementation traits, as well as disease resistance, have been used to distinguish the uniqueness of new soybean cultivars for purposes of plant variety protection. With increasing numbers of cultivars and a finite number of conventional characters, it has become apparent that such traits will not suffice to establish uniqueness. The objective of this work was to provide an initial evaluation of microsatellite or simple-sequence-repeat (SSR) DNA markers to develop unique DNA profiles of soybean genotypes. Microsatellites are DNA sequences such as (AT) n /(TA) n and (ATT) n /(TAA) n that are composed of tandemly repeated 2-5-basepair DNA core sequences. The DNA sequences flanking microsatellites are generally conserved allowing the selection of polymerase chain reaction (PCR) primers that will amplify the intervening SSR. Variation in the number of tandem repeats, "n", results in PCR product length differences. The SSR alleles present at three (AT) n /(TA) n and four (ATT) n /(TAA) n loci were determined in each of 96 diverse soybean genotypes. Between 11 and 26 alleles were found at each of the seven loci. Only two genotypes had identical SSR allelic profiles and these had very similar pedigrees. The gene diversity for the seven markers averaged 0.87 for all 96 genotypes and 0.74 for a subset of 26 North American cultivars. These are much higher than soybean gene diversity values obtained using RFLP markers, and are similar to the average values obtained for human microsatellite markers. SSR markers provide an excellent complement to the conventional markers that are currently used to characterize soybean genotypes. PMID- 24173784 TI - Inheritance of spontaneous male sterility in peas. AB - A plant with a mutant phenotype was observed in a 'Longittee' cultivar. The plant was late in maturity, had white-translucent anthers, and was male sterile. The inheritance of this mutant was studied in a cross involving the mutant and the mother parent and their F1, F2, F3 and BC1F1 generations. The results suggested that the sterile character was genetic and due to a recessive gene. PMID- 24173785 TI - Numerical comparison between powers of maximum likelihood and analysis of variance methods for QTL detection in progeny test designs: the case of monogenic inheritance. AB - Simulations are used to compare four statistics for the detection of a quantitative trait locus (QTL) in daughter and grand-daughter designs as defined by Soller and Genizi (1978) and Weller et al. (1990): (1) the Fisher test of a linear model including a marker effect within sire or grand-sire effect; (2) the likelihood ratio test of a segregation analysis without the information given by the marker; (3) the likelihood ratio test of a segregation analysis considering the information from the marker; and (4) the lod score which is the likelihood ratio test of absence of linkage between the marker and the QTL. In all cases the two segregation analyses are more powerful for QTL detection than are either the linear method or the lod score. The differences in power are generally limited but may be significant (in a ratio of 1 to 3 or 4) when the QTL has a small effect (0.2 standard deviations) and is not closely linked to the marker (recombination rate of 20% or more). PMID- 24173786 TI - Maximum-likelihood models for mapping genetic markers showing segregation distortion. 1. Backcross populations. AB - A maximum-likelihood approach is used in order to estimate recombination fractions between markers showing segregation distortion in backcross populations. It is assumed that the distortions are induced by viability differences between gametes or zygotes due to one or more selected genes. We show that Bailey's (1949) estimate stays consistent and efficient under more general assumptions than those defined by its author. This estimate should therefore be used instead of the classical maximum-likelihood estimate. The question of detection of linkage is also discussed. We show that the order of markers on linkage groups may be affected by segregation distortion. PMID- 24173787 TI - Maximum-likelihood models for mapping genetic markers showing segregation distortion. 2. F2 populations. AB - In F2 populations, gametic and zygotic selection may affect the analysis of linkage in different ways. Therefore, specific likelihood equations have to be developed for each case, including dominant and codominant markers. The asymptotic bias of the "classical" estimates are derived for each case, in order to compare them with the standard errors of the suggested estimates. We discuss the utility and the efficiency of a previous model developed for dominant markers. We show that dominant markers provide very poor information in the case of segregation distortion and, therefore, should be used with circumspection. On the other hand, the estimation of recombination fractions between codominant markers is less affected by selection than is that for dominant markers. We also discuss the analysis of linkage between dominant and codominant markers. PMID- 24173788 TI - Abundance and polymorphism of di-, tri-and tetra-nucleotide tandem repeats in chickpea (Cicer arietinum L.). AB - The abundance and polymorphism of 38 different simple-sequence repeat motifs was studied in four accessions of cultivated chickpea (Cicer arietinum L.) by in-gel hybridization of synthetic oligonucleotides to genomic DNA digested with 14 different restriction enzymes. Among 38 probes tested, 35 yielded detectable hybridization signals. The abundance and level of polymorphism of the target sequences varied considerably. The probes fell into three broad categories: (1) probes yielding distinct, polymorphic banding patterns; (2) probes yielding distinct, monomorphic banding patterns, and (3) probes yielding blurred patterns, or diffused bands superimposed on a high in lane background. No obvious correlation existed between abundance, fingerprint quality, and the sequence characteristics of a particular motif. Digestion with methyl-sensitive enzymes revealed that simple-sequence motifs are enriched in highly methylated genomic regions. The high level of intraspecific polymorphism detected by oligonucleotide fingerprinting suggests the suitability of simple-sequence repeat probes as molecular markers for genome mapping. PMID- 24173789 TI - Molecular and genetic characterization of elite transgenic rice plants produced by electric-discharge particle acceleration. AB - The recovery of transgenic rice plants expressing a number of exogenous genes was reported previously. Using immature embryo explants as the target tissue, plasmids containing both selectable and screenable marker genes were introduced into elite rice varieties via electric-discharge particle acceleration. Co integration, copy number, expression, and inheritance of these genes were analyzed. A 100% co-integration frequency was confirmed by Southern-blot analyses of R0 plants. The majority of transgenic plants contained between one and ten copies of exogenous DNA and molecular and genetic analyses of progeny indicated that all copies in almost all R0 plants were inherited as a single dominant hemizygous locus. Co-expression of unselected genes ranged from 30-66% for gus/hmr constructs, depending on the promotor used, and up to 90% for bar/hmr constructs. The integrative structures of two unlinked transgenic loci of a rare R0 plant were analyzed in detail by Southern-blot analysis of its progeny. PMID- 24173790 TI - Quality and biochemical effects of a IBL/IRS wheat-rye translocation in wheat. AB - Wheat (Triticum aestivum L.) breeders world-wide have used rye (Secale cereale L.) as a source of genes for agronomic improvement. The 1BL/1RS wheat-rye chromosomal translocation derived from the Russian cultivars 'Kavkaz' and 'Aurora' has been among the most common means of accessing useful rye genes. Unfortunately, deleterious wheat quality effects are often associated with the presence of 1RS. The identification of genetic backgrounds capable of alleviating the deleterious effects of 1RS is crucial for its continued exploitation. End-use quality parameters and flour protein composition, as measured by size-exclusion high-performance liquid chromatography (SE-HPLC) of 373 wheat lines, derived from seven 1BL/1RS breeding populations, were analyzed. In all populations, significant quality defects were detected in 1BL/1RS lines compared to non-1RS sister lines. The detrimental quality effects resulted from alteration of the ratio of flour protein composition, especially, decreased glutenin concentrations, and increased salt-water soluble protein concentrations. The end use quality of 1BL/1RS lines, however, was highly dependent on genetic backgrounds. The potential exists for improvement in quality through crosses between 1RS lines with high glutenin, or low salt-water soluble protein concentrations, and non-1RS lines with strong dough properties. PMID- 24173791 TI - The physical location of fourteen RFLP markers in rice (Oryza sativa L.). AB - A biotin-labeled in situ hybridization technique was used in order to physically map RFLP markers to the chromosomes of rice (Oryza sativa L.). Fourteen RFLP markers, associated with the ends of the linkage groups on rice chromosomes 7, 8, 11, 12, were physically mapped onto specific regions of the chromosomes. The average detection rate of in situ hybridization was 5.91%. The markers were located on seven different chromosome arms. Ten of the fourteen markers were distributed near the chromosome ends. This demonstrated that the RFLP linkage groups involved covered a wide physical distance and that the centromeric region was bisected by all but one linkage group. Two markers covered a short genetic distance but were physically distant, while two covering a longer genetic distance were physically closer together. This indicates that considerable variation can, and does, exist between genetic and physical maps.This paper is a contribution of the U.S. Department of Agriculture, Agricultural Research Service, and Missouri Agricultural Experiment Station, Journal Series No. 11 882All programs and services of the U.S. Department of Agriculture are offered on a nondiscriminatory basis without regard to race, color, national origin, religion, sex, age, marital status, or handicap. PMID- 24173792 TI - Lack of evidence for segregation of a single dominant major gene as the cause of the difference in egg weight between two highly inbred lines of chickens. AB - Data on egg weight from experimental crosses with two inbred lines of chickens suggested evidence for segregation of a single dominant major gene. Because the data could not be transformed to satisfy normality and homoscedasticity conditions, the non-parametric test of Elston and the graphical approach used by Stolk et al. were applied. Due to a bad fit of the backcross B2 (P2*F1) and the F2 groups, both methods reject the hypothesis of a dominant major gene as the the only cause of the differences in egg weight between the six genetic groups involved. PMID- 24173793 TI - Linkage Arrangement of RFLP loci in progenies from crosses between doubled haploid Asparagus officinalis L. clones. AB - A preliminary genetic map of the dioecious species Asparagus officinalis L. (2n = 20) has been constructed on the basis of restriction fragment length polymorphism (RFLP) and isozyme marker data. With DNA samples digested with either EcoRI or HindIII 61 out of 148 probes (41%) identified RFLPs in six families of doubled haploid lines obtained through anther culture. A higher level of polymorphism (65%) was observed when a single family was screened for RFLPs using six distinct restriction enzymes. Segregation analysis of the BC progenies (40-80 individuals) resulted in a 418-cM extended map comprising 43 markers: 39 RFLPs, three isozymes and one morphological (sex). These markers are clustered in 12 linkage groups and four of them exhibited significant deviations from the expected 1?1 ratio. One isozyme and three RFLP markers were assigned to the sex chromosome. PMID- 24173794 TI - Wheat phylogeny determined by RFLP analysis of nuclear DNA. 2. Wild tetraploid wheats. AB - Intra- and inter-specific variations in the nuclear DNA of Triticum dicoccoides Korn. (2n = 28, genome constitution AABB) and T. araraticum Jakubz. (2n = 28, AAGG), wild species, respectively, of the Emmer and Timopheevi group, were studied by restriction fragment length polymorphism (RFLP) analysis. Total DNAs of 32 T. dicoccoides and 24 T. araraticum accessions, collected from throughout the distribution areas of these species, were treated with two 6-bp cutters and hybridized with 30 nuclear DNA clones as probes to detect RFLPs. A total of 167 hybrid bands were observed per accession. All the enzyme-probe combinations showed RFLPs between accessions. The average genetic distance between the T. dicoccoides accessions was 0.0135 +/- 0.0031 and that between the T. araraticum accessions 0.0036 +/- 0.0015, indicative of about a four-fold intraspecific variation in T. dicoccoides as compared to T. araraticum in terms of genetic distance. No significant genetic differentiation was found for the geographical populations of these species, the genetic distance between the two species being 0.0482 +/- 0.0022. The interspecific divergence corrected for intraspecific divergence was 0.0395, about three times that for T. dicoccoides and 11 times that for T. araraticum. The results show that in the wild state the Emmer and Timopheevi groups are clearly differentiated and that T. dicoccoides has much greater variation than T. araraticum, suggesting a relatively recent origin for the latter and therefore a diphyletic origin for these species. PMID- 24173795 TI - Megagametophyte organization in diploid alfalfa meiotic mutants producing 4n pollen and 2n eggs. AB - Megagametogenesis was studied in five diploid alfalfa mutants producing 4n pollen and 2n eggs, using a stain-clearing technique. All mutants produced embryo sacs with a variable number of supernumerary nuclei both at the early (bi- and tetra nucleate) and at the late (eight-nucleate) stages of development. The presence of supernumerary nuclei is considered to be a consequence of the production of coenocytic megaspores. The production of 2n eggs was confirmed through cytological investigation by means of the diameter of the egg-cell nucleolus. The frequency of 2n eggs was lower than the frequency of binucleated macrospores as previously determined. This discrepancy may be due to environmental effects but also to the fact that binucleated macrospores may degenerate or may, after two mitotic divisions, give rise to eight-nucleated embryo sacs counted as normals. PMID- 24173796 TI - Estimation of heritability using variety trials data from incomplete blocks. AB - An assessment of the heritability of a trait is useful in formulating a breeding strategy for crop improvement. We have considered the estimation of broad-sense heritability from a single-location trial and from multi-locational trials conducted in incomplete blocks. Using residual maximum likelihood estimates of variance components, we estimated the heritability and obtained expressions for the estimate of its bias and its standard error. The estimation procedure is illustrated for 25 barley genotypes evaluated at four locations in West Asia and North Africa during 1992. PMID- 24173797 TI - Allelic relationships between genes for resistance to tomato spotted wilt tospovirus in Capsicum chinense. AB - Pepper (Capsicum chinense Jacq.) has been reported to be an important reservoir of resistance genes to tomato spotted wilt virus (TSWV). The genes for TSWV resistance present in three C. chinense lines ('PI 152225', 'PI 159236' and 'Panca') were investigated for allelism. All resistant lines were crossed with each other. Parents, F1, backcrosses and F2 populations (including reciprocals) developed from those crosses were mechanically inoculated with a highly virulent TSWV isolate. Susceptible C. annuum cv 'Magda' was used to check inoculum virulence. Fifty plants of the F1 hybrids; 'Magda' x 'PI 152225', 'Magda' x 'PI 159236', and 'Magda' x 'Panca, were also inoculated with the TSWV isolate. The resistance response in all C. chinense sources was associated with a localized, hypersensitive-like reaction that was phenotypically expressed as a prompt formation of large local lesions accompanied by premature leaf abscission. All F1 generations presented a final score of resistant; indicating that the expression of resistance to TSWV is conditioned by a dominant gene regardless of the source. The absence of segregation for resistance to TSWV that was observed in all generations of the crosses between C. chinense lines indicated that either a tightly linked group of genes exists or that the resistance is governed by the same single major gene (probably the already described Tsw gene). Previous reports have indicated that the Tsw gene is not effective against tospovirus members of serogroup II, i.e. tomato chlorotic spot virus (TCSV) and groundnut ring spot virus (GRSV). In the assay described here, all of the C. chinense lines showed, after mechanical inoculation, an identical susceptibility response to the TCSV and GRSV isolates. PMID- 24173798 TI - Standard karyotype of Triticum umbellulatum and the characterization of derived chromosome addition and translocation lines in common wheat. AB - A standard karyotype and a generalized idiogram of Triticum umbellulatum (syn. Aegilops umbellulata, 2n = 2x = 14) was established based on C-banding analysis of ten accessions of different geographic origin and individual T. umbellulatum chromosomes in T. aestivum - T. umbellulatum chromosome addition lines. Monosomic (MA) and disomic (DA) T. aestivum - T. umbellulatum chromosome addition lines (DA1U = B, DA2U = D, MA4U = F, DA5U = C, DA6U = A, DA7U = E = G) and telosomic addition lines (DA1US, DA1UL, DA2US, DA2UL, DA4UL, MA5US, (+ iso 5US), DA5UL, DA7US, DA7UL) were analyzed. Line H was established as a disomic addition line for the translocated wheat - T. umbellulatum chromosome T2DS.4US. Radiation induced wheat - T. umbellulatum translocation lines resistant to leaf rust (Lr9) were identified as T40 = T6BL.6BS-6UL, T41 = T4BL.4BS-6UL, T44 = T2DS.2DL-6UL, T47 = 'Transfer' = T6BS.6BL-6UL and T52 = T7BL.7BS-6UL. Breakpoints and sizes of the transferred T. umbellulatum segments in these translocations were determined by in situ hybridization analysis using total genomic T. umbellulatum DNA as a probe. PMID- 24173799 TI - Genome-wide analysis of the bHLH gene family in planarians identifies factors required for adult neurogenesis and neuronal regeneration. AB - In contrast to most well-studied model organisms, planarians have a remarkable ability to completely regenerate a functional nervous system from a pluripotent stem cell population. Thus, planarians provide a powerful model to identify genes required for adult neurogenesis in vivo. We analyzed the basic helix-loop-helix (bHLH) family of transcription factors, many of which are crucial for nervous system development and have been implicated in human diseases. However, their potential roles in adult neurogenesis or central nervous system (CNS) function are not well understood. We identified 44 planarian bHLH homologs, determined their patterns of expression in the animal and assessed their functions using RNAi. We found nine bHLHs expressed in stem cells and neurons that are required for CNS regeneration. Our analyses revealed that homologs of coe, hes (hesl-3) and sim label progenitors in intact planarians, and following amputation we observed an enrichment of coe(+) and sim(+) progenitors near the wound site. RNAi knockdown of coe, hesl-3 or sim led to defects in CNS regeneration, including failure of the cephalic ganglia to properly pattern and a loss of expression of distinct neuronal subtype markers. Together, these data indicate that coe, hesl-3 and sim label neural progenitor cells, which serve to generate new neurons in uninjured or regenerating animals. Our study demonstrates that this model will be useful to investigate how stem cells interpret and respond to genetic and environmental cues in the CNS and to examine the role of bHLH transcription factors in adult tissue regeneration. PMID- 24173800 TI - Dynamic feedback circuits function as a switch for shaping a maturation-inducing steroid pulse in Drosophila. AB - Steroid hormones trigger the onset of sexual maturation in animals by initiating genetic response programs that are determined by steroid pulse frequency, amplitude and duration. Although steroid pulses coordinate growth and timing of maturation during development, the mechanisms generating these pulses are not known. Here we show that the ecdysone steroid pulse that drives the juvenile adult transition in Drosophila is determined by feedback circuits in the prothoracic gland (PG), the major steroid-producing tissue of insect larvae. These circuits coordinate the activation and repression of hormone synthesis, the two key parameters determining pulse shape (amplitude and duration). We show that ecdysone has a positive-feedback effect on the PG, rapidly amplifying its own synthesis to trigger pupariation as the onset of maturation. During the prepupal stage, a negative-feedback signal ensures the decline in ecdysone levels required to produce a temporal steroid pulse that drives developmental progression to adulthood. The feedback circuits rely on a developmental switch in the expression of Broad isoforms that transcriptionally activate or silence components in the ecdysone biosynthetic pathway. Remarkably, our study shows that the same well defined genetic program that stimulates a systemic downstream response to ecdysone is also utilized upstream to set the duration and amplitude of the ecdysone pulse. Activation of this switch-like mechanism ensures a rapid, self limiting PG response that functions in producing steroid oscillations that can guide the decision to terminate growth and promote maturation. PMID- 24173801 TI - The Drosophila ubiquitin-specific protease Puffyeye regulates dMyc-mediated growth. AB - The essential and highly conserved role of Myc in organismal growth and development is dependent on the control of Myc protein abundance. It is now well established that Myc levels are in part regulated by ubiquitin-dependent proteasomal degradation. Using a genetic screen for modifiers of Drosophila Myc (dMyc)-induced growth, we identified and characterized a ubiquitin-specific protease (USP), Puffyeye (Puf), as a novel regulator of dMyc levels and function in vivo. We show that puf genetically and physically interacts with dMyc and the ubiquitin ligase archipelago (ago) to modulate a dMyc-dependent cell growth phenotype, and that varying Puf levels in both the eye and wing phenocopies the effects of altered dMyc abundance. Puf containing point mutations within its USP enzymatic domain failed to alter dMyc levels and displayed no detectable phenotype, indicating the importance of deubiquitylating activity for Puf function. We find that dMyc induces Ago, indicating that dMyc triggers a negative feedback pathway that is modulated by Puf. In addition to its effects on dMyc, Puf regulates both Ago and its cell cycle substrate Cyclin E. Therefore, Puf influences cell growth by controlling the stability of key regulatory proteins. PMID- 24173802 TI - The vertebrate-specific Kinesin-6, Kif20b, is required for normal cytokinesis of polarized cortical stem cells and cerebral cortex size. AB - Mammalian neuroepithelial stem cells divide using a polarized form of cytokinesis, which is not well understood. The cytokinetic furrow cleaves the cell by ingressing from basal to apical, forming the midbody at the apical membrane. The midbody mediates abscission by recruiting many factors, including the Kinesin-6 family member Kif20b. In developing embryos, Kif20b mRNA is most highly expressed in neural stem/progenitor cells. A loss-of-function mutant in Kif20b, magoo, was found in a forward genetic screen. magoo has a small cerebral cortex, with reduced production of progenitors and neurons, but preserved layering. In contrast to other microcephalic mouse mutants, mitosis and cleavage furrows of cortical stem cells appear normal in magoo. However, apical midbodies show changes in number, shape and positioning relative to the apical membrane. Interestingly, the disruption of abscission does not appear to result in binucleate cells, but in apoptosis. Thus, Kif20b is required for proper midbody organization and abscission in polarized cortical stem cells and has a crucial role in the regulation of cerebral cortex growth. PMID- 24173803 TI - Par3 controls neural crest migration by promoting microtubule catastrophe during contact inhibition of locomotion. AB - There is growing evidence that contact inhibition of locomotion (CIL) is essential for morphogenesis and its failure is thought to be responsible for cancer invasion; however, the molecular bases of this phenomenon are poorly understood. Here we investigate the role of the polarity protein Par3 in CIL during migration of the neural crest, a highly migratory mesenchymal cell type. In epithelial cells, Par3 is localised to the cell-cell adhesion complex and is important in the definition of apicobasal polarity, but the localisation and function of Par3 in mesenchymal cells are not well characterised. We show in Xenopus and zebrafish that Par3 is localised to the cell-cell contact in neural crest cells and is essential for CIL. We demonstrate that the dynamics of microtubules are different in different parts of the cell, with an increase in microtubule catastrophe at the collision site during CIL. Par3 loss-of-function affects neural crest migration by reducing microtubule catastrophe at the site of cell-cell contact and abrogating CIL. Furthermore, Par3 promotes microtubule catastrophe by inhibiting the Rac-GEF Trio, as double inhibition of Par3 and Trio restores microtubule catastrophe at the cell contact and rescues CIL and neural crest migration. Our results demonstrate a novel role of Par3 during neural crest migration, which is likely to be conserved in other processes that involve CIL such as cancer invasion or cell dispersion. PMID- 24173804 TI - Growth differentiation factor 5 is a key physiological regulator of dendrite growth during development. AB - Dendrite size and morphology are key determinants of the functional properties of neurons. Here, we show that growth differentiation factor 5 (GDF5), a member of the bone morphogenetic protein (BMP) subclass of the transforming growth factor beta superfamily with a well-characterised role in limb morphogenesis, is a key regulator of the growth and elaboration of pyramidal cell dendrites in the developing hippocampus. Pyramidal cells co-express GDF5 and its preferred receptors, BMP receptor 1B and BMP receptor 2, during development. In culture, GDF5 substantially increased dendrite, but not axon, elongation from these neurons by a mechanism that depends on activation of SMADs 1/5/8 and upregulation of the transcription factor HES5. In vivo, the apical and basal dendritic arbours of pyramidal cells throughout the hippocampus were markedly stunted in both homozygous and heterozygous Gdf5 null mutants, indicating that dendrite size and complexity are exquisitely sensitive to the level of endogenous GDF5 synthesis. PMID- 24173805 TI - Whole population cell analysis of a landmark-rich mammalian epithelium reveals multiple elongation mechanisms. AB - Tissue elongation is a fundamental component of developing and regenerating systems. Although localised proliferation is an important mechanism for tissue elongation, potentially important contributions of other elongation mechanisms, specifically cell shape change, orientated cell division and cell rearrangement, are rarely considered or quantified, particularly in mammalian systems. Their quantification, together with proliferation, provides a rigorous framework for the analysis of elongation. The mammalian palatal epithelium is a landmark-rich tissue, marked by regularly spaced ridges (rugae), making it an excellent model in which to analyse the contributions of cellular processes to directional tissue growth. We captured confocal stacks of entire fixed mouse palate epithelia throughout the mid-gestation growth period, labelled with membrane, nuclear and cell proliferation markers and segmented all cells (up to ~20,000 per palate), allowing the quantification of cell shape and proliferation. Using the rugae as landmarks, these measures revealed that the so-called growth zone is a region of proliferation that is intermittently elevated at ruga initiation. The distribution of oriented cell division suggests that it is not a driver of tissue elongation, whereas cell shape analysis revealed that both elongation of cells leaving the growth zone and apico-basal cell rearrangements do contribute significantly to directional growth. Quantitative comparison of elongation processes indicated that proliferation contributes most to elongation at the growth zone, but cell shape change and rearrangement contribute as much as 40% of total elongation. We have demonstrated the utility of an approach to analysing the cellular mechanisms underlying tissue elongation in mammalian tissues. It should be broadly applied to higher-resolution analysis of links between genotypes and malformation phenotypes. PMID- 24173806 TI - QUIRKY interacts with STRUBBELIG and PAL OF QUIRKY to regulate cell growth anisotropy during Arabidopsis gynoecium development. AB - Organ morphogenesis largely relies on cell division and elongation, which need to be both coordinated between cells and orchestrated with cytoskeleton dynamics. However, components that bridge the biological signals and the effectors that define cell shape remain poorly described. We have addressed this issue through the functional characterisation of QUIRKY (QKY), previously isolated as being involved in the STRUBBELIG (SUB) genetic pathway that controls cell-cell communication and organ morphogenesis in Arabidopsis. QKY encodes a protein containing multiple C2 domains and transmembrane regions, and SUB encodes an atypical LRR-receptor-like kinase. We show that twisting of the gynoecium observed in qky results from the abnormal division pattern and anisotropic growth of clustered cells arranged sporadically along the gynoecium. Moreover, the cortical microtubule (CMT) network of these cells is disorganised. A cross to botero, a katanin mutant in which the normal orientation of CMTs and anisotropic cell expansion are impaired, strongly reduces silique deviation, reinforcing the hypothesis of a role for QKY in CMT-mediated cell growth anisotropy. We also show that QKY is localised at the plasma membrane and functions in a multiprotein complex that includes SUB and PAL OF QUIRKY (POQ), a previously uncharacterised PB1-domain-containing protein that localises both at the plasma membrane and in intracellular compartments. Our data indicate that QKY and its interactors play central roles linking together cell-cell communication and cellular growth. PMID- 24173807 TI - Bazooka inhibits aPKC to limit antagonism of actomyosin networks during amnioserosa apical constriction. AB - Cell shape changes drive tissue morphogenesis during animal development. An important example is the apical cell constriction that initiates tissue internalisation. Apical constriction can occur through a phase of cyclic assembly and disassembly of apicomedial actomyosin networks, followed by stabilisation of these networks. Delayed negative-feedback mechanisms typically underlie cyclic behaviour, but the mechanisms regulating cyclic actomyosin networks remain obscure, as do mechanisms that transform overall network behaviour. Here, we show that a known inhibitor of apicomedial actomyosin networks in Drosophila amnioserosa cells, the Par-6-aPKC complex, is recruited to the apicomedial domain by actomyosin networks during dorsal closure of the embryo. This finding establishes an actomyosin-aPKC negative-feedback loop in the system. Additionally, we find that aPKC recruits Bazooka to the apicomedial domain, and phosphorylates Bazooka for a dynamic interaction. Remarkably, stabilising aPKC Bazooka interactions can inhibit the antagonism of actomyosin by aPKC, suggesting that Bazooka acts as an aPKC inhibitor, and providing a possible mechanism for delaying the actomyosin-aPKC negative-feedback loop. Our data also implicate an increasing degree of Par-6-aPKC-Bazooka interactions as dorsal closure progresses, potentially explaining a developmental transition in actomyosin behaviour from cyclic to persistent networks. This later impact of aPKC inhibition is supported by mathematical modelling of the system. Overall, this work illustrates how shifting chemical signals can tune actomyosin network behaviour during development. PMID- 24173808 TI - Pax9 regulates a molecular network involving Bmp4, Fgf10, Shh signaling and the Osr2 transcription factor to control palate morphogenesis. AB - Cleft palate is one of the most common birth defects in humans. Whereas gene knockout studies in mice have shown that both the Osr2 and Pax9 transcription factors are essential regulators of palatogenesis, little is known about the molecular mechanisms involving these transcription factors in palate development. We report here that Pax9 plays a crucial role in patterning the anterior posterior axis and outgrowth of the developing palatal shelves. We found that tissue-specific deletion of Pax9 in the palatal mesenchyme affected Shh expression in palatal epithelial cells, indicating that Pax9 plays a crucial role in the mesenchyme-epithelium interactions during palate development. We found that expression of the Bmp4, Fgf10, Msx1 and Osr2 genes is significantly downregulated in the developing palatal mesenchyme in Pax9 mutant embryos. Remarkably, restoration of Osr2 expression in the early palatal mesenchyme through a Pax9(Osr2KI) allele rescued posterior palate morphogenesis in the absence of Pax9 protein function. Our data indicate that Pax9 regulates a molecular network involving the Bmp4, Fgf10, Shh and Osr2 pathways to control palatal shelf patterning and morphogenesis. PMID- 24173809 TI - Racial and ethnic differences in health care utilization and outcomes among ulcerative colitis patients in an integrated health-care organization. AB - BACKGROUND: Current knowledge of racial disparities in healthcare utilization and disease outcomes for ulcerative colitis (UC) is limited. We sought to investigate these differences among Caucasian, African American, Asian, and Hispanic patients with ulcerative colitis in Kaiser Permanente, a large integrated health-care system in Northern California. METHODS: This retrospective cohort study used computerized clinical data from 5,196 Caucasians, 387 African-Americans, 550 Asians, and 801 Hispanics with prevalent UC identified between 1996 and 2007. Healthcare utilization and outcomes were compared at one and five-year follow-up by use of multivariate logistic regression analysis. RESULTS: Compared with whites, the male-to-female ratio differed for African-Americans (0.68 vs. 0.91, p < 0.01) and Asians (1.3 vs. 0.91, p < 0.01). Asians had fewer co-morbid conditions (p < 0.01) than whites, whereas more African-Americans had hypertension and asthma (p < 0.01). Use of immunomodulators did not differ significantly among race and/or ethnic groups. Among Asians, 5-ASA use was highest (p < 0.05) and the incidence of surgery was lowest (p < 0.01). Prolonged steroid exposure was more common among Hispanics (p < 0.05 at 1-year) who also had more UC-related surgery (p < 0.01 at 5-year) and hospitalization (<0.05 at 5 year), although these differences were not significant in multivariate analysis. CONCLUSIONS: In this population of UC patients with good access to care, overall health-care utilization patterns and clinical outcomes were similar across races and ethnicity. Asians may have milder disease than other races whereas Hispanics had a trend toward more aggressive disease, although the differences we observed were modest. These differences may be related to biological factors or different treatment preferences. PMID- 24173810 TI - Inhibitory effect of allicin on the growth of Babesia and Theileria equi parasites. AB - Allicin is an active ingredient of garlic that has antibacterial, antifungal, antiviral, and antiprotozoal activity. However, the inhibitory effects of allicin on Babesia parasites have not yet been examined. In the present study, allicin was tested as a potent inhibitor against the in vitro growth of bovine and equine Babesia parasites and the in vivo growth of Babesia microti in a mouse model. The in vitro growth of Babesia bovis, Babesia bigemina, Babesia caballi, or Theileria equi was inhibited by allicin in a dose-dependent manner and had IC50 values of 818, 675, 470, and 742 MUM, respectively. Moreover, allicin significantly inhibited (P < 0.001) invasion of B. bovis, B. bigemina, B. caballi, and T. equi into the host erythrocyte. Furthermore, mice treated with 30 mg/kg of allicin for 5 days significantly (P < 0.05) reduced the parasitemia of B. microti over the period of the study. To further examine the potential synergism of allicin with diminazene aceturate, growth inhibitory assays were performed in vitro and in vivo. Interestingly, combinations of diminazene aceturate with allicin synergistically potentiated its inhibitory effects in vitro and in vivo. These results indicate that allicin might be beneficial for the treatment of babesiosis, particularly when used in combination with diminazene aceturate. PMID- 24173811 TI - Biosynthesis of silver nanoparticles using Bacillus thuringiensis against dengue vector, Aedes aegypti (Diptera: Culicidae). AB - The present study reveals the larvicidal activity of silver nanoparticles (AgNPs) synthesized by Bacillus thuringiensis (Bt) against Aedes aegypti responsible for the diseases of public health importance. The Bt-AgNPs were characterized by using UV-visible spectrophotometer followed by scanning electron microscopy (SEM) and energy-dispersive X-ray (EDX) spectroscopy. A surface plasmon resonance spectrum of AgNps was obtained at 420 nm. The particle sizes were measured through SEM imaging ranging from 43.52 to 142.97 nm. The Bt-AgNPs has also given a characteristic peak at 3 keV in EDX image. Interestingly, the mortality rendered by Bt-AgNPs was comparatively high than that of the control against third-instar larvae of A. aegypti (LC50 0.10 ppm and LC90 0.39 ppm) in all the tested concentrations, viz. 0.03, 0.06, 0.09, 0.12, and 0.15 ppm. Hence, Bt-AgNPs would be significantly used as a potent mosquito larvicide against A. aegypti. PMID- 24173812 TI - Treatment with triterpenic fraction purified from Baccharis uncinella leaves inhibits Leishmania (Leishmania) amazonensis spreading and improves Th1 immune response in infected mice. AB - The current medications used to treat leishmaniasis have many side effects for patients; in addition, some cases of the disease are refractory to treatment. Therefore, the search for new leishmanicidal compounds is indispensable. Recently, it was demonstrated that oleanolic- and ursolic-containing fraction from Baccharis uncinella leaves eliminated the promastigote and amastigote forms of Leishmania (Leishmania) amazonensis and L. (Viannia) braziliensis without causing toxic effects for J774 macrophages. Thus, the aim of the present work was to characterize the therapeutic effect of the triterpenic fraction in L. (L.) amazonensis-infected BALB/c mice. Oleanolic- and ursolic acid-containing fraction was extracted from B. uncinella leaves using organic solvents and chromatographic procedures. L. (L.) amazonensis-infected BALB/c mice were treated intraperitoneally with triterpenic fraction during five consecutive days with 1.0 and 5.0 mg/kg of triterpenic fraction, or with 10.0 mg/kg of amphotericin B drug. Groups of mice treated with the triterpenic fraction, presented with decreased lesion size and low parasitism of the skin-both of which were associated with high amounts of interleukin-12 and interferon gamma. The curative effect of this fraction was similar to amphotericin B-treated mice; however, the final dose, required to eliminate amastigotes, was lesser than amphotericin B. Moreover, triterpenic fraction did not cause microscopic alterations in liver, spleen, heart, lung, and kidney of experimental groups. This work suggests that this fraction possesses compounds that are characterized by leishmanicidal and immunomodulatory activities. From this perspective, the triterpenic fraction can be explored as a new therapeutic agent for use against American Tegumentar Leishmaniasis. PMID- 24173813 TI - How crucial is the response format for the testing effect? AB - Combining study and test trials during learning is more beneficial for long-term retention than repeated study without testing (i.e., the testing effect). Less is known about the relative efficacy of different response formats during testing. We tested the hypothesis that overt testing (typing responses on a keyboard) during a practice phase benefits later memory more than covert testing (only pressing a button to indicate successful retrieval). In Experiment 1, three groups learned 40 word pairs either by repeatedly studying them, by studying and overtly testing them, or by studying and covertly testing them. In Experiment 2, only the two testing conditions were manipulated in a within-subjects design. In both experiments, participants received cued recall tests after a short (~19 min) and a long (1 week) retention interval. In Experiment 1, all groups performed equally well at the short retention interval. The overt testing group reliably outperformed the repeated study group after 1 week, whereas the covert testing group performed insignificantly different from both these groups. Hence, the testing effect was demonstrated for overt, but failed to show for covert testing. In Experiment 2, overtly tested items were better and more quickly retrieved than those covertly tested. Further, this does not seem to be due to any differences in retrieval effort during learning. To conclude, overt testing was more beneficial for later retention than covert testing, but the effect size was small. Possible explanations are discussed. PMID- 24173814 TI - Permeation and metabolism of Alternaria mycotoxins with perylene quinone structure in cultured Caco-2 cells. AB - The absorption of four Alternaria toxins with perylene quinone structures, i.e. altertoxin (ATX) I and II, alteichin (ALTCH) and stemphyltoxin (STTX) III, has been determined in the Caco-2 cell Transwell system, which represents a widely accepted in vitro model for human intestinal absorption and metabolism. The cells were incubated with the four mycotoxins on the apical side, and the concentration of the toxins in the incubation media of both chambers and in the cell lysate were determined by liquid chromatography coupled with diode array detection and mass spectrometry (LC-DAD-MS) analysis. ATX I and ALTCH were not metabolised in Caco-2 cells, but ATX II and STTX III were partly biotransformed by reductive de epoxidation to the metabolites ATX I and ALTCH, respectively. Based on the apparent permeability coefficients (Papp), the following ranking order for the permeation into the basolateral compartment was obtained: ATX I > ALTCH >> ATX II > STTX III. Total recovery of the four toxins decreased in the same order. It is assumed that the losses of STTX III, ATX II and ALTCH in Caco-2 cells are caused by covalent binding to cell components due to the epoxide group and/or the alpha,beta-unsaturated carbonyl group present in these toxins. We conclude from this study that ATX I and ALTCH are well absorbed from the intestinal lumen into the portal blood in vivo. For ATX II and STTX III, intestinal absorption of the parent toxins is very low, but these toxins are partly metabolised to ATX I and ALTCH, respectively, in the intestinal epithelium and absorbed as such. PMID- 24173815 TI - Neonatal tumours. AB - Neonatal or perinatal tumours frequently relate to prenatal or developmental events and have a short exposure window which provides an opportunity to study tumours in a selective sensitive period of development. As a result, they display a number of host-specific features which include occasional spontaneous maturational changes with cells still responding to developmental influences. Neonatal tumours (NNT) are studied for a number of important reasons. Firstly, many of the benign tumours arising from soft tissue appear to result from disturbances in growth and development and some are associated with other congenital anomalies. Study of these aspects may open the door for investigation of genetic and epigenetic changes in genes controlling foetal development as well as environmental and drug effects during pregnancy. Secondly, the clinical behaviour of NNT differs from that of similar tumours occurring later in childhood. In addition, certain apparently malignant NNT can 'change course' in infancy leading to the maturation of apparently highly malignant tumours. Thirdly, NNT underline the genetic associations of most tumours but appear to differ in the effects of proto-oncogenes and other oncogenic factors. In this context, there are also connections between the foetal and neonatal period and some "adult" cancers. Fourthly, they appear to arise in a period in which minimal environmental interference has occurred, thus providing a unique potential window of opportunity to study the pathogenesis of tumour behaviour. This study will seek to review what is currently known in each of these areas of study as they apply to NNT. Further study of the provocative differences in tumour behaviour in neonates provides insights into the natural history of cancer in humans and promotes novel cancer therapies. PMID- 24173817 TI - Thromboses of the pampiniform plexi after subinguinal varicocelectomy. AB - PURPOSE: To present the Authors' experience with spermatic vein thrombosis after varicocelectomy. MATERIALS AND METHODS: The medical charts of patients treated for varicocele at the Authors' Institution between January 2008 and January 2013 were reviewed; inclusion and exclusion criteria were created. Data were analyzed focusing on the clinical diagnosis of spermatic vein thrombosis after varicocelectomy performed using two different techniques. RESULTS: After revision of the medical charts and in compliance with the inclusion criteria previously established, 188 patients underwent varicocelectomy: 112 with laparoscopic technique and 76 patients with subinguinal technique. A total of five cases of spermatic vein thrombosis (2.6%) were diagnosed between 6 and 12 days after surgery. All these patients had received the subinguinal technique (6.5%). All the patients were managed conservatively. DISCUSSION: Spermatic vein thrombosis after surgery is a rare complication but its onset should be considered as a possible event in patients with inguinal and scrotal pain. To manage this condition after diagnosis surgeons may opt for a surgical or clinical approach, either with drugs or local heat, rest and scrotal support. PMID- 24173816 TI - Role of surgery in pediatric ulcerative colitis. AB - Pediatric ulcerative colitis (UC) has a more extensive and progressive clinical course than adult UC. Therefore, more aggressive initial therapies and more frequent surgical treatments are needed. The therapeutic goal is to gain clinical and laboratory control of the disease with minimal adverse effects while permitting the patient to function as normally as possible. Approximately 5-10 % of patients with UC require acute surgical intervention because of fulminant colitis refractory to medical therapy. Mucosal proctocolectomy with ileal J-pouch anal anastomosis is currently recommended as a standard curative surgical procedure for UC in both children and adults worldwide. This review will focus on the current issues regarding the surgical indications for pediatric UC, the technical details of procedures and results of most recent published series to take the most appropriate next step to improve the surgical outcomes and patients' quality of life. PMID- 24173818 TI - Accumulation and translocation of 198Hg in four crop species. AB - The uptake and transport of mercury (Hg) through vegetation play an important role in the biogeochemical cycling of Hg. However, quantitative information regarding Hg translocation in plants is poorly understood. In the present study, Hg uptake, accumulation, and translocation in 4 crops-rice (Oryza.sativa L.), wheat (Triticum L.), corn (Zea mays L.), and oilseed rape (Brassica campestris L.)-grown in Hoagland solution were investigated using a stable isotope ((198)Hg) tracing technique. The distribution of (198)Hg in root, stem, and leaf after uptake was quantified, and the release of (198)Hg into the air from crop leaf was investigated. It was found that the concentration of Hg accumulated in the root, stem, and leaf of rice increased linearly with the spiked (198)Hg concentration. The uptake equilibrium constant was estimated to be 2.35 mol Hg/g dry weight in rice root per mol/L Hg remaining in the Hoagland solution. More than 94% of (198)Hg uptake was accumulated in the roots for all 4 crops examined. The translocation to stem and leaf was not significant because of the absence of Hg(2+) complexes that facilitate Hg transport in plants. The accumulated (198)Hg in stem and leaf was not released from the plant at air Hg(0) concentration ranging from 0 ng/m(3) to 10 ng/m(3). Transfer factor data analysis showed that Hg translocation from stems to leaves was more efficient than that from roots to stems. PMID- 24173819 TI - Comparison of itraconazole, voriconazole, and posaconazole as oral antifungal prophylaxis in pediatric patients following allogeneic hematopoietic stem cell transplantation. AB - Oral antifungal prophylaxis with extended-spectra azoles is widely used in pediatric patients after allogeneic hematopoietic stem cell transplantation (HSCT), while controlled studies for oral antifungal prophylaxis after bone marrow transplantation in children are not available. This survey analyzed patients who had received either itraconazole, voriconazole, or posaconazole. We focused on the safety, feasibility, and initial data of efficacy in a cohort of pediatric patients and adolescents after high-dose chemotherapy and HSCT. Fifty consecutive pediatric patients received itraconazole, 50 received voriconazole, and 50 pediatric patients received posaconazole after HSCT as oral antifungal prophylaxis. The observation period lasted from the start of oral prophylactic treatment with itraconazole, voriconazole, or posaconazole until two weeks after terminating the oral antifungal prophylaxis. No incidences of proven or probable invasive mycosis were observed during itraconazole, voriconazole, or posaconazole treatment. A total of five possible invasive fungal infections occurred, two in the itraconazole group (4%) and three in the voriconazole group (6%). The percentage of patients with adverse events potentially related to clinical drugs were 14% in the voriconazole group, 12% in the itraconazole group, and 8% in the posaconazole group. Itraconazole, voriconazole, and posaconazole showed comparable efficacy as antifungal prophylaxis in pediatric patients after allogeneic HSCT. PMID- 24173820 TI - Alteration of the serum biomarker profiles of visceral leishmaniasis during treatment. AB - Until recently, chemotherapy for visceral leishmaniasis (VL; also known as kala azar) was severely limited by factors such as high cost, route of administration, generation of side effects and potential for resistance. Although largely effective, chemotherapies have become available with the introduction of new drugs and multi-drug regimens for VL. These could be further improved by the identification of biomarkers that are altered during effective treatment. The identification of such biomarkers in the circulation would also simplify efficacy trials. In this study, we determined immunological signatures within the serum of ethnically and geographically distinct VL patients (from Bangladesh and Brazil). Our results indicate that inflammatory and regulatory cytokines (IFNgamma, TNFalpha, IL-10, IL-17), as well as levels of growth factors (FGF, VEGF), are elevated within the serum of VL patients from these sites. The examination of samples from Brazilian VL patients during and beyond standard treatment with meglumine antimoniate identified multiple parameters that revert to levels comparable to those of healthy endemic control individuals. The consolidation of these results provides a 'response to treatment' signature that could be used within efficacy trials to rapidly and simply determine successful interruption of VL. PMID- 24173821 TI - Factors associated with the use of rapid antigen diagnostic tests in children presenting with acute pharyngitis among French general practitioners. AB - In this investigation, we wanted: (i) to describe the attitudes and declared practices of a representative sample of French general practitioners (GPs) regarding rapid antigen diagnostic tests (RADTs) for acute pharyngitis and (ii) to identify the GPs' characteristics associated with the use of an RADT in the last paediatric patient with pharyngitis. We performed a cross-sectional survey conducted in 2012 among a representative sample of 1,126 self-employed GPs in France. 60.1 % of GPs declared that they used an RADT in their last patient aged between 3 and 16 years presenting with acute pharyngitis; 29.6 % of these tests were positive. Among the GPs who did not use an RADT, 50.2 % prescribed an antibiotic, compared to 30.5 % of prescriptions among GPs who performed an RADT, whatever its result. In a multivariate analysis, GPs' age between 45 and 54 years and having attended Continuing Medical Education (CME) sessions on infectious diseases in the past year were significantly associated with an increased use of an RADT in the last patient with pharyngitis, whereas a low volume of activity, occasionally practising alternative medicine, receiving pharmaceutical representatives at the practice and declaring a consultation duration <15 min were factors associated with a decreased use of RADTs. The use of RADTs by GPs must be promoted; our findings could help define interventions to improve practice. PMID- 24173822 TI - The risk of catheter-related bloodstream infection after withdrawal of colonized catheters is low. AB - Most episodes of catheter-related bloodstream infection (C-RBSI) are documented before or at the time of catheter withdrawal. The risk of C-RBSI in the period after removing a colonized catheter in patients without bacteremia (late C-RBSI) is unknown. We assessed the risk of developing a late C-RBSI episode in an unselected population with positive catheter tip cultures and analyzed associated risk factors. We analyzed retrospectively all colonized catheter tips between 2003 and 2010 and matched them with blood cultures. C-RBSI episodes were classified as early C-RBSI (positive blood cultures were obtained <=24 h after catheter withdrawal) or late C-RBSI (positive blood cultures were obtained >=24 h after catheter withdrawal). We analyzed the risk factors associated with late C RBSI episodes by comparison with a selected group of early C-RBSI episodes. We collected a total of 17,981 catheter tips: 4,533 (25.2 %) were colonized. Of them, 1,063 (23.5 %) were associated to early C-RBSI episodes and from the remaining 3,470, only 143 (4.1 %) were associated to late C-RBSI episodes. Then, they corresponded to 11.9 % of the total 1,206 C-RBSI episodes. After comparing early and late C-RBSI episodes, we found that late C-RBSI was significantly associated with the presence of methicillin-resistant Staphylococcus aureus (MRSA, p = 0.028) and with higher mortality (p = 0.030). According to our data, patients with colonized catheter tips had a 4.1 % risk of developing late C-RBSI, which was associated with higher crude mortality. PMID- 24173823 TI - Increased metastatic potential of residual carcinoma after transarterial embolization in rat with McA-RH7777 hepatoma. AB - Transarterial chemoembolization represents a first-line non-curative therapy for hepatocellular carcinoma (HCC), although the biological changes in the remaining cancer after embolization are not completely understood. In the present study, we examined whether transarterial embolization (TAE) enhances the metastatic potential of residual HCC and investigated the mechanisms underlying embolization. The hepatoma cell line McA-RH7777, which is marked by green fluorescent protein (GFP), was used in the study. The invasion of cells cultured under hypoxia and normoxia was observed using the Transwell assay. Twenty male buffalo rats were implanted with GFP transfected McA-RH7777 tumors in the left lateral lobe of the liver. After laparotomy and retrograde placement of a catheter into the gastroduodenal artery (on the 14th day after implantation), TAE using lipiodol (0.2 ml/kg) was performed. Tumor volumes were measured before and after treatment using magnetic resonance imaging (MRI). Lung metastases were observed using fluorescence imaging, and the molecular changes of residual tumor cells were evaluated by western blotting or immunohistochemistry. The invasion assays indicated that the number of invading hypoxic cells was significantly higher than that of normoxic cells (30.2 +/- 2.46 vs. 20.4 +/- 1.89, P=0.013). Accompanying an increase in hypoxia-inducible factor-1alpha (HIF-1alpha) expression, the metastatic potential of tumor cells following hypoxia or TAE was enhanced. This enhanced metastatic potential was indicated by a significant reduction in the expression of E-cadherin and an upregulation of N-cadherin and vimentin expression. The number of lung metastases in the TAE group was 19.20 +/- 1.76, whereas this number was 11.30 +/- 1.54 in the control group, which represented a statistically significant difference (P=0.003). In conclusion, hypoxia in the residual tumor after TAE can increase the invasiveness and metastatic potential of HCC and may be responsible for the failure of TAE. PMID- 24173824 TI - Improving the representation of peptide-like inhibitor and antibiotic molecules in the Protein Data Bank. AB - With the accumulation of a large number and variety of molecules in the Protein Data Bank (PDB) comes the need on occasion to review and improve their representation. The Worldwide PDB (wwPDB) partners have periodically updated various aspects of structural data representation to improve the integrity and consistency of the archive. The remediation effort described here was focused on improving the representation of peptide-like inhibitor and antibiotic molecules so that they can be easily identified and analyzed. Peptide-like inhibitors or antibiotics were identified in over 1000 PDB entries, systematically reviewed and represented either as peptides with polymer sequence or as single components. For the majority of the single-component molecules, their peptide-like composition was captured in a new representation, called the subcomponent sequence. A novel concept called "group" was developed for representing complex peptide-like antibiotics and inhibitors that are composed of multiple polymer and nonpolymer components. In addition, a reference dictionary was developed with detailed information about these peptide-like molecules to aid in their annotation, identification and analysis. Based on the experience gained in this remediation, guidelines, procedures, and tools were developed to annotate new depositions containing peptide-like inhibitors and antibiotics accurately and consistently. PMID- 24173825 TI - Caffeine inhibits paclitaxel-induced apoptosis in colorectal cancer cells through the upregulation of Mcl-1 levels. AB - Colorectal cancer (CRC) cells have been previously observed to be resistant to paclitaxel-induced apoptosis by activation of the mitogen-activated protein/extracellular signal-regulated kinase (MEK)/ERK signaling pathway and increased expression of glucose-regulated protein 78 (GRP78). Caffeine, the most widely used neuroactive compound, has antiproliferative activity and the ability to induce cell cycle arrest and apoptosis. In the current study, the effect of concomitant use of caffeine on paclitaxel-induced apoptosis in CRC cells was investigated. The results revealed that treatment of Colo205 cells with varying caffeine concentrations did not induce apoptosis. Pretreatment of CRC cells with caffeine significantly inhibited paclitaxel-induced cytotoxicity by increasing the levels of the antiapoptotic Bcl-2 family member, Mcl-1. This effect was inhibited by pretreatment of Colo205 cells with the MEK-ERK chemical inhibitor, U0126. In addition to GRP78, these results indicated that Mcl-1 may be a downstream target of the MEK-ERK signaling pathway. Moreover, administration of caffeine may decrease chemotherapeutic responses to paclitaxel by the MEK-ERK mediated upregulation of Mcl-1. In conclusion, coadministration of cell cycle modifying agents, including caffeine should be avoided in CRC patients treated with paclitaxel. PMID- 24173827 TI - THCCOOH concentrations in whole blood: are they useful in discriminating occasional from heavy smokers? AB - Some forensic and clinical circumstances require knowledge of the frequency of drug use. Care of the patient, administrative, and legal consequences will be different if the subject is a regular or an occasional cannabis smoker. To this end, 11-nor-9-carboxy-Delta9-tetrahydrocannabinol (THCCOOH) has been proposed as a criterion to help to distinguish between these two groups of users. However, to date this indicator has not been adequately assessed under experimental conditions. We carried out a controlled administration study of smoked cannabis with a placebo. Cannabinoid levels were determined in whole blood using tandem mass spectrometry. Significantly high differences in THCCOOH concentrations were found between the two groups when measured during the screening visit, prior to the smoking session, and throughout the day of the experiment. Receiver operating characteristic (ROC) curves were determined and two threshold criteria were proposed in order to distinguish between these groups: a free THCCOOH concentration below 3 ug/L suggested an occasional consumption (<= 1 joint/week) while a concentration higher than 40 ug/L corresponded to a heavy use (>= 10 joints/month). These thresholds were tested and found to be consistent with previously published experimental data. The decision threshold of 40 ug/L could be a cut-off for possible disqualification for driving while under the influence of cannabis. A further medical assessment and follow-up would be necessary for the reissuing of a driving license once abstinence from cannabis has been demonstrated. A THCCOOH level below 3 ug/L would indicate that no medical assessment is required. PMID- 24173828 TI - Determination of amino acid enantiopurity and absolute configuration: synergism between configurationally labile metal-based receptors and dynamic covalent interactions. AB - Reliable determination of the enantiomeric excess of free amino acids can be obtained by measuring the induced circular dichroism of a multicomponent assembly formed by a modified tris(2-pyridylmethyl)amine ligand, a zinc salt, and the amino acid of interest. The systems furnish reliable information for all natural amino acids. PMID- 24173830 TI - Mammaplasty: The dermal brassiere technique. AB - CONCLUSIONS: With most methods, it is possible to obtain a good breast shape as an immediate postoperative result. The question is whether the satisfactory shape is permanent.The 7-year evaluation of the method described here has confirmed the safety of the procedure as well as the satisfactory conic breast shape it achieves. The result has proven to be lasting. Drooping of the gland is prevented by means of the dermopexy with firm fixation of the infraareolar dermal pillar to the pectoral muscle.The method is indicated even for large hypertrophies as well as in cases of ptotic breasts of normal size and when combined with augmentation by silicone prostheses for ptotic hypoplastic breasts. Careful preoperative planning allows control of scar size with satisfactory quality since the scar is not exposed to undue tension.If the technique described is carefully followed, only minor complications such as occasional extrusion of a subcutaneous dermal stitch or, seldom, cyst formation (as in all dermopexy methods) may occur. PMID- 24173829 TI - S(+)-ibuprofen destabilizes MYC/MYCN and AKT, increases p53 expression, and induces unfolded protein response and favorable phenotype in neuroblastoma cell lines. AB - Neuroblastoma is a common pediatric solid tumor that exhibits a striking clinical bipolarity: favorable and unfavorable. The survival rate of children with unfavorable neuroblastoma remains low among all childhood cancers. MYCN and MYC play a crucial role in determining the malignancy of unfavorable neuroblastomas, whereas high-level expression of the favorable neuroblastoma genes is associated with a good disease outcome and confers growth suppression of neuroblastoma cells. A small fraction of neuroblastomas harbors TP53 mutations at diagnosis, but a higher proportion of the relapse cases acquire TP53 mutations. In this study, we investigated the effect of S(+)-ibuprofen on neuroblastoma cell lines, focusing on the expression of the MYCN, MYC, AKT, p53 proteins and the favorable neuroblastoma genes in vitro as biomarkers of malignancy. Treatment of neuroblastoma cell lines with S(+)-ibuprofen resulted in a significant growth suppression. This growth effect was accompanied by a marked decrease in the expression of MYC, MYCN, AKT and an increase in p53 expression in neuroblastoma cell lines without TP53 mutation. In addition, S(+)-ibuprofen enhanced the expression of some favorable neuroblastoma genes (EPHB6, CD44) and genes involved in growth suppression and differentiation (EGR1, EPHA2, NRG1 and SEL1L). Gene expression profile and Ingenuity pathway analyses using TP53-mutated SKNAS cells further revealed that S(+)-ibuprofen suppressed molecular pathways associated with cell growth and conversely enhanced those of cell cycle arrest and the unfolded protein response. Collectively, these results suggest that S(+) ibuprofen or its related compounds may have the potential for therapeutic and/or palliative use for unfavorable neuroblastoma. PMID- 24173831 TI - Razabrasion: An alternative approach to perioral rhytides. AB - Persistence of perioral rhytides is a frequent source of patient concern following standard rhytidectomy. Dissatisfaction with the limited results and occasional complications that result from mechanical, manual, and chemical abrasive methods of management prompted application of the steel blade dermal shave technique to this problem. Manual oscillation of a sterile commercial razor blade with depth and width controlled by digital pressure eradicates all but the deepest perioral wrinkles. Eleven patients have undergone "razabrasion" within the past 19 months without complication. Local anesthesia is sufficient. Topographically distant but synchronous facial operations may be performed safely, but undermining of the shaved facial skin should be avoided for 6 months after "razabrasion". Later results will be studied to define the longevity of the effect, but we are encouraged that the method offers the most gentle, most rapid, and best controlled (as to level of dermal shave) current method of tangential dermal splitting. The paper describes the technique of "razabrasion" of perioral rhytides and reports our early results. PMID- 24173832 TI - Surgical elimination of the retracted submental fold during double chin correction. AB - In some cases of double chin, the submental fold can become quite obvious. It can persist or even be deepended following a submental fatpad resection if the incision is made following the fold. The steps involved in eliminating this fold are: (1). A curved incision is made 1 cm in front of the fold. (2). The excess fat is reduced, leaving a 1 cm layer attached to the skin. (3). The fold is filled by sliding forward a fat flap taken from the fat remaining on the skin. (4). The sutures in the fat and the skin are not superimposed, to avoid recurrance of the fold. PMID- 24173833 TI - Blindness and eyelid surgery. PMID- 24173834 TI - Inverted nipple. AB - The author presents the anatomic, embryologic, and etiologic aspects and treatment of the inverted nipple.The Pitanguy technique for correction of this deformity consists of direct cutting of the fibromuscular tilts that hold the nipple in an inverted position, by means of a transareolomamillar incision.Associated mammary hypoplasia is corrected by extending the transareolomamillar incision to the muscular level and constructing a spacious supraaponeurotic pocket where the silicone prosthesis is placed. Details of the surgical technique are described. PMID- 24173835 TI - Abdominoplasty with special attention to construction of the umbilicus: Technique and complications. AB - We present a simple technique for umbilicoplasty and some guidelines for improving the results in abdominoplasty. These include preoperative erect marking, equal and exacting retraction, formation of a suprapublic fat pad and a central raphe, and prolonged splinting of the abdominal incisions including an umbilical stent. PMID- 24173837 TI - Reduction mammaplasty-An eclectic approach. AB - In a series of 200 personally performed mammaplasties, two main approaches were used: (a) small, ptotic, and moderately hypertrophic breasts were treated by elliptical wedge excision either vertical or oblique; and (b) large hypertrophic breasts were treated by Arie-Pitanguy wedge excision, ending with an inverted T suture line. The results are discussed. PMID- 24173836 TI - History of the aesthetic surgery of the ear. PMID- 24173838 TI - Face lifting with suspensory restoration of the fibromuscular tissues of the face and neck. AB - A series of before and after slides are shown of patients who have had the author's "wall type restoration of the fibro-fatty musculo-fascial restoration of the face and neck" in conjunction with face lifting. Several sutures (2-0 white Dacron usually 8 to 10 in all) are placed together so as to tighten the fibro fatty musclo-fascial layer of the neck and face to as nearly as possible that which it had in youth. These are not the typical plication sutures but are sturdy suture material and are tied tightly. Furthermore, the tension on the tissues is distributed evenly by a whole series of sutures which additionally gives a smoother wall type reconstruction.The technique decreases the dead space in the cervico-facial dissection by at least 50 per cent and avoids suture ridging. Since using this technique and subsequent to the submission of this paper, there have been no hematomata in over 150 consecutive face lifts. PMID- 24173839 TI - The history of abdominal dermolipectomy. PMID- 24173840 TI - Ectropion after blepharoplasty prevention and treatment. AB - Ectropion is the most common serious complication following blepharoplasty for the correction of baggy eyelid deformity. Although blepharoplasty may be considered one of the most gratifying plastic operations, if an ectropion results it then becomes one of the most distressing to patient and surgeon alike.Ectropion complication of the upper eyelid is very rare. This is mainly due to the anatomy of the upper lid with its larger tarsal plate, which permits rather extensive resection of redundant and sagging skin.Ectropion of the lower lid, on the other hand, is a common and very distressing complication. The most important single cause for this complication is excessive excision of skin, which can and must be prevented in every case.I limit the skin resection in the lower lid to a wedge varying from 4 to 6 mms. below the subciliary incision line in most cases. I may resect as much as 8 mms. in severe cases of atonic and relaxed skin.I feel that with the limited resection of skin and a lateral superior tensioning of the skin and relaxed orbicularis muscle underneath ectropion is preventable even in cases of baggy lids in elderly patients.The principal causes of this complication, its prevention, and management once it has occurred are discussed in detail in this article. PMID- 24173841 TI - Abdominoplasty-Systematization of a technique without external umbilical scar. AB - The author describes an abdominoplasty emphasizing preparation of the abdominal flap, reinforcement of the muscular aponeurotic wall, treatment of the excess of cutaneous tegument, and careful handling of the umbilicus. He makes three umbilical flaps which are alternately stitched to three other flaps originating on the abdominal wall, which result in a scar hidden inside the umbilicus. PMID- 24173842 TI - Oral animation in the decision for chin augmentation. AB - Oral animation, such as opening and closing the lips, smiling, or laughing, leads to muscular tension over the skin and the soft tissues of the chin. The "S"-like labiomental line presents a variable scope of curves, from a full curve, through "lazy-S", to a straight line. The different profiles of the chin thus achieved enable the plastic surgeon during preoperative planning to decide whether or not to perform chin augmentation in addition to the required rhinoplasty. Anatomical, functional, and clinical data are presented and discussed. PMID- 24173843 TI - A new triaxial fiberoptic soft tissue retractor. AB - The triaxial configuration of this fiberoptic instrument allows for operation through a small incision site and expansion within the wound. It also has a self retaining aspect. PMID- 24173844 TI - Bipolar coagulation of vessels in aesthetic plastic surgery. AB - Bipolar coagulation for hemostasis should be used more frequently than monopolar coagulation in aesthetic plastic surgery. The advantages of the procedure are manifold: considerable reduction of the amount of current, and consequent prevention of deleterious effects on other tissues and organs; minimal devitalization of tissues during coagulation; reduction of reactive edema; total separation of the patient from the power source when coagulating forceps are not in use; avoidance of burns due to defective insulation of conductors; elimination of "spark" burns of the surgeon's fingers through punctured gloves; and freedom of the assistants' hands for other duties. PMID- 24173845 TI - History of mammaplasty. AB - CONCLUSION: This, then, is the history of mammaplasty; no doubt more remains to be said and our presentation is necessarily subjective. The tale is nonetheless a fascinating one as it testifies to the work of plastic surgeons for more than a century. The best way of bringing it to life is to perform a mammaplasty. Let us be aware that each of our acts, in its ease and simplicty, bears witness to this history and to the endeavours of the men who made it. PMID- 24173846 TI - Experiences in corrective surgery of the chin. AB - Different methods of diagnosis and classification of the deformities of the chin are described. A variety of cases with the surgical methods performed are presented demonstrating that good clinical, photographic, and X-ray analyses are the best way to choose a suitable surgical treatment to correct these important deformities of the human face. PMID- 24173847 TI - The evolution of thought concerning the justification of aesthetic plastic surgery. AB - The evolution of thought concerning the justification of aesthetic plastic surgery as a special field of endeavor in medical practice is viewed against the background of the development of this specialty.Representative writings on the psychologic, social, and philosophic aspects of aesthetic plastic surgery are reviewed in a selective manner to allow an insight into the prevailing thought of those who played a part in the development of this speciality, as well as into the factors that determined the direction of its development. PMID- 24173848 TI - Abdominoplasty: Some ideas to improve results. AB - Pregnancy produces changes in the body contour due to skeletal modifications and flaccidity of the cutaneous and musculoaponeurotic tissues. A new technique is proposed to treat the musculoaponeurotic flaccidity and thus achieve a good abdominal contour. The major oblique muscle is sutured to the rectus fasciae. The results of this procedure and the physiopathology of the modification of the abdomen during pregnancy and obesity are discussed. Possible future scientific methods are considered. PMID- 24173849 TI - The fibrous capsule around mammary implants: An investigation. AB - Physiopathology of the contracture of the fibrous wall around breast implants is reviewed. In the fine structure of the capsule, the authors have found collagen fibers in fibroblast cytoplasm, a developed Golgi complex, and rough endoplasmic reticulum, which has been unrelated so far. Some fibroblasts resemble those described by Gabbiani et al., but it cannot be concluded that the contracture depends on these fibroblasts. All findings available are discussed, and therapeutic measures based on these findings are proposed. PMID- 24173850 TI - Breast modeling after subcutaneous mastectomy. AB - The authors present their experience in two-team work in subcutaneous mastectomy, where the mastologists are responsible for the pathology of the breast and the plastic surgeon is responsible for the aesthetics and some of the complications arising from their aesthetical work. They make a minute study of existing operating techniques and present a personal contribution for breast modeling in cases of skin envelope reduction along with preservation of the neurovascular network of the nipple and the areola. They consider the secondary problems of this type of surgery and how they can be solved. PMID- 24173851 TI - Current status of liquid injectable silicone. AB - Since the inception of the recently concluded formal study, liquid injectable silicone has been both used and abused by many. Reports in both lay and professional literature reflect this experience in the form of a wide range of opinions and judgments regarding the use of this material in corrective surgery. Those intimately involved in the former study agree that, used properly, liquid injectable silicone appears to have redeeming value in at least a limited group of problem situations. These investigators further agree that its general use could lead to many problems unless its limited scope of usefulness and proper use are known, accepted, and abided by those using it. To satisfy the lingering doubts raised by the many negative reports, further controlled study is also indicated. Until there is a method of control over the general clinical use of liquid silicone and until persistent questions on its safety and efficacy, over a protracted period of time, are answered, the investigators are convinced that the substance should not be made generally available. Designed before the complexity required of a proper study was appreciated, the original research protocol lacked sufficient detail and was broad and vague in scope. The Dow-Corning Company and its investigators therefore recommended the termination of the study and set about planning a new research protocol that would supply more complete information in a much more restricted area of clinical need. This was done with the cooperation of the American Society of Plastic and Reconstructive Surgeons and was submitted for approval by the FDA along with an expanded group of clinical investigators selected with the help of the ASPRS, with consideration given to their even geographic distribution. This new research study was submitted to the FDA and approved. Accordingly, on March 1, 1978, a much more vigorous, detailed, and restrictive study, confined to major tissue defects of the head and neck, was resumed by a larger group of investigators representing the ASPRS supervised by a medical monitor acceptable to all. Hopefully, this study, which will occupy a period of 7 years and a limited number of patients, plus the rigorous efforts to trace and document those involved in the earlier study and the tracking down and full documentation of all known complications, will ultimately bring the true status of liquid injectable silicone into proper and generally acceptable perspective. PMID- 24173852 TI - Unsatisfactory results in augmentation mammoplasty: Chest and breast asymmetry. AB - Mild to moderate and at times, rather severe forms of asymmetry are overlooked preoperatively by the patient and even at times, by the physician. Preoperative awareness of breast and chest asymmetry is important in proper planning for surgery in order to gain maximum balance. Awareness of the asymmetries that may exist also enables a physician to be more realistic in stating limitations of the expected results from surgery.Unsatisfactory results, noted postoperatively, can usually be related to the anatomy evident preoperatively. Unsatisfactory results are, at times, unavoidable, but when they occur unexpectedly, one must ask if it is the breast or the chest that is at fault. The proper selection of procedure, the proper selection or variance of implants for augmentation, and the proper placement, often times in irregular fashion, of implant materials are essential for good results. A plea is made for more detailed attention to the preoperative anatomy of the breast and the thoracic cage and for better planning in augmentation surgery. PMID- 24173853 TI - The use of Silastic in face lifting. AB - Pieces of Silastic are described which are placed in the nasolabial fold and in chin regions for the purpose of filling in depressions that may exist since youth and which may, in latter life, give the face a look of age, a look that is not completely improved with face lifting alone. PMID- 24173854 TI - A new "double tie-over method" and its applications. AB - The tie-over method which has been commonly used for skin grafts has some problems. The dressing is large and grafted skin can shift easily due to lateral pressure causing hematoma and secondary necrosis. There was a stronger tendency to observe this in axillary and anal skin grafts.Thus, the "new double tie-over type dressing" (double tie-over method) was developed (2, 3) for postoperative application after subcutaneous shaving for hircismus and hyperhidrosis and excellent results were obtained. The dressing is smaller in volume and shifting of grafted skin does not occur with motion. This method was also applied for skin grafts of various areas and favorable results were obtained.This method is reported since it is an easy and safe procedure that can be applied for various types of skin graft. PMID- 24173855 TI - Experiences on aesthetic surgical treatment of the eyelids. AB - The author describes the main features any plastic surgeon must bear in mind when dealing with eyelid defects, and describes the surgical techniques for both upper and lower eyelids. He then describes his personal improvement of Silver's technique for lower eyelid aesthetic surgery, which he has used for 5 years with quite satisfactory results. PMID- 24173856 TI - Punch rhinoplasty: A complement to rhytidectomy. AB - The descent of the tip of the nose will betray aging even after a successful rhytidectomy. To ensure a youthful profile, the author presents a simple technique to correct the drooping nasal tip, provided there is no deformation of the lateral portion of the alar cartilage. A specially designed "punch" forceps removes a small portion of the membranous septum. Suturing along the line of the surgical wound achieves a true rhinopexy. In conjunction with rhytidectomy, it is performed under general anesthesia; as a separate procedure, it is performed under local anesthesia. Its simplicity and the short operation time makes this procedure quite remarkable. *** DIRECT SUPPORT *** A0225002 00011. PMID- 24173857 TI - Prominent ears : Transposition of the posterior auricular muscle on the scapha: A new technique. AB - This new method for the correction of a prominent ear is original, simple, and efficient. It consists of the retroauricular fixation of the scapha by means of three stitches of polyglycolic acid suture in the posterior auricular muscle after a wide dissection. This results in a transposition of this muscle on the scapha which assures a harmony of the latter with a gentle naturally rounded antihelix. Thus one achieves the main aims of this type of operation with a very simple technique. PMID- 24173858 TI - Identity change as a consequence of oral surgery. AB - The article stresses the need to consider the psychological significance of craniofacial deformities and their correction. The paper reviews some basic concepts of identily and self-image, particularly as they apply to the face and specifically in patients suffering facial disfigurement. The psychological problems of the repair of the disfigurement are also discussed. The continuity of body-image, self-concept and identity is presented. People with craniofacial deformities have a need to reorganize body-image and correction of the deformity requires another reorganization. A change in selfimage coincident with a change physically requires time and may require psychotherapy. The severity of the handicap of a facial disfigurement is presented. The importance of the significance of the deformity and the influence of social forces are outlined as determinates of the emotional impact. The "loss" is dealt with by such defense mechanisms as denial and undoing, both pathologic defenses which frequently break down. After reconstructive surgery, personality change does not occur simultaneous with physical change. The repair, potentially, can produce a depression related to the loss of the old identity, as well as a psychosis. Frequently, fantasied expectations of the patient can lead to much difficulty. The repair may also confront the patient with new sensory experiences. Acceptance of the change in identity is more readily accomplished by the young as opposed to the old. Problems of facial disfigurement and the work involved psychologically as a consequence of the repair of the disfigurement are illustrated in a case presentation of prognathous mandible. The need for the patient to receive proper support and help in integrating the new facial image and the need to concretize expectations for the patient, preoperatively, are stressed since these are often grossly unrealistic. PMID- 24173859 TI - Correction of the infrapalpebral depression. AB - According to the author, the infrapalpebral depression is often overlooked or refused for correction. Its anatomical relation is shown and a way of correction is proposed, which has been used successfully for several years. PMID- 24173860 TI - Secondary nasal revisions after rhinoplasties. AB - This article describes procedures for correcting some of the most common deformities after rhinoplasty. Double or triple osteotomies, partial removal of the nasal bones, autogenous cartilage transplantations, and the value of the transplantation of auricular composite grafts are discussed. PMID- 24173861 TI - Methodology in combined aesthetic surgeries. AB - This paper presents a practical methodology, based on 3343 cases, for making combined aesthetic operations a safe and quick procedure.The different medico surgical procedures which comprise this type of operation are analyzed and discussed. The results are illustrated in the figures and in the statistical data of the tables. PMID- 24173862 TI - Advances in aesthetic plastic surgery. PMID- 24173863 TI - A new technique for reduction mammaplasty. AB - A new surgical technique for reduction mammaplasty is described. Incisions are chosen according to Strombeck's procedure and deepithelialization of the major part of the skin in the resection area is carried out. The upper part of the breast with the total skin for the planned breast is separated from the lower part with the dermis flap and the nipple and the desired resections are carried out from the lower part. A dermis cone or tube is then created with the mammilla at its apex and the skin is closed around the dermis cone. PMID- 24173864 TI - The lateral transhelical approach for correction of deformities of the external ear. AB - Additional experience with the chondrocutaneous flap in the repair of auricular defects showed that (i) the entire medial surface of the auricle can be easily and rapidly exposed through this approach, and (ii) the transhelical scar on the lateral surface of the ear remains inconspicuous. The skin of the lateral surface of the ear is similar to that of the eyelids and forms flat, smooth scars which do not hypertrophy. Furthermore, these scars are hidden under the curl of the helix. Through this approach, correction of the protrusion can be accomplished by any method or combination of methods which call for manipulation on the medial surface of the auricle. The scar is remote from the site of manipulation of the cartilage. An additional advantage of this procedure is that it can be combined easily with a small reduction in the size of the scapha. PMID- 24173865 TI - Transareolar incision for augmentation mammaplasty. AB - In the past, unacceptable results were obtained in attempts to correct hypoplastic breasts, so that patients seeking augmentation mammaplasty were afraid of possible hazards. Silicone inclusions were a great advancement in biological engineering. Their implantation through the transareolar incision by Pitanguy seems to be more physiologic and gives welcome aesthetic resuls. Furthermore, the incision allows adequate undermining and good hemostasis. Because there is no inframammary scar and consequent tissue weakness, early mobilization of the prosthesis by precocious manipulation is possible, decreasing the occurrence of capsule formation. PMID- 24173866 TI - Correction of the "Simian" forehead deformity. AB - A procedure for the correction of the "simian" forehead deformity is described. PMID- 24173867 TI - Dr. Vazquez Anon's last lesson. AB - This article is offered in homage to Dr. Vazquez Anon, one of the most out standing Spanish plastic surgeons.It also is meant to draw attention to the need for a precise, detailed, and complete personality profile of each patient, requesting, in case of doubts, the help of a psychologist or psychiatrist.Dr. Vazquez Anon had frequently referred to the deep psychological problems sometimes involved in aesthetic plastic surgery, and his death is a warning to all of us.Unfortunately he gave his last lession with his life. PMID- 24173868 TI - Normal size and shape of the breast and elaboration of a natural pattern. AB - An historical resume of the female breast is furnished, and the influence that different ages and cultures had on its shape is discussed. The normal size and shape of the breast is analyzed after a study of 35 normal cases. Finally the technique for obtaining a natural pattern with 3M Scotch tape, Ref. 202, is presented, and the modifications for its adaption to a predetermined normal mammary volume (modified natural patterns) are described. The modified natural patterns are used in preoperative planning for reduction mammaplasties and the natural pattern is used to check the end result. PMID- 24173869 TI - The invisible frown plasty. AB - The sad or sinister look in young and middle-aged patients produces an unhappy attitude in these patients. An approach is recommended in which the corrugator and procerus muscles can be removed with a curette either transnasally or via a small supercilliary incision. No complications are associated with this procedure. PMID- 24173870 TI - Surgical correction of forehead wrinkles, glabellar frown, and ptosis of the eyebrows. AB - Lasting elimination of forehead wrinkles and glabellar frown may be achieved by a partial resectioning of the muscles of the forehead. In those cases in which the eyebrows are also lifted, we use a line of incision which is similar to the blepharoplasty of the upper lids used by Morel-Fatio. We carry out the resectioning of the muscle more extensively than is generally described in the literature. It has hereby been observed that the partial resectioning of the musculus frontalis leads to a smoothing out of the horizontal forehead wrinkles, without a tightening of the skin. The results were always satisfactory both for the patients and the surgeons, and the rate of complication was minimal. A result acceptable to the patient can be achieved only if she has been thoroughly informed in advance. PMID- 24173871 TI - Rhinoplasty-A new approach in the repair of the hump. AB - A variation in Cottle's technique is presented in which the hump is preserved and the difficulties arising out of making fractures in different levels are avoided. A "natural look" is obtained for the operated nose, mainly from a frontal view. PMID- 24173872 TI - "False bursa" concept in augmentation mammaplasty. AB - Natural feeling breasts are a primary objective to be achieved in the augmentation mammaplasty procedure. Rather than attempt to totally prevent a fibrous capsule from forming about the implant, it should be converted into a larger "false bursa" containing a freely mobile soft implant of modern design with no fixation patches. This relationship must be maintained through many months of the postoperative period to ensure a lasting result. Failure to achieve the false bursa concept results in a tight immobile noncompressible breast that has an unnatural feel. PMID- 24173873 TI - Postoperative fixation of the nose. AB - A method to maintain an operatively corrected nose in the desired form through the use of a transfixion plaster is described. This procedure has proved to be successful in giving a resilient fixation. PMID- 24173874 TI - Psychosocial effects of cosmetic augmentation mammaplasty. AB - In a follow-up study, 19 small-busted women who had received a cosmetic augmentation mammaplasty were contrasted with 20 small-busted control wornen and 19 average-busted control women. The augmented women showed much greater happiness with their breast, an improved body image, and more daring and revealing dress. Basic personality traits, self-concept, and the frequency of various activities were unchanged. PMID- 24173875 TI - Constriction of the capsule around breast prostheses. AB - The capsule formed around an implant contracts and tends to become spherical, a tendency limited by the consistency of the implant. Another factor in this is the size of the implantation pocket. If the pocket fits too tightly, spherical development occurs earlier and becomes more marked. A "dead space" between the tissues and the implant, on the other hand, leads to proliferation in the wall of the pocket and hence a thickened capsule.The spherical form of the breast and its firmness need not necessarily be due to fibrotic thickening of the capsule, and the diagnosis of "constrictive fibrosis" does not always apply. The same symptoms may result from contraction of a thin capsule when the implantation pocket was made too small. PMID- 24173876 TI - The "Cross-furrowed" forehead. AB - Three middle-aged men were encountered whose foreheads showed a pattern of vertical lines as well as the standard transverse furrows. The etiology of these lines is obscure. PMID- 24173877 TI - Mammometer: A new instrument for measuring "pseudocapsule firmness" after breast augmentation. AB - A new device is introduced which measures the compressability of breasts after augmentation. Since small progressive changes in breast firmness are not readily picked up by manual palpation, a more accurate and reliable method of measurement is needed. A comparison is made between manual compression and use of the mammometer. PMID- 24173878 TI - An unusual complication associated with blepharoplasty. AB - The usual complications associated with blepharoplasty are well known. This report presents a case of second-degree burns of the face which occurred while oxygen was being administered to a patient undergoing blepharoplasty and a heat producing cautery was being used for hemostasis. A possible cause for the complication is suggested. Surgeons are warned of the potential problem that may occur when this combination of factors are present. PMID- 24173879 TI - Design of a microchannel-nanochannel-microchannel array based nanoelectroporation system for precise gene transfection. AB - A micro/nano-fabrication process of a nanochannel electroporation (NEP) array and its application for precise delivery of plasmid for non-viral gene transfection is described. A dip-combing device is optimized to produce DNA nanowires across a microridge array patterned on the polydimethylsiloxane (PDMS) surface with a yield up to 95%. Molecular imprinting based on a low viscosity resin, 1,4 butanediol diacrylate (1,4-BDDA), adopted to convert the microridge-nanowire microridge array into a microchannel-nanochannel-microchannel (MNM) array. Secondary machining by femtosecond laser ablation is applied to shorten one side of microchannels from 3000 to 50 MUm to facilitate cell loading and unloading. The biochip is then sealed in a packaging case with reservoirs and microfluidic channels to enable cell and plasmid loading, and to protect the biochip from leakage and contamination. The package case can be opened for cell unloading after NEP to allow for the follow-up cell culture and analysis. These NEP cases can be placed in a spinning disc and up to ten discs can be piled together for spinning. The resulting centrifugal force can simultaneously manipulate hundreds or thousands of cells into microchannels of NEP arrays within 3 minutes. To demonstrate its application, a 13 kbp OSKM plasmid of induced pluripotent stem cell (iPSC) is injected into mouse embryonic fibroblasts cells (MEFCs). Fluorescence detection of transfected cells within the NEP biochips shows that the delivered dosage is high and much more uniform compared with similar gene transfection carried out by the conventional bulk electroporation (BEP) method. PMID- 24173880 TI - Development of an activity-based probe and in silico design reveal highly selective inhibitors for diacylglycerol lipase-alpha in brain. PMID- 24173881 TI - The relationship between gut and adipose hormones, and reproduction. AB - BACKGROUND: Reproductive function is tightly regulated by nutritional status. Indeed, it has been well described that undernutrition or obesity can lead to subfertility or infertility in humans. The common regulatory pathways which control energy homeostasis and reproductive function have, to date, been poorly understood due to limited studies or inconclusive data. However, gut hormones and adipose tissue hormones have recently emerged as potential regulators of both energy homeostasis and reproductive function. METHODS: A PubMed search was performed using keywords related to gut and adipose hormones and associated with keywords related to reproduction. RESULTS: Currently available evidence that gut (ghrelin, obestatin, insulin, peptide YY, glucagon-like peptide-1, glucose dependent insulinotropic peptide, oxyntomodulin, cholecystokinin) and adipose hormones (leptin, adiponectin, resistin, omentin, chemerin) interact with the reproductive axis is presented. The extent, site and direction of their effects on the reproductive axis are variable and also vary depending on species, sex and pubertal stage. CONCLUSIONS: Gut and adipose hormones interact with the reproductive axis as well as with each other. While leptin and insulin have stimulatory effects and ghrelin has inhibitory effects on hypothalamic GnRH secretion, there is increasing evidence for their roles in other sites of the reproductive axis as well as evidence for the roles of other gut and adipose hormones in the complex interplay between nutrition and reproduction. As our understanding improves, so will our ability to identify and design novel therapeutic options for reproductive disorders and accompanying metabolic disorders. PMID- 24173882 TI - Prognostic profiles and the effectiveness of assisted conception: secondary analyses of individual patient data. AB - BACKGROUND: At present, it is unclear which treatment strategy is best for couples with unexplained or mild male subfertility. We hypothesized that the prognostic profile influences the effectiveness of assisted conception. We addressed this issue by analysing individual patient data (IPD) from randomized controlled trials (RCTs). METHODS: We performed an IPD analysis of published RCTs on treatment strategies for subfertile couples. Eligible studies were identified from Cochrane systematic reviews and we also searched Medline and EMBASE. The authors of RCTs that compared expectant management (EM), intracervical insemination (ICI), intrauterine insemination (IUI), all three with or without controlled ovarian stimulation (COS) and IVF in couples with unexplained or male subfertility, and had reported live birth or ongoing pregnancy as an outcome measure, were invited to share their data. For each individual patient the chance of natural conception was calculated with a validated prognostic model. We constructed prognosis-by-treatment curves and tested whether there was a significant interaction between treatment and prognosis. RESULTS: We acquired data from 8 RCTs, including 2550 couples. In three studies (n = 954) the more invasive treatment strategies tended to be less effective in couples with a high chance of natural conception but this difference did not reach statistical significance (P-value for interaction between prognosis and treatment outcome were 0.71, 0.31 and 0.19). In one study (n = 932 couples) the strategies with COS (ICI and IUI) led to higher pregnancy rates than unstimulated strategies (ICI 8% versus 15%, IUI 13% versus 22%), regardless of prognosis (P-value for interaction in all comparisons >0.5), but at the expense of a high twin rate in the COS strategies (ICI 6% versus 23% and IUI 3% versus 30%, respectively). In two studies (n = 373 couples), the more invasive treatment strategies tended to be more effective in couples with a good prognosis but this difference did not reach statistical significance (P-value for interaction: 0.38 and 0.68). In one study (n = 253 couples) the differential effect of prognosis on treatment effect was limited (P-value for interaction 0.52), perhaps because prognosis was incorporated in the inclusion criteria. The only study that compared EM with IVF included 38 couples, too small for a precise estimate. CONCLUSIONS: In this IPD analysis of couples with unexplained or male subfertility, we did not find a large differential effect of prognosis on the effectiveness of fertility treatment with IUI, COS or IVF. PMID- 24173884 TI - Comparison of biodegradation performance of OECD test guideline 301C with that of other ready biodegradability tests. AB - The Organisation for Economic Co-operatoin and development (OECD) Guidelines for the Testing of Chemicals list 7 types of tests for determining the ready biodegradability of chemical compounds (301A-F and 310). The present study compares the biodegradation performance of test guideline 301C, which is applied in Japan's Chemical Substances Control Law, with the performance of the other 6 ready biodegradability tests (RBTs) listed in the guidelines. Test guideline 301C specifies use of activated sludge precultured with synthetic sewage containing glucose and peptone (301C sludge) as a test inoculum; in the other RBTs, however, activated sludge from wastewater treatment plants (WWTP sludge) is frequently employed. Analysis based on percentage of biodegradation and pass levels revealed that the biodegradation intensity of test guideline 301C is relatively weak compared with the intensities of RBTs using WWTP sludge, and the following chemical compounds are probably not biodegraded under test guideline 301C conditions: phosphorus compounds; secondary, tertiary, and quaternary amines; and branched quaternary carbon compounds. The relatively weak biodegradation intensity of test guideline 301C may be related to the markedly different activities of the 301C and WWTP sludges. These findings will be valuable for evaluating RBT data in relation to Japan's Chemical Substances Control Law. PMID- 24173883 TI - Association of vitamin D status and blood pressure response after renal denervation. AB - BACKGROUND: Vitamin D deficiency is associated with hypertension; however, it is unclear whether vitamin D influences therapeutic blood pressure reduction. Renal sympathetic denervation (RDN) reduces blood pressure in resistant hypertension. We hypothesized that vitamin D might influence blood pressure response to RDN. METHODS: Vitamin D was measured in 101 patients with resistant hypertension undergoing RDN. The associations between vitamin D status and systolic blood pressure (SBP) reduction 6 months after RDN were analyzed. RESULTS: Mean office SBP at baseline was 171.5 +/- 2 mmHg. After RDN, mean office SBP was reduced by 28.4 +/- 2.3 mmHg (p = 0.007). 85 patients (84.2 %) had SBP reductions >10 mmHg (responders). Vitamin D concentrations were lower in non-responders as compared to responders (9.9 +/- 4.5 vs. 13.7 +/- 7.4 ng/ml, p = 0.008). Non-responders (n = 16, 15.8 %), more often had a vitamin D concentration below the median as compared to responders (81 vs. 46 %, p = 0.013). The percentage of patients with normal vitamin D concentrations increased with increasing tertiles of SBP reduction (p for trend = 0.020). In patients with vitamin D concentrations below the median, SBP reduction was lower as compared to patients with a vitamin D concentration above the median (23.5 +/- 3.2 vs. 33.7 +/- 3.2 mmHg, p = 0.026). Baseline vitamin D concentrations correlated with SBP reduction (r = 0.202, p = 0.043). CONCLUSIONS: In patients with resistant hypertension, low vitamin D concentrations were associated with a decreased SBP response and a higher rate of non-response. PMID- 24173885 TI - Prolonged use of intravenous lipid emulsion in a severe tricyclic antidepressant overdose. AB - INTRODUCTION: Intravenous lipid emulsion (ILE) resuscitation is now frequently being used for severe overdoses due to lipophilic drugs. However, the optimal dose, duration, and safety are still unclear. CASE REPORT: A patient with refractory cardiovascular collapse following an amitriptyline overdose was treated with ILE with initial improvement. Instability recurred after ILE discontinuation and lipid therapy was restarted, but high-dose treatment was complicated by severe lipemia. A low-dose infusion was instead used, and the patient did not experience further toxicity despite amitriptyline levels in the toxic range for 21 days. He survived to discharge without long-term sequelae. DISCUSSION: A low-dose infusion of ILE was well tolerated and may have successfully prevented recurrent toxicity in a case of severe tricyclic antidepressant overdose. PMID- 24173886 TI - Centromeric repetitive DNA sequences in the genus Brassica. AB - Representatives of two major repetitive DNA sequence families from the diploid Brassica species B. campestris and B. oleracea were isolated, sequenced and localized to chromosomes by in situ hybridization. Both sequences were located near the centromeres of many chromosome pairs in both diploid species, but major sites of the two probes were all on different chromosome pairs. Such chromosome specificity is unusual for plant paracentromeric repetitive DNA. Reduction of stringency of hybridization gave centromeric hybridization sites on more chromosomes, indicating that there are divergent sequences present on other chromosomes. In tetraploid species derived from the diploids, the number of hybridization sites was different from the sum of the diploid ancestors, and some chromosomes had both sequences, indicating relatively rapid homogenization and copy number evolution since the origin of the tetraploid species. PMID- 24173887 TI - RAPD fingerprinting of blackcurrant (Ribes nigrum L.) cultivars. AB - Ribes nigrum germplasm was screened for random amplified polymorphic DNA (RAPD) markers. Fiftyfour markers were identified which generated individual fingerprints for each of 21 cultivars. Genetic variation within R. nigrum germplasm, as detected by RAPDs, demonstrated that the genetic basis for improvement of blackcurrant is narrower than would be expected by the analysis of parentage. PMID- 24173888 TI - RFLP patterns of gliadin alleles in Triticum aestivum L.: implications for analysis of the organization and evolution of complex loci. AB - A correspondence between RFLP patterns and gliadin alleles at the Gli-1 and Gli-2 loci was established in a set of 70 common wheat (T.aestivum L.) cultivars using gamma-gliadin (K32) and alpha-gliadin (pTU1) specific probes. All Gli-B1 and Gli D1 alleles which differed in encoded gamma-gliadins showed definite RFLP patterns after hybridization with the K32 probe. Two groups of Gli-B1 alleles, Gli-B1b like and Gli-B1e-like, were identified, and these could originate from distinct genotypes of the presumptive donor of the B-genome. Intralocus recombination and/or gene conversion as well as small deletions, gene silencing and gene amplification were assumed to be responsible for the origin of new gliadin alleles. Silent gamma-gliadin sequences were shown to exist in all of the genotypes studied. K32 also differentiated Gli-A1a from all other Gli-A1 alleles as well as the Gli-B11 allele in cultivars carrying the 1B/1R (wheat/rye) translocation. PTU1 was shown to recognize several Gli-A2 alleles, but not the Gli-B2 or Gli-D2 alleles. Moreover, this probe hybridized to chromosome 1R sequences suggesting the existence of rye gene(s), probably silent, for alpha gliadin-like proteins on chromosome 1R. PMID- 24173889 TI - Molecular analysis of the inheritance of the S-5 locus, conferring wide compatibility in Indica/Japonica hybrids of rice (O. sativa L.). AB - RFLP analysis was conducted on a population derived from a three-way cross to determine the location of the hybrid sterility locus, S-5, in relation to mapped molecular markers and to identify markers that would be useful for selection in breeding. S-5 is of interest to rice breeders because it is associated with spikelet sterility of F1 hybrids in Indica/Japonica crosses. Identification of an S-5 allele which confers fertility in Indica/Japonica hybrids when introgressed into either the Indica or the Japonica parent has been reported. Varieties carrying this S-5 (n) allele are known as "wide compatibility varieties (WCV)". Our data suggests that RFLP marker RG213 on chromosome 6 is closely linked to the S-5 locus and can be efficiently used to identify wide compatibility (WC) lines. RG213 is a single-copy genomic clone that detects three bands of different molecular weights in DNA from Japonica ('Akihikari') and Indica ('IR36') varieties and WC line ('Nekken 2'). We demonstrate that the three alleles detected by this marker could be used to trace the inheritance of the "wide compatible" phenotype in breeders' material. PMID- 24173890 TI - An extended map of the sugar beet genome containing RFLP and RAPD loci. AB - An updated map of sugar beet (Beta vulgaris L. ssp. vulgaris var 'altissima Doell') is presented. In this genetic map we have combined 248 RFLP and 50 RAPD loci. Including the loci for rhizomania resistance Rr1, hypocotyl colour R and the locus controlling the monogerm character M, 301 loci have now been mapped to the nine linkage groups covering 815 cM. In addition, the karyotype of some of the Beta vulgaris chromosomes has been correlated with existing RFLP and RAPD linkage maps. PMID- 24173891 TI - Mapping the genome of rapeseed (Brassica napus L.). I. Construction of an RFLP linkage map and localization of QTLs for seed glucosinolate content. AB - A linkage map of the rapeseed genome comprising 204 RFLP markers, 2 RAPD markers, and 1 phenotypic marker was constructed using a F1 derived doubled haploid population obtained from a cross between the winter rapeseed varieties 'Mansholt's Hamburger Raps' and 'Samourai'. The mapped markers were distributed on 19 linkage groups covering 1441 cM. About 43% of these markers proved to be of dominant nature; 36% of the mapped marker loci were duplicated, and conserved linkage arrangements indicated duplicated regions in the rapeseed genome. Deviation from Mendelian segregation ratios was observed for 27.8% of the markers. Most of these markers were clustered in 7 large blocks on 7 linkage groups, indicating an equal number of effective factors responsible for the skewed segregations. Using cDNA probes for the genes of acyl-carrier-protein (ACP) and beta-ketoacyl-ACP-synthase I (KASI) we were able to map three and two loci, respectively, for these genes. The linkage map was used to localize QTLs for seed glucosinolate content by interval mapping. Four QTLs could be mapped on four linkage groups, giving a minimum number of factors involved in the genetic control of this trait. The estimated effects of the mapped QTLs explain about 74% of the difference between both parental lines and about 61.7 % of the phenotypic variance observed in the doubled haploid mapping population. PMID- 24173892 TI - Induction of diploid androgenetic and mitotic gynogenetic Nile tilapia (Oreochromis niloticus L.). AB - Androgenesis is a potentially valuable technique for recovering fish from gene banks composed of cryopreserved sperm, developing inbred lines, and analyzing patterns of inheritance. The procedure for producing diploid organisms whose nuclear DNA is wholly of paternal origin is dependent on: (1) the denucleation of "host" eggs, and (2) the inhibition of the first mitotic division in order to double the haploid sperm chromosome complement following fertilization of host eggs. Denucleation of tilapia (Oreochromis niloticus L.) eggs was carried out using UV irradiation. Treatment durations of 5-8 min (total dose of 450-720 J/m(2)) produced acceptable yields of viable denucleated eggs [22.9+/-1.6% (+/ SE) of controls] as estimated by the survival of haploid androgenetic tilapia to 48 h post-fertilization. Successful mitotic inhibition was accomplished using a heat-shock of 42.5 degrees C for 3-4 min, applied at 2.5-min intervals from 22.5 to 30 min post-fertilization (mpf). The mean survival of androgenetic diploid fish to yolk-sac absorption for treatment groups varied from 0.4% to 5.3%, relative to the controls. Differences in the suceptibility of eggs from different females to UV irradiation were a significant factor in the overall yield of androgenetic diploids. Paternal effects did not significantly influence the androgenetic yield, suggesting that individual males would not be selected against. For comparative purposes mitotic gynogenetic "mitogyne" diploids were produced from UV-irradiated sperm. Mean survival to yolk-sac absorption varied from 0.5% to 10.64%, relative to controls. Similar optima for androgenetic and gynogenetic induction were found in the period 25-27.5 mpf (minutes post fertilization). Induction treatments would appear to be operating on the same developmental events in both these techniques, and the results suggest that the UV irradiations used do relatively little damage to the eggs beyond nuclear inactivation. The results indicate that the production of androgenetic O. niloticus is possible on a consistent basis and that the application of this technique may be useful in quantitative and conservation genetics. PMID- 24173893 TI - Screening for grain polyphenol variants from high-tannin sorghum somaclones. AB - Several hundred somaclones established from plants regenerated from embryogenic callus cultures of six high tannin sorghum lines were screened for variants with altered levels of polyphenols in the grain. Grain from over 6000 plants including the R 1 (primary), R2, and R3 generations were analyzed for total phenols, flavan 4-ols, and proanthocyanidins (condensed tannins). Although many variants which had lost the ability to synthesize chlorophyll were found, none of the somaclones tested had lost or greatly reduced the ability to synthesize any of the polyphenols assayed. However, we did observe statistically significant differences in polyphenol concentration between tissue culture-derived R1 plants and the parental controls. In the R2 generation the proportion of somaclones which differed significantly from the parents varied from 47% to 68% depending upon genotype. The average somaclonal variation rate and somaclonal variant frequency estimated in the tested population for the three polyphenol characteristics ranged from 37.3% to 40.7% and 5.3% to 7.8%, respectively. Variants with decreased levels of polyphenols were usually epigenetic and reverted back to normal levels in subsequent generations, but those with increased levels usually persisted after two meiotic cycles, indicating they are heritable. Variants with polyphenol levels increased up to 80% or decreased by 30% were selected for in the R3 generation. PMID- 24173894 TI - Assessing non-specificity of resistance in wheat to head blight caused by inoculation with European strains of Fusarium culmorum, F. graminearum and F. nivale using a multiplicative model for interaction. AB - To determine whether resistance to Fusarium head blight in winter wheat is horizontal and non-species specific, 25 genotypes from five European countries were tested at six locations across Europe in the years 1990, 1991, and 1992. The five genotypes from each country had to cover the range from resistant to susceptible. The locations involved were Wageningen, Vienna, Rennes, Hohenheim, Oberer Lindenhof, and Szeged. In total, 17 local strains of Fusarium culmorum, F. graminearum, and F. nivale were used for experimental inoculation. One strain, F. culmorum IPO 39-01, was used at all locations. Best linear unbiased predictions (BLUPs) for the head blight ratings of the genotypes were formed within each particular location for each combination of year and strain. The BLUPs over all locations were collected in a genotype-by environment table in which the genotypic dimension consisted of the 25 genotypes, while the environmental dimension was made up of 59 year-by-strain-by-location combinations. A multiplicative model was fitted to the genotype by-environment interaction in this table. The inverses of the variances of the genotype-by-environment BLUPs were used as weights. Interactions between genotypes and environments were written as sums of products between genotypic scores and environmental scores. After correction for year-by-location influence very little variation in environmental scores could be ascribed to differences between strains. This provided the basis for the conclusion that the resistance to Fusarium head blight in winter wheat was of the horizontal and non-species specific type. There was no indication for any geographical pattern in virulence genes. Any reasonable aggressive strain, a F. culmorum strain for the cool climates and a F. graminearum strain for the warmer humid areas, should be satisfactory for screening purposes. PMID- 24173895 TI - Chromosomal control of the tolerance of gradually and suddenly imposed salt stress in the Lophopyrum elongatum and wheat, Triticum aestivum L. genomes. AB - The facultatively halophytic Lophopyrum elongatum, closely related wheat, Triticum aestivum, and their amphiploid tolerate salt stress better if they are gradually exposed to it than if they are suddenly stressed. Lophopyrum elongatum has greater tolerance of both forms of salt stress than wheat, and its genome partially confers this tolerance on their amphiploid. Chromosomal control of the tolerance of both stress regimes in the L. elongatum and wheat genomes was investigated with disomic and ditelosomic addition lines and disomic substitution lines of L. elongatum chromosomes in wheat and with wheat tetrasomics. The tolerance of the sudden salt stress is principally controlled by L. elongatum chromosomes 3E and 5E and less by 1E, 2E, 6E, and 7E and the tolerance of gradually imposed salt stress principally by chromosomes 3E, 4E, and 5E, and less by chromosome 1E and 7E. Ditelosomic analysis indicated that genes conferring the tolerance of sudden stress are on chromosome arms 1EL, 5ES, 5EL, 6EL, 7ES and 7EL and those controlling the gradual stress regime are on 1ES, 1EL, 5ES, 5EL, 6ES, 7ES, and 7EL. In wheat, chromosomes in homoeologous groups 1, 3, and 7 and chromosomes in homoeologous groups 1, 4, and 6 were shown to enhance the tolerance of suddenly and gradually imposed stress, respectively. The arms of chromosome 3E individually conferred tolerance to neither stress regime. Chromosome 2E and wheat chromosomes 2B and 2D reduce the tolerance of both stress regimes in a hyperploid state. In 2E this effect was associated with arm 2EL. A potential relationship between the tolerance of these stress regimes and the expression of the early-salt induced genes is examined. PMID- 24173896 TI - Comparison of ancestral and current-generation inbreeding in an experimental strawberry breeding population. AB - Progenies from first-generation self, half-sib, full-sib, and cross fertilizations were generated to evaluate the magnitude of inbreeding depression for vegetative and production traits in strawberry. Tests were conducted to determine the linearity of trait mean depression with inbreeding rate (DeltaF) over this range of inbreeding values, as an indication of the presence of non additive epistasis. A control population, for which a similar range of coancestry had accumulated over several cycles of breeding and selection, was also generated to compare the consequences of ancestral and current-generation inbreeding. Trait means for crosses among current-generation half-sibs, full-sibs, and selfs were 2 17%, 3-12%, and 14-45% lower than for unrelated crosses among the same set of parents, respectively. Linear regression of progeny means on current generation DeltaF was significantly negative for all traits and explained 17-44% of the variance among progeny means. Mean depression was largely linear over the range of inbreeding rates tested in this population, indicating the absence of epistasis for the traits evaluated. Conversely, (F) regressions of progeny means on pedigree inbreeding coefficients, where coancestry had accumulated over several cycles of breeding and selection, were uniformly non-significant and explained 0-10% of the variance among cross means. Further, multiple regression of progeny means for current-generation relatives on pedigree F failed to improve fit significantly over regression on current-generation DeltaF alone for all traits. Together, these results suggest that pedigree inbreeding coefficients are poor predictors of changes in homozygosity when populations are developed through multiple cycles of breeding and selection. They also imply that inbreeding depression will be of minor importance for strawberry breeding populations managed with adequate population sizes and strong directional selection. PMID- 24173897 TI - Analysis of recombination rate in female and male gametogenesis in pearl millet (Pennisetum glaucum) using RFLP markers. AB - Sex as a factor affecting recovered recombination in plant gametes was investigated in pearl millet, Pennisetum glaucum, by using reciprocal three-way crosses [(AxB)xCvCx(A x B)]. The two populations were mapped at 42 loci pre selected to cover the majority of the genome. No differences in recombination distances were observed at the whole-genome level and only a few individual linkage intervals were found to differ, all in favour of increased recombination through the male. Distorted segregations found in the three-way crosses provide evidence of post-gametic selection for particular gene(s) or chromosome regions. The significance of these results for the design of pearl millet breeding programmes and inheritance experiments, as well as for other experimental strategies, is discussed. PMID- 24173898 TI - Application of two microsatellite sequences in wheat storage proteins as molecular markers. AB - In eukaryotes, tandem arrays of simple-sequence repeat sequences can find applications as highly variable and multi-allelic PCR-based genetic markers. In hexaploid bread wheat, a large-genome inbreeding species with low levels of RFLP, di- and trinucleotide tandem repeats were found in 22 published gene sequences, two of which were converted to PCR-based markers. These were shown to be genome specific and displayed high levels of variation. These characteristics make them especially suitable for intervarietal breeding applications. PMID- 24173899 TI - Magnitude of hybrid vigor retained in double haploid lines of some heterotic rice hybrids. AB - Sixty one double haploid (DH) lines were evaluated for yield components and yield and compared with the three corresponding hybrids from which they were derived through anther culture. Analysis of a 6*6 diallel experiment led to the selection of these hybrids based on their high heterosis and revealed the nature of gene action of the characters under evaluation. The DH lines along with the hybrids and parents were planted following a simple lattice design with two replications. The results show that in DH lines the values of the characters expressing predominantly additive genetic effects could reach the heterotic level of the hybrids. For characters including yield showing predominantly dominance effects, values in the DH lines were significantly lower than those of the corresponding hybrids. The promising DH lines, however, possess a higher yield potential than the better parents. PMID- 24173900 TI - Mapping of a gene determining linolenic acid concentration in rapeseed with DNA based markers. AB - Rapeseed ranks third in world oil production. An important breeding objective to improve oil quality in this crop is to lower linolenic acid concentration in the seeds. Previous reports indicate that the concentration of this acid in Brassica napus is determined by two or three nuclear genes. Using DNA-based markers, we have successfully mapped a gene determining linolenic acid concentration in an F2 population derived from crossing the cultivar 'Duplo' and alow linolenic acid line, 3637-1. Linolenic acid concentration in this population ranged from 2.1% to 10.5% with-amean of 6.2%. A RAPD marker, K01-1100, displayed significantly different frequencies between two subpopulations consisting of either high or low linolenic acid concentration individuals sampled from the two extremes of the F2 distribution. Marker K01-1100 segregated in a codominant fashion when used as an RFLP probe on DNA from individuals of this F2 population. The linolenic acid concentration means for the three resulting RFLP genotypes in the F2 population were 4.8% (homozygous 3637-1 allele), 6.4% (heterozygous), and 7.5% (homozygous 'Duplo' allele), respectively. It is estimated that this marker accounts for 26.5% of the genetic variation of linolenic acid concentration in this population. PMID- 24173901 TI - Identification of cytoplasms using the polymerase chain reaction to aid in the extraction of maintainer lines from open-pollinated populations of onion. AB - S-cytoplasm is the most common source of cytoplasmic-genic male sterility (CMS) used to produce hybrid-onion seed. Identification of the cytoplasm of a single plant takes from 4 to 8 years and is complicated by the segregation of a nuclear gene that restores fertility. Although CMS in onion may be due to an incompatibility between the mitochondrial and nuclear genomes, Southern analyses of DNA from individual plants from crosses of S- and N-cytoplasmic plants supported maternal inheritance of the chloroplast and mitochondrial DNA and, therefore, polymorphisms in the chloroplast DNA may be used to classify cytoplasms. Amplification by the polymerase chain reaction of a fragment that carries an autapomorphic 100-bp insertion in the chloroplast DNA of N-cytoplasm offers a significantly quicker and cheaper alternative to crossing or Southern analysis. Molecular characterization of N- and S-cytoplasms and frequencies of the nuclear non-restoring allele allow onion breeders to determine the proportion of plants in open-pollinated populations that maintain CMS and can significantly reduce the investment required to identify individual maintainer plants. PMID- 24173902 TI - Identification of cultivars and validation of genetic relationships in Mangifera indica L. using RAPD markers. AB - Twenty-five accessions of mango were examined for random amplified polymorphic DNA (RAPD) genetic markers with 80 10-mer random primers. Of the 80 primers screened, 33 did not amplify, 19 were monomorphic, and 28 gave reproducible, polymorphic DNA amplification patterns. Eleven primers were selected from the 28 for the study. The number of bands generated was primer- and genotype-dependent, and ranged from 1 to 10. No primer gave unique banding patterns for each of the 25 accessions; however, ten different combinations of 2 primer banding patterns produced unique fingerprints for each accession. A maternal half-sib (MHS) family was included among the 25 accessions to see if genetic relationships could be detected. RAPD data were used to generate simple matching coefficients, which were analyzed phenetically and by means of principal coordinate analysis (PCA). The MHS clustered together in both the phenetic and the PCA while the randomly selected accessions were scattered with no apparent pattern. The uses of RAPD analysis for Mangifera germ plasm classification and clonal identification are discussed. PMID- 24173903 TI - Combining ability in maize for fall armyworm and southwestern corn borer resistance based on a laboratory bioassay for larval growth. AB - The fall armyworm, Spodoptera frugiperda (J. E. Smith), and southwestern corn borer, Diatraea grandiosella Dyar, are major insect pests of maize, Zea mays L., in the southern USA. Both insects feed extensively on leaves of plants in the whorl stage of growth. A diallel cross of seven inbred lines with different levels of susceptibility to leaf feeding damage in the field was evaluated in a laboratory bioassay for fall armyworm and southwestern corn borer larval growth. Diets were prepared from lyophilized leaf tissue of field-grown plants of the inbred lines and their 21 F1 hybrids. One inbred line, Tx601, exhibited heavy leaf damage in field tests but showed moderate resistance in the laboratory bioassay. Both general and specific combining ability were highly significant sources of variation in the inheritance of fall armyworm and south-western corn borer larval growth in the laboratory bioassay. Tx601 showed excellent general combining ability for reduced larval growth of both species. PMID- 24173904 TI - Genetic analysis of anther-culture response in 6x triticale. AB - A quantitative genetic analysis was conducted to determine the inheritance of androgenetic response in hexaploid triticale. One highly-responsive genotype (Do 1 triticale) and three low-responding advanced CIMMYT lines (Rhino, Juanillo 97 and Ira Drira) were used as parents to produce a complete set of reciprocal F1, F2 and backcross generations. Estimates for genetic effects were determined using a generation-mean analysis following the method of Mather and Jinks. Both embryo induction and plant regeneration potential fitted well with the simple three parameter additive-dominance (AD) model indicating the absence of any significant epistatic effects. Highly significant additive effects were detected for embryo induction, suggesting that breeding and selection can be effective in improving the induction response of triticale. The high [d]/[h] ratio indicates dominance of the alleles causing high embryo induction. The production of regenerant plants from embryos appeared to be a more complex trait because of its high sensitivity to environmental factors. PMID- 24173905 TI - Chloroplast and mitochondrial DNA composition of triploid and tetraploid somatic hybrids between Lycopersicon esculentum and Solanum tuberosum. AB - The chloroplast (cp) DNA type and mitochondrial (mt) DNA composition of 17 somatic hybrids between a cytoplasmic albino tomato and monoploid potato (A7 hybrids) and 18 somatic hybrids between a nitrate reductase-deficient tomato and monoploid potato (C7-hybrids) were analyzed. Thirteen A7-hybrids and 9 C7-hybrids were triploids (with one potato genome); the other hybrids were tetraploid. As expected, all A7-hybrids contained potato cpDNA. Of the C7-hybrids 7 had tomato cpDNA, 10 had potato cpDNA and 1 hybrid contained both tomato and potato cpDNA. The mtDNA composition of the hybrids was analyzed by hybridization of Southern blots with four mtDNA-specific probes. The mtDNAs in the hybrids had segregated independently from the cpDNAs. Nuclear DNA composition (i.e. one or two potato genomes) did not influence the chloroplast type in the C7-hybrids, nor the mtDNA composition of A7- or C7-hybrids. From the cosegregation of specific mtDNA fragments we inferred that both tomato and potato mtDNAs probably have a coxII gene closely linked to 18S+5S rRNA genes. In tomato, atpA, and in potato, atp6 seems to be linked to these mtDNA genes. PMID- 24173906 TI - Localization of quantitative trait loci (QTL) for agronomic important characters by the use of a RFLP map in barley (Hordeum vulgare L.). AB - Two hundred and fifty doubled haploid lines were studied from a cross between two 2-row winter barley varieties. The lines were evaluated for several characters in a field experiment for 3 years on two locations with two replications. From a total of 431 RFLP probes 50 were found to be polymorphic and subsequently used to construct a linkage map. Quantitative trait loci (QTLs) were determined and localized for resistance against Rhynchosporium secalis and Erysiphe graminis, for lodging, stalk breaking and ear breaking tendency, for the physical state before harvest, plant height, heading date, several kernel parameters and kernel yield. The heritability of the traits ranged from 0.56 to 0.89. For each trait except for kernel thickness, QTLs have been localized that explain 5-52% of the genetic variance. Transgressive segregation occurred for all of the traits studied. PMID- 24173907 TI - The use of the isoenzymic marker gene Got-1 in the recognition of incompatibility S alleles in apple. AB - The S incompatibility system of apple was confirmed through the application of the gene Got-1 for glutamate oxaloacetate transaminase as a marker for the S locus. The 11S alleles proposed by Kobel et al. (1939) were confirmed through anomalous segregations for Got-1 observed in 14 semi-compatible crosses and regular segregations observed in 2 fully compatible crosses. The S allele genotypes of 'Idared' (S 3 S 7), 'Cox' (S 5 S 9) and 'Fiesta' (S 3 S 5) were determined and found to fall within the original series. By associating parental incompatibility genotypes with the segregation of Got-1 alleles, we were able to deduce the coupling of S and Got-1 alleles in 9 varieties. PMID- 24173908 TI - High prevalence of HCMV and viral load in tumor tissues and peripheral blood of glioblastoma multiforme patients. AB - Glioblastoma multiforme is the most prevalent and malignant tumor of the central nervous system. In the last few years, accumulating evidence has suggested an association between human cytomegalovirus (HCMV) infection and glioblastoma multiforme. In this study, tumor tissues and peripheral blood of patients with glioblastoma multiforme were examined for the presence of HCMV DNA. Twenty-two fresh surgical brain specimens and 20 peripheral blood samples were analyzed by real-time PCR (qPCR) and hemi-nested PCR (nPCR) for the presence of pp65 and (glycoprotein B) gB viral genomic regions, respectively. HCMV DNA was detected in the majority of the tumor samples analyzed (95% by qPCR and 91% by nPCR). About half of the patients with tumors positive for HCMV also had detectable viral DNA in their peripheral blood (47% by qPCR and 61% by nPCR). Genome copy numbers were determined and in the majority of the tumor samples cellular DNA outnumbers viral DNA (average of 1 infected cell in 33 cells). The gB genotypes were determined in HCMV-positive samples and gB2 was the most prevalent genotype in the tumor and blood samples. The results show a high prevalence of HCMV in glioblastoma multiforme samples reinforcing a possible association between HCMV infection and tumor development. PMID- 24173909 TI - Serum adipokine levels in rheumatoid arthritis patients and their contributions to the resistance to treatment. AB - The aim of this study was to determine whether disease activity and the type of therapy differentially modulate serum adipokine levels in patients with rheumatoid arthritis (RA), and whether pre-therapy adipokine levels contribute to resistance to treatment. Fasting blood samples from 40 RA patients were obtained at baseline and six months following therapeutic treatment with disease-modifying antirheumatic drugs (DMARDs) and/or tumor necrosis factor (TNF)-alpha blockers. Serum levels of adiponectin, leptin, visfatin and resistin were measured by ELISA. Baseline adipokine levels did not exhibit a statistically significant difference when comparing patients with moderate and high disease activity, based on the disease activity score in 28 joints (DAS28). Of all the adipokines, only adiponectin was significantly increased in patients responding to DMARDs and/or TNF-alpha blocker therapy, based on the American College of Rheumatology 20% improvement criteria (ACR20) at six months (2,964+/-1,237 to 3,683+/-1,511 ng/ml, P<0.01). However, adiponectin levels in non-responders did not significantly increase (3,192+/-2,090 to 3,222+/-1,150 ng/ml). By contrast, there were no statistically significant changes in leptin, resistin or visfatin levels in either the responders or non-responders. Serum adipokine (adiponectin, leptin, visfatin, and resistin) levels in RA patients did not significantly change following therapy, with the exception of adiponectin. Adipokine levels may not contribute to therapeutic resistance to DMARDs and/or TNF-alpha blocking agents. PMID- 24173910 TI - The diverse application of laser hair removal therapy: a tertiary laser unit's experience with less common indications and a literature overview. AB - We describe the diversity of indications for laser hair removal (LHR) therapy and compare our experience with the literature. Patients' case notes referred to the Birmingham Regional Skin Laser Centre between 2003 and 2011 for laser hair removal, with indications other than hirsutism, were reviewed retrospectively. Thirty-one treated patients with the following indications were identified: hair bearing skin grafts/flaps, intra-oral hair-bearing flap, Becker's naevus, localised nevoid hypertrichosis, peristomal hair-bearing skin, scrotal skin prior to vaginoplasty in male-to-female (MTF) gender reassignment, pilonidal sinus disease (PSD), pseudofolliculitis barbae (PFB) and hidradenitis suppurativa (HS). Seven patients with the following indications have been reported before: intra oral hair-bearing graft, naevoid hypertrichosis and peristomal hair-bearing skin. A clinical review of the evidence available for each indication is provided. Our experience and that in the published literature suggest that LHR is a safe, well tolerated and effective treatment modality for the indications we report, leading to significant symptom and functional improvement with high patient satisfaction. LHR appears effective in the treatment of chronic inflammatory conditions such as PSD, PFB and HS, particularly at an early disease stage. We aim to increase awareness of the diversity of laser hair removal indications and add evidence to the medical literature of the wide range of indications for this useful treatment modality. PMID- 24173911 TI - Comparative analysis of two low-level laser doses on the expression of inflammatory mediators and on neutrophils and macrophages in acute joint inflammation. AB - Synovial membrane inflammation plays an important role in osteoarthritis (OA) pathophysiology. The synovial tissue of patients with initial OA is characterized by mononuclear cell infiltration and the production of pro-inflammatory cytokines and other mediators of joint injury. The study aims to evaluate the effect of low level laser therapy (LLLT) at doses of 2 and 4 J on joint inflammation in rats induced by papain through histopathological analysis, differential counts of inflammatory cells; gene expression of IL-1beta, IL-6, and IL-10; and TNF-alpha protein expression. Male Wistar rats (20) were randomly divided (5 animals each) into a negative control group, an inflammation injury positive control group, a 2 J LLLT group subjected to injury and treated with 2 J of LLLT, and a 4-J LLLT group subjected to injury and treated with 4 J of LLLT. The animals were subjected to joint inflammation (4 % papain solution) and treated with LLLT. On the day of euthanasia, articular lavage was collected and centrifuged. The supernatant was analyzed for TNF-alpha protein expression by ELISA and IL-1beta, IL-6, and IL-10 mRNA by RT-PCR. The joint tissue was also examined histologically. ANOVA with Tukey's post hoc test was used for comparisons. All data were expressed as means +/- S.D. (p < 0.05). Both laser modalities were efficient in reducing cellular inflammation and decreasing the expression of IL 1beta and IL-6. However, the 2-J treatment led to more reduction in TNF-alpha than the 4-J treatment. A single application of LLLT with 2 J was more efficient in modulating inflammatory mediators and inflammatory cells. PMID- 24173912 TI - CEBiP is the major chitin oligomer-binding protein in rice and plays a main role in the perception of chitin oligomers. AB - CEBiP, a plasma membrane-localized glycoprotein of rice, directly binds with chitin elicitors (CE), and has been identified as a receptor for CE by using CEBiP-RNAi rice cells. To further clarify the function of CEBiP, we produced CEBiP-disrupted rice plants by applying an efficient Agrobacterium-mediated gene targeting system based on homologous recombination, which has recently been developed for rice. Homologous recombination occurred at the CEBiP locus in ~0.5 % of the positive/negative selected calli. In the self-pollinated next generation, it was confirmed that the first exon of CEBiP was replaced with the hygromycin selection cassette as designed, and that the expression of CEBiP was completely deficient in homozygous cebip lines. Affinity-labeling analysis using biotinylated N-acetylchitooctaose demonstrated that CEBiP is the major CE-binding protein in rice cultured cells and leaves, which was consistent with the result that the response to CE in cebip cells was greatly diminished. Nevertheless, we observed a significant decrease in disease resistance against Magnaporthe oryzae, the causal agent of rice blast disease, only when the cebip leaf sheaths were inoculated with a weakly virulent strain, suggesting that CE perception during the infection process of M. oryzae is limited. The response to peptidoglycan and lipopolysaccharides in cebip cells was not affected, strongly suggesting that CEBiP is a CE-specific receptor. PMID- 24173914 TI - Designing of an intensification process for biosynthesis and recovery of menaquinone-7. AB - A nutritional food rich in menaquinone-7 has a potential in preventing osteoporosis and cardiovascular diseases. The static fermentation of Bacillus subtilis natto is widely regarded as an optimum process for menaquinone-7 production. The major issues for the bulk production of menaquinone-7 are the low fermentation yield, biofilm formation and the use of organic solvents for the vitamin extraction. In this study, we demonstrate that the dynamic fermentation involving high stirring and aeration rates enhances the yield of fermentation process significantly compared to static system. The menaquinone-7 concentration of 226 mg/L was produced at 1,000 rpm, 5 vvm, 40 degrees C after 5 days of fermentation. This concentration is 70-fold higher than commercially available food products such as natto. Additionally, it was found that more than 80% of menaquinone-7 was recovered in situ in the vegetable oil that was gradually added to the system as an anti-foaming agent. The intensification process developed in this study has a capacity to produce an oil rich in menaquinone-7 in one step and eliminate the use of organic solvents for recovery of this compound. This oil can, therefore, be used for the preparation of broad range of supplementary and dietary food products rich in menaquinone-7 to reduce the risk of osteoporotic fractures and cardiovascular diseases. PMID- 24173913 TI - Identification and characterization of the microRNA transcriptome of a moth orchid Phalaenopsis aphrodite. AB - Orchids display unique phenotypes, functional characteristics and ecological adaptations that are not found in model plants. In this study, we aimed to characterize the microRNA (miRNA) transcriptome and identify species- and tissue specific miRNAs in Phalaenopsis aphrodite. After data filtering and cleanup, a total of 59,387,374 reads, representing 1,649,996 unique reads, were obtained from four P. aphrodite small RNA libraries. A systematic bioinformatics analysis pipeline was developed that can be used for miRNA and precursor mining, and target gene prediction in non-model plants. A total of 3,251 unique reads for 181 known plant miRNAs (belonging to 88 miRNA families), 23 new miRNAs and 91 precursors were identified. All the miRNA star sequences (miRNA*), the complementary strands of miRNA that from miRNA/miRNA* duplexes, of the predicted new miRNAs were detected in our small RNA libraries, providing additional evidence for their existence as new miRNAs in P. aphrodite. Furthermore, 240 potential miRNA-targets that appear to be involved in many different biological activities and molecular functions, especially transcription factors, were identified, suggesting that miRNAs can impact multiple processes in P. aphrodite. We also verified the cleavage sites for six targets using RNA ligase-mediated rapid amplification of 5' ends assay. The results provide valuable information about the composition, expression and function of miRNA in P. aphrodite, and will aid functional genomics studies of orchids. PMID- 24173915 TI - Effects of single-nucleotide polymorphisms of FMO3 and FMO6 genes on pharmacokinetic characteristics of sulindac sulfide in premature labor. AB - This study aimed to investigate the effects of polymorphisms of the flavin containing mono-oxygenase 3 (FMO3) and flavin-containing mono-oxygenase 6 (FMO6) genes on the pharmacokinetics of sulindac sulfide, the active metabolite of sulindac, in patients with preterm labor. Ten single-nucleotide polymorphisms (SNPs) were genotyped, and plasma sulindac sulfide concentrations were measured at 0, 1.5, 4, and 10 hours after drug administration. The area under the curve from time 0 to the last sampling time point (AUC(last)) for sulindac sulfide was obtained. The AUC(last) of sulindac sulfide was significantly higher in patients with variant-type homozygotes of FMO3 (rs909530) than those with ancestral alleles or heterozygotes. FMO3 (rs2266780) was in complete linkage disequilibrium with FMO6 (rs7885012), and there was marginal significance between the genotypes (P = 0.049). From multiple linear regression models, FMO3 (rs909530) was found to have significant influence on the AUClast of sulindac sulfide after adjusting for gestational age, weight, and all studied SNPs. The predictive contribution of rs909530 to the variability of sulindac sulfide AUC(last) was 27.0%. In conclusion, the results of this study could help clinicians predict the efficacies and side effects of sulindac in the development of individualized treatment of patients with preterm labor. PMID- 24173916 TI - VEGF-C and VEGF-D overexpression is more common in left-sided and well differentiated colon adenocarcinoma. AB - Tumour vessel network formation, including blood and lymph vessels, is a major step involved in the process of carcinogenesis. The discovery of vascular growth factors has led to a better understanding of tumour biology, thus, creating new possibilities for cancer treatment that targets angiogenesis within tumour associated stroma, including therapy for colon cancer patients. The present study evaluated the relationships between increased expression of lymphangiogenic factors (VEGF-C and VEGF-D) and vessel density in the tumour-surrounding stroma, patient survival and other standard prognostic factors. The expression of VEGF-C and VEGF-D and vessel density were immunohistochemically assessed in 114 primary tumour specimens from colon adenocarcinoma patients after surgical resection between January 1, 2003 and December 31, 2008. Concomittant overexpression of VEGF-C and VEGF-D was found in 51 (44.7%) colon tumours and low expression was observed in 63 (55.3%) cases. Mean vessel density was 52.87/field. A significant correlation was found between the expression of factors influencing lymph vessel growth and increased vessel density in the tumour-surrounding stroma (p=0.03). A relationship between lymphangiogenic factor overexpression and left-sided tumour location was also found (p=0.00002). Overexpression of these factors was likely to occur in well-differentiated tumours (p=0.003). No association between patient survival and the expression levels of lymphangiogenic factors was observed. The study results indicate that the overexpression of lymphangiogenic factors tends to be associated with tumours of favourable prognosis, i.e. well-differentiated and those localized in the left-side of the colon. PMID- 24173917 TI - Identification of RAPD markers linked to the Tm-2 locus in tomato. AB - Tm-2 and Tm-2a are genes conferring resistance to tomato mosaic virus in Lycopersicon esculentum. They are allelic and originated from different lines of L. peruvianum, a wild relative of tomato. In this study, random amplified polymorphic DNA (RAPD) markers linked to these genes were screened in nearly isogenic lines (NILs). To detect RAPDs differentiating NILs, 220 different 10 base oligonucleotide primers were examined by the polymerase chain reaction (PCR), and 43 of them generated 53 consistent polymorphic fragments among the NILs. Out of these 53 fragments, 13 were arbitrarily chosen and examined in respect of whether they were linked to the netted virescent (nv) gene, since nv is tightly linked to the Tm-2 locus and its phenotype is more easily distinguishable. As a result, all 13 markers were shown to be linked to nv, and hence to the Tm-2 locus. Among them, two fragments specific to the NIL carrying Tm-2 three specific to the NIL carrying Tm-2a, and four specific to both of these NILs were closely linked to nv. PMID- 24173918 TI - Nucleotide sequence of a highly repeated DNA sequence and its chromosomal localization in Allium fistulosum. AB - A highly repeated DNA sequence with a repeating unit of approximately 380bp was found in EcoRV digests of the total genomic DNA of Allium fistulosum. Three independent clones containing this unit were isolated, and their repeating units sequenced. These units showed more than 94% sequence homology, and the copy number was estimated to be about 2.8*10(6) per haploid genome. In situ hybridization, with the repeating unit as a probe, and C-banding analyses indicated that the repeated DNA sequence of A. fistulosum is closely associated with the major C-heterochromatin in the terminal regions of all 16 chromosomes at mitotic metaphase. The characters of the repeating unit are similar to those of the A. cepa unit, which is taxonomically closely related to A. fistulosum. PMID- 24173919 TI - Chloroplast DNA variation in Populus. I. Intraspecific restriction fragment diversity within Populus deltoides, P. nigra and P. maximowiczii. AB - We examined intraspecific chloroplast (cp) DNA variation within Populus deltoides, P. nigra, and P. maximowiczii by restriction fragment analysis using 16 restriction endonucleases and six heterologous probes of cloned Petunia cpDNA fragments. All three Populus species showed intraspecific cpDNA variation, which was intra- and inter-varietal in P. deltoides, intervarietal in P. nigra, and origin-specific in P. maximowiczii. Two varieties of P. deltoides, var deltoides and var occidentalis, showed distinct cp genomes/DNA. Three distinct cp genomes/DNA, separated by a loss or gain of 1 EcoRV restriction site and/or 1 restriction fragment length polymorphism (RFLP), were observed among the individuals of P. deltoides var deltoides. Within P. nigra, cpDNA of var italica was distinct from that of vars nigra and plantierensis by one RFLP and by a loss or gain of one BamHI restriction site. Populus maximowiczii clones of Chinese origin were separated from those of Japanese origin by a gain or loss of one ClaI restriction site in their cpDNA. The estimate of nucleotide substitutions per site in cpDNA was 0.07% between two varieties of P. deltoides, 0.05% between var italica and var nigra or plantierensis of P. nigra, and 0.01% between Japanese and Chinese accessions of P. maximowiczii. PMID- 24173920 TI - Chloroplast DNA variation in Populus. II. Interspecific restriction fragment polymorphisms and genetic relationships among Populus deltoides, P. nigra, P. maximowiczii, and P. x canadensis. AB - Restriction fragment analysis was conducted to determine interspecific chloroplast DNA (cpDNA) variation and genetic relationships among Populus deltoides, P. nigra, P. x canadensis (P. deltoides x P. nigra), and P. maximowiczii. Total cellular DNAs of these poplars were digested with 16 restriction endonucleases, and Southern blots of the restriction digests were probed with six different cloned cpDNA fragments from Petunia. P. deltoides, P. nigra, and P. maximowiczii each had a distinct chloroplast genome, separated by many restriction-site and restriction-fragment-length mutations, predominantly in the large single-copy region of the genome. P. x canadensis shared the same cpDNA restriction fragment patterns as P. deltoides var. deltoides. P. nigra was most diverged from P. deltoides, and P. deltoides showed close cpDNA relationships to P. maximowiczii. Nucleotide substitutions per site in cpDNA were 0.0036 between P. deltoides and P. maximowiczii, 0.0071 between P. nigra and P. maximowiczii, and 0.0077 between P. deltoides and P. nigra. We suggest that P. nigra should be classified in a new separate section, the Nigrae. PMID- 24173921 TI - Chloroplast DNA variation in Populus. III. Novel chloroplast DNA variants in natural Populus x canadensis hybrids. AB - A rare phenomenon of the occurrence of novel non-parental chloroplast DNA (cpDNA) variants in natural sexual interspecific hybrids between Populus deltoides var deltoides and P. nigra, P. x canadensis is described. Restriction fragment variation of cpDNA in 17 P. x canadensis cultivars was examined and compared with that of representative samples of P. deltoides and P. nigra using 83 combinations of 16 restriction enzymes and six Petunia hybrida cpDNA probes. Twelve cultivars had one to five novel non-parental cpDNA fragments in the chloroplast genome region homologous to the 9.0-kb PstI cpDNA fragment of Petunia from the large single-copy region. PMID- 24173922 TI - Intra- and inter-specific variations in Lens revealed by RAPD markers. AB - Randomly amplified polymorphic DNA (RAPD) markers were used to estimate intra- and interspecific variations in the genus Lens (lentil). Twenty cultivars of L. culinaris ssp. culinaris, including 11 microsperma (small-seeded) and nine macrosperma (large-seeded) types, and 16 wild relatives (four accessions each of L. culinaris ssp. orientalis, L. odemensis, L. nigricans and L. ervoides), were evaluated for genetic variability using a set of 40 random 10-mer primers. Fifty reproducibly scorable DNA bands were observed from ten of the primers, 90% of which were polymorphic. Genetic distances between each of the accessions were calculated from simple matching coefficients. A dendrogram showing genetic relationships between them was constructed by an unweighted pair-group method with arithmetical averages (UPGMA). This study revealed that (1) expect for L. ervoides, the level of intraspecific variation in cultivated lentil is lower than that in wild species, (2) L. culinaris ssp. orientalis is the most likely candidate for a progenitor of the cultivated species, and (3) microsperma and macrosperma cultivars were indistinguishable by the RAPD markers identified here. PMID- 24173923 TI - Co-segregation of the maize dwarf mosaic virus resistance gene, Mdm1, with the nucleolus organizer region in maize. AB - The mdm1 locus on the short arm of chromosome six confers resistance in maize to five strains of the maize dwarf mosaic virus (MDMV), an aphid transmitted potyvirus. The location of mdm1 in relation to RFLP and morphological loci on the short arm of chromosome six was determined using BC1 and F2 mapping populations. The following map order and distance in cM was obtained from the F2 population; jc1270-2.5-npi245-1.6-umc85/po1-0.5-mdm1/nor-0.5-bnl6.29A-0.5-npi235-0.8-npi101A 4.3-numc59. No recombination between mdm1 and the nucleolus organizer region (nor) was detected, as determined using a probe from the intergenic spacer region of the rDNA repeat. In order to resolve the relationship between mdm1 and the nor, and to recover recombinants around mdm1, a highresolution map within the polymitotic1 (po1) yellow kernel1 (y1) interval was generated using [po1 y1 tester (po1 mdm1 y1) x Pa405 (Po1 Mdm1 Y1)] F2 plants. The recessive po1 allele imparts a male-sterile phenotype when homozygous and since po1 and y1 are closely linked, the majority of fertile plants from white endosperm (y1/y1) F2 kernels will arise though a recombination event between the Pa405 Po1 allele and the y1 allele of the po1 y1 tester. Plants from 7,650 white (y1/y1) F2 kernels were examined (15,300 chromosomes) and a total of 626 F2?3 recombinant families was recovered. Analysis of these recombinants revealed that mdm1 cosegregates with the nor. This lack of recombination between mdm1 and the nor suggests that: either (1) mdm1 is located in the region flanking the nor and recombination is suppressed within that region, or (2) mdm1 is located within the nor. PMID- 24173924 TI - Molecular, cytological and morpho-agronomical characterization of hexaploid somatic hybrids in Medicago. AB - Somatic hybrid plants produced by protoplast fusion between tetraploid Medicago sativa (2n= 4x=32) and the diploid species Medicago coerulea (2n= 2x=16) have been RFLP fingerprinted to establish their nuclear composition. Although all of the chromosomes were present, molecular analysis revealed an incomplete incorporation of the alleles of the diploid parent in the fusion products. In the polycross progeny the alleles of both parents segregated in a Mendelian mode. Cytological observations indicated that in the somatic hybrid population minor abnormalities are present; these are restricted mainly to the formation of univalents and lagging chromosomes. Meiosis appeared to be more stable than has been previously reported in the hexaploids of alfalfa. The somatic hybrids grown in the field had a rather vigorous aspect, particularly with respect to the vegetative organs. Forage yield was comparable to that of thmore productive parent. The results are discussed with a view to utilizing the somatic hybrids as starting material for breeding alfalfa at the hexaploid level. PMID- 24173925 TI - Successive domestication and evolution of the Andean potatoes as revealed by chloroplast DNA restriction endonuclease analysis. AB - Five chloroplast DNA (ctDNA) types (W, T, C, S, and A) have previously been identified in the Andean tetraploid cultivated potatoes (Solanum tuberosum ssp. andigena) and three types (C, S, and A) in diploid cultivated potatoes (S. stenotomum). In this study, ctDNA types were determined for an additional 35 accessions of S. stenotomum and 97 accessions of putative ancestral wild species (15 of S. brevicaule, 26 of S. bukasovii, 4 of S. candolleanum, 25 of S. canasense, 17 of S. leptophyes, and 10 of S. multidissectum). The first five ctDNA types were also identified in S. stenotomum. The wild species were also polymorphic for ctDNA types except for S. brevicaule, which had only W-type ctDNA. T-type ctDNA was not found in any of the wild species and could have originated from W-type ctDNA after S. stenotomum arose. The other types of ctDNA evolved in wild species. The geographical distribution of each ctDNA type indicated that A-type ctDNA arose in central Peru and T-type ctDNA in the Bolivia Argentine boundary. It is implied that potatoes were successively domesticated and that, in parallel, several wild species were differentiated from time to time and place to place from the 'ancestral species' complex. Subsequent sexual polyploidization formed a wide ctDNA diversity among the Andean tetraploid potatoes, and selection from them formed the limited ctDNA diversity found in Chilean tetraploid potatoes (ssp. tuberosum). PMID- 24173926 TI - Structural changes in the plastid DNA of rice (Oryza sativa L.) during tissue culture. AB - To investigate the rearrangement of the plastid genome during tissue culture, DNA from rice callus lines, which had been derived individually from single protoplasts isolated from seed or pollen callus (protoclones), was analyzed by Southern hybridization with rice chloroplast DNA (ctDNA) clones as probes. Among 44 long-term cultured protoclones, maintained for 4, 8 or 11 years, 28 contained plastid DNA (ptDNA) from which portions had been deleted. The ptDNA of all protoclones that had been maintained for 11 years had a deletion that covered a large region of the plastid genome. The deletions could be classified into 15 types from their respective sizes and positions. By contrast, no deletions were found in the ptDNA of 38 protoclones that had been maintained for only 1 month. These results indicate that long-term culture causes deletions in the plastid genome. Detailed hybridization experiments revealed that plastid genomes with deletions in several protoclones were organized as head-to-head or tail-to-tail structures. Furthermore, ptDNAs retained during long-term culture all had a common terminus at one end, where extensive rearrangement is known to have occurred during the speciation of rice and tobacco. Morphological analysis revealed the accumulation of starch granules in plastids and amyloplasts in protoclones in which the plastid genome had undergone deletion. Our observations indicated that novel structural changes in the plastid genome and morphological changes in the plastid had occurred in rice cells during long-term tissue culture. Moreover, the morphological changes in plastids were associated with deletions in the plastid genome. PMID- 24173927 TI - Genetic variation at storage protein-coding loci of common wheat (cv 'Chinese Spring') induced by nitrosoethylurea and by the cultivation of immature embryos in vitro. AB - Electrophoretic patterns of seed storage proteins, the high-molecular-weight glutenins and gliadins, were studied in 468 plants of the common wheat cultivar 'Chinese Spring' regenerated from callus culture of immature embryos, in 115 plants grown from seeds treated with nitrosoethylurea and in 260 control plants. From 5 to 21 single grains were analysed from each plant. In these three groups, the frequency of inherited mutations causing the loss of all proteins controlled by a locus (null-mutations, probably caused by a chromosomal deficiency) was 0.69%, 2.07%, and 0.05% per locus (the differences were statistically significant), respectively, while that of mutations causing the loss of a single protein band was 0.11%, 0.33%, and 0.05%, respectively. The loss of all of the gliadins controlled by Gli-B1 or GH-B2 (mutations were probably caused by a deletion of satellites of the corresponding chromosomes), was significantly higher than the loss of gliadins controlled by genomes A and D. Gene mutations altering the electrophoretic mobility of a single protein band in the pattern were found only in the second group of plants (0.44%). Therefore, chemical mutagenesis which produced not only more mutations than cultivation of immature wheat embryos in vitro, but also a higher ratio of mutations that altered DNA sequences, can be considered as an easier and comparatively more promising way for obtaining new improved variants of loci controlling biochemical characteristics in wheat. Somaclonal variation, on the other hand, was probably mainly caused by chromosomal abnormalities and could therefore hardly be considered as a useful tool in wheat breeding. PMID- 24173928 TI - Identification of genomic regions affecting plant height in sorghum and maize. AB - The objective of this study was to use restriction fragment length polymorphisms (RFLPs) to determine the genetic location and effects of genomic regions controlling plant height in sorghum. F2 plants (152) from the cross CK60 x PI229828 were used. Genomic and cDNA clones (106) identified 111 loci distributed among ten linkage groups covering 1299 cM. Interval mapping identified four regions, each in a separate linkage group. These regions may correspond to loci (dw) previously identified by alleles with qualitative effects. Also, these regions identified in sorghum may be orthologous to those previously reported for plant height in maize. Gene effects and gene action varied among genomic regions. In each region, PI229828 alleles resulted in increased plant height. Each region accounted for 9.2-28.7% of the phenotypic variation. Positive, additive effects ranged from 15 to 32cm. Tallness was dominant or overdominant and conferred by alleles from PI229828 for three quantitative trait loci (QTL). At the fourth QTL, PI229828 contributed to increased plant height, but short stature was partially dominant. One digenic interaction was significant. The presence of a PI229828 allele at one region diminished the effects of the other region. A multiple model indicated that these four regions collectively accounted for 63.4% of the total phenotypic variation. The utility of this information for germplasm conversion through backcross breeding is discussed. PMID- 24173929 TI - Molecular phylogeny of the Pooideae (Poaceae) based on nuclear rDNA (ITS) sequences. AB - Phylogenetic relationships of the Poaceae subfamily, Pooideae, were estimated from the sequences of the internal transcribed spacer (ITS) region of nuclear ribosomal DNA. The entire ITS region of 25 species belonging to 19 genera representing seven tribes was directly sequenced from polymerase chain reaction (PCR)-amplified DNA fragments. The published sequence of rice, Oryza saliva, was used as the outgroup. Sequences of these taxa were analyzed with maximum parsimony (PAUP) and the neighbor-joining distance method (NJ). Among the tribes, the Stipeae, Meliceae and Brachypodieae, all with small chromosomes and a basic number more than x=7, diverged in succession. The Poeae, Aveneae, Bromeae and Triticeae, with large chromosomes and a basic number of x=7, form a monophyletic clade. The Poeae and Aveneae are the sister group of the Bromeae and Triticeae. On the ITS tree, the Brachypodieae is distantly related to the Triticeae and Bromeae, which differs from the phylogenies based on restriction-site variation of cpDNA and morphological characters. The phylogenetic relationships of the seven pooid tribes inferred from the ITS sequences are highly concordant with the cytogenetic evidence that the reduction in chromosome number and the increase in chromosome size evolved only once in the pooids and pre-dated the divergence of the Poeae, Aveneae, Bromeae and Triticeae.This paper reports factually on available data; however, the USDA neither guarantees nor warrants the standard of the product, and the use of the name by USDA implies no approval of the product to the exclusion of others that may also be suitable. PMID- 24173930 TI - Physical mapping and cloning of a translocation in sugar beet (Beta vulgaris L) carrying a gene for nematode (Heterodera schachtii) resistance from B. procumbens. AB - Two diploid (2n=18) sugar beet (Beta vulgaris L.) lines which carry monogenic traits for nematode (Heterodera schachtii Schm.) resistance located on translocations from the wild beet species Beta procumbens were investigated. Short interspersed repetitive DNA elements exclusively hybridizing with wild beet DNA were found to be dispersed around the translocations. The banding pattern as revealed by genomic Southern hybridization was highly conserved among translocation lines of different origins indicating that the translocations are not affected by recombination events with sugar beet chromosomes. Physical mapping revealed that the entire translocation is represented by a single Sal I fragment 300 kb in size. A representative YAC (yeast artifical chromosome) library consisting of approximately 13,000 recombinant clones (2.2 genome equivalents) with insert sizes ranging between 50 and 450 kb and an average of 130kb has been constructed from the resistant line A906001. Three recombinant YACs were isolated from this library using the wild beet-specific repetitive elements as probes for screening. Colinearity between YAC inserts and donor DNA was confirmed by DNA fingerprinting utilizing these repetitive probes. The YACs were arranged into two contigs with a total size of 215 kb; these represent a minimum of 72% of the translocation. PMID- 24173931 TI - Similarities and relationships among populations of the bulb onion as estimated by nuclear RFLPs. AB - Random nuclear restriction fragment length polymorphisms (RFLPs) were used to assess similarities and relationships among open-pollinated (OP) populations of the cultivated bulb onion (Allium cepa). Seventeen OP populations and 2 inbreds of contrasting daylength response [termed by convention as long (LD) and short (SD) day], 1 shallot (A. cepa var. ascalonicum), and one cultivar of bunching onion (Allium fistulosum) were examined with 104 cDNA clones and two to four restriction enzymes. Sixty (58%) clones detected at least 1 polymorphic fragment scorable among the OP populations and were used for analyses. The average number of polymorphic fragments per polymorphic probe-enzyme combination was 1.9, reflecting that numerous monomorphic fragments were usually present. Similarities were estimated as the proportion of polymorphic fragments shared by 2 populations. Average similarity values among LD, among SD, and between LD and SD OP populations were 0.79, 0.67, and 0.68, respectively. Relationships among the OP populations were estimated by parsimony, cluster analysis of similarities using the unweighted-pair-group method (UPGMA), and multivariate analysis using principle components. Parsimony analysis generated a strict consensus tree that grouped all but 1 LD onion with unresolved relationships to the SD OP populations. The UPGMA analysis placed together the LD storage OP populations. Principal component analysis grouped all but 2 LD onions; the other OP populations were dispersed. The results suggest that LD and SD onions do not represent distinct germ plasm, but that LD storage onions represent a derived group selected for production at higher latitudes. If it is assumed that the sampled populations are representative of all onion OP populations, the lower similarities among SD OP populations indicate that their collection and maintenance in germ plasm collections is important for the preservation of genetic diversity. PMID- 24173932 TI - In an elite cross of maize a major quantitative trait locus controls one-fourth of the genetic variation for grain yield. AB - Quantitative trait loci (QTLs) for grain yield, dry matter content and test weight were identified in an F2 segregating population derived from a single cross between two elite maize lines (B73 and A7) and testcrossed to two genetically divergent in breds. Most of the QTLs inferred were consistent across locations, indicating that the expression of the genes influencing the traits under investigation was largely independent of the environment. By using two different tester lines we found that QTLs exhibited by one tester may not necessarily be detected with the second one. Only loci with larger effects were consistent across testers, suggesting that interaction with tester alleles may contribute to the identification of QTLs in a specific fashion. Analysis across both testers revealed four significant QTLs for grain yield that explained more than 35% of the phenotypic variation and showed an overall phenotypic effect of more than 2t/ha. The major QTL for grain yield, located in the proximity of the Nucleolus Organiser Region, accounted for 24.5% of the phenotypic variation for grain yield and showed an average effect of allele substitution of approximately 1 t/ha. Marker-assisted introgression of the superior A7 allele at this locus in the B73 genetic background will not differ from qualitative trait introgression and will eventually lead to new lines having superior testcross performance. PMID- 24173933 TI - Variation of seed alpha-amylase inhibitors in the common bean. AB - Variation of seed alpha-amylase inhibitors was investigated in 1 154 cultivated and 726 non-cultivated (wild and weedy) accessions of the common bean, Phaseolus vulgaris L. Four alpha-amylase inhibitor types were recognized based on the inhibtion by seed extracts of the activities of porcine pancreatic alpha-amylase and larval alpha-amylase and larval alpha-amylase of the Mexican bean weevil, Zabrotes subfasciatus Boheman. Of the 1 880 accessions examined most (1 734) were able to inhibit porcine pancreatic alpha-amylase activity, but were inactive against the Z. subfasciatus larval alpha-amylase; 41 inhibited only the larval alpha-amylase activity, 52 inhibited the activities of the two alpha-amylases, and 53 did not inhibit the activity of either of the alpha-amylases. The four different inhibitor types were designated as alphaAI-1, alphaAI2, alphaAI-3, and alphaAI-0, respectively. These four inhibitor types were identified by the banding patterns of seed glycoproteins in the range of 14-20 kDa by using SDSpolyacrylamide gel electrophoresis. Additionally, four different banding patterns were recognized in accessions with alphaAI-1, and were designated as alphaAI-1a, 1b, 1c, and 1d. Two different patterns of the accessions lacking an alpha-amylase inhibitory activity were identified and designated as alphaAI-0a and alphaAI-0b. The largest diversity for seed alpha-amylase inhibitors was observed in non-cultivated accessions collected from Mexico where all eight inhibitor types were detected. The possible relationships between the variation of seed alpha-amylase inhibitors and bruchid resistance are discussed. PMID- 24173934 TI - The cytogenetics of a Triticum turgidum x Psathyrostachys juncea hybrid and its backcross derivatives. AB - Psathyrostachys juncea (2n = 2x = 14, NN), a source of barley yellow dwarf (BYDV) virus resistance with tolerance to drought and salinity, has been successfully hybridized in its autotetraploid form (2n = 4x = 28, NNNN) as the pollen parent to durum wheat (Triticum turgidum L.). The 2n = 4x = 28 (ABNN) F1 hybrid has a mean meiotic metaphase-I configuration of 20.29 univalents + 0.29 ring bivalents + 3.36 rod bivalents + 0.14 trivalents. Spike length, internode length, glume awn length and lemma awn length, as well as the general spike morphology of the F1 hybrid, are intermediate with those of the two parents. Pollinating the ABNN F1 hybrid has given backcross (BC)-I derivatives of an amphiploid (AABBNN) that expresses limited self-fertility. BC-2 derivatives have been obtained from these plants. Direct transfers of useful genes from Ps. juncea to wheat would require substantial genetic manipulation strategies. Both conventional and novel methodologies, which may complement each other, and so facilitate reaching an agricultural objective end point, are addressed. PMID- 24173935 TI - Robustness of statistical tests for multiplicative terms in the additive main effects and multiplicative interaction model for cultivar trials. AB - The additive main effects multiplicative interaction model is frequently used in the analysis of multilocation trials. In the analysis of such data it is of interest to decide how many of the multiplicative interaction terms are significant. Several tests for this task are available, all of which assume that errors are normally distributed with a common variance. This paper investigates the robustness of several tests (Gollob, F GH1, FGH2, FR)to departures from these assumptions. It is concluded that, because of its better robustness, the F Rtest is preferable. If the other tests are to be used, preliminary tests for the validity of assumptions should be performed. PMID- 24173936 TI - Localization of genes for bacterial canker resistance in Lycopersicon peruvianum using RFLPs. AB - A backcross population of the L. peruvianum accession LA 2157, which is resistant to bacterial canker caused by Clavibacter michiganensis ssp. michiganensis, with the susceptible L. peruvianum accession LA 2172 was evaluated for the segregation of C. michiganenis resistance and of RFLP markers in order to map the loci involved in this resistance. The development of symptoms of the disease was scored using an ordinal scale. The mapping of the disease resistance was hampered by distorted segregation ratios of a large number of markers and unexpected quantitative inheritance of the resistance. By means of the Kruskal-Wallis rank sum test, five regions on chromosomes 1, 6, 7, 8 and 10 were identified that may be involved in C. michiganensis resistance. PMID- 24173937 TI - Mapping the Sw-5 locus for tomato spotted wilt virus resistance in tomatoes using RAPD and RFLP analyses. AB - The Sw-5 locus confers dominant resistance to tomato spotted wilt virus (TSWV). To map the location and facilitate the identification of markers linked to Sw-5 we developed a pair of near-isogenic lines (NILs) and an F2 Lycopersicon esculentum x L. pennellii population segregating for resistance to TSWV. DNA from the NILs was analyzed using 748 random 10-mer oligonucleotides to discern linked molecular markers using a random amplified polymorphic DNA (RAPD) approach. One random primer (GAGCACGGGA) was found to produce a RAPD band of about 2200 bp that demonstrates linkage to Sw-5. Data from co-segregation of resistance and restriction fragment length polymorphisms (RFLPs) in a F2 interspecific population position Sw-5 between the markers CT71 and CT220 near the telomere of the long arm of chromosome 9. PMID- 24173938 TI - Implication of correlations among some common stability statistics - a Monte Carlo simulations. AB - Stability analysis of multilocation trials is often based on a mixed two-way model. Two stability measures in frequent use are the environmental variance (S i (2) )and the ecovalence (W i). Under the two-way model the rank orders of the expected values of these two statistics are identical for a given set of genotypes. By contrast, empirical rank correlations among these measures are consistently low. This suggests that the two-way mixed model may not be appropriate for describing real data. To check this hypothesis, a Monte Carlo simulation was conducted. It revealed that the low empirical rank correlation amongS i (2) and W i is most likely due to sampling errors. It is concluded that the observed low rank correlation does not invalidate the two-way model. The paper also discusses tests for homogeneity of S i (2) as well as implications of the two-way model for the classification of stability statistics. PMID- 24173939 TI - Estimation, variance and optimal sampling of gene diversity : I. Haploid locus. AB - An extension of Nei's analysis of diversity in a subdivided population is proposed for a haploid locus. The differentiation G STbecomes a natural extension of Wright's F STand generalizes Weir and Cockerham's parameter of co-ancestry by relaxing the assumption of identical correlation for all the alleles. Inter- and intrapopulation variances of the estimated diversities and differentiation are derived. Finally, the optimal sampling strategy for measuring G STwhen a fixed number of individuals can be analysed is considered. It is shown that, at a given locus, there is a unique sample size per population which yields the smallest variance of G ST,regardless of the number of populations studied. These theoretical developments are illustrated with an analysis of chloroplast DNA diversity in a forest tree. The results emphasize the necessity of sampling many populations, rather than many individuals per population, for an accurate measurement of the subdivision of gene diversity at a single locus. PMID- 24173940 TI - Diallel analysis of the latent period of stripe rust in wheat. AB - A half diallel was made amongst five wheat (Triticum aestivum L.) genotypes of which one was susceptible, while the others had adult-plant resistance, to stripe rust (Puccinia striiformis West.). The five parent and ten F1 progeny were grown in the glasshouse and were inoculated with three rust pathotypes at the seedling stage. The latent period was measured on the first leaf. Two procedures were used to analyze the half diallel. Both methods showed that the average effects of alleles were of much greater importance than was dominance in conditioning resistance in response to two of the pathotypes, while for the third pathotype dominance was important. Resistance was conditioned by partial dominance for two pathotypes whereas for the third it was determined by full dominance. Broad-sense heritabilities range from 60-73% and the number of genes involved was different (from 1 to 4), depending on the pathotype. PMID- 24173941 TI - Ribosomal DNA repeat unit polymorphism in 49 Vicia species. AB - DNA restriction endonuclease fragment analysis was used to obtain new information on the genomic organization of Vicia ribosomal DNA (rDNA), more particularly among V. faba and its close relatives and the taxa within three (Narbonensis, Villosa, Sativa) species' complexes. Total genomic DNA of 90 accessions representing 49 Vicia species was restricted with 11 enzymes, and the restriction fragments were probed with three ribosomal clones. Twenty-eight repeat unit length classes were identified. The number of length classes (1-2) per accession did not correspond to the number of nucleolar organizing regions (NORs). The number of rRNA genes was independent of the 2C nuclear DNA amount present in the taxon. Each of the 90 accessions had 2 (rarely 1)-4 DraI sites. Those taxa with the same number of DraI sites generally could be distinguished from each other by different configurations. Probing of the DNA samples digested with tetranucleotide recognition restriction endonucleases emphasized differences between divergent spacer regions and enabled relative homologies between the coding regions to be established. Overall, rDNA restriction site variation among the species showed a good correlation with taxonomic classification. The rDNA analysis indicated evolutionary relatedness of the various taxa within the Narbonensis species complex. rDNA diversity within two other species complexes (Villosa, Sativa), on the other hand, was more extensive than expected. With few exceptions, data on the two complexes give evidence of taxon-specific divergences not seen with other approaches. The restriction site variability and repeat length heterogeneity in the rDNA repeat exhibited startling differences between V.faba and its close wild relatives included in the Narbonensis species complex. This analysis provides new evidence that none of the species within the complex can be considered to be putative allies of broad bean. PMID- 24173942 TI - A comparison of Bonus and Quota mating systems for utilising the sex-determining region Y gene in terminal sire beef cattle breeding. AB - The use of the sex-determining region Y gene in terminal sire beef cattle breeding was investigated, assuming that fertile transgenic bulls carrying this gene on an autosome can be created. The benefit of these transgenic bulls arises from having an increased proportion of calves with a male phenotype. Two mating strategies utilising the transgenic bulls were devised and compared; the Quota scheme whereby a quota of normal bulls is used alongside the transgenic bulls in a breeding nucleus, and the Bonus scheme in which a phenotypic bonus is assigned to transgenic bulls indicating the added value of their offspring. Bonus and Quota breeding schemes were comparable, in terms of the value of offspring of the bulls, for the first 6 years of selection, after which time the Quota breeding scheme was superior. For time horizons less than 10 years, and large assumed phenotypic superiorities of male calves, breeding schemes with transgenic bulls were superior to traditional breeding schemes without transgenic bulls. If the time horizon was longer, or if the assumed superiority of male calves was small, then traditional breeding schemes were generally superior to those utilising transgenic bulls. Scenarios were observed, however, where transgenic bulls were always superior to normal bulls, in terms of their value as sires. Equations were derived to predict genetic gain and the equilibrium genetic lag between normal and transgenic bulls in Quota breeding schemes. PMID- 24173943 TI - A selection strategy to accommodate genotype-by-environment interaction for grain yield of wheat: managed-environments for selection among genotypes. AB - Selection for grain yield among wheat lines is complicated by large line-by environment (L * E) interactions in Queensland, Australia. Early generation selection is based on an evaluation of many lines in a few environments. The small sample of environments, together with the large L * E interaction, reduces the realised response to selection. Definition of a series of managed environments which provides discrimination among lines, which is relevant to the target production-environments, and can be repeated over years, would facilitate early generation selection. Two series of managed-environments were conducted. Eighteen managed-environments were generated in Series-1 by manipulating nitrogen and water availability, together with the sowing date, at three locations. Nine managed-environments based on those from Series-1 were generated in Series-2. Line discrimination for grain yield in the managed-environments was compared to that in a series of 16 random production-environments. The genetic correlation between line discrimination in the managed-environments and that in the production-environments was influenced by the number and combination of managed environments. Two managed-environment selection regimes, which gave a high genetic correlation in both Series-1 and 2, were identified. The first used three managed-environments, a high input (low water and nitrogen stress) environment with early sowing at three locations. The second used six managed-environments, a combination of a high input (low water and nitrogen stress) and medium input (water and nitrogen stress) with early sowing at three locations. The opportunities for using managed-environments to provide more reliable selection among lines in the Queensland wheat breeding programme and its potential limitations are discussed. PMID- 24173944 TI - Genetic linkage mapping in peach using morphological, RFLP and RAPD markers. AB - We have constructed a genetic linkage map of peach [Prunus persica (L.) Batsch] consisting of RFLP, RAPD and morphological markers, based on 71 F2 individuals derived from the self-fertilization of four F1 individuals of a cross between 'New Jersey Pillar' and KV 77119. This progeny, designated as the West Virginia (WV) family, segregates for genes controlling canopy shape, fruit flesh color, and flower petal color, size and number. The segregation of 65 markers, comprising 46 RFLP loci, 12 RAPD loci and seven morphological loci, was analyzed. Low-copy genomic and cDNA probes were used in the RFLP analysis. The current genetic map for the WV family contains 47 markers assigned to eight linkage groups covering 332 centi Morgans (cM) of the peach nuclear genome. The average distance between two adjacent markers is 8 cM. Linkage was detected between Pillar (Pi) and double flowers (Dl) RFLP markers linked to Pi and flesh color (gamma) loci were also found. Eighteen markers remain unassigned. The individuals analyzed for linkage were not a random sample of all F2 trees, as an excess of pillar trees were chosen for analysis. Because of this, Pi and eight other markers that deviated significantly from the expected Mendelian ratios (e.g., 1?2?1 or 3?1) were not eliminated from the linkage analysis. Genomic clones that detect RFLPs in the WV family also detect significant levels of polymorphism among the 34 peach cultivars examined. Unique fingerprint patterns were created for all the cultivars using only six clones detecting nine RFLP fragments. This suggests that RFLP markers from the WV family have a high probability of being polymorphic in crosses generated with other peach cultivars, making them ideal for anchor loci. This possibility was examined by testing RFLP markers developed with the WV family in three other unrelated peach families. In each of these three peach families respectively 43%, 54% and 36% of RFLP loci detected in the WV family were also polymorphic. This finding supports the possibility that these RFLP markers may serve as anchor loci in many other peach crosses. PMID- 24173945 TI - Use of a temperature-sensitive lethal mutation strain of medfly (Ceratitis capitata) for the suppression of pest populations. AB - Before the Sterile Insect Technique can be applied successfully, the size of the target population has to be reduced to a manageable level. At present this reduction is achieved by the use of insecticides. Computer simulations have been performed to examine the possibility of achieving this initial population suppression by genetic control strategies; in particular, the effect of releasing fertile males carrying a recessive temperature-sensitive lethal mutation and a Y autosome translocation has been simulated. The results show that the release of such males is most effective when applied under permissive conditions, i.e. those which allow flies homozygous for the temperature-sensitive lethal mutation to survive and spread the mutation through the population. However, combining this population replacement with a population-suppression strategy is even more effective. If the released males are partially sterile, e.g. due to the presence of a Y-autosome translocation, the population size is reduced before the restrictive conditions for the temperature-sensitive lethal mutation are reached, i.e. before the increase of temperatures in the target area eliminates all flies homozygous for this mutation. By combining these two strategies the resulting population should be low enough to apply the Sterile Insect Technique for eradication. PMID- 24173946 TI - Producing commercially attractive, uniform true potato seed progenies: the influence of breeding scheme and parental genotype. AB - The production of attractive, uniform true potato seed (TPS) progenies was investigated. Four breeding schemes were compared: intercrossing tetraploid cultivars (cv x cv); doubled dihaploids x cultivars (ddh x cv); cultivars x diploid unreduced-gamete producers (cv x FDR) and doubled dihaploids x diploid unreduced-gamete producers (ddh x FDR). Fifty three progenies and five clones were grown in a glasshouse in a randomised complete block design with three replicates of 25 plants per progeny and clone. Each plant's tubers were counted and the colour, shape, quality of skin finish, flesh colour, and commencai attractiveness (which includes yield) recorded. The most uniform progenies were also selected by visual comparison with the clones. For mean attractiveness, differences (P < 0.001) between breeding schemes and between progenies within breeding schemes were detected. The cv x cv and cv x FDR progenies were more attractive than clonal controls. There were significant additive and non-additive effects for attractiveness in all breeding schemes except cv x FDR. There were between-progeny differences (P < 0.001) for uniformity for all characters. Progenies uniform for one character could be variable for other traits. Breeding schemes gave different levels of uniformity (P < 0.001) for all characters except shape and flesh colour, but none gave low levels of variation for all traits. Doubled-dihaploid parents increased the variation in progenies. There were uniformity differences (P < 0.001) between progenies within breeding schemes for all characters. Evidence of additive and nonadditive genetic variation for uniformity in all traits was detected. In each breeding scheme, parents with good general combining ability (GCA) for uniformity in several characters were identified. Visually selected uniform progenies had parents with good GCAs for uniformity in a range of traits and high specific combining abilities (SCAs) for several traits. A desynaptic first-division restitution (FDR) clone and a male sterile doubled-dihaploid clone had the best GCAs for tuber uniformity in TPS progenies. Achieving multitrait uniformity in TPS is problematic but may be aided by the selection of parents with GCAs for uniformity coupled with progeny testing to allow for non-additive effects. PMID- 24173947 TI - Isolation, characterization and application of a species-specific repeated sequence from Haynaldia villosa. AB - A species-specific repeated sequence, pHvNAU62, was cloned from Haynaldia villosa, a wheat relative of great importance. It strongly hybridized to H. villosa, but not to wheat. In situ hybridization localized this sequence to six of seven H. villosa chromosome pairs in telomeric or sub-telomeric regions. Southern hybridization to whea-H. villosa addition lines showed that chromosomes 1V through 6V gave strong signals in ladders while chromosome 7V escaped detection. In addition to H. villosa, several Triticeae species were identified for a high abundance of the pHvNAU62 repeated sequence, among which Thinopyrum bassarabicum and Leymus racemosus produced the strongest signals. Sequence analysis indicated that the cloned fragment was 292 bp long, being AT rich (61%), and showed 67% homology of pSc7235, a rye repeated sequence. Isochizomer analysis suggested that the present repeated sequence was heavily methylated at the cytosine of the CpG dimer in the genome of H. villosa.It was also demonstrated that pHvNAU62 is useful in tagging the introduced 6VS chromosome arm, which confers a resistance gene to wheat powdery mildew, in the segregating generations. PMID- 24173948 TI - Combining-ability for cacao (Theobroma cacao L.) yield components under southern Bahia conditions. AB - The objective of this study was to assess five cacao cultivars (selfs) and 20 hybrids with regard to their general-and specific-combining ability for yield components using method 1, model I, of the diallel analysis system. The selfings and the hybrids were obtained through controlled crossings, tested in the field in a random block design with four replications and plots containing 16 plants. The experiment was set up in the Centro de Pesquisas do Cacau, in Itabuna, Bahia, Brasil, in 1975. The characteristics studied were: the number of healthy and collected fruits per plant (NHFP and NCFP), the weight of humid seeds per plant and per fruit (WHSP and WHSF), and the percentage of diseased fruits per plant (PDFP), for 5 years (1986-1990). The F-test values, highly significant for general combining ability (GCA) and specific combining ability (SCA), demonstrated the existence of variability for both effects. However, the effects of SCA were greater than those of GCA, when compared in terms of the average squared effects. This condition held for the characteristics NHFP, NCFP and WHSP, which shows the relative importance of the non-additive genetic effects over the additive effects. The reciprocal effects did not show significance. Breeding methods which explore the additive portion of genetic variance should be employed for obtaining higher-yielding cacao and high seed weight. For this, the segregant populations should involve cultivars CEPEC 1, SIAL 169 and ICS 1. Combinations involving the cultivar ICS 1 presented the most favorable results for the characteristics WHSP and WHSF, where the hybrid SIAL 169 x ICS 1 and its reciprocal were outstanding. PMID- 24173949 TI - Recombinant inbred lines for genetic mapping in tomato. AB - A cross between the cultivated tomato Lycopersicon esculentum and a related wild species L. cheesmanii yielded 97 recombinant inbred lines (RILs) which were used to construct a genetic map consisting of 132 molecular markers. Significant deviation from the expected 1:1 ratio between the two homozygous classes was found in 73% of the markers. In 98% of the deviating markers, L. esculentum alleles were present in greater frequency than the L. cheesmanii alleles. For most of the markers with skewed segregation, the direction of the deviation was maintained from F2 to F7 generations. The average heterozygosity in the population was 15%. This value is significantly greater than the 1.5% heterozygosity expected for RILs in the F7 generation. On average, recombination between linked markers was twice as high in the RILs than in the F2 population used to derive them. The utility of RILs for the mapping of qualitative and quantitative traits is discussed. PMID- 24173950 TI - Production of wide hybrids and backcross progenies between Diplotaxis erucoides and crop brassicas. AB - Intergeneric hybrids were produced between D. erucoides (?), a wild species, and four cultivated species of Brassica, B. campestris, B. juncea, B. napus and B. oleracea, through embryo rescue. The hybrid nature of these plants was confirmed through morphological and cytological studies. Backcross pollinations with the pollen of the respective cultivars yielded BC progenies in the hybrids D. erucoides x B. juncea and D. erucoides x B. napus but not in D. erucoides x B. campestris and D. erucoides x B. oleracea. The hybrid D. erucoides x B. campestris was also used as a bridge species and crossed with B. juncea to raise the hybrid and backcross progenies. F2 progenies were more amenable than f1 hybrids for raising backcross progenies. Although D. erucoides is considered to be a close relative of B. campestris and B. oleracea, incompatibility barriers of this species with different cultivars do not reflect this relationship. PMID- 24173951 TI - Comparative efficiency of four selection methods for deriving high-yielding lines in mungbean [Vigna radiata (L.) Wilczek]. AB - The comparative efficiency of four selection methods, viz., honeycomb (HC), pedigree selection (PS), single-seed descent (SSD) and the bulk method (BM), was assessed in three crosses of mungbean. The lines derived by each method, along with check varieties, were yield-tested in a compact family block design in F5 and F6 generations during summer and kharif of 1990. On the basis of the mean of the lines, the range, the number of superior lines over the best check, and the proportion of the top 10% lines in all the crosses and generations, the honeycomb method exhibited superiority over PS, SSD and BM for yield per plant and its component traits. PS, SSD and BM did not differ from each other. The honeycomb and SSD methods were found suitable for deriving superior lines for seed yield and pods per plant in mungbean. PMID- 24173952 TI - Analysis of the genetic effects for several traits in oil palm (Elaeis guineensis Jacq.) populations. I. Population means. AB - An oil palm experiment was set up in the Ivory Coast to compare the effects of crossing and selfing within two origins, Deli and La Me, on the mean and the variability of Deli x Me between-origin hybrids. The originality of the experiment lay in the crossing plan, which provided access to genetic parameters related to additivity, dominance and different components of epistasis. This first part covers the analysis of the components of the mean. The parents used were obtained from four palms, two from each origin. Those of La Me origin were half-sibs. The common parent came from a wild stand in the Ivory Coast. Those of Deli origin were from two different populations bred in Southeast Asia for several generations from a narrow genetic base. These four parents gave rise to nine Deli x La Me hybrid populations with double-cousintype links. The additive component is more important within the Deli origin than within the La Me origin. This may be explained by the large genetic divergence between the two Deli parent palms. On the other hand, the additive(*) additive epistasis is more substantial within the La Me origin, probably because of inbreeding. The discussion concentrates on how this information should be used when choosing parents to be crossed and tested and to produce improved populations. The crossing plan proposed can be of general use and is suitable for other species in a reciprocal recurrent selection programme. PMID- 24173953 TI - Use of winter wheat x Triticum tauschii backcross populations for germplasm evaluation. AB - The wild diploid goatgrass, Triticum tauschii (Coss.) Schmal., is an important source of genes for resistance to both diseases and insects in common wheat (Triticum aestivum L.) We have evaluated grain yield, kernel weight, protein concentration, and kernel hardness of 641 BC2 F1-derived families from direct crosses involving four T. aestivum cultivars and 13 T. tauschii accessions over 2 years and at two Kansas, USA, locations. On average, T. tauschii germplasm depressed grain yield and increased protein concentration, whereas kernel weight was affected either positively or negatively, depending on the T. tauschii parent. Three T. tauschii parents produced a large proportion of families with very soft endosperm. Some variation among progeny of different T. tauschii parents resulted from the segregation of genes for resistance to leaf rust (caused by Puccinia recondita Rob. ex Desm.). This study confirmed that random BC2-derived families can be used to evaluate the effects of T. tauschii genes in the field. This methodology, although laborious, can provide useful information which is not obtainable by the screening of T. tauschii accessions themselves. PMID- 24173954 TI - Allozyme variation in the eggplant, Solanum melongena L. (Solanaceae). AB - Enzyme electrophoretic studies were made in cultivated Solanum melongena L. (eggplant) and similar wild and weedy forms, several of which have been thought to be different species/taxa. Twenty-nine accessions of S. melongena, 33 accessions of weedy forms (referred to as "insanum") and 2 accessions of wild forms (referred to as "incanum") were surveyed for 29 isozyme loci. In S. melongena, 22 of the 29 loci were monomorphic, and nearly all of its genes were either also monomorphic or in similar frequencies in insanum and incanum. The results demonstrate that the three taxa have a very close genetic relationship. The high genetic identities between them (0.913-0.967) suggests that they are conspecific even though they include extensive morphological diversity. PMID- 24173955 TI - Multiple-population versus hierarchical conifer breeding programs: a comparison of genetic diversity levels. AB - Advanced-generation domestication programs for forest-tree species has raised some concerns about the maintenance of genetic diversity in forest-tree breeding programs. Genetic diversity in natural stands was compared with two genetic conservation options for a third-generation elite Pinus taeda breeding population. The breeding population was subdivided either on the basis of geographic origin and selection goals (multiple-population or MPBS option) or stratified according to genetic value (hierarchical or HOPE option). Most allelic diversity in the natural stands of loblolly pine is present in the domesticated breeding populations. This was true at the aggregate level for both multiple population (MPBS) and the hierarchical (HOPE) populations. Individual subpopulations within each option had less genetic diversity but it did not decline as generations of improvement increased. Genetic differentiation within the subdivided breeding populations ranged from 1 to 5%, genetic variability is within each subpopulation rather than among subpopulations for both MPBS (>95%) and the HOPE approaches (>98%). Nei's Gst estimates for amongpopulation differentiation were biased upwards relative to estimates of theta from Weir and Cockerham (1984). PMID- 24173956 TI - Distillable ionic liquids: reversible amide O alkylation. PMID- 24173957 TI - Entropically driven formation of ultralong helical mesostructured organosilica nanofibers. AB - Ultralong helical organosilica nanofibers (length up to millimeter) with ordered helical mesoporous channels are synthesized using achiral cationic surfactant as single-structure-directing agent and anionic citrate as counterions. The surfactant molecules form micelles for silica condensation and the counterions reduce the polarity of the surfactant-silicate micelles via electrostatic balance, leading to the self-assembly and growth of the final product. The detailed mechanistic shape-shifting studies reveal that an entropy increase is the main driving force behind the plastic deformation of the solids. PMID- 24173958 TI - The average roughness and fractal dimension of articular cartilage during drying. AB - Cartilage is a unique material in part because of it biphasic properties. The structure of cartilage is a porous matrix of collagen fibers, permeated with synovial fluid which creates a gliding and near frictionless motion in articulating joints. However, during in vitro testing or surgery, there exists potential for cartilage to dehydrate, or dry out. The effects of this drying can influence experimental results. It is likely that drying also changes joint performance in vivo. In in vitro testing of equine cartilage explants exposed to open air, the average roughness of cartilage changes from 1.85 +/- 0.78 to 3.66 +/- 1.41 um SD in a 5-h period. Significant changes in roughness in individual samples are seen within 10 min of exposure to open air. However, the multi-scale nature of cartilage, characterized by the fractal dimension, does not significantly change during the same period. The current study attempts to quantify the magnitude of error that is introduced when cartilage is removed from its native environment. PMID- 24173960 TI - Nanocomposite-strengthened dissolving microneedles for improved transdermal delivery to human skin. AB - Delivery of drugs and biomolecules into skin has significant advantages. To achieve this, herein, a nanomaterial-strengthened dissolving microneedle patch for transdermal delivery is reported. The patch comprises thousands of microneedles, which are composed of dissolving polymers, nanomaterials, and drug/biomolecules in their interior. With the addition of nanomaterials, the mechanical property of generally weak dissolving polymers can be dramatically improved without sacrificing dissolution rate within skin. In this experiments, layered double hydroxides (LDH) nanoparticles are incorporated into sodium carboxymethylcellulose (CMC) to form a nanocomposite. The results show that, by adding 5 wt% of LDH nanoparticles into CMC, the mechanical strength significantly increased. Small and densely packed CMC-LDH microneedles penetrate human and pig skin more reliably than pure CMC ones and attractively the nanocomposite strengthened microneedles dissolve in skin and release payload within only 1 min. Finally, the application of using the nanocomposite-strengthened microneedle arrays is tested for in vivo vaccine delivery and the results show that significantly stronger antibody response could be induced when compared with subcutaneous injection. These data suggest that nanomaterials could be useful for fabricating densely packed and small polymer microneedles that have robust mechanical properties and rapid dissolution rates and therefore potential use in clinical applications. PMID- 24173961 TI - Synthesis and photochemical isomerization of a propeller-shaped molecular switch. AB - Switched on! A tetra-stable switch has been synthesized in two steps, utilizing photoresponsive isoindolinone moieties. Sequential E-Z isomerization induced by 365 nm light results in a propeller switching action that is reversible using 458 nm light, acid, and high temperature. PMID- 24173962 TI - Proteasome inhibitors and knockdown of SMG1 cause accumulation of Upf1 and Upf2 in human cells. AB - The ubiquitin-proteasome system (UPS) is one of the most promising anticancer drug targets of the century. However, the involved molecular mechanisms are still unclear. The nonsense-mediated mRNA decay (NMD) pathway is a highly conserved pathway which degrades nonsense mutation-containing mRNA selectively and efficiently. In this pathway, the SMG1-Upf1-eRF (SURF) complex binds to Upf2 on the exon junction complex and finally causes degradation of nonsense-containing mRNA. To reveal the relationship between the UPS and NMD pathways, we analyzed the effects of proteasome inhibitors on Upf1 and Upf2. The data showed that treatment with proteasome inhibitors caused the accumulation of the Upf1 and Upf2 proteins in A549 cells. In addition, we found that knockdown of SMG1 also caused the upregulation of Upf1 and Upf2 proteins, which was confirmed by different target sequences of siRNA. SMG1 and UPS appear to participate in different pathways of the degradation of Upf1 and Upf2, since simultaneous treatment with both of them caused additive effects. This study demonstrated the quantitative regulation of Upf1 and Upf2 proteins by UPS and SMG1. PMID- 24173963 TI - TNFalpha blockade for inflammatory rheumatic diseases is associated with a significant gain in android fat mass and has varying effects on adipokines: a 2 year prospective study. AB - PURPOSE: To evaluate the long-term consequences of TNFalpha inhibitors on body composition and fat distribution, as well as changes in serum adipokines in patients with rheumatoid arthritis (RA) or ankylosing spondylitis (AS). METHODS: Eight patients with RA and twelve with AS requiring a TNFalpha inhibitor were prospectively followed for 2 years. Body composition was evaluated by dual X-ray absorptiometry and included measurements of total fat mass, lean mass, fat in the gynoid and android regions, and visceral fat. Serum leptin, total and high molecular weight (HMW) adiponectin, resistin, and ghrelin were also assessed. RESULTS: There was a significant gain in body mass index (p = 0.05) and a tendency for weight (p = 0.07), android fat (p = 0.07), and visceral fat (p = 0.059) increase in patients with RA, while in AS, total fat mass significantly increased (p = 0.02) with a parallel weight gain (p = 0.07). When examining the whole population of patients, we observed after 2 years a significant increase in body weight (+1.9%; p = 0.003), body mass index (+2.5%; p = 0.004), total fat mass (+11.1%; p = 0.007), and fat in the android region (+18.3%; p = 0.02). There was a substantial, albeit nonsignificant gain in visceral fat (+24.3%; p = 0.088). Lean mass and gynoid fat were not modified. No major changes were observed for serum leptin, total adiponectin, and ghrelin, while HMW adiponectin and the HMW/total adiponectin ratio tended to decrease (-15.2%, p = 0.057 and 9.3%, p = 0.067, respectively). Resistin decreased significantly (-22.4%, p = 0.01). CONCLUSIONS: Long-term TNFalpha inhibition in RA and AS is associated with a significant gain in fat mass, with a shift to the android (visceral) region. This fat redistribution raises questions about its influence on the cardiovascular profile of patients receiving these treatments. PMID- 24173964 TI - Association of dietary type with fecal microbiota in vegetarians and omnivores in Slovenia. AB - PURPOSE: The purpose of this study was to discover differences in the human fecal microbiota composition driven by long-term omnivore versus vegan/lacto-vegetarian dietary pattern. In addition, the possible association of demographic characteristics and dietary habits such as consumption of particular foods with the fecal microbiota was examined. METHODS: This study was conducted on a Slovenian population comprising 31 vegetarian participants (11 lacto-vegetarians and 20 vegans) and 29 omnivore participants. Bacterial DNA was extracted from the frozen fecal samples by Maxwell 16 Tissue DNA Purification Kit (Promega). Relative quantification of selected bacterial groups was performed by real-time PCR. Differences in fecal microbiota composition were evaluated by PCR-DGGE fingerprinting of the V3 16S rRNA region. Participants' demographic characteristics, dietary habits and health status information were collected through a questionnaire. RESULTS: Vegetarian diet was associated with higher ratio (% of group-specific DNA in relation to all bacterial DNA) of Bacteroides Prevotella, Bacteroides thetaiotaomicron, Clostridium clostridioforme and Faecalibacterium prausnitzii, but with lower ratio (%) of Clostridium cluster XIVa. Real-time PCR also showed a higher concentration and ratio of Enterobacteriaceae (16S rDNA copies/g and %) in female participants (p < 0.05 and p < 0.01) and decrease in Bifidobacterium with age (p < 0.01). DGGE analysis of the 16S rRNA V3 region showed that relative quantity of DGGE bands from certain bacterial groups was lower (Bifidobacterium, Streptococus, Collinsella and Lachnospiraceae) or higher (Subdoligranulum) among vegetarians, indicating the association of dietary type with bacterial community composition. Sequencing of selected DGGE bands revealed the presence of common representatives of fecal microbiota: Bacteroides, Eubacterium, Faecalibacterium, Ruminococcaceae, Bifidobacterium and Lachnospiraceae. Up to 4 % of variance in microbial community analyzed by DGGE could be explained by the vegetarian type of diet. CONCLUSIONS: Long-term vegetarian diet contributed to quantity and associated bacterial community shifts in fecal microbiota composition. Consumption of foods of animal origin (eggs, red meat, white meat, milk, yoghurt, other dairy products, fish and seafood) and vegetarian type of diet explained the largest share of variance in microbial community structure. Fecal microbiota composition was also associated with participants' age, gender and body mass. PMID- 24173965 TI - A Phase II multicenter, open-label, clinical and pharmokinetic trial of PM00104 in patients with advanced Ewing Family of Tumors. AB - Ewing sarcoma is a rare connective tissue tumor characterized by the translocation of the EWS gene, mainly between chromosome 11 and 22, giving rise to gene re-arrangements between the EWS gene and various members of the ETS gene family. Multi-agent chemotherapy has improved the outcome for patients with localized Ewing sarcoma, but survival of patients with recurrent/metastatic disease remains poor. An exploratory two-stage, single-arm Phase II multicenter trial of the synthetic alkaloid, PM00104, was conducted in patients with recurrent Ewing sarcoma. The primary end point of the trial was objective response rate. PM00104 was administered at a dose of 2 mg/m(2) on Days 1, 8 and 15 of a 4 week cycle. Seventeen patients were recruited. No objective responses were reported in the 16 patients evaluable for efficacy. Recruitment was closed without proceeding to the second stage of the trial. Four patients achieved stable disease as best response, and in two of these patients the stabilization was longer than 4 months. The median progression-free survival was 1.8 months (95 % CI, 0.9-3.5 months) and median overall survival was not reached (95%CI, 56.2 % at censored data). Pharmacokinetics in patients with Ewing sarcoma was similar to that previously reported in other patient populations. PM00104 showed modest activity in Ewing sarcoma at 2 mg/m(2) on a weekly schedule. There remains an unmet need for effective therapies for patients with advanced/metastatic Ewing sarcoma. PMID- 24173966 TI - NPS-1034, a novel MET inhibitor, inhibits the activated MET receptor and its constitutively active mutants. AB - The MET proto-oncogene product, which is the receptor for hepatocyte growth factor (HGF), has been implicated in tumorigenesis and metastatic progression. Point mutations in MET lead to the aberrant activation of the receptor in many types of human malignancies, and the deregulated activity of MET has been correlated with tumor growth, invasion, and metastasis. MET has therefore attracted considerable attention as a potential target in anticancer therapy. Here, we report that a novel MET kinase inhibitor, NPS-1034, inhibits various constitutively active mutant forms of MET as well as HGF-activated wild-type MET. NPS-1034 inhibited the proliferation of cells expressing activated MET and promoted the regression of tumors formed from such cells in a mouse xenograft model through anti-angiogenic and pro-apoptotic actions. NPS-1034 also inhibited HGF-stimulated activation of MET signaling in the presence or absence of serum. Furthermore, when tested on 27 different MET variants, NPS-1034 inhibited 15 of the 17 MET variants that exhibited autophosphorylation with nanomolar potency; only the F1218I and M1149T variants were not inhibited by NPS-1034. Notably, NPS 1034 inhibited three MET variants that are resistant to the MET inhibitors SU11274, NVP-BVU972, and PHA665752. Together, these results suggest that NPS-1034 can be used as a potent therapeutic agent for human malignancies bearing MET point mutations or expressing activated MET. PMID- 24173968 TI - Estimation of the bioaccumulation potential of a nonchlorinated bisphenol and an ionogenic xanthene dye to Eisenia andrei in field-collected soils, in conjunction with predictive in silico profiling. AB - In silico-based model predictions, originating from structural and mechanistic (e.g., transport, bioavailability, reactivity, and binding potential) profiling, were compared against laboratory-derived data to estimate the bioaccumulation potential in earthworms of 2 organic substances (1 neutral, 1 ionogenic) known to primarily partition to soil. Two compounds representative of specific classes of chemicals were evaluated: a nonchlorinated bisphenol containing an -OH group (4,4'-methylenebis[2,6-di-tert-butylphenol] [Binox]), and an ionogenic xanthene dye (2',4',5',7'-tetrabromo-4,5,6,7-tetrachloro-3',6'-dihydroxy-, disodium salt [Phloxine B]). Soil bioaccumulation studies were conducted using Eisenia andrei and 2 field-collected soils (a clay loam and a sandy soil). In general, the in silico structural and mechanistic profiling was consistent with the observed soil bioaccumulation tests. Binox did not bioaccumulate to a significant extent in E. andrei in either soil type; however, Phloxine B not only accumulated within tissue, but was not depurated from the earthworms during the course of the elimination phase. Structural and mechanistic profiling demonstrated the binding and reactivity potential of Phloxine B; this would not be accounted for using traditional bioaccumulation metrics, which are founded on passive-based diffusion mechanisms. This illustrates the importance of profiling for reactive ionogenic substances; even limited bioavailability combined with reactivity can result in exposures to a hazardous substance not predictable by traditional in silico modeling methods. PMID- 24173969 TI - Brachioplasty. AB - Brachioplasty seems very simple, and the surgeon, thinking that the removal of excess skin and fat is easy, is likely to find himself in trouble after surgery because of carelessness in diagnosis and in patient selection, and lack of careful surgical planning. The best way to avoid trouble in brachioplasty is to be fully aware of surgical technique and potential errors. PMID- 24173970 TI - Cryptotia. AB - The pathologic changes of the ear cartilage in cases of cryptotia (pocket ear) are discussed and the treatment for these changes is reviewed. The authors emphasize new techniques in which the ear cartilage is grafted to lengthen and to smooth the sharp crural curvature. PMID- 24173967 TI - Phase I study of dasatinib in combination with capecitabine, oxaliplatin and bevacizumab followed by an expanded cohort in previously untreated metastatic colorectal cancer. AB - PURPOSE: Dasatinib inhibits src family kinases and has anti-angiogenic properties. We conducted a phase I study of dasatinib, capecitabine, oxaliplatin, and bevacizumab (CapeOx/bevacizumab), with an expansion cohort in metastatic colorectal cancer (CRC). METHODS: Patients were enrolled in a dose escalation cohort to establish the maximum tolerated dose (MTD) and the recommended phase II dose (RP2D). Using a "3 + 3" design, twelve patients with advanced solid tumors received dasatinib (50 mg twice daily or 70 mg daily), capecitabine (850 mg/m(2) twice daily, days 1-14), oxaliplatin (130 mg/m(2) on day 1) and bevacizumab (7.5 mg/kg on day1), every 3 weeks. Ten patients with previously untreated metastatic CRC were then enrolled in an expansion cohort. Activated src (src(act)) expression was measured by immunohistochemistry, using an antibody that selectively recognizes the active conformation of src (clone 28). RESULTS: Twenty two patients were enrolled between June 2009 and May 2011. Two DLTs were observed in the 50 mg bid dasatinib cohort, and one DLT was observed in the 70 mg daily dasatinib cohort. The MTD and RP2D for dasatinib was 70 mg daily. The most common treatment-related adverse events were fatigue (20; 91 %) and diarrhea (18; 82 %). Biomarker analysis of src(act) expression demonstrated that the overall response rate (ORR) was 75 % (6/8) for patients with high src(act) expression (IHC >= 2), compared to 0 % (0/8) for patients with low srcact expression (IHC 0 or 1); (p = 0.007). CONCLUSIONS: The RP2D of dasatinib is 70 mg daily in combination with CapeOx/bevacizumab. High levels of srcact expression may predict those patients most likely to benefit from dasatinib. PMID- 24173971 TI - Correction of protruding ears: A 20-year retrospective. AB - Twenty years experience with the tubing technique has proved it to be reliable and adaptable to the usual abnormalities associated with the protruding ear. The technique is especially dependable when all components of the auricle are involved, when the antihelical fold is absent, and there is a large or protruding concha. The recurrence rate of 2.6% is quite acceptable when compared with other techniques. PMID- 24173972 TI - Various dermal flaps with L-shaped sture line in reduction mammaplasty. AB - We review our experience in reduction mammaplasty with L-shaped suture line which we have practiced for more than 7 years. The advantages, disadvantages, and specific indications of three variations of the technique, all of them leading to an L-shaped scar, are discussed. PMID- 24173973 TI - The advantages of a lower central breast segment in reduction mammaplasty. AB - A method is described, which achieves reduction in the size of the breast and allows determination of breast shape, without the distortion of breast tissue and the production of unfavorable postoperative connective tissue tensions, inherent in most currently used techniques. Aesthetically pleasing breasts can be produced more consistently by a sculptural rather than an origami-like approach. PMID- 24173974 TI - Rhinoplasty in the older patient. AB - Rhinoplasty is often indicated in the older patient, either as an isolated procedure or in continuous or staged combination with other facial rejuvenative operations. The operations must be tempered with conservatism and artistic judgment. The nose of an older person should look natural and inconspicuous and fit the patient's face. Because of possible coronary or hypertensive problems, epinephrine in the local anesthetic solution should be used in lesser concentrations, requiring a longer wait for its full vasoconstrictive effect. Nasal cartilage is tougher, and the nasal bone more brittle in the older patient. In addition to the usual complete rhinoplasty, the partial rhinoplasty is a useful operation for the older individual. PMID- 24173975 TI - Lateral crural retrodisplacement for superior rotation of the tip in rhinoplasty. AB - Three techniques for producing superior rotation of the nasal tip are presented. One merely retrodisplaces the lateral crura on the upper lateral cartilages, one horizontally shortens the lateral crura by resection of cartilage between their anterior and posterior extremities, and one transects the cartilage in a curved fashion to allow the anterior portions of the lateral crura to be rotated on the posterior portions and upper lateral cartilages. All three techniques allow maintenance of good airways and a "strong valve" tending to prevent inspiratory collapse and visible external dimpling. The procedures are based on physiologic and anatomic principles. Details of the methods and short-term and long-term results are shown. PMID- 24173976 TI - The present status of breast reconstruction following mastectomy in the female. AB - During the last 10 years increased interest has developed in reconstruction of the female breast following mastectomy. A number of methods of reconstruction are now available. These are immediate reconstruction by means of a silicone implant, delayed reconstruction by means of a silicon implant, use of local flaps with the silicone implant, and use of distant tissue and movement of tissue by microvascular anastomosis.The simplest and most efficient procedure is the one stage reconstruction which consists of insertion of a silicone prosthesis approximately 6 months following the mastectomy. This can be combined, when necessary, with an elevation and reduction of the remaining breast and the reconstruction at the same time of an areolar and nipple complex.Reconstruction of the female breast in no way jeopardizes the survival of the patients. In addition, it may bring the patient to the surgeon sooner since the knowledge of reconstruction helps to reduce the woman's fear of mutilization. PMID- 24173977 TI - Nasal obstruction after rhinoplasty. AB - Nasal obstruction is a frustrating sequel of rhinoplasty to both the patient and the surgeon. Physiologic problems are caused by altered vasomotor mechanisms of the lining. Mechanical obstruction results from (1) over-correction of the nasal supporting structures, (2) infracture of long nasal bones, (3) septal irregularities, and (4) surgical adhesions.Simple and effective techniques for correcting each of these problems are described. PMID- 24173978 TI - Late results of mammareduction plasty : Deepithelization, ribeiro procedure, and reconstructed burn-injured breasts. AB - The long-term results of a method for reducing mammary hyperplasia and ptosis are discussed. The approach combines an earlier, unpublished technique with modifications of methods reported by several investigators. A related technique has also been used in transplanting full-thickness skin grafts after burns of the breast area and in other abnormalities and wounds of the breast. PMID- 24173979 TI - Prolapse of the lacrimal gland: Findings and management during blepharoplasty. PMID- 24173980 TI - A conservative approach to rhinoplasty. AB - When a rhinoplasty is performed, one must keep in mind that the nose is a part of a whole structure, the face. In the ideal nose operation all the components of the nose are well balanced among themselves and the nose itself is a harmonic part of the face. The present article briefly reports on how the different excisions of a rhinoplasty should be done to get a well-balanced nose. The objective of the presentation is to emphasize how only a very small amount of osteocartilaginous framework can be removed to obtain a very satisfactory result. The most caudal portion of the septum is almost never removed and the tip elevation is achieved with a logical excision of both lower and upper lateral cartilages. Wedges from the alae are seldom excised, producing a more natural looking nose. In summary, we try to achieve better appearing noses that do not look operated on. PMID- 24173981 TI - A blepharoplasty technique for refinement of oriental eyelid with lateral fold. AB - A slitted palpebral opening with slightly upturned lateral corner of the eye is one of the important aesthetic characteristics of Oriental eyelids. However, this characteristic often becomes distorted from middle age onward owing to growing of the lateral fold, or plica malopalpebralis superioris, a condition that does not apply to the Oriental eyelid alone. A technique is presented for creation of a superior palpebral sulcus with lateral-lifting and simultaneous removal of the lateral fold in blepharoplasty for youthful refinement of an Oriental eyelid with lateral fold. PMID- 24173982 TI - The square chin and the pointed chin: Another refinement in facial aesthetics. AB - The authors present a simple surgical procedure for changing a pointed chin into a square one, through the resectioning of a horizontal bone fragment of the free edge of the mentum. An amount of soft tissue of this region can be resected during surgery as a secondary reshaping maneuver. A third technical detail can be added to improve the final result, using a small bone resection wedge in the middle of the mentum edge. A lazy groove on the new square chin line is obtained. A comparative, preoperative and postoperative study of the face contour is presented. PMID- 24173983 TI - The modified strombeck technique for reduction mammaplasty. AB - A modification of Strombeck's technique is described for choosing a new nipple site near the end of the operation rather than at its beginning. This modification prevents deformity, irregularity, and malpositioning of the areola. PMID- 24173984 TI - Aesthetic surgery as organopsychic therapy. AB - Abnormal anatomic variations have a wide range from small abnormalties to greater defects. Although these cannot be considered pathologic deformations, they may cause psychic problems in patients already on the border of psychic disease. It is therefore necessary to call them "organopsychic alterations." In general, the plastic correction is not carried out exclusively because of aesthetic causes, but also to heal the "psychic disease." On this basis, it is justifiable to call these aesthetic interventions "organopsychic therapy." PMID- 24173985 TI - Prominent ears: Evolution of a surgical technique. AB - The prominent ear must always be seen as an aesthetic unity made up of a large number of anatomic details so that a natural and not a surgically corrected result is obtained. To achieve this goal no standard techniques should be used. Each anatomic detail must be treated in each ear. PMID- 24173986 TI - Modification of the cutaneous muscular flap approach for lower blepharoplasty. AB - A modification of the cutaneous muscular flap approach for the treatment of baggy, wrinkled lower eyelids is presented. According to its anatomy, the pretarsal muscle is left intact when the flap is raised. This muscle is not directly related to fat bags and left in its place contributes in maintaining the normal lid physiology and avoids the complications seen with the original procedure. PMID- 24173987 TI - Giant galactoceles 1 month after bilateral augmentation mammoplasty, abdominoplasty, and tubal ligation: Case report. AB - A case report is presented of the development of giant galactoceles 1 month after bilateral augmentation mammoplasty, abdominoplasty, and tubal ligation. PMID- 24173988 TI - Extramucosal method in rhinoplasty. AB - Principles, history, terminology and technique of the extramucosal method in rhinoplasty are presented. The advantages of preserving the mucosa are reviewed: less bleeding, less swelling, fewer nasal breathing troubles, prevention of parrot's beaked nose, support for skeletal grafts, easier method for secondary rhinoplasty if it is needed, facility in measuring the skeletal resections. PMID- 24173989 TI - The preplanned rhinoplasty. AB - In aesthetic rhinoplasty performed by the extramucosal method, the "skeletization" of the nose that is obtained allowsmeasurements during the operation. Thereby, it is possible and useful to preplan the rhinoplasty with more accuracy and to inform the patient about the choice to be made. This new approach to rhinoplasty is safer and more precise and provides for (1) a choice of preplanned result (based on artistic technique and psychological reasons), (2) measurements for the plan, and (3) transfer of this plan to the patient during the operation. PMID- 24173990 TI - Midabdominoplasty. AB - Midabdominoplasty is a simple procedure requiring only local anesthetic. It is suitable for lesser abdominal deformities, such as striae, wrinkling, and relaxation, but it is not adequate for resection of lower abdominal lipodystrophy. However, it may be used for correcting diastasis of the rectus muscle or an umbilical hernia. The transverse scar line is minimal, similar to the mark at the waist left by a half-slip or panty. PMID- 24173991 TI - Aesthetic plastic correction of incomplete testicular feminization. AB - Surgery was performed for feminization of ambiguous (male) external genitalia in 1973 on a patient with incomplete testicular feminization (familial male hermaphroditism of mixed variety). Rhinoplasty and augmentation of the chin, the malar region, the breasts were also performed not only to improve the patient's sexual role but to enhance the aesthetic appearance, as an aid in better phychosocial adaptation. PMID- 24173992 TI - The presence of silicone in breast capsules. AB - The presence of silicon-containing compounds in the capsules of women undergoing secondary surgical procedures has been identified by energy dispersion X-ray analysis. The birefringence and surface configuration qualities have been examined by polarized light-microscopic and electron-microscopic methods. The data indicate that silicone polymer (polydimethyl siloxane) is present both within cells and in the intercellular matrix of the capsule; the source of this material is the silicone gel-filled implant. A histiocytic and foreign-body giant cell response was found to be associated with the silicon-containing compounds. It remains conjectural whether this chronic response is associated with the pain present in significant breast capsule formation. PMID- 24173993 TI - A convenient, effective mammary sizer. AB - In augmentation mammaplasty cases it has been impossible for the patient to relate to the doctor preoperatively exactly how large they want their new breasts to be. Many of these patients are uncomfortable because they are not given a realistic impression of how large they will be postaugmentation. We have devised a mammary sizer which gives the patient a better idea of how large she will be postaugmentation. It gives the doctor a better impression of what size implant to use to achieve the desired size. PMID- 24173994 TI - Correction of lower limb lipodystrophy. AB - The authors study various types of thigh lipodystrophy. To each type is applied a special technique. The complications are studied and the limitations given. PMID- 24173995 TI - Patient satisfaction following augmentation mammaplasty with the gel prosthesis. AB - No evaluation of patient responses to augmentation mammaplasty has been published in the medical literature. This has left the area open for opinion and speculation by both physicians and laity.All patients undergoing pure augmentation mammaplasty during 1976 were sought in four plastic surgery practices using gel prostheses in the Southwest. Responses were obtained from 159 of the 221 patients (72%). Some degree of firmness of one or both breasts was reported by 64% of the patients who responded. External capsulotomy was effective in only 1 patient in 5. Shape distortion because of capsular contracture was reported by 10% of patients. Change in nipple sensation was reported by 42% of patients; 9% found it bothersome. There was no difference statistically between the inframammary and periareolar approach. Improved self-image was reported by 91% of patients. Fifty-five percent reported a positive effect on their sexual lives. Only 3% had a negative effect.Although 91% of patients expressed satisfaction with their operations, an even greater number (97%) would have the operation again. This is a striking affirmation of this cosmetic operation as performed by board-certified plastic surgeons. Obviously, the benefits of augmentation mammaplasty outweigh any unfavorable results. PMID- 24173996 TI - Hair fixation in rhytidectomy. AB - A simple and useful way for effective fixation of hair during the entire length of rhytidectomy is proposed. This is achieved by gathering the whole scalp of hair into bundles by means of simple rubber bands, which permit lengthy surgery without the interference of hair in the operative field. PMID- 24173997 TI - A new method for tightening the orbicularis oculi muscles during blepharoplasty. AB - Long-term results in 248 patients who underwent electrocoagulation to tighten the orbicular muscles of the eyes have proved that the technique is not only safe but highly satisfactory. PMID- 24173998 TI - Alar base-wedge excisions: partial excision of the alae nasi-base of the nostrils. AB - Alar base-wedge excisions are an integral part of the rhinoplastic procedure. They tend to reduce the nostril floor, the alar height, or both. Some geometrical forms are presented relating to the individual abnormalities. Emphasis is put on the usefulness of this procedure. PMID- 24173999 TI - Some remarks on breast reduction by the "B" technique. AB - The main disadvantage of the popular techniques for breast reduction are the scars left around the breasts. We present our experience with the "B" technique for breast reduction, which creates a much smaller size scar that is well hidden under the brassiere. Our conclusion is that the "B" technique is the method of choice for most breast reductions. PMID- 24174000 TI - Experiences with inflatable implants. AB - Augmentation mammaplasty is generally associated with a high degree of patient satisfaction, but many studies now suggest that silicone gelfilled implants leak and that free gel migrates. A series of saline-filled augmentations is presented with technique that results in a small and inconspicuous incision and superior hemostasis. The advantages of these implants with regard to spherical capsular contraction are discussed. PMID- 24174001 TI - Rhinoplasty and its psychological implications: Applied psychology observations in aesthetic surgery. AB - Interest in the psychological problems that have always been associated with plastic surgery has been growing in the last 30 years, as moral and social prejudices have become less important. This interest has concentrated on the psychological mechanisms that induce patients to undergo surgery and on the selection criteria to be followed by surgeons. This report proposes a new method for tackling these problems. It is based on our experience as well as on the investigation, by means of interviews and tests (MMPI and Rorschach), of subjects requesting rhinoplasty.These elements have helped in propounding theories on the relationship between surgery and its psychological aspects, as based on three points: 1) the feelings of the individual that derive from the presence of an actual deformity or from the mere subjective feeling of one; 2) the nature and magnitude of the limitations on the patient's desire to get rid of the deformity; 3) the conflicts deriving from the contrast between subjective ideas of deformity and perfection and what can actually be achieved through surgery.Practical criteria for selection of patients are presented, including an analysis of the surgeon's emotional reactions during the first interview, which is regarded as a relationship already interpersonal and somewhat therapeutic. Anderson's questionnaire is discussed as an alternative possibility. PMID- 24174002 TI - Two consecutive abdominoplasties to solve a problem of striae. AB - Two consecutive abdominoplasties can be performed on a patient after a 2-year interval between the first and second procedure by using the same technique. This procedure has been used for specific cases of flaccid abdominal wall skin and excess striae located throughout the abdominal region, mostly above the umbilical line. Applying the conventional low horizontal incision, the amount of striae to be resected with the excess skin is not sufficient to dislocate the highest striae to a lower position. The poor result obtained in the first abdominoplasty motivates the author to perform a second one after 18 months. The second caudal dislocation of the cutaneous flap, using the same surgical technique, improves the final result by removing almost all residual striae between the navel and the horizontal scar line. A minimum amount of striae remains located a few centimeters above the final horizontal scar. No vertical compensating suture was needed and no abnormal elevation of the scar was observed. PMID- 24174003 TI - The elephant man-A tragic syndrome. AB - In 1884, Sir Frederick Treves first described a patient known as "The Elephant Man" because of grotesque facial and bodily deformities, presumably due to von Recklinghausen's neurofibromatosis. Because of these extreme deformities and disfigurements, this unfortunate man, although he was otherwise healthy, was socially ostracized and unable to live a normal life.This report concerns three modern examples of individuals whose great difficulty in enjoying life with other members of society was due to their peculiar appearances. Two of the patients suffered from neurofibromatosis and the third from multiple congenital nevi.A case is made for using the term "elephant man syndrome" for those who are made so ugly by certain congenital conditions that they are unable to function happily.A plea is made for plastic surgeons to apply their skills in these cases despite the excessive time and effort required, since aesthetic surgery here may be life saving surgery. PMID- 24174004 TI - Effect of expansion exercises on capsular constriction around silicone implants. AB - Animal experiments were used to demonstrate that capsule expansion exercises can have a positive effect on capsular constriction around silicone implants. PMID- 24174005 TI - The reduction of the hypertrophic nipple. AB - Reduction of the hypertrophied nipple core can be accomplished very simply by applying a thin split-thickness graft from the tip of the nipple to the resected nipple core. The results are esthetically acceptable. PMID- 24174007 TI - Torsoplasty. AB - Torsoplasty is a series of operations performed on the torso, from the arms to the thighs, to correct deformities caused by obesity, weight reduction, obstetrical remissness, or congenital problems. The results have been highly satisfactory and the complications minimal. PMID- 24174006 TI - Silicone fluid, attractive and dangerous: Collective review and summary of experience. AB - Silicone injection therapy for soft tissue augmentation gives excellent results when the material is applied in small amounts, especially in correcting deep folds on the forehead or in the nasolabial region. Unfortunately, one must sometimes cope with an unpleasant complication, which is not easy to overcome: the formation of a silicone granuloma, the so-called siliconoma. There is still much discussion about the etiology of this. This report surveys the different opinions expressed in the literature and presents my own experiences with the use of liquid silicone. PMID- 24174008 TI - Height, weight, and body mass index associations with gastric cancer subsites. AB - BACKGROUND: Although excess body weight has been associated with cancers of the gastric cardia, relationships with gastric cancer at other anatomic subsites are not well defined. Furthermore, subsite-specific associations with attained height have not been fully assessed. METHODS: In 1995-1996, 483,700 Whites enrolling in the multi-state NIH-AARP Diet and Health Study self-reported height and weight. Gastric cancers occurring through 31 December 2006 were ascertained from regional population-based registries. We used Cox regression models to estimate cancer hazard ratios (HRs) for sex-specific tertiles of height and weight and for body mass index (BMI) categories of the World Health Organization. RESULTS: One thousand incident cancers (48 % localized to the cardia, 4 % fundus, 6 % corpus, 3 % greater curvature, 6 % lesser curvature, 10 % antrum, 2 % pylorus, 5 % overlapping lesion, and 16 % unspecified) occurred an average of 5.4 years after enrollment. After controlling for effects of age, sex, education, and smoking, we found an inverse association between height and total noncardia cancers (i.e., fundus, corpus, greater and lesser curvatures, antrum, and pylorus), with HRs vs. tertile 1 of 0.65 and 0.71 for tertiles 2 and 3, respectively (p trend = 0.016). Trends were consistent for individual noncardia subsites. In contrast, although weight and BMI were each associated with risk of cardia cancer, neither was associated with total noncardia cancer nor individual subsites. CONCLUSION: Noncardia gastric cancer is associated with short stature but not with high body weight or obesity. The excess risk for shorter adults would be consistent with the known association of chronic H. pylori infection with growth retardation during childhood. PMID- 24174010 TI - In situ synthesis of CuO and Cu nanostructures with promising electrochemical and wettability properties. AB - A strategy is presented for the in situ synthesis of single crystalline CuO nanorods and 3D CuO nanostructures, ultra-long Cu nanowires and Cu nanoparticles at relatively low temperature onto various substrates (Si, SiO2 , ITO, FTO, porous nickel, carbon cotton, etc.) by one-step thermal heating of copper foam in static air and inert gas, respectively. The density, particle sizes and morphologies of the synthesized nanostructures can be effectively controlled by simply tailoring the experimental parameters. A compressive stress based and subsequent structural rearrangements mechanism is proposed to explain the formation of the nanostructures. The as-prepared CuO nanostructures demonstrate promising electrochemical properties as the anode materials in lithium-ion batteries and also reversible wettability. Moreover, this strategy can be used to conveniently integrate these nanostructures with other nanostructures (ZnO nanorods, Co3 O4 nanowires and nanowalls, TiO2 nanotubes, and Si nanowires) to achieve various hybrid hierarchical (CuO-ZnO, CuO-Co3 O4 , CuO-TiO2 , CuO-Si) nanocomposites with promising properties. This strategy has the potential to provide the nano society with a general way to achieve a variety of nanostructures. PMID- 24174009 TI - Identifying early indicators in bipolar disorder: a qualitative study. AB - The identification of early markers has become a focus for early intervention in bipolar disorder. Using a retrospective, qualitative methodology, the present study compares the early experiences of participants with bipolar disorder to those with unipolar depression up until their first diagnosed episode. The study focuses on differences in early home and school environments as well as putative differences in personality characteristics between the two groups. Finally we a compare and contrast prodromal symptoms in these two populations. Thirty-nine participants, 20 diagnosed with unipolar depression and 19 diagnosed with bipolar disorder, took part in the study. A semi-structured interview was developed to elicit information about participants' experiences prior to their first episode. Participants with bipolar disorder reported disruptive home environments, driven personality features, greater emotion dysregulation and adverse experiences during the school years, whereas participants with depression tended to describe more supportive home environments, and more compliant and introvert personality traits. Retrospective data collection and no corroborative evidence from other family members. No distinction was made between bipolar I and bipolar II disorder nor between melancholic and non-melancholic depression in the sample. Finally the study spanned over a 12-month period which does not allow for the possibility of diagnostic reassignment of some of the bipolar participants to the unipolar condition. These findings indicate that there may be benefits in combining both proximal and distal indicators in identifying a bipolar disorder phenotype which, in turn, may be relevant to the development of early intervention programs for young people with bipolar disorder. PMID- 24174011 TI - Stereoselective synthesis of chiral alpha-amino-beta-lactams through palladium(II)-catalyzed sequential monoarylation/amidation of C(sp(3) )-H bonds. AB - Give Me an Ar, give Me an N! Arylation of the methyl group in a simple derivative of readily available alanine under palladium catalysis was followed by intramolecular amidation at the same position to give chiral alpha-amino-beta lactams with a wide range of aryl substituents (see scheme; Phth=phthaloyl). The alpha-amino-beta-lactams were obtained in moderate to high yields with good functional-group tolerance and high diastereoselectivity. PMID- 24174012 TI - Influence of lead apron shielding on absorbed doses from panoramic radiography. AB - OBJECTIVES: This study investigated the absorbed doses in a full anthropomorphic body phantom from two different panoramic radiography devices, performing protocols with and without applying a lead apron. METHODS: A RANDO((r)) full body phantom (Alderson Research Laboratories Inc., Stamford, CT) was equipped with 110 thermoluminescent dosemeters at 55 different sites and set up in two different panoramic radiography devices [SCANORA((r)) three-dimensional (3D) (SOREDEX, Tuusula, Finland) and ProMax((r)) 3D (Planmeca, Helsinki, Finland)] and exposed. Two different protocols were performed in the two devices. The first protocol was performed without any lead shielding, whereas the phantom was equipped with a standard adult lead apron for the second protocol. RESULTS: A two-tailed paired samples t-test for the SCANORA 3D revealed that there is no difference between the protocol using lead apron shielding (m = 87.99, s = 102.98) and the protocol without shielding (m = 87.34, s = 107.49), t(54) = -0.313, p > 0.05. The same test for the ProMax 3D showed that there is also no difference between the protocol using shielding (m = 106.48, s = 117.38) and the protocol without shielding (m = 107.75, s = 114,36), t(54) = 0.938, p > 0.05. CONCLUSIONS: In conclusion, the results of this study showed no statistically significant differences between a panoramic radiography with or without the use of lead apron shielding. PMID- 24174013 TI - Letter by Fu et al. regarding the article, "Polymorphisms in the vitamin D receptor gene and the lung cancer risk". PMID- 24174014 TI - Visualization of Secale cereale DNA in wheat germ plasm by fluorescent in situ hybridization. AB - Homozygous wheat/rye (1BL/1RS or 1AS/ 1RL) translocation lines have significantly contributed to wheat production, and several other wheat/rye translocation lines show a potential promise against biotic and abiotic stresses. Detecting the presence of rye at the chromosome level is feasible by C-banding and isozyme protocols, but the diagnostic strength of genomic in situ hybridization for eventually analyzing smaller DNA introgressions has greater significance. As a first step we have applied the genomic in situ hybridization technique to detect rye chromosomes in a wheat background using germ plasm of agricultural significance. By this method rye contributions to the translocations 1BL/1RS, 1AL/1RS, 5AS/5RL and 6BS/6RL could be identified. Differential labelling has further enabled the detection of rye and Thinopyrum bessarabicum chromosomes in a trigeneric hybrid of Triticum aestivum/Th. bessarabicum//Secale cereale. PMID- 24174015 TI - Molecular identification of powdery mildew resistance genes in common wheat (Triticum aestivum L.). AB - RFLP markers for the wheat powdery mildew resistance genes Pm1 and Pm2 were tagged by means of near-isogenic lines. The probe Whs178 is located 3 cM from the Pm1 gene. For the powdery mildew resistance gene Pm2, two markers were identified. The linkage between the Pm2 resistance locus and one of these two probes was estimated to be 3 cM with a F2 population. Both markers can be used to detect the presence of the corresponding resistance gene in commercial cultivars. "Bulked segregant analysis" was applied to identify linkage disequillibrium between the resistance gene Pm18 and the abovementioned marker, which was linked to this locus at a distance of 4 cM. Furthermore, the RAPD marker OPH-111900 (5' CTTCCGCAGT-3') was selected with pools created from a population segregating for the resistance of 'Trigo BR 34'. The RAPD marker was mapped about 13 cM from this resistance locus. PMID- 24174016 TI - Paternal plastid DNA can be inherited in lentil. AB - Restriction fragment analysis was used to study the inheritance of chloroplast DNA (cpDNA) in F1 progeny from crosses between Lens culinaris ssp. orientalis and L. culinaris ssp. culinaris. Twenty-five combinations of 11 restriction enzymes and three heterologous probes from Petunia hybrida cpDNA were used to screen six accessions of L.c. culinaris and one accession of L. c. orientalis for restriction fragment length polymorphisms (RFLPs). No variation in cpDNA was observed within the subspecies L. c. culinaris, but the L. c. orientalis accession was unambiguously distinguished from all six L. c. culinaris accessions by two RFLPs. Of ten F1 progeny from L. c. orientalis x L. c. culinaris crosses, nine had only maternal cpDNA restriction fragments but one F1 plant inherited cpDNA fragments from both parents. Nuclear DNA inheritance was biparental in all ten F1 progeny. PMID- 24174017 TI - Molecular cloning of the flavanone 3beta-hydroxylase gene (FHT) from carnation (Dianthus caryophyllus) and analysis of stable and unstable FHT mutants. AB - Using a cDNA encoding the flavanone 3beta-hydroxylase (FHT) from Dianthus caryophyllus (carnation) as a probe, we isolated the FHT gene from a genomic library. Sequence analysis revealed that the FHT gene consists of three exons and two introns. Two putative light-regulated elements were identified in the promoter region by sequence comparison. Southern blot analysis indicated that a single copy of the FHT gene is in the plant genome. Furthermore, a stable and an unstable FHT mutant of D. caryophyllus, both showing almost no FHT activity, were analyzed by Southern, Northern and Western blotting. It turned out that the FHT gene is present in both mutants, but no protein was detectable in the mutant flowers. FHT mRNA in amounts comparable to that found in the wildtype is present in flowers of the stable mutant, indicating a block in translation, but not in flowers of the unstable mutant, indicating a block in transcription. The translational block of the FHT mRNA of the stable mutant was demonstrated by in vitro translation of total flower mRNA followed by the specific measurement of FHT activity. PMID- 24174018 TI - Genetic control for resistance to leaf rust in wheat-Agropyron lines: Agro 139 and Agro 58. AB - Leaf rust resistance lines of Triticum aestivum carry highly effective Lr genes from Agropyron intermedium (Host) Beauv. This Agro 58 and Agro 139 resistance segregated independently of Agropyron leaf-rust resistance genes Lr-19, Lr-24 and Lr-9 from Ae. umbellulata. Monosomic analysis showed that the Lr gene in Agro 139 was incorporated into wheat chromosome 6D. C-banding analysis could not determine the C-banding pattern of A. intermedium in wheat -Agropyron lines Agro 58 and Agro 139. It is assumed that the transfers occurred from the euchromatin regions of the Agropyron chromosomes to the euchromatin regions of the wheat chromosomes. It is suggested that the Lr gene from Agro 139 be designated LrAg (i)-1 and the Lr gene from Agro 58 designated LrAg (i)-2. PMID- 24174019 TI - A major satellite DNA of soybean is a 92-base pairs tandem repeat. AB - We report the cloning, sequencing and analysis of the major repetitive DNA of soybean (Glycine max). The repeat, SB92, was cloned as several monomers and trimers produced by digestion with XhoI. The deduced consensus sequence of the repeat is 92 base pairs long. Genomic sequences do not fluctuate in length. Their average homology to the consensus sequence is 92%. The consensus of SB92 contains slightly degenerated homologies for several 6-cutters. Therefore, many of them generate a ladder of 92-bp oligomers. The distribution of bands seems to be random, but the occurrence of sites for different 6-cutters varies widely. There is no obvious correlation between the sequences of the neighboring units of SB92 in cloned trimers. Also, there are none of the internal repetitive blocks reported for many satellite DNAs from other species. The SB92 repeat makes up 0.7% of total soybean DNA. This is equivalent to 8*10(4) copies, or 7 megabases. The repeat is organized in giant tandem blocks over 1 Mb in length, and there are fewer blocks than chromosomes. The polymorphism of these blocks is extremely high. The SB92 repeat is present in identical arrangement and number of copies in the ancestral subspecies Glycine soja. There are 10 times fewer copies of the repeat in a related species Vigna unguiculata (cowpea), and no homologies in several other more distant leguminous plants studied. PMID- 24174020 TI - Genetic improvement of production while maintaining fitness. AB - Selection for production tends to decrease fitness, in particular, major components such as reproductive performance. Under an infinitesimal genetic model restricted index selection can maintain reproductive performance while improving production. However, reproductive traits are thought to be controlled by a finite number of recessive alleles at low frequency. Culling for low reproduction may weed out the negative homozygous genotypes for reproduction in any generation, thus controlling the frequencies of alleles negative for reproduction. Restricted index selection, culling for low reproduction and a new method called empirical restricted index selection were compared for their efficiency in improving production while maintaining reproduction. Empirical restricted index selection selects animals that have on average the highest estimated breeding values for production and on average the same estimated breeding values for reproduction as the base population. An infinitesimal genetic model and models with a finite number of loci for reproduction with rare deleterious recessive alleles, which have additive, dominant or no pleiotropic effects on production, were considered. When reproduction was controlled by a finite number of loci with rare recessive alleles, restricted index selection could not maintain reproduction. The culling of 20% of the animals on reproduction maintained reproduction with all genetic models, except for the model where loci for reproduction had additive effects on production. Empirical restricted selection maintained reproduction with all models and yielded higher production responses than culling on reproduction, except when there were dominant pleiotropic effects on production. PMID- 24174021 TI - Conversion of a RAPD-generated PCR product, containing a novel dispersed repetitive element, into a fast and robust assay for the presence of rye chromatin in wheat. AB - Bulk segregant analysis was used to obtain a random amplified polymorphic DNA (RAPD) marker specific for the rye chromosome arm of the 1BL.1RS translocation, which is common in many high-yielding bread wheat varieties. The RAPD-generated band was cloned and end-sequenced to allow the construction of a pair of oligonucleotide primers that PCR-amplify a DNA sequence only in the presence of rye chromatin. The amplified sequence shares a low level of homology to wheat and barley, as judged by the low strength of hybridization of the sequence to restriction digests of genomic DNA. Genetic analysis showed that the amplified sequence was present on every rye chromosome and not restricted to either the proximal or distal part of the 1RS arm. In situ hybridization studies using the amplified product as probe also showed that the sequence was dispersed throughout the rye genome, but that the copy number was greatly reduced, or the sequence was absent at both the centromere and the major sites of heterochromatin (telomere and nucleolar organizing region). The probe, using both Southern blot and in situ hybridization analyses, hybridized at a low level to wheat chromosomes, and no hybridizing restriction fragments could be located to individual wheat chromosomes from the restriction fragment length polymorphism (RFLP) profiles of wheat aneuploids. The disomic addition lines of rye chromosomes to wheat shared a similar RFLP profile to one another. The amplified sequence does not contain the RIS 1 sequence and therefore represents an as yet undescribed dispersed repetitive sequence. The specificity of the amplification primers is such that they will provide a useful tool for the rapid detection of rye chromatin in a wheat background. Additionally, the relatively low level of cross-hybridization to wheat chromatin should allow the sequence to be used to analyse the organization of rye euchromatin in interphase nuclei of wheat lines carrying chromosomes, chromosome segments or whole genomes derived from rye. PMID- 24174022 TI - Assessment of nuclear, mitochondrial and chloroplast RFLP markers in oil palm (Elaeis guineensis Jacq.). AB - A variety of DNA probes was used to screen a diverse set of oil palm accessions in order to identify markers with a utility in genotype discrimination. This survey included samples of the commercial oil palm native to Africa (Elaeis guineensis Jacq.), the closely-related South American species [E.oleifera (HBK) Cortes] and inter-specific hybrids of the two. Of 106 major chloroplast bands none showed differences between E. guineensis and E. Oleifera. Mitochondrial and ribosomal probes were more informative inter-specifically (the former allowing identification of the maternal inheritance of mitochondria) and may be useful in hybrid breeding programmes; however, they were unable to identify polymorphism within E. guineensis. In contrast, low-copy nuclear genomic clones were able to identify intra-specific variation, though in most cases they revealed a relatively small number of allelic variants. One DNA probe showed a much larger number of band variants, revealing ten patterns amongst 13 E. guineensis accessions, and should prove useful in genetic fingerprinting and evaluation of oil-palm germplasm collections. PMID- 24174023 TI - Production and genetic characterization of near-isogenic lines in the bread-wheat cultivar Alpe. AB - Two biotypes of the bread-wheat cultivar Alpe were shown to possess contrasting alleles at each of the glutenin (Glu-B1, Glu-D1, Glu-B3 and Glu-D3) and gliadin (Gli-B1 and Gli-D1) loci on chromosomes 1B and 1D. Fourteen near-isogenic lines (NILs) were produced by crossing these biotypes and used to determine the genetic control of both low-molecular-weight (LMW) glutenin subunits and gliadins by means of one-dimensional or two-dimensional electrophoresis. Genes coding for the B, C and D groups of EMW subunits were found to be inherited in clusters tightly linked with those controlling gliadins. Southern-blot analysis of total genomic DNAs hybridized to a gamma-gliadin-specific cDNA clone revealed that seven NILs lack both the Gli-D1 and Glu-D3 loci on chromosome 1D. Segregation data indicated that these "null" alleles are normally inherited. Comparison of the "null" NILs with those possessing allele b at the Glu-D3 locus showed one B subunit, seven C subunits and two D subunits, as fractionated by two-dimensional A-PAGExSDS-PAGE, to be encoded by this allele. Alleles b and k at Glu-B3 were found to code for two C subunits plus eight and six B subunits respectively, whereas alleles b and k at Gli-B1 each controlled the synthesis of two beta-gliadins, one gamma and two omega-gliadins. The novel Gli-B5 locus coding for two omega-gliadins was shown to recombine with the Gli-B1 locus on chromosome 1B. The two-dimensional map of glutenin subunits showed alpha-gliadins encoded at the Gli-A2 locus on chromosome 6A. The use of Alpe NILs in the study of the individual and combined effects of glutenin subunits on dough properties is discussed. PMID- 24174024 TI - Coupling- and repulsion-phase RAPDs for marker-assisted selection of PI 181996 rust resistance in common bean. AB - The Guatemalan black bean (Phaseolus vulgaris L.) plant introduction (PI) 181996 is resistant to all known US races of the bean rust fungus Uromyces appendiculatus (Pers. ex Pers.) Unger var. appendiculatus [syn. U. phaseoli (Reben) Wint.]. We report on two random amplified polymorphic DNA (RAPD) markers OAC20490 tightly linked (no recombinants) in coupling phase and OAE19890 linked in repulsion phase (at 6.2+/-2.8 cM) to PI 181996 rust resistance. These RAPDs, generated by single decamer primers in the polymerase chain reaction, were identified in near-isogenic bulks of non-segregating resistant and susceptible BC4F2 (NX-040*4/PI 181996) lines. Linkage of the RAPD markers was confirmed by screening 19 BC4F2 and 57 BC4F3 individuals segregating for PI 181996 resistance. Utility of the RAPDs OAC20490 and OAE19890 was investigated in a diverse group of common bean cultivars and lines. All cultivars into which the PI 181996 resistance was introgressed had the RAPD OAC20490. A RAPD similar in size to OAC20490, observed in some susceptible common bean lines, was confirmed by Southern blotting to be homologous to the RAPD OAC20490. Use of the RAPDs OAC20490 and OAE19890 in marker-assisted selection (MAS) is proposed. The coupling-phase RAPD is most useful for MAS of resistant BCnF1individuals during traditional backcross breeding. The repulsion-phase RAPD has greatest utility in MAS of homozygous-resistant individuals in F2 or later-segregating generations. PMID- 24174025 TI - Analysis of self-incompatibility interactions in 30 resynthesized Brassica napus lines. I. Fluorescence microscopic studies. AB - Thirty Brassica napus lines have been developed through interspecific hybridization of B. oleracea and B. campestris lines with defined S-allele constitutions. These lines, which represent 29 different S-allele combinations, were tested in a diallel of test-pollinations to determine the activity of the introgressed S-alleles and intergenomic dominance relationships. Some consistent trends were observed: B. oleracea S-alleles high in the dominance series (e.g. S8, S14, S29) were always active in the resynthesized B. napus lines, whereas recessive S-alleles (S2, S15) lost their activity in some test combinations. The B. campestris S-alleles were active in most cases, although 2 alleles were partially inactivated by the recessive B. oleracea allele S15. PMID- 24174026 TI - Diploidization in megagametophyte-derived cultures of the gymnosperm Larix decidua. AB - Tested haploid embryogenic lines (n=12) of Larix dedicua Mill, initiated from megagametophyte tissue were maintained on half-strength LM medium without growth regulators. The cultures were analyzed for ploidy level after 1-9 years. All lines tested were found to have doubled (2n=24) their chromosome number at the end of the experiment, though there were a few lines that still gave occasional haploid counts. Flow cytometric data of embryogenic tissue confirmed these results. Protoplasts were stained in ethidium bromide, and cultured human leucocytes and chicken erythrocytes were used as internal standards. Haploid megagametophytes from immature seeds of L. decidua and known diploid culture lines of a related hybrid (L. x eurolepis) were also analyzed by flow cytometry. Haploid reference material had 12.3-13.6 pg DNA per cell, whereas formerly haploid callus lines had an average of 25.0 pg DNA per cell. The one exception was a known, genetically unstable line of L. decidua (34.8 pg DNA per cell). The diploid cell line of L. x eurolepis had 27.6 pg DNA per cell. The results show that spontaneous diploidization of megagametophyte lines is relatively rapid and that both haploid and dihaploid lines are embryogenic in larch. PMID- 24174027 TI - Inheritance of osmotic adjustment to water stress in three grain sorghum crosses. AB - Water stress is one of the major constraints to the grain yield of sorghum in tropical and sub-tropical areas of the world. Osmotic adjustment has been widely proposed as a plant attribute that confers adaptation to water stress. The inheritance of osmotic adjustment to water stress was investigated in a series of generations derived from the three possible bi-parental crosses between two inbred sorghum lines with a high capacity for osmotic adjustment (Tx2813 and TAM422; high-OA lines) and one with a low capacity (QL27; low-OA line). Broad sense heritability on a single-plant basis was generally found to be high. Analysis of segregation ratios by the mixture method of clustering identified two independent major genes for high osmotic adjustment. The line Tx2813 possessed a recessive gene which is given the symbol oa1; the line TAM422 possessed an additive gene which is given the symbol OA2. There was some evidence that there may be other minor genes which influence the expression of osmotic adjustment in these crosses as two putative transgressive segregants, with higher osmotic adjustment than the parents, were identified from the cross between Tx2813 and TAM422. Populations of recombinant inbred lines were developed and characterised for osmotic adjustment for two of the crosses (QL27 x TAM422, low-OA x high-OA; Tx2813 x TAM422, high-oal x high-OA2). These will be used to conduct experiments which test hypotheses about the contribution of the high-osmotic-adjustment genes to the grain yield of sorghum under a range of water-stress conditions. PMID- 24174028 TI - A quantitative genetic model for mixed diploid and triploid hybrid progenies in tree breeding and evolution. AB - Interspecific hybridization has played a critical role in tree evolution and breeding. The findings of triploidy in forest trees stimulate the development of a quantitative genetic model to estimate the nature of gene action. The model is based on clonally replicated triploid progenies derived from a two-level population and individual-within-population mating design in which offspring have a double dose of alleles from the parent and a single dose of alleles from the other parent. With the same genetic assumptions of a diploid model, except non Mendelian behavior at meiosis, and the experimental variances estimated from a linear statistical model, total genetic variances in the triploid progenies are separated into additive, dominance, and epistatic components. In addition, by combining the new model with the already existing model based on disomic expression, the partitioning of additive, dominant, and epistatic variances can be obtained for a mixed diploid/triploid F1 progeny population. This paper provides an alternative technique to study the modes of quantitative inheritance for outcrossing, long-lived forest trees in which inbred lines cannot be easily generated. The accuracy for estimating gene action using this technique is discussed. PMID- 24174029 TI - Partial resistance to late blight (Phytophthora infestans) in hybrid progenies of four South American Solanum species crossed with diploid S. tuberosum. AB - Resistant genotypes of the diploid tuber-bearing South American species Solarium arnezii x hondelmannii, S. berthaultii, S. leptophyes and S. microdontum were crossed with three diploid genotypes of S. tuberosum that varied in resistance and maturity type. The progenies were field tested for 2 years for resistance to a complex race of Phytophthora infestans. A wealth of genetic variation for resistance was found in most of the progenies. At least two susceptibility groups could be distinguished in some progenies of S. microdontum. This could be explained by the presence of several major resistance genes in the wild parent and, unexpectedly, in the susceptible parent SH 82-44-111. In most of the wild parents and in the susceptible parent SH 77-114-2988 there appeared to be minor resistance genes. General combining ability effects were predominant; small specific combining ability effects were detected in some crosses of S. microdontum. Gene action appeared dominant in some crosses. PMID- 24174030 TI - Linkage information content and efficiency of full-sib and half-sib designs for gene mapping. AB - The accuracy of a genetic map depends on the amount of linkage information contained in the data set used for construction of the map. The amount of linkage information is related to the designs employed for linkage analysis. The purpose of this study was to provide general formulations for various genotyping schemes and family structures in order to evaluate the amount of linkage information in a data set. Linkage information content (LIC) was defined as the frequency of fully informative gametes, which are gametes from doubly heterozygous parents with known linkage phases. Depending on the design, LIC is based on two generations if the parental phases are determined statistically, or three generations if the parental phases are determined genetically. Different schemes were considered in deriving LIC: (1) genotyping of one parent or two parents, and (2) genotyping of two or three generation families. The LIC for a full-sib design was found to be generally greater than for a half-sib design but requires typing a large number of individuals when at least one locus has only two alleles. The efficiency of the full-sib design is reduced significantly if a sex-specific linkage map is sought. PMID- 24174031 TI - Diallel analysis for mineral element absorption in tropical adapted soybeans [Glycine max (L.) Merrill]. AB - The Brazilian tropical adapted soybeans contains, in addition to superior morphological characters, genetic factors for tolerance to cultivation in acidic, mineral-stressed soils. However, the selection process for these hindrances has been empirical, and information on the genetics of mineral element uptake by the plant is necessary. The objective of this investigation was to identify the mode of inheritance for the absorption of phosphorus, potassium, calcium, magnesium, iron, aluminium, manganese, zinc and copper in a 9 * 9 diallel cross. General combining ability (GCA) was higher than specific combining ability (SCA), with the exception of copper, manganese and zinc, indicating predominantly additive effects. The ratios of GCA/SCA varied between 3.4 (calcium) and 8.5 (magnesium). The regression of covariance (Wr) on variance (Vr) showed that the additive dominance model explained the genetic differences in this germ plasm. However, the detection of overdominance could be related to possible heterozygosity in the parental varieties for mineral absorption. Broad-sense heritability values were higher than narrow sense heritability values for aluminium, iron, potassium, calcium and magnesium, being in the range of 67.9-86.9% and 42.0-56.6%, respectively. This is an indication that soybeans can be further improved to efficient utilisation of nutrients and to tolerate toxic factors in the soil. PMID- 24174032 TI - Physical distribution of translocation breakpoints in homoeologous recombinants induced by the absence of the Ph1 gene in wheat and triticale. AB - The physical distribution of translocation breakpoints was analyzed in homoeologous recombinants involving chromosomes 1A, 1B, 1D of wheat and 1R of rye, and the long arms of chromosome 7S of Aegilops speltoides and 7A of wheat. Recombination between homoeologues was induced by removal of the Ph1 gene. In all instances, translocation breakpoints were concentrated in the distal ends of the chromosome arms and were absent in the proximal halves of the arms. The relationship between the relative distance from the centromere and the relative homoeologous recombination frequency was best explained by the function f(x)=0.0091e(0.0592x). The pattern of recombination in homoeologous chromosomes was essentially the same as in homologues except that there were practically no double exchanges. Among 313 recombinant chromosomes, only one resulted from a double crossing-over. The distribution of translocation breakpoints in translocated arms indicated that positive chiasma interference operated in homoeologous recombination. This implies that the reduction of the length of alien chromosome segments present in translocations with wheat chromosomes may be more difficult than the production of the original recombinants. PMID- 24174033 TI - A specific oligonucleotide of the 5S rDNA spacer and species-specific elements identify symmetric somatic hybrids between Solanum tuberosum and S. pinnatisectum. AB - The nucleotide sequences of the 5S rRNA genes (5S rDNA) of two Solanum tuberosum breeding lines (R1 and B15) and of the Mexican wild species S. pinnatisectum were determined and compared with each other and to the 5S rDNA of other Solanaceae species (Lycopersicon esculentum, Nicotiana rustica and Petunia hybrida). The 5S rDNA repeats of the Solanum species are 324-329 bp in length, and they exhibit 91 95% sequence identity. Sequence variability is mainly located in a short region of the spacer separating the 5S rRNA coding regions. A synthetic 28-mer oligonucleotide constructed according to this region can be used as a specific hybridization probe to distinguish symmetric somatic hybrids between S. tubersosum breeding line B15 and S. pinnatisectum produced by protoplast fusion. Interestingly, the two Solanum breeding lines R1 and B15 differ also in this spacer region. PMID- 24174034 TI - Mapping loci controlling vernalization requirement and flowering time in Brassica napus. AB - Rapeseed cultivars (Brassica napus L.) can be classified into annual and biennial groups according to their requirement for vernalization in order to induce flowering. The genetic control of these phenotypic differences is not well understood, but this information could be valuable for the design of breeding approaches to accelerate rapeseed improvement. In order to map loci controlling this variation, a doubled haploid population, derived from a cross between annual and biennial cultivars, was evaluated for vernalization requirement and days-to flowering in a replicated field experiment using three treatments: no vernalization, 4 weeks of vernalization and 8 weeks of vernalization. A linkage map of 132 RFLP loci was used to locate loci controlling these traits. Marker segregation in one region of linkage group 9 was strongly associated with the annual/biennial growth habit in the unvernalized treatment and with days-to flowering in all three treatments. Two other regions with smaller effects on days to-flowering were also identified. PMID- 24174035 TI - Genetics of size and growth rate through sexual maturity in freshwater-reared coho salmon (Oncorhynchus kisutch). AB - Genetic parameters of size through sexual maturity have been relatively unexplored for Pacific salmon. In this study, individually tagged coho salmon were raised in freshwater, and the heritabilities of size and growth rate were estimated at several intervals between 13 and 24 months of age (spawning). Heritability estimates for size were moderate to high from 13 to 19 months of age, ranging from 0.36 to 0.50, and lower from 21 months to spawning at 24 months, ranging from 0.17 to 0.32. Heritabilities of specific growth rates estimated over 3-month intervals were moderate from 16 to 21 months of age, ranging from 0.21 to 0.34. Genetic and phenotypic correlations between sizes measured at different ages were moderate to high, ranging from about 0.7 to 1.0. Correlations between growth rate and size indicated that the larger fish were the fastest growing between 16 and 19 months of age and were slower growing between 19 and 21 months of age. PMID- 24174036 TI - Generation of PCR-based markers for the detection of rye chromatin in a wheat background. AB - Oligonucleotide primers were developed to detect the presence of four rye sequences using a PCR assay. These assays give a rye-specific signal from wheat DNA template which contains various rye chromosomes or chromosome segments. The sequences identified were associated with the nucleolar organiser region, the 5S Rrna-R1 locus, the telomere, and a widely dispersed, rye-specific repetitive element Ris-1. The primers amplified from the well-established loci Nor-R1 and 5S Rrna-R1 on rye chromosome arm 1RS, and also located a 5s-Rrna locus on chromosome 3R. The telomere-associated sequence was present on every rye chromosome, and was also present, at a low copy number, in both wheat and barley. These assays will be particularly useful for introgression programmes aimed at reducing the rye content of the 1BL.1RS wheat-rye translocation. When multiplexed, the primers will enable a rapid, simultaneous assay for a number of distinct rye loci, which can be derived from a small portion of mature endosperm tissue. PMID- 24174037 TI - Evidence for nuclear-cytoplasmic incompatibility between Allium fistulosum and A. cepa. AB - An F2 population (Allium fistulosum x A. cepa) of 20plants, 10 BC1,[(A. fistulosum x A. cepa) x A. cepa], and 50 BC2 plants, [(A. fistulosum x A. cepa) x A. cepa] x A. cepa were studied cytogenetically and characterized for four isozyme alleles plus various morphological characteristics. All of the progenies were in A. fistulosum (the bunching onion) cytoplasm. In the F2 population we observed non-random chromosomal and allelic segregation, suppression of bulb onion allelic expression, and abnormalities in mitosis and meiosis. Most BC2 plants resembled A. cepa (the bulbing onion) morphologically, but anthers, filaments, pistils, and petals were abnormal. Only 3 plants, and these were most nearly like the F1 hybrid morphologically, produced any seeds.The data and observations support the hypothesis of nuclear-cytoplasmic incompatibility interactions between the bunching and bulb onion species. PMID- 24174038 TI - Enantioselective protonation of alkenyl trifluoroacetates catalyzed by chiral tin methoxide. AB - Go catalytic! A catalytic enantioselective protonation of alkenyl trifluoroacetates was achieved by using an in situ generated chiral tin bromide methoxide as the chiral catalyst in the presence of methanol. Optically active ketones containing a tertiary stereogenic center at the alpha-position were obtained with enantioselectivities of up to 94 % ee. PMID- 24174040 TI - A theory for the effects of neutral carriers such as the macrotetralide actin antibiotics on the electric properties of bilayer membranes. AB - To develop a quantitiative theoretical treatment for the effects of neutral macrocyclic antibiotics on the electrical properties of phospholipid bilayer membranes, this paper proceeds from the known ability of such molecules to form stoichiometric, lipid-soluble complexes with cations and deduces the electrical properties that a simple organic solvent phase would have if it were made into a membrane of the thinness of the phospholipid bilayer. In effect, we postulate that the essential barrier to ion movement across a bilayer membrane is its liquid-like hydrocarbon interior and that the neutral macrocyclic antibiotics bind monovalent cations and solubilize them in the membrane as mobile positively charged complexes. Using the Poisson-Boltzmann equation to describe the equilibrium profile of the electrical potential, it is shown that an excess of the positive complexes over all the other ions is expected in the membrane as a net space charge for appropriate conditions of membrane thickness and values of the partition coefficients of the various ionic species and without requiring the presence of fixed charges. Describing the fluxes of these complexes by the Nernst Planck equation and neglecting the contribution to the electric current of uncomplexed ions, theoretical expressions are derived for the membrane potential in ionic mixtures, as well as for the limiting value of the membrane conductance at zero current when the membrane is interposed between identical solutions. The expressions are given in terms of the ionic activities and antibiotic concentrations in the aqueous solutions so as to be accessible to direct experimental test. Under suitable experimental conditions, the membrane potential is described by an equation recognizible as the Goldman-Hodgkin-Katz equation, in which the permeability ratios are combinations of parameters predicted from the present theory to be independently determinable from the ratio of membrane conductances in single salt solutions. Since this identity between permeability and conductance ratios is expected also for systems obeying the "Independence Principle" of Hodgkin and Huxley, the applicability of this principle to membranes exposed to antibiotics is discussed, and it is shown that this principle is compatible with the permeation mechanism proposed here. PMID- 24174041 TI - The cation permeability of erythrocytes in low ionic strength media of various tonicities. AB - The steady state passive efflux of salt from human red blood cells was measured in various low ionic strength media in which the osmotic pressure ranged from 200 to 600 milliosmolar. Sucrose was used as the nonpenetrating nonelectrolyte. If the flux is plotted against the log of the salt concentration, the data for each tonicity can be fitted by three straight-line segments separated by two sharp inflections, one at low external salt concentrations (0.1 to 0.3mM), confirming observations of LaCelle and Rothstein, and a second at higher salt concentrations (20 to 50 mM). As the osmolarity of the medium is increased, the inflection in every case seems to be uniquely determined by the membrane potential calculated from the Nernst equation with use of the chloride ratio. One inflection occurs at about 45 mV and the second at 170 mV in experiments at five different tonicities. Calculations from the Goldman equation suggest that the inflections represent potential-dependent changes to new permeability states. The osmotic pressure of the medium also influences the permeability. The coefficient is systematically reduced as the osmotic pressure is increased. PMID- 24174042 TI - Proton permeability and the regulation of potassium permeability in mitochondria by uncoupling agents. AB - The addition of agents that uncouple electron transfer from energy conservation (uncouplers) to state 4 mitochondria causes the following ion movements: K(+) is extruded from the mitochondria in association with phosphate and possibly other anions, but not H(+). Endogenous Ca(++) is extruded from the mitochondria, and H(+) moves in to counter-balance the Ca(++) movement; some phosphate movement may be associated with Ca(++) extrusion. The rate and extent of K(+) extrusion induced by uncoupler is dependent on the concentrations of external phosphate and divalent ions. Phosphate induces K(+) extrusion, while Mg(++) and Mn(++) inhibit it. TheV max of K(+) transport is 300 MUmoles K(+)/g protein per min. The K m for FCCP-induced potassium extrusion is 0.25 MUM at pH 7.4. The inhibitory effect of Mg(++) is noncompetitive with respect to uncoupler concentration but competitive with respect to phosphate concentration. The experimental evidence does not support the existence of high H(+) permeability in the presence of uncoupler. A correlation is observed between the rate of K(+) extrusion and the energy reserves supplied from the high energy intermediate. The action of uncoupler in inducing K(+) permeability is considered to arise through its action in depleting the energy reserves of mitochondria rather than through a specific activating effect of permeability by the uncoupler itself. The relationship of membrane potential to regulation of K(+) permeability is discussed. PMID- 24174043 TI - The cellular specificity of the effect of vasopressin on toad urinary bladder. AB - Phase and electron micrographs of toad bladders were obtained following dilution of bathing media in the presence and absence of vasopressin. Dilution of the mucosal medium alone resulted in no morphologic changes. Subsequent addition of vasopressin produced an increase in the cell volume of the granular cells, manifested by some or all of the following changes: increased area of granular cell profiles as observed in sections, rounding of the cell nucleus, displacement of the two components of the nuclear envelope, loss of nuclear heterochromatin, sacculation of the endoplasmic reticulum and the Golgi apparatus, and reduction in the electron density of the cell cytoplasm. No such morphologic changes were noted in the other cell types comprising the mucosal epithelium - the mitochondria-rich, the goblet, and the basal cells. On the other hand, dilution of the serosal bathing medium in the absence of vasopressin caused a marked increase in the cell volume of all these cell types. The results demonstrate that the action of vasopressin to enhance bulk water flow across toad bladder is exerted specifically on the apical surface of the granular cells. It is suggested that the hormonal effect on sodium transport may also be limited to the granular cells. The route of osmotic water flow and the possible role of the other mucosal epithelial cells is discussed. PMID- 24174044 TI - Contributions of unstirred-layer effects to apparent electrokinetic phenomena in the gall-bladder. AB - Passage of electric current across rabbit gall-bladder, which is preferentially permeable to cations, causes water flow towards the negative electrode, as expected for electroosmosis in a cation-selective membrane. Current passage also causes development of a "polarization potential difference", i.e. a transepithelial potential difference (p.d.) which transiently remains after cessation of current flow and decays back to zero with a half-time of 22 to 90 sec. The polarization p.d. is due to current-induced local changes of salt concentration in unstirred layers, mainly at the serosal face of the epithelium. These changes originate through the so-called transport-number effect. Calculation shows that much of the observed current-induced water flow represents an osmotic flow due to these local concentration changes, rather than representing true electroosmosis. By implication, a large component of streaming potentials in the gall-bladder is a boundary diffusion potential, owing to water flow producing local changes of salt concentration in unstirred layers. PMID- 24174045 TI - Intercellular adhesion : I. A quantitative assay for measuring the rate of adhesion. AB - A quantitative procedure for determining the early kinetics of cell aggregation (adhesion) is described. The cells used for this study were obtained by dissociation of 8-day-old embryonic chicken neural retina with crude trypsin. The method is based on determining the decrease in single cells in an aggregating population with the Coulter electronic particle counter. A variety of experiments show that the method is reproducible and capable of detecting relatively small changes in the rate of aggregation. Using a number of criteria, the loss of single cells from the population with increasing time of incubation was shown to result from the formation of aggregates, and not from other phenomena such as cell death or changes in cell permeability. The intercellular adhesions formed under these conditions were stable to mechanical shear and to ethylenediaminetetraacetate, and were partially resistant to crude trypsin. The logarithm10 of the number of single cells in the population was found to be directly related to the time of incubation. The slope of the resultant straight lines could be used as a measure of the rate of aggregation. No lag in aggregation was demonstrable under the standard assay conditions. the rate was affected by the initial cell density, speed of rotation during aggregation, temperature, and by Ca(2+) and Mg(2+). It was not affected by inhibitors of protein synthesis, metabolic inhibitors, ATP, ADP, cyclic-AMP, or horse serum at 37 degrees C. The quantitative method for determining the initial rate of adhesion should be applicable to studies on the chemistry of this process. PMID- 24174046 TI - Intercellular adhesion : II. The purification and properties of a horse serum protein that promotes neural retina cell aggregation. AB - When 8-day-old embryonic chicken neural retina is dissociated, the resulting single cells adhere to each other at a rapid rate at 37 degrees C, and slowly at 5 degrees C. However, the addition of horse serum substantially accelerates the rate of aggregation at 5 degrees C, although it shows no effect at 37 degrees C; the rate at 37 degrees C exceeded the maximum rate at 5 degrees C (i.e., in the presence of excess horse serum). The kinetics of the horse serum effect were investigated, and, based on these results, an assay was devised for the active component in the serum. The active protein, termed "neural retina aggregating protein" (NRP), was purified 48-fold from the serum, and at this stage appears close to homogeneity. The rate of aggregation of neural retina cells is significantly stimulated by adding 1 MUg of purified NRP per ml. Purified NRP shows certain properties in common with horse macroglobulins (horse Immunoglobulin M, IgM), but there are also some important differences. For example, it cross-reacts with antibodies to horse IgM, it can be reduced to subunits with thiols, and it is of high molecular weight (about 1.6*10(6)). However, NRP has a higher sedimentation value than IgM (22.4 S compared to 19 S), and purified IgM does not increase the rate of aggregation of neural retina cells at 100-fold the concentration of NRP required for optimum activity. Inhibitory activity was not detected at any stage of the purification of NRP from horse serum. However, other sera (chick and calf) were shown to reduce the normal slow rate of aggregation at 5 degrees C and to inhibit the effect of NRP. Some preliminary studies indicate NRP may be specific for neural retina cells. For example, the rate of aggregation of 5-day-old embryonic limb bud cells is unaffected by concentrations of NRP that are optimal for neural retina cells. PMID- 24174047 TI - Physiological and morphological effects of poly-L-lysine on the toad bladder. AB - Studies were carried out on the morphological and physiological effects of the binding of poly-L-lysine (polylysine; mol wt?120,000) to the apical surface membrane of the toad bladder epithelium. Paired hemibladders were mounted in chambers and exposed to polylysine concentrations of 2, 8, or 80 MUg/ml in the mucosal medium for periods of up to 2 hr. Radioautographs prepared after addition of(3)H-polylysine showed that the polymer was localized to the apical surface of the epithelium and in dense subapical masses in lysed cells. No significant morphological changes were seen in the epithelium by light or electron microscopy at polymer concentrations of 2 and 8 MUg/ml. Exposure to 80 MUg/ml lysed many epithelial cells, i.e., converted them to slightly swollen ghosts with pycnotic nuclei and empty cytoplasm, except for remnants of mitochondria and vesicular fragments of the endoplasmic reticulum. All of the superficial epithelial cells were lysed in stretched hemibladders. The plasma membranes of the lysed cells were uniformly thickened, and their intercellular attachments remained intact. In contracted hemibladders, lysed and normal-appearing cells were interspersed, and the number of lysed cells in the epithelium was proportional to the duration of exposure to high concentrations of the polycation. In parallel experiments, the effects of varying concentrations of polylysine on active Na(+) transport and osmotic flow of water were measured with and without vasopressin, aldosterone, or amphotericin B in the media. At a concentration of 2 MUg/ml of polylysine in the mucosal bathing solutions, no change in the basal rate of Na(+) transport was seen, and the response to vasopressin was unimpaired. At a concentration of 8 MUg/ml, there was a significant but small fall in electrical potential difference (PD) and in short-circuit current (SCC) and no interference with the response to vasopressin. At a concentration of 80 MUg/ml, there was a rapid curvilinear fall in SCC to 54+/-4% of the baseline value and in PD to 21+/-3% of the baseline value in a 2-hr period. Simultaneous unidirectional isotope flux studies with(22)Na and(24)Na showed a more than twofold increase in the serosal to mucosal flux but no discrepancy between net flux and SCC. Despite the inhibitory action of the polymer, the stimulatory response in Na(+) transport to vasopressin, aldosterone, and amphotericin B was relatively preserved in that the percentage increase in SCC was the same in the polymer-treated and control hemibladders. The polycation produced a small but significant increase in osmotic water flow, and striking and irreversible inhibition of the water-flow response to vasopressin. PMID- 24174048 TI - The M-antigen in HK and LK sheep red cell membranes. AB - Red cells of all high-potassium-type (HK) sheep and of more than one half of all low-potassium-type (LK) sheep contained the M-antigen and were hemolyzed by iso immune anti-M antiserum in presence of a guinea pig serum complement. It was characteristic for the hemolysis of HK red cells by the M-antiserum the all HK cells were ultimately hemolyzed at suboptimal antibody concentrations, provided the time of incubation at 37 degrees C was sufficiently long. Thus, the M antigen appears to be expressed on all red cells of an individual HK sheep. The M antibody was absorbed by HK red cells and their membranes with a high affinity, whereas M-negative LK red cells and their membranes did not bind the antibody. The ratio of the number of antibody units absorbed per cell or membrane to the number of antibody units required for lysis approached unity. The amount of antibody absorbed per membrane was unaffected by ouabain in the presence of ATP, Mg(++), Na(+), and K(+). The M-antigen activity depends on the integrity of the red cell membrane and was not detectable after lyophilization of HK membranes or in the membrane protein solubilized by n-butanol. The major M-antibody activity was found among the high molecular weight plasma proteins and may be attributed to the beta2 M globulins. Heterogeneity within the antibody fraction cannot be excluded since some hemolytic activity was detected in a chromatographic fraction containing predominantly gamma-globulin. The relationship between the M-antigen and the Na(+)-K(+) transport system in sheep red cell membranes is discussed. PMID- 24174049 TI - An estimate of the salt concentration in the lateral intercellular spaces of rabbit gall-bladder during maximal fluid transport. AB - The ability of the gall-bladder to transport water between identical bathing solutions depends on active NaCl transport, which is thought to maintain the salt concentration in the lateral intercellular spaces above bathing solution levels and thus to create a local osmotic gradient. The mean value of this gradient has been estimated by an electrical procedure, based on measuring the small diffusion potential resulting from this gradient and from the preferential cation permeability of the gall-bladder. The electrical potential difference (p.d.) in maximally transporting rabbit gall-bladders is 1.4 mV, mucosal-solution positive to serosal solution. This p. d. is reversibly abolished or greatly reduced by six procedures which abolish or greatly reduce fluid transport (low temperature, replacement of Cl(-) by SO 4 (--) , replacement of Cl(-) and HCO 3 (-) by SO 4 (- ) , replacement of Na(+) by choline, removal of HCO 3 (-) , and metabolic poisoning). The p. d. is increased by symmetrical partial replacement of NaCl by sucrose, which is expected to increase the salt concentration gradient between the lateral spaces and the bathing solutions. Since the transport mechanism of the gall-bladder is a neutral NaCl pump that cannot produce a p. d. directly, it is concluded that the observed p. d. is the expected diffusion potential. From this diffusion potential and from the measured value of a diffusion potential resulting from a known NaCl concentration gradient, the mean concentration of NaCl in the lateral spaces is calculated to be of the order of 10MM above the bathing solution value. Comparison of the external osmotic gradient required to stop water flow with the p. d. recorded under this condition of zero flow supports the validity of interpreting the p.d. in this fashion as a measure of the excess local salt concentration. PMID- 24174050 TI - Induction of intracellular ATP synthesis by extracellular ferricyanide in human red blood cells. AB - Human red blood cells rapidly convert extracellular ferricyanide into extracellular ferrocyanide. The reaction is enhanced by the addition of a substrate, adenosine. This increase of the rate of reaction is abolished by iodoacetate. The results indicate there is a flow of electrons across the membrane of metabolizing red blood cells. The reduction of extracellular ferricyanide is accompanied by the formation of intracellular ATP. The effect of an uncoupler and of inhibitors of oxidative phosphorylation on this reaction was studied under conditions where the natural rate of ATP synthesis was slightly reduced by 10(-4) moles/liter iodoacetate. ATP formation was found to be inhibited by DNP, cyanide, and, to a lesser extent, by azide. Amytal is ineffective. Ferrocyanide enhances ATP breakdown. The action of DNP requires the presence of the cell membrane. It can probably not be related to a stimulation of the membrane ATPase of Laris and Letchworth, nor can it be explained on the basis of Mitchell's chemiosmotic hypothesis by effects on the passive permeability of the erythrocyte membrane to H(+) or alkali ions. In contrast to methylene blue and other oxidants, ferricyanide does not stimulate oxygen consumption in adult red blood cells. PMID- 24174051 TI - The effect of 2,4-dinitrophenol on the properties of thin phospholipid films. AB - The properties of a system consisting of a thin phospholipid film separating two electrolyte solutions containing 1MM 2,4-dinitrophenol have been studied. Both the variation of electrical conductance as a function of pH, keeping the pH the same on both sides of the membrane, and the nonlinear variation of electrical potential difference as a function of pH difference across the membrane have been explained in terms of lipid-soluble complexes of the typeXP 2 (-) whereX is a cation andP dinitrophenate. The maximum conductance was found to be 1.4*10(-5) mhos cm(-2) at pH 4.2. PMID- 24174052 TI - The action of phloridzin and sugars on (Na(+)-K (+))-Activated ATPase. AB - The action of phloridzin and simple sugars on the (Na(+)-K(+))-activated ATPase obtained from rabbit kidney has been studied. Phloridzin 10(-4)to 10(-3) M was found to inhibit the enzyme at Na(+):K(+) ratios less than optimal for enzyme activity, whereas stimulation was noted at Na(+):K(+) ratios greater than optimal for enzyme activity. Some sugars in concentrations of 0.1 to 0.5M were found to inhibit the (Na(+)-K(+))-activated ATPase. The sugars and related compounds could be ranked according to decreasing inhibitory potency as: D-mannose>D-arabinose, D xylose>L-xylose>D-glucose>fructose, L-arabinose>D-galactose, myo-inositol, mannitol=0. No stimulatory effect or interaction with K(+) was found with these compounds. The action of these substances on the (Na(+)-K(+))-activated ATPase suggests an interaction of actively transported sugars and sodium-potassium transport at the level of the sodium pump that may be important in the biological coupling of the two systems. PMID- 24174053 TI - A transition state theory approach to the kinetics of conductance changes in excitable membranes. AB - The kinetics of ionic current mechanisms in excitable membranes are analyzed. It is assumed that there are voltage-dependent reactions occurring in the membrane which are independent of the flow of ionic current. The experimental evidence for this assumption is reviewed in the light of more recent results on the kinetics of conductance changes in cardiac membranes. Rate equations are then obtained using transition state theory and assuming that each reaction is rate limited by only one energy barrier. These equations give simple exponential functions for the voltage dependence of the rates. More complex functions may be obtained by assuming that more than one energy barrier is rate limiting. The single-barrier equations are used to estimate the energies of formation of the transition state. In most cases, the entropy of formation is positive but there is no systematic order in the estimated enthalpies. These results are contrasted with those for the ion permeation process itself which normally has a negative entropy of activation. This contrast reinforces the assumption that the reactions controlling membrane permeability are distinct from the ion permeation process itself. The significance of the positive entropy of formation of the transition state in the permeability reactions is discussed, and it is suggested that the membrane structures underlying these reactions may change their degree of hydration during the formation of the transition state. PMID- 24174054 TI - Intercellular communication and tissue growth : IV. Conductance of membrane junctions of normal and cancerous cells in culture. AB - Epithelial cells of normal rat (adult) liver and hamster embryo in tissue culture communicate through membrane junctions: the membrane regions of cell contact are highly ion-permeable. Cancerous counterparts of these cells, cells from Morris' and Reuber's liver tumors and from x-ray-transformed embryo cultures, do not communicate under the same experimental conditions. These cells also fail to communicate with contiguous normal cells. Cancerous fibroblastic cells from a variety of tissues, including cells transformed by virus, x-radiation and chemicals, communicate as well as their normal counterparts; this is so for long- and short-term cell cultures. Communication in some fibroblastic cells is sensitive to components of blood serum: normal and transformed hamster embryo fibroblasts, which communicate when cultured in medium containing fetal calf serum, appear to lose communication in medium containing calf serum; the converse holds for hamster (adult) fibroblasts and 3T3 cells. PMID- 24174055 TI - The effects of the macrotetralide actin antibiotics on the equilibrium extraction of alkali metal salts into organic solvents. AB - In order to clarify the mechanism by which neutral molecules such as the macrotetralide actin antibiotics make phospholipid bilayer membranes selectively permeable to cations, we have studied, both theoretically and experimentally, the extraction by these antibiotics of cations from aqueous solutions into organic solvents. The experiments involve merely shaking an organic solvent phase containing the antibiotic with aqueous solutions containing various cationic salts of a lipid-soluble colored anion. The intensity of color of the organic phase is then measured spectrophotometrically to indicate how much salt has been extracted. From such measurements of the equilibrium extraction of picrate and dinitrophenolate salts of Li, Na, K, Rb, Cs, and NH4 into n-hexane, dichloromethane, and hexane-dichloromethane mixtures, we have verified that the chemical reactions are as simple as previously postulated, at least for nonactin, monactin, dinactin, and trinactin. The equilibrium constant for the extraction of each cation by a given macrotetralide actin antibiotic was also found to be measurable with sufficient precision for meaningful differences among the members of this series of antibiotics to be detected. It is noteworthy that the ratios of selectivities among the various cations were discovered to be characteristic of a given antibiotic and to be completely independent of the solvent used. This finding and others reported here indicate that the size and shape of the complex formed between the macrotetralide and a given cation is the same, regardless of the species of cation bound. For such "isosteric" complexes, notable simplifications of the theory become possible which enable us to predict not only the electrical properties of a membrane made of the same solvent and having the thinness of the phospholipid bilayer but also, and more importantly, the electrical properties of the phospholipid bilayer membrane itself. These predictions will be compared with experimental data for phospholipid bilayer membranes in the accompanying paper. PMID- 24174056 TI - The effects of the macrotetralide actin antibiotics on the electrical properties of phospholipid bilayer membranes. AB - This paper, the last in a series of three, characterizes the electrical properties of phospholipid bilayer membranes exposed to aqueous solutions containing nonactin, monactin, dinactin, and trinactin and Li(+), Na(+), K(+), Rb(+), Cs(+), and NH 4 (+) ions. Not only are both the membrane resistance at zero current and the membrane potential at zero current found to depend on the aqueous concentrations of antibiotic and ions in the manner expected from the theory of the first paper, but also these measurements are demonstrated to be related to each other in the manner required by this theory for "neutral carriers". To verify that these antibiotics indeed are free to move as carriers of cations, cholesterol was added to the lipid to increase the "viscosity" of the interior of the membrane. Cholesterol decreased by several orders of magnitude the ability of the macrotetralide antibiotics to lower the membrane resistance; nevertheless, the permeability ratios and conductance ratios remained exactly the same as in cholesterolfree membranes. These findings are expected for the "carrier" mechanism postulated in the first paper and serve to verify it. Lastly, the observed effects of nonactin, monactin, dinactin, and trinactin on bilayers are compared with those predicted in the preceding paper from the salt-extraction equilibrium constants measured there; and a close agreement is found. These results show that the theory of the first paper satisfactorily predicts the effects of the macrotetralide actin antibiotics on the electrical properties of phospholipid bilayer membranes, using only the thermodynamic constants measured in the second paper. It therefore seems reasonable to conclude that these antibiotics produce their characteristic effects on membranes by solubilizing cations therein as mobile positively charged complexes. PMID- 24174057 TI - The relationship of protein and lipid synthesis during the biogenesis of mitochondrial membranes. AB - Rat liver mitochondria were fractionated into inner and outer membrane components at various times after the intravenous injection of(14)C-leucine or(14)C glycerol. The time curves of protein and lecithin labeling were similar in the intact mitochondria, the outer membrane fraction, and the inner membrane fraction. In rat liver slices also, the kinetics of(3)H-phenylalanine incorporation into mitochondrial KCl-insoluble proteins was identical to that of(14)C-glycerol incorporation into mitochondrial lecithin. These results suggest a simultaneous assembly of protein and lecithin during membrane biogenesisThe proteins and lecithin of the outer membrane were maximally labeledin vivo within 5 min after injection of the radioactive precursors, whereas the insoluble proteins and lecithin of the inner membrane reached a maximum specific acitivity 10 min after injection.Phospholipid incorporation into mitochondria of rat liver slices was not affected when protein synthesis was blocked by cycloheximide, puromycin, or actinomycin D. The injection of cycloheximide 3 to 30 min prior to(14)C-choline did not affect thein vivo incorporation of lecithin into the mitochondrial inner or outer membranes; however treatment with the drug for 60 min prior to(14)C-choline resulted in a decrease in lecithin labeling. These results suggest that phospholipid incorporation into membranes may be regulated by the amount of newly synthesized protein available.When mitochondria and microsomes containing labeled phospholipids were incubated with the opposite unlabeled fractionin vitro, a rapid exchange of phospholipid between the microsomes and the outer membrane occurred. A slight exchange with the inner membrane was observed. PMID- 24174058 TI - Cyclodepsipeptides as chemical tools for studying ionic transport through membranes. AB - This paper reports a study of the chemistry of valinomycin, enniatins and related membrane-active depsipeptides that increase alkali metal ion permeability of model and biological membranes. The antimicrobial activity of these compounds and their effect on membranes has been correlated with their cation-complexing ability. The complexing reaction has been studied by spectropolarimetric and conductimetric methods. Nuclear magnetic resonance, optical rotatory dispersion, and infrared spectrophotometric studies have revealed the coexistence of conformers of the cyclodepsipeptides in solution and have led to elucidation of the spatial structure of valinomycin, enniatin B and their K(+) complexes. The effect of the conformational properties of the cyclodepsipeptides on their complexation efficiency and selectivity, surface-active properties and behavior towards phospholipid monolayers, bimolecular phospholipid membranes and a number of biological membrane systems has been ascertained. The studies have clearly shown the feasibility of using cyclodepsipeptides with predetermined structural and conformational parameters as chemical tools for membrane studies. it is suggested that the principle of conformation-dependent cation binding through iondipole interactions may possibly lie at the basis of the mode of action of systems governing the natural ion permeability in biological membranes. PMID- 24174059 TI - Measurement of axonal membrane conductances and capacity by means of a varying potential control voltage clamp. AB - A new mode of voltage clamping in the squid giant axon is introduced and its advantages are analyzed, tested, and utilized to investigate membrane conductances and capacity. This method replaces the constant command potentials of the standard voltage clamp with potentials which vary with time. Some of the advantages in using the varying potential clamp are: (1) slowly varying potentials generate practically pureI K ; (2) rapidly varying potentials generate practically pureI Na; (3) triangular waves generate, under proper conditions, pure capacity currents and easy-to-analyze leakage currents; (4) the method gives direct, on-line display of sodium or potassium I-V characteristics within milliseconds; (5) it enables rapid and accurateE Na andE K determinations; and (6) it enables simple and accurate determination ofC m. The method was utilized to study the effects of various ions on membrane conductances and the effects of ionic composition, ionic strength, and temperature on membrane capacity. Membrane capacity was found to be practically independent of frequency in the 200 to 2,000 Hz range. Replacement of external sodium by Ca(++), by impermeable Tris(+), or even by dextrose or sucrose (low ionic-strength solutions) had negligible effects onC m.C m showed a small, positive temperature coefficient of 1.39% per degrees C in the 3 to 21 degrees C range, and little change with temperature in the 20 to 40 degrees C range. Above 40 degrees C, bothC m andg L increased considerably with temperature. PMID- 24174060 TI - Preparation and properties of thyroid cell membranes. AB - Calf and human thyroids have been disrupted by nitrogen microcavitation, and the thyroid membranes prepared by repeated centrifugation in low ionic strength buffers. Two classes of membranes were prepared by centrifugation on a discontinuous gradient of ficoll. A lighter fraction was comprised of somewhat larger vesicles; they were higher in Na(+)-K(+)-activated ATPase, phosphodiesterase, and 5'-nucleotidase than was the heavier fraction. The heavier fraction had a higher nicotinamide adenine nucleotide dehydrogenase-diaphorase activity. Thus the lighter fraction appears to have been enriched in fragments derived from the plasma membrane. PMID- 24174061 TI - Membrane changes in yeast cells caused by sulfhydryl reagents and accompanied by a selective release of sugar. AB - Iodoacetic acid or N-ethylmaleimide included in cell suspensions during measurements of sorbose exit from yeast cells caused sorbose efflux to occur at a uniform rate in contrast to the usual two-phase exit. Cells pretreated with these agents were still capable of sugar uptake, but the entire efflux now occurred at the usual initial rate. Microscopically, the vacuoles of treated cells were observed to be altered or disrupted. Vacuolar effects occurred before methylene blue was able to penetrate the external cell membrane and stain the cells. Vacuoleless cells also allowed a single rate of sorbose efflux. The selective effect upon intracellular membranes is interpreted as a disruption of the boundaries of an internal sugar compartment with the result that sugar exits from the cell at a rate controlled only by the external membrane. PMID- 24174062 TI - Bioaccumulation of trace mercury in trophic levels of benthic, benthopelagic, pelagic fish species, and sea birds from Arvand River, Iran. AB - In this study, concentration of mercury was determined in the trophic levels of benthic, benthopelagic, pelagic fish species, and river birds from Arvand River, located in the Khuzestan province in the lowlands of southwestern Iran at the head of the Persian Gulf. The order of mercury concentrations in tissues of the fish species was as follows: liver>gill>muscle and in tissues of the kingfisher species was as follows: feather>liver>kidney>muscle. Therefore, liver in fish and feather in kingfisher exhibited higher mercury concentration than the other tissues. There was a positive correlation between mercury concentrations in fish and kingfisher species with size of its food items. We expected to see higher mercury levels in tissues of female species because they are larger and can eat larger food items. The results of this study show that the highest mean mercury level were found in the kingfisher (Anas crecca), followed by benthic (Epinephelus diacanthus), benthopelagic (Chanos chanos), and pelagic fish (Strongylura strongylura). Mean value of mercury in fish species, S. strongylura were (0.61 MUg g(-1) dry weight), C. chanos (0.45 MUg g(-1) dry weight), E. diacanthus (0.87 MUg g(-1) dry weight), and in kingfisher species A. crecca was (2.64 MUg g(-1) dry weight). Significant correlation between mercury concentration in fish and kingfisher may be related to high variability of mercury in the fish. PMID- 24174063 TI - Interstitial fluid flow in canaliculi as a mechanical stimulus for cancellous bone remodeling: in silico validation. AB - Cancellous bone has a dynamic 3-dimensional architecture of trabeculae, the arrangement of which is continually reorganized via bone remodeling to adapt to the mechanical environment. Osteocytes are currently believed to be the major mechanosensory cells and to regulate osteoclastic bone resorption and osteoblastic bone formation in response to mechanical stimuli. We previously developed a mathematical model of trabecular bone remodeling incorporating the possible mechanisms of cellular mechanosensing and intercellular communication in which we assumed that interstitial fluid flow activates the osteocytes to regulate bone remodeling. While the proposed model has been validated by the simulation of remodeling of a single trabecula, it remains unclear whether it can successfully represent in silico the functional adaptation of cancellous bone with its multiple trabeculae. In the present study, we demonstrated the response of cancellous bone morphology to uniaxial or bending loads using a combination of our remodeling model with the voxel finite element method. In this simulation, cancellous bone with randomly arranged trabeculae remodeled to form a well organized architecture oriented parallel to the direction of loading, in agreement with the previous simulation results and experimental findings. These results suggested that our mathematical model for trabecular bone remodeling enables us to predict the reorganization of cancellous bone architecture from cellular activities. Furthermore, our remodeling model can represent the phenomenological law of bone transformation toward a locally uniform state of stress or strain at the trabecular level. PMID- 24174064 TI - Suppression of the invasive potential of highly malignant tumor cells by KIOM-C, a novel herbal medicine, via inhibition of NF-kappaB activation and MMP-9 expression. AB - KIOM-C, a novel herbal formula, was recently reported to be effective for treating pigs suffering from porcine circovirus-associated disease (PCVAD). In addition, administration of KIOM-C promoted clearance of influenza virus via production of antiviral cytokines, such as TNF-alpha and IFN-gamma. Since metastasis is the major cause of cancer-related death and the greatest challenge in cancer treatment, we investigated the effect of KIOM-C on the metastatic potential of HT1080 and B16F10 cells. We observed inhibitory properties of KIOM-C in colony-forming activity, migration and invasion. Matrix metalloproteinase-9 (MMP-9) activity in the resting and PMA-stimulated state in HT1080 cells was dose dependently decreased by KIOM-C treatment via suppression of NF-kappaB activation. In addition, daily oral administration of KIOM-C at doses of 170 and 510 mg/kg, the corresponding human adult daily doses, efficiently blocked lung metastasis in C57BL/6J mice following injection of B16F10 cells in the tail veins. In particular, none of the mice administered KIOM-C during the experimental period exhibited systemic toxicity, such as body weight loss or liver and kidney dysfunction. Collectively, our results suggest that KIOM-C is a potential therapeutic formula useful as a safe herbal medicine for controlling metastatic cancer. PMID- 24174066 TI - Mamma-augmentation-plasty after operation for funnel-chest deformity. AB - A technique for correction of funnel chest, a condition found in 91% of chest deformities, has been successfully used in 1141 patients. Among these were 38 females, 4 of whom had mamma-augmentation-plasty performed at the time of removal of the metal strut used in repair of the funnel chest. Great care is needed in selecting patients for the repair of funnel chest and in avoiding postoperative complications. PMID- 24174065 TI - The history of rhytidectomy. AB - CONCLUSION: Between Cantrell [23] and Cabanes [21] in the first decade of this century and the many practitioners of contemporary rhytidectomy, the concerns and labors of aesthetic plastic surgeons have a familiar tone. We have inherited their improvements and need not waste efforts which theirs have spared us in techniques. Only if we are also the grateful heirs of their subjective scientific and humanistic ideals can we carry forward surgical research to the goals implicit in their pioneering-the safe and effective prolongation of youth and retardation of aging.The evolution of aesthetic plastic surgery to its present status as a rigorously controlled medical technique received its power from the perennial drive of men and women to preserve the appearance of their body and face in consonance with the vigor of their personalities and desires. We have always known that inner psychic and spiritual changes bring about a new external radiance, but we are now discovering that the process also works in reverse: Change the external appearance-restore the lost years-of a person struggling continually against indifferent or negative social reactions, and the inner light that has died within begins to glow once more. PMID- 24174067 TI - Posterior neck lift for correction of sagging of the lower anterior neck. AB - The posterior neck lift is described as part of an overall rhytidectomy for tightening the skin of the lower anterior neck. A wide horizontal strip of skin is excised along the entire nape of the neck. Closure of the resultant defect is obtained by raising the posterolateral neck skin, which in turn has a direct effect in overcoming laxity of the lower anterior neck. The plane of dissection is in the fibrofatty tissues. The operation is easily performed and has not been associated with any untoward complications. It relies only on skin traction without any platysma muscle plasty being undertaken. PMID- 24174068 TI - Congenital inversion of the human nipple. AB - Congenital inversion of the nipple can be corrected surgically for both functional and cosmetic satisfaction. We have used the technique of Schwager et al. on 14 of 17 patients, with the aid of mammograms before and after the operation. The results proved to be highly satisfactory. PMID- 24174069 TI - Correction of the congenital short upper lip and heavy-lidded eyes. AB - Aesthetic correction of the congenitally short lip and the hooded or heavy upper eyelid will do much to improve the appearance of those afflicted with such defects. Correction of the upper lip can be successfully performed by a technique that differs from the transoral approach, and technical sculpturing of the upper eyelid beyond simple blepharoplasty can do much to alleviate the heavy-lidded appearance. PMID- 24174070 TI - Reconstructive rhinoplasty with nasal implants. AB - A new method of immobilizing nasal implants is the creation of a strong fibrotic reaction with sewn polyester (Dacron) felt. It has been applied to saddle nose deformity, as well as maxillary retrusion of flat nasal tip. Over a period of 15 years in a large number of cases, the complications have been only a temporary inflammatory reaction in 5% of the cases. PMID- 24174071 TI - Otoplasty: Excision of conchal floor cartilage. AB - In 10 consecutive otoplasties, conchal floor cartilage was excised to facilitate rotating prominent ears back against the head. The procedure is most effective in aural prominence due to deep conchae. Cosmetic improvement is as good as that achieved by excision of posterior wall cartilage, and recontouring of the antihelix fold is needed less often. The amount of cartilage to remove is easily determined, matching of asymmetrically prominent ears is simplified, and concha mastoid sutures can be placed without tension. The corrections have been followed 1-2 years without recurrence of the deformity. PMID- 24174072 TI - Subcutaneous mastectomy with immediate reconstruction and maximal vascular protection. AB - A combined reconstructive-reductive procedure after glandular resection in the breast has proved to be a highly practical and successful approach for subcutaneous mastectomy. A prosthesis may also be inserted at the time of the initial operation. The method requires that the incision be small, to protect blood supply, that there be a double-layer covering for the prosthesis, and that an L-shaped suture line be used for good aesthetic results. PMID- 24174073 TI - Submental lipectomy in the young adult. AB - A variation of the submental lipectomy is described with or without the use of a chin implant to correct a double-chin deformity in the young adult. A natural look is obtained without the need of a rhytidectomy approach. PMID- 24174074 TI - Combined medico-surgical torsoplasty. AB - A combined medico-surgical treatment of obesity illustrates the possibility of achieving harmony of body contours with minimal scarring, risks to the patient, and effort on his or her part. Daily injections of 125 IU of human chorionic gonadotrophin, combined with a special 500-calorie diet, has proven to be a successful medical treatment in more than 6,000 patients treated over a period of 12 years. It had a rapid effect in reducing body contour circumferences over the full course of treatment, and offered the patient a sense of well-being and satisfaction. Mildly overweight responded to this treatment without surgery, a "knifeless torsoplasty." High-risk obese patients were prepared for subsequent surgery. Hypertrophic deformities in a single body area were corrected into a well-proportioned silhouette. PMID- 24174075 TI - Asymmetry of the breast and the thoracic cage : A brief presentation of cases with their operative treatment. AB - The most common causes of thoracic malformation in relation to the surgery of breast augmentation or reduction are discussed in this brief outline of cases requiring surgical correction. The types of treatment commonly employed by the author to deal with soft tissue asymmetry independent of the shape of the thoracic cage itself, that is, uneven or asymmetric breasts, are demonstrated in a successive series of photographic preoperative and postoperative case studies. PMID- 24174076 TI - Implants and grafts in secondary rhinodeformities. AB - Experience in 1359 cases of secondary rhinodeformity due to excess resection, using silicone implants and cartilage autografts, is presented. This experience has been classified in three periods of 5 years each. During the first period, preshaped silicone (Silastic) implants were used. In the second period both implants and grafts were used. In the third period only cartilage autografts were used; the material was obtained from the quadrangular cartilage of the nasal septum and the auricular pavilion. The investigators emphasize the disadvantages of the implants and declare themselves 100% in favor of cartilage autografts. PMID- 24174077 TI - Two new free flaps developed from aesthetic surgery I. The lateral mammary flap. AB - A new donor site for free skin flap transfer from the breast is described. The vascular anatomy and the operative technique for raising the flap is detailed. The clinical application is illustrated by 3 case reports including 4 flap transfers. The use of the lateral mammary flap is indicated in largebreasted women when a reduction mammaplasty is required at the level of the donor site and can be combined with the microsurgical flap transfer. PMID- 24174078 TI - Two new free flaps developed from aesthetic surgery II. The inferior gluteal flap. AB - A new vascular musculocutaneous flap from the lower buttock is described that is based on the inferior gluteal vessels and includes skin from the gluteal fold and a part of the gluteus maximus muscle. The inferior gluteal flap has been clinically used either as an island flap for sacral repair or as a free flap. The results of 6 clinical cases are presented and the features of the flap are exposed. The minimum residual deformity of the buttock contour and, even in some cases of trochanteric lipodystrophy, the cosmetic improvement of the donor site appearance are emphasized. PMID- 24174079 TI - Rhinoplasty in the "Chata" nose of the Caribbean. AB - The unique blend of ethnic origins in the people of the Caribbean Islands, especially in Puerto Rico, has brought about a type of nose that we call "Chata." The classic rhinoplasty operations were inadequate, and early reconstruction attempts were unsatisfactory. Various cartilage grafts, alar sculpturing techniques, and external incisions have been used to achieve satisfactory results. PMID- 24174080 TI - Repairing errors of Nipple-areolar placement following reduction mammoplasty. AB - Although the newer techniques for reduction mammoplasty generally give excellent results, some patients may develop recurrent ptosis as a result of greater tissue elasticity, or the breast may sag beneath the inframammary line, elevating the nipple. Proper preoperative evaluation and planning can help to prevent such results, and such advanced planning is even more necessary when repair is contemplated. PMID- 24174081 TI - Abdominoplasty: Refinements and pitfalls. AB - Abdominoplasty has proved to be highly successful in reducing abdominal size and laxity in 93 patients, with few complications. The scar is inconspicuous. The method is considered preferable to the W technique. PMID- 24174082 TI - Rhinoplasty for preventing nasal cartilage growth. AB - The physiologic growth of the nose, which continues, particularly in females, throughout life, prompted us to develop a technique for preventive surgery. The method consists in producing a scar in the cartilaginous portion of the nose to prevent continued growth of that tissue and to preserve the nose without deformities. PMID- 24174083 TI - The triple "V" intraareolar approach for augmentation mammaplasty. AB - A new approach, the triple V intraareolar incision for mammary augmentation is presented. Some consideration is given to the use of organic tissue in selected cases. The use of the Cronin prosthesis is favored, preferably by areolar approach. When the areola is small, up to 2.5 cm in diameter, the triple V incision is indicated. Two lateral Vs are formed, starting from both sides of the areola, and a third one is traced just below the nipple. All the branches of the three Vs have approximately the same size, thus forming a staggered incision that provides 40% more room for the maneuvers of submammary decollement, hemostasis, and prosthesis introduction. The resulting scar is inconspicuous, hidden by the areolar pigmented skin. PMID- 24174084 TI - Lipexeresis as a means of eliminating local adiposity. AB - "Lipexeresis" is a successful method for removing excessive local fatty tissue from the female body for pathologic or for aesthetic reasons. In contrast to other surgical operations, it is highly important that no disturbing scars remain. Except for two patients who underwent operation on the lower leg, with more serious complications, the results have been very encouraging. PMID- 24174085 TI - Some problems and solutions in abdominoplasty. AB - A review of 428 abdominoplasties performed for the correction of abdominal flaccidity emphasizes the need for a wide repertory of surgical techniques to achieve an aesthetically natural appearance of the abdomen. Six details of surgical technique have considerably improved the results of abdominoplasty performed at our institute during the past 14 years. These six technical details are easy to accomplish without prolonging the total operating time. PMID- 24174086 TI - Calculation of the volume of the normal and the hypertrophic breast. AB - Using the same system as has been previously described for the Natural Pattern, we have produced a mold with Scotch tape, Ref. 202, that precisely reproduces the size and shape of normal and hypertrophic breasts. Using this mold technique, we studied the specific weight of mammary tissues, and found an average volume of 360 to 390 cc in normal women. This volume figure, varying according to height and weight of the patient, is subtracted from that of a hypertrophic gland to determine how much to resect in a breast reduction procedure. A postoperative mold is made that can be used as a control should the patient return due to recurrence of the hypertrophy. PMID- 24174087 TI - Aesthetic surgery of the upper and lower limbs. AB - Aesthetic deformities of both the upper and lower limbs are primarily a result of fat excess or flacidity. Surgical correction of these lipodystrophies should be done when clinical and physiotherapeutic methods fail to considerably reduce these deformities. The scars are generally large, conspicuous, and sometimes of poor quality, due to natural tension on the borders. The technique, success, and advisability of surgery varies for the several upper and lower limb deformities, and a number of factors, including type and placement of incision, can improve the results. PMID- 24174088 TI - Nerve injuries during rhytidectomy. Considerations after 3,203 cases. AB - The potential for injury to the nerves of the face is ever-present in rhytidectomy. Only a thorough knowledge of the anatomy, of the face, adequate surgical experience, and strict adherence to basic operating principles can avoid problems. The temporalis, paraorbitalis, genian, mandibular, and cervicoauricularis areas each offer hazards, which are detailed in this discussion, along with some technical details to avoid both temporary and permanent damage. PMID- 24174089 TI - Capsular contracture and steroid-related complications in augmentation mammoplasty. AB - An analysis of the data obtained in 91 of 161 patients (57%) who had undergone augmentation mammoplasty between 1973 and 1978 demonstrates that corticosteroids should be used with caution and that more data are needed before their efficacy is assured. Moreover, the authors believe that a better understanding of the breast contracture mechanism and specific pharmacologic agents is necessary in order to control the process of capsular contracture. PMID- 24174090 TI - A versatile standardization for mammoplasty. AB - This report presents a variable standardized technique for reductive mammoplasty, based on techniques used by Pontes and Skoog, which is easily performed, carries low risk, and gives good postoperative results. This method enables the surgeon to perform a greater variety of physiologic mammoplasties, through nipple-areola migration by the dermomammary pedicle, which is transformed easily into a dermolateral pedicle, in order to enable wider breast resections and migration of the nipple-areolar complex over greater distances. The localized submammary undermining permits greater reduction of the mammary cone base and larger filling of the upper pole.This method may be applied in any type of breast, even those which are voluminous, hard, and nonelastic. PMID- 24174091 TI - A new technique for areolar reconstruction. AB - A new technique for areolar reconstruction is presented. Donor areolar tissue is preferred, but groin or thigh skin may be used. The modification of this procedure is the placement of a strip of areolar skin as a circular mesh, so that small amounts of tissue may be used to give an irregular surface. To restore the size of the donor areola, the same principle is applied by outward expansion of the remaining areolar tissue. If the areola is small, we prefer to make the reconstruction bilateral. PMID- 24174092 TI - Blepharoplasty to form the orbitopalpebral sulcus and nasal bone graft in oriental subjects (Occidentalization). AB - The procedures of blepharoplasty and rhinoplasty have been applied successfully, alone or in combination, to the occidentalization of Oriental patients for aesthetic reasons. The blepharoplasty, using the Sayoc-Millard technique, and the rhinoplasty, using an autogenous osteoperiosteal graft from the crest of tibia, are described in detail. PMID- 24174093 TI - Blepharoplasty. Surgical versus chemical-Surgical plus chemical. AB - The decision of whether to perform a blepharoplasty is based upon consideration of a number of physical characteristics, including the presence of excess eyelid skin, of thick rugal folds, and of pads of herniated periorbital fat. Patients whose problem is thick rugal folds wil benefit most from a facelift and chemical peel; for those with weathered skin alone, a chemical peel may be sufficient to improve the appearance. In the absence of significant herniated periorbital fat of the lower lid, lower blepharoplasty is rarely indicated. In most cases, an upper blepharoplasty with a face-lift provides a satisfactory solution. PMID- 24174094 TI - The use of color-head straight pins for prominent ear correction. AB - In a modification of Mustarde's method for the correction of prominent ears, the use of color-head straight pins as a marking technique is helpful, as it simplifies the operative procedure, enabling one to place the minimum number of permanent sutures in the best positions. PMID- 24174095 TI - Reconstruction of the nipple. AB - Once reconstruction of the breast mound has been accomplished following an ablative procedure, reconstruction of the nipple and areola provides added dimension to the psychological well-being of the patient. A number of techniques are available to accomplish this satisfactorily. An areola can be created by tattooing; areolar sharing; grafting from any skin area, especially the medial thigh, labium minora or minora-majora, and the scrotum in men; and by banking the areola and nipple at the time of breast removal. The nipple can be constructed from grafts from the opposite nipple, toe tip, ear lobe, or other skin areas; cartilage or plastic implants; or by projecting the central area of the areola with purse string sutures, overgrafts, and buried grafts or implants. PMID- 24174096 TI - Recent methods of rhinoplasty for orientals. AB - Aesthetic rhinoplasty for Orientals now involves the convex dorsum, as well as the saddle, or concave, nose. The author has devised a specific method of reparation for correction of the over-developed nasal dorsum or hump with flat tip that comprises rhinoplasty in which reduction, remodeling, and implantation are carried out simultaneously. Two small implants of dimethylpolysiloxane are used to correct the acute subnasal angle and remodel the nasal tip and the nasal hump. The surgical techniques have been successfully used for Orientals during the past 15 years. PMID- 24174097 TI - Present status and future prospects for aesthetic plastic surgery. AB - The recent developments and changes in surgical procedures such as rhytidectomy, blepharoplasty, nasoplasty, otoplasty, mammoplasty, mammary reconstruction, and abdominoplasty are briefly reviewed in this article, which is substantially reduced in its overall length from the guest lecture given by the author at the Seventh International Congress of Plastic and Reconstructive Surgery held in Rio de Janeiro in May 1979, in his role as president of the International Society of Aesthetic Plastic Surgery (ISAPS). PMID- 24174098 TI - Insertion of mammary gel prosthesis with negative pressure. AB - We present a maneuver in which negative pressure is used to ease the insertion of gel prosthesis in augmentation mammoplasty and, therefore, reduce the risk of prosthetic rupture during surgery. A polyvinyl urethral catheter, inserted in the areolar incision, is attached to the surgery room vacuum pump. The negative pressure thus created allows the prosthesis to be inserted safely. PMID- 24174099 TI - The role of diazepam in skin hyperpigmentation. AB - Dermabrasion of the face for multiple conditions requiring reconstructive surgery continues to be a valuable procedure. An important complication of the procedure, however, in the form of hyperpigmentation, led to a search for the cause. When normal anatomic studies failed to indicate a valid reason for this complication in a female patient, further search revealed a biochemical reason-diazepam (Valium). Treatment with a bleaching agent, hydroquinone ointment, reversed the hyperpigmentation and led to a permanent satisfactory result. PMID- 24174100 TI - Significant details regarding treatment of prognathism using angled osteotomy of the mandibular rami. AB - A simplified technique for surgical correction of prognathism, consisting of an angled or L-shaped osteotomy in the mandibular ramus starting from the sigmoid notch and ending on the posterior border of the ascending ramus, has been performed on 365 patients. Modifications of the procedure allow for concomitant correction of mild and severe open-bite conditions. Morbidity was not significant; 12 patients experienced transient dysfunction of the facial nerve, which disappeared within an average of 60 days; in 10 patients, there was an accumulation of saliva in the preauricular area, which was relieved by 3 or 4 punctures. In some of the early open-bite cases, regression occurred, leading to modifications in the technique. There are many advantages to the procedure, including simplicity, low risk of infection, inconspicous scarring, no impairment of muscle strength, and low complication rate. PMID- 24174101 TI - The theory of natural capsular contraction around breast implants and how to prevent it. AB - Many articles have described various causes of capsular contraction around breast implants. However, even when these causes are not present, an implanted breast that is soft postoperatively may still become firm later. Such cases can be explained by the theory of natural capsular contracture, based on the observation that the human body will obliterate cavities anywhere within it unless an obturator is present to prevent it. The speed of contraction is described in this paper by presentation of clinical cases. To maintain an adequate cavity at the breast implant site, we have designed a series of exercises, using the implant as the obturator, which have markedly reduced the incidence of firm breasts. PMID- 24174102 TI - Aesthetic plastic surgery of the upper and lower limbs. AB - A single surgical approach is proposed for correction of lipodystrophy of the upper and lower limbs, coexisting deformities, and other conditions affecting these areas. The procedure has great versatility, and results are satisfactory. The inevitability of noticeable scars, however, still constitutes a problem, mandating careful evaluation of the indications and a very realistic doctor patient relationship. PMID- 24174103 TI - The Berkeley repair of the unilateral cleft lip-nose deformity: An aesthetic procedure. AB - The Berkeley procedure in the treatment of unilateral cleft lip-nose deformity approaches the deformed ala as an anatomic unit, rotating and repositioning the entire ala into a proper anatomic perspective. Between 1971 and 1978, a total of 55 patients were operated on by means of the Berkeley procedure. The results were reviewed by physicians, patients, and parents as to aesthetic acceptability and anatomic alignment. Both criteria were uniformaly rated good to excellent. There were no immediate or late complications, and the scars were determined to be acceptable to excellent. PMID- 24174104 TI - The effect of estrogen on the skin. AB - Investigative reports describing the effect of estrogen locally applied to the skin have been examined. It is apparent that physiologic doses of estrogen in postmenopausal females improve skin elasticity and increase the thickness of skin but that very large doses induce skin atrophy. The contraindications against the use of estrogen preparations are presented. PMID- 24174105 TI - Seascape analysis reveals regional gene flow patterns among populations of a marine planktonic diatom. AB - We investigated the gene flow of the common marine diatom, Skeletonema marinoi, in Scandinavian waters and tested the null hypothesis of panmixia. Sediment samples were collected from the Danish Straits, Kattegat and Skagerrak. Individual strains were established from germinated resting stages. A total of 350 individuals were genotyped by eight microsatellite markers. Conventional F statistics showed significant differentiation between the samples. We therefore investigated whether the genetic structure could be explained using genetic models based on isolation by distance (IBD) or by oceanographic connectivity. Patterns of oceanographic circulation are seasonally dependent and therefore we estimated how well local oceanographic connectivity explains gene flow month by month. We found no significant relationship between genetic differentiation and geographical distance. Instead, the genetic structure of this dominant marine primary producer is best explained by local oceanographic connectivity promoting gene flow in a primarily south to north direction throughout the year. Oceanographic data were consistent with the significant FST values between several pairs of samples. Because even a small amount of genetic exchange prevents the accumulation of genetic differences in F-statistics, we hypothesize that local retention at each sample site, possibly as resting stages, is an important component in explaining the observed genetic structure. PMID- 24174106 TI - How ticks get under your skin: insertion mechanics of the feeding apparatus of Ixodes ricinus ticks. AB - The tick Ixodes ricinus uses its mouthparts to penetrate the skin of its host and to remain attached for about a week, during which time Lyme disease spirochaetes may pass from the tick to the host. To understand how the tick achieves both tasks, penetration and attachment, with the same set of implements, we recorded the insertion events by cinematography, interpreted the mouthparts' function by scanning electron microscopy and identified their points of articulation by confocal microscopy. Our structural dynamic observations suggest that the process of insertion and attachment occurs via a ratchet-like mechanism with two distinct stages. Initially, the two telescoping chelicerae pierce the skin and, by moving alternately, generate a toehold. Subsequently, a breaststroke-like motion, effected by simultaneous flexure and retraction of both chelicerae, pulls in the barbed hypostome. This combination of a flexible, dynamic mechanical ratchet and a static holdfast thus allows the tick to solve the problem of how to penetrate skin and also remain stuck for long periods of time. PMID- 24174107 TI - Immune anticipation of mating in Drosophila: Turandot M promotes immunity against sexually transmitted fungal infections. AB - Although it is well known that mating increases the risk of infection, we do not know how females mitigate the fitness costs of sexually transmitted infections (STIs). It has recently been shown that female fruitflies, Drosophila melanogaster, specifically upregulate two members of the Turandot family of immune and stress response genes, Turandot M and Turandot C (TotM and TotC), when they hear male courtship song. Here, we use the Gal4/UAS RNAi gene knockdown system to test whether the expression of these genes provides fitness benefits for females infected with the entomopathogenic fungus, Metarhizium robertsii under sexual transmission. As a control, we also examined the immunity conferred by Dorsal-related immunity factor (Dif), a central component of the Toll signalling pathway thought to provide immunity against fungal infections. We show that TotM, but not TotC or Dif, provides survival benefits to females following STIs, but not after direct topical infections. We also show that though the expression of TotM provides fecundity benefits for healthy females, it comes at a cost to their survival, which helps to explain why TotM is not constitutively expressed. Together, these results show that the anticipatory expression of TotM promotes specific immunity against fungal STIs and suggest that immune anticipation is more common than currently appreciated. PMID- 24174108 TI - The ontogeny of home ranges: evidence from coral reef fishes. AB - The concept of home ranges is fundamental to ecology. Numerous studies have quantified how home ranges scale with body size across taxa. However, these relationships are not always applicable intraspecifically. Here, we describe how the home range of an important group of reef fish, the parrotfishes, scales with body mass. With masses spanning five orders of magnitude, from the early postsettlement stage through to adulthood, we find no evidence of a response to predation risk, dietary shifts or sex change on home range expansion rates. Instead, we document a distinct ontogenetic shift in home range expansion with sexual maturity. Juvenile parrotfishes displayed rapid home range growth until reaching approximately 100-150 mm length. Thereafter, the relationship between home range and mass broke down. This shift reflected changes in colour patterns, social status and reproductive behaviour associated with the transition to adult stages. While there is a clear relationship between body mass and home ranges among adult individuals of different species, it does not appear to be applicable to size changes within species. Ontogenetic changes in parrotfishes do not follow expected mass-area scaling relationships. PMID- 24174109 TI - Evolutionary conservatism and convergence both lead to striking similarity in ecology, morphology and performance across continents in frogs. AB - Many clades contain ecologically and phenotypically similar species across continents, yet the processes generating this similarity are largely unstudied, leaving fundamental questions unanswered. Is similarity in morphology and performance across assemblages caused by evolutionary convergence or by biogeographic dispersal of evolutionarily conserved ecotypes? Does convergence to new ecological conditions erase evidence of past adaptation? Here, we analyse ecology, morphology and performance in frog assemblages from three continents (Asia, Australia and South America), assessing the importance of dispersal and convergent evolution in explaining similarity across regions. We find three striking results. First, species using the same microhabitat type are highly similar in morphology and performance across both clades and continents. Second, some species on different continents owe their similarity to dispersal and evolutionary conservatism (rather than evolutionary convergence), even over vast temporal and spatial scales. Third, in one case, an ecologically specialized ancestor radiated into diverse ecotypes that have converged with those on other continents, largely erasing traces of past adaptation to their ancestral ecology. Overall, our study highlights the roles of both evolutionary conservatism and convergence in explaining similarity in species traits over large spatial and temporal scales and demonstrates a statistical framework for addressing these questions in other systems. PMID- 24174110 TI - Climate, not Aboriginal landscape burning, controlled the historical demography and distribution of fire-sensitive conifer populations across Australia. AB - Climate and fire are the key environmental factors that shape the distribution and demography of plant populations in Australia. Because of limited palaeoecological records in this arid continent, however, it is unclear as to which factor impacted vegetation more strongly, and what were the roles of fire regime changes owing to human activity and megafaunal extinction (since ca 50 kya). To address these questions, we analysed historical genetic, demographic and distributional changes in a widespread conifer species complex that paradoxically grows in fire-prone regions, yet is very sensitive to fire. Genetic demographic analysis showed that the arid populations experienced strong bottlenecks, consistent with range contractions during the Last Glacial Maximum (ca 20 kya) predicted by species distribution models. In southern temperate regions, the population sizes were estimated to have been mostly stable, followed by some expansion coinciding with climate amelioration at the end of the last glacial period. By contrast, in the flammable tropical savannahs, where fire risk is the highest, demographic analysis failed to detect significant population bottlenecks. Collectively, these results suggest that the impact of climate change overwhelmed any modifications to fire regimes by Aboriginal landscape burning and megafaunal extinction, a finding that probably also applies to other fire-prone vegetation across Australia. PMID- 24174111 TI - Bacterial farming by the fungus Morchella crassipes. AB - The interactions between bacteria and fungi, the main actors of the soil microbiome, remain poorly studied. Here, we show that the saprotrophic and ectomycorrhizal soil fungus Morchella crassipes acts as a bacterial farmer of Pseudomonas putida, which serves as a model soil bacterium. Farming by M. crassipes consists of bacterial dispersal, bacterial rearing with fungal exudates, as well as harvesting and translocation of bacterial carbon. The different phases were confirmed experimentally using cell counting and (13)C probing. Common criteria met by other non-human farming systems are also valid for M. crassipes farming, including habitual planting, cultivation and harvesting. Specific traits include delocalization of food production and consumption and separation of roles in the colony (source versus sink areas), which are also found in human agriculture. Our study evidences a hitherto unknown mutualistic association in which bacteria gain through dispersal and rearing, while the fungus gains through the harvesting of an additional carbon source and increased stress resistance of the mycelium. This type of interaction between fungi and bacteria may play a key role in soils. PMID- 24174112 TI - Familiarity adds to attractiveness in matters of siskin mate choice. AB - There is currently considerable controversy in evolutionary ecology revolving around whether social familiarity brings attraction when a female chooses a mate. The topic of familiarity is significant because by avoiding or preferring familiar individuals as mates, the potential for local adaptation may be reduced or favoured. The topic becomes even more interesting if we simultaneously analyse preferences for familiarity and sexual ornaments, because when familiarity influences female mating preferences, this could very significantly affect the strength of sexual selection on male ornamentation. Here, we have used mate choice experiments in siskins Carduelis spinus to analyse how familiarity and patterns of ornamentation (i.e. the size of wing patches) interact to influence mating success. Our results show that females clearly prefer familiar individuals when choosing between familiar and unfamiliar males with similar-sized wing patches. Furthermore, when females were given the choice between a highly ornamented unfamiliar male and a less ornamented familiar male, half of the females still preferred the socially familiar birds as mates. Our finding suggests that male familiarity may be as important as sexual ornaments in affecting female behaviour in mate choice. Given that the potential for local adaptation may be favoured by preferring familiar individuals as mates, social familiarity as a mate-choice criterion may become a potential area of fruitful research on sympatric speciation processes. PMID- 24174113 TI - Structure of the vortex wake in hovering Anna's hummingbirds (Calypte anna). AB - Hummingbirds are specialized hoverers for which the vortex wake has been described as a series of single vortex rings shed primarily during the downstroke. Recent findings in bats and birds, as well as in a recent study on Anna's hummingbirds, suggest that each wing may shed a discrete vortex ring, yielding a bilaterally paired wake. Here, we describe the presence of two discrete rings in the wake of hovering Anna's hummingbirds, and also infer force production through a wingbeat with contributions to weight support. Using flow visualization, we found separate vortices at the tip and root of each wing, with 15% stronger circulation at the wingtip than at the root during the downstroke. The upstroke wake is more complex, with near-continuous shedding of vorticity, and circulation of approximately equal magnitude at tip and root. Force estimates suggest that the downstroke contributes 66% of required weight support, whereas the upstroke generates 35%. We also identified a secondary vortex structure yielding 8-26% of weight support. Lift production in Anna's hummingbirds is more evenly distributed between the stroke phases than previously estimated for Rufous hummingbirds, in accordance with the generally symmetric down- and upstrokes that characterize hovering in these birds. PMID- 24174114 TI - Did postglacial sea-level changes initiate the evolutionary divergence of a Tasmanian endemic raptor from its mainland relative? AB - Populations on continental islands are often distinguishable from mainland conspecifics with respect to body size, appearance, behaviour or life history, and this is often congruent with genetic patterns. It is commonly assumed that such differences developed following the complete isolation of populations by sea level rise following the Last Glacial Maximum (LGM). However, population divergence may predate the LGM, or marine dispersal and colonization of islands may have occurred more recently; in both cases, populations may have also diverged despite ongoing gene flow. Here, we test these alternative hypotheses for the divergence between wedge-tailed eagles from mainland Australia (Aquila audax audax) and the threatened Tasmanian subspecies (Aquila audax fleayi), based on variation at 20 microsatellite loci and mtDNA. Coalescent analyses indicate that population divergence appreciably postdates the severance of terrestrial habitat continuity and occurred without any subsequent gene flow. We infer a recent colonization of Tasmania by marine dispersal and cannot discount founder effects as the cause of differences in body size and life history. We call into question the general assumption of post-LGM marine transgression as the initiator of divergence of terrestrial lineages on continental islands and adjacent mainland, and highlight the range of alternative scenarios that should be considered. PMID- 24174115 TI - Shifting mirrors: adaptive changes in retinal reflections to winter darkness in Arctic reindeer. AB - Arctic reindeer experience extreme changes in environmental light from continuous summer daylight to continuous winter darkness. Here, we show that they may have a unique mechanism to cope with winter darkness by changing the wavelength reflection from their tapetum lucidum (TL). In summer, it is golden with most light reflected back directly through the retina, whereas in winter it is deep blue with less light reflected out of the eye. The blue reflection in winter is associated with significantly increased retinal sensitivity compared with summer animals. The wavelength of reflection depends on TL collagen spacing, with reduced spacing resulting in shorter wavelengths, which we confirmed in summer and winter animals. Winter animals have significantly increased intra-ocular pressure, probably produced by permanent pupil dilation blocking ocular drainage. This may explain the collagen compression. The resulting shift to a blue reflection may scatter light through photoreceptors rather than directly reflecting it, resulting in elevated retinal sensitivity via increased photon capture. This is, to our knowledge, the first description of a retinal structural adaptation to seasonal changes in environmental light. Increased sensitivity occurs at the cost of reduced acuity, but may be an important adaptation in reindeer to detect moving predators in the dark Arctic winter. PMID- 24174116 TI - Evidence for large-scale effects of competition: niche displacement in Canada lynx and bobcat. AB - Determining the patterns, causes and consequences of character displacement is central to our understanding of competition in ecological communities. However, the majority of competition research has occurred over small spatial extents or focused on fine-scale differences in morphology or behaviour. The effects of competition on broad-scale distribution and niche characteristics of species remain poorly understood but critically important. Using range-wide species distribution models, we evaluated whether Canada lynx (Lynx canadensis) or bobcat (Lynx rufus) were displaced in regions of sympatry. Consistent with our prediction, we found that lynx niches were less similar to those of bobcat in areas of sympatry versus allopatry, with a stronger reliance on snow cover driving lynx niche divergence in the sympatric zone. By contrast, bobcat increased niche breadth in zones of sympatry, and bobcat niches were equally similar to those of lynx in zones of sympatry and allopatry. These findings suggest that competitively disadvantaged species avoid competition at large scales by restricting their niche to highly suitable conditions, while superior competitors expand the diversity of environments used. Our results indicate that competition can manifest within climatic niche space across species' ranges, highlighting the importance of biotic interactions occurring at large spatial scales on niche dynamics. PMID- 24174117 TI - The Trojan female technique: a novel, effective and humane approach for pest population control. AB - Humankind's ongoing battle with pest species spans millennia. Pests cause or carry disease, damage or consume food crops and other resources, and drive global environmental change. Conventional approaches to pest management usually involve lethal control, but such approaches are costly, of varying efficiency and often have ethical issues. Thus, pest management via control of reproductive output is increasingly considered an optimal solution. One of the most successful such 'fertility control' strategies developed to date is the sterile male technique (SMT), in which large numbers of sterile males are released into a population each generation. However, this approach is time-consuming, labour-intensive and costly. We use mathematical models to test a new twist on the SMT, using maternally inherited mitochondrial (mtDNA) mutations that affect male, but not female reproductive fitness. 'Trojan females' carrying such mutations, and their female descendants, produce 'sterile-male'-equivalents under natural conditions over multiple generations. We find that the Trojan female technique (TFT) has the potential to be a novel humane approach for pest control. Single large releases and relatively few small repeat releases of Trojan females both provided effective and persistent control within relatively few generations. Although greatest efficacy was predicted for high-turnover species, the additive nature of multiple releases made the TFT applicable to the full range of life histories modelled. The extensive conservation of mtDNA among eukaryotes suggests this approach could have broad utility for pest control. PMID- 24174118 TI - [Ventricular tachycardia : Treatment and prognostic significance]. AB - Dilative cardiomyopathy (DCM) has an incidence of 5-8/100,000 inhabitants, and hypertrophic cardiomyopathy an incidence of 1/500 inhabitants. Depending on specific risk factors both conditions have an increased risk for sudden cardiac death (SCD): in DCM reduced left ventricular ejection fraction and reduced physical capacity; and in HCM SCD in family members, left ventricular septum > 30 mm, unclear syncope, non-sustained ventricular tachycardia (VT) on holter-ECG and inadequate blood pressure response on ergometer. Especially patients with intermediary risk factors are insufficiently classified, and the lifesaving implantation of a cardioverter-defibrillator (ICD) often leads to a significant number of device-related complications. In this area additional methods like late enhancement imaging with cardio MRI, identification of genetic variation and ECG characteristics could help improve risk stratification in these patients. PMID- 24174119 TI - Assessing the impact of irrigation treatments on thiram residual trends: correspondence with numerical modelling and field-scale experiments. AB - The present study was undertaken to study the trends of transport of thiram, a dithiocarbamate pesticide, at different time and depth in the fields under real field conditions for wheat crop. Numerical simulations were carried out by solving the coupled soil-water content movement and mass transport equations using HYDRUS- 1D. The supplementary data used for paramaterization of HYDRUS-1D comprise of irrigation treatments, climatic conditions, and soil characteristics. Results focus on the effects and influence of irrigation treatments on pesticide persistence and mobility. Modelling results were in good agreement with the experimentally determined thiram concentrations. Application of the model to measured field data of thiram movement indicates that the modelling approach can provide reliable and useful estimates of the mass flux of water and non-volatile pesticide in vadose zone. For policy-makers and planners, some regulation strategies are suggested for controlling inappropriate pesticide application under deficit irrigation or rain-fed conditions. PMID- 24174120 TI - Hepatic and nephric mercury and selenium concentrations in common mergansers, Mergus merganser, from Baltic Region, Europe. AB - The subject of the present study was the piscivorous common mergansers (Mergus merganser). The total mercury (THg), methylmercury (MeHg), selenium (Se) inorganic mercury (InHg; THg - MeHg), percentage of THg that is MeHg (%MeHg), molar ratios (THg:Se, MeHg:Se, InHg:Se), and their mutual relations in livers and kidneys were determined in ducks from an Se-deficient area in Poland. The authors verified a hypothesis that, as a result of living in an Se-deficient region, mergansers from Poland should have higher THg:Se ratios than other waterbirds with similar THg tissue levels. Although a comparison of healthy mergansers from Poland and Canada showed similar THg tissue contents, the group in the present study had a few times lower Se levels and higher THg:Se ratios (overall means >1.7 in both livers and kidneys in all studied individuals) than the Canadian group and other European and North American waterbirds. The authors found significant correlations between various relations, including MeHg-THg, InHg-THg, Se-THg, %MeHg-THg, InHg/%THg-THg, %MeHg/THg-InHg, %InHg/THg-InHg, MeHg:Se-THg:Se, InHg:Se-THg:Se, InHg:Se-MeHg:Se in liver and InHg-THg, Se-THg, Se-InHg, %MeHg THg, %MeHg-InHg, %InHg/THg-InHg, THg:Se-THg, InHg:Se-THg, MeHg:Se-MeHg, THg:Se InHg, InHg:Se-InHg, and InHg:Se-THg:Se in kidney. It is likely that the main factor responsible for the high value of THG:Se ratio (>1) in mergansers from Poland is Se deficiency in central and northern Europe. Therefore, this element is unlikely to participate in the detoxification of Hg in these birds. PMID- 24174121 TI - Understanding coronary artery bypass transit time flow curves: role of bypass graft compliance. AB - OBJECTIVES: Low mean bypass graft flow (Q) and high pulsatility index (PI) measured by the transit time flow measurement method are not specific for anastomotic stenosis, but occur with competitive flow and poor coronary run-off. We hypothesized that graft compliance is responsible for these changes and that flow measured at the proximal end of the coronary bypass can be viewed as a sum of the graft capacitive flow and flow that passes through the distal anastomosis. METHODS: Transit time flow measurements (TTFMs) of 15 left internal thoracic artery (LITA) to LAD bypass grafts and 10 saphenous vein grafts (SVGs) to either the right coronary artery (RCA) or posterior descending artery (PDA) were analysed. The TTFM was performed on the proximal and distal end of the graft, and proximally with distal occlusion of the graft. Low mean bypass graft flow PI and diastolic filling (DF) measured distally and proximally were compared, and graft compliance was estimated. RESULTS: Diastolic filling was higher distally in every single case (LITA-LAD: distal DF 76 +/- 12% vs proximal 66 +/- 13%, P = 0.005; SVG-RCA/PDA: distal 72 +/- 15% vs proximal 63 +/- 12%, P = 0.018). There were no significant differences in Q and PI. Subtracting the distal from the proximal flow gave a result identical to the proximal TTFM in distally occluded grafts, confirming the presence of graft capacitive flow. Graft compliance estimated from the flow of distally occluded grafts was 0.99 +/- 0.47 MUl/mmHg for LITA grafts and 0.78 +/- 0.42 MUl/mmHg for SVG grafts. CONCLUSIONS: The study confirmed that the TTFM measured at the proximal end of the coronary bypass could be viewed as a sum of graft capacitive flow and the flow that passes through the distal anastomosis. Graft capacitive flow increases the systolic and decreases the diastolic TTFM when measured at the proximal end of the graft. It explains the higher DF when the TTFM is measured at the distal end of the graft and the increase in the PI at the proximal end when Q decreases. As the influence of graft capacitive flow on the PI in low Q can be eliminated by performing the TTFM at the distal end of the graft, we believe that the value of PI is clinically irrelevant. PMID- 24174122 TI - Advanced malignant mesothelioma mimicking acute contained thoracic aortic rupture. AB - In the emergent setting, patients presenting with acute interscapular pain along with haemodynamic instability require immediate evaluation. We describe the case of a patient in which computed tomographic scanning demonstrated a large hyper dense, periaortic collection on post-contrast imaging. Urgent endovascular repair was performed for descending thoracic aortic rupture. Her postoperative course, however, was atypical with a readmission 1 week after discharge with symptoms similar to her primary presentation. Alternative pathologies were then considered in a more elective setting in which the correct diagnosis of diffuse malignant mesothelioma was ultimately discovered in a patient with no previous exposure to occupational toxins. The tumour burden was advanced and the patient opted for palliative care. Herein, we suggest a consideration for oncological thoracic pathology in patients presenting with signs and symptoms mimicking acute thoracic aortic rupture or dissection, who may demonstrate atypical symptoms. PMID- 24174123 TI - Reappraisal of a single-centre policy on the contemporary surgical management of active infective endocarditis. AB - OBJECTIVES: We studied a contemporary cohort of adult patients treated surgically for infective endocarditis (IE) in order to evaluate the surgical approach and predictors of outcomes, in relation to the intercurrent adaptation of the 2006 ACC/AHA guidelines. METHODS: One hundred and eighty-six consecutive patients operated on for active IE from August 1999 to September 2012 were reviewed retrospectively. Clinical presentation, surgical management and outcomes in the two study periods before and after January 2007 were compared (Period 1: n = 95 and Period 2: n = 91). RESULTS: The mean (SD) follow-up was 4.3 (3.8) years and was 99.5% complete. Patients in Period 2 had more frequently associated coronary artery disease (31 vs 18%, P = 0.06), while the microbiology revealed more Staphylococcus species (43 vs 26%, P = 0.02), predominantly Staphylococcus aureus (31 vs 19%; P = 0.07), and less culture-negative cases (7 vs 17%; P = 0.05). The median delay between diagnosis and surgery was 7 days in Period 2 compared with 14 days in Period 1 (P = 0.001). Surgery in Period 2 included more root replacements for aortic valve endocarditis (11 vs 2%; P = 0.02) and mitral valve repairs (18 vs 5%; P = 0.01), while the use of homografts for aortic valve endocarditis was almost abandoned (1 vs 15%; P = 0.001). Hospital mortality was 13% and did not change significantly over both periods (P = 0.66). The independent predictors of hospital mortality were age (P = 0.03), female gender (P = 0.02), previous cardiac surgery (P = 0.02), preoperative serum creatinine level >2 mg/dl (P = 0.05), S. aureus infection (P = 0.02), emergent or salvage operation (P = 0.001) and concomitant coronary artery bypass grafting (P = 0.03). The 1-, 3-, 5- and 10-year survival were 84, 72, 64 and 57%, respectively. Late survival was negatively influenced by S. aureus endocarditis (P < 0.001) and peripheral vascular disease (P = 0.03), whereas associated coronary artery disease (P = 0.07) had a strong impact. CONCLUSIONS: Adaptation of the 2006 ACC/AHA guidelines in the contemporary management of IE led to a shorter interval between diagnosis and surgery. Despite a more extensive and earlier operative approach, IE caused by S. aureus still remains a major determinant of early and late outcomes. PMID- 24174124 TI - Ionic-liquid-assisted microwave distillation coupled with headspace single-drop microextraction followed by GC-MS for the rapid analysis of essential oil in Dryopteris fragrans. AB - A rapid, green and effective miniaturized sample preparation technique, ionic liquid-assisted microwave distillation coupled with headspace single-drop microextraction was developed for the extraction of essential oil from dried Dryopteris fragrans. 1-Ethyl-3-methylimidazolium acetate was the optimal ionic liquid as the destruction agent of plant cell walls and microwave absorption was medium. n-Heptadecane (2.0 MUL) was adopted as the suspended microdrop solvent in the headspace for the extraction and concentration of essential oil. The optimal parameters of the proposed method were an irradiation power of 300 W, sample mass of 0.9 g, mass ratio of ionic liquids to sample of 2.8, extraction temperature of 79 degrees C, and extraction time of 3.6 min. In comparison to the previous reports, the proposed technique could equally monitor all the essential oil components with no significant differences in a simple way, which was more rapid and required a much lower amount of sample. PMID- 24174125 TI - Terson syndrome in conjunction with ruptured intracranial aneurysm and penetrating intracranial injury: a review of two cases. AB - Terson syndrome, the presence of intraocular hemorrhage in the setting of acutely elevated intracranial pressure, was historically described in conjunction with acute subarachnoid hemorrhage; however, more recently, it has been associated with a gamut of intracranial pathophysiology ranging from blunt or penetrating injury to neurosurgical procedures. We describe two cases of profound intracranial injury, secondary to ballistic injury, and a ruptured intracranial aneurysm, in which posterior chamber ocular hemorrhage was noted on CT imaging. Though the outcome in such cases, as with ours, is often poor, the findings are germane to clinical care as the presence of Terson syndrome has been noted to be a negative prognostic factor in multiple clinical reviews. Additionally, clinical recovery can be impacted adversely by lasting visual deficits or retinal degradation in the absence of timely ophthalmologic intervention. PMID- 24174126 TI - Probing the effects of ligand isomerism in chiral luminescent lanthanide supramolecular self-assemblies: a europium "Trinity Sliotar" study. AB - "Trinity Sliotar" family: Chiral ligands containing pyridyl and naphthalene moieties were synthesized and characterized. These ligands were successfully used for the synthesis of Eu(III) bundles where chirality of the ligand is successfully transferred onto the lanthanide centre resulting in circularly polarized red luminescence. PMID- 24174127 TI - Intact microRNA analysis using high resolution mass spectrometry. AB - MicroRNAs (miRNAs) are small single-stranded non-coding RNAs that post transcriptionally regulate gene expression, and play key roles in the regulation of a variety of cellular processes and in disease. New tools to analyze miRNAs will add understanding of the physiological origins and biological functions of this class of molecules. In this study, we investigate the utility of high resolution mass spectrometry for the analysis of miRNAs through proof-of-concept experiments. We demonstrate the ability of mass spectrometry to resolve and separate miRNAs and corresponding 3' variants in mixtures. The mass accuracy of the monoisotopic deprotonated peaks from various miRNAs is in the low ppm range. We compare fragmentation of miRNA by collision-induced dissociation (CID) and by higher-energy collisional dissociation (HCD) which yields similar sequence coverage from both methods but additional fragmentation by HCD versus CID. We measure the linear dynamic range, limit of detection, and limit of quantitation of miRNA loaded onto a C18 column. Lastly, we explore the use of data-dependent acquisition of MS/MS spectra of miRNA during online LC-MS and demonstrate that multiple charge states can be fragmented, yielding nearly full sequence coverage of miRNA on a chromatographic time scale. We conclude that high resolution mass spectrometry allows the separation and measurement of miRNAs in mixtures and a standard LC-MS setup can be adapted for online analysis of these molecules. PMID- 24174128 TI - Non-pharmacological modulation of the autonomic tone to treat heart failure. AB - The autonomic nervous system has a significant role in the pathophysiology and progression of heart failure. The absence of any recent breakthrough advances in the medical therapy of heart failure has led to the evolution of innovative non pharmacological interventions that can favourably modulate the cardiac autonomic tone. Several new therapeutic modalities that may act at different levels of the autonomic nervous system are being investigated for their role in the treatment of heart failure. The current review examines the role of renal denervation, vagal nerve stimulators, carotid baroreceptors, and spinal cord stimulators in the treatment of heart failure. PMID- 24174129 TI - Enhanced medial collateral ligament healing using mesenchymal stem cells: dosage effects on cellular response and cytokine profile. AB - Mesenchymal stem cells (MSCs) have potential therapeutic applications for musculoskeletal injuries due to their ability to differentiate into several tissue cell types and modulate immune and inflammatory responses. These immune modulatory properties were examined in vivo during early stage rat medial collateral ligament healing. Two different cell doses (low dose 1 * 10(6) or high dose 4 * 10(6) MSCs) were administered at the time of injury and compared with normal ligament healing at days 5 and 14 post-injury. At both times, the high dose MSC group demonstrated a significant decrease in M2 macrophages compared to controls. At day 14, fewer M1 macrophages were detected in the low dose group compared to the high dose group. These results, along with significant changes in procollagen I, proliferating cells, and endothelialization suggest that MSCs can alter the cellular response during healing in a dose-dependent manner. The higher dose ligaments also had increased expression of several pro-inflammatory cytokines at day 5 (IL-1beta, IFNgamma, IL-2) and increased expression of IL-12 at day 14. Mechanical testing at day 14 revealed increased failure strength and stiffness in low dose ligaments compared to controls. Based on these improved mechanical properties, MSCs enhanced functional healing when applied at a lower dose. Different doses of MSCs uniquely affected the cellular response and cytokine expression in healing ligaments. Interestingly, the lower dose of cells proved to be most effective in improving functional properties. PMID- 24174130 TI - Characterisation of human limbal side population cells isolated using an optimised protocol from an immortalised epithelial cell line and primary limbal cultures. AB - The challenges in limbal stem cell biology largely remain in the process of identification, isolation and expansion of these adult corneal epithelial stem cells of the eye. Due to the absence of specific limbal stem cell markers, identification and isolation of putative limbal stem cells is a complicated task. The side population assay is an isolation method that utilises the ability of stem cells to efflux the DNA-binding dye Hoechst 33342 (or other vital dyes) combined with dual wavelength flow cytometry and is a valuable strategy to enrich for limbal stem cells. This assay has been used to successfully identify stem/ progenitor cell populations in a variety of tissues and cell lines. Here we optimise this assay to identify SP cell populations in both primary human limbal epithelial cultures and in an established human corneal epithelial cell line. The limbal SP fraction showed higher expression of ATP-binding cassette sub-family G member 2 (ABCG2), DeltaNp63--a common limbal stem cell marker and the stem cell marker Sox2 compared to non-SP cells (NSP). PMID- 24174132 TI - The influence of study species selection on estimates of pesticide exposure in free-ranging birds. AB - Field studies of pesticide effects on birds often utilize indicator species with the purpose of extrapolating to other avian taxa. Little guidance exists for choosing indicator species to monitor the presence and/or effects of contaminants that are labile in the environment or body, but are acutely toxic, such as anticholinesterase (anti-ChE) insecticides. Use of an indicator species that does not represent maximum exposure and/or effects could lead to inaccurate risk estimates. Our objective was to test the relevance of a priori selection of indicator species for a study on pesticide exposure to birds inhabiting fruit orchards. We used total plasma ChE activity and ChE reactivation to describe the variability in anti-ChE pesticide exposure among avian species in two conventionally managed fruit orchards. Of seven species included in statistical analyses, the less common species, chipping sparrow (Spizella passerina), showed the greatest percentage of exposed individuals and the greatest ChE depression, whereas the two most common species, American robins (Turdus migratorius) and gray catbirds (Dumatella carolinensis), did not show significant exposure. Due to their lower abundance, chipping sparrows would have been an unlikely choice for study. Our results show that selection of indicator species using traditionally accepted criteria such as abundance and ease of collection may not identify species that are at greatest risk. Our efforts also demonstrate the usefulness of conducting multiple-species pilot studies prior to initiating detailed studies on pesticide effects. A study such as ours can help focus research and resources on study species that are most appropriate. PMID- 24174133 TI - Electron flow at the polarized mercury-water interface in the presence of membrane fragments rich in Na(+)-K (+)-Activated ATPase. AB - Measurements of interfacial electron flow indicate that membrane fragments rich in Na(+)-K(+)-ATPase are capable of absorbing and releasing electrons in the form of random currents at an electrode surface. The electron transporting system, which functions in the presence or absence of substrate and activating ions, may be part of or in contact with the enzyme system, but it is not related to the ATPase activity. The observed electron transport at an electrode surface resembles physiological electron transport processes in being reversible, in extending over the same range of potential, and in being affected by some of the chemicals that interfere with electron transport and oxidative phosphorylation in mitochondria. Our experiments do not provide sufficient evidence to identify the substances that are responsible for the random currents, but the results suggest that the electro-active substances are similar to those which are involved in the reactions at the second phosphorylation site in mitochondria. Experiments with this technique provide a new approach to the study of the mechanism of biological electron transport processes and their possible relation to ATP synthesis and hydrolysis. PMID- 24174131 TI - Risk of postprandial insulin resistance: the liver/vagus rapport. AB - Ingestion of a meal is the greatest challenge faced by glucose homeostasis. The surge of nutrients has to be disposed quickly, as high concentrations in the bloodstream may have pathophysiological effects, and also properly, as misplaced reserves may induce problems in affected tissues. Thus, loss of the ability to adequately dispose of ingested nutrients can be expected to lead to glucose intolerance, and favor the development of pathologies. Achieving interplay of several organs is of upmost importance to maintain effectively postprandial glucose clearance, with the liver being responsible of orchestrating global glycemic control. This dogmatic role of the liver in postprandial insulin sensitivity is tightly associated with the vagus nerve. Herein, we uncover the behaviour of metabolic pathways determined by hepatic parasympathetic function status, in physiology and in pathophysiology. Likewise, the inquiry expands to address the impact of a modern lifestyle, especially one's feeding habits, on the hepatic parasympathetic nerve control of glucose metabolism. PMID- 24174134 TI - Coupling of ion transport in green cells ofAtriplex spongiosa leaves to energy sources in the light and in the dark. AB - The coupling of ion transport to energy sources in the light and in the dark in green cells ofAtriplex spongiosa leaves was investigated using light of different qualities, an inhibitor of electron transport (dichlorophenyl dimethyl urea), and an uncoupler (p-CF3O-carbonyl cyanide phenylhydrazone). Two different mechanisms of ion uptake were, distinguished. (1) A light-dependent Cl(-) pump which is linked to light-dependent K(+) uptake. The energy for this pump is probably derived from photosynthetic electron transport or from nicotinamide adenine dinucleotide phosphate, reduced form. This mechanism is dichlorophenyl dimethyl urea-sensitive and enhanced by uncouplers. (2) A mechanism independent of light, which operates at the same rate in the light and in the dark. This mechanism is sensitive to uncouplers. It is probably aK-Na exchange mechanism since K(+) and Cl(-) uptake and a small net uptake of H(+) are balanced by Na(+) loss. PMID- 24174135 TI - Membrane-bound 2,3-diphosphoglycerate phosphatase of human erythrocytes. AB - Gradual osmotic hemolysis of human erythrocytes reduces the cell content of whole protein, hemoglobin, 2,3-diphosphoglycerate and triosephosphate isomerase extensively, but not that of membrane protein and 2,3-diphosphoglycerate phosphatase. After the refilling of the ghosts with 2,3-diphosphoglycerate and reconstitution of the membrane, the 2,3-diphosphoglycerate phosphatase activity equals that of intact red cells. The membrane-bound 2,3-diphosphoglycerate phosphatase can be activated by sodium hyposulfite. The enzyme system of ghosts seems to differ from that of intact red cells with regard to the optima of pH and temperature. It remains to be elucidated if the membrane binding of the 2,3 diphosphoglycerate phosphatase is related to the transfer of inorganic phosphate across the red cell membrane. PMID- 24174136 TI - The effect of the polar moiety of lipids on the ion permeability of bilayer membranes. AB - Bilayer membranes were prepared with the negatively charged lipids phosphatidylglycerol and diphosphatidylglycerol, the positively charged lipid lysyl phosphatidylglycerol, the zwitterionic lipid phosphatidylethanolamine, and an uncharged glycolipid, diglucosyldiglyceride, all isolated from gram-positive bacteria. Bilayer membranes of all these lipids manifested specific resistances of 10(7) to 10(9) Omega cm(2) and capacitances of 0.3 to 0.4 MUF cm(-2). The membrane potentials of these bilayers were measured as a function of the sodium chloride, potassium chloride, and hydrogen chloride transmembrane concentration gradients (0.01 to 0.10M) and were found to be linear with the logarithm of the salt activity gradients. Membranes made from lysyl phosphatidylglycerol (one net positive charge) were almost completely chloride selective, whereas membranes from phosphatidylglycerol and diphosphatidylglycerol (one and two net negative charges, respectively) were highly cation selective. Membranes prepared with either diglucosyldiglyceride or phosphatidylethanolamine showed only slight cation selectivity. These findings indicate that the charge on the polar head group of membrane lipids plays an important role in controlling the ion-selective permeability of the bilayer. PMID- 24174137 TI - The effects of bicarbonate ions and external pH on the membrane potential and resistance ofNitella translucens. AB - The effects of bicarbonate ions on the membrane potential and resistance ofNitella translucens are shown to be primarily due to the change in pH produced by the bicarbonate acting as a buffer, and not due to the presence of an electrogenic anion pump. The mechanism by which pH affects the membrane potential is discussed in the context of recent work by other authors on this effect. PMID- 24174138 TI - An ultrastructural study of isolated rat skeletal muscle mitochondria in various metabolic states. AB - An electron microscopic examination was made of isolated rat skeletal muscle mitochondria in various functional states. Shifts in the inner membrane ultrastructure of populations of mitochondria were observed under certain conditions. However, ultrastructural transformations reported by others during rapid changes in biochemical states were not observed in skeletal muscle mitochondria. There does not appear to be a strict correlation between metabolic states and ultrastructural states in isolated rat skeletal muscle mitochondria as has been observed in isolated mitochondria from several other tissue types. PMID- 24174139 TI - Effect of poly-L-lysine on potassium fluxes in red beet tissue. AB - Poly-L-lysine concentrations (10(-6) M) which cause slight leakage of pigment from beet cells completely disrupt the kinetics of(*)K (labeled) absorption at 25 degrees C in the range 0.01 to 50MM KCl. Lower concentrations of polylysine (10( 7) to 10(-9) M) interfere with potassium fluxes at both cell membranes, initially increasing efflux across the plasma membrane and decreasing the capacity of the cytoplasm to retain ions during flux experiments at 2 degrees C. At 25 degrees C, these concentrations of polylysine increase(*)K (labeled) absorption from 0.2MM KCl, but not from 10MM KCl. These responses are discussed in relation to ion transport via the three-compartment in-series model proposed for plant cells. Particular emphasis is placed on the role of the plasma membrane in K transport from solutions of low concentration. PMID- 24174140 TI - Action of phenazine methyl sulfate, inhibitors, and uncouplers on the light induced proton transport by cells ofRhodospirillum rubrum. AB - Suspensions of log phase cells ofRhodospirillum rubrum at pH 5.5 show a light induced decrease in the pH of the medium which is reversed during the subsequent dark period. The velocity and magnitude of the pH change were the same whether the cells were bubbled with air, CO2-free air or N2 during experimentation. The pH response is temperature dependent. Phenazine methyl sulfate (PMS) at concentrations above 0.05MM stimulates the light-induced pH change. PMS at 1MM gives a 2-fold increase in the initial rate upon illumination and a 1.5-fold increase in the total change in pH after 2 min of illumination. The inhibition of the proton transport by 10 MUg/ml antimycin A or 20 MUM 2-n-heptyl-4 hydroxyquinoline-N-oxide can be partially relieved by PMS. However, inhibition of the light-induced proton transport with 0.5MM 2,4-dinitrophenol or 3 MUM carbonylcyanide-m-chlorophenylhydrazone (CCCP) cannot be overcome by addition of PMS. Valinomycin, at a concentration of 3 MUM, caused a slight stimulation of the light-induced proton transport in the presence of 200MM KCl. The inhibition of proton transport by 3 MUM CCCP was partially relieved with 3 MUM valinomycin in the presence of 200MM KCl, but the antibiotic was without effect when the cells were suspended in 200MM NaCl. The results are discussed in terms of current theories of the action of PMS, antimycin A, valinomycin, and uncouplers on the light-induced electron flow and photophosphorylation inR. rubrum. PMID- 24174141 TI - A study of sodium release in the course of ATP hydrolysis by membrane ATPase. AB - With the aid of sodium-sensitive glass electrodes, changes in sodium ion activity were studied in the course of subsequent additions of components required for ATP hydrolysis provided by Na(+)-K(+)-dependent membrane ATPase. Membrane ATPase was obtained from guinea pig kidney cortex. In the presence of ATP, Mg(++) and Na(+) in media, the addition of K(+) caused an increase in Na(+) activity. The omission of ATP or its substitution by ADP as well as the addition of Ca(++) to the media eliminated the above-mentioned increase of Na(+) activity. Quabain did not affect Na(+) release caused by the addition of K(+), although it significantly inhibited ATPase activity of the preparation. The data obtained were considered to be a direct indication of ion exchange during the course of membrane ATPase reaction. This ion-exchange stage of the reaction is not inhibited by ouabain. The ratio of sodium ions released per one inorganic phosphate formed in the course of the reaction was found to be much higher than that established for transporting membranes of intact cells. A possible cause of this difference is discussed. PMID- 24174142 TI - Studies on the chemical properties of the acetylcholine receptor site of the frog neuromuscular junction. AB - The effect of a water-soluble carbodiimide has been used to study the nature of the presumed anionic part of the acetylcholine (ACh) receptor at the frog neuromuscular junction. The ACh sensitivity has been measured by the moving fluid electrode method and by recording end plate potentials with microelectrodes. The carbodiimide blocked ACh sensitivity without marked effect on the membrane resistance or potential difference. The conditions of reversibility of the block and the results obtained with phospholipids suggest that a carboxyl group is important in the combination of ACh with the receptor. PMID- 24174143 TI - The permeability of the frog choroid plexus to nonelectrolytes. AB - Anin vitro preparation of the frog choroid plexus has been used to measure the permeability of the choroidal epithelium to 50 nonelectrolytes by an osmotic method. The method involves the measurement of nonelectrolyte reflection coefficients (sigma) by a rapid electrical procedure. For the majority of compounds tested, there was a good correlation between the rate of solute permeation and the solute's bulk-phase lipid: water partition coefficients; i.e., the higher the partition coefficient the greater the permeability. The membrane lipids of the choroid plexus differ from the membrane lipids of the gall bladder in at least three ways: (1) the lipids of the choroid plexus cannot distinguish between branched chain solutes and their straight chain isomers; (2) small polar solutes such as urea and acetamide permeate via the membrane lipids to a significant extent; and (3) the smaller selectivity ratios suggest that the lipids of the choroid plexus contain more hydrogen bonding sites (i.e., there are stronger solute: lipid intermolecular forces in the choroid plexus). The permeability characteristics of the choroid plexus are qualitatively similar to those of most other cell membranes. In addition, there is evidence for the presence of a special mechanism for the transport of sugar across this epithelium. PMID- 24174144 TI - Molecular and kinetic parameters of sugar transport across the frog choroid plexus. AB - The nature of sugar transport across the "blood-cerebrospinal fluid barrier" has been investigated using anin vitro preparation of the frog posterior choroid plexus. The permeability of 41 sugars and related compounds was measured by the rapid osmotic procedure described previously. Sugar permeation was found to be stereospecific, inhibited by 1,5-difluoro-2,4-dinitrobenzene, insensitive to anoxia, and independent of the external alkali cation composition. In addition, the transport of a sugar was inhibited by structural analogues. Transport occurred equally well from the ventricular or serosal surface of the tissue, and the rate of transport could be described formally by Michaelis-Menten kinetics. The results were analyzed in terms of the conformation of the sugars in aqueous solution. Sugars which were transported have the d-glucose chair conformation. There is a good correlation between the affinity of the sugar for the transport system and the number of hydroxyl groups attached to the equatorial plane of the ring; d-glucose with five equatorial hydroxyl groups has the greatest affinity. It is concluded that sugar transport across the choroid plexus occurs by facilitated diffusion. PMID- 24174145 TI - Electron microscopical analysis of surface charge labelling density at various stages of the erythroid line. AB - With use of the positively charged, colloidal ferric oxide labelling technique for electron microscopy of sections of rabbit marrow, a reduction in labelling density on the surface of differentiating red cell precursors was demonstrated. The number of iron particles per unit length of membrane was counted. A progressive diminution in labelling density follows cell division, reaching a minimum in the orthochromatic erythroblast, from which the nucleus is expelled. A slight increase in charge density is noted in the reticulocyte, and further increase is observed with its maturation to the erythrocyte. The results indicate that biosynthesis of n-acetyl neuraminic acid stops at the earliest recognizable stage of erythroid differentiation. PMID- 24174146 TI - Membrane structure: Morphological and chemical alterations in phospholipase-C treated mitochondria and red cell ghosts. AB - Phospholipase C fromBacillus cereus was used as a tool for the study of membrane structure. Interference and electron microscopic examination of isolated rat kidney mitochondria and human red blood cell ghosts incubated in the presence of the enzyme revealed that there were discrete areas of digestion on the membranes. These areas were distributed over the surface of the membrane but did not coalesce. These data are interpreted as giving support to the membrane model which postulates that protein does not cover the entire phospholipid layer of the membrane, but that there are areas of the membrane in which the phospholipid polar groups are in direct contact with the outside milieu. PMID- 24174147 TI - The effect of electric fields on brain cephalin and lecithin films. AB - The effect of a direct-current electric field on cephalin and lecithin films was measured using infrared spectral techniques. The intensities of the spectral bands assigned to the vibrations of the phosphate and the fatty acid chain increased to a maximum as the applied potential was increased. These changes were observed only with brain cephalin and brain lecithin films and not with synthetic lipid films. These observations may be due to changes in the alignments of the phosphate and base dipoles in the lipid molecule as the applied field is changed. The electric field strengths at which the maximum intensities of the spectral bands are observed increase as the thickness decreases. Extrapolation to the thickness of the nerve membrane yields a value of the field strength that is much larger than is to be expected in the neuron. This suggests that only the phosphate group and the hydrocarbon chain change conformation during the passage of the nerve impulse. PMID- 24174149 TI - Interactions of cytochromec with phospholipid membranes : Binding of cytochromec to phospholipid liquid crystals. AB - Cytochromec added during the formation of lecithin-cardiolipin liquid crystals in 0.015M KCl is readily bound. After successive washings with 0.15M KCl, only about 50% of this bound cytochromec is removed. The remaining cytochromec is resistant to further salt extraction, and the amount of this cytochromec that is bound varies with the concentration of added cytochromec to a maximum binding ratio of 1?70, mole ratio cytochromec to phospholipid. This binding appears to be electrostatic; it is competitively inhibited by increasing the initial molarity of KCl from 0.015 to 0.10M. Binding of cytochromec is insignificant in the absence of cardiolipin, and is affected by varying the pH. Electron microscope studies of osmium tetroxide-stained thin sections show that the liquid crystals consist of vesicles, each of which contains a large number of concentric, alternating light and dense lines. The dense lines have been identified by other workers with the polar head groups of the phospholipids on the surface of a bilayer, and the light area represents the hydrophobic interior. The addition of cytochromec causes an average decrease in the number of lines per vesicle. It increases the center-to-center distance between two neighboring light or dense lines and the width of the dense lines. On the basis of this evidence and electrostatic binding, it is concluded that cytochromec is binding on the polar surfaces of the phospholipid bilayers comprising the liquid crystalline vesicles. PMID- 24174148 TI - Ion transport and energy conservation in submitochondrial particles. AB - The combination of valinomycin and nigericin in the presence of K(+) uncouples submitochondrial particles (SMP) as evidenced by: 1) loss and release of the oligomycin-induced respiratory control; 2) inhibition of the P/0 ratio; 3) inhibition of three energy-linked reactions - pyridine-nucleotide transhydrogenation, reversal of electron-transfer, and bromthymol blue and 8 anilino-1-naphtalenesulfonate responses; and 4) change of redox state of cytochromes to the same extent obtained with conventional uncouplers. Neither antibiotic alone, in the presence of K(+), markedly affected the energized state of the system. Direct measurements of K(+) and H(+) movements showed that SMP did indeed translocate these ions in a predictable manner, i. e., a nigericin stimulated influx of K(+) to SMP, followed by a valinomycin-mediated efflux of the K(+) taken up. The NH 4 (+) -dependent uncoupling is demonstrated to be associated with the uptake of NH 4 (+) by SMP with a consequent collapse of the pH gradient established during respiration, followed by a valinomycin-mediated efflux of the NH 4 (+) taken up. The effects of cations and antibiotics can be mimicked by suitable combinations of cations and anions, suggesting that the valinomycin-mediated efflux of cations from SMP is electrophoretic in nature and can be replaced by an electrophoretic influx of appropriate anions. Analogies are drawn with observations reported on bacterial chromatophores and chloroplasts, and a general scheme is suggested. The implications of these results are discussed in terms of the current hypotheses of energy coupling in oxidative and photosynthetic phosphorylation. PMID- 24174150 TI - Interactions of cytochromec with phospholipid membranes : Reactivity of cytochromec bound to phospholipid liquid crystals. AB - Cytochromec can be bound to mixed cardiolipin-lecithin liquid crystals so that it cannot be removed by repeated washings with solutions of high ionic strength. The oxidized and reduced spectra of this cytochromec show no detectable differences from those for soluble cytochromec. Unlike soluble cytochromec, however, some 90% of the bound cytochromec is not reduced by ascorbate, and it is only slowly reduced by dithionite. The addition of redox dyes causes complete and immediate reduction in the presence of ascorbate or dithionite. It is suggested that this is because the dyes possess some degree of lipid solubility and are able to penetrate the phospholipid membrane barriers separating cytochromec from the bulk solution. The addition of detergents, such as Triton X-100, also promotes reduction of the bound cytochromec by ascorbate. A small change in the standard potential from, 273 mV for soluble cytochromec to 225 mV for the bound cytochromec was found. The bound cytochromec reacts readily with potassium cyanide to form the normal cyanide-ferricytochromec complex, differing in the rate of formation from soluble cytochromec only at alkaline pH values. The relationship of these findings to work on the membrane-bound cytochromec in mitochondria and submitochondrial particles is discussed. PMID- 24174151 TI - The role of water diffusion in the action of vasopressin. AB - Vasopressin produces a large increase in the osmotic flow of water across the toad bladder, with little apparent change in the diffusion rate of tritiated water. This discrepancy between osmotic and diffusional net flow is the basis of the pore theory of vasopressin action. The present studies show that there is in fact a large (at least 10-fold) increase in water diffusion subsequent to addition of vasopressin, which is masked by unstirred layers and by the resistance offered to diffusion by the thick layer of connective tissue and muscle supporting the bladder epithelial cells. An even higher diffusion rate would be anticipated with the complete elimination of unstirred layers, and of barriers to diffusion remaining within the epithelial layer itself. An alternative to the pore hypothesis is considered, in which vasopressin acts solely by increasing the diffusion rate of water across the luminal membrane of the epithelial cell. PMID- 24174152 TI - The comparative transport of K(+) and Rb (+) in normal and malignant rat tissuesin vivo and in liver slices, diaphragm, and tumor slicesin vitro. AB - The selectivity in the steady state uptakes of Rb(+) and K(+) has been studied in a number of normal and malignant rat tissues. The selectivity is minimal in erythrocytes and the two fastest-growing of four transplantable tumors, in which there is little discrimination between the two ions, and ranges upwards to a maximum Rb(+) uptake in liver. In each tissue, the selectivity is independent of Rb(+) concentration or of K(+) deficiency (except in skeletal muscle). In liver slicesin vitro, reduction of energy metabolism by lowering the temperature or by the addition of metabolic inhibitors reduces the Rb(+)?K(+) discrimination proportionately much more than K(+) transport. Diaphragm and slices of a transplantable tumor give similar results. With temperature reduction, there is a logarithmic relation between the Rb(+)?K(+) discrimination ratio and the respiration rate of liver slices. The results are quantitatively accounted for by simultaneous diffusion and metabolically coupled transport across a homogeneous membrane in which Rb(+) transport is more closely coupled than that of K(+) to a metabolic flux across the membrane. There is evidence that the tissue differences in Rb(+)?K(+) selectivity originate in the different levels of the coupling metabolic flux in different cell types and thus of the energy expenditure on ion transport. In contrast to the differences in steady state selectivity between Rb(+) and K(+), the initial ratio of uptakes of trace(43)K and(86)Rb, in otherwise steady state conditions, is close to unity in both liver and tumor slices, in agreement with theoretical calculations. PMID- 24174154 TI - Alpha-tocopherol in the retinal outer segment of bovine eyes. AB - alpha-Tocopherol was identified in lipid extracts of bovine retinal outer segment (ROS) preparations. Positive identification was obtained by the thin layer chromatographic characteristics of the tocopherol form and its oxidation product alpha-tocopherylquinone, and by the ultraviolet spectrum of the oxidized and KBH4 reduced form of the tocopherylquinone. In the ROS preparations used, alpha tocopherol chromanol was the predominant species, the quinone form accounting for 25% or less of the total. The concentration of alpha-tocopherol in the ROS preparations was about 0.1 mole alpha-tocopherol per mole rhodopsin, or about 1 nmole/mg, protein. Mitochondria from bovine retina contained about 0.4 nmole alpha-tocopherol per mg protein. PMID- 24174153 TI - Electron microscopic observations of the surface of L-cells in culture. AB - Techniques are described for the preparation of preshadowed replicas of both the upper and lower surfaces of L-cells in culture, and of cross sections of L-cells growing on a cellophane substrate. These revealed long slender microvilli, 800 to 1,100 A in diameter, projecting from both upper and lower surfaces of the cells. These microvilli were frequently observed to contact other cells and substrate, and to leave material behind on the substrate. The plasma membrane of the lower surface was separated from the substrate by an electron-lucent gap 200 to 300 A wide. The surface coat of the L-cell was visualized by staining with colloidal iron and ruthenium. Staining with colloidal iron was most intense on the surface of the microvilli. The gap between cell and substrate was intensely stained with ruthenium red. Enzymatic digestion of living cells revealed that both trypsin and neuraminidase reduced the staining of the cell coat by colloidal iron, whereas only trypsin altered its staining with ruthenium red. After trypsin treatment, fragments of an amorphous material with the staining characteristics of the cell coat were observed between the denuded cells. Treatment with ribonuclease, chymotrypsin or hyaluronidase did not affect the staining of the cell coat. PMID- 24174155 TI - Calcium efflux from human erythrocyte ghosts. AB - The passive Ca efflux from human red cell ghosts was studied in media of differing ion compositions and compared to the ATP-dependent Ca efflux. Cells were loaded with(45)Ca during reversible hemolysis, and the loss of radioactivity into the non-radioactive incubation medium was measured, usually for 3 hr at 37 degrees C. Analysis of the efflux curves revealed that(45)Ca efflux followed the kinetics of a simple two-compartment system. In the concentration range between 0 and 1MM Ca in the external solution ([Ca(++)] o ), the rate constant of passive Ca efflux (k min(-1), fraction of(45)Ca lost per minute into the medium) increased from 0.00732 to 0.0150 min(-1). There was no further increase at higher [Ca(++)] o . The relation between the rate constant of Ca efflux and [Ca(++)] o is thus characterized by saturation kinetics. The passive transfer system for Ca could also be activated by Sr. The alkali metal ions Na, K and Li did not seem to have any significant influence on passive Ca transfer. The passive Ca efflux was slightly inhibited by Mg and strongly inhibited by Pb. Under most experimental conditions, a fraction of 15 to 50% of the intracellular Ca seemed to be "inexchangeable". The inexchangeable fraction decreased with increasing [Ca(++)] o and increased with increasing [Ca(++)] i . It was not influenced by alkali metal ions, CN or Pb, but it could be completely removed from the cells by the addition of 0.1MM Mersalyl to the incubation medium or by hemolysis with addition of a detergent. The active ATP-dependent Ca transport differed characteristically from passive transfer; the rate constant decreased with increasing [Ca(++)] o , and the inexchangeable Ca fraction increased with increasing [Ca(++)] o . The experimental results suggest that there exists a carrier-mediated Ca-Ca exchange diffusion in the erythrocyte membrane and that only a fraction of the ghost cell population participates in the Ca exchange diffusion. PMID- 24174156 TI - The interaction of 1-anilino-8-naphthalenesulfonate with the membranes of the sarcoplasmic reticulum and various lipid compounds. AB - (1) The enzymatic removal of lipids from the vesicular membranes of the sarcoplasmic reticulum does not interfere with the fluorescence of the 1-anilino 8-naphthalenesulfonate (ANS) vesicular complex. (2) The fluorescence intensity of the ANS vesicular complex is considerably (50%) reduced by oleic acid (0.5MM) because it displaces ANS from its binding sites. (3) Stearic acid, which also combines with the membranes, interferes neither with ANS binding nor with ANS fluorescence. (4) Of all lipid compounds tested, oleylamine produces the most pronounced fluorescence enhancement of ANS. (5) The complexes formed between oleic acid and cetyltrimethyl ammonium salts or between oleic acid and polylysine produce a much higher fluorescence enhancement than the isolated components. (6) Low concentrations of ether added to ANS-containing vesicular suspensions reduce their fluorescence intensity. It returns to the initial intensity when the ether is removed. (7) A small cyclic change of the fluorescence of the vesicular ANS complex takes place during active calcium uptake. PMID- 24174157 TI - Membrane excitability and dissipative instabilities. AB - Electrical excitation is interpreted in terms of a cooperative structural transition of membrane protomers coupled with the translocation of a permeant molecule in a non-equilibrium environment. Equations for flow of permeant and for membrane conformation are derived for the simple case of a single non-charged permeant. On the basis of a few simple physical assumptions, the theory predicts several important properties of electrically excitable membranes: the steepness of the relation between membrane conductance and potential, the presence of a negative conductance, and the occurrence of instabilities following rapid perturbations of membrane environment, giving rise to some simple cases of action potentials. Several experimental tests of the membrane with its changes of electrical properties are proposed. From a thermodynamic point of view, an electrically excitable membrane, in its resting state, lies beyond a dissipative instability and consequently is in a non-equilibrium state but with stable organization, a "dissipative structure" of Prigogine. Membrane excitation following a small perturbation of the environment would correspond to a jump from such an organization to another stable organization but close to thermodynamic equilibrium. It is shown how the cooperative molecular properties of the membrane are amplified by energy dissipation at the macroscopic level. PMID- 24174158 TI - Simplified deoxypropionate acyl chains for Mycobacterium tuberculosis sulfoglycolipid analogues: chain length is essential for high antigenicity. PMID- 24174159 TI - Synthesis of substituted tetrahydrocyclobuta[b]benzofurans by palladium-catalyzed substitution/[2+2] cycloaddition of propargylic carbonates with 2-vinylphenols. AB - Radical methods: The title reaction proceeds in the presence of a palladium catalyst to deliver substituted tetrahydrocyclobuta[b]benzofurans in a stereoselective manner. A radical mechanism is discussed. PMID- 24174160 TI - Characteristic kidney pathology, gene abnormality and treatments in LCAT deficiency. AB - Lecithin:cholesterol acyltransferase (LCAT) is a key enzyme involved in reverse cholesterol transport from the peripheral tissues to the liver. LCAT deficiency, in which this enzyme is congenitally absent, is a genetic disease that impairs the esterification of free cholesterol in the plasma, leading to accumulation of phospholipids, including lecithin, in the organs of the body; the clinical manifestations include corneal opacities, normochromic anemia, renal disorder, etc. The prognosis is determined by the degree of renal dysfunction, and renal biopsy specimens reveal characteristic light- and electron-microscopic findings. The disease, transmitted by autosomal recessive inheritance, is extremely rare. There have only been 88 gene mutations of the LCAT gene reported around the world, and 13 of them are from Japan. One of the characteristics of LCAT deficiency is the strong correlations among the patterns, extent and phenotypes of these gene mutations. PMID- 24174161 TI - Postoperative renal artery thrombosis. PMID- 24174162 TI - Recent advances in amino acid analysis by capillary electromigration methods, 2011-2013. AB - This article describes the most important research published on amino acid (AA) analysis using CE during the period from June 2011 to May 2013, and follows the format of the previous articles of Smith (Electrophoresis 1999, 20, 3078-3083), Prata et al. (Electrophoresis 2001, 22, 4129-4138), and Poinsot et al. (Electrophoresis 2003, 24, 4047-4062; Electrophoresis 2006, 27, 176-194; Electrophoresis 2008, 29, 207-223; Electrophoresis 2010, 31, 105-121; Electrophoresis 2012, 33, 14-35). We present new developments in AA analysis with CE, mainly describing the use of MS or LEDs for detection following conventional or enantiomeric separation developments. In addition, in an application part, we describe neurochemical or clinical studies, metabolomics for plant extracts and biological fluids, and finally works focused on AAs in food and agricultural applications. PMID- 24174163 TI - Analysis of maximum mouth opening and its related factors in 3- to 5-year-old Taiwanese children. AB - Maximum mouth opening (MMO) can reflect the function of the dentofacial musculature and joint system, and routine oral examinations should include its assessment. To diagnose abnormalities using MMO measurements, it is necessary to establish the normal range of MMO; however, few studies have investigated this subject in Taiwan. Therefore, the purposes of this study were to determine the normal MMO range in 3- to 5-year-old preschool children and to investigate the factors correlated with MMO. We examined the interincisal distance, defined as the distance between the edges of the upper and lower incisors, in 518 preschool children (age range 3-5 years; 271 boys and 247 girls) with a plastic sliding caliper. The MMO on both sides of the mouth and mouth width (MW) was measured 3 times. No differences in MMO were found between the genders. The interincisal distance was 37.47 (+/-4.11) mm for boys and 36.93 (+/-3.85) mm for girls, whereas the mean MMO was 37.21 (+/-3.99) mm. The MMO increased with the increasing age of the children, and the mean value of MMO in children aged 3, 4, and 5 was 35.31 (+/-4.03), 36.61 (+/-3.79), and 38.31 (+/-3.88) mm, respectively. Furthermore, MMO was found to correlate with weight and MW. MMO increased by 0.19 mm per increased weight and 0.37 mm per increased MW. The mean value of MMO in 3- to 5-year-old preschool children was 37.21 (+/-3.99) mm. MMO in 3- to 5-year-old preschool children increased with age and was correlated with weight and MW. PMID- 24174165 TI - TERT promoter mutations rather than methylation are the main mechanism for TERT upregulation in adult gliomas. PMID- 24174166 TI - Confirmation of ovarian homogeneity in post-vitellogenic cultured white sturgeon, Acipenser transmontanus. AB - Assessing stage of oocyte maturity in female sturgeon by calculating oocyte polarization index (PI) is a necessary tool for both conservation propagation managers and caviar producers to know when to hormonally induce spawning. We tested the assumption that sampling ovarian follicles from one section of one ovary is sufficient for calculating an oocyte PI representative of oocyte maturity for an individual animal. Short-wavelength near-infrared spectroscopy (SW-NIR) scans were performed on three positions per ovary for five fish prior to caviar harvest. Samples of ovarian follicles were subsequently taken from the exact location of the SW-NIR scans for calculation of oocyte PI and follicle diameter. Oocyte PI was statistically different though not biologically relevant within an ovary and between ovaries in four of five fish. Follicle diameter was statistically different but not biologically relevant within an ovary in three of five fish. There were no differences in follicle diameter between ovaries. No statistical differences were observed between SW-NIR spectra collected at different locations within an ovary or between ovaries. These results emphasize the importance of utilizing both oocyte PI measurement and progesterone-induced oocyte maturation assays while deciding when to hormonally induce spawning in sturgeon females. PMID- 24174164 TI - TERT promoter mutations are highly recurrent in SHH subgroup medulloblastoma. AB - Telomerase reverse transcriptase (TERT) promoter mutations were recently shown to drive telomerase activity in various cancer types, including medulloblastoma. However, the clinical and biological implications of TERT mutations in medulloblastoma have not been described. Hence, we sought to describe these mutations and their impact in a subgroup-specific manner. We analyzed the TERT promoter by direct sequencing and genotyping in 466 medulloblastomas. The mutational distributions were determined according to subgroup affiliation, demographics, and clinical, prognostic, and molecular features. Integrated genomics approaches were used to identify specific somatic copy number alterations in TERT promoter-mutated and wild-type tumors. Overall, TERT promoter mutations were identified in 21 % of medulloblastomas. Strikingly, the highest frequencies of TERT mutations were observed in SHH (83 %; 55/66) and WNT (31 %; 4/13) medulloblastomas derived from adult patients. Group 3 and Group 4 harbored this alteration in <5 % of cases and showed no association with increased patient age. The prognostic implications of these mutations were highly subgroup specific. TERT mutations identified a subset with good and poor prognosis in SHH and Group 4 tumors, respectively. Monosomy 6 was mostly restricted to WNT tumors without TERT mutations. Hallmark SHH focal copy number aberrations and chromosome 10q deletion were mutually exclusive with TERT mutations within SHH tumors. TERT promoter mutations are the most common recurrent somatic point mutation in medulloblastoma, and are very highly enriched in adult SHH and WNT tumors. TERT mutations define a subset of SHH medulloblastoma with distinct demographics, cytogenetics, and outcomes. PMID- 24174167 TI - Effect of dietary lysine on growth, intestinal enzymes activities and antioxidant status of sub-adult grass carp (Ctenopharyngodon idella). AB - The dietary lysine requirement of sub-adult grass carp (460 +/- 1.5 g) was assessed by feeding diets supplemented with grade levels of lysine (6.6, 8.5, 10.8, 12.9, 15.0 and 16.7 g kg(-1) diet) for 56 days. The test diets (28% CP) contained fish meal, casein and gelatin as sources of intact protein, supplemented with crystalline amino acids. Weight gain (WG), feed intake and feed efficiency were significantly improved with increasing levels of lysine up to 12.9 g kg(-1) diet and thereafter declined (P < 0.05). Quadratic regression analysis of WG at 95% maximum response indicated lysine requirement was 10.9 g kg(-1) diet. Activities of trypsin, chymotrypsin, lipase, Na(+), K(+)-ATPase and alkaline phosphatase in intestine, creatine kinase activity in proximal and mid intestine responded similar to WG (P < 0.05). In addition, lipid and protein oxidation decreased with increasing levels of lysine up to certain values and increased thereafter (P < 0.05); the anti-hydroxyl radical capacity, dismutase, catalase, glutathione peroxidase, glutathione reductase, glutathione-S transferase (GST) activities and glutathione content were increased with increasing dietary lysine levels up to certain values in the detected tissues, except for hepatopancreatic GST. Requirement estimated on the basis of malondialdehyde content in intestine and hepatopancreas was 10.6 and 9.53 g lysine kg(-1) diet, respectively. PMID- 24174168 TI - Three-dimensional implant position and orientation after total knee replacement performed with patient-specific instrumentation systems. AB - Patient-specific instrumentation systems are entering into clinical practice in total knee replacement, but validation tests have yet to determine the accuracy of replicating computer-based plans during surgery. We performed a fluoroscopic analysis to assess the final implant location with respect to the corresponding preoperative plan. Forty-four patients were analyzed after using a patient specific system based on CT and MRI. Computer aided design implant models and models of the femur and tibia bone portions, as for the preoperative plans, were provided by the manufacturers. Two orthogonal fluoroscopic images of each knee were taken after surgery for pseudo-biplane imaging; 3D component locations with respect to the corresponding bones were estimated by a shape-matching technique. Assuming that the corresponding values at the preoperative plan were equal to zero, discrepancies were taken as an indication of accuracy for the systems. A repeatability test revealed that the technique was reliable within 1 mm and 1 degrees . The maximum discrepancies for all the patients for the femoral component were 5.9 mm in a proximo-distal direction and 4.2 degrees in flexion. Good matching was found between final implantations and preoperative plans with mean discrepancies smaller than 3.1 mm and 1.9 degrees . PMID- 24174170 TI - Potassium isopropoxide: for sulfination it is the only base you need! AB - PEPPSI max: KOiPr has been identified as the key ingredient for Pd-catalyzed sulfination. Potassium is essential to keep the thiol concentration low, and isopropoxide is necessary for precatalyst activation and to break up Pd-sufide based resting states. Together with the reactive Pd-PEPPSI-IPent(Cl) o-picoline catalyst, this system couples profoundly deactivated partners at RT that other catalysts cannot accomplish in refluxing toluene. PMID- 24174169 TI - Outcome of patients with esophageal perforations: a multicenter study. AB - BACKGROUND: Recent studies have suggested that stent-grafting may improve the treatment outcome of patients with esophageal perforation, but evidence on this is still lacking. METHODS: Data on 194 patients who underwent conservative (43 patients), endoclip (4 patients) stent-grafting (63 patients) or surgical treatment (84 patients) for esophageal perforation were retrieved from nine medical centers. RESULTS: In-hospital/30-day mortality was 17.5 %. Three-year survival was 67.1 %. Age, coronary artery disease, and esophageal malignancy were independent predictors of early mortality. Chi squared automatic interaction detection analysis showed that patients without coronary artery disease, without esophageal malignancy and younger than 70 years had the lowest early mortality (4.1 %). Surgery was associated with slightly lower early mortality (conservative 23.3, endoclips 25.0 %, stent-grafting 19.0 %, surgery 13.1 %; p = 0.499). One center reported a series of more than 20 patients treated with stent-grafting which achieved an early mortality of 7.7 % (2/26 patients). Stent-grafting was associated with better survival with salvaged esophagus (conservative 76.7 %, endoclips 75.0 %, stent-grafting 77.8 %, surgery 56.0 %; p = 0.019). Propensity score adjusted analysis showed that stent-grafting achieved similar early mortality (p = 0.946), but significantly higher survival with salvaged esophagus than with surgical treatment (p = 0.001, OR 0.253, 95 % CI 0.110-0.585). Primary surgical repair was associated with somewhat lower early mortality (14.6 vs. 19.0 %; p = 0.561) and better survival with salvaged esophagus (85.4 vs. 77.8 %; p = 0.337) than stent-grafting. CONCLUSIONS: Esophageal perforation was associated with a rather high mortality rate in this all-comers population. Stent-grafting failed to decrease operative mortality, but it improved survival with salvaged esophagus. The results of one of the centers indicate that increasing experience with this less invasive procedure may possibly improve the outcome of these patients. PMID- 24174171 TI - CD151 is associated with prostate cancer cell invasion and lymphangiogenesis in vivo. AB - CD151, a member of the tetraspanin family, is associated with regulation of migration of normal and tumour cells via cell surface microdomain formation. CD151 was found in our laboratory to have a prognostic value in prostate cancer and is a promoter of prostate cancer migration and invasion. These roles involve association with integrins on both cell-cell and cell-stroma levels. Furthermore, CD151 plays a role in endothelial cell motility. CD151 expression was examined in three commonly used prostate cancer cell lines. We investigated CD151 expression, angiogenesis (microvessel density; MVD) and lymphangiogenesis (lymphatic vessel density; LVD) in an orthotopic xenograft model of prostate cancer in matched tumours from primary and secondary sites. CD151 was found to be heterogeneously expressed across different prostate cancer cell lines and the levels of CD151 expression were significantly higher in the highly tumorigenic, androgen insensitive cells PC-3 and DU-145 compared to the androgen-sensitive cell line LNCaP (P<0.05). The majority of in vivo xenografts developed pelvic lymph node metastases. Importantly, primary tumours that developed metastasis had significantly higher CD151 expression and MVD compared to those which did not develop metastasis (P<0.05). We identified, for the first time, that CD151 expression is associated with LVD in prostate cancer. These findings underscore the potential role of CD151 and angiogenesis in the metastatic potential of prostate cancer. CD151 has a prognostic value in this mouse model of prostate cancer and may play a role in lymphangiogenesis. CD151 is likely an important regulator of cancer cell communication with the surrounding microenvironment. PMID- 24174172 TI - Pharmacokinetics, tolerability, and safety of the single oral administration of AGSAV301 vs Exforge: a randomized crossover study of healthy male volunteers. AB - BACKGROUND AND OBJECTIVE: Valsartan, an angiotensin receptor blocker, is often used with calcium channel blockers (CCBs) such as amlodipine to control hypertension. Recently, the fixed-dose combination (FDC) of amlodipine 10 mg/valsartan 160 mg (Exforge) was approved. Amlodipine is a racemic mixture of CCB; S-amlodipine has higher activity than R-form. Therefore, AGSAV301, the FDC of S-amlodipine 5 mg/valsartan 160 mg was recently developed. The objective of this study was to compare the pharmacokinetic (PK) characteristics of S amlodipine and valsartan when administered as one tablet each of Exforge and AGSAV301 to healthy male subjects. METHODS: This was a single-dose, randomized, open-label, two-way, two-period crossover study. Each subject received a single dose of AGSAV301 and Exforge, separated by a 3-week washout period. Plasma samples for the PK analysis of valsartan and S-amlodipine were collected at predose (0) and 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 10, 12, 16, 24, 36, 48, 72, 96, 120, and 168 h after administration. Tolerability was also evaluated. RESULTS: A total of 29 subjects were enrolled; 24 completed this study. The S-amlodipine maximum plasma concentration (C max) geometric mean ratio (GMR) between AGSAV301 and Exforge was 0.951 (90 % CI 0.983-1.014), and area under the concentration-time curve from time 0 to last measured time point (AUClast) was 0.917 (90 % CI 0.861 0.976). The GMR of valsartan C max was 0.994 (90 % CI 0.918-1.076), and the AUClast was 0.927 (90 % CI 0.821-1.047). All adverse events (AEs) were resolved without sequelae; no serious AEs were reported. Two drugs showed similar tendencies to lower blood pressure in healthy subjects. CONCLUSIONS: The PK profiles of AGSAV301 and Exforge were bioequivalent. Both drugs were also well tolerated, with comparable AE profiles and similar blood pressure-lowering tendencies in healthy volunteers, suggesting equivalent therapeutic indications. PMID- 24174173 TI - Management of microvascular angina pectoris. AB - Microvascular angina (MVA) is defined as angina pectoris caused by abnormalities of small coronary arteries. In its most typical presentation, MVA is characterized by angina attacks mainly caused by effort, evidence of myocardial ischemia on non-invasive stress tests, but normal coronary arteries at angiography. Patients with stable MVA have excellent long-term prognoses, but often present with persistent and/or worsening of angina symptoms. Treatment of MVA is initially based on standard anti-ischemic drugs (beta-blockers, calcium antagonists, and nitrates), but control of symptoms is often insufficient. In these cases, several additional drugs, with different potential anti-ischemic effects, have been proposed, including ranolazine, ivabradine, angiotensin converting enzyme (ACE) inhibitors, xanthine derivatives, nicorandil, statins, alpha-blockers and, in perimenopausal women, estrogens. In patients with 'refractory MVA', some further alternative therapies (e.g., spinal cord stimulation, pain-inhibiting substances such as imipramine, rehabilitation programs) have shown favorable results. PMID- 24174174 TI - Statins and risk of new-onset diabetes mellitus: is there a rationale for individualized statin therapy? AB - Statins (hydroxymethylglutaryl-coenzyme-A reductase inhibitors) are first-line agents for the management of hyperlipidemia in patients at high risk of cardiovascular (CV) events, and are the most commonly prescribed CV drugs worldwide. Although safe and generally well tolerated, there is growing evidence to suggest that statins are associated with an elevated occurrence of new-onset diabetes mellitus (DM). Recent experimental and clinical data have prompted the US Food and Drug Administration to add information to statin labels regarding the increased risk of development of type 2 DM. The main purpose of this review is to critically discuss the clinical evidence regarding the association of statin use with new-onset DM, the CV benefit/risk ratio with statins, and the rationale for individualized statin therapy. PMID- 24174175 TI - Potential cost-effectiveness of the nonavalent human papillomavirus (HPV) vaccine. AB - Randomized clinical trials are currently examining the efficacy of a nonavalent human papillomavirus (HPV) vaccine, including HPV-types 6/11/16/18/31/33/45/52/58. Evidence on the cost-effectiveness of the nonavalent is required for timely policy-decisions. We compared the potential cost effectiveness of the nonavalent and quadrivalent HPV vaccines. We used a multi type individual-based transmission-dynamic model of HPV infection and diseases, 70-year time-horizon, 3% discount rate and healthcare payer perspective. We calibrated the model to Canadian sexual behavior and epidemiologic data, and estimated Quality-Adjusted Life-Years (QALYs) lost and costs ($CAN 2010) from the literature. Under base-case assumptions (vaccinating 10-year-old girls, 80% coverage, 95$/dose, vaccine-type efficacy = 95%, cross-protection for the quadrivalent vaccine, duration of vaccine-type protection (cross-protection) = 20 (10) years), using the quadrivalent and nonavalent vaccines is estimated to cost $15,528 [12,056; 19,140] and $12,203 [9,331; 17,292] per QALY-gained, respectively. At equal price, the nonavalent vaccine is more cost-effective than the quadrivalent vaccine, even when assuming both shorter duration of protection (nonavalent = 20 years vs. quadrivalent = lifelong) and lower vaccine-type efficacy (nonavalent = 85% vs. quadrivalent = 95%). However, the additional cost per dose of the nonavalent vaccine should not exceed $11 to remain more cost effective than the quadrivalent vaccine, and $24 to represent a cost-effective alternative to the quadrivalent vaccine (using a $40,000/QALY-gained threshold). The nonavalent vaccine can be a cost-effective alternative to the quadrivalent vaccine, even in scenarios where nonavalent vaccine efficacy is 85%. However, because most cervical cancers are caused by HPV-16/18, it is unlikely that the nonavalent would be used if its efficacy against these types is lower than current HPV vaccines. PMID- 24174176 TI - Validation of the QTNM staging system for cancer-specific survival in patients with differentiated thyroid cancer. AB - An Australian state database was used to test the validity of the Quantitative tumor/node/metastasis (QTNM) staging system for assessing prognosis of differentiated thyroid cancer (DTC) on the basis of four variables quantified at diagnosis (histopathology, age, node involvement, and tumor size). Using the Queensland Cancer Registry (QCR), we identified 788 cases of DTC diagnosed from 1982 to 2006 with complete staging information. Causes of death were ascertained by linking the QCR database with the Australian National Death Index. Subjects were staged according to AJCC TNM 7th edition and QTNM, and cancer-specific survival (CSS) was calculated by the Kaplan-Meier method. Cancer-specific mortality was observed in 22 (2.8 %) patients, with 10-year CSS for the cohort of 97.0 % at a median follow-up of 262.8 months. QTNM stage specific cancer survival at 10 years was 99.6, 97.0, and 78.6 % for low-, intermediate-, and high-risk groups, respectively. This was comparable to the original US dataset in which the QTNM was initially studied, and it fared better at discriminating survival than the standard TNM system, where there was overlap in survival between stages. The current study validates the QTNM system in an Australian cohort and shows at least equivalent discriminatory capacity to the current TNM staging system. The QTNM utilized prognostic variables of significance to produce an optimal three stage stratification scheme. Given, its advantage in clearly discriminating between prognostic groups, clinical relevance and simplicity of use, we recommend that TNM be replaced with QTNM for risk stratification for both recurrence and CSS. PMID- 24174177 TI - Presence of more activating KIR genes is associated with Hashimoto's thyroiditis. AB - Killer cell immunoglobulin-like receptors (KIR) regulate the effector function of natural killer (NK) cells and the subset of T cells with memory phenotype. The number and type of genes that encode KIR receptors substantially varied between individuals and between populations. Specific KIR receptors are known to be associated with certain diseases. The present study was undertaken to investigate if any specific KIR gene(s) is associated with the susceptibility to Hashimoto's thyroiditis (HT), an inflammatory disease characterized by lymphocytic infiltration of the thyroid gland and the presence of autoantibodies directed against thyroglobulin and/or thyroid peroxidase. DNA from 118 patients with HT and 120 healthy controls was characterized for the presence and absence of 11 variable KIR genes using a gene-specific PCR typing system. Although no significant difference in the frequency of individual KIR genes between patients and controls was detected, more patients carry the six activating KIR genes compared with the control group (11.8 vs. 4.1 %, p = 0.032, OR = 3.09, 95 % CI 1.07-8.89). The data suggest that augmented signals from multiple activating KIR receptors might exacerbate the activation of NK cells and T cell subsets against self-antigens, thus contributing to the pathogenesis of HT. PMID- 24174178 TI - Prevalence of osteoporosis in prostate cancer survivors: a meta-analysis. AB - Androgen deprivation therapy (ADT), which is used in the treatment of prostate cancer (PCa), is associated with increased morbidity. Severe bone loss is a major consequence of androgen ablation and with an increasing number of patients undergoing this treatment, the incidence of osteoporosis and fractures can be expected to increase with a significant impact on healthcare. To evaluate the prevalence of osteoporosis, we conducted a review of the literature on bone health in men with PCa undergoing ADT. A meta-analysis was conducted using the quality effects model, and sources of heterogeneity were further explored by consideration of discordant effect sizes of included studies in the meta-analysis and examining reasons thereof. Our analyses indicate that the prevalence of osteoporosis varies between 9 and 53 % with this variation partially explained by treatment duration, disease stage, ethnicity and site of osteoporosis measurement. While it is well known that a rapid decline in bone health amongst men with PCa on ADT occurs, this meta-analysis documents the high prevalence of osteoporosis in this population and reinforces the need of preventative approaches as part of usual care of PCa patients. PMID- 24174180 TI - Stimulation of active potassium transport in LK sheep red cells by blood group-L antiserum. AB - Anti-L serum prepared by immunization of a high-potassium-type (HK) (blood type MM) sheep with blood from a low-potassium-type (LK) (blood type ML) sheep contained an antibody which stimulated four- to sixfold K(+)-pump influx in LK (LL) sheep red cells. In long-termin vitro incubation experiments, LK sheep red cells sensitized with anti-L showed a net increase in K(+) after two days of incubation at 37 degrees C, whereas HK-nonimmune (NI)-serum-treated control cells lost K(+). The antibody could be absorbed by LK (LL) sheep red cells but not by HK sheep red cells. Kinetic experiments showed that the concentration of external K(+) ([K(+)]0) required to produce halfmaximum stimulation of the pump ([Na(+)]0=0, replaced by Mg(++)) was the same (0.25 mM) in L-antiserum-treated or untreated LK cells. LK cells with different [K(+)]i (Na(+) replacement) were prepared by the p-chloromercuribenzene sulfonate (PCMBS) method. At [K(+)]0=5 mM, pump influx decreased as [K(+)]i increased from 1 to 70 mM in L-antiserum-treated LK cells, whereas LK cells treated with HK-NI-serum ceased to pump at [K(+)]i=35 mM. Exposure to anti-L serum produced an almost twofold increase in the number of pump sites of LK cells as measured by the binding of tritiated ouabain by LK sheep red cells. These findings indicate that the formation of a complex between the L-antigen and its antibody stimulates active transport in LK sheep red cells both by changing the kinetics of the pump and by increasing the number of pump sites. PMID- 24174179 TI - Management of hyperthyroidism in pregnancy. PMID- 24174181 TI - Potassium-activated phosphatase from human red blood cells : The asymmetrical effects of K(+), Na (+), Mg (++) and adenosine triphosphate. AB - The cell membrane K(+)-activated phosphatase activity was measured in reconstituted ghosts of human red cells having different ionic contents and incubated in solutions of varying ionic composition. When K(+)-free ghosts are suspended in K(+)-rich media, full activation of the phosphatase is obtained. Conversely, very little ouabainsensitive activity is detected in K(+)-rich ghosts suspended in K(+)-free media. These results, together with the fact that Na(+) competitively inhibits the effects of K(+) only when present externally, show that the K(+) site of the membrane phosphatase is located at the outer surface of the cell membrane. The Mg(++) requirements for K(+) activation of the membrane phosphatase are fulfilled by internal Mg(++). Addition of intracellular Na(+) to ATP-containing ghosts raises the apparent affinity of the enzyme for K(+), suggesting that the sites where ATP and Na(+) produce this effect are located at the inner surface of the cell membrane. The asymmetrical features of the membrane phosphatase are those expected from the proposed role of this enzyme in the Na(+) K(+)-ATPase system. PMID- 24174182 TI - Potassium-activated phosphatase from human red blood cells : The Effects of Adenosine Triphosphate. AB - The behavior of the red cell membrane K(+)-activated phosphatase is significantly altered by ATP. When ATP is added, the apparent affinity of the enzyme for its substrate and for K(+) is lowered, whereas its sensitivity to ouabain is increased. Under these conditions, addition of Na(+) raises the apparent affinity of the enzyme for K(+) to values well above those found in the absence of Na(+) and ATP. The effect of Na(+) is blocked by hydroxylamine and oligomycin. Low concentrations of Ca(++), Sr(++) or Ba(++), which have little effect in the absence of ATP, induce large increases in the K(+)-dependent phosphatase activity in the presence of ATP. This effect is associated with the loss of ouabain sensitivity of the phosphatase. The velocity vs. divalent cation concentration curves of the K(+)-dependent phosphatase and the (Na(+)+K(+))-independent ATPase activities are very similar. The effects of ATP seem to be specific for this nucleotide and are exerted at concentrations similar to those normally found in red cells. They may therefore be relevant to the proposed physiological role of the cell membrane phosphatase. PMID- 24174183 TI - The effect of vitamin D on enzyme activities in the mucosal cells of the chick small intestine. AB - A search was made for enzyme activities that are increased after vitamin D treatment of rachitic chicks. Three enzyme activities located in the brush borders of the mucosal cells of the intestine - ATPase, p-nitrophenyl phosphatase, and pyrophosphatase - were found to approximately double in activity 48 hr after vitamin D was given. The ATPase and the p-nitrophenyl phosphatase required Mg(++) for activity but could be further stimulated by addition of Ca(++). The three activities are probably caused by the same enzyme since 20 mM phenylalanine inhibited all three activities. It is unlikely that the Ca(++) stimulated ATPase is concerned with Ca(++) translocation since phenylalanine, which inhibits this enzyme, had no effect on(45)Ca transport from mucosal to serosal fluids of everted sacs of intestine. PMID- 24174184 TI - Space charge-limited conductance in lipid bilayer membranes. AB - A mathematical treatment is given for the flux of ions of one charge sign across lipid bilayer membranes. This treatment is a generalization of a previous analysis of the membrane conductance by D. Walz, E. Bamberg and P. Lauger which was restricted to systems with negligible space charge in the membrane. The present theory includes space charge effects, and it is no longer assumed that the electric field strength in the membrane is constant. It is found that the ohmic membrane conductivity lambda0 is reduced by space charges; if only ions of one charge sign are soluble in the membrane, lambda0 approaches a limiting value for increasing concentration of the permeable ion in the aqueous solution. The theory also predicts the range in which the constant field approximation is valid. It is found that space charge effects become predominant when the mean concentration of the permeable ion in the membrane exceeds 5*10(-5) M. The currentvoltage characteristic of the membrane remains practically linear even in the presence of a high space charge. It is therefore concluded that the experimentally observed nonlinearity is caused mainly by the distortion of the potential energy profile of an ion due to image forces. PMID- 24174185 TI - The effect of endotoxin on thin lipid bilayer membranes. AB - The effect of endotoxin fromSalmonella typhimurium orEscherichia coli was studied on bilayer lipid membranes (1% lecithin-1% cholesterol in n-decane) formed in buffered 0.1M NaCl solution (pH 6.8). Endotoxin was added to the buffered solution either prior to membrane formation or after stable membranes were formed. In both cases, concentrations of 110 to 720 MUg/ml endotoxin initiated a decrease in the electrical resistance of the membranes followed by their rupture. A 50 MUg/ml concentration of the agent was unable to elicit any response. Also, the addition of an equal volume of buffer solution, serving as a control, caused no decrease in membrane resistance or survival time. Treatment of the endotoxin with alkaline hydroxylamine to remove esterand amide-bound fatty acids likewise abolished the membrane effect. This is the first report of an endotoxin effect on lipid bilayer membranes. The potential correlation of this interaction of bilayer and endotoxin with the diverse biologic effects of endotoxin is discussed. PMID- 24174186 TI - Mobile membrane carrier for monosaccharide transport inRhodotorula gracilis. AB - Evidence for a mobile membrane carrier mediating the uphill monosaccharide transport in the yeastRhodotorula gracilis is based on two types of observations: (1) Countertransport was found with(14)C-labelledD-xylose,L-xylose,L-rhamnose and withL-rhamnose in a cell suspension preincubated with unlabelledD-xylose. This finding indicates, moreover, that both the hexoses and the pentose share the same membrane carrier. (2) The mobility of occupied carrier molecules is higher than that of free carrier molecules. This conclusion has been drawn from: (a) comparison of the initial rates of uptake of a labelled sugar into cells preincubated in the absence and in the presence of unlabelled sugar; (b) comparison on the half-saturation constant of transport with the dissociation constant of the sugar-carrier complex; and (c) comparison of the initial rates of efflux of a labelled sugar into sugar-free and sugar-containing medium. PMID- 24174187 TI - The temperature dependence of the facilitated transport ofD(+)-glucose across the human red cell membrane. AB - The rate of exit ofD(+)-glucose from human red cells was measured as a function of the extracellular glucose concentration over the temperature range 12 to 47 degrees C. The results were analyzed at each temperature, according to the kinetic model of Widdas and of Rosenberg and Wilbrandt, in terms of the apparent maximum exit rate (V max) and the apparent dissociation constant (K m ) of the carrier-glucose complex. When the values ofV max andK m were obtained by the same graphical method as that used by Sen and Widdas, the results were very similar to theirs insofar as the effect of temperature is concerned. In particular, the apparent standard enthalpy of dissociation (DeltaH m ) of the carrier-glucose complex does not vary with temperature, whereas the apparent activation energy (E max) for the translocation of the carrier increases strongly with decreasing temperature. It is shown that the explanation of these findings given by Dawson and Widdas is internally inconsistent. Furthermore, the graphical method as used by these authors is unreliable at higher temperatures, whereK m is large and consequently underestimatesK m . An improved modification of the method, suggested by Bolis, Luly and Wilbrandt, overcomes this difficulty and leads to more reliable values forV max andK m . These new results show thatE max decreases, and DeltaH m increases, as the temperature is raised. This behavior is shown to be consistent with the modified kinetic model for sugar transport proposed by Wilbrandt, in which the translocation rate of the loaded carrier is assumed to be different from that of the empty carrier. The changes inE max and DeltaH m with temperature are the result of the difference in true activation energies for the translocation of the loaded and empty carrier. PMID- 24174188 TI - Junction potentials, electrode standard potentials, and other problems in interpreting electrical properties of membranes. AB - As background to a detailed analysis of the cation permeation mechanism in rabbit gallbladder epithelium, this paper considers several general problems in interpretation. With regard to liquid junction potentials, the common practice of using saturated KCl bridges was insufficiently accurate for the present purposes because the resulting junctions are time-dependent and poorly understood theoretically. Time-independent and well-defined junction potentials were obtained by arranging all junctions to be of the biionic or single-salt dilution types. The magnitudes of these junction potentials were estimated in three different ways, with good agreement. Recording arrangements using either agar bridges or else Ag/AgCl electrodes also yielded good agreement after appropriate corrections for junction potentials and electrode potentials. The effects of nonelectrolytes on electrode standard potentials were measured. Two experiments were devised to determine whether transepithelially measured electrical properties of the gallbladder refer to a single membrane or to two membranes in series: the potential difference change resulting from a mucosal concentration change was measured as a function of the serosal concentration, and intracellular concentrations were altered by increasing bathing solution osmolalities with an impermeant nonelectrolyte. Both types of experiment indicated that transepithelial measurements are dominated by a single membrane. Small corrections were applied to measured potential differences to take account of unstirred-layer effects with permeant salts. PMID- 24174189 TI - Water permeability of phospholipid vesicles. AB - The water permeability of phospholipid vesicles 0.5 to 10 MU in diameter bounded by one or by several lipid bilayers was measured by following the change in turbidity of a suspension after mixing in a stopped flow apparatus. A semi empirical formulation for evaluating volume changes of vesicles with a broad size range by measurement of turbidity is developed. The rate of flow is analyzed in terms of reaction rate theory. The water permeability coefficients for phosphatidylcholine vesicles were approximately 44 MU/sec at 25 degrees C and 70 MU/sec at 37 degrees C. The activation energy for water transport was 8.25 kcal/mole. The results were consistent with the view that water permeates by dissolution and diffusion in the membrane. PMID- 24174190 TI - The effect of the polar moiety of lipids on bilayer conductance induced by uncouplers of oxidative phosphorylation. AB - Bilayer membranes were formed from decane, cholesterol, and three lipids isolated fromStaphylococcus aureus: positively charged lysyl phosphatidylglycerol (LysPG), negatively charged phosphatidylglycerol (PG), and neutral diglucosyldiglyceride (DiGluDiGly). The uncouplers of oxidative phosphorylation, 2,4-dinitrophenol (DNP) and 3-t-butyl,5-chloro,2'-chloro,4'-nitrosalicylanilide (S 13), increased the electrical conductance of all three differently charged bilayers. S 13 was found to be the most effective reagent of the known uncouplers in increasing conductance of the bilayers. The conductance induced by uncouplers was investigated as a function of pH and uncoupler concentration. The pH of maximum conductance for each uncoupling agent was dependent on both the uncoupler and the lipid; it was lower for each uncoupler in LysPG and higher in PG compared to DiGluDiGly bilayers. At a pH below the optimum for LysPG, the conductance of the positively charged membrane was 500 times and of the neutral one 10 times higher than that of the negatively charged bilayer at equal uncoupler concentration and pH. Above the pH optimum for DiGluDiGly, the conductance was approximately equal for the positive and neutral membranes, but was lower in PG bilayers. Conductance depended linearly on uncoupler concentration. The bilayer conductance induced by S 13 was entirely due to increased proton permeability in all three lipids. The findings are consistent with the role of uncouplers as "carriers" for protons across the hydrocarbon interior of lipid membranes. The differences in conductance of differently charged lipid bilayers at equal uncoupler concentration, as well as the change of pH optimum of conductance with lipid charge, can be explained in terms of an electrostatic energy contribution of the fixed lipid charges to the distribution of the uncoupler anion between the aqueous and the membrane phases. PMID- 24174191 TI - Water-soluble proteins of the human red cell membrane. AB - Procedures were developed for preparation of red cell membranes almost free of hemoglobin but with minimal loss of membrane proteins. Two water-soluble protein fractions are described, each constituting about 25% of the ghost protein. The first is ionically bonded and can be solubilized in water rapidly at pH 7.0 and more slowly at higher ionic strength solutions, with a minimal rate at 20MM. This fraction contains four major components with molecular weights ranging from 30,000 to 48,000. The second fraction can only be solubilized at an appreciable rate if Ca(++) is absent and at higher pH (9.0). It is predominantly a single molecular weight component (150,000). It tends to aggregate at higher ionic strength and in the presence of Ca(++). Evidence is presented suggesting that the water-soluble proteins are present at the inner face of the membrane. The lipids remain in a water-insoluble residue that contains four major protein components ranging in molecular weight from 30,000 to 100,000. The latter is the predominant component. Only the residue contains the Na(+)-K(+)-activated ATPase, the cholinesterase, antigenic activity and most of the sialic acid and carbohydrate. The first water-soluble fraction contains a Mg(++)-activated ATPase. The extraction of the water-soluble proteins is accompanied by anatomical changes resulting finally in the formation of small membranous vesicles. PMID- 24174192 TI - Utilization of model membranes in a test for the mechanism of ethylene action. AB - Reversible alteration of the surface tension of thin films of lipids, proteins and mixtures of both resulted when the thin films were treated with ethylene and other aliphatic gases. This effect appeared to be a nonspecific surface effect related to the molecular size of the gases. Ethylene produced no change which would ascribe to it any specific properties in this test system. The conductivity of an egg lecithin-cholesterol bilayer membrane separating two electrolytes was unaffected by all the test gases (including ethylene), but chloroform vapors markedly altered the conductivity in a reversible manner. In each of the test systems empoloyed, there was no specificity exhibited by ethylene, either qualitatively or quantitatively, indicating the mechanism of ethylene action cannot be explained as a simple physical effect on membranes. PMID- 24174193 TI - Electrical activity and metabolism in cardiac tissue: An experimental and theoretical study. AB - (1) Effects of the metabolic inhibitor 2,4-dinitrophenol (DNP) on electrical activity in frog atria were studied by means of the sucrose-gap technique and in tracer experiments. (2) Voltage-clamp studies of ionic membrane currents showed a suppression by DNP of peak Na inward current without marked changes in the kinetics of the Na-carrying system and an increase of steady state outward current to three to five times its normal value. In(42)K tracer experiments, DNP increased K resting efflux by about 10% and decreased K influx by 25 to 30%. (3) The depression of Na inward current is regarded as being caused by a partial block of Na channels and an increase of internal Na concentration after inhibition of active Na extrusion. (4) The strong rise in outward current is probably not caused by a K current since K efflux fails to show a correspondingly large change. As a possible explanation for current and flux changes, an electrogenic K pump is discussed. (5) A mathematical model of a carrier system transporting a single ion species is described. The system is designed as a direct "potential" pump. Uphill transport requires an asymmetry of the rate constants governing the cyclic formation and breakdown of carrier-ion complex. The asymmetry is brought about by an input of metabolic energy. Reduction of energy input decreases the asymmetry and induces a carrier-mediated downhill ion movement, with corresponding changes in membrane current and ion fluxes. (6) A model of electrogenic K inward transport is calculated that approximately accounts for the steady state current and the K flux changes experimentally observed after inhibition. PMID- 24174194 TI - Evidence for an electrogenic ion transport pump in cells of higher plants. AB - Cyanide (CN) and dinitrophenol (DNP) rapidly depolarize the cells of oat coleoptiles (Avena sativa L., cultivar Victory) and of pea epicotyls (Pisum sativum L., cultivar Alaska); the effect is reversible. This indicates that electrogenesis is metabolic in origin, and, since active transport is blocked in the presence of CN and DNP, perhaps caused by interference with ATP synthesis, that development of cell potential may be associated with active ion transport. Additional evidence for an electrogenic pump is as follows. (1) Cell electropotentials are higher than can be accounted for by ionic diffusion. (2) Inhibition of potential, respiration, andactive ion transport is nearly maximal, but a potential of -40 to -80 mV remains. This is probably a passive diffusion potential since, under these conditions, a fairly close fit to the Goldman constant-field equation is found in oat coleoptile cells. PMID- 24174195 TI - Discrimination between monovalent and divalent cations by hydrophobic solvent saturated membranes containing fixed negative charges. AB - Cellulose acetate-nitrate filters were saturated with hydrophobic solvent and interposed between various aqueous solutions. The membranes thus formed are cation permselective. The discrimination between a monovalent cation such as K(+) and the alkaline earth group divalent cations is very sharp. The discrimination ratio is at least a few thousand times in favor of the monovalent cation. A major part of this discrimination is caused by the very low mobility of the divalent cation within the membrane compared with that of the monovalent cation. The remainder of the discrimination is caused by the selectivity of the membranes which prefer monovalent to divalent cations. There is a clear discrepancy between Ba(++) diffusibility and mobility within, the membrane. This implies that Ba(++) may move within the hydrophobic membrane as a neutral complex. Some similarity with natural biological membranes is indicated. PMID- 24174196 TI - Ion association reactions with biological membranes, studied with the fluorescent dye 1-anilino-8-naphthalenesulfonate. AB - (1) When salts are added to buffered suspensions of membrane fragments containing the fluorochrome 1-anilino-8-naphthalenesulfonate (ANS), there is an increased fluorescence. This is caused by increased binding of the fluorochrome; the intrinsic fluorescence characteristics of the bound dye remain unaltered. These properties make ANS a sensitive and versatile indicator of ion association equilibria with membranes. (2) Alkali metal and alkylammonium cations bind to membranes in a unique manner. Cs(+) binds most strongly to rat brain microsomal material, with the other alkali metals in the order Cs(+)>Rb(+)>K(+)>Na(+)>Li(+). The reaction is endothermic and entropy driven. Monovalent cations are displaced by other monovalent cations. Divalent cations and some drugs (e. g., cocaine) displace monovalent cations more strongly. (3) Divalent cations bind to membranes (and to lecithin micelles) at four distinct sites, having apparent association constants between 50 and 0.2MM (-1). The characteristics of the titration suggest that only one species of binding site is present at any one time, and open the possibility that structural transitions of the unassociated coordination sites may be induced by divalent cation binding. Divalent cation binding at the weakest site (like monovalent cation binding) is endothermic and entropy driven. At the next stronger site, the reaction is exothermic. Monovalent cations affect divalent cation binding by reducing the activity coefficient: they do not appear to displace divalent cations from their binding sites. PMID- 24174197 TI - Different locations of carbohydrate-containing sites in the surface membrane of normal and transformed mammalian cells. AB - A soybean agglutinin was found to agglutinate mouse, rat and human cell lines transformed by viral carcinogens, but not hamster cells transformed by viral or non-viral carcinogens. Normal cells from which the transformed cells were derived were not agglutinated by this agglutinin, but they were rendered agglutinable after short incubation with trypsin or pronase. The transformed hamster cells, on the other hand, became agglutinable only after prolonged treatment with pronase. The agglutination was specifically inhibited by N-acetyl-D-galactosamine, indicating that N-acetyl-D-galactosamine-like saccharides are part of the receptor sites for soybean agglutinin on the surface membrane. Such sites exist in a cryptic form in normal cells; they are exposed in transformed mouse, rat and human cells, but become less accessible in transformed hamster cells. The receptor sites for soybean agglutinin differ from the receptors for two other plant agglutinins (wheat germ agglutinin that interacts with N-acetyl-D glucosamine-like sites and Concanavalin A that interacts with alpha-D glucopyranoside-like sites) which become exposed upon transformation of all lines tested. In normal hamster cells, the receptors for all three agglutinins become exposed after incubation with trypsin, but the exposure of N-acetyl-D galactosamine-like sites requires the longest enzyme treatment. The results indicate a difference in the location of different carbohydrate-containing sites in the surface membrane. The differences in the exposure of carbohydrate containing sites in the membrane could not be correlated with the levels of carbohydrate-splitting glycosidases in normal and transformed cells. PMID- 24174198 TI - Immunochemical studies of organ and tumor lipids XVIII. Cytolipin R determinants in the rat erythrocyte membrane. AB - Rabbit antisera to rat lymphosarcoma contain antibodies that agglutinate trypsinized rat erythrocytes. These reactions can be specifically inhibited by cytolipin R, a ceramide tetrasaccharide isolated from rat lymphosarcoma. The agglutinin in the rabbit antisera can be absorbed with untreated erythrocytes, showing that cytolipin R determinants are present in the intact rat erythrocyte membrane. Untreated erythrocytes are able to react with antibody, but presumably the number of cytolipin R determinants necessary for agglutination becomes available only after treatment with trypsin. The anti-cytolipin R antibodies in anti-rat lymphosarcoma sera that cause hemagglutination and those that fix complement with this hapten are different, since the agglutinin can be absorbed completely without appreciable decrease in complement-fixing antibody. PMID- 24174199 TI - Electrical characteristics of the ionic psn-junction as a model of the resting axon membrane. AB - As a model for the resting axon membrane, we propose the ionic psn-junction. Its electrical characteristics can be determined in close analogy to the corresponding electronic semiconductor junction. Using the "semianalytic approximation", we calculated the electrical capacity and the ionic currents. In contrast to the abrupt pn-junction, the electrical capacity of the psn-junction turns out to be practically voltage-independent, as it is observed for the squid axon membrane. The passive ionic fluxes for K(+), Na(+) and Cl(-), as the main contributions to the total charge flux, are calculated and compared with literature data on the ion fluxes through the resting squid axon membrane as measured by use of radioactive tracers. From this comparison, the ionic permeabilities can be evaluated and used to compute the resting membrane conductivity, which is found to be close to the experimental value. Further evidence in favor of the proposed asymmetrical membrane structure and possible ways of its test by the methods of protein chemistry are discussed. PMID- 24174200 TI - Volume flows and pressure changes during an action potential in cells ofChara australis : I. Experimental results. AB - Methods have been used for monitoring either volume flows or pressure changes, simultaneously with membrane potentials, in giant algal cells ofChara australis during an action potential. The volume flows were measured from the movement of a mercury bead in a capillary tube recorded by a photo-transducer. The pressure changes were measured by monitoring the deflection of a thin wedge, resting transversely across a cell, and using the same photo-transducer, the deflection of the wedge being directly related to the cell's turgor pressure. The average maximum rate of volume flow per unit area during an action potential was 0.88+/ 0.11 nliter.sec(-1).cm(-2) in the direction of an outflow from the cell (total volume outflow being about 3 nliter.cm(-2) per action potential). Similarly, the maximum rate of change of pressure was 19.6+/-3.8*10(-3) atm.sec(-1) (peak change being 19.3+/-2.9*10(-3) atm equivalent to 14.7+/-2.2 mm Hg). The volume flow and pressure changes followed the vacuolar potential quite closely, the peak rate of volume flow lagging behind the peak of the action potential by 0.17+/-0.08 sec and the peak rate of pressure change leading it by 0.09+/-0.07 sec. PMID- 24174201 TI - Volume flows and pressure changes during an action potential in cells ofChara australis : II. Theoretical considerations. AB - It has been suggested that electro-kinetic coupling may be involved in the mechanism of the action potential and that there should therefore be both consequent volume flows and pressure changes associated with such excitation. In a previous paper, such measurements were reported in cells ofChara australis, from which it is also known that during excitation there is an increase in KCl permeability and an efflux of KCl. In this paper, a number of theoretical analyses have been considered and developed pertaining to such measurements and the time-dependent relationships between apparent measured volume flows, true volume flows and turgor pressure changes in cells in various experimental situations. Such volume flows are quantitatively explained primarily from the frictional coupling of water by both K(+) and Cl(-) ions and to a lesser extent by the local osmotic flow owing to KCl enhancement at the wall-membrane interface of the cell. The measured pressure changes of 12*10(-3) to 28*10(-3) atm during excitation are also correctly predicted as the result of such a volume outflow from the cell which behaves as a hydraulically leaky elastic cylinder and thereby drops in pressure. These conclusions then indicate that the volume flows and pressure changes measured are the incidental consequences of a change in membrane permeability and do not necessarily imply any electro-kinetic mechanism for the action potential itself. PMID- 24174202 TI - The mechanism of colicin E 1 action. AB - Uncouplers of oxidative phosphorylation such as cyanide carbonyl m chlorophenylhydrazone (CCCP) foster proton (H(+)) permeability of bacterial and other membranes; counter cation movement is required for the effect of the uncoupler on proton permeability to be manifested maximally. Treatment ofEscherichia coli with colicin E 1 had little effect on the proton impermeability of the bacteria after challenge with an acid load; however, the subsequent addition of CCCP revealed that colicin E 1-treated cells became much more permeable to protons than control cells. Thus the colicin caused specific rather than generalized alterations in the membrane permeability properties, allowing the movement of some cations but not H(+). This cation permeability was confirmed directly with studies of(42)K leakage on treatment with colicin E 1. N,N'-dicyclohexylcarbodiimide blocked the fall in ATP levels usually associated with colicin E 1 action, but did not block the K(+) leakage, the inhibition of protein and nucleic acid synthesis, or the lethal effect of the colicin, suggesting that reduced availability of ATP is not the cause of these colicin E 1 induced effects. The possible primary action of the colicin E 1 molecule is discussed in relation to these data. PMID- 24174203 TI - Reevaluation of use of retardation chromatography to demonstrate selective monosaccharide "binding" by erythrocyte membranes. AB - Retardation chromatography has been reported to show stereoselective binding of the preferred sugar-transport substrate,D-glucose, by human red cell "ghosts" or by certain protein extracts of such membranes. However, no detectable differential elution of glucose (as compared with the poorly transported analogue,L-sorbose) was observed with columns of diethylaminoethanol-cellulose impregnated with ghost proteins prepared by either of the recommended procedures (using Triton X-100, or NaI followed by extensive dialysis). Celite columns bearing intact ghosts did show marked initial relative delay in glucose emergence, but this persisted only partially through the elution peak, to be followed by a nearly equivalent and much more protracted retardation of the sorbose. Moreover, this differentiation required that the columns be handled sufficiently gently as to leave intact whole-cell membranes or fairly gross vesicles; freeze-thaw treatment or abrasive stirring abolished both the early glucose retardation and the subsequent sorbose retention. Although conflicting seriously with the simple selective-binding interpretation, these phenomena accord with the suggestion that the sugarcomplexing entities on the columns continue to operate as "carriers" mediating sugar access into membrane-enclosed compartments. Effects of experimental manipulation of elution rates and of applied sugar levels lend further support to this interpretation. The capacity of the vesicular spaces so vastly exceeds that of the binding itself that resolution of the latter cannot be achieved through this approach. PMID- 24174204 TI - Residual permeability in red cell ghost preparations. PMID- 24174205 TI - Intraoral anastomosis of a prelaminated radial forearm flap in reconstruction of a large persistent cleft palate. AB - In this report, we present a case of a prelaminated radial forearm flap in reconstruction of a large persistent cleft palate with transoral single arterial and three venous anastomoses. A 17-years-old female patient presented a large cleft palate defect and complete dentition, dysmelia of both arms and bilateral thumb aplasia. A radial flap was prelaminated using oral mucosa 5 days prior to transplantation. Five days after flap prelamination, the facial artery and vein, submandibular vein, and a venous branch to the masseter muscle behind the buccinator muscle fibers were exposed through an intraoral incision lateral to the inferior right mucogingival junction. The radial artery, its bilateral accompanying veins, and the cephalic vein of transplanted flap were anastomosed transorally to the facial vessels, submandibular vein, and masseter branch. The vessel pedicle ran through the palatoglossal arch dorsal to the second upper molar. Good flow and flap perfusion were evinced, and further-on successful healing was achieved. The case encourages similar treatment in comparable situations avoiding facial nerve hazard and extraoral scars. PMID- 24174206 TI - The use of 2D-DIGE to understand the regeneration of somatic embryos in avocado. AB - Avocado embryogenic cell cultures can be classified into two groups based on their morphology when cultured on a medium containing auxin: somatic embryo (SE) and proembryonic masses (PEM) type cultures. The calli of SE-type cell lines are able to go through the maturation process, whereas the calli of PEM cell lines rarely mature. We have investigated four independent avocado cell cultures (two SE and two PEM). The aim of this study was to link the differential regeneration capacity of the four cell cultures to a proteomic pattern and to gain insight into the regeneration capacity. A 2D-DIGE analysis followed by a blind multivariate analysis was able to separate the two SE lines from the PEM lines indicating that the protein profiles of SE and PEM calli are different. Based on the variable importance, that is, the differential protein pattern, we hypothesize that the regeneration capacity in avocado is correlated to the ability to overcome the physicochemical stress stimuli associated with the in vitro culture. Our identical culture conditions do not seem to trigger an appropriate response in PEM lines. PMID- 24174208 TI - Growth of ultrathin organic semiconductor microstripes with thickness control in the monolayer precision. PMID- 24174207 TI - Neural substrates of defensive reactivity in two subtypes of specific phobia. AB - Depending on threat proximity, different defensive behaviours are mediated by a descending neural network involving forebrain (distal threat) vs midbrain areas (proximal threat). Compared to healthy subjects, it can be assumed that phobics are characterized by shortened defensive distances on a behavioural and neural level. This study aimed at characterizing defensive reactivity in two subtypes of specific phobia [snake (SP) and dental phobics (DP)]. Using functional magnetic resonance imaging (fMRI), n = 39 subjects (13 healthy controls, HC; 13 SP; 13 DP) underwent an event-related fMRI task employing an anticipation (5-10 s) and immediate perception phase (phobic pictures and matched neutral stimuli; 1250 ms) to modulate defensive distance. Although no differential brain activity in any comparisons was observed in DP, areas associated with defensive behaviours (e.g. amygdala, hippocampus, midbrain) were activated in SP. Decreasing defensive distance in SP was characterized by a shift to midbrain activity. Present findings substantiate differences between phobia types in their physiological and neural organization that can be expanded to early stages of defensive behaviours. Findings may contribute to a better understanding of the dynamic organization of defensive reactivity in different types of phobic fear. PMID- 24174209 TI - Exploring adenylylation and phosphocholination as post-translational modifications. AB - Editing the translations: Adenylylation and phosphocholination have recently been found as important post-translational modifications used by pathogenic bacteria during the infection process. This review discusses the combined use of chemical handles and specific antibodies for the identification of previously unknown substrates of these post-translational modifications in infected host cells. PMID- 24174210 TI - Systemic overexpression of antizyme 1 in mouse reduces ornithine decarboxylase activity without major changes in tissue polyamine homeostasis. AB - Polyamines, spermidine, spermine and their precursor putrescine, are ubiquitous cell components essential for normal cell growth. Increased polyamine levels and enhanced biosynthesis have been associated with malignant transformation and tumor formation, and thus, the polyamines have been considered to be a meaningful target to cancer therapies. However, clinical cancer treatment trials using inhibitors of polyamine synthesis have been unsuccessful probably due to compensatory uptake of polyamines from extracellular sources. The antizyme proteins regulate both polyamine biosynthesis and transport, and thus, the antizymes could provide an efficient approach to control cellular proliferation compared to the mere inhibition of biosynthesis. To define the role of antizymes in proliferative processes associated with the whole animal, we have generated transgenic mice overexpressing mouse antizyme 1 gene under its own regulatory sequences. Antizyme 1 protein was abundantly expressed in various organs and the expressed antizyme protein was functional as ornithine decarboxylase activity was significantly reduced in all tissues analyzed. However, antizyme 1 overexpression caused only minor changes in tissue polyamine levels demonstrating the challenges in using the "antizyme approach" to deplete polyamines in a living animal. Neither were there any changes in cellular proliferation in the proliferative tissues of transgenic animals. Interestingly though, there was occurrence of abnormally high level of apoptosis in the non-proliferating part of the colon epithelia. Otherwise, the transgenic founder mice appeared healthy and out of seven founders six were fertile. However, none of the founders could transmit the transgene suggesting that the antizyme 1 overexpression may be deleterious to transgenic gametes. PMID- 24174211 TI - Semiautomatic sizing software in emergency endovascular aneurysm repair for ruptured abdominal aortic aneurysms. AB - PURPOSE: In emergency endovascular repair (EVAR) of ruptured aneurysms of the aorta (rAAA), anatomical suitability must be determined. Semiautomatic three dimensional assessment of the aortoiliac arteries has the potential to standardise measurements. This study assesses the fitness for purpose of such a semiautomatic approach for rAAA and determined interobserver agreement on suitability. MATERIALS AND METHODS: Interobserver study with six trained observers (4 vascular surgeons, 2 radiologists) blindly assessing preoperative computed tomography angiography scans of 50 consecutive patients with rAAA. A central lumen line (CLL) was generated, and perpendicular diameters, length along the CLL, and EVAR suitability were determined using dedicated sizing software (3mensio; 3mensio Vascular; Bilthoven, The Netherlands). Success of generating a CLL, time of assessment, and interobserver agreement was determined. RESULTS: In the majority of the patients (median 76 %, range 64-78 %), a CLL was semiautomatically generated. The median duration of CLL generation and performance measurements was 7.5 min (interquartile range 5.5-10.6). Agreement on suitability was moderate for the entire group (Fleiss' kappa = 0.55, confidence interval 0.48-0.62) and ranged from moderate to good (Cohen's kappa = 0.40-0.72) between observer pairs. CONCLUSION: Assessing EVAR suitability of rAAA patients using dedicated sizing software is possible in the majority of patients. The measurements can be performed in a reasonable amount of time, and the agreement of suitability for EVAR in patients with rAAA is moderate. Improvements and additional research are necessary to replace the current axial measurement. PMID- 24174212 TI - Novel supine thoracentesis bed enabling thoracentesis via the posterior axillary line. AB - PURPOSE: This study describes on supine thoracentesis bed (STB), which helps thoracentesis of supine patient by enabling unlimited access to the posterolateral surface of a hemithorax. MATERIALS AND METHODS: Records of 15 patients who had received US-guided supine thoracentesis on STB were reviewed. We investigated the lateral or posterolateral approaches selected by the operators. We reviewed pre-procedural CT scans (obtained within 1 day) to examine if the approach of the operators could be justified in terms of depth of effusion and overlying chest wall thickness. RESULTS: The most common rationale for the use of the supine position was back or leg pain in 6 patients and hemi-or quadriplegia in 4. The operators chose the posterolateral approach in all 15 patients. On 6 concurrent CT scans, the mean depth of effusion was significantly (p < 0.004) greater in the posterolateral approach (3.0 +/- 2.2 vs. 1.5 +/- 1.9 cm). There was no significant difference in the thickness of the chest wall between the two approaches (1.6 +/- 0.3 vs. 1.8 +/- 1.0 cm, p = 0.61). CONCLUSIONS: By using STB, supine thoracentesis can be done via the posterolateral approach, which was associated with greater depth of effusion in our study, and may be superior to the conventional lateral approach. PMID- 24174213 TI - Cost-effective production of recombinant human interleukin 24 by lactose induction and a two-step denaturing and one-step refolding method. AB - Recombinant human interleukin 24 (rhIL24) is a member of the interleukin 10 (IL10) family of cytokines with novel therapeutic properties. Human IL24 possesses three N glycosylation sites and a disulfide bridge. The cost and composition of culture media is critical for commercial-scale production of recombinant proteins in E. coli. Addition of yeast extract and glucose to medium enhances rhIL24 production, and the use of lactose instead of IPTG for induction drops the cost and decreases toxicity. In addition, a two-step denaturing and one step refolding (2DR) strategy improves rhIL24 production. The 2DR strategy replaces a more conventional approach for protein solubilization and refolding. LC-MS/MS provides definitive identification and quantitative information on rhIL24. Single-step purified rhIL24 displayed biological activity on HepG2 hepatocellular carcinoma cells, but no effect on L02 cells. Proliferation analysis suggests that rhIL24 may have potential use as a medication. In the present study, we developed a simple process for producing quality product with high purity. The expression and purification of rhIL24 described here may be a step towards inexpensive large-scale production. PMID- 24174214 TI - Bioinformatics tools for genome mining of polyketide and non-ribosomal peptides. AB - Microbial natural products have played a key role in the development of clinical agents in nearly all therapeutic areas. Recent advances in genome sequencing have revealed that there is an incredible wealth of new polyketide and non-ribosomal peptide natural product diversity to be mined from genetic data. The diversity and complexity of polyketide and non-ribosomal peptide biosynthesis has required the development of unique bioinformatics tools to identify, annotate, and predict the structures of these natural products from their biosynthetic gene clusters. This review highlights and evaluates web-based bioinformatics tools currently available to the natural product community for genome mining to discover new polyketides and non-ribosomal peptides. PMID- 24174215 TI - SlnM gene overexpression with different promoters on natamycin production in Streptomyces lydicus A02. AB - Natamycin is an important polyene macrolide antifungal agent produced by several Streptomyces strains and is widely used as a food preservative and fungicide in food, medicinal and veterinary products. In order to increase the yield of natamycin, this study aimed at cloning and overexpressing a natamycin-positive regulator, slnM2, with different promoters in the newly isolated strain Streptomyces lydicus A02, which is capable of producing natamycin. The slnM gene in S. lydicus is highly similar to gene pimM (scnRII), the pathway-specific positive regulator of natamycin biosynthesis in S. natalensis and S. chattanoogensis, which are PAS-LuxR regulators. Three engineered strains of S. lydicus, AM01, AM02 and AM03, were generated by inserting an additional copy of slnM2 with an ermEp* promoter, inserting an additional copy of slnM2 with dual promoters, ermEp* and its own promoter, and inserting an additional copy of slnM2 with its own promoter, respectively. No obvious changes in growth were observed between the engineered and wild-type strains. However, natamycin production in the engineered strains was significantly enhanced, by 2.4-fold in strain AM01, 3.0-fold in strain AM02 and 1.9-fold in strain AM03 when compared to the strain A02 in YEME medium without sucrose. These results indicated that the ermEp* promoter was more active than the native promoter of slnM2. Overall, dual promoters displayed the highest transcription of biosynthetic genes and yield of natamycin. PMID- 24174216 TI - Enhancement of ansamitocin P-3 production in Actinosynnema pretiosum by a synergistic effect of glycerol and glucose. AB - Ansamitocin P-3 (AP-3), a secondary metabolite produced by Actinosynnema pretiosum, is well known for its extraordinary antitumor properties and is broadly utilized in clinical research. Through this work, we found, for the first time, that the combination of glucose and glycerol as a mixed carbon source is an appropriate approach for enhancing the production of AP-3 by A. pretiosum. The amount yielded was about threefold that obtained with glucose as the sole carbon source. In order to better understand the mechanisms that channel glycerol metabolism towards AP-3 production, the activities of some key enzymes such as glucose-6-phosphate dehydrogenase, glucose-6-phosphate isomerase, phosphoglucomutase (PGM), and fructose 1,6-bisphosphatase were assessed. The results showed that glycerol affects the production of AP-3 by increasing PGM activity. Furthermore, qRT-PCR analysis revealed that transcriptional levels of structural genes asm14 and asm24, and primary genes amir5189 and amir6327 were up regulated in medium containing glycerol. PMID- 24174217 TI - Tension pneumocephalus: a rare complication after resection of a neurogenic tumour by thoracoscopic surgery. PMID- 24174218 TI - Cardiogenic diabetes. AB - It has been well established since the Framingham studies that diabetes mellitus is a risk factor for heart failure. Several recent reports suggested that the reverse is also true, and heart failure may also predispose to diabetes. We reviewed the literature and summarized the evidence of a higher incidence of new onset diabetes in heart failure. Because a high rate of insulin resistance in heart failure is a known phenomenon, a higher incidence of diabetes in heart failure is intuitive. Although the facts confirming such connection is surprisingly scarce, we felt it was important to collect, analyze, and summarize the evidence. PMID- 24174219 TI - Octadecabacter jejudonensis sp. nov., isolated from the junction between the ocean and a freshwater spring and emended description of the genus Octadecabacter. AB - A Gram-stain-negative, non-spore-forming, non-flagellated, rod-shaped bacterial strain, SSK2-1(T), was isolated from the zone where the ocean and a freshwater spring meet at Jeju island, South Korea, and subjected to a polyphasic taxonomic study. Strain SSK2-1(T) grew optimally at 30 degrees C, at pH 7.0-8.0 and in the presence of 2.0% (w/v) NaCl. Neighbour-joining, maximum-likelihood and maximum parsimony phylogenetic trees based on 16S rRNA gene sequences revealed that strain SSK2-1(T) clustered with the type strains of two Octadecabacter species, showing 96.5-96.8% 16S rRNA gene sequence similarity. Strain SSK2-1(T) and Octadecabacter arcticus DSM 13978(T) contained Q-10 as the predominant ubiquinone and C18 : 1omega7c as the common major fatty acid. The polar lipid profile of strain SSK2-1(T) was similar to that of O. arcticus DSM 13978(T) by having phosphatidylcholine, phosphatidylglycerol and one unidentified aminolipid as the major components. The DNA G+C content of strain SSK2-1(T) was 60.1 mol%. Differential phenotypic properties, particularly temperature range for growth, oxidase activity and nitrate reduction, together with phylogenetic distinctiveness, revealed that strain SSK2-1(T) is separate from recognized species of the genus Octadecabacter. On the basis of the data presented, strain SSK2-1(T) is considered to represent a novel species of the genus Octadecabacter, for which the name Octadecabacter jejudonensis sp. nov. is proposed. The type strain is SSK2-1(T) ( = KCTC 32535(T) = CECT 8397(T)). PMID- 24174220 TI - Vagococcus entomophilus sp. nov., from the digestive tract of a wasp (Vespula vulgaris). AB - Three unknown Gram-stain-positive, catalase-negative, facultatively anaerobic and coccus-shaped strains of bacteria were isolated from the digestive tracts of wasps (Vespula vulgaris). Analysis of 16S rRNA gene sequences revealed that these strains had identical sequences and showed that Vagococcus salmoninarum, with 96.2% sequence similarity, was the closest phylogenetic neighbour. Further analyses based on hsp60 and pheS gene sequences of representatives of the family Enteroccocaceae and genotypic and phenotypic characterization using (GTG)5-PCR fingerprintings, EcoRI ribotyping, DNA G+C content, whole-cell protein profiling, cellular fatty acid profiles analysis and extensive biotyping confirmed that the investigated strains were representatives of a novel bacterial species within the genus Vagoccocus for which the name Vagoccocus entomophilus sp. nov. is proposed. The type strain is VOSTP2(T) ( = DSM 24756(T) = CCM 7946(T)). PMID- 24174221 TI - Long-term experience with reduced planning target volume margins and intensity modulated radiotherapy with daily image-guidance for head and neck cancer. AB - BACKGROUND: The purpose of this study was to compare outcomes among patients treated by intensity-modulated radiotherapy (IMRT) with daily image-guided radiotherapy (IGRT) for head and neck cancer according to the margins used to expand the clinical target volume (CTV) to create a planning target volume (PTV). METHODS: Three hundred sixty-seven consecutive patients were treated with IMRT for squamous cell carcinoma of the head and neck. The first 103 patients were treated with 5-mm CTV-to-PTV margins. The subsequent 264 patients were treated using reduced (3 mm) margins. RESULTS: The 3-year locoregional control for patients treated using 5-mm and 3-mm CTV-to-PTV margins, respectively, was 78% and 80% (p = .75). The incidence of gastrostomy-tube dependence at 1 year was 10% and 3%, respectively (p = .001). The incidence of posttreatment esophageal stricture was 14% and 7%, respectively (p = .01). CONCLUSION: The use of reduced (3 mm) CTV-to-PTV margins was associated with reduced late toxicity while maintaining locoregional control. PMID- 24174222 TI - S100A4 is upregulated via the binding of c-Myb in methylation-free laryngeal cancer cells. AB - DNA hypomethylation is correlated with the overexpression of the S100A4 gene in several types of cancers including laryngeal cancer, but the molecular mechanism is unknown. We speculated that the methylation status of the promoter affects its binding to the corresponding transcription factors. In the present study, luciferase reporter assay results indicated that the sequences -485 - +73 and 486 - -530 of the S100A4 promoter may harbor the positive and negative cis-acting elements, respectively; and moreover, the luciferase activity promoted by the sequence -485 - +73 increased and the S100A4 gene was significantly upregulated in 5-Aza-induced HEp2 cells. This implies that the methylation status of the sequence is important in regulating the expression of S100A4. Four transcription factor binding motifs including c-Myb, C/EBpalpha, Ap2 and Msx-1 in the region were predicted by P-Match software. c-Myb and C/EBpalpha but not Ap2 and Msx-1 were confirmed by EMSA and ChIP as transcription factors of S100A4. The decreased luciferase activity in methylation-free HEp2 cells transfected by the mutant c Myb motif related to the methylated cytosine suggests that the hypomethylation of the c-Myb motif upregulates the S100A4 expression in laryngeal cancer. PMID- 24174224 TI - Population genetics and forensic efficiency of twenty-one novel microsatellite loci of Chinese Yi ethnic group. AB - In this study, we investigated polymorphic distributions of allelic frequencies and forensic genetic parameters of 21 novel autosomal microsatellite loci from 110 unrelated healthy individuals of Chinese Yi ethnic group. Expected heterozygosity, power of discrimination, and polymorphic information content ranged from 0.617 to 0.812, 0.777 to 0.936 and 0.560 to 0.790. The microsatellite loci showed high forensic efficiency. The total discrimination power and cumulate probability of exclusion were 0.99999999999999999986902 and 0.999998818, respectively. Locus-by-locus allelic frequencies were compared using analysis of molecular variance (AMOVA) method, and the statistically significant differences were observed between Yi group and Russian, Tujia, Kazak, Bai, Ningxia Han, Salar, Tibetan, and Uigur groups at 5, 6, 7, 7, 7, 8, 12, and 13 loci, respectively. The results of genetic distance comparisons, genetic structure analyses, and principal component analysis all indicated that the Yi group showed relatively short genetic relationships with Russian, Salar, and Bai group. The experimental results showed that the 21 loci in the multiplex system provided highly polymorphic information and forensic efficiency for forensic individual identification and paternity testing, also basic population data for population genetics and anthropological research. PMID- 24174223 TI - Crystal structure of a putative quorum sensing-regulated protein (PA3611) from the Pseudomonas-specific DUF4146 family. AB - Pseudomonas aeruginosa is an opportunistic pathogen commonly found in humans and other organisms and is an important cause of infection especially in patients with compromised immune defense mechanisms. The PA3611 gene of P. aeruginosa PAO1 encodes a secreted protein of unknown function, which has been recently classified into a small Pseudomonas-specific protein family called DUF4146. As part of our effort to extend structural coverage of novel protein space and provide a structure-based functional insight into new protein families, we report the crystal structure of PA3611, the first structural representative of the DUF4146 protein family. PMID- 24174225 TI - Ionic flows through a single homogeneous membrane : A thermodynamic analysis. AB - The Kedem-Katchalsky equation for the flow of a mono-monovalent salt through a highly charged permselective membrane is given as a first order expansion of a single integral of the Kirkwood-Bearman-Spiegler equations. The integration is performed under the assumption that the partial frictional coefficientszeta ij are concentration independent. Conditions for the validity of the expansion are presented. A close relationship to the Goldman equation is demonstrated. If impermeable salts are present in the bathing solutions, the Kedem Katchalskypractical parameters omega, sigma, and tau1 may be ill-defined. Nevertheless, an ionic flow equation of similar form, but of significant difference, can be derived for this situation. The Kedem-Katchalsky equation for salt flow is a special case of this more general equation. PMID- 24174226 TI - Stretch-induced changes in geometry and ultrastructure of transporting surfaces of toad bladder. AB - Methods were developed for estimation of the area of the microscopic and ultramicroscopic surface of the toad bladder epithelium at various degrees of stretch. Bladder sacs fixed while containing 2.5, 5, 25 or 50 ml of mucosal fluid were studied. For a perfect, hollow elastic sphere, this range of volume corresponds to a sevenfold range of surface area. In the bladder, this increase could be achieved by unfolding of surface irregularities, with no change in surface area, or by stretching the epithelial membrane. The measured microscopic surface area increased threeinstead of sevenfold, but the ultramicroscopic surface remained constant. Thus the bladder stretches (1) by unfolding of the mucosal epithelium, and (2) by flattening of the microvilli. From measurements of the apparent thickness of the mucosal epithelium alone and of the entire bladder, we conclude that the former behaves like a flexible inelastic sheet, whereas the submucosa and serosa stretch elastically. Lateral intercellular spaces do not widen with stretch, but they do become more convoluted because of thinning of the epithelium. Thinning is unlikely to explain the increased sodium transport which follows stretching, because cytoplasmic resistance cannot approach total transepithelial resistance of this preparation. PMID- 24174227 TI - Evidence for active water transport in a corn root preparation. AB - Water flow was measured in aZea mays root preparation consisting of a segment from which the central part had been excised. It was shown that water flow had two components, one osmotic and one non-osmotic. The non-osmotic flow was inhibited by cyanide. No correlation was found between water flow and solute flow. These findings suggest that active water transport occurred in the root preparation. The mechanism of such water movement is discussed. PMID- 24174228 TI - Mechanism of lipid activation of Na, K, Mg-activated adenosine triphosphatase and K, Mg-activated phosphatase of bovine cerebral cortex. AB - Na(+), K(+), Mg(++)-activated adenosine triphosphatase and K(+), Mg(++) activatedp-nitrophenyl phosphatase prepared from a membrane fraction of bovine cerebral cortex were studied with regard to the manner of their activation by phospholipids, using phosphatidyl serine, lysolecithin, monodecyl and didecyl phosphates. The kinetic and chromatographic studies suggested the following. (1) When the enzyme proteins bind the phospholipids in a proper ratio, they attain the optimum activation. (2) The binding causes a simple conversion of the enzymes from an inactive form to a fully activated form. (3) The lipids in both micellar form and molecular dispersion activate the enzymes. (4) Of the proteins contained in the enzyme preparation, only a group of proteins possessing the ATPase and the phosphatase activities bind phospholipids, and the amount of the bound lipids is limited. PMID- 24174229 TI - Enzymatic modification of the L and M antigens in LK and HK sheep erythrocytes and their membranes : The action of neuraminidase and trypsin. AB - This paper reports on the effect of two hydrolytic enzymes, neuraminidase and trypsin, on the interaction of blood group L-positive low-potassium-type (LK) and blood group M-positive high-potassium-type (HK) sheep red cells with their respective isoimmune antisera. It was found that treatment of LK and HK red cells with neuraminidase did not change the interaction of these cells with their homologous antibodies as measured by K(+)-pump flux, complement-mediated immune hemolysis and absorption of antibody. Similarly, trypsin pretreatment of LK and HK red cells did not interfere with the hemolytic action of anti-L and anti-M antibodies, respectively. In striking contrast, however, it was observed that pretreatment of LK cells with trypsin rendered these cells insensitive to the K(+)-pump stimulating antibody present in the anti-L serum. PMID- 24174230 TI - Effect of calcium deprivation on frog skeletal muscles at different pH values. AB - Whole sartorius muscles from the frog were exposed to calcium-free solutions at different pH values. The depolarizations caused by these solutions were measured 1 hr after the solution change. When the pH was 7.2, the mean depolarization was 8 mV. At pH values of 5.1 and 8.5, the mean depolarizations were 1 and 17 mV, respectively. Similar experiments were carried out with solutions in which the main anion was sulfate instead of chloride. In these cases, the depolarization values caused by calcium deprivation at pH values of 7.2, 5.5, and 8.5 were 11, 4, and 20 mV, respectively. PMID- 24174231 TI - Interaction of cytochromec with phospholipid monolayers and bilayer membranes. AB - For the study of the interaction between oxidized cytochromec and phosphatidylinositide, two different model systems were used: (1) monolayers which were deposited after the method of Langmuir and Blodgett onto glass plates, and (2) bimolecular ("black") membranes in aqueous phase. The amount of bound protein was determined with a sensitive spectrophotometer. It was found that at low ionic strength about 10(13) cytochromec molecules per cm(2) are bound to the lipid surface, which nearly corresponds to a densely packed monolayer. At high ionic strength (~ 0.1M) or low pH (pH<3), the adsorbed protein layer becomes unstable. This result indicates that the interaction is mainly electrostatic. In accordance with this conclusion is the observation that the rate of adsorption is diffusion controlled; i.e., almost every protein molecule hitting the surface is bound. The cytochromec monolayer can be reduced by ascorbate. In contrast to ferrocytochromec in solution, the bound ferrocytochrome was found to be autoxidable. PMID- 24174232 TI - The beta-galactoside permease ofEscherichia coli. PMID- 24174233 TI - Ref cell hydrolases: Glycosidase activities in human erythrocyte plasma membranes. AB - Human erythrocyte plasma membranes were found to contain the following glycosidases: alpha- and beta-glucosidase, alpha- and beta-galactosidase, alpha- and beta-fucosidase, beta-N-acetylglucosaminidase, beta-N acetylgalactosaminidase, beta-xylosidase and alpha-mannosidase. All the enzymes except beta-fucosidase had activity interpreted to be on the external surface of the plasma membrane. The enzymes had optimum pH values of 5.2 to 5.0 and temperatures of 37 to 40 degrees C. The enzymes were not greatly activated by divalent cations but Hg(++) and Pb(++) were inhibitory. The enzyme extract of the human erythrocyte plasma membranes liberated carbohydrate from intact red cells, which lead to the speculation that the glycosidases might function to modify the erythrocyte plasma membrane. PMID- 24174234 TI - The role of intercellular channels in the transepithelial transfer of water and sodium in the frog urinary bladder. AB - Epithelial cells of frog urinary bladders fixed in different physiological states were examined by electron microscopy. It was shown: (1) that when bladders incubated with a hypotonic mucosal medium are water-permeabilized with oxytoxin, arginine-vasotocin, cyclic 3',5'-AMP and theophylline, this leads to a cellular swelling and the opening of intercellular channels; (2) that these effects are not observed when the transepithelial net water flow is suppressed by abolishing the external osmotic driving force; and (3) that modifications in the rate of active sodium transport do not change the morphological appearance of intercellular channels.These results are expecially discussed with respect to the localization to the intracellular site of the final effect of antidiuretic hormone on water permeability, and to the role of intercellular channels in the transepithelial transfer of water and sodium. PMID- 24174235 TI - The state of water in the outer barrier of the isolated frog skin. AB - The flux of water across the outer barrier of the frog skin is generally regarded as the rate-limiting step in the movement of water across the whole membrane. This paper presents some evidence that, at room temperature, the flux of water across the outer barrier occurs through water in a non-liquid state. The organization of water in a non-liquid state lowers the diffusion coefficient of water through water by several orders of magnitude. The study employs a method recently developed in this laboratory which permits measurement of unidirectional fluxes at the outermost part of an epithelial membrane mounted as a flat sheet. Only above 25 degrees C is the activation energy for the flow of tritiated water (4.3 kcal mole(-1)) similar to the one observed in free water (4.6 kcal mole( 1)). At temperatures around 15 degrees C, the energy of activation is 8.5 kcal mole(-1). At temperatures near 0 degrees C, at which the frog lives only part of the year, the energy of activation is 16.7 kcal mole(-1). PMID- 24174236 TI - Effects of phospholipase C on human erythrocytes. AB - Previous studies have shown that the bacterial exoenzyme phospholipase C permanently alters the chemical structure of erythrocyte ghosts. The present investigation has shown some of the functional, chemical and structural changes that sequentially occur when intact human red blood cells are lysed by this enzyme. Following exposure to the enzyme, membrane phospholipids were hydrolyzed with the removal of lipid phosphorus. This resulted in a shrinkage of cell size, sphering, and increased susceptibility to osmotic stress. Progressive hemolysis ensued, leaving ghosts which were characterized by focal electron-dense areas intimately associated with each membrane. These findings illustrate that the degradation of exposed phospholipids results in chemical and morphological damage to the cell membrane, which in turn alters its functional capabilities and results in lysis of the cell. Finally, these data support a newly proposed structural model of the cell membrane. PMID- 24174237 TI - Inhibition of the permeability response to vasopressin and oxytocin in the toad bladder: Effects of bradykinin, kallidin, eledoisin, and physalaemin. AB - It has been shown by means of Bentley'sin vitro preparation of the isolated urinary bladder of the toad,Bufo marinus paracnemis Lutz, that bradykinin reversibly inhibited the increase brought about by vasopressin on the permeability to water of the toad bladder. The increased hydro-osmotic response of the bladder to oxytocin was also inhibited by the kinin. The effect on water permeability was observed when bradykinin was added either to the serosal Ringer's solution or to the mucosal solution. The addition of bradykinin alone did not alter the basal osmotic water transfer across the bladder. In this context, bradykinin acted as a competitive antagonist of vasopressin (and oxytocin). Although lacking intrinsic activity, bradykinin exhibited affinity for receptor sites that are also common to the neurohypophysial hormones, causing a parallel shift of the log-dose/response curve for vasopressin without changing the maximal responses. The effects of other kinins (namely kallidin, eledoisin and physalaemin) on the toad bladder were also tested. Each of these drugs alone did not change the basal water flux across the bladder wall. Like bradykinin, these peptides inhibited the increase in water permeability evoked by vasopressin and oxytocin in the bladder. In view of the importance of neurohypophysial hormones and their target tissues to the osmotic homeostasis of amphibians, and the observation of antagonism between the kinins and the pituitary hormones coupled to the abundance of kinins in the amphibian organism, particularly in the skin and urinary bladder, teleological reasoning predicts a physiological role for the kinins, possibly functioning to dampen excesses and oscillations in membrane permeability that could occur in face of a constant and variable secretion of neurohypophysial hormone, thus adding to the homeostatic response of the amphibian organism. PMID- 24174238 TI - The mechanism of action of valinomycin on the thylakoid membrane : Characterization of the electric current density. AB - Most of the studies devoted to the mechanism by which certain antibiotics increase the ion permeability ofbiological membranes have been carried out on artificialmodel systems. Undoubtedly one of the major reasons for this was that some of the most relevant biological membrane systems are of submicroscopic dimensions and thus inaccessible to the common electrochemical measuring techniques. This holds for the inner membrane systems of chloroplasts, mitochondria, and retinal rods.Since it is not trivial that a mechanism of action found for a model membrane works as well in a biological one with a much higher structural complexity, it seemed worth-while to study the mechanism of action of ionophorous antibiotics on the above-mentioned biological membranes.In this paper, a nonelectrochemical method for measuring both the voltage and the current across the inner chloroplast membrane (or thylakoid membrane) is established in extension of earlier work. This method is used to characterize the mode of action of valinomycin on the thylakoid membrane. PMID- 24174239 TI - The movement of molecules across lipid membranes: A molecular theory. AB - The movement of molecules across membranes is discussed in terms of thermal fluctuations in the hydrocarbon chains of the membrane lipids. The thermal motion of the hydrocarbon chains results in the formation of conformational isomers, so called kink-isomers of the hydrocarbon chains. "Kinks" may be pictured as mobile structural defects which represent small, mobile free volumes in the hydrocarbon phase of the membrane. The diffusion coefficient of kinks is calculated to be 10( 5) cm(2)/sec; thus kinks diffusion is a fast process. Small molecules can enter into the free volumes of kinks and migrate across the membrane together with the kinks; thus kinks may be regarded as intrinsic carriers of lipid membranes. An expression is derived from this model for the flow of molecules through lipid membranes. The calculated value for the water permeability is compatible with measurements on lipid bilayers. PMID- 24174240 TI - Localization of ionic conductances in crayfish muscle fibers. AB - Analysis of the changes in membrane potential and conductance of isolated crayfish muscle fibers caused by rapid solution changes leads to the following conclusions. First, the extensive invagination system of this fiber presents a barrier for diffusion between bath and sarcolemma that accounts for the time lag of electrical responses to changes in bath chloride concentration. Morphological data regarding these invaginations were used in a model which simulated the fiber response on an analog computer. Second, the potassium conductance is effectively localized on the sarcolemma in direct contact with the bath (superficial sarcolemma), whereas the chloride conductance is restricted to the invaginations. This distribution of conductances is the reverse of that found in frog muscle. PMID- 24174241 TI - The effect of uncouplers of oxidative phosphorylation on lipid bilayer membranes: Carbonylcyanidem-chlorophenylhydrazone. AB - Detailed experimental data for conductivity and membrane potentials are presented for lecithin/cholesterol/decane bilayers in the presence of the uncoupler carbonylcyanidem-chlorophenylhydrazone (CCCP). These compare favorably with a theoretical model derived to explain the mechanism of action of uncouplers on bilayers. The model assumes that the weak acid uncoupler HA and its anion A(-) are the sole species which permeate the membrane. Its key feature is the recognition of the existence of unstirred aqueous layers on either side of the membrane. The model accounts for, among other things, a maximum in the transmembrane conductivity at a pH to the alkaline side of the uncoupler pK a and saturating current-voltage characteristics at high pH, both phenomena being found for CCCP. From a quantitative fit of model to data, values of 2.0*10(-3) and 11 cm/sec are deduced for the permeability coefficients of the CCCP anion and the undissociated CCCP molecule, respectively. PMID- 24174242 TI - Preparation and characteristics of lipid vesicles. AB - As determined by electron microscopy, lipid sonicated in buffer initially forms large vesicles which may be multilamellar. Prolonged sonication results in a population of vesicles of smaller, but not uniform diameters. These vesicles are bounded by only one bilayer. The lipid suspension can be partially fractionated according to size by column chromatography. A fraction of the eluate has been selected for further study. The weight-average vesicle weight and average radius of gyration are obtained by lightscattering measurements. The volume of buffer enclosed by the vesicles is determined using(14)C- or(3)H-labelled sugars as a marker. These values are in reasonable agreement with the corresponding values calculated from the size distribution of the vesicle fraction obtained by electron microscopy. PMID- 24174243 TI - Permeability of the human red blood cell tomeso-erythritol. AB - Using(14)C-erythritol, we measured net as well as unidirectional erythritol fluxes. Up to near saturation, net and unidirectional fluxes were virtually identical and linearly related to the erythritol concentration in the medium (isotonic saline). No saturation of the transfer system was observed. At 20 degrees C, a maximum of 60 to 70% of the erythritol flux could be inhibited by glucose, phlorizin, or a combination of both substances. Dinitrofluorobenzene and HgCl2 also reduce erythritol permeability. These findings confirm the earlier conclusion of F. Bowyer and W. F. Widdas that the glucose transport system is involved in erythritol permeation. Glycerol partially inhibits the glucose phlorizin-sensitive component of erythritol flux, but not the glucose-phlorizin insensitive component. Apparently glycerol has a slight affinity to that portion of the glucose transport system which is involved in erythritol transfer, whereas the glucosephlorizin-insensitive fraction of erythritol movements is not identical with the glycerol system. This latter inference is supported by the observation that, in contrast to glycerol permeability, erythritol permeability is insensitive to variations of pH or to the addition of copper. The apparent activation energy of the glucose-phlorizin-sensitive and-insensitive fractions of erythritol permeation are 22.2 and 20.7 kcal/mole, respectively. These values are not significantly different from one another. PMID- 24174244 TI - Optical properties of artificial chlorophyll membranes. AB - The composition and structure of lipid bilayer membranes containing chlorophylla have been studied with photometric and fluorometric methods. A sensitive double beam spectrophotometer is described by which the pigment concentration in the bilayer can be determined. Up to 3*10(13) chlorophyll molecules per cm(2) can be incorporated into the membrane, corresponding to a mean distance of 20 A between the porphyrin rings. At high chlorophyll concentrations, the absorption peaks are shifted toward longer wavelengths, indicating an interaction between porphyrin rings in the film. Parallel to the spectral shifts, a large decrease in the fluorescence quantum yield and a depolarization of the fluorescence are observed. These findings suggest that transfer of excitation energy takes place between neighboring chlorophyll molecules in the membrane. When an oxidating agent (K2S2O8) is added toone external phase, exactly half of the chlorophyll in the film is destroyed. This observation suggests that the chlorophyll molecules are localized in the membrane surfaces with the phytyl chains inserted into the hydrocarbon core of the membrane and the porphyrin rings facing the aqueous solution. PMID- 24174245 TI - A theory of ion permeation through membranes with fixed neutral sites. AB - Some model membranes and biological membranes behave as if ion permeation were controlled by fixed neutral sites, i.e., by groups that are polar but lack net charge. By solving the boundary conditions and Nernst-Planck flux equations, this paper derives the expected properties of four types of membranes with fixed neutral sites: model 1, a membrane thick enough that microscopic electroneutrality is obeyed; model 2, same as model 1 but with a free-solution shunt in parallel; model 3, a membrane thin enough that microscopic electroneutrality is violated; and model 4, same as model 3 but with a free solution shunt in parallel. The conductance-concentration relation and the current-voltage relation in symmetrical solutions are approximately linear for all four models. Partial ionic conductances are independent of each other for a thin membrane but not for a thick membrane. Sets of permeability ratios derived from conductances, dilution potentials, or biionic potentials agree with each other in a thin membrane but not in a thick membrane. The current-voltage relation in asymmetrical single-salt solutions is linear for a thick membrane but nonlinear for a thin membrane. Examples of potential and concentration profiles in a thin membrane are calculated to illustrate the meaning of space charge and the electroneutrality condition. The experimentally determined properties (by A. Cass, A. Finkelstein & V. Krespi) of thin lipid membranes containing "pores" of the anion-selective antibiotic nystatin are in reasonable agreement with model 3. Tests are suggested for deciding if a membrane of unknown structure has neutral sites, whether it is thick or thin, and whether the sites are fixed or mobile. PMID- 24174246 TI - The mechanism of cation permeation in rabbit gallbladder : Conductances, the current-voltage relation, the concentration dependence of anion-cation discrimination, and the calcium competition effect. AB - The questions underlying ion permeation mechanisms, the types of experiments available to answer these questions, and the properties of some likely permeation models are examined, as background to experiments designed to characterize the mechanism of alkali cation permeation across rabbit gallbladder epithelium. Conductance is found to increase linearly with bathing-solution salt concentrations up to at least 400MM. In symmetrical solutions of single alkali chloride salts, the conductance sequence is K(+)>Rb(+)>Na(+)>Cs(+)~Li(+). The current-voltage relation is linear in symmetrical solutions and in the presence of a single-salt concentration gradient up to at least 800 mV. The anion/cation permeability ratio shows little change with concentration up to at least 300MM. Ca(++) reduces alkali chloride single-salt dilution potentials, the magnitude of the effect being interpreted as an inverse measure of cation equilibrium constants. The equilibrium-constant sequence deduced on this basis is K(+)>Rb(+)>Na(+)~Cs(+)~Li(+). These results suggest (1) that the mechanism of cation permeation in the gallbladder is not the same as that in a macroscopic ion exchange membrane; (2) that cation mobility ratios are closer to one than are equilibrium-constant ratios; (3) that the rate-limiting step for cation permeation is in the membrane interior rather than at the membrane-solution interface; and (4) that the rate-controlling membrane is one which is sufficiently thick that it obeys microscopic electroneutrality. PMID- 24174247 TI - The mechanism of cation permeation in rabbit gallbladder : Dilution potentials and biionic potentials. AB - The experimental measurements of passive ion permeation in rabbit gallbladder presented in this paper include: single-salt dilution potentials as a function of concentration gradient; comparison of dilution potentials for different alkali chlorides; comparison of biionic potentials for different alkali chlorides; and biionic mixture potentials as a function of cation concentration gradient. Both dilution potentials and biionic potentials yield the permeability sequence K(+)>Rb(+)>Na(+)>Li(+)>Cs(+), a sequence consistent with simple considerations of ion-site interactions and ion hydration energies. Construction of empirical selectivity isotherms for alkali cation permeation in epithelia shows that permeability ratios are nearer one in the gallbladder and other epithelia than in most other biological membranes, indicating a relatively hydrated permeation route. Evaluation of the results of this and the preceding paper suggests the following: that cations permeate gallbladder epithelium via channels with fixed neutral sites; that the rate-controlling membrane is thick enough that microscopic electroneutrality must be obeyed; that virtually all anion conductance is in a shunt which develops with time after dissection; that apparent permeability changes with solution composition are due to the non-ideal activity factorn being less than 1.0; that effects of pH, Ca(++), and ionic strength may involve changes in the anion/cation mobility ratio owing to changes in wall charges or dipoles; and that the permeation route may reside in the tight junctions. A similar mechanism may be applicable to cation permeation in other epithelia. PMID- 24174248 TI - Microautoradiographic investigations of sulfate uptake by glands and epidermal cells of water lily (Nymphaea) leaves with special reference to the effect of poly-L-lysine. AB - The uptake of(35)S-labelled sulfate ions into hydropote cells (densely cytoplasmic gland cells) and into epidermal cells (highly vacuolated cells) ofNymphaea leaves is dependent on metabolic energy. Only a very small fraction of the accumulated(35)S is incorporated into organic macromolecules during the experimental period. Both cell types exhibit a hyperbolic isotherm for(35)S uptake from labelled K2SO4 solutions over an external concentration range of 0 to 0.5MM. Although the gland and epidermal cells behave qualitatively similarly, the glands generally absorb about twice as much(35)S per unit area of sections of the cells as do the epidermal cells. At 3 degrees C, poly-L-lysine concentrations of 10(-8) M and up to 10(-7) M enhance(35)S uptake by the epidermal and gland cells for the first 7.5 hr after application of the poly-L-lysine. Samples treated with 5*10(-7) M poly-L-lysine are indistinguishable from the controls over the same period. After longer periods of treatment with poly-L-lysine (7.5 to 24 hr), the rates of(35)S uptake were reduced by all poly-L-lysine concentrations between the range 10(-8) to 5*10(-7) M. After 7.5 hr of(35)S uptake, the control samples contained the smallest amount of label, but after an uptake period of 24 hr the amount of label in the controls is considerably larger than in samples treated with poly-L-lysine. The results suggest that poly-L-lysine increases the membrane permeability and alters the metabolic uptake of sulfate in both hydropotes and epidermal cells. PMID- 24174259 TI - Report 85: Fundamental quantities and units for ionizing radiation. AB - Definitions of fundamental quantities, and their units, for ionizing radiation are given, which represent the recommendation of the International Commission on Radiation Units and Measurements (ICRU). PMID- 24174261 TI - Action, language and neuroinformatics: an introduction. PMID- 24174262 TI - Direct medical cost and glycemic control in type 2 diabetic Saudi patients. AB - BACKGROUND: The prevalence of diabetes mellitus continues to increase globally. Furthermore, it is projected that healthcare expenditure on this epidemic will mount to US$490 billion in 2030. Information on the economic burden of diabetes care in Saudi Arabia is largely lacking. OBJECTIVES: This retrospective observational study evaluated the direct medical cost of type 2 diabetes mellitus (T2DM) in a Saudi population in relation to glycemic control at a governmental institution from a payer's perspective. METHODS: Three hundred subjects attending a university hospital were classified into three groups (n = 100 each) based on HbA1c values to <7 %, 7-9 %, and >9 %. The total direct medical costs were calculated for drug therapy, diagnostic procedures, hospitalization, and outpatient visits. The year of valuation for the costings was 2010/2011. RESULTS: The total annual direct medical cost per group was found to be US$1,384.19 for HbA1c <7 %, US$2,036.11 for HbA1c 7-9 %, and US$3,104.86 for HbA1c >9 % (p < 0.001). There was also a statistically positive relationship in the total care cost of diabetic patients and the number of co-morbidities (p < 0.001). A direct association of the cost of medications that have been disbursed for diabetic patients and the medical specialty of the treating physician (r = 0.390; p < 0.0001), and the cost of laboratory analyses (r = 0.351; p < 0.0001), was observed as also between the cost of laboratory diagnosis and days of hospitalization (r = 0.478; p < 0.0001). Multivariate analysis showed that the relationship between HbA1c and total cost is independent of age and gender, while co-morbidities remain as a significant predictor for the total cost. CONCLUSIONS: Collectively, the estimated direct annual medical cost of diabetes care in Saudi Arabia would be enormous. The current study offers more insight into the economic burden of diabetes on the country. PMID- 24174264 TI - Biological imaging using nanoparticles of small organic molecules with fluorescence emission at wavelengths longer than 1000 nm. AB - Embedded in a polymer: A hydrophobic organic molecule that fluoresces in the near infrared II (NIR-II) region was made water-soluble and biocompatible by its embedment in a polymer nanoparticle, which was then coated with hydrophilic poly(ethylene glycol) chains. The resulting nanoparticles exhibit bright fluorescence in the NIR-II window and high photostability in aqueous media and were used for in vivo imaging in mice. PMID- 24174263 TI - Dual targeting of the Warburg effect with a glucose-conjugated lactate dehydrogenase inhibitor. AB - Effective glucose diet: We report the development and activity of glucose conjugated LDH-A inhibitors designed for dual targeting of the Warburg effect (elevated glucose uptake and glycolysis) in cancer cells. Glycoconjugation could be applied to inhibitors of many enzymes involved in glycolysis or tumor metabolism. PMID- 24174265 TI - Assessing recall in mothers' retrospective reports: concerns over children's speech and language development. AB - Retrospective recall about children's symptoms is used to establish early developmental patterns in clinical practice and is also utilised in child psychopathology research. Some studies have indicated that the accuracy of retrospective recall is influenced by life events. Our hypothesis was that an intervention: speech and language therapy, would adversely affect the accuracy of parent recall of early concerns about their child's speech and language development. Mothers (n = 5,390) reported on their child's speech development (child male to female ratio = 50:50) when their children were aged 18 or 30 months, and also reported on these early concerns retrospectively, 10 years later, when their children were 13 years old. Overall reliability of retrospective recall was good, 86 % of respondents accurately recalling their earlier concerns. As hypothesised, however, the speech and language intervention was strongly associated with inaccurate retrospective recall about concerns in the early years (Relative Risk Ratio = 19.03; 95 % CI:14.78-24.48). Attendance at speech therapy was associated with increased recall of concerns that were not reported at the time. The study suggests caution is required when interpreting retrospective reports of abnormal child development as recall may be influenced by intervening events. PMID- 24174266 TI - Facile removal of high mannose structures prior to extracting complex type N glycans from de-N-glycosylated peptides retained by C18 solid phase to allow more efficient glycomic mapping. AB - The relative amount of high mannose structures within an N-glycomic pool differs from one source to another, but quite often it predominates over the larger size complex type structures carrying biologically important glyco-epitopes. An efficient method to separate these two classes of N-glycans would significantly aid in detecting the lower abundant components by MS. Capitalizing on an initial observation that only high mannose type structures were recovered in the flow through fraction when peptide-N-glycosidase F digested peptides were passed through a C18 cartridge in 0.1% formic acid, we demonstrated here that native complex type N-glycans can be retained by C18 cartridge and to be efficiently separated from both the smaller high mannose type structures, as well as de-N glycosylated peptides by stepwise elution with increasing ACN concentration. The weak retention of the largely hydrophilic N-glycans on C18 resin is dependent not only on size but also increased by the presence of alpha6-fucosylation. This was shown by comparing the resulting N-glycomic profiles of the washed and low-ACN eluted fractions derived from both a human cancer cell line and an insect cell line. PMID- 24174267 TI - A population-based study of genetic variation and psychotic experiences in adolescents. AB - Psychotic experiences are not uncommon in general population samples, but no studies have examined to what extent confirmed risk variants for schizophrenia are associated with such experiences. A total of 3483 children in a birth cohort study participated in semistructured interviews for psychotic experiences at ages 12 and 18. We examined whether (1) a composite measure of risk for schizophrenia conferred by common alleles (polygenic score) was associated with psychotic experiences, (2) variants with genome-wide evidence for association with schizophrenia were associated with psychotic experiences, and (3) we could identify genetic variants for psychotic experiences using a genome-wide association (GWA) approach. We found no evidence that a schizophrenia polygenic score, or variants showing genome-wide evidence of association with schizophrenia, were associated with adolescent psychotic experiences within the general population. In fact, individuals who had a higher number of risk alleles for genome-wide hits for schizophrenia showed a decreased risk of psychotic experiences. In the GWA study, no variants showed GWA for psychotic experiences, and there was no evidence that the strongest hits (P < 5 * 10(-5)) were enriched for variants associated with schizophrenia in large consortia. Although polygenic scores are weak tools for prediction of schizophrenia, they show strong evidence of association with this disorder. Our findings, however, lend little support to the hypothesis that psychotic experiences in population-based samples of adolescents share a comparable genetic architecture to schizophrenia, or that utilizing a broader and more common phenotype of psychotic experiences will be an efficient approach to increase understanding of the genetic etiology of schizophrenia. PMID- 24174268 TI - Residual feed intake: a nutritional tool for genetic improvement. AB - The goal of this bibliographical study was to provide information about residual feed intake (RFI), a new criterion used in the selection of beef cattle for growth rate, food ingestion, and feed efficiency. RFI is calculated as the difference between real consumption and the quantity of food an animal is expected to eat based on its mean live weight and rate of weight gain. In studies of RFI, many speculations are made among researchers about the reliability of this criterion. However, there is a high genetic correlation with characteristics related to post-weaning consumption and maturity, indicating that the biological processes that regulate consumption and efficiency in young animals are similar to the processes that regulate consumption and efficiency in animals of greater age. In contrast to feed conversion, selection based on RFI seems to select for lower rates of consumption and lower animal maintenance requirements without changing adult weight or weight gain. Therefore, we conclude that the data indicate that there are extraordinary benefits to be gained from changing the goals of selection from increased weight gain to improved nutritional efficiency. Given the importance of animal production for economic development in Brazil choosing the best selection goals for livestock improvement is essential. To include an index of feed efficiency in future goals would be desirable, and RFI may play a part in this if economic methods of implementation can be developed. PMID- 24174269 TI - Influences of non-genetic factors on early growth of Adilo lambs under smallholder management systems, southern Ethiopia. AB - Stagnant early growth and mortality are the major impediments for sheep production in southern Ethiopia. We evaluated the effects of non-genetic factors on early growth performance of lambs in Halaba district with 467 lambs owned by 60 households. Body weights (kilograms) of lambs at birth, 30, 60, 90, 120, and 150 days were 2.30 +/- 0.03, 4.45 +/- 0.11, 6.94 +/- 0.13, 10.4 +/- 0.19, 13.3 +/ 0.19, and 15.7 +/- 0.20, respectively. The average daily gain (ADG; gram) from birth to 30, 60, 90, 120, and 150 days were 71.18 +/- 8.18, 77.18 +/- 2.19, 89.20 +/- 1.98, 91.18 +/- 1.51, and 90.68 +/- 1.27, respectively. Season effect was significant (p < 0.05) for weight at birth, 30, and 120 days. Similarly, season of birth influenced (p < 0.05) ADG (gram) at all ages except from birth to 60 days. Single-born lambs were heavier over multiple births (p < 0.01), 90 (p < 0.001) and 120 days (p < 0.05) and higher (p < 0.001) ADG from birth to 90 days. There were significant interaction effects of parity by sex at birth (p < 0.01) and parity by type of birth (p < 0.001) and 90 days (p < 0.01). From the non genetic factors estimated in this study, season and type of birth, and their interaction had a more profound effect at early growth of lambs, and they need to be considered in the improvement plan of sheep under Halaba arid to semi-arid environments. Efforts geared towards planned breeding, improved nutrition, and health would assist farmers to exploit these indigenous and adaptable sheep resources efficiently. PMID- 24174270 TI - Association between severe treatment-related lymphopenia and progression-free survival in patients with newly diagnosed squamous cell head and neck cancer. AB - BACKGROUND: Severe treatment-related lymphopenia occurs commonly in many cancers and is associated with early tumor progression. Data are lacking as to whether this occurs in squamous cell head and neck cancer. METHODS: Serial total lymphocyte counts were retrospectively reviewed in patients with newly diagnosed squamous head and neck cancer undergoing chemoradiation and associated with treatment outcomes. RESULTS: The median baseline total lymphocyte count in 56 patients was 1660 cells/mm(3) , which fell by 73% to 445 cells/mm(3) 2 months after initiating chemoradiation (p < .0001). Human papillomavirus negative (HPV-) patients with a total lymphocyte count <500 cells/mm(3) at 2 months had significantly earlier disease progression than those with higher total lymphocyte counts (hazard ratio [HR], 5.75; p = .045). CONCLUSION: Baseline total lymphocyte counts were normal, but at 2 months approximately 60% of patients had severe treatment-related lymphopenia regardless of HPV status. Severe treatment-related lymphopenia in HPV- patients is independently associated with earlier disease progression. Prospective studies are needed to confirm these findings, which suggest that immune preservation is important in this cancer. PMID- 24174271 TI - The Bergen left-right discrimination test: practice effects, reliable change indices, and strategic performance in the standard and alternate form with inverted stimuli. AB - Several authors pointed out that left-right discrimination (LRD) tasks may be entangled with differential demands on mental rotation (MR). However, studies considering this interrelationship are rare. To differentially assess LRD of stimuli with varying additional demands on MR, we constructed and evaluated an extended version of the Bergen right-left discrimination (BRLD) test including additional subtests with inverted stickmen stimuli in 174 healthy participants (50?, 124?) and measured subjective reports on participants' strategies to accomplish the task. Moreover, we analyzed practice effects and reliable change indices (RCIs) on BRLD performance, as well as gender differences. Performance significantly differed between subtests with high and low demands on MR with best scores on subtests with low demands on MR. Participants' subjective strategies corroborate these results: MR was most frequently reported for subtests with highest MR demands (and lowest test performance). Pronounced practice effects were observed for all subtests. Sex differences were not observed. We conclude that our extended version of the BRLD allows for the differentiation between LRD with high and low demands on MR abilities. The type of stimulus materials is likely to be critical for the differential assessment of MR and LRD. Moreover, RCIs provide a basis for the clinical application of the BRLD. PMID- 24174272 TI - Trends in less-lethal use of force techniques by police services within England and Wales: 2007-2011. AB - The aim of this study was to determine the incidence of, and any changes in, usage patterns of the less-lethal forms of Use of Force (UoF) modalities- incapacitant spray, impact rounds, and Taser(R)--between 2007 and 2011 by English and Welsh police services. Additional information regarding the deployment and discharge of firearms was also sought. Two thousand Freedom of Information Act applications were made to 50 police services in England and Wales and related jurisdictions requesting the provision of: (a) the total number of deployments of incapacitant sprays, Taser(R), impact (baton) rounds, and armed response units (ARU); (b) the numbers and types of any resulting medical complications; and (c) the details of any local policies requiring assessment by a healthcare professional following a deployment. Responses were received from 47 police services, with only 10 of these supplying complete data. The remainder supplied incomplete data or refused to supply any data under s12 of the Freedom of Information Act (time and cost restrictions). From 2007 to 2011, the use of incapacitant sprays, Taser, and firearms have increased (incapacitant sprays deployed: 3496, 3976, 6911, 6679, 6853; Taser deployed: 499, 2659, 4560, 6943, 7203; Taser discharged: 15, 85, 161, 338, 461; firearms: 0, 7, 4, 19, 32). Baton rounds and ARU use showed greater variability over the same time period (baton rounds: 1007, 1327, 1123, 1382, 1278; ARUs: 11688, 13652, 13166, 13959, 12090). Only two services could provide details of medical consequences from use of incapacitant sprays, Taser, and baton rounds. No service could provide details of any related medical complications following use of firearms. Data collection and release are variable and inconsistent throughout English and Welsh police services and thus caution is needed in determining trends of UoF techniques. Deaths or injuries inflicted using UoF techniques result in much public scrutiny and the low level of data recorded in these cases is of concern. Common systems for recording use and adverse outcomes of UoF techniques are needed to inform the public and others who have concerns about such techniques. PMID- 24174273 TI - The utility of smallpox vaccine scars in the forensic identification process. PMID- 24174274 TI - Cardiothoracic ratio in postmortem computed tomography: reliability and threshold for the diagnosis of cardiomegaly. AB - The aim of this study was to evaluate the reliability of the cardiothoracic ratio (CTR) in postmortem computed tomography (PMCT) and to assess a CTR threshold for the diagnosis of cardiomegaly based on the weight of the heart at autopsy. PMCT data of 170 deceased human adults were retrospectively evaluated by two blinded radiologists. The CTR was measured on axial computed tomography images and the actual cardiac weight was weighed at autopsy. Inter-rater reliability, sensitivity, and specificity were calculated. Receiver operating characteristic curves were calculated to assess enlarged heart weight by CTR. The autopsy definition of cardiomegaly was based on normal values of the Zeek method (within a range of both, one or two SD) and the Smith method (within the given range). Intra-class correlation coefficients demonstrated excellent agreements (0.983) regarding CTR measurements. In 105/170 (62 %) cases the CTR in PMCT was >0.5, indicating enlarged heart weight, according to clinical references. The mean heart weight measured in autopsy was 405 +/- 105 g. As a result, 114/170 (67 %) cases were interpreted as having enlarged heart weights according to the normal values of Zeek within one SD, while 97/170 (57 %) were within two SD. 100/170 (59 %) were assessed as enlarged according to Smith's normal values. The sensitivity/specificity of the 0.5 cut-off of the CTR for the diagnosis of enlarged heart weight was 78/71 % (Zeek one SD), 74/55 % (Zeek two SD), and 76/59 % (Smith), respectively. The discriminative power between normal heart weight and cardiomegaly was 79, 73, and 74 % for the Zeek (1SD/2SD) and Smith methods respectively. Changing the CTR threshold to 0.57 resulted in a minimum specificity of 95 % for all three definitions of cardiomegaly. With a CTR threshold of 0.57, cardiomegaly can be identified with a very high specificity. This may be useful if PMCT is used by forensic pathologists as a screening tool for medico-legal autopsies. PMID- 24174275 TI - A randomized, double-blind, placebo-controlled, phase III study of the short acting beta1-adrenergic receptor blocker landiolol hydrochloride for coronary computed tomography angiography in Japanese patients with suspected ischemic cardiac disease. AB - OBJECTIVES AND BACKGROUND: The objective of this study was to investigate the image quality-improving and heart rate-lowering effects of landiolol hydrochloride (a short-acting beta1-adrenergic receptor blocker) on coronary computed tomography angiography (CCTA). During CCTA, beta-adrenergic receptor blockers have been commonly used to lower heart rate and improve image quality. METHODS: A total of 258 subjects suspected of having ischemic cardiac disease and requiring CCTA were randomized to either a landiolol hydrochloride 0.125 mg/kg group or placebo group to study the efficacy and safety of landiolol hydrochloride in a multicenter, double-blind, randomized parallel study. The primary endpoint was the diagnosable proportion (proportion of subjects whose coronary stenosis was diagnosable). RESULTS: The diagnosable proportions about the reconstruction images at mid-diastole were 68.2 and 38.2 % in the landiolol hydrochloride and placebo group, respectively, indicating significant superiority of landiolol hydrochloride over placebo (p < 0.0001). The diagnosable proportions about the optimal reconstruction images were 81.4 and 54.2 % in the landiolol hydrochloride and placebo group, respectively, indicating significant superiority of landiolol hydrochloride over placebo (p < 0.0001). The mean heart rate lowering effect was first observed soon after administration of landiolol hydrochloride, was most marked at 3-5 min, and disappeared 30 min after completion of administration. The mean heart rate-lowering proportion at that time was -19.1 +/- 8.1 % and -5.9 +/- 9.7 % in the landiolol hydrochloride and placebo groups, respectively, showing a significantly higher proportion in the landiolol hydrochloride group. CONCLUSIONS: Landiolol hydrochloride was confirmed to significantly and rapidly lower heart rate after intravenous injection, suggesting that it is a safe and useful agent for improving the image quality of CCTA. PMID- 24174276 TI - Comprehensive proteomic data sets for studying adipocyte-macrophage cell-cell communication. AB - Cellular communication is a fundamental process in biology. The interaction of adipocytes with macrophages is a key event in the development of common diseases such as type 2 diabetes. We applied an established bilayer cell co-culture system and comprehensive mass spectrometry analysis to detect proteome-wide the paracrine interaction of murine adipocytes and macrophages. Altogether, we identified 4486 proteins with at least two unique peptides of which 2392 proteins were informative for 3T3-L1 adipocytes and 2957 proteins for RAW 264.7 macrophages. Further, we observed over 12,000 phosphorylation sites of which we could assign 3,200 informative phosphopeptides with a single phosphosite for adipocytes and 4,514 for macrophages. Using protein set enrichment and phosphosite analyses, we deciphered regulatory protein pathways involved in cellular stress and inflammation, which can contribute to metabolic impairment of cells including insulin resistance and other disorders. The generated data sets provide a holistic, molecular pathway-centric view on the interplay of adipocytes and macrophages in disease processes and a resource for further studies. PMID- 24174277 TI - Improving the accuracy of protein stability predictions with multistate design using a variety of backbone ensembles. AB - Multistate computational protein design (MSD) with backbone ensembles approximating conformational flexibility can predict higher quality sequences than single-state design with a single fixed backbone. However, it is currently unclear what characteristics of backbone ensembles are required for the accurate prediction of protein sequence stability. In this study, we aimed to improve the accuracy of protein stability predictions made with MSD by using a variety of backbone ensembles to recapitulate the experimentally measured stability of 85 Streptococcal protein G domain beta1 sequences. Ensembles tested here include an NMR ensemble as well as those generated by molecular dynamics (MD) simulations, by Backrub motions, and by PertMin, a new method that we developed involving the perturbation of atomic coordinates followed by energy minimization. MSD with the PertMin ensembles resulted in the most accurate predictions by providing the highest number of stable sequences in the top 25, and by correctly binning sequences as stable or unstable with the highest success rate (~90%) and the lowest number of false positives. The performance of PertMin ensembles is due to the fact that their members closely resemble the input crystal structure and have low potential energy. Conversely, the NMR ensemble as well as those generated by MD simulations at 500 or 1000 K reduced prediction accuracy due to their low structural similarity to the crystal structure. The ensembles tested herein thus represent on- or off-target models of the native protein fold and could be used in future studies to design for desired properties other than stability. PMID- 24174278 TI - Pharmacologic pretreatment in SVG interventions. PMID- 24174279 TI - Phylogenetic analysis of canine parvovirus partial VP2 gene in India. AB - A total of 85 samples (58.0 %) were found to be positive for Canine parvovirus (CPV) by PCR assay (Hfor/Hrev primers) out of 158 suspected faecal samples of dogs collected from various states/union territories of India. Nine CPV isolates could be obtained in A-72 cell line. The sequencing of the partial VP2 gene of CPV identified the predominant CPV strain as CPV-2a (Ser297Ala) with one CPV-2b (Ser297Ala) and another CPV-2a variant strain (Ser297Gly). Several non-synonymous and synonymous mutations were also recorded in this study. The phylogenetic tree revealed that most of the CPV sequences from Tamil Nadu (Southern India) and Maharashtra (Western India) obtained during 2011 and few sequences from Northern India obtained during 2012 were grouped together along with CPV-2a (Ser297Ala) strains from China and India and followed the same evolution; although there was definitive indication of separate lineages too by few other sequences. PMID- 24174280 TI - Loss and gain of N-linked glycosylation sites in globular head and stem of HA found in A/H3N2 flu fatal and severe cases during 2013 Tunisia flu seasonal survey. AB - Glycosylation on the globular head of the hemagglutinin (HA) protein of influenza virus acts as an important target for recognition and destruction of virus by innate immune proteins of the collectin family. In the current study, we have characterized the dynamic amino acid changes at N-linked glycosylation sites of full length sequences of HA genes of 5 A/H3N2 Tunisian strains isolates from mild, severe, and fatal cases. Compared to the reference strain, A/Perth/16/2009 substitutions in potential N-glycosylation sites were observed in 5 HA genes at five different positions (45, 124, 128, 144, and 145) generating the losses and gains of N-linked glycosylation sites. Also the mutation N145S was presented in the receptor-binding site of all segments analyzed. Point mutations in several positions in the gene encoding the H3 of Tunisian strains were shown to ablate a glycan attachment site and also loss of a potential glycosylation site. The relation between these mutations and virulence of influenza A/H3N2 virus needed to be verified in the further experiments. PMID- 24174281 TI - Metal-free aryltrifluoromethylation of activated alkenes. AB - Metal-free: The first metal-free aryltrifluoromethylation of activated alkenes has been developed. With this method, trifluoromethylated isoquinolinediones, spirobicycles, oxindoles, and alpha-aryl-beta-trifluoromethylamides were obtained with high control of the regioselectivity. PMID- 24174282 TI - Two proposed early biomarker tests of ASD: more harm than good. PMID- 24174284 TI - Medial reefing without lateral release for recurrent patellar instability: midterm and long-term outcomes. AB - BACKGROUND: There is no consensus on the optimal surgical technique for recurrent patellofemoral instability. Despite many different surgical procedures discussed in the literature, there are few studies with long-term outcomes. HYPOTHESIS/PURPOSE: The purpose of this study was to compare subjective and objective preoperative data from patients with recurrent patellar instability and normal alignment to midterm and long-term outcomes after an arthroscopically assisted medial reefing technique. The hypothesis was that the previously reported successful outcomes at 60 months would be well maintained over time. STUDY DESIGN: Case series; Level of evidence, 4. METHODS: A total of 19 patients (20 knees) with recurrent patellar instability and normal bony anatomy underwent arthroscopically assisted medial reefing without lateral release. They were evaluated preoperatively and then at midterm (average, 63 months) and long-term (average, 142 months) follow-ups. Patients underwent a history assessment, physical examination, and radiographic evaluation. Outcomes evaluated included Lysholm and Tegner scores, subjective data, and examination and radiographic findings. Operative reports were reviewed for the presence of chondral lesions. Comparative statistics were utilized (P < .05). RESULTS: All patients were satisfied with their surgery results and would undergo the procedure again. There was 1 recurrent subluxation and no recurrent dislocations. Subjective symptom scores demonstrated significant improvement from preoperative to midterm and long term follow-ups for pain, instability, and swelling. Both Lysholm and Tegner scores improved significantly from preoperative to midterm and long-term follow ups. At long-term follow-up, 70% of the patients reported excellent or good results, 5 patients reported fair results, and 1 patient reported a poor result. However, Tegner activity scores decreased significantly from midterm to long-term follow-ups. Significant improvement from preoperative to midterm and long-term follow-ups was demonstrated in physical examination findings including decreases in patellar apprehension and patellar quadrant glide; however, there was no significant difference in retropatellar pain or range of motion. For radiographic measurements, the lateral patellofemoral angle was significantly improved from preoperative to midterm and long-term follow-ups. At long-term radiographic analysis, 5 knees (25%) had narrowing of the patellofemoral joint space, 10 knees (50%) revealed patellofemoral osteophytes, and 7 knees (35%) demonstrated a medial ossicle. The presence of preoperative chondral lesions resulted in significantly lower Lysholm and Tegner scores and increased findings of osteoarthritis at long-term follow-up. CONCLUSION: Arthroscopically assisted medial reefing, without lateral release, is an effective long-term treatment for patients with recurrent patellar instability and normal bony anatomy. PMID- 24174283 TI - Age-dependent role for Ras-GRF1 in the late stages of adult neurogenesis in the dentate gyrus. AB - The dentate gyrus of the hippocampus plays a pivotal role in pattern separation, a process required for the behavioral task of contextual discrimination. One unique feature of the dentate gyrus that contributes to pattern separation is adult neurogenesis, where newly born neurons play a distinct role in neuronal circuitry. Moreover,the function of neurogenesis in this brain region differs in adolescent and adult mice. The signaling mechanisms that differentially regulate the distinct steps of adult neurogenesis in adolescence and adulthood remain poorly understood. We used mice lacking RASGRF1(GRF1), a calcium-dependent exchange factor that regulates synaptic plasticity and participates in contextual discrimination performed by mice, to test whether GRF1 plays a role in adult neurogenesis.We show Grf1 knockout mice begin to display a defect in neurogenesis at the onset of adulthood (~2 months of age), when wild-type mice first acquire the ability to distinguish between closely related contexts. At this age, young hippocampal neurons in Grf1 knockout mice display severely reduced dendritic arborization. By 3 months of age, new neuron survival is also impaired. BrdU labeling of new neurons in 2-month-old Grf1 knockout mice shows they begin to display reduced survival between 2 and 3 weeks after birth, just as new neurons begin to develop complex dendritic morphology and transition into using glutamatergic excitatory input. Interestingly, GRF1 expression appears in new neurons at the developmental stage when GRF1 loss begins to effect neuronal function. In addition, we induced a similar loss of new hippocampal neurons by knocking down expression of GRF1 solely in new neurons by injecting retrovirus that express shRNA against GRF1 into the dentate gyrus. Together, these findings show that GRF1 expressed in new neurons promotes late stages of adult neurogenesis. Overall our findings show GRF1 to be an age-dependent regulator of adult hippocampal neurogenesis, which contributes to ability of mice to distinguish closely related contexts. PMID- 24174286 TI - Carcinoid syndrome caused by a serotonin-secreting pituitary tumour. AB - BACKGROUND: Neuroendocrine tumours are most frequently located in the gastrointestinal organ system or in the lungs, but they may occasionally be found in other organs. CASE: We describe a 56-year-old woman suffering from a carcinoid syndrome caused by a large serotonin-secreting pituitary tumour. She had suffered for years from episodes of palpitations, dyspnoea and flushing. Cardiac disease had been suspected, which delayed the diagnosis, until blood tests revealed elevated serotonin and chromogranin A in plasma. The somatostatin receptor (SSR) scintigraphy showed a single-positive focus in the region of the pituitary gland and MRI showed a corresponding intra- and suprasellar heterogeneous mass. After pre-treatment with octreotide leading to symptomatic improvement, the patient underwent trans-cranial surgery with removal of the tumour. This led to a clinical improvement and to a normalisation of SSR scintigraphy, as well as serotonin and chromogranin A levels. CONCLUSION: To our knowledge, this is the first reported case of a serotonin-secreting tumour with a primary location in the pituitary. PMID- 24174285 TI - Proteomic identification of rainbow trout seminal plasma proteins. AB - In the study, the combination of protein fractionation by 1DE and HPLC-ESI-MS/MS was used to characterize the rainbow trout seminal plasma proteome. Our results led to the creation of a catalogue of rainbow trout seminal plasma proteins (152 proteins) and significantly contributed to the current knowledge regarding the protein composition of fish seminal plasma. The major proteins of rainbow trout seminal plasma, such as transferrin, apolipoproteins, complement C3, serum albumin, and hemopexin-, alpha-1-antiproteinase-, and precerebellin-like protein, were recognized as acute-phase proteins (proteins that plasma concentration changes in response to inflammation). This study provides the basis for further functional studies of fish seminal plasma proteins, as well as for the identification of novel biomarkers for sperm quality. The MS data have been deposited in the ProteomeXchange with identifier PXD000306 (http://proteomecentral.proteomexchange.org/dataset/PXD000306). PMID- 24174287 TI - Perioperative changes in cortical excitability, mood, and quality of life in patients with primary hyperparathyroidism: a pilot study using transcranial magnetic stimulation. AB - OBJECTIVE: Serum calcium (Ca(2)(+)) and parathyroid hormone (PTH), amongst others, modify cortical excitability. Alterations in cortical excitability were shown in patients with epilepsy as well as hyper- or hypoparathyroidism. In patients with primary hyperparathyroidism (pHPT), preoperative elevated serum calcium and parathyroidectomy (PTx) may affect mood and quality of life. We hypothesized that perioperative changes in Ca(2)(+) and PTH in pHPT will affect cortical excitability and improve subjective health. DESIGN AND METHODS: Transcranial magnetic stimulation (TMS) was performed before and after surgery in 15 pHPT patients. We measured resting motor threshold, cortical silent period (CSP), short intracortical inhibition, and intracortical facilitation. Health questionnaires were administered before, 1 day and 6 months after PTx, along with the disease-specific Pasieka's parathyroid assessment of symptoms (PAS), which was, to our knowledge, its first use in German. RESULTS: SURGERY WAS SUCCESSFUL IN ALL PATIENTS. TMS-MEASUREMENTS REMAINED UNCHANGED WHEN ANALYZING ALL PATIENTS IN THIS PILOT STUDY. POSTOPERATIVELY, DEPRESSION DECLINED (P=0.05) AND QUALITY OF LIFE IMPROVED SIGNIFICANTLY (P=0.001) IN THE SF-36-SUBSCALES: vitality, social functioning, mental health and subjective health transition (post-hoc analysis). The PAS proved early relief of disease-specific symptoms (P<0.001). CONCLUSIONS: We found unchanged cortical excitability comparing pre- and post-PTx in this pilot study. Mood and quality of life improved postoperatively. The German PAS is valuable in detecting disease-specific changes early after PTx. PMID- 24174288 TI - Postmenopausal estrogen therapy and risk of gallstone disease: a population-based case-control study. AB - BACKGROUND: Female gender and increasing age are key risk factors for gallstone disease; therefore, postmenopausal women are at high risk. Estrogen increases cholesterol saturation of bile and may further increase gallstone risk, but population-based evidence is sparse. OBJECTIVE: Our objective was to examine the association between postmenopausal estrogen therapy and risk of gallstone disease and the impact of duration of treatment and use of opposing progestin. STUDY DESIGN: We conducted a population-based case-control study. Cases were postmenopausal women (defined as aged >=45 years) with gallstone disease identified in the period 1996-2010. For each case, we selected ten population controls matched to cases by age and sex. We defined exposure as any use of estrogen (opposed and unopposed by progestin). Cases/controls were categorized as current estrogen users if their last prescription was redeemed <90 days before gallstone diagnosis (or corresponding date for controls); all other users were categorized as former users. The reference group consisted of cases/controls with no/rare estrogen use. SETTING: Medical databases covering the population of Northern Denmark (2.4 million inhabitants through the period 1996-2010). MAIN OUTCOME MEASURE: We used conditional logistic regression to compute adjusted odds ratios (ORs) and 95 % confidence intervals (CIs) of gallstone disease in women treated with estrogen. The ORs were adjusted for relevant comorbidity, other drugs known to influence gallstone risk, and parity. RESULTS: We identified 16,386 cases with gallstone disease and 163,860 controls. A total of 1,425 cases (8.7 %) and 8,930 controls (5.4 %) were current estrogen users, yielding an adjusted OR for gallstone disease of 1.74 (95 % CI 1.64-1.85) compared with non users. The corresponding adjusted OR for former users was 1.35 (95 % CI 1.28 1.42). The results suggested a duration response for current users. Use of unopposed estrogen was associated with higher adjusted ORs than estrogen opposed by progestin. CONCLUSION: Postmenopausal estrogen therapy was associated with increased risk of gallstone disease in current and former estrogen users. Use of unopposed estrogen was associated with higher risk than use of estrogen opposed by progestin; this finding needs to be confirmed and explored further in future studies. PMID- 24174289 TI - Population-based sexual behavior surveys in China: Liuzhou compared with other prefectural cities. AB - Sexual behaviors in China are rapidly changing; simultaneously, sexually transmitted infections (STI)/HIV prevalence is increasing in the general population. To investigate these major shifts, we examined sexual behaviors and self-reported STI in one prefectural city in southern China, Liuzhou, and compared it to other prefectural cities throughout China. We used adults age 18 39 from two sets of population-based surveys that paralleled each other in both content and method. The first set was the Liuzhou survey conducted in 2008 (n = 398). The second set consisted of two national surveys collected in 2006 and 2010 (n = 2,186). Liuzhou respondents reported more active social and sexual behaviors than their national counterparts, including more socializing, dancing, drinking excessively, sexual activity among never married men and women, purchasing commercial sex among men, one-night stands among men, multiple sexual partnerships and self-reported STI among both men and women. Women in Liuzhou reported greater sexual risk behavior than their national counterparts, although overall they reported less than their male counterparts; they were also more likely to have had an abortion than women in other prefectural cities. Our findings provide a comprehensive overview of the sexual context of Liuzhou among the general population, which may help explain the greater STI/HIV prevalence in Liuzhou. PMID- 24174290 TI - The stability of Taq DNA polymerase results from a reduced entropic folding penalty; identification of other thermophilic proteins with similar folding thermodynamics. AB - The thermal stability of Taq DNA polymerase is well known, and is the basis for its use in PCR. A comparative thermodynamic characterization of the large fragment domains of Taq (Klentaq) and E. coli (Klenow) DNA polymerases has been performed by obtaining full Gibbs-Helmholtz stability curves of the free energy of folding (DeltaG) versus temperature. This analysis provides the temperature dependencies of the folding enthalpy and entropy (DeltaH and DeltaS), and the heat capacity (DeltaCp ) of folding. If increased or enhanced non-covalent bonding in the native state is responsible for enhanced thermal stabilization of a protein, as is often proposed, then an enhanced favourable folding enthalpy should, in general, be observed for thermophilic proteins. However, for the Klenow-Klentaq homologous pair, the folding enthalpy (DeltaHfold ) of Klentaq is considerably less favorable than that of Klenow at all temperatures. In contrast, it is found that Klentaq's extreme free energy of folding (DeltaGfold ) originates from a significantly reduced entropic penalty of folding (DeltaSfold ). Furthermore, the heat capacity changes upon folding are similar for Klenow and Klentaq. Along with this new data, comparable extended analysis of available thermodynamic data for 17 other mesophilic-thermophilic protein pairs (where enough applicable thermodynamic data exists) shows a similar pattern in seven of the 18 total systems. When analyzed with this approach, the more familiar "reduced DeltaCp mechanism" for protein thermal stabilization (observed in a different six of the 18 systems) frequently manifests as a temperature dependent shift from enthalpy driven stabilization to a reduced-entropic-penalty model. PMID- 24174291 TI - Optical coherence tomography evaluation of late strut coverage patterns between first-generation drug-eluting stents and everolimus-eluting stent. AB - OBJECTIVES: To compare strut coverage patterns between everolimus-eluting stent (EES) and first-generation drug-eluting stents (DES) at more than 12 months after successful implantation, using optical coherence tomography (OCT). BACKGROUND: No sufficient OCT data has been reported comparing late strut coverage patterns between EES and first-generation DES. The favorable late results after EES implantation could be related to lower rates of uncovered and malapposed struts. METHODS: A total of 66 DES (21 EES, 23 SES, and 22 PES) that were implanted at least 1 year in advance in 40 patients and met good late angiographic results were evaluated by OCT. The percentage of uncovered and malapposed struts, calculated as the ratio of uncovered or malapposed struts to total struts in all cross-sectional images per stent, was compared among the three groups. RESULTS: A total of 35,061 struts were analyzed: 11,967 from EES, 11,855 from SES, and 11m239 from PES. The average tissue coverage thickness of the struts per stent was greater in EES than in SES and PES (109 +/- 40 um vs. 72 +/- 27 um and 83 +/- 26 um, respectively; P = 0.001). The percentage of uncovered struts (1.9 +/- 4.1% in EES vs. 11.6 +/- 12.7% in SES, P = 0.01 and vs. 7.1 +/- 5.2% in PES, P < 0.001) and malapposed struts (0.1 +/- 0.3% in EES vs. 1.8 +/- 3.5% in SES, P = 0.01 and vs. 3.5 +/- 5.1% in PES, P = 0.02) was much lower in EES than in first generation DES, with no significant differences between SES and PES. CONCLUSIONS: Late strut coverage patterns are not similar between EES and first-generation DES. EES showed a lower percentage of uncovered and malapposed struts. PMID- 24174292 TI - The theta-related firing activity of parvalbumin-positive neurons in the medial septum-diagonal band of Broca complex and their response to 5-HT1A receptor stimulation in a rat model of Parkinson's disease. AB - The parvalbumin (PV)-positive neurons in the medial septum-diagonal band of Broca complex (MS-DB) play an important role in the generation of hippocampal theta rhythm involved in cognitive functions. These neurons in this region express a high density of 5-HT1A receptors which regulate the neuronal activity and consequently affect the theta rhythm. In this study, we examined changes in the theta-related firing activity of PV-positive neurons in the MS-DB, their response to 5-HT1A receptor stimulation and the corresponding hippocampal theta rhythm, and the density of PV-positive neurons and their co-localization with 5-HT1A receptors in rats with 6-hydroxydopamine lesions of the substantia nigra pars compacta (SNc). The lesion of the SNc decreased the rhythmically bursting activity of PV-positive neurons and the peak frequency of hippocampal theta rhythm. Systemic administration of 5-HT1A receptor agonist 8-OH-DPAT (0.5-128 ug/kg, i.v.) inhibited the firing rate of PV-positive neurons and disrupted rhythmically bursting activity of the neurons and the theta rhythm in sham operated and the lesioned rats, respectively. The cumulative doses producing inhibition and disruption in the lesioned rats were higher than that of sham operated rats. Furthermore, local application of 8-OH-DPAT (0.005 MUg) in the MS DB also inhibited the firing rate of PV-positive neurons and disrupted their rhythmically bursting activity in sham-operated rats, while having no effect on PV-positive neurons in the lesioned rats. The lesion of the SNc decreased the density of PV-positive neurons in the MS-DB, and percentage of PV-positive neurons expressing 5-HT1A receptors. These results indicate that the lesion of the SNc leads to suppression of PV-positive neurons in the MS-DB and hippocampal theta rhythm. Furthermore, the lesion decreases the response of these neurons to 5-HT1A receptor stimulation, which attributes to dysfunction and/or down regulation of 5-HT1A receptor expression on these neurons. These changes may be involved in cognitive impairments of Parkinson's disease. PMID- 24174293 TI - High ubiquitous mitochondrial creatine kinase expression in hepatocellular carcinoma denotes a poor prognosis with highly malignant potential. AB - We previously reported the increased serum mitochondrial creatine kinase (MtCK) activity in patients with hepatocellular carcinoma (HCC), mostly due to the increase in ubiquitous MtCK (uMtCK), and high uMtCK mRNA expression in HCC cell lines. We explored the mechanism(s) and the relevance of high uMtCK expression in HCC. In hepatitis C virus core gene transgenic mice, known to lose mitochondrial integrity in liver and subsequently develop HCC, uMtCK mRNA and protein levels were increased in HCC tissues but not in non-tumorous liver tissues. Transient overexpression of ankyrin repeat and suppressor of cytokine signaling box protein 9 (ASB9) reduced uMtCK protein levels in HCC cells, suggesting that increased uMtCK levels in HCC cells may be caused by increased gene expression and decreased protein degradation due to reduced ASB9 expression. The reduction of uMtCK expression by siRNA led to increased cell death, and reduced proliferation, migration and invasion in HCC cell lines. Then, consecutive 105 HCC patients, who underwent radiofrequency ablation with curative intent, were enrolled to analyze their prognosis. The patients with serum MtCK activity >19.4 U/L prior to the treatment had significantly shorter survival time than those with serum MtCK activity <= 19.4 U/L, where higher serum MtCK activity was retained as an independent risk for HCC-related death on multivariate analysis. In conclusion, high uMtCK expression in HCC may be caused by hepatocarcinogenesis per se but not by loss of mitochondrial integrity, of which ASB9 could be a negative regulator, and associated with highly malignant potential to suggest a poor prognosis. PMID- 24174294 TI - Divergent total synthesis of indoxamycins A, C, and F. PMID- 24174295 TI - Is there a chronic sleep stage-dependent linear and nonlinear cardiac autonomic impairment in obstructive sleep apnea? AB - RATIONALE: Obstructive sleep apnea (OSA) is a respiratory disorder that has the potential to negatively impact heart rate variability (HRV) during the sleep cycle. However, it is uncertain whether there is a chronic sleep stage-dependent linear and nonlinear cardiac autonomic impairment in OSA. The aim of this study was to perform HRV analysis in apnea-free samples as well as during stage 2 and rapid eye movement (REM) sleep in mild and moderate OSA (MiOSA and MOSA, respectively) subjects as well as health controls (NonOSA). METHODS: This study included 20 MiOSA (37 +/- 14 years), 20 MOSA (39 +/- 8 years), and 18 NonOSA (36 +/- 8 years) subjects. Subjects underwent in-laboratory overnight polysomnography with electrocardiography recording. HRV indices were obtained by analyzing the R R intervals (RRis) in 5-min apnea-free samples by the linear frequency domain [low frequency (LF), high frequency (HF) and LF/HF], Poincare plot [standard deviation (SD1) and (SD2)], recurrence plot [mean line length (Lmean)], recurrence rate (REC), determinism (DET), and Shannon entropy (ShanEn). RESULTS: The MOSA group presented with higher LF, LF/HF, and DET indices compared to NonOSA as well as a lower parasympathetic index (HF), suggesting sympathetic hyperactivity in MOSA subjects. Interestingly, MiOSA subjects failed to show the expected linear HRV difference between sleep stages, as observed in NonOSA, which may represent an early onset of autonomic impairment at this stage of OSA. CONCLUSION: In OSA patients, there is a chronic sleep stage-dependent impairment of linear and nonlinear cardiac autonomic modulation. Interestingly, this impairment may be identifiable during the early stages of the disease. PMID- 24174296 TI - More on heart rate variability in obstructive sleep apnea: confusion on a higher level or first step to unravel the cardiovascular mystery of the sleep apnea patient? PMID- 24174297 TI - Mandibular tori size is related to obstructive sleep apnea and treatment success with an oral appliance. AB - PURPOSE: Obstructive sleep apnea (OSA) is a common disorder characterized by repetitive upper airway obstruction during sleep. We aimed to investigate whether mandibular tori, exostoses that appear on the lingual surface of the lower jaw, are related to OSA and the effect of an oral appliance (OA) in OSA patients. METHODS: Six hundred snoring patients with a mean age of 52 years (range 23-75 years) and a mean respiratory disturbance index (RDI) of 15 (range 0-76), who were consecutively referred for OA treatment, were included. The size of the tori was measured on plaster casts with a digital sliding caliper. RESULTS: Twenty seven percent of the patients had mandibular tori, with a similar prevalence in snorers and patients with mild, moderate and severe OSA. Tori size differed between severity groups. Thick tori (>=2.9 mm) were associated with an RDI of <30, odds ratio (OR) 4.7 (p = 0.01), adjusted for age, gender and body mass index (BMI; kg/m(2)). Complete treatment response with OA was related to thick tori, OR = 2.5 (p = 0.02), adjusted for disease severity, age, gender, BMI (kg/m(2)), weight changes (kg) and mandibular repositioning. CONCLUSIONS: Patients with milder disease are more likely to have larger tori than patients with severe OSA. Treatment success with an OA occurs more frequently in patients with larger tori than in patients with no tori or small tori. PMID- 24174298 TI - Characterisation of the methylation pattern in the intragenic CpG island of the IGF2 gene in Bos taurus indicus cumulus cells during in vitro maturation. AB - PURPOSE: The aim of this study was to characterise the methylation pattern in a CpG island of the IGF2 gene in cumulus cells from 1-3 mm and >= 8.0 mm follicles and to evaluate the effects of in vitro maturation on this pattern. METHODS: Genomic DNA was treatment with sodium bisulphite. Nested PCR using bisulphite treated DNA was performed, and DNA methylation patterns have been characterised. RESULTS: There were no differences in the methylation pattern among groups (P > 0.05). Cells of pre-IVM and post-IVM from small follicles showed methylation levels of 78.17 +/- 14.11 % and 82.93+/-5.86 %, respectively, and those from large follicles showed methylation levels of 81.81 +/- 10.40 % and 79.64 +/- 13.04 %, respectively. Evaluating only the effect of in vitro maturation, cells of pre-IVM and post-IVM COCs showed methylation levels of 80.17 +/- 12.01 % and 81.19 +/- 10.15 %. CONCLUSIONS: In conclusion, the methylation levels of the cumulus cells of all groups were higher than that expected from the imprinted pattern of somatic cells. As the cumulus cells from the pre-IVM follicles were not subjected to any in vitro manipulation, the hypermethylated pattern that was observed may be the actual physiological methylation pattern for this particular locus in these cells. Due the importance of DNA methylation in oogenesis, and to be a non-invasive method for determining oocyte quality, the identification of new epigenetic markers in cumulus cells has great potential to be used to support reproductive biotechniques in humans and other mammals. PMID- 24174299 TI - Accu-Beads as a quality control measure for manual and automated methods of measuring sperm concentration-an observational study. AB - PURPOSE: To determine the precision and accuracy of Accu-Beads and their utility as a quality control product for manual and automated measurements of sperm concentration. METHODS: This observational study was performed at an Assisted Reproductive Technology laboratory in a tertiary-care, university hospital. To simulate sperm concentration, bead concentrations were measured with the use of a manual and an automated method. RESULTS: The manual counts did not vary significantly from the automated counts regardless of the concentration. However, the counts did vary between lots of low concentration of Accu-Beads and between the two different types of fixed counting chambers. The two bead concentrations used in this study were below the 95 % confidence interval for the values listed by the manufacturer. CONCLUSION(S): In our laboratory, Accu-Beads met enough of the requirements of a good control material to be acceptable for daily quality control use, especially if we set our own ranges of acceptability for each vial of Accu-Beads. It is necessary to evaluate each new lot of Accu-Beads when they are received and again if they are used with a different counting chamber. PMID- 24174300 TI - Brain GABA and glutamate levels in workers of two ant species (Hymenoptera: Formicidae): interspecific differences and effects of queen presence/absence. AB - Presence of amino acid neurotransmitters gamma-aminobutyric acid (GABA) and glutamate (Glu) in ant brains was reported in very few studies. To learn more about factors influencing GABA and Glu levels in ant brains, we applied high performance liquid chromatography to measure levels of these compounds in single brains of workers of 2 ant species, Myrmica ruginodis (subfamily Myrmicinae) and Formica polyctena (subfamily Formicinae) taken from queenright/queenless colony fragments and tested in dyadic aggression tests consisting of an encounter with a nestmate, an alien conspecific or a small cricket. Brain glutamate levels were higher than those of GABA in both tested species. Brain GABA levels (in MUmol/brain) and GABA : Glu ratio were higher in M. ruginodis (a submissive species) than in F. polyctena (a dominant, aggressive species) in spite of smaller brain weight of M. ruginodis. Brain glutamate levels (in MUmol/brain) did not differ between the tested species, which implies that glutamate concentration (in MUmol/mg of brain tissue) was higher in M. ruginodis. Queen absence was associated with increased worker brain GABA levels in F. polyctena, but not in M. ruginodis. No significant effects of opponent type were discovered. As GABA agonists enhance friendly social behavior in rodents, we hypothesize that elevated brain GABA levels of orphaned workers of F. polyctena facilitate the adoption of a new queen. This is the first report providing information on GABA and glutamate levels in single ant brains and documenting the effects of queen presence/absence on brain levels of amino acid neurotransmitters in workers of social Hymenoptera. PMID- 24174301 TI - Cardiac magnetic resonance infarct heterogeneity: is it ready to be used on patients for the prevention of sudden cardiac death? PMID- 24174302 TI - A synthetic chimeric peptide harboring human papillomavirus 16 cytotoxic T lymphocyte epitopes shows therapeutic potential in a murine model of cervical cancer. AB - Infection with human papillomavirus (HPV) such as HPV16 is known to be associated with cervical cancer. The E6 and E7 oncoproteins of this virus are attractive targets for T-cell-based immunotherapy to cervical cancer. In our study, software predicted, multiple H-2D(b) restricted HPV16 cytotoxic T lymphocytes (CTL) epitopes on a synthetic chimeric peptide, was used along with different immunopotentiating adjuvants such as alum, heat-killed Mycobacterium w (Mw) cells, and poly D,L-lactic-co-glycolide (PLGA) microspheres. We have shown that subcutaneous immunization with H-2D(b)-restricted HPV16 peptide was able to generate CTL-mediated cytolysis of HPV16 E6- and E7-expressing TC-1 tumor cells in vitro, as well as protect against in vivo challenge with TC-1 cells in C57BL/6 mice. In vitro, this chimeric peptide showed best efficacy with PLGA microspheres, moderate with alum, and least with Mw as adjuvant. This approach may thus provide a potential peptide-based therapeutic candidate vaccine for the control of HPV infection and hence cervical cancer. PMID- 24174303 TI - A novel technique for catheter engagement of protruding aorto-ostial stent. AB - We present a case of stenoses in the right coronary artery with a previously deployed stent showing gross protrusion into the aorta. Despite difficulty in cannulation of a guiding catheter into the coronary artery, percutaneous intervention was accomplished using a novel technique to engage the protruding stent. PMID- 24174305 TI - Differential effects of aerobic exercise, resistance training and combined exercise modalities on cholesterol and the lipid profile: review, synthesis and recommendations. AB - There is a direct relationship between chronically elevated cholesterol levels (dyslipidaemia) and coronary heart disease. A reduction in total cholesterol is considered the gold standard in preventative cardiovascular medicine. Exercise has been shown to have positive impacts on the pathogenesis, symptomatology and physical fitness of individuals with dyslipidaemia, and to reduce cholesterol levels. The optimal mode, frequency, intensity and duration of exercise for improvement of cholesterol levels are, however, yet to be identified. This review assesses the evidence from 13 published investigations and two review articles that have addressed the effects of aerobic exercise, resistance training and combined aerobic and resistance training on cholesterol levels and the lipid profile. The data included in this review confirm the beneficial effects of regular activity on cholesterol levels and describe the impacts of differing volumes and intensities of exercise upon different types of cholesterol. Evidence based exercise recommendations are presented, aimed at facilitating the prescription and delivery of interventions in order to optimize cholesterol levels. PMID- 24174304 TI - The health effects of exercising in air pollution. AB - The health benefits of exercise are well known. Many of the most accessible forms of exercise, such as walking, cycling, and running often occur outdoors. This means that exercising outdoors may increase exposure to urban air pollution. Regular exercise plays a key role in improving some of the physiologic mechanisms and health outcomes that air pollution exposure may exacerbate. This problem presents an interesting challenge of balancing the beneficial effects of exercise along with the detrimental effects of air pollution upon health. This article summarizes the pulmonary, cardiovascular, cognitive, and systemic health effects of exposure to particulate matter, ozone, and carbon monoxide during exercise. It also summarizes how air pollution exposure affects maximal oxygen consumption and exercise performance. This article highlights ways in which exercisers could mitigate the adverse health effects of air pollution exposure during exercise and draws attention to the potential importance of land use planning in selecting exercise facilities. PMID- 24174306 TI - Author's reply to Steele and Fisher: "Scientific rigour: a heavy or light load to carry?": the importance of maintaining objectivity in drawing evidence-based conclusions. PMID- 24174307 TI - Evidence for the role of isometric exercise training in reducing blood pressure: potential mechanisms and future directions. AB - Hypertension, or the chronic elevation in resting arterial blood pressure (BP), is a significant risk factor for cardiovascular disease and estimated to affect ~1 billion adults worldwide. The goals of treatment are to lower BP through lifestyle modifications (smoking cessation, weight loss, exercise training, healthy eating and reduced sodium intake), and if not solely effective, the addition of antihypertensive medications. In particular, increased physical exercise and decreased sedentarism are important strategies in the prevention and management of hypertension. Current guidelines recommend both aerobic and dynamic resistance exercise training modalities to reduce BP. Mounting prospective evidence suggests that isometric exercise training in normotensive and hypertensive (medicated and non-medicated) cohorts of young and old participants may produce similar, if not greater, reductions in BP, with meta-analyses reporting mean reductions of between 10 and 13 mmHg systolic, and 6 and 8 mmHg diastolic. Isometric exercise training protocols typically consist of four sets of 2-min handgrip or leg contractions sustained at 20-50 % of maximal voluntary contraction, with each set separated by a rest period of 1-4 min. Training is usually completed three to five times per week for 4-10 weeks. Although the mechanisms responsible for these adaptations remain to be fully clarified, improvements in conduit and resistance vessel endothelium-dependent dilation, oxidative stress, and autonomic regulation of heart rate and BP have been reported. The clinical significance of isometric exercise training, as a time efficient and effective training modality to reduce BP, warrants further study. This evidence-based review aims to summarize the current state of knowledge regarding the effects of isometric exercise training on resting BP. PMID- 24174309 TI - Proteinase-activated receptor 2 modulates corticotropin releasing hormone-induced brain-derived neurotrophic factor release from microglial cells. AB - Brain-derived neurotrophic factor (BDNF) plays a critical role in the pathogenesis of neuropathic pain, but its regulation of BDNF release is not fully understood. To further understand the regulation of BDNF release, the microglial cell line, C8-D1A (microglia, in short), were cultured as a model. The levels of BDNF were determined by enzyme-linked immunoassay. Apoptotic microglia were assessed by flow cytometry. The protease-activated receptor 2 (PAR2) was activated by tryptase. Exposure to corticotripin releasing hormone (CRH) induced BDNF release from microglia. Apoptosis was evident in microglia after activation by CRH. Tryptase-induced PAR2 activation reduced the frequency of apoptosis of microglia, but enhanced the BDNF levels in the culture medium, which was partially blocked by PAR2 antagonists. We conclude that PAR2 agonists can promote the BDNF release from microglia; the PAR2 antagonists may be a potential therapeutic target to attenuate the BDNF-related neuropathic pain. PMID- 24174308 TI - Acute exercise and hormones related to appetite regulation: a meta-analysis. AB - BACKGROUND: Understanding of the impact of an acute bout of exercise on hormones involved in appetite regulation may provide insight into some of the mechanisms that regulate energy balance. In resting conditions, acylated ghrelin is known to stimulate food intake, while hormones such as peptide YY (PYY), pancreatic polypeptide (PP) and glucagon-like peptide 1 (GLP-1) are known to suppress food intake. OBJECTIVE: The objective of this review was to determine the magnitude of exercise effects on levels of gastrointestinal hormones related to appetite, using systematic review and meta-analysis. Additionally, factors such as the exercise intensity, duration and mode, in addition to participant characteristics, were examined to determine their influence on these hormones. DATA SOURCES: Major databases (PubMed, Scopus, Google Scholar, Science Direct, Academic Search Premier and EBSCOHost) were searched, through February 2013, for original studies, abstracts, theses and dissertations that examined responses of appetite hormones to acute exercise. STUDY SELECTION: Studies were included if they evaluated appetite hormone responses during and in the hours after an acute bout of exercise and reported area under the concentration-time curve (AUC) values for more than three datapoints. Studies reporting mean or pre/post-values only were excluded. STUDY APPRAISAL AND SYNTHESIS: Initially, 75 studies were identified. After evaluation of study quality and validity, using the Physiotherapy Evidence Database scale, data from 20 studies (28 trials) involving 241 participants (77.6 % men) had their data extracted for inclusion in the meta analyses. A random-effects meta-analysis was conducted for acylated ghrelin (n = 18 studies, 25 trials) and PYY (n = 8 studies, 14 trials), with sub-group analyses and meta-regressions being conducted for moderator variables. Because the number of studies was limited, fixed-effects meta-analyses were performed on PP data (n = 4 studies, 5 trials) and GLP-1 data (n = 5 studies, 8 trials). RESULTS: The results of the meta-analyses indicated that exercise had small to moderate effects on appetite hormone levels, suppressing acylated ghrelin (effect size [ES] Cohen's d value -0.20, 95 % confidence interval [CI] -0.373 to -0.027; median decrease 16.5 %) and increasing PYY (ES 0.24, 95 % CI 0.007 to 0.475; median increase 8.9 %), GLP-1 (ES 0.275, 95 % CI -0.031 to 0.581; median increase 13 %), and PP (ES 0.50, 95 % CI 0.11 to 0.89; median increase 15 %). No significant heterogeneity was detected in any meta-analysis (using Cochrane's Q and I (2)); however, publication biases were detected for all analyses. No moderator variables were observed to moderate the variability among the studies assessing acylated ghrelin and PYY. LIMITATIONS: The majority of the present literature is acute in nature; therefore, longer-term alterations in appetite hormone concentrations and their influence on food and beverage intake are unknown. Furthermore, our review was limited to English-language studies and studies reporting AUC data. CONCLUSIONS: An acute bout of exercise may influence appetite by suppressing levels of acylated ghrelin while simultaneously increasing levels of PYY, GLP-1 and PP, which may contribute to alterations in food and drink intake after acute exercise. Further longitudinal studies and exploration into mechanisms of action are required in order to determine the precise role these hormones play in long-term appetite responses to an exercise intervention. PMID- 24174310 TI - Bacillus enclensis sp. nov., isolated from sediment sample. AB - A novel bacterial strain, designated SGD-1123(T) was isolated from Chorao Island, in Goa Province, India. The strain was found to be able to grow at 15-42 degrees C, pH 5-12 and 0-12 % (w/v) NaCl. The whole cell hydrolysates were found to contain meso-diaminopimelic acid, galactose and arabinose. The major fatty acids were identified as iso-C15:0 and anteiso-C15:0, MK-7 was identified as the predominant menaquinone and the predominant polar lipids were identified as diphosphatidylglycerol, phosphatidylglycerol, phosphatidylethanolamine and an unidentified aminolipid. The genomic DNA G+C content was determined to be 44.6 mol%. Phylogenetic analysis based on 16S rRNA gene sequences placed the isolate within the genus Bacillus and further revealed that strain SGD-1123(T) had highest sequence similarity with Bacillus aquimaris, and forms a separate clade with its closest relatives i.e. B. aquimaris, Bacillus vietnamensis and Bacillus marisflavi, with which it shares 94.5, 94.1 and 94.1 % similarity respectively. The phylogenetic, chemotaxonomic and phenotypic analyses indicated that strain SGD-1123(T) represents a novel species within the genus Bacillus, for which the name Bacillus enclensis is proposed. The type strain is SGD-1123(T) (NCIM 5450(T)=CCTCC AB 2011125(T)). PMID- 24174311 TI - Princeton_TIGRESS: protein geometry refinement using simulations and support vector machines. AB - Protein structure refinement aims to perform a set of operations given a predicted structure to improve model quality and accuracy with respect to the native in a blind fashion. Despite the numerous computational approaches to the protein refinement problem reported in the previous three CASPs, an overwhelming majority of methods degrade models rather than improve them. We initially developed a method tested using blind predictions during CASP10 which was officially ranked in 5th place among all methods in the refinement category. Here, we present Princeton_TIGRESS, which when benchmarked on all CASP 7,8,9, and 10 refinement targets, simultaneously increased GDT_TS 76% of the time with an average improvement of 0.83 GDT_TS points per structure. The method was additionally benchmarked on models produced by top performing three-dimensional structure prediction servers during CASP10. The robustness of the Princeton_TIGRESS protocol was also tested for different random seeds. We make the Princeton_TIGRESS refinement protocol freely available as a web server at http://atlas.princeton.edu/refinement. Using this protocol, one can consistently refine a prediction to help bridge the gap between a predicted structure and the actual native structure. PMID- 24174312 TI - Oxidation of ofloxacin by Oxone/Co(2+): identification of reaction products and pathways. AB - Oxidative degradation of ofloxacin (OFX) by sulfate free radicals (SO4 (-*)) in the UV/Oxone/Co(2+)oxidation process was investigated for the first time, with a special focus upon identifying the transformation products as well as understanding the reaction pathways. Thirteen main compounds were identified after the initial transformation of OFX; the detailed structural information of which were characterized by high-performance liquid chromatography-high resolution mass spectrometry and MS fragmentation analysis. The degradation pathways mainly encompassed ring openings at both the piperazinyl substituent and the quinolone moiety, indicating that the usage of SO4 (-*) aided the oxidative degradation of OFX to undergo more facile routes compared to those in previous reports by using OH(*)/h(+) as the oxidant, where the initial transformation attacks were mainly confined to the piperazine moiety. Moreover, in this study, smart control over the pH conditions of the oxidation system via different modes of Oxone dosage resulted in the selective degradation of the functional sites of OFX molecule, where it was shown that the SO4 (-*)-driven destruction of the quinolone moiety of OFX molecule favored the neutral pH conditions. This would be beneficial for the reduction of bacterial resistance against quinolones in the aqueous environment. PMID- 24174313 TI - Exposure of lead to mothers and their new born infants, residents of industrial and domestic areas of Pakistan. AB - Prenatal and early-life exposure to lead (Pb) is hypothesized to have adverse effects on childhood health. The aim of this study was to evaluate the prenatal exposure to Pb and its adverse effects on mothers and their infants who are residents of industrial (exposed) and domestic areas (referents) in Karachi, Pakistan. The biological samples (scalp hair and blood) of mother-infants pairs were analyzed for Pb levels by atomic absorption spectrometry after microwave assisted acid digestion method. The Pb levels in scalp hair and blood samples of exposed mothers were found in the range of 7.52-8.70 MUg/g and 115-270 MUg/L, respectively, which were significantly higher than those values obtained for referent mothers (p < 0.001). The Pb levels in the blood (umbilical cord) and hair of neonates of exposed mother that were found in the range of 83-178 MUg/L and 4.95-7.23 MUg/g, respectively, were significantly higher than the obtained values of referent neonates (p > 0.001). The correlation between maternal and cord blood of both groups was found in the range of 0.708-0.724 (p < 0.01). It was observed that there were higher Pb burdens in exposed mothers and their infants as compared to referent mothers-neonates. PMID- 24174314 TI - Bages-Sigean and Canet-St Nazaire lagoons (France): physico-chemical characteristics and contaminant concentrations (Cu, Cd, PCBs and PBDEs) as environmental quality of water and sediment. AB - Environmental characteristics in water and sediments of two contrasted coastal Mediterranean lagoons, Bages-Sigean and Canet-St Nazaire, were measured over a three season survey. The urban pollution (treatment plant discharges) is very important in Canet-St Nazaire lagoon reflecting untreated sewages, while in Bages Sigean, the northern part appears more impacted due to larger anthropogenic inputs. Dissolved Cd concentrations are on the whole similar in both lagoons, whereas Cu concentrations are by far higher in lagoon Canet-St Nazaire. Cu concentrations appear to be highly dependent on dissolved organic carbon whereas salinity seems to control Cd variations. Concerning the sediments, the confined northern part of lagoon Bages-Sigean shows organic carbon and total nitrogen enrichment whereas lipid concentrations are much higher in the Canet-St Nazaire lagoon. Cu complexation seems to be strongly related to organic matter as evidenced by the two significant positive relationships, on one hand between Cu and organic carbon, and on the other hand, between Cu and lipids. On the contrary, Cd concentrations appear to be mainly controlled by carbonates. PCBs and PBDEs were detected only in sediments and show relatively low concentrations compared to similar lagoon environments. Regarding the sediment quality guidelines, Cd, Cu and PCBs in both lagoons did not exceed any Probable Effect Concentration (PEC). PMID- 24174315 TI - A magnetic nanobead-based bioassay provides sensitive detection of single- and biplex bacterial DNA using a portable AC susceptometer. AB - Bioassays relying on magnetic read-out using probe-tagged magnetic nanobeads are potential platforms for low-cost biodiagnostic devices for pathogen detection. For optimal assay performance it is crucial to apply an easy, efficient and robust bead-probe conjugation protocol. In this paper, sensitive (1.5 pM) singleplex detection of bacterial DNA sequences is demonstrated in a portable AC susceptometer by a magnetic nanobead-based bioassay principle; the volume amplified magnetic nanobead detection assay (VAM-NDA). Two bead sizes, 100 and 250 nm, are investigated along with a highly efficient, rapid, robust, and stable conjugation chemistry relying on the avidin-biotin interaction for bead-probe attachment. Avidin-biotin conjugation gives easy control of the number of detection probes per bead; thus allowing for systematic investigation of the impact of varying the detection probe surface coverage upon bead immobilization in rolling circle amplified DNA-coils. The existence of an optimal surface coverage is discussed. Biplex VAM-NDA detection is for the first time demonstrated in the susceptometer: Semi-quantitative results are obtained and it is concluded that the concentration of DNA-coils in the incubation volume is of crucial importance for target quantification. The present findings bring the development of commercial biodiagnostic devices relying on the VAM-NDA further towards implementation in point-of-care and outpatient settings. PMID- 24174316 TI - Bevacizumab plus irinotecan, 5-fluorouracil, and leucovorin (FOLFIRI) as the second-line therapy for patients with metastatic colorectal cancer, a multicenter study. AB - Poor prognosis is associated with patients with metastatic colorectal cancer. To seek effective methods, we examine the efficacy and safety of bevacizumab plus FOLFIRI as a second-line chemotherapy in Chinese patients with metastatic colorectal cancer (mCRC). A total of 55 patients with previous failure of oxaliplatin-based chemotherapy were included in this study, from October 2010 to February 2012. All patients received bevacizumab (5 mg/kg) plus FOLFIRI every other week until disease progression or intolerable toxicity occurred. The response rate was 31%, and the disease-controlled rate was 76.4%. The median progression-free survival was 6 months, and the median overall survival was 17 months. Adverse events (AEs) related to chemotherapy were mild to moderate. Only the incidence of grade 3-4 neutropenia reached to 25.5%. The incidence of AEs related to bevacizumab was low. These AEs included grade 3-4 toxicities of hypertension and proteinuria 5.4 and 3.6%, respectively. Bevacizumab plus FOLFIRI is an effective and safe regimen as a second-line treatment for patients with mCRC in China. PMID- 24174317 TI - Serum lemur tyrosine kinase 3 expression in colorectal cancer patients predicts cancer progression and prognosis. AB - Lemur tyrosine kinase-3 (LMTK3) is a member of the families of serine-threonine tyrosine kinases, which has been suggested to be a possible target and marker of breast cancer. However, its definitive physiopathological function in colorectal cancer (CRC) is poorly understood at present. The aim of this study was to determine the expression levels of preoperative-soluble LMTK3 (sLMTK3) in patients' blood with CRC and to subsequently evaluate whether or not its level in serum can be used to predict cancer progression and prognosis. The expression levels of sLMTK3 were measured by sandwich enzyme-linked immunosorbent assay in blood specimens from 60 patients with CRC and 53 healthy volunteers. As a result, we found that the mean concentration of sKMTK3 in CRC patients was significantly higher than that in healthy volunteers (P = 0.012). The expression levels of sLMTK3 were significantly correlated with histological subtype, depth of tumor invasion, and tumor-node-metastasis (TNM) classification (P = 0.038, 0.021, and 0.049, respectively), but not with sex, age, tumor location, tumor size, or lymph node metastasis. Additionally, Kaplan-Meier survival curves showed that patients with high levels of sLMTK3 had a poorer overall survival rate when compared with those of patients with low levels of sLMTK3 (P = 0.041). Moreover, multivariate analysis demonstrated that sLMTK3 expression and TNM stage were independent prognostic factors for CRC patients (P = 0.047 and 0.008, respectively). These results suggest that serum LMTK3 could be a valuable biomarker for predicting the progression and prognosis of patients with CRC. PMID- 24174318 TI - Protein kinase C (PKC) as a drug target in chronic lymphocytic leukemia. AB - Protein kinase C (PKC) belongs to a family of ten serine/threonine protein kinases encoded by nine genes. This family of proteins plays critical roles in signal transduction which results in cell proliferation, survival, differentiation and apoptosis. Due to differential subcellular localization and tissue distribution, each member displays distinct signaling characteristics. In this review, we have summarized the roles of PKC family members in chronic lymphocytic leukemia (CLL). CLL is a heterogeneous hematological disorder with survival ranging from months to decades. PKC isoforms are differentially expressed in CLL and play critical roles in CLL pathogenesis. Thus, isoform specific PKC inhibitors may be an attractive option for CLL treatment. PMID- 24174319 TI - Body size preference among Yoruba in three Nigerian communities. AB - Following our previous observation of an aversion to weight reduction in Nigerians with type 2 diabetes, we measured several parameters of body dimensions and preferences in otherwise healthy adults in three communities to study the phenomenon further. The study population of 524 participants (304 F) was 99.8% of Yoruba ethnic origin with a mean age of 43.9 +/- 17.2 years. Females had a significantly (p > 0.001) higher body mass index (BMI), waist circumference, hip circumference compared to the males; the values being 24.55 +/- 5.5 vs. 21.75 +/- 3.71 kg/m(2); 84.98 +/- 12.67 vs. 80.92 +/- 9.85 cm; 96.32 +/- 12.94 vs. 89.36 +/ 8.06 cm, respectively. There was a high level of satisfaction amongst respondents with their body size (Kendall's t = 0.52, p < 0.001) which they also predicted with a high degree of certainty even without the prior use of a weighing scale. The relationship between current body size (CBI) and BMI emerged as CBI = 1.22 + 0.32 BMI. In the 41% of respondents who expressed unhappiness with their current body size, there was a strong aversion for a smaller body size and the preference was often for a bigger body figure. Strikingly, many more women than men were less dissatisfied with their bigger body sizes. Stepwise regression indicated that CBI and gender were the two most important variables that best related to casual blood sugar (RBS) among the factors entered. The mathematical relationship between these variables that emerged was: [Formula: see text] where gender = 0 for male and 1 for female. The results suggest that larger body sizes were positively viewed in these communities consistent with our previous observations in type 2 diabetes. PMID- 24174320 TI - Open loop optogenetic control of simulated cortical epileptiform activity. AB - We present a model for the use of open loop optogenetic control to inhibit epileptiform activity in a meso scale model of the human cortex. The meso scale cortical model first developed by Liley et al. (2001) is extended to two dimensions and the nature of the seizure waves is studied. We adapt to the meso scale a 4 state functional model of Channelrhodopsin-2 (ChR2) ion channels. The effects of pulsed and constant illumination on the conductance of these ion channels is presented. The inhibitory cell population is targeted for the application of open loop control. Seizure waves are successfully suppressed and the inherent properties of the optogenetic channels ensures charge balance in the cortex, protecting it from damage. PMID- 24174321 TI - Optimizing rotational atherectomy in high-risk percutaneous coronary interventions: insights from the PROTECT IotaIota study. AB - OBJECTIVE: To study rotational atherectomy (RA) outcomes in patients undergoing high-risk PCI randomized to receive hemodynamic support using either IABP or Impella 2.5 in the PROTECT II trial. BACKGROUND: RA of heavily calcified lesions is often necessary for complex PCI but can be associated with slow-flow, hypotension, and higher risk of periprocedural MI. METHODS: We compared baseline, angiographic, procedural characteristics, and outcomes of patients treated with and without RA. We examined also RA technique and outcomes. RESULTS: RA was used in 52 of 448 patients (32 with Impella vs 20 with IABP, P = 0.08). RA patients were older (72 vs. 67 yo, P = 0.0009), more likely to have prior CABG (48 vs. 32%, P = 0.017), higher STS (8.1 vs. 5.7, P = 0.012) and higher SYNTAX scores (37 vs. 29, P < 0.0001). At 90 days, RA use was associated with higher incidence of MI but no mortality difference. RA was used more aggressively with Impella resulting in higher rate of periprocedural MI (P < 0.01), with no difference in mortality between groups (P = 0.78). Repeat revascularization occurred less frequently with Impella (P < 0.001). There were no differences in 90-day major adverse events between IABP and Impella in patients undergoing RA (P = 0.29). In patients not treated with RA, fewer MAEs were observed with Impella compared with IABP (P = 0.03). CONCLUSIONS: Patients who were treated with RA had more comorbidities, and more complex and extensive coronary artery disease. In patients with Impella, more aggressive RA use resulted in fewer revascularization events but higher incidence of periprocedural MI. PMID- 24174322 TI - Multifunctionalized sequence-defined oligomers from a single building block. PMID- 24174324 TI - Can we measure autism? AB - Newly released definitions of autism spectrum disorder demonstrate the need for precise diagnoses informed by the integration of clinical, molecular, and biochemical characteristics in a patient-information commons. PMID- 24174323 TI - Translocator protein/peripheral benzodiazepine receptor is not required for steroid hormone biosynthesis. AB - Molecular events that regulate cellular biosynthesis of steroid hormones have been a topic of intense research for more than half a century. It has been established that transport of cholesterol into the mitochondria forms the rate limiting step in steroid hormone production. In current models, both the steroidogenic acute regulatory protein (StAR) and the translocator protein (TSPO) have been implicated to have a concerted and indispensable effort in this cholesterol transport. Deletion of StAR in mice resulted in a critical failure of steroid hormone production, but deletion of TSPO in mice was found to be embryonic lethal. As a result, the role of TSPO in cholesterol transport has been established only using pharmacologic and genetic tools in vitro. To allow us to explore in more detail the function of TSPO in cell type-specific experimental manipulations in vivo, we generated mice carrying TSPO floxed alleles (TSPOfl/fl). In this study we made conditional knockout mice (TSPOcDelta/Delta) with TSPO deletion in testicular Leydig cells by crossing with an anti-Mullerian hormone receptor type II cre/+ mouse line. Genetic ablation of TSPO in steroidogenic Leydig cells in mice did not affect testosterone production, gametogenesis, and reproduction. Expression of StAR, cytochrome P450 side chain cleavage enzyme, 3beta-hydroxysteroid dehydrogenase/Delta5-Delta4 isomerase type I, and TSPO2 in TSPOcDelta/Delta testis was unaffected. These results challenge the prevailing dogma that claims an essential role for TSPO in steroid hormone biosynthesis and force reexamination of functional interpretations made for this protein. This is the first study examining conditional TSPO gene deletion in mice. The results show that TSPO function is not essential for steroid hormone biosynthesis. PMID- 24174325 TI - Poking holes in rheumatoid joints. AB - Pathological mechanisms that cause cell membrane lysis and an increase in intracellular calcium may explain how rheumatoid arthritis patients develop citrullination of intracellular proteins in their joints (Romero et al., this issue). PMID- 24174326 TI - Immune-mediated pore-forming pathways induce cellular hypercitrullination and generate citrullinated autoantigens in rheumatoid arthritis. AB - Autoantibodies to citrullinated protein antigens are specific markers of rheumatoid arthritis (RA). Although protein citrullination can be activated by numerous stimuli in cells, it remains unclear which of these produce the prominent citrullinated autoantigens targeted in RA. In these studies, we show that RA synovial fluid cells have an unusual pattern of citrullination with marked citrullination of proteins across the broad range of molecular weights, which we term cellular hypercitrullination. Although histone citrullination is a common event during neutrophil activation and death induced by different pathways including apoptosis, NETosis, and necroptosis/autophagy, hypercitrullination is not induced by these stimuli. However, marked hypercitrullination is induced by two immune-mediated membranolytic pathways, mediated by perforin and the membrane attack complex (MAC), which are active in the RA joint and of importance in RA pathogenesis. We further demonstrate that perforin and MAC activity on neutrophils generate the profile of citrullinated autoantigens characteristic of RA. These data suggest that activation of peptidylarginine deiminases during complement and perforin activity may be at the core of citrullinated autoantigen production in RA. These pathways may be amenable to monitoring and therapeutic modulation. PMID- 24174327 TI - Unimolecular dual incretins maximize metabolic benefits in rodents, monkeys, and humans. AB - We report the discovery and translational therapeutic efficacy of a peptide with potent, balanced co-agonism at both of the receptors for the incretin hormones glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP). This unimolecular dual incretin is derived from an intermixed sequence of GLP-1 and GIP, and demonstrated enhanced antihyperglycemic and insulinotropic efficacy relative to selective GLP-1 agonists. Notably, this superior efficacy translated across rodent models of obesity and diabetes, including db/db mice and ZDF rats, to primates (cynomolgus monkeys and humans). Furthermore, this co agonist exhibited synergism in reducing fat mass in obese rodents, whereas a selective GIP agonist demonstrated negligible weight-lowering efficacy. The unimolecular dual incretins corrected two causal mechanisms of diabesity, adiposity-induced insulin resistance and pancreatic insulin deficiency, more effectively than did selective mono-agonists. The duration of action of the unimolecular dual incretins was refined through site-specific lipidation or PEGylation to support less frequent administration. These peptides provide comparable pharmacology to the native peptides and enhanced efficacy relative to similarly modified selective GLP-1 agonists. The pharmacokinetic enhancement lessened peak drug exposure and, in combination with less dependence on GLP-1 mediated pharmacology, avoided the adverse gastrointestinal effects that typify selective GLP-1-based agonists. This discovery and validation of a balanced and high-potency dual incretin agonist enables a more physiological approach to management of diseases associated with impaired glucose tolerance. PMID- 24174328 TI - Spherical nucleic acid nanoparticle conjugates as an RNAi-based therapy for glioblastoma. AB - Glioblastoma multiforme (GBM) is a neurologically debilitating disease that culminates in death 14 to 16 months after diagnosis. An incomplete understanding of how cataloged genetic aberrations promote therapy resistance, combined with ineffective drug delivery to the central nervous system, has rendered GBM incurable. Functional genomics efforts have implicated several oncogenes in GBM pathogenesis but have rarely led to the implementation of targeted therapies. This is partly because many "undruggable" oncogenes cannot be targeted by small molecules or antibodies. We preclinically evaluate an RNA interference (RNAi) based nanomedicine platform, based on spherical nucleic acid (SNA) nanoparticle conjugates, to neutralize oncogene expression in GBM. SNAs consist of gold nanoparticles covalently functionalized with densely packed, highly oriented small interfering RNA duplexes. In the absence of auxiliary transfection strategies or chemical modifications, SNAs efficiently entered primary and transformed glial cells in vitro. In vivo, the SNAs penetrated the blood-brain barrier and blood-tumor barrier to disseminate throughout xenogeneic glioma explants. SNAs targeting the oncoprotein Bcl2Like12 (Bcl2L12)--an effector caspase and p53 inhibitor overexpressed in GBM relative to normal brain and low grade astrocytomas--were effective in knocking down endogenous Bcl2L12 mRNA and protein levels, and sensitized glioma cells toward therapy-induced apoptosis by enhancing effector caspase and p53 activity. Further, systemically delivered SNAs reduced Bcl2L12 expression in intracerebral GBM, increased intratumoral apoptosis, and reduced tumor burden and progression in xenografted mice, without adverse side effects. Thus, silencing antiapoptotic signaling using SNAs represents a new approach for systemic RNAi therapy for GBM and possibly other lethal malignancies. PMID- 24174330 TI - What family support specialists do: examining service delivery. AB - This study describes services provided by family support specialists (FSS), peer advocates in programs for children with serious psychiatric conditions, to delineate differences between recommended components of FSS services and services actually provided. An analysis of qualitative interview and observational data and quantitative survey data from 63 staff at 21 mental health programs in New York identified that FSS and other staff have generally similar ideas about FSS services, and that these perceptions of activities are generally congruent with what FSS actually did. Implications of findings are discussed in the context of developing competencies and quality indicators for FSS. PMID- 24174332 TI - Learning from berberine: Treating chronic diseases through multiple targets. AB - Although advances have been made, chemotherapy for chronic, multifactorial diseases such as cancers, Alzheimer's disease, cardiovascular diseases and diabetes is far from satisfactory. Agents with different mechanisms of action are required. The botanic compound berberine (BBR) has been used as an over-the counter antibacterial for diarrhea in China for many decades. Recent clinical studies have shown that BBR may be therapeutic in various types of chronic diseases. This review addresses BBR's molecular mechanisms of action and clinical efficacy and safety in patients with type 2 diabetes, hyperlipidemia, heart diseases, cancers and inflammation. One of the advantages of BBR is its multiple target effects in each of these diseases. The therapeutic efficacy of BBR may reflect a synergistic regulation of these targets, resulting in a comprehensive effect against these various chronic disorders. The safety of BBR may be due to its harmonious distribution into those targets. Although the single-target concept is still the principle for drug discovery and research, this review emphasizes the concept of a multiple target strategy, which may be an important approach toward the successful treatment of multifactorial chronic diseases. PMID- 24174329 TI - A genomics-based classification of human lung tumors. AB - We characterized genome alterations in 1255 clinically annotated lung tumors of all histological subgroups to identify genetically defined and clinically relevant subtypes. More than 55% of all cases had at least one oncogenic genome alteration potentially amenable to specific therapeutic intervention, including several personalized treatment approaches that are already in clinical evaluation. Marked differences in the pattern of genomic alterations existed between and within histological subtypes, thus challenging the original histomorphological diagnosis. Immunohistochemical studies confirmed many of these reassigned subtypes. The reassignment eliminated almost all cases of large cell carcinomas, some of which had therapeutically relevant alterations. Prospective testing of our genomics-based diagnostic algorithm in 5145 lung cancer patients enabled a genome-based diagnosis in 3863 (75%) patients, confirmed the feasibility of rational reassignments of large cell lung cancer, and led to improvement in overall survival in patients with EGFR-mutant or ALK-rearranged cancers. Thus, our findings provide support for broad implementation of genome based diagnosis of lung cancer. PMID- 24174331 TI - Molecular dynamics study of HIV-1 RT-DNA-nevirapine complexes explains NNRTI inhibition and resistance by connection mutations. AB - HIV-1 reverse transcriptase (RT) is a multifunctional enzyme that is targeted by nucleoside analogs (NRTIs) and non-nucleoside RT inhibitors (NNRTIs). NNRTIs are allosteric inhibitors of RT, and constitute an integral part of several highly active antiretroviral therapy regimens. Under selective pressure, HIV-1 acquires resistance against NNRTIs primarily by selecting mutations around the NNRTI pocket. Complete RT sequencing of clinical isolates revealed that spatially distal mutations arising in connection and the RNase H domain also confer NNRTI resistance and contribute to NRTI resistance. However, the precise structural mechanism by which the connection domain mutations confer NNRTI resistance is poorly understood. We performed 50-ns molecular dynamics (MD) simulations, followed by essential dynamics, free-energy landscape analyses, and network analyses of RT-DNA, RT-DNA-nevirapine (NVP), and N348I/T369I mutant RT-DNA-NVP complexes. MD simulation studies revealed altered global motions and restricted conformational landscape of RT upon NVP binding. Analysis of protein structure network parameters demonstrated a dissortative hub pattern in the RT-DNA complex and an assortative hub pattern in the RT-DNA-NVP complex suggesting enhanced rigidity of RT upon NVP binding. The connection subdomain mutations N348I/T369I did not induce any significant structural change; rather, these mutations modulate the conformational dynamics and alter the long-range allosteric communication network between the connection subdomain and NNRTI pocket. Insights from the present study provide a structural basis for the biochemical and clinical findings on drug resistance caused by the connection and RNase H mutations. PMID- 24174333 TI - NEDD9 promotes lung cancer metastasis through epithelial-mesenchymal transition. AB - Metastasis is the major cause for high mortality of lung cancer with the underlying mechanisms poorly understood. The scaffolding protein neural precursor cell expressed, developmentally down-regulated 9 (NEDD9) has been identified as a pro-metastasis gene in several types of cancers including melanoma and breast cancer. However, the exact role and related mechanism of NEDD9 in regulating lung cancer metastasis still remain largely unknown. Here, we demonstrate that NEDD9 knockdown significantly inhibits migration, invasion and metastasis of lung cancer cells in vitro and in vivo. The pro-metastasis role of Nedd9 in lung cancer is further supported by studies in mice models of spontaneous cancer metastasis. Moreover, we find that NEDD9 promotes lung cancer cell migration and invasion through the induction of epithelial-mesenchymal transition (EMT) potentially via focal adhesion kinase activation. More importantly, NEDD9 expression inversely correlates with E-cadherin expression in human lung cancer specimens, consistent with the findings from in vitro studies. Taken together, this study highlights that NEDD9 is an important mediator promotes lung cancer metastasis via EMT. PMID- 24174335 TI - PET radiotracers for imaging P-glycoprotein: the challenge for early diagnosis in AD. AB - PET radiotracer development to target in vivo P-glycoprotein (P-gp) could be an important strategy for the early diagnosis of neurodegenerative disorders such as Alzheimer's disease (AD). Indeed, as a dysfunction of P-gp is responsible for the accumulation of beta-amyloid plaques (a hallmark of AD) in brain parenchyma, P-gp is the cause of AD onset. P-gp substrates and inhibitors are useful for imaging the activity or expression of this protein, respectively; herein we discuss the in vivo evaluation of some 11C radiotracers with P-gp-inhibitory activity, such as [11C]MC18 and [11C]MC113, as well as P-gp substrates [11C]MC266 and [11C]MC80. Moreover, the radiosynthesis of all these P-gp probes is reported. PMID- 24174334 TI - New generation drug-eluting stents for ST-elevation myocardial infarction: a new paradigm for safety. AB - OBJECTIVES: The objective of this study is to compare the long-term safety of new generation drug-eluting stents (DES) with early generation DES and bare metal stents (BMS) for ST-segment elevation myocardial infarction (STEMI). BACKGROUND: Early generation DES for STEMI have reduced target vessel revascularization, but have more very late ST compared with BMS raising concerns about their safety. New compared with early generation DES have lower rates of ST, but there are limited data in STEMI patients. METHODS: From 2003 to 2011, 3,464 STEMI patients were treated with BMS (n = 1,187), early generation DES (n = 1,525), or new generation DES (n = 752) and were followed for 1-9 years. RESULTS: Patients with new generation DES were younger, had less cardiogenic shock, and less prior infarction versus BMS, and more hypertension versus early generation DES. At 2 years, new generation DES had lower mortality (4.0% vs. 12.4%, P < 0.001), similar reinfarction (4.4% vs. 5.1%, P = 0.35), and less ST (1.4% vs. 3.8%, P = 0.031) versus BMS; and similar mortality (4.0% vs. 5.8%, P = 0.23), similar reinfarction (4.4% vs. 5.2%, P = 0.64), and trends for less ST (1.4% vs. 3.3%, P = 0.17) versus early generation DES. By Cox multivariable analyses, BMS had more ST than new generation DES (HR [95% CI] = 1.93 [1.01-3.66], P = 0.045). CONCLUSIONS: New generation DES in STEMI patients have less ST compared to BMS and trends for less ST compared to early generation DES. These data suggest a new safety paradigm and should encourage the use of new generation DES in most STEMI patients treated with primary percutaneous coronary intervention (PCI). PMID- 24174338 TI - [From the expert's office: The Reichenhaller Empfehlung of 2012--essentiell alterations and modifications]. PMID- 24174339 TI - [Acute rhinosinusitis in adults--EPOS 2012 Part II]. AB - Rhinosinusitis (RS) is an inflammatory disorder of the mucous membranes of the nose and paranasal sinuses, which are almost always affected concurrently. The EPOS2012 position paper initiated by the European Rhinologic Society and the European Academy of Allergy and Clinical Immunology is a recent comprehensive source on this common disease affecting approximately 20% of the population worldwide. Inflammation, not infection, is considered the cornerstone of RS, which is considered a temporal and pathophysiologic disease continuum with various subtypes. Acute rhinosinusitis is diagnosed, if typical symptoms last less than 12 weeks. It affects approximately 10% of the European population. Acute RS is further subdivided into acute viral, acute postviral and acute bacterial RS. Acute viral RS lasts less than 10 days with decreasing symptom intensity, while acute postviral RS is characterized by longer duration or a sudden increase of symptom severity around the 5th day ('double sickening'). Acute bacterial RS is assumed if 3 of the following 5 criteria are additionally met: Discoloured discharge (with unilateral predominance), severe local pain (with unilateral predominance), fever (>38oC), elevated ESR/CRP, and 'double sickening'. For the treatment of acute viral RS, nasal saline irrigations and OTC cold remedies are advised. In acute postviral RS, additional topical steroids are suggested. Advantages and disadvantages of antibiotic treatment in acute bacterial RS are detailed. Overall, the new EPOS position paper infers a reorientation in this area of high medical, pharmaceutical and economic relevance. PMID- 24174340 TI - [Optimizing diagnosis, medical management and planning of the operation. Optimizing drug therapy. Optimizing operation timing]. PMID- 24174341 TI - Compound heterozygous RAG2 mutations mimicking hyper IgM syndrome. PMID- 24174342 TI - Localization of liposomal mTHPC formulations within normal epithelium, dysplastic tissue, and carcinoma of oral epithelium in the 4NQO-carcinogenesis rat model. AB - BACKGROUND AND OBJECTIVE: Foslip and Fospeg are liposomal formulations of the photosensitizer mTHPC (Foscan), which is used for photodynamic therapy (PDT) of malignancies. Literature suggests that liposomal mTHPC formulations have better properties and increased tumor uptake compared to Foscan. To investigate this, we used the 4NQO-induced carcinogen model to compare the localization of the different mTHPC formulations within normal, precancerous, and cancerous tissue. In contrast to xenograft models, the 4NQO model closely mimics the carcinogenesis of human oral dysplasia. MATERIALS AND METHODS: Fifty-four rats drank water with the carcinogen 4NQO. When oral examination revealed tumor, the rats received 0.15 mg/kg mTHPC (Foscan, Foslip, or Fospeg). At 2, 4, 8, 24, 48, or 96 hours after injection the rats were sacrificed. Oral tissue was sectioned for HE slides and for fluorescence confocal microscopy. The HE slides were scored on the severity of dysplasia by the epithelial atypia index (EAI). The calibrated fluorescence intensity per formulation or time point was correlated to EAI. RESULTS: Fospeg showed higher mTHPC fluorescence in normal and tumor tissue compared to both Foscan and Foslip. Significant differences in fluorescence between tumor and normal tissue were found for all formulations. However, at 4, 8, and 24 hours only Fospeg showed a significant difference. The Pearson's correlation between EAI and mTHPC fluorescence proved weak for all formulations. CONCLUSION: In our induced carcinogenesis model, Fospeg exhibited a tendency for higher fluorescence in normal and tumor tissue compared to Foslip and Foscan. In contrast to Foscan and Foslip, Fospeg showed significantly higher fluorescence in tumor versus normal tissue at earlier time points, suggesting a possible clinical benefit compared to Foscan. Low correlation between grade of dysplasia and mTHPC fluorescence was found. PMID- 24174343 TI - Regional brain imaging of vesicular acetylcholine transporter using o-[125 I]iodo trans-decalinvesamicol as a new potential imaging probe. AB - In this study, the regional rat brain distribution of radioiodinated o-iodo-trans decalinvesamicol ([(125) I]OIDV) was determined in vivo to evaluate its potential as a single-photon emission computed tomography (SPECT) imaging probe for vesicular acetylcholine transporter (VAChT). Following intravenous injection, [(125) I]OIDV passed freely across the blood-brain barrier and accumulated in rat brain. The accumulation of [(125) I]OIDV in rat brain was significantly reduced by coadministration of (+/-)-vesamicol (0.125 umol). In contrast, the coadministration of sigma-receptor ligands, such as (+)-pentazocine (0.125 umol) as a sigma-1 receptor ligand and (+)-3-(3-hydroxyphenyl)-N-propylpiperidine (0.125 umol) as a sigma-1 and sigma-2 receptor ligands, barely affected the accumulation of [(125) I]OIDV in rat brain. These findings in vivo were corroborated by autoradiographic analysis ex vivo. The authors found that the tracer binds with pharmacological selectivity to VAChT in rat brain and predicted that it may likewise serve in translational SPECT imaging studies of this marker in the integrity of cholinergic innervations. PMID- 24174344 TI - CTCF mediates the TERT enhancer-promoter interactions in lung cancer cells: identification of a novel enhancer region involved in the regulation of TERT gene. AB - Telomerase activation is a hallmark of cancer. Although the regulation of the telomerase reverse transcriptase catalytic subunit (TERT), the rate-limiting factor for telomerase activity, has been studied intensively it remains incompletely understood. In cells devoid of telomerase activity, TERT is embedded in a region of condensed chromatin and the chromatin remodeling protein CCCTC binding factor (CTCF) has been implicated in the inhibition of TERT expression. The importance of TERT activation for cellular immortalization and carcinogenesis is attested by the fact that the gene is expressed in more than 90% of immortal cell lines and tumors and that gain of TERT is the most frequent amplification event in early stage lung cancer. This study was designed to study the mechanisms of regulation of the TERT gene expression by the CTCF transcription factor in three human lung cancer cell lines, A427, A549 and H838. Depletion of CTCF by siRNA resulted in reduced TERT mRNA levels in two (A427 and A549) of the three cell lines. A novel enhancer element was identified approximately 4.5 kb upstream of the TERT transcription start site. Chromatin immunoprecipitation experiments revealed recruitment of CTCF to this enhancer element. Chromosome conformation capture experiments demonstrated the presence of CTCF-dependent chromatin loops between this enhancer element and the TERT proximal promoter in A427 and A549 cell lines. In summary, the results show that CTCF plays an important role in maintaining TERT expression in a subset of human lung cancer cell lines. This role may be due to CTCF-dependent enhancer-promoter interactions. PMID- 24174345 TI - Syndrome classification based on manifold ranking for viral hepatitis. AB - Treatment determination based on syndrome differentiation is the key of Chinese medicine. A feasible way of improving the clinical therapy effectiveness is needed to correctly differentiate the syndrome classifications based on the clinical manifestations. In this paper, a novel data mining method based on manifold ranking (MR) is proposed to explore the relation between syndromes and symptoms for viral hepatitis. Since MR could take the symptom data with expert differentiation and the symptom data without expert differentiation into the task of syndrome classification, the clinical information used for modeling the syndrome features is greatly enlarged so as to improve the precise of syndrome classification. In addition, the proposed method of syndrome classification could also avoid two disadvantages in previous methods: linear relation of the clinical data and mutually exclusive symptoms among different syndromes. And it could help exploit the latent relation between syndromes and symptoms more effectively. Better performance of syndrome classification is able to be achieved according to the experimental results and the clinical experts. PMID- 24174346 TI - Biopesticides in the framework of the European Pesticide Regulation (EC) No. 1107/2009. AB - BACKGROUND: The European Pesticide Regulation (EC) No. 1107/2009 encourages the use of less harmful active substances. Two main concerns involve the application of cut-off criteria for pesticides without losing tools for future agriculture (especially for minor uses) and the implementation of zonal evaluations. Biopesticides are considered to have lower risks than synthetic pesticides; consequently, there is strong interest for their use in integrated pest management practices. RESULTS: This paper provides an analysis of the current European situation, starting with the first attempts to regulate the use of plant protection products and focusing on the implications of the new legislative criteria for biopesticides. CONCLUSION: It is important to be aware that biopesticides are still pesticides and fall under the same regulations as their synthetic counterparts. Although manufacturers are still reluctant to commit to such alternatives due to difficulties with approval and registration, biopesticides could be alternatives for traditional plant protection products, either as a base for the synthesis of new products or integrated with traditional plant protection products. In addition, biopesticides have to be used only as indicated on the label, which provides critical information about how to safely handle and use plant protection products. PMID- 24174347 TI - Scalable synthesis of oxazolones from propargylic alcohols through multistep palladium(II) catalysis: beta-selective oxidative Heck coupling of cyclic sulfonyl enamides and aryl boroxines. AB - A whale of a scale: The title oxidative Heck coupling proceeded with unusual beta selectivity to generate a variety of branched substituted oxazolones (see scheme; Ts=p-toluenesulfonyl). The three-step synthesis from readily available starting materials with a simple palladium catalyst and inexpensive reagents could be carried out in a single reaction vessel or scaled up for the preparation of large amounts of these amino acid precursors. PMID- 24174348 TI - Identification of oviposition attractants of the secondary screwworm, Cochliomyia macellaria (F.) released from rotten chicken liver. AB - The secondary screwworm, Cochliomyia macellaria (F.), is an important blowfly species affecting both livestock and humans. It can transmit pathogenic disease agents mechanically and is an agent of facultative myiasis, which leads to economic losses. The adult flies are attracted to decomposing carcasses, carrion, or rotten meat in order to deposit their eggs, and the hatched larvae develop on these decaying organic materials. This research was aimed to identify volatiles emitted from rotten chicken livers that were reported previously to attract gravid females. In laboratory oviposition assays, gravid females laid significantly more eggs on rotten livers than on fresh livers, and rotten chicken liver was more attractive than rotten beef liver. Volatiles from the two livers were collected using solid phase microextraction. Significantly different volatile profiles were detected from the rotten livers of beef and chicken. Electroantennography (EAG) was performed to determine antennal responses to chemicals released from the most attractive chicken liver that are candidate oviposition attractants. Seven compounds from rotten chicken liver elicited significant EAG responses from antennae of gravid females. Oviposition assays showed that the 7-component blend stimulated gravid females to lay significantly more eggs than the other combinations tested. This 7-component blend may have potential for use in monitoring and sampling populations of secondary screwworm and their associated disease epidemiology. PMID- 24174349 TI - Impact of GDP, spending on R&D, number of universities and scientific journals on research publications in pharmacological sciences in Middle East. AB - OBJECTIVES: Research in pharmacological science is vital to support the health needs of human beings. Measuring the research output provides information that forms the basis of strategic decisions. This study aimed to investigate the impact of Gross Domestic Product (GDP), spending on Research and Development (R&D), number of universities and scientific journals on research documents (papers), citable documents, citations per document and H-index in pharmacological science among Middle East countries. MATERIALS AND METHODS: All the 16 Middle East countries were included in the study. The information regarding GDP, spending on R&D, total number of universities and indexed scientific journals were collected. We recorded the total number of research documents, citable documents, citations per document and H-index in pharmacological science during the period 1996-2011. The main sources for information were World Bank, Web of Science, Journal Citation Reports (Thomson Reuters) and SCI-mago/Scopus. RESULTS: The mean per capita GDP of all the Middle East countries is 18125.49+/-5386.28 US$, spending on R&D 0.63+/-0.28% of GDP in US$, number of universities 36.56+/-11.33 and mean ISI indexed journal are 8.25+/ 3.93. The number of research documents published in pharmacological science among the Middle East countries during the period 1996-2011 is 1344.44+/-499.34; citable documents 1286.37+/-476.34; citations per document 7.62+/- 0.84; and H index is 30.68+/-6.32. There was a positive correlation between spending on R&D and citations per documents (r = 0.56, p = 0.02), H-Index (r = 0.56, p = 0.02); number of universities and research documents (r = 0.72, p = 0.002), citable documents (r = 0.72, p = 0.001); ISI indexed journals and research documents (r = 0.88, p = 0.0001), citable documents (r = 0.88, p = 0.0001), H-Index (r = 0.67, p = 0.004). However, there was no correlation between the GDP per capita and research outcome in pharmacological science. CONCLUSIONS: There is a positive association between spending on R&D, number of universities and indexed scientific journals on research outcome in pharmacological science in Middle East. PMID- 24174350 TI - Evaluation of analgesic and anti-inflammatory effect of nanoparticles of magnesium oxide in mice with and without ketamine. AB - OBJECTIVES: According to importance and increasing application of nanoparticles and their toxicity, the identification effects of nanoparticles on physiological systems are essential. Some studies show magnesium has analgesic effect in some pain models but this evaluation was not carried on nano-magnesium oxide (MgO). Thus, present study was designed to evaluation effect of Mgo nanoparticles alone and in combination with ketamine on two pain and inflammation model in mice. MATERIALS AND METHODS: At this study, adult male mice was used which had 29+/-3 gram weight. Formalin and acetic acid tests were carried. Acetic acid (1%) was intraperitoneally injected 0.3ml and the abdominal writhing was counted from 10 to 30 minutes after it. Formalin (2.5%) was injected 0.04 ml/mouse subcutaneously in plantar site of mice. The time of licking was cumulatively measured 0-5 (acute phase) and 15-25 (chronic phase) minutes later. Control (negative control), ketamine (0.1 mg/kg), MgO nanoparticles (5 and 10 mg/kg), conventional MgO (5 and 10 mg/kg) and ketamine with conventional and nanoparticles MgO groups were studied in both tests. RESULTS: Mean of writhing was significantly decreased by all drugs with comparison to control group (p = 0.0001). This decreasing was significant between conventional and nanoparticle MgO. The time of licking at both acute and chronic phases of formalin test was significantly decreased by all drugs with comparison to control group. However, this mean had significant difference with MgO nanoparticles. CONCLUSIONS: It seems that the nano-MgO induces analgesic and anti-inflammatory effects through central and peripheral mechanisms at experimental formalin and acetic acid testes and potentiates effect of ketamine. PMID- 24174351 TI - Cuprizone-induced demyelination in Wistar rats; electrophysiological and histological assessment. AB - OBJECTIVES: Multiple Sclerosis (MS) is a disease that affects the Central Nervous System by destructing myelin shield and also can affects the peripheral nervous system. Demyelination is acquired characteristics disease and appears with the degeneration of myelin which protects the axons. Cuprizone (CPZ) model is a toxic demyelination model. The purpose of this study was to develop an MS model by cuprizone exposure to Wistar rats. MATERIALS AND METHODS: Rats were separated into control and experimental groups and daily cuprizone was administered to experimental groups for 4, 5, 6 and 7 weeks. At the end of the experiments, spinal nerve conduction velocity was measured by EMG detected from the gastrocnemius muscle. After scarification, cerebrum and cerebellum of the animals were taken for histopathological investigation. RESULTS: Spinal cord nerve conduction velocity (SNCV) of control animals was 76.54 m/s. Whereas SNCV of the rats that were feed with CPZ for 6 weeks was significantly reduced to 46.35 m/s in comparison with the control group. Demyelinated areas and vacuolization were seen on the brain sections of CPZ exposed rats. CONCLUSIONS: SNCV of the rats were feed with cuprizone began tendency of decrease after 4th weeks. These reductions were observed as maximum at 6th weeks. At 7th week increments were observed at SNCV. These results indicated that 6 weeks of cuprizone feedings could be suitable to bring into existence of MS model in Wistar rats. PMID- 24174352 TI - Conversion from twice-daily to once-daily Tacrolimus administration in liver transplant patient: results of long term follow-up. AB - OBJECTIVES: The aim of this study was to assess the long term effects of once daily tacrolimus (OD-TAC) in a cohort of stable liver recipients converted from the twice daily tacrolimus (TD TAC), with a particular attention on the possible effects on renal function. PATIENTS AND METHODS: Between September 2008 and September 2010 conversion from TD-TAC to OD-TAC was proposed in adult stable liver transplant recipients who were followed as outpatients in our Transplant centre. Conversion from TC-TAC to OD-TAC was based on a 1 mg: 1 mg proportion. Tacrolimus through levels, laboratory parameters, metabolic disorders and any adverse events were evaluated at 1, 3, 6, 12 and 24 months after conversion. Renal function was evaluated using creatinine plasma levels and estimated glomerular filtration rate (GFR) derived from the Modification of Diet in Renal Disease (MDRD). Analysis of variance and t test for paired data were utilised for the comparison of the results obtained at the scheduled controls. RESULTS: Sixty five patients were enrolled in the study (50 males, 15 females, mean age 59+/-8 years). Median time since liver transplant (LT) was 39 months (range: 6 to 83 months). All patients were followed for a minimum of 12 months. Ninety per cent of patients stabilized their blood levels within 45 days. Liver function, glucose and plasma lipids concentration and arterial blood pressure remained stable during the study. Renal function improved during the 24 months of follow-up. No adverse events or acute rejection episodes were recorded during the study. CONCLUSIONS: Considering the advantage on patient compliance, the equivalent efficacy and the adequate safety of OD-TAC formulation may represent a useful option in liver transplant patients, with a possible advantage on renal function. PMID- 24174353 TI - Multicenter clinical trial on the performance and tolerability of the Hyaluronic acid-collagenase ointment for the treatment of chronic venous ulcers: a preliminary pilot study. AB - BACKGROUND: Bed debridement is important to treat chronic wounds. Effective agents should remove the necrosis but protect the granulation tissue. We evaluated the performance and tolerability of a new composite ointment containing collagenase and hyaluronic acid for chronic venous ulcers. PATIENTS AND METHODS: Subjects with class 6 venous ulcers (CEAP classification) of at least 6 months duration were prospectively recruited. The ointment was administered daily and follow-up visits were conducted on the fifth, 10th, 15th and 20th days. On each visit the necrotic area was measured with a grid. The moisture balance, odour, viability of non-necrotic areas and the presence of erythema were also assessed. Primary outcome was the percentage of subjects with complete debridement, secondary outcomes the time to complete healing, reduction of the lesion area, absence of necrotic tissue, presence of odor, erythema, hydration, any adverse events. RESULTS: One hundred subjects were enrolled in four centres. All patients achieved complete debridement of the necrotic area and a significant reduction of the total ulcer area by day 20, while other parameters improved significantly over time. Only two patients experienced a transient leg oedema. CONCLUSIONS: The combination of collagenase and hyaluronic acid is safe and effective for chronic venous ulcers. PMID- 24174354 TI - Mad honey intoxication: what is wrong with the blood glucose? a study on 46 patients. AB - OBJECTIVE: This study was designed to analyze the characteristics of adult patients with mad honey intoxication, with special emphasis on its effects on vital signs and blood glucose levels. METHODS: Patients admitted to the Emergency Department of urban hospital in the Black Sea region of Turkey over the 16-months study period due to mad honey intoxication were included. Patients' demographic and clinical characteristics, including age, sex, systolic and diastolic blood pressure, rhythm at ECG, heart rate, blood glucose levels and clinical outcomes were recorded and analyzed. RESULTS: Forty-six patients with a presumptive diagnosis of mad honey poisoning were recruited. Mean age was 52.2 (+/-17.2). Blood glucose level was normal in 28 cases (60.9%) and high in 18 (39.1%). Systolic blood pressure (SBP) was low in 40 patients (87%) and normal in six (13%). Diastolic blood pressure (DBP) was low in 42 cases (91.3%) and normal in four (8.7%). Mean glucose level in patients with low SBP was 116.1 (+/-52.9) mg/dL, vs. 120.7 (+/-23.0) mg/dL in those with normal or high SBP (p = 0.389). Mean glucose level in patients with low DBP was 118.7 (+/-51.4) mg/dL, compared to 96.0 (+/-22.8) mg/dL in those with normal or high DBP (p = 0.146). Heart rate was below or equal to 45 bpm in 28 patients (60.9%). Complete (third degree) heart block was diagnosed in one case. CONCLUSION: Mad honey was found not to cause significant decreases in blood glucose levels in humans. Hypotension, bradycardia and related clinical consequences are commonly encountered in patients diagnosed with mad honey or grayanotoxin poisoning. PMID- 24174355 TI - Advances in plastic and cosmetic surgery at home and abroad - a bibliometric analysis. AB - BACKGROUND: Plastic and cosmetic surgery is a new branch deriving from plastic surgery. Although several studies concerning advances in plastic and cosmetic surgeries have been reported, most literatures focus on specific diagnosis and treatment technology, but not the overall progress. AIM: We attempt to use bibiometric analysis to investigate main research hotspots at home and abroad, outstanding researchers and excellent institutions. MATERIALS AND METHODS: We retrieved relevant literatures published between 2007 and 2011 in five foreign and four Chinese journals. gCLUTO was used to perform double clustering analysis. Price's Law was used to analyze authors with high yield. Literature profiling was performed to construct author-keyword and institution-keyword matrix to comprehend research feature of high yield authors and research institutions. RESULTS: A total of 67 and 94 high-frequency words were obtained from English and Chinese journals. Clustering analysis indicated that research hotspots at home and abroad mainly included side-effects of augmentation mammoplasty and its therapy, eyelid plastic surgery, cartilage transplantation and/or cartilage suture in nose plastic surgery, plastic surgery in cheilopalatognathus and nasal deformity, construction of surgical flaps, and facial plastic cosmetology. In addition, several authors and institutions with high yield also had been identified and they might have different research features. CONCLUSIONS: We investigate advances, hotspots, experts and their institutions in plastic and cosmetic surgery in recent five years at home and abroad, which would provide some research directions for professionals of plastic and cosmetic surgery. PMID- 24174356 TI - Comparison antinociceptive activity of the aqueous methanolic extracts of Salvia Hypoleuca and Phytolacca americana in mice. AB - OBJECTIVES: Anti-nociceptive activity of aerial parts of Phytolacca (P.) americana and Salvia Hypoleuca were investigated, using the hot plate method in mice. MATERIALS AND METHODS: Antinociceptive activity of aerial parts of Phytolacca americana and Salvia Hypoleuca were investigated using the hot plate method. In addition, the effect of its aerial parts on morphine dependence was investigated in mice. After induction of dependence by morphine, different concentrations of plants aerial parts extract were injected to treated groups. To assess morphine withdrawal, mice were injected naloxone (5 mg/kg) i.p. on the 5th day. After four consecutive days of morphine injection, withdrawal syndrome was assessed by placing each mouse in a 30 cm high glass box and recording the frequency of escape jumps for 60 minutes. RESULTS: The aqueous methanolic extract of aerial parts of P. Americana and S. Hypoleuca produced a statistically significant increase in pain threshold after 30 min of i.p. injection of extract, in comparison with the control groups, at adose of 190 and doses of 500, 1000 and 1500 mg/kg (p < 0.001) respectibility. The activity was comparable to that of morphine (30 mg/kg i.p., p > 0.05). The anti-nociceptive activity of P. Americana and S. Hypoleuca increased until the 60th min (p < 0.05 compared to morphine). CONCLUSIONS: The results of this study support the extensive use of S. Hypoleuca and P. americana in Western Asia and America. The LD50 of extracts S. Hypoleuca and P. americana following a 14 days acute toxicity study were calculated to be a bout 1800 and 208 mg kg-1 i.p. respectability. PMID- 24174357 TI - Neuroprotective effects of LBP on brain ischemic reperfusion neurodegeneration. AB - AIM: The present study was conducted to investigate whether LBP had a protective effect on cerebral ischemic reperfusion injury and to determine the possible mechanisms. MATERIALS AND METHODS: Male Kunming (KM) mice were used to make the model cerebral artery occlusion/reperfusion (MCAO/R). The behavioral test was used to measure neurological deficit scores for evaluation of ischemic reperfusion damage of brain. The change of electroencephalograph (EEG) was monitored by Model SMUP-E Bio-electric Signals Processing System. The infarction area of brain was assessed in brain slices with 2% solution of 2,3,5-triphenyl tetrazolium chloride (TTC). Spectrophotometric assay was used to determine the activities of superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), catalase (CAT) and lactate dehydrogenase (LDH), contents of malondialdehyde (MDA) and adenosine triphosphate (ATP) of the brain. RESULTS: The results showed that LBP at doses of 20 and 40 mg/kg markedly decreased the neurological deficit scores and the infarction area in MCAO/R mice. At the same time, LBP significantly decreased MDA content, and increased SOD, GSH-Px, CAT, LDH activities in ischemic reperfusion brain. CONCLUSIONS: These suggest that LBP might act as a potential neuroprotective agent against the cerebral reperfusion induced injury in the brain through reducing lipid peroxides, scavenging free radicals, and improving the energy metabolism. PMID- 24174358 TI - Effect of methylprednisolone and edaravone administration on spinal cord injury. AB - BACKGROUND: Spinal cord injury (SCI) is one of the most devastating traumatic conditions that primarily affects young males with an annual incidence of 15-40 cases per million. AIM: To explore the superior neuroprotective effect of edaravone (ED) on spinal cord injury during maintenance therapy compared with methylprednisolone (MP). MATERIALS AND METHODS: Sprague-Dawley rat model of spinal cord injury was established by modified Allen's method. Total 114 rats were divided into two groups and then six subgroups individually: A1 (control group, normal saline injection within 8 h), B1 (MP group, MP injection within 8 h), C1(ED group, ED injection within 8 h), A2 (control group, normal saline injection after 8 h), B1 (MP group, MP injection after 8 h), C1 (ED group, ED injection after 8 h). Further, we investigated the changes of histopathology, caspase-3 and Bcl-xL positive cell. RESULTS: Haemorrhage, swelling, hyperaemia, gliocytes hyperplasia, inflammatory cells infiltration, vacuolar denaturation, and nucleus concentration could be observed, especially in control group. Caspase 3 positive cell was significantly decreased in MP and ED group within 8 h administration, but caspase-3 positive cell was only significantly decreased in ED group after 8 h administration. And B-cell lymphoma extra large (Bcl-xL) was significantly increased in ED group than MP group no matter within 8 h or after 8 h administration. CONCLUSIONS: More attention should be paid on the time point of MP administration, and ED administration seem to be more effective for maintenance therapy. PMID- 24174359 TI - Acute-phase reactants and cytokines in ischemic stroke: do they have any relationship with short-term mortality? AB - BACKGROUND: Many unknown risk factors play a role in the etiopathogenesis of stroke. The appearance of inflammatory cells within the damaged tissue after cerebral ischemia suggests that an inflammatory response may play a role in stroke pathogenesis. In our study, we examined whether an association exists between the acute-phase reactants and the levels of cytokines, the volume and diameter of the stroke, and short-term mortality in patients who were diagnosed as acute ischemic a stroke after admission to the Emergency Department. PATIENTS AND METHODS: A total of 50 consecutive patients who applied to the Emergency Service with acute ischemic stroke were enrolled in the study. Their stroke volume were calculated and serum samples were obtained as soon as they arrived into the Emergency Service. The patients were evaluated according to the Glasgow Coma Scale (GCS) and National Institutes of Health Stroke Scale (NIHSS). RESULTS: There was no significant correlations between stroke volume and levels of cytokine and acute-phase reactants in dead patient group or in living patient group. A correlation and statistical significance was found between stroke volume and hospital stay time in living patient group. In addition, GCS and NIHSS scores were correlated with stroke volume and was found a significant statistically. CONCLUSIONS: Scales such as GKS and NIHHS, which evaluate the functional state of patients, are the best indicators for defining prognosis in our daily practices. In addition, we found a positive correlation between levels of CRP (C reactive protein) and prognosis. However, we did not observe a statistically significant correlation between prognosis and other acute-phase reactants such as TNF-alpha, IL-6, IL-8, IL-10, fibrinogen, and leukocytes. PMID- 24174360 TI - The pure effects of obstructive sleep apnea syndrome on cardiac autonomic functions: heart rate turbulence analysis. AB - OBJECTIVES: To demonstrate the pure effect of obstructive sleep apnea syndrome (OSAS) on cardiac autonomic function (CAF) using heart rate turbulence (HRT) parameters. PATIENTS AND METHODS: A total of 64 patients with OSAS and 30 age- and gender-matched healthy subjects were enrolled. All subjects had normal coronary arteries and were free from diabetes mellitus (DM) and hypertension (HT). The HRT parameters (TO, turbulence onset; TS, turbulence slope) were obtained from 24-h ambulatory electrocardiogram (ECG) recordings. HRT parameters were compared between groups, and the relationship between HRT and the apnea hypopnea index (AHI) was examined. RESULTS: No between-group differences were found in age or gender. Mean TO was significantly higher in the OSAS group than in healthy controls (0.89 +/- 0.5, -0.08 +/- 0.26; p < 0.001; respectively). The mean TS did not differ between the two groups (2.81 +/- 3.06 versus 3.14 +/- 2.33; p = 0.212). The AHI was positively correlated with TO (r = 0.845, p < 0.001). The multiple logistic regression analysis revealed that after adjustment for other variables, TO was a significant and independent predictor of AHI, OR 2.394 (95% CI: 1.596-3.591). CONCLUSIONS: HRT (TO in particular) is correlated with AHI. Thus, impaired HRT may be an important factor underlying the occurrence of arrhythmia and sudden cardiac death in patients with OSAS. PMID- 24174361 TI - Screening and further analyzing differentially expressed genes in acute idiopathic pulmonary fibrosis with DNA microarray. AB - BACKGROUND: Acute idiopathic pulmonary fibrosis (IPF) is a serious and progressive form of lung disease, and millions of people suffer from this disease in the world. To provide clues for getting a better understanding of the mechanism of this disease, we identified and further analyzed the differential expressed genes in IPF. METHOD: In this study, we downloaded the gene expression microarray (GSE10667) from Gene Expression Omnibus (GEO) database. The dataset contained a total of 23 samples, including 15 normal controls and 8 diseases samples (IPF). Then, we identified the differentially expressed genes between normal and disease samples with packages in R language. Consequently, the PPI network was also constructed for the products of these DEGs, and modules in the network were analyzed by Cytoscape's plug-in Mcode and Bingo. Furthermore, enrichment analysis was performed by DAVID to illustrate the altered pathways in IPF. The drug compounds for PLK1 were screened in DrugBank. RESULTS: Atotal of 349 genes were identified as differentially expressed genes between normal and disease samples, and we constructed a protein-protein interaction network which included 200 pairs of proteins. Then three modules were identified in our network. Function of these modules were predicted to be related to protein kinase binding, extracellular matrix structural and structural constituent of cytoskeleton, respectively. Finally, we focused on module A including 18 DEGs. CONCLUSIONS: PLK1 (Polo like kinge-1) in this module was predicted as a marker gene in IPF, which was related to cell cycle pathway. Several compounds were found which may be the potential drug for IPF. PMID- 24174362 TI - The estimation of glomerular filtration rate in type 2 diabetic patients may depend on the equation used. AB - BACKGROUND: The aim of this study was to compare the estimation of glomerular filtration rate (GFR) in type 2 diabetes mellitus (DM) outpatients. PATIENTS AND METHODS: The study included 1686 subjects, aged 68+/-10 years. GFR was evaluated with five different equations: GFRMDRD186, GFRMDRD175, GFRCKD-EPI, GFRMAYO, GFRC G. RESULTS: GFR was lower than 60 ml min-1 kg-1 in 456 patients (27%) by GFRMDRD186, in 531 (31.5%) by GFRMDRD175, in 504 (30%) by GFRCKD-EPI, in 433 (26%) by GFRC-G, and in 255 (15%) by GFRMAYO. The mean differences in measuring GFR with the different formulae ranged from 1.03+/-6.20 to -14.5+/-11.9 ml min-1 1.73 m2-1. CONCLUSIONS: The evaluation of GFR with different formulae in type 2 DM patients may identify different chronic kidney disease (CKD) stages. Physicians could take advantage by the knowledge of the formula used for evaluation of renal function, for a better interpretation of values and a more appropriate use in the everyday clinical practice. PMID- 24174363 TI - Genome wide gene expression analysis of macrophages from ankylosing spondylitis patients under interferon-gamma treatment. AB - BACKGROUND: Ankylosing spondylitis (AS) is a common and highly heritable arthropathy, but the pathogenesis of which is poorly understood, especially the mechanisms in genomics. AIM: Our work is aim to study the mechanisms of AS in genomics. MATERIALS AND METHODS: we used microarray dataset GSE11886 from Gene Expression Omnibus (GEO). According to our GSEA approach on the microarray datasets related to AS, we have identified the significantly associated pathways with this disease respectively dependent and independent to the factor of interferon-gamma (IFN-gamma). RESULTS: As a result, we have identified 9 most significant pathways in the comparison of AS patients to control under none treatment, including 5 up-regulated and 4 down-regulated pathways in IFN-gamma independent study. On the contrary, 11 most significantly up-regulated pathways such as renin-angiotensin system, O-Glycan biosynthesis and gap junction in the comparison of AS patients to control under the treatment of IFN in IFN-gamma dependent study. CONCLUSIONS: These may be helpful for understanding the mechanisms of AS regulation under interferon-gamma treatment in genome wide. PMID- 24174364 TI - Analysis report for osteosarcoma expression profile. AB - BACKGROUND: Osteosarcoma is a kind of highly malignant primary bone tumor which most common in the teenage, and holds strong aggressive, earlier organs metastases mainly to lung, prone to postoperative recur. Therefore for osteosarcoma, invasion and transfer mechanism and related factors' interaction remains to be a key research subject. AIM: We aim to find biological molecules marker can be used for osteosarcoma diagnosis through contrast of osteosarcoma sample and normal tissue samples. MATERIALS AND METHODS: This analysis using human osteosarcoma expression profile data and three lesions normal tissue samples (liver, kidneys, lymph) expression data and compare them, and find significant specifically expressed genes, according to their function. RESULTS: Research shows that the cancer cell proliferation, invasion, transfer and recurrent process involve many factors interaction, of which angiogenesis is the necessary condition of tumor growth, transfer and the recurrence. CONCLUSIONS: Now the most important positive regulatory factor of angiogenesis is VEGF (vascular endothelial growth factor) and bFGF (basic fibroblast growth factor). Both of them are with a wide variety and close relationship of tumor angiogenesis and progress. PMID- 24174365 TI - Relation of -55CT polymorphism of UCP3 gene with weight loss and metabolic changes after a high monounsaturated fat diet in obese non diabetic patients. AB - AIMS: The aim of our study was to investigate the influence of -55CT polymorphism of UCP3 gene on metabolic response, weight loss and serum adipokine levels to a high monounsaturated fat hypocaloric diet in obese patients. PATIENTS AND METHODS: A sample of 128 obese patients was analyzed in a prospective way during 3 months. RESULTS: Eighty eight patients (21 males/67 females) (68.8%) had the genotype 55CC (wild genotype group) and 40 patients (8 males/32 females) (31.3%) 55CT (mutant genotype group). In wild genotype group, BMI (-1.6+/-1.3 kg/m2), weight (-4.3+/-3.7 kg), fat mass (-3.5+/-3.3 kg), waist circumference (-5.1+/-2.9 cm), total cholesterol (-7.2+/-10.6 mg/dl), LDL cholesterol (-5.3+/-12.8 mg/dl) and leptin (-4.7+/-10.1 ng/ml) decreased. In mutant genotype group, BMI (1.3+/ 2.2 kg/m2), weight (-3.0+/-1.4 kg), fat mass (-2.5+/-1.1 kg), waist circumference (-2.8+/-3.1 cm) and leptin (-5.8+/-10.7 decreased. CONCLUSIONS: In patients with 55CC UCP3 genotype, a high mono-unsaturated hypocaloric diet reduced BMI, weight, waist circumference, waist to hip ratio, fat mass, LDL-cholesterol, total cholesterol and leptin levels. Carriers of T allele had a different response than -55CC patients, with a significant decrease of the same antropometric parameters, but lower than in the wild genotype group, and without significant changes in cholesterol levels. PMID- 24174366 TI - Resting energy expenditure and gut microbiota in obese and normal weight subjects. AB - OBJECTIVES: It is suggested that gut microbiota play a role in the pathogenesis of obesity enhancing energy utilization from digested food. The influence of gut microbiota on resting energy expenditure (REE) has not been evaluated yet. AIM: The aim of the study is to assess the composition on gut microbiota and its association with REE in obese and normal weight subjects. SUBJECTS AND METHODS: REE measurement and semi-quantitative analysis of gut microbiota composition in aerobic and anaerobic conditions were performed in 50 obese and 30 normal weight subjects without concomitant diseases. RESULTS: A count of bacterial colony was greater in obese than in normal weight subjects. However, the proportion of Bacteroides spp. and Firmicutes was similar in both study groups. A positive correlation between REE (kcal/d) and total bacterial count (r = 0.26, p < 0.05), as well as between REE and the percentage of Firmicutes (r = -0.24, p < 0.05) was found. The multiple regression analysis did not prove an independent impact of total bacterial as well as Bacteroides spp. and Firmicutes counts on REE. CONCLUSIONS: The composition of gut microbiota is not associated with the level of resting energy expenditure. The proportion of Bacteroides and Firmicutes in gut microbiota is not related to body mass. PMID- 24174367 TI - Prophylactic arterial catheterization in the management of high risk patients for obstetric haemorrhage. AB - OBJECTIVES: Post-partum haemorrhage still remains one of the major causes of maternal morbidity and mortality. In case of abnormal placentation it is possible to carry out preventive and therapeutic actions. To maintain fertility in reproductive-aged women and to avoid a more radical surgery, embolization has been introduced in patients at high risk for haemorrhage. To describe a new option in the management of patients with abnormal placentation by an elective, preventive arterial catheterization and selective embolization of pelvic arteries. PATIENTS AND METHODS: A retrospective study including thirty six patients with abnormal placental invasion. All patients were prepared in the angiographic room and preventive arterial catheterization was performed before elective caesarean delivery. Materials for interventional angiography were transferred to the operating room. During surgery, selective embolization of pelvic arteries was realized in case of uncontrolled bleeding. RESULTS: Thirty six elective arterial catheterizations were performed: 4 cases (11.1%) required embolization, haemorrhage was stopped in 2 patients. Hysterectomy was performed in two cases (5.5%). No death was reported. Two humeral thrombosis (5.5%) were registered. CONCLUSIONS: Prophylactic arterial catheterization appears to be safe. The main advantage is the reduction of the interval between the onset of bleeding and the embolization. This new option of management may contribute to reduce the risk of hysterectomy and maternal death. PMID- 24174368 TI - A retrospective analysis of short and long term efficacy of RBL for hemorrhoids. AB - AIMS: Rubber band ligation is an effective treatment for hemorrhoids. A retrospective analysis was performed to evaluate its short and long-term efficacy. PATIENTS AND METHODS: From 2000 to 2008, 254 outpatients with II- degree and 114 with III-degree hemorrhoids underwent rubber band ligation. Two or three hemorrhoids were ligated per session. Each haemorrhoid was ligated with two rubber bands through a ligator. All patients were visited after two months and followed up through a telephone after two and eleven years. RESULTS: Twenty-four or forty-eight hours post treatment, 41% of patients had mild-moderate pain. Four patients showed severe pain and required for haemorrhoidectomy within a few days. Only 2% of patients experienced self-limiting rectal bleeding after one week and 6% of patients had an additional ligation within two months. Two months later, 92% of II-degree patients and 76% of III-degree patients showed no residual symptoms. After two and eleven years, the history of 314 patients (85%) were obtained, of them, 70% was asymptomatic, 27% had some residual symptoms of occasional bleeding and prolapse, and 3% needed further surgery. CONCLUSIONS: Rubber band ligation is an efficient, cost-effective and simple outpatient procedure for the second and third degree hemorrhoids with minimal complications. PMID- 24174369 TI - Development of psoriasis scalp with alopecia during treatment of Crohn's disease with infliximab and rapid response to both diseases to ustekinumab. AB - Anti tumor necrosis factor antibodies are used to treat both psoriasis and inflammatory bowel disease. Several paradoxical cases of psoriatic skin lesions induced by tumor necrosis factor antagonist therapy have been described in IBD patients in the recent years. Ustekinumab, a fully human anti-interleukin-12/-23 monoclonal antibody, is the first drug of a new class of biologic therapy approved for the treatment of moderate to severe plaque psoriasis. Data on the efficacy of ustekinumab in patients with moderate-to-severe Crohn's disease, especially in patients previously treated with infliximab, have been recently published. We report about the effectiveness of ustekinumab in the treatment of both severe scalp psoriasis lesions with alopecia and active Crohn's disease. PMID- 24174370 TI - Differential sensitivities to lactate transport inhibitors of breast cancer cell lines. AB - The tumour microenvironment is known to be acidic due to high glycolytic rates of tumour cells. Monocarboxylate transporters (MCTs) play a role in extracellular acidification, which is widely known to be involved in tumour progression. Recently, we have described the upregulation of MCT1 in breast carcinomas and its association with poor prognostic variables. Thus, we aimed to evaluate the effect of lactate transport inhibition in human breast cancer cell lines. The effects of alpha-cyano-4-hydroxycinnamate, quercetin and lonidamine on cell viability, metabolism, proliferation, apoptosis, migration and invasion were assessed in a panel of different breast cancer cell lines. MCT1, MCT4 and CD147 were differently expressed among the breast cancer cell lines and, as expected, different sensitivities were observed for the three inhibitors. Interestingly, in the most sensitive cell lines, lactate transport inhibition induced a decrease in cell proliferation, migration and invasion, as well as an increase in cell death. Results were validated by silencing MCT1 expression using siRNA. The results obtained here support targeting of lactate transport as a strategy to treat breast cancer, with a special emphasis on the basal-like subtype, which so far does not have a specific molecular therapy. PMID- 24174372 TI - Enantioselective bioaccumulation and dissipation of soil-associated metalaxyl enantiomers in tubifex. AB - Many pesticides are chiral compounds and stereochemistry is an important factor for any reaction of chiral structures in biological systems. In this study, experiment about bioaccumulation of the two metalaxyl enantiomers in Tubifex (Oligochaeta, Tubificida) was conducted in laboratory aquatic ecosystems. Terrestrial soil spiked with two dose levels of metalaxyl was employed as the artificial bottom substrate. A method of determination of metalaxyl enantiomers in tubifex tissue, soil and overlying water were developed by HPLC. During a 14 day exposure, concentrations of metalaxyl in tubifex increased with the of soil concentration, however, the enantioselective bioaccumulation was only detected at high-dose exposure group, with the preferential accumulation of (-)-(R) metalaxyl. The bioturbation activity of tubifex decreased water clarity and released soil-associated metalaxyl to overlying water. In those experiments where tubifex was exposed to metalaxyl from soil, pore water and overlying water, each route contributed to the total body burden, and our results indicated the pore water and soil are the primary exposure routes for high-dose exposure concentration treatment. PMID- 24174371 TI - Src-dependent Tks5 phosphorylation regulates invadopodia-associated invasion in prostate cancer cells. AB - BACKGROUND: The Src tyrosine kinase substrate and adaptor protein Tks5 had previously been implicated in the invasive phenotype of normal and transformed cell types via regulation of cytoskeletal structures called podosomes/invadopodia. The role of Src-Tks5 signaling in invasive prostate cancer, however, had not been previously evaluated. METHODS: We measured the relative expression of Tks5 in normal (n = 20) and cancerous (n = 184, from 92 patients) prostate tissue specimens by immunohistochemistry using a commercially available tumor microarray. We also manipulated the expression and activity of wild-type and mutant Src and Tks5 constructs in the LNCaP and PC-3 prostate cancer cell lines in order to ascertain the role of Src-Tks5 signaling in invadopodia development, matrix-remodeling activity, motility, and invasion. RESULTS: Our studies demonstrated that Src was activated and Tks5 upregulated in high Gleason score prostate tumor specimens and in invasive prostate cancer cell lines. Remarkably, overexpression of Tks5 in LNCaP cells was sufficient to induce invadopodia formation and associated matrix degradation. This Tks5-dependent increase in invasive behavior further depended on Src tyrosine kinase activity and the phosphorylation of Tks5 at tyrosine residues 557 and 619. In PC-3 cells we demonstrated that Tks5 phosphorylation at these sites was necessary and sufficient for invadopodia-associated matrix degradation and invasion. CONCLUSIONS: Our results suggest a general role for Src-Tks5 signaling in prostate tumor progression and the utility of Tks5 as a marker protein for the staging of this disease. PMID- 24174373 TI - The validation of estrogen receptor 1 mRNA expression as a predictor of outcome in patients with metastatic non-small cell lung cancer. AB - The prognostic role of estrogen receptors in lung cancer is not validated. Results from patients with early stage non-small lung cancer patients indicate a prognostic role of estrogen receptor 1 (ESR1) mRNA expression in these patients. Automated RNA extraction from paraffin and RT-quantitative PCR was used for evaluation of tumoral ESR1 and progesterone receptor (PGR) mRNA expression. The test cohort consisted of 31 patients with advanced or metastatic non-small cell lung cancer (NSCLC) patients, treated in a first-line registry trial. For validation, 53 patients from a randomized multicentre first-line study with eligible tumor samples were evaluated. There was no significant correlation of ESR1 expression with clinical characteristics. ESR1 high expression was of significant positive prognostic value in the training set with a median overall survival (OS) of 15.9 versus 6.2 months for high versus low ESR1 expression patients (p = 0.0498, HR 0.39). This could be confirmed in the validation cohort with a median OS of 10.9 versus 5.0 months in ESR1 high versus low patients, respectively (p = 0.0321, HR 0.51). In the multivariate analysis adjusted for histological subtype, gender, age and performance status, ESR1 expression remained an independent prognostic parameter for survival in both cohorts. In contrast to ESR1, PGR expression was not able to separate prognostic groups or to predict outcome significantly (for OS; p = 0.94). Our study shows that ESR1 mRNA as assessed by qPCR represents a reliable method for detecting ESR1 expression in NSCLC and that ESR1 expression is an independent prognostic factor in metastatic NSCLC. PMID- 24174374 TI - Regulation of polyunsaturated fatty acid biosynthesis by seaweed fucoxanthin and its metabolite in cultured hepatocytes. AB - The effects of a seaweed carotenoid, fucoxanthin, and its physiological metabolite, fucoxanthinol, on the biosynthesis of polyunsaturated fatty acids (PUFA) were investigated using cultured rat hepatoma BRL-3A. The metabolism of alpha-linolenic acid (18:3n-3) was suppressed by the addition of these carotenoids, resulting in a decrease in the content of eicosapentaenoic acid (20:5n-3), which suggested a down-regulation of metabolic enzymes such as fatty acid desaturase and elongase. An increase in the content of docosahexaenoic acid (22:6n-3), as observed in previous studies in vivo, might be a buffering action to maintain the membrane fluidity. The suppressive effect of fucoxanthinol on ?6 fatty acid desaturase was not at the level of gene expression but due to specific modifications of the protein via a ubiquitin-proteasome system. A proteomic analysis revealed several factors such as phosphatidylethanolamine-binding protein that might be involved in the observed action of fucoxanthin. These findings will contribute to studies on the elucidation of the precise molecular mechanisms underlying the regulation of PUFA biosynthesis by fucoxanthin. PMID- 24174375 TI - Combined and alternating paracetamol and ibuprofen therapy for febrile children. AB - BACKGROUND: Health professionals frequently recommend fever treatment regimens for children that either combine paracetamol and ibuprofen or alternate them. However, there is uncertainty about whether these regimens are better than the use of single agents, and about the adverse effect profile of combination regimens. OBJECTIVES: To assess the effects and side effects of combining paracetamol and ibuprofen, or alternating them on consecutive treatments, compared with monotherapy for treating fever in children. SEARCH METHODS: In September 2013, we searched Cochrane Infectious Diseases Group Specialized Register; Cochrane Central Register of Controlled Trials (CENTRAL); MEDLINE; EMBASE; LILACS; and International Pharmaceutical Abstracts (2009-2011). SELECTION CRITERIA: We included randomized controlled trials comparing alternating or combined paracetamol and ibuprofen regimens with monotherapy in children with fever. DATA COLLECTION AND ANALYSIS: One review author and two assistants independently screened the searches and applied inclusion criteria. Two authors assessed risk of bias and graded the evidence independently. We conducted separate analyses for different comparison groups (combined therapy versus monotherapy, alternating therapy versus monotherapy, combined therapy versus alternating therapy). MAIN RESULTS: Six studies, enrolling 915 participants, are included.Compared to giving a single antipyretic alone, giving combined paracetamol and ibuprofen to febrile children can result in a lower mean temperature at one hour after treatment (MD -0.27 degrees Celsius, 95% CI -0.45 to -0.08, two trials, 163 participants, moderate quality evidence). If no further antipyretics are given, combined treatment probably also results in a lower mean temperature at four hours (MD -0.70 degrees Celsius, 95% CI -1.05 to -0.35, two trials, 196 participants, moderate quality evidence), and in fewer children remaining or becoming febrile for at least four hours after treatment (RR 0.08, 95% CI 0.02 to 0.42, two trials, 196 participants, moderate quality evidence). Only one trial assessed a measure of child discomfort (fever associated symptoms at 24 hours and 48 hours), but did not find a significant difference in this measure between the treatment regimens (one trial, 156 participants, evidence quality not graded).In practice, caregivers are often advised to initially give a single agent (paracetamol or ibuprofen), and then give a further dose of the alternative if the child's fever fails to resolve or recurs. Giving alternating treatment in this way may result in a lower mean temperature at one hour after the second dose (MD -0.60 degrees Celsius, 95% CI -0.94 to -0.26, two trials, 78 participants, low quality evidence), and may also result in fewer children remaining or becoming febrile for up to three hours after it is given (RR 0.25, 95% CI 0.11 to 0.55, two trials, 109 participants, low quality evidence). One trial assessed child discomfort (mean pain scores at 24, 48 and 72 hours), finding that these mean scores were lower, with alternating therapy, despite fewer doses of antipyretic being given overall (one trial, 480 participants, low quality evidence)Only one small trial compared alternating therapy with combined therapy. No statistically significant differences were seen in mean temperature, or the number of febrile children at one, four or six hours (one trial, 40 participants, very low quality evidence).There were no serious adverse events in the trials that were directly attributed to the medications used. AUTHORS' CONCLUSIONS: There is some evidence that both alternating and combined antipyretic therapy may be more effective at reducing temperatures than monotherapy alone. However, the evidence for improvements in measures of child discomfort remains inconclusive. There is insufficient evidence to know which of combined or alternating therapy might be more beneficial.Future research needs to measure child discomfort using standardized tools, and assess the safety of combined and alternating antipyretic therapy. PMID- 24174376 TI - Trends in incidence of primary cutaneous malignancies in children, adolescents, and young adults: a population-based study. AB - BACKGROUND: Skin cancer incidence among young adults is rising; however, the epidemiological characteristics of primary cutaneous lymphomas and cutaneous soft tissue sarcomas (CSTS) in individuals <30 years old has not been investigated. We analyzed the incidence and time-trends of primary cutaneous malignancies in children and adolescents/young adults (AYA). PROCEDURE: SEER-17 and -13 data were used to assess the descriptive epidemiology and time-trends in incidence of primary cutaneous malignancies in children and AYA. SEERStat and Joinpoint softwares were utilized to estimate annual percent changes (APC) in incidence. RESULTS: In total, 7,814 cases (ASR = 25.66/1,000,000 habitants) of primary skin cancers in <30 years old were diagnosed in 2000-2008. Females had a higher incidence of melanoma (risk ratio (RR) = 1.95; P < 0.001) and a lower risk of developing CSTS (RR = 0.64, P < 0.001). Compared to whites, blacks have a lower incidence of melanoma (RR = 0.03, P < 0.001), and higher risk of CSTS (RR = 2.28, P < 0.001). Melanoma increased in females over a 15-year period (1992-2006) (APC = 2.5, 95%CI = 1.8; 3.2), and the incidence of cutaneous T-cell lymphomas increased over the period 1992-2008 (APC = 9.5, 95% CI = 6.7; 12.4). CSTS incidence decreased among males over the period 1992-1999 (APC = -21.4, 95% CI 27.2; -15.1), particularly due to a decrease in Kaposi sarcoma incidence (AAPC 1992-2008 = -13.6, 95% CI = -22.4;-3.8), although with a notable racial disparity (whites, AAPC = -15.2, 95% CI = -23.2;-6.4; blacks, AAPC = -10.6, 95% CI = -13.2; 7.9). CONCLUSIONS: Non-melanoma skin cancer is very rare in children and AYA. We have shown variation in time-trends in incidence as well as in incidence patterns by race, sex, age, and histologic type, highlighting the importance of descriptive epidemiology to better understand the characteristics of these malignancies. PMID- 24174377 TI - Regulating angiogenesis with light-inducible AntimiRs. AB - The inhibition of microRNAs (miRs) in a spatiotemporally defined manner by an exogenous trigger would help to specifically target the biological activity and avoid off-target effects. Novel antimiRs directed against miR-92a can be activated by irradiation (see scheme; 3'-UTR=3'-untranslated region) In this way miR-92a is inhibited, the miR-92a target integrin alpha5 is derepressed, and angiogenesis of endothelial cells is enhanced. PMID- 24174378 TI - Advanced generation anti-prostate specific membrane antigen designer T cells for prostate cancer immunotherapy. AB - BACKGROUND: Adoptive immunotherapy by infusion of designer T cells (dTc) engineered with chimeric antigen receptors (CARs) for tumoricidal activity represents a potentially highly specific modality for the treatment of cancer. In this study, 2nd generation (gen) anti-prostate specific membrane antigen (PSMA) dTc were developed for improving the efficacy of previously developed 1st gen dTc for prostate cancer immunotherapy. The 1st gen dTc are modified with chimeric immunoglobulin-T cell receptor (IgTCR) while the 2nd gen dTc are engineered with an immunoglobulin-CD28-T cell receptor (IgCD28TCR), which incorporates a CD28 costimulatory signal for optimal T cell activation. METHODS: A 2nd gen anti-PSMA IgCD28TCR CAR was constructed by inserting the CD28 signal domain into the 1st gen CAR. 1st and 2nd gen anti-PSMA dTc were created by transducing human T cells with anti-PSMA CARs and their antitumor efficacy was compared for specific activation on PSMA-expressing tumor contact, cytotoxicity against PSMA-expressing tumor cells in vitro, and suppression of tumor growth in an animal model. RESULTS: The 2nd gen dTc can be optimally activated to secrete larger amounts of cytokines such as IL2 and IFNgamma than 1st gen and to proliferate more vigorously on PSMA-expressing tumor contact. More importantly, the 2nd gen dTc preserve the PSMA-specific cytotoxicity in vitro and suppress tumor growth in animal models with significant higher potency. CONCLUSIONS: Our results demonstrate that 2nd gen anti-PSMA designer T cells exhibit superior antitumor functions versus 1st gen, providing a rationale for advancing this improved agent toward clinical application in prostate cancer immunotherapy. PMID- 24174379 TI - Integrated polymer solar cell and electrochemical supercapacitor in a flexible and stable fiber format. AB - An all-solid-state, coaxial and self-powered "energy fiber" is demonstrated that simultaneously converts solar energy to electric energy and further stores it. The "energy fiber" is flexible and can be scaled up for the practical application by the well-developed textile technology, and may open a new avenue to future photoelectronics and electronics. PMID- 24174380 TI - Efficacy and safety of artificial pneumothorax under two-lung ventilation in thoracoscopic esophagectomy for esophageal cancer in the prone position. AB - BACKGROUND: Thoracoscopic esophagectomy for esophageal cancer performed using two lung ventilation in the prone position has many advantages, such as convenient anesthesia induction and maintenance, and good oxygenation. We examined the safety of surgery and anesthetic management by following chronological changes in intraoperative respiration and hemodynamics. METHODS: We focused on the most recent and consecutive 14 cases of thoracoscopic esophagectomy for esophageal cancer in the prone position performed from November 2010 until recently. We measured the following items by use of FloTrac system : cardiac index (CI), central venous pressure (CVP), mean arterial pressure, partial pressure of oxygen in arterial blood (PaO2), partial pressure of carbon dioxide in arterial blood (PaCO2), peak airway pressure (APmax), and tidal volume. RESULTS: No major changes were observed in CI, systolic blood pressure, and TV after the start of pneumothorax (statically not significant). Conversely, CVP increased immediately after pneumothorax (p < 0.05) and decreased almost to its original level thereafter. The mean APmax value was 18-20 cm H2O [mean increase, 4.2 cm H2O; (p < 0.05)]. The mean P/F ratio and mean PaCO2 were 244.4 and 48.3 mmHg, respectively, during artificial pneumothorax. CONCLUSION: No excessive increases in airway pressure or clear circulatory depressions were observed because of artificial pneumothorax under two-lung ventilation in thoracoscopic esophagectomy for esophageal cancer in the prone position. These results suggest that artificial pneumothorax under two-lung ventilation is beneficial for maintaining stable hemodynamics and oxygenation in thoracoscopic esophagectomy in prone position. PMID- 24174381 TI - The bright future for total ankle replacements. AB - Total ankle arthroplasty is an evolving method of treatment for end-stage ankle arthritis. Although historic interest did not yield favorable results, new generation total ankle implants have demonstrated comparable results with fusion with short- and intermediate-term follow-up. Comparable outcomes, in the setting of improving surgical technique and implant options, will yield increasingly superior results. PMID- 24174382 TI - Intrauterine insemination versus fallopian tube sperm perfusion for non-tubal infertility. AB - BACKGROUND: Intrauterine insemination (IUI) is a common treatment for couples with subfertility that does not involve the fallopian tubes. It is used to bring the sperm close to the released oocyte. Another method of introducing sperm is fallopian tube sperm perfusion (FSP). Fallopian tube sperm perfusion ensures the presence of higher sperm densities in the fallopian tubes at the time of ovulation than does standard IUI. These treatments are often used in combination with ovarian hyperstimulation. OBJECTIVES: To compare intrauterine insemination versus fallopian tube sperm perfusion in the treatment of non-tubal subfertility, for live birth and pregnancy outcomes. SEARCH METHODS: We searched the Menstrual Disorders and Subfertility Group Trials Register, MEDLINE, CINAHL and EMBASE from inception to September 2013. We also searched study reference lists and trial registers. SELECTION CRITERIA: Randomised controlled trials (RCTs) comparing IUI with FSP in couples with non-tubal subfertility were included. DATA COLLECTION AND ANALYSIS: Two review authors independently selected studies for inclusion, assessed study quality and extracted the data. If studies were sufficiently similar, data were combined using a fixed-effect model to calculate pooled odds ratios (ORs) and 95% confidence intervals (CIs). A random-effects model was used if substantial statistical heterogeneity was detected. Studies that included participants with unexplained or mixed (non-tubal) subfertility were analysed separately from studies restricted to participants with mild or moderate male factor subfertility. The overall quality of evidence for the main outcomes was summarised using Grading of Recommendations Assessment, Development and Evaluation (GRADE) criteria. MAIN RESULTS: The review included 16 RCTs. Fourteen RCTs (1745 women) were included in the meta-analysis. Only three studies reported live birth per couple. No evidence of a statistically significant difference was noted between IUI and FSP in live birth (OR 0.94, 95% CI 0.59 to 1.49, three RCTs, 633 women, I(2) = 0%, low-quality evidence) or clinical pregnancy (OR 0.75, 95% CI 0.49 to 1.12, 14 RCTs, 1745 women, I(2) = 52%, low-quality evidence). These findings suggest that for a couple with a 13% chance of live birth using FSP, the chance when using IUI will be between 8% and 19%; and that for a couple with a 19% chance of pregnancy using FSP, the chance of pregnancy when using IUI will be between 10% and 20%. Nor was evidence found of a statistically significant difference between IUI and FSP in per-pregnancy of multiple pregnancy (OR 0.96, 95% CI 0.44 to 2.07, eight RCTs, 197 women, I(2) = 0%, low-quality evidence), miscarriage (OR 1.23, 95% CI 0.60 to 2.53, seven RCTs, 199 women, I(2) = 0%, low-quality evidence) or ectopic pregnancy (OR 1.71, 95% CI 0.42 to 6.88, four RCTs, 111 women, I(2) = 0%, very low quality evidence). Substantial heterogeneity was noted for the outcome of clinical pregnancy (I(2) = 54%), for which no clear explanation was provided. AUTHORS' CONCLUSIONS: Currently no clear evidence suggests any difference between IUI and FSP with respect to their effectiveness and safety for treating couples with non-tubal subfertility. However, a high level of uncertainty is evident in the findings, and additional research may be useful. PMID- 24174383 TI - Pushing tumor cells towards a malignant phenotype: stimuli from the microenvironment, intercellular communications and alternative roads. AB - The tumor microenvironment produces different types of stimuli capable of endowing tumor cells with an aggressive behavior that is characterized by increased motility, invasiveness and propensity to metastasize, gain of a tumor initiating phenotype, and drug resistance. The following classes of stimuli have been reported to promote such a malignant phenotype: (i) solid- or fluid-induced stress; (ii) altered composition of the extracellular matrix; (iii) hypoxia and low pH; (iv) innate and adaptive immune responses; (v) antitumor drugs. The simultaneous presence of more than one of these stimuli, as likely occurs in vivo, may lead to synergistic interactions in the induction of malignant traits. In many cases, the gain of a malignant phenotype is not the result of a direct effect of the stimuli on tumor cells but, rather, a stimulus-promoted cross-talk between tumor cells and other cell types within the tumor microenvironment. This cross-talk is mainly mediated by two classes of molecules: paracrine factors and adhesion receptors. Stimuli that promote a malignant phenotype can promote additional outcomes in tumor cells, including autophagy and cell death. We summarize here the available evidence about the variables that induce tumor cells to take one or the other of these roads in response to the same stimuli. At the end of this review, we address some unanswered questions in this domain and indicate future directions of research. PMID- 24174384 TI - Active mixed-valent MnO(x) water oxidation catalysts through partial oxidation (corrosion) of nanostructured MnO particles. PMID- 24174385 TI - Alternative approaches to outcomes assessment: beyond psychometric tests. AB - Outcomes assessments in clinical trials involving cognition and behavior rely upon IQ and neuropsychological assessments. These procedures provide limited evaluations of everyday functions. Some participants cannot perform cognitive tasks because they are low functioning or may represent missing data because of inability to travel. Interview-based assessments of adaptive behavior yield results that reflect everyday functions and can be done by telephone regardless of level of cognitive functioning. The design of the neurobehavioral component of the follow-up study for the management of myelomeningocele fetal surgery trial is as an example of a clinical trial that incorporates these alternatives. PMID- 24174386 TI - Charge transport over multiple length scales in supramolecular fiber transistors: single fiber versus ensemble performance. AB - Self-assembled organic fibers combine facile solution processing with the performance benefits of single crystals. Here, the first evidence is shown of band-like transport in an n-type solution-processed small molecule system, a limited role of shallow traps, and a single fiber electron mobility that is several orders of magnitude higher than that measured in fiber ensembles or spin cast films. PMID- 24174387 TI - Glial cell line-derived neurotrophic factor sensitized the mechanical response of muscular thin-fibre afferents in rats. AB - BACKGROUND: The role of glial cell line-derived neurotrophic factor (GDNF) in pain and muscular nociceptor activities is not well understood. We examined pain related behaviour and mechanical response of muscular thin-fibre afferents after intramuscular injection of GDNF in rats. METHODS: GDNF and antagonist to transient receptor potential V1 or acid-sensing ion channels were injected into rat gastrocnemius muscle and muscular mechanical hyperalgesia was assessed with a Randall-Selitto analgesiometer. Activities of single C- (conduction velocity < 2.0 m/s) and Adelta-fibres (conduction velocity 2.0-12.0 m/s) were recorded from extensor digitorum longus muscle-nerve preparations in vitro. The changes in the responses to mechanical stimuli before and after GDNF injection were recorded. RESULTS: Mechanical hyperalgesia was observed from 1 h to 1 day after GDNF (0.03 MUM, 20 MUL) injection. The decreased withdrawal threshold was temporarily reversed after intramuscular injection of amiloride (50 mM, 20 MUL), but not capsazepine (50 MUM, 20 MUL). In single-fibre recordings, both phosphate buffered saline (PBS) and GDNF failed to induce any significant discharges. GDNF significantly enhanced the mechanical response when compared with the PBS group, but only in Adelta-fibre afferents. C-fibres were not affected. Significantly lowered threshold and increased response magnitude to mechanical stimuli were observed 30 or 60-120 min after injection. These times are compatible with the timing of the onset of the hyperalgesic effect of GDNF. CONCLUSIONS: These results suggest that GDNF increased the response of muscular Adelta-fibre afferents to mechanical stimuli, resulting in muscular mechanical hyperalgesia. PMID- 24174388 TI - Effects of a year-long pedometer-based walking program on cardiovascular disease risk factors in active older people. AB - We assessed the relationship between the number of daily steps and changes in cardiovascular disease (CVD) risk factors in a year-long pedometer-based walking program for physically active older people. A total of 36 physically active older people (68.3 +/- 5.8 years) completed this 59-week program. The CVD risk parameters were measured at baseline and at weeks 21 and 59. The mean number of steps increased by week 21 and was maintained at week 59 (approximately 10 000 steps, increase in 1500 steps from the baseline; P < .05). Following a significant reduction in body mass index at week 21, systolic blood pressure levels were significantly reduced, and high-density lipoprotein cholesterol levels were significantly increased at week 59 (P < .05). In summary, even active older people can achieve further protection against CVD risks by minor, but sustained, physical activity using pedometers for a period of more than 1 year. PMID- 24174389 TI - Effectiveness of community participation in a surveillance system initiative to prevent drowning in Thailand. AB - This study had a 2-group pre-post quasiexperimental design and was conducted in 2 selected areas of Ubon Ratchathani province, Thailand. The objective was to evaluate the extent to which the surveillance system that was developed helped in drowning prevention. The development process involved extensive participation from the community. System efficiency was evaluated, and the drowning rates were compared. The system demonstrated 82.8% system sensitivity and 87% positive predictive value. There were 90.0% rescues with no injury during the study period. The relative risk of drowning injury suggests that the control area was at 5.6 times more at risk for drowning injury than the intervention area (95% CI = 1.58, 20.12). Local knowledge and participation from the community were found to be key issues in the success of the surveillance system, and such systems can be applied to other areas with similar problems. PMID- 24174390 TI - Workplace stress, job satisfaction, job performance, and turnover intention of health care workers in rural Taiwan. AB - Workplace stress (WS) has been found to affect job satisfaction (JS), performance, and turnover intentions (TIs) in developed countries, but there is little evidence from other countries and especially rural areas. In rural Taiwan, especially, there is an insufficient health care workforce, and the situation is getting worse. To demonstrate the relationship, we used a cross-sectional structured questionnaire, and data from 344 licensed professionals in 1 rural regional hospital were analyzed using the structural equation model. The results showed that WS had a positive effect on both TI and job performance (JP) but a negative effect on satisfaction. JS did improve performance. For the staff with an external locus of control, stress affected JP and satisfaction significantly. For the staff with lower perceived job characteristics, JS affected performance significantly. The strategies to decrease stress relating to work load, role conflict, family factors, and working environment should be focused and implemented urgently to lower the turnover rate of health care workers in rural Taiwan. PMID- 24174391 TI - Does the experience of discrimination affect health? A cross-sectional study of Korean elders. AB - This study was conducted among 992 Koreans aged 60 to 89 to examine the effects of perceived discrimination on the health of an ethnically homogenous older population. Perceived discrimination was measured with a self-report instrument. Health outcomes included depressive symptoms, poor self-rated health, and chronic diseases. Of the elderly Koreans surveyed, 23.5% reported having experienced discrimination based on education, age, birthplace, birth order, or gender. Among women, 23.1% reported experiencing gender discrimination, compared to 0.9% among men. Men reported education and age discrimination most frequently-9.4% and 7.7%, respectively. Those who reported experiencing any discrimination were 2.19 times more likely to report depressive symptoms (95% confidence interval = 1.50-3.22) and 1.40 times more likely to report poor self-rated health (95% confidence interval = 1.02-1.93). The health effects of educational discrimination appeared most prominent. This study supports the positive associations between perceived discrimination and poorer health, particularly mental health, in later life. PMID- 24174393 TI - Evaluation of effects of busulfan and DMA on SOS in pediatric stem cell recipients. AB - BACKGROUND: Busulfan (Bu) is a DNA-alkylating agent used for myeloablative conditioning in stem cell transplantation in children and adults. While the use of intravenous rather than oral administration of Bu has reduced inter-individual variability in plasma levels, toxicity still occurs frequently after hematopoietic stem cell transplantation (HSCT). Toxicity (especially hepatotoxic effects) of intravenous (IV) Bu may be related to both Bu and/or N,N dimethylacetamide (DMA), the solvent of Bu. In this study, we assessed the relation between the exposure of Bu and DMA with regards to the clinical outcome in children from two cohorts. METHODS: In a two-centre study Bu and DMA AUC (area under the curve) were correlated in pediatric stem cell recipients to the risk of developing SOS and to the clinical outcome. RESULT: In patients receiving Bu four times per day Bu levels >1,500 umol/L minute correlate to an increased risk of developing a SOS. In the collective cohort, summarizing data of all 53 patients of this study, neither high area under the curve (AUC) of Bu nor high AUC of DMA appears to be an independent risk factor for the development of SOS in children. CONCLUSION: In this study neither Bu nor DMA was observed as an independent risk factor for the development of SOS. To identify subgroups (e.g., infants), in which Bu or DMA might be risk factors for the induction of SOS, larger cohorts have to be evaluated. PMID- 24174394 TI - Bio-inspired band gap engineering of zinc oxide by intracrystalline incorporation of amino acids. AB - Bandgap engineering of zinc oxide semiconductors can be achieved using a bio inspired method. During a bioInspired crystallization process, incorporation of amino acids into the crystal structure of ZnO induces lattice strain that leads to linear bandgap shifts. This allows for fine tuning of the bandgap in a bio inspired route. PMID- 24174395 TI - Readability and content of patient information leaflets for endoscopic procedures. AB - BACKGROUND: Informed consent requires good communication. Patient information leaflets (PILs) may be helpful, although some PILs are too hard to read for the average patient. AIMS: We sought to examine the readability of PILs provided for patients prior to endoscopic procedures in 24 gastrointestinal and 16 respiratory departments of 24 Irish public hospitals. METHODS: Readability, measured using the Flesch Reading Ease and the Flesch-Kincaid Grade Level scores, and content of all PILs were examined. RESULTS: We received 61 PILs from 17 gastrointestinal and 7 respiratory departments, a response rate of 60 % (24/40). Overall, 38 (62 %) PILs met a minimum standard of a Reading Ease score of 60 or more. Only two (3 %) PILs met the optimal reading standard of being comprehensible to an average 10- to 11-year-old, while 35 (57 %) PILs would be comprehensible to an average 13- to 14-year-old. There were striking differences between PILs (and particular departments) in the amount of information given regarding potential complications in particular, serious complications. With the exception of PILs for endoscopic retrograde cholangiopancreatography, less than half of PILs mentioned death as a possible rare outcome. CONCLUSIONS: This study raises significant concerns about the readability and content of current Irish PILs, and it is unlikely that these issues are restricted to leaflets given prior to endoscopy. A standardised approach to developing PILs for common elective procedures, with minimum standards for readability and a uniform approach, based on current Irish legal requirements, to risk disclosure, might be helpful. PMID- 24174396 TI - The faces of pain: a cluster analysis of individual differences in facial activity patterns of pain. AB - BACKGROUND: There is general agreement that facial activity during pain conveys pain-specific information but is nevertheless characterized by substantial inter individual differences. With the present study we aim to investigate whether these differences represent idiosyncratic variations or whether they can be clustered into distinct facial activity patterns. METHODS: Facial actions during heat pain were assessed in two samples of pain-free individuals (n = 128; n = 112) and were later analysed using the Facial Action Coding System. Hierarchical cluster analyses were used to look for combinations of single facial actions in episodes of pain. The stability/replicability of facial activity patterns was determined across samples as well as across different basic social situations. RESULTS: Cluster analyses revealed four distinct activity patterns during pain, which stably occurred across samples and situations: (I) narrowed eyes with furrowed brows and wrinkled nose; (II) opened mouth with narrowed eyes; (III) raised eyebrows; and (IV) furrowed brows with narrowed eyes. In addition, a considerable number of participants were facially completely unresponsive during pain induction (stoic cluster). These activity patterns seem to be reaction stereotypies in the majority of individuals (in nearly two-thirds), whereas a minority displayed varying clusters across situations. CONCLUSION: These findings suggest that there is no uniform set of facial actions but instead there are at least four different facial activity patterns occurring during pain that are composed of different configurations of facial actions. Raising awareness about these different 'faces of pain' might hold the potential of improving the detection and, thereby, the communication of pain. PMID- 24174397 TI - A trans-selective hydroboration of internal alkynes. PMID- 24174398 TI - Repeating blood cultures in neutropenic children with persistent fevers when the initial blood culture is negative. PMID- 24174399 TI - Modeling of pharmacokinetic systems using stochastic deconvolution. AB - In environments where complete mechanistic knowledge of the system dynamics is not available, a synergy of first-principle concepts, stochastic methods and statistical approaches can provide an efficient, accurate, and insightful strategy for model development. In this work, a system of ordinary differential equations describing system pharmacokinetics (PK) was coupled to a Wiener process for tracking the absorption rate coefficient, and was embedded in a nonlinear mixed effects population PK formalism. The procedure is referred to as "stochastic deconvolution" and it is proposed as a diagnostic tool to inform on a mapping function between the fraction of the drug absorbed and the fraction of the drug dissolved when applying one-stage methods to in vitro-in vivo correlation modeling. The goal of this work was to show that stochastic deconvolution can infer an a priori specified absorption profile given dense observational (simulated) data. The results demonstrate that the mathematical model is able to accurately reproduce the simulated data in scenarios where solution strategies for linear, time-invariant systems would assuredly fail. To this end, PK systems that are representative of Michaelis-Menten kinetics and enterohepatic circulation were investigated. Furthermore, the solution times are manageable using a modest computer hardware platform. PMID- 24174401 TI - A mechanistic understanding of processing additive-induced efficiency enhancement in bulk heterojunction organic solar cells. AB - The addition of processing additives is a widely used approach to increase power conversion efficiencies for many organic solar cells. We present how additives change the polymer conformation in the casting solution leading to a more intermixed phase-segregated network structure of the active layer which in turn results in a 5-fold enhancement in efficiency. PMID- 24174400 TI - High-throughput biophysical analysis of protein therapeutics to examine interrelationships between aggregate formation and conformational stability. AB - Stabilization and formulation of therapeutic proteins against physical instability, both structural alterations and aggregation, is particularly challenging not only due to each protein's unique physicochemical characteristics but also their susceptibility to the surrounding milieu (pH, ionic strength, excipients, etc.) as well as various environmental stresses (temperature, agitation, lyophilization, etc.). The use of high-throughput techniques can significantly aid in the evaluation of stabilizing solution conditions by permitting a more rapid evaluation of a large matrix of possible combinations. In this mini-review, we discuss both key physical degradation pathways observed for protein-based drugs and the utility of various high-throughput biophysical techniques to aid in protein formulation development to minimize their occurrence. We then focus on four illustrative case studies with therapeutic protein candidates of varying sizes, shapes and physicochemical properties to explore different analytical challenges in monitoring protein physical instability. These include an IgG2 monoclonal antibody, an albumin-fusion protein, a recombinant pentameric plasma glycoprotein, and an antibody fragment (Fab). Future challenges and opportunities to improve and apply high-throughput approaches to protein formulation development are also discussed. PMID- 24174402 TI - Life-course of cardio-respiratory associations. AB - BACKGROUND: Several studies have shown that raised cardiovascular risk factors are associated with an impaired lung function in adulthood. Whether this association also exists in the young is unknown. Our aim was to study the relation between blood pressure and lung function from neonatal to elderly age. STUDY DESIGN: This was a cross-sectional study in a general population cohort. METHODS: Within the Utrecht Health Project (UHP) 6673 adults (aged 18-91 years) had spirometry and blood pressure measurements taken. In the WHeezing Illnesses STudy LEidsche Rijn (WHISTLER) study, a satellite birth cohort of the UHP, blood pressure and respiratory mechanics were measured using the single occlusion technique in 755 newborns and spirometry in 382 5-year-old participants. Linear regression analyses were performed with lung function as an independent variable and blood pressure as a dependent variable in different age groups. The analyses were adjusted for age, sex, weight and height. RESULTS: In infancy a more favorable lung function (higher compliance and lower resistance) was associated with higher blood pressure. In 5-year-old children and young adults higher forced expiratory volume in 1 second (FEV1) was associated with higher systolic blood pressure (p-values < 0.05). At the age of 5 the adjusted regression coefficient for systolic blood pressure was 4.8 mmHg/L (95% confidence interval (95% CI) -0.3 9.98). The association decreased with increasing age and reversed in the age groups above 40 years to -7.3 mmHg/L (95% CI -15.5-0.9) in those aged over 70 years of age. The association with pulse pressure showed a similar pattern. CONCLUSIONS: A positive association between the mechanical properties of the respiratory system and blood pressure in childhood and young adulthood reverses in later adulthood. PMID- 24174392 TI - Impact of weight loss on ankle-brachial index and interartery blood pressures. AB - OBJECTIVE: To assess whether weight loss improves markers of peripheral artery disease and vascular stenosis. METHODS: The Action for Health in Diabetes randomized clinical trial compared intensive lifestyle intervention (ILI) for weight loss to a control condition of diabetes support and education (DSE) in overweight or obese adults with type 2 diabetes. Annual ankle and brachial blood pressures over four years were used to compute ankle-brachial indices (ABIs) and to assess interartery blood pressure differences in 5018 participants. RESULTS: ILI, compared to DSE, produced 7.8% (Year 1) to 3.6% (Year 4) greater weight losses. These did not affect prevalence of low (<0.90) ABI (3.60% in DSE versus 3.14% in ILI; P = 0.20) or elevated (>1.40) ABI (7.52% in DSE versus 7.59% in ILI: P = 0.90), but produced smaller mean (SE) maximum interartery systolic blood pressure differences among ankle sites [19.7 (0.2) mmHg for ILI versus 20.6 (0.2) mmHg for DSE (P < 0.001)] and between arms [5.8 (0.1) mmHg for ILI versus 6.1 (0.1) mmHg for DSE (P = 0.01)]. CONCLUSIONS: Four years of intensive behavioral weight loss intervention did not significantly alter prevalence of abnormal ABI, however, it did reduce differences in systolic blood pressures among arterial sites. PMID- 24174403 TI - A cationic metal-organic framework consisting of nanoscale cages: capture, separation, and luminescent probing of Cr(2)O7(2-) through a single-crystal to single-crystal process. AB - Dichromate capture: A 3D cationic metal-organic framework consisting of distorted octahedral and tetrahedral cages was constructed by using Ag(I) and 4,4' bis(1,2,4-triazole). The complex exhibits fast exchange, high trapping capacity, and good selectivity for Cr2 O7 (2-) through single-crystal to single-crystal transformation. The complex also features a bluish violet luminescence that is distinctly quenched after Cr2 O7 (2-) exchange. PMID- 24174405 TI - Atypical RNAs in the coelacanth transcriptome. AB - Circular and apparently trans-spliced RNAs have recently been reported as abundant types of transcripts in mammalian transcriptome data. Both types of non colinear RNAs are also abundant in RNA-seq of different tissue from both the African and the Indonesian coelacanth. We observe more than 8,000 lincRNAs with normal gene structure and several thousands of circularized and trans-spliced products, showing that such atypical RNAs form a substantial contribution to the transcriptome. Surprisingly, the majority of the circularizing and trans connecting splice junctions are unique to atypical forms, that is, are not used in normal isoforms. PMID- 24174404 TI - Neural bases of food perception: coordinate-based meta-analyses of neuroimaging studies in multiple modalities. AB - OBJECTIVE: The purpose of this study was to compare the results of the three food cue paradigms most commonly used for functional neuroimaging studies to determine: i) commonalities and differences in the neural response patterns by paradigm and ii) the relative robustness and reliability of responses to each paradigm. METHODS: Functional magnetic resonance imaging studies using standardized stereotactic coordinates to report brain responses to food cues were identified using online databases. Studies were grouped by food-cue modality as: i) tastes (8 studies); ii) odors (8 studies); and, iii) images (11 studies). Activation likelihood estimation was used to identify statistically reliable regional responses within each stimulation paradigm. RESULTS: Brain response distributions were distinctly different for the three stimulation modalities, corresponding to known differences in location of the respective primary and associative cortices. Visual stimulation induced the most robust and extensive responses. The left anterior insula was the only brain region reliably responding to all three stimulus categories. CONCLUSIONS: These findings suggest visual food cue paradigm as promising candidate for imaging studies addressing the neural substrate of therapeutic interventions. PMID- 24174406 TI - Bats as animal reservoirs for the SARS coronavirus: hypothesis proved after 10 years of virus hunting. PMID- 24174407 TI - Deaminative and decarboxylative catalytic alkylation of amino acids with ketones. AB - It cuts two ways: The cationic [Ru-H] complex catalyzes selective coupling of alpha- and beta-amino acids with ketones to form alpha-alkylated ketone products. The reaction involves C?C and C?N bond cleavage which result in regio- and stereoselective alkylation using amino acids. A broad substrate scope and high functional-group tolerance is demonstrated. PMID- 24174422 TI - Report 86: Quantification and reporting of low-dose and other heterogeneous exposures. AB - The absorbed dose, the mean value of the energy imparted by ionizing radiation to a volume of interest divided by the mass of that volume, is often a very effective way to describe radiation exposures. For example, in radiation therapy and industrial radiation processing, the absorbed dose is usually adequate for predicting the results of the irradiation. However, in situations in which the heterogeneity of the energy deposition or of the target structure results in individual targets (often assumed to be a cell or a cell nucleus) receiving energy depositions that are dramatically different from the mean value, the absorbed dose does not provide sufficient information needed to fully understand the consequences of irradiation or for the use of radiation-response models. In some cases, such as microbeam irradiations, heterogeneous exposures have been created intentionally in order to study mechanisms of response to ionizing radiation. In other situations, such as background-radiation exposure, the heterogeneity occurs as a result of the low level of radiation exposure or of a small local concentration of a radioactive material. When the energy deposition is heterogeneous, the conventional description in terms of absorbed dose can be misleading because it suggests that neighboring structures will incur the same amount of damage, and that the amount received by an individual target can be decreased to as low a value as desired. In fact, the individual targets can receive highly variable energy depositions, with a mean and variance determined by the physical properties of the radiation and the target. Reliance on the mean values rather than the spectrum of individual energy depositions can lead to inappropriate conclusions about the relationship between energy deposited and the initiation of biological response. Even with the same amount of deposited energy, the spectrum of initial damage products depends on radiation quality (sometimes specified in terms of the linear energy transfer). However, the complex combinations of biomolecular processes occurring following irradiation make it unlikely that any single-parameter description of the radiation interaction will be satisfactory for understanding biological processes. This Report recommends that, in cases in which energy deposition is likely to be heterogeneous, a detailed description of the radiation field, with an appropriate description of the irradiated system, should be given. The complete description of the radiation is the energy distribution of the particle radiance as a function of time and particle type. However, simplified descriptions such as the distribution of fluence rate, the probability density of lineal energy, and the event rate, or even the absorbed dose rate and radiation quality are appropriate descriptions of the irradiation in many cases. PMID- 24174423 TI - Cardiovascular effects of alpha-linolenic acid--a possible role of glucagon-like peptide-1. PMID- 24174424 TI - O-GlcNAcylation of FoxO1 in pancreatic beta cells promotes Akt inhibition through an IGFBP1-mediated autocrine mechanism. AB - O-GlcNAcylation on serine/threonine is a post-translational modification that controls the activity of nucleocytoplasmic proteins according to glucose availability. We previously showed that O-GlcNAcylation of FoxO1 in liver cells increases its transcriptional activity. In the present study, we evaluated the potential involvement of FoxO1 O-GlcNAcylation in the context of pancreatic beta cell glucotoxicity. FoxO1 was O-GlcNAcylated in INS-1 832/13 beta cells and isolated rat pancreatic islets. O-GlcNAcylation of FoxO1 resulted in a 2-fold increase in its transcriptional activity toward a FoxO1 reporter gene and a 3 fold increase in the expression of the insulin-like growth factor-binding protein 1 (Igfbp1) gene at the mRNA level, resulting in IGFBP1 protein oversecretion by the cells. Of note, increased IGFBP1 in the culture medium inhibited the activity of the insulin-like growth factor 1 receptor (IGF1R)/phosphatidyl inositol 3 kinase (PI3K)/Akt pathway. We reveal in this report a novel mechanism by which O GlcNAcylation inhibits Akt activity through an autocrine mechanism. However, although inhibition of IGFBP1 expression using siRNA restored the PI3 kinase/Akt pathway, it did not rescue INS-1 832/13 cells from high-glucose- or O glcNAcylation-induced cell death. In contrast, FoxO1 down-regulation by siRNA led to 30 to 60% protection of INS-1 832/13 cells from death mediated by glucotoxic conditions. Therefore, whereas FoxO1 O-GlcNAcylation inhibits Akt through an IGFBP1-mediated autocrine pathway, the deleterious effects of FoxO1 O GlcNAcylation on cell survival appeared to be independent of this pathway. PMID- 24174426 TI - Influence of proinflammatory stimuli on the expression of vascular ribonuclease 1 in endothelial cells. AB - Extracellular RNA (eRNA) released under injury or pathological conditions has been identified as a yet unrecognized vascular alarm signal to induce procoagulant, permeability-promoting, and proinflammatory activities. eRNA induced functions were largely prevented by administration of RNase1 as a natural blood vessel-protective antagonist of eRNA. The aim of this study was to investigate the inflammatory regulation of endothelial cell RNase1, which is partly stored in Weibel-Palade bodies of these cells. Long-term treatment of human umbilical vein endothelial cells (HUVECs) with inflammatory agents like tumor necrosis factor alpha (TNF-alpha) or interleukin 1beta (IL-1beta), but not with eRNA, significantly decreased the release (34 +/- 5%; 34 +/- 7% of control) as well as the cellular expression (19.5 +/- 5%; 33 +/- 8% of control) of RNase1. Down-regulation of RNase1 by TNF-alpha stimulation or RNase1 siRNA knockdown increased the permeability of HUVEC monolayers, demonstrated by dearrangement of VE-cadherins at cell-cell borders. Mechanistically, cytokine-induced decrease of RNase1 expression did not involve the nuclear factor kappa B (NFkappaB) signaling pathway but epigenic modifications. Since inhibition of histone deacetylases resulted in recovery of RNase1 expression and secretion after cytokine treatment, an acetylation-dependent process of RNase1 regulation is proposed. These results indicate that cytokine-mediated down-regulation of RNase1 in endothelial cells may aggravate eRNA-induced inflammatory activities and thereby disturbs the vascular homeostasis of the extracellular RNA/RNase system. PMID- 24174425 TI - Structural and functional analysis of amphioxus HIFalpha reveals ancient features of the HIFalpha family. AB - Hypoxia-inducible factors (HIFs) are master regulators of the transcriptional response to hypoxia. To gain insight into the structural and functional evolution of the HIF family, we characterized the HIFalpha gene from amphioxus, an invertebrate chordate, and identified several alternatively spliced HIFalpha isoforms. Whereas HIFalpha Ia, the full-length isoform, contained a complete oxygen-dependent degradation (ODD) domain, the isoforms Ib, Ic, and Id had 1 or 2 deletions in the ODD domain. When tagged with GFP and tested in mammalian cells, the amphioxus HIFalpha Ia protein level increased in response to hypoxia or CoCl2 treatment, whereas HIFalpha Ib, Ic, and Id showed reduced or no hypoxia regulation. Deletion of the ODD sequence in HIFalpha Ia up-regulated the HIFalpha Ia levels under normoxia. Gene expression analysis revealed HIFalpha Ic to be the predominant isoform in embryos and larvae, whereas isoform Ia was the most abundant form in the adult stage. The expression levels of Ib and Id were very low. Hypoxia treatment of adults had no effect on the mRNA levels of these HIFalpha isoforms. Functional analyses in mammalian cells showed all 4 HIFalpha isoforms capable of entering the nucleus and activating hypoxia response element dependent reporter gene expression. The functional nuclear location signal (NLS) mapped to 3 clusters of basic residues. (775)KKARL functioned as the primary NLS, but (737)KRK and (754)KK also contributed to the nuclear localization. All amphioxus HIFalpha isoforms had 2 functional transactivation domains (TADs). Its C-terminal transactivation (C-TAD) shared high sequence identity with the human HIF-1alpha and HIF-2alpha C-TAD. This domain contained a conserved asparagine, and its mutation resulted in an increase in transcriptional activity. These findings reveal many ancient features of the HIFalpha family and provide novel insights into the evolution of the HIFalpha family. PMID- 24174428 TI - Endothelial cell adhesion to soluble vascular endothelial growth factor receptor 1 triggers a cell dynamic and angiogenic phenotype. AB - The aim of this study was to identify the molecular signals produced in human endothelial cells (ECs) by the interaction of alpha5beta1 integrin with soluble vascular endothelial growth factor receptor-1 (sVEGFR-1) present in the extracellular matrix. We generated a gene expression profile of ECs adhering to sVEGFR-1 or to fibronectin, the classic extracellular matrix ligand for alpha5beta1 integrin or in a nonadhering condition. Several biological pathways were differently modulated, 3 protein kinase C substrates [adducin, myristoylated alanine-rich protein kinase C substrate (MARCKS), and radixin] were differently expressed and phosphorylated when cells adhering to sVEGFR-1 were compared with those adhering to fibronectin. Rac1 activation and Galpha13 protein involvement through the interaction with radixin were also detected after attachment to sVEGFR-1, and these responses depended on active VEGFR-2 signaling. On sVEGFR-1, ECs exhibited a motile phenotype that was consistent with the abundant presence of MARCKS, a stabilizer of dynamic adhesions. Moreover, ECs silenced for radixin expression no longer responded to the proangiogenic VEGFR-1-derived peptide 12. We propose that the presence of sVEGFR-1 in the EC microenvironment directs alpha5beta1 integrin signaling to generate a dynamic, motile phenotype. Our findings also provide new insights into the mechanism of action of proangiogenic peptide 12, relevant to a therapeutic perspective. PMID- 24174427 TI - Advancing functional engineered cardiac tissues toward a preclinical model of human myocardium. AB - Cardiac experimental biology and translational research would benefit from an in vitro surrogate for human heart muscle. This study investigated structural and functional properties and interventional responses of human engineered cardiac tissues (hECTs) compared to human myocardium. Human embryonic stem cell-derived cardiomyocytes (hESC-CMs, >90% troponin-positive) were mixed with collagen and cultured on force-sensing elastomer devices. hECTs resembled trabecular muscle and beat spontaneously (1.18 +/- 0.48 Hz). Microstructural features and mRNA expression of cardiac-specific genes (alpha-MHC, SERCA2a, and ACTC1) were comparable to human myocardium. Optical mapping revealed cardiac refractoriness with loss of 1:1 capture above 3 Hz, and cycle length dependence of the action potential duration, recapitulating key features of cardiac electrophysiology. hECTs reconstituted the Frank-Starling mechanism, generating an average maximum twitch stress of 660 MUN/mm(2) at Lmax, approaching values in newborn human myocardium. Dose-response curves followed exponential pharmacodynamics models for calcium chloride (EC50 1.8 mM) and verapamil (IC50 0.61 MUM); isoproterenol elicited a positive chronotropic but negligible inotropic response, suggesting sarcoplasmic reticulum immaturity. hECTs were amenable to gene transfer, demonstrated by successful transduction with Ad.GFP. Such 3-D hECTs recapitulate an early developmental stage of human myocardium and promise to offer an alternative preclinical model for cardiology research. PMID- 24174429 TI - Seawater uranium sorbents: preparation from a mesoporous copolymer initiator by atom-transfer radical polymerization. PMID- 24174430 TI - Local recurrence after radical nephrectomy for kidney cancer: management and prediction of outcomes. a multi-institutional study. AB - BACKGROUND: Local recurrence (LR) after radical nephrectomy (RN) for kidney cancer is uncommon. Our objectives were to analyse characteristics and therapeutic options of LR after RN and to identify survival prognostic factors. MATERIALS AND METHODS: From a multi-institutional retrospective database, we identified 72 patients who experienced LR after RN. RESULTS: Mean time to LR was 26.5 +/- 3.3 months. The location of the recurrence was renal fossa, regional lymph node, homolateral adrenal and both renal fossa and regional lymph node for 43 (59.7%), 27 (37.5%), 9 (12.5%) and 7 (9.7%) patients, respectively. Patients were treated by surgery, systemic therapies, combination of therapies and palliative treatment in 24 (33.3%), 18 (25%), 24 (33.3%) and 6 (8.4%) cases, respectively. Within a mean follow-up of 26.4 +/- 3.3 months from the date of local recurrence, 12 (16.6%) patients were alive without disease, 30 (41.7%) patients were alive with disease, 30 patients (41.6%) died including 28 (38.8%) from the disease. In multivariate analysis, time to recurrence <1 year (P < 0.001; HR: 4.81) and surgical treatment (P = 0.027; HR: 0.33) were predictive factors. CONCLUSIONS: Local recurrence after radical nephrectomy is associated with poor prognosis. The time to recurrence and the completeness of the surgical treatment are major prognostic factors. PMID- 24174432 TI - Do children emotionally rehearse about their body image? AB - This study examined the association between propensity for emotional rehearsal, body image self-perception and weight status in Chinese Hong Kong pre adolescents. Children 8-12 years of age (n = 278) completed measurement of body mass index, body image and emotional rehearsal. Multinomial regression analyses revealed that body mass index was positively associated with body image dissatisfaction and a significant predictor of body size estimation. However, only body size underestimation was associated with lower rehearsal tendencies. The prevalence of body image dissatisfaction and body size estimation was also reported for this population. Future research is suggested for greater understanding of emotional coping in body image dissatisfaction in young children. PMID- 24174431 TI - Arthroscopic treatment of ankle anterior bony impingement: the long-term clinical outcome. AB - BACKGROUND: Arthroscopic treatment of anterior ankle bony impingement provides good results, with a tendency to decrease over time. The purpose of this study was to analyze the factors affecting long-term results. METHODS: Eighty consecutive patients with a mean age of 37.3 years were treated between 2000 and 2004. Impingement lesions were identified according to Scranton-McDermott classification. Preoperative ankle osteoarthritis was documented by van Dijk scale upon the x-rays. Bone spurs were analyzed and classified according to location and size. The associated chondral lesions were classified following the International Cartilage Repair Society (ICRS) criteria. Patient data, foot morphology, and previous traumas were recorded. Patients were evaluated after a mean of 104.6 months follow-up with the American Orthopaedic Foot and Ankle Society (AOFAS) scale. The influence of different factors on outcomes was statistically analyzed. RESULTS: The mean preoperative AOFAS score was 50.9, while at follow-up it was 70.7 (P < .05). The different grades of Scranton McDermott impingement classification did not affect the results, but the different grades of van Dijk scale significantly affected the result but not the preoperative stage. Tibial localized spurs had better outcome at follow-up. The grade of the chondral lesions significantly affected the outcome. Other factors negatively affecting the results were age, cavus foot morphology, and history of previous ankle fracture. CONCLUSION: Arthroscopic treatment provides overall good results, but the long-term presence of associated conditions such as chondral lesions, advanced age, and previous trauma are relevant as prognostic factors. Based on these results, a new classification for bony impingement syndrome system is proposed. LEVEL OF EVIDENCE: Level IV, case series. PMID- 24174433 TI - Progress in genetics and genomics of nonhuman primates. Introduction. PMID- 24174434 TI - Great ape genomics. AB - The great ape families are the species most closely related to our own, comprising chimpanzees, bonobos, gorillas, and orangutans. They live exclusively in tropical rainforests in Central Africa and the islands of Southeast Asia. Due to their close evolutionary relationship with humans, great apes share many cognitive, physiological, and morphological similarities with humans. The members of the great ape family make obvious models to facilitate the further understanding about humans' biology and history. This review will discuss how the recent addition of genome-wide data from great apes has furthered humans' understanding of these species and humanity, especially in the realm of evolutionary genetics. PMID- 24174435 TI - The value of extended pedigrees for next-generation analysis of complex disease in the rhesus macaque. AB - Complex diseases (e.g., cardiovascular disease and type 2 diabetes, among many others) pose the biggest threat to human health worldwide and are among the most challenging to investigate. Susceptibility to complex disease may be caused by multiple genetic variants (GVs) and their interaction, by environmental factors, and by interaction between GVs and environment, and large study cohorts with substantial analytical power are typically required to elucidate these individual contributions. Here, we discuss the advantages of both power and feasibility afforded by the use of extended pedigrees of rhesus macaques (Macaca mulatta) for genetic studies of complex human disease based on next-generation sequence data. We present these advantages in the context of previous research conducted in rhesus macaques for several representative complex diseases. We also describe a single, multigeneration pedigree of Indian-origin rhesus macaques and a sample biobank we have developed for genetic analysis of complex disease, including power of this pedigree to detect causal GVs using either genetic linkage or association methods in a variance decomposition approach. Finally, we summarize findings of significant heritability for a number of quantitative traits that demonstrate that genetic contributions to risk factors for complex disease can be detected and measured in this pedigree. We conclude that the development and application of an extended pedigree to analysis of complex disease traits in the rhesus macaque have shown promising early success and that genome-wide genetic and higher order -omics studies in this pedigree are likely to yield useful insights into the architecture of complex human disease. PMID- 24174436 TI - Baboons as a model to study genetics and epigenetics of human disease. AB - A major challenge for understanding susceptibility to common human diseases is determining genetic and environmental factors that influence mechanisms underlying variation in disease-related traits. The most common diseases afflicting the US population are complex diseases that develop as a result of defects in multiple genetically controlled systems in response to environmental challenges. Unraveling the etiology of these diseases is exceedingly difficult because of the many genetic and environmental factors involved. Studies of complex disease genetics in humans are challenging because it is not possible to control pedigree structure and often not practical to control environmental conditions over an extended period of time. Furthermore, access to tissues relevant to many diseases from healthy individuals is quite limited. The baboon is a well-established research model for the study of a wide array of common complex diseases, including dyslipidemia, hypertension, obesity, and osteoporosis. It is possible to acquire tissues from healthy, genetically characterized baboons that have been exposed to defined environmental stimuli. In this review, we describe the genetic and physiologic similarity of baboons with humans, the ability and usefulness of controlling environment and breeding, and current genetic and genomic resources. We discuss studies on genetics of heart disease, obesity, diabetes, metabolic syndrome, hypertension, osteoporosis, osteoarthritis, and intrauterine growth restriction using the baboon as a model for human disease. We also summarize new studies and resources under development, providing examples of potential translational studies for targeted interventions and therapies for human disease. PMID- 24174437 TI - Systems biology of the vervet monkey. AB - Nonhuman primates (NHP) provide crucial biomedical model systems intermediate between rodents and humans. The vervet monkey (also called the African green monkey) is a widely used NHP model that has unique value for genetic and genomic investigations of traits relevant to human diseases. This article describes the phylogeny and population history of the vervet monkey and summarizes the use of both captive and wild vervet monkeys in biomedical research. It also discusses the effort of an international collaboration to develop the vervet monkey as the most comprehensively phenotypically and genomically characterized NHP, a process that will enable the scientific community to employ this model for systems biology investigations. PMID- 24174438 TI - Improving genome assemblies and annotations for nonhuman primates. AB - The study of nonhuman primates (NHP) is key to understanding human evolution, in addition to being an important model for biomedical research. NHPs are especially important for translational medicine. There are now exciting opportunities to greatly increase the utility of these models by incorporating Next Generation (NextGen) sequencing into study design. Unfortunately, the draft status of nonhuman genomes greatly constrains what can currently be accomplished with available technology. Although all genomes contain errors, draft assemblies and annotations contain so many mistakes that they make currently available nonhuman primate genomes misleading to investigators conducting evolutionary studies; and these genomes are of insufficient quality to serve as references for NextGen studies. Fortunately, NextGen sequencing can be used in the production of greatly improved genomes. Existing Sanger sequences can be supplemented with NextGen whole genome, and exomic genomic sequences to create new, more complete and correct assemblies. Additional physical mapping, and an incorporation of information about gene structure, can be used to improve assignment of scaffolds to chromosomes. In addition, mRNA-sequence data can be used to economically acquire transcriptome information, which can be used for annotation. Some highly polymorphic and complex regions, for example MHC class I and immunoglobulin loci, will require extra effort to properly assemble and annotate. However, for the vast majority of genes, a modest investment in money, and a somewhat greater investment in time, can greatly improve assemblies and annotations sufficient to produce true, reference grade nonhuman primate genomes. Such resources can reasonably be expected to transform nonhuman primate research. PMID- 24174441 TI - The essential detail: the genetics and genomics of the primate immune response. AB - Next-generation sequencing technologies have led to rapid progress in the fields of human and nonhuman primate (NHP) genomics. The less expensive and more efficient technologies have enabled the sequencing of human genomes from multiple populations and the sequencing of many NHP species. NHP genomes have been sequenced for two main reasons: (1) their importance as animal models in biomedical research and (2) their phylogenetic relationship to humans and use in derivative evolutionary studies. NHPs are valuable animal models for a variety of diseases, most notably for human immunodeficiency virus/acquired immunodeficiency syndrome research, and for vaccine development. Knowledge about the variation in primate immune response loci can provide essential insights into relevant immune function. However, perhaps ironically considering their central role in infectious disease, the accumulation of sequence detail from genomic regions harboring immune response loci, such as the major histocompatibility complex and killer immunoglobulin-like receptors, has been slow. This deficiency is, at least in part, due to the highly repetitive and polymorphic nature of these regions and is being addressed by the application of special approaches to targeted sequencing of the immune response genomic regions. We discuss one such targeting approach that has successfully yielded complete phased genomic sequences from complex genomic regions and is now being used to resequence macaque and other primate major histocompatibility complex regions. The essential detail contained within the genomics of the NHP immune response is now being assembled, and the realization of precise comparisons between NHP and human immune genomics is close at hand, further enhancing the NHP animal model in the search for effective treatments for human disease. PMID- 24174439 TI - Nonhuman primate models in the genomic era: a paradigm shift. AB - Because of their strong similarities to humans across physiologic, developmental, behavioral, immunologic, and genetic levels, nonhuman primates are essential models for a wide spectrum of biomedical research. But unlike other animal models, nonhuman primates possess substantial outbred genetic variation, reducing statistical power and potentially confounding interpretation of results in research studies. Although unknown genetic variation is a hindrance in studies that allocate animals randomly, taking genetic variation into account in study design affords an opportunity to transform the way that nonhuman primates are used in biomedical research. New understandings of how the function of individual genes in rhesus macaques mimics that seen in humans are greatly advancing the rhesus macaques utility as research models, but epistatic interaction, epigenetic regulatory mechanisms, and the intricacies of gene networks limit model development. We are now entering a new era of nonhuman primate research, brought on by the proliferation and rapid expansion of genomic data. Already the cost of a rhesus macaque genome is dwarfed by its purchase and husbandry costs, and complete genomic datasets will inevitably encompass each rhesus macaque used in biomedical research. Advancing this outcome is paramount. It represents an opportunity to transform the way animals are assigned and used in biomedical research and to develop new models of human disease. The genetic and genomic revolution brings with it a paradigm shift for nonhuman primates and new mandates on how nonhuman primates are used in biomedical research. PMID- 24174440 TI - Old world monkeys and new age science: the evolution of nonhuman primate systems virology. AB - Nonhuman primate (NHP) biomedical models are critical to our understanding of human health and disease, yet we are still in the early stages of developing sufficient tools to support primate genomic research that allow us to better understand the basis of phenotypic traits in NHP models of disease. A mere 7 years ago, the limited NHP transcriptome profiling that was being performed was done using complementary DNA arrays based on human genome sequences, and the lack of NHP genomic information and immunologic reagents precluded the use of NHPs in functional genomic studies. Since then, significant strides have been made in developing genomics capabilities for NHP research, from the rhesus macaque genome sequencing project to the construction of the first macaque-specific high-density oligonucleotide microarray, paving the way for further resource development and additional primate sequencing projects. Complete published draft genome sequences are now available for the chimpanzee ( Chimpanzee Sequencing Analysis Consortium 2005), bonobo ( Prufer et al. 2012), gorilla ( Scally et al. 2012), and baboon ( Ensembl.org 2013), along with the recently completed draft genomes for the cynomolgus macaque and Chinese rhesus macaque. Against this backdrop of both expanding sequence data and the early application of sequence-derived DNA microarrays tools, we will contextualize the development of these community resources and their application to infectious disease research through a literature review of NHP models of acquired immune deficiency syndrome and models of respiratory virus infection. In particular, we will review the use of -omics approaches in studies of simian immunodeficiency virus and respiratory virus pathogenesis and vaccine development, emphasizing the acute and innate responses and the relationship of these to the course of disease and to the evolution of adaptive immunity. PMID- 24174442 TI - Haplessly hoping: macaque major histocompatibility complex made easy. AB - Major histocompatibility complex (MHC) gene products control the repertoire of T cell responses that an individual may create against pathogens and foreign tissues. This text will review the current understanding of MHC genetics in nonhuman primates, with a focus on Mauritian-origin cynomolgus macaques (Macaca fascicularis) and Indian-origin rhesus macaques (Macaca mulatta). These closely related macaque species provide important experimental models for studies of infectious disease pathogenesis, vaccine development, and transplantation research. Recent advances resulting from the application of several cost effective, high-throughput approaches, with deep sequencing technologies have revolutionized our ability to perform MHC genotyping of large macaque cohorts. Pyrosequencing of cDNA amplicons with a Roche/454 GS Junior instrument, provides excellent resolution of MHC class I allelic variants with semi-quantitative estimates of relative levels of transcript abundance. Introduction of the Illumina MiSeq platform significantly increased the sample throughput, since the sample loading workflow is considerably less labor intensive, and each instrument run yields approximately 100-fold more sequence data. Extension of these sequencing methods from cDNA to genomic DNA amplicons further streamlines the experimental workflow and opened opportunities for retrospective MHC genotyping of banked DNA samples. To facilitate the reporting of MHC genotypes, and comparisons between groups of macaques, this text also introduces an intuitive series of abbreviated rhesus MHC haplotype designations based on a major Mamu-A or Mamu-B transcript characteristic for ancestral allele combinations. The authors believe that the use of MHC-defined macaques promises to improve the reproducibility, and predictability of results from pre-clinical studies for translation to humans. PMID- 24174444 TI - In transition: primate genomics at a time of rapid change. AB - The field of nonhuman primate genomics is undergoing rapid change and making impressive progress. Exploiting new technologies for DNA sequencing, researchers have generated new whole-genome sequence assemblies for multiple primate species over the past 6 years. In addition, investigations of within-species genetic variation, gene expression and RNA sequences, conservation of non-protein-coding regions of the genome, and other aspects of comparative genomics are moving at an accelerating speed. This progress is opening a wide array of new research opportunities in the analysis of comparative primate genome content and evolution. It also creates new possibilities for the use of nonhuman primates as model organisms in biomedical research. This transition, based on both new technology and the new information being generated in regard to human genetics, provides an important justification for reevaluating the research goals, strategies, and study designs used in primate genetics and genomics. PMID- 24174445 TI - IACUC review of nonhuman primate research. AB - This article will detail some of the issues that must be considered as institutional animal care and use committees (IACUCs) review the use of nonhuman primates (NHPs) in research. As large, intelligent, social, long-lived, and non domesticated animals, monkeys are amongst the most challenging species used in biomedical research and the duties of the IACUC in relation to reviewing research use of these species can also be challenging. Issues of specific concern for review of NHP research protocols that are discussed in this article include scientific justification, reuse, social housing requirements, amelioration of distress, surgical procedures, and humane endpoints. Clear institutional policies and procedures as regards NHP in these areas are critical, and the discussion of these issues presented here can serve as a basis for the informed establishment of such policies and procedures. PMID- 24174456 TI - A chemist building paths to cell biology. AB - Galileo is reported to have stated, "Measure what is measurable and make measurable what is not so." My group's trajectory in cell biology has closely followed this philosophy, although it took some searching to find this path. PMID- 24174443 TI - Progress and prospects for genetic modification of nonhuman primate models in biomedical research. AB - The growing interest of modeling human diseases using genetically modified (transgenic) nonhuman primates (NHPs) is a direct result of NHPs (rhesus macaque, etc.) close relation to humans. NHPs share similar developmental paths with humans in their anatomy, physiology, genetics, and neural functions; and in their cognition, emotion, and social behavior. The NHP model within biomedical research has played an important role in the development of vaccines, assisted reproductive technologies, and new therapies for many diseases. Biomedical research has not been the primary role of NHPs. They have mainly been used for safety evaluation and pharmacokinetics studies, rather than determining therapeutic efficacy. The development of the first transgenic rhesus macaque (2001) revolutionized the role of NHP models in biomedicine. Development of the transgenic NHP model of Huntington's disease (2008), with distinctive clinical features, further suggested the uniqueness of the model system; and the potential role of the NHP model for human genetic disorders. Modeling human genetic diseases using NHPs will continue to thrive because of the latest advances in molecular, genetic, and embryo technologies. NHPs rising role in biomedical research, specifically pre-clinical studies, is foreseeable. The path toward the development of transgenic NHPs and the prospect of transgenic NHPs in their new role in future biomedicine needs to be reviewed. This article will focus on the advancement of transgenic NHPs in the past decade, including transgenic technologies and disease modeling. It will outline new technologies that may have significant impact in future NHP modeling and will conclude with a discussion of the future prospects of the transgenic NHP model. PMID- 24174457 TI - Teaming up: from motors to people. AB - When I reflect on how I became a cell biologist and why I love being one today, one thing that comes to mind is the many terrific collaborations I have had. The science I am most proud of from my graduate and postdoctoral training would not have been possible without working in teams with other scientists. Now, in my own group, much of our best work is being done collaboratively, both within the lab and with other labs. In this essay, I will highlight my experiences working in teams as a trainee, the role teamwork has played in my own research group, and how important I think collaborative science is for the future of biological research. PMID- 24174458 TI - A sustained passion for intracellular trafficking. AB - I am honored to be the first recipient of the Women in Cell Biology Sustained Excellence in Research Award. Since my graduate school days, I have enjoyed being part of a stimulating scientific community the American Society for Cell Biology embodies. Having found myself largely by accident in a career that I find deeply enjoyable and fulfilling, I hope here to convey a sense that one need not have a "grand plan" to have a successful life in science. Simply following one's interests and passions can sustain a career, even though it may involve some migration. PMID- 24174459 TI - Scientific approaches to science policy. AB - The development of robust science policy depends on use of the best available data, rigorous analysis, and inclusion of a wide range of input. While director of the National Institute of General Medical Sciences (NIGMS), I took advantage of available data and emerging tools to analyze training time distribution by new NIGMS grantees, the distribution of the number of publications as a function of total annual National Institutes of Health support per investigator, and the predictive value of peer-review scores on subsequent scientific productivity. Rigorous data analysis should be used to develop new reforms and initiatives that will help build a more sustainable American biomedical research enterprise. PMID- 24174460 TI - E. E. Just Award lecture. AB - What started as a game of discovery for a child with a chemistry set has resulted in a lifetime of fulfillment and dedication to science. It is deeply rewarding to continuously let my curiosity ask questions for which there are no known answers. Equally rewarding has been the opportunity to mentor young students and postdoctorate graduates through their formative years in science. PMID- 24174461 TI - A question of taste. AB - A career in science is shaped by many factors, one of the most important being our tastes in research. These typically form early and are shaped by subsequent successes and failures. My tastes run to microscopes, chemistry, and spatial organization of cytoplasm. I will try to identify where they came from, how they shaped my career, and how they continue to evolve. My hope is to inspire young scientists to identify and celebrate their own unique tastes. PMID- 24174462 TI - An enduring enthusiasm for academic science, but with concerns. PMID- 24174463 TI - Life as a professor at a small liberal arts college. AB - We present a look at what it is like to be a professor at a small college: one professor at Grinnell College, one at Oberlin College, and one at Whitman College. PMID- 24174464 TI - Creating opportunities for science PhDs to pursue careers in high school education. AB - The United States is confronting important challenges at both the early and late stages of science education. At the level of K-12 education, a recent National Research Council report (Successful K-12 STEM Education) proposed a bold restructuring of how science is taught, moving away from memorizing facts and emphasizing hands-on, inquiry-based learning and a deeper understanding of the process of science. At higher levels of training, limited funding for science is leading PhDs to seek training and careers in areas other than research. Might science PhDs play a bigger role in the future of K-12 education, particularly at the high school level? We explore this question by discussing the roles that PhDs can play in high school education and the current and rather extensive barriers to PhDs entering the teaching profession and finally suggest ways to ease the entrance of qualified PhDs into high school education. PMID- 24174465 TI - From bench to museum--an unlikely journey. PMID- 24174466 TI - Higher psychological distress is associated with unintentional injuries in US adults. AB - BACKGROUND: Links between mental illness, self-inflicted injury and interpersonal violence are well recognised, but the association between poor mental health and unintentional injuries is not well understood. METHODS: We used the 2010 National Health Interview Survey to assess the association between psychological distress and unintentional non-occupational injuries among US adults. Psychological distress was measured by the Kessler Psychological Distress Scale, a symptom scale shown to identify community-dwelling persons with mental illness. Multivariable logistic regression was used to estimate adjusted ORs (AOR) and 95% CIs. RESULTS: Of the 26,776 individuals analysed, 2.5% reported a medically attended unintentional injury in the past 3 months. Those with moderate and severe psychological distress had 1.5 (1.2 to 1.8) and 2.0 (1.4 to 2.8) times higher odds of injury, respectively, as compared to those with low distress levels, after adjusting for age, sex, race, marital status, education level, alcohol use, physical functional limitation, medical comorbidity, employment status and health insurance status. Psychological distress was significantly associated with falls (AOR 1.4 (1.1 to 1.9)) and sprain/strain injuries (AOR 2.0 (1.5 to 2.8)), but not transportation-related injuries (AOR 1.2 (0.7 to 1.9)) or fractures (AOR 1.1 (0.8 to 1.6)). CONCLUSIONS: Among community-dwelling US adults, psychological distress is significantly associated with unintentional non occupational injury, and the magnitude of association increases with severity of distress. The association between psychological distress and injury may be particularly strong for falls and sprain/strain injuries. These findings draw attention to a large group of at-risk individuals that may merit further targeted research, including longitudinal studies. PMID- 24174467 TI - Evolutionary medicine of skin cancer risk among Europeans. PMID- 24174468 TI - Genetic study pushes back timeline for first significant human population expansion. PMID- 24174469 TI - Better understanding of the HIV epidemic through an evolutionary perspective. PMID- 24174470 TI - X doesn't always mark the spot. PMID- 24174471 TI - PKCiota maintains a tumor-initiating cell phenotype that is required for ovarian tumorigenesis. AB - Protein kinase Ciota (PKCiota) has oncogenic potential and is an attractive therapeutic target for treatment of lung cancer, particularly those tumors that express elevated PKCiota. However, whether PKCiota is a viable target in ovarian cancer is unknown, and virtually nothing is known about the mechanism by which PKCiota drives ovarian tumorigenesis. Here, it is demonstrated that PKCiota maintains a tumor-initiating cell (TIC) phenotype that drives ovarian tumorigenesis. A highly tumorigenic population of cells from human ovarian cancer cell lines exhibit cancer stem-like TIC properties, including self-renewal, clonal expansion, expression of stem-related genes, enhanced transformed growth in vitro, and aggressive tumor-initiating activity in vivo. Genetic disruption of PKCiota inhibits the proliferation, clonal expansion, anchorage-independent growth, and enhanced tumorigenic properties of ovarian TICs. Biochemical analysis demonstrates that PKCiota acts through its oncogenic partner Ect2 to activate a MEK/ERK signaling axis that drives the ovarian TIC phenotype. Genomic analysis reveals that PKCiota and Ect2 are coordinately amplified and overexpressed in the majority of primary ovarian serous tumors, and these tumors exhibit evidence of an active PKCiota-Ect2 signaling axis in vivo. Finally, this study reveals that auranofin, a potent and selective inhibitor of oncogenic PKCiota signaling, inhibits the tumorigenic properties of ovarian TIC cells in vitro and in vivo. These data demonstrate that PKCiota is required for a TIC phenotype in ovarian cancer, and that auranofin is an attractive therapeutic option to target deadly ovarian TICs in ovarian cancer patients. IMPLICATIONS: PKCiota drives a tumor initiating cell phenotype in ovarian cancer cells that can be therapeutically targeted with auranofin, a small molecule inhibitor of PKCiota signaling. PMID- 24174472 TI - Safety assessment of decyl glucoside and other alkyl glucosides as used in cosmetics. AB - The Cosmetic Ingredient Review (CIR) Expert Panel assessed the safety of 19 alkyl glucosides as used in cosmetics and concluded that these ingredients are safe in the present practices of use and concentration when formulated to be nonirritating. Most of these ingredients function as surfactants in cosmetics, but some have additional functions as skin-conditioning agents, hair-conditioning agents, or emulsion stabilizers. The Panel reviewed the available animal and clinical data on these ingredients. Since glucoside hydrolases in human skin are likely to break down these ingredients to release their respective fatty acids and glucose, the Panel also reviewed CIR reports on the safety of fatty alcohols and were able to extrapolate data from those previous reports to support safety. PMID- 24174473 TI - Safety assessment of lauriminodipropionic acid, sodium lauriminodipropionate, and disodium lauriminodipropionate as used in cosmetics. AB - The Cosmetic Ingredient Review Expert Panel assessed the safety of lauriminodipropionic acid, sodium lauriminodipropionate, and disodium lauriminodipropionate as used in cosmetics. These ingredients function in cosmetics as hair-conditioning agents and surfactant-cleansing agents. The Panel reviewed relevant animal and human data related to the safety of these ingredients in cosmetics. The Panel concluded that lauriminodipropionic acid, sodium lauriminodipropionate, and disodium lauriminodipropionate are safe as cosmetic ingredients in the present practices of use and concentration. PMID- 24174474 TI - Safety assessment of bis-diglyceryl polyacyladipate-2 and bis-diglyceryl polyacyladipate-1 as used in cosmetics. AB - The Cosmetic Ingredient Review Expert Panel assessed the safety of bis-diglyceryl polyacyladipate-2 and bis-diglyceryl polyacyladipate-1 as used in cosmetics, finding that these ingredients are safe in cosmetic formulations in the present practices of use and concentration. Both ingredients are lanolin substitutes and are reported to function in cosmetics as skin-conditioning agents--emollients. The Panel reviewed available animal and clinical data in making its determination of safety. PMID- 24174475 TI - Safety assessment of alkyl glyceryl ethers as used in cosmetics. AB - Alkyl glyceryl ethers function mostly as skin-conditioning agents in cosmetic products applied to the skin and hair. The Cosmetic Ingredient Review expert panel reviewed the available animal toxicity and clinical data, including the low dermal absorption, and concluded that the alkyl glyceryl ethers are safe in the present practices of use and concentration described in this safety assessment. PMID- 24174477 TI - Preface. PMID- 24174476 TI - Safety assessment of borosilicate glasses as used in cosmetics. AB - The Cosmetic Ingredient Review Expert Panel (Panel) reviewed the safety of calcium sodium borosilicate, calcium aluminum borosilicate, calcium titanium borosilicate, silver borosilicate, and zinc borosilicate as used in cosmetics. These borosilicate glasses function mostly as bulking agents. Available animal and human data were considered along with data from a previous safety assessment of magnesium silicates. The similar structure, properties, functions, and uses of these ingredients enabled grouping them and using the available toxicological data to assess the safety of the entire group. Data submitted on calcium borosilicate, which is not a cosmetic ingredient, are also included as additional support for the safety of borosilicate glass ingredients. The Panel concluded that borosilicate glasses are safe as cosmetic ingredients in the practices of use and concentration as given in this safety assessment. PMID- 24174480 TI - Executive summary. PMID- 24174481 TI - 1. Introduction. PMID- 24174482 TI - 2. The ROC Decision Model. PMID- 24174483 TI - 3. Conventional ROC Methodology. PMID- 24174484 TI - 4. Generalizing the Results of an ROC Analysis. PMID- 24174485 TI - 5. Extensions to Conventional ROC Methodology: LROC, FROC, and AFROC. PMID- 24174486 TI - 6. Statistical analysis and power estimation. PMID- 24174487 TI - 7. Some Practical Considerations when Planning ROC Studies. PMID- 24174488 TI - Appendix A: Computer Programs for ROC Analysis Available on the Internet. PMID- 24174489 TI - APPENDIX B: An Example of Multireader, Multicase ROC Analysis Using the DBM Methodology. PMID- 24174490 TI - APPENDIX C: Estimating Case Size and Reader Number from Pilot Data. PMID- 24174494 TI - Breaking the invulnerability of cancer stem cells: two-step strategy to kill the stem-like cell subpopulation of multiple myeloma. AB - In multiple myeloma, the presence of highly resistant cancer stem cells (CSC) that are responsible for tumor metastasis and relapse has been proven. Evidently, for achieving complete response, new therapeutic paradigms that effectively eradicate both, CSCs and bulk cancer populations, need to be developed. For achieving that goal, an innovative two-step treatment combining targeting of thymidine de novo synthesis pathway and a nanoirradiation by the Auger electron emitting thymidine analogue (123/125)I-5-iodo-4'-thio-2'-deoxyuridine ((123/125)I ITdU) could be a promising approach. The pretreatment with thymidylate synthase inhibitor 5-fluoro-2'-deoxyuridine (FdUrd, 1 MUmol/L for 1 hour) efficiently induced proliferation and terminal differentiation of isolated myeloma stem-like cells. Moreover, FdUrd stimulation led to a decreased activity of a functional CSC marker, aldehyde dehydrogenase (ALDH). The metabolic conditioning by FdUrd emerged to be essential for enhanced incorporation of (125)I-ITdU (incubation with 50 kBq/2 * 10(4) cells for 4 days) and, consequently, for the induction of irreparable DNA damage. (125)I-ITdU showed a pronounced antimyeloma effect on isolated tumor stem-like cells. More than 85% of the treated cells were apoptotic, despite activation of DNA repair mechanisms. Most important, exposure of metabolically conditioned cells to (125)I-ITdU resulted in a complete inhibition of clonogenic recovery. This is the first report showing that pretreatment with FdUrd sensitizes the stem-like cell compartment in multiple myeloma to apoptosis induced by (125)I-ITdU-mediated nanoirradiation of DNA. PMID- 24174496 TI - Identification of overlapping but differential binding sites for the high affinity CXCR3 antagonists NBI-74330 and VUF11211. AB - CXC chemokine receptor CXCR3 and/or its main three ligands CXCL9, CXCL10, and CXCL11 are highly upregulated in a variety of diseases. As such, considerable efforts have been made to develop small-molecule receptor CXCR3 antagonists, yielding distinct chemical classes of antagonists blocking binding and/or function of CXCR3 chemokines. Although it is suggested that these compounds bind in an allosteric fashion, thus far no evidence has been provided regarding the molecular details of their interaction with CXCR3. Using site-directed mutagenesis complemented with in silico homology modeling, we report the binding modes of two high-affinity CXCR3 antagonists of distinct chemotypes: VUF11211 [(S)-5-chloro-6-(4-(1-(4-chlorobenzyl)piperidin-4-yl)-3-ethylpiperazin-1-yl)-N ethylnicotinamide] (piperazinyl-piperidine) with a rigid elongated structure containing two basic groups and NBI-74330 [(R)-N-(1-(3-(4-ethoxyphenyl)-4-oxo-3,4 dihydropyrido[2,3-d]pyrimidin-2-yl)ethyl)-2-(4-fluoro-3-(trifluoromethyl)phenyl) N-(pyridin-3-ylmethyl)acetamide] (8-azaquinazolinone) without any basic group. Here we show that NBI-74330 is anchored in the transmembrane minor pocket lined by helices 2 (W2.60, D2.63), 3 (F3.32), and 7 (S7.39, Y7.43), whereas VUF11211 extends from the minor pocket into the major pocket of the transmembrane domains, located between residues in helices 1 (Y1.39), 2 (W2.60), 3 (F3.32), 4 (D4.60), 6 (Y6.51), and 7 (S7.39, Y7.43). Mutation of these residues did not affect CXCL11 binding significantly, confirming the allosteric nature of the interaction of these small molecules with CXCR3. Moreover, the model derived from our in silico guided studies fits well with the already published structure-activity relationship data on these ligands. Altogether, in this study, we show overlapping, yet different binding sites for two high-affinity CXCR3 antagonists, which offer new opportunities for the structure-based design of allosteric modulators for CXCR3. PMID- 24174495 TI - Endocytic profiles of delta-opioid receptor ligands determine the duration of rapid but not sustained cAMP responses. AB - Traditional assays that monitor cAMP inhibition by opioid receptor ligands require second-messenger accumulation over periods of 10-20 minutes. Since receptor regulation occurs within a similar time frame, such assays do not discriminate the actual signal from its modulation. Here we used bioluminescence resonance energy transfer to monitor inhibition of cAMP production by delta opioid receptor (DOR) agonists in real time. cAMP inhibition elicited by different agonists over a period of 15 minutes was biphasic, with response buildup during the first 6 to 7 minutes, followed by a second phase of response decay or of no further increment. The rate at which the cAMP response disappeared was correlated with operational parameters describing ligand efficiency [log(tau/KA)] to promote Galphai activation, as well as with ligand ability to promote internalization during the time course of the assay. Thus, ligands that displayed low signaling efficiency and poor sequestration(SB235863 ([8R (4bS*,8aalpha,8abeta,12bbeta)]7,10-dimethyl-1-methoxy-11-(2 ethylpropyl)oxycarbonyl 5,6,7,8,12,12b-hexahydro-(9H)-4,8-methanobenzofuro[3,2 e]pyrrolo[2,3-g]isoquinoline hydrochloride), morphine) had minimal or no response decay. On the other hand, the decay rate was pronounced for deltorphin II, [d Pen(2), d-pen(5)]-enkephalin, met-enkephalin, and SNC-80 ((+)-4-[(alphaR)-alpha ((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-methoxybenzyl]-N,N diethylbenzamide), which displayed high signaling efficiency and internalization. Moreover, inhibition of internalization by dynasore reduced or abolished response decay by internalizing ligands. Unlike acute responses, endocytic profiles were not predictive of whether an agonist would induce prolonged cAMP inhibition over sustained (30-120 minutes) DOR stimulation. Taken together, the data indicate that ligand ability to evoke G-protein activation or promote endocytosis was predictive of response duration over short, but not over sustained periods of cAMP inhibition. PMID- 24174497 TI - Role of the N-terminal region in G protein-coupled receptor functions: negative modulation revealed by 5-HT2B receptor polymorphisms. AB - The putative role of the N-terminal region of rhodopsin-like 7 transmembrane biogenic amine receptors in agonist-induced signaling has not yet been clarified despite recent advances in 7 transmembrane receptor structural biology. Given the existence of N-terminal nonsynonymous polymorphisms (R6G;E42G) within the HTR2B gene in a drug-abusing population, we assessed whether these polymorphisms affect 5-hydroxytryptamine 2B (5-HT2B) receptor in vitro pharmacologic and coupling properties in transfected COS-7 cells. Modification of the 5-HT2B receptor N terminus by the R6G;E42G polymorphisms increases such agonist signaling pathways as inositol phosphate accumulation as assessed by either classic or operational models. The N-terminal R6G;E42G mutations of the 5-HT2B receptor also increase cell proliferation and slow its desensitization kinetics compared with the wild type receptor, further supporting a role for the N terminus in transduction efficacy. Furthermore, by coexpressing a tethered wild-type 5-HT2B receptor N terminus with a 5-HT2B receptor bearing a N-terminal deletion, we were able to restore original coupling. This reversion to normal activity of a truncated 5 HT2B receptor by coexpression of the membrane-tethered wild-type 5-HT2B receptor N terminus was not observed using a membrane-tethered 5-HT2B receptor R6G;E42G N terminus. These data suggest that the N terminus exerts a negative control over basal as well as agonist-stimulated receptor activity that is lost in the R6G;E42G mutant. Our findings reveal a new and unanticipated role of the 5-HT2B receptor N terminus as a negative modulator, affecting both constitutive and agonist-stimulated activity. Moreover, our data caution against excluding the N terminus and extracellular loops in structural studies of this 7 transmembrane receptor family. PMID- 24174498 TI - Management of bilateral ureteral trauma using ureteral stents and subsequent subcutaneous ureteral bypass devices in a cat. AB - This report describes a cat that presented with abdominal pain and worsening azotaemia following unknown trauma. Further diagnostic investigations and surgery confirmed bilateral ureteral trauma. The cat was initially managed surgically by bilateral ureteroureterostomy over ureteral stents. The clinical signs and biochemical parameters rapidly resolved, but 2 months later the cat developed signs consistent with sterile cystitis that was unresponsive to medical management. Removal of the ureteral stents resulted in severe azotaemia as a result of stricture formation at the previous ureteral anastomosis site. The ureteral stents were initially replaced with soft stents, but subsequently cut short owing to the persistence of clinical signs of cystitis. Following shortening of the ureteral stents severe azotaemia was again observed. The resulting pelvic dilatation allowed for placement of bilateral subcutaneous ureteral bypass (SUB) systems, which resulted in alleviation of all clinical signs 12 months after SUB placement. PMID- 24174499 TI - Transdermal application of methimazole in hyperthyroid cats: a long-term follow up study. AB - Transdermal methimazole is suggested as an alternative to oral therapy for hyperthyroid cats that are difficult to pill. However, no information on long term management with this treatment is available. Our objective was therefore to retrospectively evaluate the efficacy and safety of long-term transdermal methimazole treatment in hyperthyroid cats. Sixty cats with newly diagnosed hyperthyroidism and available long-term follow-up information were included. Methimazole was formulated in a pluronic lecithin organogel-based vehicle and was applied to the pinna of the inner ear. Cats were re-evaluated at regular intervals. Median (range) follow-up was 22.6 months (3.6-88.4 months). Clinical improvement was observed in all cats and side effects were rare (mild transient gastrointestinal signs: n = 3; erythema of the pinna: n = 2, necessitating a switch to oral medication). Despite a significant decrease, with median T4 concentrations within the reference interval during the follow-up period, several cats repeatedly had T4 concentrations in the thyrotoxic and hypothyroid range. Maximal and minimal daily doses during the follow-up period were 15.0 and 1.0 mg, respectively; they were significantly higher than the starting dose after 24-36 months of therapy. Although the majority of owners were highly satisfied with the treatment, several admitted not treating their cat regularly. Transdermal methimazole is a safe option for the long-term management of feline hyperthyroidism. However, it seems difficult to keep the T4 concentrations constantly within the reference interval. Higher doses can be expected after prolonged treatment and, despite the convenience of transdermal application, owner compliance should be assessed regularly. PMID- 24174500 TI - Ultrasonographic measurement of the relative thickness of intestinal wall layers in clinically healthy cats. AB - The normal sonographic thickness of the individual layers (ie, mucosa, submucosa, muscularis and subserosa-serosa) of the intestinal wall was evaluated in 20 clinically healthy cats. The mean thickness of the wall was 2.20, 2.22, 3.00 and 2.04 mm for duodenum, jejunum, ileum (fold) and ileum (between folds), respectively. The mean thickness of the mucosal layer was 1.27, 1.20, 0.46 and 0.49 mm for duodenum, jejunum, ileum (fold) and ileum (between folds), respectively, and its contribution to wall thickness was significantly greater than that of the other layers in the duodenum (57.7%) and jejunum (55.2%). The mean thickness of the submucosal layer was 0.36, 0.36, 1.49 and 0.53 mm for duodenum, jejunum, ileum (fold) and ileum (between folds), respectively, and its contribution to wall thickness was greater than that of the muscularis in the duodenum (16.3%), jejunum (16%) and ileum (fold) (49.8 %). The mean thickness of muscularis was 0.28, 0.35, 0.66 and 0.65 mm for duodenum, jejunum, ileum (fold) and ileum (between folds), respectively, with a corresponding contribution to wall thickness of 12.7 %, 14.4%, 22% and 31.6%. Finally, the mean thickness of serosa was 0.29, 0.31, 0.38 and 0.38 mm for duodenum, jejunum, ileum (fold) and ileum (between folds), respectively, with a corresponding contribution to wall thickness of 13.3%, 14.4%, 12.7 % and 18.7%. These values can provide baseline information that might be useful in evaluating intestinal disorders affecting preferentially some of the intestinal layers. PMID- 24174501 TI - Ultrasound-guided pudendal nerve block in cats undergoing perineal urethrostomy: a prospective, randomised, investigator-blind, placebo-controlled clinical trial. AB - The objective of this study was to evaluate the clinical usefulness, in terms of analgesic efficacy and safety, of ultrasound-guided pudendal nerve block performed with bupivacaine in cats undergoing perineal urethrostomy. Eighteen client-owned male cats scheduled for perineal urethrostomy were enrolled in the study and assigned to one of two treatment groups. The pudendal nerve block was performed under general anaesthesia, as described elsewhere, with 0.3 ml/kg of either saline (group C) or 0.5% bupivacaine (group B) - the total injection volume being split equally between the two sites of injection (left and right). Intra-operatively, assessment of nociception was based on the rescue analgesics requirement, as well as on the evaluation of changes in physiological parameters in comparison with the baseline values. Postoperative pain assessment was performed using three different pain scales at recovery and then 1, 2 and 3 h after recovery. Cats in group B showed lower heart rates and required fewer analgesics during surgery than group C. Postoperatively, group B had lower pain scores and needed less rescue buprenorphine than group C. Iatrogenic block related complications were not observed. In conclusion, the ultrasound-guided pudendal nerve block can be considered clinically useful in feline medicine as it provides reliable analgesia in cats undergoing perineal urethrostomy. PMID- 24174502 TI - In vitro biomechanical strain regulation of fibroblast wound healing. AB - CONTEXT: Strain-directed therapy such as vacuum compression and manual manipulative therapies are clinically effective, but their cellular and molecular mechanisms are not well understood. OBJECTIVE: To determine the effects of modeled myofascial release (MFR) on fibroblast wound healing and to investigate the potential role of nitric oxide (NO) in mediating these responses. METHODS: Using an in vitro scratch wound strain model, the authors investigated human fibroblast wound healing characteristics in response to injurious repetitive motion strain (RMS) and MFR. Secretion of NO was induced with interleukin-1beta and sodium nitroprusside and inhibited with NO synthase inhibitor L-N(G) monomethyl arginine citrate (L-NMMA) to determine the effects of NO on wound healing. Protein microarray was also performed to evaluate the expression of intracellular protein and activation of protein kinase G (PKG), extracellular signal-regulated kinase (ERK1/2), protein kinase C (PKC), and phosphoinositide 3 kinase (PI3K), the downstream effectors in the NO pathway. RESULTS: Fibroblasts that received RMS resulted in reduced wound closure rates (vs nonstrain, P<.05), which are partially attenuated by a single dose of MFR. Interleukin-1beta and exogenous NO did not appear to have an effect on nonstrained fibroblast wound healing. However, strained fibroblasts appeared to express increased sensitivity to NO. The authors also observed a 12.2% increase in NO secretion, an increase in PKG activation, and a downregulation of PKC and PI3K inhibitory domain in the combined strain group. CONCLUSION: If clinically translatable, these data suggest that mechanical strain such as vacuum compression therapy and manual manipulative therapy may modify PKC and PI3K to sensitize fibroblasts to NO and improve wound healing by promoting cell proliferation and migration by means of PKC and PKG signaling. PMID- 24174503 TI - Aortic stenosis: new thoughts on a cardiac disease of older people. AB - We have entered a new era in understanding degenerative aortic stenosis in elderly patients. With the aging of the US population and the progressive decrease in coronary heart disease prevalence in the past 50 years, aortic stenosis has become a major cardiac concern. New perspectives of the disease now lead us to see the condition in terms of the response of the left ventricle and of systemic features, rather than just in terms of the valve area itself. A new classification of aortic stenosis recognizes 4 categories based on flow state (normal or low) and valve gradient (high or low). "Paradoxical" low-flow, low gradient stenosis has a dismal prognosis in spite of a normal left ventricular ejection fraction. New measures of aortic flow and the response of the left ventricle provide new insights into the treatment of patients with this condition. PMID- 24174504 TI - Role of osteopathic structural diagnosis and osteopathic manipulative treatment for diabetes mellitus and its complications. AB - Osteopathic physicians have a unique opportunity to affect the US epidemic of type 2 diabetes mellitus (T2DM). Osteopathic physicians make up a disproportionately high number of primary care physicians who are on the front lines of managing T2DM. In addition, the unique training of osteopathic physicians allows them to direct additional diagnostic and treatment modalities toward the musculoskeletal complications of diabetes. The present review surveys the literature that explores the effects of osteopathic structural diagnosis of and osteopathic manipulative treatment for T2DM, as well as the management and prevention of complications. The authors reviewed the databases for PubMed, Google Scholar, and The Journal of the American Osteopathic Association. Although the available literature is limited, the authors identify areas in which osteopathic-focused research has shown benefits and in which future research should be directed. PMID- 24174505 TI - Tobacco dependence curricula in US osteopathic medical schools: a follow-up study. AB - CONTEXT: Tobacco use is the leading preventable cause of illness and death in the United States. A 1998 survey of US osteopathic medical schools identified deficiencies in tobacco dependence curricula. OBJECTIVE: To assess the current content and extent of tobacco dependence education and intervention skills in US osteopathic medical school curricula. DESIGN: An electronic survey. SETTING: Osteopathic medical schools with students enrolled for the 2009-2010 academic year. PARTICIPANTS: Twenty-seven osteopathic medical school deans or their designated administrators. MAIN OUTCOME MEASURES: Reported instruction in 7 basic science and 6 clinical science content areas (elective or required) and hours of tobacco dependence education were assessed and compared with the 1998 data. RESULTS: The mean (standard deviation) number of content areas reported as covered in 2010 was 10.6 (2.3) (6.1 [1.2] basic science areas, 4.6 [1.3] clinical science areas). Seventeen of 27 respondents (63%) reported that smokeless tobacco content was covered at their school, and 9 of 27 (33%) reported that the stages of change counseling technique was covered. Compared with 1998, a significant increase was noted in the percentage of schools covering tobacco dependence (92.6% in 2010 compared with 57.9% in 1998, P=.0002). Reported hours of tobacco dependence instruction were also significantly higher in 2010 compared with those in 1998 (Fisher exact test, P<.05). No statistically significant changes were found in the proportion of schools covering all 13 content areas (15.7% vs 22.2%), the proportion covering motivational interviewing in detail (26.3% vs 33.3%), or the proportion requiring curricula on smokeless tobacco (57.9% vs 59.3%). CONCLUSION: Osteopathic medical school respondents reported more instruction on tobacco dependence in 2010 compared with those in 1998. However, some important basic science and clinical science content areas are not being adequately taught in US osteopathic medical schools. PMID- 24174506 TI - Elements of manuscript submission. PMID- 24174507 TI - Thoracic splenosis more than 40 years after thoracoabdominal trauma. AB - Splenosis is a rare occurrence that is defined as autotransplantation of splenic tissue usually after splenic rupture due to trauma and subsequent splenectomy. Although splenosis most commonly occurs in the abdomen, the authors report a rare case of thoracic splenosis after remote thoracoabdominal trauma. A 62-year-old woman was found to have lower-lobe, pleural-based nodular lesions in juxtaposition to the posteromedial segment of the lung during workup for an abdominal hernia. Surgical excision of the mass confirmed the diagnosis of ectopic splenic tissue, and splenosis was diagnosed. This woman was among the rare 18% of people who are found to have splenosis in the intrathoracic space. In the workup of pulmonary nodules in patients with a history of trauma, splenosis should be a consideration. PMID- 24174508 TI - Osteopathic manipulative treatment in tarsal somatic dysfunction: a case study. AB - The authors present a case of a 24-year-old woman with left foot pain that began after an inversion injury obtained while running. The pain minimally improved with nonsteroidal anti-inflammatory medications. Clinical examination revealed a relatively normal foot with palpable changes in the bony structures at the midfoot consistent with a tarsal subluxation. Cuboid reduction was performed using high-velocity, low-amplitude manipulation, after which the patient reported immediate and near-complete pain relief. The authors also review mechanisms of injury, clinical findings, and treatment modalities for patients with tarsal subluxation. PMID- 24174509 TI - Roth spots in native valve endocarditis. PMID- 24174510 TI - What do vitamin takers and drug addicts have in common? PMID- 24174511 TI - Lupus in Africa: can we dispel the myths and face the challenges? AB - The epidemiology of systemic lupus erythematosus (SLE) in Africa is largely undetermined, and the perception persists that the incidence of SLE on the continent is very low. Recent studies as well as our own experience, however, suggest that this is not the case. We have conducted a survey amongst medical practitioners in Africa to determine their experiences of diagnosing and treating SLE patients, and the results suggest that significant numbers of African patients are presenting with SLE. The apparent low incidence rate in Africa may be the result of underdiagnosis due to poor access to health care, low disease recognition within primary health care settings, limited access to diagnostic tools and inadequate numbers of specialist physicians. Treatment of SLE in Africa is also restricted by availability and affordability of immunosuppressive drugs. We have established the African Lupus Genetics Network (ALUGEN), an informal network of clinicians and researchers in Africa who have an interest in SLE, in order to facilitate combined clinical and research efforts towards improved outcomes for African SLE patients. PMID- 24174512 TI - Pre-polysomnographic assessment using the Pittsburgh Sleep Quality Index questionnaire is not useful in identifying people at higher risk for obstructive sleep apnea. AB - BACKGROUND: Polysomnography remains the diagnostic gold standard for obstructive sleep apnea syndrome (OSAS), but it is time consuming and requires dedicated personnel and setting. It may be more useful to plan a polysomnogram based on a preliminary screening. OBJECTIVE: To verify whether a questionnaire of general quality of sleep, the Pittsburgh Sleep Quality Index (PSQI), could outperform a dedicated questionnaire (Epworth Sleep Scale: ESS) in targeting OSAS patients in an at risk population. METHODS: 254 consecutive subjects attending the outpatient clinic for respiratory diseases were clinically evaluated for sleep apnea and referred to a 12 channel night-time polysomnography. All patients were administered the ESS and the PSQI before the procedure. The correlation between the Apnoea/Hypopnoea Index (AHI) and the global score of the PSQI was calculated; Sensitivity, specificity, positive and negative predictive values (PPV and NPV, respectively), Diagnostic accuracy and the area under the receiver operating characteristic curve (AUC) were calculated. ESS performance was used as a control reference. RESULTS: The mean age was 65.8 (standard deviation: 12.1) and the study group was 68.4% male. The mean BMI was 38.5; SD 7.7. Prevalence of OSAS in the study population was 55.5%; OSAS was severe in 60.5% of OSAS patients. ESS was significantly, but weakly, correlated with the AHI (AHI vs ESS: R = 0.308; p < 0.001), whereas PSQI was not (R = 0.037; p = 0.581). Both PSQI and ESS, however, performed unsatisfactorily: sensitivity 37.8% and 69.7%; Specificity 76.1% and 31.0%; Diagnostic Accuracy 57.5% and 49.8%; PPV 60% and 48.7%; NPV 56.3% and 52.2%; AUC 0.589 and 0.509, respectively. CONCLUSIONS: The PSQI score is not helpful in the pre-polysomnographic assessment of people with suspected OSAS. Further studies are required to provide reliable pre-clinical instruments targeting patients amenable to polysomnography. PMID- 24174515 TI - Executive summary. PMID- 24174513 TI - Preface. PMID- 24174516 TI - 1. Introduction. PMID- 24174517 TI - 2. Interactions of electrons and photons with matter. PMID- 24174518 TI - 3. Description of irradiation facilities. PMID- 24174519 TI - 4. General aspects of dosimetry for radiation processing. PMID- 24174520 TI - 5. Dosimetry systems. PMID- 24174521 TI - Appendix 1. PMID- 24174522 TI - Appendix 2. PMID- 24174526 TI - Regulation of nuclear factor kappaB (NF-kappaB) in the nucleus of cardiomyocytes by G protein-coupled receptor kinase 5 (GRK5). AB - G protein-coupled receptor kinase 5 GRK5 plays a key role in regulating cardiac signaling and its expression is increased in heart failure. GRK5 activity in the nucleus of myocytes has been shown to be detrimental in the setting of pressure overload hypertrophy. The ubiquitous nuclear transcription factor kappaB (NF kappaB) is involved in the regulation of numerous genes in various tissues, and activation of NF-kappaB has been shown to be associated with heart disease. Herein, we investigated whether GRK5 can specifically regulate the NF-kappaB signaling pathway in myocytes. We found that overexpression of GRK5 increased the levels of NF-kappaB -p50 and p65 in vitro and in vivo, whereas loss of GRK5 resulted in lower cardiac NF-kappaB levels. Furthermore, increased GRK5 expression induced the phosphorylation status of p65, increased the activity of a NF-kappaB reporter, and increased NF-kappaB DNA binding activity in cultured neonatal rat ventricular myocytes. Importantly, siRNA against GRK5 presented with the opposite results in neonatal rat ventricular myocytes as p65 and p50 were decreased, and there was a loss of NF-kappaB DNA binding activity. The influence of GRK5 on NF-kappaB expression and activity was dependent on its nuclear localization as overexpression of a mutant GRK5 that cannot enter the nucleus was devoid of NF-kappaB activation or DNA binding. Our study demonstrates that a novel pathological consequence of GRK5 up-regulation in the injured and failing heart is the induction of NF-kappaB expression and activity. PMID- 24174527 TI - Carboxyl-terminal domain of transient receptor potential vanilloid 1 contains distinct segments differentially involved in capsaicin- and heat-induced desensitization. AB - Multiple Ca(2+)-dependent processes are involved in capsaicin-induced desensitization of transient receptor potential vanilloid 1 (TRPV1), but desensitization of TRPV1 by heat occurs even in the absence of extracellular Ca(2+), although the mechanisms are unknown. In this study, we tested the hypothesis that capsaicin and heat desensitize TRPV1 through distinct mechanisms involving distinct structural segments of TRPV1. In HEK293 cells that heterologously express TRPV1, we found that heat-induced desensitization was not affected by the inclusion of intracellular ATP or alanine mutation of Lys(155), both of which attenuate capsaicin-induced desensitization, suggesting that heat induced desensitization occurs through mechanisms distinct from capsaicin-induced desensitization. To determine protein domains involved in heat-induced desensitization, we generated chimeric proteins between TRPV1 and TRPV3, a heat gated channel lacking heat-induced desensitization. We found that TRPV1 with the carboxyl-terminal domain (CTD) of TRPV3 retained heat activation but was impaired in heat-induced desensitization. Further experiments using chimeric or deletion mutants within TRPV1 CTD indicated that the distal half of CTD regulates the activation and desensitization of TRPV1 in modality-specific manners. Within the distal CTD, we identified two segments that distinctly regulated capsaicin- and heat-induced desensitization. The results suggest that the activation and desensitization of TRPV1 by capsaicin and heat can be modulated differentially and disproportionally through different regions of TRPV1 CTD. Identifying the domains involved in thermal regulation of TRPV1 may facilitate the development of novel anti-hyperalgesic approaches aimed at attenuating activation and enhancing desensitization of TRPV1 by thermal stimuli. PMID- 24174528 TI - Structure of the cyanobacterial phytochrome 2 photosensor implies a tryptophan switch for phytochrome signaling. AB - Phytochromes are highly versatile photoreceptors, which occur ubiquitously in plants as well as in many light-responsive microorganisms. Here, photosynthetic cyanobacteria utilize up to three different phytochrome architectures, where only the plant-like and the single-domain cyanobacteriochromes are structurally characterized so far. Cph2 represents a third group in Synechocystis species and affects their capability of phototaxis by controlling c-di-GMP synthesis and degradation. The 2.6-A crystal structure of its red/far-red responsive photosensory module in the Pr state reveals a tandem-GAF bidomain that lacks the figure-of-eight knot of the plant/cph1 subfamily. Its covalently attached phycocyanobilin chromophore adopts a highly tilted ZZZssa conformation with a novel set of interactions between its propionates and the GAF1 domain. The tongue like protrusion from the GAF2 domain interacts with the GAF1-bound chromophore via its conserved PRXSF, WXE, and W(G/A)G motifs. Mutagenesis showed that the integrity of the tongue is indispensable for Pr -> Pfr photoconversion and involves a swap of the motifs' tryptophans within the tongue-GAF1 interface. This "Trp switch" is supposed to be a crucial element for the photochromicity of all multidomain phytochromes. PMID- 24174530 TI - Ovarian dual oxidase (Duox) activity is essential for insect eggshell hardening and waterproofing. AB - In insects, eggshell hardening involves cross-linking of chorion proteins via their tyrosine residues. This process is catalyzed by peroxidases at the expense of H2O2 and confers physical and biological protection to the developing embryo. Here, working with Rhodnius prolixus, the insect vector of Chagas disease, we show that an ovary dual oxidase (Duox), a NADPH oxidase, is the source of the H2O2 that supports dityrosine-mediated protein cross-linking and eggshell hardening. RNAi silencing of Duox activity decreased H2O2 generation followed by a failure in embryo development caused by a reduced resistance to water loss, which, in turn, caused embryos to dry out following oviposition. Phenotypes of Duox-silenced eggs were reversed by incubation in a water-saturated atmosphere, simultaneous silencing of the Duox and catalase genes, or H2O2 injection into the female hemocoel. Taken together, our results show that Duox-generated H2O2 fuels egg chorion hardening and that this process plays an essential role during eggshell waterproofing. PMID- 24174529 TI - Identification of a non-covalent ternary complex formed by PIAS1, SUMO1, and UBC9 proteins involved in transcriptional regulation. AB - Post-translational modifications with ubiquitin-like proteins require three sequentially acting enzymes (E1, E2, and E3) that must unambiguously recognize each other in a coordinated fashion to achieve their functions. Although a single E2 (UBC9) and few RING-type E3s (PIAS) operate in the SUMOylation system, the molecular determinants regulating the interactions between UBC9 and the RING-type E3 enzymes are still not well defined. In this study we use biochemical and functional experiments to characterize the interactions between PIAS1 and UBC9. Our results reveal that UBC9 and PIAS1 are engaged both in a canonical E2.E3 interaction as well as assembled into a previously unidentified non-covalent ternary complex with SUMO as evidenced by bioluminescence resonance energy transfer, nuclear magnetic resonance spectroscopy, and isothermal titration calorimetry studies. In this ternary complex, SUMO functions as a bridge by forming non-overlapping interfaces with UBC9 and PIAS1. Moreover, our data suggest that phosphorylation of serine residues adjacent to the PIAS1 SUMO interacting motif favors formation of the non covalent PIAS1.SUMO.UBC9 ternary complex. Finally, our results also indicate that the non-covalent ternary complex is required for the known transcriptional repression activities mediated by UBC9 and SUMO1. Taken together, the data enhance our knowledge concerning the mode of interaction of enzymes of the SUMOylation machinery as well as their role in transcriptional regulation and establishes a framework for investigations of other ubiquitin-like protein systems. PMID- 24174531 TI - Early B-cell factor-1 (EBF1) is a key regulator of metabolic and inflammatory signaling pathways in mature adipocytes. AB - EBF1 plays a crucial role in early adipogenesis; however, despite high expression in mature adipocytes, its function in these cells is currently unknown. To identify direct and indirect EBF1 targets in fat, we undertook a combination of transcriptional profiling of EBF1-deficient adipocytes and genome-wide EBF1 location analysis. Our results indicate that many components of metabolic and inflammatory pathways are positively and directly regulated by EBF1, including PI3K/AKT, MAPK, and STAT1 signaling. Accordingly, we observed significant reduction of multiple signaling events in EBF1 knockdown cells as well as a reduction in insulin-stimulated glucose uptake and lipogenesis. Inflammatory signaling, gene expression, and secretion of inflammatory cytokines were also significantly affected by loss of EBF1 in adipocytes, although ChIP-sequencing results suggest that these actions are indirect. We also found that EBF1 occupies some 35,000 sites in adipocytes, most of which occur in enhancers. Significantly, comparison with three other published EBF1 ChIP-sequencing data sets in B-cells reveals both gene- and cell type-specific patterns of EBF1 binding. These results advance our understanding of the transcriptional mechanisms regulating signaling pathways in mature fat cells and indicate that EBF1 functions as a key integrator of signal transduction, inflammation, and metabolism. PMID- 24174532 TI - Suppression of lysosome function induces autophagy via a feedback down-regulation of MTOR complex 1 (MTORC1) activity. AB - Autophagy can be activated via MTORC1 down-regulation by amino acid deprivation and by certain chemicals such as rapamycin, torin, and niclosamide. Lysosome is the degrading machine for autophagy but has also been linked to MTORC1 activation through the Rag/RRAG GTPase pathway. This association raises the question of whether lysosome can be involved in the initiation of autophagy. Toward this end, we found that niclosamide, an MTORC1 inhibitor, was able to inhibit lysosome degradation and increase lysosomal permeability. Niclosamide was ineffective in inhibiting MTORC1 in cells expressing constitutively activated Rag proteins, suggesting that its inhibitory effects were targeted to the Rag-MTORC1 signaling system. This places niclosamide in the same category of bafilomycin A1 and concanamycin A, inhibitors of the vacuolar H(+)-ATPase, for its dependence on Rag GTPase in suppression of MTORC1. Surprisingly, classical lysosome inhibitors such as chloroquine, E64D, and pepstatin A were also able to inhibit MTORC1 in a Rag dependent manner. These lysosome inhibitors were able to activate early autophagy events represented by ATG16L1 and ATG12 puncta formation. Our work established a link between the functional status of the lysosome in general to the Rag-MTORC1 signaling axis and autophagy activation. Thus, the lysosome is not only required for autophagic degradation but also affects autophagy activation. Lysosome inhibitors can have a dual effect in suppressing autophagy degradation and in initiating autophagy. PMID- 24174533 TI - Identification of a novel role of ZMIZ2 protein in regulating the activity of the Wnt/beta-catenin signaling pathway. AB - ZMIZ2, also named ZIMP7, is a protein inhibitor of activated STAT (PIAS)-like protein and a transcriptional coactivator. In this study, we investigated the interaction between ZMIZ2 and beta-catenin, a key regulator of the Wnt signaling pathway. We demonstrated that the expression of exogenous ZMIZ2 augments TCF (T cell factor) and beta-catenin-mediated transcription. In contrast, shRNA knockdown of ZMIZ2 expression specifically represses the enhancement of TCF/beta catenin-mediated transcription by ZMIZ2. Using Wnt3a-conditioned medium, we demonstrated that ZMIZ2 can enhance Wnt ligand-induced TCF/beta-catenin-mediated transcription. We also showed a promotional role of ZMIZ2 in enhancing beta catenin downstream target gene expression in human cells and in Zmiz2 null (Zmiz2(-/-)) mouse embryonic fibroblasts (MEFs). The regulatory role of Zmiz2 in Wnt-induced TCF/beta-catenin-mediated transcription can be restored in Zmiz2(-/-) MEFs that were infected with adenoviral expression vectors for Zmiz2. Moreover, enhancement of Zmiz2 on TCF/beta-catenin-mediated transcription was further demonstrated in Zmiz2 knockout and Axin2 reporter compound mice. Furthermore, the protein-protein interaction between ZMIZ2 and beta-catenin was identified by co immunoprecipitation and in vitro protein pulldown assays. We also observed recruitment of endogenous ZMIZ2 onto the promoter region of the Axin 2 gene, a beta-catenin downstream target promoter, in a Wnt ligand-inducible manner. Finally, a promotional role of ZMIZ2 on cell growth was demonstrated in human cell lines and Zmiz2 knockout MEFs. Our findings demonstrate a novel interaction between ZMIZ2 and beta-catenin and elucidate a novel mechanism for PIAS-like proteins in regulating Wnt signaling pathways. PMID- 24174534 TI - miR-200b and cancer/testis antigen CAGE form a feedback loop to regulate the invasion and tumorigenic and angiogenic responses of a cancer cell line to microtubule-targeting drugs. AB - Cancer/testis antigen cancer-associated gene (CAGE) is known to be involved in various cellular processes, such as proliferation, cell motility, and anti-cancer drug resistance. However, the mechanism of the expression regulation of CAGE remains unknown. Target scan analysis predicted the binding of microRNA-200b (miR 200b) to CAGE promoter sequences. The expression of CAGE showed an inverse relationship with miR-200b in various cancer cell lines. miR-200b was shown to bind to the 3'-UTR of CAGE and to regulate the expression of CAGE at the transcriptional level. miR-200b also enhanced the sensitivities to microtubule targeting drugs in vitro. miR-200b and CAGE showed opposite regulations on invasion potential and responses to microtubule-targeting drugs. Xenograft experiments showed that miR-200b had negative effects on the tumorigenic and metastatic potential of cancer cells. The effect of miR-200b on metastatic potential involved the expression regulation of CAGE by miR-200b. miR-200b decreased the tumorigenic potential of a cancer cell line resistant to microtubule-targeting drugs in a manner associated with the down-regulation of CAGE. ChIP assays showed the direct regulation of miR-200b by CAGE. CAGE enhanced the invasion potential of a cancer cell line stably expressing miR-200b. miR-200b exerted a negative regulation on tumor-induced angiogenesis. The down-regulation of CAGE led to the decreased expression of plasminogen activator inhibitor-1, a TGFbeta-responsive protein involved in angiogenesis, and VEGF. CAGE mediated tumor-induced angiogenesis and was necessary for VEGF-promoted angiogenesis. Human recombinant CAGE protein displayed angiogenic potential. Thus, miR-200b and CAGE form a feedback regulatory loop and regulate the response to microtubule targeting drugs, as well as the invasion, tumorigenic potential, and angiogenic potential. PMID- 24174535 TI - Box C/D small nucleolar RNA (snoRNA) U60 regulates intracellular cholesterol trafficking. AB - Mobilization of plasma membrane (PM) cholesterol to the endoplasmic reticulum is essential for cellular cholesterol homeostasis. The mechanisms regulating this retrograde, intermembrane cholesterol transfer are not well understood. Because mutant cells with defects in PM to endoplasmic reticulum cholesterol trafficking can be isolated on the basis of resistance to amphotericin B, we conducted an amphotericin B loss-of-function screen in Chinese hamster ovary (CHO) cells using insertional mutagenesis to identify genes that regulate this trafficking mechanism. Mutant line A1 displayed reduced cholesteryl ester formation from PM derived cholesterol and increased de novo cholesterol synthesis, indicating a deficiency in retrograde cholesterol transport. Genotypic analysis revealed that the A1 cell line contained one disrupted allele of the U60 small nucleolar RNA (snoRNA) host gene, resulting in haploinsufficiency of the box C/D snoRNA U60. Complementation and mutational studies revealed the U60 snoRNA to be the essential feature from this locus that affects cholesterol trafficking. Lack of alteration in predicted U60-mediated site-directed methylation of 28 S rRNA in the A1 mutant suggests that the U60 snoRNA modulates cholesterol trafficking by a mechanism that is independent of this canonical function. Our study adds to a growing body of evidence for participation of small noncoding RNAs in cholesterol homeostasis and is the first to implicate a snoRNA in this cellular function. PMID- 24174536 TI - GeneProf data: a resource of curated, integrated and reusable high-throughput genomics experiments. AB - GeneProf Data (http://www.geneprof.org) is an open web resource for analysed functional genomics experiments. We have built up a large collection of completely processed RNA-seq and ChIP-seq studies by carefully and transparently reanalysing and annotating high-profile public data sets. GeneProf makes these data instantly accessible in an easily interpretable, searchable and reusable manner and thus opens up the path to the advantages and insights gained from genome-scale experiments to a broader scientific audience. Moreover, GeneProf supports programmatic access to these data via web services to further facilitate the reuse of experimental data across tools and laboratories. PMID- 24174537 TI - The Database of Genomic Variants: a curated collection of structural variation in the human genome. AB - Over the past decade, the Database of Genomic Variants (DGV; http://dgv.tcag.ca/) has provided a publicly accessible, comprehensive curated catalogue of structural variation (SV) found in the genomes of control individuals from worldwide populations. Here, we describe updates and new features, which have expanded the utility of DGV for both the basic research and clinical diagnostic communities. The current version of DGV consists of 55 published studies, comprising >2.5 million entries identified in >22,300 genomes. Studies included in DGV are selected from the accessioned data sets in the archival SV databases dbVar (NCBI) and DGVa (EBI), and then further curated for accuracy and validity. The core visualization tool (gbrowse) has been upgraded with additional functions to facilitate data analysis and comparison, and a new query tool has been developed to provide flexible and interactive access to the data. The content from DGV is regularly incorporated into other large-scale genome reference databases and represents a standard data resource for new product and database development, in particular for copy number variation testing in clinical labs. The accurate cataloguing of variants in DGV will continue to enable medical genetics and genome sequencing research. PMID- 24174538 TI - Hox in motion: tracking HoxA cluster conformation during differentiation. AB - Three-dimensional genome organization is an important higher order transcription regulation mechanism that can be studied with the chromosome conformation capture techniques. Here, we combined chromatin organization analysis by chromosome conformation capture-carbon copy, computational modeling and epigenomics to achieve the first integrated view, through time, of a connection between chromatin state and its architecture. We used this approach to examine the chromatin dynamics of the HoxA cluster in a human myeloid leukemia cell line at various stages of differentiation. We found that cellular differentiation involves a transient activation of the 5'-end HoxA genes coinciding with a loss of contacts throughout the cluster, and by specific silencing at the 3'-end with H3K27 methylation. The 3D modeling of the data revealed an extensive reorganization of the cluster between the two previously reported topologically associated domains in differentiated cells. Our results support a model whereby silencing by polycomb group proteins and reconfiguration of CTCF interactions at a topologically associated domain boundary participate in changing the HoxA cluster topology, which compartmentalizes the genes following differentiation. PMID- 24174539 TI - pE-DB: a database of structural ensembles of intrinsically disordered and of unfolded proteins. AB - The goal of pE-DB (http://pedb.vib.be) is to serve as an openly accessible database for the deposition of structural ensembles of intrinsically disordered proteins (IDPs) and of denatured proteins based on nuclear magnetic resonance spectroscopy, small-angle X-ray scattering and other data measured in solution. Owing to the inherent flexibility of IDPs, solution techniques are particularly appropriate for characterizing their biophysical properties, and structural ensembles in agreement with these data provide a convenient tool for describing the underlying conformational sampling. Database entries consist of (i) primary experimental data with descriptions of the acquisition methods and algorithms used for the ensemble calculations, and (ii) the structural ensembles consistent with these data, provided as a set of models in a Protein Data Bank format. PE-DB is open for submissions from the community, and is intended as a forum for disseminating the structural ensembles and the methodologies used to generate them. While the need to represent the IDP structures is clear, methods for determining and evaluating the structural ensembles are still evolving. The availability of the pE-DB database is expected to promote the development of new modeling methods and leads to a better understanding of how function arises from disordered states. PMID- 24174540 TI - Telomeric repeats act as nucleosome-disfavouring sequences in vivo. AB - Telomeric DNAs consist of tandem repeats of G-clusters such as TTAGGG and TG1-3, which are the human and yeast repeat sequences, respectively. In the yeast Saccharomyces cerevisiae, the telomeric repeats are non-nucleosomal, whereas in humans, they are organized in tightly packaged nucleosomes. However, previous in vitro studies revealed that the binding affinities of human and yeast telomeric repeat sequences to histone octamers in vitro were similar, which is apparently inconsistent with the differences in the human and yeast telomeric chromatin structures. To further investigate the relationship between telomeric sequences and chromatin structure, we examined the effect of telomeric repeats on the formation of positioned nucleosomes in vivo by indirect end-label mapping, primer extension mapping and nucleosome repeat analyses, using a defined minichromosome in yeast cells. We found that the human and yeast telomeric repeat sequences both disfavour nucleosome assembly and alter nucleosome positioning in the yeast minichromosome. We further demonstrated that the G-clusters in the telomeric repeats are required for the nucleosome-disfavouring properties. Thus, our results suggest that this inherent structural feature of the telomeric repeat sequences is involved in the functional dynamics of the telomeric chromatin structure. PMID- 24174541 TI - P-MITE: a database for plant miniature inverted-repeat transposable elements. AB - Miniature inverted-repeat transposable elements (MITEs) are prevalent in eukaryotic species including plants. MITE families vary dramatically and usually cannot be identified based on homology. In this study, we de novo identified MITEs from 41 plant species, using computer programs MITE Digger, MITE-Hunter and/or Repetitive Sequence with Precise Boundaries (RSPB). MITEs were found in all, but one (Cyanidioschyzon merolae), species. Combined with the MITEs identified previously from the rice genome, >2.3 million sequences from 3527 MITE families were obtained from 41 plant species. In general, higher plants contain more MITEs than lower plants, with a few exceptions such as papaya, with only 538 elements. The largest number of MITEs is found in apple, with 237 302 MITE sequences. The number of MITE sequences in a genome is significantly correlated with genome size. A series of databases (plant MITE databases, P-MITE), available online at http://pmite.hzau.edu.cn/django/mite/, was constructed to host all MITE sequences from the 41 plant genomes. The databases are available for sequence similarity searches (BLASTN), and MITE sequences can be downloaded by family or by genome. The databases can be used to study the origin and amplification of MITEs, MITE-derived small RNAs and roles of MITEs on gene and genome evolution. PMID- 24174542 TI - Defining the roles of the N-terminal region and the helicase activity of RECQ4A in DNA repair and homologous recombination in Arabidopsis. AB - RecQ helicases are critical for the maintenance of genomic stability. The Arabidopsis RecQ helicase RECQ4A is the functional counterpart of human BLM, which is mutated in the genetic disorder Bloom's syndrome. RECQ4A performs critical roles in regulation of homologous recombination (HR) and DNA repair. Loss of RECQ4A leads to elevated HR frequencies and hypersensitivity to genotoxic agents. Through complementation studies, we were now able to demonstrate that the N-terminal region and the helicase activity of RECQ4A are both essential for the cellular response to replicative stress induced by methyl methanesulfonate and cisplatin. In contrast, loss of helicase activity or deletion of the N-terminus only partially complemented the mutant hyper-recombination phenotype. Furthermore, the helicase-deficient protein lacking its N-terminus did not complement the hyper-recombination phenotype at all. Therefore, RECQ4A seems to possess at least two different and independent sub-functions involved in the suppression of HR. By in vitro analysis, we showed that the helicase core was able to regress an artificial replication fork. Swapping of the terminal regions of RECQ4A with the closely related but functionally distinct helicase RECQ4B indicated that in contrast to the C-terminus, the N-terminus of RECQ4A was required for its specific functions in DNA repair and recombination. PMID- 24174543 TI - Hemolytik: a database of experimentally determined hemolytic and non-hemolytic peptides. AB - Hemolytik (http://crdd.osdd.net/raghava/hemolytik/) is a manually curated database of experimentally determined hemolytic and non-hemolytic peptides. Data were compiled from a large number of published research articles and various databases like Antimicrobial Peptide Database, Collection of Anti-microbial Peptides, Dragon Antimicrobial Peptide Database and Swiss-Prot. The current release of Hemolytik database contains ~3000 entries that include ~2000 unique peptides whose hemolytic activities were evaluated on erythrocytes isolated from as many as 17 different sources. Each entry in Hemolytik provides comprehensive information about a peptide, like its name, sequence, origin, reported function, property such as chirality, types (linear and cyclic), end modifications as well as details pertaining to its hemolytic activity. In addition, tertiary structure of each peptide has been predicted, and secondary structure states have been assigned. To facilitate the scientific community, a user-friendly interface has been developed with various tools for data searching and analysis. We hope, Hemolytik will be useful for researchers working in the field of designing therapeutic peptides. PMID- 24174544 TI - PlantTFDB 3.0: a portal for the functional and evolutionary study of plant transcription factors. AB - With the aim to provide a resource for functional and evolutionary study of plant transcription factors (TFs), we updated the plant TF database PlantTFDB to version 3.0 (http://planttfdb.cbi.pku.edu.cn). After refining the TF classification pipeline, we systematically identified 129 288 TFs from 83 species, of which 67 species have genome sequences, covering main lineages of green plants. Besides the abundant annotation provided in the previous version, we generated more annotations for identified TFs, including expression, regulation, interaction, conserved elements, phenotype information, expert curated descriptions derived from UniProt, TAIR and NCBI GeneRIF, as well as references to provide clues for functional studies of TFs. To help identify evolutionary relationship among identified TFs, we assigned 69 450 TFs into 3924 orthologous groups, and constructed 9217 phylogenetic trees for TFs within the same families or same orthologous groups, respectively. In addition, we set up a TF prediction server in this version for users to identify TFs from their own sequences. PMID- 24174545 TI - HapFABIA: identification of very short segments of identity by descent characterized by rare variants in large sequencing data. AB - Identity by descent (IBD) can be reliably detected for long shared DNA segments, which are found in related individuals. However, many studies contain cohorts of unrelated individuals that share only short IBD segments. New sequencing technologies facilitate identification of short IBD segments through rare variants, which convey more information on IBD than common variants. Current IBD detection methods, however, are not designed to use rare variants for the detection of short IBD segments. Short IBD segments reveal genetic structures at high resolution. Therefore, they can help to improve imputation and phasing, to increase genotyping accuracy for low-coverage sequencing and to increase the power of association studies. Since short IBD segments are further assumed to be old, they can shed light on the evolutionary history of humans. We propose HapFABIA, a computational method that applies biclustering to identify very short IBD segments characterized by rare variants. HapFABIA is designed to detect short IBD segments in genotype data that were obtained from next-generation sequencing, but can also be applied to DNA microarray data. Especially in next-generation sequencing data, HapFABIA exploits rare variants for IBD detection. HapFABIA significantly outperformed competing algorithms at detecting short IBD segments on artificial and simulated data with rare variants. HapFABIA identified 160 588 different short IBD segments characterized by rare variants with a median length of 23 kb (mean 24 kb) in data for chromosome 1 of the 1000 Genomes Project. These short IBD segments contain 752 000 single nucleotide variants (SNVs), which account for 39% of the rare variants and 23.5% of all variants. The vast majority 152 000 IBD segments-are shared by Africans, while only 19 000 and 11 000 are shared by Europeans and Asians, respectively. IBD segments that match the Denisova or the Neandertal genome are found significantly more often in Asians and Europeans but also, in some cases exclusively, in Africans. The lengths of IBD segments and their sharing between continental populations indicate that many short IBD segments from chromosome 1 existed before humans migrated out of Africa. Thus, rare variants that tag these short IBD segments predate human migration from Africa. The software package HapFABIA is available from Bioconductor. All data sets, result files and programs for data simulation, preprocessing and evaluation are supplied at http://www.bioinf.jku.at/research/short-IBD. PMID- 24174546 TI - The insect-phase gRNA transcriptome in Trypanosoma brucei. AB - One of the most striking examples of small RNA regulation of gene expression is the process of RNA editing in the mitochondria of trypanosomes. In these parasites, RNA editing involves extensive uridylate insertions and deletions within most of the mitochondrial messenger RNAs (mRNAs). Over 1200 small guide RNAs (gRNAs) are predicted to be responsible for directing the sequence changes that create start and stop codons, correct frameshifts and for many of the mRNAs generate most of the open reading frame. In addition, alternative editing creates the opportunity for unprecedented protein diversity. In Trypanosoma brucei, the vast majority of gRNAs are transcribed from minicircles, which are approximately one kilobase in size, and encode between three and four gRNAs. The large number (5000-10,000) and their concatenated structure make them difficult to sequence. To identify the complete set of gRNAs necessary for mRNA editing in T. brucei, we used Illumina deep sequencing of purified gRNAs from the procyclic stage. We report a near complete set of gRNAs needed to direct the editing of the mRNAs. PMID- 24174548 TI - Biophysical characterization of the C-terminal region of FliG, an essential rotor component of the Na+-driven flagellar motor. AB - The bacterial flagellar motor generates a rotational force by the flow of ions through the membrane. The rotational force is generated by the interaction between the cytoplasmic regions of the rotor and the stator. FliG is directly involved in the torque generation of the rotor protein by its interaction. FliG is composed of three domains: the N-terminal, Middle and C-terminal domains, based on its structure. The C-terminal domain of FliG is assumed to be important for the interaction with the stator that generates torque. In this study, using CD spectra, gel filtration chromatography and DSC (differential scanning calorimetry), we characterized the physical properties of the C-terminal domain (G214-Stop) of wild-type (WT) FliG and its non-motile phenotype mutant derivatives (L259Q, L270R and L271P), which were derived from the sodium-driven motor of Vibrio. The CD spectra and gel filtration chromatography revealed a slight difference between the WT and the mutant FliG proteins, but the DSC results suggested a large difference in their stabilities. That structural difference was confirmed by differences in protease sensitivity. Based on these results, we conclude that mutations which confer the non-motile phenotype destabilize the C-terminal domain of FliG. PMID- 24174547 TI - Regulation of the HDM2-p53 pathway by ribosomal protein L6 in response to ribosomal stress. AB - The HDM2-p53 loop is crucial for monitoring p53 level and human pathologies. Therefore, identification of novel molecules involved in this regulatory loop is necessary for understanding the dynamic regulation of p53 and treatment of human diseases. Here, we characterized that the ribosomal protein L6 binds to and suppresses the E3 ubiquitin ligase activity of HDM2, and subsequently attenuates HDM2-mediated p53 polyubiquitination and degradation. The enhanced p53 activity further slows down cell cycle progression and leads to cell growth inhibition. Conversely, the level of p53 is dramatically decreased upon the depletion of RPL6, indicating that RPL6 is essential for p53 stabilization. We also found that RPL6 translocalizes from the nucleolus to nucleoplasm under ribosomal stress, which facilitates its binding with HDM2. The interaction of RPL6 and HDM2 drives HDM2-mediated RPL6 polyubiquitination and proteasomal degradation. Longer treatment of actinomycin D increases RPL6 ubiquitination and destabilizes RPL6, and thereby putatively attenuates p53 response until the level of L6 subsides. Therefore, RPL6 and HDM2 form an autoregulatory feedback loop to monitor the level of p53 in response to ribosomal stress. Together, our study identifies the crucial function of RPL6 in regulating HDM2-p53 pathway, which highlights the importance of RPL6 in human genetic diseases and cancers. PMID- 24174549 TI - Methane emissions from beef and dairy cattle: quantifying the effect of physiological stage and diet characteristics. AB - The prediction of methane outputs from ruminant livestock data at farm, national, and global scales is a vital part of greenhouse gas calculations. The objectives of this work were to quantify the effect of physiological stage (lactating or nonlactating) on predicting methane (CH4) outputs and to illustrate the potential improvement for a beef farming system of using more specific mathematical models to predict CH4 from cattle at different physiological stages and fed different diet types. A meta-analysis was performed on 211 treatment means from 38 studies where CH4, intake, animal, and feed characteristics had been recorded. Additional information such as type of enterprise, diet type, physiological stage, CH4 measurement technique, intake restriction, and CH4 reduction treatment application from these studies were used as classificatory factors. A series of equations for different physiological stages and diet types based on DMI or GE intake explained 96% of the variation in observed CH4 outputs (P<0.001). Resulting models were validated with an independent dataset of 172 treatment means from 20 studies. To illustrate the scale of improvement on predicted CH4 outputs from the current whole-farm prediction approach (Intergovernmental Panel on Climate Change [IPCC]), equations developed in the present study (NewEqs) were compared with the IPCC equation {CH4 (g/d)=[(GEI*Ym)*1,000]/55.65}, in which GEI is GE intake and Ym is the CH4 emission factor, in calculating CH4 outputs from 4 diverse beef systems. Observed BW and BW change data from cows with calves at side grazing either hill or lowland grassland, cows and overwintering calves and finishing steers fed contrasting diets were used to predict energy requirements, intake, and CH4 outputs. Compared with using this IPCC equation, NewEqs predicted up to 26% lower CH4 on average from individual lactating grazing cows. At the herd level, differences between equation estimates from 10 to 17% were observed in total annual accumulated CH4 when applied to the 4 diverse beef production systems. Overall, despite the small number of animals used it was demonstrated that there is a biological impact of using more specific CH4 prediction equations. Based on this approach, farm and national carbon budgets will be more accurate, contributing to reduced uncertainty in assessing mitigation options at farm and national level. PMID- 24174551 TI - Revealing the architecture of genetic and epigenetic regulation: a maximum likelihood model. AB - Gene expression is modulated by multiple mechanisms, including genetic and/or epigenetic regulation, and associated with the processes of cellular differentiation and morphogenesis. Single nucleotide polymorphisms (SNPs) and DNA methylation play important roles in regulating gene expression. In this study, we focused on revealing the relationship between SNPs, DNA methylation and gene expression in two human populations genome-wide through proposing four regulation patterns and developed maximum likelihood estimate models. Using simulated data with different correlation coefficients between any two traits, the power of our approach showed a favourable performance and relative stability. In all, 6733 SNP CpG-gene pairs including 957 genes were obtained in Northern European ancestry (CEU) population. As the results showed, SNPs and DNA methylation had approximately the same effect on expression regulation of 49% genes, which was termed cooperative/antagonistic regulation pattern. Less than 30% of genes are controlled only by one of the factors (SNP/DNA methylation). The others showed SNPs that affect methylation have no consequent effects or crosstalk regulation on gene expression. Similar result was shown in Yourba (YRI) population. Specific genes were inferred using the different mechanisms of gene regulation involved in complex diseases by combining literature. This approach provides a method to comprehensively assess regulation patterns of gene expression in the whole genome. PMID- 24174554 TI - 1. Introduction. PMID- 24174552 TI - Preface. PMID- 24174555 TI - 2. Quantities and units in bone densitometry. PMID- 24174557 TI - 4. Concepts of quality assurance and standardization. PMID- 24174556 TI - 3. Quality and performance measures in bone densitometry. PMID- 24174558 TI - 5. X-ray Absorptiometry. PMID- 24174559 TI - 6. Quantitative computed tomography. PMID- 24174560 TI - 7. Quantitative ultrasound. PMID- 24174561 TI - 8. Summary and recommendations. PMID- 24174562 TI - 9. Terminology and abbreviations. PMID- 24174566 TI - snoStrip: a snoRNA annotation pipeline. AB - MOTIVATION: Although small nucleolar RNAs form an important class of non-coding RNAs, no comprehensive annotation efforts have been undertaken, presumably because the task is complicated by both the large number of distinct small nucleolar RNA families and their relatively rapid pace of sequence evolution. RESULTS: With snoStrip we present an automatic annotation pipeline developed specifically for comparative genomics of small nucleolar RNAs. It makes use of sequence conservation, canonical box motifs as well as secondary structure and predicts putative targets. AVAILABILITY AND IMPLEMENTATION: The snoStrip web service and the download version is available at http://snostrip.bioinf.uni leipzig.de/ PMID- 24174567 TI - MSPrep--summarization, normalization and diagnostics for processing of mass spectrometry-based metabolomic data. AB - MOTIVATION: Although R packages exist for the pre-processing of metabolomic data, they currently do not incorporate additional analysis steps of summarization, filtering and normalization of aligned data. We developed the MSPrep R package to complement other packages by providing these additional steps, implementing a selection of popular normalization algorithms and generating diagnostics to help guide investigators in their analyses. AVAILABILITY: http://www.sourceforge.net/projects/msprep PMID- 24174568 TI - Neuro-oncology: past milestones and the journey ahead. PMID- 24174569 TI - Association between radiation dose to neuronal progenitor cell niches and temporal lobes and performance on neuropsychological testing in children: a prospective study. PMID- 24174570 TI - Transcriptome changes in the porcine endometrium during the preattachment phase. AB - The porcine conceptus undergoes rapid differentiation and expansion of its trophoblastic membranes between Days 11 and 12 of gestation. Concomitant with trophoblast elongation, production of conceptus estrogen, the porcine embryonic pregnancy recognition signal, increases. Conceptus attachment to the uterine surface epithelium starts after Day 13, initiating epitheliochorial placentation. To analyze the transcriptome changes in the endometrium in the course of maternal recognition of pregnancy, deep sequencing of endometrial RNA samples of Day 12 pregnant animals (n = 4) and corresponding nonpregnant controls (n = 4) was performed using RNA sequencing (RNA-Seq). Between 30 000 000 and 35 000 000 sequence reads per sample were produced and mapped to the porcine genome (Sscrofa10.2). Analysis of read counts revealed 2593 differentially expressed genes (DEGs). Expression of selected genes was validated by the use of quantitative real-time RT-PCR. Bioinformatics analysis identified several functional terms specifically overrepresented for up-regulated or down-regulated genes. Comparison of the RNA-Seq data from Days 12 and 14 of pregnancy was performed at the level of all expressed genes, the level of the DEG, and the level of functional categories. This revealed specific gene expression patterns reflecting the different functions of the endometrium during these stages (i.e., recognition of pregnancy and preparation for conceptus attachment). Genes related to mitosis, immune response, epithelial cell differentiation and development, proteolysis, and prostaglandin signaling and metabolism are discussed in detail. This study identified comprehensive transcriptome changes in porcine endometrium associated with establishment of pregnancy and could be a resource for targeted studies of genes and pathways potentially involved in regulation of this process. PMID- 24174571 TI - Gestational modification of murine spiral arteries does not reduce their drug induced vasoconstrictive responses in vivo. AB - Dynamic control of maternal blood flow to the placenta is critical for healthy pregnancy. In many tissues, microvasculature arteries control the flow. The uterine/endometrial vascular bed changes during pregnancy include physiological remodeling of spiral arteries from constricted artery-like structures to dilated vein-like structures between Gestation Day 8 (gd8) and gd12 in mice and wk 12-16 in humans. These changes occur, in part, due to local environmental changes such as decidualization, recruitment of maternal uterine natural killer cells, and invasion of conceptus-derived trophoblasts. No current preparations permit in vivo testing of decidual microvascular reactivity. We report an in vivo intravital fluorescence microscopy model that permits functional study of the entire uterine microvascular bed (uterine, arcuate, radial, basal, and spiral arteries) in gravid C57BL/6 mice. Vascular reactivities were measured at gd8 prespiral arterial remodeling and gd12 (postremodeling) to a range of concentrations of adenosine (10(-8)-10(-6) M), acetylcholine (10(-7)-10(-5) M), phenylephrine (10(-7)-10(-5) M), and angiotensin II (10(-8)-10(-6) M). At baseline, each arterial branch order was significantly more dilated on gd12 than gd8. Each microvascular level responded to each agonist on gd8 and gd12. At gd12, vasodilation to adenosine was attenuated in uterine, arcuate, and basal arteries, while constrictor activity to angiotensin II was enhanced in uterine and arcuate arteries. The tendency for increasing vasoconstriction between gd8 to gd12 and the constrictor responses of modified spiral arteries were unexpected findings that may reflect influences of the intact in vivo environment rather than inherent properties of the vessels and may be relevant to ongoing human pregnancies. PMID- 24174572 TI - Estrogen alters remodeling of the vaginal wall after surgical injury in guinea pigs. AB - Loss of pelvic organ support (i.e., pelvic organ prolapse) is common in menopausal women. Surgical reconstruction of pelvic organ prolapse is plagued with high failure rates. The objective of this study was to determine the effects of estrogen on biomechanical properties, lysyl oxidase (LOX), collagen content, and histomorphology of the vagina with or without surgical injury. Nulliparous ovariectomized guinea pigs were treated systemically with either 50 MUg/kg/day estradiol (E2,) or vehicle. After 2 wk, vaginal surgery was performed, and animals were treated with either beta-aminopropionitrile (BAPN, an irreversible LOX inhibitor), or vehicle to determine the role of LOX in recovery of the vaginal wall from injury with or without E2. Estradiol resulted in (i) significant growth, increased smooth muscle, and increased thickness of the vagina, (ii) increased distensibility without compromise of maximal force at failure, and (iii) increased total and cross-linked collagen. In the absence of E2, BAPN resulted in decreased collagen and vaginal wall strength in the area of the injury. In contrast, in E2-treated animals, increased distensibility, maximal forces, and total collagen were maintained despite BAPN. Interestingly, LOX mRNA was induced dramatically (9.5-fold) in the injured vagina with or without E2 at 4 days. By 21 days, however, LOX levels declined to near baseline in E2-deprived animals. LOX mRNA levels remained strikingly elevated (12-fold) at 21 days in the estrogenized vagina. The results suggest that prolonged E2 induced increases in LOX, and collagen cross-links may act to sustain a matrix environment that optimizes long-term surgical wound healing in the vagina. PMID- 24174573 TI - Regulation of granulosa cell cocaine and amphetamine regulated transcript (CART) binding and effect of CART signaling inhibitor on granulosa cell estradiol production during dominant follicle selection in cattle. AB - We previously established a potential role for cocaine and amphetamine regulated transcript (CARTPT) in dominant follicle selection in cattle. CARTPT expression is elevated in subordinate versus dominant follicles, and treatment with the mature form of the CARTPT peptide (CART) decreases follicle-stimulating hormone (FSH)-stimulated granulosa cell estradiol production in vitro and follicular fluid estradiol and granulosa cell CYP19A1 mRNA in vivo. However, mechanisms that regulate granulosa cell CART responsiveness are not understood. In this study, we investigated hormonal regulation of granulosa cell CART-binding sites in vitro and temporal regulation of granulosa cell CART-binding sites in bovine follicles collected at specific stages of a follicular wave. We also determined the effect of inhibition of CART receptor signaling in vivo on estradiol production in future subordinate follicles. Granulosa cell CART binding in vitro was increased by FSH, and this induction was blocked by estrogen receptor antagonist treatment. In follicles collected in vivo at specific stages of a follicular wave, granulosa cell CART binding in the F2 (second largest), future subordinate follicle increased during dominant follicle selection. Injection into the F2 follicle (at onset of diameter deviation) of an inhibitor of the o/i subclass of G proteins (previously shown to block CART actions in vitro) resulted in increased follicular fluid estradiol concentrations in vivo. Collectively, results demonstrate hormonal regulation of granulosa cell CART binding in vitro and temporal regulation of CART binding in subordinate follicles during dominant follicle selection. Results also suggest that CART signaling may help suppress estradiol-producing capacity of the F2 (subordinate) follicle during this time period. PMID- 24174574 TI - Gonad differentiation in zebrafish is regulated by the canonical Wnt signaling pathway. AB - Zebrafish males undergo a "juvenile ovary-to-testis" gonadal transformation process. Several genes, including nuclear receptor subfamily 5, group A (nr5a) and anti-Mullerian hormone (amh), and pathways such as Tp53-mediated germ-cell apoptosis have been implicated in zebrafish testis formation. However, our knowledge of the regulation of this complex process is incomplete, and much remains to be investigated about the molecular pathways and network of genes that control it. Using a microarray-based analysis of transforming zebrafish male gonads, we demonstrated that their transcriptomes undergo transition from an ovary-like pattern to an ovotestis to a testis-like profile. Microarray results also validated the previous histological and immunohistochemical observation that there is high variation in the duration and extent of commitment to the juvenile ovary phase among individuals. Interestingly, global gene expression profiling of diverging zebrafish juvenile ovaries and transforming ovotestes revealed that some members of the canonical Wnt/beta-catenin signaling pathway were differentially expressed between these two phases. To investigate whether Wnt/beta-catenin signaling plays a role in zebrafish gonad differentiation, we used the Tg (hsp70l:dkk1b-GFP)w32 line to inhibit Wnt/beta-catenin signaling during gonad differentiation. Activation of dkk1b-GFP expression by heat shock resulted in an increased proportion of males and corresponding decrease in gonadal aromatase gene (cyp19a1a) expression. The Wnt target gene, lymphocyte enhancer binding factor 1 (lef1), was also down-regulated in the process. Together, these results provide the first functional evidence that, similarly to mammals, Wnt/beta-catenin signaling is a "pro-female" pathway that regulates gonad differentiation in zebrafish. PMID- 24174575 TI - Transcriptome analysis of the dihydrotestosterone-exposed fetal rat gubernaculum identifies common androgen and insulin-like 3 targets. AB - Androgens and insulin-like 3 (INSL3) are required for development of the fetal gubernaculum and testicular descent. Previous studies suggested that the INSL3 exposed fetal gubernacular transcriptome is enriched for genes involved in neural pathways. In the present study, we profiled the transcriptome of fetal gubernaculum explants exposed to dihydrotestosterone (DHT) and compared this response to that with INSL3. We exposed fetal (Embryonic Day 17) rat gubernacula to DHT for 24 h (10 and 30 nM) or 6 h (1 and 10 nM) in organ culture and analyzed gene expression relative to that of vehicle-treated controls using Affymetrix arrays. Results were annotated using functional, pathway, and promoter analyses and independently validated for selected transcripts using quantitative RT-PCR (qRT-PCR). Transcripts were differentially expressed after 24 h but not 6 h. Most highly overrepresented functional categories included those related to gene expression, skeletal and muscular development and function, and Wnt signaling. Promoter response elements enriched in the DHT-specific transcriptome included consensus sequences for c-ETS1, ELK1, CREB, CRE-BP1/c-June, NRF2, and USF. We observed that 55% of DHT probe sets were also differentially expressed after INSL3 exposure and that the direction of change was the same in 96%. The qRT-PCR results confirmed that DHT increased expression of the INSL3-responsive genes Crlf1 and Chrdl2 but reduced expression of Wnt4. We also validated reduced Tgfb2 and Cxcl12 and increased Slit3 expression following DHT exposure. These data suggest a robust overlap in the DHT- and INSL3-regulated transcriptome that may be mediated in part by CREB signaling and a common Wnt pathway response for both hormones in the fetal gubernaculum. PMID- 24174576 TI - The aryl hydrocarbon receptor is important for proper seminiferous tubule architecture and sperm development in mice. AB - The aryl hydrocarbon receptor (AHR) is known for its roles in xenobiotic metabolism and essential physiologic processes such as cell growth, death, and differentiation. AHR is also an important regulator of male reproductive processes. However, no studies have characterized the consequences of loss of AHR in spermatogenesis. We used Ahr knockout (Ahr(-/-)) mice to assess the effects of loss of AHR on the architecture and gene expression of the seminiferous epithelium and functional sperm outcomes. The histopathological defects of the Ahr(-/-)seminiferous epithelium included vacuoles, multinucleated giant cells, hypocellularity with widened intercellular spaces, apical sloughing, and an excess number of retained elongated spermatids. Quantitative real-time PCR revealed significant down-regulation of Testin and Magea4, indicating Sertoli cell and spermatogenic dysregulation. Moreover, the reduced expression of Hspa2, Prm1, and Prm2 as well as decreased expression of Nrf2, Sod2, and Ucp2 suggested poorly remodeled germ cells with increased vulnerability to oxidative stress. In wild-type sperm, AHR protein was localized to the acrosome and the principal piece of the mature sperm flagellum. The in vitro fertilization rate was significantly lower with Ahr(-/-) sperm as compared to wild-type sperm, and there were morphologic abnormalities of the Ahr(-/-) sperm head and tail. Taken together, our data indicate that AHR plays an important role in normal sperm development. PMID- 24174577 TI - Progesterone regulation of AVEN protects bovine oocytes from apoptosis during meiotic maturation. AB - Inhibition of progesterone (P4) synthesis by cumulus cells during bovine in vitro oocyte maturation (IVM) causes a decrease in subsequent embryo development, indicating that P4 intracellular signaling within the cumulus oocyte complex (COC) is important for oocyte developmental competence. The aim of the present study was to further elucidate, on a protein level, the downstream signaling pathway involved in P4 regulation of oocyte developmental competence. COCs were subjected to IVM for 24 h in the presence or absence of trilostane, aglepristone, or promegestone (R5020). These altered IVM conditions resulted in dynamic changes in protein expression of the progesterone receptors and the cell death-regulated proteins AVEN, BCL-xL, and active caspase 3. In addition, AVEN protein localization, caspase 3 activation, and mitochondrial distribution were studied by immunofluorescence. Inhibition of progesterone synthesis (trilostane treatment) resulted in changes in AVEN localization within the COC, corresponding to caspase 3 activation and altered mitochondrial distribution. AVEN was also found to bind BCL-xL in COCs, but this interaction was lost following treatment with trilostane. PMID- 24174579 TI - Bayesian semiparametric estimation of covariate-dependent ROC curves. AB - Receiver operating characteristic (ROC) curves are widely used to measure the discriminating power of medical tests and other classification procedures. In many practical applications, the performance of these procedures can depend on covariates such as age, naturally leading to a collection of curves associated with different covariate levels. This paper develops a Bayesian heteroscedastic semiparametric regression model and applies it to the estimation of covariate dependent ROC curves. More specifically, our approach uses Gaussian process priors to model the conditional mean and conditional variance of the biomarker of interest for each of the populations under study. The model is illustrated through an application to the evaluation of prostate-specific antigen for the diagnosis of prostate cancer, which contrasts the performance of our model against alternative models. PMID- 24174578 TI - 1,25-dihydroxyvitamin d3 reduces extracellular matrix-associated protein expression in human uterine fibroid cells. AB - Uterine fibroids (leiomyomas) are the most common benign tumors associated with excessive deposition of extracellular matrix (ECM)-associated proteins that increase fibroid tumorigenicity. Herein, we determined the expression levels of vitamin D receptor (VDR) protein in human uterine fibroids and compared these levels to those in adjacent normal myometrium. Using Western blot analysis, we found that more than 60% of uterine fibroids analyzed (25 of 40) expressed low levels of VDR. We also found that the biologically active 1,25-dihydroxyvitamin D3 (1,25[OH]2D3), which functions via binding to its nuclear VDR, induced VDR in a concentration-dependent manner and reduced ECM-associated fibrotic and proteoglycans expression in immortalized human uterine fibroid cell line (HuLM). At 1-10 nM concentrations, 1,25(OH)2D3 significantly induced (P < 0.05) nuclear VDR, which was further stimulated by higher concentrations of 1,25(OH)2D3 in HuLM cells. 1,25(OH)2D3 at 10 nM also significantly reduced (P < 0.05) the protein expression of ECM-associated collagen type 1, fibronectin, and plasminogen activator inhibitor-1 (PAI-1) in HuLM cells. We also found that 1,25(OH)2D3 reduced mRNA and protein expressions of proteoglycans such as fibromodulin, biglycan, and versican in HuLM cells. Moreover, the aberrant expression of structural smooth muscle actin fibers was reduced by 1,25(OH)2D3 treatment in a concentration-dependent manner in HuLM cells. Taken together, our results suggest that human uterine fibroids express reduced levels of VDR compared to the adjacent normal myometrium and that treatment with 1,25(OH)2D3 can potentially reduce the aberrant expression of major ECM-associated proteins in HuLM cells. Thus, 1,25(OH)2D3 might be an effective, safe, nonsurgical treatment option for human uterine fibroids. PMID- 24174580 TI - Fisher's method of combining dependent statistics using generalizations of the gamma distribution with applications to genetic pleiotropic associations. AB - A classical approach to combine independent test statistics is Fisher's combination of $p$-values, which follows the $?chi ^2$ distribution. When the test statistics are dependent, the gamma distribution (GD) is commonly used for the Fisher's combination test (FCT). We propose to use two generalizations of the GD: the generalized and the exponentiated GDs. We study some properties of mis using the GD for the FCT to combine dependent statistics when one of the two proposed distributions are true. Our results show that both generalizations have better control of type I error rates than the GD, which tends to have inflated type I error rates at more extreme tails. In practice, common model selection criteria (e.g. Akaike information criterion/Bayesian information criterion) can be used to help select a better distribution to use for the FCT. A simple strategy of the two generalizations of the GD in genome-wide association studies is discussed. Applications of the results to genetic pleiotrophic associations are described, where multiple traits are tested for association with a single marker. PMID- 24174581 TI - Clinically meaningful performance benchmarks in MS: timed 25-foot walk and the real world. AB - OBJECTIVE: Identify and validate clinically meaningful Timed 25-Foot Walk (T25FW) performance benchmarks in individuals living with multiple sclerosis (MS). METHODS: Cross-sectional study of 159 MS patients first identified candidate T25FW benchmarks. To characterize the clinical meaningfulness of T25FW benchmarks, we ascertained their relationships to real-life anchors, functional independence, and physiologic measurements of gait and disease progression. Candidate T25FW benchmarks were then prospectively validated in 95 subjects using 13 measures of ambulation and cognition, patient-reported outcomes, and optical coherence tomography. RESULTS: T25FW of 6 to 7.99 seconds was associated with a change in occupation due to MS, occupational disability, walking with a cane, and needing "some help" with instrumental activities of daily living; T25FW >=8 seconds was associated with collecting Supplemental Security Income and government health care, walking with a walker, and inability to do instrumental activities of daily living. During prospective benchmark validation, we trichotomized data by T25FW benchmarks (<6 seconds, 6-7.99 seconds, and >=8 seconds) and found group main effects on 12 of 13 objective and subjective measures (p < 0.05). CONCLUSIONS: Using a cross-sectional design, we identified 2 clinically meaningful T25FW benchmarks of >=6 seconds (6-7.99) and >=8 seconds. Longitudinal and larger studies are needed to confirm the clinical utility and relevance of these proposed T25FW benchmarks and to parse out whether there are additional benchmarks in the lower (<6 seconds) and higher (>10 seconds) ranges of performance. PMID- 24174582 TI - Nonlesional atypical mesial temporal epilepsy: electroclinical and intracranial EEG findings. AB - OBJECTIVE: Misleading manifestations of common epilepsy syndromes might account for some epilepsy surgery failures, thus we sought to characterize patients with difficult to diagnose (atypical) mesial temporal lobe epilepsy (mTLE). METHODS: We retrospectively reviewed our surgical database over 12 years to identify patients who underwent a standard anterior temporal lobectomy after undergoing intracranial EEG (ICEEG) evaluation with a combination of depth and subdural electrodes. We carefully studied electroclinical manifestations, neuroimaging data, neuropsychological findings, and indications for ICEEG. RESULTS: Of 835 patients who underwent anterior temporal lobectomy, 55 were investigated with ICEEG. Ten of these had atypical mTLE features and were not considered to have mTLE preoperatively. All of them had Engel class I outcome for 3 to 7 years (median 3.85). Five reported uncommon auras, and 3 had no auras. Scalp-EEG and nuclear imaging studies failed to provide adequate localization. None had MRI evidence of hippocampal sclerosis. However, ICEEG demonstrated exclusive mesial temporal seizure onset in all patients. Clues suggesting the possibility of mTLE were typical auras when present, anterior temporal epileptiform discharges or ictal patterns, small hippocampi, asymmetrical or ipsilateral temporal hypometabolism on PET, anterior temporal hyperperfusion on ictal SPECT, and asymmetry of memory scores. Histopathology revealed hippocampal sclerosis in 6 patients and gliosis in 2. CONCLUSIONS: Atypical electroclinical presentation may be deceptive in some patients with mTLE. We emphasize the importance of searching for typical mTLE features to guide ICEEG study of mesial temporal structures in such patients, who may otherwise mistakenly undergo extramesial temporal resections or be denied surgery. PMID- 24174583 TI - Temporal trends in new exposure to antiepileptic drug monotherapy and suicide related behavior. AB - OBJECTIVE: Because some recent studies suggest increased risk for suicide-related behavior (SRB; ideation, attempts) among those receiving antiepileptic drugs (AEDs), we examined the temporal relationship between new AED exposure and SRB in a cohort of older veterans. METHODS: We used national Veterans Health Administration databases to identify veterans aged >=65 years who received a new AED prescription in 2004-2006. All instances of SRB were identified using ICD-9 CM codes 1 year before and after the AED exposure (index) date. We also identified comorbid conditions and medication associated with SRB in prior research. We used generalized estimating equations with a logit link to examine the association between new AED exposure and SRB during 30-day intervals during the year before and after the index date, controlling for potential confounders. RESULTS: In this cohort of 90,263 older veterans, the likelihood of SRB the month prior to AED exposure was significantly higher than in other time periods even after adjusting for potential confounders. Although there were 87 SRB events (74 individuals) the year before and 106 SRB events (92 individuals) after, approximately 22% (n = 16) of those also had SRB before the index date. Moreover, the rate of SRB after AED start was gradually reduced over time. CONCLUSIONS: The temporal pattern of AED exposure and SRB suggests that, in clinical practice, the peak in SRB is prior to exposure. While speculative, the rate of gradual reduction in SRB thereafter suggests that symptoms may prompt AED prescription. PMID- 24174585 TI - Glycine receptor antibodies in stiff-person syndrome and other GAD-positive CNS disorders. PMID- 24174584 TI - Reduced CSF p-Tau181 to Tau ratio is a biomarker for FTLD-TDP. AB - OBJECTIVES: To validate the ability of candidate CSF biomarkers to distinguish between the 2 main forms of frontotemporal lobar degeneration (FTLD), FTLD with TAR DNA-binding protein 43 (TDP-43) inclusions (FTLD-TDP) and FTLD with Tau inclusions (FTLD-Tau). METHODS: Antemortem CSF samples were collected from 30 patients with FTLD in a single-center validation cohort, and CSF levels of 5 putative FTLD-TDP biomarkers as well as levels of total Tau (t-Tau) and Tau phosphorylated at threonine 181 (p-Tau181) were measured using independent assays. Biomarkers most associated with FTLD-TDP were then tested in a separate 2 center validation cohort composed of subjects with FTLD-TDP, FTLD-Tau, Alzheimer disease (AD), and cognitively normal subjects. The sensitivity and specificity of FTLD-TDP biomarkers were determined. RESULTS: In the first validation cohort, FTLD-TDP cases had decreased levels of p-Tau181 and interleukin-23, and increased Fas. Reduced ratio of p-Tau181 to t-Tau (p/t-Tau) was the strongest predictor of FTLD-TDP pathology. Analysis in the second validation cohort showed CSF p/t-Tau ratio <0.37 to distinguish FTLD-TDP from FTLD-Tau, AD, and healthy seniors with 82% sensitivity and 82% specificity. CONCLUSION: A reduced CSF p/t-Tau ratio represents a reproducible, validated biomarker for FTLD-TDP with performance approaching well-established CSF AD biomarkers. Introducing this biomarker into research and the clinical arena can significantly increase the power of clinical trials targeting abnormal accumulations of TDP-43 or Tau, and select the appropriate patients for target-specific therapies. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that the CSF p/t-Tau ratio distinguishes FTLD-TDP from FTLD-Tau. PMID- 24174587 TI - Epilepsy after TIA or stroke in young patients impairs long-term functional outcome: the FUTURE Study. AB - OBJECTIVE: To determine the influence of poststroke epilepsy on long-term functional outcome in young stroke survivors. METHODS: This study is a prospective cohort study among 537 stroke survivors with a first-ever TIA, ischemic stroke, or intracerebral hemorrhagic (ICH) stroke, aged 18 to 50 years. After a mean follow-up of 9.8 years (SD 8.4), we performed a follow-up assessment that included an evaluation for poststroke epilepsy and functional outcome. Odds ratios for poor outcome on the modified Rankin Scale (mRS) (score >2) and Instrumental Activities of Daily Living (IADL) (score <8) were calculated using logistic regression analysis. RESULTS: Forty patients (12.7%) with ischemic stroke, 4 patients (2.2%) with TIA, and 10 patients (25.6%) with ICH developed poststroke epilepsy. Ischemic stroke patients with epilepsy more often had a poor functional outcome than those without, both on the mRS and IADL (mRS score >2: 27.5% vs 9.8%, p = 0.001; IADL <8: 27.8% vs 12.6%, p = 0.02). Epilepsy was not related to functional outcome in patients with TIA and ICH. Multiple regression analysis revealed that epilepsy was an independent predictor of poor functional outcome after ischemic stroke assessed by mRS (mRS score >2: odds ratio 3.38, 95% confidence interval 1.33-8.60). In contrast, there was no such relation for IADL. CONCLUSIONS: Epilepsy after stroke in young patients is a common problem that negatively affects functional outcome, even more than 10 years after ischemic stroke. PMID- 24174586 TI - Clinical relevance and functional consequences of the TNFRSF1A multiple sclerosis locus. AB - OBJECTIVE: We set out to characterize the clinical impact and functional consequences of rs1800693(G), the multiple sclerosis (MS) susceptibility allele found in the TNFRSF1A locus. METHODS: We analyzed prospectively collected data on patients with MS to assess the role of the TNFRSF1A locus on disease course and treatment response. Using archival serum samples and freshly isolated monocytes from patients with MS and healthy subjects, we evaluated the effects of rs1800693(G) and a second risk allele, R92Q, on immune function. RESULTS: In 772 patients with MS, we see no evidence that rs1800693(G) strongly influences clinical or radiographic indices of disease course and treatment response; thus, rs1800693(G) appears to be primarily involved in the onset of MS. At the molecular level, this validated susceptibility allele generates an RNA isoform, TNFRSF1A Delta6, that lacks the transmembrane and cytoplasmic domains. While there was no measurable effect on serum levels of soluble TNFRSF1A, rs1800693(G) appears to alter the state of monocytes, which demonstrate a more robust transcriptional response of CXCL10 and other genes in response to tumor necrosis factor (TNF)-alpha. We also report that activation of the TNF-alpha pathway results in altered expression of 6 other MS susceptibility genes, including T cell activation rho GTPase activating protein (TAGAP) and regulator of G-protein signaling 1 (RGS1), which are not previously known to be responsive to TNF-alpha. CONCLUSIONS: The MS rs1800693(G) susceptibility allele affects the magnitude of monocyte responses to TNF-alpha stimulation, and the TNF pathway may be one network in which the effect of multiple MS genes becomes integrated. PMID- 24174589 TI - Do antiepileptic drugs cause suicidal behavior? PMID- 24174588 TI - Total cerebral blood flow and mortality in old age: a 12-year follow-up study. AB - OBJECTIVE: To examine the association of total cerebral blood flow (CBF) with all cause, noncardiovascular, and cardiovascular mortality in older subjects at risk of cardiovascular disease. METHODS: We included 411 subjects with a mean age of 74.5 years from the MRI substudy of the Prospective Study of Pravastatin in the Elderly at Risk. Total CBF was measured at baseline, and occurrence of death was recorded in an average follow-up period of 11.8 years. For each participant, total CBF was standardized for brain parenchymal volume. Cox regression models were used to estimate risk of all-cause, noncardiovascular, and cardiovascular mortality in relation to CBF. RESULTS: Mortality rates among participants in low, middle, and high thirds of total CBF were 52.1, 41.5, and 28.7 per 1,000 person years, respectively. Compared with participants in the high third of CBF, participants in the low third had 1.88-fold (95% confidence interval [CI]: 1.30 2.72) higher risk of all-cause mortality, 1.66-fold (95% CI: 1.06-2.59) higher risk of noncardiovascular mortality, and 2.50-fold (95% CI: 1.28-4.91) higher risk of cardiovascular mortality. Likewise, compared with participants in the high third of CBF, participants in the middle third had 1.44-fold (95% CI: 0.98 2.11) higher risk of all-cause mortality, 1.29-fold (95% CI: 0.82-2.04) higher risk of noncardiovascular mortality, and 1.86-fold (95% CI: 0.93-3.74) higher risk of cardiovascular mortality. These associations were independent of prevalent vascular status and risk factors. CONCLUSIONS: Low total CBF is linked with higher risk of all-cause, noncardiovascular, and cardiovascular mortality in older people independent of clinical cardiovascular status. PMID- 24174590 TI - Cerebral microbleeds are related to loss of white matter structural integrity. AB - OBJECTIVE: To investigate whether the presence of cerebral microbleeds, which present as focal lesions on imaging, is associated with a diffuse loss of white matter microstructural integrity in the brain. METHODS: In the prospective, population-based Rotterdam Scan Study, a total of 4,493 participants underwent brain MRI to determine microbleed status. With diffusion tensor imaging, global fractional anisotropy (FA) and mean diffusivity (MD) were measured in normal appearing white matter. Multiple linear regression models, adjusted for age, sex, cardiovascular risk factors, white matter lesions, and infarcts, were applied to investigate the independent association between microbleeds and organization of brain white matter. Analyses were repeated after stratification by APOE epsilon4 carriership. RESULTS: Presence of microbleeds was related to a lower mean FA and higher mean MD, in a dose-dependent manner, and was already apparent for a single microbleed (standardized FA: -0.13, 95% confidence interval -0.21 to -0.05; MD: 0.12, 95% confidence interval 0.05 to 0.19). For lobar microbleeds, alterations in diffusion tensor imaging measurements were solely driven by APOE epsilon4 carriers. CONCLUSIONS: Presence of microbleeds relates to poorer microstructural integrity of brain white matter, even after adjusting for cardiovascular risk and other markers of cerebral small-vessel disease. Our data suggest that microbleeds reflect diffuse brain pathology, even when only a single microbleed is present. PMID- 24174591 TI - TNFRSF1A in multiple sclerosis: a tale of soluble receptors and signaling cascades. PMID- 24174592 TI - Can the DSM-5 framework enhance the diagnosis of MCI? AB - As the field of mild cognitive impairment moves forward and various expert groups come together to update the diagnostic criteria, the framework adopted by the DSM 5 deserves consideration as a model. This framework could help disentangle cause from consequence, maximize internal consistency, and minimize redundancy and ambiguity. It could make the diagnostic criteria easier for both clinicians and researchers to implement, thus enhancing reliability of diagnosis. It could help maintain conceptual rigor by distinguishing among core diagnostic features (inclusion as well as exclusion criteria), subtypes, specifiers, associated features, and risk factors. Each level of classification, subtyping, and specification should delineate an increasingly homogeneous subgroup with an enhanced likelihood of having common underpinnings and prognosis. New knowledge could be systematically incorporated into this framework. This approach could improve the predictive value and thus the utility of the overall diagnosis. PMID- 24174594 TI - Executive summary. PMID- 24174593 TI - De novo INF2 mutations expand the genetic spectrum of hereditary neuropathy with glomerulopathy. AB - OBJECTIVE: Identification of mutations in the inverted formin-2 (INF2) gene in patients with Charcot-Marie-Tooth (CMT) disease combined with focal segmental glomerulosclerosis (FSGS) in order to expand the genetic and phenotypic spectrum. METHODS: We sequenced INF2 in 5 patients with CMT disease and FSGS. Mutations were subsequently screened in family members of the index patient and 264 control individuals. RESULTS: In 3 patients, we detected 2 novel de novo INF2 mutations (p.Leu77Arg and p.Leu69_Ser72del) and a third, most likely de novo mutation (p.Gly114Asp). One of our patients displayed intellectual disability, a phenotypic characteristic not previously associated with INF2. The same patient also showed a more pronounced sensorineural hearing loss than described before. CONCLUSIONS: In exon 2 of INF2, we identified 3 novel mutations that likely affect the protein structure and function. Our findings expand the genetic spectrum of INF2-associated disorders and broaden the associated phenotype with the co-occurrence of intellectual disability and more severe hearing loss than previously reported. De novo INF2 mutations may be more common in patients with CMT disease and FSGS in comparison to FSGS alone. Furthermore, renal dysfunction is more severe and starts earlier in life when associated with CMT disease. Our study confirms that INF2 mutations are a major cause of disease in patients with CMT disease and early signs of nephropathy. Diagnostic screening of INF2 is strongly recommended in isolated patients presenting with CMT disease and FSGS. PMID- 24174595 TI - 1. Introduction. PMID- 24174596 TI - 2. Mammography in clinical practice. PMID- 24174597 TI - 3. Production of the mammogram. PMID- 24174598 TI - 4. Digital mammography. PMID- 24174599 TI - 5. Technical aspects of image quality in mammography. PMID- 24174600 TI - 6. Patient dosimetry in mammography. PMID- 24174601 TI - 7. Measurement of image quality in mammography. PMID- 24174602 TI - 8. Conclusions. PMID- 24174603 TI - Appendix a: quality-control programs. PMID- 24174604 TI - Appendix B: Examples of Phantom and Test Tools for Mammography QC. PMID- 24174605 TI - Glossary of imaging terms. PMID- 24174612 TI - Tobacco cessation among low-income smokers: motivational enhancement and nicotine patch treatment. AB - INTRODUCTION: Despite decades of tobacco use decline among the general population in the United States, tobacco use among low-income populations continues to be a major public health concern. Smoking rates are higher among individuals with less than a high school education, those with no health insurance, and among individuals living below the federal poverty level. Despite these disparities, smoking cessation treatments for low-income populations have not been extensively tested. In the current study, the efficacy of 2 adjunctive smoking cessation interventions was evaluated among low-income smokers who were seen in a primary care setting. METHODS: A total of 846 participants were randomly assigned either to motivational enhancement treatment plus brief physician advice and 8 weeks of nicotine replacement therapy (NRT) or to standard care, which consisted of brief physician advice and 8 weeks of NRT. Tobacco smoking abstinence was at 1, 2, 6, and 12 months following baseline. RESULTS: The use of the nicotine patch, telephone counseling, and positive decisional balance were predictive of increased abstinence rates, and elevated stress levels and temptation to smoke in both social/habit and negative affect situations decreased abstinence rates across time. Analyses showed intervention effects on smoking temptations, length of patch use, and number of telephone contacts. Direct intervention effects on abstinence rates were not significant, after adjusting for model predictors and selection bias due to perirandomization attrition. CONCLUSIONS: Integrating therapeutic approaches that promote use of and adherence to medications for quitting smoking and that target stress management and reducing negative affect may enhance smoking cessation among low-income smokers. PMID- 24174613 TI - Influence of cataract surgery on repeatability and measurements of spectral domain optical coherence tomography. AB - BACKGROUNDS/AIMS: To evaluate the effect of uncomplicated cataract phacoemulsification on the measurements of macular and retinal nerve fibre layer (RNFL) in healthy subjects using two spectral domain (SD) optical coherence tomography (OCT) instruments--Cirrus OCT (Zeiss) and Spectralis OCT (Heidelberg)- and to assess the reliability of the measurements obtained with these two devices before and after cataract surgery. METHODS: The study included 60 eyes of 60 healthy subjects (22 men and 38 women, 54-88 years of age) who underwent cataract phacoemulsification. One month before and one month after surgery, three repetitions of scans were performed using the RNFL and macular analysis protocols of the Cirrus and Spectralis OCT instruments. The differences between RNFL and macular thickness measurements obtained in the two visits were analysed. Repeatability was evaluated by calculating the coefficient of variation (COV) for each of the parameters recorded and for each visit. RESULTS: The RNFL measurements obtained with the Cirrus and Spectralis OCT differed before and after surgery, and most of these differences were statistically significant (p<0.05). Macular thickness measurements using the Spectralis OCT were not significantly different between the two visits, whereas the differences found with the Cirrus OCT were statistically significant. The repeatability was better after surgical removal of the cataract, and the differences between COV in the two visits were significant with the Cirrus OCT. CONCLUSIONS: The presence of cataracts affects RNFL and macular measurements performed with SD-OCT. The repeatability of the images significantly improved after cataract phacoemulsification when using the Cirrus OCT. PMID- 24174614 TI - Brainstem cavernoma presenting with an acute isolated dilated pupil. PMID- 24174615 TI - Is there a relationship between subacromial impingement syndrome and scapular orientation? A systematic review. AB - BACKGROUND: Alterations in scapular orientation and dynamic control, specifically involving increased anterior tilt and downward rotation, are considered to play a substantial role in contributing to a subacromial impingement syndrome (SIS). Non surgical intervention aims at restoring normal scapular posture. The research evidence supporting this practice is equivocal. OBJECTIVE: The aim of this study was to systematically review the relevant literature to examine whether a difference exists in scapular orientation between people without shoulder symptoms and those with SIS. DATA SOURCES: MEDLINE, AMED, EMBASE, CINAHL, PEDro and SPORTDiscus databases were searched using relevant search terms up to August 2013. Additional studies were identified by hand-searching the reference lists of pertinent articles. REVIEW METHODS: Of the 7445 abstracts identified, 18 were selected for further analysis. Two reviewers independently assessed the studies for inclusion, data extraction and quality, using a modified Downs and Black quality assessment tool. RESULTS: 10 trials were included in the review. Scapular position was determined through two-dimensional radiological measurements, 360 degrees inclinometers and three-dimensional motion and tracking devices. The findings were inconsistent. Some studies reported patterns of reduced upward rotation, increased anterior tilting and medial rotation of the scapula. In contrast, others reported the opposite, and some identified no difference in motion when compared to asymptomatic controls. CONCLUSIONS: The underlying aetiology of SIS is still debated. The results of this review demonstrated a lack of consistency of study methodologies and results. Currently, there is insufficient evidence to support a clinical belief that the scapula adopts a common and consistent posture in SIS. This may reflect the complex, multifactorial nature of the syndrome. Additionally, it may be due to the methodological variations and shortfalls in the available research. It also raises the possibility that deviation from a 'normal' scapular position may not be contributory to SIS but part of normal variations. Further research is required to establish whether a common pattern exists in scapular kinematics in SIS patients or whether subgroups of patients with common patterns can be identified to guide management options. Non-surgical treatment involving rehabilitation of the scapula to an idealised normal posture is currently not supported by the available literature. PMID- 24174616 TI - p33 (gC1q receptor) prevents cell damage by blocking the cytolytic activity of antimicrobial peptides. AB - The innate immune system is the first line of defense against invading microbes. Its specificity relies a great deal on host pattern recognition molecules that sense pathogen-associated molecular patterns of the invading pathogen. However, full protection is not always guaranteed, and some early defense mechanisms involved in bacterial killing, such as the complement system, can also exert cytolytic activity against host cells. Although these cascades are tightly regulated, the host has to take additional precautions to prevent its cell destruction. In this study, we describe that p33, a negatively charged surface protein found on endothelial cells also known as gC1q receptor, protects host cells from a cytolytic attack by antimicrobial peptides (AMPs), such as LL37 and beta-defensin 3. To this end, we characterized the interaction of p33 with AMPs by biochemical and functional means. Our data show that p33 forms a doughnut shaped trimer that can bind up to three AMPs, and we identified a segment in p33 forming a beta-sheet that mediates the binding to all AMPs. Moreover, our results show that p33 abolishes the lytic activity of AMPs at an equimolar ratio, and it protects endothelial cells and erythrocytes from AMP-induced lysis. Taken together, our data suggest a novel protective mechanism of p33 in modulating innate immune response by neutralizing cytotoxic AMPs at the host cell surface. PMID- 24174617 TI - Regulatory T cells suppress the late phase of the immune response in lymph nodes through P-selectin glycoprotein ligand-1. AB - Regulatory T cells (Tregs) maintain tolerance toward self-antigens and suppress autoimmune diseases, although the underlying molecular mechanisms are unclear. In this study, we show that mice deficient for P-selectin glycoprotein ligand-1 (PSGL-1) develop a more severe form of experimental autoimmune encephalomyelitis than wild type animals do, suggesting that PSGL-1 has a role in the negative regulation of autoimmunity. We found that Tregs lacking PSGL-1 were unable to suppress experimental autoimmune encephalomyelitis and failed to inhibit T cell proliferation in vivo in the lymph nodes. Using two-photon laser-scanning microscopy in the lymph node, we found that PSGL-1 expression on Tregs had no role in the suppression of early T cell priming after immunization with Ag. Instead, PSGL-1-deficient Tregs lost the ability to modulate T cell movement and failed to inhibit the T cell-dendritic cell contacts and T cell clustering essential for sustained T cell activation during the late phase of the immune response. Notably, PSGL-1 expression on myelin-specific effector T cells had no role in T cell locomotion in the lymph node. Our data show that PSGL-1 represents a previously unknown, phase-specific mechanism for Treg-mediated suppression of the persistence of immune responses and autoimmunity induction. PMID- 24174618 TI - Heteromeric complexes of native collectin kidney 1 and collectin liver 1 are found in the circulation with MASPs and activate the complement system. AB - The complement system is an important part of the innate immune system. The complement cascade may be initiated downstream of the lectin activation pathway upon binding of mannan-binding lectin, ficolins, or collectin kidney 1 (CL-K1, alias CL-11) to suitable microbial patterns consisting of carbohydrates or acetylated molecules. During purification and characterization of native CL-K1 from plasma, we observed that collectin liver 1 (CL-L1) was copurified. Based on deglycosylation and nonreduced/reduced two-dimensional SDS-PAGE, we detected CL K1 and CL-L1 in disulfide bridge-stabilized complexes. Heteromeric complex formation in plasma was further shown by ELISA and transient coexpression. Judging from the migration pattern on two-dimensional SDS-PAGE, the majority of plasma CL-K1 was found in complex with CL-L1. The ratio of this complex was in favor of CL-K1, suggesting that a heteromeric subunit is composed of one CL-L1 and two CL-K1 polypeptide chains. We found that the complex bound to mannan binding lectin-associated serine proteases (MASPs) with affinities in the nM range in vitro and was associated with both MASP-1/-3 and MASP-2 in plasma. Upon binding to mannan or DNA in the presence of MASP-2, the CL-L1-CL-K1 complex mediated deposition of C4b. In favor of large oligomers, the activity of the complex was partly determined by the oligomeric size, which may be influenced by an alternatively spliced variant of CL-K1. The activity of the native heteromeric complexes was superior to that of recombinant CL-K1. We conclude that CL-K1 exists in circulation in the form of heteromeric complexes with CL-L1 that interact with MASPs and can mediate complement activation. PMID- 24174619 TI - Substrate-induced protein stabilization reveals a predominant contribution from mature proteins to peptides presented on MHC class I. AB - The origin of the MHC class I-presented peptides are thought to be primarily from newly synthesized but defective proteins, termed defective ribosomal products. Most of the data supporting this concept come from studies in which inhibitors of protein synthesis were found to rapidly block Ag presentation even when cells contained a pool of mature proteins. However, these data only indirectly address the origin of presented peptides, and in most studies, the contribution of mature functional proteins to the class I peptide pool has not been directly quantified. In this report, we address the efficiency and contribution of mature proteins using a tetracycline-inducible system to express Ags that are conditionally stabilized upon ligand binding. This system circumvents the use of general inhibitors of protein synthesis to control Ag expression. Moreover, by controlling Ag stabilization, we could investigate whether the degradation of mature Ags contributed to Ag presentation at early and/or late time points. We show that mature proteins are the major contributor of peptides presented on class I for two distinct antigenic constructs. Furthermore, our data show that the protein synthesis inhibitors used previously to test the contribution of defective proteins actually block Ag presentation in ways that are independent from blocking Ag synthesis. These data suggest that for the constructs we have analyzed, mature functional proteins, rather than defective ribosomal products, are the predominant source of MHC class I-presented peptides. PMID- 24174621 TI - Role of the menkes ATPase in the absorption of both copper and iron. PMID- 24174620 TI - Silencing the Menkes copper-transporting ATPase (Atp7a) gene in rat intestinal epithelial (IEC-6) cells increases iron flux via transcriptional induction of ferroportin 1 (Fpn1). AB - The Menkes copper-transporting ATPase (Atp7a) gene is induced in rat duodenum during iron deficiency, consistent with copper accumulation in the intestinal mucosa and liver. To test the hypothesis that ATP7A influences intestinal iron metabolism, the Atp7a gene was silenced in rat intestinal epithelial (IEC-6) cells using short hairpin RNA (shRNA) technology. Perturbations in intracellular copper homeostasis were noted in knockdown cells, consistent with the dual roles of ATP7A in pumping copper into the trans-Golgi (for cuproenzyme synthesis) and exporting copper from cells. Intracellular iron concentrations were unaffected by Atp7a knockdown. Unexpectedly, however, vectorial iron ((59)Fe) transport increased (~33%) in knockdown cells grown in bicameral inserts and increased further (~70%) by iron deprivation (compared with negative control shRNA transfected cells). Additional experiments were designed to elucidate the molecular mechanism of increased transepithelial iron flux. Enhanced iron uptake by knockdown cells was associated with increased expression of a ferrireductase (duodenal cytochrome b) and activity of a cell-surface ferrireductase. Increased iron efflux from knockdown cells was likely mediated via transcriptional activation of the ferroportin 1 gene (by an unknown mechanism). Moreover, Atp7a knockdown significantly attenuated expression of an iron oxidase [hephaestin (HEPH); by ~80%] and membrane ferroxidase activity (by ~50%). Cytosolic ferroxidase activity, however, was retained in knockdown cells (75% of control cells), perhaps compensating for diminished HEPH activity. This investigation has thus documented alterations in iron homeostasis associated with Atp7a knockdown in enterocyte-like cells. Alterations in copper transport, trafficking, or distribution may underlie the increase in transepithelial iron flux noted when ATP7A activity is diminished. PMID- 24174622 TI - Complement c3 is inversely associated with habitual intake of provitamin A but not with dietary fat, fatty acids, or vitamin E in middle-aged to older white adults and positively associated with intake of retinol in middle-aged to older white women. AB - Complement factor 3 (C3) has been identified as a novel risk factor for obesity associated cardiometabolic diseases. Data in the literature suggest that C3 concentrations may be influenced by diet. Therefore, we investigated the associations of intake of total fat, specific fatty acids, and fat-soluble vitamin E (and individual tocopherols) and vitamin A (and its dietary precursors) with circulating C3. In a white cohort [Cohort on Diabetes and Atherosclerosis Maastricht (CODAM); n = 501; 59.4 +/- 7.1 y; 61% men], associations of habitual nutrient intake (assessed by a food-frequency questionnaire) with circulating C3 were evaluated by using cross-sectional multiple linear regression analyses. Adjustments were first performed for age, sex, glucose metabolism status (i.e., impaired glucose metabolism or type 2 diabetes), and energy intake and subsequently for BMI, waist circumference, alcohol intake, smoking behavior, and season of blood collection. No associations with C3 were observed for total dietary fat intake or intake of specific fatty acids [saturated, monounsaturated, polyunsaturated, n-6 (omega-6), and n-3 (omega- 3) fatty acids], vitamin E, or individual tocopherols. We observed an inverse association with intake of provitamin A carotenoids alpha-carotene (in MUg/d; regression coefficient beta = 0.075; 95% CI: -0.140, -0.010; P = 0.025) and beta-carotene (in MUg/d; beta = 0.021; 95% CI: -0.044, 0.002; P = 0.068) with C3 (in mg/L). In contrast, and only in women, dietary retinol intake (in MUg/d) was positively associated with C3 (beta = 0.116; 95% CI: 0.014, 0.218; P = 0.026; n = 196). In conclusion, these data suggest that fasting concentrations of C3 may, in a complex manner, be modifiable by variation in dietary provitamin A carotenoids and/or retinol content of the usual diet but most likely not by variations in fat composition and vitamin E content. PMID- 24174623 TI - Estimation of serum and erythrocyte folate concentrations in the New Zealand adult population within a background of voluntary folic acid fortification. AB - National data on the blood folate status of New Zealand adults is lacking. The objective of this study was to describe the blood folate status and examine the predictors of blood folate status in a national sample of adults from New Zealand, a country with voluntary folic acid fortification. The 2008/09 New Zealand Adult Nutrition Survey was a nationwide multistage systematic random cross-sectional survey. Serum and erythrocyte folate concentrations were measured by microbiologic assay. The survey included 4721 participants aged >=15 y, 3359 of whom provided a nonfasting blood sample. Biochemical folate status was measured in 3277 participants. The median serum and erythrocyte folate concentrations were 23 and 809 nmol/L, respectively. The prevalence of biochemical folate deficiency, defined as plasma folate <6.8 nmol/L or erythrocyte folate <305 nmol/L, was 2%. Having breakfast daily compared with never eating breakfast was associated with 53% higher serum and 25% higher erythrocyte folate concentrations; consumers of fortified yeast extract spread had 17% higher serum and 14% higher erythrocyte folate concentrations than nonconsumers; daily users of folate-containing supplements compared with nonusers had 48% higher serum and 28% higher erythrocyte folate concentrations. The prevalence of biochemical folate deficiency in New Zealand adults is low. Participants who ate breakfast more frequently, consumed folate-fortified yeast, or used a daily folate supplement had higher blood folate concentrations. PMID- 24174624 TI - Whey peptides prevent chronic ultraviolet B radiation-induced skin aging in melanin-possessing male hairless mice. AB - Whey proteins or peptides exhibit various actions, including an antioxidant action, an anticancer action, and a protective action against childhood asthma and atopic syndrome. The effects of orally administered whey peptides (WPs) on chronic ultraviolet B (UVB) radiation-induced cutaneous changes, including changes in cutaneous thickness, elasticity, wrinkle formation, etc., have not been examined. In this study, we studied the preventive effects of WPs on cutaneous aging induced by chronic UVB irradiation in melanin-possessing male hairless mice (HRM). UVB (36-180 mJ/cm(2)) was irradiated to the dorsal area for 17 wk in HRM, and the measurements of cutaneous thickness and elasticity in UVB irradiated mice were performed every week. WPs (200 and 400 mg/kg, twice daily) were administered orally for 17 wk. WPs inhibited the increase in cutaneous thickness, wrinkle formation, and melanin granules and the reduction in cutaneous elasticity associated with photoaging. Furthermore, it has been reported that UVB irradiation-induced skin aging is closely associated with the increase in expression of matrix metalloproteinase (MMP), vascular endothelial growth factor (VEGF), Ki-67-, and 8-hydroxy-2'-deoxyguanosine (8-OHdG)-positive cells. WPs also prevented increases in the expression of MMP-2 and pro-MMP-9, VEGF, and Ki-67- and 8-OHdG-positive cells induced by chronic UVB irradiation. It was found that WPs prevent type IV collagen degradation, angiogenesis, proliferation, and DNA damage caused by UVB irradiation. Overall, these results demonstrate the considerable benefit of WPs for protection against solar UV-irradiated skin aging as a supplemental nutrient. PMID- 24174625 TI - Three-year efficacy, safety, and survival findings from COMFORT-II, a phase 3 study comparing ruxolitinib with best available therapy for myelofibrosis. AB - Ruxolitinib is a potent Janus kinase (JAK)1/JAK2 inhibitor that has demonstrated rapid reductions in splenomegaly and marked improvement in disease-related symptoms and quality of life in patients with myelofibrosis (MF). The present analysis reports the 3-year follow-up (median, 151 weeks) of the efficacy and safety of Controlled Myelofibrosis Study With Oral Janus-associated Kinase (JAK) Inhibitor Treatment-II (the COMFORT-II Trial), comparing ruxolitinib with the best available therapy (BAT) in 219 patients with intermediate-2 and high-risk MF. In the ruxolitinib arm, with continued therapy, spleen volume reductions of >=35% by magnetic resonance imaging (equivalent to approximately 50% reduction by palpation) were sustained for at least 144 weeks, with the probability of 50% (95% confidence interval [CI], 36-63) among patients achieving such degree of response. At the time of this analysis, 45% of the patients randomized to ruxolitinib remained on treatment. Ruxolitinib continues to be well tolerated. Anemia and thrombocytopenia were the main toxicities, but they were generally manageable, improved over time, and rarely led to treatment discontinuation (1% and 3.6% of patients, respectively). No single nonhematologic adverse event led to definitive ruxolitinib discontinuation in more than 1 patient. Additionally, patients randomized to ruxolitinib showed longer overall survival than those randomized to BAT (hazard ratio, 0.48; 95% CI, 0.28-0.85; log-rank test, P = .009). PMID- 24174626 TI - In vivo leukemogenic potential of an interleukin 7 receptor alpha chain mutant in hematopoietic stem and progenitor cells. AB - Somatic gain-of-function mutations in interleukin 7 receptor alpha chain (IL7Ralpha) have been described in pediatric T and B acute lymphoblastic leukemias (T/B-ALLs). Most of these mutations are in-frame insertions in the extracellular juxtamembrane-transmembrane region. By using a similar mutant, a heterozygous in-frame transmembrane insertional mutation (INS), we validated leukemogenic potential in murine hematopoietic stem/progenitor cells, using a syngeneic transplantation model. We found that ectopic expression of INS alone in hematopoietic stem/progenitor cells caused myeloproliferative disorders, whereas expression of INS in combination with a Notch1 mutant led to the development of much more aggressive T-ALL than with wild-type IL7Ralpha. Furthermore, forced expression of INS in common lymphoid progenitors led to the development of mature B-cell ALL/lymphoma. These results demonstrated that INS has significant in vivo leukemogenic activity and that the lineage of the resulting leukemia depends on the developmental stage in which INS occurs, and/or concurrent mutations. PMID- 24174627 TI - Human and viral interleukin-6 and other cytokines in Kaposi sarcoma herpesvirus associated multicentric Castleman disease. AB - Kaposi sarcoma herpesvirus (KSHV)-associated multicentric Castleman disease (MCD) is a polyclonal B-cell lymphoproliferative disorder. Human (h) IL-6 and a KSHV encoded homolog, viral IL-6, have been hypothesized to contribute to its pathogenesis, but their relative contributions to disease activity is not well understood. We prospectively characterized KSHV viral load (VL), viral (v) and hIL-6, and other cytokines during KSHV-MCD flare and remission in 21 patients with 34 flares and 20 remissions. KSHV-VL, vIL-6, hIL-6, IL-10, and to a lesser extent TNF-alpha, and IL-1beta were each elevated during initial flares compared with remission. Flares fell into 3 distinct IL-6 profiles: those associated with elevations of vIL6-only (2 flares, 6%), hIL-6 elevations only (17 flares, 50%), and elevations in both hIL-6 and vIL-6 (13 flares, 38%). Compared with hIL-6-only flares, flares with elevated hIL-6 plus vIL-6 exhibited higher C-reactive protein (CRP) (P = .0009); worse hyponatremia (P = .02); higher KSHV VL (P = .016), and higher IL-10 (P = .012). This analysis shows vIL-6 and hIL-6 can independently or together lead to KSHV-MCD flares, and suggests that vIL-6 and hIL-6 may jointly contribute to disease severity. These findings have implications for the development of novel KSHV-MCD therapies targeting IL-6 and its downstream signaling. This trial was registered at clinicaltrials.gov as #NCT099073. PMID- 24174628 TI - Angiogenic capacity of M1- and M2-polarized macrophages is determined by the levels of TIMP-1 complexed with their secreted proMMP-9. AB - A proangiogenic function of tissue-infiltrating monocytes/macrophages has long been attributed to their matrix metalloproteinase-9 zymogen (proMMP-9). Herein, we evaluated the capacity of human monocytes, mature M0 macrophages, and M1- and M2-polarized macrophages to induce proMMP-9-mediated angiogenesis. Only M2 macrophages induced angiogenesis at levels comparable with highly angiogenic neutrophils previously shown to release their proMMP-9 in a unique form, free of tissue inhibitor of metalloproteinases-1 (TIMP-1). Macrophage differentiation was accompanied by induction of low-angiogenic, TIMP-1-encumbered proMMP-9. However, polarization toward the M2, but not the M1 phenotype, caused a substantial downregulation of TIMP-1 expression, resulting in production of angiogenic, TIMP deficient proMMP-9. Correspondingly, the angiogenic potency of M2 proMMP-9 was lost after its complexing with TIMP-1, whereas TIMP-1 silencing in M0/M1 macrophages rendered them both angiogenic. Similar to human cells, murine bone marrow-derived M2 macrophages also shut down their TIMP-1 expression and produced proMMP-9 unencumbered by TIMP-1. Providing proof that angiogenic capacity of murine M2 macrophages depended on their TIMP-free proMMP-9, Mmp9-null M2 macrophages were nonangiogenic, although their TIMP-1 was severely downregulated. Our study provides a unifying molecular mechanism for high angiogenic capacity of TIMP-free proMMP-9 that would be uniquely produced in a pathophysiological microenvironment by influxing neutrophils and/or M2 polarized macrophages. PMID- 24174629 TI - Epstein-Barr virus latent membrane protein 2A enhances MYC-driven cell cycle progression in a mouse model of B lymphoma. AB - Elevated expression of MYC is a shared property of many human cancers. Epstein Barr virus (EBV) has been associated with lymphoid malignancies, yet collaborative roles between MYC and EBV in lymphomagenesis are unclear. EBV latent membrane protein 2A (LMP2A) functions as a B-cell receptor (BCR) mimic known to provide survival signals to infected B cells. Co-expression of human MYC and LMP2A in mice (LMP2A/lambda-MYC) accelerates B lymphoma onset compared with mice expressing human MYC alone (lambda-MYC mice). Here we show a novel role of LMP2A in potentiating MYC to promote G1-S transition and hyperproliferation by downregulating cyclin-dependent kinase inhibitor p27(kip1) in a proteasome dependent manner. Expressing a gain-of-function S10A mutant of p27(kip1) has minor effect on tumor latency. However, pretumor B cells from lambda-MYC mice expressing homozygous S10A mutant show a significant decrease in the percentage of S-phase cells. Interestingly, LMP2A is able to counteract the antiproliferative effect of the S10A mutant to promote S-phase entry. Finally, we show that LMP2A expression correlates with higher levels of MYC expression and suppression of p27(kip1) before lymphoma onset. Our study demonstrates a novel function of EBV LMP2A in maximizing MYC expression, resulting in hyperproliferation and cellular transformation into cancer cells in vivo. PMID- 24174630 TI - TRiM: an organizational response to traumatic events in Cumbria Constabulary. AB - BACKGROUND: A major incident involving multiple fatalities occurred in Cumbria, England on 2 June 2010. The Cumbrian Constabulary deployed an organizational peer support response for personnel involved known as trauma risk management (TRiM). AIMS: To examine data routinely gathered during the TRiM process to evaluate the relationship of the intervention to sickness absence. METHODS: Using incident databases, details were gathered regarding exposure to the murders and type of TRiM intervention, including an assessment of the psychological risk to the individual of developing a trauma-related mental health problem. Sociodemographic information was collated by the occupational health department. Cumulative sickness absence data in the 2 months following the murders were used as a proxy for mental health status. RESULTS: A total of 717 police officers and civilian support staff were identified. High levels of traumatic exposure were associated with subsequent receipt of a TRiM intervention. The majority of psychological risk indices reduced between the initial and subsequent evaluation. Greater traumatic exposure was associated with longer sickness absence lengths. Engagement in the TRiM process was associated with a reduction in sickness absence especially in more junior ranks. CONCLUSIONS: In this study, we found that TRiM deployed within a police force responding to a major event offered a way of structuring a response for those involved. Our data suggest that TRiM may offer a way of assessing psychological risk so that officers can be offered early supportive interventions. Our data suggest that TRiM may help to ameliorate some of the negative effects of high trauma exposure. PMID- 24174631 TI - Cat and dog sensitization in pet shop workers. AB - BACKGROUND: Sensitivity and symptoms related to animal proteins have been investigated in various occupational groups. However, data from pet shops are limited. AIMS: To investigate rates of sensitivity to cats and dogs among pet shop workers, to assess the relationship between sensitivity, allergen levels and symptoms and to investigate whether passive transport from pet shops to homes is possible. METHODS: Pet shop workers underwent interviews with a questionnaire adapted from the European Community Respiratory Health Survey. Dust samples for allergen detection were collected from pet shops using a vacuum cleaner. Skin tests were performed with common allergens. Dust samples were also obtained from the houses of 7 workers and 12 control subjects. RESULTS: Fifty-one workers from 20 pet shops were included in the study. Thirteen (25%) workers reported work related symptoms. Four workers had sensitivity to animal allergens. The mean cat/dog allergen levels from pet shops were 15.7 and 3.2 ug/g, respectively. There was no significant relationship between cat/dog allergen levels and work related symptoms and sensitivity to pets. None of the dust samples collected from the homes of pet shop workers contained cat allergens. Dog allergen was detected in only one house (0.58 ug/g). Neither cat nor dog allergens were found in the homes of the 12 control subjects. CONCLUSIONS: Although a quarter of pet shop workers reported work-related symptoms, sensitivity to cat and dog was low. These findings suggest that work-related symptoms may be due to other factors than cat and dog sensitivity. PMID- 24174632 TI - Survey of advanced radiation technologies used at designated cancer care hospitals in Japan. AB - OBJECTIVE: Our survey assessed the use of advanced radiotherapy technologies at the designated cancer care hospitals in Japan, and we identified several issues to be addressed. METHODS: We collected the data of 397 designated cancer care hospitals, including information on staffing in the department of radiation oncology (e.g. radiation oncologists, medical physicists and radiation therapists), the number of linear accelerators and the implementation of advanced radiotherapy technologies from the Center for Cancer Control and Information Services of the National Cancer Center, Japan. RESULTS: Only 53% prefectural designated cancer care hospitals and 16% regional designated cancer care hospitals have implemented intensity-modulated radiotherapy for head and neck cancers, and 62% prefectural designated cancer care hospitals and 23% regional designated cancer care hospitals use intensity-modulated radiotherapy for prostate cancer. Seventy-four percent prefectural designated cancer care hospitals and 40% regional designated cancer care hospitals employ stereotactic body radiotherapy for lung cancer. Our multivariate analysis of prefectural designated cancer care hospitals which satisfy the institute's qualifications for advanced technologies revealed the number of radiation oncologists (P = 0.01) and that of radiation therapists (P = 0.003) were significantly correlated with the implementation of intensity-modulated radiotherapy for prostate cancer, and the number of radiation oncologists (P = 0.02) was correlated with the implementation of stereotactic body radiotherapy. There was a trend to correlate the number of medical physicists with the implementation of stereotactic body radiotherapy (P = 0.07). Only 175 (51%) regional designated cancer care hospitals satisfy the institute's qualification of stereotactic body radiotherapy and 76 (22%) satisfy that of intensity-modulated radiotherapy. Seventeen percent prefectural designated cancer care hospitals and 13% regional designated cancer care hospitals had a quality assurance committee. CONCLUSIONS: The numbers of radiation oncologists and other operating staff might be essential factors in the implementation of advanced radiotherapy technologies. Small proportions of regional designated cancer care hospitals satisfy the institute's qualifications of advanced technologies. PMID- 24174633 TI - Clinical outcomes of 849 laryngeal cancers treated in the past 40 years: are we succeeding? AB - OBJECTIVE: We analyzed the clinical outcomes of 849 laryngeal cancers treated in the past 40 years, which overlapped with the era of the global treatment shift. METHODS: To compare the chronological outcomes, patients were divided into four groups according to their registration year as 1972-82, 1983-92, 1993-2002 and 2003-12; treatment trends, larynx preservation rate and overall survival rate were compared. RESULTS: There were 104, 173, 253 and 319 patients registered in 1972-82, 1983-92, 1993-2002 and 2003-12, respectively. Five-year overall survival rates were 74, 76.5, 75.6 and 82.2% in 1972-82, 1983-92, 1993-2002 and 2003-12, respectively. The five-year larynx preservation rates were 65.5, 75.7, 75.4 and 80.9% in 1972-82, 1983-92, 1993-2002 and 2003-12, respectively. CONCLUSIONS: The number of patients treated at our institute increased, and the overall survival and larynx preservation rates exhibited favorable improvements over the past four decades. In the analysis of nonsurgical options, S1 combined radiotherapy showed superiority over concurrent chemoradiotherapy and radiotherapy in larynx preservation, and S1 combined radiotherapy, concurrent chemoradiotherapy and Tegafur Uracil combined radiotherapy showed superiority over radiotherapy in overall survival. In nonsurgical approaches, proper case selection is the key to success and may be much more important than pursuing radiotherapy dose escalation. In the analysis of surgical options, laser and supracricoid laryngectomy with cricohyoidoepiglottopexy contributed to larynx preservation in early- and intermediate-stage cancers, respectively. Supracricoid laryngectomy with cricohyoidoepiglottopexy demonstrated overall survival not worse than total laryngectomy, which is the prerequisite treatment basis for larynx preservation options. We must make extra efforts in pursuing an ideal balance between nonsurgical and surgical larynx preservation options. PMID- 24174634 TI - Health secretary loses court battle over Lewisham Hospital. PMID- 24174635 TI - Re: Clinically significant lung function impairment due to current levels of respirable quartz? (authors' response). PMID- 24174636 TI - Effort--reward imbalance and medically certified absence for mental health problems: a prospective study of white-collar workers. AB - OBJECTIVE: Little is known about the effects of psychosocial work factors on objectively assessed mental health problems leading to medically certified absence. Only one study has evaluated the prospective effects of effort-reward imbalance (ERI) at work with regards to this outcome. The present study aimed to evaluate the effects of ERI on the incidence of medically certified absence for mental health problems. METHODS: The study included 2086 white-collar workers (63.3% women) employed in public organisations in Quebec city. Participants were followed over a 9-year period. Medical absences from work were collected from employers' files and psychosocial factors were measured using the ERI questionnaire. Cox regression models were used to estimate the incidence of certified sickness absence due to mental health problems that lasted 5 workdays or more, while controlling for confounders. RESULTS: Workers exposed to ERI had a higher risk of a first spell of medically certified absence for mental health problems (HR=1.38, 95% CI 1.08 to 1.76) compared with unexposed workers. Low reward was significantly associated with a high risk among men (HR=2.80, 95% CI 1.34 to 5.89) but not in women. (HR=1.24, 95% CI 0.90 to 1.73). Effort at work had no effect on certified absence. All these effects were adjusted for potential confounders. CONCLUSIONS: ERI and low reward at work were prospectively associated with medically certified absence for mental health problems. These effects seem to differ by gender. Primary prevention that is aimed at reducing these stressors should be considered to help reduce the incidence of such severe mental health problems. PMID- 24174637 TI - Analysis of the roles of mutations in thyroid hormone receptor-beta by a bacterial biosensor system. AB - Mutations in thyroid hormone receptors (TRs) often lead to metabolic and developmental disorders, but patients with these mutations are difficult to treat with existing thyromimetic drugs. In this study, we analyzed six clinically observed mutations in the ligand-binding domain of the human TRbeta using an engineered bacterial hormone biosensor. Six agonist compounds, including triiodothyronine (T3), thyroxine (T4), 3,5,3'-triiodothyroacetic acid (Triac), GC 1, KB-141, and CO-23, and the antagonist NH-3 were examined for their ability to bind to each of the TRbeta mutants. The results indicate that some mutations lead to the loss of ability to bind to native ligands, ranging from several fold to several hundred fold, while other mutations completely abolish the ability to bind to any ligand. Notably, the effect of each ligand on each TRbeta mutant in this bacterial system is highly dependent on both the mutation and the ligand; some ligands were bound well by a wide variety of mutants, while other ligands lost their affinity for all but the WT receptor. This study demonstrates the ability of our bacterial system to differentiate agonist compounds from antagonist compounds and shows that one of the TRbeta mutations leads to an unexpected increase in antagonist ability relative to other mutations. These results indicate that this bacterial sensor can be used to rapidly determine ligand-binding ability and character for clinically relevant TRbeta mutants. PMID- 24174638 TI - Multiple checkpoints for the expression of the chloroplast-encoded splicing factor MatK. AB - The chloroplast genome of land plants contains only a single gene for a splicing factor, Maturase K (MatK). To better understand the regulation of matK gene expression, we quantitatively investigated the expression of matK across tobacco (Nicotiana tabacum) development at the transcriptional, posttranscriptional, and protein levels. We observed striking discrepancies of MatK protein and matK messenger RNA levels in young tissue, suggestive of translational regulation or altered protein stability. We furthermore found increased matK messenger RNA stability in mature tissue, while other chloroplast RNAs tested showed little changes. Finally, we quantitatively measured MatK-intron interactions and found selective changes in the interaction of MatK with specific introns during plant development. This is evidence for a direct role of MatK in the regulation of chloroplast gene expression via splicing. We furthermore modeled a simplified matK gene expression network mathematically. The model reflects our experimental data and suggests future experimental perturbations to pinpoint regulatory checkpoints. PMID- 24174641 TI - Paying for migrant healthcare. PMID- 24174642 TI - Record damages are awarded in medical negligence case in India. PMID- 24174640 TI - The relation between total joint arthroplasty and risk for serious cardiovascular events in patients with moderate-severe osteoarthritis: propensity score matched landmark analysis. AB - OBJECTIVE: To examine whether total joint arthroplasty of the hip and knee reduces the risk for serious cardiovascular events in patients with moderate severe osteoarthritis. DESIGN: Propensity score matched landmark analysis. SETTING: Ontario, Canada. PARTICIPANTS: 2200 adults with hip or knee osteoarthritis aged 55 or more at recruitment (1996-98) and followed prospectively until death or 2011. MAIN OUTCOME MEASURE: Rates of serious cardiovascular events for those who received a primary total joint arthroplasty compared with those did not within an exposure period of three years after baseline assessment. RESULTS: The propensity score matched cohort consisted of 153 matched pairs of participants with moderate-severe arthritis. Over a median follow-up period of seven years after the landmark date (start of the study), matched participants who underwent a total joint arthroplasty during the exposure period were significantly less likely than those who did not to experience a cardiovascular event (hazards ratio 0.56, 95% confidence interval 0.43 to 0.74, P<0.001). Within seven years of the exposure period the absolute risk reduction was 12.4% (95% confidence interval 1.7% to 23.1%) and number needed to treat was 8 (95% confidence interval 4 to 57 patients). CONCLUSIONS: Using a propensity matched landmark analysis in a population cohort with advanced hip or knee osteoarthritis, this study found a cardioprotective benefit of primary elective total joint arthroplasty. PMID- 24174643 TI - Artifacts, intentions, and contraceptives: the problem with having a plan B for plan B. AB - It is commonly proposed that artifacts cannot be understood without reference to human intentions. This fact, I contend, has relevance to the use of artifacts in intentional action. I argue that because artifacts have intentions embedded into them antecedently, when we use artifacts we are sometimes compelled to intend descriptions of our actions that we might, for various reasons, be inclined to believe that we do not intend. I focus this argument to a specific set of artifacts, namely, medical devices, before considering an extended application to emergency contraceptive devices. Although there is some debate about whether emergency contraception has an abortifacient effect, I argue that if there is an abortifacient effect, then the effect cannot normally be a side effect of one's action. PMID- 24174644 TI - Rethinking voluntary euthanasia. AB - Our goal in this article is to explicate the way, and the extent to which, euthanasia can be voluntary from both the perspective of the patient and the perspective of the health care providers involved in the patient's care. More significantly, we aim to challenge the way in which those engaged in ongoing philosophical debates regarding the morality of euthanasia draw distinctions between voluntary, involuntary, and nonvoluntary euthanasia on the grounds that drawing the distinctions in the traditional manner (1) fails to reflect what is important from the patient's perspective and (2) fails to reflect the significance of health care providers' interests, including their autonomy and integrity. PMID- 24174645 TI - Cut children's screen time to less than two hours a day, US pediatricians say. PMID- 24174646 TI - How adaptation currents change threshold, gain, and variability of neuronal spiking. AB - Many types of neurons exhibit spike rate adaptation, mediated by intrinsic slow K(+) currents, which effectively inhibit neuronal responses. How these adaptation currents change the relationship between in vivo like fluctuating synaptic input, spike rate output, and the spike train statistics, however, is not well understood. In this computational study we show that an adaptation current that primarily depends on the subthreshold membrane voltage changes the neuronal input output relationship (I-O curve) subtractively, thereby increasing the response threshold, and decreases its slope (response gain) for low spike rates. A spike dependent adaptation current alters the I-O curve divisively, thus reducing the response gain. Both types of an adaptation current naturally increase the mean interspike interval (ISI), but they can affect ISI variability in opposite ways. A subthreshold current always causes an increase of variability while a spike triggered current decreases high variability caused by fluctuation-dominated inputs and increases low variability when the average input is large. The effects on I-O curves match those caused by synaptic inhibition in networks with asynchronous irregular activity, for which we find subtractive and divisive changes caused by external and recurrent inhibition, respectively. Synaptic inhibition, however, always increases the ISI variability. We analytically derive expressions for the I-O curve and ISI variability, which demonstrate the robustness of our results. Furthermore, we show how the biophysical parameters of slow K(+) conductances contribute to the two different types of an adaptation current and find that Ca(2+)-activated K(+) currents are effectively captured by a simple spike-dependent description, while muscarine-sensitive or Na(+) activated K(+) currents show a dominant subthreshold component. PMID- 24174647 TI - Differential contributions of basal ganglia and thalamus to song initiation, tempo, and structure. AB - Basal ganglia-thalamocortical circuits are multistage loops critical to motor behavior, but the contributions of individual components to overall circuit function remain unclear. We addressed these issues in a songbird basal ganglia thalamocortical circuit (the anterior forebrain pathway, AFP) specialized for singing and critical for vocal plasticity. The major known afferent to the AFP is the premotor cortical nucleus, HVC. Surprisingly, previous studies found that lesions of HVC alter song but do not eliminate the ability of the AFP to drive song production. We therefore used this AFP-driven song to investigate the role of basal ganglia and thalamus in vocal structure, tempo, and initiation. We found that lesions of the striatopallidal component (Area X) slowed song and simplified its acoustic structure. Elimination of the thalamic component (DLM) further simplified the acoustic structure of song and regularized its rhythm but also dramatically reduced song production. The acoustic structure changes imply that sequential stages of the AFP each add complexity to song, but the effects of DLM lesions on song initiation suggest that thalamus is a locus of additional inputs important to initiation. Together, our results highlight the cumulative contribution of stages of a basal ganglia-thalamocortical circuit to motor output along with distinct involvement of thalamus in song initiation or "gating." PMID- 24174648 TI - Activity of long-lead burst neurons in pontine reticular formation during head unrestrained gaze shifts. AB - Primates explore a visual scene through a succession of saccades. Much of what is known about the neural circuitry that generates these movements has come from neurophysiological studies using subjects with their heads restrained. Horizontal saccades and the horizontal components of oblique saccades are associated with high-frequency bursts of spikes in medium-lead burst neurons (MLBs) and long-lead burst neurons (LLBNs) in the paramedian pontine reticular formation. For LLBNs, the high-frequency burst is preceded by a low-frequency prelude that begins 12 150 ms before saccade onset. In terms of the lead time between the onset of prelude activity and saccade onset, the anatomical projections, and the movement field characteristics, LLBNs are a heterogeneous group of neurons. Whether this heterogeneity is endemic of multiple functional subclasses is an open question. One possibility is that some may carry signals related to head movement. We recorded from LLBNs while monkeys performed head-unrestrained gaze shifts, during which the kinematics of the eye and head components were dissociable. Many cells had peak firing rates that never exceeded 200 spikes/s for gaze shifts of any vector. The activity of these low-frequency cells often persisted beyond the end of the gaze shift and was usually related to head-movement kinematics. A subset was tested during head-unrestrained pursuit and showed clear modulation in the absence of saccades. These "low-frequency" cells were intermingled with MLBs and traditional LLBNs and may represent a separate functional class carrying signals related to head movement. PMID- 24174649 TI - Neuronal activity in the preoptic hypothalamus during sleep deprivation and recovery sleep. AB - The preoptic hypothalamus is implicated in sleep regulation. Neurons in the median preoptic nucleus (MnPO) and the ventrolateral preoptic area (VLPO) have been identified as potential sleep regulatory elements. However, the extent to which MnPO and VLPO neurons are activated in response to changing homeostatic sleep regulatory demands is unresolved. To address this question, we continuously recorded the extracellular activity of neurons in the rat MnPO, VLPO and dorsal lateral preoptic area (LPO) during baseline sleep and waking, during 2 h of sleep deprivation (SD) and during 2 h of recovery sleep (RS). Sleep-active neurons in the MnPO (n = 11) and VLPO (n = 13) were activated in response to SD, such that waking discharge rates increased by 95.8 +/- 29.5% and 59.4 +/- 17.3%, respectively, above waking baseline values. During RS, non-rapid eye movement (REM) sleep discharge rates of MnPO neurons initially increased to 65.6 +/- 15.2% above baseline values, then declined to baseline levels in association with decreases in EEG delta power. Increase in non-REM sleep discharge rates in VLPO neurons during RS averaged 40.5 +/- 7.6% above baseline. REM-active neurons (n = 16) in the LPO also exhibited increased waking discharge during SD and an increase in non-REM discharge during RS. Infusion of A2A adenosine receptor antagonist into the VLPO attenuated SD-induced increases in neuronal discharge. Populations of LPO wake/REM-active and state-indifferent neurons and dorsal LPO sleep-active neurons were unresponsive to SD. These findings support the hypothesis that sleep-active neurons in the MnPO and VLPO, and REM-active neurons in the LPO, are components of neuronal circuits that mediate homeostatic responses to sustained wakefulness. PMID- 24174650 TI - Cue to action processing in motor cortex populations. AB - The primary motor cortex (MI) commands motor output after kinematics are planned from goals, thought to occur in a larger premotor network. However, there is a growing body of evidence that MI is involved in processes beyond action generation, and neuronal subpopulations may perform computations related to cue to-action processing. From multielectrode array recordings in awake behaving Macaca mulatta monkeys, our results suggest that early MI ensemble activity during goal-directed reaches is driven by target information when cues are closely linked in time to action. Single-neuron activity spanned cue presentation to movement, with the earliest responses temporally aligned to cue and the later responses better aligned to arm movements. Population decoding revealed that MI's coding of cue direction evolved temporally, likely going from cue to action generation. We confirmed that a portion of MI activity is related to visual target processing by showing changes in MI activity related to the extinguishing of a continuously pursued visual target. These findings support a view that MI is an integral part of a cue-to-action network for immediate responses to environmental stimuli. PMID- 24174651 TI - Abnormal functional connectivity between motor cortex and pedunculopontine nucleus following chronic dopamine depletion. AB - The activity of the basal ganglia is altered in Parkinson's disease (PD) as a consequence of the degeneration of dopamine neurons in the substantia nigra pars compacta. This results in aberrant discharge patterns and expression of exaggerated oscillatory activity across the basal ganglia circuit. Altered activity has also been reported in some of the targets of the basal ganglia, including the pedunculopontine nucleus (PPN), possibly due to its close interconnectivity with most regions of the basal ganglia. However, the nature of the involvement of the PPN in the pathophysiology of PD has not been fully elucidated. Here, we recorded local field potentials in the motor cortex and the PPN in the 6-hydroxydopamine (6-OHDA)-lesioned rat model of PD under urethane anesthesia. By means of linear and nonlinear statistics, we analyzed the synchrony between the motor cortex and the PPN and the delay in the interaction between these two structures. We observed the presence of coherent activity between the cortex and the PPN in low (5-15 Hz)- and high (25-35 Hz)-frequency bands during episodes of cortical activation. In each case, the cortex led the PPN. Dopamine depletion strengthened the interaction of the low-frequency activities by increasing the coherence specifically in the theta and alpha ranges and reduced the delay of the interaction in the gamma band. Our data show that cortical inputs play a determinant role in leading the coherent activity with the PPN and support the involvement of the PPN in the pathophysiology of PD. PMID- 24174652 TI - Nucleus accumbens responses differentiate execution and restraint in reward directed behavior. AB - Our behavior is powerfully driven by environmental cues that signal the availability of rewarding stimuli. We frequently encounter stimuli-a bowl of candy or an alert from our smartphone-that trigger actions to obtain those rewards, even though there may be positive outcomes associated with not acting. The inability to restrain one's action in the presence of reward-associated cues is one type of impulsive behavior and a component of such maladaptive behaviors as overeating, gambling, and substance abuse. The nucleus accumbens (NAc) is ideally situated to integrate multiple cognitive and affective inputs to bias action via outputs through the basal ganglia. NAc neurons have been shown to respond to cues that predict reward availability, goal-directed behaviors aimed at obtaining them, and delivery of the reward itself. As these processes are typically associated, it is difficult to discern whether signals in the NAc are more closely related to processing reward-predictive aspects of goal-directed behavior or selection of behavioral response. To dissociate these possibilities, we recorded the activity of NAc neurons while rats performed a task in which two different cues both informed rats of reward availability but required them to either press a lever (Go) or withhold pressing (NoGo) to obtain the reward. Individual cue-responsive neurons showed either increases or decreases in activity at cue onset. Increases in activity were larger, and decreases smaller, when rats withheld lever pressing, whether correctly for NoGo trials or in error on Go trials. Thus NAc cue responses correlated with action, regardless of cue type or accuracy. PMID- 24174653 TI - Long-term measurement of muscle denervation and locomotor behavior in individual wild-type and ALS model mice. AB - The increasing number of mouse models of human degenerative and injury-related diseases that affect motor behavior raises the importance of in vivo methodologies allowing measurement of physiological and behavioral changes over an extended period of time in individual animals. A method that provides long term measurements of muscle denervation and its behavioral consequences in individual mice for several months is presented in this article. The method is applied to mSod1(G93A) mice, which model human amyotrophic lateral sclerosis (ALS). The denervation process of gastrocnemius and soleus muscles in mSod1(G93A) mice is demonstrated for up to 3 mo. The data suggest that as muscle denervation progresses, massive behavioral compensation occurs within the spinal cord that allows animals to walk almost normally until late ages. Only around the age of 84 days is the first sign of abnormal movement during walking behavior detected as an abnormal tibialis anterior activity profile that is manifested in subtle but abnormal swing movement during walking. Additionally, this method can be used with other mouse models of human diseases, such as spinal cord injury, intracerebral hemorrhage, Parkinson's diseases, and spinal muscular atrophy. PMID- 24174654 TI - Secular trends in colon and rectal cancer relative survival. AB - BACKGROUND: Treatment options for colorectal cancer (CRC) have improved substantially over the past 25 years. Measuring the impact of these improvements on survival outcomes is challenging, however, against the background of overall survival gains from advancements in the prevention, screening, and treatment of other conditions. Relative survival is a metric that accounts for these concurrent changes, allowing assessment of changes in CRC survival. We describe stage- and location-specific trends in relative survival after CRC diagnosis. METHODS: We analyzed survival outcomes for 233965 people in the Surveillance Epidemiology and End Results (SEER) program who were diagnosed with CRC between January 1, 1975, and December 31, 2003. All models were adjusted for sex, race (black vs white), age at diagnosis, time since diagnosis, and diagnosis year. We estimated the proportional difference in survival for CRC patients compared with overall survival for age-, sex-, race-, and period-matched controls to account for concurrent changes in overall survival using two-sided Wald tests. RESULTS: We found statistically significant reductions in excess hazard of mortality from CRC in 2003 relative to 1975, with excess hazard ratios ranging from 0.75 (stage IV colon cancer; P < .001) to 0.32 (stage I rectal cancer; P < .001), indicating improvements in relative survival for all stages and cancer locations. These improvements occurred in earlier years for patients diagnosed with stage I cancers, with smaller but continuing improvements for later-stage cancers. CONCLUSIONS: Our results demonstrate a steady trend toward improved relative survival for CRC, indicating that treatment and surveillance improvements have had an impact at the population level. PMID- 24174655 TI - SMYD3 as an oncogenic driver in prostate cancer by stimulation of androgen receptor transcription. AB - BACKGROUND: Androgen receptor (AR) is critical for prostate tumorigenesis and is frequently overexpressed during prostate cancer (PC) progression. However, few studies have addressed the epigenetic regulation of AR expression. METHODS: We analyzed SMYD3 expression in human PC with Western blot and immunohistochemistry. SMYD3 expression was knocked down using short hairpin RNA (shRNA) or small interfering RNA (siRNA). Cell proliferation, colony formation, and apoptosis analyses and xenograft transplantation were performed to evaluate the impact of SMYD3 depletion on PC cells. AR expression and promoter activity were determined using real-time quantitative polymerase chain reaction, western blot, and luciferase reporter assay. AR promoter association with Sp1, SMYD3, and histone modifications was assessed by chromatin immunoprecipitation. Differences in AR mRNA abundance and promoter activity were analyzed using Wilcoxon signed-rank tests, SMYD3 expression was analyzed using with Mann-Whitney U tests for unpaired samples, and tumor weight was analyzed with Student t test. All statistical tests were two-sided. RESULTS: The upregulation of SMYD3 protein expression was observed in seven of eight prostate tumor specimens, compared with matched normal tissues. Immunohistochemical analysis showed a strong SMYD3 staining in the nuclei of PC tissues in eight of 25 (32%) cases and in the cytoplasm in 23 out of 25 (92%) cases, whereas benign prostate tissue exhibited weak immunostaining. Depletion of SMYD3 by siRNA or shRNA inhibited PC cell proliferation (72 hours relative to 24 hours: control shRNA vs SMYD3 shRNA 1: mean fold change = 2.76 vs 1.68; difference = 1.08; 95% confidence interval = 0.78 to 1.38, P < .001), colony formation, cell migration, invasion, and xenograft tumor formation. Two functional SMYD3-binding motifs were identified in the AR promoter region. CONCLUSIONS: SMYD3 promotes prostate tumorigenesis and mediates epigenetic upregulation of AR expression. PMID- 24174656 TI - The impoverished brain: disparities in maternal education affect the neural response to sound. AB - Despite the prevalence of poverty worldwide, little is known about how early socioeconomic adversity affects auditory brain function. Socioeconomically disadvantaged children are underexposed to linguistically and cognitively stimulating environments and overexposed to environmental toxins, including noise pollution. This kind of sensory impoverishment, we theorize, has extensive repercussions on how the brain processes sound. To characterize how this impoverishment affects auditory brain function, we compared two groups of normal hearing human adolescents who attended the same schools and who were matched in age, sex, and ethnicity, but differed in their maternal education level, a correlate of socioeconomic status (SES). In addition to lower literacy levels and cognitive abilities, adolescents from lower maternal education backgrounds were found to have noisier neural activity than their classmates, as reflected by greater activity in the absence of auditory stimulation. Additionally, in the lower maternal education group, the neural response to speech was more erratic over repeated stimulation, with lower fidelity to the input signal. These weaker, more variable, and noisier responses are suggestive of an inefficient auditory system. By studying SES within a neuroscientific framework, we have the potential to expand our understanding of how experience molds the brain, in addition to informing intervention research aimed at closing the achievement gap between high SES and low-SES children. PMID- 24174658 TI - Olfactory wiring logic in amphibians challenges the basic assumptions of the unbranched axon concept. AB - Olfactory receptor neurons extend axons into the olfactory bulb, where they face the challenge to integrate into existing circuitry. The consensus view is that in vertebrates individual receptor neurons project unbranched axons into one specific glomerulus of the olfactory bulb. We report here that, strikingly different from the generally assumed wiring principle in vertebrate olfactory systems, axons of single receptor neurons of Xenopus laevis regularly bifurcate and project into more than one glomerulus. Specifically, the innervation of multiple glomeruli is present in all ontogenetic stages of this species, from the larva to the postmetamorphic frog. Also, we show that this unexpected wiring pattern is not restricted to axons of immature receptor neurons, but that it is also a feature of mature neurons of both the main and accessory olfactory system. This glomerular innervation pattern is unique among vertebrates investigated so far and represents a new olfactory wiring strategy. PMID- 24174657 TI - Treatment with thyroxine restores myelination and clinical recovery after intraventricular hemorrhage. AB - Intraventricular hemorrhage (IVH) remains a major cause of white matter injury in preterm infants with no viable therapeutic strategy to restore myelination. Maturation of oligodendrocytes and myelination is influenced by thyroid hormone (TH) signaling, which is mediated by TH receptor alpha (TRalpha) and TRbeta. In the brain, cellular levels of TH are regulated by deiodinases, with deiodinase-2 mediating TH activation and deiodinase-3 TH inactivation. Therefore, we hypothesized that IVH would decrease TH signaling via changes in the expression of deiodinases and/or TRs, and normalization of TH signaling would enhance maturation of oligodendrocytes and myelination in preterm infants with IVH. These hypotheses were tested using both autopsy materials from human preterm infants and a rabbit model of IVH. We found that deiodinase-2 levels were reduced, whereas deiodinase-3 levels were increased in brain samples of both humans and rabbits with IVH compared with controls without IVH. TRalpha expression was also increased in human infants with IVH. Importantly, treatment with TH accelerated the proliferation and maturation of oligodendrocytes, increased transcription of Olig2 and Sox10 genes, augmented myelination, and restored neurological function in pups with IVH. Consistent with these findings, the density of myelinating oligodendrocytes was almost doubled in TH-treated human preterm infants compared with controls. Thus, in infants with IVH the combined elevation in deiodinase-3 and reduction in deiodinase-2 decreases TH signaling that can be worsened by an increase in unliganded TRalpha. Given that TH promotes neurological recovery in IVH, TH treatment might improve the neurodevelopmental outcome of preterm infants with IVH. PMID- 24174659 TI - Spontaneous and evoked release are independently regulated at individual active zones. AB - Neurotransmitter release from synaptic vesicle fusion is the fundamental mechanism for neuronal communication at synapses. Evoked release following an action potential has been well characterized for its function in activating the postsynaptic cell, but the significance of spontaneous release is less clear. Using transgenic tools to image single synaptic vesicle fusion events at individual release sites (active zones) in Drosophila, we characterized the spatial and temporal dynamics of exocytotic events that occur spontaneously or in response to an action potential. We also analyzed the relationship between these two modes of fusion at single release sites. A majority of active zones participate in both modes of fusion, although release probability is not correlated between the two modes of release and is highly variable across the population. A subset of active zones is specifically dedicated to spontaneous release, indicating a population of postsynaptic receptors is uniquely activated by this mode of vesicle fusion. Imaging synaptic transmission at individual release sites also revealed general rules for spontaneous and evoked release, and indicate that active zones with similar release probability can cluster spatially within individual synaptic boutons. These findings suggest neuronal connections contain two information channels that can be spatially segregated and independently regulated to transmit evoked or spontaneous fusion signals. PMID- 24174660 TI - Modulation of NMDAR subunit expression by TRPM2 channels regulates neuronal vulnerability to ischemic cell death. AB - Neuronal vulnerability to ischemia is dependent on the balance between prosurvival and prodeath cellular signaling. In the latter, it is increasingly appreciated that toxic Ca(2+) influx can occur not only via postsynaptic glutamate receptors, but also through other cation conductances. One such conductance, the Transient receptor potential melastatin type-2 (TRPM2) channel, is a nonspecific cation channel having homology to TRPM7, a conductance reported to play a key role in anoxic neuronal death. The role of TRPM2 conductances in ischemic Ca(2+) influx has been difficult to study because of the lack of specific modulators. Here we used TRPM2-null mice (TRPM2(-/-)) to study how TRPM2 may modulate neuronal vulnerability to ischemia. TRPM2(-/-) mice subjected to transient middle cerebral artery occlusion exhibited smaller infarcts when compared with wild-type animals, suggesting that the absence of TRPM2 is neuroprotective. Surprisingly, field potentials (fEPSPs) recorded during redox modulation in brain slices taken from TRPM2(-/-) mice revealed increased excitability, a phenomenon normally associated with ischemic vulnerability, whereas wild-type fEPSPs were unaffected. The upregulation in fEPSP in TRPM2(-/-) neurons was blocked selectively by a GluN2A antagonist. This increase in excitability of TRPM2(-/-) fEPSPs during redox modulation depended on the upregulation and downregulation of GluN2A- and GluN2B-containing NMDARs, respectively, and on augmented prosurvival signaling via Akt and ERK pathways culminating in the inhibition of the proapoptotic factor GSK3beta. Our results suggest that TRPM2 plays a role in downregulating prosurvival signals in central neurons and that TRPM2 channels may comprise a therapeutic target for preventing ischemic damage. PMID- 24174661 TI - Netrin-1 promotes excitatory synaptogenesis between cortical neurons by initiating synapse assembly. AB - Netrin-1 is a secreted protein that directs long-range axon guidance during early stages of neural circuit formation and continues to be expressed in the mammalian forebrain during the postnatal period of peak synapse formation. Here we demonstrate a synaptogenic function of netrin-1 in rat and mouse cortical neurons and investigate the underlying mechanism. We report that netrin-1 and its receptor DCC are widely expressed by neurons in the developing mammalian cortex during synapse formation and are enriched at synapses in vivo. We detect DCC protein distributed along the axons and dendrites of cultured cortical neurons and provide evidence that newly translated netrin-1 is selectively transported to dendrites. Using gain and loss of function manipulations, we demonstrate that netrin-1 increases the number and strength of excitatory synapses made between developing cortical neurons. We show that netrin-1 increases the complexity of axon and dendrite arbors, thereby increasing the probability of contact. At sites of contact, netrin-1 promotes adhesion, while locally enriching and reorganizing the underlying actin cytoskeleton through Src family kinase signaling and m-Tor dependent protein translation to locally cluster presynaptic and postsynaptic proteins. Finally, we demonstrate using whole-cell patch-clamp electrophysiology that netrin-1 increases the frequency and amplitude of mEPSCs recorded from cortical pyramidal neurons. These findings identify netrin-1 as a synapse enriched protein that promotes synaptogenesis between mammalian cortical neurons. PMID- 24174663 TI - Kalman filtering naturally accounts for visually guided and predictive smooth pursuit dynamics. AB - The brain makes use of noisy sensory inputs to produce eye, head, or arm motion. In most instances, the brain combines this sensory information with predictions about future events. Here, we propose that Kalman filtering can account for the dynamics of both visually guided and predictive motor behaviors within one simple unifying mechanism. Our model relies on two Kalman filters: (1) one processing visual information about retinal input; and (2) one maintaining a dynamic internal memory of target motion. The outputs of both Kalman filters are then combined in a statistically optimal manner, i.e., weighted with respect to their reliability. The model was tested on data from several smooth pursuit experiments and reproduced all major characteristics of visually guided and predictive smooth pursuit. This contrasts with the common belief that anticipatory pursuit, pursuit maintenance during target blanking, and zero-lag pursuit of sinusoidally moving targets all result from different control systems. This is the first instance of a model integrating all aspects of pursuit dynamics within one coherent and simple model and without switching between different parallel mechanisms. Our model suggests that the brain circuitry generating a pursuit command might be simpler than previously believed and only implement the functional equivalents of two Kalman filters whose outputs are optimally combined. It provides a general framework of how the brain can combine continuous sensory information with a dynamic internal memory and transform it into motor commands. PMID- 24174662 TI - The major brain cholesterol metabolite 24(S)-hydroxycholesterol is a potent allosteric modulator of N-methyl-D-aspartate receptors. AB - N-methyl-D-aspartate receptors (NMDARs) are glutamate-gated ion channels that are critical to the regulation of excitatory synaptic function in the CNS. NMDARs govern experience-dependent synaptic plasticity and have been implicated in the pathophysiology of various neuropsychiatric disorders including the cognitive deficits of schizophrenia and certain forms of autism. Certain neurosteroids modulate NMDARs experimentally but their low potency, poor selectivity, and very low brain concentrations make them poor candidates as endogenous ligands or therapeutic agents. Here we show that the major brain-derived cholesterol metabolite 24(S)-hydroxycholesterol (24(S)-HC) is a very potent, direct, and selective positive allosteric modulator of NMDARs with a mechanism that does not overlap that of other allosteric modulators. At submicromolar concentrations 24(S)-HC potentiates NMDAR-mediated EPSCs in rat hippocampal neurons but fails to affect AMPAR or GABAA receptors (GABA(A)Rs)-mediated responses. Cholesterol itself and other naturally occurring oxysterols present in brain do not modulate NMDARs at concentrations <=10 MUM. In hippocampal slices, 24(S)-HC enhances the ability of subthreshold stimuli to induce long-term potentiation (LTP). 24(S)-HC also reverses hippocampal LTP deficits induced by the NMDAR channel blocker ketamine. Finally, we show that synthetic drug-like derivatives of 24(S)-HC, which potently enhance NMDAR-mediated EPSCs and LTP, restore behavioral and cognitive deficits in rodents treated with NMDAR channel blockers. Thus, 24(S)-HC may function as an endogenous modulator of NMDARs acting at a novel oxysterol modulatory site that also represents a target for therapeutic drug development. PMID- 24174664 TI - Conditional ablation of neuroprogenitor cells in adult mice impedes recovery of poststroke cognitive function and reduces synaptic connectivity in the perforant pathway. AB - The causal relationship between neurogenesis and the recovery of poststroke cognitive function has not been properly explored. The current study aimed to determine whether depleting neuroprogenitor cells (NPCs) affects poststroke functional outcome in nestin-delta-HSV-TK-EGFP transgenic mice, in which the expression of a truncated viral thymidine kinase gene and EGFP was restricted to nestin-expressing NPCs. Ganciclovir (GCV; 200 mg/kg/d) or saline was continuously administered via osmotic pumps in mice for 4 weeks before the induction of experimental stroke. Both baseline and stroke-induced type 1 and type 2 NPCs were conditionally ablated. GCV eliminated NPCs in a duration-dependent fashion, but it did not attenuate the genesis of astroglia or oligodendrocytes in the peri infarct cortex, nor did it affect infarct size or cerebral blood reperfusion after stroke. Transgenic stroke mice given GCV displayed impaired spatial learning and memory in the Barnes maze test compared with saline control or wild type stroke mice given GCV, suggesting a contributing role of stroke-induced neurogenesis in the recovery of cognitive function. However, there was no significant difference in poststroke motor function between transgenic mice treated with GCV and those treated with vehicle, despite a significant ablation of NPCs in the subventricular zone of the former. Furthermore, nestin-delta-HSV TK-EGFP mice treated with GCV had fewer retrogradely labeled neurons in the entorhinal cortex (EC) when injected with the polysynaptic viral marker PRV614 in the dentate gyrus (DG), suggesting that there might be reduced synaptic connectivity between the DG and EC following ablation of NPCs, which may contribute to impaired poststroke memory function. PMID- 24174665 TI - CAPS1 deficiency perturbs dense-core vesicle trafficking and Golgi structure and reduces presynaptic release probability in the mouse brain. AB - Ca(2+)-dependent activator protein for secretion 1 (CAPS1) plays a regulatory role in the dense-core vesicle (DCV) exocytosis pathway, but its functions at the cellular and synaptic levels in the brain are essentially unknown because of neonatal death soon after birth in Caps1 knock-out mice. To clarify the functions of the protein in the brain, we generated two conditional knock-out (cKO) mouse lines: 1) one lacking Caps1 in the forebrain; and 2) the other lacking Caps1 in the cerebellum. Both cKO mouse lines were born normally and grew to adulthood, although they showed subcellular and synaptic abnormalities. Forebrain-specific Caps1 cKO mice showed reduced immunoreactivity for the DCV marker secretogranin II (SgII) and the trans-Golgi network (TGN) marker syntaxin 6, a reduced number of presynaptic DCVs, and dilated trans-Golgi cisternae in the CA3 region. Cerebellum-specific Caps1 cKO mice had decreased immunoreactivity for SgII and brain-derived neurotrophic factor (BDNF) along the climbing fibers. At climbing fiber-Purkinje cell synapses, the number of DCVs was markedly lower and the number of synaptic vesicles was also reduced. Correspondingly, the mean amplitude of EPSCs was decreased, whereas paired-pulse depression was significantly increased. Our results suggest that loss of CAPS1 disrupts the TGN-DCV pathway, which possibly impairs synaptic transmission by reducing the presynaptic release probability. PMID- 24174666 TI - Wild-type neural progenitors divide and differentiate normally in an amyloid-rich environment. AB - Adult neurogenesis is modulated by a balance of extrinsic signals and intrinsic responses that maintain production of new granule cells in the hippocampus. Disorders that disrupt the proliferative niche can impair this process, and alterations in adult neurogenesis have been described in human autopsy tissue and transgenic mouse models of Alzheimer's disease. Because exogenous application of aggregated Abeta peptide is neurotoxic in vitro and extracellular Abeta deposits are the main pathological feature recapitulated by mouse models, cell-extrinsic effects of Abeta accumulation were thought to underlie the breakdown of hippocampal neurogenesis observed in Alzheimer's models. We tested this hypothesis using a bigenic mouse in which transgenic expression of APP was restricted to mature projection neurons. These mice allowed us to examine how wild-type neural progenitor cells responded to high levels of Abeta released from neighboring granule neurons. We find that the proliferation, determination, and survival of hippocampal adult-born granule neurons are unaffected in the APP bigenic mice, despite abundant amyloid pathology and robust neuroinflammation. Our findings suggest that Abeta accumulation is insufficient to impair adult hippocampal neurogenesis, and that factors other than amyloid pathology may account for the neurogenic deficits observed in transgenic models with more widespread APP expression. PMID- 24174667 TI - Encoding of prospective tasks in the human prefrontal cortex under varying task loads. AB - Successful realization of planned actions requires the brain to encode intentions over delays. Previous research has indicated that several regions in the rostral or anterior prefrontal cortex (PFC) encode delayed intentions. However, different processes may encode the same future task depending on task load during the delay. This difference may depend on the computational resources available when the delay is occupied with an ongoing task and when it is task-free. Here we directly investigated and compared the representation of delayed intentions in the human brain in the presence and absence of ongoing task load during the delay. We acquired fMRI data in combination with an event-based prospective memory design where human subjects remembered to perform the same future tasks over occupied and task-free delays. We used time-resolved multivoxel pattern classification and found that: (1) rostrolateral PFC (BA 46) encoded the delayed intention during both delay types; (2) rostromedial PFC (BA 10) encoded the intentions during occupied delays; whereas (3) a variety of more posterior regions, including the anterior cingulate cortex (BA 24), the supplementary motor area (BA 6), and the precuneus, encoded intentions during task-free delays. Overall, the medial PFC encoded delayed intentions more rostrally in the presence of an ongoing delay task and more caudally in its absence. Thus, rostromedial PFC may play a specialized role in the encoding of prospective memory that depends on higher computational demands (e.g., given higher task load during the delay). In contrast, the rostrolateral PFC is a more general area that encodes future intentions regardless of task load. PMID- 24174668 TI - Boosting regulatory T cells limits neuroinflammation in permanent cortical stroke. AB - Inflammatory mechanisms contribute substantially to secondary tissue injury after brain ischemia. Regulatory T cells (Tregs) are key endogenous modulators of postischemic neuroinflammation. We investigated the potential of histone deacetylase inhibition (HDACi) to enhance Treg potency for experimental stroke in mice. HDACi using trichostatin A increased the number of Tregs and boosted their immunosuppressive capacity and interleukin (IL)-10 expression. In vivo treatment reduced infarct volumes and behavioral deficits after cortical brain ischemia, attenuated cerebral proinflammatory cytokine expression, and increased numbers of brain-invading Tregs. A similar effect was obtained using tubastatin, a specific inhibitor of HDAC6 and a key HDAC in Foxp3 regulation. The neuroprotective effect of HDACi depended on the presence of Foxp3(+) Tregs, and in vivo and in vitro studies showed that the anti-inflammatory cytokine IL-10 was their main mediator. In summary, modulation of Treg function by HDACi is a novel and potent target to intervene at the center of neuroinflammation. Furthermore, this novel concept of modulating endogenous immune mechanisms might be translated to a broad spectrum of diseases, including primary neuroinflammatory and neurodegenerative disorders. PMID- 24174669 TI - Fading signatures of critical brain dynamics during sustained wakefulness in humans. AB - Sleep encompasses approximately a third of our lifetime, yet its purpose and biological function are not well understood. Without sleep optimal brain functioning such as responsiveness to stimuli, information processing, or learning may be impaired. Such observations suggest that sleep plays a crucial role in organizing or reorganizing neuronal networks of the brain toward states where information processing is optimized. Increasing evidence suggests that cortical neuronal networks operate near a critical state characterized by balanced activity patterns, which supports optimal information processing. However, it remains unknown whether critical dynamics is affected in the course of wake and sleep, which would also impact information processing. Here, we show that signatures of criticality are progressively disturbed during wake and restored by sleep. We demonstrate that the precise power-laws governing the cascading activity of neuronal avalanches and the distribution of phase-lock intervals in human electroencephalographic recordings are increasingly disarranged during sustained wakefulness. These changes are accompanied by a decrease in variability of synchronization. Interpreted in the context of a critical branching process, these seemingly different findings indicate a decline of balanced activity and progressive distance from criticality toward states characterized by an imbalance toward excitation where larger events prevail dynamics. Conversely, sleep restores the critical state resulting in recovered power-law characteristics in activity and variability of synchronization. These findings support the intriguing hypothesis that sleep may be important to reorganize cortical network dynamics to a critical state thereby assuring optimal computational capabilities for the following time awake. PMID- 24174670 TI - Distinct balance of excitation and inhibition in an interareal feedforward and feedback circuit of mouse visual cortex. AB - Mouse visual cortex is subdivided into multiple distinct, hierarchically organized areas that are interconnected through feedforward (FF) and feedback (FB) pathways. The principal synaptic targets of FF and FB axons that reciprocally interconnect primary visual cortex (V1) with the higher lateromedial extrastriate area (LM) are pyramidal cells (Pyr) and parvalbumin (PV)-expressing GABAergic interneurons. Recordings in slices of mouse visual cortex have shown that layer 2/3 Pyr cells receive excitatory monosynaptic FF and FB inputs, which are opposed by disynaptic inhibition. Most notably, inhibition is stronger in the FF than FB pathway, suggesting pathway-specific organization of feedforward inhibition (FFI). To explore the hypothesis that this difference is due to diverse pathway-specific strengths of the inputs to PV neurons we have performed subcellular Channelrhodopsin-2-assisted circuit mapping in slices of mouse visual cortex. Whole-cell patch-clamp recordings were obtained from retrobead-labeled FF(V1->LM)- and FB(LM->V1)-projecting Pyr cells, as well as from tdTomato expressing PV neurons. The results show that the FF(V1->LM) pathway provides on average 3.7-fold stronger depolarizing input to layer 2/3 inhibitory PV neurons than to neighboring excitatory Pyr cells. In the FB(LM->V1) pathway, depolarizing inputs to layer 2/3 PV neurons and Pyr cells were balanced. Balanced inputs were also found in the FF(V1->LM) pathway to layer 5 PV neurons and Pyr cells, whereas FB(LM->V1) inputs to layer 5 were biased toward Pyr cells. The findings indicate that FFI in FF(V1->LM) and FB(LM->V1) circuits are organized in a pathway- and lamina-specific fashion. PMID- 24174672 TI - Foxo3a transcriptionally upregulates AQP4 and induces cerebral edema following traumatic brain injury. AB - Increased cranial pressure due to development of edema contributes significantly to the pathology of traumatic brain injury (TBI). Induction of an astrocytic water channel protein, Aquaporin 4 (AQP4), is known to predominantly contribute to cytotoxic edema following TBI. However, the mechanism for the increase in AQP4 following 24 h of TBI is poorly understood. Here we show that transcriptional activation of a ubiquitously expressed mammalian forkhead transcription factor, Foxo3a, induces cerebral edema by increasing the AQP4 level in the controlled cortical impact model of TBI in mice. TBI stimulates nuclear translocation of Foxo3a in astrocytes and subsequently augments its binding to AQP4 promoter in pericontusional cortex. Nuclear accumulation of Foxo3a is augmented by a decrease in phosphorylation at its Ser256 residue due to inactivation of Akt after TBI. Depletion of Foxo3a in mice rescues cytotoxic edema by preventing induction of AQP4 as well as attenuates memory impairment after TBI in mice. PMID- 24174671 TI - Single-neuron mechanisms underlying cost-benefit analysis in frontal cortex. AB - Effective decision-making requires consideration of costs and benefits. Previous studies have implicated orbitofrontal cortex (OFC), dorsolateral prefrontal cortex (DLPFC), and anterior cingulate cortex (ACC) in cost-benefit decision making. Yet controversy remains about whether different decision costs are encoded by different brain areas, and whether single neurons integrate costs and benefits to derive a subjective value estimate for each choice alternative. To address these issues, we trained four subjects to perform delay- and effort-based cost-benefit decisions and recorded neuronal activity in OFC, ACC, DLPFC, and the cingulate motor area (CMA). Although some neurons, mainly in ACC, did exhibit integrated value signals as if performing cost-benefit computations, they were relatively few in number. Instead, the majority of neurons in all areas encoded the decision type; that is whether the subject was required to perform a delay- or effort-based decision. OFC and DLPFC neurons tended to show the largest changes in firing rate for delay- but not effort-based decisions; whereas, the reverse was true for CMA neurons. Only ACC contained neurons modulated by both effort- and delay-based decisions. These findings challenge the idea that OFC calculates an abstract value signal to guide decision-making. Instead, our results suggest that an important function of single PFC neurons is to categorize sensory stimuli based on the consequences predicted by those stimuli. PMID- 24174673 TI - Photolysis of caged Ca2+ but not receptor-mediated Ca2+ signaling triggers astrocytic glutamate release. AB - Astrocytes in hippocampal slices can dynamically regulate synaptic transmission in a process mediated by increases in intracellular Ca(2+). However, it is debated whether astrocytic Ca(2+) signals result in release of glutamate. We here compared astrocytic Ca(2+) signaling triggered by agonist exposure versus photolysis side by side. Using transgenic mice in which astrocytes selectively express the MrgA1 receptor, we found that receptor-mediated astrocytic Ca(2+) signaling consistently triggered neuronal hyperpolarization and decreased the frequency of miniature excitatory postsynaptic currents (EPSCs). In contrast, photolysis of caged Ca(2+) (o-nitrophenyl-EGTA) in astrocytes led to neuronal depolarization and increased the frequency of mEPSCs through a metabotropic glutamate receptor-mediated pathway. Analysis of transgenic mice in which astrocytic vesicular release is suppressed (dominant-negative SNARE mice) and pharmacological manipulations suggested that glutamate is primarily released by opening of anion channels rather than exocytosis. Combined, these studies show that photolysis but not by agonists induced astrocytic Ca(2+) signaling triggers glutamate release. PMID- 24174674 TI - Visual circuit assembly requires fine tuning of the novel Ig transmembrane protein Borderless. AB - Establishment of synaptic connections in the neuropils of the developing nervous system requires the coordination of specific neurite-neurite interactions (i.e., axon-axon, dendrite-dendrite and axon-dendrite interactions). The molecular mechanisms underlying coordination of neurite-neurite interactions for circuit assembly are incompletely understood. In this report, we identify a novel Ig superfamily transmembrane protein that we named Borderless (Bdl), as a novel regulator of neurite-neurite interactions in Drosophila. Bdl induces homotypic cell-cell adhesion in vitro and mediates neurite-neurite interactions in the developing visual system. Bdl interacts physically and genetically with the Ig transmembrane protein Turtle, a key regulator of axonal tiling. Our results also show that the receptor tyrosine phosphatase leukocyte common antigen-related protein (LAR) negatively regulates Bdl to control synaptic-layer selection. We propose that precise regulation of Bdl action coordinates neurite-neurite interactions for circuit formation in Drosophila. PMID- 24174675 TI - AKAPS act in a two-step mechanism of memory acquisition. AB - Defining the molecular and neuronal basis of associative memories is based upon behavioral preparations that yield high performance due to selection of salient stimuli, strong reinforcement, and repeated conditioning trials. One of those preparations is the Drosophila aversive olfactory conditioning procedure where animals initiate multiple memory components after experience of a single cycle training procedure. Here, we explored the analysis of acquisition dynamics as a means to define memory components and revealed strong correlations between particular chronologies of shock impact and number experienced during the associative training situation and subsequent performance of conditioned avoidance. Analyzing acquisition dynamics in Drosophila memory mutants revealed that rutabaga (rut)-dependent cAMP signals couple in a divergent fashion for support of different memory components. In case of anesthesia-sensitive memory (ASM) we identified a characteristic two-step mechanism that links rut-AC1 to A kinase anchoring proteins (AKAP)-sequestered protein kinase A at the level of Kenyon cells, a recognized center of olfactory learning within the fly brain. We propose that integration of rut-derived cAMP signals at level of AKAPs might serve as counting register that accounts for the two-step mechanism of ASM acquisition. PMID- 24174676 TI - Inducible presynaptic glutamine transport supports glutamatergic transmission at the calyx of Held synapse. AB - The mechanisms by which the excitatory neurotransmitter glutamate is recycled at synapses are currently unknown. By examining the functional expression of plasma membrane transporters at presynaptic terminals, we aim to elucidate some of the mechanisms of glutamate recycling. Using whole-cell voltage-clamp recordings from rat calyx of Held presynaptic terminals, our data show, for the first time, that the glutamate precursor glutamine causes the direct activation of an electrogenic, sodium-dependent presynaptic transporter, which supplies glutamine for generation of presynaptic glutamate and helps sustain synaptic transmission. Interestingly, the functional expression of this transporter at the presynaptic plasma membrane is dynamically controlled by electrical activity of the terminal, indicating that uptake of neurotransmitter precursors is controlled by the demand at an individual terminal. Induction of the transporter current is calcium dependent and inhibited by botulinum neurotoxin C, demonstrating the involvement of SNARE-dependent exocytosis in inserting transporters into the plasma membrane when the terminal is active. Conversely, inactivity of the presynaptic terminal results in removal of transporters via clathrin-mediated endocytosis. To investigate whether the presynaptic glutamine transporter supplies the precursor for generating the synaptically released glutamate, we measured miniature EPSCs to assess vesicular glutamate content. When the presynaptic glutamate pool was turned over by synaptic activity, inhibiting the presynaptic glutamine transporters with MeAIB reduced the miniature EPSC amplitude significantly. This demonstrates that presynaptic glutamine transport is centrally involved in the production of glutamate and assists in maintaining excitatory neurotransmission. PMID- 24174677 TI - Top-down control of visual responses to fear by the amygdala. AB - The visual cortex is sensitive to emotional stimuli. This sensitivity is typically assumed to arise when amygdala modulates visual cortex via backwards connections. Using human fMRI, we compared dynamic causal connectivity models of sensitivity with fearful faces. This model comparison tested whether amygdala modulates distinct cortical areas, depending on dynamic or static face presentation. The ventral temporal fusiform face area showed sensitivity to fearful expressions in static faces. However, for dynamic faces, we found fear sensitivity in dorsal motion-sensitive areas within hMT+/V5 and superior temporal sulcus. The model with the greatest evidence included connections modulated by dynamic and static fear from amygdala to dorsal and ventral temporal areas, respectively. According to this functional architecture, amygdala could enhance encoding of fearful expression movements from video and the form of fearful expressions from static images. The amygdala may therefore optimize visual encoding of socially charged and salient information. PMID- 24174678 TI - Differential progression of structural and functional alterations in distinct retinal ganglion cell types in a mouse model of glaucoma. AB - Intraocular pressure (IOP) elevation is a principal risk factor for glaucoma. Using a microbead injection technique to chronically raise IOP for 15 or 30 d in mice, we identified the early changes in visual response properties of different types of retinal ganglion cells (RGCs) and correlated these changes with neuronal morphology before cell death. Microbead-injected eyes showed reduced optokinetic tracking as well as cell death. In such eyes, multielectrode array recordings revealed that four RGC types show diverse alterations in their light responses upon IOP elevation. OFF-transient RGCs exhibited a more rapid decline in both structural and functional organizations compared with other RGCs. In contrast, although the light-evoked responses of OFF-sustained RGCs were perturbed, the dendritic arbor of this cell type remained intact. ON-transient and ON-sustained RGCs had normal functional receptive field sizes but their spontaneous and light evoked firing rates were reduced. ON- and OFF-sustained RGCs lost excitatory synapses across an otherwise structurally normal dendritic arbor. Together, our observations indicate that there are changes in spontaneous activity and light evoked responses in RGCs before detectable dendritic loss. However, when dendrites retract, we found corresponding changes in receptive field center size. Importantly, the effects of IOP elevation are not uniformly manifested in the structure and function of diverse RGC populations, nor are distinct RGC types perturbed within the same time-frame by such a challenge. PMID- 24174679 TI - Receptor interacting protein kinase-mediated necrosis contributes to cone and rod photoreceptor degeneration in the retina lacking interphotoreceptor retinoid binding protein. AB - Interphotoreceptor retinoid-binding protein (IRBP) secreted by photoreceptors plays a pivotal role in photoreceptor survival with an unknown mechanism. A mutation in the human IRBP has been linked to retinitis pigmentosa, a progressive retinal degenerative disease. Mice lacking IRBP display severe early and progressive photoreceptor degeneration. However, the signaling pathway(s) leading to photoreceptor death in IRBP-deficient mice remains poorly understood. Here, we show that amounts of tumor necrosis factor-alpha (TNF-alpha) in the interphotoreceptor matrix and retinas of Irbp(-/-) mice were increased more than 10-fold and fivefold, respectively, compared with those in wild-type mice. Moreover, TNF-alpha receptor 1, an important membrane death receptor that mediates both programmed apoptosis and necrosis, was also significantly increased in Irbp(-/-) retina, and was colocalized with peanut agglutinin to the Irbp(-/-) cone outer segments. Although these death signaling proteins were increased, the caspase-dependent and independent apoptotic pathways were mildly activated in the Irbp(-/-) retinas, suggesting that other cell death mechanism(s) also contributes to the extensive photoreceptor degeneration in Irbp(-/-) retina. We found that receptor interacting protein 1 and 3 (RIP1 and RIP3) kinases, the intracellular key mediators of TNF-induced cellular necrosis, were elevated at least threefold in the Irbp(-/-) retinas. Moreover, pharmacological inhibition of RIP1 kinase significantly prevented cone and rod photoreceptor degeneration in Irbp(-/-) mice. These results reveal that RIP kinase-mediated necrosis strongly contributes to cone and rod degeneration in Irbp(-/-) mice, implicating the TNF-RIP pathway as a potential therapeutic target to prevent or delay photoreceptor degeneration in patients with retinitis pigmentosa caused by IRBP mutation. PMID- 24174681 TI - State-dependent effects of transcranial oscillatory currents on the motor system: what you think matters. AB - Imperceptible transcranial alternating current stimulation (tACS) changes the endogenous cortical oscillatory activity in a frequency-specific manner. In the human motor system, tACS coincident with the idling beta rhythm of the quiescent motor cortex increased the corticospinal output. We reasoned that changing the initial state of the brain (i.e., from quiescence to a motor imagery task that desynchronizes the local beta rhythm) might also change the susceptibility of the corticospinal system to resonance effects induced by beta-tACS. We tested this hypothesis by delivering tACS at different frequencies (theta, alpha, beta, and gamma) on the primary motor cortex at rest and during motor imagery. Motor-evoked potentials (MEPs) were obtained by transcranial magnetic stimulation (TMS) on the primary motor cortex with an online-navigated TMS-tACS setting. During motor imagery, the increase of corticospinal excitability was maximal with theta-tACS, likely reflecting a reinforcement of working memory processes required to mentally process and "execute" the cognitive task. As expected, the maximal MEPs increase with subjects at rest was instead obtained with beta-tACS, substantiating previous evidence. This dissociation provides new evidence of state and frequency dependency of tACS effects on the motor system and helps discern the functional role of different oscillatory frequencies of this brain region. These findings may be relevant for rehabilitative neuromodulatory interventions. PMID- 24174680 TI - Persistent cocaine-induced reversal learning deficits are associated with altered limbic cortico-striatal local field potential synchronization. AB - Repeated exposure to cocaine is known to produce persistent deficits in behavioral flexibility. Evidence suggests that these deficits are mediated in part by a circuit involving the medial prefrontal and orbitofrontal cortices (PFC and OFC), nucleus accumbens (NAC), and basolateral amygdala (BLA). To assess the effects of cocaine on this circuit, we treated rats with cocaine daily for 14 d, followed by 4 weeks of abstinence. Animals were then tested on a cross-maze-based reversal learning and set-shifting task, after which they were anesthetized to allow for recording of spontaneous local field potential (LFP) activity simultaneously from all four regions, in addition to activity evoked from acute BLA stimulation. Cocaine-treated (COC) animals showed specific deficits in reversal learning; furthermore, spontaneous LFP oscillation power was reduced and BLA-induced oscillation power was increased in all regions compared with saline treated (SAL) rats. Theta-burst stimulation of BLA potentiated BLA-evoked responses in all regions and cocaine challenge reduced spontaneous oscillation power and evoked response amplitude, with no COC/SAL group differences. Notably, cocaine challenge produced differential changes in coherence between OFC-BLA, BLA NAC, and OFC-NAC in COC and SAL groups. These data indicate that repeated exposure to cocaine can produce changes in oscillatory LFP synchronization along limbic cortico-striatal circuits that persist long into abstinence. Furthermore, the regional specificity of these changes strongly correlates with the observed behavioral deficits. Aberrant synchronization within and between regions and consequent dysregulation of the neurocircuitry involved in executive control may contribute to the long-lasting maladaptive decision making seen in cocaine abusers. PMID- 24174683 TI - Axonal recordings from medial superior olive neurons obtained from the lateral lemniscus of the chinchilla (Chinchilla laniger). AB - Interaural time differences (ITDs) are a major cue for localizing low-frequency (<1.5 kHz) sounds. Sensitivity to this cue first occurs in the medial superior olive (MSO), which is thought to perform a coincidence analysis on its monaural inputs. Extracellular single-neuron recordings in MSO are difficult to obtain because (1) MSO action potentials are small and (2) a large field potential locked to the stimulus waveform hampers spike isolation. Consequently, only a limited number of studies report MSO data, and even in these studies data are limited in the variety of stimuli used, in the number of neurons studied, and in spike isolation. More high-quality data are needed to better understand the mechanisms underlying neuronal ITD-sensitivity. We circumvented these difficulties by recording from the axons of MSO neurons in the lateral lemniscus (LL) of the chinchilla, a species with pronounced low-frequency sensitivity. Employing sharp glass electrodes we successfully recorded from neurons with ITD sensitivity: the location, response properties, latency, and spike shape were consistent with an MSO axonal origin. The main difficulty encountered was mechanical stability. We obtained responses to binaural beats and dichotic noise bursts to characterize the best delay versus characteristic frequency distribution, and compared the data to recordings we obtained in the inferior colliculus (IC). In contrast to most reports in other rodents, many best delays were close to zero ITD, both in MSO and IC, with a majority of the neurons recorded in the LL firing maximally within the presumed ethological ITD range. PMID- 24174682 TI - Titration of GLI3 repressor activity by sonic hedgehog signaling is critical for maintaining multiple adult neural stem cell and astrocyte functions. AB - Sonic hedgehog (SHH), a key regulator of embryonic neurogenesis, signals directly to neural stem cells (NSCs) in the subventricular zone (SVZ) and to astrocytes in the adult mouse forebrain. The specific mechanism by which the GLI2 and GLI3 transcriptional activators (GLI2(A) and GLI3(A)) and repressors (GLI2(R) and GLI3(R)) carry out SHH signaling has not been addressed. We found that the majority of slow-cycling NSCs express Gli2 and Gli3, whereas Gli1 is restricted ventrally and all three genes are downregulated when NSCs transition into proliferating progenitors. Surprisingly, whereas conditional ablation of Smo in postnatal glial fibrillary acidic protein-expressing cells results in cell autonomous loss of NSCs and a progressive reduction in SVZ proliferation, without an increase in glial cell production, removal of Gli2 or Gli3 does not alter adult SVZ neurogenesis. Significantly, removing Gli3 in Smo conditional mutants largely rescues neurogenesis and, conversely, expression of a constitutive GLI3(R) in the absence of normal Gli2 and Gli3 abrogates neurogenesis. Thus unattenuated GLI3(R) is a primary inhibitor of adult SVZ NSC function. Ablation of Gli2 and Gli3 revealed a minor role for GLI2(R) and little requirement for GLI(A) function in stimulating SVZ neurogenesis. Moreover, we found that similar rules of GLI activity apply to SHH signaling in regulating SVZ-derived olfactory bulb interneurons and maintaining cortical astrocyte function. Namely, fewer superficial olfactory bulb interneurons are generated in the absence of Gli2 and Gli3, whereas astrocyte partial gliosis results from an increase in GLI3(R). Thus precise titration of GLI(R) levels by SHH is critical to multiple functions of adult NSCs and astrocytes. PMID- 24174684 TI - Functional connectivity in healthy subjects is nonlinearly modulated by the COMT and DRD2 polymorphisms in a functional system-dependent manner. AB - The dopamine system is known to modulate brain function in an inverted U-shaped manner. Recently, the functional networks of the brain were categorized into two systems, a "control system" and a "processing system." However, it remains unclear whether the inverted U-shaped model of dopaminergic modulation could be applied to both of these functional systems. The catechol-O-methyltransferase (COMT) and dopamine D2 receptor (DRD2) were genotyped in 258 healthy young human subjects. The local and long-range functional connectivity densities (FCDs) of each voxel were calculated and compared in a voxel-wise manner using a two-way (COMT and DRD2 genotypes) analysis of covariance. The resting-state functional connectivity analysis was performed to determine the functional networks to which brain regions with significant FCD differences belonged. Significant COMT * DRD2 interaction effects were found in the local FCDs of the superior portion of the right temporal pole (sTP) and left lingual gyrus (LG) and in the long-range FCDs of the right putamen and left medial prefrontal cortex (MPFC). Post hoc tests showed nonlinear relationships between the genotypic subgroups and FCD. In the control system, the sTP and putamen, components of the salience network, showed a U-shaped modulation by dopamine signaling. In the processing system, however, the MPFC of the default-mode network and the LG of the visual network showed an inverted U-shaped modulation by the dopamine system. Our findings suggest an interaction between COMT and DRD2 genotypes and show a functional system dependent modulation of dopamine signaling. PMID- 24174685 TI - CXC chemokine receptor 7 (CXCR7) affects the migration of GnRH neurons by regulating CXCL12 availability. AB - Gonadotropin-releasing hormone (GnRH) neurons are neuroendocrine cells, located in the hypothalamus, that play an essential role in mammalian reproduction. These neurons originate in the nasal placode and migrate during embryonic development, in association with olfactory/vomeronasal nerves, first in the nose, then through the cribriform plate to enter the forebrain, before settling in the hypothalamus. One of the molecules required for their early migration in the nose is the chemokine CXCL12, which is expressed in the embryonic nasal mesenchyme in an increasing ventral to dorsal gradient, presumably guiding GnRH neurons toward the forebrain. Mice lacking CXCR4, the receptor for CXCL12, exhibit defective GnRH cell movement and a significant reduction in their number, suggesting that CXCL12/CXCR4 signaling is important in the migration and survival of these neurons. Here, we investigated the role of the more recently identified second CXCL12 receptor, CXCR7, in GnRH neuron development. We demonstrate that CXCR7 is expressed along the migratory path of GnRH neurons in the nasal cavity and, although not expressed by GnRH neurons, it affects their migration as indicated by the ectopic accumulation of these cells in the nasal compartment in CXCR7(-/-) mice. Absence of CXCR7 caused abnormal accumulation of CXCL12-RFP at CXCR4 positive sites in the nasal area of CXCL12-RFP-transgenic mice and excessive CXCL12-dependent intracellular clustering of CXCR4 in GnRH neurons, suggesting internalization. These findings imply that CXCR7 regulates CXCL12 availability by acting as a scavenger along the migratory path of GnRH neurons and, thus, influences the migration of these cells in a noncell-autonomous manner. PMID- 24174687 TI - Notice of concern: Ellerby et al., Establishment of a cell-free system of neuronal apoptosis: comparison of premitochondrial, mitochondrial, and postmitochondrial phases. PMID- 24174686 TI - Coding the meaning of sounds: contextual modulation of auditory responses in the basolateral amygdala. AB - Female mice emit a low-frequency harmonic (LFH) call in association with distinct behavioral contexts: mating and physical threat or pain. Here we report the results of acoustic, behavioral, and neurophysiological studies of the contextual analysis of these calls in CBA/CaJ mice. We first show that the acoustical features of the LFH call do not differ between contexts. We then show that male mice avoid the LFH call in the presence of a predator cue (cat fur) but are more attracted to the same exemplar of the call in the presence of a mating cue (female urine). The males thus use nonauditory cues to determine the meaning of the LFH call, but these cues do not generalize to noncommunication sounds, such as noise bursts. We then characterized neural correlates of contextual meaning of the LFH call in responses of basolateral amygdala (BLA) neurons from awake, freely moving mice. There were two major findings. First, BLA neurons typically displayed early excitation to all tested behaviorally aversive stimuli. Second, the nonauditory context modulates the BLA population response to the LFH call but not to the noncommunication sound. These results suggest that the meaning of communication calls is reflected in the spike discharge patterns of BLA neurons. PMID- 24174688 TI - Suicide Prevention in College Students: A Collaborative Approach. AB - Described by Durkheim (1966) as the crudest expression of the social phenomena, suicide is of interest to clinicians, academics and researchers. Within the academic context, this issue has to be addressed and prevented. We are interested in sharing the process of participative action that led to the creation of a Suicide Prevention Program (SPP) for college students. Based on knowledge that was generated through a collaborative effort among all sectors of the academic community, we developed a prevention campaign that is culturally sensitive to our university's environment. This campaign is directed towards overcoming the stigma of seeking help and is characterized by promoting a sense of wellbeing in a holistic manner, paying attention not only to the individual, but also to elements of their sociocultural environment. PMID- 24174689 TI - Wavelet-Variance-Based Estimation for Composite Stochastic Processes. AB - This article presents a new estimation method for the parameters of a time series model. We consider here composite Gaussian processes that are the sum of independent Gaussian processes which, in turn, explain an important aspect of the time series, as is the case in engineering and natural sciences. The proposed estimation method offers an alternative to classical estimation based on the likelihood, that is straightforward to implement and often the only feasible estimation method with complex models. The estimator furnishes results as the optimization of a criterion based on a standardized distance between the sample wavelet variances (WV) estimates and the model-based WV. Indeed, the WV provides a decomposition of the variance process through different scales, so that they contain the information about different features of the stochastic model. We derive the asymptotic properties of the proposed estimator for inference and perform a simulation study to compare our estimator to the MLE and the LSE with different models. We also set sufficient conditions on composite models for our estimator to be consistent, that are easy to verify. We use the new estimator to estimate the stochastic error's parameters of the sum of three first order Gauss Markov processes by means of a sample of over 800,000 issued from gyroscopes that compose inertial navigation systems. Supplementary materials for this article are available online. PMID- 24174690 TI - From Research to Practice: Lessons Learned. AB - Research has informed practice since the origins of developmental psychology, but only recently has basic science and practice begun to be consistently integrated with one another. In addition, considerable research documents the utility of empirically-supported interventions, yet it has been difficult to implement such interventions outside of the research context. This paper describes two Randomized Clinical Trials (RCTs) for maltreated infants and preschoolers as an example of successful community, funder, and researcher partnerships. Key strengths and challenges involved in designing and conducting the studies are discussed, and the necessity of considering the developmental and cultural appropriateness of empirically-supported interventions is highlighted. Programs designed to provide data on the effectiveness of interventions initially evaluated in RCTs are presented. These initiatives indicate that it is possible to create successful evidence-based interventions, even within the complex world of the child welfare system. These studies provide information on developmental and outcome intervention differences that contribute to the scientific literature and have real-world implications for policy makers, funders, and ultimately, for children. PMID- 24174692 TI - The effect of hydroxychloroquine on symptoms of knee osteoarthritis: a double blind randomized controlled clinical trial. AB - BACKGROUND: Osteoarthritis is a degenerative joint disorder of articular cartilage and is the most common type of arthritis in the elderly. There are only a few reports regarding the use of Hydroxychloroquine in the treatment of osteoarthritis. METHODS: To investigate the effects of Hydroxychloroquine on the symptoms of mild to moderate knee osteoarthritis (Kellgren and Lawrence grade II and III), we performed a double-blind, placebo-controlled study in 44 patients. The patients were randomly assigned to two groups: one group received Hydroxychloroquine pills (200 mg twice daily) and the other group received placebo pills. Symptoms were assessed by the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) at baseline and at the end of weeks 4, 8, 12, 16, 20, and 24. RESULTS: Approximately, 98% of the patients were women at an average age of 47 years. There was no significant difference in the baseline characteristics between the two groups. In the placebo group, maximum improvement occurred at the 4(th) week; and during the remaining time, there was no significant improvement. In the Hydroxychloroquine group, maximum improvement occurred at the 8(th) week and persisted over the entire remaining follow-up period. There were significant differences between the two groups regarding the degree of reduction in the WOMAC total score and the WOMAC subscales scores of pain, stiffness, and function at the end of weeks 4, 8, 12, 16, 20, and 24. CONCLUSION: Hydroxychloroquine conferred significant improvement in the symptoms of mild to moderate knee osteoarthritis in our patients and may, accordingly, be recommended for knee osteoarthritis treatment. PMID- 24174691 TI - Concept of atherosclerosis velocity: is it a better measure of cardiovascular risk? AB - In most cases atherosclerosis is the underlying cause of vascular diseases, including heart disease and stroke. It is believed that endothelial injury is the earliest change in the artery wall and that this precedes the formation of lesions of atherosclerosis. Recent developments in the field of atherosclerosis have led to a renewed interest in the recognition of the parameter of time in the atherosclerosis process. We believe that the factors determining the time dependent rate of atherosclerosis progression are important, and it is in this context that we wish to propose for the first time the term "atherosclerosis velocity". In this review article, we summarize the existing evidence regarding atherosclerosis velocity and discuss the importance of this issue. PMID- 24174693 TI - Effects of ascorbic Acid on serum level of unconjugated estriol and its relationship with preterm premature rupture of membrane: a double-blind randomized controlled clinical trial. AB - BACKGROUND: Vitamin C is a water-soluble antioxidant that not only stimulates and protects collagen synthesis but also plays an important role in maintaining cellular integrity in a normal pregnancy. This study surveyed the effects of ascorbic acid on the serum level of unconjugated estriol and the relationship between unconjugated estriol and preterm premature rupture of membrane (PPROM). METHODS: This double-blind, randomized clinical trial recruited 60 patients with predisposing factors to PPROM. The women were randomly divided into two groups of intervention and control and received vitamin C and placebo, respectively. The intervention group received 250 mg vitamin C twice a day and the controls received the placebo only. Unconjugated estriol was measured using the ELISA. All data were extracted and recorded in a checklist and compared using descriptive statistics as well as the x (2), Fisher exact, and t tests. RESULTS: The demographic data showed no difference between the two groups. The mean level of serum unconjugated estriol was significantly lower in the intervention group than in the control group (P=0.044). Also, the frequency of PPROM was lower in the intervention group, but the difference was not significant (P>0.05). Unconjugated estriol levels were not significantly different between the healthy women and the PPROM patients. CONCLUSION: This study demonstrated that vitamin C administration decreased unconjugated estriol levels in the patients with PPROM. The findings of this study also indicated that administration of ascorbic acid was a safe and effective method to reduce the incidence of PPROM. Alteration in unconjugated estriol is an active mediator for this effect. PMID- 24174694 TI - Evaluation of Homocysteine Level as a Risk Factor among Patients with Ischemic Stroke and Its Subtypes. AB - BACKGROUND: Epidemiological research has shown that increased total homocysteine (tHcy) levels are associated with an increased risk of thromboembolic disease; however, controversy still exists over which subtype of stroke is allied to hyperhomocysteinemia. This study aimed to investigate whether elevated tHcy is an independent risk factor for ischemic stroke and to compare tHcy levels in patients with ischemic stroke subtypes. METHODS: We performed a case-control study, in which 171 ischemic stroke patients aged over 16 years and 86 age and sex-matched controls were eligible to participate and were enrolled from January 2009 to January 2010. The patients' demographic data, traditional stroke risk factors, and the results of fasting tHcy, vitamin B12, and folate of serum were collected in the first 5 days after ischemic stroke. Stroke subtypes were classified according to the Trial of Org 10172 in Acute Stroke Treatment (TOAST) criteria. SPSS software (version 13) was used for the statistical analysis of the data, and a P value smaller than 0.05 was considered statistically significant. RESULTS: The mean fasting Hcy levels was significantly higher in the cases (16.2 MUmol/L, 95% CI: 14.8 to 17.5) than in the controls (13.5 MUmol/L, 95% CI: 12.4 to 14.6) (P=0.013). The mean Hcy levels was elevated significantly in those with cardioembolic strokes compared with the controls (17.7 MUmol/L, 95% CI: 14.8 to 20.5; P=0.010). The plasma Hcy level was associated with an adjusted odds ratio of 2.17 (95% CI: 1.24 to 3.79; P=0.004) for Hcy above 15 MUmol/L concentration for all types of stroke. CONCLUSION: Our data showed that elevated serum Hcy is an independent risk factor for ischemic stroke and it has a strong association with cardioembolic subtype. PMID- 24174695 TI - Evaluation of the adequacy of general anesthesia in cesarean section by bispectral index. AB - BACKGROUND: Awareness and recall, though not common, are the major hazards of general anesthesia, especially in Cesarean section (C/S) because of the absence of benzodiazepine and opioids for a significant time during anesthesia. In this study, the Bispectral Index (BIS), end-tidal isoflurane, and hemodynamic parameters were examined to evaluate the depth of the routine general anesthetic technique in C/S. METHODS: This study was carried out on 60 parturient patients undergoing elective C/S. A standardized anesthetic technique was applied: induction with Thiopental (4-5 mg/kg) and Succinylcholine (1.5-2 mg/kg) as well as maintenance with O2, N2O, and isoflurane. Electrocardiogram, heart rate, blood pressure, Spo2, end-tidal isoflurane concentration, BIS, and any clinical signs of inadequate depth of anesthesia such as movement, sweating, lacrimation, coughing, and jerking were continuously monitored and recorded at 16 fixed time points during anesthesia. RESULTS: A median BIS of less than 70 (range: 42-68) was obtained on all occasions during surgery; however, at each milestone, at least 20% of the patients had BIS values above 60. Hemodynamic parameters increased significantly in some patients, especially during laryngoscopy and intubation. No patient experienced recall or awareness. CONCLUSION: The currently used general anesthetic technique in our center appears inadequate in some milestones to reliably produce BIS values less than 60, which are associated with lower risk of awareness. Therefore, with respect to such desirable outcomes as good Apgar and clinical status in neonates, we would recommend the application of this method (if confirmed by further studies) through larger dosages of anesthetic agents. PMID- 24174696 TI - Effect of Medium pH on Antibiotic Activity against Syrian Brucella spp. Isolates. AB - BACKGROUND: Brucellosis is an endemic zoonosis in Syria, affecting large numbers of animals. There are an increasing number of cases in humans. Brucella is a facultative intracellular pathogen, a small, non-motile, Gram-negative coccobacillus, which causes abortion in domestic animals and a febrile illness in humans. METHODS: One hundred isolates collected from different Syrian regions were confirmed to be Brucella melitensis by biochemical tests. The minimum inhibitory concentration (MIC) of 6 antibiotics, alone and in combination, was determined at pH 7.0 and pH 5.0. RESULTS: Ciprofloxacin and sparfloxacin were the most effective antibiotics tested at either pH value. In contrast, rifampicin had low activity and streptomycin was ineffective at either pH value. A combination of rifampicin-doxycycline revealed the highest synergistic activity at both test pH values (against 19/24 and 17/24 isolates, respectively) in vitro. Antagonistic activities were observed using a ciprofloxacin-streptomycin combination (against 9/24 and 13/24 isolates, respectively) as well as a ciprofloxacin-tetracycline combination (against 6/24 and 9/24 isolates, respectively). No differences were observed at both test pH values, when combining a Quinolone with rifampicin or doxycycline. CONCLUSION: Combination of a Quinolone with doxycycline demonstrated good in vitro activity against B. melitensis. Further in vivo studies are necessary to support this suggestion. PMID- 24174697 TI - Increased bcl-2 Protein Levels in Rat Primary Astrocyte Culture Following Chronic Lithium Treatment. AB - BACKGROUND: B cell CLL/lymphoma 2 protein, bcl-2, is an important anti-apoptotic factor that has been implicated in lithium's neuroprotective effect. However, most studies have focused on assessing the effects of lithium in neurons, ignoring examination of bcl-2 in astrocytes, which also influence neuronal survival and are affected in bipolar disorder. The aim of this study was to evaluate whether chronic lithium treatment also elevates bcl-2 expression in astrocytes compared with neuronal and mixed neuron-astrocyte cultures. METHODS: Rat primary astrocyte, neuronal, and mixed neuron-astrocyte cultures were prepared from the cerebral cortices of 18-day embryos. The cell cultures were treated with lithium (1 mM) or vehicle for 24 h or 7 days. Thereafter, bcl-2 mRNA and protein levels were determined by RT-PCR and ELISA, respectively. RESULTS: Chronic, but not acute, lithium treatment significantly increased bcl-2 protein levels in the astrocyte cultures compared with the vehicle-treated cultures. While lithium treatment increased bcl-2 protein levels in both neuronal and mixed neuron-astrocyte cultures, the elevations fell short of statistical significance compared with the respective vehicle-treated cultures. However, neither acute nor chronic lithium treatment affected bcl-2 mRNA levels in any of the three cell types studied. CONCLUSION: Increased bcl-2 levels in rat primary astrocyte cultures following chronic lithium treatment suggest astrocytes are also a target of lithium's action. In light of the evidence showing decreased numbers of glial cells in the post-mortem brain of patients bipolar disorder with and increased glial numbers following lithium treatment, the findings of this study indicate that lithium's action on astrocytes may account, at least in part, for its therapeutic effects in bipolar disorder. PMID- 24174698 TI - The Prevalence of Barrett's Esophagus in Outpatients with Dyspepsia in Shaheed Beheshti Hospital of Kashan. AB - Gastroesophageal reflux disease (GERD) is the main known etiological factor for Barrett's esophagus (BE), and BE is the precursor lesion of esophageal adenocarcinoma. The prevalence of BE is reported mostly from gastroenterology centers and there are only a few reported cases from outpatients with dyspepsia. A large number of patients with GERD have degrees of dyspepsia. This study primarily aimed to determine the prevalence of BE in dyspeptic patients. Outpatients with dyspepsia who referred to our Endoscopy Unit for endoscopy were included in this study. Esophageal biopsy was performed by an endoscopist, and BE diagnosis was established based on the abnormal appearance of the distal esophagus in endoscopy and also based on the presence of intestinal metaplasia in pathologic examination. The prevalence of BE was 5.4% (based on endoscopy) and 3.7% (based on pathology). Sixty-nine percent of the patients with confirmed BE were younger than 50 and 31% were over 50 years of age. Eighty-one percent of the patients with confirmed BE reported GERD symptoms as their dominant dyspepsia symptom, whereas only 20.4% of those without BE reported GERD symptoms (P<0.001). Additionally, BE had a relatively high prevalence in our dyspeptic patients. The high prevalence of GERD symptoms in BE underscores the need for endoscopy for dyspeptic patients. PMID- 24174699 TI - Pulmonary alveolar microlithiasis: a rare case report. AB - Pulmonary alveolar microlithiasis is an uncommon infiltrative pulmonary disease characterized by deposition of microliths in the alveoli. We present the case of a young adult with complaints of shortness of breath on exertion. Chest radiograph showed innumerable small, dense nodules, diffusely involving both the lungs - predominantly in the lower zones. High-resolution CT scan illustrated widespread intra-alveolar microliths, diffuse ground-glass attenuation areas, septal thickening, and black pleural lines - predominantly in the basal regions. Transbronchial biopsy confirmed the diagnosis. PMID- 24174700 TI - Diffuse hepatic calcifications in a transfusion-dependent patient with Beta thalassemia: a case report. AB - Hepatic calcification is usually associated with infectious, vascular, or neoplastic processes in the liver. We report the first case of beta-thalassemia major with isolated diffuse hepatic calcification in a 23 year old woman, who had been transfusion-dependent since the age of 6 months. She was referred to our center with a chief complaint of abdominal pain. Computed tomography scan of the abdomen revealed diffuse hepatic calcification in the right, left, and caudate lobes of the liver. Her medical history disclosed hypoparathyroidism as well as chronic hepatitis C virus infection, which was successfully treated but led to early micronodular cirrhosis on liver biopsy. Other studies done to search for the cause of hepatic calcification failed to reveal any abnormalities. We suspect that hypoparathyroidism caused liver calcification, and should be, therefore, considered in the differential diagnosis of hepatic calcification if other causative factors have been ruled out. PMID- 24174701 TI - Infective stroke. PMID- 24174702 TI - The authors' reply. PMID- 24174703 TI - Quality of publication ethics in instructions to authors. PMID- 24174704 TI - The Life Cycle of Bare Branch Families in China---A Simulation Study. AB - China is and will be characterized by a large number of men who are unable to marry: these men are often referred to as "bare branches." In this paper we define the bare branch family and divide its life cycle into three stages: the unmarried co-resident with both parents, co-resident with a surviving parent, and living alone. Using life tables and probability methods, we find that up to age 60, the bare branch male faces cumulative probabilities of 0.8 and 0.6, for his father's and mother's death, respectively. The definition of the age at which bare branch status is initialized influences the length of these stages. As the childbearing age of parents increases, the age of a bare branch at the death of his parents decreases, and the duration of his living alone lengthens. An increase in the mother's childbearing age, holding that of the father constant, shortens the stage of co-residence with both parents, and lengthens the stage of living alone. PMID- 24174705 TI - Trial and evaluation of assertion training involving nursing students. AB - BACKGROUND: The concept of assertion and conceptual/practical methods of assertion (assertiveness) training were originally developed in the United States and Europe. These principles were embraced and adapted in Japan in 1970's. However, only a few studies relating to assertion (assertiveness) have been undertaken thus far in Japan, especially so in the domain of nursing students in comparison with other countries. The purpose of this study was to design and implement assertion training with nursing students and to clarify its effects. METHODS: The participants were all volunteers, invited from a class of 3rd year nursing students. Ten students (intervention group) participated in the assertion training comprised of five sessions in February 2006. Fifty-six students (control group) were participated only in the questionnaire. Both groups were asked to complete the same questionnaire twice, before and after the assertion training. The questionnaire measured levels of assertiveness, social skills, self-esteem, social support and satisfaction with university life. The results and variances, both before and after assertion training, between the intervention group and the control group were analyzed. The effectiveness of the assertion training was determined by changes in pre and post training questionnaire scores. RESULTS: The scores for social skills in the control group had a tendency to decline while the scores for social skills in the intervention group remained constant. CONCLUSION: Although there were no statistically significant results in the intervention group, the present study highlights areas appropriate for further study. PMID- 24174706 TI - Effects of Water Temperature during Foot Bath in Young Females. AB - We examined the effects of environmental and water temperatures of foot baths on pulse rate, blood pressure, mean skin temperature, salivary amylase (SA) activity, relaxation level and thermal sensation during winter. Five females participated in the study. The subjects rested in a chair for 20 min and the above-noted physiological reactions during the last 5 min of the resting period were recorded as baseline (BASE) values. Next, the subjects received a 15-min foot bath in water at 40 degrees C (WT40) or 45 degrees C (WT45), with a 15-min recovery period. Although SA is thought to be an indicator of stress via the sympathetic nervous system, we did not find a correlation between SA activity and relaxation state. We considered the possible effect of seasonal variation on the physiological reaction to foot bathing. PMID- 24174707 TI - A Selective Review of Group Selection in High-Dimensional Models. AB - Grouping structures arise naturally in many statistical modeling problems. Several methods have been proposed for variable selection that respect grouping structure in variables. Examples include the group LASSO and several concave group selection methods. In this article, we give a selective review of group selection concerning methodological developments, theoretical properties and computational algorithms. We pay particular attention to group selection methods involving concave penalties. We address both group selection and bi-level selection methods. We describe several applications of these methods in nonparametric additive models, semiparametric regression, seemingly unrelated regressions, genomic data analysis and genome wide association studies. We also highlight some issues that require further study. PMID- 24174708 TI - Machine Learning in Computer-aided Diagnosis of the Thorax and Colon in CT: A Survey. AB - Computer-aided detection (CADe) and diagnosis (CAD) has been a rapidly growing, active area of research in medical imaging. Machine leaning (ML) plays an essential role in CAD, because objects such as lesions and organs may not be represented accurately by a simple equation; thus, medical pattern recognition essentially require "learning from examples." One of the most popular uses of ML is the classification of objects such as lesion candidates into certain classes (e.g., abnormal or normal, and lesions or non-lesions) based on input features (e.g., contrast and area) obtained from segmented lesion candidates. The task of ML is to determine "optimal" boundaries for separating classes in the multidimensional feature space which is formed by the input features. ML algorithms for classification include linear discriminant analysis (LDA), quadratic discriminant analysis (QDA), multilayer perceptrons, and support vector machines (SVM). Recently, pixel/voxel-based ML (PML) emerged in medical image processing/analysis, which uses pixel/voxel values in images directly, instead of features calculated from segmented lesions, as input information; thus, feature calculation or segmentation is not required. In this paper, ML techniques used in CAD schemes for detection and diagnosis of lung nodules in thoracic CT and for detection of polyps in CT colonography (CTC) are surveyed and reviewed. PMID- 24174709 TI - Multiplexed and Switchable Release of Distinct Fluids from Microneedle Platforms via Conducting Polymer Nanoactuators for Potential Drug Delivery. AB - We report on the development of a microneedle-based multiplexed drug delivery actuator that enables the controlled delivery of multiple therapeutic agents. Two individually-addressable channels on a single microneedle array, each paired with its own reservoir and conducting polymer nanoactuator, are used to deliver various permutations of two unique chemical species. Upon application of suitable redox potentials to the selected actuator, the conducting polymer is able to undergo reversible volume changes, thereby serving to release a model chemical agent in a controlled fashion through the corresponding microneedle channels. Time-lapse videos offer direct visualization and characterization of the membrane switching capability and, along with calibration investigations, confirm the ability of the device to alternate the delivery of multiple reagents from individual microneedles of the array with higher precision and temporal resolution than conventional drug delivery actuators. Analytical modeling offers prediction of the volumetric flow rate through a single microneedle and accordingly can be used to assist in the design of subsequent microneedle arrays. The robust solid-state design and lack of mechanical components circumvent reliability issues that challenge fragile conventional microelectromechanical drug delivery devices. This proof-of-concept study demonstrates the potential of the drug delivery actuator system to aid in the rapid administration of multiple therapeutic agents and indicates the potential to counteract diverse biomedical conditions. PMID- 24174711 TI - Elevated levels of cerebrospinal fluid and plasma interleukin-37 in patients with Guillain-Barre syndrome. AB - AIMS. Interleukin-37 (IL-37) is an anti-inflammatory cytokine. This study aims to investigate the concentrations of plasma and cerebrospinal fluid (CSF) IL-37 in patients with Guillain-Barre Syndrome (GBS). METHODS: The levels of plasma and CSF IL-37, IL-17A, IFN- gamma , and TNF- alpha in 25 GBS patients and 20 healthy controls (HC) were determined by enzyme-linked immunoabsorbent assay and flow cytometric bead array assay, respectively. The values of clinical parameters in the patients were also measured. RESULTS: The concentrations of plasma IL-37, IL 17A, IFN- gamma , and TNF- alpha and CSF IL-37 and IL-17A in patients at the acute phase of GBS were significantly higher than those in the HC. The levels of plasma IL-37, IL-17A, IFN- gamma , and TNF- alpha were positively correlated in those patients, and the levels of CSF IL-37 and IL-17A as well as the levels of plasma TNF- alpha were correlated positively with the GBS disability scale scores (GDSs) in those patients. Treatment with intravenous immunoglobulin significantly reduced the levels of plasma IL-37, IL-17A, IFN- gamma , and TNF- alpha in the drug-responding patients. CONCLUSIONS: Our findings indicate higher levels of plasma and CSF IL-37 and IL-17A and other proinflammatory cytokines in patients with GBS. PMID- 24174710 TI - Gestational exposure to a viral mimetic poly(i:C) results in long-lasting changes in mitochondrial function by leucocytes in the adult offspring. AB - Maternal immune activation (MIA) is a potential risk factor for autism spectrum disorder (ASD) and schizophrenia (SZ). In rodents, MIA results in changes in cytokine profiles and abnormal behaviors in the offspring that model these neuropsychiatric conditions. Given the central role that mitochondria have in immunity and other metabolic pathways, we hypothesized that MIA will result in a fetal imprinting that leads to postnatal deficits in the bioenergetics of immune cells. To this end, splenocytes from adult offspring exposed gestationally to the viral mimic poly(I:C) were evaluated for mitochondrial outcomes. A significant decrease in mitochondrial ATP production was observed in poly(I:C)-treated mice (45% of controls) mainly attributed to a lower complex I activity. No differences were observed between the two groups in the coupling of electron transport to ATP synthesis, or the oxygen uptake under uncoupling conditions. Concanavalin A- (ConA-) stimulated splenocytes from poly(I:C) animals showed no statistically significant changes in cytokine levels compared to controls. The present study reports for the first time that MIA activation by poly(I:C) at early gestation, which can lead to behavioral impairments in the offspring similar to SZ and ASD, leads to long-lasting effects in the bioenergetics of splenocytes of adult offspring. PMID- 24174712 TI - Increased anti-phospholipid antibodies in autism spectrum disorders. AB - Autism spectrum disorders (ASD) are characterized by impairments in communication, social interactions, and repetitive behaviors. While the etiology of ASD is complex and likely involves the interplay of genetic and environmental factors, growing evidence suggests that immune dysfunction and the presence of autoimmune responses including autoantibodies may play a role in ASD. Anti phospholipid antibodies are believed to occur from both genetic and environmental factors and have been linked to a number of neuropsychiatric symptoms such as cognitive impairments, anxiety, and repetitive behaviors. In the current study, we investigated whether there were elevated levels of anti-phospholipid antibodies in a cross-sectional analysis of plasma of young children with ASD compared to age-matched typically developing (TD) controls and children with developmental delays (DD) other than ASD. We found that levels of anti cardiolipin, beta 2-glycoprotein 1, and anti-phosphoserine antibodies were elevated in children with ASD compared with age-matched TD and DD controls. Further, the increase in antibody levels was associated with more impaired behaviors reported by parents. This study provides the first evidence for elevated production of anti-phospholipid antibodies in young children with ASD and provides a unique avenue for future research into determining possible pathogenic mechanisms that may underlie some cases of ASD. PMID- 24174714 TI - Reporting science with ethics: Your work is your reputation! PMID- 24174715 TI - The final lap.... PMID- 24174713 TI - Novel biphasic role of resolvin D1 on expression of cyclooxygenase-2 in lipopolysaccharide-stimulated lung fibroblasts is partly through PI3K/AKT and ERK2 pathways. AB - Fibroblasts, far from being merely bystander cells, are known to play a specific role in inflammation resolution after an acute injury. As the endogenous "braking signal," resolvins possess potent anti-inflammatory and pro-resolution actions. We demonstrated that the expression of COX-2 protein was significantly peaked initially at 6 hours but then also at 48 hours after LPS stimulation in lung fibroblasts. PGE2 levels also peaked at 6 hours, and PGD2 levels were increased and peaked at 48 hours. However, no significant change in the protein expression of COX-1 was observed after treatment with LPS in lung fibroblasts. Exogenous resolvin D1 inhibited the first peak of COX-2 expression as well as the production of PGE2 induced by LPS. In contrast, exogenous resolvin D1 increased the second peak of COX-2 expression as well as the production of PGD2 induced by LPS. In addition, resolvin D1 inhibited COX-2 expression at 6 hours, which was partly through PI3K/AKT and ERK2 signalling pathways. PMID- 24174716 TI - Reactive oxygen species in periodontitis. AB - Recent epidemiological studies reveal that more than two-third of the world's population suffers from one of the chronic forms of periodontal disease. The primary etiological agent of this inflammatory disease is a polymicrobial complex, predominantly Gram negative anaerobic or facultative bacteria within the sub-gingival biofilm. These bacterial species initiate the production of various cytokines such as interleukin-8 and TNF-alpha, further causing an increase in number and activity of polymorphonucleocytes (PMN) along with these cytokines, PMNs also produce reactive oxygen species (ROS) superoxide via the respiratory burst mechanism as the part of the defence response to infection. ROS just like the interleukins have deleterious effects on tissue cells when produced in excess. To counter the harmful effects of ROS, human body has its own defence mechanisms to eliminate them as soon as they are formed. The aim of this review is to focus on the role of different free radicals, ROS, and antioxidants in the pathophysiology of periodontal tissue destruction. PMID- 24174717 TI - Ribonucleic acid interference induced gene knockdown. AB - Despite major advances in periodontal regeneration over the past three decades, complete regeneration of the lost periodontium on a regular and predictable basis in humans has still remained elusive. The identification of stem cells in the periodontal ligament together with the growing concept of tissue engineering has opened new vistas in periodontal regenerative medicine. In this regard, ribonucleic acid interference (RNAi) opens a new gate way for a novel RNA based approach in periodontal management. This paper aims to summarize the current opinion on the mechanisms underlying RNAi, in vitro and in vivo existing applications in the dental research, which could lead to their future use in periodontal regeneration. PMID- 24174718 TI - Mechanized scaling with ultrasonics: Perils and proactive measures. AB - Mechanized scaling for plaque removal is a routine procedure in the practice of periodontics. Though it appears innocuous by itself, there are retinues of hazards associated with it on various organ systems in the body. Some of these unwanted effects and measures to avoid or ameliorate the same are elaborated here. Exposure to ultrasonic scaling is inevitable before any other treatment procedure. Aerosol contamination, vibrational hazards, thermal effects on the dental pulp, altered vascular dynamics, disruption in electromagnetic device, diminished hearing and dental unit waterline contamination are some of the probable off-shoots a patient has to bear. Uses of barrier devices, proper attention to usage of equipment, protection for ear and water treatment are few of solutions for the same. Though documented evidence for the existence of all effects is lacking, it is never the less significant for the overall safety of the patient. A conscientious clinician should therefore inculcate the available steps to overcome the hazards of ultrasonic scaling. PMID- 24174720 TI - Aloe vera: It's effect on gingivitis. AB - OBJECTIVE: Aloe vera is the oldest medicinal plant that has maintained its popularity over the course of time. It is widely known for its medicinal uses in wound healing, as an analgesic, and for its anti-inflammatory properties. AIM: The aim of this study is to evaluate the anti-inflammatory property of aloe vera mouthwash on plaque-induced gingivitis. MATERIALS AND METHODS: Forty-five patients who were diagnosed with plaque-induced gingivitis were included in the study. They were divided into three groups with fifteen patients in each group. Group 1 was asked to rinse with 10 ml of aloe vera mouthwash twice daily for three months. Group 2 were treated with scaling only. Group 3 patients were asked to rinse with aloe vera mouthwash and scaling was done. The clinical changes were evaluated with Loe and Silness gingival index (1963) and Muhlemann and Son's Sulcus bleeding index (1971) at baseline, after one month and three months, respectively. RESULTS: The data obtained was compared statistically. The paired 't' test was done for intragroup comparison and one-way analysis of variance with a post hoc Tukey test was used for intergroup comparison. The data was obtained at the baseline, end of first month, and end of the third month. The result suggested reduction in gingival inflammation in all the three groups, but it was more in the aloe vera mouthwash and scaling group. Hence, it was concluded that aloe vera had a significant anti-inflammatory property. Thus, it can be used as an adjunct to mechanical therapy for treating plaque-induced gingivitis. PMID- 24174719 TI - Kinetics of drug release from a biodegradable local drug delivery system and its effect on Porphyromonas gingivalis isolates: An in vitro study. AB - BACKGROUND: Conventional anti-microbial therapy largely consisted of systemic administration of various drugs effective against periodontal pathogens, but fraught with several problems. Based on the concept of local drug delivery a bioresorbable device made of pure fibrillar collagen has been developed. The aim of this study was to study the release of Tetracycline from this collagen fiber (Type I collagen) impregnated with Tetracycline and its antibacterial activity against Porphyromonas gingivalis. MATERIALS AND METHODS: Porphyromonas gingivalis was isolated from plaque samples of chronic periodontitis patients by using a CO2 incubator. DNA isolation was done followed by polymerase chain reaction (PCR) amplification to confirm the presence of bacteria. The release pattern of Tetracycline was assessed for a period of 10 days in water (group I) and Serum inoculated with Porphyromonas gingivalis (group II). RESULTS: A significant presence of Tetracycline on all days in Group I and group II and the zone of inhibition was also present in both groups with a steady decline from day 1 to day 10. CONCLUSION: Since the results were well within the therapeutic concentration of drug required to inhibit the growth of gram -ve bacteria (Porphyromonas gingivalis), this bioresorbable Tetracycline fiber has the potential for clinical application. PMID- 24174721 TI - Efficacy of xanthan based chlorhexidine gel as an adjunct to scaling and root planing in treatment of the chronic periodontitis. AB - AIM: The aim of this study was to evaluate the clinical effectiveness of locally delivered xanthan-based Chlosite((r)) gel as an adjunctive therapy to scaling and root planing in treatment of chronic periodontitis. MATERIALS AND METHODS: In a randomized controlled clinical study, 30 patients were selected. Pocket depth between 5 and 7 mm was selected and each patient had two sites on the same side of the mouth. A total of 30 control sites were scaled and root planed and 30 test sites were scaled and root planed and Chlosite((r)) gel was added. The clinical parameters, probing depth (PD), clinical attachment level (CAL), plaque index (PI) and bleeding on probing (BOP), gingival index were recorded at baseline, 6 weeks, 3 months and 6 months. STATISTICAL ANALYSIS: Paired/unpaired t-test was used, significance was placed at 5% level of significance, i.e., P < 0.05 was considered as a significant. RESULTS: From baseline to a period of 6 months, significant difference was found between test and control group for PD, CAL, PI and BOP, P value being PD (P = 0.002), CAL index (P = 0.014), respectively. CONCLUSION: Subgingival injection of xanthan-based Chlosite((r)) gel adjunct with scaling and root planing appeared to cause significant improvement compared with scaling and root planing alone in persons with chronic periodontitis. PMID- 24174722 TI - Effect of local application of tea tree (Melaleuca alternifolia) oil gel on long pentraxin level used as an adjunctive treatment of chronic periodontitis: A randomized controlled clinical study. AB - BACKGROUND: Conventional non-surgical periodontal therapy has been proven to be an effective treatment for patients with chronic periodontitis. Tea tree oil (TTO) can be used as adjunct to conventional periodontal therapy in patient with chronic periodontitis. The aim of this study was to evaluate the effectiveness of adjunctive treatment of TTO on the clinical parameters and the level of pentraxin 3 (PTX3) in chronic periodontitis. MATERIALS AND METHODS: A total of 40 patients with moderate to severe chronic periodontitis were divided into two groups, Group I received scaling and root planing (SRP) only, Group II received SRP and TTO gel. Clinical parameters were recorded and gingival crevicular fluid (GCF) samples were collected from each subject for measuring PTX3 levels at baseline, 1, 3 and 6 months after treatment. RESULTS: In all evaluation periods, there was statistically significant reduction in each of the studied clinical parameters and PTX3 level in Group II as compared with Group I. CONCLUSIONS: The local delivery of TTO gel in case of chronic periodontitis may have some beneficial effects to augment the results of the conventional periodontal therapy. Moreover, it places a focus on the value of monitoring GCF levels of PTX3 as a marker of periodontal tissue healing. PMID- 24174723 TI - Effect of hydrogen peroxide mouthwash as an adjunct to chlorhexidine on stains and plaque. AB - AIM: To investigate whether the use of an oxidizing mouth rinse as an adjunct to chlorhexidine is efficacious in reducing stains and plaque. MATERIALS AND METHODS: This study had a single-blind, three-group (n = 35 each) parallel design, including a 21 days experimental period during which group I rinsed with chlorhexidine (CHX) 0.2% alone, group II used chlorhexidine (CHX) followed by hydrogen peroxide (H2O2) 1.5%. Group III rinsed with the same mouthwashes in reverse order. Patients were randomly assigned to one of the three groups. The examination for plaque, and stains was done after 1, 2, and 3 weeks of rinsing. RESULTS: Group II showed significantly less stain intensity in comparison with group I after 14 and 21 days (P values 0.025 and 0.005, respectively). The proportion of stained surfaces was less in the group II than in the group I and was significant at the end of 1 week. The plaque formation was significantly less in groups II and III than group I at 7, 14, and 21 days. CONCLUSION: The adjunctive use of hydrogen peroxide to chlorhexidine proved to be superior to chlorhexidine alone with regard to the inhibition of plaque and development of stains. PMID- 24174724 TI - Association of salivary calcium, phosphate, pH and flow rate on oral health: A study on 90 subjects. AB - BACKGROUND AND OBJECTIVES: This study was designed to compare inorganic salivary calcium, phosphate, flow rate and pH of un-stimulated saliva and oral hygiene of healthy subjects, patients with periodontitis and dental caries and to correlate salivary calcium level with the number of intact teeth. MATERIALS AND METHODS: The present study consisted of 90 patients aged between 18 and 55 years and were divided into three groups, periodontitis, dental caries and controls. Oral hygiene index-simplified, probing pocket depth, clinical attachment level and number of teeth present, teeth with active carious lesions were recorded. Salivary flow rate and pH was recorded and subjected to biochemical investigation. Estimation of inorganic calcium and phosphate was performed by colorimetric method. RESULTS: Results showed statistically significant increase in salivary inorganic calcium and phosphate levels, poor oral hygiene status, pH and salivary flow rate in patients with periodontitis when compared with dental caries group and controls. INTERPRETATION AND CONCLUSION: Individuals who have increased salivary inorganic calcium, phosphate, pH, flow rate and maintain poor oral hygiene could be at a higher risk for developing periodontitis and may have less dental caries and more number of intact teeth. PMID- 24174725 TI - Salivary pH: A diagnostic biomarker. AB - OBJECTIVES: Saliva contains a variety of host defense factors. It influences calculus formation and periodontal disease. Different studies have been done to find exact correlation of salivary biomarkers with periodontal disease. With a multitude of biomarkers and complexities in their determination, the salivary pH may be tried to be used as a quick chairside test. The aim of this study was to analyze the pH of saliva and determine its relevance to the severity of periodontal disease. STUDY DESIGN: The study population consisted of 300 patients. They were divided into three groups of 100 patients each: Group A had clinically healthy gingiva, Group B who had generalized chronic gingivitis and Group C who had generalized chronic periodontitis. The randomized unstimulated saliva from each patient was collected and pH was tested. Data was analyzed statistically using analysis of variance technique. RESULTS: The salivary pH was more alkaline for patients with generalized chronic gingivitis as compared with the control group (P = 0.001) whereas patients with generalized chronic periodontitis had more acidic pH as compared with the control group (P = 0.001). CONCLUSION: These results indicate a significant change in the pH depending on the severity of the periodontal condition. The salivary pH shows significant changes and thus relevance to the severity of periodontal disease. Salivary pH may thus be used as a quick chairside diagnostic biomarker. PMID- 24174726 TI - Evaluation of the effect of one stage versus two stage full mouth disinfection on C-reactive protein and leucocyte count in patients with chronic periodontitis. AB - BACKGROUND: Conventional non-surgical periodontal therapy is carried out in quadrant basis with 1-2 week interval. This time lag may result in re-infection of instrumented pocket and may impair healing. Therefore, a new approach to full mouth non-surgical therapy to be completed within two consecutive days with full mouth disinfection has been suggested. In periodontitis, leukocyte counts and levels of C-reactive protein (CRP) are likely to be slightly elevated, indicating the presence of infection or inflammation. The aim of this study is to compare the efficacy of one stage and two stage non-surgical therapy on clinical parameters along with CRP levels and total white blood cell (TWBC) count. MATERIALS AND METHODS: A total of 20 patients were selected and were divided into two groups. Group 1 received one stage full mouth dis-infection and Group 2 received two stages FMD. Plaque index, sulcus bleeding index, probing depth, clinical attachment loss, serum CRP and TWBC count were evaluated for both the groups at baseline and at 1 month post-treatment. RESULTS: The results were analyzed using the Student t-test. Both treatment modalities lead to a significant improvement of the clinical and hematological parameters; however comparison between the two groups showed no significant difference after 1 month. CONCLUSION: The therapeutic intervention may have a systemic effect on blood count in periodontitis patients. Though one stage FMD had limited benefits over two stages FMD, the therapy can be accomplished in a shorter duration. PMID- 24174727 TI - Gingival crevicular blood: As a non-invasive screening tool for diabetes mellitus in dental clinics. AB - BACKGROUND: A high number of patients with periodontitis may have undiagnosed diabetes. Self-monitoring devices provide a simple method for rapid monitoring of the glucose level in the blood by utilizing a blood sample from the finger, but this method requires a needle puncture to obtain blood. It is possible that gingival crevicular blood (GCB) from routine periodontal probing may be a source of blood for glucose measurements. AIM: To establish whether GCB can be used as a non-invasive diagnostic aid in screening for diabetes mellitus during routine periodontal examination. MATERIALS AND METHODS: The study involved 50 diabetics and 50 non-diabetics, with an age range of 26-66 years. Both diabetic and non diabetic patients had moderate to severe gingivitis with at least one tooth in the maxillary anterior region showing bleeding upon probing. The Gingival Index and Oral Hygiene Index-Simplified were recorded. Blood oozing from the gingival sulcus/pocket following periodontal pocket probing was collected using a capillary tube and transferred to the test stick of a glucose self-monitoring device (Accu-Chek, Roche Diagnostic, Germany) in patients with comparable gingival and oral hygiene status. This value was compared with the peripheral fingerstick blood glucose (PFBG) value, which was obtained by pricking the finger tip at the same visit. Statistical analysis was performed using Pearson's correlation coefficient. RESULT: There was no statistically significant difference between the gingival crevicular blood glucose (GCBG) values and the PFBG values in both the diabetic (P = 0.129, NS) and the non-diabetic (P = 0.503, NS) groups. Karl Pearson's product-moment correlation coefficient was calculated, which showed a positive correlation between the two measurements in the diabetic (r = 0.943) as well as the non-diabetic (r = 0.926) groups. CONCLUSION: The results suggest that GCB can be used as a non-invasive diagnostic aid in screening for diabetes mellitus during routine periodontal examination. PMID- 24174728 TI - A comparative clinical study of the efficacy of subepithelial connective tissue graft and acellular dermal matrix graft in root coverage: 6-month follow-up observation. AB - AIMS: The purpose of this study was to compare the clinical efficacy of subepithelial connective tissue graft and acellular dermal matrix graft associated with coronally repositioned flap in the treatment of Miller's class I and II gingival recession, 6 months postoperatively. SETTINGS AND DESIGN: Ten patients with bilateral Miller's class I or class II gingival recession were randomly divided into two groups using a split-mouth study design. MATERIALS AND METHODS: Group I (10 sites) was treated with subepithelial connective tissue graft along with coronally repositioned flap and Group II (10 sites) treated with acellular dermal matrix graft along with coronally repositioned flap. Clinical parameters like recession height and width, probing pocket depth, clinical attachment level, and width of keratinized gingiva were evaluated at baseline, 90(th) day, and 180(th) day for both groups. The percentage of root coverage was calculated based on the comparison of the recession height from 0 to 180(th) day in both Groups I and II. STATISTICAL ANALYSIS USED: Intragroup parameters at different time points were measured using the Wilcoxon signed rank test and Mann Whitney U test was employed to analyze the differences between test and control groups. RESULTS: There was no statistically significant difference in recession height and width, gain in CAL, and increase in the width of keratinized gingiva between the two groups on the 180(th) day. Both procedures showed clinically and statistically significant root coverage (Group I 96%, Group II 89.1%) on the 180(th) day. CONCLUSIONS: The results indicate that coverage of denuded root with both subepithelial connective tissue autograft and acellular dermal matrix allograft are very predictable procedures, which were stable for 6 months postoperatively. PMID- 24174729 TI - A comparative evaluation of the effectiveness of guided tissue regeneration by using a collagen membrane with or without decalcified freeze-dried bone allograft in the treatment of infrabony defects: A clinical and radiographic study. AB - BACKGROUND: The present, randomized, controlled clinical and radiographic study was undertaken to compare the effectiveness of guided tissue regeneration (GTR) by using a collagen membrane barrier with or without decalcified freeze-dried bone allograft (DFDBA) in the treatment of periodontal infrabony defects characterized by unfavorable architecture. MATERIALS AND METHODS: Sixteen systemically healthy patients with 20 periodontal infrabony defects were selected for the study. Each patient had at least >= 5 mm clinical probing pocket depth (PPD) at the selected site and depth of intrabony component >= 3 mm as assessed by clinical and radiographic measurements. Baseline measurements included plaque index, papillary bleeding index, PPD, gingival recession, clinical attachment level and radiographic defect depth (DD). At the time of surgery, the defects were randomly assigned to either the test group (collagen membrane plus DFDBA) or the control group (collagen membrane only). RESULTS: At the 6-month examination, PPPD reduction was significantly greater in the GTR + DFDBA group (4.06 +/- 0.38 mm) compared with the GTR group (3.2 +/- 0.74 mm). The mean gains of clinical attachment were 3.54 +/- 0.36 mm in the test group and 2.50 +/- 0.74 mm in the control group. Radiographic DD reduction was similarly greater in the GTR + DFDBA group (2.40 +/- 0.51 mm) compared with the GTR group (1.60 +/- 0.51 mm). CONCLUSIONS: The results of the present study indicate that the use of a GTR membrane with bone graft has significantly improved all clinical parameters tested as compared with the use of bioresorbable membrane alone in the treatment of infrabony defects characterized by unfavorable architecture. PMID- 24174730 TI - Comparative evaluation of decalcified freeze dried bone allograft with and without local doxycycline in non-contained human periodontal infrabony defects. AB - BACKGROUND: Doxycycline has been advocated as useful adjuncts in periodontal therapy not only due to their antimicrobial actions, but also to their recently recognized anti-collagenolytic, anti-inflammatory, osteoclast inhibitory and fibroblast stimulating property. The purpose of the present cohort study was to evaluate the regenerative outcomes of bone graft with or without local doxycycline in non-contained infrabony periodontal defects. MATERIALS AND METHODS: 16 one or two wall infrabony defects, in 11 patients suffering from moderate to severe chronic periodontitis, aged 35-60 years, were randomly divided for bone graft, alone (control) and with doxycycline (test) for the study. At baseline, after 3 months and after 6 months of post-operative period, pocket probing depth (PPD), clinical attachment level (CAL), radiological bone fill (RBF) and alveolar height reduction were recorded. Analysis of variance and Newman-Keuls post-hoc test were used or statistical analysis. A two-tailed probability (P) value P < 0.05 was considered to be statistically significant. RESULTS: For the control group PPD reduction 2.00 +/- 0.18 mm, CAL gain 1.38 +/- 0.17 mm, RBF 0.63 +/- 0.27 mm (18.0%) was observed while in the test group PPD reduction 2.00 +/- 0.38 mm, CAL gain 1.25 +/- 0.31 mm, RBF 0.75 +/- 0.31 mm (20.7%) was evaluated. While alveolar height reduction for the control group and test group was 13% and 12.5% respectively. CONCLUSION: The study confirmed no added benefits of local doxycycline, as compared with bone graft alone, for regeneration of non-contained human periodontal infrabony defects. PMID- 24174731 TI - Clinical and radiographic evaluation of demineralized bone matrix (grafton) as a bone graft material in the treatment of human periodontal intraosseous defects. AB - PURPOSE: The purpose of this clinical trial was to evaluate the efficacy of demineralized bone matrix (DBM) as a bone graft material in the treatment of human intrabony periodontal defects as compared with control defects treated by open flap debridement (OFD) alone. MATERIALS AND METHODS: A controlled clinical trial was carried out for a period of 9 months in 11 patients (4 males and 7 females) with an age group of 25-50 years, contributing to a total of 30 defects. The selected defects were then randomly divided in to experimental sites (OFD + DBM) and control sites (OFD alone). Probing depth, clinical attachment levels and position of the gingival margin were recorded at baseline 3, 6 and 9 months post operatively. Standardized radiographs (parallel technique) were also documented at these recall intervals. RESULTS: On completion of 9 months, the mean percentage of probing depth reduction achieved in the experimental sites and control sites was 61.70%, 23.86% respectively. The mean percentage of clinical attachment level gain was 61.34% and 19.37% in the experimental and control sites respectively. In the experimental sites recession was observed to a lesser extent. CONCLUSION: The use of DBM was more effective than OFD in improving clinical parameters and radiographic bone fill as shown in the present study. However, there is a need for further long term studies. PMID- 24174732 TI - Massive pregnancy gingival enlargement: A rare case. AB - Gingival enlargement related to pregnancy is sometimes seen in the oral cavity. Pregnancy is a physiological state that brings full of changes in a woman's life. The metabolism and immunology of the body are modified by progesterone and estrogen as well as other local factors, these sex hormones may modify the oral mucosa and may lead to various periodontal diseases. A case of female patient 23 yrs of age reported during 8(th) month of pregnancy with a localised gingival enlargement affecting the buccal aspect of left maxillary central incisor upto canine. The hormonal changes occurring during pregnancy may be associated with generalized or localised gingival enlargement and the presence of local factors may accentuate the gingival response. Rarely the enlargement becomes maasive and protrude out extraorally. PMID- 24174733 TI - Peripheral ossifying fibroma. AB - Peripheral ossifying fibroma (POF) is one of the inflammatory reactive hyperplasia of gingiva. It represents a separate clinical entity rather than a transitional form of pyogenic granuloma and shares unique clinical characteristics and diverse histopathological features. We present a case of POF in a 65-year-old male patient in the posterior maxillary gingiva, the clinical presentation of which differs from the usual presentation. Differential diagnosis and some interesting facts of POF are discussed. PMID- 24174734 TI - A silent tumor of the gingiva: An unusual case report and surgical management with 1 year follow-up. AB - Neurofibroma is a benign tumor of the peripheral nerve sheath characterized by the proliferation of Schwann's cells, perineural cells, and endoneurial fibroblasts. Here, we present a case of unique variation in the observed characteristics of a neurofibroma, with no relation to neurofibromatosis (NF) type-1 or von Recklinghausen disease of the skin. A swelling was observed in the right maxillary gingiva in relation with 14-16 regions of a 25-year-old female patient. The lesion was smooth, with sessile base, painless, non-ulcerated, and with normal color. An excisional biopsy of the lesion was performed, and histologically the diagnosis was confirmed. The patient remains uneventful after 1 year of clinical follow-up. Oral cavity involvement by a solitary neurofibroma in patients with no other signs of NF is uncommon and the gingival involvement is very rare. PMID- 24174735 TI - Pyogenic granuloma of the gingiva: A misnomer? - A case report and review of literature. AB - Pyogenic granuloma is a commonly occurring inflammatory hyperplasia of the skin and oral mucosa. It is not associated with pus as its name suggests and histologically it resembles an angiomatous lesion rather than a granulomatous lesion. It is known by a variety of names such as Crocker and Hartzell's disease, granuloma pyogenicum, granuloma pediculatum benignum, benign vascular tumor and during pregnancy as granuloma gravidarum. This tumor like growth is considered to be non-neoplastic in nature and it presents itself in the oral cavity in various clinical and histological forms. Due to its frequent occurrence in the oral cavity, especially the gingiva, this article presents a case report of a large pyogenic granuloma of the gingiva and its management, reviews the literature and discusses why the term "pyogenic granuloma" is a misnomer. PMID- 24174736 TI - Acute gingival bleeding as a complication of dengue hemorrhagic fever. AB - Dengue fever is mosquito borne disease caused by dengue virus (DENV) of Flaviviridae family. The clinical manifestations range from fever to severe hemorrhage, shock and death. Here, we report a case of 20-year-old male patient undergoing orthodontic treatment presenting with acute gingival bleeding with a history of fever, weakness, backache, retro orbital pain and ecchymosis over his right arm. The hematological investigations revealed anemia, thrombocytopenia and positive dengue non-structural protein-1 antigen and also positive immunoglobulin M and immunoglobulin G antibodies for DENV. Patient was diagnosed as a case of dengue hemorrhagic fever and was immediately referred for appropriate management. This case report emphasizes the importance of taking correct and thorough medical history. PMID- 24174737 TI - Gingival squamous cell carcinoma masquerading as an aphthous ulcer. AB - Gingival squamous cell carcinoma (GSCC) is an uncommon condition of the oral cavity. It is seldom associated with classic risk factors of oral cancer and shows a predilection for females. It's close clinical resemblances to various lesions of the oral cavity may make it go unnoticed. This may lead to diagnosis at advanced stages and coupled with the proximity to underlying alveolar bone may result in subsequent morbidity and mortality. A case of GSCC camouflaged as an aphthous ulcer in a middle aged woman is presented. The article highlights the importance of early diagnosis resulting in conservative treatment approaches. PMID- 24174738 TI - An unusual clinical presentation of plasma cell gingivitis related to "Acacia" containing herbal toothpaste. AB - A 17-year-old female patient presented with unusual enlargement of the gingiva with generalized alveolar bone loss. In spite of periodontal therapy, including plaque control, scaling, root planning and surgical treatment, recurrence with the same degree of the gingival enlargement and further loss of attachment level occurred. Biopsy revealed dense infiltration of normal plasma cells separated by collagenous stroma. Discontinuation of herbal toothpaste resulted in remarkable remission of the gingival enlargement within 2 weeks. Enzyme-linked immunosorbent assay of toothpaste components disclosed "Acacia" as an etiologic antigenic agent and confirmed the diagnosis of plasma cell gingivitis (PCG). Usually, PCG is not associated with the loss of attachment. This case report appears to be the first publication to document an atypical presentation of PCG with generalized aggressive periodontitis related to the use of herbal toothpaste containing "Acacia" extract from the tree "Acacia Arabica." PMID- 24174739 TI - Spontaneous correction of pathologically migrated teeth with periodontal therapy alone. AB - Pathological tooth migration is a characteristic sign of an advanced form of chronic periodontitis. The etiology of pathological tooth migration is complex and multifactorial. Usually treatment of pathological migration includes a multidisciplinary approach. However, in some cases, spontaneous repositioning of the pathologically migrated teeth has been reported following periodontal therapy alone. In the present report, following periodontal surgery, there was a spontaneous repositioning of the migrated teeth and restoration of dento-facial esthetics. The treatment options in cases of pathological tooth migration, based on the severity, are also discussed. PMID- 24174740 TI - The perio-esthetic-restorative approach for anterior rehabilitation. AB - Ensuring clinical success begins with a careful discussion of treatment planning, comprehensively covering all variables in simple to complex cases. Procedures including the crown lengthening surgery, furcation treatment and mucogingival therapy and tooth restoration are essential treatment regimens requiring multifaceted expertise. The interplay of periodontics and restorative dentistry is present at many fronts including the response of the gingival tissue to the restorative preparations. Dental restorations and periodontal health are inseparably interrelated. The adaptation of the margins, the contours of the restoration, the proximal relationships and the surface smoothness have a critical biological impact on the gingiva and the supporting periodontal tissues. The different surgical procedures used for crown lengthening are gingivectomy/gingivoplasty, apically positioned flap with or without osseous resection and orthodontic extrusion. The paper presents crown lengthening of severely mutilated teeth to increase the clinical crown height for adequate restoration. PMID- 24174741 TI - Use of collagen as a biomaterial: An update. AB - Biomaterial science is an expanding area, which encompasses a wide range of medical knowledge involving arthroplasty, cochlear implants, heart valves designing, lenses, dental fixation and tissue engineering. Within this context, in vitro cell culture on polymer scaffolds is one of the adopted strategies for tissue creation. It consists of a specific cell line that is seeded onto a particular substrate. This scaffold should provide excellent biocompatibility, controllable biodegradability, appropriate mechanical strength, flexibility as well as the ability to absorb body fluids for delivery of nutrients. Collagen certainly fulfils these demands; therefore, it is often chosen as a biomaterial. Moreover, this protein is abundant in the animal kingdom and plays a vital role in biological functions, such as tissue formation, cell attachment and proliferation. PMID- 24174742 TI - Microbial dysbiosis in periodontitis. AB - Periodontitis is a biofilm-associated inflammatory disease of the periodontium. This disease appears to have multiple etiologies with microbial factor contributing to initiation of the disease and immunological factor of the host propagating the disease. This review is on the concept of "microbial dysbiosis" and molecular nature of periodontitis, and the scope of traditional and emerging technologies for treating this disease. PMID- 24174743 TI - Implants in adolescents. AB - Implants have gained tremendous popularity as a treatment modality for replacement of missing teeth in adults. There is extensive research present on the use of implants in adults, but there is a dearth of data available on the same in adolescents. The treatment planning and execution of implant placement in adolescents is still in its infancy. This review article is an attempt to bring together available literature. PMID- 24174744 TI - State of the Journal: My thoughts on the past and the future. PMID- 24174745 TI - Light at the end of the tunnel. PMID- 24174746 TI - Periodontal Research: Basics and beyond - Part I (Defining the research problem, study design and levels of evidence). AB - Research in the field of periodontology has witnessed a tremendous upsurge in the last two decades unveiling newer innovations in techniques, methodologies, and material science. The recent focus in periodontal research is an evidence-based approach which offers a bridge from science to clinical practice. This three part review series intends to take a reader through a maze of periodontal research, unraveling and simplifying various issues in the design, conduct and interpretation of various study designs routinely used in the field of periodontal research. This understanding would facilitate a researcher with a focused and an enhanced vision toward formulating studies which can more efficiently translate sound scientific phenomena into clinically meaningful results. PMID- 24174747 TI - Periodontal Research: Basics and beyond - Part II (Ethical issues, sampling, outcome measures and bias). AB - A good research beginning refers to formulating a well-defined research question, developing a hypothesis and choosing an appropriate study design. The first part of the review series has discussed these issues in depth and this paper intends to throw light on other issues pertaining to the implementation of research. These include the various ethical norms and standards in human experimentation, the eligibility criteria for the participants, sampling methods and sample size calculation, various outcome measures that need to be defined and the biases that can be introduced in research. PMID- 24174748 TI - Periodontal Research: Basics and beyond - Part III (Data presentation, statistical testing, interpretation and writing of a report). AB - Statistical analysis is the backbone of research and however befuddling it is to a clinician, it is crucial for a researcher to understand the various assumptions underlying the statistical methods. This paper aims at simplifying the various statistical methods that are routinely used in periodontal research. Data presentation, the relevance of clinical as against statistical significance and writing of a report are also discussed. PMID- 24174749 TI - Bone morphogenetic proteins: The anomalous molecules. AB - Bone is unique of all the tissues in the vertebrate organism. When injured, it heals by formation of new bone. Bone morphogenetic proteins (BMPs) are powerful inductors of the osteogenic activity during the embryologic bone formation phase and in cases of bone healing. They have proliferative effects on different cellular types, showing chemotactic properties and are able to induce mesenchymal cells differentiation into osteoblastic and chondroblastic line cells. Both primary cells and cell lines have been shown to respond to BMPs. Further the ability of embryonic cells to respond to BMPs by differentiating into cartilage and bone cells suggests that they are involved in the development of embryonic skeletal system. In addition, these proteins can also promote the angiogenesis, regulate the activity of some growth factors, and affect the production of these growth factors, which is helpful for the osteogenesis. BMPs have been considered as the most potent growth factors that can promote the bone regeneration. Thus, the aim of this review is to emphasize on the unique nature of the BMP molecules regarding their structure, classification, signaling mechanism, etc., as BMPs are the only molecules which show such deviation from the normal order, type. This will further help in understanding the role of BMPs and their potential advances which are necessary to facilitate the process of regeneration in periodontics. PMID- 24174750 TI - Drug addiction and periodontal diseases. AB - The prevalence of drug addiction is increasing globally. Drug abuse damages many parts of the body such as oral cavity, lungs, liver, brain, heart etc., Addicts suffer from physical, psychological, emotional and behavioral problems. Their nutrition is also compromised. There is certainly an impact of all these factors on the health of periodontium. Dentists should be aware of the effects of drugs while treating the drug addicts. This article correlates the studies done on the impact of abused drugs such as alcohol, tobacco, opiates, cannabis, amphetamines etc., on general and periodontal health. PMID- 24174751 TI - Evaluation of thickness of cementum of periodontally diseased teeth of non diabetic and type 2 diabetic patients: A scanning electron microscopy study. AB - BACKGROUND: It is suggested that diabetes plays an important role in tooth loss. The periodontal structure and alveolar bone architecture in diabetics have revealed alterations. However, changes in cementum of diabetics with periodontal disease have not been evaluated adequately. Thus, the aim of the study is to evaluate and compare the thickness of cementum in diseased and healthy areas of roots of teeth with chronic periodontitis from non-diabetic (group I) and type 2 diabetic patients (group II). MATERIALS AND METHODS: Thirty incisors indicated for extraction as a result of chronic periodontitis from group I and group II were selected. Measurements of Probing Depth (PD) and Clinical Attachment Loss (CAL) were taken prior to extractions. Area of the root surface above the CAL (notch) was designated as diseased, while the area below the CAL (notch) was designated as healthy. The extracted tooth samples were sectioned longitudinally and were evaluated by scanning electron microscopy (SEM). Descriptive statistical analysis was performed. Results of continuous measurements were presented as Mean +/- SD. RESULTS: The results showed that in both groups the thickness of cementum in diseased areas was lower in comparison to the thickness in healthy areas. The mean thickness of cementum in both healthy and diseased areas was higher in group II compared to group I, though the differences in both were not statistically significant. CONCLUSION: Within the limits of the present study, group II showed greater mean thickness of cementum in both healthy and diseased areas compared to group I, though the differences were not statistically significant. PMID- 24174752 TI - Periodontal disease and type I diabetes mellitus: Associations with glycemic control and complications. AB - OBJECTIVE: The aim of the study was to evaluate periodontal health status in patients diagnosed with type 1 diabetes mellitus (DM1) and to establish a correlation between metabolic control and periodontal health status. MATERIALS AND METHODS: Periodontal health parameters namely plaque index (PI), gingival index (GI), probing pocket depth (PPD) and clinical attachment loss (CAL) were recorded in 28 patients diagnosed with type 1 diabetes mellitus (DM1) and 20 healthy controls. Diabetes history was recorded based on the information provided by the physician and it included date of diagnosis, duration, age of diagnosis, latest values of glycosylated haemoglobin and existing diabetic complications. Statistical analysis was performed to evaluate the relationship between periodontal parameters and degree of metabolic control, the duration of the disease and the appearance of complications. RESULTS: The periodontal health in the diabetic group was compromised and they had greater bleeding index (P < 0.001), probing pocket depth (P < 0.001) and clinical attachment level (P = 0.001). Patients diagnosed for diabetes for shorter duration of time (4-7 years) showed bleeding index-disease severity correlation to be 1.760 +/- 0.434. CONCLUSION: Periodontal disease was more evident in type 1 diabetes mellitus patients and periodontal inflammation is greatly increased in subjects with longer disease course, poor metabolic control and diabetic complications. PMID- 24174753 TI - Prevalence of enamel projections and its co-relation with furcation involvement in maxillary and mandibular molars: A study on dry skull. AB - BACKGROUND: The objectives of this study were to investigate the incidence of cervical enamel projection (CEP) in molars of Indian dry human skulls and to evaluate its relationship with furcation involvement (FI). MATERIALS AND METHODS: The material consisted of 944 upper and lower first, second and third permanent molars from 89 Indian dry human skulls. CEPs were investigated from the buccal aspect of the tooth and classified according to a system describeddescribed by Masters and Hoskins. FI was measured horizontally from the buccal aspect into the furcation with a graduated probe to the nearest millimeter. Any measurement >=2 mm was considered to have positive FI. RESULTS: The results showed that CEPs was found more frequently in the mandibular than in the maxillary molars (2:1). The highest incidence of CEP was found in the mandibular second molar (14.7%) followed by the maxillary second molar (14.6%). The mandibular third molar showed the lowest incidence (5.5%). The association between CEP and FI (87.5%) was statistically significant. This favors the view of the possible role played by such anomalies in the progression of periodontal diseases. CEP in male skulls (77.4%) was significantly more prevalent than in female skulls (20.4%). No significant difference was found between the right and left side of maxillary and mandibular teeth with CEP and FI. CONCLUSION: The findings suggested the role of CEPs as a local contributing factor in localized chronic periodontitis and FI in molars. Detailed examination as well as early diagnosis of periodontal disease at the region of furcation is clinically very important. PMID- 24174754 TI - Effect of controlled-release PeriochipTM on clinical and microbiological parameters in patients of chronic periodontitis. AB - BACKGROUND: The aim of the present study was to evaluate and compare the clinical and microbiological effectiveness of PeriochipTM as an adjunct to scaling and root planing (SRP) with SRP alone in patients with chronic periodontitis. MATERIALS AND METHODS: This randomized, split mouth, 3-month clinical and microbiological trial included 30 sites in 15 patients aged 30-50 years diagnosed with chronic periodontitis. In each patient, two bilateral pockets probing 5-7 mm were randomly assigned to test and control groups. The test group received SRP plus PeriochipTM, whereas the control group received SRP alone. Clinical indices and anaerobic culture analysis was done at baseline, 1 month, and 3 months interval. Total bacterial count and analysis of four major periodontopathogenic bacteria Porphyromonas gingivalis (Pg), Prevotella intermedia (Pi), Aggregatibacter actinomycetemcomitans (Aa), and Fusobacterium nucleatum (Fn) was done. RESULTS: Significant improvement was obtained in all clinical variables in the test group as compared to the control group over the study period. Total colony counts were significantly reduced in the test group as compared to control over the period of time. At baseline Aa was recovered from 4 test group sites and 5 control group sites, Pg from 15 test group and 14 control group sites, Pi from 5 test group and 2 control group sites, Fn from 7 test and 7 control group sites. At 3 months, Aa was recovered from 1 test group and 4 control group sites, Pg from 4 test group and 8 control group sites, Pi from 1 test group and 1 control group site, Fn from 3 test and 4 control group sites. CONCLUSION: PeriochipTM placement as an adjunct to SRP, showed promising results, when compared to SRP alone. Healthy microflora can be maintained for a longer period of time and delay in the repopulation by periodontopathic microorganisms was observed. PMID- 24174755 TI - Evaluation of hemodynamic and SpO2 variability during different stages of periodontal surgery. AB - BACKGROUND: Changes in pulse rate and blood pressure are common consequences during oral surgeries. Hypoxia during surgical process is another side effect. The objective of the present study was evaluation of blood hemoglobin oxygenation and hemodynamic changes during periodontal surgery. MATERIALS AND METHODS: This clinical trial study was conducted upon 50 subjects aged 30-55 years who referred to the clinic of dental faculty of Babol University and needed periodontal surgery with modified widman flaps in the anterior section of the maxilla. Pulse rate, blood pressure, and pulse oximetric evaluations were recorded in five stages during surgery. RESULTS: The average of systolic and diastolic blood pressure had been in their maximum amount in the second stage of evaluation and minimum amounts were in the first one; while pulse rate changes were greatest in the second stage and lowest in the fifth stage. Analyzing the data revealed no significant difference in Blood Oxygen Saturation (SpO2) measurements in none of the stages evaluated. CONCLUSIONS: Blood pressure and heart rate increased significantly after the injection of anesthetic drug and in further phases they were decreased after the elimination of stimulating effect of adrenaline. SpO2 changes were not significantly prominent. PMID- 24174756 TI - A clinical evaluation of a bioresorbable membrane and porous hydroxyapatite in the treatment of human molar class II furcations. AB - BACKGROUND: The ultimate goal of periodontal therapy is predictable regeneration of a functional attachment apparatus destroyed as a result of periodontitis. Reconstructive procedures have been used with varying success during the past decades to accomplish this goal. AIM: To evaluate whether the use of porous hydroxyapatite alone or a bioresorbable membrane alone would enhance the clinical results in the treatment of class II furcation defects in human lower molars. MATERIALS AND METHODS: Fifteen patients with chronic periodontitis, aged between 39 and 49 years, with a pair of similar bilateral class II furcation defects (classification of Hamp et al.) in mandibular first molars were selected. A split mouth design was incorporated and the selected 30 furcation defects were assigned to one of the two treatment groups, i.e., Group I treated with a bioresorbable membrane from bovine-derived collagen guided tissue regeneration membrane and Group II treated using porous hydroxyapatite bone graft material on the contralateral sides. Evaluation of clinical parameters, probing depths and attachment levels, and radiographs was done preoperatively and 6 months postoperatively. RESULTS: Both the groups showed statistically significant mean reduction in probing depths and gain in clinical attachment levels and linear bone fill. Comparison between Group I and Group II showed insignificant difference. CONCLUSION: Within the limits of this study, both the treatment modalities are beneficial for the treatment of human mandibular class II furcation defects. PMID- 24174757 TI - Clinical and radiographical evaluation of a bioresorbable collagen membrane of fish origin in the treatment of periodontal intrabony defects: A preliminary study. AB - BACKGROUND: Recently, there has been interest in non-mammalian collagen sources such as fish collagen in periodontal regeneration. In the present study, collagen barrier membrane of fish origin was assessed in the treatment of periodontal intrabony defects. MATERIALS AND METHODS: Ten systemically healthy chronic periodontitis patients having a paired osseous defect in the mandibular posterior teeth were selected and randomly assigned to receive a collagen membrane (test) or open flap debridement (control) in a split mouth design. Clinical parameters such as Plaque index, Gingival bleeding index, Probing pocket depth, Relative attachment level, and Recession were recorded at baseline, 3, 6, and at 9 months, while radiographic evaluation was done to assess alveolar crestal bone level and percentage of defect fill at 6 and 9 months using autoCAD 2007 software. Student's t test (two-tailed, dependent) was used to find the significance of study parameters on continuous scale. Significance was set at 5% level of significance. Wilcoxon signed rank test was used to find the significance of percentage change of defect fill. RESULTS: The comparison between the two groups did not show any statistically significant differences in the parameters assessed (P > 0.05) but, within each group, clinical parameters showed statistically significant differences from baseline to 9 months (P < 0.05). CONCLUSION: Within the limits of the study, it can be inferred that no significant differences were found either by using collagen membrane of fish origin or open flap debridement in the treatment of periodontal intrabony defects. PMID- 24174758 TI - A split mouth randomized controlled study to evaluate the adjunctive effect of platelet-rich fibrin to coronally advanced flap in Miller's class-I and II recession defects. AB - BACKGROUND: There are various techniques developed to treat the exposed roots, a recent innovation in dentistry is the use of second generation platelet concentrate which is an autologous platelet-rich fibrin gel (PRF) with growth factors and cicatricial properties for root coverage procedures. Therefore, the present research was undertaken to study the additional benefits of PRF when used along with coronally advanced flap (CAF). MATERIALS AND METHODS: Total of 15 systemically healthy subjects presenting bilateral isolated Miller's class I and II recession were enrolled into the study. Each patient was randomly treated with a combination of CAF along with a platelet-rich fibrin (PRF) membrane on the test site and CAF alone on the control site. Recession depth, clinical attachment level (CAL), and width of keratinized gingiva (WKG) were compared with baseline at 1, 3, and 6 months between test and control sites. RESULTS: Mean percentage root coverage in the test group after 1, 3, and 6 months was 34.58, 70.73, and 100, respectively. Differences between the control and test groups were statistically significant. This study also showed a statistically significant increase in WKG in the test group (2.94 +/- 0.77 at baseline to 5.38 +/- 1.67 at 6 months). CONCLUSION: CAF is a predictable treatment for isolated Miller's class I and II recession defects. The addition of PRF membrane with CAF provides superior root coverage with additional benefits of gain in CAL and WKG at 6 months postoperatively. PMID- 24174759 TI - 2D FEA of evaluation of micromovements and stresses at bone-implant interface in immediately loaded tapered implants in the posterior maxilla. AB - AIM: The aim of the study is to evaluate the influence implant length on stress distribution at bone implant interface in single immediately loaded implants when placed in D4 bone quality. MATERIALS AND METHODS: A 2-dimensional finite element models were developed to simulate two types of implant designs, standard 3.75 mm diameter tapered body implants of 6 and 10 mm lengths. The implants were placed in D4 bone quality with a cortical bone thickness of 0.5 mm. The implant design incorporated microthreads at the crestal part and the rest of the implant body incorporated Acme threads. The Acme thread form has a 29 degrees thread angle with a thread height half of the pitch; the apex and valley are flat. A 100 N of force was applied vertically and in the oblique direction (at an angle of 45 degrees ) to the long axis of the implants. The respective material properties were assigned. Micro-movements and stresses at the bone implant interface were evaluated. RESULTS: The results of total deformation (micro-movement) and Von mises stress were found to be lower for tapered long implant (10 mm) than short implant (6 mm) while using both vertical as well as oblique loading. CONCLUSION: Short implants can be successfully placed in poor bone quality under immediate loading protocol. The novel approach of the combination of microthreads at the crestal portion and acme threads for body portion of implant fixture gave promising results. PMID- 24174760 TI - Sinus lift tissue engineering using autologous pulp micro-grafts: A case report of bone density evaluation. AB - BACKGROUND: Although autografts are the standard procedure for bone grafting, the use of bone regeneration by means of dental pulp stem cell is an alternative that opens a new era in this field. Rigenera Protocol is a new technique able to provide the surgeon autologous pulp micro-grafts. MATERIALS AND METHODS: At the Department of Oral Surgery, Don Orione Hospital, Bergamo, Italy, one patient underwent sinus lift elevation with pulp stem micro-grafts gentle poured onto collagen sponge. A CT scan control was performed after 4 months and DICOM data were processed with medical imaging software which gives the possibility to use a virtual probe to extract the bone density. Pearson's Chi-square test was used to investigate difference in bone density (BD) between native and newly formed bone. RESULTS: BD in newly formed bone is about the double of native bone. CONCLUSION: This report demonstrated that micro-grafts derived from dental pulp poured onto collagen sponge are a useful method for bone regeneration in atrophic maxilla. PMID- 24174761 TI - Multicentric peripheral ossifying fibroma: A case report and review of the literature. AB - A peripheral cement-ossifying fibroma is a benign fibro-osseous lesion of a reactive rather than a neoplastic nature, whose pathogenesis is uncertain. It predominantly affects adolescents and young adults, with the peak prevalence between 10 and 19 years, especially affecting females (two to four times more). Such lesions are commonly found on the maxillary bone. We hereby present and discuss a unique case of multicentric Peripheral Ossifying Fibroma (POF) affecting both the maxillary and the mandibular gingiva in an 11-year-old boy, with a disease duration of two months. This case is probably one of the first few cases discovered, which demonstrates that there may be a multicentric variant of the Peripheral Ossifying Fibroma. The purpose of this article is to present a case of POF and to briefly review the current literature on this condition. PMID- 24174762 TI - Peripheral odontogenic myxoma of maxillary gingiva: A rare clinical entity. AB - Odontogenic myxoma comprises 3-6% of all odontogenic tumors. Odontogenic myxomas are relatively rare benign mesenchymal tumors found exclusively in the tooth bearing areas of the jaw and are usually located centrally in the mandible. Soft tissue localization is rarely seen and is classified as peripheral myxoma. Peripheral myxoma is slow growing and less aggressive, as compared to the central myxoma. It has a low recurrence rate. Till date, only few cases of maxillary gingival myxomas are reported in the literature. Here, we present an unusual case of primary peripheral odontogenic myxoma occurring in the gingiva of anterior maxilla in a 41-year-old female patient. PMID- 24174763 TI - An unusual clinical presentation of gingival melanoacanthoma. AB - Gingival melanoacanthoma is a rare, benign pigmented lesion characterized clinically by sudden onset and rapid growth of a macular brown black lesion and histologically by acanthosis of superficial epithelium and proliferation of dendritic melanocytes. This article reports a previously undescribed case of pigmented unilateral diffuse gingival enlargement, which on histopathological examination proved to be melanoacanthoma. Intraoral examination revealed pigmented unilateral diffuse gingival enlargement in relation to second and third quadrants buccally, palatally/lingually. Based on these clinical findings, gingivectomy was performed and the excised tissue was sent for biopsy. Microscopic examination revealed acanthotic and parakeratotic surface epithelium with dendritic melanocytes distributed in basal and suprabasal layers of the epithelium. 1 year follow-up recall revealed no recurrence of lesion at the surgical sites. Our patient exhibits an unusual clinical presentation of melanoacanthoma of gingiva. Pigmented gingival overgrowth of recent origin and without any etiologic factors warrants histopathologic examination. PMID- 24174764 TI - Six year follow-up of a root coverage procedure on a lower molar tooth with lateral pedicle flap. AB - Loss of periodontal attachment and subsequent recession is one of the most common deformities that affects the periodontium. Gingival recession is a muco-gingival defect, which is commonly treated for esthetic and physiologic reasons. Adequate thickness of attached gingiva and root coverage is essential in restored teeth for proper masticatory function as well as for oral hygiene maintenance. Various root coverage procedures Nill have been proposed to correct recession defects, including coronally advanced flap and lateral pedicle flap (LPF). A case report is presented dealing with the treatment of a gingival recession on a mandibular molar tooth using LPF with a 6-year follow-up. PMID- 24174765 TI - Intentional replantation of periodontally compromised hopeless tooth. AB - Aesthetic considerations have influenced the management of dental maladies in varying degrees for many years. Even single tooth mal-alignment makes the patient to approach a dentist. Intentional replantation is a procedure in which an intentional tooth extraction is performed followed by reinsertion of the extracted tooth. Many authors agree that it should be reserved as the last resort to save a tooth after other procedures have failed or would likely to fail. The main reason of failure in replanted teeth is root resorption, specifically ankylosis or replacement resorption. Although the success rate is not always high, intentional replantation may be a treatment alternative that deserves consideration to maintain the natural dentition and avoid extraction of the tooth. Here is case report of a patient desiring alignment of malpositioned periodontally involved anterior single tooth due to various causes treated by intentional replantation. PMID- 24174766 TI - Management of chronic luxated central incisor with hopeless prognosis. AB - Traumatic injuries are the most studied yet most challenging for a dentist. Extrusive luxation injuries are usually managed by repositioning tooth in the original position and pulp sensibility is evaluated at regular periodic intervals. However, when injuries are chronic, tooth is necrotic with compromised periodontal support, treatment is a challenge. Intentional replantation utilizing growth factors in fibrin rich network of platelet rich fibrin can be a treatment modality in such patients where other restorative modalities to establish function-esthetics rehabilitation is not possible. PMID- 24174767 TI - Modified single incision technique to harvest subepithelial connective tissue graft. AB - Dental therapy in general and periodontal therapy in particular is directed increasingly at the esthetic outcome for patients. Gingival recession is one of the most common esthetic concerns associated with periodontal tissues. Although various treatment modalities have been developed, subepithelial connective tissue grafting remains the most successful and predictable technique for treatment of gingival recession. Harvesting a connective tissue graft from the palate is many times not only traumatic, but also very painful for the patient. Use of single incision to harvest the subepithelial connective tissue graft is one of the least traumatic, but relatively difficult technique to accomplish. This article presents a modified single incision technique, which is not only less traumatic and painful, but comparatively simple to employ and master. Two new instruments have been introduced to make harvesting of the connective tissue graft easier. PMID- 24174768 TI - Platform switching: A panacea for bone loss?? AB - The goal of modern implant therapy entails more than just the successful osseointegration of the implant. A successful result must also include an esthetic and functional restoration surrounded by stable peri-implant tissue levels that are in harmony with the existing dentition. In an attempt to improve long-term bone maintenance around implants, a new implant-to abutment connection referred to as "platform switching" has been proposed. It refers to the use of an abutment of smaller diameter connected to an implant neck of larger diameter. Platform switching is a simple and effective way to control circumferential bone loss around dental implants. This short communication aims to present an overview of concept of platform switching in dental implantology. PMID- 24174769 TI - Global cancer disparity highlighted. PMID- 24174770 TI - Commentary. PMID- 24174771 TI - Self-limiting symptomatic peri-ictal bradyarryhthmia due to junctional AV rhythm. AB - We report an elderly man with chronic uncontrolled localization-related epilepsy on three AEDs, who developed in-hospital symptomatic bradyarrythmia due to junctional atrio-ventricular (AV) rhythm after an episode of generalized seizure during his hospital stay. On further evaluation, the cardiac enzymes were normal and 2D-echocardiogram showed mild left ventricular hypertrophy. Patient recovered from the same with supportive treatment within few hours. We emphasize on importance of prompt recognition of this event and its implication including one of the mechanism for sudden unexplained death in epilepsy. PMID- 24174772 TI - The role of lumbar puncture and pressure-lowering therapy for transverse dural sinus thrombosis. AB - Transverse (lateral) sinus thrombosis is a well-known complication of acute otitis media and mastoiditis in the pediatric and adult population. Thrombosis involving the transverse sinus can ultimately cause elevation of intracranial pressure (ICP) as a result of decreased cerebrospinal fluid absorption. If treatment to lower ICP is not undertaken, it can lead to ophthalmological complications including irreversible vision loss. The following case report describes an 11-year-old girl who was diagnosed with AOM by her pediatrician and subsequently presented to the emergency department complaining of nausea, vomiting, headache, and diplopia. PMID- 24174773 TI - Occult spontaneous lateral intrasphenoidal encephalocele: A rare presentation. AB - Basal encephaloceles are extremely rare congenital malformations. Advanced cross sectional imaging modalities like computed tomography and magnetic resonance imaging are necessary for diagnosing the asymptomatic, occult basal encephalocele and planning the surgical approach. We present an interesting case of clinically silent right-sided lateral intrasphenoidal encephalocele through a large bony defect. PMID- 24174774 TI - Clinical importance of neuroimaging in epilepsy. PMID- 24174775 TI - Commentary. PMID- 24174776 TI - Giant cavernous carotid aneurysm with spontaneous ipsilateral ICA occlusion: Report of 2 cases and review of literature. AB - Giant aneurysms of the cavernous carotid artery are rare entities which present predominantly with features of compression of the adjacent neural structures, most commonly the III, IV, VI and V cranial nerves. Historically, treatment options included occlusion of the feeding vessel, direct surgery on the aneurysm, bypass procedures and in recent times, the use of endovascular devices. While intramural thrombus formation is commonly seen in giant aneurysms, we present 2 cases of giant cavernous aneurysms which on evaluation were found to have spontaneous occlusion of the feeding internal carotid artery secondary to thrombus formation, and review the available literature regarding the same. PMID- 24174777 TI - Isolated cysticercosis of the cauda equina. AB - Cysticercosis is the most common parasitic infection of the central nervous system. It is an endemic condition in developing countries, but the incidence rate is increasing in developed countries as well because of rising immigration. Spinal involvement is quite rare and it is usually associated with concomitant intracranial infective lesions. We present an unusual case of a 44-year-old woman who experienced a cauda equina syndrome. Magnetic resonance imaging disclosed two intradural cystic lesions at L4-L5 level. Only after histological examination the diagnosis of cysticercosis was definitively determined. The entire neuraxis evaluation confirmed that it was a rare form of isolated intradural racemosus type cysticercosis of the cauda equina. Steroids and albendazole were administered and post-operative course was uneventful. In this paper we discuss clinical, pathogenic and therapeutic aspects of this infective pathology. PMID- 24174778 TI - Commentary. PMID- 24174779 TI - Fourth ventricular ependymoma with a distant intraventricular metastasis: Report of a rare case. AB - Ependymoma is one of the uncommon tumors of the central nervous system (CNS) in the adult age group. These tumors have a distinct propensity for metastasis, both within and outside the CNS. However, dissemination at the time of first presentation and retrograde dissemination of the tumor is rare. We report the case of a patient with fourth ventricular anaplastic ependymoma who presented with left lateral ventricular metastasis which was anatomically different from the primary tumor. We describe the clinic-pathological detail of the patient and discuss the probable pathophysiological basis for this rare presentation and its significance in management of the patient. PMID- 24174780 TI - Intra cranial hydatid cyst: A case report of total cyst extirpation and review of surgical technique. AB - Hydatid cysts commonly affect liver and lung but it can also affect the brain in rare cases. We report a case of 22 year female with history of headache for one and half years. Intracranial hydatid cyst was diagnosed on computed tomography scan and magnetic resonance imaging. The cyst was delivered without rupture using hydrostatic dissection followed by post-operative anthelminthic medication. Surgery remains to be the standard management. Amongst the surgical techniques described, Dowling's technique is the most acceptable. However, care must be taken in to avoid rupture of the cyst peroperatively which can result in subsequent complications and recurrence. Albendazole and corticosteroids can be used as adjunct to surgical treatment in selective cases. PMID- 24174781 TI - Commentary. PMID- 24174782 TI - Association between anxiety and obesity: A study of a young-adult Nigerian population. AB - BACKGROUND: The relationship between anxiety and obesity is still debatable and seems to vary between cultures. The subject has been scarcely investigated in Nigeria, hence this study. MATERIALS AND METHODS: A total of 1584 young-adult Nigerians (56.4% males) of mean age 21.8 +/- 2.2 years were studied. Anxiety was assessed using the Beck's Anxiety Index (BAI), while obesity was determined using the bioelectrical impedance analysis (BIA) and body mass index (BMI) methods. Standard protocols were followed for all assessments and measurements. Appropriate descriptive statistics were carried out, while regression and correlation analyses (for continuous variables) and the Chi square tests (for categorical variables) were used to assess the relationship between anxiety and obesity. RESULTS: The degree of adiposity of the subjects (males and females alike) classified by %BF standards did not significantly (P > 0.05) affect the proportion of the population with any degree of anxiety. The proportion of population with high anxiety (for both sexes) was similar (P > 0.05) irrespective of their BMI status. All the obese (BMI-wise only) males had low anxiety, while the proportion of thin females (in the low anxiety group) was significantly (P < 0.05) higher than that of their normal weight counterparts. There was neither a significant correlation nor a significant association (P > 0.05) between the BAI scores and the studied measures of adiposity in both male and female subjects. CONCLUSION: The low prevalence of both anxiety and obesity in the studied population may explain the observed lack of association between the studied variables. These findings do not support the "jolly fat" hypothesis. PMID- 24174783 TI - Organizational issues in stroke treatment: The Swiss paradigm - Stroke units. AB - Stroke represents the leading cause of acquired disability in adults and poses a tremendous socioeconomic burden both on patients and the society. In this sense, prompt diagnosis and urgent treatment are needed in order to radically reduce the devastating consequences of this disease. Herein the authors present the new guidelines recently adopted by the Swiss Stroke Society concerning the establishment of stroke units. Standardized treatment and allocation protocols along with an acute rehabilitation concept seem to be the core of the Swiss stroke management system. Coordinated multidisciplinary care provided by specialized medical, nursing and therapy staff is of utmost importance for achieving a significant dependency and death reduction. It is believed that the implementation of these guidelines in the stroke care system would be beneficial not only for the stroke patients, but also for the health system. PMID- 24174784 TI - Cerebral aspergillosis and acute myeloid leukemia. PMID- 24174785 TI - Fulminant post-craniotomy wound infection and meningitis with pneumocephalus caused by Acinetobacter baumannii: An unusual presentation. PMID- 24174786 TI - Prevalence of depression in community dwelling elderly: Study from rural population of India. PMID- 24174787 TI - Post traumatic tubercular osteomyelitis of skull vault. PMID- 24174788 TI - Optic pathway glioma, scoliosis, Chiari type 1 malformation, and syringomyelia in a patient with neurofibromatosis type 1. PMID- 24174789 TI - Abnormal pattern visual evoked response in carotid-cavernous fistula. PMID- 24174790 TI - Extradural hematoma in Plasmodium vivax malaria: Are we alert to detect? PMID- 24174791 TI - Commentary. PMID- 24174792 TI - Endovascular balloon-assisted glue embolization of intranidal high flow fistula in brain AVM. PMID- 24174793 TI - Acute stress-related psychological impact in children following devastating natural disaster, the Sikkim earthquake (2011), India. AB - BACKGROUND: Psychological stress following natural disaster is common. Despite several earthquakes in India, data on evaluation of acute stress among the child victims in the early postdisaster period is scarce. Immediately following a devastating earthquake (6.9 Richter) at Sikkim on September, 18 2011, many children attended North Bengal Medical College, the nearest government tertiary care institution, with unusual stress symptoms. OBJECTIVE: Evaluation of acute stress symptoms in children in the immediate postearthquake period. MATERIALS AND METHODS: This was a cross-sectional study done over 4 weeks and includes all the children from 1 to 12 years presenting with unusual physical or behavioral symptoms. Those with major injuries requiring admission were excluded. They were divided into two age groups. For older children (8-12 years) the 8-item Children Impact of Event Scale (CIES) was used for screening of stress. Unusual symptoms were recorded in younger children (1-8 years) as CIES is not validated < 8 years. RESULT: A total of 84 children (2.66%) out of 3154 had stress symptoms. Maximum attendance was noted in first 3 days (65.47%) and declined gradually. In children >= 8 years, 48.78% had psychological stress, which was statistically significant on CIES scores without any gender predilection. Static posturing (41.86%), sleeplessness (32.55%), anorexia (9.30%), recurrent vomiting (13.95%), excessive crying (13.95%), or night-awakenings (4.65%) were found in younger children (n = 43) and three required admission. CONCLUSION: This study represent the first Indian data showing statistically significant psychological impact in older children (8-12 years) and various forms of physical stress symptoms in young children (1-8 years) following earthquake. PMID- 24174795 TI - Glioblastoma multiforme: A bigger challenge in resource-limited countries. PMID- 24174794 TI - Identifying elders with neuropsychiatric problems in a clinical setting. AB - OBJECTIVE: Multiple health problems among the elderly necessitate a comprehensive enquiry to detect problems early and also initiate treatment. We utilized available validated instruments to comprehensively identify older persons with neuro-psychiatric problems including dementia and comorbid medical ailments in the screening desk of the geriatric clinic. MATERIALS AND METHODS: Individuals aged 60 years and above seeking outpatient care at NIMHANS during a 2-year period (October 2008-September 2010) participated. We used General Health Questionnaire (12-item), AD8, questions to identify psychoses and neurological problems and a checklist of common medical ailments. A probable clinical diagnosis was made at the end by medical personnel based on ICD-10. RESULTS: A total of 5,260 individuals were screened and more than one-third (36.7%) were women. About 50% had psychological distress (>=2 on GHQ-12), 20.1% had probable cognitive impairment (>=2 on AD8) and about 17% had symptoms suggestive of psychoses (>=1 on Psychoses screener). More than 65% had either a neurological or neurosurgical problems (>=1 on Neurological screener) and headache was the commonest complaint. At probable diagnosis, more than 50% had a neurological problem and over 30% had psychiatric disorders. Of these the most common psychiatric illnesses were psychotic disorders (22.0%), mood disorders (21.4%) and dementia (14.4%). The most common medical comorbidity included hypertension (36.4%), visual impairment (31.8%) and joint pains (30.5%). Nearly 80% had one or more medical comorbidity in addition to psychiatric illness. The overall set of instruments took about 15 20 minutes. It systematically and comprehensively guided in evaluating the elderly for neuropsychiatric problems and hence was collated to constitute the Instruments for Comprehensive Evaluation of the Elderly (ICE-E). CONCLUSIONS: ICE E was brief, easy to administer and improved decision making even by personnel from a non-medical background. The instrument aided in systematically detecting neuro-psychiatric problems among the elderly (including psychological distress and cognitive changes) and other medical comorbidities. PMID- 24174796 TI - Decrease in white blood cell counts after thiopentone barbiturate therapy for refractory intracranial hypertension: A common complication. AB - BACKGROUND: Leucopenia has been reported after induction of thiopentone barbiturate therapy for refractory intracranial hypertension. However, the incidence and characterisitics are not well described. AIMS: We performed a retrospective review to describe the incidence and characteristics of leucopenia after induction of thiopentone barbiturate therapy. SETTING AND DESIGN: Our centre is a national referral centre for neurotrauma and surgery in a tertiary medical institution. MATERIALS AND METHODS: We performed a retrospective review of all patients who received thiopentone barbiturate therapy for refractory intracranial hypertension during an 18 month period from January 2004 to June 2005 in our neurosurgical intensive care unit. STATISTICAL ANALYSIS USED: Statistical analysis was performed using SPSS version 15.0. All data are reported as mean +/- standard deviation or median (interquartile range). The Chi square test was used to analyze categorical data and student t test done for comparison of means. For paired data, the paired t-test was used. RESULTS: Thirty eight (80.9%) out of 47 patients developed a decrease in white blood cell (WBC) count after induction of thiopentone barbiturate coma. The mean decrease in WBC from baseline to the nadir was 6.4 * 10(9)/L (P < 0.001) and occurred 57 (3-147) h after induction. The mean nadir WBC was 8.6 +/- 3.6 * 10(9)/L. Three (6.4%) patients were leucopenic, with a WBC count of 2.8, 3.1, and 3.6 * 10(9)/L. None of them were neutropenic. We did not find an association between decrease in WBC count and clinical diagnosis of infection. We did not find any association between possible risk factors such as admission GCS, maximum ICP prior to induction of barbiturate coma, APACHE II score, total duration and dose of thiopentone given, and decrease in WBC count. CONCLUSIONS: Decrease in WBC count is common, while development of leucopenia is rare after thiopentone barbiturate coma. Regular monitoring of WBC counts is recommended. PMID- 24174797 TI - Value of neuroimaging in epilepsy: An experience from Pakistan. AB - PURPOSE: To detect the possible structural brain lesions in the patients suffering from various kinds of epilepsy during the routine neuroimaging. MATERIALS AND METHODS: Prospective study of 366 epileptic patients conducted at epilepsy clinic, Rawalpindi-Islamabad Pakistan in an outpatient setting. MRI or CT scan of the brain without contrast was advised in all patients to detect any underlying pathology. RESULTS: A total 21.31% scans were found to be abnormal. Many cases of familial, idiopathic epilepsy and patients without any neurological deficit were found to have structural brain lesions, which might be responsible for their seizures. CONCLUSION: CT/MRI scan of the brain should be advised in all patients of epilepsy regardless of cause and type of epilepsy. The presence of neurological deficit should not be the sole indication for neuroimaging. PMID- 24174798 TI - Elementary school enrolment and its determinants among children with cerebral palsy in Thiruvananthapuram district, Kerala, India. AB - CONTEXT: There is enough documented evidence to prove the benefits of early and appropriate initiation of education among children with cerebral palsy (CP). AIM: To find out the proportion of children with CP who are enrolled for some kind of formal education and to study the determinants of the same. SETTING AND DESIGN: This cross sectional study was done among children, attending the special clinics at government medical college, Thiruvananthapuram. MATERIALS AND METHODS: Children between 3 and 12 years of age diagnosed with CP were subjects for the study. STATISTICAL ANALYSIS USED: Enrollment for any form of formal education was the major outcome variable. The factors associated with initiation of formal education were tested using Chi-square test or Fischer's exact test. Independent association of each factor was evaluated through binary logistic Regression analysis. RESULTS AND CONCLUSIONS: The mean (SD) age of the children (n = 86) was 5.7 (2.3) years with forty-six (53.5%) of them being girls. Diplegia was the commonest limb abnormality found. Fifty-two (60.5%) children were undergoing some kind of schooling. Those children who were less dependent physically and those who had achieved better language development were regular school goers. After binary logistic regression the ability of a child to speak in sentences (P = 0.008) and ambulatory level of the child (P = 0.019) were factors which favored, whereas delay in attaining the adaptive developmental milestone of transferring objects from one hand to another (P = 0.014) was found to be detrimental for school enrollment. PMID- 24174799 TI - Commentary. PMID- 24174800 TI - Evaluation of outcome and prognostic factors in patients of glioblastoma multiforme: A single institution experience. AB - AIMS: We present retrospective analysis of patients of glioblastoma multiforme (GBM) and discuss clinical characteristics, various treatment protocols, survival outcomes, and prognostic factors influencing survival. MATERIALS AND METHODS: From January 2002 to June 2009, 439 patients of GBM were registered in our department. The median age of patients was 50 years, 66.1% were males, and 75% underwent complete or near-total excision. We evaluated those 360 patients who received radiotherapy (RT). Radiotherapy schedule was selected depending upon pre RT Karnofsky Performance Status (KPS). Patients with KPS < 70 (Group I, n = 48) were planned for RT dose of 30-35 Gy in 10-15 fractions, and patients with KPS >= 70 (Group II, n = 312) were planned for 60 Gy in 30 fractions. In group I, six patients and in group II, 89 patients received some form of chemotherapy (lomustine or temozolomide). STATISTICAL ANALYSIS USED: Statistical analysis was done using Statistical Package for Social Sciences, version 12.0. Overall survival (OS) was calculated using Kaplan-Meier method, and prognostic factors were determined by log rank test. The Cox proportional hazards model was used for multivariate analysis. RESULTS: The median follow-up was 7.53 months. The median and 2-year survival rates were 6.33 months and 2.24% for group I and 7.97 months and 8.21% for group II patients, respectively (P = 0.001). In multivariate analysis, site of tumor (central vs. others; P = 0.006), location of tumor (parietal lobe vs. others; P = 0.003), RT dose (<60 Gy vs. 60 Gy; P = 0.0001), and use of some form of chemotherapy (P = 0.0001) were independent prognostic factors for survival. CONCLUSIONS: In patients with GBM, OS and prognosis remains dismal. Whenever possible, we should use concurrent and/or adjuvant chemotherapy to maximize the benefits of post-operative radiotherapy. Patients with poor performance status may be considered for hypofractionated RT schedules, which have similar median survival rates as conventional RT. PMID- 24174801 TI - What are the predictors of quality of life of people with epilepsy? PMID- 24174802 TI - Factors associated with death and predictors of one-month mortality from stroke in Kano, Northwestern Nigeria. AB - BACKGROUND: In resource-poor setting, identification of predictors of death is of paramount importance for clinicians, so that specific therapies and management strategies can be applied to patients at high risk of dying. This study aims to determine the factors associated with death and predictors of in-patient mortality for stroke among a cohort of stroke patients in two tertiary centers in Northwestern Nigeria. MATERIALS AND METHODS: This was a prospective study of consecutive patients with acute stroke who were admitted to tertiary hospitals in northwestern Nigeria. A single observer, using pre-defined diagnostic criteria, recorded the information of interest including length of stay, outcome (dead or alive all through 30 days), time of death. RESULT: A total of 273 patients comprising 179 male and 94 female stroke patients were recruited. One hundred and seventy-four (63.7%) had infarctive stroke while 99 (36.3%) had hemorrhagic stroke (91 intracerebral and 8 sub-arachnoid hemorrhage). One-month mortality was 37%, and the majority was patients with hemorrhagic stroke (69.6%). About two third (74.5%) of the mortalities occurred during the first week of the event. Logistic regression showed that severe systolic blood pressure, severe diastolic pressure, second or more episode of stroke, severe GCS, seizures, abnormal pupillary size, hemorrhagic stroke type, presence of aspiration pneumonitis, RBS > 200 mg/dl were independent predictors of mortality in stroke. CONCLUSION: The present study provides information on factors associated with death in stroke. GCS < 8, seizures, abnormal pupillary size, hemorrhagic stroke, aspiration pneumonitis were independent predictors of mortality. PMID- 24174803 TI - Determinants of quality of life among people with epilepsy attending a secondary care rural hospital in south India. AB - CONTEXT: Epilepsy is associated with profound physical, psychological, and social consequences. AIMS: To assess the quality of life (QOL) among people with epilepsy attending the outpatient department of a secondary care hospital and to determine the various social and demographic factors affecting it. MATERIALS AND METHODS: The QOL of 100 people with epilepsy attending the outpatient department of a community-based secondary care hospital was assessed using the WHOQOL-BREF (WHOQOL: World Health Organization QOL) questionnaire. Univariate analysis and logistic regression was done to determine the factors associated with poor QOL. RESULTS: The QOL scores for all the domains ranged between 15.7 and 74.55 with a mean score of 51.49 [standard deviation (SD) 12.3]. The mean scores in the physical, psychological, social, and environmental domains were 55.7, 37.92, 57.75, and 50.56, respectively. Age more than 30 years [odds ratio (OR): 4.33, 95% confidence interval (CI): 1.73-10.82], female gender (OR: 2.90, 95% CI: 1.16 7.28), and currently married (OR: 3.82, 95% CI: 1.21-12.11) were the factors significantly associated with lower QOL scores. CONCLUSIONS: The QOL among people with epilepsy was lower in the psychological domain. Age more than 30 years, female gender, and being married were identified as the factors associated with poor QOL scores among people with seizure disorders. PMID- 24174805 TI - Brain abscess: Awareness make a difference. PMID- 24174806 TI - Commentary. PMID- 24174804 TI - Brain abscess: Current management. AB - Brain abscess (BA) is defined as a focal infection within the brain parenchyma, which starts as a localized area of cerebritis, which is subsequently converted into a collection of pus within a well-vascularized capsule. BA must be differentiated from parameningeal infections, including epidural abscess and subdural empyema. The BA is a challenge for the neurosurgeon because it is needed good clinical, pharmacological, and surgical skills for providing good clinical outcomes and prognosis to BA patients. Considered an infrequent brain infection, BA could be a devastator entity that easily left the patient into dead. The aim of this work is to review the current concepts regarding epidemiology, pathophysiology, etiology, clinical presentation, diagnosis, and management of BA. PMID- 24174807 TI - Primary malignant peripheral nerve sheath tumor at unusual location. AB - Malignant peripheral nerve sheath tumor (MPNST) is a rare soft tissue sarcoma. Most arise in association with major nerve trunks. Their most common anatomical sites are the proximal portions of the upper and lower extremities and the trunk. MPNSTs have rarely been reported in literature to occur in other unusual body parts. We review all such cases reported till now in terms of site of origin, surgical treatment, adjuvant therapy and outcome and shortly describe our experience with two of these cases. Both of our case presented with lump at unusual sites resembling neurofibroma, one at orbitotemporal area and other in the paraspinal region with characteristic feature of neurofibroma with the exception that both had very short history of progression. They underwent gross total removal of the tumor with adjuvant radiotherapy postoperatively. At 6-month follow-up both are doing well with no evidence of recurrence. PMID- 24174808 TI - Cerebrotendinous Xanthomatosis: Report of two cases and a novel genetic mutation in an Indian patient. AB - Cerebrotendinous Xanthomatosis (CTX) is an autosomal recessive disorder of bile acid metabolism manifesting typically with the triad of neurological dysfunction, tendon xanthoma, and early onset cataract. The diagnosis is often missed and delayed as the patients do not manifest all the classical features. Early recognition and initiation of chenodeoxycholic acid therapy with Hydoxymethylglutaryl Coenzyme-A (HMG-Co-A) inhibitors is critical to prevent irreversible neurological damage and permanently disabled existence. We report about two patients, both of whom remained undiagnosed for more than 20 years. Genetic analysis in one of the patients revealed a novel genetic mutation in one of the homologous genes. The patient was found to have heterozygous mutation of CTX gene with a novel mutation in exon 1 of CYP27A1 gene. PMID- 24174809 TI - Development of screening batteries for neuropsychiatric comorbidity in elderly. PMID- 24174810 TI - REM sleep behavior disorder in Parkinson's disease: A case from India confirmed with polysomnographic data. AB - Rapid eye movement (REM) sleep behavior disorder is a condition characterized by dream enactment. This condition may accompany neurodegenerative disorders. However, only a few reports from India are available, that too, without any polysomnographic evidence. We are reporting a case of REM sleep behavior disorder with polysomnographic evidence. PMID- 24174811 TI - Chordoma of skull base presenting as nasopharyngeal mass. AB - While the nasopharynx is most commonly regarded by the otolaryngologist as a primary site of neoplastic involvement, it is also an avenue of spread of base-of the-skull tumors presenting as bulging nasopharyngeal masses. Chordoma is a relatively rare tumor of the skull base and sacrum thought to originate from embryonic remnants of the notochord. Chordomas arising from the skull base/clivus are typically locally aggressive with lytic bone destruction. The optimal treatment may be photon/proton radiotherapy alone or combined with a gross total resection, when feasible. We report a case of intracranial chordoma presenting as nasopharyngeal mass. PMID- 24174812 TI - Commentary. PMID- 24174813 TI - Extracranially located PICA aneurysm presenting with supratentorial IVH: A rare event with diagnostic pitfalls. AB - Extracranially located posterior inferior cerebellar artery (PICA) aneurysms are rare with only 21 cases reported till date. They may arise either from the proximal segment of an extracranially originating PICA or from the tip of its caudal loop when it dips below the foramen magnum. A 16-year-old female presenting with sudden onset severe headache and intraventricular hemorrhage (IVH) in the occipital horns of the lateral ventricle and the fourth ventricles, was diagnosed to have an extracranial proximal segment PICA aneurysm on a four vessel digital subtraction angiography (DSA), after initially missing it on the brain magnetic resonance imaging (MRI) with angiogram (MRA) because of its extracranial location. During surgery, the aneurysm was clipped following a far lateral suboccipital craniectomy with C1-C2 hemilaminectomy. The patient showed good recovery. Thus, we emphasize the need for a dedicated four vessel angiography to diagnose such lesions. PMID- 24174814 TI - Antioxidant and toxicological evaluation of Cassia sopherain streptozotocin induced diabetic Wistar rats. AB - BACKGROUND: Multiple-organ failure is the main cause of death in diabetes mellitus (DM). Hyperglycemia-induced oxidative stress is responsible for major diabetic complications, including multiple-organ failure. Medicinal plants possessing antioxidant activity may reduce oxidative stress and improve the functions of various organs affected by hyperglycemia. OBJECTIVES: This study was designed to evaluate the antioxidant effect of Aqueous Extract of Cassia sophera (AECS) in streptozotocin (STZ)-induced diabetic Wistar rats. MATERIALS AND METHODS: AECS (200 mg/kg body weight (bw)) and the standard antidiabetic drug glibenclamide (10 mg/kgbw) were administered orally by gavaging for 28 days. RESULTS: Oral administration of AECS inhibited STZ-induced increase in lipid peroxidation (LPO), aspartate transaminase (AST), alanine transaminase (ALT), alkaline phosphatase (ALP), bilirubin, creatinine and urea in liver of diabetic rats. Significant increase in activity of superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GPx), and a reduced level of glutathione (GSH), were observed in the liver, kidney, pancreas and testis on AECS treatment. CONCLUSION: The results demonstrate that AECS is not only useful in controlling blood glucose, but also has antioxidant potential to protect the liver, kidney, pancreas and testis against damage caused by hyperglycemia-induced oxidative stress. PMID- 24174815 TI - Antinociceptive, anti-inflammatory, antimicrobial and central nervous system depressant activities of ethanolic extract of leaves and roots of Gomphostemma parviflorum var. parviflorum wall. AB - BACKGROUND: Gomphostemma parviflorum (Lamiaceae) is a medicinal plant of Bangladesh which has been used traditionally in the treatment of painful and inflammatory conditions such as asthma, headache, fever, etc. OBJECTIVE: To investigate the antinociceptive, anti-inflammatory, central nervous system (CNS) depressant and antimicrobial activities of ethanolic extracts of leaves (GPLE) and roots (GPRE) of the plant. MATERIALS AND METHODS: The antinociceptive potentials of the extracts were studied using acetic acid-induced writhing test in mice, anti-inflammatory activity was investigated using carrageenan-induced paw edema in rats, CNS depressant activities were evaluated using pentobarbitone induced sleeping time, Hole cross and Open field tests in mice while the anti microbial activity was studied by in vitro disc diffusion method. RESULTS: The extracts GPLE and GPRE significantly (P < 0.001) and dose dependently inhibited the acetic acid-induced writhing in mice with 73.15% and 53.69% inhibition, respectively at the dose of 200 mg/kg. At the same dose GPLE and GPRE significantly inhibited carrageenan-induced rats paw edema at the end of 4 hour with 35.54% and 28.17% inhibition, respectively. The extracts significantly prolonged the pentobarbitone-induced sleeping time and decreased the locomotory activities in open field and Hole cross tests in mice. The GPLE showed strong antimicrobial activity against Gram-positive and Gram-negative bacteria with zones of inhibition ranging from 8 to 20 mm at a concentration of 400 MUg/disc. CONCLUSION: The findings of the study indicate that the leaves and roots of G. parviflorum possess antinociceptive, anti-inflammatory and CNS depressant activity and revealed the antimicrobial activities of leaves extract of the plant. The results justify the traditional use of the plant in the treatment of painful and inflammatory disorders. PMID- 24174816 TI - Inhibitory effect of mitragynine on human cytochrome P450 enzyme activities. AB - CONTEXT: To date, many findings reveal that most of the modern drugs have the ability to interact with herbal drugs. AIMS: This study was conducted to determine the inhibitory effects of mitragynine on cytochrome P450 2C9, 2D6 and 3A4 activities. METHODS AND MATERIAL: The in vitro study was conducted using a high-throughput luminescence assay. STATISTICAL ANALYSIS: Statistical analysis was conducted using one-way ANOVA and Dunnett's test with P < 0.05 vs. control. The IC50 values were calculated using the GraphPad Prism((r)) 5 (Version 5.01, GraphPad Software, Inc., USA). RESULTS: Assessment using recombinant enzymes showed that mitragynine gave the strongest inhibitory effect on CYP2D6 with an IC50 value of 0.45+/-0.33 mM, followed by CYP2C9 and CYP3A4 with IC50 values of 9.70+/-4.80 and 41.32+/-6.74 MUM respectively. Positive inhibitors appropriate for CYP2C9, CYP2D6, and CYP3A4 which are sulfaphenazole, quinidine and ketoconazole were used respectively. Vmax values of CYP2C9, CYP2D6 and CYP3A4 were 0.0005, 0.01155 and 0.0137 MUM luciferin formed/pmol/min respectively. Km values of CYP2C9, CYP2D6, and CYP3A4 were 32.65, 56.01, and 103.30 MUM respectively. Mitragynine noncompetitively inhibits CYP2C9 and CYP2D6 activities with the Ki values of 61.48 and 12.86 MUM respectively. On the other hand, mitragynine inhibits CYP3A4 competitively with a Ki value of 379.18 MUM. CONCLUSIONS: The findings of this study reveal that mitragynine might inhibit cytochrome P450 enzyme activities, specifically CYP2D6. Therefore, administration of mitragynine together with herbal or modern drugs which follow the same metabolic pathway may contribute to herb-drug interactions. PMID- 24174817 TI - Antineoplastic potential of Bryophyllum pinnatum lam. on chemically induced hepatocarcinogenesis in rats. AB - BACKGROUND: Bryophyllum pinnatum Lam. used in folk medicine in tropical Africa, tropical America, India, China and Australia contains a wide range of active compounds, well known for their haemostatic and wound-healing properties. OBJECTIVE: The present study was designed to evaluate the effect of Bryophyllum pinnatum Lam. on N-diethylnitrosamine (DENA)-induced hepatic injury in rats. MATERIAL AND METHODS: The aerial part of B. pinnatum aqueous and ethanolic extract was prepared in doses of 250 mg/kg and 500 mg/kg. Hepatic injury was induced by DENA. Acute toxicity was also carried out. RESULT: Treatment with different doses of ethanolic extract of B. Pinnatum (250 mg/kg, p.o.) was not significantly able to treat the liver injury induced by DENA, but 500 mg/kg dose of ethanolic extract of B. Pinnatum protects the liver slightly. Treatment with different doses of aqueous extract of B. Pinnatum (250 and 500 mg/kg, p.o.) significantly (P*<0.05; P**<0.01 and P***<0.001) treated the liver injury induced by DENA. CONCLUSION: It may be inferred from the present study that the hepatoprotective activities of the aqueous extract of B. Pinnatum leaves in DENA induced hepatotoxicity may involve its antioxidant or oxidative free radical scavenging activities by alleviating lipid peroxidation through scavenging of free radicals, or by enhancing the activity of antioxidants. PMID- 24174818 TI - Analysis of amide compounds in different parts of Piper ovatum Vahl by high performance liquid chromatographic. AB - BACKGROUND: Piper ovatum (Piperaceae) has been used in traditional medicine for the treatment of inflammations and as an analgesic. Previous studies have showed important biological activities of the extracts and amides from P. ovatum leaves. OBJECTIVE: In this study, a high-performance liquid chromatographic (HPLC) method was developed and validated for quantitative determination of the amides in different parts of Piper ovatum. MATERIALS AND METHODS: The analysis was carried out on a Metasil ODS column (150 * 4.6 mm, 5MUm) at room temperature. HPLC conditions were as follows: acetonitrile (A), and water (B), 1.0% acetic acid. The gradient elution used was 0-30 min, 0-60% A; 30-40 min, 60% A. Flow rate used was 1.0mL/min, and detection at 280nm. RESULTS: The validation using piperlonguminine, as the standard, demonstrated that the method shows linearity (linear correlation coefficient = 0.998), precision (relative standard deviation <5%) and accuracy (mean recovery = 103.78%) in the concentration range 31.25 - 500MUg/mL. The limit of detection and quantification were 1.21 and 4.03MUg/mL, respectively. This method allowed the identification and quantification of piperlonguminine and piperovatine in the hydroethanolic extracts of P. ovatum obtained from the leaves, stems and roots. All the extracts showed the same chromatographic profile. The leaves and roots contained the highest concentrations of piperlonguminine and the stems and leaves showed the most concentrations of piperovatine. CONCLUSION: This HPLC method is suitable for routine quantitative analysis of amides in extracts of Piper ovatum and phytopharmaceuticals containing this herb. PMID- 24174819 TI - Hepatoprotective and nephroprotective effects of Cnidoscolus aconitifolius in protein energy malnutrition induced liver and kidney damage. AB - INTRODUCTION: This study was designed to evaluate the ameliorative and hypocholesterolemic effects of dietary supplementation of Cnidoscolus aconitifolius leaf meal (CALM) on hepatic injury and kidney injury associated with protein energy malnutrition (PEM). MATERIALS AND METHODS: In this study, PEM was induced in weaning male Wistar albino rats by feeding them with low protein diet for 2 weeks. The effects of several recovery diets containing 20% soya protein or 20% C. aconitifolius in place of soya protein or 10% soya proteins with 10% C. aconitifolius or commercial rat feed were assessed in PEM rats. Plasma biochemical parameters were assessed as well. RESULTS: After the induction of PEM, results obtained showed significant increase in alkaline phosphatase (ALP), alanine aminotransferase (ALT), aspartate aminotransferase (AST), total proteins (T.P), total bilirubin (T.Bil), triglycerides, total cholesterol, low density lipoproteins (LDL), blood urea nitrogen (BUN), and creatinine with significant reduction in plasma high density lipoproteins (HDL), albumin, sodium (Na(+)), potassium (K(+)), chloride (Cl(-)), bicarbonate (HC03(-)), and phosphate (P04(2-)) in PEM rats. Upon introduction of recovery diets containing 20% soya protein or 20% C. aconitifolius in place of soya protein or 10% soya proteins with 10% C. aconitifolius or commercial rat feed for 4 weeks caused significant (P < 0.05) reduction in plasma values of ALP, ALT, AST, T.bil, T.P., LDL, total cholesterol, triglycerides, BUN, creatinine, and significant increase in HDL and complete restoration of plasma electrolytes. CONCLUSIONS: C. aconitifolius in protein deficient diets has a protective role against hepatic injury and renal damage associated with PEM. PMID- 24174820 TI - Anticonvulsant potential of ethanol extracts and their solvent partitioned fractions from Flemingia strobilifera root. AB - BACKGROUND: Flemingia strobilifera (FS) R.Br. (Fabaceae) is an important medicinal plant. In wealth of India it has been reported that roots of FS are used by santals in epilepsy, hysteria, insomnia, and to relieve pain. In Burma also the roots of F. strobilifera are used to treat epilepsy. OBJECTIVE: To investigate anticonvulsant potential of 95% ethanol extract and four subsequent fractions (petroleum ether, chloroform, ethyl acetate, and aqueous fractions of the roots of FS against pentylenetetrazole (PTZ) and maximal electroshock (MES) induced convulsions. MATERIAL AND METHODS: All the fractions and crude ethanol extract were administered (i.e., 200, 400, 600 mg/kg, p.o.) for 7 days and at the end of the treatment convulsions were induced experimentally using pentylenetetrazole and Maximal electroshock Test. Diazepam and phenytoin (4 mg/kg, i.p. and 20 mg/kg, i.p., respectively) were used as reference anticonvulsant drugs against experimentally induced convulsions. The latency of tonic convulsions and the numbers of animals protected from tonic convulsions were noted. RESULTS: High doses (200 and 300 mg/kg, p.o.) of ethyl acetate fraction and 95% ethanol crude extract (400 and 600 mg/kg, p.o.) significantly reduced the duration of seizure induced by maximal electroshock (MES). The same dose also protected from pentylenetetrzole-induced tonic seizures and significantly delayed the onset of tonic seizures. However, pet, ether, chloroform, and aqueous fraction at any of the doses used (i.e., 100, 200, 300 mg/kg, p.o.) did not show any significant effect on PTZ and MES induced convulsions. The treatment with crude ethanolic extract and ethyl acetate fraction caused signs of central nervous system depressant action in the locomotor activity test, confirmed by the potentiation of sodium pentobarbital sleeping time. Both did not cause disturbance in motor coordination assessed by rotarod test. CONCLUSION: The data suggest that crude ethanol extract and ethyl acetate fraction of roots of Flemingia strobilifera have a central nervous system depressant action and behave as a potential anticonvulsant. It may produce its anticonvulsant effect via non-specific mechanism since it reduced the duration of seizures produced by maximal electroshock as well as delayed the latency of seizures produced by pentylenetetrazole. PMID- 24174821 TI - Hepatoprotective activity of Ficus religiosa leaves against isoniazid+rifampicin and paracetamol induced hepatotoxicity. AB - BACKGROUND: The present study was designed to investigate the hepato protective effect of methanolic extract of Ficus religisoa L., Moraceae, on isoniazid rifampicin and paracetamol induced hepatotoxicity in rats. MATERIALS AND METHODS: Male Wistar albino rats were divided into six groups; group 1 served as a control received vehicle (Distilled water), group 2 served as a toxic control, received isoniazid-rifampicin (100 mg/ kg, i.p.) or paracetamol 200mg/kg, p.o in sterile water, groups 3, 4 and 5 received 100, 200 and 300mg/kg bw, p.o. methanolic extract of F. religisoa along with INH+RIF or paracetamol and group 6 received Liv 52 as reference standard. All the treatment protocols followed 21 days for INH+RIF model and seven days for paracetamol model, after treatment rats were sacrificed and blood was used for biochemical and liver was used for histological studies. RESULTS: Administration of INH+RIF and paracetamol caused a significant elevation in the levels of liver marker enzymes (P < 0.05 and P < 0.01) and thiobarbituric acid reactive substances (P < 0.001) in experimental rats. Administration of methanolic extracts of F. religisoa significantly prevented isoniazid-rifampicin and paracetamol induced elevation in the levels of serum diagnostic liver marker enzymes and TBARS level in experimental groups of rats. Moreover, total protein and reduced glutathione levels were significantly (P < 0.001) increased in treatment group. The effect of extract was compared with a standard drug, Liv 52. The changes in biochemical parameters were supported by histological profile. CONCLUSION: The methanolic extract of F. religisoa protects against isoniazid- rifampicin and paracetamol induced oxidative liver injury in rats. PMID- 24174822 TI - Protective effect of aqueous extract of seed of Psoralea corylifolia (Somraji) and seed of Trigonella foenum-graecum L. (Methi) in streptozotocin-induced diabetic rat: A comparative evaluation. AB - BACKGROUND: Psoralea corylifolia (Somraji) and Trigonella foenum-graecum L. (Methi), important medicinal plants widely used in India as folk medicine. Local people of West Bengal traditionally used the seeds of these plants to cure diabetes. OBJECTIVE: Present study was designed to investigate the antidiabetic efficacy of aqueous extract of seeds of these plants in separate or in composite manner in streptozotocin (STZ)-induced diabetic rat. MATERIALS AND METHODS: Diabetes was induced by intramuscular injection of STZ at the dose of 40 mg/ml of citrate buffer/kg body weight. Fasting blood glucose (FBG), glyclated hemoglobin (HbA1C) and activities of hexokinase, glucose-6-phosphate dehydrogenase and glucose-6-phosphatase of liver in experimental animals were assessed. Hyperlipidemic state developed in the experimental diabetic rat was assessed by measuring the levels of total cholesterol, triglyceride, and lipoproteins in serum. RESULTS: There was significant increased in the levels of FBG, HbA1C and lipid profiles along with diminution (P < 0.001) in the activities of hepatic hexokinase, glucose-6-phosphate dehydrogenase and elevation in glucose-6 phosphatase in diabetic control animals in respect to the untreated control. Significant recovery (P < 0.05) in the activities of above mentioned enzymes along with the correction in the levels of FBG, HbA1C and serum lipid profiles were noted towards the control level after the treatment of composite extract (i.e. 100 mg of Somraji: 100 mg of Methi, total 200 mg/kg body weight) than the individual extract (i.e. 200 mg of Somraji or 200 mg of Methi, per kg body weight) treatment. CONCLUSION: Results suggest that composite extract of above plant parts has more potent antidiabetic efficacy than the individual extract. PMID- 24174823 TI - Antinociceptive and anticonvulsant activities of hydroalcoholic extract of Jasminum grandiflorum (jasmine) leaves in experimental animals. AB - Jasminum grandiflorum belongs to the family Oleaceae and is known to have anti inflammatory, antimicrobial, antioxidant, and antiulcer activities. The present study was undertaken to study its analgesic and anticonvulsant effects in rats and mice. The antinociceptive activity of the hydroalcoholic extract of J. grandiflorum leaves (HEJGL) was studied using tail flick and acetic acid - induced writhing method. Similarly, its anticonvulsant activity was observed by maximal electroshock (MES) method and pentylenetetrazol (PTZ) method. Statistical analysis was performed using one-way analysis of variance (ANOVA) followed by Dunnett's test. At doses of 50, 100, and 200 mg/kg, HEJGL showed significant analgesic and anticonvulsant effects in experimental animals. In view of its analgesic and anticonvulsant activity, the JGL extract can be used in painful conditions as well as in seizure disorders. PMID- 24174824 TI - Comparative DNA profiling, phytochemical investigation, and biological evaluation of two Ficus species growing in Egypt. AB - AIM AND BACKGROUND: A comparison between two Ficus species, cultivated in Egypt, was carried out in this study. Their DNA analysis revealed that they are not closely related. MATERIALS AND METHODS: The pharmacopoeial constants of the leaves showed higher total ash and acid insoluble ash in F. lyrata than in F. platypoda. The other parameters were close in both species. Preliminary phytochemical screening revealed the presence of carbohydrate and/or glycosides, tannins, flavonoids, sterols, and triterpenes in their leaves and was detected in traces in their stems. RESULTS: Saponification of n-hexane extract of the leaves yielded 46% and 74.8% for the unsaponifiable matters and 20% and 15% for the fatty acids for F. platypoda and F. lyrata, respectively. n-Docosane (21.69%) and n-heptacosane (33.77%) were the major hydrocarbons in F. platypoda and F. lyrata, respectively. b-Sitosterol was the main sterol, palmitic (22.07%) and carboceric (35.72%) acids were the major identified saturated fatty acids in both species, while linoleic acid was the main unsaturated fatty acid (18.66% and 16.7%) in both species, respectively. The acute toxicity study revealed that the two species were safe up to 2 g/kg. The antioxidant activity using 1,1-diphenyl-2 picrylhydrazyl (DPPH) assay and pyrogallol as the standard was more significant for F. platypoda (232.6 MUg/ml) than for F. lyrata, (790.9 MUg/ml). The oral antihyperglycemic activity in diabetic rats using alloxan revealed that the 80% ethanolic extract of the leaves of F. platypoda was more active than that of the leaves of F. lyrata in decreasing the blood glucose level at 200 mg/kg/day (107.9 +/- 5.817, 127.2 +/- 4.359) and 400 mg/kg/day (64.11 +/- 4.358, 127.7 +/- 6.889), respectively, when compared with the diabetic control gliclazide (172.3 +/- 2.089). CONCLUSION: The results of this study provide evidence that the two Ficus species have antioxidant and antihyperglycemic activity, in the order F. platypoda and then F. lyrata. PMID- 24174825 TI - Modulatory of effect of fresh Amaranthus caudatus and Amaranthus hybridus aqueous leaf extracts on detoxify enzymes and micronuclei formation after exposure to sodium arsenite. AB - Vegetables are the cheapest and most available sources of important proteins, minerals, vitamins, and essential amino protein. These vegetables are commonly used in Africa for the treatment of illness. This study evaluated the protective effects of Amaranthus caudatus and A. hybridus against sodium arsenite-induced toxicity in rats. The effects of sodium arsenite and/or the plant extracts were assessed using bone marrow micronucleus assay and by measuring the activities of tumour maker enzymes such as gamma glutamyl transferase (GGT) and alkaline phosphatase (ALP) in white albino Wister rats. The study showed that sodium arsenite significantly (P < 0.05) induced the formation of micronucleated polychromatic erythrocytes and the activities of ALP and GGT when compared with control. The levels of white blood cell, hemoglobin, and lymphocyte count were altered in sodium arsenite fed rats and were reverted back to near normal levels in rats pretreated with the plant extracts. A. caudatus and A. hybridus showed significant role in protecting the detoxifying enzymes; also, A. caudatus has a more protective effect on reducing the micronuclei formation when compared with A. hybridus. This study suggests that A. caudatus and A. hybridus possess anticarcinogenic effect. PMID- 24174826 TI - Mast cell stabilization potential of Sitopaladi churna: An ayurvedic formulation. AB - BACKGROUND: Sitopaladi churna (SPC) is a popular polyherbal ayurvedic formulation used in the treatment of allergy and respiratory diseases. OBJECTIVE: The present study was aimed to justify the classical use of antiallergic claim by performing the mast cell stabilizing activity of extracts of SPC. MATERIALS AND METHODS: The protective effect of aqueous extract and methanolic extract - of SPC against compound 48/80-induced mast cell degranulation model was carried out. RESULTS: Sitopaladi churna aqueous extract (SPCA) at the dose of 300 mg/kg and Sitopaladi churna methanolic extract (SPCM) at the doses of 150 and 300 mg/kg showed better protection of mast cell degranulation (65%-74%) and were comparable to the standard drug ketotifen (79%), when peritoneal mast cells were treated with compound 48/80. The protection against mast cell degranulation was significant (P < 0.0001). CONCLUSION: From the above results, it has been justified that SPC can be used to treat allergic disorders. PMID- 24174828 TI - Message from the Editor-in-Chief. PMID- 24174827 TI - Suppression of benign prostate hyperplasia by Kaempferia parviflora rhizome. AB - BACKGROUND: Kaempferia parviflora rhizome is used as a folk medicine in Thailand for the treatment of various symptoms. In the present study, the inhibitory activities of extract from K. parviflora rhizome against 5alpha-reductase (5alphaR) were subjected. Furthermore, the effects of the extract from K. parviflorar hizome in benign prostate hyperplasia (BPH) were studied using the model mice. MATERIALS AND METHODS: Preparations of extracts from the rhizomes of K. parviflora, Curcuma zedoaria and Zingiber officinale, and methoxyflavones isolated from K. parviflora was used for 5alphaR inhibition assay. The effects of K. parviflora extract on growth suppression for the prostates and seminal vesicles were performed based on the Hershberger's method. The K. parviflora extract was administered to castrated mice for 14 days. RESULTS: K. parviflora extract showed more potent inhibitory activity on 5alphaR than C. zedoaria and Z. officinale extracts. The active principles were identified as 3,5,7,3',4' pentamethoxyflavone and 5,7,3',4'-tetramethoxyflavone by activity guided fractionation. Furthermore, K. parviflora extract suppressed the weights of prostates and seminal vesicles in BPH model rats by daily administration for 14 days. CONCLUSION: These results indicate that K. parviflora extract can be a promising agent for the treatment of BPH. PMID- 24174829 TI - Echocardiographic evaluation of left ventricular diastolic and systolic function in Saudi patients with sickle cell disease. AB - BACKGROUND AND OBJECTIVES: Sickle cell disease (SCD) is a chronic, inherited haemoglobin disorder, associated with recurrent vaso-occlusive and haemolytic crises and chronic tissue ischemia which may adversely affect any organ system. Our objectives were to evaluate the left ventricular (LV) systolic and diastolic functions in Saudi patients with SCD originally from the Eastern Province of Saudi Arabia. DESIGN AND SETTING: Prospective hospital based echocardiography study on adolescent and adult patients with SCD. METHODS: Forty-five patients with SCD were recruited for echocardiographic study while 45 patients, matched for age and sex, served as controls. Left and right ventricular dimensions and LV wall thicknesses, LV mass index (LVMI) and LV contractility variables were obtained. Left atrial dimension and volume and pulmonary artery systolic pressure (PASP) were also estimated. We also evaluated parameters of LV diastolic function, including early and late mitral flow velocities (E and A wave respectively), E/A ratio, deceleration time (MVDT), A wave duration (MVA D), LV isovolumic relaxation time (IVRT), and tissue Doppler velocities, such as lateral annular e' wave, a' wave, e'/a' ratio and E/e' ratio. RESULTS: There were increases in the LV dimensions, LV volumes, stroke volume, and LVMI of the SCD patients. The preload was increased (LV diastolic volume) and afterload was decreased (low diastolic blood pressure). The LVEF was equivalent, though there was evidence of LV diastolic dysfunction in 24%, and pulmonary hypertension (PH) in 40% of the SCD patients. The mean left atrial volume (LAV) was also increased in the SCD patients. CONCLUSION: LV diastolic dysfunction (heart failure with preserved ejection fraction) and PH may complicate cases of the Arab-Indian haplotype of SCD. PMID- 24174830 TI - Impact of diabetes on hospital adverse cardiovascular outcomes in acute coronary syndrome patients: Data from the Saudi project of acute coronary events. AB - BACKGROUND: Diabetes mellitus (DM) is a major public health problem in Saudi Arabia. DM patients who present with acute coronary syndrome (ACS) have worse cardiovascular outcomes. We characterized clinical features and hospital outcomes of diabetic patients with ACS in Saudi Arabia. METHODS: ACS patients enrolled in the Saudi Project for Assessment of Acute Coronary Syndrome (SPACE) study from December 2005 to December 2007, either with DM or newly diagnosed during hospitalization were eligible. Baseline demographics, clinical presentation, therapies, and in-hospital outcomes were compared with non-diabetic patients. RESULTS: Of the 5055 ACS patients enrolled in SPACE, 2929 (58.1%) had DM (mean age 60.2 +/- 11.5, 71.6% male, and 87.6% Saudi nationals). Diabetic patients had higher risk-factor (e.g., hypertension, hyperlipidemia) prevalences and were more likely to present with non-ST-elevation myocardial infarction (40.2% vs. 31.4%, p < 0.001), heart failure (25.4% vs. 13.9%, p < 0.001), significant left ventricular systolic dysfunction and multi-vessel disease. Diabetic patients had higher in-hospital heart failure, cardiogenic shock, and re-infarction rates. Adjusted odds ratio for in-hospital mortality in diabetic patients was 1.83 (95% CI, 1.02-3.30, p = 0.042). CONCLUSIONS: A substantial proportion of Saudi patients presenting with ACS have DM and a significantly worse prognosis. These data highlight the importance of cardiovascular preventative interventions in the general population. PMID- 24174831 TI - Noninvasive assessment of elevated pulmonary vascular resistance in children with pulmonary hypertension secondary to congenital heart disease: A comparative study between five different Doppler indices. AB - BACKGROUND: Pulmonary vascular resistance (PVR) is an important hemodynamic parameter in patients with congenital heart disease (CHD). Noninvasive estimation of PVR represents an attractive alternative to invasive measurements. METHODS: The study included 175 patients with pulmonary hypertension (PH) secondary to CHD. All patients underwent full echocardiographic study and invasive hemodynamic measurements. The study population was then subdivided into four subgroups. Each of the following Doppler indices was measured in one of these four subgroups: peak tricuspid regurgitant velocity (TRV), the ratio of the TRV to the velocity time integral of the right ventricular outflow tract (TRV/TVIRVOT), peak velocity of tricuspid annular systolic motion (TSm), heart rate corrected acceleration time and infliction time of the proximal left pulmonary artery (ATc, InTc). The data obtained was correlated with invasive PVR measurement. An ROC curve analysis was done to generate cutoff points with the highest balanced sensitivity and specificity to predict PVR > 6WU/m(2). The receiver operating characteristics (ROC) curves were compared with each other to determine the most reliable cutoff point in predicting elevated PVR > 6WU/m(2). RESULTS: There was a significant correlation between both the TRV and TSm and invasive measurement of PVR (r = 0.511, 0.387 and P value = 0.0002, 0.006 respectively). The TSm and TRV cutoff values were the most reliable to predict elevated PVR > 6 WU/m(2). A TSm cutoff value of ?16.16 cm/s provided the best balanced sensitivity (85.7%) and specificity (66.7%) to determine PVRCATH > 6 WU/m(2). A cutoff value less than 7.62 cm/s had 100% specificity to predict PVRCATH > 6 WU/m(2). A TRV cutoff value of >3.96 m/s provided the best balanced sensitivity (66.7%) and specificity (100%) to determine PVRCATH > 6 WU/m(2). Both TRV and TSm had the highest area under the ROC curve among the 5 DOPPLER indices studied. CONCLUSION: Prediction of elevated PVR in children with PH secondary to CHD could be achieved noninvasively using a number of Doppler indices. Among the five Doppler indices examined in the current study, the peak TRV and the TSm of the lateral tricuspid annulus had the highest balanced sensitivity and specificity to predict PVRI > 6 WU/m(2). PMID- 24174832 TI - Prospective observational studies of the management and outcomes in patients with atrial fibrillation: A systematic review. AB - BACKGROUND: Atrial fibrillation (AF) is a major global public health problem. Observational studies are necessary to understand patient characteristics, management, and outcomes of this common arrhythmia. Accordingly, our objective was to describe the current status of published prospective observational studies of AF. METHODS AND RESULTS: MEDLINE and EMBASE (to June 2012) and reference lists of eligible studies were searched for English-language prospective observational registries of AF (n ? 100 and follow-up ?6 months). Two reviewers independently extracted data. Disagreements were resolved by consensus. Eight prospective studies enrolled a total of 17,924 patients with AF (total 41,306 patient-years of exposure; follow-up 11 months to 9.9 years). The majority of subjects were enrolled in Europe (74%) or North America (21%), and 0.3% had rheumatic AF. The most consistently reported comorbidities were diabetes mellitus (range 5-18%), hypertension (39-68%), heart failure (5-58%), and prior stroke (4-17%). Three studies did not report all the variables necessary to calculate the currently recommended stroke risk assessment score, and no study reported all the variables required to calculate a recently validated bleeding risk score. The most consistently reported management features were oral anticoagulation (32-64%) and aspirin (28-61%) use. Calcium channel blockers were less frequently used than other rate controlling agents, and digoxin was most common in the single study from Africa (63%). Total mortality was reported in all studies, while data on stroke/systemic embolism, hospitalizations, and major hemorrhage rates were not always reported. CONCLUSIONS: Current literature on real-world management of AF is relatively limited with inadequate data to allow detailed comparisons among reports. Data on rheumatic AF and from Africa and the developing world in general are sparse. PMID- 24174833 TI - Coronary fistula between the left anterior descending coronary artery and the pulmonary artery: Two case reports. AB - Coronary artery fistulae are rare congenital or acquired connections between the coronary vessels and the cardiac chambers or other vascular structures. We present two consecutive cases of coronary fistulae between the proximal left anterior descending artery (LAD) and the main pulmonary artery. Both cases where admitted with history of acute coronary syndromes and had multivessel coronary disease along with coronary pulmonary fistulae. The two cases were managed by coronary artery bypass grafting (CABG) and repair of the fistulae. PMID- 24174834 TI - Cor triatriatum with persistent levoatrial cardinal vein late presented as severe mitral stenosis. AB - Cor triatriatum is a rare congenital cardiac anomaly that usually becomes symptomatic in the first years of life. We present a 28-year-old pregnant female patient presented with shortness of breath, palpitations and decreased exercise tolerance. Transthoracic (TTE) and transesophageal (TEE) echocardiography showed cor triatriatum, features of severe mitral stenosis and atrial septal defect (ASD). The patient underwent successful surgical correction with an uneventful postoperative course. PMID- 24174835 TI - A young male with familial hypercholesterolemia. AB - A nine-year-old Bangladeshi male with a body mass index 16.5 kg/m(2) presented with progressive tuberous xanthomata on both auricles, elbows, gluteal regions and legs since birth. His father, paternal and maternal grandfather had xanthelasma, however, the siblings had none. Examination of the cardiovascular system was otherwise normal. Laboratory investigations were performed on several occasions since he was 4 years of age and revealed extreme dyslipidaemia with very high total cholesterol (TC), low density lipoprotein cholesterol (LDL-C), triglycerides (TG), apolipoprotein B (Apo-B) and lipoprotein(a), and low apolipoprotein-A (Apo-A) levels. Repeated combination of lipid lowering agents with cholestyramine, atorvastatin and ezetimibe were virtually ineffective in improving the lipid profiles. Supplementation therapy with niacin also had no effect. In view of the unavailability in Bangladesh of lipid apheresis, the cornerstone of therapy, the management of the case becomes complicated. PMID- 24174836 TI - Atrial Myxoma-Related to Chronic Immunosuppression: A case report. AB - Although rare, atrial myxoma is the most common primary tumour of the heart. Its relation to immunosuppression in solid organ transplant is presently debateable. We report the case of a 71-year-old male patient who underwent renal transplant 17 years prior. Since that time he continued high dose immunosuppression without physician consultation and presented to us with atrial myxoma and its complications raising the question of any association between immunosuppression and the development of atrial myxoma. PMID- 24174837 TI - Coronary perforation managed with covered stent. PMID- 24174838 TI - Message from the editor in chief. PMID- 24174839 TI - NT-proBNP correlated with strain and strain rate imaging of the right ventricle before and after transcatheter closure of atrial septal defects. AB - BACKGROUND: Atrial septal defects (ASD) account for 10% of all congenital heart lesions and represent the third most congenital cardiac defect seen in adults. OBJECTIVES: Using strain and strain rate imaging (SRI) to assess right ventricular (RV) function in patients with ASD and correlate the results with the level of N-terminal pro-brain natriuretic peptide (NT-proBNP) before and after transcatheter closure. METHODS: At the Hungarian Institute of Cardiology, 27 females and 18 males (mean age 21.53 years) were diagnosed with ASD and admitted for percutaneous closure. Echocardiography was done to assess theleft ventricular (LV), RV and left atrial (LA) diameters. For assessment of systolic RV function, we measured Tricuspid annular plane systolic excursion (TAPSE), strain, and SRI. Amplatzer ASD closure was done under general anesthesia. NT-proBNP levels were measured before and three months after closure. RESULTS: ASD closure was achieved in all patients. The mean ASD diameter was 15.15 mm. The size of the occluder ranged from 10 to 24 mm. The mean LA diameter in the pre-closure group was significantly higher than the control; mean left ventricular end diastolic diameter (LVEDD) showed a non-significant difference from either the control group or the post-closure group, while the mean right ventricular end diastolic diameter (RVEDD) markedly reduced post-closure, and it was significantly higher than the control group. Global RV strain and peak systolic strain rate (PSSR) were significantly higher in ASD group than in the control. The NT-proBNP levels were found to be correlated with pulmonary arterial pressure (PAP), TAPSE, global RV strain and PSSR. CONCLUSION: Volume overload induced by ASD is associated with increased strain values, which return to normal after closure. NT-proBNP is a parameter which correlates to RV pressure, PAP and the amount of shunt volume caused by an ASD. PMID- 24174840 TI - Simplifying proximal isovelocity surface area as an assessment method of mitral valve area in patients with rheumatic mitral stenosis by fixing aliasing velocity and mitral valve angle. AB - We aimed to test the ability of a simple equation using proximal isovelocity surface area method (PISA), created by fixing the angle to 100 degrees and the aliasing velocity to 33 cm/s, to calculate mitral valve area (MVA) and assess severity in patients with rheumatic mitral stenosis (MS). METHODS AND RESULTS: In a series of 51 consecutive patients with rheumatic MS, MVA was assessed by four methods, conventional PISA equation (PISAconventional), simple PISA equation (PISAsimple), pressure half time (PHT), and planimetry (PLN) which was taken as the reference method. All methods correlated significantly with PLN with the highest correlation found in case of PISAconventional and PISAsimple (r = 0.97, 0.96, p < 0.001), while the correlation in case PHT was relatively weaker (r = 0.69, p < 0.001). Bland-Altman analysis revealed that the level of agreement with PLN was better in case of both PISA methods than PHT and, moreover, were close to each other. The number of cases that showed agreement of severity grade with planinetry was better in case of PISAconventional (42 cases) and PISAsimple (44 cases) than that in case of PHT (34 cases, p = 0.037). Finally, the measure of agreement with Cohen's Kappa test was better in case of PISAconventional and PISAsimple than that in case of PHT. CONCLUSION: Provided that aliasing velocity is fixed at 33 cm/s, PISA can effectively predict mitral valve area and severity of MS by a simple equation, with the advantage of easy and accurate calculation over other methods. PMID- 24174841 TI - Awareness, attitude, and distribution of high blood pressure among health professionals. AB - BACKGROUND: BP control is suboptimal Worldwide. Little is known about attitudes of health professionals toward their BP status. AIM: To estimate awareness, attitudes, and distribution of blood pressure among health professionals. STUDY DESIGN: Prospective cross-sectional survey. METHODS: Study was conducted among health professionals in two tertiary hospitals in Riyadh, KSA during December 2010. Socio-demographics, risk factors for high BP, awareness, and adherence to treatment were recorded. RESULTS: Six hundred and seventy-two subjects, 66.6% females, mean age 36.2 + 13.9 years. Prevalence of Hypertension (HTN) was 28%. 114 (60.6%) patients had self reported HTN in HTN group while 74 (11%) of total study population, were not aware that they have HTN which was detected on screening. Stress and lack of formal exercise were prevalent risk factors for HTN, present in 44.1% and 36.1%, of patients, respectively, while obesity was present in 19.4%. Many participants were not aware of recently recommended target value of blood pressure. 22.3% patients were irregular for their follow-up. 12.2% patients were not adherent to the treatment. Isolated systolic hypertension was more common in men. A point of serious concern was that relatively young health professionals, who were not known to be hypertensive did not monitor their BP, found to have HTN. CONCLUSION: Suboptimal awareness and lack of adherence to the treatment for BP among health professionals is of serious concern, for increased chances of cardiovascular events. Physical exercise, correction of obesity and compliance with treatment may reduce the risk of HTN-related adverse outcome in this special subset of the population. PMID- 24174842 TI - Hypocalcemic rachitic cardiomyopathy in infants. AB - Hypocalcemic cardiomyopathy in infants is characterized by heart failure in a previously normal infant with hypocalcemia without organic cardiac lesion. Vitamin D deficiency rickets is increasing in Middle East. In a six month study 136 cases of rickets were diagnosed in the main Children's Hospital in Almadinah but none of them showed evidence of cardiomyopathy. Concerned of missing this serious complication of rickets we searched pub med and present this review article. RESULTS: 61 cases of hypocalcemic cardiomyopathy were reported as case reports with two series of 16 and 15 cases from London and Delhi, respectively. The major features of these cases: the age ranged from one month to 15 months with a mean age of 5 months. All presented with heart failure and hypocalcemia. There was a minor feature of rickets in a few of the cases. All had high alkaline phosphatase. Echocardiology evidence of cardiomyopathy was found in all. Most of them responded to calcium, vitamin D and cardiotonic and diuretics. DISCUSSION: We concentrated on pathogenesis of this hypocalcemic cardiomyopathy and reviewed the literature. The evidence available supports that the most likely cause of cardiomyopathy is hypocalcemia. Hypovitamin D also contributes but hyperparathyroidism might have a protective role as we did not detect any evidence of cardiomyopathy with hyperparathyroidism and florid features of rickets. CONCLUSION: We need to look out for cardiomyopathy among infants with hypocalcemia. For prevention maternal supplementation during pregnancy and lactation with up to 2000 units of vitamin D and 400 units for their infants. PMID- 24174843 TI - Simultaneous antegrade dual AV node conduction initiates AV nodal re-entrant tachycardia (a rare initiation mechanism). AB - Typical atrioventricular nodal reentrant tachycardia (AVNRT) is the most common paroxysmal supraventricular tachycardia among adults. The concept of dual pathway physiology remains widely accepted, although this physiology likely results from the functional properties of anisotropic tissue within the triangle of Koch, rather than anatomically distinct tracts of conduction. AVNRT is typically induced with anterograde block over the fast pathway and conduction over the slow pathway, with subsequent retrograde conduction over the fast pathway. On rare occasions, anterograde AV node conduction occurs simultaneously through fast and slow pathways resulting in two ventricular beats in response to one atrial beat. We report a case of AVNRT where the tachycardia is always induced by the same mechanism described above. Successful ablation was achieved by slow pathway modification. PMID- 24174844 TI - Asymptomatic metastatic osteosarcoma to the right ventricle: Case report and review of the literature. AB - Metastatic cardiac tumors are far more common than primary tumors, and benign primary cardiac tumors are common than malignant tumors. We report a 22-year-old Saudi woman with right femur osteosarcoma who was found to have a large right ventricular mass by transthoracic and transesophageal echocardiography. Diagnosis was highly suggestive by cardiac magnetic resonance imaging (MRI) and fluorodeoxyglucose positron emission tomography/computed tomography (FDG PET/CT) scan. We performed a review of the literature for metastatic osteosarcoma of the right ventricle. PMID- 24174845 TI - Anomalous origin of the right coronary artery from the proximal left anterior descending artery and a single coronary artery anomaly: Three case reports. AB - The anomalous origin of the right coronary artery (RCA) as a branch of the left anterior descending (LAD) artery is a very rare variation of single coronary artery. We have reported three cases in the last 10 years. Among 15,000 coronary angiograms, at least 40 cases have been described previously in the literature. The vast majority of previous reports have described a single anomalous vessel with its origin after the first septal perforator of the LAD. Two of our patients presented with acute coronary syndrome and were found to have three vessel disease and left main. They underwent coronary artery bypass graft surgery (CABG) and third case presented with tachycardia had only mild coronary artery disease (CAD) and was treated medically. PMID- 24174846 TI - Impressive echocardiographic images of a rare pathology: Aneurysm of the mitral valve - Report of two cases and review of the literature. AB - Aneurysm of the mitral valve (AMV) is rarely reported. The etiology of this unusual pathology is commonly attributed to aortic valve endocarditis (AVE) with aortic regurgitation (AR) or connective tissue disease. We present two recent cases of AMV with good correlation between pre-operative trans-esophageal echocardiography (TEE), intra-operative real-time 3-dimensional echocardiography (RT-3D-Echo) and surgical findings. The importance of diligent surveillance by TEE in patients with AVE for occurrence of AMV is emphasized. The literature on this topic is briefly reviewed. PMID- 24174847 TI - Right-sided ECG chest leads and native heart ventricular fibrillation evaluation in a heterotopic cardiac transplant recipient. PMID- 24174848 TI - Message from the Editor-in-Chief. PMID- 24174850 TI - Comparison of sirolimus-, paclitaxel-, and everolimus-eluting stent in unprotected left main coronary artery percutaneous coronary intervention. AB - OBJECTIVES: This retrospective study evaluated the outcomes of patients who underwent unprotected left main coronary artery (ULMCA) percutaneous coronary intervention (PCI) with different types of drug-eluting stents (DES). BACKGROUND: The standard of care for patients with ULMCA is coronary artery bypass surgery. However, current guidelines recommend PCI in clinical conditions where there is an increased risk of adverse surgical outcomes. Clinical outcomes of patients undergoing ULMCA PCI with different types of drug-eluting stents (DES) are unknown. METHODS: Data from a multicenter international registry, which included 239 consecutive patients from four institutions who ULMCA PCI with DES, were collected. RESULTS: There were 42 patients receiving paclitaxel-eluting stent (PES), 158 patients receiving sirolimus-eluting stent (SES), and 39 patients receiving everolimus-eluting stent (EES). There was no statistical difference in major adverse cardiovascular events, cardiac death, myocardial infarction, target lesion revascularization, and stent thrombosis among PES, SES, and EES at 30 days and 1 year. CONCLUSIONS: There are no differences in clinical events among patients receiving PES, SES, and EES for ULMCA disease. PMID- 24174849 TI - Radial approach and single wiring as first intentional strategies in chronic total occlusions of the left anterior descending coronary artery. AB - BACKGROUND: Percutaneous coronary intervention (PCI) for chronic total occlusion (CTO) of the left anterior descending coronary artery (LAD) specifically is associated with improved long-term 5 years survival as compared to PCI failure. Simpler PCI techniques may be successful and safer than complex techniques which are perceived to have high failure rates and technical complexity. We aimed to describe the safety and effectiveness of first intentional single wiring and radial approach in the treatment of patients with a CTO of the native LAD coronary artery at Toulouse Rangueil university hospitals. PATIENTS AND METHODS: The study was a single center prospective registry. All patients showed evidence of myocardial viability in LAD territory. The operators' initial strategy was to start by a radial access as a first choice whenever feasible; if not, a femoral access was chosen. The initial strategy for lesion crossing in either antegrade or retrograde approaches was single wiring by lesion crossing using one guidewire (GW) as a simple technique. RESULTS: A total of 30 patients with 30 LAD CTO lesions (100%) were recorded. Mean age was 71.6 + 15 years, 77% were males and 23% were females. The access route was radial 66% of the time and femoral 54% of the time and with double access for contralateral injection in 40% of the patients. Sheaths and catheters sizes 6F were used in 53% of the patients, and 7F in 73% of the patients. Overall lesion success rate was 83% of lesions. Single wiring was the prevailing technique used in 97% of successful lesions (83% of total cases), while only 3% were by multiple wiring techniques. Successful single antegrade wiring represented 63% of our total study cases with a GW success rate of 92% of cases. Successful single retrograde wiring represented 13% of our cases with a GW success rate of 67%. Q-wave myocardial infarction (MI), stent thrombosis, stroke, emergency coronary artery bypass graft (CABG), major bleeding, radiation dermatitis, cardiac tamponade or clinical perforation requiring any hemostatic maneuvers did not occur. There was a post-procedural Troponin rise of 3x normal levels in 30% of patients, and contrast induced nephropathy in 7%. Intra-aortic balloon counterpulsation (IABCP) was used in 3% of patients and cardiac death occurred in 3% of patients. CONCLUSION: Single wiring and radial access as initial strategies in PCI for LAD-CTO lesions in either approaches antegrade or retrograde are associated with a high procedural success rate and an acceptable incidences of adverse events. PMID- 24174852 TI - A case report of a right ventricular mass in a patient with Behcet's disease: Myxoma or thrombus? AB - INTRODUCTION: Behcet's disease (BD) is a multi-system, chronic and relapsing disorder classified as "vasculitic syndrome". It typically affects young adult females between 20 and 40 years of age. There are some typical clinical manifestations associated with this disease, however, at times; rare sign and symptoms pose a challenge to the treating physician and making a definitive diagnosis. Presentations with cardiac symptoms are one of the extremely rare manifestations of the Behcet's disease. METHODS: The authors present clinical, laboratory and imaging findings of a patient who presented with a cardiac mass which was the first presenting feature or manifestation of Behcet's disease. RESULTS: A 19-year-old boy was admitted to our hospital for the investigation of "fever of unknown origin", weight loss, shortness of breath and a scrotal ulcer of recent on-set. X-ray chest and electrocardiograms were inconclusive. Transthoracic echocardiography revealed a right ventricular (RV) mass attached to the interventricular septum measuring 1.5 * 1.5 cms (Panel A). Cardiac MRI identified it as a RV Myxoma. In addition, on CT scan of the chest pulmonary embolism was noted. The patient underwent excision biopsy of the tumor under cardiopulmonary bypass via right atriotomy (Panel B). Histopathology of the mass described it as "an organizing thrombus with a few groups of interrupted myocardial fibers and some infiltration of lymphocytes and plasma cells". Moreover his HLA typing was found positive for HLA-B51 (5). In view of the above findings and associated lesions, the patient was diagnosed as a case of Behcet's disease. The medical management included immunosuppressant and anticoagulation. CONCLUSION: Behcet's disease, even in the absence of the typical clinical features, should be considered in the differential diagnosis of right ventricular mass, especially when dealing with young adults from the Mediterranean basin and the Middle-East. PMID- 24174851 TI - Clinico-radiological profile of arrhythmogenic right ventricular dysplasia at a tertiary care center: Two year experience. AB - BACKGROUND: Arrythmogenic right ventricular dysplasia (ARVD/C) refers to fibro fatty infiltration replacement of ventricular myocardium especially that of right ventricle. The clinical presentation varies from asymptomatic state to ventricular tachycardia, heart failure and even sudden death. Diagnosis is established using modified ARVD/C taskforce criteria. Among all the various modalities of diagnosis, magnetic resonance imaging (MRI) gives most comprehensive evaluation of both morphological and functional abnormalities in this disease. MRI may not only obviate need for myocardial biopsy but also give insights into the nature of disease like presence of left ventricular myocardial involvement. We present our 2 years experience of ARVD/C patents who were admitted in our center and in whom diagnosis of ARVD/C was supported by excellent MR imaging. MATERIALS AND METHODS: This study was conducted by Department of Radiology and Cardiology SKIMS, a tertiary care center for a period of 2 years. Patients with suspected ARVD/C based on clinical, electrophysiological and echocardiographic findings were subjected to MR imaging. Patients were excluded if they had history metallic implants, claustrophobia or were uncooperative. In this study stress was laid on diagnostic role of MRI in ARVD/C. RESULTS: The median age at presentation was 31 years (range 21-43 years). 80% of patients were males. Most common clinical presentation was palpatations (40%). Syncope was present in 27% and heart failure in 13%. EKG suggestive of ARVD was seen in 87%. Echocardiographic features suggestive of ARVD/C was seen in all 15 patients. Family history of premature sudden death less than 35 years old was present in one patient only. MRI evidence classical for ARVD/C was seen in 80%. CONCLUSION: Demographic features and mode of presentation of our patients is consistent with what has been rest of the world. We performed MRI in all patients to increase the specificity of our diagnosis. MR imaging allows a three-dimensional evaluation of the right ventricle and provides the most important anatomic, functional, and morphologic criteria for diagnosis of ARVD/C within one single study. MR imaging appears to be the optimal imaging technique for detection and follow-up of clinically suspected ARVD/C. PMID- 24174853 TI - Amplatzer septal occluder and atrioventricular block: A case report and literature review. AB - Transcatheter closure of secondum atrial septal defect (ASD) is an alternative option to open heart surgery with good short and long-term outcomes. For this purpose, the Amplatzer septal occluder (ASO) device is widely used. Arrhythmias are known complications of ASD device closure including atrial ectopy and heart block. We report a seven-year-old female patient who developed second degree atrioventricular block (AVB) within few hours after ASD device closure using ASO device. At the seventh post-procedure day; while under close observation; patient regained sinus rhythm which was maintained thereafter. A 3-day course of prednisolone was given. PMID- 24174854 TI - Isolated tear in left atrial appendage due to blunt trauma chest: A rare case report. AB - Blunt traumatic cardiac rupture is associated with a high mortality rate. Motor vehicle accidents account for most cardiac ruptures, but crush injury is relatively rare. We describe a case of a 72-year-old man who had the left atrial appendage ruptured through blunt trauma due to a fall from scooter. Simple suture repair of the atrial appendage was achieved after clamping the base of the left atrium to control the bleeding. He recovered without complication. Traumatic injury to left atrial appendage is rarely seen and reported. PMID- 24174855 TI - Simple D-transposition of great arteries operated at the age of 11 years. AB - The simple transposition of the great arteries is a lethal congenital heart disease. The life expectancy of unoperated patients is about 9 months. We report the original observation of a girl with unoperated simple transposition of the great arteries, who survived until the age of 11 years. An atrial switch was successfully performed according to the technique of Senning-Mustard. PMID- 24174856 TI - The practical approach to discerning between atrial lead displacement and reversal in dual chamber pacemakers. AB - We describe a 12-lead electrocardiogram image of a pacemaker malfunction due to atrial lead displacement. Facilitating the understanding of pacemaker timing cycles could explain the underlying mechanisms in this instance. This review utilizes the feature of the ventricular safety pacing interval to discern between atrial lead displacement and reversal. PMID- 24174857 TI - Acute effects of cigarette smoking on the cardiac diastolic functions. AB - BACKGROUND: Smoking is an independent risk factor for coronary heart diseases and it increases all causes of cardiovascular morbidity and mortality. AIM OF THE WORK: To assess the acute effect of cigarette smoking on ventricular diastolic functions (LV and RV) in healthy, young, and slim smokers. METHODS: Thirty volunteers who had recently commenced smoking (less than one year) and who smoked 1-2 cigarettes per day, underwent ECG, 2D and M-mode echocardiography, standard Doppler echocardiography, pulsed TDI (tissue Doppler imaging) on septal and lateral side of mitral annulus and lateral tricuspid annulus. Vp values were measured. The investigator asked them to hold smoking for at least two days after which echocardiographic examination was conducted before smoking one cigarette and the second examination conducted immediately after smoking one cigarette containing at least 0.4 mg of nicotine. RESULTS: Doppler findings over the mitral valve showed the E wave was significantly reduced from 82.7 +/- 10.4 to 74.6 +/- 10.4 after smoking; the A wave increased; the E/A ratio was reduced from 1.5 +/- 0.3 to 1.2 +/- 0.2; the E' septal significantly decreased (15.3 +/- 2.4 vs. 11.2 +/- 1.1) after smoking, and the E/E' ratio increased from 5.5 +/- 1.1 to 6.7 +/- 1.1. Doppler findings over the tricuspid valve showed the E wave was reduced from 60.6 +/- 9.7 to 52.7 +/- 9.6; the A wave increased from 42.2 +/- 6.5 to 50.1 +/- 6.6; and the E/A ratio decreased (1.45 +/- 0.25 vs. 1.06 +/- 0.19). The E' significantly decreased from 14.1 +/- 1.8 to 10.9 +/- 2.4, while the A' increased (10.2 +/- 2.4 vs. 12.7 +/- 3.6) after smoking; and the IVRT of the RV was significantly prolonged from 62.9 +/- 7.5 to 68.7 +/- 7.9 after smoking. The Vp was markedly reduced from 67.8 +/- 8 to 55.2 +/- 3.5 after smoking. These findings reflected on the LV filling pressure (LVFvp) which increased from 9.8 +/ 1.4 to 10.5 +/- 1.3 after smoking. All changes were statistically significant at P < 0.001. CONCLUSIONS: Our study reveals that cigarette smoking can result in significant acute alteration in the diastolic functions of both ventricles. PMID- 24174858 TI - Potential pro-arrhythmic effect of cardiac resynchronization therapy. AB - A decline in mortality due to pump failure has been clearly documented after cardiac resynchronization therapy (CRT), however the impact on sudden cardiac death and the development of malignant ventricular arrhythmias remains questionable. Our study aims to investigate this alleged pro-arrhythmic effect of CRT using surface electrocardiogram (ECG) markers of pro-arrhythmia. METHODS: Seventy five patients, who received CRT were included in this study. Manual measurement of corrected QT interval (QTc), Tpeak-end (Tp-e) interval, QT dispersion (QTd) and Tpeak-end dispersion during baseline 12 lead surface ECG and after applying atrial-biventricular pacing were done. Arrhythmias post CRT was recorded from ECG, 24 h holter monitoring or pacemaker programmer event recorder. RESULTS: QTc interval showed significant prolongation after CRT (498.9 +/- 50.8 vs. 476.2 +/- 41.6 msec, P = 0.0001). Comparing patients with major arrhythmogenic events (MAE) and increased frequency of premature ventricular contractions (PVCs) post CRT pacing to those patients without arrhythmias, there was a significant prolongation of the QTc interval (527 +/- 63.29 vs. 496.95 +/- 45.2 msec, P = 0.043) and Tp-e interval (94.16 +/- 9 vs. 87.41 +/- 16.37 msec, P = 0.049). While in the arrhythmogenic group, there was an insignificant decrease in QTd and Tpeak-end dispersion. CONCLUSION: QTc and Tp-e intervals are a potential predictor of occurrence of MAE and PVCs. On the other hand, Tp-e dispersion and QTd did not show a predictive potential for arrhythmia. PMID- 24174859 TI - Management of the single ventricle and potentially obstructive systemic ventricular outflow tract. AB - Multi-stage palliation is the current management strategy for the treatment of children with various single ventricle (SV) cardiac malformations. The success of this strategy depends on the presence of favorable anatomic and hemodynamic criteria. Several SV anomalies have the potential of developing systemic ventricular outflow tract obstruction (SVOTO) that might be evident early on or progress later after palliative surgeries. SVOTO could result in ventricular hypertrophy, impaired diastolic function and subendocardial ischemia with subsequent deleterious effects on the SV and disturbance of some of those criteria for a successful multi-stage palliation strategy. Careful identification of SV patients at risk of developing SVOTO and proper planning of the optimal palliation sequence beginning at the 1st stage procedure are vital factors that would affect long-term outcomes in those patients. In the current review, we describe the morphology of SV patients with potential SVOTO risk, surgical procedures that address potential or present SVOTO, and optimal timing of those procedures within the multi-stage palliation chain. We attempt to provide a treatment algorithm for various patients taking into consideration their unique anatomic and physiologic characteristics. PMID- 24174860 TI - Physician 'defiance' towards hand hygiene compliance: Is there a theory-practice ethics gap? AB - BACKGROUND: The theory-practice gap has always existed [1,2]. This gap is often cited as a culmination of theory being idealistic and impractical, even if practical and beneficial, is often ignored. Most of the evidence relating to the non-integration of theory and practice assumes that environmental factors are responsible and will affect learning and practice outcomes, hence the gap. Therefore, the author believes that to 'bridge the gap' between theory and practice, an additional dimension is required: ethics. A moral duty and obligation ensuring theory and practice integrate. In order to effectively implement new practices, one must deem these practices as worthy and relevant to their role as healthcare providers (HCP). Hence, this introduces a new concept which the author refers to as the theory-practice-ethics gap. This theory practice-ethics gap must be considered when reviewing some of the unacceptable outcomes in healthcare practice [3]. The literature suggests that there is a crisis of ethics where theory and practice integrate, and healthcare providers are failing to fulfill our duty as patient advocates. HYPOTHESIS: Physician hand hygiene practices and compliance at King Abdulaziz Cardiac Centre (KACC) are consistent with those of other physicians in the global healthcare arena. That is one of noncompliance to King Abdulaziz Medical City (KAMC) organizational expectations and the World Health Organization (WHO) requirements? METHODS: An observational study was conducted on the compliance of cardiac surgeons, cardiologists and nurses in the authors' cardiac center from January 2010 to December 2011. The hand hygiene (HH) compliance elements that were evaluated pertained to the WHO's five moments of HH recommendations. The data was obtained through direct observation by KAMC infection prevention and control practitioners. RESULTS: Physician hand hygiene compliance at KACC was consistently less than 60%, with nurses regularly encouraging physicians to be diligent with hand hygiene practices in the clinical area. CONCLUSION: Hand hygiene compliance will not improve unless evidence-based recommendations are adopted and endorsed by all healthcare professionals and providers. PMID- 24174861 TI - A case of multiple coronary microfistulas to the left ventricle and apical myocardial hypertrophy coexisting with stable angina. AB - A coronary artery fistula consists of a communication between a coronary artery and a cardiac chamber, a great artery or the vena cava. It is the most common congenital anomaly that can affect coronary perfusion. However, coronary fistulas to one of the cardiac chambers and coexisting apical myocardial hypertophy are infrequent anomalies, and usually are found unexpectedly. Herein, we report a case in which all three major coronary arteries emptied into the left ventricle with apical hypertrophy, through multiple microfistulas. PMID- 24174862 TI - Dual-site right ventricular and left ventricular pacing in a patient with left ventricular systolic dysfunction and atrial fibrillation using a standard CRT-D device. AB - In patients undergoing cardiac resynchronization therapy with defibrillator (CRT D) implantation for left ventricular systolic dysfunction (LVSD) accompanied by permanent atrial fibrillation (AF), generally, the unused atrial port is plugged at device implantation. We describe an alternative use for the atrial-port in this case report. A 43 year old gentleman with LVSD due to left ventricular non compaction (LVNC) and AF of unknown duration underwent a CRT-D implantation after optimization of cardiac failure treatment. The atrial-port which would otherwise have been plugged was connected to a high right ventricular septal (RVS) pacing lead and the shock-lead was positioned at the right ventricular apex (RVA). This approach permitted modified cardiac resynchronization in a high RVS to left ventricular (LV) and RVA pacing sequence using the high RVS and LV pacing combined with a shock vector including the RV apex. A standard CRT-D device with a minimum programmable A-V delay of 30 ms (technically RVS to LV delay in the 'DDD' pacing mode) was used. The device was programmed to a 'DDD' pacing mode (sequential multi-site ventricular pacing with some programmability). The mode switch operation was programmed 'OFF' since atrial sensing is unavailable. Device delivered shocks did not cardiovert the patient back to sinus rhythm suggesting that the AF was permanent (no prior cardioversion attempts were made on the presumption that the chances of maintaining sinus rhythm, given the underlying cardiac condition, were low). Subsequently, the patient required radio-frequency ablation of the atrio-ventricular node for conducted AF. Symptomatic, echocardiographic and radiological improvement preceded atrio-ventricular node ablation. CONCLUSION: Amongst AF patients with permanent AF undergoing CRT-D implantation, those patients who are likely to have the CRT-D device atrial-ports plugged could benefit from having both the options of (i) a RVA shock vector as well as (ii) a high RVS-pacing feasible, by utilizing the atrial-port of a conventional CRTD device for a RVS pacing lead, should a RVA shock-lead position be preferred. New device programming algorithms will be necessary to make patient customized programming in this lead configuration flexible, more useful clinically and easy. PMID- 24174863 TI - Primary pulmonary hypertension during pregnancy: A case report. AB - We describe a case of a 25-year-old pregnant woman who presented with severe primary pulmonary hypertension (PPH). Her echocardiogram showed severe right ventricular hypertrophy with dilatation and Moderate right ventricular systolic dysfunction. Right ventricle systolic pressure (RVSP) was estimated to be 125 mmHg. She had an elective caesarean section under general anaesthesia at 32 weeks of gestation. Pulmonary artery pressures measured by a pulmonary artery catheter before anaesthesia were 102 mmHg and pulmonary vascular resistance was 429. Intraoperative nitric oxide was used to reduce pulmonary artery systolic pressure (PASP). After the delivery of a healthy infant, PASP was controlled with nebulized iloprost and silandifil. Five days later she was transferred from intensive care unit after she was started on silandifil 50 mg three times daily and a small dose of warfarin. PMID- 24174864 TI - Chiari network: A case report and brief overview. AB - The Chiari network is mobile, net-like structures occasionally seen in right atrium near the opening of inferior vena cava and coronary sinus. This is usually of no clinical significance and is often diagnosed incidentally. However, sometimes it may cause diagnostic confusion with right atrial pathologies, and may favour thromboembolism by causing flow obstruction. It may be associated with infective endocarditis, arrhythmias, and migraine. Sometimes, it acts as a physical barrier during invasive procedures. The Chiari network has also been described to protect from pulmonary embolism by acting as an inferior vena cava filter due to its sieve-like effect at the cavo-atrial junction. Here, the Chiari network has been described in a case of Ebstein anomaly of tricuspid valve which produced diagnostic confusion during echocardiography. A brief overview has also been presented. PMID- 24174865 TI - Azygos lobe. PMID- 24174866 TI - Intensive Family-Based Cognitive-Behavioral Therapy for Pediatric Obsessive Compulsive Disorder: Applications for Treatment of Medication Partial- or Nonresponders. AB - Serotonin reuptake inhibitor medications and cognitive-behavioral therapy (CBT) are both effective treatments for pediatric obsessive-compulsive disorder (OCD). Despite recommendations that youth with OCD be treated with CBT alone or together with serotonin reuptake inhibitor medication, many youth are treated with medication alone or with non-CBT psychotherapy initially. Although effective, symptom remission with medication alone is rare (e.g., only 21.4% of youth achieved remission with sertraline in the Pediatric OCD Treatment Study, 2004) and residual symptoms often remain (e.g., 58% of subjects in the March et al. [1998] sertraline trial were not considered treatment responders). This paper reviews the literature on the efficacy of CBT for pediatric OCD, particularly as it relates to the treatment of youth with prior inadequate response to medication. It also describes an intensive, family-based CBT program for children and adolescents with OCD and support for its efficacy among those with prior partial- or nonresponse to medication. Finally, we present a case study of an adolescent girl with OCD who participated in the intensive treatment program after having limited benefit from medication and non-CBT psychotherapy and experienced a favorable response. PMID- 24174867 TI - A family with Wagner syndrome with uveitis and a new versican mutation. AB - PURPOSE: To report the clinical and molecular findings of a kindred with Wagner syndrome (WS) revealed by intraocular inflammatory features. METHODS: Eight available family members underwent complete ophthalmologic examination, including laser flare cell meter measurements. Collagen, type II, alpha 1, versican (VCAN), frizzled family receptor 4, low density lipoprotein receptor-related protein 5, tetraspanin 12, and Norrie disease (pseudoglioma) genes were screened with direct sequencing. RESULTS: The index case was initially referred for unexplained severe and chronic postoperative bilateral uveitis following a standard cataract surgery procedure. Clinical examination of the proband revealed an optically empty vitreous with avascular vitreous strands and veils, features highly suggestive of WS. The systematic familial ophthalmologic examination identified three additional unsuspected affected family members who also presented with the WS phenotype, including uveitis for one of them. We identified a novel c.4004-6T>A nucleotide substitution at the acceptor splice site of intron 7 of the VCAN gene that segregated with the disease phenotype. CONCLUSIONS: We present a family with WS with typical WS features and intraocular inflammatory manifestations associated with a novel splice site VCAN mutation. Beyond the structural role in the retinal-vitreous architecture, versican is also emerging as a pivotal mediator of the inflammatory response, supporting uveitis predisposition as a clinical manifestation of WS. PMID- 24174868 TI - Intestinal absorption and biliary elimination of glycyrrhizic acid diethyl ester in rats. AB - BACKGROUND: The purpose of this study was to evaluate absorption and elimination from the gastrointestinal tract of glycyrrhizic acid diethyl ester (GZ-DE) which was prepared as a prodrug of glycyrrhizic acid (a poorly absorbed compound) in rats. METHODS: After the GZ-DE solution was administered via the intravenous, intraduodenal, intraileal, and stomach routes, GZ-DE and GZ concentrations in bile were determined by high-performance liquid chromatography. The stability of GZ-DE was estimated from residual GZ-DE and GZ produced in GZ-DE solutions prepared with distilled water, a pH 1.2 solution, 0.9% NaCl solution, and phosphate-buffered solution (pH 7.4) at 37 degrees C. RESULTS: GZ-DE was eliminated into bile by the pharmacokinetic parameters of apparent distribution rate constant (4.56 +/- 0.36 per hour) and apparent elimination rate constant (0.245 +/- 0.042 per hour). After intravenous and intraduodenal administration of GZ-DE, the concentration ratio of GZ-DE to GZ in bile was approximately 4:1, and the bioavailability of GZ containing GZ-DE was three-fold higher compared with the bioavailability of GZ after intraduodenal administration. GZ-DE was immediately precipitated in pH 1.2 solution and was converted to GZ by hydrolysis in pH 7.4 solution. CONCLUSION: Improvement of intestinal absorption of GZ was made possible by administration of GZ-DE into the intestine where absorption of GZ is lower than in the strong acidic environment of the stomach. However, because the elimination rate in bile simulated from kinetic parameters of GZ-DE was higher than the conversion rate from GZ-DE to GZ by hydrolysis, it is thought that the availability of GZ as a revolutionary prodrug was not high from the viewpoint of bioavailability of GZ in the liver by intestinal administration of GZ-DE. PMID- 24174869 TI - Antioxidant effect of Arabic gum against mercuric chloride-induced nephrotoxicity. AB - The effects of Arabic gum (AG) against nephrotoxicity of mercury (Hg), an oxidative-stress inducing substance, in rats were investigated. A single dose of mercuric chloride (5 mg/kg intraperitoneal injection) induced renal toxicity, manifested biochemically by a significant increase in serum creatinine, blood urea nitrogen, thiobarbituric acid reactive substances, and total nitrate/nitrite production in kidney tissues. In addition, reduced glutathione, glutathione peroxidase, and catalase enzymes in renal tissues were significantly decreased. Pretreatment of rats with AG (7.5 g/kg/day per oral administration), starting 5 days before mercuric chloride injection and continuing through the experimental period, resulted in a complete reversal of Hg-induced increase in creatinine, blood urea nitrogen, thiobarbituric acid reactive substances, and total nitrate/nitrite to control values. Histopathologic examination of kidney tissues confirmed the biochemical data; pretreatment of AG prevented Hg-induced degenerative changes of kidney tissues. These results indicate that AG is an efficient cytoprotective agent against Hg-induced nephrotoxicity by a mechanism related at least in part to its ability to decrease oxidative and nitrosative stress and preserve the activity of antioxidant enzymes in kidney tissues. PMID- 24174870 TI - Increased adherence eight months after switch from twice daily calcineurin inhibitor based treatment to once daily modified released tacrolimus in heart transplantation. AB - BACKGROUND: Modified-release tacrolimus (TAC) is a new, once-daily oral formulation of the established immunosuppressive agent TAC. This study evaluated long-term patient adherence, as well as safety and efficacy, in stable patients after heart transplantation (HTx) who switched from a conventional twice daily calcineurin inhibitor-based regimen (TAC or cyclosporine A [CsA]) to a once-daily modified-release TAC regimen. METHODS: Stable patients were switched from conventional TAC or CsA (twice-daily dosing) to modified-release TAC (once-daily dosing) according to manufacturer's recommendations using a pre-experimental design. Self-reported adherence was assessed at baseline and 8 months after the switch with the Basel Assessment of Adherence with Immunosuppressive Medication Scale (BAASIS). Additionally, routine laboratory values were analyzed 8 months after switch. RESULTS: Of 76 patients (58 male, 18 female) initially included, 72 were available for statistical analysis, as modified-release TAC was discontinued due to diarrhea in one patient and gastrointestinal discomfort in three patients. Overall nonadherence at baseline for any of the four BAASIS items was 75.0% versus 40.3% after 8 months (P<0.0001). After 8 months, adherence was improved in 41 patients (56.9%), unchanged in 27 (37.5%), and reduced in four patients (5.6%). The BAASIS visual analog scale score improved significantly from 87.0% +/ 13.5% to 97.5% +/- 5.7% (P<0.0001). No significant changes were observed for hematological, renal, or liver function parameters after 8 months (all P=not significant). CONCLUSION: To our knowledge, this is the first study in stable patients after HTx to demonstrate a significant improvement in long-term (ie, 8 month) patient adherence after the switch to modified-release TAC. Modified release TAC was generally well tolerated. Further studies are currently underway to investigate long-term safety after HTx of various calcineurin inhibitors for prevention of rejection and occurrence of side effects. PMID- 24174871 TI - Health information, behavior change, and decision support for patients with type 2 diabetes: development of a tailored, preference-sensitive health communication application. AB - PURPOSE: Patient involvement in diabetes treatment such as shared decision-making and patient self-management has significant effects on clinical parameters. As a prerequisite for active involvement, patients need to be informed in an adequate and preference-sensitive way. Interactive Health Communication Applications (IHCAs) that combine web-based health information for patients with additional support offer the opportunity to reach great numbers of patients at low cost and provide them with high-quality information and support at the time, place, and learning speed they prefer. Still, web-based interventions often suffer from high attrition. Tailoring the intervention to patients' needs and preferences might reduce attrition and should thereby increase effectiveness. The purpose of this study was to develop a tailored IHCA offering evidence-based, preference sensitive content and treatment decision support to patients with type 2 diabetes. The content was developed based on a needs assessment and two evidence based treatment guidelines. The delivery format is a dialogue-based, tunneled design tailoring the content and tone of the dialogue to relevant patient characteristics (health literacy, attitudes toward self-care, and psychological barriers to insulin treatment). Both content and tailoring were revised by an interdisciplinary advisory committee. CONCLUSION: The World Wide Web holds great potential for patient information and self-management interventions. With the development and evaluation of a tailored IHCA, we complement face-to-face consultations of patients with their health care practitioners and make them more efficient and satisfying for both sides. Effects of the application are currently being tested within a randomized controlled trial. PMID- 24174872 TI - The function of medication beliefs as mediators between personality traits and adherence behavior in people with asthma. AB - BACKGROUND: There is evidence that both personality traits and personal beliefs about medications affect adherence behavior. However, limited research exists on how personality and beliefs about asthma medication interact in influencing adherence behavior in people with asthma. To extend our knowledge in this area of adherence research, we aimed to determine the mediating effects of beliefs about asthma medication between personality traits and adherence behavior. METHODS: Asthmatics (n=516) selected from a population-based study called West Sweden Asthma Study completed the Neuroticism, Extraversion and Openness to Experience Five-Factor Inventory, the Medication Adherence Report Scale, and the Beliefs about Medicines Questionnaire. Data were analyzed using confirmatory factor analysis and structural equation modeling. RESULTS: Three of the five investigated personality traits - agreeableness, conscientiousness, and neuroticism - were associated with both concerns about asthma medication and adherence behavior. Concerns functioned as a partial mediator for the influencing effects of agreeableness, conscientiousness, and neuroticism on adherence behavior. CONCLUSION: The findings suggest that personality traits could be used to identify individuals with asthma who need support with their adherence behavior. Additionally, targeting concerns about asthma medication in asthmatics with low levels of agreeableness or conscientiousness or high levels of neuroticism could have a favorable effect on their adherence behavior. PMID- 24174873 TI - Dyadic effects of attitude toward aging on psychological well-being of older Malaysian couples: an actor-partner interdependence model. AB - BACKGROUND: There is a growing body of literature indicating that attitudes toward aging significantly affect older adults' psychological well-being. However, there is a paucity of scientific investigations examining the role of older adults' attitudes toward aging on their spouses' psychological well-being. Therefore, the present study aimed to examine the dyadic effects of attitude toward aging on the psychological well-being of older couples. METHODS: Data for the present study, consisting of 300 couples aged 50 years and older, were drawn from a community-based survey entitled "Poverty among Elderly Women: Case Study of Amanah Ikhtiar" conducted in Peninsular Malaysia. An actor-partner interdependence model using AMOS version 20 (Europress Software, Cheshire, UK) was used to analyze the dyadic data. RESULTS: The mean ages of the husbands and wives in this sample were 60.37 years (+/-6.55) and 56.33 years (+/-5.32), respectively. Interdependence analyses revealed significant association between older adults' attitudes toward aging and the attitudes of their spouses (intraclass correlation =0.59; P<0.001), and similar interdependence was found for psychological well-being (intraclass correlation =0.57; P<0.001). The findings from AMOS revealed that the proposed model fits the data (CMIN/degrees of freedom =3.23; goodness-of-fit index =0.90; confirmatory fit index =0.91; root mean square error of approximation =0.08). Results of the actor-partner independence model indicated that older adults' psychological well-being is significantly predicted by their spouses' attitudes toward aging, both among older men (critical ratio =2.92; P<0.01) and women (critical ratio =2.70; P<0.01). Husbands' and wives' own reports of their attitudes toward aging were significantly correlated with their own and their spouses' psychological well being. CONCLUSION: The findings from this study supported the proposed Spousal Attitude-Well-Being Model, where older adults' attitudes toward aging significantly affected their own and their spouses' psychological well-being. The theoretical and practical implications of the findings are discussed. PMID- 24174874 TI - High-efficiency liposomal encapsulation of a tyrosine kinase inhibitor leads to improved in vivo toxicity and tumor response profile. AB - Staurosporine (STS) is a potent pan-kinase inhibitor with marked activity against several chemotherapy-resistant tumor types in vitro. The translational progress of this compound has been hindered by poor pharmacokinetics and toxicity. We sought to determine whether liposomal encapsulation of STS would enhance antitumor efficacy and reduce toxicity, thereby supporting the feasibility of further preclinical development. We developed a novel reverse pH gradient liposomal loading method for STS, with an optimal buffer type and drug-to-lipid ratio. Our approach produced 70% loading efficiency with good retention, and we provide, for the first time, an assessment of the in vivo antitumor activity of STS. A low intravenous dose (0.8 mg/kg) inhibited U87 tumors in a murine flank model. Biodistribution showed preferential tumor accumulation, and body weight data, a sensitive index of STS toxicity, was unaffected by liposomal STS, but did decline with the free compound. In vitro experiments revealed that liposomal STS blocked Akt phosphorylation, induced poly(ADP-ribose) polymerase cleavage, and produced cell death via apoptosis. This study provides a basis to explore further the feasibility of liposomally encapsulated STS, and potentially related compounds for the management of resistant solid tumors. PMID- 24174875 TI - Ordered nanoporous silica as carriers for improved delivery of water insoluble drugs: a comparative study between three dimensional and two dimensional macroporous silica. AB - The goal of the present study was to compare the drug release properties and stability of the nanoporous silica with different pore architectures as a matrix for improved delivery of poorly soluble drugs. For this purpose, three dimensional ordered macroporous (3DOM) silica with 3D continuous and interconnected macropores of different sizes (200 nm and 500 nm) and classic mesoporous silica (ie, Mobil Composition of Matter [MCM]-41 and Santa Barbara Amorphous [SBA]-15) with well-ordered two dimensional (2D) cylindrical mesopores were successfully fabricated and then loaded with the model drug indomethacin (IMC) via the solvent deposition method. Scanning electron microscopy (SEM), N2 adsorption, differential scanning calorimetry (DSC), and X-ray diffraction (XRD) were applied to systematically characterize all IMC-loaded nanoporous silica formulations, evidencing the successful inclusion of IMC into nanopores, the reduced crystallinity, and finally accelerated dissolution of IMC. It was worth mentioning that, in comparison to 2D mesoporous silica, 3DOM silica displayed a more rapid release profile, which may be ascribed to the 3D interconnected pore networks and the highly accessible surface areas. The results obtained from the stability test indicated that the amorphous state of IMC entrapped in the 2D mesoporous silica (SBA-15 and MCM-41) has a better physical stability than in that of 3DOM silica. Moreover, the dissolution rate and stability of IMC loaded in 3DOM silica was closely related to the pore size of macroporous silica. The colorimetric 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and Cell Counting Kit (CCK)-8 assays in combination with direct morphology observations demonstrated the good biocompatibility of nanoporous silica, especially for 3DOM silica and SBA-15. The present work encourages further study of the drug release properties and stability of drug entrapped in different pore architecture of silica in order to realize their potential in oral drug delivery. PMID- 24174876 TI - Agomelatine as monotherapy for major depression: an outpatient, open-label study. AB - BACKGROUND: Agomelatine is a novel antidepressant agonist to MT1 and MT2 subtypes of melatoninergic receptors (MT1 and MT2) and antagonist to 5-HT2C subtype of serotonergic (5-HT2C) receptors, which has shown antidepressant efficacy in short term and long-term trials as well as in clinical practice. The purpose of this study was to assess the antidepressant efficacy, safety, and the influence of agomelatine on the functioning of patient in common clinical practice. METHODS: In this open-label, 8-week, multicenter, Phase IV trial, 111 patients with mainly moderate to severe major depressive disorder (39% treatment-naive) were treated with agomelatine 25-50 mg/day for up to 8 weeks. The primary endpoint was the mean change in total Montgomery and Asberg Depression Rating Scale (MADRS). Secondary endpoints included assessment of clinical response (defined as a reduction in total MADRS score of >=50%), and change in Clinical Global Impression scales, Global Assessment of Functioning scale, Sheehan Disability Scale, and CircScreen sleep questionnaire scores. Safety and tolerability were also monitored. RESULTS: Of the 111 patients enrolled, 94 completed the study. The total MADRS score significantly decreased by the first week of treatment and continued to decline significantly until study completion, with an estimated mean change of 3.9 +/- 3.9 and 17.2 +/- 8.0 at the first and eighth week of the study (last observation carried forward analyses). All other secondary endpoints significantly improved from early treatment evaluation to study completion. A clinical response was observed in 14.1% of patients after the first week, rising to 74.5% of patients at study completion. There were 31 spontaneously reported adverse events in 17 patients, and most were mild to moderate in severity. CONCLUSION: This study showed good short-term efficacy for agomelatine in outpatients with major depressive episodes. Treatment with agomelatine achieved early and consistent responses for symptoms of depression and other dimensions of clinical and functional status. Agomelatine achieved significant improvements in daily functioning of patients, and had good tolerability. Clinically, no hepatic events were observed. PMID- 24174877 TI - Levodopa-induced dyskinesias in Parkinson's disease: emerging treatments. AB - Parkinson's disease therapy is still focused on the use of L-3,4 dihydroxyphenylalanine (levodopa or L-dopa) for the symptomatic treatment of the main clinical features of the disease, despite intensive pharmacological research in the last few decades. However, regardless of its effectiveness, the long-term use of levodopa causes, in combination with disease progression, the development of motor complications termed levodopa-induced dyskinesias (LIDs). LIDs are the result of profound modifications in the functional organization of the basal ganglia circuitry, possibly related to the chronic and pulsatile stimulation of striatal dopaminergic receptors by levodopa. Hence, for decades the key feature of a potentially effective agent against LIDs has been its ability to ensure more continuous dopaminergic stimulation in the brain. The growing knowledge regarding the pathophysiology of LIDs and the increasing evidence on involvement of nondopaminergic systems raises the possibility of more promising therapeutic approaches in the future. In the current review, we focus on novel therapies for LIDs in Parkinson's disease, based mainly on agents that interfere with glutamatergic, serotonergic, adenosine, adrenergic, and cholinergic neurotransmission that are currently in testing or clinical development. PMID- 24174879 TI - Relationships between Salivary Melatonin Levels, Quality of Sleep, and Stress in Young Japanese Females. AB - A decrease in the quality of sleep is believed to cause anxiety and worsen depression. Comparisons of salivary melatonin levels with different factors including quality of sleep, state and trait anxieties, and depression, were conducted to examine whether there is a relationship between melatonin, presumably associated with sleep, and psychological stress. The saliva of healthy young females was collected during the daytime and before they went to bed at night (when they were awake and resting in a sitting position), and salivary melatonin levels were measured. The quality of sleep was scored using the Pittsburgh Sleep Quality Index (PSQI)-a questionnaire method. State and trait anxieties, and depression were scored using other questionnaire methods: the State-Trait Anxiety Inventory (STAI) and Self-Rating Depression Scale (SDS), respectively. The following findings were obtained: (1) Salivary melatonin levels measured during the daytime and before going to bed were higher in females with a high depression score, compared to those with a low score, and there was a correlation between the depression scores and salivary melatonin levels measured at night; and (2) salivary melatonin levels measured before going to bed at night (in a sitting position) were higher in females with a high state anxiety score, suggesting a correlation between state anxiety scores and salivary melatonin levels during the night. Both depression and a sense of anxiety are forms of psychological stress. Therefore, it is assumed that, when a person is under psychological stress, the action of melatonin as a ligand on its receptor is reduced. Meaning psychological stress may induce oxidative stress in the body. On the other hand, no correlation was noted between the quality of sleep and salivary melatonin levels during the night, presumably because saliva was collected when the subjects were awake and sitting, rather than sleeping. PMID- 24174881 TI - Membranous glomerulopathy and treatment with Acthar(r): a case study. AB - Treatment options for refractory membranous nephropathy are limited. Herein we describe the case of a 46-year-old white male with membranous nephropathy who progressed during 3 years of treatment with antihypertensive agents (specifically angiotensin-converting enzyme inhibitors and angiotensin receptor blockers), diuretics, simvastatin, prednisone, cyclosporine A, and mycophenolate mofetil. Prior to initiation of treatment with H.P. Acthar(r) Gel, his proteinuria level was 9,520 mg/dL (952.0 g/L) but it decreased to 2,948 mg/dL (294.8 g/L) after 10 months of Acthar therapy. After 13 months, treatment with Acthar was halted as his 24-hour urinary protein was 1,628 mg/dL (162.8 g/L); by 15 months, it was 407 mg/dL (40.7 g/L). The patient has remained free of signs and symptoms of membranous nephropathy for 1.5 years. These results support the use of Acthar as an effective and safe therapy for patients with refractory membranous nephropathy. PMID- 24174880 TI - The role of second-line chemotherapy in small cell lung cancer: a retrospective analysis. AB - BACKGROUND: To evaluate the benefit of second-line chemotherapy with platinum based treatment in patients with recurrent small cell lung cancer (SCLC). PATIENTS AND METHODS: A total of 535 patients continued with follow-up or best supportive care if needed, and 229 patients who progressed after the completion of first-line chemotherapy were treated with second-line chemotherapy at the time of progression. In total, 103/229 patients received paclitaxel 190 mg/m(2) and carboplatin 5.5 area under the curve while 126/229 patients received etoposide 200 mg/m(2) and carboplatin 5.5 area under the curve every 28 days. RESULTS: Patients administered second-line chemotherapy lived significantly longer, with a median survival of 422 days compared to 228 days in patients with best supportive care alone (P<0.001). Patients who received paclitaxel as second-line chemotherapy lived for an average of 462 days (95% confidence interval: 409-514), versus 405 days in the etoposide group (95% confidence interval: 371-438), which was not statistically significant (P=0.086). The overall response rate was 8% for the paclitaxel group and 6% for the etoposide group. Patients with progression of the disease in more than 3 months had significantly better survival compared with those that progressed in less than 3 months (P<0.001). CONCLUSION: Continuation with carboplatin/paclitaxel or carboplatin/etoposide as second-line chemotherapy has no significant survival impact, and it did not improve response rates. PMID- 24174882 TI - Urinary angiotensinogen is a marker for tubular injuries in patients with type 2 diabetes. AB - PURPOSE: Urinary angiotensinogen has been reported as a marker for the activation of intrarenal renin-angiotensin system (RAS) in various kidney diseases. To investigate the importance of urinary angiotensinogen in diabetic nephropathy, we compared the urinary levels of angiotensinogen, albumin, and alpha1 microglobulin. MATERIALS AND METHODS: Japanese patients with type 2 diabetes at various stages of nephropathy (n=85) were enrolled, and we measured albumin/creatinine ratio (ACR) and urinary excretion of angiotensinogen and alpha1-microglobulin. We also compared the clinical data of the patients treated with or without angiotensin II receptor blockers or angiotensin-converting enzyme inhibitors (RAS inhibitors [+], n=51; RAS inhibitors [-], n=34). RESULTS: Urinary angiotensinogen levels positively correlated with ACR (r=0.367, P=3.84*10(-4)) and urinary alpha1-microglobulin (r=0.734, P=1.32 * 10(-15)), while they negatively correlated with estimated glomerular filtration ratio (eGFR) (r= 0.350, P=1.02 * 10(-3)) and high-density lipoprotein cholesterol (r=-0.216, P=0.049). Multiple regression analysis was carried out to predict urinary angiotensinogen levels by employing eGFR, ACR, and urinary alpha1-microglobulin as independent variables; only urinary alpha1-microglobulin entered the regression equation at a significant level. Although ACR was higher in the RAS inhibitors (+) group, urinary alpha1-microglobulin and angiotensinogen did not show significant increase in the RAS inhibitors (+) group. CONCLUSION: Urinary angiotensinogen is well correlated with urinary alpha1-microglobulin and reflected the tubular injuries which may be associated with the intrarenal RAS activation in patients with type 2 diabetes. PMID- 24174883 TI - Clinical use of vaginal or rectally applied microbicides in patients suffering from HIV/AIDS. AB - Microbicides, primarily used as topical pre-exposure prophylaxis, have been proposed to prevent sexual transmission of HIV. This review covers the trends and challenges in the development of safe and effective microbicides to prevent sexual transmission of HIV Initial phases of microbicide development used such surfactants as nonoxynol-9 (N-9), C13G, and sodium lauryl sulfate, aiming to inactivate the virus. Clinical trials of microbicides based on N-9 and C31G failed to inhibit sexual transmission of HIV. On the contrary, N-9 enhanced susceptibility to sexual transmission of HIV-1. Subsequently, microbicides based on polyanions and a variety of other compounds that inhibit the binding, fusion, or entry of virus to the host cells were evaluated for their efficacy in different clinical setups. Most of these trials failed to show either safety or efficacy for prevention of HIV transmission. The next phase of microbicide development involved antiretroviral drugs. Microbicide in the form of 1% tenofovir vaginal gel when tested in a Phase IIb trial (CAPRISA 004) in a coitally dependent manner revealed that tenofovir gel users were 39% less likely to become HIV-infected compared to placebo control. However, in another trial (VOICE MTN 003), tenofovir gel used once daily in a coitally independent mode failed to show any efficacy to prevent HIV infection. Tenofovir gel is currently in a Phase III safety and efficacy trial in South Africa (FACTS 001) employing a coitally dependent dosing regimen. Further, long-acting microbicide-delivery systems (vaginal ring) for slow release of such antiretroviral drugs as dapivirine are also undergoing clinical trials. Discovering new markers as correlates of protective efficacy, novel long-acting delivery systems with improved adherence in the use of microbicides, discovering new compounds effective against a broad spectrum of HIV strains, developing multipurpose technologies incorporating additional features of efficacy against other sexually transmitted infections, and contraception will help in moving the field of microbicide development forward. PMID- 24174885 TI - Differences of knowledge, attitudes, and behaviors towards epilepsy between populations in municipal and nonmunicipal areas. AB - BACKGROUND: Information on the knowledge of, and attitudes and practices towards epilepsy of the general population in Thailand is still limited, particularly with respect to the differences between populations in municipal and nonmunicipal areas. METHODS: A descriptive cross-sectional survey was conducted in a sample population of 1,000, with 500 participants each from municipal and nonmunicipal areas, in the Khon Kaen district. RESULTS: The participants in the municipal area had higher incomes and higher education than did the participants in the nonmunicipal area. Both groups had low knowledge regarding epilepsy definition, causes, and treatment, but participants in the municipal area were more knowledgeable on the causes, types, and treatment of epilepsy. With respect to attitude, there were a significantly higher number of nonmunicipal participants than municipal participants who thought epilepsy was a disgusting disorder or that persons with epilepsy were sinful, had brain damage, and could not attend school. The municipal participants showed greater knowledge of correct practice than did nonmunicipal participants with regard to the following: not driving a car; avoiding acrobatic sports, fighting, or water sport; able to eat pork, not having to resign from work; not having to quit school; and able to have sexual relations. CONCLUSION: The participants from the municipal area had better knowledge, attitudes, and practices than did the participants from the nonmunicipal area. A campaign should be carried out to promote knowledge and understanding of, and practices towards epilepsy. Different emphases should be placed on the two groups of populations and different strategies used. PMID- 24174886 TI - Use of Parathyroid Hormone Assay after Thyroidectomy: A Survey of US and European Surgeons. AB - INTRODUCTION: Hypocalcemia after thyroidectomy results in prolongation of hospitalization and patient discomfort but can be predicted by PTH assays. However, there is considerable variation in their use. METHODS: This study was undertaken to document current US and European practice patterns regarding the use of this assay. Anonymous surveys were collected in 2009-2011 from members of the American Academies of Otolaryngology-Head and Neck Surgery and Endocrine Surgery and the European, Italian, French, Spanish and British Societies of Endocrine Surgery. RESULTS: There were 356 American (3% response) and 61 European (10% response) respondents. 105 (29.8%) American and 25 (41%) European respondents reported routine PTH assay use. Fellowship trained surgeons reported increased use of the PTH assay (P = 0.004). Shorter reported average post operative hospital stay was associated with American physicians (P = 0.0001), community practice location (P = 0.0002) and routine calcium supplementation (P = 0.0015). CONCLUSIONS: Surgical training was associated with routine use of the PTH assay. Average reported hospital stay was lower for American and community practice physicians and correlated with post-operative oral calcium use. PMID- 24174887 TI - A perspective on the current issues in the DSM-5 classification of personality disorders. AB - David Kupfer chaired the DSM-5 Task Force, and Andrew Skodol the working group, on personality disorders. Various initial propositions were posted on the Internet in 2010 for comment and discussion: new general definition, new criteria, new diagnostic procedures, reduction in the number of categories, and dimensional representation. Following numerous criticisms, the Task Force's final decisions were made public on December 1, 2012. Personality disorders now figure alongside other mental disorders, because of the deletion of Axis II. The methodology concerning personality traits is in a third section to promote new studies. The new proposed hybrid system has not, to date, proven better than the categories of the DSM-IV. These various decisions are commented upon. PMID- 24174884 TI - Intravaginal rings as delivery systems for microbicides and multipurpose prevention technologies. AB - There is a renewed interest in delivering pharmaceutical products via intravaginal rings (IVRs). IVRs are flexible torus-shaped drug delivery systems that can be easily inserted and removed by the woman and that provide both sustained and controlled drug release, lasting for several weeks to several months. In terms of women's health care products, it has been established that IVRs effectively deliver contraceptive steroids and steroids for the treatment of postmenopausal vaginal atrophy. A novel application for IVRs is the delivery of antiretroviral drugs for the prevention of human immunodeficiency virus (HIV) genital infection. Microbicides are antiviral drugs delivered topically for HIV prevention. Recent reviews of microbicide IVRs have focused on technologies in development and optimizing ring design. IVRs have several advantages, including the ability to deliver sustained drug doses for long periods of time while bypassing first pass metabolism in the gut. IVRs are discreet, woman-controlled, and do not require a trained provider for placement or fitting. Previous data support that women and their male sexual partners find IVRs highly acceptable. Multipurpose prevention technology (MPT) products provide protection against unintended/mistimed pregnancy and reproductive tract infections, including HIV. Several MPT IVRs are currently in development. Early clinical testing of new microbicide and MPT IVRs will require a focus on safety, pharmacokinetics and pharmacodynamics. Specifically, IVRs will have to deliver tissue concentrations of drugs that are pharmacodynamically active, do not cause mucosal alterations or inflammation, and do not change the resident microbiota. The emergence of resistance to antiretrovirals will need to be investigated. IVRs should not disrupt intercourse or have high rates of expulsion. Herein, we reviewed the microbicide and MPT IVRs currently in development, with a focus on the clinical aspects of IVR assessment and the challenges facing microbicide and MPT IVR product development, clinical testing, and implementation. The information in this review was drawn from PubMed searches and a recent microbicide/MPT product development workshop organized by CONRAD. PMID- 24174888 TI - Dimensional models of personality: the five-factor model and the DSM-5. AB - It is evident that the classification of personality disorder is shifting toward a dimensional trait model and, more specifically, the five-factor model (FFM). The purpose of this paper is to provide an overview of the FFM of personality disorder. It will begin with a description of this dimensional model of normal and abnormal personality functioning, followed by a comparison with a proposal for future revisions to DSM-5 and a discussion of its potential advantages as an integrative hierarchical model of normal and abnormal personality structure. PMID- 24174878 TI - Molecular sources of residual cardiovascular risk, clinical signals, and innovative solutions: relationship with subclinical disease, undertreatment, and poor adherence: implications of new evidence upon optimizing cardiovascular patient outcomes. AB - Residual risk, the ongoing appreciable risk of major cardiovascular events (MCVE) in statin-treated patients who have achieved evidence-based lipid goals, remains a concern among cardiologists. Factors that contribute to this continuing risk are atherogenic non-low-density lipoprotein (LDL) particles and atherogenic processes unrelated to LDL cholesterol, including other risk factors, the inherent properties of statin drugs, and patient characteristics, ie, genetics and behaviors. In addition, providers, health care systems, the community, public policies, and the environment play a role. Major statin studies suggest an average 28% reduction in LDL cholesterol and a 31% reduction in relative risk, leaving a residual risk of about 69%. Incomplete reductions in risk, and failure to improve conditions that create risk, may result in ongoing progression of atherosclerosis, with new and recurring lesions in original and distant culprit sites, remodeling, arrhythmias, rehospitalizations, invasive procedures, and terminal disability. As a result, identification of additional agents to reduce residual risk, particularly administered together with statin drugs, has been an ongoing quest. The current model of atherosclerosis involves many steps during which disease may progress independently of guideline-defined elevations in LDL cholesterol. Differences in genetic responsiveness to statin therapy, differences in ability of the endothelium to regenerate and repair, and differences in susceptibility to nonlipid risk factors, such as tobacco smoking, hypertension, and molecular changes associated with obesity and diabetes, may all create residual risk. A large number of inflammatory and metabolic processes may also provide eventual therapeutic targets to lower residual risk. Classically, epidemiologic and other evidence suggested that raising high-density lipoprotein (HDL) cholesterol would be cardioprotective. When LDL cholesterol is aggressively lowered to targets, low HDL cholesterol levels are still inversely related to MCVE. The efflux capacity, or ability to relocate cholesterol out of macrophages, is believed to be a major antiatherogenic mechanism responsible for reduction in MCVE mediated in part by healthy HDL. HDL cholesterol is a complex molecule with antioxidative, anti-inflammatory, anti-thrombotic, antiplatelet, and vasodilatory properties, among which is protection of LDL from oxidation. HDL-associated paraoxonase-1 has a major effect on endothelial function. Further, HDL promotes endothelial repair and progenitor cell health, and supports production of nitric oxide. HDL from patients with cardiovascular disease, diabetes, and autoimmune disease may fail to protect or even become proinflammatory or pro-oxidant. Mendelian randomization and other clinical studies in which raising HDL cholesterol has not been beneficial suggest that high plasma levels do not necessarily reduce cardiovascular risk. These data, coupled with extensive preclinical information about the functional heterogeneity of HDL, challenge the "HDL hypothesis", ie, raising HDL cholesterol per se will reduce MCVE. After the equivocal AIM-HIGH (Atherothrombosis Intervention in Metabolic Syndrome With Low HDL/High Triglycerides: Impact on Global Health Outcomes) study and withdrawal of two major cholesteryl ester transfer protein compounds, one for off-target adverse effects and the other for lack of efficacy, development continues for two other agents, ie, anacetrapib and evacetrapib, both of which lower LDL cholesterol substantially. The negative but controversial HPS2-THRIVE (the Heart Protection Study 2-Treatment of HDL to Reduce the Incidence of Vascular Events) trial casts further doubt on the HDL cholesterol hypothesis. The growing impression that HDL functionality, rather than abundance, is clinically important is supported by experimental evidence highlighting the conditional pleiotropic actions of HDL. Non-HDL cholesterol reflects the cholesterol in all atherogenic particles containing apolipoprotein B, and has outperformed LDL cholesterol as a lipid marker of cardiovascular risk and future mortality. In addition to including a measure of residual risk, the advantages of using non-HDL cholesterol as a primary lipid target are now compelling. Reinterpretation of data from the Treating to New Targets study suggests that better control of smoking, body weight, hypertension, and diabetes will help lower residual risk. Although much improved, control of risk factors other than LDL cholesterol currently remains inadequate due to shortfalls in compliance with guidelines and poor patient adherence. More efficient and greater use of proven simple therapies, such as aspirin, beta-blockers, angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers, combined with statin therapy, may be more fruitful in improving outcomes than using other complex therapies. Comprehensive, intensive, multimechanistic, global, and national programs using primordial, primary, and secondary prevention to lower the total level of cardiovascular risk are necessary. PMID- 24174889 TI - Milestones in the history of personality disorders. AB - This paper analyzes the major historical milestones in the study of normal and abnormal personality, from antiquity up until the 20th century. Special attention is paid to the interaction between dimensional and typological approaches, which was a major issue during the preparation of DSM-5. Theories of personality started with the humoral theory of Greek medicine. Pinel, and later Esquirol and Prichard, are credited with the first descriptions of abnormal personalities in textbooks of psychiatry. Between the late 19th and early 20th centuries, elaborate systems of normal and abnormal personality, associating to some degree types and dimensions, were devised by a succession of European psychologists, such as Ribot, Heymans, and Lazursky. Emil Kraepelin and Kurt Schneider proposed classifications of abnormal personality types. In parallel, psychoanalysts stressed the role of early life experiences. Towards the mid-20th century, statistical methods were applied to the scientific validation of personality dimensions with pioneers such as Cattell, anticipating the five-factor model. PMID- 24174891 TI - Borderline personality disorder in adolescents: the He-who-must-not-be-named of psychiatry. AB - This article reviews the possibility and pertinence of diagnosing borderline personality disorder in adolescents. The etiology and clinical manifestations of this disorder in adolescents are discussed, and its management is addressed in terms of psychotherapy, pharmacology, hospitalization issues, and family involvement considerations. PMID- 24174890 TI - The relationship between borderline personality disorder and bipolar disorder. AB - It is clinically important to recognize both bipolar disorder and borderline personality disorder (BPD) in patients seeking treatment for depression, and it is important to distinguish between the two. Research considering whether BPD should be considered part of a bipolar spectrum reaches differing conclusions. We reviewed the most studied question on the relationship between BPD and bipolar disorder: their diagnostic concordance. Across studies, approximately 10% of patients with BPD had bipolar I disorder and another 10% had bipolar II disorder. Likewise, approximately 20% of bipolar II patients were diagnosed with BPD, though only 10% of bipolar I patients were diagnosed with BPD. While the comorbidity rates are substantial, each disorder is nontheless diagnosed in the absence of the other in the vast majority of cases (80% to 90%). In studies examining personality disorders broadly, other personality disorders were more commonly diagnosed in bipolar patients than was BPD. Likewise, the converse is also true: other axis I disorders such as major depression, substance abuse, and post-traumatic stress disorder are also more commonly diagnosed in patients with BPD than is bipolar disorder. These findings challenge the notion that BPD is part of the bipolar spectrum. PMID- 24174892 TI - Psychopathy: cognitive and neural dysfunction. AB - Psychopathy is a developmental disorder marked by emotional deficits and an increased risk for antisocial behavior. It is not equivalent to the diagnosis Antisocial Personality Disorder, which concentrates only on the increased risk for antisocial behavior and not a specific cause-ie, the reduced empathy and guilt that constitutes the emotional deficit. The current review considers data from adults with psychopathy with respect to the main cognitive accounts of the disorder that stress either a primary attention deficit or a primary emotion deficit. In addition, the current review considers data regarding the neurobiology of this disorder. Dysfunction within the amygdala's role in reinforcement learning and the role of ventromedial frontal cortex in the representation of reinforcement value is stressed. Data is also presented indicating potential difficulties within parts of temporal and posterior cingulate cortex. Suggestions are made with respect to why these deficits lead to the development of the disorder. PMID- 24174893 TI - Fear and decision-making in narcissistic personality disorder-a link between psychoanalysis and neuroscience. AB - Linking psychoanalytic studies with neuroscience has proven increasingly productive for identifying and understanding personality functioning. This article focuses on pathological narcissism and narcissistic personality disorder (NPD), with the aim of exploring two clinically relevant aspects of narcissistic functioning also recognized in psychoanalysis: fear and decision-making. Evidence from neuroscientific studies of related conditions, such as psychopathy, suggests links between affective and cognitive functioning that can influence the sense of self-agency and narcissistic self-regulation. Attention can play a crucial role in moderating fear and self-regulatory deficits, and the interaction between experience and emotion can be central for decision-making. In this review we will explore fear as a motivating factor in narcissistic personality functioning, and the impact fear may have on decision-making in people with pathological narcissism and NPD. Understanding the processes and neurological underpinnings of fear and decision-making can potentially influence both the diagnosis and treatment of NPD. PMID- 24174894 TI - Personality disorders at the interface of psychiatry and the law: legal use and clinical classification. AB - Personality disorders have a complex relationship with the law that in many ways reflects their complexity within the clinical and research communities. This paper addresses expert testimony about personality disorders, outlines how personality disorders are assessed in forensic cases, and describes how personality disorders are viewed in different legal contexts. Reasons are identified why personality disorders are not generally accepted as significant mental illness within the legal system, including high incidence of personality dysfunction in criminal populations, frequent comorbidity of personality disorders making it difficult to determine direct causation, and difficulty determining where on a continuum personality traits should be defined as illness (or not). In summary, the legal system, to a significant degree, mirrors the clinical conception of personality disorders as not severe mental diseases or defects, not likely to change, and most often, under volitional control. PMID- 24174896 TI - Caregiver-mediated approaches to managing challenging behaviors in children with autism spectrum disorder. AB - A significant proportion of children with autism spectrum disorder (ASD) are referred to mental health centers due to the presence of challenging behaviors. Because challenging behaviors in children and adolescents with ASD often result from underlying social and communication difficulties and comorbid anxiety, traditional caregiver-mediated behavior intervention techniques developed for children with disruptive behavior disorders may need to be adapted for this population. Behavioral interventions that target communication skills, social skills, anxiety, and sensory responsiveness in children with ASD may be needed. Notably, while best practice necessitates the involvement of caregivers in treating children and adolescents with ASD, few randomized control studies have examined the effectiveness of caregiver-implemented interventions in reducing challenging behaviors. This review summarizes the current literature with regard to caregiver-mediated behavioral interventions for children with ASD, and suggests areas for intervention development and research. PMID- 24174897 TI - BRAIN: innovative neurotechnologies for imaging and therapeutics. AB - Conceived with the aim of meeting the needs of the neurobiology and clinical communities, the Brain Research through Advancing Innovative Technologies (BRAIN) Initiative builds on the lessons learned from major projects in genetics, such as the Human Genome Project. It concentrates on the use of new imaging technologies in conjunction with genomics to inform therapeutic decisions. PMID- 24174895 TI - Psychopharmacologic treatment of borderline personality disorder. AB - The best available evidence for psychopharmacologic treatment of borderline personality disorder (BPD) is outlined here. BPD is defined by disturbances in identity and interpersonal functioning, and patients report potential medication treatment targets such as impulsivity, aggression, transient psychotic and dissociative symptoms, and refractory affective instability Few randomized controlled trials of psychopharmacological treatments for BPD have been published recently, although multiple reviews have converged on the effectiveness of specific anticonvulsants, atypical antipsychotic agents, and omega-3 fatty acid supplementation. Stronger evidence exists for medication providing significant improvements in impulsive aggression than in affective or other interpersonal symptoms. Future research strategies will focus on the potential role of neuropeptide agents and medications with greater specificity for 2A serotonin receptors, as well as optimizing concomitant implementation of evidence-based psychotherapy and psychopharmacology, in order to improve BPD patients' overall functioning. PMID- 24174898 TI - Structure and function of complex brain networks. AB - An increasing number of theoretical and empirical studies approach the function of the human brain from a network perspective. The analysis of brain networks is made feasible by the development of new imaging acquisition methods as well as new tools from graph theory and dynamical systems. This review surveys some of these methodological advances and summarizes recent findings on the architecture of structural and functional brain networks. Studies of the structural connectome reveal several modules or network communities that are interlinked by hub regions mediating communication processes between modules. Recent network analyses have shown that network hubs form a densely linked collective called a "rich club," centrally positioned for attracting and dispersing signal traffic. In parallel, recordings of resting and task-evoked neural activity have revealed distinct resting-state networks that contribute to functions in distinct cognitive domains. Network methods are increasingly applied in a clinical context, and their promise for elucidating neural substrates of brain and mental disorders is discussed. PMID- 24174900 TI - Functional neuroimaging and schizophrenia: a view towards effective connectivity modeling and polygenic risk. AB - We review critical trends in imaging genetics as applied to schizophrenia research, and then discuss some future directions of the field. A plethora of imaging genetics studies have investigated the impact of genetic variation on brain function, since the paradigm of a neuroimaging intermediate phenotype for schizophrenia first emerged. It was initially posited that the effects of schizophrenia susceptibility genes would be more penetrant at the level of biologically based neuroimaging intermediate phenotypes than at the level of a complex and phenotypically heterogeneous psychiatric syndrome. The results of many studies support this assumption, most of which show single genetic variants to be associated with changes in activity of localized brain regions, as determined by select cognitive controlled tasks. From these basic studies, functional neuroimaging analysis of intermediate phenotypes has progressed to more complex and realistic models of brain dysfunction, incorporating models of functional and effective connectivity, including the modalities of psycho physiological interaction, dynamic causal modeling, and graph theory metrics. The genetic association approaches applied to imaging genetics have also progressed to more sophisticated multivariate effects, including incorporation of two-way and three-way epistatic interactions, and most recently polygenic risk models. Imaging genetics is a unique and powerful strategy for understanding the neural mechanisms of genetic risk for complex CNS disorders at the human brain level. PMID- 24174899 TI - Animal models and high field imaging and spectroscopy. AB - A plethora of magnetic resonance (MR) techniques developed in the last two decades provide unique and noninvasive measurement capabilities for studies of basic brain function and brain diseases in humans. Animal model experiments have been an indispensible part of this development. MR imaging and spectroscopy measurements have been employed in animal models, either by themselves or in combination with complementary and often invasive techniques, to enlighten us about the information content of such MR methods and/or verify observations made in the human brain. They have also been employed, with or independently of human efforts, to examine mechanisms underlying pathological developments in the brain, exploiting the wealth of animal models available for such studies. In this endeavor, the desire to push for ever-higher spatial and/or spectral resolution, better signal-to-noise ratio, and unique image contrast has inevitably led to the introduction of increasingly higher magnetic fields. As a result, today, animal model studies are starting to be conducted at magnetic fields ranging from ~ 11 to 17 Tesla, significantly enhancing the armamentarium of tools available for the probing brain function and brain pathologies. PMID- 24174901 TI - Brain oscillations in neuropsychiatric disease. AB - The term "brain (or neural) oscillations" refers to the rhythmic and/or repetitive electrical activity generated spontaneously and in response to stimuli by neural tissue in the central nervous system. The importance of brain oscillations in sensory-cognitive processes has become increasingly evident. It has also become clear that event-related oscillations are modified in many types of neuropathology, in particular in cognitive impairment. This review discusses methods such as evoked/event-related oscillations and spectra, coherence analysis, and phase locking. It gives examples of applications of essential methods and concepts in bipolar disorder that provide a basis for fundamental notions regarding neurophysiologic biomarkers in cognitive impairment. The take home message is that in the development of diagnostic and pharmacotherapeutic strategies, neurophysiologic data should be analyzed in a framework that uses a multiplicity of methods and frequency bands. PMID- 24174902 TI - High-frequency oscillations and the neurobiology of schizophrenia. AB - Neural oscillations at low- and high-frequency ranges are a fundamental feature of large-scale networks. Recent evidence has indicated that schizophrenia is associated with abnormal amplitude and synchrony of oscillatory activity, in particular, at high (beta/gamma) frequencies. These abnormalities are observed during task-related and spontaneous neuronal activity which may be important for understanding the pathophysiology of the syndrome. In this paper, we shall review the current evidence for impaired beta/gamma-band oscillations and their involvement in cognitive functions and certain symptoms of the disorder. In the first part, we will provide an update on neural oscillations during normal brain functions and discuss underlying mechanisms. This will be followed by a review of studies that have examined high-frequency oscillatory activity in schizophrenia and discuss evidence that relates abnormalities of oscillatory activity to disturbed excitatory/inhibitory (E/I) balance. Finally, we shall identify critical issues for future research in this area. PMID- 24174903 TI - Molecular imaging as a guide for the treatment of central nervous system disorders. AB - Molecular imaging techniques have a number of advantages for research into the pathophysiology and treatment of central nervous system (CNS) disorders. Firstly, they provide a noninvasive means of characterizing physiological processes in the living brain, enabling molecular alterations to be linked to clinical changes. Secondly, the pathophysiological target in a given CNS disorder can be measured in animal models and in experimental human models in the same way, which enables translational research. Moreover, as molecular imaging facilitates the detection of functional change which precedes gross pathology, it is particularly useful for the early diagnosis and treatment of CNS disorders. This review considers the application of molecular imaging to CNS disorders focusing on its potential to inform the development and evaluation of treatments. We focus on schizophrenia, Parkinson's disease, depression, and dementia as major CNS disorders. We also review the potential of molecular imaging to guide new drug development for CNS disorders. PMID- 24174904 TI - Use of proton magnetic resonance spectroscopy in the treatment of psychiatric disorders: a critical update. AB - Because of the wide availability of hardware as well as of standardized analytic quantification tools, proton magnetic resonance spectroscopy ((1)H-MRS) has become widely used to study psychiatric disorders. (1)H-MRS allows measurement of brain concentrations of more traditional singlet neurometabolites like N acetylaspartate, choline, and creatine. More recently, quantification of the more complex multiplet spectra for glutamate, glutamine, inositol, and gamma aminobutyric acid have also been implemented. Here we review applications of (1)H MRS in terms of informing treatment options in schizophrenia, bipolar disorder, and major depressive disorders. We first discuss recent meta-analytic studies reporting the most reliable findings. Then we evaluate the more sparse literature focused on 1H-MRS-detected neurometabolic effects of various treatment approaches in psychiatric populations. Finally we speculate on future developments that may result in translation of these tools to improve the treatment of psychiatric disorders. PMID- 24174905 TI - Schizophrenia and abnormal brain network hubs. AB - Schizophrenia is a heterogeneous psychiatric disorder of unknown cause or characteristic pathology. Clinical neuroscientists increasingly postulate that schizophrenia is a disorder of brain network organization. In this article we discuss the conceptual framework of this dysconnection hypothesis, describe the predominant methodological paradigm for testing this hypothesis, and review recent evidence for disruption of central/hub brain regions, as a promising example of this hypothesis. We summarize studies of brain hubs in large-scale structural and functional brain networks and find strong evidence for network abnormalities of prefrontal hubs, and moderate evidence for network abnormalities of limbic, temporal, and parietal hubs. Future studies are needed to differentiate network dysfunction from previously observed gray- and white-matter abnormalities of these hubs, and to link endogenous network dysfunction phenotypes with perceptual, behavioral, and cognitive clinical phenotypes of schizophrenia. PMID- 24174906 TI - The brain's default network: origins and implications for the study of psychosis. AB - The brain's default network is a set of regions that is spontaneously active during passive moments. The network is also active during directed tasks that require participants to remember past events or imagine upcoming events. One hypothesis is that the network facilitates construction of mental models (simulations) that can be used adaptively in many contexts. Extensive research has considered whether disruption of the default network may contribute to disease. While an intriguing possibility, a specific challenge to this notion is the fact that it is difficult to accurately measure the default network in patients where confounds of head motion and compliance are prominent. Nonetheless, some intriguing recent findings suggest that dysfunctional interactions between front-oparietal control systems and the default network contribute to psychosis. Psychosis may be a network disturbance that manifests as disordered thought partly because it disrupts the fragile balance between the default network and competing brain systems. PMID- 24174908 TI - Simultaneous EEG and fMRI: towards the characterization of structure and dynamics of brain networks. AB - Progress in the understanding of normal and disturbed brain function is critically dependent on the methodological approach that is applied. Both electroencephalography (EEG) and functional magnetic resonance imaging (fMRI) are extremely efficient methods for the assessment of human brain function. The specific appeal of the combination is related to the fact that both methods are complementary in terms of basic aspects: EEG is a direct measurement of neural mass activity and provides high temporal resolution. FMRI is an indirect measurement of neural activity and based on hemodynamic changes, and offers high spatial resolution. Both methods are very sensitive to changes of synaptic activity, suggesting that with simultaneous EEG and fMRI the same neural events can be characterized with both high temporal and spatial resolution. Since neural oscillations that can be assessed with EEG are a key mechanism for multi-site communication in the brain, EEG-fMRI can offer new insights into the connectivity mechanisms of brain networks. PMID- 24174909 TI - Existence and uniqueness of solution for a class of stochastic differential equations. AB - A class of stochastic differential equations given by dx(t) = f(x(t))dt + g(x(t))dW(t), x(t 0) = x 0, t 0 <= t <= T < +infinity, are investigated. Upon making some suitable assumptions, the existence and uniqueness of solution for the equations are obtained. Moreover, the existence and uniqueness of solution for stochastic Lorenz system, which is illustrated by example, are in good agreement with the theoretical analysis. PMID- 24174907 TI - Typical and atypical brain development: a review of neuroimaging studies. AB - In the course of development, the brain undergoes a remarkable process of restructuring as it adapts to the environment and becomes more efficient in processing information. A variety of brain imaging methods can be used to probe how anatomy, connectivity, and function change in the developing brain. Here we review recent discoveries regarding these brain changes in both typically developing individuals and individuals with neurodevelopmental disorders. We begin with typical development, summarizing research on changes in regional brain volume and tissue density, cortical thickness, white matter integrity, and functional connectivity. Space limits preclude the coverage of all neurodevelopmental disorders; instead, we cover a representative selection of studies examining neural correlates of autism, attention deficit/hyperactivity disorder, Fragile X, 22q11.2 deletion syndrome, Williams syndrome, Down syndrome, and Turner syndrome. Where possible, we focus on studies that identify an age by diagnosis interaction, suggesting an altered developmental trajectory. The studies we review generally cover the developmental period from infancy to early adulthood. Great progress has been made over the last 20 years in mapping how the brain matures with MR technology. With ever-improving technology, we expect this progress to accelerate, offering a deeper understanding of brain development, and more effective interventions for neurodevelopmental disorders. PMID- 24174910 TI - Assessment of pulse oximeter perfusion index in pediatric caudal block under basal ketamine anesthesia. AB - Whether pulse oximeter perfusion index (PI) may be applied to detect the onset of caudal block in pediatric patients under ketamine intravenous basal anesthesia is investigated. 40 ASA I, 2-8-year-old boys scheduled for elective circumcision surgery were randomized into two groups. Group I: 20 patients were anesthetized by 2 mg.kg(-1) ketamine intravenous injection (IV) followed by caudal block using 1 mL.kg(-1) lidocaine (1%); Group II: 20 patients were anesthetized by 2 mg.kg( 1) ketamine IV only. PI on the toe in Group II decreased by 33 +/- 12%, 71 +/- 9% and 65 +/- 8% at 1 min, 15 min, and 30 min after ketamine injection. The maximum increase in MAP and HR after ketamine IV was 11 +/- 6% at 3 min and 10 +/- 6% at 2 min. Compared to the PI value before caudal injection of lidocaine, PI in Group I increased by 363 +/- 318% and 778 +/- 578% at 5 min and 20 min after caudal block, while no significant changes in MAP and HR were found compared to the baseline before caudal block. Thus, PI provides an earlier, more objective, and more sensitive indicator to assess the early onset of caudal block under basal ketamine anesthesia. PMID- 24174911 TI - Hydrogen-rich gas production by cogasification of coal and biomass in an intermittent fluidized bed. AB - This paper presents the experimental results of cogasification of coal and biomass in an intermittent fluidized bed reactor, aiming to investigate the influences of operation parameters such as gasification temperature (T), steam to biomass mass ratio (SBMR), and biomass to coal mass ratio (BCMR) on hydrogen-rich (H2-rich) gas production. The results show that H2-rich gas free of N2 dilution is produced and the H2 yield is in the range of 18.25~68.13 g/kg. The increases of T, SBMR, and BCMR are all favorable for promoting the H2 production. Higher temperature contributes to higher CO and H2 contents, as well as H2 yield. The BCMR has a weak influence on gas composition, but the yield and content of H2 increase with BCMR, reaching a peak at the BCMR of 4. The H2 content and yield in the product gas increase with SBMR, whilst the content of CO increases first and then decreases correspondingly. At a typical case, the relative linear sensitivity coefficients of H2 production efficiency to T, SBMR, and BCMR were calculated. The results reveal that the order of the influence of the operation parameters on H2 production efficiency is T > SBMR > BCMR. PMID- 24174912 TI - Biobanking in a constantly developing medical world. AB - Biobank is a very sophisticated system that consists of a programmed storage of biological material and corresponding data. Biobanks are created to be used in medical research, in clinical and translational medicine, and in healthcare. In the past 20 years, a large number of biobanks have been set up around the world, to support the modern research directions in medicine such as omix and personalized medicine. More recently, embryonic and adult stem cell banks have been developed. Stem cell banking was reported to be required for medical research as well as clinical transplant applications. The quality of the samples stored in a biobank is very important. The standardization is also important; the biological material stored in a biobank must be processed in a manner that allows compatibility with other biobanks that preserve samples in the same field. In this paper, we review some issues related to biobanks purposes, quality, harmonization, and their financial and ethical aspects. PMID- 24174913 TI - Cognitive intraindividual variability and white matter integrity in aging. AB - The intraindividual variability (IIV) of cognitive performance has been shown to increase with aging. While brain research has generally focused on mean performance, little is known about neural correlates of cognitive IIV. Nevertheless, some studies suggest that IIV relates more strongly than mean level of performance to the quality of white matter (WM). Our study aims to explore the relation between WM integrity and cognitive IIV by combining functional (fMRI) and structural (diffusion tensor imaging, DTI) imaging. Twelve young adults (aged 18-30 years) and thirteen older adults (61-82 years) underwent a battery of neuropsychological tasks, along with fMRI and DTI imaging. Their behavioral data were analyzed and correlated with the imaging data at WM regions of interest defined on the basis of (1) the fMRI-activated areas and (2) the Johns Hopkins University (JHU) WM tractography atlas. For both methods, fractional anisotropy, along with the mean, radial, and axial diffusivity parameters, was computed. In accord with previous studies, our results showed that the DTI parameters were more related to IIV than to mean performance. Results also indicated that age differences in the DTI parameters were more pronounced in the regions activated primarily by young adults during a choice reaction-time task than in those also activated in older adults. PMID- 24174914 TI - Rao and Wald tests for adaptive detection in partially homogeneous environment with a diversely polarized antenna. AB - This study considers Rao test and Wald test for adaptive detection based on a diversely polarized antenna (DPA) in partially homogeneous environment. The theoretical expressions for the probability of false alarm and detection are derived, and constant false alarm rate (CFAR) behaviour is remarked on. Furthermore, the monotonicities of detection probability of the two detectors are proved, and a polarization optimization detection algorithm to enhance the detection performance is proposed. The numerical simulations are conducted to attest to the validity of the above theoretical analysis and illustrate the improvement in the detection performance of the proposed optimization algorithm. PMID- 24174915 TI - Partial cutting of sternothyroid muscle during total thyroidectomy: impact on postoperative vocal outcomes. AB - BACKGROUND: Cutting the sternothyroid (ST) muscle is a useful technique to expose the superior pole of thyroid gland during thyroidectomy. In this study, we evaluated the impact of partial cutting of the ST muscle on postoperative vocal outcomes after total thyroidectomy. METHODS: A retrospective review of 57 patients who underwent total thyroidectomy with central neck dissection for micropapillary thyroid carcinoma was conducted. Group A (n = 26) included those without cutting the ST muscle, while group B (n = 31) included patients whose muscle was partially cut at the superior pole. All patients underwent voice analysis before the operation and 2 weeks and 1 month after the surgery, and the outcomes were compared between the two groups. RESULTS: There were no differences between the two groups regarding the outcomes at each time of voice analysis. Group A showed a decrease of maximum frequency 2 weeks after surgery but showed no difference after 1 month. Group B showed a mild decrease in maximum frequency 2 weeks after surgery, but the difference was not significant. CONCLUSION: Partial cutting of ST muscle during thyroidectomy is useful to expose the superior pole without significant negative impact on postoperative outcomes of vocal analysis. PMID- 24174917 TI - Analysis of face stability during excavation of Double-O-Tube shield tunnel. AB - This paper focuses on the face stability analysis of Double-O-Tube shield tunnel. This kind of analysis is significant to ensure the safety of workers and reduce the influence on the surrounding environment. The key point of the stability analysis is to determine the supporting pressure applied to the face by the shield. A collapse failure will occur when the supporting pressure is not sufficient to prevent the movement of the soil mass towards the tunnel. A three dimensional collapse failure mechanism was presented in this paper. Based on the mechanism of a single circular shield tunnel, the mechanism of Double-O-Tube shield tunnel was established by using the fact that both of the mechanisms are symmetrical. Then by means of the kinematic theorem of limit analysis, the numerical results were obtained, and a design chart was provided. The finite difference software FLAC3D was applied to investigate the face failure mechanism of DOT shield tunnel established in this paper; the critical supporting pressures of the collapse failure mechanism in different strata (sand and silt) were calculated. Through comparative analysis, the theoretical values were very close to the numerical values. This shows that the face failure mechanism of DOT shield tunnel is reasonable, and it can be applied to the sand and silt strata. PMID- 24174916 TI - Release of gentamicin and vancomycin from preformed spacers in infected total hip arthroplasties: measurement of concentrations and inhibitory activity in patients' drainage fluids and serum. AB - Gentamicin (G) and vancomycin (V) concentrations in drainage fluids obtained from patients during the first 24 hours after implantation of antibiotic-loaded polymethylmethacrylate (PMMA) spacers in two-stage revision of infected total hip arthroplasty were studied. The inhibitory activity of drainage fluids against different multiresistant clinical isolates was investigated as well. Seven hips were treated by implantation of industrial G-loaded spacers. Vancomycin was added by manually mixing with PMMA bone cement. Serum and drainage fluid samples were collected 1, 4, and 24 hours after spacer implantation. Antibiotics concentrations and drains bactericidal titer of combination were determined against multiresistant staphylococcal strains. The release of G and V from PMMA cement at the site of infection was prompt and effective. Serum levels were below the limit of detection. The local release kinetics of G and V from PMMA cement was similar, exerting a pronounced, combined inhibitory effect in the implant site. The inhibitory activity of drainage fluids showed substantial intersubject variability related to antibiotic concentrations and differed according to the pathogens tested. Gentamicin and vancomycin were released from temporary hip spacers at bactericidal concentrations, and their use in combination exerted strong inhibition against methicillin-resistant S. aureus and Coagulase Negative Staphylococci strains. PMID- 24174918 TI - Optimization of extraction parameters by using response surface methodology, purification, and identification of anthocyanin pigments in Melastoma malabathricum fruit. AB - Anthocyanins not just have various benefits in food industry but also have been used as natural colourants in cosmetic, coating products and as potential natural photosensitizers in solar cell. Thus, the main purpose of this study was to obtain information on the maximum yield of anthocyanin that can be recovered from Melastoma malabathricum fruit. Factors such as extraction temperature, extraction time, and solid to liquid ratio were identified to be significantly affecting anthocyanin extraction efficiency. By using three-level three-factor Box-Behnken design, the optimized conditions for anthocyanin extraction by acidified methanol (R (2) = 0.972) were temperature of 60 degrees C, time of 86.82 min, and 0.5 : 35 (g/mL) solid to liquid ratio while the optimum extraction conditions by acidified ethanol (R (2) = 0.954) were temperature of 60 degrees C, time of 120 min, and 0.5 : 23.06 (g/mL) solid to liquid ratio. The crude anthocyanin extract was further purified by using Amberlite XAD-7 and Sephadex LH-20 column chromatography. Identification of anthocyanins revealed the presence of cyanidin dihexoside, cyanidin hexoside, and delphinidin hexoside as the main anthocyanins in M. malabathricum fruit. PMID- 24174919 TI - Understanding infection: a primer on animal models of periprosthetic joint infection. AB - Periprosthetic joint infections are devastating complications for patients and for our health system. With growing demand for arthroplasty, the incidence of these infections is projected to increase exponentially. This paper is a review of existing animal models to study periprosthetic infection aimed at providing scientists with a succinct presentation of strengths and weaknesses of available in vivo systems. These systems represent the tools available to investigate novel antimicrobial therapies and reduce the clinical and economic impact of implant infections. PMID- 24174920 TI - A self-adaptive parameter optimization algorithm in a real-time parallel image processing system. AB - Aiming at the stalemate that precision, speed, robustness, and other parameters constrain each other in the parallel processed vision servo system, this paper proposed an adaptive load capacity balance strategy on the servo parameters optimization algorithm (ALBPO) to improve the computing precision and to achieve high detection ratio while not reducing the servo circle. We use load capacity functions (LC) to estimate the load for each processor and then make continuous self-adaptation towards a balanced status based on the fluctuated LC results; meanwhile, we pick up a proper set of target detection and location parameters according to the results of LC. Compared with current load balance algorithm, the algorithm proposed in this paper is proceeded under an unknown informed status about the maximum load and the current load of the processors, which means it has great extensibility. Simulation results showed that the ALBPO algorithm has great merits on load balance performance, realizing the optimization of QoS for each processor, fulfilling the balance requirements of servo circle, precision, and robustness of the parallel processed vision servo system. PMID- 24174921 TI - An investigation of family SES-based inequalities in depressive symptoms from early adolescence to emerging adulthood. AB - Using the life course cumulative advantage/disadvantage (CAD) perspective, this study examines the influence of early family SES on trajectories of depressive symptoms spanning from early adolescence to early adulthood, as well as variations in SES-based inequality in depressive symptoms trajectories over this period. This study looks at direct influences of family SES and SES-age interactions (exposure-dependent CAD mechanisms), as well as indirect influences through SES-linked youth experiences (path-dependent CAD mechanisms) to explain variations in SES-based inequality. Data was derived from the Add Health study- a national longitudinal survey of 14,000 adolescents. Results showed large and significant effects of early family SES and associated factors on depressive symptoms in early adolescence, but diminishing effects in middle and late adolescence, supporting the hypothesis of equalization in adolescent health across levels of SES. Disparities in depression reemerged as adolescents entered adulthood, supporting the view that SES-based health equalization is only a temporary process. These findings also strengthen the concept of life course CAD processes, stemming from family characteristics, coming into play later in life. Early family SES was directly and indirectly related to a set of transition related risks and challenges during emerging adulthood, to which young adults from families of higher SES responded more effectively than those of lower SES. This paper discusses theoretical and methodological implications of the findings. PMID- 24174922 TI - Genetic Association between Neurotrophin-3 Polymorphisms and Alzheimer's Disease in Japanese Patients. AB - BACKGROUND: Some polymorphisms of the neurotrophin family have previously been investigated as candidate genes for Alzheimer's disease (AD). In the present study, we examined whether neurotrophin-3 (NTF-3) polymorphisms are genetic risk factors in patients with AD. METHODS: From a sample of 507 subjects, we recruited 248 age-matched subjects divided into 2 groups: AD patients (n = 143) and normal controls (NCs) (n = 105). We identified 3 representative NTF-3 single nucleotide polymorphisms (SNPs): rs6332, rs6489630, and rs4930767. Next, we statistically compared the allele frequencies of each SNP between the AD and NC groups in the early-onset (<65 years) cases under a more limited age-matched condition. RESULTS: We found a significant association between rs6332 and the total group of AD patients (p = 0.013) and significant associations between both rs6332 (p = 0.033) and rs6489630 (p = 0.035) and early-onset AD patients. CONCLUSION: These results suggest that NTF-3 SNPs may not only be associated with AD itself, but also with early-onset AD in Japanese patients, assuming that the NTF-3 gene may have age-related effects on neurodegenerative diseases. PMID- 24174923 TI - Comparing clinical profiles in Alzheimer's disease and Parkinson's disease dementia. AB - BACKGROUND: Greater understanding of differences in baseline impairment and disease progression in patients with Alzheimer's disease (AD) and Parkinson's disease dementia (PDD) may improve the interpretation of drug effects and the design of future studies. METHODS: This was a retrospective analysis of three randomized, double-blind rivastigmine databases (one in PDD, two in AD). Impairment on the Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS cog), Alzheimer's Disease Cooperative Study-Activities of Daily Living (ADCS-ADL) scale, 10-item Neuropsychiatric Inventory (NPI-10) and the ADCS-Clinical Global Impression of Change (CGIC) was compared [standardized difference (Cohen's d), similar if <0.1]. RESULTS: Patients with AD or PDD had similar levels of impairment on the ADAS-cog and NPI-10. Scores on the ADCS-ADL scale (standardized difference = 0.47) and the ADAS-cog memory domain (total, 0.33; items, 0.10-0.58) were higher in AD; PDD patients were more impaired in the language (0.23) and praxis (0.34) domains. AD patients receiving placebo showed greater deterioration on the ADAS-cog (0.14) and improvement on the NPI-10 (0.11) compared with patients with PDD. CONCLUSION: Differing patterns of impairment occur in AD and PDD. PMID- 24174924 TI - Correlates of Subjective and Mild Cognitive Impairment: Depressive Symptoms and CSF Biomarkers. AB - AIMS: To improve early diagnosis of dementia disease, this study investigates correlates of cognitive complaints and cognitive test performance in patients with subjective (SCI) and mild (MCI) cognitive impairment. METHODS: Seventy patients from a memory clinic, aged 45-79, with a score of 2 (n = 23) or 3 (n = 47) on the Global Deterioration Scale, were included. CSF biomarkers [Abeta42, total tau (T-tau) and phosphorylated tau (P-tau)], depressive symptoms, cognitive performance, and complaints were examined. RESULTS: Correlation analysis showed that cognitive complaints increased with decreasing cognitive performance in SCI and decreased with decreasing performance in MCI. Linear regression models revealed that cognitive complaints were associated with depressive symptoms in both groups of patients, while cognitive performance was associated with CSF Abeta42 and P-tau in SCI and with T-tau and P-tau in MCI. CONCLUSION: These results suggest that depressive symptoms are associated with cognitive complaints, while degenerative changes are associated with objective cognitive decline in high-risk predementia states. PMID- 24174925 TI - Cognitive interventions in mild Alzheimer's disease: a therapy-evaluation study on the interaction of medication and cognitive treatment. AB - BACKGROUND/AIMS: Many studies have shown that not only pharmacological treatment but also cognitive stimulation in the early stages of Alzheimer's disease (AD) improves language processing and (other) cognitive functions, stabilizes Activities of Daily Living (ADL) and Instrumental Activities of Daily Living (IADL) functions and increases the subjective quality of life (wherein a combination of pharmacological intervention and cognitive stimulation could provide greater relief of clinical symptoms than either intervention given alone). Today, it is no longer the question of whether cognitive stimulation helps but rather what kind of stimulation helps more than others. METHODS: A sample of 42 subjects with mild AD (all medicated with an acetylcholinesterase inhibitor and well adjusted) underwent clinical and cognitive evaluation and participated in a 6-month study with 2 experimental groups (i.e. 'client centered' global stimulation vs. cognitive training) and a control group. Since the test performance also depends on the individual test, we used a wide variety of tests; we z-transformed the results and then calculated the mean value for the global cognitive status (using the Mini-Mental State Examination) as well as for the single functional areas. RESULTS: Between-group differences were found, they were overall in favor of the experimental groups. Different functional areas led to different treatment and test patterns. Client-centered, global, cognitive therapy stimulated many cognitive functions and thus led to a better performance in language processing and ADL/IADL. The subjective quality of life increased as well. The cognitive training (of working memory) improved only the ADL/IADL performance (more, however, than client-centered, global, cognitive stimulation) and stabilized the level of performance in the other three functional areas. (c) 2013 S. Karger AG, Basel. PMID- 24174926 TI - Cognitive decline predicts long-term care insurance requirement certification in community-dwelling older Japanese adults: a prospective cohort study. AB - AIM: The purpose of this prospective cohort study is to examine whether cognitive decline is an independent predictor of new long-term care insurance (LTCI) requirement certifications in Japan. METHODS: A total of 5,765 community-dwelling older Japanese adults who, at baseline, were independent in terms of their activities of daily living participated in this study and were followed up for 18 months. The outcome measure was the number of new LTCI requirement certifications during the 18-month period of the study. We collected demographic information through questionnaires and assessed cognitive skills with the Cognitive Performance Scale (CPS). The participants were divided into 3 groups according to CPS scores (0, 1, and 2 or greater). RESULTS: During the 18-month period, 399 subjects (6.9%) became newly certified for LTCI services. In a multivariate Cox proportional hazards model, older participants with a CPS score of 1 (adjusted HR: 1.39, 95% CI: 1.08-1.77) and 2 or greater (adjusted HR: 2.27, 95% CI: 1.74 2.96) were significantly more likely to receive an LTCI certification compared to those with a CPS score of 0. CONCLUSIONS: Cognitive decline is an independent predictor of new LTCI requirement certifications and the severity of cognitive decline in elderly adults is positively associated with receiving an LTCI requirement certification in Japan. PMID- 24174927 TI - Rate of conversion from prodromal Alzheimer's disease to Alzheimer's dementia: a systematic review of the literature. AB - BACKGROUND: The purpose of this study was to summarize published estimates for conversion from mild cognitive impairment or amnestic mild cognitive impairment to Alzheimer's dementia. We carried out a systematic review of English language publications to identify cohort studies published since January 2006 that reported the risk or rate of conversion. SUMMARY: Thirty-two cohort studies were identified, of which 14 reported annualized conversion rates (ACRs). Conversions over 1 year ranged from 10.2 to 33.6% (5 studies, median: 19.0%), and over 2 years from 9.8 to 36.3% (7 studies, median: 18.6%). ACRs ranged from 7.5 to 16.5% (7 studies, median: 11.0%) per person-year for studies recruiting from clinics, and from 5.4 to 11.5% (7 studies, median: 7.1%) for community samples. KEY MESSAGE: Extensive variation was observed in conversion rates due to the population sampled, diagnostic criteria, and duration, and because many studies did not account for loss to follow-up. PMID- 24174928 TI - Validity of Addenbrooke's Cognitive Examination to Discriminate between Incipient Dementia and Depression in Elderly Patients of a Private Clinic in Lima, Peru. AB - BACKGROUND/AIMS: Dementia and depression are different clinical conditions, but share common features, and can be indistinguishable in the initial disease stages. We aimed to establish whether the Peruvian version of the Addenbrooke's Cognitive Examination (ACE-Peru) can distinguish between the cognitive profile in patients with incipient dementia and that in patients with depression. METHODS: This was a cross-sectional study to assess the performance on the ACE-Peru of 193 elderly subjects (102 with dementia, 21 with depression, and 70 healthy controls). Depending on the diagnosis, there were two groups of cognitive impairment (CI) - the primary neurodegenerative (PN-CI) subtype and the secondary to depression (SD-CI) subtype - as well as a non-CI group. The area under the curve (AUC) of the receiver-operating characteristic curve was determined to compare the diagnostic performance, using the diagnosis of CI as the gold standard. RESULTS: In our sample of elderly subjects aged 59-82 years with at least 7 years of education, the ACE-Peru showed a significantly better performance than the MMSE (AUC = 0.997 vs. AUC = 0.887; p < 0.05) for the discrimination between PN-CI and SD-CI. CONCLUSIONS: The ACE-Peru is able to distinguish between the cognitive profile in patients with incipient dementia and that in patients with depression. PMID- 24174929 TI - Impact of aging mechanism on model simulated carbonaceous aerosols. AB - Carbonaceous aerosols including organic carbon and black carbon have significant implications for both climate and air quality. In the current global climate or chemical transport models, a fixed hydrophobic-to-hydrophilic conversion lifetime for carbonaceous aerosol (tau) is generally assumed, which is usually around one day. We have implemented a new detailed aging scheme for carbonaceous aerosols in a chemical transport model (GEOS-Chem) to account for both the chemical oxidation and the physical condensation-coagulation effects, where tau is affected by local atmospheric environment including atmospheric concentrations of water vapor, ozone, hydroxyl radical and sulfuric acid. The updated tau exhibits large spatial and temporal variations with the global average (up to 11 km altitude) calculated to be 2.6 days. The chemical aging effects are found to be strongest over the tropical regions driven by the low ozone concentrations and high humidity there. The tau resulted from chemical aging generally decreases with altitude due to increases in ozone concentration and decreases in humidity. The condensation coagulation effects are found to be most important for the high-latitude areas, in particular the polar regions, where the tau values are calculated to be up to 15 days. When both the chemical aging and condensation-coagulation effects are considered, the total atmospheric burdens and global average lifetimes of BC, black carbon, (OC, organic carbon) are calculated to increase by 9% (3%) compared to the control simulation, with considerable enhancements of BC and OC concentrations in the Southern Hemisphere. Model evaluations against data from multiple datasets show that the updated aging scheme improves model simulations of carbonaceous aerosols for some regions, especially for the remote areas in the Northern Hemisphere. The improvement helps explain the persistent low model bias for carbonaceous aerosols in the Northern Hemisphere reported in literature. Further model sensitivity simulations focusing on the continental outflow of carbonaceous aerosols demonstrate that previous studies using the old aging scheme could have significantly underestimated the intercontinental transport of carbonaceous aerosols. PMID- 24174930 TI - Comparison of super resolution reconstruction acquisition geometries for use in mouse phenotyping. AB - 3D isotropic imaging at high spatial resolution (30-100 microns) is important for comparing mouse phenotypes. 3D imaging at high spatial resolutions is limited by long acquisition times and is not possible in many in vivo settings. Super resolution reconstruction (SRR) is a postprocessing technique that has been proposed to improve spatial resolution in the slice-select direction using multiple 2D multislice acquisitions. Any 2D multislice acquisition can be used for SRR. In this study, the effects of using three different low-resolution acquisition geometries (orthogonal, rotational, and shifted) on SRR images were evaluated and compared to a known standard. Iterative back projection was used for the reconstruction of all three acquisition geometries. The results of the study indicate that super resolution reconstructed images based on orthogonally acquired low-resolution images resulted in reconstructed images with higher SNR and CNR in less acquisition time than those based on rotational and shifted acquisition geometries. However, interpolation artifacts were observed in SRR images based on orthogonal acquisition geometry, particularly when the slice thickness was greater than six times the inplane voxel size. Reconstructions based on rotational geometry appeared smoother than those based on orthogonal geometry, but they required two times longer to acquire than the orthogonal LR images. PMID- 24174931 TI - Clinical and Capillaroscopic Modifications of the Psoriatic Plaque during Therapy: Observations with Oral Acitretin. AB - Psoriasis is considered to be an inflammatory autoimmune disease, where angiogenesis plays an undefined pathogenetic role. The well-known changes of the superficial microvasculature in the psoriatic plaque can be easily assessed in vivo by videocapillaroscopy. In the last years, several studies reported the clinical and capillaroscopic response of the psoriatic plaque during different topical and systemic treatments. In the present work we evaluated the effects of acitretin (0.8 mg/kg/day) on videocapillaroscopic alterations and the clinical response in 11 patients affected by plaque psoriasis at the baseline (T0) and after 4 (T1), 8 (T2), and 12 (T3) weeks. A clinical improvement during the treatment with a complete clinical healing of the plaque in 7 of the 11 patients was observed. The typical "basket-weave" capillaries of the psoriatic lesions showed a reduction of 65.4% in diameter at the end of the study; only 3 patients returned to a normal capillaroscopic pattern. As observed during previous our studies, we found a discrepancy between clinical and capillaroscopic results, with a far greater improvement in the first than in the second. This finding could be in agreement with a secondary role of blood vessels in the pathogenesis and persistence of psoriatic lesions. PMID- 24174932 TI - The Prevalence of Helicobacter pylori Infection Decreases with Older Age in Atrophic Gastritis. AB - The clinical pathological characteristics of 3969 adult patients with chronic atrophic gastritis were retrospectively studied. The positivity of intestinal metaplasia and dysplasia in atrophic gastric specimens increased with age; however, H. pylori positivity and inflammatory activity decreased significantly with increased age. H. pylori infection was present in 21.01% of chronic atrophic gastritis patients, and 92.33% of the subjects with H. pylori infection were found to have simultaneous inflammatory activity. The intestinal metaplasia and dysplasia positivity markedly increased as the degree of gastric atrophy increased. In conclusion, the incidence of H. pylori infection decreased with age and correlated significantly with inflammatory activity in atrophic gastritis patients. The intestinal metaplasia and dysplasia positivity notably increased as the degree of gastric atrophy increased. Large population-based prospective studies are needed to better understand the progression of CAG. PMID- 24174933 TI - An electrosurgical endoknife with a water-jet function (flushknife) proves its merits in colorectal endoscopic submucosal dissection especially for the cases which should be removed en bloc. AB - Background. Previously, we reported that the Flushknife (electrosurgical endoknife with a water-jet function) could reduce the operation time of colorectal endoscopic submucosal dissection (ESD) however, suitable situation for the Flushknife was obscure. This subgroup analysis of a prospective randomized controlled trial was aimed to investigate the suitable situation for the Flushknife. Methods. A total of 48 superficial colorectal neoplasms that underwent ESD using either the Flexknife or the Flushknife in a referral center were enrolled. The differences of operation time between the Flexknife and the Flushknife groups in each subgroup (tumor size, location, and macroscopic type) were analyzed. Results. Median (95% CI) operation time calculated using survival curves was significantly shorter in the Flushknife group than in the Flexknife group (55.5 min [41, 78] versus 74.0 [57, 90] min; P = 0.039, Hazard Ratio HR: 0.53; 95% CI (0.29-0.97)). In particular, the HR in patients with laterally spreading tumors-nongranular type (LST-NG) in the Flushknife group was significantly smaller than in the Flexknife group (HR: 0.165->0.17; 95% CI (0.04 0.66)). There was a trend of decreasing HRs according to larger lesion size. Conclusions. The Flushknife proved its merits in colorectal ESD especially for the lesions which should be removed en bloc (LST-NG and large lesion). PMID- 24174936 TI - Bone response to surface-modified titanium implants: studies on the early tissue response to implants with different surface characteristics. AB - In a series of experimental studies, the bone formation around systematically modified titanium implants is analyzed. In the present study, three different surface modifications were prepared and evaluated. Glow-discharge cleaning and oxidizing resulted in a highly stoichiometric TiO2 surface, while a glow discharge treatment in nitrogen gas resulted in implants with essentially a surface of titanium nitride, covered with a very thin titanium oxide. Finally, hydrogen peroxide treatment of implants resulted in an almost stoichiometric TiO2, rich in hydroxyl groups on the surface. Machined commercially pure titanium implants served as controls. Scanning Auger Electron Spectroscopy, Scanning Electron Microscopy, and Atomic Force Microscopy revealed no significant differences in oxide thickness or surface roughness parameters, but differences in the surface chemical composition and apparent topography were observed. After surface preparation, the implants were inserted in cortical bone of rabbits and evaluated after 1, 3, and 6 weeks. Light microscopic evaluation of the tissue response showed that all implants were in contact with bone and had a large proportion of newly formed bone within the threads after 6 weeks. There were no morphological differences between the four groups. Our study shows that a high degree of bone contact and bone formation can be achieved with titanium implants of different surface composition and topography. PMID- 24174934 TI - Interaction of local anesthetics with biomembranes consisting of phospholipids and cholesterol: mechanistic and clinical implications for anesthetic and cardiotoxic effects. AB - Despite a long history in medical and dental application, the molecular mechanism and precise site of action are still arguable for local anesthetics. Their effects are considered to be induced by acting on functional proteins, on membrane lipids, or on both. Local anesthetics primarily interact with sodium channels embedded in cell membranes to reduce the excitability of nerve cells and cardiomyocytes or produce a malfunction of the cardiovascular system. However, the membrane protein-interacting theory cannot explain all of the pharmacological and toxicological features of local anesthetics. The administered drug molecules must diffuse through the lipid barriers of nerve sheaths and penetrate into or across the lipid bilayers of cell membranes to reach the acting site on transmembrane proteins. Amphiphilic local anesthetics interact hydrophobically and electrostatically with lipid bilayers and modify their physicochemical property, with the direct inhibition of membrane functions, and with the resultant alteration of the membrane lipid environments surrounding transmembrane proteins and the subsequent protein conformational change, leading to the inhibition of channel functions. We review recent studies on the interaction of local anesthetics with biomembranes consisting of phospholipids and cholesterol. Understanding the membrane interactivity of local anesthetics would provide novel insights into their anesthetic and cardiotoxic effects. PMID- 24174937 TI - Assessment of lead and cadmium levels in frequently used cosmetic products in Iran. AB - This study aims to investigate the content of lead and cadmium in most frequently used brands of cosmetic products (lipstick and eye shadow) in Iran. Fifty samples of lipstick (5 colors in 7 brands) and eye shadow (3 colors in 5 brands) were selected taken from large cosmetic stores in Isfahan (Iran) and lead and cadmium of them were analyzed. The results showed that the concentration of lead and cadmium in the lipsticks was within the range of 0.08-5.2 u g/g and 4.08-60.20 u g/g, respectively. The eye shadow samples had a lead level of 0.85-6.90 u g/g and a cadmium level of 1.54-55.59 u g/g. The content range of the heavy metals in the eye shadows was higher than that of the lipsticks. There was significant difference between the average of the lead content in the different brands of the lipsticks and eye shadows. Thus, the continuous use of these cosmetics can increase the absorption of heavy metals, especially Cd and Pb, in the body when swallowing lipsticks or through dermal cosmetic absorption. The effects of heavy metals such as lead can be harmful, especially for pregnant women and children. Therefore, effort must be made to inform the users and the general public about the harmful consequences of cosmetics. PMID- 24174938 TI - A model for prediction of cisplatin induced nephrotoxicity by kidney weight in experimental rats. AB - BACKGROUND: Cisplatin (cis-diamminedichloroplatinum II; CP) is used widely as an antitumor drug in clinics, but is accompanied with renal toxicity. Cisplatin induced nephrotoxicity consists of change in kidney weight, histological changes in kidney and increase in serum creatinine (Cr) and blood urea nitrogen (BUN). This study was designed to find out a model for prediction of cisplatin induced nephrotoxicity. MATERIALS AND METHODS: Pathological damage score, kidney weight, BUN, and Cr of 227 rats that were involved in different projects were determined. A total of 187 rats were treated with 7 mg/kg cisplatin and sacrificed 1 week later. RESULTS: There was a good significant correlation between normalized kidney weight and logarithmic scale of BUN and Cr. Relationship between BUN, Cr or normalized kidney weight and pathology damage score was significant. CONCLUSION: Normalized kidney weight and pathology damage score is a good predictor of renal function in cisplatin induced nephrotoxicity in experimental rats. PMID- 24174939 TI - Whether vitamin D3 is effective in reducing proteinuria in type 2 diabetic patients? AB - BACKGROUND: Nowadays Vitamin D deficiency is a notable medical condition world wide and also in Iran. Since, vitamin D can have renoprotective effect by inhibiting the renin-angiotensin system; it appears that low vitamin D level can worsen the renal injury in diabetic patients. This study demonstrates the effect of vitamin D3 therapy on reducing proteinuria in diabetic patients with concomitant diabetic nephropathy and vitamin D deficiency after controlling hypertension and use of angiotensin converting enzyme inhibitors (ACEIs) or angiotensin II type receptor blockers (ARBs). MATERIALS AND METHODS: In this randomized double blinded parallel groups clinical trial, 51 diabetic patients with proven nephropathy and vitamin D deficiency/insufficiency and stable hypertension, dyslipidemia, and hyperglycemic treatment were enrolled. The patients were divided randomly into two groups (treatment and placebo group). Patients received oral vitamin D3 (pearl 50000 IU) or placebo one pearl every week for 12 weeks. Patients were assessed at baseline and 12 weeks after intervention from the point of 25(OH) D level, and urine albumin/creatinine ration (UACR). RESULTS: Mean serum 25(OH) D concentrations were 14.06 ng/ml and 16.05 ng/ml before treatment. Furthermore, after intervention, its levels were risen to 71.23 and 17.63 in drug and placebo groups, respectively. Whereas, UACR as the main variable did not change significantly after intervention in both groups (P = 0.919). CONCLUSION: According to our finding, there was not a decrease in proteinuria in diabetic patients who received vitamin D for a period of 3 months. PMID- 24174940 TI - Comparison of levobupivacaine alone and in combination with fentanyl and sufentanil in patients undergoing transurethral resection of the prostate. AB - BACKGROUND: It was aimed to compare the efficacy and adverse effects of levobupivacaine alone and in combination with fentanyl and sufentanil during transurethral resection of the prostate (TURP) under spinal anesthesia. MATERIALS AND METHODS: In this prospective, randomized, double-blind trial, 60 patients undergoing elective TURP under spinal anesthesia were randomized into three groups. Ten milligrams of 0.5% levobupivacaine in Group-I, 7.5 mg 0.5% levobupivacaine combined with 25 MUg fentanyl in Group-II and 7.5 mg 0.5% levobupivacaine with 2.5 MUg sufentanil in Group-III were administered intrathecally. RESULTS: The time for sensorial block to reach level T10 was 10.2 +/- 2.0, 6.9 +/- 1.7 and 7.0 +/- 1.4 min in Group-I, II and III, respectively (P < 0.001). The maximum sensorial block level was T8 in all groups. The frequency of a complete motor block was higher in Group-I. The mean duration of motor block was shorter in Group-II and III than in Group-I (P < 0.001). There were no differences between groups regarding side effects (P > 0.05). The time for first analgesic request was shorter in Group-I than in the other two groups (P < 0.05). During the first postoperative 24-h period, 11 (58%) patients in Group-I, 9 (48%) patients in Group II and 9 (45%) patients in Group-III required an analgesic drug (P > 0.05). CONCLUSION: This study showed that combining lower dose levobupivacaine with fentanyl and sufentanil provides faster onset of sensorial block, lower frequency and shorter duration of motor block, and longer analgesia time in TURP under spinal anesthesia. PMID- 24174941 TI - The mid-sternal length, a practical anatomical landmark for optimal positioning of long-term central venous catheters. AB - BACKGROUND: Long-term tunneled catheters are used for the hemodialysis or chemotherapy in many patients. Proper placement of the catheter tip could reduce early and late catheter related complications. Aim of the present study was to evaluate a new formula for proper placement of tunneled hemodialysis or infusion port device by using an external anatomic landmark. MATERIALS AND METHODS: A total of 64 adult patients undergoing elective placement of tunneled Central Venous Catheter (CVC) requiring hemodialysis or chemotherapy were enrolled in this prospective study during 2011-2012 in the university hospital. The catheter length to be inserted in the right internal jugular vein (IJV) was calculated by adding two measurements (the shortest straight length between the insertion point of the needle and the suprasternal notch plus and half of sternal length). The catheter position was considered correct if the tip was positioned in the right atrium (RA) or Superior vena cava (SVC)-RA junction. RESULTS: The patients were 55.28 +/- 19.85 years of age, weighed 5.78 +/- 16.62 kg and were 166.07 +/- 10.27 cm tall. Catheters were inserted successfully in 88% of patients (n = 56). Catheter tip positions in the failures were SVC (n = 5), tricuspid valve (n = 2), and right ventricle (n = 1) in our patients. CONCLUSION: Long-term hemodialysis or port CVC could easily insert in the right IJV by using half of the sternal length as an external land marks among adult patients. PMID- 24174942 TI - Effect of ejaculation on serum prostate specific antigen level in screening and non-screening population. AB - BACKGROUND: The serum prostate specific antigen (PSA) levels are used for prostate cancer screening. Some conditions such as prostatitis, manipulation, and prostate cancer could influence on serum PSA. The impact of ejaculation on serum PSA is controversial. The aim of our study was to evaluate the relation of ejaculation and the levels of serum PSA. MATERIALS AND METHODS: In this cross sectional study, 60 healthy voluntary men below and over 50 years during the year 2009-2011 were participated. After history taking, physical examination, and identical lower urinary tract symptoms score (American Urologic Association Score = AUA); three blood samples were taken before, 1 and 24 h after ejaculation. RESULTS: Patients categorized into a non-screening group (age less than 50 years, n = 25), and screening group (age >= 50 years, n = 35). Our data showed significant PSA rising in both groups 1 h after ejaculation (P value < 0.05); however, comparison of PSA levels in both groups, before and 24 h after ejaculation showed no significant differences. Spearman coefficient of correlation was showed a positive correlation between PSA in all stage and AUA score in the second group, but there were no such correlation in the first group. CONCLUSION: There was a significant relationship between ejaculation and the levels of serum PSA in screening and non-screening patients. However, in non screening men significant rising of PSA after 1 h of ejaculation was not important clinically (not achieve to greater than 4 ng/ml). Taking a history of ejaculation in men older 50 years especially with high AUA score could prevent false positive results and subsequent un-necessary work-ups. PMID- 24174943 TI - Evaluation of effect of acarbose consumption on weight losing in non-diabetic overweight or obese patients in Kerman. AB - BACKGROUND: High prevalence of obesity and the importance of this issue as a risk factor for chronic diseases such as severe cardiovascular diseases, diabetes, and cancer necessitate the need for treatment. The aim of this study was the evaluation of acarbose effect on the weight loss in non diabetic overweight or obese patients in Kerman. MATERIALS AND METHODS: A double blind randomized controlled clinical trial was performed on 66 patients with the body mass index (BMI) between 25 and 35 kg/m(2). Patients were divided in treatment and control groups using the randomization. The treatment group took 100 mg acarbose 3 times a day for 20 weeks in combination with the low calorie diet and exercise. Control group was given placebo, low calorie diet, and exercise. BMI was measured after 20 weeks. The analyses were carried out using t-test and repeated measured ANOVA. RESULTS: Patients in acarbose and placebo group had a non significant difference in BMI at baseline. Reducing in weight was considered in every month in both groups, but this reduction was higher in the treatment group. At the 5(th) month, the difference of BMI in the treatment group was significantly lower than the placebo group (2.31 +/- 0.6 vs. 0.76 +/- 0.6 kg/m(2), P < 0.001). CONCLUSION: Acarbose, especially in combination with the low calorie diet and exercise, seems to lose weight effectively in obese and overweight patients in communities that have a high carbohydrate intake (like Persian diet). PMID- 24174944 TI - Intelligence quotient in children with congenital hypothyroidism: The effect of diagnostic and treatment variables. AB - BACKGROUND: Considering the high prevalence of congenital hypothyroidism (CH) in Isfahan, the intelligence quotient (IQ) of children with CH and the effect of diagnostic and treatment variables on it were investigated during the CH screening program. MATERIALS AND METHODS: A total of 120 children in three studied groups were studied in this comparative study the IQ score, in three subsets of verbal IQ, performance IQ and full scale IQ, of children diagnosed with transient congenital hypothyroidism (TCH) and permanent congenital hypothyroidism (PCH) was measured using revised Wechsler pre-school and primary scale of intelligence and compared with the control group. The relation between IQ score with time of treatment initiation and screening thyroid stimulating hormone (TSH) level was evaluated in all studied groups. RESULTS: Mean of verbal IQ, performance IQ, and full scale IQ score was significantly higher in the control group than CH patients (both permanent and transient) In PCH patients though it was not significant, there was a negative relationship between verbal IQ, performance IQ and full scale IQ and screening TSH and age of treatment initiation. In TCH patients, there was negative and significant relationship between verbal IQ (r = -0.40) and full scale IQ (r = -0.38) and age of treatment initiation (r = -0.46). CONCLUSION: Mean IQ score in both PCH and TCH patients were lower than the control group, which correlates negatively with treatment initiation time. Though CH screening and early treatment has improved the prognosis of patients, but early and high dose of treatment in children with CH is recommended. PMID- 24174946 TI - Retinal nerve fiber layer thickness in vitiligo patients. AB - BACKGROUND: This study was designed to investigate the effect of vitiligo on the retinal nerve fiber layer (RNFL) thickness. MATERIALS AND METHODS: This prospective study was conducted in the Department of Ophthalmology at Kirikkale University during 2010 and 2011. Sixty eight eyes of 34 vitiligo patients were included in the study. Eighty four eyes were served as control. RNFL thickness was measured by scanning laser polarimetry (Nerve Fiber Analyzer, GDx VCC: 5.3.3; Laser Diagnostic Technologies, San Diego, CA, USA). RESULTS: The mean duration of vitiligo was found to be 9.8 +/- 2.3 years. The mean average RNFL thickness outside the disc margin was significantly lower in the right eyes of vitiligo group in comparison to the controls (P = 0.02). The mean average thickness of RNFL beneath the measuring ellipse in the superior sector of both eyes were significantly lower than the controls (P = 0.004, P = 0.008, respectively). The topographical distributions of RNFL thickness in superior, inferior, nasal and temporal quadrants were similar for two groups. CONCLUSION: RNFL thickness seems to be unaffected in vitiligo patients. PMID- 24174945 TI - Septal injection in comparison with inferior turbinates injection of botulinum toxin A in patients with allergic rhinitis. AB - BACKGROUND: Botulinum toxin A (BTA) is a promising therapeutic option in the treatment of allergic rhinitis (AR). Although recent studies have introduced BTA septal injection as an alternative method, the conventional localization for the injection of BTA in patients with AR is still the nasal turbinates. This study was designed to compare the effectiveness and safety of septal BTA injection with turbinal BTA injection in patients with AR. MATERIALS AND METHODS: This open label study was performed on 50 patients with AR who were randomly allocated to septal and turbinal BTA injection groups. All patients received an injection of 40 U of BTA (Dysport((r)), Ipsen Ltd, Maidenhead, UK) in each side of the nose and were followed for 8 weeks. Prior to the intervention and 8 weeks later, symptom severity and quality of life scores were calculated using the AR symptom severity and Rhinasthma questionnaires respectively. RESULTS: Comparison of pre- and post-treatment symptom severity scores within each group showed a significant reduction of total symptom severity score and severity of sneezing, rhinorrhea, and congestion in both groups (P < 0.05). However, post-treatment symptom severity scores were not significantly different between two groups (P > 0.05). Both methods have improved the quality of life of subjects significantly (P < 0.05). Significantly more patients in the turbinal injection group reported adverse effects (four patient's vs. one, P < 0.05). CONCLUSION: Although both septal and turbinal BTA injections are effective on patients with AR, septal administration of BTA could be safer and easier method. However, further investigations are required to achieve more accurate results. PMID- 24174947 TI - Comparison of hypertension and diabetes mellitus prevalence in areas with and without water arsenic contamination. AB - BACKGROUND: Arsenic (As), one of the most significant hazards in the environment affecting millions of people around the world is associated with several diseases including cancers, Diabetes Mellitus (DM) and Hypertension (Htn). Drinking water contaminated with inorganic arsenic (iAs) is the primary route of exposure. This study was conducted to determine the difference in the prevalence of DM and Htn in areas with different levels of water contamination of As. MATERIALS AND METHODS: In this analytic ecologic study, after measurement of As level in drinking water in all urban regions of Qazvin Province (Islamic Republic of Iran), two cities with As level of 20-30 MUg/L and two with the As level <5 MUg/L were selected as exposed and unexposed groups, respectively. Measuring the prevalence of above-mentioned diseases in the 30-60 year-old population of the said regions as total sampling, the results were statistically analyzed and compared. RESULTS: The mean prevalence of Htn in exposed and unexposed areas were 7.09% and 3.73%, respectively and for DM were 4.53% and 1.99% in the said groups, respectively. There was a positive correlation between As level and Htn (P < 0.001) and between As level and DM (P < 0.001). CONCLUSION: High level of As in drinking water, even in the range of 20-30 MUg/L has a relationship with increased prevalence of DM and Htn. PMID- 24174948 TI - Partial frequency of radiation pneumonitis and its association with the energy and treatment technique in patients with breast cancer, Isfahan, Iran. AB - BACKGROUND: Breast cancer is the most common type of cancer among women, and the second cause of cancer mortality after pulmonary cancer in this gender. Radiotherapy is one of the major treatments, which locally controls the disease and prohibits in recurrency. Radiation pneumonitis is one of the radiotherapy complications, which usually occurs within 1.5-3 months after radiotherapy. As there is no precise estimation concerning this complication in Isfahan, partial frequency of radiation pneumonitis and its association with the energy and treatment technique in patients with breast cancer were evaluated. MATERIALS AND METHODS: This was an analytic cross-sectional study performed in 2010 in university referral center. A total of 382 patients with breast cancer, undergone surgery and referred for radiotherapy entered the study. A posterior and anterior and lateral X-Rays were taken as control images before starting radiotherapy and all X-Rays were repeated after 3-4 months post radiotherapy. The occurrence of radiotherapy pneumonitis was evaluated by the same radiologist. Data were analyzed through SPSS version 20. RESULTS: Out of 382 patients undergone breast conservative surgery (BCS) or modified radical mastectomy (MRM), and radiotherapy, 60 patients had pneumonitis of whom 6 patients underwent BCS and were treated by tangential field (three cases by Co 60 and three cases by PH 9). The rest of radiotherapy pneumonitis patients (n = 54) underwent MRM of whom, 42 cases were treated by one-field and 12 by two-field treatment techniques. CONCLUSION: Incidence of radiotherapy pneumonitis was different with respect to the adopted technique (one-field, two-field and tangential) (P = 0.023), with the highest association with two-field radiotherapy. PMID- 24174949 TI - Students' perception of educational environment at Public Sector Medical University of Pakistan. AB - BACKGROUND: Assessing educational environment is vital in determining the success or failure of any institute. A positive environment leads to achievements of students in learning while a negative one would hinder their accomplishments. The aim of this study was to evaluate the medical students' perceptions of their educational environment and to identify any differences related to gender and colleges affiliated with the University. MATERIALS AND METHODS: This cross sectional study involved all medical colleges affiliated with Dow University of Health Sciences from September to November 2011. DREEM questionnaire was administered to undergraduate medical students of the colleges. Mean and standard deviation of total DREEM score and five subscales were reported. The internal consistency coefficient (Cronbach's alpha) was calculated. Student's t test and one-way ANOVA were used for statistical analysis. RESULTS: Total respondents were 586 students (response rate = 90.1%), 463 (79.0%) were female. Total DREEM mean score was 114.4/200 (57.2%). Highest score was found in the domain of student's academic self-perceptions (58.7%) and lowest in domain of student's perception of learning (53.7%). The inventory was found to have good reliability, with an alpha coefficient of 0.89. There was significant difference of total DREEM score, student's perception of learning, teachers, and atmosphere between different colleges. Females perceived their educational environment to be more positive compared to male students. CONCLUSION: The undergraduate educational environment of the university is more positive than negative. Highest score was found in domain of student's academic self-perceptions and lowest in domain of student's perception of learning. PMID- 24174950 TI - Risk factors of placental abruption. AB - BACKGROUND: Placental abruption is one of the most common causes of bleeding during pregnancy. Multiple factors are known to be associated with increase of risk of placental abruption such as alcohol, cocaine use and cigarette smoking. The objective of this study was to identify risk factors for placental abruption in an Iranian women population. MATERIALS AND METHODS: In a retrospective case - control study birth records included 78 cases with placental abruption and 780 randomly selected controls were investigated. Statistical analysis for comparing the studied risk factors between groups was performed using Pearson's Chi-square test along with presenting relevant odds ratio (OR). RESULTS: From 7301 deliveries included in the study, 78 (1%) was complicated placental abruption. Women aged 35 or more likely for experiencing (OR = 3.650, 95% confidence interval [CL] = 1.57-6.83) and those who had a previous cesarean section (OR = 2.65, 95% CL = 3.91- 33.41) were in higher risk for placental abruption ([50 cases] 64% vs. [28 cases] 36% P < 0.01). CONCLUSION: The results indicate that among the placental abruption is one of the most common causes of bleeding during the pregnancy and one of the major obstetrical emergency. PMID- 24174952 TI - RIFLE criteria for acute kidney injury in the intensive care units. AB - BACKGROUND: Acute kidney injury (AKI) is commonly occurred in intensive care unit (ICU) patients. The aim of the study was a comparison of RIFLE (Risk of renal injury/Injury to the kidney/Failure of kidney function/Loss of kidney function/End stage disease) classification with other scoring systems in the evaluation of AKI in ICUs. MATERIALS AND METHODS: We performed a retrospective study on 409 ICU patients who were admitted during the 5 years period. RESULTS: At the 1(st) day of admission and time of discharge, the total and non-renal Acute Physiology and Chronic Health Evaluation II and sequential organ failure assessment scores were compared to max RIFLE criteria. In this assessment, there was concordance among the results (P < 0.05). CONCLUSION: The RIFLE classification can be used for detection of AKI in ICU patients. PMID- 24174951 TI - Inhibitory effect of a mixture containing vitamin C, lysine, proline, epigallocatechin gallate, zinc and alpha-1-antitrypsin on lung carcinogenesis induced by benzo(a) pyrene in mice. AB - BACKGROUND: This study was aimed to evaluate protective and therapeutic effects of a specific mixture, containing vitamin C, lysine, proline, epigallocatechin gallate and zinc, as well as alpha-1-antitrypsin protein on lung tumorigenesis induced by benzo(a) pyrene [B(a)P] in mice. MATERIALS AND METHODS: Swiss albino mice were divided into two main experiments, experiment (1) the mice were injected with 100 mg/kg B(a)P and lasted for 28 weeks, while experiment (2) the mice were injected with 8 doses each of 50 mg/kg B(a)P and lasted for 16 weeks. Each experiment (1 and 2) divided into five groups, group (I) received vehicle, group (II) received the protector mixture, group (III) received the carcinogen B(a)P, group (IV) received the protector together with the carcinogen (simultaneously) and group (V) received the carcinogen then the protector (consecutively). RESULTS: Total sialic acid, thiobarbituric acid reactive substances, vascular epithelial growth factor, hydroxyproline levels, as well as elastase and gelatinase activities showed significant elevation in group (III) in the two experiments comparing to control group (P < 0.001). These biochemical alterations were associated with histopathological changes. Administration of the protector in group IV and group V causes significant decrease in such parameters with improvement in histopathological alterations with improvement in histopathological alterations when compared with group III in the two experiments (P < 0.001). CONCLUSION: The present protector mixture has the ability to suppress neoplastic alteration and restore the biochemical and histopathological parameters towards normal on lung carcinogenesis induced by benzo(a) pyrene in mice. Furthermore, the present mixture have more protective rather than therapeutic action. PMID- 24174953 TI - Chronic inflammatory demyelinating polyneuropathy associated with diabetes mellitus. AB - Various forms of neuropathy are seen diabetic patients; chronic inflammatory demyelinating polyneuropathy (CIDP) seems not to be infrequent neuropathy in patients suffering from diabetes and it seems to be more common than in the general population; on the contrary, some authorities do not support pathogenetic association between diabetes mellitus (DM) and CIDP. Also, there are some controversies on the subject of CIDP treatment in diabetic patients. Some studies showed that patients with CIDP-DM considerably had recovered following treatment with immunotherapeutic modalities like (Intravenous immunoglobulin) IVIG and conversely, some else have argued against the prescription of IVIG in this group and recommend treatment with corticosteroids and provided that resistant, rituximab may be beneficial. The main limitation in most studies is the inadequate number of cases and as a result, problematic decision making in treatment. This article represents an inclusive review of diabetic CIDP presentation and treatment. PMID- 24174954 TI - Code of ethics for the national pharmaceutical system: Codifying and compilation. AB - Pharmacists as one of health-care providers face ethical issues in terms of pharmaceutical care, relationship with patients and cooperation with the health care team. Other than pharmacy, there are pharmaceutical companies in various fields of manufacturing, importing or distributing that have their own ethical issues. Therefore, pharmacy practice is vulnerable to ethical challenges and needs special code of conducts. On feeling the need, based on a shared project between experts of the ethics from relevant research centers, all the needs were fully recognized and then specified code of conduct for each was written. The code of conduct was subject to comments of all experts involved in the pharmaceutical sector and thus criticized in several meetings. The prepared code of conduct is comprised of professional code of ethics for pharmacists, ethics guideline for pharmaceutical manufacturers, ethics guideline for pharmaceutical importers, ethics guideline for pharmaceutical distributors, and ethics guideline for policy makers. The document was compiled based on the principles of bioethics and professionalism. The compiling the code of ethics for the national pharmaceutical system is the first step in implementing ethics in pharmacy practice and further attempts into teaching the professionalism and the ethical code as the necessary and complementary effort are highly recommended. PMID- 24174955 TI - Severe gastrointestinal burn with hydrochloric acid. AB - Inadvertantly or purposely, an oral intake of corrosive substances may cause life threatening problems. Early admission to the hospital, clinical and endoscopic evaluation, and early surgery when required, may reduce morbidity and mortality. We report the case of a 49-year-old male patient, who had attempted suicide, by drinking about 800 mL of 25% hydrochloric acid, and who had severe intra abdominal damage. The aim of this report is to state the fact that a good outcome is possible in severe burns caused by oral intake of corrosive substances, when fast, multidisciplinary, and appropriate management is provided on time. PMID- 24174956 TI - Bilateral internal laryngoceles mimicking asthma. AB - Laryngocele is an air-filled, abnormal dilation of the laryngeal saccule that extends upward within the false vocal fold, in communication with the laryngeal lumen. A case of 43-year-old male with bilateral internal laryngoceles, who has been treated as asthma for 4 years, is presented. The patient had dyspnea, cough, and excessive phlegm for a month and a late onset stridor. Flexible nasopharyngolaryngoscopy showed bilateral cystic enlargements of the false vocal folds and true vocal folds could not be visualized. Laryngeal CT without contrast enhancement showed bilateral internal laryngoceles. Submucosal total excision of bilateral cystic masses including parts of false vocal folds was performed. The symptoms resolved immediately after surgery. Although the incidence of internal laryngocele is rare, it should be remembered in the differential diagnosis of upper airway problems and diagnostic flexible nasopharnygolaryngoscopy is routinely indicated for airway evaluation in at-risk patients. PMID- 24174957 TI - Commentary on: The effect of allopurinol on lowering blood pressure in hemodialysis patients with hyperuricemia. PMID- 24174958 TI - Mercury promotes catecholamines which potentiate mercurial autoimmunity and vasodilation: implications for inositol 1,4,5-triphosphate 3-kinase C susceptibility in kawasaki syndrome. AB - Previously, we reviewed biological evidence that mercury could induce autoimmunity and coronary arterial wall relaxation as observed in Kawasaki syndrome (KS) through its effects on calcium signaling, and that inositol 1,4,5 triphosphate 3-kinase C (ITPKC) susceptibility in KS would predispose patients to mercury by increasing Ca(2+) release. Hg(2+) sensitizes inositol 1,4,5 triphosphate (IP3) receptors at low doses, which release Ca(2+) from intracellular stores in the sarcoplasmic reticulum, resulting in delayed, repetitive calcium influx. ITPKC prevents IP3 from triggering IP3 receptors to release calcium by converting IP3 to inositol 1,3,4,5-tetrakisphosphate. Defective IP3 phosphorylation resulting from reduced genetic expressions of ITPKC in KS would promote IP3, which increases Ca(2+) release. Hg(2+) increases catecholamine levels through the inhibition of S-adenosylmethionine and subsequently catechol-O-methyltransferase (COMT), while a single nucleotide polymorphism of the COMT gene (rs769224) was recently found to be significantly associated with the development of coronary artery lesions in KS. Accumulation of norepinephrine or epinephrine would potentiate Hg(2+)-induced calcium influx by increasing IP3 production and increasing the permeability of cardiac sarcolemma to Ca(2+). Norepinephrine and epinephrine also promote the secretion of atrial natriuretic peptide, a potent vasodilator that suppresses the release of vasoconstrictors. Elevated catecholamine levels can induce hypertension and tachycardia, while increased arterial pressure and a rapid heart rate would promote arterial vasodilation and subsequent fatal thromboses, particularly in tandem. Genetic risk factors may explain why only a susceptible subset of children develops KS although mercury exposure from methylmercury in fish or thimerosal in pediatric vaccines is nearly ubiquitous. During the infantile acrodynia epidemic, only 1 in 500 children developed acrodynia whereas mercury exposure was very common due to the use of teething powders. This hypothesis mirrors the leading theory for KS in which a widespread infection only induces KS in susceptible children. Acrodynia can mimic the clinical picture of KS, leading to its inclusion in the differential diagnosis for KS. Catecholamine levels are often elevated in acrodynia and may also play a role in KS. We conclude that KS may be the acute febrile form of acrodynia. PMID- 24174959 TI - Bortezomib reduces neointimal hyperplasia in a rat carotid artery injury model. AB - BACKGROUND AND OBJECTIVES: The ubiquitin-proteasome system is the major intracellular protein degradation pathway in the eukaryotic cells. Bortezomib inhibits 26S proteasome-induced I-kappaBalpha degradation and suppresses nuclear factor-kappa B (NF-kappaB) activation. We examined the effect of bortezomib on neointima formation after of a rat carotid artery balloon injury. MATERIALS AND METHODS: After carotid artery balloon denudation, bortezomib was immediately administered by tail vein injection (systemic treatment) and by using an F-127 pluronic gel (perivascular treatment). Two weeks after the injury, we compared the degree of neointima formation in the carotid artery and the tissue expression patterns of NF-kappaB and I-kappaBalpha. RESULTS: The systemic treatment group exhibited a 29% reduction in neointima volume at two weeks after the balloon injury. On the western blot analysis, the bortezomib group exhibited an increased I-kappaBalpha expression, which suggested the inhibition of I-kappaBalpha degradation. On immunofluorescence analysis, the nuclear import of NF-kappaB was clearly decreased in the systemic bortezomib group. The perivascular bortezomib treatment group exhibited a significant reduction in the neointimal area (0.21+/ 0.06 mm(2) vs. 0.06+/-0.01 mm(2), p<0.05), the neointima/media area ratio (1.43+/ 0.72 vs. 0.47+/-0.16, p<0.05) and the % area stenosis (45.5+/-0.72% vs. 14.5+/ 0.05%, p<0.05) compared with the control group. In situ vascular smooth muscle cell proliferation at 2 days after the injury was significantly inhibited (24.7+/ 10.9% vs. 10.7+/-4.7%, p<0.05). CONCLUSION: Bortezomib suppressed NF-kappaB activation through the inhibition of I-kappaBalpha degradation, and significantly reduced neointima formation in a rat carotid artery injury model. These data suggested that bortezomib represented a new potent therapeutic agent for the prevention of restenosis. PMID- 24174960 TI - Effect of abciximab on the levels of circulating microparticles in patients with acute myocardial infarction treated by primary angioplasty. AB - BACKGROUND AND OBJECTIVES: We investigated the effect of the additional use of abciximab during percutaneous coronary intervention (PCI) on the level of procoagulant microparticles (MPs) in patients with ST-segment elevation myocardial infarction (STEMI) who had undergone primary PCI. SUBJECTS AND METHODS: In this study, we studied 86 patients with STEMI (72 men, age 58+/-13) who had undergone primary PCI. The decision to administer abciximab immediately prior to PCI was left to the discretion of the operator. Blood samples for analysis of MPs were obtained from the femoral artery before and after PCI. MPs with procoagulant potential were measured using a commercial kit. The cellular origins of MPs were determined by antigenic capture with specific antibodies. RESULTS: Procoagulant MPs captured onto annexin V were not changed significantly after PCI {13.4+/-13.2 nM vs. 13.2+/-16.1 nM phosphatidylserine equivalent (PS eq), p=0.479}. Abciximab was used in 30 of 86 patients (35%) immediately prior to PCI. In patients who had undergone PCI without abciximab, no significant change in the level of MPs was observed after PCI. However, in the abciximab group, the level of circulating MPs was significantly decreased after PCI (12.0+/-10.7 nM vs. 7.8+/-11.7 nM PS eq, p=0.018). Levels of endothelial- and platelet-derived MPs also showed a significant reduction after PCI in the abciximab group. CONCLUSION: Primary PCI with additional abciximab significantly reduced the level of procoagulant MPs regardless of their cellular origins in patients with STEMI. PMID- 24174961 TI - Comparison of Coronary Plaque Components between Non-Culprit Lesions in Patients with Acute Coronary Syndrome and Target Lesions in Patients with Stable Angina: Virtual Histology-Intravascular Ultrasound Analysis. AB - BACKGROUND AND OBJECTIVES: The differences in plaque characteristics between non culprit lesions (NCL) in acute coronary syndrome (ACS) patients (ACS-NCL) and target lesions (TL) in stable angina (SA) patients (SA-TL) are not well understood. We used a virtual histology-intravascular ultrasound (VH-IVUS) to compare the plaque components between ACS-NCL and SA-TL. SUBJECTS AND METHODS: We compared VH-IVUS findings between 290 ACS-NCL and 276 SA-TL. VH-IVUS classified the color-coded tissue into four major components: green (fibrotic); yellow-green (fibro-fatty); white {dense calcium (DC)}; and red {necrotic core (NC)}. Thin-cap fibroatheroma (TCFA) was defined as a NC >=10% of the plaque area in at least 3 consecutive frames without overlying fibrous tissue in the presence of >=40% plaque burden. RESULTS: Although the plaque burden was significantly smaller (52+/-13% vs. 54+/-14%, p=0.044), ACS-NCL had a greater %NC area (17.9+/-11.6% vs. 14.3+/-8.7%, p<0.001) and %DC area (9.7+/-9.8% vs. 8.1+/-8.0%, p=0.032) compared with SA-TL at the minimum lumen site. By volumetric analysis, ACS-NCL had a greater %NC volume (15.8+/-9.2% vs. 13.9+/-7.4%, p=0.006) compared with SA TL. TCFA was observed more frequently in ACS-NCL compared with SA-TL (27.6% vs. 18.1%, p=0.032). Independent predictors of TCFA by multivariate analysis were ACS {odds ratio (OR): 2.204, 95% CI: 1.321-3.434, p=0.021} and high-sensitivity C reactive protein (OR: 1.101; 95% CI 1.058-1.204, p=0.035). CONCLUSION: Although the plaque burden was significantly smaller, ACL-NCL had more vulnerable plaque components compared with SA-TL, and ACS and high-sensitivity C-reactive protein were the independent predictors of TCFA. PMID- 24174962 TI - Utility of global strain by two-dimensional and three-dimensional speckle tracking for assessing left ventricular diastolic function: comparison with pressure wire analysis. AB - BACKGROUND AND OBJECTIVES: We evaluated the utility of two-dimensional (2D) and three-dimensional (3D) left ventricular (LV) global myocardial deformity parameters for assessing LV diastolic function by comparing invasive measures of LV performance. SUBJECTS AND METHODS: Echocardiography and LV pressure were assessed in 39 patients. Myocardial LV longitudinal, circumferential, and radial deformations, as well as area strain, were evaluated utilizing 2D and 3D speckle tracking software. The 2D early diastolic strain rate (2D-SRe) was measured from the 3 apical and 3 short axis views. The 3D diastolic index (3D-DI) was calculated by the % change of global strain during the first one-third of the diastolic period. LV end diastolic pressure (LVEDP) and the rate of LV pressure change (dP/dt) were collected using a pressure-conducted catheter and tau was calculated. RESULTS: dP/dtmin were related to early mitral annular velocity (e'), 2D-SRelong, 2D-SReradial, as well as 3D-DIlong, and 3D-DIas. Additionally, LVEDP was associated with the ratio of mitral early diastolic velocity (E) to 2D SRelong, 2D-SRecirc, 2D-SReradial, 3D-DIlong, 3D-DIcirc, and 3D-DIas. E/2D SRelong, E/2D-SReradial, E/3D-DIlong, and E/3D-DIas were comparable with E/e' in predicting patients with elevated LVEDP. Among those patients with E/e' of 8 to 15, E/3D-DIlong provided incremental value in identifying those with LVEDP >=15 mm Hg. CONCLUSION: 2D-SRelong, 2D-SReradial, 3D-DIlong, and 3D-DIas were related to LV relaxation, and the ratios of E to those parameters were associated with LVEDP. In addition, among patients with indeterminate E/e', E/3D-DIlong offered incremental value in predicting elevated LVEDP, suggesting it may provide supplementary information in the evaluation of LV diastolic function. PMID- 24174963 TI - The efficacy of the cystatin C based glomerular filtration rate in the estimation of safe contrast media volume. AB - BACKGROUND AND OBJECTIVES: The risk of contrast-induced nephropathy (CIN) is significantly influenced by baseline renal function and the amount of contrast media (CM). We evaluated the usefulness of the cystatin C (CyC) based estimated glomerular filtration rate (eGFRCyC) in the prediction of CIN and to determine the safe CM dosage. SUBJECTS AND METHODS: We prospectively enrolled a total of 723 patients who received percutaneous coronary intervention (PCI) and investigated the clinical factors associated with the development of CIN. Renal function was calculated as eGFRCyC and a modified diet in the renal disease (MDRD) equation, respectively. Systemic exposure of CM was calculated as CM volume to eGFR ratio. We conducted a regression analysis to evaluate the predictive role of CM volume to eGFRCyC for the risk of CIN. RESULTS: The incidence of CIN was 4.0% (29/723). The patients with CIN had a lower hemoglobin level, decreased renal function, and a higher CyC value, and had greater CM exposure. Through multivariate regression analyses, hemoglobin {odds ratio (OR) 0.743, p=0.032}, CM volume/eGFRCyC (OR 1.697, p=0.006) and CM volume/MDRD (OR 2.275, p<0.001) were found to be independent predictors for CIN. In the receiver operating characteristic curve analysis, fair discrimination for CIN was found at a CM volume/eGFRCyC level of 4.493 (C-statics=0.814), and at this value, the sensitivity and specificity were 79.3% and 80.0%, respectively. CONCLUSION: Both the CM volume/MDRD and CM volume/eGFRCyC method would be simple, useful indicators for determining the safe CM-dose based on eGFR value before PCI. However, there was no significantly different predictive value between creatinine and CyC based GFR estimations. PMID- 24174964 TI - Endovascular repair of aortoiliac aneurysm using bifurcated stent grafts with sandwich technique for preserving the internal iliac artery. AB - In this case, we describe a case of a 76-year-old male with extensive aortoiliac aneurysms treated by endovascular aneurysm repair using the sandwich technique in order to preserve left internal iliac artery perfusion. The sandwich technique refers to the deployment of multiple paralleled stent grafts into main distal and side branches in overlapping with a single proximal stent graft. The procedure was successfully performed without complications. Post-procedural CT angiography demonstrated patent stent grafts without any endoleak. The strengths and limitations of the sandwich technique need to be investigated in large-scale, long-term clinical trials. PMID- 24174965 TI - A case of dilated cardiomyopathy with massive left ventricular thrombus after use of a sibutramine-containing slimming product. AB - Sibutramine, which acts as an anti-obesity drug by inhibiting reuptake of serotonin and norepinephrine, has now been banned due to cardiovascular adverse effects. However, despite being banned, it is not uncommon for people to purchase products with sibutramine or its analogues used as adulterants in non prescription slimming products or health foods available on the internet. Sibutramine has been associated with rare but serious adverse reactions such as cardiac arrhythmia including QT interval prolongation, myocardial infarction, and cardiomyopathy, as well as increases in blood pressure and pulse rate. Here, we report a case of a 32-year-old male who presented with dilated cardiomyopathy with massive left ventricular thrombus after taking unauthorized sibutramine containing slimming pills sold over the internet. PMID- 24174966 TI - Primary cardiac angiofibroma. AB - Cardiac Angiofibroma is an uncommon intracardiac tumor. Thus far, only 4 cases of the rare intracardiac tumor have been reported. The present case-report describes an intracardiac angiofibroma in a 57-year-old healthy female. The patient was incidentally diagnosed with a left ventricle mass during echocardiography. We performed cardiac imaging, surgical excision and histological evaluation of the mass. The angiofibroma demonstrated features different from the relatively common cardiac tumors such as fibroma, myxoma and angiosarcoma. The cardiac MRI showed slightly high signal intensity on both T1 and T2, with the central core of lower signal intensity. The resected tumor was a whitish and rubbery mass. Histologically, the tumor showed the benign vascular proliferations associated with the surrounding collagen deposition. PMID- 24174967 TI - A case of aorta-right atrial tunnel presented with an asymptomatic murmur. AB - Aorta-right atrial tunnel is a rare and distinct congenital anomaly. It is a vascular channel that originates from one of the sinuses of Valsalva with a tortuous course anterior or posterior to the ascending aorta, and terminates either in the superior vena cava or in the right atrium (RA). We report a 42-year old female briefly with aorta-right atrial tunnel in which the left coronary artery arose from the tunnel and terminated into the RA. PMID- 24174968 TI - A study on clinical and pathologic features in lupus nephritis with mainly IgA deposits and a literature review. AB - OBJECTIVE: To study the clinical and pathologic features of systemic lupus erythematosus (SLE) that has atypical lupus nephritis (LN) with mainly IgA deposits. METHODS: We searched the SLE patients who had nephritis with mainly IgA deposits in our hospital and selected the information including clinical manifestations, laboratory tests, treatments, and prognosis. RESULTS: From January 2009 to June 2012, 5 patients were definitely diagnosed as SLE according to both 1982 and 2009 ACR classification criteria. But renal biopsy showed that all cases had mainly IgA deposits and were free of IgG, C1q, and fibrinogen related antigen deposits under immunofluorescent microscopy, which did not match with typical LN. There were 2 males and 3 females, aging from 31 to 64 years and with an average of (42.20 +/- 13.59) years. The 5 cases had multiple-system involvements, mainly the renal system. Compared to primary IgAN, the atypical LN showed some differences: older than primary IgAN, more women than men, no previous infection history, lower incidence of serum IgA elevation, and ACL positive rate as high as 100%. CONCLUSION: Nephritis with mainly IgAN deposits, as an atypical LN, may be a special subtype of SLE. PMID- 24174970 TI - O-glycosylation of NnTreg lymphocytes recognized by the Amaranthus leucocarpus lectin. AB - O-glycosidically-linked glycans have been involved in development, maturation, homing, and immune regulation in T cells. Previous reports indicate that Amaranthus leucocarpus lectin (ALL), specific for glycans containing galactose-N acetylgalactosamine and N-acetylgalactosamine, recognizes human naive CD27(+)CD25(+)CD4(+) T cells. Our aim was to evaluate the phenotype of CD4(+) T cells recognized by ALL in peripheral blood mononuclear cells obtained from healthy volunteers. CD4(+) T cells were isolated by negative selection using magnetic beads-labeled monoclonal antibodies; the expression of T regulatory cell phenotypic markers was assessed on ALL-recognized cells. In addition, IL-4, IL 10, IFN-gamma, and TGF-beta intracellular production in ALL (+) cells was also evaluated. The analyses of phenotypic markers and intracellular cytokines were performed through flow cytometry. ALL-recognized CD4(+) T cells were mainly CD45RA(+), CCR7(+) cells. Although 52 +/- 10% CD25(+)Foxp3(+) cells were positive to ALL, only 34 +/- 4% of ALL (+) cells corresponded to CD25(+)Foxp3(-) cells. Intracellular cytokines in freshly obtained ALL (+)CD4(+) T cells exhibited 8% of IL-4, 15% of IL-10, 2% of IFN-gamma, and 15% of TGF-beta, whereas ALL (-)CD4(+) T cells depicted 1% of IL-4, 2% of IL-10, <1% of IFN-gamma, and 6% of TGF-beta. Our results show that galactose-N-acetylgalactosamine and N-galactosamine-bearing CD4(+) T cells expressed phenotypic markers of NnTreg cells. PMID- 24174969 TI - Initial immunopathogenesis of multiple sclerosis: innate immune response. AB - Multiple sclerosis (MS) is an inflammatory, demyelinating, and neurodegenerative disease of the central nervous system. The hallmark to MS is the demyelinated plaque, which consists of a well-demarcated hypocellular area characterized by the loss of myelin, the formation of astrocytic scars, and the mononuclear cell infiltrates concentrated in perivascular spaces composed of T cells, B lymphocytes, plasma cells, and macrophages. Activation of resident cells initiates an inflammatory cascade, leading to tissue destruction, demyelination, and neurological deficit. The immunological phenomena that lead to the activation of autoreactive T cells to myelin sheath components are the result of multiple and complex interactions between environment and genetic background conferring individual susceptibility. Within the CNS, an increase of TLR expression during MS is observed, even in the absence of any apparent microbial involvement. In the present review, we focus on the role of the innate immune system, the first line of defense of the organism, as promoter and mediator of cross reactions that generate molecular mimicry triggering the inflammatory response through an adaptive cytotoxic response in MS. PMID- 24174971 TI - Immunology and oxidative stress in multiple sclerosis: clinical and basic approach. AB - Multiple sclerosis (MS) exhibits many of the hallmarks of an inflammatory autoimmune disorder including breakdown of the blood-brain barrier (BBB), the recruitment of lymphocytes, microglia, and macrophages to lesion sites, the presence of multiple lesions, generally being more pronounced in the brain stem and spinal cord, the predominantly perivascular location of lesions, the temporal maturation of lesions from inflammation through demyelination, to gliosis and partial remyelination, and the presence of immunoglobulin in the central nervous system and cerebrospinal fluid. Lymphocytes activated in the periphery infiltrate the central nervous system to trigger a local immune response that ultimately damages myelin and axons. Pro-inflammatory cytokines amplify the inflammatory cascade by compromising the BBB, recruiting immune cells from the periphery, and activating resident microglia. inflammation-associated oxidative burst in activated microglia and macrophages plays an important role in the demyelination and free radical-mediated tissue injury in the pathogenesis of MS. The inflammatory environment in demyelinating lesions leads to the generation of oxygen- and nitrogen-free radicals as well as proinflammatory cytokines which contribute to the development and progression of the disease. Inflammation can lead to oxidative stress and vice versa. Thus, oxidative stress and inflammation are involved in a self-perpetuating cycle. PMID- 24174973 TI - Rheumatoid arthritis with deficiency pattern in traditional chinese medicine shows correlation with cold and hot patterns in gene expression profiles. AB - In our precious study, the correlation between cold and hot patterns in traditional Chinese medicine (TCM) and gene expression profiles in rheumatoid arthritis (RA) has been explored. Based on TCM theory, deficiency pattern is another key pattern diagnosis among RA patients, which leads to a specific treatment principle in clinical management. Therefore, a further analysis was performed aiming at exploring the characteristic gene expression profile of deficiency pattern and its correlation with cold and hot patterns in RA patients by bioinformatics analysis approach based on gene expression profiles data detected with microarray technology. The TCM deficiency pattern-related genes network comprises 7 significantly, highly connected regions which are mainly involved in protein transcription processes, protein ubiquitination, toll-like receptor activated NF- kappa B regulated gene transcription and apoptosis, RNA clipping, NF- kappa B signal, nucleotide metabolism-related apoptosis, and immune response processes. Toll-like receptor activated NF- kappa B regulated gene transcription and apoptosis pathways are potential specific pathways related to TCM deficiency patterns in RA patients; TCM deficiency pattern is probably related to immune response. Network analysis can be used as a powerful tool for detecting the characteristic mechanism related to specific TCM pattern and the correlations between different patterns. PMID- 24174974 TI - Cytotoxicity and Modes of Action of the Methanol Extracts of Six Cameroonian Medicinal Plants against Multidrug-Resistant Tumor Cells. AB - Introduction. The present study aims at evaluating the cytotoxicity of twelve parts from six Cameroonian medicinal plants on sensitive and drug-resistant cancer cell lines. We also studied the mode of action of the most active plants, Gladiolus quartinianus, Vepris soyauxii, and Anonidium mannii. Methods. The cytotoxicity of the extracts was determined using a resazurin assay. Flow cytometry was used for cell-cycle analysis and detection of apoptosis, analysis of mitochondrial membrane potential (MMP), and measurement of reactive oxygen species (ROS). Results. At 40 g/mL, three extracts showed a growth of CCRF-CEM leukemia cells by less than 50%. This includes the extracts from G. quartinianus (GQW; 25.69%), Vepris soyauxii leaves (VSL; 29.82%), and Anonidium mannii leaves (AML; 31.58%). The lowest IC50 values below 30 MU g/mL were obtained with GQW, AML and VSL against 7/9, 8/9, and 9/9 tested cancer cell lines, respectively. The lowest IC50 values for each plant were 4.09 MU g/mL, and 9.14 MU g/mL (against U87MG.DeltaEGFR cells), respectively, for VSL and AML and 10.57 MU g/mL (against CCRF-CEM cells) for GQW. GQW induced cell cycle arrest between G0/G1 and S phases, whilst VSL and AML induced arrest in G0/G1. All three extracts induced apoptosis in CCRF-CEM cells by loss of MMP, whilst AML also enhanced production of ROS. Conclusion. The three active plants may be a source for the development of new anticancer drugs. PMID- 24174972 TI - Posttransplant lymphoproliferative disease after pediatric solid organ transplantation. AB - Patients after solid organ transplantation (SOT) carry a substantially increased risk to develop malignant lymphomas. This is in part due to the immunosuppression required to maintain the function of the organ graft. Depending on the transplanted organ, up to 15% of pediatric transplant recipients acquire posttransplant lymphoproliferative disease (PTLD), and eventually 20% of those succumb to the disease. Early diagnosis of PTLD is often hampered by the unspecific symptoms and the difficult differential diagnosis, which includes atypical infections as well as graft rejection. Treatment of PTLD is limited by the high vulnerability towards antineoplastic chemotherapy in transplanted children. However, new treatment strategies and especially the introduction of the monoclonal anti-CD20 antibody rituximab have dramatically improved outcomes of PTLD. This review discusses risk factors for the development of PTLD in children, summarizes current approaches to therapy, and gives an outlook on developing new treatment modalities like targeted therapy with virus-specific T cells. Finally, monitoring strategies are evaluated. PMID- 24174975 TI - Identification of Target Genes Involved in the Antiproliferative Effect of Enzyme Modified Ginseng Extract in HepG2 Hepatocarcinoma Cell. AB - Ginsenosides are ginseng saponins, which are the major biologically active components of Panax ginseng, often metabolized by intestinal bacteria into more effective forms. In this study, we found that the antiproliferative activity of ginseng increased after enzymatic processing of ginseng saponin (50% inhibitory concentration [IC50], >30 MU g/mL), which may be the result of the accumulation of minor saponins, such as Rh1, Rg3, compound K, and PPT constituents in ginseng saponin. Using the Agilent PrimeView Human Gene Expression Array, we found that the expression of several genes involved in apoptosis (caspase-4, Annexin A2, HSPA9, AIFM1, UQCRC2, and caspase-7) were increased in HepG2 human hepatocarcinoma cells after their treatment with enzyme-modified ginseng extract (EMGE). Furthermore, several genes implicated in cell cycle progression (CDCA3, CDCA8, CABLES2, CDC25B, CNNM3, and CCNK) showed decreased expression in HepG2 cells treated with EMGE. Finally, from flow cytometric analysis, we found that EMGE-treated HepG2 cells showed increased apoptotic sub-G1 population (24%), compared with that observed in DMSO-treated control cells (1.6%). Taken together, our results suggest that EMGE induces anticancer activity through the induction of apoptosis-related genes and cell cycle arrest via decreased expression of cell cycle regulatory genes. PMID- 24174976 TI - Inhibitory Effect of Chrysanthemum zawadskii Herbich var. latilobum Kitamura Extract on RANKL-Induced Osteoclast Differentiation. AB - Chrysanthemum zawadskii Herbich var. latilobum Kitamura, known as "Gujulcho" in Korea, has been used in traditional medicine to treat various inflammatory diseases, including rheumatoid arthritis. However, these effects have not been tested on osteoclasts, the bone resorbing cells that regulate bone metabolism. Here, we investigated the effects of C. zawadskii Herbich var. latilobum Kitamura ethanol extract (CZE) on osteoclast differentiation induced by treatment with the receptor activator of NF- kappa B ligand (RANKL). CZE inhibited osteoclast differentiation and formation in a dose-dependent manner. The inhibitory effect of CZE on osteoclastogenesis was due to the suppression of ERK activation and the ablation of RANKL-stimulated Ca(2+)-oscillation via the inactivation of PLC gamma 2, followed by the inhibition of CREB activation. These inhibitory effects of CZE resulted in a significant repression of c-Fos expression and a subsequent reduction of NFATc1, a key transcription factor for osteoclast differentiation, fusion, and activation in vitro and in vivo. These results indicate that CZE negatively regulates osteoclast differentiation and may be a therapeutic candidate for the treatment of various bone diseases, such as postmenopausal osteoporosis, rheumatoid arthritis, and periodontitis. PMID- 24174978 TI - Mindfulness and self-compassion in generalized anxiety disorder: examining predictors of disability. AB - Generalized anxiety disorder (GAD) is a condition characterized by worry and physiological arousal symptoms that causes significant disabilities in patients' lives. In order to improve psychotherapeutic interventions, a careful characterization of the deficiencies of this population as well as factors that ameliorate disability is crucial. Variables that have not traditionally been the focus of research should be considered, such as trait mindfulness and self compassion. We investigated whether GAD patients would report lower mindfulness and self-compassion levels than healthy stressed individuals. Eighty-seven GAD patients and 49 healthy controls completed the Five Facet Mindfulness Questionnaire, the Self-Compassion Scale, and measures of anxiety. Patients with GAD also completed the Sheehan Disability Scale. Results showed that GAD patients had lower mindfulness and self-compassion than healthy stressed controls, and both were negatively correlated with levels of anxiety, worry, and anxiety sensitivity. In patients, mindfulness was a better predictor of disability than actual anxiety symptom scores. These findings highlight that in the presence of anxiety symptoms, mindfulness can be a factor that helps protect against feeling disabled by the disorder. The findings thereby add an important variable to the characterization of this disorder and should be taken into consideration for future treatment development. PMID- 24174977 TI - The Aqueous Extract of Rhizome of Gastrodia elata Protected Drosophila and PC12 Cells against Beta-Amyloid-Induced Neurotoxicity. AB - This study aims to investigate the neuroprotective effect of the rhizome of Gastrodia elata (GE) aqueous extract on beta-amyloid(A beta )-induced toxicity in vivo and in vitro. Transgenic Drosophila mutants with A beta -induced neurodegeneration in pan-neuron and ommatidia were used to determine the efficacy of GE. The antiapoptotic and antioxidative mechanisms of GE were also studied in A beta -treated pheochromocytoma (PC12) cells. In vivo studies demonstrated that GE (5 mg/g Drosophila media)-treated Drosophila possessed a longer lifespan, better locomotor function, and less-degenerated ommatidia when compared with the A beta -expressing control (all P < 0.05). In vitro studies illustrated that GE increased the cell viability of A beta -treated PC12 cells in dose-dependent manner, probably through attenuation of A beta -induced oxidative and apoptotic stress. GE also significantly upregulated the enzymatic activities of catalase, superoxide dismutase, and glutathione peroxidase, leading to the decrease of reactive oxidation species production and apoptotic marker caspase-3 activity. In conclusion, our current data presented the first evidence that the aqueous extract of GE was capable of reducing the A beta -induced neurodegeneration in Drosophila, possibly through inhibition of apoptosis and reduction of oxidative stress. GE aqueous extract could be developed as a promising herbal agent for neuroprotection and novel adjuvant therapies for Alzheimer's disease. PMID- 24174979 TI - Rhodiola rosea Impairs Acquisition and Expression of Conditioned Place Preference Induced by Cocaine. AB - A novel approach to the treatment of adverse effects of drugs of abuse is one which makes use of natural products. The present study investigated the effect of Rhodiola rosea L. hydroalcoholic extract (RHO) on cocaine-induced hyperactivity and conditioned place preference (CPP) in mice. In a first experiment, mice received RHO (15, 20 or 25 mg/kg, IG), cocaine (25 mg/kg, i.p.) (COC), or a combination of both drugs (COC + RHO15, COC + RHO20, and COC + RHO25), and their locomotor activity was evaluated. In a second experiment, the effects of RHO on the acquisition, expression, and reinstatement of cocaine CPP (induced by drug priming or social defeat stress) were evaluated. RHO alone did not increase activity but potentiated the hyperactivity induced by cocaine. Rhodiola did not induce motivational effects by itself but attenuated the acquisition and expression of cocaine-induced CPP. Moreover, it was found that RHO did not block reinstatement. The results indicate that RHO is effective in reducing the rewarding properties of cocaine but is ineffective in preventing priming or stress-induced cocaine reinstatement. In light of these findings, the benefits of Rhodiola rosea L. as a treatment of cocaine addiction would seem to be limited. PMID- 24174980 TI - Gene expression profiling on the molecular action of danshen-gegen formula in a randomized placebo-controlled trial of postmenopausal women with hypercholesterolemia. AB - The Danshen-Gegen formula (DG) is a traditional Chinese herbal formula which has long been used to treat cardiovascular disease. DG was found to be a cardiovascular tonic in our recent research. However, a comprehensive investigation of the molecular mechanism of DG in cardiovascular disease has not been performed. The aim of this study was to clarify the transcriptional profiling of genes modulated by DG on postmenopausal women by using DNAmicroarray technology. We obtained 29 whole blood samples both from DG-treated and placebo treated subjects. Blood lipid profile and intima-media thickness (IMT) were measured. Affymetrix GeneChip was used to identify differentially expressed genes (DEGs), followed by validation by the real-time PCR method. The results showed that DG-treated group has a significant improvement in IMT and lipid profile as compared to placebo-treated group. For the genomic study, the DG-treated group has a higher number of DEGs identified as compared to the placebo-treated group. Two important biological processes of "regulation of systemic arterial blood pressure by hormone" and "regulation of smooth muscle proliferation" have been identified by GePS in the DG-treated group. No significant biological process and cellular components were identified in the placebo-treated group. This genomic study on the molecular action of DG in postmenopausal women gathered sufficient molecular targets and pathways to reveal that DG could improve neointima thickening and hypertension. PMID- 24174981 TI - The Inhibitory Effect of Haloxylon salicornicum on Contraction of the Mouse Uterus. AB - Haloxylon salicornicum (H. salicornicum) is a plant that is frequently taken as a tea by Bedouin women in Egypt who are experiencing difficulties during pregnancy, as well as to provide relief from dysmenorrhoea. Despite its medical use, there has been no detailed evaluation of the effect of this plant on uterine tissue. Therefore, the initial aim of this study was to determine whether H. salicornicum affected the contraction of the mouse uterus in vitro. The crude aqueous extract of H. salicornicum was found to inhibit the spontaneous contractions of the uterus, with the effect being rapid in onset and completely reversible upon washout. Subsequent purification of the plant extract resulted in the identification of synephrine and N-methyltyramine, both of which were found to have inhibitory effects on the spontaneous contractions of the uterus. The EC50 for the purified constituent identified as synephrine was 0.82 +/- 0.24 MU g/mL. The inhibitory activity of crude H. salicornicum, as well as the isolated constituents, could be prevented by pretreatment of the uterus with the beta adrenoceptor antagonist propranolol. In conclusion, the use of H. salicornicum during preterm labour appears to be justified, and its pharmacologic effect is consistent with it acting as a beta -adrenoceptor agonist. PMID- 24174982 TI - A systematic review of biopsychosocial training programs for the self-management of emotional stress: potential applications for the military. AB - Combat-exposed troops and their family members are at risk for stress reactions and related disorders. Multimodal biopsychosocial training programs incorporating complementary and alternative self-management techniques have the potential to reduce stress-related symptoms and dysfunction. Such training can preempt or attenuate the posttraumatic stress response and may be effectively incorporated into the training cycle for deploying and redeploying troops and their families. A large systematic review was conducted to survey the literature on multimodal training programs for the self-management of emotional stress. This report is an overview of the randomized controlled trials (RCTs) identified in this systematic review. Select programs such as mindfulness-Based Stress Reduction, Cognitive Behavioral Stress Management, Autogenic Training, Relaxation Response Training, and other meditation and mind-body skills practices are highlighted, and the feasibility of their implementation within military settings is addressed. PMID- 24174983 TI - An n-of-1 Trial Service in Clinical Practice: Testing the Effectiveness of Liuwei Dihuang Decoction for Kidney-Yin Deficiency Syndrome. AB - Objective. To describe the clinical use of n-of-1 RCTs for kidney-Yin deficiency syndrome that is a traditional Chinese medicine syndrome in publicly clinical practice in China. Methods. Our study included patients with kidney-Yin deficiency syndrome, using a within-patient, randomized, double-blind, crossover comparison of Liuwei Dihuang decoction versus placebo. Outcome Measures. Primary outcome measures included number of individual completion rates, response rate, and post-n-of-1 RCTs decisions. Secondary measures were the whole group score of individual Likert scale, SF-36 questionnaire. Results. Fifty patients were recruited and 3 were not completed. Forty-seven patients completed 3 pairs of periods, 3 (6.38%) were responders, 28 (59.57%) were nonresponders, and 16 (34.05%) were possible responders. Doctors and patients used the trial results to making decision. Three responders stayed on the medication management, 28 nonresponders ceased the LDD, 7 patients of the 16 possible responders could not give clear decision, and the others kept the same medication station. Among the whole group, neither the individual Likert score nor the SF-36 showed any statistical differences between LDD and placebo. Discussion. More attention should be paid to choose experienced TCM doctor as investigator and keep the simulant same with test medication in n-of-1 RCTs of TCM and sufficiently biological half-life period of Chinese medicine compound. PMID- 24174984 TI - Epimedium flavonoids counteract the side effects of glucocorticoids on hypothalamic-pituitary-adrenal axis. AB - Our previous studies demonstrated that the epimedium herb, when simultaneously used with GCs, counteracted suppressive effects of GCs on the HPA axis without adverse influence on the therapeutic action of GCs. Here, total flavones were extracted from the epimedium flavonoids (EFs) and then used to investigate whether EFs provide protective effects on the HPA axis. We found that GCs induced a significant decrease in body weight gain, adrenal gland weight gain, and plasma adrenocorticotropin (ACTH) and corticosterone levels. After treatment with EFs, body weight gain, adrenal gland weight gain, and plasma corticosterone level were significantly restored, whilst plasma ACTH level was partially elevated. EFs were also shown to promote cell proliferation in the outer layer of adrenal cortex and to enhance the migration of newly divided cells toward the inner layer. To elucidate the underlying mechanisms, the mRNA expression of insulin-like growth factor II (IGF-II) was measured, and EFs significantly upregulated IGF-II expression. Our results indicated that EFs counteract the suppression of the HPA axis induced by GCs. This may involve both the ACTH and IGF-II pathways and thereby promote regeneration of the adrenal cortex suggesting a potential clinical application of EFs against the suppressive effects of GCs on the HPA axis. PMID- 24174985 TI - The Protective Effect of Cordymin, a Peptide Purified from the Medicinal Mushroom Cordyceps sinensis, on Diabetic Osteopenia in Alloxan-Induced Diabetic Rats. AB - The aim of this study was to investigate the protective effect of cordymin on diabetic osteopenia in alloxan-induced diabetic rats and the possible mechanisms involved. The diabetic rats received daily intraperitoneal injection with cordymin (20, 50, and 100 mg/kg/day) for 5 weeks. Cordymin could restore the circulating blood glucose, glycosylated hemoglobin (HbA1c), serum alkaline phosphatase (ALP), tartrate resistant acid phosphatase (TRAP), and insulin levels in a dose-dependent manner. Also, the treatment of diabetic rats with cordymin could partially reverse the beta cells death and decrease the total antioxidant status (TAOS) in the diabetic rats. The results may directly and indirectly account for the possible mechanism of the beneficial effect of cordymin on diabetic osteopenia, which was confirmed with the increased bone mineral content (BMC) and bone mineral density (BMD) in diabetic rats (P < 0.05). All those findings indicate that cordymin may play a protective role in diabetic osteoporosis. PMID- 24174986 TI - Data collectors' field journals as tools for research. AB - With rising numbers of families giving care to elderly loved ones, novel methods and sources of data need to be used to obtain comprehensive information about family caregiving patterns. The purpose of this paper is to present the interviewers' reflective journals as a source of rich data. Data collectors interviewed Hispanic family caregivers as part of a quantitative study of caregiving patterns. The stories derived from the personal journals brought to life three themes: caregiving as responsibility; creativity in giving care; and resistance to delegating tasks. Well-written journals have the potential of enhancing the interpretation of data collected by other means and of raising the quality of interviews and data through introspection and cultural understanding of the caregiving reality. PMID- 24174987 TI - Multiscale cross-approximate entropy analysis as a measurement of complexity between ECG R-R interval and PPG pulse amplitude series among the normal and diabetic subjects. AB - Physiological signals often show complex fluctuation (CF) under the dual influence of temporal and spatial scales, and CF can be used to assess the health of physiologic systems in the human body. This study applied multiscale cross approximate entropy (MC-ApEn) to quantify the complex fluctuation between R-R intervals series and photoplethysmography amplitude series. All subjects were then divided into the following two groups: healthy upper middle-aged subjects (Group 1, age range: 41-80 years, n = 27) and upper middle-aged subjects with type 2 diabetes (Group 2, age range: 41-80 years, n = 24). There are significant differences of heart rate variability, LHR, between Groups 1 and 2 (1.94 +/- 1.21 versus 1.32 +/- 1.00, P = 0.031). Results demonstrated differences in sum of large scale MC-ApEn (MC-ApEn(LS)) (5.32 +/- 0.50 versus 4.74 +/- 0.78, P = 0.003). This parameter has a good agreement with pulse-pulse interval and pulse amplitude ratio (PAR), a simplified assessment for baroreflex activity. In conclusion, this study employed the MC-ApEn method, integrating multiple temporal and spatial scales, to quantify the complex interaction between the two physical signals. The MC-ApEn(LS) parameter could accurately reflect disease process in diabetics and might be another way for assessing the autonomic nerve function. PMID- 24174988 TI - An image registration method for colposcopic images. AB - A nonrigid body image registration method for spatiotemporal alignment of image sequences obtained from colposcopy examinations to detect precancerous lesions of the cervix is proposed in this paper. The approach is based on time series calculation for those pixels in the first image of the sequence and a division of such image into small windows. A search process is then carried out to find the window with the highest affinity in each image of the sequence and replace it with the window in the reference image. The affinity value is based on polynomial approximation of the time series computed and the search is bounded by a search radius which defines the neighborhood of each window. The proposed approach is tested in ten 310-frame real cases in two experiments: the first one to determine the best values for the window size and the search radius and the second one to compare the best obtained results with respect to four registration methods found in the specialized literature. The obtained results show a robust and competitive performance of the proposed approach with a significant lower time with respect to the compared methods. PMID- 24174989 TI - SNP selection in genome-wide association studies via penalized support vector machine with MAX test. AB - One of main objectives of a genome-wide association study (GWAS) is to develop a prediction model for a binary clinical outcome using single-nucleotide polymorphisms (SNPs) which can be used for diagnostic and prognostic purposes and for better understanding of the relationship between the disease and SNPs. Penalized support vector machine (SVM) methods have been widely used toward this end. However, since investigators often ignore the genetic models of SNPs, a final model results in a loss of efficiency in prediction of the clinical outcome. In order to overcome this problem, we propose a two-stage method such that the the genetic models of each SNP are identified using the MAX test and then a prediction model is fitted using a penalized SVM method. We apply the proposed method to various penalized SVMs and compare the performance of SVMs using various penalty functions. The results from simulations and real GWAS data analysis show that the proposed method performs better than the prediction methods ignoring the genetic models in terms of prediction power and selectivity. PMID- 24174990 TI - A wavelet relational fuzzy C-means algorithm for 2D gel image segmentation. AB - One of the most famous algorithms that appeared in the area of image segmentation is the Fuzzy C-Means (FCM) algorithm. This algorithm has been used in many applications such as data analysis, pattern recognition, and image segmentation. It has the advantages of producing high quality segmentation compared to the other available algorithms. Many modifications have been made to the algorithm to improve its segmentation quality. The proposed segmentation algorithm in this paper is based on the Fuzzy C-Means algorithm adding the relational fuzzy notion and the wavelet transform to it so as to enhance its performance especially in the area of 2D gel images. Both proposed modifications aim to minimize the oversegmentation error incurred by previous algorithms. The experimental results of comparing both the Fuzzy C-Means (FCM) and the Wavelet Fuzzy C-Means (WFCM) to the proposed algorithm on real 2D gel images acquired from human leukemias, HL-60 cell lines, and fetal alcohol syndrome (FAS) demonstrate the improvement achieved by the proposed algorithm in overcoming the segmentation error. In addition, we investigate the effect of denoising on the three algorithms. This investigation proves that denoising the 2D gel image before segmentation can improve (in most of the cases) the quality of the segmentation. PMID- 24174991 TI - Robotic surgery of the liver: Italian experience and review of the literature. AB - Robotic liver resection is a new promising minimally invasive surgical technique not yet validated by level I evidence. During recent years, the application of the laparoscopic approach to liver resection has grown less than other abdominal specialties due to the intrinsic limitations of laparoscopic instruments. Robotics can overcome these limitations above all for complex operations. A review of the literature on major hepatic surgery was conducted on PubMed using selected keywords. Two hundred and thirty-five patients in 17 series were analysed and outcomes such as operative time, estimated blood loss, length of hospital stay, complications, conversion rate, and costs were described. The most commonly performed procedures were wedge resection and segmentectomy, but the predominance of major hepatectomies performed with robotic surgery is likely due to the superior control achieved by the robotic system. The conversion and complication rates were 4.2% and 13.4%, respectively. Intracavitary fluid collections and bile leaks were the most frequently occurring morbidities. The mean operation time was 285 min. The mean intraoperative blood loss was 50-280 mL. The mean postoperative hospital stay was four to seven days. Overall survival and long-term outcomes were not reported. Robotic liver surgery in Italy has become a clinical reality that is gaining increasing acceptance; a survey was carried out on robotic surgery, which showed that it is perceived as a significant advantage for operators and a consistent gain for the patient. More than 100 robotic hepatic resections have been performed in Italy where important robotic training schools are active. Robotic liver surgery is feasible and safe in trained and experienced hands. Further evaluation is required to assess the improvement in outcomes and long-term oncologic follow-up. PMID- 24174992 TI - Treatment of comorbid anxiety and autism spectrum disorders. AB - Clinically significant anxiety occurs frequently among individuals with autism spectrum disorders (ASDs) and is linked to increased psychosocial, familial, behavioral and academic impairment beyond the core autism symptoms when present. Although efforts are underway to establish empirically supported treatments for anxiety among individuals with ASDs, this remains an emerging research area. This literature review summarizes available information on the efficacy of pharmacological and psychosocial approaches for treating anxiety and repetitive behaviors in children, adolescents and adults with ASDs. Specifically, we evaluate evidence for the use of cognitive-behavioral therapy and selective serotonin-reuptake inhibitors. Evidence is growing in support of using cognitive behavioral therapy to treat anxiety in youths with ASDs; however, mixed evidence exists for its application in treating repetitive behaviors, as well as the use of selective serotonin-reuptake inhibitors for anxiety in youths with ASDs. We conclude the article with a discussion of the strength of current information and next steps in research. PMID- 24174994 TI - THRSP (thyroid hormone responsive). PMID- 24174993 TI - Advances in the treatment of pediatric obsessive-compulsive d-cycloserine with exposure and response prevention. AB - Exposure-based cognitive-behavioral therapy and serotonin reuptake inhibitor medications are efficacious treatment options for the management of pediatric obsessive-compulsive disorder. Despite established efficacy, many youths receiving either therapy remain symptomatic after acute treatment. Regardless of the rationale for persistent symptoms, a clear need emerges for treatment options that restore functioning efficiently to symptomatic youths. One innovative approach builds upon the identified role of NMDA receptors in the fear extinction process. Instead of breaking existing connections during fear extinction, new associations develop that eventually predominate over prior associations. Recent investigations have explored augmenting exposure-based cognitive-behavioral therapy with the NMDA partial agonist d-cycloserine, with preliminary results demonstrating expedited treatment gains and moderately larger effects above exposure and response prevention therapy alone. A large randomized clinical trial is underway to evaluate the efficacy and efficiency of this therapeutic combination in pediatric obsessive-compulsive disorder. Results from this trial may translate into improved management practices. PMID- 24174995 TI - Testosterone and Abnormal Glucose Metabolism in an Inner-City Cohort. AB - BACKGROUND: Low testosterone (T) has been associated with insulin resistance and diabetes mellitus (DM) among men in population-based studies. These studies included racially diverse men, but did not target for inclusion individuals with opiate use, Hepatitis C Virus (HCV) infection, or Human Immunodeficiency Virus (HIV) infection, which disproportionately affect inner-city populations and may alter the relationship between T and DM. METHODS: We studied the association between free T (FT) and abnormal glucose metabolism among male participants in the Study of HIV, Injection Drug Use, Nutrition, and Endocrinology (SHINE). We used logistic regression to examine the relationship between log FT and both insulin resistance and prediabetes/DM. RESULTS: Of 175 men, 43 (24.6%) had low FT (FT < 52 pg/mL). There were more men in the low FT group on methadone maintenance (39.5% v. 15.2%, p=.001), but there was no difference in FT by HIV or HCV status. Overall, 23 men (13.1%) had prediabetes/DM, which was unrelated to FT (OR of prediabetes/DM for each log increase in FT = 0.56, 95% CI 0.13-2.41). FT was also not related to insulin resistance. CONCLUSIONS: The prevalence of hypogonadism was high in this inner-city cohort and was associated with methadone use. However, low FT was not related to insulin resistance or prediabetes/DM. Continued work to identify diabetes risk factors among inner-city populations will help determine targets for intervention to reduce diabetes incidence. Treatment trials of testosterone to reduce diabetes among hypogonadal men may be of particular relevance to opiate users, many of whom are hypogonadal. PMID- 24174998 TI - Definition of medical event is to be based on the total source strength for evaluation of permanent prostate brachytherapy: A report from the American Society for Radiation Oncology. AB - PURPOSE: The Nuclear Regulatory Commission deems it to be a medical event (ME) if the total dose delivered differs from the prescribed dose by 20% or more. A dose based definition of ME is not appropriate for permanent prostate brachytherapy as it generates too many spurious MEs and thereby creates unnecessary apprehension in patients, and ties up regulatory bodies and the licensees in unnecessary and burdensome investigations. A more suitable definition of ME is required for permanent prostate brachytherapy. METHODS AND MATERIALS: The American Society for Radiation Oncology (ASTRO) formed a working group of experienced clinicians to review the literature, assess the validity of current regulations, and make specific recommendations about the definition of an ME in permanent prostate brachytherapy. RESULTS: The working group found that the current definition of ME in S35.3045 as "the total dose delivered differs from the prescribed dose by 20 percent or more" was not suitable for permanent prostate brachytherapy since the prostate volume (and hence the resultant calculated prostate dose) is dependent on the timing of the imaging, the imaging modality used, the observer variability in prostate contouring, the planning margins used, inadequacies of brachytherapy treatment planning systems to calculate tissue doses, and seed migration within and outside the prostate. If a dose-based definition for permanent implants is applied strictly, many properly executed implants would be improperly classified as an ME leading to a detrimental effect on brachytherapy. The working group found that a source strength-based criterion, of >20% of source strength prescribed in the post-procedure written directive being implanted outside the planning target volume is more appropriate for defining ME in permanent prostate brachytherapy. CONCLUSIONS: ASTRO recommends that the definition of ME for permanent prostate brachytherapy should not be dose based but should be based upon the source strength (air-kerma strength) administered. PMID- 24175000 TI - Continuous localization technologies for radiotherapy delivery: Report of the American Society for Radiation Oncology Emerging Technology Committee. PMID- 24175002 TI - Enhancing the role of case-oriented peer review to improve quality and safety in radiation oncology: Executive summary. AB - This report is part of a series of white papers commissioned for the American Society for Radiation Oncology (ASTRO) Board of Directors as part of ASTRO's Target Safely Campaign, focusing on the role of peer review as an important component of a broad safety/quality assurance (QA) program. Peer review is one of the most effective means for assuring the quality of qualitative, and potentially controversial, patient-specific decisions in radiation oncology. This report summarizes many of the areas throughout radiation therapy that may benefit from the application of peer review. Each radiation oncology facility should evaluate the issues raised and develop improved ways to apply the concept of peer review to its individual process and workflow. This might consist of a daily multidisciplinary (eg, physicians, dosimetrists, physicists, therapists) meeting to review patients being considered for, or undergoing planning for, radiation therapy (eg, intention to treat and target delineation), as well as meetings to review patients already under treatment (eg, adequacy of image guidance). This report is intended to clarify and broaden the understanding of radiation oncology professionals regarding the meaning, roles, benefits, and targets for peer review as a routine quality assurance tool. It is hoped that this work will be a catalyst for further investigation, development, and study of the efficacy of peer review techniques and how these efforts can help improve the safety and quality of our treatments. PMID- 24175003 TI - Safety considerations for IGRT: Executive summary. AB - Radiation therapy is an effective cancer treatment that is constantly being transformed by technological innovation. Dedicated devices for fraction-by fraction imaging and guidance within the treatment room have enabled image guided radiation therapy (IGRT) allowing clinicians to pursue highly conformal dose distributions, higher dose prescriptions, and shorter fractionation schedules. Capitalizing on IGRT-enabled accuracy and precision requires a strong link between IGRT practices and planning target volume (PTV) design. This is clearly central to high quality, safe radiation therapy. Failure to properly apply IGRT methods or to coordinate their use with an appropriate PTV margin can result in a treatment that is 'precisely wrong'. The white paper summarized in this executive summary recommends foundational elements and specific activities to maximize the safety and effectiveness of IGRT. PMID- 24175004 TI - Concentric and eccentric: muscle contraction or exercise? PMID- 24175005 TI - Prior Effective Sample Size in Conditionally Independent Hierarchical Models. AB - Prior effective sample size (ESS) of a Bayesian parametric model was defined by Morita, et al. (2008, Biometrics,64, 595-602). Starting with an epsilon information prior defined to have the same means and correlations as the prior but to be vague in a suitable sense, the ESS is the required sample size to obtain a hypothetical posterior very close to the prior. In this paper, we present two alternative definitions for the prior ESS that are suitable for a conditionally independent hierarchical model. The two definitions focus on either the first level prior or second level prior. The proposed methods are applied to important examples to verify that each of the two types of prior ESS matches the intuitively obvious answer where it exists. We illustrate the method with applications to several motivating examples, including a single-arm clinical trial to evaluate treatment response probabilities across different disease subtypes, a dose-finding trial based on toxicity in this setting, and a multicenter randomized trial of treatments for affective disorders. PMID- 24175006 TI - Continuous sheath-free magnetic separation of particles in a U-shaped microchannel. AB - Particle separation is important to many chemical and biomedical applications. Magnetic field-induced particle separation is simple, cheap, and free of fluid heating issues that accompany electric, acoustic, and optical methods. We develop herein a novel microfluidic approach to continuous sheath-free magnetic separation of particles. This approach exploits the negative or positive magnetophoretic deflection to focus and separate particles in the two branches of a U-shaped microchannel, respectively. It is applicable to both magnetic and diamagnetic particle separations, and is demonstrated through the sorting of 5 MUm and 15 MUm polystyrene particles suspended in a dilute ferrofluid. PMID- 24175008 TI - Dielectric Function of Undoped and Doped Poly[2-methoxy-5-(3',7' dimethyloctyloxy)-1,4-phenylene-vinylene] by Ellipsometry in a Wide Spectral Range. AB - Ellipsometric measurements in a wide spectral range (from 0.05 to 6.5 eV) have been carried out on the organic semiconducting polymer, poly[2-methoxy-5-(3',7' dimethyloctyloxy)-1,4-phenylene-vinylene] (MDMO-PPV), in both undoped and doped states. The real and imaginary parts of the dielectric function and the refractive index are determined accurately, provided that the layer thickness is measured independently. After doping, the optical properties show the presence of new peaks, which could be well-resolved by spectroscopic ellipsometry. Also for the doped material, the complex refractive index, with respect to the dielectric function, has been determined. The broadening of the optical transitions is due to the delocalization of polarons at higher doping level. The detailed information about the dielectric function as well as refractive index function obtained by spectroscopic ellipsometry allows not only qualitative but also quantitative description of the optical properties of the undoped/doped polymer. For the direct characterization of the optical properties of MDMO-PPV, ellipsometry turns out to be advantageous compared to conventional reflection and transmission measurements. PMID- 24175009 TI - Simultaneous double coronary thrombosis in a 47-year-old male patient with acute myocardial infarction. AB - PATIENT: Male, 47 FINAL DIAGNOSIS: Acute myocardial infarction Symptoms: Chest pain Medication: - Clinical Procedure: - Specialty: Cardiology. OBJECTIVE: Unusual clinical course. BACKGROUND: Double myocardial infarction involving two culprit major vessels is a rarely reported presentation with high incidence of mortality. CASE REPORT: In this study, we report 47-year-old male patient who had an attack of chest pain associated with ST-segment elevation in the antero lateral leads. Pharmaco-invasive reperfusion approach was adopted with full dose tissue plasminogen activator, followed by transferring the patient to a specialized heart center for Percutaneous Coronary Intervention (PCI). Coronary angiography showed a fresh thrombus totally occluding Left Anterior Descending (LAD) and another thrombus causing distal total occlusion of a dominant Right Coronary Artery (RCA). Two Bare metal stents were placed in both lesions with Thrombolysis in Myocardial Infarction (TIMI) 3 flow post dilatation, but the patient, unfortunately, went into Ventricular Fibrillation (VF) followed by asystole and died 35 minutes later. CONCLUSIONS: Acute double vessel coronary artery thrombosis is a serious event that requires prompt diagnosis and management to prevent its complications. PMID- 24175010 TI - Bivalvular endocarditis due to Granulicatella adiacens. AB - PATIENT: Male, 50 FINAL DIAGNOSIS: Bivalvular endocarditis due to Granulicatella adiacens Symptoms: Fever * fatigue MEDICATION: - Clinical Procedure: Echocardiogram * valve replacement surgery Specialty: Infectious Diseases. OBJECTIVE: Rare disease. BACKGROUND: Infective endocarditis remains a prominent cause of morbidity and mortality worldwide. It has been estimated that 50% of cases are caused by streptococcal organisms. Abiotrophia and Granulicatella, often grouped as nutritionally variant streptococci (NVS), have become recognized as the cause of nearly 5% of infective endocarditis cases. NVS endocarditis historically has a higher rate of morbidity and mortality, partially due to difficulties in adequately culturing and treating the causative organisms. CASE REPORT: In this report, we review the complicated hospital course and successful treatment of a middle aged Hispanic gentleman who presented with systemic symptoms of fevers, chills and weight loss over 3 months. He was found to have Granulicatella infective endocarditis of the mitral and aortic valves, presumably from a dental source. Despite severe valvular insufficiency noted on echocardiogram, the patient did not initially present with any symptoms of decompensated heart failure. With adequate antibiotic therapy followed by replacement of both valves, the patient had a successful recovery. CONCLUSIONS: This case report highlights the growing role that nutritionally variant streptococcus plays in endocarditis and how crucial early identification of the organism is to proper treatment. A brief literature review is also included about the diagnosis and recommended management of nutritionally variant streptococcal endocarditis. PMID- 24175011 TI - Mitochondrial dysfunction induces formation of lipid droplets as a generalized response to stress. AB - Lipid droplet (LD) formation is a hallmark of cellular stress. Cells attempt to combat noxious stimuli by switching their metabolism from oxidative phosphorylation to glycolysis, sparing resources in LDs for generating cellular reducing power and for anabolic biosynthesis. Membrane phospholipids are also a source of LDs. To elucidate the formation of LDs, we exposed mice to hyperoxia, hypoxia, myocardial ischemia, and sepsis induced by cecal ligation and puncture (CLP). All the above-mentioned stressors enhanced the formation of LDs, as assessed by transmission electron microscopy, with severe mitochondrial swelling. Disruption of mitochondria by depleting mitochondrial DNA ( rho 0 cells) significantly augmented the formation of LDs, causing transcriptional activation of fatty acid biosynthesis and metabolic reprogramming to glycolysis. Heme oxygenase (HO)-1 counteracts CLP-mediated septic shock in mouse models. In HO-1 deficient mice, LD formation was not observed upon CLP, but a concomitant decrease in "LD-decorating proteins" was observed, implying a link between LDs and cytoprotective activity. Collectively, LD biogenesis during stress can trigger adaptive LD formation, which is dependent on mitochondrial integrity and HO-1 activity; this may be a cellular survival strategy, apportioning energy generating substrates to cellular defense. PMID- 24175012 TI - Analysis of serum and urinal copper and zinc in Chinese northeast population with the prediabetes or diabetes with and without complications. AB - This study investigated the association of copper and zinc levels in the serum or urine of patients living in northeast China, with either prediabetes or diabetes. From January 2010 to October 2011, patients with type 1 diabetes (T1D, n = 25), type 2 diabetes (T2D, n = 137), impaired fasting glucose (IFG, n = 12) or impaired glucose tolerance (IGT, n = 15), and age/gender matched controls (n = 50) were enrolled. In the T2D group, there were 24 patients with nephropathy, 34 with retinopathy, and 50 with peripheral neuropathy. Serum copper levels were significantly higher in IFG, IGT, and T2D groups. Serum zinc level was dramatically lower, and urinary zinc level was significantly higher in both T1D and T2D subjects compared with controls. The serum zinc/copper ratio was significantly lower in all the patients with IFG, ITG, T1D, and T2D. The serum copper level was positively associated with HbA1c in T2D subjects. Simvastatin treatment in T2D patients had no significant effect on serum and urinary copper and zinc. These results suggest the need for further studies of the potential impact of the imbalanced serum copper and zinc levels on metabolic syndrome, diabetes, and diabetic complications. PMID- 24175014 TI - Prenatal diagnosis of spinal muscular atrophy: clinical experience and molecular genetics of SMN gene analysis in 36 cases. AB - INTRODUCTION: prenatal diagnosis in families at risk for spinal muscular atrophy (SMA) mainly of type 1 is often applied due to the high incidence, most severe and newborn outcome of the disease. CASE: we present our clinical experience for 36 families with history of having at least one child with homozygous deletions of the SMN1 gene between. Seventeen families requested for prenatal prediction and of these cases, 8 fetuses were diagnosed to be at risk of developing the disease and the parents decided to terminate the pregnancy. Nine fetuses were detected with no homozygous deletion of the SMN1 and reached to full term delivery. Follow-up of live born children and abortion products never led to false or negative result. CONCLUSION: therefore, application of SMN1 deletion detection by simple PCR assay in families with homozygous deletion of the SMN1 gene could be suggested for prenatal prediction in such families. PMID- 24175013 TI - Skin injuries reduce survival and modulate corticosterone, C-reactive protein, complement component 3, IgM, and prostaglandin E 2 after whole-body reactor produced mixed field (n + gamma-photons) irradiation. AB - Skin injuries such as wounds or burns following whole-body gamma-irradiation (radiation combined injury (RCI)) increase mortality more than whole-body gamma irradiation alone. Wound-induced decreases in survival after irradiation are triggered by sustained activation of inducible nitric oxide synthase pathways, persistent alteration of cytokine homeostasis, and increased susceptibility to systemic bacterial infection. Among these factors, radiation-induced increases in interleukin-6 (IL-6) concentrations in serum were amplified by skin wound trauma. Herein, the IL-6-induced stress proteins including C-reactive protein (CRP), complement 3 (C3), immunoglobulin M (IgM), and prostaglandin E2 (PGE2) were evaluated after skin injuries given following a mixed radiation environment that might be found after a nuclear incident. In this report, mice received 3 Gy of reactor-produced mixed field (n + gamma-photons) radiations at 0.38 Gy/min followed by nonlethal skin wounding or burning. Both wounds and burns reduced survival and increased CRP, C3, and PGE2 in serum after radiation. Decreased IgM production along with an early rise in corticosterone followed by a subsequent decrease was noted for each RCI situation. These results suggest that RCI-induced alterations of corticosterone, CRP, C3, IgM, and PGE2 cause homeostatic imbalance and may contribute to reduced survival. Agents inhibiting these responses may prove to be therapeutic for RCI and improve related survival. PMID- 24175015 TI - Case report of prenatal diagnosis of Stuve-Wiedemann Syndrome in a woman with another child affected too. AB - OBJECTIVE: Stuve-Wiedemann Syndrome (SWS; MIM 601 559) is an autosomal-recessive syndrome characterized by myotonia with mask-like face, skeletal dysplasia and intrauterine growth restriction. Other clinical findings are pursed mouth, hypoplastic midface, congenital contractures and muscular hypotonia. We discuss about the importance of prenatal diagnosis in SWS and the possibility of survival after the first year of life in patients suffering from this disease. METHODS: we report a case of Stuve-Wiedemann Syndrome detected by morphological examination in our Operative Unit. Prenatal presumptive diagnosis was given with two dimensional and 3-D probe, during the second trimester of pregnancy. Caesarean section was performed at 38(th) week of gestation. Then diagnosis was genetically performed. RESULTS: at birth, clinical examination was concordant with the ultrasound findings. Genetic analysis also confirmed the presumptive diagnosis. Episodes of respiratory distress and hyperthermia decreased until it disappeared altogether at 1 year of age. CONCLUSION: we underline the usefulness of ultrasound study of fetal skeleton in the prenatal diagnosis. It allowed us to do an early detection of birth defects and their appropriate management. PMID- 24175016 TI - Prenatal diagnosis of giant cardiac rhabdomyoma with fetal hydrops in tuberous sclerosis. AB - INTRODUCTION: fetal rhabdomyoma is the most common fetal cardiac tumor and is often associated with tuberous sclerosis. Usually the tumors are relatively small and show no mediastinal shift. Fetal hydrops and pericardial effusion are rarely seen. CASE: in this case report we present the neonatal clinical course of a case of prenatal diagnosis of giant cardiac rhabdomyomas. CONCLUSION: an early prenatal diagnosis may help for an adequate planning of perinatal monitoring and treatment with involvement of a multidisciplinary team. PMID- 24175017 TI - Effect of vaginally administered DHA fatty acids on pregnancy outcome in high risk pregnancies for preterm delivery: a double blinded randomised controlled trial. AB - OBJECTIVES: to verify whether vaginally intake of docosahexaenoic acid (DHA), an n-3 long chain polyunsaturated fatty acid, would improve length of gestation and newborn birth weight in high risk pregnancies for preterm delivery. METHODS: this study was a randomized, double-blind, controlled, clinical trial, including women at high risk for preterm delivery. Of 74 eligible women, 31 refused to participate and 34 were enrolled and randomized with equal chance of selection, 22 were assigned to treatment group and 21 were assigned to the control group, and received placebo. One gram of DHA was administered vaginally once a day starting from 21 (1 week of gestation until 37 weeks + 0 day). The primary endpoint was to determine the length of the pregnancy and secondary endpoint the newborn weight. RESULTS: gestational age at delivery was 38.6 (SD, 1.05) weeks in the docosahexaenoic acid group and 37.6 (SD, 0.84) weeks in the placebo group (P =0.007). For women who completed the treatment and delivered at term there was a statistically difference of the weights in the two groups [3082.1 (SD, 293) gr cases vs 2699.3 (SD, 150) gr controls P <0.0001]. CONCLUSION: in high risk patients for preterm delivery, the vaginal administration of a DHA increases length of gestation and newborn birth weight. PMID- 24175018 TI - Imaging Analysis of Carbohydrate-Modified Surfaces Using ToF-SIMS and SPRi. AB - Covalent modification of surfaces with carbohydrates (glycans) is a prerequisite for a variety of glycomics-based biomedical applications, including functional biomaterials, glycoarrays, and glycan-based biosensors. The chemistry of glycan immobilization plays an essential role in the bioavailability and function of the surface bound carbohydrate moiety. However, the scarcity of analytical methods to characterize carbohydrate-modified surfaces complicates efforts to optimize glycan surface chemistries for specific applications. Time-of-Flight Secondary Ion Mass Spectrometry (ToF-SIMS) is a surface sensitive technique suited for probing molecular composition at the biomaterial interface. Expanding ToF-SIMS analysis to interrogate carbohydrate-modified materials would increase our understanding of glycan surface chemistries and advance novel tools in the nascent field of glycomics. In this study, a printed glycan microarray surface was fabricated and subsequently characterized by ToF-SIMS imaging analysis. A multivariate technique based on principal component analysis (PCA) was used to analyze the ToF-SIMS dataset and reconstruct ToF-SIMS images of functionalized surfaces. These images reveal chemical species related to the immobilized glycan, underlying glycan-reactive chemistries, gold substrates, and outside contaminants. Printed glycoarray elements (spots) were also interrogated to resolve the spatial distribution and spot homogeneity of immobilized glycan. The bioavailability of the surface-bound glycan was validated using a specific carbohydrate-binding protein (lectin) as characterized by Surface Plasmon Resonance Imaging (SPRi). Our results demonstrate that ToF-SIMS is capable of characterizing chemical features of carbohydrate-modified surfaces and, when complemented with SPRi, can play an enabling role in optimizing glycan microarray fabrication and performance. PMID- 24175019 TI - Endovascular treatment of aneurysms arising from the proximal segment of the anterior cerebral artery. AB - OBJECTIVE: Aneurysms arising from the proximal segment of the anterior cerebral artery (A1) are rare and challenging to treat. The aim of this study was to report our experience with endovascular treatment of A1 Aneurysms. METHODS: From August 2007 through May 2012, eleven A1 aneurysms in eleven patients were treated endovascularly. Six aneurysms were unruptured and 5 were ruptured. One patient with an unruptured A1 aneurysm presented with subarachnoid hemorrhage due to rupture of an anterior communicating artery aneurysm. Procedural data, clinical and angiographic results were reviewed retrospectively. RESULTS: All of the aneurysms were successfully treated with coil embolization. Six were treated with a simple technique while the remaining 5 required adjunctive technique : double catheters (n=2), balloon-assisted (n=2), and stent-assisted (n=1). The immediate angiographic control showed a complete occlusion in all cases. Procedure-related complication occurred in only one patient : parent artery occlusion, which was not clinically significant. All patients had excellent clinical outcomes but one patient was discharged with a slight disability. No neurologic deterioration or bleeding was seen during the follow-up period in this cohort of patients. Follow up angiography (mean, 20 months) was available in ten patients and revealed stable occlusion in all cases. CONCLUSION: Endovascular treatment is a feasible and effective therapeutic modality for A1 aneurysms. Tailored microcatheter shaping and/or adjunctive techniques are necessary for successful aneurysm embolization because of the projection and location of A1 aneurysms. PMID- 24175020 TI - Protocols and Results of Resident Neurosurgeon's Transfemoral Catheter Angiography Training Supervised by Neuroendovascular Specialists. AB - OBJECTIVE: Transfemoral catheter angiography (TFCA) is a basic procedure in neurovascular surgery with increasing importance in surgical and non-invasive treatments. Unfortunately, resident neurosurgeons have relatively few opportunities to perform TFCA in most institutions. We report a method developed in our hospital for training resident neurosurgeons to perform TFCA and evaluate the efficacy of this training. METHODS: From May 2011 to September 2011, a total of 112 consecutive patients underwent TFCA by one resident neurosurgeon supervised by two neuroendovascular specialists. Patients who underwent elective diagnostic procedures were included in this study. Patients who underwent endovascular treatment were excluded. Demographic data, indications for TFCA, side of approach, number of selected arteries, and complications were analyzed. RESULTS: This study included 64 males and 48 females with a mean age of 51.6 (12 81) years. All procedures were performed in the angiography suite. Common indications for procedures were as follows: stroke-induced symptoms in 61 patients (54.5%), Moyamoya disease and arteriovenous malformation in 13 patients (11.6%), and unruptured intracranial aneurysm in eight patients (7.1%). Right and left femoral puncture was performed in 98.2% and 1.8% of patients, respectively. A total of 465 selective angiographies were performed without complications. Angiographic examination was performed on 4.15 vessels per patient. CONCLUSION: TFCA can be performed safely by resident neurosurgeons based on anatomical study and a meticulous protocol under the careful supervision of neuroendovascular specialists. PMID- 24175021 TI - Anterior choroidal artery aneurysm surgery: ischemic complications and clinical outcomes revisited. AB - OBJECTIVE: Surgical results for anterior choroidal artery (AChA) aneurysms have previously been reported as unsatisfactory due to inadvertent occlusion of the AChA, while the low incidence of AChA aneurysms hampers the accumulation of surgical experience. The authors reviewed their related surgical experience to document the ischemic complications and surgical outcomes. METHODS: Identification of the AChA at its origin by rigorous visual scrutiny, careful microdissection, and meticulous clip placement to avoid the AChA origin are all crucial surgical maneuvers. A retrospective review of a surgical series of 62 consecutive cases of an AChA aneurysm between 2004 and 2012 was performed. RESULTS: All patients, except for five (8.1%) with a small residual neck, showed complete aneurysm obliteration in postoperative angiographic evaluations. There was no incidence of procedure-related permanent AChA syndrome or oculomotor nerve palsy, while three (4.8%) patients suffered from transient AChA syndrome. The clinical outcomes [the 3-month modified Rankin Scale (mRS)] of the patients were related to their preoperative World Federation of Neurologic Surgeons (WFNS) grade. As regards the 3-month mRS, significant differences were found between patients with an unruptured aneurysm (WFNS grade 0; n=20), good-grade subarachnoid hemorrhage (WFNS grade 1-3; n=30), and poor-grade subarachnoid hemorrhage (WFNS grade 4-5; n=4). CONCLUSION: In surgical treatment of AChA aneurysms, a risk of AChA insufficiency can be minimized by taking every precaution to preserve the AChA patency and intraoperative monitoring. In addition, the surgical outcome is primarily determined by the preoperative clinical state. PMID- 24175022 TI - Direct Relationship between Angiographic Characteristics of Carotid Atherosclerotic Plaque and Filling Defect in the Cerebral Protection Filters : Based on the Conventional Angiography. AB - OBJECTIVE: Neurologic complications during carotid artery stenting (CAS) are usually associated with distal embolic event. These embolic incident during CAS are highly associated with the carotid plaque instability. The current study was undertaken to identify the angiographic characteristics of carotid plaque vulnerability, which was represented as filling defect in the cerebral protection filters during CAS. METHODS: A total of 107 patients underwent CAS with use of a distal protection filter. Angiographic carotid plaque surface morphology was classified as smooth, irregular, and ulcerated. To determine predictable factors of filling defect in the protection filters, 11 variables were retrospectively analyzed which might influence filling defect in the protection filters during CAS. RESULTS: Filling defects during CAS were presented in the 33 cerebral protection filters. In multivariate analysis, angiographic ulceration [odds ratio (OR), 6.60; 95% confidence interval (CI) : 2.24, 19.4; p=0.001], higher stenosis degree (OR, 1.06; 95% CI : 1.00, 1.12; p=0.039), and coexistent thrombus (OR, 7.58; 95% CI : 1.69, 34.05; p=0.08) were highly associated with filling defect in the cerebral protection devices during CAS. Among several variables, angiographic surface ulceration was the only significant factor associated with flow stagnation during CAS (OR, 4.11; 95% CI : 1.33, 12.72; p=0.014). CONCLUSION: Plaque surface morphology on carotid angiography can be a highly sensitive marker of plaque instability during CAS. The independent risk factors for filling defect in the filter devices during CAS were plaque ulceration, stenosis degree, and coexistent thrombus. PMID- 24175023 TI - The usefulness of brain magnetic resonance imaging with mild head injury and the negative findings of brain computed tomography. AB - OBJECTIVE: To investigate the cases of intracranial abnormal brain MRI findings even in the negative brain CT scan after mild head injury. METHODS: During a 2 year period (January 2009-December 2010), we prospectively evaluated both brain CT and brain MRI of 180 patients with mild head injury. Patients were classified into two groups according to presence or absence of abnormal brain MRI finding even in the negative brain CT scan after mild head injury. Two neurosurgeons and one neuroradiologist validated the images from both brain CT scan and brain MRI double blindly. RESULTS: Intracranial injury with negative brain CT scan after mild head injury occurred in 18 patients (10.0%). Headache (51.7%) without neurologic signs was the most common symptom. Locations of intracranial lesions showing abnormal brain MRI were as follows; temporal base (n=8), frontal pole (n=5), falx cerebri (n=2), basal ganglia (n=1), tentorium (n=1), and sylvian fissure (n=1). Intracranial injury was common in patients with a loss of consciousness, symptom duration >2 weeks, or in cases of patients with linear skull fracture (p=0.00013), and also more frequent in multiple associated injury than simple one (35.7%>8.6%) (p=0.105). CONCLUSION: Our investigation showed that patients with mild head injury even in the negative brain CT scan had a few cases of intracranial injury. These findings indicate that even though the brain CT does not show abnormal findings, they should be thoroughly watched in further study including brain MRI in cases of multiple injuries and when their complaints are sustained. PMID- 24175024 TI - The usefulness of stereotactic radiosurgery for radioresistant brain metastases. AB - OBJECTIVE: We investigated the effectiveness of stereotactic gamma knife Radiosurgery (GKR) for radioresistant brain metastases with the impact upon histology. METHODS: Between April 2004 and May 2011, a total of 23 patients underwent GKR for 67 metastatic brain tumors from 12 renal cell cancers, 5 sarcomas and 6 melanomas. The mean age was 56 years (range, 18 to 79 years). Most of the patients were classified as the Radiation Therapy Oncology Group recursive partitioning analysis class II (91.3%). The synchronous metastasis was found in 6 patients (26.1%) and metachronous metastasis in 17 patients (73.9%). We analyzed the local control rate, intracranial progression-free survival (PFS) and overall survival (OS). RESULTS: The mean tumor volume for GKR was 2.24 cc and the mean prescription dose was 19.4 Gy (range, 10 to 24) to the tumor margin. Out of metachronous metastases, the median duration to intracranial metastasis was 3.3 years in renal cell cancer (RCC), 2.4 years in melanoma and 1.1 years in sarcoma (p=0.012). The total local control rate was 89.6% during the mean 12.4 months follow-up. The six-month and one-year local control rate was 90.2% and 83% respectively. Depending on the pathology, the control rate of RCC was 95.7%, sarcoma 91.3% and melanoma 80.5% during the follow-up. The common cause of local failure was the tumor bleeding in melanoma. The median PFS and OS were 5.2 and 8.4 months in RCC patients, 6.5 and 9.8 months in sarcoma, and 3.8 and 5.1 months in melanoma. CONCLUSION: The GKR can be one of the effective management options for the intracranial metastatic tumors from the radioresistant tumors. The melanoma showed a poor local control rate compared to other pathologies because of the hemorrhage. PMID- 24175025 TI - Closed-suction drainage and cerebrospinal fluid leakage following microvascular decompression : a retrospective comparison study. AB - OBJECTIVE: We performed this study to investigate whether the use of closed suction drainage following microvascular decompression (MVD) causes cerebrospinal fluid (CSF) leakage. METHODS: Between 2004 and 2011, a total of 157 patients with neurovascular compression were treated with MVD. MVD was performed for hemifacial spasm in 150 (95.5%) cases and for trigeminal neuralgia in 7 (4.5%) cases. The mean age of the patients was 49.8+/-9.6 years (range, 20-69). Dural substitutes were used in 44 (28.0%) patients. Ninety-two patients (58.6%) were underwent a 4 5 cm craniotomy using drainage (drainage group), and 65 (41.4%) did a small 2-2.5 cm retromastoid craniectomy without closed-suction drainage (no-drainage group). RESULTS: Eleven (7.0%) patients experienced CSF leakage following MVD based on the criteria of this study; all of these patients were in the drainage group. In the unadjusted analyses, the incidence of CSF leakage was significantly related with the use of closed-suction drainage following MVD (12.0% in the drainage group vs. 0% in the no-drainage group, respectively; p=0.003; Fisher's exact test). Those who received dural substitutes and the elderly (cut-off value=60 years) exhibited a tendency to develop CSF leakage (p=0.075 and p=0.090, respectively; Fisher's exact test). In the multivariate analysis, only the use of closed-suction drainage was significantly and independently associated with the development of CSF leakage following MVD (odds ratio=9.900; 95% confidence interval, 1.418 to infinity; p=0.017). CONCLUSION: The use of closed-suction drainage following MVD appears to be related to the development of CSF leakage. PMID- 24175026 TI - Factors related to outcomes of subthalamic deep brain stimulation in Parkinson's disease. AB - OBJECTIVE: Subthalamic nucleus (STN) deep brain stimulation (DBS) is an effective treatment of choice for patients with advanced idiopathic Parkinson's disease (PD) who have motor complication with medication. The objectives of this study are to analyze long-term follow-up data of STN DBS cases and to identify the factors related to outcomes. METHODS: Fifty-two PD patients who underwent STN DBS were followed-up for more than 3 years. The Unified Parkinsons Disease Rating Scale (UPDRS) and other clinical profiles were assessed preoperatively and during follow-up. A linear regression model was used to analyze whether factors predict the results of STN DBS. We divided the study individuals into subgroups according to several factors and compared subgroups. RESULTS: Preoperative activity of daily living (ADL) and the magnitude of preoperative levodopa response were shown to predict the improvement in UPDRS part II without medication, and preoperative ADL and levodopa equivalent dose (LED) were shown to predict the improvement in UPDRS part II with medication. In UPDRS part III with medication, the magnitude of preoperative levodopa response was a predicting factor. CONCLUSION: The intensity of preoperative levodopa response was a strong factor for motor outcome. And preoperative ADL and LED were strong factors for ADL improvement. More vigorous studies should be conducted to elucidate how levodopa-induced motor complications are ameliorated after STN DBS. PMID- 24175027 TI - Glioma mimicking a hypertensive intracerebral hemorrhage. AB - Here, we report a rare case of an anaplastic astrocytoma masquerading as a hypertensive basal ganglia hemorrhage. A 69-year-old woman who had been under medical management for hypertension during the past 3 years suddenly developed right hemiparesis with dysarthria. Brain computed tomography (CT) scans with contrast and CT angiograms revealed an intracerebral hemorrhage (ICH) in the left basal ganglia, without an underlying lesion. She was treated conservatively, but underwent a ventriculoperitoneal shunt operation 3 months after the initial attack due to deteriorated mental status and chronic hydrocephalus. Three months later, her mental status deteriorated further. Magnetic resonance imaging (MRI) with gadolinium demonstrated an irregular enhanced mass in which the previous hemorrhage occurred. The final histological diagnosis which made by stereotactic biopsy was an anaplastic astrocytoma. In the present case, the diagnosis of a high grade glioma was delayed due to tumor bleeding mimicking hypertensive ICH. Thus, a careful review of neuroradiological images including MRI with a suspicion of tumor bleeding is needed even in the patients with past medical history of hypertension. PMID- 24175028 TI - Anterior dislodgement of a fusion cage after transforaminal lumbar interbody fusion for the treatment of isthmic spondylolisthesis. AB - Transforaminal lumbar interbody fusion (TLIF) is commonly used procedure for spinal fusion. However, there are no reports describing anterior cage dislodgement after surgery. This report is a rare case of anterior dislodgement of fusion cage after TLIF for the treatment of isthmic spondylolisthesis with lumbosacral transitional vertebra (LSTV). A 51-year-old man underwent TLIF at L4 5 with posterior instrumentation for the treatment of grade 1 isthmic spondylolisthesis with LSTV. At 7 weeks postoperatively, imaging studies demonstrated that banana-shaped cage migrated anteriorly and anterolisthesis recurred at the index level with pseudoarthrosis. The cage was removed and exchanged by new cage through anterior approach, and screws were replaced with larger size ones and cement augmentation was added. At postoperative 2 days of revision surgery, computed tomography (CT) showed fracture on lateral pedicle and body wall of L5 vertebra. He underwent surgery again for paraspinal decompression at L4-5 and extension of instrumentation to S1 vertebra. His back and leg pains improved significantly after final revision surgery and symptom relief was maintained during follow-up period. At 6 months follow-up, CT images showed solid fusion at L4-5 level. Careful cage selection for TLIF must be done for treatment of spondylolisthesis accompanied with deformed LSTV, especially when reduction will be attempted. Banana-shaped cage should be positioned anteriorly, but anterior dislodgement of cage and reduction failure may occur in case of a highly unstable spine. Revision surgery for the treatment of an anteriorly dislodged cage may be effectively performed using an anterior approach. PMID- 24175029 TI - Differential diagnosis and management of a pituitary mass with renal cell carcinoma. AB - The small pituitary mass was incidentally found in 40-years-old women with renal cell carcinoma. The endocrinological and ophthalmological evaluation revealed no deficit and the short-term follow-up was recommended. In 6 months later, the visual disturbance was reported and the size of mass was increased. The tumor was removed totally via the trans-sphenoid approach. The post-operative endocrinological insufficiency was not noticed. During one year of follow-up period, there was no evidence of recurrence without adjuvant radiotherapy. The clinical features of pituitary metastasis from renal cell carcinoma were similar to those of pituitary adenoma. The possibility of pituitary metastasis should be kept in mind in patients with sellar mass and renal cell carcinoma. PMID- 24175030 TI - Pulsed radiofrequency neuromodulation for the treatment of saphenous neuralgia. AB - A 65-year-old male presented with pain in his right medial calf. An imaging study revealed no acute lesions, and a diagnosis of saphenous neuralgia was made by a nerve conduction study. He received temporary pain relief with saphenous nerve blocks twice in a one-week interval. Pulsed radiofrequency neuromodulation reduced pain to 10% of the maximal pain intensity. At 6 months after the procedure, the pain intensity was not aggravated even without medication. Pulsed radiofrequency neuromodulation of the saphenous nerve may offer an effective and minimally invasive treatment for patients with saphenous neuralgia who are refractory to conservative management. PMID- 24175031 TI - Hypertensive encephalopathy with reversible brainstem edema. AB - Presented here is a 36-year-old male with arterial hypertension who developed brainstem edema and intracranial hemorrhage. Magnetic resonance scan revealed diffuse brainstem hyperintensity in T2-weighted and fluid-attenuated inversion recovery images, with an increase in apparent diffusion coefficient values. After a reduction in blood pressure, rapid resolution of the brainstem edema was observed on follow-up. The patient's condition was thus interpreted as hypertensive brainstem encephalopathy. While many consider this a vasogenic phenomenon, induced by sudden, severe hypertension, the precise mechanism remains unclear. Prompt recognition and aggressive antihypertensive treatment in such patients are essential to prevent permanent or life-threatening neurologic injury. PMID- 24175032 TI - Barotrauma-induced pneumocephalus experienced by a high risk patient after commercial air travel. AB - A 49-year-old female with a history of several neurosurgical and otolaryngologic procedures for occipital meningioma and cerebrospinal fluid leaks was diagnosed with pneumocephalus after a one hour flight on a domestic jet airliner. Despite multiple operations, the air appeared to enter the cranium through a weak portion of the skull base due to the low atmospheric pressure in the cabin. The intracranial air was absorbed with conservative management. The patient was recommended not to fly before a definite diagnostic work up and a sealing procedure for the cerebrospinal fluid leak site had been performed. Recent advances in aviation technology have enabled many people to travel by air, including individuals with medical conditions. Low cabin pressure is not dangerous to healthy individuals; however, practicing consultant neurosurgeons should understand the cabin environment and prepare high risk patients for safe air travel. PMID- 24175033 TI - Acute hydrocephalus following cervical spinal cord injury. AB - We present a case of acute hydrocephalus secondary to cervical spinal cord injury in a patient with diffuse ossification of the posterior longitudinal ligament (OPLL). A 75-year-old male patient visited the emergency department with tetraparesis and spinal shock. Imaging studies showed cervical spinal cord injury with hemorrhage and diffuse OPLL from C1 to C4. We performed decompressive laminectomy and occipitocervical fusion. Two days after surgery, his mental status had deteriorated to drowsiness with dilatation of the right pupil. Findings on brain computed tomography revealed acute hydrocephalus and subarachnoid hemorrhage in the cerebellomedullary cistern, therefore, extraventricular drainage was performed immediately. Acute hydrocephalus as a complication of cervical spine trauma is rare, however, it should be considered if the patient shows deterioration of neurologic symptoms. PMID- 24175034 TI - Intracranial calcification caused by a brain abscess : a rare cause of intracranial calcification. AB - Intracranial calcifications are relatively common computed tomographic findings in the field of neurosurgery, and cysticercosis, tuberculosis, HIV, and cryptococcus are acquired intracranial infections typically associated with calcifications. However, intracranial calcification caused by a bacterial brain abscess is rare. Here, we present a rare case of intracranial calcification caused by a bacterial brain abscess, from which staphylococcus hominis was isolated. To the best of our knowledge, no previous report has been published on intracranial calcification caused by bacterial brain abscess after decompressive craniectomy for traumatic brain injury. In this article, the pathophysiological mechanism of this uncommon entity is discussed and relevant literature reviewed. PMID- 24175035 TI - Multiple Myeloma and Epidural Spinal Cord Compression : Case Presentation and a Spine Surgeon's Perspective. AB - Multiple myeloma, a multicentric hematological malignancy, is the most common primary tumor of the spine. As epidural myeloma causing spinal cord compression is a rare condition, its therapeutic approach and clinical results have been reported to be diverse, and no clear guidelines for therapeutic decision have been established. Three patients presented with progressive paraplegia and sensory disturbance. Image and serological studies revealed multiple myeloma and spinal cord compression caused by epidural myeloma. Emergency radiotherapy and steroid therapy were performed in all three cases. However, their clinical courses and results were distinctly different. Following review of our cases and the related literature, we suggest a systematic therapeutic approach for these patients to achieve better clinical results. PMID- 24175036 TI - Role of the epithelial-mesenchymal transition in bladder cancer: from prognosis to therapeutic target. AB - Bladder cancer (BC) is the second most common malignancy of urological organs. However, patients with non-muscle-invasive BC are at high risk of recurrence and progression into muscle-invasive BC, and the prognosis of patients with muscle invasive BC is limited by the high rate of metastasis. The epithelial-mesenchymal transition (EMT) is characterized by loss of cell-to-cell adhesion and cell polarity and is closely associated with the invasion and metastasis of several cancers. Given the multifocality and high rates of relapse, progression, and metastasis of BC, the EMT is likely to participate in BC as well. Numerous factors associate with the EMT, and the key regulators of the EMT are E-cadherin, N-cadherin, Twist, Snail, Slug, Zeb-1, Zeb-2, vimentin, and microRNAs. This review focuses on the current concepts regarding the EMT in cancer and the evidence for involvement of the EMT in BC. Several potential EMT targets that may be useful in the treatment of BC are also described. PMID- 24175037 TI - Management of complications after tension-free midurethral slings. AB - Since their introduction in 1996, tension-free midurethral slings (MUS) have been proven to have long-term efficacy and safety. They are considered the gold standard treatment of female stress urinary incontinence, especially in cases that are associated with urethral hypermobility. However, they are not free of complications and, although rare, some of these complications can be challenging for both patients and physicians. Some complications occur intraoperatively, whereas others appear in the early or late postoperative period. There is less controversy in the diagnosis and treatment of complications such as vaginal extrusion or urinary system erosion, whereas de novo voiding problems are at best not completely understood. Voiding dysfunction after MUS placement may vary in a wide range from urinary frequency or urgency to retention and is usually attributed to the obstructive or irritative effect of the sling. However, present urodynamic criteria for the diagnosis of female infravesical obstruction are not satisfactory, and the best management policy for de novo voiding dysfunction remains controversial. In the majority of cases, the diagnosis of obstruction leading to a urethral release surgery depends on a combination of several clinical findings. The timing of urethral release surgery varies depending on the preferences of the surgeon, and the outcome of this surgery is not always predictable. The purpose of this review was to assess the diagnosis and management of the immediate, short-term, and long-term complications of MUS in light of the current literature in an attempt to determine the best management policy. PMID- 24175038 TI - Experience of ultrasonography-guided percutaneous core biopsy for renal masses. AB - PURPOSE: We evaluated the safety and accuracy of ultrasonography-guided percutaneous core biopsy collection in patients with renal masses. MATERIALS AND METHODS: From June 2008 to August 2012, 30 percutaneous core biopsies of renal masses were performed. The biopsies obtained were small tumors (<4 cm) with ambiguous radiologic findings or that met classic renal biopsy indications. The biopsy results were compared with the final pathological results after definitive surgical treatment. Ultrasonography was performed on the day after biopsy collection to rule out any complications. RESULTS: The mean age of the patients was 57.7 years, and the mean tumor size was 3.39 cm. Twelve of the lesions were in the left kidney, and 18 were in the right kidney. All but one core biopsy contained sufficient material for histopathological analysis. The biopsy results showed 17 renal cell carcinomas (56.7%), 3 angiomyolipomas (10.0%), 2 oncocytomas (6.7%), 1 adenocarcinoma (3.3%), and 7 benign lesions (23.3%). A total of 18 cases underwent surgery, and the pathological results confirmed the initial biopsy diagnosis for 17 of 18 cases (94.4%). The one (5.9%) inaccurate biopsy result was found to be a urothelial carcinoma of the kidney. No needle tract seeding was found in the pathological specimens or on follow-up imaging. A small perinephric hematoma (1-2 cm) was seen in 5 cases (16.7%), but all patients remained hemodynamically stable. CONCLUSIONS: Ultrasonography-guided renal biopsy is a safe, effective, and accurate method for evaluating small renal masses. This procedure may help in selecting treatment modalities for small renal masses. PMID- 24175039 TI - Are hypoechoic lesions on transrectal ultrasonography a marker for clinically significant prostate cancer? AB - PURPOSE: To investigate the relationship of transrectal ultrasound (TRUS) findings with the pathological characteristics of prostate cancer (PCa). MATERIALS AND METHODS: The study was conducted retrospectively by analyzing the data for 970 patients who underwent prostate biopsies. Gleason scores and other clinical variables were compared between PCa patients with and without hypoechoic lesions on TRUS. RESULTS: Of the 970 patients, PCa was diagnosed in 291 (30%). Of these, high-grade PCa (Gleason score of 7 or more) was diagnosed in 190 (65%). The cancer detection rate was higher in patients with hypoechoic lesions (43.9%) than in those without hypoechoic lesions (21.4%, p<0.001). High-grade PCa was detected more often in patients with hypoechoic lesions than in those without hypoechoic lesions (p<0.001). Independent predictors for high-grade PCa by logistic regression analysis included hypoechoic lesions on TRUS and abnormal digital rectal examination findings. CONCLUSIONS: Patients with PCa who had hypoechoic lesions on TRUS had more aggressive pathological disease than did those without lesions. Therefore, hypoechoic lesions on TRUS could be a marker for clinically significant PCa. PMID- 24175040 TI - Effect of overexpression of glucose-regulated protein 78 and bcl-2 on recurrence and survival in patients with ureter tumors. AB - PURPOSE: The utility of the expression of glucose-regulated protein 78 (GRP78) in the evaluation of prognosis depends on the type of tumor. Hence, we aimed to examine the impact of expression of GRP78 and Bcl-2, which are used in the existing prognostic evaluation of ureter tumors, in the evaluation of recurrence and survival rates of ureter tumors. MATERIALS AND METHODS: In 53 patients who had undergone radical nephroureterectomy for a ureter tumor from March 2002 to March 2012, age, sex, T stage, nuclear grade, bladder recurrence, and survival rate were analyzed at the time of the patient's surgery depending on the extent of immunohistochemical expression of GRP78 and Bcl-2. RESULTS: GRP78 was overexpressed in 25 patients (47.2%). When GRP78 was overexpressed, there was a high T stage (p=0.001) and nuclear grade (p=0.007) and a lot of bladder recurrence (40.0%, p=0.034). Bcl-2 was overexpressed in 16 patients (30.1%), and there were no significant associations with any risk factors (p>0.05, respectively). In the multivariate analysis regarding bladder recurrence, the recurrence rate was higher with higher pT stage (p=0.048) and when GRP78 (p=0.033) was overexpressed. In the Kaplan-Meier survival analysis, although the survival rate was significantly lower in the group in which GRP78 was overexpressed (p=0.03), there was no correlation between Bcl-2 overexpression and survival rate (p=0.07). CONCLUSIONS: Patients with ureter tumors who had overexpression of GRP78 had a high T stage and nuclear grade, a lot of bladder recurrence, and a low survival rate. Therefore, if GRP78 is overexpressed in ureter tumor patients, active postoperative follow-up should be carried out. PMID- 24175041 TI - Twelve-Month Follow-up Results of Photoselective Vaporization of the Prostate With a 980-nm Diode Laser for Treatment of Benign Hyperplasia. AB - PURPOSE: This study was conducted with the use of 12 months of follow-up data to evaluate the efficacy of photoselective vaporization of the prostate (PVP) with the 980-nm diode laser for the treatment of symptomatic benign prostatic hyperplasia (BPH). MATERIALS AND METHODS: The clinical data of 84 men with symptomatic BPH who underwent PVP with the 980-nm K2 diode laser between March 2010 and October 2011 were retrospectively analyzed. Postoperative parameters, including International Prostate Symptom Score (IPSS), quality of life (QoL) score, maximum urinary flow rate (Qmax), and postvoid residual volume (PVR), were assessed and compared with preoperative baseline values. RESULTS: Mean patient age was 72.4+/-6.5 years, and mean preoperative prostate volume was 47.2+/-16.3 g. Mean operative time was 23.3+/-19.1 minutes, and total amount of energy was 128+/-85 kJ. Mean catheterization time was 23.7+/-5.9 hours. At 1 month, significant improvements were noted in IPSS (11.5+/-6.8), QoL score (2.2+/-1.3), Qmax (12.9+/-6.5 mL/s), and PVR (41.2+/-31.3 mL). Three months after surgery, all postoperative follow-up parameters showed significant improvements, and the 6- and 12-month data showed sustained improvement of postoperative follow-up parameters. Bladder neck strictures were observed in 10.7% of the patients and urge incontinence in 16.6%. CONCLUSIONS: PVP using a K2 diode laser is an effective procedure for the treatment of lower urinary tract symptoms secondary to BPH. PVP leads to an immediate and sustained improvement of subjective and objective voiding parameters. Surgeons should be vigilant for postoperative bladder neck stricture and urge incontinence. PMID- 24175042 TI - Effect of transurethral resection with hydrodistention for the treatment of ulcerative interstitial cystitis. AB - PURPOSE: Many treatment options to help relieve the symptoms of interstitial cystitis (IC) are available, but none are effective. Because no reports of transurethral ulcer resection with hydrodistention are available, we assessed the effects of such combined surgery for ulcerative IC. MATERIALS AND METHODS: Between June 2006 and June 2011, 87 female patients with IC who underwent transurethral resection with hydrodistention and were followed up for at least 12 months were included. Improvements in patients' voiding symptoms and pain were analyzed retrospectively by using a 3-day micturition chart and a 10-point visual analogue scale (VAS) before and after the operation. The global response assessment (GRA) was used to assess treatment satisfaction. RESULTS: The mean age of the 87 female patients was 59.1+/-10.1 years, and the mean follow-up period was 26.7+/-14.4 months. Mean maximum functional bladder capacity increased from 168.4+/-92.4 mL to 276.3+/-105.4 mL (1 month) and to 227.3+/-91.7 mL (12 months). The mean frequency of voiding decreased from 17.2+/-8.5 before to 10.6+/-5.3 after (1 month) surgery; however, it increased again to 13.3+/-4.8 at 12 months. The 10-point VAS score decreased from 9.1+/-0.8 to 1.2+/-0.3 (1 month); however, it increased again to 2.5+/-0.4 (3 months), 3.2+/-0.4 (6 months), and 5.3+/-0.5 (12 months) (p<0.001). Symptom improvement based on the GRA was observed in 83 of the 87 patients (95.4%) at 1 month and in 55 of 87 patients (63.2%) at 12 months. CONCLUSIONS: Transurethral resection with hydrodistention is an effective treatment option for ulcerative IC because it provides improvements in voiding symptoms and pain. PMID- 24175043 TI - Efficacy of percutaneous nephrostomy during flexible ureteroscopy for renal stone management. AB - PURPOSE: Preoperative percutaneous nephrostomy (PCN) can be applied to urinary stone patients with pyelonephritis as well as obstructive uropathy; thus, some patients undergo flexible ureteroscopy (fURS) in the presence of a PCN tube. We evaluated the effectiveness of PCN during fURS for the management of renal stones. MATERIALS AND METHODS: We retrospectively analyzed 130 consecutive patients who underwent fURS for renal stones between January 2009 and December 2011. All fURS procedures were performed by a single experienced surgeon. The patients were divided into two groups depending on the presence of PCN during the surgery: patients with PCN (group 1, n=41) and patients without PCN (group 2, n=89). To evaluate operative outcomes, we compared success rates, operative times, and complication rates. We defined success as the absence of any residual stones in the kidney or stone fragments less than 2 mm that were too small to be extracted during follow-up. RESULTS: There were no significant differences in age, sex, body mass index, stone laterality, burden, or location between the two groups. The mean operative times of groups 1 and 2 were 50.1 and 58.3 minutes, respectively (p=0.102). The success rates of groups 1 and 2 were 95.1% and 82.0%, respectively (p=0.044). There was no statistically significant difference in the complication rate between groups 1 and 2 (p=0.888). CONCLUSIONS: Flexible ureteroscopy in the presence of PCN produced a superior outcome in terms of the success rate without increasing the operative time or complication rate. PCN may be helpful to induce better outcomes of fURS. PMID- 24175044 TI - Is tubeless percutaneous nephrolithotomy a feasible technique for the treatment of staghorn calculi? AB - PURPOSE: Tubeless percutaneous nephrolithotomy (PNL) remains a challenging technique for the surgical treatment of staghorn renal calculi. Our study was designed to compare surgical outcomes between conventional and tubeless PNL. MATERIALS AND METHODS: We retrospectively enrolled consecutive patients who underwent conventional or tubeless PNL under general anesthesia performed by a single surgeon (H.J.) for the treatment of staghorn calculi between 2003 and 2012. All patients were divided into two groups: group 1 included patients who underwent conventional PNL and group 2 included patients who were managed by tubeless PNL for the treatment of staghorn calculi. Preoperative and postoperative parameters were analyzed between the two groups, including age, stone burden, complications, any interventions, and duration of hospital stay. RESULTS: A total of 165 patients (group 1, 106; group 2, 59) were enrolled in the study. No significant differences in age, sex, body mass index, or stone laterality were observed between the two groups. The mean stone burdens (+/ standard deviation) of group 1 and group 2 were 633.6 (+/-667.4) and 529.9 (+/ 362.8), respectively (p=0.271). The postoperative stone-free clearance rate was higher in group 2 (78.0%) than in group 1 (69.8%); however, the difference was not clinically significant (p=0.127). In addition, no significant differences in postoperative complications, including fever, bleeding, infection, or additional interventions, were observed between the two groups. CONCLUSIONS: Our results demonstrated that tubeless PNL has the same effectiveness and safety as conventional PNL in the treatment of staghorn calculi. Tubeless PNL may be feasible for managing renal staghorn calculi. PMID- 24175045 TI - Effects of low-dose tamsulosin on sexual function in patients with lower urinary tract symptoms suggestive of benign prostatic hyperplasia. AB - PURPOSE: The aim of the present study was to evaluate the effects of low-dose tamsulosin on sexual function in patients with lower urinary tract symptoms (LUTS) suggestive of benign prostatic hyperplasia. MATERIALS AND METHODS: A total of 138 male LUTS patients aged more than 50 years with an International Prostate Symptom Score (IPSS) >=8 were enrolled in this open-label, multicenter, prospective, noncomparative observational study. Clinical assessments included IPSS, quality of life (QoL) index, International Index of Erectile Function (IIEF), Danish Prostate Symptom Score (DAN-PSS), and an early morning erection questionnaire. The data were recorded at baseline and at 1 and 3 months after treatment with tamsulosin 0.2 mg/d. Adverse events were analyzed in all patients. RESULTS: During the study period of 3 months, the IPSS and QoL index significantly improved from baseline by -11.40+/-9.40 and -1.11+/-1.36, respectively (p<0.001). However, there were no clinically relevant changes in total IIEF score (mean difference, 1.63+/-15.50; p=0.406) or the 5 subdomains (p>0.05). Furthermore, DAN-PSS weighted scores (A*B) showed no clinically relevant changes (mean difference on Q1, Q2, and Q3: -0.45+/-2.94, 0.27+/-2.50, and -1.27+/-2.27, p>0.05). In addition, there were no clinically significant changes in responses on the early morning erection questionnaire. CONCLUSIONS: Tamsulosin at the dose of 0.2 mg significantly improved the IPSS and the QoL index compared with baseline. However, tamsulosin did not exhibit any significant impact on sexual function or any negative impact on ejaculatory function. PMID- 24175046 TI - Impact of surgical varicocele repair on pregnancy rate in subfertile men with clinical varicocele and impaired semen quality: a meta-analysis of randomized clinical trials. AB - PURPOSE: To elucidate the impact of surgical varicocele repair on the pregnancy rate through new meta-analyses of randomized clinical trials that compared surgical varicocele repair and observation. MATERIALS AND METHODS: The PubMed and Embase online databases were searched for studies released before December 2012. References were manually reviewed, and two researchers independently extracted the data. To assess the quality of the studies, the Cochrane risk of bias as a quality assessment tool for randomized controlled trials was applied. RESULTS: Seven randomized clinical trials were included in our meta-analyses, all of which compared pregnancy outcomes between surgical varicocele repair and control. There were differences in enrollment criteria among the studies. Four studies included patients with clinical varicocele, but three studies enrolled patients with subclinical varicocele. Meanwhile, four trials enrolled patients with impaired semen quality only, but the other three trials did not. In a meta-analysis of all seven trials, a forest plot using the random-effects model showed an odds ratio (OR) of 1.90 (95% confidence interval [CI], 0.77 to 4.66; p=0.1621). However, for subanalysis of three studies that included patients with clinical varicocele and abnormal semen parameters, the fixed-effects pooled OR was significant (OR, 4.15; 95% CI, 2.31 to 7.45; p<0.001), favoring varicocelectomy. CONCLUSIONS: Varicocelectomy for male subfertility is proven effective in men with clinical varicocele and impaired semen quality. Therefore, surgical repair should be offered as the first-line treatment of clinical varicocele in subfertile men. PMID- 24175047 TI - Clinical factors that predict successful posterior urethral anastomosis with a gracilis muscle flap. AB - PURPOSE: We evaluated the preoperative clinical factors that affect the surgical outcome of posterior urethral anastomosis (PUA) with a gracilis muscle flap (GMF) to determine which factors predict benefit from the use of the GMF. MATERIALS AND METHODS: This was a retrospective analysis of 49 patients who underwent a delayed PUA with a GMF. A successful clinical outcome was defined as achieving a peak urinary flow rate greater than 15 mL/s at 3 and 12 months postoperatively without evidence of stricture recurrence on a retrograde urethrogram or cystourethroscopy at 3 months postoperatively. Multiple clinical factors were evaluated by use of univariate and multivariate analyses. RESULTS: The outcome of 21 of 49 patients (42.9%) was deemed successful. The mean age of the 49 patients was 37.2+/-13.5 years and the mean follow-up duration was 43.4+/-28.0 months. The length of the urethral defect was significantly shorter in patients with a successful outcome than in patients with an unsuccessful outcome (p=0.010). The outcome differed significantly depending on whether the patients had a previously successful urethroplasty (p=0.036) or whether they had suffered a pelvic bone injury (p=0.012). Multivariate logistic regression analyses revealed that a previous urethroplasty was the only preoperative clinical factor that significantly affected the surgical outcome in PUA with a GMF (odds ratio, 0.218; 95% confidence interval, 0.050 to 0.947; p=0.042). CONCLUSIONS: A history of previous urethroplasty is a preoperative clinical factor that significantly affects the surgical outcome in PUA with a GMF; the procedure is more likely to be successful in patients who have not previously undergone urethroplasty. PMID- 24175048 TI - Nephrectomy for a renal metastasis of undiagnosed hepatocellular carcinoma arising from an orthotopic liver transplant undertaken for cryptogenic cirrhosis. AB - Urological involvement of hepatocellular carcinoma (HCC) is rare; HCC arising in an orthotopic liver transplant (OLT) is exceptionally rare. Here we report the case of a 70-year-old man who was incidentally found to have metastatic HCC in the right kidney arising from his OLT undertaken for cryptogenic cirrhosis 10 years previously. Adding to the complexity of this case was the lack of an obvious liver primary HCC at the time of the radical nephrectomy, thus making the final diagnosis all but impossible. We believe this report represents the first report of HCC metastasizing to the kidney after OLT and adds to the few reports in the literature of HCC arising in transplanted livers. PMID- 24175049 TI - Missed spermatic cord torsion in an old man. AB - The fate of testicular salvage in spermatic cord torsion depends on the duration of ischemia and the degree of torsion. Even though spermatic cord torsion (SCT) can occur at any age, it is rarely reported in older patients. If the physician does not pay close attention to this unusual situation, the lack of suspicion for SCT may result in a missed or delayed diagnosis. We report a very uncommon case of missed SCT occurring in a 63-year-old man. PMID- 24175050 TI - The Extract of Crocus sativus and Its Constituent Safranal, Affect Serum Levels of Endothelin and Total Protein in Sensitized Guinea Pigs. AB - OBJECTIVE(S): The effect of the extract of Crocus sativus and its constituent, safranal on inflammatory markers in sensitized guinea pigs was examined. MATERIALS AND METHODS: Ovalbumin (OA) sensitized guinea pigs were given drinking water alone (group S), or drinking water containing three concentrations of safranal, three concentrations of extract and one concentration of dexamethasone, (n=6, for all groups) and serum levels of endotheline-1 (ET-1) and total protein (TP) were assessed. RESULTS: Serum levels of ET-1 and TP in group S were significantly higher than control group (P<0.01 for ET-1 and P<0.001 TP). Treatment of S animals with dexamethasone, most concentrations of the extract and safranal significantly reduced serum levels of ET-1 and TP compared to group S (P <0.01 to P <0.001). The effects of one concentration of the extract and safranal were significantly higher than dexamethasone (P <0.05 to P <0.01). CONCLUSION: A preventive effect of the extract of C. sativus and its constituent safranal on serum inflammatory markers in sensitized guinea pigs was shown. PMID- 24175051 TI - Full rehabilitation with nobel clinician((r)) and procera implant bridge((r)): case report. AB - Implant surgery has been changing in different ways following improvements of computer technologies. Since its beginning, according to the original procedures of Branemark system implants, guide-lines in implants-supported prosthetic rehabilitation have been founding on the placement of fixtures in a fairly upright position, after maxillary sinus floor elevation; while in the case of interforaminal rehabilitation, an upright distal implant may need to be placed anterior to the mental foramina without nerve damage (although the consequence would have been bilateral cantilevers to provide good chewing capacity). Some authors have proposed engaging the molar/tuberosity area: Bahat and Venturelli demonstrated these areas reliable and predictable alternative to distal cantilever prostheses or sinus elevation procedures. In recent years, the immediate loading of tilted implants with a provisional restoration has been proposed for the treatment of the atrophic maxilla. Tilted posterior implants in either arches could avoid (cantilever length) and provide to a better load distribution. Further studies have showed excellent outcomes for both tilted and axial implants; indeed this protocol allows to use longer implants, improve bone anchorage and avoid bone grafting procedures. Malo at al., in a retrospective clinical study, showed important results using two posterior tilted implants and two anterior non-tilted ones in the so-called All-on-four technique (Nobel Biocare, Goteborg, Sweden). Instead of the great loss of bone (amount and quality) in long-term edentuly the clinically documented computer-guided implantology software is able, through posterior tilted implants, to improve load distribution. Many authors have reported reduced surgical invasion (sinus grafting surgery is needless), shorter treatment time, lower cost, natural aesthetic profiles and functional bite. PMID- 24175052 TI - Oral health-related quality of life in partially edentulous patients before and after implant therapy: a 2-year longitudinal study. AB - OBJECTIVES: The aim of this study was to measure the Oral Health-Related Quality of Life (OHRQoL) before and after a prosthodontic implant therapy so to determine the physical and psychological impact of implant-supported fixed partial dentures (IFPD) rehabilitation among edentulous patients. METHODS: 50 partially edentulous patients aged 40-70 years, treated with IFPD, completed the OHRQoL questionnaire before the implant surgery (Time 0) and 2 years after their whole implant prosthetic rehabilitation (Time 1). The questionnaire was proposed in a short version of Oral Health Impact Profile (OHIP-14, range 0-56) and analyzed through the 'additive method'. We evaluated statistical mean, standard deviation, median, variance and mode of all OHIP-14 domains and the statistical significance about oral changes at Time 0 and Time 1 using the Chi-square test (p-values < 0.05). RESULTS: Patients reported significant changes in mean OHIP scores (Time 0: 2.15; Time 1: 0.65; p < 0.01). The most prevalently affected domain was "functional limitation", followed by "psychological discomfort" and "physical pain". There were no significant differences dependent on age, gender and antagonistic teeth (p > 0.05). Patients with I and IV Kennedy's class edentulism showed better improvement (p < 0.05). CONCLUSIONS: Preoperative and post-treatment assessments of OHRQoL exhibited significant differences. The IFPD treatment had a positive effect on the OHRQoL, which improved better in patients with I and IV Kennedy's edentulous class. PMID- 24175053 TI - A complication following tooth extraction: chronic suppurative osteomyelitis. AB - A complication following tooth extraction: a case report of chronic suppurative osteomyelitis. OBJECTIVE: This article presents a case report about the surgery treatment of chronic suppurative osteomyelitis following a tooth extraction. METHODS: Cone beam computed tomography revealed a sequestrum bone formation that required the sequestrectomy and the debridement of the involved area. The prescription of oral penicillin and metronidazole were necessary after and before the surgery. Also 20 sessions of hyperbaric oxygen therapy were important for the healing of the marrow space. RESULTS: The histologic test confirmed the diagnosis of "Chronic suppurative osteomyelitis". Clinically the post-operative course showed no complications but a good healing of the bone tissue. Culture reports revealed two microorganisms, streptococcus viridans and staphylococcus, that are sensitive to penicillin. CONCLUSIONS: Clinical results confirmed the validity of the sequestrectomy and the debridement of the involved area for the treatment of chronic suppurative osteomyelitis. Such approach has always to be preferred because it guarantees the healing of bone tissue. PMID- 24175055 TI - An ideal cell source for bone tissue engineering? PMID- 24175056 TI - GWAS identifies 8 novel genetic loci linked to osteoarthritis. PMID- 24175057 TI - Osteoblast-secreted Wnt ligands are crucial for bone development. PMID- 24175054 TI - The anti-transglutaminase auto-antibodies in children's saliva with a suspect coeliac disease: clinical study. AB - The coeliac disease is an immune-mediated enteropathy triggered by an ingestion of gluten in genetically susceptible individuals. Like some other systemic diseases (Crohn's disease, Sjogren's syndrome) the celiac disease is able to alter the oral ecosystem and the composition of the saliva. AIM: The aim of this retrospective study has been to examine the incidence of coeliac disease (CD) in paediatric population and to search the presence of anti-transglutaminase auto antibodies (anti-tTG) in saliva, comparing and quantifying the concentration regard to the serum values of the anti-tTG auto-antibodies, before and after six months from the beginning of the free gluten diet. MATERIALS AND METHODS: 105 children (G0), aged between 5 and 13 years, belonging to the Paediatric Gastroenterology-Endoscopy Unit of PTV Hospital, University of Rome "Tor Vergata", have been examined for a diagnosis of suspected CD. RESULTS: Of a total of 105 pediatric patients (G0), only the 16.2% (G1) has showed to be positive. About the evaluation of the anti-tTG auto-antibodies in the serum, obtained from the second blood sample (T1), we can observe that 10 (G2) out of 17 children (G1) show positivity and for this reason they have been subjected to a sampling of intestinal villi to confirm the diagnosis of CD; in addition the 6.7% has been resulted positive at the first sampling of serum (T0), but negative to the second one (T1). The incidence of the CD has been resulted to be equal to 9.5%. About the evaluation of anti-tTG in the G1, we can observe that 58.8% of children are "definitely positive" to the salivary anti-tTG, while 11.8% appear to be weakly positive. About the correspondence of serum and salivary anti-tTG in Group G1, we can observe, that children positive to the anti-tTG in the serum have also the anti-tTG in the salivary fluid (sensibility 100%, specificity 71.4%). The results show that the anti-tTG salivary are present in children with CD, even though they have continued to follow the gluten free diet for 6 months. CONCLUSIONS: The presence of anti-tTG in the saliva may be considered, an additional and useful diagnostic dental marker for an initial, reproducible, non invasive, inexpensive and highly sensitive screening of CD having a predictive and precocious value compared to anti-tTG contained in the serum, as it has been already demonstrated. PMID- 24175058 TI - A case of tricuspid regurgitation and congestive cardiac failure presenting with orbital pulsation. PMID- 24175059 TI - Assessment of leukocyte trafficking in humans using the cantharidin blister model. AB - The cantharidin blister model provides an in vivo assessment of the innate inflammatory response in humans. It allows researchers to profile the acute and resolving inflammatory response in healthy and diseased states and for the design of crossover trials for the testing of new treatments for acute inflammation. Below we describe the materials and methods required to prepare, induce, aspirate and analyse the forearm cantharidin blisters, in preparation for future study design. PMID- 24175060 TI - Silent brain infarction in the presence of systemic vascular disease. AB - OBJECTIVE: To determine the prevalence of asymptomatic brain ischaemic in the presence of vascular disease in other arterial territories. DESIGN: Studies up to January 2011 were identified through comprehensive search strategies. Arcsine transformation for meta-analysis was used to calculate the standardized mean difference (SMD) and 95% confidence intervals (CI). SETTING: A systematic review and meta-analysis were performed. PARTICIPANTS: For each study, the proportion of patients positive for SBI in the presence of other systemic vascular disease was extracted and analyzed. MAIN OUTCOME MEASURES: Using a random-effects model, a pooled effect estimate interpreted as a percentage prevalence of disease was calculated. RESULTS: SBI in the presence of acute ischaemic stroke was found in 23% (SMD 0.99; P < 0.001; 95% CI 0.88-1.10); a 35% prevalence was found in patients with coronary artery disease (SMD 1.26; P < 0.001; 95% CI 0.95-1.58); and a 14% prevalence in patients with peripheral artery disease (SMD 0.48; P < 0.002; 95% CI 0.42-0.54), although the data-set in the latter is smaller. CONCLUSIONS: Patients with systemic vascular disease are at an increased risk of silent brain infarction. PMID- 24175061 TI - JRSM Cardiovascular Disease: a new journal for a global problem. PMID- 24175062 TI - Promises and challenges of pharmacogenetics: an overview of study design, methodological and statistical issues. AB - Pharmacogenetics is the study of inherited variation in drug response. The goal of pharmacogenetics is to develop novel ways of maximizing drug efficacy and minimizing toxicity for individual patients. Personalized medicine has the potential to allow for a patient's genetic information to predict optimal dosage for a drug with a narrow therapeutic index, to select the most appropriate pharmacological agent for a given patient and to develop cost-effective treatments. Although there is supporting evidence in favour of pharmacogenetics, its adoption in clinical practice has been slow because of sometimes conflicting findings among studies. This failure to replicate findings may result from a lack of high-quality pharmacogenetic studies, as well as unresolved methodological and statistical issues. The objective of this review is to discuss the benefits of incorporating pharmacogenetics into clinical practice. We will also address outstanding methodological and statistical issues that may lead to heterogeneity among reported pharmacogenetic studies and how they may be addressed. PMID- 24175063 TI - Diagnostic confusion resolved by being upbeat. AB - The classical stroke presentation - captured by the public health campaign mnemonic FAST (face, arm, speech, time) - does not apply in a large number of stroke cases; yet establishing a prompt diagnosis is imperative for optimal management. Here, we describe a patient with acute bulbar weakness, numbness in all extremities and an apparently normal magnetic resonance imaging (MRI) of the brain upon admission for whom even the fundamental question of whether this reflected a central or peripheral nervous system process was unclear. The critical localizing sign was upbeat nystagmus that denotes a brainstem cause. MRI of the brain in the second week confirmed a diagnosis of medial medullary infarction. PMID- 24175065 TI - A retrospective case-control study of modifiable risk factors and cutaneous markers in Indian patients with young coronary artery disease. AB - OBJECTIVE: Indians have the highest risk rates for coronary artery disease (CAD) among all ethnic groups. There is a paucity of data on the risk factors and clinical markers associated with premature CAD. We aimed to determine whether young CAD is due to preventable lifestyle-related factors and cutaneous clinical markers are useful in identifying at-risk patients. DESIGN: Single-centre retrospective study. SETTING: Tertiary care center. PARTICIPANTS: A total of 292 patients (age <=40 years) who presented with acute CAD between January 2005 and June 2009 and 92 age, and gender-matched controls. MAJOR OUTCOME MEASURES: Details of smoking, family history of premature CAD, waist size, blood sugar and lipid profile. Clinical evidence of arcus juvenilis, premature greying of hair and premature baldness sought. RESULTS: Dyslipidaemia (91%), smoking (74.3%), low high-density lipoprotein cholesterol (HDL-C) (68.9%), central obesity (47.7%) and greying of hair (34.9%) were the most commonly associated factors. Compared with male patients, females had greater prevalence of dyslipidaemia, low HDL-C, central obesity, hypertension, diabetes and family history of premature CAD. The presence of cutaneous markers was significantly associated with premature CAD. CONCLUSIONS: CAD in young Indian people is multifactorial; dyslipidaemia, low HDL C, smoking, hypertension, central obesity and family history of premature CAD are the most common risk factors. Smoking in men and central obesity in women are the most prevalent factors. Clinicians should be highly suspicious of patients with presence of cutaneous markers, and they should be followed intensively for lifestyle modifications. PMID- 24175064 TI - The platelet fibrinogen receptor: from megakaryocyte to the mortuary. AB - Platelets are integral to normal haemostatic function and act to control vascular haemorrhage with the formation of a stable clot. The fibrinogen receptor (glycoprotein IIb/IIIa [GPIIb/IIIa]) is the most abundant platelet integrin and, by binding fibrinogen, facilitates irreversible binding of platelets to the exposed extracellular matrix and enables the cross-linking of adjacent platelets. The vital role of GPIIb/IIIa requires tight control of both its synthesis and function. After transcription from distinct domains on chromosome 17, the two subunits of the heterodimer are carefully directed through organelles with intricate regulatory steps designed to prevent the cellular expression of a dysfunctional receptor. Similarly, exquisite control of platelet activation via bidirectional signalling acts to limit the inappropriate and excessive formation of platelet-mediated thrombus. However, the enormous diversity of genetic mutations in the fibrinogen receptor has resulted in a number of allelic variants becoming established. The Pro(33) polymorphism in GPIIIa is associated with increased cardiovascular risk due to a pathological persistence of outside-in signalling once fibrinogen has dissociated from the receptor. The polymorphism has also been associated with the phenomenon of aspirin resistance, although larger epidemiological studies are required to establish this conclusively. A failure of appropriate receptor function due to a diverse range of mutations in both structural and signalling domains, results in the bleeding diathesis Glanzmann's thrombasthaenia. GPIIb/IIIa inhibitors were the first rationally designed anti-platelet drugs and have proven to be a successful therapeutic option in high-risk primary coronary intervention. As our understanding of bidirectional signalling improves, more subtle and directed therapeutic strategies may be developed. PMID- 24175066 TI - Normal levels of inflammatory markers in treated patients with familial hypercholesterolaemia: a cross-sectional study. AB - OBJECTIVE: To assess the relationship of levels of inflammatory risk markers to presence of clinical coronary artery disease (CAD) in patients with treated heterozygous familial hypercholesterolaemia. DESIGN: A cross-sectional study of patients on the Simon Broome Familial Hyperlipidaemia Register. SETTING: Six hospital outpatient clinics in the UK. PARTICIPANTS: A total of 211 men and 199 women with heterozygous familial hypercholesterolaemia. MAIN OUTCOME MEASURES: Analysis of conventional risk factors and concentrations of high-sensitivity C reactive protein (hsCRP), lipoprotein(a), serum intercellular adhesion molecule (sICAM), interleukin-6 (IL-6) and lipoprotein-associated phospholipase A2 (LpPLA2) mass. RESULTS: CAD was present in 104 men and in 55 women; the mean ages of onset were 43.1 and 46.5 years, respectively. On univariate analysis there was a positive relationship of CAD with age, male sex, smoking, IL-6 and sICAM, and an inverse relationship with low-density lipoprotein (LDL) and LpPLA2. On multivariate analysis, age, smoking, low LDL and low LpPLA2 were associated with CAD. When LpPLA2 values were adjusted for apoB and aspirin usage, there was no significant difference between those with and without CAD. Only age and smoking were independently associated with CAD in men, and IL-6 and lipoprotein(a) in women. CONCLUSIONS: Although on univariate analysis inflammatory marker levels were associated with CAD in these patients, the majority of the associations, including that for hsCRP, disappeared when corrected for smoking and apoB. This may be because atherosclerotic plaques in these statin-treated patients were quiescent or an effect of aspirin usage. In this observational study newer risk markers were not usefully associated with the presence or absence of symptomatic CAD. PMID- 24175067 TI - Role of arterial stiffness in cardiovascular disease. AB - Propagation of the pressure wave along the arterial tree (pulse wave velocity [PWV]) is related to the intrinsic elasticity of the arterial wall. PWV is increased in stiffer arteries and, when measured over the aorta, is an independent predictor of cardiovascular morbidity and mortality. Given the predictive power of PWV, identifying strategies that prevent or reduce stiffening may be important in prevention of cardiovascular events. One view is that aortic stiffness occurs as a result of atherosclerosis along the aorta. However, there is little or no association between PWV and classical risk factors for atherosclerosis, other than age and blood pressure. Furthermore, PWV does not increase during early stages of atherosclerosis, as measured by intima-media thickness and non-calcified atheroma, but it does increase in the presence of aortic calcification that occurs within advanced atherosclerotic plaque. Age related widening of pulse pressure is the major cause of age-related increase in prevalence of hypertension and has been attributed to arterial stiffening. This review summarizes the methods of measuring aortic stiffness in humans, the pathophysiological mechanisms leading to aortic stiffness, including its association with atherosclerosis, and the haemodynamic consequences of increased aortic stiffness. PMID- 24175068 TI - Bio-repository of DNA in stroke: a study protocol of three ancestral populations. AB - Stroke is a leading cause of death and disability in the world. Identifying the genes underlying stroke risk may help us to improve our understanding of the mechanisms that cause stroke and also identify novel therapeutic targets. To have sufficient power to disentangle the genetic component of stroke, large-scale highly phenotyped DNA repositories are necessary. The BRAINS (Bio-repository of DNA in stroke) study aims to recruit subjects with all subtypes of stroke as well as controls from UK, India, Sri Lanka and Qatar. BRAINS-UK will include 1500 stroke patients of European ancestry as well as British South Asians. BRAINS South Asia aims to recruit 3000 stroke subjects and 3000 controls from across India and Sri Lanka. BRAINS-Middle East aims to enrol 1500 stroke patients from Qatar. The controls for BRAINS-Middle East will be recruited from a population based Qatari Biobank. With the addition of new recruitment centres in India and Qatar, we present an updated version of the BRAINS study protocol. This is the first international DNA biobank for stroke patients and controls from the Middle East. By investigating the influence of genetic factors on stroke risk in European, South Asian and Middle Eastern populations, BRAINS has the potential to improve our understanding of genetic differences between these groups and may lead to new population-specific therapeutic targets. PMID- 24175069 TI - The physician's role in prescribing physical activity for the prevention and treatment of essential hypertension. AB - Blood pressure control and prevention of hypertension can be achieved by both pharmacological and lifestyle interventions; one important lifestyle intervention is physical activity. Participation in regular physical activity can modestly lower blood pressure by reducing total peripheral resistance; it can also reduce the risk of developing hypertension and improve morbidity and mortality outcomes. Therefore, physical activity is a recommended intervention for the majority of hypertensive or prehypertensive patients. The precise level of physical activity required to lower blood pressure is unknown; however, in the UK, national minimum physical activity guidelines would seem appropriate for most hypertensives. Current patient physical activity levels can be assessed easily using retrospective recall questionnaires; preparticipation screening and exercise modifications for high-risk patients may reduce the risk of adverse events during subsequent exercise; and identification of a patient's willingness to increase physical activity levels may help to tailor physical activity advice. Health professional counselling or advice on physical activity is currently the most effective researched intervention. Its success can be maximized by delivering physical activity advice and counselling multiple times using different health professionals in person or over the telephone and by offering additional written materials. While the most effective methods for increasing physical activity levels in patients are probably still unclear, physical activity is an advisable intervention for the majority of hypertensive patients. PMID- 24175070 TI - Anticoagulation in atrial fibrillation: the present and the future. AB - Atrial fibrillation (AF) is the most common form of cardiac arrhythmia and associated with significant mortality and morbidity. It is a powerful predictor of future embolic stroke, such that anticoagulation is recommended in the majority of patients. For many years this has predominantly been in the form of vitamin K antagonists. However, there are well-documented difficulties with their administration that result in poor compliance and high discontinuation rates. Over recent years several oral alternative anticoagulant agents have become available with the potential to overcome many of these pitfalls. In this review, we discuss current recommendations for anticoagulant therapy in AF and how these may change in the future with the introduction of novel therapeutic options. PMID- 24175071 TI - Adrenomedullin and cardiovascular diseases. AB - The cardiovascular system is regulated by the autonomic nervous system, the renin angiotensin-aldosterone system, nitric oxide (NO) and other factors including neuropeptides. Research in neurohumoral factors has led to the development of many cardiovascular drugs. Adrenomedullin (ADM), initially isolated from the adrenal gland, has diverse physiological and pathophysiological functions in the cardiovascular system. It is produced in many organs and tissues including the vasculature. ADM has numerous actions, including vasodilation, natriuresis, antiapoptosis and stimulation of NO production. It might play a protective role in various cardiovascular pathologies, and its plasma level is elevated in patients with hypertension and heart failure. Administration of ADM is a possible therapeutic approach for treating cardiovascular diseases. A number of studies have investigated the infusion of ADM in humans, which seems to be benficial in heart failure and myocardial infarction. Instead of ADM infusion, augmentation of its endogenous level is another possible strategy. Gene therapy is feasible in animal models, but its application in humans is limited. At present, the most promising clinical application of ADM is the use of the plasma level of mid regional proadrenomedullin as a biomarker in cardiovascular diseases. It is a good marker of prognosis and survival in patients with coronary aretery disease or heart failure. PMID- 24175072 TI - Arterial stiffness. AB - Measurements of biomechanical properties of arteries have become an important surrogate outcome used in epidemiological and interventional cardiovascular research. Structural and functional differences of vessels in the arterial tree result in a dampening of pulsatility and smoothing of blood flow as it progresses to capillary level. A loss of arterial elastic properties results a range of linked pathophysiological changes within the circulation including increased pulse pressure, left ventricular hypertrophy, subendocardial ischaemia, vessel endothelial dysfunction and cardiac fibrosis. With increased arterial stiffness, the microvasculature of brain and kidneys are exposed to wider pressure fluctuations and may lead to increased risk of stroke and renal failure. Stiffening of the aorta, as measured by the gold-standard technique of aortic Pulse Wave Velocity (aPWV), is independently associated with adverse cardiovascular outcomes across many different patient groups and in the general population. Therefore, use of aPWV has been proposed for early detection of vascular damage and individual cardiovascular risk evaluation and it seems certain that measurement of arterial stiffness will become increasingly important in future clinical care. In this review we will consider some of the pathophysiological processes that result from arterial stiffening, how it is measured and factors that may drive it as well as potential avenues for therapy. In the face of an ageing population where mortality from atheromatous cardiovascular disease is falling, pathology associated with arterial stiffening will assume ever greater importance. Therefore, understanding these concepts for all clinicians involved in care of patients with cardiovascular disease will become vital. PMID- 24175073 TI - Personalized antiplatelet therapy: state of the art. AB - Overwhelming evidence exists that thrombus generation resulting from platelet activation and aggregation is the primary process involved in the occurrence of the myocardial infarction and stent thrombosis. Despite the proven clinical efficacy of dual antiplatelet therapy, wide antiplatelet response variability associated with clopidogrel therapy was demonstrated in pharmacodynamic studies where approximately one in three patients exhibited high on-treatment platelet reactivity (HPR). Generally, physicians do not objectively assess the intensity of the adenosine diphosphate-P2Y12 interaction in their high-risk patients treated with clopidogrel. Instead most clinicians use a non-selective or one-size fits-all approach. HPR and CYP2C19 LoF carriage are associated with clinical outcomes in high-risk clopidogrel-treated patients who have undergone percutaneous coronary intervention (PCI). Although we do not yet have conclusive evidence from a large-scale randomized trial that personalized antiplatelet therapy improves patient outcomes, a class IIb recommendation has been given in the guidelines to perform genotyping or phenotyping in high-risk PCI patients if a change in antiplatelet therapy will ensue based on the test results. It may be reasonable at this time to assess platelet function and perform genotyping in clopidogrel-treated high-risk patients and treat with more potent P2Y12 receptor therapy selectively. PMID- 24175074 TI - Metastatic paraganglioma: management of orthostatic hypotension - a case report. PMID- 24175075 TI - Platt versus Pickering: what molecular insight to primary hyperaldosteronism tells us about hypertension. AB - Recent genome-wide analyses have found 50 loci associated with variation in blood pressure but failed to advance understanding of the molecular basis of hypertension. Whether hypertension is not after all due to multiple common variants or is simply an order of magnitude more complex than previously suspected remains unsettled - in part because only a minority of subjects in the analyses had true hypertension. A better starting point than normotensive subjects for explaining hypertension may be the most common distinct cause of hypertension, primary hyperaldosteronism (PHA). The findings that 40% of patients with an aldosterone-producing adenoma (APA) of the adrenal have somatic gain-of function mutations in a single gene, KCNJ5, and that this gene is, less frequently, mutated in inherited cases of PHA, potentially transform the understanding and management of hypertension. Firstly, they illustrate how hypertension could be due to a multiplicity of uncommon variants. Mutations that present with abnormal electrolytes and anatomy are the easiest to detect but are likely the tip of the iceberg. Secondly, we found a genotype:phenotype pattern, with KCNJ5 mutations inducing larger APAs in the cortisol-secreting zona fasciculata in young women. Smaller APAs without KCNJ5 mutations usually present in older men with resistant hypertension, having been overlooked earlier because of their size. This reflects their compact zona glomerulosa cells. Routine measurement of plasma renin in hypertension and a new positron emission tomography/computerized tomography allow prompt diagnosis and management of PHA before resistant hypertension ensues. Wider recognition of distinct phenotypes should permit earlier, specific treatment and reduce life-time risk of complications. PMID- 24175076 TI - Cerebrovascular disease in South Asia - Part I: A burning problem. AB - Stroke is a non-communicable disease of increasing socioeconomic importance in ageing populations. According to the World Health Organization, stroke was the second most common cause of worldwide mortality. In South Asian countries demographic changes, urbanization and increased exposure to major stroke risk factors will fuel the stroke burden in the future. The prevalence of stroke in India is 44-843/100,000 (from community-based studies), 500-2000/100,000 in Bangladesh, 218/100,000 in Pakistan and 1000/100,000 in Sri Lanka and community based prevalence studies in these countries are still lacking. There are no data on stroke prevalence from Nepal. Incidence studies are still less and an Indian study reported an incidence of 145/100,000. Incidence studies from other South Asian countries are lacking. This review attempts to give an overview of the evidence so far on the burden of stroke in this part of the globe. PMID- 24175077 TI - Modern management of a patent foramen ovale. AB - A patent foramen ovale (PFO) has been associated with medical conditions such as cryptogenic stroke, migraine with aura, and decompression illness. Whether closure of the PFO has clinical benefit has been suggested from registry studies, but not yet confirmed in multiple randomized trials. Methods of diagnosis of a PFO and a summary of the current evidence for treatment is presented and discussed as a guide to patient-centred decision-making. PMID- 24175078 TI - Cerebrovascular disease in South Asia - Part II: Risk factors and prevention. AB - In South Asian countries, conventional vascular risk factors like hypertension, diabetes mellitus, cardiac disease, smoking, obesity, atrial fibrillation are the dominant ones, while other aetiologies like rheumatic heart disease, infective meningitis-related infarcts and postpartum cerebral venous thrombosis also constitute a big fraction. This review discusses the evidence of prevalence of various risk factors in South Asian countries and possible measures to combat the rising burden of cerebrovascular disease. The last part of the review discusses prevention and identification of risk factors that are unique to or especially found in patient population of South Asia. PMID- 24175080 TI - Thrombolysis of an acute stroke presentation with an incidental unruptured aneurysm. AB - Many patients with acute ischaemic stroke have contraindications to thrombolytic therapy. We describe a 45 yr old Afro-Caribbean female with HbSC disease whom was electively admitted for a cerebral angiogram to evaluate an intracavernous aneurysm measuring 20 mm in diameter. During the procedure, she suffered a right MCA territory ischaemic event with a NIHSS of 10. A CT angiogram demonstrated no dissection and no evidence of a major vessel occlusion. Tissue plasminogen activator (tPA) was administered intravenously within 60 minutes of symptom onset. She had clinical and haematological evidence of a painful sickle cell crisis and required manual exchange transfusion within a few hours of thrombolysis. This is the first reported case of the use of thrombolysis for acute stroke in a sickle cell crisis; and in the presence of such a large unruptured aneurysm. A registry of unusual thrombolysis cases might help clinicians in cases when there is little evidence to support decision-making. PMID- 24175079 TI - Cerebral microbleeds: a new dilemma in stroke medicine. AB - Cerebral microbleeds (CMBs) are an increasingly common neuroimaging finding in the context of ageing, cerebrovascular disease and dementia, with potentially important clinical relevance. Perhaps the most pressing clinical question is whether CMBs are associated with a clinically important increase in the risk of intracerebral haemorrhage (ICH), the most feared complication in patients treated with thrombolytic or antithrombotic (antiplatelet and anticoagulant) drugs. This review will summarize the evidence available regarding CMBs as an indicator of future ICH risk in stroke medicine clinical practice. PMID- 24175081 TI - Catheter-based renal denervation for treatment of resistant hypertension. AB - Hypertension is a common disease associated with important cardiovascular complications. Persistent blood pressure of 140/90 or higher despite combined use of a reninangiotensin system blocker, calcium channel blocker and a diuretic at highest tolerated doses constitutes resistant hypertension. Excess sympathetic activity plays an important pathogenic role in resistant hypertension in addition to contributing to the development of metabolic problems, in particular diabetes. Reduction of renal sympathetic activity by percutaneous catheter-based radiofrequency ablation via the renal arteries has been shown in several studies to decrease blood pressure in patients with resistant hypertension, and importantly is largely free of significant complications. However, longer term follow-up is required to confirm both long-term safety and efficacy. PMID- 24175082 TI - Keeping a finger on the pulse: Cardiovascular disease rate as a measure of sustainable development. AB - Non-communicable diseases have been somewhat neglected as a public health issue in the past, but there is now growing international consensus that they present a significant obstacle to economic development for both high- and low-income countries. Cardiovascular disease accounts for more than half of all non communicable disease deaths, and presents a promising target for curbing the non communicable disease epidemic. This article explains the pressing need for non communicable disease prevention, focusing on strategies that can be employed to decrease cardiovascular disease risk at an individual and population level, and outlines the UK's approaches to cardiovascular disease prevention in particular. Given the mounting burden of non-communicable diseases, responsible health governance and a balanced economic policy could consider the use of low cardiovascular disease rates as a measure of positive and sustainable economic development. PMID- 24175083 TI - Concomitant elective resection of pheochromocytoma and repair of aortic abdominal aneurysm. AB - Perioperative management of a patient with ischemic heart disease with coexisting abdominal aortic aneurysm and pheochromocytoma creates a difficult management dilemma, and surgical intervention in these patients carries a significant risk. The state of catecholamine excess and various other coexisting factors can lead to simultaneous occurrence of abdominal aortic aneurysm and pheocromocytoma. The purpose of this report is to present an integrated approach to the management of concomitant abdominal aortic aneurysm and pheochromocytoma, where a combined surgical approach in addressing these two lesions was preferable due to patient comorbidities and surgical implications without significant complication. PMID- 24175084 TI - Contrast-induced acute kidney injury following iodine opacification other than by intravascular injection. AB - Contrast-induced acute kidney injury (CI-AKI) classically occurs following the intravascular administration of iodinated contrast medium (CM). However, some cases of iodine-induced nephrotoxicity have been reported in patients who did not receive intravascular CM, as a consequence of iodine absorption through mucosae, burned skin or interstitial tissues. Recently, we observed the first case of CI AKI occurring after an enteroclysis without any direct intravascular injection of CM. Here, we report this case, and review other clinical situations in which renal toxicity has been reported following the non-intravascular use of iodinated compounds. PMID- 24175085 TI - Clinicopathological and immunohistological features in childhood IgA nephropathy: a single-centre experience. AB - BACKGROUND: IgA nephropathy is a glomerular disease diagnosed by renal biopsy and is characterized by a highly variable course ranging from a completely benign condition to rapidly progressive renal failure. We aimed to evaluate the clinical, histopathological and inflammatory characteristics of children with IgA nephropathy. METHODS: Data of 37 patients with IgA nephropathy diagnosed between the years 1980 and 2008 were retrospectively reviewed. Immunohistochemistry was performed in 24 patients. Expression of CD3, CD4, CD8, CD20, CD68, IL-1beta, IL 10, IL-17, TGF-beta, TNF-alpha and the newly proposed tubulointerstitial fibrosis marker nestin were evaluated. RESULTS: The median age at diagnosis was 10 years. Recurrent macroscopic haematuria (66%) was the most common clinical manifestation, and 35% of the patients had synpharyngitic presentation. A significant correlation was found between proteinuria and increase in mesangial matrix (r = 0.406, P = 0.013). The presence of CD4+ T lymphocytes and CD68+ macrophages were also significantly associated with proteinuria >1 g/day. While cytokines IL-1beta, IL-10 and TNF-alpha were mainly expressed in tubular epithelial cells, TGF-beta was evident in glomeruli but they had no correlation to clinical features and severity of the disease. Nestin was detected at the tubules in almost half of the patients with no correlation to proteinuria and tubulointersititial fibrosis. CONCLUSIONS: We found a correlation between proteinuria and mesangial matrix expansion. The presence of CD4+ T-lymphocytes and CD68+ macrophages were also significantly associated with proteinuria >1 g/day. Although there are many evidences, for immunological basis of IgA nephropathy, the immunological markers were not fully expressed in children to evaluate glomerular and tubulointerstitial inflammation, and progression of the disease. Further studies with the extended number of children are needed to shed light on the immunological basis of the disease. PMID- 24175086 TI - Medullary nephrocalcinosis in an adult patient with idiopathic infantile hypercalcaemia and a novel CYP24A1 mutation. AB - Idiopathic infantile hypercalcaemia (IIH) is an autosomal recessively inherited disease, presented in the first year of life with hypercalcaemia, precipitated by normal amounts of vitamin D supplementation. Recently loss-of-function mutations in the CYP24A1 gene, which encodes the vitamin D-metabolizing enzyme 24 hydroxylase, have been found in these patients. We describe a young man homozygous for a novel missense mutation (c.628T>C) of the CYP24A1 gene. He had suffered from severe hypercalcaemia in early childhood. At age 29 he presented with medullary nephrocalcinosis, chronic kidney disease (CKD) stage 2, microalbuminuria, mild hypertension and nephrogenic diabetes insipidus. He had mild hypercalcaemia and moderate hypercalciuria. As a novel finding, fibroblast growth factor 23 (FGF23) was elevated. PMID- 24175087 TI - Growth hormone-releasing hormone disruption extends lifespan and regulates response to caloric restriction in mice. AB - We examine the impact of targeted disruption of growth hormone-releasing hormone (GHRH) in mice on longevity and the putative mechanisms of delayed aging. GHRH knockout mice are remarkably long-lived, exhibiting major shifts in the expression of genes related to xenobiotic detoxification, stress resistance, and insulin signaling. These mutant mice also have increased adiponectin levels and alterations in glucose homeostasis consistent with the removal of the counter insulin effects of growth hormone. While these effects overlap with those of caloric restriction, we show that the effects of caloric restriction (CR) and the GHRH mutation are additive, with lifespan of GHRH-KO mutants further increased by CR. We conclude that GHRH-KO mice feature perturbations in a network of signaling pathways related to stress resistance, metabolic control and inflammation, and therefore provide a new model that can be used to explore links between GHRH repression, downregulation of the somatotropic axis, and extended longevity. DOI:http://dx.doi.org/10.7554/eLife.01098.001. PMID- 24175089 TI - Immune to defeat. AB - A dramatic example of the 'arms race' between hosts and pathogens has been observed in the response of mice to the parasite that causes toxoplasmosis. PMID- 24175088 TI - Reciprocal virulence and resistance polymorphism in the relationship between Toxoplasma gondii and the house mouse. AB - Virulence in the ubiquitous intracellular protozoon Toxoplasma gondii for its natural intermediate host, the mouse, appears paradoxical from an evolutionary standpoint because death of the mouse before encystment interrupts the parasite life cycle. Virulent T. gondii strains secrete kinases and pseudokinases that inactivate the immunity-related GTPases (IRG proteins) responsible for mouse resistance to avirulent strains. Such considerations stimulated a search for IRG alleles unknown in laboratory mice that might confer resistance to virulent strains of T. gondii. We report that the mouse IRG system shows extraordinary polymorphic complexity in the wild. We describe an IRG haplotype from a wild derived mouse strain that confers resistance against virulent parasites by interference with the virulent kinase complex. In such hosts virulent strains can encyst, hinting at an explanation for the evolution of virulence polymorphism in T. gondii. DOI:http://dx.doi.org/10.7554/eLife.01298.001. PMID- 24175090 TI - Factors influencing positive birth experiences of first-time mothers. AB - Objectives. The objective of this study was to describe first-time mothers' experiences and reflections of their first birth. Study Design. This study is a part of a larger study which was carried out in southwestern Sweden in 2008. A qualitative method with content analysis was chosen for this study. The unit of data was 14 written narratives from the first-time mothers. Results. The theme "To be empowered increases first-time mothers' chances for a positive birth experience" crossed over into all the three categories: "To trust the body and to face the pain," "Interaction between body and mind in giving birth," and "Consistency of support." Conclusion. In order to feel confident in their first childbirth, the women wanted to be confirmed and seen as unique individuals by the professionals and their partner. If professionals responded to the individual woman's needs of support, the woman more often had a positive birth experience, even if the birth was protracted or with medical complications. PMID- 24175091 TI - A supportive-educational intervention for heart failure patients in iran: the effect on self-care behaviours. AB - Background. Chronic heart failure is a major health and social problem. The promotion of self-care behaviours can potentially assist patients to effectively manage this chronic condition and prevent worsening of the disease. Formal personalized educational interventions that provide support and take into consideration the cultural context are needed. Objective. The objective of this research was to evaluate the effect of a supportive-educational intervention on self-care behaviours of heart failure patients in Iran. Methods. This research was a prospective, randomized trial of a supportive-educational intervention. Eighty heart failure patients were randomly assigned to receive the supportive educational intervention or usual care. The intervention consisted of a one-hour, nurse-led, in-person education session and postdischarge followup by telephone over three months. Data were collected at baseline, one, two, and three months. Results. The control and intervention groups did not differ in self-care scores at baseline (P > 0.05). Each of the self-care scores was significantly higher in the intervention group than the control group at 1, 2, and 3 months (P < 0.001). There were significant differences in self-care behaviours over the three months, among participants in the intervention group. Conclusion. This study provides support for the effectiveness of a supportive-educational intervention to increase self-care behaviours among Iranian patients suffering from chronic heart failure. PMID- 24175092 TI - Dissemination and Implementation Research: Intersection between Nursing Science and Health Care Delivery. PMID- 24175093 TI - Prevalence of occupational asthma and respiratory symptoms in foundry workers. AB - This cross-sectional study was conducted in a foundry factory to assess the prevalence of respiratory symptoms and occupational asthma in foundry workers. Physical examination, spirometric evaluation, chest radiograph, and a questionnaire related to respiratory symptoms were performed. Monitoring of peak expiratory flow rates, spirometric reversibility test, and high-resolution computed tomographies were performed for the participants having respiratory symptoms and/or impaired respiratory function test. A total of 347 participants including 286 workers from production department and 61 subjects who worked in nonproduction departments were enrolled in this study. It is found that phlegm (n: 71, 20.46%) and cough (n: 52, 14.98%) were the most frequent symptoms. The other symptoms were breathlessness (n: 28, 8.06%), chest tightness (n: 14, 4.03%), and wheezing (n: 7, 2.01%) . The prevalence of occupational asthma was found to be more frequent among the subjects who worked in the production department (n: 48, 16.78% ) than the other persons who worked in the nonproduction department (n: 3, 4.91%) by chi-square test (P: 0.001). To prevent hazardous respiratory effects of the foundry production, an early diagnosis of occupational asthma is very important. Cessation of cigarette smoking and using of protective masks during the working time should be encouraged. PMID- 24175094 TI - Parasympathetic response profiles related to social functioning in young children with autistic disorder. AB - Psychophysiology studies of heart rate and heart rate variability can be employed to study regulatory processes in children with autism. The objective of this study was to test for differences in respiratory sinus arrhythmia (RSA; a measure of heart rate variability) and to examine the relationship between physiologic responses and measures of social behavior. Participants included 2- to 6-year-old children with Autistic Disorder and children without autism. Heart rate and RSA were derived from ECG recordings made during a baseline period and then a stranger approach paradigm. Social and adaptive behavior was assessed by parent report. Groups did not differ in mean heart rate or RSA at baseline or in response to social challenge. However, children with autism were more likely to show a physiologic response to intrusive portions of the stranger approach than to less intrusive portions of this procedure. Nonautistic children were equally likely to respond to intrusive and less intrusive social events. Within the autistic group, physiologic response to the intrusive stranger approach corresponded to higher ratings of social adaptive behaviors. These results suggest that physiologic responses to social challenge may help understand differences in social behavioral outcomes in children with autism. PMID- 24175095 TI - Targeted antiepidermal growth factor receptor (cetuximab) immunoliposomes enhance cellular uptake in vitro and exhibit increased accumulation in an intracranial model of glioblastoma multiforme. AB - Therapeutic advances do not circumvent the devastating fact that the survival rate in glioblastoma multiforme (GBM) is less than 5%. Nanoparticles consisting of liposome-based therapeutics are provided against a variety of cancer types including GBM, but available liposomal formulations are provided without targeting moieties, which increases the dosing demands to reach therapeutic concentrations with risks of side effects. We prepared PEGylated immunoliposomes (ILs) conjugated with anti-human epidermal growth factor receptor (EGFR) antibodies Cetuximab ( alpha -hEGFR-ILs). The affinity of the alpha -hEGFR-ILs for the EGF receptor was evaluated in vitro using U87 mg and U251 mg cells and in vivo using an intracranial U87 mg xenograft model. The xenograft model was additionally analyzed with respect to permeability to endogenous albumin, tumor size, and vascularization. The in vitro studies revealed significantly higher binding of alpha -hEGFR-ILs when compared with liposomes conjugated with isotypic nonimmune immunoglobulin. The uptake and internalization of the alpha -hEGFR-ILs by U87 mg cells were further confirmed by 3D deconvolution analyses. In vivo, the alpha -hEGFR-ILs accumulated to a higher extent inside the tumor when compared to nonimmune liposomes. The data show that alpha -hEGFR-ILs significantly enhance the uptake and accumulation of liposomes in this experimental model of GBM suggestive of improved specific nanoparticle-based delivery. PMID- 24175096 TI - Histopathological correlation of atypical (c3) and suspicious (c4) categories in fine needle aspiration cytology of the breast. AB - Introduction. According to the National Cancer Institute (NCI) guidelines in 1996, breast lesions are categorized as C1 to C5 on fine needle aspiration (FNA) cytology. Very few studies are available in the English literature analyzing histopathology outcome of C3 (atypical, probably benign) and C4 (suspicious, probably malignant) lesions. Our study aims to correlate FNA cytology of breast lump diagnosed as C3 and C4 lesion with histopathological examination. Methods. During a period of 2 years, 59 cases of C3 and 26 cases of C4 were retrieved from total 1093 cases of breast FNA. All the cases were reviewed by two cytopathologists independently. The final 24 cases of C3 and 16 cases of C4 categories were correlated with histopathological diagnosis. Result. Among C3 category, 37.5% revealed malignant findings, whereas of C4 category, 87.5% were malignant on histopathology. This difference was statistically significant (P = 0.0017). Sensitivity, specificity, positive predictive values, and negative predictive value of C4 category in diagnosing breast malignancy were 60.8%, 88.2%, 87.5%, and 62.5%, respectively. Conclusion. Although FNAC is simple, safe, cost-effective and accurate method for diagnosis of breast masses, one must be aware of its limitations particularly in C3 and C4 categories. Also, since both these categories carry different probabilities of malignancy and thus different management, we therefore, support maintaining C3 and C4 categories. PMID- 24175097 TI - Detection of Mycobacterium avium Subspecies Paratuberculosis from Intestinal and Nodal Tissue of Dogs and Cats. AB - Objective. To determine prevalence of MAP in intestinal and nodal tissue from dogs and cats at necropsy at Kansas State University and to determine if an association existed between presence of MAP and gastrointestinal inflammation, clinical signs, or rural exposure. Procedures. Tissue samples were collected from the duodenum, ileum, and mesenteric and colic nodes of adult dogs (73) and cats (37) undergoing necropsy for various reasons. DNA was extracted and analyzed for insertion sequence 900 using nested PCR. Positive samples were confirmed with DNA sequencing. An online mapping system was used to determine if patients lived in an urban or rural environment based on the home address. Medical records were reviewed for clinical signs and histological findings at necropsy. Results. MAP was identified from 3/73 (4.1%) dogs and 3/37 (8.1%) cats. There was no documented association between presence of MAP and identification of histologic confirmed gastrointestinal inflammation, gastrointestinal clinical signs, or exposure to a rural environment. Conclusion and Clinical Relevance. MAP-specific DNA can be identified within the intestinal and nodal tissue of dogs and cats that do not have pathological lesions or clinical signs consistent with gastrointestinal disease. The significance of this organism's presence without associated gastrointestinal pathology is unknown. PMID- 24175098 TI - The role of 39 psoriasis risk variants on age of psoriasis onset. AB - Recent genome-wide association studies (GWAS) have identified multiple genetic risk factors for psoriasis, but data on their association with age of onset have been marginally explored. The goal of this study was to evaluate known risk alleles of psoriasis for association with age of psoriasis onset in three well defined case-only cohorts totaling 1,498 psoriasis patients. We selected 39 genetic variants from psoriasis GWAS and tested these variants for association with age of psoriasis onset in a meta-analysis. We found that rs10484554 and rs12191877 near HLA-C and rs17716942 near IFIH1 were associated with age of psoriasis onset with false discovery rate < 0.05. The association between rs17716942 and age of onset was not replicated in a fourth independent cohort of 489 patients (P = 0.94). The imputed HLA-C*06:02 allele demonstrated a much stronger association with age of psoriasis onset than rs10484554 and rs12191877. We conclude that despite the discovery of numerous psoriasis risk alleles, HLA C*06:02 still plays the most important role in determining the age of onset of psoriasis. Larger studies are needed to evaluate the contribution of other risk alleles, including IFIH1, to age of psoriasis onset. PMID- 24175100 TI - Operative treatment of hepatic hydatid cysts: a single center experience in Israel, a nonendemic country. AB - Background. Hydatid cyst disease is a zoonosis caused by Echinococcus genera. The disease is endemic to certain rural areas in the world. Operative treatment is the main component in curing hydatid cysts of the liver. Objective. Describing the unique characteristics of the hydatid cyst patients in Israel, a nonendemic country. Methods. Data was collected form 29 patients treated operatively in Rabin Medical Center from 1994 to 2007. Results. The study included 18 females and 11 males with an average age of 54.9 years. Fifty-two% of the patients immigrated as children from Arab countries to Israel, 21% were Arab-Israelis leaving in the north and center of Israel, and 24% immigrated from the former Communist Bloc. Pericystectomy was performed in 20/29, and cyst unroofing was performed in 9/29. Hydatid cysts average size was 10.7 cm, and the cysts were located in the right or left or involved both lobes in 62%, 28%, and 10% of the lesions, respectively. Postoperative mortality occurred in one case, and severe morbidity occurred in 4 patients. Conclusions. Hydatid cyst disease in Israel is uncommon and is mostly seen in distinct 3 demographic groups. Despite the relatively low patient volume, good results in terms of morbidity, mortality, and recurrence were achieved. PMID- 24175101 TI - Enhanced expression of NR2B subunits of NMDA receptors in the inherited glaucomatous DBA/2J mouse retina. AB - DBA/2J mouse has been used as a model for spontaneous secondary glaucoma. Here, we investigated changes in expression of NMDA receptor (NMDAR) subunits and Cdk5/p35/NMDAR signaling in retinas of DBA/2J mice using Western blot technique. The protein levels of NR1 and NR2A subunits in retinas of DBA/2J mice at all ages (6-12 months) were not different from those in age-matched C57BL/6 mice. In contrast, the protein levels of NR2B subunits, in addition to age-dependent change, significantly increased with elevated intraocular pressure (IOP) in DBA/2J mice at 6 and 9 months as compared with age-matched controls. Moreover, expression of Cdk5, p35 and ratio of p-NR2A(S1232)/NR2A progressively increased with time in both strains, suggestive of activated Cdk5/p35 signaling pathway. However, the changes in these proteins were in the same levels in both strain mice, except a significant increase of p35 proteins at 6 months in DBA/2J mice. Meanwhile, the protein levels of Brn-3a, a retinal ganglion cell (RGC) maker, remarkably decreased at 9-12 months in DBA/2J mice, which was in parallel with the changes of NR2B expression. Our results suggest that elevated IOP-induced increase in expression of NR2B subunits of NMDARs may be involved in RGC degeneration of DBA/2J mice. PMID- 24175102 TI - Photoinitiated polymerization of 2-hydroxyethyl methacrylate by riboflavin/triethanolamine in aqueous solution: a kinetic study. AB - The polymerization of 1-3 M 2-hydroxyethyl methacrylate (HEMA) initiated by riboflavin/triethanolamine system has been studied in the pH range 6.0-9.0. An approximate measure of the kinetics of the reaction during the initial stages (~5% HEMA conversion) has been made to avoid the effect of any variations in the volume of the medium. The concentration of HEMA in polymerized solutions has been determined by a UV spectrophotometric method at 208 nm with a precision of +/-3%. The initial rate of polymerization of HEMA follows apparent first-order kinetics and the rates increase with pH. This may be due to the presence of a labile proton on the hydroxyl group of HEMA. The second-order rate constants for the interaction of triethanolamine and HEMA lie in the range of 2.36 to 8.67 * 10(-2) M(-1) s(-1) at pH 6.0-9.0 suggesting an increased activity with pH. An increase in the viscosity of HEMA solutions from 1 M to 3 M leads to a decrease in the rate of polymerization probably as a result of the decrease in the reactivity of the flavin triplet state. The effect of pH and viscosity of the medium on the rate of reaction has been evaluated. PMID- 24175103 TI - Prosthetic rehabilitation in children: an alternative clinical technique. AB - Complete and partial removable dentures have been used successfully in numerous patients with oligodontia and/or anodontia. However, there is little information in the literature regarding the principles and guidelines to prosthetic rehabilitation for growing children. This case report describes the management of a young child with oligodontia as well as the treatment planning and the prosthetic rehabilitation technique. PMID- 24175099 TI - Role of endothelial to mesenchymal transition in the pathogenesis of the vascular alterations in systemic sclerosis. AB - The pathogenesis of Systemic Sclerosis (SSc) is extremely complex, and despite extensive studies, the exact mechanisms involved are not well understood. Numerous recent studies of early events in SSc pathogenesis have suggested that unknown etiologic factors in a genetically receptive host trigger structural and functional microvascular endothelial cell abnormalities. These alterations result in the attraction, transmigration, and accumulation of immune and inflammatory cells in the perivascular tissues, which in turn induce the phenotypic conversion of endothelial cells and quiescent fibroblasts into activated myofibroblasts, a process known as endothelial to mesenchymal transition or EndoMT. The activated myofibroblasts are the effector cells responsible for the severe and frequently progressive fibrotic process and the fibroproliferative vasculopathy that are the hallmarks of SSc. Thus, according to this hypothesis the endothelial and vascular alterations, which include the phenotypic conversion of endothelial cells into activated myofibroblasts, play a crucial role in the development of the progressive fibrotic process affecting skin and multiple internal organs. The role of endothelial cell and vascular alterations, the potential contribution of endothelial to mesenchymal cell transition in the pathogenesis of the tissue fibrosis, and fibroproliferative vasculopathy in SSc will be reviewed here. PMID- 24175104 TI - Everolimus for compassionate use in multiple Basal cell carcinomas. AB - Everolimus is an inhibitor of the mammalian target of rapamycin (mTOR) and has been shown to have antineoplastic activity in addition to its use as an immunosuppressive agent for the prevention of organ transplant rejection. We report the use of everolimus for the compassionate treatment of four elderly, nontransplant patients presenting with multiple basal cell carcinomas (BCC). All patients had a long history of BCC, had refused surgery as a current treatment option, and did not respond to alternative treatments (including topical 5 fluorouracil and imiquimod). Patients were treated with oral everolimus (1.5-3.0 mg daily) for 12 months or longer: a complete and sustained response was seen in one case, and partial responses were seen in two other cases. Everolimus was well tolerated in these elderly patients. These promising preliminary data suggest that further dose-finding, controlled clinical studies are warranted to evaluate the antineoplastic effects of everolimus in patients affected by BCC who cannot or will not undergo surgery. PMID- 24175105 TI - Alpha-methyldopa-induced autoimmune hemolytic anemia in the third trimester of pregnancy. AB - Alpha-methyldopa has been demonstrated to be safe for use during pregnancy and is now used to treat gestational hypertension. In pregnancy, alpha-methyldopa induced autoimmune hemolytic anemia does not have typical features and the severity of symptoms ranges from mild fatigue to dyspnea, respiratory failure, and death if left untreated. A case of alpha-methyldopa-induced autoimmune hemolytic anemia in a 36-year-old gravida 2, para 1 woman at 37(+6) weeks of gestation is reported herein along with the differential diagnostic procedure and the potential risks to the mother and the fetus. PMID- 24175106 TI - Long-Term Survival and Improved Quality of Life following Multiple Repeat Gamma Knife Radiosurgeries for Recurrent Glioblastoma Multiforme: A Case Report and Review of the Literature. AB - The management of glioblastoma multiforme (GBM) is in most cases complex and must be specifically tailored to the needs of the patient with the goals of extended survival and improved quality of life. Despite advancements in therapy, treatment outcomes remain almost universally poor. Salvage treatment options for the recurrence of the disease is an area of intense study. The following case highlights the utility of Gamma Knife Radiosurgery (GKRS) as a salvage treatment. In this clinical situation, three sequential GKRS treatments led to prolonged survival (beyond four years after diagnosis) and improved quality of life in a patient who was unable to receive further chemotherapy regimens and was unwilling to undergo further aggressive resection. To date, there have been few reports of three or more sequential GKRS treatment sessions utilized as salvage therapy for recurrent GBM in patients who can no longer tolerate chemotherapy. This report provides evidence that aggressive local treatment with GKRS at the time of recurrence may be appropriate, depending on a patient's individual clinical situation, and can lead to prolonged survival and improved quality of life. PMID- 24175107 TI - Diagnosis of thymic clear cell carcinoma by cytology. AB - Clear cell carcinoma of the thymus is a rare tumor. Few cases of clear-cell carcinoma of thymus have been documented (Truong et al., 1990 and Wolfe III et al., 1983). All these cases were diagnosed by histopathological examination of the tissue. Diagnosis of thymic clear cell carcinoma on cytology is extremely challenging. Here we report the first case of thymic clear cell carcinoma diagnosed by cytological examination of the pericardial fluid with the help of immunocytochemistry. Differential diagnosis included adenocarcinoma, mesothelioma, and thymic clear cell carcinoma. Thymic carcinoma with clear cell features has an aggressive clinical behavior including our case, where it was already metastasized at the time of presentation. PMID- 24175108 TI - Sequential MR Images and Radiographs of Epiphyseal Osteomyelitis in the Distal Femur of an Infant. AB - Magnetic resonance imaging (MRI) plays an important role in the diagnosis of osteomyelitis, especially during the early phase of the disease. The findings of sequential MRIs during the course of treatment in acute osteomyelitis in children have not yet been reported in the literature. We present a case of acute epiphyseal osteomyelitis in the distal femur of an infant. We monitored imaging changes by sequential MRIs and radiographs. MRI was more useful than radiograph for early diagnosis and evaluation of therapeutic response. PMID- 24175109 TI - Unexpected small urinary bladder pheochromocytoma: a nonspecific presentation. AB - Objectives. Pheochromocytoma of the urinary bladder is an extremely rare tumor that typically presents with a hypertensive crisis during micturition. Preoperatively, it may be misdiagnosed due to nonspecific symptomatology, physical, and radiologic findings. Method. We report a case of unsuspected small pheochromocytoma which was incidentally found by CT scan and confirmed by the histological aspects after transurethral resection in a 63-year-old woman. Here, we have described the clinical presentation, physical findings, laboratory investigations, and treatment provided in our case. We have also included radiological images and histopathology slides with input from both radiologists and pathologists. Surgical management and postoperative follow-up are discussed, as are details of previous published data. Results. After undergoing surgical treatment (transurethral resection), our patient is asymptomatic, with complete resolution of her pathology. Conclusion. Diagnosis is difficult before histopathological examination and should be considered in patients with no risk factors for usual bladder tumor. Our purpose is to raise clinician's awareness for this condition so that they will be more likely to diagnose it. This will facilitate prompt diagnosis and treatment and especially prevent complications due to pheochromocytoma which may be severe. PMID- 24175110 TI - Alpha 1-Antichymotrypsin, an Inflammatory Protein Overexpressed in the Brains of Patients with Alzheimer's Disease, Induces Tau Hyperphosphorylation through c-Jun N-Terminal Kinase Activation. AB - The association of inflammatory proteins with neuritic plaques in the brains of Alzheimer's disease (AD) patients has led to the hypothesis that inflammation plays a pivotal role in the development of pathology in AD. Earlier studies have shown that alpha 1-antichymotrypsin (ACT) enhances amyloid beta fibrillization and accelerated plaque formation in APP transgenic mice. Later studies from our laboratory have shown that purified ACT induces tau hyperphosphorylation and degeneration in neurons. In order to understand the mechanisms by which inflammatory proteins enhance tau hyperphosphorylation, we injected interleukin-1 beta (IL-1 beta ) intracerebroventricularly into mice expressing human ACT, human tau, or both transgenes. It was found that the hyperphosphorylation of tau in ACT and ACT/htau mice after IL-1 beta injection correlated with increased phosphorylation of c-Jun N-terminal kinase (JNK). We verified the involvement of JNK in ACT-induced tau phosphorylation by utilizing JNK inhibitors in cultured primary neurons treated with ACT, and we found that the inhibitor showed complete prevention of ACT-induced tau phosphorylation. These results indicate that JNK is one of the major kinases involved in the ACT-mediated tau hyperphosphorylation and suggest that inhibitors of this kinase may protect against inflammation induced tau hyperphosphorylation and neurodegeneration associated with AD. PMID- 24175111 TI - Effects of Flavonoids from French Marigold (Florets of Tagetes patula L.) on Acute Inflammation Model. AB - The major components patuletin and patulitrin were isolated from French marigold (florets of Tagetes patula). Patuletin and patulitrin were found to inhibit acute inflammation in mice. Oral administration of patuletin and patulitrin significantly suppressed hind-paw edema induced by carrageenin and histamine, while topical application of patuletin and patulitrin significantly inhibited ear edema induced by 12-O-tetradecanoylphorbol-13-acetate and arachidonic acid. Thus, oral and topical administration of patuletin and patulitrin inhibited acute inflammation in mice. These results suggest the anti-inflammatory efficacy of French marigold. PMID- 24175113 TI - Introduction to the international medical informatics association. PMID- 24175112 TI - Computer Tomographic Illustration of the Development of the Pulmonary Function in Bovine Neonates until the Twenty-First Day Postnatum. AB - The aim of this study was to analyze the development of the lung in newborn calves. The sample consisted of 28 Holstein Friesians calves which were examined clinically, and their chest segment was measured with computed tomography. The tests were performed on the first, sixth, and twelfth hours of life and after the first, second, and third weeks. Also, blood gases and blood counts were determined. Besides Kolmogorov-Smirnov tests, analyses of variance, t-tests (on a significance level of P < 0.05), and correlation analyses were used. The most significant changes occurred between birth and the first hour. However, there were significant differences in the gas filling between cranial and caudal and between dorsal and ventral parenchyma segments. This difference remained over the entire study period. At the end of the first week between 85 and 93% were involved in gas exchange. Only after the completion of the second week of life, the air supply was achieved throughout the whole lung. The pO2, pCO2, and pH values confirmed this. This study shows that a healthy bovine neonate needs about 2 weeks before all lung units are integrated into the gas exchange. This explains why calves in unfavorable environments often suffer from pulmonary affections. PMID- 24175114 TI - IMIA Accreditation of Health Informatics Programs. AB - OBJECTIVES: Health informatics programs usually are evaluated by national accreditation committees. Not always are the members of these committees well informed about the international level of (education in) health informatics. Therefore, when a program is accredited by a national accreditation committee, this does not always mean that the program is of an international level. The International Medical Informatics Association (IMIA) has expertise in the field of education. The IMIA Recommendations on Education in Biomedical and Health Informatics guide curricula development. The goal of this article is to show that IMIA can also play the role of accreditation agency and to present the IMIA accreditation protocol and experiences obtained with it. METHODS: The accreditation procedure used in the Netherlands and Belgium was taken as a template for the design of the IMIA accreditation protocol. In a trial period of one and a half year the protocol is tested out on six health informatics programs. RESULTS: An accreditation protocol was designed. For judging the curriculum of a program the IMIA Recommendations are used. The institution has to write a self-assessment report and a site visit committee visits the program and judges its quality, supported by the self-assessment report and discussions with all stakeholders of the program. CONCLUSIONS: After having visited three programs it appears that the IMIA accreditation procedure works well. Only a few changes had to be introduced. Writing the self-assessment report already appears to be beneficial for the management of the program to obtain a better insight in the quality of their program. PMID- 24175115 TI - Perception of Influencing Factors on Acceptance of Mobile Health Monitoring Service: A Comparison between Users and Non-users. AB - OBJECTIVES: To improve and promote mobile health monitoring services, this study investigated the perception of various factors influencing the acceptance of services between users and non-users. METHODS: This study drew 9 variables from studies related to mobile health monitoring services and the unified theory of acceptance and the use of technology model. A total of 219 samples were collected by a paper-based survey from users (n = 106) and non-users (n = 113). Analysis was carried out using a two-independent samples t-test. RESULTS: The findings indicate that users have a more positive perception of service benefits than non users. Although there were difference between users and non-users, all respondents had a positive perception of the service benefits. After users used the service, they were less concerned about the risks involved with it. However, both users and non-users had a high negative perception of service risk. Users also had a more positive perception of intimacy and communication associated with the services than non-users. Both users and non-users had a high behavioral intention to use the services. Finally, this study observed that older subjects tended to recognize the higher value of the services. CONCLUSIONS: This study provides insights to improve and invigorate mobile health monitoring services. This study also offers insights into how to increase the number of users of mobile health monitoring services in South Korea. PMID- 24175116 TI - Real-data comparison of data mining methods in prediction of diabetes in iran. AB - OBJECTIVES: Diabetes is one of the most common non-communicable diseases in developing countries. Early screening and diagnosis play an important role in effective prevention strategies. This study compared two traditional classification methods (logistic regression and Fisher linear discriminant analysis) and four machine-learning classifiers (neural networks, support vector machines, fuzzy c-mean, and random forests) to classify persons with and without diabetes. METHODS: The data set used in this study included 6,500 subjects from the Iranian national non-communicable diseases risk factors surveillance obtained through a cross-sectional survey. The obtained sample was based on cluster sampling of the Iran population which was conducted in 2005-2009 to assess the prevalence of major non-communicable disease risk factors. Ten risk factors that are commonly associated with diabetes were selected to compare the performance of six classifiers in terms of sensitivity, specificity, total accuracy, and area under the receiver operating characteristic (ROC) curve criteria. RESULTS: Support vector machines showed the highest total accuracy (0.986) as well as area under the ROC (0.979). Also, this method showed high specificity (1.000) and sensitivity (0.820). All other methods produced total accuracy of more than 85%, but for all methods, the sensitivity values were very low (less than 0.350). CONCLUSIONS: The results of this study indicate that, in terms of sensitivity, specificity, and overall classification accuracy, the support vector machine model ranks first among all the classifiers tested in the prediction of diabetes. Therefore, this approach is a promising classifier for predicting diabetes, and it should be further investigated for the prediction of other diseases. PMID- 24175117 TI - Stratified sampling design based on data mining. AB - OBJECTIVES: To explore classification rules based on data mining methodologies which are to be used in defining strata in stratified sampling of healthcare providers with improved sampling efficiency. METHODS: We performed k-means clustering to group providers with similar characteristics, then, constructed decision trees on cluster labels to generate stratification rules. We assessed the variance explained by the stratification proposed in this study and by conventional stratification to evaluate the performance of the sampling design. We constructed a study database from health insurance claims data and providers' profile data made available to this study by the Health Insurance Review and Assessment Service of South Korea, and population data from Statistics Korea. From our database, we used the data for single specialty clinics or hospitals in two specialties, general surgery and ophthalmology, for the year 2011 in this study. RESULTS: Data mining resulted in five strata in general surgery with two stratification variables, the number of inpatients per specialist and population density of provider location, and five strata in ophthalmology with two stratification variables, the number of inpatients per specialist and number of beds. The percentages of variance in annual changes in the productivity of specialists explained by the stratification in general surgery and ophthalmology were 22% and 8%, respectively, whereas conventional stratification by the type of provider location and number of beds explained 2% and 0.2% of variance, respectively. CONCLUSIONS: This study demonstrated that data mining methods can be used in designing efficient stratified sampling with variables readily available to the insurer and government; it offers an alternative to the existing stratification method that is widely used in healthcare provider surveys in South Korea. PMID- 24175118 TI - Quantitative measurement method for possible rib fractures in chest radiographs. AB - OBJECTIVES: This paper proposes a measurement method to quantify the abnormal characteristics of the broken parts of ribs using local texture and shape features in chest radiographs. METHODS: OUR MEASUREMENT METHOD COMPRISES TWO STEPS: a measurement area assignment and sampling step using a spline curve and sampling lines orthogonal to the spline curve, and a fracture-ness measurement step with three measures, asymmetry and gray-level co-occurrence matrix based measures (contrast and homogeneity). They were designed to quantify the regional shape and texture features of ribs along the centerline. The discriminating ability of our method was evaluated through region of interest (ROI) analysis and rib fracture classification test using support vector machine. RESULTS: The statistically significant difference was found between the measured values from fracture and normal ROIs; asymmetry (p < 0.0001), contrast (p < 0.001), and homogeneity (p = 0.022). The rib fracture classifier, trained with the measured values in ROI analysis, detected every rib fracture from chest radiographs used for ROI analysis, but it also classified some unbroken parts of ribs as abnormal parts (8 to 17 line sets; length of each line set, 2.998 +/- 2.652 mm; length of centerlines, 131.067 +/- 29.460 mm). CONCLUSIONS: Our measurement method, which includes a flexible measurement technique for the curved shape of ribs and the proposed shape and texture measures, could discriminate the suspicious regions of ribs for possible rib fractures in chest radiographs. PMID- 24175119 TI - Cost-benefit analysis of electronic medical record system at a tertiary care hospital. AB - OBJECTIVES: Although Electronic Medical Record (EMR) systems provide various benefits, there are both advantages and disadvantages regarding its cost effectiveness. This study analyzed the economic effects of EMR systems using a cost-benefit analysis based on the differential costs of managerial accounting. METHODS: Samsung Medical Center (SMC) is a general hospital in Korea that developed an EMR system for outpatients from 2006 to 2008. This study measured the total costs and benefits during an 8-year period after EMR adoption. The costs include the system costs of building the EMR and the costs incurred in smoothing its adoption. The benefits included cost reductions after its adoption and additional revenues from both remodeling of paper-chart storage areas and medical transcriptionists' contribution. The measured amounts were discounted by SMC's expected interest rate to calculate the net present value (NPV), benefit cost ratio (BCR), and discounted payback period (DPP). RESULTS: During the analysis period, the cumulative NPV and the BCR were US$3,617 thousand and 1.23, respectively. The DPP was about 6.18 years. CONCLUSIONS: Although the adoption of an EMR resulted in overall growth in administrative costs, it is cost-effective since the cumulative NPV was positive. The positive NPV was attributed to both cost reductions and additional revenues. EMR adoption is not so attractive to management in that the DPP is longer than 5 years at 6.18 and the BCR is near 1 at 1.23. However, an EMR is a worthwhile investment, seeing that this study did not include any qualitative benefits and that the paper-chart system was cost centric. PMID- 24175120 TI - Effect of health information technology expenditure on patient level cost. AB - OBJECTIVES: This study investigate the effect of health information technology (IT) expenditure on individual patient-level cost using California Office of Statewide Health Planning and Development (OSHPD) data obtained from 2000 to 2007. METHODS: We used a traditional cost function and applied hospital fixed effect and clustered error within hospitals. RESULTS: We found that a quadratic function of IT expenditure best fit the data. The quadratic function in IT expenditure predicts a decrease in cost of up to US$1,550 of IT labor per bed, US$27,909 of IT capital per bed, and US$28,695 of all IT expenditure per bed. Moreover, we found that IT expenditure reduced costs more quickly in medical conditions than surgical diseases. CONCLUSIONS: Interest in health IT is increasing more than ever before. Many studies examined the effect of health IT on hospital level cost. However, there have been few studies to examine the relationship between health IT expenditure and individual patient-level cost. We found that IT expenditure was associated with patient cost. In particular, we found a quadratic relationship between IT expenditure and patient-level cost. In other word, patient-level cost is non-linearly (or a polynomial of second-order degree) related to IT expenditure. PMID- 24175121 TI - Design and Realization of Integrated Management System for Data Interoperability between Point-of-Care Testing Equipment and Hospital Information System. AB - OBJECTIVES: The purpose of this study was to design an integrated data management system based on the POCT1-A2, LIS2-A, LIS2-A2, and HL7 standard to ensure data interoperability between mobile equipment, such as point-of-care testing equipment and the existing hospital data system, its efficiency was also evaluated. METHODS: The method of this study was intended to design and realize a data management system which would provide a solution for the problems that occur when point-of-care testing equipment is introduced to existing hospital data, after classifying such problems into connectivity, integration, and interoperability. This study also checked if the data management system plays a sufficient role as a bridge between the point-of-care testing equipment and the hospital information system through connection persistence and reliability testing, as well as data integration and interoperability testing. RESULTS: In comparison with the existing system, the data management system facilitated integration by improving the result receiving time, improving the collection rate, and by enabling the integration of disparate types of data into a single system. And it was found out that we can solve the problems related to connectivity, integration and interoperability through generating the message in standardized types. CONCLUSIONS: It is expected that the proposed data management system, which is designed to improve the integration point-of-care testing equipment with existing systems, will establish a solid foundation on which better medical service may be provided by hospitals by improving the quality of patient service. PMID- 24175122 TI - Correction: Lessons Learned from Development of De-identification System for Biomedical Research in a Korean Tertiary Hospital. PMID- 24175123 TI - Reliability and validity of functional performance tests in dancers with hip dysfunction. AB - STUDY DESIGN: Quasi-experimental, repeated measures. PURPOSE/BACKGROUND: Functional performance tests that identify hip joint impairments and assess the effect of intervention have not been adequately described for dancers. The purpose of this study was to examine the reliability and validity of hop and balance tests among a group of dancers with musculoskeletal pain in the hip region. METHODS: NINETEEN FEMALE DANCERS (AGE: 18.90+/-1.11 years; height: 164.85+/-6.95 cm; weight: 60.37+/-8.29 kg) with unilateral hip pain were assessed utilizing the cross-over reach, medial triple hop, lateral triple hop, and cross over hop tests on two occasions, 2 days apart. Test-retest reliability and comparisons between the involved and uninvolved side for each respective test were determined. RESULTS: Intra-class correlation coefficients for the functional performance tests ranged from 0.89-0.96. The cross-over reach test had a SEM of 2.79 cm and a MDC of 7.73 cm. The medial and lateral triple hop tests had SEM values of 7.51 cm and 8.17 cm, and MDC values of 20.81 cm and 22.62 cm, respectively. The SEM was 0.15 seconds and the MDC was 0.42 seconds for the cross over hop test. Performance on the medial triple hop test was significantly less on the involved side (370.21+/-38.26 cm) compared to the uninvolved side (388.05+/-41.49 cm); t(18) = -4.33, p<0.01. The side-to-side comparisons of the cross-over reach test (involved mean=61.68+/-10.9 cm; uninvolved mean=61.69+/ 8.63 cm); t(18) = -0.004, p=0.99, lateral triple hop test (involved mean=306.92+/ 35.79 cm; uninvolved mean=310.68+/-24.49 cm); t(18) = -0.55, p=0.59, and cross over hop test (involved mean=2.49+/-0.34 seconds; uninvolved mean= 2.61+/-0.42 seconds; t(18) = -1.84, p=0.08) were not statistically different between sides. CONCLUSION: The functional performance tests used in this study can be reliably performed on dancers with unilateral hip pain. The medial triple hop test was the only functional performance test with evidence of validity in side-to-side comparisons. These results suggest that the medial triple hop test may be a reliable and valid functional performance test to assess impairments related to hip pain among dancers. LEVEL OF EVIDENCE: 3b. Non-consecutive cohort study. PMID- 24175124 TI - The effect of double versus single oscillating exercise devices on trunk and limb muscle activation. AB - PURPOSE/BACKGROUND: Proper strengthening of the core and upper extremities is important for muscular health, performance, and rehabilitation. Exercise devices have been developed that attempt to disrupt the center of gravity in order to activate the trunk stabilizing muscles. The objective of this study was to analyze the trunk and shoulder girdle muscle activation with double and single oscillating exercise devices (DOD and SOD respectively) in various planes. METHODS: TWELVE MALE SUBJECTS PERFORMED THREE INTERVENTIONS USING BOTH DEVICES UNDER RANDOMIZED CONDITIONS: single-handed vertical orientation of DOD and SOD to produce 1) medio-lateral oscillation in the frontal plane 2) dorso-ventral oscillation in the sagittal plane and 3) single-handed horizontal orientation for superior and inferior oscillation in the transverse plane. Electromyographic (EMG) activity during the interventions of the anterior deltoid, triceps brachii, biceps brachii, forearm flexors as well as lower abdominal and back stabilizer muscles was collected, and were normalized to maximal voluntary contractions. A two way repeated measures ANOVA (2x3) was conducted to assess the influence of the devices and movement planes on muscle activation. RESULTS: The DOD provided 35.9%, 40.8%, and 52.3% greater anterior deltoid, transverse abdominus (TA)/internal oblique (IO) and lumbo-sacral erector spinae (LSES) activation than did the SOD respectively. Effect size calculations revealed that these differences were of moderate to large magnitude (0.86, 0.48, and 0.61 respectively). There were no significant differences in muscular activation achieved between devices for the triceps brachii, biceps brachii and forearm flexor muscles. Exercise in the transverse plane resulted in 30.5%, 29.5%, and 19.5% greater activation than the sagittal and 21.8%, 17.2%, and 26.3% greater activation than the frontal plane for the anterior deltoid, TA/IO and LSES respectively. CONCLUSIONS: A DOD demonstrated greater muscular activity for trunk and shoulder muscle activation but does not provide an advantage for limb activation. Overall, oscillating the devices in the transverse plane provided greater muscular activation of the anterior deltoid, TA/IO and LSES than use of the devices during frontal or sagittal plane movements. LEVEL OF EVIDENCE: 2c: Outcomes research. PMID- 24175125 TI - The reliability of the modified reverse-6 taping procedure with elastic tape to alter the height and width of the medial longitudinal arch. AB - PURPOSE/BACKGROUND: Anti-pronation-taping utilizing both inelastic and elastic tape has been advocated to reduce pain and symptoms associated with excessive foot pronation. An important question regarding the use of taping is whether it can be applied consistently from one therapist to the next, from one session to the next or from one day to the next. Thus, the purpose of this study was to determine whether the "modified" Reverse-6 taping procedure using elastic tape could be applied to produce a consistent within-day and between-day change in the height and width of the medial longitudinal arch for a single clinician as well as between clinicians. A second purpose was to determine if the amount of general clinical experience influenced this consistency. METHODS: Fifteen asymptomatic individuals (10 female and 5 male) with a mean age of 28.7 years were recruited to participate in this study. The height and width of the midfoot at 50% of each subject's foot length was measured in standing using a digital gauge and caliper. These measurements were done twice on the same day, on two different days and again by two clinicians with different levels of experience before and after having their feet taped using the "modified" Reverse-6 taping technique using elastic tape. Both clinicians received a one-hour training session on how to apply the taping technique and were also given a DVD showing the technique that they could review. In addition to descriptive statistics, intra-class correlation coefficients (ICC) were used to assess each clinician's within-day and between day reliability. Between-clinician reliability was also determined. RESULTS: The mean dorsal arch height and midfoot width before the application of tape was 62.7 and 78.9 mm. The mean dorsal arch height and width after the application of tape was 66.6 and 78.8 mm. The within-day reliability ICC(2,1) values for the two clinicians ranged from .865 to .991. The between-day reliability ICC(2,1) values for the two clinicians ranged from .874 to .985. The between-clinician reliability ICC(2,1) values ranged from .918 to .993. CONCLUSIONS: The results of this study indicate that the "modified" Reverse-6 foot taping technique using elastic tape can be used by more than one therapist for the same patient as well as from one session to the next with excellent reliability. LEVEL OF EVIDENCE: Level 2, Prospective Cohort Study. PMID- 24175126 TI - The effect of kinesio(r) tape on vertical jump and dynamic postural control. AB - INTRODUCTION AND BACKGROUND: Ankle injuries are one of the most common injuries among physically active individuals. The role of prophylactic ankle taping and bracing has been studied extensively. Kinesio((r)) Tape (KT) is a somewhat new type of taping technique gaining popularity as both treatment and performance enhancement tool. However, there is limited research on the effect of KT on functional performance. PURPOSE: The purpose of this study was to determine whether the application of Kinesio Tex((r)) Tape had an effect on vertical jump and dynamic postural control in healthy young individuals. METHODS: 52 healthy subjects free of ankle or lower extremity problems (28 males and 24 females; age: 22.12+/-2.08 years; height: 170.77+/-8.69 cm; weight: 69.90+/-12.03 kg) participated in the study. Subjects were randomly assigned to either the experimental group (KT with tension) or the control group (KT without tension). Vertical jump was measured using the VertiMetric device and dynamic postural control was assessed using the Star Excursion Balance Test (SEBT) under three conditions: (1) without taping; (2) immediately after taping; (3) 24 hours after taping with the taping remaining in situ. RESULTS: Three-way repeated measure ANOVA was conducted in order to identify differences between the experimental and the control group during the three conditions. Overall, there were no differences between groups in vertical jump maximum height, vertical jump average height, or the SEBT scores for the three time periods (pre-test, post-test, 24hrs-post test). However, the main effect of KT was moderated by a significant gender interaction, resulting in a statistically significant effect of KT for the SEBT scores in the posterior-medial direction, F(1.72, 82.57) = 4.50, p = 0.018 and the medial direction, F(1.75, 83.81) = 4.27, p = 0.021. Follow-up analyses indicated that female subjects in the KT group had increased SEBT scores between three time periods when compared to the placebo group. DISCUSSION: KT application on the ankle neither decreased nor increased vertical jump height in healthy non injured young individuals, but did increase dynamic postural control in females for certain directions. Additional study is warranted using different measures of balance to further investigate the effect of KT on dynamic postural control. LEVEL OF EVIDENCE: 2b. PMID- 24175127 TI - No association between q-angle and foot posture with running-related injuries: a 10 week prospective follow-up study. AB - BACKGROUND/PURPOSE: There is a paucity of knowledge on the association between different foot posture quantified by Foot Posture Index (FPI) and Quadriceps angle (Q-angle) with development of running-related injuries. Earlier studies investigating these associations did not include an objective measure of the amount of running performed. Therefore, the purpose of this study was to investigate if kilometers to running-related injury (RRI) differ among novice runners with different foot postures and Q-angles when running in a neutral running shoe. METHODS: A 10 week study was conducted including healthy, novice runners. At baseline foot posture was evaluated using the foot posture index (FPI) and the Q-angle was measured. Based on the FPI and Q-angle, right and left feet / knees of the runners were categorized into exposure groups. All participants received a Global Positioning System watch to allow them to quantify running volume and were instructed to run a minimum of two times per week in a conventional, neutral running shoe. The outcome was RRI. RESULTS: Fifty nine novice runners of mixed gender were included. Of these, 13 sustained a running related injury. No significant difference in cumulative relative risk between persons with pronated feet and neutral feet was found after 125 km of running (Cumulative relative risk = 1.65 [0.65; 4.17], p = 0.29). Similarly, no difference was found between low and neutral Q-angle (Cumulative relative risk = 1.25 [0.49; 3.23], p = 0.63). CONCLUSION: Static foot posture as quantified by FPI and knee alignment as quantified by Q-angle do not seem to affect the risk of injury among novice runners taking up a running regimen wearing a conventional neutral running shoe. These results should be interpreted with caution due to a small sample size. LEVEL OF EVIDENCE: 2a. PMID- 24175128 TI - Diagnostic accuracy of physical examination tests of the ankle/foot complex: a systematic review. AB - BACKGROUND: Orthopedic special tests of the ankle/foot complex are routinely used during the physical examination process in order to help diagnose ankle/lower leg pathologies. PURPOSE: The purpose of this systematic review was to investigate the diagnostic accuracy of ankle/lower leg special tests. METHODS: A search of the current literature was conducted using PubMed, CINAHL, SPORTDiscus, ProQuest Nursing and Allied Health Sources, Scopus, and Cochrane Library. Studies were eligible if they included the following: 1) a diagnostic clinical test of musculoskeletal pathology in the ankle/foot complex, 2) description of the clinical test or tests, 3) a report of the diagnostic accuracy of the clinical test (e.g. sensitivity and specificity), and 4) an acceptable reference standard for comparison. The quality of included studies was determined by two independent reviewers using the Quality Assessment of Diagnostic Accuracy Studies 2 (QUADAS 2) tool. RESULTS: Nine diagnostic accuracy studies met the inclusion criteria for this systematic review; analyzing a total of 16 special tests of the ankle/foot complex. After assessment using the QUADAS-2, only one study had low risk of bias and low concerns regarding applicability. CONCLUSION: Most ankle/lower leg orthopedic special tests are confirmatory in nature and are best utilized at the end of the physical examination. Most of the studies included in this systematic review demonstrate notable biases, which suggest that results and recommendations in this review should be taken as a guide rather than an outright standard. There is need for future research with more stringent study design criteria so that more accurate diagnostic power of ankle/lower leg special tests can be determined. LEVEL OF EVIDENCE: 3a. PMID- 24175129 TI - A proposed evidence-based shoulder special testing examination algorithm: clinical utility based on a systematic review of the literature. AB - OBJECTIVES: Attaining the highest possible level of diagnostic statistical probability assists the practitioner in making an optimal differential diagnosis between or among pathological conditions. The purpose of this manuscript is to accomplish two things. The first is to identify orthopedic shoulder physical examination special tests with the best clinical utility statistics to ease the diagnostic process through usage of an examination algorithm. The second is to expedite the diagnostic process by guiding the practitioner to select only the special tests that are necessary based on pattern recognition of common pathological conditions. METHODS: Systematic review of the literature identified the statistical clinical utility of common shoulder special tests used in physical examination, either singularly or in clusters. Quality assessment and statistical parameters were designed for inclusion criteria to determine diagnostic data for special test selection for the proposed algorithm. RESULTS: In the proposed shoulder examination algorithm, 15 of 26 special tests achieved the proposed statistical diagnostic threshold parameters for clinical utility. Achievement of proposed statistical diagnostic threshold parameters was accomplished for 6 pathological shoulder conditions; while 3 pathological shoulder conditions did not achieve these criteria. DISCUSSION: Large, randomized controlled trials that include patient history and all facets of the physical examination are lacking in the literature. Should diagnostic physical examination testing become more accurate, it is very possible that improved research can be accomplished, in order to establish clinical practice guidelines to help guide examination and treatment, patient management, and improve patient outcomes. LEVEL OF EVIDENCE: 1A. PMID- 24175130 TI - Return of normal gait as an outcome measurement in acl reconstructed patients. A systematic review. AB - BACKGROUND: Current clinical outcome measurements may overestimate the long term success of anterior cruciate ligament reconstruction (ACLR). There is a need to understand biomechanics of the knee joint during daily activities. This systematic review provides a comprehensive overview of the literature related to gait in patients following ACLR. The purpose of this systematic review was to investigate the available literature and provide a comprehensive overview of kinematic and kinetic variables that present during gait in patients after ACLR. METHODS: A literature search was performed in AMED, CINAHL, EMBASE, Medline and Scopus between January 2000 and October 2012. Inclusion criteria included articles written in English, German or Dutch, and those reporting on gait analysis in patients after ACLR. Kinematic and/or kinetic data of the uninjured and ACLR knee and healthy controls (CTRL) were outcome measurements of interest. Each study's methodological quality was assessed using the Critical Appraisal Skills Programme critical appraisal tool. RESULTS: Twenty two studies fulfilled the inclusion criteria. A total of 479 patients with a mean age of 27.3 were examined. Time between the injury and surgery and ranged from 3 weeks to 5.7 years. Gait analysis was done at a mean of 29.3 months after surgery. Gait was found to be altered in the sagittal, frontal and transverse planes after ACLR and may take months or years to normalize, if normalization occurs at all. CONCLUSION: Patients after ACLR have altered gait patterns that can persist for up to five years after surgery. It is imperative that rehabilitation techniques are examined in order to minimize changes in knee biomechanics during gait, as they have the potential to impact on the development of osteoarthritis. LEVEL OF EVIDENCE: 3a. PMID- 24175131 TI - Popliteus strain with concurrent deltoid ligament sprain in an elite soccer athlete: a case report. AB - STUDY DESIGN: Case Report (Differential diagnosis). BACKGROUND AND PURPOSE: Differential diagnosis of knee pathology after trauma may be difficult when diagnosing an isolated popliteus strain and concurrent medial deltoid ligament sprain. Upon a thorough search of the published literature, the authors found no reports delineating a popliteus strain in professional soccer in the United States. The joints most affected by injury in soccer players are the knee and ankle joints. The purpose of this case report is to describe the presentation of and difficulties encountered in diagnosing a popliteus strain in a Major League Soccer athlete. CASE DESCRIPTION: During an in-season away game, an outside defender was slide-tackled from behind when his right shank was caught in an externally rotated position underneath himself and the opposing player. The initial point of contact was made to the proximal third of the posterior right shank with an anteromedially directed force. The medial longitudinal arch of the foot was forced into a more midfoot pronated position and the subtalar joint was forced into eversion. DIAGNOSIS: The athlete was diagnosed with a moderate strain of the right popliteus muscle with a concurrent medial deltoid ligament sprain of the right ankle. This mechanism of injury, pain with passive knee flexion and internal rotation during McMurray's test, pain with Garrick's Test and magnetic resonance imaging (MRI) study confirmed the diagnosis. The athlete returned to full ninety-minute game participation after an intensive 15-day rehabilitation program. DISCUSSION: This case is unique because the injury manifested itself at multiple joints and specifically involved the popliteus muscle. The mechanism of injury can be associated with many other soft tissue injuries to the knee, and thus, may not lead the clinician initially to consider the diagnosis of a popliteus strain. Diagnosis of this entity may be difficult due to the possible shared attachment of the popliteus muscle to the lateral meniscus, and the lack of available testing methods to assess damage to the popliteus muscle. LEVEL OF EVIDENCE: Level 5. PMID- 24175132 TI - Differential diagnosis of deep gluteal pain in a female runner with pelvic involvement: a case report. AB - BACKGROUND: Gluteal injuries, proximal hamstring injuries, and pelvic floor disorders have been reported in the literature among runners. Some suggest that hip, pelvis, and/or groin injuries occur in 3.3% to 11.5% of long distance runners. The purpose of this case report is to describe the differential diagnosis and treatment approach for a patient presenting with combined hip and pelvic pain. CASE DESCRIPTION: A 45-year-old female distance runner was referred to physical therapy for proximal hamstring pain that had been present for several months. This pain limited her ability to tolerate sitting and caused her to cease running. Examination of the patient's lumbar spine, pelvis, and lower extremity led to the initial differential diagnosis of hamstring syndrome and ischiogluteal bursitis. The patient's primary symptoms improved during the initial four visits, which focused on education, pain management, trunk stabilization and gluteus maximus strengthening, however pelvic pain persisted. Further examination led to a secondary diagnosis of pelvic floor hypertonic disorder. Interventions to address the pelvic floor led to resolution of symptoms and return to running. OUTCOMES: Pain level on the Visual Analog Scale decreased from 7/10 to 1/10 over the course of treatment. The patient was able to return to full sport activity and improved sitting tolerance to greater then two hours without significant discomfort. DISCUSSION: This case suggests the interdependence of lumbopelvic and lower extremity kinematics in complaints of hamstring, posterior thigh and pelvic floor disorders. This case highlights the importance of a thorough examination as well as the need to consider a regional interdependence of the pelvic floor and lower quarter when treating individuals with proximal hamstring pain. LEVEL OF EVIDENCE: Level 4. PMID- 24175133 TI - Residents case report: deep vein thrombosis in a high school baseball pitcher following ulnar collateral ligament (ucl) reconstruction. AB - BACKGROUND AND PURPOSE: Accurate diagnosis of deep vein thrombosis in an outpatient setting is difficult; however, proper screening and prompt referral can be lifesaving. The purpose of this case report is to present the unusual findings of a Deep Vein Thrombosis (DVT) in an otherwise healthy young male following an upper extremity surgery. CASE DESCRIPTION: An 18 year-old male high school baseball pitcher presented to the clinic for his four month follow up visit after Ulnar Collateral Ligament (UCL) reconstruction surgery. Patient complained of a recent "groin strain" and "calf strain" following baseball conditioning, that upon examination demonstrated signs and symptoms consistent with a deep vein thrombosis (DVT). OUTCOMES: Following emergent referral the patient was diagnosed with multiple emboli and was treated with Lovenox and Coumadin. DISCUSSION: Lower extremity DVT is a serious and potentially life threatening disorder. Physical therapists need to be vigilant in their subjective and objective examination of any patient that presents with lower extremity pain and swelling. This case report presents the unlikely findings of a DVT in a young, healthy, male high school baseball pitcher after surgical repair of the UCL. LEVEL OF EVIDENCE: 4. PMID- 24175136 TI - The role of the sports physical therapist-marathon events. AB - The role of the Sports physical therapist (PT) as a part of the sports medical team at marathon-type events varies widely. The PT can assume the role of an emergency medical responder (EMR) whose primary role is the management of the athlete in emergency type situations. The role of the EMR extends beyond the care of the athlete to the care and safety of the spectators. In this role, the PT must be prepared to handle any type of emergency situation, which may occur from medical conditions to acute orthopedic/sports injuries, to medical conditions which may be found in the participants of the race or the spectators. Additional roles of the PT can be in pre-race education, pre-participation screening/physicals, and other concerns by the participant related to injury prevention. Regardless of the role assumed by the PT, prior planning is essential for the safety, security, and maximal performance of the participant and to make the race enjoyable and safe for everyone. LEVEL OF EVIDENCE: 5. PMID- 24175134 TI - A phased rehabilitation protocol for athletes with lumbar intervertebral disc herniation. AB - Conservative non-surgical management of a herniated lumbar intervertebral disc (HLD) in athletes is a complex task due to the dramatic forces imparted on the spine during sport participation. The demands placed upon the athlete during rehabilitation and return to sport are unique not only from a sport specific perspective, but also regarding return to the sport strength and conditioning programs utilized for sport preparation. Many prescriptions fail to address postural and motor control faults specific to athletic development, which may prevent full return to sport after suffering a HLD or predispose the athlete to future exacerbations of a HLD. Strength exercises involving squatting, deadlifting, and Olympic power lifts are large components of the typical athlete's conditioning program, therefore some progressions are provided to address potential underlying problems in the athlete's technique that may have contributed to their HLD in the first place. The purpose of this clinical commentary is to propose a framework for rehabilitation that is built around the phases of healing of the disc. Phase I: Non-Rotational/Non-Flexion Phase (Acute Inflammatory Phase), Phase II: Counter rotation/Flexion Phase (Repair Phase), Phase III: Rotational Phase/Power development (Remodeling Phase), and Phase IV: Full return to sport. This clinical commentary provides a theoretical basis for these phases based on available literature as well as reviewing many popular current practice trends in the management of an HLD. The authors recognize the limits of any general exercise rehabilitation recommendation with regard to return to sport, as well as any general strength and conditioning program. It is vital that an individual assessment and prescription is made for every athlete which reviews and addresses movement in all planes of motion under all necessary extrinsic and intrinsic demands to that athlete. LEVEL OF EVIDENCE: 5. PMID- 24175135 TI - Balance training for the older athlete. AB - As the older adult population increases in size, the number of older adults participating in sport activities will also likely increase proportionally with a concomitant increase in musculoskeletal injuries. Age-associated functional declines in muscle strength and the sensory systems, in addition to several other issues, contribute to reductions in balance that may increase fall risk There are a variety of ways to evaluate balance and fall-risk, and each older adult should be regularly screened in order to evaluate any changes in the ability to maintain postural stability. Balance training is a useful intervention in rehabilitation of postural stability impairments as well as in training programs for performance enhancement. One scientifically-based approach is Sensorimotor Training (SMT) which can be characterized as a progressive balance training program using labile surfaces to provide adequate and safe challenges to the older athlete's balance. SMT addresses both static and dynamic components of balance as well as the multitude of systems that control balance in order to train effective strategies and elicit automatic postural responses in order to enhance postural stability. The authors believe that SMT should become part of the regular training regimen for the aging athlete. For the sport and orthopedic healthcare professional, an understanding of the physiologic changes that occur with age, the means by which balance can be assessed, and how SMT programs can be developed and implemented is crucial in addressing the growing number of older athletes that they will see. LEVEL OF EVIDENCE: 5. PMID- 24175137 TI - Glenohumeral motion deficits: friend or foe? AB - In most shoulder conditions a loss of glenohumeral motion results in shoulder performance impairments. However, in the overhead athlete loss of glenohumeral internal rotation, termed glenohumeral internal rotation deficiency (GIRD), is a normal phenomenon that should be expected. Without a loss of glenohumeral internal rotation the overhead athlete will not have the requisite glenohumeral external rotation needed to throw a baseball at nearly 100 miles per hour, or serve a tennis ball at velocities of 120 miles per hour or more. Not all GIRD is pathologic. The authors of this manuscript have defined two types of GIRD; one that is normal and one that is pathologic. Anatomical GIRD (aGIRD) is one that is normal in overhead athletes and is characterized by a loss of internal rotation of less than 18 degrees -20 degrees with symmetrical total rotational motion (TROM) bilaterally. Pathologic GIRD (pGIRD) is when there is a loss of glenohumeral internal rotation greater than 18 degrees -20 degrees with a corresponding loss of TROM greater than 5 degrees when compared bilaterally. A more problematic motion restriction may be that of a loss of TROM in the glenohumeral joint. Recent evidence supports that a loss of TROM is predictive of future injury to the shoulder in professional athletes. Additionally, external rotation deficiency (ERD), the difference between external rotation (ER) of the throwing shoulder and the non-throwing shoulder of less than 5 degrees , may be another predictor of future shoulder injury and disability. LEVEL OF EVIDENCE: 5. PMID- 24175138 TI - Current concepts in shoulder examination of the overhead athlete. AB - Examination of the shoulder complex has long been described as challenging. This is particularly true in the examination of the overhead athlete who has structural differences when compared to a shoulder patient who is a non-athlete. Complexity with the examination is due to unique biomechanical and structural changes, multiple joint articulations, multiple pain patterns, and the potential of injury to structures both inside (intra-articular) and outside (extra articular) the glenohumeral joint. Repetitive stresses placed on the shoulders of overhead athletes may affect range of motion, strength, scapular position, and ultimately, the integrity of soft tissue and bony structures in any of the joints that comprise the shoulder complex. Furthermore, many shoulder examination tests thought to be unique to a single structure, joint, or condition can be positive in multiple conditions. The examination of the overhead athletes shoulder, coupled with a thorough medical history will provide a solid foundation to allow a functional physical therapy diagnosis and provide clues as to the presence of the lesion (s) causing disability. The purpose of this clinical commentary is to assist the reader to understand the unique physical characteristics of the overhead athlete, which will lead to a more accurate and reproducible evaluation of athletes who sustain injuries while participating in overhead sports. LEVEL OF EVIDENCE: 5. PMID- 24175139 TI - The recognition and treatment of superior labral (slap) lesions in the overhead athlete. AB - The overhead athlete presents with a unique profile that may predispose them to specific pathology. Injury to the superior aspect of the glenoid labrum (SLAP lesions) poses a significant challenge to the rehabilitation specialist due to the complex nature and wide variety of etiological factors associated with these lesions. A thorough clinical evaluation and proper identification of the extent of labral injury is important in order to determine the most appropriate non operative and/or surgical management. Postoperative rehabilitation is based on the specific surgical procedure that has been performed, as well as the extent, location, and mechanism of labral pathology and associated lesions. Emphasis is placed on protecting the healing labrum while gradually restoring range of motion, strength, and dynamic stability of the glenohumeral joint. The purpose of this paper is to provide an overview of the anatomy and pathomechanics of SLAP lesions and review specific clinical examination techniques used to identify these lesions in the overhead athlete. Furthermore, a review of the current surgical management and postoperative rehabilitation guidelines is provided. LEVEL OF EVIDENCE: 5. PMID- 24175140 TI - Microinstability of the shoulder in the overhead athlete. AB - The overhead throwing athlete is an extremely challenging patient in sports medicine. The repetitive microtraumatic stresses and extreme ranges of motion observed within the athlete's shoulder joint complex during the throwing motion constantly place the athlete at risk for injury. While gross instability of the shoulder is possible, microinstability is seen far more frequently and is associated with a variety of different pathologies, including rotator cuff tendonitis, internal impingement, and labral lesions. Treatment of the overhead athlete requires the understanding of several principles based on the unique physical characteristics of this type of athlete and the demands placed upon the static stabilizing structures during the act of throwing. The purpose of this paper is to describe these principles and incorporate them into in a multi-phase progressive rehabilitation program designed to prevent injuries and rehabilitate the injured athlete, both non-operatively and postoperatively. PMID- 24175141 TI - The role of the scapula. AB - Previously, the scapular musculature was often neglected in designing a rehabilitation protocol for the shoulder. In the past two decades a significant amount of research has been performed in order to help identify the role of the scapula in upper extremity function. Weakness of the scapular stabilizers and resultant altered biomechanics could result in: 1) abnormal stresses to the anterior capsular structures of the shoulder, 2) increased possibility of rotator cuff compression, and 3) decreased shoulder complex neuromuscular performance. This clinical commentary presents facts about the anatomy and biomechanics of the scapula and surrounding musculature, and describes the pathomechanics of scapular dysfunction. The focus is upon the assessment of dysfunction and retraining of the scapular musculature. LEVEL OF EVIDENCE: 5. PMID- 24175142 TI - Throwing injuries in the adolescent athlete. AB - INTRODUCTION: Adolescents ranging in age from 11-15 (early-mid adolescence) comprise the largest percentage of baseball and softball athletes in the United States. Shoulder and elbow injuries are commonly experienced by these athletes with baseball pitchers and softball position players most likely to be injured. COMMON INJURIES: Physeal injury often termed "Little League" shoulder or elbow is common and should be differentiated from soft tissue injuries such as biceps, rotator cuff, or UCL injuries. Regardless of diagnosis, rehabilitation of these athletes' shoulder and elbow injuries provide a unique challenge given their rapidly changing physical status. TREATMENT: Common impairments include alterations in shoulder range of motion, decreased muscle performance, and poor neuromuscular control of the scapula, core, and lower extremity. A criterion based, progressive rehabilitation program is presented. Discharge from formal rehabilitation should occur only when the athlete has demonstrated a resolution of symptoms, acceptable ROM, muscle performance, and neuromuscular control while progressing through a symptom free return to sport. PREVENTION OF REINJURY: Reintegration into the desired level of sport participation should be guided by the sports medicine professional with a focus on long-term durability in sport performance as well as injury prevention. A prevention program which includes parent, coach, and athlete education, regular screening to identify those athletes at the highest risk, and monitoring athletes for the development of risk factors or warning signs of injury over the course of participation is indicated. LEVEL OF EVIDENCE: 5. PMID- 24175143 TI - Diagnostic imaging of the throwing athlete's shoulder. AB - The diagnostic capabilities of advanced imaging have increasingly enabled clinicians to delineate between structural alterations and injuries more efficiently than ever before. These impressive gains have unfortunately begun to provide a reliance on imaging at the loss of quality in the clinical examination. Ideally, imaging of the shoulder complex is performed to confirm the provisional diagnosis developed from the history and clinical exam rather than to create such. This clinical commentary will provide the framework for both basic and advanced uses of imaging as well as discussion of evolving modalities. LEVEL OF EVIDENCE: 5. PMID- 24175144 TI - Pitching mechanics, revisited. AB - The overhead pitching motion is described as a coordinated sequence of body movements and muscular forces that have an ultimate goal of achieving high ball velocity and target accuracy. An understanding of the dynamic overhead throwing motion outlined in this clinical commentary can assist the clinician in addressing the unique injuries experienced by the pitcher. The potential biomechanical sources for injury have been studied utilizing videography and electromyographic techniques due to the rapid pace with which the pitching motion occurs. This clinical comentary will describe what is widely accepted as the six phases of the pitching motion and the relationship to the kinetic chain theory as well as outline the common mechanical faults that can lead to increased tissue stress and potential injury. LEVEL OF EVIDENCE: 5. PMID- 24175145 TI - Relationship between hip strength and trunk, hip, and knee kinematics during a jump-landing task in individuals with patellofemoral pain. AB - BACKGROUND/PURPOSE: Decreased strength of the hip musculature and altered mechanics of the lower extremity have been identified in individuals with patellofemoral pain (PFP). The aim of this study was to determine if a relationship exists between hip muscle strength and transverse and frontal plane motion at the hip and knee, and ipsilateral trunk flexion during a jump-landing task in individuals with PFP. METHODS: Fifteen individuals (10 females, 5 males) with PFP participated in this investigation. A three-dimensional motion analysis system was utilized to assess trunk, hip, and knee kinematics during a jump landing task. An isokinetic dynamometer was utilized to assess concentric and eccentric strength of the hip musculature. Simple correlation analyses were performed to determine the relationships between hip muscle strength and peak frontal and transverse plane hip and knee kinematics and ipsilateral trunk flexion. RESULTS: Decreased eccentric strength of the hip external rotators and abductors was significantly correlated to increased frontal plane motion at the hip and trunk, respectively (P<0.05). CONCLUSIONS: Based on these findings, eccentric strengthening exercises for the hip musculature may be an important component for clinicians to include when rehabilitating individuals with PFP who display increased frontal plane motion at the hip and trunk. LEVEL OF EVIDENCE: 2b. PMID- 24175146 TI - The role of rehabilitation following autologous chondrocyte implantation: a retrospective chart review. AB - PURPOSE/BACKGROUND: Clinical outcomes following autologous chondrocyte implantation (ACI) are influenced by multiple factors, including patient demographics, lesion characteristics, quality of the surgical repair, and post operative rehabilitation. However, it is currently unknown what specific characteristics of rehabilitation have the greatest influence on clinical outcomes following ACI. The purpose of this study was to conduct a retrospective chart review of patients undergoing ACI with the intent to describe this patient population's demographics, clinical outcomes, and rehabilitation practices. This study aimed to assess the consistency of the documentation process relative to post-operative rehabilitation in order to provide information and guide initiatives for improving the quality of rehabilitation practices following ACI. METHODS: The medical records of patients treated for chondral defect(s) of the knee who subsequently underwent the ACI procedure were retrospectively reviewed. A systematic review of medical, surgical, and rehabilitation records was performed. In addition, patient-reported outcome measures (IKDC, WOMAC, Lysholm, SF-36) recorded pre-operatively, and 3, 6, and 12 months post-operatively were extracted from an existing database. RESULTS: 20 medical charts (35.9 +/- 6.8 years; 9 male, 11 female) were systematically reviewed. The average IKDC, WOMAC, Lysholm, and SF-36 scores all improved from baseline to 3, 6 and 12 months post operatively, with the greatest changes occurring at 6 and 12 months. There was inconsistent documentation relative to post-operative rehabilitation, including CPM use, weight-bearing progression, home-exercise compliance, and strength progressions. CONCLUSIONS: Due to variations in the documentation process, the authors were unable to determine what specific components of rehabilitation influence the recovery process. In order to further understand how rehabilitation practices influence outcomes following ACI, specific components of the rehabilitation process must be consistently and systematically documented over time. LEVEL OF EVIDENCE: 2C. PMID- 24175147 TI - Concurrent validity of digital inclinometer and universal goniometer in assessing passive hip mobility in healthy subjects. AB - BACKGROUND: Hip range of motion is an important component in assessing clinical orthopedic conditions of the hip, low back and lower extremities. However it remains unclear as to what constitutes the best tool for clinical measurement. The purpose of this study was to investigate the concurrent validity of passive range of motion (ROM) measurements of hip extension and hip internal and external rotation using a digital inclinometer and goniometer. DESIGN: Criterion Standard. SETTING: Clinical research laboratory. PARTICIPANTS: 30 healthy subjects without pain, radicular symptoms or history of surgery in the low back or hip regions. MAIN OUTCOME MEASURES: Passive hip range of motion for extension, hip internal rotation and hip external rotation. A digital inclinometer and universal goniometer were utilized as the tools for comparisons between measurements. RESULTS: There was a statistically significant difference (p < 0.05) between the goniometer and digital inclinometer in measured hip ROM except for measurements of right hip external rotation (p > 0.05). The mean difference between the goniometer and digital inclinometer in left hip extension, internal rotation and external rotation were 3.5 degrees , 4.5 degrees and 5.0 degrees respectively. The mean difference between the two devices in right hip extension, internal rotation and external rotation were 2.8 degrees , 4.2 degrees and 2.6 degrees respectively. On average, the difference between the goniometer and digital inclinometer in extension was 3.2 degrees , internal rotation was 4.5 degrees and external rotation was 3.8 degrees . The digital inclinometer had greater measurement during EXT and ER. Furthermore, there was no statistically significant difference (p > 0.05) in hip ROM between the left and right side for either goniometric or digital inclinometer measurements. CONCLUSIONS: This results of this study indicate that a significant difference exists between the two devices in all measurements with exception of right hip extension. The differences were noted to be between 3-5 degrees for all planes measured. These findings suggest that caution should be used if these two devices are to be used interchangeably to quantify passive hip range of motion in either clinical practice or when comparing studies that utilize different instruments. LEVEL OF EVIDENCE: 2b. PMID- 24175148 TI - Proximal exercises are effective in treating patellofemoral pain syndrome: a systematic review. AB - BACKGROUND: Patellofemoral pain syndrome is a common disorder of the knee with multifactorial aetiology. Multimodal treatment, including exercise therapy, has been shown to be effective in the treatment of patellofemoral pain, although some patients continue to experience pain and dysfunction despite treatment. To address this, recent research has started to investigate the lumbo-pelvic and hip girdle in patellofemoral pain. PURPOSE: The aim of this systematic review was to investigate the effectiveness of proximal exercises, compared with knee exercises, for patients with patellofemoral pain, in improving pain and function. METHODS: A computer-based search (population: patients with patellofemoral pain, intervention: proximal [hip or lumbo-pelvic] exercises, comparator: knee exercises, outcome: self-reported pain and/or functional questionnaire) was undertaken. Medline, Embase, CINAHL, SportsDiscus, Cochrane Library and PEDro were searched for studies published between January 2011 and January 2013. The included studies were appraised independently using the McMaster Critical Review Form for Quantitative Studies. Data was extracted for the exercise prescription and applicable outcome measures, and a descriptive analysis undertaken. RESULTS: Eight studies (three randomized controlled trials, one clinical controlled trial, three cohort studies and one case series) of moderate to high methodological quality met the inclusion criteria. Proximal exercise programs showed a consistent reduction of pain and function in the treatment of patellofemoral pain. Knee exercise programs had variable outcomes. CONCLUSION: Proximal interventions provide relief of pain and improved function in the short and long term and therefore physical therapists should consider using proximal interventions for treatment of patellofemoral pain. LEVEL OF EVIDENCE: 3a. PMID- 24175149 TI - Post-surgical rehabilitation following fasciotomies for bilateral chronic exertional compartment syndrome in a special forces soldier: a case report. AB - BACKGROUND AND PURPOSE: The etiology of Chronic Exertional Compartment Syndrome (CECS) is still unclear. The most commonly accepted theory suggests that it is a transient but debilitating process where there is an abnormally increased intracompartmental pressure during exercise/exertion due to non-compliant expansion of the osteofascial tissues. This most commonly occurs in the lower leg. Surgical intervention is often performed for symptom relief. However, there has been limited scientifically-based publication on post-surgical rehabilitation, especially with regard to return to function in the military population. The purpose of this case report is to demonstrate the utilization of a recommended post-operative protocol in a Special Forces Soldier. CASE DESCRIPTION: The subject presented as a 25-year-old US Army Special Forces Soldier, who failed 8 weeks of conservative management for the diagnosis of CECS and subsequently underwent bilateral lower leg fasciotomies of the anterior and lateral compartments. OUTCOMES: Following recommended protocol guidelines he was progressed rapidly and within three months deployed without restriction or complications in a demanding combat zone. DISCUSSION: This case report illustrates that following clearly defined, scientifically-based rehabilitation guidelines helped in addressing all of the involved structures and musculoskeletal dysfunctions that presented following the surgical intervention for CECS in a unique subject. LEVEL OF EVIDENCE: 5. PMID- 24175150 TI - The role of prism glass and postural restoration in managing a collegiate baseball player with bilateral sacroiliac joint dysfunction: a case report. AB - BACKGROUND AND PURPOSE: Sacroiliac joint dysfunction (SIJD) is a condition affecting 15-30% of patients with low back pain seen in outpatient clinics. Currently there is no well-defined standard of care. The purpose of this case report is to discuss the multidisciplinary management between an athletic trainer and an optometrist for an athlete with bilateral SIJ dysfunction and a visual midline shift syndrome. CASE DESCRIPTION: A 21-year-old collegiate baseball player reported to the athletic training room, presenting with low back pain of three day duration, with tenderness over both posterior superior iliac spines (PSIS) (left > right). His pain at its worse was a 7/10 on the Numeric Pain Scale (NPS). The pain increased to the point that it limited his activities of daily living (ADLs) including getting dressed, putting on his shoes, sleeping, and getting in and out of a car. INTERVENTIONS: The athlete was initially treated using traditional muscle energy techniques (MET) based intervention to correct SIJD, and lumbar stabilization exercises directed by a licensed athletic trainer, as well as manipulation by a chiropractor. Three weeks of treatment did not prove to be beneficial with only a minimal (1 point on the NPRS) decrease in pain. The athlete was then referred to the head athletic trainer for consultation who prescribed orthotics, for bilateral rear-foot valgus, and Postural Restoration (PR) therapeutic exercises. After two weeks of orthotic use and PR exercises the athlete's pain decreased one additional point on the NPRS. Due to lack of progress, an optometrist was then consulted. The neuro-optometrist prescribed 2 diopter base-down prisms to be worn two hours a day, for four weeks. After four weeks of prisms and new exercises, the athlete was asymptomatic and returned to full pain-free baseball participation without further complications. OUTCOMES: The Oswestry Disability Index Questionnaire (ODI) was 48% at initial (severe disability), 40% at five weeks and 0% at discharge. The Numeric Pain Scale (NPS) score went from 7/10 to 0/10. DISCUSSION: The athlete demonstrated only minimal relief of symptoms following MET, therapeutic exercises, and chiropractic manipulation. Intervention using prism glasses and PR exercises, designed to optimize posture and correct his visual midline shift syndrome, led to complete resolution of his symptoms. EVIDENCE LEVEL: 3a. PMID- 24175151 TI - Restricted hip mobility: clinical suggestions for self-mobilization and muscle re education. AB - Restricted hip mobility has shown strong correlation with various pathologies of the hip, lumbar spine and lower extremity. Restricted mobility can consequently have deleterious effects not only at the involved joint but throughout the entire kinetic chain. Promising findings are suggesting benefit with skilled joint mobilization intervention for clients with various hip pathologies. Supervised home program intervention, while lacking specifically for the hip joint, are demonstrating promising results in other regions of the body. Application of an accompanying home program for the purpose of complementing skilled, in clinic intervention is advisable for those clients that respond favorably to such methodology. LEVEL OF EVIDENCE: 5. PMID- 24175153 TI - The dual role of IRF8 in cancer immunosurveillance. AB - For a long time, the transcription factor interferon-regulatory factor 8 (IRF8) has been recognized as a masterpiece for the development of myeloid cells, and its role as a central regulator of immune responses has now been clarified. IRF8 is also critical for tumor progression, suggesting its fundamental relevance in multiple aspects of cancer immunosurveillance. PMID- 24175152 TI - 12/15-Lipoxygenase inhibition counteracts MAPK phosphorylation in mouse and cell culture models of diabetic peripheral neuropathy. AB - BACKGROUND: Increased mitogen-activated protein kinase (MAPK) phosphorylation has been detected in peripheral nerve of human subjects and animal models with diabetes as well as high-glucose exposed human Schwann cells, and have been implicated in diabetic peripheral neuropathy. In our recent studies, leukocytetype 12/15-lipoxygenase inhibition or gene deficiency alleviated large and small nerve fiber dysfunction, but not intraepidermal nerve fiber loss in streptozotocin-diabetic mice. METHODS: To address a mechanism we evaluated the potential for pharmacological 12/15-lipoxygenase inhibition to counteract excessive MAPK phosphorylation in mouse and cell culture models of diabetic neuropathy. C57Bl6/J mice were made diabetic with streptozotocin and maintained with or without the 12/15-lipoxygenase inhibitor cinnamyl-3,4-dihydroxy-alpha cyanocinnamate (CDC). Human Schwann cells were cultured in 5.5 mM or 30 mM glucose with or without CDC. RESULTS: 12(S) HETE concentrations (ELISA), as well as 12/15-lipoxygenase expression and p38 MAPK, ERK, and SAPK/JNK phosphorylation (all by Western blot analysis) were increased in the peripheral nerve and spinal cord of diabetic mice as well as in high glucose-exposed human Schwann cells. CDC counteracted diabetes-induced increase in 12(S)HETE concentrations (a measure of 12/15-lipoxygenase activity), but not 12/15-lipoxygenase overexpression, in sciatic nerve and spinal cord. The inhibitor blunted excessive p38 MAPK and ERK, but not SAPK/ JNK, phosphorylation in sciatic nerve and high glucose exposed human Schwann cells, but did not affect MAPK, ERK, and SAPK/JNK phosphorylation in spinal cord. CONCLUSION: 12/15-lipoxygenase inhibition counteracts diabetes related MAPK phosphorylation in mouse and cell culture models of diabetic neuropathy and implies that 12/15-lipoxygenase inhibitors may be an effective treatment for diabetic peripheral neuropathy. PMID- 24175154 TI - Diagnosis and management of idiopathic normal-pressure hydrocephalus. AB - The diagnosis and management of idiopathic normal-pressure hydrocephalus (iNPH), a disorder of gait impairment, incontinence, and dementia that affects elderly patients, incorporates an organized approach using familiar principles for neurologists. The starting point is a comprehensive history and neurologic examination, review of neuroimaging, and evaluation of the differential diagnosis. Coexisting disorders should be treated before specific iNPH testing is performed. Specific iNPH testing includes assessing patient response to temporary CSF removal and testing CSF hydrodynamics. In properly selected patients, all iNPH symptoms, including dementia, can improve after shunt surgery. The longitudinal care of iNPH patients with shunts includes evaluation of the differential diagnosis of worsening iNPH symptoms and treatment of coexisting disorders. Evaluation of shunt obstruction is often indicated, and if it is found, surgical correction is likely to result in symptomatic improvement. PMID- 24175155 TI - Hydration status substantially affects chronic cerebrospinal venous insufficiency assessments. AB - We sought to determine the effect of hydration on the criteria for chronic cerebrospinal venous insufficiency (CCSVI), a proposed hypothesis for the etiology of multiple sclerosis (MS). Sixteen subjects (11 MS and 5 controls) were asked to fast overnight. The following morning, 2 CCSVI ultrasound examinations were performed: 1 in the mildly dehydrated state, and another 30-45 minutes after rehydrating with 1.5 L of Gatorade. Seven subjects fulfilled CCSVI criteria in the dehydrated state. Of these, 5 (71%) no longer fulfilled CCSVI criteria after rehydration. One additional subject met CCSVI criteria only after rehydration. Hydration status has a substantial effect on CCSVI criteria, suggesting that the sonographic findings of CCSVI may represent a physiologic rather than pathologic state. PMID- 24175156 TI - Multiple sclerosis: Five new things. AB - Preliminary studies have suggested that a high salt diet may play a role in the development of autoimmune disease and possibly multiple sclerosis (MS). Promising clinical trial results for 2 new therapies for MS have been reported. Dimethyl fumarate, also known by its investigational name BG-12, became the third oral disease-modifying therapy for MS to be Food and Drug Administration (FDA) approved in March 2013. Interestingly, dimethyl fumarate served as the active compound used for the treatment of psoriasis for decades. Alemtuzumab remains under investigation and is not currently FDA-approved for treatment of MS. Other drugs currently approved for alternative indications are being investigated for use in MS. Additionally, an investigation of alternative dosing strategies for glatiramer acetate suggests that patients may benefit from a higher dose formulation and less frequent medication administration. Advances in basic science research have identified another potential autoantigenic target in MS, KIR4.1, which may provide further insight into MS pathophysiology. PMID- 24175157 TI - Reading a cost-effectiveness or decision analysis study: Five things to consider. AB - Cost-effectiveness studies and decision analyses of neurologic practices, treatments, and technologies are increasing in the literature and have an emerging role within both medicine and neurology. Knowledge about these research approaches, how to interpret the results of such studies, as well as an understanding of their limitations will be of growing importance for the practicing neurologist. We discuss 5 aspects of these analyses to increase awareness about the uses and limitations of cost-effectiveness articles in everyday practice. PMID- 24175158 TI - Expenditures in the elderly with peripheral neuropathy: Where should we focus cost-control efforts? AB - To optimize care in the evaluation of peripheral neuropathy, we sought to define which tests drive expenditures and the role of the provider type. We investigated test utilization and expenditures by provider type in those with incident neuropathy in a nationally representative elderly, Medicare population. Multivariable logistic regression was used to determine predictors of MRI and electrodiagnostic utilization. MRIs of the neuroaxis and electrodiagnostic tests accounted for 88% of total expenditures. Mean and aggregate diagnostic expenditures were higher in those who saw a neurologist. Patients who saw a neurologist were more likely to receive an MRI and an electrodiagnostic test. MRIs and electrodiagnostic tests are the main contributors to expenditures in the evaluation of peripheral neuropathy, and should be the focus of future efficiency efforts. PMID- 24175159 TI - Cost-effectiveness analyses: Beauty and the beast? AB - In this issue of Neurology(r) Clinical Practice, Young et al.1 discuss 5 things to consider in reading a cost-effectiveness or decision analysis study. Such studies are necessary as the medical profession wrestles with caring for patients and paying for that care. The approaches discussed by Young et al. are important to digest as this type of study will be more prevalent as pressures mount in all aspects of clinical and comprehensive care. Young et al. point out the need to interpret the models and understand the meaning of the data presented. Their article provides an excellent summary of the tools and approaches widely used by policymakers and researchers, bringing some systematic evaluation to the pressures of cost vs the benefits of therapy. PMID- 24175160 TI - What is the purpose of launching the World Journal of Psychiatry? AB - The first issue of World Journal of Psychiatry (WJP), whose preparatory work was initiated on May 18, 2011, will be published on December 31, 2011. The WJP Editorial Board has now been established and consists of 103 distinguished experts from 32 countries. Our purpose of launching WJP is to publish peer reviewed, high-quality articles via an open-access online publishing model, thereby acting as a platform for communication between peers and the wider public, and maximizing the benefits to editorial board members, authors and readers. PMID- 24175161 TI - Family interventions in schizophrenia: Issues of relevance for Asian countries. AB - A growing body of research evidence has confirmed the efficacy of family interventions as adjuncts to antipsychotics for the treatment of schizophrenia. Much of the recent evidence for such interventions derives from Asian, principally Chinese, studies. These trials have shown that relatively simple forms of family-interventions have wide ranging benefits, and can be implemented successfully in routine clinical settings. With the accumulation of this evidence in their favour, family-interventions for schizophrenia in Asia are poised to take the next critical step, that of wider implementation and improved accessibility for potential users. However, several issues merit consideration. Family-interventions need to be based on a culturally-informed theory, which incorporates cultural variables of relevance in these countries. While the ideal format for conducting family-interventions is still to be determined, it is quite evident that for such interventions to be useful they need to be simple, inexpensive, needs-based, and tailored to suit the socio-cultural realities of mental health systems in Asian countries. The evidence also suggests that delivery by non-specialist personnel is the best way to ensure that such services reach those who stand to benefit most from these treatments. However, there are several existing challenges to the process of dissemination of family interventions. The major challenges include the achievement of a critical mass of trained professionals capable of delivering these interventions, and finding innovative solutions to make family-interventions more acceptable to families. If these hurdles are overcome, we could look forward to a genuine collaboration with families, who have always been the mainstay of care for the mentally ill in Asia. PMID- 24175163 TI - Graph-based network analysis in schizophrenia. AB - Over the last few years, many studies have been published using modern network analysis of the brain. Researchers and practical doctors alike should understand this method and its results on the brain evaluation at rest, during activation and in brain disease. The studies are noninvasive and usually performed with elecroencephalographic, magnetoencephalographic, magnetic resonance imaging and diffusion tensor imaging brain recordings. Different tools for analysis have been developed, although the methods are in their early stages. The results of these analyses are of special value. Studies of these tools in schizophrenia are important because widespread and local network disturbances can be evaluated by assessing integration, segregation and several structural and functional properties. With the help of network analyses, the main findings in schizophrenia are lower optimum network organization, less efficiently wired networks, less local clustering, less hierarchical organization and signs of disconnection. There are only about twenty five relevant papers on the subject today. Only a few years of study of these methods have produced interesting results and it appears promising that the development of these methods will present important knowledge for both the preclinical signs of schizophrenia and the methods' therapeutic effects. PMID- 24175162 TI - Cerebrospinal fluid and blood biomarkers in Alzheimer's disease. AB - Due to an ever aging society and growing prevalence of Alzheimer's disease (AD), the challenge to meet social and health care system needs will become increasingly difficult. Unfortunately, a definite ante mortem diagnosis is not possible. Thus, an early diagnosis and identification of AD patients is critical for promising, early pharmacological interventions as well as addressing health care needs. The most advanced and most reliable markers are beta-amyloid, total tau and phosphorylated tau in cerebrospinal fluid (CSF). In blood, no single biomarker has been identified despite an intense search over the last decade. The most promising approaches consist of a combination of several blood-based markers increasing the reliability, sensitivity and specificity of the AD diagnosis. However, contradictory data make standardized testing methods in longitudinal and multi-center studies extremely difficult. In this review, we summarize a range of the most promising CSF and blood biomarkers for diagnosing AD. PMID- 24175165 TI - Individualized music for dementia: Evolution and application of evidence-based protocol. AB - The theory-based intervention of individualized music has been evaluated clinically and empirically leading to advancement and refinement of an evidence based protocol, currently in its 5th edition. An expanded version of the protocol was written for professional health care providers with a consumer version tailored for family caregivers. The underlying mid-range theory is presented along with a seminal study that was followed by further research in the United States, Canada, Great Britain, France, Sweden, Norway, Japan and Taiwan. Key studies are summarized. Given its efficacy when implemented by research staff, studies have advanced to testing the intervention under real-life conditions when implemented and evaluated by trained nursing assistants in long-term care facilities and visiting family members. In addition, one study evaluated the implementation of music by family members in the home setting. Initial research focused on agitation as the dependent variable with subsequent research indicating a more holistic response such as positive affect, expressed satisfaction, and meaningful interaction with others. The article advances by describing on-line programs designed to train health care professionals in the assessment, implementation and evaluation of individualized music. In addition, Gerdner has written a story for a picture book intended for children and their families (in press). The story models principles of individualized music to elicit positive memories, reduce anxiety and agitation, and promote communication. The article concludes with implications for future research. PMID- 24175164 TI - Childhood stressful events, HPA axis and anxiety disorders. AB - Anxiety disorders are among the most common of all mental disorders and their pathogenesis is a major topic in psychiatry, both for prevention and treatment. Early stressful life events and alterations of hypothalamic pituitary adrenal (HPA) axis function seem to have a significant role in the onset of anxiety. Existing data appear to support the mediating effect of the HPA axis between childhood traumata and posttraumatic stress disorder. Findings on the HPA axis activity at baseline and after stimuli in panic disordered patients are inconclusive, even if stressful life events may have a triggering function in the development of this disorder. Data on the relationship between stress, HPA axis functioning and obsessive-compulsive disorder (OCD) are scarce and discordant, but an increased activity of the HPA axis is reported in OCD patients. Moreover, normal basal cortisol levels and hyper-responsiveness of the adrenal cortex during a psychosocial stressor are observed in social phobics. Finally, abnormal HPA axis activity has also been observed in generalized anxiety disordered patients. While several hypothesis have attempted to explain these findings over time, currently the most widely accepted theory is that early stressful life events may provoke alterations of the stress response and thus of the HPA axis, that can endure during adulthood, predisposing individuals to develop psychopathology. All theories are reviewed and the authors conclude that childhood life events and HPA abnormalities may be specifically and transnosographically related to all anxiety disorders, as well as, more broadly, to all psychiatric disorders. PMID- 24175166 TI - Risks of suicidality in adult patients with epilepsy. AB - AIM: To determine the prevalence and risks of suicidality in a group of patients with epilepsy. METHODS: Included were 200 adult patients and 100 matched healthy subjects. The clinical interview using The Diagnostic and Statistical Manual of Mental Disorders (4th edition), Beck Depression Inventory (2nd edition) (BDI-II), Hamilton Anxiety Rating Scale (HAM-A), Yale-Brown Obsessive Compulsive Scale (Y BOCS) and Eysenck Personality Questionnaire-Revised Rating Scale testings were used for diagnosis and assessment of severity of psychiatric symptoms. Blood concentrations of serotonin, catecholamines and dopamine were also measured. RESULTS: Suicidality was reported in 35% (compared to 9% for controls), of them 80%, 72.86%, 55.71% and 52.9% had depression, anxiety, obsession and aggression respectively. Patients with suicidality had higher scores of BDI-II (P = 0.0001), HAM-A (P = 0.0001), and Y-BOCS (P = 0.037) and lower scores of psychotic (P = 0.0001) and extroversion (P = 0.025) personality traits. Regardless the presence or absence of suicidality, patients with epilepsy had low serotonin (P = 0.006), noradrenaline (P = 0.019) and adrenaline (P = 0.0001) levels. With suicidality, significant correlations were identified between: (1) age and scores of BDI-II (r = 0.235, P = 0.0001) and HAM-A (r = 0.241, P = 0.046); (2) age at onset and concentrations of noradrenaline (r = -0.502, P = 0.024); (3) duration of illness and scores of BDI-II (r = 0.247, P = 0.041), Y-BOCS (r = 0.270, P = 0.025) and neurotic personality trait (r = -0.284, P = 0.018); and (4) doses of antiepileptic drugs and scores of psychotic personality traits (r = -0.495, P = 0.006 for carbamazepine; r = -0.508, P = 0.0001 for valproate). CONCLUSION: This is the first study which systematically estimated the prevalence and risks of suicidality in a homogenous group of patients with epilepsy. This study emphasizes the importance of epilepsy itself as a risk for suicidality and not its treatment. PMID- 24175167 TI - Positive aspects of caregiving in schizophrenia: A review. AB - Schizophrenia is a severe mental illness which is associated with significant consequences for both the patients and their relatives. Due to chronicity of the illness, the relatives of patients of schizophrenia have to bear the main brunt of the illness. Studies across the world have evaluated various aspects of caregiving and caregivers such as burden, coping, quality of life, social support, expressed emotions, and psychological morbidity. In general the research has looked at caregiving as a negative phenomenon, however, now it is increasingly recognised that caregiving is not only associated with negative consequences only, also experience subjective gains and satisfaction. This review focus on the conceptual issues, instruments available to assess the positive aspects of caregiving and the various correlates of positive aspects of caregiving reported in relation to schizophrenia. The positive aspect of caregiving has been variously measured as positive caregiving experience, caregiving satisfaction, caregiving gains and finding meaning through caregiving scale and positive aspects of caregiving experience. Studies suggests that caregivers of patients with schizophrenia and psychotic disorders experience caregiving gains (in the form of becoming more sensitive to persons with disabilities, clarity about their priorities in life and a greater sense of inner strength), experience good aspects of relationship with the patient, do have personal positive experiences. Some of the studies suggest that those who experience greater negative caregiving experience also do experience positive caregiving experience. PMID- 24175168 TI - Neuroplasticity and major depression, the role of modern antidepressant drugs. AB - The pathophysiology of depression has been traditionally attributed to a chemical imbalance and critical interactions between genetic and environmental risk factors, and antidepressant drugs suggested to act predominantly amplifying monoaminergic neurotransmission. This conceptualization may be currently considered reductive. The current literature about the pathophysiological mechanisms underlying depression, stress-related disorders and antidepressant treatment was examined. In order to provide a critical overview about neuroplasticity, depression and antidepressant drugs, a detailed Pubmed/Medline, Scopus, PsycLit, and PsycInfo search to identify all papers and book chapters during the period between 1980 and 2011 was performed. Pathological stress and depression determine relevant brain changes such as loss of dendritic spines and synapses, dendritic atrophy as well as reduction of glial cells (both in number and size) in specific areas such as the hippocampus and prefrontal cortex. An increased dendritic arborisation and synaptogenesis may instead be observed in the amygdala as a consequence of depression and stress-related disorders. While hippocampal and prefrontal functioning was impaired, amygdala functioning was abnormally amplified. Most of molecular abnormalities and biological changes of aberrant neuroplasticity may be explained by the action of glutamate. Antidepressant treatment is associated with neurogenesis, gliogenesis, dendritic arborisation, new synapse formation and cell survival both in the hippocampus and prefrontal cortex. Antidepressants (ADs) induce neuroplasticity mechanisms reversing the pathological effects of depression and stress-related disorders. The neuroplasticity hypothesis may explain the therapeutic and prophylactic action of ADs representing a new innovative approach to the pathophysiology of depression and stress-related disorders. PMID- 24175169 TI - Assessment scales for delirium: A review. AB - Over the years many scales have been designed for screening, diagnosis and assessing the severity of delirium. In this paper we review the various instruments available to screen the patients for delirium, instruments available to diagnose delirium, assess the severity, cognitive functions, motoric subtypes, etiology and associated distress. Among the various screening instruments, NEECHAM confusion scale and delirium observation scale appear to be most suitable screening instrument for patients' in general medical and surgical wards, depending on the type of rater (physician or nurse). In general, the instruments which are used for diagnosis [i.e., confusion assessment method (CAM), CAM for intensive care unit (CAM-ICU), Delirium Rating Scale-revised version (DRS-R-98), memorial selirium assessment scale, etc.] are based on various Diagnostic and Statistical Manual criteria and have good to excellent reliability and fair to good validity. Among the various diagnostic instruments, CAM is considered to be most useful instrument because of its accuracy, brevity, and ease of use by clinicians and lay interviewers. In contrast, DRS-R-98 appears to be a comprehensive instrument useful for diagnosis, severity rating and is sensitive to change and hence can be used for monitoring patients over a period. In the ICU setting, evidence suggests that CAM-ICU and Nursing Delirium Screening Scale had comparable sensitivities, but CAM-ICU has higher specificity. With regard to assessment of delirium in pediatric age group, certain instruments like Pediatric Anesthesia Emergence Delirium scale and pediatric CAM-ICU has been designed and have been found to be useful. PMID- 24175170 TI - Bipolar spectrum: Relevant psychological and biological factors. AB - The bipolar spectrum is a concept which bridges bipolar I disorder and unipolar depression. As Kraepelin described, there may be continuity across mood disorders. If this is the case, why should we discriminate for drug choice For example, it is generally accepted that mood stabilizers should be used for the bipolar spectrum, whereas antidepressants are for unipolar depression. If these disorders are diagnostically continuous, it is possible that the same drug could be effective in treating both bipolar I disorder/spectrum and unipolar depression. To resolve this question, I would like to propose my hypothesis that there is an inflexion point which constitutes the boundary between the bipolar spectrum and unipolar depression. It is likely that this inflexion point consists of temperaments as, reportedly, there are many significant differences in the presence of various temperaments between the bipolar spectrum (bipolar II, II1/2 and IV) and unipolar depression. These findings suggest that temperaments could draw a boundary between the bipolar spectrum and unipolar depression. Moreover, it has been shown that certain temperaments may be associated with several biological factors and may be associated with drug response. As such, whilst the concept of the bipolar spectrum emphasizes continuity, it is the proposed inflexion point that discriminates drug responses between the bipolar spectrum and unipolar depression. At the moment, although hypothetical, I consider this idea worthy of further research. PMID- 24175172 TI - Instruments for the assessment of social anxiety disorder: Validation studies. AB - Great progress has been observed in the literature over the last decade regarding the validation of instruments for the assessment of Social Anxiety Disorder in the Brazilian context. Particularly outstanding in this respect is the production of a group of Brazilian investigators regarding the psychometric study of the following instruments: Liebowitz Social Anxiety Scale, Social Phobia Inventory, Brief Social Phobia Scale, Disability Profile, Liebowitz Self-Rated Disability Scale, Social Phobia Safety Behaviors Scale and Self-Statements During Public Speaking Scale, which have proved to be appropriate and valid for use in the adult Brazilian population, representing resources for the assessment of social anxiety in clinical and experimental situations. PMID- 24175171 TI - Medication adherence in schizophrenia. AB - Non-adherence is a major problem in the treatment of schizophrenia. Its high prevalence, potentially severe consequences and associated costs make the study of this phenomenon a priority issue. In this article, basic non-adherence concepts of prevalence, consequences, evaluation methods, methodological restrictions of available studies, risk factors and intervention strategies, are reviewed. Studying non-adherence risk factors is a necessary step toward designing adequately oriented intervention strategies. An operative definition of adherence and good knowledge of its evaluation methods are essential to study this phenomenon. Unfortunately, most available studies contain methodological restrictions, especially concerning the evaluation methods, and an agreed operative definition of adherence has only very recently been reached. Knowing non-adherence risk factors, intervention strategies and available evidence on their effectiveness is essential in making treatment decisions in daily clinical practice. PMID- 24175173 TI - Obsessive-compulsive disorder: Evidence-based treatments and future directions for research. AB - Over the past three decades, obsessive-compulsive disorder (OCD) has moved from an almost untreatable, life-long psychiatric disorder to a highly manageable one. This is a very welcome change to the 1%-3% of children and adults with this disorder as, thanks to advances in both pharmacological and psychological therapies, prognosis for those afflicted with OCD is quite good in the long term, even though most have comorbid disorders that are also problematic. We still have far to go, however, until OCD can be described as either easily treatable or the effective treatments are widely known about among clinicians. This review focuses on the current state of the art in treatment for OCD and where we still are coming up short in our work as a scientific community. For example, while the impact of medications is quite strong for adults in reducing OCD symptoms, current drugs are only somewhat effective for children. In addition, there are unacceptably high relapse rates across both populations when treated with pharmacological alone. Even in the cognitive-behavioral treatments, which show higher effect sizes and lower relapse rates than drug therapies, drop-out rates are at a quarter of those who begin treatment. This means a sizable portion of the OCD population who do obtain effective treatments (which appears to be only a portion of the overall population) are not effectively treated. Suggestions for future avenues of research are also presented. These are primarily focused on (1) increased dissemination of effective therapies; (2) augmentation of treatments for those with residual symptoms, both for psychotherapy and pharmacotherapy; and (3) the impact of comorbid disorders on treatment outcome. PMID- 24175174 TI - Platelets in psychiatric disorders. AB - Several parallels exist between platelets and the brain, which make them interesting for studying the neurobiology of psychiatric disorders, such as Alzheimer's disease, depression, schizophrenia and anxiety disorders. Platelets store, secrete and process the amyloid precursor protein which is cleaved into the beta-amyloid (Abeta) peptides. The accumulation of Abeta in brain (plaques) and vessels (Abeta-angiopathy) is a major hallmark in AD. Platelets contain high amounts of serotonin and a dysfunction of the serotoninergic system is involved in the development of several behavior disorders, such as depression, anxiety disorders and self aggressive disturbances. Furthermore, platelets are able to take up dopamine and express various dopamine receptors, which make them to an interesting tool to study the underlying mechanisms of schizophrenia. In summary, platelets are an interesting and easily accessible cell type to study changes related to different psychiatric disorders and platelets proteins may be useful as diagnostic biomarkers for some psychiatric disorders. PMID- 24175175 TI - Platelet biomarkers in Alzheimer's disease. AB - The search for diagnostic and prognostic markers in Alzheimer's disease (AD) has been an area of active research in the last decades. Biochemical markers are correlates of intracerebral changes that can be identified in biological fluids, namely: peripheral blood (total blood, red and white blood cells, platelets, plasma and serum), saliva, urine and cerebrospinal fluid. An important feature of a biomarker is that it can be measured objectively and evaluated as (1) an indicator of disease mechanisms (markers of core pathogenic processes or the expression of downstream effects of these processes), or (2) biochemical responses to pharmacological or therapeutic intervention, which can be indicative of disease modification. Platelets have been used in neuropharmacological models since the mid-fifties, as they share several homeostatic functions with neurons, such as accumulation and release of neurotransmitters, responsiveness to variations in calcium concentration, and expression of membrane-bound compounds. Recent studies have shown that platelets also express several components related to the pathogenesis of AD, in particular to the amyloid cascade and the regulation of oxidative stress: thus they can be used in the search for biomarkers of the disease process. For instance, platelets are the most important source of circulating forms of the amyloid precursor protein and other important proteins such as Tau and glycogen synthase kinase-3B. Moreover, platelets express enzymes involved in membrane homeostasis (e.g., phospholipase A2), and markers of the inflammatory process and oxidative stress. In this review we summarize the available literature and discuss evidence concerning the potential use of platelet markers in AD. PMID- 24175176 TI - Platelets and Alzheimer's disease: Potential of APP as a biomarker. AB - Platelets are the first peripheral source of amyloid precursor protein (APP). They possess the proteolytic machinery to produce Abeta and fragments similar to those produced in neurons, and thus offer an ex-vivo model to study APP processing and changes associated with Alzheimer's disease (AD). Platelet process APP mostly through the alpha-secretase pathway to release soluble APP (sAPP). They produce small amounts of Abeta, predominantly Abeta40 over Abeta42. sAPP and Abeta are stored in alpha-granules and are released upon platelet activation by thrombin and collagen, and agents inducing platelet degranulation. A small proportion of full-length APP is present at the platelet surface and this increases by 3-fold upon platelet activation. Immunoblotting of platelet lysates detects APP as isoforms of 130 kDa and 106-110 kDa. The ratio of these of APP isoforms is significantly lower in patients with AD and mild cognitive impairment (MCI) than in healthy controls. This ratio follows a decrease that parallels cognitive decline and can predict conversion from MCI to AD. Alterations in the levels of alpha-secretase ADAM10 and in the enzymatic activities of alpha- and beta-secretase observed in platelets of patients with AD are consistent with increased processing through the amyloidogenic pathway. beta-APP cleaving enzyme activity is increased by 24% in platelet membranes of patients with MCI and by 17% in those with AD. Reports of changes in platelet APP expression with MCI and AD have been promising so far and merit further investigation as the search for blood biomarkers in AD, in particular at the prodromal stage, remains a priority and a challenge. PMID- 24175178 TI - Platelets: A possible glance into brain biological processes in schizophrenia. AB - Schizophrenia is a severe mental disorder, characterized by behavioral, emotional and cognitive disturbances, which commonly follows a chronic course. Diagnostic accuracy, management plans, treatment evaluation and prognosis are dependent on relatively subjective assessments. Despite extensive research and improvement in imaging technology, as well as modern genetic and molecular methodologies, the biological basis of this disease is still unclear. Therefore, there is a need for objective and valid biological markers. Platelets have often been used as a model in neurobiological research. The accessibility of platelets and their similarities with neurons turns them into an attractive candidate to search for biological markers for diagnosis and for unraveling pathophysiological processes relevant to the etiology of brain disorders, including schizophrenia. The present review addresses the main changes in platelet physiology observed in schizophrenia and its response to antipsychotic medication. We summarize numerous studies demonstrating impaired metabolism, uptake and receptor kinetics of schizophrenia-relevant neurotransmitters, abnormalities in membrane derived phospholipids and polyunsaturated fatty acids, as well as dysfunctions in the mitochondria. These changes fit with the various hypotheses raised for the etiology of schizophrenia, including the dopamine-glutamate hypothesis, the autoimmune hypothesis, the polyunsaturated fatty acid hypothesis and the impaired energy metabolism hypothesis. Despite extensive research in platelets, no conclusive reliable biomarker has been identified yet. This review suggests that the clinical heterogeneity and the biological complexity of schizophrenia lead to the inevitable conclusion that biomarkers will be identified only for subgroups characterized according to the different diagnostic criteria. Moreover, any biomarker would have to be an array of interrelated factors or even a set of several such arrays. PMID- 24175177 TI - Platelets and depression in cardiovascular disease: A brief review of the current literature. AB - Major depression is an independent risk factor for cardiovascular mortality and morbidity. The exact mechanisms linking depression and increased cardiovascular risk remain poorly understood. Several mechanisms have been proposed including increased platelet reactivity. This review focuses on the current literature that examines the platelet hypothesis of depression. To date studies show increased serotonin response, increased platelet serotonin receptor density, decreased serotonin transporter binding, and decreased platelet serotonin levels in individuals with depression. However other studies have shown no change in serotonin uptake. In addition to platelet serotonin specific pathways, other platelet pathways that have shown significant changes in depressed individuals include blunting of the platelet adenosine response, increased platelet thrombin response, increased glycoprotein Ib expression, increased P-selectin, beta thromboglobulin, and platelet factor four, as well as decreased platelet brain derived neurotrophic factor. However there are other studies that show conflicting evidence of increased platelet activation as measured by integrin receptor alpha2b beta3. Other conflicting data include alpha adrenergic density and platelet response to augmented serotonin. The direction of future research in platelet functional changes in depression and coronary artery disease should continue to focus on serotonin specific pathways with emphasis on potential mechanisms of specific pathway changes. PMID- 24175180 TI - Mental health and polygamy: The Syrian case. AB - AIM: To examine the psychological, self-esteem (SE), family function, marital satisfaction, life satisfaction and degree of agreement with the practice of polygamy among polygamous women with a control group from monogamous women in Syria. METHODS: Convenience sample of 136 women, 64 of whom were wives in polygamous marriages and 72 were wives in monogamous marriages participated in this study. A snowball method of sampling was used, conducted by undergraduate local female students trained to collect data according to culturally competent methods. The following research instruments were deployed: the symptoms checklist 90, the Rosenberg SE, the Life Satisfaction, family function and marital satisfaction. RESULTS: Findings revealed that women in polygamous marriages experienced lower SE, less life satisfaction, less marital satisfaction and more mental health symptomatology than women in monogamous marriages. Many of the mental health symptoms were different; noteworthy were elevated somatization, depression, hostility and psychoticism and their general severity index was higher. Furthermore, "first wife syndrome" was examined in polygamous families, comparing first with second and third wives in polygamous marriages. Findings indicated that first wives reported on more family problems, less SE, more anxiety, more paranoid ideation, and more psychoticism than second and third wives. CONCLUSION: These results are best understood through consideration of the socio-cultural and economic realities facing these women. Implications for mental health practice, policy and further research are discussed. PMID- 24175179 TI - Influence of mental stress on platelet bioactivity. AB - It is well established that various mental stress conditions contribute, or at least influence, underlying pathophysiological mechanisms in somatic, as well as in psychiatric disorders; blood platelets are supposed to represent a possible link in this respect. The anculeated platelets are the smallest corpuscular elements circulating in the human blood. They display different serotonergic markers which seem to reflect the central nervous serotonin metabolism. They are known as main effectors in haematological processes but recent research highlights their role in the innate and adaptive immune system. Platelets are containing a multitude of pro-inflammatory and immune-modulatory bioactive compounds in their granules and are expressing immune-competent surface markers. Research gives hint that platelets activation and reactivity is increased by mental stress. This leads to enhanced cross talk with the immune system via paracrine secretion, receptor interaction and formation of platelet leucocyte aggregates. Recently it has been demonstrated that the immune system can have a remarkable impact in the development of psychiatric disorders. Therefore platelets represent an interesting research area in psychiatry and their role as a possible biomarker has been investigated. We review the influence of mental stress on what is termed platelet bioactivity in this article, which subsumes the mainly immune-modulatory activity of platelets in healthy volunteers, elderly persons with chronic care-giving strain, patients with cardiovascular diseases who are prone to psychosocial stress, as well as in patients with posttraumatic stress disorder. Research data suggest that stress enhances platelet activity, reactivity and immune-modulatory capacities. PMID- 24175181 TI - Music in depression: Neural correlates of emotional experience in remitted depression. AB - AIM: To investigate neural and behavioral correlates of emotional experiences as potential vulnerability markers in remitted depression. METHODS: Fourteen remitted participants with a history of major depression and fourteen closely matched healthy control participants took part in the study. We used two psychiatric interviews (Hamilton Depression Rating Scale, Montgomery-Asberg Depression Rating Scale) and one self-report scale (Beck Depression Inventory) to assess remission. Healthy control participants were interviewed by an experienced psychiatrist to exclude those who showed any current or lifetime psychiatric or neurological disorders. To explore psychosocial and cognitive-interpersonal underpinnings of potential vulnerability markers of depression, early life stress, coping styles and alexithymia were also assessed. We induced pleasant and unpleasant emotional states using congruent combinations of music and human emotional faces to investigate neural and behavioral correlates of emotional experiences; neutral stimuli were used as a control condition. Brain responses were recorded using functional magnetic resonance imaging. Behavioral responses of pleasantness, arousal, joy and fear were measured via button-press inside the resonance imaging scanner. RESULTS: The mean age of the sample was 54.9 (+/- 11.3) years. There were no differences between remitted depressed (RD) (n = 14; 9 females and 5 males) and healthy participants (n = 14; 8 females and 6 males) regarding age, current degree of depression, early life stress, coping styles and alexithymia. On a neural level, RD participants showed reduced activations in the pregenual anterior cingulate cortex (pgACC) in response to pleasant [parameter estimates: -0.78 vs 0.32; t(26) = -3.41, P < 0.05] and unpleasant [parameter estimates: -0.88 vs 0.56; t(26)= -4.02, P < 0.05] emotional stimuli. Linear regression analysis revealed that pgACC activity was modulated by early life stress [beta = -0.48; R(2) = 0.23, F(1,27) = 7.83, P < 0.01] and task-oriented coping style [beta = 0.63; R(2) = 0.37, F(1,27) = 16.91, P < 0.001]. Trait anxiety modulated hippocampal responses to unpleasant stimuli [beta = 0.62; R(2) = 0.38, F(1,27) = 15.95, P < 0.001]. Interestingly, in their reported experiences of pleasantness, arousal, happiness and fear in response to pleasant, unpleasant and neutral stimuli, RD participants did not differ significantly from healthy control participants. Adding trait anxiety or alexithymia as a covariate did not change the results. CONCLUSION: The present study indicates that, in euthymic individuals, depression history alters neural correlates, but not the subjective dimension of pleasant and unpleasant emotional experiences. PMID- 24175182 TI - Intervention for reducing stigma: Assessing the influence of gender and knowledge. AB - AIM: To evaluate the effectiveness in reducing social stigma of an intervention and to assess the influence of gender and knowledge. METHODS: The program consisted in providing information and contact with users of mental health in order to reduce social stigma in the school environment. A total of 62 secondary school students (age 14-16 years) were evaluated with the Opinions on Mental Illness (OMI) questionnaire before and after the intervention. The subscales of the OMI were: authoritarianism, interpersonal etiology, benevolence, restrictiveness and negativism. The analysis was performed over the total sample, separating by gender and knowledge of someone with a mental disorder. t-test for repeated measures was used in the statistical analysis. RESULTS: All the OMI subscales showed a significant change after the intervention (P < 0.001), except for benevolence. Women presented significant changes in the subscales of authoritarianism and restrictiveness, while men presented changes in negativism and interpersonal etiology rather than restrictiveness (P < 0.001-0.003). Students that knew someone with a mental disorder presented significant changes in authoritarianism, interpersonal etiology, and negativism (P < 0.001-0.003) and students that do not know anyone with a mental disorder improved in restrictiveness and authoritarianism (P < 0.001-0.001). In all the subscales of the instrument the students improved their perception of mental disorders, reducing their levels of stigma. CONCLUSION: The intervention designed to reduce social stigma was effective, especially in the area of authoritarianism. The whole sample showed improved attitudes towards mental illness, although the areas were different depending on gender and knowledge. PMID- 24175183 TI - Adherence to medication: A nation-wide study from the Children's Cancer Hospital, Egypt. AB - AIM: To investigate adherence to medical regimen and predictors for non-adherence among children with cancer in Egypt. METHODS: We administered two study specific questionnaires to 304 parents of children diagnosed with cancer at the Children's Cancer Hospital in Cairo, Egypt, one before the first chemotherapy treatment and the other before the third. The questionnaires were translated to colloquial Egyptian Arabic, and due, to the high illiteracy level in Egypt an interviewer read the questions in Arabic to each parent and registered the answers. Both questionnaires consisted of almost 90 questions each. In addition, a Case Report Form was filled in from the child's medical journal. The study period consisted of 7 mo (February until September 2008) and we had a participation rate of 97%. Descriptive statistics are presented and Fisher's exact test was used to check for possible differences between the adherent and non-adherent groups. A P-value below 0.05 was considered significant. Software used was SAS version 9.3 for Windows (SAS Institute Inc., Cary, NC, United States). RESULTS: Two hundred and eighty-one (90%) parents answered the second questionnaire, regarding their child's adherence behaviour. Approximately two thirds of the children admitted to their third chemotherapy treatment had received medical recommendations upon discharge from the first or second chemotherapy treatment (181/281, 64%). Sixty eight percent (123/181) of the parents who were given medical recommendations reported that their child did not follow the recommendations. Two main predictors were found for non-adherence: child resistance (111/123, 90%) and inadequate information (100/123, 81%). In the adherent group, 20% of the parents (n = 12/58) reported trust in their child's doctor while 14 percent 8/58 reported trust in the other health-care professionals. Corresponding numbers for the non-adherent group are 8/123 (7%) for both their child's doctor and other health-care professionals. Almost all of the parents expressed a lack of optimism towards the treatment (116/121, 96%), yet they reported an intention to continue with the treatment for two main reasons, for the sake of their child's life (70%) (P = 0.005) and worry that their child would die if they discontinued the treatment (81%) (P < 0.0001). CONCLUSION: Non-adherence to medical regimen is common among children diagnosed with cancer in Egypt, the main reasons being child resistance and inadequate information. PMID- 24175184 TI - Treatment priority for suicide ideation and behaviours at an Australian emergency department. AB - AIM: To investigate the treatment priority given to self-harmers presenting to a hospital emergency department (ED) in Queensland, Australia, over the period 2005 2010. METHODS: The main outcome measure of this study was the treatment priority given to persons presenting with suicide ideation and communication (SIC) or self harming behaviour. Treatment priority was measured using the Australasian Triage Scale, which ranks patients from 1 (in need of immediate treatment) to 5 (assessment and treatment to start within 120 min). Ordered logistic regression was used to assess the broad demographic and treatment-related factors associated with more urgent triage categories and to investigate which methods of non-fatal suicidal behaviour (NFSB) were prioritised as most urgent. RESULTS: Most cases of NFSB were between 15 and 34 years. A larger proportion of persons presenting for SIC were aged 35 to 44 years. Over 50% of male presentations and 38% of female presentations were for SIC. Those cases prioritised as being more urgent had significantly greater odds of being older, presented after an act of self-harm rather than SIC, and had used multiple methods of NFSB. These individuals also had greater odds of being male and having made past presentations for SIC or NFSB. Among males, those presenting after ingestion of drugs had the greatest odds of receiving immediate attention compared to SIC. "Cutters" were considered as the least "urgent" subjects, and had a greatest risk of waiting 60 to 120 min for treatment compared to suicide ideators. Among females, those presenting with chemicals, poisons and gases had the greatest odds of receiving immediate attention compared to SIC. Females who presenting after cutting themselves had lower odds of receiving immediate treatment than those who presented with SIC. CONCLUSION: ED staff seems to judge the urgency of cases based on demographic factors such as age and gender, as well as method of NFSB. PMID- 24175185 TI - Contribution of attachment insecurity to health-related quality of life in depressed patients. AB - AIM: To examine the individual contributions of insecure attachment styles and depression symptom severity to health-related quality of life (HRQoL) in patients diagnosed with adjustment disorder (AJD) with depressed mood. METHODS: Participants were 67 patients diagnosed with International Classification of Diseases, Tenth edition AJD with depressed mood, who completed standardised self report questionnaires measuring study variables. Mean scores and SDs were computed for the outcome and predictor measures. Pearson correlations among the measures were computed. The study hypotheses were tested using analysis of variance (ANOVA) and multiple regression analyses. All analyses were performed using the SPSS-17 software package (SPSS Inc., Chicago, IL, United States). RESULTS: ANOVA showed a significant main effect of the insecure attachment styles on depression symptom severity and life satisfaction scores. The results suggest that depressive symptoms were more severe (F = 4.13, df = 2.67, P < 0.05) and life satisfaction was poorer (F = 5.69, df = 2.67, P < 0.01) in both anxious ambivalently and avoidantly attached patients compared with their securely attached counterparts, whereas the two insecure groups did not significantly differ by these variables. The anxious/ambivalent attachment style and depression symptom severity significantly contributed to HRQoL, accounting for 21.4% and 29.7% of the total variance, respectively [R(2) = 0.79; Adjusted R(2) = 0.77; F (5, 67) = 33.68, P < 0.0001], even after controlling for gender, marital and employment status confounders. CONCLUSION: The results show that the anxious/ambivalent attachment style together with depression symptom severity substantially and independently predict the HRQoL outcome in AJD with depressed mood. PMID- 24175186 TI - What is the purpose of launching the World Journal of Transplantation? AB - Congratulations to the publisher, members of the editorial board of the journal, all the authors and readers for launching the World Journal of Transplantation (WJT) as a new member of the World series journal family. Transplantations are rapidly evolving and share knowledge with a number of basic and clinical sciences: molecular biology, stem cell investigators, immune system, pharmacology, biotechnology, surgery and physicians of different organs such as the kidneys, liver, heart, lung, bone marrow and so on. The WJT is a peer reviewed open access journal centered on the different fields involved in transplant activity. If you want to share your experiences and new findings in the field of transplantation with your peers you will find the WJT a good media to publish your papers. PMID- 24175187 TI - Transplant nephrectomy. AB - About 10% of all renal allografts fail during the first year of transplantation and thereafter approximately 3%-5% yearly. Given that approximately 69 400 renal transplants are performed worldwide annually, the number of patients returning to dialysis following allograft failure is increasing. A failed transplant kidney, whether maintained by low dose immunosuppression or not, elicits an inflammatory response and is associated with increased morbidity and mortality. The risk for transplant nephrectomy (TN) is increased in patients who experienced multiple acute rejections prior to graft failure, develop chronic graft intolerance, sepsis, vascular complications and early graft failure. TN for late graft failure is associated with greater morbidity and mortality, bleeding being the leading cause of morbidity and infection the main cause of mortality. TN appears to be beneficial for survival on dialysis but detrimental to the outcome of subsequent transplantation by virtue of increased level of antibodies to mismatched antigens, increased rate of primary non function and delayed graft function. Many of the studies are characterized by a retrospective and univariate analysis of small numbers of patients. The lack of randomization in many studies introduced a selection bias and conclusions drawn from such studies should be applied with caution. Pending a randomised controlled trial on the role of TN in the management of transplant failure patients, it is prudent to remove failed symptomatic allografts and all grafts failing within 3 mo of transplantation, monitor inflammatory markers in patients with retained failed allografts and remove the allograft in the event of a significant increase in levels. PMID- 24175188 TI - Recent progress in pancreatic islet transplantation. AB - Diabetes mellitus remains a major burden. More than 200 million people are affected worldwide, which represents 6% of the world's population. Type 1 diabetes mellitus is an autoimmune disease, which induces the permanent destruction of the beta-cells of the pancreatic islets of Langerhans. Although intensive insulin therapy has proven effective to delay and sometimes prevent the progression of complications such as nephropathy, neuropathy or retinopathy, it is difficult to achieve and maintain long term in most subjects. The successes achieved over the last few decades by the transplantation of whole pancreas and isolated islets suggest that diabetes can be cured by the replenishment of deficient beta cells. However, islet transplantation efforts have various limitations, including the limited supply of donor pancreata, the paucity of experienced islet isolation teams, side effects of immunosuppressants and poor long term results. The purpose of this article is to review the recent progress in clinical islet transplantation for the treatment of diabetes and to describe the recent progress on pancreatic stem/progenitor cell research, which has opened up several possibilities for the development of new treatments for diabetes. PMID- 24175189 TI - Live liver donors: Are they at a higher risk for post-operative thrombotic complications? AB - Live liver donor transplantation to adult recipients is becoming a common practice, increasing the organ pool and providing an alternative to whole cadaveric liver transplantation. These patients are healthy adults without serious medical conditions and typically have normal coagulation profiles preoperatively. Right hepatic lobectomy is usually performed for adult recipients, while left hepatic lobectomy is performed for pediatric recipients. Removal of the whole right lobe from the donors may expose theses patients to multiple intraoperative and postoperative complications. Hypercoagulability has been identified as a serious complication which leads to thromboembolic phenomena with potential fatal consequences. The primary aim of this review is to look at possible changes in post-operative coagulation dynamics that may increase the risk for development of thromboembolic complications in live liver donors. In this article, we stress the importance of addressing the issue that conventional clotting tests (PT, INR, PTT) are unable to detect a hypercoagulable state, and therefore, we should examining alternative laboratory tests to improve diagnosis and early detection of thrombotic complications. Measurement of natural anticoagulant/procoagulant biomarkers combined with conventional coagulation studies and thromboelastography offers a more accurate assessment of coagulation disorders. This allows earlier diagnosis, permitting appropriate intervention sooner, hence avoiding potential morbidity and mortality. Biomarkers that may be evaluated include, but are not limited to: protein C, soluble P-selectin, antithrombin III, thrombin-antithrombin complex, and thrombin generation complex. PMID- 24175190 TI - Long-term renal function, complications and life expectancy in living kidney donors. AB - Living kidney transplantation is now a widely accepted treatment for end stage renal disease (ESRD) because it provides excellent outcomes for recipients. However, long-term outcomes of living kidney donors have not been well understood. Because securing the safety of the donor is essential to the continued success of this procedure, we reviewed articles discussing long-term outcomes of living kidney donors. Most studies found no decrease in long-term survival or progressive renal dysfunction in previous kidney donors. Moreover, the prevalence of hypertension was comparable to that expected in the general population, although some did report otherwise. Urinary protein showed small increases in this population and was associated with hypertension and a lower glomerular filtration rate. Quality of life following living kidney donation seems to be better than the national norm. We also encountered several reports of ESRD in previous living kidney donors. Regular follow-up of kidney donors is recommended and future controlled, prospective studies will better delineate risk factors which cause health problems following living kidney donation. PMID- 24175191 TI - Key issues in transplant tourism. AB - Access to organ transplantation depends on national circumstances, and is partly determined by the cost of health care, availability of transplant services, the level of technical capacity and the availability of organs. Commercial transplantation is estimated to account for 5%-10% (3500-7000) of kidney transplants performed annually throughout the world. This review is to determine the state and outcome of renal transplantation associated with transplant tourism (TT) and the key challenges with such transplantation. The stakeholders of commercial transplantation include: patients on the waiting lists in developed countries or not on any list in developing countries; dialysis funding bodies; middlemen, hosting transplant centres; organ-exporting countries; and organ vendors. TT and commercial kidney transplants are associated with a high incidence of surgical complications, acute rejection and invasive infection which cause major morbidity and mortality. There are ethical and medical concerns regarding the management of recipients of organs from vendors. The growing demand for transplantation, the perceived failure of altruistic donation in providing enough organs has led to calls for a legalised market in organ procurement or regulated trial in incentives for donation. Developing transplant services worldwide has many benefits - improving results of transplantation as they would be performed legally, increasing the donor pool and making TT unnecessary. Meanwhile there is a need to re-examine intrinsic attitudes to TT bearing in mind the cultural and economic realities of globalisation. Perhaps the World Health Organization in conjunction with The Transplantation Society would set up a working party of stakeholders to study this matter in greater detail and make recommendations. PMID- 24175192 TI - Antibody induction therapy in adult kidney transplantation: A controversy continues. AB - Antibody induction therapy is frequently used as an adjunct to the maintenance immunosuppression in adult kidney transplant recipients. Published data support antibody induction in patients with immunologic risk to reduce the incidence of acute rejection (AR) and graft loss from rejection. However, the choice of antibody remains controversial as the clinical studies were carried out on patients of different immunologic risk and in the context of varying maintenance regimens. Antibody selection should be guided by a comprehensive assessment of immunologic risk, patient comorbidities, financial burden as well as the maintenance immunosuppressives. Lymphocyte-depleting antibody (thymoglobulin, ATGAM or alemtuzumab) is usually recommended for those with high risk of rejection, although it increases the risk of infection and malignancy. For low risk patients, interleukin-2 receptor antibody (basiliximab or daclizumab) reduces the incidence of AR without much adverse effects, making its balance favorable in most patients. It should also be used in the high risk patients with other medical comorbidities that preclude usage of lymphocyte-depleting antibody safely. There are many patients with very low risk, who may be induced with intravenous steroids without any antibody, as long as combined potent immunosuppressives are kept as maintenance. In these patients, benefits with antibody induction may be too small to outweigh its adverse effects and financial cost. Rituximab can be used in desensitization protocols for ABO and/or HLA incompatible transplants. There are emerging data suggesting that alemtuzumab induction be more successful than other antibody for promoting less intensive maintenance protocols, such as steroid withdrawal, tacrolimus monotherapy or lower doses of tacrolimus and mycophenolic acid. However, the long-term efficacy and safety of these unconventional strategies remains unknown. PMID- 24175193 TI - Hepatic veno-occlusive disease after hematopoietic stem cell transplantation: Prophylaxis and treatment controversies. AB - Hepatic veno-occlusive disease (VOD), also known as sinusoidal obstruction syndrome, is a major complication of hematopoietic stem cell transplantation and it carries a high mortality. Prophylaxis for hepatic VOD is commonly given to transplant recipients from the start of conditioning through the early weeks of transplant. However, high quality evidence from randomized controlled trials is scarce with small sample sizes and the trials yielded conflicting results. Although various treatment options for hepatic VOD are available, most have not undergone stringent evaluation with randomized controlled trial and therefore it remains uncertain which treatment offers real benefit. It remains controversial whether VOD prophylaxis should be given, which prophylactic therapy should be given, who should receive prophylaxis, and what treatment should be offered once VOD is established. PMID- 24175194 TI - Ischaemic/reperfusion injury: Role of infliximab. AB - Ischaemia/reperfusion (I/R) injury is an underlying complex interrelated patho physiological process which effects the outcome of many clinical situations, in particular transplantation. Tumor necrosis factor (TNF)-alpha is a pleiotropic inflammatory cytokine; a trimeric protein encoded within the major histocompatibility complex which plays a pivotal role in this disease process. This review is based at looking into an update, particularly the new insights in the mechanisms of action of TNF antagonist such as infliximab. Infliximab may thus play a dual role in the field of transplantation where it might not only down regulate the I/R injury, it may also have a beneficial role in the reduction of acute rejection. PMID- 24175195 TI - New options for the management of hyperparathyroidism after renal transplantation. AB - The persistence and severity of hyperparathyroidism (HPT) post-renal transplantation is relatively frequent and primarily associated with the timing and its magnitude in the pre-transplant period and with the presence of parathyroid adenomas. HPT after renal transplantation is clinically manifested with hypercalcemia, hypophosphatemia, bone pain, fractures, and in more serious cases with cardiovascular calcifications that affect the survival. The primary clinical objective for patients with secondary HPT after renal transplantation is to obtain a level of parathyroid hormone (PTH) adequate to the renal transplanted function and to normalize levels of calcium, phosphorus and vitamin D. In many cases during this period, the development of hypercalcemia and/or hypophosphatemia makes it necessary to take different therapeutic measures. The use of vitamin D or its analogues has been extrapolated from the management of pre-transplant HPT obtaining variable outcomes, although its use is limited by its capacity to produce hypercalcemia. Calcimimetics are drugs that have proven be effective in reducing PTH levels in patients with HPT on dialysis and has been effective in reducing up to 50% PTH levels in moderate to severe HPT in post renal transplantation.When HPT persists after renal transplantation and does not respond to medical treatment, invasive management by percutaneous ethanol injection therapy of parathyroid glands or parathyroidectomy should be considered. The emergence of new methods for the management of HPT expands the availability of therapeutic tools for transplant patients. PMID- 24175196 TI - Effects of exercise in renal transplant recipients. AB - Even after a successful renal transplantation, the renal transplant recipients (RTRs) keeps on suffering the consequences of the uremic sickness. Cardiovascular risk, work capacity, and quality of life do not improve according to expectations since biological and psychological problems are not completely solved by pharmacological treatment. Furthermore, post-transplant treatment, per se, induces additional problems (i.e., side effects of drugs). It becomes, indeed, very important to insert "non-pharmacological" therapies able to reverse this trend. Exercise may represent an important contribution in the solution of this problem. In fact, many studies have demonstrated, in the last two decades, that physical training is able both, to improve graft function, work capacity and quality of life, and to reduce cardiovascular risk. In conclusion, if the analysis of the available data suggests that an appropriate dose of physical training represent a useful, safe and non-pharmacologic contribution to RTR treatment, it becomes a kidney transplantologist responsibility to introduce exercise in the current therapy of RTRs. PMID- 24175198 TI - Donating in good faith or getting into trouble Religion and organ donation revisited. AB - There is worldwide shortage of organs for solid-organ transplantation. Many obstacles to deceased and live donation have been described and addressed, such as lack of understanding of the medical process, the issue of the definition of brain death, public awareness of the need for transplants, and many others. However, it is clear that the striking differences in deceased and live donation rates between different countries are only partly explained by these factors and many cultural and social reasons have been invoked to explain these observations. We believe that one obstacle to both deceased and live donation that is less well appreciated is that of religious concerns. Looking at the major faiths and religions worldwide, it is reassuring to see that most of them encourage donation. However, there is also scepticism amongst some of them, often relating to the concept of brain death and/or the processes surrounding death itself. It is worthwhile for transplant teams to be broadly aware of the issues and also to be mindful of resources for counselling. We believe that increased awareness of these issues within the transplant community will enable us to discuss these openly with patients, if they so wish. PMID- 24175197 TI - Current state of renal transplant immunosuppression: Present and future. AB - For kidney transplant recipients, immunosuppression commonly consists of combination treatment with a calcineurin inhibitor, an antiproliferative agent and a corticosteroid. Many medical centers use a sequential immunosuppression regimen where an induction agent, either an anti-thymocyte globulin or interleukin-2 receptor antibody, is given at the time of transplantation to prevent early acute rejection which is then followed by a triple immunosuppressive maintenance regimen. Very low rejection rates have been achieved at many transplant centers using combinations of these agents in a variety of protocols. Yet, a large number of recipients suffer chronic allograft injury and adverse events associated with drug therapy. Regimens designed to limit or eliminate calcineurin inhibitors and/or corticosteroid use are actively being pursued. An ideal immunosuppressive regimen limits toxicity and prolongs the functional life of the graft. This article contains a critical analysis of clinical data on currently available immunosuppressive strategies and an overview of therapeutic moieties in development. PMID- 24175199 TI - Antineoplastic effects of mammalian target of rapamycine inhibitors. AB - Cancer after transplantation is the third cause of death and one of the more relevant comorbidities. Aim of this review is to verify the role of different pathogenetic mechanisms in cancer development in transplant patients and in general population as well. In particular has been outlined the different role exerted by two different families of drug as calcineurin inhibitor and mammalian target of rapamycin (mTOR) inhibitor. The role of mTOR pathways in cell homeostasis is complex but enough clear. As a consequence the mTOR pathway deregulation is involved in the genesis of several cancers. Hence the relevant role of mTOR inhibitors. The authors review the complex mechanism of action of mTOR inhibitors, not only for what concerns the immune system but also other cells as endothelial, smooth muscle and epithelial cells. The mechanism of action is still now not completely defined and understood. It implies the inhibition of mTOR pathway at different levels, but mainly at level of the phosphorylation of several intracellular kinases that contribute to activate mTOR complex. Many prospective and retrospective studies in transplant patients document the antineoplastic role of mTOR inhibition. More recently mTOR inhibitors proven to be effective in the treatment of some cancers also in general population. Kidney cancers, neuroendocrine tumors and liver cancers seem to be the most sensitive to these drugs. Best results are obtained with a combination treatment, targeting the mTOR pathway at different levels. PMID- 24175200 TI - Polyomavirus-associated nephropathy. AB - Polyomaviruses BK and JC are ubiquitous viruses with high seroprevalence rates in general population. Following primary infection, polyomaviruses BK and JC persist latently in different sites, particularly in the reno-urinary tract. Reactivation from latency may occur in normal subjects with asymptomatic viruria, while it can be associated to nephropathy (PVAN) in kidney transplantat recipients. PVAN may occur in 1%-10% of renal transplant patients with loss of the transplanted organ in 30% up to 80% of the cases. Etiology of PVAN is mainly attributable to BK virus, although approximately 5% of the cases may be due to JC. Pathogenesis of PVAN is still unknown, although viral replication and the lack of immune control play a major role. Immunosuppression represents the condicio sine qua non for the development of PVAN and the modulation of anti-rejection treatment represents the first line of intervention, given the lack of specific antiviral agents. At moment, an appropriate immunemodulation can only be accomplished by early identification of viral reactivacation by evaluation of polyomavirus load on serum and/or urine specimens, particularly in the first year post-trasplantation. Viro-immunological monitoring of specific cellular immune response could be useful to identify patients unable to recover cellular immunity posttransplantation, that are at higher risk of viral reactivation with development of PVAN. Herein, the main features of polyomaviruses BK and JC, biological properties, clinical characteristics, etiopathogenesis, monitoring and diagnosing of PVAN will be described and discussed, with an extended citation of related relevant literature data. PMID- 24175201 TI - Where are we at with short bowel syndrome and small bowel transplant. AB - Intestinal failure can be defined as the critical reduction of functional gut mass below the minimal amount necessary for adequate digestion and absorption to satisfy body nutrient and fluid requirements in adults or children. Short bowel syndrome (SBS) is characterized by a state of malabsorption following extensive resection of the small bowel. SBS may occur after resection of more than 50% and is certain after resection of more than 70% of the small intestine, or if less than 100 cm of small bowel is left. Several treatment modalities other than total parenteral nutrition, including hormones (recombinant human growth hormone, glucagon-like peptide-2) and tailoring surgeries (Bianchi procedure, serial transverse enteroplasty), had been proposed, however these were either experimental or inefficient. Small bowel transplant is a rather new approach for SBS. The once feared field of solid organ transplantation is nowadays becoming more and more popular, even in developing countries. This is partially secondary to the developments in immunosuppressive strategy. In this regard, alemtuzumab deserves special attention. There are more complex surgeries, such as multivisceral transplantation, for multi-organ involvement including small bowel. This latter technique is relatively new when compared to small bowel transplant, and is performed in certain centers worldwide. In this review, an attempt is made to give an insight into small bowel syndrome, small bowel transplantation, and related issues. PMID- 24175202 TI - Effect of ureteric stents on urological infection and graft function following renal transplantation. AB - AIM: To compare urological infections in patients with or without stents following transplantation and to determine the effect of such infections on graft function. METHODS: All 285 recipients of kidney transplantation at our centre between 2006 and 2010 were included in the study. Detailed information including stent use and transplant function was collected prospectively and analysed retrospectively. The diagnosis of urinary tract infection was made on the basis of compatible symptoms supported by urinalysis and/or microbiological culture. Graft function, estimated glomerular filtration rate and creatinine at 6 mo and 12 mo, immediate graft function and infection rates were compared between those with a stent or without a stent. RESULTS: Overall, 196 (183 during initial procedure, 13 at reoperation) patients were stented following transplantation. The overall urine leak rate was 4.3% (12/277) with no difference between those with or without stents - 7/183 vs 5/102, P = 0.746. Overall, 54% (99/183) of stented patients developed a urological infection compared to 38.1% (32/84) of those without stents (P = 0.0151). All 18 major urological infections occurred in those with stents. The use of stent (Wald chi(2) = 5.505, P = 0.019) and diabetes mellitus (Wald chi(2) = 5.197, P = 0.023) were found to have significant influence on urological infection rates on multivariate analysis. There were no deaths or graft losses due to infection. Stenting was associated with poorer transplant function at 12 mo. CONCLUSION: Stents increase the risks of urological infections and have a detrimental effect on early to medium term renal transplant function. PMID- 24175204 TI - Residual renal function in peritoneal dialysis with failed allograft and minimum immunosuppression. AB - Immunosuppression (IS) is often withdrawn in patients with end stage renal disease secondary to a failed renal allograft, and this can lead to an accelerated loss of residual renal function (RRF). As maintenance of RRF appears to provide a survival benefit to peritoneal dialysis (PD) patients, it is not clear whether this benefit of maintaining RRF in failed allograft patients returning to PD outweigh the risks of maintaining IS. A 49 year-old Caucasian male developed progressive allograft failure nine years after living-donor renal transplantation. Hemodialysis was initiated via tunneled dialysis catheter (TDC) and IS was gradually withdrawn. Two weeks after IS withdrawal he developed a febrile illness, which necessitate removal of the TDC and conversion to PD. He was maintained on small dose of tacrolimus (1 mg/d) and prednisone (5 mg/d). Currently (1 year later) he is doing exceedingly well on cycler-assisted PD. Residual urine output ranges between 600-1200 mL/d. Total weekly Kt/V achieved 1.82. RRF remained well preserved in this patient with failed renal allograft with minimal immunosuppressive therapy. This strategy will need further study in well-defined cohorts of PD patients with failed allografts and residual RRF to determine efficacy and safety. PMID- 24175205 TI - Face up to challenge of virology world. AB - Welcome to the World Journal of Virology (WJV), a new member of the World Journal Series. The World Journal Series was first launched as a peer-reviewed scientific journal covering aspects of research, diagnostics and clinical practice in biomedicine in 1995. WJV is an online and open-access peer-reviewed periodical focusing on virology. WJV covers a variety of topics in different areas of virology, including advances in basic research, updates in nomenclature, the development of novel diagnostic assays, the epidemiology of viral disorders and, new developments in the clinical management of viral diseases, including new vaccines and antiviral therapeutics. The purpose in launching the WJV is to promote knowledge exchange related to the classic human viruses as well as newly emerging viruses and their associated clinical disorders. Continually updating knowledge in a timely manner in this field where information related to the unceasing evolution of viruses is becoming available at a rapid pace is challenging. Thanks to the World-Wide-Web we are able to provide a podium for all authors and readers of WJV to address this challenge. I would like to acknowledge the Baishideng publisher, the members of the editorial board, and all contributing authors involved in this inaugural issue of the WJV. I sincerely hope all readers, i.e. future contributing authors, will like WJV and we look forward to your input in assisting WJV to grow and mature. PMID- 24175203 TI - Is it time to give up with calcineurin inhibitors in kidney transplantation? AB - Calcineurin inhibitors (CNIs) represent today a cornerstone for the maintenance immunosuppressive treatment in solid organ transplantation. Nevertheless, several attempts have been made either to minimize their dosage or to avoid CNIs at all because these drugs have the severe side effect of chronic nephrotoxicity. This issue represents a frontier for renal transplantation. The principal problem is to understanding whether the poor outcome over the long-term may be ascribed to CNIs nephrotoxicity or to the inability of these drugs to control the acute and chronic rejection B cells mediated. The authors analyze extensively all the international trials attempting to withdraw, minimize or avoid the use of CNIs. Few trials undertaken in low risk patients with an early conversion from CNIs to proliferation signal inhibitors were successful, but the vast majority of trials failed to improve CNIs side effects. To date the use of a new drug, a co stimulation blocker, seems promising in avoiding CNIs with similar efficacy, better glomerular filtration rate and an improved metabolic profile. Moreover the use of this drug is not associated with the development of donor-specific anti human leukocyte antigen antibodies. This point has a particular relevance, because the failure of CNIs to realize good outcomes in renal transplantation has recently ascribed to their inability to control the acute and chronic rejections B-cell mediated. This paper analyzes all the recent studies that have been done on this issue that represents the real frontier that should be overcome to realize better results over the long-term after transplantation. PMID- 24175206 TI - Delivery strategies for novel vaccine formulations. AB - A major challenge in vaccine design is to identify antigen presentation and delivery systems capable of rapidly stimulating both the humoral and cellular components of the immune system to elicit a strong and sustained immunity against different viral isolates. Approaches to achieve this end involve live attenuated and inactivated virions, viral vectors, DNA, and protein subunits. This review reports the state of current antigen delivery, and focuses on two innovative systems recently established at our labs. These systems are the filamentous bacteriophage fd and an icosahedral scaffold formed by the acyltransferase component (E2 protein) of the pyruvate dehydrogenase complex of Bacillus stearothermophilus. PMID- 24175207 TI - Emerging and re-emerging viruses: A global challenge illustrated by Chikungunya virus outbreaks. AB - In recent decades, the issue of emerging and re-emerging infectious diseases, especially those related to viruses, has become an increasingly important area of concern in public health. It is of significance to anticipate future epidemics by accumulating knowledge through appropriate research and by monitoring their emergence using indicators from different sources. The objective is to alert and respond effectively in order to reduce the adverse impact on the general populations. Most of the emerging pathogens in humans originate from known zoonosis. These pathogens have been engaged in long-standing and highly successful interactions with their hosts since their origins are exquisitely adapted to host parasitism. They developed strategies aimed at: (1) maximizing invasion rate; (2) selecting host traits that can reduce their impact on host life span and fertility; (3) ensuring timely replication and survival both within host and between hosts; and (4) facilitating reliable transmission to progeny. In this context, Arboviruses (or ARthropod-BOrne viruses), will represent with certainty a threat for the coming century. The unprecedented epidemic of Chikungunya virus which occurred between 2005 and 2006 in the French Reunion Island in the Indian Ocean, followed by several outbreaks in other parts of the world, such as India and Southern Europe, has attracted the attention of medical and state authorities about the risks linked to this re-emerging mosquito-borne virus. This is an excellent model to illustrate the issues we are facing today and to improve how to respond tomorrow. PMID- 24175208 TI - Porcine reproductive and respiratory syndrome virus vaccines: Immunogenicity, efficacy and safety aspects. AB - Porcine reproductive and respiratory syndrome virus (PRRSV) infection is the leading cause of economic casualty in swine industry worldwide. The virus can cause reproductive failure, respiratory disease, and growth retardation in the pigs. This review deals with current status of commercial PRRS vaccines presently used to control PRRS. The review focuses on the immunogenicity, protective efficacy and safety aspects of the vaccines. Commercial PRRS modified-live virus (MLV) vaccine elicits delayed humoral and cell-mediated immune responses following vaccination. The vaccine confers late but effective protection against genetically homologous PRRSV, and partial protection against genetically heterologous virus. The MLV vaccine is of concern for its safety as the vaccine virus can revert to virulence and cause diseases. PRRS killed virus (KV) vaccine, on the other hand, is safe but confers limited protection against either homologous or heterologous virus. The KV vaccine yet helps reduce disease severity when administered to the PRRSV-infected pigs. Although efforts have been made to improve the immunogenicity, efficacy and safety of PRRS vaccines, a better vaccine is still needed in order to protect against PRRSV. PMID- 24175209 TI - Serological diagnosis of Epstein-Barr virus infection: Problems and solutions. AB - Serological tests for antibodies specific for Epstein-Barr virus (EBV) antigens are frequently used to define infection status and for the differential diagnosis of other pathogens responsible for mononucleosis syndrome. Using only three parameters [viral capsid antigen (VCA) IgG, VCA IgM and EBV nuclear antigen (EBNA)-1 IgG],it is normally possible to distinguish acute from past infection: the presence of VCA IgM and VCA IgG without EBNA-1 IgG indicates acute infection, whereas the presence of VCA IgG and EBNA-1 IgG without VCA IgM is typical of past infection. However, serological findings may sometimes be difficult to interpret as VCA IgG can be present without VCA IgM or EBNA-1 IgG in cases of acute or past infection, or all the three parameters may be detected simultaneously in the case of recent infection or during the course of reactivation. A profile of isolated EBNA-1 IgG may also create some doubts. In order to interpret these patterns correctly, it is necessary to determine IgG avidity, identify anti-EBV IgG and IgM antibodies by immunoblotting, and look for heterophile antibodies, anti-EA (D) antibodies or viral genome using molecular biology methods. These tests make it possible to define the status of the infection and solve any problems that may arise in routine laboratory practice. PMID- 24175210 TI - Roles of the two distinct proteasome pathways in hepatitis C virus infection. AB - Hepatitis C virus (HCV) infection often causes chronic hepatitis, liver cirrhosis, and hepatocellular carcinoma. The development of a HCV cell culture system enabled us to investigate its whole HCV life cycle and develop a better understanding of the pathogenesis of this virus. Post-translational modification plays a crucial role in HCV replication and in the maturation of viral particles. There is growing evidence also suggesting that the ubiquitin-proteasome pathway and the ubiquitin-independent proteasome pathway are involved in the stability control of HCV proteins. Many viruses are known to manipulate the proteasome pathways to modulate the cell cycle, inhibit apoptosis, evade the immune system, and activate cell signaling, thereby contributing to persistent infection and viral carcinogenesis. The identification of functional interactions between HCV and the proteasome pathways will therefore shed new light on the life cycle and pathogenesis of HCV. This review summarizes the current knowledge on the involvement of the ubiquitin-dependent and -independent proteasome pathways in HCV infection and discusses the roles of these two distinct mechanisms in HCV pathogenesis. PMID- 24175212 TI - Molecular and clinical aspects of hepatitis D virus infections. AB - Hepatitis D virus (HDV) is a defective virus with circular, single-stranded genomic RNA which needs hepatitis B virus (HBV) as a helper virus for virion assembly and infectivity. HDV virions are composed of a circular shape HDV RNA and two types of viral proteins, small and large HDAgs, surrounded by HBV surface antigen (HBsAg). The RNA polymerase II from infected hepatocytes is responsible for synthesizing RNAs with positive and negative polarities for HDV, as the virus does not code any enzyme to replicate its genome. HDV occurs as co-infection or super-infection in up to 5% of HBsAg carriers. A recent multi-center study highlighted that pegylated interferon alpha-2a (PEG-IFN) is currently the only treatment option for delta hepatitis. Nucleotide/nucleoside analogues, which are effective against HBV, have no relevant effects on HDV. However, additional clinical trials combining PEG-IFN and tenofovir are currently ongoing. The molecular interactions between HDV and HBV are incompletely understood. Despite fluctuating patterns of HBV viral load in the presence of HDV in patients, several observations indicate that HDV has suppressive effects on HBV replication, and even in triple infections with HDV, HBV and HCV, replication of both concomitant viruses can be reduced. Additional molecular virology studies are warranted to clarify how HDV interacts with the helper virus and which key cellular pathways are used by both viruses. Further clinical trials are underway to optimize treatment strategies for delta hepatitis. PMID- 24175213 TI - Selection of RNAi-based inhibitors for anti-HIV gene therapy. AB - In the last decade, RNA interference (RNAi) advanced to one of the most widely applied techniques in the biomedical research field and several RNAi therapeutic clinical trials have been launched. We focus on RNAi-based inhibitors against the chronic infection with human immunodeficiency virus type 1 (HIV-1). A lentiviral gene therapy is proposed for HIV-infected patients that will protect and reconstitute the vital immune cell pool. The RNAi-based inhibitors that have been developed are short hairpin RNA molecules (shRNAs), of which multiple are needed to prevent viral escape. In ten distinct steps, we describe the selection process that started with 135 shRNA candidates, from the initial design criteria, via testing of the in vitro and in vivo antiviral activity and cytotoxicity to the final design of a combinatorial therapy with three shRNAs. These shRNAs satisfied all 10 selection criteria such as targeting conserved regions of the HIV-1 RNA genome, exhibiting robust inhibition of HIV-1 replication and having no impact on cell physiology. This combinatorial shRNA vector will soon move forward to the first clinical studies. PMID- 24175211 TI - West Nile virus: A re-emerging pathogen revisited. AB - West Nile virus (WNV), a flavivirus of the Flaviviridae family, is maintained in nature in an enzootic transmission cycle between avian hosts and ornithophilic mosquito vectors, although the virus occasionally infects other vertebrates. WNV causes sporadic disease outbreaks in horses and humans, which may result in febrile illness, meningitis, encephalitis and flaccid paralysis. Until recently, its medical and veterinary health concern was relatively low; however, the number, frequency and severity of outbreaks with neurological consequences in humans and horses have lately increased in Europe and the Mediterranean basin. Since its introduction in the Americas, the virus spread across the continent with worrisome consequences in bird mortality and a considerable number of outbreaks among humans and horses, which have resulted in the largest epidemics of neuroinvasive WNV disease ever documented. Surprisingly, its incidence in human and animal health is very different in Central and South America, and the reasons for it are not yet understood. Even though great advances have been obtained lately regarding WNV infection, and although efficient equine vaccines are available, no specific treatments or vaccines for human use are on the market. This review updates the most recent investigations in different aspects of WNV life cycle: molecular virology, transmission dynamics, host range, clinical presentations, epidemiology, ecology, diagnosis, control, and prevention, and highlights some aspects that certainly require further research. PMID- 24175215 TI - History of polio vaccination. AB - Poliomyelitis is an acute paralytic disease caused by three poliovirus (PV) serotypes. Less than 1% of PV infections result in acute flaccid paralysis. The disease was controlled using the formalin-inactivated Salk polio vaccine (IPV) and the Sabin oral polio vaccine (OPV). Global poliomyelitis eradication was proposed in 1988 by the World Health Organization to its member states. The strategic plan established the activities required for polio eradication, certification for regions, OPV cessation phase and post-OPV phase. OPV is the vaccine of choice for the poliomyelitis eradication program because it induces both a systemic and mucosal immune response. The major risks of OPV vaccination are the appearance of Vaccine-Associated Paralytic Poliomyelitis cases (VAPP) and the emergence of Vaccine Derived Polioviruses strains. The supplementary immunization with monovalent strains of OPV type 1 or type 3 or with a new bivalent oral polio vaccine bOPV (containing type 1 and type 3 PV) has been introduced in those regions where the virus has been difficult to control. Most countries have switched the schedule of vaccination by using IPV instead of OPV because it poses no risk of vaccine-related disease. Until 2008, poliomyelitis was controlled in Romania, an Eastern European country, predominantly using OPV. The alternative vaccination schedule (IPV/OPV) was implemented starting in September 2008, while beginning in 2009, the vaccination was IPV only. The risk of VAPP will disappear worldwide with the cessation of use of OPV. The immunization for polio must be maintained for at least 5 to 10 years using IPV. PMID- 24175214 TI - Innate and adaptive immune responses against picornaviruses and their counteractions: An overview. AB - Picornaviruses, small positive-stranded RNA viruses, cause a wide range of diseases which is based on their differential tissue and cell type tropisms. This diversity is reflected by the immune responses, both innate and adaptive, induced after infection, and the subsequent interactions of the viruses with the immune system. The defense mechanisms of the host and the countermeasures of the virus significantly contribute to the pathogenesis of the infections. Important human pathogens are poliovirus, coxsackievirus, human rhinovirus and hepatitis A virus. These viruses are the best-studied members of the family, and in this review we want to present the major aspects of the reciprocal effects between the immune system and these viruses. PMID- 24175217 TI - Viral evolution and transmission effectiveness. AB - Different viruses transmit among hosts with different degrees of efficiency. A basic reproductive number (R0) indicates an average number of cases getting infected from a single infected case. R0 can vary widely from a little over 1 to more than 10. Low R0 is usually found among rapidly evolving viruses that are often under a strong positive selection pressure, while high R0 is often found among viruses that are highly stable. The reason for the difference between antigenically diverse viruses with low R0, such as influenza A virus, and antigenically stable viruses with high R0, such as measles virus, is not clear and has been a subject of great interest. Optimization of transmissibility fitness considering intra-host dynamics and inter-host transmissibility was shown to result in strategies for tradeoff between transmissibility and diversity. The nature of transmission, targeting either a naive children population or an adult population with partial immunity, has been proposed as a contributing factor for the difference in the strategies used by the two groups of viruses. The R0 determines the levels of threshold heard immunity. Lower R0 requires lower herd immunity to terminate an outbreak. Therefore, it can be assumed that the outbreak saturation can be reached more readily when the R0 is low. In addition, one may assume that when the outbreak saturation is reached, herd immunity may provide a strong positive selection pressure that could possibly result in an occurrence of escape mutants. Studies of these hypotheses will give us an important insight into viral evolution. This review discusses the above hypotheses as well as some possible mechanistic explanation for the difference in transmission efficiency of viruses. PMID- 24175216 TI - Human T-lymphotropic virus proteins and post-translational modification pathways. AB - Cell life from the cell cycle to the signaling transduction and response to stimuli is finely tuned by protein post-translational modifications (PTMs). PTMs alter the conformation, the stability, the localization, and hence the pattern of interactions of the targeted protein. Cell pathways involve the activation of enzymes, like kinases, ligases and transferases, that, once activated, act on many proteins simultaneously, altering the state of the cell and triggering the processes they are involved in. Viruses enter a balanced system and hijack the cell, exploiting the potential of PTMs either to activate viral encoded proteins or to alter cellular pathways, with the ultimate consequence to perpetuate through their replication. Human T-lymphotropic virus type 1 (HTLV-1) is known to be highly oncogenic and associates with adult T-cell leukemia/lymphoma, HTLV-1 associated myelopathy/tropical spastic paraparesis and other inflammatory pathological conditions. HTLV-1 protein activity is controlled by PTMs and, in turn, viral activity is associated with the modulation of cellular pathways based on PTMs. More knowledge is acquired about the PTMs involved in the activation of its proteins, like Tax, Rex, p12, p13, p30, HTLV-I basic leucine zipper factor and Gag. However, more has to be understood at the biochemical level in order to counteract the associated fatal outcomes. This review will focus on known PTMs that directly modify HTLV-1 components and on enzymes whose activity is modulated by viral proteins. PMID- 24175218 TI - Emergence of Toscana virus in the mediterranean area. AB - Toscana virus (TOSV) is an arthropod-borne virus, identified in 1971, from Phlebotomus perniciosus and Phlebotomus perfiliewi in central Italy. TOSV belongs to the Phlebovirus genus within the Bunyaviridae family. As other bunyaviruses, the genome of TOSV consists of 3 segments (S for small, M for Medium, and L for Large) respectively encoding non structural and capsid proteins, envelope structural proteins, and the viral RNA-dependant RNA-polymerase. It is transmitted by sand flies. Therefore its distribution is dictated by that of the arthropod vectors, and virus circulation peaks during summertime when sandfly populations are active. Here, we reviewed the epidemiology of TOSV in the old world. First evidence of its pathogenicity for humans, specifically its propensity to cause central nervous system (CNS) infections such as meningitis and encephalitis, was reported in central Italy. After 2000, it was recognized that TOSV had a much larger geographic distribution than initially believed, and was present in most of the Western European countries located on the northern border of the Mediterranean Sea (Portugal, Spain, France, Greece, Croatia) as well as eastern countries such as Cyprus and Turkey. In the countries where TOSV is present, it is among the three most prevalent viruses in meningitis during the warm seasons, together with enteroviruses and herpesviruses. Up to now, epidemiological data concerning Northern Africa and other countries located south of the Mediterranean are scarce. TOSV must be considered an emerging pathogen. Despite the important role played by TOSV in CNS infections, it remains a neglected agent and is rarely considered by physicians in diagnostic algorithms of CNS infections and febrile illness during the warm season, probably because of the lack of information. PMID- 24175219 TI - Infectious laryngotracheitis virus in chickens. AB - Infectious laryngotracheitis (ILT) is an important respiratory disease of chickens and annually causes significant economic losses in the poultry industry world-wide. ILT virus (ILTV) belongs to alphaherpesvirinae and the Gallid herpesvirus 1 species. The transmission of ILTV is via respiratory and ocular routes. Clinical and post-mortem signs of ILT can be separated into two forms according to its virulence. The characteristic of the severe form is bloody mucus in the trachea with high mortality. The mild form causes nasal discharge, conjunctivitis, and reduced weight gain and egg production. Conventional polymerase chain reaction (PCR), nested PCR, real-time PCR, and loop-mediated isothermal amplification were developed to detect ILTV samples from natural or experimentally infected birds. The PCR combined with restriction fragment length polymorphism (RFLP) can separate ILTVs into several genetic groups. These groups can separate vaccine from wild type field viruses. Vaccination is a common method to prevent ILT. However, field isolates and vaccine viruses can establish latent infected carriers. According to PCR-RFLP results, virulent field ILTVs can be derived from modified-live vaccines. Therefore, modified-live vaccine reversion provides a source for ILT outbreaks on chicken farms. Two recently licensed commercial recombinant ILT vaccines are also in use. Other recombinant and gene deficient vaccine candidates are in the developmental stages. They offer additional hope for the control of this disease. However, in ILT endemic regions, improved biosecurity and management practices are critical for improved ILT control. PMID- 24175220 TI - Evaluation of virus-specific cellular immune response in transplant patients. AB - Virus-specific immune responses have a major impact on the outcome of the infection. Viral agents that are characterized by latency, such as herpesviruses and polyomaviruses, require a continuous immune control to reduce the extent of viral reactivation, as viral clearance cannot be accomplished, independently from the anti-viral treatment. In transplant patients, morbidity and mortality related to viral infections are significantly increased. In fact, the key steps of activation of T-cells are major target for anti-rejection immunosuppressive therapy and anti-viral immune response may be altered when infected cells and cellular effectors of immune response coexist in a transplanted organ. The role of cellular immune response in controlling viral replication and the main methods employed for its evaluation will be discussed. In particular, the main features, including both advantages and limitations, of available assays, including intracellular cytokine staining, major histocompatibility complex - multimer based assays, Elispot assay, and QuantiFERON test, will be described. The potential applications of these assays in the transplant context will be discussed, particularly in relation to cytomegalovirus and polyomavirus BK infection. The relevance of introducing viro-immunological monitoring, beside virological monitoring, in order to identify the risk profile for viral infections in the transplant patients will allows for define a patient-tailored clinical management, particular in terms of modulation of immunosuppressive therapy and anti-viral administration. PMID- 24175221 TI - Roles of the PI3K/Akt pathway in Epstein-Barr virus-induced cancers and therapeutic implications. AB - Viruses have been shown to be responsible for 10%-15% of cancer cases. Epstein Barr virus (EBV) is the first virus to be associated with human malignancies. EBV can cause many cancers, including Burkett's lymphoma, Hodgkin's lymphoma, post transplant lymphoproliferative disorders, nasopharyngeal carcinoma and gastric cancer. Evidence shows that phosphoinositide 3-kinase/protein kinase B (PI3K/Akt) plays a key role in EBV-induced malignancies. The main EBV oncoproteins latent membrane proteins (LMP) 1 and LMP2A can activate the PI3K/Akt pathway, which, in turn, affects cell survival, apoptosis, proliferation and genomic instability via its downstream target proteins to cause cancer. It has also been demonstrated that the activation of the PI3K/Akt pathway can result in drug resistance to chemotherapy. Thus, the inhibition of this pathway can increase the therapeutic efficacy of EBV-associated cancers. For example, PI3K inhibitor Ly294002 has been shown to increase the effect of 5-fluorouracil in an EBV-associated gastric cancer cell line. At present, dual inhibitors of PI3K and its downstream target mammalian target of rapamycin have been used in clinical trials and may be included in treatment regimens for EBV-associated cancers. PMID- 24175222 TI - Hepatitis viruses and non-Hodgkin's lymphoma: A review. AB - Non-Hodgkin's lymphoma (NHL) is among the haematological malignancies with high prevalence worldwide, causing estimated 355 900 new cases and 191 400 deaths in 2008. High prevalence of NHL is documented in economically more developed areas while low prevalence is observed in less developed areas of the globe. A wide array of environmental factors have been reported to be either directly involved or in modifying the risk of NHL development. In addition to these factors, a number of infectious agents, chiefly viruses have also been implicated in the development of NHL. This article reviews the available literature to discuss the role of hepatitis viruses in NHL development, possible mechanisms of lymphomagenesis and also identify the areas in which further research is required to better understand this disease. A brief discussion on the clinical aspects such as classification, staging, treatment approaches have also been included in this article. PMID- 24175223 TI - Antiviral treatment to prevent chronic hepatitis B or C-related hepatocellular carcinoma. AB - Antiviral treatment is the only option to prevent or defer the occurrence of hepatocellular carcinoma (HCC) in patients chronically infected with hepatitis B virus (HBV) or hepatitis C virus (HCV). The approved medication for the treatment of chronic HBV infection is interferon-alpha (IFNalpha) and nucleos(t)ide analogues (NAs), including lamivudine, adefovir dipivoxil, telbivudine, entecavir and tenofovir disoproxil fumarate. IFNalpha is the most suitable for young patients with less advanced liver diseases and those infected with HBV genotype A. IFNalpha treatment significantly decreases the overall incidence of HBV related HCC in sustained responders. However, side effects may limit its long term clinical application. Orally administered NAs are typically implemented for patients with more advanced liver diseases. NA treatment significantly reduces disease progression of cirrhosis and therefore HCC incidence, especially in HBV e antigen-positive patients. NA-resistance due to the mutations in HBV polymerase is a major limiting factor. Of the NA resistance-associated mutants, A181T mutant significantly increases the risk of HCC development during the subsequent course of NA therapy. It is important to initiate treatment with NAs that have a high genetic barrier to resistance, to counsel patients on medication adherence and to monitor virological breakthroughs. The recommended treatment for patients with chronic HCV infection is peg-IFN plus ribavirin that can decrease the occurrence of HCC in those who achieve a sustained virological response and have not yet progressed to cirrhosis. IFN-based treatment is reserved for patients with decompensated cirrhosis who are under evaluation of liver transplantation to reduce post-transplant recurrence of HCV. More effective therapeutic options such as direct acting antiviral agents will hopefully increase the response rate in difficult-to-treat patients with HCV genotype 1. However, the risk of HCC remains in cirrhotic patients (both chronic HBV and HCV infection) if treatment is initiated after cirrhosis is established. Future research should focus on investigating new agents, especially for those patients with hepatic decompensation or post-transplantation. PMID- 24175224 TI - Betanodavirus: Mitochondrial disruption and necrotic cell death. AB - Betanodaviruses cause viral nervous necrosis, an infectious neuropathological condition in fish that is characterized by necrosis of the central nervous system, including the brain and retina. This disease can cause mass mortality in larval and juvenile populations of several teleost species and is of global economic importance. The mechanism of brain and retina damage during betanodavirus infection is poorly understood. In this review, we will focus recent results that highlight betanodavirus infection-induced molecular death mechanisms in vitro. Betanodavirus can induce host cellular death and post apoptotic necrosis in fish cells. Betanodavirus-induced necrotic cell death is also correlated with loss of mitochondrial membrane potential in fish cells, as this necrotic cell death is blocked by the mitochondrial membrane permeability transition pore inhibitor bongkrekic acid and the expression of the anti apoptotic Bcl-2 family member zfBcl-xL. Moreover, this mitochondria-mediated necrotic cell death may require a caspase-independent pathway. A possible cellular death pathway involving mitochondrial function and the modulator zfBcl xs is discussed which may provide new insights into the necrotic pathogenesis of betanodavirus. PMID- 24175225 TI - Hepatitis C virus resistance to new specifically-targeted antiviral therapy: A public health perspective. AB - Until very recently, treatment for chronic hepatitis C virus (HCV) infection has been based on the combination of two non-viral specific drugs: pegylated interferon-alpha and ribavirin, which is effective in, overall, about 40%-50% of cases. To improve the response to treatment, novel drugs have been designed to specifically block viral proteins. Multiple compounds are under development, and the approval for clinical use of the first of such direct-acting antivirals in 2011 (Telaprevir and Boceprevir), represents a milestone in HCV treatment. HCV therapeutics is entering a new expanding era, and a highly-effective cure is envisioned for the first time since the discovery of the virus in 1989. However, any antiviral treatment may be limited by the capacity of the virus to overcome the selective pressure of new drugs, generating antiviral resistance. Here, we try to provide a basic overview of new treatments, HCV resistance to new antivirals and some considerations derived from a Public Health perspective, using HCV resistance to protease and polymerase inhibitors as examples. PMID- 24175226 TI - Reprogramming the host: Modification of cell functions upon viral infection. AB - Viruses and their hosts have co-evolved for million years. In order to successfully replicate their genome, viruses need to usurp the biosynthetic machinery of the host cell. Depending on the complexity and the nature of the genome, replication might involve or not a relatively large subset of viral products, in addition to a number of host cell factors, and take place in several subcellular compartments, including the nucleus, the cytoplasm, as well as virus induced, rearranged membranes. Therefore viruses need to ensure the correct subcellular localization of their effectors and to be capable of disguising from the cellular defensive mechanisms. In addition, viruses are capable of exploiting host cell activities, by modulating their post-translational modification apparatus, resulting in profound modifications in the function of cellular and viral products. Not surprisingly infection of host cells by these parasites can lead to alterations of cellular differentiation and growing properties, with important pathogenic consequences. In the present hot topic highlight entitled "Reprogramming the host: modification of cell functions upon viral infection", a number of leading virologists and cell biologist thoroughly describe recent advances in our understanding of how viruses modulate cellular functions to achieve successful replication and propagation at the expenses of human cells. PMID- 24175227 TI - High-throughput RNA interference screens integrative analysis: Towards a comprehensive understanding of the virus-host interplay. AB - Viruses are extremely heterogeneous entities; the size and the nature of their genetic information, as well as the strategies employed to amplify and propagate their genomes, are highly variable. However, as obligatory intracellular parasites, replication of all viruses relies on the host cell. Having co-evolved with their host for several million years, viruses have developed very sophisticated strategies to hijack cellular factors that promote virus uptake, replication, and spread. Identification of host cell factors (HCFs) required for these processes is a major challenge for researchers, but it enables the identification of new, highly selective targets for anti viral therapeutics. To this end, the establishment of platforms enabling genome-wide high-throughput RNA interference (HT-RNAi) screens has led to the identification of several key factors involved in the viral life cycle. A number of genome-wide HT-RNAi screens have been performed for major human pathogens. These studies enable first inter viral comparisons related to HCF requirements. Although several cellular functions appear to be uniformly required for the life cycle of most viruses tested (such as the proteasome and the Golgi-mediated secretory pathways), some factors, like the lipid kinase Phosphatidylinositol 4-kinase IIIalpha in the case of hepatitis C virus, are selectively required for individual viruses. However, despite the amount of data available, we are still far away from a comprehensive understanding of the interplay between viruses and host factors. Major limitations towards this goal are the low sensitivity and specificity of such screens, resulting in limited overlap between different screens performed with the same virus. This review focuses on how statistical and bioinformatic analysis methods applied to HT-RNAi screens can help overcoming these issues thus increasing the reliability and impact of such studies. PMID- 24175228 TI - Architecture and biogenesis of plus-strand RNA virus replication factories. AB - Plus-strand RNA virus replication occurs in tight association with cytoplasmic host cell membranes. Both, viral and cellular factors cooperatively generate distinct organelle-like structures, designated viral replication factories. This compartmentalization allows coordination of the different steps of the viral replication cycle, highly efficient genome replication and protection of the viral RNA from cellular defense mechanisms. Electron tomography studies conducted during the last couple of years revealed the three dimensional structure of numerous plus-strand RNA virus replication compartments and highlight morphological analogies between different virus families. Based on the morphology of virus-induced membrane rearrangements, we propose two separate subclasses: the invaginated vesicle/spherule type and the double membrane vesicle type. This review discusses common themes and distinct differences in the architecture of plus-strand RNA virus-induced membrane alterations and summarizes recent progress that has been made in understanding the complex interplay between viral and co opted cellular factors in biogenesis and maintenance of plus-strand RNA virus replication factories. PMID- 24175229 TI - Innate host responses to West Nile virus: Implications for central nervous system immunopathology. AB - West Nile virus (WNV) is an emerging neurotropic flavivirus that has recently spread to America and Southern Europe via an enzootic/epizootic bird-mosquito bird transmission cycle. The virus can occasionally infect humans through mosquito bites, and man-to-man transmission has also been reported via infected blood or organ donation. In the human host, WNV causes asymptomatic infection in about 70%-80% of cases, while < 1% of clinical cases progress to severe neuroinvasive disease; long-term neurological sequelae are common in more than 50% of these severe cases. The pathogenesis of the neuroinvasive form of WNV infection remains incompletely understood, and risk factors for developing severe clinical illness are largely unknown. The innate immune response plays a major role in the control of WNV replication, which is supported by the fact that the virus has developed numerous mechanisms to escape the control of antiviral interferons. However, exaggerated inflammatory responses lead to pathology, mainly involving the central nervous system. This brief review presents the salient features of innate host responses, WNV immunoevasion strategies, and WNV induced immunopathology. PMID- 24175231 TI - Viral proteins and Src family kinases: Mechanisms of pathogenicity from a "liaison dangereuse". AB - To complete their life cycle and spread, viruses interfere with and gain control of diverse cellular processes, this most often occurring through interaction between viral proteins (VPs) and resident protein partners. Among the latter, Src family kinases (SFKs), a class of non-receptor tyrosine kinases that contributes to the conversion of extracellular signals into intracellular signaling cascades and is involved in virtually all cellular processes, have recently emerged as critical mediators between the cell's infrastructure and the viral demands. In this scenario, structural or ex novo synthesized VPs are able to bind to the different domains of these enzymes through specific short linear motifs present along their sequences. Proline-rich motifs displaying the conserved minimal consensus PxxP and recognizing the SFK Src homology (SH)3 domain constitute a cardinal signature for the formation of multiprotein complexes and this interaction may promote phosphorylation of VPs by SFKs, thus creating phosphotyrosine motifs that become a docking site for the SH2 domains of SFKs or other SH2 domain-bearing signaling molecules. Importantly, the formation of these assemblies also results in a change in the activity and/or location of SFKs, and these events are critical in perturbing key signaling pathways so that viruses can utilize the cell's machinery to their own benefit. In the light of these observations, although VPs as such, especially those with enzyme activity, are still regarded as valuable targets for therapeutic strategies, multiprotein complexes composed of viral and host cell proteins are increasingly becoming objects of investigation with a view to deeply characterize the structural aspects that favor their formation and to develop new compounds able to contrast viral diseases in an alternative manner. PMID- 24175230 TI - Paramyxovirus evasion of innate immunity: Diverse strategies for common targets. AB - The paramyxoviruses are a family of > 30 viruses that variously infect humans, other mammals and fish to cause diverse outcomes, ranging from asymptomatic to lethal disease, with the zoonotic paramyxoviruses Nipah and Hendra showing up to 70% case-fatality rate in humans. The capacity to evade host immunity is central to viral infection, and paramyxoviruses have evolved multiple strategies to overcome the host interferon (IFN)-mediated innate immune response through the activity of their IFN-antagonist proteins. Although paramyxovirus IFN antagonists generally target common factors of the IFN system, including melanoma differentiation associated factor 5, retinoic acid-inducible gene-I, signal transducers and activators of transcription (STAT)1 and STAT2, and IFN regulatory factor 3, the mechanisms of antagonism show remarkable diversity between different genera and even individual members of the same genus; the reasons for this diversity, however, are not currently understood. Here, we review the IFN antagonism strategies of paramyxoviruses, highlighting mechanistic differences observed between individual species and genera. We also discuss potential sources of this diversity, including biological differences in the host and/or tissue specificity of different paramyxoviruses, and potential effects of experimental approaches that have largely relied on in vitro systems. Importantly, recent studies using recombinant virus systems and animal infection models are beginning to clarify the importance of certain mechanisms of IFN antagonism to in vivo infections, providing important indications not only of their critical importance to virulence, but also of their potential targeting for new therapeutic/vaccine approaches. PMID- 24175232 TI - Viral manipulation of cellular protein conjugation pathways: The SUMO lesson. AB - Small ubiquitin-like modifier (SUMO)ylation is a key post-translational modification mechanism that controls the function of a plethora of proteins and biological processes. Given its central regulatory role, it is not surprising that it is widely exploited by viruses. A number of viral proteins are known to modify and/or be modified by the SUMOylation system to exert their function, to create a cellular environment more favorable for virus survival and propagation, and to prevent host antiviral responses. Since the SUMO pathway is a multi-step cascade, viral proteins engage with it at many levels, to advance and favor each stage of a typical infection cycle: replication, viral assembly and immune evasion. Here we review the current knowledge on the interplay between the host SUMO system and viral lifecycle. PMID- 24175235 TI - What is the purpose of launching the World Journal of Nephrology? AB - The launch of the World Journal of Nephrology (WJN) has distinct purposes. Its main purpose is to incorporate the fields of diabetes, hypertension, urology, cardiology and neurology, which are related to kidney disease, and to make all of our readers, contributors and allied health professionals feel at home with the WJN. The WJN aims to rapidly report new theories, methods and techniques for prevention, diagnosis, treatment, rehabilitation and nursing skill in the field of nephrology. The WJN will cover diagnostic imaging, disorders of kidney development, renal obstruction, atrophy and regeneration, kidney tumors, renal pharmacology and therapy, renal replacement therapies including transplantation, and Chinese herbal medicine. The WJN issues will include an editorial, frontier, invited review of articles and commentaries in addition to original articles submitted. The WJN will solicit articles from investigators in areas of diabetes and hypertension, and high priority will be given to those articles with an emphasis on the prevention of dialysis. Final decision for publication will be based on the merit of the article, language and lucidity. PMID- 24175234 TI - How virus persistence can initiate the tumorigenesis process. AB - Human oncogenic viruses are defined as necessary but not sufficient to initiate cancer. Experimental evidence suggests that the oncogenic potential of a virus is effective in cells that have already accumulated a number of genetic mutations leading to cell cycle deregulation. Current models for viral driven oncogenesis cannot explain why tumor development in carriers of tumorigenic viruses is a very rare event, occurring decades after virus infection. Considering that viruses are mutagenic agents per se and human oncogenic viruses additionally establish latent and persistent infections, we attempt here to provide a general mechanism of tumor initiation both for RNA and DNA viruses, suggesting viruses could be both necessary and sufficient in triggering human tumorigenesis initiation. Upon reviewing emerging evidence on the ability of viruses to induce DNA damage while subverting the DNA damage response and inducing epigenetic disturbance in the infected cell, we hypothesize a general, albeit inefficient hit and rest mechanism by which viruses may produce a limited reservoir of cells harboring permanent damage that would be initiated when the virus first hits the cell, before latency is established. Cells surviving virus generated damage would consequently become more sensitive to further damage mediated by the otherwise insufficient transforming activity of virus products expressed in latency, or upon episodic reactivations (viral persistence). Cells with a combination of genetic and epigenetic damage leading to a cancerous phenotype would emerge very rarely, as the probability of such an occurrence would be dependent on severity and frequency of consecutive hit and rest cycles due to viral reinfections and reactivations. PMID- 24175233 TI - Effects of human immunodeficiency virus on the erythrocyte and megakaryocyte lineages. AB - Anaemia and thrombocytopenia are haematological disorders that can be detected in many human immunodeficiency virus (HIV)-positive patients during the development of HIV infection. The progressive decline of erythrocytes and platelets plays an important role both in HIV disease progression and in the clinical and therapeutic management of HIV-positive patients. HIV-dependent impairment of the megakaryocyte and erythrocyte lineages is multifactorial and particularly affects survival, proliferation and differentiation of bone marrow (BM) CD34+ haematopoietic progenitor cells, the activity of BM stromal cells and the regulation of cytokine networks. In this review, we analyse the major HIV-related mechanisms that are involved in the genesis and development of the anaemia and thrombocytopenia observed in HIV positive patients. PMID- 24175236 TI - Cytoprotection behind heme oxygenase-1 in renal diseases. AB - Renal insults are considered a public health problem and are linked to increased rates of morbidity and mortality worldwide. The heme oxygenase (HO) system consists of evolutionary specialized machinery that degrades free heme and produces carbon monoxide, biliverdin and free iron. In this sense, the inducible isoform HO-1 seems to develop an important role and is widely studied. The reaction involved with the HO-1 molecule provides protection to injured tissue, directly by reducing the toxic heme molecule and indirectly by the release of its byproducts. The up regulation of HO-1 enzyme has largely been described as providing antioxidant, antiapoptotic, anti-inflammatory and immunomodulatory properties. Several works have explored the importance of HO-1 in renal diseases and they have provided consistent evidence that its overexpression has beneficial effects in such injuries. So, in this review we will focus on the role of HO-1 in kidney insults, exploring the protective effects of its up regulation and the enhanced deleterious effects of its inhibition or gene deletion. PMID- 24175237 TI - Urinary stone disease and obesity: Different pathologies sharing common biochemical mechanisms. AB - The prevalence of urolithiasis is increasing in parallel with the escalating rate of obesity worldwide. It has previously been speculated that obesity is a potential risk factor for urinary stone disease. The possibility that common biochemical mechanisms underlie both obesity and urolithiasis is remarkable. Better understanding of possible common mechanisms of these diseases could potentially lead to a better management of urinary stone prevention. The prevention of urinary stone formation gives clinicians an acceptable reason to encourage lifestyle modification and weight loss through a regular diet. In this review, the association of obesity with urinary stone disease, possible common biochemical mechanisms, effects of dietary habits and weight loss on stone formation, as well as difficulties in surgical management of obese individuals with urolithiasis are discussed. PMID- 24175238 TI - Epidemiology, pathophysiology, clinical characteristics and management of childhood cardiorenal syndrome. AB - Cardiorenal syndrome (CRS) is a new term recently introduced to describe the acute or chronic comorbid state of the heart and kidney that has been long known and frequently managed in very sick individuals. The tight and delicate coordination of physiological functions among organ systems in the human body makes dysfunction in one to lead to malfunction of one or more other organ systems. CRS is a universal very common morbidity in the critically ill, with a high mortality rate that has received very little research attention in children. Simultaneous management of heart and renal failures in CRS is quite challenging; the therapeutic choice made for one organ must not jeopardize the other. This paper reviews the epidemiology, pathophysiology, clinical characteristics and management of acute and chronic CRS in children. PMID- 24175239 TI - Arterial stiffness, vascular calcification and bone metabolism in chronic kidney disease. AB - Patients with chronic kidney disease (CKD) have an extremely poor cardiovascular outcome. Arterial stiffness, a strong independent predictor of survival in CKD, is connected to arterial media calcification. A huge number of different factors contribute to the increased arterial calcification and stiffening in CKD, a process which is in parallel with impaired bone metabolism. This coincidence was demonstrated to be part of the direct inhibition of calcification in the vessels, which is a counterbalancing effect but also leads to low bone turnover. Due to the growing evidence, the definition of "CKD mineral bone disorder" was created recently, underlining the strong connection of the two phenomena. In this review, we aim to demonstrate the mechanisms leading to increased arterial stiffness and the up-to date data of the bone-vascular axis in CKD. We overview a list of the different factors, including inhibitors of bone metabolism like osteoprotegerin, fetuin-A, pyrophosphates, matrix Gla protein, osteopontin, fibroblast growth factor 23 and bone morphogenic protein, which seem to play role in the progression of vascular calcification and we evaluate their connection to impaired arterial stiffness in the mirror of recent scientific results. PMID- 24175240 TI - Collapsing focal segmental glomerulosclerosis: Current concepts. AB - Collapsing focal segmental glomerulosclerosis (cFSGS), also known as collapsing glomerulopathy is currently classified under the rubric of FSGS. However, its defining morphological features are in stark contrast to those observed in most other variants of FSGS. During the early stage of the disease, the lesion is characterized pathologically by an implosive segmental and/or global collapse of the glomerular capillary tufts, marked hypertrophy and hyperplasia of podocytes, and severe tubulointerstitial disease. With advancement of the disease, segmental and/or global glomerulosclerosis is also observed in association with the collapsing lesions. The etiology of this enigmatic disorder is still elusive, but a growing list of diseases/conditions is being reported in association with this morphological pattern of renal parenchymal injury. The pathogenesis of cFSGS involves discreet epithelial cell injury leading to cell cycle dysregulation and a proliferative cellular phenotype. From the clinical perspective, cFSGS is notorious for its propensity to affect black people, a high incidence and severity of nephrotic syndrome, marked resistance to empirical therapy, and rapid progression to end-stage renal disease. The lesion has also been reported in transplanted kidneys either as recurrent or de novo disease, frequently leading to graft loss. Most cases have been reported in western countries, but the lesion is also being increasingly recognized in the tropical regions. The recent increase in reporting of cFSGS partly reflects a true increase in the incidence and partly a detection bias. There is no specific treatment for the disorder at present. Newer insights into the pathogenesis may lead to the development of targeted and specific therapy in near future. There is an urgent need to increase awareness of the lesion among pathologists and nephrologists, especially those from developing countries, to ensure accurate diagnosis and appropriate managment. With the accumulation of more and more data, it is hoped that the prevailing confusion about the nosological identity of the lesion will also be resolved in a more logical way. PMID- 24175241 TI - Vascular calcification in chronic kidney disease: Pathogenesis and clinical implication. AB - Cardiovascular disease is the leading cause of death among patients with chronic kidney disease (CKD). Vascular calcification (VC) is one of the independent risk factors associated with cardiovascular disease and cardiovascular mortality in both the general population and CKD patients. Earlier evidence revealed substantially higher prevalence of VC in young adults on chronic hemodialysis compared to the general population in the same age range, indicating the influence of CKD-related risk factors on the development of VC. Pathogenesis of VC involves an active, highly organized cellular transformation of vascular smooth muscle cells to bone forming cells evidenced by the presence of bone matrix proteins in the calcified arterial wall. VC occurs in both the intima and the media of arterial wall with medial calcification being more prevalent in CKD. In addition to traditional cardiovascular risks, risk factors specific to CKD such as phosphate retention, excess of calcium, history of dialysis, active vitamin D therapy in high doses and deficiency of calcification inhibitors play important roles in promoting the development of VC. Non-contrast multi-slice computed tomography has often been used to detect coronary artery calcification. Simple plain radiographs of the lateral lumbar spine and pelvis can also detect VC in the abdominal aorta and femoral and iliac arteries. Currently, there is no specific therapy to reverse VC. Reduction of calcium load, lowering phosphate retention using non-calcium containing phosphate binders, and moderate doses of active vitamin D may attenuate progression. Parenteral sodium thiosulfate has also been shown to delay VC progression. PMID- 24175242 TI - Bone disease in pediatric idiopathic hypercalciuria. AB - Idiopathic hypercalciuria (IH) is the leading metabolic risk factor for urolithiasis and affects all age groups without gender or race predominance. IH has a high morbidity with or without lithiasis and reduced bone mineral density (BMD), as described previously in pediatric patients as well as in adults. The pathogenesis of IH is complex and not completely understood, given that urinary excretion of calcium is the end result of an interplay between three organs (gut, bone and kidney), which is further orchestrated by hormones, such as 1,25 dihydroxyvitamin D, parathyroid hormone, calcitonin and fosfatonins (i.e., fibroblast growth-factor-23). Usually, a primary defect in one organ induces compensatory mechanisms in the remaining two organs, such as increased absorption of calcium in the gut secondary to a primary renal loss. Thus, IH is a systemic abnormality of calcium homeostasis with changes in cellular transport of this ion in intestines, kidneys and bones. Reduced BMD has been demonstrated in pediatric patients diagnosed with IH. However, the precise mechanisms of bone loss or failure of adequate bone mass gain are still unknown. The largest accumulation of bone mass occurs during childhood and adolescence, peaking at the end of the second decade of life. This accumulation should occur without interference to achieve the peak of optimal bone mass. Any interference may be a risk factor for the reduction of bone mass with increased risk of fractures in adulthood. This review will address the pathogenesis of IH and its consequence in bone mass. PMID- 24175243 TI - Fanconi-Bickel syndrome as an example of marked allelic heterogeneity. AB - Renal tubular acidosis (RTA) encompasses many renal tubular disorders characterized by hyperchloremic metabolic acidosis with a normal anion gap. Untreated patients usually complain of growth failure, osteoporosis, rickets, nephrolithiasis and eventually renal insufficiency. Fanconi-Bickel syndrome (FBS) is an example of proximal RTA due to a single gene disorder; it is caused by defects in the facilitative glucose transporter 2 gene that codes for the glucose transporter protein 2 expressed in hepatocytes, pancreatic beta-cells, enterocytes and renal tubular cells. It is a rare inherited disorder of carbohydrate metabolism manifested by huge hepatomegaly [hence it is classified as glycogen storage disease (GSD) type XI; GSD XI], severe hypophosphatemic rickets and failure to thrive due to proximal renal tubular dysfunction leading to glucosuria, phosphaturia, generalized aminoaciduria, bicarbonate wasting and hypophosphatemia. The disorder has been reported from all parts of Europe, Turkey, Israel, Arabian countries, Japan and North America. Many mutant alleles have been described, its exact frequency is unknown and there is no single mutation found more frequently than the others. The presence of consanguinity in affected families suggests an autosomal recessive pattern of inheritance. New cases of FBS have been recently reported in the Middle and Far East in collaboration with specialized centers. Two novel mutations have been discovered in two unrelated Egyptian families. The first was two bases deletion, guanine and adenine, (c.253_254delGA) causing a frameshift mutation (p. Glu85fs) and the second is mutation in exon6 in splicing acceptor site with intron5 (c.776-1G>C or IVS5-1G>A). Moreover, a new different mutation was described in a 3 year old Indian boy. PMID- 24175244 TI - Vascular access today. AB - The number of patients with chronic kidney disease requiring renal replacement therapy has increased worldwide. The most common replacement therapy is hemodialysis (HD). Vascular access (VA) has a key role for successful treatment. Despite the advances that have taken place in the field of the HD procedure, few things have changed with regards to VA in recent years. Arteriovenous fistula (AVF), polytetrafluoroethylene graft and the cuffed double lumen silicone catheter are the most common used for VA. In the long term, a number of complications may present and more than one VA is needed during the HD life. The most common complications for all of VA types are thrombosis, bleeding and infection, the most common cause of morbidity in these patients. It has been estimated that VA dysfunction is responsible for 20% of all hospitalizations. The annual cost of placing and looking after dialysis VA in the United States exceeds 1 billion dollars per year. A good functional access is also vital in order to deliver adequate HD therapy. It seems that the native AVF that Brescia and Cimino described in 1966 still remains the first choice for VA. The native forearm AVFs have the longest survival and require the fewest interventions. For this reason, the forearm AVF is the first choice, followed by the upper-arm AVF, the arteriovenous graft and the cuffed central venous catheter is the final choice. In conclusion, VA remains the most important issue for patients on HD and despite the technical improvements, a number of problems and complications have to be resolved. PMID- 24175245 TI - Kidney donation after cardiac death. AB - There is continuing disparity between demand for and supply of kidneys for transplantation. This review describes the current state of kidney donation after cardiac death (DCD) and provides recommendations for a way forward. The conversion rate for potential DCD donors varies from 40%-80%. Compared to controlled DCD, uncontrolled DCD is more labour intensive, has a lower conversion rate and a higher discard rate. The super-rapid laparotomy technique involving direct aortic cannulation is preferred over in situ perfusion in controlled DCD donation and is associated with lower kidney discard rates, shorter warm ischaemia times and higher graft survival rates. DCD kidneys showed a 5.73-fold increase in the incidence of delayed graft function (DGF) and a higher primary non function rate compared to donation after brain death kidneys, but the long term graft function is equivalent between the two. The cold ischaemia time is a controllable factor that significantly influences the outcome of allografts, for example, limiting it to < 12 h markedly reduces DGF. DCD kidneys from donors < 50 function like standard criteria kidneys and should be viewed as such. As the majority of DCD kidneys are from controlled donation, incorporation of uncontrolled donation will expand the donor pool. Efforts to maximise the supply of kidneys from DCD include: implementing organ recovery from emergency department setting; improving family consent rate; utilising technological developments to optimise organs either prior to recovery from donors or during storage; improving organ allocation to ensure best utility; and improving viability testing to reduce primary non function. PMID- 24175246 TI - Different modes of renal proximal tubule regeneration in health and disease. AB - Tissues are equipped with reasonable strategies for repair and regeneration and the renal proximal tubule (PT) is no exception. New information has become available on the mode of PT regeneration in mammals. Unlike the intestinal epithelium with a high rate of turnover maintained by the stem cell system, the kidney has low turnover under normal physiological conditions. The PT seems to be maintained physiologically by hyperplasia, a regenerating system with self renewal of mature tubular cells. This mode of regeneration is advantageous for effective replenishment of randomly isolated and eliminated tubular cells by self renewal of adjacent cells. On the other hand, it has been suggested that dedifferentiation of mature tubular cells plays a role in regeneration after acute kidney injury. Recent studies employing genetic labeling and DNA-labeling techniques have confirmed that the proliferation of preexisting injured mature tubular cells contributes mainly to PT regeneration in ischemic reperfusion injury. This mode of regeneration is beneficial with regard to the rapid reparation of focally injured tubules often induced by ischemic reperfusion injury. What happens, however, when the PT is homogeneously injured with almost no remaining surviving cells Is the PT equipped with another backup regeneration system, e.g., the stem cell system Is it possible that certain types of renal injuries evoke a stem cell response whereas others do not This review focuses on all three possible modes of tissue regeneration (compensatory hyperplasia, dedifferentiation and stem cell system) in mammals and their involvement in PT regeneration in health and disease. PMID- 24175247 TI - Vitamin E-derived copolymers continue the challenge to hemodialysis biomaterials. AB - Improving material biocompatibility has been a continuous effort and remains a major goal of dialysis therapy. In this respect, vitamin E-modified copolymers have been used to produce a generation of biomaterials that has offered new clinical challenges and the chance of further improving the quality of synthetic hemodialyser membranes. This mini review article describes the evolution of these copolymers that only recently have been adopted to develop new vitamin E-modified polysulfone hemodialysers. Biomaterial characteristics and clinical aspects of these membranes are discussed, starting from the most recent contributions that have appeared in the literature that are of interest for the community of nephrology and dialysis specialists, as well as biomaterial scientists. PMID- 24175249 TI - Creatinine, urea, uric acid, water and electrolytes renal handling in the healthy oldest old. AB - RENAL PHYSIOLOGY IN THE HEALTHY OLDEST OLD HAS THE FOLLOWING CHARACTERISTICS, IN COMPARISON WITH THE RENAL PHYSIOLOGY IN THE YOUNG: a reduced creatinine clearance, tubular pattern of creatinine back-filtration, preserved proximal tubule sodium reabsorption and uric acid secretion, reduced sodium reabsorption in the thick ascending loop of Henle, reduced free water clearance, increased urea excretion, presence of medulla hypotonicity, reduced urinary dilution and concentration capabilities, and finally a reduced collecting tubules response to furosemide which expresses a reduced potassium excretion in this segment due to a sort of aldosterone resistance. All physiological changes of the aged kidney are the same in both genders. PMID- 24175248 TI - Peritoneal dialysis associated infections: An update on diagnosis and management. AB - Peritoneal dialysis (PD) is associated with a high risk of infection of the peritoneum, subcutaneous tunnel and catheter exit site. Although quality standards demand an infection rate < 0.67 episodes/patient/year on dialysis, the reported overall rate of PD associated infection is 0.24-1.66 episodes/patient/year. It is estimated that for every 0.5-per-year increase in peritonitis rate, the risk of death increases by 4% and 18% of the episodes resulted in removal of the PD catheter and 3.5% resulted in death. Improved diagnosis, increased awareness of causative agents in addition to other measures will facilitate prompt management of PD associated infection and salvage of PD modality. The aims of this review are to determine the magnitude of the infection problem, identify possible risk factors and provide an update on the diagnosis and management of PD associated infection. Gram-positive cocci such as Staphylococcus epidermidis, other coagulase negative staphylococcoci, and Staphylococcus aureus (S. aureus) are the most frequent aetiological agents of PD associated peritonitis worldwide. Empiric antibiotic therapy must cover both gram positive and gram-negative organisms. However, use of systemic vancomycin and ciprofloxacin administration for example, is a simple and efficient first-line protocol antibiotic therapy for PD peritonitis - success rate of 77%. However, for fungal PD peritonitis, it is now standard practice to remove PD catheters in addition to antifungal treatment for a minimum of 3 wk and subsequent transfer to hemodialysis. To prevent PD associated infections, prophylactic antibiotic administration before catheter placement, adequate patient training, exit-site care, and treatment for S. aureus nasal carriage should be employed. Mupirocin treatment can reduce the risk of exit site infection by 46% but it cannot decrease the risk of peritonitis due to all organisms. PMID- 24175250 TI - Metabolic bone diseases in kidney transplant recipients. AB - Metabolic bone disease after kidney transplantation has a complex pathophysiology and heterogeneous histology. Pre-existing renal osteodystrophy may not resolve completely, but continue or evolve into a different osteodystrophy. Rapid bone loss immediately after transplant can persist, at a lower rate, for years to come. These greatly increase the risk of bone fracture and vertebral collapse. Each patient may have multiple risk factors of bone loss, such as steroids usage, hypogonadism, persistent hyperparathyroidism (HPT), poor allograft function, metabolic acidosis, hypophosphatemia, vitamin D deficiency, aging, immobility and chronic disease. Clinical management requires a comprehensive approach to address the underlying and ongoing disease processes. Successful prevention of bone loss has been shown with vitamin D, bisphosphonates, calcitonin as well as treatment of hypogonadism and HPT. Novel approach to restore the normal bone remodeling and improve the bone quality may be needed in order to effectively decrease bone fracture rate in kidney transplant recipients. PMID- 24175251 TI - Chronic kidney disease in acute coronary syndromes. AB - Chronic kidney disease (CKD) is associated with a high burden of coronary artery disease. In patients with acute coronary syndromes (ACS), CKD is highly prevalent and associated with poor short- and long-term outcomes. Management of patients with CKD presenting with ACS is more complex than in the general population because of the lack of well-designed randomized trials assessing therapeutic strategies in such patients. The almost uniform exclusion of patients with CKD from randomized studies evaluating new targeted therapies for ACS, coupled with concerns about further deterioration of renal function and therapy-related toxic effects, may explain the less frequent use of proven medical therapies in this subgroup of high-risk patients. However, these patients potentially have much to gain from conventional revascularization strategies used in the general population. The objective of this review is to summarize the current evidence regarding the epidemiology and the clinical and prognostic relevance of CKD in ACS patients, in particular with respect to unresolved issues and uncertainties regarding recommended medical therapies and coronary revascularization strategies. PMID- 24175252 TI - Role of renal proximal tubule transport in thiazolidinedione-induced volume expansion. AB - Thiazolidinediones (TZDs), pharmacological activators of peroxisome-proliferator activated receptors gamma (PPARgamma), significantly improve insulin resistance and lower plasma glucose concentrations. However, the use of TZDs is associated with plasma volume expansion, the mechanism of which has been a matter of controversy. Originally, PPARgamma-mediated enhanced transcription of the epithelial Na channel (ENaC) gamma subunit was thought to play a central role in TZD-induced volume expansion. However, later studies suggested that the activation of ENaC alone could not explain TZD-induced volume expansion. We have recently shown that TZDs rapidly stimulate sodium-coupled bicarbonate absorption from renal proximal tubule (PT) in vitro and in vivo. TZD-induced transport stimulation was dependent on PPARgamma/Src/EGFR/ERK, and observed in rat, rabbit and human. However, this stimulation was not observed in mouse PTs where Src/EGFR is constitutively activated. Analysis in mouse embryonic fibroblast cells confirmed the existence of PPARgamma/Src-dependent non-genomic signaling, which requires the ligand binding ability but not the transcriptional activity of PPARgamma. The TZD-induced enhancement of association between PPARgamma and Src supports an obligatory role for Src in this signaling. These results support the view that TZD-induced volume expansion is multifactorial. In addition to the PPARgamma-dependent enhanced expression of the sodium transport system(s) in distal nephrons, the PPARgamma-dependent non-genomic stimulation of renal proximal transport may be also involved in TZD-induced volume expansion. PMID- 24175253 TI - Proton pump inhibitor-induced hypomagnesemia: A new challenge. AB - Proton pump inhibitors (PPIs) are commonly used in clinical practice for the prevention and treatment of peptic ulcer, gastritis, esophagitis and gastroesophageal reflux. Hypomagnesemia has recently been recognized as a side effect of PPIs. Low magnesium levels may cause symptoms from several systems, some of which being potentially serious, such as tetany, seizures and arrhythmias. It seems that PPIs affect the gastrointestinal absorption of magnesium. Clinicians should be vigilant in order to timely consider and prevent or reverse hypomagnesemia in patients who take PPIs, especially if they are prone to this electrolyte disorder. PMID- 24175254 TI - Urgent call for reconsideration of chronic kidney disease. AB - CIRCULATING TOXINS NAMELY: free radicals, cytokines and metabolic products induce glomerular endothelial dysfunction, hemodynamic maladjustment and chronic ischemic state;this leads to tubulointerstitial fibrosis in chronic kidney disease (CKD). Altered vascular homeostasis observed in late stage CKD revealed defective angiogenesis and impaired nitric oxide production explaining therapeutic resistance to vasodilator treatment in late stage CKD. Under current practice, CKD patients are diagnosed and treated at a rather late stage due to the lack of sensitivity of the diagnostic markers available. This suggests the need for an alternative therapeutic strategy implementing the therapeutic approach at an early stage. This view is supported by the normal or mildly impaired vascular homeostasis observed in early stage CKD. Treatment at this early stage can potentially enhance renal perfusion, correct the renal ischemic state and restore renal function. Thus, this alternative therapeutic approach would effectively prevent end-stage renal disease. PMID- 24175255 TI - Erectile dysfunction in hemodialysis: A systematic review. AB - Men with chronic renal failure (CRF) on hemodialysis have been frequently associated with erectile dysfunction (ED), with an of between 20% to 87.7%. As a result of the multi-system disease processes present in many uremic men, it is apparent that the pathogenesis of ED is most probably multifactorial. Factors to be considered include peripheral vascular disease, neurogenic abnormalities, hormonal disturbances and medications used for treatment of conditions associated with CRF. These physiological abnormalities may be supplemented by significant psychological stresses and abnormalities resulting from chronic illness. Treatment must start with the determination and treatment of the underlying causes. In addition to psychological treatment, further lines of treatment of ED in CRF can be classified as 1st line (medical treatment which includes oral phosphodiesterase-5 inhibitors and hormone regulation), 2nd line (intracavernosal injection, vacuum constriction devices and alprostadil urethral suppositories) or 3rd line (surgical treatment). Renal transplantation improves the quality of life for some patients with CRF and subsequently it may improve erectile function in a significant number of them, however still there is high incidence of ED after transplantation. PMID- 24175256 TI - Hepcidin and HFE protein: Iron metabolism as a target for the anemia of chronic kidney disease. AB - The anemia of chronic kidney disease and hemodialysis is characterized by chronic inflammation and release of cytokines, resulting in the upregulation of the iron hormone hepcidin, also increased by iron therapy and reduced glomerular filtration, with consequent reduction in iron absorption, recycling, and availability to the erythron. This response proves advantageous in the short-term to restrain iron availability to pathogens, but ultimately leads to severe anemia, and impairs the response to erythropoietin (Epo) and iron. Homozygosity for the common C282Y and H63D HFE polymorphisms influence iron metabolism by hampering hepcidin release by hepatocytes in response to increased iron stores, thereby resulting in inadequate inhibition of the activity of Ferroportin-1, inappropriately high iron absorption and recycling, and iron overload. However, in hemodialysis patients, carriage of HFE mutations may confer an adaptive benefit by decreasing hepcidin release in response to iron infusion and inflammation, thereby improving iron availability to erythropoiesis, anemia control, the response to Epo, and possibly survival. Therefore, anti-hepcidin therapies may improve anemia management in hemodialysis. However, HFE mutations directly favor hemoglobinization independently of hepcidin, and reduce macrophages activation in response to inflammation, whereas hepcidin might also play a beneficial anti-inflammatory and anti-microbic action during sepsis, so that direct inhibition of HFE-mediated regulation of iron metabolism may represent a valuable alternative therapeutic target. Genetic studies may offer a valuable tool to test these hypotheses and guide the research of new therapies. PMID- 24175257 TI - Treatment of young patients with lupus nephritis using calcineurin inhibitors. AB - Recent advances in the management of lupus nephritis, together with earlier renal biopsy and selective use of aggressive immunosuppressive therapy, have contributed to a favorable outcome in children and adolescents with systemic lupus erythematosus (SLE). Nevertheless, we believe that a more effective and less toxic treatment is needed to attain an optimal control of the activity of lupus nephritis. Recent published papers and our experiences regarding treatment of young patients with lupus nephritis using calcineurin inhibitors are reviewed. Although it has been reported that intermittent monthly pulses of intravenous cyclophosphamide (IVCY) are effective for preserving renal function in adult patients, CPA is a potent immunosuppressive agent that induces severe toxicity, including myelo- and gonadal toxicity, and increases the risk of secondary malignancy. Thus, treatment for controlling lupus nephritis activity, especially in children and adolescents, remains challenging. Cyclosporine A (CsA) and tacrolimus (Tac) are T-cell-specific calcineurin inhibitors that prevent the activation of helper T cells, thereby inhibiting the transcription of the early activation genes of interleukin (IL)-2 and suppressing T cell-induced activation of tumor necrosis factor-alpha, IL-1beta and IL-6. Therefore, both drugs, which we believe may be less cytotoxic, are attractive therapeutic options for young patients with lupus nephritis. Recently, a multidrug regimen of prednisolone (PDN), Tac, and mycophenolate mofetile (MMF) has been found effective and relatively safe in adult lupus nephritis. Since the mechanisms of action of MMF and Tac are probably complementary, multidrug therapy for lupus nephritis may be useful. We propose as an alternative to IVCY, a multidrug therapy with mizoribine, which acts very similarly to MMF, and Tac, which has a different mode of action, combined with PDN for pediatric-onset lupus nephritis. We also believe that a multidrug therapy including CsA and Tac may be an attractive option for young patients with SLE and lupus nephritis. PMID- 24175258 TI - Treatment of dyslipidemia in chronic kidney disease: Effectiveness and safety of statins. AB - Several cardiovascular (CV) risk factors may explain the high rate of CV death among patients with chronic kidney disease (CKD). Among them both traditional and uremia-related risk factors are implicated and, moreover, the presence of kidney disease represents "per se" a multiplier of CV risk. Plasma lipid and lipoprotein profiles are changed in quantitative, but above all in qualitative, structural, and functional ways, and lipoprotein metabolism is influenced by the progressive loss of renal function. Statin therapy significantly reduces cholesterol synthesis and both CV morbidity and mortality either directly, by reducing the lipid profile, or via pleiotropic effects; it is supposed to be able to reduce both the progression of CKD and also proteinuria. These observations derive from a post-hoc analysis of large trials conducted in the general population, but not in CKD patients. However, the recently published SHARP trial, including over 9200 patients, either on dialysis or pre-dialysis, showed that simvastatin plus ezetimibe, compared with placebo, was associated with a significant low-density lipoprotein cholesterol reduction and a 17% reduction in major atherosclerotic events. However, no benefit was observed in overall survival nor in preserving renal function in patients treated. These recent data reinforce the conviction among nephrologists to consider their patients at high CV risk and that lipid lowering drugs such as statins may represent an important tool in reducing atheromatous coronary disease which, however, represents only a third of CV deaths in patients with CKD. Therefore, statins have no protective effect among the remaining two-thirds of patients who suffer from sudden cardiac death due to arrhythmia or heart failure, prevalent among CKD patients. The safety of statins is demonstrated in CKD by several trials and recently confirmed by the largest SHARP trial, in terms of no increase in cancer incidence, muscle pain, creatine kinase levels, severe rhabdomyolysis, hepatitis, gallstones and pancreatitis; thus confirming the handiness of statins in CKD patients. Here we will review the latest data available concerning the effectiveness and safety of statin therapy in CKD patients. PMID- 24175259 TI - Roles of adaptor proteins in podocyte biology. AB - Podocytes covering the glomerular basement membrane over the glomerular capillary consist of three morphologically and functionally different segments, the cell body, major processes and extending finger-like foot processes (FPs). The FPs of neighboring podocytes are connected by a continuous adherent junction structure named the slit diaphragm (SD). The extracellular SD is linked to the intracellular, a highly dynamic, cytoskeleton through adaptor proteins. These adaptor proteins, such as CD2-associated protein, zonula occludens 1, beta catenin, Nck and p130Cas, located at the intracellular SD insertion area near lipid rafts, have important structural and functional roles. Adaptor proteins in podocytes play important roles as a structural component of the podocyte structure, linking the SD to the cytoskeletal structure and as a signaling platform sending signals from the SD to the actin cytoskeleton. This review discusses the roles of adaptor proteins in the podocyte cytoskeletal structure and signaling from the SD to the actin cytoskeleton. PMID- 24175260 TI - Pericytes synthesize renin. AB - AIM: To investigate renin expression in pericytes during normal kidney development and after deletion of angiotensinogen, the precursor for all angiotensins. METHODS: We examined the distribution of renin expressing cells by immunoshistochemistry in the interstitial compartment of wild type (WT) and angiotensinogen deficient (AGT -/-) mice at different developmental stages from embryonic day 18 (E18: WT, n = 4; AGT -/-, n = 5) and at day 1 (P1: WT, n = 5; AGT -/-, n = 5), 5 (P5: WT, n = 7; AGT -/-, n = 8), 10 (P10: WT, n = 3; AGT -/-, n = 5), 21 (P21: WT, n = 7; AGT -/-, n = 5), 45 (P45: WT, n = 3; AGT -/-, n = 3), and 70 (P70: WT, n = 2; AGT -/-, n = 2) of postnatal life. We quantified the number of pericytes positive for renin at all the developmental stages mentioned above and compared the results of AGT -/- mice to their WT counterparts. RESULTS: In WT mice, renal interstitial pericytes synthesize renin in early life supporting a lineage relationship with renin cells in the vasculature. The number of pericytes positive for renin per area of 0.32 mm(2) (density) in WT mice was maintained from fetal life till weaning age (E18 = 4.25 +/- 0.63, P1 = 3.75 +/- 0.48, P5 = 3.75 +/- 0.48, P10 = 4 +/- 0.71, P21 = 3.8 +/- 0.58) and markedly decreased in adult life (P45 = 1.2 +/- 0.37, P70 = 0.8 +/- 0.20). On the other hand, in AGT -/- mice the density of pericytes expressing renin was not significantly different from WT mice at E18 and P1: E18 = 5.75 +/- 0.50 vs 4.25 +/- 0.63 (P = 0.106), P1 = 9.25 +/- 3.50 vs 3.75 +/- 0.48 (P = 0.175) but significantly increased from P5 till P70: P5 = 38.25 +/- 5 vs 3.75 +/- 0.48 (P = 0.0004), P10 = 173 +/- 7.50 vs 4 +/- 0.70 (P = 5.24567 * 10(-7)), P21 = 83 +/- 6.70 vs 3.8 +/- 0.58 (P = 2.97358 * 10(-6)), P45 = 49 +/- 3.50 vs 1.2 +/- 0.37 (P = 8.18274 x 10(-7)) and P70 = 17.8 +/- 2.30 vs 0.8 +/- 0.20 (P = 3.51151 * 10( 5)). The AGT -/- mice showed a marked increase in the number of pericytes per field studied starting from P5, reaching its peak at P10, and then a gradually decreasing until P70. CONCLUSION: Interstitial pericytes synthesize renin during development and the number of renin-expressing pericytes increases in response to a homeostatic threat imposed early in life such as lack of angiotensinogen. PMID- 24175261 TI - Uric acid and chronic kidney disease: A time to act? AB - A role for uric acid in the pathogenesis and progression of renal disease had been proposed almost a century ago, but, too hastily dismissed in the early eighties. A body of evidence, mostly accumulated during the last decade, has led to a reappraisal of the influence of uric acid on hypertension, cardiovascular, and renal disease. The focus of this review will be solely on the relationship between serum uric acid and renal function and disease. We will review experimental evidence derived from animal and human studies, evidence gathered from a number of epidemiological studies, and from the few (up to now) studies of uric-acid-lowering therapy. Some space will be also devoted to the effects of uric acid in special populations, such as diabetics and recipients of kidney allografts. Finally we will briefly discuss the challenges of a trial of uric acid-lowering treatment, and the recent suggestions on how to conduct such a trial. PMID- 24175262 TI - Arteriovenous fistulas and digital hypoperfusion ischemic syndrome in patients on hemodialysis. AB - AIM: To determine survival parameters as well as characteristics of patients with this syndrome. METHODS: The investigation was conducted over a period of eight years, as a prospective, non-randomized, clinical study which included 204 patients, treated by chronic hemodialysis. Most patients received hemodialysis 12 h per week. As vascular access for hemodialysis all subjects had an arteriovenous fistulae. Based on surveys the respondents were divided into groups of patients with and without digital hypoperfusion ischemic syndrome. Gender, demographic and anthropometric characteristics, together with comorbidity and certain habits, were recorded. During this period 34.8% patients died. RESULTS: Patients with digital hypoperfusion ischemic syndrome were older than those without ischemia (P = 0.01). Hemodialysis treatment lasted significantly longer in the patients with digital hypoperfusion ischemic syndrome (P = 0.02). The incidence of cardiovascular disease (P < 0.001) and diabetes mellitus (P = 0.01), as well as blood flow through the arteriovenous fistula (P = 0.036), were higher in patients with digital hypoperfusion ischemic syndrome. Statistically significant differences also existed in relation to oxygen saturation (P = 0.04). Predictive parameters of survival for patients with digital hypoperfusion ischemic syndrome were: adequacy of hemodialysis (B = -3.604, P < 0.001), hypertension (B = -0.920, P = 0.018), smoking (B = -0.901, P = 0.049), diabetes mellitus (B = 1.227, P = 0.005), erythropoietin therapy (B = 1.274, P = 0.002) and hemodiafiltration (B = 1.242, P = 0.033). Kaplan-Meier survival analysis indicated that subjects with and without digital hypoperfusion ischemic syndrome differed regarding the length of survival (P < 0.001), i.e., patients with confirmed digital hypoperfusion ischemic syndrome died earlier. CONCLUSION: Survival was significantly longer in the patients without digital hypoperfusion ischemic syndrome. PMID- 24175263 TI - Inflammatory status in chronic renal failure: The role of homocysteinemia and pro inflammatory cytokines. AB - AIM: To evaluate determinants of inflammatory markers in chronic renal failure patients according to the level of glomerular filtration rate. METHODS: One hundred fifty four patients (Age: 44 +/- 06 years; male/female: 66/88) with chronic renal failure (CRF) were divided into 6 groups according to the National Kidney Foundation (NKF) classification. They included 28 primary stage renal failure patients (CRF 1), 28 moderate stage renal failure patients (CRF 2), 28 severe stage renal failure patients (CRF 3), 18 end-stage renal failure patients (CRF 4), 40 hemodialysis (HD) patients, and 12 peritoneal dialysis (PD) patients. Tumor necrosis factor-alpha (TNF-alpha), interleukin-1beta (IL-1beta), interleukin-6 (IL-6) and C-reactive protein (CRP) were analyzed by immunosorbent assay kit (ELISA) (Cayman Chemical's ACETM EIA kit). Immunoassay methods were used for total homocysteine (tHcy) (fluorescence polarization immunoanalysis HPLC, PerkinEmer 200 series), transferrin (MININEPHTM human transferin kit: ZK070.R), ferritin (ADVIA Centaur) and fibrinogen analysis (ACL 200). Differences between groups were performed using SPSS 20.0 and data are expressed as the mean +/- SD. RESULTS: Results showed that in comparison with CRF 1 group and other groups, TNF-alpha and IL-6 levels were respectively more elevated in HD (16.38 +/ 5.52 pg/mL vs 0.39 +/- 0.03 pg/mL, 11.05 +/- 3.59 pg/mL vs 8.20 +/- 0.22 pg/mL, P < 0.001) and PD (14.04 +/- 3.40 pg/mL vs 0.39 +/- 0.03 pg/mL, 10.15 +/- 1.66 pg/mL vs 8.20 +/- 0.22 pg/mL, P < 0.001). IL-1beta levels were increased in HD (9.63 +/- 3.50 pg/mL vs 3.24 +/- 0.10 pg/mL, P < 0.001) and CRF 4 (7.76 +/- 0.66 pg/mL vs 3.24 +/- 0.10 pg/mL, P < 0.001) patients than in CRF 1 and in the other groups. Plasma tHcy levels were higher in HD (32.27 +/- 12.08 MUmol/L) and PD (28.37 +/- 4.98 MUmol/L) patients compared to the other groups of CRF (P < 0.001). The serum CRP level was significantly increased in HD (18.17 +/- 6.38 mg/L) and PD (17.97 +/- 4.85 mg/L) patients compared to the other groups of CRF patients (P < 0.001). The plasma fibrinogen level was more elevated in HD (6.86 +/- 1.06 g/L) and CRF 4 (6.05 +/- 0.57 g/L) than in the other groups (P < 0.001). Furthermore; the ferritin level was higher in HD (169.90 +/- 62.16 ng/mL) and PD (90.08 +/- 22.09 ng/mL) patients compared to the other groups of CRF (P < 0.001). The serum transferrin value was significantly decreased especially in PD (1.78 +/ 0.21 g/L) compared to the other groups (P < 0.001). We found a negative correlation between glomerular filtration rate (GFR), TNF-alpha levels (r = 0.75, P < 0.001), and tHcy levels (r = -0.68, P < 0.001). We observed a positive correlation between GFR and transferrin levels (r = 0.60, P < 0.001). CONCLUSION: CRF was associated with elevated inflammatory markers. The inflammation was observed at the severe stage of CRF and increases with progression of renal failure. PMID- 24175264 TI - Hepcidin-25 negatively predicts left ventricular mass index in chronic kidney disease patients. AB - AIM: To assess the correlation between the serum hepcidin-25 level and left ventricular mass index. METHODS: This study was a cross-sectional study conducted between March 2009 and April 2010. Demographic and biochemical data, including the serum hepcidin-25 level, were collected for chronic kidney disease (CKD) patients. Two-dimensional echocardiography was performed to determine the left ventricle mass (LVM), left ventricular mass index (LVMI), interventricular septum thickness (IVSd), left ventricle posterior wall thickness (LVPW), right ventricular dimension (RVD), left atrium (LA) and ejection fraction (EF). RESULTS: A total of 146 patients with stage 1 to 5 CKD were enrolled. Serum hepcidin-25 levels were 16.51 +/- 5.2, 17.59 +/- 5.32, 17.38 +/- 6.47, 19.98 +/- 4.98 and 22.03 +/- 4.8 ng/mL for stage 1 to 5 CKD patients, respectively. Hepcidin-25 level was independently predicted by the serum ferritin level (beta = 0.6, P = 0.002) and the estimated glomerular filtration rate (beta = -0.48, P = 0.04). There were negative correlations between the serum hepcidin level and the LVM and LVMI (P = 0.04 and P = 0.005, respectively). Systolic blood pressure (BP) was positively correlated with the LVMI (P = 0.005). In the multivariate analysis, a decreased serum hepcidin-25 level was independently associated with a higher LVMI (beta = -0.28, 95%CI: -0.48 - -0.02, P = 0.006) after adjusting for body mass index, age and systolic BP. CONCLUSION: A lower serum hepcidin level is associated with a higher LVMI in CKD patients. Low hepcidin levels may be independently correlated with unfavorable cardiovascular outcomes in this population. PMID- 24175265 TI - Calcitriol-induced hypercalcemia in a patient with granulomatous mycosis fungoides and end-stage renal disease. AB - An 86-year-old man, diagnosed as having mycosis fungoides in May 2008 and treated with repeated radiation therapy, was admitted to our hospital for initiation of hemodialysis due to end-stage renal disease (ESRD) in April 2012. On admission, his corrected serum calcium level was 9.3 mg/dL, and his intact parathyroid hormone level was 121.9 pg/mL (normal range 13.9-78.5 pg/mL), indicating secondary hyperparathyroidism due to ESRD. After starting hemodialysis, urinary volume diminished rapidly. The serum calcium level increased (12.7 mg/dL), and the intact parathyroid hormone level was suppressed (< 5 pg/mL), while the 1,25 dihydroxyvitamin D3 (calcitriol) level increased (114 pg/mL, normal range: 20.0 60.0 pg/mL) in June 2012. The possibilities of sarcoidosis and tuberculosis were ruled out. Skin biopsies from tumorous lesions revealed a diagnosis of granulomatous mycosis fungoides. The serum soluble interleukin-2 receptor levels and the degrees of skin lesions went in parallel with the increased serum calcium and calcitriol levels. Therefore, the patient was diagnosed as having calcitriol induced hypercalcemia possibly associated with granulomatous mycosis fungoides. Granulomatous mycosis fungoides is rare, and its association with calcitriol induced hypercalcemia has not been reported. Careful attention to calcium metabolism is needed in patients with granulomatous mycosis fungoides, especially in patients with ESRD. PMID- 24175266 TI - Conduits for coronary bypass: strategies. AB - Strategic planning is integral to any operation but complexity varies immensely and therefore the effort necessary to create the optimal plan. The previous three reports have discussed individual conduits and herein is an attempt to present approaches to common situations which the author favors. Although much has been learned over 45 years about use and subsequent behavior of venous and arterial grafts we continue to learn and, as a result, evolve new strategies or modify those now popular. Thus the reader must recognize that in spite of trying to be balanced and inclusive all surgeons have personal opinions and also prejudices which influence the approach taken and which may not be the optimal one for others or for the patient. PMID- 24175267 TI - Influence of mesenchymal stem cells on cryopreserved tracheal allografts in rabbits. AB - BACKGROUND: Ischemic injury and the rejection process are the main reasons for graft failure in tracheal transplantation models. To enhance the acceptance, we investigated the influence of mesenchymal stem cells (MSCs) on tracheal allografts. METHODS: Extracted tracheal grafts from New Zealand white rabbits were cryopreserved for 4 weeks and orthotopically transplanted (control group A, n=8). In group B (n=8), cyclosporin A (CsA, 10 mg/kg) was injected daily into the peritoneal cavity. In group C (n=8), MSCs (1.0*10(7) cells/kg) from the same donor of the tracheal allograft, which had been pre-cultured for 4 weeks, were infused intravenously after transplantation. In group D (n=8), MSCs were infused and CsA was injected daily. Four weeks after transplantation, gross and histomorphological assessments were conducted for graft necrosis, measuring the cross-sectional area of the allograft, determining the degree of epithelization, lymphocytic infiltration, and vascular regeneration. RESULTS: The morphologic integrity of the trachea was retained completely in all cases. The cross sectional areas were decreased significantly in group A (p=0.018) and B (p=0.045). The degree of epithelization was enhanced (p=0.012) and the lymphocytic infiltration was decreased (p=0.048) significantly in group D compared to group A. The degree of vascular regeneration did not differ significantly in any of the groups. There were no significant correlations among epithelization, lymphocytic infiltration, and vascular regeneration. CONCLUSION: The administration of MSCs with concurrent injections of CsA enhanced and promoted epithelization and prevented lymphocytic infiltration in tracheal allografts, allowing for better acceptance of the allograft. PMID- 24175268 TI - Atrial septal defect closure: comparison of vertical axillary minithoracotomy and median sternotomy. AB - BACKGROUND: This study aims to evaluate whether or not the method of right vertical axillary minithoracotomy (RVAM) is preferable to and as reliable as conventional sternotomy surgery, and also assesses its cosmetic results. METHODS: Thirty-three patients (7 males, 26 females) with atrial septal defect were admitted to the Cardiovascular Surgery Clinic of Cukurova University from December 2005 until January 2010. The patients' ages ranged from 3 to 22. Patients who underwent vertical axillary minithracotomy were assigned to group I, and those undergoing conventional sternotomy, to group II. Group I and group II were compared with regard to the preoperative, perioperative and postoperative variables. Group I included 12 females and 4 males with an average age of 16.5+/ 9.7. Group II comprised 14 female and 3 male patients with an average age of 18.5+/-9.8 showing similar features and pathologies. The cases were in Class I-II according to the New York Heart Association (NYHA) Classification, and patients with other cardiac and systemic problems were not included in the study. The ratio of the systemic blood flow to the pulmonary blood flow (Qp/Qs) was 1.8+/ 0.2. The average pulmonary artery pressure was 35+/-10 mmHg. Following the diagnosis, performing elective surgery was planned. RESULTS: No significant difference was detected in the average time of the patients' extraportal circulation, cross-clamp and surgery (p>0.05). In the early postoperative period of the cases, the duration of mechanical ventilator support, the drainage volume in the first 24 hours, and the hospitalization time in the intensive care unit were similar (p>0.05). Postoperative pains were evaluated together with narcotic analgesics taken intravenously or orally. While 7 cases (43.7%) in group I needed postoperative analgesics, 12 cases (70.6%) in group II needed them. No mortality or major morbidity has occurred in the patients. The incision style and sizes in all of the patients undergoing RVAM were preserved as they were at the beginning. Furthermore, the patients of group I were mobilized more quickly than the patients of group II. The patients of group I were quite pleased with the psychological and cosmetic results. No residual defects have been found in the early postoperative period and after the end of the follow-up periods. All of the patients achieved functional capacity per NYHA. No deformation of breast growth has been detected during 18 months of follow-up for the group I patients, who underwent RVAM. CONCLUSION: To conclude, the repair of atrial septal defect by RVAM, apart from the limited working zone for the surgeon in these pathologies as compared to sternotomymay be considered in terms of the outcomes, and early and late complications. And this has accounted for less need of analgesics and better cosmetic results in recent years. PMID- 24175269 TI - Comparison of Early Clinical Results of Transcatheter versus Surgical Aortic Valve Replacement in Symptomatic High Risk Severe Aortic Stenosis Patients. AB - BACKGROUND: Transcatheter aortic valve implantation (TAVI) has been an alternative to conventional aortic valve replacement (AVR) in old and high risk patients. The goal of this study is to compare the early outcomes of conventional AVR vs. TAVI in high risk severe AS patients. METHODS: From January 2008 to July 2012, 44 high risk severe aortic stenosis patients underwent conventional AVR, and 15 patients underwent TAVI. We compared echocardiographic data, periprocedural complication, and survival. The mean follow-up duration was 14.5+/ 10 months (AVR), and 6.8+/-3.5 months (TAVI), respectively. RESULTS: AVR group was younger (78.2+/-2.4 years vs. 82.2+/-3.0 years, p<0.001) and had lower operative risk (Euroscore: 9.4+/-2.7 vs. 11.0+/-2.0, p=0.044) than TAVI group. There was no significant difference in early mortality (11.4% vs. 13.3%, p=0.839), and 1 year survival (87.4%+/-5.3% vs. 83.1%+/-1.1%, p=0.805). There was no significant difference in postoperative functional class. There was no significant difference in periprocedural complication except vascular complication (0% [AVR] vs. 13.3% [TAVI], p=0.014). TAVI group had more moderate and severe paravalvular leakage. CONCLUSION: In this study, both groups had similar periprocedural morbidity, and mortality. However, TAVI group had more greater than moderate paravalvular leakage, which can influence long-term outcome. Since more patients are treated with TAVI even in moderate risk, careful selection of the patients and appropriate guideline need to be established. PMID- 24175270 TI - Florida sleeve repair for aortic root aneurysm. AB - A 74-year-old man was diagnosed with aortic root aneurysm and two-vessel coronary disease. Echocardiographic assessment revealed an enlarged sinus of Valsalva 60 mm in diameter with mild aortic regurgitation. Florida sleeve repair was performed using a vascular graft combined with coronary artery bypass grafting. The postoperative course was uncomplicated and follow-up echocardiographic evaluations showed an aortic root diameter of 38 mm without aortic insufficiency up to 1 year after surgery. PMID- 24175271 TI - Surgical treatment of post-infarction left ventricular free wall rupture: three cases review. AB - Left ventricular free wall rupture (LFWR) is rare, but is one of the most serious complications of myocardial infarction and is associated with high mortality. Several operative techniques have been attempted, but early diagnosis and prompt surgical management are crucial for a positive patient outcome. We report three cases of LFWR successfully treated with surgical methods. PMID- 24175272 TI - Left atrial myxoma presenting with unusual cystic form. AB - Cardiac myxomas are the most common primary benign tumors of uncertain etiology. They usually present as polypoid or oval-shaped masses projecting into a heart chamber from the interatrial septum and have a soft, gelatinous consistency without a cystic structure. We report a case of left atrial myxoma with a single cystic form. PMID- 24175273 TI - Two-stage endovascular repair for concurrent penetrating atherosclerotic ulcers of the thoracic and abdominal aorta. AB - We report a case of concurrent saccular aneurysms caused by a penetrating atherosclerotic ulcer of the thoracic and abdominal aorta that were successfully treated by staged endovascular repair. Even though surgical open repair or endovascular repair is the treatment option, use of endovascular repair is now accepted as an alternative treatment to surgery in selected patients. To prevent contrast medium-induced nephropathy and spinal cord ischemia caused by a simultaneous endovascular procedure, a saccular aneurysm of the descending thoracic aorta was excluded by stent graft, followed by the placement of a bifurcated stent graft in the infrarenal abdominal aorta one month later. PMID- 24175274 TI - A giant popliteal artery aneurysm treated with exclusion and bypass using a saphenous vein. AB - While popliteal artery aneurysm is the most common form of peripheral artery aneurysm, it is a rare condition in the general population. Furthermore, a giant popliteal artery aneurysm has not previously been reported in Korea. A 67-year old male presented with left thigh pain that had begun 4 months earlier and was aggravated when in a sitting position. We found a giant aneurysm on the left popliteal artery and performed a bypass from the common femoral artery to the distal popliteal artery below the knee, using the autologous greater saphenous vein, and excluded the aneurysm at the sites of anastomoses. PMID- 24175275 TI - Surgical treatment for an invasive leiomyosarcoma of the inferior vena cava. AB - A 49-year-old woman presented with right lumbar pain and edema in both legs. Computed tomography showed a large low attenuated mass around and in the S7 segment of the liver involving the right kidney and multiple enlarged mesenteric lymph nodes. There were multiple variably sized discrete nodules in both lungs. Cavography showed subtotal occlusion of the inferior vena cava (IVC). She was successfully treated by wide resection and IVC reconstruction with partial cardiopulmonary bypass and metastasectomy. PMID- 24175276 TI - Giant cell tumor arising from anterior arc of the rib. AB - A primary giant cell tumor of the rib is very rare. The most common site of a giant cell tumor arising from the rib is the posterior arc. A giant cell tumor arising from the anterior arc of the rib is extremely rare. The treatment of a giant cell tumor of the rib is not well defined. Generally, a complete surgical resection is performed in a patient with a primary giant cell tumor of the rib. We report a case of a giant cell tumor arising from the anterior arc of the rib that was treated with a wide excision and chest wall reconstruction. PMID- 24175277 TI - Preanesthetic cardiopulmonary bypass for mechanical mitral valve dysfunction. PMID- 24175278 TI - Vacuum-assisted closure therapy as an alternative treatment of subcutaneous emphysema. AB - Vacuum-assisted closure therapy is an alternative method for a massive subcutaneous emphysema treatment. It is easily applicable and shows rapid effectiveness in massive subcutaneous emphysema, intractable with chest tube drainage. PMID- 24175279 TI - Single-incision video-assisted thoracoscopic surgery for benign mediastinal diseases: experiences in single institution. AB - With advancement of the technique of video-assisted thoracic surgery (VATS), some surgeons have made great efforts to reduce the number of incisions in the conventional three- or four-port approach. Several studies on cases treated by single-incision VATS and their short-term outcomes were reported. Here, we present our experience with single-incision VATS for the treatment of benign mediastinal diseases. PMID- 24175280 TI - Antiadherent and antibiofilm activity of Humulus lupulus L. derived products: new pharmacological properties. AB - New antimicrobial properties of products derived from Humulus lupulus L. such as antiadherent and antibiofilm activities were evaluated. The growth of gram positive but not gram-negative bacteria was inhibited to different extents by these compounds. An extract of hop cones containing 51% xanthohumol was slightly less active against S. aureus strains (MIC range 31.2-125.0 MUg/mL) than pure xanthohumol (MIC range 15.6-62.5 MUg/mL). The spent hop extract, free of xanthohumol, exhibited lower but still relevant activity (MIC range 1-2 mg/mL). There were positive coactions of hop cone, spent hop extracts, and xanthohumol with oxacillin against MSSA and with linezolid against MSSA and MRSA. Plant compounds in the culture medium at sub-MIC concentrations decreased the adhesion of Staphylococci to abiotic surfaces, which in turn caused inhibition of biofilm formation. The rate of mature biofilm eradication by these products was significant. The spent hop extract at MIC reduced biofilm viability by 42.8%, the hop cone extract by 74.8%, and pure xanthohumol by 86.5%. When the hop cone extract or xanthohumol concentration was increased, almost complete biofilm eradication was achieved (97-99%). This study reveals the potent antibiofilm activity of hop-derived compounds for the first time. PMID- 24175281 TI - Skeletal muscle regeneration on protein-grafted and microchannel-patterned scaffold for hypopharyngeal tissue engineering. AB - In the field of tissue engineering, polymeric materials with high biocompatibility like polylactic acid and polyglycolic acid have been widely used for fabricating living constructs. For hypopharynx tissue engineering, skeletal muscle is one important functional part of the whole organ, which assembles the unidirectionally aligned myotubes. In this study, a polyurethane (PU) scaffold with microchannel patterns was used to provide aligning guidance for the seeded human myoblasts. Due to the low hydrophilicity of PU, the scaffold was grafted with silk fibroin (PU-SF) or gelatin (PU-Gel) to improve its cell adhesion properties. Scaffolds were observed to degrade slowly over time, and their mechanical properties and hydrophilicities were improved through the surface grafting. Also, the myoblasts seeded on PU-SF had the higher proliferative rate and better differentiation compared with those on the control or PU-Gel. Our results demonstrate that polyurethane scaffolds seeded with myoblasts hold promise to guide hypopharynx muscle regeneration. PMID- 24175282 TI - Gradient evolution of body colouration in surface- and cave-dwelling Poecilia mexicana and the role of phenotype-assortative female mate choice. AB - Ecological speciation assumes reproductive isolation to be the product of ecologically based divergent selection. Beside natural selection, sexual selection via phenotype-assortative mating is thought to promote reproductive isolation. Using the neotropical fish Poecilia mexicana from a system that has been described to undergo incipient ecological speciation in adjacent, but ecologically divergent habitats characterized by the presence or absence of toxic H2S and darkness in cave habitats, we demonstrate a gradual change in male body colouration along the gradient of light/darkness, including a reduction of ornaments that are under both inter- and intrasexual selection in surface populations. In dichotomous choice tests using video-animated stimuli, we found surface females to prefer males from their own population over the cave phenotype. However, female cave fish, observed on site via infrared techniques, preferred to associate with surface males rather than size-matched cave males, likely reflecting the female preference for better-nourished (in this case: surface) males. Hence, divergent selection on body colouration indeed translates into phenotype-assortative mating in the surface ecotype, by selecting against potential migrant males. Female cave fish, by contrast, do not have a preference for the resident male phenotype, identifying natural selection against migrants imposed by the cave environment as the major driver of the observed reproductive isolation. PMID- 24175283 TI - Prevention of atherosclerosis progression by 9-cis-beta-carotene rich alga Dunaliella in apoE-deficient mice. AB - INTRODUCTION: beta-Carotene-rich diet has been shown to be inversely associated with the risk of coronary heart disease. However, clinical trials using synthetic all-trans-beta-carotene failed to demonstrate a beneficial effect. We therefore sought to study the effect of natural source of beta-carotene, the alga Dunaliella, containing both all-trans and 9-cis-beta-carotene on atherosclerosis. In a previous study we showed that 9-cis-beta-carotene-rich powder of the alga Dunaliella inhibits early atherogenesis in low-density lipoprotein receptor knockout mice. AIMS: The aims of the current work were to study whether diet enriched with Dunaliella powder would inhibit the progression of established atherosclerosis in old male apoE-deficient mice and to compare the effect of Dunaliella on lipid profile and atherosclerosis in a low-versus high-fat diet fed mice. METHODS: In the first experiment, young mice (12 weeks old) were allocated into 3 groups: (1) low-fat diet; (2) low-fat diet + Dunaliella powder (8%); (3) low-fat diet + beta-carotene-deficient Dunaliella. In the second experiment, old mice (7 months old) with established atherosclerotic lesions were allocated into 4 groups: (1) low-fat diet; (2) low-fat diet + Dunaliella; (3) high fat-diet; (4) high-fat diet + Dunaliella. RESULTS: In young mice fed a low-fat diet, a trend toward lower atherosclerotic lesion area in the aortic sinus was found in the Dunaliella group compared with the control group. In old mice with established atherosclerotic lesion, Dunaliella inhibited significantly plasma cholesterol elevation and atherosclerosis progression in mice fed a high-fat diet. CONCLUSION: The results of this study suggest that a diet containing natural carotenoids, rich in 9-cis-beta-carotene, has the potential to inhibit atherosclerosis progression, particularly in high-fat diet regime. PMID- 24175285 TI - The predictive prognostic values of serum TNF-alpha in comparison to SOFA score monitoring in critically ill patients. AB - BACKGROUND: The use of inflammatory markers to follow up critically ill patients is controversial. The short time frame, the need for frequent and serial measurement of biomarkers, the presence of soluble receptor and their relatively high cost are the major drawbacks. Our study's objective is to compare the prognostic values of serum TNF-alpha and SOFA score monitoring in critically ill patients. PATIENTS AND METHODS: A total of ninety patients were included in the study. Forty-five patients developed septic complication (sepsis group). Forty five patients were critically ill without evidence of infectious organism (SIRS group). Patients' data include clinical status, central venous pressure, and laboratory analysis were measured. A serum level of TNF-alpha and SOFA score were monitored. RESULTS: Monitoring of TNF-alpha revealed significant elevation of TNF alpha at 3rd and 5th days of ICU admission in both groups. Monitoring of SOFA score revealed significant elevation of SOFA scores in both groups throughout their ICU stay, particularly in nonsurvivors. Positive predictive ability of SOFA score was demonstrated in critically ill patients. CONCLUSION: Transient significant increase in serum levels of TNF-alpha were detected in septic patients. Persistent elevation of SOFA score was detected in nonsurvivor septic patients. SOFA score is an independent prognostic value in critically ill patients. PMID- 24175284 TI - The pyridoxal 5'-phosphate (PLP)-dependent enzyme serine palmitoyltransferase (SPT): effects of the small subunits and insights from bacterial mimics of human hLCB2a HSAN1 mutations. AB - The pyridoxal 5'-phosphate (PLP)-dependent enzyme serine palmitoyltransferase (SPT) catalyses the first step of de novo sphingolipid biosynthesis. The core human enzyme is a membrane-bound heterodimer composed of two subunits (hLCB1 and hLCB2a/b), and mutations in both hLCB1 (e.g., C133W and C133Y) and hLCB2a (e.g., V359M, G382V, and I504F) have been identified in patients with hereditary sensory and autonomic neuropathy type I (HSAN1), an inherited disorder that affects sensory and autonomic neurons. These mutations result in substrate promiscuity, leading to formation of neurotoxic deoxysphingolipids found in affected individuals. Here we measure the activities of the hLCB2a mutants in the presence of ssSPTa and ssSPTb and find that all decrease enzyme activity. High resolution structural data of the homodimeric SPT enzyme from the bacterium Sphingomonas paucimobilis (Sp SPT) provides a model to understand the impact of the hLCB2a mutations on the mechanism of SPT. The three human hLCB2a HSAN1 mutations map onto Sp SPT (V246M, G268V, and G385F), and these mutant mimics reveal that the amino acid changes have varying impacts; they perturb the PLP cofactor binding, reduce the affinity for both substrates, decrease the enzyme activity, and, in the most severe case, cause the protein to be expressed in an insoluble form. PMID- 24175286 TI - Frataxin mRNA isoforms in FRDA patients and normal subjects: effect of tocotrienol supplementation. AB - Friedreich's ataxia (FRDA) is caused by deficient expression of the mitochondrial protein frataxin involved in the formation of iron-sulphur complexes and by consequent oxidative stress. We analysed low-dose tocotrienol supplementation effects on the expression of the three splice variant isoforms (FXN-1, FXN-2, and FXN-3) in mononuclear blood cells of FRDA patients and healthy subjects. In FRDA patients, tocotrienol leads to a specific and significant increase of FXN-3 expression while not affecting FXN-1 and FXN-2 expression. Since no structural and functional details were available for FNX-2 and FXN-3, 3D models were built. FXN-1, the canonical isoform, was then docked on the human iron-sulphur complex, and functional interactions were computed; when FXN-1 was replaced by FXN-2 or FNX-3, we found that the interactions were maintained, thus suggesting a possible biological role for both isoforms in human cells. Finally, in order to evaluate whether tocotrienol enhancement of FXN-3 was mediated by an increase in peroxisome proliferator-activated receptor-gamma (PPARG), PPARG expression was evaluated. At a low dose of tocotrienol, the increase of FXN-3 expression appeared to be independent of PPARG expression. Our data show that it is possible to modulate the mRNA expression of the minor frataxin isoforms and that they may have a functional role. PMID- 24175287 TI - Appendicostomy in preschool children with anorectal malformation: successful early bowel management with a high frequency of minor complications. AB - AIM: The aim of this study is to evaluate postoperatively bowel symptoms of antegrade colon enema through appendicostomies in preschool children with anorectal malformation (ARM). METHOD: 164 children with ARM operated on with posterior sagittal anorectal plasty were included. The malformations were classified according to Krickenbeck classification. Seventeen children in preschool age had an appendicostomy. The bowel symptoms according to the Krickenbeck follow-up were analysed pre- and postoperatively. All complications were registered. A questionnaire on the use of the appendicostomy was answered. RESULTS: The median age (range) at the time of the appendicostomy was 4 (1-6) years. The observation time was 5 (0.5-14) years. The main indications for appendicostomy were incontinence and noncompliance to rectal enemas. Postoperatively there was a significant decrease in soiling and constipation (P < 0.001). The total complication rate was 43% with infections (29%), stenosis (12%), and retrograde leakage (0). The median time required for giving enema in the appendicostomy was 45 minutes (range: 15-120) once a day varying from 2 times/week to 3 times/day. And: complications are less frequent than in older children. CONCLUSION: Appendicostomy in preschool children with ARM is a way to achieve fecal cleanness before school start. The infection rate was high, but other complications are less frequent than in older children. PMID- 24175288 TI - Stage-stratified analysis of prognostic significance of Bax-interacting factor-1 expression in resected colorectal cancer. AB - BACKGROUND/AIM: Bax-interacting factor-1 (Bif-1) plays a crucial role in apoptosis and autophagy. The aim of this study was to evaluate Bif-1 protein expression and its prognostic significance in colorectal cancer (CRC). METHODS: We analyzed Bif-1 protein expression in 251 resected specimens from patients with CRC by immunohistochemistry using tissue microarray. RESULTS: Low Bif-1 expression was observed in 131 patients (52.2%) and high Bif-1 expression in 120 patients (47.8%). No significant differences were observed in clinicopathological parameters between patients with high and low Bif-1 expression. Kaplan-Meier survival analysis showed no difference in survival between patients with high and low Bif-1 expression. Stratified analysis of Bif-1 according to TNM stage demonstrated that low Bif-1 expression was significantly associated with a poor outcome in patients with stages I and II (P = 0.034). Stratified multivariate analysis demonstrated that low Bif-1 expression was an independent indicator of poor prognosis (hazard ratio, 0.459; 95% confidence interval, 0.285-0.739; P = 0.001). CONCLUSION: Patients with low levels of Bif-1 expression have shortened survival rates in CRC of stages I and II. This suggests that Bif-1 protein expression may be a useful prognostic marker in early-stage CRC. PMID- 24175289 TI - Effects of flavonoids on rumen fermentation activity, methane production, and microbial population. AB - This research was carried out to evaluate the effects of flavone, myricetin, naringin, catechin, rutin, quercetin, and kaempferol at the concentration of 4.5% of the substrate (dry matter basis) on the rumen microbial activity in vitro. Mixture of guinea grass and concentrate (60 : 40) was used as the substrate. The results showed that all the flavonoids except naringin and quercetin significantly (P < 0.05) decreased the dry matter degradability. The gas production significantly (P < 0.05) decreased by flavone, myricetin, and kaempferol, whereas naringin, rutin, and quercetin significantly (P < 0.05) increased the gas production. The flavonoids suppressed methane production significantly (P < 0.05). The total VFA concentration significantly (P < 0.05) decreased in the presence of flavone, myricetin, and kaempferol. All flavonoids except naringin and quercetin significantly (P < 0.05) reduced the carboxymethyl cellulase, filter paperase, xylanase, and beta -glucosidase activities, purine content, and the efficiency of microbial protein synthesis. Flavone, myricetin, catechin, rutin, and kaempferol significantly (P < 0.05) reduced the population of rumen microbes. Total populations of protozoa and methanogens were significantly (P < 0.05) suppressed by naringin and quercetin. The results of this research demonstrated that naringin and quercetin at the concentration of 4.5% of the substrate (dry matter basis) were potential metabolites to suppress methane production without any negative effects on rumen microbial fermentation. PMID- 24175290 TI - Elevated expression of fractalkine (CX3CL1) and fractalkine receptor (CX3CR1) in the dorsal root ganglia and spinal cord in experimental autoimmune encephalomyelitis: implications in multiple sclerosis-induced neuropathic pain. AB - Multiple sclerosis (MS) is a central nervous system (CNS) disease resulting from a targeted autoimmune-mediated attack on myelin proteins in the CNS. The release of Th1 inflammatory mediators in the CNS activates macrophages, antibodies, and microglia resulting in myelin damage and the induction of neuropathic pain (NPP). Molecular signaling through fractalkine (CX3CL1), a nociceptive chemokine, via its receptor (CX3CR1) is thought to be associated with MS-induced NPP. An experimental autoimmune encephalomyelitis (EAE) model of MS was utilized to assess time dependent gene and protein expression changes of CX3CL1 and CX3CR1. Results revealed significant increases in mRNA and the protein expression of CX3CL1 and CX3CR1 in the dorsal root ganglia (DRG) and spinal cord (SC) 12 days after EAE induction compared to controls. This increased expression correlated with behavioural thermal sensory abnormalities consistent with NPP. Furthermore, this increased expression correlated with the peak neurological disability caused by EAE induction. This is the first study to identify CX3CL1 signaling through CX3CR1 via the DRG/SC anatomical connection that represents a critical pathway involved in NPP induction in an EAE model of MS. PMID- 24175292 TI - Potential impact of a free online HIV treatment response prediction system for reducing virological failures and drug costs after antiretroviral therapy failure in a resource-limited setting. AB - OBJECTIVE: Antiretroviral drug selection in resource-limited settings is often dictated by strict protocols as part of a public health strategy. The objective of this retrospective study was to examine if the HIV-TRePS online treatment prediction tool could help reduce treatment failure and drug costs in such settings. METHODS: The HIV-TRePS computational models were used to predict the probability of response to therapy for 206 cases of treatment change following failure in India. The models were used to identify alternative locally available 3-drug regimens, which were predicted to be effective. The costs of these regimens were compared to those actually used in the clinic. RESULTS: The models predicted the responses to treatment of the cases with an accuracy of 0.64. The models identified alternative drug regimens that were predicted to result in improved virological response and lower costs than those used in the clinic in 85% of the cases. The average annual cost saving was $364 USD per year (41%). CONCLUSIONS: Computational models that do not require a genotype can predict and potentially avoid treatment failure and may reduce therapy costs. The use of such a system to guide therapeutic decision-making could confer health economic benefits in resource-limited settings. PMID- 24175291 TI - The role of calprotectin in pediatric disease. AB - Calprotectin (CP) is a calcium- and zinc-binding protein of the S100 family expressed mainly by neutrophils with important extracellular activity. The aim of the current review is to summarize the latest findings concerning the role of CP in a diverse range of inflammatory and noninflammatory conditions among children. Increasing evidence suggests the implication of CP in the diagnosis, followup, assessment of relapses, and response to treatment in pediatric pathological conditions, such as inflammatory bowel disease, necrotizing enterocolitis, celiac disease, intestinal cystic fibrosis, acute appendicitis, juvenile idiopathic arthritis, Kawasaki disease, polymyositis-dermatomyositis, glomerulonephritis, IgA nephropathy, malaria, HIV infection, hyperzincemia and hypercalprotectinemia, and cancer. Further studies are required to provide insights into the actual role of CP in these pathological processes in pediatrics. PMID- 24175293 TI - In vitro and in vivo survival and colonic adhesion of Pediococcus acidilactici MTCC5101 in human gut. AB - The present study aims to investigate the probiotic nature of Pediococcus acidilactici MTCC5101 by an in vitro assay of bacterial adherence to intestinal epithelial cells of human gastrointestinal (GI) tract using Caco-2 cell line. Further to assess the in vivo survival in the GI tract, oral feeding was carried out with the help of 10 healthy volunteers. The effect on wellness was assessed by studying blood biochemical parameters of the volunteers. The survival of the bacteria was assessed using PCR-based detection of P. acidilactici MTCC5101 in fecal samples. The probiotic nature of P. acidilactici MTCC 5101 was strengthened by its adherence to the intestinal epithelial Caco-2 cell line in the in vitro SEM observations. Oral feeding study for assessing the survival of bacteria in GI tract of volunteers showed the strain to be established in the GI tract which survived for about 2 weeks after feeding. PMID- 24175294 TI - Arsenate retention by epipsammic biofilms developed on streambed sediments: influence of phosphate. AB - Natural geological conditions together with the impact of human activities could produce environmental problems due to high As concentrations. The aim of this study was to assess the role of epipsammic biofilm-sediment systems onto As (V) sorption and to evaluate the effect of the presence of equimolar P concentrations on As retention. A natural biofilm was grown on sediment samples in the laboratory, using river water as nutrient supplier. Sorption experiments with initial As concentrations 0, 5, 25, 50, 100, 250, and 500 MUg L(-1) were performed. The average percentage of As sorbed was 78.9 +/- 3.5 and 96.9 +/- 6.6% for the sediment and biofilm-sediment systems, respectively. Phosphate decreased by 25% the As sorption capactity in the sediment devoid of biofilm, whereas no significant effect was observed in the systems with biofilm. Freundlich, Sips, and Toth models were the best to describe experimental data. The maximum As sorption capacity of the sediment and biofilm-sediment systems was, respectively, 6.6 and 6.8 MUg g(-1) and 4.5 and 7.8 MUg g(-1) in the presence of P. In conclusion, epipsammic biofilms play an important role in the environmental quality of river systems, increasing As retention by the system, especially in environments where both As and P occur simultaneously. PMID- 24175295 TI - Microbiological profile of adenoid hypertrophy correlates to clinical diagnosis in children. AB - OBJECTIVE: Adenoid hypertrophy is a common condition in childhood, which may be associated with recurring acute otitis media (RAOM), otitis media with effusion (OME), and obstructive sleep apnea syndrome (OSAS). These different clinical characteristics have some clinical overlap; however, they might be explained by distinct immunologic and infectious profiles and result in various histopathologic findings of adenoid specimens. METHODS: A total of 59 children with adenoid hypertrophy undergoing adenoidectomy were studied. Three series of identical adenoid specimens were processed to hematoxylin-eosin (H.E.) and Gram staining and to respiratory virus specific real-time PCR, respectively. RESULTS: According to the clinical characteristics, patients were recruited into three groups: RAOM (n = 25), OME (n = 19), and OSAS (n = 15). Bacterial biofilms were detected in 21 cases, while at least one of the studied respiratory viruses was detected in 52 specimens. RAOM cases were significantly associated with biofilm existence (n = 20, P < 0.001). In contrast, OME group was characterized by the absence of bacterial biofilm and by normal mucosa. Showing a statistically significant correlation, all OME cases were positive for human bocavirus (HBoV, P < 0.001). CONCLUSIONS: Bacterial biofilms might contribute to the damage of respiratory epithelium and recurring acute infections resulting in RAOM. In OME cases persisting respiratory viruses, mainly HBoV, can cause subsequent lymphoid hyperplasia leading to ventilation disorders and impaired immunoreactivity of the middle ear cleft. PMID- 24175296 TI - Impact of genetic variants of apolipoprotein E on lipid profile in patients with Parkinson's disease. AB - The pathogenesis of Parkinson's disease (PD) seems to involve genetic susceptibility to neurodegeneration. APOE gene has been considered a risk factor for PD. This study aimed to evaluate the association of APOE polymorphism with PD and its influence on lipid profile. We studied 232 PD patients (PD) and 169 individuals without the disease. The studied polymorphism was analyzed by PCR/RFLP. The Fisher's exact test, chi-square, ANOVA, and t-test (P < 0.05) were applied. The APOE3/3 genotype was prevalent in PD patients and Controls (P = 0.713) followed by APOE3/4 (P = 0.772). Both groups showed recommended values for lipid profile, with increase in the values of total cholesterol and LDLc, as well as decreased values of triglycerides in PD patients compared with Controls (P < 0.05 for all of them). Increased levels of HDLc, in PD patients, were associated with the APOE3/3 versus APOE-/4 genotypes (P = 0.012). The APOE polymorphism does not distinguish PD patients from Controls, as opposed to the lipid profile alone or in association with APOE. Furthermore, a relationship between increase of HDLc levels and APOE3 in homozygous was found in PD patients only. PMID- 24175297 TI - Altered mRNA expression related to the apoptotic effect of three xanthones on human melanoma SK-MEL-28 cell line. AB - We previously demonstrated that alpha-mangostin, gamma-mangostin, and 8 deoxygartanin have significant cytotoxic effects on human melanoma SK-MEL-28 cell line. The current study revealed the underlying mechanisms. alpha-Mangostin (7.5 MUg/mL) activated caspase activity, with a 3-fold and 4-fold increased caspase 8 and 9 activity, respectively. The molecular mechanisms were investigated by qRT PCR for mRNA related to cell cycle arrest in G1 phase (p21(WAF1) and cyclin D1), apoptosis (cytochrome C, Bcl-2, and Bax), and survival pathways (Akt1, NFkappaB, and IkappaBalpha). alpha-Mangostin significantly upregulated mRNA expression of cytochrome C and p21(WAF1) and downregulated that of cyclin D1, Akt1, and NFkappaB. gamma-Mangostin significantly downregulated mRNA expression of Akt1 and NFkappaB and upregulated p21(WAF1) and IkappaBalpha. 8-Deoxygartanin significantly upregulated the mRNA expression of p21(WAF1) and downregulated that of cyclin D1 and NFkappaB. The three xanthones significantly inhibited the mRNA expression of the BRAF V600E mutation. Moreover, alpha-mangostin and gamma mangostin significantly downregulated Akt phosphorylation at Ser473. In conclusion, the three xanthones induced an inhibitory effect on SK-MEL-28 cells by modulating the molecular targets involved in the apoptotic pathways. PMID- 24175298 TI - Helical irradiation of the total skin with dose painting to replace total skin electron beam therapy for therapy-refractory cutaneous CD4+ T-cell lymphoma. AB - A 36-year-old woman was diagnosed with a therapy-refractory cutaneous CD4+ T-cell lymphoma, T3N0M0B0, and stage IIB. Helical irradiation of the total skin (HITS) and dose painting techniques, with 30 Gy in 40 fractions interrupted at 20 fractions with one week resting, 4 times per week were prescribed. The diving suit was dressed whole body to increase the superficial dose and using central core complete block (CCCB) technique for reducing the internal organ dose. The mean doses of critical organs of head, chest, and abdomen were 2.1 to 29.9 Gy, 2.9 to 8.1 Gy, and 3.6 to 15.7 Gy, respectively. The mean dose of lesions was 84.0 cGy. The dosage of left side pretreated area was decreased 57%. The tumor regressed progressively without further noduloplaques. During the HITS procedure, most toxicity was grade I except leukocytopenia with grade 3. No epitheliolysis, phlyctenules, tumor lysis syndrome, fever, vomiting, dyspnea, edema of the extremities, or diarrhea occurred during the treatment. HITS with dose painting techniques provides precise dosage delivery with impressive results, sparing critical organs, and offering limited transient and chronic sequelae for previously locally irradiated, therapy-refractory cutaneous T-cell lymphoma. PMID- 24175299 TI - Frequency and characteristics of infections caused by extended-spectrum beta lactamase-producing organisms in neonates: a prospective cohort study. AB - This prospective cohort study was conducted to determine the frequency of infections caused by extended-spectrum beta-lactamase- (ESBL-) producing organisms, various bacteria producing ESBL, antibiotic susceptibility of these organisms, and the risk factors associated with these infections in a neonatal intensive care unit in a tertiary care hospital in North India. Of the 150 neonates enrolled in the study, 47 culture-positive neonates were included in the study cohort and were divided into two groups: ESBL-positive (8 neonates) and ESBL-negative (39 neonates) cohorts. Various organisms were isolated from 72 culture samples in these 47 neonates. Of these, 10 culture samples grew ESBL positive organisms and 62 samples grew ESBL-negative organisms. The frequency of ESBL-producing organisms was found to be 5.3%. ESBL infection incidence densities were found to be 3.4 per 1000 patient-days. Klebsiella (60%) was the most common organism producing ESBL followed by Escherichia coli (30%) and Pseudomonas (10%). Eighty percent of the ESBL-producing organisms were sensitive to piperacillin tazobactam. Risk factors found significant by univariate analysis (P < 0.05) were preterm, low birthweight, perinatal asphyxia, respiratory distress syndrome, anaemia, metabolic acidosis, prolonged mechanical ventilation (>7 days), length of hospitalization, length of level 3 stay, prior antibiotic use, central venous catheter duration, peripherally inserted central venous catheter duration, and total parenteral nutrition duration. Factors that retained significance in the logistic regression model were duration of hospital stay (adjusted OR: 0.958, CI: 0.920-0.997, and P value = 0.037) and gestational age (adjusted OR: 1.39, CI: 1.037-1.865, and P value = 0.028). There was no significant difference in the mortality between the two groups. PMID- 24175300 TI - JIS definition identified more Malaysian adults with metabolic syndrome compared to the NCEP-ATP III and IDF criteria. AB - Metabolic syndrome (MetS) is a steering force for the cardiovascular diseases epidemic in Asia. This study aimed to compare the prevalence of MetS in Malaysian adults using NCEP-ATP III, IDF, and JIS definitions, identify the demographic factors associated with MetS, and determine the level of agreement between these definitions. The analytic sample consisted of 8,836 adults aged >=30 years recruited at baseline in 2007-2011 from the Cardiovascular Risk Prevention Study (CRisPS), an ongoing, prospective cohort study involving 18 urban and 22 rural communities in Malaysia. JIS definition gave the highest overall prevalence (43.4%) compared to NCEP-ATP III (26.5%) and IDF (37.4%), P < 0.001. Indians had significantly higher age-adjusted prevalence compared to other ethnic groups across all MetS definitions (30.1% by NCEP-ATP III, 50.8% by IDF, and 56.5% by JIS). The likelihood of having MetS amongst the rural and urban populations was similar across all definitions. A high level of agreement between the IDF and JIS was observed (Kappa index = 0.867), while there was a lower level of agreement between the IDF and NCEP-ATP III (Kappa index = 0.580). JIS definition identified more Malaysian adults with MetS and therefore should be recommended as the preferred diagnostic criterion. PMID- 24175301 TI - Racial/ethnic disparities in chronic diseases of youths and access to health care in the United States. AB - Racial/ethnic minorities are 1.5 to 2.0 times more likely than whites to have most of the major chronic diseases. Chronic diseases are also more common in the poor than the nonpoor and this association is frequently mediated by race/ethnicity. Specifically, children are disproportionately affected by racial/ethnic health disparities. Between 1960 and 2005 the percentage of children with a chronic disease in the United States almost quadrupled with racial/ethnic minority youth having higher likelihood for these diseases. The most common major chronic diseases of youth in the United States are asthma, diabetes mellitus, obesity, hypertension, dental disease, attention deficit/hyperactivity disorder, mental illness, cancers, sickle-cell anemia, cystic fibrosis, and a variety of genetic and other birth defects. This review will focus on the psychosocial rather than biological factors that play important roles in the etiology and subsequent solutions to these health disparities because they should be avoidable and they are inherently unjust. Finally, this review examines access to health services by focusing on health insurance and dental insurance coverage and access to school health services. PMID- 24175302 TI - Differentially methylated loci distinguish ovarian carcinoma histological types: evaluation of a DNA methylation assay in FFPE tissue. AB - Epigenomic markers can identify tumor subtypes, but few platforms can accommodate formalin-fixed paraffin-embedded (FFPE) tumor tissue. We tested different amounts of bisulfite-converted (bs) DNA from six FFPE ovarian carcinomas (OC) of serous, endometrioid, and clear cell histologies and two HapMap constitutional genomes to evaluate the performance of the GoldenGate methylation assay. Methylation status at each 1,505 CpG site was expressed as beta-values. Comparing 400 ng versus 250 ng bsDNA, reproducibility of the assay ranged from Spearman r(2) = 0.41 to 0.90, indicating that beta-values obtained with a lower DNA amount did not always correlate well with the higher amount. Average methylation for the six samples was higher using 250 ng (beta-value = 0.45, SD = 0.29) than with 400 ng (beta value = 0.36, SD = 0.32). Reproducibility between duplicate HapMap samples (r(2) = 0.76 to 0.92) was also variable. Using 400 ng input bsDNA, THBS2 and ERG were differentially methylated across all histologic types and between endometrioid and clear cell types at <0.1% false discovery rate. Methylation did not always correlate with gene expression (r(2) = -0.70 to 0.15). We found that lower bsDNA overestimates methylation, and, using higher bsDNA amounts, we confirmed a previous report of higher methylation of THBS2 in clear cell OC, which could provide new insight into biological pathways that distinguish OC histological types. PMID- 24175303 TI - The fold variant BM4 is beneficial in a therapeutic Bet v 1 mouse model. AB - BACKGROUND: Specific immunotherapy using recombinant allergens is clinically effective; still wild-type allergens can provoke treatment-induced side effects and often show poor immunogenicity in vivo. Thus, we tested the low IgE-binding, highly immunogenic fold variant BM4 in a Bet v 1 mouse model. METHODS: Recombinant BM4 was used as active vaccine ingredient to treat mice sensitized to Bet v 1. As controls, mice were treated with either Bet v 1 or sham, and the humoral as well as cellular immune response was monitored. Moreover, lung function and lung inflammation were analysed. RESULTS: BM4 was more effective than wild-type Bet v 1 in inducing Bet v 1-specific blocking antibodies as well as IFN-gamma and IL-10 producing T cells. Further, birch pollen induced lung inflammation could be ameliorated significantly by BM4 treatment as demonstrated by a reduction of airway hyperresponsiveness and drastically decreased eosinophil counts in bronchoalveolar lavage fluids. CONCLUSION: The study outlines the high potential of BM4 as vaccine candidate for the treatment of Bet v 1-mediated birch pollen allergies. PMID- 24175304 TI - First evidence of increased plasma serotonin levels in Tako-Tsubo cardiomyopathy. AB - BACKGROUND: There is no data about the serotonergic activity during the acute phase of Tako-Tsubo Cardiomyopathy (TTC). The objective of our study was to investigate evidence of serotonin release from patients with TTC in comparison with patients with ST elevation myocardial infarction (STEMI) and healthy control subjects (HCS). METHODS AND RESULTS: Plasma serotonin levels in 14 consecutive patients with TTC were compared with those in 14 patients with STEMI and 14 HCS. Plasma serotonin levels at admission were markedly higher in patients with TTC and STEMI as compared to HCS (3.9 +/- 4.6, P = 0.02 versus control; 5.7 +/- 5.6, P = 0.001 versus control; and 1 +/- 0.4 ng/mL, resp.). There was no difference in serotonin levels between patients with TTC and those with STEMI (P = 0.33). CONCLUSION: This finding suggests that serotonin could participate to the pathophysiology of TTC. PMID- 24175305 TI - Molecular identification of Ancylostoma caninum isolated from cats in southern China based on complete ITS sequence. AB - Ancylostoma caninum is a blood-feeding parasitic intestinal nematode which infects dogs, cats, and other mammals throughout the world. A highly sensitive and species-specific PCR-RFLP technique was utilised to detect the prevalence of A. caninum in cats in Guangzhou, southern China. Of the 102 fecal samples examined, the prevalence of A. caninum in cats was 95.1% and 83.3% using PCR-RFLP and microscopy, respectively. Among them, the prevalence of single hookworm infection with A. caninum was 54.90%, while mixed infections with both A. caninum and A. ceylanicum were 40.20%. Comparative analysis of three complete ITS sequences obtained from cat-derived A. caninum showed the same length (738 bp) as that of dog-derived A. caninum. However, the sequence variation range was 98.6% 100%, where only one cat isolate (M63) showed 100% sequence similarity in comparison with two dog-derived A. caninum isolates (AM850106, EU159416) in the same studied area. The phylogenetic tree revealed A. caninum derived from both cats and dogs in single cluster. Results suggest that cats could be the main host of A. caninum in China, which may cause cross-infection between dogs and cats in the same area. PMID- 24175306 TI - New guar biopolymer silver nanocomposites for wound healing applications. AB - Wound healing is an innate physiological response that helps restore cellular and anatomic continuity of a tissue. Selective biodegradable and biocompatible polymer materials have provided useful scaffolds for wound healing and assisted cellular messaging. In the present study, guar gum, a polymeric galactomannan, was intrinsically modified to a new cationic biopolymer guar gum alkylamine (GGAA) for wound healing applications. Biologically synthesized silver nanoparticles (Agnp) were further impregnated in GGAA for extended evaluations in punch wound models in rodents. SEM studies showed silver nanoparticles well dispersed in the new guar matrix with a particle size of ~18 nm. In wound healing experiments, faster healing and improved cosmetic appearance were observed in the new nanobiomaterial treated group compared to commercially available silver alginate cream. The total protein, DNA, and hydroxyproline contents of the wound tissues were also significantly higher in the treated group as compared with the silver alginate cream (P < 0.05). Silver nanoparticles exerted positive effects because of their antimicrobial properties. The nanobiomaterial was observed to promote wound closure by inducing proliferation and migration of the keratinocytes at the wound site. The derivatized guar gum matrix additionally provided a hydrated surface necessary for cell proliferation. PMID- 24175307 TI - In vivo spinal posture during upright and reclined sitting in an office chair. AB - Increasing numbers of people spend the majority of their working lives seated in an office chair. Musculoskeletal disorders, in particular low back pain, resulting from prolonged static sitting are ubiquitous, but regularly changing sitting position throughout the day is thought to reduce back problems. Nearly all currently available office chairs offer the possibility to alter the backrest reclination angles, but the influence of changing seating positions on the spinal column remains unknown. In an attempt to better understand the potential to adjust or correct spine posture using adjustable seating, five healthy subjects were analysed in an upright and reclined sitting position conducted in an open, upright MRI scanner. The shape of the spine, as described using the vertebral bodies' coordinates, wedge angles, and curvature angles, showed high inter subject variability between the two seating positions. The mean lumbar, thoracic, and cervical curvature angles were 29 +/- 15 degrees , -29 +/- 4 degrees , and 13 +/- 8 degrees for the upright and 33 +/- 12 degrees , -31 +/- 7 degrees , and 7 +/- 7 degrees for the reclined sitting positions. Thus, a wide range of seating adaptation is possible through modification of chair posture, and dynamic seating options may therefore provide a key feature in reducing or even preventing back pain caused by prolonged static sitting. PMID- 24175308 TI - Actin, RhoA, and Rab11 participation during encystment in Entamoeba invadens. AB - In the genus Entamoeba, actin reorganization is necessary for cyst differentiation; however, its role is still unknown. The aim of this work was to investigate the role of actin and encystation-related proteins during Entamoeba invadens encystation. Studied proteins were actin, RhoA, a small GTPase involved through its effectors in the rearrangement of the actin cytoskeleton; Rab11, a protein involved in the transport of encystation vesicles; and enolase, as an encystment vesicles marker. Results showed a high level of polymerized actin accompanied by increased levels of RhoA-GTP during cell rounding and loss of vacuoles. Cytochalasin D, an actin polymerization inhibitor, and Y27632, an inhibitor of RhoA activity, reduced encystment in 80%. These inhibitors also blocked cell rounding, disposal of vacuoles, and the proper formation of the cysts wall. At later times, F-actin and Rab11 colocalized with enolase, suggesting that Rab11 could participate in the transport of the cyst wall components through the F-actin cytoskeleton. These results suggest that actin cytoskeleton rearrangement is playing a decisive role in determining cell morphology changes and helping with the transport of cell wall components to the cell surface during encystment of E. invadens. PMID- 24175309 TI - Protective effect of spin-labeled 1-ethyl-1-nitrosourea against oxidative stress in liver induced by antitumor drugs and radiation. AB - This study was carried out to investigate possible protection effect of 1-ethyl-3 [4-(2,2,6,6-tetramethylpiperidine-1-oxyl)]-1-nitrosourea (SLENU), synthesized in our laboratory, against oxidative liver injuries induced in mice treated by antitumor drugs: doxorubicin (DOX), bleomycin (BLM), or gamma irradiation (R). Specifically, alterations in some biomarkers of oxidative stress, such as lipid peroxidation products measured as malondialdehyde (MDA) levels and activities of the antioxidant enzymes, superoxide dismutase (SOD) and catalase (CAT), were studied in liver homogenates isolated from tumor bearing C57 black mice after i.p. treatment with solutions of DOX (60 mg/kg), BLM (60 mg/kg), or after total body gamma-irradiation with a single dose of 5 Gy. The same biomarkers were also measured after i.p. pretreatment of mice with SLENU (100 mg/kg). Statistical significant increased MDA levels and SOD and CAT enzymes activities were found in the liver homogenates of tumor bearing mice after alone treatment with DOX or gamma-irradiation compared to the control mice, while these parameters were insignificantly increased after BLM administration compared to the same controls. PMID- 24175310 TI - Formulation and evaluation of chitosan-chondroitin sulphate based nasal inserts for zolmitriptan. AB - Bioadhesive nasal dosage forms are an attractive method for overcoming rapid mucociliary clearance transport in the nose and for delivering the drug directly to brain. The present study was designed to formulate chondroitin sulphate (CS) and chitosan (CH) nasal inserts employing zolmitriptan, an antimigraine drug. The interpolymer complexes (IPC) formed between -COO(-) and -OSO3(-) groups of CS and -NH3(+) group of CH were characterized by infrared spectroscopy (IR), differential scanning analysis (DSC), and zeta potential studies. The unloaded and loaded nasal inserts were evaluated for water uptake studies, and bioadhesive strength studies, scanning electron microscopic studies (SEM). The in vitro drug release and in situ permeation studies were carried out on loaded nasal inserts. The DSC and IR studies confirmed the formation of a complex between the two polymers. The results indicated that the formulation F1 (CH : CS; 30 : 70) was demonstrating the highest bioadhesive strength and zeta potential. The presence of porous structure in the nasal inserts was confirmed by the SEM analysis. Further, in vitro and in situ release studies demonstrated that formulations F9 and F11 (drug : polymer; 1 : 10) were releasing 90% and 98% zolmitriptan over a period of 8 h. It can be concluded that nasal inserts formulated from chitosan chondroitin sulphate (CH-CS) interpolymer complex (IPC) can be used for delivery of antimigraine drug to brain. PMID- 24175312 TI - Bottom-up assembly of a surface-anchored supramolecular rotor enabled using a mixed self-assembled monolayer and pre-complexed components. AB - Three different routes to rotor-type systems on a gold surface provide sparse and dense layers of rotors with best control exerted using mixed ordered monolayers that guide the creation of the potential molecular machine components from solution. PMID- 24175311 TI - Redox-capacitor to connect electrochemistry to redox-biology. AB - It is well-established that redox-reactions are integral to biology for energy harvesting (oxidative phosphorylation), immune defense (oxidative burst) and drug metabolism (phase I reactions), yet there is emerging evidence that redox may play broader roles in biology (e.g., redox signaling). A critical challenge is the need for tools that can probe biologically-relevant redox interactions simply, rapidly and without the need for a comprehensive suite of analytical methods. We propose that electrochemistry may provide such a tool. In this tutorial review, we describe recent studies with a redox-capacitor film that can serve as a bio-electrode interface that can accept, store and donate electrons from mediators commonly used in electrochemistry and also in biology. Specifically, we (i) describe the fabrication of this redox-capacitor from catechols and the polysaccharide chitosan, (ii) discuss the mechanistic basis for electron exchange, (iii) illustrate the properties of this redox-capacitor and its capabilities for promoting redox-communication between biology and electrodes, and (iv) suggest the potential for enlisting signal processing strategies to "extract" redox information. We believe these initial studies indicate broad possibilities for enlisting electrochemistry and signal processing to acquire "systems level" redox information from biology. PMID- 24175313 TI - A stable bimetallic Au-Ag/TiO2 nanopaper for aerobic oxidation of benzyl alcohol. AB - Well-dispersed small Au-Ag bimetallic nanoparticles (sub-3 nm) on one dimensional TiO2 nanobelts were synthesized by a facile successive photodeposition-galvanic replacement method. Based on these Au-Ag/TiO2-NB nanostructures, a porous paper like monolithic catalyst was fabricated and exhibited synergistically enhanced activity and stability for catalyzing aerobic oxidation of benzyl alcohol. PMID- 24175314 TI - Homopolymer vesicles with a gradient bilayer membrane as drug carriers. AB - We report an unusual homopolymer vesicle, which has a soft bilayer membrane composed of oligo(ethyleneoxy) side chains (OEs) with a gradually decreased packing density from the centre of the membrane to both margins, exhibiting thermo-responsive zeta potential and dispersibility and showing potential applications for anti-cancer drug delivery. PMID- 24175315 TI - High-rate synthesis of Cu-BTC metal-organic frameworks. AB - The reaction conditions for the synthesis of Cu-BTC (BTC = benzene-1,3,5 tricarboxylic acid) were elucidated using a continuous-flow microreactor-assisted solvothermal system to achieve crystal size and phase control. A high-rate synthesis of Cu-BTC metal-organic frameworks with a BET surface area of more than 1600 m(2) g(-1) (Langmuir surface area of more than 2000 m(2) g(-1)) and with a 97% production yield could be achieved with a total reaction time of 5 minutes. PMID- 24175316 TI - A mechanistic investigation of hydrodehalogenation using ESI-MS. AB - The rate of hydrodehalogenation of aryl iodides with a palladium catalyst in methanol exhibits a strong primary kinetic isotope effect from both CD3OD and CH3OD, suggesting that deprotonation plays a major role in the mechanism. PMID- 24175317 TI - 2-(Aryl-sulfonyl)oxetanes as designer 3-dimensional fragments for fragment screening: synthesis and strategies for functionalisation. AB - 2-Sulfonyl-oxetanes have been prepared, affording non-planar structures with desirable physicochemical properties for fragment based drug discovery. The oxetane motif was formed by an intramolecular C-C bond formation. The fragments were further functionalised via organometallic intermediates at the intact oxetane and aromatic rings. PMID- 24175318 TI - [18F]fluorination of o-carborane via nucleophilic substitution: towards a versatile platform for the preparation of 18F-labelled BNCT drug candidates. AB - The mono-[(18)F]fluorination of o-carborane via nucleophilic substitution is reported. The new radiochemical transformation uses cyclotron produced [(18)F]F( ) and a carboranyl iodonium salt. Further derivatization of the (18)F-labelled carborane is achieved by formation of the C(c)-lithio salt and reaction with an aldehyde. PMID- 24175319 TI - Carbon dioxide entrapment in an organic molecular host. AB - 4-Phenoxyphenol crystallises to yield discrete ~60 A(3) cavities that are capable of enclathrating small solvent molecules; the cavities are capped by constricted 6-membered hydrogen-bonded rings and these potential apertures do not appear to facilitate gated porosity when the material is subjected to static CO2 pressure. PMID- 24175320 TI - Nanoporous selenium as a cathode material for rechargeable lithium-selenium batteries. AB - Nanoporous selenium was prepared by a simple mechanical method adopting nano CaCO3 as a template. When used as a cathode, it can exhibit relatively high capacity and good cycling behaviour. These results present great promise for this new cathode material for rechargeable lithium batteries of high energy density. PMID- 24175321 TI - Rhodium-catalyzed carbene transfer to alkynes via 2-furylcarbenes generated from enynones. AB - A rhodium-catalyzed carbene transfer to alkynes is reported. Easily available enynones served as the carbene source replacing diazocompounds. The overall process involved a cyclization-cyclopropenation-ring enlargement sequence. PMID- 24175322 TI - Efficient synthesis of trifluoromethylated cyclopentadienes/fulvenes/norbornenes from divinyl ketones. AB - The synthetic methods of trifluoromethylated cyclopentadienes/fulvenes/norbornenes have been developed using 3-CF3-1,4-dien-3 ols as the synthons, which can be easily prepared by the regiospecific 1,2 addition of the Ruppert-Prakash reagent (TMSCF3) to divinyl ketones. All the reactions are carried out under mild, metal-free conditions to afford the corresponding products in high to excellent yields. PMID- 24175324 TI - Synthesis of substituted nitroolefins: a copper catalyzed nitrodecarboxylation of unsaturated carboxylic acids. AB - A novel, mild and convenient method for the nitrodecarboxylation of substituted cinnamic acid derivatives to their nitroolefins is achieved using a catalytic amount of CuCl (10 mol%) and tertbutyl nitrite (2 equiv.) as a nitrating agent in the presence of air. This reaction provides a useful method for the synthesis of beta,beta-disubstituted nitroolefin derivatives, which are generally difficult to access from other conventional methods. Additionally, this reaction is selective as the E-isomer of the acid derivatives furnishes the corresponding E nitroolefins. One more salient feature of the method is, unlike other methods, no metal nitrates or HNO3 are employed for the transformation. PMID- 24175323 TI - Catalytic cascade hydroalkoxylation/isomerization/ [4 + 2] cycloaddition using enyne alcohols as latent dienes or dienophiles. AB - Enyne alcohols can react as precursors of either dienes or dienophiles with different substrates after hydroxylation and isomerization by gold catalysis. As such, oxa-bridged tricyclo[5.2.2.02,6]-undec-8-ene-3,5-dione derivatives have been obtained by the Diels-Alder reaction and tetrahydro-1H-furo[3,4-c]pyran derivatives could be accessed by the hetero-Diels-Alder cycloaddition. PMID- 24175325 TI - [AWMF: more than guideline development]. PMID- 24175326 TI - Synthesis and properties of imidazolo-fused benzotriazinyl radicals. AB - 1,3-Diphenylbenzo[e][1,2,4]triazin-7(1H)-one, the oxidation product of 1,3 diphenyl-1,4-dihydro-1,2,4-benzotriazin-4-yl (Blatter's radical), reacts with N' arylbenzamidines in PhMe at ca. 100 degrees C in the presence of N,N diisopropylethylamine (Hunig's base) (1 equiv.) to give N'-aryl-N-(1,7-dihydro-7 oxo-1,3-diphenylbenzo[e][1,2,4]triazin-6-yl)benzimidamides in 49-95% yield. In neat AcOH heated at ca. 120 degrees C, N'-aryl-N-(1,7-dihydro-7-oxo-1,3 diphenylbenzo[e][1,2,4]triazin-6-yl)benzimidamides cyclodehydrate to give the novel 8-substituted 1,3,7-triphenyl-4,8-dihydro-1H-imidazo[4,5 g][1,2,4]benzotriazin-4-yls in 13-81% yield. During the optimization of this cyclodehydration an additional oxazole fused benzotriazinyl radical 1,3,7 triphenyl-1,4-dihydro[1,3]oxazolo[4,5-g][1,2,4]benzotriazin-4-yl was isolated as a side product and characterized. The CV and EPR data of the imidazolo- and oxazolo-fused radicals are presented as well as single crystal X-ray structures of 1,3,7-triphenyl-1,4-dihydro-[1,3]oxazolo[4,5-g][1,2,4]benzotriazin-4-yl and 1,3,7,8-tetraphenyl-4,8-dihydro-1H-imidazo[4,5-g][1,2,4]benzotriazin-4-yl. PMID- 24175327 TI - Concise asymmetric synthesis of a (1R,2S)-1-amino- 2-vinylcyclopropanecarboxylic acid-derived sulfonamide and ethyl ester. AB - The development and demonstration of short, robust and chromatography-free sequences for the preparation of a (1R,2S)-1-amino-2-vinylcyclopropane-carboxylic acid-derived sulfonamide and ethyl ester in >=99% ee are described. Both compounds are common building blocks in multiple preparations of potent HCV NS3 protease inhibitors. The robustness of the asymmetric cyclopropanation of (E)-N benzylideneglycine ethyl ester under phase transfer catalysis conditions is significantly improved based on a detailed mechanistic investigation that included an analysis of the catalyst decomposition pathway, a postulated model for the stereo-selectivity that was guided by calculations and rigorous quality control of the starting materials and reagents. Wet milling has been demonstrated to dramatically accelerate this phase transfer reaction. A bench stable benzylidene-protected primary 1-amino-2-vinylcyclopropane amide intermediate was isolated and its reliable enantiomeric enrichment was achieved by a controlled crystallization process. A chemical resolution procedure was identified using di p-toluoyl-(D)-tartaric acid to access (1R,2S)-1-amino-2-vinyl cyclopropanecarboxylic ester in high ee. PMID- 24175328 TI - A three step continuous flow synthesis of the biaryl unit of the HIV protease inhibitor Atazanavir. AB - The development of multistep continuous flow reactions for the synthesis of important intermediates for the pharmaceutical industry is still a significant challenge. In the present contribution the biaryl-hydrazine unit of Atazanavir, an important HIV protease inhibitor, was prepared in a three-step continuous flow sequence in 74% overall yield. The synthesis involved Pd-catalyzed Suzuki-Miyaura cross-coupling, followed by hydrazone formation and a subsequent hydrogenation step, and additionally incorporates a liquid-liquid extraction step. PMID- 24175329 TI - Pyrene functionalized triphenylamine-based dyes: synthesis, photophysical properties and applications in OLEDs. AB - Pyrene functionalized triphenylamine-based dyes TP, TCP and TCCP were synthesized via alternate Heck and Wittig reactions. It was found that they could emit strong green light with high fluorescence yields because the formation of the excimer from a pyrene unit was suppressed completely. Moreover, the nondoped organic light-emitting diodes using TP, TCP and TCCP as the emitters as well as the hole transporting materials were fabricated, and gave green electroluminescence. Notably, the device based on TP exhibited good performance with a low turn-on voltage of 2.80 V, a high maximum luminance of 29 880 cd m-2 at 9.5 V, a high current efficiency of 3.34 cd A-1, and a high power efficiency of 2.67 lm w-1. It suggested that pyrene functionalized triphenylamine derivatives may have applications in non-doped OLEDs. PMID- 24175330 TI - An amide based dipodal Zn(2+) complex: nano-molar detection of HSO(4) (-) in a semi-aqueous system. AB - A new chromogenic dipodal Zn2+ complex (4) bearing an amide group has been synthesized. The anion binding profile of this sensor was investigated with fluorescence and UV-Vis spectroscopy. The receptor 4 has high affinity for HSO4 - with a binding constant of 3.5 * 104 M-1 and a detection limit of 50 nM. The binding ability was confirmed with spectroscopic methods and density functional theory calculation (DFT). PMID- 24175331 TI - Diastereoselective synthesis of the C14-C29 fragment of amphidinol. AB - An efficient stereoselective synthesis of the C14-C29 fragment highlighting a coupling reaction between a 1,3-dithiane derivative and an alpha-branched aldehyde was realized. This highly convergent synthesis involved two chiral pools, L-malic acid and (+)-camphorsulfonic acid, which are the starting compounds to control the six stereogenic centers present in the C14-C29 fragment of amphidinol 3. PMID- 24175332 TI - 6-Oxopyriphlorins. AB - Reaction of 2,6-pyridinedicarbaldehyde with a series of tripyrranes in the presence of trifluoroacetic acid, followed by oxidation of a pyriphlorin intermediate with silver(I) acetate, gave 6-oxopyriphlorins in moderate to good yields. The oxophlorin analogues were nonaromatic porphyrinoids that gave bright green colored solutions. Protonation with TFA afforded species that were attributed to mono- and dicationic structures. The proton NMR spectra in TFA CDCl3 showed downfield shifts to the meso-protons and upfield shifts to the interior NH resonances that indicated the presence of a weakly diatropic dicationic species. Reaction of a 6-oxopyriphlorin with nickel(II) acetate in DMF or palladium(II) acetate in acetonitrile afforded the corresponding metallo derivatives. PMID- 24175333 TI - Histidine-functionalized water-soluble nanoparticles for biomimetic nucleophilic/general-base catalysis under acidic conditions. AB - Cross-linking the micelles of 4-dodecyloxybenzyltripropargylammonium bromide by 1,4-diazidobutane-2,3-diol in the presence of azide-functionalized imidazole derivatives yielded surface-cross-linked micelles (SCMs) with imidazole groups on the surface. The resulting water-soluble nanoparticles were found, by fluorescence spectroscopy, to contain hydrophobic binding sites. The imidazole groups promoted the photo-deprotonation of 2-naphthol at pH 6 and catalyzed the hydrolysis of p-nitrophenylacetate (PNPA) in aqueous solution at pH >= 4. Although the overall hydrolysis rate slowed down with decreasing solution pH, the catalytic effect of the imidazole became stronger because the reactions catalyzed by unfunctionalized SCMs slowed down much more. The unusual ability of the imidazole-SCMs to catalyze the hydrolysis of PNPA under acidic conditions was attributed to the local hydrophobicity and the positive nature of the SCMs. PMID- 24175334 TI - Diastereotopic group selectivity and chemoselectivity of alkylidene carbene reactions on 8-oxabicyclo[3.2.1]- oct-6-ene ring systems. AB - alpha-Hydroxyalkylidene carbenes, generated from thermolysis of alpha,beta-epoxy N-aziridinylimines, undergo diastereotopic group selective 1,5 C-H insertion reactions on 2,4-dimethyl-8-oxabicyclo[3.2.1]oct-6-ene ring systems. Protection of a tertiary alcohol at C-3 of the bridged oxabicycle as a trimethylsilyl ether reverses the sense of diastereoselectivity. 1,5 C-H insertion into a methine adjacent to an OBn group, 1,5 O-R insertion into a tertiary alcohol (R = H) or silylether (R = TMS) at C-3 to form spirocyclic dihydrofurans, 1,2-rearrangement to an alkyne and fragmentation to a ketone are competing major pathways for 2 benzyloxy-substituted 8-oxabicyclo[3.2.1]oct-6-ene systems. Dihydrofuran formation is shown to be a result of substitution on the oxabicyclic ring system through comparison with other methods of alkylidene carbene formation. PMID- 24175335 TI - Convenient synthesis of (68)Ga-labeled gadolinium(III) complexes: towards bimodal responsive probes for functional imaging with PET/MRI. AB - A killer application? Recently, fully integrated full-body positron-emission tomography (PET) and magnetic-resonance imaging (MRI) scanners were brought to market, allowing simultaneous recording of complementary 3D data sets. By using bimodal PET/MRI probes (see figure), in vivo 3D mapping of various parameters with medical relevance could become feasible. PMID- 24175336 TI - Porphyrin-POSS molecular hybrids. AB - Porphyrin-POSS hybrid: Porphyrin-POSS molecular hybrid composites (see scheme; POSS = polyhedral oligomeric silsesquioxanes) were synthesized and structurally characterized, allowing the realization of truly homogenous dispersion of basic functional building blocks between organic and inorganic components at the molecular level. These materials allow the optimization of aggregation/association behavior and thus the functional optical properties of the porphyrinato zinc compounds. PMID- 24175337 TI - Mesoporous Ta(3)N(5) microspheres prepared from a high-surface-area, microporous, amorphous precursor and their visible-light-driven photocatalytic activity. AB - A light Ta3N5: Mesoporous Ta3N5 microspheres were synthesized by thermally nitriding a high-surface-area, microporous, amorphous Ta2O5 precursor at 750 degrees C, which is lower than the 900 degrees C needed for the complete nitridation of micrometer-sized Ta2O5 powder. The mesoporous Ta3N5 microspheres show significantly enhanced visible-light photoactivity in the degradation of methylene blue (MB) compared with similar photocatalysts reported under similar conditions. PMID- 24175338 TI - Palladium-catalysed carbonylative alpha-arylation of acetone and acetophenones to 1,3-diketones. AB - Three COmponent -arylation: A carbonylative ketone -arylation process employing acetone for the first time, as well as acetophenones, is described (see scheme). The reaction tolerates a range of (hetero)aryl iodides and several functionalised aryl ketone coupling partners. Only low pressures of molecular CO are applied and no additional solvent is necessary. PMID- 24175339 TI - Palladium-catalyzed carbonylative synthesis of quinazolinones from 2 aminobenzamide and aryl bromides. AB - C from CO! A straightforward procedure for the carbonylative synthesis of quinazolinones from readily available 2-aminobenzamide and aryl bromides has been developed. In the presence of a palladium catalyst, various quinazolinones were produced in moderate to excellent yields. Remarkably, no chromatography was needed for purification (see scheme). PMID- 24175340 TI - Enantioselective access to bicyclo[4.2.0]octanes by a sequence of [2+2] photocycloaddition/reduction/fragmentation. AB - Tricks of the trade: Because intramolecular Cu-catalyzed access to bicyclo[4.2.0]octanes is not feasible, an oxygen bridge was introduced to facilitate the [2+2] photocycloaddition. Starting from compounds similar to 1, products such as 2 could be obtained enantioselectiviely in three steps after ring-opening metathesis (see scheme). PMID- 24175341 TI - [Letter to the editor article "hyperglycaemic crisis in patients with diabetes mellitus". reply]. PMID- 24175342 TI - alpha-Isocupreine, an enantiocomplementary catalyst of beta-isocupreidine. AB - Complementary chemistry! alpha-Isocupreine (-ICPN) was synthesized for the first time in one step from quinine by treatment with CF3SO3H (see scheme). This compound serves as an enantiocomplementary catalyst to beta-isocupreidine (beta ICD) in the Morita-Baylis-Hillman reaction. PMID- 24175343 TI - Highly water-dispersible surface-modified Gd(2)O(3) nanoparticles for potential dual-modal bioimaging. AB - Water-dispersible and luminescent gadolinium oxide (GO) nanoparticles (NPs) were designed and synthesized for potential dual-modal biological imaging. They were obtained by capping gadolinium oxide nanoparticles with a fluorescent glycol based conjugated carboxylate (HL). The obtained nanoparticles (GO-L) show long term colloidal stability and intense blue fluorescence. In addition, L can sensitize the luminescence of europium(III) through the so-called antenna effect. Thus, to extend the spectral ranges of emission, europium was introduced into L modified gadolinium oxide nanoparticles. The obtained EuIII-doped particles (Eu:GO-L) can provide visible red emission, which is more intensive than that without L capping. The average diameter of the monodisperse modified oxide cores is about 4 nm. The average hydrodynamic diameter of the L-modified nanoparticles was estimated to be about 13 nm. The nanoparticles show effective longitudinal water proton relaxivity. The relaxivity values obtained for GO-L and Eu:GO-L were r1=6.4 and 6.3 s-1 mM-1 with r2/r1 ratios close to unity at 1.4 T. Longitudinal proton relaxivities of these nanoparticles are higher than those of positive contrast agents based on gadolinium complexes such as Gd-DOTA, which are commonly used for clinical magnetic resonance imaging. Moreover, these particles are suitable for cellular imaging and show good biocompatibility. PMID- 24175344 TI - Synthesis of PAF, an antifungal protein from P. chrysogenum, by native chemical ligation: native disulfide pattern and fold obtained upon oxidative refolding. AB - The folding of disulfide proteins is of considerable interest because knowledge of this may influence our present understanding of protein folding. However, sometimes even the disulfide pattern cannot be unequivocally determined by the available experimental techniques. For example, the structures of a few small antifungal proteins (PAF, AFP) have been disclosed recently using NMR spectroscopy but with some ambiguity in the actual disulfide pattern. For this reason, we carried out the chemical synthesis of PAF. Probing different approaches, the oxidative folding of the synthetic linear PAF yielded a folded protein that has identical structure and antifungal activity as the native PAF. In contrast, unfolded linear PAF was inactive, a result that may have implications concerning its redox state in the mode of action. PMID- 24175345 TI - [A new playing field emerges in care and welfare]. AB - Two distinct changes in Dutch care provisions coincide. On the one hand emancipated civilians want to take, or are stimulated to take, more responsibility, on the other budget cuts restrict access to and the quality of care. Self-help and informal care are back on the agenda. As a consequence a new playing field emerges that requires politicians and professionals to balance their care responsibilities with the demands of informal care, social networks, housing, financial capacities, formal public care provisions, and the mechanism that are able to craft and calibrate these different demands. As a result of this new emerging playing field more and more civilians are organizing themselves in voluntary care associations, which are based on the principles of reciprocity and mutuality. They contribute to the dynamics of the new playing field by forcing national and local politicians and care professionals to reconsider their positions and policies. Their demand for more tailored care services requires a pro-active, risk taking, and innovative attitude of those responsible. PMID- 24175346 TI - [Letter to the Editor]. PMID- 24175347 TI - [Letter to the Editor: A common phenomenon in Psychiatry: yawning]. PMID- 24175348 TI - Sport-for-development interventions: whom do they reach and what is their potential for impact on physical and mental health in low-income countries? PMID- 24175349 TI - Fixing clearance as early as lead optimization using high throughput in vitro incubations in combination with exact mass detection and automatic structure elucidation of metabolites. AB - New enabling MS technologies have made it possible to elucidate metabolic pathways present in ex vivo (blood, bile and/or urine) or in vitro (liver microsomes, hepatocytes and/or S9) samples. When investigating samples from high throughput assays the challenge that the user is facing now is to extract the appropriate information and compile it so that it is understandable to all. Medicinal chemist may then design the next generation of (better) drug candidates combining the needs for potency and metabolic stability and their synthetic creativity. This review focuses on the comparison of these enabling MS technologies and the IT tools developed for their interpretation. PMID- 24175350 TI - [Neuropathies in cryoglobulinemia]. PMID- 24175351 TI - [Hereditary thrombophilias and stroke].